Stereoselective aldol coupling of α,β-acetylenic ketones promoted by MgI2

A highly stereoselective synthesis of (Z)-β-iodovinyl ketone has been achieved with the tandem formation of CC and CI bonds in a three-component reaction. This new catalysis utilizes MgI₂ as a Lewis acid as well as an iodine source for a Michael-type addition. α,β-Acetylenic ketone is initially converted to an active β-iodo allenolate intermediate and then can be attacked by a variety of aldehydes to afford Z-selective Baylis-Hillman adducts in excellent yields.     

Concise syntheses of (+)-austrodoral and (+)-austrodoric acid Based on H2O2 mediated oxidative ring contraction

Asymmetric synthesis of the marine nor-sesquiterpenoid (+)-austrodoric acid and (+)-austrodoral in seven and nine steps respectively from Wieland-Miescher ketone was described herein. The synthesis featured an oxidative ring contraction of α-formyl cyclic ketone mediated by H₂O₂ to forge the hydrindane scaffold together with the contiguous quaternary carbon centers simultaneously.     

A novel synthesis, including asymmetric synthesis, of α-quaternary α-amino acid methyl esters from ketones via sulfinyloxiranes

Sulfinyloxiranes were synthesized from ketones and chloromethyl p-tolyl sulfoxide in two steps in almost quantitative yields. The sulfinyloxiranes were treated with NaN₃ in the presence of NH₄Cl to afford α-azido aldehydes, which were oxidized with iodine in the presence of KOH in methanol to give α-azido methyl esters in good overall yields. Catalytic hydrogenation of the α-azido esters afforded α-quaternary α-amino acid methyl esters in quantitative yields. Starting from β-tetralone and optically pure (R)-chloromethyl p-tolyl sulfoxide, an asymmetric synthesis of optically pure (R)-(+)-methyl 2-aminotetraline-2-carboxylate was realized in good overall yields.     

An enantioselective total synthesis of pinnaic acid

An enantioselective and convergent total synthesis of marine natural product pinnaic acid has been achieved. Our general synthetic approach is featured with an asymmetric hydrogenation of racemic γ-keto ester 3, a diastereoselective methylation on the α-methylene of the (1R,5R)-lactone 4, and a diastereoselective Michael addition of the tertiary nitro cyclopentane. The central azaspiro[4.5]decane was constructed utilizing reductive cyclization of the δ-nitroketone followed by highly stereoselective reduction of the cyclic imine with NaBH₄. Ultimately, successive use of triethyl-2-phosphonopropionate and Heathcock's phosphorane 18 to elaborate C5 and C13 side chains completed the total synthesis of pinnaic acid.     

Synthesis of juniperonic acid

Synthesis of juniperonic acid [(all-Z)-5,11,14,17-eicosatetraenoic acid], has been achieved in eight steps and in 19% overall yield starting from eicosapentaenoic acid.     

Enantioselective synthesis of 2-ethyl-2,3-dihydrobenzofuran carboxylic acid, direct precursor of (+)-efaroxan, from a Baylis-Hillman adduct

We describe herein a new and straightforward enantioselective approach to R-(+)-2-ethyl-2,3-dihydrofuran carboxylic acid, the direct precursor of (+)-efaroxan, an α₂ adrenoreceptor antagonist, which is indicated to be used for the treatment of neurodegenerative diseases (Alzheimer and Parkinson), migraine and type II diabetes. Our goal was accomplished using a Baylis-Hillman adduct as starting material. The dihydrobenzofuran acid was obtained in eight steps with an overall yield of 14%.     

Cycloaddition approach to benzo-annulated indane-based α-amino acid derivatives

Synthesis of various benzo-annulated indane-based α-amino acid (AAA) derivatives are reported via a [4+2] and [2+2+2] cycloaddition reactions as key steps. Here, o-xylylene based AAA moiety has been used as a reactive intermediate and by adopting this strategy various indane-based constrained AAA derivatives are prepared.     

Investigations into the selective oxidation of vicinal diols to α-hydroxy ketones with the NaBrO3/NaHSO3 reagent: pH dependence, stoichiometry, substrates and origin of selectivity

The NaBrO₃/NaHSO₃ reagent is one of the few oxidizing agents that chemoselectively oxidizes vicinal diols to α-hydroxy ketones with little overoxidation to the corresponding vicinal-dione or dicarboxylic acid. Oxidation reactions performed with this reagent showed strong pH dependence. cis-Vicinal diols reacted faster than trans-vicinal diols to the α-hydroxy ketone product. Hydroxy functional groups at axial ring positions were more readily oxidized than equatorial hydroxy groups. The application of the NaBrO₃/NaHSO₃ reagent for the chemoselective oxidation of vicinal diols was limited to simple systems and failed with more complex monosaccharide compounds probably due to acid catalyzed dehydrogenation reactions. Despite the simple reaction set-up and good selectivity towards the α-hydroxy ketone product, the actual oxidation reaction mechanism is highly complex and postulated to involve at least six different equilibria with a plethora of bromine containing species. A possible oxidation reaction mechanism is discussed.     

Diastereoselective total synthesis of (+)-morusimic acid B, an amino acid from Morus alba

An efficient, flexible and diastereoselective synthesis of the naturally occurring pyrrolidine amino acid, (+)-morusimic acid B, has been accomplished. Starting from chiral, optically active (+)-(3S)-hydroxy butyric acid methyl ester the key steps of our synthesis are diastereoselective α-alkylation of its dianion to introduce the main part of the side chain, Curtius rearrangement of the hydrazide derivative to a 2-oxazolidinone followed by N→π-cyclization with mercury(II) acetate to generate the cis-2,5-disubstituted pyrrolidine ring. The remote C-3 stereocentre is established after chain elongation with the dianion of methyl acetoacetate and asymmetric hydrogenation of the resulting β-oxoester with Noyori's Ru(II)-(R)-BINAP catalyst.     

Asymmetric approach towards the total synthesis of (+)-actinopyllic acid

This paper describes our efforts towards the asymmetric total synthesis of (+)-actinophyllic acid. Starting from the chiral oxazolidinone 9, an azocino [4,3-b]indolyl intermediate (5) possessing the A/B/C ring system and the C16 quaternary stereogenic center of actinophyllic acid has been synthesized. Key steps include a LHMDS-promoted condensation to establish the critical C2–C16 bond and a successive four-step transformation to assemble the eight-membered C-ring of the target molecule.     

PhI- and polymer-supported PhI-catalyzed oxidative conversion of ketones and alcohols to α-tosyloxyketones with m-chloroperbenzoic acid and p-toluenesulfonic acid

Various ketones were converted to the corresponding α-tosyloxyketones with mCPBA and p-toluenesulfonic acid in the presence of a catalytic amount of iodobenzene. Moreover, secondary alcohols were directly converted to the corresponding α-tosyloxyketones using mCPBA and catalytic amounts of iodobenzene and potassium bromide, followed by treatment with p-toluenesulfonic acid in a one-pot manner. Poly(4-iodostyrene) could be also used as a recyclable catalyst for the same α-tosyloxylation of ketone     

1-Amino-3,3-difluorocyclobutanecarboxylic acid

A new fluorinated analogue of 1-aminocyclobutane-1-carboxylate (ACBC) - 1-amino-3,3-difluorocyclobutanecarboxylic acid (6) - has been synthesized in six steps from acetone. The key step of the synthesis is a transformation of a ketone group into the CF₂-group using morpholino-sulphur trifluoride.     

A novel synthesis of cyclic α-amino aldehydes, amino alcohols, and α-amino acid methyl esters from cyclic ketones through sulfinylaziridines

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from cyclic ketones and chloromethyl p-tolyl sulfoxide in three steps in good yields, with N-lithio arylamines gave sulfinylaziridines in high yields. On treatment with N-lithio aniline or N-lithio p-chloroaniline, the sulfinylaziridines gave α-amino aldehydes in high yields. The α-amino aldehydes were converted to amino alcohols and α-amino acid methyl esters in moderate to good yields. This procedure offers an efficient method for synthesis of cyclic α-quaternary α-amino aldehydes, amino alcohols, and α-amino acid derivatives from cyclic ketones.     

Reaction of 3-chloroallyltrimethylsilane with acid chloride and exploitation of a new regioselective synthesis of αβ-unsaturated epoxide

α-Chloro-βγ-unsaturated ketone (2) was synthesized from the reaction of 3-chloroallyltrimethylsilane (1) with acid chloride. The ketone was converted into αβ-unsaturated epoxide (3) regioselectively in good yield via reduction with NaBH₄ or LiAlH₄ followed by treatment with NaOH. Treatment with methyl lithium instead of reduction gave homologous epoxide (5).     

Enantiomeric synthesis of carbocyclic d-4′-C-methylribonucleosides as potential antiviral agents

An efficient synthetic approach for the preparation of enantiomerically pure carbocyclic d-4′-C-methylribonucleosides 3a–f is reported. The key intermediate, d-2,3-O-cyclohexylidene-4-methylcyclopentenone 8, was prepared starting from d-ribose in eight steps via an oxidative rearrangement. Conjugate addition of a catalytic vinylcopper(I) reagent to the α,β-unsaturated ketone 8 yielded cyclopentyl alcohol 10, which bears a quaternary stereogenic carbon at the C4-position. The cyclopentyl alcohol 10 was subsequently coupled with 6-chloropurine or 2-amino-6-chloropurine via an S_N2 reaction, followed by a series of functional group transformations and deprotections to furnish purine ribonucleosides 3a–c. Pyrimidine bases were constructed on cyclopentylamine 29 using a linear approach, which furnished the pyrimidine nucleosides 3d–f.     

A highly stereoselective total synthesis of (±)-isoalantolactone

(±)-Isoalantolactone (1) has been synthesized by a highly stereoselective route from the versatile bicyclic ketone, trans-5-methylene-9-methyl-2-decalone 2. Three major points in the synthesis involve (a) introduction of the acetic acid side chain; (b) stereoselective reduction of the ketone function yielding cis-lactone 6; and (c) introduction of the α-methylene group onto the butyrolactone ring.     

Iodine/DMSO promoted oxidation of benzylic Csp3–H bonds to diketones – A mechanistic investigation

This article describes a mechanistic investigation into the I₂/DMSO mediated benzylic C_sp³–H oxidation of an α-methylene ketone. The electron paramagnetic resonance (EPR) spectrum centred at g = 2.0011 supports the involvement of iodine and benzylic radicals, as the α-iodinated compound 2-iodo-1,2-diphenylethanone was isolated as a key reactive intermediate. The oxidation reaction relies, primarily, on DMSO as a source of oxygen in benzil, proven by the reaction of benzyl phenyl ketone with diphenyl sulfoxide (DPSO).     

The first enantioselective synthesis of (S)-5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine: a key intermediate for the preparation of SIB-1508Y

The first enantioselective synthesis of (S)-5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine is described via intramolecular hydroboration–cycloalkylation of an azido-olefin intermediate. The chiral homoallylic alcohol was efficiently synthesized by enantioselective reduction of the corresponding ketone using (+)-diisopinocamphenylchloroborane as the key reaction. The total synthesis of (S)-SIB-1508Y was achieved with an enantiomeric excess (e.e.) of 94% in ten steps and in 18% overall yield from the commercially available 5-bromo-3-pyridinecarboxylic acid.     

Synthetic Studies towards Pheromones by Cyanide-Catalyzed Ring Transformation of α-Hydroxy-β-oxoesters to δ-Valerolactones

The cyanide-catalyzed ring-transformation of α-hydroxy-β-oxoesters to δ-lactones with exocyclic ester moiety is the key transformation for the preparation of racemic 5-hexadecanolide (15 % over nine steps) and 6-acetoxy-5-hexadecanolide (22 % over eight steps), two insect pheromones. The benzyloxycarbonyl moiety is transformed via the acid chloride to the undecanoyl side chain. After reduction of the ketone to the secondary alcohol, this functional group was either reduced via the chloro compound to furnish the 5-hexadecanolide. On the other hand, stereoselective reduction of the ketone gave secondary alcohol with the wrong relative configuration, which was established by X-ray single-crystal structure. Inversion was achieved by reaction of the methanesulfonate with cesium acetate yielding (R*,S*)-6-acetoxy-5-hexadecanolide with the relative configuration also present in the natural product.     

The stereoselective total synthesis of (+)-18-(6S,9R,10R)-bovidic acid

An expedient stereoselective total synthesis of 18-carbon (+)-(6S,9R,10R)-bovidic acid, isolated from the pelage and skin of a gaur B. frontalis is described using l-proline catalysed sequential α-aminoxylation and Horner-Wadsworth-Emmons olefination of aldehyde, cross metathesis and tandem Sharpless asymmetric dihydroxylation-S_N2 cyclization reaction as the key steps.