Enantioselective Simmons-Smith Cyclopropanations

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). ... 

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... 

The alkylboronic ester of chiral diol was used as the most efficient chiral ligand for the enantioselective Simmons-Smith cyclopropanation of substituted allylic alcohols (Equation (252)).1056-1059... 

The first examples of the enantioselective Simmons-Smith cyclopropanations mediated by a chiral catalyst are very recent. Scheme 6.33 shows three catalysts for the cyclopropanation of rrans-cinnamyl alcohol. The most selective appears to be Charette s dioxaborolane (Scheme 6.33c, [120-122], which also affords the highest yield of product, although this procedure is only suitable for small scale.With other olefins, such as cis and trans disubstituted alkenes and P,P-trisubstituted alkenes, the yields are nearly as good and the enantioselectivities are 96-97%. An important finding in this study [120] was that, in addition to the Lewis acid (boron) that binds the alcohol, a second atom to chelate the zinc is also necessary. In the... 

Three- and four-membered rings are versatile intermediates for further transformation. Tsutomu Katsuki of Kyushu University developed Angew. Chem. Int. Ed. 2008, 47, 2450) an elegant Al(salalen) catalyst for the enantioselective Simmons-Smith cyclopropanation of allylic alcohols such as 3. Kazuaki Ishihara of Nagoya University found J. Am. Chem. Soc. 2007,129, 8930) chiral amine salts that effected enantioselective 2-1-2 cycloaddition of a-acyloxyacroleins such as 5 to alkenes to give the cyclobutane 7 with high enantio- and diastereocontrol. 

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. 

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... 

Besides Cu and Rh, various other metals are known to catalyze the decomposition of diazo compounds [6,7,8,9,10]. Palladium complexes, e.g., are efficient catalysts for the cyclopropanation of electron-deficient C-C double bonds with diazoalkanes [19,20, 21], in contrast to Cu and Rh catalysts which are better suited for reactions with electron-rich olefins. Unfortunately, attempts to develop chiral Pd catalysts for enantioselective cyclopropanation have not been successful so far [22]. More promising results have been obtained with cobalt and ruthenium complexes. These and other chiral metal catalysts, that have been studied besides Cu and Rh complexes, are discussed in chap. 16.3. The same chapter also covers a new direction of research that has recently been taken with the development of catalytic enantioselective Simmons-Smith reactions. 

A number of enantioselective Simmons-Smith-type cyclopropanations have been disclosed, of which three classic examples are discussed in this section [19]. In the first, Charette described the use of a dioxaborolane (111, Scheme 15.13) as an effective chiral controller group [68]. The presence of the basic amide C=0 was found to be critical for directing the cyclopropanation reagent to a single olefin diastereoface. Treatment of allylic alcohols such as 110 with 111 and Zn(CH2l)2 led to the formation of intermediate boronates that subsequently underwent cyclopropanation with excellent yields and enantioselectivities. An impressive iterative application of this method was showcased by Charette in a total synthesis of the natural product U-1065305 (113), a cholesterol transferase inhibitor [69]. 

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. 

In 1992 Kobayashi et al. [47] reported the first catalytic and enantioselective cyclo-propanation using the Furukawa modification [48] of the Simmons-Smith reaction of allylic alcohols in the presence of a chiral bis(sulfonamide)-Zn complex, prepared in-situ from the bis(sulfonamide) 63 and diethylzinc. When cinnamyl alcohol 62 was treated with EtgZn (2 equiv.), CHgIg (3 equiv.), and the bis(sulfonamide) 63 (12 mol %) in dichloromethane at -23 °C, the corresponding cyclopropane 64 was obtained in 82 % yield with 76 % ee (Sch. 26). They proposed a transition state XXIII (Fig. 5) in which the chiral zinc complex interacts with the oxygen atom of the allylic alkoxide and the iodine atom of iodomethylzinc moiety. They also reported the use of the bis(sulfonamide)-alkylaluminum complex 65 as the Lewis acidic component catalyzing the Simmons-Smith reaction [49]. 

The diastereoselective and enantioselective preparation of cyclopropanes has attracted attention since chiral cyclopropanes were found to occur in many natural products [11]. Moreover, cyclopropanes are useful intermediates in organic synthesis. There are many methods of cyclopropane ring opening that transfer stereochemical information from the substrate to acyclic products in a stereocontrolled manner [12]. Among the methods used for the preparation of cyclopropanes from olehns, the Simmons-Smith and related reactions as well as reactions of diazoalkanes catalyzed by rhodium, copper and cobalt salts have frequently been applied [13]. The preparatively simple Makosza reaction [14] has scarcely been used. 

Several procedures deal with optically active auxiliaries employed in stoichiometric amounts or more, but which are not covalently bonded to one of the reagents. These catalysts influence Simmons-Smith type cyclopropanations of allylic alcohols with moderate to excellent enantiose-lectivities. Whereas the reaction of ( )-3-phenyl-2-propen-l-ol (1) with diethylzinc and diiodo-methane in the presence of (17 ,25 )-A,-methylephedrine (2 equivalents) gives an enantiomeric excess of only 24% under optimized conditions107, the same reaction with (/ ,/f)-diethyl tartrate (1.1 equivalents) as ligand affords (1 ) ,27t)-fra i-l-hydroxymethyl-2-phenylcyclopropane (2) with up to 79% ee108, Similar results are achieved with the corresponding (Z)-olefin, and even higher enantioselectivities are obtained for dimethylphenylsilyl-substituted allylic alcohols such as 3109. 

Enantioselective cyclopropanation of allylic alcohols Enantiosclective cyclo-propanation of allylic alcohols is possible with the Simmons-Smith reagent catalyzed by this C2-symmetric disulfonamidc 1, R = C6H4N02-p. 

Wolfgang Oppolzer s muscone synthesis is the first enantioselective macrocycli-sation. [195] It starts with pentadec-14-ynal, which is converted by hydro-boration and transmetaUation into the corresponding organozinc compound. The ring closure takes place in the presence of catalytic amounts of a diethylzinc/ (-)ejco-3-(diethylamino)bomeol adduct. After work-up, the cyclic allyl alcohol is obtained in 75 % yield and with an ee of 92 %. The hydroxy-group directs the diastereoselective cyclopropanation (Simmons-Smith reaction). The final steps are a Swern oxidation and selective ring-opening of the cyclopropane under Birch conditions. 

The Simmons-Smith reaction is the conversion of olefins to cyclopropanes by the use of halomethylzinc halides or related agents. Charette et al. found that a catalytic amount of chiral titanium-TADDOLate complex 78 was able to induce an enantioselective cyclopropanation of allylic alcohols. After optimisation of the catalytic structure, good yields and enantioselec-tivities were obtained, especially when 3-aryl and 3-heteroaiyl substituted allylic alcohols were used (Scheme 7.47). However, the reaction required the use of a high catalyst loading (25 mol%). 

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