Enantioselective and regioselective nickel-catalyzed multicomponent coupling of chiral allenes, aromatic aldehydes, and silanes

A detailed account of the development of a recently developed, nickel-catalyzed multicomponent coupling of chiral allenes, aromatic aldehydes, and silanes is described. The axial chirality of the allene is transferred completely to the product, a trisubstituted Z-allylic alcohol protected as a silyl ether. A very high preference for sp rather than sp² coupling is observed, and differentially substituted allenes undergo highly site-selective coupling. These transformations represent the first enantioselective multi-component coupling processes of allenes.     

Enantioenriched synthesis of Escitalopram using lithiation-borylation methodology

The asymmetric synthesis of Escitalopram has been completed using a lithiation-borylation reaction as the key step. Suitably functionalized enantioenriched carbamate (er 98:2) and boronic ester coupling partners were prepared and following deprotonation with s-BuLi and borylation, the tertiary alcohol was obtained in 42% yield and 93:7 er. The lithiation-borylation reaction was found to tolerate nitrile, benzylic alcohol and N-Boc functionalities. The tertiary alcohol was converted to Escitalopram in three further steps.     

The total synthesis of (S)-2,4-dihydroxy-1-butyl (4-hydroxyl) benzoate

This study is the first synthesis of (S)-2,4-dihydroxy-1-butyl (4-hydroxy) benzoate, a newly discovered natural product with anti-tumor properties from the fungus, Penicillium auratiogriseum. The key steps are a 1,3 diol protection followed by the coupling of p-anisic acid to the protected alcohol and subsequent de-protection steps.     

First example of carbohydrate-based Prins cyclization: a novel class of sugar-annulated tetrahydropyrans

The secondary homoallylic alcohol derived from d-glucose undergoes smooth coupling with aldehydes in the presence of molecular iodine under mild reaction conditions to produce 7-iodofurano[3,2-b]pyrans in good yields. This method is highly stereoselective, affording cis-tetrahydropyrans exclusively.     

Coupling reactions of aryl bromides with 1-alkynols catalysed by a tetraphosphine/palladium catalyst

cis,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/[PdCl(C₃H₅)]₂ system catalyses efficiently the coupling reactions of aryl halides with a variety of alkynols such as propargyl alcohol, but-1-yn-4-ol, pent-1-yn-5-ol or hex-1-yn-6-ol. The catalyst can be used at low loading. Higher reaction rates were observed in the presence of but-1-yn-4-ol, pent-1-yn-5-ol or hex-1-yn-6-ol than with propargyl alcohol. The protection of the alcohol functions as an ether or a silyloxy group led generally to similar or better results than the reactions performed with the unprotected alcohols.     

Protecting group directed ring-closing metathesis (RCM): the first total synthesis of an anti-malarial nonenolide

The first synthesis of a newly found naturally occurring anti-malarial nonenolide is described. A pivotal step in the synthesis is the ring-closing metathesis of a dienoic ester prepared by coupling an acid and alcohol that were stereoselectively synthesized from (S)-α-hydroxy-γ-butyrolactone and 1,2-O-isopropylidene d-glyceraldehyde, respectively.     

Nickel-catalyzed arylative substitution of homoallylic alcohols

Direct coupling of unactivated alcohols remains a challenge in synthetic chemistry. Current approaches to cross-coupling of alcohol-derived electrophiles often involve activated alcohols such as tosylates or carbonates. We report the direct arylative substitution of homoallylic alcohols catalyzed by a nickel-bisphosphine complex as a facile method to generate allylic arenes. These reactions proceed via formation of an allylic alcohol intermediate. Subsequent allylic substitution with arylboroxine nucleophiles enables the formation of a variety of allylic arenes. The presence of p-methoxyphenylboronic acid is crucial to activate the allylic alcohol to achieve high product yields.

Arylative substitutions of homoallylic alcohols with arylboron nucleophiles demonstrate the utility of unactivated alcohols as coupling partners in transition metal-catalyzed cross-coupling chemistry.     

Chemoenzymatic synthesis of symmetrically structured triacylglycerols possessing short-chain fatty acids

Synthesis of symmetrically structured triacylglycerols possessing bioactive n−3 polyunsaturated fatty acids (eicosapentaenoic acid or docosahexaenoic acid) at the 2-position and a short-chain fatty acid (C₂, C₄, C₆) located at the end-positions by a highly efficient two-step chemoenzymatic process is described. Full regiocontrol devoid of any acyl-migration side reactions was obtained in both a lipase promoted step to introduce the short-chain fatty acids exclusively into the primary alcohol positions of glycerol using activated vinyl esters at low temperature and a subsequent coupling reaction involving free EPA and DHA using EDAC as a coupling agent.     

Synthesis and anti-HIV activities of phosphate triester derivatives of 3′-fluoro-2′,3′-dideoxythymidine and 3′-azido-2′,3′-dideoxythymidine

Fatty acyl-glycol phosphate triester conjugates of 3′-fluoro-2′,3′-dideoxythymidine (FLT) were prepared in three steps from the reaction of diisopropylphoramidous dichloride with fatty acyl-substituted glycols, followed by a coupling reaction with FLT and oxidation with tert-butyl hydroperoxide (t-BuOOH). Additionally, a number of fatty alcohols were reacted with diisopropylphoramidous dichloride to produce the phosphitylating intermediates, which underwent coupling reactions with 3′-azido-2′,3′-dideoxythymidine (AZT) and FLT followed by oxidation with t-BuOOH to yield fatty alcohol phosphate triester derivatives of AZT and FLT.     

Total synthesis of 1-(Z)-atractylodinol

The total synthesis of 1-(Z)-atractylodinol, a natural polyacetylenic alcohol with several biological activities, has been achieved using a newly developed telluride synthon and a novel use for the Negishi type coupling reaction employing vinyl tellurides.     

Synthesis, spectroscopic, redox, catalytic and antimicrobial properties of some ruthenium(II) Schiff base complexes

A new series of mixed ligand semicarbazone or thiosemicarbazone complexes of Ru(II) having the general formula [RuCO(EPh₃)(B)L] (where E = P or As; B = PPh₃, AsPh₃ or Pyridine; L = dibasic tridentate ligand derived by the condensation of ethylacetoacetate/methylacetoacetate and thiosemicarbazide/semicarbazide) have been synthesized and characterized by physico-chemical, spectroscopic and electrochemical studies. A comparative study on the catalysis of oxidation of benzyl alcohol, cyclohexanol, cinnamyl alcohol, n-butanol, n-propanol and iso-butyl alcohol has been done with N-methylmorpholine-N-oxide and molecular oxygen as co-oxidants. Catalytic activity studies of the complexes in coupling reactions have been carried out. The antibacterial properties of the complexes have also been examined.     

Arylation of β-methallyl alcohol catalyzed by Pd(OAc)2 in combination with P(t-Bu)3: application to fragrance synthesis

Pd(OAc)₂ in combination with P(t-Bu)₃ catalyzes the coupling of β-methallyl alcohol with 1-bromo-3,4-(methylenedioxy)benzene (1a), 1-bromo-4-methoxybenzene (1b), or 1-bromo-4-tert-butylbenzene (1c). The reaction affords the corresponding 2-methyl-3-aryl-propanals, which are valuable floral fragrances. With 1a or 1b high reaction rates are obtained at 130 °C using NMP/water mixtures and an inorganic base such as Na₂CO₃. The chemoselectivity of the reaction is almost complete, so that the process appears practically feasible. In contrast, the coupling of β-methallyl alcohol with 1c proceeds with low reaction rates.     

Chromium-mediated fluoroalkenylation reactions of 1,1-dibromo-1-fluoroalkane and 1-bromo-1-fluoroalkene derivatives

CrCl₂- and NiCl₂-mediated coupling reactions of E/Z mixture of 1-bromo-1-fluoroalkenes with aldehydes proceeded in a high stereoselectivity to give the corresponding (Z)-2-fluoroallylic alcohol derivatives. On the other hand, in the reaction of 1,1-dibromo-1-fluoroalkane with CrCl₂, (Z)-fluoroalkene derivative was formed via α-elimination reaction of the chromium carbenoid intermediate accompanying the concomitant 1,2-shift of β-hydrogen.     

Mechanism of action of base-catalyzed oxygenation of phenol derivatives

Cyclopropyl derivative of 2,6-di-tert-butylphenol is synthesized as a probe to investigate the mechanism of base-catalyzed autooxidation of phenol derivatives. Our study indicates that one electron reduction of molecular oxygen from phenolate gives phenoxyl radical 3, a key intermediate of autooxidation. The coupling of phenoxyl radical and superoxide radical gives peroxylate anion 4 and produces the final epoxy alcohol adduct 6.     

Selective alkylation and Suzuki coupling as an efficient strategy for introducing functional anchors to the ethylene-bis(indenyl) ligand

Chiral ansa-ethylene-bis(indenyl)-metal complexes, EBI-MX₂, are useful pre-catalysts for a wide variety of reactions, including hydrogenations, hydrosilylations, and polymerization reactions. In order to immobilize these complexes onto heterogeneous supports, a new methodology was developed to introduce functional anchors to the ethylene-bis(indenyl) ligand, EBI. This was accomplished by selective alkylation of indene to form toluene-4-sulfonic acid 2-(3H-inden-1-yl)-ethyl ester, which was then used to alkylate 6-bromoindene. The selective introduction of an aryl bromide then undergoes coupling reactions with aryl borates via the Suzuki coupling to efficiently introduce an alkenyl or alcohol, functional anchor in a simple four step synthesis.     

Rotational isomerism—22: An nmr study of oh..π bonding and the conformations of benzyl alcohol and derivatives

The conformations of benzyl alcohol, the ortho and para nitro and methoxy derivatives and benzyl methyl ether have been investigated by NMR in CCL₄ and DMSO solutions. The ³J(CH.OH) and ²J(H.C.H) couplings (the latter via the ²J(H.C.D)coupling)and the OH chemical shift (in DMSO and ∞ dil^XXX as conformational probes. The δ_∞ (OH) for ROH (R = Me, Et, iPr) is also given.The results provide no support for the existence of an intramolecular H-bond in benzyl akohol The endo conformation of the OH proton (anti to a CH proton) is favoured by ca. 1 kcal mole^?1 over the exo conformation (H anti to phenyl) and these conformers are responsible for the separate OH frequencies observed in the IR spectrum. The results do not support an extreme conformation of the phenyl ring (C.C.C.O dihedrals of 0 or 90°) but are consistent with either an 6?0° conformation of the phenyl ring or a freely rotating model. In ortho nitrobenzyl alcohol intramolecular H-bonding is present, but in ortho methoxy benzyl alcohol little or no bonding to the substituent occurs.     

Ugi-type four-component reaction for a novel synthesis of 5-oxo-perhydrofuro[3,2-b]pyran carboxylate derivatives

The four-component coupling (4CC) of sugar hydroxyaldehyde, Meldrum’s acid, isocyanide, and a secondary alcohol in dichloromethane has been accomplished at room temperature in a highly stereoselective manner to produce a novel class of carbohydrate derivatives, 5-oxo-perhydrofuro[3,2-b]pyrans in good yields with trans-selectivity. The stereochemistry of the products was assigned by various NMR experiments.     

Highly convergent one-pot four-component regioselective synthesis of 4H-benzo[f]chromenes via annulation of β-oxodithioesters

Highly efficient regioselective protocol for the synthesis of hitherto unreported 4H-benzo[f]chromenes has been developed by one-pot four-component coupling of aromatic aldehydes, β-naphthol, β-oxodithioesters, and primary alcohols in the presence of InCl₃. This transformation presumably proceeds via domino Knoevenagel condensation/Michael addition/intramolecular cyclodehydration/transesterification sequence creating four new bonds and one stereocenter in a single operation. Further, alcohol plays dual role as a reactant as well as reaction medium.     

Aminol initiated Prins cyclization for the synthesis of octahydro-1H-pyrano [3,4-c]pyridine and hexahydro-1H-furo[3,4-c]pyrrole derivatives

Various aldehydes undergo smooth coupling with a branched homoallylic alcohol appended N-tosyl amine (1 & 3) in the presence of 10 mol % BF₃·OEt₂ at room temperature to afford a novel class of 1,8-disubstituted octahydropyrano[3,4-c]pyridine and 1,6-disubstituted hexahydrofuro[3,4-c]pyrrole derivatives in good yields, respectively.     

Synthesis of new triphenylphosphines with pending ethynyl substituents

The straightforward isolation and characterization of new triphenylphosphines possessing a pendent ethynyl substituent on one or several peripheral aryl ring(s) are reported. The synthesis of this family of compounds is achieved by retro-Favorsky reactions from the corresponding propargylic alcohol derivatives, themselves obtained following a classic Sonogashira-type coupling between the ad hoc bromophenyl phosphines and 2-methylbut-3-yn-2-ol.