Highly stereoselective aziridine ring-opening with phenylselenide anion and selective intramolecular aldol closure for the enantiopure synthesis of γ-aminocyclopentene derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.07.070

A practical and enantiopure synthesis for the preparation of key intermediates of conformationally locked γ-amino acid and nucleoside analogues is described. First, a highly stereoselective aziridine ring-opening reaction with phenylselenide anion was emp

Full text of DOI:10.1016/j.tetlet.2009.07.070

Tetrahedron Letters 50 (2009) 5572–5574
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Highly stereoselective aziridine ring-opening with phenylselenide anion
and selective intramolecular aldol closure for the enantiopure synthesis of
c-aminocyclopentene derivatives
José Alvano Pérez-Bautista a, Martha Sosa-Rivadeneyra a, Leticia Quintero a, Herbert Höpfl b,
Farid Andrés Tejeda-Dominguez a, Fernando Sartillo-Piscil a,
*
a Centro de Investigación de la Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP), 14 Sur Esq, San Claudio, San Manuel, 72570 Puebla, Mexico
b Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, 62209 Cuernavaca, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and enantiopure synthesis for the preparation of key intermediates of conformationally locked
Received 2 June 2009
Revised 11 July 2009
Accepted 14 July 2009
Available online 18 July 2009
c
-amino acid and nucleoside analogues is described. First, a highly stereoselective aziridine ring-opening
reaction with phenylselenide anion was employed for the stereoselective synthesis of the chiral amino-
selenide (1S,2S,10S)-8, which after N-benzylation was transformed into the corresponding allyl amine
(1S,10S)-7 by oxidation with H2O2. Then, dihydroxylation–dehomologation of (1S,10S)-7 with (OsO4/
NMO, NaIO4) selectively afforded the desired
-amino acid (S)-2 via an intramolecular selective aldol-condensation catalyzed by an internal base.
Ó 2009 Elsevier Ltd. All rights reserved.
c-aminocyclopentene aldehyde (S)-1 and its corresponding
c
Chiral
role as intermediates for the preparation of conformationally
locked carbocyclic nucleosides2 and -amino acid3 analogues,
and have been proven to provide very important information about
the conformation and puckering of the ribose carbohydrate ring
that has permitted to study the outcome of reactions between
some prodrugs and specific enzymes,2b,4 and about the active con-
formation of GABA at receptors.3b,5
c
-aminocyclopentene derivatives1 A play an important
densation of the chiral amino dialdehyde (1S,10S)-6, which can be
generated via sequential dihydroxylation–dehomologation of allyl
amine (1S,10S)-7. The latter is obtained by a stereoselective aziri-
dine ring-opening reaction with phenylselenide anion9 followed
by an oxidative syn elimination (Scheme 1).
The synthetic route seems to be simple; however, the selective
intramolecular aldol-condensation reactions have been proven to
be difficult to achieve,10 and the stereoselective two-step synthesis
of allyl amines from aziridines by ring-opening with phenylselenide
anion has curiously not been reported yet. Although well-known for
epoxides,11 to the best of our knowledge, this is the first report on a
stereoselective synthesis of an allyl amine starting from chiral
aziridine.
c
O
(R or S)
NH2
R
(R = H or OH)
A
Since many of the methods reported for the preparation of chi-
ral 3-aminocyclopentene derivatives require resolution into their
optical antipodes, the development of new synthetic routes for
their selective and stereoselective construction is of great
importance.
As result of our continuing investigations on the enantioselec-
tive synthesis of biologically important GABA6 and nucleoside ana-
logues,7 herein, we report a highly selective and stereoselective
selective intramolecular
aldol condensation reaction
H
Ph
H
O
Ph
NBn
O
H
O
H
NBn
R
R = H: (1S,1'S)-1
R = OH: (1S,1'S)-2
(1S,1'S)-6
synthesis for the optically pure N-protected c-aminocyclopentene
aldehyde (1S,10S)-1 and its corresponding amino acid (1S,10S)-2
stereoselective ring-opening
followed by an oxidative
syn-elimination
using the chiral aziridine (S)-58 as starting material.
H
Ph
H
Our general strategy for the construction of the chiral c-amino-
cyclopentene ring consists of a selective intramolecular aldol-con-
NBn
H
N
+
PhSe
Ph
(S)-5
(1S,1'S)-7
* Corresponding author. Tel./fax: +52 2222 295500x7391.
E-mail address: fsarpis@siu.buap.mx (F. Sartillo-Piscil).
Scheme 1. Strategic plan for the synthesis of (S)-1 and (S)-2.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.070

J. A. Pérez-Bautista et al. / Tetrahedron Letters 50 (2009) 5572–5574
5573
As indicated in Table 1, addition of phenylselenide anion, gener-
ated from diphenyldiselenide and NaBH4, to chiral aziridine (S)-5
afforded a mixture of the trans-aminoselenides (1S,2S,10S)-8 and
(1R,2R,10S)-9 with high stereoselectivity (91:9) and high yield
(95%).12 During our effort to improve the stereoselectivity of this
reaction even more, we noted that the stereoselectivity did not in-
crease neither at lower temperatures (entries 2–7) nor in the pres-
ence of Lewis acids (Table 1, entries 4–7). On the contrary, yield
and stereoselectivity diminished slightly when using Lewis acids.13
The absolute configuration of the major diastereoisomer
(1S,2S,10S)-8 was determined by single-crystal X-ray diffraction of
its corresponding HCl salt14 (Fig. 1).
base or another additive;10d however, we were very surprised to
see that this step was not necessary, since a selective intramolecular
aldol-condensation occurredeven in the absenceof an externalbase,
thus the chiral aminoaldehyde (1S,10S)-1 was obtained in good yield,
and its corresponding amino acid (1S,10S)-2 was obtained if Jones
reagent was added.16
Since 1,4-non-symmetric dialdehydes have been proven to be
very stable and generally chiral or nonchiral bases are needed for
selective aldol ring-closures,10 it seems logical to postulate that
the N-protected amino group plays a key role in the selective intra-
molecular aldol-condensation, and a model that accounts for the
influence of the internal base is given in Scheme 3.
The aminoselenide (1S,10S)-7 was obtained upon treatment of
aminoselenide (1S,2S,10S)-8 with an excess of H2O2 in methanol
at reflux for 9 h, followed by N-benzylation with BnBr and Na2CO3
(Scheme 2). It should be mentioned that classical oxidizing
agents15 such as O3, NaIO4, t-BuOOH, and mCPBA did not work in
this case.
According to Scheme 3, the amine group acts as an internal base
that catalyzes the ring closure. In order to prove the key role of the
amine group in this unprecedented intramolecular aldol-conden-
sation, we prepared the amide (S)-11 with the expectation that
the nitrogen lone pair is delocalized toward a carbonyl group, so
the proposed internal hydrogen bonding will be attenuated
and the spontaneous condensation must not occur. The result
was as we expected, very high yield of dialdehyde (1S,10S)-1217
was obtained when amide (S)-11 was treated with OsO4/NMO
and NaIO4 (Scheme 4). However, it is important to mention that
Initially, within our strategic plan for the conversion of (1S,10S)-7
into (1S,10S)-1 or (1S,10S)-2, we postulated the isolation of dialde-
hyde (1S,10S)-6 followed by the treatment with a chiral/nonchiral
Table 1
1. H2O2, MeOH
reflux for 6 h
Stereoselective ring-opening of chiral aziridine (S)-5a,b
SePh
H
H
N
2. BnBr, Na2CO3
CH3CN
Ph
Ph
Bn
N
Ph
SePh
H
H
SePh
H
(1S,1'S)-7
H
(1S,2S,1'S)-8
PhSeSePh
NaBH4, EtOH
+
53%
N
N
N
Ph
Ph
H
Ph
(1S,2S,1'S)-8
H
(S)-5
(1R,2R,1'S)-9
O
cat OsO4, NMO
NaIO4 in acetone
(Jones reagent)
NBn
(1S,1'S)-7
R
Entry
Conditions
Ratio of 8:9
Yield (%)
:60%
: 52%
R = H: (1S,1'S)-1
R = OH: (1S,1'S)-2
1
2
3
4
5
6
7
0 °C, 4 h
91:09
90:10
88:12
85:15
76:24
75:25
75:25
95
90
90
80
76
60
70
Not observed
ꢀ30 °C, 6 h
ꢀ78 °C, 6 h
ꢀ78 °C, BF3ꢁOEt2, 2 h
ꢀ78 °C, AlCl3, 2 h
ꢀ78 °C, LiClO4, 2 h
ꢀ78 °C, Ti(i-PrO)4, 2 h
Ph
NBn
(1S,1'S)-6
O
O
a
Yield of products determined after purification.
Diastereomeric ratio determined by NMR.
b
Scheme 2. Selective synthesis of (1S,10S)-1 and (1S,10S)-2.
Ph
Bn
H
N
O
(1S,1'S)-1
O
(1S,1'S)-7
Scheme 3. Model proposed to account for the influence of the internal base on the
selective intramolecular aldol-condensation of (1S,10S)-7.
H
H
AcCl
N
N
NaH
THF, reflux
85%
Ph
Ph
H
O
(1S,1'S)-10
(1S,1'S)-11
O
O
H
cat. OsO4, NMO
NaIO4
92%
(1S,1'S)-11
N
Ph
O
(1S,1'S)-12
Figure 1. Perspective view of the molecular structure of (1S,2S,10S)-8 HCl salt.
Scheme 4. Demonstration of amine group acting as an internal base.

5574
J. A. Pérez-Bautista et al. / Tetrahedron Letters 50 (2009) 5572–5574
was stirred for 6 h. When the consumption of the starting aziridine was
completed (monitored by TLC), the reaction mixture was quenched with water
(50 mL) and the organic phase was extracted with ethyl acetate (3 ꢂ 50 mL).
The combined organic layers were dried with anhydrous Na2SO4 and
concentrated under reduced pressure. The yellow oil residue was purified by
flash silica gel chromatography (eluent:hexane/ethyl acetate 30:1). (1S,2S,10S)-
[(10-Phenylethyl)-(2-phenylselenyl-cyclohexyl)amine]; (1S,2S,10S)-8: Yield 86%;
keeping the dialdehyde in a chloroform solution for several days at
room temperature (inside NMR tube), a small amount of the con-
densation product is formed.
In conclusion, we are pleased to report the first selective intra-
molecular aldol-condensation catalyzed by an internal base, which
is based on an internal hydrogen bonding. The enormous utility of
this reaction was showcased in the synthesis of optically pure
½ ꢃ
a 2D0 = +69.23 (c = 2.0, CHCl3); 1H NMR (CDCl3, 400 MHz) d: 1.01 (m, 1H), 1.16
(m, 2H), 1.33 (d, 3H, J = 6.8 Hz), 1.53 (m, 3H), 1.81 (m, 1H), 2.08 (m, 2H), 2.53
(td, 1H, J = 9.6, 4.0 Hz), 3.01 (m, 1H), 3.82 (q, 1H, J = 6.4 Hz), 7.14–7.29 (m, 8H),
7.54 (m, 2H); 13C NMR (CDCl3, 100 MHz) d: 24.2, 24.4, 26.7, 33.7, 33.8, 50.8,
56.5, 59.4, 126.3, 126.4, 127.3, 128.7, 135.1, 146.8; HRMS (EI) m/z found
359.1140, calcd. for C20H25NSe 359.1152. (1R,2R,10S)-[(10-Phenyl-ethyl)-(2-
N-protected
responding
c
c
-aminocyclopentene aldehyde (1S,10S)-1 and its cor-
-amino acid (1S,10S)-2. Although this route was exclu-
sively designed for the synthesis of the above-mentioned GABA
and nucleoside precursors, we expect that these results can also
phenylselenyl-cyclohexyl)]amine; (1S,2S,10S)-9: Yield 8%; ½a 2D0
= ꢀ82.72 (c = 1.8,
ꢃ
CHCl3); 1H NMR (CDCl3, 400 MHz) d: 1.10 (m, 1H), 1.17–1.33 (m, 2H), 1.35 (d,
3H, J = 6.9 Hz), 1.53–1.63 (m, 2H), 2.03 (m, 2H), 2.13–2.26, (m, 2H) 2.43(s, 1H),
3.04 (ddd, 1H, J = 11.7, 9.9, 3.9 Hz), 3.93 (q, 1H, J = 6.6 Hz), 7.15–7.42 (m, 10H);
13C NMR (CDCl3, 100 MHz) d: 24.3, 24.9, 27.1, 32.2, 34.1, 51.0, 54.1, 56.8, 126.6,
126.8, 127.4, 128.4, 128.8, 135.3, 145.2. HRMS (EI) m/z found 359.1151, calcd.
for C20H25NSe 359.1152.
be applied to the synthesis of further complex substituted
c-
aminocyclopentene derivatives. Further results on the application
of this new route for the synthesis of new GABA, and nucleosides
derivatives will be reported soon.
13.
A similar negative effect on the yields and stereoselective outcome of
aziridines ring-opening with azide was observed in: Chandrasekhar, M.;
Acknowledgments
Sekar, G.; Singh, V. K. Tetrahedron Lett. 2000, 41, 10079.
14. Crystal data: C20H26ClNSe, Mr = 394.83 gmolꢀ1
,
0.10 ꢂ 0.28 ꢂ 0.60 mm3,
We thank CONACyT for financial support (grants: 62203 and
91435 for FSP and MSR, respectively). We also thank Mr. Vladimir
Carranza-Tellez for technical assistance.
triclinic, space group P-1, T = 293(2) K, a = 7.5474(9), b = 9.0498(11)
c =16.145(2) Å,
Z = 2, calcd = 1.347,
independent reflections (Rint = 0.038), R1 = 0.075 for 6002 reflections with I >2
(I) and wR2 = 0.173 for all data, 411 parameters, GOF = 1.16 (CCDC 723281).
a
= 99.491(2), b = 97.620(2),
l
c
= 113.462(2) °, V = 973.5(2) Å3,
q
= 2.066 mmꢀ1, 2hmax = 25.00, 9488 measured and 6734
r
References and notes
15. (a) Selenium in Natural Products Synthesis; Nicolaou, K. C., Petasis, N. A., Eds.;
CIS, Inc., 1984. Chapter 4; (b) Nishibayashi, Y.; Uemura, S. In Organoselenium
Chemistry–A Practical Approach; Back, T. G., Ed.; Oxford University Press:
Oxford, 1999; p Chapter 11; (c) Nishibayashi, Y.; Uemura, S.. In Topics in Current
Chemistry: Organoselenium Chemistry; Wirth, T., Ed.; Springer: Berlin, 2000; Vol.
208, p 201.
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1991, 921; (c) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571; (d)
Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S. R.; Earl, R. A.;
Guedj, R. Tetrahedron 1994, 50, 10611.
2. (a) Marquez, V. E.; Lim, M.-I. Med. Res. Rev. 1986, 6, 1; (b) Rodriguez, J. B.;
Marquez, V. E.; Nicklaus, M. C.; Mitsuya, H.; Barchi, J. J. J. Med. Chem. 1994, 37,
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Nucleotides Nucleic Acids 2002, 21, 65.
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Qiu, J.; Pingsterhaus, J. M.; Silverman, R. B. J. Med. Chem. 1999, 42, 4727; (c)
Ordoñez, M.; Cativiela, C. Tetrahedron: Asymmetry 2007, 18, 3.
4. Marquez, V. E.; Lim, B. B.; Barchi, J. J., Jr.; Nicklaus, M. C. Conformational Studies
and Anti-HIV Activity of Mono- and Difluorodideoxy Nucleosides. In
Nucleosides and Nucleotides as Antitumor and Antiviral Agents; Chu, C. K.,
Baker, D. C., Eds.; Plenum Press: New York and London, 1993; p 265.
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430, 185.
6. (a) Rodríguez, V.; Sánchez, M.; Quintero, L.; Sartillo-Piscil, F. Tetrahedron 2004,
60, 10809; (b) Rodríguez, V.; Quintero, L.; Sartillo-Piscil, F. Tetrahedon Lett.
2007, 48, 4305; (c) Rodríguez, V.; Quintero, L.; Sartillo-Piscil, F. Tetrahedon
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9. (a) Zhang, W.-X.; Ye, K.; Ruan, S.; Chen, Z.-X.; Xia, Q.-H. Chin. J. Chem. 2007, 25,
1758; (b) Besev, M.; Engman, L. Org. Lett. 2000, 2, 1589; (c) Braga, A. L.; Lüdtke,
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Paixão, M. W.; Marin, G. Synlett 2005, 11, 1675.
16. Sequential dihydroxylation–dehomologation-aldol-condensation of allyl amine
(1S,10S)-7: To
10 mL of
a
solution of allyl amine (1S,10S)-7 (0.050 g, 0.17 mmol) in
mixture of acetone/H2O (10/1), 4-methylmorpholine N-oxide
a
(0.060 g, 0.51 mmol) and osmium tetroxide (0.0034 mmol, 0.034 mL of a 0.1 M
tert-butanol solution) were added. The resulting solution was stirred for 16 h at
room temperature. When the consumption of the starting amine was
completed (monitored by TLC), the reaction mixture was quenched with
water (20 mL) and the organic phase was extracted with CH2Cl2 (3 ꢂ 30 mL).
The combined organic layers were dried with anhydrous Na2SO4, filtered, and
the solvent was evaporated carefully under reduced pressure. The residue was
dissolved in ethanol (10 mL) and sodium periodate (0.07 g, 0.32 mmol) was
slowly added at 0 °C. The reaction mixture was allowed to react for 2 h and
filtered, whereupon the solvent was evaporated carefully under reduced
pressure and the residue extracted with CH2Cl2 (50 mL). The organic layer was
washed with water and brine, dried with Na2SO4, and concentrated under
reduced pressure. The crude product was purified by flash chromatography on
silica gel (eluent:hexane/ethyl acetate 5:1) to afford the c-aminocyclopentene
aldehyde (1S,10S)-1 in 60% yield; ½a 2D0
ꢃ
ꢀ84.66 (c 0.03, CHCl3); 1H NMR d: 1.40
(d, 3H, J = 6.6 Hz), 1.90–2.00 (m, 1H), 2.07–2.18 (m, 1H), 2.28–2.39 (m, 1H),
2.55 (m, 1H), 3.67 (q, 2H, J = 15.0 Hz), 3.91 (q, 1H, J = 6.9 Hz), 4.28 (m, 1H,), 6.42
(s, 1H), 7.23 (m, 4H), 7.24–7.42 (m, 6H), 9.62 (s, 1H); 13C NMR (CDCl3,
100 MHz) d: 6.1, 16.7, 26.9, 50.9, 57.6, 64.2, 126.8, 126.9, 127.6, 128.2, 128.3,
154.9, 158.1, 189.8; HRMS (FAB+) m/z found 305.1887, calcd. for C21H23NO,
305.1780. The corresponding c
-aminocyclopentene acid (1S,1S0)-2 is obtained
when 2 equiv of Jones reagent is added into the flask containing the (1S,10S)-1
reaction crude. Purification by flash chromatography on silica gel
(eluent:hexane/ethyl acetate 3:1) afforded the
c-aminocyclopentene acid
(1S,10S)-2 in 52% yield. White solid, mp 127–128 °C; ½a 2D0
ꢀ171.6 (c 1.0,
ꢃ
CHCl3). 1H NMR d: 1.25 (s, 2H), 1.35 (d, 3H, J = 6.6 Hz), 1.88–2.00 (m, 1H), 2.04–
2.17 (m, 1H), 2.35–2.45 (m, 1H), 2.57 (m, 1H), 3.67 (q, 2H, J = 15 Hz), 3.88
(q, 1H, J = 6.6 Hz), 4.19 (m, 1H,), 6.57 (s, 1H), 7.23 (m, 4H), 7.28–7.42 (m, 6H);
13C NMR d: 16.6, 27.4, 29.9, 50.7, 57.5, 64.4, 126.7, 126.8, 127.6, 128.1, 128.2,
128.3, 135.9, 141.2, 143.9, 148.8, 170.1 HRMS (EI) m/z found 322.1804, calcd.
for C21H23NO2, 322.1807.
10. (a) Heathcock, C. H.. In Comprensive Organic Synthesis; Trost, B., Ed.; Pergamon:
Oxford, 1991; Vol. 2, p 156; (b) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.;
Siret, P.; Keck, G. E.; Gras, J.-L. J. Am. Chem. Soc. 1978, 100, 8031; (c) Woodward,
R. B.; Sondheimer, F.; Taub, D.; Heusler, K.; McLamore, W. M. J. Am. Chem. Soc.
1952, 74, 4223; (d) Snyder, S. A.; Corey, E. J. Tetrahedron Lett. 2006, 47, 2083.
11. Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95, 2697.
12. Stereoselective ring-opening of N-[(S)-1-phenylethyl]cyclohexyl aziridine (1S)-5
17. (1S,10S)-[(N-1,4-Diformylbutyl)-N-(10 phenylethyl)]acetamide; (1S, 10S)-12: 1H
NMR d: 1.55–1.82 (m, 2H), 1.67 (d, 3H, J = 7.2 Hz), 2.29 (m, 2H), 2.36 (s, 3H),
2.48 (q, 2H, J = 6.4 Hz), 2.99 (dd, 1H, J = 8.0, 4.4 Hz), 5.22 (q, 1H, J = 7.2 Hz), 7.37
(m, 5H), 9.06 (s, 1H), 9.77 (s, 1H); 13C NMR (CDCl3, 100 MHz) d: 18.2, 20.0, 29.2,
43.7, 56.3, 61.6, 127.0, 128.4, 129.0, 139.2, 170.6, 198.6, 202.1.
with phenylselenide anion: To
a solution of diphenyldiselenide (2.33 g,
7.45 mmol) and sodium borohydride (1.13 g, 19.84 mmol) in methanol
(50 mL) at 0 °C, N-[(S)-1-phenylethyl]cyclohexyl aziridine (S)-58 (1 g,
4.96 mmol) dissolved in methanol (15 mL) was added. The resulting solution