Conjugate addition of amines to chiral 3-aziridin-2-yl-acrylates

Article abstract of DOI:10.1016/j.tetlet.2010.02.087

Conjugate addition of benzylamine to chiral methyl cis-3-aziridin-2-yl-acrylates was successfully proceeded to yield 3-aziridin-2-yl-3-benzylaminopropionates in high yield with high stereoselectivity. The addition products were used for the asymmetric syn

Full text of DOI:10.1016/j.tetlet.2010.02.087

Tetrahedron Letters 51 (2010) 2181–2183
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Conjugate addition of amines to chiral 3-aziridin-2-yl-acrylates
b
b,
Doo-Ha Yoon a, Hyun-Joon Ha a, , Bong Chan Kim , Won Koo Lee
*
*
a Department of Chemistry and Protein Research Centre for Bio-Industry, Hankuk University of Foreign Studies, Yongin 449-719, Republic of Korea
b Department of Chemistry, Sogang University, Seoul 121-742, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Conjugate addition of benzylamine to chiral methyl cis-3-aziridin-2-yl-acrylates was successfully pro-
ceeded to yield 3-aziridin-2-yl-3-benzylaminopropionates in high yield with high stereoselectivity. The
addition products were used for the asymmetric synthesis of vicinal diamine derivatives including 4-
amino-5-methylpyrrolidin-2-one, 3,4-diaminopentanoate, and 5-chloromethyl-4-alkoxycarbonylmethy-
limidazolidin-2-one.
Received 28 December 2009
Revised 11 February 2010
Accepted 16 February 2010
Available online 19 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated with respect to the memory of
Professor Chi Sun Hahn
Keywords:
Conjugate addition
Amine
Aziridin-2-yl-acrylates
Diamine
Synthesis of stereochemically well-defined 1,2-diamines is still
a great challenge to many organic chemists due to their vast utili-
ties as catalysts, metal-ligands, and sub-unit of some natural
O
H2N
NH2
products.1 Especially b,
c-diamino acids and their cyclic forms like
R
HN
NH
R
CO2H
O
4-aminopyrrolidin-2-one and imidazolidin-2-one have unique
properties as peptidomimetics2 and as constituents of biologically
active molecules including renin-inhibitory statin analogs,3 anti-
fungal and cytotoxic microsclerodermins,4 and antipsychotic
nemonapride.5 Furthermore, the reduced form of 4-aminopyrroli-
din-2-one provides an entry into the 3-aminopyrrolidine family
of alkaloids (Fig. 1).6
N
H
NH2
R
CO2R'
β,γ-diamino acid
imidazolidine-2-one
4-aminopyrrolidin-2-one
Figure 1. b,c-Diamino acids, 4-aminopyrrolidin-2-ones, and imidazolidine-2-ones.
many valuable compounds such as unnatural amino acids,9 sphin-
ganine,10 phytosphingosine,11 ceramide analogs,12 and terminal
1,2-diamines.13 Homologation by two carbons and introduction
of one more amino group adjacent to the aziridine-ring will be able
Considering the vast utilities of these compounds, limited
methods are available and most of which is based on
a-amino
acids as starting material through homologations followed by
introducing one more amine functionality.7 These known methods
were suffered from the limited sources of starting substrates and
the multi-reaction steps including low yield. In this Letter is de-
scribed a general and facile synthetic method to access enantiome-
to provide a good synthetic intermediate toward the targeted b,c-
diamino acids and their cyclic forms.
At first trans- and cis-3-[{(10R)-phenylethylaziridine}-(2R)- and
(2S)-yl]-acrylates were selectively prepared from aziridine-2-car-
boxaldehyde.8 The reaction of [(1R)-phenylethylaziridine]-(2R)-
carboxaldehyde with (EtO)2POCH2CO2R yielded trans-3-[{(10R)-
phenylethylaziridin}-(2S)-yl]-acrylate in more than 95% yield with
the ratio of 98:2 regardless of R (methyl and ethyl). The same reac-
tion with Ph3PCH2CO2R leading to alkyl cis-3-[{(10R)-phenylethy-
rically pure anti b,c-diamino acids and their cyclic forms using
chiral aziridine.
During last several years we have shown that enantiomerically
pure aziridine-2-carboxylate is a configurationally stable surrogate
of
a
- or b-amino acids.8 Homologation and proper functionaliza-
tion of carboxylate followed by aziridine ring opening provided
laziridin}-(2R)- and (2S)-yl]-acrylates,
1
and 2, was also
successfully provided in more than 93% yield with the ratio of
88:12 (R = Me) and 86:14 (R = Et). Interestingly, only the cis and
trans isomers bearing methyl ester were chromatographically
* Corresponding authors. Tel.: +82 31 3304369; fax: +82 31 3304566 (H.-J.H.);
tel.: +82 2 7058449; fax: +82 2 7010967 (W.K.L.).
E-mail addresses: hjha@hufs.ac.kr (H.-J. Ha), wonkoo@sogang.ac.kr (W.K. Lee).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.087

2182
D.-H. Yoon et al. / Tetrahedron Letters 51 (2010) 2181–2183
Table 1
Addition of benzylamines to methyl cis-3-[{(10R)-phenylethylaziridin}-(2R)-yl]-acrylate (1)
Me
Me
Me
NHR
NHR
RNH2
Ph
N
Ph
N
Ph
N
CO2Me
CO2Me
H
CO2Me
H
H
3A (erythro)
3B (threo)
Yieldb (%)
1
Entry
RNH2
Temp (°C)
Timea (h)
Ratioc (3A:3B)
1
2
3
4
5
PhCH2NH2 (a)
PhCH2NH2 (a)
PhCH2NH2 (a)
(R)-Ph(CH3)CHNH2 (b)
(S)-Ph(CH3)CHNH2 (c)
rt
0
ꢀ40
50
50
14
24
20
7
95
91
98
95
97
2.9:1
2.9:1
4.0:1
3.3:1
>99:1
7
a
b
c
The reaction was carried out with amine in MeOH.
Yields, not optimized.
Ratios, determined by 1H NMR.
of the phenylethyl group of the aziridine ring and (S)-a-methyl-
benzylamine nucleophile.
The inseparable diastereomeric mixture of 3Aa and 3Ba obtained
from entry 2 in Table 1 was further reacted with triphosgene and
NaH to yield 4-chloromethyl-5-methoxycarbonylmethylimdazoli-
din-2-ones 5 and 6 (Scheme 1).14
O
Me
Ph
Cl
Me
NHBn
CO2Me
i
N
NBn
CO2Me
Ph
N
H
3Aa, 3Ba
5, 6
The coupling constants of two vicinal hydrogens at C4 and C5 of
compounds 5 (major) and 6 (minor) were 7.5 and 3.0 Hz, respec-
tively. On the basis of these values we could determine the stereo-
chemistry of 3Aa and 3Ba as erythro and threo, respectively.14,15
A similar selectivity was observed with methyl cis-3-[{(10R)-
phenylethylaziridin}-(2S)-yl]-acrylate (2) as the starting substrate
and benzylamine (a) to give a erythro (4Aa) and threo (4Ba) mix-
ture with the ratio as 2.3:1 and 2.6:1 (entries 1–3 of Table 2). Both
Scheme 1. Reagents and conditions: (i) (1) NaH, Cl3COCOOCCl3, ꢀ10 °C, THF, 3 h.
separable (Rf values, 0.75 and 0.70 for cis and trans, hexane/EtOAc,
1:1 (v/v)).
Conjugate addition of benzylamine (a) to methyl trans- and cis-
3-[{(10R)-phenylethylaziridin}-(2R)-yl]-acrylate in MeOH showed
the big difference on the reactivity and stereoselectivity between
two substrates. The cis isomer 1 is much more reactive to yield
the expected diastereomeric mixture 3Aa and 3Ba in a 2.9:1 ratio
at room temperature while trans is quite sluggish with no selectiv-
ity (Table 1, entry 1) The ratio obtained of 3Aa was changed by
lowering the reaction temperature to 0 °C and ꢀ45 °C as 2.9:1
and 4.0:1, respectively (Table 1, entries 2 and 3). Addition of chiral
amines for the possible improvement of diastereoselectivity was
the chiral nucleophiles (R)-a-methylbenzylamine (b) and (S)-a-
methylbenzylamine (c) with 2 yielded addition products with poor
selectivities as 1.2:1 and 2.1:1, respectively (entries 4 and 5 of
Table 2).
The drastic difference in the stereoselectivity was observed
during the addition reaction of the chiral nucleophiles (R)-
ylbenzylamine (b) and (S)- -methylbenzylamine (c) to either 1 or
2 (entries 4 and 5 in Table 1 and Table 2). This implies the partic-
ipation of the -methylbenzyl group at the ring nitrogen and the
a-meth-
a
a
succeeded with (R)- and (S)-
yield addition products. In case of (R)-
not much improvement was observed in terms of selectivity to
give 3.3:1 (3Ab:3Bb) (entry 4). However, the addition of (S)-
a-methylbenzylamine (b and c) to
coming nucleophile resulted the ‘matched’ (entry 5 in Table 1)
and ‘mismatched’ cases (entry 4 in Table 1, and entries 4 and 5
in Table 2) in the transition state during the course of the
reaction.16
The possible transition state stems from the most stable con-
former of 2-substituted aziridine with two substituents X and Y
a
-methylbenzylamine (b)
a
-
methylbenzylamine (c) yielded a single isomer 3Ac as a sole
product judged by NMR and HPLC analyses (entry 5). This high
selectivity arisen from the right match between 2R configuration
Table 2
Addition of benzylamines to methyl cis-3-[{(10R)-phenylethylaziridin}-(2S)-yl]-acrylate (2)
Me
Me
Me
NHR
NHR
RNH2
Ph
N
Ph
N
Ph
N
CO2Me
CO2Me
H
CO2Me
H
H
4B (threo)
Yieldb (%)
2
4A (erythro)
Entry
RNH2
Temp (°C)
Timea (h)
Ratioc (4A:4B)
1
2
3
4
5
PhCH2NH2 (a)
PhCH2NH2 (a)
PhCH2NH2 (a)
(R)-Ph(CH3)CHNH2 (b)
(S)-Ph(CH3)CHNH2 (c)
rt
0
ꢀ40
50
50
14
24
30
8
96
91
95
82
95
2.3:1
2.3:1
2.6:1
1.2:1
2.1:1
8
a
b
c
The reaction was carried out with amine in MeOH.
Yields, not optimized.
Ratios, determined by 1H NMR.

D.-H. Yoon et al. / Tetrahedron Letters 51 (2010) 2181–2183
2183
Acknowledgments
RNH2
re
H
H
Y
X
N
H
H
This work was supported by the HUFS Grant (2010) and Korea
Science and Engineering Foundation (R01-2007-000-20037-0 for
H.-J.H and KRF-2008-C00481 and NRF-2009-0081956 for W.K.L.).
X
N
CO2Me
Ph
Y
si
N
(b)
(a)
RNH2
(C)
Me
Supplementary data
Figure 2. (a), (b) Front and side views of the aziridine with two substituents X and
Y at N1 and C2. (c) View of methyl cis-3-[{(10R)-phenylethylaziridin}-(2R)-yl]-
acrylate (1) and the possible approaching faces of the amine nucleophile in the
transition state model.
Supplementary data (experimental procedures and character-
ization data for all new compounds) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2010.02.087.
Me
Me
References and notes
BocHN
Me
NH2
ii
HN
Ph
i
Ph
N
CO2Me
1. For reviews on the chemistry of 1,2-diamines, see: (a) Kotti, S. R. S. S.;
Timmons, C.; Li, G. Chem. Biol. Drug Design. 2006, 67, 101; (b) Fache, F.; Schulz,
E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000, 100, 2159; (c) Lucet, D.; Le
Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580.
2. (a) Hoang, C. T.; Alezra, V.; Guillot, R.; Kouklovsky, C. Org. Lett. 2007, 9, 2521;
(b) Lehmann, T.; Michel, D.; Glänzel, M.; Waibel, R.; Gmeiner, P. Heterocycles
1999, 51, 1389.
Me
CO2H
NHBoc
O
N
H
H
3Ac
8
7
Scheme 2. Reagents and conditions: (i) (1) H2 (1 atm), Pd(OH)2, rt. 4 h, (2) (Boc)2O,
MeOH, rt, two steps 89%. (ii) LiOH, EtOH/H2O = 5:1 (v/v) 50 °C, 8 h, rt, ion-exchange
column, 82%.
3. Jones, D. M.; Sueiras-Diaz, J.; Szelke, M.; Leckie, B. J.; Beattie, S. R.; Morton, J.;
Neidle, S.; Kuroda, R. J. Pept. Res. 1997, 50, 109.
4. (a) Skropeta, D. Nat. Prod. Rep. 2008, 25, 1131; (b) Hoang, C. T.; Nguyen, V. H.;
Alezra, V.; Kouklovsky, C. J. Org. Chem. 2008, 73, 1162; (c) Bewley, C. A.; Debitus,
C.; Faulkner, D. J. J. Am. Chem. Soc. 1994, 116, 7631.
5. Iwanami, S.; Takashima, M.; Hirata, Y.; Hasegawa, O.; Usuda, S. J. Med. Chem.
1981, 24, 1224.
situated in trans-relationships as shown in Figure 2 (a) and (b). This
trans-relationship was also observed in many crystalline structures
of aziridines.17 Putting both substituents of phenylethyl (X) and
methoxycarbonylethenyl (Y) groups generates the structure (c) in
Figure 2 with possible two faces, re and si, for the nucleophile to
come.
Among two possible directions re face attack is more favorable
rather than si face away from the steric hindrance, which is the
controlling factor to yield the erythro adduct as the major product
6. For more recent examples, see: (a) Jin, J.; An, M.; Sapienza, A.; Aiyar, N.;
Naselsky, D.; Sarau, H. M.; Foley, J. J.; Salyers, K. L.; Knight, S. D.; Keenan, R. M.;
Rivero, R. A.; Dhanak, D.; Douglas, S. A. Bioorg. Med. Chem. Lett. 2008, 18, 3950;
(b) Fish, P. V.; Barta, N. S.; Gray, D. L. F.; Ryckmans, T.; Stobie, A.; Wakenhut, F.;
Whitlock, G. A. Bioorg. Med. Chem. Lett. 2008, 18, 4355; (c) Wakenhut, F.; Fish, P.
V.; Fray, M. J.; Gurrell, I.; Mills, J. E.; Stobie, A.; Whitlock, G. A. Bioorg. Med.
Chem. Lett. 2008, 18, 4308.
7. (a) Pinheiro, S.; da Silva Júnior, R. C.; de Souza, A. S.; de M Carneiro, J. W.; Muri,
E. M. F.; Antunes, O. A. C. Tetrahedron. Lett. 2009, 50, 2402; (b) Hoang, C. T.;
Bouillere, F.; Johannesen, S.; Zulauf, A.; Panel, C.; Pouilhes, A.; Gori, D.; Alezra,
V.; Kouklovsky, C. J. Org. Chem. 2009, 74, 4177. and references cited therein.
8. Lee, W.-K.; Ha, H.-J. Aldrichimica Acta 2003, 36, 57. and references cited therein.
9. Park, C. S.; Choi, H. G.; Lee, H.; Lee, W. K.; Ha, H.-J. Tetrahedron: Asymmetry
2000, 11, 3283.
10. Yun, J. M.; Sim, T. B.; Hahm, H. S.; Lee, W. K.; Ha, H.-J. J. Org. Chem. 2003, 68,
7675.
11. Yoon, H. J.; Kim, Y.-W.; Lee, B. K.; Lee, W. K.; Kim, Y.; Ha, H.-J. Chem. Commun.
2007, 79.
12. Ha, H.-J.; Hong, M. C.; Ko, S. W.; Kim, Y. W.; Lee, W. K.; Park, J. Bioorg. Med.
Chem. Lett. 2006, 16, 1880.
13. Lee, B. K.; Kim, M. S.; Hahm, H. S.; Kim, D. S.; Lee, W. K.; Ha, H.-J. Tetrahedron
2006, 62, 8393.
along with the additional stereodifferentiation by (R)-a-methyl-
benzylamine. This stereochemical pathway is opposite to the reac-
tion with chelation-controlled transition state to yield the threo
product.14
The addition product 3Ac was further treated with an atmo-
spheric pressure of hydrogen in the presence of Pd(OH)2 catalyst
followed by reaction with (Boc)2O to yield (4R,5S)-4-t-butyloxy-
carbonylamino-5-methylpyrrolidin-2-one (7) in a 89% yield. Hydro-
lysis of 7 followed by anion exchange column afforded the known
(3R,4S)-4-amino-3-t-butyloxycarbonylaminopentanoic acid (8) in a
82% yield (Scheme 2).18 The addition product 3Ac will be served
as a synthetic intermediate for the preparation of various chiral dia-
mines through aziridine ring opening with various nucleophiles.8
In conclusion, the conjugate addition of benzylamine to chiral
methyl cis-3-[{(10R)-phenylethyl-aziridin}-(2R)- and (2S)-yl]-acry-
lates provides the erythro adduct, 3-(aziridin-2-yl)-3-benzylamino-
propionate as the major product. Additional stererodifferentiation
14. Suh, M.-J.; Kim, S. W.; Beak, S. I.; Ha, H.-J.; Lee, W.-K. Synlett 2004, 489.
15. (a) Pelletier, S. M.-C.; Ray, P. C.; Dixon, D. J. Org. Lett. 2009, 11, 4512; (b) Park, C.
S.; Kim, M. S.; Sim, T. B.; Pyun, D. K.; Lee, C. H.; Choi, D.; Lee, W. K.; Chang, J.-W.;
Ha, H.-J. J. Org. Chem. 2003, 68, 43.
16. In our early work we observed that the configuration of (a)-methylbenzyl
group at N1 of aziridine affected drastically the reactivity on the substitution
reaction of 2-sulfonyloxymethylaziridines. Han, S.-M.; Ma, S.-h.; Ha, H.-J.; Lee,
W. K. Tetrahedron 2008, 64, 11110.
17. (a) Lee, K.-D.; Suh, J.-M.; Park, J.-H.; Ha, H.-J.; Choi, W. G.; Park, C. S.; Chang, J.
W.; Lee, W. K.; Dong, Y.; Yun, H. Tetrahedron 2001, 57, 8267; (b) Dong, Y.; Yun,
H.; Park, C. S.; Lee, W.-K.; Ha, H.-J. Acta Crystallogr., Sect. C 2003, 59, 659.
18. Kano, S.; Yokomatsu, T.; Iwasawa, H.; Shibuya, S. Chem. Pharm. Bull. 1988, 36,
3341.
by (S)-a-methylbenzylamine to the substrate (2R)-acrylates
yielded a single enantiomeric adduct in high yield which was used
as the precursor for the substituted nitrogen-containing heterocy-
cles and enantiomerically pure b,c-diaminoacids.