Asymmetric Simmons-Smith cyclopropanation

Sigmatropic rearrangement 677, 697 Sihca gel membranes 1082 Silphinene, electrosynthesis of 1183, 1187 Silver compounds, as oxidants 1307-1311 Silybin, synthesis of 1308, 1310 Silydianin 1180 Silylation, of phenols 934, 935 Silylcyanation, asymmetric 694, 695, 702 Simmons-Smith cyclopropanation, asymmetric 694... 

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. 

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... 

The reaction was first carried out with the substrate bearing the chiral auxiliary. Scheme 5-64 shows the asymmetric cyclopropanation reaction using 2,4-pentandiol as a chiral auxiliary.115 Scheme 5-65 illustrates the use of optically pure 1,2-frafts-cyclohexanediol as a chiral auxiliary in asymmetric Simmons-Smith cyclopropanation.116 Excellent yield and diastereoselectivity are obtained in most cases. 

From the multitude of synthetic work in the field of cyclopropanation, we will focus on the asymmetric synthesis of cyclopropanes. Besides the known stereocontrolled addition of diazocompounds to olefins (diazo-method) [6] the stereocontrolled Simmons-Smith cyclopropanation has received significant attention in the last ten years. The latter will be discussed further. 

Asymmetric Simmons-Smith cyclopropanation using no covalent-bound auxiliary but a chiral catalyst have only been successful with allylic alcohols so far. Fujisawa had shown that allylic alcohols such as 38 are converted into the corresponding alcoholate by Et2Zn (1.1 equivalents) first [31]. Addition of diethyltartrate (1.1 equivalents) results in the formation of an intermediate 39, which is cyclopropanated under Furukawa conditions (Et2Zn + CH2I2) to give compound... 

The examples mentioned above illustrate the progress in the field of stereocontrolled cyclopropanation. Nowadays, the asymmetric Simmons Smith cyclopropanation may well be mentioned in the line with other asymmetric reactions like epoxidation or dihydroxylation. Fligh enan-tioselectivity and diastereoselectivity can be... 

The excellent affinity of the alkylzinc reagent for ethereal oxygen in the Simmons-Smith cyclopropanation of allylic alcohols and ethers has been exploited for the asymmetric cyclopropanation of a, -unsaturated aldehydes and ketones using homochiral protecting groups. ... 

Asymmetric Simmons-Smith Cyclopropanation General Procedure ... 

Recently reported uses of optically pure stilbene diol in asymmetric synthesis include. (1) the dimethyl ether as a ligand for effecting enantioselective conjugate addition (2) the preparation of a,p-unsaturated ketals for achieving diastereoselective Simmons-Smith cyclopropanation <3 (3) the preparation of enantlomercially pure p-halohydrins i and (4) the preparation of chirai crown... 

A process for the asymmetric cyclopropanation of the enol ethers of cyclic and acyclic ketones has been developed by Tai [109-111]. In this process, a 2-symmetric acetal is isomerized to a hydroxy enol ether which serves as substrate or the Simmons-Smith cyclopropanation, as shown in Scheme 6.29. The stereoselectivity is nearly perfect, but a mechanistic hypothesis has not been proposed. The auxiliary may be removed either by hydrolysis, to give the methyl ketone, or by oxidation of the alcohol and p-elimination [111]. 

Scheme 6.33. Asymmetric catalysts for the Simmons-Smith cyclopropanation of trani-cinnamyl alcohol (a) [123]. (b) [124]. (c) [120,122]. (d) Transition state model for catalyst c [120]. Only one zinc and the transfer methylene are shown other atoms associated with the Simmons-Smith reagent are deleted for clarity.

Simmons-Smith reaction. Asymmetric methylene transfer to allyl glycosides containing a free hydroxyl group at C-2 arises from its directing effect. Both /3-l-glucopyranosides and their a-o- analogs have been exploited for the access of chiral cyclopropanes. 

Cheap and readily available cyclopentadecanone is alpha-brominated to (30) and ketalised with (29), and the resulting a-bromoketal (31) subjected to base induced elimination of HBr, giving (32). The key asymmetric step is now at hand. The Simmons-Smith cyclopropanation proceeds with very high facial selectivity, giving almost entirely the diastereomer of (33) shown. The result is rationalised on the basis of zinc chelation by the oxygens of the ketal. The synthesis is completed by acid hydrolysis of the ketal (the chiral diol may be recovered for reuse), reductive opening of the cyclopropane ring under Birch conditions, and re-oxidation of the alcohol back to the ketone. 

These early studies on zinc carbenoids provide an excellent foundation for the development of an asymmetric process. The subsequent appearance of chiral auxiliary and reagent-based methods for the selective formation of cyclopropanes was an outgrowth of a clear understanding of the achiral process. However, the next important stage in the development of catalytic enantioselective cyclopropanations was elucidation of the structure of the Simmons-Smith reagent. 

As part of an independent study of catalytic asymmetric cyclopropanation, Denmark et al. described a systematic investigation of the effect of addition order, stoichiometry and catalyst structure on sulfonamide-catalyzed Simmons-Smith cyciopropanations. Although early studies had shown promising levels of enantios-electivity, higher selectivity would be required for this to be a synthetically useful transformation. The principal issues that were addressed by this study included ... 

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