Diastereoselective access to trans -2-substituted cyclopentylamines

Article abstract of DOI:10.1021/ol102038x

A highly diastereoselective synthesis of trans-2-substituted cyclopentylamines via a tandem hydrozirconation/Lewis acid-mediated cyclization sequence applied to butenyl oxazolidines is described. The method allows an easy preparation of diversely substituted cyclopentylamines which appear to be useful synthetic intermediates. This was further illustrated by the syntheses of (±)-Rodocaine, (±)-trans-pentacin, and enantiomerically enriched trans-cyclopentane-1,2-diamine.

Full text of DOI:10.1021/ol102038x

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5128-5131
Diastereoselective Access to
trans-2-Substituted Cyclopentylamines
´
Antoine Joosten, Emilie Lambert, Jean-Luc Vasse,* and Jan Szymoniak*
Institut de Chimie Mole´culaire de Reims, CNRS (UMR 6229) and UniVersite´ de Reims,
51687 Reims Cedex 2, France
jean-luc.Vasse@uniV-reims.fr; jan.szymoniak@uniV-reims.fr
Received August 27, 2010
ABSTRACT
A highly diastereoselective synthesis of trans-2-substituted cyclopentylamines via a tandem hydrozirconation/Lewis acid-mediated cyclization
sequence applied to butenyl oxazolidines is described. The method allows an easy preparation of diversely substituted cyclopentylamines
which appear to be useful synthetic intermediates. This was further illustrated by the syntheses of (()-Rodocaine, (()-trans-pentacin, and
enantiomerically enriched trans-cyclopentane-1,2-diamine.
The cyclopentylamine moiety is frequently encountered in
naturally occurring molecules, especially alkaloids, and it
constitutes a valuable building block for the preparation of
biologically active molecules. Among them, 2-aminocyclo-
pentanecarboxylic acids display various biological applica-
tions.1 For example, cispentacin A (Figure 1), isolated from
Figure 1. Cyclopentylamines A and B.
Bacillus cereus, is an antifungal agent.2 In addition to their
intrinsic biological properties, 2-aminocyclopentanecarboxy-
lic acids can be incorporated into peptides instead of
proteinogenic R-amino acids for modifying the original
activity.1 Also, trans-cyclopentanediamine B is intensively
used as a valuable tool for SAR studies. For example, its
incorporation into peptide nucleic acids results in a confor-
mation constraint, improving bindings to DNA and RNA.3
Furthermore, ligands based on the trans-cyclopentane-1,2-
diamine scaffold offer interesting perspectives in asymmetric
catalysis.4
Whereas access to both isomers of 2-aminocyclopentan-
ecarboxylic acids5 and to trans-cyclopentane-1,2-diamine
derivatives6 is well documented in the literature, no general
synthetic method is available for the preparation of diversely
(3) (a) Myers, M. C.; Witschi, M. A.; Lariona, N. V.; Franck, J. M.;
Haynes, R. D.; Hara, T.; Grajkowski, A.; Appella, D. H. Org. Lett. 2003,
5, 2695–2698. (b) Pokorski, J. K.; Witschi, M. A.; Purnell, B. L.; Appella,
D. H. J. Am. Chem. Soc. 2004, 126, 15067–15073. (c) Zhang, N.; Appella,
D. H. J. Am. Chem. Soc. 2007, 129, 8424–8425.
(1) (a) Gademann, K.; Hinterman, T.; Schreiber, J. V. Curr. Med. Chem.
1999, 6, 905–925. (b) Juaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem. 1999,
6, 983–1004. (c) Scarborough, R. M. Curr. Med. Chem. 1999, 6, 971. (d)
Fulop, F. Chem. ReV. 2001, 101, 2181–2204.
(2) (a) Iwamoto, T.; Tsujii, E.; Ezaki, M.; Fujie, A.; Hashimoto, S.;
Okuhara, M.; Kohsaka, M.; Imanaka, H.; Inamoto, Y.; Sakane, K. J.
Antibiotics 1990, 43, 1–7. (b) Kawabata, K.; Inamoto, Y.; Sakane, K.;
Iwamoto, T.; Hashimoto, S. J. Antibiot. 1990, 43, 513–518.
(4) (a) Larrow, J. F.; Jacobsen, E. N. Top. Organomet. Chem. 2004, 6,
123–152. (b) Dominguez, B.; Hodnett, N. S.; Lloyd-Jones, G. C. Angew.
Chem., Int. Ed. 2001, 40, 4289–4291. (c) Daly, A. M.; Gilheavy, D. G.
Tetrahedron: Asymmetry 2003, 14, 127–137.
10.1021/ol102038x  2010 American Chemical Society
Published on Web 10/18/2010

substituted cyclopentylamines. In fact, most of the reported
procedures imply the ring opening of aziridines,7 which is
not suitable to all classes of nucleophilic agents.
Recently, we described an efficient stereoselective ap-
proach to 2-substituted pyrrolidines, based on a tandem
hydrozirconation/Lewis acid-mediated cyclization starting
from N-allyloxazolidines (Scheme 1, path a).8 We thought
Table 1. Effect of the Lewis Acids and HCl on the
Ring-Closure Step
entry
acid
dr
yield (%)
Scheme 1
.
Access to 2-Substituted Pyrrolidines and Extension
of the Method to Cyclopentylamines
1
2
3
4
5
6
HCl (1 M)
HCl (4 M)
AlCl3
TiCl4
BF3·OEt2
TMSOTf
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
84
64
83
49
89
92
aqueous solution of HCl instead of the Lewis acid (entries 1
and 2) similar results were obtained, whereas hydrolysis
products would have been expected.
To extend the scope of the reaction, a range of diversely
substituted oxazolidines 1b-l (for experimental procedures,
see Supporting Information) were synthesized and submitted
to the same reaction conditions.
The reaction appears as quite general and proceeds
smoothly irrespective of the substituent, giving access to
diversely substituted cyclopentylamines. Thus, cyclopenty-
lamines substituted at the 2-position with aromatic (Table
2, entries 1-3), heteroaromatic (entry 4), and aliphatic
that the reaction could be extended toward the exo mode
cyclization to afford cyclopentylamines (path b). An analo-
gous radical cyclization of unsaturated oximes and hydra-
zones has been reported.9
To check this approach, the oxazolidine 1a derived from
2-benzylaminoethanol was first obtained as a 1.3:1 mixture
of diastereomers and subjected to the hydrozirconation/
cyclization sequence (Table 1). By using several Lewis acids
(entries 3-6), the expected cyclopentylamine 2a was ob-
tained in excellent to moderate yields and remarkably as the
sole trans isomer.10 It is noteworthy that when using an
Table 2. Synthesis of Cyclopentylamines 2
(5) For asymmetric synthesis of cispentacin, see: (a) Aggarwal, V. K.;
Roseblade, S. J.; Barrell, J. K.; Alexander, R. Org. Lett. 2002, 4, 1227–
1229. (b) Aggarwal, V. K.; Roseblade, S.; Alexander, R. Org. Biomol. Chem.
2003, 1, 684–691. For asymmetric synthesis of trans-pentacin, see: (c)
Chippendale, A. M.; Davies, S. G.; Iwamoto, K.; Parkin, R. M.; Smethurst,
C. A. P.; Smith, A. D.; Rodriguez-Solla, H. Tetrahedron 2003, 59, 3253–
3265.
(6) For the preparation of trans-diaminocyclopentane by resolution, see:
(a) Gonza´lez-Sab´ın, J.; Gotor, V.; Rebolledo, F. J. Org. Chem. 2007, 72,
1309–1314. (b) Pena, C.; Gonza´lez-Sab´ın, J.; Rebolledo, F.; Gotor, V.
Tetrahedron: Asymmetry 2008, 19, 751–755. (c) Xu, Q.; Appella, D. H. J.
Org. Chem. 2006, 71, 8655–8657.
entry
R
dr
yield (%)
1
2
Ph
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
96:4
52:48
>95:5
>95:5
>95:5
89 (2a)
88 (2b)
78 (2c)
79 (2d)
89 (2e)
92 (2f)
98 (2g)
91 (2h)
77 (2i)
74 (2j)
81 (2k)
78 (2l)
2-Br-C6H4
4-MeO-C6H4
N-Boc-indolyl
n-C6H11
3
(7) Schneider, C. Angew. Chem., Int. Ed. 2009, 48, 2–5. (b) Page,
M. F. Z.; Jalisatgi, S. S.; Maderna, A.; Hawthorne, M. F. Synthesis 2008,
555–563. (c) Blyumin, E. V.; Gallon, H. J.; Yudin, A. K. Org. Lett. 2007,
9, 4677–4680. (d) Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.;
Furusho, S.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 16438–
16439. (e) Minakata, S.; Okada, Y.; Oderaotoshi, Y.; Komatsu, M. Org.
Lett. 2005, 7, 3509–3512.
4a
5
6
7
8
9
10
11
12
i-Pr
NBn2
(CH2)3-OBn
OBn
(8) Vasse, J.-L.; Joosten, A.; Denhez, C.; Szymoniak, J. Org. Lett. 2005,
7, 4887–4889.
OTr
CH2OTr
(9) (a) Godineau, E.; Schenk, K.; Landais, Y. J. Org. Chem. 2008, 73,
6983–6993. (b) Miyata, O.; Muroya, K.; Kobayashi, T.; Yamanaka, R.;
Kajisa, S.; Koide, J.; Naito, T. Tetrahedron 2002, 58, 4459–4479. (c) Bartell,
P. A.; McLaren, K. L.; Ting, P. C. J. Am. Chem. Soc. 1988, 110, 1633–
1634.
Ph-CHdCH-CH2
a The reaction was carried out without isolating the oxazolidine which
appears to be unstable.
(10) The trans relative configuration in 1a was deduced from NOESY
experiment.
(entries 5 and 6) chains bearing N- (entry 7) or O-protected
functions (entries 8, 10, and 11) were prepared in good yields
as the sole trans diastereomer except in the case of the R )
OBn group, for which no stereoselectivity was observed
Org. Lett., Vol. 12, No. 22, 2010
5129

(entry 9). In this case, the absence of selectivity might
originate from a detrimental OBn chelation on zirconium.
In fact, when switching the benzyl to a bulky trityl, less prone
to metal chelation, a complete stereoselectivity was obtained
(entry 10). Cyclopentylamine bearing an unsaturated chain
could also be obtained owing to the chemoselective hy-
drozirconation in this case (entry 12).
tion afforded the amino acid, isolated as its methyl ester 411
after TMSCHN2 treatment.
To further illustrate the synthetic potential of the method,
the preparation of (()-Rodocaine 7,12 an ophthalmic anes-
thesia, was undertaken (Scheme 4). The synthesis began by
To account for the observed high trans stereoselectivity,
we assume that the Lewis (or protic) acid activation
preferentially generates an iminium with a perpendicular
orientation of one of the larger substituents of the adjascent
stereocenter (the R group or the zirconium-containing chain)
(Scheme 2). Accordingly, each of the two favored transition
Scheme 4. Synthesis of (()-Rodocaine
Scheme 2. Plausible Origin of the trans Selectivity
applying the deprotection/N-Boc protection sequence to 2h
to give 3h. Subsequent hydrogenolysis and condensation with
mesyl chloride provided the bicyclic precursor. The cycliza-
tion step was promoted by adding NaHMDS to give the
annulated heterocycle 5. Boc removal and coupling with
bromo amide 613 afforded the target molecule 7 in 45%
overall yield starting from 2h.
The asymmetric version of this methodology was initiated
by exploring the synthesis of N-Boc-protected trans-cyclo-
pentane-1,2-diamine, starting from commercially available
(S)-N-Boc-2-allylglycine. The required aldehyde was pre-
pared after BOP coupling with a Weinreb amine, followed
by LAH reduction.14
With optically pure aldehyde in hand, condensation with
N-benzylaminoethanol provided the cyclopentylamine pre-
cursor 1m (Scheme 5). The sequential hydrozirconation/
cylization sequence was next applied to afford 2m. Addi-
tional debenzylation and the oxidative hydroxyethyl chain
removal gave the monoprotected diamine 3m in 84% ee
[([R]20D ) +13.4, c 1, EtOH); lit., ([R]20D ) +16.0)].15 The
observed partial racemization is assumed to occur at the
iminium formation stage.16
states leads to the major trans isomer, whereas the two
unfavored transition states correspond to the minor cis
isomer.
The synthetic interest of such a method is related to the
possibility of obtaining the free amine. For that purpose, a
two-step sequence was developed by hydrogenolysis and
Pb(OAc)4 oxidative cleavage of the hydroxyethyl fragment,
the product being isolated in the N-Boc protected form
(Scheme 3). Applied to 2k, this sequence gave 3k, a trans-
pentacin precursor. Further alcohol deprotection and oxida-
In summary, we described a highly diastereoselective
method for the preparation of trans-2-substituted cyclopen-
tylamines. High substituent flexibility of the method allows
a simple access to valuable building blocks as illustrated by
Scheme 3
. Access to the Boc-Protected
trans-2-Aminocyclopentanoate 4
(11) (a) Tang, W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003, 125,
9570–9571. (b) Gardiner, J.; Anderson, K. H.; Downard, A.; Abell, A. D.
J. Org. Chem. 2004, 69, 3375–3382.
(12) Henshall, T.; Parnell, E. W. J. Chem. Soc 1962, 661. Hermans,
H.; Hubert, K. F.; Knaeps, G. A.; Willems, J. J. M. U.S. Patent No.
3,679,686, 1972.
(13) 6 was prepared in 83% yield from the corresponding acyl chloride
and aniline derivative according to: Tenthorey, P. A.; DiRubio, R. L.;
Feldman, H. S.; Takman, B. H. J. Med. Chem. 1979, 22, 1182–1186.
(14) Rishel, M. J.; Hecht, S. M. Org. Lett. 2001, 3, 2867–2869.
(15) The enantiomeric excess was confirmed by chiral HPLC after
derivatization. See ref 6a.
(16) In this case, BF3·OEt2 was added at -10°C, and addition at higher
temperature increases the racemization.
5130
Org. Lett., Vol. 12, No. 22, 2010

More interestingly, access to optically pure 2-substituted
pent-4-enal derivatives is well-established,17 allowing a
nonracemic extension of such a method.
Scheme 5. Synthesis of (S,S)-Cyclopentane-1,2-diamine (3m)
Acknowledgment. Financial support of this work by
CNRS, ANR, and the Ministe`re de l’Enseignement Supe´rieur
et de la Recherche is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL102038X
(17) For the synthesis of optically pure 2-substituted pent-4-enal
derivatives via the diastereoselective allylation of pseudoephedrine-derived
amides followed by reduction, see: (a) Myers, A. G.; Yang, B. H.; Chen,
H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116, 9361–9362. (b) Myers,
A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W. J. Am. Chem. Soc. 1995,
117, 8488–8489. (c) Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W.
J. Am. Chem. Soc. 1997, 119, 656–673. (d) Myers, A. G.; Schnider, P.;
Yoon, T.; Kung, D. W. J. Org. Chem. 1999, 64, 3322–3327.
the synthesis of (()-Rodocaine. Moreover, the asymmetric
version could be envisioned as demonstrated by the synthesis
of enantiomerically enriched trans-cyclopentane-1,2-diamine.
Org. Lett., Vol. 12, No. 22, 2010
5131