Reactions asymmetric cyclopropanation

Based on these mechanisms and ligand structures, various transition-state models to explain the stereochemistry of asymmetric cyclopropanation reactions have been proposed. For details, see the reviews17- 1 and the references cited for Figure 12. 

Certain transition metal complexes catalyze the decomposition of diazo compounds. The metal-bonded carbene intermediates behave differently from the free species generated via photolysis or thermolysis of the corresponding carbene precursor. The first catalytic asymmetric cyclopropanation reaction was reported in 1966 when Nozaki et al.93 showed that the cyclopropane compound trans- 182 was obtained as the major product from the cyclopropanation of styrene with diazoacetate with an ee value of 6% (Scheme 5-56). This reaction was effected by a copper(II) complex 181 that bears a salicyladimine ligand. 

In addition to the above ligands 189-191, bis(oxazolinyl)pyridine compounds 192-194 have also been applied in asymmetric cyclopropanation reactions, but only moderate enantioselectivity has been achieved.101... 

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. 

Finally, let us look at some important examples in which asymmetric cyclopropanation reactions are used in the asymmetric construction of subunits of biologically active organic molecules. 

The compound curacin A 207 is a novel antimitotic agent isolated from the Caribbean cyanobacterium Lyngbya majuscula. The compound consists of a disubstituted thiazoline bearing a chiral cyclopropane ring and an aliphatic side chain. Scheme 5-67 depicts the construction of the cyclopropane ring using an asymmetric cyclopropanation reaction.122... 

Chapter 2 to 6 have introduced a variety of reactions such as asymmetric C-C bond formations (Chapters 2, 3, and 5), asymmetric oxidation reactions (Chapter 4), and asymmetric reduction reactions (Chapter 6). Such asymmetric reactions have been applied in several industrial processes, such as the asymmetric synthesis of l-DOPA, a drug for the treatment of Parkinson s disease, via Rh(DIPAMP)-catalyzed hydrogenation (Monsanto) the asymmetric synthesis of the cyclopropane component of cilastatin using a copper complex-catalyzed asymmetric cyclopropanation reaction (Sumitomo) and the industrial synthesis of menthol and citronellal through asymmetric isomerization of enamines and asymmetric hydrogenation reactions (Takasago). Now, the side chain of taxol can also be synthesized by several asymmetric approaches. 

S. Arai, K. Nakayama, T. Ishida, T. Shioiri, Asymmetric Cyclopropanation Reaction under Phase-Transfer Catalyzed Conditions , Tetrahedron Lett. 1999, 40, 4215-4218. 

More recently, Burgess et al. (34) used the same approach in the synthesis of a constrained phenylalanine derivative, 3-phenyl-2,3-methanophenylalanine (123). Libraries of metal complexes were screened to determine the best combination for the asymmetric cyclopropanation reaction (35). The ligands shown below were combined with AgSbFg, (CuOTf)2 PhH, RuC12(C10H14)]2, Sc(OTf)3, where tri-... 

Carbenoids derived from the aryldiazoacetates are excellent donor/acceptor systems for the asymmetric cyclopropanation reaction [22]. Methyl phenyldiazoacetate 3 cyclopropanation of monosubstituted alkenes catalyzed by Rh2(S-DOSP)4 is highly diaster-eo- and enantioselective (Tab. 14.5) [22]. Higher enantioselectivities can be obtained when these reactions are performed at -78°C, as the catalyst maintains high solubility and activity at this temperature. The phenyldiazoacetate system has been evaluated using many popular rhodium(II) and copper catalysts the rhodium(ll) prolinates have proven to be superior catalysts for this class of carbenoids [37, 38]. 

It is also interesting to point out that bipyridine RZnCHiX complexes are not reactive in the cyclopropanation reaction due to the high basicity of the bipyridine ligand. However, the addition of zinc iodide promotes the cyclopropanation reaction since uncomplexed IZnCH2X can be formed via an iodide-halomethyl group exchange. This approach has been used in catalytic asymmetric cyclopropanation reactions vide infra). 

The range of alkenes that may be used as substrates in these reactions is vast Suitable catalysts may be chosen to permit use of ordinary alkenes, electron deficient alkenes such as a,(3-unsaturated carbonyl compounds, and very electron rich alkenes such as enol ethers. These reactions are generally stereospecific, and they often exhibit syn stereoselectivity, as was also mentioned for the photochemical reactions earlier. Several optically active catalysts and several types of chiral auxiliaries contained in either the al-kene substrates or the diazo compounds have been studied in asymmetric cyclopropanation reactions, but diazocarbonyl compounds, rather than simple diazoalkanes, have been used in most of these studies. When more than one possible site of cyclopropanation exists, reactions of less highly substituted alkenes are often seen, whereas the photochemical reactions often occur predominantly at more highly substituted double bonds. However, the regioselectivity of the metal-catalyzed reactions can be very dependent upon the particular catalyst chosen for the reaction. 

Finally, several complexes of chiral /J-thioxoketones have been prepared510 and the cobalt complex 149 has found an interesting synthetic application as catalyst in asymmetric cyclopropanation reactions (equation 157)511. 

Recent editions of Organic Reaction Mechanisms have highlighted a number of carbene and nitrene CH-insertion reactions. This field has now been reviewed with a focus on enantioselective reactions catalysed typically by dirhodium species.5 The use of C2-symmetric box ligands in asymmetric cyclopropanation reactions has been discussed in the context of a wider review of these ligands as a source of asymmetry.6... 

Zhang s group developed highly active chiral (porphyrin)cobalt(II) complexes 327b-d, which catalyzed the cyclopropanation reactions of styrenes [356-358] and even of ot,(3-unsaturated esters or nitriles [358, 359] by diazoacetates. Nitrodi-azoacetates [360] or sulfonyldiazomethane [361] also proved to be useful in asymmetric cyclopropanation reactions of styrenes, acrylic derivatives, and in some cases even simple olefins with good to high de and moderate to excellent ee (highlight [362]). 

However, the development of cyclopropane synthesis through zirconocene chemistry is still in its infancy. The reactions presented in this chapter have only recently been reported for the most part, and not systematically studied. Further investigations appear to be desirable. Practical procedures involving optimized reaction conditions and simpler reagents would be welcomed. Advances should focus on the development of catalytic and asymmetric cyclopropanation reactions. 

Charette, A B, Cote, B, Marcoux, J E, Carbohydrates as chiral auxiliaries asymmetric cyclopropanation reaction of acyclic olefins, J. Am. Chem. Soc., 113, 8166-8167, 1991. 

Acetals of a,j8-unsaturated aldehydes with 3-0-alkylated derivatives of 1,2-0-isopropylidene- -D-fructopyranose and l,2-0-isopropylidene-/l-D-psicopyranose, which are readily available from D-fructose, were cyclopropanated with diethylzinc/diiodomethane with good stereoselectivity. The acetals were hydrolyzed and the aldehydes reduced to give cyclopropyl-substituted alcohols e.g. cyclopropanation of 103 to give 104 and hydrolysis and reduction to R,2R)-2-phenylcyclopropylmethanol (105). Extensive studies were carried out, with both exo- and endo-acQta structures, to determine the effects of the structure of the acetals on the enantioselec-tivity. Among various isomeric compounds, the asymmetric cyclopropanation reaction provided good enantioselectivity (consistent attack on the same face) with high chemical yields especially with en sfo-acetals of l,2-0-isopropylidene-3-0-(4-phenylbenzyl)-iS-D-fructopyranose. 

Nishiyama and coworkers reported that chiral ruthenium(II) bisfoxazoli-nyl)pyridine complexes were efficient catalysts for the asymmetric cyclopropanation reaction of terminal olefins [42,43]. The fra s-RuCl2(pybox-i-Pr)(ethyl-ene) complex 26 was produced from a mixture of optically active bis(2-oxazolin-... 

Asymmetric cyclopropanation reactions using chiral metal catalysts with heterocyclic ligands 00MI53. 

Asymmetric cyclopropanation reactions have been developed by using diiodomethane and diethyl zinc in the presence of a chiral Lewis acid. A particularly effective chiral Lewis acid, introduced by Charette, is the dioxaborolane 112, which induces high levels of optical purity in the resultant cyclopropanes derived from allylic alcohols (4.90). This methodology has been used in natural product synthesis, such as in the preparation of the antifungal agent FR-900848 (4.91). ... 

New advances of asymmetric cyclopropanation reactions using chiral metal catalysts including metal complexes with oxazoline, porphyrin, bipyridine, and terpyridine derivatives 07CJO438. 

In 2009 Mayr et al. demonstrated experimentally that electrostatic activation was indeed responsible for the more than 10 -fold acceleration in the asymmetric cyclopropanation reaction of the 38-derived zwitterion with sulfur ylides, as well as for the high stereoselectivity of this reaction. ... 

A number of chiral acetal derivatives have also proved effective in asymmetric cyclopropanation reactions, with auxiliaries based on tartaric acid proving to be partieularly usefiil. In the case of cyclic a,P unsaturated compounds, di-O-benylthreitol derivatives (see 51) imdergo efficient and diastereoselective Simmons-Smith reactions to give the cyclopropanated products SS. ... 

Charette has shown the utility of dioxaborolanes as catalyst for asymmetric cyclopropanation reaction (59) (Figure 15). 

Davies et al. carried out a comparative study on the catalytic activities of Rh2(S-DOSP)4 (3), RhjlR-BNP)4 (4), and Rh2(S-PTAD)4 (5) toward asymmetric cyclopropanation reactions (Table 9.2, entries 3-9) [94]. In general, Rh2(S-DOSP)4 was found to be the most effective catalyst for asymmetric intermolecular cyclopropanation of methyl aryldiazoacetates with styrene. Rh2(S-PTAD)4 exhibited lower levels of enantioinduction with 4-substituted aryldiazoacetates but it proved to be superior with the 4-methoxy substituted aryldiazoacetate (Table 9.2, entry 4, 96% ee) [94, 98]. Rh2(i -BNP)4, however, functions as an extremely effective catalyst with all the aryldiazoacetates substituted with three methoxy groups (88-97% ee). The asymmetric inductions varied with the aryl groups on the aryl diazoacetate but the choice of olefin had no effect on the selectivity. 

Synthesis of the chiral catalysts to introduce enantioselectivity in carbene transfer reactions is a subject of great interest. Often copper and rhodium chiral catalysts are of choice for the carbene transfer reactions. In some reports, immobilized chiral dirhodium (II) catalyst were employed successfully in asymmetric cyclopropanation reactions. Ubeda and coworkers reported the immobilization of chiral Rh2(02CR)2(PC)2 (PC = ort/io-metalated phosphine) compounds on cross-linked polystyrene (PS) resin by an... 

The simple C9 ethers derived from the natural cinchona alkaloids are infrequently applied in organocatalysis. A relatively recent example concerns an asymmetric cyclopropanation reaction with the C9 O-methyl derivatives of 1 and 4, respectively (Scheme 6.13) [35]. The functionalized cyclopropanes were obtained in excellent diastereo- and enantioselectivity as well as in high yields. 

Halogenated ligands were also employed in the asymmetric cyclopropanation reaction. For example, a rhodium complex with brominated TTL ligand 185 promoted the chiral synthesis of cyclopropanes from active methylene compounds in the presence of iodosylbenzene (Scheme 1.86) [132]. Cyclopropanes 186 were obtained in good optical purity. 

A polymer-supported chiral BOX ligand served as a good catalyst for the asymmetric cyclopropanation. For example, Salvador and coworkers reported a chiral BOX containing polystyrene 229 promoted the asymmetric cyclopropanation reaction to give optically active cyclopropanes 230 in good yields with high enantioselectivity (Scheme 1.106) [160]. Polymer 229 was not soluble in reaction solvent therefore, it was readily separated from the reaction mixture. The polymer-supported catalyst 229 was useful at least live times. 

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