Total synthesis of 3,4-dihydroxyprolines, -threo- -norvaline and (2S,3R,4R)-2-amino-3,4-dihydroxytetrahydrofuran-2-carboxylic acid methyl ester

The Henry reaction between -glyceraldehyde and ethyl nitroacetate allowed the practical development of a diastereoselective synthesis of 3,4,5-trihydroxy-2-nitropentanoic acid esters, which were reduced to polyoxamic acids, which were used in a new diastereoselective synthesis of 3,4-dihydroxyprolines and new enantioselective syntheses of -threo- -norvaline and (2S,3R,4R)-2-amino-3,4-dihydroxytetrahydrofuran-2-carboxylic acid methyl ester.     

Stereocontrol of the Schiff Base of Substituted Benzaldehyde to Staudinger Cycloaddition Reaction

Syntheses of 4 novel chiral azetidin-2-one derivatives,which were characterized by ^1H NMR,IR,specific rotation and elemental analysis,through Staudinger cycloaddition reaction of Schiff base of benzaldehyde with chlorine substitution at different position in benzene ring,were described.For the first time,this type of 3S,4R configuration azetidin-2-one monocrystals with many chiral centers [(3S,4R)-3-hydroxy-N-[(S)-(1-phenyl)ethyl]-4-(2‘‘-chlorophenyl)-azetidin-2-one monocrystal]were obtained,the structures of which were determined by X-ray diffraction analysis.The effects of Schiff base of benzaldehyde with chlorine substitution at different position in benzene ring on stereoselectivity of Staudinger cycloaddition reaction products were discussed and the results are showed as below:2-chlorophenyl Schiff base favored to yield 3S,4R configuration product,but 4-chlorophenyl Schiff base favored to yield 3R,4S configuration product.The reaction orientation of 2,4-dichlorophenyl Schiff base was determined by corporate effect of 2- and 4-chlorine,and that of the 4-chlorine was more obvious.In contrast to 4-chlorophenyl,although the main product was 3R,4S configuration,3-chlorophenyl owned lower selectivity.     

Total Synthesis of (+)‐Gracilamine Based on an Oxidative Phenolic Coupling Reaction and Determination of Its Absolute Configuration

The enantioselective total synthesis of (+)‐gracilamine ( 1 ) is described. The strategy features a diastereoselective phenolic coupling reaction followed by a regioselective intramolecular aza‐Michael reaction to construct the ABCE ring system. The configuration at C3a in 1 was controlled by the stereocenter at C9a, which was selectively generated (91 % ee) by an organocatalytic enantioselective aza‐Friedel–Crafts reaction developed by our research group. This synthesis revealed that the absolute configuration of (+)‐gracilamine is 3aR, 4S, 5S, 6R, 7aS, 8R, 9aS.     

Chromium‐Mediated Dearomatization: Application to the Synthesis of Racemic 15‐Acetoxytubipofuran and Asymmetric Synthesis of Both Enantiomers

An efficient dearomatization process of [Cr(arene)(CO)₃] complexes initiated by a nucleophilic acetaldehyde equivalent is detailed. It generates in a one‐pot reaction three C? C bonds and two stereogenic centers. This process allowed a rapid assembly of a cis‐decalin ring system incorporating a homoannular diene unit in just two steps starting from aromatic precursors (Scheme 2). The method was applied to the total synthesis of the eudesmane‐type marine furanosesquiterpene (±)‐15‐acetoxytubipofuran ( 2 ). Two routes were successfully used to synthesize the γ‐lactone precursor of the furan ring. The key step in the first approach was a Pd‐catalyzed allylic substitution (Scheme 3), while in the second approach, an Eschenmoser–Claisen rearrangement was highly successful (Scheme 4). The Pd‐catalyzed allylic substitution could be directed to give either the (normal) product with overall retention as major diastereoisomer or the unusual product with inversion of configuration (see Table). For the synthesis of the (?)‐enantiomer (R,R)‐ 2 of 15‐acetoxytubipofuran, an enantioselective dearomatization in the presence of a chiral diether ligand was implemented (Scheme 7), while the (+)‐enantiomer (S,S)‐ 2 was obtained via a diastereoselective dearomatization of an arene‐bound chiral imine auxiliary (Scheme 8). Chiroptical data suggest that a revision of the previously assigned absolute configuration of the natural product is required.     

An Expedient Approach to the Benzopyran Core: Application to Synthesis of the Natural Products(±)-Xyloketals and(±)-Alboatrin

A mild and efficient protocol for the synthesis of the benzopyran ring has been described and a series of chromans compounds is reported, the yield is from 72% to 95%. The diadduct tended to angular product and showed good regioselectivity. This strategy was applied for the benzopyran derived natural products (±)‐xyloketals and (±)‐alboatrin. The crystal of compound 9 exhibited centro‐symmetric space group, containing two isomers in one unit. The relative configurations were 1R,10R,15S and 34S,22R,30S, respectively.     

Minor Enantiomer Recycling: Metal Catalyst,Organocatalyst and Biocatalyst Working in Concert

A minor enantiomer recycling one‐pot procedure employing two reinforcing chiral catalysts has been developed. Continuous regeneration of the achiral starting material is effected via selective enzyme‐catalyzed hydrolysis of the minor product enantiomer from Lewis acid–Lewis base catalyzed addition of acyl cyanides to prochiral aldehydes in a two‐phase solvent system. The process provides O‐acylated cyanohydrins in close to perfect enantioselectivities, higher than those obtained in the direct process, and in high yields. A combination of a (S,S)‐salen Ti Lewis acid and Candida antarctica lipase B provides the products with R absolute configuration, whereas the opposite enantiomer is obtained from the (R,R)‐salen Ti complex and Candida rugosa lipase.     

Highly Diastereoselective Synthesis of Syn‐1,3‐Dihydroxyketone Motifs from Propargylic Alcohols via Spiroepoxide Intermediates

Syn dihydroxyketone motifs are embedded in a wide range of biologically active natural products, however the development of stereoselective synthetic methods to assemble these structures has proven a challenging task. We report a highly diastereoselective method for the synthesis of syn dihydroxyketones from propargylic alcohols, with wide scope for application in natural product synthesis. The reaction sequence involves regioselective cyclisation of propargylic alcohols with incorporation of a triketone to give enol dioxolanes that are then diastereoselectively epoxidised to form unusual spiroepoxide intermediates. Hydrolysis affords syn dihydroxyketones as essentially single diastereisomers. The reaction sequence is operationally simple, of wide substrate scope, and remarkably can be efficiently carried out as a one‐pot process with no loss of overall yield or diastereoselectivity.     

Further Syntheses of Optically Active Verrucarinic Acid, 43rd Communication of Verrucarins and Roridins

Two new syntheses of verrucarinic acid (2S, 3R-dihydroxy-3-methylpentanoic acid) and its derivatives, suitably protected for the further conversion to macrocyclic trichothecenes, are described. The first one makes use of a diastereoselective alkylation of a (?)-(S)-malic acid ester and the regioselective reductin of one carboxyl function toa methyl group. The second approach involves a stereoselective addition of an allylsilane to a chiral glyoxylate.     

Highly Enantioselective Formation of α‐Allyl‐α‐Arylcyclopentanones via Pd‐Catalysed Decarboxylative Asymmetric Allylic Alkylation

A highly enantioselective Pd‐catalysed decarboxylative asymmetric allylic alkylation of cyclopentanone derived α‐aryl‐β‐keto esters employing the (R,R)‐ANDEN‐phenyl Trost ligand has been developed. The product (S)‐α‐allyl‐α‐arylcyclopentanones were obtained in excellent yields and enantioselectivities (up to >99.9 % ee). This represents one of the most highly enantioselective formations of an all‐carbon quaternary stereogenic center reported to date. This reaction was demonstrated on a 4.0 mmol scale without any deterioration of enantioselectivity and was exploited as the key enantioselective transformation in an asymmetric formal synthesis of the natural product (+)‐tanikolide.     

Substrate‐Dependent Stereospecificity of Tyl‐KR1: An Isolated Polyketide Synthase Ketoreductase Domain from Streptomyces fradiae

The stereospecificity of an enzymatic reaction depends on the way in which a substrate and its enantiomer bind to the active site. These binding modes cannot be easily predicted. We have studied the stereospecificity and stereoselectivity of the ketoreductase domain Tyl‐KR1 of the tylactone polyketide synthase from Streptomyces fradiae by analysing the stereochemical outcome of the reduction of five different keto ester substrates. The absolute configuration of the Tyl‐KR1 reduction products was determined by using vibrational circular dichroism (VCD) spectroscopy combined with quantum chemical calculations. The conversion of only one of the tested substrates, 2‐methyl‐3‐oxovaleric acid N‐acetylcysteamine thioester, afforded the expected anti‐(2R,3R) configuration of the α‐methyl‐β‐hydroxyl ester product, representing the stereochemistry observed for the physiological polyketide product tylactone. For all other substrates, which were modified with respect to the type of ester and/or the chain length (C₄ instead of C₅), the opposite configuration (anti‐(2S,3S)) was obtained with significant enantio‐ and diastereoselectivity. Inversion of both stereocentres suggests completely different binding modes invoked by only minor modifications of the substrate structure.     

Versatile One‐Step One‐Pot Direct Aldol Condensation Promoted by MgI2

A true one‐step one‐pot aldol‐reaction procedure has been developed for the synthesis of β‐hydroxy ketones and esters. The reaction can be run at room temperature by simply mixing four components in CH₂Cl₂, with medium‐to‐high yields of aldol products obtained after regular workup. Mechanistically, the process probably proceeds via Mg‐enolate formation of the ketone or ester component, followed by addition to the electrophilic aldehyde.     

One‐Pot Sequential Organocatalysis: Highly Stereoselective Synthesis of Trisubstituted Cyclohexanols

A highly diastereoselective (d.r. >99:1) and enantioselective (ee value up to 96 %) synthesis of trisubstituted cyclohexanols was achieved by using a one‐pot sequential organocatalysis that involved a quinidine thiourea‐catalyzed tandem Henry–Michael reaction between nitromethane and 7‐oxo‐hept‐5‐en‐1‐als followed by a tetramethyl guanidine (TMG)‐catalyzed tandem retro‐Henry–Henry reaction on the reaction products of the tandem Henry–Michael reaction. Through a mechanistic study, it has also been demonstrated that similar results may also be achieved with this one‐pot sequential organocatalysis by using the racemic Henry product as the substrate.     

Stereocontrolled Synthesis of syn‐β‐Hydroxy‐α‐Amino Acids by Direct Aldolization of Pseudoephenamine Glycinamide

β‐Hydroxy‐α‐amino acids figure prominently as chiral building blocks in chemical synthesis and serve as precursors to numerous important medicines. Reported herein is a method for the synthesis of β‐hydroxy‐α‐amino acid derivatives by aldolization of pseudoephenamine glycinamide, which can be prepared from pseudoephenamine in a one‐flask protocol. Enolization of (R,R)‐ or (S,S)‐pseudoephenamine glycinamide with lithium hexamethyldisilazide in the presence of LiCl followed by addition of an aldehyde or ketone substrate affords aldol addition products that are stereochemically homologous with L ‐ or D ‐threonine, respectively. These products, which are typically solids, can be obtained in stereoisomerically pure form in yields of 55–98 %, and are readily transformed into β‐hydroxy‐α‐amino acids by mild hydrolysis or into 2‐amino‐1,3‐diols by reduction with sodium borohydride. This new chemistry greatly facilitates the construction of novel antibiotics of several different classes.     

Total Synthesis of (−)-(2R)-Dihydromyricoidine

An asymmetric synthesis of the spermidine alkaloid (?)-(2R)-dihydromyricoidine ( 5 ) was performed by employing two ring-enlargement reactions. The chiral center was introduced by a diastereoselective Michael addition of perhydropyridazine ( 7 ) to the α,β-unsaturated ester 6 . The (Z)-C?C bond was obtained by a selective Wittig reaction. The synthetic compound 5 was found to have a negative value for the specific rotation. This is in contrast to that of the natural product reported in the literature. Therefore, as an outcome of this synthesis, the absolute configuration of the natural alkaloid should be inverted to be as shown in structure V .     

Zinc Hydrogensulfate as an Efficient Catalyst for Preparation of β-Amido Carbonyl Compounds

A one‐pot and efficient three‐component condensation of benzaldehyde derivatives, enolizable ketones or ketoesters, acetyl chloride, and acetonitrile or benzonitrile under ambient conditions in the presence of zinc hydrogensulfate for the synthesis of β‐amido carbonyl compounds is described. The simple experimental procedure, high to excellent yields of products and preparation of diastereoselective β‐acetamido ketoesters are strong features of the presented method.     

CuII‐Containing 1‐Aminocyclopropane Carboxylic Acid Oxidase Is an Efficient Stereospecific Diels–Alderase

In the context of developing ecofriendly chemistry, artificial enzymes are now considered as promising tools for synthesis. They are prepared in particular with the aim to catalyze reactions that are rarely, if ever, catalyzed by natural enzymes. We discovered that 1‐aminocyclopropane carboxylic acid oxidase reconstituted with Cu^II served as an efficient artificial Diels–Alderase. The kinetic parameters of the catalysis of the cycloaddition of cyclopentadiene and 2‐azachalcone were determined (K_M=230 μm , k_app=3 h^?1), which gave access to reaction conditions that provided quantitative yield and >99 % ee of the (1S,2R,3R,4R) product isomer. This unprecedented performance was rationalized by molecular modeling as only one docking pose of 2‐azachalcone was possible in the active site of the enzyme and this was the one that leads to the (1S,2R,3R,4R) product isomer.     

Asymmetric Synthesis of the cis‐ and trans‐3,4‐Dihydro‐2,4,8‐trihydroxynaphthalen‐1(2H)‐ones

A short and efficient protocol for the asymmetric synthesis of cis‐ and trans‐3,4‐dihydro‐2,4,8‐trihydroxynaphthalen‐1(2H)‐one ( 1 and 2 , resp.) is described, with a phthalide annulation as the key step. Introduction of a OH substituent at position 2 was performed by Sharpless dihydroxylation of a silyl enol ether or by means of an N‐sulfonyloxaziridine. The absolute configuration of each isomer was determined via Mosher‐ester derivatives. By comparison with previously recorded CD spectra of our natural sample, we established that the natural trans‐ and cis‐isomers from Ceratocystis fimbriata sp. platani were the (?)‐(2S,4S)‐isomer (?)‐ 2 and the (+)‐(2S,4R)‐isomer (+)‐ 1 , respectively.     

Synthesis of chiral hydroxythiolanes as potential catalysts for asymmetric organozinc additions to carbonyl compounds

Optically active 3‐hydroxythiolane was stereospecifically synthesized from L ‐aspartic acid and oxidized to give both diastereomeric S‐oxides, which were chromatographically separated and their configuration was determined. Starting from natural (+)‐(R,R)‐tartaric acid, C₂‐symmetric trans‐(R,R)‐3,4‐dihydroxythiolane was stereospecifically synthesized for the first time. Some of its monofunctionalized derivatives as well as its S‐oxide were also obtained and characterized. meso‐cis‐3,4‐Dihydroxythiolane was obtained in a similar way from meso‐tartaric acid and subjected to desymmetrization either by a lipase‐promoted acetylation or hydrolysis of the corresponding O,O'‐diacetyl derivative, to give a chiral monoacetate with ee up to 36%. After its oxidation two diastereomeric sulfoxides were obtained which were separated by chromatography. The crystalline one was subjected to X‐ray analysis and its absolute configuration was determined as 1S, 3S, 4R. All the optically active products were checked as potential catalysts for asymmetric addition of diethylzinc to benzaldehyde. However, they proved to have a very low catalytic activity: yields of the products were in the range 10–90% but ee only up to 10%. A conclusion was drawn that in this type of reaction neither is the hydroxy sulfide (sulfoxide) moiety capable of properly binding diethylzinc, nor does the sulfinyl group exert its normal stereoinduction. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:93–222, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20076     

Asymmetric Mannich‐Type Synthesis of N‐Phosphinyl α‐Aminophosphonic Acid Monoesters

A convenient diastereoselective synthesis of diisopropyl (2R,3R)‐3‐{{{(R/S)‐aryl[(diethoxyphosphinyl)amino]methyl}hydroxyphosphinyl}oxy}‐2‐hydroxybutanedioate through Mannich‐type reactions is reported. The reactions take place under mild conditions in good yields, and this makes it possible to introduce various substituents at the α‐position to the P‐atom of α‐aminophosphonates. The chiral diisopropyl (4R,5R)‐2‐chloro‐1,3,2‐dioxaphospholane‐4,5‐dicarboxylate ( 3 ) was found to be a good phosphonylating agent in this stereoselective reaction.     

Effective asymmetric synthesis of the key chiral building blocks of 20(S)- and 20(R)-camptothecins

Abstract  

An effective diastereoselective synthesis of (S)-N,N-diethyl-2-formyl-2-(methoxymethoxy)butanamide and (S)-2-formyl-2-(methoxymethoxy)butanoic acid ethyl ester, which are two key chiral building blocks for the synthesis of 20(S)-camptothecins, has been developed by employing an asymmetric bromolactonization using (R)-proline. The (R) compounds were also synthesized to obtain 20(R)-camptothecin.