Radical cyclization of sugar-derived beta-(alkynyloxy)acrylates: synthesis of novel fused ethers

[formula: see text] Tributyltin radical mediated cyclization of carbohydrate-derived beta-(alkynyloxy)acrylates leading to highly functionalized cis- and trans-fused bicyclic ethers of various ring sizes is described. The efficacy of the radical cyclization is nicely illustrated in the iterative construction of a trans-fused tricyclic tetrahydropyran.     

Diastereoselectivity of polar and radical couplings in electrophilic substitutions of rigid 2-lithio-N-methylpyrrolidines

N-Methyl trans-fused perhydroisoindolines substituted with a tributylstannyl group in the 2-position have been prepared and used as precursors of the corresponding alpha-aminoorganolithiums. The steric course of the reactions of these and other conformationally rigid organolithiums with various electrophiles is summarized and compared with the steric course of the unsubstituted analogs. A mechanistic rationale for the steric course of electrophilic substitutions of these organolithiums is discussed. Pathways involving both polar electrophilic substitutions and radical couplings were observed with different electrophiles.     

Simple Designs for the Construction of Complex Trans-Fused Polyether Toxin Frameworks. A Convergent Strategy Based on Hydroxy Ketone Cyclization of C-Linked Oxacycles

A single, unified convergent strategy for the stereocontrolled synthesis of trans-fused polyethers was developed. It was demonstrated that the epimerization and reductive intramolecular coupling of hydroxy ketones in reactions with silane-Lewis acids (SI-LA) to generate ethers in C-linked oxacycles is affected by its conformational preference in a predictable manner. The obtained results make evident that the influence of hydrogen bonding between a hemiketal hydroxyl and a 1,3-diaxial C-O bond is regular and predictable and that convergent synthesis of trans-fused polyethers may confidently be conducted on driving ring closure to oxane rings under thermodynamic conditions     

alpha,beta-Unsaturated and cyclopropyl acyl radicals, and their ketene alkyl radical equivalents. Ring synthesis and tandem cyclisation reactions

Treatment of the alpha,beta-unsaturated selenyl esters 12 and 14 with Bu(3)SnH-AIBN produces the corresponding 2-cyclohexenones 13 and 15 respectively via presumed alpha-ketene alkyl radical intermediates, viz. 10. By contrast, the 2,7-diene esters 34 and 39 undergo tandem radical cyclisations producing diquinanes, e.g.(76%), and the corresponding allene-substituted alpha,beta-unsaturated selenyl ester 48 gives the cyclooctadienone 56 on treatment with Bu(3)SnH-AIBN in refluxing benzene. The selenyl ester 19 derived from chrysanthemic acid produces a mixture of the gamma,delta-unsaturated aldehyde 22 and the corresponding dimer 25a on treatment with Bu(3)SnH-AIBN. Furthermore, in the presence of methanol the only product from this reaction was the bis(methyl ester) dimer 25b, thereby lending further credence to the involvement of ketene alkyl radical intermediates in these reactions, and in the aforementioned reactions involving 2,6- and 2,7-diene selenyl esters. Treatment of the cyclopropane selenyl esters and , containing keto- and oxy-group functionality in their side-chains, with Bu(3)SnH-AIBN led to excellent syntheses of the enol lactone 66 (76%) and the trans-fused bicyclo[6.1.0]nonane 67 (80-95%) respectively.     

A furoindoline synthesis by remote radical functionalization

The preliminary results of an investigation toward a synthesis of furoindolines from 3-(2-hydroxyethyl)indolines by remote radical functionalization are described. Using an oxidative radical cyclization, it was discovered that the intramolecular hydrogen abstraction was only successful when the resulting radical (and hence carbocation) was resonance stabilized by adjacent tertiary amine and phenyl groups. The successful cyclization affords diastereomeric furoindolines, one of which contains a highly strained trans-fused 5,5-ring system. This furoindoline synthesis contains a rare example of an alkoxy radical promoted hydrogen atom transfer of a proton attached to a nitrogen-substituted carbon.     

On the Diels-Alder reactions of pentadienyl maleates and citraconates

Reactions between conjugated dienols and maleic anhydride provide either cis-fused or trans-fused bicyclic products as major products, depending upon how the reaction is carried out. Simply mixing the two reactants together generally leads to cis-fused lactone acids in thermal reactions which proceed viaintermolecular Diels-Alder reaction followed by intramolecular esterification. Pre-forming the maleate half ester derivative followed by heating affords predominantly trans-fused lactone acids in good yields by way of an intramolecular Diels-Alder (IMDA) reaction. Sorbyl citraconate half esters undergo a rapid thermolytic fragmentation in refluxing toluene to form the dienol and citraconic anhydride. The resulting diene-dienophile pair undergo an intermolecular cycloaddition followed by a rapid intramolecular esterification to give cis-fused bicyclic lactone acids as major products. The IMDA reaction of citraconic half esters is sufficiently rapid in DMSO to dominate over fragmentation: the exo-cycloadduct is formed almost exclusively. Nine literature reports of endo-selective IMDA reactions of triene acids are erroneous; the cycloadditions proceed in an intermolecular manner.     

A concise approach for the total synthesis of pseudolaric acid A

A new strategy for the stereoselective total synthesis of natural product pseudolaric acid A (1) was accomplished in 16 steps from commercially available starting material, featuring a samarium diiodide (SmI(2))-mediated intramolecular alkene-ketyl radical cyclization and a ring-closing metathesis (RCM) reaction to stereoselectively cast the unusual trans-fused [5-7]-bicyclic core of pseudolaric acid A (1).     

Application of 4,5-O,N-oxazolidinone protected thiophenyl sialosyl donor to the synthesis of α-sialosides

The synthesis of a novel oxazolidinone sialosyl donor is reported. The introduction of a trans-fused ring enhances reactivity and stereoselectivity in glycosylation reactions for the synthesis of α-sialosides. The oxazolidinone ring can also be removed under basic conditions to afford the deprotected amine, which can be further functionalized.     

Palladium(II)-catalyzed intramolecular 1,4-oxyacyloxylation of conjugated dienes. A stereocontrolled route to fused six-membered lactones and pyrans

Stereocontrolled palladium(II)-catalyzed intramolecular 1,4-oxidations of dienyl acids and alcohols proceed under mild conditions to give fused delta-lactones and pyrans, respectively, in good yields. The stereo- and regioselectivity was affected by the presence of LiCl and solvent composition (HOAc/acetone). The products obtained were used for further functionalizations using copper(I)-mediated reactions. Stoichiometric reactions of preformed dibutylcyanocuprates with pyrans containing an allylic acetate gave cis- and trans-fused ring systems with high gamma-selectivity and in high yields.     

Stereoselective convergent synthesis of a trans-fused polycyclic ether ring system including a 4-hydroxy-5-methyl-tetrahydropyran ring

[reaction: see text] Stereoselective convergent synthesis of a trans-fused 6-6-6-6-membered tetracyclic ether ring system including 4alpha- or 4beta-hydroxy-5-methyl-tetrahydropyran was achieved. The key reactions involve the acetylide-aldehyde coupling of two tetrahydropyrans, intramolecular hetero-Michael cyclization of enone, stereoselective reduction of enone, hydroboration, intramolecular acetalization, and stereoselective reduction of the acetal with Et(3)SiH-TMSOTf.     

Cation Clock Permits Distinction Between the Mechanisms of α- and β-O- and β-C-Glycosylation in the Mannopyranose Series: Evidence for the Existence of a Mannopyranosyl Oxocarbenium Ion

The use of a cationic cyclization reaction as a probe of the glycosylation mechanism has been developed and applied to the 4,6-O-benzylidene-protected mannopyranoside system. Cyclization results in the formation of both cis- and trans-fused tricyclic systems, invoking an intermediate glycosyl oxocarbenium ion reacting through a boat conformation. Competition reactions with isopropanol and trimethyl(methallyl)silane are interpreted as indicating that β-O-mannosylation proceeds via an associative S(N)2-like mechanism, whereas α-O-mannosylation and β-C-mannosylation are dissociative and S(N)1-like. Relative rate constants for reactions going via a common intermediate can be estimated.     

Structural investigations of isomeric 2,4-diphenyl-7,8-benzohexahydrothiochromenes

Structural investigations were carried out by means of PMR spectroscopy and x-ray diffraction analysis, and the type of fusion of the heterorings and alicyclic rings in isomeric 2,4-diphenyl-7,8-benzohexahydrothiochromenes previously obtained by the disproportionation and ionic and catalytic hydrogenation of 2,4-diphenyl-7,8-benzo-5, 6-dihydrothiochromene was established. The predominant realization of a diastereomer with trans-fused heterorings and alicyclic rings in all of the reactions mentioned above was demonstrated; the possibility of the formation of the eis isomer in the catalytic reduction of benzodihydrothiochromene was confirmed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1060–1063, August, 1980.     

Enantiospecific total synthesis of lairdinol A

The synthesis of lairdinol A, a component of the host-selective phytotoxin depsilairdin, was achieved in 12 steps (18% overall yield) without the use of protecting groups starting with the Diels-Alder reaction of (R)-carvone with 3-trimethylsilyloxy-1,3-pentadiene. The key step established the trans ring fusion by preferential epoxidation of a trans-fused enone in an equilibrating mixture of the cis-fused and trans-fused diastereomers (i.e., equivalent to a dynamic kinetic resolution of these isomers). The synthesis confirms the absolute configurations of lairdinol A and its enantiomer, cyperusol C.     

Influence of ring fusion stereochemistry on the stereochemical outcome in photo-induced Diels–Alder reaction of fused bicycloheptenone derivatives

Photo-isomerization of cis-cycloheptenone fused to a ring with a defined stereochemistry at the ring fusion to its trans-stereoisomer and in situ Diels–Alder reaction with cyclic and acyclic dienes have been investigated. The reaction was found to proceed through one of the two possible isomerized trans-enones that produce the thermodynamically more stable adduct with a trans-fused seven-membered ring system. This protocol has been employed to construct a tetracycle with trans-fused 6-7 ring system, the core structure present in several terpenes. The observed selectivity has been supported by computational method.     

Construction of fused bis(pyran) units from enones via a hydrosilylation-dihydroxylation-acetalization-reduction sequence

HWE coupling of two simple bifunctional fragments provides enones that can be subjected to a four-step sequence to furnish trans-fused bis(pyrans) in good overall yield.     

Total synthesis of brevetoxin-B

Brevetoxin-B (BTX-B), produced by the red tide organism, Gymnodium breve Davis, is the first member of marine polycyclic ethers to be structurally elucidated and one of the most potent neurotoxins. The structural feature is a trans-fused polycyclic ether ring system with 23 stereocenters. Its unique, complex structure and potent biological activity have attracted the attention of synthetic organic chemists. Total synthesis of BTX-B has been accomplished via the coupling of the ABCDEFG and IJK-ring segments, each ether ring of which was stereoselectively and efficiently constructed on the basis of SmI2-induced intramolecular cyclization, 6-endo-cyclization of hydroxy epoxide, ring-closing olefin metathesis, and SmI2-induced intramolecular Reformatsky-type reaction. Several kinds of double reactions at the left and right sides were efficiently used through the synthesis.     

Pseudo-two-dimensional structures (HXYH)3n2H6n (XY = GaN, SiC, GeC, SiSi, or GeGe; n = 1-3): density functional characterization of structures and energetics

Hybrid density functional calculations with effective core potential basis sets are performed for monomeric group 13/15 and group 14/14 analogues of cyclohexane, as well as for three different pseudo-two-dimensional structures that can be formed from expanding one and two concentric rings around the central one (trans-fused chairs, a rolling combination of trans- and cis-fused chairs, and cis-fused boats). Varying contributions from torsional strain, angle strain, electrostatics, and nontraditional H-H hydrogen bonding lead to different orderings and magnitudes of motif energies in the various systems: Homoatomic SiSi and GeGe systems prefer the trans-fused chair alternative and heteroatomic systems GaN, SiC, and GeC prefer the rolling chair. Decomposition of structure energies into characteristic fragment contributions indicates that pseudo-one-dimensional rods of poly(imidogallane) are thermodynamically more stable than any of the pseudo-two-dimensional structures.     

Synthesis of (+)-8-deoxyvernolepin and its 11,13-dihydroderivative. A novel reaction initiated by sulfene elimination leads to the 2-Oxa-cis-decalin skeleton

The title compounds are interesting candidates for antifungal screening. This paper describes the enantiospecific synthesis of these compounds starting from (+)-costunolide isolated from a commercially available extract. We used two novel reactions as key synthetic steps in this work: the acid-induced cyclization of an delta,epsilon-epoxy ester, which stereoselectively gave a hydroxymethyl-substituted delta-lactone, with the hydroxyalkyl group in the desired beta-equatorial disposition, and a reaction cascade, initiated by a base-promoted sulfene elimination, which led to a 10-oxiranyl-2-oxa-cis-decalin from the mesylate of a trans-fused delta-lactone. We also found that the reaction between selenium dioxide and the 1,5-diene system of elemanolides gave selenadecalins analogous to natural eudesmanolides. Our results prove that the synthetic strategy employed, on the basis of biomimetic concepts, is a useful procedure for the enantiospecific preparation of (+)-vernolepin-related compounds from accessible germacrolides.     

Lactone synthesis via dyotropic rearrangement. Stereospecific construction of fused butyrolactones with three contiguous asymmetric centers

Substituted trans-fused cyclohexano butyrolactones are accessible via dyotropic rearrangement of β-lactones, wherein all three adjacent chiral centers are simultaneously fixed.     

Optimising stereoselectivity in intramolecular Diels-Alder reactions of pentadienyl acrylates: synthetic and computational investigations into the "steric directing group" approach

Experimental conditions for the intramolecular cycloaddition of four related pentadienyl acrylates 3, 4, 5 and 6 are reported. In contrast with several previous reports, pentadienyl acrylates do undergo synthetically useful intramolecular Diels-Alder reactions: 3, 4, 5 and 6 cyclise at reasonable rates at temperatures of 132-180 degrees C at atmospheric pressure in moderate to good yields. The stereochemical outcome of each of these reactions was accurately measured and the results are in good agreement with transition structure populations predicted using B3LYP/6-31+G(d) theory. The parent system 3 cyclises with moderate endo selectivity; the presence of either a C5-methyl substituent or a C3-bromine atom results in a slight shift towards the trans-fused exo stereoisomer but--overall--a less selective reaction. The presence of both C3-Br and C5-CH3 substituents results in a marked improvement in stereoselectivity with the exo,lk-product predominating. Interpretation of B3LYP/6-31+G(d) transition structures allows insights into the improvement in stereoselectivity obtained by incorporating a removable "steric directing group" into a 5-methyl-1,3,8-nonatriene precursor.