CATION-STABILIZING AUXILIARIES IN POLYENE CYCLIZATIONS .6. THE FLUORINE ATOM AS A CATION-STABILIZING AUXILIARY IN BIOMIMETIC POLYENE CYCLIZATIONS .3. USE TO EFFECT REGIOSPECIFIC CONTROL

The fluorine atom substituted at the pro-C-13 position (steroid numbering) has been shown to be an effective cation-stabilizing (C-S) auxiliary in the acid-catalyzed cyclization of the polyene substrates 6, 7, and 8. The preparation of 6, 7, and 8 employed the known fragmentation of cyclic epoxy hydrazones to construct the methylacetylenic and gem-dimethyl groups. The fluoroolefinic ketal Claisen and cyclopropylcarbinol rearrangements established the 3(E) and 11(E) trisubstituted alkenes. Stereoselective routes were developed for the 7(Z) (found in substrates 6 and 7) and 7(E) tetrasubstituted fluoroolefinic bond in 8. The Wittig rearrangement of stannyl ether 21 provided the Z-stereoisomer 26 predominately (7:3, 85% yield), while the Ireland enolate Claisen rearrangement of acetate 20 produced predominately the E-stereoisomer 25 (4:1, 69% yield). Cyclopentenols 6 and 8 possessed the methylacetylene terminator group, while in 7 this group was convertod to the propargylsilane terminator. Cyclization with stannic chloride or trifluoroacetic acid gave high yields of pentacyclic compounds. In all cases, the fluorine atom controlled the regiochemistry of the cyclization, giving exclusively products with a 6-membered ring C. Thus, cyclopentcnol 8 afforded pentacycle 55 in 80% yield, while cyclopentenol 6 gave pentacycle 53 in 56% yield, retaining the fluorine atom at C-13 and possessing the anti-trans-anti-trans-anti-trans backbone, with a total of seven chiral centers, as shown by X-ray crystallographic analysis. The cyclopentenol 7, similarly, was cyclized to give what is almost certainly the tetracycle 56. The regiocontrol over the ring C closure effected by the fluorine atom acting as a C-S auxiliary may be regarded as inferential documentation of the proposed point-charge stabilization mechanism of the enzymatic process by which squalene oxide similarly undergoes an anti-Markovnikov closure of ring C. Application of this methodology to the synthesis of the pentacyclic triterpenoid beta-amyrin is described in the next paper in this series.