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.     

Synthesis of (+)-1,3,5,7 -tetrakis[2-(1S,3S,5R,6S,8R,10R)-D3-trishomocubanylbuta-1,3-diynyl]adamantane : The first optically active organic molecule with t symmetry and of known absolute configuration

(-)-(1S,3S,5R,6S,8R,10R)-Trishomocubanethanoic acid (5) of known absolute configuration and absolute rotation was converted into (+)-(1S,3S,5S,6S,8R,10R)-2-bromoethynyl-D₃-trishomocubane (27) of C₃ symmetry. 1,3,5,7-Tetraethynyladamantane (22), with Td symmetry, was prepared from 1,3,5,7-tetrakis(hydroxymethyl)adamantane(13). Coupling of the C₃-component 27 with the Td component 22 was successfully accomplished by Chodkiewicz and Cadiot's procedure providing (+)-1,3,5,7-tetrakis[2-(1S,3S,5R,6S,8R,10R)-D₃-trishomocubanylbuta-1,3-diynyl]adamantane(4) whose highest attainable static and time-averaged dynamic symmetry are T and (C₃)⁴ XXX T,respectively.     

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.     

3-(((1S,3S)-3-((R)-Hydroxy(4-(trifluoromethyl)phenyl)methyl)-4-oxocyclohexyl)methyl)pentane-2,4-dione: Design and Synthesis of New Stereopure Multi-Target Antidiabetic Agent

The chiral drug candidates have more effective binding affinities for their specific protein or receptor site for the onset of pharmacological action. Achieving all carbon stereopure compounds is not trivial in chemical synthesis. However, with the development of asymmetric organocatalysis, the synthesis of certain vital chiral drug candidates is now possible. In this research, we have synthesized 3-(((1S,3S)-3-((R)-hydroxy(4-(trifluoromethyl)phenyl)methyl)-4-oxocyclohexyl)methyl)pentane-2,4-dione (S,S,R-5) and have evaluated it potential as multi-target antidiabetic agent. The stereopure compound S,S,R-5 was synthesized with a 99:1 enantiomeric ratio. The synthesized compound gave encouraging results against all in vitro antidiabetic targets, exhibiting IC₅₀ values of 6.28, 4.58, 0.91, and 2.36 in α-glucosidase, α-amylase, PTP1B, and DPPH targets, respectively. The molecular docking shows the binding of the compound in homology models of the respective enzymes. In conclusion, we have synthesized a new chiral molecule (S,S,R-5). The compound proved to be a potential inhibitor of the tested antidiabetic targets. With the observed results and molecular docking, it is evident that S,S,R-5 is a potential multitarget antidiabetic agent. Our study laid the baseline for the animal-based studies of this compound in antidiabetic confirmation.     

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.