Hydrogen-mediated reductive coupling of conjugated alkynes with ethyl (N-Sulfinyl)iminoacetates: synthesis of unnatural alpha-amino acids via rhodium-catalyzed C-C bond forming hydrogenation

Rhodium-catalyzed hydrogenation of 1,3-enynes 1a-8a and 1,3-diynes 9a-13a at ambient temperature and pressure in the presence of ethyl (N-tert-butanesulfinyl)iminoacetate and ethyl (N-2,4,6-triisopropylbenzenesulfinyl)iminoacetates, respectively, results in reductive coupling to afford unsaturated alpha-amino acid esters 1b-13b in good to excellent yields with exceptional levels of regio- and stereocontrol. Further hydrogenation of the diene containing alpha-amino acid esters 1b-8b using Wilkinson's catalyst at ambient temperature and pressure results in regioselective reduction to afford the beta,gamma-unsaturated alpha-amino acid esters 1c-8c in good to excellent yields. Exhaustive hydrogenation of the unsaturated side chains of the Boc- and Fmoc-protected derivatives of enyne and diyne coupling products 14b-16b occurs in excellent yield using Crabtree's catalyst at ambient temperature and pressure providing the alpha-amino acid esters 14d-16d, which possess saturated side chains. Finally, cross-metathesis of the Boc-protected reductive coupling product 14b with cis-1,4-diacetoxy-2-butene proceeds readily to afford the allylic acetate 14e. Isotopic labeling studies that involve reductive coupling of enyne 1a and diyne 9a under an atmosphere of elemental deuterium corroborate a catalytic mechanism in which oxidative coupling of the alkyne and imine residues is followed by hydrogenolytic cleavage of the resulting metallacycle. A stereochemical model accounting for the observed sense of asymmetric induction is provided. These studies represent the first use of imines as electrophilic partners in hydrogen-mediated reductive carbon-carbon bond formation.     

Ruthenium-catalyzed C-C bond forming transfer hydrogenation: carbonyl allylation from the alcohol or aldehyde oxidation level employing acyclic 1,3-dienes as surrogates to preformed allyl metal reagents

Under the conditions of ruthenium-catalyzed transfer hydrogenation, commercially available acyclic 1,3-dienes, butadiene, isoprene, and 2,3-dimethylbutadiene, couple to benzylic alcohols 1a-6a to furnish products of carbonyl crotylation 1b-6b, carbonyl isoprenylation 1c-6c, and carbonyl reverse 2-methyl prenylation 1d-6d. Under related transfer hydrogenation conditions employing isopropanol as terminal reductant, isoprene couples to aldehydes 7a-9a to furnish identical products of carbonyl isoprenylation 1c-3c. Thus, carbonyl allylation is achieved from the alcohol or the aldehyde oxidation level in the absence of preformed allyl metal reagents. Coupling to aliphatic alcohols (isoprene to 1-nonanol, 65% isolated yield) and allylic alcohols (isoprene to geraniol, 75% isolated yield) also is demonstrated. Isotopic labeling studies corroborate a mechanism involving hydrogen donation from the reactant alcohol or sacrificial alcohol (i-PrOH).     

Rhodium-catalyzed reductive cyclization of 1,6-diynes and 1,6-enynes mediated by hydrogen: catalytic C-C bond formation via capture of hydrogenation intermediates

Catalytic hydrogenation of carbon-, nitrogen- and oxygen-tethered 1,6-diynes 1a-9a and 1,6-enynes 10a-18a using cationic Rh(I) precatalysts at ambient temperature and pressure enables reductive carbocyclization to afford 1,2-dialkylidene cyclopentanes 1b-9b and monoalkylidene cyclopentanes 10b-18b, respectively, in good to excellent yields and as single alkene stereoisomers. Notably, the 1,3-diene and alkene containing cyclization products 1b-9b and 10b-18b are not subject to over-reduction under the conditions of catalytic hydrogenation in which they are formed. Reductive cyclization 1,6-diyne 1a and 1,6-enyne 10a performed under an atmosphere of D(2) provides the carbocyclization products deuterio-1b and deuterio-10b, respectively, which incorporate two deuterium atoms. The collective data are consistent with a catalytic mechanism involving heterolytic activation of elemental hydrogen (H(2) + Rh(+)X(-) --> Rh-H + HX) followed by Rh(I)-mediated oxidative cyclization of the 1,6-diyne or 1,6-enyne substrates to afford (hydrido)Rh(III)-based metallocyclopentadiene and metallocyclopentene intermediates, respectively. These transformations represent the first examples of metal-catalyzed reductive carbocyclization mediated by hydrogen.     

Highly enantioselective direct reductive coupling of conjugated alkynes and alpha-ketoesters via rhodium-catalyzed asymmetric hydrogenation

Catalytic hydrogenation of 1,3-enynes 1a-7a in the presence of ethyl pyruvate and related activated ketones using chirally modified cationic rhodium catalysts results in reductive coupling to afford dienylated alpha-hydroxy esters 1b-7b and 3c-3f with exceptional levels of regio- and enantiocontrol. These studies represent the first highly enantioselective direct catalytic reductive couplings of alkynes to ketones. As illustrated by the conversion of 6b to 6c-6h, the diene containing the side chain of the coupling products is subject to diverse chemo- and regioselective manipulation. Reductive coupling of enyne 6a and ethyl pyruvate using elemental deuterium provides the monodeuterated product deuterio-6b, consistent with a catalytic mechanism involving alkyne-carbonyl oxidative coupling followed by hydrogenolytic cleavage of the resulting oxametallacycle, as corroborated by ESI-MS analysis.     

Diastereo- and enantioselective hydrogenative aldol coupling of vinyl ketones: design of effective monodentate TADDOL-like phosphonite ligands

We report the first enantioselective reductive aldol couplings of vinyl ketones, which were achieved through the design of a novel monodentate TADDOL-like phosphonite ligand. Specifically, hydrogenation of commercially available methyl vinyl ketone (MVK) or ethyl vinyl ketone (EVK) in the presence of aldehydes 1a-7a using cationic rhodium catalysts modified by chiral TADDOL-like phosphonite ligands AP-I and AP-IV produces aldol adducts 1b-7b and 1c-7c with excellent control of relative and absolute stereochemistry. The absolute stereochemical assignments of the aldol adducts are made in analogy to that determined for the 5-bromophthalimido derivative of aldol adduct 1b and the 2-bromo-5-nitrobenzoate of 3b, which were established by single-crystal X-ray diffraction analysis using the anomalous dispersion method.     

Asymmetric synthesis of 2,3-dihydrofurans and of unsaturated bicyclic tetrahydrofurans through alpha-elimination and migratory cyclization of silyloxy alkenyl aminosulfoxonium salts. Generation and intramolecular O,Si-bond insertion of chiral disubstituted beta-silyloxy alkylidene carbenes

Treatment of the bis(allylsulfoximine)titanium complexes derived from the beta-methyl-substituted acyclic allylic sulfoximines 13a and 13b with aldehydes gave with high selectivities the corresponding sulfoximine-substituted homoallylic alcohols which were isolated as the silyl ethers 15a-h. Methylation of sulfoximines 15a-h afforded the aminosulfoxonium salts 5a-h which upon treatment with LiN(H)tBu gave in high yields the enantio- and diastereomerically pure silyl-substituted 2,3-dihydrofurans 4a-h. Treatment of the titanium complexes derived from the cyclic allylic sulfoximines 17a, 17b, and ent-17c with p-MeOC(6)H(4)CHO delivered with high selectivities the corresponding sulfoximine-substituted cyclic homoallylic alcohols which were isolated as the silyl ethers 18a, 18b, and ent-18c, respectively. Methylation of sulfoximines 18a, 18b, and ent-18c furnished the aminosulfoxonium salts 8a, 8b, and ent-8c, respectively, whose treatment with LiN(H)t-Bu gave the enantio- and diastereomerically pure fused bicyclic 2,3-dihydrofurans 6a, 6b, and ent-6c, respectively, in good yields. It is proposed that the 1-alkenyl aminosulfoxonium salts 5a-h, 8a, 8b, and ent-8c react with the base under alpha-elimination and formation of the acyclic and cyclic beta-silyloxy alkylidene carbenes 2a-h, 7a, 7b, and ent-7c, respectively, which then undergo a 1,5-O,Si-bond insertion and 1,2-silyl migration. The cyclic aminosulfoxonium salts 8a, 8b, and ent-8c upon treatment with 1,8-diazabicyclo[5.4.0]-7-undecene did not undergo an alpha-elimination but suffered a novel migratory cyclization with formation of the enantio- and diastereomerically pure bicyclic tetrahydrofurans 9a, 9b, and ent-9c, respectively. It is proposed that the 1-alkenyl sulfoxonium salts 8a, 8b, and ent-8c are isomerized to the allylic aminosulfoxonium salts 10a, 10b, and ent-10c, respectively, which then suffer an intramolecular substitution of the (dimethylamino)sulfoxonium group by the silyloxy group followed by a desilylation. The syntheses of the 2,3-dihydrofurans 4a-h, 6a, and 6b and of the tetrahydrofurans 9a and 9b are accompanied by the formation of sulfinamide 16 of >or=98% ee, which can be converted via sulfoxide 28 of >or=98% to the starting sulfoximine 11 of >or=98% ee.     

Enantioselective reductive coupling of 1,3-enynes to glyoxalates mediated by hydrogen: asymmetric synthesis of beta,gamma-unsaturated alpha-hydroxy esters

Catalytic hydrogenation of 1,3-enynes 1a-8a in the presence of ethyl glyoxalate at ambient pressure and temperature using a rhodium catalyst modified by (R)-(3,5-tBu-4-MeOPh)-MeO-BIPHEP results in highly regio- and enantioselective reductive coupling to furnish the corresponding alpha-hydroxy esters 1b-8b. As demonstrated by the elaboration of alpha-hydroxy ester 1b, the terminal and internal olefin moieties embodied by the diene side chain are subject to selective manipulation, one over the other.     

Ruthenium catalyzed C-C bond formation via transfer hydrogenation: branch-selective reductive coupling of allenes to paraformaldehyde and higher aldehydes

Under the conditions of ruthenium-catalyzed transfer hydrogenation employing 2-propanol as the terminal reductant, 1,1-disubstituted allenes 1a- h engage in reductive coupling to paraformaldehyde to furnish homoallylic alcohols 2a- h. Under identical transfer hydrogenation conditions, 1,1-disubstituted allenes engage in reductive coupling to aldehydes 3a- f to furnish homoallylic alcohols 4a- n. In all cases, reductive coupling occurs with branched regioselectivity to deliver homoallylic alcohols bearing all-carbon quaternary centers.     

Cobalt-Catalyzed Regiodivergent and Enantioselective Intermolecular Coupling of 1,1-Disubstituted Allenes and Aldehydes

Catalytic enantioselective coupling of 1,1-disubstituted allenes and aldehydes through regiodivergent oxidative cyclization followed by stereoselective protonation or reductive elimination promoted by chiral phosphine-Co complexes is presented. Such processes represent unprecedented and unique reaction pathways for Co catalysis that enable catalytic enantioselective generation of metallacycles with divergent regioselectivity accurately controlled by chiral ligands, affording a wide range of allylic alcohols and homoallylic alcohols that are otherwise difficult to access without the need of pre-formation of stoichiometric amounts of alkenyl- and allyl-metal reagents in up to 92 % yield, >98 : 2 regioselectivity, >98 : 2 dr and >99.5 : 0.5 er.     

Synthesis of 1,2-five-ring-annellated barrelenes via the intramolecular Diels-Alder reaction of acetylenic derivatives

The intramolecular Diels-Alder reaction conducted with acetylenic acylureas, obtained from carbodiimides, and the acetylenic acid 5 and its derivatives 13 gave the 1,2-annellated barrelene 14 (from 13a ) and the benzobarrelenes 8 (from 5 ) and 15 (from 13b ); in the case of 3-butynoic acid ( 1 ),[1,3]-H shift were observed. The formation of the azabarrelenes 16 (from 13c ) as an intermediate is postulated which looses HCN to afford the indolinone 17 . The acylureas 6 and 9 underwent isocyanate cleavage instead of [4+2] cyclization.     

新型1,2,3-三唑类化合物的合成及抗菌构效关系

根据活性基团拼接原理, 以4-取代-苯胺为原料, 经重氮化、 关环和缩合反应合成了17个化合物1-(4-取代苯基)-5-取代苯基亚氨基-4-取代-1,2,3-三唑(7a~7c和13a~13d)和1-(4-取代苯基)-5-取代苄基氨基-4-取代-1,2,3-三唑(5a~5c, 10a~10c和14a~14d), 其中化合物5a~5c, 7b, 7c, 10a, 10c, 13b~13d和14b~14c为新化合物, 对所制备化合物的结构进行了表征. 生物活性测试结果表明, 所有化合物均表现出一定的抑菌活性, 对大肠杆菌的抑菌活性均优于氟康唑; 化合物7a和10c对金黄色葡萄球菌的抑制活性明显优于氟康唑; 而化合物13a和13d则对白色念球菌表现出良好的抑制活性, 与三氯生相当.     

Enantioselective reductive cyclization of 1,6-enynes via rhodium-catalyzed asymmetric hydrogenation: C-C bond formation precedes hydrogen activation

Asymmetric hydrogenation of 1,6-enynes using chirally modified cationic rhodium precatalysts enables enantioselective reductive cyclization to afford alkylidene-substituted carbocycles and heterocycles in a completely atom economical fashion. Good to excellent yields and exceptional levels of asymmetric induction are observed across a structurally diverse set of substrates. Mechanistic studies involving hydrogen-deuterium crossover experiments, along with the observance of nonconjugated cycloisomerization products 14c and 15c, suggest rhodium(III) metallocyclopentene formation occurs in advance of hydrogen activation. This oxidative coupling-hydrogenolytic cleavage motif should play a key role in the design of related hydrogen-mediated couplings.     

Rhodium-catalyzed reductive mannich coupling of vinyl ketones to N-sulfonylimines mediated by hydrogen

Catalytic hydrogenation of methyl vinyl ketone (MVK) and ethyl vinyl ketone (EVK) in the presence of N-(o-nitrophenylsulfonyl)imines 8a-13a at ambient pressure with tri-2-furylphosphine-ligated rhodium catalysts enables formation of Mannich products 8b-13b and 8c-13c with moderate to good levels of syn-diastereoselectivity. As revealed by an assay of various N-protecting groups, excellent yields of reductive Mannich product also are obtained for N-arylimines 1a-4a, although diminished levels of syn-diastereoselectivity are observed. Coupling of MVK to imine 8a under a deuterium atmosphere provides deuterio-8b, which incorporates a single deuterium atom at the former enone beta-position.     

Synthesis and Synthetic Application of Phosphonoketene Dithioacetals. New Synthesis of Dithioallenes and (alpha-Dithiocarboxyvinyl)phosphonates

Phosphonoketene dithioacetals 3a-e were obtained in good yields by the reaction of ethyl phosphonoacetates 1a,b with 2-4 equiv of thiols 2a-c in the presence of an alkylaluminum dichloride or dialkylaluminum chlorides. Reaction of 2,2-dithio-1-phosphonovinyl anions with aldehydes afforded allylic alcohols 4-7, 11-18 in good to moderate yields. Treatment of the alcohols 4-6 with t-BuOK in THF led to symmetrical [2 + 2] cycloadducts 20-22 of 1,1-(ethylenedithio)allenes in moderate yields, while a similar reaction of the alcohols 11-13 produced a mixture of symmetrical and unsymmetrical [2 + 2] cycloadducts of 1,1-(trimethylenedithio)allenes,23a-25a and 23b-25b, in 55-94% yields. The alcohol 15 on a similar treatment gave 3-tert-butyl-1,1-bis(ethylthio)allene (26) in quantitative yield. The structures of 20 and 23b were determined by X-ray analysis. Treatment of the alcohols 15 and 18 with trifluoromethanesulfonic acid/n-Bu(4)NX (X = Br, I) or triphenylphosphine/CBr(4) in CH(2)Cl(2) afforded alpha-phosphonodithioacryclic acid esters 34 and 35 in 25-52% yields. The tandem Michael-Wittig reaction of 35 with sodium salt of 2-pyrrolecarbaldehyde in DMF gave ethyl 3-phenyl-3H-cyclopenta[a]pyrrole-2-dithiocarboxylate (36) in 25% yield.     

A general,highly enantioselective method for the synthesis of D and L alpha-amino acids and allylic amines

Catalytic and enantioselective synthesis of amino acids is a subject of intense interest in the field of asymmetric catalysis. Traditionally, researchers have concentrated their efforts largely on the design and discovery of enantiopure catalysts for the Strecker reaction, alkylation of tert-butyl gylcinate-benzophenone, electrophilic amination of carbonyl compounds, and hydrogenation of N-acyl-aminoacrylic acid; however, the scope of these reactions is limited. In this paper, we report on a different approach to amino acids based on an expeditious route to enantiopure allylic amines. A highly enantioselective and catalytic vinylation of aldehydes leads to allylic alcohols that are then transformed to the allylic amines via Overman's [3,3]-sigmatropic rearrangement of imidates. Oxidative cleavage of the allylic amines furnishes the amino acids in good yields and excellent ee's. The scope and utility of this method are demonstrated by the synthesis of challenging allylic amines and their subsequent transformation to valuable nonproteinogenic amino acids, including both D and L configured (1-adamantyl)glycine.     

Studies on the Cu(I)-catalyzed regioselective anti-carbometallation of secondary terminal propargylic alcohols

A highly regioselective Cu(I)-catalyzed anti-carbometallation of secondary terminal propargylic alcohols with 1 degrees alkyl or aryl Grignard reagents affording 2-substituted allylic alcohols was developed. By using this method, optically active allylic alcohols can be prepared from the optically active propargylic alcohols without obvious loss of the enantiopurity. The cyclic organometallic intermediate formed may undergo an iodination or a Pd(0)-catalyzed coupling reaction to afford stereo-defined allylic alcohols.     

Enantioselective arylative cyclization of allenyl aldehydes with arylboronic acids under Pd(II)-diphosphine catalysis

A Pd(OAc)2-SEGPHOS combination catalyzes the first enantioselective arylative cyclization of allenyl aldehydes with arylboronic acids to provide cis-fused five- and six-membered cyclic homoallylic alcohols. The excellent diastereo- and enantioselectivity and the fact that the reaction proceeds at room temperature in the absence of any additives make the process highly practical.     

Highly stereoselective three-component reactions of phenylselenomagnesium bromide,acetylenic sulfones,and saturated aldehydes/ketones or alpha,beta-unsaturated enals or enones

beta-Phenylseleno-alpha-tolylsulfonyl-substituted alkenes were synthesized via the three-component conjugate-nucleophilic addition of acetylenic sulfones, phenylselenomagnesium bromide, and carbonyl compounds, such as aldehydes, aliphatic ketones, or alpha,beta-unsaturated enals or enones. The reaction is highly regio- and stereoselective with moderate to good yields. Functionalized allylic alcohols were obtained in the case of aldehydes and aliphatic ketones. In the case of alpha,beta-unsaturated enones, functionalized allylic alcohols or functionalized gamma,delta-unsaturated ketones were obtained, depending on the structures of the ketones.     

Transition metal-catalyzed asymmetric reactions using P-chirogenic diaminophosphine oxides: DIAPHOXs

This review describes the development of a new class of chiral phosphorus ligands: amino acid-derived P-chirogenic diaminophosphine oxides, DIAPHOXs, and their application to several transition metal-catalyzed asymmetric allylic substitution reactions. Pd-catalyzed asymmetric allylic alkylation with cyclic beta-keto esters as prochiral nucleophiles was initially examined using P-chirogenic diaminophosphine oxide 1a, resulting in highly enantioselective construction of quaternary stereocenters. Mechanistic investigations revealed that 1a is activated by N,O-bis(trimethylsilyl)acetamide-induced tautomerization to afford a trivalent diamidophosphite species 13, which functions as the actual ligand. Pd-catalyzed asymmetric allylic substitutions of both acyclic and cyclic substrates were also examined using various nucleophiles such as malonate derivatives, nitromethane, aliphatic amines, and aromatic amines, providing a variety of chiral compounds with good to excellent enantioselectivity. In addition, Ir-catalyzed asymmetric allylic amination and alkylation of terminal allylic carbonates were examined using structurally optimized P-chirogenic diaminophosphine oxides, and the corresponding branched products were obtained in a highly regio- and enantioselective manner. Furthermore, the developed catalytic asymmetric process was successfully applied to the catalytic enantioselective synthesis of biologically active compounds, (R)-preclamol, (R)-baclofen hydrochloride, and (-)-paroxetine.     

Enantioselective synthesis of allylic alcohols by the sequential aminoxylation-olefination reactions of aldehydes under ambient conditions

A novel, highly enantioselective synthesis of O-amino-substituted allylic alcohols by the sequential asymmetric alpha-aminoxylation/Wadsworth-Emmons-Horner olefination reactions of aldehydes is presented.