High Diastereocontrol Research Articles

Rearrangement of Spirocyclic Oxindoles with Lithium Amide Bases

Spirocyclohexa-2,5-dienes were shown to rearrange at -40 degrees C, when treated with 1 equiv of LDA. Alkyl halides and aldehydes then reacted with the resulting phenanthridinone lithium enolate intermediates, with distinct regioselectivities and high diastereocontrol, to afford functionalized dearomatized phenanthridinones which were elaborated further. A mechanistic scheme involving a diisopropylamine-mediated proton transfer was proposed to rationalize the rearrangement.

Toward the total synthesis of ritterazine N

AbstractZr-mediated equilibrating cyclocarbonylation of a designed triene led with high diastereocontrol to the ABC 6-6-5 tricyclic core of ritterazine N. The 5-5 EF spiroketal side chain of ritterazine N was prepared by equilibrating cyclization of an acyclic keto diol. The two components were coupled, and the D ring was assembled by intramolecular aldol condensation.

Preparation of the 5/5-Spiroketal of the Ritterazines

The enantiomerically pure 5/5-spiroketal required for the synthesis of the ritterazines has been prepared with high diastereocontrol by ring closure followed by equilibration.

Diastereocontrolled Synthesis of Enantioenriched 3,4-Disubstituted β-Prolines

Enantioenriched 3,4-disubstituted beta-prolines have been prepared with a high diastereocontrol through a carbometalation reaction or through a domino Michael addition/carbometalation reaction.

Chiral Ytterbium Complex‐Catalyzed Direct Asymmetric Aldol‐Tishchenko Reaction: Synthesis of anti‐1,3‐Diols

The asymmetric aldol-Tishchenko reaction of aromatic aldehydes with aliphatic and aromatic ketones has been developed as an efficient strategy for the synthesis of anti-1,3-diols in good yield with high diastereocontrol and good levels of enantioselectivity. This domino-type reaction is catalyzed by a chiral ytterbium complex that promotes both the aldol reaction through enolization of the carbonyl compound and the Evans-Tishchenko reduction of the aldol intermediate. The stereochemistry of the resulting diols is also investigated and finally proved by using CD techniques.

Mn-Mediated Coupling of Alkyl Iodides and Chiral N-Acylhydrazones: Optimization, Scope, and Evidence for a Radical Mechanism

Stereoselective radical additions have excellent potential as mild, nonbasic carbon-carbon bond constructions for direct asymmetric amine synthesis. Efficient intermolecular radical addition to C=N bonds with acyclic stereocontrol has previously been limited mainly to secondary and tertiary radicals, a serious limitation from the perspective of synthetic applications. Here, we provide full details of the use of photolysis with manganese carbonyl to mediate stereoselective intermolecular radical addition to N-acylhydrazones. Photolysis (300 nm) of alkyl halides and hydrazones in the presence of Mn2(CO)10 and InCl(3) as a Lewis acid led to reductive radical addition; diastereomer ratios ranged from 93:7 to 98:2 at ca. 35 degrees C. The reaction tolerates additional functionality in either reactant, enabling subsequent transformations as shown in an efficient asymmetric synthesis of coniine. A series of hydrazones bearing different substituents on the oxazolidinone auxiliary were compared; consistently high diastereocontrol revealed that the identity of the substituent had little practical effect on the diastereoselectivity. Further mechanistic control experiments confirmed the intermediacy of radicals and showed that independently prepared alkyl- or acylmanganese pentacarbonyl compounds do not undergo efficient addition to the N-acylhydrazones under thermal or photolytic (300 nm) conditions. These Mn-mediated conditions avoid toxic tin reagents and enable stereoselective intermolecular radical additions to C=N bonds with the broadest range of alkyl halides yet reported, including previously ineffective primary alkyl halides.

Zn(pybox)‐Complex‐Catalyzed Asymmetric Aqueous Mukaiyama‐Aldol Reactions.

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Computationally guided organometallic chemistry: preparation of the heptacyclic pyrazine core of ritterazine N.

Diels-Alder cycloaddition of 10 followed by Wittig homologation and intramolecular diene cyclozirconation of the resulting triene under equilibrating conditions led to the tricyclic 6-6-5 ketone 5 with high diastereocontrol. The derived alpha-azido ketone 16 cyclized efficiently to the heptacyclic pyrazine core of ritterazine N.

Zn(pybox)-Complex-Catalyzed Asymmetric Aqueous Mukaiyama-Aldol Reactions

Catalytic asymmetric aldol reactions in aqueous media have been developed using chiral zinc complex. The aldol products have been obtained in high yields, high diastereocontrol, and good level of enantioselectivity. Various aromatic and alpha,beta-unsaturated aldehydes and silyl enol ethers derived from ketones can be employed in this reaction to provide the aldol adducts in good to high yield. The elaborated catalytic system has been found as selective for aliphatic aldehydes as well.

Regio‐ and stereoselectivity in the Paternò‐Büchi reaction on furan derivatives

The photochemical coupling reaction between 2,3‐dihydrofuran and benzaldehyde was studied by using DFT/B3LYP/6 − 31G + (d, p) method. The regiocontrol of the attack of the benzaldehyde on the double bond is related to the different stabilities of the biradical intermediates. The endo stereoselectivity of the reaction depends on the superposition between HSOMO and LSOMO in the biradical intermediate. In the photochemical reaction between furan and benzaldehyde also the regiocontrol depends on the relative stability of the possible biradical intermediates. The exo stereoselectivity of the coupling reaction depends on the superposition between the HSOMO and LSOMO of the biradical intermediate. The reaction of chiral phenylglyoxylates with furan gave the corresponding adducts with de = 15–95%. The stereocontrol can be explained considering the energy gap between the biradical intermediates in the coupling reaction. When the reaction was performed in the presence of zeolite, the diastereoisomeric excess increased. The reaction of benzoin and 2‐phenylpropiophenone with furan gave the cycloadduct with high diastereocontrol. All the products were obtained with de > 98%. The Paterrnò‐Büchi reaction between 2‐furylmethanols with aromatic carbonyl compounds also showed high regio‐ and stereocontrol. On the contrary, when 5‐methyl derivatives were used, a lack of regiocontrol was observed. Furthermore, with aliphatic carbonyl compounds, no diastereoselectivity was observed. These results were explained assuming the attack of the excited carbonyl compound on the same side as the hydroxyl group, through the formation of a hydrogen bond or of a complex. This type of attack gave the biradical intermediate in preferential conformations. The relative energies of these conformers account for the observed diastereoselectivity.

New Enantioselective Entry to Cycloheptane Amino Acid Polyols

[reaction: see text] A diversity-oriented protocol has been developed for the assembly of densely hydroxylated cycloheptane amino acids via succession of a vinylogous Mukaiyama aldol reaction (VMAR), a Morita-Baylis-Hillman reaction (MBHR), and an intramolecular pinacol coupling reaction (IPCR). The plan utilizes D- or L-configured glyceraldehyde derivatives as "chiral" surrogates of glyoxal and N-[(tert-butoxycarbonyl)-2-(tert-butyldimethylsilyl)oxy]pyrrole as the synthetic equivalent of the alpha,gamma-dianion of gamma-aminobutanoic acid. The parallel, asymmetric syntheses of four cycloheptane representatives proceed with high diastereocontrol and virtually complete enantioselectivity in ten steps and overall yields of 15-37%.

A stereoselective remote homochiral boronate ester-mediated aldol reaction

As part of a program aimed at exploring the utility of remote asymmetric centres to control the addition of nucleophiles to carbonyl functions, it was discovered that homochiral ester derivatives of β-boronate carbonyl compounds do not control the addition of alkyllithium, Grignard or cuprate-based nucleophiles. However, use of a lithium ester enolate nucleophile exhibits medium to high remote diastereocontrol in aldol additions to carbonyl functions.

Catalytic Addition Methods for the Synthesis of Functionalized Diazoacetoacetates and Application to the Construction of Highly Substituted Cyclobutanones

[reaction: see text] Methyl 3-(trialkylsilanyloxy)-2-diazo-3-butenoate undergoes Lewis acid-catalyzed Mukaiyama aldol addition with aromatic and aliphatic aldehydes in the presence of low catalytic amounts of Lewis acids in nearly quantitative yields. Scandium(III) triflate is the preferred catalyst and, notably, addition proceeds without decomposition of the diazo moiety. Diazoacetoacetate products from reactions with aromatic aldehydes undergo rhodium(II)-catalyzed ring closure to cyclobutanones with high diastereocontrol. Examples of complimentary Mannich-type addition reactions with imines are reported.

A Model Study toward the Total Synthesis of N-Deacetyllappaconitine

[reaction: see text] A model study leading to the preparation of the AEF rings of N-deacetyllappaconitine is described. The conjugate addition to the alpha-alkyl cyclohexenone 10 proceeded with high diastereocontrol. The Mannich cyclization of 16 to 4 was accomplished by heating with Rexyn-300 and Na(2)SO(4).

Direct asymmetric aldol-Tishchenko reaction of aliphatic ketones catalyzed by syn-aminoalcohol–Yb(iii) complexes

The asymmetric direct aldol condensation of aldehydes with ethyl- and propylketones is catalyzed by syn-alpha-aminoalcohol-Yb(OTf)3 complexes, yielding the anti-1,3-diol monoesters with high diastereocontrol and good enantioselectivity. Three adjacent stereogenic centers are created in a simultaneous aldol condensation and Evans-Tishchenko reduction in an acyclic system.

The First Example of a Catalytic Asymmetric Aldol‐Tishchenko Reaction of Aldehydes and Aliphatic Ketones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The first example of a catalytic asymmetric aldol-Tishchenko reaction of aldehydes and aliphatic ketones

A number of combinations of Lewis acids and chiral ligands has been screened for the enantioselective direct tandem aldol condensation––Evans–Tishchenko reduction of aldehydes and ketones. Chiral ytterbium complexes were found to catalyze the condensation of aromatic aldehydes with 3-pentanone (and other ketones) giving rise to the anti-1,3-diol monoesters in good yield, and with high diastereocontrol and moderate levels of enantioselectivity. Three adjacent stereogenic centers are created in one reaction sequence in acyclic systems.

Diastereoselective rhodium(II)-catalyzed sulfonium ylide formation-[2,3]-sigmatropic rearrangement reaction of chiral non-racemic allylic sulfides

The tandem sulfonium ylide formation-[2,3]-sigmatropic rearrangement reaction of chiral non-racemic secondary allylic sulfides, ( E)- 9 and ( Z)- 10, is found to proceed with high diastereocontrol. The C-5 stereocenter bearing the sulfide group is essential for high diastereoselectivity in the reaction. Transition state conformers are proposed to explain the high diastereoselectivity in the formation of the diastereomeric products, 18a and 18b. The method is applied to the synthesis of ( R)-4-(4-chlorophenyl)-2-butyrolactone. Modest enantioselectivity (63% ee) was achieved and this is attributed to partial racemization during the formation of the secondary allylic sulfide 22.

The use of the aza-Diels–Alder reaction in the synthesis of pinidine and other piperidine alkaloids

The imine Ph 2CHNCHCO 2Et, generated from benzhydrylamine and ethyl glyoxylate, provides a Diels–Alder adduct with 1,3-pentadiene from which a range of cis-2,6-disubstituted piperidines can be accessed; the benzhydryl group confers high diastereocontrol for derivatising the six-membered ring, allowing access to 2,5,6-trisubstituted piperidines, and to 2,6-disubstituted piperidines such as pinidine.

Enantioselective construction of cyclic quaternary centers: (-)-mesembrine.

The preparation of the crystalline amide 2 is reported. Conjugate addition to 2 proceeded with the expected high diastereocontrol to give 3. This set the stage for subsequent intramolecular alkylidene C-H insertion to give, after ozonolysis and aldol condensation, (-)-mesembrine 1. Amide 2 should be a useful chiron for the enantioselective construction of cyclic quaternary centers.