An efficient approach to bridged-bicyclic rings via intramolecular diazo ketone insertion

Article abstract of DOI:10.1016/S0040-4039(02)00878-X

A regioselective intramolecular diazo ketone insertion reaction of chiral cyclohexenones is described. The methodology shows potential utility in the syntheses of bicyclo[4.2.1]nonan-9-one, bicyclo[4.3.1]decan-10-one and cyclooctanoid rings.

Full text of DOI:10.1016/S0040-4039(02)00878-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4711–4715
An efficient approach to bridged-bicyclic rings via intramolecular
diazo ketone insertion
Lei Chen, Xuqing Zhang* and Arthur Schultz†
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
Received 9 April 2002; accepted 10 April 2002
Abstract—A regioselective intramolecular diazo ketone insertion reaction of chiral cyclohexenones is described. The methodology
shows potential utility in the syntheses of bicyclo[4.2.1]nonan-9-one, bicyclo[4.3.1]decan-10-one and cyclooctanoid rings. © 2002
Elsevier Science Ltd. All rights reserved.
Bicyclo[4.2.1]nonan-9-one and bicyclo[4.3.1]decan-10-
one are two typical bridged-bicyclic rings which consti-
tute key structural units in many natural products. Two
recent examples, CP-263,114 and CP-225,917, which
are squalene synthase and farnesyl transferase
inhibitors, have received increasing attention due to
their interesting structures and pharmacological proper-
ties.1 The bridged ketone bonds in bicyclo[4.2.1]nonan-
9-one and bicyclo[4.3.1]decan-10-one structures have
potentials of cleavage to give eight- and nine-membered
rings. These skeletons, especially eight-membered rings,
are widely presented in many cyclooctanoid natural
products, primarily among terpenoids.2 The synthetic
protocols of cyclooctanoid rings have recently been
summarized in a review article.3 Typically, eight- or
nine-membered rings can be formed from appropriate
precursors directly by cycloaddition, sigmatropic rear-
rangement, cyclization and coupling reactions or indi-
rectly through cycloaddition–fragmentation, ring
expansion, reductive and oxidative processes. Among
all these methods, the process involving diazo ketone
insertion and subsequent rearrangement shows high
efficiency and generality (Scheme 1).4 Here we describe
an efficient and regioselective method on syntheses of
various bicyclo[4.2.1]nonan-9-one, bicyclo[4.3.1]decan-
10-one and cyclootanoid rings through diazo ketone
insertion process.
Initial studies centered on the chiral cyclohexenones 6.
The preparation of the precursor 6a was shown in
Scheme 2. Birch reduction–alkylation of the benzamide
4 with 1-iodo-3-azido-propane as the alkylating agent
followed by the hydrolysis of the corresponding 1,4-
diene provided the cyclohexenone 5a in 75% yield as a
single diastereomer. Chemoselective hydrogenation of
5a using Lindlar catalysis in the presence of acetic
anhydride afforded the corresponding acetamide 6a in
91% yield.5 Analog syntheses afforded 6b, 6c, 6d and
6e.6 Treatment of the acetamide 6a with N2O4 in
CH2Cl2 gave the nitroso amide intermediate 7a. With-
out purification, 7a were converted into 8a in ꢀ30%
yield and some bridged ketone ring-opened adducts by
treatment with a catalytic amount of K2CO3 in
methanol. The methoxide apparently not only catalyzed
N2
O
O
O
N2
3
1
2
Scheme 1.
* Corresponding author. Present address: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Medicinal Chemistry, 1000 Rt.
202, Box 300, Raritan, NJ 08869, USA. Tel.: (908) 704-5319; fax: (908) 526-6469; e-mail: xzhang5@prius.jnj.com
† Deceased on Jan. 20, 2000.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00878-X

4712
L. Chen et al. / Tetrahedron Letters 43 (2002) 4711–4715
the insertion and rearrangement processes, but also
catalyzed the fragmentation of the bridged ketone 8a.
Replacement of K2CO3 in MeOH with LiOH in refluxing
THF resulted in a much cleaner product 8a in 80% yield.7
In this procedure, the acetate ion generated was a much
weakernucleophilethanthemethoxidesothatthebridged
ketone 8a was inactive toward the reaction condition.
Table 1 summarized the results of the diazo ketone
insertion reactions on various precursors 6a–6e. In all
these reactions, only bicyclo[4.2.1]nonan-9-ones 6a, 6b,
6d and bicyclo[4.3.1]decan-10-ones 6c, 6e were obtained
without any detectable amount of bicyclo[5.2.0]nonan-2-
one or bicyclo[5.3.0]decan-2-one isomers,8 which demon-
strated that these reactions proceeded in a highly
regioselective manner. This result was also reported from
Gutsche and Srikrishna’s papers.4 In the diazonium
alkoxide (Scheme 2), electrostatic attraction between the
diazonium and the alkoxide maintains a cis orientation
of two groups. Since the axial CꢀC bond and the CꢀN
bond are anti parallel, the following rearrangement and
elimination of N2 gives the bicyclo[4.2.1]nonan-9-one 8a.
yield. Sequential reduction of the azide 11 with Lindlar
catalysis in the presence of acetic anhydride followed by
treatment of the resulting acetamide with N2O4 provided
the corresponding nitrosoamide. The nitrosoamide was
then treated with K2CO3 in MeOH to afford the bicy-
clo[4.2.1]non-9-one 12 in 65% yield.10 MeLi addition of
the bridged ketone 12 occurred from re face to afford the
t-alcohol 13. Subsequent deprotection of TBS ether with
TBAF and oxidation of the alkene with mCPBA fur-
nished the epoxide 14. The stereochemistry of 14 was
confirmed by X-ray diffraction analysis (Fig. 1).
Attemptsatremovalofthechiralauxiliaryefficientlyfrom
8a were unsuccessful except for a few harsh conditions.
Thus, we designed and conducted a modified synthetic
route for easy removal of the chiral auxiliary (Scheme 3).
Birch reduction–alkylation of the MOM protected chiral
benzamide 9 with I(CH2)3N3, followed by acid-catalyzed
acyl migration and subsequent protection of the resulting
s-amine with chloromethylformate generated the azido
b-keto ester 10 in overall 62% yield.9 Reduction of 10 to
the diol by LiBH4 followed by selective protection of the
primary alcohol with TBSCl and re-oxidation of the
secondary alcohol afforded the cyclohexenone 11 in 64%
Figure 1. Molecular structure of 14.
AcHN
N3
OMe
1) K, NH3, t-BuOH;
ICH2CH2CH2N3
O
OMe
OMe
O
O
H2, 60 psi, Lindlar
NaOAc, Ac2O, EtOAc
O
O
Me
Me
Me
N
N
N
OMe
2) 6 N HCl, MeOH
4
6a, 91%
5a, 75% 2 steps
N2O4, NaOAc
NO
AcN
COA*
N2
O
OMe
A*
N2
O
O
OMe
O
O
LiOH, THF, reflux
O
Me
N
Me
O
N
Me
Me
7a
8a, 72% from 6a
OMe
A* =
N
Scheme 2.

L. Chen et al. / Tetrahedron Letters 43 (2002) 4711–4715
4713
Table 1.
N3
N3
OMOM
O
O
CO2Me
N
1) K, NH3, t-BuOH
ICH2
1) LiBH4
2) TBSCl, imidazole Me
Me
CH2CH2N3
Me
O
N
OTBS
3) PCC
O
2) HCl/MeOH
3) ClCOOMe, NaHCO3
OMe
O
11, 64%
9
10, 62%
1) Lindlar, H2,
Ac2O, NaOAc
2) N2O4, NaOAc
3) K2CO3/MeOH
O
HO
HO
Me
Me
HO
O
TBSO
Me
MeLi
TBSO
Me
1) TBAF
Me
2) mCPBA
12, 65%
13
14, 70% from 12
Scheme 3.

4714
L. Chen et al. / Tetrahedron Letters 43 (2002) 4711–4715
O
O
TBSO
Me
MsO
Me
1) TBAF
2) MsCl, Et3N
NaOH
Me
COOH
12
16, 71% for 3 steps
15
Scheme 4.
With these results in hand, we carried out several
simple steps to cleave the bridged ketone bond of 12
(Scheme 4). Deprotection of the hydroxy group of 12
followed by mesylation of the resulting alcohol
afforded the mesylate 15. Grob-type fragmentation of
15 by treatment with NaOH gave eight-membered ring
acid 16 in overall 71% yield.11
5. Corey, E. J.; Nicolaou, K. C.; Balanson, R. D.; Machida,
Y. Synthesis 1975, 9, 590.
6. For preparation of a-iodo-v-azido alkane, see: Khoukhi,
M.; Vaultier, M.; Carrie, R. Tetrahedron Lett. 1986, 27,
1031.
7. Typical procedure for preparation of bicyclo[4.2.1]non-9-
one or bicyclo[4.3.1]decan-10-one compounds, from 6a to
8a: To a cooled (−30°C) solution of amide 6a (1.252 g,
3.572 mmol) in CH2Cl2 (50 mL) was added NaOAc
(0.967 g, 1.20 mmol). Dinitrogen tetraoxide was bubbled
into the amide solution until the dark blue color was
maintained for 30 min. The solution, upon warming to
−10°C, was stirred at −10 to 0°C over a period of
20–30 min. During this time the initial blue color changed
into a bright yellow color. The reaction mixture was
washed with an ice-cooled 10% K2CO3 solution and then
brine. After drying with anhydrous Na2SO4, the solvent
was removed to leave the nitroso amide 7a as a yellow oil
(ꢀ1.28 g), which was used in the next step without
further purification. To the solution of 7a (1.28 g, 3.373
mmol) in THF (100 mL) was added LiOH·H2O (0.141 g,
3.373 mmol) and the resulting solution was refluxed
overnight. A saturated NH4Cl solution (ꢀ50 mL) was
added to quench the reaction. The mixture was extracted
with ether (25 mL×3), dried over Na2SO4 and concen-
trated to give crude 8a as a yellow oil. Chromatography
(silica gel, 2:1 hexane/EtOAc) purification gave 8a (0.776
g, 80%) as a light yellow oil. 1H NMR (500 MHz, CDCl3)
l 5.87 (1H, s), 4.31–4.29 (1H, m), 2.28–2.20 (2H, m),
2.14–2.06 (3H, m), 3.34 (3H, s), 2.70–2.69 (1H, m), 2.50
(1H, m), 2.28–2.20 (2H, m), 2.14–2.06 (3H, m), 1.96–1.84
(3H, m), 1.81 (3H, s), 1.80–1.69 (3H, m). 13C NMR (125
MHz, CDCl3) l 214.1, 168.8, 154.8, 138.0, 124.4, 72.2,
59.2, 57.9, 47.1, 46.9, 33.1, 33.0, 28.7, 27.7, 27.0, 24.9,
24.7. CI-MS, m/z (relative intensity) 292 (M++1, 100%).
IR (film, cm−1) 2929 1736, 1631, 1400. Anal. calcd for
C17H25NO3: C, 70.07; H, 8.65; N, 4.81. Found: C, 69.89;
H, 8.66; N, 4.86. [h]2D5 −236 (CDCl3, c 1.2).
In summary, we have developed a regioselective diazo
ketone insertion method to synthesize bicylo[4.2.1]-
nonan-9-one and bicyclo[4.3.1]decanan-10-one rings.
The bridged ketone bonds can be efficiently cleaved to
afford eight-membered rings. The method should be
useful for the syntheses of bridged-bicyclic rings and
cyclooctanoid natural products.
Acknowledgements
This work was supported by a grant from the National
Institutes of Health (Grant Number GM 26568). We
thank Dr. Fook S. Tham for the X-ray structure
determination.
References
1. (a) Dabrah, T. T.; Harwood, H. J., Jr.; Huang, L. H.;
Jankovich, N. D.; Kaneko, T.; Li, J. C.; Lindsey, S.;
Moshier, P. M.; Subashi, T. A.; Therrien, M.; Watts, P.
C. J. Antibiot. 1997, 50, 1; (b) Tan, Q.; Danishefsky, S. J.
Angew. Chem., Int. Ed. Engl. 2000, 39, 4509; (c) Nico-
laou, K. C.; Jung, J.-K.; Yoon, W. H.; He, Y.; Zhong,
Y.-L.; Baran, P. S. Angew. Chem., Int. Ed. Engl. 2000, 39,
1829; (d) Starr, J. T.; Carreira, E. M. Angew. Chem., Int.
Ed. Engl. 2000, 39, 1415.
2. (a) Norte, M.; Cataldo, F.; Sanchez, A.; Gonzalez, A.-G.;
Rivera, P.; Castillo, M. Tetrahedron Lett. 1993, 34, 5143;
(b) Adesomoju, A. A.; Okogun, J. I.; Cava, M. P.;
Carroll, P. J. Phytochemistry 1983, 22, 2535; (c) Burke, J.
W.; Doskotch, R. W.; Ni, C.-Z.; Clardy, J. J. Am. Chem.
Soc. 1989, 111, 5831; (d) Hensens, O. D.; Zink, D.;
Williamson, J. M.; Lotti, V. J.; Chang, R. S. L.; Goetz,
M. A. J. Org. Chem. 1991, 56, 3399; (e) Sultanbawa, M.
U. S.; Surendrakumar, S.; Bladon, P. Phytochemistry
1987, 26, 799.
8. These two skeletons were not detected from the diazo
ketone insertion reactions.
O
bicyclo[5.3.0]decan-2-one
O
bicyclo[5.2.0]nonan-2-one
3. Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881.
4. (a) Bailey, D. M.; Bowers, J. E.; Gutsche, C. D. J. Org.
Chem. 1963, 28, 610; (b) Vettel, P. R.; Coates, R. M. J.
Org. Chem. 1980, 45, 5430; (c) Srikrishna, A.;
Ramachary, D. B. Tetrahedron Lett. 1999, 40, 1605.
9. (a) Schultz, A. G.; Sundararaman, P.; Macielag, M.;
Lavier, F. P.; Welch, M. Tetrahedron Lett. 1985, 26,
4575; (b) Schultz, A. G.; McCloskey, P. J. Heterocycles
1987, 25, 437.

L. Chen et al. / Tetrahedron Letters 43 (2002) 4711–4715
4715
10. Treatment of the nitroso amide precursor with 1.0 equiv.
of LiOH in refluxing THF resulted in a tricyclic pyrazo-
line, which was derived from intramolecular dipolar
cycloaddition of azide to alkene.
11. Spectrographic data of 16. 1H NMR (500 MHz, CDCl3) l
11.0 (1H, br), 6.10 (1H, s), 4.84 (1H, s), 4.78 (1H, s),
3.06–2.99 (1H, m), 2.93–2.86 (1H, m), 2.69–2.64 (1H, m),
2.39–2.35 (1H, m), 2.00–1.93 (3H, m), 1.86–1.74 (2H, m),
1.81 (3H, s). 13C NMR (125 MHz, CDCl3) l 146.2, 135.5,
130.2, 116.7, 76.6, 40.4, 32.9, 30.8, 30.0, 28.7, 27.6. CI-
MS, m/z (relative intensity) 181 (M++1, 100%). Anal.
calcd for C11H16O2: C, 73.30; H, 8.95. Found: C, 72.93;
H, 8.93%.
H
N
N
OTBS
Me
O