过渡金属催化的烯炔环异构化反应研究

环状化合物的合成是有机化学中一个重要的课题，具有高官能团化的环状结构是合成天然化合物及其他具有生命活性化合物的重要前体。过渡金属催化的烯炔环异构化反应具有条件温和，原子经济性高等特点，但在多数研究中仍存在依赖偕二甲基效应提高反应性以及大位阻控制产物选择性等限制，本研究以本组已取得的由镍-NHC催化烯炔与醛合成环状结构的成果为基础，以解决上述问题为目标，发展了烯炔在醇的参与下一步完成环异构化并由电子效应得到特定非对映异构体为主要产物的一种新的方法。
在本方法学中，小分子醇被开发出来取代了以往更为危险的氢气作为还原剂，配合镍-NHC催化系统在室温条件下完成了1,7-杂烯炔通过还原环异构化机制生成六元杂环的过程。四种特征结构的1,7-杂烯炔被应用到该环异构化的体系中，分别为：炔丙式-Z结构、烯丙式-Z结构、内炔式以及具有连续取代结构烯炔，拓宽了环异构化反应的底物应用范围。此外，在一例氘代甲醇标记实验的帮助下，一种可能的机理路径被提出。本研究的特殊之处在于，在没有引入手性物种的前提下完成了具有高选择性的1,3-二取代六元杂环的合成；且通过对杂原子电性的控制，能在不改变催化体系及其他条件的前提下取得得到相反异构体的效果，且收率可观。
本研究应用较新的利用电子效应控制反应特性的思路，完成了镍-NHC催化烯炔在醇的配合下选择性得到特定非对映异构体的还原环异构化过程，为手性杂环的合成提供了新的选择。

The synthesis of cyclic compounds is amajor issue in organic chemistry. The highly functionalized cyclic structure is an important precursor for the synthesis of natural compounds and other bio-active compounds. The transitionmetal-catalyzed enyne cycloisomerization reaction has themerits ofmild conditions and high atomic economy. However, the scope of thiskind of reaction is limited because the substrates are designed under Thorpe-Ingold effect and bulky substituents are used to achieved better selectivity. Based on our previous research of the nickel-NHC-catalyzed cyclization of enyne with aldehyde, amethod of enyne reductive cycloisomerization employing alcohol as reductant was developed, which has achieved a high diastereoselectivity with the aid of electronic effect.
In this study, simple alcohol was developed as reductant rather than dangerous hydrogen gas that once used. The use of 1,7-enyne broaden the scope of enyne cycloisomerization, where 1,6-enyne were usedmore often in the past. The highlight of this research was that without the help of optically active species, the synthesis of 1,3-disubstituted six-memberedring with high selectivity was achieved. Besides, the other isomer with the opposite configuration could be obtained without change the condition of the existing reaction but only toalterthe electronic character of the substrates. The yield was satisfying. A possiblemechanismwas proposed based on the labelling experiment.
Overall, a newmethod of utilizing the electronic effect to control the reaction pathway was presented. With that, we successfully realized the divergent synthesis of 6-oxarings by nickel-NHC catalyzed enyne cycloisomerization employing alcohol as reductant. This can be an interesting alternative choice for diastereoselective heterocyclicmolecule synthesis.

[1] Trost B M, Lautens M. Cyclization via Isomerization: A Palladium(2+)-Catalyzed Carbocyclization of 1,6-Enynes to 1,3- and 1,4-Dienes[J]. Journalof the American Chemical Society, 1985, 107 (6): 1781-1783.
[2] Trost B M. Palladium-Catalyzed Cycloisomerizations of Enynes and RelatedReactions[J]. Accounts of Chemical Research, 1990, 23 (2): 34-42.
[3] Ojima I, Tzamarioudaki M, Donovan R J, et al. Transition Metal-CatalyzedCarbocyclizations in Organic Synthesis[J]. Chemical Reviews, 1996, 96 (2):635-662.
[4] Nakamura I, Yamamoto Y. Transition-Metal-Catalyzed Reactions inHeterocyclic Synthesis[J]. Chemical Reviews, 2004, 104 (5): 2127-2198.
[5] Watson I D G, Toste F D. Catalytic Enantioselective Carbon-Carbon BondFormation Using Cycloisomerization Reactions[J]. Chemical Science, 2012,3 (10): 2899-2919.
[6] Wanzlick H W S, H J. Direct Synthesis of A Mercury Salt-CarbeneComplex[J]. Angewandte Chemie International Edition, 1968(7): 141-142.
[7] Igau A, Grutzmacher H, Baceiredo A, Bertrand G.Analogous .Alpha.,.Alpha.'-Bis-Carbenoid, Triply Bonded Species:Synthesis of A Stable .LaMbda.3-phosphino Carbene-.LaMbda.5-Phosphaacetylene[J]. Journal of the American Chemical Society, 1988, 110(19): 6463-6466.
[8] Arduengo A J, Harlow R L, Kline M. A Stable Crystalline Carbene[J].Journal of the American Chemical Society, 1991, 113 (1): 361-363.
[9] Wöhler F, Liebig J. Untersuchungen über das Radikal der Benzoesäure[J].Annalen der Pharmacie, 1832, 3: 249-282.
[10] 屈孟男, 何金梅. 氮杂环卡宾在有机催化中的研究进展[J]. 有机化学,2011, 31(9):1388-1394
[11] Breslow R. On the Mechanism of Thiamine Action. IV.1 Evidence fromStudies on Model Systems[J]. Journal of the American Chemical Society,1958, 80 (14): 3719-3726.
[12] Sheehan J C, Hunneman D H. Homogeneous Asymmetric Catalysis[J].Journal of the American Chemical Society, 1966, 88 (15): 3666-3667.
[13] Rao W, Sally Koh M J, Chan P W H. Gold-Catalyzed Cycloisomerization of1,7-Enyne Esters to Structurally Diverse cis-1,2,3,6-Tetrahydropyridin-4-y1Ketones[J]. Journal of Organic Chemistry, 2013, 78 (7): 3183-3195.
[14] O'Brien C J, Kantchev E A B, Organ M G, et al. Easily Prepared Air- andMoisture-Stable Pd–NHC (NHC=N-Heterocyclic Carbene) Complexes: AReliable, User-friendly, Highly Active Palladium Precatalyst for the Suzuki–Miyaura Reaction[J]. Chemistry – A European Journal, 2006, 12 (18): 4743-4748.
[15] Hopkinson M N, Richter C, Glorius F, et al. An Overview of N-HeterocyclicCarbenes[J]. Nature, 2014（ 510） : 485-496.
[16] Sanford M S, Love J A.; Grubbs R H. Mechanism and Activity of RutheniumOlefin Metathesis Catalysts[J]. Journal of the American Chemical Society，2001, 123 (27):6543-6554.
[17] Tekavec T N, Louie J. Nickel-Catalyzed Cycloadditions of UnsaturatedHydrocarbons, Aldehydes, and Ketones[J]. The Journal of OrganicChemistry, 2008, 73 (7): 2641-2648.
[18] Tekevac T N, Louie J. Nickel-Catalyzed Cycloaddition of UnsaturatedHydrocarbons and Carbonyl Compounds[J]. Organic Letters, 2005, 7 (18):4037-4039.
[19] Zhang L, Sun J, Kozmin S A. Gold and Platinum Catalysis of Enyne Cycloisomerization[J]. Advanced Synthesis & Catalysis, 2006, 348 (16‐ 17):2271-2296.
[20] Hu Y, Bai M, Zhou Q, et al. Metal-catalyzed Enyne Cycloisomerization inNatural Product Total Synthesis[J]. Organic Chemistry Frontiers, 2017, 4(11): 2256-2275.
[21] Zhao J P, Chan S C, Ho C Y. Substituted 1,3-Cyclohexadiene Synthesis byNHC–Nickel(0) Catalyzed
[2+2+2] Cycloaddition of 1,n-Enyne[J].Tetrahedron, 2015, 71 (26): 4426-4431.
[22] He L, Ho C Y. Nitrate-Enhanced NHC-NiH Catalyzed Tail-to-Tail VinylEther Dimerization[J]. Synlett, 2014, 25 (19): 2738-2742.
[23] Ho C Y, He L. Shuffle Off the Classic β-Si Elimination by Ni-NHCCooperation: Implication for C–C Forming Reactions Involving Ni-alkyl-β-silanes[J]. Chemical Communications, 2012, 48 (10): 1481-1483.
[24] Ho C Y, Jamison T F. Highly Selective Coupling of Alkenes and AldehydesCatalyzed by [Ni(NHC){P(OPh)3}]: Synergy between a Strong σ-Donor anda Strong π-Acceptor[J]. Angewandte Chemie International Edition, 2007, 46(5): 782-785.
[25] Hayashi Y, Hoshimoto Y, Ogoshi S, et al. Nickel(0)-CatalyzedIntramolecular Reductive Coupling of Alkenes and Aldehydes or Ketoneswith Hydrosilanes[J]. ChemInform, 2016, 52 (37): 6237-6240.
[26] Ogoshi S, Hoshimoto Y, Ohashi M. Nickel-Catalyzed Tishchenko Reactionvia Hetero-Nickelacycles by Oxidative Cyclization of Aldehydes withNickel(0) Complex[J]. Chemical Communications, 2010, 46 (19): 3354-3356.
[27] Thakur A, Louie J. Advances in Nickel-Catalyzed Cycloaddition ReactionsTo Construct Carbocycles and Heterocycles[J]. Accounts of ChemicalResearch, 2015, 48 (8): 2354-2365.
[28] Böing C, Hahne J, Leitner W, et al. Stereoselective Nickel-Catalyzed Cycloisomerization of 1,6-Dienes[J]. Advanced Synthesis & Catalysis, 2008, 350(7‐ 8): 1073-1080.
[29] Ikeda S I, Daimon N, Odashima K, et al. Catalytic Cycloisomerization ofEnynes by Using a Nickel-Zinc-Acid System[J]. Chemistry – A EuropeanJournal, 2006, 12 (6): 1797-1806.
[30] Diccianni J B, Heitmann T, Diao T. Nickel-Catalyzed ReductiveCycloisomerization of Enynes with CO2[J]. The Journal of OrganicChemistry, 2017, 82 (13): 6895-6903.
[31] Phillips J H, Montgomery J. Mechanistic Insights into Nickel-CatalyzedCycloisomerizations [J]. Organic Letters, 2010, 12 (20): 4556-4559.
[32] Trost B M, Rise F. Reductive Cyclization of 1,6- and 1,7-Enynes[J]. Journalof the American Chemical Society, 1987, 109 (10): 3161-3163.
[33] Trost B M, Lee D C, Rise F. A New Palladium Catalyst for IntramolecularCarbametalations of Enynes[J]. Tetrahedron Letters, 1989, 30 (6): 651-654.
[34] Madhushaw R J, Lo C Y, Liu R S, et al. Rutheniun-CatalyzedCycloisomerization of o-(Ethynyl)phenylalkenes to Diene Derivatives viaSkeletal Rearrangement[J]. Journal of the American Chemical Society, 2004,126 (47): 15560-15565.
[35] Grigg R, Stevenson P, Worakun T. Rhodium (1) Catalysed RegiospecificCyclisation of 1,6-Enynes to Methylenecyclohex-2-enes[J]. Tetrahedron,1988, 44 (15): 4967-4972.
[36] Cao P, Wang B, Zhang X. Rh-Catalyzed Enyne Cycloisomerization[J].Journal of the American Chemical Society, 2000, 122 (27): 6490-6491.
[37] Chatani N, Inoue H, Murai S, et al. Iridium(I)-Catalyzed Cycloisomerizationof Enynes [J]. The Journal of Organic Chemistry, 2001, 66 (12): 4433-4436.
[38] Trost B M, Tanoury G J, MacPherson D T, et al. Pd-CatalyzedCycloisomerization to 1,2-Dialkylidenecycloalkanes[J]. Journal of theAmerican Chemical Society, 1994, 116 (10): 4255-4267.
[39] Nevado C, Cárdenas D J, Echavarren A M. Reaction of Enol Ethers withAlkynes Catalyzed by Transition Metals: 5-Exo-dig versus 6-Endo-digCyclizations via Cyclopropyl Platinum or Gold Carbene Complexes[J].Chemistry – A European Journal, 2003, 9 (11): 2627-2635.
[40] Geier M J. GagnéM R. Diastereoselective Pt Catalyzed Cycloisomerizationof Polyenes to Polycycles[J]. Journal of the American Chemical Society,2014, 136 (8): 3032-3035.
[41] Hayashi Y, Gotoh H, Shoji M, et al. Cysteine-Derived Organocatalyst in aHighly Enantioselective Intramolecular Michael Reaction[J]. Journal of theAmerican Chemical Society, 2005, 127 (46): 16028-16029.
[42] Kerr M S, Rovis T. Enantioselective Synthesis of Quaternary Stereocentersvia A Catalytic Asymmetric Stetter Reaction[J]. Journal of the AmericanChemical Society, 2004, 126 (29): 8876-8877.
[43] Liu Q, Rovis T. Asymmetric Synthesis of Hydrobenzofuranones viaDesymmetrization of Cyclohexadienones Using the Intramolecular StetterReaction[J]. Journal of the American Chemical Society, 2006, 128 (8): 2552-2553.
[44] Read de Alaniz J, Rovis, T. A Highly Enantio- and DiastereoselectiveCatalytic Intramolecular Stetter Reaction[J]. Journal of the AmericanChemical Society, 2005, 127 (17): 6284-6289.
[45] Pei T, Widenhoefer R A. Palladium-Catalyzed Asymmetric DieneCyclization/Hydrosilylation Employing Functionalized Silanes andDisiloxanes[J]. The Journal of Organic Chemistry, 2001, 66 (23): 7639-7645.
[46] Selim K B, Lee B K, Sim T. Stereoselective Total Synthesis of the E-isomerof Putative Lucentamycin A[J]. Tetrahedron Letters, 2012, 53 (44): 5895-5898.
[47] Huo X, Zhang J, Zhang W, et al. Ir/Cu Dual Catalysis: Enantio- andDiastereodivergent Access to α,α-Disubstituted α-Amino Acids BearingVicinal Stereocenters[J]. Journal of the American Chemical Society, 2018,140 (6): 2080-2084.
[48] France S P, Hussain S, Turner N J, et al. One-Pot Cascade Synthesis of Monoand Disubstituted Piperidines and Pyrrolidines using Carboxylic AcidReductase (CAR), ω-Transaminase (ω-TA), and Imine Reductase (IRED)Biocatalysts[J]. ACS Catalysis, 2016, 6 (6): 3753-3759.
[49] Breit B, Demel P, Studte C. Stereospecific and Stereodivergent Constructionof Quaternary Carbon Centers through Switchable Directed/NondirectedAllylic Substitution[J]. Angewandte Chemie International Edition, 2004, 43(29): 3786-3789.
[50] Seel S, Thaler T, Knochel P, et al. Highly Diastereoselective Arylations ofSubstituted Piperidines[J]. Journal of the American Chemical Society, 2011,133 (13): 4774-4777.
[51] Comins D L, Kuethe J T, Brooks C A, et al. Diels−Alder Reactions of NAcyl-2-alkyl(aryl)-5-vinyl-2,3-dihydro-4-pyridones[J]. The Journal ofOrganic Chemistry, 2005, 70 (13): 5221-5234.
[52] Huang J M, Dong Y. Zn-Mediated Electro Chemical Allylation of Aldehydesin Aqueous Ammonia[J]. Chemical Communications, 2009, (26): 3943-3945.
[53] Akeroyd N, Pfukwa R, Klumperman B. Triazole-Based Leaving Group forRAFT-Mediated Polymerization Synthesized via the Cu-Mediated Huisgen1,3-Dipolar Cycloaddition Reaction[J]. Macromolecules, 2009, 42 (8): 3014-3018.
[54] Hu J, Kong B, Gong P, et al. Highly Stereoselective Synthesis ofImidazolidines through the Palladium(0)-Catalyzed Three-ComponentReaction of 2,3-Allenylamines, Organic Halides, and Imines[J].ChemCatChem, 2017, 9 (3): 403-406.
[55] Gaillard S, Bantreil X, Nolan S P, et al. Synthesis and Characterization ofIPrMe-Containing Silver(I), Gold(I) and Gold(III) Complexes[J]. DaltonTransactions, 2009, (35): 6967-6971.
[56] Elie M, Sguerra F, Gaillard S, et al. Designing NHC–Copper(I)Dipyridylamine Complexes for Blue Light-Emitting Electro ChemicalCells[J]. ACS Applied Materials & Interfaces, 2016, 8 (23): 14678-14691.