A Case Study on the Resolution of the 1‐i‐Butyl‐3‐methyl‐3‐phospholene 1‐Oxide via Diastereomeric Complex Formation Using TADDOL Derivatives and via Diastereomeric Coordination Complexes Formed from the Calcium Salts of O,O′‐Diaroyl‐(2R,3R)‐tartaric Acids

The resolution of 1‐i‐butyl‐3‐methyl‐3‐phospholene 1‐oxide was studied applying TADDOL [(−)‐(4R,5R)‐4,5‐bis(diphenylhydroxymethyl)‐2,2‐dimethyldioxolane], spiro‐TADDOL [(−)‐(2R,3R)‐α,α,α′,α′‐tetraphenyl‐1,4‐dioxaspiro[4.5]decan‐2,3‐dimethanol], or the acidic and neutral Ca²⁺ salts of (−)‐O,O′‐dibenzoyl‐ and (−)‐O,O′‐di‐p‐toluoyl‐(2R,3R)‐tartaric acid as the resolving agent. The absolute configuration of the P‐asymmetric center was determined by circular dichroism spectroscopy and related quantum chemical calculations. In one instance, the single crystal of the diastereomeric complex incorporating i‐butyl‐3‐phospholene oxide and spiro‐TADDOL was subjected to X‐ray analysis, which suggested a feasible hypothesis for the efficiency of the resolution process under discussion that may be an example for the “solvent‐inhibited” resolution.     

Ni‐Catalyzed Asymmetric Cycloisomerization of Dienes by Using TADDOL Phosphoramidites

A library of α,α,α,α‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol (TADDOL)‐based phosphoramidites has been synthesized and applied in the Ni‐catalyzed cycloisomerization of different dienes. Through the systematic variation of the three structural motifs of the lead structure, that is, the amine moiety, the protecting group, and the aryl substituents, the ligand features could be optimized for the asymmetric cycloisomerization of the model substrate diethyl diallylmalonate. The substrate scope of the new catalytic system was extended to other diallylic substrates, including unsymmetrical dienes. Overall remarkably high activities of up to approximately 13 500 h^?1, very high selectivities toward five‐membered exo‐methylenecyclopentanes, and enantioselectivities of up to 92 % ee have been achieved.     

Preparation and Characterization of New C2‐ and C1‐Symmetric Nitrogen,Oxygen, Phosphorous,and Sulfur Derivatives and Analogs of TADDOL. Part II

TADDOL (=α,α,α′,α′‐Tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol) and the corresponding dichloride are converted to TADDAMINs (=(4S,5S)‐2,2,N,N′‐tetramethyl‐α,α,α′,α′‐tetraphenyl‐1,3‐dioxolan‐4,5‐dimethanamines) (Scheme 2) and ureas, 12 – 15 , and to TADDOP derivatives with seven‐membered O? P? O ester rings (Schemes 3 and 4). Cl/P‐Replacement via the Michaelis? Arbuzov reaction (Scheme 7) on mono‐ and dichlorides, derived from TADDOL, are described. It was not possible to obtain phosphines with the P‐atom attached to the benzhydrylic C‐atom of the TADDOL skeleton (Schemes 6 and 7). The X‐ray crystal structures (Figs. 1 and 2) of ten of the more than 30 new TADDOL derivatives are discussed. Full experimental details are presented.     

Pd‐Catalyzed Asymmetric Intramolecular Arylative Dearomatization of para‐Aminophenols†

Asymmetric arylative dearomatization reactions of para‐aminophenols are realized by a Pd‐catalyst consisting of a TADDOL (α,α,α',α'‐tetraaryl‐2,2‐disubstituted 1,3‐dioxolane‐4,5‐dimethanol)‐derived chiral phosphoramidite ligand. The tetracyclic products bearing the key skeleton of Erythrina alkaloids are afforded in reasonable yields (up to 73%) with good to excellent enantioselectivity (up to 97% ee). Concise total synthesis of (–)‐3‐demethoxyerythratidinone is achieved by employing this method as the key step.     

Highly Enantioselective Protonation of the 3,4‐Dihydro‐2‐ methylnaphthalen‐1(2H)‐one Li‐Enolate by TADDOLs

A series of nine TADDOLs (=α,α,α′,α′‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanols) 1a – 1i , have been tested as proton sources for the enantioselective protonation of the Li‐enolate of 2‐methyl‐1‐tetralone (=3,4‐dihydro‐2‐methylnaphthalen‐1(2H)‐one). The enolate was generated directly from the ketone (with LiN(i‐Pr)₂ (LDA)/MeLi) or from the enol acetate (with 2 MeLi) or from the silyl enol ether (with MeLi) in CH₂Cl₂ or Et₂O as the solvent (Scheme). The Li‐enolate (associated with LiBr/LDA, or LiBr alone) was combined with 1.5 – 3.0 equiv. of the TADDOL at −78° by addition of the latter or by inverse addition. 2‐Methyl‐1‐tetralone of (S)‐configuration is formed (≤80% yield) with up to 99.5% selectivity if and only if (R,R)‐TADDOLs ( 1d , e , g ) with naphthalen‐1‐yl groups on the diarylmethanol unit are employed (Table). The reactions were carried out on the 0.1‐ to 1.0‐mM scale. The selectivity is subject to non‐linear effects (NLE) when an enantiomerically enriched TADDOL 1d is used (Fig. 1). The performance of TADDOLs bearing naphthalen‐1‐yl groups is discussed in terms of their peculiar structures (Fig. 2).     

Enantioselective Synthesis of 1,12‐Disubstituted [4]Helicenes

A highly enantioselective synthesis of 1,12‐disubstituted [4]carbohelicenes is reported. The key step for the developed synthetic route is a Au‐catalyzed intramolecular alkyne hydroarylation, which is achieved with good to excellent regio‐ and enantioselectivity by employing TADDOL‐derived (TADDOL=α,α,α,α‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol) α‐cationic phosphonites as ancillary ligands. Moreover, an appropriate design of the substrate makes the assembly of [4]helicenes of different substitution patterns possible, thus demonstrating the synthetic utility of the method. The absolute stereochemistry of the newly prepared structures was determined by X‐ray crystallography and characterization of their photophysical properties is also reported.     

Internally Reuse Waste: Catalytic Asymmetric One‐Pot Strecker Reaction of Fluoroalkyl Ketones,Anilines and TMSCN by Sequential Catalysis

We report a highly enantioselective one‐pot facile synthesis of fluorinated C^α‐tetrasubstituted amino nitriles from α‐fluoroalkyl α‐aryl ketones, anilines, and TMSCN through a sequential p‐TsOH catalyzed ketimine formation and chiral bifunctional tertiary amine mediated asymmetric Strecker reaction. This one‐pot approach has two important advantages. First, it greatly improves the overall yield of the synthesis of chiral C^α‐tetrasubstituted fluorinated aminonitriles from ketones, because the purification of α‐fluorinated ketimines by column chromatography suffers from great yield loss. Second, it represents the first example of asymmetric tandem reactions that can simultaneously reuse the by‐product and catalyst from the upstream step as a promoter and an additive to improve the reactivity and enantioselectivity of the subsequent catalytic enantioselective reaction, respectively. It could utilize the by‐product H₂O generated in‐situ from the ketimine formation step to activate TMSCN to form HCN, and concurrently reuse the remaining p‐TsOH acid as an additive to improve enantioselectivity.     

Catalytic Asymmetric Inverse‐Electron‐Demand Hetero‐Diels−Alder Reactions

In this review, the recent developments in catalytic asymmetric inverse‐electron‐demand hetero‐Diels−Alder reaction, which is recognized as one of the most powerful routes to construct highly functionalized and enantioenriched six‐membered heterocycles, are described. The article is organized on the basis of different kinds of electron‐deficient heterodienes, including α,β‐unsaturated ketones/aldehydes, o‐benzoquinones, α,β‐unsaturated imines, N‐aryl imines, o‐benzoqinone imides, and other aza‐olefins.     

Preparation of TADOOH,a Hydroperoxide from TADDOL,and Use in Highly Enantioface‐ and Enantiomer‐Differentiating Oxidations

Replacement of one OH group in TADDOL (=α,α,α′,α′‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol) by an OOH group gives a stable, crystalline chiral hydroperoxy alcohol TADOOH (={(4R,5R)‐5‐[(hydroperoxydiphenyl)methyl]‐2,2‐dimethyl‐1,3‐dioxolan‐4‐yl}diphenylmethanol) 3 , the crystal structure of which resembles those of numerous other TADDOL derivatives (Fig. 2). The new hydroperoxide was tested as chiral oxidant in three types of reactions: the epoxidation of enones with base catalysis (Scheme 2), the sulfoxidation of methyl phenyl sulfide (Scheme 3), and the Baeyer‐Villiger oxidation of bicyclic and tricyclic cyclobutanones, rac‐ 10a – d with kinetic resolution (Scheme 4, Fig. 3, and Table). Products of up to 99% enantiomer puritiy were isolated (the highest values yet observed for oxidations with a chiral hydroperoxide!). Mechanistic models are proposed for the stereochemical courses of the three types of reactions (Schemes 5 and 6, and Fig. 4). Results of AM1 calculations of the relative transition‐state energies for the anionic rearrangements of the exo Criegee adducts of TADOOH to the enantiomeric bicyclo[3.2.0]heptan‐6‐ones are in qualitative agreement with the observed relative rates (Table and Fig. 5).     

Ligand‐Controlled Regiodivergent Enantioselective Rhodium‐Catalyzed Alkene Hydroboration

Regiocontrol in the rhodium‐catalyzed boration of vinyl arenes is typically dominated by the presence of the conjugated aryl substituent. However, small differences in TADDOL‐derived chiral monophosphite ligands can override this effect and direct rhodium‐catalyzed hydroboration of β‐aryl and β‐heteroaryl methylidenes by pinacolborane to selectively produce either chiral primary or tertiary borated products. The regiodivergent behavior is coupled with enantiodivergent addition of the borane. The nature of the TADDOL backbone substituents and that of the phosphite moiety function synergistically to direct the sense and extent of regioselectivity and enantioinduction. Twenty substrates are shown to undergo each reaction mode with regioselectivity values reaching greater than 20:1 and enantiomer ratios reaching up to 98:2. A variety of subsequent transformations illustrate the potential utility of each product.     

Enantioselective Catalytic Aldehyde α‐Alkylation/Semipinacol Rearrangement: Construction of α‐Quaternary‐δ‐Carbonyl Cycloketones and Total Synthesis of (+)‐Cerapicol

An enantioselective aldehyde α‐alkylation/semipinacol rearrangement was achieved through organo‐SOMO catalysis. The catalytically generated enamine radical cation serves as a carbon radical electrophile that can stereoselectively add to the alkene of an allylic alcohol and initiate ensuing ring‐expansion of cyclopropanol or cyclobutanol. This tandem reaction enables the production of a wide range of nonracemic functionalizable α‐quaternary‐δ‐carbonyl cycloketones in high yields and excellent enantioselectivity from simple aldehydes and allylic alcohols. As a key step, the intramolecular reaction was also successfully applied in the asymmetric total synthesis of (+)‐cerapicol.     

Asymmetric Synthesis of α‐Substituted N‐Methylsulfonamides

A novel amine auxiliary for the asymmetric synthesis of α‐substituted N‐methylsulfonamides is described. The reaction of 4‐([1,1′‐biphenyl]‐4‐yl)‐2,2‐dimethyl‐1,3‐dioxan‐5‐amine ( 16 ) with various aliphatic sulfonyl chlorides afforded the corresponding sulfonamides, which were lithiated and subsequently reacted with electrophiles to give the corresponding products in high yields and good‐to‐excellent asymmetric inductions (de 83–95%). Racemization‐free cleavage of the auxiliary led to the α‐alkylated N‐methylsulfonamides in acceptable yields and high enantiomer purities (ee 91 to ≥98).     

Reaction Optimization,Scalability, and Mechanistic Insight on the Catalytic Enantioselective Desymmetrization of 1,1‐Diborylalkanes via Suzuki–Miyaura Cross‐Coupling

A method for enantioselective desymmetrization of 1,1‐diborylalkanes through a stereoselective Pd‐catalyzed Suzuki–Miyaura cross‐coupling has been thoroughly optimized. The most effective ligand was found to be a α,α,α,α‐tetra‐aryl‐1,3‐dioxolane‐4,5‐dimethanol (TADDOL)‐derived phosphoramidite. Results show that in order to achieve high selectivity, a suitable balance between the sterics of the aryl groups and the amino group on the ligand must be achieved. While the base has been known to facilitate transmetallation in cross‐coupling reactions, mechanistic studies on this desymmetrization process reveal that the base, in the presence of KHF₂, likely plays an additional role in the hydrolysis of the pinacol boronates to the corresponding boronic acids. Through an in depth optimization of the chiral ligand and mechanistic studies, it was possible to obtain ee values over 90 % for several aryl bromides and to develop a reliably scalable process (up to one gram of 1,1‐diborylalkane substrate).     

Palladium‐Catalyzed Asymmetric Aminohydroxylation of 1,3‐Dienes

A Pd^II‐catalyzed asymmetric aminohydroxylation of 1,3‐dienes with N‐tosyl‐2‐aminophenols was developed by making use of a chiral pyridinebis(oxazoline) ligand. The highly regioselective reaction provides direct and efficient access to chiral 3,4‐dihydro‐2H‐1,4‐benzoxazines in high yield and enantioselectivity (up to 96:4 e.r.). The reaction employs readily available N‐tosyl‐2‐aminophenols as a unique aminohydroxylation reagent and is complementary to known asymmetric aminohydroxylation methods.     

酒石酸衍生物促进的醛酮不对称烷基加成反应研究进展

酒石酸分子具有含两个手性碳原子的对称结构, 且价廉易得. 因此, 酒石酸及其衍生物在不对称合成领域被广泛应用, 其中α,α,α’,α’-四苯基-2,2-二甲基-1,3-二氧环戊烷-4,5-二甲醇(简称TADDOL)及其类似物、手性酰氧硼烷(简称CAB)等促进的不对称催化反应研究得更为深入和细致. 综述了近年来TADDOL和CAB等作为手性配体在二乙基锌试剂与醛酮、烯丙基有机金属试剂以及烷基铈试剂与醛的加成反应中的应用, 同时简要地介绍了各手性配体的催化效果.     

立体选择性合成2-(a-噻吩甲酰基)-3-取代苯基-4-乙氧羰基-5-甲基-反式-2,3-二氢呋喃

溴化(a-噻吩甲酰基)甲基三苯鉮1与3-取代苯甲叉基-2,4-戊二酮 2以碳酸钾为碱,在苯中55℃条件下反应,可以较好的收率、高立体选择性地生成反-2-(a-噻吩甲酰基)-3-取代苯基-4-乙氧羰基-5-甲基-2,3-二氢呋喃3。产物结构均经波谱予以确定。本文还提出了生成产物的可能机理。     

Asymmetric Synthesis of 2,4,5‐Trisubstituted Δ2‐Thiazolines

Δ²‐Thiazolines are interesting heterocycles that display a wide variety of biological characteristics. They are also common in chiral ligands used for asymmetric syntheses and as synthetic intermediates. Herein, we present asymmetric routes to 2,4,5‐trisubstituted Δ²‐thiazolines. These Δ²‐thiazolines were synthesized from readily accessible/commercially available α,β‐unsaturated methyl esters through a Sharpless asymmetric dihydroxylation and an O→N acyl migration reaction as key steps. The final products were obtained in good yields with up to 97 % enantiomeric excess.     

α‐ZrP/Uracil/Cu2+ nanoparticles as an efficient catalyst in the Morita‐Baylis‐Hillman reaction

A facile synthesis of uracil‐Cu²⁺ nanoparticles immobilized on alpha‐zirconium hydrogen phosphate (α‐ZrP), abbreviated as α‐ZrP/Uracil/Cu²⁺, was presented. This compound was synthesized by the thermal method and used as a reusable catalyst for the Morita‐Baylis‐Hillman reaction without any additives. First, (3‐ iodopropyl) trimethoxysilane as a linker is reacted with α‐ZrP support to give the α‐ZrP/IPTMOS. Addition of uracil and then the addition of copper (II) acetate to α‐ZrP/IPTMOS results in the production of selected catalyst. The Morita‐Baylis‐Hillman reaction catalyzed by α‐ZrP/Uracil/Cu^{2 +} demonstrated high product yield, short reaction time and a straightforward work‐up. The catalyst with enough outside surface was easily recovered using centrifugation and reused five times without a significant reduction in its activity.     

N‐(tert‐Butoxycarbonyl)‐O‐allyl‐l‐seryl‐α‐aminoisobutyryl‐l‐valine methyl ester: a protected tripeptide with an allylated serine residue

The title compound [systematic name (6S,12S)‐methyl 6‐(allyloxymethyl)‐12‐isopropyl‐2,2,9,9‐tetramethyl‐4,7,10‐trioxo‐3‐oxa‐5,8,11‐triazatridecan‐13‐oate], C₂₁H₃₇N₃O₇, containing the little studied O‐allyl‐l ‐serine residue [Ser(All)], crystallizes in the monoclinic space group C2 with one molecule in the asymmetric unit. The compound is an analogue of the Ser140‐Val142 segment of the water channel aquaporin‐4 (AQP4). It forms a distorted type‐II β‐turn with a P_II–3_10L–P_II backbone conformation (P_II is polyproline II). The overall backbone conformation is markedly different from that of the CO(Pro139)–Val142 stretch of rat AQP4, but is quite similar to the corresponding segment of human AQP4, despite significant differences at the level of the individual residues. The side chain of the Ser(All) residue adopts a gauche conformation relative to the backbone CO—C^α and C^α—N bonds. The H atoms of the two CH₂ groups in the Ser(All) side chain are almost eclipsed. The crystal packing of the title compound is divided into one‐molecule‐thick layers, each layer having a hydrophilic core and distinct hydrophobic interfaces on either side.     

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.