Chiral Catalyst Controlled Diastereoselection and Regioselection in Intramolecular Carbon−Hydrogen Insertion Reactions of Diazoacetates

Abstract

Individual enantiomers of substituted cyclohexyl diazoacetates or 2-octyl diazoacetates matched with a configurationally suitable chiral dirhodium(II) carboxamidate catalyst provide an effective methodology for the synthesis of lactones with exceptional diastereo- and regiocontrol. Enantiomerically pure (1S,2R)-cis-2-methylcyclohexyl diazoacetate forms the all-cis-(1R,5R,9R)-9-methyl-2-oxabicyclo[4.3.0]nonan-3-one with complete diastereocontrol in reactions catalyzed by dirhodium(II) tetrakis[methyl 1-(3-phenylpropanoyl)-2-oxoimidazolidine-4(R)-carboxylate], Rh2(4(S)-MPPIM)4, but the configurational mismatch results in a mixture of products. The same diazoacetate produces (1S,5R)-5-methyl-2-oxabicyclo[4.3.0]nonan-3-one with virtually complete selectivity by catalysis with dirhodium(II) tetrakis[methyl 2-oxopyrrolidine-5(S)-carboxylate], Rh2(5(S)-MEPY)4. Similarly high stereo- and regiocontrol is also achieved with enantiomerically pure trans-2-methylcyclohexyl diazoacetates. Product control from insertion reactions of d- or l-menthyl diazoacetate and (+)-neomenthyl diazoacetate from the configurational match with dirhodium(II) catalyst results in the formation of one C−H insertion product in high yield. The exceedingly high product diastereoselection observed in these reactions is consistent with virtually exclusive insertion into equatorial C−H bonds. The catalyst-dependent selective formation of a cis-disubstituted γ-butyrolactone or a β-lactone from 2-octyl diazoacetate has been achieved. Control of product diastereoselectivity and regioselectivity in C−H insertion reactions is explained by conformational suitability in configurational match/mismatch of catalyst and carbene.

Alcohols or Masked Alcohols as Directing Groups for C–H Bond Functionalization

“…For example, Doyle and co-workers reported chiral rhodium(II) carboxamidate-catalyzed intramolecular CH insertion reactions with enantiomerically pure 2-substituted cyclohexyl diazoacetate 36, which were derivatized from an alcohol (Scheme 17). 24 By using different chiral catalysts (a matched vs. mismatched situation), excellent site-selectivity was achieved with complete diastereocontrol. They further expanded the substrate scope to steroidal diazoacetates 39, in which the fivemembered ring product 40 is predominantly formed over the four-membered ring β-lactone product by using the chiral [Rh 2 (5R-MEPY) 4 ] catalyst.…”

Enantioselective β-Lactone Formation from Phenyldiazoacetates via Catalytic Intramolecular Carbon-Hydrogen Insertion

“…[1][2][3][4] They exhibit a high preference for the formation of five-membered rings and, in the absence of conformational restrictions, 5 reactivity follows the order tertiary> secondary>> primary. 6 There are few examples of insertion reactions favoring ring sizes other than five in these reactions, 1,[7][8][9] even when electronic influences would justify them. 10 Recently, Davies and coworkers have demonstrated that aryldiazoacetates exhibit much higher levels of selectivity in C-H insertion reactions.…”

“…7 The corresponding b-lactone, if formed at all, is a very minor product. In contrast, diazo decomposition of cyclohexyl phenyldiazoacetate 6 gives the corresponding b-lactone product 7 17 with near exclusivity (Table 2), and the catalyst had virtually no influence on regioselectivity.…”

Catalytic asymmetric C–H insertion reactions of α-diazocarbonyl compounds

“…The reaction is believed to proceed via equatorial C-H bond insertion, with the cis-and trans-isomeric products resulting from equilibration between the two possible cyclohexyl chair conformations of the diazoacetate. Such a preference for equatorial C-H bond insertion over axial insertion has been widely observed in carbenoid reactions of cyclohexyl diazoacetates, 10,116,121,122 with only very few exceptions being noted to date. As previously discussed, the choice of catalytic system can often be a key decision in determining the regiochemical outcome of intramolecular C-H insertion reactions.…”