Protonation-assisted conjugate addition of axially chiral enolates: Asymmetric synthesis of multisubstituted β-lactams from α-amino acids

Article abstract of DOI:10.1002/chem.201201339

β-Lactams with contiguous tetra- and trisubstituted carbon centers were prepared in a highly enantioselective manner through 4-exo-trig cyclization of axially chiral enolates generated from readily available α-amino acids. Use of a weak base (metal carbon

Full text of DOI:10.1002/chem.201201339

DOI: 10.1002/chem.201201339
Protonation-Assisted Conjugate Addition of Axially Chiral Enolates:
Asymmetric Synthesis of Multisubstituted b-Lactams from a-Amino Acids
Tomoyuki Yoshimura, Masatoshi Takuwa, Keisuke Tomohara, Makoto Uyama,
Kazuhiro Hayashi, Pan Yang, Ryuichi Hyakutake, Takahiro Sasamori,
Norihiro Tokitoh, and Takeo Kawabata*[a]
Abstract: b-Lactams with contiguous
tetra- and trisubstituted carbon centers
were prepared in a highly enantioselec-
tive manner through 4-exo-trig cycliza-
tion of axially chiral enolates generated
from readily available a-amino acids.
Use of a weak base (metal carbonate)
in a protic solvent (EtOH) is the key
to the smooth production of b-lactams.
Use of the weak base is expected to
generate the axially chiral enolates in a
very low concentration, which undergo
intramolecular conjugate addition with-
out suffering intermolecular side reac-
tions. Highly strained b-lactam enolates
thus formed through reversible intra-
molecular conjugate addition (4-exo-
trig cyclization) of axially chiral eno-
lates undergo prompt protonation by
EtOH in the reaction media (not
during the work-up procedure) to give
b-lactams in up to 97% ee.
Keywords: amino acids · axial chir-
ality · b-lactams · conjugate addi-
tion · protonation
Introduction
late intermediate A.[1,2] This method could be used for the
construction of five- and six-membered nitrogen heterocy-
cles, but not four-membered ones.[4]
We sought to apply this method to the synthesis of b-lac-
tams with contiguous tetra- and trisubstituted stereocenters
starting from commercially available a-amino acids
(Scheme 2).[5,6] b-Lactams are expected to be produced
through 4-exo-trig cyclization of axially chiral enolates such
as B. However, we had expected that this process might be
unfavorable because the conjugate addition of enolate B
We previously reported enantioselective intramolecular con-
jugate addition reactions of enolates derived from a-amino
acid derivatives through memory of chirality (Scheme 1).[1–3]
should give highly strained b-lactam enolate C with a labile
1
ꢀ
C C bond (1.63 ꢀ by DFT calculations when M=Cs, R =
R2 =R3 =R4 =Me, see the Supporting Information). Because
conjugate addition of the enolates is reversible, enolates B
and C would coexist and both are prone to undergo inter-
molecular side reactions, which would give a complex mix-
ture. In accordance with this assumption, b-lactam synthesis
by reversible intramolecular conjugate addition of enolates
has rarely been reported.[7] A hypothetical route to over-
come this problem is shown in Scheme 2. The preferential
preconditions for b-lactam formation might involve genera-
tion of a low concentration of enolate B to avoid intermo-
lecular side reactions, and prompt protonation of the b-
lactam enolate C immediately after its formation to stabilize
the labile bond.[8] With this hypothesis in mind, we exam-
ined the conditions suitable for b-lactam formation.
Scheme 1. Asymmetric intramolecular conjugate addition through an ax-
ially chiral enolate (KHMDS=potassium hexamethyldisilazide).
A piperidine derivative with contiguous tetra- and trisubsti-
tuted stereocenters was prepared from an a-amino acid de-
rivative in 97% ee without the use of external chiral sources
such as chiral catalysts or chiral auxiliaries. It has been pro-
posed that the reactions proceed through axially chiral eno-
[a] Dr. T. Yoshimura, M. Takuwa, K. Tomohara, M. Uyama,
Dr. K. Hayashi, P. Yang, R. Hyakutake, Dr. T. Sasamori,
Prof. Dr. N. Tokitoh, Prof. Dr. T. Kawabata
Institute for Chemical Research
Results and Discussion
Kyoto University
Uji 611-0011 (Japan)
Fax : (+81)774-383197
E-mail: kawabata@scl.kyoto-u.ac.jp
The precursor for asymmetric b-lactam synthesis through
memory of chirality was designed as follows. The choice of
the nitrogen substituents is critical for the generation of ax-
ially chiral enolates with high enantiomeric purity. Both a
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201339.
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Chem. Eur. J. 2012, 18, 15330 – 15336

FULL PAPER
Scheme 2. Strategy for b-lactam synthesis through the reversible intramolecular conjugate addition of enolates followed by protonation.
substituent containing a carbonyl group and an alkyl sub-
stituent are necessary for this purpose.[1,2] Because the b-
lactam precursor in Scheme 2 already has an amide carbonyl
group on the nitrogen, an alkyl substituent is suitable for
the second substituent. We chose a p-methoxybenzyl (PMB)
group as the alkyl substituent of the nitrogen because it is
easy to remove (Scheme 3). b-Lactam precursor 1 was readi-
ly obtained from l-phenylalanine ethyl ester in two steps in
at ambient temperature.[13] However, a complex mixture was
again obtained (Table 1, entry 4). Thus, even weaker bases,
such as metal carbonates, were examined. Treatment of 1
with 1.5 equivalents of Cs2CO3 in CH3CN at 208C for 36 h
gave the desired b-lactams 2a (93% ee) and 2b (91% ee) as
a 63:37 diastereomeric mixture in 89% combined yield
(Table 1, entry 5). Treatment of 1 with Cs2CO3 in CH3CN at
508C for 23 h gave 2a and 2b in a higher diastereomeric
ratio (88:12) in 99% combined yield and in 83 and 81% ee,
respectively (Table 1, entry 6). Rb2CO3 and K2CO3 were less
effective for the reaction. The reaction of 1 with Rb2CO3 at
508C for 90 h gave a mixture of 2a and 2b in poor yield
(34%; Table 1, entry 7). A higher temperature and longer
reaction time were required for the reaction of 1 with
K2CO3 in CH3CN, which gave a 62:38 mixture of 2a and 2b
in 80 and 82% ee, respectively (Table 1, entry 8). Use of
metal carbonates was found to be effective for the b-lactam
formation. The success of intramolecular conjugate addition
using metal carbonates was expected to be due to the gener-
ation of a very low concentration of enolates (pKa values of
Scheme 3. Preparation of b-lactam precursors from l-phenylalanine ethyl
ester.
57% overall yield through p-methoxybenzylation followed
by acylation with an acid chloride of mono tert-butyl ester
of fumaric acid.[9]
ꢀ
HCO3 and the a-proton of a-amino acid derivatives are de-
The conditions for the asym-
metric conjugate addition of an
enolate derived from 1 were ex-
amined (Table 1). The use of
KHMDS,[10] lithium tetrame-
thylpiperidide (LTMP),[11] or
Table 1. Effects of bases, solvents, and additives on asymmetric intramolecular conjugate addition.[a]
Entry Base[b]
Solvent
Additive
[equiv]
t [8C]
T [h]
Yield 2a/2b[d,e,f] ee of 2a ee of 2b
lithium
diisopropylamide
G
[%][c]
[%][g]
[%][g]
(LDA) as a base gave a com-
plex mixture (Table 1, en-
tries 1–3), probably due to the
intermolecular side reactions of
enolate B and/or enolate C, as
expected (Scheme 2). Accord-
ing to the hypothesis presented
in Scheme 2, we next examined
bases with lower pKa values
(weaker bases) to decrease the
[h]
1
2
3
4
5
6
7
8
KHMDS THF
–
–
–
–
–
–
–
–
ꢀ78
ꢀ78
ꢀ78
20
20
50
2
2
2
–
–
–
–
–
–
–
–
–
–
–
–
–
[h]
LTMP
LDA
THF
THF
[h]
[h]
KOH
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
2
–
–
–
Cs2CO3
Cs2CO3
Rb2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Rb2CO3
K2CO3
36
23
90
89
99
34
94
99
99
82
94
98
99
63:37
88:12
64:36
62:38
41:59
87:13
52:48
44:56
50:50
41:59
93
83
84
80
87
88
93
95
94
93
91
81
77
82
90
86
95
96
95
97
50
reflux 111
9
phenol (1.0)
20
20
20
0
20
20
0.5
10
11
12
13
14
CH3CN CF3CH2OH (1.0)
0.3
0.1
1
1
1.5
EtOH
EtOH
EtOH
EtOH
–
–
–
–
concentrations of enolates
B
and C. We examined the use of
powdered KOH in dimethyl
sulfoxide (DMSO),[12] which
was previously found to be an
excellent base for asymmetric
[a] Run with a substrate concentration of 0.1 m. [b] 1.2 or 1.5 Equivalents of the base were used for entries 1–3
or 4–14, respectively. [c] Yield of the diastereomeric mixture. [d] The ratio was determined by 1H NMR spec-
troscopic analysis (400 MHz) before separation of the diastereomers. [e] Relative stereochemistry was deter-
mined by NOESY experiments of each of the pure diastereomers (see the Supporting Information). [f] The ab-
solute configuration was tentatively assigned by analogy to 4a. [g] The ee of the pure diastereomer obtained
after HPLC separation. [h] Complex mixture.
intramolecular
alkylation
through axially chiral enolates
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15331

T. Kawabata et al.
duced to be ca. 10 and ca. 24, respectively, in H2O)[12,14] as
for 0.1 h, the diastereomeric ratio changed to 91:9 when the
reaction was conducted for 10 h, although there was a slight
loss of enantioselectivity (91% ee for 2a and 85% ee for
2b; Table 2, entries 1 vs. 2). Diastereomer 2b was formed as
the major product when the reaction of 1 was conducted at
a lower temperature (08C) and for a short reaction time
(0.2 h; Table 2, entry 3). This observation indicates that 2b
is the kinetically favored diastereomer and that 2a is the
thermodynamically favored diastereomer. A similar trend
was also observed in the intramolecular conjugate addition
reactions of l-valine-derived 3 and l-tryptophan-derived 5
(Table 2, entries 7–12). Whereas treatment of 3 with Cs2CO3
in EtOH at 208C for 1 h gave a 76:24 mixture of 4a and 4b
in a combined yield of 78% and in 91 and 95% ee, respec-
tively, that for 5.5 h gave 4a as the sole detectable diaster-
eomer in 62% yield and 88% ee (Table 2, entries 7 and
8).[15] Upon treatment of 5 with Cs2CO3 in EtOH at 208C
for 0.5 h, a 43:57 mixture of 6a and 6b was obtained in a
combined yield of 92% and in 93 and 92% ee, respectively
(Table 2, entry 10). On the other hand, a 88:12 mixture of
6a and 6b was obtained in a combined yield of 75% by the
reaction of 5 with Cs2CO3 for 5 h (Table 2, entry 11).[15]
These results indicate that b-lactams 2a, 4a, and 6a are ther-
modynamically favored diastereomers. Use of (Z)-1 instead
of 1 gave a 50:50 mixture of 2a and 2b in a combined yield
of 88% and in diminished 73 and 77% ee, respectively
(Table 2, entry 6). We also found that the use of only cata-
lytic amounts of Cs2CO3 was effective for b-lactam forma-
tion. Treatment of 1 with 0.1 equivalent of Cs2CO3 in EtOH
at 208C for 2 h gave a 38:62 mixture of 2a and 2b in a com-
bined yield of 96% and in 95
well as protonation of b-lactam enolate C by the conjugate
ꢀ
acid HCO3 . We then investigated the effects of additional
ꢀ
proton sources. Because the pKa value of HCO3 is about 10
(in H2O), we examined additives with pKa values similar to
ꢀ
that of HCO3 , such as phenol (pKa ca. 10) and CF3CH2OH
(pKa ca. 12). The addition of only one equivalent of phenol
or trifluoroethanol significantly accelerated the reaction
(36 h vs. 0.5 h (by phenol) or 0.3 h (by trifluoroethanol),
Table 1, entries 5 vs. 9 or 10). Because the addition of
proton sources was found to be effective for accelerating the
reaction, we then examined the reaction in a pure protic sol-
vent. The reaction in EtOH proceeded more quickly and
was completed in 0.1 h to give a 52:48 mixture of 2a and 2b
in a combined yield of 82% and in 93 and 95% ee, respec-
tively (Table 1, entry 11). The yield and enantioselectivity of
the reaction were slightly improved by conducting the reac-
tion at 08C (94% combined yield in 95 and 96% ee for 2a
and 2b, respectively; Table 1, entry 12). The use of Rb2CO3
or K2CO3 as a base was also effective for the reaction in
EtOH. The former gave a 50:50 mixture of 2a and 2b in a
combined yield of 98% and in 94 and 95% ee, respectively,
and the latter gave a 41:59 mixture of 2a and 2b in a com-
bined yield of 99% and in 93 and 97% ee, respectively, al-
though both cases required slightly longer reaction times
than that with Cs2CO3 (Table 1, entries 11 vs. 13 or 14).
We then investigated the effects of the reaction time for
the b-lactam formation from 1 and Cs2CO3 in EtOH
(Table 2). Whereas a 52:48 mixture of 2a and 2b was ob-
tained by the reaction of 1 with Cs2CO3 in EtOH at 208C
and 95% ee, respectively
Table 2. Effects of the reaction time on the b-lactam syntheses from various a-amino acid derivatives with
(Table 2, entry 4). Similarly, use
of catalytic amounts of Cs2CO3
in EtOH was effective for other
enantioselective b-lactam syn-
theses (Table 2, entries 5, 9, and
12).
Cs2CO3 in EtOH.[a]
The absolute configuration of
4a was determined to be
(3S,4S) by an X-ray crystallo-
Entry
Substrate
R
Cs2CO3
[equiv]
Product
t
Yield
[%][b]
a/b[c,d]
52:48
ee of a
ee of b
G
[h]
[%][e]
[%][e]
1
2
1
1
1
1
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
iPr
1.5
1.5
1.5
0.1
0.3
1.5
1.5
1.5
0.1
1.5
1.5
0.1
2a, 2b[f]
2a, 2b[f]
2a, 2b[f]
2a, 2b[f]
2a, 2b[f]
2a, 2b[f]
4a, 4b[h]
4a, 4b[h]
4a, 4b[h]
6a, 6b[f]
6a, 6b[f]
6a, 6b[f]
0.1
10
0.2
82
80
32
96
88
88
78
62
70
92
75
83
93
91
–
95
97
95
85
–
graphic
analysis
of
7
91:9
42:58
38:62
40:60
50:50
3[g]
4
(Figure 1),[16] which was ob-
tained by removal of the tert-
butyl group of a 76:24 mixture
of 4a (91% ee) and 4b (95%
ee), condensation of the result-
ing carboxylic acid with p-io-
doaniline, and separation of the
major diastereomer. A single
crystal for X-ray analysis was
obtained from 7 (>99% ee),
which had been prepared by re-
2
95
95
77
95[j]
–
5
6
7
1
0.7
2.5
1
(Z)-1[i]
73
3
3
3
5
5
5
76:24
91[j]
88[j]
93[j]
93
8[k]
9
iPr
iPr
5.5
>99:<1
87:13
17
94[j]
92
85
91
10
11[k]
12
0.5
5
3.5
43:57
88:12
48:52
89
92
[a] Run with a substrate concentration of 0.1 m. [b] Yield of the diastereomeric mixture. [c] The ratio was de-
termined by 1H NMR spectroscopic analysis (400 MHz) before separation of the diastereomers. [d] Relative
stereochemistry was determined by NOESY experiments of each of the pure diastereomers (see the Support- crystallization of 7 (91% ee)
ing Information). [e] The ee of the pure diastereomer obtained after HPLC separation. [f] The absolute config-
obtained by the above proce-
dure. Thus, intramolecular con-
jugate addition of 3 was found
uration was tentatively assigned by analogy with 4a. [g] Run at 08C. [h] The absolute configuration was deter-
mined by X-ray analysis of 7 derived from 4a (See text). [i] See ref.[9] [j] The ee was determined after conver-
sion into 7 or its C(3)-epimer. [k] Run in tBuOH/EtOH (4:1) at 308C.
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Synthesis of Multisubstituted b-Lactams
FULL PAPER
spectively.[17] Alternatively, treatment of 2b (96% ee) with
1.5 equivalents of Cs2CO3 in EtOH at 208C for 10 h gave a
92:8 mixture of 2a and 2b in 66% combined yield and in 90
and 89% ee, respectively. These results clearly indicate the
equilibrium between 2a and 2b and that the former is the
thermodynamically favored diastereomer.
A rationale for the stereochemical course of b-lactam for-
mation is shown in Scheme 5. A conformational search of 1
gave stable conformers, I and II.[18] Deprotonation of con-
ꢀ
former II with Cs2CO3, in which the C(a) H bond is anti-
Figure 1. X-ray structure of 7.
ꢀ
periplanar with respect to the neighboring N C(COCH=
CHCO2tBu) bond, would be preferable to that of conformer
ꢀ
I, in which the C(a) H bond is antiperiplanar with respect
ꢀ
to proceed with an inversion of configuration at the newly
formed tetrasubstituted carbon center.
to the neighboring N C
N
based on our rationale for previous stereochemical results,
in which deprotonation of N-Boc-N-alkyl-a-amino acid de-
rivatives preferentially took place from the conformer in
The diastereomeric ratio of 2a and 2b obtained by the re-
actions of 1 depended on the reaction time (Table 2, en-
tries 1 vs. 2), which suggests that there is an equilibrium be-
tween 2a and 2b, through a retro-conjugate addition proc-
ess. To examine this issue, diastereomerically pure 2a and
2b were obtained by HPLC separation and independently
treated under the conditions used for b-lactam formation
(Scheme 4). Treatment of 2a (92% ee) with 1.5 equivalents
of Cs2CO3 in EtOH at 208C for 10 h gave a 93:7 mixture of
2a and 2b in 50% combined yield and 84 and 77% ee, re-
ꢀ
which the C(a) H bond is antiperiplanar with respect to the
ꢀ
neighboring N C
(Boc) bond.[10,13,19] Deprotonation of con-
former II would give enantiomerically enriched enolate D
with a chiral (aS)-C-N axis. The other chiral enolate E with
a chiral (aS)-C-N axis would be formed by fast rotation of
ꢀ
the C C bond (blue curved arrow). Enolate D would under-
go intramolecular conjugate addition from its si-face to give
b-lactam enolate F with an inversion of configuration at the
newly formed tetrasubstituted carbon. Similarly, enolate E
would give b-lactam enolate G with the same absolute con-
figuration as that of F at the tetrasubstituted carbon. Proto-
nation of F and G by the solvent (EtOH) and/or the conju-
ꢀ
gate acid (HCO3 ) would give b-lactams 2b and 2a, respec-
tively. Equilibrium between 2a and 2b affects the ratio be-
tween them. Thermodynamically more stable diastereomers
2a, 4a, and 6a were obtained as the major products when
Scheme 4. Thermodynamic equilibrium between 2a and 2b.
Scheme 5. A possible mechanism for b-lactam formation through the reversible intramolecular conjugate addition of the axially chiral enolates.
Chem. Eur. J. 2012, 18, 15330 – 15336
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T. Kawabata et al.
the reactions were run for prolonged reaction times
(Table 2, entries 2, 8, and 11). The decrease in enantiomeric
purity of 2, 4, and 6 was less than 12% during the equilibri-
um process between chiral enolates. This would indicate
(Scheme 6). Compound 9 was employed as a precursor for
the silyl ketene acetal because its enolate does not undergo
4-exo-trig cyclization, and, instead, could be trapped as the
ꢀ
that the interconversion between D and E through C C
bond rotation (blue curved arrow) is faster than racemiza-
ꢀ
tion of the axially chiral enolates D and E through C N
bond rotation (red curved arrow). For the expected racemi-
zation barriers of enolates D and E, see text below.
It is assumed that the equilibrium between 2a and 2b is
ꢀ
initiated by the deprotonation of C(1’) H of 2a and 2b.
However, it could alternatively result from the deprotona-
ꢀ
Scheme 6. Preparation and the rotational barrier of the C N bond of
(Z)-10 (TBSOTf=tert-butyldimethylsilyl triflate).
ꢀ
tion of C(3) H of 2a and 2b. To investigate this possibility,
2a was treated under conditions identical to those shown in
Scheme 4, except for the use of EtOD instead of EtOH.
Thus, 65% deuterium incorporation was observed at C(1’)
of 2-d, whereas no deuterium incorporation was detected at
C(3) (Figure 2). This indicates that the equilibrium between
silyl ketene acetal. Two methyl groups of the tert-butyldime-
thylsilyl group of (Z)-10 appeared as two diastereotopic sin-
glets in its H NMR spectra measured at 208C, suggesting
1
ꢀ
restricted rotation along the C N bond. The rotational bar-
rier was determined to be 20.3 kcalmolꢀ1 from Dn (31.2 Hz)
and the coalescence temperature (1288C). The half-life of
racemization of axially chiral enolates D and E are estimat-
ed to be about 1 min at 208C (standard temperature em-
ployed for the b-lactam formation in Table 2), based on the
assumption that racemization barriers of the axially chiral
enolates D and E are comparable to the rotational barrier
Figure 2. Deuterated product 2-d and compound 8.
¼
ꢀ
of the C N bond of (Z)-10, and that DS of the unimolecu-
lar process for the bond rotation is nearly zero. Thus, race-
ꢀ
mization through C N bond rotation seems slower than the
ꢀ
ꢀ
2a and 2b is initiated by deprotonation of C(1’) H followed
interconversion between D and E through C C bond rota-
ꢀ
by retro-conjugate addition, C C bond rotation (blue
tion. Another aspect may be worth mentioning; b-Lactams
were obtained in 80 to 82% ee through the asymmetric con-
jugate addition of the axially chiral enolate performed even
at 818C (Table 1, entry 8). The half-life of racemization of
enolates D and E might also be estimated to be about 0.2 s
at 818C. Asymmetric conjugate addition was found to be
still possible at such a high temperature through axially
chiral enolate intermediates.[21]
curved arrow), conjugate addition, and protonation, as
shown in Scheme 5. Another interesting phenomenon is that
enolates D and E themselves do not seem to suffer protona-
tion by EtOH, because their protonation should significantly
diminish the ee values of 2a and 2b. In fact, significant race-
mization was observed in 8 under the standard conditions
used for intramolecular conjugate addition (Figure 2). When
8 (>99% ee) was treated with 1.5 equivalents of Cs2CO3 in
EtOH at 208C for 15 min, 8 with 18% ee was recovered in
96% yield. The observed racemization was assumed to
come about as a result of protonation of the enolate gener-
ated from 8 because the enolate is unlikely to undergo 5-
endo-trig cyclization to give a g-lactam enolate. In contrast,
intramolecular conjugate addition of enolates D and E
through 4-exo-trig cyclization would proceed faster than pro-
tonation of themselves by EtOH. This avoids the racemiza-
tion of D and E, and, instead, promotes b-lactam formation
in a highly enantioselective manner. Overall, the prompt
protonation of b-lactam enolates F and G is essential for b-
lactam formation, whereas the protonation of enolates D
and E to give the starting material 1 should be slower than
intramolecular conjugate addition of the enolates.[20]
Conclusion
b-Lactams with contiguous tetra- and trisubstituted carbon
centers were prepared in a highly enantioselective manner
from readily available a-amino acids. To the best of our
knowledge, this is the first example of the asymmetric syn-
thesis of b-lactams through the reversible intramolecular
conjugate addition of enolates. Use of a weak base (metal
carbonate) in a protic solvent (EtOH) is the key to the
smooth production of b-lactams. The present method pro-
vides unique access to optically active b-lactams that are
still of great importance in the field of medicinal chemis-
try.[22] b-Lactams are also useful equivalents of protected b-
amino acids as well as versatile precursors of N-heterocyclic
compounds for the synthesis of natural products.[23]
To estimate the rates of racemization of axially chiral eno-
lates D and E, the rotational barrier of the C N bond of the
related enolate equivalent, silyl ketene acetal (Z)-10, was
ꢀ
determined by variable-temperature NMR measurements
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Synthesis of Multisubstituted b-Lactams
FULL PAPER
Watson, M. Helliwell, M. Chambers, Chem. Commun. 2003, 2582–
2583.
Experimental Section
ꢀ
[8] The length of the labile C C bond of b-lactam enolate C (M=Cs,
Cyclization of 1 with Cs2CO3 in EtOH (Table 1, entry 11): A mixture of 1
(3.91 g, 8.40 mmol) and Cs2CO3 (4.10 g, 12.6 mmol) in EtOH (90 mL)
was stirred for 0.1 h at 208C, then the reaction was quenched by addition
of sat. NH4Cl. After removal of volatiles, the aqueous layer was extracted
with EtOAc and the extracts were dried over Na2SO4, filtered, and con-
centrated. The residual oil was purified by silica gel column chromatogra-
phy (EtOAc/hexane=3:7) to give a 52:48 diastereomeric mixture of 2a
and 2b (3.20 g, 2a: 93% ee, 2b: 95% ee) as a colorless oil. Compound
2a: colorless oil; 93% ee. For physical data, determination of the enan-
tiomeric excess, 1H NMR, NOESY, 13C NMR spectra of 2a and 2b, see
the Supporting Information.
R1 =R2 =R3 =R4 =Me) was calculated to be 1.63 ꢀ by DFT calcula-
tions (see the Supporting Information), whereas the corresponding
bond length of C(3) C(4) of b-lactam 7 was shown to be 1.574 ꢀ by
ꢀ
X-ray analysis.
[9] b-Lactam precursor 1 and its Z isomer were alternatively obtained
by amidation of N-PMB-phenylalanine ethyl ester with maleic anhy-
dride followed by esterification of the resulting carboxylic acid with
(Boc)2O/DMAP. See the Supporting Information.
[10] KHMDS is a suitable base for the intramolecular alkylation and in-
tramolecular conjugate addition of a-amino acid derivatives with a
retention of configuration through memory of chirality. See: a) T.
Kawabata, S. Kawakami, D. Majumdar, J. Am. Chem. Soc. 2003,
125, 13012–13013; b) See also ref. [1].
[11] LTMP is a suitable base for the intramolecular alkylation of a-
amino acid derivatives with an inversion of configuration through
memory of chirality, see: T. Kawabata, S. Matsuda, S. Kawakami, D.
Monguchi, K. Moriyama, J. Am. Chem. Soc. 2006, 128, 15394–
15395.
[12] KOH in DMSO is a strong base that can abstract the a-proton of
esters (pKa values of H2O and a proton of esters in DMSO are 31
and 18–30, respectively). KOH in DMSO seems to be an even stron-
ger base than KHMDS in DMSO based on their pKa values: pKa
values of H2O and HMDS in DMSO are 31 and 30, respectively.
See: a) F. G. Bordwell, Acc. Chem. Res. 1988, 21, 456–463; b) N. V.
Mashchenko, M. G. Matveeva, I. L. Odinets, E. I. Matrosov, E. S.
Petrov, M. I. Terekhova, A. K. Matveev, T. A. Mastryukova, M. I.
Kabachnik, Zh. Obshch. Khim. 1988, 58, 1973–1979; c) R. P. Bell,
The Proton in Chemistry, Cornell University Press, Ithaca, New
York 1959.
Acknowledgements
We are grateful to Professor Masaharu Nakamura, Kyoto University, for
useful suggestions about DFT calculations and the catalytic use of the
base.
[1] T. Kawabata, S. Majumdar, K. Tsubaki, D. Monguchi, Org. Biomol.
Chem. 2005, 3, 1609–1611.
[2] For reviews on asymmetric synthesis through memory of chirality,
see: a) T. Kawabata, K. Fuji, Top. Stereochem. 2003, 23, 175–205;
b) H. Zhao, D. C. Hsu, P. R. Carlier, Synthesis 2005, 1–16; c) T. Ka-
wabata, Asymmetric Synthesis and Application of a-Amino Acids, in
ACS Symposium Series 1009, 2009, pp. 31–56. For recent examples
of asymmetric synthesis based on memory of chirality, see: d) P. R.
Carlier, H. Zhao, S. L. MacQuarrie-Hunter, J. C. DeGuzman, D. C.
Hsu, J. Am. Chem. Soc. 2006, 128, 15215–15220; e) L. Kolaczkow-
ski, D. M. Barnes, Org. Lett. 2007, 9, 3029–3032; f) M. Branca, D.
Gori, R. Guillot, V. Alezra, C. Koulovsky, J. Am. Chem. Soc. 2008,
130, 5864–5865.
[3] We highly appreciate Cozzi and Siegelꢂs suggestion on memory of
chirality (F. Cozzi, J. S. Siegel, Org. Biomol. Chem. 2005, 3, 4296–
4298). While we completely agree with their definition of stereo-
chemistry, we have used the term “memory of chirality” from the
following viewpoint. “Memory of chirality” represents the phenom-
ena in which static chirality (mostly central chirality) is preserved as
transient chirality (mostly axial chirality) in the reactive intermedi-
ate, and then regenerated as static chirality in the product (T. Kawa-
bata, K. Yahiro, K. Fuji, J. Am. Chem. Soc. 1991, 113, 9694–9696).
[4] D. Monguchi, S. Majumdar, T. Kawabata, Heterocycles 2006, 68,
2571–2578.
[13] T. Kawabata, K. Moriyama, S. Kawakami, K. Tsubaki, J. Am. Chem.
Soc. 2008, 130, 4153–4157.
[14] The reaction of 1 with KHMDS at ꢀ108C under dilute conditions
(0.01m in EtOH) also gave a mixture of 2a and 2b in 79% yield.
[15] The mixed solvent tBuOH/EtOH (4:1), was used to avoid ester ex-
change during the long reaction time in the presence of Cs2CO3. For
example, treatment of 3 with Cs2CO3 in EtOH for 10 h gave 4 in
only 31% yield, due to the ester exchange.
[16] Crystal data of 7: C25H29IN2O5; M=564.40; space group P21(#4);
a=11.8641 (4) ꢀ, b=6.7776(2) ꢀ, c=15.5120(5) ꢀ, a=908, b=
90.788(2)8, g=908; V=1247.20(7) ꢀ3; Z=2; 1calcd =1.503 mgmꢀ3
;
MoKa radiation; l=0.71069 ꢀ; m=1.321 mmꢀ1; T=103(2) K. The
final R1 and wR2 were 0.0302 and 0.0628 for 332 parameters.
CCDC-743570 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[5] Asymmetric synthesis of b-lactams by the intramolecular alkylation
through memory of chirality has been reported, see: a) G. Gerona-
Navarro, M. A. Bonache, R. Hernz, M. T. Garcꢃa-Lꢄpez, R. Gon-
zꢅlez-MuÇiz, J. Org. Chem. 2001, 66, 3538–3547; b) M. A. Bonache,
G. Gerona-Navarro, M. Martꢃn-Martꢃnez, M. T. Garcꢃa-Lꢄpez, P.
Lꢄpez, C. Cativiela, R. Gonzꢅlez-MuÇiz, Synlett 2003, 1007–1011;
c) M. A. Bonache, G. Gerona-Navarro, C. Garcꢃa-Aparicio, M.
Alꢃas, M. Martꢃn-Martꢃnez, M. T. Garcꢃa-Lꢄpez, P. Lꢄpez, C. Cati-
viela, R. Gonzꢅlez-MuÇiz, Tetrahedron: Asymmetry 2003, 14, 2161–
2169; d) M. A. Bonache, C. Cativiela, M. T. Garcꢃa-Lꢄpez, R. Gon-
zꢅlez-MuÇiz, Tetrahedron Lett. 2006, 47, 5883–5887.
[6] An interesting method for the synthesis of b-lactams with contigu-
ous tetra- and trisubstituted carbon centers was recently reported in
which the stereochemistry was controlled by the chirality of the in-
tramolecular electrophile. See: P. Pꢆrez-Faginas, F. OꢂReilly, A.
OꢂByrne, C. Garcꢃa-Aparcio, M. Martꢃn-Martꢃnez, M. J. Pꢆrez de Va-
ga, M. T. Garcꢃa-Lꢄpez, R. Gonzꢅlez-MuÇiz, Org. Lett. 2007, 9,
1593–1596.
[17] The main reasons for the low recovery of 2 involve ester exchange
(ca. 20%) and decomposition.
[18] The stable conformers I and II were generated by a molecular mod-
eling search (MCMM 50,000 steps) with OPLS 2005 force field with
GB/SA solvation model for n-butanol using MacroModel (V. 9.0).
The difference in potential energies between I and II was estimated
to be 0.22 kcalmolꢀ1 (II is more stable than I). The corresponding s-
trans conformer of the a,b-unsaturated amide moiety was not found
among the low-energy conformers within 10 kcalmolꢀ1 (see the Sup-
porting Information).
[19] T. Kawabata, H. Suzuki, Y. Nagae, K. Fuji, Angew. Chem. 2000, 112,
2239–2241; Angew. Chem. Int. Ed. 2000, 39, 2155–2157, also see
refs. [2a,c,10,11,13].
[20] Protonation of tetrasubstituted enolates D and E is assumed to be
slower than that of trisubstituted enolates F and G, due to the differ-
ence in the steric environments at the sp2 carbon atoms suffering
protonation. Protonation of enolates D and E is also expected be
minimized by the higher rate of the intramolecular conjugate addi-
tion than the intermolecular protonation.
[7] b-Lactam synthesis through irreversible intramolecular conjugate
addition of a-lithio amides has been reported, see: J. Clayden, D. W.
Chem. Eur. J. 2012, 18, 15330 – 15336
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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T. Kawabata et al.
[21] Recently, a highly enantioselective cascade rearrangement of ene-
diynes has been reported that proceeds at 808C through memory of
chirality, see: M. Nechab, D. Campolo, J. Maury, P. Perfetti, N. Van-
thuyne, D. Siri, M. P. Bertrand, J. Am. Chem. Soc. 2010, 132, 14742–
14744.
[23] B. Alcaide, P. Almendros, C. Aragoncillo, Chem. Rev. 2007, 107,
4437–4492.
[22] For a recent example, see: C. Palomo, J. M. Aizpurua, E. Balentovꢅ,
A. Jimenez, J. Oyarbide, R. M. Fratile, J. I. Miranda, Org. Lett. 2007,
9, 101–104.
Received: April 19, 2012
Revised: July 16, 2012
Published online: October 11, 2012
15336
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 15330 – 15336