Executing and rationalizing the synthesis of a difluorinated analogue of a ring-expanded calystegine B2

A difluorinated analogue of a ring-expanded calystegine B(2) and some N-protected species were prepared via microwave-mediated transannular ring-opening of an epoxyketone. The diastereofacial selectivity of the epoxidation reaction, which delivers the key intermediate, and the regioselectivity of the transannular reactions were analyzed by density functional theory (DFT) methods. The epoxidation stereoselectivity arises from simple steric control, whereas the ring-closure reactions are subject to thermodynamic control.     

The practical synthesis of a novel and highly potent analogue of bryostatin

Macrocycle 1 is a new highly potent analogue of bryostatin 1, a promising anti-cancer agent currently in human clinical trials. In vitro, 1 displays picomolar affinity for PKC and exhibits over 100-fold greater potency than bryostatin 1 when tested against various human cancer cell lines. Macrocycle 1 can be generated in clinically required amounts by chemical synthesis in only 19 steps (LLS) and represents a new clinical lead for the treatment of cancer.     

Total synthesis and antifungal activity of a carbohydrate ring-expanded pyranosyl nucleoside analogue of nikkomycin B

In a study aimed at investigating an as yet unknown structure-activity relationship of the nikkomycin family of antifungal peptidyl nucleoside antibiotics, the present research reports the synthesis and antifungal evaluation of a carbohydrate ring-expanded pyranosyl nucleoside analogue of nikkomycin B. Employing a convergent synthetic route, independent synthesis of the N-terminal amino acid side chain and a stereoselective de novo construction of the desired pyranosyl nucleoside amino acid fragment was followed by peptidic coupling of the two components, leading to the first synthesis of a carbohydrate ring-enlarged pyranosyl nikkomycin B analogue. In vitro biological evaluation of the above analogue against a variety of human pathogenic fungi demonstrated significant antifungal activity against several fungal strains of clinical significance.     

Multicomponent coupling approach to (+/-)-frondosin B and a ring-expanded analogue

[reaction: see text] A recently discovered multicomponent coupling reaction is used to give direct access to a late intermediate in the synthesis of frondosin B. This intermediate can also be efficiently converted to a ring-expanded analogue of frondosin B by sustained heating of the reaction mixture. An unprecedented tandem 1,7-hydrogen shift, 8pi-electrocyclization is proposed to explain the formation of this ring-expanded species.     

A concise,selective synthesis of the polyketide spacer domain of a potent bryostatin analogue

[reaction: see text] A concise, asymmetric synthesis of the polyketide spacer domain portion (C1-C13) of a highly potent bryostatin analogue was developed. The route utilizes asymmetric hydrogenation methodology to install the C3, C5, and C11 stereocenters, while a substrate directed syn reduction sets the C9 stereocenter. The spacer domain 1 is obtained in 10 steps with a 25% overall yield and is readily incorporated into the synthesis of 2.     

Toward the total synthesis of spirastrellolide A. Part 3: intelligence gathering and preparation of a ring-expanded analogue

Different methods for the formation of the C.25-C.26 bond of spirastrellolide A () are evaluated that might qualify for the end game of the projected total synthesis, with emphasis on metathetic ways to forge the macrocyclic frame.     

Total syntheses of bryostatins: synthesis of two ring-expanded bryostatin analogues and the development of a new-generation strategy to access the C7-C27 fragment

Herein, we report the synthesis of novel ring-expanded bryostatin analogues. By carefully modifying the substrate, a selective and high-yielding Ru-catalyzed tandem enyne coupling/Michael addition was employed to construct the northern fragment. Ring-closing metathesis was utilized to form the 31-membered ring macrocycle of the analogue. These ring-expanded bryostatin analogues possess anticancer activity against several cancer cell lines. Given the difficulty in forming the C16-C17 olefin at a late stage, we also describe our development of a new-generation strategy to access the C7-C27 fragment, containing both the ring B and C subunits.     

Synthesis of diastereomeric,deoxy and ring-expanded sulfone analogues of aigialomycin D

Several analogues of the fungal natural product aigialomycin D (AmD) have been synthesised. These include the stereoisomer 5′R,6′S-AmD, 2,4-di-deoxyAmD, 1′,2′,7′,8′-tetrahydroAmD and a 15-membered macrocyclic sulfone. Growth inhibitory activities of these compounds against the HL-60 leukaemic cell line were measured. The ring-expanded sulfone and tetrahydro-analogue were found to have similar IC₅₀ values to the natural product, whereas the 5′R,6′S-stereoisomer was inactive. Energy minimisation of AmD and the synthesised analogues resulted in a range of lowest energy conformers, from planar, open arrangements of the macrocycle in AmD and tetrahydroAmD to bent, L-shaped structures for the sulfone. The synthesis of methyl orsellinate was investigated and optimised as part of this work. A stereodivergent route to both enantiomers of the diol fragment from d-ribose was also achieved.     

Synthesis of a simplified bryostatin C-ring analogue that binds to the CRD2 of human PKC-alpha and construction of a novel BC-analogue by an unusual Julia olefination process

[structure: see text] The synthesis of two truncated bryostatin analogues 2 and 3 is described. High-field NMR measurements on the C-ring analogue 3 in C(2)H(3)CN containing 25% (2)H(2)O have shown that it binds to the CRD2 of human PKC-alpha at virtually the same position as phorbol-13-acetate (PA) and bryostatin 1 (1). NMR titration studies have also revealed that 3 binds to the CRD2 with a potency similar in magnitude to PA but much less potently than 1.     

Synthesis of a C-glycoside analogue of beta-D-galactosylthreonine

A C-linked analogue of beta-D-galactosylthreonine has been prepared from 2,3,4,6-tetra-O-benzyl-D-galactopyranolactone (1) in 14 steps. Three stereogenic centers were created during the synthesis, with the anomeric center of the C-glycoside being generated first by addition of a Grignard reagent to 1 and subsequent reduction of the intermediate hemiacetal with triethylsilane. The two stereogenic centers in the threonine moiety were both established by alkylation of Evans' chiral N-acyloxazolidinone enolates.     

Synthesis of a new cyclic analogue of luliberin

A new cyclic analogue of luliberin possessing the capacity for stimulating ovulation in sexually mature and infantile rats and also exhibiting a pronounced prolongation of its influence on a number of behavioral reactions of animals has been synthesized.     

Synthesis of dysiherbaine analogue

Synthesis of dysiherbaine analogue 4, which corresponds to 8,9-epi-neodysiherbaine A, is described. The synthesis features a concise route to the bicyclic ether skeleton through stereoselective C-glycosylation to set the C₆ stereocenter and 5-exo ring-closure to form the tetrahydrofuran ring. The results of preliminary biological studies of 4 are also provided.     

Synthesis of a novel Boc-protected cyclopropane-modified proline analogue

The synthesis of the Boc derivative of a novel member of the cyclopropane-modified proline library, Boc-protected 5-azaspiro[2.4]heptane-6-carboxylic acid, is reported. The synthesis was performed in six steps starting from (2S,4R)-4-hydroxyproline using a modified Simmons-Smith reaction as the key step. The reaction conditions for all the steps were carefully selected to avoid racemization at the chiral centers in the intermediates and the final product.     

Synthesis of a bisubstrate analogue targeting estrogen sulfotransferase

Sulfotransferases catalyze the transfer of a sulfuryl group from the eukaryotic sulfate donor 3'-phosphoadenosine 5'-phosphosulfate to an acceptor biomolecule. Sulfotransferases have been linked with several disease states, prompting our investigation of specific sulfotransferase inhibitors. Presented herein is the synthesis and evaluation of a bisubstrate analogue designed to inhibit estrogen sulfotransferase. The synthesis utilizes a novel, orthogonally protected 3'-phosphoadenosine 5'-phosphate (PAP) derivative allowing the selective functionalization of the 5'-phosphate with a sulfate acceptor mimic. Kinetic studies revealed significant inhibitory activity and provide guidance for improved inhibitor design.     

Synthesis and cytotoxicity of a biotinylated CC-1065 analogue

Background  

The use of pretargeting technology for cancer imaging and treatment has made significant progress in the last few years. This approach takes advantage of the fact that biotin binds strongly to proteins avidin and streptavidin. Thus, a non-toxic tumor cell specific antibody is conjugated with avidin/streptavidin, and is administered to patients. After the antibody binds to tumor cells (usually 24–48 h); a clearing agent is given to remove the residual circulating antibodies in blood. Lastly, a toxic biotin-radioisotope conjugate is administered. Due to the small size of the biotin-radioisotope molecule and tight binding between biotin and avidin/streptavidin, the biotin-radioisotope rapidly binds to tumor cells with high specificity. CC-1065 (1) is one of a few classes of extremely potent antitumor agents, and a biotinalyted CBI-bearing CC-1065 analogue is a promising candidate to be used in the pretargeting technology to treat cancer.     

Synthesis and biological evaluation of a beauveriolide analogue library

Synthesis of beauveriolide III (1b), which is an inhibitor of lipid droplet accumulation in macrophages, was achieved by solid-phase assembly of linear depsipeptide using a 2-chlorotrityl linker followed by solution-phase cyclization. On the basis of this strategy, a combinatorial library of beauveriolide analogues was carried out by radio frequency-encoded combinatorial chemistry. After automated purification using preparative reversed-phase HPLC, the library was tested for inhibitory activity of CE synthesis in macrophages to determine structure-activity relationships of beauveriolides. Among them, we found that diphenyl derivative 7{9,1} is 10 times more potent than 1b.     

Synthesis of sphingomyelin difluoromethylene analogue

As a new sphingomyelinase inhibitor, a novel sphingomyelin CF₂ analogue was designed and synthesized. One key step of this synthesis is the very mild hydrolysis of the oxazolidinone ring, a suitable intermediate for the introduction of a diethyl difluoromethylphosphonate group, by utilizing the characteristic electron withdrawing nature of the nosyl group at the oxazolidinone ring in an alcoholic solvent to produce the corresponding carbonate attaching at the secondary hydroxy group. The synthesized CF₂ analogue inactivated toward B. cereus sphingomyelinase with nearly the same attitude as the nitrogen analogue that we previously reported.     

Synthesis of a nitrogen analogue of sphingomyelin as a sphingomyelinase inhibitor

[structure: see text] Sphingomyelin nitrogen analogue 1 was designed and synthesized as a sphingomyelinase inhibitor. The synthesis was established by continuous Hofmann rearrangement and Crutius rearrangement as key steps in constructing the 3-hydroxy-1,2-diamine structure in the backbone of 1. This analogue showed moderate inhibitory activity toward SMase isolated from B. cereus.     

Synthesis and reactivity of a phosphine-stabilized monogermanium analogue of alkynes

The synthesis of the first isolable C-phosphino-Ge-aminogermyne, stabilized by a phosphine ligand, has been achieved. X-ray diffraction analysis indicates a quite long Ge-C bond whose length is between that of a single and a double bond but consistent with the theoretically predicted values for a germyne bearing π-donating substituents. The isomerization of this germyne derivative affords a new stable N-heterocyclic germylene through migration of the original phosphine ligand from germanium to the carbon center.