Biocatalytic approaches toward the synthesis of both enantiomers of trans-cyclopentane-1,2-diamine

Article abstract of DOI:10.1021/ol026574l

(graph presented) A lipase-catalyzed double monoaminolysis of dimethyl malonate by (±)-trans-cyclopentane-1,2-diamine allows the sequential resolution of the latter compound, affording an enantiopure bis(amidoester), which is subsequently transformed into

Full text of DOI:10.1021/ol026574l

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3627-3629
Biocatalytic Approaches toward the
Synthesis of Both Enantiomers of
trans-Cyclopentane-1,2-diamine
Amparo Luna, Ignacio Alfonso, and Vicente Gotor*
Departamento de Qu´ımica Orga´nica e Inorga´nica, Facultad de Qu´ımica,
UniVersidad de OViedo, 33071-OViedo, Spain
Vgs@sauron.quimica.unioVi.es
Received July 22, 2002
ABSTRACT
A lipase-catalyzed double monoaminolysis of dimethyl malonate by (±)-trans-cyclopentane-1,2-diamine allows the sequential resolution of the
latter compound, affording an enantiopure bis(amidoester), which is subsequently transformed into an optically active polyamine. As an
alternative, both enantiomers of the diamine can be obtained from enantiopure (+)- or (−)-2-aminocyclopentanol, prepared by enzymatic
resolution.
Many biologically valuable products contain a 1,2-diamino
moiety.1 In recent years, chiral synthetic diamine derivatives
have been employed as medicinal agents, in particular in
chemotherapy.2 Their use in organic synthesis has also
increased considerably, especially in the field of catalytic
asymmetric induction.3 The easy availability of both enan-
tiomers of the target compound in very high ee is one of the
limitations for the use of some optically active diamines.
Related to this, nonracemic trans-cyclopentane-1,2-diamine
(1) has been synthesized through a multistep sequence, and
high ees are obtained only after several recrystallization steps,
which lead to a low overall yield.4 It is, therefore, of
considerable interest to develop an efficient method for
preparing optically active trans-cyclopentane-1,2-diamine (1)
that minimizes the number of synthetic steps and maximes
the yield and ee of this important compound. Lipase-
catalyzed kinetic resolution of racemates is one the most
frequently used strategies for the preparation of optically
active compounds.5 Moreover, when the substrate structure
allows the coupling of two sequential kinetic resolutions, the
second step can improve the enantiomeric purity of the
product.6 Racemic diamines are very interesting bifunctional
substrates that can undergo a sequential biocatalytic resolu-
(1) (a) Otsuka, M.; Masuda, T.; Haupt, A.; Ohno, M.; Shiraki, T.; Sugiura,
Y.; Maeda, K. J. Am. Chem. Soc. 1990, 112, 838. (b) Stubbe, J.; Kozarich,
J. W. Chem. ReV. 1987, 87, 1107. (c) Kulanthaivel, P.; Hallock, Y. F.;
Boros, C.; Hamilton, S. M.; Janzen, W. P.; Ballas, L. M.; Loomis, C. R.;
Jiang, J. B.; Katz, B.; Steiner, J. R.; Clardy, J. J. Am. Chem. Soc. 1993,
115, 6452. (d) Rosenberg B.; VanCamp, L.; Trosko, J. E.; Masour, V. H.
Nature 1969, 222, 385.
(2) (a) Gust, R.; Burgemeister, A.; Mannschreck, A.; Scho¨nenberger, H.
J. Med. Chem. 1990, 33, 2535. (b) Kelland, L. R.; Abel, G.; McKeage, M.
J.; Jones, M.; Goddard, P. M.; Valenti, M.; Murrer, B. A.; Harrap, K. R.
Cancer Res. 1993, 53, 2581. (c) Khokhar, A. R.; Al-Baker, S.; Shamsuddin,
S.; Siddik, Z. H. Bioorg. Med. Chem. Lett. 1997, 40, 112. (d) Reedijk, J.
Chem. Commun. 1996, 801.
(3) (a) Lucet, D.; Le Gall, T.; Mioskowski C. Angew. Chem., Int. Ed.
1998, 37, 2580. (b) Blazis, V. J.; Koeller, K. J.; Spilling, C. D.
Tetrahedron: Asymmetry 1994, 5, 499. (c) Conlon, D. A.; Yasuda, N. AdV.
Synth. Catal. 2001, 1, 343. (d) Togni, A.; Venanzi, L. M. Angew. Chem.,
Int. Ed. 1994, 33, 497.
(4) Toftlund, H.; Pedersen, E. Acta Chem. Scand. 1972, 26, 4019.
(5) (a) Faber K. Biotransformations in Organic Chemistry, 4th ed.;
Springer: Heidelberg, 2000. (b) Theil, F. Chem. ReV. 1995, 95, 2203.
(6) Guo, Z.-W.; Wu, S.-H.; Chen, C.-S.; Girdaukas, G.; Sih, C. J. J.
Am. Chem. Soc. 1990, 112, 4942.
10.1021/ol026574l CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/21/2002

(benzyloxycarbonyl) derivative (S,S)-5, whose chiral HPLC
analysis showed an 87% ee. In this case, we obtained a very
high apparent enantioselectivity (E > 200)12 calculated from
both ee values.
Scheme 1a
The formation of (R,R)-3 involves two biocatalytic steps
[diamine to mono(amidoester) to bis(amidoester)] and,
therefore, the above-mentioned enantiopurity of (R,R)-3 has
to be clearly determined by the enantioselectivities of both
steps. To study the enantioselectivity shown by the CALB
in each step, we have calculated E1 and E2 values. The lability
of 1 toward oxidation, as well as the final persistence of
trace amounts of mono(amidoester) (detected in the deriva-
tization process of 4), made the accurate determination of
the reaction conversion c difficult. For these reasons, E1 was
determined when a 2:1 molar ratio of diamine:acyl donor
was used and the reaction stopped at the mono(amidoester)
stage (Scheme 1). In this process, substrate 1 and product 6
were isolated as their benzyl carbamates (S,S)-5 and (R,R)-
7, with 83 and 66% ees, respectively. The enantioselectivity
(E1 ) 21) and conversion (c ) 44%) were determined from
these values.12 This enantioselectivity value is not high
enough to get the product in enantiopure form, so the second
aminolysis step must also be enantioselective.
a Reaction conditions: (a) 1:1 molar ratio of (()-trans-1/2,
CALB, 1,4-dioxane, 30 °C; (b) 2 N HCl; (c) CbzCl, Na2CO3, H2O;
(d) 2:1 molar ratio of (()-trans-1:2, CALB, 1,4-dioxane, 30 °C, 1
h; (e) NH3, MeOH; (f) BH3‚THF, 6 N HCl, 4 N NaOH.
tion. This strategy has been successfully used for the
preparation of optically active trans-cyclohexane-1,2-di-
amine.7 With a suitable acyl donor, the appropriate enzyme
can catalyze the enantioselective monoacylation of the
diamine and subsequent enantioselective acylation of the
resulting optically enriched monoamide, thus affording an
enantiomerically pure diamide. The potential importance of
trans-cyclopentane-1,2-diamine (1) led us to explore the
resolution of this diamine8 by means of two sequential
aminolysis reactions, using dimethyl malonate (2) as the acyl
donor and Candida antarctica lipase (CALB) as the catalyst.
The selection of the acyl donor is associated to the synthetic
utility of the resulting products for the preparation of optically
active polyamines and macrocycles.9 It is remarkable that,
although (()-trans-cyclohexane-1,2-diamine is commercially
available, the (()-trans-cyclopentane-1,2-diamine is not.
Therefore, it has been scarcely studied, and it would be of
great interest to find an efficient procedure for obtaining
enantiopure trans-cyclopentane-1,2-diamine.
Enantioselectivity of the second step (E2) was also
determined from the single-step aminolysis reaction between
racemic mono(amidoester) 6 and dimethyl malonate 2
(Scheme 2).
Scheme 2a
Commercially available (()-trans-cyclopentane-1,2-diol
was transformed into (()-trans-cyclopentane-1,2-diamine (1)
using a procedure described in the literature.10
A one-pot double-acylation reaction (Scheme 1) using an
equimolecular mixture of (()-trans-1 and 2 with CALB11
in 1,4-dioxane (9 h) afforded enantiopure bis(amidoester)
(R,R)-3. The unreacted (S,S)-1 was isolated as its diammo-
nium salt, (S,S)-4, formed by treatment of the reaction
mixture with 2 N HCl. To determine the optical purity of
(S,S)-1, its salt (S,S)-4 was converted into the N,N′-bis-
a Reaction conditions: (a) 1:0.5 molar ratio of (()-trans-1/CbzCl,
Na2CO3, CH2Cl2; (b) ClC(O)CH2CO2Me, Et3N, CH2Cl2; (c) H2,
Pd-black, MeOH; (d) 2:1 molar ratio of (()-trans-6/1, CALB, 1,4-
dioxane, 30 °C, 3 h; (e) CbzCl, Na2CO3, H2O.
Compound 6 was prepared from (()-trans-1 by mono-
protection with benzyloxycarbonyl group, treatment with
malonyl chloride monomethyl ester, and finally removal of
the Cbz group (50% yield). Enzymatic aminolysis of (()-
trans-6 and 2 (molar ratio ) 2:1) yielded a mixture of (S,S)-
6, isolated as its carbamate (S,S)-7, and the bis(amidoester)
(R,R)-3 both in enantiomerically pure forms (ee > 99%).
Conversion (c ) 49%) and enantioselectivity (E2 > 200)
were also determined from these values.12
(7) Alfonso, I.; Astorga, C.; Rebolledo, F.; Gotor, V. Chem. Commun.
1996, 2471.
(8) Dominguez, B.; Hodnett, N. S.; Lloyd-Jones, G. C. Angew. Chem.,
Int. Ed. 2001, 40, 4289.
(9) (a) Alfonso, I.; Rebolledo, F.; Gotor, V. Tetrahedron: Asymmetry
1999, 10, 367. (b) Alfonso, I.; Rebolledo, F.; Gotor, V. Tetrahedron:
Asymmetry 1999, 10, 2515. (c) Alfonso, I.; Dietrich, B.; Rebolledo, F.;
Gotor, V.; Lehn, J. M. HelV. Chim. Acta 2001, 280. (d) Alfonso, I.;
Rebolledo, F.; Gotor, V. Chem. Eur. J. 2000, 6, 3331.
(10) (a) Or, Y. S.; Phan, L. T.; Chan, D. T.; Spina, K. P.; Halla, R.;
Elliot, R. L. WO Patent 9 717 356, 1997; Chem. Abstr. 1997, 127, 34467.
(b) Ongeri, S.; Aitken, D. J.; Husson, H.-P. Synth. Commun. 2000, 30, 2593.
(11) Catalyst can be reused several times.
In this biocatalytic process, CALB clearly shows the same
stereochemical preference toward the (R,R)-enantiomer of
the substrate in both steps. This fact and the strategy of the
(12) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem.
Soc. 1982, 104, 7294.
3628
Org. Lett., Vol. 4, No. 21, 2002

new antidiarrheals in AIDS-related cases,17 and as anticancer
agents.18 Polyamine 11 is a C6-C10-fused N,N′-bis(3-
aminopropyl)cadaverine. This spermine analogue has been
found to be formed in Saccharomyces cereVisiae19 and
mycorrhizal and phytopathogenic fungi.20 Moreover, the
introduction of a chiral rigid cyclic moiety in the structure
could confer novel and interesting properties to the com-
pound.21 Treatment of (R,R)-3 with ammonia in methanol
and subsequent reduction of the resulting tetraamide with
BH3‚THF afforded polyamine (R,R)-11 with 80% yield,
calculated from the starting bis(amidoester) (R,R)-3. Synthetic
and biological applications of these compounds are currently
under investigation.
Scheme 3a
a Reaction conditions: (a) MsCl, Et3N, CH2Cl2, 0 °C; (b) NaN3,
DMF, 60 °C; (c) H2, Pd-C, MeOH; (d) CbzCl, Na2CO3, H2O.
sequential resolution are the keys to the successful prepara-
tion of enantiopure (R,R)-3. As can be deduced from the
above results, enantiopure products cannot be obtained with
the first aminolysis reaction (E1), but the second biocatalytic
process (E2) is sufficiently enantioselective to produce bis-
(amidoester) 3 and mono(amidoester) 7 both in enantiomeri-
cally pure forms. This conclusion is extracted after mea-
surement of the two enantioselectivity values from the
sequential aminolysis reactions.
On the other hand, we have previously reported a practical
and efficient procedure for the resolution of (()-cis-N-Cbz-
2-aminocyclopentanol.13 In this case, the product and the
substrate were recovered in 99% ee. We carried out an
alternative synthesis using these enantiomers as starting
material (Scheme 3).14 First, mesylation of hydroxycarbamate
8 led to product 9, which was then substituted using NaN3
in DMF for obtaining 10, which was followed by hydroge-
nation with Pd/C to give the corresponding diamines (R,R)-1
or (S,S)-1, both isolated as N,N′-bis(benzyloxycarbonyl)
derivatives (91% yield).
Acknowledgment. Financial support of this work by the
Spanish Ministerio de Ciencia y Tecnolog´ıa (Project PPQ-
2001-2683) and by Principado de Asturias (Project GE-
EXP01-03) is gratefully acknowledged. A.L. thanks CON-
ACYT (Mexico) for a predoctoral fellowship.
Supporting Information Available: Experimental pro-
cedures, 1H and 13C NMR spectra, and HPLC chromatograms
of all products. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL026574L
(15) (a) Campbell, D. R.; Morris, D. R.; Bartos, D.; Daves, G. D., Jr.;
Bartos, F. AdVances in Polyamine Research; Raven Press: New York, 1978.
(b) Goldenburg, S. H.; Algranati, J. D. The Biology and Chemistry of
Polyamines; JCSU Press: Oxford, 1990. (c) Kuksa, V.; Buchan, R.; Kong
Thoo Lin, P. Synthesis 2000, 9, 1189.
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J. S. J. Med. Chem. 1995, 38, 425.
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B.; Feng, Y.; Wu, Q.; Gao, F. J. Med. Chem. 1996, 39, 2461.
(18) (a) Casero, R. A.; Woster, P. M. J. Med. Chem. 2001, 44, 1. (b)
Zou, Y.; Wu, Z.; Sirisoma, N.; Woster, P. M.; Casero, R. A., Jr.; Weiss, L.
M.; Rattendi, D.; Lane, S.; Bacchi, C. J. Bioorg. Med. Chem. Lett. 2001,
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(2), 255.
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A.; Sarkar, A.; Reddy, V. K.; Marton, L. J.; Basu, H. S.; Frydman, B. J.
Med. Chem. 2001, 44, 390. (c) Havis, N. D.; Walters, D. R. J. Agric. Food
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Finally, the enantiopure (R,R)-3 is easily transformed into
the polyamine 11 (Scheme 1). Polyamines are polycationic
compounds, which are essential for cell growth and divi-
sion.15 These compounds have wide-ranging therapeutic
applications in neurological diseases,16 in development of
(13) Luna, A.; Astorga, C.; Fu¨lo¨p, F.; Gotor, V. Tetrahedron: Asymmetry
1998, 9, 4483.
(14) Acylated product was hydrolyzed using CALB in Pr2O/EtOH
i
Org. Lett., Vol. 4, No. 21, 2002
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