Simmons-Smith transform

Without question, the most powerful method for cyclopropane formation by methylene transfer is the well-known Simmons-Smith reaction [6]. In 1958, Simmons and Smith reported that the action of a zinc-copper couple on diiodomethane generates a species that can transform a wide variety of alkenes into the corresponding cyclopropanes (Scheme 3.3) [7]. 

As part of an independent study of catalytic asymmetric cyclopropanation, Denmark et al. described a systematic investigation of the effect of addition order, stoichiometry and catalyst structure on sulfonamide-catalyzed Simmons-Smith cyciopropanations. Although early studies had shown promising levels of enantios-electivity, higher selectivity would be required for this to be a synthetically useful transformation. The principal issues that were addressed by this study included ... 

Androstenolone, 1, can be transformed microbiologically to the 7a,15a-dihy-droxy derivative 2 by the action of Colletotrichium Uni. During formation of the acetal (3), inversion takes place on C-7. Acidic cleavage of 3 results in the triol, 4, which can also be produced by direct acidic catalysis from 2 [12,13]. After selective protection to the 3/l,15a-dipivalate (5), the 15/1,16/1-methylene compound, 6, can be synthetized, and then stereoselectively transformed to the 5/ ,6/ -epoxide, 7. This reacts with triphenylphosphine and tetrachloromethane in pyridine to produce the 7a-chloro derivative, 8. On treatment with zinc and acetic acid, 8 can be converted to the key compound 9, which has a 5/i-hydroxy-6-ene structure. Compound 9 can then be methylenated stereoselectively in the 6/1,7/1 position by the Simmons-Smith method. The last three steps - 10 —> 11 —> 12 — drospirenone -include the build-up of the spironolactone ring, after which water is lost from the molecule and oxidation affords drospirenone. 

Upon reaction with the Simmons-Smith reagent104) or m-chloroperbenzoic acid,105 cyclooctyne is transformed at least in part to products of the bicyclo-[3.3.0]octane type. 

Vinylcyclopropanols can be prepared either from the readily available cyclopro-panone hemiacetaP, from 1-hydroxycyclopropanecarboxaldehyde derivativesfrom a,a -dichloroacetone, from the silver Simmons-Smith cyclopropanation of a-ethylenic ketone silyl enol ethers from the dye-sensitized photo-oxygenation of alkylidene-cyclopropanes or from the ring-opening of oxaspiropentanes (cf. Section III.C). Consequently, they become participants of choice in a number of useful chemical transformations (see also Section IV.A). 

Cohen has used a soluble version of the Simmons-Smith reagent to promote the 3,2-rearrangement of allylic sulfides (Scheme 52). He has also applied this methodology to the synthesis of sarkomycin (225). The allylic sulfide (221), easily available via a Petrow reaction, was first alkylated and the sulfo-nium ylide was then generated by a fluoride-promoted desilylation. Rearrangement of the ylide (223) gave the homoallylic sulfide (224) which was eventually transformed into sarkomycin (Scheme 53). 

Duodomethane. 13,110-115 275-276 16,184-185 17,155 18, 139-140 19,128 Cyclopropanation. 1-Alkenylsilanols are transformed into cyclopropylsilanols by the Simmons-Smith reaction. A Grignard reagent may replace the zinc or diethylzinc... 

Using Simmons-Smith type reagents, hydroxy and alkoxy groups in the allylic or homoallylic position exhibit a very strong syn-directing effect on methylene transfer, which usually overrides the steric influence of further substituents in an alkene2,5 (see Table 2 for the transformation of simple cyclic alkenes)29 32. 

Since probe experiments disclosed convincingly to us that the double bond in the intact sidechain of acetoxycrenulide is more reactive to Simmons-Smith cyclopropanation than cyclooctenyl double bonds, the decision was made to introduce the isopropenyl group in the final stages of the synthesis. Accordingly, ester 146, which is easily produced from (/ )-citronellol [81], was transformed into... 

CyclopropanationJ The title compound, prepared from ArOH, Et2Zn, and CH2I2, is a modified Simmons-Smith reagent, with which alkenes are transformed into cyclopropanes in excellent yields (6 examples, 90-98%). In terms of reactivity, the zinc phenoxide is comparable to bis(chloromethyl)zinc, but more reactive than bis(iodomethyl)zinc and Furukawa s reagent. 

Methylenation of ketonesP The combination Zn-TiCU transforms CH2I2 into a methylenating agent. The Wittig-like reaction is accelerated by PbCh. Traces of lead are found to suppress the reactivity of Zn toward CH2I2, but the reactivity (for the Simmons-Smith reaction) is recovered by adding Me SiCI. 

Alcoholysis of epoxides. FeCl.i is an effective catalyst for the transformation. Oxidative cleavage of trimethylsiloxycyclopropanes. This method of enone generation, in combination with conjugate addition, enolate trapping, and Simmons-Smith reaction, complete the sequence of ring expansion that also incorporates a substituent at the y-position of a lower homolog. Thus 4-alkyl-2-cyclohexenones are readily prepared from cyclopentenone. 

Four ring forming transforms have been considered at length by the LHASA development group - the Diels Alder addition, the Robinson Annelation, the Simmons-Smith reaction, and iodo-lactonization. The first three of these have been fully implemented in LHASA and the fourth is completely flow charted and awaits only coding into the chemistry data base language. 

Diazo compounds. Besides diazomethane and the Simmons-Smith reagent, diazocarbonyl compounds (diazomethylketones I), and particularly diazoesters (diazoacetates II, diazomalonates III and a-diazo 3-keto-esters IV) are widely used because they are versatile intermediates for further transformations (acids, alcohols,. ..). 

Zinc and Mercury.—As in previous years, reports of new transformations and methodologies involving zinc have been at a low level. A useful high-yielding conversion has been published, however, of allylic thioethers such as (84) into homoallylic thioethers (85). The initial ylide formation with a homogeneous solution of diethylzinc and methylene (R = H) or ethylidene (R = Me) iodide is followed by a 2,3-sigmatropic rearran ment to the observed products, and the poor yields found in previous experiments can be avoided by quenching the reaction mixture with acetaldehyde. Conventional Simmons-Smith cyclo-propanation of these compounds fails, as does the cyclopropanation of cyclohexene in the presence of various thioethers. 

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. 

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