bomethoxy group was introduced stereoselectively via 4,6-
bishydrocyanation of 11R-hydroxycanrenone (2c), but
regioselective dehydration of the 11R hydroxyl was prob-
lematic. Thus, a need existed for a new method for the
introduction of a carbon substituent at C-7 of the steroid
nucleus.
Furylation was investigated as an alternative to hydrocya-
nation because the furan ring has frequently been employed
as a surrogate for carboxylic acid in natural product total
synthesis.8 To effect conjugate furylation in high yield, it
was necessary to employ the protic Lewis acid conditions
of Poirier and Dujardin,9 as no reaction occurred under
aprotic Lewis acid conditions (e.g., TiCl4, CH2Cl2, -30 °C).
Four dienone substrates were studied (2a-d; Table 1). The
Although furan is a popular surrogate for carboxylic acid
in synthesis, no general method exists for unmasking. Two
methods are most frequently used: (1) periodate/catalytic
RuO2;13 and (2) ozonization. However, the former method
requires a large molar excess of periodate, which is prohibi-
tively expensive for commercial applications, and the latter
gives highly variable yields (11-89% depending on the other
functionality in the substrate).14 Attempts to degrade furan
adduct 3a by ozonization (5/1 MeOH/CH2Cl2, -78 °C)
resulted in rapid and selective cleavage of the distal double
bond to give enol acetate 4 (as a 1:1 mixture of epimers)
cleanly, followed by slower and apparently nonselective
cleavage of the three remaining double bonds to give a
complex mixture of polar products containing little or none
of the desired carboxylic acid 5 (Scheme 1). Thus, a more
Table 1. Furylation of Steroidal Dienones
Scheme 1. Standard Ozonization Approach to Furan
Degradation
dienone
X
Y
7R/âa
yieldb (%)
∆
∆
9(11)-canrenone
9(11)-canrenone
2a
2a
2b
2c
2d
π bond
π bond
91/9
92/8
78/22
99/1
89/11
72.9
77.7c
69.5d
86.2e
75.5
effective method for the degradation of furans to carboxylic
acids was needed.
canrenone
11R-hydroxycanrenone
9(11)R-epoxycanrenone
a Determined by LC analysis of the crude product mixture at the reaction
endpoint. b Yield of R isomer after isolation/purification. c Solvent was
acetonitrile. d Reaction time was 88 h, with double the amount of reagents.
e Average of two runs.
H
H
H
OH
-O-
Because furan 3a can be opened to the enedione cis-6,
which can be isomerized to trans-6 in high yield (see Scheme
2 for conditions), degradation of both cis-6 and trans-6 was
studied. It was found that ozone cleaves the enedione double
bond of trans-6 cleanly to give (after reduction of the
hydroperoxide)15 the R-ketoaldehyde methanol adduct 7 in
essentially pure form. Baeyer-Villiger oxidation with basic
hydrogen peroxide16 gave the carboxylic acid 5 in 82.4%
yield (crystallized, overall from 3a, without isolation of any
most cost-effective results were obtained with ∆9(11)-can-
renone 2a because it is readily synthesized from crude soy
sterols by a short sequence of microbiological10 and chemi-
cal11 steps and, although furylation was not completely
stereoselective (R/â ) 91/9), the â adduct is efficiently
removed because it is an oil. A single crystallization of the
crude product afforded crystals of 3a that contained no more
than 0.1% of the â isomer or any other impurity, with the
loss of only 4.1% yield of the R isomer to the filtrate.
Although 11R-hydroxycanrenone 2c undergoes furylation
more stereoselectively (R/â ) 99/1),12 the adduct 3c is
difficult to dehydrate to 3a regioselectively.
(13) (a) Mukaiyama, T.; Tsuzuki, R.; Kato, J. Chem. Lett. 1985, 837
[yield of carboxylic acid from furan: 78%]. (b) Dondoni, A.; Junquera, F.;
Merchan, F. L.; Merino, P.; Scherrmann, M.-C.; Tejero, T. J. Org. Chem.
1997, 62, 5484 [51-69%]. (c) Dondoni, A.; Franco, S.; Junquera, F.;
Merchan, F. L.; Merino, P.; Tejero, T. J. Org. Chem. 1997, 62, 5497 [46-
87%].
(14) (a) Schmid, G.; Fukuyama, T.; Akasaka, K.; Kishi, Y. J. Am. Chem.
Soc. 1979, 101, 259 [yield of carboxylic acid from furan: 55%]. (b) Asher,
V.; Becu, C.; Anteunis, M. J. O.; Callens, R. Tetrahedron Lett. 1981, 22,
141 [30%]. (c) Danishefsky, S.; Maring, C. J. Am. Chem. Soc. 1985, 107,
7762 [50%]. (d) Dziewiszek, K.; Zamojski, A. Carbohydr. Res. 1986, 150,
163 [11%]. (e) Ramalingam, K.; Nanjappan, P.; Kalvin, D. M.; Woodard,
R. W. Tetrahedron 1988, 44, 5597 [80%]. (f) Kusakabe, M.; Kitano, Y.;
Kobayashi, Y.; Sato, F. J. Org. Chem. 1989, 54, 2085 [87-95%]. (g)
Bodurow, C. C.; Boyer, B. D.; Brennan, J.; Bunnell, C. A.; Burks, J. E.;
Carr, M. A.; Doecke, C. W.; Eckrich, T. M.; Fisher, J. W.; Gardner, J. P.;
Graves, B. J.; Hines, P.; Hoying, R. C.; Jackson, B. G.; Kinnick, M. D.;
Kochert, C. D.; Lewis, J. S.; Luke, W. D.; Moore, L. L.; Morin, J. M., Jr.;
Nist, R. L.; Prather, D. E.; Sparks, D. L.; Vladuchick, W. C. Tetrahedron
Lett. 1989, 30, 2321 [77%]. (h) Dondoni, A.; Marra, A.; Scherrmann, M.-
C. Tetrahedron Lett. 1993, 34, 7323 [40-60%]. (i) Caron, S.; Stoermer,
D.; Mapp, A. K.; Heathcock, C. H. J. Org. Chem. 1996, 61, 9126 [0%]. (j)
Kruger, J.; Carreira, E. M. Tetrahedron Lett. 1998, 39, 7013 [78-87%].
(15) The ratio of hydroxyhydroperoxide 11 to alcohol 7 in the crude
ozonolysate was 31.9/68.1.
(7) Ng, J. S.; Wang, P. T.; Baez, J. A.; Liu, C.; Anderson, D. K.; Lawson,
J. P.; Erb, B.; Wieczorek, J.; Mucciariello, G.; Vanzanella, F.; Kunda, S.
A.; Letendre, L. J.; Pozzo, M. J.; Sing, Y.-L. L.; Yonan, E. E. U.S. Patent
6,180,780 B1, January 30, 2001.
(8) Lipshutz, B. H. Chem. ReV. 1986, 86, 795.
(9) (a) Poirier, J.-M.; Dujardin, G. Heterocycles 1987, 25, 399. (b)
Dujardin, G.; Poirier, J.-M. Bull. Soc. Chim. Fr. 1994, 131, 900.
(10) Wovcha, M. G.; Antosz, F. J.; Knight, J. C.; Kominek, L. A.; Pyke,
T. R. Biochim. Biophys. Acta 1978, 531, 308.
(11) (a) Beaton, J. M.; Huber, J. E.; Padilla, A. G.; Breuer, M. E. U.S.
Patent 4,127,596, November 28, 1978. (b) Miller, P. C.; Pozzo, M. J.; Chou,
S. K. US 2004/0024202 A1, February 5, 2004.
(12) The anomalously high 7R selectivity is attributable to a destabilizing
interaction between the incipient 7â bond and the carbon-oxygen bond in
the transition state leading to the 7â isomer, see: Cieplak, A. S. Chem.
ReV. 1999, 99, 1265.
(16) (a) Nukaya, H.; Inaoka, Y.; Ishida, H.; Tsuji, K.; Suwa, Y.;
Wakabayashi, K.; Kosuge, T. Chem. Pharm. Bull. 1993, 41, 649. (b)
Hollingsworth, R. I. J. Org. Chem. 1999, 64, 7633.
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Org. Lett., Vol. 8, No. 10, 2006