Cyclopropanation catalytic asymmetric

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 ... 

The catalytic asymmetric cyclopropanation of an alkene, a reaction which was studied as early as 1966 by Nozaki and Noyori,63 is used in a commercial synthesis of ethyl (+)-(lS)-2,2-dimethylcyclo-propanecarboxylate (18) by the Sumitomo Chemical Company (see Scheme 5).64 In Aratani s Sumitomo Process, ethyl diazoacetate is decomposed in the presence of isobutene (16) and a catalytic amount of the dimeric chiral copper complex 17. Compound 18, produced in 92 % ee, is a key intermediate in Merck s commercial synthesis of cilastatin (19). The latter compound is a reversible... 

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. 

Tab. 14.4 Catalytic asymmetric cyclopropanation using methyl phenylvinyidiazoacetate.

I 74 Rhodium(ll)-Stabilized Carbenoids Containing Both Donor and Acceptor Substituents Tab. 14.5 Catalytic asymmetric cyclopropanation using methyl phenyidiazoacetate (3). 

Catalytic asymmetric cyclopropanations via carbene transfer to alkenes were reviewed by Singh and co-workers in 1997," Doyle and Protopopova in 1998," and mostly recently by Doyle in 2000." The reaction can be catalyzed by copper," rhodium," and other metals." Bis(oxazolines) are known to be among the most effective ligands for this cyclopropanation reaction (see Chapter 9). 

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). 

FIGURE 9. Enantioselectivities for the catalytic asymmetric cyclopropanation with ligand 25... 

Highly efficient catalytic asymmetric cyclopropanation can be effected with copper catalysts complexed with ligands of type 2.3 These bis(oxazolines) are prepared by reaction of dimethylmalonyl dichloride with an a-amino alcohol. As in the case of ligands of type 1, particularly high stereoselectivity obtains when R is /-butyl. Cyclopropanation of styrene with ethyl diazoacetate catalyzed by copper complexed with... 

The first catalytic asymmetric cyclopropanation using an ylide as catalyst was reported by Aggarwal et al. in 1997 [95, 96]. Phenyl diazomethane was added slowly to a mixture containing sulfide 12, an enone and Rh2(OAc)4 (1 mol%). A sulfur ylide was generated in situ from the sulfide and phenyl diazomethane in the presence of the transition-metal catalyst (see Scheme 10.20), as in the epoxidations discussed earlier (see Section 10.2.1.3). 

Scheme 10.21 Catalytic asymmetric cyclopropanation using chiral sulfides.

Scheme 10.22 Catalytic asymmetric cyclopropanation using sulfur ylides via an alkylation/deprotonation route.

Table 10.4 Catalytic asymmetric cyclopropanation with 41a using sulfide alkylation/deprotonation route (according to Scheme 10.22).

Scheme 10.24 Catalytic asymmetric cyclopropanation using telluronium salts.

Fig. 10.5 Catalytic asymmetric cyclopropanation using N-ylides derived from 53a-d. Catalyst, yield (% ee) are shown for each product. 53a,c favored the (+)-enantiomer, while 53b,d favored the (—)-enantiomer in all cases.

Doyle, M. P Protopopova, M. N. New Aspects of Catalytic Asymmetric Cyclopropanation, Tetrahedron 1998, 54, 7919-7946. 

Table 7.1 Catalytic asymmetric cyclopropanation of styrene and diazoacetates with Ru-Pybox catalysts.

It is worth recalling that the asymmetric cyclopropanation of styrene with ethyl diazoacetate, reported in 1966 by Noyori and co-workers, appears to be the first example of transition metal catalyzed enantioselective reaction in homogeneous phase. This reaction remains a landmark in asymmetric cyclopropanation. On a general standpoint, catalytic asymmetric cyclopropanation continues to attract much attention, due in part to the marked trends toward marketing more and more optically active molecules as the optically pure eutomer. This topic has been much studied in connection, inter alia, with the synthesis of valuable intermediates such as chrysanthemic acid derivatives and cilastatin. The subject has been recently reviewed [17]. 

The first example of the use of a chiral catalyst for asymmetric cyclopropanation was published by Nozaki and co-workers in 1966 [32]. Although these early studies were characterized by low levels of enantiocontrol, they were the forerunner to recent discoveries which have established catalytic asymmetric cyclopropanation as a reliable method for producing a range of substituted cyclopropanes in high enantiomeric purity. The appHcation of chiral copper catalysts is discussed in Chapter 16.1 the emphasis here is on rhodium (II) catalysts. 

It is apparent that significant progress has been made towards the development of an efficient catalytic, asymmetric cyclopropanation using zinc-derived reagents but there is still room for much further improvement. More specifically, the design of better catalysts to increase the scope of the reaction and to improve the enantioselectivities is one of the top research priorities in this area. Furthermore, the simplification of reaction protocol would greatly contribute to make this approach attractive to synthetic chemists and competitive with the other asymmetric, catalytic cyclopropanation reactions. 

Davies has further exploiled his previously reporied approach to (he tropanc skeleton related to cocaine based on the rhodium catalyzed decomposition of the vinyidiazomethane 81 in the presence of A/-Boc-pyrroIe (82) <01BMCL487>. Reduction of the non-conjugated double bond followed by A -deprotection and N-alkylation provided substrate 83 which was susceptible to conjugate addition of nucleophiles such as 84 in the presence of CuBr to afford 3-p-aryl tropanes which exhibited potent binding affinity for both the dopamine and serotonin transporters. Additionally, this author described the synthesis of various methyl heteroaryldiazoacetate analogues of 81, (me of which possessed an indole function, for use in catalytic asymmetric cyclopropanations . 

Cyclopropanation Reactions. Davies and Nagashima reported the first example of a catalytic asymmetric cyclopropanation of alkenes on a solid support. Carbene dimerization represents a limitation in solution phase, lowering yields and necessitating additional purification steps. Immobilization of the olefin 97 on a polystyrene diethylsilyl resin followed by reaction with various diazoacetates in the presence of a rhodium catalyst generated the cyclopropanes 98 and 99 in high yield and enabled the removal of dimerization products 102 through a simple wash step (Scheme 6.23). The products 100 and 101 were cleaved as a mixture of diastereomers from the resin under mild conditions. The stereoselectivity of the reaction was not influenced by the solid support, but rather by the catalyst selection most important, >90% ee was observed under these conditions. 

Catalytic asymmetric cyclopropanations of alkenes on solid support was studied by Davies and Nagashima (Scheme 7.14). Reaction of an immobilized 1,1-diarylethylene 68 with a set of seven different aryldiazoacetates 69 with 1 mol% of the chiral catalyst... 

Table 20.3 Catalytic asymmetric cyclopropanation via carbene generation of ylides.

Active methylene compounds are very reactive nucleophiles and their halo-derivatives are actively used for catalytic asymmetric cyclopropanation through the MIRC process. Rios and coworkers demonstrated catalytic asymmetric cyclopropanation between 2-bromo malonate and unsaturated aldehydes in the presence of proline-derived organocatalyst 2 (Scheme 1.1) [4]. The reaction smoothly progressed in chloroform at room temperature (rt) and highly enantioselective cyclopropanation was achieved. 

Organocatalysts successfully promoted catalytic asymmetric cyclopropanation. A pioneering study by Kunz and MacMillan showed that chiral benzo-fused proline 24 gave chiral cyclopropane 25 from an a,(3-unsaturated aldehyde and sul-fonium ylides (Scheme 1.19) [33]. Kinetic studies to rationalize the asymmetric induction were also performed [34]. 

Catalytic asymmetric cyclopropanation has bear actively investigated. Shi and coworkers developed Val-Pro dipeptide catalysts 109, which effectively catalyzed cyclopropanation of... 

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