Stereocontrolled synthesis of trisubstituted cyclopropanes: expedient, atom-economical, asymmetric syntheses of (+)-Bicifadine and DOV21947.

[reaction: see text] An expedient, atom-economical, asymmetric synthesis of 1-aryl-3-azabicyclo[3.1.0]hexanes, including (+)-Bicifadine and DOV21947, in a single-stage through process without isolation of any intermediates has been developed. The key of this synthesis is the in-depth mechanistic understanding of the complicated epoxy nitrile coupling at each reaction stage. Therefore, the desired trisubstituted cyclopropane can be prepared in high ee and yield by controlling the reaction pathway through manipulating the nitrile anion aggregation state.

Intramolecular aromatic 1,5-hydrogen transfer in free radical reactions III. Reactivity of diaryl ketones, ethers, thioethers, sulfoxydes, and sulfones. An experimental and theoretical study.

[reaction: see text] Experiments show that free radical hydrogen shift is significant in the Pschorr cyclization of diphenyl ethers (X = O) and thioethers (X = S) and does not take place with sufoxides (X = SO) and sulfones (X = SO(2)). DFT calculations of the product ratios, activation energies, rate constants for H-transfers, and ring-closings at the UB3PW91/6-31G(d,p) level are in excellent agreement with the experimental results reported here and elsewhere in the literature.

Chiral recognition of cyclic alpha-hydroxyketones by CD-sensitive zinc tetraphenylporphyrin tweezer.

A combined chemical/chiroptical microscale protocol for the determination of absolute configurations of cyclic alpha-hydroxyketones is described. The hydroxyl group in cyclic alpha-hydroxyketones is converted into (3-aminopropylamino)acetate (NH2CH2CH2CH2NHCH2COOR), or more generally, according to a newly developed protocol, into (3-hydroxypropylamino)acetate group (HOCH2CH2CH2NHCH2COOR). The resultant conjugated compound forms a 1:1 host-guest complex with a dimeric zinc porphyrin tweezer, which exhibits exciton-coupled bisignate CD spectrum centered around the 420-nm porphyrin Soret band due to induced helicity between the two porphyrins in the complex. The absolute configurations of the alpha-stereogenic center is then determined by comparison of the sign of the observed CD exciton couplet of the complex with that of the preferred porphyrin twist predicted by the Merck Molecular Force Field (MMFFs) method.

Asymmetric synthesis of cyclic hydroxy ketones derived from enol ethers via sharpless asymmetric dihydroxylation. A study in the correlation of the enol ether chain length and enantioselectivity.

The Sharpless asymmetric dihydroxylation reaction of enol ethers derived from their corresponding cyclic ketones, gave alpha-hydroxyketones with high enantioselectivity. The enantiomeric excess was found to be proportional to the length of the unbranched enol ether chain with a maximum ee for the pentyl enol ether. An efficient synthesis of alpha-hydroxy chromanone in >90% ee was demonstrated using this method.

Development of a new and practical route to chiral 3,4-disubstituted cyclopentanones: asymmetric alkylation and intramolecular cyclopropanation as key C-C bond-forming steps.

An efficient and practical asymmetric synthesis of (+)-trans-3-hydroxymethyl-4-(3-fluorophenyl)cyclopentanone (1) is described. An asymmetric Mo-catalyzed alkylation reaction was used to establish the first stereocenter and a Cu-catalyzed intramolecular diastereoselective cyclopropanation reaction was used to set the second stereocenter. The last step involved a one-pot ring-opening/deprotection/hydrolysis/decarboxylation sequence that furnished the desired product in good yield.