Chiral building-blocks by chemoenzymatic desymmetrization of 2-ethyl-1,3-propanediol for the preparation of biologically active natural products

2-Ethyl-1,3-propanediol 1 and its related di-O-acetate 2 were desymmetrized by partial chemoenzymatic acetylation and deacetylation, by Pseudomonas fluorescens lipase (Amano P.; PFL), to (R)-1-O-acetyl-2-ethyl-1,3-propanediol 3. On treatment of 3 with I₂/Ph₃P/imidazole the related (S)-1-O-acetyl-2-ethyl-3-iodopropanol 4 was obtained and transformed into the corresponding triphenylphosphonium salt 5. Reaction of [(S)-3-acetoxy-2-ethylpropylidene]triphenylphosphorane 6, prepared from 5, with 2,3:4,5-di-O-isopropylidene-β-d-arabino-hexos-2-ulopyranose 7 gave (Z)-3-C-acetoxymethyl-1,2,3,4,5-pentadeoxy-6,7:8,9-di-O-isopropylidene-β-d-manno-dec-4-ene-6-ulo-6,10-pyranose 8 which was hydrogenated to 9 and subsequently deacylated to 10. Treatment of 10 with Me₂CO/H⁺ caused a rearrangement to (3R,4R,5S,6R,9R)-9-ethyl-5-hydroxy-3,4-isopropylidenedioxy-1,7-dioxaspiro[5.5]undecane 11, which closely matched the skeleton of the talaromycins.     

Enzymatic desymmetrization of 2-amino-2-methyl-1,3-propanediol: asymmetric synthesis of (S)-N-Boc-N,O-isopropylidene-α-methylserinal and (4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one

We report herein, the novel enzymatic desymmetrization of 2-tert-butoxycarbonylamino-2-methyl-1,3-propanediol 1. This method makes it possible to prepare (S)-N-Boc-N,O-isopropylidene-α-methylserinal 3, which is a chiral building block for the synthesis of a variety of α-substituted alanine derivatives. Moreover, optically active (4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one 4, one of the key intermediates in the synthesis of a novel immunosuppressant, has been prepared by this methodology.     

Synthesis and ring opening reactions of 2-glyco-1,4-dimethyl-3-nitro-7-oxabicyclo[2.2.1]hept-5-enes

The high-pressure asymmetric Diels-Alder reactions of d-galacto- (1a) and d-manno-3,4,5,6,7-penta-O-acetyl-1,2-dideoxy-1-nitrohept-1-enitol (1b) with 2,5-dimethylfuran (2) afforded mixtures of cycloadducts, from which the (2S,3R)-3-exo-nitro (3a and 3b), (2R,3S)-3-exo-nitro (4a and 4b), and (2R,3S)-1′,2′,3′,4′,5′-penta-O-acetyl-1′-C-(1,4-dimethyl-3-endo-nitro-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl)-d-galacto-pentitol (5b) were isolated pure. Deacetylation of these compounds led to new chiral mono-, bi-, and tricyclic ethers, being their asymmetric centers arising from the chiral inductor used in the cycloaddition reaction. A ring opening mechanism through a 1-nitro-1,3-cyclohexadiene intermediate has been proposed.     

Polyhydroxylated pyrrolidines, III. Synthesis of new protected 2,5-dideoxy-2,5-iminohexitols from d-fructose

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-β-d-fructopyranose (6) was straightforwardly transformed into 5-azido-3-O-benzoyl-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (8), after treatment under modified Garegg's conditions followed by reaction of the resulting 3-O-benzoyl-4-O-benzyl-5-deoxy-5-iodo-1,2-O-isopropylidene-α-l-sorbopyranose (7) with lithium azide in DMF. O-debenzoylation at C(3) in 8, followed by oxidation and reduction caused the inversion of the configuration to afford the corresponding β-d-psicopyranose derivative 11 that was transformed into the related 3,4-di-O-benzyl derivative 12. Cleavage of the acetonide of 12 to give 13 followed by O-tert-butyldiphenylsilylation afforded a resolvable mixture of 14 and 15. Compound 14 was transformed into (2R,3R,4S,5R)- (17) and (2R,3R,4S,5S)-3,4-dibenzyloxy-2′,5′-di-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (18) either by a tandem Staudinger/intramolecular aza-Wittig process and reduction of the resulting intermediate Δ²-pyrroline (16), or only into 18 by a high stereoselective catalytic hydrogenation. When 15 was subjected to the same protocol, (2S,3S,4R,5R)- (21) and (2R,3S,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (22) were obtained, respectively.     

Synthesis and epimerization of 10-N-(6-deoxy-1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl)-(11aS)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione

The reaction of the 1,2:3,4-di-O-isopropylidene-6-O-tosyl-α-d-galactopyranose 2 with (11aS)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione 1, prepared from l-proline and isatoic anhydride, gave two products which were previously reported as conformational isomers. In this work, an X-ray crystallographic study showed these to be the diastereomeric pair (11aS)- and (11aR)-10-N-(6-deoxy-1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-diones as a consequence of C(11a) epimerization in the benzodiazepine moiety during glycosylation under basic reaction conditions. The hydrosolubility of the deprotected products were compared with those of the analogous benzodiazepine derivatives.     

Studies on the Michael addition of naphthoquinones to sugar nitro olefins: first synthesis of polyhydroxylated hexahydro-11H-benzo[a]carbazole-5,6-diones and hexahydro-11bH-benzo[b]carbazole-6,11-diones

A strategy for the synthesis of the novel (6bR,7R,8S,9S,10S,10aR)-8-(benzyloxy)-7,9,10-trihydroxy-6b,7,8,9,10,10a-hexahydro-11H-benzo[a]carbazole-5,6-dione is reported. The key steps were the Michael addition of 2-hydroxy-1,4-naphthoquinone to 1-nitrocyclohexene or 3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-nitro-α-d-xylo-hex-5-enefuranose and the diastereoselective intramolecular Henry reaction of 3-O-benzyl-5,6-dideoxy-5-C-(3′-hydroxy-1′,4′-naphthoquinon-2′-yl)-1,2-O-isopropylidene-6-nitro-α-d-glucofuranose to give the key (1S,2S,3S,4R,5R,6R)-3-(benzyloxy)-1,2,4-trihydroxy-5-(3′-hydroxy-1′,4′-naphthoquinon-2′-yl)-6-nitrocyclohexane. When 2-hydroxy-1,4-naphthoquinone was replaced by (1,4-dimethoxynaphthalen-2-yl)lithium, the novel (1R,2S,3S,4R,4aS,11bS)-2-(benzyloxy)-1,3,4-trihydroxy-1,2,3,4,4a,5-hexahydro-11bH-benzo[b]carbazole-6,11-dione was obtained.     

Highly enantioselective preparation of C2-symmetrical diols: microbial hydrolysis of cyclic carbonates

A new type of microbial enantioselective hydrolysis of C₂-symmetrical cyclic carbonates is disclosed. During the screening test of the five-membered substrate (4,5-dimethyl-1,3-dioxolan-2-one 5), Pseudomonas diminuta was selected as the best strain to perform the stereoselective hydrolysis. The reaction of dl-5 with this microorganism in aqueous media containing THF as the co-solvent afforded (S,S)-5 and (R,R)-butanediol 1 in excellent yields. It was found that the ring size did not affect the reactivity and enantioselectivity although the enzyme had a high substrate specificity for the side chain. A six-membered cyclic carbonate, dl-4,6-dimethyl-1,3-dioxan-2-one 6, was smoothly hydrolyzed with higher enantioselectivity to afford the optically active (S,S)-6 and (R,R)-2,4-pentanediol 2.     

Synthesis of enantiomerically pure diethyl (R)- and (S)-2-hydroxy-3-(1,2,3-triazol-1-yl)propylphosphonates

The synthesis and ee determination of diethyl 3-azido-2-hydroxypropylphosphonates from 2,3-epoxypropylphosphonates have been optimised. Enantiomerically enriched diethyl (R)- and (S)-2-hydroxy-3-(1,2,3-triazol-1-yl)propylphosphonates (R)-3a–j and (S)-3a–h as well as (S)-3j were synthesised from diethyl (R)- and (S)-2,3-epoxypropylphosphonates in a reaction sequence including azidolysis followed by 1,3-dipolar cycloaddition with selected alkynes.     

(3R,4S)-3,4,5-Trihydroxy-4-methylpentylphosphonic acid, an isosteric phosphonate analogue of 2-C-methyl-d-erythritol 4-phosphate, a key intermediate in the new pathway for isoprenoid biosynthesis

2-C-Methyl-d-erythritol 4-phosphate (MEP) is the first intermediate in the mevalonate-independent pathway for isoprenoid biosynthesis presenting the branched C₅ isoprene skeleton. Enantiopure (3R,4S)-3,4,5-trihydroxy-4-methylpentylphosphonic acid (MEP_N), an isosteric phosphonate analogue of MEP was synthesized from 1,2-O-isopropylidene-α-d-xylofuranose.     

Synthesis of 3 or 3,3′-substituted BINOL ligands and their application in the asymmetric addition of diethylzinc to aromatic aldehydes

Three new substituted BINOL ligands (R)-3-[4,6-bis(dimethylamino)-1,3,5-triazin-2-yl]-1,1′-bi-2-naphthol (R)-1, (R)-3,3′-bis[4,6-bis(dimethylamino)-1,3,5-triazin-2-yl]-1,1′-bi-2-naphthol (R)-2 and 2,4-bis(2,2′-dihydroxy-1,1′-binaphthalen-3-yl)-6-(p-tolyl)-1,3,5-triazine (R,R)-3 have been obtained by directed ortho-lithiation or Suzuki cross-coupling process. Ligand (R)-1 shows improved catalytic properties for the asymmetric diethylzinc addition to aromatic aldehydes.     

Asymmetric C–C bond forming reactions with chiral crown catalysts derived from d-glucose and d-galactose

New chiral monoaza-15-crown-5 derivatives anellated to methyl-4,6-O-benzylidene-α-d-glucopyranoside 2a, 2e, 2g–i and to methyl-4,6-O-benzylidene-α-d-galactopyranoside 3a, 3e, 3i have been synthesized. These crown ethers showed significant asymmetric induction as phase transfer catalysts in the Michael addition of 2-nitropropane to chalcone (87% ee), in the Darzens condensation of phenacyl chloride with benzaldehyde (71% ee) and in the self-condensation of phenacyl chloride (64% ee) to give 14. The absolute configurations of (−)-(2R,3S)-epoxy-3-(4-chlorophenyl)-1-phenyl-1-propanone 12 and (−)-4-chloro-(2R,3S)-epoxy-1,3-diphenyl-1-butanone 14 have also been determined by X-ray diffraction.     

Synthesis of a variety of optically active hydroxylated heterocyclic compounds using epoxide hydrolase technology

Novel epoxide hydrolases in Yarrowia lipolytica have been shown to hydrolyse a variety of functionalised epoxides with good to excellent stereoselectivity and at high volumetric productivities. Individual biotransformation products have been converted into optically active (R)-(tetrahydrofuran-2-yl)methanol (6), (S)-N-benzyl-3-hydroxypyrrolidine (7), (S)-3-hydroxytetrahydrothiophene (8), (S)-N-benzyl-3-acetoxypiperidine (10), (S)-3-hydroxytetrahydrofuran (16) and (R)-[(S)-N-benzylpyrrolidin-2-yl](phenyl)methanol (20).     

Synthesis of novel chiral phosphines from α,α-trehalose

New disaccharide chiral phosphines, such as 4,6-O-benzylidene-2-(diphenylphosphino)-2-deoxy-α-d-altropyranosyl-(1,1)-4,6-O-benzylidene-2-(diphenylphosphino)-2-deoxy-α-d-altropyranoside 1 and 2-(diphenylphosphino)-2-deoxy-4,6-O-isopropylidene-α-d-altropyranosyl-(1,1)-2-(diphenylphosphino)-2-deoxy-4,6-O-isopropylidene-α-d-altropyranoside 9, were prepared from α,α-trehalose. We also succeeded in the synthesis of polyhydroxy chiral diphosphine 2-(diphenylphosphino)-2-deoxy-α-d-altropyranosyl-(1,1)-2-(diphenylphosphino)-2-deoxy-α-d-altropyranoside 5 by deprotection of isopropylidene groups.     

Lipase mediated resolution of 1,3-butanediol derivatives: chiral building blocks for pheromone enantiosynthesis. Part 3

(R,S)-1,3-Butanediol 5 was kinetically resolved by enzymatic acetylation with vinyl acetate under the presence of Chirazyme™ L-2, c–f, yielding (S)-1-O-acetyl-1,3-hydroxybutane 6 and (R)-1,3-di-O-acetyl-1,3-butanediol 7 with enantiomeric excesses of 91% (E=67.3). Compounds 6 and 7 were easily transformed into the corresponding (S)-3-O-(2-methoxyethoxymethyl)-3-hydroxybutanal 10 and (R)-3-benzyloxybutanal 19, through a protection–deprotection and functional group interchange methodology. Subsequent reaction of 10 and 19 with 3-(methoxycarbonylpropionylmethylene)triphenylphosphorane afforded methyl (E,S)-8-O-(2-methoxyethoxymethyl)-4-oxo-5-nonenoate 12 and (E,R)-8-benzyloxy-4-oxo-5-nonenoate 20. The alkenes 19 and 20 were then catalytically hydrogenated to the corresponding saturated esters 13 and 21. Treatment of 13 and 21 with 1,2-ethanedithiol/F₃B·OEt₂ afforded dithioketals 14 and 22, which were respectively reduced to (S)-1,8-dihydroxy-4-nonanone ethylidenedithioketal 15 and (R)-8-O-benzyl-1,8-dihydroxy-4-nonanone ethylidenedithioketal 23. Finally, deprotection of 15 by catalytic hydrogenation under acidic conditions gave the expected (5S,7S)-(−)-7-methyl-1,6-dioxaspiro[4.5]decane 1. The (5R,7R)-(+)-1 enantiomer was analogously prepared from 23. Both compounds were formed by this procedure with an e.e. of 91%.     

Polyhydroxylated pyrrolidines. Part 4: Synthesis from d-fructose of protected 2,5-dideoxy-2,5-imino-d-galactitol derivatives

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-5-O-methanesulfonyl-β-d-fructopyranose (5) was straightforwardly transformed into its d-psico epimer (8), after O-debenzoylation followed by oxidation and reduction, which caused the inversion of the configuration at C(3). Compound 8 was treated with lithium azide yielding 5-azido-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-α-l-tagatopyranose (9) that was transformed into the related 3,4-di-O-benzyl derivative 10. Cleavage of the acetonide in 10 to give 11, followed by regioselective 1-O-pivaloylation to 12 and subsequent catalytic hydrogenation gave (2R,3S,4R,5S)-3,4-dibenzyloxy-2,5-bis(hydroxymethyl)-2′-O-pivaloylpyrrolidine (13). Stereochemistry of 13 could be determined after O-deacylation to the symmetric pyrrolidine 14. Total deprotection of 14 gave 2,5-imino-2,5-dideoxy-d-galactitol (15, DGADP).     

Formation of chiral tertiary homoallylic alcohols via Evans aldol reaction or enzymatic resolution and their influence on the Sharpless asymmetric dihydroxylation

Enantioenriched tertiary homoallylic alcohol derivatives (S)-2c and (S)-2a were obtained via Evans aldol methodology and enzymatic resolution of racemic tertiary acetate 2e, respectively. In order to study asymmetric 1,3-induction of the stereogenic center present in 2, congener (R)-2a as well as its O-protected derivatives (R)-2b-d were submitted to Sharpless asymmetric dihydroxylation to yield the diastereomeric 1,2,4-triol derivatives (2R,4R)- and (2S,4R)-3a-d, revealing that neither the substrate nor the Sharpless catalyst exert any stereocontrol. Similar observations were made for the less bulky alkynyl-substituted derivative 12b. However, by using a directed dihydroxylation, the anti product (2R,4R)-3a was favored.     

Synthesis and characterization of cyclopentadienyl/alkoxo titanium dichlorides: structural analysis of monocyclopentadienyl titanium dichlorides with ligands derived from menthol and borneol

A variety of monocyclopentadienyl alkoxo titanium dichloride and bisalkoxo titanium dichloride complexes have been prepared and characterized by spectroscopic techniques. The titanium derivatives containing both cyclopentadienyl and various alkoxo ligands [Ti(η⁵-C₅H₅)(OR)Cl₂] (1-5) have been synthesized from the reaction of [Ti(η⁵-C₅H₅)Cl₃] with 1 equivalent of the corresponding alcohol in THF in the presence of triethylamine (ROH = Adamantanol, 1R,2S,5R-(−)-menthol, 1S-endo-(−)-borneol, cis-1,3-(−)-benzylideneglycerol, 1,2:3,4-di-O-isopropylidene-α-d-galactopyranose). The bisalkoxo titanium dichloride derivatives [TiCl₂(OR)₂] (6-10) have been prepared by a redistribution reaction between Ti(OR)₄ and TiCl₄ compounds 6-8 (OR = Adamantanoxy, (1R,2S,5R)-(−)menthoxy, (1S-endo)-(−)-borneoxy) and by reaction of [Ti(OR)₂(OPrⁱ)₂]₂ with CH₃COCl compounds 9 and 10 (OR = 1,2:3,4-di-O-isopropylidene-α-d-galactopyranoxy, and 1,2:5,6-di-O-isopropylidene-α-d-glucofuranoxy). The molecular structures of 2 and 3 have been determined by single crystal X-ray diffraction studies.     

Fine tuning of the structure of phosphine–phosphoramidites: application for rhodium-catalyzed asymmetric hydrogenations

Diastereomers of (4-(diphenylphosphino)pentan-2-yl)-N-isopropyl-{dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxa-phosphepin-2-yl}-4-amine, (S)-(2S,4S)-1, and (S)-(2R,4R)-3; the octahydro derivative 4 of (S)-(2S,4S)-1, and derivative 2 of (S)-(2S,4S)-1 containing a 1,3-propanediyl backbone, have been synthesized and used for rhodium-catalyzed asymmetric hydrogenations of prochiral olefins in order to study the role of the stereogenic elements in the backbone and in the terminal moiety. The central chirality in the bridge has been found to determine the configuration of the product with a cooperative effect from the terminal groups. Excellent ee’s (up to 99.9%) were obtained in the hydrogenation of methyl (Z)-α-acetamidocinnamate using a rhodium complex with the matched arrangement (S)-(2S,4S)-1. The hydrogenation is accomplished in a highly enantioselective manner by using green solvents such as propylene carbonate.     

Synthesis of ‘thianthrene dimer’ by the coupling reaction of stannylthianthrenes in the presence of copper catalysts

The coupling reaction of 1-tributylstannylthianthrene (5) and 2-tributylstannylthianthrene (7) in the presence of copper catalysts at rt afforded the thianthrene dimer 1,1′-bithianthrene (3), 2,2′-bithianthrene (8), and 1,2′-dithianthrene (9) in high yields. Also we obtained thianthrene oxide dimer (R,R) (S,S)-1-(10-S-monoxythianthrene-1-yl)thianthrene-10-S-monoxide (12) and (R,S) (S,R)-1-(10-S-monoxythianthrene-1-yl)thianthrene-10-S-monoxide (13) from 1-tributylstannyl-10-S-monoxythianthrene (10) under the same reaction condition. The final structural conformation of 3, 8, 9, and 12 was performed by X-ray crystallographic analysis. Further, the solvent effects in the coupling reactions were also examined.     

One-pot acylation and fractional crystallization: preparation of optically active serinol monobenzoates

Mono-O-acylation of (R)-2-(α-methylbenzyl)amino-1,3-propanediol 1 with 4-nitrobenzoyl chloride and DMAP in dichloromethane at room temperature gave crystals of optically active (2S,αR)-3-hydroxy-2-(α-methylbenzyl)aminopropyl 4-nitrobenzoate hydrochloride [(2S)-2a·HCl] in 33% yield by fractional crystallization. Optically active oxazolidinones, aziridines, and serinol derivatives were synthesized from the benzoate (2S)-2a.