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Synlett 2010(4): 567-570  
DOI: 10.1055/s-0029-1219346
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Asymmetric Synthesis of Piperidines and Octahydroindolizines

Stephen G. Davies*, Deri G. Hughes, Paul D. Price, Paul M. Roberts, Angela J. Russell, Andrew D. Smith, James E. Thomson, Oliver M. H. Williams
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
e-Mail: steve.davies@chem.ox.ac.uk;
Further Information

Publication History

Received 30 November 2009
Publication Date:
25 January 2010 (online)

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Abstract

The conjugate addition of a homochiral lithium amide to a ξ-hydroxy-α,β-unsaturated ester, followed by a one-pot, ring-­closure-N-debenzylation protocol has been used in the asymmetric syntheses of (S)-coniine and (R)-δ-coniceine (isolated as the corresponding hydrochloride salts) and the bicyclic core of stellettamide A.

Key words

asymmetric synthesis - lithium amides - piperidines - ­coniine - δ-coniceine

    References and Notes

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10

ξ-Hydroxy-α,β-unsaturated ester 13 was prepared in
55% yield [96:4 E/Z ratio] via the one-pot treatment of
δ-valerolactone with DIBAL-H, tert-butyl 2-(diethoxy-phosphoryl)acetate and BuLi at -78 ˚C. See ref. 9 for details.

13

For a related example, see ref. 11a.

15

Data for ( S )-Coniine Hydrochloride (34˙HCl)
Mp 208 ˚C (lit.¹6 mp 214 ˚C); [α]D ²³ +9.2 (c 0.33 in EtOH) {lit.¹6 [α]D ²³ +9.4 (c 0.3 in EtOH)}. ¹H NMR (400 MHz, CDCl3): δ = 0.94 [3 H, t, J = 7.3 Hz, C(3′)H 3], 1.36-2.04 [10 H, m, C(3)H 2, C(4)H 2, C(5)H 2, C(1′)H 2, C(2′)H 2], 2.75-2.86 [1 H, m, C(6)H A], 2.87-3.00 [1 H, m, C(6)H B], 3.40-3.53 [1 H, br m, C(2)H], 9.19 [1 H, br s, NH A], 9.49 (1 H, br s, NHB].

17

Data for ( R )-δ-Coniceine Hydrochloride (37˙HCl)
Mp 175 ˚C; [α]D ²³ -1.5 (c 1.0 in EtOH). IR (KBr): νmax = 3477 (NH) cm-¹. ¹H NMR (400 MHz, CD3OD): δ = 1.56-2.35 [10 H, m, C(1)H 2, C(2)H 2, C(6)H 2, C(7)H 2, C(8)H 2], 2.92-3.22 [3 H, m, C(3)H A, C(5)H A, C(8a)H], 3.55-3.68 [2 H, m, C(3)H B, C(5)H B]. ¹³C NMR (125 MHz, CD3OD): δ = 20.5, 23.5, 24.4, 29.2, 29.5 [C(1), C(2), C(6), C(7), C(8)], 52.8, 53.6 [C(3), C(5)], 68.0 [C(8a)]. HRMS (ESI+): m/z (%) = 126 (100) [M + H]+. HRMS (ESI+): m/z calcd for C8H16N+ [M + H]+: 126.1283; found: 126.1278.

21

Data for (1 R ,8a R )-1-(Hydroxymethyl)octahydro-indolizine (40)
[α]D ²³ -35.8 (c 0.50 in EtOH). ¹H NMR (400 MHz, CDCl3): δ = 1.13-1.37 (2 H, m), 1.40-1.69 (3 H, m), 1.74-1.87 (4 H, m), 1.90-2.13 (3 H, m), 3.05-3.40 [2 H, m, C(3)H A, C(5)H A], 3.46 [1 H, dd, J = 10.2, 2.4 Hz, C(1′)H A], 3.86 [1 H, dd, J = 10.2, 2.8 Hz, C(1′)H B], 3.95 (1 H, br s, OH). ¹³C NMR (100 MHz, CDCl3): δ = 24.1, 25.3, 25.4, 26.7 [C(2), C(6), C(7), C(8)], 41.0 [C(1)], 53.6, 53.9 [C(3), C(5)], 64.6 [C(1′)], 66.2 [C(8a)]. HRMS (ESI+): m/z (%) = 156 [M + H]+.

23

Some discrepancies exist between the reported characteri-sation data for 40 and its epimer; these will be highlighted in a forthcoming publication from this laboratory. However, our synthesis unambiguously confirms the relative and absolute configuration of 40.