5256
1-01, sa
COMMUNICATIONS TO THE EDITOR
The trans-umbellularic acid was isolated in 56.5y0 3-methyl ether (I) possesses a hypocholesterolemic : (4.38 g.) yield, m.p. 189-190°, [ c r ] I 6 ~ - 5.2' uterotrophic activity ratio about 800 times that (acetone) ; its infrared spectrum was identical of estradiol-17P in rodents on a normal diet (vide with that of an authentic sample. This represents infra). 2.iY0 asymmetric synthesis. l5 The fluorination of active methylene comOn the basis of the above asymmetric syntheses pounds by perchloryl fluoride was first described the following absolute configurations are assigned in 195Sj2and this reagent subsequently has been to (-)-cis (11) and (-)-trans (111)-umbellularic used to fluorinate steroids a t the C-2,3a-f C-4,3c acid. The establishment of the absolute configura- C - 6 , 3 c * 3 g and C - 2 1 3 c , 3 d positions. I n these syntion of cis-umbellularic acid enables one now to theses, steroidal /3-dicarbonyl compounds, 3b,3d- 3f assign absolute configurations t o ( - ) -umbellulone, enamines, 3a,3c enol ethers3c and enol acetates3g (+)-thujane, (+)-sabinene and their deriva- have been used to advantage. tives, 16a,b,c We now have found that 16-formylestrone 3methyl ether4 when treated with perchloryl fluoride in tert-butyl alcohol containing potassium tert-butoxide, a t room temperature, furnishes di1, N,CHCOOEt rectly 16,16-difluoroestrone 3-methyl ether (I) 2, -OH (m.p. 126-125'; '[a]D f 167"; ' ::A: 5.63, 6.22, 6.35, 6.68, 7.98, 8.44 p). This represents the first reported example of a-fluorination of the cyclopentanone system by perchloryl fluoride, and the first reported insertion of a gem-difluoro groupCOOH ing into the steroid nucleus by fluorination of a Pdicarbonyl system.6 + " d ; O O H Zinc and acetic acid reduction of I proceeded H,' H" smoothly to give estrone 3-methyl ether. CleavCOOH COOH age of the methyl ether group of I , using hydriodic >--L acid-acetic acid, gave 16,16-difluoroestrone (11) (-)-II(lR: 2R) (-)-III(1R: 2s) (m.p. 173-175'; [ a ] D 161'; '?A:: 2.88, 5.64, 6.20, 6.66 p). Reduction of I with sodium (15) An authentic sample was resolved t o give optically pure acid, borohydride in 2-propanol furnished 16,16-dim.p. 1 5 5 O and [ a 1 1 6 D -194.0°. fluoroestradiol 3-methyl ether (111) (m.p. 123-127' ; (161 (a) Based on t h e correlations described in J . L. Simonson's "The Terpenes." Vol. 11, 1-60, 533, Cambridge Press, England, 1919. [a]D 71'; Az,U$' 2.92, 6.20, 6.36, 6.68, 7.98 p). (b) Prof. James H. Brewster has kindly informed me t h a t his method Conversion of I to 16,16-difluoro-17a-ethynylof predicting [MID values gives, when applied to t h e thujane terpenes, estradiol 3-methyl ether (IV) (m.p. 141-143' ; confi$urations consistent with our findings. His calculations indicate [a]D 20'; A",?' 2.96, 3.08, 4.76, 6.22, 6.34, t h a t the 2-methyl group in (+)-isothujone is Lrans t o t h e S s o p r o p y l group contrary to the assumption made in (a). (c) Confirmation of 6.56, 8.1 p) was accomplished by the sodium the assignment given by Brewster is found in t h e work of L. Tschugaev acetylide-dimethyl sulfoxide p r ~ c e d u r e . ~ Cataand W. Fomin (Compt. r e n d . , 161, 1088 (1910)). who showed t h a t lytic reduction of IV using palladized strontium (+)-a-thujane has a lower index of refraction and density t h a n ( + I carbonate in pyridine gave 16,16-difluoro-l7a&thujane, which indicates t h a t the methyl and isopropyl groups in ( & ) - a - t h u j a n e ,and therefore in (+)isothujone, are trans. vinylestradiol 3-methyl ether (V) (m.p. 132-137' ; 37'; A?:' 2.86, 6.22, 6.34, 6.68, 8.12, 8.58 DEPaRTMENT OF CHEMISTRY H. M. WALBORSKY [ a ] D FLORIDA STATEUNIVERSITY T. SUCITA p). Finally, reaction of I with methylmagnesium FLORIDA, ASD TALLAHASSEE, iodide in tetrahydrofuran-ether furnished 16,lGISSTITUTE FOR CHEMICAL RESEARCH KYOTO UNIVERSITY &I. O H X O difluoro-17a-methylestradiol 3-methyl ether (VI) [ a ] D f 38'; A?:,' 2.85, 6.22, TAKATSUKI, JAPAN Y. INOUYE(m.p. 143-145'; 6.32, 6.66, 8.10, 8.55 p). RECEIVED AUGUST 3, 1960
"4
+
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+
16,lB-DIFLUOROESTRONE DERIVATIVES. A NEW SERIES OF CHOLESTEROL LOWERING AGENTS Sir :
In recent years, attempts have been made' to synthesize steroidal compounds (related to the natural estrogens) which might alter blood cholesterol and phospholipid levels without exhibiting undesirable estrogenic activity. Compounds of this type could be expected to find therapeutic use in the treatment of atherosclerosis. 11-e wish to report here the synthesis of a series of 16,IG-difluoroestrone derivatives, several members of which display remarkably diminished uterotrophic activity, as compared to estradiol17/3,together with substantial serum cholesterol loweriiig properties. Thus, 16,16-difluoroestrone (1) Cf.G. P. Mueller, W. F. Jobns, D.L. Cook and R. A. Edgren, Tars JOURNAL, SO, 1760 (1868),
( 2 ) C. E. Inman. E. A. Tyczkowsti, R. E. Oestdin:: and F. L. Scott, E x p p r i r n i i a , 14, 355 (1958); C. E. I n m a n , R. E. Oesterling and E. A. Tyczkowski, THISJOURNAL. 80, 0533 (19.58). (3) R . B. Gabbard and E . V. Jensen, J . Oig Chem., 23, 1406 (1958): (b) H. A I . Kissman, A. M. Small and M J. Weiss, THISJ O U R N A L , 81, 1262 (1959); 82, 2312 (19bO); (c) S. Nakanishi, K. Morita and E . V. Jensen. i b i d . , 81, 5259 (1959); (d) J , Edwards and H. J. Ringold, ibid., 81, 5262 (1959): (e) A. H. N a t h a n , J. C . Babcock and J. A. Hogs, J . Org. Chem., 24, 1395 (1959); THISJOURNAL,82, 1436 (1960), (f) A. H. S a t h a n , B. J . Magerlein and J. A . Hogg, J . Org. Chem., 24, 1517 (1959); (g) R. A l . Bloom, V. V. Bogert and R,Pinson, C h m . a n d I z d . 1317 (1959). (4) J . C . Bardhan. J . Chem. SOC.,1848 (19%). ( 5 ) All melting points were taken on the Kofler block. All rotations mere measured in diox3ne s Jution. Satisfactory analyses have been obtained for all t h e new compounds described herein (6) T h e conversion of a 21-ethoxalyl-20-ketosteroidto the 21,L'Idifluoro-20-ketone, using perchloryl fluoride. has been repnrted recently (ref. 3c and 3d) and the further fluorination of the 21,21.difluoro-20keto system t o the 21,21,21-trifluoro compound also h a s been described (ref. 3c). Enamines of Ad-3-ketosteroids have been reported with perchluryl fluoride. (ref. 3c) t o yield 4,4-difluoro-3-keto-A~-steroids (7) J. A. Campbell, J. C . Babcock and J. A . Hop5, T m s JOURNAL, 80, 4717 (1968).
COMMUNICATIONS TO THE EDITOR
Oct. 5, 1960
5257
The hypocholesterolemic activity of compounds I-VI was determined in adult, male rats (Charles River), fed stock diet ad lib. The compounds were suspended in peanut oil and injected subcutaneously for four days. Total serum cholesterol was determined by the method of Zak8 and the results are presented in the accompanying table. The estrogenic potencies were obtained by the uterotrophic response in the sexually immature mouseg following subcutaneous administration. lo
R‘
and the olefins would have deuterium on both C3 and C4. On the other hand, if B is not a storage form for this amyl cation, only (CH&C+RESULTS O B T A I N E D USING E S T R A D I O L - 1 7 P A S S T A N D A R D CD2-CH3would be produced and the olefins would Serum cholesterol be labeled on Cs on!y. lowering Uterotrophic Reduction of trimethylacetic acid with lithium Comacti\.ity activity standard = 1 R R‘ pound standard = 1 aluminum deuteride provided the 1,l-dideuterioI 0.42 0.0005 CHs =o neopentyl alcohol. De-oxidation of this neopent(0.13-0.93) oxide ion was carried out with aqueous potassium I1 2.0 0.0001-0.006” H =O hydroxide and bromoform. The two Cg olefins (1.&2.7) were separated with vapor phase chromatography I11 0.88 0.0011 CHs (OH , to provide the pure compounds which were ex(0.73-1 .O) ‘H amined with infrared and proton magnetic resonance spectroscopies. None of these examinations yielded IV 4.3 0.02-0.03 CH3 (OH , evidence for deuterium labeling on C4 of either (2.5-6.2) ’C=CH olefin. The infrared spectrum of 2-methyl-2-butene V 0.65 0.0005-0.004511 CH3 (OH , (0.63-0.66) ‘CH=CH% showed a sharp vinyl deuterium a b s o r p t i ~ n ~ , ~ a t 4.48 p and was devoid of additional absorption VI -1.0 0.0004-0.002311 CHa /OH bands up t o 5.5p, consistent with C3 labeling only. ‘CHs The 2-methyl-1-butene showed C-D absorptions (8) B. Zak, Tech. Bull. Regislvy M e d . Technologists, 27,71 (1957). between 4.55 p and 4.75 p, yielding no additional (9) Carworth Farms, strain CF-1. information regarding Cs and C4 labeling. (10) We wish t o express our gratitude t o Dr. Milton Eider and Proton magnetic resonance spectra does not reveal Mr. Arthur Watnick for the uterotrophic assays. vinyl hydrogen in the 2-methyl-2-butene or =C(11) T h e large range is a result of non-parallel slopes shown b y the dose-response cuxves. CHD- in the 2-methyl-1-butene. With respect NATURAL PRODUCTS C. H. ROBINSON to the 2-methyl-2-butene the evidence is not strong, RESEARCH DEPARTMENT N.F. BRUCE because the sample was small, and the vinyl E. P. OLIVETO hydrogen absorption of undeuterated olefin is of BIOCHEMISTRY DEPARTMENT S. TOLKSDORF SCHERING CORPORATION M. STEINBERGlow intensity. The other olefin shows exactly BLOOMFIELD, NEWJERSEY P. L. PERLMANthe spectrum4 expected for 2-methyl-3,3-dideuterio1-butene, a quartet of vinyl hydrogens a t 185.4 RECEIVED AUGUST19, 1960 C.P.S. with relative intensity 2.0, a triplet of allylic methyl hydrogens a t 68.2 C.P.S. with relative inPROTONATED CYCLOPROPANE INTERMEDIATES tensity 3.0, and a quintet of alkyl methyl hydroIN THE NEOPENTYL CARBONIUM ION SYSTEM gens a t 40.8 C.P.S. with relative intensity 3.0, Sir : all J values falling between 1.1 and 1.4 C.P.S. It was suggested’ recently that protonated No other absorptions were evident, particular care cyclopropanes might be important transient stor- being used to search the 70 to 80 C.P.S. region where age configurations for certain carbonium ions, allylic methylene proton absorptions were anticiparticularly those involved in Wagner-Meerwein pated. rearrangements. The neopentyl carbonium ion The evidence cited supports the conclusion that system was chosen for a critical test. the 1,l-dideuterioneopentyl carbonium ion system T o learn whether appreciable storage in the form yields rearranged olefins with deuterium labeling of a protonated cyclopropane occurred, this re- on C3 only, thus excluding as significant interaction was carried out with 1,l-dideuterioneopentyl mediates any species in which the migrating methyl alcohol. If equilibration between A and B occurs and the original methylene groups are equivalent, a t rates competitive with conversion to t-amyl such as protonated cyclopropanes, etc. cation, then ( CH3)3CCD20H would be converted (2) E.G. Hoffmann, Ann., 818,276 (1958). (3) t o (CH3)zCB-CHZ-CDZHand ( C H S ) ~ C @ - C D ~ - C H ~ , P. S. Skell and R . G. Allen, THISJ O U R N A L , 81, 5383 (1959); ~
(1) P.S. Skell and 1. Starer, THISJOURNAL, 82, 2971 (1960).
also other unpublished work from this laboratory. (4) 40 Mc. equipment; tetramethylsilane internal reference.
