Sergey N. Osipov

Synthesis of α-trifluoromethyl substituted α-amino acid derivatives from methyl 3,3,3-trifluoro-2-diazopropionate

Abstract New derivatives 2–7 of α-trifluoromethyl substituted amino acids are synthesized via tranformation of ammonium ylides formed on reaction of methyl 3,3,3-trifluoro-2-diazopropionate with amines and amides, respectively.

Synthesis of Fluorine-Containing Cyclic α-Amino Acid and α-Amino Phosphonate Derivatives by Alkene Metathesis

The electrophilic imino esters XF2CC(=NPG)CO2Me and imino phosphonates CF3CC(=NPG)P(O)(OR)2 (PG = SO2Ph, Cbz, Boc) were transformed by nucleophilic and then electrophilic additions into fluorine-containing amino esters and amino phosphonates with two pendent alkene chains (XF2C)(CH2=CH(CH2)nC(NPG)(Z)(CH2)mCH=CH2 [Z = CO2Me, P(O)(OR)2]. The ring-closing metathesis was performed on the α-amino ester dienes with Ru=CHPh(Cl)2(PCy3)2 catalyst and afforded five-, six-, and seven-membered cyclic amino esters, whereas the α-aminophosphonate dienes were transformed with RCM catalyst [Ru=C=C=CPh2(Cl)(PCy3)(p-cymene)]OTf to give six- and seven-membered cyclic α-amino-α-(trifluoromethyl)phosphonates.

Fluorine-containing α-alkynyl amino esters and access to a new family of 3,4-dehydroproline analogues

New α-alkynyl, α-CF3 amino esters have been prepared from electrophilic imines and used to produce 3-alkenyl-3,4-dehydroproline derivatives, ia enyne metathesis with the precatalyst [RuCCCPh2(Cl)(PCy3)(arene)]O3SCF3. These new conjugated fluorine-containing dienes are active substrates for the Diels–Alder reaction and lead to a new class of bicyclic amino esters.

Ruthenium-Catalysed Synthesis of Fluorinated Bicyclic Amino Esters through Tandem Carbene Addition/Cyclopropanation of Enynes

The reaction of fluorinated 1,6- and 1,7-enynes, containing the moiety N(PG)C(CF(3))(CO(2)R), with diazo compounds in the presence of [RuCl(cod)(Cp*)] (cod=cycloocta-1,5-diene, Cp*=C(5)Me(5) , PG=protecting group) as the catalyst precursor leads to the formation of fluorinated 3-azabicyclo[3.1.0]hexane-2-carboxylates and 4-azabicyclo-[4.1.0]heptane-3-carboxylates. This catalytic transformation was applied to various protecting groups and has proved to be a selective and a general synthetic tool to form constrained proline or homoproline derivatives in good yields. Z stereoselectivity of the created alkenyl group is obtained with N(2)CHSiMe(3), whereas N(2)CHCO(2)Et favours selectively the E configuration for the same double bond. The diastereoselectivity exo/endo depends on the size of the created ring. The X-ray structures of two products have been determined, showing the stereochemistry of the compounds. The reaction can be understood by initial [2+2] addition of the Ru=CHY bond, generated from diazoalkane, with the C≡CH bond of the enyne leading to a key bicyclic ruthenacyclobutane, which promotes the cyclopropanation, rather than metathesis. This selective formation of bicyclic [n.1.0] compounds results from the ruthenium-catalysed creation of three carbon-carbon bonds in a single step under mild conditions.

Asymmetric synthesis of α-trifluoromethyl substituted aminoacids via 3-hydroxy-3-trifluoromethyl-2,5-diketopiperazines

Abstract The diastereoselective reaction of organometallic compounds (RMgX, R2Cd) with in situ generated trifluoromethyl substituted cyclic acyl imines representing homochiral α-electrophilic 3,3,3-trifluoroalanine equivalents gives 3-alkyl-3-trifluoromethyl-2,5-diketopiperazines. The corresponding homochiral dipeptide esters are obtained on acidolysis in methanol.

New efficient syntheses of α-diflyoromethyl- and α-trifluoromethyl-ornithine

Abstract A new efficient method for the preparation of ornithine derivatives 3–5 is described. The key step of the synthesis is the regioselective alkylation of imine 2 with propargyl amine 1 .

Methyltrifluoropyruvate imines possessing N-oxalyl and N-phosphonoformyl groups—precursors to a variety of α-CF3-α-amino acid derivatives

Convenient routes to methyl 2-oxalylimino- and 2-(phosphonoformimido)-3,3,3-trifluoropropanoates have been elaborated, based on the reaction of methyl trifluoropyruvate with ethyl oxamate or diethyl carbamoylphosphonate, respectively, followed by dehydration. The compounds obtained are useful synthetic intermediates toward a variety of novel 3,3,3-trifluoroalanine derivatives that are potential drug candidates.

Stereoselective Alkane Oxidation with meta-Chloroperoxybenzoic Acid (MCPBA) Catalyzed by Organometallic Cobalt Complexes

Cobalt pi-complexes, previously described in the literature and specially synthesized and characterized in this work, were used as catalysts in homogeneous oxidation of organic compounds with peroxides. These complexes contain pi-butadienyl and pi-cyclopentadienyl ligands: [(tetramethylcyclobutadiene)(benzene)cobalt] hexafluorophosphate, [(C4Me4)Co(C6H6)]PF6 (1); diiodo(carbonyl)(pentamethylcyclopentadienyl)cobalt, Cp*Co(CO)I2 (2); diiodo(carbonyl)(cyclopentadienyl)cobalt, CpCo(CO)I2 (3); (tetramethylcyclobutadiene)(dicarbonyl)(iodo)cobalt, (C4Me4)Co(CO)2I (4); [(tetramethylcyclobutadiene)(acetonitrile)(2,2′-bipyridyl)cobalt] hexafluorophosphate, [(C4Me4)Co(bipy)(MeCN)]PF6 (5); bis[dicarbonyl(B-cyclohexylborole)]cobalt, [(C4H4BCy)Co(CO)2]2 (6); [(pentamethylcyclopentadienyl)(iodo)(1,10-phenanthroline)cobalt] hexafluorophosphate, [Cp*Co(phen)I]PF6 (7); diiodo(cyclopentadienyl)cobalt, [CpCoI2]2 (8); [(cyclopentadienyl)(iodo)(2,2′-bipyridyl)cobalt] hexafluorophosphate, [CpCo(bipy)I]PF6 (9); and [(pentamethylcyclopentadienyl)(iodo)(2,2′-bipyridyl)cobalt] hexafluorophosphate, [Cp*Co(bipy)I]PF6 (10). Complexes 1 and 2 catalyze very efficient and stereoselective oxygenation of tertiary C–H bonds in isomeric dimethylcyclohexanes with MCBA: cyclohexanols are produced in 39 and 53% yields and with the trans/cis ratio (of isomers with mutual trans- or cis-configuration of two methyl groups) 0.05 and 0.06, respectively. Addition of nitric acid as co-catalyst dramatically enhances both the yield of oxygenates and stereoselectivity parameter. In contrast to compounds 1 and 2, complexes 9 and 10 turned out to be very poor catalysts (the yields of oxygenates in the reaction with cis-1,2-dimethylcyclohexane were only 5%–7% and trans/cis ratio 0.8 indicated that the oxidation is not stereoselective). The chromatograms of the reaction mixture obtained before and after reduction with PPh3 are very similar, which testifies that alkyl hydroperoxides are not formed in this oxidation. It can be thus concluded that the interaction of the alkanes with MCPBA occurs without the formation of free radicals. The complexes catalyze oxidation of alcohols with tert-butylhydroperoxide (TBHP). For example, tert-BuOOH efficiently oxidizes 1-phenylethanol to acetophenone in 98% yield if compound 1 is used as a catalyst.

New carborane-containing amino acids and their derivatives. Crystal structures of n-protected carboranylalaninates

New alanine derivatives containing both the carboranyl and trifluoromethyl groups were synthesized by the reaction of organometallic derivatives of o-carborane with methyl trifluoropyruvate imines. When using the 1R-(−)-menthoxycarbonyl protecting group at the nitrogen atom, one of diastereomers was isolated and characterized. Trifluoromethyl-carboranylalanine methyl esters containing different protecting groups at the nitrogen atom were studied by X-ray diffraction. Both complete and partial deprotection of the amino and carboxy groups was performed.

Intramolecular cyclization of acetylene-containing α-amino carboxylates and α-amino phosphonates: synthesis of α-CF3-substituted dehydroprolines and their P-analogs

CF3-Containing α-arylpropargyl-α-amino carboxylates and α-arylpropargyl-α-amino phosphonates on treatment with the Brønsted or Lewis acids undergo cyclization involving the free NH2 group and triple bond to yield the corresponding dehydroprolines and their phosphorus analogs.