Diazoacetamides synthesis

Liu W-J, Chen Z-L, Chen Z-Y, Hu W-H. Dirhodium catalyzed intramolecular enantioselective C—H insertion reaction of A-cumyl-A-(2-/)-anisylethyl)diazoacetamide synthesis of (—)-rolipram. Tetrahedron Asymm. 2005 16 1693-1698. 

Catalysed cyclopropanation using diazoacetamides is rather less well developed. Doyle and coworkers have reported the intermolecular cyclopropanation of styrene with N,N-dimethyl diazoacetamide to give a cyclopropyl adduct in 74% yield (equation 3S)64. A further example is found in a synthesis of a-(carboxycyclopropyl)glycine 27 where an intramolecular cyclopropanation of the diazoacetamide is the key step (equations 39)65,66. 

Diazoacetamides are also exceptional substrates for dirhodium carboxamidate-catalyzed reactions, although with these substrates a mixture of /3-lactam and y-lactam products are formed [8]. The rhodium carboxamidate catalyst can have a major effect on the ratio of products formed. A good synthetic example is the Rh2(4S-MPPIM)4)-catalyzed synthesis of (-)-hcliotridanc 11 (Scheme 5) [9]. The key C-H insertion step of 9 generated the indolizidine 10 in 86 % yield and 96 % de, whereas reaction of 9 with achiral catalysts tended to favor the opposite diaster-eomer. 

The reaction of a-methoxycarbonyl-a-diazoacetamides is best catalyzed by Rh2(S-PTTL)4 or related catalysts [2,10]. Again, there is competition between /3-lac-tam and y-lactam formation. The chemistry has been applied to the synthesis of a variety of/3-lactam derivatives, as illustrated in Scheme 6 [11]. Rh2(S-PTTL)4-cata-... 

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. 

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]. 

Examples of enantioselective intramolecular C-H insertion reactions of diazoacetamides are known and though less extensive than those with diazoester substrates, there already are indications that excellent levels of stereocontrol are attainable. It is very likely that catalyst development will extend further the scope of this approach to the enantioselective synthesis of iY-heterocycles. 

Hashimoto needed a step to remove the methoxycarbonyl group, Hu et al. proposed an alternative synthesis via the same approach. The a-diazoacetamide 5 prepared in four steps from the isovanillin 2 was treated in the presence of 1 mol% Rh2[(4/ )-MEOX]4 in methylene chloride to afford the expected lactam 6 in 64% yield albeit in lower enantiomeric excess (46% ee). After removal of the cumyl protecting group and two recrystallizations, 1 was isolated in 88% ee (Scheme 23.4). 

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