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. Author manuscript; available in PMC: 2017 May 25.
Published in final edited form as: Tetrahedron Lett. 2016 May 25;57(21):2233–2235. doi: 10.1016/j.tetlet.2016.04.022

A mild and efficient approach to enantioenriched α-hydroxyethyl α,β-unsaturated δ-lactams

Seo-Jung Han 1, Brian M Stoltz 1,*
PMCID: PMC4864989  NIHMSID: NIHMS781429  PMID: 27182092

Abstract

A straightforward approach toward enantioenriched α-substituted α,β-unsaturated δ-lactams is described. Although a considerable number of approches toward α,β-unsaturated δ-lactams have been reported, there are relatively few examples of enantioenriched α,δ-disubstituted α,β-unsaturated δ-lactams formation. The δ-stereocenter was formed by addition of allylmagnesium bromide to an N-tert-butylsulfinyl imine. The α,β-unsaturated δ-lactam was furnished by ring-closing metathesis. Although Baylis-Hillman chemistry failed on this cyclic compound, introduction of the hydroxyethyl group prior to ring-closing metathesis was successful. A Baylis-Hillman reaction was used to introduce the substituent at the α-position of the α,β-unsaturated lactam.

Keywords: δ-Lactams, Ring-closing metathesis, Asymmetric allylation, Baylis-Hillman reaction

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Unsaturated lactam derivatives are important building blocks for the synthesis of natural products, pharmaceutical compounds, and peptides.1 Accordingly, methods for preparing α,β-unsaturated lactams are of interest to synthetic chemists.2 In particular, δ-substituted α,β-unsaturated δ-lactams are widely encountered in biologically active molecules and thus, various methodologies have been developed for preparing enantioenriched δ-substituted α,β-unsaturated δ-lactams.3 In addition, a considerable number of approaches to afford α-substituted α,β-unsaturated δ-lactams have been reported.4 However, only few studies toward enantioenriched α,δ-disubstituted α,β-unsaturated lactams have been reported.5 In this report, we describe a mild and efficient approach toward optically active α-hydroxyethyl δ-substituted α,β-unsaturated lactams.

In the course of a synthesis project, we planned to prepare secondary alcohol 1 (Scheme 1). For the indicated research effort, we were in need of an enantiomerically enriched δ-lactam, but the configuration of the hydroxyethyl group was inconsequential. The desired alcohol 1 was expected to be formed by a Baylis-Hillman reaction of α,β-unsaturated δ-lactam 2. We envisioned that lactam 2 could be produced by ring-closing metathesis of amide 3.

Scheme 1.

Scheme 1

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Retrosynthesis of secondary alcohol 1

The synthesis commenced with the construction of amine 9, which was adapted from Ellman and Nelson protocols (Scheme 2). Protection of diol 4 with TBSCl furnished bis-silyl ether 5, which was converted to aldehyde 6 by ozonolysis. Condensation with (R)-tert-butanesulfinamide auxiliary produced tert-butylsulfinyl imine 7.6,7 1,2-addition of allylmagnesium bromide to tert-butylsulfinyl imine 7 generated adduct 8 in high diastereoselectivity. Cleavage of the silyl and tert-butanesulfinyl groups under acidic conditions afforded chiral amine 9.

Scheme 2.

Scheme 2

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Synthesis of chiral amine 9

With chiral amine 9 in hand, α,β-unsaturated lactam formation was explored (Scheme 3). Silylation of amine 9 followed by acylation generated metathesis precursor 10. We were delighted to find that ring-closing metathesis of 10 with Hoveyda-Grubbs 2nd generation catalyst smoothly produced lactam 11.3a,8,9 Protection of the nitrogen of amide 11 with MeI or Boc2O afforded the corresponding intermediates 2a and 2b. Unfortunately, attempted Baylis-Hillman reactions to furnish alcohol 1a or 1b, respectively, were unsuccessful.10,11

Scheme 3.

Scheme 3

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Synthesis of α,β-unsaturated lactams 2

Alternatively, we decided to employ the Baylis-Hillman reaction at an earlier stage (Scheme 4). Reaction of methyl acrylate (12) with acetaldehyde and subsequent hydrolysis furnished acid 13. Coupling of acid 13 and amine 14 with EDCI and HOBt proceeded smoothly to provide amide 15. To our delight, ring-closing metathesis of 15 occurred with catalyst 16, delivering the desired 2:3 mixture of two diastereomers of lactam 1c.12

Scheme 4.

Scheme 4

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Synthesis of α-substituted α,β-unsaturated lactam 1c

In summary, the preparation of a potentially versatile α-substituted α,β-unsaturated lactam is described. The chirality at the δ-position of the lactam was established by using a tert-butanesulfinamide auxiliary. The α,β-unsaturated lactam was efficiently provided by ring-closing methathesis. Ultimately, a Baylis-Hillman reaction was used to deliver the substitution at the α-position of the α,β-unsaturated lactam but had to be incorporated prior to ring-closing metathesis. We believe that this method can be applied to synthesize various α-substituted α,β-unsaturated lactams, which could be valuable precursors toward natural products and pharmaceutical compounds.

Supplementary Material

Acknowledgments

The authors wish to thank the NIH-NIGMS (R01GM080269-01), Amgen, and Caltech for financial support. S.-J.H thanks Fulbright (Foreign Student Program, No. 15111120) and the Ilju Foundation of Education & Culture (Pre-doctoral Research Fellowship) for financial support. Dr. Mona Shahgholi (Caltech) and Naseem Torian (Caltech) are acknowledged for high-resolution mass spectrometry assistance.

Footnotes

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Supplementary Material

Supplementary data associated with this article can be found, in the online version, at XXXXXXXXXXXX.

References and notes

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Supplementary Materials

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