(S : R). This indicates that there is interconversion between the
diastereomeric complexes (either directly or via their uncom-
plexed forms) and that these complexes react at different rates,
with the minor complex reacting faster.
for Synthesis, Pergamon, Oxford, 2002; (c) Organolithiums in
Enantioselective Synthesis, ed. D. M. Hodgson, Springer-Verlag,
Heidelberg, 2003; (d) R. E. Gawley and I. Coldham, in
The Chemistry of Organolithium Compounds, ed. Z. Rappoport
and I. Marek, Wiley, Chichester, 2004, p. 997; (e) D. Hoppe and G.
Christoph, in The Chemistry of Organolithium Compounds, ed. Z.
Rappoport and I. Marek, Wiley, Chichester, 2004, p. 1055.
2 P. Beak, S. T. Kerrick, S. Wu and J. Chu, J. Am. Chem. Soc., 1994,
116, 3231.
3 (a) W. F. Bailey, P. Beak, S. T. Kerrick, S. Ma and K. B. Wiberg,
J. Am. Chem. Soc., 2002, 124, 1889; (b) M. J. McGrath, J. L. Bilke
and P. O’Brien, Chem. Commun., 2006, 2607; (c) I. Coldham, P.
O’Brien, J. J. Patel, S. Raimbault, A. J. Sanderson, D. Stead and
D. T. E. Whittaker, Tetrahedron: Asymmetry, 2007, 18, 2113.
4 (a) I. Coldham, S. Dufour, T. F. N. Haxell, S. Howard and G. P.
Vennall, Angew. Chem., Int. Ed., 2002, 41, 3887; (b) I. Coldham, J.
J. Patel and G. Sanchez-Jimenez, Chem. Commun., 2005, 3083;
(c) I. Coldham, S. Dufour, T. F. N. Haxell, J. J. Patel and G.
Sanchez-Jimenez, J. Am. Chem. Soc., 2006, 128, 10943.
5 I. Coldham, J. J. Patel, S. Raimbault and D. T. E. Whittaker,
Chem. Commun., 2007, 4534.
Hence, this chemistry provides a general method to access
enantiomerically enriched 2-substituted piperidines.14 Either
enantiomer can be prepared by choice of the diastereomer (or
enantiomer) of the chiral ligand. This chemistry therefore
provides a solution to the poor yields and/or low levels of
asymmetric induction obtained using either asymmetric de-
protonation of N-Boc-piperidine or asymmetric substitution
with different electrophiles of N-Boc-2-lithiopiperidine by
dynamic kinetic resolution.
Notes and references
z General procedure: N-Boc-piperidine 1 (0.3 g, 1.6 mmol) and
TMEDA (0.27 mL, 1.8 mmol) in Et2O (3 mL) were treated with sec-
BuLi (1.4 mL, 1.8 mmol, 1.3 M in hexanes) at ꢀ78 1C. After 3 h, the
6 P. Beak, D. R. Anderson, M. D. Curtis, J. M. Laumer, D. J. Pippel
and G. A. Weisenburger, Acc. Chem. Res., 2000, 33, 715.
7 (a) T. Mukaiyama, Tetrahedron, 1981, 37, 4111; (b) D. J. Gallagher,
S. Wu, N. A. Nikolic and P. Beak, J. Org. Chem., 1995, 60,
8148.
deprotonated ligand
7 [prepared by adding sec-BuLi (1.6 mL,
2.0 mmol, 1.3 M in hexanes) to 7 (0.42 g, 1.9 mmol) in Et2O (3 mL)
at 0 1C] was added. The mixture was warmed to ꢀ40 1C. After 90 min
the mixture was cooled to ꢀ78 1C and the electrophile TMSCl (0.6 mL,
4.8 mmol) was added. The mixture was allowed to warm slowly (over
18 h) to room temperature and MeOH (2 mL) was added. The solvent
was evaporated and the residue was purified by column chromatogra-
phy on silica, eluting with light petroleum (bp 40–60 1C)–EtOAc (98 : 2)
to give the piperidine (S)-3 (213 mg, 51%), [a]D22 + 18.5 (0.5, CHCl3),
8 R. K. Dieter, N. Deo, B. Lagu and J. W. Dieter, J. Org. Chem.,
1992, 57, 1663.
9 For racemic proton abstraction using sec-BuLi, Et2O, TMEDA,
see P. Beak and W. K. Lee, J. Org. Chem., 1993, 58, 1109.
10 Kinetic studies are ongoing to determine the barrier for enantio-
merization, but equilibration takes place at and above ꢀ40 1C in
Et2O–TMEDA.
lit.5 for (S)-3, er 95 : 5, [a]D + 36.4 (1.95, CHCl3); other data as
24
reported;3 er 79 : 21 determined by GC [b-cyclodextrin-permethylated
120 fused silica capillary column 30 m ꢃ 0.25 mm i.d., 20% permethy-
lated b-cyclodextrin in SPB-35 poly(35% diphenyl/65% dimethyl)
siloxane, nitrogen carrier at 14 psi, retention times 31.5 min (major)
and 32.4 min (minor) (at 85 1C)]. The chiral ligand 7 can be recovered
by column chromatography, eluting with CH2Cl2–MeOH (7 : 3),
followed by evaporation of the solvent, acid/base wash (acidify with
2 M HCl, wash with CH2Cl2, basify with NaOH pellets and extract
with CH2Cl2) and distillation under reduced pressure.
11 T. R. Hoye, B. M. Eklov and M. Voloshin, Org. Lett., 2004, 6,
2567.
12 (a) R. K. Dieter, G. Oba, K. R. Chandupatla, C. M. Topping, K.
Lu and R. T. Watson, J. Org. Chem., 2004, 69, 3076; (b) J. P. N.
Papillon and R. J. K. Taylor, Org. Lett., 2002, 4, 119.
13 D. Passarella, A. Barilli, F. Belinghieri, P. Fassi, S. Riva, A.
Sacchetti, A. Silvani and B. Danieli, Tetrahedron: Asymmetry,
2005, 16, 2225.
14 For alternative procedures involving organolithiums, see (a) T. J.
Wilkinson, N. W. Stehle and P. Beak, Org. Lett., 2000, 2, 155;
(b) C. Serino, N. Stehle, Y. S. Park, S. Florio and P. Beak, J. Org.
Chem., 1999, 64, 1160.
1 For reviews, see (a) A. Basu and S. Thayumanavan, Angew. Chem.,
Int. Ed., 2002, 41, 716; (b) J. Clayden, Organolithiums: Selectivity
ꢁc
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4176 | Chem. Commun., 2008, 4174–4176