Total synthesis of discodermolide: optimization of the effective synthetic route

An efficient and modulable total synthesis of discodermolide (DDM), a unique marine anticancer polyketide is described including related alternative synthetic approaches. Particularly notable is the repeated application of a crotyltitanation reaction to yield homoallylic (Z)-O-ene-carbamate alcohols with excellent selectivity. Advantage was taken of this reaction not only for the stereocontrolled building of the syn-anti methyl-hydroxy-methyl triads of DDM, but also for the direct construction of the terminal (Z)-diene. Of particular interest is also the installation of the C13=C14 (Z)-double bond through a highly selective dyotropic rearrangement. The preparation of the middle C8-C14 fragment in two sequential stages and its coupling to the C1-C7 moiety was a real challenge and required careful optimization. Several synthetic routes were explored to allow high and reliable yields. Due to the flexibility and robust character of this approach, it might enable a systematic structural variation of DDM and, therefore, the elaboration and exploration of novel discodermolide structural analogues.     

Cystobactamid 507: Concise Synthesis,Mode of Action,and Optimization toward More Potent Antibiotics

Lack of new antibiotics and increasing antimicrobial resistance are among the main concerns of healthcare communities nowadays, and these concerns necessitate the search for novel antibacterial agents. Recently, we discovered the cystobactamids—a novel natural class of antibiotics with broad-spectrum antibacterial activity. In this work, we describe 1) a concise total synthesis of cystobactamid 507, 2) the identification of the bioactive conformation using noncovalently bonded rigid analogues, and 3) the first structure–activity relationship (SAR) study for cystobactamid 507 leading to new analogues with high metabolic stability, superior topoisomerase IIA inhibition, antibacterial activity and, importantly, stability toward the resistant factor AlbD. Deeper insight into the mode of action revealed that the cystobactamids employ DNA minor-groove binding as part of the drug–target interaction without showing significant intercalation. By designing a new analogue of cystobactamid 919-2, we finally demonstrated that these findings could be further exploited to obtain more potent hexapeptides against Gram-negative bacteria.     

Synthesis of beta-analogues of C-mannosyltryptophan, a novel C-glycosylamino acid found in proteins

alpha-C-Mannosyltryptophan (alpha-C-Man-Trp) has been found to be a novel post-translational modification of tryptophan found from some biologically important glycoproteins. In order to analyze the biological functions of alpha-C-Man-Trp, we have developed an efficient synthetic strategy for alpha-C-Man-Trp and its glucose and galactose analogues, starting from alpha-C-glycosidation of the corresponding hexapyranoside derivatives with tinacetylene. According to the synthetic routes, we describe here syntheses of beta-anomers of C-Man-Trp, and its glucose and galactose analogues from the corresponding beta-C-glycosylacetylenes. During this study, we have developed a highly stereocontrolled synthesis of beta-C-mannosylacetylene that is required for the synthesis of beta-C-Man-Trp, while the precedented method gave an anomeric mixture of the C-mannosylacetylene. The synthetic C-Man-Trp and its analogues were analyzed by HPLC.     

Chemical synthesis and molecular recognition of phosphatase-resistant analogues of phosphatidylinositol-3-phosphate

The remodeling of phosphatidylinositol polyphosphates in cellular membranes by phosphatases and kinases orchestrates the signaling by these lipids in space and time. To provide chemical tools to study the changes in cell physiology mediated by these lipids, three new metabolically stabilized (ms) analogues of phosphatidylinositol-3-phosphate (PtdIns(3)P) were synthesized. We describe herein the total asymmetric synthesis of 3-methylphosphonate, 3-(monofluoromethyl)phosphonate and 3-phosphorothioate analogues of PtdIns(3)P. From differentially protected D-myo-inositol key intermediates, a versatile phosphoramidite reagent was employed in the synthesis of PtdIns(3)P analogues with diacylglyceryl moieties containing dioleoyl, dipalmitoyl, and dibutyryl chains. In addition, we introduce a new phosphorylation reagent, (monofluoromethyl)phosphonyl chloride, which has general applications for the preparation of "pKa-matched" monofluorophosphonates. These ms-PtdIns(3)P analogues exhibited reduced binding activities with 15N-labeled FYVE and PX domains, as significant 1H and 15N chemical shift changes in the FYVE domain were induced by titrating ms-PtdIns(3)P analogues into membrane-mimetic dodecylphosphocholine micelles. In addition, the PtdIns(3)P analogues with dioleoyl and dipalmitoyl chains were substrates for the 5-kinase enzyme PIKfyve; the corresponding phosphorylated ms-PI(3,5)P2 products were detected by radio-TLC analysis.     

Diastereoselective one-pot Wittig olefination-Michael addition and olefin cross metathesis strategy for total synthesis of cytotoxic natural product (+)-varitriol and its higher analogues

A stereoselective route for the total synthesis of anticancer marine natural product (+)-varitriol (1) is detailed herein. The impressive biological activity and interesting structural features of natural (+)-varitriol fuelled us to undertake the synthesis of some higher analogues (1a-j) of this molecule. The key features of the synthetic strategy include one-pot Wittig olefination followed by a highly diastereoselective oxa-Michael addition to assemble stereochemically pure tetrasubstituted THF moiety of the natural varitriol and olefin cross metathesis to couple the aromatic part with tetrasubstituted THF moiety. The total synthesis of title natural product is efficient with 21.8% overall yield for 9 linear steps from D-ribose and thus facilitates the more scaled-up practical route for the synthesis of 1 and its analogues as well. The synthetic (+)-varitriol (1) and its analogues were screened for their cytotoxicity. The present synthetic approach paves the way for preparation of numerous analogues of the title natural product for drug development.     

Total synthesis of the marine alkaloid halitulin

The structure of the strongly cytotoxic marine alkaloid halitulin (1) has been confirmed by total synthesis and its absolute configuration determined as (15S). The synthesis follows a strategy previously reported by one of us and uses an efficient preparation of the quinoline-7,8-diol unit by modified Baeyer-Villiger and Skraup reactions. The O-benzyl protecting groups were removed in the last step of the synthesis by transfer hydrogenolysis without concomitant reduction of the quinoline ring. The method can be applied for the synthesis of halitulin analogues.     

Alanine scan of [L-Dap(2)]ramoplanin A2 aglycon: assessment of the importance of each residue

In efforts that define the importance of each residue and that identify key regions of the molecule, an alanine scan of the ramoplanin A2 aglycon, a potent antibiotic that inhibits bacterial cell wall biosynthesis, is detailed. As a consequence of both its increased stability (lactam vs lactone) and its "relative" ease of synthesis, the alanine scan was conducted on [Dap2]ramoplanin A2 aglycon, which possesses antimicrobial activity equal to or slightly more potent than that of ramoplanin A2 or its aglycon. Thus, 14 key analogues of the ramoplanin A2 aglycon, representing a scan of residues 3-13, 15, and 17, were prepared enlisting a convergent solution-phase total synthesis that consolidated the effort to a manageable level. The antimicrobial activity of the resulting library of analogues provides insight into the importance and potential role of each residue of this complex glycopeptide antibiotic.     

Studies toward the synthesis of pinolidoxin, a phytotoxic nonenolide from the fungus Ascochyta pinodes. Determination of the configuration at the C-7, C-8, and C-9 chiral centers and stereoselective synthesis of the C(6)-C(18) fragment

The absolute stereochemistry at the C-7, C-8, and C-9 chiral centers of pinolidoxin (1) has been determined by chemical and spectral methods. First, the synthesis of four stereoisomeric fully benzoylated 2,3-erythro-1,2,3,4-heptanetetrols, corresponding to the C(6)-C(18) portion of the natural substance, has been accomplished starting from meso-tartaric acid. As next step, the selection of the synthetic tetrabenzoate possessing "natural" stereochemistry (10a'), suitable for absolute configuration determination, has been carried out by correlation with its "natural" homologue derived from degradation of pinolidoxin. Determination of the stereochemistry at the title chiral centers has been carried out by application of the Mosher's method both to 7a', a compound stereochemically related to 10a', and to pinolidoxin itself. The stereoselective synthesis of a protected form of the C(6)-C(18) portion of pinolidoxin, to be used in its total synthesis, has also been accomplished starting from commercially available D-erythronolactone.     

Macrolactamization versus macrolactonization: total synthesis of FK228, the depsipeptide histone deacetylase inhibitor

The cyclic depsipeptide FK228 is the only natural product histone deacetylase (HDAC) inhibitor that has advanced to clinical trials as an anticancer agent. While currently obtained by fermentation, total synthesis is an attractive alternative that will facilitate the preparation of unnatural analogues. The previous total syntheses of FK228 featured macrocylization by ester bond formation from a seco-hydroxy acid. Such routes are operationally jeopardized by the steric hindrance of the carboxylic acid and the sensitivity of the allylic alcohol toward elimination. We report a strategically different approach whereby the ester bond is formed intermolecularly at an early stage and macrocyclization is efficiently achieved by amide bond formation.     

Glucose-based surfactants with hydrogenated, fluorinated, or hemifluorinated tails: synthesis and comparative physical-chemical characterization

(Hemi)fluorinated hydrophobic chains have been found to minimize the denaturating propensity of surfactants toward membrane proteins. The work reported herein deals with the synthesis of a new series of non-ionic glucose-based surfactants endowed with a hybrid hemifluorocarbon chain. The convergent synthesis is based on a one-pot reduction/alkylation of hemifluorinated thioacetate and glucosylated trishydroxymethyl acrylamidomethane using NaBH4 in methanol. This "mild" alkylation was studied in order to improve yields and to pass up the use of an excess of commercially unavailable hemifluorinated thiols. The physical-chemical properties in aqueous solution of this novel series were studied by surface tension measurement and dynamic light scattering (DLS), as well as their behavior upon reverse-phase chromatography, and were compared with those of their hydrogenated and perfluorinated analogues. The atypical effect of the additional ethyl tip to the fluorinated chain was demonstrated by higher critical micellar concentration values and abnormal hydrophobicities measured by reverse-phase chromatography. Moreover, according to Israelachvili's concept, DLS studies showed that surfactants bearing bulkier polar head self-assemble into small and well-defined aggregates, suggesting the formation of spherical micelles rather than the cylindrical ones usually observed with classical fluorinated surfactants.     

Chiron approach to the synthesis of yashabushidiol B, (3S,5S)-1-(4′-hydroxyphenyl)-7-phenylheptane-3,5-diol, and its 4′-methoxy analogue

The total synthesis of yashabushidiol B 4, a linear diarylheptanoid containing a 1,3-diol system and its analogues 5 and 6 has been achieved by utilizing intermediate 7, which was derived from d-glucose. The Wittig reaction is the key step of our synthetic strategy.     

Asymmetric Total Synthesis of Propindilactone G,Part 1: Initial Attempts towards the Synthesis of Schiartanes

Our first‐generation synthetic study towards the total synthesis of propindilactone G ( 1 ) and its analogues is reported. The key synthetic steps were an intramolecular Pauson–Khand reaction (PKR) and a vinylogous Mukaiyama reaction (VMAR). The stereoselective synthesis of the CDE ring moiety with an all‐carbon quaternary center through a PKR was difficult, whilst a VMAR afforded a product with the opposite stereochemistry at the C20 position on the side chain. These results led us to redesign our synthetic strategy for the total synthesis of compound 1 .     

常用中药藁本中新化合物的结构, 合成及活性研究

藁本是常用中药。中国药典收录的藁本有两种植物: 中国藁本(Ligusticumsinense Oliv. )和辽藁本(L. jeholense Thell), 另外新疆藁本(Conioselinumvaginatum Thell)做为藁本代用品在新疆地区广泛应用。我们对三种藁本植物中的化学成分进行深入研究, 从中共分到30种单体化合物并进行结构鉴定, 其中4种新化合物。初步药理实验发现从新疆藁本中分到的几个化合物具明显降酶保肝活性; 从中国蒿本中分到的蒿本酚显示较强的免疫抑制活性, 为探讨构效关系,作者完成了这些具活性成分的合成研究, 并合成一些结构类似物, 详细的活性研究还在进行中。     

Total synthesis and biological evaluation of (-)-apicularen A and its analogues

The total synthesis of (-)-apicularen A (1), a highly cytostatic 12-membered macrolide, and its analogues is described. The convergent and distinct approach not only provides 1, but also opens the opportunity to synthesize C10-C11 functional analogues of 1. The key steps of the total synthesis include assembling of iodoalkene 12 and aldehyde 13by Nozaki-Hiyama-Kishi (NHK) coupling, stereospecific construction of 2,6-trans-disubstituted dihydropyran by Pd(II)-catalyzed 1,3-chirality transfer reaction, and Yamaguchi macrolactonization. The (17E,20Z,22Z)-heptadienoylenamine moiety in the side chain is installed by an efficient Cu(I)-mediated coupling to complete the synthesis. Analogues of C11-epi-, C11-deoxy-C10-α-hydroxy-, and C10-C11 dehydrated apicularen A 3-5 were also prepared. Cytostatic activities of (-)-apicularen A and the three analogues for three different cancer cell lines are described.     

Metal-free catalysts for the hydrolysis of RNA derived from guanidines, 2-aminopyridines, and 2-aminobenzimidazoles

2-aminopyridine and 2-aminobenzimidazole were chosen as structural analogues to substitute guanidinium groups in receptor molecules designed as phosphoryl transfer catalysts. Shifting the pKa of the guanidinium analogues toward 7 was expected to raise catalytic activities in aqueous buffer. Although the pKa's of both heterocycles are similar (6.2 and 7.0), only 2-aminobenzimidazole led to active RNA cleavers. All cleavage assays were run with fluorescently labeled substrates and a DNA sequencer. RNase contaminations would degrade RNA enantioselectively. In contrast, achiral catalysts such as 9b and 10b necessarily induce identical cleavage patterns in RNA and its mirror image. This principle allowed us to safely rule out contamination effects in this study. The most active catalysts, tris(2-aminobenzimidazoles) 9b and 10b, were shown by fluorescence correlation spectroscopy (FCS) to aggregate with oligonucleotides. However, at very low concentrations the compounds are still active in the nonaggregated state. Conjugates of 10b with antisense oligonucleotides or RNA binding peptides, therefore, will be promising candidates as site specific artificial ribonucleases.     

Chemoenzymatic approach to enantiopure streptogramin B variants: characterization of stereoselective pristinamycin I cyclase from Streptomyces pristinaespiralis

Streptogramin B antibiotics are cyclic peptide natural products produced by Streptomyces species.In combination with the synergistic group A component, they are "last line of defense" antimicrobial agents against multiresistant cocci. The racemization sensitivity of the phenylglycine (Phg(7)) ester is a complex challenge in total chemical synthesis of streptogramin B molecules. To provide fast and easy access to novel streptogramin antibiotics, we introduce a novel chemoenzymatic strategy in which diversity is generated by standard solid phase protocols and stereoselectivity by subsequent enzymatic cyclization. For this approach, we cloned, overproduced, and biochemically characterized the recombinant thioesterase domain SnbDE TE of the pristinamycin I nonribosomal peptide synthetase from Streptomyces pristinaespiralis. SnbDE TE catalyzes regioselective ring closure of linear peptide thioester analogues of pristinamycin I as well as stereoselective cyclization out of complex in situ racemizing substrate mixtures, enabling synthesis of Streptogramin B variants via a dynamic kinetic resolution assay. A remarkable substrate tolerance was detected for the enzymatic cyclization including all the seven positions of the peptide backbone. Interestingly, SnbDE TE was observed to be the first cyclase from a macrolactone forming NRPS which is additionally able to catalyze macrolactamization of peptide thioester substrates. An N-methylated peptide bond between positions 4 and 5 is mandatory for a high substrate turnover. The presented strategy is potent to screen for analogues with improved activity and guides our understanding of structure--activity relationships in the important class of streptogramin antibiotics.     

A simple, rapid and mild one pot synthesis of benzene ring acylated and demethylated analogues of harmine under solvent-free conditions

A simple, rapid, solvent-free, room temperature one pot synthesis of benzene ring acylated and demethylated analogues of harmine using acyl halides/acid anhydrides and AlCl(3) has been developed. Eight different acyl halides/acid anhydrides were used in the synthesis. The resulting mixture of products was separated by column chromatography to afford 10- and 12-monoacyl analogues, along with 10,12-diacyl-11-hydroxy products. In five cases the corresponding 10-acyl-11-hydroxy analogues were also obtained. Yields from the eight syntheses (29 products in total) were in the 6-34% range and all compounds were fully characterized.     

Modification in the side chain of solomonsterol A: discovery of cholestan disulfate as a potent pregnane-X-receptor agonist

Seven synthetic analogues of the PXR (pregnane-X-receptor) potent natural agonist solomonsterol A were prepared by total synthesis. Their activity toward PXR was assessed by transactivation and RT-PCR assays. The study discloses cholestan disulfate (8) as a new, simplified agonist of PXR. By in vitro studies on hepatic cells we have demonstrated that this compound is a potent PXR agonist and functional characterization in human macrophages and hepatic stellate cells provided evidence that cholestan disulfate (8) has the ability to modulate the immune response triggered by bacterial endotoxin as well as to counter-activate hepatic stellate cell activation induced by thrombin. Because inhibition of immune-driven circuits might have relevance in the treatment of inflammation and liver fibrosis, the present data support the development of cholestan disulfate (8) in preclinical models of inflammatory diseases.     

The total synthesis and biological evaluation of nafuredin-γ and its analogues

Nafuredin (1) is converted to nafuredin-γ (2) under mild basic conditions and both compounds exhibit the same inhibitory activity and selectivity against NADH-fumarate reductase (complex I). The total synthesis of 2 was achieved by a convergent approach using Stille coupling. The structural elements required for inhibitory activity against NADH-fumarate reductase (complex I) were then investigated by evaluation of nafuredin-γ (2) and its structural analogues.