Substrates Simmons-Smith cyclopropanation

The discovery of viable substrate-direction represents a major turning point in the development of the Simmons-Smith cyclopropanation. This important phenomenon underlies all of the asymmetric variants developed for the cyclopropanation. However, more information regarding the consequences of this coordinative interaction would be required before the appearance of a catalytic, asymmetric method. The first steps in this direction are found in studies of chiral auxiliary-based methods. 

The reaction was first carried out with the substrate bearing the chiral auxiliary. Scheme 5-64 shows the asymmetric cyclopropanation reaction using 2,4-pentandiol as a chiral auxiliary.115 Scheme 5-65 illustrates the use of optically pure 1,2-frafts-cyclohexanediol as a chiral auxiliary in asymmetric Simmons-Smith cyclopropanation.116 Excellent yield and diastereoselectivity are obtained in most cases. 

Cyclopropanation reactions have generated appreciable interest since the products have potential for chemical manipulation and as enzyme inhibitors.60 A notable early finding is that addition at either side of a double bond can be induced by manipulation of the structures of the substrates. For example, compound 171 is obtained from ethyl 4,6-di-0-acetyl-2,3-dideoxy-a-D-eryt/zro-hex-2-enopyranoside by Simmons-Smith cyclopropanation (diiodomethane and Zn-Cu couple) followed by conversion of the C-4 group from an ester to a carbonyl. On the other hand, the substrate with a carbonyl group instead of the ester at C-4 cyclopropanates to give the a-lyxo product 172.198... 

A process for the asymmetric cyclopropanation of the enol ethers of cyclic and acyclic ketones has been developed by Tai [109-111]. In this process, a 2-symmetric acetal is isomerized to a hydroxy enol ether which serves as substrate or the Simmons-Smith cyclopropanation, as shown in Scheme 6.29. The stereoselectivity is nearly perfect, but a mechanistic hypothesis has not been proposed. The auxiliary may be removed either by hydrolysis, to give the methyl ketone, or by oxidation of the alcohol and p-elimination [111]. 

Cyclopropanation with organometallic carbenoid reagents is one of the most popular. Advantages include broad substrates generality, tolerance of a variety of functional groups, and high stereoselectivity. Among the many efforts, the Simmons-Smith cyclopropanation is the most notable. 

Simmons—Smith Cyclopropanation. Simmons-Smith cyclopropana-tions have been known for many years as an efficient method for cyclopropanation via methylene transfer to olefinic substrates. Although a stoichiometric amount of reagent is mostly required, the superior reactivity and selectivity make the method inseparable from cyclopropanation. The classical Simmons-Smith cyclopropanation involves a zinc carbenoid reagent (IZnCH2l) generated by the oxidative addition of metallic zinc to diiodomethane by a copper metal as an activator (48). This somewhat cumbersome procedure was later replaced by other more easily accessible and reproducible methods. The benchmark replaces the... 

The year 1958 represents a pivotal moment for the cyclopropanation reaction of olefins. At that time, Simmons and Smith at DuPont reported the reaction of diiodomethane and Zn/Cu couple in the presence of olefins to afford cyclopropanes [56]. An important further advance in the Simmons-Smith cyclopropanation reaction resulted from Dauben s observation that cyclo-hex-2-enol underwent syn-selective methenylation [57, 58]. Additionally, the reaction was noted to be accelerated by the resident allylic hydroxyl group in the substrate. As a representative example, treatment of 87 with CH2I2 and Zn/Cu furnished 88 as a single diastereomer moreover, the parent hydrocarbon (4,4,10-trimethyl-A -octalin) failed to react under similar condi-... 

Although the rationalization of the reactivity and selectivity of this particular substrate is distinct from that for chiral ketals 92-95, it still agrees with the mechanistic conclusions gained throughout the study of Simmons-Smith cyclopropa-nations. StOl, the possibility of the existence of a bimetallic transition structure similar to v (see Fig. 3.5) has not been rigorously ruled out. No real changes in the stereochemical rationale of the reaction are required upon substitution of such a bimetallic transition structure. But as will be seen later, the effect of zinc iodide on catalytic cyclopropanations is a clue to the nature of highly selective reaction pathways. A similar but unexplained effect of zinc iodide on these cyclopro-panation may provide further information on the true reactive species. 

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 Simmons-Smith reaction is an efficient and powerful method for synthesizing cyclopropanes from alkenes [43]. Allylic alcohols are reactive and widely used as substrates, whereas a,j8-unsaturated carbonyl compounds are unreactive. In 1988, Ambler and Davies [44] reported the electrophilic addition of methylene to a,/3-unsaturated acyl ligands attached to the chiral-at-metal iron complex. The reaction of the racemic iron complex 60 with diethylzinc and diiodomethane in the presence of ZnCl2 afforded the c/s-cyclopropane derivatives 61a and 61b in 93 % yield in 24 1 ratio (Sch. 24). 

The diastereoselective and enantioselective preparation of cyclopropanes has attracted attention since chiral cyclopropanes were found to occur in many natural products [11]. Moreover, cyclopropanes are useful intermediates in organic synthesis. There are many methods of cyclopropane ring opening that transfer stereochemical information from the substrate to acyclic products in a stereocontrolled manner [12]. Among the methods used for the preparation of cyclopropanes from olehns, the Simmons-Smith and related reactions as well as reactions of diazoalkanes catalyzed by rhodium, copper and cobalt salts have frequently been applied [13]. The preparatively simple Makosza reaction [14] has scarcely been used. 

Cyclopropanes can be synthesized from many organic gem-dihalides using copper and a trace of iodine as catalysts.37 This procedure is comparable to the Simmons-Smith reaction in yields and is more convenient because of a wider range of substrates available. 

Other methods used to improve the cyclopropanation in Simmons Smith reactions are ultrasonic cavitation and the use of catalytic amounts of titanium(IV) chloride to promote the reaction. A much better method is to use 1 mol% of acetyl chloride (based on zinc) and dibromo-methane in the presence of zinc dust and copper(I) chloride in diethyl ether. This system not only strongly accelerates alkene cyclopropanation, but also causes no special problems with Lewis acid sensitive substrates. Acetyl chloride works as a promoter by reacting with... 

Normally the chiral auxiliaries are introduced and removed in the asymmetric synthesis of Simmons-Smith reactions of allylic alcohols to provide mostly /rani-disubstituted cyclopropanes. Stereoselective syntheses of c -disubstituted cyclopropanes are difficult to achieve. Starting from (Z)-3-phenylprop-2-en-l-ol (80a) and (Z)-6-phenylhex-2-en-l-ol (80b), the corresponding c -disubstituted cyclopropanes 81a and 81b were prepared by first treating them with diethylzinc followed by diethyl (- -)-(/ ,7 )-tartrate (DET). A zinc-bridged intermediate is assumed to be formed first. This is subsequently treated with diethylzine and diiodomethane to give the products 81. The reaction conducted at — 12 "C gave the cyclopropanated products 81a and 81b with 70 and 81% ee, respectively.This method has the advantages that the introduction of the chiral auxiliary to the substrate and its removal are not neccessary and that both cis- and trans-disubstituted cyclopropanes could be prepared from (Z)- and ( )-allylic alcohols, repectively. 

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. 

Cyclopropanation of enol sttyl ethers. Cyclopropanation of these substrates with the Simmons-Smith reagent has been reported by several laboratories (4, 588-589). Cyclopropanation can also be effected with diethylzinc-methylene iodide in ether or in n-pentane under controlled conditions (70-80% yields). This reagent can also be used to convert cyclic enol silyl ethers (1) to spiro ethers... 

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