1-Menthyl diazoacetate

Suga and Ibata [44] prepared binaphtyldiimine derivatives 36 (Scheme 19) affording 98% ee as best selectivity for the transformation of 1,1-diphenyl-ethylene with Z-menthyl diazoacetate. The authors performed PM3 calculations and proposed an optimized structure of the copper complex to explain the high enantioselectivity observed with 1,1-disubstituted olefins. 

Asymmetric synthesis of 2,5-dimethyl-2,4-hexadiene (28) and /-menthyl diazoacetate (29) with chiral copper complexes (30) was successfully conducted by Aratani et al. [13] to afford the (1 A)-chrysanthem ic acid /-menthyl ester (31) in high optical and chemical yield. Since this finding, a lot of chiral copper complexes have been reported and applied to the asymmetric synthesis of (IR)-chrysanthemate. However, these copper complexes required more than 1 mol% of the catalyst and the cis/trans ratio still remains unsatisfactory. Moreover, /-menthyl ester was crucial for the high enantioselectivity. Given an industrial production of... 

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. 

All reactions conducted neat in alkene using /-menthyl diazoacetate in the presence of catalyst. bDiastereomer ratio (dr) determined by gas chromatography (GC) analysis. 

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%. 

The Rh(II)-catalyzed reaction has been further extended to enantio-selective cyclopropenation of alkynes by diazo esters (Scheme 96) (230). The yield and selectivity are moderate, but optically active cyclopropenes are otherwise very difficult to obtain. An interesting double stereodifferentiation is seen in the reaction of (+)- or (—)-menthyl diazoacetate. 

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] ... 

Methyl diazoacetates were used extensively in earlier work because menthyl esters were amenable to separation by chromatographic methods. However, advances in chiral separation technologies have significantly reduced the need for chiral auxiliaries today, and enantiomeric separations of even simple esters are now routine. Selectivities obtained with menthyl diazoacetates are now of mainly historical interest. 

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. 

Virtually identical results, except in the opposite stereocontrol sense, are obtained with the use of Rh2(5S-MEPY)4. With d-menthyl diazoacetate and the same series of alkynes, selecti vibes as high as >97 3 diastereomer ratio have been achieved (Table 5.10), but diastereoselectivi-ties with diazoacetates having other chiral auxiliaries did not show any improvement in diastereocontrol [109]. 

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. 

Enantioeontrol in cyclopropenation reactions is obviously highly dependent on the carboxylate substituent of the dirhodium(II) carboxamide ligand and on the carboxylate substituent of the intermediate carbene. High enantioseleetivity is achieved with the use of Rh2(MEPY)4 catalysts and menthyl diazoacetates in reactions with 1-alkynes, and further enhancement in % ee can be anticipated. 

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. 

These reactions are subject to significant double diastereose-lection with (+)- and (—)-menthyl diazoacetates. With ethyl diazoacetate, enantiomeric excesses are moderate (54-69% ee), but... 

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). 

The early salen-type catalysts 143 of Aratani gave moderate results when menthyl diazoacetate was used,32 but more modern versions, such as the salen-Co catalyst 145 of Katsuki33 are much more impressive. You saw such catalysts in the last chapter under Jacobsen epoxidation. 

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. 

Doyle s catalysts have also been applied to asymmetric intermolecular cyclo-propanation, mainly in the styrene-diazoester reaction. Diazoesters include EDA, dicyclohexylmethyl diazoacetate, and d-menthyl diazoacetate. In general the effectiveness of Doyle s rhodium (II) carboxamidates in enantiocontrol is lower... 

Similar examples of product control induced by chiral catalysts have been found with tra 5-2-methylcyclohexyl diazoacetate, Eq. (51), (+)- and (-)-menthyl diazoacetate, Eq. (52), (+)-neomenthyl diazoacetate, Eq. (53), and (+)- and (-)-2-octyl diazoacetate, Eq. (54). The very high levels of diastereoselectivity exhibited by the cyclohexyl diazoacetate cyclisations is due to the preference for C-H insertion to occur at equatorial C-H bonds [66]. 

Yields in parentheses refer to the diazo decomposition of (+)-menthyl diazoacetate. 

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