A Highly Stereoselective Synthesis of C(11)‐Functionalized Aromatic Steroids by an Intramolecular Benzocyclobutene‐Olefin ‐Cycloaddition. Preliminary Communication

Abstract

SummaryThe racemic cis-anti-trans-steroids 9 to 11 have been synthesized in a highly stereoselective manner starting from 4-methoxybenzocyclobutene carboxylic acid via the key step 8 -+ 9. (cf. Scheme 2).The total synthesis of steroids is a continuing challenge for the organic chemist. From 1939 up to the present numerous often exciting and even some practical routes to this pharmaceutically important class of compounds have been developed1). Based on our pioneering work on intramolecular quinodimethane cycloadditions [6-81 a new approach to this skeleton via the generalized sequence I + I T --f 111 (Scheme 1)appeared feasible. Consideration of models of all four possible transitions states for the intramolecular cycloaddition of 11, points towards kinetically favoured formation of adducts I11 with anti-disposed H-C(8) and H-C( 14), caused by steric interactions of the angular methyl group. In addition, one may expect [7] that the trans-or cis-B,C-ring fusion in I11 will be controlled by the influence of a sp3-or sp2-carbon functional group C = Z on the endolexo mode of the addition I1 -+ 111. In fact, highly stereoselective formation of trans-anti-trans products has been observed in a related I)Reviews: [l-51.

Conjugated nitrosoalkenes as Michael acceptors in carbon–carbon bond forming reactions: a review and perspective

“…The high efficiency and stereoselectivity of the enolate addition to nitrosoalkenes make this strategy perspective for application in total synthesis that has been recognized since 1970s. Thus, Oppolzer and co-workers exploited the Michael addition of enolates to nitrosoalkenes in their studies towards syntheses of 3-methoxy-9β-estra(1,3,5(10))trien(11,17)dione ( 25 ) (1977) [ 31 ] and (+/−)-isocomene (1981) [ 32 ]. The key carbon–carbon bond formation step in the synthesis of steroid 25 was the stereoselective reaction of α-bromooxime 26 with lithium enolate 27 to give oxime 28 via the Michael addition to transient nitrosoalkene NSA6 [ 31 ].…”

Conjugated nitrosoalkenes

“…a-Bromo oximes have been used to alkylate lithium enolates prepared from substituted cyclopentanones. 100,101 The reactions of nitrosoalkenes with other stabilised carbanions are presented in Table 4. In many cases, EtONa and EtOH are used as the base and the solvent, respectively; in some cases, Na 2 CO 3 in CH 2 Cl 2 93 or in Bu t OMe 17 or piperidinium acetate in THF 96 are also employed.…”

The Enantioselective Synthesis of 3‐Methoxy‐1, 3, 5 (10)‐estratrien‐11, 17‐dione by a Thermal Intramolecular Cycloaddition Reaction. Preliminary communication

“…In continuation of our work on intramolecular o-quinodimethane cycloaddi-tions2) [ l ] [2] a stereoselective synthesis of the racemic 3-methoxy-1,3,5 (10)-9pestratrien-1 1,17-dion-1 1 -oxime-o-benzyl ether 3 (with cis-anti-trans configuration) via the intermediates 1 and 2 has been developed (Scheme I) [3]. In view of the efficient and highly stereocontrolled preparation of 1 this synthesis compares favorably with other approaches to racemic estrone derivatives via benzocyclobuteneprecursors [4].…”