Synthesis and structure of novel (S)-1,6-dialkylpiperazine-2,5-diones and (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones

Eleven (S)-1,6-dialkylpiperazine-2,5-diones and five (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones were prepared in three steps from the corresponding (S)-α-amino acid esters comprising of reductive N-alkylation, N-acylation and cyclisation. The synthesis of (S)-1,6-dialkylpiperazine-2,5-diones has a broad scope allowing preparation of diketopiperazines with primary and secondary alkyl groups at N(1), while the synthesis of (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones is limited to compounds with primary alkyl groups at N(1). Reductive alkylation of amino acid ester hydrochlorides by catalytic hydrogenation in the presence of a carbonyl compound proved to be a simple, efficient and general method for the preparation of stable (storable) α-alkylamino acid ester hydrochlorides. The structures of the novel compounds were determined by NMR and X-ray diffraction.     

Synthesis and absolute configuration of two diastereoisomeric (1R,2S,3R)-and (1S,2S,3R)-2-amino-1-(2-furyl)-1,3-butandiols

The synthesis of (1R, 2S, 3R) and (1S, 2S, 3R)-2-(N-benzoylamino)-1-(2-furyl)-1, 3-butandiols (15) and (16) from D-threonine is described. The assignment of absolute configuration of the newly formed asymmetric center at C-1 was based on the ¹H-NMR spectra of O-isopropylidene derivatives 17 and 18.     

Stereoselective synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin

A stereoselective approach for the synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin from l-ascorbic acid has been described. The key steps are highly stereoselective nucleophilic addition reaction on aldehyde 8 and also a single pot transformation of 15 to (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin. The later tandem reaction which involves the hydrogenation of double bond, debenzylation, MOM deprotection and bicyclic ketal formation was carried under Pd/C, H₂ followed by acid treatment.     

Dihydroboronium derivatives of (S,S)-1,2-bis(t-butylmethylphosphino)ethane as convenient chiral ligand precursors

Dihydroboronium derivatives of (S,S)-1,2-bis(t-butylmethylphosphino)ethane (t-Bu-BisP*) were prepared and used as chiral diphosphine ligand precursors in Rh-catalyzed asymmetric hydrogenation of methyl (Z)-acetamidocinnamate to afford the hydrogenation product in up to 94% enantioselectivity.     

Synthesis of (+)-(3S,7S,10S)- and (+)-(3S,7S,10R)-3,7,10-trimethylboratrane. Amplification of enantiomeric purity in the reacti

The synthesis is described of the two enantiomerically pure isomers (+)-(3S,7S,10S)- and (+)-(3S,7S,10R)-3,7,10-trimethylboratr The structures were determined by ¹H- and ¹³C-NMR spectroscopy. A method for increasing the enantiomeric purity by trimerization reactions of partially-resolved (S) propylene oxide is proposed. The reaction was studied from the kinetic viewpoint and interpreted according to a binomial probability scheme. The experimental findings point to a rapid growth in enantiomeric purity for the (SSS) trimer compared with the starting material, whilst no increase was found for the (SSR) trimer.     

Synthesis and regioselective substitution of C-6 alkoxy derivatives of (S)-nicotine

Enantiopure (S)-6-alkoxynicotine derivatives have been synthesized in two steps from (S)-nicotine via (S)-6-iodonicotine. Deprotonation and substitution at the C-5 position of the pyridine ring of (S)-6-methoxynicotine were achieved using mesityllithium as the base at 0 °C. Conditions for the C-4 lithiation/substitution of (S)-6-isopropoxynicotine and (S)-5-chloro-6-methoxynicotine were also developed.     

Enantioselective synthesis of (2S,3′R,7′Z)-N-(3′-hydroxy-7′-tetradecenoyl)-homoserine lactone

A concise enantioselective total synthesis of (2S,3′R,7′Z)-N-(3′-hydroxy-7′-tetradecenoyl)-homoserine lactone is described. Key feature of this protocol is a catalytic asymmetric hydrogenation and a prophenol-zinc-catalyzed diazo addition to imine reaction as genesis of chirality. Moreover, flexibility is built in the synthesis to generate enantioenriched analogs using catalytic amount of enantioenriched C₂-symmetric ligands.     

Straightforward synthesis of (R,R/S,S)-2-[2-(2-aryl)-1-phenyl-ethyl]-morpholines: a new class of inhibitors of the norepinephrine transporter

Diastereoselective synthesis of (R,R/S,S)-2-[2-(2-aryl)-1-phenyl-ethyl]-morpholines 6 has been achieved through the preparation of key E-enol-triflate 4 and its further coupling with benzylzinc reagents and final hydrogenation.     

Catalytic and chemoselective deprotection of S,S- and S,O-acetals and ketals in the presence of their O,O-analogs with electrophilic halogens under neutral conditions

A novel and catalytic method is described for the selective deprotection of S,S- and S,O-acetals and ketals in the presence of their O,O-analogs to their corresponding carbonyl compounds based on the use of N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), 2,4,4,6-tetrabromo-2,5-cyclohexadiene-1-one (TABCO), trichlorocyanuric acid (TCCA) or molecular bromine as sources of electrophilic halogens in the presence of DMSO as the source of oxygen in CHCl₃.     

Mononuclear ruthenium(II) complexes bearing the (S,S)-Pr-pybox ligand

The complexes trans-[RuCl₂(L){(S,S)-ⁱPr-pybox}] ((S,S)-ⁱPr-pybox = 2,6-bis[4′-(S)-isopropyloxazolin-2′-yl]pyridine, L = PMe₃ (1), P(OMe)₃ (2), PPh₂(CH₂CHCH₂) (3), CNBn (5), CNCy (6) and MeCN (7)) have been synthesized by substitution of ethylene on the precursor trans-[RuCl₂(η²-C₂H₄){(S,S)-ⁱPr-pybox}]. This complex also reacts with cyclooctadiene (cod) or norbornadiene (nbd) and NaPF₆, in refluxing methanol, giving the coordination compounds [RuCl(η⁴-cod){(S,S)-ⁱPr-pybox}][PF₆] (8) and [RuCl(η⁴-nbd){(S,S)-ⁱPr-pybox}][PF₆] (9). The structures of complexes [RuCl(CO)(PPh₃)(H-pybox)][BF₄] (H-pybox = 2,6-bis(dihydrooxazolin-2′-yl)pyridine) (4), 6 and 8, have been resolved by X-ray diffraction methods. The catalytic activity of the new complexes in transfer hydrogenation of acetophenone has also been examined.     

Diastereoselective route to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane, a pheromone component of the wasp Paravespula vulgaris

A diastereoselective approach to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane 1 and 1a is described. The route starts with an alkylation reaction among the cyclopentanone N,N-dimethylhydrazone 6 and the chiral iodides (R)-3 or (S)-3, derived from the enantiomers of ethyl β-hydroxybutyrate, controlling the estereocenter at C-2 of the molecules. The alkylated products 7 and 7a were easily transformed into the 1,8-O-TBS-1,8-dihydroxy-5-nonanones 9 and 9a in four steps, and a subsequent stereoselective spiroketalization, in acidic media, afforded a Z:E mixture (1:2) of compounds 1 and 1a.     

Stereoselective synthesis of (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methylundecanoic acid δ-lactone

A stereoselective synthesis of the pentaketide lactone (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methylundecanoic acid δ-lactone has been achieved.     

Asymmetric synthesis of (2S,3R)-(−)-epi-CP-99,994 using sulfinimine-derived anti-2,3-diamino esters

A differentially protected C-3 N-sulfinyl, C-2 N,N-(diphenylmethylene) 2,3-diamino ester was employed in the synthesis of the amino piperidine (2S,3R)-(−)-epi-CP-99,994. Key steps in the synthesis included the chemoselective hydrolysis of the C-2 N,N-(diphenylmethylene) group and its reprotection as a dibenzylamino group.     

Synthesis of (4R,15R,16R,21S)- and (4R,15S,16S,21S)-rollicosin

A convergent synthesis of (4R,15R,16R,21S)-rollicosin (1) and (4R,15S,16S,21S)-rollicosin (2) was accomplished. Hydroxy lactone 6a and/or 6b were synthesized from 4-pentyn-1-ol, and α,β-unsaturated lactone 7 was synthesized from γ-lactone 8 and 5-hexen-1-ol. Inhibitory activity of these compounds was examined with bovine heart mitochondrial complex I.     

Microwave-assisted synthesis of methyl (1S,2R,4S,5S)-7-aza-5-hydroxybicyclo[2.2.1]heptane-2-carboxylate through unexpected stereoselective substitution reaction

Methyl (1S,2R,4S,5R)-7-aza-5-bromo-bicyclo[2.2.1]heptane-2-carboxylate was synthesized in high yield in short time from methyl (1R,2S,4R,5R)-2-amino-4,5-dibromocyclohexanecarboxylate through intramolecular cycloamination under microwave-assisted conditions. The following substitution reaction by trifluoro-acetate anion also took place in microwave-assisted conditions to afford methyl (1S,2R,4S,5S)-7-aza-5-hydroxy-bicyclo[2.2.1]heptane-2-carboxylate. In the acyloxylation reaction, unusual endo-selectivity was observed owing to 7-azabicyclo[2.2.1]heptane skeleton.     

Synthesis of both syn and anti diastereoisomers of Boc-dolaproine from (S)-proline through DKR using ruthenium-catalyzed hydrogenation: a dramatic role of N-protecting groups

The natural (2R,3R)-Boc-dolaproine and its unnatural (2S,3S) diastereoisomer were synthesized involving as key transformation the Ru(II)-promoted hydrogenation of the β-keto-α-methyl ester derived from (S)-N-Boc-proline. Interestingly, the asymmetric hydrogenation of this β-keto ester N-protected as an amine hydrochloride salt, provided the corresponding anti (2S,3R)- and (2R,3S)-β-hydroxy-α-methyl esters with significant level of selectivities through dynamic kinetic resolution.     

Transformation of esters into allyl halides via substituted cyclopropanols. Application in the synthesis of (2S,3R,7R/S)-3,7-dimethyltridec-2-yl acetate and propionate, sex attractants of pine sawfly Diprion pini

A convenient new approach to the synthesis of the acetate and the propionate of (2S,3R,7R/S)-3,7-dimethyltridecan-2-ol, sex attractants of Diprion pini L., using the cyclopropanation of the ethoxycarbonyl group in O-THP protected ethyl (S)-lactate with ethylmagnesium bromide in the presence of titanium(IV) isopropoxide followed by C-2-C-3 cyclopropane ring opening as the key steps has been performed.     

A concise synthesis of (2S,4R)- and (2S,4S)-4-methylglutamic acid

A concise, multi-gram scale method for producing the bioactive and enantiomerically pure epimers, (2S,4R)- and (2S,4S)-glutamic acids, in a single synthetic scheme is described.     

Synthesis and absolute configuration of (1S,8S)-as-hydrindacene-1,8-diol as determined by the circular dichroism exciton chirality method

2,3,6,7-Tetrahydro-as-indacene-1,8-dione 4 was prepared in 4 steps starting from 2-methyl-furan by modification of a literature procedure. Appliance of Noyori’s asymmetric transfer hydrogenation, resulted in (1S,8S)-1,2,3,6,7,8-hexahydro-as-indacene-1,8-diol 5 in high yield (81%) and excellent enantioselectivity (>99% ee) or (8S)-8-hydroxy-3,6,7,8-tetrahydro-2H-as-indacen-1-one 6 in moderate yield (58%) and equally high enantioselectivity (98.5% ee), depending on the conditions. The asymmetric reduction was expected to yield the (S)-alcohols using the (S,S)-Ts-DPEN ligand, which was confirmed by the appliance of the exciton chirality method on the corresponding bis(p-dimethylamino)benzoate 7.     

Synthesis and properties of S,R-alternating octinaphthalenes

(S,R,S,R,S,R,S)- and (S,R,S,S,S,R,S)-octinaphthalenes were synthesized by oxidative coupling of (S,R,S)-quaternaphthalene, and differences due to axis chirality of (S,R,S,R,S,R,S)-, (S,R,S,S,S,R,S)-, (S,S,S,R,S,S,S)-, and (S,S,S,S,S,S,S)-octinaphthalenes were compared using the R_f values on TLC, specific optical rotations, ¹H NMR chemical shifts of the hydroxy groups, and CD spectra. A clear CD additivity was found in the Δ? values of the ¹L_a transition around 290 nm, which are proportional to the difference between the numbers of S and R binaphthalene units.