Reagent-controlled stereoselective synthesis of lignan-related tetrahydrofurans

The reaction of ring-closing metathesis-derived cyclic allylsiloxanes 3 with aldehydes in the presence of a Lewis acid gives 2,3,4-trisubstituted tetrahydrofurans related to the furanolignan family of natural products. The reactions proceed with complete 3,4-trans stereoselectivity, whereas the C-2 stereochemistry depends on both the aldehyde and Lewis acid used. When boron trifluoride etherate is used with aliphatic or electronically neutral aryl aldehydes, the reactions favor the production of the 2,3-cis isomer 8, whereas electron-rich aryl aldehydes lead to the 2,3-trans isomer 9 by Lewis acid-mediated isomerization of the kinetically favored cis isomer. The isomerization can be avoided by use of TMSOTf as a promoter, and hence, the stereochemistry can be tuned by appropriate choice of reagent. Cleavage of the pendant 3-ethenyl group installs the 3-hydroxymethyl group common to the furanolignans.     

Simple Methods for Determining Relative Stereochemistry of Kainoid Amino Acids by (1)H NMR Chemical Shifts

The kainoid amino acids are biologically important compounds because they show remarkable neuroexcitatory and excitotoxic activities. For exhibiting potent activity, the stereochemical relationship of the substituents on the pyrrolidine ring is crucial. We found simple methods for determining the relative stereochemistry of these compounds on the basis of the (1)H NMR chemical shifts of H-2 and H-4 in D(2)O solution. The signals of H-2 appear at fields higher than 4.2 ppm when the compounds have 2,3-trans stereochemistry whereas, in the 2,3-cis compounds, they appear lower than 4.2 ppm, irrespective of the C-4 substituent. This criterion holds when the solution is in the range of pD 3-8. Moreover, when an epimeric pair at C-2 is available and the spectra are recorded at the same or nearly equal pD, the H-2 chemical shift of the 2,3-trans isomer is higher than that of the corresponding 2,3-cis isomer. Similarly, the relative stereochemistry between C-3 and C-4 can be determined from the chemical shift of H-4. The signals of H-4 of the 3,4-cis isomers appear at lower fields than those of the corresponding 3,4-trans isomers in each pair of C-4 epimers when the spectra are recorded at the same or nearly equal pD. This holds for the compounds bearing an unsaturated substituent at C-4. All these phenomena can be rationalized by the anisotropic effect of the pi-electron system in the C-2 and C-4 substituents.     

Functionalized tetrahydrofurans from alkenols and olefins/alkynes via aerobic oxidation-radical addition cascades

Aerobic oxidation of alkyl- and phenyl-substituted 4-pentenols (bishomoallyl alcohols), catalyzed by cobalt(II) complexes in solutions of γ-terpinene or cyclohexa-1,4-diene, stereoselectively gave tetrahydrofurylmethyl radicals. Cyclized radicals were trapped with monosubstituted olefins (e.g., acrylonitrile, methyl acrylate), (E)- and (Z)-1,2-diacceptor-substituted olefins (e.g., dimethyl fumarate, fumarodinitrile, N-phenyl maleic imide), and ester-substituted alkynes (e.g., ethyl propynoate). Oxidation-addition cascades thus furnished side-chain-substituted (CN, CO(2)R, COR, or SO(2)R) di- and trisubstituted tetrahydrofurans in stereoselective reactions (2,3-trans, 2,4-cis, and 2,5-trans). A diastereomerically pure bistetrahydrofuran was prepared in a cascade consisting of two aerobic oxidations, one alkyne addition, and one final H-atom transfer.     

Endocyclic cleavage in glycosides with 2,3-trans cyclic protecting groups

An endocyclic pathway is proposed as a reaction mechanism for the anomerization from the β (1,2-trans) to the α (1,2-cis) configuration observed in glycosides carrying 2,3-trans cyclic protecting groups. This reaction occurs in the presence of a weak Lewis or Br?nsted acid, while endocyclic cleavage (endocleavage) in typical glycosides was observed only when mediated by protic media or strong Lewis acids. To rationalize the behavior of this class of compounds, the reaction mechanism and the promoting factors of the endocleavage are investigated using quantum-mechanical (QM) calculations and experimental studies. We examine anomerization reactions of thioglycosides carrying 2,3-trans cyclic protecting groups, employing boron trifluoride etherate (BF(3)·OEt(2)) as a Lewis acid. The estimated theoretical reactivity, based on a simple model to predict transition state (TS) energies from the strain caused by the fused rings, is very close to the TS energies calculated by the TS search along the C1-C2 bond rotation after the endo C-O bond breaking. Excellent agreement is found between the predicted TS energies and the experimental reactivity ranking. The series of calculations and experiments strongly supports the predominance of the endocyclic rather than the exocyclic mechanism. Furthermore, these investigations suggest that the inner strain is the primary factor enhancing the endocleavage reaction. The effect of the cyclic protecting group in restricting the pyranoside ring to a (4)C(1) conformation, extensively discussed in conjunction with the stereoelectronic effect theory, is shown to be a secondary factor.     

Glycosidation-anomerisation reactions of 6,1-anhydroglucopyranuronic acid and anomerisation of beta-D-glucopyranosiduronic acids promoted by SnCl(4)

The reaction of silylated nucleophiles with 6,1-anhydroglucopyranuronic acid (glucuronic acid 6,1-lactones) catalysed by tin(IV) chloride provides 1,2-trans or 1,2-cis (deoxy)glycosides in a manner dependent on the donor structure. The alpha-glycoside was obtained for reactions of the donor with the 2-acyl group and 2-deoxydonors, whereas the 2-deoxy-2-iodo donor gave the beta-glycoside. Experimental evidence shows that when 1,2-cis-glycoside formation occurs, the anomerisation of initially formed 1,2-trans-glycosides catalysed by SnCl(4) is possible. The anomerisation of beta-D-glucopyranosiduronic acids was found to be faster, in some cases, than anomerisation of related beta-D-glucopyranosiduronic acid esters and beta-D-glucopyranoside derivatives and the rates are dependent on the structure of the aglycon. Moreover, the rates of anomerisation of beta-D-glucopyranuronic acid derivatives can be qualitatively correlated with rates of hydrolysis of beta-D-glucopyranosiduronic acids. Mechanistic possibilities for the reactions are considered.     

Aza-Baylis-Hillman reactions of N-tosylated aldimines with activated allenes and alkynes in the presence of various Lewis base promoters

[reaction: see text] The attempted aza-Baylis-Hillman reactions of N-tosylated aldimines with ethyl 2,3-butadienoate, ethyl penta-2,3-dienoate, penta-3,4-dien-2-one, methyl propiolate, and but-3-yn-2-one have been systematically investigated in the presence of various nitrogen or phosphine Lewis base promoters. We found that a series of nitrogen-containing heterocyclic compounds, as "abnormal" aza-Baylis-Hillman reaction products, can be formed in the presence of an appropriate Lewis base promoter. The Lewis base and solvent effects in these reactions have been discussed along with the corresponding plausible mechanism.     

Head-to-head polymers. XV. A facile synthesis of 2,3-disubstituted succinates and butanediols-1,4

A synthetic approach that makes symmetrically 2,3-dialkyl-substituted succinates and compounds prepared from 2,3-dialkyl-substituted succinates easily available has been developed. Coupling of α-bromoalkanoic esters with a zinc/copper couple produced in about 40% yield 2,3-disubstituted succinates which were reduced with LiAlH₄ to 2,3-disubstituted butanediols-1,4 in nearly quantitative yields. Some 2,3-disubstituted butanediols-1,4 were cyclodehydrated under reduced pressure with KHSO₄ to 3,4-disubstituted tetrahydrofurans or acetylated and the diacetyl compounds pyrolyzed at 525°C to 2,3 disubstituted butadienes-1,3. The length of the alkyl chains of the 2,3-dialkylsuccinates and consequently the 2,3-dialkylbutanediols-1,4 ranged from C₂ to C₁₆. 2,3-Disubstituted butanediols-1,4, 2,3-disubstituted butadienes-1,3, and 3,4-disubstituted tetrahydrofurans are interesting monomers for polymerization experiments.     

Lewis acids as α-directing additives in glycosylations by using 2,3-O-carbonate-protected glucose and galactose thioglycoside donors based on preactivation protocol

Catalytic or stoichiometric amounts of Lewis acids were found to be very effective α-directing additives in the stereoselective glycosylations of diverse 2,3-O-carbonate-protected glucose and galactose thioglycoside donors by preactivation protocol. The poor stereoselectivities of 4,6-di-O-acetyl-2,3-O-carbonate protected thioglycoside donors in glycosyl coupling reactions were greatly improved, and excellent α-stereoselectivities were achieved by the addition of 0.2 equiv of BF(3)·OEt(2). On the other hand, the β-selectivities of 4,6-di-O-benzyl-2,3-O-carbonate-protected thioglucoside donor toward glycosylations were reversed completely to the α-selectivities by the use of 1 equiv of SnCl(4), making the stereoselectivity controllable. Furthermore, the poor stereoselectivities of 4,6-di-O-benzyl-2,3-O-carbonate-protected thiogalactoside donor in glycosylations were also improved by using SnCl(4) as additive.     

4,5-Unsubstituted 2,3-dihydroisoxazoles in the synthesis of racemic 4-substituted isoxazolidine-5-carbonitriles

The synthesis of novel types of the 4-hydroxy- and 4-bromosubstituted isoxazolidines is described. Dihydroxylation reactions of 4,5-unsubstituted 2,3-dihydroisoxazoles proceed from the less hindered side and provide the major 3,4-trans-isoxazolidine-4,5-diols in good yields. On the other hand, the hydroxybromination reaction of the model 3-phenyl-2,3-dihydroisoxazole predominantly proceeds with 3,4-cis selectivity. Isoxazolidine-5-carbonitriles have been prepared from isoxazolidines possessing a good leaving group at C5 by treatment with TMSCN in the presence of TMSOTf.     

AlCl3-promoted highly regio- and diastereoselective [3 + 2] cycloadditions of activated cyclopropanes and aromatic aldehydes: construction of 2,5-diaryl-3,3,4-trisubstituted tetrahydrofurans

The AlCl(3)-catalyzed [3 + 2] cycloaddition reaction of diethyl trans-2,3-disubstituted cyclopropane-1,1-dicarboxylates and aromatic aldehydes was carried out under mild conditions to provide a series of diethyl 2,5-diaryl-4-benzoyltetrahydrofuran-3,3-dicarboxylates in moderate to good yields with excellent diastereoselectivities. While common 2,5-cis products were obtained with electron-neutral or electron-poor aryl aldehydes, the much less common 2,5-trans products were obtained in excellent diastereoselectivities when electron-rich aryl aldehydes were used. The relative configurations of those typical products were confirmed by X-ray crystallographic analyses.     

Stereoselective synthesis of 2,4,5-trisubstituted piperidines by carbonyl ene and Prins cyclisations

An approach to 2,4,5-trisubstituted piperidines is reported, in which the key step is the Prins or carbonyl ene cyclisation of aldehydes of the type 1. Prins cyclisation catalysed by concentrated hydrochloric acid in CH(2)Cl(2) at -78 degrees C afforded good yields of two of the four possible diastereomeric piperidines, with the 4,5-cis product 7 predominating in a diastereomeric ratio of up to 94:6. The diastereoselectivity of the cyclisation decreased as the 2-substituent increased in size, becoming unselective for very bulky 2-substituents. In contrast, cyclisation catalysed by MeAlCl(2) in CH(2)Cl(2) or CHCl(3) at temperatures of between 20-60 degrees C, favoured the 4,5-trans diastereomer 8, in a diastereomeric ratio of up to 99:1. The low-temperature cyclisations catalysed by HCl proceed under kinetic control via a mechanism involving the development of significant carbocationic character, in which the 4,5-cis cation is more stable than the 4,5-trans cation as a result of overlap with the neighbouring oxygen. The cyclisations catalysed by MeAlCl(2) proceed under thermodynamic control, affording the product in which both the 4- and 5-substituents are equatorial.     

Asymmetric total synthesis of botcinins C, D, and F

Stereoselective total synthesis of botcinins C, D, and F is effectively carried out through asymmetric aldol reactions, 6-endo ring closure, and SmI2-mediated 3,4-trans or -cis stereoselective intramolecular Reformatsky reaction. Rapid esterification of the main skeleton of botcinins with the chiral side chain using MNBA and DMAP produced botcinin D, an antifungal chemical against a pathogen of rice blast disease.     

Diastereoselective intramolecular alpha-amidoalkylation reactions of L-DOPA derivatives. Asymmetric synthesis of pyrrolo[2,1-a]isoquinolines

[reaction: see text] Stereocontrolled intramolecular alpha-amidoalkylation reactions of L-DOPA-derived succinimides have been studied. Addition of MeLi to nonracemic succinimides 9a-d yields oxoamides, which are cyclized upon treatment with Lewis or protic acids to afford (5S,10bS)-trans 11 or (5S,10bR)-cis 12pyrroloisoquinolines with variable diastereoselectivities, but with high enantiomerical purities (ee 99%).     

Cyclopropane-aldehyde annulations at quaternary donor sites: stereoselective access to highly substituted tetrahydrofurans

A diastereoselective synthesis of pentasubstituted tetrahydrofurans via a Lewis acid catalyzed (3 + 2)-annulation of quaternary donor site cyclopropanes and aldehydes is described. The reaction is catalyzed by Sn(OTf)(2), SnCl(4), or Hf(OTf)(4) in yields up to 95% and diastereomeric ratios as high as 99:1.     

Cis and trans selective 1,4-addition of a lithium dithioester enolate to 4-O-TBS-2-cyclohexenone

The 1,4-addition of the lithium enolate of methyldithioacetate (LMDTA) to (+/-)-4-O-TBS-2-cyclohexenone (3) can be varied from being highly 3,4-trans selective to being highly 3,4-cis selective simply by varying the reaction temperature. This stereodivergency allows expedient syntheses of the corresponding trans and cis methyl esters 6t and 6c and derived bicyclic ketolactones 7t and 7c.     

Reaction of 2-silylmethylcyclopropyl ketones with in situ oxirane-derived aldehydes and formation of 2-hydroxymethyl tetrahydrofurans

The enolates formed from Lewis acid treatment of (2-trimethylsilylmethyl)cyclopropyl alkyl and aryl ketones reacted with aldehydes formed in situ from alkoxy-, aryl- and vinyl-substituted oxiranes to generate aldol products in good yields. Selected aldol products were conveniently transformed into highly substituted tetrahydrofurans under oxidative conditions.     

Diastereoselective synthesis of oxazolo[3,4-b]tetrahydroisoquinolin-3-ones via Lewis acid TMSOTf-mediated Pictet–Spengler reaction

An alternative and efficient method to stereoselectively synthesize oxazolo[3,4-b]tetrahydroisoquinolin-3-ones via a Pictet–Spengler reaction promoted by Lewis acid TMSOTf from readily available (S)-4-benzyl-2-oxazolidinone with various aromatic, aliphatic, and cyclic aldehydes under room temperature is described.     

1,2-migration of 2'-oxoalkyl group and concomitant synthesis of 2-C-branched O-, S-glycosides and glycosyl azides via 1,2-cyclopropanated sugars

Treatment of 2'-oxoalkyl 2-O-Ms(Ts)-alpha-C-mannosides (4, 5, and 6) with base resulted in 1,2-cyclopropanation via an intramolecular SN2 reaction due to their 1,2-trans-diaxial configurations. The 1,2-cyclopropanated sugars (10 and 13) were reacted with various alcohols, thiols, and sodium azide to produce 2-C-branched O- and S-glycosides and glycosyl azides (11, 14-28) in good to excellent yields. In contrast, 1,2-cis 2'-oxoalkyl 2-O-Ms(Ts)-alpha-C-glucoside 9 formed an acyclic conjugated aldehyde (31) under basic conditions, which occurred by 1'-enolation followed by beta-elimination. An intramolecular Michael addition from 31 produced 2-O-Ms-beta-C-glucoside 30 as a major product. However, due to the electron-withdrawing effect exerted by 2-O-Ms compound 31 also undergoes a C2 epimerization to form 32. Thereafter, the intramolecular Michael addition led to the formation of both 1,2-trans 2'-oxoalkyl 2-O-Ms-alpha-C-mannoside 4 and its beta-anomer (33). Because beta-elimination/Michael addition and C2 epimerization are reversible reactions, equilibriums among 9, 31, 30, 32, 33, and 4 were established, which included the transformation of 1,2-cis C-glucoside 9 into 1,2-trans C-mannoside 4. The subsequent 1,2-cyclopropanation of 4 was an irreversible reaction yielding 1,2-cyclopropanated 10 and further conversion to 1,2-migration products (11 and 12).     

Stereoselective 6-exo cyclization of amidyl radicals. An experimental and theoretical study

Unsaturated primary amidyl radicals of Z-configurations underwent efficient chemo- and stereoselective 6-exo cyclization reactions via chair-conformational transition states, leading to the predominant formations of 3,6-trans, 4,6-cis, or 5,6-trans substituted δ-lactams.     

Synthesis of enantiomerically pure perhydrofuro[3,4-b]pyrans and perhydrofuro[3,4-b]furans

Olefinic diols, prepared from (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde via olefination and hydrolysis, were converted into enantiomerically pure hydroxy substituted tetrahydrofuran derivatives by cyclization using N-phenylselenophthalimide and BF₃. The PhSe group in the C-4 position of these tetrahydrofurans was then substituted by an allyl group using allyltributylstannane in the presence of AIBN. The selenium promoted cyclizations of the allyl tetrahydrofurans in which the OH and the allyl groups are trans to each other formed the enantiopure perhydrofuro[3,4-b]pyrans, while the cyclization of the allyl tetrahydrofurans in which the OH and the allyl groups are cis gave rise to the perhydrofuro[3,4-b]furans. These bicyclic products were finally deselenenylated with triphenyltin hydride and AIBN.