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On exposure to visible light, mycolactone A/B, the causative toxin of Buruli ulcer, rearranges to a mixture of four photo-mycolactones apparently via a rare photochemically-induced [4πs + 2πa] cycloaddition. In order to prevent the rearrangement, two C6′-C7′ dihydromycolactone analogs 6′α-15 and 6′β-15 were designed and synthesized. 6′α-15 and 6′β-15 were shown to be stable under not only photochemical, but also acidic and basic conditions. Cytotoxicity was tested against arbitrarily chosen four cell lines (human Hek-293, human lung carcinoma A-549, human melanoma LOX-IMVI, and mouse L-929), thereby revealing that: (1) both analogs maintain potent cytotoxicity; (2) 6′β-15 exhibits significantly higher potency against human cell lines than 6′α-15; (3) in comparison with parent mycolactone A/B, 6′β-15 exhibits equal potency against human Hek-293, whereas significantly lower potency against human lung carcinoma A-549 and human melanoma LOX-IMVI.

With use of the LiTMP-induced Hodgson cyclopropanation of an epoxide-olefin to a bicyclo[3.1.0]hexanol as the key step, a stereoselective total synthesis of photo-mycolactones was achieved. Each of the four diastereomeric epoxide-olefins, selectively prepared from (R)- and (S)-glycidols, yielded the corresponding unique bicyclo[3.1.0]hexanol. Four bicyclo[3.1.0]hexanols 16, dia-16, 19, and dia-19 were converted into four primary alcohols 17, dia-17, 20, and dia-20, the intermediates used in the previous work on photo-mycolactones. This synthesis confirmed the stereochemistry previously proposed for photo-mycolactones.

The C1-C19 building block 46 of halichondrin Bs was synthesized via a selective activation/coupling of β-bromoenone 34 with aldehyde 35 in a Ni/Cr-mediated reaction. The first phase of study was a method development to effect a coupling of a "naked" vinylogous anion with an aldehyde. The study with the coupling of 9 + 10 → 11 revealed: (1) β-bromoenone 9b is a better nucleophile than the corresponding β-iodo- and β-chloroenones 9a,c; (2) (Me)2Phen(OMe)2·NiCl2 13b is a better Ni-catalyst than (Me)2Phen(H)2·NiCl2 13a; and (3) a low Ni-catalyst loading, for example, 0.05-0.1 mol % Ni-catalyst against 10 mol % Cr-catalyst, is crucial for an effective coupling. The second phase of study was a method development to realize a selective activation/coupling of polyhalogenated nucleophiles such as 34. The competition experiment of 10 + 9b over 10 + 31a-c revealed: (1) (Me)2Phen(OMe)2·NiCl2 13b is more effective than (Me)2Phen(H)2·NiCl2 13a for the required selective activation/coupling; (2) a low Ni-catalyst loading, for example, 0.05-0.1 mol % Ni-catalyst against 10 mol % Cr-catalyst, is crucial for discriminating β-bromoenone 9b from the three types of vinyl iodides 31a-c. The third phase of study was an application of the developed method to execute the proposed coupling of 34 + 35 → 36. For this application, a polyether-type Ni-catalyst 37c, readily soluble in the reaction medium, was introduced to achieve the selective activation/coupling with higher efficiency. With use of ion-exchange resin-based device, the coupling product 36 was transformed to the C1-C19 building block 46 of halichondrin Bs without purification/separation of the intermediates.

A unified synthesis of the C1-C19 building blocks 8-10 of halichondrins A-C was developed from the common synthetic intermediates 26a,b. Acetylenic ketones 26a,b were in turn synthesized via selective activation/coupling of polyhalogenated nucleophiles 23a,b with aldehyde 11 in a (Ni)/Cr-mediated coupling reaction. Compared with Ni/Cr-mediated couplings of vinyl iodides and aldehydes, this (Ni)/Cr-mediated coupling exhibited two unique features. First, the coupling was found to proceed with a trace amount or no added Ni-catalyst. Second, TES-Cl, a dissociating agent to regenerate the Cr-catalyst, was found to give a better yield than Zr(Cp)2Cl2. An adjustment of the oxidation state was required to transform acetylenic ketones 26a,b into C1-C19 building blocks 8 and 9 of halichondrins A and B, respectively. In the halichondrin B series, a hydroxyl-directed (Me)4NBH(OAc)3 reduction of E- and Z-β-alkoxy-enones 30 was found cleanly to achieve the required transformation, whereas a DMDO oxidation of E-vinylogous ester 27 allowed to introduce the C13 hydroxyl group with a high stereoselectivity in the halichondrin A series. In the halichondrin C series, Hf(OTf)4 was used to convert the double oxy-Michael product 28 into C1-C19 building block 10.

The right halves of halichondrins A-C were synthesized by coupling the common C20-C37 building block 9 with the C1-C19 building blocks 10a-c, respectively. Catalytic, asymmetric Ni/Cr-mediated coupling was used for three C-C bond formations. For all cases, the stereochemistry was controlled with the Cr catalyst prepared from the chiral sulfonamide identified via the toolbox approach. For (3 + 4)-, (6 + 7)-, and (9 + 10)-couplings, the stereoselectivity of 28:1,40:1, and ∼20:1 was achieved by the Cr catalysts prepared from (S)-H, (S)-I, and (R)-L, respectively. Unlike the first and second couplings, the third coupling used the structurally complex nucleophile. It was demonstrated that the coupling efficiency was excellent even with the electrophile/nucleophile molar ratio = 1.0/1.1. In addition, the third coupling was achieved with the substrate bearing a free hydroxyl group. The products obtained in the Ni/Cr-mediated couplings were converted to the right halves of halichondrins A-C in excellent overall yields. The right halves of halichondrins A-C (1a-c) were synthesized in 28, 24, and 24 steps from commercial d-galactal in 13.4%, 21.1%, and 16.7% overall yield, respectively.

Recently reported Pd-mediated one-pot ketone synthesis from an unactivated alkyl bromide and a thioester has been extended to a macrocyclic ketone synthesis. In situ generation of alkylzinc halide via single electron transfer (SET), using NbCpCl4 and CrCl3, was the key for the success of macrocyclization. A new convergent synthesis of eribulin has been achieved, using (1) catalytic asymmetric Ni/Cr-mediated coupling to form the C19–C20 bond, (2) base-induced cyclization to form the methylenetetrahydrofuran ring, and (3) Pd-mediated one-pot ketone synthesis to form the macrocyclic ketone.

Low-temperature NMR experiments and molecular modeling have been used to characterize the conformational behavior of a covalently cross-linked DNA base pair model. The data suggest that Watson–Crick or reverse Watson–Crick hydrogen bonding geometries have similar energies and can interconvert at low temperatures. This low-temperature process involves rotation about the crosslink CH 2 C(5′) (ψ) carbon–carbon bond, which is energetically preferred over the alternate CH 2 N(3) (φ) carbon–nitrogen bond rotation.

Glycosidation of a mannosyl donor in the presence of the Mukaiyama catalyst was found to give exceptionally high alpha/beta selectivity. A systematic study was conducted to reveal that selective beta-to-alpha anomerization accounts for the observed high alpha/beta stereoselectivity. Furthermore, the Mukaiyama catalyst was shown to exhibit an unusual level of substrate and anomer selectivity for the anomerization. On the basis of the combined anomeric and delta2 effects, a mechanistic rationale was proposed, thereby suggesting the minimum structural moiety essential for the anomerization in question. With this analysis, beta-talo-, beta-altro-, and beta-idopyranosides are predicted to exhibit a reactivity profile similar to beta-mannopyranosides, but all other pyranosides should not. This prediction was verified by using beta- and alpha-talopyranosides as an example.

A second-generation synthesis of synthetic 3-O-methyl-D-mannose-containing polysaccharides (sMMPs) is reported. The glycosidation of donor B and acceptor C, prepared from a common precursor A in two and one steps, respectively, is effected by t-butyldimethylsilyl trifluoromethanesulfonate to furnish only the desired alpha-anomer D in high yields. Unlike the first-generation synthesis, this synthesis gives the desired product free from contamination of scrambling products. A three-step protocol is used to deprotect D to furnish sMMPs.

[structure: see text] The C5-C10 relative stereochemistry of sagittamide A was predicted, with the use of the 3JH,H profiles assembled from the spin-coupling constants reported in the literature. The predicted relative stereochemistry was then confirmed by a total synthesis of two relevant remote diastereomers. The absolute configuration of sagittamide A was established through a detailed 1H NMR analysis of the two remote diastereomers, followed by doping experiments of them with the authentic natural product.

The NMR profiles (13C-δ, 1H-δ, 1H(OH)-δ, and 3JH,H) of syn- and anti-diols— 3a,b in achiral solvents were found to be very similar to each other. Contrarily, their Δδ (Δδ=δ(R,R)-2−δ(S,S)-2) behaviors in chiral bidentate NMR solvent (R,R)- and (S,S)-BMBA-p-Me ( 2 ) were found to be significantly different. On the basis of this NMR characteristic, a method has been developed to predict both the relative and absolute configurations of acyclic secondary 1,2-diols.

Structurally simplified macrocyclic ketone analogues of halichondrin B were prepared by total synthesis and found to retain the potent cell growth inhibitory activity in vitro, stability in mouse serum, and in vivo efficacy of the natural product.

In connection with the de elopment of a practical synthesis of the right half, and its analog E7389, of halichondrin B, an efficient and scalable synthesis of the two major building blocks is reported. In addition, a new synthesis of the C20–C26 segment via a regiospecific and stereoselecti e SN2' process is presented. A sulfonamide class of ligands is shown to be effective for asymmetric Ni/Cr-mediated reactions under both stoichiometric and catalytic conditions, and the X-ray structure reveals this class of ligands to be tridentate. On the basis of three X-ray structures, a possible mechanism is suggested for this process. Stable and crystalline Cr(III)/sulfonamide complexes are shown to be effective for catalytic Cr-mediated coupling reactions of allyl, alkenyl, and alkyl halides with aldehydes, and some examples for application of the stoichiometric and catalytic asymmetric processes are presented.

[reaction: see text] Via an X-ray analysis, the sulfonamide bearing R(1) = i-Pr, R(2) = Me, and R(3) = Me is shown to be a tridentate ligand to a Cr(III) salt. This class of ligands, represented by R(1) = t-Bu, R(2) = 2-naphthyl, and R(3) = Me, is effective to achieve an asymmetric Ni/Cr-mediated coupling reaction and, with the C14-C38 segment of halichondrins, its synthetic potential has been demonstrated. A possible mechanism is suggested for the process.

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 total synthesis of halichondrin A, the phantom member in the halichondrin class of natural products, is reported. The highlights of synthesis include: (1) synthesis of C1-C19 building block 6b via a catalytic asymmetric Cr-mediated coupling of 12 and 13b; (2) synthesis of the right-half of 19 via an asymmetric Ni/Cr-mediated coupling, followed by base-induced furan formation, and Shiina macrolactonization; (3) synthesis of enone 20 via Ni/Cr-mediated coupling of 5 with 19, followed by oxidation; (4) synthesis of halichondrin A from 20, with use of a newly discovered, highly selective TMSOTf-mediated equilibration of C38-epi-halichondrin A to halichondrin A. Two pieces of evidence are presented unambiguously to establish the structure of halichondrin A thus synthesized: one is the synthesis of norhalichondrin A (24) from 19 and 23, and the other is the study of the proton chemical shift difference between synthetic halichondrin A and known members of this class of natural products.

[structure: see text] Three additional NMR databases, 1-3, in a chiral solvent are presented. The C.21-C.38 portion of oasomycin A is used to demonstrate the scope and limitation of the universal NMR database approach in a chiral solvent for assignment of relative and absolute stereochemistry without degradation and/or derivatization.

[structure: see text] An NMR database approach in a chiral solvent allows us to predict both relative and absolute stereochemistry of an unknown compound without degradation and/or derivatization. N,alpha-Dimethylbenzylamine (DMBA) is a suitable solvent for this purpose. Using the C.5-C.10 portion of oasomycin A, the feasibility and reliability of this approach is demonstrated.

A concise and practical route has been developed for a synthesis of the CH 2 -bridged base pairs represented by the type- II structure. The structural studies suggest the possibility that these base pairs mimic the molecular architecture of Watson–Crick hydrogen-bonded base pairs.

Using the diastereoisomeric triols 1a – d (Fig. 1) and examples summarized in Fig. 2, the central C-atom of acyclic 1,3,5-triols is demonstrated to exhibit a distinctive chemical shift that is dependent on the 1,3- and 3,5-relative configuration, but is independent of the functionalities present outside of this structural motif. These NMR characteristics are then used to predict the relative configuration of several natural products (Fig. 7). In addition, an example is given to show the possibility of assembling an NMR database for a larger array of functional groups from NMR databases of smaller arrays of functional groups.

[formula: see text] Using the C.5-C.10 portion of the oasomycin class of natural products, the reliability and usefulness of an NMR database for the stereochemical assignment of acyclic compounds has been demonstrated. The predicted relative stereochemistry based on the NMR database has unambiguously been established via synthesis.

[formula: see text] Using triol 1 as a representative example of natural products containing two contiguous propionate units, 13C and 1H NMR databases for the stereochemical assignment of acyclic compounds have been created. Chemical shift increments due to the presence of additional functional groups as well as solvent effects are discussed.

A conformational analysis of methyl -C-lactoside (5) is carried out (Table 1), which suggests the preferred solution conformation of 5 to be described as a mixture of conformers A ( = 300; = 60) and B ( = 300; = 300) to a first approximation. Applying a modified Karplus equation for the vicinal coupling constants observed for the H.a and H.1' protons of 5, the dihedral angle ( = O.5'-C.1'-C.a-C.4) was deduced to be approximately +280. Nuclear Overhauser effect (NOE) experiments were then conducted on 5-D2 and its parent methyl -O-lactoside in a 7:3 mixture of pyridine-d5 and methanol-d4, qualitatively demonstrating that the conformational characteristics of both methyl -C- and -O-lactosides at the free states are represented as a mixture of two conformers A and B, but their relative population may be different. Through X-ray analysis, it has been definitively established that the conformation ( = 297(7) and = 120(2)) of C-lactose bound to peanut lectin is practically identical to the conformation ( = 291(6) and = 118(9)) of its parent O-lactose bound to the same protein.

The most active compound of the extraordinarily cytotoxic spongipyrans, spongistatin 1, isolated from marine sponges, appeared to be identical to altohyrtin A. The total synthesis of this macrolide has now firmly established the relative and absolute stereochemistry proposed by Kitagawa (see picture below), and has also verified that altohyrtin A and spongistatin 1 are identical.

A unified total synthesis is reported to access all of the possible diastereomers of pteriatoxins A-C, with the use of an intramolecular Diels-Alder reaction as the key step to form the carbo-macrocyclic core structure. The C34/C35-diol protecting groups were found to have significant effects on both the exo/endo-selectivity and the exo-facial selectivity of the intramolecular Diels-Alder process.

Tolyporphin chromophore 2 has been synthesized by performing a doubleretroaldol/oxidation sequence on an octahydroporphyrin precursor 18 prepared by using the Eschenmoser sulfide-contraction/iminoester-condensation method.

By addressing the relative stereochemistry of the four acyclic portions via organic synthesis, the complete relative stereochemistry of maitotoxin (MTX) has been established as 1B. The relative stereochemistry of the C.1−C.15 portion was elucidated via a two-phase approach: (1) the synthesis of the eight diastereomers possible for model C, representing the C.1−C.11 portion, and the eight diastereomers possible for model D, representing the C.11−C.15 portion, and the comparison of their proton and carbon NMR characteristics with those of MTX, concluding that 9 and 35 represent the relative stereochemistry of the corresponding portions of MTX; (2) the synthesis of the two remote diastereomers 51 and 52, and comparison of their proton and carbon NMR characteristics with those of MTX, concluding that 51 represents the relative stereochemistry of the C.1−C.15 portion of MTX. The relative stereochemistry of the C.35−C.39, C.63−C.68, and C.134−C.142 acyclic portions was established via (1) the synthesis of the ...

Palytoxin (PTX), a potent toxin isolated from the marine soft coral Palythoa tuberculosa increases the cationic permeability of red cell membranes and inhibits the (Na + ,K + )-activated ATPase, effects that are completely reversed by ouabain. It has also been shown to compete with ouabain for a binding site and it has been suggested that it binds to the Na + ,K + -pump molecule in cells. In a search for analogues of PTX that would bind covalently and could thus be used to identify and characterize the binding site, we have used compounds which differed from PTX at one end or at both ends simultaneously. In order to determine whether these derivatives could be used to replace palytoxin, we tested their potency to induce an increased cation flux, compete with ouabain for its binding site, and inhibit the isolated, purified (Na + ,K + -ATPase). The results obtained indicate that departures from the PTX structure at one end or at both ends simultaneously substantially decrease the ability of the compounds to increase the cationic permeability of red blood cells and to inhibit the (Na + ,K + -ATPase). These actions were found to be com- pletely reversed by ouabain, but the analogues are two to three orders of magnitude less potent that PTX in competing with ouabain for its binding site. These results suggest that both ends of the palytoxin molecule participate in the interactions of the toxin with its receptor and that modifications in these regions of the molecule produce significant alterations in its binding and subsequent action on red cell membranes.

The 13 C NMR behaviors of several cyclic and biaryl secondary alcohols as well as acyclic tertiary alcohols have been studied in the chiral bidentate NMR solvent BMBA- p -Me ( 1 ). An empirical rule has been advanced to correlate the absolute configuration of each type of alcohols with the 13 C chemical shift behaviors in ( R , R )- and ( S , S )-BMBA- p -Me.

A concise, stereoselective, and scalable synthesis of the C20–C26 building block of halichondrins and Eribulin is reported. The synthesis relies on three key transformations: regiospecific Ru-catalyzed intramolecular hydrosilylation, highly stereoselective SN2′ substitution, and selective conversion of a C–Si to C–I bond. It is carried out in a 5-pot/4-workup operation without chromatographic purification, except for filtration through a silica-gel plug, to give the C20–C26 building block (dr > 200:1; ee > 99%) in ca. 60% overall yield from epoxide 1.

A stereoselective intramolecular Diels-Alder reaction has been developed using annelated furans to produce functionalized steroidal nuclei, which can serve as advanced intermediates in the synthesis of batrachotoxin.

The oxazepane ring system present in batrachotoxin has been synthesized within the framework of an advanced intermediate via a novel Michael reaction.

The relative and absolute stereochemistry of the backbone of fumonisin B2 is established to be 7a.

NMR chemical shift, 3JHH, 3JCH, nuclear Overhauser enhancement, and optical rotation data suggest that C-sucrose undergoes a conformational change in methanol containing Ca2+, whereas the parent O-sucrose does not.

A single, unified strategy for the stereocontrolled synthesis of α,α-, α,β-, and β,β-C-trehaloses (1-3) was developed. The solution conformations of C-trehaloses 1-3, as well as their permethyl derivatives, were determined on the basis of vicinal coupling constants observed in the 1 H NMR spectra. The preferred conformations for α,α- and β,β-C-trehaloses (1 and 3), shown in Figure 1, were predicted and experimentally proven. A diamond-lattice analysis of α,β-C-trehalose (2), shown in Figure 2, revealed the relative stability of the three staggered conformers to be 2A> 2B>2C, and the experimental data were found to be consistent with this trend

International audience; The first total synthesis of halichondrin C has been completed, highlighted by development of the synthetic method to construct the C8-C14 polycycle. Cr-mediated coupling reactions are used seven times to form a new C C bond. The acid stability of halichondrin C is studied, demonstrating that the macrolactone stabilizes the C8-C14 polycycle, relative to the one present in the C1-C16 model.

An efficient, stereoselective synthesis of an enantiomerically pure C-ring precursor 14-S of O-cinnamoyltaxicins-I and -II has been achieved from 3-methyl-2-cyclohexen-1-ol, using a [2,3] Wittig rearrangement as the key step.

A practical, scalable synthesis of the C.1C.13 segment of halichondrin B has been developed starting from L-mannonic-γ-lactone, using C-allylation/oxy-Michael cyclization and Ni(II) Cr(II) -mediated vinyltrimethylsilane addition to set the C.6 C.3 and C.11 stereocenters, respectively.

The tricyclic enone 12, containing the taxane ring system, has been synthesized, using an intramolecular Ni(II)/Cr(II)-mediated coupling of β-iodoenone aldehyde 11 as the key step.

This presentation concerns (1) the preferred solution conformation of mono-, di-, and ai-C-glycosides in comparison to their parent glycosides and (2) the preferred local and global solution conformation of the marine natural product palytoxin.

Remarkable selectivity is exhibited in the photooxidation of 20-methoxychlorin methyl ester (1) to exclusively yield the C1-C20 bond cleaved product 2. This selectivity lends strong support to the hypothesis that a hydroxy or equivalent group at C20 directs the C1-C20 bond cleavage that transforms chlorophylls into krill and dinoflagellate luciferins.

[structure: see text] Examples of (13)C NMR desymmetrization of meso compounds are presented. On analysis of the NMR profiles of 1,3-diols, the additivity is recognized to predict the NMR profiles of 1,3,5-tirols.