Stereoselective Synthesis of Tetrahydropyran D-Ring of Methyl Sartortuoate

A stereoselective synthesis of functionalized tetrahydropyran D‐ring of methyl sartortuoate ( 1 ) was achieved starting from geraniol in a high yield. Sharpless asymmetric kinetic resolution, asymmetric dihydroxylation as well as asymmetric epoxidation were applied as key steps to establish all the four stereocenters of the D‐ring.     

Massive parallel catalyst screening: toward asymmetric MCRs

[reaction: see text]. Hundreds of Lewis acid/ligand combinations have been screened for stereochemical induction in the Passerini multicomponent reaction. The combination of titan tetraisopropylate and (4S,5S)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane was found to give enantiomeric excesses between 32% and 42% in several examples. The absolute stereo induction of one example was determined chemically and by means of X-ray crystallography. This comprises the first asymmetric Passerini reaction and the first example of a stereochemical induction in an isocyanide based multicomponent reaction by a chiral Lewis acid.     

Asymmetric thio-claisen rearrangement induced by an enantiopure alkylsulfinyl group. Unusual preference for a boat transition state in the acyclic series.

Ketene aminothioacetals 2a-c and 5a-b bearing an enantiopure vinylic alkylsulfinyl substituent were readily prepared from (R)-2-cyclohexylsulfinyl-N,N-dimethylethanethioamide 1 with full control of the geometry of their double bonds. They underwent a Claisen rearrangement upon heating at THF reflux to afford alpha-sulfinyl gamma-unsaturated thioamides 3a-c and 6a-b. With all substrates the asymmetric induction of the sulfinyl group was excellent. The determination of the absolute configurations of thioamides 3a-c and 6a-b was achieved either by X-ray crystallographic analysis or by chemical correlation. The stereochemical course of this [3,3] sigmatropic transposition was explained by an electronic model. Interestingly the Claisen rearrangement of the (ZE)-cinnamyl substrates 5b was shown to proceed through a boat transition state rather than a chair transition state; such a preference is quite unusual for acyclic systems.     

First asymmetric aminohydroxylation of acrylamides

The first examples of the asymmetric aminohydroxylation of acryl amides are reported. This was accomplished with chiral acrylamides as substrates, which undergo diastereoselective oxidative transformation within the so-called ‘second catalytic cycle’ with diastereomeric excesses reaching 100:0. The reaction relies solely on the stereochemical information provided by the enantiomerically pure starting materials. A stereochemical model for the observed asymmetric induction is provided.     

Combining spiro-fused cyclohexadienone – tetrahydrofuran ring system with glycine: Asymmetric synthesis of a new class of α-amino acid derivatives

Herein, we present the asymmetric synthesis of spiro-fused cyclohexadienone – tetrahydrofuran-embedded glycine derivatives as a new class of nonproteinogenic α-amino acid derivatives. Starting from commercially available 2-allylphenols, key β-hydroxy-α-amino esters were synthesized via high-yielding multi-step reaction sequences involving Sharpless asymmetric dihydroxylation as the chirality induction step. PhI(OAc)₂-mediated oxidative dearomatization – spirocyclization of phenol-tethered β-hydroxy-α-amino esters efficiently produced the corresponding spiro-fused cyclohexadienone – tetrahydrofuran-embedded glycine derivatives, providing a general route to this hitherto-unreported class of compounds that are equipped with three privileged scaffolds (cyclohexadienone – tetrahydrofuran – α-amino ester).     

(S)-Proline-derived new chiral ligands with phosphino,organosulfur or organoselenenyl functionality as an enantiocontrollable coordinating element

The synthesis of (S)-proline-derived chiral ligands bearing phosphino, organosulfur or selenenyl groups and their use as chiral ligands in palladium-catalyzed asymmetric allylic alkylations has been accomplished. In particular, the (S)-proline-derived phosphine ligands bearing alkylsulfenyl groups provided high enantioselectivity, and the degree of asymmetric induction was dependent upon the steric bulk of the alkyl substituents in sulfenyl groups. The stereochemical results are rationalized by a plausible mechanism involving the assistance of chelates formed by the participation of the two preferred heteroatoms involved.     

Congeners of Troeger's base as chiral ligands

(S)-(+)-Troeger's base can be deprotonated and alkylated without loss of stereochemical integrity. An examination of the ability of Troeger's base and several derivatives prepared in this fashion to effect asymmetric induction in the addition of diethylzinc to aromatic aldehydes was conducted. Enantiomeric excesses as high as 86% were achieved, providing evidence that Troeger's base represents a chiral framework which can be modified to produce ligands for catalytic asymmetric synthesis.     

Chiral sulfoxide ligands bearing nitrogen atoms as stereocontrollable coordinating elements in palladium-catalyzed asymmetric allylic alkylations

Palladium-catalyzed asymmetric allylic alkylations were studied by using chiral sulfoxide ligands bearing nitrogen atoms as coordinating elements, such as chiral α-sulfinylacetamides, β or γ-amino sulfoxides, and β-sulfinyl sulfonamides. The effects of the chiral sulfinyl functions on the asymmetric induction were demonstrated. Use of (S)-2-pyrrolidinophenyl p-tolyl sulfoxide or (S)-2-(N-butyl-N-methylaminomethyl)phenyl p-tolyl sulfoxide as chiral ligands in the palladium-catalyzed asymmetric allylic alkylations provided the highest enantioselectivity (50 or 58% e.e., respectively) among chiral sulfoxide ligands examined by us. The participation of the sulfinyl groups in these catalytic asymmetric reactions is rationalized, and the mechanism for the asymmetric induction is proposed on the basis of the stereochemical outcome obtained.     

Stereoselective Mannich Reactions in the Synthesis of Enantiopure Piperidine Alkaloids and Derivatives

Piperidine alkaloids are members of the alkaloid family that is characterized by the presence of a six-membered nitrogen-containing heterocycle. Piperidine alkaloids are found mainly in plants and often exhibit interesting biological and pharmacological activities. Despite the accumulation of these natural products in plants, relatively low quantities of alkaloids are produced in absolute terms and thus synthesis of alkaloids and derivatives thereof remains relevant to identify targets for drug discovery. Throughout the years, researchers have come up with a myriad of methods to synthesize piperidine derivatives. This review describes methods that employ stereoselective Mannich reactions to create the core of piperidine alkaloids. Asymmetric induction in the Mannich reaction has been achieved by a range of methods that have been divided into three conceptual approaches: (1) chiral pool-based (internal asymmetric induction), (2) chiral auxiliary-based (relayed asymmetric induction) and (3) asymmetric catalysis-based (external asymmetric induction). Of each approach, we describe the reaction mechanism and rationalize the stereochemical outcome of the Mannich products.     

On the Mechanism of Oxazoline-Directed Metalations: Evidence for Nitrogen-Directed Reactions

We recently described a method for the synthesis of ferrocene complexes possessing planar chirality which relies on the asymmetric deprotonation of chiral ferrocenyloxazolines. The unexpected stereochemical outcome of these reactions led us to examine whether the metalation is directed by the oxygen or the nitrogen of the oxazoline. In this paper, we describe the synthesis of a constrained ferrocenyloxazoline (compound 13) in which oxygen- and nitrogen-directed metalations provide different stereochemical outcomes. Our results show that nitrogen is responsible for the directive effects of the oxazoline when alkyllithium reagents are used to deprotonate the ferrocene. The implications of this result on the origin of asymmetric induction in the metalation of the unconstrained ferrocenyloxazolines 19 and 20 are discussed.     

Sulfur-containing optically active polymers. V. Synthesis and chiroptical properties of optically active poly(γ-ketosulfide)s prepared by polyaddition of 1,3-dimercaptobenzene to 4,4-dimethyl-2,5-cyclohexadien-1-one or to trans,trans-2,5-heptadien-3-one in the presence of chiral amines

Optically active poly(γ-ketosulfide)s having the asymmetric centers disposed along the main chain have been prepared by step polyaddition of 1,3-dimercaptobenzene to 4,4-dimethyl-2,5-cyclohexadiene-1-one, or to trans, trans-2,5-heptadiene-3-one, in the presence of catalytic amounts of chiral amines. The extent of asymmetric induction on the resulting polymeric product is found to be higher when the alicyclic ketone reagent is employed and is enhanced by lowering the catalyst concentration. The comparison of stereochemical features and chiroptical properties of appropriate low molecular weight analogues with those of the polymeric derivatives indicates that a comparable asymmetric induction occurs in polymers and model compounds, and that the former systems do not display appreciable evidence of ordered secondary structures, in agreement with a low stereoregularity degree along the macromolecular backbone. © 1996 John Wiley & Sons, Inc.     

STEREOSELECTIVE REACTIONS OF CHIRAL AMINES WITH RACEMIC CHLOROPHOSPHINES

Racemic chlorophosphines react stereoselectively with chiral l-phenylethylamines or amino acid esters to give diastereomerically enriched aminophosphines 3, which were isolated as diastereomerically pure crystalline borane complexes. Oxidation, thionation, the reaction with methyl iodide provide optically active derivatives of aminophosphines. (R,S)- and (S,S)-stereomers of phosphinic acid amides were separated by crystallization and a flash-chromatography. The stereochemical properties of phosphorus acid amides were investigated. The mechanism of asymmetric induction at the trivalent phosphorus atom was rationalized.     

Size- and shape-dependent polarizabilities of sandwich and rice-ball Co(n)Bz(m) clusters from density functional theory

The dipole polarizabilities of Co(n)Bz(m), (n, m = 1-4, m = n, n + 1) clusters are studied by means of an all-electron gradient-corrected density functional theory and finite field method. The dipole moments are relatively large for most of the clusters, implying their asymmetric structures. The total polarizability increases rapidly as cluster size, whereas the average polarizability shows "odd-even" oscillation with relatively large values at (n, n + 1). The polarizabilities exhibit clear shape-dependent variation, and the sandwich structures have systematically larger polarizability and anisotropy than the rice-ball isomers. The dipole polarizabilities are further analyzed in terms of the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gap, ionization potential, and electron delocalization volume. We conclude that the polarizability variations are determined by the interplay between the geometrical and electronic properties of the clusters.     

Studies on enantioselective allylic oxidation of olefins using peresters catalyzed by Cu(I)-complexes of chiral pybox ligands

Enantioselective allylic oxidation of olefins with various peresters, using a catalytic amount of Cu(I)-pybox complex, can be tuned to achieve high asymmetric induction (up to 98% ee) by choosing a unique combination of a ligand and a perester at room temperature. The asymmetric induction in the reaction strongly depends on the nature of the substituents attached to the aryl ring of peresters. The presence of a gem-diphenyl group at C-5 and secondary or tertiary alkyl substituents at the chiral center (C-4) of the oxazoline rings is crucial for high enantioselectivity. A pi-pi stacking model has been proposed and discussed to explain the stereochemical outcome of the reaction.     

Intramolecular Diels-Alder reactions using chiral ruthenium Lewis acids and application in the total synthesis of ent-ledol

One-point binding chiral ruthenium Lewis acids incorporating the C(2)-symmetric electron-poor bidentate phosphinite ligand BIPHOP-F and a Cp or an indenyl 'roof' can efficiently catalyze asymmetric intramolecular Diels-Alder reactions of trienes to form bicyclic adducts with good to excellent asymmetric induction. This reaction forms the key step in a total synthesis of ent-ledol in 96% ee. The synthesis also helps to clarify the stereochemical assignment of ledol and inconsistencies in the measured optical rotation.     

Stereoselective total synthesis of (+)-anamarine via cross-metathesis protocol

A convergent stereoselective total synthesis of (+)-anamarine via cross-metathesis (CM) protocol starting from 2-butyn-1,4-diol and vinyl lactone is reported. Other key features of the strategy include the use of Sharpless asymmetric epoxidation, Sharpless dihydroxylation, and Red-Al reduction.     

Catalyst electronic polarizability and enantiomeric excess in asymmetric hydrogenation

In the classical rhodium-diphosphine complexes-catalyzed asymmetric hydrogenation of enamide substrates, examination on the role of catalyst electronic polarizability in the origin of enantioselectivity reveals its linear free energy relationship with the product enantiomeric ratio that is much more pronounced than analogous correlation with steric effect in the same systems. From a conceptually novel scenario, this work suggests that the often-overlooked chiral catalyst local polarizability property may function as a controlling force in enantioselection thus has important implication in rational catalyst design.     

Diastereoselective addition of trimethylsilyl cyanide to chiral O‐, S‐ and N‐heterocyclic aldimines

Systematic investigation of asymmetric trimethylsilylcyanation of heterocyclic azomethines has been realized. The addition of trimethylsilyl cyanide to optically active furan, thiophene and pyridine aldimines, derived from (R)‐ and (S)‐1‐phenylethylamine, was studied in the presence of Lewis acids, and a series of the corresponding α‐amino nitriles was obtained in fair to good yields (up to 91%). Unsaturated nitriles were also formed from pyridine imines. The sense of asymmetric induction and the degree of diastereoselectivity in the synthesis of α‐amino nitriles were determined by means of ¹H NMR. The stereochemical outcome is a result of the same sense of asymmetric induction: Re face attack to the (S)‐imines and Si face addition to the (R)‐imines took place. The (R,R)‐ (up to 81%) or (S,S)‐ (up to 87%) α‐amino nitriles predominated in the products obtained from the all furan, thiophene and pyridine (R)‐ or (S)‐imines respectively. Copyright © 2002 John Wiley & Sons, Ltd.     

A triazine core for a new class of Sharpless asymmetric dihydroxylation ligands

Sharpless asymmetric dihydroxylation ligands were synthesized using a triazine spacer group in two, high yielding steps from cheap, readily available starting materials. The ligands, gave good enantioselectivities in the asymmetric dihydroxylation of alkenes and may provide a very economic alternative to current systems.     

1,3-asymmetric induction—VI : Stereochemistry of the reactions between organo-metals and β-asymmetric amino-ketones

The stereochemical course of the reaction between organo-metals and β-asymmetric amino-ketones has been investigated by varying the nature of the reagent and the substituents in the substrate, as well as the distance of the amino-group from the reaction center.The relative configurations of the diastereomeric amino-alcohols obtained were assigned, thus determining the direction of the predominant attack by the nucleophile.The stereoselectivity was found to be strongly dependent on the factors investigated, particularly on the nature of the amino-group and of the reagent.No single model of asymmetric induction proved to be suitable for the prediction of the stereochemical results in the above reactions.