1,6-Conjugate addition of para-quinone methides using gem-diborylcarbanions: Practical access to gem-diborylalkanes bearing vicinal tertiary/quaternary stereocenters

A novel,efficient and pragmatic method to prepare gem-diboron products with vicinal tertiary/quaternary stereocenters using LiTMP-mediated 1,6-conjugate addition of gem-diborylalkanes to para-quinone methides was described for the first time.The results showed that various gem-diboron products with vicinal tertiary and quaternary stereocenters could be formed within 15 min at ambient temperature.This simple protocol has also been applied for the efficient synthesis of the analogue of Bedaquiline.

Synthetic studies towards daphniyunnine B: Construction of AC bicyclic skeleton with two vicinal all carbon quaternary stereocenters

The AC bicyclic skeleton of daphniyunnine B with the required 3 stereocenters(C4,C5 and C8)was accomplished in a concise route which featured two Claisen-type rearrangement reactions to construct the required vicinal all carbon quaternary stereocenters(C5 and C8)and an intramolecular iodocyclization reaction to assemble the cis-confused bicyclic lactam.

Asymmetric construction of all-carbon quaternary stereocenters in the total synthesis of natural products

Structure units containing all-carbon quaternary stereogenic center are found in many bioactive natural products. However, enantioselective construction of this type of structure units has been a formidable challenge for synthetic community due to the steric hindrance enforced by all-carbon quatemary stereocenters. In this review, we present the achievements made by Chinese scientists in the area of asymmetric synthesis of all-carbon quaternary stereocenters in natural products during the past two years.

Highly enantioselective construction of CF_(3) -bearing all-carbon quaternary stereocenters: Chiral spiro-fused bisoxazoline ligands with 1,1'-binaphthyl sidearm for asymmetric Michael-type Friedel-Crafts reaction

A novel class of chiral spiro-fused bisoxazoline ligands possessing a deep chiral pocket was prepared.The developed ligands have been employed in the nickel-catalyzed highly enantioselective Michael-type Friedel-Crafts reaction, affording the products bearing a trifluoromethylated all-carbon quaternary stereocenter with moderate to excellent yields(up to 99%) and good to excellent enantioselectivies(up to> 99.9% ee). Moreover, a proposed model of chiral pocket revealed that the attack of indole from the Re-face of β-CF_(3)-β-disubstituted nitroalkene was favorable.

Catalytic diastereoselective construction of multiple contiguous quaternary carbon stereocenters via [2+2] cycloaddition and mechanistic insight

Multiple contiguous quaternary carbon stereocenters(CQS) are highly challenging, yet important structural motifs in organic synthesis. Here, we describe a visible light induced catalytic [2 + 2] cycloaddition approach that constructed up to four CQS in a pentacyclic fused ring system diastereoselectively, from the readily accessible dienamides with pendent heteroaryls. Variously substituted dienamides have been cyclized with heteroaryls to provide a range of novel CQS-containing scaffolds(26 examples, up to 96%yield and >20:1 dr ratio). Mechanistic studies revealed that it may proceed through an uncommon β-C radical initiated 7-endo cyclization from the biradical intermediate.

Nickel-Catalyzed Enantioselective C(sp^(3))–H Arylation of Ketones with Aryl Ethers via Selective C_(Ar)–O Cleavage to Construct All-Carbon Quaternary Stereocenters

We designed thenickel-catalyzed enantioselective C(sp^(3))–H arylation of ketones with phenol-derived aryl pyrimidyl ethers via selective cleavage of the C(aryl)–O bond to construct all-carbon quaternary stereocenters.This method exhibits good functional group compatibility and broad substrate scope.Drug molecule donepezil can directly transform into corresponding highly optically pure derivatives with this developedmethodology.Mechanistic studies reveal that C(aryl)–O cleavage of aryl pyrimidyl ether probably proceeded by means of an anionic organo-Ni(0)intermediate.

Construction of three stereocenters via hydrogenative desymmetrization of 2,2,5-trisubstituted cyclohexane-1,3-diones

A Ru-catalyzed hydrogenative desymmetrization of 2,2,5-trisubstituted cyclohexane-1,3-diones was developed for construction of three stereocenters including two coherent and discontiguous chiral centers and a chiral quaternary carbon with excellent enantio-and diastereoselectivities.Stereodivergent synthesis of four stereoisomers could be conducted with high enantioselectivities.The desymmetrization could be achieved at gram scale without loss of reactivity and optical purity,and a formal synthesis of bioactive molecule(-)-isocelorbicol was completed.

亚甲胺叶立德参与的不对称1,3-偶极环加成构建含连续季碳中心的螺四氢吡咯衍生物

Cu(I)催化的亚甲胺叶立德和亚环丙基乙酸乙酯参与的不对称endo-1,3-偶极环加成反应,高效构建了多官能化、含有多个连续季碳中心的5-氮杂-[2,4]庚烷化合物.此反应具有广泛的底物适用性,α-取代的和α-非取代的亚甲胺叶立德和亚环丙基乙酸乙酯都能很好的参与反应,并以很高的产率、优秀的非对映选择性(95:5–>98:2 d.r)和对映选择性(87%–98%ee)生成相应的在2,3,4位上含有连续季碳中心的螺四氢吡咯化合物.

Highly Site-and Enantioselective N-H Functionalization of N-Monosubstituted Aniline Derivatives Affording Pyrazolones Bearing a Quaternary Stereocenter

Chiral phosphoric acid catalyzed the regio-and enantioselective N-H functionalization of N-alkylaniline with pyrazolones derived ketimines as electrophiles,providing a variety of chiral pyrazolones containing a tetrasubstituted stereocenter bearing a new N,N'-acetal motif in excellent yields and high enantioselectivities.This strategy was featured by low catalyst loading,mild conditions,and high efficiency and selectivity.

3-吡咯氧化吲哚参与不对称构建手性季碳中心的研究进展

氮杂季碳手性中心结构存在于许多生物活性分子或药物分子中,C3位含有氮原子的3,3’-二取代氧化吲哚结构更是许多具有生物活性的天然产物或药物分子的核心骨架,以3-吡咯氧化吲哚作为亲核试剂不对称合成结构多样的3,3’-二取代氧化吲哚类化合物是一种可行的构建含氮杂季碳手性中心化合物的方法。综述了3-吡咯氧化吲哚通过分子内反应和分子间反应两种形式参与构建3,3’-二取代氧化吲哚类化合物的研究进展,并对构建含氮杂季碳手性中心化合物进行了展望。

Highly enantio-stereoselective Ni-catalyzed reductive cyclization to cyclopentanes with chiral quaternary centres of trisubstituted allylic siloxanes

The construction of chiral quaternary carbon stereocenters is a significant challenge in asymmetric synthesis.Catalytic synthesis of these structures with trisubstituted allylic alcohols is highly important. However, most ofthe reported methodologies required noble transition-metals. Herein we reported the first highly asymmetricstereoselective synthesis of cyclopentanes bearing chiral quaternary carbon stereocenters of trisubstituted allylicsiloxanes by reductive cyclization of all carbon 1,6-alkynones with the non-noble nickel catalysis of Ni(cod)2 withP-chiral monophosphine ligand (S)-BIDIME. Various multi-substituted functionalized cyclopentanes were obtained in high yields (up to 96%), excellent enantioselectivities (up to >99% ee) and perfect stereoselectivities(>99:1 E/Z). Thirty-two examples were successfully established for this method. Clarified mechanism studieswere investigated first time by React-IR and DFT calculations to understand and explain the ligand-control ofexcellent enantio-stereoselectivity. Gram-scale reaction and control experiments were carried out. A new reactiondesign was proposed for further application of this type of catalysis.

Construction of Acyclic Quaternary Carbon Stereocenters via Enantioselective Nickel Catalysis

The construction of acyclic quaternary carbon stereocenters,which are ubiquitous in many bioactive compounds,pharmaceuticals and natural products,has been a long persuit in synthetic organic chemistry.Among numerous methods,enantioselective nickel-catalysis has attracted incremental attention in recent years.This review summarizes the recent development in the asymmetric strategies,research progress,mechanistic investigations for the generation of acyclic quaternary carbon stereocenters via enantioselective nickel catalysis.

高对映选择性的有机催化的硝基烷烃对N-Boc靛红亚胺的不对称aza-Henry反应

研究实现了高对映选择性的硝基烷烃对N-Boc靛红亚胺1的不对称aza-Henry反应,来构建胺基季碳氧化吲哚.发现在金鸡纳碱衍生的叔胺-酚羟基双功能催化剂C5的作用下,10种不同取代的N-Boc靛红亚胺与硝基甲烷的反应均能顺利进行,以66%~91%的对映选择性得到目标产物,产物的绝对构型通过X-ray单晶衍射加以确定.硝基乙烷和硝基丙烷也能高对映选择性地参与反应,但非对映选择性不佳.

Remote Stereocontrol of All-Carbon Quaternary Centers via Cobalt-Catalyzed Asymmetric Olefin Isomerization

Asymmetric olefin isomerization has become a powerful tool for positional migration of C=C double bonds to afford valuable chiral olefins.However,the synthesis of optically active all-carbon quaternary stereocenters via this strategy is still rare.Herein,we report a cobaltcatalyzed desymmetric olefin isomerization to access 1-methylcyclohexenes bearingβ-quaternary stereocenters in a chemo-,site-,and stereoselective fashion.Preliminary mechanistic studies have revealed the Co-H insertion/β–Helimination reaction pathway and the origin of remote stereocontrol of all-carbon quaternary centers.The gram-scale synthesis and stereoretentive transformations of spirocyclic products demonstrate the synthetic utility of this reaction.

A General Protocol toward Oxindoles Bearing C_(3)-Allylic Quaternary Stereocenter via Domino Reaction:A Concise Synthesis of Heterocycle-Fused Indoline Alkaloids

An efficiently catalytic method toward the synthesis of indolin-2-ones featuring an allylic derived C_(3)-quaternary stereocenter via an intramolecular Heck cyclization/Suzuki coupling of N-substituted-N-(2-bromophenyl)acrylamides and organoboron reagents was successfully developed by using a 1,3-bis(2,6-diisopropylphenyl)acenaphthoimidazol-2-ylidene(AnIPr)-ligated oxazoline palladacycle.It enabled a very broad substrate scope tolerating different functional groups,electronic properties and steric bulkiness.Notably,it revealed a great potential to build diverse heterocycle-fused indoline alkaloids via the same intermediate 3-allyl-1,3-dimethylindolin-2-one.

过渡金属催化的关键反应在异戊烯基吲哚生物碱全合成中的研究进展

异戊烯基吲哚生物碱是一类结构有趣和重要的天然产物家族化合物,其典型结构特征是有一个吲哚环或其衍生物(即螺环氧化吲哚或假吲哚),由一个或多个异戊烯基或异戊烯基的残基修饰.异戊烯基吲哚生物碱组成了一个庞大和结构多样化的具有广泛且重要的生物活性天然产物家族化合物.自然界以焦磷酸二甲基烯丙基(DMAPP)和焦磷酸异戊烯基(IPP)为起始原料,生物合成了许多异戊烯基吲哚生物碱,而异戊烯基吲哚生物碱的吲哚核心通常来源于L-色氨酸,或者少部分来源于吲哚-3-甘油磷酸酯.异戊烯基化是几乎所有生物普遍存在的过程,是有机合成中的关键转化.近年来,异戊烯基吲哚生物碱因其独特的结构单元和多样的生物学活性,受到合成化学家和药理学家的持续深入研究.迄今为止,发展一类直接和高效的方法来合成结构多样的异戊烯基吲哚生物碱是非常理想的,同时也是非常具有挑战性的研究工作.综述了近期过渡金属催化的关键反应在异戊基化吲哚生物碱全合成中的研究进展.

基于分子内交叉氧化偶联反应来非对映选择性构建全碳季碳中心

立体位阻拥挤C—C键,尤其是包含全碳季碳中心C—C键的构建一直是现代有机合成化学的挑战.利用硝酸铈铵(CAN)诱导的双烯醇硅醚化合物分子内交叉氧化偶联反应来非对映选择性地构建连续全碳季碳中心以及叔碳中心.该方法在相对温和的反应条件下,以CAN作为单电子氧化剂,高产率、高非对映选择性地构建立体位阻拥挤的C—C键.本研究提供了一种通过分子内交叉氧化偶联反应来实现两个不同片段高效连接的有效手段,可以应用到复杂天然产物的全合成研究中去.

Copper（I）-Catalyzed Asymmetric [3＋2]-Cycloaddition of α-Substituted Iminoesters with α-Trifluoromethyl α,β-Unsaturated Esters

Reported herein is an example of highly regio-, diastereo-and enantioselective Cu（I）-catalyzed intermolecular [3＋2] cycloaddition reaction of a-substituted iminoesters with α-trifluoromethyl α,β-unsaturated esters. This novel strategy provided a facile access to pyrrolidines with two skipped （aza）quaternary stereocenters including a CF3 all-carbon quaternary stereocenter. A broad substrate scope was observed and high yields （up to 94%） with excellent diastereoselectivity （up to 〉20 ： 1 d.r.） and enantioselectivity （up to 98% ee） were obtained.

叔丁醇钠催化的δ-腈基-δ-芳基-双取代的对亚甲基苯醌和二芳基氧磷的磷氢化反应研究

报道了一种高效的δ-腈基-δ-芳基-双取代的对亚甲基苯醌和二芳基氧磷的1,6-共轭加成反应,合成了含有氰基取代的季碳中心的二芳基甲烷膦氧化合物.在温和的反应条件下此磷氢化反应能够顺利进行,以74%〜92%的收率得到目标产物.另外,该反应具有优秀的官能团兼容性,展示出了很好的底物范围.所合成的含有氰基取代季碳中心的二芳基(多取代甲基)膦氧化合物在发展新的配体方面具有潜在的应用价值.

聚偏二氯乙烯负载金鸡纳碱催化剂的合成及其对不对称Michael反应的催化性能

将天然的金鸡纳碱——辛可宁与聚偏二氯乙烯进行接枝反应,制备了聚偏二氯乙烯负载辛可宁的催化剂.将制备的催化剂用于催化不对称Michael反应,并探索了溶剂、催化剂用量、温度、底物等不同条件对其催化性能的影响.结果表明,该催化剂在甲苯中有很高的催化活性和较好的立体选择性,Michael反应中部分产率达到80%以上,e.e值达到72%,且该催化剂具有一定的重复使用性能.