Electroreductive intramolecular coupling of chiral α-imino esters: Stereoselective synthesis of mixed ketals of cis-2,4-disubstituted azetidine-3-ones

Article abstract of DOI:10.1021/ja036975b

The electroreduction of chiral aromatic α-imino esters prepared from (S)-α-amino acids, such as (S)-valine, (S)-leucine, and (S)-phenylalanine, in the presence of chlorotrimethylsilane and triethylamine afforded four-membered cyclized products, mixed ketals of cis-2,4-disubstituted azetidine-3-ones, stereospecifically (>99% de, 85-99% ee). The best result of the electroreductive cyclization was obtained using Bu₄NClO ₄ as a supporting electrolyte and a Pt cathode. The absolute stereochemistry of the obtained single stereoisomers was confirmed to be 2R,3R,4S by X-ray crystallography. Calculations for the transition states of the cyclization support the stereospecific formation of the (2R,3R,4S)-isomers.

Full text of DOI:10.1021/ja036975b

Published on Web 08/30/2003
Electroreductive Intramolecular Coupling of Chiral r-Imino
Esters: Stereoselective Synthesis of Mixed Ketals of
cis-2,4-Disubstituted Azetidine-3-ones
Naoki Kise,* Hiroshi Ozaki, Noriaki Moriyama, Yasuo Kitagishi, and Nasuo Ueda
Contribution from the Department of Biotechnology, Faculty of Engineering, Tottori UniVersity,
Koyama, Tottori 680-8552, Japan
Received June 30, 2003; E-mail: kise@bio.tottori-u.ac.jp
Abstract: The electroreduction of chiral aromatic R-imino esters prepared from (S)-R-amino acids, such
as (S)-valine, (S)-leucine, and (S)-phenylalanine, in the presence of chlorotrimethylsilane and triethylamine
afforded four-membered cyclized products, mixed ketals of cis-2,4-disubstituted azetidine-3-ones, ster-
eospecifically (>99% de, 85-99% ee). The best result of the electroreductive cyclization was obtained
using Bu NClO as a supporting electrolyte and a Pt cathode. The absolute stereochemistry of the obtained
4 4
single stereoisomers was confirmed to be 2R,3R,4S by X-ray crystallography. Calculations for the transition
states of the cyclization support the stereospecific formation of the (2R,3R,4S)-isomers.
Introduction
Scheme 1
Reductive cross-coupling of imines with carbonyl compounds
is a promising method for the synthesis of functionalized amino
compounds such as â-amino alcohols. Indeed, reductive inter-
molecular coupling of aromatic imines with aldehydes or ketones
1
2
has been successfully realized using NbCl3(DME) and SmI2
as a reducing agent. On the other hand, we have reported that
electroreduction is also a useful tool for the reductive cross-
coupling of aromatic imines with a variety of carbonyl com-
molecular coupling of chiral R-imino esters derived from readily
available (S)-R-amino acids and aromatic aldehydes. The condi-
tions for the electroreduction were optimized, the scope and
limitations of the reductive cyclization were explored, and the
stereostructure of the stereospecifically formed azetidines was
confirmed by X-ray crystallography. Furthermore, the transition
states for the electroreductive intramolecular coupling were
calculated with semiempirical, ab initio, and DFT methods to
explain theoretically the stereospecific formation of the multi-
substituted azetidines.
3
pounds. To the best of our knowledge, reductive intramolecular
coupling of imino esters has so far been achieved only by the
electrochemical method. In particular, the electroreduction of
the chiral R-imino ester 1a prepared from (S)-valine methyl ester
and benzaldehyde gave a four-membered cyclized product, a
mixed ketal of (2R,3R,4S)-2-isopropyl-4-phenylazetidine-3-one,
stereospecifically (Scheme 1). Because this result is very inter-
esting and is only one example, we decided to scrutinize this
type of reaction in more detail. Azetidine-containing natural pro-
ducts are rare apart from â-lactams, although some azetidine
Results and Discussion
Conditions for the electroreduction of N-benzylidene (S)-
valine methyl ester (1a) were investigated as summarized in
Table 1. To verify the reproducibility of the previously reported
4
alkaloids have been known. However, a number of synthetic
multisubstituted azetidines have been reported and utilized as
5
chiral ligands. Most of the methods that have so far been report-
3
results, we initially carried out the electroreduction of 1a in
ed for the stereoselective synthesis of multisubstituted azetidines
5
,6
are based on intramolecular nucleophilic substitution. In this
paper, we report our further study on the electroreductive intra-
(
6) For recent reports for the diastereoselective synthesis of racemic multi-
substituted azetidines by nucleophilic substitution, see: (a) Salgado, A.;
Dejaegher, Y.; Verniest, G.; Boeykens, M.; Gauthier, C.; Lopin, C.; Tehrani
K. A.; De Kimpe, N. Tetrahedron 2003, 59, 2231. (b) Salgado, A.;
Boeykens, M.; Gauthier, C.; Declercq, J.-P.; De Kimpe, N. Tetrahedron
2002, 58, 2763. By selenium-induced cyclization of homoallylamines,
see: (c) Pannecoucke, X.; Outurquin, F.; Paulmier, C. Eur. J. Org. Chem.
2002, 995. By bromo-amination of N-cinnamyl tosylamides, see: (d) Robin,
S.; Rousseau, G. Eur. J. Org. Chem. 2000, 3007. Recent reports for the
asymmetric synthesis of multisubstituted azetidines by nucleophilic sub-
stitution, see: (e) Yoda, H.; Uemura, T.; Takabe, K. Tetrahedron Lett.
2003, 44, 977. (f) Agami, C.; Couty, F.; Evano, G. Tetrahedron: Asymmetry
2002, 13, 297. (g) Agami, C.; Couty, F.; Rabasso, N. Tertrahedron Lett.
2002, 43, 4633. (h) Concell o´ n, J. M.; Riego, E.; Bernad, P. L. Org. Lett.
2002, 4, 1299. (i) Concell o´ n, J. M.; Bernad, P. L.; P e´ rez-Andr e´ s, J. A.
Tetrahedron Lett. 2000, 41, 1231. (j) Liu, D.-G.; Lin, G.-Q. Tetrahedron
Lett. 1999, 40, 337.
(
1) Roskamp, E, J.; Pedersen, S. F. J. Am. Chem. Soc. 1987, 109, 6551.
2) (a) Machrouhi, F; Namy, J.-L. Tetrahedron Lett. 1999, 40, 1315. (b) Tanaka,
Y; Taniguchi, N.; Uemura, M. Org. Lett. 2002, 4, 835.
(
(
3) Shono, T.; Kise, N.; Kunimi, N.; Nomura, R. Chem. Lett. 1991, 2191.
4) (a) Kobayashi, J.; Cheng, J.; Ishibashi, M.; Walchli, M. R.; Yamamura,
S.; Ohizumi, Y. J. Chem. Soc., Perkin Trans. 1 1991, 1135. (b) Alvi, K.
A.; Jaspars, M.; Crews, P. Bioorg. Biomed. Chem. Lett. 1994, 4, 2447.
5) (a) Couty, F.; Prim, D. Tetrahedron: Asymmetry 2002, 13, 2619. (b)
Hermsen, P. J.; Cremers, J. G. O.; Thijs, L.; Zwanenburg, B. Tetrahedron
Lett. 2001, 42, 4243. (c) Guanti, G.; Riva, R. Tetrahedron: Asymmetry
(
(
2
001, 12, 605. (d) Wilken, J.; Erny, S.; Wassmann, S.; Martens, J.
Tetrahedron: Asymmetry 2000, 11, 2143. (e) Shi, M.; Jiang, J.-K.
Tetrahedron: Asymmetry 1999, 10, 1673.
10.1021/ja036975b CCC: $25.00 © 2003 American Chemical Society
J. AM. CHEM. SOC. 2003, 125, 11591-11596
9
11591

A R T I C L E S
Kise et al.
Table 1. Electroreductive Coupling of 1a to 2a
Scheme 2
entry
solventa
additiveb
cathode
yield (%) of 2ac
Scheme 3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
Bu4NClO4/THF
Bu4NClO4/THF
Bu4NClO4/THF
Bu4NClO4/DMF
Bu4NBF4/THF
Bu4NPF6/THF
Bu4NBr/THF
CTMS/TEA
none
CTMS
Pb
Pb
Pb
Pb
Pb
Pb
Pb
Pb
Pb
Pt
Au
Ag
Cu
Zn
Sn
Al
53
d
0
45
0
e
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
49
54
51
43
Bu4NCl/THF
LiClO4/THF
d
0
0
1
2
3
4
5
6
Bu4NClO4/THF
Bu4NClO4/THF
Bu4NClO4/THF
Bu4NClO4/THF
Bu4NClO4/THF
Bu4NClO4/THF
Bu4NClO4/THF
62
57
54
51
48
49
45
Table 2. Electroreductive Coupling of 1 to 2a
a
.3 M electrolyte in solvent. 5 equiv to 1a. c Isolated yields. 85-
b
0
d
e
8
8% ee. Complex mixture was obtained with a small amount of 3. 1a
was recovered.
the presence of 5 equiv of chlorotrimethylsilane (CTMS) and
triethylamine (TEA) in 0.3 M Bu4NClO4/THF (entry 1).
Actually, (2R,3R,4S)-4-isopropyl-3-methoxy-2-phenyl-3-(trim-
ethylsiloxy)azetidine (2a′) was produced as a single stereoisomer
together with small amounts of simply reduced amine 3 (<5%
entry
1
R′′
R
2
yield (%)b
1
2
3
4
5
6
7
8
9
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
p-MeOC6H4
m-MeOC6H4
o-MeOC6H4
3,4-(MeO)2C6H3
p-FC H4
p-NCC6H4
1-naphthyl
2-naphthyl
2-naphthyl
t-Bu
Me
Me
Me
Me
Me
Me
Me
Me
t-Bu
Me
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
60
55
41
52
47
34
38
60
52
7
yield), hydrodimer 4 (<5% yield), and N-R-trimethysilylated
product 5 (<10% yield). The cyclized product 2a′ was isolated
1
as its N-benzoyl derivative 2a in 53% yield and 88% ee (by H
6
NMR with Eu(hfc)3) after treatment with BzCl-TEA, to
simplify the purification of the somewhat unstable free azetidine
2
a′. The electroreduction of 1a alone gave amine 3 (<20%
c
10
0
yield) as only one isolatable product (entry 2). This result shows
that CTMS is indispensable to promote the electroreductive
intramolecular coupling. The addition of 5 equiv of CTMS to
a
The electroreduction was carried out in 0.3 M Bu4NClO4/THF.
b
Isolated yields: 2g-2n (85-90% ee), 2o (>99% ee). c 1p was recovered.
1
2
a was the optimal condition (1 equiv of CTMS, 23% yield of
a; 2 equiv, 40%; 3 equiv, 47%; 8 equiv, 50%). Although the
N-benzylidene (S)-valine ethyl ester (1b) and tert-butyl ester
(1c) were subjected to electroreduction (Scheme 2). The
corresponding azetidine derivatives were produced stereospe-
cifically in moderate yields even from sterically hindered tert-
butyl ester (2c: 52% yield). It is noted that the enantiomeric
presence of TEA is not essential, the yield of 2a decreased to
some extent in the absence of TEA (entry 3). In DMF, the
substrate 1a was completely recovered (entry 4). Several
tetrabutylammonium salts, which dissolve well in THF, were
employed as a supporting electrolyte and gave comparable yields
of 2a (entries 1 and 5-8). The electroreduction with LiClO4,
however, produced a complex mixture in which a small amount
of 3 (<10% yield) was detected (entry 9). In addition, the
intramolecular coupling was less affected by the choice of
cathode material; all cathode materials tested afforded 2a in
moderate yields (entries 11-16). Consequently, the best yield
of 2a (62% yield, 88% ee) was obtained with Bu4NClO4 as a
supporting electrolyte and a Pt cathode (entry 10).
1
excess of 2c was determined to be >99% by H NMR with
Eu(hfc)3, while 2a (88% ee) and 2b (90% ee) were obtained in
slightly lower ee values. This fact shows that tert-butyl ester
1c entirely resists racemization under the conditions of elec-
troreduction. Second, N-benzylideneamines prepared from some
other R-amino acid methyl esters were employed (Scheme 3).
3
As previously reported, N-benzylidene glycine methyl ester (1d)
brought about poor results (6: 20% yield), probably due to the
instability of the starting imine 1d. On the other hand, chiral
N-benzylideneamines 1e and 1f derived from (S)-leucine and
(S)-phenylalanine methyl ester, respectively, also gave azetidines
2
a and 2f stereospecifically in yields similar to that obtained
with 1a. Finally, the effect of aryl-substitution on 1a was
examined as exhibited in Table 2. Whereas para- and meta-
(
7) We have already reported the reductive dimerization of 1a to 5 with Zn-
MsOH: Kise, N.; Oike, H.; Okazaki, E.; Yoshimoto, M.; Shono, T. J. Org.
Chem. 1995, 60, 3980.
Next, we explored a range of substrates for this intramolecular
coupling under the same conditions as entry 10 in Table 1. First,
11592 J. AM. CHEM. SOC.
9
VOL. 125, NO. 38, 2003

Intramolecular Coupling of Chiral R-Imino Esters
A R T I C L E S
Table 3. 1H NMR Chemical Shifts of 1a in the Presence of CTMS
CTMS (eq)
CHdN(δ)
NCHCO (δ)
0
8.24
8.53
8.77
8.82
8.85
8.91
8.22
3.67
4.15
4.47
4.53
4.56
4.62
3.65
0
1
2
3
5
5
.5
.0
.0
.0
.0
.0
a
a
5
equiv of TEA was added.
1
1
a‚CTMS complex was obvious from H NMR analysis of 1a;
a lower field shift was measured in the imino and carbonyl-R
methyne protons of 1a by addition of CTMS to a solution of
1a in CDCl3 (Table 3). The formation of the 1a‚CTMS complex
seems to not be necessary for the reductive coupling, because
it dissociated into free 1a by addition of TEA. Nevertheless,
the reduction can be caused from 1a‚CTMS by the equilibrium
of the formation of 1a‚CTMS even in the presence of TEA.
The reduction potential of the iminium salt 1a‚CTMS is
estimated to be less negative than that of 1a, although reproduc-
ible data could not be obtained from the CV measurement of
Figure 1. X-ray crystal structure of 2c.
1
a‚CTMS. The radical A is generated by one-electron transfer
to 1a‚CTMS and subsequent N-silylation, and then undergoes
further one-electron transfer to form anion B. The carbanion in
B attacks the ester carbonyl intramolecularly, and the following
O-silylation of the resulting O-anion C yields D. After N-
desilylation of D during workup, the product 2a′ is obtained.
Of the four possible isomers of 2a, the 2R,3R,4S-isomer was
formed predominantly as described above. The stereochemistry
is determined kinetically in the cyclization step from anion B
to C. Therefore, we calculated the transition states for the
cyclization to compare their energies by semiempirical, ab initio,
Figure 2. NOE enhancements in 2c.
substitutions of an electron-donating group did not hinder the
cyclization (entries 1, 2, 4, 8, and 9), ortho-substitution and a
para-substituted electron-withdrawing group inhibited it (entries
3
and 5-7). All of the azetidines 2 were obtained as single
stereoisomers. Unfortunately, aliphatic imine 1p was not reduced
under the same conditions (entry 10).
3
In the preliminary report, the stereostructure of 2a′ was
8
and DFT methods. All calculations reveal that the transition
assigned by NOE experiments of its N-methoxycarbonylated
analogue (Scheme 1). To ascertain the stereoconfiguration, we
tried an X-ray crystallographic analysis of 2. Fortunately, only
state (R,R,S)-TS giving (2R,3R,4S)-2a is the most stable of the
9
four transition states (Figure 3, Table 4). These computational
results support the stereospecificity in the electroreductive
cyclization of 2.
2
c crystallized among 2a-c and 2e-o, and its 2R,3R,4S
configuration was confirmed conclusively (Figure 1). Addition-
ally, reasonable NOE enhancements were observed in the H
NMR spectrum of 2c (Figure 2). These results imply that the
other azetidines 2 derived from chiral (S)-1 also possess
1
Conclusion
This paper describes a novel electroreductive intramolecular
coupling of aromatic R-imino esters to give four-membered
nitrogen heterocycles, azetidines. The presence of CTMS is
essential for the electroreductive coupling. The present reaction
provides a new method for the stereospecific synthesis of the
2R,3R,4S configuration, although each stereoconfiguration could
not be determined directly.
The presumed reaction mechanism of the electroreductive
cyclization is illustrated in Scheme 4. The formation of an imine
Scheme 4
J. AM. CHEM. SOC.
9
VOL. 125, NO. 38, 2003 11593

A R T I C L E S
Kise et al.
Typical Procedure for Electroreduction of 1. A 0.3 M solution
of Bu
4 4
NClO in THF (15 mL) was placed in the cathodic chamber of
a divided cell (40 mL beaker, 3 cm diameter, 6 cm height) equipped
2
2
with a platinum cathode (5 × 5 cm ), a platinum anode (2 × 1 cm ),
and a ceramic cylindrical diaphragm (1.5 cm diameter). A 0.3 M
solution of Bu
(
(
4
NClO
inside the diaphragm). Imino ester (1a) (219 mg, 1 mmol), CTMS
0.64 mL, 5 mmol), and triethylamine (0.70 mL, 5 mmol) were added
4
in DMF (4 mL) was placed in the anodic chamber
to the cathodic chamber. After 300 C of electricity was passed at a
constant current of 100 mA at room temperature, the catholyte was
evaporated in vacuo. To the residue were added Et
M NaHCO (30 mL). Insoluble Bu NClO was filtered off, and the
filtrate was extracted with Et O three times. After removal of the
2
O (30 mL) and 1
3
4
4
2
solvent, the residue was dissolved in THF (5 mL). To the solution were
added benzoyl chloride (0.12 mL, 1 mmol) and TEA (0.21 mL, 1.5
mmol) at room temperature. The suspended mixture was stirred for 6
h, diluted with 1 M NaHCO (10 mL), and then extracted with Et O
3 2
three times. The crude mixture was purified by column chromatography
Figure 3. Optimized structures (RB3LYP/6-31G*) of transition states for
the intramolecular coupling of 1a.
on silica gel (hexanes-ethyl acetate, 50:1) to give 2a in 62% yield.
The enantiomeric excess of 2a was measured by H NMR with Eu-
1
(
3
hfc) . The products 2a, 2b, and 2e-o were isolated as colorless pastes
Table 4. Relative Energies (kcal/mol) between Stereoisomers of
Transition States for the Intramolecular Coupling of 1a
or amorphous solids. Only 2c was obtained as a single crystal by
recrystallization from hexanes-ethyl acetate.
method
(R,R,S)-TS
(R,S,S)-TS
(S,R,S)-TS
(S,S,S)-TS
(
2R,3R,4S)-1-Benzoyl-4-isopropyl-3-methoxy-2-phenyl-3-(trime-
thylsiloxy)azetidine (2a). 88% ee. Colorless paste. R 0.61 (hexanes-
ethyl acetate, 5:1). [R]25
-14.5 (c ) 1.03, CHCl ). IR (neat): 1653,
603, 1580, 1497, 881, 843, 700 cm . H NMR (CDCl ): δ -0.26
RHF/AM1
RHF/PM3
RHF/6-31G*
RB3LYP/6-31G*
0
0
0
0
0.94
1.42
1.78
1.80
1.42
3.50
5.75
3.63
2.64
6.79
5.09
5.10
f
D
3
-
1 1
1
3
(
(
7
s, 9H), 1.06 (d, 3H, J ) 6.2 Hz), 1.18 (d, 3H, J ) 6.8 Hz), 2.27-2.42
m, 1H), 4.35 (d, 1H, J ) 11.1 Hz), 4.90 (s, 1H), 7.05-7.12 (m, 2H),
.21-7.44 (m, 8H). 13C NMR (CDCl
): δ 0.95 (q), 19.71 (q), 20.11
(
2R,3S,4S)-isomers of the mixed ketals of cis-2,4-disubstituted
3
(
1
1
q), 29.50 (d), 50.19 (q), 75.02 (d), 79.63 (d), 100.48 (s), 127.47 (d),
azetidine-3-ones from (S)-R-amino acids. The 2R,3R,4S stereo-
chemistry was confirmed with certainty by X-ray crystal-
lography. Calculations for the transition states of the reductive
cyclization gave convincing explanations for the stereospecific
formation of the (2R,3R,4S)-azetidines.
28.12 (d), 128.16 (d), 128.37 (d), 128.92 (d), 130.63 (d), 133.48 (s),
38.13 (s), 175.67 (s). Anal. Calcd for C23 Si: C, 69.48; H, 7.86;
H31NO
3
N, 3.52. Found: C, 69.63; H, 7.88; N, 3.36.
. R
0.58 (hexanes-ethyl acetate, 10:1). [R]25
CHCl ). IR (neat): 1736, 1601, 839, 752, 702 cm
CDCl ): δ -0.03 (s, 9H), 0.89 (d, 3H, J ) 7.0 Hz), 0.96 (d, 3H, J )
.0 Hz), 1.74-1.92 (m, 1H), 2.91 (d, 1H, J ) 6.2 Hz), 3.69 (s, 3H),
5
f
D
-109 (c ) 1.47,
-
1
1
3
. H NMR
(
7
3
Experimental Section
13
General. All 1H and 13C NMR spectra were measured on a JEOL
7.03-7.27 (m, 5H). C NMR (CDCl ): δ -3.89 (q), 18.63 (q), 19.61
(
3
q), 31.72 (d), 50.94 (q), 54.90 (d), 66.19 (d), 125.05 (d), 126.84 (d),
GX-270 spectrometer with tetramethylsilane (TMS) as an internal
standard. IR spectra were recorded on a Shimadzu FTIR-8300 infrared
spectrometer. Optical rotations were obtained on a Jasco DIP-360 digital
polarimeter. Column chromatography was performed on silica gel 60
or neutral alumina (Activity III). THF was distilled from sodium
benzophenone ketyl radical. CTMS, TEA, and DMF were distilled from
1
6
27.62 (d), 142.06 (s), 175.80 (s). Anal. Calcd for C16
6.48; H, 9.27; N, 4.77. Found: C, 69.63; H, 7.88; N, 3.36.
(2R,3R,4S)-1-Benzoyl-3-ethoxy-4-isopropyl-2-phenyl-3-(trimeth-
ylsiloxy)azetidine (2b). 90% ee. Colorless solid. R 0.54 (hexanes-
ethyl acetate, 5:1). [R]23
11.4 (c ) 0.98, CHCl ). IR (KBr): 1720,
1643, 1602, 1578, 1500, 934, 916, 881, 843, 700 cm . H NMR
(CDCl ): δ -0.27 (s, 9H), 1.04 (d, 3H, J ) 6.5 Hz), 1.18 (d, 3H, J )
2
H27NO Si: C,
f
D
3
-
1
1
CaH . Aromatic R-imino esters 1 were synthesized by treatment of
2
R-amino acid esters with aromatic aldehydes in dichloromethane in
the presence of magnesium sulfate at room temperature and isolated
by distillation in vacuo (1a, 1b, 1e-n, and 1p) or by recrystallization
from hexanes-ethyl acetate (1c and 1o). Only 1d was used without
purification, because 1d decomposed during distillation.
3
7.0 Hz), 1.22 (t, 3H, J ) 7.3 Hz), 2.27-2.42 (m, 1H), 3.44-3.56 (m,
1H), 3.60-3.72 (m, 1H), 4.36 (d, 1H, J ) 10.8 Hz), 4.94 (s, 1H), 7.05-
7.12 (m, 2H), 7.22-7.43 (m, 8H). 13C NMR (CDCl
): δ -1.00 (q),
15.06 (q), 19.75 (q), 20.09 (q), 29.55 (d), 57.92 (t), 75.31 (d), 79.81
3
(
(
d), 99.89 (s), 127.47 (d), 128.09 (d), 128.16 (d), 128.34 (d), 128.92
d), 130.64 (d), 133.46 (s), 138.23 (s), 175.69 (s). Anal. Calcd for
(
8) The calculations were carried out using the Gaussian 98W program: Frisch,
M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi,
R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz,
J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J. Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-
Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98W, revision A.9;
Gaussian, Inc.: Pittsburgh, PA, 1998.
24 3
C H33NO Si: C, 70.03; H, 8.08; N, 3.40. Found: C, 70.12; H, 8.12;
N, 3.19.
2R,3R,4S)-1-Benzoyl-3-tert-butoxy-4-isopropyl-2-phenyl-3-(tri-
methylsiloxy)azetidine (2c). >99% ee. Colorless solid. R 0.56
(hexanes-ethyl acetate, 5:1). mp 97-98 °C. [R]21
-8.7 (c ) 1.0,
CHCl ). IR (KBr): 1647, 1495, 880, 843, 766, 702 cm . H NMR
(CDCl ): δ -0.24 (s, 9H), 1.07 (d, 3H, J ) 6.2 Hz), 1.19 (d, 3H, J )
.0 Hz), 1.40 (s, 3H), 2.40-2.55 (m, 1H), 4.84 (d, 1H, J ) 10.0 Hz),
(
f
D
-1
1
3
3
7
4
1
3
.97 (s, 1H), 7.05-7.13 (m, 2H), 7.21-7.39 (m, 8H). C NMR
): δ 1.34 (q), 20.07 (q), 30.19 (d), 30.45 (q), 76.28 (s), 76.55
d), 82.74 (d), 99.52 (s), 127.44 (d), 127.77 (d), 127.91 (d), 128.64
(d), 130.25 (d), 130.43 (d), 133.80 (s), 138.38 (s), 175.69 (s). Anal.
(
9) It was confirmed that the optimized structures had only one imaginary
frequency according to the vibration analysis. The imaginary frequency
was verified to be consistent with the intramolecular coupling by displaying
the vibrational mode using the Gauss View program.
(CDCl
3
(
11594 J. AM. CHEM. SOC.
9
VOL. 125, NO. 38, 2003

Intramolecular Coupling of Chiral R-Imino Esters
A R T I C L E S
Calcd for C26
H, 8.48; N, 3.12.
-Methoxy-1-methoxycarbonyl-2-phenyl-3-(trimethylsiloxy)aze-
tidine (6). Colorless paste. R 0.37 (hexanes-ethyl acetate, 5:1). IR
H
37NO
3
Si: C, 71.03; H, 8.48; N, 3.19. Found: C, 71.07;
1.9, 7.6 Hz). 13C NMR (CDCl
(d), 50.29 (q), 55.02 (q), 72.17 (d), 75.36 (d), 100.80 (s), 110.35 (d),
120.72 (d), 126.56 (s), 127.33 (d), 127.88 (d), 129.16 (d), 129.74 (d),
3
): δ 0.71 (q), 19.78 (q), 20.12 (q), 29.35
3
130.35 (d), 133.66 (s), 156.82 (s), 175.66 (s). Anal. Calcd for C24
NO Si: C, 67.41; H, 7.78; N, 3.28. Found: C, 67.52; H, 7.88; N, 3.10.
(2R,3R,4S)-1-Benzoyl-4-isopropyl-3-methoxy-2-(3,4-dimethoxy-
phenyl)-3-(trimethylsiloxy)azetidine (2j). 90% ee. Colorless paste. R
f
33
H -
f
-
1
1
(neat): 1828, 1713, 1605, 1497, 941, 868, 845, 756, 698 cm . H
4
NMR (CDCl ): δ -0.05 (s, 9H), 3.33 (s, 3H), 3.62 (s, 3H), 4.04 (dd,
3
1
7
6
H, J ) 1.1, 8.9 Hz), 4.19 (d, 1H, J ) 8.9 Hz), 5.22 (s, 1H), 7.23-
1
3
27
.38 (m, 5H). C NMR (CDCl
1.95 (t), 75.58 (d), 97.62 (s), 127.35 (d), 127.76 (d), 136.21 (s), 157.15
Si: C, 58.22; H, 7.49; N, 4.53. Found:
3
): δ 0.81 (q), 49.75 (q), 52.42 (q),
0.61 (hexanes-ethyl acetate, 2:1). [R]
D
3
-8.0 (c ) 0.88, CHCl ). IR
(neat): 1651, 1605, 1593, 1580, 1516, 924, 845, 799, 733, 712, 696
-
1 1
(
s). Anal. Calcd for C15
C, 58.32; H, 7.53; N, 4.38.
2R,3R,4S)-1-Benzoyl-4-isobutyl-3-methoxy-2-phenyl-3-(trimeth-
ylsiloxy)azetidine (2e). 86% ee. Colorless solid. R 0.45 (hexanes-
). IR (KBr): 1649,
601, 1580, 1495, 885, 845, 721, 700 cm . H NMR (CDCl ): δ -0.23
s, 9H), 1.04 (d, 6H, J ) 5.9 Hz), 1.73-1.86 (m, 3H), 3.33 (s, 3H),
.70 (t, 1H, J ) 6.8 Hz), 5.07 (s, 1H), 7.05-7.16 (m, 2H), 7.23-7.40
H23NO
4
3
cm . H NMR (CDCl ): δ -0.21 (s, 9H), 1.07 (d, 3H, J ) 6.5 Hz),
1.18 (d, 3H, J ) 6.8 Hz), 2.25-2.41 (m, 1H), 3.32 (s, 3H), 3.88 (s,
3H), 3.93 (s, 3H), 4.32 (d, 1H, J ) 10.5 Hz), 4.83 (s, 1H), 6.80 (dd,
1H, J ) 1.6, 8.4 Hz), 6.88 (d, 1H, J ) 8.4 Hz), 6.92 (d, 1H, J ) 1.6
(
f
2
3
13
ethyl acetate, 5:1). [R]
D
0.02 (c ) 1.06, CHCl
3
Hz), 7.08-7.16 (m, 2H), 7.24-7.34 (m, 3H). C NMR (CDCl
3
): δ
-1 1
1
(
4
3
0.98 (q), 19.43 (q), 20.10 (q), 29.55 (d), 50.08 (q), 55.68 (q), 55.88
(q), 74.68 (d), 79.30 (d), 100.43 (s), 110.96 (d), 111.94 (d), 121.54
(d), 127.39 (d), 128.09 (d), 130.55 (d), 130.73 (s), 133.39 (s), 148.85
(s), 175.46 (s). Anal. Calcd for C25
3.06. Found: C, 65.78; H, 7.80; N, 2.90.
(2R,3R,4S)-1-Benzoyl-4-isopropyl-3-methoxy-2-(4-fluorophenyl)-
3-(trimethylsiloxy)azetidine (2k). 87% ee. Colorless paste. R 0.4
(hexanes-ethyl acetate, 5:1). [R]23
27.0 (c ) 1.1, CHCl ). IR (neat):
1651, 1603, 1508, 928, 883, 853, 719, 704 cm . 1H NMR (CDCl
):
1
3
(m, 8H). C NMR (CDCl
3
): δ 0.99 (q), 22.53 (q), 23.38 (q), 25.31
5
H35NO Si: C, 65.61; H, 7.71; N,
(d), 39.40 (t), 50.37 (q), 68.77 (d), 78.37 (d), 100.53 (s), 127.56 (d),
1
1
27.75 (d), 128.00 (d), 128.19 (d), 128.78 (d), 130.32 (d), 133.80 (s),
37.44 (s), 173.75 (s). Anal. Calcd for C24 Si: C, 70.03; H, 8.08;
H33NO
3
f
N, 3.40. Found: C, 70.21; H, 8.13; N, 3.16.
2R,3R,4S)-1-Benzoyl-4-benzyl-3-methoxy-2-phenyl-3-(trimeth-
ylsiloxy)azetidine (2f). 88% ee. Colorless paste. R 0.39 (hexanes-
). IR (neat): 1645,
D
3
-
1
(
3
f
δ -0.23 (s, 9H), 1.06 (d, 3H, J ) 6.5 Hz), 1.17 (d, 3H, J ) 7.0 Hz),
2.22-2.38 (m, 1H), 3.33 (s, 3H), 4.34 (d, 1H, J ) 10.8 Hz), 4.86 (s,
2
6
ethyl acetate, 5:1). [R]
602, 1578, 1495, 885, 841, 754, 721, 698 cm . H NMR (CDCl
δ -0.28 (s, 9H), 2.80 (s, 3H), 3.27-3.50 (m, 2H), 4.80 (dd, 1H, J )
D
-1.3 (c ) 0.75, CHCl
3
-
1
1
13
1
3
):
1H), 7.06-7.15 (m, 4H), 7.18-7.22 (m, 2H), 7.24-7.34 (m, 3H).
NMR (CDCl
C
3
): δ 1.05 (q), 19.70 (q), 20.11 (q), 29.65 (d), 50.34 (q),
1
3
3
.5, 10.5 Hz), 5.06 (s, 1H), 7.08-7.42 (m, 15H). C NMR (CDCl
3
):
74.84 (d), 78.79 (d), 100.38 (s), 115.36 (d, JCCF ) 21.7 Hz), 127.56
(d), 128.06 (d), 130.72 (d, JCCCF ) 8.4 Hz), 130.74 (d), 133.55 (d),
134.19 (s, JCCCCF ) 2.8 Hz), 162.56 (s, JCF ) 245.4 Hz), 175.82 (s).
δ 1.00 (q), 35.99 (t), 50.75 (q), 71.48 (d), 78.55 (d), 101.04 (s), 126.08
(
(
d), 127.58 (d), 127.67 (d), 128.03 (d), 128.25 (d), 129.31 (d), 129.81
d), 130.31 (d), 133.88 (s), 137.19 (s), 138.21 (s), 173.69 (s). Anal.
Anal. Calcd for C26
64.08; H, 7.70; N, 2.71.
(2R,3R,4S)-1-Benzoyl-4-isopropyl-3-methoxy-2-(4-cyanophenyl)-
6
H37NO Si: C, 64.04; H, 7.65; N, 2.87. Found: C,
Calcd for C27
H, 7.12; N, 3.11.
2R,3R,4S)-1-Benzoyl-4-isopropyl-3-methoxy-2-(4-methoxyphen-
yl)-3-(trimethylsiloxy)azetidine (2g). 88% ee. Colorless paste. R 0.46
). IR
neat): 3447, 1650, 1611, 1580, 1514, 984, 926, 883, 843, 797, 702,
3
H31NO Si: C, 72.77; H, 7.01; N, 3.28. Found: C, 72.95;
(
3-(trimethylsiloxy)azetidine (2l). 85% ee. Colorless paste. R
(hexanes-ethyl acetate, 2:1). [R]24
f
0.63
f
D
-39.7 (c ) 0.88, CHCl
3
). IR
2
5
(hexanes-ethyl acetate, 5:1). [R]
D
-7.5 (c ) 1.00, CHCl
3
(neat): 2230, 1734, 1701, 1655, 1609, 1580, 935, 881, 847, 733, 702
-
1 1
(
6
3
cm . H NMR (CDCl ): δ -0.24 (s, 9H), 1.05 (d, 3H, J ) 6.5 Hz),
-
1 1
75 cm . H NMR (CDCl
3
): δ -0.23 (s, 9H), 1.06 (d, 3H, J ) 6.5
1.17 (d, 3H, J ) 6.8 Hz), 2.16-2.34 (m, 1H), 3.34 (s, 3H), 4.39 (d,
1H, J ) 10.8 Hz), 4.95 (s, 1H), 7.08-7.20 (m, 3H), 7.29-7.36 (m,
Hz), 1.17 (d, 3H, J ) 6.8 Hz), 2.25-2.40 (m, 1H), 3.32 (s, 3H), 3.86
2H), 7.41-7.46 (m, 2H), 7.69-7.74 (m, 2H). 13C NMR (CDCl
): δ
(
7
s, 3H), 4.31 (d, 1H, J ) 10.8 Hz), 4.83 (s, 1H), 6.90-6.95 (m, 2H),
3
1
3
.07-7.14 (m, 2H), 7.18-7.33 (m, 6H). C NMR (CDCl
3
): δ -0.99
1.05 (q), 19.56 (q), 19.93 (q), 29.53 (d), 50.44 (q), 75.11 (d), 78.54
(d), 100.28 (s), 111.92 (s), 118.31 (s), 127.67 (d), 127.72 (d), 129.41
(d), 130.85 (d), 132.08 (d), 133.22 (s), 143.47 (s), 175.50 (s). Anal.
(q), 19.70 (q), 20.11 (q), 29.54 (d), 50.16 (q), 55.27 (q), 74.70 (d),
7
1
9.20 (d), 100.53 (s), 113.79 (d), 127.42 (d), 128.17 (d), 130.27 (d),
30.36 (s), 130.57 (d), 133.58 (s), 159.51 (s), 175.72 (s). Anal. Calcd
Calcd for C24
H, 7.20; N, 6.45.
(2R,3R,4S)-1-Benzoyl-4-isopropyl-3-methoxy-2-(1-naphthyl)-3-
(trimethylsiloxy)azetidine (2m). 90% ee. Colorless paste. R 0.51
30 2 3
H N O Si: C, 68.21; H, 7.16; N, 6.63. Found: C, 68.27;
for C24
.85; N, 3.23.
2R,3R,4S)-1-Benzoyl-4-isopropyl-3-methoxy-2-(3-methoxyphen-
yl)-3-(trimethylsiloxy)azetidine (2h). 87% ee. Colorless paste. R 0.42
). IR (neat):
651, 1603, 1585, 1491, 935, 845, 716, 700 cm-1. 1H NMR (CDCl
):
4
H33NO Si: C, 67.41; H, 7.78; N, 3.28. Found: C, 67.48; H,
7
(
f
(hexanes-ethyl acetate, 5:1). [R]26
1.2 (c ) 0.89, CHCl
). IR (neat):
f
D
3
2
3
-1
(hexanes-ethyl acetate, 5:1). [R]
D
2.6 (c ) 2.9, CHCl
3
1719, 1651, 1599, 1578, 1512, 941, 885, 845, 799, 779, 733, 712 cm .
1
1
3
3
H NMR (CDCl ): δ -0.55 (s, 9H), 1.03 (d, 3H, J ) 6.5 Hz), 1.26 (d,
δ -0.22 (s, 9H), 1.05 (d, 3H, J ) 6.2 Hz), 1.18 (d, 3H, J ) 6.8 Hz),
.26-2.42 (m, 1H), 3.32 (s, 3H), 3.83 (s, 3H), 4.33 (d, 1H, J ) 11.1
Hz), 4.88 (s, 1H), 6.85-6.94 (m, 3H), 7.08-7.15 (m, 2H), 7.26-7.34
3H, J ) 6.8 Hz), 2.25-2.41 (m, 1H), 3.37 (s, 3H), 4.47 (d, 1H, J )
10.8 Hz), 5.88 (s, 1H), 6.93-7.01 (m, 2H), 7.13-7.21 (m, 1H), 7.35-
2
7.51 (m, 4H), 7.58-7.66 (m, 1H), 7.71-7.78 (m, 1H), 7.84-8.00 (m,
1
3
13
(m, 4H). C NMR (CDCl
3
): δ -1.03 (q), 19.66 (q), 20.16 (q), 29.57
3H). C NMR (CDCl
3
): δ 0.80 (q), 19.83 (q), 20.05 (q), 29.58 (d),
(
1
1
d), 50.19 (q), 55.25 (q), 75.16 (d), 79.57 (d), 110.49 (s), 113.85 (d),
14.23 (d), 121.35 (d), 127.57 (d), 128.18 (d), 129.44 (d), 130.73 (d),
33.40 (s), 139.74 (s), 159.70 (s), 175.56 (s). Anal. Calcd for C24H -
33
50.29 (q), 75.57 (d), 75.75 (d), 100.97 (s), 123.21 (d), 125.44 (d), 125.60
(d), 126.01 (d), 127.60 (d), 127.75 (d), 128.31 (d), 128.51 (d), 130.62
(d), 131.11 (s), 133.03 (s), 133.57 (s), 133.95 (s), 175.31 (s). Anal.
NO
(
4
Si: C, 67.41; H, 7.78; N, 3.28. Found: C, 67.58; H, 7.90; N, 3.01.
2R,3R,4S)-1-Benzoyl-4-isopropyl-3-methoxy-2-(2-methoxyphen-
0.38
). IR
neat): 1720, 1651, 1603, 1580, 1493, 932, 883, 843, 754, 719, 704
Calcd for C27
H, 7.47; N, 2.99.
(2R,3R,4S)-1-Benzoyl-4-isopropyl-3-methoxy-2-(2-naphthyl)-3-
(trimethylsiloxy)azetidine (2n). 88% ee. Colorless solid. R 0.5
). IR
): δ -0.36 (s,
9H), 1.08 (d, 3H, J ) 6.8 Hz), 1.25 (d, 3H, J ) 7.0 Hz), 2.35-2.52
(m, 1H), 4.42 (d, 1H, J ) 10.8 Hz), 5.09 (s, 1H), 6.98-7.06 (m, 2H),
7.20-7.29 (m, 3H), 7.47-7.58 (m, 3H), 7.67 (s, 1H), 7.77-7.84 (m,
3
H33NO Si: C, 72.44; H, 7.43; N, 3.13. Found: C, 72.54;
yl)-3-(trimethylsiloxy)azetidine (2i). 90% ee. Colorless paste. R
f
2
1
(hexanes-ethyl acetate, 5:1). [R]
D
-1.6 (c ) 1.26, CHCl
3
f
2
3
(
(hexanes-ethyl acetate, 5:1). [R]
D
1
-74.8 (c ) 3.6, CHCl
3
-
1
1
-1
cm . H NMR (CDCl
3
): δ -0.24 (s, 9H), 1.04 (d, 3H, J ) 6.8 Hz),
(KBr): 1647, 845, 733, 712 cm . H NMR (CDCl
3
1
3
8
.18 (d, 3H, J ) 7.0 Hz), 2.48-2.63 (m, 1H), 3.33 (s, 3H), 3.58 (s,
H), 4.32 (d, 1H, J ) 11.1 Hz), 5.47 (s, 1H), 6.82 (dd, 1H, J ) 0.8,
.4 Hz), 7.05-7.13 (m, 3H), 7.23-7.36 (m, 4H), 7.65 (dd, 1H, J )
J. AM. CHEM. SOC.
9
VOL. 125, NO. 38, 2003 11595

A R T I C L E S
Kise et al.
1
2
H), 7.85-7.93 (m, 2H). 13C NMR (CDCl
0.16 (q), 29.57 (d), 50.29 (q), 75.20 (d), 79.76 (d), 100.60 (s), 126.13
3
): δ 0.97 (q), 19.78 (q),
monochromated Mo KR radiation. The structure was solved by direct
methods with SIR92 and expanded using Fourier techniques with
DIRDIF99. The non-hydrogen atoms were refined anisotropically.
Hydrogen atoms were refined isotropically. The final cycle of full-
matrix least-squares refinement on F 2 was based on 5876 observed
reflections and 317 variable parameters and converged with unweighted
(
(
(
d), 126.18 (d), 126.23 (d), 127.53 (d), 127.83 (d), 128.16 (d), 128.21
d), 129.91 (d), 130.71 (d), 133.02 (s), 133.08 (s), 133.36 (s), 135.58
s), 175.81 (s). Anal. Calcd for C27H33NO Si: C, 72.44; H, 7.43; N,
3
3
.13. Found: C, 72.52; H, 7.43; N, 3.04.
2R,3R,4S)-1-Benzoyl-4-isopropyl-3-tert-butoxy-2-(2-naphthyl)-
-(trimethylsiloxy)azetidine (2o). >99% ee. Colorless paste. R 0.57
). IR
neat): 1651, 1601, 1580, 1508, 1468, 934, 895, 845, 797, 754, 708
(
and weighted agreement factors of R
1
) 0.059 and wR ) 0.195. All
2
3
f
calculations were performed using the CrystalStructure crystallographic
software package.
2
3
(hexanes-ethyl acetate, 5:1). [R]
D
-75.3 (c ) 1.0, CHCl
3
(
Crystal Data of 2c. C26
H
37
O
3
NSi, FW ) 439.67, monoclinic, P2
1
-
1 1
cm . H NMR (CDCl
3
): δ -0.33 (s, 9H), 1.09 (d, 3H, J ) 6.2 Hz),
.26 (d, 3H, J ) 6.5 Hz), 1.43 (s, 9H), 2.46-2.66 (m, 1H), 4.90 (d,
H, J ) 10.3 Hz), 6.98-7.05 (m, 2H), 7.20-7.27 (m, 3H), 7.44-7.60
(
1
D
No. 4), colorless block, a ) 10.3906 Å, b ) 9.6213(1) Å, c )
1
1
(
3
3.4593(5) Å, â ) 95.347(2)°, V ) 1339.69(3) Å , T ) 298 K, Z ) 2,
3
-1
calcd ) 1.090 g/cm , µ ) 1.12 cm , GOF ) 1.002.
1
3
m, 4H), 7.74-7.81 (m, 1H), 7.84-7.90 (m, 2H). C NMR (CDCl
3
):
δ 1.39 (q), 20.15 (q), 20.18 (q), 30.31 (d), 30.55 (q), 76.47 (s), 76.78
Supporting Information Available: A crystallographic CIF
file for 2c. A drawing of the electrolysis cell, H and C spectra
of 2c, and the results of calculations for the transition states
PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
1
13
(
(
(
d), 82.94 (d), 99.75 (s), 125.81 (d), 125.91 (d), 126.44 (d), 127.56
d), 127.70 (d), 127.75 (d), 128.00 (d), 130.55 (d), 132.84 (s), 132.89
s), 133.80 (s), 136.07 (s), 175.86 (s). Anal. Calcd for C30H39NO Si:
3
(
C, 73.58; H, 8.03; N, 2.86. Found: C, 73.64; H, 8.04; N, 2.79.
X-ray Crystallographic Analysis of 2c. All measurements were
made on a Rigaku RAXIS imaging plate area detector with graphite
JA036975B
11596 J. AM. CHEM. SOC.
9
VOL. 125, NO. 38, 2003