Cyclopropanation menthyl diazoacetate

Aratani et al. (21) subsequently found that the use of chiral menthyl diazoacetate esters led to higher trans/cis ratios and improved facial selectivity. A number of bulky diazoesters provided high enantioselectivity in the cyclopropanation reaction, but trans selectivity was highest with /-menthyl esters, Eq. 6. It seems clear from these and subsequent studies that the menthyl group is used because of its bulk and ready availability. The chirality present in the ester has a negligible effect on facial selectivity in the cyclopropanation reaction. Slow addition of diazoester is required (7 h at ambient temperature) for high yields presumably to suppress the formation of fumarate byproducts. 

These catalysts were shown to have some generality beyond trisubstituted alke-nes. In particular, Z-menthyl diazoacetate leads to moderately selective cyclopropane formation with a number of alkenes. These are illustrated in Table I. 

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. 

Cyclopropanations using bis(oxazoline) catalysts are not limited to reactions of styrene many different types of olefins can be used in cyclopropanations. The work of Masamune and co-workers included an example using 2,3,3-trimethylbutene with his bu-box complex 2a and /-(—)-menthyl diazoacetate. The product was obtained in 60% yield, trans/cis ratio of 95 5, trans ee of 80% and cis ee of 91%. 

With a series of substituted ethylenes, diastereoselectivities for cyclopropanation with chiral menthyl diazoacetates generally increase with increasing substitution about the C-C double bond (Table 5.2). 

TABLE 5.2. Diastereoselective Cyclopropanation of Alkenes with /-menthyl Diazoacetate (/-MDA) Catalyzed by the Aratani Catalyst 2 (A = CH3) [5] ... 

As with the Aratani catalysts, enantioselectivities for cyclopropane formation with 4 and 5 are responsive to the steric bulk of the diazo ester, are higher for the trans isomer than for the cis form, and are influenced by the absolute configuration of a chiral diazo ester (d- and 1-menthyl diazoacetate), although not to the same degree as reported for 2 in Tables 5.1 and 5.2. 1,3-Butadiene and 4-methyl- 1,3-pentadiene, whose higher reactivities for metal carbene addition result in higher product yields than do terminal alkenes, form cyclopropane products with 97% ee in reactions with d-men thy 1 diazoacetate (Eq. 5.8). Regiocontrol is complete, but diastereocontrol (trans cis selectivity) is only moderate. 

The capabilities of 5-8 for enantioselective cyclopropanation were determined (34) from reactions at room temperature of d- and/or /-menthyl diazoacetate (MDA) with styrene (Table 1), which allows direct comparison with results from both the Aratani (A-Cu) and Pfaltz (P-Cu) catalysts (19, 24). Cyclopropane product yields ranged from 50 to 75%, which were comparable to those obtained with chiral copper catalysts, but enantiomeric excesses were considerably less than those reported from use of either P-Cu or A-Cu. Furthermore, these reactions were subject to exceptional double diastereoselectivity not previously seen to the same degree with the chiral copper catalysts. Although chiral oxazolidinone ligands proved to be promising, the data in Table 1 suggested that steric interactions alone would not sufficiently enhance enantioselectivities to advance RI12L4 as an alternative to A-Cu or P-Cu. 

Table 1. Diastereoselectivities for the Cyclopropanation of Styrene by Menthyl Diazoacetate with Chiral Rhodium(H) Oxazolidinone Catalysts...

The use of Rh2(5/ -MEPY)4 and Rh2(55-MEPY)4 for reactions with menthyl diazoacetates (MDA) also produces an enormous double diastereoselection not previously observed to the same degree in cyclopropanation reactions. With methyl propargyl ether, for example, Rh2(5/ -MEPY)4 catalyzed reactions of d-MDA yield 16 (R = CH3OCH2) in 98% diastereomeric excess (de), but /-MDA produces its diastereoisomer in only 40% de with Rh2(55-MEPY)4, /-MDA gives the higher de (98%) and d-MDA gives the lower de (43%). Similar results are obtained from reactions of MDA with 1-hexyne and 3,3-dimethyl-1-propyne. The diazocarboxylate substituent obviously plays a critical role in establishing the more effective carbene orientation for addition to the alkyne. 

Other terminal olefins were transformed to the corresponding cyclopropane esters with Z-menthyl and d-menthyl diazoacetates with high stereoselectivity up to 98% ee (Scheme 3). Intramolecular reaction of the phenyl-allyl ester 9 was carried out to give the bicyclic compound 10 with 86% ee and 93% yield. The enantioselectivity for intramolecular cyclopropanation of the 3-methylbutenyl ester 11 was compared with chiral Cu(I), Rh(II), and Ru Pybox catalysts Rh>Ru>Cu [26]. 

Dirhodium(ll) tetrakis[methyl 2-pyrrolidone-5(R)-oarboxylate], Rh2(5R-MEPV)4, and its enantiomer, Rh2(5S-MEPY)4, which is prepared by the same procedure, are highly enantioselective catalysts for intramolecular cyclopropanation of allylic diazoacetates (65->94% ee) and homoallylic diazoacetates (71-90% ee),7 8 intermolecular carbon-hydrogen insertion reactions of 2-alkoxyethyl diazoacetates (57-91% ee)9 and N-alkyl-N-(tert-butyl)diazoacetamides (58-73% ee),10 Intermolecular cyclopropenation ot alkynes with ethyl diazoacetate (54-69% ee) or menthyl diazoacetates (77-98% diastereomeric excess, de),11 and intermolecular cyclopropanation of alkenes with menthyl diazoacetate (60-91% de for the cis isomer, 47-65% de for the trans isomer).12 Their use in <1.0 mol % in dichloromethane solvent effects complete reaction of the diazo ester and provides the carbenoid product in 43-88% yield. The same general method used for the preparation of Rh2(5R-MEPY)4 was employed for the synthesis of their isopropyl7 and neopentyl9 ester analogs. 

With the chiral bis(semicorrinato)copper(II) complex 9 developed by Pfaltz, enan-tioselectivities for cyclopropanes from monosubstituted alkenes are significantly higher than with Aratani s catalysts. Again, enantiocontrol can be increased by utilizing bulky diazoacetic esters (see Houben-Weyl, Vol.E19b, plll2). For menthyl diazoacetate and alkenes such as styrene, hept-l-ene, buta-1,3-diene and penta-1,3-diene, de values of 92-97% have been obtained. However, cyclopropanation of 1,2-disubstituted and trisubstituted alkenes occurs with lower chemical yield and asymmetric induction when catalyst 9 rather than 7 (R = Me) was used. ... 

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 chiral copper catalyst derived from 3-(trifluoroacetyl)camphor was reported to induce up to 100% ee in the cyclopropanation of styrene with diazodime-done [65] but no further studies of this reaction have been published since. Recently, the same catalyst was used for the cyclopropanation of 2,5-dimethyl-2,4-hexadiene [66] and up to 87% ee was reported for the trans-product derived from menthyl diazoacetate. 

Rhodium complexes generated from A-functionalized (S)-proline 3.60 [933, 934, 935] or from methyl 2-pyrrolidone-5-carboxylates 3.61 [936, 937, 938] catalyze the cyclopropanation of alkenes by diazoesters or -ketones. Diastereoisomeric mixtures of Z- and E-cydopropylesters or -ketones are usually formed, but only the Z-esters exhibit an interesting enantioselectivity. However, if intramolecular cyclopropanation of allyl diazoacetates is performed with ligand 3.61, a single isomer is formed with an excellent enantiomeric excess [936,937], The same catalyst also provides satisfactory results in the cyclopropanation of alkynes by menthyl diazoacetate [937, 939] or in the intramolecular insertion of diazoesters into C-H bonds [940]. 

This copper catalyst was also used to prepare specifically deuterated cyclopropane derivatives in optically active form79-80. The cyclopropanation of a more complex olefin methyl (2 )-3-isopropyl-6-methyl-2,5-heptadienoate can be achieved with surprisingly high cc when ( —)-menthyl diazoacetate is employed in the presence of the S-catalyst82. In this case a detailed description of various reaction parameters on the ee has been presented82. 

The reaction of styrene with (15,35,4/ )-menthyl diazoacetate [Eq. (a)] leads to the incorporation of two new stereocenters into the cyclopropane ring. The cis and trans isomers are formed each consisting of an enantiomeric pair. With the [Rh2(55-mepy)4] catalyst 86 % ee is achieved in the cis series and 48 % ee in the trans series. [16]... 

In the catalysis shown in Equation (a) a double stereoselection is involved. The formation of the new asymmetric centers in the cyclopropane ring is influenced by the men-thyl group contained in the substrate (15,35,4/ )-menthyl diazoacetate and by the mepy ligand contained in the catalyst. The two influences are referred to as substrate and catalyst control, respectively. With regard to the efficiency it has to be noted that whe-... 

Natural Cyclopropanes.—The synthesis of a 2 3 mixture of cis-and tra 5-isomers of racemic ethyl chrysanthemate by addition of ethyl diazoacetate to 2,5-dimethyl-hexa-2,4-diene in the presence of copper powder was first reported in 1924. Aratani et al. have now shown that when the addition is carried out with 1-menthyl diazoacetate in the presence of the chiral (R) copper complex (17), an asymmetric synthesis can be effected leading to a 72 28 mixture of trans-[90% (-l-)-enantiomer] and ci s-[60% (-H )-enantiomer] isomers. Two interesting and new... 

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