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. Author manuscript; available in PMC: 2009 Apr 28.
Published in final edited form as: Tetrahedron Lett. 2007 Nov 19;48(47):8270–8273. doi: 10.1016/j.tetlet.2007.09.129

Asymmetric Synthesis of (+)-Iso-6-Cassine via Stereoselective Intramolecular Amidomercuration

Satwinder Singh 1, Om V Singh 1, Hyunsoo Han 1,*
PMCID: PMC2674249  NIHMSID: NIHMS33747  PMID: 19404485

Abstract

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The first asymmetric synthesis of (+)-iso-6-cassine is described. Lipase-catalyzed resolution, enantioselective Overman rearrangement, and diastereoselective intramolecular amidomercuration were used for the installation of the three stereocenters in (+)-iso-6-cassine, and cross-metathesis was employed for the attachment of the side-chain.

Keywords: intramolecular amidomercuration; 2,6-dialkylpiperidines; 2,6-disubstituted 3-piperidinols; double stereodifferentiation; (+)-iso-6-cassine

Substituted piperidine ring systems constitute the core structures of many chemically and biologically important compounds,1 and thus have been a focus of many synthetic studies.2 Particularly, electrophile-induced stereoselective heterocyclization reactions have provided a convenient tool for the construction of such ring systems from the corresponding linear precursors.3 In this context, we recently reported that Hg(II)-mediated tandem Overman rearrangement and intramolecular amidomercuration reactions could be a very efficient method for the stereoselective formation of cis- and trans- 2,6-dialkyl piperidine ring systems.4 The highlight of the report is dominant trans stereoselection by N-trichloroacetyl (TCA) protection group in the Hg(II)-mediated intramolecular amidomercuration reactions of 5-alkenyl amides (H at the C4 in eq 1).

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A literature survey revealed that allylic alkoxy/hydroxy groups could also exhibit stereodirecting effects in the Hg(II)-mediated intramolecular amidomercuration reactions.5 These prompted us to investigate “matching” and “mismatching” effects (double stereodifferentiation) by allylic p-methoxybenzyloxy (PMBO) group and N-trichloroacetyl group in the Hg(II)-mediated intramolecular amidomercuration reactions of 4-alkoxy-5-alkenyl amides I (PMBO at the C4 in eq 1).6 Furthermore, the amidomercuration products of I contain 2,6-disubstituted 3-piperidinol structures II, which have been found in many bioactive alkaloids such as julifloridine,7 cassine,8 Bao Gong Teng A,9 juliprosine,10 clavepictines,11 and lepadines12 (Figure 1). Therefore, the development of the highly diastereoselective amidomercuration reactions of I would be of particular use for the stereoselective/asymmetric synthesis of such alkaloids.13

Figure 1.

Figure 1

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Various 2,6-disubstituted 3-piperidinol alkaloids

The requisite optically pure 4-PMBO-5-alkenyl amides I for double stereodifferentiation studies could be accessed from the optically pure allylic alcohols 3 and 4. As shown in Scheme 1, 3 and 4 were obtained via the lipase-catalyzed kinetic resolution of the readily available racemic allylic alcohol 114 with vinyl acetate as an acyl donor in THF.15 At 46% conversion, the ee’s of the acetate 2 and the remaining alcohol 3 were 97% and 83%, respectively. The optical purity of 3 was further improved to 99% (at 12% conversion) by subjecting 3 to the second round of the resolution. The transesterification reaction of 2 with MeOH in the presence of K2CO3 provided the optically pure allylic alcohol 4.

Scheme 1.

Scheme 1

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Synthesis of optically pure allylic alcohols.

Scheme 2 depicts how the optically pure allylic alcohols 3 and 4 were converted to the optically pure I (= the compounds 9 and 10). The hydroxy group of 3 was protected by PMBCl and KH in DMF to give the PMB ether 5. Acidic hydrolysis of 5 followed by the modified Horner-Wadsworth-Emmons olefination of the resulting aldehyde generated the α,β-unsaturated ester 6.16 DIBAL reduction of 6 furnished the allylic alcohol 7, which upon treatment with CCl3CN and DBU in CH2Cl2 at 4 °C transformed into the trichloroacetimidate 8.17 Enantioselective Overman rearrangement reaction of the imidate 8 by a chiral cobalt oxazoline palladacycle III [(S)-(+)-COP-Cl] in CH2Cl2 gave rise to the N-trichloroacetyl derivative 9 of the optically pure I.18 The N-trichloroacetyl derivative 10 of the optically pure I, where the stereochemistry of the PMBO group at C4 is opposite to that in 9, was obtained by applying Scheme 2 to the compound 4.

Scheme 2.

Scheme 2

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Synthesis of substrates for the amidomercuration.

Double stereodifferentiation studies were conducted with 9 and 10, and the results are given in Scheme 3. Compound 9 represented a matched case, since the 2,6-trans-directing effect of the N-trichloroacetyl group and the 2,3-cis-directing effect of the PMBO group were expected to reinforce each other to give the diastereomer 11 in a high diastereoselectivity.4,5 Indeed, the amidomercuration reaction of 9 with Hg(TFAO)2 in the presence of K2CO3 (to prevent the deprotection of the PMB group as well as the establishment of the equilibrating amidomercuration conditions by trifluoroacetic acid generated during the amidomercuration reaction) in nitromethane produced the 2,6-trans diastereomer 11 in >20:1 diastereoselectivity, and the trichloroacetyl group was deprotected under the conditions. When 9 was subjected to K2CO3 in nitromethane, the trichloroacetyl group was not deprotected even after a prolonged reaction time. Furthermore, the amidomercuration product of 9 (the compound 12) was independently prepared by treating 11 with trichloroacetyl chloride and Et3N in CH2Cl2. Upon exposure to the amidomercuration conditions, 12 was converted to 11 in almost quantitative reaction yield. These results indicated that the amidomercuration reaction took place on 9, not on the amine resulting from the trichloroacetyl deprotection of 9, and the deprotection of the trichloroacetyl group occurred after the amidomercuration to give 11.

Scheme 3.

Scheme 3

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Double stereodifferentiation in the amidomercuration.

Surprisingly, the amidomercuration reaction of the mismatched diastereomer 10 also proceeded with >20:1 diastereoselectivity in favor of the 2,6-trans diastereomer 14, despite the expectation that the N-trichloroacetyl group and the allylic PMBO group should oppose each other. These results indicate that the stereochemical outcome of the amidomercuration reactions is completely governed by the N-trichloroacetyl group, and the allylic PMBO group has little effect. In both cases, diastereoselectivities of the amidomercuration reactions were determined by measuring the relative integration of the diastereomeric methyl groups at C-2 after the reductive demercuration of the mercurial compounds 11 and 14 followed by the Cbz protection of the resulting amines to 13 and 15, respectively.

For the confirmation of the stereochemistry of 13 and a synthetic utility of the developed reactions, compound 13 was elaborated to (+)-iso-6-cassine (Scheme 4). Cross metathesis reaction of the olefin 13 with dodec-11-en-2-one using the 2nd generation Grubbs’ catalyst19 in refluxing CH2Cl2 afforded 16 as a mixture of E and Z isomers. Deprotection of the PMB group by CAN20 followed by hydrogenation gave rise to (+)-iso-6-cassine (17), 1H and 13C NMR spectra of which matched those in the literature.21

Scheme 4.

Scheme 4

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Asymmetric synthesis of (+)-iso-6-cassine

In summary, it has been shown that stereoselection in the Hg(II)-mediated intramolecular amidomercuration reactions of 5-alkenyl amides with a pedant allylic PMBO group is completely governed by N-TCA group, and the stereochemistry of the allylic PMBO group has little effect on the cyclization stereochemistry. The developed intramolecular amidomercuration reactions were used for the first asymmetric synthesis of (+)-iso-6-cassine. The origin and generality of the dominant 2,6-trans directing effect by the N-trichloroacetyl group in the intramolecular amidomercuration reactions are currently under investigation, and the results will be reported in due course

Acknowledgments

Financial support from the National Institutes of Health (GM 08194) and The Welch Foundation (AX-1534) is gratefully acknowledged.

Footnotes

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