Directed Simmons-Smith cyclopropanation

Carl R. Johnson, Michael R. Barbachyn fi-Hydroxysulfoximine-Directed Simmons-Smith Cyclopropanations. Synthesis of (-)- and (+)-Thujopsene, J. Am. Chem. Soc. 104,4290-4291 (1982)... 

A combination of resolution and diastereofacial cyclopropanation has been used to prepare a variety of cyclopropyl ketones with high optical purity77. Optically active lithiated (S)-N,S-dimethyl-S-phenylsulfoximine (17) is added to prostereogenic enones such as 16, and the resulting diastereomeric allylic alcohols 18 are separated by column chromatography. Hydroxyl-directed Simmons-Smith cyclopropanation (see Section 1.6.1.5.1.2.) provides intermediates which are thermally decomposed to release the optically pure cyclopropyl ketones 20 and the sulfoximine 19. 

Consider the C2-symmetrical precursor 28, in which both acetoxy groups are homotopic (identical). Desymmetrization by hydrolysis of just one acetyl residue could be readily achieved late in a projected synthesis. This would enable a hydroxyl-directed Simmons-Smith cyclopropanation. Mitsunobu esterihcation (with inversion of configuration) would then set the stage for a concluding alkyne metathesis [39] (Scheme 3.24). This approach does not yet address the formation of the stereogenic center in the middle of the target structure, be it by oxidation to a ketone and stereoselective reduction. 

The landmark report by Winstein et al. (Scheme 3.6) on the powerful accelerating and directing effect of a proximal hydroxyl group would become one of the most critical in the development of the Simmons-Smith cyclopropanation reactions [11]. A clear syw directing effect is observed, implying coordination of the reagent to the alcohol before methylene transfer. This characteristic served as the basis of subsequent developments for stereocontrolled reactions with many classes of chiral allylic cycloalkenols and indirectly for chiral auxiliaries and catalysts. A full understanding of this phenomenon would not only be informative, but it would have practical applications in the rationalization of asymmetric catalytic reactions. 

The discovery of viable substrate-direction represents a major turning point in the development of the Simmons-Smith cyclopropanation. This important phenomenon underlies all of the asymmetric variants developed for the cyclopropanation. However, more information regarding the consequences of this coordinative interaction would be required before the appearance of a catalytic, asymmetric method. The first steps in this direction are found in studies of chiral auxiliary-based methods. 

Upon removal of the auxiliary, an enantioenriched product could be obtained. The application of chiral auxiliary-based methods to Simmons-Smith cyclopropanation not only provided a useful synthetic strategy, but it also served to substantiate earlier mechanistic hypotheses regarding the directing influence of oxygen-containing functional groups on the zinc reagent [6dj. 

An early stage in the synthesis of the antifungal metabolite FR-900848 exploited a double Simmons-Smith cyclopropanation directed by two di-isopropyl tartrate acetals [Scheme 2.42] 9192 The diastereoselectivity of the reaction can be attributed to intramolecular delivery of a zinc carbenoid co-ordinated to one of the ester carbonyls and an oxygen of the dioxolane ring.93 Note the use of the Noyori protocol (see above) for the bis-dioxolanation of the highly reactive mu-conaldehyde ... 

The combination of the chromatographic separation of enan-tiopure p-hydroxysulfoximine diastereomers and reductive elimination results in a method of ketone methylenation with optical resolution. The technique is illustrated in the synthesis of the ginseng sesquiterpene (—)-p-panasinsene and its enantiomer (eq 5). The addition of the enantiopure lithiosulfoximine to prochiral enones or the diastereoface selective addition to racemic enones results in the formation of two diastereomeric adducts. The hydroxy group in these adducts can be used to direct the Simmons-Smith cyclopropanation (eq 6 and eq 7). Catalytic osmylation of such adducts is directed by the anti effect of the hydroxy augmented by chelation by the methylimino group (eq 7). ... 

SCHEME 10.3 Simmons-Smith cyclopropanations directed by sugar-derived chiral auxiliaries. 

The adduct (157) derived in>m (5)-(141) and an a,p-unsaturated ketone (156) undergoes Simmons-Smith cyclopropanation which is directed by the coexisting p-hydroxysulfoximine chiral center. As outlined in Scheme 36, this is a new methodology for optical activation of cyclopropyl ketones (159). Indeed, optically active tricyclic ketones (-)-(161) and (-f)-(161) were synthesiz firm a bicyclic ketone (160) in optical purities of 96% and 94%, respectively (equation 36). 

Besides serving as a useful tool for resolution, the sulfoximine addition adduct can be utilized to direct such reactions as the Simmons-Smith cyclopropanation and 0s04 addition to an alkene. ... 

The lactone-directed intramolecular Diels-Alder cycloaddition was the key step in D.F. Taber s synthesis of trans-dihydroconfertifolin. During the endgame, the Simmons-Smith cyclopropanation was utiiized to install the gem-dimethyl group at C4. The trisubstituted alkene was cyclopropanated in excellent yield and the resulting cyclopropane was subjected to catalytic hydrogenation. 

Stereoselective samarium-based Simmons-Smith cyclopropanation of cyclopentyl allylic alcohols is the key step in the synthesis of the precursor of 1,25-dihydroxy vitamin D3.128 The desired chirality was generated in one case under the influence of the two stereogenic centers on the (R,/ )-butane-2,3-diol acetal 121 and in the other case was directed entirely by the allylic hydroxy group of 122. 

An attempt was made to synthesize the bicyclic retinoids (247) directly by Simmons-Smith cyclopropanation of ethyl retinoate (24). Only isomerized starting material was obtained (Dawson et aL, 1981b). It was therefore necessary to develop a separate, multistage procedure for the synthesis of (247). Initially, cyclopropanated p-cyclocitral (243) was reacted with the weakly nucleophilic anion of the phosphonate (244), generated by means of sodium hydride in di-methylsulfoxide. This procedure, too, failed to give the desired molecule (247), and the product obtained was merely the derivative (245) containing an expanded ring. 

---