Preparation of enantiopure 2-acylazetidines and their reactions with chloroformates

Article abstract of DOI:10.1016/j.tetlet.2006.11.033

Enantiopure 1-phenylethylazetidine-2-carboxylates and 2-acylazetidines were prepared and reacted with chloroformates to yield α-chloro-γ-amino butyric acid esters and ketones from ring opening reaction of azetidinium ion intermediate in a completely regio- and stereoselective manner.

Full text of DOI:10.1016/j.tetlet.2006.11.033

Tetrahedron Letters 48 (2007) 269–271
Preparation of enantiopure 2-acylazetidines and their
reactions with chloroformates
Sang-ho Ma,a Doo Ha Yoon,a Hyun-Joon Haa,* and Won Koo Leeb,*
aDepartment of Chemistry, Hankuk University of Foreign Studies, Yongin, Kyunggi-Do 449-791, Republic of Korea
bDepartment of Chemistry and Interdisciplinary Program of Integrated Biotechnology, Sogang University,
Seoul 121-742, Republic of Korea
Received 16 October 2006; revised 3 November 2006; accepted 7 November 2006
Available online 28 November 2006
Abstract—Enantiopure 1-phenylethylazetidine-2-carboxylates and 2-acylazetidines were prepared and reacted with chloroformates
to yield a-chloro-c-amino butyric acid esters and ketones from ring opening reaction of azetidinium ion intermediate in a completely
regio- and stereoselective manner.
Ó 2006 Elsevier Ltd. All rights reserved.
Nitrogen containing cyclic compounds (1) with N-alkyl
substituents react with chloroformate to yield ammo-
nium ion intermediate (I) with free chloride (Scheme
1). This intermediate can take two different reaction
pathways which would be either dealkylation (pathway
‘a’) or ring opening (pathway ‘b’). When the ring size
is five or six such as pyrrolidine (n = 2) and piperidine
(n = 3), dealkylation reactions are dominant. This path-
way ‘a’ has been used for debenzylation or demethyl-
ation.1 However, when the ring size is small as aziridine
(n = 0), only ring opening reaction occurs to afford chloro-
amine (3) that is further cyclized in the fashion of II to
yield the cyclic carbamate (4).2 However, the same reac-
tion with azetidine (n = 1) remains to be undisclosed yet.
Up to now disputable pieces of information are known.3
Thereby, we decided to study the reaction of substituted
azetidines with chloroformates to clarify the possible
reaction pathways ‘a’ and ‘b’ in Scheme 1.
At first we elaborated azetidine-2-carboxylate and 2-
acylazetidine in optically pure forms some of which
are very valuable.4 L-Azetidine-2-carboxylate is a repre-
sentative example that was first isolated from Conval-
laria majaris.5 It is also found in naturally occurring
peptides such as mugineic acid,6 nicotianamine7 and in
pharmacologically important melagatran.8 Even though
Scheme 1.
Keywords: Azetidine-2-carboxylate; 2-Acylazetidine; Chloroformate; Ring opening; a-Chloro-c-amino butyric acid esters.
*
Corresponding authors. Tel.: +82 313304369; fax: +82 313304566 (H.-J.H.); tel.: +82 2 705 8449 (W.K.L.); e-mail addresses: hjha@hufs.ac.kr;
wonkoo@sogang.ac.kr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.033

270
S. Ma et al. / Tetrahedron Letters 48 (2007) 269–271
a few asymmetric syntheses of azetidine-2-carboxylate
are reported,9 a simple and easy route to obtain both
enantiomers in optically pure forms is still necessary.
Methyl 2,4-dibromobutanoate10 was reacted with (2R)-
phenylethylamine to yield orthogonally protected and
chromatographically separable diastereomeric mixture
of (2S,1R0)-(5) and (2R,1R0)-1-1-phenylethylazetidine-
2-carboxylate (6) in 78% yield with almost 1:1 ratio.
Each of those diastereomers were hydrolyzed in 5 N
HCl and then hydrogenolysis yielded enantiomerically
pure (2S)- (S-7) and (2R)-azetidine-2-carboxylic acid
(R-7) in more than 95% yield (Scheme 2).9
and vinyl chloroformates yielded the ring-opened prod-
ucts (10b and 10c) in similar yields of 69% and 79%. The
reactions for (2S,1R0)-1-phenylethyl-2-acylazetidines
(9b or 9c) proceeded in the same manner with methyl
chloroformate to afford 10d and 10e in 68% and 70%
yields, respectively (Scheme 4).
Recently we showed that the nucleophilic nitrogen in the
small ring aziridine would react with acid chloride to
yield ring-opened or ring-expanded products depending
on the characteristic of the reactants.13 All of the reac-
tions show common pathways with the formation of
aziridinium ion from the reaction of nucleophilic ring
nitrogen with acid chloride and the subsequent ring
opening by the chloride. What we observed in this study
showed that the reaction of the substituted azetidines
took the similar pathway as that of the substituted azir-
idines. The similar reaction pathways of azetidines and
aziridines lead to the ring opening reaction with chloro-
formate which originates from the ring strain14 of the
intermediate I as shown in Scheme 1. The larger ring
compounds than azetidine such as pyrrolidine and
piperidine are free from ring strain. Thereby the same
reaction proceeds to dealkylation instead of ring open-
ing. We conclude that the ring strain energy would be
the key to decide the direction between ‘a’ and ‘b’ in
Scheme 1 for the reactions of nitrogen containing cyclic
compounds with chloroformates.
Methyl (2S)-azetidine-2-carboxylate (5) was reacted
with methoxymethylamine to yield the amide (8) that
was readily reacted with methyl, ethyl, and phenyl-
magnesium bromide to afford the corresponding 2-acyl-
aziridines (9a, 9b, and 9c) in 83%, 89%, and 92% yields,
respectively (Scheme 3).11
At first methyl (2S,1R0)-1-phenylethylazetidine-2-carb-
oxylate (5) was reacted with methyl chloroformate to
yield the acyclic chlorinated compound (10a) as a single
isomer in 74% yield implying that the reaction is com-
pletely regio- and stereospecific.12 We found that the
reaction of N-alkylazetidine with methyl chloroformate
took the ring opening pathway as ‘b’ in Scheme 1. Fur-
thermore, the ring opening reaction occurred at the C-2
position regiospecifically with the inversion of configu-
ration via azetidinium ion intermediate (III) as i and
not as ii in Scheme 4. The same reactions with ethyl
In case of aziridines we observed that chlorinated acyclic
product (3, n = 0) was readily cyclized in the manner II
of Scheme 1 to yield oxazolidin-2-one (4, n = 0) in high
yield.2 The same reaction from azetidines yielded only
acyclic products without the formation of any detectable
amount of cyclic products. Instead we cyclized the
chlorinated product (10a) under reflux in DMF to afford
the cyclic 1,3-oxazinan-2-one (11) as a diastereomeric
mixture with the ratio of 2:1. The reluctance of intra-
molecular cyclization gave an opportunity to prepare enan-
tiopure a-substituted-c-aminoketones by substitution of
the chloride with various external nucleophiles. The
reactions were successful to give optically pure a-cycano,
a-thiocyano, and a-azidio-c-aminobutyrates (12–14)
in 85%, 82%, and 94% yields, respectively (Scheme 5).
The stereochemical pathways are expected to be
inversion of configurations during ring opening and
Scheme 2.
Scheme 3.
Scheme 4.

S. Ma et al. / Tetrahedron Letters 48 (2007) 269–271
271
References and notes
1. (a) Bhat, R. G.; Ghosh, Y.; Chandrasekaran, S. Tetra-
hedron Lett. 2004, 45, 7983; (b) Campbell, A. L.;
Pilipauskas, D. R.; Khanna, I. K.; Rhodes, R. A.
Tetrahedron Lett. 1987, 28, 2331; (c) Olofson, R. A.;
Martz, J. T.; Senet, J.-P.; Piteau, M.; Malfroot, T. J. Org.
Chem. 1984, 49, 2081; (d) Kapnang, H.; Charles, G.
Tetrahedron Lett. 1983, 24, 3233; (e) Montzka, T. A.;
Matiskella, J. D.; Partyka, R. A. Tetrahedron Lett. 1974,
15, 1325.
2. (a) Sim, T. B.; Kang, S. H.; Lee, K. S.; Lee, W. K.; Ha,
H.-J. J. Org. Chem. 2003, 68, 104; (b) Park, C. H.; 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.
Scheme 5.
3. (a) Barrett, A. G. M.; Dozzo, P.; White, A. J. P.; Williams,
D. J. Tetrahedron 2002, 58, 7303; (b) Tonder, J. E.;
Hansen, J. B.; Begtrup, M.; Petterson, I.; Rimvall, K.;
Christensen, B.; Ehrbar, U.; Olesen, P. H. J. Med. Chem.
1999, 42, 4970; (c) Baumann, H.; Duthaler, R. O. Helv.
Chim. Acta 1988, 71, 1035; (d) Nitta, Y.; Yamaguchi, Y.;
Tanaka, T. Heterocycles 1986, 24, 25.
4. De Kimpe, N. In Comprehensive Heterocyclic Chemistry
II; Padwa, A., Ed.; Pergamon: New York, 1996; Vol. 1, pp
507–589.
5. Fowden, L. Nature 1955, 176, 347.
6. Takemoto, T.; Nomoto, K.; Fushiya, S.; Ouchi, R.;
Kusano, G.; Hikino, H.; Takagi, S.; Matsuura, Y.;
Kakudo, M. Proc. Jpn. Acad., Ser. B 1978, 54, 469.
7. Kinoshita, E.; Yamakoshi, J.; Kikuchi, M. Biosci. Bio-
technol. Biochem. 1993, 57, 1107.
8. Ericksson, B. I.; Carlsson, S.; Halvarsson, M.; Risberg, B.;
Mattsson, C. Thromb. Haemostasis 1997, 78, 1404.
9. Couty, F.; Evano, G.; Vargas-Sanchez, M.; Bouzas, G. J.
Org. Chem. 2005, 70, 9028, and references are cited
therein.
10. Methyl 2,4-dibromobutanoate was prepared from com-
mercial 2,4-dibromobutyryl chloride and methanol and
used for next reaction without any purification steps.
11. Yun, J. M.; Sim, T. B.; Hahm, H. S.; Lee, W. K.; Ha, H.-J.
J. Org. Chem. 2003, 68, 7675–7680.
Scheme 6.
the subsequent substitution with an external nucleo-
phile. This was proved by conversion of methyl a-azido-
c-aminobutyrate
(14)
which
originated
from
(2S,1R0)-1-phenylethylazetidine-2-carboxylate (5) into
the known amino acid. Azidoamine (14) was hydrolyzed
with KOH and hydrogenated in the presence of (Boc)2O
to give 2,4-di-t-butyloxycarbonyldiaminobutanoic acid
(15). This was further hydrolyzed with 5 N HCl to yield
(2S)-diaminobutanoic acid dihydrochloride (16) in 50%
yield. ([a]D 12.1 (c 0.51, H2O) lit.15 [a]D 12 (c 1, H2O)).
The configuration of the asymmetric carbon center at
the a-position was completely retained to show that
the ring opening reaction of the azetidine-2-carboxylates
and the subsequent substitutions occurred in complete
inversion manner (Scheme 6).
12. Representative example of the formation of acyclic chlo-
rinated compounds (10a). To a solution of methyl
(2S,1R0)-1-phenylethylazetidine-2-carboxylate (5, 145 mg,
0.66 mmol) in 10 mL of CH3CN was added methyl
chloroformate (187 mg, 1.98 mmol), and the mixture was
stirred for 8 h in refluxing CH3CN. The mixture was
cooled to room temperature and added by saturated
NaHCO3 solution slowly. The aqueous layer was washed
with brine and extracted with EtOAc. The combined
organic extracts were dried, filtered, and concentrated
under reduced pressure. Purification by silica gel flash
chromatography (EtOAc/n-hexane, 20:80) provided
In summary, enantiopure 1-phenylethylazetidine-2-
carboxylates and 2-acylazetidines were prepared and
reacted with chloroformates to yield a-chloro-c-amino
butyric acid esters and ketones from ring opening
reaction of azetidinium ion intermediates in completely
regio- and stereoselective manner.
22
153 mg (74%) of 10a as a colorless oil: ½aꢀD +27.2 (c 2.4,
1
EtOAc); H NMR (200 MHz, CDCl3) 7.34–7.22 (m, 5H),
5.59–5.43 (m, 1H), 4.13 (q, J = 6.7 Hz, 1H), 3.68 (s, 3H),
3.66 (s, 3H), 3.11 (t, J = 7.2 Hz, 2H), 1.98–2.13 (m, 2H),
1.53 (d, J = 6.7 Hz, 3H); 13C NMR (50.3 MHz, CDCl3)
169.5, 156.9, 140.9, 128.5, 128.0, 127.4, 79.6, 55.2, 53.9,
52.7, 40.3, 34.6, 17.2. Anal. Calcd for C15H20ClNO4: C,
57.4; H, 6.42; N, 4.46. Found: C, 57.6; H, 6.29; N, 4.75.
13. Kim, Y.; Ha, H.-J.; Yun, H.; Lee, B. K.; Lee, W. K.
Tetrahedron 2006, 62, 8844.
Acknowledgements
We acknowledge the financial supports from the Korea
Science and Engineering Foundation and Korea
Research Foundation (Program through the Center
for Bioactive Molecular Hybrids and R01-2005-000-
10032-0 to H.-J.H. and KRF-2002-070-C00060 to
W.K.L.). Partial support of HUFS Grant is also grate-
fully acknowledged.
14. Pihlaja, K.; Taskinen, E. Phys. Methods Heterocycl.
Chem. 1974, 6, 199.
15. AldrichÒ catalog for (S)-2,4-diaminobutanoic acid, No.
237760.