Cyclopropanes asymmetric

Diazo-3,6-dihydropyran-2-one 21 is a stable vinylcarbene precursor. Its reaction with 1,4-cyclohexadiene is highly dependent on the chiral Rh catalyst used but results in both C-H insertion and cyclopropanation. Asymmetric cyclopropanation also occurs with various alkenes and reduction of the products provides a route to cycloheptadienes <06JA16038>. 

Hydroxyphenylcyclohexanes Cyclohexanols—see Cahx[4]cyclohexanols Cyclohexanones—see Cahx [4] cyclohexanones Cyclohexenones—see Aryl-2-cyclohexenones 4-Cyclohexylphenol, formation of 613 Cyclopentadiene 5-carboxyUc acid 1057 Cyclopropanation, asymmetric 697 Cytochrome P-450 linked microsomal Papaver enzyme 1216 Cytotoxicity 654 CZE 971-974... 

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... 

Asymmetric cyclopropanation. Asymmetric cyclopropanation of styrene can be effected with chiral vinyl or-diazo esters with Rh2(OAc)4 or rhodium(ll) octanoate as catalyst. The products can be converted into optically active cyclopropylamino acids. Of several chiral auxiliaries, (R)-(—)-pantolactone is the reagent of choice. 

Asymmetric cyclopropanation was actively investigated in the last 10 years and an enormous number of reports were published. For example, proline-daived Rh2(5-DOSP)4 160 was used for asymmetric cyclopropanation. Asymmetric cyclopropanation of iV-Boc-pyrrole 161 and fitran 162 was carried out by Davies and coworkers (Scheme 1.76) [121]. Face selectivity was influenced by steric and electronic effects on the acceptor unit iV-Boc-pyrrole 161 underwent asymmetric double cyclopropanation to give chiral azatricycloheptane... 

Reagent-controlled asymmetric cyclopropanation is relatively more difficult using sulfur ylides, although it has been done. It is more often accomplished using chiral aminosulfoxonium ylides. Finally, more complex sulfur ylides (e.g. 64) may result in more elaborate cyclopropane synthesis, as exemplified by the transformation 65 66 ... 

Heterocycles as ligands in complex catalysts for asymmetric cyclopropanation 98T7919. 

Catalytic, enantioselective cyclopropanation enjoys the unique distinction of being the first example of asymmetric catalysis with a transition metal complex. The landmark 1966 report by Nozaki et al. [1] of decomposition of ethyl diazoacetate 3 with a chiral copper (II) salicylamine complex 1 (Scheme 3.1) in the presence of styrene gave birth to a field of endeavor which still today represents one of the major enterprises in chemistry. In view of the enormous growth in the field of asymmetric catalysis over the past four decades, it is somewhat ironic that significant advances in cyclopropanation have only emerged in the past ten years. 

From a historical perspective it is interesting to note that the Nozaki experiment was, in fact, a mechanistic probe to establish the intermediacy of a copper carbe-noid complex rather than an attempt to make enantiopure compounds for synthetic purposes. To achieve synthetically useful selectivities would require an extensive exploration of metals, ligands and reaction conditions along with a deeper understanding of the reaction mechanism. Modern methods for asymmetric cyclopropanation now encompass the use of countless metal complexes [2], but for the most part, the importance of diazoacetates as the carbenoid precursors still dominates the design of new catalytic systems. Highly effective catalysts developed in... 

This review outlines developments in zinc-mediated cyclopropanation from the initial reports in the 1950s through to the current state of the art methods. The presentation will rely heavily on how the evolution of mechanistic understanding aided in the rationalization and optimization of each new advance in the asymmetric process. 

The discussion of the catalytic, asymmetric variants will incorporate a significant emphasis on the interplay of mechanistic investigations and synthetic optimization studies to provide a unified picture of the cyclopropanation methods. Finally, recent insights provided by computational analysis of the transition structures for cyclopropanation will be discussed. 

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. 

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 powerful influence of an oxygen substituent on the rate and stereoselectivity of cyclopropanation augured well for the development of a chiral auxiliary based approach to asymmetric synthesis [54]. The design of the chiral auxiliary would take into account ... 

There are three main criteria for design of this catalytic system. First, the additive must accelerate the cyclopropanation at a rate which is significantly greater than the background. If the additive is to be used in substoichiometric quantities, then the ratio of catalyzed to uncatalyzed rates must be greater than 50 1 for practical levels of enantio-induction. Second, the additive must create well defined complexes which provide an effective asymmetric environment to distinguish the enantiotopic faces of the alkene. The ability to easily modulate the steric and electronic nature of the additive is an obvious prerequisite. Third, the additive must not bind the adduct or the product too strongly to interfere with turnover. 

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 ... 

The catalytic asymmetric cyclopropanation of an alkene, a reaction which was studied as early as 1966 by Nozaki and Noyori,63 is used in a commercial synthesis of ethyl (+)-(lS)-2,2-dimethylcyclo-propanecarboxylate (18) by the Sumitomo Chemical Company (see Scheme 5).64 In Aratani s Sumitomo Process, ethyl diazoacetate is decomposed in the presence of isobutene (16) and a catalytic amount of the dimeric chiral copper complex 17. Compound 18, produced in 92 % ee, is a key intermediate in Merck s commercial synthesis of cilastatin (19). The latter compound is a reversible... 

Chrysanthemumic acid may exist in four stereoisomers, because of the two asymmetric carbon atoms in the cyclopropane ring. The natural acid has the D-trans configuration and this has been shown to be more insecticidally active than any of the other isomers or the racemic form. Harper et al, (4,18) have synthesized, separated, and optically resolved all of the isomers of this acid. 

Asymmetric versions of the cyclopropanation reaction of electron-deficient olefins using chirally modified Fischer carbene complexes, prepared by exchange of CO ligands with chiral bisphosphites [21a] or phosphines [21b], have been tested. However, the asymmetric inductions are rather modest [21a] or not quantified (only the observation that the cyclopropane is optically active is reported) [21b]. Much better facial selectivities are reached in the cyclopropanation of enantiopure alkenyl oxazolines with aryl- or alkyl-substituted alkoxy-carbene complexes of chromium [22] (Scheme 5). 

The Rh2(DOSP)4 catalysts (6b) of Davies have proven to be remarkably effective for highly enantioselective cydopropanation reactions of aryl- and vinyl-diazoacetates [2]. The discovery that enantiocontrol could be enhanced when reactions were performed in pentane [35] added advantages that could be attributed to the solvent-directed orientation of chiral attachments of the ligand carboxylates [59]. In addition to the synthesis of (+)-sertraline (1) [6], the uses of this methodology have been extended to the construction of cyclopropane amino acids (Eq. 3) [35], the synthesis of tricyclic systems such as 22 (Eq. 4) [60], and, as an example of tandem cyclopropanation-Cope rearrangement, an efficient asymmetric synthesis of epi-tremulane 23 (Eq. 5) [61]. 

The search for the racemic form of 15, prepared by allylic cyclopropanation of farnesyl diazoacetate 14, prompted the use of Rh2(OAc)4 for this process. But, instead of 15, addition occurred to the terminal double bond exclusively and in high yield (Eq. 6) [65]. This example initiated studies that have demonstrated the generality of the process [66-68] and its suitability for asymmetric cyclopropanation [69]. Since carbon-hydrogen insertion is in competition with addition, only the most reactive carboxamidate-ligated catalysts effect macrocyclic cyclopropanation [70] (Eq. 7), and CuPF6/bis-oxazoline 28 generally produces the highest level of enantiocontrol. 

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... 

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