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J. Am. Chem. SOC. 993,115,9327-9328 9327

Enantioselective Total Synthesis of MiroestroltE. J. Corey' and Laurence I . W u

Department of Chemistry, Harvard U niversityCamb ridge, Massachusetts 02138Received July 23, 1993

Th e Thai medicinal plant Pueraria mirifica (Thai kwao keur) ,which has a fascin ating history in the folk medicine of southeastAsia, contains the un usual estrogenic phenol m iroestrol (l), irstisolated more tha n fifty years ago.I4 Th e assignment of structure(without absolute configuration) was made in 1960 n th e basisof X-ray diffract ion ~tudies .~he synthesis of miroestrol hasremained since tha t time as a classical unsolved p roblem, de spitea num ber of attempts.6 Reported herein is the first total synthesisof 1 by a rou te which is enantioselective and convergent. Th ering system was constructed by a novel transannu lar dou ble cation-olefin cyclization w hich, surpr isingly, may also be involved in thebiosynthesis.On the basis of t he large positive optical rotation of miroestrol,[CY] ; '300,4b nd th e octant rule for ketones, it seemed likelythat the absolute configuration i s tha t expressed by 1, and thisbecame the ultimate synthetic target. Th e retrosyntheticallyderived plan of synthesis led to the bicyclic vinylstannane 7 andthe a-bromo-a&enone 13 as key intermediates.The bicyclic acid 3, mp 201-203O, was prepared from4-methoxysalicylaldehyde (2 ) by sequential 0-cyanoethylation,aldol cyclization an d hydrolysis of cyano to carbox yl (all reactionand mp temperatures in "C ) (Scheme I) . Conversion of 3 to theacyl azide? Cu rtius rearrangem ent, and acid-catalyzed hydrolysisof the resulting vinyl isocyanate provided ketone 4.* Demeth-ylation of 4 (to form a phenolic ketone, m p 148-149O) ollowedby silylation with tri-i-propylsilyl (T IP S) trif late gave the silylether-ketone 5. Reaction of the enolate 5 with the Hendrickson-McM urry reagent9J0afforded th e corresponding conjugated enoltriflate 6 which underwent coupling with the cu pra te reagent"from tri-n-butylstannyllithium and CuCN to form the keyvinylstannane 7.The a-bromo-a&enone component 13was prepared startingfrom 3-brom0-4-methoxyphenol,~~hich was converted quan-titatively by etherification to 8 with prenyl bromide-potassiumcarbonate in acetone at 23' for 12 (Schem e 11). M ontmorilloniteKSF clayI3 catalyzed the rearrangem ent of 8 to an ortho prenylphenol which upon oxidation with PhI( 0A c)Z at 23O fo r 1 h

t Dedicated to Her Royal Highness Princess Chulabhorn of Thailand onthe Occasion of her 36th birthday.(1) For an interesting account of the history of miroestrol, see: Cain, J.C . Nature 1960, 188, 774.(2 ) First isolation: Schoeller, W.; Dohrn, M.; Hohlweg, W. Notunvis-senschaften 1940, 28, 532.(3 ) Biological studies: (a) Vatn a, S. hai .Sci . Bul l . 1934,4 ,3 . (b ) Jones,H . E. H. ; Pope, G. S. .Endocrinol. 1960,20,229. (c) Pope, G. S.; rundy,H. M.; Jones, H. E. H.; Tait, S.A. S. . Endocrinol. 1958, 17, xv.(4) Chemical studies: (a) Butenandt, A. Natunvissenschaften 1940, 28,533. (b) Bounds, D. G.; Pope, G. S. J . Chem. SOC. 960, 3696.(5 ) Stru cture : Taylo r, N. E.; Hodgkin, D. C.; Rollett, J. S.J. Chem. SOC.1960, 3685.(6 ) See, or example: (a) Weigele, M. Dim. Abstr . E 1965,26,6245. (b )Van Rheenen, V. H. Diss. Abstr . B 1966,27, 1103. (c) Minard, R. D. Diss.Abstr. E 1969,30, 133. (d) Miyano, M.; Dorn, C. R. J . Org. Chem. 1972,37, 268. (e) Findlay, J. A.; Mebe, P.; Stern, M . D. ; Givner, M. L. Con. .Chem. 1980,58, 1427.(7 ) Shioi ri, T.; Ninomiya, K. ; Yamada, S. . Am . Chem. SOC. 972, 94,6023.(8 ) Wise,L.D.;DeWald,H.A.;Hawkins,E.S.;Reynolds,D.M.;Heffner,T. G.; M eltzer, L. T.; Pugsley, T. A. J . Med . Chem. 1988, 31, 688.(9 ) McMurry, J. E.; Scott, W. J. Tetrahedron L ett . 1983, 24, 979.(10) Hendrickson, J. B.; Bergeron, R. Tetrahedron L ett . 1973, 4607.( 1 1 ) Gilbertson, S. R.; Challener, C. A,; Bos, M. E.; Wulff, W. D.

(12) Irvine, F. M.; Smith, J. C. J. Chem. SOC. 927, 74.(13) Dauben, W . G.; Cogen, J. M.; Behar, V. Tetrahedron L ett . 1990,31,Tetrahedron L ett . 1988, 29, 4795.

3241.0002-7863/93/1515-9327$04.00/0

Scheme ICHO 1. Debco, CH2rCHCNreflux, 24 h, 85%

M e0 reflux, 24 h, 90%aoH.10%aq.NaOH *2 31. (PhOhP(=O)NaEtsN, 45 'C2. toluene,80 "C 78%

1.6 N HCI, reflux

0 1. BBr3,CH2CIz-20 "C, 16 h, 8636a2. TIPSOTf,CHzCI2 me ^4,6-lutldine, -20 " Cs o 16 h, 91%

0 1. BBr3,CH2CIz-20 "C, 16 h, 8636a2. TIPSOTf,CHzCI2 me ^2,6-lutldine, -20 " Cs o A3 16 h, 91% _.jT.hb7:;.-400cHMDS, Tf2NPh

a O T f DA,uCN, usSnHHF-78 "C, 0.5 h*TlPSO 88% TlPSO

6 7

Scheme II02

BrOM e

n1. Montm orlllonlte KSFbenzene, 15 h, 60%2. Phl(OAc)2, MeOH

23 "C, 1 h, 08% Br M e 0 OMe8 9

PPTS, benzene 90%I2R,4R)-pentnnediolreflux, 8 hPh,COOH, KHMDSTHF, -35 OC, 24 h Br

56%Br

11 101. DIBAL, THF10 mln, 65% (84%)

( lO: l : l ) , 3 h , 94%2. acet oneM Z0/70% HCIO,1**OH6 h, 89%2.AUHg,THF *1% H20,O"C Br15 min, 65%

Br0

12 13afforded the quinone mono ketal9. Transketalization of 9 with(2R,4R)-pentane-2,4-diolielded the chiral ketal-dienone 10,[a]:: +43O (c = 1.5, CHC13).I4 Epoxidation of 10 withtritylhydroperoxide using potassium hexamethyldisilazide as basecatalyst occurred with 85: 5 diastereoselectivity favoring epoxide11, CY]::+164O (c =1.3, CHCl3), R ~ 0 . 5 4silica gel tlc with 4:lhexane-ether), over the diastereomer, [ CY ] : : -72O (c = 0.9,CHCl3), RJ 0.44. After chromatographic separation pure 11was isolated in 56% yield from lO.I5 Redu ction of epoxy ketone

(14) The conformation of this ketal-dien one is indicated to be that shownin 10 by the observance of positive NO E effects in the 500-M Hz 'H NM Rspectrum of 10 between the dienone @-H nd cis axial CH3 (2%) and carbinolC-H (9%) protons.0 1993American C hemical Society

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9328 J . Am . Chem. SOC..Vol. 115, No. 20 , 1993 Communications to the Editorthe presence of diisobutylaluminum chloride this ketone wasrapidly an d cleanly transformed into the isomeric pentacyclicketone 15,m p 145.5-147O,[a]::+119' (c =0.7,CHCl3). Thishighly efficient reactio n, which gene rates the bridged ring systemof miroestrol in a single step, ma y be regarded as a transannu lardouble cation-olefin cyclization in which the initiation step iscoordination of the catalytic Lewis acid to the u,@-enone arbonylfollowed by transann ular linkage of the enone &carbon and th edoub le bond of the prenyl unit. Th e resulting tertiary carb ocationthen attach es to the benzylic carbon of the chromene unit to formthe second new ring in 15. Alternatively th e conversion 14-5may be viewed as a Lewis acid catalyzed transannu lar Diels-Alder reaction of an unusua l type (inverse electron deman d) withan electron-rich dienophile and an electron-deficient dienecomponent. As anticipated, the formation of 15 ro m 14was notobserved under ther mal Diels-Alder conditions, which led onlyto complex decomposition. Treatmen t of the a,&enone 15withtriethylam ine resulted in isomerization to th e thermodynamicallymore stable B,y-enone 16,m p 95-96', [u ]L3 153O (c =0.7,CHCl3). The destabilization of ketone 15 relative to the j 3 , yisomer 16 s partly du e to a twisting abo ut the O=C-C, bondin 15 which rotates the O=C and a,& C= C *-orbitals to anangle of ca 70' an d removes mast of th e a-conjugation. Oxidationof 16 with selenium dioxide produced the corresponding u-hy-droxy-&yenone, mp 138-139', [u] i3192' (c =0.4,CHCls),which upon desilylation gave totally synthetic miroestrol, mp265-267' (decomp), [u] i3289' (c =0.2, tOH ), [lit.4b mp268-270' (decomp), [a]: +301 (c =1.1,EtOH)] .Although we could not lo cate an au thentic sample of miroestrol,we were able to obtain ca 500 g of the dried root of Puerariamirifica thanks to th e generosity of Profs. Duang Budd hasukhand Yuthan a Sm itasiri of Chiang M ai University. Extraction of200 g of this material with THF a t 23' and chromatographicpurification of t he extra ct on silica gel (3 columns followed bypreparative tlc) afforded 1.2 mg of miroestrol, which showed[a]::286' (c =0.1, tOH) and IH and 13C NM R, mass, andIR spectra that were identical with those of synthetic 1. Thechromatographic mobilities of natural and synthetic 1 n severaldifferen t solvent systems were also identical, a s was mp behavior.

In t he course of the isolation of 1 ro m P. mirifica we obtainedca 1 mg of another compound whose 500M H z H N M R spectrumwas similar to tha t of the synthetic intermediate 14. This new,unstabl e substance was identified as 17 y analysis of NM R andmass spectral data . If 17 s a biosynthetic precursor of miroestrol,the possibility arises that the biosynthesis of miroestrol mightinvolve the s ame sort of cationic double annulation th at servedas a key step in the above described to tal synthesis of 1,a ratherinteresting coincidence.Th e series of reactions which leads from the simple startingmaterials 2 nd 8 o miroestrol 1 includes several which requir ethe special reaction conditions and reagents specified herein. Inaddition to the key double annulation process, 14- 5,othernoteworthy transformations include 9- 0,lO- 1,ll- 12,13- 4 and 15- 6- . A simpler version of th is synthesisof 1 has been used to prepare (A)-1 -methyl ether.

Acknowledgment. This research was supported by the Nation alScience Foundation and the National Institutes of Health. W eare indebted to our Thai colleagues, Profs. Buddhasukh andSmitasiri, for their help in obtaining Pueraria mirifica.Supplemen tary Materia l Available: Characterization data forcompounds3-17 and 1 (4 p). Ordering information is given onany current masthead page.

Scheme IIIn p s o A

Br QoH 013

Pd(PPhd4toluene90 C, 2 h80%

TIPSO+ 14

n p s o7

HOTPS H-OTlPS

EtSN, CH ~C IZ..,Me-eflux, 18 h, 90%0Q OTIPS161. SO? ,1-BUOOH2. RBUaNF, THFCH#32,60 h, 63%0 "C, 5 mln, 94%IHYoH 6TIPS15

OH1 17

11 with diisobutylaluminum hydride afforded after chromatog-raphy the corresponding allylic alcohol, [ u ] k3+85' (c = 1,CHC13),Rf0.34 silica gel tlc with 3:l:l hexane-ether-CHzC12),in 65% yield along with 31% of the diastereomeric alcohol,-8' (c =1.2,CHC13), Rf0.27. The minor diastereomerwas oxidized to 11 and reduced to provide an additional amount

of the major isomer (total yield with one recycle, 84%), whichupon deketalization gave 12. Silylation of 12 nd epoxide cleavagewith aluminu m amalgam I6 furnished 13, [a]::-82' (c = 1,The coupling of the key components 7 and 13 proceededsmoothly in the presence of a Pd( 0) catalyst to form th e tricyclicketone 14,[a]:: 28O (c =0.8, HC13) (Schem e 111). At 0 in(15) The stereochemistry of the predominating epoxide 11corresponds tothat expected for reaction of the more stable conformer of 10.( 16 ) Corey, E. J.; Ensley, H. E. J . Org. Chem. 1973, 38 , 3187.

CHCl3).