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.).     

Asymmetric Hydroformylation of Vinylfurans Catalyzed by {(11bS)‐4‐{[(1R)‐2′‐Phosphino[1,1′‐binaphthalen]‐2‐yl]oxy}dinaphtho[2,1‐d:1′,2′‐f]‐ [1,3,2]dioxaphosphepin}rhodium(I) [RhI{(R,S)‐binaphos}] Derivatives

The asymmetric hydroformylation of 2‐ and 3‐vinylfurans ( 2a and 2b , resp.) was investigated by using [Rh{(R,S)‐binaphos}] complexes as catalysts ((R,S)‐binaphos = (11bS)‐4‐{[1R)‐2′‐phosphino[1,1′‐binaphthalen]‐2‐yl]oxy}dinaphtho[2,1‐d:1′,2′‐f][1,3,2]dioxaphosphepin; 1 ). Hydroformylation of 2 gave isoaldehydes 3 in high regio‐ and enantioselectivities (Scheme 2 and Table). Reduction of the aldehydes 3 with NaBH₄ successfully afforded the corresponding alcohols 5 without loss of enantiomeric purity (Scheme 3).     

Study on the Mechanism of Formation of 1‐Methylheptyl Phenyl Ether by the Isourea Method

The formation of (1R)‐1‐methylheptyl phenyl ether from (2S)‐octan‐2‐ol via its isourea derivative (S)‐ 1 follows a borderline mechanism. The intermediacy of a carbocation (see (S)‐ 2 ) can be demonstrated (Scheme 1). However, the extremely high inversion of configuration and the olefinic by‐products are also indicative of an S_N2 mechanism.     

Synthesis of the Spermidine Alkaloids (−)‐(2R,3R)‐ and (−)‐(2R,3S)‐3‐Hydroxycelacinnine: Macrocyclization with Oxirane‐Ring Opening and Inversion via Cyclic Sulfamidates

The two epimers (?)‐ 1a and (?)‐ 1b of the macrocyclic lactam alkaloid 3‐hydroxycelacinnine with the (2R,3R) and (2R,3S) absolute configurations, respectively, were synthesized by an alternative route involving macrocyclization with the regio‐ and stereoselective oxirane‐ring opening by the terminal amino group (Schemes 2 and 6). Properly N‐protected chiral trans‐oxirane precursors provided (2R,3R)‐macrocycles after a one‐pot deprotection‐macrocyclization step under moderate dilution (0.005–0.01M ). The best yields (65–85%) were achieved with trifluoroacetyl protection. Macrocyclization of the corresponding cis‐oxiranes was unsuccessful for steric reasons. Inversion at OH? C(3) via nucleophilic displacement of the cyclic sulfamidate derivative with NaNO₂ led to (2R,3S)‐macrocycles. The synthesized (?)‐(2R,3S)‐3‐hydroxycelacinnine ((?)‐ 1b ) was identical to the natural alkaloid.     

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.     

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.     

Stereoselective Synthesis of [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐D‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐L‐valine]cyclosporin A

Addition of various amines to the 3,3‐bis(trifluoromethyl)acrylamides 10a and 10b gave the tripeptides 11a – 11f , mostly as mixtures of epimers (Scheme 3). The crystalline tripeptide 11f ₂ was found to be the N‐terminal (2‐hydroxyethoxy)‐substituted (R,S,S)‐ester HOCH₂CH₂O‐D ‐Val(F₆)‐MeLeu‐Ala‐O^tBu by X‐ray crystallography. The C‐terminal‐protected tripeptide 11f ₂ was condensed with the N‐terminus octapeptide 2b to the depsipeptide 12a which was thermally rearranged to the undecapeptide 13a (Scheme 4). The condensation of the epimeric tripeptide 11f ₁ with the octapeptide 2b gave the undecapeptide 13b directly. The undecapeptides 13a and 13b were fully deprotected and cyclized to the [5‐[4,4,4,4′,4′,4′‐hexafluoro‐N‐(2‐hydroxyethoxy)‐D ‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐hexafluoro‐N‐(2‐hydroxyethoxy)‐L ‐valine]]cyclosporins 14a and 14b , respectively (Scheme 5). Rate differences observed for the thermal rearrangements of 12a to 13a and of 12b to 13b are discussed.     

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.     

Naphthyl Groups in Chiral Recognition: Structures of Salts and Esters of 2‐Methoxy‐2‐naphthylpropanoic Acids

The crystal structures of salt 8 , which was prepared from (R)‐2‐methoxy‐2‐(2‐naphthyl)propanoic acid ((R)‐MβNP acid, (R)‐ 2 ) and (R)‐1‐phenylethylamine ((R)‐PEA, (R)‐ 6 ), and salt 9 , which was prepared from (R)‐2‐methoxy‐2‐(1‐naphthyl)propanoic acid ((R)‐MαNP acid, (R)‐ 1 ) and (R)‐1‐(p‐tolyl)ethylamine ((R)‐TEA, (R)‐ 7 ), were determined by X‐ray crystallography. The MβNP and MαNP anions formed ion‐pairs with the PEA and TEA cations, respectively, through a methoxy‐group‐assisted salt bridge and aromatic CH???π interactions. The networks of salt bridges formed 2₁ columns in both salts. Finally, (S)‐(2E,6E)‐(1‐²H₁)farnesol ((S)‐ 13 ) was prepared from the reaction of (2E,6E)‐farnesal ( 11 ) with deuterated (R)‐BINAL‐H (i.e., (R)‐BINAL‐D). The enantiomeric excess of compound (S)‐ 13 was determined by NMR analysis of (S)‐MαNP ester 14 . The solution‐state structures of MαNP esters that were prepared from primary alcohols were also elucidated.     

Regio‐ and Stereoselective 1,3‐Oxathiolane Formation in the Reaction of Thiolactones with Optically Active Oxiranes

The reactions of 3H‐isobenzofuran‐1‐thione ( 1 ) with (S)‐2‐methyloxirane ( 2 ) and (R)‐2‐phenyloxirane ( 6 ) in the presence of SiO₂ in anhydrous CH₂Cl₂ led to two pairs of diastereoisomeric spirocyclic 1,3‐oxathiolanes, i.e., 3 and 4 with a Me group at C(5′), and 7 and 8 with a Ph group at C(4′), respectively (Schemes 2 and 3). In both cases, 3H‐isobenzofuran‐1‐one ( 5 ) was formed as a main product. The analogous reactions of 3,4‐dihydro‐2H‐[1]benzopyran‐2‐thione ( 9 ) and 3,4,5,6‐tetrahydro‐2H‐pyran‐2‐thione ( 14 ) with 2 and 6 yielded four pairs of the corresponding diastereoisomeric spirocyclic compounds 10 and 11, 12 and 13, 15 and 16 , and 18 and 19 , respectively (Schemes 4–7). In the reaction of 14 with 6 , the 1,3‐oxathiolane 20 with a Ph group at C(2) was also formed. The structures of 3, 7, 8, 10, 19 , and 20 were established by X‐ray crystallography (Figs. 1–4). In contrast to the thiolactones 1, 9 , and 14 , the thioesters 21a – 21d did not react with (R)‐2‐phenyloxirane ( 6 ) either in the presence of SiO₂ or under more‐drastic conditions with BF₃?Et₂O or SnCl₄ (Scheme 8). The results show that spirocyclic 1,3‐oxathiolanes can be prepared from thiolactones with oxiranes. The nucleophilic attack of the thiocarbonyl S‐atom at the SiO₂‐activated oxirane ring proceeds with high regio‐ and stereoselectivity via an S_N2‐type mechanism.     

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.     

Efficient Synthesis of (−)‐(R)‐Muscone by Enantioselective Protonation

A new synthesis of (?)‐(R)‐muscone ((R)‐ 1 ) by means of enantioselective protonation of a bicyclic ketone enolate as the key step (see 6 →(S)‐ 4 in Scheme 2) is presented. The C₁₅ macrocyclic system is obtained by ozonolysis (Scheme 7).     

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.     

Thermal [2+3]‐Cycloadditions of trans‐1‐Methyl‐2,3‐diphenylaziridine with CS and CC Dipolarophiles: An Unexpected Course with Dimethyl Dicyanofumarate

The thermal reaction of trans‐1‐methyl‐2,3‐diphenylaziridine (trans‐ 1a ) with aromatic and cycloaliphatic thioketones 2 in boiling toluene yielded the corresponding cis‐2,4‐diphenyl‐1,3‐thiazolidines cis‐ 4 via conrotatory ring opening of trans‐ 1a and a concerted [2+3]‐cycloaddition of the intermediate (E,E)‐configured azomethine ylide 3a (Scheme 1). The analogous reaction of cis‐ 1a with dimethyl acetylenedicarboxylate ( 5 ) gave dimethyl trans‐2,5‐dihydro‐1‐methyl‐2,5‐diphenylpyrrole‐3,4‐dicarboxylate (trans‐ 6 ) in accord with orbital‐symmetry‐controlled reactions (Scheme 2). On the other hand, the reactions of cis‐ 1a and trans‐ 1a with dimethyl dicyanofumarate ( 7a ), as well as that of cis‐ 1a and dimethyl dicyanomaleate ( 7b ), led to mixtures of the same two stereoisomeric dimethyl 3,4‐dicyano‐1‐methyl‐2,5‐diphenylpyrrolidine‐3,4‐dicarboxylates 8a and 8b (Scheme 3). This result has to be explained via a stepwise reaction mechanism, in which the intermediate zwitterions 11a and 11b equilibrate (Scheme 6). In contrast, cis‐1,2,3‐triphenylaziridine (cis‐ 1b ) and 7a gave only one stereoisomeric pyrrolidine‐3,4‐dicarboxylate 10 , with the configuration expected on the basis of orbital‐symmetry control, i.e., via concerted reaction steps (Scheme 10). The configuration of 8a and 10 , as well as that of a derivative of 8b , were established by X‐ray crystallography.     

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.     

Synthesis and Optical Resolution of the Floral Odorant (±)‐2,3‐Dihydro‐2,5‐dimethyl‐1H‐indene‐2‐methanol,and Preparation of Analogues

The title compound (±)‐ 1 , a recently discovered, valuable, floral‐type odorant, has been synthesized by a straightforward procedure (Scheme 1). To determine the properties of the enantiomers of 1 , their separation by preparative HPLC and the determination of their absolute configuration by X‐ray crystallography were carried out (Figure). Furthermore, the analogues 2 – 6 were synthesized, either from differently methylated 2‐methylindan‐1‐ones (Schemes 2 and 3) or, in the case of the 2,4,6‐trimethylated homologue 6 , by a completely different synthetic approach (Scheme 4). An evaluation of (+)‐(S)‐ 1 , (−)‐(R)‐ 1 , and (±)‐ 1 showed only minor differences in terms of odor (Table).     

Metabolism of Deuterated threo‐Dihydroxy Fatty Acids in Saccharomyces cerevisiae: Enantioselective Formation and Characterization of Hydroxylactones and γ‐Lactones

Biotransformation of (±)‐threo‐7,8‐dihydroxy(7,8‐²H₂)tetradecanoic acids (threo‐(7,8‐²H₂)‐ 3 ) in Saccharomyces cerevisiae afforded 5,6‐dihydroxy(5,6‐²H₂)dodecanoic acids (threo‐(5,6‐²H₂)‐ 4 ), which were converted to (5S,6S)‐6‐hydroxy(5,6‐²H₂)dodecano‐5‐lactone ((5S,6S)‐(5,6‐²H₂)‐ 7 ) with 80% e.e. and (5S,6S)‐5‐hydroxy(5,6‐²H₂)dodecano‐6‐lactone ((5S,6S)‐5,6‐²H₂)‐ 8 ). Further β‐oxidation of threo‐(5,6‐²H₂)‐ 4 yielded 3,4‐dihydroxy(3,4‐²H₂)decanoic acids (threo‐(3,4‐²H₂)‐ 5 ), which were converted to (3R,4R)‐3‐hydroxy(3,4‐²H₂)decano‐4‐lactone ((3R,4R)‐ 9 ) with 44% e.e. and converted to ²H‐labeled decano‐4‐lactones ((4R)‐(3‐²H₁)‐ and (4R)‐(2,3‐²H₂)‐ 6 ) with 96% e.e. These results were confirmed by experiments in which (±)‐threo‐3,4‐dihydroxy(3,4‐²H₂)decanoic acids (threo‐(3,4‐²H₂)‐ 5 ) were incubated with yeast. From incubations of methyl (5S,6S)‐ and (5R,6R)‐5,6‐dihydroxy(5,6‐²H₂)dodecanoates ((5S,6S)‐ and (5R,6R)‐(5,6‐²H₂)‐ 4a ), the (5S,6S)‐enantiomer was identified as the precursor of (4R)‐(3‐²H₁)‐ and (2,3‐²H₂)‐ 6 ). Therefore, (4R)‐ 6 is synthesized from (3S,4S)‐ 5 by an oxidation/keto acid reduction pathway involving hydrogen transfer from C(4) to C(2). In an analogous experiment, methyl (9S,10S)‐9,10‐dihydroxyoctadecanoate ((9S,10S)‐ 10a ) was metabolized to (3S,4S)‐3,4‐dihydroxydodecanoic acid ((3S,4S)‐ 15 ) and converted to (4R)‐dodecano‐4‐lactone ((4R)‐ 18 ).     

Regio‐ and Stereoselectivity in the Lewis Acid‐ and NaH‐Induced Reactions of Thiocamphor with (R)‐2‐Vinyloxirane

The reaction of the enolizable thioketone (1R,4R)‐thiocamphor (= (1R,4R)‐1,7,7‐trimethylbicyclo[2.2.1]heptane‐2‐thione; 1 ) with (R)‐2‐vinyloxirane ( 2 ) in the presence of a Lewis acid such as SnCl₄ or SiO₂ in anhydrous CH₂Cl₂ gave the spirocyclic 1,3‐oxathiolane 3 with the vinyl group at C(4′), as well as the isomeric enesulfanyl alcohol 4 . In the case of SnCl₄, an allylic alcohol 5 was obtained in low yield in addition to 3 and 4 (Scheme 2). Repetition of the reaction in the presence of ZnCl₂ yielded two diastereoisomeric 4‐vinyl‐1,3‐oxathiolanes 3 and 7 together with an alcohol 4 , and a ‘1 : 2 adduct’ 8 (Scheme 3). The reaction of 1 and 2 in the presence of NaH afforded regioselectively two enesulfanyl alcohols 4 and 9 , which, in CDCl₃, cyclized smoothly to give the corresponding spirocyclic 1,3‐oxathiolanes 3, 10 , and 11 , respectively (Scheme 4). In the presence of HCl, epimerization of 3 and 10 occurred to yield the corresponding epimers 7 and 11 , respectively (Scheme 5). The thio‐Claisen rearrangement of 4 in boiling mesitylene led to the allylic alcohol 12 , and the analogous [3,3]‐sigmatropic rearrangement of the intermediate xanthate 13 , which was formed by treatment of the allylic alcohol 9 with CS₂ and MeI under basic conditions, occurred already at room temperature to give the dithiocarbonate 14 (Schemes 6 and 7). The presented results show that the Lewis acid‐catalyzed as well as the NaH‐induced addition of (R)‐vinyloxirane ( 2 ) to the enolizable thiocamphor ( 1 ) proceeds stereoselectively via an S_N2‐type mechanism, but with different regioselectivity.     

The Absolute Configuration of (+)‐Ethyl cis‐1‐Benzyl‐3‐hydroxypiperidine‐4‐carboxylate and (+)‐4‐Ethyl 1‐Methyl cis‐3‐Hydroxypiperidine‐1,4‐dicarboxylate; a Revision

Discrepancies between chiroptical data from the literature and our determination of the structure of the title compounds (+)‐ 5 and (+)‐ 9a were resolved by an unambiguous assignment of their absolute configuration. Accordingly, the dextrorotatory cis‐3‐hydroxy esters have (3R,4R)‐ and the laevorotatory enantiomers (3S,4S)‐configuration. The final evidences were demonstrated on both enantiomers (+)‐ and (?)‐ 5 by biological reduction of 4 by bakers' yeast and stereoselective [Ru^II(binap)]‐catalyzed hydrogenations of 4 (Scheme 2), by the application of the NMR Mosher method on (+)‐ and (?)‐ 5 (Scheme 3), as well as by the transformation of (+)‐ 5 into a common derivative and chiroptical correlation (Scheme 4).     

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.