Cyclopropanations, enantioselective

Carbenoid complexes with heterocyclic ligands as catalysts in enantioselective cyclopropanation of olefins 97S137. 

Catalytic, enantioselective cyclopropanation enjoys the unique distinction of being the first example of asymmetric catalysis with a transition metal complex. The landmark 1966 report by Nozaki et al. [1] of decomposition of ethyl diazoacetate 3 with a chiral copper (II) salicylamine complex 1 (Scheme 3.1) in the presence of styrene gave birth to a field of endeavor which still today represents one of the major enterprises in chemistry. In view of the enormous growth in the field of asymmetric catalysis over the past four decades, it is somewhat ironic that significant advances in cyclopropanation have only emerged in the past ten years. 

These early studies on zinc carbenoids provide an excellent foundation for the development of an asymmetric process. The subsequent appearance of chiral auxiliary and reagent-based methods for the selective formation of cyclopropanes was an outgrowth of a clear understanding of the achiral process. However, the next important stage in the development of catalytic enantioselective cyclopropanations was elucidation of the structure of the Simmons-Smith reagent. 

For a reaction as complex as catalytic enantioselective cyclopropanation with zinc carbenoids, there are many experimental variables that influence the rate, yield and selectivity of the process. From an empirical point of view, it is important to identify the optimal combination of variables that affords the best results. From a mechanistic point of view, a great deal of valuable information can be gleaned from the response of a complex reaction system to changes in, inter alia, stoichiometry, addition order, solvent, temperature etc. Each of these features provides some insight into how the reagents and substrates interact with the catalyst or even what is the true nature of the catalytic species. 

O Connor, S.P. Catalytic, Enantioselective Cyclopropanation of Allylic Alcohols PhD Thesis, University of Illinois, Urbana-Champaign, 1993. 

Metalloporphyrins have proved their efficiency as ruthenium carbonyl hg-ands for the enantioselective cyclopropanation of styrene [50,51]. 

The directive effect of allylic hydroxy groups can be used in conjunction with chiral catalysts to achieve enantioselective cyclopropanation. The chiral ligand used is a boronate ester derived from the (VjA jA N -tetramethyl amide of tartaric acid.186 Similar results are obtained using the potassium alkoxide, again indicating the Lewis base character of the directive effect. 

Enantioselective Cyclopropanation. Enantioselective versions of both copper and rhodium cyclopropanation catalysts are available. The copper-imine class of catalysts is enantioselective when chiral imines are used. Some of the chiral ligands that have been utilized in conjunction with copper salts are shown in Scheme 10.10. 

Several chiral ligands have been developed for use with the rhodium catalysts, among them are pyrrolidinones and imidazolidinones.207 For example, the lactamate of pyroglutamic acid gives enantioselective cyclopropanation reactions. 

Scheme 10.10. Chiral Copper Catalysts Used in Enantioselective Cyclopropanation...

Scheme 10.12 gives some examples of enantioselective cyclopropanations. Entry 1 uses the W.s-/-butyloxazoline (BOX) catalyst. The catalytic cyclopropanation in Entry 2 achieves both stereo- and enantioselectivity. The electronic effect of the catalysts (see p. 926) directs the alkoxy-substituted ring trans to the ester substituent (87 13 ratio), and very high enantioselectivity was observed. Entry 3 also used the /-butyl -BOX catalyst. The product was used in an enantioselective synthesis of the alkaloid quebrachamine. Entry 4 is an example of enantioselective methylene transfer using the tartrate-derived dioxaborolane catalyst (see p. 920). Entry 5 used the Rh2[5(X)-MePY]4... 

Cyclopropanation reactions involving ethyl diazoacetate and olefins proceed with high efficiency in aqueous media using Rh(II) carboxy-lates. Nishiyama s Ru(II) Py-box and Katsuki s Co(II) salen complexes that allow for highly enantioselective cyclopropanations in organic solvents can also be applied to aqueous cyclopropanations with similar results. In-situ generation of ethyl diazoacetate and cyclopropanation also proceeds efficiently (Eq. 3.33).135... 

In another reaction dendritic pyridine derivatives such as 82 or 83 were tested as co-catalysts for enantioselective cyclopropanation of styrene with ethyl diazoacetate [102]. Using catalyst 82, enantiomer ratios of up to 55 45 were obtained. However, with catalyst 83 bearing larger branches yields and selectivities did not increase. The relatively low selectivities were rationalized by the presence of a large number of different conformations that this non-rigid system may adopt. 

Easily available copper(II) tartrate has also been used for an enantioselective cyclopropanation. From 3-methoxystyrene and 4-bromo-l-diazo-2-butanone, the cyclopropanes cis/trans-204 were obtained the mainly formed frans-isomer displayed an enantiomeric excess of 46% i99>. This reaction constituted the opening step of asymmetric total syntheses of equilenin and estrone. 

It has already been mentioned that prochirality of the olefin is not necessary for successful enantioselective cyclopropanation with an alkyl diazoacetate in the presence of catalysts 207. What happens if a prochiral olefin and a non-prochiral diazo compound are combined Only one result provides an answer to date The cyclopropane derived from styrene and dicyanodiazomethane shows only very low optical induction (4.6 % e.e. of the (25) enantiomer, catalyst 207a) 9S). Thus, it can be concluded that with the cobalt chelate catalysts 207, enantioface selectivity at the olefin is generally unimportant and that a prochiral diazo compound is needed for efficient optical induction. As the results with chiral copper 1,3-diketonates 205 and 2-diazodi-medone show, such a statement can not be generalized, of course. 

Enantioselective cyclopropanation of monoolefins 214 has also been performed. With the already mentioned chiral catalysts 195a and 209-213 rather high enantiomeric excess was achieved in some cases (Table 16), and the vinylcyclopropane structure was obtained in a subsequent dehydrohalogenation step. 

Use of a chiral diazo ester proved less rewarding in terms of enantioselective cyclopropanation. Only very low enantiomeric excesses were obtained when styrene was cyclopropanated with the carbenoid derived from diazoacetic esters 219 bearing a chiral ester residue 214). 

In 1974, Nakamura and Otsuka reported enantioselective cyclopropanation of terminal olefins, using bis[(l)-camphorquinone-o -dioximato]cobalt(II) complex (96) as the catalyst. Although dia-stereoselectivity was modest, good enantioselectivity was attained (Scheme 69).263-265 Cyclopropanation using CoII(salen) as the catalyst was also examined, but the enantioselectivity was low.265... 

Lo and Fu112 have reported a new type of planar-chiral ligand 203 for the enantioselective cyclopropanation of olefins. As shown in Scheme 5-62, asymmetric cyclopropanation in the presence of chiral ligand 203 proceeds smoothly, giving the cyclopropanation product with high diastereoselectivity and enantioselectivity. 

Ukaji et al.117 reported an enantioselective cyclopropanation reaction in which moderate enantiomeric excess was obtained when a stoichiometric amount of diethyl tartrate was used as a chiral modifier. Takahashi et al.118 achieved better results using the C2-symmetric chiral disulfonamide 205 as the chiral ligand. 

Figure 5-15 shows a possible transition state for the enantioselective cyclopropanation of cinnamyl alcohol in the presence of dioxaborolane 206. This model predictes the absolute configuration of the products. 

Chiral enamines have been used as ligands for Cu(I) in the enantioselective cyclopropanation of styrene (66). Copper(I) complexes of the quinolinyl ligand 94 provides modest enantioselectivities, although cis-trans selectivity is very low. 

K. A. Woerpel, Ph.D. Thesis, Bis(oxazoline)-Copper Complexes as Catalysts for Enantioselective Cyclopropanation of Olefins, Harvard University, Cambridge, MA, 1992. 

Enantioselective cyclopropanations using enantiomerically pure tungsten [54], iron [458,483,630], and ruthenium [581] carbene complexes have also been at-... 

Some diazoalkanes cyclopropanate olefins in the absence of any catalyst [658-660]. Thus, for instance, upon generation from A -cyclopropyl-A -nitrosourea at 0 °C diazocyclopropane spontaneously cyclopropanates methylenecyclopropanes [658]. Thermal, uncatalyzed cyclopropanations of unactivated olefines with aryldiazome-thanes can already occur at only slightly elevated temperatures (e.g. at 80 °C with 1-naphthyldiazomethane [661]). Henee, for enantioselective cyclopropanations with a chiral catalyst, low reaction temperatures should be chosen to minimize product formation via the uncatalyzed pathway. 

Cyclopropanations with diazomethane can proceed with surprisingly high diastereo-selectivities (Table 3.4) [643,662-664]. However, enantioselective cyclopropanations with diazomethane and enantiomerically pure, catalytically active transition metal complexes have so far furnished only low enantiomeric excesses [650,665] or racemic products [666]. These disappointing results are consistent with the results obtained in stoichiometric cyclopropanations with enantiomerically pure Cp(CO)(Ph3P)Fe=CH2 X , which also does not lead to high asymmetric induction (see Section 3.2.2.1). 

The directive effect of allylic hydroxyl groups can be used in conjunction with chiral catalysts to achieve enantioselective cyclopropanation. The chiral ligand used is a boronate... 

A homogeneous solution of the bis(iodomethyl)zinc DME complex in dichloromethane can be prepared by adding diethylzinc to 1 equivalent of 1,2-dimethoxyethane in dichloromethane followed by 2 equivalents of diiodomethane . The presence of DME makes the preparation of the reagent safer by ensuring that the mixture is constantly homogeneous. This reagent has been useful in enantioselective cyclopropanation reactions vide infra). 

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