Natural products syntheses based on the biotransformation using biocatalyst

This review summarizes the chemoenzymatic synthesis of the biologically active natural products based on a combination of chemical diastereoselectivity and enzymatic enantioselectivity using biocatalyst. Asymmetric reduction of 2-methyl-3-keto ester with yeast gave the optically active syn-2-methyl-3-hydroxy ester, which was converted to natural product such as (-)-oudemansin B. Asymmetric hydrolysis of 3-acetoxy-2-methy esters possessing syn- or anti-structure afforded the optically active 3-hydroxy-2-methyl esters and 3-acetoxy-2-methy esters corresponding to the starting material. One of these optically active 3-hydroxy-2-methyl esters was converted to aglycone of macrolide, venturicidins A and B possessing 10 chiral centers. Both primary alcohols possessing a chiral center at β-position of hydroxyl group and secondary alcohols were subjected to the lipase-assisted acylation in the presence of acyl donor to afford the optically active esters and the optically active alcohols corresponding to the starting material. These optically active compounds were converted to the biologically active natural products such as bisabolane type sesquiterpenes, decaline type diterpenes or triterpenes, nikkomycin B, (+)-asperlin, (-)-chuangxinmycin, (-)-indolmycin, cystothiazoles melithiazols, myxothiazols and piericidins possessing antifungal and cytotoxicic activities, inhibition of NADH oxidation, etc. Reaction of primary alcohol and glucose using immobilized β-glucosidase gave alkyl β-glucosides in high yield. Pentaacetate of allyl β-glucoside was subjected to Mizoroki-Heck type reaction with phenylboronic acid derivatives to give phenylpropenoid β-D-glucopyranosid congeners.     

Synthesis and its application to the synthesis of biologically active natural products of new and versatile chiral building blocks

This article describes a design and synthesis of new and versatile chiral building blocks and its application to the biologically active natural product synthesis. The chiral building blocks were prepared using a biocatalysis in an enantiomerically pure state. As an application of the above chiral building blocks to the synthesis of biologically active natural product, we demonstrated the diastereodivergent synthesis of the 3-piperidinol alkaloids cassine, spectaline, prosafrinine, iso-6-cassine, prosophylline, prosopinine, and also established the flexible route to the 5,8-disubstituted indolizidine or 1,4-disubstituted quinolizidine type of Dendrobates alkaloids. As another application to the synthesis of biologically active alkaloids, we accomplished the first enantioselective total synthesis of marine alkaloids clavepictines A, B, and pictamine using a highly stereoselective Michael type quinolizidine ring closure reaction as the crucial step, and the first total synthesis of a marine alkaloid lepadin B was also achieved using aldol cyclization controlled by a A strain.     

Development of new methods in asymmetric reactions and their applications

Several novel methods using chiral reagents and biocatalysts for asymmetric reactions are described. Among those reactions, asymmetric reduction via a novel tandem Michael addition/Meerwein-Ponndorf-Verley reduction of acyclic alpha,beta-unsaturated ketones using a chiral mercapto alcohol, asymmetric synthesis of allene-1,3-dicarboxylate via crystallization induced asymmetric transformation, and improved asymmetric nitroolefination of lactones and lactames at alpha-carbon using new chiral reagents were developed. In the reactions using biocatalysts, asymmetric dealkoxycarbonylation of bicyclic beta-keto diesters having sigma-symmetry with lipase or esterase to give optically active beta-keto esters, the asymmetric reduction of bicyclic 1,3-diketones having sigma-symmetry with Baker's yeast to give optically active keto alcohols, and the asymmetric aldol reaction of glycine with threonine aldolase were also developed. The above mentioned products were effectively utilized as chiral building blocks for the asymmetric synthesis of natural products and drugs.     

Metal-free direct biaryl coupling reaction of heteroaromatic compounds via iodonium intermediate

Biaryl compounds are versatile building blocks in the synthesis of natural products, pharmaceuticals, agricultural chemicals and π-conjugated organic materials. This review describes a recent progress for the biaryl cross-coupling reaction of heteroaromatic compounds using hypervalent iodine reagent. Our novel biaryl coupling reaction is a unique method for constructing various heteroaromatic biaryls without use of transition metal catalysts. From mechanistic point of view, the coupling reaction was realized through stable iodine intermediate generated from heteroaroamatic compound and iodine (III) reagent.     

Chemical studies on the analgesic indole alkaloids from the traditional medicine (Mitragyna speciosa) used for opium substitute

The leaves of a tropical plant, Mitragyna speciosa Korth. (Rubiaceae), have been traditionally used as a substitute for opium. By phytochemical studies on the constituents of the plant growing in Thailand as well as in Malaysia, several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids including new natural products were isolated. The structures of these new compounds were elucidated by the modern spectroscopic methods and/or chiral-total syntheses. The chiral total synthesis of (-)-mitragynine, a major component of this plant, was achieved. Potent opioid agonistic properties of mitragynine, which acts on mu- and delta-opioid subtype receptors, and of mitragynine pseudoindoxyl, whose analgesic activity is more potent than that of morphine, were clarified in in vitro experiments. The essential structural features in mitragynine for revealing the analgesic activity were elucidated by pharmacological evaluation of the natural and synthetic mitragynine derivatives.     

Efficient chiral control based on five-membered heterocyclic and related systems

The synthetic potential of some simple five-membered heterocycles, including 2-oxazolone, 1,3-dihydro-2-imidazolone and 2-thiazolone as building blocks for chiral polyfunctional compounds as well as chiral heterocyclic auxiliaries for asymmetric synthesis is reviewed. The stereodefined introduction of easily replaceable groups to the 4,5-olefinic moiety of the 2-oxazolone ring to give versatile chiral synthons, followed by stereospecific and stepwise substitution, provides a working and versatile strategy for achieving a chiral synthesis, which leads to the preparation of a wide variety of 2-amino alcohols of biological interest. Sterically constrained chiral 2-oxazolidinones and the derived conformationally rigid amino alcohols, which are derived from cycloaddition reactions of the 2-oxazolone to cyclic dienes such as 9,10-dimethylanthracene and hexamethylcyclopentadiene, represent excellent chiral auxiliaries and chiral ligands which are of general use in asymmetric synthesis. The strategy developed using 2-oxazolone can also be used in the cases of the structurally similar 1,3-dihydro-2-imidazolone and 2-thiazolone derivatives.     

A strategic approach to the development of capillary electrophoresis chiral methods for pharmaceutical basic compounds using sulfated cyclodextrins.

Enantioseparations of basic pharmaceutical compounds were investigated using different types of sulfated cyclodextrins as chiral selectors. A general strategy for method development was described, together with enantiomeric separations of a number of pharmaceutical related compounds. Based on this strategy, systematic method development approaches for several selected compounds were performed by modifying method parameters, such as the concentration of the chiral selectors, buffer pH, type of organic modifiers, buffer type, temperature and applied voltage. The results of the investigation elucidated the separation mechanism. Many practical aspects were also discussed through several specific examples in order to demonstrate how to develop and validate a precise, sensitive, accurate and rugged separation.     

Synthesis and applications of novel, highly efficient HPLC chiral stationary phases: a chiral dimension in drug research analysis

This review provides an overview of the synthesis and application of stable and versatile HPLC chiral stationary phases (CSPs), with emphasis placed on the binding strategies developed to anchor several structurally different chiral selectors to silica-gel microparticles. In addition, selected applications relating to the use of these CSPs for the direct resolution of racemates of biological and pharmaceutical relevance will be described. This review discusses enantioselective molecular recognition and dynamic stereochemistry of stereolabile compounds with reference to receptor-based chiral stationary phases (CSPs) and dynamic HPLC on CSPs, respectively.     

Sesquiterpenes from Alisma plantago-aquatica

Six sesquiterpenes, including three guaiane type sesquiterpenes (1–3), one oplopanone type sesquiterpene (4), one xanthane type sesquiterpene (5) and one salvialane type sesquiterpene (6), were isolated from Alisma plantago-aquatica for the first time. The structures of these six compounds were elucidated as alismoxide (1), alismol (2), orientalol B (3), oplopanone (4), gibberodione (5), and 7α,10α-epoxy-salvialan-10β-ol (6), respectively, among which 6 was a new natural product. Xanthane type and salvialane type sesquiterpenes were obtained from the genus Alisma for the first time. In addition, a plausible biosynthetic pathway for all isolates was discussed.     

Synthesis and properties of N-substituted saccharin derivatives

Four different routes for the synthesis of saccharin containing peptides were studied. While reactions between saccharin sodium and alpha-halogeno acids were limited to two examples, reactions of sulfobenzoic anhydride (4) or saccharin-N-carboxylate (6) with amino acid esters yielded the ring opened products 5 and 7. Finally, we found, that the reaction between the benzoxathiol derivative 8 and amino acid derivatives represents a versatile route to the peptidic compounds 9 and 11. Hydrolysis and hydrogenolysis were studied, and by combination of the different routes the "saccharin tripeptides" 18 were obtained. Structures and stereochemistry were elucidated by spectroscopic and chromatographic methods. Selected compounds were tested as sweeteners or as inhibitors of elastase, but no exiting results were found.     

Asymmetric reactions based on activation and structure control of molecule--asymmetric reaction of lithiated nucleophiles

The methodology we developed relies on an external chiral coordinating reagent that forms a deaggregated chelate complex with organolithium reagents. Under the positive control of a chiral dimethyl ether of stilbenediol 4, an asymmetric conjugate addition reaction of organolithium reagents with unsaturated imines and esters proceeded successfully to yield the corresponding addition products with reasonably high stereoselectivity. The sense of stereochemistry is predictable based on a coordination model. The methodology has been extended to a catalytic asymmetric 1,2-addition reaction of organolithium reagents with imines. An enantiotopic group differentiating the opening of cyclohexene oxide with organolithium was also mediated by a chiral ligand. The asymmetric Horner-Wadsworth-Emmons reaction of phosphonates and Peterson reaction of alpha-silylester with 4-substituted cyclohexanone were another successful extension of the methodology. A three-component reagent of lithium ester enolate, lithium amide, and chiral diether reacts with imines to afford beta-lactam with reasonably high enantioselectivity. Tridentate aminoether ligands were also shown to affect the catalytic asymmetric addition of lithium ester enoaltes to imines, giving beta-lactams with high enantioselectivity. Asymmetric conjugate addition of lithium amide to enoates was mediated by a chiral diether ligand to give the beta-aminoester with high yield and enatioselectivity. The methodology has been successfully applied to an asymmetric synthesis of biologically potent compounds. Dihydrexidine, a promising anti-Parkinsonism candidate, and salsolidine, a representative isoquinoline alkaloid, have been synthesized using asymmetric addition reactions of organolithium reagents as the key steps.     

Efficient one-pot, three-component synthesis of a library of pyrrolo[1,2-c]pyrimidine derivatives

Herein is reported a simple and efficient one-pot three-component synthesis of pyrrolo[1,2-c]pyrimidine derivatives starting from various substituted pyrimidines, 2-bromoacetophenones, and electron deficient alkynes in epoxides acting both as reaction medium and HBr scavanger. This method proved to be very lucrative and avoids formation of ylide inactivation products. The synthesis represents an environmentally benign alternative to classical methods. The new library of compounds was briefly characterized regarding the improved Lipinski rule to asses the potential drug-likeness of the compounds. The majority of compounds are statisfing the Lipinski rule.     

A novel total synthesis of kinsenoside and goodyeroside A relying on the efficient reaction of the chiral 2(5H)-furanones

A new total synthesis of the bioactive compounds, kinsenoside (1) and goodyeroside A (2), has been accomplished from readily available starting materials. The chiral 2(5H)-furanone 5a and its enantiomer 5b were employed as the key chiral intermediates to construct the chiral glycosides 8a and 8b with the appropriate stereochemistry. The spectral data of the target compounds and their acetylated derivatives 1a and 2b are identical with those of the natural and corresponding acetylated products.     

多糖聚合物手性固定相高效液相色谱法拆分二苯甲醇类手性化合物

目的：对6个氯取代的二苯甲醇类手性化合物建立HPLC分析方法。对拆分反应进行监测,并用于拆分产物光学纯度的分析测定。方法：在正相高效液相模式下,采用Chiralcel OD—H和Chiralcel OB-H两种纤维素类手性柱以及Chiralpak AD—H直链淀粉类手性柱,以正己烷-异丙醇或正己烷-异丙醇-三氟乙酸溶剂系统为流动相,流速：0．5ml·min^-1,检测波长：210nm。结果：采用上述方法,基线拆分了合成手性中枢性镇咳药左旋盐酸氯哌啶[（-）cloperastine hydrochloride]的主要原料4-氯二苯甲醇等6个氯取代的二苯甲醇类手性化合物,建立了快速的手性高效液相色谱法。结论：本方法简便准确,可对手性合成反应进行监测和中间体质量控制;同时．对4-氯二苯甲醇和3-氟二苯甲醇的高效液相手性分析方法进行了对比研究。     

Carbon-carbon bond formation based on alkenylphosphonates]

We have been engaged in the development of asymmetric conjugate addition reactions of lithium thiolates, organolithiums and organocopper reagents under the control of external chiral ligands and we have also developed an efficient asymmetric Horner-Wadsworth-Emmons (HWE) reaction using an external chiral Ligand. We attempted to synthesize axial chiral allenes by combination of these conjugate addition reaction and HWE reaction. In the course of this study, we found that Michael-aldol reaction of alkenylphosphonates 1 using LDA and aldehydes results in the direct formation of alpha,beta-unsaturated hydroxyphosphonate 4, which was efficiently converted to allene by treatment with KH or KH-18-crown-6. Furthermore, allenes were synthesized by sequential double HWE reaction in one-flask manner starting from methylenebisphosphonate 8. The key to success is a metal exchange of intermediate lithium alkoxide 4-Li to potassium alkoxide 4-K by the addition of t-BuOK. As our continuous study of carbon-carbon bond formation based on alkenylphosphonates, a cyclization reaction of bisalkenylphosphonate 6 was developed. Although the treatment of 6 with organolithium reagents afforded a mixture of addition-cyclization product 9 and deprotonation-cyclization product 10, the treatment of 6 with LDA gave 10 selectively. These cyclization methods were applied to the synthesis of efficient chiral phosphine ligands.     

Acid-base catalysis of chiral Pd complexes: development of novel asymmetric reactions

Using a unique character of the chiral palladium complexes 1 and 2, several types of novel catalytic asymmetric reactions have been developed. In contrast to the conventional Pd(0)-catalyzed reactions, these complexes function as an acid-base catalyst. Thus active methine compounds were activated to form chiral palladium enolates, which underwent the enantioselective Michael reaction and Mannich-type reaction with up to 99% ee. Interestingly, these palladium enolates acted cooperatively with a strong protic acid activating the electrophiles, formed concomitantly during the formation of the enolates, whereby the C-C bond-forming reaction was promoted. In addition, this palladium enolate chemistry was also applicable to the electrophilic asymmetric fluorination reactions, and thus various carbonyl compounds including beta-ketoesters, beta-ketophosphonates, and oxindoles were fluorinated in a highly enantioselective manner (up to 98% ee). It is advantageous that these reactions were carried out in environmentally friendly alcoholic solvents such as ethanol, and exclusion of air and moisture is not necessary.     

脱氧三尖杉酯碱和高三尖杉酯碱的立体专一性合成

本文报道脱氧三尖杉酯碱(Ⅵa)和高三尖杉酯碱(Ⅵc)的不对称合成。采用(+)R-对甲苯亚磺酰基乙酸叔丁酯(Ⅰ)与相应的三尖杉碱酮酸酯(Ⅱa)、(Ⅱb)进行立体选择性缩合反应,经过若干步骤,合成了具有C₂′R构型的(Ⅵa)和(Ⅵc)。中间产物(Ⅲa),(Ⅲb)或(Ⅲc)以铝汞齐脱硫得(Ⅳa、(Ⅳc)。再以三氟醋酸处理,选择性水解叔丁酯得(Ⅴa)、(Ⅴc)。最后以重氮甲烷甲酯化。再次证实了(+)R-对甲苯亚磺酰基乙酸叔丁酯(Ⅰ)具有较高的立体选择性反应。     

一种β，γ-不饱和醛的合成及其光化学反应研究

目的设计合成β,γ-不饱和醛,并研究其光化学反应机制,为天然产物及其中间体的光化学合成提供新的参考。方法以异丁醛为原料,经缩合、醛基保护、氧化、Wittig反应、脱水、脱保护基6步反应制得目标化合物。用高压汞灯照射目标化合物后所得产物与β,γ-不饱和甲基酮进行比较分析。结果目标化合物的结构经高分辨质谱、核磁共振谱确证。目标化合物经光照后发生NorrishI型裂解反应,与β,γ-不饱和甲基酮相比,没有发生ODPM重排反应。结论甲基对β,γ-不饱和酮（醛）的光化学反应行为有一定的影响。     

allo-aromadendrane- and picrotoxane-type sesquiterpenes from Dendrobium moniliforme

Eight sesquiterpenes, four stilbene derivatives along with two lignans have been isolated from lipophilic fraction of stems of Dendrobium moniliforme (Orchidaceae). Among the eight sesquiterpenes, one allo-aromadendrane-type and four picrotoxane-type sesquiterpenes were identified to be new compounds, and alpha-dihydropicrotoxinin was isolated as a new natural product. Their structures were established on the basis of spectroscopic analysis.     

Development of boomerang-type intramolecular cascade reactions and application to natural product synthesis]

Intramolecular cascade reaction has received much attention as a powerful methodology to construct a polycyclic framework in organic synthesis. We have been developing "boomerang-type cascade reaction" to construct a variety of polycyclic skeletons efficiently. In the above reactions, a nucleophilic function of substrates changes the character into an electrophile after the initial reaction, and the electrophilic group acts as a nucleophile in the second reaction. That is, the reaction center stepwise moves from one functional group back to the same one via other functional groups. The stream of the electron concerning the cascade reaction is like a locus of boomerang. We show here three different boomerang-type reactions via ionic species or free radicals. 1) Diastereoselective Michael-aldol reaction based on the chiral auxiliary method and enantioselective Michael-aldol reaction by the use of external chiral sources. 2) Short and efficient total syntheses of longifolane sesquiterpenes utilizing intramolecular double Michael addition as a key step. 3) Development of boomerang-type radical cascade reaction of halopolyenes to construct terpenoid skeletons and its regioselectivity.