Towards the synthesis of [15]-membered stevastelins through the 2,3-epoxy analogues

A synthetic approach to the [15]-membered stevastelins, a novel class of immunosuppressant agents, is reported based on a macrolactamization route to the 2,3-epoxy derivative 6. The synthesis of this compound was achieved via a stereoselective epoxidation of the allylic alcohol 13, followed by a coupling reaction with a variety of peptide derivatives to give the epoxy peptides 7-10. After an extensive study of cyclizations with these precursors, the best result was achieved with the macrolactamization of 8 in the presence of DEPC, to obtain the epoxy cyclic depsipeptide 6 in 42% yield. From this product, an epoxy analogue of stevastelin B, compound 27, was prepared. Finally, the synthesis of the natural product was attempted through the opening of the oxirane ring contained in 6 and 26, with a variety of methyl cuprate reagents, but without success.     

Synthesis of [13]-membered macrocyclic stevastelins via a transesterification reaction as the key step: total synthesis of stevastelin C3

A new synthesis of stevastelin C3 (3), a [13]-membered ring component of the stevastelin family, whose structure was recently revised, is reported. Initially, a macrolactonization approach was attempted to generate the [13]-membered macrolactone but this met with failure, so a translactonization reaction was tried to obtain the targeted stevastelin C3 (3) from the corresponding [15]-membered ring counterpart. Unfortunately, this strategy did not prove successful, and, consequently, we opted to undertake a transesterification reaction from 23, as a means to accommodate the requisite aminoacid moiety at the correct position, to obtain 24. From 24, and through intermediates 25-28, the acyclic precursor of the [13]-membered ring macrolactone, compound 30, was efficiently prepared. By utilizing the synthetic course developed by Chida, we took 30 forward and completed the total synthesis of stevastelin C3 (3).     

Total synthesis of stevastelins B3 and C3: structure confirmation of stevastelin B3 and revision of stevastelin C3

The total synthesis of stevastelin B3, stevastelin C3 and 5-deoxy derivative of stevastelin C3, novel 13-membered cyclic depsipeptides, is described. This study unambiguously confirmed the proposed absolute structure of stevastelin B3, and revealed that the structure of stevastelin C3 is incorrect. The correct structure of stevastelin C3 was established by the total synthesis to be 5-deoxy derivative of the proposed structure.     

Synthesis and conformational analysis of stevastelin C3 analogues and their activity against the dual-specific vaccina H1-related phosphatase

The biological activity of macrocyclic natural products depends on their conformational properties. For both the elucidation of enzyme binding affinities as well as the development of selective drugs, rigid macrocyclic scaffolds carry high potential. In this study, 13-membered cyclodepsipeptides based on the structure of naturally occurring stevastelins were studied in detail. Six diastereomeric stevastelin C3 analogues and four phosphorylated derivatives were synthesized. The synthesis of linear precursors was achieved on solid support by starting from stereoisomerically pure 2-methyl-3-hydroxy acids. Subsequent macro-lactamization gave the cyclic depsipeptides in very good yields (36-62%). The conformational space of these stevastelin C3 analogues was computationally investigated. On the basis of NMR spectroscopic data, homogeneous conformations were determined for each benzylated depsipeptide and the influence of phosphorylation on the overall conformation was investigated. Importantly, phosphorylation was found to significantly weaken the conformational preferences of the 13-membered depsipeptides. Finally, the cyclic depsipeptides were tested for activity against phosphatases. Inhibitory activity on vaccina H1-related phosphatase was observed depending on the derivatization of the cycles. The activity profiles are discussed in the light of the structural data.     

Regioselective Opening Reaction of Epoxides with Diphenyl Diselenides

The oxirane ring opening[1] with various nuclephiles is an important synthetic transformation to allow easy ac cess to a large number of functionalized intermediates that are required during the synthesis of natural products. [2]The reaction of epoxides with phenylselenolate ion gave the organic selenides[3] which were formed via trans opening of the epoxides with the selenolate ion. However, many of methods suffer from lack of generality, poor regioselectivity and low temperature ( - 78 ℃ ). [4]     

Synthetic studies on stevastelins. 2. Synthesis of lipidic- and peptidic-modified analogues

[Chemical reaction: See text] The synthesis of a series of stevastelin analogues with modification of the susbstituent at the C-2 position of the stearic acid chain (compounds 28 and 31), variation of the amino acids (compounds 41, 42, 73, and 78), or lacking the lipidic chain (compound 91) is described. The replacement of L-valine and L-threonine with other amino acids proceeded without difficulties for the synthesis of analogues 41 and 42; however, the substitution of L-serine with simple amino acids, such as glycine or L-alanine, proved to be elusive, which was adscribed to factors of conformational flexibility. Finally, the substitution with L-valine or L-threonine proceeded without difficulties to provide the analogues 73 and 78 respectively.     

Synthesis of 2'-C-beta-fluoromethyluridine

[reaction: see text] 2'-C-beta-Fluoromethyluridine (17) represents both a potentially important biological agent and a tool for biochemical analysis. Here we describe the first synthesis of this compound starting from uridine. The key steps include protection of the uracil base with methoxyethoxymethyl (MEM) chloride, conversion to the corresponding 2'-C-alpha-epoxide, and regioselective opening of the oxirane ring with potassium fluoride/hydrogen fluoride. Subsequent acetylation of the 3'- and 5'-hydroxyl groups enables MEM removal using B-bromocatecholborane. Deacetylation generates the parent nucleoside, 2'-C-beta-flurormethyluridine.     

Total synthesis of (-)-stevastelin B

The total synthesis and an unambiguous structure confirmation of stevastelin B 1, a novel 15-membered cyclic depsipeptide, are described; the fatty acid moiety in 1, prepared stereoselectively from L-quebrachitol was converted into the amino carboxylic acid, whose macrolactamization by Shioiri's procedure effectively constructed the cyclic structure of 1.     

Total synthesis of stevastelin B3

The total synthesis of stevastelin B3 was achieved using, as a key step, a method developed by us for the synthesis of 2-methyl-1,3-diols by Ti(III)-mediated diastereo- and regioselective opening of trisubstituted 2,3-epoxy alcohols, to carry out the stereoselective construction of its propionate-derived fatty acid segment.     

A one-pot sequence for the efficient synthesis of highly functionalized macrocarbocycles or bridged 2,8-dioxabicyclo[3.2.1]octanes from 1-nitrobicyclic compounds

The reaction of 1-nitrobicyclo[n.3.1]alkane-(6 + n)ones with sodium borohydride followed by acidic workup led to ring opening via a one-pot sequence comprising the retro-Dieckmann-type opening of the α-nitroketone structural fragment, followed by aldehyde reduction and a final Nef reaction, leading to highly functionalized 12 to 14-membered carbocyclic ketones bearing three stereocenters, which are adjacent in some of the compounds. The reactions starting from 1-nitrobicyclo[9.3.1]pentadecan-15-ones could be adjusted to give macrocyclic 2,8-dioxabicyclo[3.2.1]octanes containing an additional bridge by diastereoselective formation of a third ring and a fourth stereocenter through acid-promoted intramolecular ketal formation. This is a very interesting ring system related to the core of the zaragozic acid family of natural products.     

New silicon-mediated, sequential ring expansions of n-sized 2-cycloalkenones into hydroxyolefinic n + m + p medium-sized lactones: short synthesis of (-)-phoracantholide-J

[reaction: see text] In only four steps from 2-cyclopentenone and 2-cyclohexenone, sequential three- or four-atom and then one- to three-atom ring enlargements produce nine- to 12-membered hydroxyolefinic lactones on a gram scale. 2-Cyclopentenone undergoes this serial 5 + 3 + 2 process to form 10-membered ring natural (-)-phoracantholide-J in six linear steps and 26% overall yield.     

Nucleophilic addition to electron-rich heteroaromatics: dearomatizing anionic cyclizations of pyrrolecarboxamides

[reaction: see text] Despite its electron-rich nature, a pyrrole ring is susceptible to intramolecular nucleophilic attack by organolithiums. The resulting dearomatizing anionic cyclization yields new 5- or 7-membered heterocyclic rings. Formation of a new 5-membered ring, by cyclization of an N-benzylpyrrolecarboxamide, is accompanied by ring opening of the original pyrrole to yield 3-aminovinylpyrrolinones. Formation of a new 7-membered ring, by cyclization of an N-allyl pyrrolecarboxamide, yields bicyclic pyrroloazepinones.     

Experimental and theoretical study of the reaction between bicyclo[2.2.1]hept-5-en-endo-2-ylmethylamine and 2-[(2-allylphenoxy)methyl]oxirane

In reactions of bicyclo[2.2.1]hept-5-en-endo-2-ylmethylamine with 2-[(2-allylphenoxy)methyl]oxirane alongside the product of amine monoalkylation a compound was obtained and isolated by chromatography on silica gel resulting from the reaction of the monoalkylated substance with the initial epoxide. The structure of new aminoalcohols and the regiochemistry of the oxirane opening were examined using IR, 1H NMR, and mass spectra. The features of the reaction mechanism were considered applying quantum-chemical calculations in the level of theory PCM/B3LYP/6-3aG(d).     

Microwave-assisted intramolecular Suzuki-Miyaura reaction to macrocycle, a concise asymmetric total synthesis of biphenomycin B

[reaction: see text] A concise and efficient total synthesis of biphenomycin B has been accomplished featuring a key microwave-assisted intramolecular Suzuki-Miyaura reaction for formation of the 15-membered meta,meta-cyclophane 20.     

Synthesis of new 14-membered macrolide antibiotics via a novel ring contraction metathesis

[reaction: see text] A novel ring opening ring closing metathesis (ROM-RCM) was demonstrated for cyclic conjugated dienes, effecting the excision of a C(2)H(2) unit and a net ring contraction. Applying the ring contraction metathesis, new 14-membered ring macrolide antibiotics were synthesized in a single step from existing 16-membered ring macrolides. This new class of macrolide antibiotics will provide access to new therapeutics for the treatment of macrolide-resistant bacterial infections.     

Synthesis of the C1-C9 fragment of callipeltoside-A

[reaction: see text] The C1-C9 fragment of callipeltoside (17) was prepared in 12 steps and 7.2% overall yield from bicyclic lactone (+)-4. Key steps include a stereoselective epoxidation and further regiocontrolled nucleophilic opening of the oxirane ring to install two vicinal stereocenters (C5 and C6), and the use of bis(trimethylsilyl) peroxide and a catalytic amount of Sn(IV) chloride for the chemoselective Baeyer-Villiger oxidation of unsaturated cyclopentanone 15.     

Umamidierungsreaktionen an cyclischen Amino-amid-Systemen. 3. Mitteilung über Umamidierungsreaktionen

Transamidation Reactions with Cyclic Amino-amides Lactames which are substituted at the nitrogen atom by a 3-aminopropyl residue are transformed under base catalysis to cyclic amino-amides enlarged by 4 ring atoms. The formed ring must be at minimum 12-membered. Scheme 2 illustrates this result: the 8-membered 7 is transamidated in 96% yield to the 12-membered ring 8 (in the presence of potassium 3-aminopropylamid in 1, 3-propanediamine), the 9-membered 10 to the 13-membered ring 11 (97%) and the 11-membered 14 to the 15-membered ring 15 . Furthermore, the 13-membered ring 27 (Scheme 5) is transformed to the 17-membered 28 . In the case of the 15-membered lactame 15 it is demonstrated that 14 is not formed back under the conditions of the transamidation. Large ring lactames which are substituted at the nitrogen atom by a 3-(alkylamino) propyl group lead under base catalysis to an equilibrium mixture, e.g. the 17-membered 26 is in equilibrium with the 21-membered 29 . This result is similar to the behavior of the corresponding open-chain amino-amides [2]. Because of transannular interactions, the 11-membered ring 2 is not stable: transamidation of the 7-membered 1 (Scheme 1) doesn't give the expected 2 , but its water elimination product 3 in small yield. The N-tosyl derivative of 2 , namely 20 , is synthesized by an independent route (Scheme 3). Detosylation of 20 yields the 7-membered 1 instead of 2 . Concerning the mechanism of this interesting reaction see Scheme 4.     

Vinyl ethers and sulfides containing antioxidant functional groups

Methods for the synthesis of compounds combining in the molecule fragments of known antioxidants with reactive vinyloxy and vinylthio groups have been developed. Transesterification of methyl 3-[3,5-di(tert-butyl)-4-hydroxyphenyl]propionate with 2-(vinyloxy)- or 2-(vinylthio)-ethanol furnished the high yields of 2-(vinyloxy)- and 2-(vinylthio)ethyl 3-[3,5-di(tert-butyl)-4-hydroxyphenyl]propionates. The reaction of 2-[(vinyloxy)ethoxymethyl]- and 2-[(vinylthio)-ethoxymethyl]oxiranes with 2,2,6,6-tetramethylpiperidin-4-ol and 4-aminodiphenylamine proceeds with the oxirane ring opening and leads to the corresponding vinyloxy and vinylthio derivatives of 2,2,6,6-tetramethylpiperidin-4-ol and mono- and bisvinyloxy and -vinyl- thio derivatives of 4-aminodiphenylamine at the primary amino group.     

Stevastelins,a novel group of immunosuppressants,inhibit dual-specificity protein phosphatases

Background: Since the molecular target of the immunosuppressive reagents FK506 and cyclosporin A was revealed to be protein phosphatase PP2B (calcineurin), many researchers have been screening the protein phosphatase inhibitors from microbial metabolites to develop new immunosuppressive reagents. We isolated stevastelin B, which is composed of valine, threonine, serine and 3,5-dihydroxy-2,4-dimethyl stearic acid, and stevastelin A, which is a sulphonylated derivative of stevastelin B. To understand the action mechanism of stevastelins A and B, we synthesized a series of stevastelin derivatives and investigated their structure-activity relationships.Results: A series of stevastelin derivatives have been systematically synthesized. Stevastelin B inhibited gene expression that is dependent on interleukin-2 (IL-2) or IL-6 promoters in situ, but it had no inhibitory activity against any protein phosphatases in vitro. In contrast, stevastelin A, which is a sulphonylated derivative of stevastelin B, inhibited the phosphatase activity of a dual-specificity phosphatase, VH1-related human protein (VHR), in vitro, but it had no inhibitory activity against gene expression or cell-cycle progression in situ.Conclusions: Stevastelin B is a novel immunosuppressant. It inhibited IL-2 or IL-6 dependent gene expression but did not inhibit the phosphatase activity of calcineurin. The structure-activity relationships show that the acidic functional group on the threonine residue and the stearic acid moiety in the stevastelin molecule are important for inhibitory effects on the dephosphorylation activity of VHR in vitro. Stevastelin B might be sulphonylated or phosphorylated after incorporation into the target cell, and then it interacts with protein tyrosine phosphatases and regulates cell-cycle progression.     

[4 + 2] Heterocyclization for Efficient Formation of Substituted Quinoxalines through Carbon–Oxygen Bonds Cleavage

A new domino strategy for efficient synthesis of highly functionalized quinoxaline derivatives via [4 + 2] heterocyclization involving ring‐opening of oxirane process has been developed. The reaction promoted by Cs₂CO₃ was easy to perform in a simple operation from common and inexpensive starting materials. The bisfunctionalization of quinoxaline framework including C2 benzylation and C3 arylation was readily achieved in domino fashion that involved the cleavage of three C–O bonds of 1,3‐diaryl‐2,3‐epoxypropan‐1‐one.