noting at this point that the enzymatic desymmetrization of
prochiral diamines has been successfully achieved for the
first time using organic solvents, in contrast with the
hundreds of examples of the desymmetrization of diols,
ketones, diesters, or other related compounds.8
With these results, we decided to extend our methodology
in order to develop a general strategy for the desymmetri-
zation of other prochiral diamines. 1,3-Diaminopropane
derivatives are important enzyme inhibitors. Moreover, this
core can be found in a wide range of biologically active
compounds,9 so the possibility of using a chemoenzymatic
methodology would make the easy preparation of interesting
orthogonally protected derivatives possible. Certain com-
pounds differing in the substitution present in the aromatic
ring were prepared in this way in order to go on and study
in detail their enzymatic desymmetrisation.
Diamines 27-29 were considered at this point, and their
chemical synthesis was achieved following a strategy similar
to that used in the case of 4, using diols 18-20 as key
precursors for the overall preparation (Scheme 2). The diols
were obtained following a described procedure from chloride
acids 11 and 12, respectively,10 to later extend our methodol-
ogy in the preparation of diamines 27-29, which were
isolated after a clean hydrogenation step and purified through
a simple filtration. Enzymatic desymmetrization was im-
mediately attempted in the same efficient reaction conditions
employed for 4, obtaining the corresponding monocarbamates
(R)-30-32 with good isolated yields (68-72%) and high
enantiomeric excesses (86-96%) after 72 h at 30 °C,
demonstrating the validity of this new approach for the
production of enantiomerically enriched amines.
Different attempts were made to obtain suitable crystals
for X-ray diffraction analysis from hydrochloride or hydro-
bromide salts, but all of them were unsuccessful. Fortunately,
at the same time that 1H NMR analysis was done, adequate
crystals were obtained of the Mosher’s amide prepared by
reaction of optically active (-)-32 with (S)-(+)-R-methoxy-
R-trifluoromethylphenyl acetic acid chloride shown in Figure
1.11
Table 1. Enzymatic Desymmetrization of 4 Using 1 equiv of
Allyl Carbonates 6 or 7 in 1,4-Dioxane at 30 °C and 250 rpm
entry enzyme carbonate time (h) yielda (%) eeb (%)
1
2
3
4
CAL-B
CAL-B
PSL-C
PSL-C
6
7
6
7
96
46
96
96
75
77
63
73
71
0
90
37
a Isolated yield after flash chromatography. b Determined by HPLC after
adequate derivatization (see the Supporting information).
tivity with carbonate 7 but very high selectivity with diallyl
carbonate (entries 3 and 4). In all cases, the same stereopref-
erence was observed and the corresponding dicarbamate
compound was not detected, the longer reaction failing to
significantly increase the conversion of the process. No
reaction was observed with other reagents such as dimethyl
carbonate or dibenzyl carbonate after 10 days of reaction at
30 °C. Initially, the absolute configuration of the resulting
carbamate was assigned R in comparison with the results
obtained in the enzymatic desymmetrisation of diol 1 using
P. cepacia lipase.7
Once this enzymatic desymmetrization approach had been
efficiently achieved, we decided to optimize the reaction
conditions in order to find adequate parameters to isolate
the optically active monocarbamate 9 in a high level of
enantiopurity. To this end, the PSL-catalyzed reaction was
conducted using different organic solvents (1,4-dioxane,
t
THF, MeCN, BuOMe, Et2O, and toluene), the best results
being obtained in 1,4-dioxane, due to the high solubility of
the starting material and the stability showed by the diamine
in this solvent. The influence shown through the use of
different quantities of carbonate, temperatures, or the type
or quantity of PSL-C slightly affects the results obtained in
the enzymatic processes.
The desymmetrization of diamine 4 was scaled up to
approximately 1 mmol of substrate using the optimum
reaction conditions (PSL-C I as biocatalyst in double amount
respect to the starting material and 1 equiv of diallyl
carbonate in 1,4-dioxane at 30 °C) and avoiding as much as
possible the manipulation of the diamine in moist conditions.
The results obtained were better than those of previous
studies on a smaller scale, with a total selectivity in the
enzymatic process affording (R)-9 in enantiopure form and
73% isolated yield after 70 h at 30 °C. This fact can be
explained by the easy handling of the starting material; after
the hydrogenation step and purification by filtration, the
diamine can be placed directly in the vessel used for the
enzymatic process, so there is no time for the oxidation of
this unstable substrate under air conditions. It is worthwhile
As can be seen, both stereogenic centers from the acid
residue and the 2-position of the diamine fragment present
(R)-configuration, which agrees with the hypothesis previ-
ously put forward, which considered the same preference
for the lipases in the enzymatic desymmetrization of
(9) (a) Haque, T. S.; Skillman, A. G.; Lee, C. E.; Habashita, H.; Gluzman,
I. Y.; Ewing, T. J. A.; Goldberg, D. E.; Kuntz, I. D.; Ellman, J. A. J. Med.
Chem. 1999, 42, 1428-1440. (b) Salim, E. I.; Wanibuchi, H.; Morimura,
K.; Kim, S.; Yano, Y.; Yamamoto, S.; Fukushima, S. Carcinogenesis 2000,
21, 195-203.
(10) Katz, C. E.; Aube, J. J. Am. Chem. Soc. 2003, 125, 13948-13949.
(11) Colorless crystal, crystal dimensions 0.22 × 0.06 × 0.02 mm3;
C24H27F3N2O4 (Mr ) 464.48); monoclinic, space group P21, a ) 13.1146-
(15) Å, b ) 9.4909(6) Å, c ) 19.586(3) Å, â ) 103.373(15)°, V ) 2371.7-
(5) Å3, Z ) 2, Dx ) 1.301 Mg m-3, µ ) 0.882 mm-1. λ ) 1.54180 Å (Cu
KR). Data collection at 100(2) K, 2θmax 104.62°, 7935 measured reflections
and 4192 independent reflections (Rint 0.070). Final value of R1 (F2 > 2σ-
(F2)) ) 0.0521, wR2 (F2 > 2σ(F2)) ) 0.0877. Residual electron density
0.216/-0.220 e Å-3. Data collection was made using the program CrysAlis
CCD. Crystal structure was solved by direct methods using the program
Sir2004. Anisotropic least-squares refinement was carried out with SHELXL-
97. Absolute configuration was determined as R,R from the Friedel Pairs
and the reference of one known center. Structure details were deposited at
the CSD database (CCDC-651954 Cambridge).
(7) Bertucci, C.; Petri, A.; Felix, G.; Perini, B.; Salvadori, P. Tetrahe-
dron: Asymmetry 1999, 10, 4455-4462.
(8) See, for example: (a) Stampfer, W.; Kosjek, B.; Moitzi, C.; Kroutil,
W.; Faber, K. Angew. Chem., Int. Ed. 2002, 41, 1014-1017. (b) Lo´pez-
Garc´ıa, M.; Alfonso, I.; Gotor, V. Tetrahedron: Asymmetry 2003, 14, 603-
609. (c) Lo´pez-Garc´ıa, M.; Alfonso, I.; Gotor, V. J. Org. Chem. 2003, 68,
648-651. (d) Che`nevert, R.; Courchesne, G.; Jacques, F. Tetrahedron:
Asymmetry 2004, 15, 3587-3590.
Org. Lett., Vol. 9, No. 21, 2007
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