A Convenient Stereoselective Synthesis of (1R,2S,3R,4S)-3-(Neopentyloxy)isoborneol

A convenient preparation of (1R,2S,3R,4S)-3-(neopentyloxy)isoborneol (= (1R,2S,3R,4S)-3-(2,2-dimethyl-propoxy)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol; 1a ), a valuable chiral auxiliary, is described. The synthesis involves six steps starting from the readily available camphorquinone ( 5 ) and gives 1a in 48% overall yield. The key step is the chemoselective hydrolysis of the less hindered 1,3-dioxolane moiety in the camphorquinone di-acetal 4 .     

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.     

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.     

C45- and C50-Carotehoids. Part 8. Synthesis of (all-E,2S,2′S)-bacterioruberin, (all-E,2S,2′S)-monoanhydrobacterioruberin, (all-E,2S,2′S)-bisanhydrobacterioruberin, (all- E,2R,2′R)-3,4,3′,4′-tetrahydrobisanhydro- bacterioruberin,and (all-E,S)-2-isopentenyl-3,4-dehydrorhodopin

Starting from (R)-3-hydroxybutyric acid ((R)- 10 ) the C₄₅- and C₅₀-carotenoids (all-E,2S,2′S)-bacterioruberm ( 1 ), (all-E,2S,2′S)-monoanhydrobacterioruberin ( 2 ), (all-E,2S,2′S)-bisanhydrobacterioruberin ( 3 ), (all-E,2R,2′R)-3,4,3′,4′-tetrahydrobisanhydrobacterioruberin ( 5 ), and (all-E,S)-2-isopentenyl-3,4-dehydrorhodopin ( 6 ) were synthesized. By comparison of the chiroptical data of the natural and the synthetic compounds, the (2S)- and (2′S)-configuration of the natural products 1–3 and 6 was established.     

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.     

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.     

(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.     

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.     

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F 3 was achieved from the chiral bithiazole-type primary alcohols [(S)- and (R)-4-ethoxycarbonyl-2′-(1-hydroxymethylethyl)-2,4′-bithiazoles 8], which were obtained based on the enzymatic resolution of racemic alcohol 8 and its acetate 9. From a direct comparison by means of chiral HPLC between natural cystothiazole F 3 and synthetic compounds [(4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles 3], natural cystothiazole F 3 was found to be a 33:67 diastereomeric mixture [(4R,5S,6E,14S)-3:(4R,5S,6E,14R)-3 = 33:67].     

Stereochemische Korrelationen zwischen (2R,4′R,8′R)-α-Tocopherol, (25S,26)-Dihydroxycholecalciferol, (–)-(1S,5R)-Frontalin und (–)-(R)-Linalol

Stereochemical Correlations between (2R,4′R,8′R)-α-Tocopherol, (25S,26)-Dihydroxycholecalciferol, (–)-(1S,5R)-Frontalin and (–)-(R)-Linalol The optically active C₅- and C₄-building units 1 and 2 with their hydroxy group at a asymmetric C-atom were transformed to (–)-(1S,5R)-Frontalin ( 7 ) and (–)-(3R)-Linalol ( 8 ) respectively; 1 and 2 had been used earlier in the preparation of the chroman part of (2R,4′R,8′R)-α-Tocopherol ( 6a , vitamin E), and for introduction of the side chain in (25S,26)-Dihydroxycholecalciferol ((25S)- 4 ), a natural metabolite of Vitamin D₃. The stereochemical correlations resulting from these converions fit into a coherent picture with those correlations already known from literature and they confirm our earlier stereochemical assignments. A stereochemical assignment concerning the C(25)-epimers of 25,26-Dihydroxycholecalciferol that was in contrast to our findings and that initiated the conversion of 1 and 2 to 7 resp. 8 for additional stereochemical correlations has been corrected in the meantime by the authors [26].     

Efficient enantioselective synthesis of (2R,3R)- and (2S,3S)-3-hydroxyleucines and their diastereomers through dynamic kinetic resolution

(2R,3R)- and (2S,3S)-3-Hydroxyleucines, components of cyclodepsipeptides, papuamides and polyoxypeptins, were efficiently synthesized along with their diastereomers from the corresponding β-keto-α-amino acid ester through dynamic kinetic resolution using RuCl₂(binap)-catalyzed hydrogenation.     

Synthesis of chiral 1,5-disubstituted pyrrolidinones via electrophile-induced cyclization of 2-(3-butenyl)oxazolines derived from (1R,2S)- and (1S,2R)-norephedrine

Starting from (1R,2S)- and (1S,2R)-norephedrine, enantiomers of the corresponding 2-(3-butenyl)oxazolines were prepared in a two-step process. The cyclization of the intermediate alkenylamides with phenylselenyl bromide afforded cyclic imidates instead of the expected pyrrolidinones. The electrophile-induced cyclizations of 2-alkenyloxazolines with bromine or iodine produced diastereomeric mixtures of chiral 1,5-disubstituted pyrrolidinones. The ring closure of the all-cis (1R,2S,5R)-diastereomer 7 with NaH resulted in the tetrahydropyrrolo[2,1-b]oxazol-5-one derivative 18, which was alternatively prepared by the cyclocondensation of (1R,2S)-norephedrine with levulinic acid.     

Stereoselective synthesis of (3S,4R)-3,4-dimethyl-(S)-glutamine and the absolute stereochemistry of the natural product from papuamides and callipeltin

(3S,4R)-3,4-Dimethyl-(S)-glutamine, a common component of cyclodepsipeptides, papuamide A and callipeltin A, was stereoselectively prepared from (S)-pyroglutamic acid. The stereostructure of natural dimethylglutamine was unambiguously confirmed to be (2S,3S,4R) by comparison of the CD and NMR spectra of the synthetic 3,4-dimethylpyroglutamic acid with the hydrolysate of callipeltin A.     

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.     

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.     

Uncommon transformations of methyl (1S,2S,3R,4R)-2,3-isopropylidenedioxy-5-iodomethyl-2-tetrahydrofurylacetate initiated by bases

Methyl (1S,2S,3R,4R)-2,3-isopropylidenedioxy-5-iodomethyl-2-tetrahydrofurylacetate prepared in two stages from D-ribose acetonide underwent a series of uncommon transformations under the treatment with bases providing the following different products depending on the base applied: methyl 3-(5-acetyl-2,2-dimethyl-1,3-dioxol-4-yl)propionate (DBU), methyl 2,3-isopropylidenedioxy-7-oxabicyclo[2.2.1]heptane-6-carboxylate (t-BuOK), methyl {(5R)-2,2-dimethyl-5-[(2R)-oxiranyl]-1,3-dioxolan-4-ylidene}propionate and methyl-(E)-3-{(4S,5R)-2,2-dimethyl-5-[(1R)-(2-oxiranyl)]-1,3-dioxolan-4-yl}-2-propenoate (t-BuOK and LDA).     

1,3-Dipolar cycloaddition of a chiral nitrone to (E)-1,4-dichloro-2-butene: a new efficient synthesis of (2S,3S,4R)-4-hydroxyisoleucine

1,3-Dipolar cycloaddition of a chiral nitrone derived from (?)-menthone to (E)-1,4-dichlorobut-2-ene was the key step in a novel 5 step synthesis of (2S,3S,4R)-4-hydroxyisoleucine, obtained in 21% overall yield with high enantiopurity.     

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.     

Synthesis and analytical properties of (S)-(+)-2-methoxy-2-(9-phenanthryl)propionic acid

2-Methoxy-2-(9-phenanthryl)propionic acid was synthesized as a novel chiral resolving agent. The absolute configuration of (+)-2-methoxy-2-(9-phenanthryl)propionic acid was determined to be S by using X-ray structural analysis of the (1R,2S,5R)-menthyl ester. In the crystal, the methoxyl and carbonyl groups of the ester are in a syn-periplanar position. The syn-periplanar conformations of (1R,2S,5R)-menthyl esters were also observed by the NMR analyses in CDCl₃. The utility of (S)-(+)-2-methoxy-2-(9-phenanthryl)propionic acid was exemplified by the resolution of (±)-3-octanol.     

Stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadecan-2-ol and its propionate,the sex pheromones of pine sawflies

The stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadecan-2-ol (diprionol) and its propionate, the sex pheromones of pine sawflies (Neodiprion sp. and other), in high enantiomeric purity was achieved from (1R,3S)-2,2-dichloro-3-methylcyclopropanecarboxylic acid. The carbon skeleton of diprionol was formed via copper-catalyzed cross-coupling reactions and diastereoselective methylation of the intermediate chiral α-methylbranched aldehyde with MeTi(Oi-Pr)₃ in the presence of [(R,R)-TADDOL]Ti(Oi-Pr)₂. The latter transformation leads to a syn-adduct with high stereoselectivity, which depends on the presence and configuration of the α-stereogenic center in the aldehyde. The diastereomeric purity of (2S,3S,7S)-diprionol can be substantially increased via crystallization of its 3,5-dinitrobenzoate.