利用薯蓣皂甙元完整骨架形式合成1α,25-二羟基维生素D3

首次利用薯蓣皂甙元的完整骨架经16步反应以7.6%的总收率合成了骨化三醇(1α,25-二羟基维生素D₃)的光化反应前体. 3-苄基保护的薯蓣皂甙元经还原开E/F环产生3,16,26-胆甾三醇-3-苄醚(5). 除去化合物5 C-16羟基后, 其C-26羟基经消除和羟基化反应转移到C-25位. 目标分子A/B环结构单元通过薯蓣皂甙元A/B环的官能团转化被构筑. 按照已知的光化反应, (1S,3R)-胆甾-5,7-二烯-1,3,25-三醇能被转化成为1α,25-二羟基维生素D₃.     

Synthesis of (2S,4S)-4-Hydroxyproline from D-Glucose

Diacetone-D-glucose 1 gives 3- O -methylxanthate 2 on reaction with NaH/Me I. Reductive deoxygenation of compound 2 by Bu₃SnH gives the corresponding 3-deoxy glucose derivative 3 and on acid-catalyzed regioselective deprotection of C-5,6-acetonide gives the diol 4. The diol on oxidative cleavage with NaIO₄ gives the aldehyde 5, which on further condensation with benzylamine followed by reduction with NaBH₄ gives the amine 7. Z-Protection of the amine followed by methanolysis gives methyl furanoside 9. Reaction of 9 with methanesulfonyl chloride/Et₃N gives the corresponding C-3-O-mesylate derivative 10. Catalytic hydrogenation of compound 10 (Pd/C/H₂/MeOH 3 kg) gives bicyclic oxaazo compound 11, due to deprotection of the N-benzyl- and Z-protecting groups and intramolecular nucleophilic displacement of the C-2- O-mesylate by the C-5 amine in a one-pot reaction. Z-Protection of the amine 11 followed by acid-catalyzed hydrolysis gives acetal 13. Reduction of acetal by use of NaBH₄ gives Z-prolinol 14. Selective oxidation of diol 14 by (2,2,6,6-tetramethylpiperidin-1-yl)-oxyl (TEMPO)/[(bis)(acetoxy)iodo]benzene (BAIB) and NaClO₂/NaH₂PO₄, followed by Z-deprotection, gives the title compound I in 3.5% overall yield from D-glucose.     

Total synthesis of (3Z,9Z,6S,7R) and (3Z,9Z,6R,7S)-6,7-epoxy-3,9-octadecadienes

(3Z,9Z,6S,7R)-6,7-epoxy-3,9-octadecadiene (1) and (3Z,9Z,6R,7S)-6,7-epoxy-3,9-octadecadiene (2) have been stereoselectively synthesized in eight steps from 2-pentyn-1-ol with an overall yield of 8%. The key steps involved the Sharpless asymmetric dihydroxylation of (2E)-oct-2-en-5-yn-1-ol (6). The new synthetic method is suitable for multigram-scale preparation of 1 and 2 and might be used for producing sufficient quantities of the sex pheromone components for management of the pest of tea plantations.     

Metabolism of Deuterated Isomeric 6,7‐Dihydroxydodecanoic Acids in Saccharomyces cerevisiae – Diastereo‐ and Enantioselective Formation and Characterization of 5‐Hydroxydecano‐4‐lactone (=4,5‐Dihydro‐5‐(1‐hydroxyhexyl)furan‐2(3H)‐one) Isomers

The chemical synthesis of deuterated isomeric 6,7‐dihydroxydodecanoic acid methyl esters 1 and the subsequent metabolism of esters 1 and the corresponding acids 1a in liquid cultures of the yeast Saccharomyces cerevisiae was investigated. Incubation experiments with (6R,7R)‐ or (6S,7S)‐6,7‐dihydroxy(6,7‐²H₂)dodecanoic acid methyl ester ((6R,7R)‐ or (6S,7S)‐(6,7‐²H₂)‐ 1 , resp.) and (±)‐threo‐ or (±)‐erythro‐6,7‐dihydroxy(6,7‐²H₂)dodecanoic acid ((±)‐threo‐ or (±)‐erythro‐(6,7‐²H₂)‐ 1a , resp.) elucidated their metabolic pathway in yeast (Tables 1–3). The main products were isomeric ²H‐labeled 5‐hydroxydecano‐4‐lactones 2 . The absolute configuration of the four isomeric lactones 2 was assigned by chemical synthesis via Sharpless asymmetric dihydroxylation and chiral gas chromatography (Lipodex ^® E). The enantiomers of threo‐ 2 were separated without derivatization on Lipodex ^® E; in contrast, the enantiomers of erythro‐ 2 could be separated only after transformation to their 5‐O‐(trifluoroacetyl) derivatives. Biotransformation of the methyl ester (6R,7R)‐(6,7‐²H₂)‐ 1 led to (4R,5R)‐ and (4S,5R)‐(2,5‐²H₂)‐ 2 (ratio ca. 4 : 1; Table 2). Estimation of the label content and position of (4S,5R)‐(2,5‐²H₂)‐ 2 showed 95% label at C(5), 68% label at C(2), and no ²H at C(4) (Table 2). Therefore, oxidation and subsequent reduction with inversion at C(4) of 4,5‐dihydroxydecanoic acid and transfer of ²H from C(4) to C(2) is postulated. The 5‐hydroxydecano‐4‐lactones 2 are of biochemical importance: during the fermentation of Streptomyces griseus, (4S,5R)‐ 2 , known as L‐factor, occurs temporarily before the antibiotic production, and (?)‐muricatacin (=(4R,5R)‐5‐hydroxy‐heptadecano‐4‐lactone), a homologue of (4R,5R)‐ 2 , is an anticancer agent.     

Hydroxylation of a vitamin D A-ring fragment

Summary When the benzoate of (S)-(Z)-2-(5-(tert-butyldimethylsiloxy)-2-methylencyclohexyliden)-ethanol (5) is treated with 2.5 equivalents of Hg(OOCCF₃)₂ in dryTHF, a smooth and selective allylic hydroxylation occurs. The C-1 functionalized vitamin D A-ring synthon6 is isolated in 65 to 70% yield in a single step.

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Hydroxylierung eines Vitamin D A-Ring-Fragments (Kurze Mitt.)

Zusammenfassung Umsetzung des Benzoats von (S)-(Z)-2-(5-(tert-Butyldimethylsiloxy)-2-methylencyclohexyliden)-ethanol (5) mit 2.5 Äquivalenten Hg(OOCCF₃)₂ in trockenemTHF führt zu einer selektiven allylischen Hydroxylierung. Damit ist das an C-1 funktionalisierte Vitamin D A-Ring-Fragment6 in einem einzigen Schritt in einer Ausbeute von 65 bis 70% zugänglich.

     

Pheophytin analogues from the medicinal lichen Usnea diffracta

A new pheophytin, (13²S, 17S, 18S)-13²-hydroxy-20-chloro-ethylpheophorbide a (3), along with two known analogues (1–2) were isolated from the lichen Usnea diffracta Vainio (Parmeliaceae). Among them, compound 3 was a rare C-20-chloro type pheophytin obtained from lichens. Their structures were elucidated by extensive spectroscopic analysis, and all the compounds were obtained for the first time from U. diffracta. Compounds (1–3) were evaluated for their xanthine oxidase (XO) inhibitory activities in vitro, and the results showed that 1–3 possessed significant enzyme inhibitory actions with IC₅₀ values of 46.9 ± 3.8, 75.9 ± 7.4 and 42.1 ± 1.7 μg/mL, respectively.     

Synthesis and Structural Analysis of Higher Analogs of Sucrose

ABSTRACT

Three sucrose monoalcohols with free hydroxyl groups at C-1', C-6, and C-6' (1, 4, and 6) were prepared selectively and in good yield from 2,3,3',4,4'-penta-O-benzylsucrose. These compounds were oxidized to aldehydes and reacted with stabilized ylide, Ph₃P=CHCO₂Me to afford appropriate α,β-unsaturated esters 10, 11, and 12. Each olefin was cis-hydroxylated with OsO₄/NMO to stereoisomeric diols 13/14, 15/16, and 17/18, configurations of which were assigned by chemical correlation and CD evaluation. Stereoselectivity of the osmylation reaction was surprisingly low (ca 3:2), especially as compared to a similar process performed on simple derivatives of 6,7-unsaturated methyl glycosides for which the ratio of isomeric diols was assigned as 10:1. The osmylation of 11 (derivative homologated by a C₂-unit at the glucose part) did not obey Kishi's rule. Horner-Emmons reaction of sucrose aldehyde 7 with a sugar-derived phosphonate 22 afforded α,β-unsaturated derivative 24, homologated by a C₇-unit at the glucose end.     

Asymmetric Sulfonium Ylide Mediated Cyclopropanation: Stereocontrolled Synthesis of (+)‐LY354740

The reaction of ester‐stabilized sulfonium ylides with cyclopentenone to give (+)‐ 5 ((1S,5R,6S)‐ethyl 2‐oxobicyclo[3.1.0]hexane‐6‐carboxylate), an important precursor to the pharmacologically important compound (+)‐LY354740, has been studied using chiral sulfides operating in both catalytic (sulfide, Cu(acac)₂, ethyl diazoacetate, 60 °C) and stoichiometric modes (sulfonium salt, base, room temperature). It was found that the reaction conditions employed had a major influence over both diastereo‐ and enantioselectivity. Under catalytic conditions, good enantioselectivity with low diastereoselectivity was observed, but under stoichiometric conditions low enantioselectivity with high diastereoselectivity was observed. When the stoichiometric reactions were conducted at high dilution, diastereoselectivity was reduced. This indicated that base‐mediated betaine equilibration was occurring (which is slow relative to ring closure at high dilution). Based on this model, conditions for achieving high enantioselectivity were established as follows: use of a preformed ylide, absence of base, hindered ester (to reduce ylide‐mediated betaine equilibration), and low concentration. Under these conditions high enantioselectivity (95 % ee) was achieved, albeit with low diastereocontrol. Our model for selectivity has been applied to other sulfonium ylide mediated cyclopropanation reactions and successfully accounts for the diastereoselectivity observed in all such reported reactions to date.     

Application of the AAA reaction to the synthesis of the furanoside of C-2-epi-hygromycin A: a total synthesis of C-2-epi-hygromycin A

A strategy for stereocontrolled syntheses of furanoside type of natural products is developed for a glycosyl aryl ether. This strategy resolves the issue of low diastereoselectivity typical of normal glycosidation methods for furanosides. All the stereochemistry ultimately derives from a desymmetrization of a 2,5-diacyloxy-2,5-dihydrofuran using Pd catalyzed asymmetric allylic alkylation which sets both the absolute stereochemistry and 1,4-relative stereochemistry. Diastereo-controlled elaboration of the 3,4-double bond then completes the synthesis. A new conjunctive reagent, 1-nitro-1-phenylsulfonyl-ethane, is developed to serve as an acyl anion equivalent. The utility of a phenol as a nucleophile in the Pd catalyzed glycosylation is demonstrated. From this strategy emerged a short, practical synthesis of C-2-epi-hygromycin A.     

Two new steroids with cytotoxicity from the marine sponge Dactylospongia elegans collected from the South China Sea

A new steroid, (3S,5R,9R,10S,13R,17R,20R,24S,22E)-ergosta-6,8,22-triene-3,25-diol (1), and its sulfonated analogue (2) together with a known one, 5α,8α-epidioxy-cholest-6-en-3β-ol (3) were isolated from the marine sponge Dactylospongia elegans collected from the South China Sea. The new structures including absolute configurations were established by the HRESIMS and 1D and 2D NMR analysis coupled with the X-ray crystal analysis. Both of 1 and 2 exhibited cytotoxicity against cancer cell line MCF-7 with IC₅₀ values of 9.7 and 8.5 μM, respectively.     

An Efficient Approach to the Synthesis of Ethyl Esters of 2,6-Anhydro-3-Deoxy-D-Gluco And D-Allo-Heptanoates

ABSTRACT

An efficient synthesis of analogues of DAH (3-deoxy-D-arabino-hept-2-ulosonic acid) and DRH (3-deoxy-D-ribo-hept-2-ulosonic acid) is described. The route exploits a previously published highly double-stereoselective hetero Diels-Alder reaction catalyzed by a chiral salenCo(II) complex. Asymmetric dihydroxylation followed by selective reduction leads to stereoselective introduction of hydroxy groups at C-4 and C-5. Oxidative cleavage of the C-6 side-chain, in situ reduction of the resulting aldehyde and deprotection afford the desired targets, which may be useful precursors to the simple analogues of the anti-influenza agent GG167.     

Conformational Analysis. XIX properties and reactions of 1,3-oxathianes VIII A 1H NMR conformational study of methyl-substituted derivatives

The addition of thioacetic acid to unsaturated alcohols or acids was utilized to obtain mercaptoalkanols which were condensed with suitable carybonyl compounds to prepare 24 methyl-substituted 1,3-oxathianes. The ¹H NMR spectra of the 1,3-oxathiane products were recorded at 60, 100 and/or 300 MHz and fully analysed. The results are best explained by a chair form which is completely staggered in the C-4? C-5? C-6 moiety ψ₄₅ or (ψ₅₆=60±1°). 1,3-Oxathianes having syn-axial 2,4- (and/or 2,6-) methyl-methyl interactions exist appreciably, if not exclusively, in twist forms. The vicinal coupling constants lead to the conformational free energies of axial methyl groups at C-4, ΔG°=7.4±0.4 kJ mol^?1, and at C-5, ΔG°=3.7±0.3 kJ mol^?1, in good agreement with previous estimates. They also show that both r-4,cis-5,trans-6- and r-4,trans-5,trans-6- trimethyl-1,3-oxathianes greatly favour the chiar form where the methyl group at C-4 is axial. The chair-twist energy parameters are reestimated at ΔH°_CT 27.0 kJ mol^?1, ΔS°_CT 11.6J mol^?1K^?1, and ΔG°_CT(298) 23.5 kJ mol^?1 for a 2,5-twist form.     

Total Synthesis of Eliglustat via Diastereoselective Amination of Chiral para-Methoxycinnamyl Benzyl Ether

Eliglustat (Cerdelga^®, Genzyme Corp. Cambridge, MA, USA) is an approved drug for a non-neurological type of Gaucher disease. Herein, we describe the total synthesis of eliglustat 1 starting from readily available 1,4-benzodioxan-6-carbaldehyde via Sharpless asymmetric dihydroxylation and diastereoselective amination of chiral para-methoxycinnamyl benzyl ethers using chlorosulfonyl isocyanate as the key steps. Notably, the reaction between syn-1,2-dibenzyl ether 6 and chlorosulfonyl isocyanate in the mixture of toluene and hexane (10:1) afforded syn-1,2-amino alcohol 5 at a 62% yield with a diastereoselectivity > 20:1. This observation can be explained by competition between the S_Ni and the S_N1 mechanisms, leading to the retention of stereochemistry.     

5-Keto-Mannose (D-Lyxo-Hexos-5-Ulose) in Aqueous Solution-Isomeric Composition Dominated by α/β D-Fructofuranose Related Structures

Abstract

Selective C-6 hydroxyl triphenylmethylation of methyl 2,3-O-isopropylidene-α-D-mannofuranose (1), followed by C-5 hydroxyl oxidation and sequential removal of protecting groups in aqueous acid, yielded D-lyxo-hexos-5-ulose (5-keto-mannose, 5) as a mixture of isomeric forms. The isomeric mixture of 5 in D₂O solution was carefully examined using ¹H and ¹³C NMR techniques and structural assignments were made for seven isomers. The most prevalent form of 5 observed was the ketofuranose isomer 2S, 5R-D-lyxo-hexo-5,2-furanos-5-ulose 1-hydrate (5a, 52%), with its 2S, 5S-ketofuranose anomer (5b) being the next most abundant (14%). Also identified in the mixture were the α and β-hexofuranos-5-uloses 5c (6%) and 5d (< 2%), the pyranose structure 1R,5R-lyxo-hexopyranos-5-ulose 5e (10%), and the anhydro isomer 1R,5R-1,6-anhydro-D-lyxo-hexopyranos-5-ulose (5f, 5%), present in ¹ C ₄ conformation. Limited spectral information suggests that the remaining isomer 5g (8%) is a hydrated acyclic aldehyde form of 5.     

Stereoselective synthesis of the lichen metabolite, (+) montagnetol and its congeners as antimicrobial agents

Abstract

In view of structural diversity, (+) montagnetol, the major metabolite of the fruticose lichen, Roccella montagnei was synthesized along with three of its congeners by employing highly efficient protocols. (+) Montagnetol (2?R, 3S; 11) and (-) montagnetol (2S, 3R; 5) were synthesized in 7 and 9 steps, respectively, from L-ascorbic acid. The two new congeners 3 (2?R, 3R) and 6 (2S, 3S), which differ in configuration at C-2 and C-3 positions of the (+) montagnetol, were synthesized from (?) diethyl D-tartrate and (+) diethyl L-tartrate, respectively. The synthesized compounds were evaluated in vitro for antimicrobial activity against two Gram-positive (S. aureus and E. coli) and two Gram-negative (S. typhi and P. aeruginosa) bacteria and one fungal strain Candida albicans. Interestingly, the congener 3 showed promising anti-bacterial activity (MIC: 0.062?µg/ml) against P. aeruginosa, whereas the congener 6 displayed potent anti-fungal activity (MIC: 0.062?µg/ml) against C. Albicans.     

Unexpected fluorous solvent effect on oxidation of 1-thioglycosides

Oxidation of various 1-thioglycopyrano- and furanosides with H₂O₂/Ac₂O/SiO₂ was performed in CH₂Cl₂/aprotic perfluorinated solvent mixtures (100:0 to 1:19, v/v). Reactions appeared much faster at a solvent ratio of 1:1 without significant over-oxidation to sulfones and modification of diastereoselectivity. Nevertheless, the nature of both the glycosyl moiety and the protecting group influenced the (S_S):(R_S) product ratio.     

Synthesis and structural studies of C-5 aryl- and C-6 alkyl-substituted pyrimidine derivatives

C-5 and C-6 disubstituted pyrimidine derivatives 2–7 were synthesized. Introduction of the aryl rings at C-5 of pyrimidine moiety in 5 and 6 was performed using palladium-catalyzed Stille cross-coupling reaction. The novel C-6 fluorophenylalkylated 5-phenylpyrimidine derivative (7) was prepared by lithiation of 5-phenylpyrimidine (6) and subsequent reaction of thus obtained organolithium intermediate with p-fluoroacetophenone. The structures of 3, 4 and 6 were determined by X-ray crystal structure analysis. Both methoxy groups in these structures adopt a synperiplanar conformation with respect to the N1 and N3 atoms of the pyrimidine ring. The molecules of 3 and 4 are linked through weak Br···Br interactions into zig-zag chains. The molecules of 6 are assembled into layers by one C–H···O hydrogen bond, C–H···π and aromatic π···π stacking interactions.     

The Isomeric Composition of D-Xylo-hexos-5-ulose (5-Keto-glucose) in Aqueous Solution

Abstract

1,2-O-Isopropylidene-α-D-xylo-hexofuranos-5-ulose (2) was deprotected in aqueous acid solution to give a mixture of at least six isomeric forms and one anhydro form of the parent ketoaldohexose, D-xylo-hexos-5-ulose (3), commonly referred to as 5-keto-glucose. Structural assignment of each form was made based on high field ¹H and ¹³C NMR studies of the mixture in aqueous (D₂O) solution. The dominant isomeric form of 3 was observed to have the pyranose structure 1R,5R-D-xlyo-hexo-pyranos-5-ulose (3a, 67 %) with the next most abundant form being an anhydro structure, 1S,5S-l,6-anhydro-D-xylo-hexopyranos-5-ulose (3c, 18 %). Included among the other isomers were the a and β-1,4-furanose (3d, 3e) and 1-aldehydrol β-5,2-furanose (3f) structures. The isomer present in least amount (3g, > 1 %) is assigned as the α-anomer of 3f. Experimentally determined J_C-1,H-1 values were useful in support of assigned isomer structures.     

(E)‐2‐[2‐(1‐Naphthyl)­vinyl]‐3‐tosyl‐2,3‐di­hydro‐1,3‐benzo­thia­zole

The title compound, C₂₆H₂₁NO₂S₂, which consists of a benzo­thia­zole skeleton with α‐naphthyl­vinyl and tosyl groups at positions 2 and 3, respectively, was prepared by palladium–copper‐catalyzed heteroannulation. The E configuration of the mol­ecule about the vinyl C=C bond is established by the benzothiazole–naphthyl C—C—C—C torsion angle of 177.5 (4)°. The five‐membered heterocyclic ring adopts an envelope conformation with the Csp³ atom 0.380 (6) Å from the C₂NS plane. The two S—C [1.751 (4) and 1.838 (4) Å] and two N—C [1.426 (5) and 1.482 (5) Å] bond lengths in the thia­zole ring differ significantly.     

Stereoselective Synthesis of the Urinary Metabolite N-Acetyl-S-(3,4-dihydroxybutyl)cysteine

On exposure to the potential carcinogen 1,3-butadiene, the major urinary metabolite in humans is N-acetyl-S-(3,4-dihydroxybutyl)cysteine. A novel, stereoselective synthesis of this cysteine–butadiene metabolite has been developed that is suitable for the production of either diastereomer for use in occupational exposure analysis. L-Cysteine and 4-bromo-1-butene are coupled via an S_N2 reaction to give the core structure. A Sharpless asymmetric dihydroxylation using the dihydroquinidine (DHQD) ligand provided the terminal 1,2-diol with the 3-hydroxyl group in the R configuration.

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