Stereoselective synthesis of the obscure mealybug pheromone by hydrogenation of a tetrasubstituted alkene precursor

An improved diastereoselective synthesis of (1R^∗,2R^∗,3S^∗)-1-acetoxymethyl-2,3,4,4-tetramethylcyclopentane 1, the sex pheromone of the obscure mealybug, Pseudococcus viburni, is described. The key step was diastereoselective catalytic hydrogenation of the tetrasubstituted double bond in 2,3,4,4-tetramethyl-cyclopent-2-enone 4 to give the thermodynamically less favored cis-2,3,4,4-tetramethyl-cyclopentanone 3a.     

Synthetic studies directed toward amphidinol 2: elucidation of the relative configuration of the C1-C10 fragment

Model compounds (11 and 12) for the C1-C10 tetrahydropyran fragment of amphidinol 2 were prepared from (2S)-benzyloxypropanal in 9 steps. The synthetic route relied on diastereoselective diene-aldehyde cycloaddition, stereoselective C-allylation, and reagent based enantioselective aldehyde allylation. Comparison of the NMR spectra for models 11 and 12 with that for amphidinol 2 indicated that the C1-C10 segment of the natural product possesses the 2R^∗,4R^∗,6R^∗,7S^∗,8R^∗,10S^∗relative configuration.     

Extremely high regio- and stereoselective C-C bond formation of substituted γ-hydroxylactams: synthesis of macronecines based on their structural duality

With a view to develop a new synthetic entry for the necine bases, treatment of functionalized γ-hydroxylactams was found to undergo quite high regio- and diastereoselective carbon-carbon bond formation reactions, affording the corresponding structurally dualistic alkylated lactams in satisfactory yields. The reaction was further applied to the practical and efficient synthesis of (±)-macronecine [(1S^∗,2R^∗,7aR^∗)-1-hydroxymethyl-2-hydroxypyrrolizidine] and (±)-2-epi-macronecine [(1S^∗,2S^∗,7aR^∗)-1-hydroxymethyl-2-hydroxypyrrolizidine].     

Unexpected cleavage of the N-N bond in the reactions of 3-pyrazolidinone-1-azomethine imines with HCN

Treatment of (1Z,4R^∗,5R^∗)-1-arylmethylidene-4-benzamido-5-phenylpyrazolidin-3-one 1-azomethine imines 4a-d with potassium cyanide in the presence of acetic acid resulted in addition of HCN to the exocyclic CN double bond followed by β-eliminative N-N single bond cleavage (ring opening) to give the N-[(1R^∗,2R^∗)-3-amino-2-benzamido-3-oxo-1-phenylpropyl]benzimidoyl cyanides 6a-d in 28-85% yields. Reaction of dipole 4e with HCN furnished stable intermediate, (1′S^∗,4R^∗,5R^∗)-4-benzamido-1-[cyano(mesityl)methyl]-5-phenylpyrazolidin-3-one (5e), in 76% yield. The structure of compound 6c was determined by X-ray diffraction.     

Diastereoselective synthesis of 5-benzylthio- and 5-mercaptohexahydropyrimidin-2-ones

A three-stage diastereoselective synthesis of (4R^∗,5R^∗,6S^∗)-5-mercapto-4-methyl-6-phenylhexahydropyrimidin-2-one has been developed. The first stage involves the formation of 4-hydroxy-5-(4-methoxybenzylthio)-4-methyl-6-phenylhexahydropyrimidin-2-one by the reaction of N-[(phenyl)(tosyl)methyl]urea with the sodium enolate of 1-(4-methoxybenzylthio)propan-2-one. Reduction of the obtained compound by NaBH₄-CF₃COOH and removal of the p-methoxybenzyl protecting group results in the target compound.     

Studies on the factors controlling the stereoselectivity in electrophilic iodocyclization of alkylidenecyclopropyl ketones

An efficient electrophilic iodocyclization of alkylidenecyclopropyl ketones with N-iodosuccinimide (NIS) or I₂ in aqueous CH₃CN affording 3-oxabicyclo[3.1.0]hexan-2-ols is described. NIS is a better electrophilic iodocyclization reagent than I₂. Four chiral centers were formed within one step. The stereochemistry was established by the X-ray diffraction studies of compounds 2e-2h, 2n, and 2c. It is quite interesting to observe that the substituent of the cyclopropane ring plays an important role in determining the relative stereochemistry at the 4-position: with R² being an acyl or ester group a mixture of (1S^∗,2R^∗,4S^∗,5R^∗)-2 (major) and (1R^∗,2R^∗,4R^∗,5R^∗)-2 (minor) was formed with moderate selectivity while the reaction of the substrates with R² being sulfonyl and p-methylphenylsulfonyl or R¹ being phenyl afforded (1R^∗,2R^∗,4S^∗,5S^∗)-2 or (1S^∗,2R^∗,4S^∗,5R^∗)-2f as the only product. The reaction is general for a range of different substrates to afford the products in moderate to high yields.     

Regio- and stereoselective cycloadditions of (1Z,4R,5R)-1-arylmethylidene-4-benzoylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides to methyl methacrylate

[3+2] Cycloadditions of (1Z,4R^∗,5R^∗)-1-arylmethylidene-4-benzoylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides 1a-e to methyl methacrylate gave the 1-CO₂Me regioisomers 3/3′, exclusively, in 1-67% yields. Stereocontrol was dependent on the ortho-substituents at the 1′-aryl group in dipole 1: ortho-unsubstituted dipoles 1a-c gave the major (1R^∗,3R^∗,5R^∗,6R^∗)-isomers 3a-c, whilst ortho-disubstituted dipoles gave the major (1R^∗,3S^∗,5R^∗,6R^∗)-isomers 3′d,e. The structures of cycloadducts were determined by NMR and X-ray diffraction.     

A mechanistic study on the intramolecular ionic Diels-Alder reaction of 2-methyl-3,9,11-tridecatriene-2-ol and 2,11-dimethyl-1,3,9,11-dodecatetraene

Intramolecular ionic Diels-Alder reaction of 2-methyl-3,9,11-tridecatriene-2-ol (1) was studied under acidic conditions. Treatment of 2-methyl-3,9,11-tridecatriene-2-ol (1) with trifluoromethanesulfonic acid yielded 7-methyl-8-isopropenyl-1,2,3,4,4aR^∗,7R^∗,8R^∗,8aS^∗-octahydronaphthalene (4) and (1Z)-1-((E)-but-2-enylidene)-2-(2-methylpropenyl)cyclohexane (5) through regioselective intramolecular ionic Diels-Alder reaction. The reaction appeared to proceed partly through a stepwise mechanism involving a carbocation intermediate. However, a concerted pathway rather than a stepwise one is suggested to be involved in the acid-catalyzed intramolecular Diels-Alder reaction of 2,11-dimethyl-1,3,9,11-dodecatetraene (13).     

Gomadalactones A, B, and C: novel 3-oxabicyclo[3.3.0]octane compounds in the contact sex pheromone of the white-spotted longicorn beetle, Anoplophora malasiaca

The ether extract of the females of white-spotted longicorn beetle Anoplophora malasiaca showed activity as contact sex pheromone to males. The extract was fractionated, and a pheromonal activity was revealed only when three fractions; n-hexane, n-hexane/EtOAc 9:1, and EtOAc were blended. The relative structures of gomadalactone A, B, and C, three active components isolated from the EtOAc fraction, were determined by spectroscopic studies to be (1S^∗,4R^∗,5S^∗)-5-hydroxy-4-[(E)-7-hydroxy-4-methylhept-3-enyl]-4,8-dimethyl-3-oxabicyclo[3.3.0]octan-7-en-2,6-dione, (1R^∗,4R^∗,5R^∗)-5-hydroxy-4-[(E)-7-hydroxy-4-methylhept-3-enyl]-4,8-dimethyl-3-oxabicyclo[3.3.0]octan-7-en-2,6-dione, and (1S^∗,4R^∗,5S^∗,8S^∗)-5-hydroxy-4-[(E)-7-hydroxy-4-methylhept-3-enyl]-4,8-dimethyl-3-oxabicyclo[3.3.0]octan-2,6-dione, respectively.     

Diastereoselective synthesis of (2S)-2-[(R)-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-one

Double asymmetric induction in Michael reactions has been studied. Enantioselective alkylation of a cyclic ketone (1-indanone) with α-phenyl-nor-gramine was carried out. The relative configuration of (2S^∗)-2-[(R^∗)-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-one was established by X-ray diffraction. The relative configuration of (R^∗,R^∗,S^∗)- and (S^∗,R^∗,S^∗)-2-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-ols was established by ¹H NMR studies.     

Electrocatalytic cascade multicomponent assembling: stereoselective one-pot synthesis of the substituted 3-azabicyclo[3.1.0]hexane-1-carboxylate system from aldehyde, malononitrile, malonate and methanol

Electrolysis of aromatic aldehydes, malononitrile and malonate in methanol in an undivided cell in the presence of sodium bromide-sodium methoxide as double mediatory system results in the stereoselective formation of methyl (1R^∗,5R^∗,6R^∗) 6-substituted 5-cyano-4,4-dialkoxy-2-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylates in 50-70% yields.     

Synthesis of ent-ambrox® from (−)-nidorellol

Using ozonolysis of the acid-catalyzed cyclized products of (−)-nidorellol and air-autoxidation as the key steps, (+)-ambrox was obtained in 53% overall yield. In the course of our synthesis, we discovered that (−)-nidorellol provided (+)-ambrox instead of the expected product, (−)-ambrox. Thus the absolute configuration of (−)-nidorellol was proved to be trans-(5R^∗,7R^∗,8R^∗,9S^∗,10R^∗)-labda-12,14-diene-7α,8β-diol, which is opposite to that illustrated in a previous report.     

Diastereoselective addition of organozinc and organomagnesium reagents to 2-(2′-pyrimidyl)ferrocenecarbaldehyde

Addition of diisopropylzinc, diethylzinc, and isopropylmagnesium chloride to readily available 2-(2′-pyrimidyl)ferrocenecarbaldehyde takes place with high diastereoselectivity to afford exclusively the α-ferrocenyl alcohol of (R^∗,pR^∗) configuration. On the other hand, the addition of ethyl- and methylmagnesium bromide leads to diastereomeric mixtures in which the major isomer has the (S^∗,pR^∗) configuration. A unified mechanistic model accounting for this stereochemical outcome is proposed.     

One-pot synthesis of conformationally restricted spirooxindoles

Diastereomeric three-, five- and six-membered spirocycloalkyloxindoles were successfully synthesized in a rapid and convenient manner from readily accessible starting materials in moderate to high yields using 1-methyl-3-acetonitriloxindole after a one-pot base-mediated double-alkylation strategy. It was found that the diastereoselection is dependent on the reaction conditions and the spirocycloalkyl ring size, with the 3R^∗,8R^∗ diastereomers being thermodynamically favored under the basic reaction conditions for three- and five-membered rings, and the 3R^∗,8S^∗ diastereomer in the case of six-membered rings, as predicted by DFT calculations. The relative stereochemistry was supported by 2D NMR spectra and X-ray crystal structural analysis. The conformational rigidity of the spirocycloalkyloxindoles in solution was established based on NMR experimental and theoretical DFT approaches.     

trans-α-Necrodyl isobutyrate, the sex pheromone of the grape mealybug, Pseudococcus maritimus

Headspace volatiles of virgin female grape mealybugs contained a single compound that elicitited responses from antennae of males in GC-electroantennogram analyses. The structure, identified as (R^∗,R^∗)-trans-(3,4,5,5-tetramethylcyclopent-2-en-1-yl)methyl 2-methylpropanoate, an irregular, non-head-to-tail monoterpenoid, was confirmed by synthesis.     

Synthesis of a lactone natural product found in Greek tobacco

A short and stereoselective synthesis of (3R^∗,4R^∗,7R^∗)-3,7-epoxy-4,8-dimethyl-8-nonen-4-olide, a natural product isolated from cured tobacco leaves, has been completed in six steps and 22% overall yield. A samarium(II) iodide mediated reductive cyclisation has been used to construct the functionalised tetrahydropyranol core and subsequent sequential stereoselective addition of methyllithium and lactonisation furnished the natural product.     

Diastereoselective synthesis of 1-alkyl-2,4,6-trioxoperhydropyrimidine-5-spiro-3′-(1′,2′,3′,4′-tetrahydroquinolines)

Knoevenagel products formed by the condensation of N-monoalkyl barbituric acids with o-tert-amino benzaldehydes undergo tert-amino effect reactions (T-reactions) yielding 1-alkyl-2,4,6-trioxoperhydropyrimidine-5-spiro-3′-(1′,2′,3′,4′-tetrahydroquinoline) derivatives as a mixture of (S^∗,S^∗)- and (S^∗,R^∗)-diastereomers. Mostly, the major diastereomer has the S^∗,S^∗-configuration. According to X-ray diffraction data in the solid form and NOE data in solution, diastereoselectivity of the T-reactions can be associated with the structure of the Knoevenagel products whose conformation is fixed by the strong intramolecular C-H?π interaction.     

Total synthesis of (±)-luminacin D

A 15-step synthesis of (±)-luminacin D from ethyl pent-2-ynoate is reported. The pivotal step involves the formation of the central C-2′/C-3′ bond of the natural product by condensation of the titanium enolate derived from aromatic ketone 1 with aldehyde 2a. A remote asymmetric centre in aldehyde 2a exerts control over the stereochemical course of this reaction, with the major adduct (3a, 54% yield) possessing the required (2′S^∗,3′R^∗,5′R^∗)-stereochemistry. This assignment was unambiguously established by X-ray crystallography of late stage synthetic intermediate, 17. Further manipulation of 3a (six steps) yielded synthetic (±)-luminacin D spectroscopically identical to material isolated from Streptomyces sp. Mer-VD1207 by Naruse et al.     

Synthesis of a novel tetrahydroisoquinoline pentacyclic framework

N-Acyliminium cyclization of 6-substituted (3R^∗,6R^∗,11aS^∗)-3-arylmethyl-pyrazino[1,2-b]isoquinoline-1,4-diones gave with very good yields a novel tetrahydroisoquinoline pentacyclic core framework (29), while this reaction failed in all-cis-isomers to give instead conjugated enamines by deprotonation. Electronic and steric factors that govern the approach to both diastereomers from 6-substituted pyrazino[1,2-b]isoquinoline-1,4-diones have been studied.     

Central-to-axial chirality transfer and induced circular dichroism in 6,7-dihydro-5H-dibenz[c,e]azepine derivatives of α- and β-amino esters

DAZ-Xaa^∗-OMe amino ester derivatives with Xaa^∗ = d/l-Ala, d/l-Val, l-Leu, l-Ile, l-Ser, l-β³-HAla, l-β³-HVal, l-β³-HLeu, (1S,2S)/(1R,2R)-ACHC (2-aminocyclohexanecarboxylic acid) and (1S,2S)/(1R,2R)-ACPC (2-aminocyclopentanecarboxylic acid), N-blocked as 6,7-dihydro-5H-dibenz[c,e]azepines (DAZ), have been synthesized and evaluated for the determination of the absolute configuration of α- and β-amino esters through the induced circular dichroism of the biphenyl chromophore.