attention.4 The reason is the excellent asymmetric induction
properties they show, usually, when complexed with transition
metals.5 However, increasing efforts in the development of new
classes of diamine ligands are being reported in the literature.1b
Easy and versatile routes to new optically active diamine cores
are required since new ligands would lead to significant different
catalytic activities.
Enzymatic Desymmetrization of Prochiral
2-Substituted-1,3-Diamines: Preparation of
Valuable Nitrogenated Compounds
Nicola´s R´ıos-Lombard´ıa, Eduardo Busto,
Eduardo Garc´ıa-Urdiales, Vicente Gotor-Ferna´ndez, and
Vicente Gotor*
Enzymes are now recognized as efficient catalysts in the
preparation of chiral compounds.6 The mild reaction conditions
under which they operate, their selectivity and substrate
promiscuity, and the recent advances in protein, medium, and
substrate engineering have accounted for this fact.7 For those
cases in which the substrate is prochiral or meso, it can be
enantioselectively desymmetrized with a maximum theoretical
yield of 100%, thus avoiding the typical substrate “waste” of
kinetic resolutions. Enantioselective enzymatic desymmetriza-
tions have been successfully applied to the synthesis of many
valuable compounds.8 However, little attention has been paid
to prochiral or meso diamines.9 We have recently reported the
first enantioselective methodology to prepare optically active
2-monosubstituted propane-1,3-diamine derivatives by using
lipase from Pseudomonas cepacia (PCL) as catalyst and
prochiral 2-substituted propane-1,3-diamines as substrates,10
compounds for which even the regioselective monofunctional-
ization is a challenging task.11 Here we report on the synthesis
and subsequent PCL-catalyzed desymmetrization of a wide set
of 2-substituted propan-1,3-diamines using readily available
commercial compounds as starting materials. The analysis of
the resulting structure-enantioselectivity profile shows the type
of compounds that can be successfully obtained by means of
this methodology.
Departamento de Qu´ımica Orga´nica e Inorga´nica, Instituto
UniVersitario de Biotecnolog´ıa de Asturias, UniVersidad de
OViedo, c/Julia´n ClaVer´ıa s/n OViedo 33071, Spain
ReceiVed NoVember 21, 2008
A wide range of prochiral 1,3-diamines were first efficiently
synthesized and subsequently desymmetrized by using lipase
from Pseudomonas cepacia as catalyst and diallyl carbonate
as alkoxycarbonylating agent. In all cases, the amino
carbamates of R-configuration were recovered. Final selective
cleavage of the N-allyloxycarbonyl moiety was carried out
under mild reaction conditions, which demonstrates the high
versatility and potential of this chemoenzymatic route as a
source of intermediates in the synthesis of related optically
active nitrogenated derivatives.
First, substitution at the 4-position of the phenyl ring was
explored by adding to the previously described series of amines
(8a-d)10 bulkier substituents such as the trifluoromethyl (8e)
or the phenyl (8f) moieties. Next, the methoxy group was
selected as the probe to examine the preferred position of the
phenyl ring for monosubstitution (8g,h) and polysubstitution
(8i,j). The synthetic route described for the enzymatic desym-
(4) See for instance: Lin, G.-Q.; Xy, M.-H.; Zhong, Y.-W.; Sun, X.-W. Acc.
Chem. Res. 2008, 41, 831–840.
(5) Lemaire, M., Mangeney, P., Eds. Chiral Diazaligands for Asymmetric
Synthesis; Springer-Verlag: Berlin, Germany, 2005.
(6) For recent monographies on the topic, see: (a) Gotor, V., Alfonso, I.,
Garc´ıa-Urdiales, E., Eds. Asymmetric Organic Synthesis with Enzymes; Wiley:
Weinheim, Germany, 2008. (b) Patel, R. N., Ed. Biocatalysis in the Pharmaceuti-
cal and Biotechnology Industry; CRC Press: Boca Raton, FL, 2007. (c)
Bornscheuer, U. T., Kazlauskas, R. J., Eds. Hydrolases in Organic Synthesis;
Wiley: Weinheim, Germany, 2006.
(7) (a) Sheldon, R. A. Chem. Commun. 2008 3352-3365. (b) Reetz, M. T.
In AdVances in Catalysis, Vol. 49; Gates, B. C., Knözinger, K., Eds.; Elsevier:
San Diego, 2006.; Chapter 1, pp 1-69. (c) Morley, K. L.; Kazlauskas, R. J.
Trends. Biotechnol. 2005, 23, 231-237. (d) Kazlauskas, R. J. Curr. Opin. Chem.
Biol. 2005, 9, 195-201.
(8) Garc´ıa-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. ReV. 2005, 105, 313–
354.
(9) (a) Orsat, B.; Alper, P. B.; Moree, W.; Mak, C.-P.; Wong, C.-H. J. Am.
Chem. Soc. 1996, 118, 712–713. (b) Banfi, L.; Guanti, G.; Riva, R. Tetrahedron:
Asymmetry 1999, 10, 3571–3592.
Optically active diamines are central to chemistry. They are
bidentate ligands able to form chiral complexes and supramo-
lecular entities and confer them with enantioselectivity in the
different asymmetric transformations in which they participate.1
Moreover, they can be used as linkers in solid phase synthesis,
surface and bioconjugate chemistries, as monomers for the
preparation of chiral polymers,2 and as building blocks in the
synthesis of pharmaceuticals and agrochemicals.3 Among all
the classes of diamines described in the literature, C2-sym-
metrical 1,2-diamines have received, by far, most of the
(1) (a) Kizirian, J.-C. Chem. ReV. 2008, 108, 140–205. (b) Hems, W. P.;
Groarke, M.; Zanotti-Gerosa, A.; Grasa, G. A. Acc. Chem. Res. 2007, 40, 1340–
1347. (c) Ema, T.; Tanida, D.; Sakai, T. J. Am. Chem. Soc. 2007, 129, 10591–
10596.
(2) (a) Lee, J.-K.; Suh, Y.-W.; Kung, M. C.; Downing, C. M.; Harold, H. H.
Tetrahedron Lett. 2007, 48, 4919–4923. (b) de Abajo, J.; de la Campa, J. G.
Plast. Eng. 2005, 70, 541–602.
(3) (a) Sebela, M.; Tylichova, Pec, M. P. J. Neural Transm. 2007, 114, 793–
798. (b) Nagarajan, S. R.; et al. Bioorg. Med. Chem. 2007, 15, 3783–3800. (c)
Weinhardt, K.; Wallach, M. B.; Marx, M. J. Med. Chem. 1985, 28, 694–698.
(10) Busto, E.; Gotor-Ferna´ndez, V.; Montejo-Bernardo, J.; Garc´ıa-Granda,
S.; Gotor, V. Org. Lett. 2007, 9, 4203–4206.
(11) (a) Tang, W.; Fang, S. Tetrahedron Lett. 2008, 49, 6003–6006. (b)
Bender, J. A.; Meanwell, N. A.; Wang, T. Tetrahedron 2002, 58, 3111–3128.
(c) Pittelkow, M.; Lewinsky, R.; Christensen, R.; Bolstadt, J. Synthesis 2002,
2195–2202.
10.1021/jo8025912 CCC: $40.75
Published on Web 02/27/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2571–2574 2571