LETTER
Synthesis of Both Enantiomers of Phenylglycine Using (-)-Sparteine
1107
isomer. This dramatic change in the enantioselectivity can
occur at the deprotonation step or at the carboxylation
step.
Table 2 Yields and enantiomeric excesses obtained in the prepara-
tion (S)-Moc-protected phenylglycines (S)-3 and (S)-3-d1 using (-)-
4◊s-BuLi as pre-formed chiral base.
To confirm which proton was abstracted during the depro-
tonation step, we examined the silyl rearrangement of the
compounds 1a and 1b (Scheme 3). Indeed, we have re-
ported recently the enantioselective migration of a silicon
group from nitrogen to carbon for N-silyl N-Boc benz-
ylamine.9 The experimental procedure involved the gen-
eration of the benzylic lithium intermediates at -78oC for
3h, and warming to 0oC for 2h, followed by the usual
work-up.
low enantiomeric excesses observed. We are currently in-
vestigating the stability of benzyllithium intermediates,
and optimizing the processes leading to both (R) and (S)
N-Moc protected phenylglycine. These results will be
published in due course.
R3Si
Ph
H
H
H
1) Et2O, (-)4.s-BuLi, -78°C, 3h
Moc
Moc
N
In summary, we reported a new approach to generate both
enantiomers of the N-Moc phenylglycine. We observed
that inversion of configuration was not only a solvent ef-
fect but combined effects between stereoselective carbox-
ylation and steric hindrance. This methodology will be
helpful in the future to prepare chiral synthons for the syn-
thesis of peptidomimetics incorporating unnatural amino-
acids.
N
Ph
2) 0oC, 2h
3) H3O+
H
SiR3
5a SiR3 = TMS
5b SiR3 = TBDMS
1a SiR3 = TMS
1b SiR3 = TBDMS
Scheme 3
With both 1a and 1b, we observed that the molecules re-
arrange with excellent yields (up to 80%). Most impor-
tantly, we also obtained the same [a]D sign for 5a and 5b.
These observations strongly suggest that the same abso-
lute configuration is generated in 5a and 5b and that the
same proton is abstracted by the chiral complex. There-
fore, the deprotonation step is not responsible for the in-
version of configuration observed in the process described
in Scheme 2. The inversion occurs most probably during
the carboxylation step. It is possible that the bulkier TB-
DMS protecting group forces CO2 to add by inversion in-
stead of retention as shown with related systems by
Schlosser.3
Acknowledgment
The financial support of Merck Frosst Canada, the NSERC of Ca-
nada, the Université Laval, and the Fonds FCAR du Québec is gra-
tefully acknowledged.
References and Notes
(1) a) Voyer, N.; Roby, J.; Chénard, S.; Barberis, C. Tetrahedron
Lett. 1997, 38, 6505; b) Voyer, N.; Roby, J. Tetrahedron Lett.
1995, 36, 6627.
(2) (+)-sparteine is not commercially available. For a leading
reference on the use of (-)-sparteine in enantioselective
deprotonation see: a) Beak, P.; Basu, A.; Gallagher, D. J.;
Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29,
552.; b) Hoppe, D.; Hense, T., Angew. Chem. Int. Ed. Engl.
1997, 36, 2282.
(3) Schlosser, M.; Limat, D. J. Am. Chem. Soc., 1995, 117, 12342.
(4) Carsten, A.; Hoppe, D. Tetrahedron, 1994, 50, 6097. See also
Ref. 2b.
(5) Faibish, N. C.; Park, Y. S.; Lee, S.; Beak, P. J. Am. Chem.
Soc., 1997, 119, 11561. See also ref. 2a.
(6) Roby, J.; Voyer, N. Tetrahedron Lett., 1997, 38, 191.
(7) Typical procedure: At -78oC, 1.1 eq. of s-BuLi (1.24 mmol)
was added to freshly distilled (-)-sparteine (Sigma-Aldrich) in
3mL of solvent. The mixture was stirred for 15 min then
cannulated to a solution of 1a or 1b (1.13 mmol) in 1.5 mL of
solvent. The resulting mixture was stirred at -78oC for 3h
before CO2 was bubbled through (20 min). After quenching
with 2N HCl, the organic layer was separated and extracted
with 1N NaOH. The alkaline layer was acidified with 2N HCl
and extracted with ether. The organic phase was separated,
dried over MgSO4, and evaporated to give the crude products
3. Trituration with hexane yielded pure 3 as a white powder
which was characterized by 1H and 13C NMR and mass
spectrometry.
To confirm that the deprotonation step was not responsi-
ble of this inversion of stereochemistry, we generated the
racemic deuterated 1c and proceeded to the deprotona-
tion/carbonylation sequence as shown in Scheme 4. In ac-
cord with Beak,5 a decrease in the yield and ee (Table 2)
was observed indicating that the reaction proceeds
through an enantioselective deprotonation. Therefore, the
carbonylation step is responsible for the inversion of con-
figuration observed with the TBDMS substrate 1b.
Y
CO2H
Y
1. (-)4.s-BuLi, -78°C, solvent
Moc
Ph
NHMoc
N
Ph
2. CO2
TBDMS
(S)-3
3. H3O +
Y = H (S)-3
Y = D (S)-3-d1
1b Y = H
1c Y = D
Scheme 4
Moreover, differents mode of reaction of CO2 with benz-
ylic organolithiums have also been observed.10 This lack
of selectivity of CO2 probably explains, at least in part, the
(8) Enantiomeric excesses were determined by polarimetry with
authentic materials (synthesized from commercially
phenylglycine (Aldrich)), and by 1H NMR in C6D6 using a
Synlett 1999, No. 07, 1106–1108 ISSN 0936-5214 © Thieme Stuttgart · New York