A biocatalytic approach to synthesizing optically active orthogonally protected trans-cyclopentane-1,2-diamine derivatives

Article abstract of DOI:10.1021/jo062205h

(Chemical Equation Presented) A straightforward chemoenzymatic synthesis of optically active trans-N,N-dialkylcyclopentane-1,2-diamines has been efficiently developed starting out from their analogous (±)-trans-2-(N,N- dialkylamino)-cyclopentanols. The ro

Full text of DOI:10.1021/jo062205h

A Biocatalytic Approach to Synthesizing Optically Active
Orthogonally Protected trans-Cyclopentane-1,2-Diamine Derivatives
Javier Gonza´lez-Sab´ın, Vicente Gotor,* and Francisca Rebolledo*
Departamento de Qu´ımica Orga´nica e Inorga´nica, Facultad de Qu´ımica, UniVersidad de OViedo,
33071-OViedo, Spain
Vgs@fq.unioVi.es; frV@fq.unioVi.es
ReceiVed October 24, 2006
A straightforward chemoenzymatic synthesis of optically active trans-N,N-dialkylcyclopentane-1,2-
diamines has been efficiently developed starting out from their analogous (()-trans-2-(N,N-dialkylamino)-
cyclopentanols. The route involves the one-pot stereospecific transformation of the racemic amino alcohols
into racemic diamines and a subsequent kinetic resolution by means of lipase-B from Candida antarctica-
catalyzed acylation reactions. The careful selection of both the alkyl substituents present in the diamine
and the derivatization strategy applied to the enzymatic reaction enabled the easy preparation of other
synthetically valuable optically active trans-cyclopentane-1,2-diamines derivatives.
Introduction
cite platinum 1,2-diamino complexes as anticancer drugs4 and
some cyclohexane-1,2-diamine derivatives as highly selective
κ-opioid agonists.5 Moreover, vicinal diamines have also shown
great utility in other areas such as coordination chemistry or
asymmetric catalysis.6 For all these reasons, it is easy to
understand the intensive efforts that chemists have devoted to
the development of new and efficient methods to prepare these
compounds.
The 1,2-diamino moiety is present in the structure of a great
variety of natural products such as biotin (vitamin H),1 the
alkaloid slaframine,2 or balanol,3 an inhibitor of the protein
kinase C. Furthermore, the therapeutic properties of many
synthetic optically active 1,2-diamines have been explored in
different areas of medicinal chemistry. Among these, we may
The commercially available enantiopure trans-cyclohexane-
1,2-diamine has perhaps been the most used diamine for the
synthesis of ligands and receptors.7 It is thus common to find
this diamine as the structural key of many catalysts in a wide
range of asymmetric process applications; for instance, addition
of organozinc compounds to aldehydes and ketones,8 hydroge-
(1) (a) Eisenberg, M. A. In Escherichia coli and Salmonella typhimu-
rium: Cellular and Molecular Biology; Neidhardt, F. C., Ed.; American
Society for Microbiology: Washington, DC, 1987; Vol. 1, pp 544-550.
(b) Marquet, A. Pure Appl. Chem. 1993, 65, 1249-1252.
(2) Gardiner, R. A.; Rinehart, K. L., Jr.; Snyder, J. J.; Broquist, H. P.
J. Am. Chem. Soc. 1968, 90, 5639-5640.
(3) Kulanthaivel, P.; Hallock, Y. F.; Boros, C.; Hamilton, S. M.; Janzen,
W. P.; Ballas, L. M.; Loomis, C. R.; Jiang, J. P.; Katz, B.; Steiner, J. R.;
Clardy, J. J. Am. Chem. Soc. 1993, 115, 6452-6453.
(4) (a) Brunner, H.; Hankofer, P.; Holzinger, U.; Treittinger, B.;
Scho¨nenberger, H. Eur. J. Med. Chem. 1990, 25, 35-44. (b) Brunner, H.;
Hankofer, P.; Holzinger, U.; Treittinger, B. Chem. Ber. 1990, 123, 1029-
1038. (c) Gust, R.; Burgemeister, T.; Mannschreck, A.; Scho¨nenberger, H.
J. Med. Chem. 1990, 33, 2535-2544. (d) Kelland, L. R.; Abel, G.;
McKeage, M. J.; Jones, M.; Goddard, P. M.; Valenti, M.; Murrer, B. A.;
Harrap, K. R. Cancer Res. 1993, 5, 2581-2586. (e) Kim, D.-K.; Kim,
Y.-W.; Kim, H.-T.; Kim, K. H. Bioorg. Med. Chem. Lett. 1996, 6, 643-
646. (f) Khokhar, A. R.; Al-Baker, S.; Shamsuddin, S.; Siddik, Z. H. J.
Med. Chem. 1997, 40, 112-116. (g) Reedijk, J. Chem. Commun. 1996,
801-806.
(5) (a) Szmuszkovicz, J.; Von Voigtlander, P. F. J. Med. Chem. 1982,
25, 1125-1126. (b) Szmuszkovicz, J. Eur. Pat. Appl. EP 126612, 1984;
Chem. Abstr. 1985, 102, 184969b. (c) Clark, C. R.; Halfpenny, P. R.; Hill,
R. G.; Horwell, D. C.; Hughes, J.; Jarvis, T. C.; Rees, D. C.; Schofield, D.
J. Med. Chem. 1988, 31, 831-836. (d) Costello, G. F.; James, R.; Shaw,
J. S.; Slater, A. M.; Stutchbury, N. C. J. J. Med. Chem. 1991, 34, 181-
189. (e) Barlow, J. J.; Blackburn, T. P.; Costello, G. F.; James, R.; Le Count,
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10.1021/jo062205h CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/17/2007
J. Org. Chem. 2007, 72, 1309-1314
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Gonza´lez-Sab´ın et al.
biocatalytic and nonenzymatic processes: the stereospecific
transformation of (()-trans-2-(N,N-dialkylamino)cyclopentanols
into (()-trans-cyclopentane-1,2-diamines and the subsequent
enzymatic resolution are the key steps. Some of the diamines
(Figure 1) were also chosen for their pharmacological properties;
1b is an analogue of the anticholinergic vesamicol,15 and 1c is
precursor of CCR-3 chemokine receptor antagonists.16 In
addition, diamines 1a and 1d bear easily removable substituents,
which allowed us to differ both amino groups for the modular
synthesis of a novel set of derivatives with potential synthetic
utility.
FIGURE 1. Selected trans-N,N-dialkylcyclopentane-1,2-diamines.
Results and Discussion
Synthesis of Racemic Diamines 1a-d. Diamines (()-1a-d
(Scheme 1) were prepared from the analogous (()-trans-2-(N,N-
dialkylamino)cyclopentanols (2a-d)17 following the strategy
developed for the synthesis of racemic N,N-disubstituted
cyclohexane-1,2-diamines.18 Thus, the one-pot treatment of (()-
2a-d with mesyl chloride and subsequently with aqueous
ammonia afforded trans-diamines (()-1a-d as the only product,
in very good yields (>85%). We expected this reaction to
proceed via an aziridinium intermediate as in the case of the
cyclohexane-1,2-diamines. Once the mesylation of alcohol takes
place, the resulting mesyl derivative would experience an
intramolecular SN2 reaction with the formation of the meso-
aziridinium ion (Az), which would be attacked by the ammonia
leading to the final trans-diamine (Scheme 1).
nation of prochiral ketones,9 or epoxidation and cyclopropana-
tion of olefins.10 In contrast, applications of nonracemic trans-
cyclopentane-1,2-diamine still remain almost unexplored due
to the complexity of the reported syntheses and their poor yields.
Since the pioneering work of Toftlund and Pedersen,11 only a
few approaches have appeared for this compound, and in
general, the enantiopure diamine is only obtained after multistep
sequences with low overall yields.12
Continuing with our interest in the synthesis of optically active
1,2-diamines, and encouraged both by the scarcity of reported
syntheses of cyclopentane-1,2-diamine and by the promising
utility of some of its derivatives as chiral ligands13 and
precursors of improved peptide nucleic acids (PNAs),14 we
focused our research on the development of efficient routes for
preparing optically active N,N-disubstituted trans-cyclopentane-
1,2-diamines. The strategy described in this article combines
SCHEME 1. Preparation of Racemic Diamines 1a-d
(7) For an excellent review, see: (a) Bennani, Y. L.; Hanessian, S. Chem.
ReV. 1997, 97, 3161-3196. For some recent examples of the utility of trans-
cyclohexane-1,2-diamine derivatives in asymmetric catalysis, see: (b)
Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170-7171. (c)
Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964-8965.
(d) Evans, D. A.; Seidel, D. J. Am. Chem. Soc. 2005, 127, 9958-9959. (e)
Aoyama, H.; Tokunaga, M.; Kiyosu, J.; Iwasawa, T.; Obora, Y.; Tsuji, Y.
J. Am. Chem. Soc. 2005, 127, 10474-10475. For some examples of
macrocyclic receptors containing the trans-cyclohexane-1,2-diamine unit,
see: (f) Pan, Z.; Still, W. C. Tetrahedron Lett. 1996, 37, 8699-8702. (g)
Alfonso, I.; Rebolledo, F.; Gotor, V. Chem.-Eur. J. 2000, 6, 3331-3338.
(h) Alfonso, I.; Dietrich, B.; Rebolledo, F.; Gotor, V.; Lehn, J.-M. HelV.
Chim. Acta. 2001, 84, 280-295. (i) Lee, K. H.; Lee, D. H.; Hwang, S.;
Lee, O. S.; Chung, D. S.; Hong, J.-I. Org. Lett. 2003, 5, 1431-1433.
(8) (a) Garc´ıa, C.; Walsh, P. J. Org. Lett. 2003, 5, 3641-3644. (b) Li,
H.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 6538-6539.
(9) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045-
2061.
As the configuration of cyclopentane derivatives cannot be
assigned from values of coupling constants, the trans configu-
ration of these diamines 1a-d was assigned by comparison with
the configurationally known trans-amino alcohols 2a-d.17
Accordingly, we carried out NOE measures on the trans-amino
alcohol 2a and the acetamide 3a, obtained by acetylation of 1a
(with unknown relative configuration).19 Two signals, OH (or
NH) and H-2, were irradiated for both compounds, and the NOE
enhancements of the other two depicted signals (Figure 2) were
(10) McGarrigle, E. M.; Gilheany, D. G. Chem. ReV. 2005, 105, 1563-
1602.
(11) Optically active trans-cyclopentane-1,2-diamine was prepared for
the first time by applying the classical recrystallization with tartaric acid.
However, high enantiomeric excesses were obtained only after several
recrystallization cycles, which led to a low overall yield: Toftlund, H.;
Pedersen, E. Acta Chem. Scand. 1972, 26, 4019-4030.
(12) (a) Ongeri, S.; Aitken, D. J.; Husson, H.-P. Synth. Commun. 2000,
30, 2593-2597. (b) Luna, A.; Alfonso, I.; Gotor, V. Org. Lett. 2002, 4,
3627-3629. (c) de Parrodi, C. A.; Walsh, P. J. Synlett 2004, 13, 2417-
2420. (d) Myers, M. C.; Witschi, M. A.; Larionova, N. V.; Franck, J. M.;
Haynes, R. D.; Hara, T.; Grajkowski, A.; Apella, D. H. Org. Lett. 2003, 5,
2695-2698.
(13) (a) Dominguez, B.; Hodnett, N. S.; Lloyd-Jones, G. C. Angew.
Chem., Int. Ed. 2001, 40, 4289-4291. (b) Gouin, S. G.; Gestin, J.-F.; Joly,
K.; Loussouarn, A.; Reliquet, A.; Meslin, J. C.; Deniaud, D. Tetrahedron
2002, 58, 1131-1136. (c) Hoffmann, R. W.; Klute, W.; Dress, R. K.;
Wenzel, A. J. Chem. Soc., Perkin Trans. 2 1995, 1721-1726. (d) Daly,
A. M.; Gilheany, D. G. Tetrahedron: Asymmetry 2003, 14, 127-137.
(14) (a) Pokorski, J. K.; Witschi, M. A.; Purnell, B. L.; Appella, D. H.
J. Am. Chem. Soc. 2004, 126, 15067-15073. (b) Pokorski, J. K.; Nam,
J.-M.; Vega, R. A.; Mirkin, C. A.; Appella, D. H. Chem. Commun. 2005,
2055-2056.
FIGURE 2. Selected signals of 2a and 3a for NOE experiments.
compared in each case. Irradiation of the H-2 signal of 2a causes
a strong NOE on the OH signal, which increased much more
than that of H-1, as expected due to the trans configuration.
The same effect was observed when we irradiated the H-2 signal
of the acetamide 3a. Moreover, the NOE enhancement of both
(15) Marshall, I. G.; Parsons, S. M. Trends Neurosci. 1987, 10, 174-
177.
(16) Du, B.; Daisy, J. J. PCT Int. Appl. 2003, WO 2003022799 A1;
Chem. Abstr. 2003, 138, 254963.
1310 J. Org. Chem., Vol. 72, No. 4, 2007

Synthesizing trans-Cyclopentane-1,2-Diamine DeriVatiVes
FIGURE 3. ESI-MS spectrum of the reaction mixture of (()-2a and mesyl chloride.
SCHEME 2a
H-1 signals was similar (see details of these experiments in the
Supporting Information). We likewise observed strong NOE in
the H-2 signals of both the amino alcohol and the acetamide
after irradiation of the corresponding OH or NH signal. From
these results, we can deduce that compounds 2a and 3a, and
by extension 1a, have the same trans configuration.
This trans configuration supports the notion that the reaction
proceeds through the meso-aziridinium ion20 intermediate (Az,
Scheme 1). Analysis of the ESI-MS spectrum of the reaction
mixture obtained just a few minutes after mixing the amino
alcohol 2a and mesyl chloride allowed us to detect the meso-
aziridinium ion (m/z ) 188) as the base peak (Figure 3), in
addition to other species such as the starting protonated amino
alcohol (m/z ) 206), and their mesyl (m/z ) 284) and chloride
(m/z ) 224) derivatives. This last species could have trans
configuration if formed by ring opening of the aziridinium ion
(Az), or cis configuration if generated by the SN2 attack of the
chloride anion on the mesylated amino alcohol. These results
indicate that, although the mediation of the aziridinium ion in
the process is clear, the trans-diamine may also proceed non-
exclusively from this intermediate, as well as from a hypothetic
chlorine byproduct of cis configuration. The involvement of
either trans-mesyl and trans-chlorine derivatives is ruled out
because both intermediates should lead to the cis-diastereomer.
An additional proof supports the premise that trans-diamines
are only formed through the meso-aziridinium: when enan-
tiopure amino alcohol (1R,2R)-2a17 was submitted to the same
a Reagents and conditions: (i) 3 N aq HCl; (ii) H2, Pd-C 10%; (iii) 6
N aq HCl, reflux.
reaction conditions, a complete loss of optical activity took place
and racemic trans-diamine (()-1a was isolated.
Enzymatic Resolution of Racemic Diamines 1a-d. Fol-
lowing the excellent results obtained with N,N-disubstituted
cyclohexane-1,2-diamines,18 we designed the CAL-B-catalyzed
resolution of diamines (()-1a-d by aminolysis processes under
the simplest reaction conditions (i.e., employing ethyl acetate
as acyl donor and solvent). Thus far, CAL-B (Novozyme SP-
435) has proven to be the most effective catalyst for the
aminolysis reaction in organic solvent.21 The results presented
in Table 1 show that lipase displayed good enantioselectivities
with diamines 1a, 1b, and 1d (E22 > 65) and only moderate
enantioselectivity with 1c (E ) 20). In the enzymatic reaction
of (()-1b, the resulting mixture formed by the acetamide 3b
and the diamine 1b was easily separated by flash chromatog-
raphy. In the other cases, the isolation of both the diamine and
acetamide was facilitated by derivatization of the reaction
(17) Synthesized by ring opening of cyclopentene oxide with the
corresponding secondary amine: Gonza´lez-Sab´ın, J.; Rebolledo, F.; Gotor,
V. Biotechnol. J. 2006, 1, 835-841.
(18) Gonza´lez-Sab´ın, J.; Rebolledo, F.; Gotor, V. Chem.-Eur. J. 2004,
10, 5788-5794.
(19) We chose acetamide 3a instead of diamine 1a due to the clearer 1H
NMR spectrum.
(20) For some applications of aziridinium ions in synthesis, see: (a)
Couturier, M.; Tucker, J. L.; Andresen, B. M.; DeVries, K. M.; Vanderplas,
B. C.; Ito, F. Tetrahedron: Asymmetry 2003, 14, 3517-3523. (b) Pio-
trowska, D. G.; Wro´blewski, A. E. Tetrahedron 2003, 59, 8405-8410. (c)
Andrews, D. R.; Dahanukar, V. H.; Eckert, J. M.; Gala, D.; Lucas,
B. S.; Schumacher, D. P.; Zavialov, I. A. Tetrahedron Lett. 2002, 43, 6121-
6125. (d) Chuang, T. H.; Sharpless, K. B. Org. Lett. 2000, 2, 3555-3557.
(21) For some recent reviews, see: (a) Gotor-Ferna´ndez, V., Busto, E.,
Gotor, V. AdV. Synth. Catal. 2006, 348, 797-812. (b) Van Rantwijk, F.;
Sheldon, R. A. Tetrahedron 2004, 60, 501-519. (c) Alfonso, I.; Gotor, V.
Chem. Soc. ReV. 2004, 33, 201-209.
(22) Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem.
Soc. 1982, 104, 7294-7299.
J. Org. Chem, Vol. 72, No. 4, 2007 1311

Gonza´lez-Sab´ın et al.
TABLE 1. Enzymatic Resolution of Racemic Diamines (()-1a-da
a All the reactions were carried out at 28 °C and 200 rpm. b Conversion: c ) ees/(ees + eep). c Enantiomeric ratio calculated according to ref 22.
mixtures with benzyl chloroformate (in the case of 1c) or di-
tert-butyl dicarbonate (for 1a and 1d). Hence, the remaining
(1S,2S)-diamines were transformed into the corresponding Cbz
or Boc derivatives, the resulting mixtures of carbamate and
acetamide also being separated by flash chromatography. In all
the processes, both the remaining substrate and product were
obtained in high yields (>40%), bearing in mind the limiting
yield of 50% allowed in a kinetic resolution. Moreover, free
diamines (1S,2S)-1a, 1c, and 1d were quantitatively recovered
after removal of the benzyloxycarbonyl (H2, 10% Pd-C) or
tert-butoxycarbonyl (HCl 3 N) groups.
To improve the enantioselectivity of these processes, some
changes in the reaction conditions were accomplished using
compound 1a as a model substrate. Thus, tert-butyl methyl ether
(TBME) was tested as solvent and methyl methoxyacetate or
R-methylbenzyl acetate as acyl donors.23 The reaction with
methyl methoxyacetate was very fast, and enantiopure carbamate
(1S,2S)-4a was isolated after only 3 h (c ) 55%, E ) 89). The
corresponding aminolysis of R-methylbenzyl acetate proceeded
not only slightly slower but also with less enantioselectivity
(E ) 47). Finally, when we applied the best reaction conditions
(methyl methoxyacetate and TBME) to the resolution of 1c,
the process took place with poor enantioselectivity (E ) 10).
For our further synthetic goals regarding diamines 1a and
1d, it would be desirable to obtain these compounds and their
acetamide derivatives with high optical purity. To do so, an
accurate control of the percentage of conversion in the enzymatic
process is required. Despite the slightly higher enantioselectivity
when using TBME and methyl methoxyacetate, we chose the
first conditions employing only ethyl acetate due to the
simplicity and lower cost of this methodology. Thus, remaining
amines (1S,2S)-1a and (1S,2S)-1d, isolated as the corresponding
carbamates (1S,2S)-4a and (1S,2S)-4d, were obtained in enan-
tiomerically pure form after 10 and 21 h of reaction, respectively
(c ) 55%). Acetamides (1R,2R)-3a and (1R,2R)-3d of 95% ee
were likewise obtained after only 2.5 and 5 h, respectively
(c ) 42%).
In all cases, enantiomeric excesses were determined by HPLC
using a chiral column. Configuration (1S,2S) for the remaining
diamine 1d was established after transformation of its carbamoyl
(23) Gonza´lez-Sab´ın, J.; Rebolledo, F.; Gotor, V. Tetrahedron: Asym-
metry 2004, 15, 481-488.
1312 J. Org. Chem., Vol. 72, No. 4, 2007

Synthesizing trans-Cyclopentane-1,2-Diamine DeriVatiVes
SCHEME 3a
a Reagents and conditions: (i) 3 N aq HCl; (ii) Pd(dba)2, dppb, mercaptobenzoic acid; (iii) H2, Pd-C 10%; (iv) 3 N HCl in MeOH; (v) solid NaOH,
extraction with CH2Cl2; (vi) 6 N aq HCl, reflux.
derivative 4d into trans-cylopentane-1,2-diamine 11 (Scheme
3) and comparison of the sign of its specific rotation with the
reported value for (1S,2S)-(-)-11.11 This means that CAL-B
follows Kazlauskas’ rule,24 showing stereopreference toward the
(1R,2R)-enantiomer of the racemic diamine. Taking into account
this result, the structural resemblance between diamines reported
here, and the stereopreference shown for CAL-B with the
analogous cyclohexane-1,2-diamines, we have tentatively as-
signed the (1S,2S) configuration to the other remaining diamines
1a-c and the (1R,2R) configuration to the corresponding
acetamides 3a-c.
Selective Cleavage of Protecting Groups of the Optically
Active Compounds 1a and 1d. Diamines 1a and 1d, bearing
the easily removable benzyl and allyl groups within their
structures, were deliberately chosen with the aim of preparing
some orthogonally protected trans-cyclopentane-1,2-diamine
derivatives. This was why their enzymatic crude products were
derivatized with di-tert-butyl dicarbonate. Thus, both compounds
isolated from the enzymatic reactions of 1a, the aminocarbamate
(1S,2S)-4a (ee >99%) and the aminoacetamide (1R,2R)-3a (ee
) 95%), contain orthogonal protective groups: Boc and benzyl
in the case of 4a, and acetamide and benzyl in the case of 3a
(Scheme 2). Effectively, the selective removal of these groups
led to very high yields of both enantiomers of trans-N-benzyl-
N-methylcyclopentane-1,2-diamine [(1S,2S)-1a and (1R,2R)-1a],
as well as the derivatives (1S,2S)-6 and (1R,2R)-7, which are
precursors of the monosubstituted N-methylcyclopentane-1,2-
diamine.
isolated from the enzymatic reactions bear a set of three
removable protecting groups: (i) Boc or Ac, (ii) N-allyl, and
(iii) N-benzyl (Scheme 3). First, the acid treatment of 4d and
3d led to both enantiomers of 1d in excellent yields. Next, we
planned the cleavage of the two protective groups over the other
nitrogen atom of (1S,2S)-4d and (1R,2R)-3d. As the allyl group
reacts in the conditions used for the debenzylation, we first
carried out selective deallylation, isolating the N-benzyl deriva-
tives (1S,2S)-8 and (1R,2R)-12.25 Subsequent hydrogenolysis
of these compounds afforded (1S,2S)-9 and (1R,2R)-13 in
quantitative yields. Finally, from the acid treatment of 9 and
13, both enantiomers of the trans-cyclopentane-1,2-diamine
were isolated as free diamines [(1S,2S)-11 and (1R,2R)-11] or
as their dihydrochloride salts (10).
Analysis of Schemes 2 and 3 reveals the plethora of optically
active cyclopentane-1,2-diamine derivatives that can be prepared
following a very simple methodology. In addition to the
interesting monoalkyl derivatives bearing in turn an additional
transformable function (8 and 12), note should be taken of the
easy accessibility to N-methylated compounds (6 and 7), which
are difficult to prepare by conventional methods. In addition,
the monoprotected diamines are common synthetic intermediates
in the synthesis of PNA monomers, and the carbamate 9 is a
key building block of a novel class of modified PNAs with an
increased binding affinity and sequence specificity to comple-
mentary DNA.14 On the other hand, as in the case of trans-
cyclohexane-1,2-diamine,26 the N,N′-unsymmetrical derivatives
of the cyclopentylic analogues could be highly valuable
molecules in both asymmetric catalysis and medicinal chemistry.
In the case of diamine 1d, the aminocarbamate (1S,2S)-4d
(ee > 99%) and the aminoacetamide (1R,2R)-3d (ee ) 95%)
(25) Allyl group was selectively removed employing a Pd(0) catalyst
and mercaptobenzoic acid as allyl group scavenger: Lemaire-Audoire, S.;
Savignac, M.; Geneˆt, J. P. Tetrahedron Lett. 1995, 36, 1267-1270.
(24) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J. Org. Chem. 1991, 56, 2656-2665.
J. Org. Chem, Vol. 72, No. 4, 2007 1313

Gonza´lez-Sab´ın et al.
(75.5 MHz, CDCl3): δ 20.9 (CH2), 23.0 (CH2), 33.4 (CH2), 38.0
(CH3), 54.2 (CH), 59.4 (CH2), 73.7 (CH), 126.6 (CH), 128.0 (CH),
128.5 (CH), 139.8 (C); IR (neat): nu bar 3362 cm-1; MS (ESI+)
m/z (%): 205.1 (100) [M + H]+, 227.1 (15) [M + Na]+; elemental
analysis (%) calcd for C13H20N2: C, 76.42; H, 9.87; N, 13.71.
Found: C, 76.51; H, 9.70; N, 13.59.
Conclusion
We have developed a new chemoenzymatic protocol for the
preparation of optically active trans-N,N-dialkylcyclopentane-
1,2-diamines starting out from the structurally analogous (()-
trans-2-(N,N-dialkylamino)cyclopentanols. The adequate ar-
rangement of protecting groups attached to the nitrogen atoms
allowed us to isolate orthogonally protected derivatives in high
yields and ee. The synthetic value of these compounds was also
demonstrated by the selective deprotection of each group on
the nitrogen atoms under mild reaction conditions. Both the
efficacy of the syntheses included here as well as the structural
variety of the compounds make this strategy one of the most
appropriate methods for preparing nonracemic trans-cyclopen-
tane-1,2-diamine derivatives.
General Procedure for the Enzymatic Acetylation of Racemic
Diamines 1a-d. Ethyl acetate (12 mL) was added under nitrogen
atmosphere to a mixture of racemic diamine 1a-d (2.0 mmol) and
CAL-B (200 mg). The resulting mixture was shaken at 28 °C and
200 rpm. The enzyme was subsequently filtered and washed with
ethyl acetate. For the reactions of 1a and 1d, the resulting solution
was cooled to 0 °C and then treated with di-tert-butyl dicarbonate
(1.3 mmol). After 12 h, the solvent was evaporated and both the
acetamide and carbamate present in the residue were separated by
flash chromatography (ethyl acetate/methanol mixtures). Similarly,
benzyl chloroformate was used in the derivatization process for
the reaction of 1c. For the reaction of 1b, after filtration of the
enzyme, the corresponding acetamide and the remaining diamine
were separated by flash chromatography using ethyl acetate/
methanol 3:1.
Experimental Section
General Procedure for the Preparation of Racemic Diamines
1a-d. The corresponding (()-trans-2-(N,N-dialkylamino)cyclo-
pentanol17 (2a-d, 25 mmol) was dissolved in anhydrous diethyl
ether (45 mL), and triethylamine (39 mmol) was added. The solution
was cooled to 0 °C, and mesyl chloride (29.7 mmol) was added
dropwise. A white precipitate formed that made stirring difficult.
After 30 min, triethylamine (49 mmol) was added. After the reaction
mixture was allowed to warm to room temperature, concd aq NH3
(50 mL) was added and the resulting two-phase reaction mixture
was vigorously stirred for 16 h. The layers were separated, and the
light-yellow aqueous layer was extracted with Et2O (3 × 30 mL).
The combined organic layers were washed with brine (20 mL),
dried with Na2SO4, and evaporated under reduced pressure to give
the crude product, which was purified by distillation or flash
chromatography (ethyl acetate/methanol mixtures).
(1R,2R)-N-[2-(N′-Benzyl-N′-methylamino)cyclopentyl]aceta-
mide [(1R,2R)-3a]: Yield: 46%; mp 82-84 °C; [R]20 -27.8 (c
D
1.0 in CHCl3) 94% ee; 1H NMR (300 MHz, CDCl3): δ 1.25-1.40
(m, 1H), 1.50-1.80 (m, 4H), 1.98 (s, 3H, CH3), 2.05-2.25 (m +
s, 4H), 2.80 (c, 1H, J ) 11.7 Hz), AB system (δA 3.50, δB 3.64,
JAB ) 19.4 Hz, CH2-Ph), 4.16 (q, 1H, J ) 11.7 Hz), 5.68 (brd,
1H, NH, J ) 8.2 Hz), 7.20, 7.40 (m, 5H, Ph); 13C NMR (75.5
MHz, CDCl3): δ 21.1 (CH2), 23.4 (CH3), 23.5 (CH2), 31.5 (CH2),
38.0 (CH3), 51.9 (CH), 58.9 (CH2), 70.0 (CH), 126.9 (CH), 128.2
(CH), 128.7 (CH), 139.4 (C), 169.7 (CdO); IR (neat): nu bar 3307,
1636 cm-1; MS (EI+) m/z (%): 246.2 (5) [M]+, 187.2 (70), 91.0
(100); elemental analysis (%) calcd for C15H22N2O: C, 73.13; H,
9.00; N, 11.37. Found: C, 73.26; H, 8.78; N, 11.25.
(()-trans-N-Benzyl-N-methylcyclopentane-1,2-diamine [(()-
1a]: Prepared from (()-trans-2-(N-benzyl-N-methylamino)cyclo-
pentanol (2a). Yield: 92%; bp 95-97 °C (0.5 Torr); 1H NMR (200
MHz, CDCl3): δ 1.25-1.45 (m, 1H), 1.50-1.80 (m, 4H), 1.85-
2.00 (m, 1H), 2.15 (s, 3H, CH3), 2.45 (brs, 2H, NH2), 2.56 (c, 1H,
J ) 7.8 Hz), 3.12 (c, 1H, J ) 7.8 Hz), AB system (δA 3.45, δB
3.58, JAB ) 13.3 Hz, CH2-Ph), 7.20-7.40 (m, 5H, Ph); 13C NMR
Acknowledgment. This article is dedicated to Professor
V´ıctor Riera on the occasion of his retirement. We thank Novo
Nordisk Co. for the generous gift of the CALB. This work was
supported by the Ministry of Education and Science (Spain;
Project MEC-04-CTQ-04185).
Supporting Information Available: Additional experimental
procedures and chiral HPLC analyses data for the optically active
compounds, copies of 1H and 13C NMR spectra, and copies of chiral
HPLC chromatograms. This material is available free of charge
via the Internet at http://pubs.acs.org.
(26) (a) Boyd, E.; Coumbarides, G. S.; Eames, J.; Jones, R. V. H.;
Stenson, R. A.; Suggate, M. J. Tetrahedron Lett. 2005, 46, 3473-3478.
(b) Bisai, A.; Bhanu Prasad, B. A.; Singh, V. K. Tetrahedron Lett. 2005,
46, 7935-7939. (c) Holbach, M.; Zheng, X.; Burd, C.; Jones, C. W.; Weck,
M. J. Org. Chem. 2006, 71, 2903-2906.
JO062205H
1314 J. Org. Chem., Vol. 72, No. 4, 2007