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Catalytic hydrogenation of PSa and PSm diace- which completely substantiatesKlyne’s formulation tates followed by alkaline hydrolysis yielded the for cholesterol. Marker and Turnerlg converted known DPSa and DPSml2 which were found to be diosgenin to cholesterol by a route which could not identical to D20-iSa and D20-iSm, respectively. affect the acid stable C ~ configuration O (I) found in Mild oxidation of 20-iSa and 20-ism with Cr03- all natural steroidal sapogenins. Marker and copyridinels gave the respective 3 keto derivatives; workersZ0s2lalso showed that diosgenin, tigogenin 3 keto-20-iSa (m.p. 15lo, [ a I z 5+20°, ~ strong ke- and smilagenin all have the same side chain, a fact tonic band a t 1714 kr.; Calcd. for C27H4203: C, also confirmed by infrared s t u d i e ~ . ~Conse.~ 78.21; H, 10.21. Found: C, 78.24; H, 10.04); quently the side chain configurations of cholesterol 3 keto-20-ism (m.p. 162”, [ a I z 5-55’; ~ ketonic and smilagenin a t CZOare identical. We have shown band a t 1714 kr.; Calcd. for C27H4203: C, 78.21; that the CZO configuration of smilagenin is 20-alpha. H, 10.21. Found: C, 78.14; H, 10.18). Reflux Hence cholesterol and most other natural sterols with alcoholic HC1 resulted in formation of the and bile acids which have been related to it have known 3 keto-Sa (sarsasapogenone), map. 223’ and the 20-alpha configuration with respect to the rest 3 keto-Sm (smilagenone), m.p. 188’ identical with of the molecule. the products of CrO3-pyridine oxidation of Sa and These findings confum by an independent route Sm. the previous conclusions of Wieland and Miescher.22 Mild oxidation of 20-iSa and 20-ism with Cr03- These workers showed that A5-3P-acetoxy-bisnoracetic acid yielded amorphous acids which on treat- cholenic acid could be converted to A6-pregnen-3P,ment with KOH in t-butyl alcohol were smoothly 20a-diol as a result of the action of perbenzoic acid. cleaved to the known 16-pregnen-3,20-dione, (m.p. Turnerza later showed that this type of reaction 20&201O, [ a I z 5 D +69.3’, Am,, 239 mp, log E 3.98). proceeds with retention of configuration. Hence Similar treatment of DBO-iSa and D20-ism also the bisnor-cholenic acid and the longer chain bile resulted in formation of 16-pregnen-3,20-dione. acids from which it can be derived have the 20Under similar oxidative conditions the linkage be- alpha configuration. tween C ~ and O C22 in Sa, Sm, DSa, DSrn is not af(19) R. E. Marker and D. L. Turner, THISJ O U R N A L , 63, 767 11941) fected. (20) R . E. Marker, T. Tsukamotu and D. L. Turner, rbid., 62, 2525 The data presented permit a reasonably certain (1940). (21) R. E. Marker, E. Rohrmann and E. M. J o n e s , i b i d . , 62, 1162 assignment of configuration of steroidal sapogenins a t (220. Molecular models constructed for the two (1 940). (22) P. Wieland and K. Miescher, Hclc. Chim. Acfa, 32, 1922 (1949). possible geometrical isomers show that I is under (23) R. B. Turner, THISJ O U R N A L , 72, 878 (1950). relatively little strain whereas in I1 the methyl UNITEDSTATESDEPARTMENT OF AGRICULTURE groups attached to carbons 13 and 20 put a tre- AGRICULTURAL RESEARCH SERVICE MONROE E. WALL EDDY UTILIZATION RESEARCH BRANCHC. ROLAND mendous strain on ring E. The configuration I1 is EASTERN 18, PENNSYLVANIA SAMUEL SEROTA assigned to 20-isosapogenins. It is in accord with PHILADELPHIA RECEIVED MARCH 13, 1954 the facile oxidative cleavage of such compounds and their dihydro analogs, and with the formation of pseudosapogenins on refluxing with acetic anhy- STEROIDAL SAPOGENINS. XX. CONFIGURATION dride. Configuration I is assigned to the more staOF SPIROKETAL SIDE CHAIN AT CARBON 22’ ble naturally occurring steroidal sapogenins. For- Sir : mation of 20-isosapogenins is not confined to sarsasaIn a recent communication Scheer, Kostic and pogenin and smilagenin but has been observed with Mosettigz state that Saa and Sm are not isomeric a t diosgenin, tigogenin and hecogenin indicating it is a both C22 and C Zas ~ previously believed4 but differ general reaction. only a t Czs. We feel this view is incorrect. Not The configuration of cholesterol and related ster- only is there excellent evidence available to show ols and bile acids a t CZOis still unsettled. Fieser that Sa and Sm are isomeric a t (222, but in view of and Fieser assigned the non-relative designations the establishment of the configuration of steroidal 20-a or 20-b to differentiate the side chains of such sapogenins a t Cz01 it is now possible for the first ~ t e r 0 i d s . l ~Based largely on optical rotation dif- time to designate the actual configuration of Sa and ferences, they later assigned (in terms of their C20 Sm at CZZ. convention) the relative configuration 20-beta to The evidence that Sa and Sm are isomeric at CZZ the side chains of cholesterol and bile acids.16*16 is convincing: (a) Sa and Sm have different infraKlyne” deduced from the X-ray studies of Carlisle red spectra in the region 850-1350 K.6p6 These are and Crowfootls that the cholesterol side chain has believed to be due to the vibrations of the -C-0-Cthe 20-alpha configuration. 0-C- spiroketal system constrained by the two E There is now available direct chemical evidence and F rings. When this system is disrupted, as in (12) R. E. Marker and E . Rohrmann, THISJOURNAL, 62, 521 (1 940). (13) G. I. Poos,G.E. Arth, R. E. Beylen and L. H. Sarett, ibid., 76, 422 (1953). (14) L. F. Fieser and M. Fieser, “Natural Products Related to Phenanthrene,”3rd ed., Reinhold Publ. Corp., New York, h‘. Y.. 1949,
(1) Paper XIX. M. E. Wall, C. R. Eddy and S. Serota, THISJOUR7 6 , 2849 (1954). (2) I . Scheer, R. B. Kostic and E. Mosettig, THIS JOURNAL, 76, 4871 (1953). (3) Abbreviations used in this paper: Sa = sarsasapogenin, Sm similagenin, P pseudo, D = dihydro, 20-i = 20-iso. Thus D20-
pp. vi-viii.
iSa
(15) L. F. Fieser and M. Fieser, ref. 14, pp. 412-419. (16) L. F. Fieser and M. Fieser, Expc~ienria,4, 285 (1948). (17) W. Klyne, C h c m i s l ~ yand Induslry, 426 (1951). (18) C. H. Carlule and D. Crowfoot, Prec. Roy. Soc. (London), 184A, 64 (1946).
(4) R. E. Marker and E. Rohrmann, THISJOURNAL, 61, 846 (1939). (6) M. E. Wall, C. R. Eddy, M. L. McClennan and M. E. Klumpp, Anal. Chcm., 94, 1337 (1952).
NAL,
-
-
-
dihydro 20-isosarsasapogenin.
(6) R . N. Jones, E. Katzenellenbogen and K. Dobriner, THIS 7% 168 (1953).
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formation of dihydrosapogenins, these characteris- and DSm retain configuration a t CZZduring hytic bands disappear.6.6 As we have shown previ- drogenation. We wish to present evidence that ously, Sa and Sm are identical a t CZO and isomerism during catalytic hydrogenation the configuration of a t C Z has ~ no effect on infrared spectra. There- DSm a t CzZprobably is changed from that of Sm fore the spectral differences between Sa and Sm and becomes identical to that of DSa, whereas DSa must be due to isomerism a t CZZ. (b) Prolonged does not change configuration. On catalytic hydrogenation 20-iSa and 20-ism refluxing of 22b-spirostanes, such as Sa or its dihydroxy analog, with alcoholic hydrochloric acid give dihydro derivatives D20-iSa and D20-iSn1 converts them to the isomeric 22a s e r i e ~ . ~ This * ~ * ~ identical to those obtained from similar hydrogencan be possible only if Sa and Sm were isomeric a t ation of PSa and PSm diacetates.’ Therefore, the CZZ. (c) Djerassi, Martinez, and RosenkranzQ location of the hydrogen atom a t CZOin dihydrohave shown that Sa under proper conditions forms pseudosapogenins is known, ;.e., it is identical to a 23-dibromide whereas Sm an,d other 22a-spiro- that of 20-isosapogenins as in IB and IIB.l0 Since stanes form only 23-monobromides. We have con- catalytic hydrogenation of an olefinic bond usually firmed this. Again this difference is possible only if results in a cis configuration,ll we assign formulaSa and Sm are isomeric a t CZZ. tions IIIA and IIIB, Fig. 2, to D20-ism = PDSm The bromination data in conjunction with the and D20iSa = PDSa. Entrance of the hydrogen established configuration a t C201 permits, for the atoms on the rear faces of C20 and Czz is in complete first time, assignment of configuration a t Cz2. accord with the structures of PSa and PSm in Molecular models corresponding to IA and IIA4in which the front faces of Czo-Czzare almost comFig. 1 were constructed. On account of the hin- pletely shielded by methyl groups attached to CIS drance of the methyl group attached to Czo it is im- and C20. possible to construct a 23-dibromide of IA. Therefore it is Sm. X 23-dibromide can easily be constructed from IIA. Therefore it is Sa. By analogy we assign configurations IB and IIB to 20-iSin and 20-iSa, respectively.‘ In this case 20-ism should form a dibromide and experiments to confirm this will be reported a t a later date. ,?;--,,
I-A
7
Smilageiiin R = H, R I
CHI
I-B 20-Isosmilagenin
R = CHs, R1
=
H IIIB, DpoiSa = DPSa, R = CH3, RI = Rz = H, R3 =
CHI
-( CHp)p--C--CH20H
11-A Sarsasapogeniri R = €1, R1 = CH, 11-13 20-Isosarsasapogenin R = CH3, R1 = H
Fig. 1.-Configurations of sarsasapogenin and smilagenin and their 20-isoanalogs a t carbons 20 and 22.
Scheer, Kostic and Mosettig2 converted Sa and Sin to identical 16,22-epoxycoprostan-3P-olderivatives via catalytic hydrogenation, selective tosylation a t C Z ~followed , by LiAlH4 reduction. Using a somewhat modified procedure involving catalytic hydrogenation of the 3-acetates, tosylation a t CZq, replacement of tosyl with iodine, followed b jr nnc.‘ acetic acid reduction, hydrolysis, and formation of the nicely crystalline 3-3,5-dinitrobenzoates, we confirmed these workers’ findings : lG,23-epoxycoprostan-3P-01-3[3,5-dinitrobenzoate, m.p. 23G237”, [ a ] D Z b +6.2”. Calculated for C~H48N207: C, 68.51; H, 8.12. Found: C, 68.38; H, 8.201. This, however, does not prove that Sa and Sm are identical at C Z ~ .This would be true only if DSa (7) M. E. Wall, C. R . Eddy, S . Serota and R. F. Miainger. ibid., 71, 4437 (1953). ( 8 ) We have confirmed Marker’s findings in regard to the conversion of Sa to Smd and have found the spectral differences associated with 22b- and 22a-spirostane.b@ (9) C. Djerassi, H. Martinez and G. Roaenkranz, J. 011. Chcm., 16, 303 (1951).
H IVA, DSIII, R I = CH1, R = RZ
H, Ra = H -( CHz)L-C-CH,OH CHI IVB, DSa, R1 = CHy, R = Rs = €1, R3 = CH3 -( CH~)Z-C--CH~OH H Fig. 2.-Configuration of dihydro and dihydro 20-iso-analogs of sarsasapogenin and smilagenin.
From a consideration of the formulations in Figs, 1 and 2, it is seen that catalytic hydrogenation of 20-ism (IB) to form D20-ism (IIIA) involves a change in CZZconfiguration to that identical with D20-iSa (IIIB). Formation of IIIB from 20-iSa (IIB) does not involve a change in CZzconfiguration. Hence D20-ism and D20-iSa are now isomeric only a t (226. It is most probable that hydrogenation of Sm (IA) and Sa (IIA) t o DSm (IVA) and DSa (IVB), respectively, involves a similar mechanism. Accordingly, the formation of the same 16,22-epoxy-coprostan-3~-ol from Sm and Sa (IO) Hydrogenation of sapogenins does not affect the configuration a t Cn. For example Sa, which is stable to CrOa oudation, hydrogenates to DSa likewise stable, 20-iSa unstable to CrOa oxidation, hydrogenate to D2O-iSa which is equally unstable. (11) G. W. Wheland, “Advanced Organic Chemistry,” 2nd ed., John Wiley and Sons, Inc., New York, N. Y., 1040, pp. 207-298.
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is not incornkatible with Czz isomerism of these sapogenins.
(7570), m.p. 130-151", [o(]D- ti&" (c 1.16) (Anal. Calcd. for C29H60O: C, S3.99; H, 12.15. Found: C, 83.54; H, 11.98), and converted to the correUNITEDSTATES DEPARTMENT OF AGRICULTURE AGRICULTURAL RESEARCH SERVICE MONROE -48' E. WALL sponding acetate (III), m.p. 136-137", [.ID EASTERN U T I L I Z A T I O N RESEARCH BRANCHS A M U E L S E R O T A (c 2.15) (Anal. Calcd. for C31H6202: C, 81.52; PHILADELPHIA 18, PENSSYLVAXIA H, 11.48. Found: C, 81.21; H, 11.34). TreatRECEIVED MARCH13, 1954 ment of (111) in carbon tetrachloride with N-bromosuccinimide, followed by collidine, gave 3P-aceto~y-4,4-dimethyl-A~~~-cholestadiene (IV) (56T H E SYNTHESIS OF LANOSTENOL 5870)~ 1ll.p. 151-152" (VaC.),*[ a ] D -107" (C 1.27), Sir: We wish to record the conversion of cholesterol XXma, 273 mp ( E 11,200), 282 mp (E 11,000)9( A n d . into the naturally occurring tetracyclic triterpene Calcd. for C31H6002: C, 81.88; H, 11.08. Found. lanostenol (dihydrolanosterol) (I). These results C, 81.86; H, 11.00), which was converted by hydrogen chloride in chloroform (-40°),followed by
\A,'\/
\ A M
\
/'
1
constitute the first total synthesis' of a tetracyclic triterpene, and provide rigorous confirmation in anhydrous ammonia in methanol (-(.io"), to 3ddetail of the remarkable structural and stereochem- a~etoxy-4,4-dimethyl-A~~~~-cholestadiene (V), 1ii.p. ical relationships, between the lanostane group 123-125' (vac.), [ a ] -140" ~ (c 1.24), Amax, 244 and the steroids, which have been brought to light mp (e 11,000) (Anal. Calcd. for C31H&: C, in recent years through degradative,2 d e d ~ c t i v e , ~81.88; H, 11.08. Found: C, 81.88; H, 11.05). bi~chemical,~ and physicalj studies. Oxidation of (V) by perphthalic acid in ether, folDirect methylation of either A4- or A5-choles- lowed by hydrolysis with ethanolic potash, gave ZL tenone-36 in dry tert-butanol with potassium tert- tviol (75%), very probably (VI),I0 m.p. 240-241' butoxide ( 3 moles) and methyl iodide (6 moles) V\/ v gave 4,4-dimethyl-A5-cholestenone-3 (11) (63cT,), II 1 n . p . 176-177", [ a ] +1 ~ (c 2.07)7 (Anal. Calcd. for C29H480: C, 84.40; H, 11.72. Found: C, S4.14; H, 11.91), which was reduced by lithium aluminum hydride to 4,4-dimethylcholesterol v\ \/ \ /'.,'V
\/\/y
I
Ho' A,\
lKP\'\ /
\TI
/\ *,\,/-/
/' \'/\/-----
( I ) For total synthebis of cholesterol, see K. B. \Voudwartl, I;. Scmdheimer and D. Taub, THISJOURNAL, 73, 3548 (1951); R. B. Woodward, F. Sondheirner, D. Taub, K. Heusler and W. M. 31cLamore, ibid., 7 4 , 4223 (1952); H. A t . E. Cardwell, J. W. Cornforth, S. R. Duff, H. Holtermann and R. Robinson, J . Chem. Soc., 361 (1953). (2) W. Voser, &I. V. .Mijovic, H. Heusser, 0.Jeger and L. Ruzicka, Eielu. Chim. Acta, 35, 2414 (19521, and many earlier papers; C. S. Barnes, D. H. R. Barton, A. R. H. Cole, J . S. Fawcett, and B. R . Thomas, J . Chem. Soc., 571 (l953), and earlier papers. (3) W. Klyne, J. Chem. SOL, 2916 (1952); C. S. Barnes, D. H. R . Batton, J. S. Fawcett and B. R. Thomas, i b i d . , 576 (1953). (4) E. Kyburz, B. Riniker, H. R. Schenk, H. Heusser and 0. Jeger, Helw. Chim. A c t a , 36, 1891 (1953); R. B. Woodward and K. Bloch, THISJOURNAL, 75, 2023 (1953). ( 5 ) R. G. Curtis, J. Fridrichsons and A. McL. Mathieson, Nafurc, 170, 321 (1952): J. Fridrichsons and A. h k L . Mathieson, J . Chcm. SOC.,2159 (1953). (6) For a rapid and convenient preparation of these ketones from cholesterol, see L. F. Fieser, TEISJOURNAL, 7 5 , 5421 (1953). (7) All rotations were measured in chloroform.
\
' VI1
(vac.) (Anal. Calcd. for C29H5003: C, 77.97; H, 11.28), which with hydrogen chloride in ethanol furnished 3P-hydro~y-4,4-dimethyl-l5-keto-A~(~~)cholestene (VII) (30y0), m.p. 161-162' (vac.), [oI]D + 1 3 5 O (C 1.44), Xma,. 261 lllp (E 14,700)) II< (C=O, C=C) 5.89 p, 6.15 p (Anal. Calcd. for C29H4802: C, 81.25; H, 11.29. Found: C, 80.99, H, 11.08). The benzoate of (VII), m.p. 154-155' (vac.), [ a ] +137" ~ (6 1.56), Lima,, 232 mp ( e 17,000), 260 mp (E 16,600), I R (OC=O 4- C=O, C=C) 5.84 5.88 1, 6.15 p (Anal. Calcd. for C36H6203: C, 81.15; H, 9.84. Found: C, 80.85; H, 9.92) on direct methylation in dry tert-butanol with potassium tert-butoxide (56 moles) and methyl iodide (112 moles) gave 3P-benzoyloxy-4,4,14-trimethyl- 15-keto- A'-cholestene (IX) (67yO), m.p. 212-213' (vac.), [ a ]+84" ~ (c 1.42), AXma,. 229 mp ( E 15,200), 273 mp ( E 1020), 281 mp ( E SOO), IR
+
( 8 ) Taken in a capillary sealed off a t a pressure of 3 mm. (9) All ultraviolet spectra were measured in 95% ethanol. (10) Cf.C. S. Barnes, D. H. R. Barton and G . F. Laws, Chenrislvy and I n d u s t r y , 616 (1953); D. H. R. Barton and G. F. Laws, J . Chefit. ,sot., 52 (19%).
