Allyl diazoacetate

Chiral dirhodium(II) carboxamidate catalysts are, by far, the most effective for reactions of allylic diazoacetates [44, 45] and allylic diazoacetamides [46]. Product yields are high, catalyst loading is low (less than 1 mol%), and enan-tioselectivities are exceptional (Scheme 6). The catalysts of choice are the two... 

A comparison of several of the PY and IM types of catalysts in intramolecular reactions of allylic diazoacetates led to a consistent model for the enantioselectivity. The highest e.e. values are observed for ds-substituted allylic esters. Both R and R1 are directed toward the catalyst and introduce steric interactions that detract from enantioselectivity.208... 

The Ru(Pybox- -Pr) complex (91), which induces high trans- and enantioselectivity in intermolecular cyclopropanation, has also been applied to the cyclization of allyl diazoacetates (Scheme 80) 252 The enantioselectivity observed depends largely on the susbstitution pattern of the allyl moiety. 

The Ru porphyrin complex (8) has also been used as a catalyst for the cyclization of allylic diazoacetates,258 albeit with limited success only the cyclization of F-cinnamyl diazoacetate shows high enantioselectivity (Scheme 81). It is noteworthy that a carbenoid species prepared from allyl o-phenyl-o-diazoacetate and complex (8) has been isolated and subjected to X-ray diffraction analysis, though it does not undergo the desired cyclization. In the structure, the carbene plane lies almost halfway between the two adjacent Ru—N bonds. 

The Ru-Schiff base complex (95) with the cis-[3 structure serves as a good catalyst for the cyclization of E- and tri-substituted allyl diazoacetates (Scheme 83).262... 

Co(salen)s (107a) and (107b), which bear the same ligands as (106a) and (106a), respectively, catalyze the cyclization of E- and tri-substituted allyl diazoacetates with good to high enantioselectivity.293... 

In the simplest case, the reaction of allyl diazoacetate, the catalyst (iS )-198 or (f )-198 in a concentration as low as 0.1 mol% can still catalyze the formation of enantiomeric-3-oxabicyclo[3.1.0]hexan-2-ones with 95% ee (Scheme 5-60). Substituted alkyl diazoacetates undergo intramolecular cyclopropanation, with similarly high enantiomeric excess (Scheme 5-61).110... 

Crotyl diazoacetate has been prepared by the procedure described here and by the reaction of diazomethane with crotyl chloroformate. The lower homolog, allyl diazoacetate, has been )repared by the reaction of allyl glycinate with nitrous acid and by the successive conversion of allyl chloroacetate to the corresponding azide, iminophosphorane, and, finally, the diazo ester. ... 

Kinetic resolution (enantiomer differentiation) of cycloalkenyl diazoacetates has been achieved (for example, according to Eq. 3) [34]. In these cases one enantiomer of the racemic reactant matches with the catalyst configuration to produce the intramolecular cyclopropanation product in high enantiomeric excess, whereas the mismatched enantiomer preferentially undergoes hydride abstraction from the allylic position [35] to yield the corresponding cycloalkenone. With acyclic secondary allylic diazoacetates the hydride abstraction pathway is relatively unimportant, and diastereoselection becomes the means for enantiomer differentiation [31]. 

Fig. 15.2 Immobilized chiral dirhodium(ll) pyrrolidinone-carboxylates and their application to intramolecular cyciopropanation of allyl diazoacetate [40].

Doyle, Martin, Muller, and co-workers communicated exceptional enantiocontrol for intramolecular cyclopropanation of a series of allyl diazoacetates (Eq. 5.16) by using dirhodium(II) tetrakis(methyl 2-oxopyrrolidine-5-carboxylates), Rh2(MEPY)4, in either their R- or S-configurations [87], and they have fully elaborated these results in a subsequent report [88],... 

TABLE 5.7. Enantioselective Intramolecular Cyclopropanation of Allyl Diazoacetates [87,88,91]... 

Intramolecular cyclopropanation of the next higher homologs of the allyl diazoacetates (Eq 5.19) catalyzed by Rh2(MEPY)4 give moderate-to-high percent of ee s for the addition product and isolated yields are also high (Table 5.9) [88]. 

Once again, cis-disubstituted olefins lead to higher enantioselectivities than do trans-disubstituted olefins, but here the differences are not as great as they were with allyl diazoacetates. Both allylic and homoallylic diazoacetamides also undergo highly enantioselective intramolecular cyclopropanation (40-43) [93,94], However, with allylic a-diazopropionates enantiocontrol i s lower by 10-30% ee [95], The composite data suggest that chi ral dirhodium(II) carboxamide catalysts are superior to chiral Cu or Ru catalysts for intramolecular cyclopropanation reactions of allylic and homoallylic diazoacetates. 

Dirhodium(II) tetrakis(carboxamides), constructed with chiral 2-pyrroli-done-5-carboxylate esters so that the two nitrogen donor atoms on each rhodium are in a cis arrangement, represent a new class of chiral catalysts with broad applicability to enantioselective metal carbene transformations. Enantiomeric excesses greater than 90% have been achieved in intramolecular cyclopropanation reactions of allyl diazoacetates. In intermolecular cyclopropanation reactions with monosubsti-tuted olefins, the cis-disubstituted cyclopropane is formed with a higher enantiomeric excess than the trans isomer, and for cyclopropenation of 1-alkynes extraordinary selectivity has been achieved. Carbon-hydro-gen insertion reactions of diazoacetate esters that result in substituted y-butyrolactones occur in high yield and with enantiomeric excess as high as 90% with the use of these catalysts. Their design affords stabilization of the intermediate metal carbene and orientation of the carbene substituents for selectivity enhancement. 

Intramolecular cyclopropanation of allyl diazoacetates gives rise to interesting cyclopropane-fused y-butyrolactones. A chiral ruthenium bis(oxa-zolinyl)pyridine complex 85 was employed for the catalytic cyclization of trans-cinnamyl diazoacetate 83 at room temperature to obtain an optically active lactone 84 in 93% yield with 86% ee (Eq. 34, Fig. 2) [85]. Chiral porphyrin and salen complexes of ruthenium 86 [86] and 87 [87] also catalyzed the asymmetric intramolecular cyclopropanation of 83 to afford 84 in similar yields and enantiomeric excess. 

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. 

This collection begins with a series of three procedures illustrating important new methods for preparation of enantiomerically pure substances via asymmetric catalysis. The preparation of 3-[(1S)-1,2-DIHYDROXYETHYL]-1,5-DIHYDRO-3H-2.4-BENZODIOXEPINE describes, in detail, the use of dihydroquinidine 9-0-(9 -phenanthryl) ether as a chiral ligand in the asymmetric dihydroxylation reaction which is broadly applicable for the preparation of chiral dlols from monosubstituted olefins. The product, an acetal of (S)-glyceralcfehyde, is itself a potentially valuable synthetic intermediate. The assembly of a chiral rhodium catalyst from methyl 2-pyrrolidone 5(R)-carboxylate and its use in the intramolecular asymmetric cyclopropanation of an allyl diazoacetate is illustrated in the preparation of (1R.5S)-()-6,6-DIMETHYL-3-OXABICYCLO[3.1. OJHEXAN-2-ONE. Another important general method for asymmetric synthesis involves the desymmetrization of bifunctional meso compounds as is described for the enantioselective enzymatic hydrolysis of cis-3,5-diacetoxycyclopentene to (1R,4S)-(+)-4-HYDROXY-2-CYCLOPENTENYL ACETATE. This intermediate is especially valuable as a precursor of both antipodes (4R) (+)- and (4S)-(-)-tert-BUTYLDIMETHYLSILOXY-2-CYCLOPENTEN-1-ONE, important intermediates in the synthesis of enantiomerically pure prostanoid derivatives and other classes of natural substances, whose preparation is detailed in accompanying procedures. 

Semicorrinato)copper catalysts have also been used for intramolecular cyclopropanation reactions of alkenyl diazo ketones (eq 9 and eq 10). In this case the (semicorrinato)copper catalyst derived from complex (5) proved to be superior to related methylene-bis(oxazoline)copper complexes. Interestingly, analogous allyl diazoacetates react with markedly lower enantioselectivity under these conditions, in contrast to the results obtained with chiral Rh complexes which are excellent catalysts for intramolecular cyclopropanations of allyl diazoacetates but give poor enantioselectivities with alkenyl diazo ketones (see Dirhodium(II) Tetrakis(methyl 2-pyrrolidone-5(S -carboxylate ) Moderate enantioselectivities in the reactions... 

Rh2(5/ -MEPY)4 catalysts for enantiocontrol are evident in results obtained with a series of allyl diazoacetates (eq 1). Both high product yields and enantiomeric excess (ee s) are characteristic. Intramolecular cyclopropanation of (Z)-alkenes proceeds with a higher level of enantiocontrol than does intramolecular cyclopropanation of ( )-alkenes. In preparative scale reactions, less than 0.25 mol% of catalyst can be employed to achieve high yields of pure product. ... 

On the other hand, the exceptional capabilities of these catalysts for enantiocon-trol are evident in results obtained in intramolecular cyclopropanations, which usually occur with greater enantioselectivity than they do with copper catalysts. The example shown in eq. (8) illustrates the synthesis of a strained bicyclic lactone from a readily available allyl diazoacetate [24]. Similarly, high enantioselec-tivities for intramolecular cyclopropanations of homoallylic diazoacetates and homoallylic diazoacetamides have been reported [24 b]. A comparative evaluation of enantiocontrol for cyclopropanation of allylic diazoacetates with chiral Cu, Rh", and Ru" catalysts showed the superiority of Rh-based catalysts in these intramolecular reactions [24 c], an observation that cannot however be extrapolated to different substrates [24 d]. 

A polyethylene-bound soluble recoverable dirhodium(II) tetrakis(2-oxapyrrolidine-(55 )-carb-oxylate) was also highly efficient in enantioselective intramolecular cyclopropanation of allyl diazoacetates and could be used repeatedly without significant loss of enantiocontrol. Some enantiomerically pure, secondary allylic diazoacetates showed the expected substrate-induced diastereofacial selectivity in intramolecular cyclopropanation, when they were decomposed with bis(A-n-r/-butylsalicylamidinato)copper(II). ° This selectivity could be significantly enhanced or reversed with the chiral catalyst 30 or its antipode. Furthermore, catalysts 30 and 32 allowed a highly efficient kinetic resolution of racemic secondary allylic diazoacetates. 

It is equally significant that these high levels of enantio control are consistently attainable with an entire range of ds-disubstituted allyl diazoacetates and with trisubstituted analogues, a selection of which is summarized in Table 1 and Eq. (19). The trisubstituted systems include those prepared from nerol (93% ee), Eq. (22) and geraniol (95% ee), Eq. (23). 

Table I.Enantioselective intramolecular cyclopropanation of allylic diazoacetates (n=l) catalyzed by Rh2(5S-MEPY)4, Eq. (19)...

Similarly, significant improvements with methallyl and ( -butyl)allyl diazoacetates can be achieved by switching catalysts from Rh2(MEPY)4 to Rh2(MP-PIM)4. Allyl diazo esters other than diazo acetates have not yet been examined in detail. Encouragingly, Doyle s group [41] have found that high levels of enantio-control in intramolecular cyclopropanation can be realized with allyl diazopropionates and the Rh2(4S-MEOX)4 catalyst, Eq. (25). 

In a useful extension of this methodology for enantioselection in intramolecular cyclopropanation, Doyle s group have used chiral rhodium (II) carbox-amidates to effect enantiomer differentiation in reactions of racemic secondary allylic diazoacetates [47]. The catalyst-enantiomer matching approach has also been applied very successfully to intramolecular C-H insertion reactions vide infra). The (R)- and (S)-enantiomers, (10) and (11), respectively, of cyclohex-2-en-1 -yl diazoacetate are displayed in Scheme 7. On exposure to Rh2(4i -MEOX)4 the (R)-enantiomer (10) undergoes cyclopropanation to form tricyclic ketone... 

This methodology has made available several of the tricyclic lactones (14-17) in Scheme 7 with ee of 94% or better. With acyclic racemic secondary allylic diazoacetates, enantiomer differentiation has also been demonstrated. 

In spite of the low reactivity of 1,2-disubstituted and trisubstituted olefins in the intermolecular cyclopropanation, some allyl diazoacetates were easily cyclopropanated to give the corresponding 3-oxabicyclo[3.1.0]hexan-2-one derivatives [44]. The trans isomers gave good results (from 76 to 86% ee),but low enan-tioselectivities were observed for the cis derivatives, Eq. (9). The diazo substrates containing a 2-alkyl substituent did not undergo intramolecular cyclopropanation under a variety of reaction conditions. In these cases, carbene dimers were the only isolated products. 

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]. 

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