Simmons-Smith cyclopropanations

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. 

Recently, Charette et al. have also demonstrated this behavior in the stereoselective cyciopropanations of a number of enantiopure acyclic allylic ethers [47]. The high degree of acyclic stereocontrol in the Simmons-Smith cyclopropanation has been extended to synthesis several times, most notably in the synthesis of small biomolecules. Schollkopf et al. utilized this method in their syntheses of cyclopropane-containing amino acids [48 a, b]. The synthesis of a cyclopropane-containing nucleoside was also preformed using acyclic stereocontrol [48c]. 

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. 

Tab. 3.7 N-Methylephedrine reagent modification in Simmons-Smith cyclopropanation...

Fig. 3.26 Frontier molecular orbital analysis for the Simmons-Smith cyclopropanation. [Dargel, T.K. Koch, W.J. Chem. Soc., Perkin Trans. 1996, 2, 877. Reproduced by pemiission of The Royal Society of Chemistry]...

This study suggests a radically new explanation for the nature of Lewis acid activation in the Simmons-Smith cyclopropanation. The five-centered migration of the halide ion from the chloromethylzinc group to zinc chloride as shown in TS2 and TS4 has never been considered in the discussion of a mechanism for this reaction. It remains to be seen if some experimental support can be found for this unconventional hypothesis. The small energy differences between all these competing transition states demand caution in declaring any concrete conclusions. 

The Simmons-Smith cyclopropanation method has also found application for the a-methylation of ketones via an intermediate cyclopropane. The starting ketone—e.g. cyclohexanone 9—is first converted into an enol ether 10. Cyclopropanation of 10 leads to an alkoxynorcarane 11, which on regioselective hydrolytic cleavage of the three-membered ring leads to the semiketal 12 as intermediate, and finally yields the a-methylated ketone 13 ... 

The stereoselectivity of conjugate addition and cyclopropanation of the chiral nitrovinyldioxolanes 17 can be effectively controlled <96TL6307>, and good selectivity is observed in the ultrasound-promoted cycloaddition of nitrile oxides to alkenyldioxolanes 18 <95MI877,95JOC7701 >. Asymmetric Simmons-Smith cyclopropanation of 19 proceeds with... 

Scheme 6.20 Simmons-Smith cyclopropanations of allylic alcohols with cyclohexanediamine-derived bis(snlfonamides) ligands.

Several catalytic systems have been reported for the enantioselective Simmons Smith cyclopropanation reaction and, among these, only a few could be used in catalytic amounts. Chiral bis(sulfonamides) derived from cyclo-hexanediamine have been successfully employed as promoters of the enantioselective Simmons-Smith cyclopropanation of a series of allylic alcohols. Excellent results in terms of both yield and stereoselectivity were obtained even with disubstituted allylic alcohols, as shown in Scheme 6.20. Moreover, this methodology could be applied to the cyclopropanation of stannyl and silyl-substituted allylic alcohols, providing an entry to the enantioselective route to stannyl- and silyl-substituted cyclopropanes of potential synthetic intermediates. On the other hand, it must be noted that the presence of a methyl substituent at the 2-position of the allylic alcohol was not well tolerated and led to slow reactions and poor enantioselectivities (ee<50% ee). ... 

In 1998, Kurt and Halm reported the preparation of resin-based bis(sulfo-namides) ligands in order to extend the precedent methodology to the solid phase. Therefore, the solid-phase catalyst depicted in Scheme 6.21 was found to be able to mediate the Simmons-Smith cyclopropanation of cinnamyl alcohol with an enantioselectivity of 65% ee. 

Other bis(sulfonamides) ligands based on more flexible diamines have been investigated by Denmark et al. as promoters for the enantioselective Simmons-Smith cyclopropanation of cinnamyl alcohol. This study has revealed a... 

Scheme 6.21 Simmons-Smith cyclopropanation of cinnamyl alcohol with resin-based bis(sulfonamides) ligand.

The final stages of the synthesis involved introduction of the final methyl group by Simmons-Smith cyclopropanation and reductive opening of the cyclopropane ring. 

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