Stereocontrolled synthesis of 3-substituted azetidinic amino acids

Article abstract of DOI:10.1055/s-2006-933125

A set of enantiomerically pure N-disubstituted β-amino alcohols was chlorinated by treatment with thionyl chloride. This reaction gave a mixture of regioisomeric chlorides that could be equilibrated to the more stable regioisomer by heating in DMF. The chlorides thus obtained were engaged in an intramolecular anionic ring-closure and gave access to fully protected enantio- and diastereomerically pure 2,3-cis-disubstituted azetidinic amino acids. One of the latter was deprotected and included in a short peptide sequence. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-933125

LETTER
781
Stereocontrolled Synthesis of 3-Substituted Azetidinic Amino Acids
S
ynthesis of 3-Substitu
a
ted Azetidi
n
nic Amino A
g
cids aleswaran Sivaprakasam,a François Couty,*a Gwilherm Evano,a B. Srinivas,b R. Sridhar,b K. Rama Raob
a
SIRCOB, UMR 8086, Université de Versailles, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France
E-mail: couty@chimie.uvsq.fr
b
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad – 500007, India
Received 19 October 2005
which is then opened by the chloride anion (Figure 1).7
When an aryl group is present in the substrate, such as in
aziridinium 4, then the chloride anion exclusively attacks
the benzylic position, giving one regioisomeric chloride
Abstract: A set of enantiomerically pure N-disubstituted b-amino
alcohols was chlorinated by treatment with thionyl chloride. This
reaction gave a mixture of regioisomeric chlorides that could be
equilibrated to the more stable regioisomer by heating in DMF. The
chlorides thus obtained were engaged in an intramolecular anionic with overall retention of configuration compared to the
ring-closure and gave access to fully protected enantio- and dia-
starting amino alcohol. In contrast, when an alkyl-sub-
stereomerically pure 2,3-cis-disubstituted azetidinic amino acids.
stituted aziridinium 5 is involved, the opening by the
One of the latter was deprotected and included in a short peptide
chloride anion is not regioselective, giving two regio-
sequence.
isomeric chlorides and thus hampering the generality of
this synthesis.
Key words: azetidines, amino acids, amino alcohols, asymmetric
synthesis
We recently reported a synthesis of functionalized azet-
Me
Cl–
Cl–
idines from b-amino alcohols based on a 4-exo-tet anionic
ring-closure.1 Key steps involved in this synthesis rely on
(i) a chlorination of the hydroxyl in a N-disubstituted b-
amino alcohol 1 and (ii) an intramolecular alkylation of
the produced chloride 2 induced by deprotonation a to the
EWG group, to give functionalized azetidine 3 in good
overall yield (Scheme 1). Given the availability of b-ami-
no alcohols in enantiomerically pure form, this synthesis
provides an original entry to the preparation of azetidines
and led us to explore the reactivity of this understudied
class of heterocycles towards ring expansions2 or ring-
opening3 processes. This anionic ring-closure was found
to be general and compatible with nitriles,1 esters4 or
phosphonates5 acting as EWG group. The electrophilic
partner was also experienced with an a,b-unsaturated
ester, providing azetidinic amino acids evaluated as
ligands for the glutamate receptors and transporters.6
N
R
N
R
EWG
EWG
+
+
5
4
non-regioselective opening
regioselective opening
Figure 1
We wish to report herein a solution to this regioselectivity
problem involving alkyl-substituted aziridinium inter-
mediates, thus extending considerably the scope of this
reaction. This was applied to the synthesis of enantio-
merically pure 3-substituted azetidinic amino acids8 that
can be envisioned as conformationally constrained amino
acids the latter being the topic of extensive research for
synthetic and medicinal chemists.9
The b-amino alcohol substrates 7–15 were prepared in
order to study the regioselectivity of the chlorination step
(Table 1). These compounds were made either from com-
mercially available enantiomerically pure b-amino alco-
hols (for 7–12) or from (S)-O-benzyl tyrosinol10 following
a two-step sequence involving N-benzylation (PhCHO, 4
Å MS, then NaBH4) and N-alkylation with either bro-
moacetonitrile (for 7–9: K2CO3, MeCN) or tert-butyl
bromoacetate (for 10–15: NaHCO3, NaI, DMF). Amino
alcohols 14 and 15 were prepared from the corresponding
epoxides by reaction with either isopropylamine or
benzylamine in the presence of b-cyclodextrin (b-CD)
following our previously described methodology.11 The
resulting amino alcohols 16, 17 were obtained with good
yields and high ee (Scheme 2) and were transformed into
14 and 15 through the above-described two-step
procedure.
Ar
Ar
EWG
OH
SOCl2
Cl
N
Ar
EWG
EWG
N
R
N
R
R
1
2
3
Scheme 1
However, this synthetic sequence relies heavily on the
chlorination step, whose regioselectivity was found to be
dependent on the substitution pattern in the starting amino
alcohol 1. As a matter of fact, chlorination of a b-amino
alcohol induces the formation of an aziridinium ion,
SYNLETT 2006, No. 5, pp 0781–0785
1
7.
0
3.
2
0
0
6
Advanced online publication: 09.03.2006
DOI: 10.1055/s-2006-933125; Art ID: D32205ST
© Georg Thieme Verlag Stuttgart · New York

782
M. Sivaprakasam et al.
LETTER
OPh
All these b-amino alcohols were chlorinated by treatment
with thionyl chloride in CH2Cl2 to furnish a regioisomeric
mixture of chlorides in good yields. Heating this mixture
in DMF at 65 °C for the time specified in Table 1 resulted
in a complete equilibration to give the secondary chlorides
18–26. These conditions were adjusted in order to mini-
mize degradation and the secondary chlorides were ob-
tained in high overall yields and >98% regioisomeric
purity.
OH
O
β-cyclodextrin
O
RNH2
NHR
16 R = i-Pr, 80%, >98% ee
17 R = Bn, 75%, >99% ee
Scheme 2
Table 1 Regioselective Chlorination of b-Amino Alcohols
R2
R2
OH
Cl
Cl
SOCl2, CH2Cl2, reflux, 2 h
Cl
DMF, 65 °C
+
a
R2
N
R1
EWG
7–15
b
N
R1
EWG
R2
N
R1
EWG
N
R1
EWG
18–24
Entry Substrate
Step a
Yield (%),
Step b
Yield (%),
Product
Overall yield
(%)a
regioisomeric ratio time for equilibration
OH
Cl
90
95
1
85
88
N
CN
7
(1:1)
65 h
CN
N
Bn
18
Bn
OH
Cl
93
(1:1)
95
60 h
2
N
CN
8
CN
N
Bn
19
Bn
OH
90
(1:1)
98
65 h
Cl
3
88
N
CN
9
CN
20
Bn
N
Bn
OH
Cl
80
95
4
5
6
76
85
83
(1:1)
65 h
N
CO2t-Bu
10
N
CO2t-Bu
21
Bn
Bn
OH
Cl
90
(2:1)
95
60 h
N
CO2t-Bu
11
N
CO2t-Bu
22
Bn
Bn
OH
Cl
92
(1:1)
95
80 h
N
CO2t-Bu
12
N
CO2t-Bu
23
Bn
Bn
BnO
Cl
OH
93
(2:3)
95
65 h
7
88
N
CO2t-Bu
24
BnO
PhO
N
CO2t-Bu
13
Bn
Bn
PhO
PhO
OH
Cl
N
90
(2:1)
95
60 h
8
9
85
64
N
CO2t-Bu
14
CO2t-Bu
25
PhO
Cl
N
OH
83
(4:1)
77
60 h
CO2t-Bu
N
CO2t-Bu
26
15
Bn
Bn
a Yield of pure isolated product.
Synlett 2006, No. 5, 781–785 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Substituted Azetidinic Amino Acids
783
occurred with total 2,3-cis-diastereoselectivity. Results of
these experiments are summarized in Table 2.
R2
R2
Cl
Cl
EWG
+
R1
N
N
R1
EWG
R2
N
R1
EWG
Particularly noteworthy in these experiments is the high
2,3-cis-diastereoselectivity observed in the course of the
cyclization. The 2,3-relative configuration in the pro-
duced azetidines was determined by NOE experiments
performed with 36 and 39 (NOE enhancements are shown
in Figure 2). The optical purity of the azetidine 36 and ent-
36 was determined by NMR using (S)-a-(trifluorometh-
yl)benzyl alcohol as chiral solvent13 and was found to be
greater than 95%, demonstrating that no erosion of the
optical purity occurred during the equilibration process.
The rationalization of the observed cis-2,3-diastereoselec-
tivity is not simple. The first question to be answered is
whether the reaction is kinetically controlled or if further
enolization of the produced azetidine induces a thermo-
dynamic control. In order to address this point, we have
treated azetidine 36 under the conditions of the cyclization
(LiHMDS in THF–HMPA) followed by quenching at
0 °C with methanol-d4. Since the starting product was
recovered unchanged and did not show any incorporation
of deuterium, we can conclude that it is not enolized in the
reaction mixture. This observation is, however, not
sufficient to conclude that a kinetic control is operating,
since we cannot rule out an enolization of a 2,3-trans
azetidine into the observed 2,3-cis isomer.
thermodynamic chloride
kinetic chloride
Cl
N
Cl
Ph
N
OMe
MeOH, reflux
+
Ph
Ph
+ 19
N
CN
28
19
27
CN
6
CN
:
4
Scheme 3
The high regioselectivity obtained in this chlorination can
be explained by the occurrence of an equilibration through
an intermediate aziridinium ion (Scheme 3). Upon heat-
ing in DMF, both primary and secondary chlorides can
produce an aziridinium ion through intramolecular alkyl-
ation. Chloride anion can then re-attack this electrophilic
intermediate to give either primary or secondary chloride.
The accumulation of the secondary chloride in the reac-
tion mixture can be explained by the fact that it is less
prone to give back the aziridinium ion, due to the crowd-
ing of the electrophilic center. It should be noted that a
very similar behavior with azetidinium ions has been re-
cently reported.12 The long reaction times required for
equilibration suggest that the opening at the less hindered
position to give back the primary chloride is a more rapid
process. Therefore, the primary chloride is the kinetic
product, and the secondary chloride the thermodynamic
product and these compounds are obtained without ero-
sion of the optical purity, as demonstrated by the high op-
tical purity of the azetidines derived from these products
(vide supra). The kinetic opening by a nucleophile at the
less hindered position can be easily evidenced: heating a
6:4 mixture of chlorides derived from 8 in MeOH gave a
mixture of primary ether 28 and unreacted secondary
chloride 19: no trace of secondary ether could be detected
in the reaction mixture.
H
H
H
H
CO2t-Bu
CO2t-Bu
H
H
N
Ph
N
H
H
CH3
OPh
36
39
Figure 2 NOE enhancements in 36 and 39.
In order to demonstrate that these azetidinic amino acids
are suitable for peptide chemistry, amino acid 36 was in-
cluded in a tripeptide, as shown in Scheme 4. Thus,
cleavage of the tert-butyl ester in 36 with TFA was
followed by coupling with L-AlaOMe to give 42. N-de-
benzylation of 42 was then followed by coupling with L-
N-Boc-Ala, to furnish tripeptide 43 with modest yield.
The use of the BOP reagent proved to be necessary for this
step to attain a reasonable yield.
The regioselectivity issue being solved, we next focused
on the nucleophilic ring-closure in order to form the azet-
idine ring. Therefore, chlorides 18–20 bearing a cyano-
methyl moiety on the nitrogen were treated with LiHMDS
at –78 °C, following our previously described conditions.1
Cyclization occurred in high yield with 18 and 19, but not
with 20, in which the electrophilic center is more sterical-
ly crowded. However, the 2,3-diastereoselectivity was
low in all cases, and the diasteroisomers were not easily
separable. We therefore switched to the use of chlorides
21–26, bearing a large tert-butyl ester, hoping to increase
the diastereoselectivity. As a matter of fact, the enolates
derived from these esters proved to be less reactive than
their amino nitrile homologues, and it was crucial to use
HMPA as an additive (10% volume with THF) to induce
the cyclization with these substrates. Nonetheless, under
these conditions, cyclized compounds were obtained in
good yields, and we were pleased to note that cyclization
a, b
N
N
O
Bn
Bn
CO2t-Bu
HN
42
36
CO2Me
c,d
O
N
O
HN
43
BocHN
CO2Me
Scheme 4 Reagents and conditions: (a) TFA, CH2Cl2, r.t., 0.5 h,
95%; (b) L-AlaOMe·HCl, Et3N, BOP, MeCN, 16 h, r.t., 65%; (c)
Pd(OH)2, H2, MeOH, AcOH, r.t., 3 h, 95%; (d) L-N-BocAla, Et3N,
BOP, MeCN, 16 h, r.t., 50%.
Synlett 2006, No. 5, 781–785 © Thieme Stuttgart · New York

784
M. Sivaprakasam et al.
LETTER
Table 2 Intramolecular Alkylation of Chlorides 18–26
Entry
1
Substrate
Conditions
Products
Yield (%)a
CN
Bn
CN
Bn
LiHMDS, THF,
–78 °C to –10 °C
18
95
60
+
N
N
(2 : 3)
30
29
CN
CN
LiHMDS, THF,
–78 °C to 0 °C
+
2
3
19
20
N
N
Bn
N
Bn
N
(1 : 2)
32
31
CN
Bn
CN
Bn
LiHMDS, THF,
–78 °C to 0 °C
+
25
(1 : 2)
33
34
CO2t-Bu
LiHMDS, THF–HMPA
–78 °C to 0 °C
4
5
21
22
73
80
N
Bn
35
CO2t-Bu
LiHMDS, THF–HMPA
–78 °C to 0 °C
N
Bn
36
CO2t-Bu
Bn
LiHMDS, THF–HMPA
–78 °C to –20 °C
6
7
23
24
85
N
37
CO2t-Bu
LiHMDS, THF–HMPA
–78 °C to –40 °C
50b
BnO
N
Bn
38
OPh
CO2t-Bu
LiHMDS, THF–HMPA
–78 °C to 0 °C
8
9
25
26
50
75
N
39
OPh
CO2t-Bu
LiHMDS, THF–HMPA
–78 °C to 0 °C
N
Bn
40
a Yield of pure isolated product.
b A 20% yield of elimination product was produced with this substrate.
In conclusion, we have shown that diastereo- and enantio-
merically pure cis-2,3-substituted azetidines can be pre-
pared in a straightforward way from b-amino alcohols.14
Applications of these azetidinic amino acids will be re-
ported in due course.
References and Notes
(1) Agami, C.; Couty, F.; Evano, G. Tetrahedron: Asymmetry
2002, 13, 297.
(2) (a) Couty, F.; Durrat, F.; Prim, D. Tetrahedron Lett. 2003,
44, 5209. (b) Couty, F.; Durrat, F.; Evano, G.; Prim, D.
Tetrahedron Lett. 2004, 45, 7525.
(3) Couty, F.; Durrat, F.; Evano, G. Synlett 2005, 1666.
(4) Couty, F.; Evano, G.; Rabasso, N. Tetrahedron: Asymmetry
2003, 14, 2407.
Acknowledgment
IFCPAR (Indo-French Centre for the promotion of advanced
research) is gratefully acknowledged for financial support.
Synlett 2006, No. 5, 781–785 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Substituted Azetidinic Amino Acids
785
(5) Agami, C.; Couty, F.; Rabasso, N. Tetrahedron Lett. 2002,
43, 4633.
(6) Bräuner-Osborne, H.; Bunch, L.; Chopin, N.; Couty, F.;
Evano, G.; Jensen, A. A.; Kusk, M.; Nielsen, B.; Rabasso, N.
Org. Biomol. Chem. 2005, 3, 3926.
(14) All new compounds were characterized by 1H NMR and 13
NMR spectroscopy, mass spectral analysis, and for most
relevant compounds, by elemental analysis.
C
Typical Procedure for the Preparation of Chloride 19.
To a solution of amino alcohol 11 (1.20 g, 4.30 mmol) in
(7) For related examples of chlorination of b-amino alcohols,
see: (a) Weber, K.; Kuklinski, S.; Gmeiner, P. Org. Lett.
2000, 2, 647. (b) Chong, H.; Ganguly, B.; Broker, G. A.;
Rogers, R. D.; Brechbiel, M. W. J. Chem. Soc., Perkin
Trans. 1 2002, 2080. (c) Couty, F.; Evano, G.; Prim, D.
Tetrahedron Lett. 2005, 46, 2253.
CH2Cl2 (30 mL) was added SOCl2 (0.64 mL, 8.81 mmol) at
0 °C and it was then refluxed for 3 h. After the completion of
the reaction, the excess SOCl2 was neutralized by a sat. aq
solution of NaHCO3 (10 mL). Extraction of the reaction
mixture using Et2O followed by usual workup gave a
mixture of chlorides (2:1 ratio) that were purified by flash
chromatography (EtOAc–PE 1:9, 1.15 g, 90%).The formed
chlorides (1.15 g) were then dissolved in DMF (10 mL) and
heated at 60 °C for 60 h. DMF was removed under vacuo and
the obtained chloride was filtered on silica gel (EtOAc–PE
1:9) and gave pure chloride 22 (1.09 g, 95%) as a thick oil.
Rf 0.85 (EtOAc–PE 9:1); [a]D20 –6.6 (c 0.7, CHCl3). 1H
NMR (300 MHz, CDCl3): d = 1.37 (br s, 12 H), 2.80 (dd,
J = 13.7, 6.8 Hz, 1 H), 2.93 (dd, J = 13.7, 6.8 Hz, 1 H), 3.19
(s, 2 H), 3.78 (d, J = 3.4 Hz, 2 H), 3.87–3.94 (m, 1 H), 7.14–
7.20 (m, 5 H). 13C NMR (75 MHz, CDCl3): d = 23.0, 28.2,
55.7, 56.2, 58.7, 62.5, 81.0, 127.2, 128.7, 128.9, 139.0,
170.7. MS (CI, NH3 gas): m/z (%) = 320 (27) [M + K+], 264
(8), 242 (61).
(8) For other syntheses of azetidinic a-amino acids, see:
(a) Kozikowski, A. P.; Tückmantel, W.; Reynolds, I. J.;
Wrobleski, J. T. J. Med. Chem. 1990, 33, 1561.
(b) Kozikowski, A. P.; Liao, Y.; Tückmantel, W.; Wang, S.;
Pshenichkin, S.; Surin, A.; Thomsen, C.; Wrobleski, J. T. J.
Bioorg. Med. Chem. Lett. 1996, 6, 2559. (c) Hanessian, S.;
Fu, J. M.; Chiara, J.-L.; Di Fabio, R. Tetrahedron Lett. 1993,
34, 4157. (d) Hanessian, S.; Bernstein, N.; Yang, R.-Y.;
Maguire, R. Bioorg. Med. Chem. Lett. 1999, 9, 1437.
(e) Couty, F.; Evano, G.; Rabasso, N. Tetrahedron:
Asymmetry 2003, 14, 2407. (f) Jiang, J.; Shah, H.; DeVita,
R. J. Org. Lett. 2003, 5, 4101. (g) Gerona-Navarro, G.;
Angeles Bonache, M.; Alías, M.; Pérez de Vega, M. J.;
García-López, T.; Pilar López, M.; Cativiela, C.; González-
Muñiz, R. Tetrahedron Lett. 2004, 45, 2193. (h) Sajjadi, Z.;
Lubell, W. D. J. Peptide Res. 2005, 65, 298. (i) Couty, F.;
Evano, G.; Vargas-Sanchez, M.; Bouzas, G. J. Org. Chem.
2005, 70, 9028.
(9) Hart, P. A.; Rich, D. H. In The Practice of Medicinal
Chemistry, 3rd ed.; Wermuth, C. G., Ed.; Academic Press:
London, 2000.
(10) Čaplar, V.; Raza, Z.; Katalenić, D.; Žinić, M. Croat. Chem.
Acta 2003, 76, 23.
(11) Rajender Reddy, L.; Bhanumati, N.; Rama Rao, K. Chem.
Commun. 2000, 2321.
(12) Concellón, J. M.; Pablo, L. B.; Pérez-Andrés, J. A.
Tetrahedron Lett. 2000, 41, 1231.
Typical Procedure for the Azetidine Formation, Starting
with Chloride 22.
To a solution of chloride 22 (1.50 g, 5.04 mmol) in THF (20
mL) and HMPA (2 mL) was added dropwise at –90 °C a
solution of LiHMDS (1 M solution in THF, 7.56 mL, 7.56
mmol). The reaction was monitored by TLC and then
quenched by the addition of an aq sat. solution of NH4Cl (10
mL) at 0 °C. Extraction of the reaction mixture using Et2O
gave, after usual workup, a residue that was purified by flash
chromatography (EtOAc–PE 1:9) to give cis-azetidine 36
(1.05 g, 80%). Rf 0.85 (EtOAc–PE 15:85); [a]D20 +91.3 (c
0.4, CHCl3). 1H NMR (200 MHz, CDCl3): d = 1.23 (d,
J = 7.0 Hz, 3 H), 1.40 (s, 9 H), 2.58–2.69 (m, 1 H), 2.90–3.10
(m, 2 H), 3.54 (d, J = 12.5 Hz, 1 H), 3.68 (d, J = 8.0 Hz, 1
H), 3.74 (d, J = 12.5 Hz, 1 H), 7.18–7.39 (m, 5 H). 13C NMR
(75 MHz, CDCl3): d = 15.5, 28.2, 28.6, 56.8, 61.6, 67.3,
80.6, 127.0, 128.2, 129.2, 137.5, 170.8. MS (CI, NH3 gas):
m/z (%) = 300 (10), 284 (74), 262 (28) [M+], 206 (100).
Anal. Calcd for C16H23NO2 (%): C, 73.53; H, 8.87; N, 5.36.
Found: C, 73.39; H, 9.01; N, 5.42.
(13) Pirkle, W. H.; Hoekstra, M. S. J. Am. Chem. Soc. 1976, 98,
1832.
Synlett 2006, No. 5, 781–785 © Thieme Stuttgart · New York