CONMUNICATIONS TO THE EDITOR
Oct. 5, 1960
Of some thirty Senecio alkaloids of known structures,' jacobine is now the first member of the family whose stereochemistry is completely formulated with the absolute configuration also established. The stereochemical correlation of this alkaloid with other members of the Senecio family (in particular, seneciphylline,* integerrimine' and senecionine') will be undertaken.sslO-ll
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the addition of ethyl diazoacetate to (-)-menthyl P,P-dimethylacrylate should yield (-)-I predominantly. This prediction has been verified experimentally (vide infra) and provides cogent support for the use of the Prelog-Cram model. 'P
O
H
\ /
(8) S . Masamune, Chcm. and I n d . , 21 (1959). (9) Satisfactory analyses and ultraviolet and infrared spectra were obtained for all the new compounds described herein. (10) T h e author is deeply indebted t o Dr. R. B. Bradbury, Swinburne Technical College, Australia, for his helpful suggestions and generous gifts of natural products, without which this work would not have been completed. (11) This investigation was supported by a grant (RG-6646) from the National Institute of Health, Public Health Service.
DEPARTMENT OF CHEMISTRY UNIVERSITYOF WISCONSIN MADISON 6, WISCONSIN
n
SATORU MASAMUNE
(+)-I
2, -OH
RECEIVED JULY 26, 1960 CYCLOPROPANES. VII. THE ABSOLUTE CONFIGURATION OF trans-CARONIC AND cis AND trans-UMBELLULARIC ACIDS1
Sir: It was shown recently that the addition of diazodiphenylmethane to (-)-menthyl acrylate and (-)-menthyl methacrylate resulted in partial asymmetric syntheses2 On the basis of the Prelog3-Cram4 model5 the absolute configurations were assigned tentatively to the 2,2-diphenylcyclopropanecarboxylic acids that were obtained. We wish to report evidence in support of the use of this model, and to assign absolute configurations to cis and trans-umbellularic acids. H&p3
C CH;'H 3 y f $ ; \
'H (-)-I (1R: 3R)
'\CH3
H//' (+)-I (1% 3s) I
The absolute configuration of trans-caronic acid has been previously establishedBand has the configuration shown above. This fact provides one with the means of determining whether the Prelog-Cram model can be used for establishing absolute configurations by the addition of diazo derivatives to m,P-unsaturated menthyl esters. Using this model one would predict that the addition of diazodimethylmethane to (-)-dimenthy1 fumarate would produce (+)-I in excess, whereas (1) This work was supported, in part, by a grant from the National Sdence Foundation. (2) F. J. Impastato, L. Barash and H. M. Walborsky, THISJOURNAL, 81, 1514 (1959). (3) V. Prelog, el al., Helv. Chim. Acta, 36, 308 (1953). (4) D. J . Cram and F. A. Abd Elhafez, THISJOURNAL, 74, 5828 (1952). (5) Using a transoidal coplanar configuration for the H system and a staggered orientation of the asymmetric center such t h a t two substit/"\ C C uent$ (L and M) or ( H and M) flank the \ / \\ A'\, carbonyl and the third is in the plane of t h e 0 L M coplanarity.
/
(6) lished
L. Cromble and S. € Harper, I. J. Chem. Soc., 470 (1954), estab-
absolute configuration of chrysanthemum-carboxylk a d d . Chrysanthemum.carboxylic acid has been degraded to caronic acid
Ethyl diazoacetate (4.8 g., 0.042 mole) was added slowly to (-)-menthyl P,P-dimethylacrylate' (10.0 g., 0.042 mole) a t 130-140'. The reaction mixture was distilled to remove unreacted acrylate (7.3 g.) which was treated once more with an equivalent amount of ethyl diazoacetate to yield a total of 2.4 g. (65%) of crude adduct.8 The adduct was subjected to complete saponificationgato yield purecaronk acid (27%),9b[ a ] " D - 5.05' (ethanol), m.p. 205-207') whose infrared spectrum was identical with an authentic sample.1° The observed optical rotation corresponds to 15.9y0 asymmetric synthesis. lo To a xylene solution of dimethyldiazomethane" was added a solution of (-)-dimethyl fumarate (31.4 g.) in xylene a t 0-5' to yield, upon removal of solvent, an oily product. The oil (10.0 g.) was heated with copper powder (1.0 g.) at 160-170' until nitrogen evolution ceased and the product distilled to yield 5.3 g. (56%) of the adduct ester. Complete sap~nificationg~yielded trans-caronic acid (0.20 g., 25%),12 m.p. 206-212', [ ~ ] * O D 2.0' (ethanol). This corresponds to 6.3% asymmetric synthesis. Ethyl diazoacetate (5.0 g.) was added slowly to (-)-menthyl a-is~propylacrylate~~ (11.3 g.) a t 80' until nitrogen evolution ceased. The addition product was saponifiedg" and the mixture of cis and trans acids separated to yield 1.25 g. (14.7%) of cis-umbellularic acid, map. 107-110°, [ ~ L ] ~ - 5.4' (CHC13)) whose infrared spectrum was identical with that of an authentic ~amp1e.l~This represents 6% asymmetric synthesis.
+
(see H. Staudinger and L. Ruzicka, Relo. Chim. Acta., 7 , 201 (1924)). (ethanol); i t gave the correct (7) M.p. 35-36", [ a l l a D -80.4' elemental analysis, as did all other new substances reported here. (8) A fraction b.p. 160-168° a t 0 6 mm. was collected. Complete fractionation was avoided. T h e yield is based on recovered (-)menthyl &&dimethylacrylate. (9) (a) As evidenced by the absence of carbonyl absorption a t 1720 cm -8 in the neutral fraction. (b) T h e cis isomer was not isolated. (10) A. Fredga and A. SkitrBm, Arkiv. Kcmi,8, 433 (1955). (11) P. C. Guha and D. K.Sankaran, Be?., 70, 1688 (1937). (12) T h e infrared spectrum showed slight contamination b y fumaric acid. (13) B.p. 64-6S0 a t 0.1 mm., tt1ZD 1.4648, [P]'~D -81.6' (ethanol). (14) H. N. Rydon, J. Chcm. S a c , 829 (103F)
~ D
5256
1-01, sa
COMMUNICATIONS TO THE EDITOR
The trans-umbellularic acid was isolated in 56.5y0 (4.38 g.) yield, m.p. 189-190°, [ c r ] I 6 ~ - 5.2' (acetone) ; its infrared spectrum was identical with that of an authentic sample. This represents 2.iY0 asymmetric synthesis. l5 On the basis of the above asymmetric syntheses the following absolute configurations are assigned to (-)-cis (11) and (-)-trans (111)-umbellularic acid. The establishment of the absolute configuration of cis-umbellularic acid enables one now to assign absolute configurations to ( - ) -umbellulone, (+)-thujane, (+)-sabinene and their derivatives,16a,b,c
3-methyl ether (I) possesses a hypocholesterolemic : uterotrophic activity ratio about 800 times that of estradiol-17P in rodents on a normal diet (vide infra). The fluorination of active methylene compounds by perchloryl fluoride was first described in 195Sj2and this reagent subsequently has been used to fluorinate steroids a t the C-2,3a-f C-4,3c C - 6 , 3 c * 3 g and C - 2 1 3 c , 3 d positions. In these syntheses, steroidal /3-dicarbonyl compounds,3b,3d- 3f enamines, 3a,3c enol ethers3c and enol acetates3g have been used to advantage. 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
+
+-
+
+
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).
