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

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.

azaspirocycle - pinnaic acid - ring-closing metathesis

References

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<A NAME="RD19704ST-9">9</A>

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.

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<A NAME="RD19704ST-12">12</A>

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.

<A NAME="RD19704ST-13">13</A>

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.

<A NAME="RD19704ST-14">14</A>

Data for ketone 16: [α]_D ²⁸ -6.2 (c 1.0 in CHCl₃). IR (CDCl₃): ν_max = 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.

<A NAME="RD19704ST-15">15</A>

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): ν_max = 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.

<A NAME="RD19704ST-16">16</A> Martin Castro AM. Chem. Rev.  2004,  104:  2939 

<A NAME="RD19704ST-17">17</A>

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.