Simmons-Smith cyclopropane synthesis

Carl R. Johnson, Michael R. Barbachyn fi-Hydroxysulfoximine-Directed Simmons-Smith Cyclopropanations. Synthesis of (-)- and (+)-Thujopsene, J. Am. Chem. Soc. 104,4290-4291 (1982)... 

Recently, Charette et al. have also demonstrated this behavior in the stereoselective cyciopropanations of a number of enantiopure acyclic allylic ethers [47]. The high degree of acyclic stereocontrol in the Simmons-Smith cyclopropanation has been extended to synthesis several times, most notably in the synthesis of small biomolecules. Schollkopf et al. utilized this method in their syntheses of cyclopropane-containing amino acids [48 a, b]. The synthesis of a cyclopropane-containing nucleoside was also preformed using acyclic stereocontrol [48c]. 

The final stages of the synthesis involved introduction of the final methyl group by Simmons-Smith cyclopropanation and reductive opening of the cyclopropane ring. 

Dihalocydopropanes readily undergo reductive dehalogenation under a variety of conditions. Suitable choice of reagents and reaction conditions will allow the synthesis of monohalocyclopropanes or the parent cyclopropanes.19 " The ease of reduction follows the expected order I > Br > Cl > F. In general, complete reduction of dibromo and dichloro compounds is accomplished by alkali metal in alcohol,99-102 liquid ammonia103 or tetrahydrofuran (equations 28 and 29).104 The dihalocydopropanes can be reduced conveniently with LAH (equation 30).105 LAH reduction is particularly suited for difluoro compounds which are resistant to dissolving metal reductions.19 106 It is noteworthy that the sequence of dihalocar-bene addition to an alkene followed by the reduction of the dihalocyclopropyl compounds (equation 31) provides a convenient and powerful alternative to Simmons-Smith cyclopropanation, which is not always reliable. 

Conversion of the methyl ester of 1-adamantane carboxylic acid to 1-ada-mantyl dimethylcarbinol (66) by reaction with CH3Mgl followed by dehydration and subsequent hydrogenation provides a convenient route to 1-iso-propyladamantane (66a) 164> 20°). Simmons-Smith cyclopropanation of 1-isopropenyladamantane (67) followed by hydrogenolysis of the cyclopropane ring gives 1-r-butyladamantane (68) 204>. An alternative synthesis... 

Corey exploited the remarkable configurational stability of cyclopropyllithiums in his synthesis of hybridalactone. The stannane 28 was made by Simmons-Smith cyclopropanation of the allylic alcohol 27 and resolved by formation of an O-methyl mandelate ester. Transmetallation of 29 with 2 equiv. BuLi gave an organolithium which retained its stereochemistry even in THF over a period of 3 h at 0 °C, finally adding to 31 to give 32. 

Some of the evidence for this comes from a reaction that not only throws light on to the mechanism of Simmons-Smith cyclopropanations, but makes them of even greater value in synthesis. When an allylic alcohol is cyclopropanated, the new methylene group adds stereoselectively to the same face of the double bond as the alcohol group. 

From the multitude of synthetic work in the field of cyclopropanation, we will focus on the asymmetric synthesis of cyclopropanes. Besides the known stereocontrolled addition of diazocompounds to olefins (diazo-method) [6] the stereocontrolled Simmons-Smith cyclopropanation has received significant attention in the last ten years. The latter will be discussed further. 

An early stage in the synthesis of the antifungal metabolite FR-900848 exploited a double Simmons-Smith cyclopropanation directed by two di-isopropyl tartrate acetals [Scheme 2.42] 9192 The diastereoselectivity of the reaction can be attributed to intramolecular delivery of a zinc carbenoid co-ordinated to one of the ester carbonyls and an oxygen of the dioxolane ring.93 Note the use of the Noyori protocol (see above) for the bis-dioxolanation of the highly reactive mu-conaldehyde ... 

The combination of the chromatographic separation of enan-tiopure p-hydroxysulfoximine diastereomers and reductive elimination results in a method of ketone methylenation with optical resolution. The technique is illustrated in the synthesis of the ginseng sesquiterpene (—)-p-panasinsene and its enantiomer (eq 5). The addition of the enantiopure lithiosulfoximine to prochiral enones or the diastereoface selective addition to racemic enones results in the formation of two diastereomeric adducts. The hydroxy group in these adducts can be used to direct the Simmons-Smith cyclopropanation (eq 6 and eq 7). Catalytic osmylation of such adducts is directed by the anti effect of the hydroxy augmented by chelation by the methylimino group (eq 7). ... 

The lactone-directed intramolecular Diels-Alder cycloaddition was the key step in D.F. Taber s synthesis of trans-dihydroconfertifolin. During the endgame, the Simmons-Smith cyclopropanation was utiiized to install the gem-dimethyl group at C4. The trisubstituted alkene was cyclopropanated in excellent yield and the resulting cyclopropane was subjected to catalytic hydrogenation. 

Sigmatropic rearrangement 677, 697 Sihca gel membranes 1082 Silphinene, electrosynthesis of 1183, 1187 Silver compounds, as oxidants 1307-1311 Silybin, synthesis of 1308, 1310 Silydianin 1180 Silylation, of phenols 934, 935 Silylcyanation, asymmetric 694, 695, 702 Simmons-Smith cyclopropanation, asymmetric 694... 

The last step in the synthesis of sesquiterpenoids africanol (44) and isoafricanol (45) employed the Simmons-Smith cyclopropanation with diethylzinc/diiodomethane. The addition occurred from the less hindered convex face bearing a hydroxy group to give the sesquiterpenes in good yield. ... 

Stereoselective samarium-based Simmons-Smith cyclopropanation of cyclopentyl allylic alcohols is the key step in the synthesis of the precursor of 1,25-dihydroxy vitamin The... 

Recently reported uses of optically pure stilbene diol in asymmetric synthesis include. (1) the dimethyl ether as a ligand for effecting enantioselective conjugate addition (2) the preparation of a,p-unsaturated ketals for achieving diastereoselective Simmons-Smith cyclopropanation <3 (3) the preparation of enantlomercially pure p-halohydrins i and (4) the preparation of chirai crown... 

Stereoselective samarium-based Simmons-Smith cyclopropanation of cyclopentyl allylic alcohols is the key step in the synthesis of the precursor of 1,25-dihydroxy vitamin D3.128 The desired chirality was generated in one case under the influence of the two stereogenic centers on the (R,/ )-butane-2,3-diol acetal 121 and in the other case was directed entirely by the allylic hydroxy group of 122. 

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... 

Simmons-Smith cyclopropanation, 456 Simmons-Smith reaction, 455 six-centered transition state, 264 Smiles-type rearrangement, 7 SOCI2, 19, 159 sodium azide, 365, 375 sodium borohydride, 416 sodium hexamethyldisilazide, 290 sodium hydride, 372, 375. 383 sodium in liquid ammonia, 440 sodium iodide, 379 sodium phenylselenide, 458 sodium trifluoroethoxide, 447 solid phase synthesis, 25 Sonogashira conditions, 409 Sonogashira coupling, 411 spartadienedione, 144 spontaneous csdodimerization, 23 S-shaped and C-shaped diastereomers, 83 stainless steel reactor, 283... 

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