Asymmetric synthesis of functionalized azetidines through intramolecular Michael additions

Article abstract of DOI:10.1055/s-2003-38353

Enantiopure 2-cyano azetidines were prepared in good yields from β-amino alcohols. This synthesis is based on two important steps: (i) Wittig olefination of a transient amino aldehyde derived from a N-cyanomethylated β-amino alcohol and (ii) a 4-exotet ring closure through the intramolecular Michael addition of a lithiated α-amino nitrile. The former step is stereoselective. The thus produced functionalized azetidines were transformed into conformationnally constrained analogues of glutamic acid.

Full text of DOI:10.1055/s-2003-38353

726
LETTER
Asymmetric Synthesis of Functionalized Azetidines through Intramolecular
Michael Additions
A
symmetric Synth
b
esis of Func
e
lz
etidines Carlin-Sinclair,a François Couty,*a Nicolas Rabassoa,b
a
SIRCOB, UMR 8086, Université de Versailles, 45, Avenue des Etats-Unis, 78035, Versailles Cedex, France
E-mail: couty@chimie.uvsq.fr
b
Laboratoire de Synthèse Asymétrique, UMR 7611, Université Pierre et Marie Curie, 4 Place Jussieu, 75005 Paris, France
Received 13 December 2002
study of the variation of the electophilic partner in this
ring closure. This letter reports our preliminary results for
intramolecular conjugated additions of metallated a-ami-
no nitriles onto a,b-unsaturated esters (e.g., intramolecu-
Abstract: Enantiopure 2-cyano azetidines were prepared in good
yields from b-amino alcohols. This synthesis is based on two impor-
tant steps: (i) Wittig olefination of a transient amino aldehyde de-
rived from a N-cyanomethylated b-amino alcohol and (ii) a 4-exo-
tet ring closure through the intramolecular Michael addition of a lar 4-exo-trig Michael additions, Scheme 1).
lithiated a-amino nitrile. The former step is stereoselective. The
thus produced functionalized azetidines were transformed into con-
COOEt
formationnally constrained analogues of glutamic acid.
Cl
R1
EWG
R3
EWG
Key words: Michael additions, amino acids, nitrogen heterocycles,
ring closure, asymmetric synthesis
N
N
R2
R2
R3
4-exo-tet
anionic ring closure
4-exo-trig
anionic ring closure
R1
R2
OH
Azetidines (e.g., four membered nitrogen heterocycles)
have so far been less studied than other nitrogen heterocy-
cles of small and medium size. A particularly striking ex-
ample concerns the chemistry of their nor homologues,
the aziridines, which have gained considerable attention1
in the last decades, when efficient methodologies have be-
come available for their preparation in enantiomerically
pure form.2 This is however not the case for the azetidine
ring, for which a general enantioselective synthesis is still
lacking. In fact, asymmetric syntheses of this heterocycle
suffer from indirect and lengthy procedures such as reduc-
tion of enantiopure b-lactams,3 bis-alkylation of 1,3-sul-
fonates with primary amines4 or intramolecular N-
alkylation involving 1,3-amino alcohols,5 all these start-
ing substrates being already quite elaborate compounds.
Chemical,6 as well as enzymatic7 resolutions have also
provided some solutions to afford C2-symmetric or a-sub-
stituted azetidines and the thus produced azetidine ligands
have demonstrated their efficiency in various processes
based on enantioselective catalysis.8
NH
R3
Scheme 1
The starting compounds necessary to test this ring
closure10 were prepared following the sequence depicted
in Scheme 2. Thus, (S)-alaninol 1 and (S)-phenylglycinol
were N-benzylated and N-cyanomethylated to afford 2
and 39a in good yields. Transformation of these alcohols
into the required substrate for Michael addition required
oxidation prior to Wittig olefination. Since a-amino alde-
hydes are known to be susceptible to racemization,11 this
operation was conducted in one pot (Swern oxidation at
low temperature followed directly by addition of the
ylide).12 Under these conditions, no racemization could be
detected, as verified by chiral HPLC13 for the compound
5, which is the most sensitive due to the presence of a ben-
zylic position. Treatment of enamino ester 4 with LiH-
MDS at low temperature induced the desired Michael
addition to afford 2-cyano azetidines 6 and 7 as a 56/44
mixture of isomers. No other isomers could be detected in
the crude reaction mixture. These compounds could be
separated by chromatography to give 6 and 7 in respective
isolated yields of 41% and 32%. In the case of the phe-
nylglycinol-derived substrate 5, this reaction afforded
azetidines 8 and 9 with the same diastereoisomeric ratio
but with a lower yield of 58%. Again, these compounds
could be separated by chromatography (Scheme 2).
We recently reported a straighforward synthesis of aze-
tidines starting from commercially available b-amino al-
cohols.9 The key step of this methodology involves the
formation of a C-C bond through intramolecular alkyla-
tion of an a-amino stabilized carbanion [EWG = CN,9a
9b
CO2R9b or PO(OEt)2 in Scheme 1]. This 4-exo-tet ring
closure affords in a few steps, starting with cheap com-
pounds available from the chiral pool, various functional-
ized azetidines. In order to demonstrate the generality of
this ring closure and extend the diversity of the substitu-
ents on the produced azetidine ring, we undertook the
The relative configuration of the substituents in azetidines
6 and 7 was determined on the basis of NOE experiments,
as shown in Figure 1. In fact, the examination of the
values of 3J coupling constants in these heterocycles does
Synlett 2003, No. 5, Print: 10 04 2003.
Art Id.1437-2096,E;2003,0,05,0726,0728,ftx,en;D28102ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Asymmetric Synthesis of Functionalized Azetidines
727
CO2Et
c
OH
c
OH
OH
a, b
R
N
CN
CN
CN
N
NH2
N
Me
Me
Ph
2
Bn
4: R = Me
5: R = Ph
3
1
Bn
Bn
EtO2C
CN
Bn
EtO2C
CN
d
+
N
N
R
R
Bn
7: R = Me
9: R = Ph
6: R = Me
8: R = Ph
Scheme 2 Reagents and conditions: (a) i. Benzaldehyde, 4 Å MS, DCM ii. NaBH4, EtOH. 63%; (b) BrCH2CN, K2CO3, DMF, 68%;
(c) Swern oxidation –78 °C, then Ph3P=CHCO2Et, 73% (4), 83% (5) (d) LiHMDS, –78 °C, THF, 73% (6 + 7), 58% (8 + 9).
not give clear cut information about the relative stereo-
chemistries.14 In case of azetidines 8 and 9, the relative
configurations were determined by X-ray crystallography
performed on 9.15
H
CO2Et
N
Li
Me
N
Me
N
The diastereoselectivity of this intramolecular Michael
addition deserves comment. First of all, we were able to
get some experimental evidence for thermodynamic con-
trol operating in this reaction. Indeed, when diastereoiso-
merically pure isolated 6 or 7 were put under the same
conditions used for ring closure (LiHMDS, –78 to 0 °C),
an equilibration occured that gave in both cases a mixture
of 6 and 7 showing roughly the same ratio observed in the
initial ring closure. Furthermore, lithiation of 9 at –78 °C
immediately followed by deuteration with CD3OD gave
a-deuterated ester 9 exclusively. These observations sug-
gest the occurrence of a retro-Michael process that induc-
es a base-catalyzed equilibration between 6 and 7.
Secondly, the exclusive formation of 3,4-trans isomers in
these ring closures can be explained by considering the
different transition states of this reaction, two of them in-
volving substrate 4 (R = Me) being depicted in Figure 2.
In the course of the cyclization following transition state
A, a severe A1,3 strain is developed between the methyl
substituent of the azetidine ring and the olefinic proton of
the unsaturated ester, forbidding this pathway. This is not
the case in transition state B, leading to 6.
Bn
Bn
CO2Et
Li
N
B
A
H
Figure 2
products. The regioselectivity of this enolisation is how-
ever reversed when substrate 13, devoid of a stereogenic
center at the allylic position, was used in this reaction. In
this case, enolization at low temperature, followed by
quenching with MeOH gave exclusively a Z/E mixture of
enamines 14, as shown by NMR spectra of the crude reac-
tion product (Scheme 3).
CO2Et
EtO
O
CO2Et
a
a
.
N
N
CN
NLi
N
CN
Bn
Bn
11
3
10
Bn
CO2Et
CO2Et
b
c
HN
Bn
CN
N
CN
N
CN
Bn
14
12
13
Bn
CN
H
H
H
H
H3C
Scheme 3 Reagents and conditions: (a) LiHMDS, –78 °C, THF;
(b) (E)-4-bromo ethylcrotonate, K2CO3, CH3CN 88%; (d) LiHMDS,
–78 °C, THF, then MeOH.
H3C
N
N
CN
EtOOC
EtOOC
H
H
Amino nitriles are versatile moieties,16 their most well-
known transformation being their hydrolysis into a-amino
acids. This reaction was tested with azetidinic substrates 6
and 7 as depicted in Scheme 4. Thus, hydrolysis with con-
centrated HCl gave amino diacids 15 and 16 with no de-
tectable epimerization. Debenzylation, followed by ion
exchange purification (DOWEX 50 × 8) gave amino acids
17 and 18 that can be viewed as constrained analogues of
N-methyl glutamic acid or as nor homologues of kainoids.
Figure 1
The successful outcome of this reaction implies a chemi-
oselective enolization: only the amino nitrile moiety is
enolized by LiHMDS to give metallated amino nitrile 10
and the proton located at the stereocenter is not abstracted
by the base. Indeed, this latter process would generate an
ester aminodienolate 11 that should give unobserved by-
Synlett 2003, No. 5, 726–728 ISSN 0936-5214 © Thieme Stuttgart · New York

728
A. Carlin-Sinclair et al.
LETTER
2000, 11, 2143. (d) See ref. 7b. (e) Yamaguchi, M.;
Shiraishi, T.; Hirama, M. J. Org. Chem. 1996, 61, 3520.
(f) Starmans, W. A. J.; Thijs, L.; Zwanenburg, B.
CO2H
CO2H
CO2H
CO2H
H
b
a
Tetrahedron 1998, 54, 629. (g) Couty, F.; Prim, D.
Tetrahedron: Asymmetry 2002, 13, 2619.
6
, HCl
N
N
Me
Me
Bn
(9) (a) Agami, C.; Couty, F.; Evano, G. Tetrahedron:
Asymmetry 2002, 13, 297. (b) Agami, C.; Couty, F.;
Rabasso, N. Tetrahedron Lett. 2002, 43, 4633.
15
17
CO2H
CO2H
(10) To the best of our knowledge, intramolecular Michael
additions leading to four-membered rings were not
previously reported. Intramolecular Michael additions
involving metallated amino nitrile have been little reported.
For a recent example leading to a pyrrolidine ring see:
Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem.
2000, 112, 4239.
CO2H
H
CO2H
b
a
7
, HCl
Bn
N
N
Me
Me
16
18
Scheme 4 Reagents and conditions: (a) 6 N HCl, CCl4, 80 °C,
quant.; (b) H2, Pd/C, EtOH then DOWEX 50 × 8, 66% (17), 80%
(18).
(11) (a) Jurczak, J.; Golebiowski, A. Chem. Rev. 1989, 89, 149.
(b) Reetz, M. Chem. Rev. 1999, 99, 1121.
(12) Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198.
(13) HPLC was performed using a WELK 0-1 column of 250 mm
length and of 4 mm diameter. The flow rate was 1mL/mn
and the pressure 39kg/cm2. (Heptane–iso-propanol = 95/5 +
0.5% of acetic acid). Using these conditions, tr for 6 was
23.85 min and 22.00 min for ent-6.
In conclusion, we have shown that intramolecular
Michael additions of metallated amino nitriles can lead
efficiently to a new class of enantiomerically pure con-
strained amino acids starting from readily available b-
amino alcohols. The scope of this anionic ring closure
leading to strained azetidines17 is presently under study in
our group.
(14) Kingsbury, C. A.; Soriano, D. S.; Podraza, K. F.; Cromwell,
N. H. J. Heterocycl. Chem. 1982, 19, 82.
(15) Compound 9 crystallized in the space group P21 21 21
(Orthorhombic crystal system) with a = 5.558(2) Å,
b = 17.627(5) Å, c = 19.730(4) Å, and dcalcd = 1.15 g/cm3.
The intensity data were mesured on a Enraf-Nonius CAD4
diffractometer (Mo radiation). There were 1988 independent
reflexions of which 1118 were considered observed. Final
discrepancy indices were R = 0.0757 and wR = 0.0880.
Crystallographic data have been deposited (number 199691)
at the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK.
(16) Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359.
(17) All new compounds gave satisfactory spectral and analytical
data. Selected data: Compound 6. Oil, Rf = 0.47 (Et2O–
cyclohexane = 1/1). [a]D25 = –15.8 (c 0.5, CHCl3). IR(neat):
2980, 2925, 2863, 2238, 1726, 1491, 1450 cm–1. 1H NMR
(250 MHz): d = 1.02 (d, J = 5.9 Hz, 3 H, Me), 1.19 (t, J = 7.1
Hz, 3 H, Me), 2.42 (d, J = 3.1 Hz, 1 H, CHHCO), 2.45 (d,
J = 0.9 Hz, 1 H, CHHCO), 2.52–2.67 (m, 1 H, CHCH2), 2.90
(qd, J = 6.0, 7.5 Hz, 1 H, CHMe), 3.35 (d, J = 7.4 Hz, 1 H,
CHCN), 3.64 (AB syst., 2 H, J = 12.9 Hz, CH2Ph), 4.08 (q,
J = 7.4 Hz, 2 H, CH2O), 7.19–7.27 (m, 5 H, Ar). 13C NMR
(62.9 MHz): d = 14.3 (Me), 20.6 (Me), 36.7 (CH2CH), 41.0
(CHCH2), 54.3 (CHCN), 60.8 and 61.2 (CH2), 65.8 (CHMe),
119.0 (CN), 128.0, 128.6, 129.4 (CH Ar), 135.7 (Cq Ar),
170.6 (C=O). Anal. Calcd For C16H20N2O2: C, 70.56; H,
7.40; N, 10.29. Found: C, 70.54; H, 7.51; N, 10.24.
Compound 17: Rf = 0.25 (EtOH–NH3–H2O = 9/3/1).
[a]D25 = +9.5 (c 0.2, H2O). 1H NMR (200 MHz, D2O): 1.51
(d, J = 7.0 Hz, 3 H, Me), 2.38–2.91 (m, 3 H, CHCH2), 4.21
(quint., J = 8.8 Hz, 1 H, CHMe), 4.33 (d, J = 8.6 Hz, 1 H,
CHCOOH). 13C NMR (75.5 MHz): d = 21.3 (Me), 43.6
(CH2CH), 45.3 (CHCH2), 62.4 and 63.0 (CH), 176.3 and
181.5 (C=O). MS (CI, CH4): m/z (%) = 174 (22) [MH+] 173
(55), 156 (100), 130 (26), 128 (35). HRMS: Anal. Calcd For
C7H12NO4 [MH+]: 174.0766. Found: 174.0764.
Acknowledgments
Chantal Robert-Labarre is acknowledged for NOE experiments per-
formed on compounds 6 and 7.
References
(1) For a recent review on applications of aziridines, see:
Zwanenburg, B.; ten Holte, P. Top. Curr. Chem. 2001, 216,
96.
(2) (a) Jacobsen, E. N. In Comprehensive Asymmetric Catalysis,
Vol 2; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.;
Springer-Verlag: Berlin, 1999, 607–618. (b) For recent
examples see: Loncaric, C.; Wulff, W. D. Org. Lett. 2001,
23, 3675. (c) Guthikonda, K.; Du Bois, J. J. Am. Chem. Soc.
2002, 124, 13672.
(3) Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K. J. Org.
Chem. 1991, 56, 5263.
(4) Marinetti, A.; Hubert, P.; Genêt, J. P. Eur. J. Org. Chem.
2000, 1815.
(5) Barluenga, J.; Fernandez-Mari, F.; Viado, A. L.; Aguilar, E.;
Olano, B. J. Org. Chem. 1996, 61, 5659.
(6) Kozikowski, A. P.; Tückmantel, W.; Liao, Y.; Manev, H.;
Ikonomovic, S.; Wrobleski, J. T. J. Med. Chem. 1993, 36,
2706.
(7) (a) Guanti, G.; Riva, R. Tetrahedron: Asymmetry 1995, 12,
2921. (b) Hermsen, P. J.; Cremers, J. G. O.; Thijs, L.;
Zwanenburg, B. Tetrahedron Lett. 2001, 42, 4243.
(8) (a) Behnen, W.; Mehler, T.; Martens, J. Tetrahedron:
Asymmetry 1993, 4, 1413. (b) Shi, M.; Jiang, J. K.
Tetrahedron: Asymmetry 1999, 10, 1673. (c) Wilken, J.;
Erny, S.; Wassman, S.; Martens, J. Tetrahedron: Asymmetry
Synlett 2003, No. 5, 726–728 ISSN 0936-5214 © Thieme Stuttgart · New York