Abstract

Reaction of ethyl diazoacetate in the presence of styrene using copper catalysis afforded the desired cyclopropane in good yields. The level of diastereocontrol was found to be dependent on both the electronic and structural features of the copper catalyst. Five copper salts were surveyed where copper(II) acetylacetonate affected the highest level of diastereocontrol (46% dr) and copper(I) hexaflurophosphate the lowest, 2% dr.

Introduction

The cyclopropanation of styrene using diazoesters and metal ligand complexes has been studied extensively (Doyle et al. 1997; Doyle and Forbes 1998). Under appropriate conditions, cyclopropanation can be affected to induce high diastereoselectivity and enantioselectivity (Scheme 1) (Evans et al. 1991). Unfortunately, a trend of high enantiocontrol and low diastereocontrol is observed with a number of substituted olefins. In order to achieve the highest diastereocontrol within a series of olefins, it is necessary to employ extremely large diazoesters, such as BDA (2,6-di-tert-butylphenyl diazoacetate, R = BHT) (Doyle et al. 1997). Aside from ethyl diazoacetate, all other diazo esters must be synthesized, making this technology less appealing. The levels of diastereocontrol are not only insensitive to changes within a particular series of olefins, but also to the ligand employed in the ligand-metal complexes. This is surprising given that ligated groups on several transition metal complexes have been found to have a significant influence on enantiocontrol in both inter- and intramolecular cyclopropanation reactions (Doyle et al. 1997). Yet to be understood are what features on the metal complexes influence the diastereotopicity of these processes.

The most commonly employed transition metals are derived from rhodium and copper. Among the dirhodium(II) catalysts studied, the highest levels of stereocontrol are observed with dirhodium(II) carboxamidates (2), 36% dr (Doyle et al. 1997). Unfortunately, when compared to the levels of stereocontrol achieved with copper catalysis (50% dr, Scheme 1), rhodium-mediated intermolecular cyclopropanation reactions are inferior (Doyle et al. 1990). As with dirhodium(II) complexes, copper(I) and copper(II) catalysts are very versatile reagents due to the number of different complexes that can be formed (Chart 1). Excellent levels of stereoselectivity have been achieved using a copper metal-bis(oxazoline) complex protocol. Yet to be examined is a systematic survey on achiral copper-mediated processes. We now report our initial results on the intermolecular cyclopropanation of styrene using ethyl diazoacetate with a series of achiral copper salts (4-6).

Methods

Metal complexes of bis-oxazoline ligands control the conformation of the metal carbene so efficiently that only one of the two possible approaches of the substrate to the metal carbene is permitted (Doyle et al. 1997; Pfaltz 1993; Singh et al. 1997). This is the enantiocontrol. The diastereocontrol, formation of the next stereocenter, is poor. Product analysis reveals the ester bearing carbon as the constant in overall stereoselectivity. Control of the stereocenter adjacent to the ester is poor. Yet to be explained is why this ring closure proceeds with low levels of diastereocontrol when levels of enantiocontrol exceed 99%. Furthermore, both diazo carbonyl compounds and olefins are achiral, mandating that the origin of stereocontrol lies with the metal complexes which are typically employed in 1.0 mol %.

Results

Shown below in Table 1 are the results of the study. Each entry was performed in triplicate in order to ensure reproducibility. All data represent the average of two runs. Standard reaction conditions were as follows: a solution of ethyl diazoacetate was added slowly to a refluxing CH2Cl2 solution consisting of styrene and catalyst. Upon completion of addition, the reaction mixture was concentrated in vacuo, passed through a silica gel chromatography column using CH2Cl2, and purified via bulb-to-bulb distillation. The diastereoselectivity was obtained via 1H NMR on the crude cyclopropane (1) using the OCH2CH3 as diagnostic resonances [cis: 3.86 (q, J = 7.1, 0.4 Hz, 2H, CH2O); trans: 4.13 (q, J = 7.1, 1.3 Hz, 2H, CH2O)]. Spectral data obtained was in agreement with the literature values (Evans et al. 1991).

The highest level of diastereoselectivity was obtained using copper(II) acetylacetonate (4a) as catalyst (46% dr, 72% yield). Upon changing the electronic nature of this catalyst, a drop in diastereocontrol was observed, copper(II) trifluoroacetylacetonate (4b) (42% dr, 70% yield) and copper(II) hexafluoroacetylacetonate (4c) (26% dr, 73% yield). This is consistant with the stereoelectronic trends observed with the dirhodium(II) series (Doyle et al. 1997; Padwa et al. 1994). A more reactive, and thus less selective, metal carbene is produced as electron removing groups are employed. Upon switching to copper(II) trifluoromethanesulfonate (5), whose steric environment is quite different to the copper(II) acetylacetonate series, a moderate level of diastereocontorol is observed (20% dr, 74% yield). The final catalyst tested was copper(I) hexafluorophosphate (6). The lowest level of diastereoselectivity was observed with this metal complex (2% dr, 69% yield). Surprisingly, by simply changing 1.0 mol % of the reactions medium, a 44% change in diastereocontrol is observed. Furthermore, copper(II) or copper(I) salts in the presence of external chelating ligands such as bis(oxazolines) (7) afford a similar level of diastereocontrol (~55%) with styrene and ethyl diazoacetate when compared to copper(II) acetylacetonate (4a) (Evans et al. 1991). Only when changes occur to the diazoester's alkoxy group are levels greater that 75:25 (cis:trans) observed, indicating that structurally unique metal complexes must be developed. Reports on higher levels of diastereocontrol using ethyl diazoacetate and styrene exist; however, limitations such as diminished reactivity or minimal substrate generality occur with these protocols (Nishiyama et al. 1994). Efforts to improve the diastereocontrol of intermolecular cyclopropanation reactions are underway and will be reported in due course.