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

doi:10.1055/s-0029-1219346

LETTER

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;

Abstract

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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

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References

References and Notes

<A NAME="RD34409ST-1A">1a</A> Shin J. Seo Y. Cho KW. Rho J.-R. Sim CJ. J. Nat. Prod. 1997, 60: 611

<A NAME="RD34409ST-1B">1b</A> Saporito RA. Garraffo HM. Donnelly MA. Edwards AL. Longino JT. Daly JW. Proc. Natl. Acad. Sci. U.S.A. 2004, 101: 8045

<A NAME="RD34409ST-1C">1c</A> Daly JW. McNeal E. Gusovsky F. Ito F. Overman LE. J. Med. Chem. 1988, 31: 477

<A NAME="RD34409ST-1D">1d</A> Asano N. Nash RJ. Molyneux RJ. Fleet GWJ. Tetrahedron: Asymmetry 2000, 11: 1645

<A NAME="RD34409ST-1E">1e</A> Karpas A. Fleet GWJ. Dwek RA. Petursson S. Namgoong SK. Ramsden NG. Jacob GS. Rademacher TW. Proc. Natl. Acad. Sci. U.S.A. 1988, 85: 9229

<A NAME="RD34409ST-1F">1f</A> Goss PE. Baptiste J. Fernandes B. Baker M. Dennis JW. Cancer Res. 1994, 54: 1450

<A NAME="RD34409ST-2">2</A> Holmes AB. Smith AL. Williams SF. J. Org. Chem. 1991, 56: 1393

<A NAME="RD34409ST-3A">3a</A> Pilli RA. Zanotto PR. Böckelmann MA. Tetrahedron Lett. 2001, 42: 7003

<A NAME="RD34409ST-3B">3b</A> Yamazaki N. Dokoshi W. Kibayashi C. Org. Lett. 2001, 3: 193

<A NAME="RD34409ST-4">4</A> Lindsay KB. Pyne SG. J. Org. Chem. 2002, 67: 7774

<A NAME="RD34409ST-5">5</A> O’Brien P. Porter DW. Smith NM. Synlett 2000, 1336

<A NAME="RD34409ST-6">6</A> For a review, see: Davies SG. Smith AD. Price PD. Tetrahedron: Asymmetry 2005, 16: 2833

<A NAME="RD34409ST-7A">7a</A> Davies SG. Kelly RJ. Price-Mortimer AJ. Chem. Commun. 2003, 2132

<A NAME="RD34409ST-7B">7b</A> Davies SG. Burke AJ. Garner AC. McCarthy TD. Roberts PM. Smith AD. Rodriguez-Solla H. Vickers RJ. Org. Biomol. Chem. 2004, 2: 1387

<A NAME="RD34409ST-7C">7c</A> Davies SG. Haggitt JR. Ichihara O. Kelly RJ. Leech MA. Price Mortimer AJ. Roberts PM. Smith AD. Org. Biomol. Chem. 2004, 2: 2630

<A NAME="RD34409ST-7D">7d</A> Abraham E. Candela-Lena JI. Davies SG. Georgiou M. Nicholson RL. Roberts PM. Russell AJ. Sánchez-Fernández EM. Smith AD. Thomson JE. Tetrahedron: Asymmetry 2007, 18: 2510

<A NAME="RD34409ST-7E">7e</A> Abraham E. Davies SG. Millican NL. Nicholson RL. Roberts PM. Smith AD. Org. Biomol. Chem. 2008, 6: 1655

<A NAME="RD34409ST-7F">7f</A> Abraham E. Brock EA. Candela-Lena JI. Davies SG. Georgiou M. Nicholson RL. Perkins JH. Roberts PM. Russell AJ. Sánchez-Fernández EM. Scott PM. Smith AD. Thomson JE. Org. Biomol. Chem. 2008, 6: 1665

<A NAME="RD34409ST-7G">7g</A> Davies SG. Fletcher AM. Roberts PM. Smith AD. Tetrahedron 2009, 65: 10192

<A NAME="RD34409ST-8A">8a</A> Davies SG. Nicholson RL. Price PD. Roberts PM. Smith AD. Synlett 2004, 901

<A NAME="RD34409ST-8B">8b</A> Davies SG. Nicholson RL. Price PD. Roberts PM. Savory ED. Smith AD. Thomson JE. Tetrahedron: Asymmetry 2009, 20: 756

<A NAME="RD34409ST-9">9</A> Davies SG. Díez D. Dominguez SH. Garrido NM. Kruchinin D. Price PD. Smith AD. Org. Biomol. Chem. 2005, 3: 1284

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.

<A NAME="RD34409ST-11A">11a</A> Enders D. Wiedemann J. Liebigs Ann. 1997, 4: 699

<A NAME="RD34409ST-11B">11b</A> Molander GA. Harris CR. J. Org. Chem. 1997, 62: 7418

<A NAME="RD34409ST-11C">11c</A> Li N. Piccirilli JA. J. Org. Chem. 2004, 69: 4751

<A NAME="RD34409ST-12">12</A> Holmes AB. Smith AL. Williams SF. J. Org. Chem. 1991, 56: 1393

For a related example, see ref. 11a.

<A NAME="RD34409ST-14">14</A> β-Amino aldehydes are known to be unstable with respect to retro-Michael reactions; see: Carruthers W. Moses RC.
J. Chem. Soc., Perkin Trans. 1 1988, 2251

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, NH_B].

<A NAME="RD34409ST-16">16</A> Munchof MJ. Meyers AI. J. Org. Chem. 1995, 60: 7084

Data for ( R )-δ-Coniceine Hydrochloride (37˙HCl)
Mp 175 ˚C; [α]_D ^²³ -1.5 (c 1.0 in EtOH). IR (KBr): ν_max = 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.

<A NAME="RD34409ST-18">18</A> Yamazaki N. Dokoshi W. Kibayashi C. Org Lett. 2001, 3: 193

<A NAME="RD34409ST-19">19</A> Within this area, Monterrey et al. have shown that alkylation of N-Cbz protected piperidin-2-yl-acetates with ethyl bromo-acetate can lead to successful ring closure by removal of the N-Cbz protecting group in a tandem hydrogenolysis-hydrogenation step to give the corresponding hexahydro-indolizin-3-one; see: Monterrey IMG. González-Muñiz R. Herranz R. Garcia-López MT. Tetrahedron 1995, 51: 2729

The anti-configuration of the alkylation was assigned on the basis of the established preferential anti-alkylations of lithium β-amino enolates, see:

<A NAME="RD34409ST-20A">20a</A> Davies SG. Walters IAS. J. Chem. Soc., Perkin Trans. 1 1994, 1129

<A NAME="RD34409ST-20B">20b</A> Ledoux S. Célérier J.-P. Lhommet G. Tetrahedron Lett. 1999, 40: 9019

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]⁺.

Both diastereomers of 1-(hydroxymethyl)octahydro-indolizidine (40) have previously been reported, see:

<A NAME="RD34409ST-22A">22a</A> Nagao Y. Dai W. Ochiai M. Tsukagoshi S. Fujitalc E. J. Org. Chem. 1990, 55: 1148

<A NAME="RD34409ST-22B">22b</A> Pandey G. Lakshmaiah G. Gadre SM. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1996, 35: 91

<A NAME="RD34409ST-22C">22c</A> Bertrand S. Hoffmann N. Pete J. Eur. J. Org. Chem. 2000, 2227

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.