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I. Coldham et al. / Tetrahedron: Asymmetry 18 (2007) 2113–2119
40–60 ꢁC). The ligands TMEDA and (ꢀ)-sparteine were
obtained from commercial suppliers and were distilled un-
der reduced pressure prior to use. Column chromatography
was performed on silica gel (230–400 mesh). Infrared
spectra were recorded on a Nicolet Magna 550 FT-IR
spectrometer or on a Perkin–Elmer Spectrum RX1/FT
O
O
O
O
1.3 equiv. sBuLi, Ligand
Et2O, –78 °C
then TMSCl
N
N
SiMe3
–
Boc
Boc
1
IR system with a DuraSampl IR-II diamond ATR. H and
13C NMR spectra were recorded on Brucker instruments
at various field strengths as indicated. Chemical shifts are
reported in parts per million (ppm) relative to solvent sig-
nals and coupling constants, J, are given in Hz (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet). Mass
spectra were run on a Micromass GCT instrument or
Micromass LCT. Low resolution mass spectra were re-
corded using a Thermoquest CE Trace GCMS2000 series
instrument fitted with a Restek RTX-5MS (Cross bond
5% diphenyl, 95% dimethyl polysiloxane 15 m column)
with helium as the carrier gas using either EI or CI mode.
Microanalysis was performed on a Carlo Erba 1110
instrument.
24
Ligand 2
0%
47%
6%
53%
25 er
11
20
21
er 60:40
er 60:40
er 47:53
Scheme 5. Deprotonation of piperidine 24.
under a kinetic resolution, in which one of the rotamers (of
one chair conformation) reacts faster than the other. This
theory would be supported if higher enantiomer ratios were
obtained by running the reaction to less than 50% yield.
Therefore the reaction using ligand 11 was repeated with
only 0.65 equiv of sec-BuLi. This gave product 23 in 24%
yield with a slightly increased enantiomer ratio (er 63:37).
Although this increase in enantioselectivity is not large, it
is significant and supports the likelihood that there is no
rotation of the N-Boc group at ꢀ78 ꢁC. The enantiomer
ratio (er 87:13) for product 23 using ligand 21, in which
48% yield is obtained, may therefore be about optimal.
This represents the best result reported for the asymmetric
deprotonation of a piperidine.
3.2. General procedure for the lithiation
To the chiral ligand (0.70 mmol) in Et2O (2 mL) was added
sec-BuLi (0.50 mL, 0.70 mmol, 1.4 M) (or 0.97 mL,
1.35 mmol for amino-alcohol ligands 10 and 18) at
ꢀ78 ꢁC. After 15 min, N-Boc-piperidine (100 mg,
0.54 mmol) was added dropwise. After 6 h, Me3SiCl
(146 mg, 1.35 mmol) or PhMe2SiCl (138 mg, 0.81 mmol)
was added and the mixture was allowed to warm to room
temperature over 16 h. MeOH (1 mL) was added, the sol-
vents removed under reduced pressure and the residue
purified by column chromatography on silica, eluting with
petrol–EtOAc (97:3), to give either product 3 or 7 (yields
given in Table 1), as an oil.
Finally, we studied substrate 24, bearing an acetal at the 4-
position of the piperidine ring (Scheme 5). This substrate
seems to be less suited to this chemistry and gives similar
or lower yields in comparison to that using N-Boc-piper-
idine, although ligand 21 was higher yielding than expected.
However in all cases, product 25 was formed with low
enantioselectivity (absolute configuration not determined).
Spectroscopic data for compound 3 were identical to that
reported.5 The enantiomer ratio of product 3 was deter-
mined by chiral stationary phase GC using b-cyclo-
dextrin-permethylated 120 fused silica capillary column
30 m · 0.25 mm i.d. [20% permethylated b-cyclodextrin in
SPB-35 poly(35% diphenyl/65% dimethyl)siloxane, nitro-
gen carrier at 14 psi], retention times 27.6 min (major)
and 28.3 min (minor) (at 85 ꢁC). The absolute configura-
tion of the major enantiomer of product 3 was verified
by preparation of an authentic sample of (S)-3 according
to the literature.5
It is clear that the asymmetric deprotonation of N-Boc-pip-
eridines is more difficult than that of the homologous N-
Boc-pyrrolidines. Calculations at the B3P86/6-31+G* level
suggest that the activation energy for removal of a proton
in N-Boc-piperidine is some 2–3 kcal/mol higher than that
for the removal of a proton in the 5-membered ring ana-
logue.5 The lithiation is clearly sensitive to sterics within
the ligand and this makes it difficult to design a chiral
ligand that is efficient both in terms of promoting a high
yield and simultaneously a high enantioselectivity in the
deprotonation of this substrate. Despite this, some promis-
ing results have been obtained, particularly using ligand 21;
this ligand can provide high enantioselectivities and leads
to reasonable yields using a substrate, such as N-Boc-4-
phenylpiperidine, which is more reactive than N-Boc-
piperidine.
Data for compound 7: mmax (film)/cmꢀ1 2930 (C–H), 1680
(C@O); dH (500 MHz, DMSO-d6, 80 ꢁC) 7.60–7.55 (2H,
m, Ph), 7.41–7.35 (3H, m, Ph), 4.00–3.50 (2H, br,
NCH2), 3.09–2.70 (1H, br, NCH), 1.73–1.57 (2H, m,
CH2), 1.57–1.28 (4H, br, 2 · CH2), 1.41 (9H, s, t-Bu),
0.42 (3H, s, SiMe), 0.36 (3H, s, SiMe); dC (63 MHz,
DMSO-d6, 80 ꢁC) 153.7, 138.4, 133.2, 128.34, 127.2, 77.9,
44.9, 43.1, 27.7, 25.3, 25.1, 22.4, ꢀ2.8, ꢀ3.0. Found (ES):
MNa+, 342.1853. C18H29NO2NaSi requires 342.1865;
GC–MS m/z (ES) 342 (100%, MNa+). Found: C, 67.72;
H, 8.85; N, 4.18. C18H29NO2Si requires C, 67.66; H,
9.15; N, 4.38. The enantiomer ratio of product 7 was deter-
mined by HPLC on a Chiralcel OD column; the resolution
between the enantiomers of the compound was achieved
3. Experimental
3.1. General
Experiments were carried out under an inert atmosphere of
nitrogen. Solvents were purified using a Grubbs solvent
purification system.16 Petrol refers to light petroleum (bp