SCHEME 1. Selective Red u ction of
N,N-d i-Boc-r-a m in o Diester s to Sem ia ld eh yd es
F ir st P r a ctica l P r otection of r-Am in o Acid s
a s N,N-Ben zyloxyca r ba m oyl Der iva tives
J . Nicola´s Herna´ndez and V´ıctor S. Mart´ın*
Instituto Universitario de Bio-Orga´nica “Antonio Gonza´lez”,
Universidad de La Laguna, C/ Astrof´ısico Francisco
Sa´nchez, 2, 38206 La Laguna, Tenerife, Spain
vmartin@ull.es
SCHEME 2. Com p a r a tive Resu lts in th e
P r ep a r a tion of Meth yl Di-N,N-ca r ba m oyl
Asp a r ta tes w ith Boc2O a n d Cbz2O
Received February 11, 2004
Abstr a ct: The consecutive treatment of N-Cbz amino
protected compounds with LiHMDS and CbzCl provides a
practical method for the preparation of N,N-benzyloxycar-
bamoyl (N,N-di-Cbz) derivatives in good yield. When R-ami-
no acids are used the protection occurs without racemization.
The method is compatible with a wide range of other
functional and protecting groups. The procedure is also valid
for the synthesis of mixed N,N-carbamoyl derivatives.
The benzyloxycarbonyl (Cbz) group is extensively used
in the synthesis for amino protection including R-amino
acids.1 This protecting group is very convenient since it
is easily removable by catalytic hydrogenation without
any side reactions.1 The introduction of two carbamoyl
derivatives at the nitrogen atom in R-amino diesters
strongly modifies the relative reactivity of both esters.
Thus, we have reported the selective reduction to the
corresponding semialdehyde of the ω-group in long-chain
N,N-di-Boc-R-amino diesters (Scheme 1).2 Such aldehydes
can be easily homologated by Wittig-type reactions and
further transformed into the corresponding saturated
compounds by simple hydrogenation providing a reliable
method to a broad range of unnatural R-amino acids.2a
We pondered that the use of N,N-di-Cbz derivatives
may have the same features of the corresponding N,N-
di-Boc regarding the selectivity but increasing the ad-
vantage of simultaneous cleavage and saturation of
double bonds with a simple hydrogenation. Many meth-
ods are available in the literature to protect amines as
N-Cbz derivatives,1 but N,N-di-Cbz-protected compounds
are scarcely reported probably due to the unavailability
of practical methods for such diprotection.3 In fact, most
of such derivatives are prepared by substitution reactions
by using dibenzyl imino dicarboxylate salts as the nu-
cleophile over the suitable substrate.4
Contrary to the N,N-di-Boc preparation that is simply
performed by the reaction of the corresponding N-Boc
derivative with di-tert-butyl dicarbonate under basic
conditions,5 the treatment of dimethyl N-Cbz-aspartate
(1) with dibenzyl dicarbonate6 provided a tiny amount
of the corresponding N,N-di-Cbz (2) protected R-amino
acid (Scheme 2).
We wondered that the failure in the introduction of the
protecting group could be due the inappropriate use of
DMAP as base in the reaction. We investigated an
alternative system that successfully accomplished such
conversion without affecting the absolute configuration
of the R-amino acid unit. Interestingly we found that the
treatment of 1 with sodium bis(trimethylsilylamide)
(NaHMDS), in THF, at -78 °C and benzylchloroformate
(CbzCl) provided an improvement in the preparation of
the N,N-di-Cbz derivative (Table 1, entry 1) compared
with the above-described conditions. Interestingly when
NaH was used as the base under similar reaction
conditions no reaction was observed (entry 3).7 Even more
satisfactory was the fact that the addition of HMPA
provided excellent yield of 2.8 After a series of experi-
ments we found that the optimal conditions in terms of
yield were achieved using lithium bis(trimethylsilyla-
mide) (LHMDS) as base, at -78 °C, using a 5:1 mixture
of THF and HMPA (entry 7). It should be mentioned that
under similar conditions when 2 equiv of base and
alkylating agents are used the substrate undergoes
stereoselective alkylation at C-3.9 From the practical
point of view it must also be emphasized that the reaction
(1) Greene, T. W.; Wuts, P. G. M. In Protective Groups in Organic
Synthesis; Wiley: New York, 1999; pp 518-525 and references therein.
(2) (a) Padro´n, J . M.; Kokotos, G.; Mart´ın, T.; Markidis, T.; Gibbons,
W.; Mart´ın, V. S. Tetrahedron: Asymmetry 1998, 9, 3381-3394. (b)
Kokotos, G.; Padro´n, J . M.; Mart´ın, T.; Gibbons, W.; Mart´ın, V. S. J .
Org. Chem. 1998, 63, 3741-3742.
(3) (a) Wipf, P.; Kim, Y. J .Org. Chem. 1993, 58, 1649-1650. (b)
Arnone, A.; Bravo, P.; Capelli, S.; Fronza, G.; Meille, S. V.; Zanda, M.
J . Org. Chem. 1996, 61, 3375-3387.
(4) (a) Cainelli, G.; Galleti, P.; Giacomini, D. Synlett 1998, 611-
612. (b) Cainelli, G.; DaCol, M.; Galleti, P.; Giacomini, D. Synlett 1997,
923-924. (c) Chong, J . M.; Park, S. B. J . Org. Chem. 1992, 57, 2220-
2222. (d) Degerbeck, F.; Fransson, B.; Grehn, L.; Ragnarsson, U. J .
Chem. Soc., Perkin Trans. 1 1992, 245-253. (e) Takeuchi, Y.; Nabetani,
M.; Takagi, K.; Hagi, T.; Koizumi, T. J . Chem. Soc., Perkin Trans. 1
1991, 49-53.
(5) Almeida, M. L. S.; Grehn, L.; Ragnarsson, U. J . Chem. Soc.,
Perkin Trans. 1 1988, 1905-1911.
(6) Sennyey, G.; Barcelo, G.; Senet, J .-P. Tetrahedron Lett. 1986,
27, 5375-5376.
(7) Benoiton, N. L.; Akyurekli, D.; Chen, F. M. F. Int. J . Peptide
Protein Res. 1995, 45, 466-470.
(8) The experimental animal carcinogen HMPA must be manipu-
lated with special caution since it is readily absorbed through the skin.
(9) Hanessian, S.; Margarita, R.; Hall, A.; Luo, X. Tetrahedron Lett.
1998, 39, 5883-5886.
10.1021/jo049759+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/17/2004
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J . Org. Chem. 2004, 69, 3590-3592