Regio- and stereoselective route to tetrasubstituted olefins by the palladium-catalyzed three-component coupling of aryl iodides, internal alkynes, and arylboronic acids

[reaction: see text] The Pd-catalyzed three-component coupling of readily available aryl iodides, internal alkynes, and arylboronic acids provides a convenient, one-step, regio- and stereoselective route to tetrasubstituted olefins in good to excellent yields, although electron-poor aryl iodides and dialkylalkynes normally afford only low yields under our standard reaction conditions. The proper combination of substrates and reaction conditions is important for high yields. The presence of water generally substantially increases the yields of the desired tetrasubstituted olefins. The reaction involves cis-addition of the aryl group from the aryl iodide to the less hindered or more electron-rich end of the alkyne, while the aryl group from the arylboronic acid adds to the other end. A modified, room-temperature procedure has also been successfully developed, which works very well for some substrates. Tamoxifen and its derivatives are synthesized in a concise, regio- and stereoselective manner by applying our synthetic protocol.     

Carbolithiation of diphenylacetylene as a stereoselective route to (Z)-tamoxifen and related tetrasubstituted olefins

Carbolithiation of diphenylacetylene can be exploited to generate (E)-1-lithio-1,2-diphenylalkyl-1-enes which can be reacted in situ with triisopropylborate to stereoselectively provide (E)-1,2-diphenyl-1-alkylene boronic acids. These tetrasubstituted vinylboronic acids served as versatile intermediates for the generation of tetrasubstituted olefins with retention of stereochemistry. The application of this method for the stereoselective synthesis of (Z)-tamoxifen and related analogues is described.     

Sulfoxides in Julia-Lythgoe olefination: efficient and stereoselective preparation of di-, tri-, and tetrasubstituted olefins

[reaction: see text] A novel modification of the classical Julia-Lythgoe olefination, using sulfoxides instead of sulfones, affords, after in situ benzoylation and SmI2/HMPA- or DMPU-mediated reductive elimination, 1,2-di-, tri-, and tetrasubstituted olefins in moderate to excellent yields and E/Z selectivity. The conditions are mild, and the procedure is broadly applicable.     

Development of an efficient, regio- and stereoselective route to libraries based on the beta-D-glucose scaffold

The design and execution of an efficient synthetic route for the sequential functionalization of the five hydroxyl substituents of beta-D-glucose has been achieved. This strategy, based on the stereoselective glycosidation of thioglycosides, provides a new approach for the parallel construction of a wide variety of beta-D-glucose analogues and as such holds promise for solid-support library syntheses.     

A palladium-catalyzed regio- and stereoselective four-component coupling reaction

Pd(PPh(3))(4) catalytically assembles sulfenamide, alkyne, carbon monoxide, and diphenyl diselenide regio- and stereoselectively in a one-pot four-component coupling reaction to yield (Z)-beta-selenyl acrylamides. The reaction proceeds in good to excellent yields (60-95%) and is tolerant of a range of functional groups on both the nitrogen of the sulfenamide and the alkyne. Moderate selectivities ranging from 4:1 to 7:1 beta-selenyl to beta-sulfenyl acrylamide have been observed despite the initial concentration of 2:1 selenium to sulfur in the reaction. The chalcogeno selectivity was found to depend directly on CO pressure; increased pressure decreased selectivity for selenium over sulfur.     

Highly regio- and chemoselective palladium-catalyzed propargylallylation of activated olefins: a novel route to 1,7-enyne derivatives

An efficient method for the synthesis of 1,7-enyne derivatives via phosphine-palladium-catalyzed three-component assembling of activated olefins, allylic chlorides, and allenylstannanes is described. Substituted arylethylidene malononitriles 1a-g (RCH=C(CN)(2): R = C(6)H(5) (1a), p-ClC(6)H(4) (1b), p-OMeC(6)H(4) (1c), p-NO(2)C(6)H(4) (1d), 1-naphthyl (1e), 2-furyl (1f), and 2-thienyl (1g)) undergo propargylallylation with allylic chlorides 2a-e (allyl chloride (2a), methallyl chloride (2b), 4-chloropent-2-ene (2c), cinnamyl chloride (2d), and 3-chlorocyclohexene (2e)) and n-tributylallenylstannane (n-Bu(3)SnCH=C=CH(2), 3a) in the presence of Pd(PPh(3))(4) in toluene to afford the corresponding 1,7-enyne derivatives 4a-m in good to excellent yields. The catalytic reaction is highly regioselective, with the propargyl group adding to the carbon where the R group is attached and the allyl group adding to the carbon connected to the CN groups of activated olefins 1a-g. The present catalytic reaction is successfully extended to substituted arylethylidene-1,3-indanediones 5a-j (RCH = (1,3-indanedione): R = C(6)H(5) (5a), p-ClC(6)H(4) (5b), p-BrC(6)H(4) (5c), p-OMeC(6)H(4) (5d), p-NO(2)C(6)H(4) (5e), p-CNC(6)H(4) (5f), p-biphenyl (5g), 1-naphthyl (5h), 2-thienyl (5i), and 2-benzo[b]furane-2-yl (5j)) and substituted 2,2-dimethyl-5-(arylethylidene)-1,3-dioxane-4,6-diones 7a,b (RCH = (1,3-dioxane-4,6-dione): R = p-NO(2)C(6)H(4) (7a), p-OMeC(6)H(4) (7b)). The three-component assembling of these substrates with allylic chlorides (2a,b,d,e) and n-tributylallenylstannane (n-Bu(3)SnCH=C=CH(2), 3a) proceeds smoothly to afford the corresponding 1,7-enyne derivatives 6a-m and 8a-d in good to excellent yields. The catalytic propargylallylation can be further applied to the activated dienes, C(6)H(5)CH=CH=CR(2) (R(2) = (CN)(2) (9a), 1,3-indanedione (9b), 2,2-dimethyl-1,3-dioxane-4,6-dione (9c)), with allylic chlorides (2a,b,d) and allenylstannane 3a to give regio- and chemoselective 1,2-addition products 10a-h in good to excellent yields. A plausible mechanism based on an eta(1)-allenyl eta(3)-allyl palladium intermediate is proposed to account for the catalytic three-component reaction.     

Highly regio- and stereoselective synthesis of tetrasubstituted olefins by the three-component tandem reaction of allylzinc bromide, acetylenic sulfone, and halohydrocarbon

[reation: see text]. Tetrasubstituted olefins containing a 1,4-diene structural unit can be regio- and stereoselectively constructed in one pot by the allylzincation of acetylenic sulfones, followed by Negishi cross-coupling with halohydrocarbons in the presence of catalytic Ni(PPh3)2Cl2.     

Single-isomer tetrasubstituted olefins from regioselective and stereospecific palladium-catalyzed coupling of beta-chloro-alpha-iodo-alpha,beta-unsaturated esters

The efficient regioselective and stereospecific synthesis of tetrasubstituted olefins using a mild and convenient method is disclosed. 2-Alkynyl esters are selectively converted to E-beta-chloro-alpha-iodo-alpha,beta-unsaturated esters by exposure to Bu4NI in refluxing dichloroethane. These products are produced cleanly, regio- and stereoselectively, and in high yields. Single-isomer tetrasubstituted olefins bearing four different carbon substituents are then synthesized by sequential palladium-catalyzed coupling reactions. Selectivity results from reactivity differences in the intermediate substrates.     

An efficient and stereoselective route to 1-deoxy-5-hydroxy sphingosine analogues

A short and efficient synthesis of 1-deoxy-5-hydroxy sphingolipid is described. The key steps involved are a Jacobsen hydrolytic kinetic resolution (HKR) and Shibasaki’s asymmetric Henry reaction.     

Highly regio- and stereoselective synthesis of tetrasubstituted cyclobutenes via cyclodimerization of alkynes mediated by zirconium

Zirconium-induced cyclodimerization of a variety of heteroaryl-substituted alkynes is described. This method provides a facile synthesis of tetrasubstituted cyclobutenes with high regio- and diastereoselectivity. A ligand-induced reductive elimination mechanism accounting for this novel cyclodimerization is suggested.     

Total synthesis of capsanthin using lewis acid-promoted regio- and stereoselective rearrangement of tetrasubstituted epoxide.

The synthesis of capsanthin 1 was accomplished via the C15-cyclopentyl ketone 13 prepared by Lewis acid-promoted regio- and stereoselective rearrangement of the epoxide 12.     

Carbon-carbon bond formation in regio- and stereoselective palladium-catalyzed cyclization of allene-substituted conjugated dienes.

Regio- and stereoselective palladium-catalyzed reactions of allene-substituted 1,3-dienes 1 in acetic acid at room temperature lead to cyclization with formation of a carbon-carbon bond between the middle carbon of the allene and the terminal carbon of the 1,3-diene. Two different types of reactions, both that constitute 1,4-carboacetoxylations of the 1,3-diene, have been developed. In one of the reactions, Pd(II) catalyzes the oxidation of 1 to bicyclic compounds 2, and in the other, Pd(0) catalyzes the transformation of 1 to bicyclic compounds 3. The products 2 are useful for further synthetic transformations and undergo Diels-Alder reactions with dienophiles to give polycyclic ring systems.     

Highly regio- and stereoselective synthesis of 1,3-enynes from unactivated ethylenes via palladium-catalyzed cross-coupling

An efficient procedure for regio- and stereoselective synthesis of a series of conjugated enynes by a simple Pd-catalyzed cross-coupling reaction of unactivated ethylenes and ethynyl bromide has been developed. The reaction proceeds smoothly in DMF to give the corresponding products in good to excellent yields. The protocol can tolerate a broad range of functional groups on the substrates.     

Nickel-catalyzed addition of alkenylzirconium reagents to bicyclic olefins: a highly regio- and stereoselective ring-opening reaction

A highly regio- and stereoselective ring-opening addition of alkenylzirconium reagents to bicyclic olefins catalyzed by nickel complexes was described. Treatment of 7-oxa- and 7-azabenzonorbornadienes (1a-e) with various terminal alkenylzirconium reagents 2a-f (Cp(2)ZrClCH=CHR; R = t-Bu, n-Pr, n-Oct, 1-cyclohexenyl, SiMe(3), and Ph) in the presence of Ni(PPh(3))(2)Cl(2) and Zn powder (or a combination of ZnCl(2) and NEt(3)) in dry THF at 50 degrees C afforded the corresponding cis-2-alkenyl-1,2-dihydronaphthalene derivatives 3a-l in moderate to excellent yields. Under similar reaction conditions, internal alkenylzirconium reagents 2g,h (Cp(2)ZrClCR=CHR: R = Et and n-Pr) also undergo ring-opening addition to oxanorbornadienes 1a and 1d to give cis-2-alkenyl-1,2-dihydronaphthalene derivatives 4a-c in good yields. Possible pathways involving the transfer of alkenyl group in the alkenylzirconium reagent to the Ni(II) center followed by migration of the alkenyl group from the Ni(II) center to the carbon-carbon double bond of 7-oxanorbornadiene or the reaction of 7-oxanorbornadiene with Ni(0) to form a Ni(II)-pi-allyl prior to the transfer of the alkenyl group as key steps for the catalytic reaction were proposed and discussed.     

Novel efficient routes to heparin monosaccharides and disaccharides achieved via regio- and stereoselective glycosidation

A new methodology for the synthesis of heparin building blocks has been developed. We describe novel efficient routes to both L-iduronic acid and D-glucuronic acid acceptors. Glycosylation with thioglycosides donors gave corresponding disaccharides in a regio- and stereoselective fashion. An improved approach to synthesizing azido-glucose thioglycoside donor to render azido-sugar from mannose via nucleophilic substitution is described. [reaction: see text]     

Palladium-catalyzed three-component transformation of homoallenols: a regio- and stereoselective route to 1,5-amino alcohols

A palladium-catalyzed three-component transformation of enantioenriched homoallenols with aryl halides and amines has been developed to selectively afford (Z)-configured 1,5-amino alcohols in good-to-excellent yields without any epimerization.