Highly trans-selective synthesis of β-lactams by tandem phenoxide anion-catalyzed Mannich-type addition and cyclization

Article abstract of DOI:10.1246/cl.2005.994

Highly trans-selective synthesis of β-lactams by tandem Lewis base-catalyzed Mannich-type addition and cyclization was established; that is, reaction of benzylideneanilines and trimethylsilyl enolates derived from S-ethyl thioates proceeded smoothly to af

Full text of DOI:10.1246/cl.2005.994

994
Chemistry Letters Vol.34, No.7 (2005)
Highly trans-Selective Synthesis of ꢀ-Lactams by Tandem Phenoxide
Anion-catalyzed Mannich-type Addition and Cyclization
Eiki Takahashi, Hidehiko Fujisawa, Toshiharu Yanai, and Teruaki MukaiyamaÃ
Center for Basic Research, The Kitasato Institute (TCI), 6-15-5 Toshima, Kita-ku, Tokyo 114-0003
(Received February 24, 2005; CL-050240)
Highly trans-selective synthesis of ꢀ-lactams by tandem
Table 1. Screening of Lewis base catalyst
Lewis base-catalyzed Mannich-type addition and cyclization
was established; that is, reaction of benzylideneanilines and
trimethylsilyl enolates derived from S-ethyl thioates proceeded
smoothly to afford the corresponding ꢀ-lactams in good to high
yields with high trans-selectivity by using Lewis base catalyst
such as lithium phenoxide or tetrabutyl ammonium phenoxide
in DMF at À45 ꢀC or THF at À78 ꢀC, respectively.
Entry
Cat.
Temp/ꢀC Time/h Yielda/% trans:cis
1
2
3
4
5
6
—
AcOLi
PhCO2NBu4
PhOLi
PhOLi
rt
12
24
24
8
n.d.b
trace
tracec
96
—
—
—
88:12
98:2
99:1
À45
À45
rt
ꢀ-Lactams are important compounds for their biological
activities and there are various methods developed for their
syntheses. Of those methods, one-pot synthesis of ꢀ-lactams be-
tween aldimine and silyl enolate attracted much attention be-
cause of their utilities and several useful methods have thus been
reported:1 i.e. Ojima et al. reported one-pot synthsis of ꢀ-lactams
between silyl ketene acetals with aldimines by using a stoichio-
metric amounts of a Lewis acid such as TiCl4.1a,1b Annunziata
et al. reported the first catalytic one-pot synthsis of ꢀ-lactam
from aldimines and silyl ketene thioacetals derived from 2-
pyridyl thioesters by using a Lewis acid such as Yb(OTf)3.1c
Recently, Matsukawa et al. introduced an useful reaction by us-
ing highly nucleophilic tris(2,4,6-trimethoxyphenyl)phosphine
as a catalyst.1d
In the course of our investigation on the activation of
trimethylsilyl (TMS) enolates by a Lewis base catalyst,2–4 one-
pot syntheses of ꢀ-lactams by tandem Lewis base-catalyzed
Mannich-type addition and cyclization were recently found.5
Since the diastereoselection of this reaction was moderete, a
highly diastereoselective synthesis of ꢀ-lactam was studied in
order to increase its utility. In this communication, we would
like to describe highly trans-selective one-pot syntheses of ꢀ-
lactams by tandem Lewis base-catalyzed Mannich-type addition
and cyclization.
À45
À60
1
12
12
32
12
PhOLi
aYield was determined by H NMR analysis (270 MHz) using
1,1,2,2-tetrachloroethane as an internal standard. bn.d.; not
detected. Solvent; THF.
c
product, at room temperature. Further, the use of silyl ketene
thioacetal 3 derived from S-tert-butyl thiopropionate gave the
ꢀ-lactam 2 dominantly in good yield with moderate trans-selec-
tivity.
Taking these results into consideration, trans-selective tan-
dem Lewis base-catalyzed Mannich-type addition and cycliza-
tion was then attempted by using silyl ketene thioacetal 3
(Table 1). It was considered that the selectivity of the reaction
could be controlled if the reaction was carried out at lower
temperature. In the first place, therefore, reaction of 1 with 3
was tried at À45 ꢀC by using 10 mol % of AcOLi in DMF or
PhCO2NBu4 in THF, but only a trace amount of ꢀ-lactam was
formed (Entries 2 and 3). Then, Lewis base catalysts were
screened and the corresponding ꢀ-lactam was found to afford
in 32% yield. However, the ratio of trans:cis was successfully in-
creased up to 98:2 when 10 mol % of PhOLi was used at À45 ꢀC.
In our previous communication, it was shown that reaction
between benzylideneaniline 1 and TMS enolate derived from
methyl propionate afforded the corresponding ꢀ-lactam 2 in
moderate trans-selectivity together with ꢀ-amino ester, a co-
Table 2. Screening of silyl ketene thioacetal
Entry Silyl enolate
R
Time/h Yielda/% trans:cis
1
2
3
4
5
SPh
S-c-hex 5
4
12
12
12
6
3
trace
19
85
91
99:1
—
99:1
98:2
95:5
S-i-Pr
S-n-Bu
SEt
6
7
8
6
6
9
6
98
97:3
aYield was determined by H NMR analysis (270 MHz) using
1,1,2,2-tetrachloroethane as an internal standard.
1
Scheme 1.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.7 (2005)
995
Table 3. Tandem PhONBu4-catalyzed Mannich-type addition
and cyclization of imine 1 and silyl keten thioacetal 9
Table 4. Tandem PhONBu4-catalyzed Mannich-type addition
and cyclization of various imines and silyl keten thioacetal 9
Entry
Ar1
Ar2
Yielda/% trans:cis
Entry Temp/ꢀC Solv. Time/h Yielda/% trans:cis
1
2
3
4
5
6
7
8
9
4-ClC6H4
4-BrC6H4
4-CF3C6H4
4-MeOC6H4
2-Naphthyl
4-Me2NC6H4
3-Pyridyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
quant.b
97b
91
>99:1
>99:1
>99:1
99:1
1
2
3
4
À45
À45
À78
À78
DMF
THF
THF
THF
6
12
6
96
quant.
87
97:3
97:3
99:1
99:1
77c
12
95
74
98:2
98:2
>99:1
97:3
98:2
aYield was determined by 1H NMR analysis (270 MHz) using
1,1,2,2-tetrachloroethane as an internal standard.
51c,d
94b
92b
81c
4-ClC6H4
4-MeOC6H4
In order to improve the efficiency of this reaction, silyl
ketene thioacetals were screened by using PhOLi at À45 ꢀC in
DMF (Table 2). It was found that the yields depended on the
nature of silyl ketene thioacetals employed. When the reaction
was tried by using silyl ketene thioacetals such as 4 or 5, only
a trace amount of ꢀ-lactam 2 was formed. On the other hand,
the yield increased when silyl enolate 7 or 8 was used. Further,
both high yield and trans-selectivity were attained when silyl
ketene thioacetal 9 was used. This concluded that silyl ketene
thioacetal 9 was an appropriate donor of this reaction.
The optimization of the reaction conditions was further tried
by taking tandem phenoxide anion-catalyzed Mannich-type
addition of imine 1 with silyl ketene thioacetal 9 and cyclization
of the resulted adduct, as a model (Table 3). Then, high yield and
excellent trans-selectively (trans:cis = 99:1) were eventually
attained when the reaction was carried out by using 10 mol %
of tetrabutylammonium phenoxide (PhONBu4) in THF at
À78 ꢀC (Entry 4).
Ph
aYield was determined by 1H NMR analysis (270 MHz) using
1,1,2,2-tetrachloroethane as an internal standard. bIsolated
yield. c20 mol % of catalyst and 2 equiv. of silyl enolate were
used at À45 ꢀC. DMF was used instead of THF.
d
cable to the syntheses of various ꢀ-lactams in one-pot process.
Further development of this reaction is now in progress.
This study was supported in part by the Grant of the 21st
Century COE Program from Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
References
1
a) I. Ojima, S. Inaba, and K. Yoshida, Tetrahedron Lett.,
1977, 3643. b) I. Ojima, S. Inaba, and M. Nagai, Synthesis,
1981, 545. c) R. Annunziata, M. Cinquini, F. Cozzi, V.
Molteni, and O. Schupp, J. Org. Chem., 61, 8293 (1996).
d) S. Matsukawa and K. Obu, Chem. Lett., 33, 1626 (2004).
Aldol reaction: a) T. Mukaiyama, H. Fujisawa, and T.
Nakagawa, Helv. Chim. Acta, 85, 4518 (2002). b) T.
Nakagawa, H. Fujisawa, Y. Nagata, and T. Mukaiyama,
Bull. Chem. Soc. Jpn., 77, 1555 (2004). c) H. Fujisawa, T.
Nakagawa, and T. Mukaiyama, Adv. Synth. Catal., 346,
1241 (2004).
Mannich-type reaction: a) H. Fujisawa, E. Takahashi, T.
Nakagawa, and T. Mukaiyama, Chem. Lett., 32, 1036
(2003). b) E. Takahashi, H. Fujisawa, and T. Mukaiyama,
Chem. Lett., 33, 936 (2004). c) E. Takahashi, H. Fujisawa,
and T. Mukaiyama, Chem. Lett., 33, 1426 (2004). d) E.
Takahashi, H. Fujisawa, and T. Mukaiyama, Chem. Lett.,
34, 84 (2005).
The scope of acceptor aldimines in tandem PhONBu4-cata-
lyzed Mannich-type addition and cyclization was investigated
by using silyl ketene thioacetal 9 (Table 4). Then it was found
that the aromatic aldimines smoothly reacted with 9 and afforded
the corresponding ꢀ-lactams in high yields with excellent trans-
selectivities. The reaction also proceeded smoothly even in the
case of using aldimines having a basic function (Entries 6 and 7).
This reaction was further tried by using silyl ketene thioace-
tal 10 (Eq 1). The reaction also proceeded smoothly to afford the
corresponding ꢀ-lactam in good yield with excellent trans-selec-
tivity.
2
3
4
5
Strecker-type reaction: a) E. Takahashi, H. Fujisawa, T.
Yanai, and T. Mukaiyama, Chem. Lett., 34, 318 (2005).
b) E. Takahashi, H. Fujisawa, T. Yanai, and T. Mukaiyama,
Chem. Lett., 34, (2005), in press.
E. Takahashi, H. Fujisawa, T. Yanai, and T. Mukaiyama,
Chem. Lett., 34, 216 (2005).
Thus, highly trans-selective tandem Lewis base-catalyzed
Mannich-type addition and cyclization of forming ꢀ-lactam
was developed by the combined use of silyl ketene thioacetals
derived from S-ethyl thioates and Lewis base catalyst such as
PhOLi or PhONBu4. This method is quite practical and is appli-
Published on the web (Advance View) June 11, 2005; DOI 10.1246/cl.2005.994