Enol Tosylate Research Articles

Stereoconvergent and -divergent Synthesis of Tetrasubstituted Alkenes by Nickel-Catalyzed Cross-Couplings.

We report the development of a method to diastereoselectively access tetrasubstituted alkenes via nickel-catalyzed Suzuki-Miyaura cross-couplings of enol tosylates and boronic acid esters. Either diastereomeric product was selectively accessed from a mixture of enol tosylate starting material diastereomers in a convergent reaction by judicious choice of the ligand and reaction conditions. A similar protocol also enabled a divergent synthesis of each product isomer from diastereomerically pure enol tosylates. Notably, high-throughput optimization of the monophosphine ligands was guided by chemical space analysis of the kraken library to ensure a diverse selection of ligands was examined. Stereoelectronic analysis of the results provided insight into the requirements for reactive and selective ligands in this transformation. The synthetic utility of the optimized catalytic system was then probed in the stereoselective synthesis of various tetrasubstituted alkenes, with yields up to 94% and diastereomeric ratios up to 99:1 Z/E and 93:7 E/Z observed. Moreover, a detailed computational analysis and experimental mechanistic studies provided key insights into the nature of the underlying isomerization process impacting selectivity in the cross-coupling.

Stereoretentive Iron-catalyzed Cross-coupling of an Enol Tosylate with MeMgBr

Stereoretentive Iron-catalyzed Cross-coupling of an Enol Tosylate with MeMgBr

Preparation of E-1,3-diaminoethenyl functional groups by the reaction of enol tosylate of alpha-formylglycine with primary and secondary amines

Article history: Received October 21, 2015 Received in revised form December 20, 2015 Accepted 12 January 2016 Available online 14 January 2016 The E-1,3-diaminoethenyl functional group is a potentially useful synthon. A number of examples of E-1,3-diaminoethenyl functional groups were prepared in good yield starting from an E-enol tosylate of a serine based diketopiperazine and 1°or 2° amine nucleophiles. The reaction proceeds via a stereoselective nucleophilic substitution pathway. © 2016 Growing Science Ltd. All rights reserved.

Catalyst-Directed Diastereoselective Isomerization of Allylic Alcohols for the Stereoselective Construction of C(20) in Steroid Side Chains: Scope and Topological Diversification.

The stereoselective construction of C20 in steroidal derivatives by a highly diastereoselective Ir-catalyzed isomerization of primary allylic alcohols is reported. A key aspect of this strategy is a straightforward access to geometrically pure steroidal enol tosylate and enol triflate intermediates for subsequent high yielding stereoretentive Negishi cross-coupling reactions to allow structural diversity to be introduced. A range of allylic alcohols participates in the diastereoselective isomerization under the optimized reaction conditions. Electron-rich and electron-poor aryl or heteroaryl substituents are particularly well-tolerated, and the stereospecific nature of the reaction provides indifferently access to the natural C20-(R) and unnatural C20-(S) configurations. Alkyl containing substrates are more challenging as they affect regioselectivity of iridium-hydride insertion. A rationale for the high diastereoselectivities observed is proposed for aryl containing precursors. The scope of our method is further highlighted through topological diversification in the side chain and within the polycyclic domain of advanced and complex steroidal architectures. These findings have the potential to greatly simplify access to epimeric structural analogues of important steroid scaffolds for applications in biological, pharmaceutical, and medical sciences.

Structure-reactivity study of O-tosyl Cinchona alkaloids in their new synthesis and in hydrolysis to 9-epibases. Unexpected formation of cinchonicine enol tosylate accelerated by microwave activation

New methods for O-tosylation of the natural Cinchona alkaloids have been discovered as a biphasic processes with Bu 3N as a catalyst. The optimized excess of tosyl chlo ride, necessary for transformation of each of the four alkaloids into O-tosyl derivative, decreases in the following order: quinine, quinidine, cinchonidine and cinchon ine. The same decreasing order has been noticed for the hydrolysis rate of the appropriate tosylates to 9-epibases. Difficult conversion of O-tosylcinchonine in the hydrolytic medium of aqueous tartaric acid gives 9-epicinchonine together with parallel formation of cinchonicine en ol tosylate. The latter product is obtained as the main when both cinchonine and cinchonidine tosylates react in the presence of salicylic acid under controlled microwave heating. On the basis of X-ray structure of the new alkene product, the stereoselective syn -E2 quinuclidine ring opening process, competing to the SN2 hydrolysis is postulated for this transformation.

Stereoselective Total Syntheses of Insect Juvenile Hormones JH 0 and JH I

Total syntheses of juvenile hormones JH 0 and JH I have been achieved by a new iterative enol tosylate homologation strategy.

New Efficient Asymmetric Synthesis of Taranabant, a CB1R Inverse Agonist for the Treatment of Obesity

Taranabant (1) is a cannabinoid-1 receptor (CB1R) inverse agonist that was recently in late-stage clinical development for the treatment of obesity. The previously employed synthesis exhibited a number of shortcomings for continuing development, and in this paper we report an improved synthesis of the target molecule that is suitable for large-scale implementation. Palladium-catalyzed amidation of an enol tosylate afforded a stereodefined tetrasubstituted enamide, and asymmetric hydrogenation thereof provided the target molecule.

Novel Generation of 3,3,3-Trifluoropropynyllithium and Transformation of the Carbonyl Adducts to Trifluoromethyl-Substituted Allenes

A novel method for the generation of 3,3,3-trifluoro­propynyllithium is reported, which involves treatment of trifluoromethyl-substituted enol tosylate, prepared from 1,1-dichloro-3,3,3-trifluoroacetone, with two equivalents of butyllithium. ­Palladium-catalyzed coupling reaction of sulfonates of the carbonyl adducts with organozinc reagents gave trifluoromethyl-containing tri- and tetrasubstituted allenes.

Suzuki coupling reactions of 2,4,6-trialkoxyphenylboronic acids with enol triflates: asymmetric synthesis of a lactone template for calyxin assemblage

Suzuki coupling reactions between 2,4,6-trialkoxyphenylboronic acids and enol triflates have been found to occur in excellent yield, while the use of an enol tosylate failed to give any of the desired product. This coupling reaction has led to the synthesis of a lactone which could serve as a precursor to several calyxin analogues.

CFC‐ or HFC‐Free Approach to α‐Substituted β,γ,γ‐Trifluoroallyl Alcohols by the Reaction of β‐Fluoro‐β‐trifluoromethylated Enol Tosylate with Grignard Reagents.

AbstractFor Abstract see ChemInform Abstract in Full Text.

CFC- or HFC-Free Approach to α-Substituted β,γ,γ-Trifluoroallyl Alcohols by the Reaction of β-Fluoro-β-trifluoromethylated Enol Tosylate with Grignard Reagents

The reaction of β-fluoro-β-trifluoromethylated enol tosylate with Grignard reagents giving the corresponding β,γ,γ-tri­fluoroallyl alcohols as well as heteropoly acid-mediated ethanolysis of the allyl alcohols affording (Z)-β-substituted α-fluoro-α,β-un­saturated esters is described.

Synthesis and characterization of β- O-tosyldehydroserine as a precursor of dehydroamino acids

β- O-Tosyldehydroserine 3 is prepared directly by the oxidation of the corresponding serine derivative 1 with dimethyl sulfoxide which is activated by p-toluenesulfonyl chloride. The enol tosylate 3 retains reactivities characteristic of aldehydes like those expected for the corresponding dehydroserine derivative 2. A typical reaction of 3 includes substitution of the tosyl group with nucleophiles such as primary and secondary amines, leading to other dehydroamino acids.

Conjugate addition of lithium diorganocuprate reagents to the enol tosylate of a 1,2-diketone

The conjugate addition of lithium diorganocuprate reagents to the enol tosylate of 1,2-cyclohexanedione has been investigated. The intermediate enolates eliminate para-toluenesulfmate ion to generate the alkylated 1,2-dicarbonyl system.

Stereoselective dienyl ether syntheses from malonaldehyde trans-enol ethers: (E)-buta-1,3-dienyl, and (E,Z)- and (E,E)-4-chlorobuta-1,3-dienyl ethers of a protected sugar; conversion of the latter into functionalized chiral disaccharide precursors

Condensation of the enol tosylate of malonaldehyde with the sodium alcoholate NaOR derived from ‘diacetone glucose’ gave in 92% yield the almost pure trans-enol ether RO–CHCH–CHO (1). This could be readily condensed with suitable Wittig phosphoranes to give either the buta-1,3-dienyl ether (2)(87% yield; more than 90%trans), or a mixture of 4-chlorobuta-1,3-dienyl ethers (85%) of ‘diacetone glucose;’ the main components were the (E,Z)-diene (5)(45%) and the (E,E)-diene (4)(45%). Cycloaddition of diethyl mesoxalate to the diene (4) gave a mixture of two 3-chloro-2, 2-bisethoxycarbonyl-3,6-dihydro-2H-pyran-6-yl ethers, the (3S,6S)-derivative (6)(69%) and the (3R,6R)-derivative (7)(19%). Free-radical reduction of these chlorides (6) and (7) with tributylstannane led to mainly rearranged products: the 2, 2-bisethoxycarbonyl-5, 6-dihydro-2H-pyran-6-yl ethers, (6S)(9) and (6R)(11). In the same way, nucleophilic substitution of the chloride (6) with azide led to the (5S)-5-azido-derivative (12) of the dihydropyran (9). Catalytic reduction of the double bond and the azido group in (12), followed by N-acetylation, gave the saturated (S)-acetamido derivative (13), which could be deethoxycarbonylated to give two disaccharides with a 2-acetamido-2-deoxyhexopyranosyl non-reducing unit. We consider that the above overall sequence of reactions is a useful extension of the cycloaddition method of disaccharide synthesis.

Reactions of acid anhydrides—III : Dimerizations of 3-oxo-steroids

Steroidal ketone 1 reacts with trichloroacetyl p-toluenesulphonate to give in addition to the enol tosylate 3 a dimeric ketone 4 together with its enol esters 5 and 6. The dimeric ketone 4 was also obtained when ketone 1 was treated with trichloroacetic anhydride and p-toluenesulphonic acid. High concentrations of reactants and presence of acid favoured the formation of the dimeric products. It is suggested, that the dimerization occurs by an acid catalysed aldol-type condensation, while the anhydrides act as dehydrating agents converting the initially formed dimeric ketol to the β,γ-unsaturated ketone 4. Formation of dimeric ketone 4 was also observed when the α-bromoketone 8 was treated with zinc and ethyl chlorocarbonate. In the presence of zinc and zinc chloride however, ketone 8 yielded the dimeric β-diketone 12.

Reactions of acid anhydrides—II : Reactions of ketones with mixed sulphonic-carboxylic anhydride, isopropenyl acetate, and acetic anhydride

The reactions of unsymmetrically substituted ketones with trichloroacetyl p-toluenesulphonate, isopropenyl acetate and acetic anhydride were investigated. Trichloroacetyl p-toluenesulphonate converted the saturated ketone 2 to the enol tosylate 5 but testosterone acetate 6 to the corresponding dienol trichloroacetate 7b. Reaction of the ketones 1,2 and 10 with isopropenyl acetate or acetic anhydride in the presence of acid led to isomeric enol acetates 3,4 and 11. The ratio of the isomeric enol acetates differed according to the acid used, when isopropenyl acetate was employed, but was independent of the acid, when acetic anhydride was used. It is suggested that the formation of enol acetates involves addition of either acetic anhydride (when acetic anhydride is used) or mixed anhydride (when isopropenyl acetate or the mixed anhydride is used) to give a gem disubstituted intermediate.