The Chemistry of Bridged Lactams and Related Heterocycles

1. INTRODUCTION

The amide bond is one of the most important functional groups in chemistry and biology.¹ Due to the strong resonance interaction between n_N and π^*_C=O orbitals (Figure 1),² the vast majority of amides are planar; however, some deviations from planarity have been often observed in peptides^3–14 and small molecules alike.^15–34 Other notable properties of amides resulting from the amide bond resonance^1,2 include (i) relatively short N–C(O) bonds, (ii) high rotational barrier for cis-trans isomerization (typically 15–20 kcal/mol), (iii) resistance of the carbonyl group towards nucleophilic addition and hydrolysis, (iv) minimized ability to engage in coordination at the nitrogen atom, and (v) lower C=O infrared stretching frequencies and more upfield shifts in ¹³C NMR spectra as compared to other carboxylic acid derivatives. Perhaps because the planar geometry of amides is such an intrinsic part of how we understand amide chemistry, distorted amides that deviate from these norms have attracted the widespread attention of organic chemists.^3–59 To do so, a number of methods to modify the spatial arrangement of substituents around the amide bond have been devised in the last two decades (Figure 2). They include (i) steric repulsion,^11–34 (ii) conformational effects (ring or allylic strain),^35–43 (iii) electronic delocalization (as manifested in amides of XXN–C(O) type where X is an electronegative substituent),^44–54 and (iv) steric restriction^55–59. Of these four classes, geometrically-restricted amides (bridged, twisted amides)^55–59 are particularly interesting because these amides do not necessarily suffer from excessive steric hindrance around the amide bond^11–43or the severe electronic influence of neighboring substituents.^44–54 Moreover, bridged amides can be more easily modified and diversified when compared to other classes of distorted amides,⁵⁹ and thus represent one of the most straightforward and wide-ranging methods of constraining an amide bond into a non-planar conformation.

Figure 1.

Resonance descriptions of the amide bond.

Figure 2.

Types of distorted amide bonds: a) steric repulsion; b) conformational effects; c) anomeric amides; d) steric restriction.

In this article, we will provide a comprehensive survey of the synthesis and reactivity of bridged lactams that have been published between 1938 – when Lukeš proposed for the first time⁶⁰ that incorporating the amide bond nitrogen atom into a bridgehead position in a bicyclic system would result in a distortion of the resulting bond – until 2012. Owing to the fact that the lone pair of electrons of the nitrogen atom is no longer in conjugation with the adjacent π orbitals of the carbonyl group,^1,2 bridged amides have properties that differ from those of planar amides. These include enhanced reactivity toward amide bond hydrolysis^61–66 and toward nucleophilic attack at the carbonyl atom,^67–69 different regiochemistry of amide protonation and alkylation reactions,^70–74 different spectroscopic^16–18,75 and physical properties.^76–83 Besides the insight that such compounds provide into the nature of the amide bond, twisted amides are analogous to the transition state encountered by peptides as they undergo cis-trans isomerisation,^84–87 a critical feature of protein folding.

Bridged lactams have been the subject of previous reviews,^55–59 however a comprehensive review on this topic has not been published prior to this work. In contrast, other strained molecules^88,89 including sterically-hindered amides,^90–94 anomeric amides^95–97 and anti-Bredt olefins,^98–105 have been frequently reviewed in recent years.

The review is arranged by the type of bridged lactams and their method of synthesis. We limited the scope of the review to compounds in which the overall sum of carbon atoms forming the core 1-azabicyclo scaffold is less than or equal to ten. Amides contained in more flexible systems generally have properties analogous to planar amide bonds despite their bridged structures. Some derivatives of bridged lactams (bridged enamines, iminium ions, and sultams) featuring the relevant bond at the bridgehead position in 1-azabicyclo scaffold are also covered. Due to the geometric restriction, these compounds can differ in chemical properties from their planar counterparts in a manner similar to bridged/planar amides.

The general structures of bridged lactams and their derivatives that will be reviewed are presented in Figure 3. Bridged lactams are divided depending on the placement of N–C(O) bond on either one-carbon (3) or larger bridge (2). Such division is justified by different chemical properties of these two classes of lactams and supported by distinct methods of their synthesis. In general, bridged lactams of the type 3 are more strained and more reactive than their analogs 2. Furthermore, quinuclidone and admanatanone-derived amides are presented at the beginning of the review because of their historical importance to the advances in the field of bridged lactams, and also because these two classes of compounds provided some of the most strained amide bonds reported to date. The section focusing on the reactivity of bridged lactams emphasizes that the chemical properties of these compounds differ from those of standard amides. In particular, we discuss the hydrolytic behavior, reactivity of the nitrogen atom, reactivity of the carbonyl group, chemical properties of derivatives of bridged lactams. Finally, the specific application of bridged lactams in natural product synthesis and a selection of natural products containing bridged amide bonds are presented.

Figure 3.

Scope of the review: a) types of bridged lactams; b) heterocycles with 1-aza-bridged scaffold.

We hope that this review will serve as a useful reference for chemists involved in probing the effect of amide bond geometry on chemical and biological properties of amides, and those interested in using twisted amides as tools in physical, organic and biological chemistry.

2. GENERAL PROPERTIES OF BRIDGED LACTAMS

2.1. Distortion Parameters of Bridged Lactams

In 1971, Winkler and Dunitz introduced three independent parameters to quantitatively define distortion of amide bonds: twist angle (τ), pyramidalization at nitrogen (χ_N), and pyramidalization at carbon (χ_C) (Figure 4).¹⁰⁶ Twist angle describes the magnitude of rotation around the N–C(O) bond, while χ_N and χ_C define the tetrahedralcharacter of the nitrogen and carbon atom, respectively. A twist angle of 0° corresponds to a planar amide bond and of 90° corresponds to a fully orthogonal bond; χ_N and χ_C are 0° for planar bonds, and 60° for fully pyramidalized amide bonds.

Figure 4.

Winkler-Dunitz distortion parameters of amide bonds.

To date, two bridged lactams with perfectly perpendicular amide bonds have been structurally characterized (see 52,¹⁰⁷ Scheme 7 and 78,¹⁰⁸ Scheme 16). The remaining bridged lactams display distorted geometries of amide bonds characterized by medium τ and χ_N values. Importantly, for all reported bridged lactams, the χ_C values are close to 0° regardless of the degree of distortion. This tendency reflects the predominant contribution of the amino ketone form to the resonance structure of amides (Figure 1, A and B).^109,110 In this context it is important to note the work by Wiberg and coworkers on the thermochemical stability of amides arising from the third major resonance contributor (Figure 1, C) in which the resonance overlap takes place primarily between carbon and nitrogen with little π electron transfer to oxygen.^76,109,110 Here, we will discuss distortion parameters of specific amides in the section focused on the synthesis of bridged lactams. Moreover, since a large number of bridged lactams with varying Winkler-Dunitz parameters have been characterized, these structurally-defined analogues provide an accurate gauge of the degree of distortion in cases when the X-ray values are not available.

Scheme 7.

Synthesis of 2-Quinuclidonium Tetrafluoroborate by Tani and Stoltz

Scheme 16.

Synthesis of 1-Aza-2-adamantanone (“the Most Twisted Amide”) by Kirby

Besides Winkler-Dunitz parameters, distortion of amide bonds can be quantified by the sum of three bond angles at nitrogen (θ).³⁹ For an ideally sp³ hybridized atom θ = 328.4°, while for an sp² atom θ = 360.0°. In addition, Yamada has proposed a qualitative description of distorted amides based on twist angle and pyramidalization at nitrogen: type A amides with perpendicularly twisted N–C(O) bonds and non-pyramidalized nitrogen atoms, type B amides with planar N–C(O) bonds and sp³ nitrogen atoms, and type C amides with perpendicular N–C(O) bonds and pyramidalized nitrogen atoms.^91,92

2.2. Bond Lengths of Bridged Lactams

Upon increased distortion of amide bonds, the length of N–C(O) bond significantly increases, while the C=O bond only slightly shortens.^1,15,111 This tendency reflects significantly larger contribution of the amino ketone resonance form to the resonance structure of non-planar amides (Figure 1), and indicates a gradual pyramidalization of nitrogen occurring with rotation around the N–C(O) bond.^109,110 As a specific example, in a perfectly perpendicular 1-aza-2-adamantanone (78)¹⁰⁸ the N–C(O) bond of 1.475 Å is 0.15 Å longer than the corresponding bond in the planar N-methyl-δ-valerolactam (1.325 Å),¹¹¹ while the C=O bond of 1.196 Å is 0.037 Å shorter the same bond in the N-methyl-δ-valerolactam (1.233 Å). In this review, the bond lengths of structurally-characterized bridged amides will be given together with their distortion parameters.

2.3. Spectroscopic Properties of Bridged Lactams

Infrared C=O stretching frequencies of amide bonds are sensitive to changes in the extent of resonance stabilization of the nitrogen lone pair, while carbonyl shifts in ¹³C NMR spectra of amides respond to changes in the charge density of the carbonyl carbon.¹¹² Due to the limited resonance contribution of the zwitterionic form B (Figure 1), IR and ¹³C NMR spectra of bridged lactams^16–18 are characterized by increased ν_C=O values and more downfield ¹³C=O resonances as compared to planar amides. In general, IR and ¹³C NMR values of amide bonds in bridged lactams appear in the region between those for isolated ketones and planar amides. For example, in the perfectly perpendicular 1-aza-2-adamantanone (78), the carbonyl group resonates at 1732 cm⁻¹ IR, while the ¹³C NMR signal appears at 200.0 ppm.¹⁰⁸ In this review, spectroscopic properties of bridged lactams will be discussed only in specific cases and the reader is suggested to consult the primary literature to obtain values of interest.

2.4. Analogy of Bridged Lactams to Bridgehead Olefins

Due to the partial double bond character, bridged amides have been frequently referred to as anti-Bredt lactams.^55–59 In general, bridged lactams are more stable and easier to prepare than the corresponding bridgehead olefins because the amide nitrogen atom can adopt sp³ geometry in the amino ketone resonance form without violating the octet rule. In contrast, the only alternative resonance structures for anti-Bredt olefins do not possess closed-shell octets and represent high-energy species.^98–105 The importance of the amino ketone resonance form in bridged lactams is manifested by low values of χ_C and the progressive shortening of the C=O bond with increased distortion of the amide bond.^55–59

To allow prediction of stability and reactivity of bridgehead olefins, in 1981, Schleyer introduced “olefin strain” energy parameter¹¹³ (defined as the difference between the strain energy of the olefin and that of its parent hydrocarbon and directly related to the enthalpy of hydrogenation) as a guide to evaluate accessibility of bridgehead olefins under experimental conditions. Bridged olefins with olefin strain energy lower than 17 kcal/mol were suggested to be isolable, those with olefin strain energy between 17 and 21 kcal/mol classified as observable, and those with olefin strain energy higher than 21 kcal/mol were grouped as unstable.¹¹³ Despite outlined above differences between bridged amides and bridged olefins,^114–116 Schleyer’s olefin strain energy provides a useful predictive tool for evaluating the stability and likelihood of isolation of bridged lactams. Figure 5 presents structures of several of the more common ring systems of bridged lactams, the year of their first synthesis, and the corresponding bridged olefins with their olefin strain energy as calculated by Schleyer.^117–127 From comparison of these values, it is evident that even highly strained bridged lactams are stable enough for isolation (for example, compare bridged olefins 10, 11, 17 with bridged lactams 18, 19, 25). Furthermore, in the group of superficially similar bridged lactams 20–24, the structure 23 is predicted to be the least stable on the basis of the Schleyer's olefin strain energy; indeed, a successful synthesis of this type of bridged lactams has not been reported so far. In contrast, lactams represented by 20 and 24 have been extensively studied in recent years, which led to many insights into the properties of distorted amide bonds,^55–59 in part, because of the stability of the parent lactam scaffolds.

Figure 5.

Comparison of anti-Bredt olefins and lactams: a) calculated olefin strain energy of bridged olefins by Schleyer; b) year of synthesis of the corresponding bridged lactam. (please use double-column format for Figure 5)

2.5. Chemical and Biological Significance of Distorted Amides

Non-planar amides have been frequently employed to investigate fundamental properties of amide bonds, such as proton exchange,^70–72 bonding,^128–131 rotational barriers,^76–77 chemical reactivity.^67–69 The effect of amide distortion has been leveraged to control chemical transformations^132–140 including hydrolysis,^61–66 acylation,^132–134 desymmetrization¹³⁵ and kinetic resolution^136,137 of alcohols. Bridged lactams have been applied as intermediates in the synthesis of bioactive natural products^141–192 and are even present in the structures of several alkaloids.^193–207 Moreover, bridged lactams have been used as model systems²⁰⁸ for activation of traditionally inert C–N bonds^209–213 in transition metal catalyzed processes.

The study of distorted amides also has important biological consequences. Twisted amides have been invoked in variety of enzymatic transformations including peptide hydrolysis,^61,214–216 protein splicing^217–220 and cis-trans isomerization of peptidyl-proline bonds.^84–86 Inhibition of the latter process is of considerable interest in treatment of drug-resistant cancer cells²²¹ and neurodegenerative diseases.²²² Furthermore, bridged lactams have been utilized as models for activated peptide units^223–225 in acylation of serine,^226–228 aspartate^229,230 and cysteine proteases,²³¹ and reported as novel lead structures^232–236 and as constrained analogues^237–246 in medicinal chemistry. Finally, it is worth noting that distorted amide bonds, while not twisted per se, are key structural elements of penicillin and other β-lactam antibiotics.^247,248

3.SYNTHESIS OF HISTORICALLY IMPORTANT BRIDGED LACTAMS

3.1.Quinuclidone Derivatives

In 1924, Julius Bredt formulated his famous rule, suggesting that bridgehead carbon-carbon double bonds in the camphene and pinene series would be incapable of existence due to the insufficient overlap between their π orbitals.²⁴⁹ Fourteen years later, in 1938, Rudolf Lukeš applied Bredt’s rule to the amide zwitterionic resonance structure, proposing that bicyclic bridged lactams featuring amide nitrogen atom at the bridgehead position would be “sterically impossible” (Scheme 1).⁶⁰ Being unsuccessful in preparing bridged amides 27 and 29 by condensation under thermal conditions, Lukeš correctly predicted that if such amides were ever made they would exhibit properties of ketones rather than amides.⁶⁰ At about the same time, R. B. Woodward attempted synthesis of related bicyclic 2-quinuclidones 31 (Scheme 1).²⁵⁰ Although Woodward was unsuccessful in his studies, he also concluded that such compounds would represent a new type of aminoketone (see his comments to this effect in a footnote included in Doering’s paper,²⁵¹ discussed below).

Scheme 1.

Early Attempts of Synthesis of Bridged Lactams

In 1946, during studies on the autoxidation of quininone, Doering reported the first synthesis (but not isolation) of a bridged lactam (Scheme 2).²⁵¹ Treatment of the potassium enolate of quninone 32 with molecular oxygen afforded quinic acid 33 and amino ester 34. The amino ester 34 was proposed to arise from a rapid alcoholysis of the corresponding bridged lactam 32c by tert-butanol, which was used as a solvent for the reaction. The inability to directly isolate 32c and its subsequent in situ transformation forecasted the increased reactivity of twisted amides embedded in unsubstituted quinuclidin-2-one scaffolds.

Scheme 2.

Synthesis of 2-Quinuclidone during Autoxidation of Quininone by Doering and Chanley

In 1957, Yakhontov reported that the intramolecular condensation of amino acyl chloride 38, afforded the parent quinuclidin-2-one (Scheme 3).²⁵² However, the isolation of the bridged lactam 18 as reported by Yakhontov has been questioned in the literature on several occasions^253,254,107 because of the propensity of unsubstituted quinuclidin-2-ones to polymerize, vigorous conditions utilized for the synthesis of lactam 18 and the lack of any characterization data save elemental analysis of nitrogen.²⁵²

Scheme 3.

Synthesis of Unsubstituted 2-Quinuclidone by Yakhontov

During the same time period, Pracejus found that in contrast to the parent 2-quinuclidone 18, the dimethyl analogue 44 could be reliably prepared using an intramolecular condensation of the corresponding amino acyl chloride (Scheme 4).²⁵³ Subsequently, the research groups of Pracejus^254,255 and Yakhontov^256–258 studied the synthesis of 2-quinuclidones 46, in which bridged amide bonds were protected from nucleophilic opening by the presence of methyl substitutents near the amide moieties (Scheme 5). More recently, Greenberg optimized the conditions for preparation of 6,6,7,7-tetramethyl-2-quinuclidone 46c (Scheme 6).²⁵⁹ It was found that the previously published method for the synthesis of qunuclidone 46c^256,257 gives almost exclusively polymeric material. Using high dilution techniques, the highly-strained lactam 46c was obtained in modest yield.²⁵⁹

Scheme 4.

Synthesis of 6,6-Dimethyl-2-Quinuclidone by Pracejus (please use double-column format for Scheme 4)

Scheme 5.

Synthesis of Substituted 2-Quinuclidones by Pracejus and Yakhontov

Scheme 6.

Improved Synthesis of 6,6,7,7-Tetramethyl-2-Quinuclidone by Greenberg

In 2006, Tani and Stoltz achieved an unambiguous synthesis of the iconic twisted amide, 2-quinuclidone, using an intramolecular Schmidt reaction as the key step (Scheme 7).¹⁰⁷ This method allowed for the rigorously anhydrous conditions required for isolation of the unstable lactam 52 (in water, its t_1/2 was found to be less than 15 s).¹⁰⁷ The Schmidt reaction produced the parent 2-quinuclidone protected as its trifluoroborate salt, thus preventing the lactam from extensive polymerization. To our knowledge, this was the first example of an N-protonated amide bond to be characterized by X-ray crystallography. The initial Schmidt reaction afforded a mixture of lactams 52 and 53 resulting from migration of the two possible alkyl groups to nitrogen (Scheme 8), from which the desired compound was isolated by crystallization. Through careful optimization, it was found that the use of HBF₄ in ether as a solvent provided the best system for this reaction, while other acids resulted in lower regioselectivity. The X-ray structure of the protonated amide 52 indicated a fully orthogonal amide bond (τ = 90.9°; χ_N = 59.5°; χ_C = 0.2°; N–C(O) = 1.526 Å; C=O = 1.192 Å).¹⁰⁷

Scheme 8.

Proposed Mechanism for Schmidt Reaction of 3-Azidoalkyl Ketone 51

Subsequently, Stoltz reported a gas-phase synthesis of the protonated 2-quniclidonium 52 (Scheme 9).²⁶⁰ Using kinetic proton affinity measurements, the authors determined that lactam 52 is characterized by a much higher basicity (proton affinity = 965 kJ/mol) than typical amides (proton affinity = 880–900 kJ/mol), which is consistent with a low degree of amide resonance in 52.²⁶⁰ DFT calculation suggested that N-protonation of 52 is favored over O-protonation by approximately 90 kJ/mol.²⁶⁰ These studies are in a good agreement with earlier DFT calculations carried out by Greenberg, which suggested that N-protonation of 52 is favored over O-protonation by 100 kJ/mol.^70,71

Scheme 9.

Synthesis of Unsubstituted 2-Quinuclidone in a Gas Phase by Stoltz

In comparison with simple 2-quinuclidones, their benzo-substituted analogues are less prone to hydrolysis and polymerization. In 1980, Blackburn reported the synthesis of lactam 60 by intramolecular amide coupling reaction under standard conditions in high yield (Scheme 10).²⁶¹ Shortly thereafter, Brown and coworkers reinvestigated the synthesis of this and related benzoquinuclidones.^223–225 Under their conditions, DCC was applied as a more efficient coupling reagent (Scheme 11).²²³ Utilizing a similar protocol, Brown has accomplished the synthesis of related benzo-fused bridged lactams (Scheme 12).^224,225 Notably, these lactams did not require special precautions during synthesis and isolation despite highly-strained structures. X-ray structures of amides 64a–c indicated a progressive decrease of amide bond distortion in the series 64a (τ = 30.7°; χ_N = 57.2°; χ_C = 9.0°; N–C(O) = 1.401 Å; C=O = 1.216 Å), 64b (τ = 33.2°; χ_N = 52.8°; χ_C = 11.0°; N–C(O) = 1.413 Å; C=O = 1.225 Å), and 64c (τ = 15.3°; χ_N = 38.6°; χ_C = 4.3°; N–C(O) = 1.370 Å; C=O = 1.233 Å).²⁶² Interestingly, lactams 64a and 64b were characterized by almost completely pyramidal nitrogen atoms with only moderate tortional distortion of p-orbitals. Subsequently, a similar divergence between χ_N and τ values has also been found in other types of bridged lactams (see Section 4.3). Infrared stretching frequencies of C=O bonds demonstrated that lactam 60 is the most twisted compound in the series 60 (1755 cm⁻¹), 64a (1705 cm⁻¹), 64b (1712 cm⁻¹), and 64c (1677 cm⁻¹).^223–225

Scheme 10.

Synthesis of Benzo-2-Quinuclidone by Blackburn

Scheme 11.

Synthesis of Benzo-2-Quinuclidones by Brown

Scheme 12.

Synthesis of Expanded Ring Systems of Benzo-2-Quinuclidones by Brown

Additional examples of synthesis of 2-quinuclidones include oxidation of amines to the corresponding lactams under Gif conditions (Scheme 13)²⁶³ and stereoselective rearrangement of modified Cinchona alkaloids to bridged lactams as reported by Hoffmann (Scheme 14).^264,265 Both are reminiscent of the attempted reactions reported by Doering (cf. Scheme 2),²⁵¹ but are low yielding and limited to specific cases.

Scheme 13.

Synthesis of 2-Quinuclidones under Gif Conditions by Jankowski

Scheme 14.

Synthesis of 2-Quinuclidones from Modified Cinchona Alkaloids by Hoffmann

3.2. Adamantanone Derivatives

Due to the enforced proximity in rigid molecular frameworks, derivatives of adamantane are useful templates to study stereoelectronic effects. In 1990, Rebek reported a remarkable rate enhancement in cyclization reactions involving nitrogen atoms of lactam and imide functions prepared from Kemp triacid (Scheme 15).²⁶⁶ The involvement of bridged imide 71a and imidinium 72a was inferred on the basis of racemization of optically active precursors²⁶⁷ and deuterium labeling studies.

Scheme 15.

Synthesis of Bridged Imides from Kemp Triacid by Rebek

In 1998, Kirby, while studying the reverse anomeric effect,^268,269 achieved the synthesis of 1-aza-2-adamantanone 78 (Scheme 16).^270,108 The amino acid precursor 77 was prepared from the commercially available Kemp triacid 73 in an eight-step sequence.¹⁰⁸ A proximity-induced cyclization carried out by sublimation afforded lactam 78 in quantitative yield. The X-ray structure of amide 78 indicated a perfectly perpendicular amide bond (τ = 90.5°; θ = 325.7°; N–C(O) = 1.475 Å; C=O = 1.196 Å).¹⁰⁸ Moreover, the chemical^271,108 (see Sections 7.1–7.2) and spectroscopic properties¹⁰⁸ (see Section 2.3) of 78 are in full agreement with keto-amine-like character of the amide bond in this system. Like the unstabilized 2-qunuclidone 52 prepared by Stoltz,¹⁰⁷ lactam 78 also undergoes rapid hydrolysis in water (t_1/2< 50s).²⁷²

The methyl substituents in 1-aza-2-adamantanone derivatives like 78 help to keep the amino group in close proximity to the carboxylic acid, thus facilitating condensation to the lactam(Figure 6).^273,274 Accordingly, computational studies on the stability of 78 revealed that methyl substituents destabilize the amino acid form and contribute to the overall stability of Kirby’s amide.²⁷⁵

Figure 6.

Role of methyl substituents in synthesisof 1-aza-2-adamantanones from the corresponding amino acids.

In 2003, Coe prepared bridged lactam 85, which is a higher homologue of 1-aza-adamantanone, as an intermediate in the synthesis of nicotinic receptor ligands (Scheme 17).²³² The key reaction involved base-catalyzed condensation of the open-form amino ester to the bridged lactam 85 under thermal conditions. The final precursor 84 was quickly assembled from cyclopentene 81, using Heck reaction and reductive amination as key transformations. The infrared stretching frequency of the C=O group (1728 cm⁻¹) and instability to the aqueous conditions were consistent with a highly-strained structure of lactam 85.

Scheme 17.

Synthesis of Benzo-1-aza-2-adamantanone by Coe

4. SYNTHESIS OF BRIDGED LACTAMS WITH N–(CO) BOND ON TWO-CARBON OR LARGER BRIDGE, ([m.(≥ 2).n] Type)

The synthesis of bridged lactams with the N–(CO) bond placed on a bridge having two or more carbons is challenging because of the strain associated with distorted amide bonds and general lack of stabilizing features on the lactam skeleton (cf. alkyl-quinuclidones and adamantine-derived lactams). In some cases, the high reactivity of non-planar amide bonds may be incompatible with the reaction conditions used for their synthesis. In this section, bridged lactams are classified based on the reaction type employed for their preparation. Condensation reactions that directly form the amide bond can be used to prepare this type of lactams. However, alternative approaches with the amide bond already present in the precursor usually lead to more strained and diverse examples.

4.1. Condensation Reactions Forming N–C(O) Bond

The first synthesis of a 1-azabicyclo[3.3.1]nonan-2-one derivative was reported by Walker and coworkers in 1949 (Scheme 18).²⁷⁶ During studies on hydrogenation reactions catalyzed by copper chromite, these researches performed an intramolecular condensation of the cyano diester 86 to the bridged lactam 87, which was further reduced under the reaction conditions to 1-azabicyclo[3.3.1]nonane 88 in 39% yield. Concurrently, Albertson reported that the hydrogenation of another cyano ester 89 over Raney nickel catalyst gave two compounds, one of which was originally assigned as bridged lactam 90 (Scheme 19a).²⁷⁷ However, upon reinvestigation of this transformation, Albertson found that the compound originally proposed as lactam 90 was more consistent with the bicyclic enaminone 93 (Scheme 19b).²⁷⁸

Scheme 18.

Synthesis of 1-Azabicyclo[3.3.1]nonan-2-one 87 by Walker

Scheme 19.

a) Condensation to 1-Azabicyclo[3.3.1]nonan-2-one by Albertson; b) Revision of Proposed Structure of 90

In 1980, Hall reported the synthesis of 1-azabicyclo[3.3.1]nonan-2-one 96 applying vacuum pyrolysis conditions (Scheme 20).²⁷⁹ Although the yield was very low, lactam 96 could be separated from the polymer 97 by sublimation from the reaction mixture. The condensation of the corresponding acid chloride using a protocol developed by Yakhontov and Pracejus for the synthesis of 2-quinuclidones (Schemes 3–5)^252–258 was unsuccessful in this case. Based on its infrared stretching frequency of 1680 cm⁻¹, stability in water, and moderate tendency to undergo polymerization, Hall proposed lactam 96 to be only slightly distorted from planarity.²⁷⁹ However, subsequent structural characterization of related lactams containing [3.3.1] bridged system^280–283 and mechanistic studies by Greenberg^284,70,71 clearly demonstrate that 1-azabicyclo[3.3.1]nonan-2-ones are sufficiently non-planar to protonate at nitrogen and display other keto-amine-like characteristics.

Scheme 20.

Synthesis of 1-Azabicyclo[3.3.1]nonan-2-one by Hall

In 1981, Buchanan improved the synthesis of 1-azabicyclo[3.3.1]nonan-2-ones by using a gem-dialkyl effect to facilitate cyclization to the bridged amides (Scheme 21).^280,281 With substrate 99 containing a phenyl substitutent at C–3 position (cf. the methyl groups in the Kirby’s 1-aza-2-adamantanone, Figure 6), both thermal cyclization under high vacuum and condensation from the corresponding acyl chloride afforded the desired lactam 87, albeit again in low yield. It is worth noting, that in analogy to bridged lactams featuring [2.2.2] ring system (Section 3.1), the classic intramolecular amine-acid chloride condensation approach provides synthetically more useful results when 1-azabicyclo[3.3.1]nonan-2-one scaffolds are stabilized by additional substitutents (cf. Schemes 26 and 27). On the basis of NMR studies, Buchanan concluded that lactam 87 exists in solution in the chair-boat conformation.²⁸⁰ Related compounds, such as lactam 96 (Scheme 20)²⁷⁹ and the analogous anti-Bredt olefin, bicyclo[3.3.1]non-1-ene,²⁸⁵ also favor the chair–boat conformation, which has been explained on the basis of their preference to place the trans double bond in the larger ring.¹⁰² Buchanan reported the X-ray structure of lactam 87 (τ = 20.8°; χ_N = 48.8°; χ_C = 5.9°; N–C(O) = 1.374 Å; C=O = 1.201 Å).²⁸² These values together with the infrared stretching frequency of 1695 cm⁻¹ indicate a moderate distortion of the amide bond in 87.

Scheme 21.

Synthesis of 5-Phenyl-1-Azabicyclo[3.3.1]nonan-2-one by Buchanan

Scheme 26.

Synthesis of Quinolino-1-Azabicyclo[3.3.1]nonan-2-ones by Cuny

Scheme 27.

a) Synthesis of Aza-Bridged Lactams by Denzer and Ott; b) Synthesis of Bridged Lactam Precursors via Dearomatization of Quinazolines

The synthesis of 1-azabicyclo[3.3.1]nonan-2-ones was further improved when Steliou introduced Bu₂SnO as an efficient promoter for difficult lactamizations.²⁸⁶ Under high dilution (0.005 M), the synthesis of lactam 96 was thus achieved in 77% yield (Scheme 22). However, this reagent was ineffective for synthesis of eight-membered and larger lactams. Subsequently, Sim applied Bu₂SnO in the synthesis of the structurally-related 1-azabicyclo[3.3.1]nonane-2,6-dione (Scheme 23).²⁸³ The X-ray structure of lactam 103 (τ = 16.3°; χ_N = 49.1°; χ_C = 5.8°; N–C(O) = 1.377 Å; C=O = 1.217 Å),²⁸³ and the infrared stretching frequency of 1680 cm⁻¹ mirror the properties of 87.²⁸² This study further confirmed that lactams with the N–C(O) bond placed at one of the larger bridges are characterized by large χ_N values and moderate twist angles (cf. lactams 64a–c prepared by Brown (Scheme 12)).²⁶² A tin-mediated lactamization protocol was also employed by Gerlach in a rare example of the synthesis of an enantiomerically-enriched bridged lactam (Scheme 24).²⁸⁷ Earlier, Pracejus had prepared lactams 44 and 46a–b in enantiomerically enriched form by resolution of the intermediate amino esters with dibenzoyl-d-tartaric acid.^253–255

Scheme 22.

Improved Synthesis of 1-Azabicyclo[3.3.1]nonan-2-one by Steliou

Scheme 23.

Application of Bu₂SnO in Synthesis of 1-Azabicyclo[3.3.1]nonane-2,6-dione by Sim

Scheme 24.

Application of Bu₂SnO in Synthesis of (+)-(R)-1-Azabicyclo[3.3.1]nonan-2-oneby Gerlach

In another study, Najera noticed a significant difference in cyclization rates between diastereoisomeric amino esters to form bridged lactams 107 (Scheme 25).²⁸⁸ The endo lactam was obtained quantitatively during removal of the benzyl group, whereas amino lactam 106 was more resistant to condensation. However, the corresponding lactam 107-exo was generated in a separate step after treatment of the amino ester with LDA. Based on NOE analysis, these authors proposed that lactam 107-endo exists in a twist boat-boat conformation due to steric interactions between the axial methyl group and an axial hydrogen atom, while the lactam 107-exo adopts the usual chair-boat conformation.

Scheme 25.

Synthesis of 4-Methyl-5-tosyl-1-azabicyclo[3.3.1]nonan-2-ones by Najera

As is the case with benzo-2-quinuclidones (see Schemes 10–12),^{223–225,261,262} appendage of a fused aromatic ring improves the stability of 1-azabicyclo[3.3.1]nonan-2-ones. Cuny reported intramolecular lactamization to yield quinolino-substituted 1-azabicyclo[3.3.1]nonan-2-ones using thionyl chloride (Scheme 26).²⁸⁹ Modification of the reaction conditions resulted in the concomitant introduction of the chloride in the 2-position of quinoline ring. Lactam 110 was further derivatized via nucleophilic aromatic substitution. Denzer and Ott reported the synthesis of two different ring systems of bridged lactams, while studying new 1,5-benzodiazocine derivatives with potential biological activity (Scheme 27).²⁹⁰ The amino acid precursors were readily prepared by dearomatization of the corresponding quinazolines. Cyclization using mixed anhydride protocol offered an advantage over the standard conditions with thionyl chloride/triethylamine in terms of yields of isolated products. The highly twisted nature of amide bonds in these lactams was confirmed by infrared stretching frequencies (112: 1720 cm⁻¹; 114: 1780 cm⁻¹), rapid hydrolysis in water, and chemical reactivity (see Schemes 116 and 137). Compound 114 is one of the very few examples of reported bridged lactams bearing a [3.2.1] scaffold.

Scheme 116.

Hydrolysis of Medium Bridged Twisted Lactams by Aubé

Scheme 137.

Reactions of Medium-Bridged Twisted Lactams with Heteroatom Nucleophiles by Aubé

4.2. Heck Reactions

Grigg has pioneered the use of Heck reaction for the synthesis of bridged lactams featuring the N–(CO) bond on external bridge (Scheme 28).^291,292 With a catalyst system consisting of Pd(OAc)₂ and PPh₃, 6-exo-trig and 7-exo-trig cyclizations of enamide substrates occurred in high yields to generate a variety of bridged amide scaffolds. Isomerization of the double bond in products was rarely observed. An attempt to form the bridged lactam with a [3.2.1] ring system was unsuccessful, reflecting a high ring strain present in the transition state (Scheme 29).²⁹² Subsequently, Grigg extended this method by combining the Heck reaction with ring-closing metathesis (RCM) in a tandem process (Scheme 30).^293,294 In a telescoped sequence, bridged lactams 124a and 118a were prepared from simple acyclic starting materials in a one-pot transformation.²⁹⁴ This methodology was also employed for the synthesis of analogous bridged sulfonamides (see Section 6.5).^291–294 More recently, Paquette reported the synthesis of [4.3.1], [3.3.2] and [4.3.2] bridged lactams via Heck reaction utilizing similar conditions to those reported by Grigg (Scheme 31).²⁹⁵ The enamide substrates were synthesized by RCM of acyclic dienes, again providing an efficient route to bridged lactams.

Scheme 28.

Synthesis of Bridged Lactams via Heck Reaction by Grigg

Scheme 29.

Unsuccessful Synthesis of 1-Azabicyclo[3.2.1]oct-3-en-7-one via Heck Reaction by Grigg

Scheme 30.

Synthesis of Bridged Lactams via Tandem RCM-Heck Reaction by Grigg

Scheme 31.

Synthesis of Bridged Lactams via Heck Reaction by Paquette (please use double-column format for Scheme 31)

Judd and coworkers developed an exceptional tandem reaction sequence for the synthesis of bridged lactams employing the Heck reaction as a key step (Scheme 32).²⁹⁶ Starting from commercially available reagents, sequential Ugi and RCM reactions rapidly provided advanced intermediates. The subsequent Heck reaction was accomplished under microwave irradiation conditions using Pd(PPh₃)₂Cl or immobilized palladium catalysts to deliver bridged lactams 133 in high yields and short reaction times. The X-ray structures of lactams 133 indicate significant degrees of pyramidalization at nitrogen (133a: τ = 33.4°; χ_N = 49.1°; 133b: τ = 7.1°; χ_N = 35.3°; 133c: τ = 17.6°; χ_N = 26.2°; 133d: τ = 19.8°; χ_N = 31.1°; 133e: τ = 19.8°; χ_N = 15.9°).²⁹⁶ Impressively, this study provided full structural characterization of four different ring systems of bridged lactams. Currently, the Heck reaction is one of the most reliable methods for the synthesis of bridged lactams with the N–(CO) bond on a larger bridge.

Scheme 32.

a) Synthesis of Bridged Lactams via Heck Reactionby Ribelin; b) Synthesis of Bridged Lactam Precursors via Tandem Ugi-RCM Reaction

4.3. Diels-Alder Reactions

Shea reported the synthesis of bridged lactams containing bridgehead olefins via thermal type II intramolecular acyl-imino Diels-Alder reaction (Scheme 33).^297,298 Heating the acetoxy amides under high dilution conditions resulted in elimination of acetic acid and [4+2] cycloaddition of the intermediate N-acyl imines. Under the optimized conditions, the reactions were not allowed to reach full conversion because of the thermal instability of the bridged lactams. The synthesis of lactam 142a required a strictly inert atmosphere because the bridgehead olefin present in 142a readily formed the corresponding epoxide upon exposure to air (see Scheme 154).²⁹⁸ On the other hand, the lower yield of lactam 142d was postulated to result from a competing ene reaction of the N-acyl imine intermediate.²⁹⁸ In all of these Diels-Alder reactions, only one regioisomer was observed due to a short tether between the reactive functionalities (Scheme 34) – products resulting from the exo transition state were not detected.

Scheme 33.

Synthesis of Bridged Lactams via Type II Acyl Imino Diels-Alder Reaction by Shea

Scheme 154.

Reactivity of 1-Azabicyclo[3.3.1]non-5-en-2-one Bearing Anti-Bredt Olefin by Shea

Scheme 34.

Proposed Mechanism for Diels-Alder Reaction of Acetoxyamides 141

The X-ray structures of analogues 142a–c were solved.²⁹⁸ As expected, they show a progressive decrease of the amide bond distortion in the series 142a (τ = 16.7°; χ_N = 54.9°; χ_C = 1.4°; N–C(O) = 1.399 Å; C=O = 1.215 Å), 142b (τ = 7.5°; χ_N = 46.4°; χ_C = 1.2°; N–C(O) = 1.375 Å; C=O = 1.219 Å), and 142c (τ = 0.9°; χ_N = 38.2°; χ_C = 0.2°; N–C(O) = 1.376 Å; C=O = 1.224 Å). Similar to other lactams with the N–C(O) bond placed on the larger bridge, lactams 142 were found to have pyramidalized nitrogen atoms and small twist angles. Furthermore, infrared and NMR spectroscopy provide a clear indication of the gradual changes in the electronic properties of the amide bonds in these lactams (ν_C=O [cm⁻¹] a: 1703; b: 1660; c: 1645; d: 1641; δ_C=O [ppm] a: 182.6; b: 180.6; c: 177.4; d: 173.7).²⁹⁸ Interestingly, in the ¹³C NMR spectra, all of the carbonyl carbons were observed closer to the region expected for a typical amide rather than ketone, while the IR and NMR values of the least distorted lactam 142d are in the region expected for a planar amide. Structural properties of non-planar olefins, including those in compounds 142, have been recently reviewed.^56,104

4.4. Carbene Insertion Reactions

The synthesis of strained non-planar lactams using carbenes is an attractive strategy due to the high reactivity of these intermediates,^299–301 which are capable to overcome strain associated with the formation of bridged amide bonds. In 1995, Doyle demonstrated the synthesis of 1-azabicyclo[5.2.1]decan-9-one 145 via Rh-catalyzed C–H insertion reactions with excellent enantioselectivity (Table 1, entries 2–4).³⁰² The less flexible, one-carbon shorter, analogue 144a afforded exclusively the fused lactam 146 (entry 1). Rh₂(4S-MACIM)₄ catalyst (entry 4) gave the opposite enantiomer of 145 than Rh₂(4S-MEOX)₄ or Rh₂(5S-MEPY)₄ (entries 2–3).

Table 1.

Synthesis of 1-Azabicyclo[5.2.1]decan-9-one via Rh-Catalyzed C–H Insertion by Doyle

entry	n	144	Rh2L4	ratio of 145:146	combined yield (%)	ee of 145 (%)	ee of 146 (%)
1	0	144a	Rh2(5S-MEPY)4	1:99	67	n/a	97
2	1	144b	Rh2(4S-MEOX)4	74:26	95	98	15
3	1	144b	Rh2(5S-MEPY)4	33:67	67	97	30
4	1	144b	Rh2(4S-MACIM)4	61:39	81	96	66

More recently, Aszodi and coworkers reported Rh- and Cu-catalyzed N–H insertion reactions to generate strained lactams containing a [3.2.1] scaffold as a part of their studies on bridged analogues of carbapenem and carbacephem antibiotics (Table 2).²³³ A remote alkyl substitutent exerted significant influence on the competing C–H insertion process, leading instead to the fused derivative 149 from precursor 147 where R = Et. Williams has applied a similar N–H insertion reaction to prepare some of the most strained bridged lactams isolated to date (see Section 5.1).^303,304

Table 2.

Synthesis of 1-Azabicyclo[3.2.1]octan-7-onesvia N–H Insertion by Aszodi

entry	R	147	catalyst	yield of 148 (%)	yield of 149 (%)
1	H	147a	Rh2(OAc)4	40	42
2	Et	147b	Rh2(OAc)4	5	80
3	Et	147b	Cu(acac)2	30	n/a

4.5. Reactions via Radical Intermediates

Sundberg developed the synthesis of indole-containing bridged lactams featuring a [5.3.1] ring system using Witkop photocyclization (Scheme 35).³⁰⁵ It was determined that these reactions proceed smoothly in methanol. Sodium carbonate was used as an additive to prevent hydrolysis of the ketal moiety in certain starting materials. An attempt to form a [6.2.2] ring system from the corresponding 4-piperidylmethyl substrate was unsuccessful.³⁰⁵ The authors observed a new type of atropoisomerism in the resulting bridged lactams, with half-lives for the interconversion of atropoisomers 152 and 153 between 2.5 and 8 h at 170 °C (Figure 7).³⁰⁵

Scheme 35.

Synthesis of Indole-1-azabicyclo[5.3.1]undecan-2-onesvia Witkop Photocyclization by Sundberg

Figure 7.

Atropoisomers formed in Witkop photocyclization of (N-chloroacetylpiperidyl)indole 150.

Subsequently, Sundberg reported the photocyclization in the 3-piperidylmethyl series to yield bridged lactams with a [6.3.1] ring system (Scheme 36).³⁰⁶ In this case, yields and diastereoselectivities were slightly improved, while the barrier for interconversion between atropoisomers was lower than in the [5.3.1] ring system (t_1/2 in the range of hours at 140 °C). The X-ray structure of lactam 155b³⁰⁶ revealed that lengths of the N–C(O) bond of 1.356 Å and the C=O bond of 1.235 Å are comparable with those encountered in planar amides.

Scheme 36.

Synthesis of Indole-1-azabicyclo[6.3.1]dodecan-2-ones via Witkop Photocyclization by Sundberg

In the course of studying radical cyclization of allenamides, Hsung reported the synthesis of benzo-fused bridged lactam 157 with a [4.2.1] ring system (Scheme 37).³⁰⁷ The product was proposed to arise from 7-endo/5-endo alkene/allene cyclization of an aryl radical intermediate. Beckwith found that the fragmentation of methyl xantates 159, using tributyltin hydride and di-tert-butylperoxide in refluxing toluene, afforded the corresponding ethylidene-substituted bridged lactams containing a [5.3.1] ring system (Scheme 38).³⁰⁸

Scheme 37.

Synthesis of Benzo-1-azabicyclo[4.2.1]nonan-2-one via Radical Cyclization by Hsung

Scheme 38.

Synthesis of 1-Azabicyclo[5.3.1]undecan-10-ones via Radical Fragmentation by Beckwith

4.6. Miscellaneous Examples

During synthetic studies on iso-indolobenzazepine alkaloids, Ruchirawat and coworkers discovered the Friedel-Crafts cyclization of N-benzylbenzazepinones 161 to dibenzo-fused bridged lactams 162 (Scheme 39a).³⁰⁹ In a related work, the same group investigated the use of acyclic amide acetals 163, which participated in a sequential Friedel-Crafts cyclization to afford bridged lactams 164 (Scheme 39b).³¹⁰ As a part of their research on indole alkaloids, Dolby and Sakai reported a tandem fragmentation–transannular cyclization to give bridged lactam 166 with a [6.2.2] ring system (Scheme 40).^311,312 In the context of studies on bis-nor-meptazinols as cholinesterase inhibitors,³¹³ Qiu and co-workers reported the X-ray structure of lactam 167a³¹⁴ (Figure 8; 167a: τ = 14.4°; χ_N = 27.8°; χ_C = 2.5°; N–C(O) = 1.347 Å; C=O = 1.243 Å). Finally, Wärnmark and coworkers reported^315,316 the synthesis of bridged lactams 167b and 167c via direct oxidation of the parent amine (Tröger’s base) at the benzylic position with KMnO₄ in 25–28% yields (Figure 8). The X-ray structure of the bis-twisted lactam was solved³¹⁵ and indicates significant distortion of the amide bond in 167c (τ = 43.7°; χ_N = 57.6°; χ_C = 4.8°; N–C(O) = 1.437 Å; C=O = 1.209 Å).

Scheme 39.

Synthesis of Bridged Lactams via Friedel-Crafts Reaction by Ruchirawat

Scheme 40.

Synthesis of Indole-1-azabicyclo[6.2.2]dodecan-10-one via Fragmentation/Transannular Condensationby Dolby

Figure 8.

Benzofused bridged lactams: a) Benzo-1-azabicyclo[4.3.1]decan-9-one by Qiu; b) Bridged lactams derived from Tröger’s base by Wärnmark.

5. SYNTHESIS OF BRIDGED LACTAMS WITH N–(CO) BOND ON ONE-CARBON BRIDGE, ([m.1.n] Type)

Bridged lactams featuring the N–(CO) bond on one-carbon bridge are typically more strained than their two-carbon bridged and larger analogues (see Figure 5). Carbene insertion, ring expansion and transannular condensation reactions forming directly the N–(CO) bond are powerful methods for the assembly of this class of compounds. In general, other synthetic methods are less efficient and/or limited to specific structural types. The majority of successful approaches to non-planar one-carbon bridged lactams involve generation of a high-energy intermediate.

5.1. Carbene Insertion Reactions

In 1986, Williams reported the synthesis of highly distorted bridged lactams containing [4.1.1] ring system using Rh-catalyzed carbene N–H insertion chemistry (Scheme 41).^303,304 The reaction of diazo β-keto esters 168 proceeded smoothly in the presence of catalytic Rh₂(OAc)₄ in refluxing benzene to afford bridged lactams in 20–70% yields. Lactams 169 with a sterically-undemanding substituent at the C–8 position (such as 169a) exhibited limited stability at room temperature (t_1/2 ~ 1 h in CDCl₃, IR = 1795 cm⁻¹). This was proposed to be due to the nucleophilic opening of the strained lactam moiety from the unshielded α face (Figure 9a).³⁰⁴ Higher stability was observed in isopropyl analogues such as 169b–e, in which the i-Pr group hindered the Bürgi-Dunitz trajectory (169b–c: stable in CDCl₃, IR = 1795 cm⁻¹; 169d–e: t_1/2 ~12 h in CDCl₃ at −30 °C, IR = 1805–1810 cm⁻¹). Further improvement was achieved by blocking the bridgehead position to prevent abstraction of the bridgehead methine proton and possible fragmentation (Figure 9b).³⁰⁴ The lactam 169f proved to be significantly more stable than previous analogues, however it decomposed when stored neat at room temperature. The crystalline analogues 169g–h were found to be stable in CDCl₃ solution over several days. The X-ray structure of 169h³⁰⁴ (IR = 1785 cm⁻¹) revealed pyramidalized nitrogen atom (θ = 326.8°, which may be compared with θ = 325.7° for Kirby’s amide¹⁰⁸ and θ = 324.0° for trimethylamine)³⁰⁴ and a long N–C(O) bond of 1.418 Å. Several 1,3-bridged 2-azetidinones and bridged analogues of β-lactam antibiotics inspired by the William’s work have been reported.^242–246

Scheme 41.

Synthesis of 1-Azabicyclo[4.1.1]octan-7-onesvia Rh-Catalyzed N–H Insertion by Williams

Figure 9.

Design of 1-azabicyclo[4.1.1]octan-7-ones with increased stability: a) nucleophilic attack on lactam carbonyl group; b) deprotonation of bridgehead methine proton.

5.2. Schmidt Reactions

The intramolecular Schmidt reaction^317–320 has been applied to the synthesis of one-carbon bridged lactams. To date, this method has been used to prepare [4.3.1], [5.3.1], [3.2.1], [4.2.1], and [5.2.1] ring systems of these heterocycles. While two constitutional isomers can, in principle, be formed from the intramolecular Schmidt reactions of 2-azidoalkylketones (Scheme 42),³¹⁷ the latter pathway (path b) requires particular circumstances to compete with the much more commonly observed path a, which leads to fused bicyclic lactams.^318–320 In the last decade, four complementary methods that allow synthesis of bridged lactams via Schmidt reaction have been developed: (1) axial 2-azidoalkyl tethers,²⁰⁸ (2) cation–π interactions involving diazonium cation intermediates,^321,322 (3) cation–n interactions involving diazonium cation intermediates,^323,324 and (4) two-carbon 2-azidoalkyl tethers.³²⁵ In addition, Schmidt reaction of 2-azidoalkylacetals affords bridged orthoamides, which can be converted into bridged lactams.³²⁶

Scheme 42.

Regiochemical Options in the Intramolecular Schmidt Reaction of 2-Alkylazido Ketones

In 2005, Aubé reported the synthesis of tricyclic bridged lactams 177 via a tandem Diels-Alder/Schmidt reaction (Table 3).²⁰⁸ This class of bridged lactams was first encountered five years earlier in the context of a total synthesis of stenine.^327–329 Mechanistically, an intramolecular Diels-Alder reaction of triene 175 afforded cis-decalone 178, in which the carbon bearing the azidoalkyl side chain is axial relative to the cyclohexanone ring embedded in the bicyclic intermediate (Scheme 43).³²⁷ The bridged lactams were obtained by subsequent C→N migration and loss of N₂. The intermediate 178-eq containing the leaving N₂group in a pseudoequatorial position led to the fused lactam 176, whereas migration of the bond antiperiplanar to the pseudoaxial N₂⁺ afforded the lactam 177. The X-ray structure of lactam 177b indicated that it contains a half-way rotated amide bond (τ = 51.5°; χ_N = 36.1°; χ_C = 12.8°; N–C(O) = 1.387 Å; C=O = 1.218 Å;²⁰⁸ see also compound 511b in Figure 15).

Table 3.

Synthesis of Tricyclic Bridged Lactams via Domino Diels-Alder/Schmidt Reaction by Aubé

entry	ketoazide 175	R1	R2	yield of 176 (%)	yield of 177 (%)
1	175a	(CH2)2OBn	H	43	24
2	175b	4-Br-C6H4	H	43	23
3	175c	C6H5	H	46	23
4	175d	H	H	41	22
5	175e	H	i-Pr	43	28
6	175f	H	Ph	85	0

Scheme 43.

Proposed Mechanism for Domino Diels-Alder/Schmidt Reaction of Keto-Azidotrienes 175 (please use double-column format for Scheme 43)

Figure 15.

a) Bridged Lactam Bearing Epoxide by Paquette; b) Tricyclic Bridged Lactam by Aubé

Subsequent work led to an improved sequence in which a cation–π directed Schmidt reaction afforded bicyclic bridged lactams as the major products (Scheme 44).^321,322 In this case, the combination of an axial azidoalkyl tether and an aromatic group positioned in a 1,3-diaxial relationship with the diazonium cation in the key azidohydrin intermediate 179-ax (Scheme 45) resulted in high selectivity for the rearrangement to bridged lactams. Electron-rich aromatic groups led to high yields, while electron-poor aromatic groups were less effective, providing strong support for the proposed cation–π interactions.³²² The X-ray structure of lactam 181b (τ = 43.2°; χ_N = 33.8°; χ_C = 16.3°; N–C(O) = 1.363 Å; C=O = 1.234 Å)³³⁰ confirmed that the amide bond in the [4.3.1] bicyclic system is significantly distorted from planarity.

Scheme 44.

Synthesis of Bridged Lactams via Cation-π-Directed Schmidt Reaction by Aubé

Scheme 45.

Proposed Mechanism for Schmidt Reaction of 2-Aryl-2-Alkylazido Ketones 179

The Aubé group also reported the synthesis of bicyclic bridged lactams using conformationally-flexible 2-azidoalkylketone substrates containing an α-heteroatomic group (Scheme 46).³²³ A thiomethyl substitutent in the α-position gave the best results in terms of yields and selectivity. A stabilizing 1,3-diaxial interaction between the diazonium cation and thiomethyl group in the azidohydrin intermediate 182a (Scheme 47) was proposed to explain the regioselectivity of this transformation.³²³ Recently, cation–π and cation–n directed Schmidt reactions have been investigated using density functional theory, confirming the role of non-bonding interactions involving the diazonium cation on the regioselectivity of the rearrangement.³²⁴

Scheme 46.

Synthesis of Bridged Lactams via Cation–n Directed Schmidt Reaction by Aubé

Scheme 47.

Proposed Mechanism for Schmidt Reaction of 2-Alkylazido Ketones 182

Murphy reported that the intramolecular Schmidt reaction of conformationally-flexible 2-azidoalkylketones containing a two-carbon tether affords predominantly bridged isomers (Table 4).³²⁵ Several five-, six- and seven-membered azidoketone substrates produced one-carbon bridged lactams 186, which were converted to the corresponding amino esters 187. The authors observed that the bridged lactam 186a containing a [3.2.1] ring system was unstable to the aqueous work-up conditions due to the high strain associated with the non-planar amide bond.³²⁵ Moreover, 185b participated in a competing fragmentation pathway driven by the aryl group.³²⁵ The preference for bridged lactams in these examples was explained on the basis of strain developing during the C→N migration to the alternative fused four-membered ring lactams (as also observed in another context^331,332).

Table 4.

Synthesis of Bridged Lactams via Schmidt Reaction of 2-(2-Azidoethyl) Ketones by Murphy

entry	n	185	R	acid	yield of 186 (%)	yield of 187 (%)
1	0	185a	H	TfOH	n/a	89a
2	0	185b	4-MeO-C6H4	TfOH	n/a	22a,b
3	1	185c	H	TfOH	n/a	94a
4	1	185d	4-MeO-C6H4	TiCl4	97	n/a
5	2	185e	H	TfOH	41	83

^aYield from 185.

^bMsCl instead of TsCl.

Additional examples of bridged lactams prepared by Schmidt reactions have been reported by Aubé²⁰⁸ and Murphy³²⁵ (Scheme 48). Although yields were moderate, this methodology offers a concise route to these lactams. The X-ray structure of lactam 190c (τ = 35.9°; χ_N = 43.7°; χ_C = 12.4°; N–C(O) = 1.375 Å; C=O = 1.219 Å)³³³ shows a significantly distorted amide bond and is in good agreement with other bridged lactams featuring a [4.3.1] ring system.

Scheme 48.

Other Examples of Bridged Lactams Synthesized via Intramolecular Schmidt Reaction

In 2010, Aubé reported that 2-azidoalkylketals undergo Schmidt reaction via iminium ion intermediates to give bridged orthoamides (Table 5a).³²⁶ The α-amino ketals 193 could be readily transformed into the parent twisted lactams (Table 5b).³²⁶ The synthesis of bridged orthoamides provided the first examples of any intramolecular Schmidt reaction affording exclusively bridged products.^331,332,326

Table 5.

a) Synthesis of Bridged Orthoamides via Schmidt Reaction of 2-Azidoalkyl Ketals by Aubé; b) Conversion of Bridged Orthoamides to Bridged Lactams

entry	191	n	R1	R2	yield of 193 (%)
1	191a	1	t-Bu	C6H5	88
2	191b	1	t-Bu	4-MeO-C6H4	92
3	191c	1	t-Bu	4-NO2-C6H4	94
4	191d	1	H	C6H5	59
5	191e	1	H	SPh	78a
6	191f	0	H	C6H5	91

b)

^aTMSOTf.

5.3. Condensation Reactions Forming N–C(O) and C–C or N–C Bonds

Transannular amidation reactions of medium-size ring amino esters have emerged as a versatile method for the synthesis of one-carbon bridged lactams due to the release of transannular strain during the formation of bicyclic systems.

In 1987, using a transannular cyclization under thermal conditions, Schill developed the synthesis of indole-derived bridged lactams 195 as potential precursors to higher analogues of vinca alkaloids (Scheme 49).^334–339 The condensation between the amine and pentafluorophenyl esters was applied to the successful synthesis of three different ring systems of bridged lactams.^336–338 The presence of an additional substituent (cf. 195b)³³⁶ was found to be crucial in obtaining bridged products. In contrast, the cyclization of the indole-derived amino acids was less general, affording only a [4.4.1] ring system in modest yield (Scheme 50).³³⁸ Magnus and coworkers reported the synthesis of a related bridged lactam 199 containing a [4.3.1] ring system as a part of their studies towards the synthesis of vinblastine (Scheme 51a).^340,341 The transannular cyclization between the methyl ester and amine proceeded smoothly under thermal conditions.³⁴⁰ The nine-membered ring precursor was efficiently prepared from the tetracyclic amine 200 via ring fragmentation and nucleophilic trapping of the resulting iminium ion (Scheme 51b).³⁴⁰More recently, Dennison and coworkers applied a transannular condensation reaction to prepare a complex bridged lactam 205 from the vincristine metabolite 204 to facilitate the structural assignment of 204 (Scheme 52).³⁴²

Scheme 49.

Synthesis of Indole-Derived Bridged Lactams via Transannular Amidation by Schill

Scheme 50.

Synthesis of Indole-Derived Bridged Lactams via Transannular Amide Coupling by Schill

Scheme 51.

a) Synthesis of 6-Phenyl-1-azabicyclo[4.3.1]decan-10-one by Magnus; b) Synthesis of Nine-Membered Ring Precursor

Scheme 52.

Synthesis of Bridged Lactam from Vincristine Metabolite by Dennison (please use double-column format for Scheme 52)

In 2009, Aubé reported the synthesis of six different ring systems of one-carbon bridged lactams via a tandem RCM-transannular amidation sequence (Scheme 53).³⁴³ The medium-size ring precursors were obtained in high yields from simple dienes using Hoveyda-Grubbs II catalyst. The transannular cyclization took place under thermal conditions with Cs₂CO₃ or DBU as a base, affording highly strained bridged lactams in the process.

Scheme 53.

Synthesis of One-Carbon Bridged Lactamsvia Tandem RCM/Transannular Amidation by Aubé

One-carbon bridged lactams have also been prepared by other condensation reactions forming C–C or C–N bonds (Schemes 54–55, Table 6). However, in contrast to the transannular amidation reactions,^336–343 these approaches are limited to specific examples. Arata reported the Dieckmann condensation of amido ester 209 to give the corresponding bridged lactam in 30% yield (Scheme 54a).³⁴⁴ Waly found that a sequential treatment of N-acetylaminonitrile 211 with NaH and KOt-Bu afforded the bridged trione 212 (Scheme 54b),³⁴⁵ while Smet reported the synthesis of lactam 214 from 4-bromoisatin (Scheme 54c).³⁴⁶ Nazarenko proposed the intermediacy of bridged lactam 216 in the intramolecular condensation of 1,4-benzothiazin-3-one derivative 215, ultimately affording the more stable 217 from the lactam viaintramolecular transacylation (Scheme 55).³⁴⁷ Chibale reported the synthesis of tetracyclic bridged lactams based on thiolactone-isatin scaffolds (Table 6).²³⁵ The X-ray structures of lactams 220c–220e indicated moderate distortions from planarity despite flexible ring systems (220c: τ = 10.4°; χ_N = 5.1°; χ_C = 0.7°; N–C(O) = 1.357 Å; C=O = 1.227 Å; 220d: τ = 5.3°; χ_N = 1.1°; χ_C = 3.0°; N–C(O) = 1.355 Å; C=O = 1.223 Å; 220e: τ = 0.6°; χ_N = 8.9°; χ_C = 4.5°; N–C(O) = 1.361 Å; C=O = 1.223 Å).²³⁵

Scheme 54.

Other Examples of Synthesis of One-Carbon Bridged Lactams via Condensation Reactions: a) 1-Azabicyclo[4.2.1]nonane-5,9-dione by Arata; b) 1-Azabicyclo[3.3.1]nonane-4,6,9-trione by Waly; c) 1-Azabicyclo[4.2.1]nonan-9-one by Smet

Table 6.

Synthesis of Tetracyclic Bridged Lactams from Thiolactone-Isatin Hybrids by Chibale

entry	n	218	ratio of 220 221	combined yield (%)	ring system of 220
1	1	218a	0:100	36	[5.2.1]
2	2	218b	0:100	18	[6.2.1]
3	3	218c	78:22	45	[7.2.1]
4	4	218d	16:84	31	[8.2.1]
5	5	218e	29:71	21	[9.2.1]

Scheme 55.

Synthesis of Benzo-4-thia-1-azabicyclo[3.2.1]octan-8-one 216 by Nazarenko

5.4. RCM Reactions

Doodeman and Hiemstra carried out an extensive study to probe the synthesis of one-carbon bridged lactams using RCM.³⁴⁸ In a systematic screening of dienes that could afford bridged lactams with eight different ring systems ranging from [4.3.1] to [8.2.1], only one bridged lactam containing a [6.2.1] ring was formed in low yield (Scheme 56). Since polymeric material was obtained in many cases despite high dilution conditions, it is apparent that the starting planar lactam was unable to achieve a suitable conformation in sufficient amounts to permit cyclization.

Scheme 56.

Synthesis of 1-Azabicyclo[6.2.1]undecan-11-one via RCM by Doodeman and Hiemstra

5.5. Aziridinium rearrangement

Aziridinium ions are known to undergo regioselective ring opening with a wide range of nucleophiles and this type of rearrangement has been used extensively to make planar nitrogen-containing heterocycles.^349,350 In 1970, Arata reported the synthesis of bridged lactam 225 containing a [4.4.1] ring system via aziridinium rearrangement using a one-pot protocol (Scheme 57).^351,352 The proposed mechanism is outlined in Scheme 58,³⁵² and involves the following steps: (1) tautomerization of enamine 224 to iminium ion, (2) addition of the trichloromethyl moiety, (3) formation of the aziridinium 224b, (4) regioselective nucleophilic ring opening to the trichloroderivative 224c, and (5) hydrolysis to give the bridged lactam 225. Subsequently, Miyano and coworkers studied a related rearrangement in the 1-azabicyclo[3.3.1]nonane system (Scheme 59).^353,354 In their case, the reaction was carried out step-wise and the trichloromethyl analogue 227 was isolated.³⁵³ This intermediate then underwent rearrangement to 1-azabicyclo[3.3.1]nonane 229 upon heating in pyridine. Hydrolysis to the corresponding bridged lactam has not been reported for this example.³⁵⁴

Scheme 57.

Synthesis of Chloro-Substituted Bridged Lactam via Aziridinium Rearrangement by Arata

Scheme 58.

Proposed Mechanism for Rearrangement of 224

Scheme 59.

Synthesis of 5,9,9-Trichloro-1-azabicyclo[3.3.1]nonane by Miyano

5.5. Fragmentation Reactions

Fragmentation reactions have been used to prepare relatively flexible ring systems of one-carbon bridged lactams. In 1994, Bremner reported a photolysis of vinylogous chloroacetamides in water-acetonitrile for the synthesis of bridged lactams containing [6.2.1] and [6.3.1] scaffolds (Scheme 60).³⁵⁵ Improved yields were obtained in acidified aqueous solutions, which could be due to the involvement of iminium 230a in the photoinduced electron transfer step (Scheme 61). The authors proposed that the addition of water could occur at the stage of iminium aromatic cation 230c, which then could undergo C–C bond fragmentation to give bridged lactams. The X-ray structures of 231a and 231b have been solved (231a: θ = 356.4; N–C(O) = 1.322 Å; C=O = 1.236 Å; 231b: θ = 359°; N–C(O) = 1.333 Å; C=O = 1.235 Å).³⁵⁵ These values are comparable to those of planar N-methyl-δ-valerolactam (see Section 2.2).

Scheme 60.

Synthesis of Bridged Lactams viaPhotolysis of Chloroacetamides by Bremner

Scheme 61.

Proposed Mechanism for Cyclization/Fragmentation of 230

Schuman and coworkers reported the photo-oxidation of the tricyclic enamine 232, yielding bridged lactams with a [7.3.1] ring system (Scheme 62).³⁵⁶ The authors proposed that the bridged lactam 233 arose from a singlet oxygen reaction with the electron-rich double bond to give the corresponding dioxetane, which then underwent retro [2+2] (Scheme 63a).³⁵⁶ The trioxygenated lactams 234 and 235 were formed in a sequence starting with the intermolecular redox reaction between the enamine 232 and intermediate 232a, followed by standard steps of the photosensitized oxygen transfer process (Scheme 63b).³⁵⁶

Scheme 62.

Synthesis of 1-Azabicyclo[7.3.1]tridecan-13-onesvia Oxidation of Enamines by Schumann

Scheme 63.

Proposed Mechanism for Oxidation/Fragmentation of Enamines 232 and 232a

During their studies on reactions of arenesulfonylazides with strained indoles, Bailey and coworkers reported an oxidative rearrangement of pyrrolo[1,2–a]indole 236 leading to a benzofused bridged lactam bearing a [6.2.1] ring system (Scheme 64).³⁵⁷ The formation of lactam 237 was not observed in apolar solvents. The reaction involves (1) nucleophilic addition of 236 to the azide, (2) hydration of the imnium 236c, and (3) oxidative cleavage of the C–C bond to give bridged lactam 237 (Scheme 65). The X-ray structure of an oxime derivative of bridged lactam 237 has been solved (θ = 356.6; N–C(O) = 1.372 Å; C=O = 1.215 Å),³⁵⁸ and indicates some differences from the related bridged lactam 231a.

Scheme 64.

Synthesis of 1-Azabicyclo[6.2.1]undecan-11-one by Bailey

Scheme 65.

Proposed Mechanism for Oxidative Fragmentation of 236

5.6. Rearrangements of Nitrogen Ylides

Synthesis of bridged lactams in reactions proceeding via ylide intermediates is a promising approach, however such reactions are not well developed. In 1993, Rudler reported the synthesis of one-carbon bridged lactams containing [5.1.2] and [6.1.2] ring systems using nitrogen ylides, obtained by thermolysis of aminocarbene complexes of chromium (Scheme 66).³⁵⁹ By performing the theromolysis in cyclohexane, the ylides could be isolated in 52–84% yields. Their subsequent thermolysis in toluene afforded bridged lactams 240 in moderate yields. When nitrogen was a part of 6- or 7-membered ring, the rearrangement afforded bridged lactams; however, only fused lactams were obtained from azetidine-and pyrrolidine-containing chromium complexes. The authors proposed that the reaction starts with intramolecular alkyne and carbon monoxide insertion to give 239b (Scheme 67).³⁵⁹ Addition of the tertiary amine to the ketene group in the vinylketene generates intermediate 239c, which then rearranges to the corresponding lactams.

Scheme 66.

Synthesis of Bridged Lactams via Rearrangement of Nitrogen Ylides by Rudler

Scheme 67.

Proposed Mechanism for Rearrangement of 239

Chuche reported the application of spiro pyrazolium ylides to the synthesis of bridged pyrazolin-5-ones (Scheme 68).³⁶⁰ Intermediates 242a could be isolated in good yields by performing flow pyrolysis at 325–350 °C. However, the thermolysis at 400 °C led directly to the bridged pyrazolin-5-ones. The infrared stretching frequencies of 1765 and 1760 cm⁻¹ for 243a and 243c, respectively, indicated significant distortion of amide bonds.

Scheme 68.

Synthesis of 1,4-Bridged Pyrazolin-5-ones via Rearrangement of Spiro Pyrazolium Ylides by Chuche

5.7. Miscellaneous Examples

Kutney reported the synthesis of bis-indole-derived bridged lactams containing [6.3.1] scaffolds via oxidation and Polonovski reaction of the corresponding bridged amines (Scheme 69).^361,362 Williams attempted to prepare bridged lactam 251 with the unprecedented [3.2.1] ring system. Despite obtaining promising spectroscopic properties from a neat sample, this material underwent polymerization upon isolation (Scheme 70).³⁰⁴ Toshimitsu reported the use of intramolecular amidoselenation reaction towards the synthesis of bridged lactams,³⁶³ however the originally-assigned bridged structure 254 was later found to be incorrect (Scheme 71).^364,365 A similar tendency of amides to cyclize via oxygen rather than nitrogen atom was also described by Smissman and coworkers in the context of their work on bridged barbituric acid derivatives (see Section 6.2.2).^366–371

Scheme 69.

Synthesis of Vinblastine-Derived Bridged Lactams by Kutney

Scheme 70.

Attempted Synthesis of 1-Azabicyclo[3.1.1]heptan-6-one by Williams

Scheme 71.

Attempted Synthesis of 1-Azabicyclo[3.2.1]octan-8-onesvia Amidoselenation by Toshimitsu

6. SYNTHESIS OF BRIDGED LACTAMS WITH COMPLEX RING SYSTEMS AND RELATED HETEROCYCLES

6.1. Bridged Lactams with Complex Ring Systems

In this section, we discuss the synthesis of bridged lactams embedded in more complex ring systems. It is also possible to classifythese compounds by the type of reaction used for their synthesis (condensation reactions forming N–C(O) bond^372–374 or reactions involving radical intermediates).^375–377 Bridged monothioimide 263 (Scheme 73)³⁷⁵ and bridged imides 269 (Scheme 74)^376,377 can be also classified as heteroatom-containing derivatives of bridged lactams.

Scheme 73.

a) Synthesis of Bridged Monothioimidevia Photochemical Fragmentation/Photocyclization by Sakamoto; b) Rearrangement of One-Carbon Higher Analog

Scheme 74.

Synthesis of Complex Bridged Imides via [2+2] Photocycloaddition by Booker-Milburn

In 1992, during synthetic studies toward the alkaloid stemofoline, Thomas reported the synthesis of bridged lactams containing a rigid tropane-type scaffold (Scheme 72).^372–374 Lithium–halogen exchange, followed by intramolecular organolithium addition to carbamates 257 gave tetrahedral intermediates 258, which collapsed to bridged amides upon warming to room temperature. When the reactionswere quenched at −78 °C, transannular ester migration occurred. The X-ray structure of bridged lactam 259c³⁷² (N–C(O) = 1.432 Å) and its infrared stretching frequency of 1746 cm⁻¹indicated non-planar character of the amide bond. However, it should be noted that the synthesis and chemical properties (see Scheme 144)³⁷³ of lactams 259 are strongly influenced by the presence of the tropanone ring system.

Scheme 72.

Synthesis of Tropane-Derived Bridged Lactams in Synthetic Studies towards Stemofoline by Thomas

Scheme 144.

Reduction of Tropane-Derived Bridged Lactam by Thomas

In 1990, Sakamoto reported the synthesis of bridged monothioimide via Norrish type I reaction of a thiocarbonyl group (Scheme 73a).³⁷⁵ The authors suggested that the ring strain in the five-membered ring precursor 262 played an important role in the cleavage of C–C(S) bond. In agreement with this hypothesis, the substrate 264 containing a six-membered ring underwent an alternative [2+2] cycloaddition to give the fused enamide 265 (Scheme 73b).

In 2009, Booker-Milburn reported the synthesis of tetracyclic bridged imides 267 via intramolecular [2+2] photocycloaddition (Scheme 74).³⁷⁶ This reaction relies on the use of sensitizers to control [2+2]³⁷⁶ over [5+2]³⁷⁷ mode of cycloaddition of N-alkenyl maleimide substrates (Scheme 75). In the presence of benzophenone sensitizer, [2+2] cycloaddition occurred with high selectivity, while under direct irradiation conditions the synthesis of tricyclic azepines 268 was achieved.³⁷⁶ All bridged imides were isolated as single diastereoisomers. The authors proposed that a sufficiently long lifetime of the triplet excited state allowed the side chain to achieve the lowest energy conformation for the cycloaddition. The X-ray structure of 267f³⁷⁷ indicated that the endocyclic imide carbonyl group (N–C(O) = 1.412 Å; C=O = 1.198 Å) is less planar than the exocyclic carbonyl group (N–C(O) = 1.394 Å; C=O = 1.221 Å).

Scheme 75.

Proposed Mechanism for Photocycloaddition of Imides 266 (please use double-column format for Scheme 75)

6.2. Heteroatom-Containing Derivatives of Bridged Lactams

A sampling of heteroatom-containing derivatives of bridged lactams is depicted in Figure 10a. In general, heterocycles containing heteroatoms adjacent to amide bonds (such as, bridged ureas and bridged urethanes; see Section 6.2.1) are easier to synthesize than the parent bridged lactams because of the stabilizing resonance interaction involving the amide bond and the additional heteroatom (Figure 10b). Another class of heteroatom-containing derivatives of bridged lactams consists of bridged oxazinolactams and bridged diazines (see Section 6.2.2), in which the bridgehead nitrogen atom is accompanied by an α-heteroatom. Amide bonds in these compounds are subjected to similar strain to those in the parent lactams, however transannular interactions in medium-sized rings often contribute to the distortion of these compounds. Finally, bridged imides (such as, barbiturates, oxazolidinediones and hydantoins; see Figure 11 for structures, Section 6.2.3) exhibit a ring-size dependent inhibition of the amide bond resonance and their synthesis can be problematic.

Figure 10.

a) Heteroatom-containing derivatives of bridged lactams; b) Stabilizing resonance interaction in bridged ureas and urethanes.

Figure 11.

Design of conformationally-constrained analogues by Smissman: a) anticonvulsant and anti-steroid drugs containing planar amide bonds; b) potential analogues containing bridged amide bonds (“smissmanones”).

6.2.1. Bridged Ureas and Urethanes

The first successful synthesis of a bridged urea was reported by Hall in 1972 (Scheme 76).³⁷⁸ Treatment of an easily accessible diamine 274 with phosgene at 0 °C resulted in the net acylation of both nitrogen atoms to afford bridged urea 275 in moderate yield. In contrast, the reaction at −75 °C gave the corresponding bis-carbamoyl chloride, which was converted into 275 using Ag₂CO₃ in refluxing acetonitrile in lower yield.³⁷⁸ The infrared frequency of 275 of 1650 cm⁻¹ was in the region expected for planar tetraalkylureas, indicating that this compound is not particularly strained. In 1980, Hall reported the synthesis of another bridged urea 278 via depolymerization of a polymeric pre-urea under high vacuum (Scheme 77).³⁷⁹

Scheme 76.

Synthesis of 3-Alkyl-1,3-diazabicyclo[3.3.1]nonan-2-ones by Hall

Scheme 77.

Synthesis of 1,3-diazabicyclo[3.3.1]nonan-2-ones by Hall

Concurrently, Hall developed the synthesis of bridged urethanes using phosgene as a carbonyl source (Scheme 78).^380,381 The optimum conditions for the synthesis of bridged urethane 281 containing a [3.3.1] ring system proceeded via chloroformate salt 280 (Scheme 78a), while the urethane 284 containing a [3.2.1] ring system was obtained via an alternative route involving an N-carbamoyl chloride (Scheme 78b).³⁸⁰ The first of these reactions proceeds via O→N rearrangement prior to the lactamization step. The infrared frequencies of bridged urethanes (281: 1710 cm⁻¹; 284: 1770 cm⁻¹) were found to be higher than those of the corresponding planar urethanes (1,3-oxazinan-2-one: 1700 cm⁻¹; oxazolidin-2-one: 1730 cm⁻¹). In contrast to these results, treatment of 276 with phosgene resulted in only 5% yield of 278 (Scheme 77), possibly due to competitive formation of a bis phosgene adduct at the free nitrogen atom in the initially formed intermediate.³⁷⁹

Scheme 78.

Synthesis of Bridged Urethanes by Hall: a) 3-Oxa-1-azabicyclo[3.3.1]nonan-2-one; b) 6-oxa-1-azabicyclo[3.2.1]octan-7-one

Scheme 79.

Synthesis of β-Lactamase Inhibitor Containing 1,6-Diazabicyclo[3.2.1]octan-7-one Scaffold by Mangion

Recently, Mangion and coworkers reported the synthesis of β-lactamase inhibitor MK-7655 featuring a bridged urea (Scheme 79).²³⁴ A protocol employing triphosgene in the presence of Hünig’s base, followed by treatment with dilute phosphoric acid gave the highest yield. Other carbonyl sources than triphosgene proved ineffective in promoting the cyclization to the bridged urea. The authors proposed that phosphoric acid aids in conversion to 286 by hydrolyzing the intermediate trichloromethyl carbamate. The bridged urea 286 proved sufficiently stable to allow synthesis of MK-7655 in three more steps.

6.2.2. Bridged Oxazinolactams, Oxazinourethanes and Diazines

In 2000, Shea reported the synthesis of bridged oxazinolactams and oxazinourethanes using type II intramolecular nitroso Diels-Alder reaction (Scheme 80).³⁸² This study followed the successful application of acyl-imino Diels-Alder reaction to the synthesis of bridged lactams by the Shea group (see Scheme 33).^297,298 The reactive N-acylnitroso dienophiles 290 were generated in situ from the corresponding hydroxamic acids.³⁸² Oxidation using Et₄NIO₄led to bridged oxazinolactams containing [4.3.1] and [5.3.1] ring systems in high yield. Other oxidants were used for preparation of bridged oxazinourethanes (such as 289c–d).³⁸² The synthesis of [6.3.1] ring system required milder conditions due to decomposition of the acylnitroso dienophile.³⁸³ This result was explained on the basis of developing transannular strain in the transition state leading to the 9-membered ring. Ultimately, the desired [6.3.1] oxazinolactam was formed when the N-acylnitroso dienophile was generated thermally from the dimethyl-acetylene cycloadduct (Scheme 81).³⁸³ In this case, the more flexible tether led to competitive formation of the regioisomeric bridged oxazinolactam containing [6.2.2] ring system. The X-ray structures of oxazinolactams bearing [4.3.1], [5.3.1] and [6.3.1] ring systems showed that N-oxy amide bonds exhibit comparable degree of strain to the analogous bridged lactams³⁸³ (289a: τ = 3.5°; χ_N = 54.8°; χ_C = 0.4°; N–C(O) = 1.406 Å; C=O = 1.217 Å; 289b: τ = 10.4°; χ_N = 52.6°; χ_C = 1.5°; N–C(O) = 1.398 Å; C=O = 1.219 Å; 293: τ = 16.4°; χ_N = 49.0°; χ_C = 4.1°; N–C(O) = 1.388 Å; C=O = 1.219 Å; see Section 4.3 for data on the corresponding bridged lactams²⁹⁸). The authors proposed that the release of transannular interactions in medium-sized rings led to the counterintuitive increase of twist angles with larger ring sizes in this series.

Scheme 80.

Synthesis of Unsubstituted Bridged Oxazinolactams via Type II N-Acylnitroso Diels-Alder Reaction by Shea

Scheme 81.

Synthesis of Unsubstituted [6.2.1] Bridged Oxazinolactamvia Type II N-Acylnitroso Diels-Alder Reaction by Shea

Shea extended this methodology to substituted bridged oxazinolactams (Scheme 82).³⁸⁴ Interestingly, 2-alkyl and 2-oxy-substituted hydroxamic acid precursors resulted in complementary diastereoisomers of the bridged products. This outcome was explained by dipole minimalization in the transition state. High diastereoselectivity was also observed with 3- and 4-substituted hydroxamic acid substrates.

Scheme 82.

Synthesis of Substituted Bridged Oxazinolactams via Type II N-Acylnitroso Diels-Alder Reaction by Shea

Following this account, Shea achieved the synthesis of bridged 1,2-diazines via type II intramolecular N-acylazo Diels-Alder reaction (Scheme 83).³⁸⁵ Initially, the required acylazo dienophiles were generated in situ from the corresponding hydrazides using n-Bu₄NIO₄ as the oxidant. Subsequently, a two-step protocol involving NBS-promoted synthesis of acylazo precursors and ZnCl₂-catalyzed Diels-Alder cycloaddition was developed. This methodology was applied to the synthesis of bridged diazines containing [4.3.1] and [5.3.1] ring systems. The X-ray structures of bridged 1,2-diazines were found to match those of the corresponding bridged oxazinolactams (298a: τ = 0.8°; N–C(O) = 1.394 Å; C=O = 1.216 Å; 298b: τ = 17.6°; N–C(O) = 1.401 Å; C=O = 1.219 Å).³⁸⁵ An unsuccessful attempt to prepare a related bridged diazine with a [3.2.1] ring system was reported by Hoornaert and coworkers.³⁸⁶

Scheme 83.

Synthesis of Bridged 1,2-Diazines via Type II N-Acylazo Diels-Alder Reaction by Shea

In 2005, Shea reported an asymmetric synthesis of bridged oxazinourethane 301 (Scheme 84).³⁸⁷ Treatment of the hydroxamic acid precursor with tert-butyl hydrogenperoxide in the presence of a catalytic amount of ruthenium salen complex 302 at 15 °C under high dilution conditions afforded the desired product with high levels of enantioinduction and in excellent yield. The authors proposed a catalytic cycle, in which the active Ru(IV) catalyst 302b performs a dual role: (1) dehydrogenation of the N-hydroxy formate ester 300 to produce an ion pair 302c, and (2) catalysis of the Diels-Alder reaction to give the bridged oxazinourethane 301 (Scheme 85).

Scheme 84.

Asymmetric Synthesis Bridged Oxazinolactams via Dual Function Catalysis by Shea

Scheme 85.

Proposed Mechanism for Diels-Alder Reaction of Substrate 300

6.2.3. Bridged Barbiturates, Oxazolinediones and Hydantoins (“Smissmanones”)

In a 1964 report, in analogy to known drugs containing planar imide bonds, Smissman proposed bridged bicyclic imides 307–310 as potential anticonvulsant agents (Figure 11).²³⁷ However, over the next 20 years, Smissman and coworkers found that synthesis of the proposed bridged imides 307–310 was more difficult than initially expected.^366–371 Attempts to prepare bridged barbituric acids, bridged amides or bridged imides via intramolecular alkylation approaches (Scheme 86)^366–370 or via intramolecular condensation methods (Scheme 87)³⁷¹ were unsuccessful due to the propensity of the tested precursors to react with electrophiles at the oxygen rather than nitrogen atom. Moreover, Smissman found that structures of bridged imides reported in literature by other groups were incorrect (Scheme 88).^388,389

Scheme 86.

Early Attempts to Synthesize Bridged Lactams from Barbituric Acids by Smissman: a) Alkylation of 5-Iodoalkylbarbituric Acid; b) Electrophilic Activation of N-Allylbarbituric Acid; c) Alkylation of N-Haloalkylbarbituric Acid

Scheme 87.

Early Attempts to Synthesize Bridged Lactams from Amides and Imides by Smissman: a) Intramolecular Condensation; b) Intramolecular N-Alkylation

Scheme 88.

Revision of Initially Reported Structures of Bridged Barbituric Acids: a) Barbituric Acid 322 Reported by Meltzer and Lewis; b) Barbituric Acid 325 Reported by Baumler (please use double-column format for Scheme 88)

Inspired by Smissman’s work,³⁹⁰ in 1984, Brouillette accomplished the synthesis of bridged 2,4-oxazolinediones containing [4.2.1] and [5.2.1] ring systems using acylation of α-hydroxy lactams with aryl chloroformate as a key step (Scheme 89).³⁹¹ Thus, the reaction of lactams 330 with 4-nitrophenyl chloroformate in refluxing toluene provided bridged oxazolinediones 331b–c in 44–90% yields. Under the same experimental conditions, the corresponding oxazolidinedione containing a [3.2.1] scaffold was not formed, likely because of the higher strain present in this ring system.³⁹¹ The X-ray structure of oxazolinedione 331b³⁹¹ indicated that the endocyclic amide bond is more distorted than the exocyclic bond (i.e., the endocyclic N–C(O) bond is 0.038 Å longer and the endocyclic C=O bond 0.014 Å shorter than the corresponding N–C(O) and C=O exocyclic bonds). Later, the X-ray structure of bridged oxazolidinedione 331c was reported by Kubicki (331c: endocyclic N–C(O) = 1.368 Å; C=O = 1.211 Å; exocyclic N–C(O) = 1.383 Å; C=O = 1.193 Å).³⁹²

Scheme 89.

Synthesis of Bridged 2,4-Oxazolinediones by Brouillette

Subsequently, Brouillette achieved the first synthesis of bridged hydantoins containing [4.2.1]³⁹³ and [5.2.1]²⁴⁰ ring systems (Scheme 90). The exposure of carboxyamides 335 to Pb(OAc)₂ resulted in the Hoffman rearrangement to the intermediate isocyanates, which underwent intramolecular attack by the lactam nitrogen atom to afford the desired bridged hydantoins in 48–67% yields. The conditions using 2,6-lutidine in the absence of alcohol proved crucial for the efficient intramolecular N-alkylation of the intermediate isocyanates. Bridged hydantoins were distinguished from the potential O-alkylated products on the basis of ¹⁵N NMR experiments (336b: bridgehead nitrogen atom 139.1 ppm; 7-methoxy-3,4,5,6-tetrahydro-2H-azepine: 233.1 ppm).³⁹³

Scheme 90.

Synthesis of Bridged Hydantoines by Brouillette

Finally, Brouillette revised³⁹⁴ the structure of bridged barbituric acid 338 as originally reported by Smissman³⁹⁵ (Scheme 91), while Gmünder and Lindenmann reported the attempted synthesis of bridged barbituric acid 341 with an alternative bond connectivity (Scheme 92).³⁹⁶ These examples underline the difficulty of ring closure using N-alkylation and N-acylation via amide nitrogen atom to obtain strained lactams. In recognition of Smissman’s work, bridged amides with the general structures 307–310 are generally referred to as “smissmanones”.²⁴¹

Scheme 91.

Revision of Structure of Bridged Barbituric Acid Initially Reported by Smissman

Scheme 92.

Attempted Synthesis of Bridged Barbituric Acid by Gmünder and Lindenmann

6.3. Bridged Enamines

Enamines in which nitrogen atom is placed at the bridgehead position in a bicyclic ring system are subject to similar geometrical restrictions as bridged lactams.³⁹⁷ In cases where resonance interaction between the nitrogen lone pair and the π electrons of the double bond is limited, the characteristic nucleophilicity of the carbon atom of enamines decreases with HOMO orbital localized at the nitrogen atom in these systems.

In 1985, Doering published a seminal report on the conjugative interaction of bridged enamines using compound 347 containing a [3.2.2] ring system (Scheme 93).³⁹⁸ The required enamine was prepared from 1-azabicyclo[2.2.2]octan-3-one 344 in a four-step sequence (Scheme 93a). The final step involved equilibration of the allyl amine 346 to the bridged enamine with LiNMe₂–HMPA and subsequent fractional crystallization of the corresponding HI salt. Doering demonstrated that the bridged enamine 347 can be equilibrated to 346 using LiNMe₂–HMPA or RuH(NO)(PPh₃)₃ (Scheme 93b).³⁹⁸ The equilibrium constant of 1.0 for both reactions indicates the lack of conjugative interaction between the enamine nitrogen and the olefin double bond in this [3.2.2] ring system. In contrast, planar enamines favor the enamine form by approx. 4 kcal/mol.³⁹⁷

Scheme 93.

a) Synthesis of 1-Azabicyclo[3.2.2]non-2-ene by Doering; b) Equilibrium between Bridged Allylic Amine and Enamine

In 2006, Crawley and Funk reported the synthesis of bridged enamine containing a [3.3.2] ring system during their approach to communesin B (Scheme 94).³⁹⁹ The enamine 349 was formed via a gold-catalyzed 7-exo-dig cyclization of a piperidine nitrogen onto a tethered alkyne in 348. Later, it was found that this cyclization also proceeded spontaneously at room temperature.³⁹⁹ The X-ray structure of enamine 349 has been reported (θ = 337.6°; N–C(CH₂) = 1.444 Å; C=CH₂ = 1.329 Å).³⁹⁹

Scheme 94.

Synthesis of Bridged Enamine via Au-Catalyzed Hydroamination by Funk

In 2008, Ellman reported the synthesis of endocyclic bridged enamines with a [4.3.1] scaffold via a C–H activation/alkenylation/electrocyclization sequence (Scheme 95).⁴⁰⁰ A catalyst generated in situ from [Rh(coe)₂Cl]₂ and the electron-rich monophosphine ligand (4-NMe₂)PhPEt₂ (used in 1:1 ratio) was identified as optimal for this transformation. The reaction efficiency was highly dependent on the substitution of α,β-unsaturated aldimine moiety and the length of tether connecting the alkyne. The proposed mechanism, shown in Scheme 96,⁴⁰⁰ involves generation of the hydrido(vinyl)rhodium intermediate 351a, its addition to the alkyne in a 2,1-fashion, reductive elimination to give the cyclic aza-triene 351c, and electrocyclization under the reaction conditions.

Scheme 95.

Synthesis of Bridged Bicyclic Enamines by Tandem Rh-Catalyzed C–H Activation/Alkenylation/Electrocyclization by Ellman

Scheme 96.

Proposed Mechanism for Synthesis of 352

Pearson reported the synthesis of bridged enamines via an intramolecular Schmidt reaction^318–320 using azidoalkyl olefins or azidoalkyl alcohols (Scheme 97).⁴⁰¹ Azides tethered to five-membered rings afforded mixtures of regioisomeric bridged enamines with [2.2.2] and [3.2.1] scaffolds, while six-membered ring precursors led exclusively to [3.2.2] bridged systems. The use of alkyl-substituted substrates (cf. aryl as in 356) resulted in olefin isomerization in the final products. The mechanism of this rearrangement proceeds via (1) generation of the carbocation, (2) its trapping by the tethered azide, (3) 1,2-carbon migration with expulsion of nitrogen to give bridged iminium ion, and (4) deprotonation to give the twisted enamine product (Scheme 98). The enamine is reprotonated at nitrogen under the reaction conditionsbut the basic work-up gives the final neutral product. Other bridged enamines based on the quinuclidine skeleton^402–405 have been reviewed.^406,407

Scheme 97.

Synthesis of Bridged Enamines viaIntramolecular Schmidt Reaction by Pearson

Scheme 98.

Proposed Mechanism for Schmidt Reaction of Azidoalkyl Alcohols

Bridged enamines have also been prepared from bridged lactams (see Section 7.2.4).^108,408

6.4. Bridged Iminium Ions

Iminium ions containing nitrogen atom at the bridgehead position cannot achieve full resonance stabilization and are typically considered as carbocations.^{409–412,102} Although several bridgehead imines and iminium ions have been reported,^413–419 only a few of these compounds bear nitrogen atom at the bridgehead position in a bicyclic system.^{420–424,353,354}

During studies on solvolysis of modified Cinchona alkaloids containing good leaving groups at the C–9 position, Hoffmann discovered their rearrangement to 1-azabicyclo[3.2.2]nonanes via bridged iminium ions (Scheme 99).⁴²⁰ High yields were obtained in both the quinine (Scheme 99a) and quinidine (Scheme 99b) series.⁴²⁰ In these systems, 1,2-alkyl shift to give strained non-planar iminium ions is favored by stereoelectronic factors. The participation of the aziridinium ions was ruled out on the basis of control experiments probing the ability of activated Cinchona alkaloids to undergo self-quaternization reactions. This rearrangement was subsequently described as “the first Cinchona rearrangement”.^421,422

Scheme 102.

Synthesis of Bridged Sultams via Heck Reaction by Paquette

Hoffmann also reported the synthesis of enantiomerically pure 1-azabicyclo[3.2.2]nonanes in quincorine (Table 7) and quincoridine (Table 8) series.⁴²³ Treatment of β-amino iodides 366 and 369 with methanol in the presence of AgOBz resulted in stereoselective rearrangement to α-amino ethers via bridged iminium ions. Other silver salts proved less efficient in promoting the reaction or led to partial epimerization of the desired products. The reaction showed good functional group compatibility, tolerating alkynes, ketones, and esters. Notably, the bridged iminium ions were found to be configurationally stable and no equilibration between the quincorine and quincoridine series was observed.

Table 7.

Rearrangement of Quincorine-Derived 2-Iodomethyl-2-Azabicyclo[2.2.2]octanes via Bridged Iminium Ions by Hoffmann

entry	366	R1	R2	AgX	yield of 368 (%)
1	366a	CH=CH2	H	AgOAc	10
2	366a	CH=CH2	H	AgOTf	30
3	366a	CH=CH2	H	AgOBz	86
4	366b	Et	H	AgOBz	66
5	366c	CO2Me	H	AgOBz	75
6	366d	O=		AgOBz	76
7	366e	C≡C-Ph	H	AgOBz	82
8	366f	C≡CH	H	AgNO3	61

Table 8.

Rearrangement of Quincoridine-Derived 2-Iodomethyl-2-Azabicyclo[2.2.2]octanes via Bridged Iminium by Hoffmann

entry	369	R1	R2	AgX	yield of 371 (%)
1	369a	CH=CH2	H	AgOBz	74
2	369b	Et	H	AgOBz	62
3	369c	O=		AgOBz	72
4	369e	C≡C-Ph	H	AgOBz	70

Applying the same concept, Hoffmann developed the synthesis of functionalized 1-azabicyclo[3.2.2]nonanes from quincorine (Table 9) and quincoridine (Table 10).⁴²⁴ A wide range of carbon, nitrogen and sufur nucleophiles was used to capture bridged iminium ions 373 and 376 with complete diastereoselectivity.

Table 9.

Reactions of Quincorine-Derived Bridged α-Amino Ether 372 with Nucleophiles via Bridged Iminium Ion 373 by Hoffmann

entry	RX	R	yield of 374 (%)
1	Me3SiCN	-CN	83
2	Me3SiN3	-N3	81
3	Bu3SnC≡CH	-C≡CH	39
4	Me2C=C(OMe)OSiMe3	-C(CO2Me)Me2	66

Table 10.

Reactions of Quincoridine-Derived Bridged α-Amino Ether 375 with Nucleophiles via Bridged Iminium Ion 376 by Hoffmann

entry	RX	R	yield of 377 (%)
1	Me3SiCN	-CN	68
2	Me3SiN3	-N3	75
3	Bu3SnC≡CH	-C≡CH	70
4	allylMgBr	-CH2CH=CH2	48
5	Me3SiCH2C≡CH	-CH=C=CH2	24
6	Me2C=C(OMe)OSiMe3	-C(CO2Me)Me2	70
7	Me3SiSC6H5	-SC6H5	59

Miyano reported the formation of bridged iminium ions in 1-azabicyclo[3.3.1]nonane system (Scheme 100).^353,354 Aziridinium rearrangement of pyrrolizidine 227 provided the bicyclic precursors 229/378 (Scheme 100a; see also Section 5.5). The unexpected stability of these products was proposed to arise from the gauche conformation between the lone pair of electrons at nitrogen and the two C–Cl bonds.³⁵³ Both chlorine atoms could be displaced by alkoxides upon heating in alcoholic solvents via bridged cation 379 (Scheme 100b).³⁵⁴ Extensive NMR studies suggested that introduction of two substituents at the C–9 position in 1-azabicyclo[3.3.1]nonane system forces the ring in a double-chair conformation (cf. Section 4.1).

Scheme100.

a) Synthesis of 1-Azabicyclo[3.3.1]nonanes by Miyano; b) Generation of Bridged Iminium Ions from 1-Azabicyclo[3.3.1]nonanes

6.5. Bridged Sultams

In contrast to amide bonds, incorporation of a sulfonamide moiety into a bridged bicylic ring system does not result in its hyperreactivity.⁴²⁵ Bridged sulfonamides (sultams) are the area of considerable current interest due to their potential application in medicinal chemistry^426,427 and stereoselective synthesis.^428,429 The chemistry of fused sultams has been recently reviewed.⁴³⁰

In the last twenty years, three general approaches to the synthesis of bridged sultams have been reported: i) Heck reactions,^{292–295,431–436} ii) radical cyclization reactions,^437–439 iii) alkylation reactions.^440,441

In 1991, Grigg demonstrated that Heck cyclizations of ortho-bromoarylsulfonamides onto tethered alkenes proceed in good yields to give the corresponding bridged sultams (Scheme 101).²⁹² In contrast to the analogous Heck reaction leading to bridged lactams (see Schemes 28 and 29),^291–294 sulfonamide-containing substrates allowed for the preparation of sultams bearing [3.2.1] and [3.2.2] ring systems.²⁹² This trend was explained by the lower rotational barrier around the N–S(O)₂ bond in sulfonamides as compared to the N–C(O) bond in amides. The regioselectivity of the reaction leading to the [3.2.2] ring system was significantly improved by using a catalyst system comprising of Pd(OAc)₂, PPh₃, and Tl₂CO₃.²⁹² Subsequently, Grigg investigated cascade and one-pot RCM-Heck reactions to prepare bridged sultams.^293,294 Recently, a similar Heck reaction protocol was utilized by Paquette to construct bridged sultams containing [4.3.1] and [4.2.1] ring systems (Scheme 102),^295,431 while Evans reported the synthesis of bridged sultams containing [3.2.1] scaffolds via a tandem Heck reaction/hydrogenation process (Scheme 103).^432–436

Scheme 101.

Synthesis of Bridged Sultams via Heck Reaction by Grigg

Scheme 103.

Synthesis of Bridged Sultams via Tandem Heck Reaction/Hydrogenation by Evans

In 1999, Paquette reported a seminal study on the synthesis of bridged sultams via intramolecular radical cyclization reactions of cyclic unsaturated halomethylsulfonamides (Scheme 104).⁴³⁷ This reaction was successfully applied to the synthesis of five different ring systems of unsubstituted bridged sultams, however bridged sultam containing a [2.2.1] scaffold did not form under these reaction conditions. The X-ray structure of 392c indicated O–S–N–lone pair dihedral angles of −90° and 40°. In contrast, the lone pair of electrons at nitrogen in planar sulfonamides is found in a plane bisecting the O–S–O angle. Despite these structural differences, all bridged sultams 392 were found to be hydrolytically stable. Using radical cyclization reaction, Paquette also reported the synthesis of bridged disulfonimide with a [3.2.2] ring system (Scheme 105),⁴³⁸ and complex tricyclic bridged sultams.⁴³⁹ The X-ray structure of 394⁴³⁸ showed a large θ value (394: θ = 345.8°; 392c: θ = 325.2°), indicating a relatively flexible sulfonimide bond in this compound.

Scheme 104.

Synthesis of Bridged Sultams via Radical Cyclization by Paquette

Scheme 105.

Synthesis of Bridged Disulfonimide via Radical Cyclization by Paquette

Subsequently, available ring systems of bridged sulfonamides have been expanded to include bridged sultams bearing sulfur atom at the apex position.^440,441 In 2006, Paquette reported the synthesis of a bridged sultam containing a [4.2.1] ring system via an intramolecular alkylation reaction (Scheme 106a).⁴⁴⁰ Attempts to close the bicyclic system via RCM proved unsuccessful (Scheme 106b).⁴⁴⁰ More recently, de Meijere and coworkers demonstrated that related bridged sultams can be generated by dialkylation of simple monocyclic precursors (Scheme 107).⁴⁴¹ The X-ray structures of several bridged sultams have been reported (400a: θ = 310.2°; 400b: θ = 325.3°; 400d: θ = 340.0°; 400e: θ = 341.6°),⁴⁴¹ and indicate progressive decrease of the pyramidalization at nitrogen in this series.

Scheme 106.

a) Synthesis of “Apex” Bridged Sultam by Paquette; b) Unsuccessful Approach via RCM

Scheme 107.

Synthesis of Bridged Sultams via Double Alkylation by de Meijere

An alternative approach to bridged sultams was reported by Hanson and coworkers (Scheme 108).⁴⁴² As a part of the reaction pairing strategy to access structurally diverse sultams,^443–445 these researchers developed a sequential sulfonylation-S_NAr protocol starting from ortho-flurobenzenesulfonyl chloride and cyclic amino alcohols to afford bridged sultams with [4.2.1] and [5.2.1] ring systems in good overall yields.⁴⁴² This protocol was recently employed for the synthesis of a 40-member library of bridged sultams bearing [4.2.1] scaffolds.⁴⁴⁶

Scheme 108.

Synthesis of Benzofused Bridged Sultams via Sulfonylation/S_NAr of Amino Alcohols by Hanson

Finally, Blakey reported the synthesis of heteroatom-derived bridged sultams via rhodium-catalyzed allene sulfonamidation (Scheme 109).⁴⁴⁷ The reaction showed good substrate scope, allowing for the synthesis of densly functionalized sulfonamides. The mechanism was proposed to involve (1) sulfonamidation to give 2-amidoallylcations, (2) rearrangement to strained N-sulfonylimino-cyclopropanes, and (3) formal [3+3] cycloaddition with acyclic nitrones (Scheme 110).

Scheme 109.

Synthesis of Heteroatom-Derived Bridged Sultams via Rh-Catalyzed Allene Sulfamidation by Blakey

Scheme 110.

Proposed Mechanism for Synthesis of 407

7. REACTIVITY OF BRIDGED LACTAMS AND RELATED HETEROCYCLES

Due to the limited n_N→π^*_C=O conjugation, distorted amides exhibit reactivity dissimilar to traditional amides.^57–59 In general, the C=O group is more electrophilic than in planar amides, while the nitrogen atom might behave as a basic amine. Both of these properties depend on the degree of twist of the amide bond; in extreme cases, the amide bond reacts as an isolated amino-ketone rather than an amide, however it is also hydrolytically labile. Conversely, bridged lactams in which the amide bond is close to planarity tend to react as traditional amides and are hydrolytically stable.

For the purpose of this review reactions of bridged lactams are classified depending on the reacting center of the amide bond (that is, carbonyl group or nitrogen atom), and the type of reaction. Because of its historical importance, the hydrolysis of distorted amide bonds is addressed separately. Reactions of heteroatom-containing derivatives of bridged lactams, bridged enamines and bridged sultams are also addressed in this section.

7.1. Hydrolysis of Bridged Lactams

Planar amide bonds are remarkably stable to hydrolysis, with half-life for neutral hydrolysis at room temperature counted in hundreds of years.⁴⁴⁸ Due to their enhanced electrophilicity, bridged lactams are more susceptible to hydrolysis than planar amides.⁶¹ Bridged lactams characterized by large twist angles are hydrolytically unstable, which complicates their synthesis, isolation, and examination of physico-chemical properties, especially in nucleophilic solvents including water.

Between 1958 and 1965, Pracejus studied the hydrolysis of 2-quinuclidones and their hydrochloride salts (Scheme 111).^253,254 Near pH = 5, the half-life for methanolysis of the bridged lactam 44 was less than 5 minutes; however, this compound hydrolyzed only very slowly in water at 20 °C (Scheme 111a).²⁵⁴ Under basic conditions, the lactam 44 underwent solvolysis 10⁴ faster than the planar 2-azabicyclo[2.2.2]octan-3-one at 100-times higher alkali concentration.²⁵⁴ The hydrochloride salt 409 was found to be even more labile towards hydrolysis and alcoholysis than the parent amide (Scheme 111b).²⁵⁴ Furthermore, methyl-substituted 2-quinuclidones were found to hydrolyze in the order corresponding to the degree of steric shielding of the amide bond by the neighboring methyl substituents (44 > 46b (endo) > 46a (exo); see Figure 12 for structures of 46a–b).²⁵⁴

Scheme 111.

a) Hydrolysisof 6,6-Dimethylquinuclidin-2-one; b) Hydrolysis of 6,6-Dimethyl-2-quinuclidinium Chloride by Pracejus

Figure 12.

Determination of pK_a of 2-quinuclidones by Pracejus (44, 46a–b) and Yakhontov (46c)

Pracejus determined the pK_a of methyl-substituted 2-quinuclidones to be 5.33–5.60,²⁵⁴ while Yakhontov established the pK_a of a tetramethyl-substituted 2-quinuclidone at 6.37 (Figure 12).^256,257 Although these values are consistent with the high basicity of the amide nitrogen in this [2.2.2] ring system, methyl-substituted 2-quinuclidones did not succeed as good models for reactivity of bridged lactams due to steric hindrance around amide bonds.

In the early 1980s, Blackburn²⁶¹ and Brown²⁶² independently studied the rate of hydrolysis of benzo-fused bridged lactams derived from 2-quinuclidones (Scheme 112). Blackburn observed an increase of seven and nine orders of magnitude in the rate of basic and acidic hydrolysis of the 2-quinuclidone 60, respectively, as compared to the planar 1-phenyl-2-piperidone.²⁶¹ Brown measured the rate of hydrolysis of several 2-quinuclidone derivatives characterized by different distortion parameters, finding a good relationship between the rate of hydrolysis and twist angles.²⁶² However, for two of these lactams the correlation was better when pyramidalizations at nitrogen were also considered (Table 11).²⁶²

Scheme 112.

a) Hydrolysis of Benzo-2-quinuclidone by Blackburn; b) Hydrolysis of Extended Ring Systems of Benzo-2-quinuclidones by Brown

Table 11.

Winkler-Dunitz Distortion Parameters and Hydrolysis Rate Constants of Benzo-2-quinuclidones by Brown

entry	ring system	τa [deg]	χNa [deg]	χCa [deg]	k3b [M−1s−1]	k3/K3c [M−1s−1]
1	[2.2.2]	90.0d	63.4d	0.0d	2.6 × 102	2.3 × 104
2	[3.2.2]	30.7	57.2	9.0	6.0 × 101	5.6 × 101
3	[2.3.2]	33.2	52.8	11.0	1.7 × 101	3.0 × 101
4	[3.3.2]	15.3	38.6	6.7	5.1 × 10−4	1.2 × 10−4
5	planar acetanilidee	1.5	3.7	−1.5	2.2 × 10−5	2.2 × 10−7

^aDetermined by X-ray crystallography.

^bRate constant for base hydrolysis.

^cRate constant for acid hydrolysis.

^dCalculated values.

^eN-(4-bromo-2-methylphenyl)-N-methylacetamide.

In 1998, Kirby reported the unusual hydrolytic behavior of perpendicularly twisted 1-aza-2-adamantanone (Scheme 113).^272,108 This lactam was rapidly hydrolyzed to the ring-opened amino acid when dissolved in water (t_1/2 < 50 s). Similarly, the half-life of 0.3 s for acidic hydrolysis at pH = 5 showed that 1-aza-2-adamantanone is significantly more reactive than methyl-substituted 2-quinuclidones (cf. Scheme 111). The pK_a value of 5.2 indicated the expected high basicity of the lactam nitrogen atom.¹⁰⁸ Interestingly, below pH 4 1-aza-2-adamantanone was quantitatively converted into the protonated orthoamide 412, which at pH = 4.3 existed in equilibrium with the open-form amino acid. Furthermore, the amino acid 411 gave the parent bridged lactam when dissolved in neutral methanol (Scheme 114).¹⁰⁸

Scheme 113.

a) Hydrolysis of 1-Aza-2-adamantanone; b) Proposed Mechanismfor Hydrolysis by Kirby

Scheme 114.

Synthesis of 1-Aza-2-adamantanone from the Corresponding Amino Acid by Kirby

Stolz reported that the perpendicularly twisted 2-quinuclidone 52 is rapidly hydrolyzed in water with t_1/2 < 15 s (Scheme 115).¹⁰⁷ This compound was also unstable in other nucleophilic solvents, including DMSO, pyridine and MeOH, which led to the nucleophilic cleavage of the amide bond.

Scheme 115.

Hydrolysis of 2-Quinuclidonium Tetrafluoroborate by Stoltz

Aubé studied the hydrolysis of one-carbon bridged lactams characterized by medium twist angles (Scheme 116).⁴⁴⁹ Tricyclic and bicyclic lactams were found to be stable in aqueous solutions under biologically relevant pH conditions (pH = 4–10), however these compounds rapidly hydrolyzed under more acidic or basic pH conditions. Their stability was proposed to result from incorporation of the amide bond into a one-carbon bridge placed across medium-sized heterocycles, where it benefits from the scaffolding effects of medium-sized rings. The spontaneous re-formation of amide 175b from the seco-amide form 416 in water is a notable feature of such systems.

Studies on the hydrolytic stability of bridged lactams bearing the amide bond on the external bridge in a bicyclic system have also been reported. Judd and coworkers found that lactam 133a containing a [3.3.1] ring system was significantly more labile under acidic conditions than the regioisomeric lactams with [4.3.1] ring systems (Figure 13).²⁹⁶ Denzer and Ott discovered that the hydrolytic behavior of bridged lactams containing an additional nitrogen atom at the bridgehead position in [3.3.1] and [3.2.1] ring systems corresponds to the degree of strain associated with the bridged amide bond (Scheme 117).²⁹⁰ Hall investigated the hydrolytic stability of a family of unsubstituted bridged lactams,²⁷⁹ bridged ureas^378,379 and bridged urethanes^380,381 (Table 12 and Figure 14). Derivatives containing a [3.3.1] ring system were relatively stable under the tested reaction conditions, while the bridged urethane containing a [3.2.1] scaffold rapidly hydrolyzed in water.³⁸⁰

Figure 13.

Hydrolysis of Bridged Homologues of1-Azabicyclo[3.3.1]nonan-2-oneby Judd

Scheme 117.

Hydrolysis of Aza-Bridged Lactams by Denzer and Ott

Table 12.

Hydrolysis of Bridged Lactams and Ureas by Hall

entry	X	lactam	conditions	result
1	CH2	96	D2O, 28 °C, 7 d	96
2	CH2	96	D2O, 100 °C, 6 h	96
3	CH2	96	D2O, HCl (g), 28 °C	95 HCl (quant)
4	N-H	278	D2O, 70 °C, 2 h	278
5	N-H	278	D2O, HCl (g), 28 °C	420 HCl (quant)
6	N-H	278	D2O, KOH, 70 °C, 2 h	278
7	N-iPr	275	D2O, 100 °C, 20 h	275
8	N-iPr	275	3 M NaOH, 100 °C, 6 h	420 (quant)

Figure 14.

Hydrolysis of bridged urethanes by Hall.

Wärnmark investigated acid-catalyzed hydrolysis of twisted bis-amide 167c derived from Tröger’s base (see Figure 8 for structure of 167c).³¹⁵ A complete hydrolysis was observed in a 0.58 N solution of HCl within 400 min, while kinetic and ¹⁸O labeling studies suggested irreversible collapse of the protonated tetrahedral intermediate.³¹⁵

Arata reported an interesting rearrangement of the one-carbon bridged lactam 225 bearing a leaving group at the bridgehead position on treatment with NaOH (Scheme 118).³⁵² Finally, several theoretical studies addressing the hydrolysis of non-planar lactams have been published.^62–66

Scheme 118.

Hydrolysis of 6-Chloro-1-Azabicyclo[4.4.1]undecan-11-one by Arata

7.2. Reactivity of Nitrogen Atom of Bridged Lactams

Two types of reactions of bridged lactams involving the nitrogen atom have been reported: (1) reactions with electrophiles leading to derivatives with intact bicyclic skeleton, and (2) reactions proceeding with scission of the C–NC(O) bond, following electrophilic activation of the lactam nitrogen atom.

7.2.1. N-Protonation and N-Methylation

Although oxygen is the protonation site of planar amide bonds, the limited n_N→π^*_C=O donation in bridged lactams leads to the enhanced basicity of nitrogen.^70,71 In general, even moderately distorted bridged lactams favor N-protonation over O-protonation.^70,71,284

Pracejus and Yakhontov were the first to show that bridged lactams undergo protonation and methylation reactions at the nitrogen atom (Scheme 119).^253–257 The potential products resulting from the cleavage of C–NC(O) bonds were not observed in these systems.

Scheme 119.

N-Protonation and N-Methylation of 2-Quinuclidones by Pracejus and Yakhontov

Kirby demonstrated that 1-aza-2-adamantanone readily forms quaternary ammonium salts upon treatment with Meerwein’s reagent or HCl (Scheme 120).¹⁰⁸ The latter product, isolated as the N-protonated hydrate 427, may be considered as a model for a cationic tetrahedral intermediate in acid-catalyzed acyl transfer reactions.⁴⁵⁰ The X-ray structure of 427¹⁰⁸ was characterized by a long C–N bond of 1.552 Å and significantly shortened C–O bonds of 1.382 Å. The stability of 427 resulted from the torsional restriction imposed by the adamantane scaffold.

Scheme 120.

N-Methylation and N-Protonation of 1-Aza-2-adamantanone by Kirby

In an important study, Brown found that methylation of the bridged lactam containing a [3.2.2] ring system takes place at nitrogen, while the less distorted analogue with a [3.3.2] ring system reacts at the oxygen atom under the same experimental conditions (Scheme 121).⁴⁵¹ Using DFT calculations, Greenberg predicted that related bridged lactams display higher electron density at nitrogen as compared to planar amides.^70,71 Recently, Greenberg reported that protonation of the relatively undistorted 1-azabicyclo[3.3.1]nonan-2-one also proceeds at nitrogen (Scheme 122).²⁸⁴ This finding is important in the light of the hydrolytic stability of 96 (see Table 12)²⁷⁹ and its unstrained structure (see lactam 87 for the amide bond distortion parameters in the [3.3.1] ring system: τ = 20.8°, χ_N = 48.8°, χ_C = 5.9°).^282,283

Scheme 121.

N-Methylation vs. O-Methylation of Benzo-2-quinuclidones by Brown

Scheme 122.

N-Protonation vs. O-Protonation of 1-Azabicyclo[3.3.1]nonan-2-one by Greenberg

Aubé reported several examples of N-protonated and N-methylated lactams bearing a [4.3.1] scaffold (Scheme 123).³³⁰ The structures of three of these analogues were examined by X-ray crystallography and provided the first direct crystallographic comparison between any twisted lactam and its corresponding salt. The distortion parameters and bond lengths of the N-protonated lactam 434b³³⁰ indicated a significant increase of pyramidalization around the C–N amide bond compared to its neutral analogue (434b: τ = 81.9°; χ_N = 52.1°; χ_C = 1.4°; N–C(O) = 1.502 Å; C=O = 1.192 Å; the corresponding bridged lactam 177b: τ = 51.5°; χ_N = 36.1°; χ_C = 12.8°; N–C(O) = 1.387 Å; C=O = 1.218 Å).³³⁰

Scheme 123.

N-Protonation and N-Methylation of Medium Bridged Twisted Lactams by Aubé

7.2.2. Cleavage of C–NC(O) Bond

Electrophilic activation of the nitrogen atom in bridged lactams may result in the scission of the adjacent C–N bond. Thus, Yakhontov reported cleavage reactions of the C–NC(O) bond in the tetramethyl-substituted 2-quinuclidone using PhLi, PCl₅ and acetone cyanohydrin (Scheme 124).^256,257 The nucleophile had a pronounced effect on the reaction outcome (cf. Table 14). This reaction was limited to systems capable of forming tertiary carbocations (Scheme 125).^256,257

Scheme 124.

Reactions of 6,6,7,7-Tetramethylquinuclidin-2-one with Cleavage of C–NC(O) Bond by Yakhontov

Table 14.

Reactions of 6,6,7,7-Tetramethylquinuclidin-2-one with Cleavage of Amide Bond by Yakhontov

entry	RH	conditions	447	yield (%)
1	H2O	100 °C, 0.5 h	447a	94
2	MeOH	65°C, 5 h	447b	76
3	morpholine	Δ, 12 h	447c	97
4	NH2OH	EtOH, 78 °C, 2 h	447d	62
5	NH2NH2	xylenes, Δ Dean-Stark, 5 h	447e	63
6	NH2NHPh	xylenes, Δ Dean-Stark, 12 h	447f	64

Scheme 125.

Proposed Mechanism for Synthesis of 436

Aubé reported that one-carbon bridged lactams undergo C–NC(O) bond cleavage reactions under very mild conditions (Scheme 126).²⁰⁸ The mechanism of the MeI-mediated scission was proposed to proceed via the amidinium ion, while the cleavage mediated by DDQ to involve the initial single-electron transfer from the amide bond.²⁰⁸ In all cases, the σ C–N bond furthest away from co-planarity with the carbonyl group in the neutral lactam was selectively cleaved. Tricyclic and bicyclic bridged lactams were also found to participate in regioselective hydrogenolysis reactions of the C–NC(O) bond using Pd(OH)₂ in alcoholic solvents (Scheme 127).²⁰⁸ The activation of bridged lactams by hydrogen bonding to nitrogen was proposed to play an important role in facilitating these reactions. In another study, medium-bridged bicyclic lactams containing an internal double bond showed increased reactivity towards the C–NC(O) bond hydrogenolysis (Table 13).³⁴³ Recently, Aubé reported the cleavage of a C–NC(S) bond in bridged thioamide containing a [4.3.1] ring system (Scheme 128).⁴⁵²

Scheme 126.

Cleavage of C–NC(O) Bond in Medium-Bridged Twisted Lactams by Aubé: a) Amidinium Salts; b) Oxidative Cleavage

Scheme 127.

Hydrogenolysis of C–NC(O) Bond in Medium-Bridged Twisted Lactams by Aubé

Table 13.

Hydrogenolysis of C–NC(O) Bond in Medium-Bridged Twisted Lactams by Aubé

entry	208	m	n	ring system	ratio of 443:444	combined yield (%)
1	208b	1	0	[4.2.1]	100:0	74
2	208a	1	1	[4.3.1]	25:75	95
3	208f	1	2	[4.4.1]	50:50	54
4	208c	2	0	[5.2.1]	100:0	72
5	208d	2	1	[5.3.1]	100:0	79
6	208e	3	0	[6.2.1]	100:0	89

Scheme 128.

a) Synthesis of Bridged Thioamide by Aubé; b) Proposed Mechanism Involving Cleavage of C–NC(S) Bond

7.3. Reactivity of Carbonyl Group of Bridged Lactams

The geometric constraints of non-planar amides modify the chemistry of the affected carbonyl group and its derivatives. Typically, amide bonds in bridged lactams are more electrophilic than those in planar amides because of the limited amide bond resonance.^67–69 Moreover, torsional restriction imposed by bicyclic scaffolds of bridged lactams often permit isolation of stable tetrahedral intermediates of the amide bond addition reactions.⁴⁵⁰

For the purpose of this review, the reactivity of carbonyl group of bridged lactams has been classified into the following classes: (1) reactions with heteroatom nucleophiles proceeding with cleavage of amide bonds, (2) reactions with heteroatom nucleophiles proceeding without cleavage of amide bonds, (3) reduction reactions, (4) reactions with organometallic and related reagents, and (5) miscellaneous reactions.

7.3.1. Reactions with Heteroatom Nucleophiles with Cleavage of Amide Bonds

Yakhontov was first to demonstrate the nucleophilic ring opening of bridged lactams with a variety of nucleophiles, such as water, alcohols, amines and hydrazines (Table 14).^256,257 The resulting piperidines were isolated in good yields after the basic workup. Yakhontov also observed an unexpected transacylation of the twisted amide bond during reduction of the sterically-hindered 2-quinuclidone 46c with LiAlH₄ (Scheme 129). The parent bridged lactam reacted in situ with the amino alcohol product to give amino ester product 449. Concurrently, Pracejus reported a rapid alcoholysis of another 2-quinuclidone under acidic conditions (Scheme 130).^253,254 These reactions confirm that amide bonds in bicyclic 2-quinuclidines exhibit properties of isolated amino-ketones.

Scheme 129.

Reduction of 6,6,7,7-Tetramethylquinuclidin-2-one by Yakhontov

Scheme 130.

Alcoholysis of 6,6-Dimethylquinuclidin-2-one by Pracejus

The susceptibility of non-planar amides to nucleophiles has been reported to complicate the synthesis and isolation of some bridged lactams.²⁵⁰ Aszodi and coworkers reported a facile aminolysis of the amide bond in a [3.2.1] bridged lactam 451 during the attempted removal of its p-nitrobenzyl group (Scheme 131).²³³ Later, this undesired side reaction was minimized by performing the hydrogenolysis in acetone to in situ convert the reactive 4-toluidine into the less nuclophilic N-isopropylaniline.²³³ Murphy subjected hydrolytically-unstable bridged lactams, prepared by an intramolecular Schmidt reaction, to methanolysis under mild conditions with TfOH and MeOH to facilitate identification of these compounds (Scheme 132).³²⁵

Scheme 131.

Aminolysis of [3.2.1] Bridged Lactam by Aszodi

Scheme 132.

Alcoholysis of One-Carbon Bridged Lactams by Murphy

Hall developed a series of polymerization reactions^453–455,55 of bridged lactams relying on the inherent strain of amide bonds (Table 15a).^{279,378–381} Lactam 96 containing a [3.3.1] scaffold²⁷⁹ was more reactive than the corresponding bridged ureas^378,379 and urethanes.^380,381 The analogous planar lactams, ureas and urethanes did not polymerize under the same reaction conditions (Table 15b).

Table 15.

a) Polymerization of 1-Azabicyclo[3.3.1]nonan-2-one and Related Compounds by Hall; b) Planar Derivatives Inert to Polymerization

entry	X	m	lactam	T [°C]	t (h)	polymerization
1	CH2	1	96	100	0.3	+
2	O	0	281	105	20	+
3	O	1	284	105	27	+
4	N-H	1	278	98	2	+
5	N-iPr	1	275	200	17	−

b)

7.3.2. Reactions with Heteroatom Nucleophiles without Cleavage of Amide Bonds

Diols,^108,408 hydrazines^232,408 and amines⁴⁰⁸ have been used as successful nucleophiles to give bridged derivatives of twisted lactams without cleavage of the amide bond. In all reported examples to date, scaffolding effects of adamantane-type or medium-sized rings stabilize the final products.

Kirby and coworkers reported the synthesis of a bridged hemiaminal from 1-aza-2-adamantanone using standard conditions for ketal formation (Scheme 133).¹⁰⁸ The same research group prepared a bridged tosylhydrazone as a precursor to amino carbene 459 (Scheme 134),²⁷¹ which subsequently was shown to react as a singlet carbene.²⁷¹

Scheme 133.

Synthesis of Bridged Amino-Ketal from 1-Aza-2-adamantanone by Kirby

Scheme 134.

Synthesis and Reactions of Aminocarbene from 1-Aza-2-adamantanone by Kirby

In their search for novel ligands of nicotinic receptor, Coe and coworkers reported the synthesis and Wolff-Kishner reduction of a bridged amino hydrazone to give the tricyclic amine 463 (Scheme 135).²³² Impressively, the synthesis of 463 could be conducted on 10–95 mmol scale directly from the ring-opened amino ester 84 (see Scheme 17) without isolating the intermediate bridged lactam and amino hydrazone in excellent overall yields (64–85%). During the course of this study, mixed ethanol-hydrazine intermediates were detected by APCI MS analysis (Scheme 136).²³² The bridged hydrazone 462 was obtained upon removal of solvent.

Scheme 135.

Wolff-Kishner Reduction of Bridged Lactam by Coe

Scheme 136.

Proposed Mechanism for Synthesis of Bridged Amidine 462

Finally, Aubé reported the synthesis of bridged amino ketals and amidines from moderately distorted tricylic lactams containing [4.3.1] ring system (Scheme 137).⁴⁰⁸ These reactions demonstrate that the amide bond does not need to be fully perpendicular to exhibit ketone-like properties.

7.3.3. Reduction of Carbonyl Group

The reduction of bridged lactams occurs under mild conditions to give hemiaminals, which are frequently isolated because of the geometrical constraints prohibiting their further reduction via bridged iminium ions.⁴⁵⁰

Denzer and Ott were among the first to demonstrate the reduction of bridged lactams with NaBH₄, which is considered unreactive towards planar amides (Scheme 138).²⁹⁰ The resulting hemiaminal collapsed to the aldehyde, which underwent further reduction. Interestingly, hydrogenation of 469 over PtO₂ resulted in the cleavage of methylene bridge to afford 1,5-benzodiazocinone 471. Subsequently, Coe and coworkers used NaBH₄ or LiAlH₄ to obtain isolable hemiaminal product from an adamantane-derived bridged lactam (Scheme 139).²³² It was proposed that the bis-axially bridged piperidine ring system provided an additional degree of stabilization in this system. Aubé reported that moderately distorted medium-bridged lactams efficiently react with NaBH₄, and that the resulting hemiaminals are stable to reaction and isolation conditions (Scheme 140).⁴⁰⁸ In some cases, mixtures of hemiaminals and primary alcohols were obtained (Scheme 141).⁴⁰⁸ When an electron-withdrawing group was α to the twisted amide bond, an unusual C–C bond cleavage reaction was observed to occur completely exclusive to breakage of the alternative C–N bond (Scheme 141).⁴⁰⁸

Scheme 138.

Reduction of 1,5-Diazabicyclo[3.3.1]nonan-2-one by Denzer and Ott

Scheme 139.

Reduction of Adamantane-Derived Bridged Lactam by Coe

Scheme 140.

Reduction of Medium-Bridged Twisted Lactams with Formation of Isolable Hemiaminals by Aubé

Scheme 141.

Reduction of Medium-Bridged Twisted Lactams with Collapse of Hemiaminals by Aubé

Arata studied the reduction of one-carbon bridged lactam containing a leaving group α to the twisted amide bond (Scheme 142a).³⁵² Thus, lactam 225 was converted to hemiaminal 479 by electron transfer reduction using Na/NH₃,or by the two-stage hydrogenolysis of the C–Cl bond, followed by amide bond reduction with LiAlH₄. Notably, the product of this reaction was the hemiaminal instead of fully reduced amine, as would be expected for planar amides under LAH reduction conditions. However, bridged hemiaminal 479 could be readily converted into the parent 1-azabicyclo[4.4.1]undecane (Scheme 142b). In contrast to the above conversions, the direct reduction of lactam 225 with LiAlH₄ afforded quinazoline 478. The proposed mechanism for this reaction is shown in Scheme 143.

Scheme 142.

a) Reduction of Chloro-Substituted Bridged Lactam by Arata; b) Synthesis of 1-Azabicyclo[4.4.1]undecane

Scheme 143.

Proposed Mechanism for Rearrangement of 225

Several examples documenting the reduction of bridged lactams in total synthesis of natural products have been reported. The Thomas group utilized hemiaminal 481, prepared by LiAlH₄ reduction of the bridged lactam 480, as a precursor to the corresponding tricyclic amine in their approach towards the tropane alkaloid stemofoline (Scheme 144).^372,373 Attempts to deoxygenate the bridged hemiaminal by employing S-methyl xanthate or halides under free-radical conditions were unsuccessful.³⁷³ Ultimately, the desired tricyclic amine was prepared in high yield via an intermediate acetate. Several alkaloids from Amaryllidaceae family contain bridged hemiaminals in a [3.2.1] benzofused ring system (Scheme 145).^183,188 The Wildman group investigated the reduction of oxohaemanthidine 484 to the corresponding hemiaminal using NaBH₄ in methanol,¹⁸³ while Hendrickson and coworkers synthesized 6,11-dihydroxycrinene 487 under similar conditions.¹⁸⁸ Dolby and Sakai studied the reduction of a bridged lactam bearing a relatively flexible [6.2.2] ring system (Scheme 146).^311,312 In this case, standard treatment with LiAlH₄ achieved exhaustive reduction to the corresponding amine. This suggests that the properties of the amide bond in the [6.2.2] ring system embodied in 488 are similar to those of planar amides. Finally, Harley-Mason determined that a bridged lactam containing a [5.2.2] ring system gives a stable hemiaminal on treatment with triethyloxonium tetrafluoroborate, followed by reduction with sodium borohydride (Scheme 147).¹⁵⁵ Attempts to prepare the corresponding amine were unsuccessful, leading only to the reduction of the ester group in the starting material. The bridged hemiaminal 490 was subsequently used as a key intermediate in the synthesis of indole alkaloid condylocarpine (see Scheme 178).¹⁵⁵

Scheme 145.

Reduction of Bridged Lactams Derived from Amaryllidaceae Alkaloids by: a) Wildman; b) Hendrickson

Scheme 146.

Reduction of Indole-1-azabicyclo[6.2.2]dodecan-10-one by Dolby

Scheme 147.

Synthesis of Bridged Hemiaminal from Bridged Lactam by Harley-Mason

Scheme 178.

Synthesis of Indole Alkaloids by Harley-Mason: a) Tubifoline and Condyfoline; b) Geissoschizoline; c) Fluorocurarine; d) Condylocarpine (please use double-column format for Scheme 178)

7.3.4. Reactions with Organometallic and Related Reagents

Besides hydride, addition of more sterically-demanding organometallic reagents to bridged lactams has been reported to yield stable hemiaminals.⁴⁵⁰

By subjecting bicyclic and tricyclic bridged lactams containing a [4.3.1] ring system to organometallic reagents of increasing steric demand, Aubé has shown that the resulting adducts can range from products having stable tetrahedral carbon to the collapsed amino ketone isomers (Tables 16–17).⁴⁰⁸ Bicyclic lactams afforded the corresponding amino ketones (Table 16), but in contrast the parent tricyclic lactams were found to be more effective in stabilizing the hemiaminal products (Table 17). The observed difference in reactivity was explained on the basis of the scaffolding effect provided by the additional six-membered ring in the latter system. In some cases, intermediary products featuring intramolecular N^…C=O interactions involving n_N→π^*_C=O transitions in nine-membered amino ketones were observed.⁴⁰⁸

Table 16.

Addition of Organometallic Reagents to Medium-Bridged Bicyclic Lactams by Aubé

entry	RLi/RMgX	R	491	yield (%)
1	MeLi	Me	491a	89
2	MeMgI	Me	491a	73
3	n-BuLi	n-Bu	491b	83
4	sec-BuLi	sec-Bu	491c	93
5	tert-BuLi	tert-Bu	491d	80

Table 17.

Addition of Organometallic Reagent to Medium-Bridged Tricyclic Lactams by Aubé

entry	177	RLi	R	487/488	yield (%)
1	177d	MeLi	Me	487a	95
2	177d	sec-BuLi	sec-Bu	487b	80
3	177d	tert-BuLi	tert-Bu	488a	90
4	177e	MeLi	Me	487c	92
5	177e	sec-BuLi	sec-Bu	487d	88
6	177e	tert-BuLi	tert-Bu	488b	90

The same group established that bridged lactams can function as effective substrates for the synthesis of bridged α-aminoepoxides using dimethylsulfonium methylide under Corey-Chaykovsky epoxidation conditions (Scheme 148).⁴⁵⁶ The success of this reaction relied on both the increased electrophilicity of distorted amide bonds and the stability of these bridged aminoepoxides to the reaction and isolation conditions due to the limited n_N→σ^*_C-O delocalization.

Scheme 148.

Corey-Chaykovsky Epoxidation of Bridged Lactams by Aubé

Olefination of bridged lactams provides facile access to bridged enamines featuring decreased overlap between the lone pair of electrons of nitrogen and the olefin π systems (see Section 6.3).^397–398 Kirby demonstrated that 1-aza-2-adamantanone undergoes the Wittig reaction to give a bridged enamine under standard conditions employed for olefination of ketones (Scheme 149a),¹⁰⁸ Aubé utilized a Petasis olefination to afford exo-cyclic enamine with a [4.3.1] ring system (Scheme 149b),⁴⁰⁸ while Wärnmark functionalized Tröger’s base-derived bridged lactams using the less reactive carbethoxymethylene-triphenylphosphorane under thermal conditions (Scheme 149c).³¹⁶

Scheme 149.

a) Wittig Olefination of 1-Aza-2-adamantanone by Kirby; b) Petasis Olefination of Medium Bridged Twisted Lactams by Aubé; c) Wittig Olefination of Tröger’s Base-Derived Twisted Lactams by Wärnmark

During synthetic studies on Aspidosperma alkaloids, Ban demonstrated that under certain conditions cyanide adds to bridged lactam containing a [6.3.1] ring system (Scheme 150).⁴⁵⁷ Structure of 499 was confirmed by X-ray crystallography. The proposed mechanism for this rearrangement involves cleavage of the bridged amide bond to give the reactive amino acyl cyanide, which undergoes further transformations (Scheme 151).

Scheme 150.

Cyanide-Induced Rearrangement of Indole-1-azabicyclo[6.3.1]dodecan-12-one by Ban

Scheme 151.

Proposed Mechanism for Cyanide-Induced Rearrangement of Lactam 498

7.3.5. Other Reactions Involving Carbonyl Group

Ban has studied¹⁶⁴ the alkylation of bridged lactams with a [6.3.1] ring system at the bridgehead position⁴⁵⁸ (Table 18). In this system, the bridgehead enolate was readily formed in the presence of LDA at −78 °C, but only a few electrophiles could be used to install C-electrophiles.¹⁶⁴ For example, when the bridgehead enolate was treated with methyl bromoacetate, the corresponding α-bromo lactam was formed as the major product.

Table 18.

Alkylation of Indole-1-azabicyclo[6.3.1]dodecan-12-one at Bridgehead Position by Ban

entry	RX	R	502	yield (%)
1	EtI	Et	502a	84
2	allylBr	allyl	502b	71
3	ICH2CO2Me	I	502c	42
4	BrCH2CO2Me	Br	502d	34
5	ClCH2CO2Me	COCH2Cl	502e	66
6	(CO2Me)2	COCO2Me	502f	90

Schill reported a Friedel-Crafts-type α-arylation of bridged lactam featuring [5.4.1] ring system (Scheme 152).³³⁷Although these authors also accomplished a related α-arylation of [4.4.1] ring system,³³⁹ the reaction of a bridged lactam with [4.3.1] scaffold was unsuccessful due to its instability to the reaction conditions.³³⁶

Scheme 152.

α-Arylation of Indole-1-azabicyclo[5.4.1]dodecan-12-one by Schill

Finally, Judd demonstrated that a complex bridged lactam containing an α,β-unsaturated amide bond on the external bridge in a [4.3.1] ring system could be further functionalized by rhodium-catalyzed conjugate addition of boronic acid with complete diastereoselectivity (Scheme 153).²⁹⁶

Scheme 153.

Rh-Catalyzed Conjugate Addition of Boronic Acid to 1-Azabicyclo[4.3.1]dec-7-en-9-one by Judd

7.4. Miscellaneous Reactions of Bridged Lactams

Shea reported oxidation and hydrolysis reactions of a bridged lactam containing an additional bridgehead olefin in a [3.3.1] ring system (Scheme 154).²⁹⁸ The authors proposed a complex mechanism involving two molecules of the bridged lactam. The moderate yield of the hydrolysis was proposed to be a result of decomposition of the bridged lactam under the reaction conditions.

Paquette investigated photocyclization reactions of bridged lactams containing diene motifs (Schemes 155–156).²⁹⁵ The required substrates were prepared from the monounsaturated bridged lactams via a bromination/elimination sequence (Scheme 155).²⁹⁵ The best results in the elimination step were achieved using TBAF in DMSO as a solvent at high temperature.⁴⁵⁹ Upon irradiation with 300 nm light, bridged lactam 508, containing a [4.3.1] ring system, underwent disrotatory ring closure to cyclobutene, while bridged lactam 509 with a [4.3.2] scaffold was unreactive under the same conditions (Scheme 156).²⁹⁵ On the basis of computational studies, the authors proposed that a non-planar arrangement of the diene moiety in lactam 509 contributed to this divergence in reactivity. It is worth noting that under similar irradiation conditions bridged sultams react with a preferential cleavage of the N–SO₂ bond (see Section 7.7.2).^295,431

Scheme 155.

Synthesis of Bridged Lactams with Endocyclic Diene Motifs by Paquette

Scheme 156.

Photochemical Reactions of Bridged Lactams Bearing Endocyclic Dienes by Paquette

The X-ray structures of oxidation products derived from two other bridged lactams have been reported (Figure 15). Lactam 511a was prepared by epoxidation of the corresponding olefin by Paquette (511a: τ = 9.6°; χ_N = 28.3°; χ_C = 3.3°; N–C(O) = 1.363 Å; C=O = 1.231 Å).⁴⁶⁰ The observed diastereoselectivity is similar to that observed in the epoxidation of related bridged sultams (see Scheme 166).⁴³⁴ Aubé reported the X-ray structure of lactam 511b prepared by Sharpless dihydroxylation/acylation of the corresponding olefin.²⁰⁸ As indicated by its Winkler-Dunitz parameters (τ = 72.4°; χ_N = 49.8°; χ_C = 7.1°; N–C(O) = 1.418 Å; C=O = 1.212 Å), this lactam contains one of the most distorted amide bonds isolated to date.

Scheme 157.

Reactivity of Bridged Oxazinolactamsby Shea: a) Reduction; b) Alkylation

7.4. Reactivity of Heteroatom-Containing Derivatives of Bridged Lactams

In contrast to bridged lactams, the reactivity of their heteroatom-containing derivatives has been sparsely studied. Relevant studies on these heterocycles are limited to transformations of bridged oxazinolactams and 1,2-diazines developed by Shea.^383–385

Bridged oxazinolactams, prepared in the intramolecular N-acylnitroso Diels-Alder reaction (see Section 6.2.1),^382–384 have been shown to undergo hydrogenation of the bridgehead olefin over Pd/C, while Na(Hg) chemoselectively cleaved the N–O bond (Scheme 157a).^383,384 Shea has also achieved highly diastereoselective alkylation of bridged oxazinolactams using reactive electrophiles (Scheme 157b).³⁸⁴ The alkylation occurs from the more accessible exo face, providing complementary stereochemical outcome to the isomers obtained directly from the N-acylnitroso Diels-Alder reaction (Scheme 82).³⁸⁴ This methodology has been applied to the stereocontrolled synthesis of seven- and eight-membered lactams (Scheme 158),³⁸⁴ and later expanded to include bridged 1,2-diazines (Scheme 159).³⁸⁵

Scheme 158.

Stereoselective Synthesis of Medium Ring Lactams from Oxazinolactams by Shea

Scheme 159.

Reactivity of Bridged 1,2-Diazines by Shea

In 2007, Shea and coworkers reported the use of bridged oxazinolactams in their approach towards synthesis of stenine (Scheme 160).⁴⁶¹ The intramolecular N-acylnitroso Diels-Alder reaction of diene 520 gave the bridged tricyclic lactam 521 in good yield and diastereoselectivity. Reduction with Na(Hg) afforded the azepane 522, which was elaborated to the key intermediate 523 in four steps.

Scheme 160.

Application of Bridged Oxazinolactams in Synthetic Studies towards Stenine by Shea (please use double-column format for Scheme 160)

7.5. Reactivity of Bridged Enamines

Although planar enamines are nucleophilic at carbon, bridged enamines are expected to exhibit properties of isolated amino-olefins as a result of the limited n_N→π^*_C=C overlap.^397,398 (Doering memorably commented “Of the conventional chemistry of enamines not a vestige remains.”³⁹⁸) However, reports on the reactivity of bridged enamines are relatively rare compared to bridged lactams.

Kirby showed that the bridged enamine derived from 1-aza-2-adamantane is alkylated at nitrogen using MeI in high yield (Scheme 161a).¹⁰⁸ This finding is in good agreement with the reactivity of another bridged enamine containing nitrogen at the apex position in a [3.3.1] ring system reported by Kresge (Scheme 161b).⁴⁶² The ammonium salt 525 was characterized by the X-ray crystallography (θ = 326.4°; N–CH₃ = 1.503 Å; N–C(=CH₂) = 1.474 Å; C=CH₂ = 1.301 Å).¹⁰⁸

Scheme 161.

a) N-Methylation of 3,5,7-Trimethyl-2-methylene-1-azaadamantane by Kirby; b) N-Protonation of 9-Methyl-9-Azabicyclo[3.3.1]non-1-ene by Kresge

Ellman examined the reactivity of endocyclic bridged enamines containing a bridgehead double bond (Scheme 162).⁴⁰⁰ The alkylation with Me₂SO₄ also proceeded at the nitrogen atom, while the reduction with NaBH₄ afforded 529 as the only isolated product. Mechanistic investigation suggested that this reduction proceeds via the corresponding iminium ion. Finally, hydrogenation over Pd/C afforded the fully saturated bicyclic amine as a single diastereoisomer. The X-ray structure of ammonium salt 528 has been reported (θ = 333.6°; N–CH₃ = 1.511 Å; N–CH(=C) = 1.490 Å; CH=C = 1.330 Å).⁴⁰⁰

Scheme 162.

Reactivity of Endocyclic [4.3.1] Bridged Enamines by Ellman

Pearson studied the reactivity of bridged enamines prepared by the intramolecular Schmidt reaction (Scheme 163).⁴⁰¹ It was found that hydrogenation and bromination reactions of these enamines proceed in high yields to give bicyclic amines bearing a close resemblance to core common to several Cinchona alkaloids.

Scheme 163.

Reactivity of Bridged Enamines Prepared by Schmidt Reaction by Pearson: a) [3.2.2] Scaffold; b) [2.2.2] Scaffold

7.6. Reactivity of Bridged Sultams

While bridged sultams contain non-planar sulfonamide bonds, these compounds do not show any signs of hyperreactivity.⁴³⁷ It means that their properties can be examined under the conditions which would result in rapid decomposition of the analogous bridged lactams.

7.6.1. General Reactivity

The first reactions of bridged sultams were described in 2001 by Paquette. It was shown that a sultam containing [4.2.1] ring system undergoes smooth deprotonation with tert-butyllithium to give, after quenching with allyl or benzyl bromide, the substitution products in good yields (Scheme 164).⁴³⁸ The same ring system was found to be stable to highly oxidizing conditions with chromyl acetate, providing the α-amino acetate and the bridged keto-sultam in good selectivity (Scheme 164).^438,431 Paquette also reported the synthesis of bridged sultams containing diene motifs via bromination/olefination of the corresponding olefins under relatively harsh conditions (Scheme 165).^{295,440,431,459} The diene products were later used in the photocyclization studies.^295,440,431

Scheme 164.

Alkylation and Oxidation of Bridged Sultams by Paquette

Scheme 165.

Bromination/Elimination of Bridged Sultams by Paquette

More recently, Evans studied reactions of unsaturated benzofused bridged sultams with bromine and m-CPBA (Scheme 166).⁴³⁴ In all cases, complete diastereoselectivity was observed, which was ascribed to the steric effect of the aryl group. Interestingly, the bridged sultam bearing an electron-rich aromatic ring participated in a cationic rearrangement upon treatment with bromine in CHCl₃.⁴³⁴ Proposed mechanism for this transformation is outlined in Scheme 167.

Scheme 166.

Bromination and Epoxidation of Benzo-Bridged Sultams by Evans

Scheme 167.

Proposed Mechanism for Synthesis of 544

The groups of Paquette⁴⁶³ and Evans⁴³⁴ further extended the ability to functionalize bridged sultams by developing a set of cross-coupling reactions (Table 19). Halogen-lithium exchange followed by quenching with diverse electrophiles or palladium-catalyzed cross-coupling with aryl boronic acids proceeded efficiently, delivering a variety of functionalized bridged sultams.⁴⁶³ Evans also demonstrated that hydrogenation of unsaturated bridged sultams bearing [3.2.1] ring system proceeds with high diastereoselectivity (Scheme 168).⁴³⁴ In contrast to hydrogenolysis of bridged lactams (see Section 7.2.2),²⁰⁸ the cleavage of N–SO₂ bond was not observed.

Table 19.

Cross-coupling Reactions of Bridged Sultams by Paquette and Evans

entry	conditions	R	548	yield (%)
1	MeLi/Me2SO4	-CH3	548a	70
2	MeLi/BrCH2Ph	-CH2Ph	548b	58
3	tBuLi/ClCOtBu	-C(O)tBu	548c	44
4	tBuLi/ClCOOBn	-C(O)OBn	548d	33
5	MeLi/TMSCl	-SiMe3	548e	40
6	tBuLi/Bu3SnCl	-SnBu3	548f	57
7	tBuLi/PhSeCl	-SePh	548g	55
8	Pd(PPh3)4, CuI, HC≡CC4H9	-C≡CC4H9	548h	10
9	PPh3, Pd(OAc)2 Cs2CO3, ArB(OH)2	C6H5	548i	63
10	as above	2-MeO-C6H4	548j	76
11	as above	4-MeO-C6H4	548k	84
12	as above	2-Naphthyl	548l	84

Scheme 168.

Hydrogenation of Bridged Sultams by Evans

A single example of an unusual desulfonylative indolization of a bridged sultam was reported by Paquette.⁴⁶⁴

7.6.2. Photochemical Reactions

Photochemical reactions of bridged sultams have been used to probe the effect of non-planar geometry of sulfonamide bonds on their reactivity.^431,295

In 2004, Paquette reported the rearrangement of a bridged sultam with a [4.2.1] bis-unsaturated scaffold to a complex heterocycle containing cyclobutene, thietane dioxide and pyrrolidine rings (Scheme 169).⁴³¹ The proposed mechanism involves (1) homolytic cleavage of the N–SO₂ bond, (2) rebonding to give the bicyclic isomer, (3) thermally-induced [1,5]-hydrogen shift, and (4) photo-induced disrotatory closure to the cyclobutene ring. This reaction constituted the first example of a σ N–SO₂ bond cleavage in a bridged sulfonamide.

Scheme 169.

Photoinduced Cleavage of SO₂–N Bond of Bridged Sultams by Paquette

In line with the previous report, Paquette observed the photochemical rearrangement of a related benzofused-bridged sultam to a dihydroazepine heterocycle via N–SO₂ bond cleavage and [1,5]-sulfonyl migration (Scheme 170a).²⁹⁵ In this case, minor quantities of the alternative cyclobutene product were formed via a photo-induced disrotatory closure. Later, Paquette attempted photochemical reactions of a bridged sultam featuring the sulfur atom at the apex position (Scheme 170b).⁴⁴⁰ However, under a variety of conditions, polymerization was found to be the predominant reaction pathway. In one case only, a cyclobutene product was isolated in low yield.⁴⁴⁰

Scheme 170.

Photoisomerization and Cycloaddition of Bridged Sultams by Paquette: a) Benzo[4.3.1] Ring System; b) [4.2.1] Ring System

Paquette also reported photoinduced di-π-methane rearrangement of benzofused bridged sultams bearing a [3.2.1] ring system (Table 20).⁴⁶³ Upon irradiation with 300 nm light, a series of functionalized substrates gave formal contraction products 554. Despite a potential to give two regioisomeric outcomes, in all examples the rebonding step occurred distal to the sulfonamide bond.

Table 20.

Di-π-methane Rearrangement of Bridged Sultams by Paquette

entry	382/548	R	554	yield (%)
1	382a	H	554a	48
2	548a	CH3	554b	40
3	548b	CH2Ph	554c	50
4	548c	C(O)tBu	554d	40
5	548d	C(O)OBn	554e	55
6	548e	SiMe3	554f	64
7	548f	SnBu3	554g	49
8	548g	SePh	554h	23
9	548h	C≡CC4H9	554i	50

7.6.3. Double Reduction

Bridged sultams have been shown to simultaneously undergo the reduction of both N–SO₂ and SO₂–C bonds to give planar nitrogen-containing heterocycles.^432–435

Evans applied the double reduction of aromatic bridged sultams to the synthesis of pyrrolidines bearing various functional groups (Scheme 171).^432–434 The reaction can be conducted by treatment of the bridged sultams with lithium or sodium metal in ammonia.⁴³² The use of lithium/ethylenediamine (Benkeser reduction) afforded partially dearomatized products, while sodium naphthalenide led to extensive decomposition.⁴³²

Scheme 171.

Synthesis of Pyrrolidines via Double Reduction of Bridged Sultams by Evans

Evans utilized the double reduction methodology to establish all-carbon quaternary stereocenter in the total synthesis of mesembrane (Scheme 172).⁴³⁴ The required bridged sultam was prepared in high yield via Heck reaction; however, the double reduction was achieved in modest yield due to the competing removal of one of the methoxy groups. The reaction was sensitive to the conditions used; for example sodium and lithium naphthalenide afforded the final product with higher selectivity, however in lower yields.

Scheme 172.

Total Synthesis of Mesembrane via Double Reduction of Bridged Sultams by Evans

8. APPLICATION OF BRIDGED LACTAMS IN TOTAL SYNTHESIS

Bridged lactams have been used on several occasions in total synthesis of natural products.^141–192 The ability to provide a rigid molecular framework and to attenuate the basicity of a nitrogen atom are among strategic advantages of applying bridged lactams in target-oriented synthesis. Moreover, in recent years a number of natural products containing bridged amide bonds have been isolated,^193–207 suggesting that bridged lactams may be more prevalent in nature than had been previously considered. In the final section of this review, we will cover representative examples of bridged lactams used in total synthesis, with discussion focused on the role of bridged amide bonds.

8.1. Lycopodium Alkaloids

In 2008, Dake reported the total synthesis of Lycopodium alkaloid, (+)-fawcettidine (Scheme 173).¹⁴¹ The congested tetracyclic framework of this alkaloid was introduced by conjugate addition of the thiolate anion to give a complex bridged lactam 564 in 76% yield. Sequential functional group manipulations transformed 564 into the sulfone 565, which was subjected to the Ramberg-Bäcklung ring contraction to afford another bridged lactam containing a [4.3.1] ring system. This intermediate was rapidly converted into (+)-fawcettidine in three steps, including an LAH reduction that suggests that this particular lactam, while in a bridged framework, is not unusually twisted.

Scheme 173.

Total Synthesis of Fawcettidine by Dake (please use double-column format for Scheme 173)

8.2. Communesins

Communesins are indole alkaloids containing a 1-azabicyclo[3.2.2]nonane moiety.¹⁴² In 2010, Ma reported the first total synthesis of the potently cytotoxic (−)-communesin F using bridged lactam 569 to construct the 1-azabicyclo[3.2.2]nonane core of this molecule (Scheme 174a).¹⁴³ Treatment of the allylic alcohol 568 with MsCl and Et₃N provided the required lactam 569 in 63% yield. After mesylate displacement with sodium azide, the intermediate 570 was subjected to an unprecedented Staudinger reaction with the bridged amide, using PPh₃ at 80 °C, to give the amidine 571 in 83% yield. Subsequent reduction and acetylation afforded the natural product. In this case, the inherent strain of the amide bond in the bridged lactam 570 enabled the rapid synthesis of (−)-communesin F.

Scheme 174.

a) Total Synthesis of Communesin F by Ma; a) Total Synthesis of Communesins A and B by Ma (please use double-column format for Scheme 174)

In 2011, Ma reported another elegant use of bridged lactams during the total synthesis of (−)-communesins A and B (Scheme 174b).¹⁴⁴ Oxidative cross-coupling of the dianion derived from 573 afforded the bridged lactam 574 as a single diastereoisomer in a respectable 73% yield. The obtained stereochemical outcome was proposed to arise from a favorable π-stacking interaction between nitrophenyl and indole rings. The lactam 574 was advanced to the cyanide 575, which was subjected to the sequential reduction/reductive amination to afford the aminal 576 in 92% yield. This reaction most likely proceeds via the intermediate amino aldehyde, however the mechanism involving a bridged iminium ion cannot not be excluded. The aminal 576 required only four more steps to complete the synthesis of (−)-communesins A and B.

Biogenetically, communesins have been proposed to originate from two oxidized molecules of tryptamine.¹⁴² In 2003, Stoltz put forward a biomimetic hypothesis for the origin of communesins A and B, in which the key step was a Diels-Alder reaction between the quinine methide imine 579 and aurantioclavine derivative 578 to give the highly twisted bridged lactam 580 (Scheme 175a).^145,146 It was postulated that the amide bond in 580 would then undergo transamination by the tethered primary amine to afford 581, another key intermediate in the biosynthesis.

Scheme 175.

a) Biomimetic Proposal for Synthesis of Communesins A and B by Stoltz; b) Biomimetic Proposal for Synthesis of Communesin B by Funk; c) Total Synthesis of Perophoramidine by Funk (please use double-column format for Scheme 175)

In 2004, Funk proposed a similar biomimetic pathway for the synthesis of communesin B (Scheme 175b).¹⁴⁷ Funk validated this biomimetic proposal during the total synthesis of a related natural product perophoramidine (Scheme 175c).¹⁴⁷ The coupling of indole 586 and 3-bromo-3-alkylindolin-2-one 587 afforded the intermediate 589 in 89% yield and ≥20:1 diastereoselectivity. The mechanism for this transformation may involve hetero Diels-Alder reaction to give bridged lactam 588, as proposed in the biomimetic hypothesis, or a conjugate addition pathway. The subsequent transamidation of 589 provided the pentacycle 590, which required only 9 steps to furnish the natural product. Recently, the Funk group synthesized communesin F utilizing a similar indol-2-one cycloaddition to rapidly generate the tetracyclic core of this natural product.¹⁴⁸ These studies also featured a bridged lactam (analogous to 569, Scheme 174a) and prepared via trimethylaluminum-mediated condensation of the corresponding amino ester.

8.3. Cripowellins

The aglycon of cripowellins contains an intriguing 1-azabicyclo[5.3.2]dodecan-2-one ring system, in which the amide bond is placed on the larger external bridge. In 2005, Moon and coworkers reported a rapid synthesis of the skeleton of cripowellins by employing ring expansion reaction under reductive conditions (Scheme 176a).¹⁴⁹ The precursor 594 was efficiently prepared via oxidative cyclization of the acylic amine 592. The key step proceeded in 51% yield using sodium naphthalenide to afford the bridged keto amide 595 in the following sequence of events: (i) nitrogen deprotection, (ii) nucleophilic addition to the tetrahedral intermediate 595, and (iii) C–C bond fragmentation.

Scheme 176.

a) Approach to Cripowellin Aglycon by Moon; b) Synthesis of 1-epi-Aglycon of Cripowellins A nd B by Enders (please use double-column format for Scheme 176)

In the same year, Enders reported asymmetric synthesis of the 1-epi aglycon of cripowellins (Scheme 176b).^150,151 In this approach, the bridged ring system was constructed via the intramolecular Heck reaction of the 9-membered precursor 601, which in turn was easily prepared by the ring-closing metathesis of the appropriately rigidified diene. The asymmetry was introduced by a rare Sharpless asymmetric dihydroxylation of a skipped diene (Scheme 176b, box). The conditions used for the Heck reactions had a significant effect on the outcome of the pivotal cyclization; the neutral conditions employing PPh₃ and Et₃N in DMF led to the disibstituted Z-olefin 602, while under cationic conditions (dppp, Ag₂CO₃, toluene) the anti-Bredt olefin 603 was formed as a mixture of E and Z isomers. From intermediate 603, the completion of the synthesis required only four additional steps.

8.4. Quinine Derivatives

The 1946 oxidative degradation of quininone (via 5-vinylquinuclidin-2-one) by Doering and Chanley marks the first synthesis and the first reaction of any bridged lactam (see Scheme 2).²⁵¹ Subsequently, this process has been applied to the synthesis of piperidines¹⁵² and isoquinolinones¹⁵³ from Cinchona alkaloids.

Recently, Doris and coworkers reported the total synthesis of (+)-mequitazine using oxidative degradation of quinine via an unisolated bridged lactam, 5-vinylquinuclidin-2-one, as the key step (Scheme 177).¹⁵⁴ Oxidation of quinine under Swern conditions provided the required quininone. This intermediate was reacted with potassium tert-butoxide in the presence of oxygen to deliver, after alcoholysis of the transient bridged amide bond, the vinyl piperidine in 60% yield. Transannular closure and coupling with phenothiazine completed the synthesis of (+)-mequitazine.

Scheme 177.

Synthesis of Mequitazine by Doris (please use double-column format for Scheme 177)

8.5. Aspidosperma and Strychnos Alkaloids

In classic studies on Strychnos-type alkaloids, Harley-Mason investigated the use of bridged lactams (Scheme 178).¹⁵⁵ In particular, his group developed efficient synthesis of bridged lactam 611 containing a [5.2.2] ring system,¹⁵⁵ which then served as a key intermediate in the synthesis of tubifoline,¹⁵⁶ condyfoline¹⁵⁶ and geissoschizoline¹⁵⁷ (Schemes 178a and b). A similar strategy relying on bridged lactams bearing the same bicyclic scaffold¹⁵⁸ was utilized in the rapid syntheses of several other alkaloids, including fluorocurarine¹⁵⁹ (Scheme 178c), condylocarpine¹⁵⁵ (Scheme 178d), tubotaiwine,¹⁶⁰ dihydronorfluorocurarine,¹⁶¹ and tubifolidine.¹⁵⁶ Interestingly, as early as in 1975, Harley-Mason explicitly proposed that lactams in which the amide bond is non-planar might be useful in the synthesis of complex alkaloids.¹⁵⁵

In 1981, Ban and coworkers reported the total synthesis of quebrachamine using the bridged lactam 621 containing a [6.3.1] ring system (Scheme 179).¹⁶² The requisite lactam was prepared via an intramolecular N-alkylation of 620 using NaH in the presence of KI/18-crown-6, followed by alkylation at the bridgehead position in very good overall yield (see also Table 18). Reduction of 621 followed divergent pathways depending on the conditions used for this step: with LiAlH₄ in refluxing dioxane, quebrachamine was formed, whereas in THF, 1,2-dehydroaspidospermidine was obtained via the bridged hemiaminal 623. Using similar strategy, Ban prepared other aspidosperma alkaloids,^162–164 including 1-acetylaspidoalbidine,¹⁶⁴ deoxyaspidodispermine¹⁶⁴ and 1-acetylaspidospermidine.¹⁶³ Recently, Movassaghi¹⁶⁵ reported the use of structurally-related bridged lactams featuring a [6.3.1] ring system¹⁶⁶ in the synthesis of complex dimeric aspidosperma alkaloids.

Scheme 179.

Synthesis of Quebrachamine and 1,2-Dehydroaspidospermidine by Ban (please use double-column format for Scheme 179)

The groups of Ziegler^167,168 and Bosch¹⁶⁹ utilized bridged lactam 626 bearing the amide bond on the larger external bridge in a [6.3.1] scaffold in an alternative approach to quebrachamine (Scheme 180a). The lactam 626 was prepared from the carboxylic acid 625 by treatment with PPA at 90 °C. This reaction is thought to proceed via the highly reactive acylated intermediate 627.¹⁶⁸ Subsequent reduction of the bridged lactam with LiAlH₄ provided the final alkaloid. Similar synthetic approaches have been reported in the total synthesis of dihydrocleavamine,^170–172 tabersonine¹⁷³ and cleavamine¹⁷⁴ by the research groups of Bosch,^170,171 Lesma,¹⁷² Ziegler,¹⁷³ and Hanaoka¹⁷⁴ (Scheme 180b–d). In general, only modest yields have been obtained in the reduction of these bridged lactams.

Scheme 180.

Synthesis of Indole Alkaloids via Friedel-Crafts Acylation of Bridged Amides: a) Quebrachamine by Ziegler and Bosch; b) Dihydrocleavamine by Bosch and Lesma; c) Tabersonine by Ziegler; d) Cleavamine by Hanaoka (please use double-column format for Scheme 180)

Another elegant example of the use of bridged lactams was reported by Bosch in the total synthesis of (−)-tubifoline (Scheme 181a).^175,176 Witkop photocyclization of chloroacetamide 637 gave the late stage intermediate 638 containing bridged amide bond in a [5.2.2] ring system as an inconsequential mixture of the double bond isomers. Tandem lactam/olefin reduction and oxidative cyclization using PtO₂/O₂ transformed the lactam 638 into the natural product. Similar Witkop photocyclizations to give bridged lactams in the synthesis of Strychnos alkaloids have been reported independently by Snieckus¹⁷⁷ and Ishikura.¹⁷⁸

Scheme 181.

a) Application of Bridged Amide in Total Synthesis of Tubifoline by Bosch; b) Application in Bridged Amide in Total Synthesis of Strychnine by Magnus

Magnus utilized the bridged lactam 641 featuring the amide bond on the shorter external bridge in a [5.2.2] ring system as an early stage intermediate in the total synthesis of strychnine (Scheme 181b).¹⁷⁹ Conjugate addition of the enolate 640 afforded the bridged lactam 641 in 65–98% yield, forming the F ring of strychnine. It was found that the yield of the conjugate addition was significantly improved when the sulfoxide precursor was used. The next step involved oxidation to the α-keto amide via Pummerer rearrangement.

Büchi^180,181 and Narisada¹⁸² independently reported the total synthesis of velbamine, a degradation product of oncolytic vinblastine and vincristine alkaloids, using bridged lactams as key intermediates (Scheme 182). The approach by Büchi relied on retroaldol cleavage of the β-hydroxyketone 644 to reveal the bridged lactam 645 embedded in a [6.3.1] ring system (Scheme 182a).^180,181 This intermediate was converted into velbamine in five more steps. In contrast, Narisada showed that the analogous bridged lactam 650 could be obtained via fragmentation of 649 under oxidative conditions using Pb(OAc)₄ in comparable yield (Scheme 182b).¹⁸² The methoxy group was eliminated under acidic conditions to give bridged enamide 651, which was converted into velbamine using standard functional group manipulations.

Scheme 182.

Total Synthesis of Velbanamine: a) Büchi; b) Narisada (please use double-column format for Scheme 182)

8.6. Amaryllidaceae Alkaloids

Wildman reported the synthesis of bridged lactams from several Amaryllidaceae alkaloids, such as haemanthidine, oxohaemanthidine and apohaemanthidine, using oxidation with MnO₂ (Scheme 183a).¹⁸³ When oxohaemanthidine was treated with NaOAc/HOAc, the conjugated lactone was formed via hydrolysis of the bridged amide bond and lactonization.^184,185 After methylation to 652, this product was used to correlate two common Amaryllidaceae alkaloids, heamanthidine and pretazettine (Scheme 183a).^184,185

Scheme 183.

Bridged Lactams in Total Synthesis of Amaryllidaceae Alkaloids: a) Oxohaemanthidine, Oxodihydrohaemanthidine, Oxoapohaemanthidine and Pretazzetine; b) Dihydrocrinine; c) 6,11-Dioxocrinene; d) Haemanthidine (please use double-column format for Scheme 183)

Irie and coworkers reported the use of a related bridged lactam 659 to install the tricyclic core of dihydrocrinine (Scheme 183b).^186,187 Transannular conjugate addition of the precursor 658 under ketalization conditions stereoselectively afforded the required lactam. Lower yields of lactam 659 were observed with NaH, NaOtBu and NaNH₂.¹⁸⁷ Interestingly, the minor product isolated in this reaction was the bridged ethylene orthoamide resulting from the reaction of the twisted amide bond with ethylene glycol (not shown; cf. Table 5 and Scheme 133).¹⁸⁷ Similarly, the formation of stable hemiaminals on treatment with LiAlH₄ (659→660) that required additional steps to effect full reduction to the amine indicates that bridged amide bonds in these systems possess a significant ketonic character.

Finally, Hendrickson reported the total synthesis of dioxocrinene 486 featuring the bridged amide bond (Scheme 183c)¹⁸⁸ and haemanthidine using the bridged lactam 664 as the key intermediate (Scheme 183d).¹⁸⁹ Both lactams were constructed from the corresponding esters 662–663 via a sequence involving hydrolysis, homologation with diazomethane, and treatment with dry HCl to effect the cyclization (Scheme 183c–d).^188,189 The ester precursors 662–663 were easily prepared via Curtuis rearrangement followed by Friedel–Crafts cyclization, highlighting the efficiency of this strategy. Hendrickson studied the quasi-amide bond properties of some of the prepared bridged lactams, finding these compounds to be sensitive towards hydrolysis/methanolysis and able to be reduced with the mild reducing agent NaBH₄.¹⁸⁸

8.7. Kopsia Alkaloids

In 2001, Magnus reported the total synthesis of kopsijasminilam, a complex Kopsia alkaloid containing a bridged amide in a pentacyclic ring system (Scheme 184a).^190,191 The transannular cyclization of eleven-membered precursor 665 set the stage for the key Diels-Alder reaction. The Diels-Alder adduct was obtained on treatment of the cyanide 666 with acryloyl chloride. Substituents other than cyanide at the hemiaminal carbon, including OH, OMe or SPh, resulted in decomposition during the Diels-Alder step. Polonovski fragmentation of the N-oxide 668 gave the spirocyclic bridged lactam 670 in 90% yield. The synthesis was completed by conjugate reduction/oxidation using catalytic Mn(dpm)₃/PhSiH₃ under oxygen atmosphere. Magnus utilized a similar concept based on the peroxyaminal fragmentation of the intermediate 672 in the total synthesis of pauciflorine B (Scheme 184b).^190,191

Scheme 184.

Total Synthesis of Kopsijasminilam by Magnus; b) Total Synthesis of and Pauciflorine B by Magnus; c) Total Synthesis of Kopsijasminilam by Kuehne (please use double-column format for Scheme 184)

At about the same time, Kuehne applied an alternative fragmentation strategy in the total synthesis of kopsijasminilam (Scheme 184c).¹⁹² The key precursor 676 was prepared from alkaloid minovincine. Treatment of 676 with NaCN in refluxing ethanol-water resulted in the nitrogen-assisted fragmentation to give the pentacyclic cyanide 677 in 89% yield. The bridged lactam 678 was obtained after oxidation with potassium tert-butoxide in the presence of oxygen. This intermediate was converted to kopsijasminilam in five more steps.

8.8. Natural Products Containing Bridged Amide Bonds

Several natural products containing bridged amide bonds have been isolated from Stemona,^193–196 Daphnum,^197–202 Kopsia,²⁰³ Strychnos,²⁰⁴ Iboga,²⁰⁵ Amaryllidaceae⁴⁶⁵ and Lycopodium species^206,207 (Schemes 185–189).

Scheme 185.

Stemona Alkaloids Containing Bridged Amide Bonds (please use double-column format for Scheme 185)

Representative bridged lactams in the the structural class of Stemona alkaloids are tuberostemoninols (680–682),¹⁹³ neotuberostemoninol (683),¹⁹⁴ sessilifoliamide I (684),¹⁹⁵ and maireistemoninol (685),¹⁹⁶ in which the amide bond is placed on a one-carbon bridge in a [4.3.1] ring system, and the biogenetically-related neotuberostemonone (686)¹⁹⁶ and epoxytuberostemonone (687)¹⁹⁶ containing [6.4.1] bridged systems (Scheme 185). The X-ray structures and spectroscopic properties of neotuberostemoninol (683)¹⁹⁴ and sessilifoliamide I (684)¹⁹⁵ indicate that amide bonds in these compounds aresignificantly distorted from planarity (683: τ = 49.6°; χ_N = 30.8°; χ_C = 12.7°; N–C(O) = 1.402 Å; C=O = 1.215 Å; ν_C=O 1682 cm⁻¹; ¹³C_C=O 184.7 ppm; 684: τ = 43.9°; χ_N = 35.3°; χ_C = 11.0°; N–C(O) = 1.390 Å; C=O = 1.232 Å; ν_C=O 1656 cm⁻¹; ¹³C_C=O 182.4 ppm).

Daphnum alkaloids containing bridged amide bonds include daphmanidins B–D (688–690),^197,198 daphnezomines F, G, and U (691–693),^199,200 daphhimalenine A (694),²⁰¹ and daphnicyclidine J (695),²⁰² which feature 1-azabicyclo[5.2.2]undecane, 1-azabicyclo[5.2.1]decane and 1-azabicyclo[6.2.2]dodecane ring systems (Scheme 186). Infrared stretching frequencies and ¹³C NMR shifts of daphhimalenine A (694)²⁰¹ confirm that the amide bond in this alkaloid is non-planar (ν_C=O 1687 cm⁻¹; ¹³C_C=O 183.8 ppm).

Scheme 186.

Daphnum Alkaloids Containing Bridged Amide Bonds (please use double-column format for Scheme 186)

Pericidine (696)²⁰³ and henningsamides (697–699)²⁰⁴ are Kopsia and Strychnos alkaloids, respectively, which contain the amide bond in a [5.2.2] ring system, while 3-oxocoronaridine (700)²⁰⁵ and 3-oxovoacangine (701)²⁰⁵ are oxygenated Iboga alkaloids with bridged amide bonds embedded in complex caged tricyclic structures (Scheme 187). Kopsijasminilam (671) and pauciflorine B (674) (Scheme 187) have been mentioned in the previous section in the context of their synthesis (see Section 8.7);^190–192 two other Kopsia alkaloids, deoxykopsijasminilam (702) and pauciflorine A (703)^190–192 share their unprecedented skeleton (Scheme 187). The Amaryllidaceae alkaloids containing bridged amide bonds, cripowellins A and B (598–599) (Scheme 188),⁴⁶⁵ have been already discussed in this review (see Section 8.3).^149–151

Scheme 187.

Indole Alkaloids Containing Bridged Amide Bonds (please use double-column format for Scheme 187)

Scheme 188.

Cripowellins Containing Bridged Amide Bonds (please use double-column format for Scheme 188)

Finally, several Lycopodium alkaloids, such as phlegmariurines A–C (704–706)²⁰⁶ and lycoposerramine E (707)²⁰⁶ feature bridged amide bonds placed in a [5.3.4] ring system. These compounds belong to the fawcettimine class of Lycopodium alkaloids²⁰⁷ and can be regarded as degradation products of fawcettidine (see Scheme 173).

9. CONCLUSIONS AND OUTLOOK

In the course of 75 years of inquiry, the chemistry of bridged lactams has provided numerous examples of fascinating molecules. Due to the restricted conformation, these lactams cannot benefit from the full resonance stabilization typical to planar amides. The initial interest in bridged lactams was fuelled by the imagination of organic chemists to test the stability of anti-Bredt amides. Over the years, it has been demonstrated that non-planar amides are highly susceptible to hydrolysis, and in general difficult to prepare or isolate. In the last decade, improved mechanistic understanding and the emergence of new synthetic methods have allowed the synthesis of bridged lactams containing perfectly orthogonal amide bonds. Remarkably, many of these perpendicularly twisted amides have been structurally characterized. Furthermore, new structural classes of bridged lactams have been invented and applied to probe the effect of amide bond distortion on its reactivity. The N-activation of amide bonds, detailed studies on amide bond hydrolysis, structural characterization of N-protonated lactams, and the synthesis of hydrolytically-robust bridged lactams have been described. A large number of bridged lactams have been characterized by X-ray crystallography, which in combination with IR, and ¹³C NMR spectroscopic data, makes it possible to estimate the relationship between twist angle and chemical reactivity of these compounds. The importance of bridged lactams is further underlined by their successful application to access complex building blocks in target-oriented synthesis and their tantalizing potential as lead structures in medicinal chemistry.

While progress has been considerable, many areas remain to be explored. Expanding the family of highly-strained bridged lactams, systematic examination of their follow-up chemistry, additional insight into the quantitative evaluation of amide bonds, and application of the new reactivity manifolds of non-planar lactams to simple amides are among the challenges that need to be addressed. Finally, as mechanical distortion plays a key role in the enzymatic activation of amide bonds, non-planar lactams will continue to give us a glimpse into the molecular level of enzymatic catalysis.

Scheme 99.

Generation of Bridged 1-Aza Iminium Ions by Hoffmann: a) Quinine Series; b) Quinidine Seires; c) Structures of Quinine and Quinidine

Scheme 189.

Lycopodium Alkaloids Containing Bridged Amide Bonds (please use double-column format for Scheme 189)