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Synlett 2010(3): 387-390  
DOI: 10.1055/s-0029-1219200
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Enantioselective Synthesis of (+)-l-733,060 and (+)-CP-99,994: Application of an Ireland-Claisen Rearrangement/Michael Addition Domino Sequence

Narciso M. Garrido*, Mercedes García, M. Rosa Sánchez, David Díez, Julio G. Urones
Departamento de Química Orgánica, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008 Salamanca, Spain
Fax: +34(923)294574; e-Mail: nmg@usal.es;
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Publication History

Received 12 October 2009
Publication Date:
19 January 2010 (online)

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Abstract

An efficient asymmetric synthesis of (+)-l-733,060, (-)-(2S,3R)-1 and (+)-CP-99,994, starting from a Baylis-Hillman adduct, is described. The key steps include a novel domino reaction: stereoselective Ireland-Claisen rearrangement, asymmetric Michael addition, and piperidone ring formation through a one-pot reaction hydrogenolysis/lactamization and a stereoselective inversion of a hydroxy group.

Key words

domino reactions - chiral piperidines - asymmetric synthesis - chiral auxiliaries - δ-amino acids

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11

When the reaction was run for 12 h, the ratio of 4 to 5 was 1:5.

14

To our knowledge, this is the first anionic allylic acetate rearrangement. Nevertheless, Prof. Matthias C. McIntosh et al. (personal communication) have observed a product that could be derived from such a rearrangement in a bis-allylic ester system.

15

A diastereomeric excess of 89% was measured by ¹H NMR spectroscopic analysis of the crude product and >95% after crystallization. With a t-Bu ester of 4 we achieved >95% de in the crude material (ref. 9). An ee of >95% is consistent with the high optical purity of the lithium amide used.

19

Physical Data of (-)-(2S,3R)-1: [α]D ²6 -36.0 (c 0.85, CHCl3). IR (film): 2929, 2857, 1373, 1346, 1278, 1174, 1133, 887, 843, 756, 700 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.46 (dq, J = 12.6, 4.0 Hz, 1 H, H-4), 1.67-1.89 (m, 1 H, H-5), 1.83 (d, J = 13.1 Hz, 1 H, H-5), 2.26-2.35 (m, 1 H, H-4), 2.72 (td, J = 11.8, 1.8 Hz, 1 H, H-6), 3.09 (d, J = 11.4 Hz, 1 H, H-6), 3.40 (dt, J = 9.8, 4.1 Hz, 1 H, H-3), 3.52 (d, J = 9.0 Hz, 1 H, H-2), 4.06 (d, J = 12.3 Hz, 1 H, OCH AH), 4.44 (d, J = 12.3 Hz, 1 H, OCHH B), 7.26-7.45 (m, 7 H, ArH), 7.68 (s, 1 H, ArHF para ). ¹³C NMR (100 MHz, CDCl3): δ = 24.9 (CH2, C-5), 31.3 (CH2, C-4), 46.6 (CH2, C-6), 67.6 (CH, C-2), 70.0 (CH2, OCH2), 81.3 (CH, C-3), 121.1 (CH, ArF para ), 121.9 (C, CCF3), 123.2 (C, q, J = 271.0 Hz, CCF3), 124.6 (C, CCF3), 127.2 (2 × CH, ArF ortho ), 127.9 (3 × CH, Ph ortho + para ), 128.3 (2 × CH, Ph meta ), 131.3 (C, q, J = 33.0 Hz, CCF3), 141.1 (C, C ipsoF ), 141.6 (C, C ipso ). HRMS (ESI): m/z [M + H]+ calcd for C20H20ONF6: 404.1449; found: 404.1421.

25

All compounds were fully characterized by a range of methods including high-resolution mass spectrometry; the physical and spectroscopic data of reported compounds were in full agreement with those reported in the literature.