Catalytic Asymmetric Synthesis of 3, 4-Disubstituted Cyclohexadiene

Letter Cite This: Org. Lett. 2018, 20, 4111−4115

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Catalytic Asymmetric Synthesis of 3,4-Disubstituted Cyclohexadiene Carbaldehydes: Formal Total Synthesis of Cyclobakuchiols A and C Vidyasagar Maurya and Chandrakumar Appayee* Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar, Gujarat 382355, India

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S Supporting Information *

ABSTRACT: The first catalytic approach for the asymmetric synthesis of 3,4-disubstituted cyclohexadiene carbaldehydes through an inverse-electrondemand Diels−Alder reaction is described. A variety of arylacetaldehydes and α,β,γ,δ-unsaturated aldehydes are tested under the mild reaction conditions catalyzed by L-proline to obtain the trans diastereomeric products with good yields and high enantioselectivities. The scope of this methodology is further extended to the asymmetric synthesis 3,4disubstituted cyclohexane carbaldehydes and their derivatives. The practicality of this method is demonstrated by the gram-scale synthesis. This methodology is successfully applied for the formal total synthesis of cyclobakuchiol A, an antipyretic and anti-inflammatory agent, and cyclobakuchiol C.

T

he asymmetric synthesis of substituted cyclohexanes1 is one of the most useful areas of research in synthetic organic chemistry owing to the fact that chiral cyclohexane motifs are ubiquitous in many bioactive natural products such as terpenoids,2 alkaloids,3 and steroids.4 In recent times, there has been a strong urge to develop new organocatalytic methodologies for the construction of chiral cyclohexane frameworks.5 Multisubstituted cyclohexane carbaldehyde derivatives have been synthesized by organocatalytic cascade or domino reactions.6 Chiral disubstituted cyclohexane carbaldehyde derivatives have likewise been accessed through organocatalytic cascade7 or [4 + 2] cycloaddition reactions.8 Chiral 3,4-disubstituted cyclohexane carbaldehyde derivatives are common motifs in many antipyretic and anti-inflammatory agents9 and potent psychotropic cannabinoids10 (Figure 1). These bioactive molecules have mostly been synthesized through chiral pool synthesis.9,10c,11 To the best of our knowledge, there is no catalytic method for the asymmetric synthesis of 3,4-disubstituted cyclohexane carbaldehydes so far reported in the literature. Herein, we report the first catalytic approach for the asymmetric synthesis of 3,4-disubstituted cyclohexadiene carbaldehydes through an inverse-electron-demand Diels− Alder reaction starting from α,β,γ,δ-unsaturated aldehydes and arylacetaldehydes (Scheme 1). When phenylacetaldehyde 1a was treated with α,β,γ,δunsaturated aldehyde 2c in the presence of L-proline 3a in CHCl3 at room temperature (Table 1, entry 1), formation of the 3,4-disubstituted cyclohexadiene carbaldehyde 4c was observed as a single diastereomer in the crude reaction mixture, and this was reduced using NaBH 4 to the corresponding alcohol 5c for further characterization (52% © 2018 American Chemical Society

Figure 1. Bioactive chiral 3,4-disubstituted cyclohexane carbaldehyde derivatives.

yield, 81% ee). Under similar reaction conditions, catalyst 3b produced alcohol 5c in 47% yield with 80% ee (entry 2). Surprisingly, the bulky catalyst 3d had also produced the same enantiomer of 5c, though with moderate enantioselectivity (74% ee) and in poor yield (entry 4). The addition of acetic acid along with the catalyst 3d did not improve the reaction outcome (entry 5). In the case of catalysts 3c, 3e, and 3f, the formation of alcohol 5c was not observed, but the decomposition of aldehyde 1a was noticed (entry 3 and entries 6 and 7). Received: May 28, 2018 Published: June 19, 2018 4111

DOI: 10.1021/acs.orglett.8b01667 Org. Lett. 2018, 20, 4111−4115

Letter

Organic Letters Scheme 1. Catalytic Asymmetric Synthesis of 3,4Disubstituted Cyclohexadiene Carbaldehydes through Inverse-Electron-Demand Diels−Alder (IEDDA) Reaction

Scheme 2. Substrate Scope for the Asymmetric Synthesis of 3,4-Disubstituted Cyclohexadiene Carbaldehyde Derivatives

Table 1. Optimization of the Reaction Conditionsa

entry

3

solvent

t (h)

yieldb (%)

eec (%)

1 2 3 4 5d 6 7 8 9 10 11 12 13 14 15g

3a 3b 3c 3d 3d 3e 3f 3a 3a 3a 3a 3a 3a 3a 3a

CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CH2Cl2 dichloroethane toluene MTBE DMSO DMF CH3CN CH3CN

17 17 24 17 24 24 24 17 24 24 17 24 24 17 28

52 47

81 80 e

10 8

74 57 e e

50 51 39 14 16

82 81 73 76 84 f

40 70

86 92

enantiomeric excess of the aldehydes 4a−c was determined after conversion to the corresponding alcohols 5a−c using NaBH4. Hence, remaining products 4 were reduced using NaBH4 to the corresponding alcohol 5 for further characterization. Unsaturated aldehydes containing the longer chain (2d) or bulky isobutyl group (2e) were also tested in the reaction with 1a and formed alcohols 5d and 5e, respectively. Diphenyl-substituted product 5f was obtained with moderate enantioselectivity (72% ee) when aromatic unsaturated aldehyde 2f was used. Arylacetaldehydes 1b−f smoothly reacted with 2a under the optimized reaction conditions to give products 5g−k in good yields and high enantioselectivities. The reaction of para-substituted phenylacetaldehydes 1b−d with unsaturated aldehyde 2c containing a long alkyl chain furnished products 5l−n in good yields and high enantioselectivities (up to 95% ee). Arylacetaldehyde 1c reacted with 2g, containing a silyloxymethyl group, to form aldehyde 4o in 74% yield and 95% ee. The reactions of other alkyl aldehydes with 2c were found to be ineffective.12 The absolute configuration of the products 4 was assigned on the basis of the single-crystal X-ray analysis of 2,4-

a

Reactions were performed with 2c (0.25 mmol), 1a (0.375 mmol), and catalyst (0.05 mmol) in solvent (250 μL) unless otherwise noted. b Isolated yield after column chromatography. cDetermined by HPLC analysis on a chiral stationary phase. dAcOH (0.05 mmol) was added. e 1a was decomposed. fUnidentified mixture of products was formed. g Reaction was carried out at 0 °C. MTBE = methyl tert-butyl ether.

Several solvents were screened for the formation of alcohol 5c, catalyzed by L-proline 3a (entry 8−14), and higher enantioselectivity (86% ee) with moderate yield (40%) was witnessed when CH3CN was used as a solvent (entry 14). The reaction of 1a with 2c catalyzed by 3a in CH3CN at 0 °C, followed by reduction using NaBH4, gave alcohol 5c in 70% isolated yield and 92% ee (entry 15). After the successful reaction optimization, the substrate scope of the arylacetaldehydes 1 and α,β,γ,δ-unsaturated aldehydes 2 was investigated (Scheme 2). α,β,γ,δ-Unsaturated aldehydes 2a−c having different chain lengths reacted with phenylacetaldehyde 1a to form products 4a−c in good isolated yields with high enantioselectivities (up to 92% ee). The 4112


Letter

Organic Letters dinitrophenylhydrazone 6j obtained from the reaction of pbromophenylacetaldehyde 1e and unsaturated aldehyde 2a followed by the reaction with 2,4-dinitrophenylhydrazine (Scheme 3).

aiming for the formation of a diastereomeric mixture of products. However, a single diastereomer of racemic-4a was observed in the 1H NMR of the crude reaction mixture (Scheme 5) indicating the possibility of a concerted reaction pathway.

Scheme 3. Synthesis and Single-Crystal X-ray Structure of 2,4-Dinitrophenylhydrazone 6j

Scheme 5. Formation of Racemic-4a as a Single Diastereomer Catalyzed by Pyrrolidine

On the basis of the reaction results, we propose a possible mechanism for the formation products 4 through an inverseelectron-demand Diels−Alder reaction (Scheme 6). AccordScheme 6. Proposed Reaction Mechanism for the Formation of 3,4-Disubstituted Cyclohexadiene Carbaldehydes 4

We further explored the scope of this methodology for the synthesis of 3,4-disubstituted cyclohexane carbaldehydes and their derivatives (Scheme 4). Hydrogenation of 4b produced Scheme 4. Synthesis of 3,4-Disubstituted Cyclohexane Carbaldehyde Derivatives

cyclohexane carbaldehyde 7b in 74% yield and a 1.8:1 diastereomeric ratio.13 The major diastereomer 7b was purified by silica gel column chromatography and further converted to the corresponding alcohol 8b (99%) using NaBH4. The newly generated chiral center of 7b during hydrogenation was assigned on the basis of the COSY and NOESY spectral analysis of 8b (see the Supporting Information). Aldehyde 7b was also converted to the chiral cyclohexane carboxylic acid 9b using Pinnick oxidation (95%). L-Proline is known for its coordination with the electrophile through hydrogen bonding,14 and the catalyst 3d is known for the reversal of facial selectivity15 (as compared to L-proline) using steric bulk. Surprisingly, both L-proline and the bulky catalyst 3d produced the same enantiomer of the product 5c (Table 1, entries 1 and 4). Moreover, single diastereomers of 4 (trans product) were obtained from the reactions of 1 and 2 catalyzed by L-proline. Hence, an achiral catalyst, pyrrolidine, was used in the reaction of 1a and 2a under the optimized reaction conditions

ingly, catalyst 3a reacts with aldehyde 1 to form an enamine intermediate A, and another molecule of 3a reacts with unsaturated aldehyde 2 to generate an iminium intermediate B. An inverse-electron-demand Diels−Alder reaction of intermediates A and B through a possible transition state TS1 gives an endo-adduct C, which further enolizes to form an enamine intermediate D. Upon elimination of catalyst 3a, enamine intermediate D generates an iminium intermediate E, which further hydrolyses to give product 4 along with the regeneration of catalyst 3a. To demonstrate the scalability of this methodology with the readily available catalyst L-proline and starting materials, we performed a gram-scale reaction of 2a (2 g) with 1a (1.5 4113


Letter

Organic Letters

alcohol 12 were in good agreement with that reported9a in the literature. In conclusion, we have developed the first catalytic method for the asymmetric synthesis of 3,4-disubstituted cyclohexadiene carbaldehydes catalyzed by L-proline. Several arylacetaldehydes 1 and α,β,γ,δ-unsaturated aldehydes 2 were successfully tested under the optimized reaction conditions to obtain the products with good yields and high stereoselectivities. We have also showcased the scope of this methodology for the asymmetric synthesis 3,4-disubstituted cyclohexane carbaldehydes and their derivatives. With the reaction results and the observed stereochemistry of the product through single-crystal X-ray analysis, a possible mechanism involving an inverse-electron-demand Diels− Alder reaction is proposed. The practicality of this methodology is demonstrated by the gram-scale synthesis of the product 4a. Using this methodology, a formal total synthesis of cyclobakuchiol A, an antipyretic and anti-inflammatory agent, and cyclobakuchiol C have been successfully accomplished. Asymmetric synthesis of cyclobakuchiol B9a and the other potent psychotropic cannabinoids10 using this scalable mild reaction as a key step is currently underway in our laboratory.

equiv) catalyzed by L-proline to produce 4a (3 g) in 73% isolated yield with 90% ee (Scheme 7). Scheme 7. Gram-Scale Synthesis of Product 4a

After the successful development of the scalable catalytic method, its application toward the formal total synthesis of the natural products cyclobakuchiol A, an antipyretic and antiinflammatory agent and cyclobakuchiol C, was envisaged (Scheme 8). Accordingly, 4o was subjected to hydrogenation Scheme 8. Formal Total Synthesis of Cyclobakuchiols A and C

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01667. Complete experimental procedures and characterization of new products, NMR spectra, and HPLC chromatograms (PDF) Accession Codes

CCDC 1835614 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chandrakumar Appayee: 0000-0003-1165-4918 Notes

The authors declare no competing financial interest.

reaction to secure the corresponding 3,4-disubstituted cyclohexane carbaldehyde in a 1.8:1 diastereomeric ratio. The diastereomeric mixture of aldehydes was proceeded further for the enolization (the removal of a chiral center at the α-carbon) followed by methylation (creating a chiral center at the αcarbon in a 98:2 diastereomeric ratio) to obtain α-methylated aldehyde, which reacted further with Wittig reagent to form 10 in 49% yield (for three steps) and 98:2 diastereomeric ratio. Direct Jones oxidation of the TBS ether 10 to the carboxylic acid followed by treatment with TMSCHN2 resulted in the ester 11 in 64% isolated yield (for two steps). MeLi addition to the ester 11 conveniently produced alcohol 12, which had previously been used as a key intermediate by Kobayashi in the total synthesis of cyclobakuchiol A in two steps11a and cyclobakuchiol C in one step.9a The spectroscopic data of

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ACKNOWLEDGMENTS The authors are grateful to the SERB, India, for Extra Mural Research funding (EMR/2014/000207) and IIT Gandhinagar for financial support. We thank IISER Bhopal for the singlecrystal X-ray facility and Prof. Sanjay Mandal, IISER Bhopal, for the useful discussion.

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Catalytic Asymmetric Synthesis of 3, 4-Disubstituted Cyclohexadiene

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