Biomedical subjects
Publications and source records attributed to Lanny S Liebeskind.
A new method for the synthesis of nitriles is described. As a complement to the classic cyanation of aryl halides using cyanide sources and a transition metal catalyst, the palladium-catalyzed cross-coupling of thiocyanates with boronic acids in the presence of copper(I) thiophene-2-carboxylate (CuTC) affords nitriles in good to excellent yields.
Bao Gong Teng A, an optically active tropane alkaloid with hypotensive and miotic activity isolated from the Chinese herb Erycibe obtusifolia Benth, was synthesized by an "organometallic chiron" strategy in which single enantiomers of TpMo(CO)(2)(eta(3)-pyridinyl) complexes are produced in quantity and then elaborated easily and efficiently to generate, after demetalation, highly enantiopure advanced synthetic intermediates possessing the tropane core.
The direct internal nucleophilic functionalization of a pi-bound carbon of neutral TpMo(CO)2(5-oxo-eta3-pyranyl) and TpMo(CO)2(5-oxo-eta3-pyridinyl) complexes by enolates represents a new reaction profile for neutral TpMo(CO)2(eta3-allyl) complexes. This Mo-mediated "1,5-Michael reaction" proceeds in good to excellent yields and provides, after demetalation, a new and efficient synthetic approach to oxa- and aza[3.2.1]bicyclics of high enantiomeric purity.
Thiol esters and organoindium reagents undergo palladium-catalyzed cross-coupling under mild conditions to give ketones in moderate to excellent yields. Aryl and primary/secondary alkyl organoindium reagents can be used as coupling partners. This method has two advantages over the cross-coupling of thiol esters with boron and tin reagents: (1) no added copper reagent is required to mediate the reaction and (2) for the case of alkyl transfer, no added base is required to activate organoindium reagents for cross-coupling as is required for the coupling of alkyl boron reagents with thiol esters.
[reaction: see text] A mild method for the reductive amination of aryl boronic acids with nitroso aromatic compounds is reported. This C-N bond formation is mediated by a stoichiometric amount of CuCl as both a catalyst and a reducing agent. Alternatively, 10% Cu(I)-3-methylsalicylate (CuMeSal) catalyzes the same reaction in the presence of either ascorbic acid or hydroquinone as the terminal reducing agent. Diarylamines bearing a variety of functional groups can be obtained in good yields.
Thiol esters and B-alkyl-9-BBN derivatives couple in the presence of a copper(I) carboxylate mediator and a palladium catalyst. In contrast to copper-mediated, palladium-catalyzed cross-couplings of thioorganics with boronic acids, the current coupling reaction of 9-BBN derivatives is facilitated by the addition of a base such as Cs(2)CO(3). Under optimized conditions, a variety of thiol esters react with different B-alkyl-9-BBN derivatives giving ketones in moderate to excellent yields.
[reaction: see text] A general demonstration of orthogonal selectivity of the Liebeskind-Srogl cross-coupling protocol compared to the Suzuki-Miyaura and Stille variants is reported.
[reaction: see text] A versatile approach to ketone synthesis is described. The reaction relies on the palladium-catalyzed, copper diphenylphosphinate-mediated coupling of thiol esters with organostannanes under neutral reaction conditions. This reaction complements the previously described coupling of thiol esters with boronic acids that used dual thiophilic-borophilic activation methodology.
The first Mo-mediated [5+3] cycloadditions are reported. 3-Substituted pyranyl and pyridinyl molybdenum pi-complexes participate in enantiocontrolled [5+3] cycloadditions and provide a new and efficient synthetic approach to oxa- and aza[3.3.1]bicyclics of high enantiomeric purity. The reaction proceeds in good to excellent yields and with complete regio- and endo-selectivities; it diverts to a [2+3] cycloaddition pathway when 2-substituted heterocycle pi-complexes are used. This methodology, coupled with a variety of general demetalation protocols, holds much promise in synthetic applications.
[reaction: see text] Heteroaromatic thioethers and aryl, heteroaryl, and alkenylstannanes participate in a palladium-catalyzed, copper(I)-mediated cross-coupling reaction at 50 degrees C in THF.
A conceptually new approach to the enantiocontrolled synthesis of 2,6-disubstituted piperidines was achieved by desymmetrization of meso-2,6-dimethoxy-eta-(3,4,5)-dihydropyridinylmolybdenum complexes. After protection of the piperidine nitrogen as a urethane derived from (+)- or (-)-trans-2-(alpha-cumyl)cyclohexyl (TCC), a sequential, one-pot methoxide abstraction/nucleophilic addition/methoxide abstraction/nucleophilic addition generated good yields of 2,6-disubstituted-eta-(3,4,5)-dihydropyridinylmolybdenum complexes. This sequence proceeds by way of a highly diastereoselective methoxide abstraction (>40:1). High yielding protodemetalation and N-deprotection provided a simple and enantiocontrolled synthetic entry to a variety of 2,6-disubstituted piperidines. This new method was used for the total synthesis of (-)-dihydropinidine and (-)-andrachcinidine.
[reaction: see text] A new synthesis of thioethers is described. The reaction of boronic acids with aryl, heteroaryl, and alkyl N-thioimides in the presence of catalytic quantities of a Cu(I) carboxylate affords good to excellent yields of thioethers. This reaction takes place in the absence of a base under mild conditions (THF, 45-50 degrees C, 2.5-12 h) and represents an interesting complement to known methods for thioether synthesis.
An efficient and general oxidative demetalation of (eta(3)-allyl)molybdenum complexes using pyridinium dichromate allows the introduction of a carbonyl group at an allylic terminus of the pi-system. The process takes place with high regiocontrol and can lead to the preparation of unsaturated ketones and lactones of high enantiopurity.
[reaction: see text] Pi-deficient heteroaromatic thioethers undergo efficient palladium-catalyzed cross-coupling with boronic acids mediated by copper(I) thiophene-2-carboxylate.
[reaction: see text] A new method for the synthesis of protected benzamidines is described. The commercially available 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea guanidylation reagent, after SEM-protection, functions as an amidine-forming cross-coupling partner under Liebeskind-Srogl conditions. In the presence of copper(I) thiophenecarboxylate (CuTC), the palladium-catalyzed cross-coupling of the SEM-protected thiopseudourea reagent with boronic acids affords fully protected benzamidines in good to excellent yield (40-91%).
The total synthesis of echinochrome A is described. Both key intermediates 5 and 8 were efficiently prepared from diisopropyl squarate 7. Nucleophilic addition of aryllithium 8 to 5, followed by thermal ring-expansion/cyclization of the 1,2-adduct 4, furnished hydroquinone 3. Oxidation and full deprotection of 3 gave the title compound.