Enantioselectivity catalytic cyclopropanation

Fig. 5.42 Enantioselective catalytic cyclopropanation. (From httpy/www-gaunt.ch.cam.ac.uk/graphics/ methods.gif).

Fig. 5.43 Mechanism of enantioselective catalytic cyclopropanation. (From httpj/www-gaunt.ch.cam. ac.uk/organocatalysis.sbtml).

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 is an important synthetic method, and enantioselective catalytic reactions of olefins and diazoacetates provide access to valuable products with biological activity. In general, these reactions are conducted in anhydrous solvents and in several cases water was found to diminish the rate or selectivity (or both) of a given process. Therefore it came as a surprise, that the Cyclopropanation of styrene with (+)- or (-)-menthyl diazoacetates, catalyzed by a water-soluble Ru-complex with a chiral bis(hydroxymethyldihydrooxazolyl)pyridine (hm-pybox) ligand proceeded not only faster but with much Wgher enantioselectivity (up to 97 % e.e.) than the analogous reactions in neat THF or toluene(8-28 % e.e.) (Scheme 6.34) [72]. The fine yields and enantioselectivities may be the results of an accidental favourable match of the steric and electronic properties of hm-pybox and those of the menthyl-dizaoacetates, since the hydroxyethyl or isopropyl derivatives of the ligand proved to be inferior to the hydroxymethyl compound. Nevertheless, this is the first catalytic aqueous cyclopropanation which may open the way to other similar reactions in aqueous media. 

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. 

Under homogeneous eonditions [73], various ehiral Sehiff base-Cu(II or I) or Ru(II) complexes have been used as ehiral catalyst precursors and from all of them the most efficient systems are formed with oxazolines and bis-oxazolines. Thus after their first use by Masamune [74], oxazoline-derived ligand have been extensively employed in homogeneous enantioselective catalytic reaction particularly in cyclopropanation [75]. Thus nitrogenanchoring ligands on organic polymers are mainly formed by immobilized oxazolines. 

Johansson CCC, Bremeyer N, Ley SV, Owen DR, Smith SC, Gaimt MJ (2006) Enantioselective Catalytic Intramolecular Cyclopropanation Using Modified Cinchona Alkaloid Organocatalysts. Angew Chem Int Ed 45 6024... 

Johansson, C. C., Bremeyer, N., Ley, S. V., Owen, D. R., Smith, S. C., Gaunt, M. J. (2006). Enantioselective catalytic intramolecular cyclopropanation using modified cinchona alkaloid organocatalysts. Angewandte Chemie - International Edition, 45, 6024-6028. 

As expected, increasing the size of the R group increases enantioselection, and the buttressing effect on the bis-oxazoline ring caused by the geminal disubstitution in 10 provides further enhancement of enantiocontrol. From the results in Table S.4, however, the ligand s R substituent has only a minor influence on the trans.cis of cyclopropane products. To increase product diastereoselectivity, Evans [40] increased the size of the ester substituent from ethyl to te/t-butyl and then to the bulky BHT ester, previously reported by Doyle [43] to provide exceptional diastereocontrol in catalytic cyclopropanation reactions. Applications of these catalysts to alkenes other than styrene have demonstrated the potential generality of their uses for asymmetric intermolecular cyclopropanation (Table 5.5). 

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. 

These two compounds with S configuration on their oxazohne rings were tested as copper(I) catalysts for the cyclopropanation of styrene, the hgand 9 with S axial chirality being much more enantioselective than 10 with the R configuration. Thus, the catalytic system CuOTf-(S,S)-bis(oxazolyl)-binaphthyl (9, R = Bu) led to excellent enantioselectivities, particularly for the cyclopropanation of styrene with (-menthyldiazoacetate 95% ee for the trans-cyclopropane and 97% ee for the cis, with trans/cis = 68/32. 

Similar conclusions concerning the effect of the anion and impurities in the ionic liquid on the cyclopropanation reaction have been drawn in a recently published study [47]. Ionic liquids with the formula [bmim][X], where X = OTf, NTf2, PFe, and BF4, were used. The catalyst used in this study was 6b-Cu(OTf). In all cases, good enantioselectivities (89-97% ee) were obtained and these are similar to those obtained in chloroform. The influence of the presence of halogen anions was tested by the addition of 5% [bmim] [Cl] or [bmim][Br] to [bmim][BF4]. In both cases, a catalytically inactive solution was obtained, showing the detrimental effect of these anions on the reaction. 

The solids were used as catalysts in the benchmark cyclopropanation reaction between styrene and ethyl diazoacetate (Scheme 7). As far as the nature of the clay is concerned, laponite was foimd to be the best support for the catalytic complexes. The best enantioselectivity results (Table 7) were obtained with ligand 6b (69% ee in trans cyclopropanes and 64% ee in cis cyclopropanes) but the recovered solid showed a lower activity and enantioselectivity, which was attributed to partial loss of the chiral ligand from the support. In general, the use of the three chiral ligands led to enantioselectivity results that were intermediate between those obtained in homogeneous phase with CuCl2 and Cu(OTf)2 as catalyst precursors. This seemed to indicate that the sohd behaved as a counterion with an intermediate coordinating abihty to the copper centers. 

Several catalytic systems have been reported for the enantioselective Simmons Smith cyclopropanation reaction and, among these, only a few could be used in catalytic amounts. Chiral bis(sulfonamides) derived from cyclo-hexanediamine have been successfully employed as promoters of the enantioselective Simmons-Smith cyclopropanation of a series of allylic alcohols. Excellent results in terms of both yield and stereoselectivity were obtained even with disubstituted allylic alcohols, as shown in Scheme 6.20. Moreover, this methodology could be applied to the cyclopropanation of stannyl and silyl-substituted allylic alcohols, providing an entry to the enantioselective route to stannyl- and silyl-substituted cyclopropanes of potential synthetic intermediates. On the other hand, it must be noted that the presence of a methyl substituent at the 2-position of the allylic alcohol was not well tolerated and led to slow reactions and poor enantioselectivities (ee<50% ee). ... 

Katsuki et al. have reported that the CoIII(salen) ((98) X = I, Y = t-Bu) bearing an apical halide ligand shows high trara-selectivity in the cyclopropanation of styrene and its derivatives, albeit with moderate enantioselectivity (Scheme 71).267 The enantioselectivity is influenced, however, by the natures of the apical ligand and the 5,5 -substituents, and high enantio- and traMs-selectivity has been realized by their appropriate tuning ((98) X = Br, Y = OMe).268 It is noteworthy that the CoIII(salen) complex bearing substituents at C3 and C3 shows no catalytic activity. 

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). 

Mixed ( )-cinnamyl acetals 460 undergo the enantioselective carbolithiation readily in the presence of stoichiometric or catalytic amounts, as low as 1 mol%, of (—)-sparteine (11) (equation 126) °. When quenching the reaction mixture of 461, 462 below —50°C with MeOH/HCl, the alcohols 463 are obtained with good yields and excellent ee values. However, upon warming to 20 °C, a 1,3-cycloelimination from conformation 462 gives rise to the formation of optically active trani-cyclopropanes 464 °. 

---