Chapter 1 Principles of Asymmetric Synthesisw3pharm.u-shizuoka-ken.ac.jp/yakka/Japanese/manabeCLASS/...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

Chapter 1

Principles of

Asymmetric Synthesis

chiral

achiral

12

31

2

3

NMe334 kJ/mol

PMe3133 kJ/mol

atropisomer

inversion barrier

P

P

Ph

Ph

MeO

OMe

DIPAMP

ZrCl

ClFe

PPh2

PCy2

JOSIPHOS

C2

C2

C2 symmetry C1 symmetryCn : 360 / n

180O rotation

C3 symmetry

2

2

2

1

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

...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

“classical” resolution

R CO2

NH3

R CO2

NH3

R CO2H

NH

R CO2H

NH

H

O

H

O

MeO

MeO N

N

OOH

H

H

H

R CO2

NH

H

O

MeO

MeO N

N

OOH

H

H

H

R CO2

NH

H

O

NaOHH2O

R CO2

NH

H

ONaOHH2O

R CO2

NH3pure salt

pH ~6

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.

O LDA;EtI H3O+

O

Et

82% from imine94% ee

H2N

Ph

OMeN

Ph

OMeN

Ph

OMeEt

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

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

OLi

LiBr, PhCH2Br

O

CH2Ph

92% ee

N NH

O OMe

Ph

(1 equiv)

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

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.

∆∆G‡ (kJ/mol)

% ee

23 oC

% op

% ee

Optical Purity vs. Enantiomeric Excess

CO2H

HO2C

in CHCl3

Horeau, A. Tetrahedron Lett. 1969, 3121.

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

35

10

20

100

1000

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

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。

宿題１

●教科書p 208、問題1.b.

●教科書p 354、問題3.e.

Chapter 2

Asymmetric Hydrogenation

(catalytic)hydrogenation

Hydrogenation

homogeneous

heterogeneous

Wilkinson’s catalyst

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

catalyst for hydrogenation (1966)

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 CO2Me96%

>49%

4%

26%

PtO2 or Pd/BaSO4(cat.)

H2

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.

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

NHAc88% ee

(R)-CAMP

P

Cy

Me

OMe

PhCO2H

NHAc

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

PhCO2H

NHAc85% ee

(R,R)-DIOP

O

O PPh2

PPh2

PhCO2H

NHBz

H2[Rh((R)-binap)(MeOH)2]+ClO4

– (cat.)Ph

CO2H

NHBz100% ee

(R)-BINAP

PPh2

PPh2

「演習で学ぶ有機反応機構」化学同人 A019

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

O PPh2

PPh2

DIOPKagan, et al. (1971)

FePPh2

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

PS

S

PhCO2R

NHAc PRh

P ON

Ph

CO2R

H

H2

PRh

PO N

Ph

CO2R

H

H

HP

RhP O N

Ph

CO2RH

H

S

PhCO2R

NHAc

AB

CD

PRh

PON

Ph

RO2C

H

B'

turnover-limiting step

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

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

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

OTBSOAc

Route to a Key Intermediate of Carbapenem

DKR

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

BINAP/1,2-Diamine–Ru(II) Complex

OH2 (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


N

NH2

Ph

Ph

Ts

Ru

Cl

(0.5 mol %)KOH (0.6 mol%)

O OH

>99% yield97% ee

2-propanol28 °C

N

NH2

Ph

Ph

Ts

Ru

Cl

(0.1 mol %)HCO2H / Et3N

100% yielddl : meso = 98.6 : 1.4>99% ee

DMF40 °C

O

O

OH

OH

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

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. ）

宿題2

●教科書p 208、問題1.c.

●教科書p 210、問題3.a.

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

OH

OCO

R

O

‡

RCO3H

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-BuOOHTriton® 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.

Lisｔ, F.; Kuhnen, L. Erdol. Kohle 1967, 20, 192. Sheng, M. N.; Zajacek, J. G. J. Org. Chem. 1970, 35, 1839.

O

O

OH OH

relative rateVO(acac)2t-BuOOH

1.00

>200

Henbest epoxidation

V

O

O

OO

RO

t-Bu

Epoxidation of Allyl Alcohols

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.

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

R3 OHO

R2 R1

R3 OHO

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.

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)

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

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

E OR

OR

HO

t-BuOOH

Catalyst Structure and Proposed “Loaded” Catalyst

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

Ph Ph

O

O

OO

OO

O

(30 mol %)

OXONE®, K2CO3

CH3CN/dimethoxymethane0.05 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

O

OO

OO

OHSO5

O

OO

OO

OO

OSO3

O

OO

OO

OO

O

OO

O O

OO

Ph

Ph

‡

PhO

dioxirane

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.

Ph Ph

O

N N

O O

t-Bu t-Bu

t-But-BuMn

Cl

H H

(5 mol %)NaOCl (aq.)

CH2Cl2

81% yield92% ee

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.

PhPh

PhPh

OH

OH

N

OAcN

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 HO2 Fe(CN)6

3–2 H2O2 Fe(CN)6

4–

organic

aqueous

Catalytic Cycle

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.）

宿題3

●教科書p 212、問題6.a.b.

Chapter 4

Frontier Orbitals

Atomic Orbital (AO)

E

1s

2s

3s

2p

3p

antibonding MO

bonding MO

Molecular Orbital (MO)

E

*

H H

H2


E

*

*


E

*

C

Cl

C Cl

C Cl

Hybridization

sp3

HC

H

HH

HC

H

HH

HC

H

HH

HC

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.

E

Butadiene

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

LUMOLUMO

HOMO

HOMO

LUMOLUMO

HOMO

LUMO

HOMO

Diels–Alder Reaction

LUMO

HOMO LUMO

HOMO

LUMO

HOMO

[4 + 2]

[2 + 2]

Salem–Klopman Equation

∆E = –∑(qa+qb)abSab + ∑ ab k<l

QkQlRkl

+ ∑ ∑ – ∑ ∑occ unocc occ unocc

r rs s

2(∑cracsbab)2ab

Er–Es

occ-occ Coulomb

occ-unocc

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

–2

–

– +2

2–

2

2

2

2

+2

2

2

3

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

-Effect

HOMO

kHOO kHO

5

2

3

KHOO KHO

–4

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

Ambident Nucleophile

charge controlfrontier orbital control

“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?

+ kC

kO

kC kO

宿題4

●教科書p 442、問題1.i.

●教科書p 443、問題2.a.

Chapter 5

Diels−Alder Reaction

s-trans s-cis

diene

dienophile

Konovalov

LUMO

HOMO

normal electron-demand

reverse electron-demand

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

Stereospecificity

CO2Me

CO2Me

+

CO2Me

CO2Me

CO2Me

CO2Me

+

CO2Me

CO2Me

+

CO2Me

CO2Me

+

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

MeO2C

OMeCO2Me

OMe

CO2Me

OMe

CO2Me

OMeCO2Me

OMe

CO2Me

OMe

CO2Me

EtO

O OH

HEtO

OH

HEtO

regio

endo/exo

stereo (facial)

Regioselectivity

OMe

Me3SiO

+CHO

benzenereflux

OMe

Me3SiO

CHO H+

O

CHO

Danishefsky’s diene

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

NMe2

t-BuMe2SiO

+toluene20 ºC

t-BuMe2SiO

NMe2

87%(>25 : 1 endo : exo)

CHOCHO

N

t-BuMe2SiO

+toluene

0 ºC to rt(94%) 85% ee

CHO

Ph Ph

1) LiAlH4

2) HFCH3CN(83%)

O

OH

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

LUMO

HOMO

Coefficients of Frontier Orbitals

large-largesmall-small

large-smallsmall-large


Z X C

Z X C

Z X C

endo/exo-selectivity

secondary orbital overlap

OHC

H HO

H

H

OHC HO

H

endo/exo-selectivityelectrostatic repulsion


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

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 CN

Cu(BF4)2(cat.)

0 ºC>90%

MeO

CN

ClKOH

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.

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

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

MeOH

(–)-fusarisetin A

宿題5

●教科書p 443、問題3.a.b.

Chapter 6

Sigmatropic Rearrangement

[3,3]-Sigmatropic Rearrangement

Cope rearrangement

Claisen rearrangement

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

H H

H

H

H

RR

O O

Me Me

H

O

H

H

HH

Me

HO

H

H

H H

Me

H

H

MeMe

O O

R R

Me Me

O O

Me Me

H

O

H

H

MeH

Me

HO

H

H

Me H

Me

H

H

MeMeMe Me

Me Me

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

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

OEtOEt

H+

OEt

OEt

OHO

OEtEtO

O

OEt

O

OEt

O

OEt

H

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.

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

Carroll–Claisen Rearrangement

Eschenmoser–Claisen Rearrangement

OH

NMe2

OMeOMe

NMe2

OMe

OHO

NMe2MeO

O

NMe2

O

NMe2

O

NMe2

H


Mislow rearrangement

S O S O

[2,3]-Wittig rearrangement


Cope rearrangement

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

suprafacial-suprafacial

1

m

n

1'

[m,n]

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


cf. BeckmannCurtiusBaeyer–Villiger

2 electrons

Wagner–Meerwein rearrangement

[1,n]-Shift

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

Antarafacial Shift....(4n) electrons

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.

R

OH

100 ºC

R

OHHD +

R

OHD H

[1,7]-Shift

4 electrons

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。

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