Evolution of organocatalyst~focused on MacMillan’s work~2015.5.9 (Sat)
Takumi Matsueda (M1)1

Contents

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

5. Summary2

An explosion of interest in organocatalyst

1. Introduction

Enantioselective organocatalyst was
found in 2000 (by MacMillan)

discovery of organocatalyst

Organocatalyst is one of the mostimportant catalyst in organic chemistry

MacMillan, D. C. Nature, 2008, 455, 304-308

 Insensitive to oxygen & moisture Non-toxic
 Inexpensive and easy to prepare A wide variety of organic reagent
3

Prof. David W. C. MacMillan

1. Introduction

The pioneer of organocatalyst

MacMillan catalyst= enantioselective C=O activationCareer

1987-1991 Undergraduate degree in chemistry at the University of Glasgow
1991-1996 Doctoral studies at the University of California (Prof. Larry E. Overman)
1996-1998 Postdoctoral research fellow at Harvard University (Prof. David A. Evans)
1998-2000 His independent research career at the University of California, Barkeley
2000-2006 the Department of Chemistry at the California Institute of Technology
2006-2011 the Department of Chemistry at Princeton University
2011-present James S. McDonnell Distinguished University Professor of
the Department of Chemistry at Princeton University

4

Aldehyde activation

1. Introduction

4 main types of aldehyde activation

5

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

5. Summary

6

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, 4243-4244

7

LUMO-activation by imidazolidinone

2. HOMO, LUMO-activation

Mukaiyama Michael addition

MacMillan, et al., J. Am. Chem. Soc., 2003, 125, 1192-1194

Hydride reduction

MacMillan, et.al., J. Am. Chem. Soc., 2005, 127, 32-33

Amine addition

MacMillan, et al., J. Am. Chem. Soc., 2006, 128, 9328-9329

8

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, 6798-6799

Oxidation

MacMillan, et al., J. Am. Chem. Soc., 2003, 125, 10808-10809

9HOMO-activation by imidazolidinone
Chlorination

2. HOMO, LUMO-activation

Fluorination

not 6-membered ring TS... imidazolidinone catalyst
MacMillan, et al., J. Am. Chem. Soc., 2004, 126, 4108-4109
MacMillan, et al., J. Am. Chem. Soc., 2005, 127, 8826-8828 10

HOMO, LUMO-activation

2. HOMO, LUMO-activation

enantioselective ...

11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, 15051-15053

12

Cascade cycle

2. HOMO, LUMO-activation

13

Problem of organocascade reaction

2. HOMO, LUMO-activation

Problem: diastereoselectivity

Solution: use different catalyst at respective cycle

Cycle specificorganocascade reaction
LUMO-activation

HOMO-activation

14

Cycle-specific organocascade reaction 2. HOMO, LUMO-activation

MacMillan, et al., Angew. Chem. Int. Ed., 2009, 48, 4349-4353

15

Limitation of electrophile

2. HOMO, LUMO-activation

16

Application of cascade reaction

2. HOMO, LUMO-activation

Timeline

MacMillan, et al., Angew. Chem. Int. Ed., 2009, 48, 4349-4353

17

Summary of organocascade reaction

2. HOMO, LUMO-activation

enantioselective...

imidazolidinone only

cyclic specific catalysts18

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

5. Summary

19

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, 582-585

20

SOMO-activation by CAN

3. SOMO activation

CAN = (NH4)2CeiV(NO3)6
1e- oxidant (CeIV -> CeIII)arylationcyclization

MacMillan, et al., Science, 2007, 316, 582-585

21

Catalytic cycle of SOMO-activation

3. SOMO activation

MacMillan, et al., Angew. Chem. Int. Ed., 2010, 49, 6106-6110

22

Mechanistic study

3. SOMO activation
2 eq H2O

without H2O

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)

Enamine formation+: Lewis acidity of Cerium cation―: hydrolysis by H2O
CANCe(NO3)3･6H2O

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, 6106-6110

23

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, 77-80

24About photoredox catalyst

3. SOMO activation

activation by visible light and 2 types of quenching route

A=1e- accepter, D=1e- donor
MLCT=metal to ligand charge transfer
ISC=intersystemcrossing

MacMillan, et al., Chem. Rev., 2013, 113, 5322-5363

25

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, 77-80

26

Catalytic cycle

3. SOMO activation

Ered(oxidant side) – Ered(reductant side)>0 : proceed<0 : NR

MacMillan, et al., Science, 2008, 322, 77-80

27

Ir(ppy)3 catalyst

3. SOMO activation

Ir cat. passes reductive quenching route

MacMillan, et al., J. Am. Chem. Soc., 2010, 132, 13600-13603

28

SOMO-b-activation

3. SOMO activation

New type of enamine activation

MacMillan, et al., Science, 2013, 339, 1593-1596

29

b-allylation - mechanism

3. SOMO activation

MacMillan, et al., Science, 2013, 339, 1593-1596

30

Michael addition of SOMO-b-activation

3. SOMO activation

entry9: reaction time12 h / entry10: without DABCOMacMillan, et al., J. Am. Chem. Soc., 2014, 136, 6858-6861

31

Limitation of b-allylation

3. SOMO activation

SOMO-b-accepter

Accepter should stabilize radical anion. (EWG aryl / ketyl radical)
Not radical accepter (alkylation)32

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

5. Summary

33

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

Alkylation by oranic dye catalyst

4. Metal-free SOMO activation

Konig, B. et al., Angew. Chem. Int. Ed., 2011, 50, 951-954

35

Consecutive PET

4. Metal-free SOMO activation

PDI gains high reductivity from photoactivation by two photons-1.5~2.0 V-0.88 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 onlyKonig, B. et al., Science, 2014, 346, 725-728

36

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

5. Summary

37

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)2Cl2, Ir(ppy)3
alkylationIr(ppy)3
stable radical anion partnerb-arylation
g-hydroxyketone
radicalic Michael addition

Imidazolidinone only→HCl, HF addition
Cyclic specific catlyst→Hydride reduction+aldol, oxidation, amination
38

Summary-2

5. Summary

photoredox catalyst

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

Appendix

40

Synthesis of imidazolidinone from amino acid

MacMillan, et al., Org. Synth., 2011, 88, 42-53

41

Hydride reduction of E/Z mixture

amine cat accelerate isomerization of E/Z intermediate42Imidazolidinone & imidazolidinone cascade-20 ℃ 30 h → -10 ℃ 12 h43

Aldol reaction by imidazolidinone catalyst

aldol reaction ... proceeds at 4 ℃

MacMillan, et al., Angew. Chem. Int. Ed., 2004, 43, 6722-6724

44

Redox potential of photoredox catalysts

MacMillan, et. al., Chem. Rev., 2013, 113, 5322-5363

cyclic voltammetry date of Ir(dmppy)2(dtbppy)2

MacMillan, et al., J. Am. Chem. Soc., 2014, 136, 6858-6861

45a-alkylation

entrylightRu(bpy)3Cl2

yield

115-W fluorescent bulb

○84%2-○no rxn

315-W fluorescent bulb-<10%4UV (300-350 nm)

->80%

5

MLCT absorption band (465 nm)○84% *6MLCT absorption band-

<5%*90min

MacMillan, et al., Science, 2008, 322, 77-80

46

Deprotonation of b-position47

Benzydrol addtion to allylic radical

J. S. Bradshow, J. Org. Chem, 1966, 31, 237-240

H. Nozaki, et al., Tetrahedron, 1968, 24, 6557-6562

48

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
entry4,6,7-9 ... 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, 951-954

49

Metal-free catalytic SOMO-activation
Meerwein reaction

40-86%

transition metals : CuCl, TiCl3, Pd
mechanism : radicalic intermediate

R is electron rich ... low yieldelectron poor ... high yirld

B. Konig, et al., J. Am. Chem. Soc., 2012, 134, 2958-2961

50

Reduction potential of aryl chloride

J-M. Saveant, et al., J. Am. Chem. Soc., 2004, 126, 16051-16057

51

PDI photocatalyst substrate52

Mechanism study

4. Metal-free SOMO activation

radical trap by TEMPO

chemical production of PDI radical

B. Konig, et al., Science, 2014, 346, 725-728

53

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, 725-728

54

Q&A55

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

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

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