A novel synthesis of bicyclo[3.3.0]octane ring system via a desymmetric C-H insertion reaction

Article abstract of DOI:10.1055/s-2006-941603

An optically active bicyclo[3.3.0]octane ring was synthesized by an intramolecular C-H insertion reaction. Upon treatment with a catalytic amount of Rh₂(S-DOSP)₄, a chiral-auxiliary-containing diazoester underwent a C-H insertion reaction to give the desired bicyclo[3.3.0]octane system. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-941603

LETTER
1583
A Novel Synthesis of Bicyclo[3.3.0]octane Ring System via a Desymmetric
C–H Insertion Reaction
N
ovel Synthesis
o
of Bicyclo[
s
3.3.0]octa
h
ne Ring Syst
i
em yuki Kan,*a Tohru Inoue,b Yuichiro Kawamoto,b Mitsuhiro Yonehara,b Tohru Fukuyama*b
a
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka-shi 422-8526, Japan
Fax +81(54)2645747; E-mail: kant@u-shizuoka-ken.ac.jp
b
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58028694; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Received 1 March 2006
OBn
Abstract: An optically active bicyclo[3.3.0]octane ring was syn-
thesized by an intramolecular C–H insertion reaction. Upon treat-
ment with a catalytic amount of Rh2(S-DOSP)4, a chiral-auxiliary-
containing diazoester underwent a C–H insertion reaction to give
the desired bicyclo[3.3.0]octane system.
OBn
OR
H
cat. Rh2(S-DOSP)4 (2)
O
N2
O
(84%, 86% de)
Key words: bicyclo[3.3.0]octane ring, C–H insertion, piperidinyl
mandelamide, chiral auxiliary, Rh2(S-DOSP)4
OR
H
O
O Rh
O
O
2 =
N
Me
O Rh
4
Br
Br
SO2Ar
N
R =
Recently, Rh carbenoid mediated C–H insertion reactions
have attracted much attention because the reactions
proceed under mild conditions and are compatible with
numerous functional groups.1 Although many chiral
rhodium catalysts have been investigated,2 there are few
versatile methods, which are applicable to a large-scale
synthesis. During the course of our total synthesis of (–)-
ephedradine A, we found that treating aryldiazoester 1,
1
3
O
(Ar = p-C12H25C6H4)
O
O
H
OR
OR
O
H
cat. Rh*
N2
4
5
3
which has a chiral auxiliary, with Rh2(S-DOSP)4 catalyst
Scheme 1 C–H insertion reaction for constructing dihydrobenzo-
(2) causes a C–H insertion reaction that gives 3 in high
yield and diastereoselectivity (Scheme 1).4 This reaction
is applicable to large-scale preparations (50 g scale) since
this reaction utilizes an inexpensive chiral auxiliary and
proceeds at room temperature.
furan and cyclopentanone
OMs
CN
CO2H
1) LiAlH4
THF
DIBAL
NaCN
CH2Cl2
–78 °C
68%
DMSO
70 °C
2) MsCl, Et3N
CH2Cl2
Inspired by this finding, we investigated similar intramo-
lecular C–H insertions of the carbenoid generated from 4,
which should provide optically active bicyclo[3.3.0]oc-
tane ring 5 (Scheme 1).5 Herein we report a novel synthe-
sis of bicyclo[3.3.0]octane ring by a desymmetric C–H
insertion reaction of diazoester 4.
7
8
6
83% (3 steps)
O
R2
CHO
CO2Et
N
N2
CO2Et
HO
11
cat. SnCl2
CH2Cl2
DMAP
O
toluene, reflux
As shown in Scheme 2, C–H insertion substrates 4a and
4b were readily prepared in a seven-step sequence from 3-
cyclopetenecaboxylic acid 6.6 Reduction of 6 with lithium
aluminum hydride, mesylation, and subsequent displace-
ment by NaCN provided nitrile 8. After DIBAL-H reduc-
tion of 8, conversion to b-ketoester 10 from aldehyde 9
was performed using Roskamp’s procedure.7 After incor-
10
9
O
O
R2
N
O
AcHN
SO2N3
O
N2
DBU
MeCN, 0 °C
4a: R2 = Me 40% (3 steps)
4b: R2 = Ph 54% (3 steps)
porating chiral alcohol 11a or 11b8 into the ester 10,9,10
a
Scheme 2 Preparation of C–H insertion precursor 4a and 4b
diazo transfer reaction was conducted by treatment with
p-acetamidobenzenesulfonyl azide and DBU to provide
C–H insertion precursor 4a or 4b, respectively.
With the requisite diazoesters 4a and 4b in hand, the C–H
insertion reaction with a chiral rhodium catalyst was in-
vestigated (Table 1).10 Initially, the insertion reaction of
4a with 10 mol% of Rh2(S-DOSP)4 (2) was tested accord-
ing to the protocol for the synthesis of ephedradine A.3
The reaction proceeded smoothly to afford 5a in 94%
yield and a 43% de.11 C–H insertion product 5a (entries 1
and 2) possessed the same configuration 3S,7S12 regard-
SYNLETT 2006, No. 10, pp 1583–1585
2
1
.0
6
.2
0
0
6
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-941603; Art ID: U02206ST
© Georg Thieme Verlag Stuttgart · New York

1584
T. Kan et al.
LETTER
less of the chirality of the catalyst. Thus, asymmetric in- Since the phenyl group of the chiral auxiliary played a key
duction solely depended on the chiral auxiliary and not the role in the asymmetric induction, we then focused on the
catalyst. Since other catalysts did not enhance the selec- amide moiety. As shown in Table 2, the selectivity was
tivity, reagent control of this reaction was difficult (entries enhanced in six-membered ring amide derivatives 4d and
314 and 415). In order to increase the selectivity, the chiral 4e. The highest diastereoselectivity was attained by com-
auxiliary of 4 was changed to a bulky phenyl derivative bining diazoester 4d and 2, which afforded 5d in 55%
from the corresponding methyl group. The diastereoselec- yield and 78% de. In this reaction, the carbenoid inter-
tivity was significantly enhanced when 4b was combined mediate interacted with the carbonyl group of the chiral
with 2 and afforded 5b in 61% yield and 68% de.
auxiliary as illustrated in 12.16 Thus, the C–H insertion
reaction proceeded from the opposite face of the bulky
phenyl group of 12. The attachment of the piperidine
amide to the phenyl group explains the high stereoselec-
tivity of 4d.17,18
Table 1 C–H Insertion Reactions of 4a and 4b
O
O
O
Rh catalyst
(10 mol%)
OMe
O
OR
H
In conclusion, novel construction of bicyclo[3.3.0]octane
derivatives were efficiently developed by combining
Davies’ Rh catalyst and a piperidinyl mandelate chiral
auxiliary. The bicyclo[3.3.0]octane skeleton is a useful
synthetic intermediate for natural products19 and medici-
nal compounds.20 Further optimization and exploitation of
this methodology are currently under investigation in our
laboratories.
N2
CH2Cl2, r.t.
H
R2
N
R =
4a: R2 = Me
4b: R2 = Ph
5a: R2 = Me
5b: R2 = Ph
O
Entry Substrate
Rh catalyst
Yield (%) de (%)
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4b
4b
4b
4b
Rh2(S-DOSP)4
Rh2(R-DOSP)4
Rh2(S-PTTL)4
Rh2(S-PTPA)4
Rh2(S-DOSP)4
Rh2(R-DOSP)4
Rh2(S-PTTL)4
Rh2(S-PTPA)4
94
54
51
59
61
65
47
53
43
36
48
50
68
46
43
51
References and Notes
(1) For a review on C–H insertion reactions: Doyle, M. P.;
McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds: From
Cyclopropanes to Ylides; Wiley: New York, 1998.
(2) For a review on asymmetric C–H insertion reactions:
Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103,
2861.
(3) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119,
9075.
(4) (a) Kurosawa, W.; Kobayashi, H.; Kan, T.; Fukuyama, T.
Tetrahedron 2004, 60, 9615. (b) Kurosawa, W.; Kan, T.;
Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 8112.
(c) Kurosawa, W.; Kan, T.; Fukuyama, T. Synlett 2003,
1028.
Table 2 C–H Insertion Reactions of 4c–f
O
O
O
(5) For a similar double asymmetric induction in C–H insertion
reaction, see: Hashimoto, S.; Watanabe, N.; Kawano, K.;
Ikegami, S. Synth. Commun. 1994, 24, 3277.
(6) Depres, J. P.; Green, A. E. Org. Synth., Coll. Vol. X 2004,
228.
OR
2 (10 mol%)
OR
O
H
N2
CH2Cl2, r.t.
H
R3
Ph
N
R3
R =
(7) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54,
3258.
O
(8) Chiral alcohols 11a and 11b were synthesized from the
corresponding lactate and mandelate, respectively. A similar
reaction has been reported, see: Devine, P. N.; Dolling,
U.-H.; Heid, R. M. Jr.; Tschaen, D. M. Tetrahedron Lett.
1996, 37, 2683.
Entry
Substrate (-NR3R3)
4c (pyrrolidine)
4d (piperidine)
Yield (%)
de (%)
68
1
2
3
4
61
55
59
66
78
(9) Taber, D. F.; Amedio, J. C. Jr.; Patel, Y. K. J. Org. Chem.
1985, 50, 3618.
4e (morpholine)
4f (dimethylamine)
75
(10) Initially, we tested a reagent controlled C–H insertion
reaction of diazoester 13, which was readily available from
10. Utilizing several chiral rhodium catalysts, the yield and
the selectivity of 14 were unsatisfactory as shown in
Scheme 3.
70
O
O
R
O
(11) Diastereoselectivity of 5 was determined by the 1H NMR
spectra of 15, which was readily converted from 5, as shown
in Scheme 4.
Rh
O
Rh
O
2
O
C–H insertion
4d
5d
4
N
R'
12
Synlett 2006, No. 10, 1583–1585 © Thieme Stuttgart · New York

LETTER
Novel Synthesis of Bicyclo[3.3.0]octane Ring System
1585
of diastereomers and their enols. IR (film): 2937, 2858,
1755, 1726, 1657, 1446, 1398, 1352, 1230, 1161, 1005, 852
cm–1. 1H NMR (400 MHz, CDCl3): d = 10.3 (br, 0.2 H), 10.2
(br, 0.04 H), 7.48–7.32 (m, 5 H), 6.42 (s, 0.4 H), 6.24 (s, 0.6
H), 5.77–5.59 (m, 2 H), 3.83–3.13 (m, 7 H), 2.78–2.68 (m, 2
H), 2.22–2.05 (m, 2 H), 1.44–1.27 (m, 5 H), 1.06–1.04 (m, 1
H). 13C NMR (100 MHz, CDCl3): d = 216.3, 169.3, 166.8,
166.6, 165.8, 164.0, 135.0, 134.2, 132.8, 131.7, 129.6,
129.4, 129.3, 128.7, 128.6, 128.5, 127.7, 103.1, 75.4, 74.6,
73.0, 59.6, 59.0, 53.3, 51.7, 46.7, 45.3, 43.9, 41.1, 40.6, 40.3,
36.4, 34.7. HRMS (FAB): m/z calcd for C22H26NO4 [MH+]:
368.1861; found: 368.1858 [MH+].
O
O
O
Rh catalyst
(10 mol%)
OAllyl
O
OAllyl
H
N2
CH2Cl2
H
14
Yield (%) ee (%)
13
Rh catalyst
Rh2(S-DOSP)4
Rh2(S-PTTL)4
Rh2(S-PTPA)4
30
16
58
43
11
4
Scheme 3
Compounds 15a and 15b: to a solution of 5d (8.9 mg, 0.023
mmol) in THF (0.3 mL) was added NaHMDS in THF (34
mL, 0.034 mmol, 1.5 equiv) at 0 °C. After stirring for 30 min
at the same temperature, BOMCl (5.0 mL, 0.035 mmol, 1.5
equiv) was added. After stirring for 30 min, the reaction
mixture was quenched by sat. aq NH4Cl, extracted with
EtOAc. The organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The
residue was purified by preparative TLC (50% EtOAc in
hexane) to afford 15a (4.9 mg, 0.010 mmol, 44 %) as a
colorless oil and its isomer 15b (0.6 mg, 0.0012 mmol, 5%)
as a colorless oil.
O
BOM
OR
NaHMDS
BOMCl
H
5
THF
O
H
15
Scheme 4
Analytical Data for Compound 15a.
O
[a]D21 +94.2 (c 0.165, CHCl3). IR (neat film): 2937, 2856,
1708, 1657, 1450, 1378, 1217, 1144, 1016 cm–1. 1H NMR
(400 MHz, CDCl3): d = 7.50–7.28 (m, 10 H), 6.41 (s, 1 H),
5.79 (dd, J = 5.6, 2.3 Hz, 1 H), 5.58 (dd, J = 5.6, 2.0 Hz, 1
H), 5.15 (d, J = 4.3 Hz, 2 H), 4.66 (s, 2 H), 4.07 (dd, J = 8.2,
2.0 Hz, 1 H), 3.62 (m, 1 H), 3.49–3.41 (m, 3 H), 3.03 (dd,
J = 18.0, 9.9 Hz, 1 H), 2.91 (m, 1 H), 2.68 (m, 1 H), 2.45
(ddd, J = 17.4, 4.7, 2.1 Hz, 1 H), 2.10 (m, 1 H) 1.54–1.45 (m,
5 H), 1.16 (m, 1 H), 13C NMR (700 MHz, CDCl3): d = 167.8,
166.8, 164.0, 146.0, 140.9, 137.2, 135.7, 133.5, 129.2,
129.0, 128.9, 128.6, 128.5, 128.3, 128.2, 127.7, 109.1, 92.8,
72.7, 71.9, 54.5, 43.8, 42.3, 40.8, 39.2, 34.7, 29.7, 25.7, 24.7,
24.2. HRMS–FAB: m/z calcd for C30H34NO5 [MH+]:
488.2437; found: 488.2445 [MH+].
H
1) allyl alcohol, DMAP, toluene
2) pyrrolidine, Pd(PPh3)4, MeCN
5
H
16
Scheme 5
(12) The absolute configuration of 5 was determined as 2R,3R by
comparing the optical rotation with that of reported
compound 16, see ref. 13. Preparation of 16 from 5 was
performed by a decarbonylation reaction (Scheme 5).
(13) Kashihara, H.; Suemune, H.; Kawahara, T.; Sakai, K.
Tetrahedron Lett. 1987, 28, 6489.
Analytical Data for Compound 15b.
(14) Watanabe, N.; Ogawa, T.; Ohtake, Y.; Ikegami, S.;
Hashimoto, S. Synlett 1996, 85.
[a]D22 +15.3 (c 0.090, CHCl3). IR (neat film): 2935, 1709,
1654, 1454, 1215, 1018 cm–1. 1H NMR (400 MHz, CDCl3):
d = 7.52–7.28 (m, 10 H), 6.42 (s, 1 H), 6.18 (dd, J = 5.7, 2.3
Hz, 1 H), 5.66 (dd, J = 5.7, 2.1 Hz, 1 H), 5.12 (s, 2 H), 4.65
(s, 2 H), 3.98 (dd, J = 8.2, 2.0 Hz, 1 H), 3.61–3.39 (m, 4 H),
3.03 (dd, J = 18.3, 9.8 Hz, 1 H), 2.88 (m, 1 H), 2.67 (m, 1 H),
2.50 (m, 1 H), 2.10 (m, 1 H), 1.54–1.45 (m, 5 H), 1.16 (m, 1
H), 13C NMR (100 MHz, CDCl3): d = 167.3, 166.7, 163.7,
157.1, 136.9, 135.5, 133.3, 128.8, 128.7, 128.4, 128.2,
128.1, 111.3, 92.6, 72.2, 70.3, 54.4, 46.3, 43.3, 40.6, 39.0,
34.3, 25.4, 24.5, 24.0. HRMS–FAB: m/z calcd for
C30H34NO5 [MH+]: 488.2437; found: 488.2428 [MH+].
(19) (a) For a pentalenolactone, see: Mori, K.; Tsuji, M.
Tetrahedron 1988, 44, 2835. (b) For a jasmonic acid
analogue, see: Toshima, H.; Nara, S.; Fujino, Y.; Ichihara,
A. Bioscience, Biotechnology, and Biochemistry 2000, 64,
2702.
(15) (a) Watanabe, N.; Ogawa, T.; Ohtake, Y.; Ikegami, S.;
Hashimoto, S. Synlett 1996, 85. (b) Hashimoto, S.;
Watanabe, N.; Ikegami, S. Tetrahedron Lett. 1990, 31, 5173.
(16) A similar interaction was observed in Rh carbenoid
mediated intermolecular cyclopropanation, see: Davies, H.
M. L.; Huby, N. J. S.; Cantrell, W. R. Jr.; Olive, J. L. J. Am.
Chem. Soc. 1993, 115, 9468.
(17) The C–H insertion 4d reaction with Rh2(OAc)4 proceeded
smoothly to afford 5a in 94% yield and a 43% de.
(18) Experimental procedure for the C–H insertion reaction of
diazoester 4d and confirmation of the diastereoselectivity by
conversion of 13a and 13b from 5d are described below.
Compound 5d: to a solution of diazoester 4d (17.5 mg, 0.044
mmol) in CH2Cl2 (0.4 mL) was added Rh2(S-DOSP)4 (8.4
mg, 0.0044 mmol, 10 mol%) at r.t. After stirring for 5 min at
the same temperature, the reaction mixture was concentrated
under reduced pressure. The residue was purified by
preparative TLC (50% EtOAc in hexane) to afford 5d (8.9
mg, 0.023 mmol, 55%, 78% de) as a yellow oil and mixture
(20) For an isocarbacyclin, see: (a) Hashimoto, S.; Shinoda, T.;
Ikegami, S. Chem. Commun. 1988, 1137. (b) Hashimoto,
S.; Miyazaki, Y.; Ikegami, S. Synlett 1996, 324.
Synlett 2006, No. 10, 1583–1585 © Thieme Stuttgart · New York