386.1 (100, [M + H]+), 376.1 (26), 368.1 (11), 270.1 (64), 226.1 (42)
[HRMS Found: (M + Na)+ 408.1601. C22H27NNaO3S M, requires
408.1609].
(1H, td, J 9.4 and 4.1, CH-OH), 4.94 (1H, s, CHH), 4.98 (1H, s,
=
=
CHH), 7.16–7.33 (5H, m, Ar CH); dC (75 MHz, CDCl3) 21.2
(CH3), 37.0 (N-CH-CH2-CH), 38.8 (Ph-CH2), 43.7 (N-CH2), 53.4
=
(N-CH2-CH), 54.4 (N-CH), 66.4 (CH-OH), 113.3 ( CH2), 126.4
(Ar CH), 128.7 (2 × Ar CH), 129.1 (2 × Ar CH), 139.6 (Cq),
144.4 (Cq); m/z (ES+) 232.1 (65%, [M + H]+), 214.1 (100) [HRMS
Found: (M + H)+ 232.1700. C15H22NO requires M, 232.1701].
Typical procedure for Brønsted acid-catalysed cyclisation:
(2S,4R,5S)-2-benzyl-4-hydroxy-5-isopropenyl-1-
(p-toluenesulfonyl)piperidine (7b)
Concentrated hydrochloric acid (37%, 130 lL, 1.54 mmol) was
added to a solution of aldehyde 1b (197 mg, 0.51 mmol) in CH2Cl2
(15 mL) at −78 ◦C. The solution was stirred at −78 ◦C overnight,
after which water was added and the aqueous phase was extracted
with CH2Cl2. The combined organic phases were washed with
brine, dried over MgSO4 and concentrated in vacuo to afford the
crude piperidine. Purification by flash column chromatography
(silica; eluent 1 : 2 EtOAc–hexane, Rf = 0.36) afforded piperidine
7b as a colourless thick oil (160 mg, 81%): [a]2D7 −16.1 (c 0.18
Acknowledgements
We thank the Engineering and Physical Sciences Research Council
for a studentship to C. A. M. C., the University of Birmingham
for financial support and Dr J. T. Williams for some preliminary
experiments.
References
1 J. A. Findlay in The Alkaloids, ed. A. Brossi, Academic Press, London,
1985, vol. 26, pp. 89–183; A. R. Pinder, Nat. Prod. Rep., 1986, 3, 171–
180; A. R. Pinder, Nat. Prod. Rep., 1987, 4, 527–537; A. R. Pinder, Nat.
Prod. Rep., 1989, 6, 67–78; A. R. Pinder, Nat. Prod. Rep., 1990, 7, 447–
455; A. R. Pinder, Nat. Prod. Rep., 1992, 9, 491–504; A. O. Plunkett,
Nat. Prod. Rep., 1994, 11, 581–590; D. O’Hagan, Nat. Prod. Rep., 1997,
14, 637–651; D. O’Hagan, Nat. Prod. Rep., 2000, 17, 435–446.
2 P. S. Watson, B. Jiang and B. Scott, Org. Lett., 2000, 2, 3679–3681.
3 For reviews see: S. Laschat and T. Dickner, Synthesis, 2000, 1781–
1813; P. M. Weintraub, J. S. Sabol, J. M. Kane and D. R. Borcherding,
Tetrahedron, 2003, 59, 2953–2989; M. G. P. Buffat, Tetrahedron, 2004,
60, 1701–1729.
in CHCl3); mmax (neat)/cm−1 3530 (OH), 3027 ( CH), 2923 (mas
=
=
=
=
CH2), 1644 (C C aliphatic), 1599 (C C aromatic), 1495 (C C
=
aromatic), 1453 (C C aromatic), 1340 (mas SO2), 1157 (ms SO2),
1105 (C–O); dH (300 MHz, CDCl3) 1.55–1.68 (2H, stack, N-CH-
=
CHH and OH), 1.76 (3H, s, C-CH3), 1.93 (1H, dd, J 14.3 and
2.0, N-CH-CHH), 2.23 (1H, br d, J 11.8, N-CH2-CH), 2.39 (3H, s,
Ph-CH3), 2.87 (1H, dd, J 13.0 and 6.6, Ph-CHH), 3.19 (1H, dd, J
13.0 and 9.6, Ph-CHH), 3.43 (1H, dd, J 13.6 and 12.1, N-CHH),
3.64 (1H, dd, J 13.6 and 3.9, N-CHH), 4.04 (1H, app d, J 2.0, CH-
=
4 (a) T. A. Johnson, M. D. Curtis and P. Beak, J. Am. Chem. Soc., 2001,
123, 1004–1005; A. J. Souers and J. A. Ellman, J. Org. Chem., 2000,
65, 1222–1224; C. Shu, A. Alcudia, J. Yin and L. S. Liebeskind, J. Am.
Chem. Soc., 2001, 123, 12477–12487; J. M. Harris and A. Padwa, J. Org.
Chem., 2003, 68, 4371–4381; S. J. Hedley, W. J. Moran, D. A. Price and
J. P. A. Harrity, J. Org. Chem., 2003, 68, 4286–4292; B. B. Toure and
D. G. Hall, Angew. Chem., Int. Ed., 2004, 43, 2001–2004; E. Poupon,
D. Francois, N. Kunesch and H. P. Husson, J. Org. Chem., 2004, 69,
3836–3841; J. T. Kuethe and D. L. Comins, J. Org. Chem., 2004, 69,
2863–2866; C. Y. Legault and A. B. Charette, J. Am. Chem. Soc., 2005,
127, 8966–8967; R. P. Wurz and G. C. Fu, J. Am. Chem. Soc., 2005, 127,
12234–12235; G. S. Kauffman, P. S. Watson and W. A. Nugent, J. Org.
Chem., 2006, 71, 8975–8977; G. A. Cortez, R. R. Schrock and A. H.
Hoveyda, Angew. Chem., Int. Ed., 2006, 46, 4534–4538; M. Terada, K.
Machioka and K. Sorimachi, J. Am. Chem. Soc., 2007, 129, 10336–
10337.
OH), 4.20–4.30 (1H, m, N-CH), 4.74 (1H, s, CHH), 5.05 (1H, s,
=
CHH), 7.17–7.29 (7H, m, Ar CH), 7.53 (2H, d, J 8.1, Ar CH);
=
dC (75 MHz, CDCl3) 21.6 (Ph-CH3), 22.9 ( C-CH3), 31.5 (N-CH-
CH2), 38.3 (CH2), 38.9 (CH2), 46.2 (N-CH2-CH), 53.3 (N-CH),
=
64.8 (CH-OH), 112.5 ( CH2), 126.3 (Ar CH), 127.2 (2 × Ar CH),
128.5 (2 × Ar CH), 129.7 (2 × Ar CH), 129.8 (2 × Ar CH), 138.2
(Cq), 139.4 (Cq), 143.1 (Cq), 144.2 (Cq); m/z (ES+) 408.1 (90%, [M
+ Na]+), 386.1 (26, [M + H]+), 368.1 (9), 286.0 (27), 274.0 (100)
[HRMS Found: (M + Na)+ 408.1598. C22H27NNaO3S M, requires
408.1609].
Typical detosylation procedure: (2S,4S,5S)-2-benzyl-4-hydroxy-5-
isoproprenyl piperidine (36b)
5 J. T. Williams, P. S. Bahia, B. Kariuki, N. Spencer, D. Philp and J. S.
Snaith, J. Org. Chem., 2006, 71, 2460–2471.
To a solution of piperidine 8b (99 mg, 0.26 mmol) in THF (1.5 mL)
at −78 ◦C was added a freshly prepared solution of sodium
naphthalenide (1.0 M in THF, 1.18 mL, 1.18 mmol). After 5 min
the reaction was quenched with MeOH (0.3 mL), warmed up to
room temperature, diluted with water and acidified to pH 1 with
aqueous HCl. The aqueous phase was washed with Et2O, basified
to pH 9 with aqueous NaOH (2 M) and extracted with EtOAc.
The combined organic phases were washed with brine, dried over
MgSO4 and concentrated in vacuo to afford piperidine 36b as a
white powder (52 mg, 87%): [a]2D3 −49 (c 0.98 in CHCl3); mp 119–
121 ◦C (from CH2Cl2–hexane); (Found: C, 77.80; H, 9.22; N, 6.19.
C15H21NO requires C, 77.88; H, 9.15; N, 6.05%); mmax (film)/cm−1
6 For a review see: B. B. Snider in Comprehensive Organic Synthesis,
ed. B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, vol. 2,
pp. 527–561.
7 M. Ishibashi, Y. Ohizumi, T. Sasaki, H. Nakamura, Y. Hirata and J.
Kobayashi, J. Org. Chem., 1987, 52, 450–453; J. Kobayashi, K. Naitoh,
Y. Doi, K. Deki and M. Ishibashi, J. Org. Chem., 1995, 60, 6941–
6945. For minor structural revision see: T. Kiguchi, Y. Yuumoto,
I. Ninomiya, T. Naito, K. Deki, M. Ishibashi and J. Kobayashi,
Tetrahedron Lett., 1992, 33, 7389–7390; M. Ishibashi, K. Deki and
J. Kobayashi, J. Nat. Prod., 1995, 58, 804–806.
8 A. J. Freyer, A. D. Patil, L. Killmer, N. Troupe, M. Mentzer, B. Carte,
L. Faucette and R. K. Johnson, J. Nat. Prod., 1997, 60, 986–990.
9 Y. Doi, M. Ishibashi and J. Kobayashi, Tetrahedron, 1996, 52, 4573–
4580; D. Ma and H. Sun, J. Org. Chem., 2000, 65, 6009–6016; N.
Langlois, Org. Lett., 2002, 4, 185–187; B. M. Trost and D. R. Fandrick,
Org. Lett., 2005, 7, 823–826; F. A. Davis, J. Zhang, X. Li, H. Xu and
C. DeBrosse, J. Org. Chem., 2005, 70, 5413–5419; M. Haddad, M.
Larcheveque and H. M. Tong, Tetrahedron Lett., 2005, 46, 6015–6017;
K. Tanaka, T. Maesoba and H. Sawanishi, Heterocycles, 2006, 68, 183–
192.
=
=
3306 (OH, NH), 2917 (mas CH2), 1641 (C C aliphatic), 1602 (C C
=
=
aromatic), 1493 (C C aromatic), 1455 (C C aromatic), 1090 (C–
O); dH (300 MHz, CDCl3) 1.63 (1H, ddd, J 12.9, 9.9 and 5.1,
N-CH-CHH), 1.79 (3H, s, CH3), 1.91 (1H, br s, OH and NH),
1.97 (1H, dt, J 12.9 and 3.7, N-CH-CHH), 2.07–2.15 (1H, m,
N-CH2-CH), 2.72 (1H, dd, J 13.4 and 6.4, N-CHH), 2.86–2.94
(3H, stack, N-CHH and Ph-CH2), 3.32–3.41 (1H, m, N-CH), 3.99
10 A preliminary account of this work has been published: C. A. M. Cariou
and J. S. Snaith, Org. Biomol. Chem., 2006, 4, 51–53.
11 M. McKennon, A. Meyers, K. Drauz and M. Schwarm, J. Org. Chem.,
1993, 58, 3568–3571.
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