First Practical Protection of α-Amino Acids as N, N-Benzyloxycarbamoyl Derivatives

Article abstract of DOI:10.1021/jo049759+

The consecutive treatment of N-Cbz amino protected compounds with LiHMDS and CbzCl provides a practical method for the preparation of N,N-benzyloxycarbamoyl (N,N-di-Cbz) derivatives in good yield. When α-amino 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.

Full text of DOI:10.1021/jo049759+

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
3590
J . Org. Chem. 2004, 69, 3590-3592

TABLE 1. Syn th esis of Dim eth yl (S)-N,N-d iCbz
Asp a r ta te w ith CbzCl
TABLE 3. Syn th esis of N,N-Dica r ba m oyl Com p ou n d s
fr om N-Ca r ba m oyl Der iva tives w ith LHMDS/THF -HMP A
entry
basea
solvent
THF
THF-HMPA
THF
THF
THF-HMPA
THF
temp (°C)
yield (%)b
1
2
3
4
5
6
7
NaHMDS
NaHMDS
NaH
KHMDS
KHMDS
LHMDS
LHMDS
-78
-78
0
-78
-78
-78
-78
48
80
10
85
66
93
THF-HMPA
a
b
1.3 equiv of base was used in all cases. The reaction time
was 30 min.
TABLE 2. Com p a r a tive Use of CbzCl-LHMDS/
THF -HMP A a n d Cbz2O-DMAP /CH3CN for th e
P r ep a r a tion of N,N-d i-Cbz Com p ou n d s
a
Method A: CbzCl (1.3 equiv), LHMDS (1.25 equiv), THF-
b
HMPA, -78 °C. 0.5 h. Method B: Cbz2O (5 equiv), DMAP (0.2
equiv), CH3CN, rt.3a
SCHEME 4. Selective Clea va ge of
N,N-d i-Cbz-P r otected Am in es w ith Lith iu m
Br om id e
SCHEME 3. Evid en ce of Con figu r a tion a l
Ma in ten a n ce d u r in g th e N,N-d i-Cbz P r otection of
r-Am in o Acid s
use of substrates with free hydroxy groups (Table 3, entry
8) provides null conversion to the desired N,N-protected
derivative, probably due to competitive proton exchange.
When such hydroxy groups are protected as tetrahydro-
pyranyl or silyl ethers the protection occurs smoothly
(Table 3, entries 5 and 6). The procedure can be extended
to other carbamoyl derivatives. Thus the preparation of
mixed dimethyl N,N-BocCbz-aspartate was possible from
dimethyl N-Boc-aspartate following the present proce-
dure (Table 3, entry 7). It should be pointed out that such
protection is not possible with the standard Cbz2O/DMAP
method.10 The diprotection needs to be performed over
the N-carbamoyl compounds since free amino derivatives
remain unchangeable under the reaction conditions
(Table 3, entry 9).
One additional feature of the protection of a nitrogen
as its N,N-Cbz derivative is the possibility of selective
cleavage of just one carbamoyl group leading to the
corresponding N-Cbz compound (Scheme 4).10
In summary, we have reported a practical way to
accomplished the protection of primary amino compounds
to the corresponding N,N-Cbz derivatives that is compat-
ible with a broad range of protecting groups and func-
tional groups. The methodology can be extended for the
is very fast (30 min) and the method permits the use of
benzylchloroformate (CbzCl) as protecting reagent in-
stead of the more expensive dibenzyl dicarbonate (Cbz2O).
To ponder the advantage of our procedure we per-
formed additional reactions and compared them with the
method using dibenzyl dicarbonate. In all tested cases
excellent yields were reached including those of R-amino
acids and amines (Table 2).
An additional concern relative to our procedure is the
possibility that the basic treatment may affect the
stereochemical integrity of the vicinal stereocenter and
mainly when R-amino acids are used as substrates. To
check this point, crude 2 obtained from dimethyl (S)-
aspartate 1, [R]25 +22.8 (c 4.0, CHCl3), was submitted
D
to hydrogen atmosphere, using Pd/C (10%) as catalyst.
The crude dimethyl aspartate was again N-Cbz protected
producing 1 that after chromatographic separation showed
a virtually identical specific rotation, [R]25 +23.2 (c 4,
D
CHCl3), proving that the whole procedure is applicable
in the N,N-di-Cbz protection of R-amino acids without
any racemization (Scheme 3).
The method is compatible with a wide range of protect-
ing and functional groups (Tables 2 and 3). However, the
(10) Herna´ndez, J . N.; Ram´ırez, M. A.; Mart´ın, V. S. J . Org. Chem.
2003, 68, 743-746.
J . Org. Chem, Vol. 69, No. 10, 2004 3591

column chromatography to afford 2 (399 mg, 93% yield) as an
preparation of mixed N,N-dicarbamoyl compounds. When
the method is applied to R-amino acids the stereochem-
istry geminal to the amino group remains unaffected. In
addition, the selective cleavage of one carbamoyl group
leads to the corresponding N-Cbz amino compound.
oil: [R]25 -34.7 (c 10, CHCl3); 1H NMR (CDCl3) δ 2.82 (dd, 1H,
D
16.7 Hz, 7.2 Hz), 3.27 (dd, 1H, 16.7 Hz, 6.6 Hz), 3.54 (s, 3H),
3.63 (s, 3H), 5.29 (d, 2H, 4 Hz), 5.56 (t, 1H, 6.9 Hz), 7.33 (s, 10H);
13C NMR (CDCl3) δ 35.2 (t), 51.9 (q), 52.0 (q), 55.4 (d), 69.3 (t),
128.0 (d), 128.1 (d), 128.3 (d), 128.5 (d), 128.6 (d), 134.8 (s), 152.8
(s), 169.4 (s), 170.8 (s); IR (CHCl3) (cm-1) 2954, 1751, 1517, 1455,
1295, 1102; HRMS calcd for C22H24NO8 (M + 1)+, 430.1503,
Exp er im en ta l Section
found 430.1502; MS m/ z 430 (M + 1)+. Anal. Calcd for C22H23
-
Gen er a l P r oced u r e for t h e P r ot ect ion of P r im a r y
Am in es a s It s Di-Cb z-P r ot ect ed Der iva t ives: P r ep a r a -
tion of Dim eth yl (2S)-2-{(P h en ylm eth oxy)-N-[ben zyloxy-
ca r bon yl]ca r bon yla m in o}bu ta n e-1,4-d ioa te (2). To a stirred
solution of dimethyl (2S)-2-[(phenylmethoxy)carbonylamino]-
butane-1,4-dioate (1) (295 mg, 1 mmol) in THF (17 mL) and
HMPA (20 mmol, 3.4 mL) was added LHMDS (1.3 mL, 1 M, 1.3
equiv) at -78 °C. The mixture was additionally stirred for 15
min at -78 °C and CbzCl (200 µL, 1.4 mmol) was slowly added
by syringe. The reaction mixture was stirred for 0.5 h after which
time TLC showed complete conversion. Then the reaction
mixture was quenched with a saturated aqueous solution of NH4-
Cl and extracted with AcOEt. The combined organic phases were
washed with brine, dried over MgSO4, and filtered and the
solvent was evaporated. The crude was purified by silica gel
NO8: C, 61.53; H, 5.40; N 3.26. Found: C, 61.51; H, 5.7; N, 3.51.
Ack n ow led gm en t . This research was supported
by the Ministerio de Ciencia y Tecnolog´ıa of Spain
(PPQ2002-04361-C04-02) and the Canary Islands Gov-
ernment. J .N.H. thanks the Cabildo Insular de Tenerife
for financial support.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra and preparation for the compounds of Tables 2
and 3. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O049759+
3592 J . Org. Chem., Vol. 69, No. 10, 2004