Catalytic enantioselective protonation of lithium enolates with chiral imides

The catalytic enantioselective protonation of simple enolates was achieved using a catalytic amount of chiral imides and stoichiometric amount of achiral proton sources. Among the achiral proton sources examined in the protonation of the lithium enolate of 2,2,6-trimethylcyclohexanone catalyzed by (S,S)-imide 1, 2, 6-di-tert-butyl-p-cresol (BHT) and its derivatives gave the highest enantiomeric excess. For example, 90% ee of (R)-enriched ketone was obtained when (S,S)-imide 1 (0.1 equiv) and BHT (1 equiv) were used. Use of 0.01 equiv of the chiral catalyst still caused a high level of asymmetric induction. For catalytic protonation of the lithium enolate of 2-methylcyclohexanone, chiral imide 6 possessing a chiral amide portion was superior to (S,S)-imide 1 as a chiral proton source and the enolate was effectively protonated with up to 82% ee.     

First synthesis of the chiral mixed O/S ligands, 1,2-sulfinyl thiols: application as chiral proton sources in enantioselective protonations of enolates

A suitable method for the preparation of the chiral mixed O/S ligands 1,2-sulfinyl thiols is described. These compounds have then been used as a chiral proton source in the enantioselective protonation of 2-methyl tetralone enolate and the results are compared with those obtained from the analogous alcohols. A theoretical model is proposed to explain the different behaviors exhibited in the protonation reaction for each of these proton sources. Configurational assignments for the new chiral thiols have been carried out by means of X-ray analysis.     

Enantioselective Borylative Dearomatization of Indoles through Copper(I) Catalysis

The enantioselective borylative dearomatization of a heteroaromatic compound has been achieved using a copper(I) catalyst and a diboron reagent. This reaction involves the regio‐ and enantioselective addition of active borylcopper(I) species to indole‐2‐carboxylates, followed by the diastereoselective protonation of the resulting copper(I) enolate to give the corresponding chiral indolines, which bear consecutive stereogenic centers.     

Deracemization of silyl enol ethers

The deracemization by enantioselective protonation of silyl enol ethers was tested using 2,2-dimethyl 5-phenyl 1,3-dioxolan 4-one 1. The results obtained, especially with pantolactone as a chiral proton donor, are better than when the deracemization is carried out with the lithium enolate of 1.     

N-sulfinyl beta-amino Weinreb amides: synthesis of enantiopure beta-amino carbonyl compounds. Asymmetric synthesis of (+)-sedridine and (-)-allosedridine

[reaction: see text] N-Sulfinyl beta-amino Weinreb amides are prepared by condensation of sulfinimines with the potassium enolate of N-methoxy-N-methylacetamide. These new chiral building blocks are useful for the asymmetric synthesis of beta-amino carbonyl compounds, as illustrated here by the concise enantioselective syntheses of sedum alkaloids (+)-sedridine and (-)-allosedridine.     

The Enantioselective Dakin–West Reaction

Here we report the development of the first enantioselective Dakin–West reaction, yielding α‐acetamido methylketones with up to 58 % ee with good yields. Two of the obtained products were recrystallized once to achieve up to 84 % ee. The employed methylimidazole‐containing oligopeptides catalyze both the acetylation of the azlactone intermediate and the terminal enantioselective decarboxylative protonation. We propose a dispersion‐controlled reaction path that determines the asymmetric reprotonation of the intermediate enolate after the decarboxylation.     

Enantioselective Protonation of Enolates and Enols

Enantioselective protonation, until recently a largely overlooked reaction, has, in the last five years, developed into a field of intense research activity. The progress achieved parallels or complements that obtained in the understanding of enolate structures and reactivities. The conceptual simplicity and attractiveness of enantioselective protonation results from the fact that after reaction, the chiral proton donor is regenerated in its original protonated form by an extractive workup. Enantioselective protonation has been applied to the synthesis of amino acids, antiinflammatory agents (2-arylpropanoic acids), and fragrance compounds such as (S)-α-damascone, for which its industrial feasibility has been demonstrated.     

Investigation into the enantioselective protonation of enolate Schiff bases with (R)-pantolactone

The effect of several factors on the enantioselective protonation of the enolates of α-amino acid derivatives with (R)-pantolactone were studied. The highest stereoselectivity (74–76% e.e.) was generally observed by associating lithium chloride with LHMDS and by using the optimum temperature for the formation of the enolate.     

Efficient Synthesis of (−)‐(R)‐Muscone by Enantioselective Protonation

A new synthesis of (?)‐(R)‐muscone ((R)‐ 1 ) by means of enantioselective protonation of a bicyclic ketone enolate as the key step (see 6 →(S)‐ 4 in Scheme 2) is presented. The C₁₅ macrocyclic system is obtained by ozonolysis (Scheme 7).     

Asymmetric vinylogous Mukaiyama aldol reaction of aldehyde-derived dienolates

Unsaturated aldehydes are exquisite building blocks for further transformations in polyketide synthesis. Besides standard transformations that take advantage of the aldehyde functionality, the conjugate addition of hydrides followed by internal protonation allows access to alpha chiral aldehydes. Even though vinylogous Mukaiyama aldol reactions have been used in natural product syntheses before, the first enantioselective Mukaiyama aldol reaction of aldehyde-derived dienolates is described.     

Amino alcohol-mediated enantioselective syntheses of α-substituted indanones and tetralones,ammonium enolates as key intermediates

Optically active 2-substituted-1-indanones or 2-substituted-1-tetralones are isolated from amino alcohol-mediated asymmetric domino reactions of α-disubstituted ketones, β-ketoesters, enol carbonates, α,β-unsaturated ketones, a silyl enol ether, or a β-ketoacid, with some of these reactions occurring under UV-light irradiation or Pd catalysis. The absence of a relationship between the nature of the substrate and the absolute configuration of the ketone produced is due to the protonation of a common ammonium enolate as the key enantioselective step. The enantioselectivity depends on various factors, which indicates the occurrence of side pathways.     

A highly enantio- and diastereoselective catalytic intramolecular Stetter reaction

A highly enantio- and diastereoselective intramolecular Stetter reaction has been developed. Subjection of alpha,alpha-disubstituted Michael acceptors to an asymmetric intramolecular Stetter reaction results in a highly enantioselective conjugate addition and a diastereoselective proton transfer. Available evidence suggests the diastereoselective protonation occurs via intramolecular delivery to the sterically more hindered face of the enolate. The scope of the trisubstituted Michael acceptors has been examined and found to be broad with respect to the size of the alpha-substituent and nature of the Michael acceptor. Aliphatic and aromatic aldehydes were examined and found to afford the desired product in good overall yield with high enantio- and diastereoselectivity.     

The Knight route to cyclopiazonic acid: enantioselective synthesis of a key intermediate

The indole alkaloid α-cyclopiazonic acid (CPA) is one of the few known inhibitors of sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) besides thapsigargin and artemisinin. Inhibitors of SERCA hold promise as novel anticancer and antimalarial drugs. Since its structure elucidation three racemic syntheses of α-cyclopiazonic acid have been published. We report now the first enantioselective and high yielding synthesis of a key-intermediate of the Knight synthesis, currently the most efficient route to CPA. Our synthesis is based on a diastereoselective 1,4-cuprate addition followed by an enolate azidation of an indolylacrylic acid modified with the Evans auxiliary.     

Catalyst‐Enabled Site‐Divergent Stereoselective Michael Reactions: Overriding Intrinsic Reactivity of Enynyl Carbonyl Acceptors

A site‐divergent stereoselective Michael reaction system is developed based on the identification of two distinct catalysts. Cinchonidine‐derived thiourea catalyzes the 1,4‐addition of prochiral azlactone enolates to enynyl N‐acyl pyrazoles in a highly diastereo‐ and enantioselective manner to give stereochemically defined alkynes, while P‐spiro chiral triaminoiminophosphorane catalytically controls the stereoselective 1,6‐addition and the consecutive γ‐protonation of the vinylogous enolate intermediate to afford Z,E‐configured conjugated dienes. This 1,6‐adduct serves as a valuable precursor for the synthesis of a 2‐amino‐2‐deoxy sugar.     

(-)-(S)-Nakinadine B: first asymmetric synthesis

(-)-(S)-Nakinadine B has been synthesized for the first time (in 9 steps and 17% overall yield from commercially available atropic acid) using the conjugate addition of lithium dibenzyl-amide to an N-α-phenylacryloyl SuperQuat derivative with in situ diastereoselective enolate protonation as the key step.     

Catalytic Enantioselective Synthesis of C1‐ and C2‐Symmetric Spirobiindanones through Counterion‐Directed Enolate C‐Acylation

A catalytic enantioselective route to C₁‐ and C₂‐symmetric 2,2′‐spirobiindanones has been realized through an intramolecular enolate C‐acylation. This reaction employs a chiral ammonium counterion to direct the acylation of an in situ generated ketone enolate with a pentafluorophenyl ester. This reaction constitutes the first example of a direct catalytic enantioselective C‐acylation of a ketone and provides an efficient and highly enantioselective route to axially chiral spirobiindanediones. These products can be diastereoselectively derivatized, offering access to a range of functionalized spirocyclic architectures.     

Enantioselective Syntheses of Substituted γ‐Butyrolactones

The previously described chiral 2‐acyloxathianes 5 (Scheme I) are used in two different enantioselective syntheses of γ‐butyrolactones. In one synthesis, Grignard addition, cleavage and reduction to carbinols RR'C(OH)CH₂OH is followed by tosylation, malonate homologation, lactonization, and removal of the carbomethoxy group to give optically active γ‐lactones. A modification of this synthesis (Scheme I) leads to optically active α‐methylene‐γ‐lactones. In the second synthesis, reaction of a bromomagnesium enolate with ketones 5 leads to β‐hydroxyesters, which, by appropriate sequences of reduction and cleavage (Scheme II) are converted to optically active α‐ or β‐hydroxy‐γ‐lactones.     

Total synthesis and determination of the stereochemistry of 2-amino-3-cyclopropylbutanoic acid,a novel plant growth regulator isolated from the mushroom Amanita castanopsidis Hongo

The unknown stereostructure of 2-amino-3-cyclopropylbutanoic acid 1, a novel plant growth regulator isolated from the mushroom Amanita castanopsidis Hongo, was determined to be (2S,3S)-2 through its racemic and enantioselective syntheses employing the chelate-enolate Claisen rearrangement as a key step.     

Total syntheses of cladoacetals A and B: confirmation of absolute configurations

The first enantioselective syntheses of cladoacetals A (1a, overall yield: 16%) and B (1b, overall yield: 34%) from crotonaldehyde in nine and seven steps, respectively, have been accomplished. Sharpless asymmetric dihydroxylation, Suzuki coupling, and acid-catalyzed intramolecular acetalization were the key steps in the syntheses. The absolute configuration of natural (+)-cladoacetal A was affirmed to be 1S,3S,4R, whereas that of (-)-cladoacetal B was affirmed to be 1R,3S,4S.     

Enantioselective total and formal syntheses of paroxetine (PAXIL) via phosphine-catalyzed enone α-arylation using arylbismuth(V) reagents: a regiochemical complement to Heck arylation

Exposure of dihydropyridinone 1 to the arylbismuth(V) reagent (p-F-Ph)₃BiCl₂ in the presence of substoichiometric quantities of tributylphosphine (10 mol %) results in aryl transfer to the transiently generated (β-phosphonio)enolate to provide the α-arylated enone 2. This transformation, which represents a regiochemical complement to the Mizoroki-Heck arylation, is used strategically in concise formal and enantioselective total syntheses of the blockbuster antidepressant (−)-paroxetine (PAXIL).