5-Methyl-4H-1,3-dioxins,new chiral building blocks: transformation into (R)- and (S)-4-hydroxymethyl-4-methyl-1,3-dioxolanes via oxidation and rearrangement and determination of the absolute configuration

5-Methyl-4H-1,3-dioxins obtained by asymmetric double-bond isomerization have been transformed into 4-hydroxymethyl-4-methyl-1,3-dioxolanes by m-chloroperbenzoic acid oxidation, ring contraction and reduction. The stereochemical course of this transformation has been studied, while the relative configuration of the intermediate oxidation product and the absolute configuration of the resulting camphanyl ester of 2-tert-butyl-4-hydroxymethyl-4-methyl-1,3-dioxolane was established by X-ray crystallography. From these results, the absolute configuration of the dioxins has been deduced.     

Asymmetric 1,3-dipolar cycloaddition of chiral sulphinylethenes with 1-methyl-3-oxido-pyridinium and some nitrones

1,3-Dipolar cycloaddition of (R)-(+)-p-tolyl vinyl sulphoxide 1 with 1-methyl-3-oxidopyridinium 6 proceeded in a diastereoselective manner to afford the exo and endo cycloadducts 11a,b and 12a in 36%, 7% and 29% yield, respectively. The absolute configuration of 11a was determined by its transformation to (1S)-(−)-2-tropanol (−)-15. Attempts to the cycloaddition of the sulphinylethenes 17–19 with the pyridinium 6 were nsuccessful under several conditions. The reaction of the sulphoxide 20 with pyrroline 1-oxide 21 gave an inseparable mixture of products. The cycloaddition of 20 with 3,4,5,6-tetrahydropyridine 1-oxide22 afforded a mixture of four adducts in ca. 90% yield. High level of diastereoselectivity was achieved for the endo cycloaddition affording the adduct 23 in 33% isolated yield. The absolute configuration of 23 was confirmed by a single-crystal X-ray diffraction study. The stereochemical course of the reaction was discussed based on the absolute configuration of the products.     

Ti(IV)-catalyzed asymmetric sulfenylation of 1,3-dicarbonyl compounds

The electrophilic enantioselective sulfenylation of 1,3-dicarbonyl compounds with phenylsulfenyl chloride is effectively catalyzed by [Ti(TADDOLato)] complexes. The corresponding products are obtained in moderate to high yields. The highest ee values (up to 97 %) are obtained in toluene at room temperature and with a typical catalyst loading of 5 mol %. Bulky ester groups and sterically undemanding substituents at the alpha-position were found to be crucial structural features of the starting materials in order to assure high enantioselectivity. The absolute configuration of one of the chiral products has been determined. The stereochemical course of the reaction is similar to that of analogous [Ti(TADDOLato)]-catalyzed atom-transfer reactions. A common side-reaction the sulfenylated products undergo is a deacylation leading to racemic alpha-sulfenylated esters.     

Catalytic Asymmetric 1,3‐Dipolar Cycloaddition of β‐Fluoroalkylated α,β‐Unsaturated 2‐Pyridylsulfones with Nitrones for Chiral Fluoroalkylated Isoxazolidines and γ‐Amino Alcohols

2‐Pyridylsulfone‐ and fluoroalkylated group‐activated olefins underwent highly efficient diastereo‐ and enantioselective 1,3‐dipolar cycloadditions across various aromatic and aliphatic nitrones in the presence of a chiral Ni^II/bis(oxazoline) catalyst. The process was tuned by 4 Å molecular sieves, chiral bis(oxazoline) ligands, reaction solvents, and temperature. A wide array of optically pure fluoroalkylated isoxazolidines were obtained, thus facilitating the asymmetric synthesis of an enantioenriched α‐trifluoromethylated γ‐amino alcohol in gram‐scale and a trifluoromethylated derivative of 1,3‐oxazinan‐2‐one with potential pharmaceutical interest. A stereochemical model, based on the absolute configuration of one adduct and some control experiments, was postulated to account for the observed endo‐ and enantioselectivity.     

A Stereospecific `2‐Aza‐divinylcyclopropane' Rearrangement

The stereochemical course of the thermal 2‐aza‐Cope rearrangement of the optically pure acyl azide (−)‐(1S)‐ 5 was investigated by determination of the absolute configuration of the rearrangement product (1R,8S)‐ 9 . The reaction proceeds by a sequence of stereospecific steps from 5 to an equilibrating mixture of exo‐ and endo‐isocyanates 6 and 7 . The endo‐isomer 7 undergoes Cope rearrangement to the putative intermediate 8 , which is trapped and characterized as the adduct 9b of butan‐1‐ol. The absolute configuration of 9b was determined by its reduction to the amide 20 , and determination of the X‐ray structure of the N‐camphanoylamide 21 derived from camphanic acid of known absolute configuration.     

Coulomb Explosion Imaged Cryptochiral (R,R)‐2,3‐Dideuterooxirane: Unambiguous Access to the Absolute Configuration of (+)‐Glyceraldehyde

The absolute configuration of (R,R)‐2,3‐dideuterooxirane, which has been independently determined using Coulomb explosion imaging, has been unambiguously chemically correlated with the stereochemical key reference (+)‐glyceraldehyde. This puts the absolute configuration of D (+)‐glyceraldehyde on firm experimental grounds.     

Desymmetrization of N‐Sulfonated Aziridines by Alkyllithium Reagents in the Presence of Chiral Ligands

The stereochemical course of the rearrangement of the N‐sulfonylaziridines 5, 15 , and 25 in the presence of s‐BuLi/(?)‐sparteine to the bicyclic sulfonamides 4, 16 , and 17 , respectively, has been investigated chemically and by X‐ray structure analysis. The absolute configurations of the products were, in all cases, opposite to those of the alcohols formed upon rearrangement of the corresponding epoxides. Similarily, the allylic sulfonamide 10 , resulting from rearrangement of 7‐[(4‐methylphenyl)sulfonyl]‐7‐azabicyclo[4.1.0]heptane ( 7 ) under the same reaction conditions, had the (R)‐configuration, while cyclohexen‐3‐ol, obtained upon rearrangement of cyclohexene oxide, is known to be (S)‐configured. Deuterium labelling showed that the rearrangement of 7 proceeds via enantioselective α‐elimination to a carbene, which undergoes a 1,2‐H shift.     

Regio- and stereoselective 6-exo-trig radical cyclisations onto chiral perhydro-1,3-benzoxazines: synthesis of enantiopure 3-alkylpiperidines

Enantiopure 3-alkyl substituted piperidines are prepared by diastereoselective 6-exo-trig cyclisation of perhydro-1,3-benzoxazines derived from (−)-(8)-amino menthol. The diastereoselective cyclisation is promoted by tributyltin hydride, and the competitive 1,5-hydrogen migration depends on the position of the acceptor double bond and the radical site.     

A General Strategy for the Catalytic,Highly Enantio‐ and Diastereoselective Synthesis of Indolizidine‐Based Alkaloids

Sixteen indolizidine‐based alkaloids (IBAs) that were isolated as poison constituents of the skin of frogs were synthesized in a highly flexible and stereoselective manner. As a key step, a three‐component, organocatalytic, highly enantio‐ and diastereoselective vinylogous Mukaiyama–Mannich reaction was employed furnishing optically highly enriched butyrolactams as central intermediates on a multigram scale. The attached six‐membered ring was constructed through cyclization of the pendant enoate moiety onto the pyrrolidine ring. The absolute configuration of the bridgehead chiral center and the adjacent 8‐position was established in the initial vinylogous Mannich reaction, whereas the 3‐ and 5‐substituents were introduced through organometallic addition at a late stage of the synthesis with full stereochemical control from the substrate. With this strategy, simple as well as even more complex alkaloids were accessible in good overall yields as single stereoisomers. These syntheses also served to establish the absolute and relative configuration of those IBAs that had never been synthesized before.     

Mechanism of an alcohol-trapping reaction in the direct and benzophenone-sensitized photodenitrogenation of a spiroepoxy-substituted azoalkane: solvent effects and stereochemical deuterium labeling

The spin-state-dependent reactivity, singlet versus triplet, of the 2-spiroepoxy-1,3-cyclopentane-1,3-diyl DR2 has been assessed through alcohol-trapping reactions for which the effect of solvent acidity on the product distribution of the alcohol trapping products 2 versus 3 + 4 and stereochemical deuterium-labeling studies have been performed. The proposed mechanism for the solvent effect on the product ratio (2/3 + 4) reveals the importance of the hydrogen-bonded intermediates I1 and I2 in the trapping reactions; the stereochemical deuterium-labeling results clarify the dipole structure trapped by the alcohol. The dipoles DP1 and DP2, in which the configuration between the epoxide oxygen and the deuterium atoms is retained, are inferred for the direct photodenitrogenation reactions (singlet state), whereas for the benzophenone-sensitized photoreactions (triplet state), after ISC, the ring-opened dipole DP3 is implied as the intermediate that is trapped by the alcohol.     

Samarium diiodide mediated cascade radical cyclisations—synthesis of the eudesmane tricyclic framework

Radical cascade cyclisation of methylenecyclopropyl cyclohexanone adducts, using samarium diiodide to generate an initial ketyl radical, provide a short route to tricyclic ethers, and the stereochemical outcome can be influenced by the solvent used for the reaction.     

On the absolute stereochemistry of the photochemical rearrangement of 2,5-cyclohexadienones to lumiketones

Specification of the absolute configurations of starting material and product in the photochemical rearrangement of a 2,5-cyclohexadienone to a bicyclo[3.1.0]hexen-2-one (lumiketone) permits unambiguous determination of the stereochemistry at two crucial stages in the generally accepted reaction mechanism, namely the electrocyclic ring closure to give a 3,5-bonded intermediate, and the subsequent [1,4]-sigmatropic shift. The stereochemical course of the latter process in turn allows specification of whether the rearrangement is occurring directly from an electronically excited intermediate or a ground state zwitterion. An unconstrained monocyclic chiral cyclohexadienone has been studied in which steric constraints are minimal, and in which the system should have free choice of available pathways. The absolute configuration of the resolved dienone was determined by X-ray crystallographic analysis of a derivative containing a chiral center of known configuration. The absolute configuration of the resultant optically active diastereomeric lumiketones has been assigned from the Cotton effects observed on the corresponding dihydrolumiketones, assuming these chiroptical effects are governed by a normal Octant Rule instead of the Inverse Octant Rule which empirically correlates such data for cyclopropyl ketones lacking polarizable substituents. The limitations on these assignments are discussed, as well as alternative efforts to obtain completely unambiguous stereochemical assignments for the lumiketones. On the basis of these assignments, it is concluded that the sigmatropic shift proceeds with inversion of configuration at the migrating carbon, consistent with reaction via a ground state zwitterion.     

Reduction of O-methyl oxime ethers of conjugated cyclohexenones with aluminum hydride

The reduction of representative O-methyl oxime ethers 1–4 with aluminum hydride in tetrahydrofuran yielded allylic amines and saturated aziridines as the main products. The stereochemical course of the reduction to aziridines depends on the oxime ether configuration. Thus, E–3, E–4 and Z–3, Z–4 gave 15, 16 and 21, 22 , respectively, with high stereoselectivity. Higher reactivity of Z than E isomers was utilized for the preparation of pure E isomers of oxime ethers from E, Z mixtures.     

Zur kenntnis der ätherischen öle 6. Mitteilung [1] die thermische cyclisation des (−)-(r)-Linalools. Die struktur der Plinole und einiger derivate mit Iridan-Gerüst [2]

On heating linalool, all the four possible diastereomeric plinols are formed by way of an intramolecular Alder “ene”-synthesis. The knowledge of their absolute configuration, shown to be 2A - 2D , allows a discussion of the stereochemical course of this reaction.     

Iodoenolcyclisation of 2-(1,3-disubstituted-1-allyl)-1,3-dicarbonyl compounds: diastereoselective synthesis of tetrasubstituted dihydrofurans

The I₂-induced cyclisation of 2-alkenyl-1,3-dicarbonyl compounds with the mono- and di-substituted double bond occurred with good diastereoselectivity. A study of stereochemical aspects for different substituents on the allyl side chain was carried out. When the substituents were alkyl groups, the trans isomers formed preferentially, in the case of aromatic substituents the reaction lead instead to cis isomers.     

Absolute Configuration from Different Multifragmentation Pathways in Light‐Induced Coulomb Explosion Imaging

The absolute configuration of individual small molecules in the gas phase can be determined directly by light‐induced Coulomb explosion imaging (CEI). Herein, this approach is demonstrated for ionization with a single X‐ray photon from a synchrotron light source, leading to enhanced efficiency and faster fragmentation as compared to previous experiments with a femtosecond laser. In addition, it is shown that even incomplete fragmentation pathways of individual molecules from a racemic CHBrClF sample can give access to the absolute configuration in CEI. This leads to a significant increase of the applicability of the method as compared to the previously reported complete break‐up into atomic ions and can pave the way for routine stereochemical analysis of larger chiral molecules by light‐induced CEI.     

Total Synthesis and Structure Revision of Didemnaketal B

Didemnaketal B, a structurally complex spiroacetal that exhibits potent HIV‐1 protease inhibitory activity, was originally discovered by Faulkner and his colleagues from the ascidian Didemnum sp. collected at Palau. Its absolute configuration was proposed on the basis of degradation/derivatization experiments of the authentic sample. However, our total synthesis of the proposed structure of didemnaketal B questioned the stereochemical assignment made by Faulkner et al. Here we describe in detail our first total synthesis of the proposed structure 2 of didemnaketal B, which features 1) a convergent synthesis of the C7–C21 spiroacetal domain by means of a strategy exploiting Suzuki–Miyaura coupling, 2) an Evans syn‐aldol reaction and a vinylogous Mukaiyama aldol reaction for the assembly of the C1–C7 acyclic domain, and 3) a Nozaki–Hiyama–Kishi reaction for the construction of the C21–C28 side chain domain. The NMR spectroscopic discrepancies observed between synthetic 2 and the authentic sample as well as careful inspection of the Faulkner’s stereochemical assignment led us to postulate that the absolute configuration of the C10–C20 domain of 2 has been erroneously assigned. Accordingly, the total synthesis of the revised structure 65 was achieved to show that the NMR spectroscopic properties of synthetic 65 were in good agreement with those of the authentic sample. Furthermore, application of the phenylglycine methyl ester (PGME) method to the C7–C21 spiroacetal domain enabled us to establish the absolute configuration of didemnaketal B.     

Cleavage of ethereal bond : IX. The reducing action of Grignard reagents on 1,3-benzoxathiole and 1,3-benzodioxole derivatives

Some reactions of 1,3-benzoxathioles and 1,3-benzodioxoles with Grignard reagents were examined in order to verify whether or not reduction products were present in addition to the substitution and elimination products previously observed. The reaction mixtures contain reduction products whenever the Grignard reagent has β-hydrogen atoms, in which case the reagent is likely to act as a hydride transfer agent. The product distribution also depends on steric hindrance by the halogen. 1,3-Benzodioxoles react with isopropylmagnesium bromide to give mixtures of alkanes and alkenes, the former arising from a double hydride ion migration, and the latter from a reduction and elimination process.     

Enantioselective total syntheses of (+)-arborescidine A, (-)-arborescidine B, and (-)-arborescidine C

Described are the first enantioselective total syntheses of (+)-arborescidine A ((+)-1), (-)-arborescidine B ((-)-2), and (-)-arborescidine C ((-)-3), via routes that proceeded in five steps and 50% overall yield, eight steps and 61% overall yield, and nine steps and 51% overall yield, respectively, from 6-bromotryptamine (7). The syntheses feature the use of the Noyori catalytic asymmetric hydrogen-transfer reaction to introduce chirality in dihydro-beta-carbolines 6 and 8. On the basis of an ample precedent from Noyori's work, the reduction produces dihydro-beta-carbolines, and ultimately the natural products, possessing the R absolute configuration. The synthetic arborescidines displayed optical rotations that were opposite in sign those of the natural products, thereby supporting the S configuration for natural arborescidines A (1) and B (2) and the (3S,17S) configuration for natural arborescidine C (3). Our results are in agreement with the initial stereochemical assignment by Pa?s and co-workers, and are counter to their recently revised assignment.     

Subrutilane—A Hexacyclic Sesterterpene from Streptomyces subrutilus

Mining of a terpene synthase from Streptomyces subrutilus resulted in the identification of the hexacyclic sesterterpene subrutilane, besides eight pentacyclic side products. Subrutilane represents the first case of a saturated sesterterpene hydrocarbon. Its structure, including the absolute configuration, was unambiguously determined through X-ray crystallographic analysis and stereoselective deuteration. The cyclisation mechanism to subrutilane and its side products was investigated in all detail by isotopic labelling experiments and DFT calculations. The subrutilane synthase (SrS) also converted (2Z)-GFPP into one major product. Additional compounds were obtained from the substrate analogues (7R)-6,7-dihydro-GFPP and (2Z,7R)-6,7-dihydro-GFPP with blocked reactivity at the C6−C7 bond. Interestingly, the early steps of the cyclisation cascade with (2Z)-GFPP and the saturated substrate analogues were analogous to those of GFPP, but then deviations from the natural cyclisation mode occur.