高等有机合成：高等有机合成

分类：化学格式：ppt 日期：2006年09月14日

高等有机合成
Advanced Organic Synthesis
绪论
一、有机合成的历史回顾
二、有机合成化学的发展趋势
三、学习内容和方法
四、重要参考书及期刊
五、课程安排
一、有机合成的历史回顾
1,尿素的合成（ 1828年，德国化学家 Wohler）
N H 4 O C N
H 2 N N H 2
O
有机化学的开始
2,颠茄酮的合成
1) 1902年，德国化学家 Willstatter (1915年获 Noble 化学奖）
21 steps,overall yield 0.7%
2） 1917年，英国化学家 Robinson (1947年获 Noble 化学奖）
3 steps,overall yield 90%
Robinson为什么能是发现这条合成路线？
R 1
N H
R 2
+ H C H O +
R 3
R 4
O
R 3
R 4
OR 1
N
R 2
Mannich Reaction (1912)
3,维生素 B12 的合成（ Woodward,1977年）
在 Woodward及 Eschenmoser 领导下,经过两个
实验室,100多位科学家的共同努力，于 1977年完成
了维生素 B12的全合成工作。
将有机合成作为一种艺术展现在世人面前。
因在 1945-1954年人工合成了奎宁、类固醇、
马钱子碱、羊毛甾醇、麦角碱等近 20种复杂天然
产物而 1965 年获 Noble 化学奖
4,E,J,Corey,(1990年获 Noble 化学奖 )
如果说 Woodward 一生奋斗的成就是将有机合成
作为一种艺术展现在世人面前, 那么 Corey 则是将
有机合成从艺术转变成为科学的一个关键人物。他
的逆合成分析是现代有机合成化学的重要基石, 推
动了 20世纪 70年代以来整个有机合成领域的蓬勃发
展。
逆合成分析 (Retrosynthetic analysis)
? Woodward (1981) 红霉素的全合成
? Y,Kishi (1987) 海葵毒素的全合成
? S,L,Schreiber et al (1993) FK-1012 的全合成
? K,C,Nicolaou & S,L,Schreiber（ 1994）
紫杉醇（ Taxol)的全合成
5,K,C,Nicolaou & S,L,Schreiber
? K,C,Nicolaou,et al,The art and science of total synthesis
at the dawn of twenty-first century,Angew,Chem,Int,Ed,
Engl.,2002,39,44
? S,L,Schreiber,et al,Target-oriented and diversity-
oriented organic synthesis in drug discovery,Science,2000,
287,1 964
高立体选择性（ High Stereoselectivity)
原子经济性反应（ Atom Economical Reaction)
绿色化学（ Green Chemistry)
二、有机合成化学的发展趋势
1,新试剂、新反应、新方法的发现永无止境
H
N
N C l
E p i b a t i d i n e
i s o l a t e d f r o m s k i n s o f t h e
E c u a d o r a n p o i s o n f r o g
E p i p e d o b a t e s t r i c o l o r
D a l y,J o h n W, e t a l,
J, A m, C h e m, S o c,
( 1 9 9 2 ),1 1 4 ( 9 ),3 4 7 5 - 8
E D 5 0, 0, 0 0 5 m g / k g s, c,
1, 5 m g / k g i, p,
D a l y,J o h n W, e t a l,
K i, ( + ) 0, 0 4 5 n M ;
( - ) 0, 0 5 8 n M,
i n m i c e,h o t p l a t e t e s t
n A C h R
C o r e y,E, J, e t a l, U S A,
J, O r g, C h e m, ( 1 9 9 3 ),
5 8 ( 2 1 ),5 6 0 0 - 2,
F i r s t p a t e n t,
U S 8 4 5 0 4 2 ( 1 9 9 3 )
F i r s t t o t a l s y n t h e s i s o f ( + ) a n d ( - ) - E P
G e n e r a l I n t r o d u c t i o n o f E p i b a t i d i n e
? Epibatidine 的研究
N
R "
R '
+
N R
R "
R "
R
N B o c
S O 2 T o l
H
N B o c
S O
2
T o l
+
N
R "
R '
+
N R
R "
R "
R
N
R "
R '
+ N
R "
R "Y ( O T f ) 3
? Y(OTf)3-catalyzed novel Mannich reaction of N-alkoxy-
carbonylpyrroles,formaldehyde and primary amine
hydrochlorides
C,X,Zhuan,J,C,Dong,T,M,Cheng,R,T,Li*,Tetrahedron
Letters,2001,43(3),461-463
N
R
+ R ' C H O + R " N H 2 H C l
.
Y ( O T f ) 3 ( 1 0 % m m o l e )
N
N
R '
R "
N
R
C H N H R "
R '
A
B
? Aldol 缩合反应的研究 R C H O + R ' C H 2 C H O
O H
-
经典的方法
T i C L
4
定向 A l d o l 缩合
L - P r o l i n e
有机小分子催化
R C H C H C H O
O H
R '
2,与生命科学和材料科学的联系越来越紧密
C o m b i n a t o r i a l C h e m i s t r y
组合化学
药物化学
M e d i c i n a l C h e m i s t r y
材料科学
M a t e r i a l S c i e n c e s
三、学习内容和方法
? 内容
有机合成
反应的学习
反应的应用（有机化合物合成路线设计）
分子骨架的形成
官能团之间的转换
C - C 单键的形成
C - C 双键的形成
氧化反应
还原反应
取代反应
1,对重要的基础有机反应要能够熟练运用
新化合物的合成
比葫芦画瓢
逆合成分析
2,跟踪文献，尽可能将最新的试剂、反应和方法应用于
自己的研究工作中。
3,学习别人的思路，创造性地借鉴和运用
? 方法
四、重要参考书及期刊
? 参考书
1,F,A,Carey 著，王积涛译，高等有机化学,B,反应与合成，高
等教育出版社,1986。
2,岳保珍，李润涛，有机合成基础，北京医科大学出版社,2000。
3,吴毓林，姚祝军，现代有机合成化学，科学出版社,2001。
4,W,Carruthers 著，李润涛等译，有机合成的一些新方法，河南大
学出版社,1991。
5,黄宪，王彦广，陈振初，新编有机合成化学，化学工业出版社，
2003。
6,王咏梅等，高等有机化学习题解答，南开大学出版社,2002。
7,Dale L,Boger,Modern Organic Synthesis,The Scripps Research
Institute,Tsri Press,1999,
8,Comprehensive Organic Synthesis,Vol,1-9
? 期刊
1,Angew,Chem,Int,Ed,
2,J,Am,Chem,Soc,
3,J,Org,Chem,
4,Org,Letters
5,Chem,Commun,
6,Tetrahedron
7,Tetrahedron Letters,
8,Tetrahedron Asymm,
9,Synthesis
10,Synlett
11,Synth,Commun,
12,Eur,J,Chem,
13,Eur,J,Org,Chem,
14,Heterocyclics
15,J,Heterocyclic Chem,
16,J,Med,Chem,
17,Bioorg,Med,Chem,
18,Bioorg,Med,Chem,Lett,
19,Eur,J,Med,Chem,
20,J,Comb,Chem,
五、课程安排
1,进度安排
2,讲授原则
复习老反应，补充新反应,
重点讲进展，强调学思路。
3,考试
1）写综述一篇（近 5年的进展）（ 40%）
2）笔试（ 60%）
Chapter 2
Formation of Carbon-Carbon
Single Bonds
一,General Principles
烷化反应,E = 烷化剂
缩合反应,E = 醛、酮、酯等
Michael 加成,E =
Mannich 反应
E W G~
C H
A
B
H
B a s e
C H
A
B
-
E +
C H
A
B
E
二,影响反应的主要因素
a,反应底物（ Substrate)
-NO2 > -COR > SO2R > -CN > -CO2R > -Ph,SOR
A和 B至少要有一个是 EWG
CH2
A
B
A和 B应该能使其 ?-碳上的 H活化的基团，通常为吸电子
基（ Electron withdraw group EWG）。
b,碱（ Base）
常用的碱,Ph3C- > (Me2CH)2N- > EtO- > OH- > R3N
碱的选择取决于底物的反应活性
理想的碱,碱性强，亲核性弱，并不进攻那些较敏感的基团，另外
能溶于非极性溶剂中。
c,溶剂（ Solvent)
Solvent O- alkylation C-alkylation 反应速度
常用的非质子极性溶剂（ polar aprotic solvent),
DMF DMSO HMPA
P
O
M e 2 N N M e 2
N M e 2
d,亲电试剂（ Electrophilic reagent)
所有能与负碳离子发生反应的碳正离子或分子。
例,RX,R-SO3H,RCO2Et,RCOR’
这四种影响因素之间是相互联系，相互影响的。在分析
一个具体反应时，应该综合分析考虑这四种影响因素。
R O T s
R C l
R B r
R I
反应速度
H a r d a l k y l a t i n g a g e n t
S o l f t a l k y l a t i n g a g e n t
三、烷基化反应 (Alkylation)
O O
1,O-alkylation & C-alkylation
Example 1
Example 2 Degree of substitution of alkylating agent,
Example 3
OA c O
A c O
A c O
O A c
B r
+
M e
C O
2
E t
O
K
2
C O
3
/ T B A B
C H
3
C N
r, t,
OA c O
A c O
A c O
O A c
M e
C O
2
E t
O
K
2
C O
3
/ T B A B
C H
3
C N
r, t,
OA c O
A c O
A c O
O A c
M e
E t O
2
C
O
+
OA c O
A c O
A c O
O A c
O H +
OA c O
A c O
A c O
O A c
6 2 %
R, T, L i e t a l, S y n t h, C o m m u n, 1 9 9 7,2 7 ( 8 ),1 3 5 1 - 1 3 5 7
2,区域选择性（ Regioselectivity)
区域选择性受热力学控制和动力学控制的反应条件影响
很大,
热力学控制条件下主要生成取代基较多的烯醇 ;
动力学控制条件下主要生成取代基较少的烯醇 ;
Example 1
Example 2
3,立体选择性（ Steroselectivity)
烯醇化合物的立体选择性形成,将为不对
称合成提供平台,
Example 1
Example 2
Example 3
Example 4
4,二羰基化合物的 ? -烷基化反应 ( ?-Alkylation of 1,3-
dicarbonyl compounds)
R
R '
O O 2 e q u i v, B a s e
R
R '
O O
1 ) R " X
2 ) H 2 O
R
R '
O O
R "
J,Am,Chem,Soc.,1974,90,1082; 1963,85,3237; 1965,87,82,
M e M e
O O 1 ) 2 K N H
2 / l i q, N H 3
2 ) n - B u B r M e
O O
C 4 H 9 8 2 %
Example 1
M e
O O
M e M e
O
烷基化难易次序,
P h C H 2 - > C H 3 - > - C H 2 -
M e O E t
O O
1 ) 1 e q u i v N a O H / T H F / H M P A
2 ) 1 e q u i v, n - B u L i
O E t
O O
B r
O T H P
O E t
O
O
O T H P
s e v e r i a l s t e o s
O
O
O
1 ) 2 e q u i v, L D A
2 ) C
6
H
5
S e B r
O
O
O
S e C
6
H
5
1 ) H
2
O
2
,C H
2
C l
2
,0
o
C
2 ) - 2 5
o
C
O
O
O
d i p l o d i a l i d e A
Example 2
C
6
H
5
S
M e
O O
C
6
H
5
S
C H
2
O O
2 e q u i v N a H / T H F / H M P A
C
6
H
5
S
O O
C
4
H
9
- n
n - C
4
H
9
B r
H
3
O
+
Z n
/
A c
O
H
C C
l
4
/ R
e f l
u x
O
C
4
H
9
- n
O
C
4
H
9
- n
Example 3
继承与发展
5,芳基卤化物与烯醇盐的反应 (Reactions of aromatic
halide with enolates)
C O 2 E t
C O 2 E t
+ C 6 H 5 B r
过量 N a N H 2
l i q, N H 3
C O 2 E t
C O 2 E t
C 6 H 5
Example
B r
l i q, N H
3
N a N H
2
C O
2
E t
C O 2 E t
C O 2 E t
C O 2 E t
C O 2 E t
C O
2
E t
H
3
O
+
C O
2
E t
C O 2 E t
Mechanism
关键是要有形成苯炔的条件。
N
C O C H 3
B r
K N H 2 / N H 3
N
C O C H 3
M e O 2 C
N
C O C H 3
M e O 2 C
6,酮和酯的烷基化反应 (Alkylations of ketones and esters)
XY C O 2 R 'R
R
O
R '
a b
O
~ ~
O
~ ~
O
~ ~R X
R
A l d o l C o n d e n s a t i o n
OO H
~ ~
~~
避免 Aldol 缩合反应发生的方法,
烷化剂要待酮完全转化为烯醇式后再加入。
常用的碱,NaNH2,KNH2,NaH,Ph3CNa 等；有副产物。
LDA,LTMP,LHMDS 等效果很好。
C 6 H 5
O
1 ) N a N H 2 / C 6 H 6,R e f l u x
2 )
B r
C 6 H 5
O
8 8 %
Example 1
Example 2
C O
2
M e
1 ) L D A / T H F,- 7 8
o
C
2 )
B r
C O
2
M e
1 ) L D A / T H F,- 7 8
o
C
2 ) B r
C O
2
M e
9 0 %
? 不对称酮的选择性烷基化反应 (Selective alkylation
of asymmetric ketones)
R
O
R '
a b
? 在一个 ?? - 位引入一个活化基 (略）
如,Dieckmann Reaction; Claisen condensation
? 制成结构专属性的烯醇负离子
? 在取代基较多的 ? - 位烷基化 (烯醇硅醚法 )
O
M e 1 ) N a H / G D M E
2 ) M e 3 S i C l / E t 3 N
O S i M e 3
M e
O S i M e 3
M e+
7 8 % 2 2 %
O S i M e 3
M e
M e L i / G D M E
2 5
o
C
O L i
M e
+ M e 4 S i
C 6 H 5 C H 2 C l
O L i
M e
O
M e
C
6
H
5
O
M e
C
6
H
5
+
8 4 % 7 %
碱性条件
M e 3 S i O
R 1
R 2
R 3 L e w i s a c i d
R X M e 3 S i O
R 1
R 2
R 3
R
X - O
R 1
R 2
R 3
R
L e w i s a c i d, T i C l 4,S n C l 4,Z n C l 2
酸性条件
O S i M e 3
M e
C H 2 C l 2 / - 2 3 o C
O
M e
M e
4 8 %
1 ) t - B u X / T i C l 4
2 ) N a 2 C O 3
M e
M e
? 在取代基较少的 ? - 位烷基化 (烯胺法,Stork Enamine Synthesis)
? 通常，用活泼的卤代烷，可以高产率生成 C-烷基化产物；
但对于一般的卤代烃,C-烷基化产物收率较底。若用
LDA在低温下反应，则对各种卤代烃均可得到高收率的
C-烷基化产物。
? 对于不对称酮，主要在取代基较少的 ? - 位发生烷基化。
N N
O
N H
E
+ C - a l k y l a t i o n
N - a l k y l a t i o n
N
+ C l
H 3 O +
O
9 6 %
O N
H
N 1 ) L D A
D M E / - 6 0 o C
2 ) M e I
3 ) H 3 O +
O
9 8 %
Example 1
Example 2
7,对映选择性烷基化反应（ Enantioselective alkylations)
? 利用手性胺
H
N
C
6
H
5
O M e
L D A
H
N
C
6
H
5
O M e
L i
C
2
H
5
I
H
N
C
6
H
5
O M e
C
2
H
5
H
O
C
2
H
5
H
H
N
C 6 H 5
O M e
O
C 2 H 5
H
1 ) L D A / T H F,- 2 0 o C
2 ) E t I
3 ) H 3 O + y i e l d 8 2 %
9 4 % e e
? 利用二甲基肼
O N N M e 2
O
o v e r a l l y i e l d 9 5 %
M e 2 N N H 2
N
L D A
T H F,0
o
C
N M e
2
L i
+
M e I
N N M e
2
N a I O 4
E t O H / H 2 O
N N M e 2
M e 1 ) L D A
2 ) M e I
N N M e 2
M e M e N a I O
4
E t O H / H 2 O
O
M e M e
y i e l d 9 5 %
9 7 % t r a n s
扩展,二甲基腙锂化合物的另一应用
二甲基腙锂化合物容易转化成有机铜化合物，而有机铜化
合物在 C-C键的形成中很有用。
L i C H 2 C H = N N M e 2
C u I ( i - P r ) 2 S
T H F,- 2 0
o
C
C H 2 C H = N N M e 2C u L i
2
O
1 )
2 ) H
3
O
+
O
C H O
C H
2
C H = N N M e
2C u L i
2
M i c h a e l a d d i t i o n
7 0 %
? 利用 SAMP 和 RAMP
N
N H 2
O M e
N
N H 2
O M e
( S ) - 1 - a m i n o - 2 - ( m e t h o x y m e t h y l ) p y r r o l i d i n e
S A M P
( R ) - 1 - a m i n o - 2 - ( m e t h o x y m e t h y l ) p y r r o l i d i n e
R A M P
O
+
N
N H
2
O M e
N
N
O M e
1 ) L D A
2 ) C
3
H
7
I
1 ) M e I
y i e l d 6 0 %
9 9, 5 % e e
N
N
O M e
M e
C
3
H
7
H
2 ) H
3
O
+
O
M e
C
3
H
7
H
若用 RAMP,
则得到另一
种对映异构
体。
? 羧酸的 ?-不对称烷基化
H N O
O
H N O
O
C 6 H 5
N O
O
C
6
H
5
M e
O
L D A / T H F
- 7 8
o
C
N O
O
C
6
H
5
M e
O
L i
P h C H
2
B r
N O
O
C
6
H
5
M e
O
P h C H
2
P h C H
2
O L i
P h C H
2
O H
M e
O
P h C H
2
O C H
2
P h
7 5 %,> 9 9, 1
H
2
/ P d
M e
O
P h C H
2
O H
Example
8,极性翻转（ Umpolung)
? 俞凌翀，刘志昌，极性转换及其在有机合成中的应用，科学出
版社,1991
Example 1 安息香缩合
C 6 H 5 C H O
C N
-
C 6 H 5 C H
O
C N
C
6
H
5
C
O H
C N
C
6
H
5
C H O
C 6 H 5 C
O H
C N
C
H
O
C 6 H 5 C
6 H 5 C
O
C
H
O H
C 6 H 5
- C N
-
Example 2 醛氰醇法
C H 3 C H O
C N
-
C H 3 C
O H
C N
C 6 H 5 C H
O S i M e
3
C N
C H 3 C
O H
C N
H 3 O
M e 3 S i C l 1 ) L D A
2 ) B r
C H
3
C
O S i M e
3
C N
O H
C H
3
C
O
8 5 %
Example 3 1,3 –二噻烷法
S H
S H
+ R C H O
H C l / C H 3 C l
S
S
R
H
B u L i
S
S
R
L i
R ' X
S
S
R
R ' H
3 O
+
/ H g
2 +
O
R
R '
不易发生 Michael 加成反应。
Example 4 乙基乙硫甲基亚砜法
S
SC
2
H
5
O
C
2
H
5
1 ) L D A
2 ) R X
S
SC 2 H 5
O
C
2
H
5
R
1 ) R ' X
2 ) H
3
O
+
R '
R
O
1 )
O
2 ) H
3
O +
R
O
O
M i c h e a l a d i t i o n
1,4 – 二酮
四、缩合反应 (Condensation)
1,Aldol Reaction
2,Michael Addition
3,Mannich Reaction
4,Claisen Condensation
5,Dieckmann Condrnsation
6,Darzen’s Reaction
7,Reformatsly reaction
1,Aldol Reaction (condensation)
1) 经典 Aldol 反应的两大缺点
? 不同醛、酮之间的反应常得到混合产物；
? 立体选择性差
2) 定向醇醛缩合反应（ Directed Aldol condensation)
Metood 1 Preformed Lithium Enolates
? Z-enolates give predominantly syn (or threo) aldol products
(thermodynamic enolates),
? E-enolates give predominantly anti (or erythro) aldol products
(kinetic enolates),
Example 1
- Steric size of R1 affects diastereoselectivity
? Origin of Diastereoselectivity
a,Z-enolates
? Diastereoselectivity for Z-enolate (giving syn aldol product) is maximized when
R1 and R3 are sterically demanding (R1/R3 interaction is maximized),
? Diastereoselectivity also increases as metal is changed to boron,This is attritubted
to a tighter T.S,(B–O bond shorter,so R1/R3 steric interactions are magnified in T.S,
for anti product),
? When R2 is very large the R3/R2 gauche interaction > R1/R3 1,3-diaxial interaction
(Why?),
b,E-enolates
? Diastereoselectivity increases as R1 and R3 become sterically large,and a
switch to the boron enolate will increase selectivity,
? Diastereoselectivity may switch when R2 is very large (Why?),
? Effect of R1
? Effect of R3
? Effect of R2
Metood 2 Preformed Boron Enolates
a,Z-enolate Preparation and Reactions
b,E-enolate Preparation and Reactions
- Originally difficult to control but,
c,Examples of more recent methods to control boron enolate geometry
Aldol Condensation with Chiral Enolates
? Ti enolate promoted Evans aldol (non-Evans syn aldol)
? Chelated and non-chelated Ti enolates
Metood 3 Acid-Catalysed Directed Aldol Reactions
R
1
R
2
O S i M e
3
R
3
T i C l
4
C H
2
C l
2
R
1
R
2
R
3
O
S i M e
3
O
R
4
R
5
T i C l
3
C l
C l
-
- M e
3
S i C l
R
1
R
2
R
3
O
T i C l
3
O
R
4
R
5
H
2
O
R
1
R
2
R
3
O H
O
R
4
R
5
该方法是
在酸性条件
下反应；但
立体选择性
较差。
3) 有机小分子催化醇醛缩合反应
（ Small Organic Molecules Catalysted Aldol Reactions)
O
O
O
O
O
O
A l d o l a s e A n t i b o d y 3 8 C 2
B a r b a s,C, F,,I I I e t a l, J, A m, C h e m,
S o c, 1 9 9 7,1 1 9,8 1 3 1
L - P r o l i n e
H a j o s - E d e r - S a u e r - W i e c h e r t r e a c t i o n
H a j o s,Z, G, e t a l, J, O r g, C h e m, 1 9 7 4,3 9,1 6 1 5
E d e r,U, ; S a u e r ; G,,W i e c h e r t,R, A n g e w, C h e m,
I n t, E d, E n g l, 1 9 7 1,1 0,4 9 6
H o w e v e r,t h e p r o l i n e - c a t a l y z e d d i r e c t i n t e r m o l e c u l a r a s y m m e t r i c a l d o l r e a c t i o n
h a s n o t b e e n d e s c r i b e d, F u r t h e r,t h e r e a r e n o a s y m m e t r i c s m a l l - m o l e c u l e a l d o l
c a t a l y s t s t h a t u s e a n e n a m i n e m e c h a n i s m, B a s e d o n o u r o w n r e s u l t s a n d
S h i b a s a k i ' s w o r k o n l a n t h a n u m - b a s e d s m a l l - m o l e c u l e a l d o l c a t a l y s t s,w e r e a l i z e d
t h e g r e a t p o t e n t i a l o f c a t a l y s t s f o r t h e d i r e c t a s y m m e t r i c a l d o l r e a c t i o n,
O
H
N O
2
O
D M S O
N O
2
O O H
O
H
N O
2
O
D M S O
N O
2
O O H
O
H
O
D M S O
O O H
R
R
+
L - p r o l i n e
3 0 m o l %
6 8 % ( 7 6 % e e )
+
d i f f e r e n t
a m i n o a c i d
3 0 m o l %
+
L - p r o l i n e
3 0 m o l %
L - p r o l i n e i s b e s t
y i e l d, 5 4 - 9 7 % ; % e e, 6 0 - 9 6 %
O
H N
H O
O
H
N
H O
O
H
O H
N
O
O
H
N
H O
O
H
N
O
O
H
O
H
R
H
R C H O N
O
O
H
O H
R
H
2
O
N
O
O
H
O H
O H
R
H
O
O H
R
H N
H O
O
H
+
- H
2
O
-
+
a b c
d
+
-
+
-
+
g
e f
P r o p o s e d E n a m i n e M e c h a n i s m o f t h e
P r o l i n e - c a t a l y z e d A s y m m e t r i c A l d o l R e a c t i o n
C a r l o s F, B a r b a s I I I e t, a l, J, A m, C h e m, S o c, 2 0 0 0,1 2 2 ( 1 0 ),2 3 9 5 - 6
C a t a l y t i c A s y m m e t r i c S y n t h e s i s o f a n t i - 1,2 - D i o l s
O H
H R
O
O
D M S O
O O H
O H
+
L - P r o l i n e
2 0 - 3 0 m o l %
r, t,
2 4 - 7 2 h
s y n, a n t i, 1 5, 1 - 2 0, 1 ; y i e l d, 3 8 - 9 5 % ; % e e, 6 7 - 9 9 %
C a r l o s F, B a r b a s I I I e t, a l, J, A m, C h e m, S o c, 2 0 0 0,1 2 2 ( 3 0 ),7 3 8 6 - 7
P r o l i n e - C a t a l y z e d A s y m m e t r i c A l d o l R e a c t i o n s b e t w e e n
H
O
O
O O H
+
L - P r o l i n e
1 0 - 2 0 m o l %
3 - 7 d
y i e l d, A 2 2 - 3 5 %,B 3 5 - 5 0 % ; % e e, 3 6 - 7 3 %
R R
O
R+
2 0 v o l %
A B
O O H
R
O
R
A
B
H
O
R
O
L - P r o l i n e
L - P r o l i n e
N
C O
2
-
H
R
+
O
N
C O
2
H
R
O
- P r o l i n e
C o m p o u n d B w a s f o r m e d v i a M a n n i c h C o n d e n s a t i o n
K e t o n e s a n d a - U n s u b s t i t u t e d A l d e h y d e s
B e n j a m i n l i s t e t a l, O r g, L e t t, 2 0 0 1,3 ( 4 ),5 7 3 - 5 7 5
C H C l
3
R
O
R ' A r C H O
R
O
R '
A r
O H
+
a m i n o a c i d
B a r b a s,C, F, e t a l, J, A m, C h e m, S o c, 2 0 0 1,1 2 3 ( 2 2 ),5 2 6 0 - 5 2 6 7
H
O
X
H
O
X
O H
+
H
O
Y Y
e n a n t i o s e l e c t i v e
c a t a l y s t
H
O
M e
H
O
M e
O H
M e
N
H
C O
2
H
H R
2
O
H
O
R
1
R
2
O H
1 0 m o l %
D M F,4
o
C
a n t i, s y n, 3, 1 - 2 4, 1
% e e, 9 1, 9 9
H
O
R
1
+
L - p r o l i n e
y i e l d, 7 5 - 8 8 %
M a c M i l l a n D, W, C, e t a l, J, A m, C h e m, S o c, 2 0 0 2,1 2 4 ( 2 4 ),6 7 9 8 - 6 7 9 9
1 0 m o l %
D M F,4
o
C
8 0 % y i e l d,4, 1 a n t i, s y n,9 9 % e e
T h e F i r s t D i r e c t a n d E n a n t i o s e l e c t i v e C r o s s - A l d o l R e a c t i o n o f A l d e h y d e s
Novel Small Organic Molecules for a Highly
Enantioselective Direct Aldol Reaction
J,AM,CHEM,SOC,2003,125,5262-5263
Zhuo Tang,?,? Fan Jiang,§ Luo-Ting Yu,? Xin Cui,? Liu-Zhu
Gong,*,? Ai-Qiao Mi,?Yao-Zhong Jiang,? and Yun-Dong Wu*
Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan
Province,Chengdu Institute of Organic Chemistry,Chinese Academy of Sciences,
Chengdu,610041,China,College of Chemical Engineering,
Sichuan UniVersity,Chengdu,610065,China,and State Key Laboratory of
Molecular Dynamics and Stable Structures,College of Chemistry and Molecular
Engineering,Peking UniVersity,Beijing,100871,China
2,Michael Addition Reaction
E W G
C H 2
R R ' "
R '
" R
E W G '
+, B
R ' "
C HC
R '
R "
E W G 'G W E
C H
R
E W G,E W G ' = - C H O,- C O -,- C O R,- C N,- N O 2,- S O 2 R e t a l,
? Applications,Synthesis of 1,5-dicarbonyl compounds
? General Scheme
? Development,Asymmetry Michael Addition Reaction O
+
C O 2 B n
C O 2 B n
1 0 m o l % L i - A l - ( R ) - B i N o l
T H F,r, t,,7 2 h
O
C H ( C O 2 B n ) 2
H
8 8 %,9 9 % e e
A r a i T, e t a l,,A n g e w, C h e m, I n t, E d,,1 9 9 6,3 5,1 0 4
? 手性金属配位化合物催化
N
H
N
O
M e
M e
M e
P h
R
1 O
-
O
N
R
Z
ON
Z
R
ON
Z
R
1
C H O C H O
R R
1
X R O
R
C H O
X
A
N
R
X
Z O
M e N O
2
- H
2
O
T H F - H
2
O
N
R
X
Z
D i e l s - A l d e r R e a c t i o n
1,3 - D i p o l a r C y c l o a d d i t i o n
+
+ +
+
2 0 m o l % A - H C l
2 3
o
C
y i l e d, 7 2 - 9 0 % ;
% e e, 8 3 - 9 6 %
e n d o e x o
e n d o, e x o, 8 0, 2 0 - 9 9, 1
% e e, 9 0 - 9 9 %
y i e l d, 6 6 - 9 8 %
J, A m, C h e m, S o c, 2 0 0 0,1 2 2 ( 1 7 ),4 2 4 3 - 4 2 4 4
J, A m, C h e m, S o c, 2 0 0 0,1 2 2 ( 4 0 ),9 8 7 4 - 9 8 7 5
+
2 0 m o l %
A - H C l O
4
- 2 0
o
C
2 0 m o l % A - T F A
y i l e d, 7 4 - 8 7 % ;
% e e, 8 9 - 9 7 %
J, A m, C h e m, S o c, 2 0 0 1,
1 2 3 ( 1 8 ),4 3 7 0 - 4 3 7 1
O
Macmillan Group’s Work
? Small Organic Molecule catalyzed asymmetric Michael reactions
N
R
X
Z O
+
2 0 m o l % A - T F A
T H F - H
2
O N
R
X
Z7 4 - 8 7 %
9 1 - 9 9 % e e
J, A m, C h e m, S o c, 2 0 0 1,
1 2 3 ( 1 8 ),4 3 7 0 - 4 3 7 1
N
H
N
O M e
M e
M e
P h
A
N
M e O
+
2 0 m o l % A - T F A
8 5 %
5 6 % e e
M e
N
M e
O
M e
C H
2
C l
2
,- 4 0
o
C
N
H
N
O M e
P h
M e
M e
M e
B
O
N
R O
+
2 0 m o l % B - T F A
M e
N
M e
O
R
C H
2
C l
2
- i - P r O H
H X = T F A S o l v e n t, C H 2 C l 2 - i - P r O HO p t i m a l c o n d i t i o n s,
N
M e O
+
2 0 m o l % B - H X
M e
N
M e
O
M e
s o l v e n t
7 4 - 8 9 %
> 9 0 % e e
N
M e O
+
R
N
R
O
M e
2 0 m o l % B - T F A
C H
2
C l
2
- i - P r O H
7 0 - 9 4 %
> 8 9 % e e
Z
Y
Z
Y
J o e l F, A u s t i n a n d D a v i d W, C, M a c M i l l a n *,J, A m, C h e m, S o c, 2 0 0 2,1 2 4 ( 7 ),1 1 7 2 - 1 1 7 3
The First Enantioselective Organocatalytic Mukaiyama-Michael Reaction,
O
R
3
S i O M e O
M e
O
O
O
H
O H
M e
O
O
H
O
R
3
S i O M e O
N
H
N
O
M e
M e
M e
M e
P h
+
L e w i s A c i d
( M u k a l y a m a - A l d o l
)
+
A m i n e
C a t a l y s t
L e w i s a c i d c a t a l y s i s, 1,2 - a d d i t i o n
O r g a n o c a t a l y s i s, 1,4 - a d d i t i o n ( M u k a l y a m a - M i c h a e l ) C a t a l y s t
R
O
O
O
M e
O
T M S O R
O+
A m i n e
C a t a l y s t
M e
R = M e,P r,i - P r,P h,C H2 O B z,C O 2 M e
Y i e l d, 7 7 - 8 7 %,% e e, 8 4 - 9 9
M e
O
O
O
R
O
T M S O M e
O+
A m i n e
C a t a l y s t
R
R = H,M e,E t,C O 2 M e
Y i e l d, 7 3 - 8 7 %,% e e, 9 0 - 9 8
S,P,Brown,N,C,Goodwin,and D,W,C,MacMillan*,J,Am,
Chem,Soc,2003,125(5),1192-1194
3,Mannich Reaction
? General Scheme
R 2 C H
O
+ + R 3 C H 2 C R 4
O
H +N HR
R 1
N C H C H C R 4
R
R 1
O
R 3
R 2
? 胺组份氨、伯胺、仲胺
? 醛组份 HCHO,PhCHO,RCHO
可分别发生三、双、单 Mannich 反应
? 活泼 H 组份
醛,酮,活泼亚甲基化合物、酚类化合物、杂环、炔等。
H
H
N H M e
M e
O
H C H O
N
M e
O
M e
Example 2
Example 1
O
+ H C H O + H N M e 2 H C l
.
O
N M e
2
O
O E t
O O
M i c h a e l a d d i t i o n O
C O
2
E t
H
3
C
O
A l d o l r e a c t i o n
C O
2
E t
O
1 ) O H
2 ) H / - C O
2
-
+ O
? Development,Asymmetry Mannich Reaction
? Lewis acid-catalyzed asymmetric Mannich reactions
(a) Fujii,A.; Hagiwara,E.; Sodeoka,M,J,Am,Chem,Soc,1999,121,
5450;
(b) Ishitani,H.; Ueno,M.; Kobayashi,S,J,Am,Chem,Soc,2000,122,
8180;
(c) Ishihara,K.; Miyata,M.; Hattori,K.; Yamamoto,H,J,Am,Chem,
Soc,1994,116,10520;
(d) Ishitani,H.; Ueno,M.; Kobayashi,S,J,Am,Chem,Soc,1997,119,
2060;
(e) Ferraris,D.; Yong,B.; Dudding,T.; Leckta,T,J,Am,Chem,Soc,
1998,120,4548;
(f) Ferraris,D.; Young,B.; Cox,C.; Dudding,T.; Drury,W,J.,III;
Ryzhkov,L.; Taggi,A,E.; Lectka,T,J,Am,Chem,Soc,2002,124,
67,
(g) Kobayashi,S.; Hamada,T.; Manabe,K,J,Am,Chem,Soc,2002,
124,5640,
(a) Notz,W.; Sakthivel,K.; Bui,T.; Zhong,G.; Barbas,C,F.,III Tetrahedron Lett,
2001,42,199;
(b) Juhl,K.; Gathergood,N.; Jorgensen,K,A,Angew,Chem.,Int,Ed,2001,40,2995;
(c) Yamasaki,S.; Iida,T.; Shibasaki,M,Tetrahedron 1999,55,8857;
(d) List,B,J,Am,Chem,Soc,2000,122,9336;
(e) Co′rdova,A.; Notz,W.; Zhong,G.; Betancort,J,M.; Barbas,C,F.,III J,Am,Chem,
Soc,2002,124,1842;
(f) Co′rdova,A.; Watanabe,S.-i.; Tanaka,F.; Notz,W.; Barbas,C,F.,III J,Am,Chem,
Soc,2002,124,1866,
? Small Organic Molecule catalyzed asymmetric Mannich reactions
T h e D i r e c t C a t a l y t i c A s y m m e t r i cT h r e e - C o m p o n e n t M a n n i c h R e a c t i o n
O
D M S O
O
+
L - P r o l i n e
3 5 m o l %
r, t,
H R
O
O
D M S O
+
L - P r o l i n e
1 2 - 4 8 h
C H O N H
2
O M e
+
1 2 h
5 0 %
N H - P M P
9 4 % e e
3 5 m o l %
p - a n i s i d i n e ( 1, 1 e q, )
O
N H - P M P
R
R =
N O
2
i - P r - i - B u - n - B u -
y i e l d, 3 5 - 9 0 % ;
e e, 7 3 - 9 6 %
O
D M S O
O
+
L - P r o l i n e
3 5 m o l %
r, t,
C H O N H 2
O M e
+
1 2 h
5 0 %
N H - P M P
R
1
R
2
R
2
R
1
a, R
1
= H,R
2
= M e,9 9 % e e ;
b, R
1
= H,R
2
= O M e,9 8 % e e,y i e l d 9 3 %
R
1
= M e,R
2
= H,9 4 % e e ; t o t a l y i e l d 9 6 %
B e n j a m i n L i s t, J, A m, C h e m, S o c, 2 0 0 0,1 2 2 ( 3 8 ),9 3 3 6 - 7
The Direct and Enantioselective,One-Pot,Three-
Component,Cross-Mannich Reaction of Aldehydes
Angew,Chem,Int,Ed,2003,42,3677 –3680
Y,Hayashi,W,Tsuboi,I,Ashimine,T,Urushima,Dr,M,Shoji
Department of Industrial Chemistry,Faculty of Engineering
Tokyo University of Science,Kagurazaka
Three-component Mannich reaction with various acceptor aldehydes
N-methyl-2-
pyrrolidinone
(NMP)
Three-component Mannich reaction with various donor aldehydes,
4,Claisen Condensation
? General Scheme
2 R C H 2 C O 2 E t
B,
R C H 2 C C H C O 2 E t
R
O
? Mechanism
R C H C O E t
O
B,
H
R C H C O E t
O
-
+ R C H C
OH
O E t
R C H C
OH
O E t
R C H C O E t
O
-
- E t O
-
R C H
2
C C H C O
2
E t
R
O
? 一种酯的自身缩合
? Scope of application
? 一种含 ?-H 的酯与一种不含 ?-H的酯之间的缩合
? Examples
N
C O 2 E t + N a H
N
C O C H C O 2 E t
E t
E t C H 2 C O 2 E t
C O 2 E t
C O 2 E t
+ P h C H 2 C O 2 E t
E t O N a
E t O H
C O C H C O 2 E t
P h
C O 2 E t
- 1 7 5 o C
- C O
C HP h
C O 2 E t
C O 2 E t
? Directed Claisen condensation
L D A R C H C O
2 E t
R ' C O C l R C H C O 2 E t
C O R 'R C H 2 C O 2 E t
C O 2 M e
C O 2 M e
N
L i
C O 2 M e
O
5,Dickmann Condensation
( C H 2 ) n
C O 2 E t
C O 2 E t B,
( C H 2 ) n - 1
O
C O 2 E t
分子内 C l a i s e n 缩合反应
Chapter 3
Formation of Carbon-Carbon
Doule Bonds
1,?-Elemination reactions （ ?-消去反应）
C C
H X
C C + H X
X = - O H,- O C O R,卤素,- O S O 2 A r,- N + R 3,- S + R 2 e t a l,
R e g i o s e l e c t i v i t y
S a y t z e f f r u l e
H o f m a n n r u l e
X = - O H,- O C O R,卤素,- O S O 2 A r,
X = - N + R 3,- S + R 2
S t e r e o s e l e c t i v i t y
S y n e l i m i n a t i o n
A n t i e l i m i n a t i o n
H o f m a n n e l i m i n a t i o n s
S a y t z e f f e l i m i n a t i o n s
A n t i e l i m i n a t i o n
I,The Synthetic Methods of Alklenes
2,Pyrolytic syn eliminations（顺式热消去反应）
C C
H O
C C + R C O 2 H
R
O
3 0 0 ~ 5 0 0 o C
Applications,Synthesis of terminal alkenes from primary acetates
Disadvantages,High reaction temperature
C H 3 C H 2 C H 2 C H 2 O C O C H 3 5 0 0 o CN
2
C H 3 C H 2 C H = C H 2 1 0 0 %
C C
H O
C C + H S C S R
S R
S
1 0 0 ~ 2 0 0 o C
O
Cope
reaction
C C
H N R 2
C C + R 2 N O H
O
1 0 0 ~ 2 0 0 o C
Chugave
reaction
反应条件比对应的酯热消去温和。
3,Wittig and related reactions （ Wittig 及有关反应）
? Wittig Reaction
G,Wittig received the 1979 Nobel Prize in Chemistry for "many
significant contributions to Organic Chemistry" which included not
only the Wittig reaction,but also PhLi prepared by metal- halogen
exchange,benzyne,and the Wittig rearrangement,
C
O
R ' ( H )R + C H
R " '
R "
X + C C
R " '
R "
R
R '
( H )
P h 3 P
? General Scheme
? Mild reaction conditions;
? The position of the double bond is unambiguous,
? Features O
M e M g I1 )
2 ) H
+
H O M e
C H 2
P h 3 P = C H 2
- H 2 O
C H 3 C H 2
+
? Representative Examples
Example 1
Example 2
Example 3
Example 4
? Mechanism
[2 + 2] cycloaddition,
-
P h 3 P - C H 2 C H 3 + E t C H O +
D M F + L i
C 6 H 6 + L i
Z / E
9 6 / 4
0 / 1 0 0
P h C H = C H E t P h 3 P O
? Influence of solvent on the selectivity
? Activity and stereoselectivity of Yild
P h 3 P - C H R
-
R = a l k y l, E D G
R =
R = E W G
a l k e n y l o r a l k y n y l
S t e r e o s e l e c t i v i t y
Z - ( m a j o r )
Z / E ( m i x t u r e )
E - ( m a j o r )
S t a b i l i t y
i n c r e a s e
? Schl?sser modification,allows the preparation of trans vs,cis olefins,
Schl?sser Angew,Chem.,Int,Ed,Eng,1966,5,126,
? Stabilized Ylides
- Stabilized ylides are solid; stable to storage,not particularly sensitive to
moisture,and can even be purified by chromatography,
- Because they are stabilized,they are much less reactive than alkyl ylides,
They react well with aldehydes,but only slowly with ketones,
- The first step,involving the addition to the aldehyde,is slow and
reversible with stabilized ylides,
? Influence of solvent on the selectivity
? Wadsworth–Horner–Emmons Reaction
Horner Chem,Ber,1958,91,61; 1959,92,2499,
Wadsworth,Emmons J,Am,Chem,Soc,1961,83,1733,
Reviews,Org,React,1977,25,73–253,
Comprehensive Org,Syn.,Vol,1,761,
? Preparation of Phosphonate Esters
Arbuzov J,Russ,Phys,Chem,Soc,1906,38,687,
- Arbuzov Rearragement
- The same approach to the preparation of ?-ketophosphonates is not successful,
- But can use variation on Claisen conditions,
? Modifications and Scope
- LiCl / tertiary amines (DBU,iPr2NEt,Et3N)
Masamune,Roush Tetrahedron Lett,1984,25,2183,
? Can substitute for conventional conditions and is
especially good for base sensitive substrates,
-Hindered phosphonates and hindered aldehydes increase E-selectivity ( trans),
- Still–Gennari modification selective for Z-alkenes ( cis),
- Additional Z-selective stabilized phosphonates,
? Selected diarylphosphonates provide High Z-selectivity as well,
? Peterson Reaction
Reviews,Org,React,1990,38,1,
Peterson reaction offers an alternative to Wittig procedure,They are
more reactive and sterically less demanding than a Wittig reagent and the
volatile byproduct (Me3SiOH/ Me3SiOSiMe3) is simpler to remove than
Ph3PO,It does,however,require a second step to promote elimination of
the ?-hydroxysilane,
M e 3 S i C H 2 M C O+ C C
O S i M e 3
+ M e 3 S i O -
- The elimination is stereospecific,
acid-promoted being anti and base-promoted being syn,
Hudrlik,Peterson J,Am,Chem,Soc,1975,97,1464,
? Stabilized Peterson Reagents
- The stabilized Peterson reagents give predominantly
the most stable trans olefins ( E)
- Additional examples,
4,The Tebbe Reaction and Related Titanium-stabilized Methylenations
(Tebbe反应及与有关稳定化钛试剂的亚甲基化反应）
- Tolerates ketal and alkene derivatives,
Scope defined by Evans and Grubbs J,Am,Chem,Soc,1980,102,3270,
Extended to tertiary amides by Pine J,Org,Chem,1985,50,1212,
For an analogous use of Cp2TiMe2,
Petasis J,Am,Chem,Soc,1990,112,6392,
5,Sulphoxide-sulphenate rearragement,Synthesis of allyl alcohols
(亚砜 -次磺酸酯重排：烯丙醇类化合物的合成 )
C H 2
H C
CH
2
S
O
R
C H 2
H C
C H 2
S
O
R
C H 2
H C
C H 2
S
O
R
S
/ M e O H
2 5 o C
C H C H 2 O HH 2 C
Combined with alkylation of sulphoxides the reaction provides a
versatile synthesis of di- and tri-substituted allylic alcohols
Evans and Andrews,Acc,Chem,Res.,1974,7,147
S
C 6 H 5
O H
H
O
S
C 6 H 5
O
1, L D A / T H F
6 0
o
C
2, M e I
S
C 6 H 5
O
M e
S
C 6 H 5
O
M e
O S C 6 H 5
( M e O ) 3 P / M e O H
2 5
o
C
O H
7 4 %
( M e O ) 3 P / M e O H
O H
1, n - B u L i
2, C
6
H
5
S C l
O S C 6 H 5
S
C
6
H
5
O
1, L D A / T H F
6 0
o
C
2, M e I
S
C 6 H 5
O
M e
O H
M e
?-alkylation of allylic alcohlos
Example 1
Example 2
6,Alkenes from sulphones (由砜制备烯烃）
- Julia Olefination
Review,Comprehensive Org,Syn.,Vol,1,792,
- Example,
Julia Tetrahedron Lett,1973,4833,
Julia developed a more recent,single-step variant
that avoids the reductive elimination
Julia Bull,Soc,Chim.,Fr,1993,130,336,
S O 2 C 6 H 5 B u L i / T H F
- 7 8
o
C
S O 2 C 6 H 5
L i 1, C 6 H 5 C H O
2, ( C H 3 C O ) 2 O
S O 2 C 6 H 5
C 6 H 5
O C O C H 3
N a - H g
M e O H - M e C O 2 E t
C 6 H 5
9 3 %
Julia,M,et al.,Tetrahedron Lett.,1973,4833
Kocienski,P,J,et al.,J,Chem,Soc,Perkin I,1978,829,
- Example,
- Ramberg–Backlund reaction
Org,React,1977,25,1,
Base - SO2
C H S H
R
R '
1, H C H O / H C l
2, [ O ]
C H S O
2
C H
2
C l
R
R '
N a O H
C
R
R '
C H
2
S
O
2
C H S O
2
C l
R
R '
+ C H
2
N
2
C
R
R '
C H
2
Nicolaou K,C,et al.,J,Am Chem,Soc.,1992,114,7360,
Boockman R,K,et al.,J,Am Chem,Soc.,1991,113,9682,
Alvarze E,et al.,J,Am Chem,Soc.,1995,117,1437,
7,Decarboxylation of ?-lactones (?-内酯的脱羧反应）
O
C OR 1
R 2
R
R 3
1 4 0 ~ 1 6 0 o C
R 1
R 2
R
R 3
+ C O 2
O H
C O 2 HC H 3
C 6 H 5 C H 2
H
C 6 H 5
1 4 0 ~ 1 6 0 o CC 6 H 5 S O 2 C l
P y r i d i n e
0 o C
O
C OC H 3
C 6 H 5 C H 2
H
C 6 H 5
C H 3
C 6 H 5 C H 2
H
C 6 H 5
( > 9 9 % E )
Reformatsky
Reaction Note,No stilbene was formed
Synthesis of tri- or
tetrasubsituted
alkenes
Example 1
C O 2 H
O H M e
2 N C H ( O M e ) 2
D M F,5 0 o C
7 0 %
Fehr C,et al,Tetrahedron Lett.,1992,33,2465
M e
C C F 2 C O 2 HM e
O H
P h S O 2 C l / P y
C H C l 3,0 o C
M e
C C F 2M e
O C
O
- C O 2
M e
C C F 2
M e
8 7 %
Molbier W,R,et al,J,Org,Chem.,1995,60,5378
Example 2
Example 3
Mulzer J.,et al.,J,Chem,Soc,Chem,Commun.,1979,52
1 4 0
o
C
2 L D A
C
O L i
O
R ' C H
L i
+
R " C H O
R ' C H
2
C O
2
H
H
H O
" R
C O
2
H
R '
H
C
6
H
5
S O
2
C l
P y r i d i n e
O
C O
R
'
H
H
R
"
R
'
H
H
R
"
N
N
C O
2
E t
C O
2
E t
P h
3
P / T H F
2 2
o
C
H
O P P h
3
R "
C O
2
R '
H
- C O
2
- P h
3
P = O
R
'
H
H
R
"
6 3 % ; > 9 9 % E
R ' = C
6
H
5
-,R " = M e
7 5 % ; > 9 7 % Z
R ' = C
6
H
5
-,R " = M e
8,Stereoselective synthesis of tri- and tetra- substituted alkenes
( 三、四取代烯烃的立体选择性合成）
? The first step is highly stereoselective,
? The R4 and the larger of the groups R1 and R2 are anti to each other,
? Early Method
C C
R
3
O
R
1
C l
R
2
R
4
M g B r
C C
R
3
H O
R
1
C l
R
2
R
4
N a O H
C C
R
3 R
2
R
4
O
R
1
N a I / M e C O
2
H
C C
R
3
H O
R
1
I
R
2
R
4
S n C l
2
/ P O C l
3
P y
C C
R
3 R 2
R
4
R
1
E x a m p l e, R
1
= H,R
2
= M e,R
3
= M e,R
4
= E t ; Y i e l d 8 1 %
Cornforth,J,W,et al.,J,Chem,Soc.,1959,112
? Development
Method 1
Corey,E,J,et al.,J,Am,Chem,Soc.,1967,89,4246,
C
C
R
C H 2 O H
1, L i A l H
4
/ M e O N a
2, I
2
,- 7 8
o
C
C C
R
C H
2
O HI
H
L i M e
2
C u
C C
R
C H 2 O HM e
H
1, L i A l H 4 / A l C l 3
2, I 2,- 7 8 o C
C C
R
C H 2 O HH
I
L i M e 2 C u
C C
R
C H 2 O HH
M e
N o t e, T h e s u b s t i t u e n t s o r g i n a l l y
p r e s e n t i n t h e p r o p a r g y l a l c o h o l
a r e t r a n s t o e a c h o t h e r
Example
( 54%; 97% E)
( C H 2 ) 2 C C C H 2 O H
1, L i A l H 4 / M e O N a / T H F
2, I
2
3, M e 2 C u L i
C H 2 O H
Method 2
Example,R = Et,Yield 72%
Zweifel,G,et al.,J,Am,Chem,Soc.,1967,89,2754,
C
C
R
R
i s o - B u 2 A l H
CC
RR
H A l ( i s o - B u ) 2
1, I 2 / T H F,- 5 0 o C
2, H 3 O +CC
RR
H I
C CM e M e
i s o - B u 2 A l H
CC
M eM e
H A l ( i s o - B u )
2
M e L i / E t 2 O
- 3 0
o
C
CC
M eM e
H A l ( i s o - B u )
2
M e
L i
+
H
3
O
+
C O
2
CC
M eM e
H C O
2 H
7 6 %
E
Zweifel,G,et al.,J,Am,Chem,Soc.,1967,89,5085,
C
C
M e
M e
L i [ i s o - B u
2
A l H M e ] CC
M e
M e
H
A l ( i s o - B u )
2
M e
L i
+
H
3
O
+
C O
2
CC
M e
M e
H
C O
2
H
7 2 % Z
1, ( H C H O ) n
2, H
3
O
+
CC
M e
M e
H
C H
2
O H
6 8 % Z
9,Oxidative decarboxylation of carboxylic acids
( 羧酸的氧化脱羧反应）
Sheldon,R,A.,et al.,Organic Reactions,1972,19,279,
Jahngen,B,G,E.,J,Org,Chem.,1974,39,1650,
与 Dieal-
Alder 反应结合，
是制备环状烯烃
的好方法。
C O 2 H
C O 2 H
P b ( O A c ) 4 / O 2
P y,
7 6 %
C O 2 H
C O 2 H
P b ( O A c ) 4
C 6 H 6
R e f l u x
Example 1
P b ( O A c ) 4 / C u ( O A c ) 2, H 2 O
P y,C 6 H 6
M e
C O 2 H
R e f l u x
+
2, 7, 1
C O 2 H P b ( O A c )
4 / C u ( O A c ) 2, H 2 O
C 6 H 6,R e f l u x
7 7 %
Tanzawa T,et al,Tetrahedron Lett.,1992,33,6783
Example 2
Example 3
10,Alkenes from arylsulphonylhydrazones (由芳基磺酰腙制备烯烃）
R
R '
N N H S O 2 A r
B u L i
R
R '
N
B u L i
N
S O 2 A r
R
R '
N
N
S O 2 A r
R
R '
N
N
- A r S O
2
H
L i
R
R '
L i
E
+
R
R '
E
R
R '
O
R
R '
N N H S O 2 A r
A r S O 2 N H N H 2 1, 2 e q, B u L i
2, E +
R
R 'E
Kolonko K.,et al,J,Org,Chem.,1978,43,1404;
Adlington R,M.,et al,Acc,Chem,Res.,1983,16,55
Mechanism
C 6 H 5
N N H T o s
1, 2 e q, B u L i
2, D 2 O
C 6 H 1 4 - T M E D A
C 6 H 5
D
7 4 %
Less substituted alkene
Example 1
C
6
H
1 3M e
N N H S O
2
i - P r
i - P r
P r - i
2 e q, B u L i
C
6
H
1 4
- T M E D A
C
6
H
1 3
L i
M e C H O
C
6
H
1 3
H O
C O
2
C
6
H
1 3
C O
2
H
H
2
O
C
6
H
1 3
H
Example 2
11,Fragmentation Reactions (裂解反应）
X
R
Oa b H
B a s e
R O
X = leaving group,e.g.,-OSO2C6H4CH3-p,-OSO2CH3
100% stereospecific
Example
12,Olefin Inversion Reactions (烯烃构型转换反应）
R '
R R R '
? Deoxygenation of epoxides (with retention of geometry)
Other examples
13,Srereospecific synthesis of alkenes from 1,2-diols
(由 1,2-二醇立体选择性地合成烯烃）
Corey–Winter Olefin Synthesis
Corey J,Am,Chem,Soc,1963,85,2677,
Corey J,Am,Chem,Soc,1965,87,934,
Eastwood Aust,J,Chem,1964,17,1392,
Eastwood Tetrahedron Lett,1970,5223,
Burgstahler,Boger Tetrahedron 1976,32,309,
14,[3,3]-Sigmatropic Rearrangements
? Claisen and Cope Rearrangement
Examples
Evans J,Am,Chem,Soc,1975,97,4765,
Burgstahler J,Am,Chem,Soc,1961,83,198,
Carnduff J,Chem,Soc.,Chem,Commun,1967,606,
? Thio-Claisen Rearrangement
- An advantage of the thio-Claisen rearrangement is
that the precursor can be deprotonated and alkylated,
Corey J,Am,Chem,Soc,1970,92,5522,
Yamamoto J,Am,Chem,Soc,1973,95,2693 and 4446,
Block J,Am,Chem,Soc,
1985,107,6731,
?The Carroll Reaction
Carroll J,Chem,Soc,1940,704,1266,
Hartung J,Chem,Soc,1941,507,
Cope J,Am,Chem,Soc,1943,65,1992,
Tanabe J,Am,Chem,Soc,1980,102,862,
15,[2,3]-Sigmatropic Rearrangements
Review,Comprehensive Org,Syn.,Vol,6,pp 834,873–908,
Org,React,1994,46,105–209,
- Analogous to [3,3]-sigmatropic rearrangement except it enlists a localized
charge (anion) in place of a double bond,
Examples
Julia Tetrahedron Lett,1974,2077,
Lythgoe J,Chem,Soc.,Chem,Commun,1972,757,
Evans Tetrahedron Lett,1973,4691,
? Amino-Claisen Rearrangement
- This reaction occurs best when nitrogen is converted to the ammonium salt,
Gilbert Tetrahedron Lett,1984,25,2303,
Stille J,Org,Chem,1991,56,5578,
Nakai Chem,Lett,1990,2069,
Sato J,Am,Chem,Soc,1990,112,1999,
II,Olefin Synthesis Exemplified with Juvenile Hormone
(保幼激素的合成）
Juvenile Hormone （ HJ)
1,Trost Synthesis,J,Am,Chem,Soc,1967,89,5292,
2,Syntex Synthesis,J,Am,Chem,Soc,1968,90,6224,
3,Corey Synthesis,J,Am,Chem,Soc,1968,90,5618,
4,Johnson Synthesis,J,Am,Chem,Soc,1968,90,6225,
5,Corey Synthesis,J,Am,Chem,Soc,1970,92,6635,6636,6637,
6,Johnson Synthesis,J,Am,Chem,Soc,1970,92,4463,
7,Stotter–Kondo Synthesis,J,Am,Chem,Soc,1973,95,4444,
J,Chem,Soc.,Chem,Commun,1972,1311,
8,Still Synthesis,Tetrahedron Lett,1979,593,
9,Other Syntheses,
(1),Trost Synthesis
Wadsworth–Horner–Emmons Reaction
Stereoselectivity
- not much difference between Me and H
(second atom steric effect)
- both isomers obtained from the Wadsworth–
Horner–Emmons reaction (Modern
improvements now available)
Retrosynthetic Analysis
- repeating subunits recognized
- repeating reactions utilized
J,Am,Chem,Soc,1967,89,5292,
(2),Syntex Synthesis
J,Am,Chem,Soc,1968,90,6224,
Robinson Annulation
Alkylation Diastereoselectivity
Directed Epoxidation Reaction
Fragmentation Reaction
Selective Reduction
- saturated vs,a,b-unsaturated carbonyl
- ring strain associated with 5-membered
ring carbonyl released on reduction
- attack from least hindered face
THP Protecting Group
- if R group contains chiral centers,
diastereomers result
- removed by mild acid
Thermodynamic Enolate
- severe 1,3-diaxial interaction in chair-like
T.S,axial alkylation
- no steric incumberance to axial alkylation on
least hindered face of twist boat T.S,
LiAlH(OtBu)3 Reduction
- large reagent,usually equatorial H– delivery
- 1,2-interaction (torsional strain) relatively
invariant to Nu– size
- 1,3-steric interaction highly dependent on
Nu– size
- due to absence of axial C(3)–H,large reagent
now gives axial delivery
Epoxidation
- in Et2O,coordination of peracid to
solvent gives delivery from the least
hindered a-face
- in CH2Cl2,H-bonding of OH to
peracid provides delivery to the less
accessibleb-face
- Teranishi J,Am,Chem,Soc,1979,101,
159,
Fragmentation Reaction
- utilized to control C=C bond
stereochemistry
- trans periplanar orientation of breaking
bonds
- dictates Z olefin geometry in product
3,Corey Synthesis
Dissolving Metal Reductions
Cyclic Precursors to Trisubstituted Olefins
Oxidative Cleavage of Enol Ethers
LiAlH4 Reduction of Propargyl Alcohols
Cuprate Coupling Reactions
Allylic Alcohol Oxidation
J,Am,Chem,Soc,1968,90,5618,
Stereospecific Synthesis of Trisubstituted Olefins
MnO2 Oxidation
- mild oxidation of allylic alcohols
- direct,mild method for oxidation
to a methyl ester
Epoxidation
- selective
- in polar solvent the molecule
folds up such that the terminal
C=C is more accessible
4,Johnson Synthesis,
Trimethyl
pyridine
J,Am,Chem,Soc,1968,90,6225,
5,Corey Synthesis,J,Am,Chem,Soc,1970,92,6635,6636,
1,5-H Shift Diimide Reduction
- less substituted C=C
reduced more rapidly
- generated in-situ
6,Johnson Synthesis,J,Am,Chem,Soc,1970,92,4463,
Olefinic Ketal Claisen Reaction
- selectivity dependent on
1,3-interaction in chair-like T.S,
- second Claisen more selective
due to larger R group vs,CO2Me
7,Stotter–Kondo Synthesis,J,Am,Chem,Soc,1973,95,4444,J,Chem,Soc.,Chem,Commun,1972,1311,
8,Still Synthesis,Tetrahedron Lett,1979,593,
[2,3]-Sigmatropic Rearrangement
Chapter 4
Conversion of Functional Groups
O H O H
O H N R R '
1,Addition of Carbon-Carbon Double Bonds
O
E p o x i d a t i o n
A d d i t i o n
H A
A = H,O H,X,O C O R
X X
X O H
2,Halogenation of Alcohols
? General Methods
R O H R
H X
P X
3
G e n a r a l r e a g e n t s
R - O S O
2
R '
X
S O C l
2
Org,Lett.,2002,4(4),553-555
? TCT/DMF Method
? Development
2,4,6-trichloro[1,3,5]triazine
TCT
Table 1,Conversion of Aliphatic Alcohols into the
Corresponding Alkyl Halides
a For complete conversion of the alcohol,b The corresponding chloride is formed also,
Table 2,Conversion of Diols and Unsaturated and ?-amino
Alcohols into the Corresponding Alkyl Halides
a For complete conversion of the alcohol,b The corresponding chloride is formed also,
Mechanism
? Me3SiCl
O H M e 3 S i C l
D M S O
r, t,
C l 9 5 %
该方法对苄醇、伯醇、烯丙醇、
叔醇，室温下反应迅速，收率高。
J,Org,Chem,1995,60,2638
N
R
R ' R "
3,Formation of Amines
? General Methods
R N O 2
R C N
R C O N R ' 2
R e d u c t i o n
R R ' C N R " R ' "
N - A l k y l a t i o n
R X
R O H
R O S O 2 A r
R e a r r a g e m e n t
H o f m a n n 重排
C u r t i u s 反应
L o s s e n 重排
S c h m i d t 反应
R N H
2
O
O H
-
R N
O
B r
R C l
O
R N
O
N
N
R O H
O
R N
O
N
N
H
+
R O E t
O
R N H N H
2
O
E t O H
H N O
3
- H
2
O
R N H O H
O
R N H
O
R ' C O
2
H O R '
O
+ H N
3
-
+
+ N
2
H
4
+ B r
2
-
+ N a N
3
-
+
- R ' C O
2
H
- B r
-
- N
2
- N
2
O C N R
H
2
O
R N H
2
H o f m a n n
C u r t i u s
S c h m i d t
S c h m i d t
L o s s e n
- C O
2
与氮烯有关的重排反应
? Synthesis primary amine
? Gabriel Synthesis
,B
N
O
O
-
R X
N R
O
O
,X
-
N H
O
O
R X R N H 2+ +
H
2
N N H
2
N H
N H
O
O
2 ) H
2
N N H
2
1 ), B
Harsh hydrolysis conditions
? Improvement
Synthesis,1990,8,735; 1995,7,756
Synlett,1996,2,179;
Synth,Commun.,1999,29,2685
Synthesis of Arylamines from
amination of Aryl Halides
? Development
? Early Palladium-Catalyzed Amination
N
R
R '
B u 3 S nB r
" R " R
N
R
R '+
[ L 2 P d C l2 ]
L = p ( o - C 6 H 4 M e ) 3
+ B u 3 S n B r
M, K o s u g i,M, K a m e y a m a,T, M i g i t a,C h e m, L e t t, 1 9 8 3,9 2 7 - 9 2 8
该反应仅限于仲胺与电中性的卤代苯。
NM e O
2
C C O
2
M e
M eH
2
N
B r
[ P d ( P P h
3
)
4
]
NM e O
2
C C O
2
M e
M e
H N
D, L, B o g e r,e t a l,,T r t r a h e d r o n L e t t,,1 9 8 4,2 5,3 1 7 5
D, L, B o g e r,e t a l,,J, O r g, C h e m, 1 9 8 5,5 0,5 7 8 2 - 5 7 8 9 ; 5 7 9 0 - 5 7 9 3
要求等当量的有机钯催化剂。
J,Am,Chem,Soc.,1994,116,5969-5970
P,Patt,Hartig et,al,
P dL L 3 A r B r
B r
P d
B r
P d
L
A r
L
L
R 3 S n N R 2 A r N R
2 + P d 0
发现 Pd 可循环使用
从 1985 到 1994 近 10 年没有关于 Pd 催化胺化反应的报道。
存在的问题,1）要将胺变成锡胺化物；
2）不适应于伯胺；
3）反应速度较慢；
4）催化剂用量较大。
? Initial Tin-free Amination of ArX
X
B r + H N R R '
L 2 P d C l 2
L - P ( o - C 6 H 4 M e ) 3
B a s e
X
N R R '
Hartwig and Buchwald,
Angew,Chem,Int,Edu.,1995,34,1348-1350;
Tetrahedron Lett,1995,36,3609
Room Temperature Catalytic
Amination of Aryl Iodides
J,Org,Chem,1997,62,6066-6068
John P,Wolfe and Stephen L,Buchwald*
Department of Chemistry,Massachusetts Institute of
Technology,Cambridge,Massachusetts 02139
Table 2,Room Temperature Catalytic Amination of Aryl Iodides
Table 2,Continued
A Highly Active Catalyst for
Palladium-Catalyzed Cross-Coupling Reactions,
Room-Temperature Suzuki Couplings and
Amination of Unactivated Aryl Chlorides
David W,Old,John P,Wolfe,and Stephen L,Buchwald*
J,Am,Chem,Soc,1998,120,9722-9723
Amination Reactions of Aryl Halides with Nitrogen-Containing
Reagents Mediated by Palladium/Imidazolium Salt Systems
Gabriela A,Grasa,Mihai S,Viciu,Jinkun Huang,and Steven P,Nolan*
Department of Chemistry,University of New Orleans,New Orleans,Louisiana 70148
J,Org,Chem,2001,66,7729-7737
Imes ·HCl
Imes,1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene
Ipr,1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)
Imidazolium Chloride Ligands
Table 2,Amination of Aryl Chlorides with Various Amines
Table 2 Continued
Table 3,Amination Involving Aryl Bromides and Idodides with Various Amines
Most interesting in these studies involving an aryl bearing both chloro and iodo (or bromo)
substituents is the observation that bromo and iodo functionalities can be converted at room
temperature (entries 3 and 4) and the remaining chloro functionality can subsequently be
converted at moreelevated temperatures,This could prove to be a significant advantage in
process chemistry,
Table 4,Influence of Palladium(0)/Imidazolium
Salt Ratio on Amination Reactions
Table 5,Amination of Chlopyridines and
Bromopyridines with Various Amines
General catalytic cycle for amination reaction,
Table 6,Amination of Aryl Chlorides withBenzophenone Imine
Table 7,Amination of Aryl Bromides with
Benzophenone Imine
Table 9,Effect of the Imidazolium Chlorides and Bases
on N-Aryl Substitution of Indole with Bromobenzene
Table 10,Amination of Aryl Bromides with Various Indoles
The standard amination
conditions did not affect
the arylation of indoles,
Table 10 Continued
Synthesis of Linezolid Intermediate
Linezolid is
member of a new
class of antibiotics,
An Improved Method for the Palladium-
Catalyzed Amination of Aryl Iodides
Mayssam H,Ali and Stephen L,Buchwald*
Department of Chemistry,Massachusetts Institute of Technology,
Cambridge,Massachusetts 02139
J,Org,Chem,2001,66,2560-2565
Table 2,Amination of Aryl Iodides with NaOt-Bu as Base
Table 2,Continued
Table 3,Amination of Aryl Iodides with Cs2CO3 as Base
Cs2CO3
Pd-Catalyzed Intermolecular Amidation of Aryl
Halides,The Discovery that Xantphos Can Be
Trans-Chelating in a Palladium Complex
Jingjun Yin and Stephen L,Buchwald*
Contribution from the Department of Chemistry,Massachusetts Institute
of Technology,Cambridge,Massachusetts 02139
J,AM,CHEM,SOC,2002,124,6043-6048
CuI,K3PO4
Table 1,Cu-Catalyzed Amination of Aryl Bromides
Table 1,Continued
Table 2,Copper-Catalyzed Amination of ortho-Substituted
And Heteroaryl Bromides
Table 3,Intramolecular Copper-Catalyzed
Amination of Aryl Halides
Table 4,Solvent-Free Cu-Catalyzed Amination of Aryl Bromides
Solvent-
free
Amino acid-mediated Goldberg reactions
between amides and aryl iodides
Wei Deng,Ye-Feng Wang,Yan Zou,Lei Liu*,and Qing-Xiang Guo*
Department of Chemistry,University of Science and Technology of
China,Hefei 230026,China
Tetrahedron Letters 45 (2004) 2311–2315
Table 1,Yields of the coupling reaction between caprolactam
and iodobenzene under different conditions
a Isolated yield,b 5 mol %,c 20 mol %,
Table 3,Yields of the CuI-catalyzed coupling reactions between
iodobenzene and various amides (base K3PO4,solventdioxane,
temperature 100oC,reaction time 24 h)
Table 4,Yields of the CuI-catalyzed coupling reactions between various
aryl halides and amides (ligandglycine,base K3PO4,solvent
dioxane,temperature100 oC,reaction time 24 h)
Mechanism
R
B r
H N
R '
R "
D M F
R
H N
R '
R "
+
P d ( O A c ) 2,D p p f
1 3 0
o
C o r 1 8 0
o
C
4 m i n
M i c r o w a v e H e a t i n g
R ' R " N H = p r i m a r y a m i n e,s e c o n d a r y a m i n e,b e n z y l a m i n e,A r N H 2
Y i e l d s, 4 8 - 8 5 %
Palladium-Catalyzed Amination of Aryl Bromides
Using Temperature-Controlled Microwave Heating
Yiqiang Wan,Mathias Alterman,Anders Hallberg
Synthesis,2002,11,1597-1600
Mats Larhed and Anders Hallberg
DDT,6 (8),406 - 416,2001
Microwave-assisted High-speedchemistry,
A New Technique in Drug Discovery
Figure 2,Examples of palladium (Pd)-catalyzed Heck arylations demonstrating retained regioselectivities under Microwaveinduced
flash-heating conditions,
Microwave-assisted intramolecular
and two-component reactions
Figure 4,Examples of fast microwave-assisted organic
reactions on polymeric supports,
Microwave-assisted multi-component reactions
The drug discovery process and the foreseen impact of microwave
chemistry on automated medicinal/combinatorial chemistry
Chapter 5
Application of Organometallic
Reagents in Organic Synthesis
金属有机试剂
过渡金属有机试剂
八隅体电子构型( s,p )
稀土金属试剂
Sc,Y,La(镧系）
17种
非过渡金属有机试剂
(s,p,d,f 1-14)
十八隅体电子构型
( s,p,d 0 - 1 0 )
5.1 基本原理
5.1.1 非过渡金属试剂的特性
? 电负性
? 反应活性
主族 Li-R < Na-R < K-R < Rb-R < Cs-R
副族 Cu-R > Ag-R > Au-R ; Zn-R > Cd-R > Hg-R
主副族比较 Li-R > Cu-R; Be-R > Zn-R; Mg-R >> Zn-R
同一周期 Li-R > Be-R > B-R; Na-R > Mg-R > Al-R;
.,,, > C
M g C u L i C d N a K < C
非金属
金属
O S N X
? 反应性
? 特性总结
a,含有 C-M 键
b,C-M键中 C为电负性的
c,C-M键中的 C原子常被亲核试剂进攻
? 金属有机试剂中常见的金属部分
Na,K,Li,Mg,Zn,Cu,Fe,Pd,Ni,Ti
C n o n - m e t a lN u -
? + ? -
H O - + C H 3 - I C H 3 O H + I -
E + C M
? - ? +
M e - M+ C H 3 M e + M + -I+C H 3 - I
5.1.2 金属试剂的制备通法
1) 卤代烃与金属反应
R - B r + 2 L i R - L i + L i B r
2）有机金属化合物与卤代烃的交换
R - X + R ' - M R - M + R ' - X
P h - B r + B u - L i P h L i + B u B r
3）有机金属化合物与金属盐的交换
2 R - L i + C d C l 2 R 2 C d + 2 L i C l
M 的电正性 C - M 的稳定性
M 的电正性 C - M 的稳定性
4) 烃的金属化
R C C H + C 2 H 5 M g B r R C C M g B r
+ B u L i + B u HL i ?
?
5.1.3 结构与反应性
M K N a L i M g C d
% 离子性 5 1 4 7 4 3 3 5 1 5
离子键极性共价键
反应性降低
5.2 有机镁试剂（ Grignard reagents）
通常表示为,RMgX,以乙醚溶液使用
实际存在方式,
M g
B r
R
O E t 2
O E t 2
M g
E t 2 O
R
M g
O E t 2
RB r
B r
单体二聚体
5.2.1 制备
R - X + M g R M g X
E t 2 O
R, 烷基, 芳基, 烯丙基, 烯基, 苄基
X, I > B r > C l > > F
M e I E t B r
? 通常用乙醚作溶剂，但制备芳基和烯基类 G-试剂
时，要用 THF作溶剂，以便提高温度，使反应进行
完全。
5.2.2 特殊的反应性
M g X E
E
E +
正常
反常
M g X
M g X
C
R R '
O
C H 3
M g
B r
O H
R '
R
+
5.2.3 在合成上的应用
? 烷烃的制备
R - M g X + M e X R - M e + M g X 2
A r C H 2 M g C l
A r C H 2 M e + M g C l ( O S O 2 O M e )
M e 2 S O 4
A r C H 2
n - C 4 H 9 O T s
C 4 H 9 - n + M g C l ( O T s )
碳链非异构
化产物
? 醇的制备
R C H O
R C O R '
R C O
2
R '
O
R " M g X
R R "
O H
伯或仲醇
O H
R
R '
" R
叔醇
O H
R
" R
" R
R " C H
2
C H
2
O H
O
+ R M g X
O
M e M g X
O HM e
M g X
O
O
H
1 ) R M g X
2 ) H +
O H
R
O H
R
+
O
R
1,4 - a d d i t i o n1,2 - a d d i t i o n
选择性
差
? 醛的制备
C H 3 ( C H 2 ) 4 M g B r + H C ( O C 2 H 5 ) 3 H
+ / H
2 O C H
3 ( C H 2 ) 4 C H O
4 5 % ~ 5 0 %
C 2 H 5 O
CC 2 H 5 O
O C 2 H 5
H
R M g X
H C
O C 2 H 5
O C 2 H 5
+
R M g X
R C H
O C 2 H 5
O C 2 H 5
R C H
O
H
+
/ H 2 O
增加一个碳原子
C
R
R
O
B r M g C C O E t C
R
R
O H
C C O E t
C
R
R
O H
C H
C
R
R
O H
C H
2
C H O
C H O H
+
1 ) 加成
H
+
/ H
2
O
2 ） H
+
C
R
R
C H C H O
C
R
R
O H
C H C H O E t
[ H ]
O
O C H
3
O C H
3
C H O
B r M g C C O E t
? 酮的制备
a,
R M g X + C N
R '
C NR ' M g X
R
H +
C N H
R '
R
H 2 O
- N H 3
C O
R '
R
b,R M g X + C N R " 2R '
H
+
C O
R '
R
O
C N R " 2
R '
O
M g X
R
+ M g X + R " 2 N H
+
P h C O C l + M g C l - 7 8
o C H + / H
2 O C O P h
C H 3 ( C H 2 ) 5 M g B r + n - C 3 H 7 C O C l
- 3 0 o C H + / H 2 O
C H 3 ( C H 2 ) 5 C O C 3 H 7 - n
c,
5.3 有机锂试剂（ Organolithium reagents）
活性,RNa > RLi > RMgX
5.3.1 制备
R - B r + 2 L i R - L i + L i B r
P h - B r + B u - L i P h L i + B u B r
- configurationally stable
- retention of configuration
5.3.2 反应
? 能克服位阻的影响
O
M g X+
+ L i
O L i
H
+
O H
? 与 ?,?-不饱和酮主要发生 1,2-加成
P h P h
O
P h M g B r
P h L i
P h P h
OP h
P h P h
O H
P h
1,4 - 主要产物
1,2 - 主要产物
? 与羧酸,CO2反应生成酮
R ' C
O
O L iR L i + R ' C
O L i
O L i
R
H + / H 2 O
R C
O
R '
C O O H C C H 3
O
1, 4 e q, C H 3 Li
2, T M S ? Cl
3, H + / H 2 O
92%
R M g B r1 )
2 ) H +
2 R L i1 )
2 ) H
+
C O 2
R C O R
R C O 2 H
5.4 有机锌试剂（ Organozine reagents）
? Reformatsky 反应及扩展
P h C H O + B r C H 2 C O O C 2 H 5 C H 2 C O O C 2 H 5C HP h
O H
1, Z n
2, H + / H 2 O
O
B r
O
C H P h
O H
+ P h C H = O
Zn
Et 2 A l C l
CC HR
B r
O C 2 H 5
O
+ R C N
Zn
C C
R
C 2 H 5 O O C
R '
N H 2
C H C
R
C 2 H 5 O O C
R '
OH + / H
2 O
―一锅煮, 制备 ?,?- 不饱和羰基化合物, Zn催化
R C H O + B r C H 2 C O 2 C H 3 + n - B u 3 P ( A s ) Z n R C H C H C O 2 C H 3
R C H O + B r C H 2 C O N R R ' + n - B u 3 P Z n R C H C H C O N R R '
R C H O + B r C H 2 C N + n - B u 3 P Z n R C H C H C N
将三步的 Wittig反应压缩为“一锅”法完成。
沈延昌,金属有机化合物的化学反应,
化学工业出版社,2000.7,P 60-78
C
2
H
5
O C ( C H
2
)
n
I
O
C
2
H
5
O C ( C H
2
) n Z n I
O
R C ( C H
2
)
n
O
C O O C
2
H
5
CR C l
O
Z n C u
R C H ( C H
2
)
n
O T M S
C O O C
2
H
5
R C H C H C H
2
X
R C H C H C H
2
( C H
2
)
n
C
O
O E t
R C H O
T M S C l
? Lombardo’s试剂（ Zn + CH2Cl2 + TiCl4）
CR R
O
CR R
O T i
C H 2 Z n
?
T i
CR R
C H 2
Z n C H
2 Z n
C 4 H 9 C O O C H 3 + ( C H 3 ) 2 C H C H B r 2
C 4 H 9
C C
C H 3 O
C H ( C H
3
)
2
H
T i C l
4
Z n
A Direct Catalytic Asymmetric Mannich-type
Reaction to syn-Amino Alcohols
Barry M,Trost* and Lamont R,Terrell
Department of Chemistry,Stanford UniVersity,Stanford,
California 94305-5080
J,Am,Chem,Soc,2003,125,338-339
Scheme 1,Generation of Dinuclear Zinc Catalysts
Table 1,Additions to Glyoxalate Imines
Table 2,Additions to Aldimines
Multiple Component Reactions,An Efficient Nickel-
Catalyzed Reformatsky-Type Reaction and Its
Application in the Parallel Synthesis of ?-Amino
Carbonyl Libraries
James C,Adrian,Jr.*,? and Marc L,Snapper?
Chemistry Department,Union College,Schenectady,New
York 12308,and Department of Chemistry,
Merkert Chemistry Center,Boston College,Chestnut Hill,
Massachusetts 02467
J,Org,Chem,2003,68,2143-2150
TABLE 1,Comparison of Catalytic Activity
(a) Sibille,S.; d’Incam,E.; Leport,L.; Massebiau,M.-C.;
Pe′richon J,Tetrahedron Lett,1987,28,55-58,
(b) Mcharek,S.; Sibille,S.; Ne′de′lec,J.-Y.; Pe′richon J,J,
Organomet,Chem,1991,401,211-215,
(c) Conan,A.; Sibille,S.; Pe′richon J,J,Org,Chem,1991,56,
2018-2024,
TABLE 2,Effect of Catalyst Loading
SCHEME 3,Proposed Catalytic Cycle
TABLE 3,3CC Nickel-Catalyzed Reformatsky Reaction Affording
Compounds with the ?-Amino Carbonyl Core Structure
Table 3,Continued
Synthesis,2004,5,683-691
5.5 有机镉试剂（ Organocadmium reagents）
2 R - L i + C d C l 2 R 2 C d + 2 L i C l
? 制备
? 反应活性远低于 RMgX 和 RLi
? 反应
2 R C O C l + R ' 2 C d R C O R ' + C d C l 2
R C O C l
R ' M g X
R ' L i
R ' 2 C d
R C O R '
R C O R '
R C O R '
只适用于制备
位阻较大的酮
5.6 有机铜化合物（ Organocopper compounds）
RCu R2CuLi
5.6.1 制备
R L i + C u I R C u + L i I
2 R L i + C u I R 2 C u L i + L i I
HH + R 2 C u L i
R
C u
R
- L i +
5.6.2 反应
? 与 ?,? -不饱和羰基化合物反应
O
C H 3
+ ( C H 3 ) 2 C u L i O
C H 3H 3 C
98%
( C H 3 ) 6 C O O C H 3
O
+ ( C H 2 = C H ) 2 C u L i
( C H 2 ) 6 C O O C H 3
O
C H C H 2
66%
均为 1,4-
加成产
物
? 与卤化物反应
R X + R ' 2 C u L i R R '
H
3
C
H
H
C l
L i
H
3
C
H
H
L i
C u I,- 7 8
o
C
n - C
8
H
1 7
I
H
3
C
H
H
C
8
H
1 7
- n
9 0 - 9 3 %
C
1 0
H
2 1
B r + B u
2
C u L i 8 0 %C
1 4
H
3 0
B r + B u
2
C u L i
B u
8 0 %
? 与环氧化物反应
O
C H 2C H 3
+ ( C H 3 ) 2 C u L i C H 3 C H 2 C H C H 2 C H 3
O H
88%
O
C H 3
1 ) R 2 C u L i
2 ) H +
C H 3
O H
R
从位阻较小的一侧，取代基较少的碳原子上进攻。
5.7 有机钯化合物（ Organopalladium compounds）
形成过渡
金属络合
物中间体
在配位体
上进行化
学反应
去络合
反应
过渡金属参与有机反应的三个阶段
[ ( C 2 H 4 ) P d C l ]2 1 9 3 8
化学计量到催化循环
1 9 5 6, S m i d t,
G e r m a n,E a c k e r C o m p a n y
[ M 2 P d C l4 ] 4,M = L i,N a,K
[ ( P h C N )2 P d C l2 ]
[ P d ( O C O C H3 ) 2 ]
[ P d ( O C O C F3 ) 2 ]
P d
2 +
P d C l2
P d 0 [ P d ( P P h ) 4 ]
[ P d ( P P h ) 4 ]
[ P d L 4 ]
? ? 络合物
CH
2
= C H
2
+ P d C l
2 C H
2
C H
2
P d
+ +
P d
+
C H
2
C H
2
P d
+ +
N u
C H
2
C H
3
N u
C H C H
2
N u
N u
?
[ H ]
- P d
-H +
o
C 8 H 1 7 C H C H 2 + H 2 O
C 8 H 1 7 C H 3
O
P d C l 2
C u C l 2 O 2
C H 2 C H C H 2 C
C H 3
C H 3
C H O C H
3 C C H 2 C
C H 3
C H 3
C H O
O
C u C l 2 P d C l 2
H 2 O D M F O 2
78%
Wacker 反应
? ?3-烯丙络合物
P d + C H 2 C H C H 2 B r ? ? 3 C 3 H 5 ) P d B r 2
黄色固体 d p 1 3 5 ℃
R C H 2 C H C H 2
R C H C H C H 2
O C C H 3
O
P d C l 2
P d 0
H H
H
HR
P d
+ +
制备
反应
P d + +
H H
HR
N u ?
P d + +
C H 2
R
H H
N u ?? Pd 0
?? H +
R
C H C H C H 2 N u
C H 3 O O C
O C
O
C H 3
C H 3 O O C
C H ( C O O C 2 H 5 ) 2
P d ( P P h 3 ) 4
N a C H ( C O O C 2 H 5 ) 2
57%
? Pd络合物的氧化加成反应（ Heck Reaction)
R X R ' R "
P P h 3
R
R "
H
R '
+
P d ( O A c )2
R P d X
R '
R ' '
R '
R ' '
R P d X
S y n 加成
R ' H
R
R ' '
H
P d X
R R '
H
R ' '
H
p d X
H
R
R '
R "
? H P d x
S y n 清除
C O O C H 3C H + C H 2B r C H C H C O O C H 3( P P h 3 ) 2 P d ( O A c ) 2
8 5 %
R 3 N
I
B r
C O O HC H + C H 2
C H
B r
C H C O O H
P d ( O A c ) 2
8 2 %
O
C H 3
N
B r
N
C H 3
O
P d ( O A c ) 2,P P h 3
E t 3 N
8 5 %
Heck Reaction (Review)
1,Heck,R,F.; Nolley,J,P.,Jr,J,Am,Chem,Soc,1968,90,
5518;
2,Heck,R,F,Acc,Chem,Res,1979,12,146;
3,R,F,Heck,Organic Reactions,1982,27,345;
4,A,de,Meijere and F,E,Meyer,Angew,Chem,Int,Ed,
Engl.,1994,33,2379;
5,W,Cabri and I,Candiani,Acc,Chem,Res.,1995,28,2;
6,G,T,Grisp,Chem,Soc,Rev.,1998,27,427
7,Amatore,C.; Jutand,A,Acc,Chem,Res,2000,33,341,
Oxidative Heck-Type Reaction Involving
Cleavage of a Carbon-Phosphorus Bond of
Arylphosphonic Acids
Atsushi Inoue,Hiroshi Shinokubo,* and Koichiro Oshima*
Department of Material Chemistry,Graduate School of Engineering,
Kyoto UniVersity,Kyoto 606-8501,Japan
J,AM,CHEM,SOC,2003,125,1484-1485
Table 2,Oxidative Heck-Type Reaction of Arylphosphonic Acids
Direct Coupling of Benzene with Olefin Catalyzed by
Pd(OAc)2 Combined with Heteropolyoxometalate
under Dioxygen
Takahiro Yokota,Masayuki Tani,Satoshi Sakaguchi,and Yasutaka Ishii
Department of Applied Chemistry,Faculty of Engineering,
Kansai UniVersity,Suita,Osaka 564-8680,Japan
J,AM,CHEM,SOC,2003,125,1476-1477
? 偶联反应
C C
H
R
H
P d + + X
+ R ' M C C
H
R
H
P d R '
C C
H
R
H
R '
+ P d 0
催化剂,Pd(PPh3)4
C C
H
C 6 H 1 3
H
I
C C
B r M g
H
H
H
+ C C
H
C 6 H 1 3
H
C H C H 2
P d ( P P h 3 ) 4
R C C H R C C C uCu + R C C R ' + P d 0R 'P dX
R X + R 1 B ( R 2 ) 2 L 2 P d ( 0 )N a O R 3 R R '
R X L
2
P d ( 0 )+
氧化加成
P d
L
L X
R
R
1
B ( R
2 )
2 +
N a O R
3
R
1
B ( R
2 )
2
O R
3
P d
L
L X
R
+
R
1
B ( R
2 )
2
O R
3
金属转移化
异构化
P d
L
L R
1
R
+
-
-
B ( R
2 )
2
R
3
O
还原消除
R R
1
L
2
P d ( 0 )+
Suzuki Reaction
Suzuki Reaction
1,N,Miyaura and A,Suzuki,Chem,Rev,1995,95,2457
2,A,Suzuki,Puer Appl,Chem.,1994,66,213;
3,N,Miyaura and A,Suzuki,Org.Syn.,Coll.Vol,VIII,1993,
532;
4,B.E,Huff,T,M,Koenig et al.,Org,Syn.,1996,75,53;
5,F.E,Goodson,T.L,Wallow and B.M,Novak,Org,Syn,
1996,75,61;
6,F.S,Ruel,M.P,Braun and C.R,Johnson,Org,Syn.,1996,
75,69
7,Miyaura,N,Top,Curr,Chem,2002,219,11-59,
8,Suzuki,A,In Metal-Catalyzed Cross-Coupling Reactions;
Diederich,F.,Stang,P,J.,Eds.; Wiley-VCH,New York,
1998; Chapter 2,
9,J,Hassan,,M,Se′vignon; C,Gozzi; E,Schulz; and M,
Lemaire Chem,Rev,2002,102,1359-1469
Boronic Acids,New Coupling Partners in Room-
Temperature Suzuki Reactions of Alkyl Bromides,
Crystallographic Characterization of an Oxidative-
Addition Adduct Generated under Remarkably
Mild Conditions
Jan H,Kirchhoff,Matthew R,Netherton,Ivory D,Hills,1 and Gregory C,Fu*
Department of Chemistry,Massachusetts Institute of Technology,
Cambridge,Massachusetts 02139
J,Am,Chem,Soc,2002,124,13662-13663
Table 1,Suzuki Cross-Coupling of n-OctBr with PhB(OH)2 (5% Pd(OAc)2,
10% ligand,rt),Effect of Additive,Solvent,and Ligand
n - B u B r + P h B ( O H ) 2 n - B u - P h
Table 2,Pd/P( t-Bu)2Me-Catalyzed Suzuki Cross-Couplings of
Alkyl Bromides with Boronic Acids
Mechanism
Di-2-pyridylmethylamine-Based
Palladium Complexes as New
Catalysts for Heck,Suzuki,and
Sonogashira Reactions in Organic
and Aqueous Solvents
Table 1,Heck Coupling Reactions Catalyzed by 4
Table 2,Suzuki Coupling Reactions Catalyzed by Complex 4b
Table 3,Sonogashira Coupling Reactions Catalyzed by 4b
The Palladium-Catalyzed Addition of
Organoboronic Acids to Alkynes**
Chang Ho Oh,* Hyung Hoon Jung,Ki Seong Kim,and Nakjoong Kim
Angew,Chem,Int,Ed,2003,42,805-808
Table 1,Pd-catalyzed hydroalkylation of alkynes 1 with organoboronic acids 2
Suzuki Cross-Couplings of Unactivated
Secondary Alkyl Bromides and Iodides
Jianrong (Steve) Zhou and Gregory C,Fu*
Contribution from the Department of Chemistry,
Massachusetts Institute of Technology,
J,AM,CHEM,SOC,2004,126,1340-1341
BP
In this communication,we report the first method for achieving
Suzuki cross-couplings of unactivated secondary alkyl halides
Transition-Metal-Free Suzuki-Type Coupling Reactions
Nicholas E,Leadbeater* and Maria Marco
Angew,Chem,Int,Ed,2003,42,1407
? CO插入反应
C C
C
2
H
5
H
C
2
H
5
I
C C
C
2
H
5
H
C
2
H
5
C O O C
4
H
9
+ C O
Pd I 2 ( P P h 3 ) 2
n - B u O H
C C
C H
3
I
H
C H
O H
C H
3
O
C H
3
O
C H
3
99%
P d ( P P h 3 ) 2 Cl 2
CO
5.8 有机镍化合物
? ?3-烯丙基镍络合物的制备
B r
N i
B r
N i RR
+ 2 N i ( C O ) 42 C H 2 = C H C H 2 B r
B r
N i
B r
N i
R = H,C H 3,C O 2 C 2 H 5,e t c,
? ?3-烯丙基镍络合物偶联反应
B r
N iR2 R ' X +
2
C H 22 R ' C C H 2
R
R’ R 收率
4-羟基环己基 CH3 88%
C6H5 CH3 98%
B r N i
B r
2
O A c
B r
B r
t￡ ?
O
C l
O O O
[ N i ( P P h 3 ) 2 C O D ]
N
B r
[ N i C l L 2 ] / M e M g B r
M e
N
M e
O
C H 2 B r
C H 2 B r
O
N i ( C O ) 4
O
O
1,5-cyclo-
octadiene
N C B r2 N C C N
N i ( C O D ) 2
C
O
R
O H
+ R ' M g X
N i C l2 ( d p p e )
R R '
O
d p p e = P h 2 P C H 2 C H 2 P P h 2
? 镍络合物催化格氏试剂的反应
60-75%
E,Wenkert,et,al.,J,Chem,Soc.,Chem,Commun.,617(1984)
O P h
C l 2 N i
P
P
E t
y i e l d 8 5 %
e, e, % 9 7, 7 %
+ E t M g B r
*
* *
G,Consiglio,et,al.,J,Chem,Soc.,Chem,Commun.,112(1983)
5.9 有机钛试剂
5.9.1 两类重要钛试剂
R ' T i ( O R )3试剂 A
T i ( O R ) 4 + T i C l 4 T i ( O R ) 3 C l + T i ( O R ) C l 3
T i ( O R ) 3 C l + R ' M g C l R ' T i ( O R ) 3 + M g C l 2
试剂 B (Tebbe’s Reagent)
Cp 2 T iC l 2 + A l( C H 3 ) 3 C p
2 T i A l( C H 3 ) 2
C l
F,N,Tebbe,G,W,Parshall and G,S,Reddy,J,Amer,Chem,Soc.,
100,3611(1978)
Cp2Ti=CH2
5.9.2 试剂 A的反应
C O O E t
O
C O O E t
O H
1, M e T i ( O R ) 3
2, H +
R e a g e n t s
M e L i 6 5 % 3 5 %
M e M g B r 6 6 % 3 4 %
M e T i ( O P r - i ) 3 8 8 % 1 2 %
M e T i ( O P h ) 3 9 3 % 7 %
H
P h
C H 3
O H
C H 3H
H
P h
C H 3
O H
C H 3
H
2, H +
1, M e T i X 3H
C H OP h
C H 3
C H O
O H
R
*
R T ( O R * )
3
,R = M e,O R * = O
O
T i
R ' O
R
O
O
R = M e,R ' = E t
R = M e,R ' = P r - i
R = C
6
H
5
,R ' = P r - i
e, e, %
8
1 2
2 3
2 8
5 9
8 8
与格氏试剂相比
的两个优点,
1）当与醛, 酮羰
基反应时, 酯基,
氰基, 环氧基,
卤原子不受影响；
2）与醛加成时有
高立体选择性。
5.9.3 试剂 B (Tebbe's 试剂 ) 的反应
C p
2
T i
C l
A i M e
2
O
R
X
O
C p
2
T i
R
X
+
R
X
+ ( C p
2
T i O ) n
R
O T i C l C p
2
R
O
H
+
X = H,R,O R,N R
2
X = C l,O
2
C R
Tebbe 试剂与 Wittig
试剂相比的优点,
1）对位阻较大的羰
基仍能反应；
2）可与酯反应生成
醚，与酰胺反应生
成烯胺，与酰卤或
酸酐反应生成甲基
酮。
P h O E t
O
O
P h O E t
C p 2 T i = C H 2 9 7 %
R
O T i C l C p2
R
O
H +
R C l
O
C p 2 T i = C H 2
R = E t,t - B u -,n - C1 0 H 2 1,C 6 H 5 C H 2,m - M e O P h -,e t, a l,
3 7 - 9 7 %
J,Am,Chem,
Soc,102,3271
(1980)
J,Am,Chem,
Soc,105,1664
(1983)
R O E t
O
C p 2 T i = C H 2
8 2 %
R O E t
R = M e
9 6 %R = P h
Related Books
1,Rod,Bates,Organic Synthesis Using Transition
Metals,Sheffield Academic Press,2000
2,陆熙炎，杜灿屏,金属有机化合物的化学反应，
化学工业出版社,2000
3,黄耀曾，钱长涛等，金属有机化合物在有机合成
中的应用，上海科学技术出版社,1990
Chapter 6
Diels-Alder Reaction and
Development
Discovery
? Wieland ( Ber,1906,39,1492) described the 1:1 dimerization
of conjugated dienes in what was probably the first report of a
Diels–Alder reaction,
?Albrecht (Thiele) Reaction,Ann,1906,348,31,
? Staudinger Structure,
Die Ketene,Stuttgart
1912,59,
? Diels and Alder
Ann,1928,460,98,
? In fact,von Euler had correctly,but tentatively,identified the 2:1
adduct of isoprene with p-benzoquinone before Diels and Alder's
work,von Euler,Josephson Ber,1920,53,822,
Diastereoselectivity
a,cis Principle,
? Geometry of dienophile and diene are maintained in
the [4 + 2] cycloadduct,
e.g,
b,Alder's Endo Rule,
Stereoselective
Endo product and endo transition state predominate even though exo products
are usually more stable; endo is the kinetic product,
Result,Both cis rule and endo rule
Diels–Alder reaction very useful,diastereoselective
c,Factors influencing endo selectivity of the Diels–Alder reaction
? Endo transition state is favored by stabilizing secondary
orbital interactions,
? Endo selectivity often increases with the use of Lewis acid
catalysis,
? Endo selectivity often increases with increase in pressure of
reaction,
? Endo selectivity also increases with decreases in temperature
at which the reaction is conducted,
J,AM,CHEM,SOC,2002,124(1),11
Enantioselective Rare-Earth Catalyzed
Quinone Diels-Alder Reactions
David A,Evans* and Jimmy Wu
Department of Chemistry and Chemical Biology,HarVard
UniVersity,Cambridge,Massachusetts 02138
J,AM,CHEM,SOC,2003,125,10162-10163
Hydroxyapatite-Bound Cationic Ruthenium
Complexes as Novel Heterogeneous Lewis Acid
Catalysts for Diels-Alder and Aldol Reactions
Kohsuke Mori,Takayoshi Hara,Tomoo Mizugaki,Kohki Ebitani,
and Kiyotomi Kaneda*
Department of Chemical Science and Engineering,Graduate
School of Engineering Science,Osaka UniVersity,
1-3 Machikaneyama,Toyonaka,Osaka 560-8531,Japan
J,AM,CHEM,SOC,2003,125,11460-11461
Figure 1,Proposed structures of (A) RuHAP,(B) cationic RuHAP-(I) and
(II) (I,X = SbF6; II,X = OTf),and (C) Ru-enolate intermediate (X =
OTf),
Table 1,RuHAP-(I)-Catalyzed Diels-Alder Reaction
Table 2,RuHAP-(II)-Catalyzed Aldol Reaction Using Nitriles
N
H
N
O M e
M e
M e
P h
X R O
R
C H O
X
A
D a v i d,W, C, M a c M i l l a n,J, A m, C h e m, S o c, 2 0 0 0,1 2 2 ( 1 7 ),4 2 4 3 - 4 2 4 4
+
2 0 m o l % A - H C l
2 3
o
C
y i l e d, 7 2 - 9 0 % ;
% e e, 8 3 - 9 6 %
Small Organic Molecular Enantioselective Catalysts
M e
O
+
E t
2 0 m o l %
H
2
O,0
o
C
N
H
N
O M e
R
3
R
2
R
1 H C l O
4
E t
O
M e
T h e b e s t c a t a l y s t 5, y i e l d, 8 9 % ; e n d o, e x o = 2 5, 1 ; % e e = 9 0
c a t a l y s t A, y i e l d 2 0 % ; e n d o, e x o = 7, 1 ; % e e = 0
R
1
= B n,R
2
= 5 - M e - f u r y l,R
3
= HC a t a l y s t 5,
X
R
O
X
C O R '
R
+
2 0 m o l % A - H C l
R '
I s O K?
R
1
O
+
R
2
2 0 m o l %
H
2
O,0
o
C R
2
O
R
1
C a t, 5
2 0 m o l % H C l O
4
+
2 0 m o l %
E t O H,- 3 0
o
C
C a t, 5
2 0 m o l % H C l O
4
C O E t
X
X
O
E t
y i e l d s, 7 8 - 9 0 % ; e n d o, e x o > 1 0 0, 1 ; % e e = 8 5 - 9 8
J o e l F, A u s t i n a n d D a v i d W, C, M a c M i l l a n *,J, A m, C h e m, S o c, 2 0 0 2,1 2 4 ( 1 1 ),2 4 5 8 - 2 4 3 0
Tandem Diels-Alder Cycloadditions in
Organic Synthesis
Jeffrey D,Winkler
Department of Chemistry,The University of
Pennsylvania,Philadelphia,Pennsylvania 19104
Chem,Rev,1996,96,167-176
Reactions of Bicyclic Bis-Dienes
Visnick,M.; Battiste,M,J,Chem,Soc.,Chem,Commun,1985,1621,
Acetylenic Bis-Dienophiles
Goldberg,D.; Hansen,J.; Giguere,R,Tetrahedron Lett,1993,8003,
Nahm,S.; Weinreb,S,Tetrahedron Lett,1981,3815,
Exocyclic Bis-Dienes
Hosomi,A.; Masunari,T.; Tominaga,Y.; Yanagi,T.; Hojo,M,
Tetrahedron Lett,1990,6201,
Masked Bis-Dienes
Bluestone,H.; Bimber,R.; Berkey,R.; Mandel Z,
J,Org,Chem,1961,26,346,
Swarbrick,T.; Marko,I,Kennard,L,Tetrahedron Lett,1991,2549,
Marko,I.; Seres,P.; Swarbrick,T.; Staton,I.; Adams,H,
Tetrahedron Lett,1992,5649,
Reddy,G.; Bhatt,M,Tetrahedron Lett,1980,3627,
Chapter 7
Oxidation Reactions
氧化反应的概念
碳原子周围电子云密度的降低，即碳原子氧
化数 (氧化态，氧化值 )升高的反应。
广义的概念
狭义的概念
加氧反应和 /或脱氢反应。
氧化反应的分类
1,碳原子上的氢被吸电子的基团或原子取代
C H
2
R C O
2
H
N O
2
H N O
3
R C H
3
C l
2
R C H
2
C l
2,碳碳相联接转变成与吸电子基团或原子相联接
O
O H
O H
2 H C H O
B r
B r
3,脱氢
P h
+ 2 H 2
P h + 2 H 2
4,功能团的氧化
R C H 2 O H R C H O R C O 2 H
C 6 H 5 N O C 6 H 5 N O 2
? 选择性高
? 反应条件温和
? 环境友好
? 原料便宜易得
理想的氧化反应
? Epoxidation reactions,
--------- Oxidation of Carbon-Carbon Double Bonds
Comprehensive Org,Syn.,Vol,1,819; Vol,7,357,390,
R O O H
O
+ C C R O H
O
+
O
Peracid Oxidation
1,Peracid Reactivity,
The lower the pKa,the greater the reactivity
(i.e.,the better the leaving group)
R a t e i n c r e a s e s, R = C H 3 < C 6 H 5 < m - C l C 6 H 4 < H < p - O 2 N C 6 H 4 < < C F 3
C O 2 H
p K a o f a c i d ( R C O 2 H ), 4, 8 4, 2 3, 9 3, 8 3, 4 2, 9 0
2,Mechanism,
R
R
R
R
O
O O
C R 1
O
H
R
R
R
R
R
R
R
R
O O HR 1 C
O
过氧酸对双键发生亲电进攻，形成环氧化合物。
3,Stereochemistry,
R R
m - C P B A
R R
O
R R
O
+
R = H 2 0 m i n, 2 5
o
C 9 9 % 1 %
R = C H 3 2 4 h,2 5
o
C,< 1 0 % 9 0 %
a,Stereochemistry of olefin is maintained,diastereospecific,
b,Reaction rate is insensitive to solvent polarity concerted
mechanism without intermediacy of ionic intermediates,
c,Less hindered face of olefin is epoxidized,
R O R E W G
> >
4,Chemoselectivity,
>>> > >
--Electrophilic reagent,most nucleophilic C=C reacts fastest,
--Examples,
m - C P B A
- 1 0
o
C,1 h
O
c i s, t r a n s 1, 1
C 6 H 5 C O 3 H
C H C l 3,1 0 m i n, 0 o C, O
C
6
H
5
C O
3
H
H O 2 C
O H
O
H
H
C
6
H
6
- d i o x a n e
2 5
o
C,2 4 h
H O 2 C
O H
O
H
H
O
8 0 %
C O 2 H
H
H
O
H
O H
C o n c a v e f a c e
h i n d e r e d t o w a r d
p e r a c i d a t t a c k
C o n v e x f a c e
o p e n t o p e r a c i d
a t t a c k
5,Diastereoselectivity
? Endocyclic Olefins
H
M e
H
M e
()
D e s t a b i l i z i n g s t e r i c i n t e r a c t i o n
b e t w e e n r e a g e n t a n d a x i a l M e
A t t a c k p r i n c i p a l l y
f r o m t h i s f a c e
? Exocyclic Olefins
M e
M e
M e
()
m o r e h i n d e r e d f a c e
l e s s h i n d e r e d f a c e
R C O 3 H
M e
M e
M e
O
M e
M e
M e
O
+
l e s s s t a b l e p r o d u c t
- - S o l v e n t d e p e n d e n t C C l 4 7 5 % 2 5 %
C 6 H 6 8 0 % 2 0 %
C H 2 C l 2 o r C H C l 3 8 3 % 1 7 %
Henbest,J,Chem,Soc.,Chem,Commun.,1967,1085,
----The effective size of the reagent increases with increasing
solvent polarity,i.e,the solvation shell of the reagent increases
in size
H
H
H
H
H
R C O 3 H
H
H
H
H
H
O H
H
H
H
H
O
+
4 1, 5 9
---Small reagent preference,axial attack and 1,3-diaxial
interactions vary with size of the reagent,
---Large reagent preference,equatorial attack and 1,2-
interactions (torsional strain) are relatively invariant with the
size of the reagent,
Carlson,J,Org,Chem.,1967,32,1363,
? Allylic Alcohols (endocyclic)
O R
m - C P B A
O R
O
O R
O
+
R = C O C H 3 2 0
o
C C 6 H 6 4 3 % 5 7 % 3 8 % y i e l d
R = H 5
o
C C 6 H 6 9 % 9 1 % 8 6 % y i e l d
Henbest J,Chem,Soc.,1957,1958; Proc.Chem,Soc,1963,159,
O H
B u
- t
m - C P B A
O H
O
B u
- t
O H
O
B u
- t
+
P r e f e r s e q u a t o r i a l p o s i t i o n,
l o c k o i n g c o n f o r m a t i o n o f s u b s t r a t e,
4 % 9 6 %
R
O
H
R
O
O
H
O
1 2 0
o
---Metal-catalyzed epoxidations of allylic alcohols
Sharpless Aldrichimica Acta 1979,12,63,
? Allylic Alcohols (exocyclic)
Vedejs and Dent.,J.Am.Chem,Soc.,1989,111,6861,
? Acyclic Allylic Alcohols
Generalizations,
Eclipsed Conformations in m-CPBA Epoxidation
Bisected Conformations in Metal-Catalyzed Epoxidation
R
1
O H
t h r e o e r y t h r o
m - C P B A 6 0 4 0
V O ( a c a c )
2
,
t -
B u O O H 2 0 8 0
H O
R
1
H
H
H
H
t h r e o
H v s, a l k y l e c l i p s i n g
i n t e r a c t i o n w i t h d o u b l e
b o n d h a s l i t t l e t o n o e f f e c t
o n s e l e c t i v i t y, H e c l i p s i n g
i n t e r a c t i o n s l i g h t l y m o r e
s t a b l e,
R
1
= M e
R
1
=
i -
P r
m - C P B A 6 1 3 9
V O ( a c a c )
2
,
t -
B u O O H 2 0 8 0
R
1
= E t
m - C P B A 5 8 4 2
V O ( a c a c )
2
,
t -
B u O O H 1 5 8 5
H
H
H
e r y t h r o
O M e t
R
1
H
H,H e c l i p s i n g i n
e r y t h r o T, s, f a v o r e d
o v e r H,a l k y l e c l i p s i n g
i n t h r e o T, S,
Examples,
R
1
O H
R
2
t h r e o e r y t h r o
m - C P B A 4 5 5 5
V O ( a c a c ) 2,
t -
B u O O H 5 9 5 H O
H
M e
M e
H
H
e r y t h r o
R
1
,R
2
= M e
R
1
= M e
m - C P B A 4 1 5 9
V O ( a c a c ) 2,
t -
B u O O H 2 9 8
B u
H
H
e r y t h r o
O M e t
M e
H
H,B u e c l i p s i n g i n
e r y t h r o T, s, f a v o r e d
o v e r M e,B u e c l i p s i n g
i n t h r e o T, S,
E r y t h r o s l i g h t l y f a v o r e d
d u e t o M e,M e g a u c h e
i n t e r a c t i o n i n t h r e o T, S,
R
2
=
n -
B u
(continued)
(continued)
? Homoallylic Alcohols (高烯丙系 )
--Alternative chair has two axial substituents,
--Intermolecular oxygen delivery occurs through most stable chair-like
transition state,
M e
O T B D P S
P h
M e
O H V O ( O n - P r ) 3
t - B u O O H
C H 2 C l 2,9 5 %
O
V
O
M e
O T B D P S
H
P h
M e
H
L
L O t - B u
M e
O T B D P S
P h
M e
O H O
M e
O T B D P S
P h
M e
O A c m - C P B A
C H 2 C l 2,2 5
o
C
9 4 %
M e
O T B P S
M e
H
P h
O A c ()
m i n o r
m a j o r
V S,
M e
O T B D P S
P h
M e
O A c O
5, 1
--H-Eclipsed conformation,
--Epoxidation from least hindered face;
--Not a directed epoxidation!
--Diadtereoselectivity still good and through H-eclipsed conformation,
(continued)
Schreibe,Tetrahedron Lett,1990,31,31
Hanessian,J,Am Chem Soc,1990,112,5276,
? Other Directed Epoxidations
-- Studies suggest axial –NHCBZ delivers syn epoxide while equatorial
does not,
R
N H C B Z
m - C P B A
C H 2 C l 2,2 5
o
C
R
N H C B Z
O
+
R
N H C B Z
O
R = N H C B Z 8 6 % 1 0 0 0
= C H 2 O H 8 3 % 1 0 0 0
= C H 2 O A c 7 2 % 1 0 0 0
= C O 2 M e 5 9 % 1 0 0 0
= C H 2 O T B D P S 5 4 % 0 0
Mohamadi Tetrahedron Lett,1989,30,1309,
6,Scope and Limitations
P e r a c i d + O
a,Olefin geometry is maintained,
b,Reaction is diastereospecific,the stereochemistry of the
reactant and product bear a definite relationship to one another,
c,Reaction can be buffered to prevent epoxide opening,
d,At higher temperatures,a free radical scavenger may be used
to avoid peracid decomposition,
e,Common Side Reactions,
? Baeyer-Villiger Reactions of Ketones (and aldehydes)
O
m - C P B A
O
O
n o t
OO
? Oxidation of amines
m - C P B AN + N O -
--Nitrogen must be protected (e.g,as amide) or another reagent
selected,
? Imine oxidation
m - C P B AN
R
N
R
O
? Sulfur oxidation
m - C P B AR
S
R R S
O
R R
S
O O
R
+
7,Epoxidation of Electron-Deficient Olefins
a,?,?-unsaturated esters,can choose a strong peracid or vigorous
reaction conditions,
b,?,?-unsaturated ketone,Baeyer-Villiger competes with epoxidation
M e
C O 2 C H 3
C F 3 C O 3 H
N a 2 H P O 4
C H 2 C l 2,r e f l u x
M e
C O 2 C H 3O 8 4 %
Emmons,J,Am.Chem.Soc.,
1955,77,89,
C O 2 C H 3
P h
N a 2 H P O 4
C H 2 C l 2,r e f l u x
C O 2 C H 3O
P h
4 7 %m - C P B A
MacPeek,J,Am,Chem,Soc,
1959,81,680,
R R 1
O
E p i o x i d a t i o n B a e y e r - V i l l i g e r R e a c t i o n
Solution,different conditions (reagents) are neede,
? Additional Methods for Epoxidation of Olefins
1,H2O2,NaOH
O
H 2 O 2,N a O H
O -
O O
H
O
O 7 0 %
H 2 O 2,N a O H
M e M e
C O 2 C H 3
O
M e M e
C O 2 C H 3H
H 2 O 2,N a O H
M e
M e
C O 2 C H 3
--The following reaction is diastereoselective (not diastereospecific)
M e M e
C O 2 C H 3
M e
M e
C O 2 C H 3
O -
O C H 3
M e
H
M e
O
OH
The reaction occurs via a reversible process,
Similarly,
tBuOOH/Triton B Payne J,Org,Chem.,1961,26,651,
Ph3COOH/R4NOH Corey J,Am,Chem,Soc,1988,110,649,
tBuOOH/nBuLi Cegg Tetrahedron,1988,29,48889,
2,Peroxyimidate
R C N H 2 O 2
R
N H
O
O
H
O + R N H
O
--This reagent permits the use of neutral reaction conditions,
Unlike m-CPBA,the reagent behaves as a large reagent and thus
aproaches from the equatorial face of an exocyclic double bond,
H
H
H
H
()
()
m - C P B A
s m a l l r e a g e n t,b u t t h e i n t e r a c t i o n
w i l l i n c r e a s e w i t h s i z e o f t h e r e a g e n t
P h C N / H 2 O 2
l a r g e r e a g e n t,b u t t h e i n t e r a c t i o n w i l l
n o t v a r y w i t h s i z e,p r e d o m i n a t e l y
e q u a t o r i a l a t t a c k,
C a r l s o n,J, O r g, C h e m,,1 9 6 7,
3 2,1 3 6 3, ( m - C P B A & P h C N / H 2 O 2 )
V e d e j s,J, A m, C h e m, S o c,,
1 9 8 9,1 1 1,6 8 6 1, ( m - C P B A )
--Analogous Reagent,
P h N = C = O
+
H 2 O 2
P h
N O O
HO
H
C h r i s t l A n g e w, C h e m,,I n t, E d, E n g,,
1 9 8 0,1 9,4 5 8,
3,Sulfur Ylides
O
B u
- t
B u
- t
O
B u
- t
OO -
B u
- t
H
H
S
+
()
O
- B u
- t
S
+
H
H()
1 3 %
8 7 %
E q u a t o r i a l D e l i v e r y
1,2 - i n t e r a c t i o n d i s f a v o r e d
A x i a l D e l i v e r y
1,3 - i n t e r a c t i o n f a v o r e d o v e r 1,2
--This is the result of kinetic control,reaction gives the
thermodynamically less stable epoxide product,
Corey,Chaykovsky,J,Am,Chem,Soc.,1965,87,1353,
B u
- t
O
O
-
B u
- t
H
HS +
O
-
O
B u
- t
S
+ H
H
O
()
1 0 0 %
O
B u
- t
-
O
B u
- t
S
+
H
H
a x i a l a t t a c k
p r e d o m i n a n t
e q u a t o r i a l
a t t a c k
r a p i d l y g o e s
o n t o p r o d u c t
f a i l s t o g o o n
t o p r o d u c t
b a c k s i d e a t t a c k n o t p o s s i b l e d u e
t o d e s t a b i l i z i n g 1,3 - i n t e r a c t i o n s
Initial reaction is reversible and is not capable of generating the
axial delivery product because of the destabilizing 1,3- interactions
in the transition state required for epoxide closure,
O
B u - t
M e
S +
M e
C H 2 -
O
+
7 7 %
M e
S +
M e
M e I -
O
D i m e t h o x o s u l f o n i u m m e t h y l i d e
S m a l l r e a g e n t t h a t p r e f e r s a x i a l d e l i v e r y
B u - t
O
B u - t
O
0 1 0 0
M e
S +
M e
C H 2 -
O
N a H,T H F
r e f l u x
t h e r m o d y n a m i c
p r o d u c t
Summary of Exocyclic Epoxide Formation
X
O
O
o r
X = O S
X = C H
2
m - C P B A
a x i a l
a t t a c k
X
X
X = O S
+
O
C H
2
-
X = C H
2
e q u a t o r i a l
a t t a c k
R O
O
H
N H
X
X
S u l f u r y l i e d e s d e l i v e r " C H
2
"
P e r a c i d e s d e l i v e r " O "
4,Dimethyl Dioxirane (DMDO)
Murray J.Am,Chem Soc,1986,108,2470,Acc.Chem,Res.,1989,22,205
O O
D M D O
a c e t o n e,9 6 %
O O
O
A d a m T e t r a h a d r o n L e t t,,1 9 8 9,3 0,4 2 2 3,
O
O
O
C F
3
C F
3
O
O
C u r c i T e t r a h e d r o n L e t t,,1 9 8 9,3 0,2 5 7
O
B o y d T e t r a h e d r o n L e t t,,1 9 8 9,3 0,1 2 3,
A mild neutral reagent
.
O
O
C r a n d a l l J, O r g, C h e m, S o c,,1 9 8 9,1 1 1,6 6 6 1,
T e t r a h e d r o n L e t t,,1 9 8 8,2 9,4 7 9 1,
O
B n O
B n O
O B n
O
B n O
B n O
O B n
O
D n i s h e f s k y J, A m, C h e m, S o c,,1 9 8 9,1 1 1,6 6 6 1,
R
3
S i O
O
R
3
S i O
O S i R
3
O
S t a b l e a n d c h a r a c t e r i z a b l e
D a n i s h e f s k y,J, O r g, C h e m,1 9 8 9,5 4,4 2 4 9,
5,Summary of Other Methods of Epoxide Formation
a,Cyclization of Halohydrins
+ X 2 + H 2 O
H O
X
O
t -
B u
N X S / H
2
O O H
t -
B u
C H
2
X
+
O H
t -
B u
C H
2
X t -
B u
O
t -
B u
O
+
t -
B u
+
X
t -
B u
X
+
a x i a l
e q u a t o r i a l
H
2
O H
2
O
N C S - H
2
O 9 0, 1 0 9 0, 1 0
N B S - H
2
O 8 2, 1 8
N I S - H
2
O 5 5, 4 5
I n c r e a s e d r e a g e n t s i z e y i e l d s i n c r e a s e d e q u a t o r i a l a p p r o a c h
T h e e l e c t r o p h i l i c r e a g e n t s b e h a v e a s s m a l l r e a g e n t s a n d a p p r o a c h
f r o m t h e a x i a l d i r e c t i o n
v s
3 1, 6 9
F o r m - C P B A
c o m p l e m e n t a r y
s t e r e o c h e m i s t r y
m a j o r m i n o r
b,Cyclization of 1,2-diols
R
O H
O H
T s C l
R
O T s
O H O
R
- - P r i m a r y a l c o h o l > s e c o n d a r y a l c o h o l f o r t o s y l a t i o n r e a c t o n
c,Epoxides from Carbonyl compounds
1 ), O + L i R
R
1
C l
O
R
R
1
2 ), O
+ S C H 2
O
O + S C H
2
O
O
3 ), O
R
H
+ C l
X
O
O
R
X
O
ON
O
R
R = O R,
D a r z e n ' s C o n d e n s a t i o n
Generalized by Darzen through years 1904~1937,
Asymmetric variants / Evans Chiral Oxazolidinone
Lantos J,Am,Chem,Soc.,1986,108,4595,
? Catalytic Asymmetric Epoxidation
1,Sharpless Catalytic Asymmetric Epoxidation
(AE Reaction)
Key reference,Asymmetric Synthesis,Vol,5,Morrison J,D,Ed,
Chapter 7 and 8
Reviews,Katsuki,Martin Org,React.,1996,48,1,
Comprehensive Org,Syn.,Vol,7,389~436,
Sharpless J,Am.Chem,Soc.,1980,102,5974; 1981,103,6237;
1984,106,6430; 1987,109,1279,5765;
1991,113,106,113; 1987,109,1279
(1) The enantiofacial selectivity of the reaction is general and
dependable for assignments,
R
2
R
1
R
3
O H
( S,S ) - D - ( - ) - t a r t r a t e
( R,R ) - L - ( + ) - t a r t r a t e
t -
B u O O H,T i ( O
i
P r )
4
C H
2
C l
2
,- 2 0
o
C
D E T o r D I P T
O
R
3
R
2
R
1
O H
4 A m o l e c u l a r s i e v e s a n h y d r o u s
" O " 非天然
" O " 天然
7 0 ~ 9 0 %
> 9 0 % e, e,
(2),Selectivity is catalyst depent,
Ti(OiPr)4 95% e.e,Zr(OiPr)4 10% e.e,
Al(OtBu)3 5% e.e,Hf(OiPr)4 3% e.e,
MoO2(acac)2 15% e.e,Nb(OEt)3 5% e.e,
VO(OiPr)3 17% e.e,Ta(OiPr)5 39% e.e,
Sn(OiPr)4 NR
(3),Sharpless Asymmetric Epoxidiation H O O H
R O 2 C C O 2 R
C
2
s y m m e t r y
O
T i O
T i
O
R O
R O
O
E
R O
O
t -
B u
O
E
E
O
O
H
H
R '
E = C O 2 R
--Match of Ti/Tartrate such that a single complex dominates the chemistry,
--Ligand acceleration of reaction,
--Steric and stereoelectronic feactures of reaction control enantioselectivity
the best known and practical asymmetric reaction
Scope
R 2 R 1
R 3 O H
Epoxidation with Titanium-Tartrate Catalysts
U n s u b s t i t u t e d ( R
1
= R
2
= R
3
= H ) 9 5 % 1 5 %
t r a n s - d i s u b s t i t u t e d ( R
1
= R
3
= H ) R
2
= C H
3
> 9 5 % 4 5 %
R
2
= n - C
1 0
H
2 1
> 9 5 % 7 9 %
R
2
= ( C H
3
)
2
C H = C H
2
> 9 5 % 8 0 %
R
2
= M e
3
S i > 9 5 % 6 0 %
R
2
=
t -
B u > 9 5 %
R
2
= A r ~ 9 5 % 0 ~ 9 0 %
R
2
= C H
2
O B n 9 8 % 8 5 %
R
2
= > 9 5 % 7 8 ~ 8 5 %
e, e, y i e l d
R
2
= > 9 5 % 7 0 %
R
2
= > 9 9 % 7 6 %
R
2
= > 9 9 % 7 0 %
R
2
= > 9 3 % 7 0 ~ 8 8 %
O
O
O
O
B n O
B n O
O
B n O
O
O
OP h
O S i E t
3
B n O
R
(continued) R 2 R 1
R 3
O H
e, e, y i e l d
C i s - d i s u b s t i t u t e d ( R
2
= R
3
= H ) R
1
= n - C 1 0 H 2 1 9 0 % 8 2 %
R
1
= C H 2 P h 9 1 % 8 3 %
R
1
= C H 2 O P h 9 6 % 8 4 %
R
1
= 9 6 % 5 5 %
O
O
1,1 - d i s u b s t i t u t e d ( R
1
= R
2
= H ) R
3
= - C y c l o h e x y l > 9 5 % 8 2 %
R
3
= n - C 1 4 H 2 9 > 9 5 % 5 1 %
R
3
=
t -
B u 8 5 %
(continued)
R 2 R
1
R 3
O H
e, e, y i e l d
t r a n s - 1,1,2 - t r i s u b s t i t u t e d ( R
1
= H ) R
3
= R
2
= P h > 9 5 % 8 1 %
R
3
= M e,R
2
= E t > 9 5 % 7 9 %
R
3
= M e,R
2
= > 9 5 % 7 0 %
R
3
= M e,R
2
= > 9 5 % 9 2 %
A c O
O
O
C i s - 1,1,2 - t r i s u b s t i t u t e d ( R
2
= H ) R
3
= C H
3
,R
1
= B n 9 1 % 9 0 %
1,2,2 - t r i s u b s t i t u t e d ( R
3
= H ) R
2
= ( C H
2
)
2
C H = C ( C H
3
)
2
,R
1
= C H
3
> 9 5 % 7 7 %
R
2
= C H
3
,R
1
= ( C H
2
)
2
C H = C ( C H
3
)
2
9 4 % 7 9 %
t e t r a s u b s t i t u t e d R
3
= C H
3
,R
2
= P h,R
1
= B n 9 4 % 9 0 %
O H 9 4 % 9 0 %
(4),Kinetic Resolution,Sharpless,J,Am.Chem.Soc.,1981,103,6237 Pure Appl,Chem.,1983,55,589,
-- Sharpless epoxidation product is different from the directed
oxidation of allylic alcohols by peracids (m-CPBA)
(5),Payne Rearrangement Payne J.Org,Chem.,1962,27,3819,
Base-catalyzed (NaOH,aq.) migration of ?,?-epoxy alcohol,
? In general,the more substituted epoxide is favored as the reaction product,
? However,steric factors and relative alcohol acidities (1° > 2° > 3° ) are additional
factors which determine the ultimate composition of the equilibrium mixture,
O
H C H 2 O H
R O H 2 C H R O H
2 C
O H
O
P h S H R O H
2 C
O H
O H
S P h
? The more reactive epoxide can be trapped by strong nucleophiles (e.g.,PhSH),
2,Jacobsen Epoxidation
--Unactivated alkenes
M n
N
O
N
O
B u - t
t - B u
C l
B u - tt - B u
H H
Jacobsens J,Am.Chem.,1991,113,7063,
Example,
Boger,Boyce Synlett 1997,515,
3,Chiral Dioxiranes
O
O D M D O
O
O
O
O
O
O
H
o x o n e
C H 3 C N
O
O
O
O
O
O
H
O
C h i r a l D i o x i r a n ec a t a l y t i c
a m o u n t s
Shi,J.Am,Chem Soc,1996,118,9806
J,Am.Chem,Soc.,1997,119,11224,
J,Org,Chem.,1997,62,2328,
P h
P h
S h i ' s C a t,
( p H 1 0,K
2
C O
3
)
O
H P h
P h
H
O T B S
C
3
H
7
S h i ' s C a t,
( p H 1 0,K
2
C O
3
)
O
H
C
3
H
7
H
O T B S
P h
S h i ' s C a t,
( p H 1 0,K
2
C O
3
)
P h
O
7 3 % y i e l d
> 9 5 % e e
8 0 % y i e l d
9 3 % e e,
6 9 % y i e l d
9 1 % e e,
--Examples of trans and trisubstituted olefins
---pH 10 (K2CO3,KHCO3) sppresses Baeyer-Villiger reaction of Ketone
precursor,
---C2 symmetric Chiral Ketone
Yang J,Am,Chem,Soc,1996,118,11311; 1998,120,5943,
(过硫酸氢钾制剂）
Polymer Supported
Poly Amino Acids
Itsuno J,Org,Chem,1990,55,6047,
Vega Angew,Chem.,Int,Ed,Eng,1980,19,929,
? Baeyer-Villiger and Related Reactions
Ref,Comprehensive Org,Syn.,Vol,7,671-688,
Org,React.,1957,9,73; 1993,43,251,
R
R 1
O R
2 O O H
O
R O
R 1
O
N a O H
R O H
O
+ R 1 O H
Baeyer,Villiger Ber.,1899,32,3625; 1900,33,858,
Baeyer,1905 Nobel Prize in Chemistry
R
R 1
O
R 2 O O H
O
R O
R 1
O
R
R 1
O -
O O R 2
O
+ R 2
O
O -
Mechanism,Peracid nucleophilic addition reaction
a,Alkyl group that migrates dose so with retention of configuration
b,The more electron-rich (most substituted) alkyl grou migration in
preference (in general),
t-alkyl>s-alkyl >benzyl>phenyl>n-alkyl>methyl
Mehtyl ketones invariably provide acetate,
--Examples,
O
P h C O 3 H
C H C l
3
,2 5
o
C
O
O
7 1 %
C H O
X
X = H
X = O C H 3
P h C O 3 H
X
O
O H
O
H
X
O
+
9 0 % 0 %
1 9 % 7 3 %
O
C H
3
C O
3
H
O
O
O
-
O
O
O
- - N u c l e o p h i l i c a t t a c k f r o m l e a s t h i n d e r e d
e x o f a c e
- - M o s t s u b s t i t u t e d ( e l e c t r o n - r i c h )
c a r b o n m i g r i t e s
2 h,2 5
o
C,8 8 %
m i g r a t i n g C - C b o n d a n d O - O b o n d
b e t r a n s - a n t i p e r i p l a n a r
O
H
O
O
R O
R m R
..
.,
O
C H
3
C O
3
H
OO
O
-
O
O
O
5 d,2 5
o
C,9 4 %
T r a n s - p e r i p l a n a r b o n d
? Benzylic Hydroperoxide Rearrangement
--Alternative to Baeyer-Villiger reaction
N
H
R O H
O
+
R L i
N a B H
4
W o u l d b e o x i d i z e d b y P e r a c i d
B F
3
,O E t
2
,H
2
O
2
N
+
H
R
O
B F
3
-
O
+
H
B F
3
-
N
H
O H
Boger,Coleman
J,Org.Chem.,1986,51,5436,
J,am.Chem.Soc.,1987,109,2717,
Tetrahedron Lett.,1987,28,1027,
Boger,Yohannes J,Org,Chem,1987,52,5283,
Urea-H2O2 a safe alternative to H2O2
H
2
N N H
2
O
H
2
O
2
O H
O H
OO
O H
O M e
O
O
O M e
O
O
O
O
O
O
O
O
6
O
6
P h
O
P h
O
O
O
S
S
O O
+
N
N
+
O
-
O
-
N
N
? Beckmann Rearrangement and Related reaction
----- An analogous reaarangement reaction can be utilized to
prepare lactam and amide
1,Beckmann Rearrangement
N
O
S
P h
O
O 1 2 h,0
o
C
H 2 O
N +
O
H H
N O
H
-- Prepared from the oxime,
--A wide range of leaving groups and catalysts have been
utilized,
Beckmann,Ber,1886,89,988,
a,Group anti to oxime leaving group migrates,
b,The alkyl group migrates with retention of configuration,
2,Curtius rearrangement Curtius Ber.,1890,23,3023,
R C O 2 H R
O
N 3 R N = C = O
H 2 O o r
R ' O H R N H 2 o r R
N O R '
O
H
--(PhO)2P(O)N3 (DPPA),
direcy conversion of carboxylic acids to acyl azides
--R group migrates with retention of configuration,
N C O 2 M eM e O 2 C
H O 2 C M e
B r
D P P A,E t 3 N
C 6 H 6,r e f l u x
7 2 %
N C O 2 M eM e O 2 C
H 2 N M e
B r
X
O B n
C O
2
H
D P P A,E t 3 N
t -
B u O H
X
O B n
N H B O C
3,Hofmann Rearrangement
R N H 2
O
R N
O
B r
H
R N -
O
B r O = C = N R
Hofmann,Ber,1881,14,2725
N
N C O N H 2
O M e
O T B S
N a O B r,C H 3 O H
- 4 0
o
C,t h e n 6 0
o
C
> 8 0 %
N
N N H C O 2 M e
O M e
O T B S
-- Reagent employed include basic hypohalides,
Pb(OAc)4,PhI(O2CCF3),PhIO
-- R group migrates with retention of configuration,
4,Schmidt Reaction
A,Conversion of Ketones to Amides
R R
O R
N
O H
N
H
R
N+ - H
2 O
R
N N
R
N
+
H 2 O
- H +
t a u t o m e r i z a t i o n R N
O
R
H
H N 3
P r o t i c o r
L e w i s A c i d
C a t a l y s t
--Most studies of Schmidt variants,similar to Beckmann rearrangement,
--Asymmetric Variant utilizes chiral alkyl azide donors which provide
products in high diastereoselectivity,
-- Bicycle ketone slightly favor migration of less substituted group,opposite
of beckmann,
-- Reactivity,dialkyl ketone >alkyl,aryl ketone>diaryl Ketone
>Carboxylic acid or alcohol
O
B n
C O
2
E t
N a N
3
,2, 5 e q u i v
M e S O
3
H,9 e q u i v,
C H C l
3
,r e f l u x,8 3 %
> 9 5 % e e
N H
O
B n
C O
2
E t
O
B u
-
t
+
O H N
3
B F
3
,O E t
2
N a H C O
3
,9 e q u i v,
P C C
N a H,T H F 5 7 %
N H
t
B u
O
B,Conversion of Carboxylic Acids to Amines
R O H
O
+ H N 3
H
+
C a t,
R N = C = O
H 2 O
R N H 2
R O H
O
H
+
R
O
+
+ H N 3 R N = N
+
= N
-
O
R
O
H
N N
+
N
R N = C = OR N H 2
-- Acid catalyst usually H2SO4,PPA,TFA-TFAA,or some Lewis acid,
--Good results when R=alkyl,hindered alkyl or aryl,
-- Advantage in process length over Hofmann and Curtis rearrangements,
but more drastic conditions,
C O 2 H
C O 2 H
M e
H
N a N 3,H 2 S O 4
C H C l 3,7 6 % N H
2
N H 2
M e
H
C,Conversion of Aldehydes to Nitriles
R H
O
+ H N 3 H
+ C a t, R N
N
O
B r
H
N a N
3
,S i C l
4
M e C N,5 0 %
N
N C
B r
H
M e O
H O
C H O
N a N
3
,H
2
S O
4
M e O
H O
C N
7 0 %
--Acid catalyst usually H2SO4,can be Lewis acid,
-- Schmidt reaction is the usual byproduct under these conditions to provide
formamide,
--More common method is to conversion aldehyde to oxime with
hydroxylamine,followed by dehydration
-- Aromatic aldehydes are good substrates,
5,Lossen Rearrangement
R 1 N O H
O
H
R
2
X R 1 N O R
2
O
H
B a s e
R 1 N O R
2
O
- - O R
2
R 1 N = C = O
H y d r o x a m i c A c i d
p r e o a r e d r e a d i l y f r o m
c a r b o x y l i c a c i d e s,
e s t e r o r a c y l h a l i d e s
- - R
2
X u s u a l l y A c C l,A r S O 2 C l,R P O 2 C l
- - r a t e o f r e a c t i o n p r o p o r t i o n a l t o t h e a c i d i t y o f l e a v i n g g r o u p c o n j u g a t e a c i d,
- - R
1
m i g r a t e s w i t h r e t e n t i o n o f c o n f i g u r a t i o n
F
F
O
-
H
3
N
+
O H
O
N H
O H
O
T s C l
N a O H,H
2
O
8 0 %
F
F
O H
O
N H
2
H
H
N
O
O
O S
O
O
N a O H,H
2
O
8 0 %
H
H
N H
2
O H
O
? Olefin Osmylation (Dihydroxylation)
First use,Criegee Justus Liebigs Ann,Chem,1936,522,75,
Milas J,Am,Chem,Soc,1936,58,1302,
Mechanism
Scope Comprehensive Org,Syn.,Vol,7,pp 437–448,
Chem,Rev,1980,80,187,
? OsO4 is an electrophilic reagent,and it behaves as a large reagent,
? Strained,unhindered olefins react faster than unstrained,sterically
hindered olefins,
? Electron-rich olefins react faster than electron-deficient olefins,
? Diastereospecific,with attack on the C=C from the least hindered face,
-Alternative reagents to OsO4,
- but OsO4 is expensive,volatile,and toxic
- various improvements,
KMnO4,Synthesis 1987,85,
Yields rarely as high as OsO4 but less hazardous and less
expensive especially for large scale
RuO4 or RuO2–2H2O/RuCl3–H2O + cooxidant
More vigorous than OsO4 and olefin cleavage is observed
Diastereoselectivity
a,Endocyclic Olefins
b,Acyclic Systems
- Also observed with allylic ethers
- Higher diastereoselectivity of Z vs,E isomer implies
eclipsed conformation important,
c,Exocyclic Olefins Vedejs J,Am,Chem,Soc,1989,111,6861
d,H-Bonding and Directed Dihydroxylation
Diol Stereochemistry Comparision
m-CPBA
OsO4
Via Bromohydrin
--Epoxidation on most hindered face of olefin(to gve different epoxide from
m-CPBA),
--trans diaxial ring opening (to give same hydrolysis product as from m-CPBA
oxidation)
Prevost
Neighboring Group
Participation
trans-diol
Woodward
J,Am,Chem,Soc,1958,80,209,
Compt,rend,1933,196,1128,
cis-diol
? Asymmetric Dihydroxylation reaction catalyst by
OsO4 and related Reagents
1,Catalytic Methods
R
R 1
R 2 R 2
R 1 R 1R
3
R 2
7 4 ~ 9 3 % e e 8 2 ~ 8 8 % e e 9 4 ~ 9 9 % e e 8 4 ~ 9 3 % e e
R 1
R 2
R 1
R 2
R 3
R 1
O
Good or excellent selectivity
Poor selectivity
H NN H
P h P h
C 2 - s y m m e t r y i n l i g a n d
Corey J,Am.Chem,Soc.,1987,109,6213,
? Shapless Catalytic Asymmetric Aminohydroxylation
(AA)
a,Sulfonamide variant
-?,?-unsaturated esters,
R S
O
O
N
N a
C l
-?,?-unsaturated amides,
reaction works well without a ligand,
b,Carbamate variant
-?,?-unsaturated esters,
R O
O
N
N a
C l
-Styrenes,
c,Amide variant
R
O
N H
B r
? Oxidation of Alcoholks
Chromium-based
Oxidation Reagents
Collins reagents,CrO3-py2,alkaline oxidant
Jones Reagents,CrO3 in aq,H2SO4/acetone
Pyridinium Chlorochromate (PCC)
H C l + C r O 3 + P y r, N
+
H
C r
O
O
C l
O -
.
Pyridinium Dichromate (PDC),
H 2 O + C r O 3 + P y r,
N +
H
.
2
C r 2 O 7 2 -
Manganese-based
Oxidation reagents
MnO2 Activated MnO2
KMnO4 / H2SO4
KMnO4 / t-BuOH-5% NaH2PO4 aq,buffer
R4NMNO4
Cu(MnO4)2-6H2O and Ba(MnO4)2
Other Oxidation Reagents
NaOCl / NaClO2
Ag2O / Ag2CO3
m-CPBA / NaIO4
Dess-Martin oxidation
I
O
O
A c O O A cO A c
I
O
O
H O O
I B X
p e r i o d i n a n e
Nitroxide
Openauer Oxidation,
Cl3CCHO,Al(OiPr)3
Chapter 8
Reduction Reactions
Introduction and Review
1,Conception and Classification
? 有机化合物中碳原子总的氧化态 (oxidation state)降低的反应,
Reduction
? 有机分子增加氢或 /和减少氧的反应,
分类
根据所采用
的方法分类
根据反应前后物质
结构的变动分类
催化氢化
氢负离子还原
溶解金属还原
氢解反应
加氢反应
2,Catalytic hydrogenation
2.1 Heterogenous hydrogenation
（非均相催化氢化 / 多相催化）
? 非均相催化
催化剂,Pt,Pd,Raney-Ni,Pt,Pd,
吸附在载体上, 如,C,CaCO3
特点：活性高, 根据底物不同, 可在常温, 常压下反应；
也可在高温, 高压下反应。
缺点：很贵, 含硫化合物会使其中毒失活
不同功能团氢化难易程度
Functional group Hydrogenation products
RCOCl RCHO
RNO2 RNH2
RCH=CHR (Z-)
RCHO RCH2OH
RCH=CHR RCH2CH2R
RCOR RCH(OH)R
ArCH2X ArCH3
RCH2NH2
RCO2R’ RCH2OH + R’OH
RCONHR’ RCH2NHR’
RC CR
RC N
R R
易
难
2.2 Homogenous hydrogenation (均相催化氢化 )
催化剂,Rh 或 Ru的络合物
常用,（ PPh3） 3RhCl (TTC)
（ PPh3） 3RuClH
优点
1) 均相反应, 溶解度好, 收率明显提高, 室温, 常压反应；
2）立体选择性高；
3）有硫化物存在不会中毒失活；
4）改变不同的配体, 可得到不同性能的催化剂, 前景广阔。
3,Metal hydride reduction
Metal hydride
亲核性氢负离子还原剂
LiAlH4
NaBH4
No,Metal hydride Solvent
1,LiAlH4 Ether,THF,diglyme
2,LiAlH[OC(CH3)3]2 THF,diglyme
3,NaAlH2(OCH2CH2OCH3)2 [RED-Al] Ben,Tol,Xylene
4,NaBH4 W,ethanol,diglyme
5,NaBH3(CN) W,methanol,DMSO
6,LiBH4 THF,diglyme
7,AlH3 Ether,THF
8,AlH[CH2CH(CH3)2]2 [DIBAL-H] Toluene,DME
Solvents for metal hydride reductions
Products of metal hydride reductions
R e d u c t i o n
R e d u c i n g a g e n t
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
1 2 3 4 5 6 7 8
R C H O R C H
2
O H V V V V V V V V
R C O R R C H ( O H ) R
V V V V V V V V
R C O C l R C H 2 O H
V a V V V V
L a c t o n e d i o l
V X V b X V V c
E p o x i d e a l c o h o l
V X V b X V V
R C O
2
R ' R C H
2
O H + R ' O H V d V b X V V a
R C O
2
H R C H
2
O H V X V X X V V a
R C O N R
2 R C H 2 N R 2 e X V X X X V X
R C N R C H
2
N H
2 V X X X X X V a
R N O
2 R N H 2 f X X X X X
R X R H
V X V X V X X
R C C R R C H = C H R ( Z ) V
a,Reduction proceeds to the aldehyde stage only; b,very slow reaction
c,Reducton proceeds to lactol stage only; d,phenyl esters give aldehydes,
e,Some amides are reduced to aldehydes; f,where R is aliphatic; if R is aromatic,
Azoarenes are formed; g,X= halogen or OSO2R’,
Boron regents
亲电性氢负离子还原剂 ----- 易还原羧基
-----hydroboration
Boranes
金属氢化物与 Lewis Acid 配合后，还原活性变化
3 N a B H 4 + 4 B F 3 2 B 2 H 6 + 3 N a B F 3
H 2 B
H
H
B H 2
O
+ 2 O B H 3
------易还原双键
C O O H C H
2
O H
C H C H C H
2
C H
2
C O C H O C H O H C H 2 O H
C N C H 2 N H 2
C
O
C C H C
O H
( C H
2
) n
C
C H
2
O
O
( C H
2
) n
C H
2
O H
C H
2
O H
C O O R C H 2 O H R O H
C O O
-
n r
C O C l
n r
N O
2
n r
硼烷还原的功能团
Selectivity,reagent,solvent and reaction condition
Asymmetric reduction,chiral reducing agents
4,Dissolving metal reduction（溶解金属还原）
Active metals,Li,Na,K,Mg,Ca,Zn,Sn,Fe
Proton donor,water,ethanol,acid
A B
e
A + B
A + B
e
A + B
2 H
+
A H + B H
A A
A B
e
A B
2 H +
A B
e
H
+
A B A BH H
A B H
e
A B H
H
+
A BH H
B A A B
2 H
+
H B A A B H
氢解
氢化还原
C O
M g / H g
N a / E t O H
Z n / H C l
C H 2 C C
O H O HC l e m m e n s e n r e d u c t i o n
B i m o l e c u l a r r e d u c t i o n
C H O H
C H O H
C O + M C O
-
M
+
C C
O
-
O
-
2 M
+
R O H
C O H
M
C O H
H
+
H
+
C C
O H O H
e.g,Reduction of carbonyl group,three types of product
Confoemational Analysis & Stereochemistry of
Hydride reduction reaction of Carbonyl Groups
----Topic one
A,Conformational Effects of Carbonyl Groups on Reactivity
O
H
H
D i h e d r a l
a n g e l 4
o
S P
2
S P
3
1 2 0
o
1 0 9, 5
o
O
H a x
H
i n t r o d u c e s
t o r s i o n a l s t r a i n
E c l i p s e d c o n f o r m a t i o n
o f c a r b o n y l g r o u p
T h i s t o r s i o n a l s t r a i n a c c o u n t s f o r t h e
i n c r e a s e d r e a c t i v i t y o f s i x - m e m b e r e d
r i n g c y c l i c k e t o n e o v e r a c y c l i c k e t o n e s,
O
H
H
N u -
O HH
H
N u
()
t h e t o r s i o n a l s t r a i n 1,3 - d i a x i a l i n t e r a c t i o n s
The addition to
cyclohexanones is
favorable
1,Reversible Reactions
O
H O C N
H C N
K e q f o r
c y c l o h e x a n o n e_ _ _ _ _ _ _ _ _ _ _ _ _
a c y c l i c k e t o n e
~ 7 0
Thermodynamically more favorable for cyclohexanone
Torsional strain
Effect of SP2 hybridization
2,Irreversible Reactions
O
H O H
r a t e ( K ) f o r
c y c l o h e x a n o n e_ _ _ _ _ _ _ _ _ _ _ _ _
a c y c l i c k e t o n e
~ 3 3 5
L i A l H 4
One can selectively reduce a cyclic carbonyl in the presence
of an acyclic carbonyl,under kinetic or thermodynamic conditions,
Synthetic consideration
B,Reaction of Carbonyl Groups
- Each reagent will display competitive reactions among the three primary pathways,
Nature of each reagent and the nature of X will determine the course,
C,Reversible Reduction Reactions,Stereochemistry
O
t - B u + A l O
3
i P r O H O H
t - B u
O H
t - B u+
9 5 % 5 %
--Meerwein-Pondorff-Verley Reduction
The reverse reaction is Oppenauer Oxidation
Reversible Reduction
Mechanism,reversible intramolecular hydride transfer
O
t -
B u
H
H
A lO
H
a x i a l H
-
d e l i v e r y O
t -
B u
H
H
A l
O
H
O
t -
B u
A l
OH
H
H
()
E q u a t o r i a l H
-
d e l i v e r y
O
t -
B u
A l
O
H
H
H
S t e r i c i n t e r a c t i o n
--Since it is freely reversible,one obtains the most stable alcohol
from the reduction,The reaction is driven to completion by use of
excess reagent and by distilling off the acetone formed in the
reaction,
D,Irreversible Reduction Reactions,Strereochemistry
1,Cyclic Ketones O
t -
B u
H
H
H H
L i A l H 4 O H
t -
B u
H
H
H H
H O H
t -
B u
H
H
H H
H
+
9 0, 1 0
N e a r l y t h e s a m e r a t i o o b t a i n e d u n d e r t h e s e
k i n e t i c a n d a b o v e t h e r m o d y n a m i c c o n d i t i o n s,
O
t -
B u
H
H
H H
L i
L i
A l
H
H
H
H
A lH
H
H
H
()
()
1,3 - i n t e r a c t i o n
1,2 - i n t e r a c t i o n
--Difference in the relative rates,1,2-interactons
slow the equatorial addition by a factor of ~10,
--LiAlH4 = small reagent
Favor axial hydride delivery
--1,3-interactions are more remote(i.e,smaller),when compared to the
1,2-interactions (larger),
-- The destabilizing 1,3-interactions increase as the size of the reagent
increases or with the size of the 1,3-diaxial substituents while the
1,2-interactions are not nearly so sensitive to the size of reagents or the
size of the substituents,
O
R
H H
H
H
S m a l l H
-
r e a g e n t
L a r g e H
-
R e a g e n t
O
H
H
M e
M e
M e
L i A l H
4
O H
H
H
M e
M e
M e
H
O H
H H
M e
M e
M e
H
+
4 5, 5 5
I n c r e a s e d s t e r i c h i n d e r a n c e o f t h e 1,3 - d i a x i a l i n t e r a c t i o n s
( M e / r e a g e n t ) m a k e a x i a l h y d r i d e d e l i v e r y m o r e d i f f i c u l t,
M e
H
M e
H
H
O
L i A l H
4
M e
H
M e
H
H
O H
H
M e
H
M e
H
H
O H
H
+
1 0 0, 0
S e r i o u s 1,3 - i n t e r a c t i o n s p r e c l u d e a x i a l d e l i v e r y o f t h e h y d r i d e,
b u t t h e a x i a l M e ' s h a v e n o t e f f e c t o n t h e 1,2 - i n t e r a c t i o n s,
O
H
H
M e
M e
M e
L i A l H
4
5 2 - 6 3, 3 7 - 4 8
N a B H
4
5 5 - 6 4, 3 6 - 4 5
L i A l ( O M e )
3
H 9 2 - 9 8, 2 - 8
O H
H
H
M e
M e
M e
H
O H
H H
M e
M e
M e
H
+
R e a g e n t
L a r g e r e a g e n t, g r e a t e r s e l e c t i v i t y f o r e q u a t o r i a l H
-
d e l i v e r y,
Examples,
O
H H
H
H
t -
B u
B H - K +
O H
H H
H
H
t -
B u
H
O H
H H
H
H
t -
B u
H
+
3, 5, 9 6, 5
M u c h l a r g e r e a g e n t !
Effect of the size of the reagent,
O
t -
B u
O
M e
M e
M e
O
M e
O O
M e
M e
M e
R e a g e n t % a x i a l O H % a x i a l O H % a x i a l O H % e n d o O H % e n d o O H
N a B H
4
2 0 2 5 5 8 8 6 1 4
L i A l H
4
8 2 4 6 3 8 9 8
L i A l ( O M e )
3
H 9 6 9 9 2 ~ 9 8 9 8 1
L i A l ( O
t
B u )
3
H 9 3 6 9 5 9 4 6
(
s
B u )
3
B H L i 9 3 9 8 9 9, 8 9 9, 6 0, 4
( M e
2
C H C H M e )
3
B H L i > 9 9 > 9 9 - > 9 9 n o r e a c t i o n
L i M e B H
3
2 1 3 6 6 - -
Comparison of Diastereoselectivity of Hydride reducing reagents,
Origin of Diastereoselectivity
O
H
H
H
H
n o
n o
()
y e s
S t e r i c
i n t e r a c t i o n s
y e s
E c l i p s e d c o n f o r m a t i o n
T o r s i o n a l S t r a i nThe direction of attack is not from the
axial or equatorial vector,but with a
109.5o approach of the nucleophile,
O
R
R
9 0 o
O
R
R
1 0 9, 5 o ( 1 0 5 o +_ 5 o )
v e r s u s
Dunitz angle
Good overlap and good approaches bond
Angle required of SP3 hybridization,Better
?-?* overlap for nucleophilic addition,
Tetrahedron 1974,30,1563,
--Cyclic Ketones,Steric vs,Torsional interactions
()
H a
H e
H a
H e
H a
H a
H e
H a
O
N u
-
N u
-
--As the nucleophile gets larger,this steric interaction
with the C3-axial H gets worse-equatorial approach
becomes the preferred line of attack,
-- For C2 and C6-H substituents,this torsional
interaction is worse than the steric interaction of
Nu-/ C3 and C5-H’s (for small,unhindered Nu-)
--All H- reduction have transition states that resemble rectant geometry,
--Diastereoselectivity is influenced by,
a,Steric interactions (1,3-diaxial interactions);
b,Torsional strain (1,2-interactions);
c,Remote electronic effects (electrostatic interactions),
-- In contrast to early theories of ―product development control‖ / late
transition state vs ―steric approach control‖ / early transition state,
Examples,
C H
3
H
O
H
? - f a c e
? - f a c e
N u
-
()
m a j o r
L i A l H
4
C H
3
H
H O
H
H
7 0 ~ 9 0 %
--locked trans diaxial ring fusion
--preferential axial delivery of reagent,
--equatorial OH is major product
--addition of Nu- from ?-face (equatorial
delivery) suffers from repulsive interaction
with axial Me,
C H 3
O H
? - f a c e
? - f a c e
N u
-
()
m a j o r
L i A l H 4
C H 3
H
H O
H
H
s i n g l e 1,3 - d i a x i a l
i n t e r a c t i o n
m a j o r p r o d u c t
--vs
C H
3
O
? - f a c e
? - f a c e
()
m a j o r
C H
3
O H
H
H
-
L a r g e H
-
/ C H
3
i n t e r a c t i o n
C H
3
O
H
m a j o rH
-
C H
3
H O
H
s m a l l e r H
-
/ C H
3
i n t e r a c t i o n
H
-
--but
2,Acyclic Carbonyl Groups
Review,Comprehensive Org,Syn.,Vol.1,49~75,
--Cram’s Rule J,Am,Chem,Soc.,1952,74,5828,
Empirical and no mechanistic interpretation is imposed on model,
J,Am,Chem,Soc.,1959,81,2748,
(cheletion-controlled addition)
--Prelog Helv,Chim,Acta,1953,36,308,(1,3-inducton)
-- Felkin (or Felkin-Ahn) model
Tetrahedron Lett.,1968,2199,2205
Tetrahedron Lett.,1976,155,159,
Nouv,J,Chim.,1977,1,61,
a,Cram’s Rule O
S
L
M
RN u
-
O
-
S
L
M
RN u
-- Empirical Model
-- Large group L eclipsed with R and not the carbonyl,Nu-
approach from side of small (S) group,
-- Stereoselectivity observed usually modest,
b,Felkin-Ahn Model O
R
L
S
M
O
R
L
S
N u
-
() ()
v e r s u s
L
M
S
N u
R
O
-
-
O
N u
R
L
M
S
M
t h e s t e r i c a l l y n e x t m o s t d e m a n d i n g s u b s t i t u e n t i s g a u c h e t o c a r b o n y l
s t e r i c a l l y m o s t d e m a n d i n g g r o u p i s p e r p e n d i c u l a r t o
t h e p l a n e o f t h e c a r b o n y l,a n t i t o i n c o m i n g n u c l e o p h i l e
m i n i m i z e s t o r s i o n a l
s t r a i n i n t r a n s i t i o n s t a t e
--Large group (L) trans antiperiplanar to forming bond,
--L is either the largest group (sterically) or the group whose bond to the ?-carbon
provides the greatest ?-?* overlap (e,g,halide,alkoxy group),
-- computational studies of Ahn confirmed this is the most stable transition state and
extended it to ?-chloroketones,In the latter case,this minimized destabilizing
electrostatic interactions between the halogen (electronegative group) and the
incoming nucleophile,
O
R
L
S
M ()
O
R
L
S
N u
-
M
N u
-
v e r s u s
Felkin-Ahn Model
O
N u
-
Nucleophile prefers approach that minimizes torsional
Stain and incorporates Burgi-Dunitz trajectory.primary
Interaction is now between the Nu- and the small or
medium substituent,
O O
O
C l
M e M g C l
- 7 5
o
C,T H F
H O O
O
C l
M e
H
O
O
M e
H
O
9 2 %
O E t
C l
R H
M e -
C l
R HM e
E tH O
R
H C lM e
E tH O
C l
H R
H O
M e
E t
O
E t
R
M e
H
Johnson,J,Am,Chem,Soc.,1968,90,6225,
c,Comparative Examples of Diastereoselection
M e
R
O
S i M e
3
N u
-
M e
R
O H
N u
M e
3
S i
M e
R
S i M e
3
B u
H O
+
B u
4
N F
F e l k i n P r o d u c t
M e
R
O H
N u
M e
R
O H
N u
+
N u
-
M e
R
O
H
R = P h
n -
B u L i > 1 0 0, 1 5, 1
R = P h M e L i > 4 0, 1 4, 1
R = P h > 1 0 0, 1 2, 1
R = P h 1 1, 1 1, 7, 1
R =
n
B u L i > 3 0, 1 1, 6, 1
M e L i > 1 0 0, 1 1, 9, 1
> 3 0, 1 1, 1
1 1, 1 2, 5, 1
R =
n
B u L i 1 5, 1 3, 5, 1
M e L i 2 1, 1 2, 1
> 1 0 0, 1 1, 5, 1
3, 5, 1 2, 1
S i M e
3
S i M e
3
S i M e
3
M g B r
M g B r
M g B r
F o r m 1 F o r m 2
O
R
L
M
S N u
-
O
S i M e 3
L
M
S N u
-
I n c r e a s e s i z e,i n c r e a s e
d i a s t e r e o s e l e c t i v i t y
--Diastereoselection
depends on the size of
the ketone substituent
M e
P h
O
R M e
P h
O H
R
R r a t i o
M e 7 4, 2 6
E t 7 6, 2 4
i
P r 8 3, 1 7
t
B u 9 8, 2
--Diastereoselectivity depends on size of nucleophile
M e
P h
O
M e
M e
P h
O H
M e
M e
P h
O H
M e
+
N u
-
L i A l H 4 7 4 2 6
(
s
B u ) 3 B H L i > 9 9 < 1
d,Chelation-controlled addition 螯合控制
羰基 ?,?-位羟基、氨基、烷氧基，金属离子，螯合成环
--Review,Acc,Chem,Res.,1993,26,462,
O
R
X
M e t
S L
N u
-
R
O M e t
N u
S
L
X
1,2 - c h e l a t i o n X = O H,O R
O
L
S
O
R
M e t
R
N u
-
L
S
O R
N u
R
O H
C a n u s u a l l y p r o v i d e e x c e l l e n t
d i a s t e r e o s e l e c t i v i t y
O
M e t
O
R
H
R
L
R s
R
N u
-
1,3 - c h e l a t i o n
s y n - 1,3 - d i o l
RR
O H
R s
O H
R
L
N u
a x i a l d e l i v e r y o n m o s t s t a b l e
c h a i r - l i k e t r a n s i t i o n s t a t e,
--Examples of 1,2-chelation-control
O
O
O
H
R
O O
M e M g B r
> 9 5, 5
O
O
H O
H
R
M e
O
O
O
H
R
M e
O O
B r M g
O
O
H O
H
R
M e
Z o a p a t a n o l
- - - t o i n v e r t t h e s t e r e o c h e m i s t r y
Nicolao,
J,Am,Chem,Soc
1980,102,6611,
C H 3
O
O H
O T B S
O P h
M g B r C H 3
O H
O T B S
O P h
O H
5 0, 1 s t e r e o s e l e c t i v i t y
M o n e n s i n
Still,
J,Am,Chem,Soc.,
1980,102,2117,2120
--Note that non chelation-controlled addition exhibit relatively modest
stereoselectivities,but chelation-controlled addition can exhibt very good
stereocontrol,
OB n O
O M e t
H H
O A c
M e M g B r O
B n O
O H
H H
O A cM e
O
R
O
M e t
H
N u
-
O
N u
H O
H
R
R = C H 3 N u
-
= P h M g I 1 0 0, 0
P h M e M g B r o r M e L i 1 0 0, 0
P h L i A l H 4 8 4, 1 6
P h (
s
B u ) 3 B H L i 1 0 0, 0
C H 3 (
s
B u ) 3 B H L i 7 8, 2 2
O
H
O
M e t
R
N u -
O
H
N u O H
R
C h e l a t i o n M o d l e C h e l a t i o n - c o n t r o l l e d p r o d u c t
O
H
OR
N u -
O
H
R O H
N u
F e l k i n M o d e l
F e l k i n m o d e l p r e d i c t e d p r o d u c t
Two modles
predictation
O
OO
O
H C 7 H 1 5 n B u M
- 7 8
o
C
H
C 7 H 1 5
H O B u
M E M O
H
C 7 H 1 5
B u
M E M O
O H
+
I I I
S o l v e n t I I I
p e n t a n e 9 0 1 0
C H 2 C l 2 9 3, 5 6, 5
E t 2 O 9 0 1 0
T H F 1 0 0 0
M = M g B r
S o l v e n t I I I
p e n t a n e 6 7 3 3
C H 2 C l 2 7 5 2 5
E t 2 O 5 0 5 0
T H F 4 1 5 9
M = L i
螯合离子及溶剂的影响
M e
O
R
C 7 H 1 5H
O
M
N u
-
M e
O
R O
C 7 H 1 5
H
N u
-
F e l k i n m o d e lC h e l a t i o n m o d e l
Li+; THF
?-烷氧基取代基的影响
H C
7 H 1 5
H O B u
R O
R O
O
H C 7 H 1 5 n
B u M g B r
T H F,- 7 8
o
C
R = M E M > 9 9, 1
M O M > 9 9, 1
M T M > 9 9, 1
C H 2 P h 9 9, 5, 0, 5
C H 2 O C H 2 P h 9 9, 1
T H P 7 5, 2 5
H
C
7
H
1 5
H O B u
R O
R O
O
H C 7 H 1 5
- 7 8
o
C
N u
-
R = C H 2 P h M e M g C l E t 2 O > 9 9, 1
M e L i T H F 6 0, 4 0
R = T B S M e M g C l E t 2 O 6 0, 4 0
T H F 1 0, 9 0 M g C l
c h e l a t i o n - c o n t r o l l e d
F e l k i n a d d i t i o n
Still,Tetrahedron Lett.,1980,21,1031,
Reetz,J,Chem,Soc.,Chem,Commun.,1986,1600,
R
1
O H
R
2
O
Z n ( B H
4
)
2
E t
2
O,0
o
C
R
1
O H
R
2
O H
a n t i - 1,2 - d i o l
c h e l a t i o n - c o n t r o l l e d a d d i t i o n
v e r s u s
R
1
O T B S
R
2
O
1, R e d - A l,
t o l u e n e,- 7 8
o
C
2, B u
4
N F
R
1
O H
R
2
O H
s y n - 1,2 - d i o l
F e l k i n a d d i t i o n
还原产物的立体控制
Z n ( B H 4 ) 2
R
O
O B n
E t 2 O,- 3 0
o
C R
H O
O B n
K - s e l e c t r i d e
T H F,- 9 5
o
C
R
H O
O B n
9 0, 1 0 9 5, 5
F e l k i n a d d i t i o n c h e l a t i o n - c o n t r o l l e d
-- 1,3-Chelation-Contralled Additions
(?-chelation-controlled addition) R ' R ' '
O
H
O H
C h e l a t i o n c o n t r o l w i t h
e x t e r n a l H
-
d e l i v e r y
R '
R ' '
O
H
O
M
L L
H
-
O
M
O
L
L
H
R '
R ' '
H
-
c o n t r o l l e d w i t h
i n t e r a l H
-
d e l i v e r y
R ' '
B
O
O
R '
H L
L
H
R ' R ' '
O HO H
S y n - 1,3 - d i o l
R ' R ' '
O HO H
a n t i - 1,3 - d i o l
Tetrahedron,1984,40,2233;
Tetrahedron Lett.,1987,28,155; 1986,27,3009,
R3B/NaBH4,Et2BOCH3-NaBH4 in THF-MeOH
Dibal-H (>98:2)
Aluminum Hydride Reducing Agents
less reactive,more selective
- Examples,
Borohydride Reducing Agents
Hydride Reductions of Functional Groups
Reactions of Borane (BH3)
Characteristics of Hydride Reducing Agents
? NaCNBH3
? LiBH4
? Zn(BH4)2
Review,Narasimhan Aldrichim,Acta 1998,31,19,
? NaBH4/CeCl3 (catalytic amount (0.1 equiv))
Luche J,Am,Chem,Soc,1981,103,5454; 1978,100,2226,
- Readily enolizable carbonyl can be reduced,
clean addition,no enolization
Imamoto J,Am,Chem,Soc,1989,111,4392,
Reagent comparisions for 1,2- vs,1,4-reduction
? NaBH4–CoCl2
Selective reduction of nitriles,
- Good for 1,2- vs,1,4-reduction,
Garner Org,Syn,1992,70,18,
Asymmetric Reductions
?烯烃双键的不对称催化氢化
SP2 杂化碳
?羰基化合物的不对称还原
?亚胺的不对称还原
?不对称氢转移反应
R N H A c
C O 2 H H
2
R
N H A c
C O 2 H
*
C h i r a l R h C a t a l y s t
P
R ' R ' ' R ' ' '
* P
R ' R ' ' R
*
P
R ' R ' ' R *
*
手性二磷配体的设计策略, 活跃的研究领域
?碳碳双键的不对称催化氢化
NR
P P h
2
P P h
2
P
P
R
R
R
R
N
N
P P h
2
P P h
2
P h
P h
D E G H O S
D u P H O S P N N P
P P h
2
P P h
2
P P h
2
P P h
2
P P O P H O S
N O R P H O S
P P h
2
N ( C H
3
)
2
P P h
2
F e
B P P F A
c - C
6
H
1 1
P P h
2
P P h
2
P
M e O
P
O M e
P P h
2
P h
2
P
M e
M e
C Y C P H O S
( R,R ) - D I P A M P
( S,S ) - C H O R A P H O S
用于催化不对称氢化反应的手性膦配体
P P h
2
P P h
2
( R ) - B I N A P
N
P h
2
P
P P h
2
C O
2
B u
-
t
( S,S ) - B P P M
OO
P P h
2
P h
2
P
D I O P
P P h
2
P P h
2
( R,R ) - D P C P
P P h
2
P P h
2
( + ) - D I P M C
P P h
2
P P h
2
( 2 R,3 R ) - N O R P H O S
P P h
2
P P h
2
( - ) - M E N O
N
M e
O P P h
2
M e
O P P h
2 P P h
2
N
M e
M e
P P h
2
P P
M e
RM e
R
R = c - C
5
H
9
,c - C
6
H
1 1
,
t -
B u,C E t
3
,1 - a d a m a n t y l
B I S P *
N
P P
PP
P r
i
M e
M e
i
P r
X
X
P h
2
P P P h
2
( R ) - B I P H E M P,R = P h,X = M e
( R ) - B I P H E R,R = c - H e x,X = M e
M e O B I P H E P,R = P h,X = O M e
O
O
O
O
N
P P
1、烯酰胺的不对称氢化
R N H A c
C O 2 H
H 2,R h ( I I )
C h i r a l l i g a n d R N H A c
C O 2 H
*
烯酰胺 / Rh complex /H2 ?-氨基酸
潜 (前 )手性 Prochirality
磷配体 e.e% 构型
R=Ph R=H
(R,R)-DIPAMP 96(S) 94(S)
(S,S)-CHIRAPHOS 99 (R) 91 (R)
(S,S)-NORPHOS 95(S) 90(R)
(R,R)-DIOP 85(R) 73(R)
(S,S)-BPPM 91(R) 98.5(R)
(S)-BINAP 100(R) 98(R)
(S,R)-BPPFA 93(S)
(S,S)-SKEWPHOS 92(R)
(S,S)-CYCPHOS 88(R)
(S,S)-Et-DuPHOS 99(S) 99.4(S)
R N H A c
C O 2 H
H 2,R h ( I I )
C h i r a l l i g a n d R N H A c
C O 2 H
*
Catalytic Mechanism
P h
N H A c
C O
2
H
H
R h
S
S
P
P
* +
k
1
'
k
- 1
'
k
1
' '
k
- 1
' '
N
P h
O
M e
R h
P
P
M e O O C
H
*
+
N
P h
O
M e
R h
P
P
C O O M e
H
*
+
k
2
' [ H
2
]
k
2
' ' [ H
2
]
N
P h
O
M e
R h
P
P
M e O O C
H
H
H
*
+
N
P h
O
M e
R h
P
P
C O O M e
H
H
H
*
+
k
3
'
k
3
'
S
S
螯合
吸氢
Halpern,Brown,1980
k
3
'
k
3
'
S
S
O N H
M e
C O O M e
P h
R h
S
P
P
H
*
OH N
M e
M e O O C
P h
R h
S
P
P
H
*
k
4
'
k
4
'- [ R h ( P P ) S 2 ]
+
*
- [ R h ( P P ) S
2
]
+
*
M e
O
N C O O M e
P h
HH
M e
O
NM e O O C
P h
H H
负氢转移
还原脱除
H O P P h
2
P h 2 P O
H
HP h
2 P O
O P P h 2
H
H
P h 2 P O
H
O P P h 2
( R,R ) - ( S,S ) - ( 1 R,1 ' R,2 S,2 ' S ) -
N H P P h 2
N H P P h 2
N H P P h 2
N H P P h 2
N H P P h 2
N H P P h 2
N H P P h 2
N H P P h 2
( R ) - B D P A B ( S ) - B D P A B ( R ) - H 8 - B D P A B ( S ) - H
8 - B D P A B
螺环瞵配体
手性双氨基瞵配体,
2、手性 Rh-二茂铁基膦络合物催化的丙烯酸的不对称氢化
Hayashi,
Ito,
1987,
P P h
2
N ( C H
3
) C H
2
C H
2
R
2
C H
3
P P h
2
H
F e
M e
A r
M e
C O O H
+
R h - ( R ) - / ( S ) - 1 a
C H M e
2
A r C O O H
H
1 a N R 2 =
1 b N R 2 = N B u 2
1 c N R 2 = N E t 2
1 d N R 2 = N
N
2 a A r = P h
2 b A r = 4 - C l P h
2 c A r = 4 - M e O P h
2 d A r = 2 - n a p h t h y l
H
2
3
R
A r
M e
C O O H
R h - ( R ) - / ( S ) - 1 a
H 2
A r C O O H
H
M e
H
R
E - 4 a R = E t
E - 4 b R = P h
5
P P h 2
N ( C H 3 ) C H 2 C H 2 R 2
C H 3
P P h 2
H
F e +
―增强底物功能团与手性配体之间的亲和性相互作用可以提高立体选择性”
―手性氨基二茂铁”
烯烃配体溶剂时间 (h) 产物 e.e.%构型
2a 1a THF/MeOH (90/10) 30 3a 98.4(S)
2a 1a THF/MeOH (80/20) 20 3a 97.6(S)
2a 1a i-PrOH 20 3a 97.0(S)
2a 1a MeOH 5 3a 95.8(S)
2a 1b THF/MeOH (80/20) 20 3a 97.9(S)
2a 1c THF/MeOH (80/20) 30 3a 98.1(S)
2a 1d THF/MeOH (80/20) 30 3a 98.2(S)
2b 1a THF/MeOH (80/20) 40 3b 97.4(S)
2c 1a THF/MeOH (80/20) 40 3c 96.7(S)
2d 1a THF/MeOH (80/20) 65 3d 97.3(S)
E-4a 1a i-PrOH 100 5a 97.3(2S,3R)
E-4b 1a THF/MeOH (80/20) 100 5b 92.1(2S,3R)
由手性二茂铁基瞵 -铑配合物催化的三取代丙烯酸的不对称氢化
P P h 2
C H E t 2
C H E t 2
P P h 2
F e
( R,R ) - F e r r o P H O S
Kang,1998
[Rh(COD)2}BF3 / (R,R)-FerroPHOS / H2 / 2 atom,20~30 oC
脱氢氨基酸,e.e,% ~99.9%
空气稳定性
3、钴络合物催化的 ?,?-不饱和酯的不对称氢化
NN
C N
R R
H
1 a R = C H 2 O S i M e 2 B u
t
1 b R = C H 2 O E t
1 c R = C M e 2 O H
半咕啉型手性 C 2 对称螯合配体
C H 3
R '
C O O E t
N a B H
4
,1 m o l % C O C l
2
,1, 2 m o l % 1 a
C H 3
R '
C O O E t
*
2 a R ' = P h C H 2 C H 2 -
2 b R ' =
2 c R ' = ( C H 3 ) 2 C H -
2 d R ' = P h
H 3 C
C H 3
3 a R ' = P h C H 2 C H 2 -
3 b R ' =
3 c R ' = ( C H 3 ) 2 C H -
3 d R ' = P h
H 3 C
C H 3
底物产率 % e.e,(%) 构型
E-2a 97 94 (R)-(+)
Z-2a 95 94 (S)-(-)
E-2b 95 94 (R)-(+)
Z-2b 94 94 (S)-(-)
E-2c 84 96 (S)-(-)
Z-2c 86 90 (R)-(+)
E-2d 95 81 (S)-(+)
Z-2d 97 73 (R)-(-)
?,?-不饱和羧酸酯的对映选择性还原
4、开链烯醇酯的不对称氢化
PP
D u P H O S
R
O A c 3 0 p s i H
2
R h ( I ) / D u P H O S,T H F,M e O H
y i e l d 9 7 %
R
H
O A c
C H 3
2 a R = n - C 5 H 1 1,e, e, 9 4 %
2 b R = P h,e, e, 9 4 %1
R
O A c
3 0 p s i H 2
R h ( I ) / D u P H O S,T H F o r M e O H
y i e l d > 9 7 % R
H
O A c
C H 3
H
O A c
C H 3
R
R = n - C 5 H 1 1,e, e, 9 8, 5 %
R = P h,e, e, 9 7, 8 %
R = C H 2 C H 2 O C H 2 P h,e, e, > 9 8 %
中等程度的对映选择性
二烯基酯 (烯炔基酯 )
5、应用实例
Noyori,1987,
BINAP-Ru(II) 二羧酸络合物
P
P
A r 2
A r 2
R u
O
O
O
O
M e
M e
R u - ( R ) - B I N A P
O H
R u - ( S ) - B I N A P
> 3 0 a t m H
2
,M e O H,2 0
o
C
M e
O H
( R ) - 香茅醇拢牛醇
M e
O H
R u - ( S ) - B I N A P
O H
R u - ( S ) - B I N A P
橙花醇
( S ) - 香茅醇
9 8 % e, e,
9 8 % e, e,
N A c
M e O
M e O
O M e
O M e
R u - ( R ) - B I N A P,E t O H,C H 2 C l 2,2 3
o
C
4 a t m,H 2,定量
N A c
M e O
M e O
O M e
O M e
> 9 9, 5 % e, e,
M e O
C O 2 H
R u - ( S ) - B I N A P,1 3 5 a t m H 2
M e O
C O 2 H
M e
( S ) - 萘普生,Y 9 2 %,e, e, 9 7 %
生物碱的合成,
萘普生的合成,
Z-烯酰胺
L i / E t 2 N H
N E t
2
[ R h ( R ) - B I N A P C O D ]
+
M e
N E t
2 H
2
O / H
+
M e
C H O
O H
( R ) - 9 5 % e, e,月桂烯 N,N - 二乙基橙花胺
( R ) - C i t r o n e l l a l 香茅醛 ( - ) - m e n t h o l 薄荷醇
Takasago Co.,
1500 t/year
(S)-Cotronellal
O H
R h - ( R ) - B I N A P
R
O HRR
O
H O
V E
O
O V K
维生素 E,K侧链的合成,
?羰基化合物的不对称还原
催化氢化 /化学选择性,金属氢化物还原
1、用 BINAL-H还原
LiAlH4,NaBH4,BH3.THF 的活性与选择性的改造
手性配体修饰的金属氢化物
——活泼氢数目减至最少，获得高度的化学选择性
——手性配体的引入,提高对映面的选择性
1951,手性配体改造 LAH
1979,Noyori,手性联萘酚修饰 BINAL-H
O
O
A l
O R ' '
H
L i
( S ) - B I N A L - H
O
O
A l
H
O R ' '
L i
( R ) - B I N A L - H
R ' R
O
( R ) - B I N A L - H
R ' R
H O H
( R ) -
R ' R
H
O H
( S ) - B I N A L - H
( S ) -
手性 LAH还原剂, R,温度的影响
产物的对映选择性可控 !
A l
O
L i
O
C
R ' '
R
R '
O
O
S
S
A l
O
L i
O
C
R ' '
R '
R
O
O
S
R
R’,R / 电性因素 / 立体空间因素
优势构象非优势构象 n-?排斥
芳香酮的还原,
O
R
( R ) - B I N A L - H
H O
R
H
( R ) -
R
H O H
( S ) - B I N A L - H
( S ) -
酮 BINAL-H 构型产物
产率 % e.e.% 构
型
C6H5COCH3 R 61 95 R
C6H5COC2H5 S 62 98 S
C6H5CO-n-C3H7 S 78 100 S
C6H5CO-n-C4H9 S 64 100 S
C6H5COCH(CH3)2 S 68 71 S
C6H5COC(CH3)3 R 80 44 R
?-Tetralone R 91 62 R
炔基酮 /烯基酮还原的立体选择性
( R ) - B I N A L - H( S ) - B I N A L - H
O
R 2
R 1
H O
R 2
R 1
H
O H
R 2
R 1
H
( S ) - ( R ) -
( R ) - B I N A L - H
( S ) - B I N A L - H
O
R 2R 1
( S ) - ( R ) -
O H
R 2R 1
H H O
R 2R 1
H
光学活性的烯丙醇 / 炔丙醇的制备
C O
2
C H
3
H O
H
C H
3
O C O
H O
O H
O
O
O R
H O H
T H P O
T H P O H O H
C O
2
C H
3
( S ) -,1 0 0 % d, e,
( S ) -,R = C O P h,9 8 % d, e,
( S ) -,R = T H P,9 9 % d, e,
( S ) -,R = H,1 0 0 % d, e,
X
H
O H
X = B r,9 6 % d, e,
X = I,9 7 % d, e,
二烷基酮的对映选择性不高 !
A l
O
L i
O
C
R ' '
R
R '
O
O
S
S
A l
O
L i
O
C
R ' '
R '
R
O
O
S
R
苄基甲基酮 (S)-1-苯基 -2-醇 e.e.% 13%
2-辛酮 (S)-2-辛醇 e.e.% 24%
R
O
D ( R ) - B I N A L - H( S ) - B I N A L - H R
H O
D
H
R
O H
D
H
( S ) - ( R ) -
醛 BINAL-H
构型
醇产物
产率 % e.e,% 构型
香茅醛 -1-d S 91 91/84 S
橙化醛 -1-d S 90 72 S
E,E-法尼醛
1-d
R 91 88 R
Z,E-法尼醛
1-d
R 93 82 R
苯甲醛 -1-d R 75 82 R
2、过渡金属络合物催化的羰基氢化
酮的不对称氢化
-----制备手性醇
BINAP-Ru(II)
P P h 2
P P h 2
( R ) - B I N A P
P P h 2
P P h 2
( S ) - B I N A P
R
O C 2 H 5
O O
N H B o C
B I N A P - R u
H 2
R
O C 2 H 5
O H O
N H B o C
+
R
O C 2 H 5
O H O
N H B o C
t h r e o - e r y t h r o -
a R = P h C H 2 -
b R = M e 2 C H C H 2 -
c R = C y c l o h e x y l m e t h y l -C O O H
O H
N H 2
S
S
S t a t i n
底物催化剂产物
产率 %
threo:erythro
a RuBr2-(R)-
BINAP
97 >99:1
a RuBr2-(S)-BINAP 96 9:91
b RuBr2-(R)-
BINAP
99 >99:1
c RuBr2-(R)-
BINAP
92 >99:1
手性二醇, 1,2-,1,3-,1,4- 二醇 / 制备手性配体
二酮的不对称氢化
Chan,1997,
O O
R u - ( R ) - o r - ( S ) - B I N A P
H C l,H 2
O H O H
o r
O H O H
( R,R ) - ( S,S ) -
y i e l d > 9 5 %,> 9 9, 9 % e, e,
BINAP-Ru(II)(OOCCH3)2
BINAP-Ru(II)(OOCCH3)2 / 2 CF3COOH
BINAP-Ru(II)(OOCCH3)2 / 2 HCl
增加酸性
引入配位杂原子
简单二烷基酮的还原一般选择性较低！
Noyori,1995,
RuCl2-[(S)-BINAP](DMF)n,S,S-1,2-二苯基乙二胺 /KOH,isopropyl alcohol
A r
O
R
R u ( I I ) - P h o s p h i n e d i a m i n e
K O H,( C H 3 ) 2 C H O H A r
O H
R
H 2,4 a t m,2 8
o
C,6 h
y i e l d > 9 9 %
9 7 % e, e
O
R u
C l
C l
N H 2
N H 2
P
P
**
H 2
O H
9 4 % e, e
1 0 0 % y i e l d
开发稳定、高效的催化剂,
R u
C l
C l
N H 2
N H 2
P
P
**
R h
C l
H
P
P
H
S
*
O
S
R h
C l
H
P
P
H
O
*
S
R h
C l
S
P
P
H
O
*
R O H,S o r B H
+
R O
-
,B
O H
R h
C l
H
P
P
*
H
2
Zhang,1998,
-----弱碱能加速简单酮的 Rh催化氢化反应
P
R
R
P
M e
R
P e n n P h o s R = M e,P r
i
O
[ R h ( C O D ) C l 2 ] 2
l u t i d i n e,M e O H,2 4 h,2 0
o
C
P e n n P h o s
O H
r, t,3 0 a t m,底物, [ R h ( C O D ) 2 C l 2 ], C a t = 1, 0, 0, 0 0 5, 0, 0 1
反应酮 Lutidine 当
量
KBr 当量时间 h Yield
%
e.e,%
1 0.4 _ 24 97 95
2 0.4 _ 53 94 95
3 0.8 1.0 88 95 93
4 0.8 1.0 56 99 73
5 0.8 1.0 48 96 75
6 0.8 1.0 75 66 85
7 0.8 1.0 94 99 84
8 0.8 1.0 106 90 92
9 0.8 1.0 96 51 94
O
O
O
O
O
O
O
O
O
Rh-PennPhos体系催化简单酮的不对称氢化
3、硼杂噁唑烷催化体系
硼烷衍生物,硼杂噁唑烷, Chemzyme 化学酶
1981,Hirao; Itsuno; Corey,CBS催化剂 (Corey-Bakshi-Shibata)
N
O
B
H
P h
P h
R
1 a R = H
1 b R = M e
1 c R = B u
N
O
B
H
P h
P h
H
2
N
B
O
H
P h
P h
H
3
N
O
B
R
H
4 a R = H
4 b R = M e
N
O
B
H
N A P
- ?
R
? -
N A P
5 a R = H
5 b R = C H
3
5 c R = n - B u
N
O
B
H
P h
P h
R
6 a R = H
6 b R = M e
N
O
B
M e
P h
7
CBS 催化剂举例
2 R 1 R 2 C O + B H 3 ( S ) - 1 b,T H F1 m i n,,2 5 o C ( R 1 R 2 C H O ) 2 B H R 1 R 2 C H O H
酮 BH3当量 (S)-1b当量产物构型 (e.e,%)
C6H5COCH3 2.0 1 R(97)
C6H5COCH3 1.0 0.1 R(97)
C6H5COCH3 1.2 0.025 R(95)
C6H5COC2H5 1.2 0.05 R(86)
C6H5COC2H5 1.0 0.05 R(88)
C6H5COC2H5 0.6 0.05 R(90)
t-BuCOCH3 0.6 0.05 R(88)
t-BuCOCH3 0.6 0.1 R(92)
?-tetralone 0.6 0.05 R(89)
C6H5COCH2Cl 0.6 0.05 S(97)
N
O
B
H
P h
P h
M e
B H
3
,T H F
N
O
B
H
P h
P h
M eH
3
B
R
S
R
L
O
N
O
B
H
P h
P h
M e
B
O
R
S
R
L
H
H
H
B H
3
N
O
B
H
P h
P h
M e
H
2
B
-
O
+
R
S
R
L
H
H
R s R
L
O B H
2
H
R s R
L
O H
CBS催化反应机理,
P h
O
O
O
O
C 5 H 1 1 -
n
O
1 0 % 1 b
0, 6 e q, B H 3, T H F
P h
O
O
O
O
C 5 H 1 1 -
n
O H
H
8 2 % e, e,
前列腺素合成,酮基的选
择性还原 ;
C-15 位的立体化学控制
0, 6 e q, B H
3
,T H F
C l
O
1 b
C l
O H
H
y i e l d > 9 9 %
e, e, 9 4 %
N a I
9 7 % ~ 9 9 %
I
O H
H
C H
3
N H
2
> 9 9 %
N
O HH
H
1, N a H
2,
3, H C l
C lF
3
C
N
+
O
H
C F
3
H
2
C l
-
( R ) - 氟西汀
?-蒎烯衍生
O B
N H
R
( + ) - 1
O B
N H
R
( - ) - 1
O
H
B
N
B
C H 3
P h
H 3 C
C H 3
C H 3
O
H
H 2
C H 3
P h C H 3
O H
底物产物温度时间 h 产率 % e.e,%
Ph Et
O
Ph CH2Cl
O
Ph CO2Me
O
Ph Me
O
M e(CH 2)4 M e
O
Ph Et
OH
Ph CH2Cl
OH
Ph CO2Me
OH
Ph Me
OH
Me(CH2)4 Me
OH
0~5 4 95 92
25~30 4 93 81
0~5 1 93 76
25~30 1 96 90
0~5 6 65 59
0~5 2 >90 93
0~5 2 >90 37
Brown,H,C.,1961,
(+)-(Ipc)2BCl,(Ipc)2BH,IpcBH2 B C l) 2 B H) 2
二异松莰烯基硼烷 ----仅对 Z-烯烃显示极好的选择性
Masamune,S,1985,
--反 -2,5-二甲基硼杂环戊烷 DMB
---Z-/E-二取代烯烃、三取代烯烃
B
H
D M B
非硼杂噁唑烷类催化剂
H
H 2 N
P h
P h
O H
S
H
H 2 N
P h
P h
O H
S
N
R '
H
H
R
R
O H
H
R ' = H,M e
?-氨基醇类化合物
实现酮的对映选择性还原
改良的 LAH
硼杂噁唑烷
手性配体配位的过渡金属催化
R
N
O
B
H
P h
P h
B
B C l
)
2
O x a z a b o r o l i d i n e s
C o r e y
A l p h i n e - B o r a n e
M i d l a n d
I c p
2
B C l
B r o w n
B
H
B o r a l a n e ( D M B )
M a s a m u n e
L i
B I N A L - H
N o y o r i
O
O
A l
H
O R ' '
P
P
A r
2
A r
2
R u
O
O
O
O
M e
M e
R u - B I N A P
N o y o r i
?亚胺的不对称还原
亚胺的不对称还原制备手性仲胺与由酮制备醇同样重要
P
P
R
R
R
R
D u P H O S
Burk,1993,
[Rh(COD)(DuPHOS)]+CF3SO3-
E t O
2
C
N
N P h
O
H
N
P h 2 P
C O 2 B u
t
P P h 2
( 2 S,4 S ) - B P P M
(2S,4S)-BPPM/ BiI3/ H2
O
N
F
F
M e
( 2 S,4 S ) - B P P M
B i I 3,H 2
O
N H
F
F
M eS N
N
M e
O
N
F
M e
C O 2 H
O
左氟沙星
Buchwald,1992~1994
二茂钛催化剂,T i
F F
S
S
活性高，空气稳定,
高对映选择性
?不对称氢转移反应
不对称氢转移还原,易于操作，不使用活性的金属氢化物或氢气
手性磷 /手性氮配体
Noyori,1997
N
R u
N
T s
H
R
1,3,5 - 三甲基苯,甲基异丙基苯
R 1
R 2
O
c a t, R u ( I I )
M e 2 C H O H
R 1
R 2
O H
e, e, 9 9 %
c a t, R u ( I I )
M e 2 C H O H
O
N H C b z
O H
N H C b z
O H
N H C b z
( 3 S,4 S ) - ( 3 R,4 S ) -
( R,R ) - C a t, 9 7 %,e, e, 9 9 %
( S,S ) - C a t, 9 7 %,e, e, 9 9 %
R 1 R 2
O
N H
O H
0, 2 5 m o l % R u C l 2 ( p - c y m e n e )
2, 5 m o l % i - P r O K / i - P r O H
R 1 R 2
O H
简单的氨基醇作为手性配体,
R1 R2 时间 h e.e,%
Me
Me
Et
n-Pr
n-Bu
n-C6H13
1.5
1.5
1.5
1.5
1.5
1.5
94
97
93
92
95
95
Recent Development of
Asymmetric Reductions
A Metal-Free Transfer Hydrogenation,
Organocatalytic Conjugate Reduction of
?,? -Unsaturated Aldehydes**
Jung Woon Yang,Maria T,Hechavarria Fonseca,
Nicola Vignola,and Benjamin List*
Angew,Chem,Int,Ed,2004,43,6660 –6662
Received,August 28,2004
Catalyst screening for the iminium catalytic conjugate reduction
of ?,? - unsaturated aldehydes,
Organocatalytic conjugate reduction of ?,? - unsaturated aldehydes
Continue
Proposed mechanism of iminium catalysis
In summary,we have developed the first metal-free
catalytic transfer hydrogenation,This novel iminium
catalytic conjugate reduction of a,b-unsaturated aldehydes
is highly efficient and chemoselective,It requires low
catalyst loadings and tolerates various functional groups
that are sensitive to the conditions of standard
hydrogenations and alternative conjugate reductions,
Metal-Free,Organocatalytic
Asymmetric Transfer Hydrogenation
of Unsaturated Aldehydes**
Jung Woon Yang,Maria T,Hechavarria Fonseca,
Nicola Vignola,and Benjamin List*
Angew,Chem,Int,Ed,2005,44,108 –110
Received,October 26,2004
Organocatalytic asymmetric transfer hydrogenation of ?,
? - unsaturated aldehydes,
Continue
Proposed mechanism of the organocatalytic
asymmetric transfer hydrogenation,
Attractive features of this process
1) Its high yields,chemo-,and enantioselectivities;
2) Its enantioconvergence;
3) its simplicity and practicability,
Enantioselective Organocatalytic
Hydride Reduction
Ste′phane G,Ouellet,Jamison B,Tuttle,and David W,C,MacMillan*
DiVision of Chemistry and Chemical Engineering,California
Institute of Technology,Pasadena,California 91125
J,AM,CHEM,SOC,2005,127,32-33
Received October 10,2004;
EOHR,Enantioselective organocatalytic hydride reduction
Effect of Catalyst and Solvent on EOHR
Effect of Dihydropyridine Component on EOHR
Effect of Aldehyde Substituents on EOHR
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In summary,we have developed
the first organocatalytic hydride
reduction,an operationally simple
reaction that allows the enantioand
chemoselective transfer of hydrogen
from Hantzsch esters to geometrically
impure enals,

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