Cyclopropanation Simmons-Smith type

The Simmons-Smith-type cyclopropanation of olefins is one of the most well-known reactions of carbenes and carbenoids. However, cyclopropanation of simple olefins with magnesium carbenoids is usually very difficult and only cyclopropanation of allylic alcohols was reported. Thus, treatment of allylic alcohols (23) in CH2CI2 at —70°C with i -PrMgCl and diiodomethane for 48 to 60 h afforded cyclopropanes in up to 82% yield as a mixture of syn- and and-isomers. In this reaction, 5yn-isomers were mainly or exclusively obtained (synianti = 5 1-400 1) (equation 10). 

Cyclopropanation.1 CH2I2 is used in cyclopropanation of the Simmons-Smith type, but it is about 20 times more expensive than CH2Br2. CH2Br2 in combination with Zn/CuCl can be used for cyclopropanation, particularly when sonication is used to promote the heterogeneous reaction in ether. Reaction times are 2-4 hours, and yields range from 30-70%. 

Cyclopropanation of Allylic Alcohols. Simmons-Smith type cyclopropanation of the allylic alcohol 22 in the presence of a catalytic amount of the bis-sulfonamide la leads to formation of the corresponding cyclopropane 23 in high yield and selectivity (eq 6, Table 3). The reaction is rapid (< 1 h) and can be performed at low temperature (either 0 °C or —20 °C). Substrate scope encompasses both di- and tri-substimted allylic alcohols (24 and 26). However, substimtion at the 2 position, as in 28, leads to a drastic decrease in selectivity. The presence of additional oxygenated functionality (30) in the proximity of the alkene also lessens selectivity." The method is limited to the cyclopropanation of allylic alcohols. Other alkene-containing substrates, such as allylic ethers, homo-allylic alcohols and allylic carbamates, do not react with high selectivity. 

This method is comparable to similar, catalytic Sim-mons-Smith-type methods employing the titanium TADDOL catalyst 20 (95 5 er) or the Ci-symmetric bis-sulfonamide catalyst 32 (93 7 er) for the cyclopropanation of the allylic alcohol 22 (eq 6). However, due to the preliminary nature of these earlier investigations, substrate scope and generality have not been extensively documented. All of the aforementioned methods are limited by their dependence on the allylic alcohol functionality. Only one method for Simmons-Smith-type cyclopropanation of other substrate classes has been developed. Use of a stoichiometric, chiral dioxaborolane [CAS 161344-85-0] additive allows for selective cyclopropanation of allylic ethers, homo-ally lie alcohols and allylic carbamates. ... 

The organoaluminum-mediated cyclopropanation had unique selectivity not observable in Simmons-Smith type reactions [95], Treatment of geraniol with i-Bu3Al (2 equiv.)-methylene iodide (1 equiv.) in CH2CI2 at room temperature for 5 h produced cyclopropanation products in 75 % combined yields in the ratio 76 1 4. Consequently, methylene transfer by the aluminum method occurs almost exclusively at the C(6)-C(7) olefinic site far from the hydroxy group of geraniol and the C(2) -C(3) ole-finic bond was left intact. In sharp contrast, the zinc method resulted in the opposite regioselectivity via hydroxy-assisted cyclopropanation, as shown in Sch, 62. 

The 2-oxabicyclo[3.1.0]hexane nucleoside 166 was obtained via a Simmons-Smith type cyclopropanation reaction of intermediate 164, followed by glycosidation with several natural heterocyclic bases <05JOC6891 05NNNA383>. A restricted version of puromycin built on a bicyclo[3.1.0]hexane template was synthesized by Choi via Mitsunobu coupling of a 3-azido-substituted carbocyclic moiety with 6-chloropurine to give compound 167 <02OL589>. 

The zinc-based Simmons-Smith type procedures frequently require rather harsh conditions in order to provide acceptable cyclopropane yields. Also, the discrimination between allylic alcohols, homoallylic alcohols and olefins without a hydroxyl group is often not very pronounced. These drawbacks are avoided by a new method which substitutes samarium metal (or samarium amalgam) for zinc (Table 4)43. This cnahlcs only allylic alcohols to be cyclo-propanated under very mild conditions, even for highly crowded substrates. The hydroxy-directed diastereofacial selectivity is good to excellent for cyclic olefins. Due to this property, the method has been applied to the stereoselective synthesis of 1,25-dihydroxycholecalciferol44. 

Several procedures deal with optically active auxiliaries employed in stoichiometric amounts or more, but which are not covalently bonded to one of the reagents. These catalysts influence Simmons-Smith type cyclopropanations of allylic alcohols with moderate to excellent enantiose-lectivities. Whereas the reaction of ( )-3-phenyl-2-propen-l-ol (1) with diethylzinc and diiodo-methane in the presence of (17 ,25 )-A,-methylephedrine (2 equivalents) gives an enantiomeric excess of only 24% under optimized conditions107, the same reaction with (/ ,/f)-diethyl tartrate (1.1 equivalents) as ligand affords (1 ) ,27t)-fra i-l-hydroxymethyl-2-phenylcyclopropane (2) with up to 79% ee108, Similar results are achieved with the corresponding (Z)-olefin, and even higher enantioselectivities are obtained for dimethylphenylsilyl-substituted allylic alcohols such as 3109. 

Dimethylsulfonium methylide and dimethylsulfoxonium methylide also differ in their reachons with a,p-unsaturated carbonyl compounds. The sulfonium ylide reacts at the carbonyl group to form an epoxide, but with the sulfoxonium ylide a cyclopropane derivative is obtained by Michael addihon to the carbon-carbon double bond. The difference is again due to the fact that the kinehcally favoured reachon of the sulfonium yhde with the carbonyl group is irreversible, whereas the corresponding reaction with the sulfoxonium yhde is reversible, allowing preferenhal formahon of the thermodynamically more stable product from the Michael addihon. For example, the cyclopropane 112 is obtained from the reaction of dimethylsulfoxonium methylide with the enone 111 (1.105). Other methods for the formahon of cyclopropanes include carbene and Simmons-Smith-type... 

The asymmetric synthesis of cyclopropanes has attracted continual efforts in organic synthesis, due to their relevance in natural products and biologically active compounds. The prevalent methods employed include halomethylmetal mediated processes in the presence of chiral auxiliaries/catalysts (Simmons-Smith-type reactions), transition-metal-catalyzed decomposition of diazoalkanes, Michael-induced ring closures, or asymmetric metalations [8-10,46], However, the asymmetric preparation of unfunctionahzed cyclopropanes remains relatively undisclosed. The enantioselective activation of unactivated C-H bonds via transition-metal catalysis is an area of active research in organic chemistry [47-49]. Recently, a few groups investigated the enantioselective synthesis of cyclopropanes by direct functionalization reactions. 

A modified Simmons-Smith reaction has been used in the stereoselective synthesis of a naturally occurring substance called U-106305 containing six cyclopropane rings. In the synthesis, four of the six rings arise by Simmons-Smith-type cyclopropanation. The red lines in the structural formula identify the bonds to the CH2 groups that are introduced in this way the blue lines identify bonds that originated with the iiutial reactant. 

Interestingly, reaction of zirconacyclopentadienes with a Simmons-Smith type of carbene reagent afforded zirconacyclopentene-cyclopropane fused intermediates 26, which reacted further with CO to generate 1,2,3,5-tetra-substitued benzenes 27 via a novel skeletal rearrangement, as shown in Scheme 11.11 [12],... 

A number of enantioselective Simmons-Smith-type cyclopropanations have been disclosed, of which three classic examples are discussed in this section [19]. In the first, Charette described the use of a dioxaborolane (111, Scheme 15.13) as an effective chiral controller group [68]. The presence of the basic amide C=0 was found to be critical for directing the cyclopropanation reagent to a single olefin diastereoface. Treatment of allylic alcohols such as 110 with 111 and Zn(CH2l)2 led to the formation of intermediate boronates that subsequently underwent cyclopropanation with excellent yields and enantioselectivities. An impressive iterative application of this method was showcased by Charette in a total synthesis of the natural product U-1065305 (113), a cholesterol transferase inhibitor [69]. 

Commonly known methods for the preparation of bkyclopropylidenes of types 55-62 (Fig. 3) are the cyclopropanations of appropriately cyclopropanated al-lenes according to the Gaspar-Roth [60] or modified Simmons-Smith protocol [61] or addition of cyclopropylidene generated in situ from AT-nitroso-N-cyclo-propylurea [62,63]). Along these routes, the compounds 55 [63], 58-60 [33,64, 65], and 62 [33,64] were obtained in low to moderate yields (Scheme 11). 

The addition of different types of carbenes onto bicyclopropylidene (1) is a common method for the preparation of [3]triangulane derivatives as well as branched trianguianes and normally proceeds without complications (for a review see [77]). Thus, the cyclopropanation under Gaspar-Roth [60] or modified Simmons-Smith [111] conditions gave dispiro[2.0.2.1]heptane ([3]triangulane, 97) in 80 [105] and 15% yield [5], respectively (Scheme 23). The palladium(II) acetate-catalyzed cycloprop anation of 1 with diazomethane, however, gave a number of products resulting from insertion of one or more than one methylene units into an initially formed palladacyclobutane 115 [112,113] (Scheme 23). 

Polymerization. Monomers. The cyclopropane type monomers are prepared either by addition of the dichlorocarbene or by the Simmons-Smith reaction on the corresponding olefins. Most of these compounds have been described. Spiropentane is prepared by the Applequist method (I, 2), by the reaction of zinc with C(CH2Br)4 in alcohol in the presence of ethylenediaminetetraacetic acid (EDTA). This hydrocarbon is purified until a single NMR signal is obtained at t = 9.28. 

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). 

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