Ru(II)-catalyzed asymmetric cyclopropanation using chiral diphenylphosphino(oxazolinyl)quinoline ligands

Several chiral 8-diphenylphosphino-2-oxazolinylquinolines were synthesized starting from 2-cyano-8-hydroxyquinoline. These N,N,P-chelates were successfully employed in the Ru(II)-catalyzed asymmetric cyclopropanation reactions of diazo-alkenes. The catalytic system exhibited good reactivity and high thermal stability and provided high yields in the intramolecular cyclopropanation, albeit somewhat decreased enantioselectivities compared to known catalytic systems. A dramatic dependency of the enantioselectivity on the substituents of the oxazoline ring was observed.     

Asymmetric cyclopropanation catalyzed by fluorous bis(oxazolines)–copper complexes

Fluorous bis(oxazoline)–copper(I) complexes generated in situ were tested as catalysts in the metal-catalyzed cyclopropanation of styrene with various α-diazoacetates. Under optimized conditions in CH₂Cl₂, quite good yields were obtained. Diastereoselectivities were found to be substrate and, to a lesser extent, ligand dependent, with trans/cis ratios ranging from 62/38 (cyclopropanation with α-ethyldiazoacetate 2a using ligand 1a) to 98/2 (cyclopropanation with methyl phenyldiazoacetate 2c using ligand 1b). Enantioselectivities up to 84% ee for the trans-isomer and 81% ee for the cis-isomer were observed using ligand 1b. Fluorous bis(oxazoline)–copper(I) complexes could be very easily separated from the products by simple precipitation using hexane, and recycled without loss of stereo- as well as enantioselectivities.     

Guide to enantioselective dirhodium(II)-catalyzed cyclopropanation with aryldiazoacetates

Catalytic enantioselective methods for the generation of cyclopropanes have been of long standing pharmaceutical interest. Chiral dirhodium(II) catalysts prove to be an effective means for the generation of diverse cyclopropane libraries. Rh₂(R-DOSP)₄ is generally the most effective catalyst for asymmetric intermolecular cyclopropanation of methyl aryldiazoacetates with styrene. Rh₂(S-PTAD)₄ provides high levels of enantioinduction with ortho-substituted aryldiazoacetates. The less-established Rh₂(R-BNP)₄ plays a complementary role to Rh₂(R-DOSP)₄ and Rh₂(S-PTAD)₄ in catalyzing highly enantioselective cyclopropanation of 3-methoxy substituted aryldiazoacetates. Substitution on the styrene has only moderate influence on the asymmetric induction of the cyclopropanation.     

Single-chiral bis(oxazolinyl)pyridine (pybox). Efficiency in asymmetric catalytic cyclopropanation

Single-chiral bis(oxazolinyl)pyridine ligands were examined as ligands for ruthenium-catalyzed asymmetric catalytic cyclopropanation of olefins: enantioselectivities up to 94% for the trans-cyclopropane were observed.     

Chemical reactivity of 6-diazo-5-oxo-l-norleucine (DON) catalyzed by metalloporphyrins (Fe,Ru)

The transfer of the metallocarbene derived from N- and O-protected 6-diazo-5-oxo-l-norleucine (DON) catalyzed by metalloporphyrins undergoes dimerization, cyclopropanation, N-H and S-H insertion reactions, respectively. An efficient and direct synthesis of 5-oxo-l-pipecolic acid from DON is described from unprotected 6-diazo-5-oxo-l-norleucine.     

Insights on Rh(II) carbenoid reactivity

A computational study on a range of Rh(II) carbenoids shows how carbenoid stability and cyclopropanation diastereoselectivity can be affected by certain properties of the carbenoid substituents. The results of the study imply that substituents capable of π-interactions are stabilising and cis-directing, and that the trans-directing abilities are affected by steric effects as well as the polarity of carbonyl groups.     

Stereoselective synthesis of (R)- and (S)-Ipsdienols, pheromone components of bark beetles of the Ips family

(R)- and (S)-Ipsdienols, components of pheromones of bark beetles of the Ips family, were synthesized with high enantiomeric purity (>98%) from 8-chloro-2-methyl-6-methylideneoct-2-en-4-ol prepared from ethyl 3-chloropropionate via cyclopropanation according to Kulinkovich. 8-Chloro-2-methyl-6-methylideneoct-2-en-4-ol was converted into the corresponding hydrogen phthalate whose stereoisomeric salts with (R)- and (S)-1-phenylethanamines were separated by crystallization, and subsequent hydrolysis of the latter and dehydrohalogenation with potassium tert-butoxide gave targeted (R)- and (S)-ipsdienols.     

(2-Formyl-1-phenylcyclopropyl)phosphonates as building blocks for (2-aminomethyl-cyclopropyl)phosphonates

A diastereomeric mixture of dimethyl (2-formyl-2-methyl-1-phenylcyclopropyl)phosphonate ((Z)-6, (E)-6) was obtained by thermally induced cyclopropanation of α-methylacrolein with α-diazobenzylphosphonate 5. Application of proline or proline-derived organocatalysts accelerated the reaction, but had a minor effect on the Z/E ratio of 6. By reaction with benzylamine or methyl esters of glycine, (S)-alanine, and (S)-phenylalanine, the Z/E-mixture of 6 was converted into cyclopropylaldimines, which after reduction gave the corresponding N-substituted (2-aminomethyl-cyclopropyl)phosphonates.     

Asymmetric synthesis of (R)-[2,2-2H2]-1-aminocyclopropane-1-phosphonic acid (ACPP derivative) conformationally constrained ACC analogue using a chiral sulfinyl auxiliary

The asymmetric cyclopropanation of vinylphosphonate using (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide was applied to obtain a dideuterated cyclopropyl sulfoxide. A three-step synthesis of enantiopure (+)-(1R)-1-amino-2,2-dideuteriocyclopropanephosphonic acid (+)-17-d₂ was developed.     

Highly efficient and enantioselective cyclopropanation of styrene with diazoacetates using a new copper-(Schiff-base) catalyst

A new copper-(Schiff-base) complex, derived from (S)-2-amino-1,1-di(3,5-di-t-butylphenyl)propanol, 2-hydroxy-5-nitrobenzaldehyde and copper acetate monohydrate, was used as an efficient catalyst for the cyclopropanation of styrene with diazoacetates, affording ees of up to 98%.     

Rh(II)-Catalyzed asymmetric carbene transfer with ethyl 3,3,3-trifluoro-2-diazopropionate

The asymmetric cyclopropanation of 1,1-diphenylethylene (2) with ethyl 3,3,3-trifluoro-2-diazopropionate (1) in the presence of chiral Rh(II) catalysts affords cyclopropane 3 with yields and enantioselectivities of up to 72 and 40%, respectively. Similar results are obtained for asymmetric cyclopropenation of hex-1-yne (4), although enantioselectivity is lower. The cyclopropanation of mono-substituted olefins (8a-8e) with 1 leads to cis/trans-mixtures of cyclopropanes 9a-9e with a maximum ee of 75% for 4-methoxystyrene (8c).     

Stereoselectivity in metal carbene and Lewis acid-catalyzed reactions from diastereomeric dirhodium(II) carboxamidates: Menthyl N-acetyl-2-oxoimidazolidine-4(S)-carboxylates

The influence of a chiral menthyl group as the pendant ester substituent on the N-acetyl-2-oxoimidazolidine-4S-carboxylate ligands in chiral dirhodium(II) imidazolidinone catalysts has been examined. Significant match/mismatch influences are evident in the observed stereocontrol for carbon–hydrogen insertion reactions with diazoacetates, but these effects are minimal in cyclopropanation reactions. Steric restrictions prevent effective enantiocontrol in hetero-Diels–Alder reactions using these menthyl-substituted catalysts.     

Olefin cyclopropanation with aryl diazocompounds upon catalysis by a dirhodium(II) complex

A dirhodium(II) complex with N-perfluorooctylsulfonylprolinate ligands is found to catalyze the cyclopropanation of olefins with simple aryl diazomethanes. In contrast to previously reported dirhodium(II) catalysts, the present complex works well not only with very electron-rich olefins such as enol ethers, but also with styrenes. Consequently, the present catalyst allows to prepare functionalized diarylcyclopropanes in moderate yields with good diastereoselectivity for the cis product, whereas the enantioselectivity of the reaction appears negligible.     

A scalable synthesis of (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid

A stereoselective and scalable synthesis of (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (3a) is described. Key to the success of the devised route was the realization that the stereoselectivity of a cyclopropanation step could be controlled by the composition of the functional group at C-α.     

Synthesis of (Het)aryl 2-(2-hydroxyaryl)cyclopropyl Ketones

A simple general method for the synthesis of 1-acyl-2-(ortho-hydroxyaryl)cyclopropanes, which belong to the donor–acceptor cyclopropane family, has been developed. This method, based on the Corey–Chaykovsky cyclopropanation of 2-hydroxychalcones, allows for the preparation of a large diversity of hydroxy-substituted cyclopropanes, which can serve as promising building blocks for the synthesis of various bioactive compounds.     

A cyclopropanol approach to the synthesis of the C13-C21 fragment of epothilones from diethyl (S)-malate

A convenient new approach to the synthesis of the C13-C21 epothilone fragment using the cyclopropanation of the ethoxycarbonyl groups in O-THP protected diethyl (S)-malate with ethylmagnesium bromide in the presence of titanium(IV) isopropoxide followed by site-selective cyclopropane cleavage as the key steps has been performed.     

cis-Enhanced cyclopropanation catalysts: reaction chemistry of three isomers of Rh2[N(C6H5)COCH3]4

The catalytic activities of three structural isomers of Rh₂[N(C₆H₅)COCH₃]₄ in cyclopropanation reactions were surveyed. These studies showed cis cyclopropanation selectivity with bulky alkenes for 2,2-cis- and 2,2-trans-Rh₂[N(C₆H₅)COCH₃]₄.     

Asymmetric cyclopropanation of (5S,SS)-3-p-tolylsulfinyl-5-ethoxyfuran-2(5H)-one with sulfonium ylides: influence of the sulfur ylide substituents on stereoselectivity

The cyclopropanation of title compound 1 with various sulfur ylides has been examined. A very high π-facial selectivity was observed in the reaction with diphenylsulfonium ylides, Ph₂SCRR′ (anti attack with respect to the alkoxy group in 1 is clearly preferred) whereas the endo-selectivity was found when R ≠ R′ is dependent on their relative size. Reactions with dimethylsulfonium ylides Me₂SCRR′ occurred with a moderate π-facial selectivity and exo-selectivity, the former being dependent on the solvent polarity. The stereochemical course of the cyclopropanation reactions is rationalized in terms of steric and electrostatic interactions.     

A flexible and modular stereoselective synthesis of (9R,10S)-dihydrosterculic acid

(9R,10S)-Dihydrosterculic acid has been prepared from (S_S,S_S)-1,1-bis(p-tolylsulfinyl)methane in a sequence involving an asymmetric Corey–Chaykovsky cyclopropanation and two sulfoxide/lithium exchange reactions. In most steps, the reaction conditions had to be optimized for the unbranched alkyl substituents, which were prone to Evans–Mislow rearrangements and subsequent degradation.