Stereocontrolled Synthesis of (2R,3S)‐2‐Methylisocitrate,a Central Intermediate in the Methylcitrate Cycle

2‐Methylisocitrate (=3‐hydroxybutane‐1,2,3‐tricarboxylic acid) is an intermediate in the oxidation of propanoate to pyruvate (=2‐oxopropanoate) via the methylcitrate cycle in both bacteria and fungi (Scheme 1). Stereocontrolled syntheses of (2R,3S)‐ and (2S,3R)‐2‐methylisocitrate (98% e.e.) were achieved starting from (R)‐ and (S)‐lactic acid (=(2R)‐ and (2S)‐2‐hydroxypropanoic acid), respectively. The dispiroketal (6S,7S,15R)‐15‐methyl‐1,8,13,16‐tetraoxadispiro[5.0.5.4]hexadecan‐14‐one ( 2a ) derived from (R)‐lactic acid was deprotonated with lithium diisopropylamide to give a carbanion that was condensed with diethyl fumarate (Scheme 3). The configuration of the adduct diethyl (2S)‐2‐[(6S,7S,14R)‐14‐methyl‐15‐oxo‐1,8,13,16‐tetraoxadispiro[5.0.5.4]hexadec‐14‐yl]butanedioate ( 3a ) was assigned by consideration of possible transition states for the fumarate condensation (cf. Scheme 2), and this was confirmed by a crystal‐structure analysis. The adduct was subjected to acid hydrolysis to afford the lactone 4a of (2R,3S)‐2‐methylisocitrate and hence (2R,3S)‐2‐methylisocitrate. Similarly, (S)‐lactic acid led to (2S,3R)‐2‐methylisocitrate. Comparison of 2‐methylisocitrate produced enzymatically with the synthetic enantiomers established that the biologically active isomer is (2R,3S)‐2‐methylisocitrate.     

Einfache Umwandlung von(–)-(R)-3-Hydroxybuttersäure in das (+)-(S)-Enantiomere und dessen Lacton(‒)-(S)-4-Methyloxetan-2-on

Simple Conversion of (R)-3-Hydroxybutanoic Acid to the (S)-Enantiomer and its Lactone (–)-(S)-4-Methylixetan-2-one Condensation of ( R )-3-hydroxybutanoic acid (1) with ethyl orthoacetate gives a 2-ethoxy-substituted (1,3)dioxanone 2 which is thermally labile: at ca. 100°, two competing processes commence, one leading to ethyl ( R )-3-acetoxybutanoate ( 3 ), the other one - with complete inversion of configuration - to the ( S )-4-methylixetan-2-one ( 4 ) and ethyl acetate. These can be readily separated by fractional distillation. Thus, enantiomerically pure ( S )-3-hydroxybutanoic acid (ent- 1 ) and l-2-alkyl-3-hydroxybutanoic-acid derivatives (such as 6 and 8 ) become available from the biopolymer PHB, the precursor to the acid 1 .     

A new simple preparation of -alloisoleucine suitable for large-scale manufacture

-Alloisoleucine ( -aIle) was obtained by the resolution of the epimer mixture of -isoleucine ( -Ile) and -aIle, which was formed by epimerization of -Ile, with a resolving agent such as (2S,3S)-dibenzoyltartaric acid ((2S,3S)-DBTA) or (2S,3S)-di-4-toluoyl-tartaric acid ((2S,3S)-DTTA).     

Asymmetric Syntheses of the Macrocyclic Spermine Alkaloids (−)‐(S)‐Protoverbine, (−)‐(S)‐Buchnerine,and Their Naturally Occurring Congenial Alkaloids

Asymmetric syntheses of the following 17‐membered macrocyclic spermine alkaloids are presented: (−)‐(S)‐protoverbine (=(8S)‐8‐phenyl‐1,5,9,13‐tetraazacycloheptadecane‐6‐one; 1 ), (+)‐(S)‐protomethine (=(2S)‐2‐phenyl‐1,5,9,14‐tetraazabicyclo[12.3.1]octadecan‐4‐one; 2 ), (−)‐(S)‐buchnerine (=(8S)‐8‐(4‐methoxyphenyl)‐1,5,9,13‐tetraazacycloheptadecane‐6‐one; 8 ), (+)‐(S)‐verbamethine (=(+)‐(2S)‐9‐[(E)‐phenylprop‐2‐enoyl]‐2‐phenyl‐1,5,9,14‐tetraazabicyclo[12.3.1]octadecan‐4‐one; 4 ), (−)‐(S)‐verbacine (=(−)‐(8S)‐1‐[(E)‐phenylprop‐2‐enoyl]‐8‐phenyl‐1,5,9,13‐tetraazacycloheptadecan‐6‐one; 3 ), (−)‐(S)‐verbasikrine (=(−)‐(8S)‐1‐[(E)‐3‐(4‐methoxyphenyl)prop‐2‐enoyl]‐8‐phenyl‐1,5,9,13‐tetraazacycloheptadecan‐6‐one; 26 ), (−)‐(S)‐isoverbasikrine (=(−)‐(8S)‐1‐[(Z)‐3‐(4‐methoxyphenyl)prop‐2‐enoyl]‐8‐phenyl‐1,5,9,13‐tetraazacycloheptadecan‐6‐one; 25 ), (+)‐(S)‐verbamekrine (=(+)‐(2S)‐9‐[(E)‐3‐(4‐methoxyphenyl)prop‐2‐enoyl]‐2‐phenyl‐1,5,9,14‐tetraazabicyclo[12.3.1]octadecan‐4‐one; 23 ), and (+)‐(S)‐isoverbamekrine (=(+)‐(2S)‐9‐[(Z)‐3‐(4‐methoxyphenyl)prop‐2‐enoyl]‐2‐phenyl‐1,5,9,14‐tetraazabicyclo[12.3.1]octadecan‐4‐one; 24 ). Effective methods for ¹H‐NMR determination of the enantiomeric purity in which (S)‐2‐hydroxy‐2‐phenylacetic acid and (S)‐2‐acetoxy‐2‐phenylacetic acid are used as shift reagents for 1, 8 , and related macrocyclic alkaloids are described.     

Synthesis of Ahod Moiety of Ralstonin A Using Amino Acid Schiff Base Ni(II)-Complex Chemistry

Reported here is the asymmetric synthesis of N-Boc-protected (2S,3S)-3-amino-2-hydroxyoctadecanoic acid, a component of ralstonin A and ralstoamide A. Key synthetic steps include alkylation of chiral Ni(II) complex of glycine Schiff base, conversion of COOH to keto acid (CO−COOH) and reduction of the carbonyl group to generate α-hydroxy functionality. The structure and absolute configuration of (2S,3S)-N-Boc-3-amino-2-hydroxyoctadecanoic acid was shown to be identical to that of the naturally occurring compound.     

Triflic Acid-Promoted Formylation of Ceramide in Dimethylformamide

The protected ceramide: N‐((2S,3S,4R)‐3,4‐bis(benzyloxy)‐1‐hydroxyoctadecan‐2‐yl)tetracosanamide, was attempted to introduce a triflate as a leaving group followed by a nucleophilic substitution with azido group in one‐pot manner. Unexpectedly, the oxazole ring formed via a thermodynamically favored intramolecular cyclization was opened to generate the original ceramide by triflic acid. In addition, the residual acid promoted a formylation of the primary hydroxy group in DMF.     

Asymmetrische Michael-Additionen. Stereoselektive Alkylierung chiraler,nicht racemischer Enolate durch Nitroolefine. Herstellung enantiomerenreiner γ-Aminobuttersäure- und Bernsteinsäure-Derivate

Asymmetric Michael-Additions. Stereoselective Alkylation of Chiral, Non-racemic Enolates by Nitroolefins. Preparation of Enantiomerically Pure γ-Aminobutyric and Succinic Acid Derivatives Chiral, non-racemic lithium enolates ( E , F , G ) of 1,3-dioxolan-4-ones, methyl 1,3-oxazolidin-4-carboxylates, methyl 1,3-oxazolin-4-carboxylates, 1,3-oxazolidin-5-ones, and 1,3-imidazolidin-4-ones derived from (S)-lactic acid ( 2a ), (S)-mandelic acid ( 2b ), and (S)-malic acid ( 2c ), or from (S)-alanine ( 10 ), (S)-proline ( 11 ), (S)-serine ( 12 ), and (S)-threonine ( 13 ), are added to nitroolefins. Michael adducts ( 3 – 9 , 14 – 18 ) are formed (40–80%) with selectivities generally above 90% ds of one of the four possible stereoisomers. Conversions of these nitroalkylated products furnish the α-branched α-hydroxysuccinic acids 28 and 29 , the α-hydroxy-γ-amino acid 25 , the α,γ-di-amino acid 32 , the substituted γ-lactames 19 – 22 , and the pyrrolidine 23 . The relative and absolute configuration of the products from dioxolanones and nitropropene are derived by chemical correlation and NOE measurements indicating that the steric course of reaction is to be specified as 1k, ul-1,3. The mechanism is discussed.     

Chirale Synthesebausteine durch Kolbe-Elektrolyse enantiomerenreiner β-Hydroxy-carbonsäurederivate. (R)- und (S)-Methyl-sowie (R)-Trifluormethyl-γ-butyrolactone und -δ-valerolactone

Chiral Building Blocks for Syntheses by Kolbe Electrolysis of Enantiomerically Pure β-Hydroxybutyric-Acid Derivatives. (R)- and (S)-Methyl-, and (R)-Trifluoromethyl-γ-butyrolactones, and -δ-valerolactones The coupling of chiral, non-racemic R* groups by Kolbe electrolysis of carboxylic acids R*COOH is used to prepare compounds with a 1.4- and 1.5-distance of the functional groups. The suitably protected β-hydroxycarboxylic acids (R)- or (S)-3-hydroxybutyric acid, (R)-4,4,4-trifluoro-3-hydroxybutyric acid (as acetates; see 1 – 6 ), and (S)-malic acid (as (2S,5S)-2-(tert-butyl)-5-oxo-1,3-dioxolan-4-acetic acid; see 7 ) are decarboxylatively dimerized or ‘codimerized’ with 2-methylpropanoic acid, with 4-(formylamino)butyric acid, and with monomethyl malonate and succinate. The products formed are derivatives of (R,R)-1,1,1,6,6,6-hexafluoro-2,5-hexanediol (see 8 ), of (R)-5,5,5-trifluoro-4-hydroxypentanoic acid (see 9,10 ), of (R)- and (S)-5-hydroxyhexanoic acid (see 11 ) and its trifluoro analogue (see 12, 13 ), of (S)-2-hydroxy- and (S,S)-2,5-dihydroxyadipic acid (see 23, 20 ), of (S)-2-hydroxy-4-methylpentanoic acid (‘OH-leucine’, see 21 ), and of (S)-2-hydroxy-6-aminohexanoic acid (‘OH-lysine’, see 22 ). Some of these products are further converted to CH₃- or CF₃-substituted γ- and δ-lactones of (R)- or (S)-configuration ( 14 , 16 – 19 ), or to an enantiomerically pure derivative of (R)-1-hydroxy-2-oxocyclopentane-1-carboxylic acid (see 24 ). Possible uses of these new chiral building blocks for the synthesis of natural products and their CF₃ analogues (brefeldin, sulcatol, zearalenone) are discussed. The olfactory properties of (R)- and (S)-δ-caprolactone ( 18 ) are compared with those of (R)-6,6,6-trifluoro-δ-caprolactone ( 19 ).     

Scyphiphorins A and B,Two New Iridoid Glycosides from the Stem Bark of a Chinese Mangrove Scyphiphora hydrophyllacea

Two new iridoid glycosides, named scyphiphorins A ( 1 ) and B ( 2 ), together with four known compounds, geniposidic acid (=(1S,4aS,7aS)‐1‐(β‐D ‐glucopyranosyloxy)‐1,4a,5,7a‐tetrahydro‐7‐(hydroxymethyl)cyclopenta[c]pyran‐4‐carboxylic acid; 3 ), 4‐(4‐hydroxy‐3‐methoxybenzyl)butan‐2‐one, oleanolic acid (=(3β)‐3‐hydroxyolean‐12‐en‐28‐oic acid), and stigmasterol β‐D ‐glucoside (=(3β,22E)‐stigmasta‐5,22‐dien‐3‐yl β‐D ‐glucopyranoside), were isolated for the first time from the stem bark of a Chinese mangrove, Scyphiphora hydrophyllacea Gaertn . f. The structures of compounds 1 and 2 were determined as 10‐O‐benzoylgeniposidic acid and 10‐O‐[(2E,6R)‐8‐hydroxy‐2,6‐dimethyl‐1‐oxooct‐2‐en‐1‐yl]geniposidic acid, respectively, on the basis of spectroscopic data and chemical methods, including 2D NMR techniques.     

Aromastoffe der roten Passionsfrucht. Zwei neue Edulanderivate

Aroma Constituents of the Purple Passion Fruit. Two New Edulan Derivatives The isolation of (2R*, 4S*, 4aS*, 8aS*)-4,4a-epoxy-4,4a-dihydroedulan ( 1 ), and (2R*, 3S*, 8aS*)-3-hydroxyedulan ( 2 ), two new constituents of the purple passion-fruit (Passiflora edulis SIMS ), is reported. Racemic epoxide 1 was synthesized by oxidation of edulan 6 with peracidic acid, and racemate of alcohol 2 was obtained by reduction of ketone 7 , one of the chromic acid oxidation-products of edulan 6 .     

Molecular Clefts Derived from 9,9′-spirobi[9H-fluorene] for enantioselective complexation of pyranosides and dicarboxylic acids

The molecular clefts (R)- and (S)- 3 , incorporating 9,9′-spirobi[9H-fluorene] as a spacer and two N-(5,7-dimethyl-1,8-naphthyridin-2-yl)carboxamide (CONH(naphthy)) units as H-bonding sites were prepared via the bis(succinimid-N-yl esters) of (R)-and (S)-9,9′-spirobi[9H-fluorene]-2,2′-dicarboxylic acid ( 5 ). Derivative 6 , with one CONH(naphthy) unit and one succinimid-N-yl ester residue allowed easy access to spirobifluorene clefts with two different H-bonding sites, as exemplified by the synthesis of 4 . Binding studies with (R)- and (S)- 3 and optically active dicarboxylic acids in CDCl₃ exhibited differences in free energy of the formed diastereoisomeric complexes (Δ(ΔGº)) between 0.5 and 1.6 kcal mol^?1 (T 300 K). Similar enantioselectivities were observed with the spirobifluorene clefts (R)- and (S)- 1 , bearing two N-(6-methylpyridin-2-yl)carboxamide (CONH(py)) H-bonding sites. The thermodynamic quantities ΔHº and ΔSº for the recognition processes with (R)- and (S)- 1 were determined by variable-temperature ¹H-NMR titrations and compared to those with (R)- and (S)- 2 , which have two CONH(py) moieties attached to the 6,6′-positions of a conformationally more flexible 1,1′-binaphthyl cleft. All association processes showed high enthalpic driving forces which are partially compensated by unfavorable changes in entropy. Pyranosides bind to the optically active clefts 1 and 3 in CDCl₃ with ?ΔGº = 3.0–4.3 kcal mol^?1. Diastereoisomeric selectivities up to 1.2 kcal mol^?1 and enantioselectivities up to 0.4 kcal mol^?1 were observed. Cleft 4 and N-(5,7-dimethyl-1,8-naphthyridin-2-yl)acetamide ( 25 ) complexed pyranosides 22–24 as effectively as 3 indicating that only one CONH(naphthy) site in 3 associates strongly with the sugar derivatives. Based on the X-ray crystal structure of 3 , a computer model for the complex between (S)- 3 and pyranoside 22 was constructed. Molecular-dynamics (MD) simulations showed that differential geometrical constraints are at the origin of the high enantioselectivity in the complexation of dicarboxylic acid (S)- 7 by (R)- and (S)- 1 and (R)- and (S)- 3 .     

Optically active imidazole-containing polymers

In order to investigate the stereospecificity of enzyme-catalyzed reactions, an optically active copolymer of 4(5)-vinylimidazole and 2,5(S)-dimethyl-1-hepten-3-one was synthesized, and its effects on the solvolytic rates, in ethanol-water, of the p-nitrophenyl and 4-carboxy-2-nitrophenyl esters of 3(R)- and 3(S)-methylpentanoic acid and of the commercially available N-carbobenzoxy-(R)- and (S)-phenylalanine p-nitrophenyl esters were investigated. The optically active comonomer was prepared by thermal decomposition of solid (+)-1-piperidino-2,5(S)-dimethylheptan-3-one hydrochloride, which was obtained from the reaction of 2(S)-methylbutyllithium with 3-piperidino-2-methylpropionitrile. The 3(R)-methylpentanoic acid was prepared in 92% optical purity from L -alloisoleucine via diazotization in concentrated hydrobromic acid and subsequent reductive debromination with zinc amalgam in dilute hydrochloric acid. In the optically active copolymer-catalyzed solvolyses of the optically active esters performed at pH values of 6–8 no significant differences between the solvolytic rates of (R) and (S) isomers of substrates were observed. Poly-L -histidine was also employed as a catalyst for the solvolyses of these substrates. At pH 6.0 in ethanol–water the latter catalyst also failed to exhibit specificity towards (R) and (S) substrates.     

Solid‐state conformations of linear depsipeptide amides with an alternating sequence of α,α‐disubstituted α‐amino acid and α‐hydroxy acid

Depsipeptides and cyclodepsipeptides are analogues of the corresponding peptides in which one or more amide groups are replaced by ester functions. Reports of crystal structures of linear depsipeptides are rare. The crystal structures and conformational analyses of four depsipeptides with an alternating sequence of an α,α‐disubstituted α‐amino acid and an α‐hydroxy acid are reported. The molecules in the linear hexadepsipeptide amide in (S)‐Pms‐Acp‐(S)‐Pms‐Acp‐(S)‐Pms‐Acp‐NMe₂ acetonitrile solvate, C₄₇H₅₈N₄O₉·C₂H₃N, ( 3b ), as well as in the related linear tetradepsipeptide amide (S)‐Pms‐Aib‐(S)‐Pms‐Aib‐NMe₂, C₂₈H₃₇N₃O₆, ( 5a ), the diastereoisomeric mixture (S,R)‐Pms‐Acp‐(R,S)‐Pms‐Acp‐NMe₂/(R,S)‐Pms‐Acp‐(R,S)‐Pms‐Acp‐NMe₂ (1:1), C₃₂H₄₁N₃O₆, ( 5b ), and (R,S)‐Mns‐Acp‐(S,R)‐Mns‐Acp‐NMe₂, C₃₀H₃₇N₃O₆, ( 5c ) (Pms is phenyllactic acid, Acp is 1‐aminocyclopentanecarboxylic acid and Mns is mandelic acid), generally adopt a β‐turn conformation in the solid state, which is stabilized by intramolecular N—H…O hydrogen bonds. Whereas β‐turns of type I (or I′) are formed in the cases of ( 3b ), ( 5a ) and ( 5b ), which contain phenyllactic acid, the torsion angles for ( 5c ), which incorporates mandelic acid, indicate a β‐turn in between type I and type III. Intermolecular N—H…O and O—H…O hydrogen bonds link the molecules of ( 3a ) and ( 5b ) into extended chains, and those of ( 5a ) and ( 5c ) into two‐dimensional networks.     

Herstellung enantiomerenreiner Derivate von 3-Amino- und 3-Mercaptobuttersäure durch SN2-Ringöffnung des β-Lactons und eines 1,3-Dixoanons aus der 3-Hydroxybuttersä ure

Preparation of Enantiomerically Pure Derivatives of 3-Amino- and 3-Mercaptobutanoic Acid by S_N2 Ring Opening of the β-Lactone and a 1,3-Dioxanone Derived from 3-Hydroxybutanoic Acid From (S)-4-methyloxetan-2-one ( 1 ), the β-butyrolactone readily available from the biopolymer ( R )-polyhydroxybutyrate (PHB) and various C, N, O and S nucleophiles, the following compounds are prepared:(s)-2-hydroxy-4-octanone ( 3 ), (R)-3-aminobutanoic acid ( 7 ) and its N-benzyl derivative 5 , (R)-3-azidobutanoic acid ( 6 ) (R)-3-mercaptobutanoic acid ( 10 ), (R)-3-(phenylthio)butanoic acid ( 8 ) and its sulfoxide 9 . The (6R)-2,6-dimethyl-2-ethoxy-1,3-dioxan-4-one ( 4 ) from (R)-3-hydroxybutanoic acid undergoes S^N2 ring opening with benzylamine to give the N-benzyl derivative (ent- 5 ) of (S)-3-aminobutanoic acid in 30?40% yield.     

Artabotryols A – E,New Lanostane Triterpenes from the Seeds of Artabotrys odoratissimus

Six new lanostane triterpenes, artabotryols A, B, C1, C2, D, and E ( 1, 2, 3a, 3b, 4 , and 5 , resp.) have been isolated from the seeds of Artabotrys odoratissimus (Annonaceae). Their structures have been established as (3α,22S,25R)‐3‐hydroxy‐22,26‐epoxylanost‐8‐en‐26‐one ( 1 ), (3α,22S,25R)‐22,26‐epoxylanost‐8‐ene‐3,26‐diol ( 2 ), (3α,22S,25R,26R)‐26‐methoxy‐22,26‐epoxylanost‐8‐en‐3‐ol ( 3a ), (3α,22S,25R, 26S)‐26‐methoxy‐22,26‐epoxylanost‐8‐en‐3‐ol ( 3b ), (3α,22S,25R)‐3,22‐dihydroxylanost‐8‐en‐26‐oic acid ( 4 ) and (3α,7α,11α,22S,25R)‐3,7,11‐trihydroxy‐22,26‐epoxylanost‐8‐en‐26‐one ( 5 ) by spectroscopic studies and chemical correlations.     

Bruceines K and L from the Ripe Fruits of Brucea javanica

Bruceine K ( 1 ), a pentacyclic C₂₀‐quassinoid bearing a unique 12,20‐epoxy moiety, and bruceine L ( 2 ), along with the ten known compounds (6S,7E)‐6,9,10‐trihydroxy‐ and (6S,7E)‐6,9‐dihydroxymegastigma‐4,7‐dien‐3‐one ( 3 and 4 , resp.), cleomiscosins A–C, luteoline, quercetine, bruceantinol, pinoresinol, and thevetiaflavone, were isolated from the ripe fruits of Brucea javanica. Bruceines K ( 1 ) and L ( 2 ) were determined to be (1β,2α,11β,12β,14ξ,15β)‐12,20‐epoxy‐1,2,11,13,14,15‐hexahydroxypicras‐3‐en‐16‐one and (1β,2α,11β,12β,15β)‐13,20‐epoxy‐1,2,11,12‐tetrahydroxy‐16‐oxo‐15‐(senecioyloxy)picras‐3‐en‐21‐oic acid methyl ester (senecioic acid=3‐methylbut‐2‐enoic acid), respectively, on the basis of NMR (¹H‐ and ¹³C‐NMR, DEPT, ¹H,¹H‐COSY, NOESY, HMQC, and HMBC) and ESI‐MS data. Among the known compounds, (6S,7E)‐6,9,10‐trihydroxy‐ and (6S,7E)‐6,9‐dihydroxymegastigma‐4,7‐dien‐3‐one ( 3 and 4 , resp.), cleomiscosin C, luteoline, quercetine, and thevetiaflavone were isolated for the first time from the Brucea plants.     

Characterization of novel isobenzofuranones by DFT calculations and 2D NMR analysis

Phthalides are frequently found in naturally occurring substances and exhibit a broad spectrum of biological activities. In the search for compounds with insecticidal activity, phthalides have been used as versatile building blocks for the syntheses of novel potential agrochemicals. In our work, the Diels–Alder reaction between furan‐2(5H)‐one and cyclopentadiene was used successfully to obtain (3aR,4S,7R,7aS)‐3a,4,7,7a‐tetrahydro‐4,7‐methanoisobenzofuran‐1(3H)‐one and (3aS,4R,7S,7aR)‐3a,4,7,7a‐tetrahydro‐4,7‐methanoisobenzofuran‐1(3H)‐one ( 2 ) and (3aS,4S,7R,7aR)‐3a,4,7,7a‐tetrahydro‐4,7‐methanoisobenzofuran‐1(3H)‐one and (3aR,4R,7S,7aS)‐3a,4,7,7a‐tetrahydro‐4,7‐methanoisobenzofuran‐1(3H)‐one ( 3 ). The endo adduct ( 2 ) was brominated to afford (3aR,4R,5R,7R,7aS,8R)‐5,8‐dibromohexahydro‐4,7‐methanoisobenzofuran‐1(3H)‐one and (3aS,4S,5S,7S,7aR,8S)‐5,8‐dibromohexahydro‐4,7‐methanoisobenzofuran‐1(3H)‐one ( 4 ) and (3aS,4R,5R,6S,7S,7aR)‐5,6‐dibromohexahydro‐4,7‐methanoisobenzofuran‐1(3H)‐one and (3aR,4S,5S,6R,7R,7aS)‐5,6‐dibromohexahydro‐4,7‐methanoisobenzofuran‐1(3H)‐one ( 5 ). Following the initial analysis of the NMR spectra and the proposed two novel unforeseen products, we have decided to fully analyze the classical and non‐classical assay structures with the aid of computational calculations. Computation to predict the ¹³C and ¹H chemical shifts for mean absolute error analyses have been carried out by gauge‐including atomic orbital method at M06‐2X/6‐31+G(d,p) and B3LYP/6‐311+G(2d,p) levels of theory for all viable conformers. Characterization of the novel unforeseen compounds ( 4 ) and ( 5 ) were not possible by employing only the experimental NMR data; however, a more conclusive structural identification was performed by comparing the experimental and theoretical ¹H and ¹³C chemical shifts by mean absolute error and DP4 probability analyses. Copyright © 2016 John Wiley & Sons, Ltd.     

Addition of Chiral Glycine,Methionine, and Vinylglycine Enolate Derivatives to Aldehydes and Ketones in the Preparation of Enantiomerically Pure α-Amino-β-Hydroxy Acids

Chiral enolates of imidazolidinones and oxazolidinones from the title amino acids react with carbonyl compounds to afford the corresponding alcohols in excellent yields (see Scheme 5). Furthermore, the addition to aldehydes proceeds with high diastereoselectivity to give, after acid hydrolysis, threo-α-amino-β-hydroxy acids of high enantiomeric purity. Some of the threo-α-amino-β-hydroxy acids prepared in this work are the proteinogenic (S)-threonine ( 26 ), the naturally occurring (S)-3-phenylserine ( 28 ), and (S)-3-hydroxyleucine ( 27 ) as well as the unnatural (S)-4,4,4-trifluorothreonine ( 30 ) and (S)-3-(4-pyridyl)serine ( 31 ). The N-methylamide of (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoic acid ( 32 ), the unique amino acid in the immunosuppressive cyclosporine, was prepared by the new method. This report presents also information suggesting that both steric and stereoelectronic effects are responsible for the good stereoselectivities observed.     

Convenient Synthesis of Some Novel Pyridazinone‐Bearing Triazole Moieties

The chemoselective reactions of 2‐(5‐mercapto‐4‐phenyl‐4H‐[1,2,4]triazol‐3‐ylmethyl)‐6‐p‐tolyl‐4,5‐dihydro‐2H‐pyridazin‐3‐one ( 3 ) with different electrophiles were evaluated. Triazole 3 reacted with alkyl halides in the presence of triethylamine in alcohol to give the corresponding S‐substituted derivatives. On the basis of S‐chemoselective reactions of triazole 3 , a series of amino acid 10a – d and dipeptide derivatives 12a – d were prepared via azide coupling of the corresponding hydrazides 9 and 15 with amino acid ester hydrochlorides, respectively. N‐Substituted triazoles 6a – c or 7a – d attached to pyridazin‐3‐one moiety were successfully formed by the reaction of 3 with activated acrylic acid derivatives or with amines. Antibacterial activities of the synthesized derivatives were investigated through correlation with Escherichia coli FabH inhibitory activities using molecular modeling docking software. The antimicrobial activity of synthesized compounds was evaluated, showing best inhibition zone for N‐substituted carboxylic acid 5a and N‐substituted nitrile 5c parallel to the molecular modeling studies.     

Dynamic Kinetic Resolution of 2,3‐Dihydrobenzo[b]furans: Chemoenzymatic Synthesis of Analgesic Agent BRL 37959

An efficient asymmetric synthesis of (S)‐2,3‐dihydrobenzo[b]furan‐3‐carboxylic acid ( 8 a ) and (S)‐5‐chloro‐2,3‐dihydrobenzo[b]furan‐3‐carboxylic acid ( 8 b ) was established. Key to the success was the highly stereoselective enzymatic kinetic resolution of the corresponding methyl or ethyl esters that was further developed into a dynamic process. As a reliable and fast tool for analysing the enantiomeric excess, HPLC coupled with a CD detector was utilized. The route was completed by a Friedel–Crafts acylation of ethyl (S)‐5‐chloro‐2,3‐dihydrobenzo[b]furan‐3‐carboxylate ( 7 c ) followed by saponification leading to (S)‐5‐chloro‐2,3‐dihydrobenzo[b]furan‐3‐carboxylic acid ( 2 ), an analgesic agent.