Stereoselectivity Simmons-Smith reaction

Chemo- and stereoselective reduction of (56) to (55) is achieved In highest yield by sodium borohydride in ethanol. The isolated ketone is reduced more rapidly than the enone and (55) is the equatorial alcohol. Protection moves the double bond out of conjugation and even the distant OH group in (54) successfully controls the stereochemistry of the Simmons-Smith reaction. No cyclopropanation occurred unless the OH group was there. Synthesis ... 

The synthesis of drospirenone (see Fig. 17.1) was unusually complicated, with the new structural elements being methylene groups at positions 6)5,7)5 and 15)5,16)5. Originally, in 1966, the 15)5,16)5-methylene group [9,10] had been introduced into the steroid skeleton in the process of another Schering project, and good yields were obtained. The major problem in the synthesis was stereoselective 6)5,7)5-methylenation the key compound for this was the 5)5-hydroxy-6-ene structure A, from which the 6j8,7)5-methylene compound B was synthetized stereoselectively by means of a Simmons-Smith reaction (Zn-Cu/CH2Br2) (Fig. 17.6). 

The reaction is known as the Simmons-Smith reaction, after the two chemists at the DuPont chemical factory who discovered it in 1958. Even after several decades, it is the most important way of making cyclopropane compounds, though nowadays a variant that uses more easily handled starting materials is often used. Diethyl zinc replaces the Zn/Cu couple of the traditional Simmons-Smitji reaction. In this example, a double cyclopropanation on a C2 symmetric diene derived from tartaric acid gives very good stereoselectivity for reasons we will soon discuss. 

When Ireland wanted to introduce a cyclopropane ring stereoselectively into a pentacyclic system containing an enone, he first reduced the ketone to an alcohol (DIBAL gave only the equatorial alcohol) that controlled the stereochemistry of the Simmons-Smith reaction. Oxidation with Cr(VI) put back the ketone. 

An auxiliary-directed asymmetric Simmons-Smith reaction was used by a Hoff-mann-La Roche group88 for the synthesis of an ethynyl cyclopropane that served as the A-ring precursor to Vitamin D derivatives [Scheme 2.41]. High diastereoselectivity was achieved with the aid of the dioxolane ring prepared from (/ft/f)-(-)-butane-2,3-diol. The acid conditions for hydrolysis of the dioxolane ring were mild enough to leave the cyclopropane ring unperturbed. Dia-stereoselective cyclopropanation of acetals derived from 1,2-di-O-benzyl-L-threi-tol have also been reported 90... 

This type of coordination is useful for highly stereoselective syntheses of cyclopropane derivatives. Reaction of A -cyclohexenyl methyl ether with the Simmons-Smith reagent gives CM-2-bicyclo[4.1.0]heptyl methyl ether without the trans isomer 103). The Simmons-Smith reaction with 7-tCT f-hutoxynorbornadiene gives syn-exo- IV) and syn-endo isomer (V) without the anti isomers 260). 

An asymmetric Simmons-Smith reaction was reported by Kang et al. [18]. The reaction of (3-D-fructopyranoside 13 with a,(3-unsaturated aldehydes gave enrfo-acetals 14 along with exo-isomers 15 in a ratio of about 1.5 1. The enrfo-acetals afforded the best selectivity, typically giving (2/f,3/f)-hydroxymethyl cyclopropanes 17 with up to 85% ee. It should be noted that the corresponding exo-acetals 15 underwent the cyclopropanation reaction with lower stereoselectivity. In these cases, the group cannot effectively block either side of the alkene in contrast to the endo-isomer [18] (Scheme 10.3). 

The fact that the Simmons-Smith reaction is regio- and stereoselective enabled the preparation of tritium containing cyclopropane derivatives useful for biological studies. The tritiated diiodomethane was prepared by reduction of iodoform with sodium arsenite in the presence of tritiated water. The carbene generated from tritiodiiodomethane and triisobutylaluminum in chloroform underwent regioselective addition to the unhindered double bond in perillyl alcohol (34). ... 

Normally the chiral auxiliaries are introduced and removed in the asymmetric synthesis of Simmons-Smith reactions of allylic alcohols to provide mostly /rani-disubstituted cyclopropanes. Stereoselective syntheses of c -disubstituted cyclopropanes are difficult to achieve. Starting from (Z)-3-phenylprop-2-en-l-ol (80a) and (Z)-6-phenylhex-2-en-l-ol (80b), the corresponding c -disubstituted cyclopropanes 81a and 81b were prepared by first treating them with diethylzinc followed by diethyl (- -)-(/ ,7 )-tartrate (DET). A zinc-bridged intermediate is assumed to be formed first. This is subsequently treated with diethylzine and diiodomethane to give the products 81. The reaction conducted at — 12 "C gave the cyclopropanated products 81a and 81b with 70 and 81% ee, respectively.This method has the advantages that the introduction of the chiral auxiliary to the substrate and its removal are not neccessary and that both cis- and trans-disubstituted cyclopropanes could be prepared from (Z)- and ( )-allylic alcohols, repectively. 

Synthesis of model compounds and structural units are being investigated. A double Simmons-Smith reaction on the l,3-dioxolane-4,5-diylbis(alkene) 107 afforded the product 108 with excellent stereoselectivity. The required asymmetry in the double cyclopropanation was the result of coordination of the zinc carbenoid reagent by the Lewis basic dioxolane ring oxygen prior to each cyclopropanation event. The cyclopropanated product was converted to ( )-l,2-bis[(l 5,25)-2-methylcyclopropyl]ethene, a relevant model for the complete structural assignment of FR-900848. 

All disconnections are the same on cyclopropane, requiring a carbene equivalent which will add to an unactivated double bond. Diazomethane will do this, but one of the best carbene sources is CH2I2 with a zinc-copper couple (the Simmons-Smith reaction ). This works particularly well on allylic alcohols (31), no doubt because of hydrogen bonding between the OH group and the reagent. The reaction is then totally stereoselective. 

The Simmons-Smith reaction is influenced by a suitably situated hydroxy group in the alkene substrate. With allylic and homoallylic alcohols or ethers, the rate of the reaction is greatly increased and, in five- and six-membered cyclic allylic alcohols, the product in which the cyclopropane ring is cis to the hydroxy group is formed stereoselectively (4.89). These effects are ascribed to co-ordination of the oxygen atom to the zinc, followed by transfer of methylene to the same face of the adjacent double bond. 

Allylic alcohols are also cyclopropanated over 100 times faster than their unfunctionalized alkene equivalents. Coordination between the zinc atom and the hydroxyl group in the transition state explains both the stereoselectivity and the rate increase. Unfortunately, while the Simmons-Smith reaction works well when a methylene (CH2) group is being transferred, it is less good with substituted methylene groups (RCH or R2C ). 

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