薬化学特論w3pharm.u-shizuoka-ken.ac.jp/yakka/japanese/manabeclass/...noyori, r. asymmetric...

平成24年度

薬化学特論

●教科書の５，８，９章の中から抜粋した内容

●評価：最終試験（11月14日）

●プリントはウェブサイト（薬化HP →「眞鍋担当授業」 → 「薬化学特論」）からダウンロード可

1

Chapter 1

Principles of

Asymmetric Synthesis

chiral

achiral

2

R1

N

R2

R3R1

P

R2

R3

NMe3

34 kJ/molPMe3

133 kJ/mol

atropisomer

inversion barrier

3

P

P

Ph

Ph

MeO

OMe

DIPAMP

ZrCl

Cl

Fe

PPh2

PCy2

JOSIPHOS

C2 symmetry C1 symmetryCn : 360 / n

180O rotation

C3 symmetry

CO2HHO

HO CO2H

BH R2

R1

4

optically active

racemic

誤用例1「・・・・BINAPは、炭素‐炭素単結合

の回転が妨げられているため、光学活性な分子構造をもつ。」

誤用例2「・・・・以前に我々はラセミ体の1を合成した。今回、キラルな1の合成に成功したので報告する。」

1

HN

HO2C H

H

5

...Current usage of the term ‘chiral’ in a generalized manner such as, ‘chiral synthesis, ‘chiral approach’, etc. is misleading and incorrect....

Hanessian, S. Total Synthesis of Natural Products: The ‘Chiron’ Approach; Pergamon Press: Oxford, 1983, p 21.

► chiral pool synthesis

► resolution

► asymmetric synthesis (narrow definition)

Synthesis of Optically Active Compounds(Asymmetric Synthesis)

“classical” resolutionkinetic resolution

diastereoselectiveenantioselective stoichiometric

catalytic

absolute asymmetric synthesis

6

“classical” resolution

R CO2

NH3

R CO2

NH3

R CO2H

NH

R CO2H

NH

H

O

H

O

MeO

MeO N

N

OO

H

H

H

H

R CO2

NH

H

O

MeO

MeO N

N

OO

H

H

H

H

R CO2

NH

H

O

NaOHH2O

R CO2

NH

H

ONaOHH2O

R CO2

NH3pure salt

pH ~6

O O

R*

OLi

RX

7

Enders, D.; Eichenauer, H. Chem. Ber. 1979, 112, 2933.

ON

NH2OMe

(SAMP)

NN

OMe

LDA;Me2SO4

NN

OMe O3

O

70% overall yield99% ee

Meyers, A. I. et al. J. Am. Chem. Soc. 1981, 103, 3081.

Hashimoto, S.; Koga, K. Tetrahedron Lett. 1978, 573.

Koga, K. et al. J. Am. Chem. Soc. 1994, 116, 8829.

Koga, K. et al. J. Chem. Soc., Chem. Commun. 1990, 1657.

8

enantiomeric excess (ee)enantiomeric ratio (er)optical purity (op)optical yieldasymmetric yield

% ee ∆∆G‡ (kJ/mol)–100 oC

∆∆G‡ (kJ/mol)23 oC

ratio ratio

99.9 10.9 17.7 99.95:0.05 1999

99.5 8.63 14.7 99.75:0.25 399

99 7.63 13.0 99.5:0.5 199

98 6.62 11.3 99:1 99

95 5.28 9.05 97.5:2.5 39

90 4.23 7.25 95:5 19

80 3.18 5.41 90:10 9

70 2.51 4.27 85:15 5.7

60 2.01 3.39 80:20 4

50 1.59 2.72 75:25 3

30 0.88 1.51 65:35 1.9

10 0.29 0.50 55:45 1.2

Energy differences between two isomers as a function of ee and temp.

Cf.) Koskinen, A. AsymmetricSynthesis of Natural Products; John Wiley & Sons, 1993.

9

∆∆G‡ (kJ/mol)

% ee

23 oC

% op

% ee

Optical Purity vs. Enantiomeric Excess

CO2H

HO2C

in CHCl3

Horeau, A. Tetrahedron Lett. 1969, 3121.

10

selectivity factor (s) = kfast / kslow

Fu, G. C. et al. J. Am. Chem. Soc. 2002, 124, 10296.

0.25 0.5 0.75 1

0.25

0.5

0.75

1

Cf.) Sharpless, K. B., et al. J. Am. Chem. Soc. 1981, 103, 6237.

0 25 50 75 100

100

75

50

25

0

% ee remaining starting material

% conversion

s = 2

3

5

10

20

100

1000

11

OMe

OO

OMe

OO

OMe

OHO

OMe

OHO

+

major minor

OMe

OHO

OMe

OHO

+

Dynamic Kinetic Resolution

100% conversion, dr = 99:1, 92% ee

Noyori, R. et al. J. Am. Chem. Soc. 1989, 111, 9134.

Ph

O

H+ Et2Zn

Ph

OH

Et

96% yield82% ee

t-BuN

OH

(11% ee, 2 mol %)

Ph

O

H+ Et2Zn

Ph

OH

Et

92% yield95% ee

(15% ee, 8 mol %)

NMe2

OH

Asymmetric amplification

Oguni, N. et al. J. Am. Chem. Soc. 1988, 110, 7877.


Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108, 2353. - - - nonlinear effects

12

練習問題１

柴﨑らによって開発されたヘテロバイメタリック錯体（下図）は、様々な不斉反応の触媒として用いられている（参考文献：Acc. Chem. Res. 2009, 42, 1117.）。中心のランタニドが正八面体型をとるとき、この錯体にはどのようなCn軸が存在するか？すべての軸を図に書き入れ、それぞれCnのnがいくつなのかも示せ（n > 1）。

練習問題２下の速度論的分割（Vedejs, E. et al. J. Org. Chem. 1996, 61, 430.）のselectivity factor (s)を、未反応の出発物質のeeから計算して求めよ。

13

Chapter 2

Asymmetric Hydrogenation

(catalytic)hydrogenation

Hydrogenation

homogeneous

heterogeneous

Wilkinson’s catalyst

oxidation state: Rh(I)valence electrons: 16e

catalyst for hydrogenation (1966)

14

大野桂二、佐治木弘尚, Organic Square (Wako) 2008, 22, 2.

Heterogeneous Pd Catalysts for Hydrogenation

Birch, A. J.; Williamson, D. H. Org. React. 1976, 24, 1.

Wilkinson’s catalyst RhCl(PPh3)3

RhCl(PPh3)3(cat.)

H2

R R R R

R

R

R

R

> > > > >

CO2Me CO2Me CO2Me

96%

>49%

4%

26%

PtO2 or Pd/BaSO4(cat.)

H2

15

RhL L

Cl L

RhL S

Cl L

RhL H

Cl L

H2

H

S

R

RhL H

Cl L

H

R

RhL

Cl L

H

S

H

R

H

R

H

Catalytic Cycle

oxidative addition

insertionturnover-limiting step

reductive elimination

◆dihydride◆hydrogen-first mechanism

Crabtree, R. Acc. Chem. Res. 1979, 12, 331.

Crabtree’s catalyst

TOF (h–1) of hydrogenation

TON = turnover number = moles of product / moles of catalystTOF = turnover frequency = TON / time

mechanism: Ir(III) and Ir(V) rather than Ir(I) and Ir(III) ?Hall, M. B.; Burgess, K. Chem. Eur. J. 2005, 11, 6859.

16

Crabtree, R. H.; Davis, M. W. J. Am. Chem. Soc. 1986, 51, 2655.

Stork, G.; Kahne, D. E. J. Am. Chem. Soc. 1983, 105, 1072.

Directing EffectsOH, CO2Me, C=O, or OMe

Catalytic Asymmetric Hydrogenation

PhCO2H

NHAc

H2RhBF4[((R)-camp)2(cod)] (cat.)

PhCO2H

NHAc

88% ee(R)-CAMP

P

Cy

Me

OMe

PhCO2H

NHAc

H2RhCl[(R,R)-diop] (cat.)

PhCO2H

NHAc

85% ee(R,R)-DIOP

O

OPPh2

PPh2

PhCO2H

NHBz

H2

[Rh((R)-binap)(MeOH)2]+ClO4– (cat.)

PhCO2H

NHBz

100% ee(R)-BINAP

PPh2

PPh2

AcHN CO2H

NaOAcAc2O

reflux reflux

H2O–acetone+ PhCHO

AcHN CO2H

Ph

「演習で学ぶ有機反応機構」化学同人 A019

17

CAMPKnowles, et al. (1972)

P

Cy

Me

OMe

BINAPNoyori, et al. (1980)

PPh2

PPh2

PhP

MeBu

Horner, et al. (1968)Knowles, et al. (1968)

O

OPPh2

PPh2

DIOPKagan, et al. (1971)

Fe

PPh2

PPh2

NMe2

BPPFAHayashi, Kumada, et al. (1974)

N

Boc

Ph2P

PPh2

BPPMAchiwa (1976)

PPh2

PPh2

chiraphosBosnich, et al. (1977)

P

PC6H4-2-OMe

Ph

C6H4-2-OMe

Ph

DIPAMPKnowles, et al. (1975)

Akabori, S. et al. Nature 1956, 178, 323.

Catalytic Cycle

Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York, 1994.Cf.) For hydrogen-first mechanism in cationic Rh catalysis: Gridnev, I. D.; Imamoto, T. Acc. Chem. Res. 2004, 37, 633.

◆dihydride◆olefin-first mechanism

PRh

P

S

S

PhCO2R

NHAc PRh

P ON

Ph

CO2R

H

H2

PRh

PO N

Ph

CO2R

H

H

H

PRh

P O N

Ph

CO2R

H

H

S

PhCO2R

NHAc

AB

CD

PRh

PON

Ph

RO2C

H

B'

turnover-limiting step

18

Curtin–Hammett Principle

Seeman, J. I. et al. J. Am. Chem. Soc. 1980, 102, 7741.

Tani, K.; Yamagata, S.; Akutagawa, S.; Kumobayashi, S.; Takemoto, T.; Takaya, H.; Miyashita, A.; Noyori, R.; Otsuka, S. J. Am. Chem. Soc. 1984, 106, 5208. 芥川進有合化 1986, 44, 513.

NEt2

NEt2

99% yield98.5% eeTON = 8000

P

P

R R

R RP

P

RR

RR

Rh ClO4

R = Me

7 tons

6.7 kg

OH (–)-menthol

Enantioselective Isomerization

19

Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York, 1994.

Morris, R. H. In Handbook of Homogeneous Hydrogenation; de Vries, J. G.; Elsevier, C. J., Eds.; Wiley-VCH: Weinheim, 2007.

◆monohydrideCatalytic Cycle

20

Hydrogenation of Ketones

Enantioselective Hydrogenation

Kinetic Resolution

Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York, 1994.

O

OMe

O

NHBz

H2Ru(II)-cat.

OH

OMe

O

NHBz

1) HCl2) NaOH

OH

OH

O

NH2

PPh3

NO H

OTBSTBSClimi.

RuCl3·nH2OAcO2HAcONa

NO H

OTBS

OAc

N

S

S S

N

S

Route to a Key Intermediate of Carbapenem

DKR

Shimizu, H. et al. Acc. Chem. Res. 2007, 40, 1385.

21

BINAP/1,2-Diamine–Ru(II) Complex

O

H2 (8 atm)catalyst (0.2 mol%)

OH

100% yield96% ee

catalyst =

PR2

R2P

Ru

Cl

Cl

R = 4-tolyl

NH2

H2N Ph

Ph

+ KOH

For mechanistic studies, see: Noyori, R. et al. J. Am. Chem. Soc. 2003, 125, 13490.Bergens, S. H. et al. J. Am. Chem. Soc. 2008, 130, 11979.

P

PRu

H

X NH2

H2N

OO

H H

H2

P

PRu

X NH2

HN

Asymmetric Transfer Hydrogenation


Ikariya, T. et al. Org. Lett. 1999, 1, 1119.

22

練習問題3下の反応は、水素の代わりに重水素、あるいはメタノールの代わりに重メタノールを用いて行った不斉水素化の結果である。式1および2の結果は、Morrisらの反応機構から説明できる。一方、基質としてアルコール類を用いたときには、式3および4のような結果となった。この結果は、反応機構がカルボン酸基質とアルコール基質とで異なることを示している。アルコール基質のときにはどのような反応機構が働くと考えられるか？実験結果と矛盾しない触媒サイクルを提唱せよ。（参考文献：Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York, 1994. ）

23

Chapter 3

Asymmetric Epoxidation

Epoxidation with Peroxy Acids

Freccero, M.; Gandolfi, R.; Sarzi-Amadè, M.; Rastelli, A. J. Org. Chem. 2000, 65, 2030.Singleton, D. A.; Merrigan, S. R.; Liu, J.; Houk, K. N. J. Am. Chem. Soc. 1997, 119, 3385.

more likely

morereactive

24

Grieco, P. A. et al. J. Am. Chem. Soc. 1977, 99, 5773.

Epoxidation under Basic Conditions

trans-decalin half-chair

1,3-diaxial interaction

O

OO

MeO

H

t-BuOOH

Triton® B

THF

Triton® B = benzyltrimethylammonium hydroxide in H2O

O

OO

MeO

H

O

O

OO

MeO

H

O

Ot-Bu

transition metal-catalyzed epoxidation

Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307.Henbest, H. B.; Wilson, R. A. I. J. Chem. Soc. 1957, 1958.Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95, 6136.

O

O

OH OH

relative rate

VO(acac)2t-BuOOH

1.00

>200

Henbest epoxidation

V

O

O

OO

RO

t-Bu

Epoxidation of Allyl Alcohols

25

Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95, 6136.

Early Examples of Asymmetric Epoxidationof Allyl Alcohols

Sharpless, K. B. et al. J. Am. Chem. Soc. 1977, 99, 1990.

Yamada, S. et al. J. Am. Chem. Soc. 1977, 99, 1988.

26

R2 R1

R3 OHR

H

R2 R1

R3 OHH

R

[O]

[O]

slow

fast

Essence of Sharpless Asymmetric Epoxidation

Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I. Ed.; Wiley-VCH: New York; 2000.

R2 R1

R3 OH

R2 R1

R3OH

O

R2 R1

R3OH

O

Ti(Oi-Pr)4t-BuOOH

CH2Cl2

CO2Et

OHEtO2C

HO

L-(+)-diethyl tartrate(natural)

CO2Et

OHEtO2C

HO

D-(–)-diethyl tartrate(unnatural)

[O]

[O]

Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.Sharpless, K. B., et al. J. Am. Chem. Soc. 1987, 109, 5765.

Katsuki, T. In Comprehensive Asymmetric Synthesis, Vol II; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer:Berlin; 1999.

BnO OH

OBn

OBn

ClCH2SO2O

Sharplessepoxidation

L-(+)-DET

D-(–)-DET

BnO OH

OBn

OBn

ClCH2SO2O

BnO OH

OBn

OBn

ClCH2SO2O

O

O

single isomer

single isomer

Kajimoto, T.; Wong, C.-H. Tetrahedron Lett. 1995, 36, 8247.

27

Sharpless, K. B., et al. J. Am. Chem. Soc. 1981, 103, 6237.

Kinetic Resolution of Racemic Allylic Alcohols

OH

H

OH

H

OH

H

O O

+

(+)-DIPTTi(Oi-Pr)4

CH2Cl2–20 ºC

erythro threo98 : 2(S)

OH

H

OH

H

OH

H

O O

+

(+)-DIPTTi(Oi-Pr)4

CH2Cl2–20 ºC

erythro threo38 : 62(R)

fast

slow

kfast/kslow = 104

Combination of asymmetric synthesis and kinetic resolution can deliver products with very high ee.

Schreiber, S. L., et al. J. Am. Chem. Soc. 1987, 109, 1525.

OHTi(Oi-Pr)4 (1.1 equiv)t-BuOOH (2.0 equiv)(–)-DIPT (1.3 equiv)

CH2Cl2–25 ºC

80–85% yield

OH

OH

O

O

major

minor

0.5 h: 88% ee

1 h : 94% ee

1.5 h: >99.3% ee

28

OH

O

OH

O

OH

O

OH

O

OH

O

OH

O

OH

O

OH

O

OH

O

OH

O

OH

O

OH

OO O O OO O O O

k1k1 k2 k3 k4

OH

Finn, M. G.; Sharpless, K. B. J. Am. Chem. Soc. 1991, 113, 113.Katsuki, T. In Comprehensive Asymmetric Synthesis, Vol II; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer:Berlin; 1999.

TiO

TiO

O

O

O

RO

O

t-Bu

OR

O

RO

E

E

E

O

TiO

TiO

O

O

OR

RO

O

OR

O

RO

E

EOR

OR

HO

t-BuOOH

Catalyst Structure and Proposed “Loaded” Catalyst

29

Na2(EDTA) is used to prevent trace-metal-catalyzed peroxide decomposition.

Ph Ph

O

O

O

O

OO

O

(30 mol %)

OXONE®, K2CO3

CH3CN/dimethoxymethane

0.05 M Na2B4O7 10H2O of aqueous

Na2(EDTA) (4x10-4 M) solution

OXONE® = 2KHSO5 · KHSO4 · K2SO4

94% yield95.5% ee

Shi, Y. et al. J. Am. Chem. Soc. 1997, 119, 11224.

Asymmetric Epoxidation of Unfunctionalized Olefins

dioxirane

30

Mn–Salen-Catalyzed Asymmetric Epoxidation

Jacobsen, E. N. et al. J. Am. Chem. Soc. 1991, 113, 7063. Jacobsen, E. N. et al. J. Am. Chem. Soc. 1990, 112, 2081. Katsuki, T. et al. Tetrahedron Lett. 1990, 31, 7345.

Dihydroxylation with Osmium Tetroxide

catalytic reaction

Criegee, R.; Marchand, B.; Wannowius, H. Liebigs Ann. Chem. 1942, 550, 99.

acceleration by tertiary amines

Milas, N. A.; Sussman, S. J. Am. Chem. Soc. 1936, 58, 1302.

31

PhPh

PhPh

OH

OH

N

OAc

N

OMe

(1.1 equiv)

OsO4 (1.1 equiv)

toluene

LiAlH4

90% yield83.2% ee

PhPh

PhPh

OH

OH

(1 mol%)

K2OsO2(OH)4 (0.2 mol%)K3Fe(CN)6 (3 equiv), K2CO3 (3 equiv)

CH3SO2NH2 (1 equiv)

t-BuOH/H2O

>80% yield>99.5% ee

NNO O

N N

MeO OMe

N

H

N

H

Asymmetric Dihydroxylation (AD)

Sharpless, K. B., et al. J. Am. Chem. Soc. 1980, 102, 4263.

Sharpless, K. B., et al. J. Org. Chem. 1992, 57, 2768.

.

OOs

O

O

O

R

+ L

Os O

OO

O

L

R

R

R

HO

R

OH

R

+ L

2 HO2 H2O

Os

O

O

HO

HO

OH

OH

2–

Os

O

O

HO

HO

O

O

2– 2 HO

2 HO

2 Fe(CN)63–

2 H2O

2 Fe(CN)64–

organic

aqueous

Catalytic Cycle

32

Two Proposed Mechanisms

Hoffmann, R., et al. J. Am. Chem. Soc. 1986, 108, 1867.Corey, E. J., et al. J. Am. Chem. Soc. 1996, 118, 11038.

Sharpless, K. B., et al. J. Am. Chem. Soc. 1997, 119, 1840.Houk, K. N.; Sharpless, K. B.; Singleton, D. A., et al. J. Am. Chem. Soc. 1997, 119, 9907.

練習問題4あなたは今、(–)-laulimalideの全合成の計画を立てている。その最終ステップで6個のC=C二重結合のうち1個だけを選択的に（しかも立体選択的に！）エポキシ化する計画（下式）は、無謀だろうか、それとも勝算はあるだろうか？理由とともに述べよ。

（参考：Mulzer, J.; Öhler, E. Angew. Chem. Int. Ed. 2001, 40, 3842. Paterson, I.; De Savi, C.; Tudge, M. Org. Lett. 2001, 3, 3149. Wender, P. A.; Hegde, S. G.; Hubbard, R. D.; Zhang, L. J. Am. Chem. Soc. 2002, 124, 4956.）

33

Chapter 4

Frontier Orbitals

Atomic Orbital (AO)

E

1s

2s

3s

2p

3p

34

antibonding MO

bonding MO

Molecular Orbital (MO)

E

*

H H

H2


E

*

*

35


E

*

C

Cl

C Cl

C Cl

36

H

C

H

H H

H

C

H

H H

Hybridization

sp3

H

C

H

HH

H

C

H

HH

H

C

H

HH

H

C

H

HH

Siegbahn, K., et al. Chem. Phys. Lett. 1968, 1, 613.阿武聰信，量子化学基礎の基礎，化学同人，1996.

37

E

Butadiene

38

Staggered vs. Eclipsed Conformation of Ethane

See: Pophristic V.; Goodman, L. Nature 2001, 411, 565.See also: Bickelhaupt, M.; Baerends, E. J. Angew. Chem. Int. Ed. 2003, 42, 4183.

Weinhold, F. Angew. Chem. Int. Ed. 2003, 42, 4188.Mo, Y.; Gao, J. Acc. Chem. Res. 2007, 40, 113.

HOMO

LUMO

LUMO

HOMO

39

HOMO

LUMO

LUMO

HOMO

LUMO

HOMO

Diels–Alder Reaction

‡

H HH H

H HH H

H H

H H

H H

H H

40

LUMO

HOMO LUMO

HOMO

H HH H

H HH H

LUMO

HOMO

[4 + 2]

[2 + 2]

Salem–Klopman Equation

∆E = –∑(qa+qb)abSab + ∑ ab k<l

QkQl

Rkl

+ ∑ ∑ – ∑ ∑occ unocc occ unocc

r rs s

2(∑cracsbab)2ab

Er–Es

occ-occ Coulomb

occ-unocc

41

Hard and Soft Acids and Bases (HSAB)

Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533.Fleming, I. （竹内敬人, 友田修司訳），フロンティア軌道法入門，講談社サイエンティフィク，1978.

acid

base

hard borderline soft

(A) HO– + Br2 HOBr + Br–

(B) HO– + H+ H2O

(C) + Br2 + Br–CH2

CH2

CH2

CH2Br

(D) + H+CH2

CH2

CH2

CH3

(A) < (B)

(C) > (D)

42

Hard and Soft Acids and Bases (HSAB)

acid

base

hard soft

high positive charge

low polarizability

high-energy LUMO

high negative charge

low polarizability

low-energy HOMO

low positive charge

high polarizability

low-energy LUMO

low negative charge

high polarizability

high-energy HOMO

Jencks, W. P.; Carriuolo, J. J. Am. Chem. Soc. 1960, 82, 1778.

pKa

log k2

O2N O

O

0 2 4 6 8 10 12 14

–4

–3

–2

–1

0

1

2

3

4

5

HO

HOO

NH3

pyridine

O

O

F

N3

H2NOH

ClOH2NNH2

43

-Effect

HOMO

Fleming, I. Molecular Orbitals and Organic Chemical Reactions, John Wiley & Sons: West Sussex, 2009.

Ambident Nucleophile

charge controlfrontier orbital control

44

“From the hard and soft acids and bases (HSAB) theory,it was deduced that the substitution of hydrides in BH4

– by alkoxy groups increases the hardness of the reagent. The attack of the conjugate enone system is then enhanced at the hard site, i.e., carbon 2.”

Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.

Luche Reduction（ルーシュ還元）1,2-reduction 1,4-reduction

練習問題5下に示したエノラートアニオンのエチル化反応では、C-エチル体とO-エチル体の2つの生成物が生じうる。それぞれの生成速度定数の比（kc / ko）を測定したところ、脱離基（X）の種類によってkc / koの値が大きく異なることがわかった（下表）。この実験結果をどのように解釈したらいいだろうか?

O

OEt

O

Et X+

O

OEt

O

O

OEt

OEt

Et

Na+ kC

kO

kC / kO

X

> 100

I

60

Br

6.6

TsO

3.7

TfO

45

Chapter 5

Diels−Alder Reaction

diene

dienophile

46

Konovalov

HOMO

HOMO

LUMO

LUMO

LUMO

HOMO

47

normal electron-demand

reverse electron-demand

Fields, D. L.; Regan, T. H.; Dignan, J. C. J. Org. Chem. 1968, 33, 390.

48

Stereospecificity

+

CO2Me

CO2Me

+

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

MeO2C

OMe

CO2Me

OMe

CO2Me

OMe

CO2Me

OMe

CO2Me

OMe

CO2Me

OMe

CO2Me

EtO

O OH

HEtO

OH

HEtO

regio

endo/exo

stereo (facial)

49

Regioselectivity

Danishefsky’s diene

Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807.

50

Rawal’s diene

Kozmin, S. A.; Rawal, V. H. J. Org. Chem. 1997, 62, 5252.Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1997, 119, 7165.

Regioselectivity

51

LUMO

HOMO

Z

Z

Coefficients of Frontier Orbitals

large-largesmall-small

large-smallsmall-large


52

Z X C

Z X C

Z X C

53

endo/exo-selectivity

secondary orbital overlap

OHC

H HO

H

H

OHC H

O

H

HO

H

54

endo/exo-selectivity

electrostatic repulsion


H

O

H

(+)

(+)

HH

H

O

H

H

H (+)

(+)

Ohfune, Y.; Tomita, M. J. Am. Chem. Soc. 1982, 104, 3511.

N

O

Boc

TBSO

+

OTMStoluene135 ºC

N

O

Boc

TBSO H

H

OTMS

HN

HO2C H

H

CO2H

HO2C

(–)-domoic acid

regio-, endo/exo-, and facial selectivities

55

Lewis (Brønsted) acid-accelerated Diels–Alder reaction

Yates, P.; Eaton, P. J. Am. Chem. Soc. 1960, 82, 4436.

Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem. Soc. 2005, 127, 5334.

MeO

+

Cl CNCu(BF4)2

(cat.)

0 ºC>90%

MeO

CN

Cl

KOH

H2O/DMSO80%

MeO

O

O

AcO

O

OMe

Corey lactone

CO2H

OHHO

HO

H

H

(±)-PGF2

Corey, E. J. et al. J. Am. Chem. Soc. 1969, 91, 5675.

56

O

H

O

H

H

X

X

Hashimoto, S.-I.; Komeshima, N.; Koga, K. J. Chem. Soc. Chem. Commun. 1979, 437.

Catalytic Asymmetric Diels–Alder Reaction

57

練習問題6下に示した反応の主生成物として化合物１が得られる理由を考察せよ（立体化学についても考察せよ）。

Myers, A. G. et al. J. Am. Chem. Soc. 2005, 127, 8292.

練習問題7下に示した(−)-fusarisetin A全合成中の分子内Diels−Alder反応の直前に、I2・sunlampで処理している理由は何か、考察せよ。

Theodorakis, E. A. et al. J. Am. Chem. Soc. 2012, 134, 5072.

OO

Ph3P

61% (E:Z = 3:2)

OI2 (cat.), sunlamp

then Et2AlCl, –78 ºC

82% (d.r. > 10:1)

CHO

H

H

H

H

H

H

O

NO O

H

OH

Me

OH

(–)-fusarisetin A

58

Chapter 6

Sigmatropic Rearrangement

[3,3]-Sigmatropic Rearrangement

Cope rearrangement

Claisen rearrangement

59

Claisen Rearrangement

O

OO

OMeO

HO

63%

Nicolaou, K. C.; Li, J. Angew. Chem. Int. Ed. 2001, 40, 4264.

Stereochemistry

H

O

H

H

HH

H

HO

H

H

HH

H

H

H

RR

O O

Me Me

H

O

H

H

HH

Me

HO

H

H

HH

Me

H

H

MeMe

O O

R R

Me Me

O O

Me Me

H

O

H

H

MeH

Me

HO

H

H

MeH

Me

H

H

MeMeMe Me

Me Me

60

Ziegler, F. E.; Piwinski, J. J. J. Am. Chem. Soc. 1982, 104, 7181.

(Anionic) Oxy-Cope Rearrangement

Schreiber, S. L.; Santini, C. Tetrahedron Lett. 1981, 22, 4651.

O

O

O

OO

O

18-crown-6

61

Aza-Cope Rearrangement

Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc. 1995, 117, 5776.

aza-Cope–Mannich

Johnson–Claisen Rearrangement

OH

OEt

OEt

OEt

H+

OEt

OEt

OHO

OEtEtO

O

OEt

O

OEt

O

OEt

H

62

Johnson–Claisen Rearrangement

Takahashi, T. et al. J. Org. Chem. 1986, 51, 3393.

Ireland–Claisen Rearrangement

O

O

LDATHF

–78 ºC

LDATHF/HMPA

–78 ºC

O

LiO

O

LiO

Me3SiCl

Me3SiCl

O

TMSO

O

TMSO

O

TMSO

O

TMSO

HMPA: hexamethylphosphoramide

HMPT: hexamethylphosphorous triamide

Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868.

63

Stork, G. et al. J. Am. Chem. Soc. 1998, 120, 1337.

Carroll–Claisen Rearrangement

Eschenmoser–Claisen Rearrangement

OH

NMe2

OMe

OMe

NMe2

OMe

OHO

NMe2MeO

O

NMe2

O

NMe2

O

NMe2

H

64


Mislow rearrangement

S O S O

[2,3]-Wittig rearrangement


Cope rearrangement

65

total number of electrons = (4n + 2) ....... allowed

suprafacial-suprafacial

1

m

n

1'

[m,n]

[1,n]-Shift (Suprafacial Shift)....(4n + 2) electrons


66

cf. BeckmannCurtiusBaeyer–Villiger

2 electrons

Wagner–Meerwein rearrangement

[1,n]-Shift

Suprafacial Shift....(4n + 2) electrons

Antarafacial Shift....(4n) electrons

1

n

H

[1,n]

1

n

H

67

Hoeger, C. A.; Okamura, W. H. J. Am. Chem. Soc. 1985, 107, 268.Fleming, I. Molecular Orbitals and Organic Chemical Reactions, John Wiley & Sons: West Sussex, 2009.

[1,7]-Shift

4 electrons

68

Woodward–Hoffmann rule

A ground-state pericyclic change is

symmetry-allowed when the total number of

(4q+2)s and (4r)a components is odd.

Woodward, R. B.; Hoffmann, R. Angew. Chem. Int. Ed. 1969, 8, 781.

練習問題8Johnson-Claisen転位およびEschenmoser-Claisen転位を利用した以下の２つの合成スキームに関して、A～Fの化合物として妥当なものは何か? 構造式で記せ。

薬化学特論w3pharm.u-shizuoka-ken.ac.jp/yakka/japanese/manabeclass/...noyori, r. asymmetric...

Documents