Application of Donor/Acceptor-Carbenoids to the Synthesis of Natural Products

Abstract

The metal catalyzed reactions of diazo compounds have been broadly used in organic synthesis. The resulting metal-carbenoid intermediates are capable of undergoing a range of unconventional reactions, and due to their high energy, they are ideal for initiating a cascade sequence leading to rapid the rapid generation of structural complexity. This tutorial review will be give an overview of the most versatile reactions of donor/acceptor carbenoids, an exciting class of intermediates capable of highly selective reactions. This will include cyclopropanation, [4 + 3] cycloaddition, and C–H functionalization methodologies. The application of this chemistry to the synthesis of a range of natural products will be described.

Metal carbenoid intermediates are capable of a range of unusual reactions that can lead to novel strategies for synthesis.^1–5 They are conveniently prepared by metal-catalyzed extrusion of nitrogen from diazo compounds. Their reactivity is highly dependent on the carbenoid structure, and consequently, they have been classified into three major groups, acceptor, acceptor/acceptor and donor/acceptor (Figure 1).^6,7 Typical acceptor groups are keto, nitro, cyano, phosphonyl and sulfonyl, while typical donor groups are vinyl, aryl and heteroaryl. The metal carbenoids generally display electrophilic character; thus, acceptor groups will tend to make the carbenoids more reactive and less selective, and the reverse would be the case for donor groups. Consequently, the applications of carbenoids lacking a donor group in total synthesis mostly involve intramolecular reactions. A beautiful example of the synthetic potential of this type of application is the intramolecular cyclization/cycloaddition cascade reactions reviewed by Padwa in this thematic issue.⁸ An emerging area in total synthesis is the use of donor/acceptor-carbenoids because they display much greater selectivity than the conventional carbenoids. The applications of this versatile class of carbenoids will be highlighted in this review.

Figure 1.

Classes of metal carbenoids

EAG = Electron Accepting Group (CO₂R, COR, CONR₂, CN, PO(OR)₂, SO₂R, NO₂, CF₃)

EDG = Electron Donating Group (vinyl, aryl, heteroaryl)

The chemistry of the donor/acceptor carbenoids has expanded greatly in recent years, and a number of impressive examples have emerged of the applications of these intermediates to the synthesis of complex targets. Representative targets are shown in Scheme 1.^9–15 In all of these syntheses the carbenoid transformation is involved in a crucial disconnection and installs key stereocenters in the natural product targets. This tutorial will describe the reactivity of donor/acceptor carbenoids, in the context of their application to total synthesis, and will illustrate the controlling elements behind the stereoselective transformations. The ground rules for this chemistry described herein will hopefully spur others to consider the use of carbenoid reactions as powerful disconnections for the synthesis of complex targets.

Scheme 1.

Representative natural products synthesized using donor/acceptor carbenoids

Metal-stabilized carbenoids are readily generated by metal-catalyzed decomposition of diazo compounds as illustrated in Scheme 2. Due to the enhanced stability of donor/acceptor carbenoids, they are capable of a variety of regio- and stereoselective reactions. When chiral catalysts are used, especially those derived from dirhodium tetracarboxylates, a variety of complex chiral building blocks can be rapidly assembled. The two most widely used reactions of donor/acceptor carbenoids in total synthesis have been cyclopropanation^4,6 and C—H functionalization.⁷ The cyclopropanes can be readily rearranged or ring-opened in a stereocontrolled manner, leading to the synthesis of a wide variety of potential targets.⁴ C—H Functionalization is orthogonal to the normal strategies of synthesis relying on functional group interconversions. and consequently, have led naturally to unconventional retrosynthetic disconnections.³

Scheme 2.

Cyclopropanation and C—H functionalization

Intermolecular Cyclopropanation of Alkenes

The intermolecular cyclopropanation chemistry of donor/acceptor carbenoids is routinely highly diastereoselective (>20: 1 dr). A representative example is the Rh₂(S-DOSP)₄-catalyzed reaction of styryldiazoacetate 1 with styrene, which generates the vinylcyclopropane 2 in 98% ee and >20 : 1 dr (Scheme 3).¹⁶ The vinylcyclopropane is a valuable chiral building block, which has been converted to the cyclopropane amino acids 3a and 3b,¹⁶ the cyclopropanedicarboxylate 4, which can then be stereoselectively ring-expanded under Lewis acid catalyzed conditions with aldehydes,¹⁷ or ring-opened by a cuprate reagent, ultimately leading to the synthesis of the antidepressant (+)-sertraline 5.¹⁸

Scheme 3.

Intermolecular cyclopropanation applied to synthesis.

Intramolecular Cyclopropanation of an Indole

An elegant application of an intramolecular cyclopropanation was recently described by Qin in the total synthesis of (±)-communesin F (9).¹⁵ The key step is the copper(I) triflate-catalyzed reaction of α-aryl-α-diazo ester 6, which led to the formation of the cyclopropane 7 in 88% yield as a 1.6 : 1 mixture of diastereomers (Scheme 4). The formation of a diastereomeric mixture was inconsequential because this mxture converged to a single diastereomer 8 upon reduction of the azide and amino opening of the cyclopropane. With the central pentacyclic core installed in 8, the synthesis of (±)-communesin F (9) was completed.

Scheme 4.

Total Synthesis of (±)-communesin F

Intermolecular [4 + 3] Cycloaddition with Pyrroles

The intermolecular cyclopropanation between vinylcarbenoids and dienes is a broadly useful transformation, because the resulting cis-divinylcyclopropanes undergo a Cope rearrangement to generate cycloheptadienes in a stereodefined manner.¹⁹ Thus the synthetic sequence is a formal [4 + 3] cycloaddition between the vinylcarbenoids and dienes. An early example of the utilization of this chemistry is the total synthesis of (±)-ferruginine (13) (Scheme 5).²⁰ The key step is the dirhodium tetraoctaonate-catalyzed [4 + 3] cycloaddition between the vinyldiazoketone 10 and the pyrrole 11 to generate the tropane system 12 in 73% yield, which is readily converted to (±)-ferruginine.

Scheme 5.

Synthesis of (±)-ferruginine

The [4 + 3] cycloaddition approach to tropanes has been extended to enantioselective systems. The first approach used α-hydroxy esters as chiral auxiliaries as illustrated in Scheme 6.²¹ When S-lactate was used as the chiral auxiliary (14), the tropane 15 was formed in 64% yield and 66% de. More recently, the chiral dirhodium catalyst, Rh₂(R-PTAD)₄ was shown to be very effective in the reaction of the siloxyvinyldiazoacetate 16 with N-Boc-pyrrole to generate the tropane 17 in 84% ee.²² Both 15 and 17 can be readily converted to intermediates that were used for the synthesis of ferruginine.

Scheme 6.

Asymmetric [4 + 3] cycloadditions with pyrroles

More elaborate systems can be used in the [4 + 3] cycloaddition with pyrroles as illustrated in the dirhodium tetraoctanoate-catalyzed reaction with the pyrrole 18 to generate the tropane 19 in 90% yield (Scheme 7).¹² This was a key step in Kende’s elegant total synthesis of (±)-isostemofoline, as the tropane 19 is well functionalized to complete the total synthesis. In principle, this strategy could also be applied to the enantioselective synthesis of isostemofoline because the Rh₂(R-PTAD)₄-catalyzed reaction of 16 with 18 generated the tropane 19 in 84% ee.²²

Scheme 7.

Total synthesis of (±)-isostemofoline

Intermolecular [4 + 3] Cycloaddition with Dienes

The [4 + 3] cycloaddition between vinylcarbenoids and dienes can be highly regioselective. An impressive example of this feature is the key transformation used in the total synthesis of (±)-tremulenolide and (±)-tremulenediol (Scheme 8).¹¹ The rhodium catalyzed reaction of vinyldiazoacetate 22 in the presence of (E, Z)-diene 21 generated the cycloheptadiene 24 as a single regioisomer and diastereomer in 49% yield. Donor/acceptor carbenoids are very sensitive to steric influences during cyclopropanation. In this case, selective cyclopropanation of the (Z) double bond occurs to generate the divinylcyclopropane 23. The Cope rearrangement of 23 proceeds through a boat transition state to generate 24 as a single diastereomer. The cis-olefin in cycloheptadiene 24 was selectivity hydrogenated by Wilkinson’s catalyst to form cycloheptene 25 in 90% yield. The acetyl group was hydrolyzed with aqueous potassium carbonate followed by in situ lactonization to complete the synthesis of (±)-tremulenolide A (26). Alternatively, DIBAL reduction of the two ester groups in cycloheptene 25 resulted in the synthesis of (±)-tremulenediol A (27).

Scheme 8.

Synthesis of (±)-tremulenolide and (±)-tremulenediol

The [4 + 3] cycloaddition strategy can be conducted with heteroaryldiazoacetates as illustrated in the formal synthesis of (+)-frondosin B (34) (Scheme 9).²³ Reaction of heteroaryldiazoacetate 28 with trans-piperylene 29 in the presence of Rh₂(R-DOSP)₄ followed by immediate hydrogenation of the product using Pd/C produced the reduced [4 + 3] cycloadduct 33 in 57% yield over the two steps, with excellent diastereoselectivity (>30: 1 dr), and enantioselectivity (97% ee). In this case the cis-divinylcyclopropane 30 undergoes a Cope rearrangement to form 31, which then undergoes a stereoselective tautomerization to regenerate the aromatic benzofuran ring in 32. Tricycle 33 was then further advanced to an intermediate used in the Danishefsky’s synthesis of (+)-frondosin B.²⁴

Scheme 9.

Formal synthesis of (+)-frondosin B

An enantioselective [4 + 3] cycloadditon was a crucial step for the synthesis of (+)-5-epi-vibsanin E (38) (Scheme 10).¹⁰ Reaction of vinyldiazoacetate 16 with triene 35 in the presence of 0.5 mol % of Rh₂(R-PTAD)₄ produced the cycloheptadiene 36 in 65% yield, resulting is the formation of a quaternary stereocenter with good enantiocontrol (90% ee). The cycloheptadiene 36 was then converted to the tricyclic core 37 of the vibsanin natural products, which could then be elaborated to (+)-5-epi-vibsanin E (38). This strategy has also been applied to the synthesis of (±)-vibsanin E.²⁵

Scheme 10.

Total synthesis of (+)-5-epi-vibsanin E

The use of chiral catalysis in the [4 + 3] cycloaddition can overcome the inherent directing nature of a chiral substrate. An intriguing example of this has been reported by Sarpong in a parallel kinetic resolution approach to the cyathane and cyanthiwigin diterpenes. (Scheme 11)²⁶ The Rh₂(R-DOSP)₄-catalyzed reaction of the (+)-enantiomer 39 preferentially forms the tricycle 41 while the reaction with the (−)-enantiomer 43 generated preferentially 44, a different diastereomer of the tricycle. 41 is a potential precursor to (−)-cyanthiwigin G (42) while 44 is a potential precursor to (+)-cyanthin A₃ (45)

Scheme 11.

Diasteoselective entry to the cyathane and cyanthiwigin diterpenes

Intramolecular C—H Insertion

Catalytic intramolecular C—H insertion reaction of metal-carbenoids is a powerful tool for the formation of five-membered rings and occasionally other ring sizes.^2,7 The reaction with acceptor-substituted carbenoids has been widely employed in numerous syntheses of natural products. ^2,7 The donor/acceptor variant, illustrated in generic form in the conversion of 46 to 47 (Scheme 12), has been integral to several recent total syntheses of natural products, which will be highlighted here.

Scheme 12.

Intramolecular C—H functionalization

C—H Insertion proceeds with retention of configuation at the C—H bonds. This phenomenon was exploited by Taber in his synthesis of (−)-hamigeran B (Scheme 13).²⁷ Reaction of α-aryl-α-diazoketone 48 in the presence of Rh₂(S-PTTL)₄ led to the C—H insertion product 49 in 83% yield, with full stereocontrol of the quaternary center. The reaction, however, produced a mixture of diastereomers alpha to the cabonyl. This stereocenter was readily equilibrated to the desired configuration during the subsequent steps in the synthesis of (−)-hamigeran B (50).

Scheme 13.

Synthesis of (−)-hamigeran B

Fukuyama and coworkers utilized an intramolecular C—H functionalization of an α-aryl-α-diazoacetate to generate benzofurans as a key step in the synthesis of (−)-ephedradine A (53) (Scheme 14).^9,13 The enantioselective catalysis of the basic transformation was established in model studies.^28,29 The optimized conditions used in the synthesis were a combination of a chiral catalyst and a chiral auxiliary. Reaction of diazoacetate 51, bearing a chiral auxiliary, with Rh₂(S-DOSP)₄ yielded the dihydrobenzofuran 52 with a diastereomer ratio of 13:1. The dihydrofuran 52 was then converted in a series of steps to (−)-ephedradine A. (53)

Scheme 14.

Synthesis of (−)-ephedradine A.

A modified method for the synthesis of a chiral precursors of (−)-ephedradine A has been reported using Rh₂(S-PTAD)₄ as catalyst. Rh₂(S-PTAD)₄ gives much higher asymmetric induction in this type of reaction compared to Rh₂(S-DOSP)₄, leading to reasonable asymmetric induction without the aid of a chiral auxiliary.³⁰ Reaction of aryldiazoacetate 54 in the presence of Rh₂(S-PTAD)₄ generated the cis benzofuran 55 in 72% yield, with high diastereoselectivity (dr ~14:1), and good enantioselectivity (79% ee) (Scheme 15). Epimerization with sodium hydroxide lead to the trans benzofuran 56, which is the diastereomer required for the total synthesis of 53.

Scheme 15.

Chiral catalyst approach to (−)-ephedradine A precursor.

Fukuyama and coworkers have extended the intramolecular C—H insertion to even more elaborate systems.³¹ The key step in the synthesis of (−)-serotobenine (59) uses an indolyldiazoacetate as substrate (Scheme 16). Once again, a combination of a chiral catalyst and a chiral auxiliary was used to induce asymmetric induction whereby the Rh₂(S-DOSP)₄-catalyzed reaction of the indolyldiazoacetate 57 generated the fused dihydrobenzofuran 58 in 92% yield, with high asymmetric induction (dr~96:4). Conversion of 58 to (−)-serotobenine (59) was achieved in a series of steps.

Scheme 16.

Asymmetric synthesis of (−)-serotobenine

Intermolecular C—H Insertion

Donor/acceptor carbenoids undergo highly regioselective and stereoselective C—H insertions. ⁷ Although acceptor-substituted carbenoids will undergo intermolecular C—H insertions into substrates such as cyclohexane and tetrahydrofuran, overall, the range of substrates capable of selective functionalization with this type of carbenoid is limited.³² In contrast, donor/acceptor carbenoids display great regioselectivity, controlled by a delicate balance of steric and electronic influences. Furthermore, in the presence of chiral catalysts, highly enantioselective reactions can be achieved.

The intermolecular C—H insertion can be considered as a C—H functionalization strategy, complimenting many of the classic reactions of organic synthesis, as illustrated in Scheme 17. For example, C—H insertion α to oxygen, generates β-hydroxy esters, ³³ products that are typically derived from an aldol reaction. The analogous C—H insertion α to nitrogen, generates β-amino esters,³⁴ the typical products of a Mannich reaction.

Scheme 17.

C—H functionalization as a strategic reaction

A wide variety of pharmaceutical agents have been synthesized using an enantioselective intermolecular C—H functionalization as the key step. Two examples are illustrated in Scheme 18. Rh₂(R-DOSP)₄-catalyzed allylic C—H insertion into cyclohexadiene by the thiophenyldiazoacetate 60 generated 61, which was converted in two steps to the cholinesterase inhibitor, (+)-ceitedil (62).³⁵ N-methyldisilazane 63 is an effective substrate for C—H functionalization because the N-methyl group is electronically activated while the nitrogen is sterically protected. Rh₂(R-DOSP)₄-catalyzed reaction of the aryldiazoacetate 64 with 63 generated the β-amino ester 65 in 93% yield, which was converted in two steps to (S)-venlafaxine (66), an enantiomer of the antidepressant (±)-venlafaxine.³⁶ Other pharamaceutical targets that have been made using C—H functionalization strategies include (+)-methylphenidate^34,37,38 and (+)-indatraline.³⁹

Scheme 18.

C—H functionalization applied to the synthesis of pharmaceutical targets

Selective intermolecular C—H insertion can occur at primary, secondary or tertiary C—H bonds by careful manipulation of steric and electronic influences. A C—H insertion at a primary benzylic position was used in the synthesis of (+)-imperanene and (−)-α-conidendrin (Scheme 19).⁴⁰ Both natural products could be derived from the reaction of the stryryldiazoacetate 67 with the catechol derivative 68 by using the appropriate ennatiomer of the catalysts. The C—H insertion product 69 was formed in 91% ee in the Rh₂(R-DOSP)₄-catalyzed reaction and was readily converted to (+)- imperanene (70). The enantiomeric product ent-69 was converted to (−)-α-conidendrin (71), in which the original stereocenter of the C—H insertion product controls the stereochemistry of the other two stereocenters in the natural product.

Scheme 19.

Total synthesis of (+)-imperanene and (−)-α-conidendrin.

Combined C—H Activation/Cope Rearrangement

The most unusual reaction of donor/acceptor carbenoids is the combined C—H activation/Cope rearrangenement.⁴¹ The reaction generates products that are formally derived from a C—H functionalization, followed by a Cope rearrangement. Interestingly, the C—H functionalization product was found not an intermediate in this reaction as it is thermodynamically the most stable product. It has been proposed that the reaction is as illustrated in Scheme 20, initially following the C—H functionalization pathway to 72, but is then interrupted by the Cope rearrangement, forming the observed product 73.⁴¹

Scheme 20.

Proposed pathway for the combined C—H activation/Cope rearrangement

The concerted nature of the combined C—H activation/Cope rearrangement causes the reaction to be highly diasteresoselective. This is clearly seen in the reaction of two model substrates 74 and 76 (Scheme 21).⁴² In both cases, the C—H functionalization products. 75 and 77, are produced with very high diastereoselectivity and enantioselectivity. The predominant diastereomer is consistent with the Cope rearrangement occurring through a chair transition state as illustrated in Scheme 20.

Scheme 21.

Model substrates for the combined C—H activation/Cope rearrangement

The combined C—H activation/Cope rearrangement has been applied to the synthesis of the antidepressant (+)-sertraline as illustrated in Scheme 22.⁴³ The Rh₂(S-DOSP)₄-catalyzed reaction of the vinyldiazoacetate 78 with 1,3-cyclohexadiene generated the 1,4-cyclohexadine 79 in 99% ee. A four-step sequence converted 79 to the 4-aryltetralone 80, and this represents a formal synthesis of (+)-sertraline (5).

Scheme 22.

Formal synthesis of (+)-sertraline

Due to the high asymmetric induction possible in the reactions of donor/acceptor carbenoids, these intermediates are capable of reacting differentially with the two enantiomers of a chiral substrate. An impressive example of this phenomenon is seen in the kinetic resolution of racemic dihydronaphthalenes.⁴⁴ As illustrated in the model study shown in Scheme 23, one enantiomer of 81 undergoes a combined C—H activation/Cope rearrangement to form 82, while the other enantiomer of 81 is cyclopropanated to form 83. Both 82 and 83 are formed with very high diastereo- and enantiocontrol.

Scheme 23.

Kinetic resolution of racemic dihydronaphthalenes

The enanatiodivergent reactions of dihydronaphthalenes has been applied to the synthesis of various natural products. The first example shown in Scheme 24 describes a concise synthesis of (+)-erogorgiaene (87).⁴⁴ Reaction of the vinyldiazoactete 84 with the racemic dihydronapthalene 85 generates all three stereogenic centers present in (+)-erogorgiaene. Hydrogenation followed by lithium aluminum reduction of the initially formed product generated the alcohol 86 in 90% ee, in 62% yield (considering that only one of the enantiomers of 85 is forming 86). The completion of the synthesis of (+)-erogorgiaene (87) is readily achieved by oxidation of the alcohol in 86 followed by a Wittig reaction.

Scheme 24.

Total synthesis of (+)-erogorgiaene

The enantiodivergent reactions have been extended to more elaborate systems as illustrated in Scheme 25 with the total synthesis of (−)-colombiasin A (90) and (−)-elisapterosin B (91).¹⁴ The reaction of the racemic dihydronapthalene 88 and the vinyldiazoacetates 84 generated a 1:1 mixture of cyclopropanation and C—H functionalization products. Direct hydrogenation and reduction of the crude product generated the alcohol 89 with excellent diastereocontrol and enantiocontrol. The completion of the synthesis of total synthesis of (−)-colombiasin A (90) and (−)-elisapterosin B (91) was achieved using standard chemistry. A variety of related natural products have also been prepared.^45,46

Scheme 25.

Total synthesis of (−)-colombiasin A and (−)-elisapterosin B

In summary, this tutorial describes the scope of novel synthetic disconnection that can be achieved using donor/acceptor-substituted carbenoids as key intermediates. Due to their greater selectivity, these intermediates are capable of highly selective intermolecular reactions not accessible by acceptor-substituted carbenoids. The selectivity is controlled by a delicate balance of steric and electronic effects. The cyclopropanation chemistry of these intermediates is now firmly established. In particular, the tandem cyclopropanation/Cope rearrangement has resulted in numerous examples in total synthesis. The C–H functionalization methodology is still emerging, but the impressive applications in total synthesis already achieved indicate the great potential for future growth in this area of chemistry.

Biographies

Huw M. L. Davies was born in Aberystwyth, Wales, UK. He began is idependent academic career at Wake Forest University. In 1995 he moved to the University at Buffalo, the State University of New York, where he held the positions of UB Distinguished Professor and Larkin Professor of Organic Chemistry. In 2008, he joined the faculty at Emory University as the Asa Griggs Candler Professor of Chemistry. His research program covers design of chiral catalysts, development of new synthetic methodology, total synthesis of biologically active natural products, and development of chiral therapeutic agents. A major current research theme in his group is catalytic asymmetric C–H fucntionalization.

Justin R. Denton was born in Cooperstown, New York in 1982. He received a B.S. degree in Chemistry from SUNY Environmental Science and Forestry & Syracuse University in 2004. He went on to earn a Ph.D. in Organic Chemistry from the State University of New York at Buffalo under the guidance of Prof. Huw M. L. Davies in 2008, where he focused on the development of new synthetic methodologies utilizing donor/acceptor-substituted rhodium carbenoids. He is currently a post-doctoral researcher at Obiter Research in Champaign, Illinois. Justin’s current research interests are in the realm of green chemistry, specifically directed towards developing more economically efficient methodologies for synthesis.