Stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine

The stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine from (R)-1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)piperidin-2-one is described. The key steps involved are α-hydroxylation of quiral lactam with O₂, stereoconvergent reduction of (R)- or (S)-3-(benzyloxy)-piperidin-2-one with Red-Al® which afforded in both cases the trans-bicyclic oxazolidine in high stereoselectivity after chromatographic purification and a stereospecific Grignard addition to chiral bicyclic oxazolidine.     

Polyhydroxylated pyrrolizidines. Part 4: Total asymmetric synthesis of unnatural hyacinthacines from a protected derivative of DGDP

(1R,2R,3S,5R,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine [(+)-3-epi-hyacinthacine A₃] 1 and (1R,2R,3S,7aR)-1,2-dihydroxy-3-hydroxymethylpyrrolizidine [(+)-3-epi-hyacinthacine A₂] 2 have been synthesized by Wittig's methodology using aldehyde 6, prepared from (2R,3R,4R,5S)-3,4-dibenzyloxy-N-benzyloxycarbonyl-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl) pyrrolidine 3 (a partially protected DGDP), and the appropriated ylides, followed by cyclization through an internal reductive amination process of the resulting α,β-unsaturated ketone 7 and aldehyde 8, respectively, and total deprotection.     

Studies towards the synthesis of (1R,2S)- and (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonates and (1S,2S)- and (1R,2S)-2,3-epoxy-1-hydroxypropylphosphonates

The trans-configured fosfomycin analogue, diethyl (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonate, was synthesised by the intramolecular Williamson reaction of diethyl (1S,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate. The cis-analogue was obtained as O-ethyl or O,O-diethyl (1R,2S)-1,2-epoxy-3-hydroxypropylphosphonates, when (1R,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate or its 3-O-trityl derivative were used as starting materials, respectively. The intramolecular Williamson cyclisations of diethyl (1S,2R)- and (1R,2S)-1-benzyloxy-3-hydroxy-2-mesyloxypropylphosphonates led to diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, respectively, with the concomitant formation of diethyl (E)-1-benzyloxy-3-hydroxyprop-1-en-1-phosphonate. From diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, enantiomerically pure diethyl (1S,2S)- and (1R,2S)-1,2-dihydroxypropylphosphonates were obtained by catalytic hydrogenation, while diethyl (1S,2S)- and (1R,2S)-3-acetamido-1,2-dihydroxypropylphosphonates were produced after epoxide ring opening with dibenzylamine, acetylation and hydrogenolysis.     

Solid-state structure determination and solution-state NMR characterization of the (2R,4R)/(2S,4S)- and (2R,4S)/(2S,4R)-diastereomers of the agricultural fungicide propiconazole,the (2R,4S)/(2S,4R)-symmetrical triazole constitutional isomer,and a ditriazole analogue

Single-crystal X-ray diffraction analysis was used to determine the structure of a racemic diastereomer of the agricultural fungicide propiconazole [1-(2-(2,4-dichlorophenyl)-4-n-propyl-1,3-dioxolane-2-yl-methyl)-1-H-1,2,4-triazole] and of two by-products (a symmetrical 1,3,4-triazole racemic-constitutional isomer and a propiconazole ditriazole analogue). All three crystalline racemic-diastereomers had (2R,4S)/(2S,4R)-stereochemistry in which then-propyl group was observed in atrans-to-phenyl disposition. Propiconazole (2R,4S)/(2S,4R)-diastereomer gives crystals belonging to the monoclinic space group P2₁,/a, and, at 293 K,a=8.1192(3),b=18.9769(6),c=10.7137(4) å,Β=99.765(3)?,V=1626.8(1) å³, Z=4,R(F)=0.060, andR _w(F)=0.058. The constitutional isomer by-product (2R,4S)/(2S,4R)-1-(2-(2,4-dichlorophenyl)-4-n-pro-pyl-1,3-dioxolane-2-yl-methyl)-1-H-1,3,4-triazole gives crystals belonging to the monoclinic space group P2₁/n, and, at 293 K,a=11.1763(6),b=10.7716(4),c=14.5804(8) å,Β=107.445(4)?,V=1674.6(1) å³, Z=4,R(F)=0.043, andR _w(F)=0.043. The ditriazole byproduct (2R,4S)/(2S,4R)-1-(2-(2-chloro-4-(1,2,4-triazole-1-yl)phenyl)-4-n-propyl-1,3-dioxolane-2-yl-methyl)-1-H-1,2,4-triazole gives crystals belonging to the triclinic space groupP¯ 1, and, at 193 K,a=5.3329(8),b=8.3738(7),c=20.240(2) å, α=84.213(6)?,Β=87.20(1)?,γ=86.23(1)?,V=896.5(2) å³, Z=2,R(F)=0.046, andR _w(F)=0.051. The presence of both propiconazole (2R.4S)- and (2S,4R)-enantiomers enables the formation of a crystalline racemic modification, while the diastereomeric propiconazole (2R,4R)- and (2S,4S)-enantiomers are viscous oils. In the absence of its enantiomorphic partner, the propiconazole (2R,4S)- or (2S,4R)-enantiomers remain as viscous oils rather than form chiral crystals.     

Synthesis of 2-amino-1,3-dihydroxypropylphosphonates from Garner aldehyde

In the presence of triethylamine or ionic fluoride catalysts, the addition of dimethyl or diethylphosphite to Garner aldehyde proceeded with good (1:9) diastereoselectivity leading to a separable mixture of (1S,2S)- and (1R,2S)-hydroxyphosphonates. Almost equal amounts (43:57) of the respective phosphonates were formed when titanium(IV) isopropoxide was applied as a catalyst. The e.e.s of the hydroxyphosphonates reached 93–97% in the reactions catalysed by Ti(OiPr)₄ and dropped to 80–91% when triethylamine was used to catalyse the reaction.     

Presence or absence of a nonlinear effect according to the asymmetric catalyst preparation in the alkylation of benzaldehyde

The addition of Et₂Zn on benzaldehyde in the presence of a stoichiometric amount of Ti(Oi-Pr)₄ catalysed by (1R,2R)-bis(trifluoromethanesulfonamido)-cyclohexane 1a has been revisited. A nonlinear effect was present or absent, depending on the catalyst preparation. An asymmetric amplification has been observed when Ti(Oi-Pr)₄ was added to 1a followed by Et₂Zn and then benzaldehyde (Ohno procedure). In the alternate procedure (Walsh), where Et₂Zn and 1a were premixed, there is linearity. Mechanistic implications are discussed.     

New analogues of fosfomycin—synthesis of diethyl (1R,2R)- and (1S,2R)-1,2-epoxy-3-hydroxypropylphosphonates

The trans-configured fosfomycin analogue, diethyl (1R,2R)-1,2-epoxy-3-hydroxypropylphosphonate, was synthesised via the intramolecular Williamson reaction from 3-O-protected (trityl or TBDMS) or even unprotected diethyl (1S,2R)-2,3-dihydroxy-1-mesyloxypropylphosphonate, which was obtained from the known diethyl (1S,2R)-2,3-O-cyclohexylidene-1,2,3-trihydroxypropylphosphonate. On the other hand, the cis-analogue, diethyl (1S,2R)-1,2-epoxy-3-hydroxypropylphosphonate, could only be prepared from diethyl (1R,2R)-2-hydroxy-1-mesyloxy-3-trityloxypropylphoshonate.     

Expedient asymmetric synthesis of (2S,3S)-Boc-phenylalanine epoxide,a key intermediate for the synthesis of biologically active compounds

The asymmetric synthesis of (2S,3S)-3-(tert-butoxycarbonyl)amino-1,2-epoxy-4-phenylbutane [(2S,3S)-Boc-phenylalanine epoxide] has been achieved in six steps and in 55% overall yield from the N-benzylimine derived from (R)-2,3-O-isopropylidene-glyceraldehyde. The required vic-aminodiol intermediate was obtained through a highly diastereoselective addition of benzylmagnesium chloride to the N-benzylimine in the presence of BF₃·OEt₂ as an imine precomplexing agent.     

Diastereoselective synthesis of chiral α-aminoorganotributyltins via ring-opening of 2-tributylstannyloxazolidines

Reactions of 2-tributylstannyloxazolidines 2a-d (cis or trans), derived from (R)-phenylglycinol protected as N-carbamate, with lithium diorganocuprates in presence of boron trifluoride in diethyl ether provide the corresponding functionalized tributylstannyl-α-aminoalcohols 3-10 with diastereoselectivities close to 85:15 in favour of the (S,R)-isomer. The stereochemical trend is preserved using allyltributyltin as nucleophile and TiCl₂(Oi-Pr)₂ as Lewis acid in dichloromethane. The assignments of the (S,R) or (R,R) configurations in 3-10 were achieved on the basis of physicochemical data combined with a radiocrystallographic structure. Stereochemical preferences were rationalized by consideration of the interactions occurring in the iminium intermediates.     

Convenient access to sterically hindered C2 chiral 2,2,5,5-tetraphenyltetrahydrofuran-3,4-diols: intramolecular selective 1,4-cyclocondensation of (2R,3R)- and (2S,3S)-1,1,4,4-tetraphenylbutanetetraols

Sterically hindered C₂ chiral (3R,4R)- and (3S,4S)-2,2,5,5-tetraphenyltetrahydrofuran-3,4-diols have been conveniently prepared in a very high yield via heterogeneous intramolecular selective 1,4-cyclocondensation of (2R,3R)- and (2S,3S)-1,1,4,4-tetraphenylbutanetetraol in concentrated hydrohalic acids, respectively. Preliminary examination of additives for the Barbas–List reaction showed that in certain cases, the hindered C₂ chiral tetrahydrofuran-3,4-diols were better chiral auxiliaries than enantiopure (R)- and (S)-1,1′-bi-2-naphthols.     

First asymmetric synthesis of pyrrolizidine alkaloids, (+)-hyacinthacine B1 and (+)-B2

An enantiomerically and diastereomerically pure route has been developed for the first asymmetric synthesis of (1S,2R,3R,5R,7aR)- and (1S,2R,3R,5S,7aR)-1,2-dihydroxy-3,5-dihydroxymethylpyrrolizidine, hyacinthacine B₁ and B₂, featuring efficient and stereodefined elaboration via the asymmetric dihydroxylation (AD) of the functionalized homochiral pyrrolidine derivative prepared from (S)-(−)-2-pyrrolidone-5-carboxylic acid.     

A scalable synthesis of (R)-3-(2-aminopropyl)-7-benzyloxyindole via resolution

(±)-3-(2-Aminopropyl)-7-benzyloxyindole 1, assembled from 7-benzyloxyindole 3 in 59% overall yield, is resolved with O,O′-di-p-toluoyl l-(2R,3R)-tartaric acid 7 into (R)-1, a key intermediate of AJ-9677 2 (selective adrenaline β₃-agonist) in 99.5% e.e. and 36% overall yield. The unwanted enantiomer (S)-1 (61.9% e.e.; recovered in 57% yield from the crystallization filtrate) can be reused in another round of resolution after its enantiomeric purity is lowered to 3.7% by Raney Co treatment under a hydrogen atmosphere.     

Synthetic route towards (5R,2′S,5′S,6′S)-ribosyl-diazepanone,an analogue core of the liposidomycins

The synthesis of (5R,2′S,5′S,6′S)-ribosyl-diazepanone, an analogue core of liposidomycins is described. The core ribosyl seven-membered heterocycle of nucleoside antibiotic liposidomycins was formed by reductive amination of an α-ribosylamino ester derived from d-ribose, and an amino aldehyde derived from methyl 4-triisopropylsilyloxy-3-oxobutanoate, followed by a peptidic coupling reaction.     

Enzymatic desymmetrization of meso cis-2,6- and cis,cis-2,4,6-substituted piperidines. Chemoenzymatic synthesis of (5S,9S)-(+)-indolizidine 209D

The stereoselective acylation of meso piperidines 3a,b by vinyl acetate (solvent and acyl donor) in the presence of Candida antarctica lipase gave the corresponding (2S,6R) and (2S,4R,6R) monoesters 2a,b in high enantiomeric purity. (5S,9S)-(+)-Indolizidine 209D was prepared in eight steps from (2S,6R)-2a.     

New chiral phosphine-phosphonites derived from (2R,3R)-dimethyl tartrate, (S)-binaphthol and (1R,2S)-ephedrine

The reaction of 2-lithiophenyldiphenylphosphine with phosphorus trichloride afforded the new unsymmetric phosphine, dichloro(2-diphenylphosphinophenyl)phosphine (4). Condensation of 4 with (a) (2R,3R)-dimethyl tartrate or (b) (S)-binaphthol in the presence of triethylamine gave new chiral phosphine-phosphonite ligands, (2R,3R)-[2-(2′-(diphenylphosphino)phenyl)-4,5-bis(carbomethoxy)-1,3,2-dioxaphospholane] ((2R,3R)-5) and (S)-[2-(diphenylphosphino)benzene][1,1′-binaphthalen-2,2′-diyl]phosphonite] ((S)-6). The analogous reaction of 4 with (1R,2S)-ephedrine using N-methylmorpholine as the base, gave [2-(2′-(diphenylphosphino)phenyl)-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine] (7) as a 95:5 mixture of diastereoisomers.     

Use of CaH2 as a reductive hydride source: reduction of ketones and imines with CaH2/ZnX2 in the presence of a Lewis acid

A new combination reagent of CaH₂/ZnX₂ effectively reduced a variety of ketones and imines to the corresponding alcohols and amines, respectively, in the presence of a catalytic amount of a Lewis acid such as Ti(O-i-Pr)₄, Al(O-i-Pr)₃, B(O-i-Pr)₃ and ZnF₂.     

Studies on the transformation of nitrosugars into iminosugars III: synthesis of (2R,3R,4R,5R,6R)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol and (2R,3R,4R,5R,6S)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol

A divergent synthesis of the two novel polyhydroxylated azepanes (2R,3R,4R,5R,6R)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol and (2R,3R,4R,5R,6S)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol from d-mannose is described. The method involves a Henry reaction between dimethyl-tert-butylsilyl 2,3-O-isopropylidene-α-d-lyxo-pentodialdo-1,4-furanoside and 2-nitroethanol followed by a reductive ring closure of the resulting epimeric nitro aldols. Glycosidase inhibition tests showed that (2R,3R,4R,5R,6S)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol exhibits a weak but selective inhibition against α-l-fucosides.     

The synthesis of the insect pheromone (2S,3R,7R)-3,7-dimethyltridec-2-yl acetate from racemic 3,4-dimethyl-γ-butyrolactone by diastereoselective chiral resolution

The insect pheromone (2S,3R,7R)-3,7-dimethyltridec-2-yl acetate 1-Ac was prepared from diastereomerically enriched (2S¹,3R¹,7R)-1, which in turn was obtained by the coupling of racemic 3,4-dimethyl-γ-butyrolactone with (7S)-2-methyloctyllithium, followed by a Wolff–Kishner reduction of the resulting ketone. Conversion of (2S¹,3R¹,7R)-1 to the corresponding alkyl hydrogen phthalate and diastereomer salt formation with (S)-PhCHMeNH₂ provided after several crystallizations individual diastereomer, which was later transformed into target 1-Ac after hydrolysis and acylation.     

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

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

Catalytic asymmetric oxidation of 1H-benzimidazolyl pyridinylmethyl sulfides with cumene hydroperoxide catalyzed by a titanium complex with (S,S)-N,N′-dibenzyl tartramide ligand

A chiral titanium complex, formed in situ from Ti(Oi-Pr)₄, (S,S)-N,N′-dibenzyl tartramide and water was found to serve as an efficient catalyst for the asymmetric oxidations of 1H-benzimidazolyl pyridinylmethyl sulfides with cumene hydroperoxide (CHP) in the absence of a base. Several proton pump inhibitors (PPIs), such as esomeprazole, lansoprazole, rabeprazole and pantoprazole were obtained in high yield (up to 92%) and excellent enantiomeric excess (up to 96%).