Regioselective double nucleophilic addition reaction leading to the synthesis of β-lactams

Article abstract of DOI:10.3987/COM-08-S(N)43

β-Lactams were prepared in a regio-and stereoselective manner using the double nucleophilic addition of ketene silyl acetals and ketene silyl thioacetals to α,β-unsaturated imines followed by base-promoted cyclization. An attempted approach to 2-aryl carb

Full text of DOI:10.3987/COM-08-S(N)43

HETEROCYCLES, Vol. 76, No. 1, 2008
203
HETEROCYCLES, Vol. 76, No. 1, 2008, pp. 203 - 208. © The Japan Institute of Heterocyclic Chemistry
Received, 18th March, 2008, Accepted, 24th April, 2008, Published online, 28th April, 2008. COM-08-S(N)43
REGIOSELECTIVE DOUBLE NUCLEOPHILIC ADDITION REACTION
LEADING TO THE SYNTHESIS OF β-LACTAMS
Atsushi Takahashi, Shiho Kawai, Iwao Hachiya, and Makoto Shimizu*
Department of Chemistry for Materials, Graduate School of Engineering
Mie University, Tsu, Mie 514-8507, Japan. E-mail: mshimizu@chem.mie-u.ac.jp
Abstract – β-Lactams were prepared in a regio- and stereoselective manner using
the double nucleophilic addition of ketene silyl acetals and ketene silyl
thioacetals to α,β-unsaturated imines followed by base-promoted cyclization. An
attempted approach to 2-aryl carbapenem is also described.
We have already found that in the presence of an appropriate Lewis acid, a mixture of two different
nucleophiles reacts with α,β-unsaturated aldimines to give double addition products in a regioselective
manner in good yields, i. e., ketene silyl acetals and their thio analogues undergo 1,4- and 1,2-additions,
respectively.1 This approach avoids unnecessary isolation processes of relatively unstable imino
intermediates2 to give amino esters in good yields.
R2
H
Met
Nu1 N
R2
H
R2
H
Nu1 N
Nu1 NHR2
Nu2
N
1) Lewis Acid, -Nu2
2) H+
Lewis Acid, -Nu1
R1
R1
R1
R1
Met
(H)
Scheme 1
When dialkoxy ketene silyl acetal (2), an acyl anion equivalent, is used as the first nucleophile, this
methodology offers a facile synthetic route to a γ-amino carbonyl synthon (3), which in turn is
transformed into 2,3,5-trisubstituted pyrrole (4).3 Further examination into the use of the adducts arising
from the addition of ketene silyl acetals as the first nucleophiles and ketene silyl thioacetals as the second
ones led to a facile synthesis of β-lactams in a regioselective manner. This paper reports these reactions in
detail.
-----------------------------------
This paper is dedicated to Professor Dr. Ryoji Noyori on the occasion of his 70th birthday.

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HETEROCYCLES, Vol. 76, No. 1, 2008
P
EtO OEt
AlCl3
H2O
NP
EtO
EtO
OTMS
OEt
P
N
R2
EtO2C
EtO2C
HN
TMS-R2
1. H2SO4
2. DDQ
R1
H
R1
R2
R1
2
1
4
3
CO2Et
R1
R1
PMP
CO2Et
R1
1. AlCl3, MS 4A (H2O)
PMP
O
PMP
H
iPrMgCl
N
HN
N
R1
O
R1
R1
OTMS
OTMS
StBu
StBu
R
R
R
2.
R2
R2
R2
OEt
,
PMP = p-MeOC6H4
Scheme 2
The initial examination was carried out to find optimum double nucleophilc addition conditions using the
addition of the diethoxy ketene silyl acetal (2) and ketene silyl thioacetal (5) to α,β-unsaturated aldimine
(1). Table 1 summarizes the results.
Table 1. Double Nucleophilic Addition to the α,β-Unsaturated Aldimine (1) under Various Conditionsa
1. AlCl3 (1.0 eq), MS 4A (H2O, 1 eq)
CH2Cl2, 0 ˚C, 15 min
CO2Et
CO2Et
PMP
O
PMP
H
PMP
O
EtO
EtO
Ph
EtO
EtO
Ph
N
HN
HN
OTMS
OTMS
StBu
EtO
EtO
StBu
Ph
2.
OEt
EtO OEt
,
OEt
6
2
5
1
7
CH2Cl2, -78 ˚C to rt
Entry
2 (equiv)
1.0
5 (equiv)
1.5
Time (h)
6/%b
59
syn : anti of 6c
83 : 17
95 : 5
7/%b
10
5
1
2
3
4
5
6
7
8
14.0
11.5
14.0
12.0
11.5
14.0
9.5
1.0
2.0
58
1.1
1.5
65
92 : 8
10
5
1.1
2.0
76
89 : 11
90 : 10
93 : 7
1.3
1.7
80
7
1.3
2.0
63
23
16
4
1.5
1.5
58
81 : 19
92 : 8
1.5
2.0
o
11.5
70
aReaction was carried out at -78 C to rt according to the typical procedure (Ref. 4). bIsolated yield.
cDetermined by 1H NMR and/or HPLC.
In all the cases examined, the reaction proceeded in a regioselective manner to give the adduct (6) as a
major product in good yields with syn-selectivity. The best yield of the double addition product was

HETEROCYCLES, Vol. 76, No. 1, 2008
205
obtained when 2 (1.3 equiv) and 5 (1.7 equiv) were used, where the by-product (7) was formed in 7%
yield (Entry 5). Under these conditions several ketene silyl thioacetels were subjected to the addition
reaction to the imine (1), and Table 2 summarizes the results.
Table 2. Double Nucleophilic Addition to the α,β-Unsaturates Aldimine (1)a
1. AlCl3 (1.0 eq), MS 4A (H2O, 1 eq)
CH2Cl2, 0 ˚C, 15 min
CO2Et
PMP
O
PMP
H
N
HN
OTMS
OTMS
SR2
StBu
Ph
Ph
2.
R1
,
OEt
R1
10
8
1
9
CH2Cl2, -78 ˚C to rt
Entry
R1
H
R2
tBu
tBu
Et
Time (h)
12.0
10/%b
79
Diastereomer Ratioc
>99 (syn) : 1 (anti)
92 : 0 : 0
1
2
3
4
Et
12.5
42
8
:
:
:
Et
11.5
81
82 : 13
52 : 42
5 : 0
6 : 0
OTBS
tBu
11.0
59
aReaction was carried out according to the typical procedure (Ref. 4). bIsolated yield. cDetermined by
1H NMR and/or HPLC.
When disubstituted ketene silyl tert-butylthioacetal was used, the reaction gave the adduct (10) in a
regioselective manner in good yield with high syn-selectivity (Entry 1), whereas trisubstitued analogues
gave moderate yields of the adducts (Entries 2 and 4). Although diastereoselectivity was somewhat lost,
the yield was improved using the ethylthio derivative (Entry 3).
We next examined cyclization of the adducts into β-lactams under various conditions. Among the bases
i
t
i
examined (tBuMgCl, PrMgCl, LiHMDS, and NaHMDS), the use of BuMgCl, PrMgCl, and LiHMDS
gave satisfactory results.5
CO2Et
HN
CO2Et
PMP
PMP
O
CO2Et
HN
PMP
PMP
O
CO2Et
iPrMgCl (3.0 eq)
tBuMgCl (2.0 eq)
N
O
N
O
Ph
StBu
Et2O, 0 ˚C to rt
2.5 h
Et2O, 0 ˚C to rt
14.0 h
Ph
StBu
Ph
Ph
Et
Et
10a
11 72%
12 79%
10b
CO2Et
PMP
O
1. AlCl3 (1.0 eq), MS 4A (H2O, 1 eq)
CH2Cl2, 0 ˚C, 15 min
CO2Et
EtO
PMP
PMP
H
iPrMgCl (3.0 eq)
EtO
TMSO
Ph
N
N
TMSO
HN
O
Et2O, 0 ˚C to rt
5 h
OTMS
OEt
EtO
Ph
Ph
OEt
TMSO OEt
OEt
2.
(2.5 eq)
TMSO
TMSO
1
13
14 88%
15 75%
CH2Cl2, -78 ˚C to rt, 12 h
Scheme 3

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HETEROCYCLES, Vol. 76, No. 1, 2008
In particular, a single diastereomer (12)6 was obtained starting from the adduct (10b) under these
cyclization conditions. Use of the ketene silyl acetal (13) as the first and the second nucleophiles led to
the formation of the β-lactam (15) possessing protected ketones as a mixture of several diastereomers.
This class of β-lactam may be used for the synthesis of 2-aryl carbapenem derivatives of which we are
actively exploring an efficient synthesis.7 For this purpose, the transformation of the adduct (6) (see,
Table 1) into β-lactam was also attempted.
O
CO2Et
EtO
EtO
PMP
O
EtO
EtO
PMP
O
HN
LiHMDS (3.0 eq)
N
StBu
Ph
StBu
Et2O, 0 ˚C to rt 12 h
Ph
6
16 11%
1. PhI(OAc)2
CO2Et
HN
Boc
O
EtO
EtO
MeOH : AcOH (8 : 1), rt, 0.5 h
1. Na2CO3, rt, 0.5 h
MeSO3H
6
2. HCl, rt, 0.5 h
2. Boc2O, CH2Cl2
rt, 13.0 h
Ph
StBu
MeCN, 0 °C, 1.5 h
3. Na2S2O3, rt, 0.5 h
17 15%
EtO2C
Ph
EtO2C
EtO2C
Ph
O
O
NH
O
iPrMgCl (3.0 eq)
Et2O, 0 ˚C to rt, 5 h
N
N
Ph
StBu
OH
O
H H
18 63%
19
20
EtO2C
EtO2C
Ph
1. MeSO3H, MeCN
0 °C, 1.5 h
LiHMDS (4.0 eq)
Et2O, 0 ˚C to rt ,17 h
NH
Ph
O
N
17
StBu
2. DDQ, MeCN
rt, 2.0 h
22
21 11%
Scheme 4
Under several basic conditions, however, the adduct (6) did not give β-lactam, and instead, δ-lactam (16)
was always formed in low yield. We then turned our attention, first, to construct the dihydropyrrole ring.
The PMP protecting group was removed with PhI(OAc)2 followed by Boc protection to give 17 in 15%
overall yield. Cyclization was effected with MeSO3H to give the dihydropyrrolle (18) in 63% yield.3
However, an attempted cyclization into 2-phenyl carbapenem (19) only gave a trace amount of the
desired compound. In contrast to the dihydropyrrole (18), the pyrrole (21) prepared by the
cyclization–DDQ oxidation of 17 underwent cyclization into an unstable bicyclic β-lactam (22) in low

HETEROCYCLES, Vol. 76, No. 1, 2008
207
yield (<22%). We are currently investigating appropriate cyclization conditions for 18 and transformation
methods via 22 to synthesize 2-aryl carbapenems of biological interest.7
In conclusion, we have found that a double nucleophilic addition to α,β-unsaturated aldimines offers a
useful method for the synthesis of β-lactams using two different nucleophiles (ketene silyl acetals and
their thio analogues), where the regio- and diastereoselectivies are noteworthy.
REFERENCES AND NOTES
1. M. Shimizu, M. Kamiya, and I. Hachiya, Chem. Lett., 2005, 34, 1456, and earlier references cited
therein.
2. M. D. Stadnichuk, A. V. Khramchikhin, Y. L. Piterskaya, and I. V. Suvorova, Russ. J. Gen. Chem.,
1999, 69, 593.
3. M. Shimizu, A. Takahashi, and S. Kawai, Org. Lett., 2006, 8, 3585.
4. Typical experimental procedure for the double nucleophilic addition is as follows: Under an argon
atmosphere, a suspension of AlCl3 (26.7 mg, 0.20 mmol) and Molecular Sieves 4A containing H2O
o
(1 eq) in CH2Cl2 (2.0 mL) were stirred at 0 C for 15 min. To the resulting solution was added a
solution of N-p-methoxyphenylcinnamylidenamine (1) (47.6 mg, 0.20 mmol) in CH2Cl2 (2.0 mL) at
-78 oC, and the mixture was stirred for 10 min. A solution of 1-ethoxy-2-methyl-1-
trimethylsiloxypropene (8) (48.3 mg, 0.26 mmol) in CH2Cl2 (1.0 mL) was added to the mixture.
After stirring for 5 min, a solution of 1-tert-butylthiotrimetylsiloxyetene (9a) (61.7 mg, 0.30 mmol)
in CH2Cl2 (1.0 mL) was added to the resulting mixture. The mixture was gradually warmed to rt
during 12.0 h. Saturated aqueous NaHCO3 (5 mL) was added to quench the reaction. The mixture
was extracted with EtOAc (10 mL x 3). The combined extracts were dried over Na2SO4 and
concentrated in vacuo to give a crude product. Purification on silica gel TLC (toluene : EtOAc = 40 :
1 as an eluent, developed three times) gave the adduct (10a) (76.9 mg, 79 %). Rf = 0.21
1
(n-hexane/AcOEt = 7 : 1); light pink oil; H NMR (500 MHz, CDCl3) δ: 1.01 (s, 3H), 1.15 (s, 3H),
1.21-1.27 (m, 3H), 1.41 (s, 9H), 1.55-1.60 (m, 1H), 2.17-2.23 (m, 1H), 2.37 (dd, J = 7.3, 14.4 Hz,
1H), 2.59 (dd, J = 4.3, 14.4 Hz, 1H), 3.06-3.39 (m, 3H including a double doublet at 3.38 ppm, J =
2.2, 12.2 Hz, 1H), 3.70 (s, 3H), 4.08-4.19 (m, 2H), 6.32-6.35 (m, 2H), 6.66-6.68 (m, 2H), 7.10-7.12
(m, 2H), 7.21-7.28 (m, 3H).
Cyclization into β-lactam (12): To a solution of the adduct (10a) (66.5 mg, 0.137 mmol) in Et2O (4.0
mL) was added a THF solution of tert-butylmagnesium chloride (0.54 M, 0.51 mL, 0.275 mmol) at 0
oC, and with stirring the whole mixture was gradually warmed to rt during 14.0 h. Saturated aqueous
NaCl (5 mL) was added to quench the reaction. The mixture was extracted with EtOAc (10 mL x 3).
The combined extracts were dried over Na2SO4 and concentrated in vacuo to give a crude product.

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HETEROCYCLES, Vol. 76, No. 1, 2008
Purification on silica gel TLC (n-hexane : EtOAc = 7 : 1 as an eluent, developed twice) gave
β-lactam (11) (39.1 mg, 72 %) as a single isomer. Rf = 0.21 (n-hexane/AcOEt = 7 : 1); colorless oil;
1H NMR (500 MHz, CDCl3) δ: 1.00 (s, 3H), 1.16 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H), 2.02-2.09 (m, 1H),
2.24 (dd, J = 1.8, 15.3 Hz, 1H), 2.29-2.32 (m, 1H), 2.68 (dd, J = 5.2, 15.3 Hz, 1H), 3.12 (dd, J = 2.5,
11.0 Hz, 1H), 3.79 (s, 3H), 3.86-3.93 (m, 1H), 4.07-4.16 (m, 2H), 6.83-6.86 (m, 2H), 7.16-7.29 (m,
7H).
5. (a) E. J. Corey, C. P. Decicco, and R. C. Newbold, Tetrahedron Lett., 1991, 32, 5287. (b) M.
Shimizu, M. Tachi, and I. Hachiya, Chem. Lett., 2004, 33, 1394. (c) M. Shimizu, M. Tachi, S.
Fukushima, and I. Hachiya, Heterocycles, 2005, 66, 75. (d) M. Shimizu, Y. Hayashi, R. Hamanaka,
and I. Hachiya, Heterocycles, 2007, 73, 191.
6. The relative stereochemistry of the β-lactam (12) was determined by transforming into the bicyclic
1
lactam (23), and examination of the coupling constants in the H-NMR spectrum established the
relative stereochemistry.
CO2Et
PMP
N
O
CO2Et
H
N
O
O
CAN
iPrMgCl
Et2O
O
N
Ph
H2O/CH3CN
Ph
Et
Ph
Et
12
Et
23
7. D. H. Shi, F. Baker, L. Cama, and B. G. Christensen, Heterocycles, 1984, 21, 29; N. Yasuda, L.
Xavier, D. L. Rieger, Y. Li, A. E. DeCamp, and U.-H. Dolling, Tetrahedron Lett., 1993, 34, 3211; R.
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