Rhodium-catalyzed 1,4-addition of alkenylzirconocene chlorides to electron deficient alkenes

The 1,4-conjugated addition of alkenylzirconocene chloride complexes to α,β-enones, α,β-enoic acid esters, and α,β-enoic acid amides can be efficiently achieved by the use of [RhCl(cod)]₂ catalyst. A high diastereoselectivity (95% yield, 90% de) was obtained through the reaction of α,β-enoic acid amide derived from Oppolzer's sultam and 2-butenoyl chloride, while the use of Evans' chiral oxazolidinone as a chiral auxiliary in place of Oppolzer's sultam gave a poor diastereoselectivity (98% yield, 26% de).     

Asymmetric 1,4-addition of alkenylzirconium reagents to α,β-unsaturated ketones catalyzed by chiral rhodium complexes

Highly enantioselective 1,4-addition of alkenylzirconocene chlorides to α,β-enones was found to be catalyzed by a chiral rhodium complex generated from [Rh(cod)(MeCN)₂]BF₄ and (S)-BINAP. The reaction can be applied to either cyclic or acyclic enones and the optical yield was up to 99% ee. The reaction mechanism would involve the transmetalation between the alkenylzirconocene chloride and the rhodium complex to give the alkenylrhodium species as a key intermediate.     

Regio- and stereoselective synthesis of highly functionalized vinyl ethers via coiodination of acetylenic ketones

A Cu(OTf)₂-catalyzed highly regio- and stereoselective coiodination of acetylenic ketones was reported, providing a mild and convenient method for the synthesis of (Z)-β-carbonyl-β-iodoenol ethers in good yields.     

Acylzirconocene chloride: Formation of carbocycles by palladium-catalyzed cascade reaction

Acylzirconocene chloride complex as an acyl group donor reacts with ω-carbonyl α,β-enones or with bis-enones to give carbocyclic compounds under 10 mol% Pd(OAc)₂-catalyzed conditions, and each reaction was accelerated by the addition of a stoichiometric amount of Me₂Zn. The formation of the carbocycles from ω-carbonyl α,β-enones was considered to be a result of a series of reactions; (i) the formation of Pd(II)-intermediate by an electron transfer from the Pd(0)-catalyst to an α,β-enone function in an initial step, (ii) an acyl group transfer from the acylzirconocene complex to the Pd(II)-intermediate (transmetalation), (iii) the reductive elimination of Pd(0)-metal, and (iv) an intramolecular addition of metal enolate to ω-carbonyl group. On the other hand, the reaction of bis-enones with acylzirconocene chloride under the identical condition afforded reductive cyclization product, bicyclo[3.3.0] octane derivatives, in which acyl group from acylzirconocene complex was not incorporated.     

Rh(I)-catalyzed addition of alkenylzirconocene chlorides to aldimine derivatives

[RhCl(COD)]₂ (2 mol%) catalyzed reactions of alkenylzirconocene chloride complexes to N-Ts, -PO(OEt)₂ and COOR aldimine derivatives were efficiently carried out in dioxane at room temperature to give allylic amine derivatives in excellent yields. This is the first example of the catalytic addition reactions of alkenylzirconocene chloride complexes to aldimine derivatives.     

Catalytic addition of alkenylzirconocene chloride to 3,4-dihydroisoquinoline and its enantioselective reaction

The addition of alkenylzirconocene chloride to 3,4-dihydroisoquinoline in the presence of a stoichiometric amount of acylating agent such as (Boc)₂O or ClCOOC₂H₅ was carried out in the presence of a catalytic amount of Cu(I) (10 mol %) to give an alkenylation-carbamation product. The enantioselective addition (56-75%ee) of the alkenylzirconocene chloride was also achieved under Cu(I)/chiral amine (10 mol %) conditions.     

Asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680

The asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680 are reported. Conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to the requisite (E)-α,β-unsaturated ester followed by in situ enolate oxidation with (?)-(camphorsulfonyl)oxaziridne (CSO) gave the corresponding anti-α-hydroxy-β-amino esters. Sequential Swern oxidation followed by diastereoselective reduction gave the corresponding syn-α-hydroxy-β-amino esters. Subsequent N-debenzylation (i.e., hydrogenolysis for microginin 612, and NaBrO₃-mediated oxidative N-debenzylation for microginins 646 and 680) followed by acid catalysed ester hydrolysis gave the corresponding syn-α-hydroxy-β-amino acids, the N-terminal components of microginins 612, 646 and 680, in good yield. An analogous strategy for elaboration of the enantiopure anti-α-hydroxy-β-amino esters facilitated the asymmetric synthesis of the corresponding C(2)-epimeric α-hydroxy-β-amino acids.     

Stereoselective ring-opening reactions with AcBr and AcCl. A new method for preparation of some haloconduritols

The actions of AcX (X=Br, Cl) on 7-oxa-bicyclo[2.2.1]hept-5-ene-2,3-diol diacetates and a transoid-epoxide prepared from the acetonide of cyclohexa-3,5-diene-cis-1,2-diol were studied. H₂SO₄-catalyzed cleavage of exo-cis-7-oxa-bicyclo[2.2.1]hept-5-ene-2,3-diol diacetate with AcCl gave (1α,2α,3α,6β)-6-chloro-4-cyclohexene-1,2,3-triol triacetate, from which the corresponding chloroconduritol was obtained by trans-esterification (MeOH/HCl). A similar reaction of the exo-diacetate with AcBr in the presence of H₂SO₄ resulted in bromine addition. The formation of bromine from the reaction of AcBr and H₂SO₄ was observed by independent experiments. H₂SO₄-catalyzed reaction of endo-cis-7-oxa-bicyclo[2.2.1]hept-5-ene-2,3-diol diacetate with AcX (X=Br, Cl) gave (1α,2α,3β,6β)-6-halo-4-cyclohexene-1,2,3-triol triacetates. The reaction of the transoid-epoxide with AcX (X=Br, Cl) with no catalyst gave also (1α,2α,3β,6β)-6-halo-4-cyclohexene-1,2,3-triol triacetates.     

Synthesis and properties of block poly(styrene amides) and poly(styrene esters)

Three series of block copolymers, namely, polystyrenecaproamide (I), polystyrenehexamethyleneadipamide (II), and poly(styreneethylene terephthalate) (III), were prepared, and the properties of the copolymers in relation to the block sequence lengths and the compositions were studied. Styrene was polymerized in the presence of aluminum chloride and thionyl chloride to give ω,ω′-dichloropolystyrenes of various degrees of polymerization from 12.0 to 51.0, which were either ammonolyzed to ω,ω′-diaminopolystyrene or hydrolyzed to ω,ω′-dihydroxypolystyrene. ω,ω′-Diaminopolystyre was treated with adipic acid to give the corresponding salts, namely, ω,ω′-diammoniumpolystyrene adipate, which was melt-polymerized either with ε-amino-n-caproic acid to give polystyrenecaproamide (I) or with hexamethylenediammonium adipate to give polystyrenehexamethyleneadipamide (II). ω,ω′-Dihydroxypolystyrene was melt-polymerized with dimethyl terephthalate and ethylene glycol to give poly(styreneethylene terephthalate) (III). All the block copolymers were of high enough molecular weight to be cast or spun into films or filaments. Upon polymerization, the increase of the block sequence of PSt units increased the amide content but decreased the ester content of the resulting copolymers. Also, an increase in n decreased the inherent viscosities of the copolymers at a constant monomer feed f_c counted by the polymer equivalent of PSt but increased the inherent viscosities at a constant monomer feed r_c counted by the monomer equivalent of PSt. The melting points of the copolymers decreased with increasing n values. Also, an increase in n decreased the densities of I and III but increased the density of II at a constant amide or ester composition F_c counted by polymer units but increased the densities of I, II, and III at a constant amide or ester composition R_c counted by the monomer unit.     

非那雄胺合成工艺改进

非那雄胺能抑制5α-还原酶的活性,明显降低二氢睾酮水平,是一种治疗良性前列腺增生的有效药品。该合成工艺以甾烯酮酸为原料,将其与氯化亚砜反应,无须分离即与叔丁胺反应得17β-酰胺化合物,再氧化开环,环合,氢化,脱氢合成了非那雄胺。经元素分析、IR、1HNMR、13CNMR、MS分析表征了其结构。该法无须使用昂贵的2,2-二吡啶二硫化物和剧毒药品苯亚硒酸酐,且以乙酸铵代替氨气,降低了对设备的要求和腐蚀,更适用于工业生产。     

syn-Selective dihydroxylation of γ-amino-α,β-unsaturated (Z)-esters from d-serine: stereoselective synthesis of d-iminolyxitol

An efficient and stereoselective synthesis of d-iminolyxitol, a potent α-galactosidase inhibitor, is achieved in 11 steps over 45% overall yield from N-Boc-O-Bn-d-serine. The key step involves the OsO₄-catalyzed syn-selective dihydroxylation reaction of the acyclic γ-amino-α,β-unsaturated (Z)-ester controlled by an N-diphenylmethylene group.     

Diastereoselective synthesis of functionalized tetrahydro-γ-carbolines via a [3 + 3] cycloaddition of 2,2′-diester aziridines with β-(indol-2-yl)-α,β-unsaturated ketones

A Sc(OTf)₃-catalyzed [3 + 3] cycloaddition of 2,2′-diester aziridines with β-(indol-2-yl)-α,β-unsaturated ketones was developed, affording polysubstituted tetrahydro-γ-carbolines in single diastereoisomers in good to excellent yields.     

Oxetane from A-nor-steroides: 2-alpha, 5-oxido-A-nor-5-alpha-cholestane, 2-beta, 5-oxido-A-nor-5-beta-cholestane and 2-alpha-ethyl-2-beta,2'-oxido-A-nor-5-alpha-cholestane

Treatment of 2β-tosyloxy-A-nor-5α-cholestane-5-ol ( 2 ) with t-butoxide in t-butanol gave 2α, 5-epoxy-A-nor-5α-cholestane ( 3 ) in quantitative yield. When A-nor-5β-cholestane-2α, 5-diol ( 4 ) was treated with tosyl chloride in pyridine 2β-chloro-A-nor-5β-cholestane-5-ol ( 7 ) and 2α-tosyloxy-A-nor-5β-cholestane-5-ol ( 8 ) were obtained. Whereas the chloride 7 was resistant to t-butoxide the tosylate 8 was transformed into an 1 : 1 mixture of 2α, 5-epoxy-5β-cholestane ( 10 ) and 2ξ-t-butoxy-A-nor-5β-cholestane-5-ol ( 11 ). In 2α-tosyloxy-A-nor-5α-cholestane-5-ol ( 12 ) substitution occurred as the only reaction. Both oxetanes 3 and 10 isomerize after heating above 50° and in polar or protic solvents to form A-nor-Δ³⁽⁵⁾-cholestene-2α-ol ( 6 ) and -2β-ol ( 14 ) respectively. Also, 2, 5-diols are encountered. 2α-Ethyl-2β, 2′-epoxy-A-nor-5α-cholestane ( 23 ) was synthesized starting from A-nor-5α-cholestane-2-one ( 17 ). The intermediates were the ester 16 , the diol 18 , the hydroxy-tosylate 19 and the chlorhydrin 20 . The spirocyclic oxetane 23 was reduced by LiAlH₄ in dioxane (not in ether). By chromatography on silica gel 23 was isomerized to the homoallylic alcohol 21 and transformed into 2-methylene-A-nor-5α-cholestane ( 24 ) by fragmentation. The IR. and NMR. spectra of the new oxetanes were compared with those of a series of known oxetanes.     

Stereospecific approach to α,β-disubstituted nitroalkenes via coupling of α-bromonitroalkenes with boronic acids and terminal acetylenes

(Z)-α-Bromo-β-substituted nitroethylenes undergo facile Suzuki coupling with aryl, heteroaryl, and vinylboronic acids in the presence of Pd(PPh₃)₄ as catalyst to afford (E)-α,β-disubstituted nitroethylenes in high yield (up to 95%) and complete specificity. Similar coupling of α-bromonitroethylenes with terminal acetylenes (Sonogashira coupling) provides a novel route to (E)-nitroenynes. These Pd-catalyzed coupling methods offer a convenient and stereospecific entry into a diverse array of synthetically and biologically useful α,β-disubstituted nitroethylenes.     

SiCl4-catalyzed/PR3-mediated β-C(sp3)−H functionalization of nitrones to α,β-unsaturated imines and aromatic heterocycles

A novel method of SiCl₄-catalyzed/PR₃-mediated β-C(sp³)?H functionalization of nitrones with aldehydes/ketones to α,β-unsaturated imines was developed. The synthesis of α,β-unsaturated imines mainly invovles deoxygenation and aldol condensation, each proceeding under a cooperation effect between Lewis acid and Lewis base. In addition, both the acidity and hydrolytic stability of the weak SiCl₄ were supposed to be enhanced by coordination with phosphine oxide (R?=?Et) or phosphoric triamide (R?=?NMe₂) that originated from deoxygenation of nitrones by PR₃. In the case of 6-membered nitrone, a [1,3]-hydride shift within the resulted α,β-unsaturated imines renders the aromatization leading to 3,5-dialkylpyridines.     

Synthesis and transformations of metallacycles 42. Cp2ZrCl2-Catalyzed cycloalumination of 3-methylidenespiro[cyclobutane-1,3′-(5′α)-cholestane] with Et3Al

A Cp₂ZrCl₂-catalyzed cycloalumination of 3-methylidenespiro[cyclobutane-1,3′-(5′α)-cholestane] with Et₃Al gives 3-ethyl-3-aluminadispiro[cyclopentane-1,1′-cyclobutane-3′,3″-(5″α)-cholestane] in 84% yield.     

Spirocyclic Amide Acetal Synthesis by [CpRu]-Catalyzed Condensations of α-Diazo-β-Ketoesters with γ-Lactams

The synthesis of spirocyclic amide acetals (33–93 %) has been achieved through Ru(II)-catalyzed condensations of N-carbamate protected pyrrolidinones with metal carbenes derived from α-diazo-β-ketoesters. Thanks to the mildness of the diazo decomposition conditions induced by a 1 : 1 combination of [CpRu(MeCN)₃][BAr_F] and 1,10-phenanthroline, the formation of the sensitive products is possible. Full characterization of this carbonyl-ylide mediated process is provided by DFT calculations.     

钯催化反应中的β-氢消除反应

总结了作者小组发展的Pd(II)催化的反应, 在卤离子或含氮配体(吡啶、联吡啶、菲咯啉等)存在下淬灭碳—钯键以再生二价钯物种. 卤离子和含氮配体是完成反应的催化循环和高得率所必需的, 它们的主要作用是抑制β-氢消除反应. 对于Pd(0)催化的反应, 控制β-氢消除也是使偶联反应多样化的一个关键, 已发现有许多配体适用于脂肪族化合物的偶联反应. 最近, 又报道了应用卤离子和菲咯啉衍生物为配体应用于这一目的.     

Synthesis of substituted β-carbolines via gold(III)-catalyzed cycloisomerization of N-propargylamides

Indole-substituted N-propargylamides undergo a gold(III)-catalyzed cyclization to give oxazoles or β-carbolinones, depending on the substitution pattern at the amide nitrogen. Secondary amides furnished oxazoles via a 5-exo-dig cyclization, while tertiary indole-2-carboxamides cycloisomerized to give 2,9-dihydro-β-carbolin-1-ones upon treatment with catalytic amounts of gold(III) chloride. An optimized procedure was developed to prepare several new N-benzyl-β-carbolinones as well as the corresponding β-carbolines, which are of interest as core structures found in various natural products such as the harman, ervolanine, and lavendamycin class of alkaloids.     

Construction of α-phosphonolactams via rhodium (II)-catalyzed intramolecular C?H insertion reactions

The Rh(II)-catalyzed intramolecular C H insertion reactions of N,N-dialkyl-α-diazo-α-(diethylphosphono)acetamides 2a , f–j in CHCl₃ or ClCH₂CH₂Cl were found to give monocyclic and bicyclic α-phosphono-β-lactams, 3a and 3f–j , in 43–67% yields via regiospecific α-C H insertion of the N-alkyl groups. Similar treatment of N-benzyl-N-isopropyl-α-diazo-α-(diethylphosphono)acetamide ( 2b ) and the corresponding N-isobutyl-N-methylacetamide 2d in ClCH₂CH₂Cl afforded mixtures of β-lactams 3b (35%) and and 3b ′ (16%), β-lactam 3d (47%), and γ-lactam 4d (10%), respectively, each of which is formed by the competitive C H insertion reaction between benzylic and isopropyl α-C H bonds and between methyl α-C H and methine β-C H bonds, respectively. For the formation of β-lactams, the selectivity in the rhodium-mediated C H insertion in ClCH₂CH₂Cl follows the order methyl > methine > benzylic α-C H bond on N-substituents. The N,N-dibutyl-α-diazo homologue 2c and Nα[α-diazo-α-(diethylphosphono)acetyl]-2-methylindoline ( 2k ) exclusively produced γ-lactams 4c (67%) and 4k (81%) via insertion into the methylene β-C H and methyl β-C H bonds. tert-Butyl N-[α-diazo-α-(dibenzylphosphono)acetyl]-piperidine-2-carboxylate ( 2m ) on similar treatment, followed by deprotection of the benzyl ester afforded the 7-phosphono carbacepham 6 in 32% overall yield. Similar Rh(II)-catalyzed cyclization of N-methyl-N[4-benzyloxy-α-(diethylphosphono)-phenyl(diethyl-phosphono)methyl]-α-diazo-acetamide ( 2n ) led to 1-[4′-benzylphenyl(diethylphosphono)methyl] -3-(diethyl-phosphono)azetidin-2-one ( 3n ) in 78% yicld. The phosphono group at C-7 of 3f was converted into the acetylamino group via a four-step reaction. Application of chiral rhodium(II) carboxylates 12a–c to the insertion reactions of 2b , c produced α-phosphono-β-and γ-lactams, 3b and 4c , in 6–24% ee and 25–29% ee, respectively.