Cyclopropanation Evans

The data from Masamune s papers underscore the impressive range the results can cover when the substituents are varied. The last reaction utilises a very bulky ester group to make practically one diastereomer in 94% e.e. The catalyst is CuC104 or CuOTf. For styrene cyclopropanation Evans [7] found a similar relationship between the steric bulk of the ester group of the diazocompound and the selectivity for trans products. 

Subsequently, Lowenthal and co-workers,3 la,9 Evans et al.,31b and Muller et al.98 reported chiral bis(oxazoline) ligands 185, 186, and 83 as shown in Figure 5-12. The gem-dimethyl [(bis)oxazoline] 83-coordinated copper catalyst is the most widely used ligand. The catalyst is prepared in situ by mixing ligand 83 with an equal molar amount of CuOTf. Asymmetric cyclopropanation of isobutylene with ethyl diazoacetate (EDA) gives ethyl 2,3-dimethylcyclopro-pane carboxylate with >99% ee. 

Evans suggests that the catalyst resting state in this reaction is a 55c Cu alkene complex 58, Scheme 4 (35). Variable temperature NMR studies indicate that the catalyst complexes one equivalent of styrene which, in the presence of excess alkene, undergoes ready alkene exchange at ambient temperature but forms only a mono alkene-copper complex at -53°C. Addition of diazoester fails to provide an observable complex. These workers invoke the metallacyclobutane intermediate 60 via a formal [2 + 2] cycloaddition from copper carbenoid alkene complex 59. Formation of 60 is the stereochemistry-determining event in this reaction. The square-planar S Cu(III) intermediate 60 then undergoes a reductive elimination forming the cyclopropane product and Complex 55c-Cu, which binds another alkene molecule. 

Scheme 4. Mechanism proposed by Evans for the cyclopropanation of alkenes. [Adapted from (35).]...

The stereoselectivities in this reaction are governed by steric interactions in the formation of metallacyclobutane 60 (35). Of two possible intermediates (Fig. 5), 61 suffers from steric interactions between the ligand and the ester functionality. Avoidance of these interactions and minimization of 1,2-interaction in the metallacyclobutane leads to the formation of the observed major enantiomer and dias-tereomer (trans). The model suggests that increased diastereoselectivity should be observed with increasing steric bulk of the diazoester, a relationship that has already been established as discussed (cf. Eqs. 24 and 26). It is interesting to note that this model loosely corresponds to the stereochemical model proposed by Aratani for the Sumitomo cyclopropanation with one important difference the Aratani model is based on a tetrahedral metal while the Evans-Woerpel model is predicated on square-planar copper. Applying the Aratani model to the Evans ligand would predict formation of the opposite enantiomer as the major product (35). 

The groundwork for this study was laid in the bis(oxazoline)-copper-catalyzed cyclopropanation reaction reported by Evans, Masamune, Pfaltz, and their coworkers (32-34) (cf. Section II.A.6). Indeed, two of these early papers reported that the same catalysts were capable of effecting nitrenoid transfer to acceptor alkenes in moderate ee. 

Evans et al. (34) reported preliminary results showing that 55c CuOTf is moderately selective in mediating the aziridination of styrene, producing the heterocycle in 61% ee. Lowenthal and Masamune (44) mention in a footnote to their cyclopropanation paper that the copper complex of camphor-derived bis(oxa-zoline) (103) provides the aziridine of styrene in 91% yield and 88% ee. However, this reaction has been found to be irreproducible (76,77) and further reports of aziridination from the Masamune laboratories have not appeared. 

For intermolecular cyclopropanations with unsubstituted diazoacetates the highest asymmetric inductions can be achieved with the copper(I) complexes of C2-symmetric, bidentate ligands developed by Pfaltz (e.g. 1) and Evans (2). The chiral rhodium(II) complexes known today do not generally lead to such high enantiomeric excesses as copper complexes in intermolecular cyclopropanations. For intramolecular cyclopropanations, however, chiral rhodium(II) complexes are usually superior to enantiomerically pure copper complexes [1374]. 

In 1991, Evans and co-workers employed CuOTf-derived complexes of bis-(oxazoline) ligands 2, 3, 7b, 38, and 45 in the same cyclopropanation reaction of... 

For the diligent reader, thermochemical conventions are well-discussed in D. D. Wagman, W. H. Evans, V. B. Parker, R. H. Schumm, I. Halow, S. M. Bailey, K. L. Churney and R. L. Nuttall, The NBS Tables of Chemical Thermodynamic Properties Selected Valuesfor Inorganic and C, and C2 Organic Substances in SI Units , J. Phys. Chem. Ref. Data, 11 (1982), Supplement 2. However, the various subtleties expressed in this source, such as the above-cited ambiguities in temperature and pressure, have but negligible effect on any of the conclusions about cyclopropane and its derivatives in this chapter the data are too inexact and the concepts we employ are simply too sloppy to be affected. 

Cu complexes with bis-oxazoline ligands 6 that were first reported by Masamune and co-workers [39] have incited considerable interest because of the exceptional enantiocontrol that can be achieved with their use as catalysts for cyclopropanation reactions. Concurrent investigations by Evans [40], who added 7 Masamune, who provided 8 and 9 [41] and Pfaltz [42], who investigated a similar series, established that the C2-symmetric bis-oxazoline ligands are suitable alternatives to semicorrin ligands for Cu in creating a highly enantioselective environment for intermolecular cyclopropanation. For the first time, diazoacetates with ester substituents as small as ethyl could be used to achieve enantioselectivity >90% ee in reactions with styrene (Table 5.4). 

The trans .cis (or E/Z) ratios of cyclopropane products are higher than those obtained with styrene, and the diastereomer ratio or enantiomer ratio for the trans( ) isomer is generally >90 10. Although these reactions are usually performed with 1.0 mol % of catalyst, Evans has optimized the cyclopropanation of isobutylene to a 0.25 mol scale [40], by using only 0.1 mol % of catalyst, and obtained a 91 % yield of the (S)-cyclopropane enantiomer whose enantiopurity... 

More recently, Pfaltz has reported high enantioselectivities for the cyclopropanation of monosubstituted alkenes and dienes with diazo carbonyl compounds using chiral (semicorrinato)copper complexes (P-Cu) (23-25), and Evans, Masamune, and Pfaltz subsequently discovered exceptional enantioselectivities in intermolecular cyclopropanation reactions with the analogous bis-oxazoline copper complexes (26-28). With the exception of the chiral (camphorquinone dioximato)cobalt(II) catalysts (N-Co) reported by Nakamura and coworkers (29,30), whose reactivities and selectivities differ considerably from copper catalysts, chiral complexes of metals other than copper have not exhibited similar promise for high optical yields in cyclopropanation reactions (37). 

The discovery, isolation and final synthesis of a whole group of new compounds essential to health in a balanced diet was another triumph of the chemist. These compounds called vitamins A, Ba or G, C, D, E, K, and several others closely associated with vitamin Ba, such as niacin, pantothenic acid, inositol, para-amino benzoic acid, choline, pyndoxine (Be), biotin (H), folic acid and Bn, prevent deficiency diseases such as xerophthalmia (an eye disease), beriberi, pellagra, scurvy, rickets, sterility (in rats), excessive bleeding and so forth. Professors Elmer V. McCollum and Herbert M. Evans, and Joseph Goldberger were among the early American pioneers in this field of research. Drugs, anaesthetics, and medicines like procaine, cyclopropane, dramamme, ephedrine, aspirin, phenace-tin, urotropin, veronal, quinine, and strychnine have been synthesized to alleviate the pains of mankind. The essential... 

There are now several catalysts capable of achieving high levels (>90%) of enantio-selectivity in cyclopropanation over a range of alkenes. The most successful of these are those with chiral ligands 156,157 and 158. The catalysts developed by the groups of Pfaltz 156189-194 Masamune Evans 158 are all based on copper(II) or copper(I)... 

Enantioselective Cyclopropanation of Alkenes. Cationic Cu complexes of methylenebis(oxazolines) such as (1), which have been developed by Evans and co-workers, are remarkably efficient catalysts for the cyclopropanation of terminal alkenes with diazoacetates. The reaction of styrene with ethyl diazoacetate in the presence of 1 mol % of catalyst, generated in situ from Copper(I) Trifluoromethanesulfonate and ligand (1), affords the (rans -2-phenylcyclopropanecarboxylate in good yield and with 99% ee (eq 3). As with other catalysts, only moderate transicis selectivity is observed. Higher transicis selectivities can be obtained with more bulky esters such as 2,6-di-r-butyl-4-methylphenyl or dicyclohexylmethyl diazoacetate (94 6 and 95 5, respectively). The efficiency of this catalyst system is illustrated by the cyclopropanation of isobutene, which has been carried out on a 0.3 molar scale using 0.1 mol % of catalyst derived firom the (R,R)-enantiomer of ligand (1) (eq 4). The remarkable selectivity of >99% ee exceeds that of Aratani s catalyst which is used in this reaction on an industrial scale. 

For the cyclopropanation of terminal mono- and disubstituted alkenes, the cationic Cu complex derived from ligand (1) is clearly the most efficient catalyst available today, giving consistently higher enantiomeric excesses than related neutral semicorrin or bisoxazoline Cu complexes of type (3), - which can induce enantiomeric excesses of up to 92% ee in the cyclopropanation of styrene with ethyl diazoacetate. High enantioselectivities, ranging between the selectivities of the Evans catalyst (eq 3) and complex (3) (M = Cu, R = t-Bu), have also been observed with cationic Cu complexes of azasemicorrins. ... 

The reaction is included in this chapter because recent work by Newman-Evans and Carpenter has allowed the rearrangement of a number of deuterated analogues to be studied, and the products of these reactions are labeled cyclopropanes. It is included in this section because it is nominally a retro-vinylcyclopropane rearrangement. 

In rhodium(II)-catalyzed intermolecular cyclopropanation reactions, chiral dirhodium(II) carb-oximidates provide only limited enantiocontrol. " Tetrakis(5-methoxycarbonyl-2-pyrrolidonato)dirhodium [18, Rh2(MEPY)J, in both enantiomeric forms of the carboxamide ligands, produces the highest enantioselectivities. As can be seen for the cyclopropanation of styrene with diazoacetates, a high level of double diastereoselectivity results from the combination of this chiral catalyst with /- or d-menthyl diazoacetate, but not with diazoacetates bearing other chiral residues.In terms of trans/cis selectivity and enantioselectivity for styrene giving 19 this catalyst is comparable to the Aratani catalysts, but they cannot match the high enantiocontrol of the chiral copper catalysts developed by Pfaltz, Masamune, and Evans vide supra). 

A crucial discovery in aziridination catalysis was made by Evans in the early 1990s, when he demonstrated that low-valent metal ions typically used for cyclopropanation were competent catalysts for the aziridination of alkenes with Phl=... 

Given the significant existing knowledge-base in asymmetric catalytic cyclo-propanation (Chap. 16), the discovery that metal ions useful for catalysis of carbene transfer to alkenes were also effective for nitrene transfer to the same substrates opened a clear new direction for research in asymmetric aziridination. Brief mention of the asymmetric catalysis of the aziridination of styrene was made in two early reports on (bisoxazoline)copper-catalyzed asymmetric cyclopropanations [20,21], and subsequently new methods for copper-catalyzed asymmetric aziridination were revealed in two independent studies published simultaneously by Jacobsen and Evans [22,23]. 

The cyclopropanation reaction with metal salts is readily amenable to asymmetric induction in the presence of a chiral ligand, and some excellent enantioselectivi-ties have been achieved. Particularly effective are the bisoxazoline ligands, developed by Pfaltz, Masamune and Evans. Both enantiomers of the chiral ligand are available and the reaction is amenable to a wide variety of different alkenes. For example, very high selectivity in favour of the cyclopropane 118 was achieved using only small amounts of the bisoxazoline ligand 117 and copper triflate (4.94). 

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