Copper asymmetric cyclopropanation

From a historical perspective it is interesting to note that the Nozaki experiment was, in fact, a mechanistic probe to establish the intermediacy of a copper carbe-noid complex rather than an attempt to make enantiopure compounds for synthetic purposes. To achieve synthetically useful selectivities would require an extensive exploration of metals, ligands and reaction conditions along with a deeper understanding of the reaction mechanism. Modern methods for asymmetric cyclopropanation now encompass the use of countless metal complexes [2], but for the most part, the importance of diazoacetates as the carbenoid precursors still dominates the design of new catalytic systems. Highly effective catalysts developed in... 

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... 

Chelucci et al. [41] synthesized further chiral terpyridines derived from (-)-yd-pinene, (-i-)-camphor, and (-l-)-2-carene and tested their ability to chelate copper or rhodium for the asymmetric cyclopropanation of styrene. The copper catalysts were poorly efficient and selective in this reaction. The corresponding rhodium complexes led to the best result (64% ee) with the ligand derived from (-l-)-2-carene (ligand 33 in Scheme 17). 

Other types of new AT-containing ligands have been described as effective chiral inductors for copper-catalyzed asymmetric cyclopropanation. Hence, Fu and Lo [42] prepared a new planar-chiral hgand, namely the C2-symmetric bisazaferrocene (structure 34 in Scheme 18), which was fbimd to be efficient for the cyclopropanation of various olefins with large diastereomeric excesses and ee values up to 95%. 

In 1966, Nozaki et al. reported that the decomposition of o-diazo-esters by a copper chiral Schiff base complex in the presence of olefins gave optically active cyclopropanes (Scheme 58).220 221 Following this seminal discovery, Aratani et al. commenced an extensive study of the chiral salicylaldimine ligand and developed highly enantioselective and industrially useful cyclopropanation.222-224 Since then, various complexes have been prepared and applied to asymmetric cyclo-propanation. In this section, however, only selected examples of cyclopropanations using diazo compounds are discussed. For a more detailed discussion of asymmetric cyclopropanation and related reactions, see reviews and books.17-21,225... 

Intermolecular cyclopropanation of olefins poses two stereochemical problems enantioface selection and diastereoselection (trans-cis selection). In general, for stereochemical reasons, the formation of /ra ,v-cyclopropane is kinetically more favored than that of cis-cyclopropane, and the asymmetric cyclopropanation so far developed is mostly /ram-selective, except for a few examples. Copper, rhodium, ruthenium, and cobalt complexes have mainly been used as the catalysts for asymmetric intermolecular cyclopropanation. 

Recently, several mechanistic studies have been performed by means of calculations based on density functional theory. - Pfaltz s model proposed for asymmetric cyclopropanation using copper-semicorrin or -bis(oxazolines) complex has been supported by calculation.295 Another calculation also supports the parallel approach.296... 

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. 

The next major contribution in asymmetric cyclopropanation was the introduction of chiral semicorrin ligands 184 by Fritschi et al.95 This ligand has been used for coordinating with copper and has been found to provide improved enantiocontrol in the cyclopropanation of monosubstituted olefins. Copper(I), coordinated by only one semicorrin ligand, is believed96 to be the catalytically active oxidation state. The copper(I) oxidation state can be reached directly... 

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. 

Chapter 2 to 6 have introduced a variety of reactions such as asymmetric C-C bond formations (Chapters 2, 3, and 5), asymmetric oxidation reactions (Chapter 4), and asymmetric reduction reactions (Chapter 6). Such asymmetric reactions have been applied in several industrial processes, such as the asymmetric synthesis of l-DOPA, a drug for the treatment of Parkinson s disease, via Rh(DIPAMP)-catalyzed hydrogenation (Monsanto) the asymmetric synthesis of the cyclopropane component of cilastatin using a copper complex-catalyzed asymmetric cyclopropanation reaction (Sumitomo) and the industrial synthesis of menthol and citronellal through asymmetric isomerization of enamines and asymmetric hydrogenation reactions (Takasago). Now, the side chain of taxol can also be synthesized by several asymmetric approaches. 

The use of chiral copper complexes in asymmetric synthesis was inaugurated in 1966 when the first homogeneous asymmetric metal-catalyzed reaction was reported a copper catalyzed cyclopropanation (2). At the end of 1999, more than 25 distinct reactions were reported wherein the use of a chiral copper complex had induced an enantioselective transformation. The field grew quickly and the best is most likely yet to come. 

Jacobsen and co-workers (61) demonstrated that diimine-copper complexes are moderately selective for the asymmetric cyclopropanation of 1,2-dihydro-naphthalene, Eq. 44. A correlation was found between selectivities in the asymmetric aziridination and the asymmetric cyclopropanation catalyzed by the same species. Jacobsen argues that this supports the notion that the two processes follow similar mechanistic pathways. These workers also studied the complexation event between alkenes and Cu(I)-diimine complexes by NMR and by crystallographic characterization (62). For a thorough treatment of these results, see Section II.B.3. 

In their seminal report on homogeneous asymmetric copper-catalyzed cyclopropanation, Nozaki et al. (2) showed that racemic 2-phenyloxetane reacts with the diazoester-derived carbenoid to form cis and trans tetrahydrofurans (THF) in optically active form. Unfortunately, the extent of asymmetric induction could not be determined. 

Since the first experiments with chiral copper complexes reported by Nozaki [650] and Aratani [1027] many different catalysts have been examined, both for intermolecular and intramolecular cyclopropanations (for a review, see [1369]). Syntheses of natural products [955,1370] and drugs [1371] using asymmetric cyclopropanation with chiral electrophilic carbene complexes have been reported. A selection of useful catalysts is given in Figure 4.20 (see also Experimental Procedure 4.1.1). 

The cyclopropane aldehyde 156 was identified as a versatile chiral building block for the enantioselective synthesis of 4,5 disubstituted y-butyrolactones of type 158 or 159. Both enantiomers of 156 can be easily obtained in a highly diastereo- and enantioselective manner from fixran-2-carboxylic ester 154 using an asymmetric copper-catalyzed cyclopropanation as the key step followed by an ozonolysis of the remaining double bond (Scheme 25) [63]. Addition of... 

Bis-oxazoline ligands can also be produced by oxidative coupling of the copper derivative of diastereoisomerically pure 306 (Scheme 145) . Further lithiations of the product 317, which was produced as single diastereoisomer, occur (as in Scheme 143) at the second site adjacent to the oxazoline, giving, for example, 318, despite the (presumably) less favourable stereochemistry of the lithiation step. Bisoxazolines 318 direct the asymmetric copper-catalysed cyclopropanation of styrene using diazoacetate. 

Carbenoids derived from the aryldiazoacetates are excellent donor/acceptor systems for the asymmetric cyclopropanation reaction [22]. Methyl phenyldiazoacetate 3 cyclopropanation of monosubstituted alkenes catalyzed by Rh2(S-DOSP)4 is highly diaster-eo- and enantioselective (Tab. 14.5) [22]. Higher enantioselectivities can be obtained when these reactions are performed at -78°C, as the catalyst maintains high solubility and activity at this temperature. The phenyldiazoacetate system has been evaluated using many popular rhodium(II) and copper catalysts the rhodium(ll) prolinates have proven to be superior catalysts for this class of carbenoids [37, 38]. 

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). 

Asymmetric cyclopropanations of alkenes and alkynes with a-diazocarbonyl compounds have been extensively explored in recent years and a number of very effective chiral catalysts have been developed2. Copper complexes modified with such chiral ligands as salicy-laldimines 38202,203, semicorrins 39204 208, bis(oxazolines) 40209-2" and bipyridines 41212 have... 

One of the earliest examples of such catalysis was demonstrated in 1966 by the Japanese chemist Hitosi Nozaki, who reacted styrene and ethyl diazoacetate in the presence of a chiral Schiffbase-Cu11 complex [72-74], Although the initial enantios-electivity was modest (<10% ee), the principle was proven. Some years later, the companies Sumitomo and Merck used similar copper catalysts for asymmetric cyclopropanation on a multikilogram scale, in the production of various insecticides and antibiotics [75]. One of Nozaki s PhD students at that time was Rioji Noyori, who later developed the BINAP asymmetric hydrogenation catalysts for which he received the 2001 Nobel Prize in Chemistry [7[. 

Asymmetric cyclopropanation. Three laboratories have reported that copper complexes of chiral bis(oxazolines) are effective catalysts for asymmetric cyclopropanation of alkenes with diazoacetates. Bis(oxazolines) such as 1 are readily available by condensation of a-amino alcohols with diethyl malonate followed by cyclization, effected with dichlorodimethyltin or thionyl chloride. Cyclopropanation of styrene with ethyl diazoacetate catalyzed by copper complexes of type 1 indicates... 

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... 

For example, Jacobsen has studied the asymmetric aziridination of alkenes using (diimine)-copper(I)-catalysts 85. The results support the intermediacy of a discrete Cu(III)-nitrene intermediate and thus suggests mechanistic similarity (particularly regarding transition state geometry) to asymmetric cyclopropanation [95JA5889]. 

The copper(l)-catalyzed asymmetric cyclopropanation of methyl furan-2-carboxylate with ethyl diazoacetate was achieved by the use of the bisoxazoline ligand 12 to provide the o o-isomer of 2-oxa[3.0.1 ]bicyclohexene 13, as shown in Scheme 5 <2003CEJ260>. The product was transformed into 1,2,3-trisubstituted cyclopropane by ozonolysis... 

Asymmetric Copper-Catalyzed Cyclopropanation. Since the pioneering work of Nozaki and his co-workers, several chiral ligands have been designed to achieve high enantio and diastereoselectivity in copper-catalyzed asymmetric cyclopropanation of olefins. Masamune introduced C2-symmetric bisoxa-... 

The copper(l) triflate complex of 1 has been evaluated in the asymmetric cyclopropanation of styrene with ethyl diazoacetate (eq 3). The trans- and cis -2-phenylcyclopropane carboxylates were isolated in 88% yield as a 70 30 ratio of diastereomers in 43% and 44% enantioselectivity. These enantioselectivities are not as high as observed with other bis(oxazoline) ligands. 

Chelucci, G., Muroni, D., Pinna, G. A., Saba, A., Vignola, D. Chiral 2-(2-phenylthiophenyl)-5,6,7,8-tetrahydroquinolines new N-S ligands for asymmetric catalysis. Palladium-catalyzed allylic alkylation and copper-catalyzed cyclopropanation reactions. J. Mol. Catal. A Chemical 2003, 191, 1-8. 

Like BINOL, salicylaldehyde imines have become very important in asymmetric catalysis and a variety of polydentate ligands prepared from chiral monoamines and diamines are employed in oxidation reactions, carbenoid reactions and Lewis acid catalyzed reactions. As in the previous section, this section emphasizes the effect of the phenol moiety on the asymmetric catalysis. An imine derived from a chiral 1-phenethylamine and salicylaldehyde was employed in the copper catalyzed asymmetric cyclopropanation by Nozaki, Noyori and coworkers in 1966, which is the first example of the asymmetric catalysis in a homogeneous system . Salicylaldehyde imines with ethylenediamine (salen) have been studied extensively by Jacobsen and Katsuki and their coworkers since 1990 in asymmetric catalysis. Jacobsen and coworkers employed the ligands prepared from chiral 1,2-diamines and Katsuki and coworkers sophisticated ligands possess chirality not only at the diamine moiety but also at the 3,3 -positions. 

Table 7.11 Asymmetric cyclopropanation of styrene with ethyl diazoacetate catalyzed by bisoxazoline-copper complexes in an ionic liquid.

Aryl-5,5-bis(oxazolin-2-yl)-l,3-dioxanes 169 have been easily prepared in three steps from diethyl bis(hydroxymethyl)malonate, amino alcohols, and aromatic aldehydes. They have been used for the copper-catalyzed asymmetric cyclopropanation of styrene with ethyl diazoacetate in up to 99% ee for the trawx-cyclopropane (maximum transicis ratio = 77/23) <05TA1415>. The same reaction performed on 2,5-dimethyl-2,4-hexadiene with tert-butyl diazoacetate in the presence of copper catalysts bearing ligand 170, prepared from arylglycines, exhibited remarkable enhancement of the rrawx-selectivity (transicis ratio = 87/13), with 96% ee for the trans product <05JOC3292>. 

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