Asymmetric synthesis of chiral synthons bearing alkynyl group via organoaluminum-promoted pinacol-type rearrangement

A method is described for the synthesis of chiral alkynyl ketones and alkynols via trimethylaluminum-promoted pinacol-type rearrangement where alkynyl groups behave as “the staying group”, followed by stereoselective reduction leading to the latter.     

Asymmetric synthesis of axially chiral benzamides and anilides by enantiotopic lithiation of prochiral arene chromium complexes

Axially chiral benzamides and anilides were prepared by enantiotopic lithiation at the distinguished benzylic methyl of prochiral tricarbonylchromium complexes of N,N-diethyl 2,6-dimethylbenzamide (1) and N-methyl-N-acyl 2,6-dimethylaniline (14 and 21) with a chiral lithium amide base followed by electrophilic substitution in good yields with high optical purity. The resulting axially chiral chromium-complexed benzamides and anilides were oxidized under air to give chromium-free axially chiral benzamides and anilides in an enantiomerically active form without axial bond rotation at room temperature.     

Access to dienophilic ene-triketone synthons by oxidation of diketones with an oxoammonium salt

Here we describe the oxidation of 1,3-cyclohexanediones with 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (Bobbitt's salt) to generate 5-ene-1,2,4-triones in moderate-to-good (40-80%) yields. This inexpensive oxidant facilitated an unprecedented cascade of oxidation and elimination to yield novel ene-triketones. The reactivity of these products was explored in the Diels-Alder reaction and provided moderate-to-good yields of cycloaddition products. The products described in this study represent unique, densely functionalized, and versatile building blocks for the synthesis of more complex molecules.     

Zirconium-catalyzed enantiotopic group-selective synthesis of hydrindanes

When a THF solution of 12b and (S)-(EBTHI)ZrBINOL (10 mol%) was refluxed in the presence of BuMgCl (4 equiv.) for 4 h, zirconium-catalyzed enantiotopic group-selective cyclization proceeded and hydrindane 13b with 87% ee was obtained in 35% yield.     

Asymmetric synthesis of a selective endothelin A receptor antagonist

An asymmetric synthesis of a selective endothelin A receptor antagonist 1b is described. Asymmetric conjugate addition of aryllithium derived from 18 to the chiral oxazoline 17 followed by hydrolysis afforded 15 in 96% ee via purification as (S)-(-)-1-phenylethylamine salt. Pd(OAc)(2)/dppf (1,1'-bis(diphenylphosphino)ferrocene) catalyzed carbonylation followed by chemoselective addition of aryllithium derived from 23 which gave ketone 24. Diastereoselective reduction of the ketone with catecholborane followed by concomitant activation of the resulting alcohol and cyclization gave the late intermediate 26. Introduction of amino moiety on the pyridine ring by imidoyl rearrangement followed by deprotection and purification by crystallization furnished the enantiomerically pure target molecule 1b in 8% overall yield from 16.     

Asymmetric synthesis of ethoxydienamines in superbasic medium mediated by chiral sulfinyl group

The direct addition of metalated alkoxydiene 2, obtained from α,β-unsaturated acetal 1 through a LIC-KOR-promoted conjugated elimination reaction, to enantiopure sulfinimines 3 (both R and SN-sulfinyl imines) afforded N-sulfinyl alkoxydienyl amines 4 with high diastereoselectivity. Functionalized enantiopure alkoxydienyl amines 5 were then easily obtained upon the selective removal of the chiral auxiliary under mild conditions. Moreover, the further hydrolysis of the alkoxydienyl moiety gave access to protected enantiopure β-keto amines 7.     

Asymmetric synthesis of cyclic β-hydroxyallylsilanes via sequential allyltitanation-ring closing metathesis

Highly enantioenriched cyclic β-hydroxyallylsilanes have been prepared via enantioselective allylation of unsaturated aldehydes using a chiral allyltitanium reagent, followed by a ring-closing metathesis. Functionalized rings of various sizes have been synthesized and the electronic effect of the silicon group in the RCM reaction has been studied. The resulting cyclic β-hydroxyallylsilanes reacted stereoselectively with a variety of electrophilic reagents. A first application of this method to the synthesis of a highly functionalized dihydropyrane is reported.     

Asymmetric synthesis of N-protected amino acids by the addition of organolithium carboxyl synthons to ROPHy/SOPHy-derived aldoximes and ketoximes

A new asymmetric synthesis of alpha-amino acids is described in which the key step is the highly diastereoselective addition of organolithium carboxyl synthons (2-furyllithium, phenyllithium, vinyllithium) to (R)- and (S)-O-(1-phenylbutyl) oximes to give hydroxylamines, with vinyllithium being the most satisfactory nucleophilic reagent. Subsequent reductive cleavage of the N-O bond in hydroxylamines, followed by N-protection, and oxidative cleavage of the carboxyl precursor gave a range of N-protected amino acids and esters. The method was exemplified by the synthesis of a range of derivatives of non-proteinogenic amino acids such as 4-bromophenylalanine, tert-leucine, norvaline, cyclohexyl- and aryl-glycines, 2-amino-8-oxodecanoic acid (Aoda) and alpha-methylvaline.     

Asymmetric synthesis of benzylic quaternary difunctionalized carbons mediated by a remote sulfinyl group

Enantiomerically enriched α-aryl α-cyanoacetates and α-aryl α-acylacetonitriles bearing a benzylic quaternary stereocenter have been readily synthesized by stereoselective reaction of 2-alkyl-2-[2-(p-tolylsulfinyl)phenyl]acetonitriles with different acylating and alkoxycarbonylating reagents under basic conditions. The stereoselectivity of the reactions proved closely dependent on the nature of the intermediate carbanionic species, the evolution of which was effectively controlled by a sulfinyl group as a remote chiral auxiliary.     

Dilithiated synthons: synthesis of cyclic ethers

Recent advances in the generation of dilithiated synthons by arene-catalyzed lithiation of the corresponding dichloro compounds in the presence of carbonyl compounds (Barbier-type reaction conditions) as the key step are described. Further cyclization of the generated diols under different reaction conditions affords a variety of mono-, bi-, and spirocyclic ethers.     

Asymmetric synthesis of beta-lactams using chiral-memory effect on photochemical gamma-hydrogen abstraction by thiocarbonyl group

Optically active beta-lactams were synthesized via photochemical intramolecular gamma-hydrogen abstraction reaction of thioimides involving a highly-controlled chiral-memory effect.     

Total synthesis of the ionophore antibiotic ionomycin. Asymmetric synthesis of the C1-C10 and C11-C16 synthons

Asymmetric synthesis of the synthons 1 and 3 are described. Absolute stereochemical relationships in these intermediates have been established via chiral enolate and directed hydrogenation processes.     

Syn-anti isomerization of aldols by enolization

A variety of aldol adducts are shown to undergo efficient syn-anti isomerization in the presence of imidazole by an enolization mechanism. Isomerizations are high yielding and occur with little or none of the usual byproducts arising from competing elimination or retroaldol reactions. Most substrates reach equilibrium within 0.3-3 days at ambient temperature in chloroform, benzene, or dichloromethane containing 0.3-1 M imidazole. The process is particularly facile for aldols derived from tetrahydro-4H-thiopyran-4-one with rate constants for equilibration varying over ca. 1 order of magnitude for the adducts studied; structurally related aldols derived from cyclohexanone isomerized ca. 3-4 times slower. Isomerization of the acyclic aldol 5-hydroxy-4-methyl-5-phenyl-3-pentanone required heating to 60 degrees C but was achieved with minimal (<5%) retroaldol or elimination. A methoxymethyl ether derivative isomerized 30-40 times slower than the parent aldol. Isomerization of alpha,alpha'-disubstituted aldols and alpha,alpha'-bisaldols indicated low regioselectivity in the enolization. The synthetic utility of the process was demonstrated with the effective preparation of aldol stereoisomers unobtainable by direct methods.     

The synthesis of some cyclic diketones isolated from coffee

The syntheses of several alkylated derivatives of cyclopentane-1,2-dione(cyclopent-2-en-2-ol-1-one), four of which have been previously identified in roasted coffee², are described.     

Regioselective synthesis of trifluoromethyl group containing allylic amines by palladium-catalyzed allylic amination and sequential isomerization

The palladium-catalyzed regioselective allylic amination of the α-trifluoromethyl group-substituted allyl acetate has been accomplished using Pd(OAc)₂/DPPE and [Pd(π-allyl)(cod)]BF₄/DPPF as catalysts. The selective formation of the γ-product was attained in the presence of Pd(OAc)₂/DPPE, while the α-product was obtained using [Pd(π-allyl)(cod)]BF₄/DPPF. We also succeeded in the regioselective synthesis of the enantiomerically enriched aminated product from chiral allyl acetate using Pd(OAc)₂/DPPE and [Pd(π-allyl)(cod)]BF₄/(S)-BINAP. Furthermore, we found that kinetic resolution had occurred during the isomerization step from the γ-type product to the α-type product by the [Pd(π-allyl)(cod)]BF₄/(S)-BINAP catalyst.     

Asymmetric synthesis of diarylmethylamines: preparation of selective opioid delta receptor ligands

Two different methods were used for the construction of optically active diarylmethylamines. Diastereoselective alkylation on an aldimine/oxazolidine 2a/2b derived from (R)/(S)-phenylglycinol or enantioselective reduction of 4-[η⁶-chromium tricarbonylbenzoyl] bromobenzene using chiral oxazoborolidine followed by amine introduction to furnish optically active diarylmethylamines.     

Asymmetric ring opening of meso epoxides with TMSCN catalyzed by (pybox)lanthanide complexes

The asymmetric ring opening of meso epoxides with TMSCN is catalyzed by (pybox)YbCl3 complexes, yielding the beta-trimethylsilyloxy nitrile ring-opened products with good enantioselectivities (83-92% ee). The reaction exhibits a second-order kinetic dependence on catalyst concentration and a first-order dependence on epoxide concentration, consistent with a bimetallic pathway involving simultaneous activation of epoxide and cyanide.     

Asymmetric synthesis by vapor phase pyrolysis

The first vapor phase asymmetric synthesis was successfully carried out by FVP of a 2,4-pentanediol (PD)-tethered substrate carrying cyclohexene and diazo ester moieties at high temperature up to 400°C. The intramolecular [2+2] cycloaddition of the ketene was strictly stereocontrolled by the entropy term.