080407羰基反应2

Shanghai Jaiotong University, Spring 2008
Degree of chelate organization may be regulated by choice of solvent and protecting group
O Me
Me Me OR
LiAlH4 -10 °C
Reaction of Carbonyl Group-2
Shanghai Jaiotong University, Spring 2008
Felkin Model
Shanghai Jaiotong University, Spring 2008
Addition of Enolate & Enol Nucleophiles
Me MgBr Chelate Model
TBSO
Me Me
OH OCH2OBn
diastereoselection 50 : 1
TBSO
Me
O OCH2OBn
Me-MgBr Chelate Model
TBSO
Me Me
OH OCH2OBn
W. C. Still & Co-workers, Tetrahedron Lett. 1980, 21, 1031
O Me–M
Me OH
HO Me
H
H
Me–Li Me–Ti(OiPr)3 Yb(OYf)3 +Me–Li
35% 6% 18%
H
65% 94% 82%
H Me
O Me–M
H Me
Me OH
HO H
Me
Me
MeMg–Br Me–Ti(OiPr)3 Yb(OYf)3+MeMg–Br
32% 11% 32%
68% 89% 68%
OH Me
R OR
OH Me
R OR
(OR)
Solv. Ratio
Overman Tet Lett. 1982, 23, 2355
R = CH2OBn R = CH2OBn R = SiPh2(t)Bu
THF
Et2O THF
30 : 70 2 : 98 95 : 5
Note that SiPh2(t)Bu group prevents chelation.
H
H
The most stereoselective
O [H]
Reductions
H OH
HO H
H
H
KBH(s-Bu)3 , 3
:
97
Li in liq. NH3 99
:1
NPh [H]
H NHPh
H
PhH
:
99
Al/Hg/MeOH, 90
: 10
Shanghai Jaiotong University, Spring 2008
Chelation provides a powerful control element
in carbonyl addition reactions
R R
O
O R
M
Nu-M
R R
Nu
H+
O
O R
M
R R Nu OH
O R
RM OO
R
R
Nu-M
RM OO Nu
R
R
H+
R O
R
OH Nu R
Reviews Reetz, Angew. Chem. Int. Ed. 1984, 23, 556-569 Reetz, Accts. Chem. Res. 1993, 26, 462-468 (pdf)
diastereoselection >100 : 1
path A
O
RL
R
OR
path B
path C
OR
R CO
H
RL
H:
RL
O RO
CR H
H:
RL
MO
O R
CR H
H:
OH
RL
R
OR
Felkin-Anh
OH
RL
R
OR
Anti-Felkin-Anh
OH
RL
R
OR
Chelation model
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Model
Chelate Chelate F-A: RL=OR
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Addition of Carbon Nucleopiles
path A
O
RL
H
OR
OR
H CO
H
RL
Nu
RL
path B
Chelation model
path C
X = OCOPh X = OAc X = NMe2
96 : 4 95 : 5 >99 : 1
Shanghai Jaiotong University, Spring 2008
If chelation is considered……
O Me
Ph X
PhMe2Si–H TFA, 0 °C
OH Me
Ph X
H
H
HO Ph
H
PhMg–Br
51%
PhMg–OTf
27%
PhMg–OTs
15%
PhMg-SO3mesityl 10%
49% 73% 85% 90%
Reetz, Angew. chem. Int. Ed. 1992, 31, 343
Shanghai Jaiotong University, Spring 2008
20 : 80 >99 : 1 >99 : 1 5 : 95
G. Keck & Co-workers, Tetrahedron Lett. 1984, 25, 265
Shanghai Jaiotong University, Spring 2008
Chelation model
TBSO
Me
O OCH2OBn
59% 79% 95%
Reetz, Angew. Chem. Int. Ed. 1992, 31, 343
Shanghai Jaiotong University, Spring 2008
Enhancing C=O face selectivity by changing the organometal
Enhancing C=O face selectivity by modifying the ligands on a given organometal.
H Me
O PhMgX
H Me
Ph OH
PhMg–Br PhMg–OTs PhMg-SO3Mesityl
41% 21% 5%
HO H
Ph
Me
Shanghai Jaiotong University, Spring 2008
Shanghai Jaiotong University, Spring 2008
The Issues Associated with the Reduction Process
Steric Effects: Attack across equatorial C=O face sterically more favorable. Torsional Effects: However, attack across the axial face of the C=O group avoids development of eclipsing interactions in the transition state.(Note the dihedral angle sign changes between reactants & products shown above). These "torsional effects" favor axial attack.
Shanghai Jaiotong University, Spring 2008
Stereoselective Organometallic Addition Reactions
O R¨CM
H
HC C Li Et MgBr i-Pr MgBr t-Bu MgBr
OH
R
H 12% 47% 82% 100%
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Product Development & Steric Approach Control: Dauben, JACS 1956, 78, 2579
Shanghai Jaiotong University, Spring 2008
Shanghai Jaiotong University, Spring 2008
Prediction of Hydrides addition to Carbonyl Group (Reaction)
For "small" hydride reagents such as LiAlH4, torsional effects are felt to be dominant and this explains the predisposition for axial attack. For "large" hydride reagents such as H–BR4, steric effects now are dominant and this explains the predisposition for equatorial attack.