Search

[structure: see text] The first total synthesis of the mycolactones is reported. This work unambiguously confirms our earlier relative and absolute stereochemical assignment of the mycolactones.

A personal perspective is given on the research programs which have originated from, or are related to, the marine natural product palytoxin. The subjects discussed include: acyclic stereocontrol, Ni(II)/Cr(II)-mediated coupling reaction, stereochemical assignment via organic synthesis, universal NMR database, chiral NMR solvents, conformational analysis of C - and O -glycosides, diamond-lattice analysis, Type II O blood group determinant C - and O -trisaccharides, s MMP/ s MGP, and CH 2 -bridged Watson-Crick base-pair models.

A novel mycolactone has been identified from Mycobacterium marinum infecting freshwater fish.

A highly efficient, scalable, and stereoselective synthesis of the mycolactone core is reported. The synthesis consists of 14 longest linear steps, with 19% overall yield.

A boronate-assisted fluorogenic chemosensor in a solid phase is developed, selectively to detect the mycolactones produced by the human pathogen Mycobacterium ulcerans.

An efficient synthesis of the C.27–C.38 segment of halichondrins is accomplished, using the Ireland-Claisen rearrangement, Ni(II)/Cr(II)-mediated coupling and Michael reactions as the key steps.

This paper presents a brief review on the history of the development of Ni(II)/Cr(II)-mediated coupling reaction and its application to natural products syntheses. During the synthetic studies on the marine natural product palytoxin, we recognized the trans-allylic benzylether benzoate to be the key intermediate for the synthesis of the C.8-C.22 segment (ref. 1-4). We had planned to synthesize this substance from the aldehyde or its synthetic equivalent, which seemed possible through routine synthetic operations. However, we soon realized that standard synthetic routes such as Wittig and aldol approaches were not as practical as we had hoped. reaction utilizing organocuprates gave, at least in the model series, very promising results. However, in spite of extensive efforts, we were unable to generate the desired organocuprate reagent from the trans-iodoolefin , Among the many possibilities attempted, a coupling

Stereochemistry can be predicted: The stereoselective synthesis of the C21-C38 degradation product derived from oasomycins A and B has confirmed the stereochemistry predicted from a comparitive study of the NMR chemical shifts of the C21-C38 portion of the natural products with those obtained for its diastereomers.

A catalytic enantioselective propargylation in the presence of 10 mol % of Cr catalyst prepared from Cr(III) bromide and (R)-sulfonamide E furnishes homopropargyl alcohol 8 in 78% yield with 90% ee. Coupled with the workup based on Amano-lipase, this method provides a practical synthesis of optically pure 8 on a multigram scale. With maintenance of its optical purity, 8 has been converted to 1b, the C14−C19 building block of halichondrins and E7389, in two steps.

With bioactivity-guided phenotype screenings, a potent anti-inflammatory compound f152A1 has been isolated, characterized and identified as the known natural product LL-Z1640-2. Metabolic instability precluded its use for the study on animal disease models. Via total synthesis, a potent, metabolically stabilized analog ER-803064 has been created; addition of the (S)-Me group at C4 onto f152A1 has resulted in a dramatic improvement on its metabolic stability, while preserving the anti-inflammatory activities.

With focus on the steric effects present in the transition states for the [3,3]-sigmatropic rearrangement, the substrate 5 has been designed to improve the overall stereoselectivity of the Ireland-Claisen rearrangement. Experimentally, it has been found that (1) only Z-6 rearranges to 7 at 80 degrees C and (2) E-6 isomerizes to Z-6 at 80 degrees C, thereby allowing the transformation of 5 into 7 in an almost quantitative yield. To illustrate the usefulness of this approach, two additional examples are given.

Palytoxin (PTX), isolated from the marine soft coral Palythoa tuberculosa, increases the cation conductance of human red cell membranes. In the presence of 10(-10) M PTX and 10(-5) M DIDS, the membrane potential approximates the equilibrium potential for Na+ or K+ rather than Cl-. Even in the absence of DIDS, the Na+ and K+ conductances were greater than the Cl- conductance. The selectivity of the PTX-induced cation conductance is K+ greater than Rb+ greater than Cs+ greater than Na+ greater than Li+ much greater than choline+ greater than TEA+ much greater than Mg2+. Measurements of K+ efflux revealed two apparent sites for activation by PTX, one with a Kal of 0.05 nM and a maximum flux, nu max1, of 1.4 mol/liter of cells per h and another with a Ka2 of 98 nM and a nu max2 of 24 mol/liter of cells per h. These effects of PTX are completely blocked by external ouabain (300 microM) and prevented by internal vanadate (100 microM). When the PTX channels are open, the Na,K pumps do not catalyze ATP hydrolysis. Upon thorough washout of cells exposed to about five molecules of PTX/pump, the Na,K pump of these cells operates normally. Blockage of the positively charged NH2 terminus of PTX with a p-bromobenzoyl group reduces the potency of the compound to induce Na and K fluxes by at least a factor of 100, and to compete with the binding of [3H]ouabain by at least a factor of 10. These data are consistent with the conclusion that PTX binds reversibly to the Na,K pumps in the red cell membrane and opens a (10-pS) channel equally permeable to Na and K at or near each pump site.

Four monocyclic precursors were assembled in the total synthesis of the proposed structure 1-A of (+)-tolyporphin A O,O-diacetate (X=Ac). Comparison of the spectroscopic data demonstrated that synthetic tolyporphin O,O-diacetate did not match the O,O-diacetate prepared from natural (+)-tolyporphin A (X=H), calling for a structural revision of this class of natural products. On the basis of a series of NMR experiments including synthetic intermediates, the structure of tolyporphin A is concluded to be 1-B, in which the configurations of quaternary centers C7 and C17 are opposite to those in the originally proposed structure.

Four monocyclic precursors were assembled in the total synthesis of the proposed structure 1-A of (+)-tolyporphin A O,O-diacetate (X=Ac). Comparison of the spectroscopic data demonstrated that synthetic tolyporphin O,O-diacetate did not match the O,O-diacetate prepared from natural (+)-tolyporphin A (X=H), calling for a structural revision of this class of natural products. On the basis of a series of NMR experiments including synthetic intermediates, the structure of tolyporphin A is concluded to be 1-B, in which the configurations of quaternary centers C7 and C17 are opposite to those in the originally proposed structure.

The sulfonamide-based ligand B was found to exhibit an outstanding crystallinity and perform well as a ligand for Cr-mediated catalytic asymmetric 2-haloallylation and allylation. The new ligand has an appealing advantage over the first generation ligand; its high crystallinity allows effective recovery of the ligand from a reaction in a pure form.

Iterative use of Cr-mediated catalytic asymmetric allylation could give a simple access to 1,3-polyols. Using syn/syn- and anti/anti-1,3,5-triols as representative examples, the feasibility of this approach is studied, thereby demonstrating that (1) the pre-existing TMS-protected alcohol at the beta-position does not give a significant effect on the Cr-mediated catalytic asymmetric allylation and (2) this synthetic route furnishes the expected syn/syn- and anti/anti-1,3,5-triols at the useful level of asymmetric induction and yield.

The sulfonamide-based ligand B was found to exhibit an outstanding crystallinity and perform well as a ligand for Cr-mediated catalytic asymmetric 2-haloallylation and allylation. The new ligand has an appealing advantage over the first generation ligand; its high crystallinity allows effective recovery of the ligand from a reaction in a pure form.

The proposed structure 9 of mycolactone F, isolated from the fish pathogen Mycobacterium marinum, was synthesized from the core alcohol 7 and unsaturated acid 6. The 1H NMR spectrum of synthetic 9 matched well the reported 1H NMR spectrum of natural mycolactone F, thereby demonstrating the structure of mycolactone F to be 9 or its remote diastereomer 10. In order to develop an analytical method to distinguish them, 10 was synthesized from 7 and the antipode of 6. With the use of synthetic materials, a chiral HPLC method was developed to differentiate 10 from 9. This analytical method was then applied to the natural product, thereby establishing that the complete structure of mycolactone F surprisingly is 10, rather than 9. Intriguingly, the absolute configuration of the unsaturated fatty acid of mycolactone F from the fish pathogen M. marinum corresponds to the antipode of that present in natural mycolactones A/B and C from the human pathogen M. ulcerans.

Properties of a recombinant aequorin were investigated in comparison with those of natural aequorin. In chromatographic behaviour the recombinant aequorin did not match any of ten isoaequorins tested, although it was very similar to aequorin J. Its sensitivity to Ca2+ was found to be higher than that of any isoaequorin except aequorin D. The recombinant aequorin exhibited no toxicity when tested in various kinds of cells, even where samples of natural aequorin had been found to be toxic. Properties of four recombinant semi-synthetic aequorins (fch-, hcp-, e- and n-types), prepared from the recombinant apo-aequorin and synthetic analogues of coelenterazine, were approximately parallel with those of corresponding semi-synthetic aequorins prepared from natural apo-aequorin. Both recombinant e-aequorin and natural e-aequorin J luminesced with high values of the luminescence intensity ratio I400/I465, although the ratios were not pCa-dependent. The recombinant aequorin and recombinant semi-synthetic aequorins are highly suited for monitoring cellular Ca2+.

Synthese totale enantiomerique des mycalamides A et B, avec etablissement sans ambiguite des configurations absolues. La comparaison des resultats de 1H, 13C, RMN, IR, masse {α} O et chromatographie sur couche mince avec les mycalamides A et B naturels montre une parfaite identite

The Luc gene from the firefly Photinus pyralis has been isolated by cloning it in pcDV1 PL plasmid primer and Honjo linker and the Phot gene isolated from Aequorea victoria using the polymerase chain reaction. A method has been established using SP6 RNA polymerase for transcribing and translating bioluminescent genes in vitro. It should now be possible to engineer these genes to measure intracellular ATP and the covalent modification of proteins in single, live cells, providing unique insights into the molecular basis of disease.

First and second generation total syntheses of mycolactones A and B are reported. The first generation total synthesis unambiguously confirmed our earlier assignment of the relative and absolute stereochemistry of mycolactones A and B. Knowledge of the chemical properties of the mycolactones accumulated through the first generation total synthesis allowed us to implement several major improvements to the original synthesis, including: (1) optimizing the choice of protecting groups, (2) eliminating the unnecessary adjustment of protecting groups, and (3) improving the overall stereoselectivity and synthetic efficiency. The second generation total synthesis consists of 21 longest linear steps, with 8.8% overall yield.

[Structure: see text] Pinnatoxins B and C were synthesized from diols (34R)-3b and (34S)-3a, respectively, in a stereochemically controlled manner. Through extensive analysis of the 1H NMR spectra of synthetic PnTXs B and C, the diagnostic NMR signals were first identified to differentiate (34S)- and (34R)-diastereomers and then used to establish the C34 configuration of natural PnTXs B and C as 34S and 34R, respectively.

[reaction: see text] With use of 1 mol % of Cr catalyst 5, surprisingly efficient Cr-mediated couplings of aldehydes with various types of nucleophiles have been realized. The catalyst set of Cr catalyst 5 and Ni catalyst 4 is used for alkenylation, alkynylation, and arylation, whereas the catalyst set of Cr catalyst 5 and CoPc (cobalt phthalocyanine) is used for 2-haloallylation, alkylation, and propargylation. Only the Cr catalyst 5 is required for allylation. The reaction rates in DME and THF have been found significantly faster than that in MeCN.

The feasibility of catalytic Ni/Cr-mediated macrocyclization was demonstrated for the two substrates chosen from the halichondrin area. With 5 mol % of Ni and Cr catalysts, the macrocyclization was realized without use of high-dilution techniques. The reported method has a number of appealing features, including user-friendliness, easy workup, apparent scalability, and cost-effectiveness. In addition, all the required reagents are commercially available or obtainable in one or two steps from commercially available chemicals.

The batrachotoxins are a unique class of steroidal alkaloids isolated in minute quantities from the skins of poison arrow frogs (genus Phyllobates) as well as from the skins and feathers of New Guinea birds (genus Pitohui and Iflita) and exhibit various unique structural features, including a steroid-based pentacyclic core skeleton, an intramolecular 3-hemiketal, and a seven-membered oxazapane ring. These compounds are extremely potent neurotoxins (batrachotoxin (2), LD50 in mice 2 μg/kg) that act as selective and irreversible Na+-channel activators. In this paper, we review historical background of isolations and structure determinations of batrachotoxins and our studies on the total synthesis of (-) -batrachotoxinin A (1). Strategic bond-forming events include the stereospecific epoxidation of the double bond (9→10), a new Garst-Spencer protocol to construct 3, 4-disubstituted furan (14b→17b), the stereoselective intramolecular furan Diels-Alder reaction to assemble the steroidal skeleton (20d→22d), a novel intramolecular oxy-Michael reaction to close the oxazapane ring (31→33), an organocerium addition to form the α-enone (39b→40), and the simultaneous reduction and optical resolution of the racemic ketone to provide both enantiomers of a molecule (rac-41→43, 44).

[structure: see text] By total synthesis, mycolactone C has been established as an approximately 1:1 mixture of Z-Delta4'5'- and E-Delta4'5'-geometric isomers of C12'-deoxymycolactones A and B.

[structure: see text] The complete stereostructure of the natural product (+)-glisoprenin A had been predicted via a novel application of chiral lanthanide shift reagents. Confirmation of the predicted stereostructure of (+)-glisoprenin A and validation of the chiral lanthanide shift approach have now been achieved through total synthesis.

[structure: see text] The complete stereostructure of glisoprenin A has been predicted via analysis of the 13C NMR behaviors in the presence of (R)- and (S)-Pr(tfc)3.

A structurally simplified macrolactone analogue of halichondrin B was identified that retains the potent cell growth inhibitory activity of the natural product in vitro.