β-Lactam synthesis by diastereoselective condensation of chiral 3-(p- tolylsulfinyl)-2-furaldimine and ester enolates

Article abstract of DOI:10.3987/COM-00-8913

Highly diastereoselective condensation of chiral sulfinyl-substituted furaldimine with lithium ester enolates has been achieved, affording (3R)- syn-β-lactams and/or (3R)-syn-β-amino esters, as the major products.

Full text of DOI:10.3987/COM-00-8913

HETEROCYCLES, Vol. 53, No. 7, 2000, pp. 1479 - 1483, Received, 6th April, 2000
β
-LACTAM SYNTHESIS BY DIASTEREOSELECTIVE CONDEN-
SATION OF CHIRAL 3-(p-TOLYLSULFINYL)-2-FURALDIMINE AND
ESTER ENOLATES
Yoshitsugu Arai,* Shinya Yoneda, Tsutomu Masuda, and Yukio Masaki
Gifu Pharmaceutical University, 5-6-1 Mitahora-Higashi, Gifu 502-8585, Japan
Abstract- Highly diastereoselective condensation of chiral sulfinyl-substituted
furaldimine with lithium ester enolates has been achieved, affording (3R)-syn-β-
lactams and/or (3R)-syn-β-amino esters, as the major products.
The Lewis acid-promoted1 and -catalyzed2 condensations of imines with silyl ketene acetals or ester
enolates are the powerful methods for preparing β-lactams and β-amino esters.3 To effect high levels of
asymmetric induction, chiral versions of the condensation have also been devised by the use of imines
with a chiral auxiliary,1,4 chiral ester enolate derivatives,5 and chiral Lewis acids.6 Most studies on these
enantioselective reactions, however, have dealt with 1,3-asymmetric inductions. On the other hand, little
work has been done on the remote asymmetric induction for the imine—enolate condensations. As part of
our own efforts to develop remote asymmetric induction using chiral sulfoxides, we previously reported
the lanthanoid triflate-catalyzed Mukaiyama aldol reaction of sulfinyl aldehyde (1) with such silyl ketene
acetals as 2.7 Remote stereocontrol of 1 in this reaction led us to examine the condensation of the
aldimine (3) derived from 1 in 74% yield.
O
S
O
S
At first we undertook the reaction of 3 with 2 in
the presence of a lanthanoid triflate, Yb(OTf)
•
•
•
•
Me
Me
OSiMe
p-Tol
3
p-Tol
3
H
H
O
since lanthanoid triflates are effective for the
aldol condensation of the aldehyde (1).7 The
reaction proceeded smoothly; however,
diastereoisomeric β-amino esters (4) and (5)
O
OEt
O
N
1
2
3
OMe
were produced in a ratio of 1:1 (Table 1, Entry 1).8
We thus next turned to the use of ester enolate (6) for the reaction. Table 1 indicates the metal effect of
the addition reaction of 6, which shows the lithium enolate (6) (M = Li) is superior to other metal
enolates for both the diastereoselectivities and the yields. The reaction was carried out by the use of Et O
2
or THF as solvent.9 Attempts to use zinc and titanium enolates10 (6) (M = ZnCl, TiCl ) were
3
unsuccessful, resulted in the recovery of starting material (3). In contrast to the reaction with 2, β-amino
esters (4) and (5) were not produced11; whereas, β-lactams (7) and (8) were obtained exclusively. It is
probable that the products distribution (β-lactam vs β-amino ester) depends on the reaction conditions
(amounts of enolate and/or the solvent used) and a kind of the enolates. In some case where the reaction

was carried out with less than 2 equiv of the Li enolate (Entries 4 and 5), the reaction gave not only β-
lactams but also β-amino esters. Instead, the use of more than 2 equiv of the enolate resulted in the
exclusive formation of β-lactams and in good yields.12 The stereochemical assignment of C(3) center in
major β-lactam (7) was confirmed by single crystal X-Ray analysis.13
a
Table 1. Condensation of 3 with Enolates (2) and (6)
Entry
Enolate
(M)
(Equiv) Solvent Time/h yield/%
Product Ratio
50:50 (4:5)
94:6 (7:8)
de/%
0
b
1
2
3
4
5
6
7
2
6
6
6
6
6
6
2
THF
15
1
98
70
93
67
85
84
99
c
MgBr
4
Et O
88
80
91
97
91
95
2
d
AlCl
Li
4
THF
THF
1
90:10 (7:8)
2
e
1.5
1.5
4
1
95.5:4.5 (7:8)
98.5:1.5 (7:8)
95.5:4.5 (7:8)
97.5:2.5 (7:8)
e
Li
Et O
1
2
Li
THF
1
Li
4
Et O
1
2
a
Reaction was carried out at −78 °C for 15 min and then the reaction mixture was allowed to room
b
temperature over a period of 45 min except for Entry 1. The reaction was conducted at room
c
temperature in the presence of 0.2 equiv of Yb(OTf) as a promotor. Prepared from the lithium
3
d
e
enolate and MgBr •Et O. Prepared from the lithium enolate and AlCl . With the use of less than
2
2
3
2 equiv of LDA, the amino esters (4) and (5) were also produced in 7—11% yields.
6: R = Et, R1 = R2 = Me, M = metal
9: R = t-Bu, R1= R2 = H, M = Li
12: R = Et, R1 = H, R2 = Me, M = Li
(E)-17: R = Me, R1= H, R2 = OTBDMS, M = Li
(Z)-17: R = Me, R1= OTBDMS, R2 = H, M = Li
R1
R2
OM
OR
PMP = p-methoxyphenyl
TBDMS = t-butyldimethylsilyl
O
O
S
O
S
O
S
S
p-Tol
R1
p-Tol
R1
R2
CO2R
R2
CO2R
p-Tol
p-Tol
S
R
R
S
O
O
O
O
NH
NH
N
N
PMP
PMP
PMP
O
O
PMP
4: R = Et, R1 = R2 = Me
10: R = t-Bu, R1= R2 = H
18: R = Me, R1 = H, R2 = OTBDMS
19: R = Me, R1 = OTBDMS, R2 = H
5: R = Et, R1= R2 = Me
11: R = t-Bu, R1= R2 = H
7
8
O
O
O
O
S
S
S
S
p-Tol
4
p-Tol
R2
p-Tol
p-Tol
R2
R2
3
R2
O
O
O
O
N
N
N
N
PMP
O
O
PMP
O
PMP
O
PMP
15: R2 = Me
22: R2 = OTBDMS
16: R2 = Me
23: R2 = OTBDMS
13: R2 = Me
20: R2 = OTBDMS
14: R2 = Me
21: R2 = OTBDMS

Some results of the condensation with other enolates are summarized in Table 2. When the reaction was
carried out with the lithium enolate (9) under the similar conditions, (3R)-β-amino ester (10) was
obtained exclusively, accompanied by a small amount of (3S)-isomer (11) (96% de, 98% yield).14 On the
other hand, the condensation of 3 with a trisubstituted lithium enolate (12) gave rise to syn-β-lactam (13)
and anti-β-lactam (15) as the major isomers, respectively.15 The major syn-β -lactam (13) was isolated in
isomerically pure form, and the stereochemistry was unequivocally established by single crystal X-Ray
analysis.13 Although the anti relationship of the major β-lactam (15) was assumed by the vicinal coupling
3— 5
1
constant between C(3) and C(4) protons (J
>J
)
anti
in the H NMR spectrum, the absolute
syn
stereochemistry was confirmed by transformation of 13 into 15 by isomerization experiments. With the
silyloxy enolate (17) {(E)-enolate enriched16}, (3R)-amino esters (18) and (19)14 were produced as the
major syn- and anti-products, accompanied by small amounts of (3R)-β-lactams (20) and (22). Amino
esters (18) and (19) obtained were cyclized respectively into 20 and 22 upon treatment with lithium
hexamethyldisilazide.3,5
a
Table 2. Condensation of 3 with Lithium Enolates
Entry Enolate
Product
syn : anti
—
de/% (syn/anti)
96
Yield/%
98
1
2
3
9
10 and 11
b
12
17
13—16
67:33
84:16
89/71
89
c
18 and 19
>98/>98
80
a
All the reaction was conducted in ca. 0.3 mmol scale with 4 equiv of the lithium enolate in
THF at −78 °C (15 min), and then the mixture was allowed to warm to room temperature (45
b
min). Small amounts of the corresponding amino esters were also produced in variable yields.
c
The ratio of the amino esters was not determined. The β-lactams (20) and (22) were also
produced in 8% and <1% yields, respectively; however, the formation of (21) and (23) was not
1
detected in the H NMR spectrum of the crude product.
Although the detailed reaction mechanism is not clear, it is likely that the facts obtained are consistent
with the stereochemical outcome which involves the conventional Zimmerman—Traxler chair transition
state model17 (Figure 1). With the lithium enolates, a chelating model A would be favored over a
transition state B. The six-membered chelate B should not be attained preferentially by a severe steric
repulsion of the alkoxy group with the bulky p-tolyl substituent.
O
S
O
S
O
(3R )-β-lactams
or
(3R )-β-amino esters
O
(3S )-β-lactams
or
(3S )-β-amino esters
OR
R2
OR
Li
Li
R2
N
O
PMP
N
O
R1
R1
PMP
A
B
Figure 1

In summary, chirally functionalized β-lactams were synthesized from the imine and the lithium enolate
with high diastereoselectivities and in excellent yields. In sharp contrast to 1,2- or 1,3-asymmetric
inductions in imine—ester enolate condensations reported previously, our results obtained revealed that
1,4-stereocontrol (= remote asymmetric induction) has been achieved by the use of the sulfinyl
furaldimine (3). Further studies are in progress on the condensation with other enolates.
ACKNOWLEDGMENT
We thank Dr. Motoo Shiro (Rigaku Corporation) for carrying out the X-Ray analysis. This work was
partially supported by the Ministry of Education, Science, Sports and Culture (No. 11672110), to which
we are grateful.
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8.
9.
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3
acetals with sulfinimines: R. Kawecki, J. Org. Chem., 1999, 64, 8724.
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(4).
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data; 7: C H NO S, M = 409.5, monoclinic, space group P2 /c(No 14), a = 11.072(4) Å, b =
23 23
4
1
3
−3
9.032(5) Å, c = 21.936(5) Å, β = 101.95(3)°, V = 2146(1) Å , D
= 1.267 g cm , Z = 4; Number
calc
of reflections observed (I>3σ(I)) = 1901, R = 0.056, R = 0.094; 13: C H NO S, M = 395.5,
w
22 21
4
triclinic, space group P1(No 2), a = 11.244(2) Å, b = 11.755(3) Å, c = 8.168(2) Å, α = 99.05(1)°, β
3
−3
= 109.73(1)°, γ = 91.52(2)°, V = 999.9(4) Å , D
= 1.313 g cm , Z = 2; Number of reflections
calc
observed (I>3σ(I)) = 3584, R = 0.045, R = 0.067.
w
All new compounds have been characterized by IR, NMR, and MS spectrometry. Selected physical
data: 3: mp 60—61 °C (hexane—EtOAc);
−444° (c 1.0, CHCl ); 7: mp 150—152 °C (Et O),
3 2
−30.9° (c 1.3, CHCl ); 10: An oil;
−69.4° (c 0.3, CHCl3); 13: mp 113—114 °C (Et O),
2
3
+20.8° (c 0.8, CHCl ).
3
14. Stereochemical assignments are by analogy with the results obtained with 2 and 6.
15. THF was used as solvent since when the reaction was carried out in Et O and/or in the presence of
2
HMPA, β-amino esters were also produced in variable yield. Judging from preliminary experiments
in the presence of HMPA, the ratio of syn- and anti-esters was reversed, affording the anti-β-amino
esters preferentially. For example, a report of the reversal in diastereoselection in HMPA—THF,
see: T. Chiba, M. Nagatsuma, and T. Nakai, Chem. Lett., 1984, 1927.
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