A new selective cleavage of N,N-dicarbamoyl-protected amines using lithium bromide

Article abstract of DOI:10.1021/jo026300b

A mild and new procedure for the selective cleavage of an alkoxycarbonyl group (Boc, CBz) in N,N-dicarbamoyl-protected amino compounds is described. The method is based on the use of lithium bromide in acetonitrile and is compatible with a large range of other functionalities present in the substrates. Compared with other reported methodologies, the procedure is particularly useful for the Cbz-selective cleavage in N,N-Ts,Cbz-diprotected amines. A rationalization of the selectivity supported by ab initio calculations is also presented.

Full text of DOI:10.1021/jo026300b

A New Selective Clea va ge of N,N-Dica r ba m oyl-P r otected Am in es
Usin g Lith iu m Br om id e
J . Nicola´s Herna´ndez, Miguel A. Ram´ırez, and V´ıctor S. Mart´ın*
Instituto Universitario de Bio-Orga´nica “Antonio Gonza´lez”, Universidad de La Laguna,
C/ Astrofı´sico Francisco Sa´nchez, 2, 38206 La Laguna, Tenerife, Spain
vmartin@ull.es
Received August 9, 2002
A mild and new procedure for the selective cleavage of an alkoxycarbonyl group (Boc, CBz) in N,N-
dicarbamoyl-protected amino compounds is described. The method is based on the use of lithium
bromide in acetonitrile and is compatible with a large range of other functionalities present in the
substrates. Compared with other reported methodologies, the procedure is particularly useful for
the Cbz-selective cleavage in N,N-Ts,Cbz-diprotected amines. A rationalization of the selectivity
supported by ab initio calculations is also presented.
SCHEME 1
The tert-butoxycarbonyl (Boc) and the benzyloxycar-
bonyl (Cbz) groups are extensively used in synthesis for
amino protection including with amino acids.1 In the
literature many methods can be found for the removal
of such groups in N-protected amines,1 but only a few
can be found to selectively cleave an alkoxycarbonyl
group in N,N-dicarbamoyl-protected amines.2 We found
that the selective reduction of N,N-di-Boc-R-amino di-
esters derived from natural R-amino acids (glutamic or
aspartic acids) or the homologated compounds produced
ω-semialdehydes in very good yields and with complete
integrity at the stereocenter.3 Although the introduction
of the second N-Boc group is crucial for such selectivity,
several changes in the reactivity of the vicinal ester were
also produced. For instance, the alkaline hydrolysis of
N,N-di-Boc-R-amino esters produced partial racemization,3b
despite the occurrence of hydrolysis of N-Boc-R-amino
esters without any epimerization.4
result prompted us to apply these conditions to a series
of N,N-di-Boc-R-amino-protected derivatives. However, in
most cases the reaction proceeds sluggishly and with low
conversions. As an alternative, we now report on a new
and mild method to selectively deprotect an N-Boc group
in N,N-di-Boc-protected amines and R-amino acids, in
this case taking place without any detectable racemiza-
tion. The use of lithium bromide in acetonitrile proved
to be an excellent combination to achieve selectivity,
mildness, and generality in the desired conversion.
To explore the scope and limitations of our method, we
investigated a series of N,N-di-Boc-R-amino-protected
compounds with different protecting groups and func-
tionalities (Table 1). We found the procedure to be highly
general, yielding the corresponding N-Boc amino deriva-
tives. Particularly interesting is the possibility of apply-
ing the methodology to R-amino acids having an ω-alde-
hyde in their structure (entry 3).3 When a hydroxy group
is present in the substrates, the behavior depends on the
position of such a group relative to the N,N-di-Boc amino
derivatives. Thus, when that functionality was far from
the reacting position, almost no influence was detected
(entry 5). However, when the hydroxy group was close
to the nitrogen, a negative influence arose (entry 10). The
possible chelating competition was demonstrated by use
of the corresponding silyl-protected compound, in which
case the selective N-Boc cleavage was performed straight-
forwardly.
During our work directed to the synthesis of R-diamino
acid derivatives, we found that treatment of the N,N-di-
Boc-R-amino epoxy ester in Scheme 1 with NaN3 pro-
duced the cleavage of a N-Boc group.5 This promising
(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) Van Benthem, R. A. T. M.; Hiemstra, H.; Speckamp, W. N.
J . Org. Chem. 1992, 57, 6083-6085. (b) Stafford, J . A.; Brackeen, M.
F.; Karanewsky, D. S.; Valvano, N. L. Tetrahedron Lett. 1993, 34,
7873-7876. (c) Burkhart, F.; Hoffmann, M.; Kessler, H. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1191-1193. After the experimental work
presented herein was completed two new methods appeared in the
literature: (d) Yadav, J . S.; Subba Reddy, B. V.; Reddy, K. S. Synlett
2002, 468-470. (e) Yadav, J . S.; Reddy, B. V. S.; Srinivasa-Reddy, K.;
Bhaskar-Reddy, K. Tetrahedron Lett. 2002, 43, 1549-1551.
(3) (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, 3741-3744. (c) Sutherland, A.; Caplan, J . F.;
Vederas, J . C. J . Chem. Soc., Chem. Commun. 1999, 555-556. (d)
Sutherland, A.; Vederas, J . C. J . Chem. Soc., Chem. Commun. 1999,
1739-1740.
Considering that the method works with the N,N-di-
Boc moiety, we wondered if the methodology can be
extended to other situations in which the nitrogen is
doubly protected with an additional protecting group
besides the N-Boc protection (Table 2). We found that
(4) Bodanszky, M.; Bodanszky, A. In The Practice of Peptide
Synthesis; Springer-Verlag: Berlin, 1984, 177.
(5) Herna´ndez, N.; Mart´ın, V. S. J . Org. Chem. 2001, 66, 4934-
4938.
10.1021/jo026300b CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/31/2002
J . Org. Chem. 2003, 68, 743-746
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Herna´ndez et al.
TABLE 1. Selective Clea va ge of N,N-Di-Boc-P r otected Am in es a n d r-Am in o Acid s Usin g LiBr in CH3CN
when another carbamoyl-based protecting group, such as
Cbz, is used, the cleavage of the N,C-bond is randomly
performed, yielding almost equivalent amounts of both
N-monoprotected amino derivatives (entry 1). However,
when the additional protecting group is a carboxylic acyl
derivative (e.g. acetate) the cleavage of the N-Boc group
was not performed (entry 2). In both cases, however, the
use of magnesium perchlorate produced the selective
cleavage of the N-Boc group.2b The procedure worked very
well when the other ester functionality is a sulfonate, in
which case the N-carbamoyl cleavage was performed in
excellent yields (entries 3 and 4).7 Interestingly, under
the magnesium method, the N-Cbz,Ts-amino acid re-
mained unaffected (entry 3). Finally, the procedure is
respectful of N-Boc-protected secondary and N-Cbz-
protected primary amines (entries 5 and 6). Although our
comparative experimental work has been performed
between magnesium and lithium salts, the newly de-
scribed procedures using cerium(III)-NaI,2d Zn-MeOH,2e
and In-MeOH2e seems to give results closer to those
using magnesium salts than the result obtains by our
method.
The mechanism proposed by Stafford et al.2b for the
cleavage of N-Boc amines catalyzed by Mg(ClO4)2 based
on the formation of a six-membered chelate seems
roughly applicable to our method. However, in our
previous study, we were able to show that the lithium
and magnesium salts behave differently. It should be
remembered that LiBr allows the cleavage of both benzyl
and tert-butyl carbamoyl derivatives, but the magnesium
system only cleaves the latter type. Moreover, we found
that lithium perchlorate is not active as a catalyst, and
when using N-Cbz derivatives, we have been able to
detect benzyl bromide as a reaction product. To explain
these experimental observations, we believe that the
anion is very important,8 but differences are also probably
related to structural changes produced in the chelation
with the metal.
To find a possible explanation of such differences and
the possible role of externals anions, we performed some
calculations over the structures of tert-butyl N-methyl-
N-acetylcarbamate associated with the Li+ and Mg2+
cations. We chose this molecule considering both struc-
tural simplicity and as an extreme in the comparative
action of both metals, since only the magnesium cleavage
operated.9 The B3LYP/6-31G*10 calculations suggested
that the structure A (Scheme 2), in which both carbonyls
(6) (a) Garner, P. Tetrahedron Lett. 1984, 25, 5855-5858. (b) Garner,
P.; Ramakanth, S. J . Org. Chem. 1986, 51, 2609-2612. (c) Kozikowski,
A. P.; Nieduzak, R. T.; Konoike, T.; Springer, J . P. J . Am. Chem. Soc.
1987, 109, 5167-5175. (d) Garner, P.; Park, J . M. J . Org. Chem. 1987,
52, 2361-2364. (e) Garner, P.; Park, J . M., Malecki, E. J . J . Org. Chem.
1988, 53, 4395-4398. (f) McKillop, A.; Taylor, R. J . K.; Watson, R. J .;
Lewis, N. Synthesis 1994, 8, 31-33.
(8) External iodide is also necessary to achieve complete conversion
when the cerium(III) method is used. See ref 2d.
(9) Ram´ırez, M. A.; Herna´ndez, J . N.; Mart´ın, V. S. Manuscript in
preparation.
(7) For the use and removal of N-arylsulfonyl protecting groups,
see: (a) Roemmele, R. C.; Rappoport, H. J . Org. Chem. 1988, 53, 2367-
2371. (b) Ferraris, D.; Young, B.; Cox, C.; Dudding, T.; Drury, W. J .;
Ryzhkov, L.; Taggi, A. E.; Lectka, T. J . Am. Chem. Soc. 2002, 124,
67-77.
(10) B3LYP: (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988,
37, 785-789. (b) Becke, A. D. J . Chem. Phys. 1993, 98, 5648-5652.
6-31G*: (c) Hehre, W. J .; Radom, L.; Schleyer, P. V. R.; Pople, J . A. In
Ab Initio Molecular Orbital Theory; Wiley-Interscience: New York,
1986.
744 J . Org. Chem., Vol. 68, No. 3, 2003

Cleavage of N,N-Dicarbamoyl-Protected Amines
TABLE 2. Com p a r a tive Stu d y of th e Clea va ge of N-Ca r ba m oyl-P r otected r-Am in o Acid s w ith a n Ad d ition a l P r otection
a t th e Nitr ogen Usin g Lith iu m a n d Ma gn esiu m Sa lts
a
Conditions: (A) LiBr, CH3CN, 65 °C; (B) Mg(ClO4)2, CH3CN, room temperature.
SCHEME 2
(panel b). This result is coincident with the experimental
observations that indicate a greater decarboxylative
facility for magnesium salt-assisted breaking, provided
that the break of the C2-O3 bond is assumed to be the
rate-controlling process (Scheme 3).
Con clu sion s
are chelated with the cation, is clearly more stable (10.4
and 13.6 kcal/mol, for lithium and magnesium, respec-
tively) than B.11
A new and mild procedure to selectively cleave a
carbamoyl group in N,N-dicarbamoyl-protected amines
is reported. The procedure is very mild and simple to use,
being compatible with a wide range of additional protect-
ing groups in the substrate. The method is particularly
useful for the Cbz-selective cleavage in N,N-Ts,Cbz-
diprotected amines. In addition, we have performed ab
initio calculations over a simplified system showing that
the Mg(II) chelation produces an almost neat cleavage
between the tert-butyl group and the oxygen of the
oxycarbonyl group of the carbamoyl group to be decar-
boxylated. The lithium, however, produces just a weak-
The most prominent facts of our analysis involve the
tert-butyl oxygen (C2-O3) bond. A detailed analysis of
the electronic density12 using the Laplacian of the charge
2
density, ∇ F,13 shows a neat difference when considering
the nature of that bond in the structures of the Li+ and
Mg2+ complex (Figure 1). The lithium shows a weak
covalent bond (panel a), but this interaction becomes
roughly ionic in the case of the magnesium complex
(11) The 6-31G* Gaussian basis set and the hybrid functional
B3LYP, to include electronic correlation, was used with the Gaussian
98W program: Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria,
G. E.; Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery,
J . A., J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B. G.; Chen,
W.; Wong, M. W.; Andres, J . L.; Head-Gordon, M.; Replogle, E. S.;
Pople, J . A. Gaussian 98, revision A.6; Gaussian, Inc.: Pittsburgh, PA,
1998.
(12) The method used was that developed by Bader et al. in their
theory “Atom in Molecules (AIM)”: (a) Bader, R. F. W. In Atoms in
Molecules: A Quantum Theory; The International Series of Monographs
of Chemistry; Halpen, J ., Green, M. L. H., Eds.; Clarendon Press:
Oxford, 1990; pp 1-438. (b) Bader, R. F. W. Chem Rev. 1991, 91, 893-
928. (c) Popelier, P. In Atoms in Molecules: An Introduction; Prentice
Hall: Harlow, 2000; pp 1-164. (d) Gilespie, R. J .; Popelier, P. L. A. In
Chemical Bonding and Molecular Geometry: From Lewis to Electron
Densities; Oxford University Press: Oxford, 2001; pp 134-268. The
program used was AIM2000, Version 1.0, designed by Biegler-Ko¨nig,
F. and programed by Biegler-Ko¨nig, F.; Bayles, D.; Scho¨nbohm J ., with
chemical advice by Bader, R. F. W.
(13) The Laplacian of the electron density shows where the electron
density is locally concentrated or depleted as assumed.
J . Org. Chem, Vol. 68, No. 3, 2003 745

Herna´ndez et al.
2
2
F IGURE 1. Contour plots of the Laplacian of the electron density,∇ F, for chelated structures: (a) Li+ and (b) Mg2+. ∇ F < 0
2
(continuous lines) represents covalent interactions; ∇ F > 0 (dotted lines) shows noncovalent interactions.
Gen er a l P r oced u r e for th e Selective Clea va ge of
Dica r ba m oyl-P r otected Am in es Usin g Lith iu m Br om id e.
P r ep a r a tion of Dim eth yl (2S)-2-[(ter t-Bu toxy)ca r bon yl-
a m in o]bu ta n e-1,4-d ioa te (1b). To a stirred solution of
dimethyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-butane-1,4-
dioate 1a 3 (223.6 mg, 0.62 mmol) in acetonitrile (7 mL) placed
into a round-bottomed flask (25 mL) equipped with a stopper
was added commercially available lithium bromide (163 g, 1.9
mmol). The mixture was warmed with stirring to 65 °C for 10
h, at which time the reaction was completed. The reaction
mixture was concentrated and purified by silica gel chroma-
tography to yield 1b (157 mg, 97% yield) as a white solid: mp
SCHEME 3
66-65 °C; [R]25 ) +28.02 (c 5, CHCl3); 1H NMR (CDCl3) δ
D
1.36 (s, 9H), 2.77 (dd, J ) 4.75 Hz, 16.9 Hz, 1H), 2.92 (dd, J )
4.1 Hz, 16.95 Hz, 1H), 3.61 (s, 3H), 3.67 (s, 3H), 4.48 (br, 1H),
5.47 (br, 1H); 13C NMR (CDCl3) δ 28.2 (q), 36.5 (t), 49.9 (d),
51.8 (q), 52.5 (q), 79.9 (s), 155.3 (s), 171.4 (s), 171.2 (s); IR
(CHCl3) (cm-1) 3374, 2979, 1742, 1438, 1166, 1046; HRMS
calcd for C11H19NO6 (M - 1)+ 261.1212, found 261.1225; MS
m/ z 284 (M + Na)+, 262 (M + 1)+, 206 (M - t-Bu)+, 162 (M -
Boc)+. Anal. Calcd for C11H19NO6: C, 50.57; H, 7.33; N 5.36.
Found: C, 50.54; H, 7.36; N, 5.36.
ness of such a bond, providing a reasonable indication of
the necessary presence of external anions to produce the
selective cleavage.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. NMR spectra were measured at
400 or 300 MHz (1H) and 75 MHz (13C), and chemical shifts
are reported relative to internal Me4Si (δ ) 0). Optical
rotations were determined for solutions in chloroform or carbon
tetrachloride. Melting points are reported in degrees Celsius
and are uncorrected. Column chromatography was performed
on Merck silica gel, 60 Å and 400-500 mesh. Compounds were
visualized by use of UV light and/or 2.5% phosphomolybdic
acid in ethanol and/or ninhydrin both in ethanol stain with
heating. All solvents were purified by standard techniques.14
Reactions requiring anhydrous conditions were performed
under argon. Anhydrous magnesium sulfate was used for
drying solutions.
Ack n ow led gm en t. We thank the DGES (PB98-
0443-C02-01) of Spain, FEDER (1FD97-0747-C04-01),
and the Canary Islands Government for supporting this
research. N.H. thanks the Consejer´ıa de Educacio´n,
Cultura y Deportes of the Canary Islands Government
and the M. E. C. of Spain for a fellowship. We also
express our appreciation to Dr. Toma´s Mart´ın for his
suggestions and discussions.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra and preparation for the new compounds and Cartesian
coordinates and total energy for the full-optimized B3LYP/6-
31G(d) structures (GAUSSIAN 98). This information is avail-
able free of charge via the Internet at http://pubs.acs.org.
(14) Armarego, W. L. F.; Perrin, D. D. In Purification of Laboratory
Chemicals, 4th ed; Butterworth-Heinemann: Oxford, 1996.
J O026300B
746 J . Org. Chem., Vol. 68, No. 3, 2003