A biomimetic approach to the synthesis of an antiviral marine steroidal orthoester

Orthoesterol B, a marine natural product exhibiting antiviral activities, contains a [3.2.1]-bicyclic orthobutyrate bridging the steroid side chain and ring D. A biosynthetic reaction was proposed by which rearrangement of an epoxy ester results in the formation of the orthoester moiety. Steroidal model compounds incorporating 16-butyroxy and 20,22-epoxy groups were synthesized from tigogenin and were shown to rearrange to orthoesters under mild acidic catalysis.     

A theoretical study of the molecular structure of a series of synthetic and natural brassinosteroids in relation to their biological activity

In the approximation of molecular mechanics and PM3 quantum chemical methods, a conformational analysis of the side chain of five representatives of steroid phytohormones is performed: synthetic (22S,23S)-(epi- and homobrassinolides) and natural (two stereoisomers of (22R,23R)-24-epibrassinolide and (22R,23R)-28-homobrassinolide). It is shown that the 22R,23R-diol structure in the steroid side chain enhances its flexibility as compared to the 22S,23S-configuration. This leads to a high possibility of the occurrence of two conformers of natural brassinosteroids in the solution. In one of these conformers, hydroxyl can form an intermolecular hydrogen bond instead of forming an intramolecular hydrogen bond within the diol system of the side chain, which is important for hormone-receptor interactions.     

Mechanistic studies of the biomimetic epoxy ester-orthoester and orthoester-cyclic ether rearrangements

The relative rates of acid-catalyzed rearrangements of epoxy esters to [3.2.1]bicyclic orthoesters, the subsequent rearrangements of these ortho esters to substituted tetrahydrofurans, and the rates of orthoester hydrolysis at pH 4.75 were measured in NMR kinetics experiments. The ease of formation and stabilities of these orthoesters compared favorably with the OBO-type [2.2.2]bicyclic orthoesters typically used as protecting groups of carboxylic acids. Studies with 13C NMR-detected 18O-labeling show that epoxy ester rearrangement takes place preferentially via 6-exo cyclization, although the 7-endo process competes when the distal center of the epoxide is disubstituted. The ortho ester-cyclic ether rearrangement was shown by 18O-labeling to occur exclusively via intermediacy of a five-membered dioxonium ion. The structures of the hydrolysis products also indicate the intermediacy of a dioxolanium ion during hydrolysis. The implications for a hypothetical biosynthesis of marine polyether toxins are discussed.     

STUDY ON THE SYNTHESIS OF BRASSINOLIDE AND RELATED COMPOUNDS 15.FORMAL SYNTHESIS OF BRASSINOLIDE VIA STEREOSELECTIVE SULFENATE-SULFOXIDE TRANSFORMATION

A formal synthesis of the natural growth promoting steroidbrassinolide is described,which involves construction of side chainby 1,3-sulfoxide-hydroxyl transposition with methylation from(24S)-22-E-24-sulfoxide 6 and(24R)-22-E-24-sulfoxide 9,respectively to(22S)-23-E-24-methyl compound 4.     

Synthesis and thermal self-crosslinking reaction of polymer containing spiro ortho ester and carboxylic acid

Polymers with both pendant spiro ortho ester and carboxylic acid moieties were synthesized by partial esterification of poly(methacrylic acid), poly(methacrylic acid-co-methyl methacrylate), or poly(methacrylic acid-co-styrene) with halomethylated spiro ortho esters in the presence of 1,8-diazabicyclo[5,4,0]undecene-7 in dimethyl sulfoxide. The extent of esterification increased with increasing reaction temperature. The reaction of polymeric carboxylic acids with chloromethylated spiro ortho esters proceeded to 80% of conversion at 100°C for 120 h. In contrast, the degree of esterification with bromomethylated spiro ortho ester reached 80% at 60°C within 24 h. Thermo-crosslinking of polymers having pendant spiro ortho ester moiety and carboxylic acid could be effected in films. The rate of spiro ortho ester ring-opening increased with increasing reaction temperature and with increasing content of carboxylic acid groups in the polymer. Further, the rates of gel production were also measured. The polymer containing an equimolar mixture of spiro ortho ester moieties and carboxylic acids exhibited the highest reactivity. In addition, it was found that thermal crosslinking reaction of the polymer occurred with minimum volume shrinkage.     

A novel insertion reaction of epoxy compounds into phenyl ester linkages in polymer chains

The insertion reaction of various epoxy compounds such as phenyl glycidyl ether (PGE), methyl glycidyl ether, butyl glycidyl ether (BGE), and styrene oxide into the phenyl ester linkage in the polymer chain was investigated using quaternary ammonium salts as catalysts in diglyme, anisole, sulfolane, o-dichlorobenzene, or DMSO at 100–150°C. The reaction of PGE with poly[4-(4-nitrobenzoyloxy)styrene] (polymer 1a ) proceeded almost quantitatively to give the corresponding polymer using tetrabutylammonium bromide (TBAB) as catalyst in diglyme at 100°C for 24 h. The reactions of BGE with poly(4-nitrophenyl methacrylate), and copolyarylate derived from 2,2-bis(4-hydroxyphenyl)-1,1,1,3,3,3-hexafluoropropane and iso- and terephthaloyl chlorides also produced the corresponding polymers with 86 and 89 mol% new structural units, respectively, using TBAB in sulfolane at 150°C for 24 h. Furthermore, it was found that the degree of insertion of the epoxy compound into the ester linkage in the polymer chain was affected by the kind of epoxy compound, reaction solvent, catalyst concentration, substituent group on the phenyl ester, and structure of the polymer. Chiral polymers were also synthesized with high degrees of insertion by the reaction of chiral epoxides such as (R)-1,2-epoxyhexane, (R)-1,2-epoxyheptane, and (R)-1,2-epoxydecane with polymer 1a and poly(2,4-dichlorophenyl methacrylate) using TBAB in diglyme at 120°C for 24 h.     

Masked omega-lithio ester enolates: synthetic applications

The protocol of lithiation by means of lithium and a catalytic (5% molar) amount of DTBB (4,4'-di-tert-butylbiphenyl), applied to omega-chloro ortho ester 6 under Barbier-type conditions gives, after final acid-catalyzed methanolysis, the corresponding functionalized esters 8 or 9 (for chlorotrimethylsilane as electrophile) or, after ortho ester deprotection and acid catalyzed treatment, the delta-lactones 11. The procedure is also practical for bicyclic ortho esters 14: the beta-chloro OBO ester derivate generates the gamma- lactones 15 and the gamma-chloro OBO ester gives corresponding esters 8.     

A new cucurbitacin D related 16,23-epoxy derivative and its isomerization products

[reaction: see text] A new (23S,24Z)-16,23-epoxy cucurbitacin derivative was isolated from Ecballium elaterium L. (Cucurbitaceae) fruit juice along with known cucurbitacin derivatives. Structure elucidation of these derivatives was accomplished by NMR spectroscopy and mass spectrometry from HPLC-MS data. Isomerization of the epoxy derivative was monitored by 1D and 2D NMR experiments. The configuration of the reaction products was elucidated as (23R,24E) and (23R,24Z), and a mechanism for the acid-catalyzed rearrangement process is proposed.     

Synthesis of cis‐Hedione® and Methyl Jasmonate via Cascade Baylis–Hillman Reaction and Claisen Ortho Ester Rearrangement

The exocyclically unsaturated conjugated keto esters 10 , obtained via a Claisen ortho ester rearrangement of the allylic hydroxy ketones 9 , were either directly hydrogenated or partially isomerized into the endocyclically unsaturated tetrasubstituted didehydrojasmonoid intermediates 14 , prior to a more selective hydrogenation with Pd/C in cyclohexane to the disubstituted oxocyclopentaneacetates 15 (Scheme 2). The key intermediates 9 were obtained either by a four‐step sequence, including acetal protection/deprotection from enone 1 , in the specific case of hydroxy ketone 9a (Scheme 1), or more directly and generally by a Baylis–Hillman reaction from cyclopent‐2‐en‐1‐one ( 16 ) and the appropriate aldehydes 17 (Scheme 2). The judicious choice of these aldehydes opens versatile modifications for the stereoselective introduction of the partially cis‐ or epimerized trans‐C(2) jasmonoid side chain, while the Baylis–Hillman reaction, catalyzed by chiral [1,1′‐binaphthalene]‐2,2′‐diols (BINOLs) 19 (Scheme 3), may be efficiently conducted in a one‐pot cascade fashion including the ortho ester Claisen rearrangement.     

Structural requirements in chiral diphosphine-rhodium complexes—XI: Asymmetric homogeneous hydrogenation of z-α-acylaminocinnamic acids and esters with (1s, 2s)-trans-1,2-bis(diphenylphosphinomethyl) cyclohexane/rhodium(i) complexes

Z-α-acylaminocinnamate esters were hydrogenated with neutral rhodium(I) complexes containing (1S, 2S)-trans-1,2-bis(diphenylphosphinomethyl)cyclohexane. Increasing the steric bulk of the alcohol moiety of the ester function results in increased enantioface differentiation in favor of the re-si prochiral face to yield an excess of the S-amino acid derivatives. In the series of N-acetylphenylalanine ester products (resulting from hydrogenation of Z-α-acetamidocinnamate esters) the optical purity increased from 1% ee-(R) [Me]; 20% ee-(S) [Et]; 47% ee-(S) [i-Pr]; to 58% ee-(S) [t-Bu]. Increasing the steric bulk of the acyl function (NHCOR, where R is an alkyl moiety) favors the reduction of the si-re prochiral face [in the methyl ester substrates] to yield an excess of the R-amino acid derivatives. In the series of N-acylphenylalanine methyl ester products (resulting from hydrogenation of Z-methyl α-acylaminocinnamates) the optical purity increased from 1% ee-(R) [Me]; 13% ee-(R) [i-Pr]; to 15% ee-(R) [t-Bu and 1-adamantyl]. The α-formamido and α-benzamido substrates gave hydrogenation products having 22% ee-(R) [H] and 35% ee-(R) [Ph]. In the corresponding free acids, increasing the steric bulk of the acyl function (NHCOR, where R is an alkyl moiety) results in almost no change in the optical purity of the reduction products. In the series of N-acylphenyl-alanine products (resulting from hydrogenation of Z-α-acylaminocinnamic acids) the optical purity was 35% ee-(S) [Me]; 31% ee-(S) [i-Pr]; 33% ee-(S) [t-Bu]; and 35% ee-(S) [1-adamantyl]. The α-benzamido substrate gave a hydrogenation product having 8% ee-(S).     

Facile Orthoester Formation in a Model Compound of the Taxol Oxetane: Are Biologically Active Epoxy Esters,Orthoesters, and Oxetanyl Esters Latent Electrophiles?

A steroidal oxetanyl ester was synthesized in eight steps as a biomimetic model of taxol oxetane. The model compound was surprisingly reactive under acidic conditions, rearranging in the absence of H₂O to a [2.2.1]‐bicyclic orthoester. Both the oxetanyl ester and the orthoester readily hydrolyze to produce the same triol monoacetate. On the basis of the oxetanyl ester/orthoester rearrangement, a novel biochemical function is suggested for the epoxy esters and oxetanyl esters found in taxoids whereby dioxonium ions, generated from these functional groups, react with cellular proteins to form mixed orthoesters or ethers. A similar process could be involved in the mechanism of action of natural orthoesters such as resiniferatoxin.     

Cationic polymerization of 1-phenyl-4-ethyl-2,6,7-trioxabicyclo[2.2.2]octane

Cationic polymerization of bicyclo ortho ester, 1-phenyl-4-ethyl-2,6,7-trioxabicyclo[2.2.2]octane, was carried out with Lewis acids and cation sources to obtain the polyether containing ester group in the side chain. It was found that boron trifluoride etherate was the most active initiator in the Lewis acids. Magnesium perchlorate and triphenylcarbenium tetrafluoroborate, which have lower nucleophilic counter ions, initiated effectively the polymerization of bicyclo ortho ester.     

Novel synthesis of the ortho ester derivative of 4,5-epoxymorphinan

[reaction: see text]. A method was found for the novel synthesis of ortho ester derivatives that are potentially useful as selective epsilon opioid receptor ligands. An unexpected 17-(cyclopropylmethyl)-4,5alpha-epoxy-6alpha-hydroxy-3,7,7-trimethoxy-8-oxa-6,14-endoethanomorphinan was produced when 17-(cyclopropylmethyl)-4,5alpha-epoxy-3-methoxy-6alpha,14-dihydroxy-6beta-(1,3-dithia-2-yl)-morphinan was treated in methanol with trimethyl orthoformate and CuO/CuCl2. This ortho ester derivative was then converted to an ester with acid. The structure of the ortho ester was determined by 2D NMR (HMBC) and mass spectra.     

Preparation of 2,3-dihydroselenolo[2,3-b]pyridines and related compounds by free-radical means

Photolysis of the thiohydroximate ester derivative 21 of 2-carboethoxy-2-(2-(benzylseleno)pyridin-3-yl)tridecylcarboxylic acid (20) affords 2-dodecyl-2-carboethoxy-2,3-dihydroselenolo[2,3-b]pyridine (22) in 89% yield in a process presumably involving intramolecular homolytic substitution by a tertiary alkyl radical at selenium with loss of a benzyl radical. Alternatively, rearrangement of O-(omega-haloalkyl)esters 34 of 2-carboethoxy-N-hydroxypyridine-2-selone affords azonianaphthalenium halides 37 in 79% yield.     

Synthesis of ortho substituted arylboronic esters by in situ trapping of unstable lithio intermediates

[reaction: see text] Ortho lithiation-in situ boration using lithium 2,2,6,6-tetramethylpiperidide (LTMP) in combination with triisopropylborate (B(OiPr)(3)) is a highly efficient and experimentally straightforward process for the preparation of ortho substituted arylboronic esters. The mild reaction conditions allow the presence of functionalities such as ester or cyano groups or halogen substituents that are usually not compatible with the conditions used in directed ortho metalation of arenes. The arylboronic esters underwent Suzuki-type cross-coupling with a range of aryl halides, furnishing biaryls in 53-94% yield.     

Application of [2,3]Wittig and [3,3]Claisen rearrangements in steroid side chain synthesis. A highly stereocontrolled entry to either (22 S)- or (22 R)-hydroxy-23-carboxylic acid

An efficient approach to either (22 S)- or (22 R)-hydroxy-23-carboxylic acid side chain is described which relies on the stereochemical transmission via [2,3]Wittig or [3,3]Claisen sigmatropic rearrangement, respectively.     

Synthesis of beta-amino-alpha-hydroxy esters and beta-amino-alpha-azido ester by Sharpless asymmetric aminohydroxylation, byproducts analysis

[reaction: see text] Synthesis of enantiomerically pure beta-amino-alpha-hydroxy esters (1, 2) and beta-amino-alpha-azido ester (3) using Sharpless AA as a key step is described. A hitherto unreported side reaction, the oxidation of the beta-hydroxy-alpha-amino ester (5) into the alpha,alpha-di-tert-butyloxycarbamoyl-beta-ketoester (8) under AA conditions, is documented.     

Xyloccensins O and P, unique 8,9,30-phragmalin ortho esters from Xylocarpus granatum

Two unique 8,9,30-phragmalin ortho esters, xyloccensins O (1) and P (2), were isolated from the mangrove plant Xylocarpus granatum. They are a new type of ortho ester of phragmalin. The structures were determined by spectroscopic and single-crystal X-ray diffraction techniques. The biogenetic pathway to these new phragmalins was also proposed. [structure: see text]     

Syntheses and polymerization of (meth)acrylates containing spiro ortho ester moieties

Acrylates and methacrylates bearing pendant spiro ortho ester groups ( 3 ) were prepared by the reaction of (meth)acrylic acid with bromomethyl spiro ortho esters ( 2 ) in the presence of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). These monomers were copolymerized with styrene (St) at 60°C in the presence of α,α'-azobisisobutyronitrile (AIBN) to give the corresponding copolymers with M?_n 6000-17000 and their compositions were in proportion to the feed ratios. Similarly, the copolymerization of 3 with acrylonitrile (AN) was carried out at 60°C to obtain the corresponding copolymers with the similar compositions to the feed ratios. Two kinds of 3 -St copolymers with different compositions were treated with BF₃OEt₂ in refluxing methylene dichloride affording the crosslinked polymers quantitatively. Slight expansion in volume was observed during the crosslinking.     

A highly stereoselective construction of beta-glycosyl linkages by reductive cleavage of cyclic sugar ortho esters

The preparation of beta-glycosides by the reductive cleavage of spiro sugar ortho esters is described in this report. This procedure is based on a concept completely different from those of other methods for glycosylation. Twelve sugar ortho esters that commonly possess perhydrospiro[2H-pyran-2,2'-pyrano[3,2-d][1,3]dioxin] ring systems in their molecules were reduced by LiAlH(4)/AlCl(3) or NaCNBH(3)/AlCl(3). Among these ortho esters, those (9a-12a) prepared from the D-sugar lactones (1-4) and 2, 3-di-O-benzyl-alpha-D-glucopyranoside (7) or those (19a, 20a) prepared from the L-sugar lactones (5, 6) and 2, 3-di-O-benzyl-alpha-D-galactopyranoside (8) were selectively converted into beta-(1 --> 4)-glycosides (9b-12b or 19b, 20b) in excellent yields by the treatment of LiAlH(4)/AlCl(3). In contrast, the ortho esters (13a-16a or 17a, 18a) that were prepared from combinations of the D-sugar lactones and 8 or those of the L-sugar lactones and 7 were efficiently reduced with NaBH(3)CN/AlCl(3) to afford beta-(1 --> 6)-glycosides (13b-16b or 17b, 18b) selectively. It was remarkable that the resulting disaccharides were obtained with extremely high beta-selectivity even in the cases with mannosyl or rhamnosyl glycosides. Moreover, these products would be useful units for the construction of branched saccharides, because the newly formed hydroxy groups could be again glycosylated without further deprotection procedures. The high regio- and stereoselectivity was totally explained by considering the structures and the conformations of these ortho ester molecules and the stereoelectoronic effects of their spiro ring systems. In addition, the preparation of the sugar ortho esters with glucosamine derivatives and the reactivity of these ortho esters are described in this report. N-Phthaloyl glucosamine derivatives (21, 22) were efficiently reacted with the benzyl-protected gluconolactone (1) in the presence of TMSOMe and TMSOTf to afford ortho esters (23a-c). After the conversion of the phthalimido functionality to the dibenzyl amino group, glucosylideneglucosamine (25) was reduced with LiAlH(4)/AlCl(3) to afford beta-(1 --> 4)-glycoside (26) selectively.