Carbocycloaddition Strategies for Troponoid Synthesis

Abstract

Tropone is the prototypical aromatic 7-membered ring, and can be found in virtually any undergraduate textbook as a key example of non-benzenoid aromaticity. Aside from this important historical role, tropone is also of high interest as a uniquely reactive synthon in complex chemical synthesis as well as a valuable chemotype in drug design. More recently, there has been growing interest in the utility of tropones for catalysis and material science. Thus, synthetic strategies capable of synthesizing functional tropones are key to fully exploiting the potential of this aromatic ring system. Cycloaddition reactions are particularly powerful methods for constructing carbocycles, and these strategies in turn have proven to be powerful for generating troponoids. The following review article provides an overview of strategies for troponoids wherein the 7-membered carbocycle is generated through a cycloaddition reaction. Representative examples of each strategy are also provided.

1. Introduction

Tropone was one of the first non-benzenoid aromatic systems ever discovered,¹ and is described in most undergraduate organic chemistry textbooks as the prototypical aromatic 7-membered ring. It can also be found embedded in a number of different natural products with varying physical and biological properties (Figure 1),² including the antioxidant thujaplicins (i.e., 2),³ the HIV Ribonuclease H-inhibiting manicol (4),⁴ the antimalarial puberulic acid (5),⁵ and the red pigment rubrolone (3).⁶ By far the most widely studied tropone is the natural product colchicine (1),⁷ which is an FDA-approved therapeutic for the treatment of gout⁸ and familial Mediterranean fever,⁹ and is highly significant in the field of oncology due to its tubulin-inhibiting properties.¹⁰ Studies on colchicine have largely dominated the tropone literature, and over half of all manuscripts published to date that describe a tropone describe colchicine.¹¹

Figure 1.

Examples of tropone-containing natural products.

Outside of colchicine, there are numerous examples highlighting the unique and valuable properties of tropone. For example, the medicinal chemistry potential of hydroxylated tropones (i.e., tropolones, α-hydroxytropolones) is very diverse (Scheme 2A).¹² As a result, synthetic tropolones have been identified that are potent inhibitors of histone deacetylase (7),¹³ hepatitis C NSC helicase (8),¹⁴ and hepatitis B Ribonuclease H (9),¹⁵ just to describe a few. Tropone-containing molecules have also been useful as a synthon within the synthetic organic chemistry community, for example in thermal [6 + 4] cycloaddition chemistry (10 + 11 → 12)¹⁶ or photochemical [2 + 2] cyclization-based cascades (13 → 14, Scheme 2B).¹⁷ Tropone has also been of interest as a catalyst, including for chlorination (17 → 18, Scheme 2C),¹⁸ and a tropone-embedded polymer has been used as an acid-sensitive sensory material (i.e., 19, Scheme 2D).¹⁹

Scheme 2.

Summary of 7-membered ring forming carbocyloadditions described in current review.

As a result of the value of this chemotype, there has been considerable interest in the synthesis of tropones and tropolones dating back to their discovery.²⁰ However, despite these efforts, tropone synthesis can present barriers to completing target synthesis,²¹ which in turn limit studies aimed at optimizing the function of tropone-containing molecules. Another major barrier is that there is no single, highly general approach with tried-and-true value in tropone synthesis. Instead, the tropone synthesis literature is diverse and complex, with many strategies available, each with their own value towards a specific type of tropone. Given the breadth of strategies, identifying the best one for a given target has the potential to be onerous. The present article attempts to distil the literature on tropone synthesis by focusing on a specific and powerful sub-class of strategies based around 7-membered carbocycle-forming cycloadditions. (Scheme 2) Carbocycloaddition reactions are particularly valuable strategies for all-carbon ring annulation,²² and various 7-membered carbocycloaddition reaction have been developed as a result, many of which have been employed in troponoid synthesis. We thus describe these general strategies, and provide illustrative examples. We have chosen to limit these approaches to only those strategies wherein the 7-membered carbocycle is generated during the cycloaddition step to provide focus. It is our hope that this mini-review will complement the various reviews that have emerged recently on tropone synthesis,²³ and serve as a valuable resource for those interesting in making, using, and developing tropone-containing molecules.

2. (2 + 1) Approaches

2.1. From cyclohexene or cyclohexadiene

Cyclopropanation with cyclohexenes, cyclohexadienes, or their precursors can generate bicyclo[4.1.0]heptanes, which can be converted into tropones (Scheme 3).²⁴ It is common in these strategies to employ halogen-bearing cyclopropanation reagents, as they provide a handle for a down-stream elimination that will bring the system closer to the appropriate oxidation state.

Scheme 3.

Overview of cyclohexene and cyclohexadiene-based oxidation conditions.

A representative example of this strategy can be observed in the synthesis of γ-thujaplicins from TES-protected isopropylphenols (i.e., 32, Scheme 4).²⁵ Birch reduction provides a 1,4-diene with an electronically rich silyl enol ether (33). Following a three-step cyclopropanation/desilylation/epoxidation sequence, treatment of 35 with acid promotes Grob-type ring-opening to afford the 7-membered carbocycle. It also facilitates full aromatization to generate chlorotropone 37 by way of epoxide ring-opening and double-elimination. This compound was subsequently advanced to γ-thujaplicin (27) through a hydrolysis with acetic acid.

Scheme 4.

Cyclopropanation approach to γ-thujaplicinol (27).

1,3-Dienes have also been used as precursors to tropones via cyclopropanation chemistry.²⁶ One widely-exploited strategy involves the use of some combination of bromoform-based cyclopropanation and dihydroxylation, which can then be advanced to a number of valuable tropone building blocks with value in total synthesis.²⁷ Just this year, the strategy was included in the synthesis of gukulenin B,²⁸ illustrating its contemporary value and interest. As a representative example, trimethylstannane-bearing tropones 43 and 44 have been synthesized by leveraging dibromocyclobutene (39, Scheme 5).²⁹ Following oxidation of diol 40, spontaneous ring-opening at room temperature provides tropolone 44. Alternatively, if the oxidation is done at colder temperatures, product 41 can be isolated and advanced to α-methoxyenone 42, enabling the regioselective synthesis of methoxytropone 43.

Scheme 5.

Synthesis of stannane-appended troponoids 43 and 44 from 1,3-diene 38.

Cyclopropanation strategies have also been employed with cyclohexenes (i.e. Scheme 6). In these instances, the targets are an additional oxidation state removed from the tropone. One representative example is in the synthesis of 2,6-dimethyltropone 31.³⁰ Following silyl enol ether generation and cyclopropanation of 45 to generate 46, an acid-mediated ring opening provides α-chloroenone 48. Radical-mediated installation of a bromide (48 → 49), followed by elimination of both this bromide and the chloride, provided the target molecule.

Scheme 6.

Synthesis of dimethyl tropone 31.

2.2. From benzenes

Tropones and tropolones can also be accessed from cyclopropanation of benzene derivatives (Scheme 7).³¹ In these instances, the ring-systems will often undergo an electrocyclic ring-opening of the cyclopropanes to generate cycloheptatrienes (i.e., Buchner ring-expansion), which then must be oxidized to the appropriate ring-systems. The range of strategies for the subsequent oxidation are dynamic, and can be accomplished by either formal loss of H₂, or through introduction of oxygenation.

Scheme 7.

Overview of benzene cyclopropanation approaches to tropones.

A representative example of the Buchner reaction/oxidation approach from an oxygenated benzenoid can be seen as far back as the 50s, in a classic synthesis of stipitatic acid (55) from 1,3,4-trimethoxybenzene (61, Scheme 8A).³² In this instance, bromine was used as an external oxidant to convert Buchner-derived cycloheptatrienone 64 into the natural product. More recently, the intramolecular Buchner reaction product derived from a diazoketone-tethered anisole (65) was converted to tropone 67 through cyclopropanation followed by selenium dioxide oxidation.³³

Scheme 8.

Buchner reaction approaches to tropones with oxygenated benzenes and an exogenous oxidant. (A) Cyclopropanation approach to stipitatic acid (55) leveraging bromine as oxidant. (B) Intramolecular Buchner reaction followed by selenium dioxide oxidant to generate 67.

Given the aromaticity of tropone, there are also instances in which air is capable of converting Buchner products into the corresponding tropones and tropolones. For example, it was recently described that dioxolane-substituted cycloheptatriene 70, generated from the known Buchner reaction between ethyl diazoacetate (62) and 1,3-benzodioxole (68), can undergo clean autoxidation to tropolone 71 after a few days under a stream of compressed air (Scheme 9A).³⁴ A similar autoxidation was also serendipitously discovered during studies on a catalytic asymmetric dearomatization of phenol derivatives.³⁵ In this latter instance, lactam-fused cycloheptatriene 73, generated through an intramolecular cyclopropanation of 72, led to production of tropone 74 (Scheme 9B).

Scheme 9.

Buchner/autoxidation approaches to tropones and tropolones. (A) Oxidation of dioxolane-fused, and (B) lactam-fused cycloheptatrienes.

One slightly different variant of the Buchner reaction/oxidation approach can be viewed in a total synthesis of hainanolidol (58, Scheme 10).³⁶ In this instance, Buchner-derived cycloheptene 76 has a ketone that is later reduced to alcohol 77. Acid-mediated conditions promote both the hydrolysis of the methyl enol ether and elimination of water, affording a product that can tautomerize to the tropone form of hainanolidol (77 → 58). Thus, in this instance, the cycloheptatriene is formally oxidized to the tropone while the alcohol is reduced to the methylene.

Scheme 10.

Buchner reaction approach to hainanolidol (58).

While the above examples demonstrate instances wherein the tropone carbonyl oxygen arises from the oxygen of an anisole, there are instances in which the oxidation also facilitates an oxygenation. One of the earliest examples of this strategy was with the selenium dioxide oxidation of Buchner-generated cycloheptatriene (79 → 80, Scheme 11),³⁷ and recent examples have shown that this can be done with electrochemistry and other oxidants.³⁸ There are also instances of adding to the tropolone through addition of 2 oxygens (79 → 81).³⁹

Scheme 11.

Examples of oxygenation of cycloheptatriene 79.

A particularly elegant strategy for installation of oxygen atoms on Buchner cycloadducts is through the generation and subsequent reactions on cyclic peroxide 83 (Scheme 12).⁴⁰ These cyclic peroxides can be generated through singlet oxygen-mediated cycloaddition reactions on benzodioxole-generated Buchner products 70. Four separate conditions were thus employed on this intermediate to generate 4 different tropone-based molecules – tropolone 71, 7-hydroxytropolone 56, 3-hydroxytropolone 84, and the acetal-protected variant of the 3-hydroxytropolone (85).

Scheme 12.

Divergent synthesis of tropones from endoperoxide 83.

2.3. From o-quinone ketals

An alternative to oxidizing after the Buchner cycloaddition is to oxidize before the cyclopropanation (Scheme 13).⁴¹ Specifically, the cyclopropanation of o-quinone ketals (86 → 87), which can be generated through oxidation of appropriately functionalized benzenes, can rapidly eliminate to generate tropone-based targets (87 → 88). This has been primarily employed with methyl ketals and liberation of methanol to generate functionalized methoxytropones, and was a strategy highlighted in the early 90s through the synthesis of colchicine (1)⁴² and imerubrine (6).⁴³

Scheme 13.

Overview of o-quinone ketal routes to tropolones.

A highlight to this approach can be viewed through a recent total synthesis of (–)-colchicine (Scheme 14).⁴⁴ This synthesis can be viewed as a revisitation of a prior 1996 synthesis, streamlined considerably by employing recent synthetic chemistry advances – including in asymmetric catalysis – to rapidly generate enantiomerically pure 91 in only 4 steps from isovanillin (Scheme 14). The preparation of 91 was the major advancement to the synthesis. The 1996 asymmetric synthesis leveraged related intermediate 90,⁴² which took 9 steps to synthesize and required conversion of the alcohol to the acetamide further downstream in the synthesis. However, the general strategy to synthesize the tropone – oxidation of the phenol to the quinone (91 → 92) followed by cyclopropanation (92 → 93) and ring-opening (93 → 1) – closely mirrored the 1996 route. This improved synthesis – which was only 7 steps total – is the shortest synthesis of (–)-colchicine reported to date, and was used to synthesize 3 g of the natural product.

Scheme 14.

Generation of (–)-colchicine through quinone cyclopropanation.

An alternative quinone-based approach to methoxytropones can also be accomplished through mild thermolysis of bromoform/quinone ketal cycloadducts (Scheme 15).⁴⁵ This is a curious reaction, as it proceeds with a formal reduction (via loss of MeOBr). It has been proposed that this reaction is initially activated by hydrogen atom activation from adventitious water, and then subsequently driven by the liberated MeOBr.

Scheme 15.

Methoxytropone synthesis through formal loss of MeOBr.

3. (2 + 2) Approaches

3.1. From chloroketene

The (2 + 2) cycloaddition between cyclopentadiene and dichloroketene leads to 5–4 ring-systems, and these can be expanded to 7-membered rings through the introduction of acid or base (i.e., Scheme 16).⁴⁶ The ring-opening product tropolone has an oxygen not at the position of the chloride, but rather on one of the cyclopentadiene carbons. This rearrangement is believed to proceed by way of an oxyallylcation intermediate (98), which then situates the alcohol at the ring-juncture to facilitate a Grob fragmentation (99 → 100). ⁴⁷

Scheme 16.

Overview of dichloroketene-cyclopentadiene (2 + 2) routes to tropolone.

One representative example of the impact on this rearrangement can be observed through the rapid 2-step synthesis of the isopropenyl-appended α-dolabrin from dichloroketene precursor, 104, and dimethylfulvene (103) (Scheme 17A).⁴⁸ In this instance, a regioselective (2 + 2) cycloaddition afforded 105, which subsequently led to the hydroxyl group α- to the isopropenyl group following the oxyallyl cation rearrangement. The dichloroketene (2 + 2) strategy has also been studied in the synthesis of 102,⁴⁹ which has been advanced to colchicine (Scheme 17B).⁵⁰ The nucleophilic behavior of cyclopentadiene anion was leveraged to access compound 107, which successfully underwent the (2 + 2)/ring-opening sequence to access tropolone 102.

Scheme 17.

Examples of dichloroketene/cyclopentadiene (2 + 2) routes to tropolones. (A) Synthesis of α-dolabrin (101) from dimethylfulvene (103). (B) Synthesis of 102, a synthetic precursor to colchicine.

3.2. Photochemical (2 + 2)

Cycloadducts derived from photochemical (2 + 2) reactions have also been advanced to troponoids. The earliest work in this area stemmed from the pioneering work of de Mayo on photochemistry of enol ethers,⁵¹ which the lab highlighted in the synthesis of stipitatonic acid (113, Scheme 18).⁵² Other examples include the total synthesis of rubrolone aglycon (114),⁵³ and the rapidly dimerizing tropone 115.⁵⁴

Scheme 18.

Photochemical (2 + 2) routes to tropones.

One of the complicating factors in photochemical routes to tropolones is the ability for the cycloadducts themselves to undergo further rearrangements (Scheme 19A). For example, the cycloadduct 117, derived from α-ethoxyenone 116 and acetylene can further rearrange to cycloadduct 118, possibly through a oxa-di-π-methane rearrangement intermediate 120.⁵⁵ This molecule is known to undergo thermal ring-opening to form 119. The presence of oxa-di-π-methane rearrangement is supported by observations of these molecules in other (2 + 2) processes. For example, the cycloaddition between enone 121 and 1-hexyne (122) leads to the observance of ‘head-to-head’ cycloaddition product 123 as well as 124, which would result from the oxa-di-π-methane rearrangement of the ‘head-to-tail’ cycloadduct (Scheme 19B). Conveniently, 123 and 124 each provide the same tropolone (125) after additional irradiation, effectively ‘correcting’ any poor regioselectivity from the cycloaddition.

Scheme 19.

Rearrangements of photochemical (2 + 2) cycloadducts, and impact on tropone synthesis. (A) Rearrangement of α-ethoxyenone-acetylene cycloadducts to generate β-methoxytropone 119. (B) Cycloaddition with 1-hexyne, and conversion of (2 + 2) regioisomers to β-butyltropone 125.

One recent examples of the photochemical (2 + 2) approach has been in the synthesis of tropolone ortho quinone methide precursor 133, which has been used to access the quinone methide 134, which can be trapped through hetero-Diels-Alder reactions to generate molecules such as deoxyepolone B (135) and other structurally related dihydropyran-fused tropolones.⁵⁶ The synthesis of 133 is accomplished through an intermolecular (2 + 2) of 130, followed by a 2-step oxidation to the α-methoxyenone 132, and finally the ring-opening/elimination sequence.

4. (2 + 2 + 2 + 1) Approaches

One of the more recently described cycloaddition-based approaches to tropones is through a rhodium-catalyzed carbonylative (2 + 2 + 2+ 1) reaction (Scheme 21).⁵⁷ This method is a particularly powerful strategy for the construction of tropones, and is unique among the cycloaddition approaches described in that it leads directly to tropones. One of the major challenges of the approach, however, is competing (2 + 2 + 2) cycloaddition reactions, which can lead to benzene rather than tropone (138). The prevalence of this byproduct is substrate-scope specific, and more flexible tethers lead to greater formation of benzenoid products. For example, large differences in both conversion and tropone:benzene product ratio can be observed by changing the length of one of the tethers (140 vs. 141, Scheme 21B). Various other tricyclic tropone molecules can be generated by changing the nature of the tethers (i.e., 143 and 144).

Scheme 21.

(2 + 2 + 2+ 1) Cycloaddition approach to tropones. (A) Overview of strategy and (B) representative examples.

5. (4 + 2) Approaches

Diels-Alder reactions can also be employed in troponoid synthesis (Scheme 22).⁵⁸ These routes take advantage of cyclopropenone derivatives (i.e., 146), and use a leaving group strategy to generate the norcaradienes (i.e., 149) which can undergo Cope rearrangement to access the tropones. Cyclopropenone, cyclopronenone acetals, and tetrahalocyclopropenes have been used as the source of alkene. Various sources of dienes have been used with various leaving groups.

Scheme 22.

Overview of Diels-Alder approach to tropones.

5.1. From cyclopropenone and derivatives

A few representative examples of the sequence with cyclopropenones are described in Scheme 23. In the first example, diethylamine diene 157 reacts with diphenyl cyclopropenone (156) to generate 2,7-diphenyltropone (151) in a single step (Scheme 23A).⁵⁹ This proceeds through elimination of diethylamine followed by a Cope ring-expansion. In a second example, cyclopropenone (159) can react with either cyclopentadienone 160 or isobenzofuran 163 (Scheme 23B).⁶⁰ The reaction with 160 led directly to the tetraphenyltropone 162, presumably through extrusion of carbon monoxide from 161. The reaction with 163 leads to a stable cycloadduct, 164, that can undergo an acid-mediated rearrangement to generate tropolone 152.

Scheme 23.

(4 + 2) Routes to tropolones using (A) diphenylcyclopropenone and (B) cyclopropenone as dienophile.

Cyclopropenone ketals can also be used as cyclopropenone surrogates. These cyclopropenone derivatives are highly versatile, and can react with electron rich, poor, and neutral dienes (Scheme 24A). Similar to the case with cyclopropenone, with appropriate leaving groups, these cycloadducts can rearrange to troponoids through norcaradiene intermediates (i.e., 170).⁶¹ In one instance, this intermediate was accessed through base-assisted elimination of an appended methyl ether (Scheme 24A), and in the other instance the cycloaddition with electron-withdrawing substituted α-pyrones facilitated decarboxylation (Scheme 24B). This likely proceeds via isomer 178, as the alternative stereoisomers (i.e., 179) are thermally stable. This general strategy has been successfully applied in the total synthesis of imerubrine-type molecules (i.e., 154)⁶² and rubrolone aglycon (114, Scheme 22).⁶³

Scheme 24.

(4 + 2) Routes to tropolones using cyclopropenone acetal as dienophile.

5.2. From tetrahalocyclopropenes

Tetrahalocyclopropenes have also been successfully employed in this general strategy. For example, tetrachlorocyclopropene (180) is capable of reacting with Danishefsky’s diene and related dienes to provide direct access to trichlorotropones (Scheme 25).⁶⁴ This provides a slightly different approach to tropones than those from cyclopropenone and cyclopropane ketal in that the tropone carbonyl comes from the diene, and this provides versatility to the regioselectivity afforded.

Scheme 25.

[4 + 2] Cycloaddition routes to polyhalogenated tropones leveraging tetrachlorocyclopropene (180).

Diels-Alder cycloadducts formed between tetrahalocyclopropenes and furans can generate 7-membered carbocycles.⁶⁵ This reaction has been used towards the synthesis of β-functionalized tropolones, such as β-thujaplicin (2, Scheme 26).¹³ In this instance, tetrabromocyclopropene (192) and furan (193) can form oxabicycle 196, which then undergoes silver-mediated hydrolysis of geminal dibromide (196 → 197). Compound 197 is a valuable linchpin for β-functionalized tropolones, as one can carry out regioselective cross-coupling to diversify the scaffold, and then generate the tropolone through a reductive ring-opening.

Scheme 26.

(4 + 2) cycloaddition approach to β-thujaplicin (2) and phenyl-substituted tropolone 200.

6. (4 + 3) Approaches

An alternative approach to tropones based on dienes are (4 + 3) approaches, which take advantage of dipolar cycloaddition reactions with oxyallyl cations (202, Scheme 27).⁶⁶ The products generated from this approach are formally 2 oxidation and/or elimination steps away from the tropone structure. There are few different approaches to the oxyallyl cation formation, and these approaches impact how this latter formation can occur.

Scheme 27.

Overview of (4 + 3) approaches to tropones.

6.1. From 1,3-dihaloketones

One method to generate oxyallyl cations is through 1,3-dibromoacetone derivatives (210 and 215, Scheme 28). Once the cycloheptenones are generated, tropones can then be generated through double elimination chemistry – either through initial introduction of bromides (i.e., Scheme 28A),⁶⁷ or by elimination of components of the diene (i.e., Scheme 28B).⁶⁸

Scheme 28.

Dibromoacetone as the dipole precursor for (4 + 3) Cycloaddition approach to tropones.

Polychlorinated ketones can also serve as an oxyallyl cation precursor, forming the dipole upon treatment with base (sodium trifluorethoxide or triethylamine) in trifluoroethanol (Scheme 29). The resultant chlorides can be reduced with zinc if desired, and formal loss of water can be performed using trimethysilyl triflate and triethylamine (i.e., Scheme 29A).⁶⁹ However, there is the potential for added versatility to this strategy. An example can be viewed in the total synthesis of the natural product β-thujaplicinol (204, Scheme 29B).⁷⁰ First, the geminal dichlorides can be converted to a methyl ketal with sodium methoxide in methanol, which interestingly resolves the regioselectivity of the cycloadduct (214 and 215 → 216). Following reduction of the chloride, base-mediated rearrangement can lead to the oxygenated tropone, which can subsequently be demethylated to generate the α-hydroxytropolone natural product. Adding further to this versatility, the enolizable protons can also be trapped with an electrophile, leading to tropolones with substitution α- to the tropolone oxygen (Scheme 29C). Finally, an alternative strategy for generating methoxytropolones can be viewed in the synthesis of imerubrine (6), where the reduced bicycles are re-oxidized with periodate and methanol, and converted to 222. In this case, full elimination of the bridgehead oxygen with the aforementioned TMS triflate/triethylamine provides the methoxytropone (Scheme 29D).⁷¹

Scheme 29.

Polychlorinated acetone as dipole precursor in route to tropones.

6.2. From α,α-dimethoxyacetone

Oxylallyl cations can also be accessed through the treatment of an α,α-dimethoxyacetone-derived silyl enol ether with TMSOTf. When carried out in the presence of furan-containing molecules, 7-membered oxabicycles are generated (Scheme 30A),⁷² thereby providing an alternative approach to that described in Scheme 29D. This strategy has been implemented in the total synthesis of colchicine (1)⁷³ as well as imerubrine (6),⁷¹ each of which leverages the aforementioned TMSOTf-based ring-opening. Of synthetic significance, while the approach often suffers from poor regioselectivity, it has been shown through studies on the total synthesis of colchicine⁷³ that remote changes can alter this regioselectivity – possibly through steric versus hydrogen-bond direction. This necessitated the use of a Boc-protected amine in place of an acetamide to gain the appropriate regiochemistry (228 vs. 229, Scheme 30B) for the natural product’s total synthesis.

Scheme 30. α,α-Dimethoxyacetone as cation precursor in methoxytropone synthesis.

(A) Overview of approach, along with some molecules made through ring-opening/elimination sequence. (B) Major products from cycloaddition towards colchicine total synthesis, demonstrating noteworthy regioselectivity differences.

6.3. From cyclopropene ketal thermolysis

Another [4 + 3] cycloaddition strategy for 7-membered carbocycles is to thermalize cyclopropenone ketals in the presence of dienes (Scheme 31). This approach is regioselectively different from that aforementioned (4 + 3) approaches carbonyl – as well as (4 + 2) with cyclopropene ketals (see Scheme 24) - in terms of the placement of the carbonyl. This approach can be performed with α-pyrones as the diene source, and the tropone can either be generated via thermolytic decarboxylation (234 → 80, Scheme 31A), or through a ring-opening/re-aromatization sequence (233 → 235).⁷⁴ This approach was also used in a formal synthesis of colchicine (Scheme 31B).⁷⁵

Scheme 31.

Cyclopropenone-ketal thermolysis approach to tropones.

7. (5 + 2) Approaches

Tropones can also be generated through (5 + 2) approaches, which generally – but not always - rely upon dipolar cycloadditions with cyclic carbonyl or imine ylides. An advantage to this approach is that the 2-carbon component is an alkene or an alkyne, which are abundant. However, the approaches can differ substantially based upon the nature of the 5 C component.

7.1. From oxidopyridinium

One type of cycloaddition partner that have been used in tropone synthesis are oxidopyrydinium ions (Scheme 33). These can be generated either directly through methylation of 3-hydroxypyrydine, or through the oxidation of appropriately functionalized cyclic amines. Following cycloaddition reactions with electron-deficient dipolarophiles, the cycloadducts can be activated for elimination through treatment with haloalkanes to activate the amine, which can then undergo ring-opening (and if necessary, oxidation) to generate aminotropones. When the dipolarophile is an alkene, the ring-opened cycloadducts can potentially undergo autoxidation (ie, Scheme 33A).⁷⁶ However, when the dipolarophile is an alkyne, the bicycles can undergo a ring-opening/aromatization without any need for oxidation (ie, Scheme 33B/C). ⁷⁷ This latter strategy has been leveraged in the total syntheses of stipitatic acid (55) and β-thujaplicin (2).

Scheme 33.

Examples of [5 + 2] Cycloaddition approaches to tropones using oxidopyrydinium ylides.

7.2. From acetoxypyranose elimination

The utility of the oxidopyrylium (5 + 2) cycloaddition provide an alternative strategy to tropone synthesis.⁷⁸ A classic way to make oxidopyrylium ions is through acetate elimination of an acetoxypyranose,⁷⁹ which are themselves made through oxidation of furan (i.e., 261 → 261.1, Scheme 24A). It is common for this approach to be carried out in an intramolecular fashion, with the furan pre-functionalized with a dipolarophile tether (i.e., 261). The additional ring made through this strategy can afford additional ring systems, which can be beneficial in complex target-oriented synthesis. Two examples of this can be seen in the total syntheses of colchicine (1, Scheme 34A)⁸⁰ and hainanolidol (58, Scheme 34B).⁸¹ In the case of colchicine, the oxidopyrylium (5 + 2) cycloaddition leads to cycloadduct 262, which generates both 7-membered carbocycles in the natural product. 262 is then converted into a familiar α-methoxyketone scaffold, 263, which are well precedented to undergo TMS triflate ring-opening (see Scheme 29D and 30), and thus leads to colchicine 1. In the case of hainanolidol, the intermolecular oxidopyrylium cycloaddition generates complex caged structure 265. After several steps to modify the structure to generate 268, hainanolidol can be accessed through an elegant singlet oxygen/elimination sequence.

Scheme 34.

Examples of intramolecular oxidopyrylium (5 + 2) cycloaddition approaches to tropone natural products.

Similar oxidopyrylium cycloaddition approaches to tropones and tropolones can also be carried out in an intermolecular fashion (Scheme 35). In one representative example, acetoxypyranose elimination in the presence of 272 leads to a mixture of 4 compounds, both diastereomers of 273 and 274 (Scheme 35A).⁸² After modifying each regioisomer to install a β-methoxy group (i.e., 275), they can undergo base-mediated ring-opening and oxidation to generate either 277 or 278. These molecules can be subsequently demethylated, to converge to a benzo-variant of rubrolone aglycone (see 246 in Scheme 32 vs. 114 in Scheme 22). In another example, acetoxypyranose 279 can react with acrylonitrile or an oxygenated variant to generate oxabicycles 282 or 281, respectively (Scheme 35B).⁸³ Ring-opening can take place through either treatment of iodo-285 with zinc in the case of 281,^83a or through the use of LDA with the enolizable proton α- to the cyano group in 282.^83b Subsequent oxidation of each employing TFAA/DMSO leads to tropolones 284 and 288.

Scheme 35.

Examples of intermolecular oxidopyrylium (5 + 2) approaches to tropone structures.

Scheme 32.

Overview of (5 + 2) approaches to tropones.

7.3. From 3-hydroxy-4-pyrones

Oxidopyrylium ylides can also be generated from 3-hydroxy-4-pyrones,⁸⁴ and these have also been advanced to tropones (Scheme 36). ⁸⁵ To date, this strategy has been primarily carried out with kojic acid-derived oxidopyrylium ylide (Scheme 36A), which can react with various alkyne dipolarophiles to generate a number of oxabicycles (i.e., 291). These oxabicycles can then undergo triflic acid-mediated rearrangements to generate methoxytropolones (i.e., 292).⁸⁶ An alternative procedure employs boron trichloride, which in certain cases can go directly to α-hydroxytropolones (i.e., 293).⁸⁷ One example of this approach can be viewed in a solid-supported synthesis of α-hydroxytropolone 298, leveraging oxidopyrylium dimer 294 as an ylide source (Scheme 36B).⁸⁸ This sequence takes advantage of the ability of oxidopyrylium dimers of this type to undergo nucleophilic aromatic substitution in the presence of alcohols (296 → 297).⁸⁹ Thus, after on-bead cycloaddition, hydroxytropolones can be generated through a ring-opening that simultaneously releases the tropolone from the bead.

Scheme 36.

Examples of intermolecular oxidopyrylium (5 + 2) approaches to tropone structures employing 3-hydroxy-4-pyrones.

Maltol-derived ylides have also been used in the synthesis of tropolones (Scheme 36C).⁹⁰ In this instance, the alternative placement of the methyl group leads to an alternative hydroxytropolone or methoxytropolone regioisomer. To date, this strategy has only been shown on bicycle 301, which leads to a mixture of 306 and 307 after treatment with boron trichloride. In alternative substrates with aryl substitution, the cycloadducts will undergo ring-contractions,⁹¹ illustrating the natural preference for 6-membered rings over 7-membered rings. This happens with both boron trichloride (i.e., 304) as well as triflic acid (i.e., 305). Thus, the success of this latter approach may be highly substrate specific.

7.4. From diazotransfer

Oxidopyrylium ylides can be formally viewed as a carbonyl ylide 1,3-dipole embedded within a 6-membered ring structure. As such, carbonyl ylide-generating diazotransfer reactions, where a 6-membered ring is generated during the diazo transfer, provide a similar strategy to tropone synthesis as oxidopyrylium ylides (Scheme 37). Aryl-fused oxidopyrylium ylides (i.e. 309, Scheme 37A), for example, have been generated through diazotransfer with a tether.⁹² Upon treatment to either Bronsted or Lewis acids, these can undergo a ring-opening/aromatization to generate aryl-fused tropolones.

Scheme 37.

Overview of diazotransfer strategies in troponoid synthesis.

The diazotransfer strategy has also been reported in the synthesis of colchicine (Scheme 37B).⁹³ In this latter instance, reduction of cycloadduct 315 followed by TMSOTf/NEt3 conditions provides diol 317. The diol can then be oxidized to the tropolone with TFAA/DMSO and methylated to generate colchicine precursor 319, which can be advanced to the natural product. Tropone analog 316 can also be generated from 315 through treatment with a strong Lewis acid. A final example can also be found in the synthesis of harringtonolide (334, Scheme 37C).⁹⁴ In this latter instance, the oxabicycle generated from diazotransfer cycloaddition of 320 is converted into the tropone by generation of silyl enol ether followed by a ring-opening/aromatization sequence (322 → 323).

7.5. From p-quinone ketals

Another (5 + 2) approach to tropones is through p-quinone-based cycloaddition reactions, which can lead to highly substituted tropolones (Scheme 37C).⁹⁵ Bicycle 326 was prepared from the (5 + 2) cycloaddition of p-quinone monoketal 324 and (E)-isosafrole 325 – by way of 326. The cycloadduct can then undergo a hydrolytic ring-opening (326 → 327), followed by 2-step oxidative elimination of the carboxylic acid (327 → 329). Methylation and oxidation finally furnishes tropolone 242.

7.6. From 3-acyloxy-1,4-enyne

A final example of (5 + 2) approaches to tropolones is through rhodium-catalyzed (5 + 2) cycloaddition of a 3-acyloxy-1,4-enyne (331) and a propargylic alcohol (332) to generate tropones (Scheme 39).⁹⁶ The reaction proceeded with 1,2-acyloxy migration to yield cycloheptatriene 335, which can then be converted to the corresponding tropones through an elimination (335 → 337) and hydrolysis (337 → 338).

Scheme 39.

Tropone synthesis from 3-acyloxy-1,4-enynes and propargylic alcohols.

8. Summary and Conclusions

Numerous strategies have been described wherein carbocycloaddition reactions are used to generate 7-membered carbocyclic rings, and further modified to generate tropones. These strategies have proven effective in the generation of a wide range of various functional tropones, and have also been exploited in the synthesis of various tropone-containing natural products. The continued advancement of carbocycloaddition reactions, and methods to convert these molecules into tropones, should help diversify the tropone literature, and promote more widespread utility of tropones in modern scientific research.

Scheme 1.

Examples of diverse functions established by tropone-containing molecules. (A) Representative examples of tropolones with medically relevant activities. (B) Representative examples of tropones as synthons for stereochemically dense bicyclic structures. (C) Example of tropone as a catalyst for chlorination, with the proposed catalytic cycle. (D) Tropone-containing polythiophene for usage as sensory material.

Scheme 20.

(2 + 2) Cycloaddition approach to deoxyepolone B (135).

Scheme 38.

Synthesis of tropone 242 from p-quinone monoketal 324 and olefin 325.