スライド 1

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あきひろしんまつ
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1 Evolution of organocatalyst ~focused on MacMillan s work~ (Sat) Takumi Matsueda (M1) 1

2 Contents 1. Introduction 2. HOMO, LUMO-activation 3. SOMO-activation 4. Metal-free SOMO-activation 5. Summary 2

organocatalyst Organocatalyst is one of the most important catalyst in organic chemistry

3 An explosion of interest in organocatalyst 1. Introduction Enantioselective organocatalyst was found in 2000 (by MacMillan) discovery of organocatalyst Organocatalyst is one of the most important catalyst in organic chemistry MacMillan, D. C. Nature, 2008, 455, Insensitive to oxygen & moisture Non-toxic Inexpensive and easy to prepare A wide variety of organic reagent 3

4 Prof. David W. C. MacMillan 1. Introduction The pioneer of organocatalyst MacMillan catalyst = enantioselective C=O activation Career Undergraduate degree in chemistry at the University of Glasgow Doctoral studies at the University of California (Prof. Larry E. Overman) Postdoctoral research fellow at Harvard University (Prof. David A. Evans) His independent research career at the University of California, Barkeley the Department of Chemistry at the California Institute of Technology the Department of Chemistry at Princeton University 2011-present James S. McDonnell Distinguished University Professor of the Department of Chemistry at Princeton University 4

5 Aldehyde activation 1. Introduction 4 main types of aldehyde activation 5

6 1. Introduction 2. HOMO, LUMO-activation 3. SOMO-activation 4. Metal-free SOMO-activation 5. Summary 6

7 The birth of MacMillan catalyst 2. HOMO, LUMO-activation LUMO-activated Diels-Alder reaction Selectivity of iminium cation formation *5 mol% cat. (entry 5) MacMillan, et al., J. Am. Chem. Soc., 2000, 122,

8 LUMO-activation by imidazolidinone 2. HOMO, LUMO-activation Mukaiyama Michael addition Hydride reduction MacMillan, et al., J. Am. Chem. Soc., 2003, 125, MacMillan, et.al., J. Am. Chem. Soc., 2005, 127, Amine addition MacMillan, et al., J. Am. Chem. Soc., 2006, 128,

9 HOMO-activation by proline 2. HOMO, LUMO-activation Homo aldol Cross aldol R=Et,iPr,iBu,Cy,Ph MacMillan, et al., J. Am. Chem. Soc., 2002, 124, Oxidation MacMillan, et al., J. Am. Chem. Soc., 2003, 125,

10 HOMO-activation by imidazolidinone 2. HOMO, LUMO-activation Chlorination Fluorination not 6-membered ring TS... imidazolidinone catalyst MacMillan, et al., J. Am. Chem. Soc., 2004, 126, MacMillan, et al., J. Am. Chem. Soc., 2005, 127,

11 HOMO, LUMO-activation enantioselective HOMO, LUMO-activation 11

12 Organocascade reaction 2. HOMO, LUMO-activation enantioselective C-Nu and C-E bond formation in one-pot reaction 2 chiral carbon + temp: -60~-40 yield: 67-97% dr: >25~9:1 ee: 99% Nu - E + MacMillan, et al., J. Am. Chem. Soc., 2005, 127,

13 Cascade cycle 2. HOMO, LUMO-activation 13

14 Problem of organocascade reaction 2. HOMO, LUMO-activation Problem: diastereoselectivity Solution: use different catalyst at respective cycle LUMO-activation HOMO-activation Cycle specific organocascade reaction 14

15 Cycle-specific organocascade reaction 2. HOMO, LUMO-activation MacMillan, et al., Angew. Chem. Int. Ed., 2009, 48,

16 Limitation of electrophile 2. HOMO, LUMO-activation 16

17 Application of cascade reaction 2. HOMO, LUMO-activation Timeline MacMillan, et al., Angew. Chem. Int. Ed., 2009, 48,

18 Summary of organocascade reaction 2. HOMO, LUMO-activation enantioselective... imidazolidinone only cyclic specific catalysts 18

19 1. Introduction 2. HOMO, LUMO-activation 3. SOMO-activation 4. Metal-free SOMO-activation 5. Summary 19

20 The concept of SOMO-activation 3. SOMO activation low ionization potential of enamine... 3p electron system and radicalic addition MacMillan, et al., Science, 2007, 316,

21 SOMO-activation by CAN 3. SOMO activation CAN = (NH4)2Ce iv (NO3)6 1e - oxidant (Ce IV -> Ce III ) arylation cyclization MacMillan, et al., Science, 2007, 316,

22 Catalytic cycle of SOMO-activation 3. SOMO activation MacMillan, et al., Angew. Chem. Int. Ed., 2010, 49,

23 Mechanistic study 3 features of SOMO-activation by CAN Enamine selective oxidation Water concentration is critical (2 eq is good) Kinetic role of CAN is masked (heterogeneous) 3. SOMO activation 2 eq H 2 O without H 2 O Enamine formation +: Lewis acidity of Cerium cation : hydrolysis by H 2 O CAN Ce(NO 3 ) 3 6H 2 O same reactivity for enamine formation concentration of CAN: 0.03M (anhydrous), 0.39M (water 2 eq) The role of water: hydrolysis of enamine, solve CAN MacMillan, et al., Angew. Chem. Int. Ed., 2010, 49,

24 Combination with photoredox catalyst 3. SOMO activation First report of photoredox catalyst in organic chemistry Catalytic amount of redox reagent (CAN: 2 eq) MacMillan, et al., Science, 2008, 322,

25 About photoredox catalyst 3. SOMO activation activation by visible light and 2 types of quenching route MLCT=metal to ligand charge transfer ISC=intersystemcrossing A=1e - accepter, D=1e - donor MacMillan, et al., Chem. Rev., 2013, 113,

26 a-alkylation 3. SOMO activation Olefin, benzyl tolerate (Ru cat don t produce allylic radical and benzyl radical) Wide scope of substituent of phenyl moiety Addition of tertially alkyl moiety to a-position of C=O MacMillan, et al., Science, 2008, 322,

27 Catalytic cycle 3. SOMO activation E red (oxidant side) E red (reductant side) >0 : proceed <0 : NR MacMillan, et al., Science, 2008, 322,

28 Ir(ppy) 3 catalyst 3. SOMO activation Ir cat. passes reductive quenching route MacMillan, et al., J. Am. Chem. Soc., 2010, 132,

29 SOMO-b-activation 3. SOMO activation New type of enamine activation MacMillan, et al., Science, 2013, 339,

30 b-allylation - mechanism 3. SOMO activation MacMillan, et al., Science, 2013, 339,

31 Michael addition of SOMO-b-activation 3. SOMO activation entry9: reaction time12 h / entry10: without DABCO MacMillan, et al., J. Am. Chem. Soc., 2014, 136,

32 Limitation of b-allylation 3. SOMO activation SOMO-b-accepter Accepter should stabilize radical anion. (EWG aryl / ketyl radical) Not radical accepter (alkylation) 32

33 1. Introduction 2. HOMO, LUMO-activation 3. SOMO-activation 4. Metal-free SOMO-activation 5. Summary 33

34 Environmental friendly photocatalyst 4. Metal-free SOMO activation HOMO, LUMO-activation... imidazolidinone or proline catalyst (organocatalyst) SOMO-activation... imidazolidinone + photoredoxcatalyst (Ru, Ir) potentially toxic for environment Use organic dye for photoredox catalyst low cost non toxic (= environmental friendly) activated by visible light (especially green light) 34

35 Alkylation by oranic dye catalyst 4. Metal-free SOMO activation Konig, B. et al., Angew. Chem. Int. Ed., 2011, 50,

Consecutive PET PDI gains high reductivity from photoactivation by two photons 4. Metal-free SOMO activation -1.5~2.0 V -0.

36 Consecutive PET PDI gains high reductivity from photoactivation by two photons 4. Metal-free SOMO activation -1.5~2.0 V V Stability of PDI - is important for second activation Exceeds reduction energy of PDI * - to Ar-Cl (high reduction energy) Potential to stronger photoredox catalyst than Ru, Ir R = EWG only Konig, B. et al., Science, 2014, 346,

37 1. Introduction 2. HOMO, LUMO-activation 3. SOMO-activation 4. Metal-free SOMO-activation 5. Summary 37

38 Summary 5. Summary Imidazolidinone activation Diels-Alder, Hydride reduction Mukaiyama-Michael Proline activation (6-membered ring TS) Imidazolidinone activation (not 6-membered ring TS) CAN (2 eq) activation low IP of enamine addition of water allylation Photoredox Ru(bpy) 2 Cl 2, Ir(ppy) 3 alkylation Ir(ppy) 3 stable radical anion partner b-arylation g-hydroxyketone radicalic Michael addition Imidazolidinone only HCl, HF addition Cyclic specific catlyst Hydride reduction +aldol, oxidation, amination 38

39 Summary-2 photoredox catalyst 5. Summary Metal photoredox Metal-free photoredox high reactivity easy to change reactivity (ligand modification) high cost potential toxic low cost non toxic (= environmental friendly) stability (catalyst is radical reactant) 39

40 Appendix 40

41 Synthesis of imidazolidinone from amino acid MacMillan, et al., Org. Synth., 2011, 88,

42 Hydride reduction of E/Z mixture amine cat accelerate isomerization of E/Z intermediate 42

43 Imidazolidinone & imidazolidinone cascade h h 43

44 Aldol reaction by imidazolidinone catalyst aldol reaction... proceeds at 4 MacMillan, et al., Angew. Chem. Int. Ed., 2004, 43,

45 Redox potential of photoredox catalysts MacMillan, et. al., Chem. Rev., 2013, 113, cyclic voltammetry date of Ir(dmppy)2(dtbppy)2 MacMillan, et al., J. Am. Chem. Soc., 2014, 136,

46 a-alkylation entry light Ru(bpy) 3 Cl 2 yield 1 15-W fluorescent bulb 84% 2 - no rxn 3 15-W fluorescent bulb - <10% 4 UV ( nm) - >80% 5 MLCT absorption band (465 nm) 84% * 6 MLCT absorption band - <5% *90min MacMillan, et al., Science, 2008, 322,

47 Deprotonation of b-position 47

48 Benzydrol addtion to allylic radical J. S. Bradshow, J. Org. Chem, 1966, 31, H. Nozaki, et al., Tetrahedron, 1968, 24,

49 Searching for metal-free photoredox catalyst ちなみにお値段の方は mmol 単位の値段で Ru(bpy)2Cl2 $62.5 Ir(ppy)3 $630 EosinY $2.66 entry3,5,10... degradation observed entry4,6, stable under light エオシンが比較的高い反応性と安定性を有していることからエオシンをチョイスした Konig, ACIE, 2011, 50,

50 Metal-free catalytic SOMO-activation Meerwein reaction 40-86% transition metals : CuCl, TiCl 3, Pd mechanism : radicalic intermediate R is electron rich... low yield electron poor... high yirld B. Konig, et al., J. Am. Chem. Soc., 2012, 134,

51 Reduction potential of aryl chloride J-M. Saveant, et al., J. Am. Chem. Soc., 2004, 126,

52 PDI photocatalyst substrate 52

53 Mechanism study 4. Metal-free SOMO activation radical trap by TEMPO chemical production of PDI radical B. Konig, et al., Science, 2014, 346,

54 Evidence of PDI radical anion photoactivation Aryl radical trapping PDI radical anion production by addition of (Et2N)4S2O4 (= chemical reductant of PDI)... no reduction of 4-Br-acetophenone B. Konig, et al., Science, 2014, 346,

55 Q & A 55

56 この研究の最終目的は何か? 触媒量の金属のみの使用で酸化剤還元剤を必要としない photoredox catalyst は atom economy や不要な副産物を生みにくいという点で環境負荷のない合成法を可能にしています現在はそれらを用いた反応のバリエーションを増やしている段階だと考えられますが最終的には全合成医薬品合成においてクリーンな合成方法を確立することにあるのではないかなと思います Ru,Ir 以外で photoredox catalyst となる例はある? Photoredox catalyst は Ru,Ir が使われる場合がほとんどでそれ以外のケースではエオシンのような色素が使われるケースもありますが Cu を使った光酸化還元反応もあります 56

57 p26 でアルデヒドの α 位はラセミ化しないのか? MacMillan らの結果をみるにラセミ化はあまり起こってないことが分かりますその理由としては amine catalyst が置換後のアルデヒドに攻撃しにくくなっていることが挙げられるのではないかと考えられます反応前のアルデヒドより立体的に混んでいる生成物がアミンの攻撃に耐性があるためイミンやエナミンの生成が妨げられ結果としてラセミ体になりにくいという可能性が考えられます Ru と Ir の使い分け方 Appendix の p45 の表を参考に光励起されてから酸化的パス (E*/E-) のエネルギー差と還元的パス (E+/E*) のエネルギー差を比べてみると Ru は酸化的パスのエネルギーが大きく Ir は還元的パスのエネルギーが大きいことが分かりますそのため傾向として言えることは比較的酸化されにくい基質があるときは Ru の方が適切で還元されにくい基質があるときは Ir が適切であるということです例えば p28 の SOMO-activation の例ではカップリングパートナーが還元されにくいため Ru は使えず Ir で反応を回しています 57

58 SOMO-activation と SOMO-β-activation の違いはどこに起因するのか? SOMO-activation におけるカップリングパートナーは photoredox catalyst によって一電子還元された不安定なラジカルでエナミンに対してすぐ反応してしまうと考えられます一方で SOMO-β-activation の場合はカップリングパートナー側がラジカルを安定化するような置換基 ( 電子求引基 ) を持つことでエナミンへの付加が抑制されることでエナミン側に脱プロトンされる隙が生じたのではないかと考えられます ( つまり基質依存ではないかと思います ) また SOMO-activation の場合においてエナミンの酸化に先立ってラジカルの付加が起こっているという実験結果からもラジカル自体の不安定さが反応性に影響していることが示唆されます SOMO-β-activation の β 位にラジカルが生じる機構は? 考えられる機構としては以下のようなものが挙げられます 58

スライド 1

スライド 1 1 Organic reaction on water 2016. 10. 1. (sat.) Takumi Matsueda (M2) Today s topic 2 1. Introduction 2. Investigation of on water -Bulk & surface water -Theoretical study (Diels-Alder) 3. Application of