一种新的α-(2-甲基-3-呋喃硫基)酮类香料化合物的制备方法

研究了以4-庚酮、5-壬酮和2,6-二甲基-4-庚酮为原料,通过烯醇化、氧化和亲核取代等反应,制备3-(2-甲基-3-呋喃硫基)-4-庚酮、4-(2-甲基-3-呋喃硫基)-5-壬酮和2,6-二甲基-3-(2-甲基-3-呋喃硫基)-4-庚酮3个香料化合物的方法.首先酮在碱性条件下与三甲基氯硅烷反应得到相应的烯醇硅醚,4-庚酮和5-壬酮形成烯醇硅醚产率均在80%以上,2,6-二甲基-4-庚酮形成烯醇硅醚产率略低,约70%.烯醇硅醚用间氯过氧苯甲酸氧化,得到α-羟基酮,产率均在85%左右.α-羟基酮与甲磺酰氯反应,得到相应的甲磺酸酯,然后在碱性条件下甲磺酸酯与2-甲基-3-呋喃硫醇反应生成α-(2-甲基-3-呋喃硫基)酮类香料化合物,产率在80%左右.最终产物通过1HNMR,13CNMR及MS进行了表征.     

3-羟基-4-苯基-2-丁酮的合成

分别以(E)-1-苯基-1-丁烯-3-酮和4-苯基-2-丁酮为起始原料合成了3-羟基-4-苯基-2-丁酮。以(E)-1-苯基-1-丁烯-3-酮为起始原料,经过环氧化和还原两步反应得到产物;第1步环氧化反应,用双氧水作氧化剂,产率64%;第2步α,β-环氧酮在Pd/C催化作用下用甲酸还原,得到产物3-羟基-4-苯基-2-丁酮,产率67%;该路线总产率为43%。以4-苯基-2-丁酮为起始原料,经过烯醇硅醚中间体氧化得到产物;4-苯基-2-丁酮在六甲基二硅胺作用下与三甲基碘硅烷反应得到4-苯基-2-丁烯-2-基三甲基硅醚,产率为75%;第2步烯醇硅醚用间氯过氧苯甲酸氧化,得到产物3-羟基-4-苯基-2-丁酮,产率达71%;该路线总产率为53%。以(E)-1-苯基-1-丁烯-3-酮为起始原料的合成路线总产率略低,但操作简单,试剂价廉易得,是更为实用可行的合成路线。     

手性香料化合物γ-内酯的不对称合成

以丙二酸和脂肪醛为起始原料,通过Knoevenagel缩合、酯化、Sharpless不对称双羟基化、消除和还原五步反应制备了一系列光学活性的γ-内酯.首先丙二酸与脂肪醛在哌啶的催化作用下得到(E)-3-烷烯羧酸,产率70%左右;(E)-3-烷烯羧酸转化为甲酯后,用Sharpless不对称双羟基化试剂AD-mix-α或AD-mix-β氧化,得到光学活性的3-羟基-4-烷基-γ-内酯,双羟基化反应产率85%左右;将3-羟基-4-烷基-γ-内酯的羟基转化为甲磺酸酯后,通过消除反应,得到光学活性的4-烷基-α,β-不饱和-γ-内酯,产率80%左右;然后用Pd/C催化加氢还原,得到光学活性的4-烷基-γ-内酯,产率90%左右.所有产物的结构都通过1HNMR或GC-MS进行了确认,最终产物的对映体过量(ee)值通过手性GC进行了测定.     

光学活性香料化合物3-甲硫基己醇及其乙酸酯的制备

以(E)-2-己烯醛为起始原料,通过还原、Sharpless不对称环氧化、区域选择性还原、SN2亲核取代等反应制备光学活性的3-甲硫基己醇和3-甲硫基己基乙酸酯。首先(E)-2-己烯醛通过NaBH4还原得到(E)-2-己烯醇,产率91%。(E)-2-己烯醇通过Sharpless不对称环氧化,得到光学活性的2,3-环氧己醇,化学产率86%,产物ee值94%。2,3-环氧己醇用Red-Al进行区域选择性还原得到光学活性的1,3-己二醇,产率82%。将1,3-己二醇的伯羟基选择性转化为乙酸酯,3位羟基转化为甲磺酸酯,然后与自制的甲硫醇钾反应,经过SN2亲核取代反应后得到3-甲硫基己醇,三步反应总产率59%。3-甲硫基己醇用乙酸酐酯化得到3-甲硫基己基乙酸酯,产率87%。最终产物3-甲硫基己醇和3-甲硫基己基乙酸酯ee值均在94.0%左右。     

亚胺培南母核的合成研究

以市场易得的4-AA和2-重氮乙酰乙酸对硝基苄酯为原料,先将2-重氮乙酰乙酸对硝基苄酯与三甲基碘硅烷反应得到烯醇硅醚化物,再与4-AA进行aldol反应,不经分离直接水解得到化合物(5),最后经卡宾环合反应得到亚胺培南母核,即4-硝基苄基-(5R,6S)-6-[1R]-1-羟基乙基]-3,7-二酮-1-氮杂双环[3.2.0]庚烷-2-羧酸酯,产物结构经1H-NMR和MS进行确认,以4-AA计总收率达83%。该法合成亚胺培南母核产品收率和纯度高,操作简单,适合工业化生产。     

维兰特罗关键手性中间体的合成工艺改进

(5R)-5-(2,2-二甲基-4H-1,3-苯并二氧杂环己烯-6-基)-1,3-唑烷-2-酮(Ⅰ)是合成维兰特罗的关键手性中间体。以2-溴-1-(2,2-二甲基-4H-1,3-苯并二氧杂环己烯-6-基)乙酮(Ⅱ)为原料,通过还原、胺化和成环反应得到目标产物的消旋体Ⅷ,然后再用L-(+)-酒石酸拆分得到目标产物Ⅰ,ee值为90%。产物结构经1HNMR确认。     

食用香料(R)-γ-内酯类的制备

该文研究了(R)-γ-内酯的制备方法。首先高烯丙基醇在脂肪酶CAL-B催化作用下进行拆分,得到(R)-高烯丙基醇和(S)-高烯丙基醇乙酸酯。经过3次拆分后,对映体过量值(ee)可达95%以上,两个构型产物的收率在40%左右。(S)-高烯丙基醇乙酸酯经水解和Mitsunobu反应转化为相反构型的产物,收率66%左右。(R)-高烯丙基醇与乙酸酐反应得到(R)-高烯丙基醇乙酸酯,收率91%左右。(R)-高烯丙基醇乙酸酯与硼烷四氢呋喃溶液作用,然后在铬酐的醋酸水溶液作用下氧化,中间产物不经过提纯分离直接进行水解关环,得到(R)-γ-内酯,收率72%左右。产物ee值在94%以上。     

食用香料(R)-gamma-内酯类的制备

本文研究了(R)-gamma-内酯的制备方法。首先高烯丙基醇在脂肪酶CAL-B催化作用下进行拆分,得到(R)-高烯丙基醇和(S)-高烯丙基醇乙酸酯。经过三次拆分后,对映体过量（ee）可达95%以上,两个构型产物的收率在40%左右。(S)-高烯丙基醇乙酸酯经水解和Mitsunobu反应转化为相反构型的产物,收率66%左右。(R)-高烯丙基醇与乙酸酐反应得到(R)-高烯丙基醇乙酸酯,收率91%左右。(R)-高烯丙基醇乙酸酯与硼烷四氢呋喃溶液作用,然后在铬酐的醋酸水溶液作用下氧化,中间产物不经过提纯分离直接进行水解关环,得到(R)-gamma-内酯,收率72%左右。产物ee值在94%以上。     

(S)-5-氯-2-甲氧羰基-2-羟基-1-茚酮的合成

(S)-5-氯-2-甲氧羰基-2-羟基-1-茚酮是合成手性杀虫剂茚虫威的重要中间体。以5-氯-2-甲氧羰基-1-茚酮(Ⅰ)为起始原料,经不对称羟基化反应合成了目标产物。探讨了不同溶剂、氧化剂、催化剂等对反应收率和产品ee值的影响。合成反应的优化条件是:n(Ⅰ)∶n(辛可宁)∶n(过氧化氢异丙苯)=1∶0.2∶1.2,CH2Cl2作溶剂,室温反应5h。后处理方法为,用乙酸乙酯重结晶代替柱分离得到目标产物,收率达82%以上,ee值92%以上。产物[α]D20=+108.8°(10g/L,CHCl3),熔点160.1～162.3℃。用FTIR、1HNMR、13CNMR和MS对产品进行了表征。研究结果为该产品在合作企业中的工业开发实验提供了重要依据。     

2，3-戊二酮的合成研究

乙醛和丙醛经3-乙基-4-甲基- 5-(2-羟乙基) -1,3-噻唑溴盐催化交叉偶联反应生成C5偶姻为主的偶姻混合物,偶姻混合物再经H2O2间接氧化、分离制备了2,3-戊二酮。优化的偶联反应条件是：m（乙醛）：m（丙醛）: m(催化剂)：m(Na2CO3)=110：90:2:1;反应温度120~130℃;压力为1MPa。乙醛和丙醛转化率分别达到94%和95%,C5偶姻产率为48.8%,偶姻总产率为90%。混合偶姻在浓H2SO4存在下,用质量分数30%H2O2/FeSO4·7H2O氧化, m（FeSO4·7H2O）：m（浓H2SO4）：m（H2O）：m（偶姻）：m（30%H2O2）=11：2：4：2：3,2,3-戊二酮相对于偶姻的总质量产率为45.5%,邻二酮产物总产率为84%。经常压分馏,可以分别得到质量分数≥98%的2,3-戊二酮、丁二酮和3,4-己二酮产品。铁离子氧化剂重复使用,邻二酮化合物收率没有明显下降。该合成方法不使用有机溶剂,采用双氧水间接氧化,是一种绿色的合成方法。     

N-烯丙基酰胺的不对称双羟化反应

用1∶1的叔丁醇和水作溶剂,在0℃条件下,不同酰基取代的N-烯丙基酰胺在Sharp less催化剂作用下发生不对称双羟化反应,生成手性二醇的产率高达89%,其中N-烯丙基苯甲酰胺获得了50%的对映选择性。     

Aqueous Asymmetric Mukaiyama Aldol Reaction Catalyzed by Chiral Gallium Lewis Acid with Trost‐Type Semi‐Crown Ligands

The combination of Ga(OTf)₃ with chiral semi‐crown ligands ( 1a – e ) generates highly effective chiral gallium Lewis acid catalysts for aqueous asymmetric aldol reactions of aromatic silyl enol ethers with aldehydes. A ligand‐acceleration effect was observed. Water is essential for obtaining high diastereoselectivity and enantioselectivity. The p‐phenyl substituent in aromatic silyl enol ether ( 2 h ) plays an important role and increases the enantioselectivity up to 95% ee. Although aliphatic silyl enol ethers provided low enantioselectivities and silylketene acetal is easily hydrolyzed in aqueous alcohol, the aldol reactions of silylketene thioacetal ( 12 ) with aldehydes in the presence of gallium‐Lewis acid catalysts give the β‐hydroxy thioester with reasonable yields and high diastereo‐ (up to 99 : 1) and enantioselectivities (up to 96% ee).     

Electrophilic Additions to Highly Reactive Enol Ethers. The Particular Role of Resonance in Determining the Kinetic Selectivity Evidenced by Extensive Comparison of Olefin Bromination and Hydration

The kinetic selectivity of aliphatic enol ethers, EtOCR = CHR' (R and R′ = H or Me), towards electrophiles, I₂, Br₂ and H₃O⁺, is expressed by the kinetic effect of a methyl substituent in the α position with respect to the ethoxy group, k_α-Me/k_H. As expected from the reactivity–selectivity principle, RSP, these selectivities are small, 16, 18 and 330, respectively, as compared to those observed for less reactive olefins. However, a more general comparison of the selectivities of various XCH = CH₂ olefins (X = Br, Me, Ph, OAc, OEt) reveals anomalies in their behavior with respect to the RSP: (i) enol ether iodination and bromination exhibit the same selectivity although their rates differ by 4 powers of ten, (ii) enol acetate and enol ether show similar selectivities in bromination but the rate of acetate is 3 × 10⁵ times smaller than that of ether and (iii) in hydration the selectivities of these two olefins are similar to that of styrene although rates range over 7 powers of ten from styrene to enol ether. In contrast with what was previously observed for homogeneous series of R-substituted styrenes (Ph(R)C = CH₂), there is no reactivity–selectivity relationship for electrophilic additions to XCH = CH₂ olefins. There is a parallelism, however, between the selectivities and the transition-state position estimated by the Brønsted exponents for hydration and by the Winstein–Grunwald coefficients for solvent effects on halogenations. These results are discussed in terms of different resonance effects on transition states and on reactivities which could arise from differences in the relative contributions of thermodynamic and intrinsic kinetic (Hammond effects) factors on the selectivities.     

Highly selective asymmetric synthesis of 2-hydroxy fatty acid methyl esters through chiral oxazolidinone carboximides

Highly selective asymmetric synthesis of 2-hydroxy fatty acid methyl esters has been accomplioshed through chiral imide enolates. Five chiral oleic acid imides were prepared by reaction of oleioc acid with pivaloyl chloride followed by reaction with five different lithiated chiral oxazolidinones including (R)-(+)-4-benzyl-2-, (S)-(-)-4-benzyl-2-, (4R,5S)-(+)-4-methyl-5-phenyl-2-, (4S,5R)-(-)-4-methyl-5-phenyl-2-, and (R)-(+)-4-isopropyl-2-oxazolidinones in 88–92% yileds. The chiral imides were reacted with NaN(Me₃Si)₂ at −78°C to give enolates, which subsequently reacted with 2-(phenylsulfonyl)-3-phenyloxaziridine to give hydroxylated products in 78–83% yields. Methanolysis of the hydroxylated products with magnesium methoxide gave methyl 2-hydroxyoleate. Enantiomeric excesses (ee) of the products were determined to be very high (98–99% ee) by ¹H nuclear magnetic resonance study after esterification of the hydroxy group with (S)-(+)-O-acetylmandelic acid. Enantioselective hydroxylation of other fatty acids including elaidic, petroselinic, vaccenic, and linoleic was evaluated under the similar conditions using (4R, 5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary to give 98% ee values for all cases.     

托尼卟吩结构模型中D环结构单元的合成

由乙酰乙酸乙酯(1)为原料经过肟化、还原缩合成环等反应首先合成knorr吡咯(4),然后再由knorr吡咯经氧化反应得到2,4-二乙氧羰基-3-甲基-5-甲酰基吡咯(5),5经皂化反应得到2-羧基-3-甲基-4-乙氧羰基-5-甲酰基吡咯(6),6再经溴化反应得到2-溴-3-甲基-4-乙氧羰基-5-甲酰基吡咯(7),最后,7通过皂化及脱羧得到托尼卟吩结构模型的重要中间体D环结构单元2-溴-3-甲基-5-甲酰基吡咯(Ⅴ)。合成产物的结构都通过1HNMR、IR和GC-MS或MS得到了表征。同时对第二步中氧化反应中的氧化剂以及第四步溴化反应中的溶剂进行了研究。结果表明,氧化反应中的最佳氧化剂为硝酸铈铵,产率达到91.5%,溴化反应中的最佳溶剂为甲醇,反应产率达到58%。     

First Tandem Asymmetric Conjugate Addition of Alkenyl Nucleophiles and Silyl Trapping of the Intermediate Enolates

The tandem asymmetric conjugate addition of alkyl or aryl groups to enones and subsequent silyl trapping has already been achieved and yields valuable silyl enol ethers. Herein, the first method for the respective addition of alkenyl groups is reported, which is based on a rhodium(I)‐catalyzed addition of readily available alkenylzirconocenes. As prerequisite for silyl trapping, the initially formed enolates have to be transmetalated from zirconium to lithium by treatment with methyllithium prior to addition of the silyl chloride. Starting from 5‐ to 7‐membered cycloalkenones, the respective silyl enol ethers were obtained in excellent yields and ≥93% ee; an acyclic substrate furnished a moderate enantioselectivity. Besides trimethylsilyl chloride, the silylation was also performed with tert‐butyldimethylsilyl chloride, and the synthetic scope was evaluated by employing five different alkenyl groups. Moreover, the mechanism of this sequence was elucidated by ¹H NMR studies, and the efficiency of catalyst control was exemplified by synthesis of a cis‐3,5‐disubstituted cyclohexanone which, due to strong substrate control, cannot be obtained by copper‐catalyzed conjugate addition.

     

Synthesis of Multisubstituted Silyloxy-based Donor-Acceptor Cyclobutanes by an Acid-Catalyzed [2+2] Cycloaddition

This account summarizes our recent efforts on the acid-catalyzed [2+2] cycloaddition of silyl enol ethers with α,β-unsaturated esters, giving donor-acceptor (D -A) cyclobutanes and their related reactions. The cycloaddition generally produces multisubstituted cyclobutanes in good yields with high diastereoselectivity. We found that aluminum Lewis acids and triflic imide (Tf₂NH) had good catalytic activity. The retro [2+2] cycloaddition proceeded at higher reaction temperatures, and in some cases, diastereoselectivity switching of cycloadducts was observed. A microflow protocol was established for Tf₂NH-catalyzed [2+2] cycloaddition. Although the cycloaddition usually requires cryogenic conditions in a batch reactor, the microreactor system enabled the production of D -A cyclobutanes, even at ambient temperature. [2+2] Cycloaddition of allylsilanes and alkyl enol ethers, instead of silyl enol ethers, afforded the corresponding D -A cyclobutanes.     

Improved Synthesis of Pyrroles and Indoles via Lewis Acid‐Catalyzed Mukaiyama–Michael‐Type Addition/Heterocyclization of Enolsilyl Derivatives on 1,2‐Diaza‐1,3‐Butadienes. Role of the Catalyst in the Reaction Mechanism

The Mukaiyama–Michael‐type addition of various silyl ketene acetals or silyl enol ethers on some 1,2‐diaza‐1,3‐butadienes proceeds at room temperature in the presence of catalytic amounts of Lewis acid affording by heterocyclization 1‐aminopyrrol‐2‐ones and 1‐aminopyrroles, respectively. 1‐Aminoindoles have been also obtained by the same addition of 2‐(trimethylsilyloxy)‐1,3‐cyclohexadiene on some 1,2‐diaza‐1,3‐butadienes and subsequent aromatization. Mechanistic investigations indicate the coordination by Lewis acid of the enolsilyl derivative and its 1,4‐addition on the azo‐ene system of 1,2‐diaza‐1,3‐butadienes. The migration of the silyl group from a hydrazonic to an amidic nitrogen, its acidic cleavage and the final internal heterocyclization give the final products. Based on NMR studies and ab initio calculations, a plausible explanation for the migration of the silyl protecting group is presented.