Synthesis Simmons-Smith reaction

Small ring synthesis. Simmons-Smith reactions using CH2l2-Et2Zn as reagent are enantioselective in the presence of chiral rrans-I,2-cyclohexanedisulfonamides... 

This reaction is called the Smmons-Smith reaction and is one of the few methods avail able for the synthesis of cyclopropanes Mechanistically the Simmons-Smith reaction seems to proceed by a single step cycloaddition of a methylene (CH2) unit from lodomethylzmc iodide to the alkene... 

The synthesis of 11 jS-hydroxy-A -3-ketones (17) from A ° -compounds (16) has been carried out by the homoallylic hydroxyl-assisted Simmons-Smith reaction. 

The Simmons-Smith reaction is well suited for the synthesis of spirocyclic compounds. It has for example been applied for the construction of the fifth cyclopropane ring in the last step of a synthesis of the rotane 8 ... 

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 ... 

Furthermore, cyclopropane structures have often served as intermediates in organic synthesis. For these reasons, olefin cyclopropanation has proved to be a useful tool for synthetic organic chemists. This has led to the development of several methods for cyclopropanation reactions,91 including the metal-catalyzed reactions of diazo compounds with olefins, as well as the Simmons-Smith reaction. 

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. 

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 synthesis of substituted glutamic acid analogues has been pursued by many routest94-106 using asymmetric alkylation, Simmons-Smith reactions, Diels-Alder reactions, and nickel complexes of glycine or alanine equivalents. 

Scheme 23 Synthesis of (Carboxycyclopropyl)glycine Derivatives via the Simmons-Smith Reaction 99 ...

Scheme 24 Synthesis of a y,y-Disubstituted Glutamic Acid via an Asymmetric Simmons-Smith Reaction 97-1081...

The methods for stereocontrolled synthesis of cyclopropylboronic esters have been studied (Scheme 29). The palladium-catalyzed reaction of diazoalkanes (method A), Simmons-Smith reaction (method B), or asymmetric Simmons-Smith reaction using chiral diamines such as 270 (method C) for chiral or achiral 1-alkenylboronic esters... 

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). 

As (—)-pulegone is not readily available, subsequent work addressed the natural enantiomer by different methods [12], but all completed their synthesis via Snider s enone (17). Asaoka utilised a TMS group as temporary directing volume (Scheme 5) [12a]. Cossy applied a photore-ductive cyclopropane ring opening, which was obtained by a diastereoselective Simmons-Smith reaction [12b]. Schmalz finally used a planar-chiral arene complex to synthesise enone 17 with interesting CrfCO), chemistry [12c]. 

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... 

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