The synthesis and characterisation of N-(1-carbamoyl-1,1-dialkyl-methyl)-(S)-prolinamides and related pyrrolidin-2-yl-4,5-dihydro-1H-imidazol-5-ones as potential enantioselective organocatalysts

The acylation of substituted 2-aminopropanamides with (2S)-Boc-proline, (2S)-Cbz-proline and (2S)-Bn-proline was used to prepare substituted 1-protected N-(1-carbamoyl-1,1-dialkyl-methyl)-(S)-prolinamides (74-89%), whose subsequent deprotection gave N-(1-carbamoyl-1,1-dialkyl-methyl)-(S)-prolinamides (94-95%). The enantiomerically pure N-(1-carbamoyl-1,1-dialkyl-methyl)-(S)-prolinamides obtained were tested as organocatalysts for the aldol reaction of cyclohexanone with 4-nitrobenzaldehyde, with yields ranging from 38% to 79% ee. The highest enantioselectivity (89% ee) was achieved by catalysis with N-(1-carbamoyl-cyclopentyl)-(S)-prolinamide (methanol, l0% HCl). By the action of sodium methoxide, Boc-N-(1-carbamoyl-cyclopentyl)-(S)-prolinamide was quantitatively cyclised to 2-(1-Boc-pyrrolidin-2-yl)-1,3-diazaspiro[4.4]non-1-en-4-one, which was accompanied by racemisation at the stereogenic centre of the proline skeleton. Alternatively, the substituted 4,4-dialkyl-2-pyrrolidin-2-yl-4,5-dihydro-1H-imidazol-5-ones were prepared by oxidation of 4,4-dialkyl-2-((2S)-1-Boc-pyrrolidin-2-yl)-4,5-dihydro-1H-imidazolidin-5-ones (54-69%). In an acid medium, 2-pyrrolidin-2-yl-1,3-diazaspiro[4.4]non-1-en-4-one and (4S)-4-isopropyl-4-methyl-2-pyrrolidin-2-yl-4,5-dihydro-1H-imidazol-5-one underwent racemisation. Conversely, the free base of (2S)-2-pyrrolidin-2-yl-1,3-diazaspiro[4.4]non-1-en-4-one very easily underwent oxidation to give the achiral 2-(4,5-dihydro-3H-pyrrol-2-yl)-1,3-diazaspiro[4.4]non-1-en-4-one.     

Chemoenzymatic synthesis of (5S)- and (5R)-hydroxymethyl-3,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-one: a precursor of thiolactomycin and determination of its absolute configuration

A convenient enantioselective synthesis of (5S)- and (5R)-hydroxymethyl-3,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-one, a key intermediate in the synthesis of thiolactomycin has been carried out by a Carica papaya lipase-mediated resolution protocol to provide (R)-2 in a 94% ee and its enantiomer (S)-9 in a 98% ee. The absolute configuration at the C-5 position has been determined by Mosher’s method.     

Aryl radical cyclizations of N-(2-halobenzoyl)-cyclic ketene-N,S-acetals

2-Ethylthiazolines react with 2-halobenzoyl chlorides to form N-(2-halobenzoyl)-cyclic ketene-N,S-acetals, which undergo stereo-controlled radical cyclizations to afford (R,S,S)-3-alkyl-10-methyl-2,3,10,10a-tetrahydrothiazolo[3,2-b]isoquinolin-5-one and (R,R,S)-3-alkyl-10-methyl-2,3,10,10a-tetrahydrothiazolo[3,2-b]isoquinolin-5-one.     

Stereoselective synthesis of 5-[(1S)-N-Boc-amino-(2S)-(3-fluorophenyl)ethyl]-dihydrofuran-2-one

A short, efficient, and highly diastereoselective synthesis of 5-[(1S)-N-Boc-amino-(2S)-(3-fluorophenyl)ethyl]-dihydrofuran-2-one (1) is described. Use of phthalic anhydride as thiolate scavenger effectively preserves the chiral integrity of the α-aminoketone 4 product obtained from the reaction of organozincate 3 with thioester 2.     

Chiral 1,4-benzodiazepines. IX. Attempts at a preparation of 7-chloro-5-phenyl-3(S)methyl-1,4-benzodiazepin-2-one through C(5)?C(5a) bond formation

During attempts at preparation of 7-chloro-5-phenyl-3(S)methyl-1,4-benzodiazepin-2-one ( 9 ) by cyclisation of N'-α-chlorobenzylidene-(S)alanyl-p-chloroaniline ( 7 ) and the related o,p-dichloroaniline derivative ( 8 ), it was observed that the intermediate products, both N'-benzylidene-(S)alanyl-p-chloroaniline ( 5 ), as well as the related o,p-dichloroaniline derivative ( 6 ), undergo cyclisation to N-(p-chlorophenyl)-2-phenyl-4(S)methylimidazolidin-5-one ( 17 ), and N-(o,p-dichlorophenyl)imidazolidin-5-one ( 18 ), respectively. Isolation and properties of the side products, N'-benzylated-(S)alanyl-p-chloro-, and o,p-dichloroanilines ( 15 and 16 ), as well as of N'-benzoylated-(S)alanyl-p-chloroanilines ( 19 and 20 ) are described.     

Constrained Dipeptide Surrogates: 5- and 7-Hydroxy Indolizidin-2-one Amino Acid Synthesis from Iodolactonization of Dehydro-2,8-diamino Azelates

The constrained dipeptide surrogates 5- and 7-hydroxy indolizidin-2-one N-(Boc)amino acids have been synthesized from L-serine as a chiral educt. A linear precursor ∆⁴-unsaturated (2S,8S)-2,8-bis[N-(Boc)amino]azelic acid was prepared in five steps from L-serine. Although epoxidation and dihydroxylation pathways gave mixtures of hydroxy indolizidin-2-one diastereomers, iodolactonization of the ∆⁴-azelate stereoselectively delivered a lactone iodide from which separable (5S)- and (7S)-hydroxy indolizidin-2-one N-(Boc)amino esters were synthesized by sequences featuring intramolecular iodide displacement and lactam formation. X-ray analysis of the (7S)-hydroxy indolizidin-2-one N-(Boc)amino ester indicated that the backbone dihedral angles embedded in the bicyclic ring system resembled those of the central residues of an ideal type II’ β-turn indicating the potential for peptide mimicry.     

New synthesis of (5S*,7aS*)-5-benzyloxy-5,6,7,7a-tetrahydrocyclopenta[c]pyran-3(1H)-one

To increase the efficiency of the recently suggested total synthesis of iso- and neuroprostanes, a possibility of transformation of its side products, i.e., syn- and anti-2-[(2S*,5S*)-2-benzyloxy-5-hydroxymethyl-Z-cyclopentylidene]ethanaldoximes, to (5S*,7aS*)-5-benzyloxy-5,6,7,7a-tetrahydrocyclopenta[c]pyran-3(1H)-one was studied.     

Synthesis of new aryl substituted furan-2(5H)-ones using the Suzuki-Miyaura reaction

A series of novel 5-arylidenefuran-2(5H)-ones and 5-arylidene-4-arylfuran-2(5H)-ones were synthesized via the Suzuki-Miyaura reactions of fimbrolide derivatives 5-(bromomethylene)furan-2(5H)-one and 4-bromo-5-(bromomethylene)furan-2(5H)-one, respectively. A regioselective Suzuki-Miyaura reaction on 4-bromo-5-(bromomethylene)furan-2(5H)-one allowed the synthesis of unsymmetrically substituted 5-arylidene-4-arylfuran-2(5H)-ones. The crystal structure of the intermediate 5-arylidene-4-bromofuran-2(5H)-one revealed interesting Br?O halogen bonding.     

A facile synthesis of (Z)-5-(substituted)-2-(methylthio)thiazol-4(5H)-one using microwave irradiation and conventional method

A new effective approach to the synthesis of some new (Z)-5-(substituted)-2-thioxothiazolidin-4-one 3a–l and (Z)-5-(substituted)-2-(methylthio)thiazol-4(5H)-one 5a–l is reported under microwave irradiation as well as conventional conditions.     

EPC syntheses from bicyclic dixoanones; (−)-5-epidehydrofukinone

(?)-5-Epidehydrofukinone ((?) -15 ) has been synthesized from (2S,4aS,5S,8aS)-4a,5-dimethyl-2-(tert-butyl)-perhydro-4H-1,3-benzodioxan-4-one ( 4a ), a counpound readily available by yeast reduction of ethyl 2-oxocyclohexanecarboxylate.     

Formal Synthesis of (-)-Serricornin

A formal synthesis of sex pheromone (-)-serricornin was achieved via (4S,5S)-5-ethyl-4-methyltetrahydrofuran-2-one prepared from lipase PS-resolved (4S,5R)-4-methyl-5-acetyloxymethyltetrahydrofuran-2-one.     

Structural elucidation of the β-turn inducing (S)-[3-amino-4-oxo-2,3-dihydro-5H-benzo[b][1,4]thiazepin-5-yl] acetic acid (DBT) motif

X-ray diffraction analysis of Boc-DBT-NH₂ (DBT = (S-[amino]-5-carbethoxymethyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one) showed that this constrained dipeptide mimetic adopts a type II′ β-turn in the solid state. IR and NMR studies indicated that the folded conformation is retained in solution.     

Synthesis of (5S*,4aS*,7aS*)-5-hydroxyhexahydro-cyclopenta[c]pyran-3(1H)-one

(5S*,4aS*,7aS*)-5-Hydroxyhexahydrocyclopenta[c]pyran-3(1H)-one, the promising isoprostane building block, was synthesized using intramolecular [3+2] cycloaddition of silyl nitronate generated from 4-benzyloxy-3-nitroocta-2,7-diene on the key step.     

Prostaglandin chemistry—V : Synthesis of new prostaglandin synthons; 4(R)-(+)- and 4(S)-(−)-t-butyldimethylsiloxycyclopent-2-en-1-one

Optically active prostaglandin intermediates, 4(R)-(+)- and 4(S)-(?)-hydroxycyclopent-2-en-1-one derivatives, were synthesized from 3(R),5(R)-diacetoxycyclopent-1-ene, 3(R)-acetoxy-5(R)-hydroxycyclopent-1-ene and 3(S),5(S)-dihydroxycyclopent-1-ene obtained by microbiological hydrolysis of 3,5-diacetoxycyclopent-1-ene. The absolute configurations of all these compounds were determined by the exciton chirality method and the induced CD method. The optical purities were determined by NMR measurements of the diastereomeric esters of a versatile optically pure acid, (+)-α-methoxy-α-trifluoromethylphenylacetic acid.     

A new synthetic approach to 5-dethia-4-methyl-5-oxacephems

Starting from (l)-ethyl lactate and 4-vinyloxy-azetidin-2-one the diastereomeric (4S,6R)- and (4S,6S)-4-methyl-5-oxa-3-methylene and 3-oxo-cephams were obtained. The formation of the cepham skeleton proceeds with a diastereomeric excess up to 80%, depending on catalyst and reaction conditions. For comparison, the corresponding racemic cephams lacking a methyl at C-4 or with a gem-dimethyl group at C-4 were synthesized.     

Synthesis of (22S, 23S)-homobrassinolide and brassinolide from stigmasterol

(22S, 23S)-Homobrassinolide (2α, 3α, 22S, 23S-tetrahydroxy-24S-etyl-B-homo-7-oxa-5α-cholestan-6-one) and brassinolide (2α, 3α 22R, 23R-tetrahydroxy-24S-methyl-B-homo-7-oxa-5α-cholestan-6-one) were synthesized from stigmasterol and shown to promote plant growth.     

Synthesis of lithium,sodium, cesium,and calcium salts of (E)-4- or (E,S)-3-methyl-2-(5-arylisoxazol-3-yl)-methyleneaminobutanoic, (E,S)-4-methyl-2- or (E,2S,3S)-3-methyl-2-(5-arylisoxazol-3-yl)methyleneaminopentanoic,and (E)-6-(5-arylisoxazol-3-yl)methyleneaminohexanoic acids

Preparative method for the synthesis of lithium, sodium, cesium, and calcium salts of (E)-4-(5-arylisoxazol-3-yl)methyleneaminobutanoic, (E)-6-(5-arylisoxazol-3-yl)methyleneaminohexanoic, (E,S)-3-methyl-2-(5-arylisoxazol-3-yl)methyleneaminobutanoic, (E,S)-4-methyl-2-(5-arylisoxazol-3-yl)methyleneaminopentanoic and (E,2S,3S)-3-methyl-2-(5-arylisoxazol-3-yl)methyleneaminopentanoic acids was developed by reacting 5-phenyl(4-tolyl)isoxazole-3-carbaldehydes with amino acids like 4-aminobutyric and 6-aminocaproic acids, L-valine, L-leucine or L-isoleucine in the presence of lithium hydride, sodium methoxide, cesium carbonate or calcium hydride in boiling methanol.     

Stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine

The stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine from (R)-1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)piperidin-2-one is described. The key steps involved are α-hydroxylation of quiral lactam with O₂, stereoconvergent reduction of (R)- or (S)-3-(benzyloxy)-piperidin-2-one with Red-Al® which afforded in both cases the trans-bicyclic oxazolidine in high stereoselectivity after chromatographic purification and a stereospecific Grignard addition to chiral bicyclic oxazolidine.     

Synthesis of diarylheptanoids, (5S)-5-acetoxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-3-heptanone and (3S,5S)-3,5-diacetoxy-1,7-bis(4-hydroxy-3-methoxyphenyl)heptane

The total syntheses of the first examples of diarylheptanoid natural products (5S)-5-acetoxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-3-heptanone 1, and (3S,5S)-3,5-diacetoxy-1,7-bis(4-hydroxy-3-methoxyphenyl)heptane 2 isolated from the rhizomes of Zingiber officinale were accomplished using Sharpless epoxidation and cross-metathesis reactions as the key steps.     

Palladium complex of 6-(2-hydroxy-5-methylphenyl)-3-(pyridin-2-yl)-1,2,4-triazin-5(2<Emphasis Type="Italic">H</Emphasis>)-one: Synthesis,structure, and catalytic activity

Palladium(II) complex with 6-(2-hydroxy-5-methylphenyl)-3-(pyridin-2-yl)-1,2,4-triazin-5(2H)-one was synthesized for the first time. The ligand was prepared from 3-(pyridin-2-yl)-1,2,4-triazin-5(2H)-one and 4-methylphenol via nucleophilic substitution of hydrogen (S_N^H reaction). The complex was readily soluble in basic medium, and it effectively catalyzed Mizoroki-Heck reaction.