4604
J . Org. Chem., Vol. 43, No. 24, 1978
Danishefsky and Etheredge
(12) U. R. Ghatak, Sh. K. Alam, P.C. Chakraborti, and 6.C. Ranu, J. Chem. Soc., Perkin Trans. 1. 1669 11976). (13) GT S . Krishna Rao and Sukh Dev, J. Indian Chem. Soc., 34, 255 (1957). (14) U. R. Ghatak and EL. Sanyal, J. Chem. SOC.,Chem. Commun., 876 (1974).
(15) J. F. McOmie, M. L. Watts, and D. E. West, Tetrahedron, 24, 2289 (1968). (16) Wear'e deeply indebted to Professor J. W. ApSimon for kindly providing us with an 80 MHz NMR spectrum of our synthetic sample of 10; however, no comparison data with their sample has been available.
Synthesis of dl-Epigriseofulvin Samuel Danishefsky* and Sarah Jane Etheredge Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 Received June 27. 1978 Iliels-Alder reaction o f (Z)-2-ethylidene-7-chloro-4,6-dimethoxycoumaran-3-one with l,l-dimethoxy-3-(trimethylsilyloxy)-1,3-butadiene,followed by acidification, affords dl-epigriseofulvin.
Recently we described some cycloaddition reactions of the 1,l-disubstituted diene 1 with electrophilic dienophiles.l,Z
PMe lrG-x 0
I1
+
4
(Me!,Si
(Mc),Si
I
a
Acid-catalyzed unraveling of the adducts of 1 with a,p-unsaturated carbonyl systems affords specific monoenol ethers of P-diketones. I t was of interest to examine the extension of this reaction to include a-alkylidinecycloalkanones as dienophiles, thereby providing a route to structurally defined spirocyclic pmethoxyenones. With this in mind, we addressed the synthesis of griseofulvin (6),3,4an antifungal agent of some importance. Our results are described herein.
That 4 is, in fact, a single substance was suggested by its NMR spectrum [(CDC13)6 1.95 (3, d , J = 6 Hz), 5.98 (4, J = 6 Hz)]. Since only one isomer was available to us, we could not a t this stage assign its configuration. This was ascertained through its cycloaddition with compound 1. Reaction of 4 with 1 was carried out in toluene a t 115 "C. Two procedures were employed to convert the resultant adduct 7 into the desired P-methoxyenone. In method A the
OSi Me0
\
-
0''
CI
H
'Me
7
M
CI 8
w
residue, upon evaporation of the toluene, was directly chromatographed on silica gel. Elution with ethyl acetate-benzene afforded a mixture of dl-epigriseofulvin ( 5 ) and its P-methoxy derivative 8. This mixture was treated with tosyl acid-benzene under reflux for 2 h to afford an 82%yield of essentially pure 5.
4
Iw
5 R :n; R'= Me (epigriseofulvinl
u
6 R
H
(griseofulvin)
The known4d coumaranone (2) was treated with lithium diisopropylamide in tetrahydrofuran. The resultant enolate, a t -78 OC, reacted instantaneously with acetaldehyde to afford a nearly quantitative yield of a stereoisomeric mixture of @-aldols3 [(CDC1:3)2CHCH3 doublets a t 6 1.35 and 1.391. While in some cases a given P-aldol can be converted to a geometrically defined alkylidenecycloalkanone by trans elimination of a suitably activated derivative of the alcoho1,j a recent finding of I
