Synthesis of polyhydroxylated pyrrolizidine and indolizidine compounds and their glycosidase inhibitory activities

The synthesis of the natural product 3-epi-casuarine and two tricyclic ether bridged analogues, plus 7-deoxy-3,6-diepi-casuarine, 7-epi-australine, 1-epi-castanospermine and 1,6-diepi-castanospermine is described. The glycosidase inhibitory activities of these compounds, along with that of uniflorine A and other polyhydroxylated pyrrolizidines and indolizidines that we have published before, are reported.     

5-epi-Sinuleptolide from Soft Corals of the Genus Sinularia Exerts Cytotoxic Effects on Pancreatic Cancer Cell Lines via the Inhibition of JAK2/STAT3, AKT,and ERK Activity

Pancreatic ductal adenocarcinoma is one of the most lethal malignancies: more than half of patients are diagnosed with a metastatic disease, which is associated with a five-year survival rate of only 3%. 5-epi-Sinuleptolide, a norditerpene isolated from Sinularia sp., has been demonstrated to possess cytotoxic activity against cancer cells. However, the cytotoxicity against pancreatic cancer cells and the related mechanisms are unknown. The aim of this study was to evaluate the anti-pancreatic cancer potential of 5-epi-sinuleptolide and to elucidate the underlying mechanisms. The inhibitory effects of 5-epi-sinuleptolide treatment on the proliferation of pancreatic cancer cells were determined and the results showed that 5-epi-sinuleptolide treatment inhibited cell proliferation, induced apoptosis and G2/M cell cycle arrest, and suppressed the invasion of pancreatic cancer cells. The results of western blotting further revealed that 5-epi-sinuleptolide could inhibit JAK2/STAT3, AKT, and ERK phosphorylation, which may account for the diverse cytotoxic effects of 5-epi-sinuleptolide. Taken together, our present investigation unveils a new therapeutic and anti-metastatic potential of 5-epi-sinuleptolide for pancreatic cancer treatment.     

Isolation synthesis and glycosidase inhibition profile of 3-epi-casuarine

3-epi-Casuarine, the first naturally occurring stereoisomer of casuarine, was isolated from Myrtus communis L. The glycosidase inhibition profile and NMR spectra of 3-epi-casuarine are compared with those of casuarine; the change in configuration at one of the six stereogenic centres causes a dramatic change in the conformation of the bicyclic system. The key step in the 6% overall yield synthesis of 3-epi-casuarine from d-gluconolactone is the efficient cyclization of a completely unprotected pentahydroxyaminomesylate to the pyrrolizidine nucleus. A low yield synthesis of casuarine is also reported.     

8-epi-erythronolide B and its metabolic fate in fermentations of Streptomyces erythreus

8-epi-erythronolide B (4) has been isolated as a product formed from the acid treatment of erythronolide B (3). When this compound was fed to a blocked mutant of the erythromycin producing organism, Streptomycetes erythreus (Abbott 2NU153), nearly quantitative yields of 3-O-(α-l-mycarosyl)-8-epi-erythronolide B (10) were obtained. The much desired 8-epi-erythromycins (2) were not realized.     

Synthesis of 2α- and 2β-substituted-14-epi-previtamin D3 and their genomic activity

2α- and 2β-Substituted analogs of 14-epi-previtamin D₃ were synthesized and isolated after thermal isomerization of 14-epi-vitamin D₃ triene at 80 °C. The VDR binding affinity and transactivation activity of osteocalcin promoter in HOS cells were tested, and the 2α-methyl-substituted analog was found to have greater genomic activity than 14-epi-previtamin D₃. We found that modification at the C2 position of the seco-steroidal skeleton afforded interesting effects for biological genomic activity for the previtamin D form as well as the natural vitamin D form.     

Concise stereoselective synthesis of marine sesterterpene, 16-deacetoxy-12-epi-scalarafuran acetate and its 14-epimer via intramolecular Diels-Alder addition

The stereoselective synthesis of C12 oxygenated marine scalaranic sesterterpene 16-deacetoxy-12-epi-scalarafuran acetate and its 14-epimer were described. A highly stereoselective intramolecular Diels-Alder addition was designed as the key step to construct the ring D, and the absolute configurations of natural 16-deacetoxy-12-epi-scalarafuran acetate was supported by the X-ray diffraction analysis of single crystal of corresponding 16-deacetoxy-12-epi-scalarafuran.     

Synthesis of (2R, 3R)-epigallocatechin-3-O-(4-hydroxybenzoate), a novel catechin from Cistus salvifolius, and evaluation of its proteasome inhibitory activities

The total and semi syntheses of (2R,3R)-epigallocatechin-3-O-(4-hydroxybenzoate), a novel catechin from Cistus salvifolius, were accomplished. The proteasome inhibition and cytotoxic activities of the synthetic compound and its acetyl derivative were studied and compared with (2R,3R)-epigallocatechin-3-gallate (EGCG), the active component from green tea.     

High-Performance Liquid Chromatographic Analysis of Triterpenoids in Commercial Frankincense

A reversed-phase high-performance liquid chromatographic procedure has been developed: it is a simple and specific method for the determination of fifteen pentacyclic triterpenic compounds (α-boswellic acid, 3-O-acetyl-α-boswellic acid, β-boswellic acid, 3-O-acetyl-β-boswellic acid, α-amyrin, β-amyrin, lupeol, 3-epi-α-amyrin, 3-epi-β-amyrin, 3-epi-lupeol, α-amyrenone, β-amyrenone, lupenone, lupeolic acid and 3-O-acetyl-lupeolic acid) found in the most commonly traded frankincense, usually called “Eritrean-type” olibanum. In addition, the chromatographic comparison between fresh commercial resins and botanically certified ones was described in order to determine the geographical and/or the botanical origins of commercial frankincense. According to previous botanical studies, it appears difficult to make an unequivocal distinction between Boswellia carteri and B. sacra. On the other hand, Boswellia frereana (considered as a source of high-grade frankincense) shows a characteristic chromatogram and could be unambiguously distinguished from the other producing species of commercial frankincense. In a chemical point of view, Boswellia carteri and B. sacra were more especially characterized by the presence of lupeolic acid, boswellic acids and their respective O-acetyl derivatives, whereas 3-epi-lupeol was the major compound in B. frereana methanolic extracts.     

A divergent approach for the synthesis of some polyhydroxy pyrrolidines and piperidines from ribosylamine

A simple and efficient synthesis of 1,4-dideoxy-1,4-imino-d-ribitol, 1,4-dideoxy-1,4-imino-l-lyxitol, N-benzyl derivative of d-ribitol, 3,4,5-trihydroxy-piperidine, l-4-epi-isofagomine and d-3-epi-isofagomine, which are glycosidase inhibitors has been described from the commercially available d-ribose as a starting material.     

An asymmetric approach to 5-O-carbamoyl-2-epi-polyoxamic acid and the total synthesis of 2′′-epi-polyoxin J

A stereospecific synthetic approach to 5-O-carbamoyl-2-epi-polyoxamic acid has been developed. The asymmetric nucleophilic addition of 2-lithiofuran to a tert-butanesulfinyl imine was employed as the key step to construct the C-2 stereocenter and 2′′-epi-polyoxin J has been synthesized for the first time. Significantly, the synthesis provides a facile method for the large scale and stereoselective preparation of 5-O-carbamoyl-2-epi-polyoxamic acid and some related diastereoisomers of polyoxins and its analogues because of its simple operation, excellent yield, and high stereoselectivity. This will be convenient for research of the polyoxins’ structure–activity relationship and to search for more potent and effective anticandidal agents.     

An efficient stereocontrolled synthesis of (−)-10-epi-5β,11-dihydroxyeudesmane and (−)-4,10-epi-5β,11-dihydroxyeudesmane

A concise and efficient synthesis of (−)-10-epi-5β,11-dihydroxyeudesmane 1 and (−)-4,10-epi-5β,11-dihydroxyeudesmane 2, via (−)-10-epi-γ-eudesmol 5, was accomplished starting from (+)-dihydrocarvone. The salient feature of our synthesis is the utilization of substrate-directable epoxidation and homogeneous hydrogenation to control the stereochemistry at the C-4 and C-5 positions of the title compounds.     

The combined use of stereoelectronic control and ring closing metathesis for the synthesis of (−)-8-epi-swainsonine

A novel and efficient synthesis of (−)-8-epi-swainsonine 2 is reported. Stereocontrolled diol formation from the bicyclic alkene 3 followed by a stereoselective vinylation of the aldehyde and ring closing metathesis gave the indolizidine ring system, which was converted into (−)-8-epi-swainsonine 2.     

Total synthesis of 4-epi-atpenin A5 as a potent nematode complex II inhibitor

It is clear that atpenins and their analogs are useful chemical tools for elucidation of complex II functionality and that they could act as lead compounds for the development of novel helminth complex II-specific inhibitors. Recently, we discovered 4-epi-atpenin A5 as a potent nematode complex II inhibitor during our SAR studies of atpenin A5. This result led us to embark on a concise total synthesis of 4-epi-atpenin A5. In this study, we describe the total synthesis of 4-epi-atpenin A5. Importantly, this was more concise and practical synthesis than our previous total synthesis of atpenin A5.     

Total Synthesis of 6-Deoxydihydrokalafungin,a Key Biosynthetic Precursor of Actinorhodin,and Its Epimer

In this article, we report the total synthesis of 6-deoxydihydrokalafungin (DDHK), a key biosynthetic intermediate of a dimeric benzoisochromanequinone antibiotic, actinorhodin (ACT), and its epimer, epi-DDHK. Tricyclic hemiacetal with 3-siloxyethyl group was subjected to Et₃SiH reduction to establish the 1,3-cis stereochemistry in the benzoisochromane, and a subsequent oxidation/deprotection sequence then afforded epi-DDHK. A bicyclic acetal was subjected to AlH₃ reduction to deliver the desired 1,3-trans isomer in an approximately 3:1 ratio, which was subjected to a similar sequence to that used for the 1,3-cis isomer that successfully afforded DDHK. A semisynthetic approach from (S)-DNPA, an isolable biosynthetic precursor of ACT, was also examined to afford DDHK and its epimer, which are identical to the synthetic products.     

Stereoselective synthesis of (+)-boronolide and (−)-5-epi-boronolide

Stereoselective synthesis of boronolide and 5-epi-boronolide was achieved from d-(−)-tartaric acid. The key step involves the reduction of a keto Weinreb amide for the synthesis of boronolide, and a single pot construction of a diketone from the bis-Weinreb amide of tartaric acid and subsequent reduction with L-Selectride for 5-epi-boronolide.     

Syntheses of (±)-9-epi-hederacine A and (±)-9-epi-hederacine B

Racemic syntheses of 9-epi-hederacine A and 9-epi-hederacine B have been achieved. Key transformations include a transannular hemiaminal formation for construction of the azabicyclo[3.2.1]octane core fused to a cyclopentane ring.     

Polyhydroxylated pyrrolizidines. Part I: Short and highly stereocontrolled syntheses of hyacinthacines

Two short and highly stereocontrolled syntheses for 7a-epi-hyacinthacine A₂ (7-deoxyalexine) 3 and 5,7a-diepi-hyacinthacine A₃ 4 are, respectively, reported herein. An appropriately protected polyhydroxypyrrolidine, (2R,3R,4R,5S)-3,4-dibenzyloxy-N-benzyloxycarbonyl-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine 5, readily available from d-fructose, was chosen as the chiral starting material.     

Influence of intramolecular hydrogen bonds in the enzyme-catalyzed regioselective acylation of quinic and shikimic acid derivatives

Selective mono-functionalization of 3-epi, 4-epi-, and 5-epi quinic and shikimic acid derivatives has been accomplished by enzymatic acylation with Candida antarctica lipase A (CAL-A). We propose that the selectivity of this lipase is related to both the inherent receptor selectivity and the degree of intramolecular hydrogen bonding in the ligand. Conformational analysis of the hydroxyl protons has been carried out by ¹H NMR spectroscopy. We have shown that exchange of the hydroxyl protons by acid catalysis provides a useful method for the detection of intramolecular hydrogen bonds. The interpretation of exchange rates and coupling constants determines the direction of the H-bonds as conditioned by the relative acceptor and donor properties of the hydroxyl groups. The selectivity of the acylation agrees fully with the effectiveness of H-bonding networks in polyol compounds and with the higher reactivity of the equatorial hydroxyl groups.     

A new eudesmane sesquiterpene glycoside from Parepigynum funingense

A new eudesmane sesquiterpene glycoside,1α,6β-dihydroxy-5,10-bis-epi-eudesm-4(15)-ene-6-O-β-D-glucopyranoside(2), together with a known analogue compound,1α,6β-dihydroxy-5,10-bis-epi-eudesm-3-ene-6-O-β-D-glucopyranoside(1),were isolated from the roots of Parepigynumfuningense.The structure of 2 was determined by 1D and 2D NMR spectroscopy.Compound 1 was isolated from this plant for the first time.     

Asymmetric synthesis of d-fagomine and its diastereoisomers

A divergent strategy for the asymmetric syntheses of d-fagomine and three of its diastereoisomers has been developed. The diastereoselective conjugate addition of an enantiopure lithium amide to an α,β-unsaturated ester was used as the key step to install the correct configuration required for the C(5)-stereogenic centre within the targets. In situ enolate oxidation generated the corresponding anti-α-hydroxy-β-amino ester, which possessed the correct configuration required for the C(4)-stereogenic centre within both d-fagomine and d-3-epi-fagomine. Subsequent epimerisation of this key anti-α-hydroxy-β-amino ester upon oxidation and diastereoselective reduction gave the corresponding syn-α-hydroxy-β-amino ester, which possessed the correct configuration required for the C(4)-stereogenic centre within both d-4-epi-fagomine and d-5-epi-fagomine. Elaboration of both α-hydroxy-β-amino esters upon reduction to the corresponding aldehydes followed by aldol reaction generated the requisite C(3)-stereogenic centres within the target compounds, then cyclisation and deprotection gave the enantiopure iminosugars in good overall yields, as single diastereoisomers (>99:1 dr).