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. Author manuscript; available in PMC: 2009 Jan 28.
Published in final edited form as: Tetrahedron Lett. 2008 Jan 28;49(5):870–872. doi: 10.1016/j.tetlet.2007.11.170

α-Amino 1,3-Dithioketal Mediated Asymmetric Synthesis of Piperidines (L-733,060) and Tetrahydrofuran Glycines

Franklin A Davis 1,*, Tokala Ramachandar 1
PMCID: PMC2344145  NIHMSID: NIHMS39208  PMID: 19180171

Abstract

Sulfinimine-derived α-amino 1,3-dithianes, α-amino carbonyl chiral building blocks, are utilized in asymmetric syntheses of (+)-(tetrahydrofuran-2-yl)glycine and the 2,3-disubstituted piperidine (+)-L-733,060.

Enantiomerically pure α-amino aldehydes and ketones, generally prepared from α-amino acids, are widely used chiral building blocks for asymmetric synthesis.1 However, α-amino carbonyl compounds are notoriously unstable and rapidly epimerize and self-condense even when suitably N-protected. Many of these problems can be avoided by using N-sulfinyl α-amino 1,3-dithianes 1, new sulfinimine-derived chiral building blocks for α-amino aldehyde and ketone synthesis (Scheme 1).2,3 These building blocks are readily prepared in high diastereomeric purity by addition of 2-lithio-1,3-dithianes to sulfinimines.4 Acid hydrolysis affords the enantiomerically pure free amine, leaving the carbonyl group protected, resulting in unique opportunities for functional group manipulation. We employed these α-amino 1,3-dithianes in highly diastereoselective asymmetric syntheses of functionalized prolines including (−)-3-hydroxy-3-methyl proline (2)2 and (−)-2,3-trans-3,4-cis-dihydroxyproline (3).3 As an extension of this methodology, we describe the concise asymmetric synthesis of the 2,3-disubstituted piperidine (2S,3S)-(+)-L-733,060 (4) and the unnatural constrained α-amino acid (+)-(2R,2'S)-(+)-2-(tetrahydrofuran-2-yl)glycine (THFG 5) from a common intermediate.

Scheme 1.

Scheme 1

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The key strategy employed in our synthesis of hydroxy prolines (−)-2 and (−)-3 was the cyclization of a 2-hydroxyethyl moiety (R') in 1 to form the pyrrolidine ring. Cyclization of a 3-hydroxypropyl group (R') in 1 would produce a piperidine ring. Addition of 2-lithium-1,3-dithiane 75 to (S)-(+)-N-(benzylidene)-p-toluenesulfinamide (6)6 gave N-sulfinyl α-amino 1,3-dithiane (SS,S)-(+)-8 in 94% de and 81% yield of the major diastereoisomer (Scheme 2). Hydrolysis of (+)-8 with 1,3-dibromo-5,5-dimethylhydantoin (9) in aqueous acetone not only hydrolyzes the thioketal group, but also oxidizes the N-sulfinyl group to the N-tosyl protecting group affording (S)-(−)-10 in 73% yield for the one pot sequence. Reduction of the amino ketone with NaBH4 gives the expected syn alcohol (1S,2S)-(+)-11 (dr = 10:1) in 87% yield of the major diastereoisomer. Selective tosylation of the primary alcohol in (+)-12 was readily accomplished with TsCl/pyridine affording (1S,2S)-(+)-13 in 87% yield.

Scheme 2.

Scheme 2

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Next treatment of amino alcohol (+)-13 with Et3N gave the expected, kinetically favored, furan (+)-14 in 83% yield (Scheme 3). Oxidation of the phenyl group in (+)-14 with RuCl3/NaIO4 gave the carboxylic acid 15, which was isolated as the methyl ester with TMSCHN2 affording (2R,2'S)-(+)-5 in 54% for the two steps.7 Conformationally constrained unnatural amino acids such as (+)-5 are in demand for the synthesis of constrained peptide surrogates, which have increased potency, stability, bioavailability, and selectivity.

Scheme 3.

Scheme 3

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To prepare a piperidine from (+)-11 required protection of the 2-hydroxy group as the OTBS ether. Treatment of (+)-16 with p-TSA at 0 °C for less than 30 min made it possible to selectively deprotect the primary OTBS, affording (+)-17 in 82% yield (Scheme 4). With TsCl/Et3N, (+)-17 gave piperidine (+)-18 in 88% yield and the hydroxy piperidine (+)-19 was obtained in 90% yield using TBAF. Etherification of the hydroxy group with NaH and 3,5-bis(trifluoromethyl)benzyl bromide gave (2S,3S)-(+)-20. Finally N-tosyl deprotection with Na/Liq. NH3 at −78 °C afforded the (2S,3S)-(+)-L-733,060 (4) in 78% yield (Scheme 4).8,9 (+)-L-733,060 (4) is a potent neurokinin substance P receptor antagonist which exhibits strong antiemetic activity.10

Scheme 4.

Scheme 4

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In summary, the utility of α-amino 1,3-dithianes as chiral building blocks for the asymmetric synthesis of heterocycles has been demonstrated by the preparation of amino furan (+)-THFG-5 and 2,3-disubstituted piperidine (+)-L-733,060 (4) from common amino diol intermediate (+)-11.12 In particular, our synthesis of (+)-4 in 11 steps under nine operations (18% overall yield) from sulfinimine (+)-6 is one of the most concise to date. 2,3-Disubstituted piperidines are structural units found in natural products and several drug candidates,11 and the structural diversity of available sulfinimine-derived α-amino 1,3-dithianes make this protocol well suited for enantiomer and analog synthesis.10

Acknowledgments

This work was supported by grants from the National Institute of General Medicinal Sciences (GM57878 and GM51982).

Footnotes

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