Electroreductive intramolecular coupling of aromatic imino esters: Is four-membered cyclization much more favorable than six-membered cyclization?

Article abstract of DOI:10.1021/ol053144x

The electroreduction of an aromatic imino ester prepared from (S)-glutamic acid in the presence of chlorotrimethylsilane and triethylamine afforded a four-membered cyclized product, a mixed ketal of cis-2,4-disubstituted azetidine-3-one, stereospecificall

Full text of DOI:10.1021/ol053144x

ORGANIC
LETTERS
2
006
Vol. 8, No. 7
323-1325
Electroreductive Intramolecular Coupling
of Aromatic Imino Esters: Is
Four-Membered Cyclization Much More
Favorable than Six-Membered
Cyclization?
1
Naoki Kise,* Yuuki Hirano, and Yoshi Tanaka
Department of Biotechnology, Faculty of Engineering, Tottori UniVersity, Koyama,
Tottori 680-8552, Japan
kise@bio.tottori-u.ac.jp
Received December 28, 2005
ABSTRACT
The electroreduction of an aromatic imino ester prepared from (S)-glutamic acid in the presence of chlorotrimethylsilane and triethylamine
afforded a four-membered cyclized product, a mixed ketal of cis-2,4-disubstituted azetidine-3-one, stereospecifically. Calculations for the transition
states by the DFT method support the predominant formation of the azetidine. The electroreduction of an aromatic imino ester prepared from
(S)-aspartic acid gave almost equal amounts of a diastereomerically pure mixed ketal of cis-2,4-disubstituted azetidine-3-one and a diastereomeric
mixture of 2,5-disubstituted pyrollidine-3-one.
Reductive intramolecular coupling of imino esters is a
promising method for the construction of cyclic amines. We
have recently reported that the reductive intramolecular
coupling of aromatic R-, â-, and γ-imino esters was realized
by electroreduction in the presence of chlorotrimethylsilane
reductive coupling of imino ester 1 prepared from (S)-
glutamic acid dimethyl ester and benzaldehyde (Scheme 2).
Contrary to our expectations, a mixed ketal of cis-2,4-
1
2
2
(CTMS) to give azetidines, pyrrolidines, and piperidines,
Scheme 2
respectively (Scheme 1). In this context, we attempted the
Scheme 1
disubstituted azetidine-3-one 2 was obtained stereospecifi-
cally as the only cyclized product; no piperidine was
(
1) Kise, N.; Ozaki, H.; Moriyama, N.; Kitagishi, Y.; Ueda, N. J. Am.
Chem. Soc. 2003, 125, 11591-11596.
2) Kise, N.; Ohya, K.; Arimoto, K.; Yamashita, Y.; Hirano, Y.; Ono,
T.; Ueda, N. J. Org. Chem. 2004, 69, 7710-7719.
(
1
0.1021/ol053144x CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/28/2006

produced. This result shows that four-membered cyclization
is much more favorable than six-membered cyclization in
the reductive intramolecular coupling of 1. To the best of
our knowledge, this is the first example where four-
membered cyclization completely predominates over six-
membered cyclization, although a number of four-membered
cyclizations have been reported.3 We describe herein the
results of experimental and theoretical studies on the elec-
troreductive cyclization of 1. The transition states of the
cyclization were calculated to elucidate the selective forma-
tion of 2. Furthermore, we examined the electroreductive
intramolecular coupling of imino ester 3 derived from (S)-
aspartic acid dimethyl ester and obtained a diastereomerically
pure mixed ketal of cis-2,4-disubstituted azetidine-3-one 4
and a mixture of cis- and trans-2,5-disubstituted pyrollidine-
,4
3-one 5 (Scheme 3).
Scheme 3
Figure 1. X-ray crystal structures of dl-2, dl-4, trans-5, and cis-5.
acid had a pastelike composition.
According to our previous reports,1,2 the reaction mech-
anism of the reductive intramolecular coupling of 1 can be
presumed as depicted in Scheme 4. Two-electron transfer
and N-silylation to 1 afford anion A. The four- and
six-membered cyclized products B and C are formed by the
intramolecular attack of the carbanion in A to the R- and
ω-methoxycarbonyl groups, respectively. The experimental
result shows that the four-membered cyclization of A is much
faster than the corresponding six-membered cyclization.
Therefore, we calculated the transition states for the cycliza-
tion of A by the DFT method at the B3LYP/6-31+G**
The electroreduction of 1 and subsequent benzoylation of
the resulting mixture were carried out according to our
reported method (Scheme 2).1 An N-benzoyl mixed ketal
,5
of cis-2,4-disubstituted azetidine-3-one 2 was isolated in 56%
1
yield and 92% ee (by H NMR with Eu(hfc)
3
) as a single
stereoisomer together with N-R-trimethylsilylated amine 6
20% yield). Surprisingly, the corresponding six-membered
cyclized product, N-benzoyl piperidine 7, could not be
detected. Fortunately, racemic 2 derived from dl-glutamic
acid crystallized and the stereostructure of 2 could be
determined to be 2R,3R,4S by X-ray crystallography (Figure
(
6
level. Four diastereomeric transition states TSB and TSC
1), although optically active 2 obtained from (S)-glutamic
were obtained for each of the four- and six-membered
Scheme 4
1324
Org. Lett., Vol. 8, No. 7, 2006

Figure 2. Optimized structures (B3LYP/6-31+G**) and relative energies of transition states for the four- (TSB) and six-memberd cyclization
TSC) of the anion A.
(
cyclizations, respectively. The optimized structures and their
relative energies of the transition states are exhibited in
Figure 2. The results of calculations bring the following
findings: (1) the transition states for the four-membered
cyclization TSB are much lower in energy (∼10 kcal/mol)
than those for the six-membered cyclization TSC; (2) the
transition state (R,R,S)-TSB is the most favorable of the four
transition states giving four possible stereoisomers of four-
membered cyclized products. These computational outcomes
agree well with the stereospecific formation of 2R,3R,4S-2.
Next, the electroreduction of 3 and the following benzoy-
lation were carried out under the same conditions as above
(Scheme 3). Because the products could not be separated,
the mixture was treated with 1 M HCl for 30 min to give
three products: N-benzoyl-mixed ketal of cis-2,4-disubsti-
tuted azetidine-3-one 4 (36% yield, 34% ee), N-benzoyl
trans-2,5-disubstituted pyrrolidine-3-one, trans-5 (20% yield),
and its cis isomer cis-5 (17% yield). The stereostructures of
these products were confirmed by X-ray crystallographic
analysis (Figure 1). These results suggest that four-membered
cyclization is comparable to five-membered cyclization in
the reductive intramolecular coupling of 3.
7
(3) For recent reviews, see the following. (a) Formation of four-membered
heterocycles through electrophilic heteroatom cyclization: Robin, S.;
Rousseau, G. Eur. J. Org. Chem. 2002, 3099-3114. (b) Formation of four-
membered carbocycles: Hartley, R. C.; Caldwell, S. T. Perkin 1 2000, 477-
In conclusion, the electroreduction of aromatic imino ester
5
01.
1
derived from (S)-glutamic acid dimethyl ester in the
(4) For recent reports for the asymmetric synthesis of multisubstituted
azetidines, see: (a) Burtoloso, A. C. B.; Correia, C. R. D. J. Organomet.
Chem. 2005, 690, 5636. (b) De Talanc e´ , V. L.; Banide, E.; Bertin, B.;
Comesse, S.; Kadouri-Puchot, C. Tetrahedron Lett. 2005, 46, 8023. (c)
Br a¨ uner-Osborne, H.; Bunch, L.; Chopin, N.; Couty, F.; Evano, G.; Jensen,
A. A.; Kusk, M.; Nielsen, B.; Rabasso, N. Org. Biomol. Chem. 2005, 3,
presence of CTMS gave azetidine 2 stereospecifically. The
overwhelming preference of four-membered cyclization to
six-membered cyclization in the reductive intramolecular
coupling of 1 is well explained by the DFT calculations for
the transition states. On the other hand, the electroreduction
of imino ester 3 prepared from (S)-aspartic acid dimethyl
ester produced almost equal amounts of four- and five-
membered cyclized products, 4 and 5.
3
7
926. (d) Mendler, B.; Kazmaier, U.; Huch, V.; Veith, M. Org. Lett. 2005,
, 2643. (e) Couty, F.; Evano, G.; Vargas-Sanchez, M.; Bouzas, G. J. Org.
Chem. 2005, 70, 9028.
5) Similarly to our previous report, a complex mixture was formed in
the absence of CTMS.
6) The calculations were carried out using the Gaussian 03W program:
1
(
(
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; 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.; Gonzalez, C.; Pople, J. A. Gaussian
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research (C) (No. 16550097) from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan.
Supporting Information Available: A PDF file of
1
13
experimental procedures, H and C NMR spectra of 2, 4,
trans-5, and cis-5, and the results of calculations for the
transition states. Crystallographic CIF files for dl-2, dl-4,
trans-5, and cis-5. This material is available free of charge
via the Internet at http://pubs.acs.org.
0
3, revision B.02; Gaussian, Inc.: Pittsburgh, PA, 2003.
7) 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.
OL053144X
Org. Lett., Vol. 8, No. 7, 2006
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