Acid zeolites as alcohol racemization catalysts: screening and application in biphasic dynamic kinetic resolution

Acid zeolites were screened as heterogeneous catalysts for racemization of benzylic alcohols. The most promising zeolites appeared to be H-Beta zeolites, for which the optimal reaction conditions were studied in further detail. The zeolite performance was compared to that of homogeneous acids and acid resins under similar reaction conditions. In a second part of the research, H-Beta zeolites were applied in dynamic kinetic resolution (DKR) of 1-phenylethanol, which was conducted by means of a two-phase approach and which resulted in yields smoothly crossing the 50% border up to 90%, with an enantiomeric excess of >99%. To explore the applicability of this biphasic methodology, several other substrates were examined in the standard racemization reaction and in the biphasic dynamic kinetic resolution.     

膜反应器中萘普生甲酯的动态拆分

在碱催化连续原位消旋条件下,利用CRL脂肪酶（Candida rugosa lipase）催化的萘普生甲酯立体选择性水解反应。动态拆分制备（S）－普生。使用硫水硅橡胶膜隔离生物催化拆分反应和碱催化消旋反应,解决了常规动态拆分反应中生物催化剂难以承受原位化学消旋苛刻反应条件的难题。为了利于从水－有机溶剂乳化体系中分离产物和克服产物抑制,将亲水半透膜引入搅拌罐反应器,在该膜反应器中进行动态拆分反应。当转化率超过60％时,产物（S）－萘普生的对映体过量值（eep)仍在96％以上,在反应过程中还发现CRL脂肪酶同工酶的转化。     

Y型分子筛固载(1S,2S)-DPEN-Ru(TPP)2催化苯乙酮不对称加氢

采用自由配体法将(1S,2S)-DPEN(1,2-diphenyl-1,2-ethylene-diamine)-Ru(TPP)2(TPP=三苯基膦,triphenylphosphine)配合物封装于NaY沸石分子筛超笼中,制备了(1S,2S)-DPEN-Ru(TPP)2/Y主客体材料(1S,2S)-DPEN=1,2-二苯基-1,2-乙二胺).采用等离子体发射光谱ICP、粉末X射线衍射(XRD)、紫外光谱(UV-Vis)、氮吸附等物理化学手段对所制备材料进行了表征.结果表明,(1S,2S)-DPEN-Ru(TPP)2配合物封装于Y型分子筛超笼中保持了原有的物理化学性能;作为苯乙酮不对称加氢催化剂,在优化条件下,苯乙酮的转化率可达100%,(R)-苯乙醇的对映体过量值(ee值)可达61.0%.该催化剂具有良好的稳定性和重复使用性.     

Chemoenzymatic dynamic kinetic resolution of acyloins

[Reaction: see text]. Acyloins (alpha-hydroxy ketones) are important building blocks in organic synthesis, e.g., for the total synthesis of epothilones. Optically pure acyloins can be obtained by lipase-catalyzed kinetic resolution (KR) of the racemate with, for example, Burkholderia cepacia lipase, but this process suffers from a yield limitation of 50%. To devise a dynamic kinetic resolution (DKR), we studied the racemization of two different acyloins and corresponding esters with various amine bases and ion exchangers. No combination of base and solvent was found that could selectively racemize the acyloin or corresponding ester under the conditions needed for a DKR. In contrast to bases, acidic resins (ARs) were found to racemize the acyloins selectively in n-hexane and in water. Unfortunately, the AR deactivated the lipase, preventing a one-pot DKR. Minor side reactions involving the AR, the substrate acyloin, and the vinyl ester acyl donor were also observed. However, an efficient DKR was made possible by the spatial separation of lipase and ion exchanger, with enzymatic transesterification and AR-catalyzed racemization taking place simultaneously in two compartments connected by a pump loop. The conversion of substrate alcohol was 91%, the selectivity toward the product butyrate ester 90%, and the enantiomeric excess of the (S)-product 93% ee.     

Thiazolylalanine-derived catalysts for enantioselective intermolecular aldehyde-imine cross-couplings

Catalytic asymmetric cross-coupling reactions between aldehydes and N-acylimines have been discovered that employ thiazolylalanine derivatives as catalysts. Alkylation of the thiazolyl moiety, followed by in situ generation of the derived thiazolium ylide using a tertiary amine base, leads to the active catalyst. alpha-Amidoketone products are isolated in up to 90% yield with up to 87% enantiomeric excess (>98% ee after a single recrystallization). The use of a hindered base to suppress product racemization was stimulated by a mechanistic study that revealed an isotope effect on the racemization rate of the product.     

Asymmetric reduction of acetophenone in membrane reactors: comparison of oxazaborolidine and alcohol dehydrogenase catalysed processes

The enantioselective reduction of acetophenone was studied in two different ways. Chemical borane reduction using a homogeneously soluble polymer-bound oxazaborolidine catalyst was carried out in a continuously operated membrane reactor and yielded (R)-phenylethanol in good enantiomeric excess with high space–time yields. An enzymatic reduction using a dehydrogenase two-enzyme system as the catalyst and formate as the hydrogen source was carried out in an extractive bi-membrane reactor and yielded (S)-phenylethanol in excellent enantiomeric excess with a low enzyme consumption. A comparison of the two systems with respect to space–time yield, total turnover number and other parameters is made.     

Acid Zeolites as Alcohol Racemization Catalysts: Screening and Application in Biphasic Dynamic Kinetic Resolution

Acid zeolites were screened as heterogeneous catalysts for racemization of benzylic alcohols. The most promising zeolites appeared to be H‐Beta zeolites, for which the optimal reaction conditions were studied in further detail. The zeolite performance was compared to that of homogeneous acids and acid resins under similar reaction conditions. In a second part of the research, H‐Beta zeolites were applied in dynamic kinetic resolution (DKR) of 1‐phenylethanol, which was conducted by means of a two‐phase approach and which resulted in yields smoothly crossing the 50 % border up to 90 %, with an enantiomeric excess of >99 %. To explore the applicability of this biphasic methodology, several other substrates were examined in the standard racemization reaction and in the biphasic dynamic kinetic resolution.     

Mechanism of the chemo–bio catalyzed cascade synthesis of <Emphasis Type="Italic">R</Emphasis>-1-phenylethyl acetate over Pd/Al<Subscript>2</Subscript>O<Subscript>3</Subscript>, lipase,and Ru-catalysts

One-pot synthesis of R-1-phenylethyl acetate was investigated starting from acetophenone hydrogenation performed over Pd/Al₂O₃ and PdZn/Al₂O₃ catalysts followed by acylation of the intermediate secondary alcohol, R-1-phenylethanol, over an immobilized lipase. Furthermore, the performance of a third type of catalyst, Ru supported on hydroxyapatite (HAP) was evaluated for racemization of S-1-phenylethanol in one pot together with the two other catalysts. The main objectives of this work were to separate the effects of different catalysts and to reveal the reaction mechanism. For this purpose not only acetophenone, but also (R,S)-1-phenylethanol, S-1-phenylethanol, R-1-phenylethyl acetate, and styrene were used as reactants in combination with Pd/Al₂O₃, lipase and Ru/HAP as catalysts. The results revealed that the main side product, ethylbenzene, was formed in two different ways, via dehydration of (R,S)-1-phenylethanol to styrene, followed by its rapid hydrogenation to ethylbenzene, and via debenzylation of the desired product, R-1-phenylethyl acetate to ethylbenzene. The true one-pot synthesis, however, was demonstrated over Shvo’s catalyst, but Ru/HAP was not sufficiently active in the racemization step. Ru/Al₂O₃ was a promising catalyst for racemization of S-1-phenylethanol and for dynamic kinetic resolution of (R,S)-1-phenylethanol, when using only small amounts of the acyl donor ethyl acetate. The challenge in racemization is that the activity of heterogeneous Ru catalysts was inhibited by esters.     

Catalytic, highly enantioselective Friedel-Crafts reactions of aromatic and heteroaromatic compounds to trifluoropyruvate. A simple approach for the formation of optically active aromatic and heteroaromatic hydroxy trifluoromethyl esters.

A new catalytic enantioselective synthetic method for the formation of optically active aromatic and heteroaromatic hydroxy-trifluoromethyl ethyl esters is presented. This catalytic enantioselective Friedel-Crafts reaction of trifluoromethyl pyruvate with aromatic and heteroaromatic compounds is catalyzed by a chiral bisoxazoline copper(II) complex and proceeds in good yield and with high enantiomeric excess. For a series of substituted indoles, the corresponding 3-substituted hydroxy-trifluoromethyl ethyl esters are formed in up to 93% yield and 94% ee. Pyrrole and 2-substituted pyrroles also react with trifluoromethyl pyruvate in a highly enantioselective aromatic electrophilic reaction and up to 93% ee and good yields are obtained. Furanes and thiophenes give the corresponding 2-hydroxy-trifluoromethyl ethyl esters in high enantiomeric excess; however, the yields of the products are only moderate. Various types of aromatic compounds react in this catalytic reaction with trifluoromethyl pyruvate to give the aromatic electrophilic addition product in good yield. To obtain high enantiomeric excess (> 80% ee) it is necessary that aromatic amines are protected with sterically demanding protecting groups such as benzyl or allyl. This prevents coordination of the amine nitrogen atom to the catalyst, as aromatic amines having a N,N-dimethyl group probably coordinate to the catalyst, leading to a significant reduction of the enantioselective properties of the catalyst. On the basis of the experimental results and the absolute configuration of the formed chiral center, the mechanism for the catalytic enantioselective Friedel-Crafts reaction is discussed.     

苯甘氨酰胺结晶诱导的动态动力学拆分

以取代水杨醛为消旋催化剂,通过加入手性助剂,实现了苯甘氨酰胺结晶诱导的动态动力学拆分.在优化条件下,单程收率达82％以上,光学纯度达99％ ee.手性助剂可以回收,含消旋催化剂的母液可以循环套用,三次套用的平均收率高达99％,光学纯度＞99％ ee.     

Michael reactions carried out using a bench-top flow system

The Michael reaction between methyl 1-oxoindan-2-carboxylate and methyl vinyl ketone was achieved successfully by pumping solutions of the reactants in toluene through a fluid bed of Amberlyst A21 at 50 degrees C. The use of a fluid bed reactor is attractive as it allows gel-type beads, i.e. the type of bead used in most studies of polymer-supported (PS) organic reactions, to be used satisfactorily in a flow system. When polymer-supported cinchonidine was used in place of Amberlyst A21, the Michael product was obtained in high yield with an enantiomeric excess (ee) of 51%. This % ee is comparable to that achieved when the reaction was catalysed by cinchonidine itself.     

非水相中微生物脂肪酶催化转酯化拆分(R,S)-α-苯乙醇

研究了非水有机溶剂体系中脂肪酶不对称转酯化拆分(R,S)-α-苯乙醇反应,比较了15种不同微生物来源的脂肪酶,从中优选出催化活性及对映选择性较高的脂肪酶Lipase PS,系统考察了影响该酶催化不对称转酯化反应的关键因素,获得了优化的催化拆分工艺条件.结果表明,脂肪酶Lipase PS在非水反应体系中,以正己烷为反应介...     

脂肪酶催化一步酯化协同拆分合成S-萘普生淀粉酯前药

利用CRL脂肪酶选择性催化外消旋萘普生甲酯与玉米淀粉进行转酯化反应合成光学纯S-萘普生淀粉酯前药,同时达到拆分外消旋萘普生的目的。考察了有机溶剂、脂肪酶用量、底物浓度比、反应温度对酯化协同拆分反应的影响,结果表明在异辛烷中脂肪酶CRL可以催化S-萘普生甲酯与淀粉发生转酯化反应同时完成外消旋萘普生的拆分,并且在脂肪酶用量为10%、底物浓度比为1:3、异辛烷用量为15mL、反应温度为60℃的条件下反应6d,外消旋萘普生甲酯的转化率为27.2%,产物对应体过量值eep高达99.4%可以作为萘普生的前药进行应用。     

Chemo-enzymatic synthesis of (S)-α-cyano-3-phenoxybenzyl alcohol

A chemo-enzymatic process for the preparation of (S)-α-cyano-3-phenoxybenzyl alcohol (S-CPBA), an important intermediate in the synthesis of many pyrethroids, was developed. The process consists of four stages, including lipase-mediated resolution. The first stage, the synthesis of racemic α-cyano-3-phenoxybenzyl acetate (CPBAc) from m-phenoxybenzaldehyde (m-PBA) and sodium cyanide in the presence of a phase transfer catalyst, resulted in a 75% yield with 95% purity. The second key step is the resolution of the racemic ester by a highly enantioselective lipase from Pseudomonas sp. The immobilized enzyme carried out the transesterification reaction to nearly full conversion (46% out of 50%) with an enantiomeric excess of >96%. The enzymatic reaction was accomplished in a batch system as well as in a fluidized bed column. The reaction was found to be inhibited by accumulation of the product and to a lesser extent, by the aldehyde. The separation of the enantiomerically pure alcohol from the undesired ester was performed by chromatographic techniques, as well as by extraction with hexane. The final racemization step of the (R)-ester was easily attained with the use of triethylamine in diisopropyl ether or toluene. The process was shown to be feasible on a gram scale and shows potential for scale up.     

Asymmetric synthesis of 1,3-aminoketals

The asymmetric synthesis of α-chiral 1,3-aminoketals 1, useful chiral building blocks for piperidine preparation, was achieved in seven steps involving highly diastereoselective 1,4-addition of Davies’ lithium amide to an α,β-unsaturated ester. Problems of partial racemization observed during transformation of the ester moiety into a keto function, via a Weinreb amide, were solved using non-conventional experimental conditions. This procedure allowed the preparation of the title compounds in >90% enantiomeric excess.     

Suppression of racemization in the carbonylation of amino acid-derived aryl triflates

The carbonylation of enantiopure phenylglycine-derived aryl triflates was achieved to afford 4-carboxyphenylglycine analogs with high enantiomeric excesses (88 to >99% ee). Amide analogs of phenylglycine were well-tolerated in the hydroxy- and methoxycarbonylation processes, providing efficient access to benzoic acid and ester building blocks. The % ee of the product was dependent on the relative steric bulk of both the amino acid substrate and the requisite amine base, with ⁱPr₂NEt proving optimal in minimizing product racemization.     

用环境友好催化剂俣成丙酸苄酯的研究

应用环境友好催化剂H－β沸石催化苯甲醇与丙酸的酯化反应,合成了丙酯苄酯。研究结果表明,H－β沸石 具有较高的催化活性。考察了苯甲醇／丙酸摩尔比、催化剂用量、反应温度、反应时间和带水剂环己烷用量对酯产率的影响。在典型反应条件（苯甲醇／丙酸摩尔比＝1.15:1、10.5gH－β沸石/摩尔丙酸、反应温度160℃ 、反应时间3.5h和20mL环己烷／摩尔丙酸）下,所得丙酸苄酯的产率为77％,该催化剂易于回收且可重复使用,具有良好的活性稳定性,并研究了用某些金属阳离子改性的β沸石的催化活性。     

用芹菜茎催化对映选择性还原芳香酮

研究了用芹菜茎薄片在温和与环境友好的条件下催化芳香酮的对映选择性还原反应, 制备得到具有光学活性的(S)-1-芳基醇, 产物的对映选择性符合Prelog规则. 考察了pH值、反应时间、反应温度、底物浓度等因素对底物芳香酮的转化率和产物(S)-1-芳基醇的对映体过量值的影响, 并优化了这些反应条件. 文中还研究了底物的构效关系, 发现羰基两边取代基的空间效应和电子效应明显影响底物的转化率和产物的对映体过量值. 在合适的条件下底物苯乙酮的转化率高达100%, 产物(S)-1-苯基乙醇的对映体过量值大于99.0%. 苯丙酮、对甲基苯乙酮和对氯苯乙酮等其它芳香酮的转化率达到中等程度, 但所得(S)-1-芳基醇的最大对映体过量值均大于99.0%.     

酰胺类酸性离子液体催化Oxa-Michael加成反应

设计合成并表征了N-甲基吡咯烷酮磷酸盐([NMPH]H2PO4)、己内酰胺磷酸盐([NHCH]H2PO4)、N,N'-二甲基甲酰胺磷酸盐([DMFH]H2PO4)和N,N'-二甲基乙酰胺磷酸盐([DMEH]H2PO4)等酰胺类质子酸离子液体;将其用于β-苯乙醇和丁烯酮的Oxa.Michael加成反应中,考察了离子液体阳...     

Highly enantioselective organocatalytic trifluoromethyl carbinol synthesis--a caveat on reaction times and product isolation

Aldol reactions with trifluoroacetophenones as acceptors yield chiral α-aryl, α-trifluoromethyl tertiary alcohols, valuable intermediates in organic synthesis. Of the various organocatalysts examined, Singh's catalyst [(2S)-N-[(1S)-1-hydroxydiphenylmethyl-3-methylbutyl]-2-pyrrolidinecarboxamide] was found to efficiently promote this organocatalytic transformation in a highly enantioselective manner. Detailed reaction monitoring ((19)F-NMR, HPLC) showed that, up to full conversion, the catalytic transformation proceeds under kinetic control and affords up to 95% ee in a time-independent manner. At longer reaction times, the catalyst effects racemization. For the product aldols, even weak acids (such as ammonium chloride) or protic solvents, can induce racemization, too. Thus, acid-free workup, at carefully chosen reaction time, is crucial for the isolation of the aldols in high (and stable) enantiomeric purity. As evidenced by (19)F-NMR, X-ray structural analysis, and independent synthesis of a stable intramolecular variant, Singh's catalyst reversibly forms a catalytically inactive ("parasitic") intermediate, namely a N,O-hemiacetal with trifluoroacetophenones. X-ray crystallography also allowed the determination of the product aldols' absolute configuration (S).