Enantioselective intramolecular cyclopropanation of α-diazo-β- keto sulfones: Asymmetric synthesis of bicyclo[4.1.0]heptanes and tricyclo[4.4.0.0]decenes

Article abstract of DOI:10.1016/j.tetlet.2003.09.215

Catalytic asymmetric synthesis of some new chiral building blocks useful for natural product synthesis is described. The intramolecular cyclopropanation (IMCP) reaction of α-diazo-β-keto sulfones affording bicyclo[4.1.0]heptanes such as 9a-d is found to p

Full text of DOI:10.1016/j.tetlet.2003.09.215

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9007–9011
Enantioselective intramolecular cyclopropanation of
a-diazo-b-keto sulfones: asymmetric synthesis of
bicyclo[4.1.0]heptanes and tricyclo[4.4.0.0]decenes
Masahiro Honma and Masahisa Nakada*
Department of Chemistry, School of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku,
Tokyo 169-8555, Japan
Received 25 August 2003; revised 24 September 2003; accepted 30 September 2003
Abstract—Catalytic asymmetric synthesis of some new chiral building blocks useful for natural product synthesis is described. The
intramolecular cyclopropanation (IMCP) reaction of a-diazo-b-keto sulfones affording bicyclo[4.1.0]heptanes such as 9a–d is
found to proceed with high enantioselectivity (93–98% ee). The yield is moderate due to the competing intramolecular C–H
insertion reaction. As intramolecular C–H insertion reaction is not observed in the reaction of the substrates possessing a
quaternary carbon at the allylic position, the reactions of 19a and 19b proceed with high enantioselectivity (95% ee) and yield. It
was also found that the substrates possessing an ether group, such as 19a and 19b, could be used in this enantioselective IMCP
reaction.
© 2003 Elsevier Ltd. All rights reserved.
The preparation of new chiral building blocks is impor-
tant for the synthesis of many bioactive natural prod-
ucts because such new compounds enable easier and
more efficient natural product synthesis. We have
recently reported a highly enantioselective intramolecu-
lar cyclopropanation (IMCP) reaction of a-diazo-b-
keto sulfones (Scheme 1).1 This catalytic enantio-
selective reaction easily affords products, bicyclo-
[3.1.0]hexanes 3, tricyclo[4.3.0.0]nonenes 6, and tri-
cyclo[4.4.0.0]decenes 7. Since these products are highly
crystalline and purified easily by a single recrystalliza-
tion to be enantiomerically pure compounds, this cata-
lytic enantioselective IMCP reaction would be
advantageous for the preparation of new chiral building
blocks.
building blocks for the synthesis of many natural prod-
ucts, asymmetric synthesis of such compounds is very
important. Accordingly, we decided to carry out studies
on the enantioselective IMCP reactions to prepare chi-
ral building blocks possessing six-membered-ring sys-
tems, and herein we report enantioselective preparation
of new chiral bicyclo[4.1.0]hexanes and tricyclo[4.4.0.0]-
decenes.
We have reported extensive studies on enantioselective
IMCP reactions of the substrates 2 and 4 to generate
cyclopentanone derivatives.1 However, enantioselective
IMCP reactions to generate cyclohexanone derivatives
other than the reaction of 5 have not been examined
(Scheme 1). Since cyclohexanone derivatives are useful
Keywords: asymmetric synthesis; cyclopropanation; enantioselection;
intramolecular reaction.
* Corresponding author. Tel.: +813-5286-3240; fax: +813-5286-3240;
e-mail: mnakada@waseda.jp
Scheme 1. Enantioselective intramolecular cyclopropanation
(IMCP) of a-diazo-b-keto sulfones.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.215

9008
M. Honma, M. Nakada / Tetrahedron Letters 44 (2003) 9007–9011
First, the most simple substrate, 8a, was prepared,2
and its enantioselective IMCP reaction was investi-
gated. The reaction of 8a was carried out in toluene
with the asymmetric catalyst prepared in situ by
(CuOTf)2–C6H6 and bisoxazoline ligand 1a.
was also obtained as an inseparable mixture with 10a
(10a:11a=20:1). The mechanism for the formation of
11a has not yet been clarified.
To improve the yield of 9a, the reaction condition for
8a was examined. First, other copper catalysts, that is,
(CuOTf)2–toluene (entry 2) and CuSbF6 (entry 3),
were examined. However, neither the enantioselectivity
nor yield increased, and by-products 10a and 11a
formed again.5 Then, the reaction of 8a was examined
in other solvents. THF, CH2Cl2, (CH2Cl)2, and ben-
zene (entry 4, 5, 6, 7) were found to be applicable for
this reaction, but the yield was somewhat lowered in
all cases.6
The reaction of 8a with 1a completed at room temper-
ature within 2 h to provide 9a with high enantioselec-
tivity (92% ee,3 58%, entry 1, Table 1). However, some
by-products formed. The structure of the major by-
product was elucidated as 10a by 1H, 13C NMR,
HRMS, and IR.4 Thus, the reaction of 8a accompa-
nied CꢀH insertion reaction, forming 10a. Another
by-product, 11a, which is a denitrogen product of 8a,
Table 1. Enantioselective IMCP reaction of a-diazo-b-keto sulfones 8a–d
Entry
Product
Ligand
Solvent
Temp. (°C)a
Time (h)a
Ee (%)b
9
Yield (%)c
10+11 (10/11)d
9
1
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9b
9b
9b
9b
9b
9c
9c
9c
9c
9c
9d
9d
9d
9d
9d
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
None
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
1a
1b
1c
Toluene
Toluene
Toluene
THF
rt
rt
rt, 50
rt
rt
rt
rt
rt
rt
rt
rt
rt, 50
rt
rt
rt
rt
rt
50
50
50
50
50
50
50
50
50
50
2
1.5
2, 96
2
12
72
2
92 (1R)e
88 (1R)e
86 (1R)e
92 (1R)e
92 (1R)e
93 (1R)e
91 (1R)e
91 (1R)e
88 (1R)e
89 (1R)e
0
58
43
50
33
52
44
50
53
28
41
34
26
44
42
35
62
31
36
16
23
31
33
41
32
26
43
32
19 (20/1)
8 (8/1)
26 (>99/1)
9 (2/1)
11 (11/1)
6 (3/1)
13 (20/1)
16 (9/1)
14 (30/1)
14 (14/1)
5 (3/1)
2f
3g
4
5
6
7
CH2Cl2
(CH2Cl)2
Benzene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
8
9
4
17
14
11
3, 5
17
12
7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
0
9 (1/1)
87 (1R)e
68 (1R)e
84 (1R)e
93 (1R)e
0
14 (8/1)
14 (14/1)
10 (8/1)
15 (18/1)
4 (2/1)
19 (4/1)
14 (2/1)
8 (4/1)
17 (4/1)
14 (1/1)
12 (4/1)
29 (2/1)
10 (3/1)
15 (3/1)
26 (1/1)
2
3
1.5
3.5
2
16
6
1.5
1.5
3.5
4
90 (1R)e
67 (1R)e
94 (1R)e
98 (1R)e
0
90 (1R)e
84 (1R)e
94 (1R)e
98 (1R)e
0
1d
1e
3
a Reaction was carried out at the indicated temperatures for the indicated times, respectively.
b Ee determined by HPLC. For HPLC conditions, see Ref. 3.
c Isolated yields.
d Ratios determined by 1H NMR.
e Absolute configuration of 9a–9d was determined by X-ray crystallographic analysis.
f (CuOTf)2·toluene was used.
g CuSbF6 was used.

M. Honma, M. Nakada / Tetrahedron Letters 44 (2003) 9007–9011
9009
The reactions of 8a with other ligands, 1b, 1c, and 1d
were examined. As shown in entries 8–10, enantioselec-
tivity and yield was not improved in all cases. Though
ligand 1d was the most effective for the enantioselective
IMCP reactions of 2 and 4 (Scheme 1),1 ligand 1a was
found to be the best in the reaction of 8a. The reaction
of 8a with the achiral ligand 1e was carried out to
prepare the racemic standard sample for HPLC analy-
sis (entry 11), because the reaction of 8a with no ligand
was slow and required heating (entry 12). As a result,
formation of 10a and 11a decreased, but the yield of 9a
did not increase.7 It was found that by-products (10
and 11) always form (entries 1–12); therefore, the for-
mation of 10 and 11 is not related to the type of copper
salt or solvent, or the structure of the ligand.
Figure 1. Proposed model A.
and 20b by this catalytic enantioselective IMCP reac-
tion.10 The preparation of 19a is shown in Scheme 2.
The known alcohol 1211 was converted to TBS ether 13
(97%), followed by debenzylation to afford 14 (94%).
Dess–Martin oxidation12 of 14 gave 15 in 90% yield,
and the following Horner–Wadsworth–Emmons reac-
tion generated 16 (99%). Alkene 16 was reduced by
magnesium (88%), and the resultant 17 was reacted
with methylsulfone to afford 18 (92%). Keto sulfone 18
was easily converted to diazo compound 19a by TsN3
and triethylamine (90%). The same operations
described above provided 19b as well.
Examined next was the reaction of 8b (entries 13–17).2
The reaction of 8b with 1d afforded 9b highly enan-
tioselectively (93% ee, 62%, entry 16)a. This result dif-
fers from that given in 8a. Thus, ligand 1d was best,
showing relationships between the ligand and the enan-
tioselectivity similar to those seen in the reactions of 2
and 4.1
In the reactions of 2 and 4, the mesitylsulfones had
showed higher enantioselectivity compared with the
corresponding phenylsulfones.1 Therefore, the enan-
tioselective IMCP reactions of mesitylsulfones 8c2 and
8d2 were investigated next. The products, 9c and 9d,
were obtained with high enantioselectivity (98% ee,3
entries 21 and 26) with ligand 1d. The same trend in
increment of enantioselectivity in the order of 1d, 1c,
1a, and 1b, that had been observed in the reaction of 2
and 4, was found (entries 18–21, 23–26). Unfortunately,
the yields of 9c and 9d were low, and formation of
by-products, 10c, 10d, 11c, and 11d, could not be
avoided.
As shown in Table 2, the IMCP reaction of 19a with
ligand 1a proceeded smoothly at room temperature,
and 20a was obtained with high enantioselectivity (95%
ee, 89%, entry 1). The reaction of 19a with ligand 1d
resulted in slightly reduced enantioselectivity (93% ee,
86% yield, entry 2). The reaction of 19b with ligand 1a
also formed 20b with high enantioselectivity (95% ee),
but the yield was somewhat lowered (73%, entry 3). In
As products 9a–d were highly crystalline, the absolute
structure of each was determined successfully by X-ray
crystallographic analysis. These results and the [h]D
values of the products3 indicate that all products in
Table 1 possess 1R configuration, and the outcome of
the enantioselectivity of 9 is well explained by model A
(Fig. 1). Thus, the cyclopropanation reactions are
thought to occur preferentially at the re-face (defined
by the CuꢁCꢀC arrangement) of the chiral catalyst–car-
bene complexes.
We also investigated other enantioselective IMCP reac-
tions to prepare new tricyclic cyclopropanes, that is, the
reactions of the substrates providing new tricy-
clo[4.4.0.0]decenes. We are interested in the IMCP reac-
tions of 19a and 19b, because the corresponding
products 20a and 20b would be good chiral building
blocks for the synthesis of bioactive polycyclic natural
products.8 However, an ether group in the substrate
could react with the carbene complex to form oxonium
ylide, reducing the yield of the desired product.9 There-
fore, we prepared phenylsulfones 19a and 19b, possess-
ing a bulky TBS ether and a less bulky benzyl ether,
respectively, to examine the possibility of forming 20a
Scheme 2. Reagents and conditions: (a) TBSCl, imidazole,
DMAP, DMF, CH2Cl2, rt, 10 h, 97%; (b) Li, liq. NH3, THF,
−20°C, 20 min, 94%; (c) Dess–Martin reagent, NaHCO3,
CH2Cl2, rt, 2 h, 90%; (d) (EtO)2P(O)CH2CO2Et, t-BuOK,
THF, −78°C to 0°C, 99%; (e) Mg, MeOH, 0°C, 88%; (f)
CH3SO2Ph, n-BuLi, THF, 0°C, 92%; (g) TsN3, TEA,
CH3CN, 0°C to rt, 6 h, 90%.

9010
M. Honma, M. Nakada / Tetrahedron Letters 44 (2003) 9007–9011
Table 2. Enantioselective IMCP reaction of a-diazo-b-keto sulfones 19a and 19b
Entry
Product
Ligand
Time (h)
Ee (%)a
Yield (%)b
1
2
3
4
20a
20a
20b
20b
1a
1d
1a
1d
0.5
3
1
95 (7R)c
93 (7R)c
95 (7R)d
89 (7R)d
89
86
73
31
1
a Ee determined by HPLC. For HPLC conditions, see Ref. 13.
b Isolated yields.
c Absolute configuration determined by X-ray crystallographic analysis.
d Absolute configuration determined by the comparison of optical rotation.
the reaction of 19b, the result obtained with 1a (95% ee,
73%, entry 3) was superior to that obtained with 1d
(89% ee, 31%, entry 4). This reduced yield of 20b may
be explained by the oxonium ylide formation;14 how-
ever, no product corresponding to the oxonium ylide
formation was isolated.
X-Ray crystallographic analysis of the crystalline p-
bromobenzoate15 derived from 20a was successfully
carried out (Fig. 2). This analysis unambiguously eluci-
dated the absolute structure of 20a. The absolute struc-
ture of 20b was determined as shown in Table 2
through comparison of the [h]D value of 20b with that
of the same compound derived from 20a.16 That is, 20a
was desilylated with TBAF (quant.), and the resultant
alcohol was treated with benzyl trichloroacetimidate
and TMSOTf to afford 20b (52%).
Figure 2. X-Ray crystal structure of the p-bromobenzoate
derived from 20a.
Based on the structure determination described above,
the C-7 configuration of both compounds, 20a and 20b,
is confirmed as R; hence, the outcome of the enantio-
selectivity of 20a and 20b is found to be well explained
by model A% shown in Figure 3. In the reactions of 20a
and 20b, the steric repulsion between the 1,4-cyclohexa-
diene moiety and the isopropyl group of the ligand is so
large that the less bulky ligand 1a and phenyl sulfone
would be effective enough to achieve high enantioselec-
tivity.
Figure 3. Proposed model A%.
tion. Work on natural product synthesis using the new
enantiomerically pure compounds described herein is
now in progress, and the details will be reported in due
course.
In summary, highly enantioselective preparation of
some new chiral building blocks has been developed.
The enantioselective IMCP reaction of a-diazo-b-keto
sulfones affording bicyclo[4.1.0]heptanes such as 9a–d is
found to proceed with high enantioselectivity (93–98%
ee) and moderate yield. As CꢀH insertion reaction is
not observed in the reaction of the substrates possessing
a quaternary carbon at the allylic position, the reac-
tions of 19a and 19b proceed with high enantioselectiv-
ity (95% ee) and yield. It was also found that the
substrates possessing an ether group, such as 19a and
19b, could be used in this enantioselective IMCP reac-
Acknowledgements
We thank Material Characterization Central Labora-
tory, Waseda University, for technical support of the
X-ray crystallographic analysis. This work was finan-
cially supported in part by 21COE ‘Practical Nano-
Chemistry’.

M. Honma, M. Nakada / Tetrahedron Letters 44 (2003) 9007–9011
9011
References
1998, 98, 911–935; (c) Padwa, A.; Krumpe, K. E. Tetra-
hedron 1992, 48, 5385–5453; (d) Padwa, A.; Hornbuckle,
S. F. Chem. Rev. 1991, 91, 263–309; (e) Adams, J.; Spero,
D. M. Tetrahedron 1991, 47, 1765–1808; (f) Doyle, M. P.
Chem. Rev. 1986, 86, 919–939.
1. 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,
2860–2861.
10. Since the reaction of 7 was sluggish as previously
reported, the IMCP reaction of the mesityl sulfones cor-
responding to 19a and 19b was not examined.
11. Zutterman, F.; Mungheer, D. W. R.; Clercq, P. D.;
Vanderwalle, M. Tetrahedron 1979, 35, 2389–2396.
12. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1991, 113,
7277–7287; (b) Frigerio, M.; Santagostino, M.; Sputore,
S. J. Org. Chem. 1999, 64, 4537–4538.
13. Ee was determined by HPLC (254 nm); 20a: Daicel
Chiral Cell OD-H 0.46 cm f×25 cm; hexane/iso-
propanol=9/1; flow rate=0.5 mL/min; retention time:
12.2 min for ent-20a, 15.2 min for 20a. 20b: Daicel Chiral
Cell OD-H 0.46 cm f×25 cm; hexane/isopropanol=9/1;
flow rate=0.5 mL/min; retention time: 23.1 min for
ent-20b, 25.0 min for 20b.
2. For the preparation of sulfones, see Ref. 1.
3. Ee was determined by HPLC (254 nm); 9a: [h]2D1 −97.4 (c
1.27, CHCl3, 99% ee); Daicel Chiral Cell OD-H 0.46 cm
f×25 cm; hexane/isopropanol=3/1; flow rate=0.5 mL/
min; retention time: 22.8 min for ent-9a, 25.0 min for 9a.
9b: [h]2D3 −139.8 (c 0.98, CHCl3, >99% ee); Daicel Chiral
Cell AS-H 0.46 cm f×25 cm; hexane/isopropanol=3/1;
flow rate=0.5 mL/min; retention time: 38.4 min for 9b,
48.9 min for ent-9b. 9c: [h]2D8 +30.3 (c 1.11, CHCl3,
>99.5% ee); Daicel Chiral Cell AS-H 0.46 cm f×25 cm;
hexane/isopropanol=3/1; flow rate=0.5 mL/min; reten-
tion time: 22.5 min for 9c, 25.9 min for ent-9c. 9d: [h]D22
−191.6 (c 1.03, CHCl3, >99.5% ee); Daicel Chiral Cell
AS-H 0.46 cm f×25 cm; hexane/isopropanol=3/1; flow
rate=0.5 mL/min; retention time: 13.1 min for ent-9d,
16.2 min for 9d.
14. Structure of some by-products was not fully character-
ized.
4. 10a: IR(KBr): 2932, 1748, 1448, 1308, 1150, 1080, 824
15. TBS ether 20a was desilylated by TBAF (quant.), and the
resultant alcohol was converted with p-bromobenzoyl
chloride and pyridine to the crystalline p-bromobenzoate
(93%).
cm−1 1H NMR (400 MHz, CDCl3): l=7.88 (d, J=7.8
;
Hz, 2H), 7.68 (t, J=7.3 Hz, 1H), 7.58 (dd, J=7.8, 7.3
Hz, 2H), 5.88 (ddd, J=17.1, 10.5, 6.3 Hz, 1H), 5.13 (d,
J=17.1 Hz, 1H), 5.11 (d, J=10.5 Hz, 1H), 3.59–3.54 (m,
2H), 2.51–2.32 (m, 3H), 1.82–1.71 (m, 1H); 13C NMR
(100 MHz, CDCl3): l=205.8, 138.0, 137.7, 134.1, 129.0,
129.0, 116.1, 73.9, 41.3, 38.4, 26.3; HRMS (FAB): m/z
calcd for C13H14O3SH+ 251.0742, found 251.0770. 10a–d
were obtained as a single diastereomer. The relative
configuration of 10a–d is surmised to be trans on the
basis of their thermodynamic stability. Ee of 10a–d was
not determined.
16. 20a: [h]2D5 +80.9 (c 0.11, CHCl3, 96% ee); IR(KBr): 2956,
2932, 2896, 2860, 1708, 1448, 1310, 1286, 1258, 1180,
1152, 1118, 1086, 840, 778, 756 cm−1 1H NMR (400
;
MHz, CDCl3): l=7.85 (d, J=8.1 Hz, 2H), 7.64 (t, J=7.3
Hz, 1H), 7.53 (dd, J=8.1, 7.3 Hz, 2H), 5.63 (ddd, J=
10.5, 3.4, 2.4 Hz, 1H), 5.24 (d, J=10.5 Hz, 1H), 3.64 (d,
J=9.5 Hz, 1H), 3.62 (d, J=9.5 Hz, 1H), 2.65 (d, J=9.8
Hz, 1H), 2.50–2.35 (m, 1H), 2.25–2.10 (m, 3H), 2.07–1.95
(m, 2H), 1.60–1.50 (m, 1H), 0.93 (s, 9H), 0.09 (s, 6H); 13C
NMR (100 MHz, CDCl3): l=201.3, 139.4, 133.6, 128.8,
128.7, 128.3, 126.3, 69.9, 48.4, 36.2, 35.0, 31.3, 27.0, 25.9,
22.4, 19.8, 18.4, −5.3; HRMS (FAB): m/z calcd for
5. Also examined catalyst was CuI, but many unidentified
products formed.
6. The product was obtained as a complex mixture when
Et2O, DMF, or DMSO was used as the solvent.
7. Other examples using achiral ligand 1e (entries 17, 22 and
27) show no improvement of the by-product formation
and yield.
C23H32O4SSiH+ 433.1869, found 433.1869. 20b: [h]3D7
+
130.7 (c 0.64, CHCl3, 95% ee); IR(KBr): 2864, 1706,
1
1448, 1310, 1288, 1182, 1152, 1086 cm−1; H NMR (400
MHz, CDCl3): l=7.83 (d, J=8.3 Hz, 2H), 7.62 (t, J=7.3
Hz, 1H), 7.48 (dd, J=8.3, 7.3 Hz, 2H), 7.45–7.30 (m,
5H), 5.68 (ddd, J=10.3, 3.4, 2.4 Hz, 1H), 5.30 (d, J=10.3
Hz, 1H), 4.62 (d, J=12.2 Hz, 1H), 4.58 (d, J=12.2 Hz,
1H), 3.53 (d, J=8.8 Hz, 1H), 3.50 (d, J=8.8 Hz, 1H),
2.75 (d, J=9.8 Hz, 1H), 2.52–2.44 (m, 1H), 2.26 (dd,
J=8.3, 7.3 Hz, 1H), 2.17–2.12 (m, 2H), 2.06–1.95 (m,
2H), 1.60–1.54 (m, 1H); 13C NMR (100 MHz, CDCl3):
l=201.1, 139.3, 137.9, 133.6, 128.8, 128.7, 128.4, 128.2,
127.7, 127.6, 126.5, 77.0, 73.5, 48.6, 36.0, 33.9, 31.8, 27.6,
22.7, 19.7; HRMS (FAB): m/z calcd for C24H24O4SH+
409.1473, found 409.1456. 20b (from 20a): [h]3D4 +130.7 (c
0.77, CHCl3, 95% ee).
8. These chiral building blocks would be useful for the total
synthesis of the natural products possessing a hydroxy
group at C-19 such as oubain, which has been used for
more than two centuries in the clinical treatment of
congestive heart failure, and bufadienolides, which
exhibit potent antitumor activity. For the structure of
oubain, see: Arnaud, M. Compt. Rend. Acad. 1888, 107,
1011. For the structure of recently isolated bufadienolides
possessing a formyl group at C-19, see: Watanabe, K.;
Mimaki, Y.; Sakagami, H.; Sashida, Y. J. Nat. Prod.
2003, 66, 236–241.
9. Reviews: (a) Padwa, A. J. Organomet. Chem. 2001, 617–
618, 3–16.; (b) Doyle, M. P.; Forbes, D. C. Chem. Rev.