enantioselectivity with a broader range of substrates than
the Cinchona-based catalysts, including substrates such
as 1b.15,16 However, these catalysts required multistep
sequences, which is a disadvantage with respect to the
Cinchona-based catalysts that can be obtained in 1À2 steps
from low-cost, easy to access commercially available start-
ing materials. Therefore we sought a substrate that would
combine the high levels of enantioselectivity observed with
the Cinchona-based catalysts along with an easy and mild
route to deprotection. Despite major advancements in this
field, we recognized that acid-labile protecting groups
present on the side chains are not easily carried through
a sequence from asymmetric alkylation products 2 to
provide Fmoc protected derivatives, which is unfortunate
because acid-labile protecting groups are routinely used in
Fmoc solid-phase synthesis. To address this issue, we
report a new glycine benzophenone imine substrate for
the asymmetric alkylation reaction that incorporates a
cumyl ester 1c in place of the most common protecting
group, tert-butyl ester 1a. Like 1a, 1c affords high enan-
tioselectivities in the asymmetric alkylation reaction. How-
ever 1cholds the advantage over 1athat both the N- and C-
terminal protecting groups can be cleaved simultaneously
under mild conditions by hydrogenolysis while maintain-
ing acid-labile, side chain protecting groups.
the two steps. Using a method from the literature,18
alkylation of diphenyl ketimine19 with 6 in MeCN at 60 °C
gave the alkylation substrate 1c in 85% yield, making
1c available in three steps and 77% overall yield from
2-phenyl-2-propanol.
Scheme 1. Synthesis of Cumyl Ester Protected Glycine Benzo-
phenone Imine
With the glycine-derived substrate 1c in hand, optimal
conditions for the asymmetric alkylation reaction were
developed using BnBr as the electrophile (Table 1). Alky-
lation of 1c with CsOH as the base and chiral phase-
transfer catalyst 3 in CH2Cl2, or a mixture of toluene and
CH2Cl2 (7:3), at low temperatures (À78 or À50 °C) furn-
ished the product 2a in good ee (87À91%), but in low to
moderate yield (48À62%, entries 1À3). Using CHCl3 in
place of CH2Cl2 raised the ee slightly to 94% when the
reaction was carried out at À50 °C (entry 4). Lowering the
temperature to À78 °C slowed the reaction considerably,
giving 2a in only 42% yield, and did not enhance enantios-
electivity (entry 5). Following these reactions over time
indicated that the starting material 1c was often consumed
before BnBr. Therefore using a slight excess of 1c with
respect to BnBr (1.4 equiv) was deemed optimal, providing
2a in higher yield (86%) and 94% ee (entry 6).
After the optimized conditions for the asymmetric alky-
lation reaction with 1c were developed, the scope of the
method was explored using different electrophiles (Table
2). First, alkylation of the benzyl ester substrate 1b7 with
5-(bromomethyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-
pyridine20 was performed (entry 1) under the optimized
conditions to provide a point of comparison for the cumyl
ester 1c, because both C-terminal protecting groups can
be removed by hydrogenation.20 The product 2b was ob-
tained in reasonable yield but only 80% ee under these
conditions. In contrast, alkylation of the cumyl ester 1c
with the same electrophile under the same conditions
furnished the product 2c in good yield (79%) and excellent
ee (94%), illustrating that optimization of the subst-
Figure 1. Asymmetric alkylation of tert-butyl and benzyl ester
glycine imine by chiral phase transfer catalysts.
Synthesis of the cumyl ester substrate 1c started from
commercially available 2-phenyl-2-propanol (5, Scheme 1).
Treatment of 5 with Cl3CCN and a catalytic amount of
NaH furnished a known trichloracetimidate17 that was
reacted with bromoacetic acid, giving 6 in 90% yield over
(15) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125,
5139–5151.
(16) Ooi, T.; Uematsu, Y.; Kameda, M.; Maruoka, K. Angew.
Chem., Int. Ed. 2002, 41, 1551–1554.
(17) Yue, C.; Thierry, J.; Potier, P. Tetrahedron Lett. 1993, 34, 323–
326.
(18) Eils, S.; Rossen, K.; Jahn, W.; Klement, I. Eur. Patent 1207151,
2002.
(19) Pickard, P. L.; Tolbert, T. L. Org. Synth. 1964, 44, 51.
(20) Jabre, N. D.; Respondek, T.; Ulku, S. A.; Korostelova, N.;
Kodanko, J. J. J. Org. Chem. 2010, 75, 650–659.
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