Enantioselective synthesis of cis-4-formyl-β-lactams via chiral N-heterocyclic carbene-catalyzed kinetic resolution

Article abstract of DOI:10.1002/adsc.200800071

An efficient synthesis of optically pure cis-4-formyl-β-lactams (up to 99% ee) by a chiral NHC-catalyzed ring expansion reaction has been realized, featuring the ready availability of both the substrate and the catalyst, and the mild reaction conditions. The current method is also suitable for the synthesis of enantioenriched 4-formyl-β-lactams and succinimides containing quaternary carbon centers.

Full text of DOI:10.1002/adsc.200800071

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DOI: 10.1002/adsc.200800071
Enantioselective Synthesis of cis-4-Formyl-b-lactams via Chiral
N-Heterocyclic Carbene-Catalyzed Kinetic Resolution
Gong-Qiang Li,a Yi Li,a Li-Xin Dai,a and Shu-Li Youa,*
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-5492-5087; e-mail: slyou@mail.sioc.ac.cn
Received: January 30, 2008; Published online: May 9, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An efficient synthesis of optically pure
cis-4-formyl-b-lactams (up to 99% ee) by a chiral
NHC-catalyzed ring expansion reaction has been
realized, featuring the ready availability of both the
substrate and the catalyst, and the mild reaction
conditions. The current method is also suitable for
the synthesis of enantioenriched 4-formyl-b-lactams
and succinimides containing quaternary carbon cen-
ters.
which were derived from chiral auxiliaries in multiple
steps. A direct catalytic asymmetric synthesis of cis-4-
formyl-b-lactam remains rare and highly desirable.
Recently, N-heterocyclic carbenes (NHCs) have
been utilized for a variety of transformations by the
means of umpolung,[7] reversing of the reactivity of al-
dehydes, providing an unconventional access to some
important target molecules.[8,9] We recently found that
in the presence of an NHC catalyst cis-4-formyl-b-lac-
tams could undergo the ring expansion reaction to
afford succinimide derivatives [Eq. (1)].[10]
Keywords: asymmetric catalysis; 4-formyl-b-lac-
tams; kinetic resolution; N-heterocyclic carbene;
organocatalysis
The b-lactam skeleton is the key structural unit re-
sponsible for the antibacterial properties of the most
widely employed antibacterial agents to date.[1] Partic-
ularly, the cis-4-formyl-b-lactams are versatile build-
ing blocks for the synthesis of many biologically im-
In addition, the kinetic resolution version of this
portant targets such as monobactams, isocephams, transformation was attempted with a chiral NHC
carbapenems, b-hydroxyaspartates, hydroxybutanoic (Scheme 1), and the cis-4-formyl-b-lactam could be
acids, biotin, and sphingolipids.[2] As a consequence, recovered with a moderate ee of 64%. It should be
numerous methods for the synthesis of cis-4-formyl-b- noted that the aldehyde was further reduced by
lactams were developed, which also accelerated the NaBH4 to its corresponding alcohol 3a for the ease of
rapid development of versatile transformations based handling. To the best of our knowledge, this is the
on this material.[3] The most convenient synthesis of first report for the catalytic asymmetric synthesis of
cis-4-formyl-b-lactams is the [2+2]cyclocondensation cis-4-formyl-b-lactams. Encouraged by these results,
of ketenes with diimines, namely the Staudinger reac- we further explored readily available chiral NHCs
tion,[4] mainly due to the ready availability of both and realized a highly efficient kinetic resolution to de-
starting materials. Over the past several decades, the liver optically pure cis-4-formyl-b-lactams. In this
asymmetric Staudinger reaction has been extensively paper, we report our preliminary results.
studied to deliver optically pure b-lactams.[5] Howev-
Initially, several chiral NHC precursors (Figure 1)
er, only limited methods are useful for the direct syn- were examined for the kinetic resolution of cis-4-
thesis of optically pure cis-4-formyl-b-lactams. Most formyl-b-lactam 1a. The results are summarized in
of the current synthesis of optically pure cis-4-formyl- Table 1.
b-lactams still use chiral starting materials such as al-
In the presence of 5 mol% of chiral NHC precursor
dehydes, acids/acid halides and amines,[6] most of 4 and DBU at room temperature, the ring expansion
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Enantioselective Synthesis of cis-4-Formyl-b-lactams
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Scheme 1. Chiral NHC-catalyzed kinetic resolution of (Æ)-1a.
succinimide 2a in 39% yield with 27% ee and 3a in
40% yield with 99% ee, respectively. N-Heterocyclic
carbene catalysts derived from precursors 6 and 7
proved unable to catalyze the ring expansion reaction
(entries 3 and 4, Table 1). By utilizing triazolium salt
5, different bases were examined in order to minimize
the racemization of ring expansion product 2a. In the
presence of 5 mol% of 5, with 5 mol% of Cs2CO3 or
DIPEA as a base, partial racemization of 2a was also
observed, and 2a was obtained with 24% ee and 17%
ee, respectively. In both cases, 3a can still be obtained
Figure 1. Several readily available chiral NHC precursors.
reaction was stopped at 50% conversion of the start- with excellent ees (98% ee and 99% ee, respectively).
1
ing material (by H NMR). Succinimide 2a was ob- Unfortunately, no reaction occurred when 5 mol% of
tained in 38% yield with 9% ee, and cis-4-formyl-b- K3PO4 or t-BuOK were used as the base.
lactam 1a was recovered and reduced to its corre-
To understand further the mechanism of racemiza-
sponding alcohol 3a in 34% yield with 64% ee tion of 2a, enantiopure (À)-1a was subjected to the
(entry 1, Table 1). Triazolium salt 5, with a bulky ring expansion reaction with the imidazolium chloride
2,4,6-trimethylphenyl substituent was found to be a (1 mol%) and DBU (1 mol%) in CH2Cl2 [Eq. (2)].[10a]
better catalyst for the kinetic resolution, affording After refluxing for 5 h, the succinimide 2a was almost
Table 1. Screening different chiral NHC catalysts and bases.[a]
Entry
Catalyst (cat.)
Base
2a
3a
Yield [%][b]
ee [%][c]
Yield [%][b]
ee [%][c]
1
2
4
5
6
7
5
5
5
5
DBU
DBU
DBU
DBU
K3PO4
Cs2CO3
KO-t-Bu
DI
38
39
/
/
/
32
/
9
27
/
/
/
24
/
30
34
40
/
/
/
34
/
17
64
99
/
/
/
98
/
35
3[d]
4[d]
5[d]
6
7[d]
8
PEA
99
[a]
Reaction conditions: 5 mol% of cat., 5 mol% of base, 0.25 mmol of (Æ)-1a in 1.0 mL CH2Cl2 at 258C. The reaction mix-
1
ture was quenched and charged with NaBH4 when the conversion of (Æ)-1a was 50% (by H NMR).
[b]
[c]
[d]
Isolated yields.
Determined by chiral HPLC analysis.
No reaction.
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reaction. The reaction time varied from 4.5 to 72 h.
As summarized in Table 2, either N-(2,4,6-trimethyl-
phenyl)- or N-(4-methoxyphenyl)-substituted sub-
strates afford the chiral cis-4-formyl-b-lactams 1 with
high enantioselectivities (entries 1–7). Substrates bear-
ing either electron-donating groups (4-OMe, entries 2
and 5) or electron-withdrawing groups (2-Br, 4-Br, 4-
Cl, entries 3, 6, and 7) were well tolerated in the reac-
tion, affording their accordant alcohols 3 in 30–47%
yield with 80–>99% ee. The substrate having a heter-
ocyclic substituent such as a 2-thienyl group occurred
with 56% ee (entry 8). Notably, the cis-4-formyl-b-lac-
tams 1j and 1k containing quaternary carbon centers
underwent the kinetic resolution giving their corre-
sponding succinimides 2 and cis-4-formyl-b-lactams in
excellent yields with moderate ees (entries 10 and 11).
completely racemized (1% ee). In addition, when the trans-4-Formyl-b-lactam 1i bearing
a quaternary
succinimide 2a (27% ee) was refluxed under the same carbon center has also been tested and relatively
conditions, the succinimide was recovered with only lower ees of both ring expansion product and starting
3% ee [Eq. (3)]. When (À)-1a (99% ee) was tested material were obtained (entry 9). Unfortunately, sub-
with 5 mol% thiazolium bromide and 5 mol% DBU, strates bearing alkyl groups such as n-pentyl and iso-
as reported by Alcaide et al.,[10b] severe racemization propyl afforded their corresponding cis-4-formyl-b-
was also observed (2% ee). Therefore, the low ee of lactams with 36% and 19% ee, respectively (entries 12
2a might be due to the acidic nature of the chiral and 13).
center in the succinimide derivative.
To determine the absolute stereochemistry of the
In the presence of 5 mol% of 5 and DBU, various product 3, a single crystal of 3f was obtained. An X-
structurally diversified (Æ)-cis-4-formyl-b-lactams ray analysis disclosed that the absolute configuration
have been tested to investigate the generality of the of 3f is (3R,4R) (Figure 2).[11]
Table 2. Kinetic resolution of (Æ)-cis-4-formyl-b-lactam 1 by chiral NHC 5.[a]
Entry
1
R1
R2
R3
t [h]
2 [%][b]
2 ee [%][c]
3 [%][b]
3 ee [%][c]
1
2
3
1a
1b
1c
1d
1e
1f
1g
1h
1i
Mes
Mes
Mes
Ph
PMP
2-Br-C6H4
Ph
PMP
4-Br-C6H4
4-Cl-C6H4
2-thienyl
Et
Ph
Ph
H
H
H
H
H
H
H
H
Ph
Et
Me
H
40
36
55
14
4.5
8
39
36
35
50
40
37
38
26
48
47
41
28
34
27
0
0
26
0
0
0
0
29
À44
44
0
40
30
46
47
45
32
37
30
49
44
35
30
37
99
>99
84
80
95
99
97
56
30
58
54
36
19
4
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
Mes
5[d]
6
7[d,e]
8[d]
9
72
7
12
45
24
48
40
10[d,f]
11[d]
12
13
1j
1k
1l
n-C5H11
i-Pr
1m
Mes
H
10
[a]
Reaction conditions: see the Experimental Section.
Isolated yields.
Determined by chiral HPLC analysis.
The reaction was run at 208C.
[b]
[c]
[d]
[e]
[f]
The concentration of (Æ)-1g was 0.08 mol/L.
The conversion of (Æ)-1j was 58%.
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Enantioselective Synthesis of cis-4-Formyl-b-lactams
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Figure 2. X-Ray structure of the compound (3R, 4R)-3f.
In summary, we have reported a novel efficient syn- Acknowledgements
thesis of optically pure cis-4-formyl-b-lactams by a
We gratefully acknowledge the Knowledge Innovation Pro-
gram of the Chinese Academy of Sciences, the National Natu-
ral Science Foundation of China, and the Science and Tech-
nology Commission of Shanghai Municipality (07pj14106,
07JC14063) for generous financial support.
chiral NHC-catalyzed ring expansion reaction. This
reaction features the ready availability of both the
substrate and the catalyst, and mild reaction condi-
tions. Notably, with the current method, enantioen-
riched 4-formyl-b-lactams and succinimides contain-
ing quaternary carbon centers can be obtained in ex-
cellent yields with mild enantioselectivities. Further
exploration of the reaction’s scope and applications of
the methodology in organic synthesis are currently
underway.
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