Stereospecific reactions Simmons-Smith reaction

The Simmons-Smith reaction has been used to great advantage in the conversion of 19-nor steroids to the naturally occurring 10)5-methyl steroids as well as the unnatural lOa-methyl steroids. Thus methylenation of androst-5(10)-ene-3a,17 -diol (9) proceeds in an autoclave at elevated temperatures with stereospecific a-face addition to give the 5a,10a-methylene compound (10) in 85% yield. 

The Simmons-Smith reaction (Section 14.12) Methylene transfer from iodo-methylzinc iodide converts alkenes to cyclopropanes. The reaction is a stereospecific syn addition of a CH2 group to the double bond. 

Taking 1,2-disubstituted cyclopropane as an example, retro synthesis analysis shows that there are three possible ways to disconnect the three-membered ring—a, b, and c as shown in Figure 5-11. Route a involves the addition of methylene across a double bond, and this is often a stereospecific conversion or Simmons-Smith reaction.92 One can clearly see that route b or c will encounter the issue of cis/trans-product formation. 

Among methods of preparing optically active cyclopropane compounds, the Simmons-Smith reaction, first reported in 1958, is of significance. This reaction refers to the cyclopropanation of alkene with a reagent prepared in situ from a zinc-copper alloy and diiodomethane. The reaction is stereospecific with respect to the geometry of the alkene and is generally free from side reactions in contrast to reactions involving free carbenes. 

The Simmons-Smith reaction " and its variants are widely used for the stereospecific synthesis of cyclopropane compounds. The methodology involves the use of copper-treated zinc metal (the zinc-copper couple) with diiodomethane to add methylene to a carbon-carbon double bond. Alternative use of diazomethane in catalytic reactions does not offer the same synthetic advantages and is usually avoided because of safety considerations. As significant as is the Simmons-Smith reaction for cyclopropane formation, its employment for organic synthesis was markedly advanced by the discovery that allylic and homoallylic hydroxyl groups accelerate and exert stereochemical control over cyclopropanation of alkenes (e.g, Eq. 21), and this acceleration has been explained by a transition state model... 

The acid group in the side chain of substituted glutamic acids can be introduced by ethyl diazoacetate via the Simmons-Smith reaction (Scheme 23).[wl This reaction is not stereospecific and four isomers are obtained, which can be separated and further converted into the derivatives 73A-D. 

The Simmons-Smith reaction is stereospecific. The relative position of substituents in the alkene reactant is retained in the cyclopropane product, as shown for the conversion of c -3-hexene to cw-l,2-diethylcyclopropane. 

Simmons-Smith reaction. Stereospecific synthesis of cyclopropanes by treatment of olefins with methylene iodide and zinc-copper couple. 

Although the addition of carbene to a double bond to make a cyclopropane is well known, it is not particularly useful synthetically because of the tendency for extensive side reactions and lack of selectivity for thermally or photochemically generated carbenes. Similar processes involving carbenoids (species that are not free carbenes) are much more useful from the preparative standpoint [91,92]. For example, metal catalyzed decomposition of diazoalkanes usually results in addition to double bonds without the interference of side reactions such as C-H insertions. Consider the possible retrosynthetic approaches to a 1,2-disubstituted cyclopropane shown in Figure 6.8. Disconnection a entails the addition of a methylene across a double bond, a conversion that is often stereospecific e.g., the Simmons-Smith reaction [93]). Disconnections b and c are more problematic, since the issue of cis/trans product isomers (simple diastereoselection) arises. 

A modified version of the Simmons-Smith reaction uses dibromomethane and in situ generation of the Cu-Zn couple. Sonication is used in this procedure to promote reaction at the metal surface. Cyclopropanation can also be affected with a combination of CH2I2 and an alkylzinc reagent. The reaction is stereospecific and strongly regioselective. Thus, it has been found that cyclopentenol gives only the mdo-bicyclic alcohol (Scheme 5.34). The mechanism of the Simmons-Smith reaction appears to be carbene transfer from the metal to the alkene without any free carbene being released (Scheme 5.35). 

This reaction is called the Simmons-Smith reaction and is one of the few methods available for the synthesis of cyclopropanes. The reaction is stereospecific. Substituents that were cis in the alkene remain cis in the cyclopropane. 

Simmon-Smith reactions are accelerated by oxygen, radical initiators and UV irradiation. All additions are stereospecific. Hence, it is considered that free carbene does not exist in the reactions. The reaction mechanism is not known. Simmon-Smith reactions are shown in eq. (5.34) and (5.35). The active zinc metal is usually... 

The Simmons-Smith reaction is stereospecific. The relative position of substituents in the... 

The first substance examined in the steroid field was 3j6-hydroxycholest-4-ene (1) and the epimeric 3a-alcohol (3). These compounds react stereospecifically in dry ether with the Simmons-Smith reagent to yield the isomeric cyclopropyl carbinols (2) and (4) in 90 % and 67 % yields, respectively. The rate of this reaction is about one fifth of that observed with simple cyclic car-binols. ... 

Cyclopropanation with Halomethylzinc Reagents. A very effective means for conversion of alkenes to cyclopropanes by transfer of a CH2 unit involves reaction with methylene iodide and a zinc-copper couple, referred to as the Simmons-Smith reagent.169 The reactive species is iodomethylzinc iodide.170 The transfer of methylene occurs stereospecifically. Free CH2 is not an intermediate. Entries 1 to 3 in Scheme 10.9 are typical examples. 

---