新型(S)-(α-萘取代)脯氨醇衍生物的合成及其催化二烷基锌与醛的不对称加成反应

以天然手性产物L-脯氨酸为原料,经酯化、氨基保护和格氏反应,得到一种新型光学活性的脯氨醇衍生物((S)-N-苄基-2-吡咯烷-α,α-二(α-萘基)甲醇1).1经过催化氢解,得到另一种光学活性脯氨醇衍生物((S)-2-吡咯烷-α,α-二(α-萘基)甲醇2).将1和2作为有机催化剂,用于催化二烷基锌和醛的不对称加成反应.分别考察了影响对映选择性的催化剂结构、催化剂用量、溶剂、反应温度等各种因素.结果表明,当催化剂用量为5%、溶剂为甲苯、反应温度为-10℃,1作催化剂时,所得仲醇的对映体过量达82?,产率高达100%.     

硅胶催化的选择性去除N-Boc保护基

发现了在回流的甲苯中, 以硅胶为催化剂, 多种N-Boc保护的伯胺、仲胺、氨基酸的氨基都可以迅速脱除Boc. 该方法具有条件温和、操作简便、反应时间短和产率高等优点. 同时, 其它常用的保护基Cbz和Fmoc等在同样的条件下不受影响.     

主链含双层倍半硅氧烷的C_2-对称双脯氨酰胺手性聚合物催化剂的合成及在不对称Aldol反应中的应用

以双夹板形的笼型倍半硅氧烷(DDSQ)和叔丁基氧羰基(Boc)保护的C2-对称双脯氨酰胺为底物,通过硅氢加成反应和脱Boc反应,制得主链含DDSQ的C2-对称双脯氨酰胺手性聚合物催化剂;对其化学结构、分子量及热失重性能进行了表征.将制备的聚合物催化剂应用于催化不对称Aldol反应,探讨了其催化性能.结果表明,催化产物均具有较高的产率和立体选择性,且该催化剂便于分离纯化,循环使用6次后催化活性未见明显下降.     

二芳基脯氨醇衍生物催化的硝基烯参与的多组分不对称串联合成研究进展

硝基烯是一类重要的有机合成子,以硝基烯烃为原料,二芳基脯氨醇衍生物催化的多组分不对称串联反应是构建复杂手性化合物的重要方法,被广泛应用于有机合成和新药开发领域.根据构建的目标化合物类型,较全面地总结了基于二芳基脯氨醇衍生物催化、硝基烯为合成子的多组分不对称串联反应的合成研究,从反应的催化剂体系、反应机理、实验结果、反应优点、存在的问题和局限性等方面进行介绍,并对今后的发展做出展望.     

高活性脯氨酰胺类化合物的合成及催化Michael加成反应的研究

以L-脯氨酸为原料,通过上保护基,酯化,氨化,脱保护基等步骤合成BOC-L-脯氨,再与苯甲酸与萘酚酸等衍生物在无水无氧条件下合成了高活性脯氨酰胺类有机小分子催化剂,并用于催化二苯乙烯基酮衍生物与蒽酮的加成反应,产率高达80%以上,同时还考察了不同条件下对催化产率的影响。该加成反应条件温和,操作简便且产率高。     

二苯基脯氨醇及其衍生物对前手性酮的不对称催化还原研究进展

对(S)-α,α-二苯基脯氨醇及其衍生物对前手性酮的不对称催化还原研究进行了综述, 表明它们具有催化还原产率高、对映选择性好的作用, 是一类性能优秀的不对称还原反应的有机小分子催化剂.     

手性酰亚胺衍生物的合成及其在不对称Aldol反应中的应用

由（S）-脯氨醇衍生的N-Boc-2-氨甲基吡咯烷与与邻苯二甲酸酐经缩合、脱Boc反应,合成了手性酰亚胺化合物4,研究了该类有机小分子催化剂在辅助添加剂2,4-二氯苯甲酸存在下,催化丙酮或环己酮与邻硝基苯甲醛的不对称Aldol反应,产物的产率分别为75%,82%,e.e.值分别为34%,29%。     

手性酰亚胺衍生物的合成及其在不对称Aldol反应中的应用

由(S)-脯氨醇衍生的N-Boc-2-氨甲基吡咯烷与邻苯二甲酸酐经缩合、脱Boc反应,合成了手性酰亚胺化合物(S)-N-(吡咯烷-2-基甲基)苯邻二甲酰亚胺(4),研究了其在辅助添加剂2,4-二氯苯甲酸存在下,催化丙酮或环己酮与邻硝基苯甲醛的不对称Aldol反应,产物的产率分别为75%,82%,ee值分别为34%,29%。     

点击化学制备新型手性配体交换色谱固定相

采用点击化学反应制备了一种新型L-脯氨酰胺衍生物键合手性配体交换色谱固定相.硅胶与γ-氯丙基三乙氧基硅烷反应后,再与叠氮化钠反应制备得到叠氮化硅胶. 在甲醇溶液中,以溴化亚铜为催化剂,叠氮化硅胶与合成的手性选择子N-炔丙基脯氨酰胺,室温反应48 h,而键合上手性官能团.手性选择子的键合量达0.47 mmol/g,操作简单,反应条件温和.制备的手性固定相以0.2 mmol/L Cu(Ac)2水溶液为流动相,在配体交换模式下拆分了8种D,L-氨基酸,对映体选择因子α在1.14～2.42之间.手性分离能力和稳定性研究表明,点击化学在手性配体交换色谱固定相的制备中具有极大潜力.     

硅烷化剂-苯基二甲基氯硅烷的合成研究

苯基二甲基氯硅烷是一种空间位阻封闭剂,保护剂。由于分子中的Si-Cl键很活泼所以能与有机化合物中含活泼氢的官能团（如羟基、羰基、羧基、氨基等）反应,取代其中的活泼氢,其衍生物在酸及碱条件下比三甲基醚类更为稳定。有机化合物中的活泼氢被硅烷基取代后,变成化学稳定性很高的中间产物,且其它基团的反应活性不受影响;反应结束后,通过催化水解或醇解反应,可在不影响分子中其余部分前提下脱去硅烷基,恢复被保护的活泼氢。     

A general thermolabile protecting group strategy for organocatalytic metal-organic frameworks

We present a general strategy for incorporating organocatalytic moieties into metal-organic frameworks (MOFs). The organocatalytic units are protected by a thermolabile protecting group during MOF synthesis and then unveiled by a simple postsynthetic heating step. The strategy is exemplified using a thermolabile tert-butoxycarbonyl (Boc) protecting group for a proline moiety, the removal of which endows the resulting cubic zinc(II) IRMOF with catalytic activity for asymmetric aldol reactions. The bulky Boc groups also prevent framework interpenetration, producing open MOFs that can admit relatively large substrates.     

Asymmetric Disulfonimide‐Catalyzed Synthesis of δ‐Amino‐β‐Ketoester Derivatives by Vinylogous Mukaiyama–Mannich Reactions

An organocatalytic asymmetric synthesis of δ‐amino‐β‐ketoester derivatives has been developed. A chiral disulfonimide (DSI) serves as a highly efficient precatalyst for a vinylogous Mukaiyama–Mannich reaction of readily available dioxinone‐derived silyloxydienes with N‐Boc‐protected imines, delivering products in excellent yields and enantioselectivities. The synthetic utility of this reaction is illustrated in various transformations, including a new C? C bond‐forming reaction, which provide useful enantioenriched building blocks. The methodology is applied in a formal synthesis of (?)‐lasubin.     

Total synthesis of sanjoinine A (frangufoline)

Sanjoinine A (1) was synthesized from a 14-membered cyclopeptide prepared from a Garner aldehyde derived from -serine. The key steps in the synthesis were the catalytic asymmetric reduction of ketone 2(b) and the final removal of the Boc group.     

Synthesis of Pyrrolidine Derivatives by a Platinum/Brønsted Acid Relay Catalytic Cascade Reaction

A new catalytic reaction for the synthesis of pyrrolidine derivatives is presented. The method implies the coupling of N‐Boc‐protected alkynamine derivatives and appropriate alkenes or alkynes in a process catalysed by a platinum/triflic acid catalytic binary system. This reaction is believed to proceed through a cascade process implying an initial platinum‐catalysed cycloisomerization of the alkynamine derivative followed by a triflic acid promoted nucleophilic addition of the alkene or alkyne and trapping of the cationic species formed by the Boc group. Not only simple alkenes and alkynes were used in this reaction but also allyltrimethylsilane and propargyltrimethylsilane. Particularly, when allyltrimethylsilane is used as the alkene counterpart interesting bicyclic compounds containing a trimethylsilane group are obtained. However, when propargyltrimethylsilane is used in the presence of water we observed the formation of a related bicyclic compound lacking the trimethylsilane group and containing an exocyclic carbon?carbon bond.     

Mechanistic studies on the catalytic asymmetric Mannich-type reaction with dihydroisoquinolines and development of oxidative Mannich-type reactions starting from tetrahydroisoquinolines

Detailed mechanistic studies on our recently reported asymmetric addition reactions of malonates to dihydroisoquinolines (DHIQs) catalyzed by chiral Pd(II) complexes were carried out. It was found that an N,O-acetal was generated in situ by the reaction of DHIQ with (Boc)2O, and cooperative action of the Pd(II) complex as an acid-base catalyst allowed the formation of a chiral Pd enolate and a reactive iminium ion via alpha-fragmentation. The iminium ion was also accessible via oxidation with DDQ as an oxidant, and a catalytic asymmetric oxidative Mannich-type reaction was achieved with tetrahydroisoquinolines (THIQs) as starting materials. This oxidation protocol was applicable to N-acryloyl-protected THIQs, allowing the efficient synthesis of optically active tetrahydrobenzo[a]quinolizidine derivatives via intramolecular Michael reaction.     

An experimental and in situ IR spectroscopic study of the lithiation-substitution of N-Boc-2-phenylpyrrolidine and -piperidine: controlling the formation of quaternary stereocenters

A general and enantioselective synthesis of 2-substituted 2-phenylpyrrolidines and -piperidines, an important class of pharmaceutically relevant compounds that contain a quaternary stereocenter, has been developed. The approach involves lithiation-substitution of enantioenriched N-Boc-2-phenylpyrrolidine or -piperidine (prepared by asymmetric Negishi arylation or catalytic asymmetric reduction, respectively). The combined use of synthetic experiments and in situ IR spectroscopic monitoring allowed optimum lithiation conditions to be identified: n-BuLi in THF at -50 °C for 5-30 min. Monitoring of the lithiation using in situ IR spectroscopy indicated that the rotation of the tert-butoxycarbonyl (Boc) group is slower in a 2-lithiated pyrrolidine than a 2-lithiated piperidine; low yields for the lithiation-substitution of N-Boc-2-phenylpyrrolidine at -78 °C can be ascribed to this slow rotation. For N-Boc-2-phenylpyrrolidine and -piperidine, the barriers to rotation of the Boc group were determined using density functional theory calculations and variable-temperature (1)H NMR spectroscopy. For the pyrrolidine, the half-life (t(1/2)) for rotation of the Boc group was found to be ～10 h at -78 °C and ～3.5 min at -50 °C. In contrast, for the piperidine, t(1/2) was determined to be ～4 s at -78 °C.     

Efficient synthesis of orthogonally protected anti-2,3-diamino acids

An asymmetric synthesis of anti-2,3-diamino acids is reported. The enolates of N,N-dibenzylated β³-amino esters were treated with di-tert-butyl azodicarboxylate (DBAD) to afford their N′,N″-di-Boc-2-hydrazino derivatives with excellent anti diastereoisomeric ratio. Final Boc removal and reductive cleavage of the hydrazino bond led to the expected 2,3-diamino esters having only one free amino group. In comparison with other asymmetric C-2 amination procedures, this method does not need the use of expensive chiral reagents and/or chiral auxiliaries, while leads to products which can be orthogonally protected.     

Enantioselective synthesis of pyrrolidine-, piperidine-, and azepane-type N-heterocycles with α-alkenyl substitution: the CpRu-catalyzed dehydrative intramolecular N-allylation approach

A cationic CpRu complex of chiral picolinic acid derivatives [(R)- or (S)-Cl-Naph-PyCOOCH(2)CH═CH(2)] catalyzes asymmetric intramolecular dehydrative N-allylation of N-substituted ω-amino- and -aminocarbonyl allylic alcohols with a substrate/catalyst ratio of up to 2000 to give α-alkenyl pyrrolidine-, piperidine-, and azepane-type N-heterocycles with an enantiomer ratio of up to >99:1. The wide range of applicable N-substitutions, including Boc, Cbz, Ac, Bz, acryloyl, crotonoyl, formyl, and Ts, significantly facilitates further manipulation toward natural product synthesis.     

叔丁氧羰基单端基保护己二胺的合成

以己二胺为原料，叔丁氧羰基酸酐(Boc2O)为保护剂，合成了Boc单端基保护己二胺。并用IR和^1H NMR对产物进行了表征。该化合物可用作氨基酸的N-羰基环内酸酐(NCA)开环聚合法合成结构明晰的两嵌段聚氨基酸的引发剂，因而具有良好的应用前景。     

Catalytic Asymmetric Phase‐Transfer Michael Reaction and Mannich‐Type Reaction of Glycine Schiff Bases with Tartrate‐Derived Diammonium Salts

Catalytic asymmetric Michael and Mannich‐type reactions of glycine Schiff bases with chiral two‐center organocatalysts, tartrate‐derived diammonium salts (TaDiASs), are described. On the basis of conformational studies, optimized TaDiASs with a 2,6‐disubstituted cyclohexane spiroacetal were newly designed. These TaDiASs catalyzed the asymmetric Michael and Mannich‐type reactions of glycine Schiff bases with higher enantioselectivity than previous catalysts. In the Mannich‐type reaction, aromatic N‐Boc‐protected imines (Boc=tert‐butoxycarbonyl) as well as enolizable alkyl imines were applicable. As a synthetic application of the catalytic asymmetric Mannich‐type reaction with the optimized TaDiASs, we developed a catalytic asymmetric total synthesis of (+)‐nemonapride, which is an antipsychotic agent.