A synthetic sequence leading to the total synthesis of hydrochrysene derivatives poss-ssing the tratls-anti-trans backbone is described. The introduction of a ketonic function into ring C of these compounds is also given. I t is noted that these substances allow entry into the synthesis of intermediates which have a n open ring C.Recently we reported in the first paper of this series ( I ) , a synthetic sequence leading t o the total synthesis of various hydrochrysene analogues. We also indicated that these compounds could serve as effective intermediates for the synthesis of a variety of steroidal derivatives which are not readily accessible from the naturally occurring steroidal compounds. We would now like to present further studies which allow entry into the transanti-trans series of hydrochrysene analogues. This series, of course, provides the stereochemical backbone which correlates with that of the natural steroid.In our previous paper we were able to show that the ketol, I , besides providing entry into the cis-syn-cis hydrochrysene series, can also be converted into the tetracyclic ketone, 11. I t is obvious that the appropriate reductions of the styrene double bond and the unsaturated carbonyl group in I1 lead to the generation of new asymmetric centers a t the ring junctures. Consequently stereospecific reductions of this ketone would lead to a produck with well-defined stereochemistry a t the asymmetric carbon atoms. Of the various methods which were available, the Birch reduction was of distinct advantage since the stereochemistry of this method, when applied to the hydrochrysene analogues, has been studied in considerable detail in the fine researches of Johnson and his co-workers (2). We therefore subjected the ketone, 11, t o the action of sodium (or lithium) in liquid ammonia in the presence of anhydrous ethanol-reaction conditions which were very successful in a related series (2). The expected alcohol, 111, which now possessed four new asymmetric centers, could only be isolated in a very poor yield and even then only after considerable difficulty in separation from the undesirable side products. The side products indicated that the aromatic ring was being reduced and it was therefore apparent that the reduction of the olefinic bond of the p-methoxystyrene chromophore presented a somewhat different problem to that experienced by Johnson in the m-methoxystyrene series. We therefore spent a considerable amount of time in attempting to develop optimum conditions for this reduction. We initially concentrated our efforts on varying the amount of alkali metal (sodium or lithium) relative to the amount of ketone used, and on varying the length of time for the reduction. In all these cases, we were not able to show any substantial improvement to the original yield of the alcohol. We then turned our attention t o the use of solutions of alkali metals in amine solvents and found an excellent improvement in the yield of the reduction. When a solution of the ketone in tetrahydrofuran was

A synthetic seq~~ellce leading to the total synthesis of several hydrochrysene derivatives is described. I t is noted that these derivatives may provide entry into the synthesis of various interesting steroidal analogues.Recently a considerable effort has been put forth to study the effect of substituents attached to the steroid skeleton on the biological properties of these con~pounds. Indeed, dranlatic effects have been obtained for substitutents such as methyl, hydroxyl, and halogen, particularly fluorine, when these groups are situated a t rather specific positions on the nucleus. Related to these studies, the removal of angular methyl groups, as in 1s-nor and 19-nor steroids, or of illethylene groups from the ring skeleton to generate ring-contracted steroidal nuclei has also been accompanied with very important alterations in the biological activity of these molecules (1, 2).All of the above studies have involved the use of the naturally occurring steroids as starting materials, and although these are obviously the logical choice in most cases, they offered certain limitations in synthesizing some of the steroidal derivatives which were of interest in our studies between structure and biological activity. For this reason, we initiated investigations directed toward the total synthesis of steroidal analogues, with particular enlphasis on intermediates which would readily lend themselves to the iiltroduction of substituents or alterations of the act~ial skeleton not coilveilieiltly possible from the natural steroids. This paper outlines the total synthesis of hydrochrysene derivatives which fulfill this aim.Of the various approaches which were available, the one utilizing the Robinsoni\/Iannich base reaction originally developed by Robinson and co-workers (3) and so successfully applied in the elegant researches of Johnson and co-workers (4) was selected. Condensation of 6-methoxy-2-tetralone (I) with 1-diethylamino-3-pentanone inethiodide, in the presence of sodium methoxide, provided an isomeric inixture of the tricyclic ketones (I1 and 111). The arrallgeilleilt of the double bond in the tricyclic ketone permits its migration into conjugation with either the aroinatic ring or with the carbonyl function (I1 F), 111). It was not surprising, therefore, to find that our product was an oily mixture of both isomers. The ultraviolet spectrum of this mixture indicated a broad band in the 250-260 mp region and the infrared spectrum indicated the presence of saturated and unsaturated carbonyl functions (5.86 and 6.05 p). Careful chromatography of this mixture, first on alumina and then on silica gel, allowed the separation into the two respective isomers, I1 (A,,,, 253 mp, infrared 6.05 p) and I11 (A,,,,, 275 mp, infrared 5.S5 p). I11 general, this separation involved considerable losses, and for preparative purposes, in the subsequent condensation, the isomeric mixture was employed. I t is pertinent to point out that a similar mixture was encountered by Johi~soi~ and co-worlters in a sinlilar reaction (5).