Cinnamyl alcohol cyclopropanation

Another point for structural diversification is the sulfonamide group. Imai had already shown that a wide variety of groups could be introduced at this position to optimize the reaction. Since a wide variety of sulfonyl chlorides are commercially available, a number of different types of groups could be examined (Scheme 3.34). Testing of a variety of aryl and alkyl groups on the 1,2-cyclohexanediamine backbone demonstrates that the simple methanesulfonamide 122 is clearly superior or equal to many other analogs in the cyclopropanation of cinnamyl alcohol (Table 3.11). Another concern which was directly addressed by this survey was the question of catalyst solubility. 

Employing protocol V with the methanesulfonamide catalyst 122, a 93 7 er can be obtained in the cyclopropanation of cinnamyl alcohol. This high selectivity translates well into a number of allylic alcohols (Table 3.12) [82]. Di- and tri-substi-tuted alkenes perform well under the conditions of protocol V. However, introduction of substituents on the 2 position leads to a considerable decrease in rate and selectivity (Table 3.12, entry 5). The major failing of this method is its inability to perform selective cyclopropanations of other hydroxyl-containing molecules, most notably homoallylic alcohols. 

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.

Figure 5-15 shows a possible transition state for the enantioselective cyclopropanation of cinnamyl alcohol in the presence of dioxaborolane 206. This model predictes the absolute configuration of the products. 

Denmark and coworkers have reported an in-depth study of this reaction and highlighted the effect of the many variables to optimize the enantioselectivities . They have shown that the rate and selectivity of the catalytic enantioselective cyclopropanation of cinnamyl alcohol utilizing the bis(sulfonamide) 25 was greatly dependent on the order of addition of the reagents . The independent preformation of the ethylzinc aUcoxide and bis(iodomethyl)zinc was also found to be very important for high enantiocontrol (equation 94, Figure 9). 

Asymmetric cyclopropanation of olefins can also be achieved by the Simmons-Smith reaction (231). Reaction of ( )-cinnamyl alcohol and the diiodomethane-diethylzinc mixed reagent in the presence of a small amount of a chiral sulfonamide gives the cyclopropylcarbinol in up to 75% ee (Scheme 97) (232a). ( )-Cinnamyl alcohol can be cyclopro-... 

By protecting cinnamyl alcohol 37 as an acetal, ee is improved further, and new modes of reactivity are opened up. At -50 °C, 67 carbolithiates in the presence of catalytic (-)-sparteine and leads to the alcohol 69 in 90-95% ee. On warming to 20 °C, however, 68 undergoes a cyclisation with substitution at the C-0 bond to give the cyclopropane 70, also in >90% ee.41... 

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]. 

They later found that the disulfonamide-modified zinc complexes were much more effective catalysts. The reaction of several allyfic alcohols with diethylzinc and methylene iodide in the presence of differently substituted arylsulfona-mides derived ligands was examined in detail (Scheme 3). Although the p-trif-luoromethylbenzenesulfonamide catalyst (entry 5) facilitated the cyclopropana-tion of cinnamyl alcohol (2), the enantioselectivity observed was slightly lower than that observed with the o-nitro- or the p-nitrobenzenesulfonamide ligand (entries 2 and 4). Substitution at the meta-position resulted in a significant decrease of the enantioselectivity, probably due to steric reasons (entries 3 and 6). The cyclopropanation of (Zj-ciimamyl alcohol (3) and ( )-5-phenyl-2-penten-... 

The effect of solvent was also studied and complexing solvents such as THF or Et20 inhibited the cyclopropanation reaction. Furthermore, the presence of an unprotected allylic alcohol was found to be essential, since the methyl or benzyl ether derived from cinnamyl alcohol afforded almost racemic cyclopropanes. This method has also been extended to the enantioselective cyclopropanation of vinylsilanes and -stannanes (Scheme 4) [13]. The corresponding optically active silyl- and stannyl-substituted cyclopropyhnethanols were obtained in the presence of the chiral N,iV-bis(p-nitrobenzenesulfonyl)-l,2-cyclohexane-diamine 9. 

The different parameters involved in the enantioselective cyclopropanation of allylic alcohols using disulfonamide-derived ligands were also extensively studied by Denmark. He has shown that the rate and selectivity of the cyclopropanation reaction of cinnamyl alcohol using bis(iodomethyl)zinc and the... 

Denmark has also shown that the uncatalyzed ethylidenation of cinnamyl alcohol using bis(l-iodoethyl)zinc produced the cyclopropanes 13 and 14 in a 71 29 ratio (Scheme 7) [19]. This ratio decreased to 65 35 (13 14) in the presence of the disulfonamide 11. Both compounds had modest enantiomeric excesses. 

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... 

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.

The cyclopropanation of cinnamyl alcohol is a good example of the use of dioxaborolane ligand 3 as chiral additive to synthesize chiral cyclopropanes. 

The acidic site was first removed by replacing the boron center by a tetrahedral carbon. Racemic cyclopropylmethanol was obtained in quantitative yield when cinnamyl alcohol was cyclopropanated in the presence of dimethyl tartramide 5 under the usual conditions (Eq 4). This information suggests that the boron is necessary to bring the substrate and the ligand together and that the chiral additive does not act strictly as an activator of the bis(iodomethyl)zinc reagent. 

Mixed ( )-cinnamyl acetals 460 undergo the enantioselective carbolithiation readily in the presence of stoichiometric or catalytic amounts, as low as 1 mol%, of (—)-sparteine (11) (equation 126) °. When quenching the reaction mixture of 461, 462 below —50°C with MeOH/HCl, the alcohols 463 are obtained with good yields and excellent ee values. However, upon warming to 20 °C, a 1,3-cycloelimination from conformation 462 gives rise to the formation of optically active trani-cyclopropanes 464 °. 

Jorgensen et al. found that reduction of an allylic alcohol by lithium aluminum hydride can be carried beyond the stage of the saturated alcohol to give a cyclopropane. Thus a cinnamyl acid, ester, aldehyde, or ketone on reduction with 100% excess LiAlHj in refluxing tetrahydrofurane or dimethoxyethane affords a phenyl-cyclopropane in yield of 45-80%. The reaction complements the Simmons-Smith synthesis. 

The fact that cinnamyl methyl ether underwent cyclopropanation under similar conditions to afford the corresponding cyclopropane as an almost racemic mixture indicates that the free hydroxy group is necessary for producing an effective chiral environment. This can presumably take place through complexation as a zinc alkoxide. The authors propose that a trinuclear zinc complex 89, in which both the oxygen atom of a zinc alkoxide and iodine atom of iodo-methylzinc contribute to the Lewis character, must be close to the transition structure of the reaction. This might account also for the distinct enantioselectivity between the allylic alcohol and its methyl ether. 

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