Catalytic asymmetric intramolecular cyclopropanation of 2-diazo-3-oxo-6-heptenoic acid esters

Article abstract of DOI:10.1055/s-2007-967964

This manuscript describes studies on the catalytic asymmetric intramolecular cyclopropanation (IMCP) of 2-diazo-3-oxo-6-heptenoic acid esters. The enantioselectivity depends on the bulkiness of the ester moiety, and the 2,6-di-tert-butyl-4-methylphenyl es

Full text of DOI:10.1055/s-2007-967964

LETTER
579
Catalytic Asymmetric Intramolecular Cyclopropanation of 2-Diazo-3-oxo-6-
heptenoic Acid Esters
Cyclopropanation
i
of 2-D
i
r
azo-3-ox
o
o-6-hepteno
y
ic AcidEste
u
rs ki Takeda, Masahiro Honma, Ryoji Ida, Takashi Sawada, Masahisa Nakada*
Department of Chemistry, Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
Fax +81(3)52863240; E-mail: mnakada@waseda.jp
Received 15 November 2006
metric IMCP of a-diazo-b-keto ester 1 reported so far is
Abstract: This manuscript describes studies on the catalytic asym-
not high (up to 56% ee7a) so far as we know.
metric intramolecular cyclopropanation (IMCP) of 2-diazo-3-oxo-
6-heptenoic acid esters. The enantioselectivity depends on the bulk-
iness of the ester moiety, and the 2,6-di-tert-butyl-4-methylphenyl
ester of 2-diazo-3-oxo-6-heptenoic acid provided the product with
78% ee, suggesting that the catalytic asymmetric IMCP of a-diazo-
b-keto esters could be a key reaction for the enantioselective syn-
thesis of natural products as well as artificial molecules.
We have developed the catalytic asymmetric IMCP of
a-diazo-b-keto sulfone 4 and other a-diazo-b-keto
sulfones to afford corresponding cyclopropanes with
excellent enantioselectivity (Scheme 2).7 This catalytic
asymmetric IMCP is useful for preparing new enantiopure
chiral building blocks toward natural products syn-
theses. Indeed, our recent reports on the enantioselective
total synthesis of natural products, (–)-allocyathin B2,7e
(–)-malyngolide,7f and (–)-methyl jasmonate,7g proved the
wide applicability and practical potential of the catalytic
asymmetric IMCP of a-diazo-b-keto sulfones.
Key words: asymmetric catalysis, cyclopropanation, a-diazo-b-
keto ester, enantioselectivity, intramolecular reaction
2-Oxobicyclo[3.1.0]hexan-1-carboxylic acid ester (2,
Scheme 1) is a useful intermediate for preparing natural
products as well as chiral artificial molecules because a
cyclopropane ring in the molecule is reactive due to the
attached two electron-withdrawing groups, a ketone and
an ester, thereby it opens easily under various conditions
to form new bonds, providing various cyclopentanone
derivatives.1
H
CuOTf
(10 mol%)
ligand 3d
(15 mol%)
SO2Mes
SO2Mes
N2
O
O
4
87%, 93% ee
5
H
intramolecular
cyclopropanation
R1 R1
3a: R1 = Me, R2 = i-Pr
O
3b: R1 = Me, R2 = t-Bu
3c: R1 = Et, R2 = i-Pr
3d: R1 = Bn, R2 = i-Pr
O
CO2R
CO2R
N
N
(IMCP)
N2
O
R2
O
R2
1
2
Scheme 2 Catalytic asymmetric intramolecular cyclopropanation
of a-diazo-b-keto sulfones
Scheme 1 Catalytic asymmetric intramolecular cyclopropanation
of 2-diazo-3-oxo-6-heptenoic acid esters
During these studies, we felt that potentiality of the cata-
lytic asymmetric IMCP of a-diazo-b-keto ester 1 would
be high for the enantioselective synthesis of chiral mole-
cules because a-diazo-b-keto ester 1 is easily prepared via
alkylation of acetoacetic acid ester. In addition, the data
on the catalytic asymmetric IMCP of a-diazo-b-keto sul-
fones have been accumulated, suggesting the possibility
of developing the catalytic asymmetric IMCP of a-diazo-
b-keto esters. Consequently, we were encouraged to re-
examine the catalytic asymmetric IMCP of a-diazo-b-
keto esters, and we herein report the results of our studies
on the catalytic asymmetric IMCP of 2-diazo-3-oxo-6-
heptenoic acid esters.
Consequently, 2 has been used as a starting material for
natural product synthesis in a racemic form2 as well as in
an optically active form,3 and the chiral 2 has been pre-
pared mostly via the diastereoselective intramolecular
cyclopropanation of the corresponding a-diazo-b-keto
ester 1 incorporating a chiral auxiliary as the ester.3,4
Needless to say, a reaction providing 2 with high enantio-
selectivity is favorable regarding efficiency, so that some
excellent enantioselectivities have been reported for the
catalytic asymmetric intramolecular cyclopropanation
(IMCP) of diazomethyl ketones,1,5 a-diazo acetates,1 and
a-diazo acetamidates.1,5 Nonetheless, as reported earlier
by some research groups5a,6 and described shortly in our
previous report,7a enantioselectivity of the catalytic asym-
We found that enantioselectivity in the catalytic asymmet-
ric IMCP of a-diazo-b-keto sulfone 4 greatly depended on
the structure of the aryl sulfone;7 that is, the steric bulk of
the aryl sulfonyl group was a major factor in discriminat-
ing the enantiofacial selectivity of the carbene center of
the intermediate.
SYNLETT 2007, No. 4, pp 0579–0582
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1.
0
3.
2
0
0
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Advanced online publication: 21.02.2007
DOI: 10.1055/s-2007-967964; Art ID: U13506ST
© Georg Thieme Verlag Stuttgart · New York

580
H. Takeda et al.
LETTER
Consequently, we prepared a-diazo-b-keto esters incor- (35% ee, entry 4). These results in entries 1–4 were differ-
porating a bulky ester moiety according to the methods ent from those of the catalytic asymmetric IMCP of a-di-
shown in Schemes 3 and 4. 1-Methyl-1-phenylethyl ester azo-b-keto sulfone 4 because ligand 3d, and sometimes
7, 2,4,6-trimethylphenyl ester 9, and 2,6-di-tert-butyl-4- ligand 3c, gave the highest ee in the reaction of 4.
methylphenyl ester 10 were selected for this study. The
ester 7 was prepared via the transesterification of 6 with
1-methyl-1-phenylethyl alcohol (93%), followed by ally-
lation (83%) and diazotransfer reaction to provide 7
We next examined the catalytic asymmetric IMCP reac-
tion of 7 incorporating a more bulky 1-methyl-1-phenyl-
ethyl ester. The reaction by use of ligand 3a provided the
product with 48% ee (entry 5), which was lower than the
(93%). More bulky 2,4,6-timethylphenol and 2,6-di-tert-
ee in entry 1. This result was rather surprising because we
butyl-4-methylphenol were surmised to hardly react with
expected that a substrate incorporating a bulky ester group
6 under the conditions shown in Scheme 3; hence 9 and 10
could show a higher enantioselectivity; however, in the
were prepared from 8. Thus 3-oxo-6-heptenoic acid,
reaction of 7 with ligand 3c, the product 12 was generated
which was prepared by saponification of 8, was reacted
with 50% ee (entry 7), which was higher than the ee in
entry 3. The same result was obtained in entries 4 (35%
with 2,4,6-trimethylphenol and 2,6-di-tert-butyl-4-meth-
ylphenol by use of DCC (Scheme 4), to afford the corre-
ee) and 8 (52% ee), supporting our expectation described
sponding 3-oxo-6-heptenoic acid esters, followed by the
above. In the reaction of 7 with ligand 3b, which was car-
ried out at 50 °C, the ee of the product was the lowest
(11% ee, entry 6) in all the reactions of 7.
reaction with TsN3 and TEA to provide 9 (62%, 3 steps)
and 10 (48%, 3 steps), respectively. Methyl ester 1a was
also prepared from 8 with TsN3 and Et3N (91%).
In analogy with the catalytic asymmetric IMCP of a-di-
azo-b-keto sulfone 4, the reaction of 9 incorporating a
1) HOCMe2Ph,
MeCO2Na, toluene
reflux, 93%
2,4,6-trimethylphenyl ester, which is also a bulky ester,
was examined. The reaction of 9 with ligand 3a provided
13 with 53% ee (entry 9), which was comparable to the ee
CO2Me
CO2CMe2Ph
2) NaH, n-BuLi, THF
allylbromide, 83%
3) TsN3, Et3N
O
N2
in entry 1, and the reaction with ligand 3c afforded 13 with
66% ee (entry 11). In the reaction with ligand 3d (entry
12), the enantiomeric excess of the product was slightly
higher (69% ee) than in entry 11. The reaction with ligand
3b provided 13 with lowest ee (–1% ee, entry 10) again in
this study.
O
6
7
MeCN, r.t., 93%
Scheme 3 Preparation of 7
1) 1 M KOH
MeOH, r.t.
2) DCC, R3OH
CH2Cl2, r.t.
Finally, the reaction of 10, incorporating the most bulky
2,6-di-tert-butyl-4-methylphenyl ester in this study, was
carried out. The reaction of 10 with ligand 3a provided the
product 14 with 92% yield and 77% ee (entry 13). The
reaction of 10 with ligand 3b afforded the product with
low ee (10% ee, entry 14), which was consistent with the
results in entries 2, 6, and 10. These results could arise
from the highly congested ligand 3b, that is, 3b would not
be suitable for the reactions of 1a, 7, 9, and 10. The reac-
tion of 10 with ligand 3c, possessing two ethyl groups at
the bisoxazoline junction, proceeded slowly at 50 °C and
required 45.5 hours to afford 14 in 56% yield (entry 15)
with highest ee (78% ee) in this study. The ee of the prod-
uct 14 obtained by use of ligand 3d (entry 16), which has
been usually a most effective ligand in the catalytic asym-
metric IMCP of a-diazo-b-keto sulfones, was slightly
lower (74% ee) than those in entries 13 and 15.
CO2R3
CO2Me
3) TsN3, TEA,
MeCN, 40 °C
N2
O
O
8
9
(R3 = 2,4,6-trimethylphenyl)
62% (3 steps)
10 (R3 = 2,6-di-tert-butyl-
4-methylphenyl)
48% (3 steps)
Scheme 4 Preparation of 9 and 10
The catalytic asymmetric IMCP reactions of 1a, 7, 9, and
10 were carried out in toluene with CuOTf (10 mol%) and
ligand 3a–d (15 mol%) usually at 50 °C and at more ele-
vated temperature when the reaction was sluggish. Results
of the IMCP reactions are summarized in Table 1.
The absolute configurations of 12, 13, and 149 were deter-
mined as shown in Scheme 5. Since the absolute configu-
ration of the product 11 in entry 1 was unambiguously
determined by comparing its sign of specific rotation to
that in the literature,3 11 was converted into 12, 13, and 14
by saponification and subsequent condensation with the
corresponding alcohols by DCC, determining the absolute
structure. The specific rotations of all the products in
Scheme 5 had a minus sign, which were the same as those
in Table 1. These results clearly determined the absolute
structures as shown in Table 1.
As previously reported, enantioselectivity of the catalytic
asymmetric IMCP reaction of methyl ester 1a with ligand
3a (entry 1) was not high (56% ee),7a but was better than
those of entries 2–4. Enantioselectivity of the reaction
with ligand 3b was very low (7% ee, entry 2). This was
interesting because the ligand 3b was expected to be most
effective for this enantioselective reaction, since its bulky
tert-butyl group on the oxazoline ring would effectively
discriminate the enantioface of the copper–carbene com-
plex generated in situ. In the case of 1a, ee of the product
11 obtained with ligand 3c (38% ee, entry 3) was lower
than that in entry 1, and ligand 3d did not increase the ee
Synlett 2007, No. 4, 579–582 © Thieme Stuttgart · New York

LETTER
Cyclopropanation of 2-Diazo-3-oxo-6-heptenoic Acid Esters
581
Table 1 Catalytic Asymmetric IMCP Reactions of 1a, 7, 9, and 108
R1 R1
H
CuOTf (10 mol%)
ligand (15 mol%)
O
O
CO2R3
CO2R3
N
N
toluene
1R
N2
O
R2
R2
O
1a (R3 = Me)
11 (R3 = Me)
3a: R1 = Me, R2 = i-Pr
3b: R1 = Me, R2 = t-Bu
3c: R1 = Et, R2 = i-Pr
3d: R1 = Bn, R2 = i-Pr
7 (R3 = 1-methyl-1-phenylethyl)
9 (R3 = 2,4,6-trimethylphenyl)
12 (R3 = 1-methyl-1-phenylethyl)
13 (R3 = 2,4,6-trimethylphenyl)
14 (R3 = 2,6-di-tert-butyl-4-methylphenyl)
10 (R3 = 2,6-di-tert-butyl-4-methylphenyl)
Entry
1
Substrate
Ligand
3a
Temp (°C)a
Time (h)a
14
Yield (%)b
ee (%)
Abs. Configne [a]DT (CHCl3)
[a]D24 –9.20 (c 0.80)
1a
1a
1a
1a
7
50
68
43
57
57
77
20
87
90
74
87
82
87
92
58
56
53
56c
7c
1R
1R
1R
1R
1R
1R
1R
1R
1R
1R
1R
1R
1R
1R
1R
1R
2
3b
3c
50, 80
50
16, 3
19
3
38c
35c
48d
11d
50d
52d
53d
–1d
66d
69d
77d
10d
78d
74d
4
3d
3a
50
56
5
50
1
6
7
3b
3c
50
16
7
7
50
1
8
7
3d
3a
50
7
[a]D26 –29.2 (c 0.50)
9
9
50
1.5
16
10
11
12
13
14
15
16
9
3b
3c
50
9
50
1.5
7
9
3d
3a
50
[a]D28 –10.9 (c 0.80)
[a]D28 –23.0 (c 0.45)
10
10
10
10
50
3.5
5, 24
45.5
27.5
3b
3c
50, 70
50
3d
50
a Reaction was carried out at the indicated temperatures for the indicated times, respectively.
b Isolated yields.
c Determined by 1H NMR using Eu(hfc)3.
d Determined by HPLC. For details, see ref. 9.
e Absolute configuration determined by comparison of optical rotation to the known literature value.
This sense of enantioselectivity is the same as that ob- In summary, the catalytic asymmetric IMCP of 2,6-di-
served in the catalytic asymmetric IMCP of a-diazo-b- tert-butyl-4-methylphenyl ester (10) afforded the product
keto sulfone 4, and would be well explained by the pro- 14 with high ee (up to 78% ee), indicating that a substrate
posed model7a similarly.
bearing a bulky ester group would show high enantio-
selectivity. To the best of our knowledge, this is the best
result in the catalytic IMCP of 2-diazo-3-oxo-6-heptenoic
acid esters, suggesting that the catalytic asymmetric
IMCP of a-diazo-b-keto esters would be potentially key
reactions for the enantioselective synthesis of natural
products as well as artificial molecules. Therefore, further
studies into the IMCP of other 2-diazo-3-oxo-6-heptenoic
acid derivatives possessing substituents in the alkene
moiety and a chiral menthyl ester of 2-diazo-3-oxo-6-hep-
tenoic acid are now under investigation.
H
12 28% (2 steps)
1) 1 M KOH
[α]D23 –30.1 (c 0.50, CHCl3)
13 11% (2 steps)
MeOH, r.t.
1R
[α]D24 –9.20 (c 0.80, CHCl3)
14 3% (2 steps)
[α]D26 –16.4 (c 0.45, CHCl3)
CO2Me
2) DCC, R3OH
O
DCE, reflux
11
56% ee
Scheme 5 Conversion of 11 into 12, 13, and 14
Synlett 2007, No. 4, 579–582 © Thieme Stuttgart · New York

582
H. Takeda et al.
LETTER
(6) (a) For the attempted catalytic asymmetric IMCP of 2-diazo-
3-oxo-6-heptenoic acid esters, see ref. 5a. (b) He, M.;
Tanimori, S.; Ohira, S.; Nakayama, M. Tetrahedron 1997,
53, 13307. (c) Mühler, P.; Boléa, C. Helv. Chim. Acta 2001,
84, 1093.
Acknowledgment
This work was financially supported in part by a Waseda University
Grant for Special Research Projects and a Grant-in-Aid for Scienti-
fic Research on Priority Areas (Creation of Biologically Functional
Molecules; No. 17035082) from the Ministry of Education, Culture,
Sports, Science, and Technology (MEXT), Japan. We are also
indebted to 21COE ‘Practical Nano-Chemistry.’ The fellowship
for young scientists to M.H. from JSPS is also gratefully acknow-
ledged.
(7) (a) Honma, M.; Sawada, T.; Fujisawa, Y.; Utsugi, M.;
Watanabe, H.; Umino, A.; Matsumura, T.; Hagihara, T.;
Takano, M.; Nakada, M. J. Am. Chem. Soc. 2003, 125,
2860. (b) Honma, M.; Nakada, M. Tetrahedron Lett. 2003,
44, 9007. (c) Sawada, T.; Nakada, M. Adv. Synth. Catal.
2005, 347, 1527. (d) Takeda, H.; Nakada, M. Tetrahedron:
Asymmetry 2006, 17, 2896. Total synthesis of natural
products utilizing the catalytic asymmetric IMCP of a-
diazo-b-keto sulfones: (e) (–)-Allocyathin B2: Takano, M.;
Umino, A.; Nakada, M. Org. Lett. 2004, 6. (f) (–)-
Malyngolide: Miyamoto, H.; Iwamoto, M.; Nakada, M.
Heterocycles 2005, 66, 61. (g) (–)-Methyl jasmonate:
Takeda, H.; Watanabe, H.; Nakada, M. Tetrahedron 2006,
62, 8054.
References and Notes
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Tetrahedron 1998, 54, 7919. (e) Doyle, M. P. Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; YHC
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(8) General Procedure.
A toluene azeotroped [CuOTf]2·toluene (7.7 mg, 0.0148
mmol, 10 mol% as CuOTf) was placed in a dried flask under
Ar atmosphere. To this flask was added toluene (4 mL) and
then a solution of toluene azeotroped ligand 3c (13.1 mg,
0.0445 mmol, 15 mol%) in toluene (2 × 0.5 mL) via a
cannula. The mixture was stirred at r.t. for 0.5 h and then a
solution of toluene azeotroped 2,6-di-tert-butyl-4-methyl-
phenyl 2-diazo-3-oxo-6-heptenoate (10, 110.0 mg, 0.297
mmol) in toluene (2 × 0.5 mL) was added to the light blue
solution via a cannula. The reaction mixture was stirred at 50
°C for 45.5 h, quenched with a mixture of sat. aq NH4Cl
solution (1 mL) and NH4OH aq solution (3 mL), and
extracted with Et2O (2 × 2 mL). The combined organic layer
was washed with brine (2 mL), dried over Na2SO4, and eva-
porated. The residue was purified by flash chromatography
(hexane–EtOAc, 10:1) to afford 2-oxobicyclo[3.1.0]hexane-
1-carboxylic acid 2,6-di-tert-butyl-4-methylphenyl ester
(14, 57.0 mg, 56%, 78% ee) as a white solid. The absolute
configuration was determined as described in the text. The
ee was determined as described in ref. 9: [a]D28 –23.0 (c 0.45,
CHCl3, 78% ee). IR (KBr): nmax = 2984, 1761, 1727, 1324,
1264, 1189, 1139, 1076, 1033, 781, 714 cm–1. 1H NMR (400
MHz, CDCl3): d = 7.09 (s, 1 H), 7.08 (8) (s, 1 H), 2.76 (ddd,
J = 8.1, 5.4, 5.4 Hz, 1 H), 2.38–2.06 (m, 9 H including d =
2.31, s, 3 H), 1.37 (s, 9 H), 1.30 (s, 9 H). 13C NMR (100
MHz, CDCl3): d = 205.3, 169.2, 145.7, 142.1, 141.7, 134.5,
126.9, 38.2, 35.3, 35.1, 34.2, 34.0, 31.4 (4), 31.4, 23.3, 21.5,
20.8. HRMS–FAB: m/z calcd for C22H30O3 + H: 343.2273;
found: 343.2285.
(c) Nemoto, H.; Wu, X. M.; Kurobei, H.; Minemura, K.;
Ihara, M.; Fukumoto, K.; Kametani, T. J. Chem. Soc., Perkin
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H.; Fukumoto, K.; Kametani, T. J. Chem. Soc., Perkin
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Venkatesan, A. M.; Augelli-Szafran, C. E.; Yasmin, A.
Tetrahedron Lett. 1991, 32, 2339. (g) Moriarty, R. M.; Kim,
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S.; Tsubota, M.; He, M.; Nakayama, M. Synth. Commun.
1997, 27, 2371.
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(5) (a) Dauben, W. G.; Hendricks, R. T.; Luzzio, M. J.; Ng, H.
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(9) Compound 12: DAICEL CHIRALCEL OD-H ∅ 0.46 cm ×
25 cm; hexane–2-PrOH = 9:1; flow rate = 0.5 mL/min); tR =
15.0 min for ent-12, 18.2 min for 12.
Compound 13: DAICEL CHIRALPAK AS-H ∅ 0.46 cm ×
25 cm; hexane–2-PrOH = 4:1; flow rate = 0.5 mL/min); tR =
25.8 min for ent-13, 28.8 min for 13.
Compound 14 was converted into its oxime, which was
benzoylated and subjected to HPLC analysis: DAICEL
CHIRALCEL OD-H ∅ 0.46 cm × 25 cm; hexane–2-PrOH =
14:1; flow rate = 0.2 mL/min); tR: 25.8 min for ent-14, 28.8
min for 14.
Synlett 2007, No. 4, 579–582 © Thieme Stuttgart · New York