Synlett 2004(13): 2295-2298  
DOI: 10.1055/s-2004-831335
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Chiral Base Desymmetrisation-Ring-Closing Metathesis Route to Chiral Azaspirocycles: Synthesis of Core Structures Related to Pinnaic Acid and Halichlorine

Timothy Huxford, Nigel S. Simpkins*
School of Chemistry, The University of Nottingham, University Park, Nottingham NG7 2RD, UK
Fax: +44(115)9513564; e-Mail: nigel.simpkins@nottingham.ac.uk;
Further Information

Publication History

Received 18 July 2004
Publication Date:
08 September 2004 (online)

Abstract

A range of highly functionalised chiral azaspirocycles was synthesised, starting from a piperidine diester that is available in 90% ee from a chiral base desymmetrisation. The approach depends upon the use of Grignard addition reactions or a Claisen rearrangement to provide intermediates capable of undergoing ring-closing metathesis. A number of intermediates related to the core structure of pinnaic acid were synthesised by concise routes using the approach.

9

In ref.8, Clive reports only a 69% ee was possible in the preparation of 7, whereas we have observed 90-95% ee in several runs. We are presently in communication with Professor Clive in order to resolve this disparity.

12

It appears that the basic tertiary amine interferes with the organometallic chemistry; and in the radical reactions we suspected 1,6-hydrogen atom abstraction from the N-CH2Ph group.

13

Analysis of allylic alcohol 10, in the form of its 4-nitroben-zoate ester revealed the stereochemistry shown. We thank Dr A. J. Blake of this school for this result, full details of which will be published later.

14

Data for ketone 16: [α]D 28 -6.2 (c 1.0 in CHCl3). IR (CDCl3): νmax = 2930 (s), 2858 (s), 1737 (s), 1588 (m), 1453 (m), 1362 (m), 1089 (s) cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.96 (9 H, s, t-Bu), 1.26-1.30 (1 H, m), 1.50-1.54 (3 H, m), 1.67-1.78 (2 H, m), 1.97-2.06 (4 H, m), 2.14 (1 H, m, 2-H), 2.31 (1 H, m, 2-H), 2.61 (1 H, m, 7-H), 2.89 (1 H, dd, J = 9.9, 8.4 Hz, CH2OSi), 3.21 (1 H, d, J = 15.9 Hz, NCH2Ph), 3.33 (1 H, d, J = 15.9 Hz, NCH2Ph), 3.56 (1 H, dd, J = 9.9, 3.8 Hz, CH2OSi), 7.07-7.14 (3 H, m, Ar), 7.23-7.27 (2 H, m, Ar), 7.27-7.35 (4 H, m, Ar), 7.36-7.45 (6 H, m, Ar). 13C NMR (100 MHz, CDCl3): δ = 17.7 (CH2), 19.2 (C), 19.8 (CH2), 25.9 (CH2), 26.9 (CH3), 29.3 (CH2), 31.3 (CH2), 37.2 (CH2), 56.9 (CH2), 62.3 (CH), 67.6 (CH2), 71.6 (C), 126.3 (CH), 127.2 (CH), 127.5 (CH), 127.8 (CH), 129.5 (CH), 129.5 (CH), 133.7 (C), 133.9 (C), 135.5 (CH), 135.6 (CH), 142.0 (C), 220.0 (C=O). HRMS (APCI): m/z calcd for C33H42NO2Si [M + H]: 512.2985; found: 512.2999.

15

The Claisen rearrangement gave a mixture of intermediates, assigned as 19/22 in a ca. 1:4 ratio. So far we have been able to isolate only the metathesis product derived from the major component. Data for ester 24: [α]D 27 -4.2 (c 1.0 in CHCl3). IR (CDCl3): νmax = 2957 (s), 2930 (s), 2858 (s), 1726 (s), 1588 (w), 1427 (m) cm-1. 1H NMR (500 MHz, CDCl3): δ = 0.96 (9 H, s, t-BuSi), 1.17 (3 H, t, J = 7.3 Hz, Me), 1.45-1.69 (5 H, m), 1.97 (1 H, br d, J = 13.0 Hz), 2.13 (1 H, dd, J = 14.9, 10.7 Hz, CH2CO2), 2.25 (1 H, dd, J = 17.2, 2.3 Hz, 4-H), 2.54 (1 H, d, J = 17.2 Hz, 4-H), 2.58-2.63 (2 H, m, 7-H and CH2CO2), 3.05 (1 H, m, 1-H), 3.07 (1 H, dd, J = 9.9, 7.6 Hz, CH2OSi), 3.30 (1 H, d, J = 17.4 Hz, NCH2Ph), 3.55 (1 H, dd, J = 9.9, 3.8 Hz, CH2OSi), 3.85 (1 H, d, J = 17.4 Hz, NCH2Ph), 4.05 (2 H, m, OCH2Me), 5.56 (1 H, br dd, J = 6.1, 1.9 Hz, 2-H), 5.71 (1 H, br dd, J = 6.1, 2.3 Hz, 3-H), 7.10 (1 H, m, Ar), 7.14-7.19 (4 H, m, Ar), 7.28-7.31 (4 H, m, Ar), 7.36-7.40 (2 H, m, Ar), 7.42-7.45 (4 H, m, Ar). 13C NMR (125 MHz, CDCl3): δ = 14.2 (CH3), 19.2 (C), 20.2 (CH2), 27.0 (CH3), 29.9 (CH2), 33.1 (CH2), 35.7 (CH2), 37.6 (CH2), 49.8 (CH), 53.9 (CH2), 60.3 (CH2), 63.6 (CH), 68.1 (CH2), 68.7 (C), 125.9 (CH), 126.8 (CH), 127.6 (CH), 127.9 (CH), 129.5 (CH), 132.8 (CH), 133.8 (C), 133.9 (C), 135.5 (CH), 135.6 (CH), 143.2 (C), 173.4 (C=O). HRMS (APCI): m/z calcd for C37H48NO3Si [M + H]: 582.3403; found: 582.3398.

17

This assignment is based on gradient NOE enhancements seen between the methine at C-1 of the cyclopentene (C*) and the methylene of the N-Bn group. By contrast no such enhancement to the methylene of the CH2CO2Et substituent was seen.