Trost, Verhoeuen
(16) (17) (18) (19)
Steroid Side Chain uia Organopalladium Chemistry
hedron Lett., 3019 (1972); J. Meinwald, A. M. Chalrners, T. E. Pliske, and T. Eisner, Chem. Commun., 86 (1969). B. M. Trost and L. S. Melvin Jr., J. Am. Chem. Soc., 98, 1204 (1976). E. J. Corey, N. W. Gilrnan, and B. E. Ganern, J. Am. Chem. Soc., 90, 5616 (1968). (a) 0.P. Vig, J. C. Kapur, J. Singh, and 8.Vig, Indian J. Chem., 674 (1969); (b) B. A. Nagasarnpagi, L. Yankov, and S. Dev, Tetrahedron Lett., 189 (1967). For alternative syntheses of geranylgeraniol, see L. Ruzicka and G. Fir-
3435
rnenich, Helv. Chim. Acta, 22, 392 (1939); A. Caiiezi and H. Schinz. Helv. Chim. Acta, 35, 1649 (1952); t. N. Nazarov, B. P. Gussev, and V. I. Gunar, Zh. Obshch. Khim, 28, 1444 (1958) (Chem. Abstr., 53, 1102i (1959)):L. J. Altman, L. Ash, R. C. Kowerski, W. W. Epstein, B. R. Larsen, H. C. Rilling. F. Muscio, and D. E. Gregonis. J. Am. Chem. Soc.,94, 3257 (1972). (20) Y. Takahashi, S. Sakai, and Y. Ishii, Chem. Commun., 1092 (1967); Y . Takahashi, K. Tsukiyarna, S.Sakai, and Y. Ishii, Tetrahedron Lett., 1913 (1970). (21) M. Julia and J. M. Paris, Tetrahedron Lett., 4833 (1973).
Stereocontrolled Approach to Steroid Side Chain via Organopalladium Chemistry. Partial Synthesis of Sa-Cholestanone Barry M. Trost* and Thomas R. Verhoeven Contribution from the Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706. Received October 20, 1977
Abstract: Stereocontrolled introduction of an acyclic unit onto a cyclic system was accomplished using .rr-allylpalladium chem-
istry. Using stoichiometric palladium chemistry, methyl 3-methoxy-l9,24-bisnor-20-isocholane1,3,5( 10)-tetraenoate was synthesized from estrone methyl ether. Thus, steroids epimeric at C(20) to the natural series are available from the 17-keto compounds. Adternatively, steroids possessing the natural configuration at C(20) are available from the starting materials via a catalytic palladium reaction. Estrone methyl ether was converted to methyl 3-methoxy- 19,24-bisnorchoIane-l,3,5(lO)-tetraenoate. A partial synthesis of 5a-cholest-24-enone and Sa-cholestanone was achieved from testosterone.
Introduction The total synthesis of steroids represents one of the great challenges to synthetic chemists and has culminated in several elegant and practical approaches to this ring One problem in steroid synthesis that has received considerably less attention is the stereocontrolled introduction of the cholesteryl side chain. The importance of this problem is heightened by the interest in ecdysones (insect molting hormones), the metabolites of vitamin D, and other unusual steroids possessing substituted side chains. Biosynthetic and metabolism studies of cholesterol have generated a need for modified side chains. Furthermore, the stereocontrolled attachment of an acyclic side chain onto a ring system constitutes an oftentimes encountered problem. The methodology developed for the steroid system should have broader applicability. The problem factors down into two major concerns-( 1) the ability to add the necessary carbon framework with appropriate substitution for further elaboration and (2) the creation of stereochemistry at C ( 17) and C(20). To circumvent the latter difficulty, several approaches have used a bisnorcholanic acid derivative in which both these centers already exist in the proper s t e r e ~ c h e m i s t r y .Indeed, ~ a recent synthesis of a 24,25-dihydroxy system employed this ~ t r a t e g yThe . ~ center at C ( 17) is not a major problem since catalytic reduction of AI6 or A17(20)steroids does introduce hydrogen in the 17a c ~ n f i g u r a t i o n .The ~ main difficulty rests in the creation of C(20). Reduction of or A20(22)unsaturated steroids has led to the R configuration a t C(20) with varying degrees of cont r 0 1 . ~ ,Most ~ recently, the formation of the (E)-A20(22)unsaturated isomer via a wittig reaction on a 17-acetyl steroid followed by catalytic hydrogenation has been claimed to give only the natural configuration a t C(20),7 although this has been q ~ e s t i o n e d Alkylation .~~ of the enolate of a 170-carbomethoxymethyl steroid with 4-methylpentyl bromide is also reported to give a single epimer.8 A most elegant solution to 0002-7863/78/1500-3435$01 .OO/O
the problem involved the introduction of the side chain with correct stereochemistry via a Claisen-Johnson rearrangement concomitant with creation of the D ring.g The fact that the reduction of AI6 unsaturated steroids provides the desired configuration a t C ( 17) allows simplification of the problem to one of allylic alkylation with stereochemical control a t a n acyclic carbon. Using palladium as a template to provide conformational rigidity to direct the stereochemistry appeared to be a reasonable approach to the general problem of stereocontrol in conformationally nonrigid (e.g., acyclic or macrocyclic) systems. Depending upon the stereochemistry of formation of the new C-C bond with the complexed species, either 1 or 2 would be required. The req-
,Pd, 1
2
Y
uisite complexes should be available from olefination procedures on a C(17) ketone. Indeed, the ready availability of 17-keto steroids makes them most attractive as starting materials. We, therefore, undertook an investigation of the stereochemistry of alkylation of ir-allylpalladium complexes which has resulted in the ability to form either epimer.I0 Results Our investigation began with estrone methyl ether (3) which was converted to the 17-ethylidene derivative 4 via the Wittig reaction." W e find that use of potassium tert-butoxide in refluxing THF to be the better conditions (81%) compared with dimsylsodium in MezSO (5%) in our hands. The Z configuration is assigned in analogy to the literature. A small amount of the E isomer is detectable in the N M R spectrum (6 0.78) of the crude mixture which was removed in the subsequent 0 1978 American Chemical Society
3436
Journal of the American Chemical Society
Scheme I. Preparation and Alk) lation of Bis[chloro(16,17,19-q33-nietlioxy-19-norprefna-l,3,5(10),17(20)-tetraene)palladium(II)]
/
1OO:ll
1 May 24, 1978
Scheme 11. Preparation and Alkylation of (20S)-3-MetIiouyaceto\ynorpregna-1,3,5(10),16-tetraene (17)
0 CH3.H OAc
L
A
#-=
CH30
-
h
16
Z 20 r C O z H
18
{&OH
N
Q'R=CH,
?OR
13
A
1L
OR
A
R=H
Y
11
A
recrystallization. Treatment with sodium tetrachloropalladite under our standard conditionsI2 gave the a-allylpalladium complex 5 in 67% isolated yield. NMR spectroscopy allows the assignment of the syn stereo~hemistry.'~ In particular, anti protons or methyl groups are shielded by the palladium relative to the syn substituents. Thus, in complexes 6 and 7 this effect 66.37
61.19
6
A
61.39
LI
L
63.L2
I
8
7
c
4 I
C H g .-OH p
H 63.81
c i
61.1~~ lH63.71 ~3
.Pd. CI
crystalline acids 13 and 13' (Scheme I). The melting points of the two samples were identical, but, most significantly, the mixture melting (which ultimately proved to be the best technique to differentiate the C(20) isomers) led to no depression. To discern the stereochemistry, hydroxylation and lactonization gave the crystalline hydroxy lactone 14 (mp 250-251 "C). On the basis of cis-a-hydroxylation, the stereochemistry a t C(16) and C(17) is assigned as shown. Europium(+3) induced shifts differentiates between 2 0 s and 20R. In particular, in the 2 0 s configuration, the C(21) methyl group should be more deshielded than the C(18) methyl group because of its closer proximity to the europium which complexes preferentially to the hydroxyl group. On the other hand, in the 20R isomer 15, the distances for nearest approach for the C( 18) and
L
9
A
is clearly seen and is independent of ligand.13CThe stereochemistry of 9 has been independently established by x-ray ~ r y s t a l l o g r a p h yIn . ~ ~5, the signals for the methyl protons, Ha, and H b appear at 6 1.26, 3.56, and 3.74-in excellent accord with the shifts expected for the syn not anti isomer. The assignment of the palladium on the a face is based upon steric considerations and the fact the absorption for the angular methyl group (6 1 .OO) is almost the same as in the starting olefin 4. A strong shielding by palladium would be expected if it were on the fl face. Alkylation of 5 required activation by phosphorus ligands.I5 While triphenylphosphine, hexamethylphosphorous triamide, and bis( 1,2-diphenylphosphino)ethane(6) can be employed, best results were obtained with the bidentate ligand 6. Both the sodium salt of dimethyl malonate and methyl phenylsulfonylacetate led to alkylation exclusively at C(20) to give 10 and 11 in 81 and 82% yield, respectively. T o determine the configuration a t C(20), 10 was decarbomethoxylated to 12 with lithium iodide-sodium cyanide in hot D M F (46%)16 or preferably with tetramethylammonium acetate in H M P A a t 100 "C (87-91%).17 Desulfonylation of 11 with calcium in refluxing liquid ammonia gave a compound 12' identical by N M R and IR spectroscopy with that obtained by decarbomethoxylation of 10. Because of the known difficulty in differentiating isomers a t C(20), both samples of 12 (Le., 12 and 12') from 10 and 11, respectively, were hydrolyzed to the
15
N
C(21) methyl groups are -4.8 and 5.0 A (from Dreiding models) and similar shifts are anticipated (vide infra). Table I summarizes the shift data which clearly attest to the S configuration. Thus, alkylation of the a-allyl complex proceeds on the face opposite p a 1 l a d i ~ m . I ~ An alternative approach to allylic alkylation generates the intermediate a-allylpalladium complex from allylic derivatives such as allylic acetates upon treatment with a palladium(0) ~ o m p l e x . ' *For ~ ~this ~ approach, the allylic acetate must be available in a stereocontrolled fashion. Scheme I1 outlines the sequence. Epoxidation gives a single crystalline (mp 90.5-92 "C) epoxide 16 in quantitative yield assigned the a configuration based upon steric approach control. Base catalyzed epoxide ring opening was sensitive to reaction conditions.20.21 In most cases, a mixture of 17 and the vinyl alcohol 17a re&OH
suiting from anti-Markownikoff elimination toward the methyl group was observed. However, addition of 5 equiv of lithium diethylamide in hexane to a solution of 16 in hexane containing 2 equiv of H M P A gave a 74% yield of a homogeneous crystalline acetate (mp 124.5-126 "C) after workup with acetyl chloride. The stereochemistry a t C(20) is unaffected by this reaction and thus can be assigned S . Addition of the allylic acetate to a THF solution of tetrakis(tripheny1phosphine)palladium and excess triphenylphos-
Trost, Verhoeven
1 Steroid Side Chain uia Organopalladium Chemistry
3437
Table I. Eu(dpm)3a Induced Proton Shiftsb on 14 % Eu(dpm)3
Substituent
0
3.3
7.8
11.0
16.7
23.4
33.4
Total shift, Hz
C- 18 methyl C-21 methyl C-16 methine
0.80 1.27 4.53
0.82 1.27 4.64
0.85 1.33 4.92
0.92 1.45 5.32
1.06 1.65 6.10
1.32 2.02 7.20
1.67 2.57 9.40
87 130 487
Europium tris(dipivaloy1methide).
All shifts are in parts per million internal Me4Si a t 100 M H z unless otherwise stated.
Table 11. Eu(dpm)ja Induced Proton Shiftsb on 15 % Eu(dpm)3
a
Substituent
0
0.9
2.6
8 .o
11.6
15.2
17.0
22.4
30.0
Total shift, Hz
C-18 methyl C-21 methyl C- 16 methine 21-HR
0.96 1.15 4.30 3.19
0.96 1.16 4.33 3.20
0.97 1.19 4.40 3.26
1.11 1.30 5.26 3.78
1.15 1.37 5.50 3.91
1.22 1.44 5.96 4.18
1.32 1.53 6.53 4.50
1.47 1.67 7.51 5.05
1.81 1.98 9.39 6.17
85 83 509 298
Europium tris(dipivaloy1methide).
All shifts are in parts per million from internal Me4Si a t 100 MHz unless otherwise stated.
Schcme 111. Prcparation and Alkqlation of (Z)-3-\Iethosy-l6aacetos~norpre~na-l.3.5~10).17~20)-tctraenc
allylic alkylation. The fact that the new carbon-carbon bond formed at the same carbon that bore acetate raised the question of the intermediacy of a true a-allylpalladium complex. To answer this question the allylically related acetate 21b was synthesized and alkylated (see Scheme 111). Oxidation of olefin 4 with selenium dioxide22gave the allylic alcohol 21a in 65% yield contaminated by the corresponding
QR=H
b)R=Ac H C02CH3
21b
4
-
-
23
2L
dc02cH3
L18
h
phine a t room temperature followed by addition of a solution of dimethyl sodiomalonate in T H F led after refluxing for 20 h to an 83% yield of a homogeneous alkylation product 18. However, the great similarity of its properties, chromatographic and spectroscopic, to those of 10 did not allow us to conclude their identity or nonidentity. Decarbomethoxylation using the tetramethylammonium acetate procedure produced 19 whose properties also very closely resembled those of 12. Hydrolysis led to a crystalline carboxylic acid whose melting point (162.5-164 "C) was virtually identical with that of 13; however, a mixture melting point led to a severe melting point depression (mmp 139-155 "C). Thus, alkylation via the catalytic procedure gave a different stereochemistry from and complementary stereochemistry to that f r o m the stoichiometric procedure! To confirm the epimeric nature of 19, it was converted to the hydroxy lactone 15, mp 202-203 O C , which was clearly quite distinct in its properties from those of 14. Most significantly, the europium(+3) induced 'H N M R shifts (see Table 11) gave a similar overall shift of the 18- and 21-methyl groups as expected (vide supra). In this case the HRproton at C(21) could be easily discerned as a dd ( J = 16, 7 Hz) a t 6 3.19. The fact that it shifts -3.5 times more than the C-21 methyl group confirms the conclusion based upon the relative shifts of the two methyl groups. T o confirm the catalytic activity of the palladium(0) complex, a control experiment involved alkylation of 17 under identical conditions but in the absence of the complex. Only elimination product was observed, it being formed a t a very slow rate. It is interesting to note the regiospecificity of this
ketone 22 (26% yield). The alcohol was directly converted to the allylic acetate 21b (mp 108-109 "C) in usual fashion. The stereochemistry of 21b was assigned on the basis of N M R spectroscopy and mechanistic considerations. The Z configuration of the olefin was clearly indicated by the similarity of the proton shifts. In particular, the C(18) and C(21) methyl groups experience a deshielding due to steric compression in the Z isomer compared to the E isomer. For example, 4 exhibits the C ( 18) methyl a t 6 0.92, whereas the corresponding E isomer exhibits this methyl group at 6 0.79. The appearance of the 18- and 21-methyl groups of 21b (6 0.90 and 1.74) a t virtually the identical positions with those of 4 suggests the same olefin configuration. Europium(+3) induced shifts (1 8.8 mol %) also support this assignment since the vinyl proton at C(20) (A6 = 240 Hz) shifts four times more than the 21methyl group (A6 = 59 Hz). Mechanistically, initial attack of selenium dioxide should occur on the a face to give allylselenic acid 23.22bSigmatropic rearrangement on the /3 face would lead to the 16P-hydroxy Eisomer; 2,3 shift on the less hindered a face should produce 16a-hydroxy Z-A'7(20) isomer. The fact that the olefin geometry is clearly Z suggests that the configuration of the hydroxyl group is a. Confirmation of this conclusion came from reduction of enone 22 with DIBAL which gave a mixture \
22
N
of alcohols in which one isomer greatly predominated and differed from 21a. Based upon the antieipated preference for CY hydride attack, it was assigned the 16p configuration 25 (6 5.54 (1 H , q), 4.42 (1 H , m), 1.77 (3 H , d), 1.07 (3 H, s)). Alkylation of 21b proved substantially more difficult than that of 17. N o reaction occurred in THF under conditions identical with that used for 17. To achieve partial alkylation, heating in MeZSO at 120 OC with dimethyl sodiomalonate and
Journal of the American Chemical Society / 1OO:l I
3438
Scheme I\'. S>nthesis of Sa,A24Cholestenone and Sa-Cholestanone
26
28
29
21
QR=H b)R=Ac
H SoZPh
l/v
S02Ph
8S%X96%
S0,PI
