The carbonyl ene reaction
Literature Seminar(M1)Sachiyo Nakanowatari2010/09/30 @W5 18:00reference

Mikami, K.; Shimuzu, M. Chem. Rev. 1992, 92, 1021-1050
Clarke, M. L.; France, M. B. Tetrahedron 2008, 64, 9003-9031'Lewis Acid Catalyzed Carbonyl-Ene Reaction' Ober, M. 2003,(http://www.scs.illinois.edu/denmark/presentations/2003/gm-2003-12-16.pdf) 09/29/10 accessed1

Contents
Part 1-Basics

Part 2-

1. Introduction

The catalytic asymmetriccarbonyl ene reaction

2. Definition
3. History
4. Mechanism
5. Diastereoselectivity

1. Mikami's Ti- BINOL catalyst
2. Evans's Cu -BOX catalyst
3. Other Metals
4. Organocatalyst
5. Summary2Ｐａｒｔ １－Ｂａｓｉｃｓ
Mainly based on:
三上幸一、寺田真浩、清水正毅、中井武「有機合成化学」（ 1990 ） vol. 48, No. 4, p292-303
Mikami, K.; Shimuzu, M. Chem. Rev. 1992, 92, 1021-1050
Berrisford, D. J.; Bolm, C. ACIE 1995, 34, 1717-1719

3

Ｋｏｉｃｈｉ Ｍｉｋａｍｉ
・Born in 1953 and received his B.S. degree
and Ph.D. from Tokyo Institute of Technology
with Takeshi Nakai.
・Joined the faculity of TIT in 1982, where heis currently Professor of applied chemistry.
From 1982 to 1983 he was a postdoctral fellow
at the Yale University with Frederick E. Ziegler.
・His major research interests are thedevelopments of new methods and strategies
for organic synthesis, the asymmetric catalysis
of synthetic organic reactions, and theirapplication to natural product synthesis. His
current research interests also include
photochemistry andfluorine chemistry.

4

Masahiro

TeradaBorn in 1964, received his B. S. degree and Ph.
D. from Tokyo Institute of Technology
●

●●

●

●

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1989-1997, Assistant Professor Faculty ofEngineering, Tokyo Institute of Technology
1997-2001, Assistant Professor Graduate Schoolof Science and Engineering, Tokyo Institute ofTechnology
2001-2006, Associate Professor Graduate Schoolof Science, Tohoku University
2006-present, Professor Graduate School ofScience, Tohoku University
1999-2000, Visiting Researcher Harvard
University, Prof. Matthew D. Shair
2005-2006, Visiting Associate Professor Catalysis
Research Center, Hokkaidou University
5Ene Reaction(Alder-Ene Reaction)●Ene Reaction●Thermal reaction; Highertemperature(more than 150℃ due tothe high activationbarrier)side reaction●Lewis acid （ AlMe2Cl,SnCl4, BF3 OEt2, Sc(OTf)3,Yb(OTf)3 etc. ）Variation;●Carbonyl ene reaction●

Conia reaction●

Singlet-oxygen ene reaction●Metallo-ene reaction

Recen 40 years:●●1980s-:Chiral Lewis Acidcomplex
2008-:Organocatalyst

6Named Reactions●Prins Reaction
Acid-catalyzed addition of olefins to formaldehyde to give 1, 3-diols(3), allylicalcohols(4), or meta-dioxanes(5):●Conia Reaction(Conia-Ene Reaction)
The intramolecular ene reaction of unsaturated ketones, in which thecarbonyl functionality serves as the ene component, viaits tautomer, andolefinic moiety serves as the enophile:

7

Thermal vs LA promoted

Lewis Acid Catalyzed Carbonyl-Ene Reaction' Ober, M. 2003

8

Thermal vs LA promoted

Lewis Acid Catalyzed Carbonyl-Ene Reaction' Ober, M. 2003
9

Diaselectivity●●A dramatic changeoverin diastereoselectivity bychanging the Lewis acid
Conventional 5
membered ring model
does not explain theresult.

10

Lewis Acid Catalyzed Carbonyl-Ene Reaction' Ober, M. 2003

Diastereoselectivity -Chairlike Model

11

Ｐａｒｔ 2- The catalytic asymmetric
Carbonyl ene reaction
Mainly based on:
Clarke, M. L.; France, M. B.
Tetrahedron 2008, 64, 9003-9031
In addition to guiding chemists
towards reactions
that proceed effectively,
we hope this review has also
highlighted some of thechallenges that lie ahead.
12

The development of Asymmetric Catalyst●●●●In 1988 and 1989; Pioneering workof Yamamoto(first;1988)'s
aluminum-based and Mikami'stitanium-based BINOL complex
In 1995; Evan's Cu- Box
catalyst(direct interaction between
Metal and carbonyl oxgen)
Other metals(Cr, Co, Pd, Pt, Ni, Sc,In etc.)
In 2008 organocatalyst

by Teradaand Rueping independently●Polymer supported13

Ti-BINOL TS●3; favored TS structure●4; sterically disfavored●●Ene reaction like this is
caliculated to be exothermic
by ca.20kcal/mol.
The reaction of the Lewisacid coordinated aldehyde
will be much more exothermic-possibly 30kcal/mol→TS should be SM like
14

Corey, E. J.; Barnes-Seeman, D.; Lee, T. W.; Goodman, S. N. Tetrahedron 1997, 38, 6513-6516

BINOL-Ti●●●ＮＬＥ -1

4A MS; water donor & Base to trap
HXNLE←isostructural dinuclear
chelate complex 184.
Homochiral dimer is far more
active than heterochiral mesodimer(R,S).

Mikami, K.; Terada, M. Tetrahedron 1992, 48,5671–5680.

●Positeve Non Linear Effect
15

BINOL-Ti●ＮＬＥ -2

The meso isomer is formed preferentially, leaving excess enantiomerically pureBINOL.
Mikami, K.; Terada, M. Tetrahedron 1992, 48, 5671–5680.

16

Asymmetric synthesis by enantiomer-selective activation ofracemic catalysts asymmetric activation

17
図：「研究室訪問２」 LANDFALL vol.31,p10

Mikami, K.; Matsukawa, S. Nature 1997, 385, 613-615

Asymmetric synthesis by enantiomerselective activation of racemic catalysts(2)Mikami, K.; Matsukawa, S. Nature 1997, 385, 613-615

18

「これまで」； Mikami's titanium
BINOL system has been usedby Roche on a multi 100-kg
scale in a pilot process.

19Structural Elucidation of Catalytically Active Species

Terada, M. 2007 J. Synth. Org. Chem.
In Japan Vol. 65, No. 8, 748-760

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Asymmetric Hetero Diels-Alder Reactions and Ene
Reactions Catalyzed by Chiral Copper(I1) Complexes

Jorgensen, K. A. J. Org. Chem. 1995, 60,5757

21

Asymmetric Hetero Diels-Alder Reactions and Ene
Reactions Catalyzed by Chiral Copper(I1) Complexes

22Cu-BOX catalyst

Evans, D. A. J. Am. Chem. Soc., 2000, Vol. 122, No. 33,23

Carbonyl-Ene Reactions Catalyzed by Box- Cu(II)Complexes Proceed by a Facile Stepwise Mechanism:DFT and ONIOM (DFT:PM3) Studies(1)BOX リガンド（4）と銅（Ⅱ）錯体を触媒としたカルボニルーエン反応（Scheme 1）の反応機構のDFTによる研究がなされた。筆者らはDFT法と、DFT法よりも簡便なONIOM法の両方を用いて各計算を行った（Figure 2）。結果、ONIOMは正確な静止構造を算出したが、正確なエネルギーの算出にはDFTレベルの計算が必要であると結論付けた。また、計算結果を踏まえて、筆者らはこの反応はステップ・ワイズに進行すると結論づけた。ＴＳ 3のエネルギーがＴＳ 2 より高いことから、５のような４員環の中間体を経ずに進行する。更に、この反応における錯体金属の役割について、β水素転移がメタセシスや酸化的付加と異なり、錯体金属の直接の関与無しに起こることから、錯体金属は単に求電子性を上げる活性化の役割を果たしているとした。

Morao, I.; McNamara, J. P.; Hiller, I. H. J. AM. CHEM. SOC. 2003, 125, 628-629

24

Enantioselective Syn-Selective Sc-Catalyzed
Ene Reactions(1)Evans, D. A.; Wu, J. J. AM. CHEM. SOC. 2005, 127, 8006-8007

25

Syn-Selective ScCatalyzed
Ene Reactions(2)Evans, D. A.; Wu, J. J. AM. CHEM. SOC.
26
2005, 127, 8006-8007

Enantioselective
Syn-Selective
ScandiumCatalyzed EneReactions(3)27Evans, D. A.; Wu, J. J. AM. CHEM. SOC. 2005, 127, 8006-8007

Remarkably Broad Substrate Scope(1)Zheng, K.; Shi, J.; Liu, X.; Feng, X. J. Am. Chem. Soc.2008, 130, 15770-15771
四川大学

Table 1. Optimization of theReaction Conditions

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Remarkably Broad Substrate Scope(2)Zheng, K.; Shi, J.; Liu, X.; Feng, X.
J. Am. Chem. Soc.2008, 130,15770-15771

Table 2. Substrate Scope for theCatalytic Asymmetric
Carbonyl-Ene Reaction

29Organocatalyst Aza-ene-type reaction catalyzed
by chiral Bronsted acid-the first example of the activation of aldehydes by using chiral phosphoric acid to efficiently accelerate
an aza-ene-type reaction

Terada, M.; Soga, K.; Momiyama,N. ACIE 2008, 47, 4122-4125
30

Organocatalyst Carbonyl-ene reaction catalyzed
by chiral Bronsted acid-the first example of the highly enantioselective carbonyl-ene
reaction with chiral phosphoric acidRueping, M.; Theissmann, T.;
Kuenkel, A.; Koenigs, R.
Angew. Chem. Int. Ed.
2008, 47, 6798-6801
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Sumary32