The absolute configuration of (2S,4S)‐ and (2R,4R)‐2‐tert‐butyl‐4‐methyl‐3‐(4‐tolyl­sulfon­yl)‐1,3‐oxazolidine‐4‐carbaldehyde

The title enanti­omorphic compounds, C₁₆H₂₃NO₄S, have been obtained in an enanti­omerically pure form by crystallization from a diastereomeric mixture either of (2S,4S)‐ and (2R,4S)‐ or of (2R,4R)‐ and (2S,4R)‐2‐tert‐butyl‐4‐methyl‐3‐(4‐tolyl­sulfon­yl)‐1,3‐oxazolidine‐4‐carbaldehyde. These mixtures were prepared by an aziridination rearrangement process starting with (S)‐ or (R)‐2‐tert‐butyl‐5‐methyl‐4H‐1,3‐dioxine. The crystal structures indicate an envelope conformation of the oxazolidine moiety for both compounds.     

1,3‐Oxathiolanes from the Reaction of Aromatic and Enolized Thioketones with Monosubstituted Oxiranes

The reactions of 4,4′‐dimethoxythiobenzophenone ( 1 ) with (S)‐2‐methyloxirane ((S)‐ 2 ) and (R)‐2‐phenyloxirane ((R)‐ 6 ) in the presence of a Lewis acid such as BF₃?Et₂O, ZnCl₂, or SiO₂ in dry CH₂Cl₂ led to the corresponding 1 : 1 adducts, i.e., 1,3‐oxathiolanes (S)‐ 3 with Me at C(5), and (S)‐ 7 and (R)‐ 8 with Ph at C(4) and C(5), respectively. A 1 : 2 adduct, 1,3,6‐dioxathiocane (4S,8S)‐ 4 and 1,3‐dioxolane (S)‐ 9 , respectively, were formed as minor products (Schemes 3 and 5, Tables 1 and 2). Treatment of the 1 : 1 adduct (S)‐ 3 with (S)‐ 2 and BF₃?Et₂O gave the 1 : 2 adduct (4S,8S)‐ 4 (Scheme 4). In the case of the enolized thioketone 1,3‐diphenylprop‐1‐ene‐2‐thiol ( 10 ) with (S)‐ 2 and (R)‐ 6 in the presence of SiO₂, the enesulfanyl alcohols (1′Z,2S)‐ 11 and (1′E,2S)‐ 11 , and (1′Z,2S)‐ 13 , (1′E,2S)‐ 13 , (1′Z,1R)‐ 15 , and (1′E,1R)‐ 15 , respectively, as well as a 1,3‐oxathiolane (S)‐ 14 were formed (Schemes 6 and 8). In the presence of HCl, the enesulfanyl alcohols (1′Z,2S)‐ 11 , (1′Z,2S)‐ 13 , (1′E,2S)‐ 13 , (1′Z,1R)‐ 15 , and (1′E,1R)‐ 15 cyclize to give the corresponding 1,3‐oxathiolanes (S)‐ 12 , (S)‐ 14 , and (R)‐ 16 , respectively (Schemes 7, 9, and 10). The structures of (1′E,2S)‐ 11 , (S)‐ 12 , and (S)‐ 14 were confirmed by X‐ray crystallography (Figs. 1–3). These results show that 1,3‐oxathiolanes can be prepared directly via the Lewis acid‐catalyzed reactions of oxiranes with non‐enolizable thioketones, and also in two steps with enolized thioketones. The nucleophilic attack of the thiocarbonyl or enesulfanyl S‐atom at the Lewis acid‐complexed oxirane ring proceeds with high regio‐ and stereoselectivity via an S_n 2‐type mechanism.     

Chiral Heterospirocyclic 2H‐Azirin‐3‐amines as Synthons for 3‐Amino‐2,3,4,5‐tetrahydrofuran‐3‐carboxylic Acid and Their Use in Peptide Synthesis

The heterospirocyclic N‐methyl‐N‐phenyl‐5‐oxa‐1‐azaspiro[2.4]hept‐1‐e n‐2‐amine (6 ) and N‐(5‐oxa‐1‐azaspiro[2.4]hept‐1‐en‐2‐yl)‐(S)‐proline methyl ester ( 7 ) were synthesized from the corresponding heterocyclic thiocarboxamides 12 and 10 , respectively, by consecutive treatment with COCl₂, 1,4‐diazabicyclo[2.2.2]octane, and NaN₃ (Schemes 1 and 2). The reaction of these 2H‐azirin‐3‐amines with thiobenzoic and benzoic acid gave the racemic benzamides 13 and 14 , and the diastereoisomeric mixtures of the N‐benzoyl dipeptides 15 and 16 , respectively (Scheme 3). The latter were separated chromatographically. The configurations and solid‐state conformations of all six benzamides were determined by X‐ray crystallography. With the aim of examining the use of the new synthons in peptide synthesis, the reactions of 7 with Z‐Leu‐Aib‐OH to yield a tetrapeptide 17 (Scheme 4), and of 6 with Z‐Ala‐OH to give a dipeptide 18 (Scheme 5) were performed. The resulting diastereoisomers were separated by means of MPLC or HPLC. NMR Studies of the solvent dependence of the chemical shifts of the NH resonances indicate the presence of an intramolecular H‐bond in 17 . The dipeptides (S,R)‐ 18 and (S,S)‐ 18 were deprotected at the N‐terminus and were converted to the crystalline derivatives (S,R)‐ 19 and (S,S)‐ 19 , respectively, by reaction with 4‐bromobenzoyl chloride (Scheme 5). Selective hydrolysis of (S,R)‐ 18 and (S,S)‐ 18 gave the dipeptide acids (R,S)‐ 20 and (S,S)‐ 20 , respectively. Coupling of a diastereoisomeric mixture of 20 with H‐Phe‐O^tBu led to the tripeptides 21 (Scheme 5). X‐Ray crystal‐structure determinations of (S,R)‐ 19 and (S,S)‐ 19 allowed the determination of the absolute configurations of all diastereoisomers isolated in this series.     

Asymmetric Syntheses of New Polyhydroxylated Quinolizidines: Cross‐Aldol Reactions of 7‐Oxabicyclo[2.2.1]heptan‐2‐one and 3a,4a,7a,7b‐Tetrahydro[1,3]dioxolo[4,5]furo[2,3‐d]isoxazole‐3‐carbaldehyde Derivatives

The cross‐aldolization of (−)‐(1S,4R,5R,6R)‐6‐endo‐chloro‐5‐exo‐(phenylseleno)‐7‐oxabicyclo[2.2.1]heptan‐2‐one ((−)‐ 25 ) and of (+)‐(3aR,4aR,7aR,7bS)‐ ((+)‐ 26 ) and (−)‐(3aS,4aS,7aS,7bR)‐3a,4a,7a,7b‐tetrahydro‐6,6‐dimethyl[1,3]dioxolo[4,5]furo[2,3‐d]isoxazole‐3‐carbaldehyde ((−)‐ 26 ) was studied for the lithium enolate of (−)‐ 25 and for its trimethylsilyl ether (−)‐ 31 under Mukaiyama's conditions (Scheme 2). Protocols were found for highly diastereoselective condensation giving the four possible aldols (+)‐ 27 (`anti'), (+)‐ 28 (`syn'), 29 (`anti'), and (−)‐ 30 (`syn') resulting from the exclusive exo‐face reaction of the bicyclic lithium enolate of (−)‐ 25 and bicyclic silyl ether (−)‐ 31 . Steric factors can explain the selectivities observed. Aldols (+)‐ 27 , (+)‐ 28 , 29 , and (−)‐ 30 were converted stereoselectively to (+)‐1,4‐anhydro‐3‐{(S)‐[(tert‐butyl)dimethylsilyloxy][(3aR,4aR,7aR,7bS)‐3a,4a,7a,7b‐tetrahydro‐6,6‐dimethyl[1,3]dioxolo[4,5]‐furo[2,3‐d]isoxazol‐3‐yl]methyl}‐3‐deoxy‐2,6‐di‐O‐(methoxymethyl)‐α‐D ‐galactopyranose ((+)‐ 62 ), its epimer at the exocyclic position (+)‐ 70 , (−)‐1,4‐anhydro‐3‐{(S)‐[(tert‐butyl)dimethylsilyloxy][(3aS,4aS,7aS,7bR)‐3a,4a,7a,7b‐tetrahydro‐6,6‐dimethyl[1,3]dioxolo[4,5]furo[2,3‐d]isoxazol‐3‐yl]methyl}‐3‐deoxy‐2,6‐di‐O‐(methoxymethyl)‐α‐D ‐galactopyranose ((−)‐ 77 ), and its epimer at the exocyclic position (+)‐ 84 , respectively (Schemes 3 and 5). Compounds (+)‐ 62 , (−)‐ 77 , and (+)‐ 84 were transformed to (1R,2R,3S,7R,8S,9S,9aS)‐1,3,4,6,7,8,9,9a‐octahydro‐8‐[(1R,2R)‐1,2,3‐trihydroxypropyl]‐2H‐quinolizine‐1,2,3,7,9‐pentol ( 21 ), its (1S,2S,3R,7R,8S,9S,9aR) stereoisomer (−)‐ 22 , and to its (1S,2S,3R,7R,8S,9R,9aR) stereoisomer (+)‐ 23 , respectively (Schemes 6 and 7). The polyhydroxylated quinolizidines (−)‐ 22 and (+)‐ 23 adopt `trans‐azadecalin' structures with chair/chair conformations in which H−C(9a) occupies an axial position anti‐periplanar to the amine lone electron pair. Quinolizidines 21 , (−)‐ 22 , and (+)‐ 23 were tested for their inhibitory activities toward 25 commercially available glycohydrolases. Compound 21 is a weak inhibitor of β‐galactosidase from jack bean, of amyloglucosidase from Aspergillus niger, and of β‐glucosidase from Caldocellum saccharolyticum. Stereoisomers (−)‐ 22 and (+)‐ 23 are weak but more selective inhibitors of β‐galactosidase from jack bean.     

New Optically Active 2H‐Azirin‐3‐amines as Synthons for Enantiomerically Pure 2,2‐Disubstituted Glycines: Synthesis of Synthons for Tyr(2Me) and Dopa(2Me), and Their Incorporation into Dipeptides

The synthesis of novel unsymmetrically 2,2‐disubstituted 2H‐azirin‐3‐amines with chiral auxiliary amino groups is described. Chromatographic separation of the mixture of diastereoisomers yielded (1′R,2S)‐ 2a , b and (1′R,2R)‐ 2a , b (c.f. Scheme 1 and Table 1), which are synthons for (S)‐ and (R)‐2‐methyltyrosine and 2‐methyl‐3′,4′‐dihydroxyphenylalanine. Another new synthon 2c , i.e., a synthon for 2‐(azidomethyl)alanine, was prepared but could not be separated into its pure diastereoisomers. The reaction of 2 with thiobenzoic acid, benzoic acid, and the amino acid Fmoc‐Val‐OH yielded the monothiodiamides 11 , the diamides 12 (cf. Scheme 3 and Table 3), and the dipeptides 13 (cf. Scheme 4 and Table 4), respectively. From 13 , each protecting group was removed selectively under standard conditions (cf. Schemes 5–7 and Tables 5–6). The configuration at C(2) of the amino acid derivatives (1R,1′R)‐ 11a , (1R,1′R)‐ 11b , (1S,1′R)‐ 12b , and (1R,1′R)‐ 12b was determined by X‐ray crystallography relative to the known configuration of the chiral auxiliary group.     

Syntheses of Enantiomerically Pure 2‐Substituted Pyrrolidin‐3‐ones via Lithiated Alkoxyallenes – An Auxiliary‐Based Synthesis of both Enantiomers of the Antibiotic Anisomycin

The hydrochlorides of both enantiomers of the antibiotic anisomycin were prepared starting with the ‘diacetone‐fructose’‐substituted allene 1 and the N‐Boc‐protected imine precursor 2a . Addition of an excess of lithiated 1 to 2a provided a 2 : 1 mixture 3a of diastereoisomers, which were cyclized to 4a under base promotion (Scheme 2). The two diastereoisomers of 4a were separated and converted into enantiomerically pure pyrrolidin‐3‐ones (2R)‐ 5a and (2S)‐ 5a . A similar sequence yielded the N‐Tos‐protected compounds (2R)‐ 5b and (2S)‐ 5b . Compounds 5a were converted into silyl enol ethers 6 and by subsequent regio‐ and stereoselective hydroboration into pyrrolidine derivatives 7 (Scheme 3). Straightforward functional‐group transformations led to the hydrochlorides 9 of anisomycin (Scheme 3). The (2R) series provided the hydrochloride (2R)‐ 9 of the natural occurring enantiomer, whereas the (2S) series furnished the antipode (2S)‐ 9 . The overall sequence to the natural product involved ten steps with eight purified intermediates and afforded an overall yield of 8%. Our stereochemically divergent approach to this type of hydroxylated pyrrolidines is highly flexible and should easily allow preparation of many analogues.     

New Optically Active 2H‐Azirin‐3‐amines as Synthons for Enantiomerically Pure 2,2‐Disubstituted Glycines

The synthesis of novel 2,2‐disubstituted 2H‐azirin‐3‐amines with a chiral amino group is described. Chromatographic separation of the diastereoisomer mixture yielded the pure diastereoisomers (1′R,2R)‐ 4a – e and (1′R,2S)‐ 4a – e (Scheme 1, Table 1), which are synthons for the (R)‐ and (S)‐isomers of isovaline, 2‐methylvaline, 2‐cyclopentylalanine, 2‐methylleucine, and 2‐(methyl)phenylalanine, respectively. The configuration at C(2) of the synthons was determined by X‐ray crystallography relative to the known configuration of the chiral auxiliary group. The reaction of 4 with thiobenzoic acid, benzoic acid, and the dipeptide Z‐Leu‐Aib‐OH ( 12 ) yielded the monothiodiamides 10 , the diamides 11 (Scheme 2, Table 3), and the tripeptides 13 (Scheme 3, Table 4), respectively.     

Metabolism of Deuterated Isomeric 6,7‐Dihydroxydodecanoic Acids in Saccharomyces cerevisiae – Diastereo‐ and Enantioselective Formation and Characterization of 5‐Hydroxydecano‐4‐lactone (=4,5‐Dihydro‐5‐(1‐hydroxyhexyl)furan‐2(3H)‐one) Isomers

The chemical synthesis of deuterated isomeric 6,7‐dihydroxydodecanoic acid methyl esters 1 and the subsequent metabolism of esters 1 and the corresponding acids 1a in liquid cultures of the yeast Saccharomyces cerevisiae was investigated. Incubation experiments with (6R,7R)‐ or (6S,7S)‐6,7‐dihydroxy(6,7‐²H₂)dodecanoic acid methyl ester ((6R,7R)‐ or (6S,7S)‐(6,7‐²H₂)‐ 1 , resp.) and (±)‐threo‐ or (±)‐erythro‐6,7‐dihydroxy(6,7‐²H₂)dodecanoic acid ((±)‐threo‐ or (±)‐erythro‐(6,7‐²H₂)‐ 1a , resp.) elucidated their metabolic pathway in yeast (Tables 1–3). The main products were isomeric ²H‐labeled 5‐hydroxydecano‐4‐lactones 2 . The absolute configuration of the four isomeric lactones 2 was assigned by chemical synthesis via Sharpless asymmetric dihydroxylation and chiral gas chromatography (Lipodex ^® E). The enantiomers of threo‐ 2 were separated without derivatization on Lipodex ^® E; in contrast, the enantiomers of erythro‐ 2 could be separated only after transformation to their 5‐O‐(trifluoroacetyl) derivatives. Biotransformation of the methyl ester (6R,7R)‐(6,7‐²H₂)‐ 1 led to (4R,5R)‐ and (4S,5R)‐(2,5‐²H₂)‐ 2 (ratio ca. 4 : 1; Table 2). Estimation of the label content and position of (4S,5R)‐(2,5‐²H₂)‐ 2 showed 95% label at C(5), 68% label at C(2), and no ²H at C(4) (Table 2). Therefore, oxidation and subsequent reduction with inversion at C(4) of 4,5‐dihydroxydecanoic acid and transfer of ²H from C(4) to C(2) is postulated. The 5‐hydroxydecano‐4‐lactones 2 are of biochemical importance: during the fermentation of Streptomyces griseus, (4S,5R)‐ 2 , known as L‐factor, occurs temporarily before the antibiotic production, and (?)‐muricatacin (=(4R,5R)‐5‐hydroxy‐heptadecano‐4‐lactone), a homologue of (4R,5R)‐ 2 , is an anticancer agent.     

Diastereoselective Electrophilic Amination of Chiral 1‐Benzoyl‐2,3,5,6‐tetrahydro‐3‐methyl‐2‐(1‐methylethyl)pyrimidin‐4(1H)‐one for the Asymmetric Syntheses of α‐Substituted α,β‐Diaminopropanoic Acids

The chiral compounds (R)‐ and (S)‐1‐benzoyl‐2,3,5,6‐tetrahydro‐3‐methyl‐2‐(1‐methylethyl)pyrimidin‐4(1H)‐one ((R)‐ and (S)‐ 1 ), derived from (R)‐ and (S)‐asparagine, respectively, were used as convenient starting materials for the preparation of the enantiomerically pure α‐alkylated (alkyl=Me, Et, Bn) α,β‐diamino acids (R)‐ and (S)‐ 11 – 13 . The chiral lithium enolates of (R)‐ and (S)‐ 1 were first alkylated, and the resulting diasteroisomeric products 5 – 7 were aminated with ‘di(tert‐butyl) azodicarboxylate’ (DBAD), giving rise to the diastereoisomerically pure (≥98%) compounds 8 – 10 . The target compounds (R)‐ and (S)‐ 11 – 13 could then be obtained in good yields and high purities by a hydrolysis/hydrogenolysis/hydrolysis sequence.     

Enantioselective Synthesis of 2‐(2‐Arylcyclopropyl)glycines: Conformationally Restricted Homophenylalanine Analogs

Starting from simple aromatic aldehydes and acetylfuran, (E)‐1‐(furan‐2‐yl)‐3‐arylprop‐2‐en‐1‐ones ( 2 ) were synthesized in high yields. Cyclopropanation of the C?C bond with trimethylsulfoxonium iodide (Me₃SO⁺I^?) furnished (furan‐2‐yl)(2‐arylcyclopropyl)methanones 3 in 90–97% yields. Selective conversion of cyclopropyl ketones to their (E)‐ and (Z)‐oxime ethers 5 and oxazaborolidine‐catalyzed stereoselective reduction of the C?N bond followed by separation of the formed diastereoisomers, furnished (2‐arylcyclopropyl)(furan‐2‐yl)methanamines 6 in optically pure form and high yield. Oxidation of the furan ring of (S,S,S)‐, (S,R,R)‐, (R,S,S)‐, and (R,R,R)‐ 6a afforded the four stereoisomers of α‐(2‐phenylcyclopropyl) glycine ( 1a ).     

Synthesis and Absolute Configuration at C(8) of ‘p‐Menthane‐3,8,9‐triol’ Derived from (–)‐Isopulegol

Two diastereoisomers of the new, potentially insecticidal ‘p‐menthane‐3,8,9‐triol’ (=(2S)‐ and (2R)‐ 2‐[(1R,2R,4R)‐2‐hydroxy‐4‐methylcyclohexyl]propane‐1,2‐diol; (8S)‐ and (8R)‐ 1 ), have been synthesized from (–)‐isopulegol by both conventional dihydroxylation and catalytic Sharpless dihydroxylation (Scheme). The absolute configuration at C(8) of the corresponding orthoformate adduct (8S)‐ 3a was determined by ¹H‐NMR and X‐ray crystallographic analysis (Figure).     

One‐Pot,Asymmetric and Diastereoselective Four‐Component Synthesis of Polyfunctional (Z)‐Alkenyl Methyl Sulfones with Three Stereogenic Centers

The reaction of 1‐(trimethylsilyloxy)cyclopentene ( 9 ) with (±)‐1,3,5‐triisopropyl‐2‐(1‐(RS)‐{[(1E)‐2‐methylpenta‐1,3‐dienyl]oxy}ethyl)benzene ((±)‐ 4a ) in SO₂/CH₂Cl₂ containing (CF₃SO₂)₂NH, followed by treatment with Bu₄NF and MeI gave a 3.0 : 1 mixture of (±)‐(2RS)‐2{(1RS,2Z,4SR)‐2‐methyl‐4‐(methylsulfonyl)‐1‐[(RS)‐1‐(2,4,6‐triisopropylphenyl)ethoxy]pent‐2‐en‐1‐yl}cyclopentanone ((±)‐ 10 ) and (±)‐(2RS)‐2‐{(1RS,2Z)‐2‐methyl‐4‐[(SR)‐methylsulfonyl]‐1‐[(SR)‐1‐(2,4,6‐triisopropylphenyl)ethoxy]pent‐2‐en‐1‐yl}cyclopentanone ((±)‐ 11 ). Similarly, enantiomerically pure dienyl ether (−)‐(1S)‐ 4a reacted with 1‐(trimethylsilyloxy)cyclohexene ( 12 ) to give a 14.1 : 1 mixture of (−)‐(2S)‐2‐{(1S,2Z,4R)‐2‐methyl‐4‐(methylsulfonyl)‐1‐[(S)‐1‐(2,4,6‐triisopropylphenyl)ethoxy]pent‐2‐enyl}cyclohexanone ((−)‐ 13a ) and its diastereoisomer 14a with (1S,2R,4R) or (1R,2S,4S) configuration. Structures of (±)‐ 10 , (±)‐ 11 , and (−)‐ 13a were established by single‐crystal X‐ray crystallography. Poor diastereoselectivities were observed with the (E,E)‐2‐methylpenta‐1,3‐diene‐1‐ylethers (+)‐ 4b and (−)‐ 4c bearing ( 1 S )‐1‐phenylethyl and (1S)‐1‐(pentafluorophenyl)ethyl groups instead of the Greene's auxiliary ((1S)‐(2,4,6‐triisopropylphenyl)ethyl group). The results demonstrate that high α/β‐syn and asymmetric induction (due to the chiral auxiliary) can be obtained in the four‐component syntheses of the β‐alkoxy ketones. The method generates enantiomerically pure polyfunctional methyl sulfones bearing three chiral centers on C‐atoms and one (Z)‐alkene moiety.     

Reaction of Optically Active Oxiranes with Thiofenchone and 1‐Methylpyrrolidine‐2‐thione: Formation of 1,3‐Oxathiolanes and Thiiranes

The SnCl₄‐catalyzed reaction of (?)‐thiofenchone (=1,3,3‐trimethylbicyclo[2.2.1]heptane‐2‐thione; 10 ) with (R)‐2‐phenyloxirane ((R)‐ 11 ) in anhydrous CH₂Cl₂ at ?60° led to two spirocyclic, stereoisomeric 4‐phenyl‐1,3‐oxathiolanes 12 and 13 via a regioselective ring enlargement, in accordance with previously reported reactions of oxiranes with thioketones (Scheme 3). The structure and configuration of the major isomer 12 were determined by X‐ray crystallography. On the other hand, the reaction of 1‐methylpyrrolidine‐2‐thione ( 14a ) with (R)‐ 11 yielded stereoselectively (S)‐2‐phenylthiirane ((S)‐ 15 ) in 56% yield and 87–93% ee, together with 1‐methylpyrrolidin‐2‐one ( 14b ). This transformation occurs via an S_N2‐type attack of the S‐atom at C(2) of the aryl‐substituted oxirane and, therefore, with inversion of the configuration (Scheme 4). The analogous reaction of 14a with (R)‐2‐{[(triphenylmethyl)oxy]methyl}oxirane ((R)‐ 16b ) led to the corresponding (R)‐configured thiirane (R)‐ 17b (Scheme 5); its structure and configuration were also determined by X‐ray crystallography. A mechanism via initial ring opening by attack at C(3) of the alkyl‐substituted oxirane, with retention of the configuration, and subsequent decomposition of the formed 1,3‐oxathiolane with inversion of the configuration is proposed (Scheme 5).     

Asymmetric Reaction of Simple Nitro Compounds with Chiral 1,3‐Oxazolidin‐2‐ones

The chiral oxazolidinone 1 (=[(3aS,6R,7aR)‐tetrahydro‐8,8‐dimethyl‐2‐oxo‐4H‐3a,6‐methano‐1,3‐benzoxazol‐3‐yl](oxo)acetaldehyde) was found to react stereoselectively with simple nitro compounds in the presence of Al₂O₃ or Bu₄NF?3 H₂O (TBAF) as catalysts, affording the diastereoisomeric nitro alcohols 3 – 6 with good asymmetric induction. When Al₂O₃ was used, the (S)‐configuration at the center bearing the OH group was generated, with the relative syn‐configuration for the major diastereoisomers. In the case of the nitro‐aldol reaction catalyzed by TBAF, an opposite asymmetric induction was found for two nitro compounds. In contrast to 1 , compound 12 (=((4R,5S)‐4‐methyl‐2‐oxo‐5‐phenyl‐1,3‐oxazolidin‐3‐yl)(oxo)acetaldehyde), a derivative of Evans auxiliary, gave rise to poor asymmetric induction in Henry reactions.     

Stereoselective Synthesis of 8‐Oxabicyclo[3.2.1]octane‐2,3,4,6,7‐pentols and Total Asymmetric Synthesis of 2,6‐Anhydrohepturonic Acid Derivatives and of β‐C‐manno‐Pyranosides Suitable for the Construction of (1→3)‐C,C‐Linked Trisaccharides

Enantiomerically pure (+)‐(1S,4S,5S,6S)‐6‐endo‐(benzyloxy)‐5‐exo‐{[(tert‐butyl)dimethylsilyl]oxy}‐7‐oxabicyclo[2.2.1]heptan‐2‐one ((+)‐ 5 ) and its enantiomer (−)‐ 5 , obtained readily from the Diels‐Alder addition of furan to 1‐cyanovinyl acetate, can be converted with high stereoselectivity into 8‐oxabicyclo[3.2.1]octane‐2,3,4,6,7‐pentol derivatives (see 23 – 28 in Scheme 2). A precursor of them, (1R,2S,4R,5S,6S,7R,8R)‐7‐endo‐(benzyloxy)‐8‐exo‐hydroxy‐3,9‐dioxatricyclo[4.2.1.0^2,4]non‐5‐endo‐yl benzoate ((−)‐ 19 ), is transformed into (1R,2R,5S, 6S,7R,8S)‐6‐exo,8‐endo‐bis(acetyloxy)‐2‐endo‐(benzyloxy)‐4‐oxo‐3,9‐dioxabicyclo[3.3.1]non‐7‐endo‐yl benzoate ((−)‐ 43 ) (see Scheme 5). The latter is the precursor of several protected 2,6‐anhydrohepturonic acid derivatives such as the diethyl dithioacetal (−)‐ 57 of methyl 3,5‐di‐O‐acetyl‐2,6‐anhydro‐4‐O‐benzoyl‐D ‐glycero‐D ‐galacto‐hepturonate (see Schemes 7 and 8). Hydrolysis of (−)‐ 57 provides methyl 3,5‐di‐O‐acetyl‐2,6‐anhydro‐4‐O‐benzoyl‐D ‐glycero‐D ‐galacto‐hepturonate 48 that undergoes highly diastereoselective Nozaki‐Oshima condensation with the aluminium enolate resulting from the conjugate addition of Me₂AlSPh to (1S,5S,6S,7S)‐7‐endo‐(benzyloxy)‐6‐exo‐{[(tert‐butyl)dimethylsilyl]oxy}‐8‐oxabicyclo[3.2.1]oct‐3‐en‐2‐one ((−)‐ 13 ) derived from (+)‐ 5 (Scheme 12). This generates a β‐C‐mannopyranoside, i.e., methyl (7S)‐3,5‐di‐O‐acetyl‐2,6‐anhydro‐4‐O‐benzoyl‐7‐C‐[(1R,2S,3R,4S,5R,6S,7R)‐6‐endo‐(benzyloxy)‐7‐exo‐{[(tert‐butyl)dimethylsilyl]oxy}‐4‐endo‐hydroxy‐2‐exo‐(phenylthio)‐8‐oxabicyclo[3.2.1]oct‐3‐endo‐yl]‐L ‐glycero‐D ‐manno‐heptonate ((−)‐ 70 ; see Scheme 12), that is converted into the diethyl dithioacetal (−)‐ 75 of methyl 3‐O‐acetyl‐2,6‐anhydro‐4,5‐dideoxy‐4‐C‐{[methyl (7S)‐3,5,7‐tri‐O‐acetyl‐2,6‐anhydro‐4‐O‐benzoyl‐L ‐glycero‐D ‐manno‐heptonate]‐7‐C‐yl}‐5‐C‐(phenylsulfonyl)‐L ‐glycero‐D ‐galacto‐hepturonate ( 76 ; see Scheme 13). Repeating the Nozaki‐Oshima condensation to enone (−)‐ 13 and the aldehyde resulting from hydrolysis of (−)‐ 75 , a (1→3)‐C,C‐linked trisaccharide precursor (−)‐ 77 is obtained.     

Optical Resolution of 5‐Oxo‐1‐Phenyl‐Pyrazolidine‐3‐Carboxylic Acid as a New Organocatalyst for Organic Reactions

Optical resolution of racemic 5‐oxo‐1‐phenyl‐pyrazolidine‐3‐carboxylic acid 2 with L‐amino acid methyl ester via the diastereomers formation was investigated. Treatment of racemic 5‐oxo‐1‐phenyl‐pyrazolidine‐3‐carboxylic acid 2 with L‐valine methyl ester gave diastereomers with a total yield of 86%. The diastereomeric dipeptides can be easily separated by flash column chromatography. Acidic cleavage of the derived diastereomers gave both the optically pure (+)‐(R)‐ and (‐)‐(S)‐5‐oxo‐1‐phenyl‐pyrazolidine‐3‐carboxylic acid ((+)‐(R)‐ 2 and (‐)‐(S)‐ 2 ) with a total yield of 94% and 95%, respectively.     

Regio‐ and Stereoselectivity of the SiO2‐Catalyzed Reaction of Thiocamphor (=1,7,7‐Trimethylbicyclo[2.2.1]heptane‐2‐thione) with Optically Active Monosubstituted Oxiranes

The reactions of the enolizable thioketone (1R,4R)‐thiocamphor (=(1R,4R)‐1,7,7‐trimethylbicyclo[2.2.1]heptane‐2‐thione; 1 ) with (S)‐2‐methyloxirane ( 2 ) in the presence of a Lewis acid such as SnCl₄ or SiO₂ in anhydrous CH₂Cl₂ led to two diastereoisomeric spirocyclic 1,3‐oxathiolanes 3 and 4 with the Me group at C(5′), as well as the isomeric β‐hydroxy thioether 5 (Scheme 2). The analogous reactions of 1 with (RS)‐, (R)‐, and (S)‐2‐phenyloxirane ( 7 ) yielded two isomeric spirocyclic 1,3‐oxathiolanes 8 and 9 with Ph at C(4′), an additional isomer 13 bearing the Ph group at C(5′), and three isomeric β‐hydroxy thioethers 10, 11 , and 12 (Scheme 4). In the presence of HCl, the β‐hydroxy thioethers 5, 10, 11 , and 12 isomerized to the corresponding 1,3‐oxathiolanes 3 and 4 (Scheme 3), and 8, 9 , and 13 , respectively (Scheme 5). Under similar conditions, an epimerization of 3, 8 , and 9 occurred to yield the corresponding diastereoisomers 4, 14 , and 15 , respectively (Schemes 3 and 6). The structures of 9 and 15 were confirmed by X‐ray crystallography (Figs. 1 and 2). These results show that the Lewis acid‐catalyzed addition of oxiranes to enolizable thioketones proceeds with high regio‐ and stereoselectivity via an S_n 2‐type mechanism.     

Ring Enlargement and Sulfur‐Transfer Processes in SiO2‐Catalyzed Reactions of Thiocarbonyl Compounds with Optically Active Oxiranes

The reactions of 1,3‐dioxolane‐2‐thione ( 3 ) with (S)‐2‐methyloxirane ((S)‐ 1 ) and with (R)‐2‐phenyloxirane ((R)‐ 2 ) in the presence of SiO₂ in anhydrous dichloroalkanes led to the optically active spirocyclic 1,3‐oxathiolanes 8 with Me at C(7) and 9 with Ph at C(8), respectively (Schemes 2 and 3). The analogous reaction of 1,3‐dimethylimidazolidine‐2‐thione ( 4a ) with (R)‐ 2 yielded stereoselectively (S)‐2‐phenylthiirane ((S)‐ 10 ) in 83% yield and 97% ee together with 1,3‐dimethylimidazolidin‐2‐one ( 11a ). In the cases of 3‐phenyloxazolidine‐2‐thione ( 4b ) and 3‐phenylthiazolidine‐2‐thione ( 4c ), the reaction with (RS)‐ 2 yielded the racemic thiirane (RS)‐ 10 , and the corresponding carbonyl compounds 11b and 11c (Scheme 4 and Table 1). The analogous reaction of 4a with 1,2‐epoxycyclohexane (= 7‐oxabicyclo[4.1.0]heptane; 7 ) afforded thiirane 12 and the corresponding carbonyl compound 11a (Scheme 5). On the other hand, the BF₃‐catalyzed reaction of imidazolidine‐2‐thione ( 5 ) with (RS)‐ 2 yielded the imidazolidine‐2‐thione derivative 13 almost quantitatively (Scheme 6). In a refluxing xylene solution, 1,3‐diacetylimidazolidine‐2‐thione ( 6 ) and (RS)‐ 2 reacted to give two imidazolidine‐2‐thione derivatives, 13 and 14 (Scheme 7). The structures of 13 and 14 were established by X‐ray crystallography (Fig.).     

The diastereoisomers methyl 5‐(S)‐[2‐(R)/(S)‐methoxycarbonyl)‐2,3,4,5‐tetrahydropyrrol‐1‐ylcarbonyl]‐1‐(4‐methylphenyl)‐4,5‐dihydropyrazole‐3‐carboxylate

The title diastereoisomers, methyl 5‐(S)‐[2‐(S)‐methoxy­carbonyl)‐2,3,4,5‐tetra­hydro­pyrrol‐1‐yl­carbonyl]‐1‐(4‐methyl­phenyl)‐4,5‐di­hydro­pyrazole‐3‐carboxyl­ate and methyl 5‐(S)‐[2‐(R)‐methoxycarbonyl)‐2,3,4,5‐tetrahydropyrrol‐1‐ylcarbonyl]‐1‐(4‐methyl­phenyl)‐4,5‐di­hydro­pyrazole‐3‐carboxylate, both C₁₉H₂₃N₃O₅, have been studied in two crystalline forms. The first form, methyl 5‐(S)‐[2‐(S)‐methoxy­carbonyl)‐2,3,4,5‐tetrahydropyrrol‐1‐ylcarbonyl]‐1‐(4‐methylphenyl)‐4,5‐di­hydro­pyrazole‐3‐carboxyl­ate–methyl 5‐(S)‐[2‐(R)‐methoxy­carbonyl)‐2,3,4,5‐tetra­hydro­pyrrol‐1‐yl­carbonyl]‐1‐(4‐methylphenyl)‐4,5‐dihydropyrazole‐3‐carboxylate (1/1), 2(S),5(S)‐C₁₉H₂₃N₃O₅·2(R),5(S)‐C₁₉H₂₃N₃O₅, contains both S,S and S,R isomers, while the second, methyl 5‐(S)‐[2‐(S)‐methoxycarbonyl)‐2,3,4,5‐tetrahydro­pyrrol‐1‐ylcarbonyl]‐1‐(4‐methyl­phenyl)‐4,5‐di­hydro­pyrazole‐3‐carboxyl­ate, 2(S),5(S)‐C₁₉H₂₃N₃O₅, is the pure S,S isomer. The S,S isomers in the two structures show very similar geometries, the maximum difference being about 15° on one torsion angle. The differences between the S,S and S,R isomers, apart from those due to the inversion of one chiral centre, are more remarkable, and are partially due to a possible rotational disorder of the 2‐­(methoxycarbonyl)tetrahydropyrrole group.     

One pot diastereoselective synthesis of new chiral spiro‐1,3,4‐thiadiazoles and 1,4,2‐oxathiazoles from (1R)‐thiocamphor

Herein we report an efficient one pot synthesis of new chiral 4,5‐dihydro‐4‐arylspiro[1,3,4‐thiadiazole]‐5,2′‐camphane‐2‐carboxylic acid ethyl esters 5–7 and 4,5‐dihydro‐3‐arylspiro[1,4,2‐oxathiazole]‐5,2′‐camphane 11–13 , using 1,3‐dipolar cycloaddition of nitrilimines 2–4 and nitrile oxides 8–10 to (1R)‐thiocamphor 1 respectively. The structure of the newly prepared 1,3,4‐thiadiazoles 5–7 (obtained as pure diastereoisomers) were fully established via spectroscopic analysis and X‐ray structural analysis which proved the absolute configuration of the C5 spiranic carbon to be (R). NMR spectral analysis were also very useful to show the new 1,4,2‐oxathiazoles 11–13 are mixtures of two (5R)/(5S) diastereoisomers with the ratio 6:4,7:3 and 6:4 respectively.