Synthesis and anticonvulsant activities of (R)-(O)-methylserine derivatives

Efficient procedures for the synthesis of (R)-N-benzyl-2-amino-3-methoxypropionamide ((R)-3), 2-acetamido-3-methoxypropionic acid (4), and O-methylserine (5) are described beginning from (R)-Cbz-serine ((R)-7). The reactions proceeded with little or no racemization and permitted the synthesis of the potent anticonvulsant (R)-N-benzyl-2-acetamido-3-methoxypropionamide ((R)-2). The anticonvulsant activities of 2–4 were determined revealing the surprising activity of (R)-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.     

Chemoenzymatic synthesis of (5S)- and (5R)-hydroxymethyl-3,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-one: a precursor of thiolactomycin and determination of its absolute configuration

A convenient enantioselective synthesis of (5S)- and (5R)-hydroxymethyl-3,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-one, a key intermediate in the synthesis of thiolactomycin has been carried out by a Carica papaya lipase-mediated resolution protocol to provide (R)-2 in a 94% ee and its enantiomer (S)-9 in a 98% ee. The absolute configuration at the C-5 position has been determined by Mosher’s method.     

Natural product synthesis from (8aR)- and (8aS)-bicyclofarnesols: synthesis of (+)-wiedendiol A, (+)-norsesterterpene diene ester and (−)-subersic acid

Both enantiomers (8aR)-7 and (8aS)-7 of bicyclofarnesol were synthesized from the enzymatic resolution products (1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-5 (98% ee) and acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aS)-6 (>99% ee), respectively. The formal synthesis of (+)-wiedendiol 1 was achieved via a coupling reaction of an ate complex derived from 1,2,4-trimethoxybenzene with allyl bromide (8aS)-8 derived from (8aS)-7. The total synthesis of (+)-norsesterterpene diene ester 2 was achieved, based on the synthesis of (13E,10S)-α,β-unsaturated aldehyde 12, derived from (8aS)-7, followed by the selective construction of the (3E,5E)-diene moiety including a C(2)-stereogenic centre in (+)-2. The total synthesis of (−)-subersic acid 3 was carried out based on a Stille coupling between allyl trifluoroacetate congener 25c, derived from (8aR)-7, corresponding to the diterpene part, and aryl stannane congener 26 in the presence of Pd catalyst and CuI as an additive.     

Synthesis of enantiomerically pure (Z)-(2′R)-1-O-(2′-methoxyhexadec-4′-enyl)-sn-glycerol present in the liver oil of cartilaginous fish

Synthesis of enantiopure (Z)-(2′R)-1-O-(2′-methoxyhexadec-4′-enyl)-sn-glycerol 1, the principal methoxylated glyceryl ether found in Nature, is described by a highly convergent five-step process taking place in 27% overall yield. The synthesis is based on an ether bond formation between the chiral synthon (R)-2,3-O-isopropylidene-sn-glycerol and (Z)-(R)-1-chlorohexadec-4-en-2-ol employing ground potassium hydroxide and tetra-n-butylammonium bromide as a catalyst under solvent free conditions.     

Boron trifluoride etherate-assisted ring opening of ethylene oxide by a chiral organolithium: enantioselective synthesis of (R)-N-Boc-2-(2-hydroxyethyl)pyrrolidine

A practical synthesis of (R)-N-Boc-2-(2-hydroxyethyl)pyrrolidine in high enantiomeric purity is described. The synthesis involves BF₃·Et₂O-assisted ring opening of ethylene oxide by a homochiral carbanion (R)-3, which is derived from sparteine-mediated asymmetric deprotonative lithiation of 1-Boc-pyrrolidine.     

First stereoselective synthesis of (4aS,5R)-4,4a,5,6,7,8-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone

The synthesis of enantiomerically pure (4aS,5R)-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone (−)-1 is described for the first time. The synthesis starts from (R)-3-methylcyclohexanone and involves the preparation of Piers enol lactone 6 in its enantiopure form as the key intermediate. Treatment of (+)-6 with methyl lithium followed by an intramolecular aldol reaction gives the bicyclic enone (−)-1.     

Synthesis of (R)- and (S)-4-hydroxyisophorone by ruthenium-catalyzed asymmetric transfer hydrogenation of ketoisophorone

The first synthesis of (R)- and (S)-4-hydroxyisophorone by catalytic transfer hydrogenation of ketoisophorone is reported. Ruthenium catalysts containing commercially available chiral amino alcohols afforded 4-hydroxyisophorone in up to 97% selectivity and 97% ee. (R)- or (S)-4-Hydroxyisophorones with >99% ee were isolated by crystallization. The catalyst precursors [RuCl₂((S,R)-ADPE)(η⁶-p-cymene)] ((S,R)-ADPE=(1S,2R)-amino-1,2-diphenylethanol-N) and (R_Ru)-[RuCl((S,R)-ADPE⁻¹)(η⁶-p-cymene)] (ADPE⁻¹=amino-1,2-diphenylethanolato-N,O) were isolated for the first time and the X-ray crystal structure of the latter determined.     

(R)- and (S)-N-(Benzyloxycarbonyl)-3,4-epoxybutylamine. New 4-amino-2-hydroxybutyl synthons for the synthesis of hypusine reagents and (R)-6- and (S)-7-hydroxyspermidine

The synthesis and application of the chiral reagents (R)- and (S)-N-(benzyloxycarbonyl)-3,4-epoxybutylamine is described for the first time. These 4-amino-2-hydroxybutyl synthons are successfully employed in the assembly of two hydroxylated triamines, (R)-6- and (S)-7-hydroxyspermidine, and a previously described hypusine reagent, (2S,9R)-11-[(benzyloxycarbonyl)amino]-7-(benzyloxycarbonyl)-2-[(9-fluorenylmethoxycarbonyl)amino]-9-(tetrahydropyran-2-yloxy)-7-azaundecanoic acid, useful for solution- and solid-phase peptide synthesis.     

Enzyme-catalyzed preparation of methyl (R)-N-(2,6-dimethylphenyl)alaninate: a key intermediate for (R)-metalaxyl

A biocatalytic approach for the production of (R)-metalaxyl, mefenoxam, has been developed. A practical synthesis of methyl (R)-N-(2,6-dimethylphenyl)alaninate, a key intermediate for (R)-metalaxyl, has been developed by the use of lipase-catalyzed hydrolytic kinetic resolution and chemical racemization of the remaining ester. At high concentrations in aqueous media (300 g/L) lipases were stable and gave moderate to good conversions and excellent enantioselectivities (>98% ee). A simple extraction procedure was used to separate the acid product from the remaining ester and the acid was esterified with methanol to give methyl (R)-N-(2,6-dimethylphenyl)alaninate without any reduction in enantiomeric excess (>98% ee). Subsequent chemical coupling with methoxyacetyl chloride provided enantiomerically pure (R)-metalaxyl (>98% ee) without racemization.     

Racemization of (S)-(+)-10,11-dimethoxyaporphine and (S)-(+)-aporphine: efficient preparations of (R)-(−)-apomorphine and (R)-(−)-aporphine via a recycle process of resolution

Efficient preparations of (R)-(−)-apomorphine (R)-1 and (R)-(−)-aporphine (R)-2 based on a recycle process of resolution are described. In this recycle process of resolution, (RS)-(±)-10,11-dimethoxyaporphine 3 as the precursor of 1, and (RS)-(±)-aporphine 2 were successfully resolved into both enantiomers with (+)-dibenzoyltartaric acid (DBTA). The desired (R)-3 and (R)-2 were obtained and then, respectively, transformed to compound (R)-1, the hydrochloride salt of (R)-1, diacetate compound 4 and the hydrochloride salt of (R)-2; while the undesired (S)-3 and (S)-2 were racemized to obtain a racemate, which was suitable for further resolution. A method for the racemization of the undesired (S)-3 and (S)-2 was extensively studied, in order to obtain high-yielding racemization conditions. A plausible mechanism for the racemization of (S)-3 and (S)-2 was also proposed.     

Synthesis of (S)-(−)- and (R)-(+)-O-methylbharatamine using a diastereoselective Pomeranz–Fritsch–Bobbitt methodology

Laterally lithiated (S)-(−)- and (R)-(+)-o-toluamides 6 with a chiral auxiliary derived from (S)- and (R)-phenylalaninol, respectively, were used as the building blocks and chirality inductors in the asymmetric modification of the Pomeranz–Fritsch–Bobbitt synthesis of isoquinoline alkaloids. Their addition to imine 2 proceeded with partial cyclization, giving isoquinolones (+)-7 and (−)-7 along with acyclic products, (−)-8 and (+)-8, respectively. LAH-reduction of (+)-7 and (−)-7, followed by cyclization, afforded both enantiomers of the alkaloid, (S)-(−)- and (R)-(+)-O-methylbharatamine 5, in 32% and 40% overall yield and with 88% and 73% ees, respectively.     

Chemoenzymatic synthesis of (3R,4S)- and (3S,4R)-3-methoxy-4-methylaminopyrrolidine

An efficient and a convenient enantioselective synthesis of (3R,4S)-3-methoxy-4-methylaminopyrrolidine has been carried out by a lipase-mediated resolution protocol. This method describes the preparation of (±)-1-Cbz-cis-3-azido-4-hydroxypyrrolidine starting from commercially available diallylamine followed by ring-closing metathesis (RCM) via S_N2 displacement reactions. Pseudomonas cepacia lipase immobilized on diatomaceous earth (Amano PS-D) provides (3R,4S)-11 and (3S,4R)-12 in an excellent enantiomeric excess.     

An enantioselective synthesis of (R)-4-piperidinylglycine

An efficient process for the synthesis of (R)-N-t-Boc-4-piperidinylglycine 8a, an unnatural amino acid, via enantioselective rhodium-catalyzed hydrogenation of the Cbz-enamide 5a is described. Subsequent deprotection of 8a affords unprotected (R)-4-piperidinylglycine 9 in good yield.     

Intramolecular reductive amination strategy to the synthesis of (R)-N-Boc-2-hydroxymethylmorpholine, N-(3,4-dichlorobenzyl)(R)-2-hydroxymethylmorpholine, and (R)-2-benzylmorpholine

A concise high yielding enantioselective synthesis of (R)-N-Boc-2-hydroxymethylmorpholine, N-(3,4-dichlorobenzyl)(R)-2-hydroxymethylmorpholine, and (R)-benzylmorpholine has been achieved by employing proline-catalyzed asymmetric α-aminooxylation of aldehyde and palladium-catalyzed intramolecular reductive amination of azido aldehyde as the key steps.     

Stereoselective synthesis of tetrahydroisoquinoline alkaloids: (−)-trolline, (+)-crispin A, (+)-oleracein E

Tetrahydroisoquinoline alkaloids, (S)-(−)-trolline, (R)-(+)-crispin A, and (R)-(+)-oleracein E, have been synthesized stereoselectively from the both enantiomers of common intermediate (S)-4 and (R)-4. The key step in the synthesis include a stereoselective Bi(OTf)₃-catalyzed intramolecular 1,3-chirality transfer reaction of chiral non-racemic amino allylic alcohols (S)-6 and (R)-6 to construct both enantiomers of (E)-1-propenyl tetrahydroisoquinoline 4.     

Synthesis of D-(6R) - and D-(6S) -(6-2H1) glucose

Chemical synthesis ofD-(6R)- and D(6S)-(6-²H₁) glucose is described comprising (i) formation of 6-²H₁)-3-o-benzyl-5,6-dideoxy-l, 2-0-isopropylidene-α-D-xylo-hex-5-ynofuranose from D-glucose; (ii) stereospecific reduction of the deuterated acetylene functionality to (E)- or (Z)-deuterated olefin; (iii) stereospecific cis-dihydroxylation of the deuterated olefin; and (iv) separation of stereoisomers based on the intrinsic chirality of D-glucose and subsequent deprotection.     

Enantioselective synthesis of (R)-deoxydysibetaine and (−)-4-epi-dysibetaine

Enantioselective synthesis of (R)-deoxydysibetaine and (−)-4-epi-dysibetaine was achieved by employing a samarium iodide-promoted reductive carbon-nitrogen bond cleavage of a proline derivative, as a key reaction.     

Asymmetric synthesis of (−)-(S,S)-homaline

The asymmetric synthesis of (−)-(S,S)-homaline was achieved in 8 steps from commercially available starting materials using the diastereoselective conjugate addition of the novel lithium amide reagent lithium (R)-N-(3-chloropropyl)-N-(α-methyl-p-methoxybenzyl)amide to methyl cinnamate to install the correct stereochemistry. Subsequent functional group manipulation of the resultant β-amino ester and Sb(OEt)₃-mediated macrolactamisation was followed by homodimerisation to give (−)-(S,S)-homaline in 18% overall yield, representing the first asymmetric, and by far the most efficient synthesis of this natural product reported to date.     

Resolution of 1-phenyl-2-(p-tolyl)ethylamine via diastereomeric salt formation

(S)-1-Phenyl-2-(p-tolyl)ethylamine (S)-1, used for the industrial scale resolution of chrysanthemic acids, was obtained via resolution of the racemate with the hemiphthalate of (S)-isopropylidene glycerol (R)-2. The maximum experimental efficiency [69% yield and >99% e.e. of (S)-1] was achieved by a simple precipitation of (S)-1·(R)-2 from the solution of the 1:1 diastereomeric salt mixture in 93/7 isopropanol/water at saturation of the more soluble (R)-1·(R)-2 salt. Such an experimental efficiency was consistent with 0.79 maximum theoretical resolvability, derived from the solubilities of the two diastereomeric salts, and with DSC data, which indicated that the (S)-1·(R)-2/(R)-1·(R)-2 system is a binary mixture exhibiting an eutectic with composition approximately corresponding to a 0.2 molar ratio of (S)-1·(R)-2.