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Stereoselective reduction of C-2 substituted steroid C-3 ketones with lithium tris-(R,S-1,2-dimethylpropyl)-borohydride and sodium borohydride
STEREOSELECT~~ REDUCTION OF C-2 SUBSTrTUTED STEROID C-3 KETONES WITH LITHILJ TRIS-(R,S-l,Z-DLiiETHYLPROPYL)BOROHYDRIDE AND SODfrJM BOROHYDRIDE John F. Templeton, V. P. Sashi Kumar, R. K. Cupta, and Anne M. Friesen Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2 Received August 6, 1986 Revised January 27, 1987 ABSTRACT The effect of C-2 substitution on the stereoselective reduction of steroid C-3 ketones with lithium tris-(R,S-l,Z-dimethylpropyl)-borohydride and sodium borohydride was investigated. The C-2 mono- and di-substituted chloro and methyl derivatives were predominantly reduced to one of the epimeric alcohols. The Zcl-chloro and Za-methyl derivatives of 17pacetoxy-5n-androstan-hone undergo stereoselective reduction wirh lithium tr~s-(R,S-l,Z-dimet~~ylprnpyl)-borohydride to the axial (B) alcohol as observed in the unsubstituted compound,whereas sodium borohydride gives predominantly the equatorial (38) alcohol. The 2g-ehloro, 2b-methyl, 2,2-dichloro, and 2,2-dimethyl derivatives are reduced predominantly to the equatorial (38) alcohol by both reagents.
Lithium
tris-(R,S-l,~-dimeth~lpropyl)-~~orohydr~de (LS-Selectride)
is a valuable reagent for the stereoselective and regioseleetive reduction of steroid ketones (l-3) forming thataxial alcohols at C-3,
Axial
alcohols at C-3 in both natural and synthetic steroids are frequently formed as metabolites.
Investigation of the reduction of C-Z substi-
tuted steroid C-3 ketones with this reagent and with sodium borohydride was
carried
out
to determine
the effect
of
adjacent groups
on the
stereochemistry of ketone reduction. EXPERIMENTAL Alcohol epimers (Table 1) were separated with HPLC (Waters M45 instrument, RI detector, with a n-Porasil (10 p> column) in 10% ethyl acetate/ hexanc (unsubstituted and Za-chloro) or 1% e~llanol/d~~hloromethane (all others). Alcohol fractions were collected and H Nl.fR (CDC13) spectra recorded (Bruker AM3OO) to establish fraction homogeneity and alcohol stereochemistry (C-3H coupling) (4). Column chromatography was carried out on silica gel (Merck type 60 H for TLC). In all cases the lcorresponding alcohols obtained from either reagent showed identical H NMR spectra (see Table 2). TLC was performed on silica gel (Merck type 60 H) and eluted with chloroform (2n-chloro) or 25% ethyl acetate/hexane (all others).
STEROIDS 48 / 5-G
November-December
1986 (339-346)
339
340
Templeton
et al
LS-Selectride: Reduction of the ketones (1 mmol) was carried out in freshlv , distilled dry tetrahydrofuran (6O‘mL), cooled in an acetone/dry ice bath under argon by addition of lithium tris-(R,S-1,2-dimethylpropyl)-horohydride (1.1 mL of a 1 M retrahydrofuran solution, LS-Selectride, Aldrich Chemical Co., Milwaukee, WI). Reactions were stopped at the times indicated when no starting ketone remained: the unsubstituted (20 min), 2a-chloroketone (Ic) (3 h), 24-chloroketone (Ie) (1 h), 2a-methylketone (Id) (4 h), 2@-methylketone (If) (1.5 h at O'C), 2,2-dichloroketone (IIIa) (20 min), 2,2-dimethylketone (IIIb) (4 h at O'C),as determined by TLC (Table 1). The reaction mixture was poured into ice-water containing an excess of mineral acid, stirred for 2 h and extracted with ether. Sodium borohydride: Reductions were performed by addition of NaBH4 (1 mmol) to a solution of the ketone (I mmol) in 95% ethanol (17 mL), the mixture stirred at room temperature for 20 min, poured into excess cold mineral acid,and ether extracted (TLC indicated reactions were complete after 5-10 min). Epimeric mixtures were obtained from both the LS-selectride and BaBH, reductions below as shcwn in Table 1. Redugtion of 178-acetoxy-5a-androstan-3-one (Ia) From LS-Selectride: 3n-alcohol (IIa) m.n. 184-185°C from dichloromethane/methanol (lit. (5)m.p. 186-187°C). From NaBH : Ia (500 mg) gave the 3S-alcohol (IIbj (300 mg) m.p. 149-151°C from d4chioromethane/methan01 (lit. (6) m.p. 150-151'C). Reduction of 1X3-acetoxy-Za-chloro-5o-androstan-3-one (Ic) The 2a-chloroketone was prepared by the method of Beereboom -et al (7) m.p. 180-18S'C (lit. (7) m.p. 185-i87'C); further recrystallization from dichloromethane/cyclohexane gave m.p. 198-2Ol'C. From LS-Selectride: 3~ alcohol (11~) m.p. 202-206.5"C from dichloromethane/methanol (lit. (8) m.p. 206-209°C). From NaBH : Ic (500 mg) gave the 3B-alcohol (IId) (50 mg) m.p. 198-201'C from ft-lchloromethane/methanol (lit. (8) m.n. 193-196°C). Reduction of Z&methyl-17$-propionyloxy-5n-androstan-3-one (Id) From LS-Selectride: 3a-alcohol (IIe) m.n. 167-169'C from dichlorom~thane/methanol (lit. (9) m.p. 168-170°C): From NaBN : gave the 3@-alcohol (IIf) (250 mg) m.p. 161-163°C from ~i~h~~ro~~a~~~ methanol (lit, (9) m.p. 162-163'C). 178-Methoxy-5a-androst-2-ene (Va) 17B-Hydroxy-5a-androst-2-ene (Vb) (0.4 g) (prepared by hydrolysis of the 17B-acetate (Vc) (10,ll)) was treated with sodium hydride (48 mg) and iodomethane (0.13 mL) as described by Brown and Barton (12) to give the methyl ether (320 mg) m.p. 58-59°C from methanol. Anal. C,83.18; H,f1.03. C H 0 requires C,83.27; H,11.18. 17~-Methoxy-~,~-oxido-~~~n a gostane (Via) To a stirred solution of 178-methoxy-5a-androst-2-ene (Va) (1.0 g) in dichloromethane (10 mL) at 0°C was added m-chloroperbenzoic acid (0.6 9). After 2 h excess aqueous sodium sulfite was added to give on ether extraction the 2o,3a-epoxide (0.72 g) m.p. 108-110°C. Anal. C,79.02; H,10.88. C H 0 requires C,78.90; H,10.59. 25132 2 178-methoxy-.W17@-Methoxy-2@-methyl-5u-an rostan-k-01 (Iii) and androstan-3-one (Ib) 17S-Methoxy-&,h-epoxy-5ol-androstane (Via) (306 mg) was treated et al (13) to give with l~thiumdimet~yl cuprate as described by Johnson -a product wh' +I. on passing through a silica gel column in 25% ethyl
STEREOSELECTIVE
REDUCTlON
OF KETONES
341
acetate/hexane, gave 178-yth oxy-5c+androstan-3-one (Ib) (65 mg) m.p. 118-120°C from methanol. H NMR was identical with that of the material prepared as described below. Anal. C,78.67; H,10.79. Ci,.JH3202 requires C,78.90, H,10.59. Further elution gave I78-methoxy-2B-methyl-5cl-androstan-3@ol (Iii) (70 mg) m.p. 159-161°C from acetone. Anal. C,78.77; H,11.46. C H 0 requires C,78.70; H,11.32. 21 36 $ 17B-Methoxy-5a-androstan-3-one ( b) To 17B-hydroxy-5a-androstan-3-one (500 mg) in dimethylformamide (10 mL) was added silver oxide (400 mg) and iodomethane (2 mL), and the mixture was stirred for 24 h. The reaction was filtered, diluted with water, and extracted with dichloromethane to give a residue which, on chromatography on silica,gave on elution with 25% dichloromethane/hexane the 17g-methoxy derivative (100 mg) m.p. 120-122°C from methanol. 17~-Methoxy-2~-methyl-5a-androstan-3-one (If) 178-Methoxy-2~-methyl-So-androstan-~-01 (Iii) (200 mg) in acetone at 0°C was treated with an excess of Jones reagent (14) for 10 min. Dilution with water and ether extraction yielded l?B-methoxy-28-methyl5a-androstan-3-one (120 mg) m.p. 68-72°C from methanol. Anal. C,79.36; H,ll,Ol. C H 0 requires C,79.19; H,10.76. Reduction of 17S-methoxy-2~~m~$h~l-5a-androstan-3-one (If) From NaBH : If (200 mg) gave the 3B-alcohol (IIj) (150 mg) m.p. 162-164°C from4methanol. Anal. C,78.74; H,11.56. C H 0 requires C,78.70; H,11.32. ic2 loro- 5a- androstan-3-one (IIIa) Reduction of 17B-acetoxy-2fJ-d6 The dichloroketone (IIIaf m.p. 166-168°C was prepared as described in reference 15 (lit. (15) m.p. 166-16a0c). Prom LS-Selectride: 38alcohoi (IVa) m.p. 165-167°C from dichloromethane/methanol (lit. (15) m.p. 165-167°C). ;la-Chloro-5a-androstane-b,l7B_diol 17-acetate (IIg) The chlorohydrin m.p. 213-215'C (lit. (16) m.p. 215-217'C) was prepared from the- 2a,3a-epoxide as described by Guzman -et al (16). 178-Acetoxy-2S-chloro-5a-androstan-3-one (Ie) To the chlorohydrin (IIg) (400 mg) in dichloromethane (10 mL) was added pyridinium trifluoroacetate (100 mg) and pyridinium dichromate (4 9). After 8 h the reaction mixture was passed through a column of silica in dichloromethane, and the eluate was washed with aqueous 5% sodium bisulfite and evaporated to give a residue which, on repeated recrystallization from dichloromethane/methanol,gave the 2f-chloroketone (100 mg) m.p. 150-154"C,free from the Zcl-chloroepimer by H NMR. Anal. C,68.52; H,8.46; Cl, 9.81. C21H3103C1 requires C,68.74; H,8.52; C1,9.66. -Reduction of 17@-acetoxy-2B-chloro-5a-androstan-3-one (Ie) Prom NaBH,: Ie (ZOO mg) gave the 3F-alcohol (IIh) (100 mg) m.p. 174-175°C from4di=bloromethane /methanol. Anal. C,68.36; H,8.97; C1,9.78. C21H3303Cl requires C,68.37; H,9.02; C1,9.61. From LS-Selectride: Ie (100 mg) gave on HPLC separation the 3S-alcohol (IIh) (73 mg) m.p. 175-176°C and the 3a-alcohol (IIg) (27 mg) m.p. 212-214°C. 2,2-Dimethyl-l7B-methoxy-5a-androstan-3-one 178-methoxy(IIIb) and 2,2,4,--trimethyl-5a-androstan-3-one (VII). 17B-Methoxy-5a-androstan-3-one (Ib) (290 mg) was added to a solution of 0.4 M potassium t-butoxide in t-butanol (20 mL) in an argon
342
Templeton
et a/
atmosphere. Iodomethane (2 mL) was added and the mixtur-2 refluxed for 1 h as in the method of Mazur and Sondheimer (17). li i: reaction mixture was diluted with water and extracted with ether to give a product which on chromatography over silica gel gave on elution with 5% dichloromethane/cyclohexane the trimethylketone (VII) (50 mg) m.p. 119-120°C frcm dichloromethanelmethanol. Anal. C,80.00; H,11.02. C,,H O2 requires C,79.71; H,11.05. Further elution witfi3 ?oO L dichloromethane/cyclohexane gave the dimethylketone (IIIb) (158 mg) m.p.123-124'C from dichloromethane/methanol. Anal. C,79.36; H,ll.Ol. C H 0 requires C,79.46; H,10.91. Reduction of 2,2-dimethyl-?'?S%e$hoxy-5a-androstan-3-one (IIlb) From LS-Selectride: IIIb (85 mg) gave after HPLC separation the 3a-alcohol (JVb) (75 mg) m.p. 18i-188°C from dichloromethnne/methanol; Anal. C,79.32; H,11.74. C H 0 requires C,78.99; H,11.45, and the 3S-alcohol (IVc) (10 mg) m.p. 22 1%-2183"C from dichloromethane/methanol. Anal. C,79.11; H,11.81. C2 I-138O2 requires C,78.99; H,11.45. 2B-Methyl-5n-cholestan-3n-o 3 and 5a-cholestan-3-one 2a,3a-Epoxy-5n-cholestane (2 g) was treated with lithiumdimethyl cuprate as described by Johnson -et al (13) to give a product which,on chromatography over silica gel, gave on elution with hexane: first, the C-3 ketone (0.35 g) mlp. 127-129°C from dichloromethane/methanol (lit. (19) m.p. 127-129"C), H NMR (fZ713CH 1.00 ppm) (20) was identical with C Nd was in agreement with published an authentic sample and the values (21); second, the ZB-methyl-3a-alcohol (1.12 g;) m.p. 122-124°C from dichloromethane/methanol (lit. (22) 122-128OC). RESULTS
AND
Whereas
DISCUSSION
the C-3 ketone is reduced by sodium borohydride to give
predominantly the equatorial (30) alcohol in the 2a-unsubstituted (18), 2a-chloro (a), 2B-chloro, 2n-methyl
(9), 2B-methyl, 2,2-dichloro
(153
and 2,2-dimethyl C-3 ketones (see Table l),reduction with lithium tris(R,S-1,2-dimethylpropyl)-borohydride gives with the axial alcohol in the unsubstituted
high stereoselectivity
(2,3), 2d-chloro,and
2a-methyl
compounds, but predominantly the equatorial alcohol with the 2S-chloro, 2S-methyl, 2,2-dichlorb, and 2,2-dimethyl derivatives.
The introduction
of the axial 2S-substituent therefore reverses the stereochemistry of the reduction.
Approach of the reagent from the &face would be inhib-
ited by the presence of the C-2 axial substituent, and therefore *face reduction occurs.
These results demonstrate that the stereoselectivity
of the reagent is unaffected by the presence of an adjacent equatorial
STEREOSELECTIVE
REDUCTION
OF KETONES
343
OR
Ia Ib IC
Id Ie If
R=Ac, X=H R=Me, X=H R=Ac, X=aCl R=Prop., X=Me R=Ac, X=BCl R=Me, X=gMe
111s IIIb
R=Ac, X=Cl R=Me, X=Me
TABLE 1.
IIa IIb IIC IId IIe IIf IIg IIh Iii IIj
R=Ac, X=H, aOH R=Ac, X=H, @OH R=Ac, X=&l, aOH R=Ac, X=&l, BOH R=Prop., X=uMe, oOH R=Prop., X=aMe, @OH R=Ae, X=&Z, o.OH R=Ae, X=BCl, 8OH R=Me, X=BMe, oOH R=Me, X=BMe, 8OH
IVa IVb IVc
R=Ac, X=Cl, @OH R=Me, X=Me, aOH R=Me, X=Me, BOH
STEREOS~LECTIVE REDUCTION OF STEROID C-3 KETONES WITH BOROHYDRIDE RFAGENTS
.5ot-Androstan-3-one derivative
Li[CH(CH3)CH(CH3)2]BH %3aOH
2-unsubstituted (178-acetoxy)(Ia) 2a-chloro(l78-acetoxy)(Ic) Zcr-methyl (17~propionyloxy)(Id) 2&chloro(l7&acetoxy)(fe) 2&methylf17&methoxy)(If) 2,2-dichloro (178-acetoxy)(IIIa) 2,2-dimethyl (178-methoxy)(IIIb)
X3BOH
lOO(IIa) * 100(11c) * lOO(IIe) * 25(IIg) 75(IIh) * lOO(IIj) * lOO(IVa) 15(IVb) 85(IVc)
NaBH4 X3aOH
%38OH
lO(IIa) 90(IIb) 4O(IIc) 60(IId) 24(IIe) 76(IIf) lO(IIg) 90(IIh) 5(IIi) 95(IIj) * lOO(IVa) lZ(IVb,)88(IVc)
1 Relative percentages of C-3 epimers were estimated from H NMR. Complete reduction of the ketone to the mixture of epimers (by TLC) was obtained in all reactions. *Not detected by 1H NMR or HPLC.
344
Templeton
et a/
substituent in the steroid C-3 ketone but is reversed in the 28- and 2,2_disubstituted derivatives which possess a B-face substituent. 17B-Acetoxy-2B-chloro-5cr-androstan-3-one (Ie) methoxy-5a-androstan-3-one
(If) were
prepared
as
and shown
2B-methyl-170in Scheme
I.
Treatment of 2a,3a-epoxy-5a-cholestane with lithiumdimethyl cuprate has been reported (13) to give the C-2 ketone as a major byproduct as well as 2S-methyl-5a-cholestan-3a-01.
Repetition of this experiment, however,
gave the C-3 ketone clearly distinguishable from the C-2 13 C NMR lH NMR (20) and epoxy-br-androstane
(21).
ketone
by
Similar treatment of ITS-methoxy-2u, 3o.-
(Via) gave 17B-methoxy-2R-methyl-5cl-androstan-3c+ol
(Iii) and the corresponding C-3 ketone, 178-methoxp-5cl-androstan-3-one (Ib).
Formation
of
the C-3
ketone
mechanism (13) for the reaction.
is consistent with
the proposed
Synthesis of 17B-methcxy-5c+androstan-
3-one (Ib) from 17B-hydroxy-5a-androstan-3-one gave a product identical with
that obtained from reaction of the 2a,3a-epoxide with dimethyl-
lithium cuprate. 2S-methyl-3-ketone
Oxidation of the 2B-methyl-3a-alcohol (Iii) gave the (If).
Opening the epoxide
(VIb) with hydrochloric
acid gave predominately the 2B-chloro-3a-alcohoi dized to the 2S-chloro-3-ketone (Ie).
(ITg) which was oxi-
1.21 1.07
1.05
0.86 0.87 0.76 0.76 1.07
0.81 0.76
0.79
0.74 0.73 0.76 0.74 0.76
IIIa IIIb
IVa
IVb IVC Va Via VII
1.05 1.06 0.85 0.87
0.78 0.77 0.77 0.74
II& IIh IIL IIj
4.58,dd,J=7.2,9.0 Hz
2.03
3.21,dd,J=7.5,8.2 Hz 3.19,t,J=8.2 Hz 3.21,dd,J=8.0,8.5 Hz 3.21,t,J=8.0 Hz 3.20,t,J=8.3 Hz
4.59,dd,J=7.0,9.0 Hz 3.19,t,J=8.2 Hz
4.58,dd,J=7.8,9.0 Hz 4.58,dd,J=J.8.9.2 Hz 3.18,t,J=9.0 Hz 3.16,t,J=8.2 Hz.
2.03
2.03 2.02
5.4,ll.O Hz(3aH) 2.31,d,J=15.0 Hz (1aH); 3.05,d,.J=15.0 Hz (IaH) 1.00 & 1.16 (2a & 2RMe); 2.43,dd,J=13,5,15.9
HZ
TABLE 2. 1H MEfR SPECTRA OF 5~-~DROST~~ D~RIVAT~V~Sa C-13CH, C-lOCH, 17&OAc 17crH NO. Other Ib 0.77 -. 1.01 * 3.21.t,J=8.3 Hz 3.34 (l.7!3-OMef 1.10 .54,dd,J=6.3;12.8 Hz (1BH); 4.57,dd,J=6.0,13.3 Hz(2BH) 2.04 4.59;dd,J=7.4,9.4 Hz 0.81 Ic .OO,d,J=6.4 Hz (2aMe),1.13,t,J=7.5 Hz (OCOCH2CH3), 0.81 1.07 4.58,dd,J=?.8,9.2 Hz Id .31,dd,J=7.5,15.0 Hz (OCOCH2CH3) 0.80 1.15 .g5,dd,J=13.7,15.6 Hz (4BH); 4.36,octet,J=1.2,3.7, 6.8 Ie 2.04 4.5Y,dd,J=7.8,9.3 Hz Hz (2aH) If 0.75 0.76 3.22,dd,J=8.0,8.5 Hz 3.34 (17B-OMe) 0.78 0.79 2.03 4.59,dd,J=7.8,9.1 Hz 4.05,m,(38H) IIa IIb 0.78 0.81 2.03 4.58,dd,J=7.8,9.1 Hz 3.59,m,(3aH) 0.78 2.03 4.58,dd,J=7.8,9.3 Hz 4.OO,w%=7 Hz (38H); 4.23,octet,J=2.7,4.6,12.7 Hz(2BH) TLC 0.83 3.88,sextet,J=5,1,10.3,10.3 Hz (3aH); 3.94,octet,J=4.6, IId 0.78 0.86 2.03 4.58,dd,7.8,9.0 Hz 9.7,12.4 Hz (2BH) IIe 0.77 0.79 4.59,dd,J=7.8,9.0 Hz 0.92,d,J=6.9 Hz (2aMe); 1.13,t,J=7.5 Hz (OCOCH2CH3); 2.31,dd,J=7.5,15.0 Hz (OCWH2CH ); 3.77 (3aH) IIF 0.77 0.82 4.58,dd,J=7.8,9.2 Hz 0.97,d,J=6.3 Hz (2aMe); 1.13,t,3=7.5 Hz (OCOCH2CHj,i, 2.32,dd,J=7.5,15.0 Hz (OCOCH2CH3); 3,13,sextet,J= . ,
346
Templeton
et a/
Reaction of 17S-methoxy-5cl-androstan-3-one (Ib) with excess iodomethane in potassium t-butoxide (17) gave a mixture of the Z,Z-dimethyland 2,2,4o_trimethylketones (IIIb and VII). ACKNOWLEDGMENTS
We thank the Medical Research Council of Canada for financial support and Diane Smith, Faculty of Pharmacy, University of Manitoba for assistance with the HPLC. We are grateful to the Lilly Research Laboratories, Indiana, USA,for a sample of 17S-propionyloxy-5o-androstan-3-one (dromostanolone propionate). REFERENCES
1. 2. 3. 4.
5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
19. 20. 21. 22.
Contreras, R. and Mendoza, L., STEROIDS 2, 121 (1979). Gondos, G. and Orr, J.C., J. CHEM 1239 sot CHEM COMMUN (1982). Templeton, J.F. and Jackson, C.C., STEROIDS 41, 485 (1983). Bridgeman, J.E., Cherry, P.C., Clegg, A.S., Evans, J.M.3 Jones, E.R.H., Kasal, A., Kumar, V., Meakins, G.O., Morisawa, Y., Richards, E.E.,and Woodgate, P.D., J CHEM SGC (C), 250 (1970). ApSimon, J.W., Demarco, P.V., Mathieson, D.W., Craig, W.G.3 Karim, A ., Saunders, L.,and Whalley, W.B., TETRAHEDRON 6, 119 (1970). De Vinar, A.R. and Romo, A., J ORG CHEM 6, 1490 (1959). Beereboom, J.J., Djerassi, C., Ginsburg, D., and Fieser. L-F., J AM CHEM SOC II, 3500 (1953). Wong, F., Mallory, R.A., Cotter, M.L., and Hirsch, A.F., STEROIDS 3_l, 605 (1978). Cross, A.D., Edwards, J.A., Orr, J.C., Berkoz, B., Cervantes, L-3 Calzada, M.C., and Bowers, A., J MED CHEM 6, 162 (1963). 7_, 577 (1964). Wolff, M.E., Ho, W.,and Kwok, R., J MED CHEM Templeton, J.F. and Kim, R.S., STEROIDS 7, 581 (1976). Brown, C.A. and Barton, D., SYNTHESIS, 434 (1974). CHEM 38 Johnson, C.R., Herr, R.W., and Wieland, D.M., J 0~ _' 4263 (1973). Bowden, K., Heilbron, I.M., Jones, E.R.H., and Weedon, B.C.L.9 J CHEM SOC, 39 (1946). Templeton, J.F., Kumar, S., and Zeglam. T-H.3 SYNTH CGMMUN g, 1333 (1984). PTI, Guzman, A., de Montollano, P.O.,and Crabbe, P., J CHEM SOC 91 (1973). Mazur, Y. and Sondheimer, F., J AM CHEM SGC 82, 3995 (1960). Wheeler, D.M.S. and Wheeler, M.M., in: Orgazc Reactions in Steroid Chemistry (Eds. Fried, J. and Edwards, J.A.), Vol 1, Van Nostrand Reinhold, New York (1972), pp 77-80. Serini, A. and Koster, H., CHEM BER 2, 1766 (1938). Bhacca, N.S. and Williams, D.H., Applications of nmr Spectroscopy in Organic Chemistry, Holden-Day, San Francisco (1964), p 19. Blunt, J.W. and Stothers, J.B., 3 MAGN RESON 48, 323 (1982). Djerassi, C., Finch, N., Cookson, R.C.,and Bird, C.W., J AM CHEM sot 82, 5488 (1960).
Lithium
tris-(R,S-l,~-dimeth~lpropyl)-~~orohydr~de (LS-Selectride)
is a valuable reagent for the stereoselective and regioseleetive reduction of steroid ketones (l-3) forming thataxial alcohols at C-3,
Axial
alcohols at C-3 in both natural and synthetic steroids are frequently formed as metabolites.
Investigation of the reduction of C-Z substi-
tuted steroid C-3 ketones with this reagent and with sodium borohydride was
carried
out
to determine
the effect
of
adjacent groups
on the
stereochemistry of ketone reduction. EXPERIMENTAL Alcohol epimers (Table 1) were separated with HPLC (Waters M45 instrument, RI detector, with a n-Porasil (10 p> column) in 10% ethyl acetate/ hexanc (unsubstituted and Za-chloro) or 1% e~llanol/d~~hloromethane (all others). Alcohol fractions were collected and H Nl.fR (CDC13) spectra recorded (Bruker AM3OO) to establish fraction homogeneity and alcohol stereochemistry (C-3H coupling) (4). Column chromatography was carried out on silica gel (Merck type 60 H for TLC). In all cases the lcorresponding alcohols obtained from either reagent showed identical H NMR spectra (see Table 2). TLC was performed on silica gel (Merck type 60 H) and eluted with chloroform (2n-chloro) or 25% ethyl acetate/hexane (all others).
STEROIDS 48 / 5-G
November-December
1986 (339-346)
339
340
Templeton
et al
LS-Selectride: Reduction of the ketones (1 mmol) was carried out in freshlv , distilled dry tetrahydrofuran (6O‘mL), cooled in an acetone/dry ice bath under argon by addition of lithium tris-(R,S-1,2-dimethylpropyl)-horohydride (1.1 mL of a 1 M retrahydrofuran solution, LS-Selectride, Aldrich Chemical Co., Milwaukee, WI). Reactions were stopped at the times indicated when no starting ketone remained: the unsubstituted (20 min), 2a-chloroketone (Ic) (3 h), 24-chloroketone (Ie) (1 h), 2a-methylketone (Id) (4 h), 2@-methylketone (If) (1.5 h at O'C), 2,2-dichloroketone (IIIa) (20 min), 2,2-dimethylketone (IIIb) (4 h at O'C),as determined by TLC (Table 1). The reaction mixture was poured into ice-water containing an excess of mineral acid, stirred for 2 h and extracted with ether. Sodium borohydride: Reductions were performed by addition of NaBH4 (1 mmol) to a solution of the ketone (I mmol) in 95% ethanol (17 mL), the mixture stirred at room temperature for 20 min, poured into excess cold mineral acid,and ether extracted (TLC indicated reactions were complete after 5-10 min). Epimeric mixtures were obtained from both the LS-selectride and BaBH, reductions below as shcwn in Table 1. Redugtion of 178-acetoxy-5a-androstan-3-one (Ia) From LS-Selectride: 3n-alcohol (IIa) m.n. 184-185°C from dichloromethane/methanol (lit. (5)m.p. 186-187°C). From NaBH : Ia (500 mg) gave the 3S-alcohol (IIbj (300 mg) m.p. 149-151°C from d4chioromethane/methan01 (lit. (6) m.p. 150-151'C). Reduction of 1X3-acetoxy-Za-chloro-5o-androstan-3-one (Ic) The 2a-chloroketone was prepared by the method of Beereboom -et al (7) m.p. 180-18S'C (lit. (7) m.p. 185-i87'C); further recrystallization from dichloromethane/cyclohexane gave m.p. 198-2Ol'C. From LS-Selectride: 3~ alcohol (11~) m.p. 202-206.5"C from dichloromethane/methanol (lit. (8) m.p. 206-209°C). From NaBH : Ic (500 mg) gave the 3B-alcohol (IId) (50 mg) m.p. 198-201'C from ft-lchloromethane/methanol (lit. (8) m.n. 193-196°C). Reduction of Z&methyl-17$-propionyloxy-5n-androstan-3-one (Id) From LS-Selectride: 3a-alcohol (IIe) m.n. 167-169'C from dichlorom~thane/methanol (lit. (9) m.p. 168-170°C): From NaBN : gave the 3@-alcohol (IIf) (250 mg) m.p. 161-163°C from ~i~h~~ro~~a~~~ methanol (lit, (9) m.p. 162-163'C). 178-Methoxy-5a-androst-2-ene (Va) 17B-Hydroxy-5a-androst-2-ene (Vb) (0.4 g) (prepared by hydrolysis of the 17B-acetate (Vc) (10,ll)) was treated with sodium hydride (48 mg) and iodomethane (0.13 mL) as described by Brown and Barton (12) to give the methyl ether (320 mg) m.p. 58-59°C from methanol. Anal. C,83.18; H,f1.03. C H 0 requires C,83.27; H,11.18. 17~-Methoxy-~,~-oxido-~~~n a gostane (Via) To a stirred solution of 178-methoxy-5a-androst-2-ene (Va) (1.0 g) in dichloromethane (10 mL) at 0°C was added m-chloroperbenzoic acid (0.6 9). After 2 h excess aqueous sodium sulfite was added to give on ether extraction the 2o,3a-epoxide (0.72 g) m.p. 108-110°C. Anal. C,79.02; H,10.88. C H 0 requires C,78.90; H,10.59. 25132 2 178-methoxy-.W17@-Methoxy-2@-methyl-5u-an rostan-k-01 (Iii) and androstan-3-one (Ib) 17S-Methoxy-&,h-epoxy-5ol-androstane (Via) (306 mg) was treated et al (13) to give with l~thiumdimet~yl cuprate as described by Johnson -a product wh' +I. on passing through a silica gel column in 25% ethyl
STEREOSELECTIVE
REDUCTlON
OF KETONES
341
acetate/hexane, gave 178-yth oxy-5c+androstan-3-one (Ib) (65 mg) m.p. 118-120°C from methanol. H NMR was identical with that of the material prepared as described below. Anal. C,78.67; H,10.79. Ci,.JH3202 requires C,78.90, H,10.59. Further elution gave I78-methoxy-2B-methyl-5cl-androstan-3@ol (Iii) (70 mg) m.p. 159-161°C from acetone. Anal. C,78.77; H,11.46. C H 0 requires C,78.70; H,11.32. 21 36 $ 17B-Methoxy-5a-androstan-3-one ( b) To 17B-hydroxy-5a-androstan-3-one (500 mg) in dimethylformamide (10 mL) was added silver oxide (400 mg) and iodomethane (2 mL), and the mixture was stirred for 24 h. The reaction was filtered, diluted with water, and extracted with dichloromethane to give a residue which, on chromatography on silica,gave on elution with 25% dichloromethane/hexane the 17g-methoxy derivative (100 mg) m.p. 120-122°C from methanol. 17~-Methoxy-2~-methyl-5a-androstan-3-one (If) 178-Methoxy-2~-methyl-So-androstan-~-01 (Iii) (200 mg) in acetone at 0°C was treated with an excess of Jones reagent (14) for 10 min. Dilution with water and ether extraction yielded l?B-methoxy-28-methyl5a-androstan-3-one (120 mg) m.p. 68-72°C from methanol. Anal. C,79.36; H,ll,Ol. C H 0 requires C,79.19; H,10.76. Reduction of 17S-methoxy-2~~m~$h~l-5a-androstan-3-one (If) From NaBH : If (200 mg) gave the 3B-alcohol (IIj) (150 mg) m.p. 162-164°C from4methanol. Anal. C,78.74; H,11.56. C H 0 requires C,78.70; H,11.32. ic2 loro- 5a- androstan-3-one (IIIa) Reduction of 17B-acetoxy-2fJ-d6 The dichloroketone (IIIaf m.p. 166-168°C was prepared as described in reference 15 (lit. (15) m.p. 166-16a0c). Prom LS-Selectride: 38alcohoi (IVa) m.p. 165-167°C from dichloromethane/methanol (lit. (15) m.p. 165-167°C). ;la-Chloro-5a-androstane-b,l7B_diol 17-acetate (IIg) The chlorohydrin m.p. 213-215'C (lit. (16) m.p. 215-217'C) was prepared from the- 2a,3a-epoxide as described by Guzman -et al (16). 178-Acetoxy-2S-chloro-5a-androstan-3-one (Ie) To the chlorohydrin (IIg) (400 mg) in dichloromethane (10 mL) was added pyridinium trifluoroacetate (100 mg) and pyridinium dichromate (4 9). After 8 h the reaction mixture was passed through a column of silica in dichloromethane, and the eluate was washed with aqueous 5% sodium bisulfite and evaporated to give a residue which, on repeated recrystallization from dichloromethane/methanol,gave the 2f-chloroketone (100 mg) m.p. 150-154"C,free from the Zcl-chloroepimer by H NMR. Anal. C,68.52; H,8.46; Cl, 9.81. C21H3103C1 requires C,68.74; H,8.52; C1,9.66. -Reduction of 17@-acetoxy-2B-chloro-5a-androstan-3-one (Ie) Prom NaBH,: Ie (ZOO mg) gave the 3F-alcohol (IIh) (100 mg) m.p. 174-175°C from4di=bloromethane /methanol. Anal. C,68.36; H,8.97; C1,9.78. C21H3303Cl requires C,68.37; H,9.02; C1,9.61. From LS-Selectride: Ie (100 mg) gave on HPLC separation the 3S-alcohol (IIh) (73 mg) m.p. 175-176°C and the 3a-alcohol (IIg) (27 mg) m.p. 212-214°C. 2,2-Dimethyl-l7B-methoxy-5a-androstan-3-one 178-methoxy(IIIb) and 2,2,4,--trimethyl-5a-androstan-3-one (VII). 17B-Methoxy-5a-androstan-3-one (Ib) (290 mg) was added to a solution of 0.4 M potassium t-butoxide in t-butanol (20 mL) in an argon
342
Templeton
et a/
atmosphere. Iodomethane (2 mL) was added and the mixtur-2 refluxed for 1 h as in the method of Mazur and Sondheimer (17). li i: reaction mixture was diluted with water and extracted with ether to give a product which on chromatography over silica gel gave on elution with 5% dichloromethane/cyclohexane the trimethylketone (VII) (50 mg) m.p. 119-120°C frcm dichloromethanelmethanol. Anal. C,80.00; H,11.02. C,,H O2 requires C,79.71; H,11.05. Further elution witfi3 ?oO L dichloromethane/cyclohexane gave the dimethylketone (IIIb) (158 mg) m.p.123-124'C from dichloromethane/methanol. Anal. C,79.36; H,ll.Ol. C H 0 requires C,79.46; H,10.91. Reduction of 2,2-dimethyl-?'?S%e$hoxy-5a-androstan-3-one (IIlb) From LS-Selectride: IIIb (85 mg) gave after HPLC separation the 3a-alcohol (JVb) (75 mg) m.p. 18i-188°C from dichloromethnne/methanol; Anal. C,79.32; H,11.74. C H 0 requires C,78.99; H,11.45, and the 3S-alcohol (IVc) (10 mg) m.p. 22 1%-2183"C from dichloromethane/methanol. Anal. C,79.11; H,11.81. C2 I-138O2 requires C,78.99; H,11.45. 2B-Methyl-5n-cholestan-3n-o 3 and 5a-cholestan-3-one 2a,3a-Epoxy-5n-cholestane (2 g) was treated with lithiumdimethyl cuprate as described by Johnson -et al (13) to give a product which,on chromatography over silica gel, gave on elution with hexane: first, the C-3 ketone (0.35 g) mlp. 127-129°C from dichloromethane/methanol (lit. (19) m.p. 127-129"C), H NMR (fZ713CH 1.00 ppm) (20) was identical with C Nd was in agreement with published an authentic sample and the values (21); second, the ZB-methyl-3a-alcohol (1.12 g;) m.p. 122-124°C from dichloromethane/methanol (lit. (22) 122-128OC). RESULTS
AND
Whereas
DISCUSSION
the C-3 ketone is reduced by sodium borohydride to give
predominantly the equatorial (30) alcohol in the 2a-unsubstituted (18), 2a-chloro (a), 2B-chloro, 2n-methyl
(9), 2B-methyl, 2,2-dichloro
(153
and 2,2-dimethyl C-3 ketones (see Table l),reduction with lithium tris(R,S-1,2-dimethylpropyl)-borohydride gives with the axial alcohol in the unsubstituted
high stereoselectivity
(2,3), 2d-chloro,and
2a-methyl
compounds, but predominantly the equatorial alcohol with the 2S-chloro, 2S-methyl, 2,2-dichlorb, and 2,2-dimethyl derivatives.
The introduction
of the axial 2S-substituent therefore reverses the stereochemistry of the reduction.
Approach of the reagent from the &face would be inhib-
ited by the presence of the C-2 axial substituent, and therefore *face reduction occurs.
These results demonstrate that the stereoselectivity
of the reagent is unaffected by the presence of an adjacent equatorial
STEREOSELECTIVE
REDUCTION
OF KETONES
343
OR
Ia Ib IC
Id Ie If
R=Ac, X=H R=Me, X=H R=Ac, X=aCl R=Prop., X=Me R=Ac, X=BCl R=Me, X=gMe
111s IIIb
R=Ac, X=Cl R=Me, X=Me
TABLE 1.
IIa IIb IIC IId IIe IIf IIg IIh Iii IIj
R=Ac, X=H, aOH R=Ac, X=H, @OH R=Ac, X=&l, aOH R=Ac, X=&l, BOH R=Prop., X=uMe, oOH R=Prop., X=aMe, @OH R=Ae, X=&Z, o.OH R=Ae, X=BCl, 8OH R=Me, X=BMe, oOH R=Me, X=BMe, 8OH
IVa IVb IVc
R=Ac, X=Cl, @OH R=Me, X=Me, aOH R=Me, X=Me, BOH
STEREOS~LECTIVE REDUCTION OF STEROID C-3 KETONES WITH BOROHYDRIDE RFAGENTS
.5ot-Androstan-3-one derivative
Li[CH(CH3)CH(CH3)2]BH %3aOH
2-unsubstituted (178-acetoxy)(Ia) 2a-chloro(l78-acetoxy)(Ic) Zcr-methyl (17~propionyloxy)(Id) 2&chloro(l7&acetoxy)(fe) 2&methylf17&methoxy)(If) 2,2-dichloro (178-acetoxy)(IIIa) 2,2-dimethyl (178-methoxy)(IIIb)
X3BOH
lOO(IIa) * 100(11c) * lOO(IIe) * 25(IIg) 75(IIh) * lOO(IIj) * lOO(IVa) 15(IVb) 85(IVc)
NaBH4 X3aOH
%38OH
lO(IIa) 90(IIb) 4O(IIc) 60(IId) 24(IIe) 76(IIf) lO(IIg) 90(IIh) 5(IIi) 95(IIj) * lOO(IVa) lZ(IVb,)88(IVc)
1 Relative percentages of C-3 epimers were estimated from H NMR. Complete reduction of the ketone to the mixture of epimers (by TLC) was obtained in all reactions. *Not detected by 1H NMR or HPLC.
344
Templeton
et a/
substituent in the steroid C-3 ketone but is reversed in the 28- and 2,2_disubstituted derivatives which possess a B-face substituent. 17B-Acetoxy-2B-chloro-5cr-androstan-3-one (Ie) methoxy-5a-androstan-3-one
(If) were
prepared
as
and shown
2B-methyl-170in Scheme
I.
Treatment of 2a,3a-epoxy-5a-cholestane with lithiumdimethyl cuprate has been reported (13) to give the C-2 ketone as a major byproduct as well as 2S-methyl-5a-cholestan-3a-01.
Repetition of this experiment, however,
gave the C-3 ketone clearly distinguishable from the C-2 13 C NMR lH NMR (20) and epoxy-br-androstane
(21).
ketone
by
Similar treatment of ITS-methoxy-2u, 3o.-
(Via) gave 17B-methoxy-2R-methyl-5cl-androstan-3c+ol
(Iii) and the corresponding C-3 ketone, 178-methoxp-5cl-androstan-3-one (Ib).
Formation
of
the C-3
ketone
mechanism (13) for the reaction.
is consistent with
the proposed
Synthesis of 17B-methcxy-5c+androstan-
3-one (Ib) from 17B-hydroxy-5a-androstan-3-one gave a product identical with
that obtained from reaction of the 2a,3a-epoxide with dimethyl-
lithium cuprate. 2S-methyl-3-ketone
Oxidation of the 2B-methyl-3a-alcohol (Iii) gave the (If).
Opening the epoxide
(VIb) with hydrochloric
acid gave predominately the 2B-chloro-3a-alcohoi dized to the 2S-chloro-3-ketone (Ie).
(ITg) which was oxi-
1.21 1.07
1.05
0.86 0.87 0.76 0.76 1.07
0.81 0.76
0.79
0.74 0.73 0.76 0.74 0.76
IIIa IIIb
IVa
IVb IVC Va Via VII
1.05 1.06 0.85 0.87
0.78 0.77 0.77 0.74
II& IIh IIL IIj
4.58,dd,J=7.2,9.0 Hz
2.03
3.21,dd,J=7.5,8.2 Hz 3.19,t,J=8.2 Hz 3.21,dd,J=8.0,8.5 Hz 3.21,t,J=8.0 Hz 3.20,t,J=8.3 Hz
4.59,dd,J=7.0,9.0 Hz 3.19,t,J=8.2 Hz
4.58,dd,J=7.8,9.0 Hz 4.58,dd,J=J.8.9.2 Hz 3.18,t,J=9.0 Hz 3.16,t,J=8.2 Hz.
2.03
2.03 2.02
5.4,ll.O Hz(3aH) 2.31,d,J=15.0 Hz (1aH); 3.05,d,.J=15.0 Hz (IaH) 1.00 & 1.16 (2a & 2RMe); 2.43,dd,J=13,5,15.9
HZ
TABLE 2. 1H MEfR SPECTRA OF 5~-~DROST~~ D~RIVAT~V~Sa C-13CH, C-lOCH, 17&OAc 17crH NO. Other Ib 0.77 -. 1.01 * 3.21.t,J=8.3 Hz 3.34 (l.7!3-OMef 1.10 .54,dd,J=6.3;12.8 Hz (1BH); 4.57,dd,J=6.0,13.3 Hz(2BH) 2.04 4.59;dd,J=7.4,9.4 Hz 0.81 Ic .OO,d,J=6.4 Hz (2aMe),1.13,t,J=7.5 Hz (OCOCH2CH3), 0.81 1.07 4.58,dd,J=?.8,9.2 Hz Id .31,dd,J=7.5,15.0 Hz (OCOCH2CH3) 0.80 1.15 .g5,dd,J=13.7,15.6 Hz (4BH); 4.36,octet,J=1.2,3.7, 6.8 Ie 2.04 4.5Y,dd,J=7.8,9.3 Hz Hz (2aH) If 0.75 0.76 3.22,dd,J=8.0,8.5 Hz 3.34 (17B-OMe) 0.78 0.79 2.03 4.59,dd,J=7.8,9.1 Hz 4.05,m,(38H) IIa IIb 0.78 0.81 2.03 4.58,dd,J=7.8,9.1 Hz 3.59,m,(3aH) 0.78 2.03 4.58,dd,J=7.8,9.3 Hz 4.OO,w%=7 Hz (38H); 4.23,octet,J=2.7,4.6,12.7 Hz(2BH) TLC 0.83 3.88,sextet,J=5,1,10.3,10.3 Hz (3aH); 3.94,octet,J=4.6, IId 0.78 0.86 2.03 4.58,dd,7.8,9.0 Hz 9.7,12.4 Hz (2BH) IIe 0.77 0.79 4.59,dd,J=7.8,9.0 Hz 0.92,d,J=6.9 Hz (2aMe); 1.13,t,J=7.5 Hz (OCOCH2CH3); 2.31,dd,J=7.5,15.0 Hz (OCWH2CH ); 3.77 (3aH) IIF 0.77 0.82 4.58,dd,J=7.8,9.2 Hz 0.97,d,J=6.3 Hz (2aMe); 1.13,t,3=7.5 Hz (OCOCH2CHj,i, 2.32,dd,J=7.5,15.0 Hz (OCOCH2CH3); 3,13,sextet,J= . ,
346
Templeton
et a/
Reaction of 17S-methoxy-5cl-androstan-3-one (Ib) with excess iodomethane in potassium t-butoxide (17) gave a mixture of the Z,Z-dimethyland 2,2,4o_trimethylketones (IIIb and VII). ACKNOWLEDGMENTS
We thank the Medical Research Council of Canada for financial support and Diane Smith, Faculty of Pharmacy, University of Manitoba for assistance with the HPLC. We are grateful to the Lilly Research Laboratories, Indiana, USA,for a sample of 17S-propionyloxy-5o-androstan-3-one (dromostanolone propionate). REFERENCES
1. 2. 3. 4.
5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
19. 20. 21. 22.
Contreras, R. and Mendoza, L., STEROIDS 2, 121 (1979). Gondos, G. and Orr, J.C., J. CHEM 1239 sot CHEM COMMUN (1982). Templeton, J.F. and Jackson, C.C., STEROIDS 41, 485 (1983). Bridgeman, J.E., Cherry, P.C., Clegg, A.S., Evans, J.M.3 Jones, E.R.H., Kasal, A., Kumar, V., Meakins, G.O., Morisawa, Y., Richards, E.E.,and Woodgate, P.D., J CHEM SGC (C), 250 (1970). ApSimon, J.W., Demarco, P.V., Mathieson, D.W., Craig, W.G.3 Karim, A ., Saunders, L.,and Whalley, W.B., TETRAHEDRON 6, 119 (1970). De Vinar, A.R. and Romo, A., J ORG CHEM 6, 1490 (1959). Beereboom, J.J., Djerassi, C., Ginsburg, D., and Fieser. L-F., J AM CHEM SOC II, 3500 (1953). Wong, F., Mallory, R.A., Cotter, M.L., and Hirsch, A.F., STEROIDS 3_l, 605 (1978). Cross, A.D., Edwards, J.A., Orr, J.C., Berkoz, B., Cervantes, L-3 Calzada, M.C., and Bowers, A., J MED CHEM 6, 162 (1963). 7_, 577 (1964). Wolff, M.E., Ho, W.,and Kwok, R., J MED CHEM Templeton, J.F. and Kim, R.S., STEROIDS 7, 581 (1976). Brown, C.A. and Barton, D., SYNTHESIS, 434 (1974). CHEM 38 Johnson, C.R., Herr, R.W., and Wieland, D.M., J 0~ _' 4263 (1973). Bowden, K., Heilbron, I.M., Jones, E.R.H., and Weedon, B.C.L.9 J CHEM SOC, 39 (1946). Templeton, J.F., Kumar, S., and Zeglam. T-H.3 SYNTH CGMMUN g, 1333 (1984). PTI, Guzman, A., de Montollano, P.O.,and Crabbe, P., J CHEM SOC 91 (1973). Mazur, Y. and Sondheimer, F., J AM CHEM SGC 82, 3995 (1960). Wheeler, D.M.S. and Wheeler, M.M., in: Orgazc Reactions in Steroid Chemistry (Eds. Fried, J. and Edwards, J.A.), Vol 1, Van Nostrand Reinhold, New York (1972), pp 77-80. Serini, A. and Koster, H., CHEM BER 2, 1766 (1938). Bhacca, N.S. and Williams, D.H., Applications of nmr Spectroscopy in Organic Chemistry, Holden-Day, San Francisco (1964), p 19. Blunt, J.W. and Stothers, J.B., 3 MAGN RESON 48, 323 (1982). Djerassi, C., Finch, N., Cookson, R.C.,and Bird, C.W., J AM CHEM sot 82, 5488 (1960).