right : left ratio
20.000 : 1
Chirality in Tools
Helix CChhiirralaityliintayrt in Art
The Molecular Base of Chirality
left-alanine
right-alanine
The Letters of Life: 20 Amino Acids
PCy2 Me Fe PPh2
JosiPHOS (Togni, 1994)
PPh2
PPh2
PhanePHOS (Pye, 1997)
Diphosphine Ligands with Smaller Dihedral Angle
PPh2 PPh2
H3C H3C
PPh2 H3CO PPh2 H3CO
PPh2 PPh2
L -Dopa
CO2H
NHAc 95% ee
H3C O
P
P
O CH3
(R,R)-DIPAMP
Knowles (JACS 1975, 97, 2567)
Excellent Example of Diphosphine Ligands
Diphosphine Ligands with Central Chirality
OH
+
OH
Birman (TA 1999, 10, 125)
N+ Cl HO
H
N
Toluene
Inclusion Solid
+
Mother Liquid
OH HO
HO OH
(S)-
>99.5% ee (85% Y)
(R)-
>99.5% ee (80% Y)
J.-G. Deng, Q.-L. Zhou, T. Ye et al., TA 2002, 13, 1363
H8-BINAP (Takaya, 1991)
θ
R2P
PR2
Diphosphine Ligands with A Wider Dihedral Angle ?
(S)-1,1'-Spirobiindane
(S)-9,9′-spirobifluorene
New Chiral Framework: Spirobiindane
不对称合成的工业应用
Chiral Drug Sales (Millions)
1998 1999 2000 2001 Total 99,389 115,001 133,000 147,200
C&EN 2002, Jun. 10, 43
目前国际上正在开发的新 药80％为手性药物。
HO
CO2H
HO
NH2
L-Dopa (Monsanto, 1975) 不对称合成第一个工业化例子
P
Ph
Pr
CH3
Knowles (JCSCC 1968, 1445) Horner (Angew Chem. Int. Ed. 1968, 7, 942)
The First Breakthrough in Phosphine Ligand: DIOP
HO2C NHAc + H2
Rh / L*
Rh / L* Ph NHAc + H2
Dihedral angle θ (CAChe MM2)
BINAP 73o
89% ee
BIPHEMP 72o
93% ee
MeO-BIPHEMP 68o
96% ee
O
O
PPh2
O
PPh2
O SEGPHOS
65o
99% ee
θ
Ph2P
PPh2
Ru
O
H2, Ru-Diphosphine
OH 35 atm, MeOH, 65 oC
Synthesis of Spirobiindane Diphosphines
OH Tf2O OH 100%
OTf Ar2POH, "Pd" OTf
80-90%
P(O)Ar2 OTf
Cl3SiH 75-90%
PAr2 OTf
Ar2POH, "Pd" 88-92%
PAr2 P(O)Ar2
Cl3SiH 80-85%
Br +
Br
MgBr
OMe
Pd(PPh3)4 THF, 40oC, 48h
60%
Br OMe
a) n-BuLi
b) Me2CO3 75%
NaBr/H2O2
MsOH
O
100%
Br
O
Br 40oC, 5h
73%
MeO
OMe
OMe OMe
Br
OMe H2/Pd
OMe BBr3
OH
MeO
100% MeO
81% HO
不对称催化合成
Asymmetric Catalysis
1. Heterogeneous Asymmetric Catalysis 2. Homogeneous Asymmetric Catalysis
------Asymmetric Catalysis with Organic Molecules ------Asymmetric Catalysis with Metal Complexes
手性化合物对映异构体常常具有不同的性质
香芹酮
H O
(R)- 薄荷味
H O
(S)- 臭蒿味
健康糖 HO2C
NH2 H N
CO2CH3
O CH2Ph
(S,S)- 甜味
HO2C
NH2 H N
CO2CH3
O CH2Ph
(S,R)- 苦味
沙利度胺（反应停）——人间悲剧
O
O HN
N OO
(S)-thalidomide
C2
C2
Spiro[4,4]-nonane
R *
* * R
(S)-1,1'-Spirobiindane
PAr2 PAr2
(S)-SDP 1) Stable? Yes 2) Rigid? Yes 3) Selective? ???
Resolution of 1,1’-Spirobiindane-7,7-diol by Inclusion Crystallization with N-Benzylcinchonidium Chloride
OMe
PPh2 Me PPh2 Me
N
PPh2 MeO PPh2 MeO
N
PPh2 PPh2
BINAP (Noyori, 1980)
BIPHEMP (Schmid, 1988)
OMe
P-PHOS (Chan, 2000)
O
O
PPh2
O
PPh2
O
SEGPHOS (Takasago, 2001)
Diphosphine Ligands with Planar Chirality
OH HO
(S)-1,1'-Spirobiindane-7,7-diol
PAr2 PAr2
(S)-SDP
OH
HO
???
PAr2 PAr2
(S)-9,9′-spirobifluorene-1,1′-diol
(S)-SFDP
SFDP is extremely rigid and has largest dihedral angle !
H3CO
O N CH2Cl
(S)-Metolachlor (Novatis, 1996) 不对称合成最大的工业化例子 （20,000 吨/年）
¾ 手性螺环磷配体的设计合成 螺环磷配体在不对称氢化反应中的应用 螺环磷配体在不对称C-C键形成反应中的应用
Pioneering Chiral Phodphine Ligand for Asymmetric Catalysis
Br
Chiral Resolution of 9,9’-Spirobifluorene-1,1-diol
OMe O
HO
OH +
N
N
O OMe
SBIFOL
(2R,3R)-Tetracyclohexylsuccinamide
EtOH
Inclusion Complex
Synthesis of Racemic 9,9’-Spirobifluorene-1,1-diol
Br +
Br
MgBr
Pd(PPh3)4
OMe
Br a) n-BuLi b) ClCO2Et
OMe 1
Br2 Br
COOH PPA
OMe 4
Li Br
OMe O 5
Br
Br
Br
COOMe NaOH
COOH
北京大学，2005-5-20
手性与手性合成
周其林
南开大学 元素有机化学国家重点实验室
Handedness - Chirality
Right hand and left hand
• image and mirror image • non-superposable
The Vineyard Snail
手性化合物种类
Ph
H
OH
H3C
Ph
HO
H
CH3
Central chirality
CO2H H3C
O2N Cl
Axial chirality
HO2C CH3
NO2 Cl
SiMe3
CHO Fe