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Notes and references
1 S. Okuda, H. Kataoka and K. Tsuda, Chem. Pharm. Bull., 1965, 13, 491.
2 For representative syntheses of racemic (ꢁ)-lupinine 1, see: (a) T. Iwashita,
T. Kusumi and H. Kakisawa, J. Org. Chem., 1982, 47, 230; (b) P. A. Grieco
´´
and D. T. Parker, J. Org. Chem., 1988, 53, 3325; (c) J. P. Celerier,
M. Haddad, C. Saliou and G. Lhommet, Tetrahedron, 1989, 45, 6161;
(d) K. Paulvannan, J. B. Schwarz and J. R. Stille, Tetrahedron Lett., 1993,
34, 215; (e) M. J. Wanner and G. J. Koomen, J. Org. Chem., 1996, 61, 5581.
3 For representative syntheses of enantiopure (+)-lupinine 1 and (ꢀ)-lupinine
´´
1, see: (a) S. Ledoux, E. Marchalant, J. P. Celerier and G. Lhommet, Tetra-
hedron Lett., 2001, 42, 5397; (b) P. Mangeney, L. Hamon, S. Raussou, N.
Urbain and A. Alexakis, Tetrahedron, 1998, 54, 10349; (c) C. Morley, D. W.
Knight and A. C. Share, J. Chem. Soc., Perkin Trans. 1, 1994, 2903; (d) D. H.
Hua, S. W. Miao, A. A. Bravo and D. J. Takemoto, Synthesis, 1991, 970.
´
4 (a) A. M. Lourenço, P. Maximo, L. M. Ferreira and M. M. A. Pereira,
Stud. Nat. Prod. Chem., 2002, 27, 233; (b) J. P. Michael, Nat. Prod.
Rep., 2005, 22, 603; (c) J. P. Michael, Nat. Prod. Rep., 2007, 24, 191;
(d) J. P. Michael, Nat. Prod. Rep., 2008, 25, 139.
5 K. Saito, S. Tsai, S. Ohmiya, H. Kubo, H. Otomasu and I. Murakoshi,
Chem. Pharm. Bull., 1986, 34, 3982.
Scheme 2 [PMP = p-methoxyphenyl].
6 S. Takano and K. Shishido, Chem. Pharm. Bull., 1984, 32, 3892.
7 (a) S. G. Davies, R. L. Nicholson, P. D. Price, P. M. Roberts, A. J. Russell,
E. D. Savory, A. D. Smith and J. E. Thomson, Tetrahedron: Asymmetry,
2009, 20, 758; (b) S. G. Davies, J. A. Lee, P. M. Roberts, J. E. Thomson and
C. J. West, Tetrahedron Lett., 2011, 52, 6477; (c) S. G. Davies, J. A. Lee,
P. M. Roberts, J. E. Thomson and C. J. West, Tetrahedron, 2012, 68, 4302;
(d) S. G. Davies, A. L. A. Figuccia, A. M. Fletcher, P. M. Roberts and
J. E. Thomson, Tetrahedron, 2014, 70, 3601.
8 (a) S. G. Davies, A. L. A. Figuccia, A. M. Fletcher, P. M. Roberts and J. E.
Thomson, Org. Lett., 2013, 15, 2042. See also: (b) S. G. Davies, D. G. Hughes,
P. D. Price, P. M. Roberts, A. J. Russell, A. D. Smith, J. E. Thomson and
O. M. H. Williams, Synlett, 2010, 567; (c) S. G. Davies, A. M. Fletcher, D. G.
Hughes, J. A. Lee, P. D. Price, P. M. Roberts, A. J. Russell, A. D. Smith,
J. E. Thomson and O. M. H. Williams, Tetrahedron, 2011, 67, 9975.
9 (a) E. A. Brock, S. G. Davies, J. A. Lee, P. M. Roberts and J. E. Thomson,
Org. Lett., 2011, 13, 1594; (b) E. A. Brock, S. G. Davies, J. A. Lee,
P. M. Roberts and J. E. Thomson, Org. Biomol. Chem., 2013, 11, 3187.
10 E. A. Brock, S. G. Davies, J. A. Lee, P. M. Roberts and J. E. Thomson,
Org. Lett., 2012, 14, 4278.
11 For reviews of this methodology, see: (a) S. G. Davies, A. D. Smith and P. D.
Price, Tetrahedron: Asymmetry, 2005, 16, 2833; (b)S.G.Davies,A.M.Fletcher,
P. M. Roberts and J. E Thomson, Tetrahedron: Asymmetry, 2012, 23, 1111.
12 The deprotection and cyclisation of o,o0-dichloro substituted
imino-aldol adducts, via a similar approach, has previously been
reported; see: A. C. Cutter, I. R. Miller, J. F. Keily, R. K. Bellingham,
M. E. Light and R. C. D. Brown, Org. Lett., 2011, 13, 3988.
13 M. Baenzinger, L. Gobbi, B. P. Riss, F. Schaefer and A. Vaupel,
Tetrahedron: Asymmetry, 2000, 11, 2231.
14 D. Enders and J. Wiedemann, Liebigs Ann., 1997, 699.
15 J. F. Costello, S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry,
1994, 5, 1999.
16 (a) S. G. Davies and I. A. S. Walters, J. Chem. Soc., Perkin Trans. 1, 1994, 1129;
(b) S. G. Davies, E. M. Foster, C. R. McIntosh, P. M. Roberts, T. E. Rosser,
A. D. Smith and J. E. Thomson, Tetrahedron: Asymmetry, 2011, 22, 1035.
17 (a) J. R. Hermet, M. J. McGrath, P. O’Brien, D. W. Porter and J. Gilday,
Chem. Commun., 2004, 1830; (b) C. Morley, D. W. Knight and A. C. Share,
Scheme 3 [PMP = p-methoxyphenyl].
27 which was immediately treated with LiAlH4 to give (ꢀ)-lupinine 1
in 50% yield (from 25) and 499 : 1 dr (Scheme 3). The spectroscopic
data,18 and specific rotation, for our samples of (ꢀ)-lupinine 1 were
in excellent agreement with literature values12,19 [a]D20 ꢀ 12.0 (c 0.4 in
EtOH); lit.12 for ent-1 [a]3D0 + 12.7 (c 0.35 in EtOH), thereby confirming
the assigned configurations within intermediates 24–27.
In conclusion, a concise and efficient asymmetric synthesis
of (ꢀ)-lupinine has been developed. The key steps in this
synthesis involved the preparation of an enantiopure b-amino
ester, upon conjugate addition of a lithium amide reagent to a
z-substituted a,b-unsaturated ester, followed by ring-closure.
Concomitant N-debenzylation, via an E1-type deprotection
step, was also observed during the cyclisation which gave the
corresponding piperidine in good yield. Subsequent alkylation
of this enantiopure piperidine scaffold, followed by a second
ring-closure/concomitant N-debenzylation step formed the
quinolizidine motif. Finally, reduction with LiAlH4 then gave
(ꢀ)-lupinine in 8 steps from commercially available starting
materials. The application of this methodology in the synthesis
of other azabicyclic ring systems is currently under investigation
within our laboratories.
´
J. Chem. Soc., Perkin Trans. 1, 1994, 2903; (c) I. M. G. Monterrey, R. Gonzalez-
˜
´
Muniz, R. Herranz and M. T. Garcia-Lopez, Tetrahedron, 1995, 51, 2729.
18 Spectroscopic data for (ꢀ)-lupinine 1: nmax (ATR) 3323 (O–H), 2933, 2857,
2807, 2763 (C–H); dH (400 MHz, C6D6) 0.94–1.06 (1H, m, C(8)HA), 1.15–1.25
(2H, m, C(1)H, C(9)HA), 1.25–1.44 (4H, m, C(2)HA, C(3)HA, C(7)H2), 1.49–
1.58 (2H, m, C(6)HA, C(8)HB), 1.63–1.80 (4H, m, C(2)HB, C(4)HA, C(9)HB,
C(9a)H), 2.23–2.37 (1H, m, C(3)HB), 2.44–2.56 (2H, m, C(4)HB, C(6)HB), 3.75
(1H, app d, J 10.7, CHAHBOH), 4.18 (1H, dd, J 10.7, 4.8, CHAHBOH); dH
(400 MHz, CDCl3) 1.21–1.34 (1H, m, CH2), 1.49–1.64 (6H, m, C(1)H, CH2),
1.71–1.91 (4H, m, CH2), 1.98–2.08 (1H, m, CH2), 2.10–2.23 (2H, m, C(9a)H,
CH2), 2.79–2.88 (2H, m, C(4)HA, C(6)HA), 3.70 (1H, d, J 10.8, CHAHBOH),
4.17 (1H, ddd, J 10.8, 4.6, 1.2, CHAHBOH); dC (100 MHz, C6D6) 23.3 (C(3)),
25.0 (C(8)), 25.9 (C(7)), 29.9 (C(9)), 31.6 (C(2)), 38.9 (C(1)), 57.3 (C(6)), 57.4
(C(4)), 65.2 (C(9a)), 65.7 (CH2OH); m/z (ESI+) 170 ([M+H]+, 100%); HRMS
(ESI+) C10H20NO+ ([M+H]+) requires 170.1539; found 170.1541.
19 D. S. Rycroft, D. J. Robins and I. H. Sadler, Magn. Reson. Chem., 1992,
30, S15.
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