Enantioselective total synthesis of (+)-azimine and (+)-carpaine

[reaction: see text] The enantioselective total syntheses of (+)-azimine and (+)-carpaine have been developed, starting with (S)-1,2,4-butanetriol as a single source of chirality. The key common feature in these syntheses involves stereoselective intramolecular hetero-Diels-Alder reaction of an acylnitroso compound. The critical macrocyclic dilactonization of the N-Cbz derivatives of azimic acid and carpamic acid was efficiently achieved by using the Yamguchi macrocyclization conditions.     

Highly enantioselective synthesis of 2,6-disubstituted and 2,2,6-trisubstituted dihydropyrones: a one-step synthesis of (R)-(+)-hepialone and its analogues

An efficient enantioselective approach to chiral dihydropyrones has been developed by the hetero-Diels-Alder (HDA) reactions of (E)-4-methoxy-2-trimethylsiloxy-penta-1,3-diene (diene 1) with aldehydes and pyruvates. It has been found that the readily accessible (R)-BINOL-Ti(OiPr)(4) (1.1:1) complex was a very effective catalyst for this reaction. Aromatic, heteroaromatic, conjugated, and aliphatic aldehydes afforded the corresponding products in moderate to high isolated yields (up to 99%) with excellent enantioselectivities (up to 99% ee). The first example of highly enantioselective synthesis of 2,2,6-trisubstituted dihydropyrones by the catalytic reaction of diene 1 with pyruvates was reported. The isolated intermediates indicated that this asymmetric HDA reaction proceeded in a Mukaiyama aldol pathway. On the basis of the absolute configurations of the products, a possible mechanism was proposed. Moreover, the catalytic system could be used to synthesize a series of enantioenriched beta-hydroxyketones 4. Finally, this methodology was successfully applied for the one-step synthesis of the important natural product (R)-(+)-Hepialone with 88% isolated yield and 94% enantioselectivity.     

Catalytic Asymmetric Hetero-Diels-Alder Reactions of Carbonyl Compounds and Imines

Asymmetric catalysis is a challenge for chemists: How can we design catalysts to achieve the goal of forming optically active compounds? This review provides the reader with an overview of the development of catalytic asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imines. Since its discovery, the Diels-Alder reaction has undergone intensive development and is of fundamental importance for synthetic, physical, and theoretical chemists. The Diels-Alder reaction has been through different stages of development, and at the beginning of the 21st century catalytic Diels-Alder reactions are one of the main areas of focus. The preparation of numerous compounds of importance for our society is based on cycloaddition reactions to carbonyl compounds and imines. There are several parallels between the reactions of carbonyl compounds and those of imines, which, however, begin to vanish on entering the field of catalytic reactions. Why? From a mechanistic point of view some similarities can be drawn, but the synthetic development of catalytic enantioselective hetero-Diels-Alder reactions of imines are several years behind those of the carbonyl compounds. For hetero-Diels-Alder reactions of carbonyl compounds there a number of different chiral catalysts, and great progress has been achieved in developing enantioselective reactions for unactivated and activated carbonyl compounds. In contrast the development of catalytic enantioselective hetero-Diels-Alder reactions of imines is in its infancy and only few catalytic reactions have been published. This review will focus on the most important developments, and discuss the synthetic and mechanistic aspects of enantioselective hetero-Diels-Alder reactions of carbonyl compounds catalyzed by chiral Lewis acids. For the hetero-Diels-Alder reactions of imines, the diastereoselective reactions of optically substrates catalyzed by Lewis acids will be presented first, followed by the catalytic enantioselective reactions.     

Total synthesis of (+)-cyperolone

The total synthesis of (+)-cyperolone, an eudesmane-derived sesquiterpenoid from Cyperus rotundus, is described. The de novo synthesis was accomplished via a 15 step sequence starting from (R)-(-)-carvone. The synthetic route features a platinum-catalyzed cycloisomerization to rapidly construct the bicyclic core from a 3-silyloxy-1,5-enyne intermediate.     

Recent developments in the enantioselective synthesis of polyfunctionalized pyran and chromene derivatives

Recent developments in the synthesis of 4H- and 2H-pyrans as well as structurally related chromene derivatives that have enabled the enantioselective synthesis of these scaffolds have been surveyed. The role of chiral catalysts in orienting initial reactions of active methylenes, methines and methyl ketones, to unsaturated ketones and nitriles in multi-component reactions or Friedel–Craft alkylations of phenols is discussed to show their involvement in transition states leading to end products. Chromene synthesis via [4+2] cycloadditions, [3+3] and [4+2] annulations as well as ring opening and recyclization leading to high enantio- and diasteroselectivity is also demonstrated. The enantioselectivity in such catalytic asymmetric reactions despite starting with non-chiral starting materials is discussed. On the other hand, in surveying ring opening and recyclization, the starting materials are chiral and the chiral center was not part of the reaction leading to the final product.     

Amino acid catalyzed direct enantioselective formation of carbohydrates: one-step de novo synthesis of ketoses

The amino acid-catalyzed direct enantioselective one-step de novo synthesis of carbohydrates using dihydroxyacetone phosphate mimetics as donors and aldehydes or in situ generated imines as acceptors is presented. The addition of water significantly accelerates as well as improves the enantioselectivity of the biomimetic aldol and Mannich reactions. The C₃+C_n methodology presented herein is a direct entry to orthogonally protected C-5 and C-6 ketoses (e.g., ribulose, tagatose and piscose) and deoxy- and aminosugars such as 4-amino-4-deoxy-fructose.     

Enantioselective synthesis of (-)-roccellaric acid

[reaction in text] A new strategy for the synthesis of anti-4,5-disubstituted gamma-butyrolactones starting from inexpensive furan-2-carboxylic methyl ester was developed. By applying this methodology, the enantioselective synthesis of (-)-roccellaric acid ((-)-17) was accomplished using a copper(I)-catalyzed asymmetric cyclopropanation, a tin(IV)-catalyzed retroaldol/lactonization sequence of cyclopropanols, and a ruthenium-catalyzed intermolecular metathesis reaction as key steps.     

The first general enantioselective catalytic Diels-Alder reaction with simple alpha,beta-unsaturated ketones

The first general approach to enantioselective catalysis of the Diels-Alder reaction with simple ketone dienophiles has been accomplished. The use of iminium catalysis has enabled enantioselective access to a fundamental Diels-Alder reaction variant that has previously been unavailable using chiral Lewis acid catalysis. A new chiral amine catalyst has been developed that allows a variety of monodentate cyclic and acyclic ketones to successfully participate in enantioselective [4 + 2] cycloadditions. A wide spectrum of cyclic and acyclic diene substrates can also be accommodated in this new organocatalytic transformation. A computational model is provided that is in accord with the sense of enantioinduction observed for all reactions conducted during the course of this study.     

Enantioselective catalysis of the hetero-Diels-Alder reaction between Brassard's diene and aldehydes by hydrogen-bonding activation: a one-step synthesis of (S)-(+)-dihydrokawain

The first catalytic enantioselective hetero-Diels-Alder reaction between Brassard's diene and aldehydes has been achieved through hydrogen-bonding activation using TADDOL derivatives as catalysts to afford the corresponding delta-lactone derivatives in moderate-to-good yields and with high enantioselectivities (up to 91 % ee). The reactions can be carried out either under solvent-free conditions or in toluene. On the basis of the absolute configurations of the products and the hydrogen-bonding interaction pattern between TADDOL (alpha,alpha,alpha',alpha'-tetraaryl-1,3-dioxolan-4,5-dimethanol) and the carbonyl group disclosed by X-ray diffraction analysis, a possible mechanism for the catalytic reaction has been proposed. To demonstrate the usefulness of the methodology, a natural product, (S)-(+)-dihydrokawain, has also been prepared in 50 % isolated yield and with 69 % enantioselectivity in one step starting from 3-phenylpropionaldehyde by using this methodology. Therefore, this catalytic system is one of the most direct approaches to the construction of delta-lactone units, which will make the methodology very attractive for the synthesis of a variety of biologically important compounds and natural products.     

Enantioselective total synthesis of (-)-zampanolide, a potent microtubule-stabilizing agent

An enantioselective total synthesis of zampanolide has been accomplished using a novel DDQ/Br?nsted acid promoted cyclization as the key reaction. The synthesis features cross-metathesis to construct the trisubstituted olefin and a ring-closing metathesis to form the macrolactone. The final N-acyl aminal formation was stereoselectively accomplished by an organocatalytic reaction.     

Enantioselective total synthesis of iso-cladospolide B, cladospolide C and cladospolide B from tartaric acid

The enantioselective synthesis of the natural products cladospolide B, cladospolide C, and iso-cladospolide B has been accomplished from tartaric acid. Key reactions in the synthetic sequence include the elaboration of a γ-hydroxy amide derived from tartaric acid via alkene cross metathesis, Yamaguchi lactonization, and ring closing metathesis.     

Concise asymmetric total synthesis of obolactone

The first efficient asymmetric synthesis of obolactone 1 has been accomplished in 11 steps and with a 15% overall yield in which Brown's enantioselective allylation reactions and ring-closing metathesis reaction are key steps.     

Organocatalytic Strategies for the Development of the Enantioselective Inverse-electron-demand Hetero-Diels-Alder Reaction

Cycloaddition reactions, in particular Diels-Alder reactions, have attracted a lot of attention from organic chemists since they represent one of the most powerful methodologies for the construction of carbon-carbon bonds. In particular, inverse-electron-demand hetero-Diels-Alder reactions have been an important breakthrough for the synthesis of heterocyclic compounds. Among all their variants, the organocatalytic enantioselective version has been widely explored since the asymmetric construction of diversely functionalized scaffolds under reaction conditions encompassed within the green chemistry field is of great interest. In this review, a profound revision on the latest advances on the organocatalytic asymmetric inverse-electron demand hetero-Diels-Alder reaction is shown.     

Enantioselective synthesis of the antiinflammatory agent (-)-acanthoic acid.

An enantioselective synthesis of the potent antiinflammatory agent (-)-acanthoic acid (1) is described. The successful strategy departs from (-)-Wieland-Miescher ketone (10), which is readily available in both enantiomeric forms and constitutes the starting point toward a fully functionalized AB ring system of 1. Conditions were developed for a regioselective double alkylation at the C4 center of the A ring, which produced compound 32 as a single stereoisomer. Construction of the C ring of 1 was accomplished via a Diels-Alder reaction between sulfur-containing diene 43 and methacrolein (36), which after desulfurization and further functionalization yielded synthetic acanthoic acid. The described synthesis confirms the proposed stereochemistry of the natural product and represents a fully stereocontrolled entry into an underexplored class of biologically active diterpenes.     

Enantioselective Synthesis of Tropanes: Brønsted Acid Catalyzed Pseudotransannular Desymmetrization

The enantioselective synthesis of tropanols has been accomplished through chiral phosphoric acid catalyzed pseudotransannular ring opening of 1-aminocyclohept-4-ene-derived epoxides. The reaction proceeds together with the desymmetrization of the starting material and leads to the direct formation of the 8-azabicyclo[3.2.1]octane scaffold with excellent stereoselectivity. The synthetic applicability of the reaction was demonstrated by the enantioselective synthesis of the two natural products (−)-α-tropanol and (+)-ferruginine.     

Enantioselective Synthesis of Tropanes: Brønsted Acid Catalyzed Pseudotransannular Desymmetrization

The enantioselective synthesis of tropanols has been accomplished through chiral phosphoric acid catalyzed pseudotransannular ring opening of 1‐aminocyclohept‐4‐ene‐derived epoxides. The reaction proceeds together with the desymmetrization of the starting material and leads to the direct formation of the 8‐azabicyclo[3.2.1]octane scaffold with excellent stereoselectivity. The synthetic applicability of the reaction was demonstrated by the enantioselective synthesis of the two natural products (?)‐α‐tropanol and (+)‐ferruginine.     

Total synthesis of salinosporamide A

Total synthesis of potent proteasome inhibitor salinosporamide A (1) has been accomplished, which features strictly substrate-controlled operations starting with the only chiral center of (R)-pyroglutamic acid. The consecutive quaternary carbons within 1 have been efficiently constructed by manipulation of two intramolecular reactions: (1) carbonate-mediated internal acylation of imidate ester (4 --> 14) and (2) selenocyclization of aldehyde to exocyclic methylene group (5 --> 18).     

Acid-base catalysis of chiral Pd complexes: development of novel catalytic asymmetric reactions and their application to synthesis of drug candidates

Using the unique character of the chiral Pd complexes 1 and 2, highly efficient catalytic asymmetric reactions have been developed. In contrast to conventional Pd(0)-catalyzed reactions, these complexes function as an acid-base catalyst. Thus active methine and methylene compounds were activated to form chiral palladium enolates, which underwent enantioselective carbon-carbon bond-forming reactions such as Michael reaction and Mannich-type reaction with up to 99% ee. Interestingly, these palladium enolates acted cooperatively with a strong protic acid, formed concomitantly during the formation of the enolates to activate electrophiles, thereby promoting the C-C bond-forming reaction. This palladium enolate chemistry was also applicable to electrophilic enantioselective fluorination reactions, and various carbonyl compounds including beta-ketoesters, beta-ketophosphonates, tert-butoxycarbonyl lactone/lactams, cyanoesters, and oxindole derivatives could be fluorinated in a highly enantioselective manner (up to 99% ee). Using this method, the catalytic enantioselective synthesis of BMS-204352, a promising anti-stroke agent, was achieved. In addition, the direct enantioselective conjugate addition of aromatic and aliphatic amines to alpha,beta-unsaturated carbonyl compound was successfully demonstrated. In this reaction, combined use of the Pd complex 2 having basic character and the amine salt was the key to success, allowing controlled generation of the nucleophilic free amine. This aza-Michael reaction was successfully applied to asymmetric synthesis of the CETP inhibitor torcetrapib.     

Direct one-pot highly enantioselective assembly of polyketide and carbohydrate synthons

A short, direct, catalytic, enantioselective synthesis of polyketide segments and carbohydrates is presented. The novel, direct, one-pot, organocatalytic asymmetric tandem cross-aldol/Horner-Wittig-Emmons reactions assemble polyketide and carbohydrate derivatives in good yield with 93-98% ee. The one-pot catalytic asymmetric tandem reaction was applied to a highly enantioselective formal de novo synthesis of the rare carbohydrate, l-altrose.     

A concise synthesis of pinellic acid using a cross-metathesis approach

A new enantioselective synthesis of pinellic acid, a trihydroxy unsaturated fatty acid exhibiting oral adjuvant activity for nasally administered influenza vaccine, has been accomplished using a cross-metathesis reaction between two terminal olefin intermediates as the key step. This synthesis is the shortest to date, furnishing pinellic acid in 17% overall yield via only seven steps from a readily available known dihydroxy ester.