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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4 For very recent formal syntheses of both (±)-halichlorine and (±)-pinnaic acid, and further references, see: Matsumura Y. Aoyagi S. Kibayashi C. Org. Lett.  2004,  6:  965 

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8 Clive has also recognised the possibility of applying our chiral base reaction to this problem, see: Yu M. Clive DLJ. Yeh VSC. Kang S. Wang J. Tetrahedron Lett.  2004,  45:  2879 

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.

10 Langer F. Schwink L. Devasagayaraj A. Chavant P.-Y. Knochel P. J. Org. Chem.  1996,  61:  8229 

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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): 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.

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): 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.

16 Martin Castro AM. Chem. Rev.  2004,  104:  2939 

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.