New approach to the steroid BCD-ring system using tandem radical cyclization

Full text of DOI:10.1021/jo962388f

1912
J . Org. Chem. 1997, 62, 1912-1913
New Ap p r oa ch to th e Ster oid BCD-Rin g
System Usin g Ta n d em Ra d ica l Cycliza tion
Takashi Takahashi,* Satoshi Tomida,
Yasuharu Sakamoto, and Haruo Yamada
Department of Chemical Engineering, Tokyo Institute of
Technology, 2-12-1 Ookayama, Meguro, Tokyo 152, J apan
Received December 20, 1996
Syntheses of polycyclic skeletons, such as steroids and
terpenes, have a central place in the development of
regio- and stereochemically controlled synthetic meth-
odology.1 The elaboration of ring-fused carbocycles based
upon “tandem cyclizations” such as cation cyclization,2
radical cyclization,3 and tandem Heck cyclization4 offer
efficient methods for the rapid and stereocontrolled
synthesis of polycyclic skeletons. We have developed
efficient approaches to the steroid CD ring based upon
the double Michael reaction,5 sequential Claisen rear-
rangement,6 and Pd-catalyzed cyclization.7 We have also
described a unique synthesis of the steroid ABC ring
system using a transannular Diels-Alder reaction.8
Recently, a tandem radical cyclization using an acyl
radical intermediate to synthesize the steroid skeleton
(A f B f C f D) has been reported.9 We report here
an alternative approach (D f C f B) to the steroid BCD-
ring 4 using a “tandem radical cyclization”,10 with a view
toward the syntheses of progesterone (1), 11R-hydroxy-
progesterone (2), a key intermediate for hydrocortisone,
and Proscar (3),11 an inhibitor of enzyme human prostatic
5R-reductase (Figure 1).
F igu r e 1. Retrosynthesis of 4 and tandem radical cyclization
giving 5.
In our synthetic plan (Figure 1), acyclic iodide 7 is the
key intermediate for the tandem radical cyclization,
which involves the first cyclization to generate the D-ring
via a 5-exo-trig closure (7 f 6) and the subsequent second
cyclization to provide the C-ring via a 6-exo-trig closure
(6 f 5). Cyclization of the B ring in 5 using an acyl
anion, followed by a base-induced isomerization of the
resulting cyclized product, should provide the stable
10R,17â-BCD ring 4.12,13 It is well known that 5-exo-trig
F igu r e 2. Flexible reactant models of the tandem radical
cyclization.
cyclizations are generally preferred over 6-endo-trig
closures, and introduction of an activating group on the
alkene terminus accelerates 6-exo-trig cyclization.3d,14
Thus, the regiochemical outcome of the cyclization would
be directed to give the desired steroid CD ring system.
However, it is still difficult to predict the stereochemical
outcome of the acyclic radical cyclizations of 7 because
of the many conformational possibilities and relative
stereochemistry between the C(13)-methyl and C(17)
methyl ketone. For the quantitative modeling of the
radical cyclization of 7, the MM2 transition-state model15
(flexible reactant model) was applied to the tandem
radical cyclizations of 17â-8 and 17R-8 (t-BuMe2SiO
group is replaced by a hydrogen; see Figure 2). On the
basis of the assumption of a stepwise process for this
tandem radical cyclization, we constructed MM2 transi-
tion-state structures for all possible ring closures by using
Monte Carlo (MC) random-search16 to find the initial
structures. The extended MM2* force field17 and Houk’s
radical cyclization parameters18 were applied to minimize
the energies. MM2 calculations and a Boltzmann dis-
(1) Blickenstaff, R. T.; Ghosh, A. C.; Wolf, G. C. Total Synthesis of
Steroids; Academic: New York, 1974.
(2) For a review see: (a) J ohnson, W. S. Bioorg. Chem. 1976, 5, 51-
98. (b) Taylor, S. K. Org. Prep. Proc. Int. 1992, 24, 247-284.
(3) For recent reviews: (a) Stork, G. In Current Trends in Organic
Synthesis; Nozaki, H., Ed.; Pergamon: Oxford, 1983; p 359. (b) Giese,
B. Radicals in Organic Synthesis: Formation of Carbon-Carbon
Bonds; Pergamon: Oxford, 1986. (c) J asperse, C. P.; Curran, D. P.;
Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286. (d) Curran, D. P. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Semmel-
hack, M. F., Ed.; Pergamon: Oxford, 1991; Vol. 4, p 779.
(4) Negishi, E.; Coperet, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. Rev.
1996, 96, 365-393.
(5) (a) Takahashi, T.; Naito, Y.; Tsuji, J . J . Am. Chem. Soc. 1981,
103, 5261-5263. (b) Takahashi, T.; Okumoto, H.; Tsuji, J .; Harada,
N. J . Org. Chem. 1984, 49, 948-950.
(6) (a) Takahashi, T.; Yamada, H.; Tsuji, J . J . Am. Chem. Soc. 1981,
103, 5259-5261. (b) Takahashi, T.; Yamada, H.; Tsuji, J . Tetrahedron
Lett. 1982, 23, 233-234.
(7) Takahashi, T.; Miyazawa, M.; Ueno, H.; Tsuji, J . Tetrahedron
Lett. 1986, 27, 3881-3884.
(13) Throughout this manuscript, steroid numbering is used for
convenience, even when the intermediates do not have a steroid
skeleton.
(8) (a) Takahashi, T.; Shimizu, K.; Doi, T.; Tsuji, J .; Fukazawa, Y.
J . Am. Chem. Soc. 1988, 110, 2674-2676. (b) Takahashi, T.; Sakamoto,
Y.; Doi, T. Tetrahedron Lett. 1992, 33, 3519-3522.
(14) Beckwith, A. L. J .; Moad, G. J . Chem. Soc., Chem. Commun.
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(9) (a) Chen, L.; Gill, G. B.; Pattenden, G. Tetrahedron Lett. 1994,
35, 2593-2596. (b) Batsanov, A.; Chen, L.; Gill, G. B.; Pattenden, G.
J . Chem. Soc., Perkin. Trans. 1 1996, 45-55. (c) Zoretic, P. A.; Chen,
Z.; Zhang, Y. Tetrahedron Lett. 1996, 37, 7909-7912.
(10) Takahashi, T.; Katouda, W.; Sakamoto, Y.; Tomida, S.; Yamada,
H. Tetrahedron Lett. 1995, 36, 2273-2276.
(15) Eksterowicz, J . E.; Houk, K. N. Chem. Rev. 1993, 93, 2439-
2461.
(16) Chang, G.; Guida, W. C.; Still, W. C. J . Am. Chem. Soc. 1989,
111, 4379-4386.
(17) All modeling calculations reported in this paper were carried
out using MacroModel V.4.0 software. Mohamadi, F.; Richards, N. G.
J .; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.;
Hendrickson, T.; Still, W. C. J . Comput. Chem. 1990, 11, 440-467.
(11) Prous, J .; Castaner, J . Drugs. Future 1991, 16, 996-1000.
(12) For the isomerization of 20-ketopregnanes see: Rubin, M. B.
Steroids 1963, 2, 561-581.
S0022-3263(96)02388-2 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 7, 1997 1913
Sch em e 1a
was transformed to γ-iodo ketone 7 in three steps: (1)
addition of methyllithium (85% yield), (2) conversion of
the resulting alcohol into the iodide,20 and (3) deprotec-
tion of the acetal (57% yield for two steps). In these
transformations, isomerization of the 17-acetyl group did
not take place and HPLC analysis showed a 75:25
mixture of the 17R- and 17â-methyl ketone 7.
Without separation of the 17R- and 17â-epimers, the
tandem radical cyclization of iodide 7 was carried out in
the following way.21 Treatment of 7 with tributyltin
hydride (1.9 equiv) in the presence of AIBN (0.33 equiv)
at benzene reflux gave in 93% yield the CD-ring 17 with
the desired trans-anti-trans (B/C/D) relative stereochem-
istry. In this cyclization, none of the cis ring-fused
bicycles were detected by HPLC and NMR analyses.
Selective cyanohydrin formation of the aldehyde in 17,
deprotection of the trimethyl- and tert-butyldimethylsilyl
groups, tosylation of the primary alcohol, and reprotec-
tion of the cyanohydrin with ethyl vinyl ether gave the
protected cyanohydrin 5 in 41% overall yield. Cyclization
of 5 (98% yield) and acid treatment of the cyclized
product, followed by base treatment of the resulting
cyanohydrin (10% NaOH (aq) and then K2CO3/MeOH)
gave an 80:20 mixture of the BCD-ring 4 and its 17R-
isomer in 85% combined yield. The structure of 4 was
established by X-ray crystallographic analysis.22 None
of the 10â-methyl derivatives were detected in a crude
mixture by HPLC and NMR analyses.
a
Synthesis of 4: (a) SeO2, TBHP, salicyclic acid, CH2Cl2 then
Me2S, AcOH; MnO2, benzene/CH2Cl2, 36%; (b) ethylene glycol,
triethyl orthoformate, p-TsOH, benzene; K2CO3, MeOH; MnO2,
benzene, 62%; (c) LDA, ethyl acetate, THF, -78 °C; NaBH4, LiCl,
MeOH, 90%; (d) t-BuMe2SiCl, Et3N, CH2Cl2, 69%; (e) 15, heptanoic
acid, xylene, 140 °C, 80%; (f) MeLi, THF, -78 °C, 85%; (g) I2, PPh3,
imidazole, benzene; THF/AcOH/H2O ) 4:1:1, 0 °C, 57%; (h) AIBN
(0.33 equiv), n-Bu3SnH (1.9 equiv), benzene, reflux, 93%; (i)
Me3SiCN, ZnI2; 1 MHCl, THF; TsCl, pyridine, CH2Cl2; ethyl vinyl
ether, PPTS, benzene, 41%; (j) LiN(TMS)2, THF, 68 °C, 98%; (k)
PPTS, MeOH; 2% NaOH (aq), THF; K2CO3, MeOH, 85%.
tribution of the transition-state structures of 17â-methyl
ketone 8 suggest that the first cyclization of 17â-8 should
give a 70:28 mixture of the 17â-trans-9 and its cis-isomer
and that the 6-endo-trig closure products would be formed
in less than 2% yield. On the basis of this analysis, the
second 6-exo-trig cyclization of the major radical inter-
mediate 17â-9 was examined. These calculations and a
Boltzmann distribution suggest that the second cycliza-
tion of 17â-9 should provide the exclusive formation
(>99%) of 17â-10 with the trans-anti-trans (B/C/D) rela-
tive stereochemistry. In a similar manner, the analysis
of tandem radical cyclization of the 17R-methyl ketone 8
was conducted. The first cyclization of 17R-8 should give
a 78:13:9 mixture of the 17R-trans-9 and its cis-isomer
and 6-endo-trig products, and the subsequent cyclization
via the major radical intermediate 17R-9 should provide
exclusively (99%) the CD-ring 17R-10 having the trans-
anti-trans (B/C/D) relative stereochemistry. Overall, the
MM2 transition-state calculations suggest that the initial
radical cyclizations of both the 17â- and 17R-form of 7
introduce the D-ring of 5 with the correct trans-stereo-
chemistry between the C(13)-methyl (18-methyl) and
C(14)-hydrogen and the subsequent cyclizations provide
the C-ring of 5 with the desired trans-anti-trans (B/C/D)
relative stereochemistry.
The key intermediate 7 was prepared in the following
way (Scheme 1). Two-step oxidation (SeO2 then MnO2)
of the terminal methyl group in geranyl acetate (11) gave
the R,â-unsaturated aldehyde 12 in 36% yield. Protection
of the aldehyde 12 with ethylene glycol, methanolysis of
the acetyl group, and MnO2 oxidation of the resulting
allylic alcohol afforded the R,â-unsaturated aldehyde 13
in 62% overall yield. 1,2-Addition of the lithium enolate
of ethyl acetate at -78 °C, and reduction of the resulting
ester provided diol 14 in 90% overall yield. Selective
protection of the primary alcohol with t-BuMe2SiCl (69%
yield) and Claisen rearrangement of the resulting sec-
ondary alcohol with the cyclic orthoester 1519 afforded a
75:25 mixture of the 17R- and 17â-epimers 16 in 80%
yield. Without separation of these epimers, γ-lactone 16
An efficient synthesis of the steroid BCD-ring system
having a 17â-methyl ketone was accomplished using a
tandem radical cyclization and subsequent cyanohydrin
alkylation. Moreover, conformational analysis utilizing
the “MM2 transition-state model” predicts the stereo-
selectivity in the radical cyclization, and in general,
considerations of stereochemical control based upon ab-
initio and MM2 calculations might have predictive value
in the design of key synthetic intermediates.
Ack n ow led gm en t. This work was supported by a
Grant-in-Aid for J SPS Fellows (No. 5167) from the
Ministry of Education, Science, Sports and Culture,
J apan. We are indebted to Asahi Chemical Industry
Co. Ltd. for the X-ray crystallographic analysis of 4 and
to Taiho Pharmaceutical Co. Ltd. for measurement of
mass spectra.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the synthesis of the BCD-ring system 4, the transition-
state modeling of the radical cyclization of iodide 8, and X-ray
crystallographic data for 4 (27 pages).
J O962388F
(19) Meerwein, H.; Borner, P.; Fuchs, O.; Sasse, H. J .; Schrodt, H.;
Spille, J . Chem. Ber. 1956, 89, 2060-2079.
(20) Classon, B.; Liu, Z.; Samuelsson, B. J . Org. Chem. 1988, 53,
6126-6130.
(21) After separation of the 17R- and 17â-epimers of 7, their tandem
radical cyclizations were also examined. The 17â-methyl ketone 7
provided 17 having 17â-acetyl group and the trans-anti-trans relative
stereochemistry in the C-ring with more than 74% stereoselectivity,
and the 17R-methyl ketone 7 afforded 17 having a 17R-acetyl group
and the trans-anti-trans relative stereochemistry in the C-ring with
more than 78% stereoselectivity.
(22) The authors have deposited atomic coordinates for the BCD-
ring system
4 with the Cambridge Crystallographic Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.
(18) Spellmeyer, D. C.; Houk, K. N. J . Org. Chem. 1987, 52, 959-
974.