chemistry 5.511 synthetic organic chemistry iweb.mit.edu/5.511/www/10-10-07.pdf · synthesis...
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Strategies for StereocontrolledSynthesis
Lecture 3October 10, 2007
Rick L. DanheiserMassachusetts Institute of Technology
Chemistry 5.511Synthetic Organic Chemistry I
Strategies for StereocontrolledSynthesis
O
O OH
CO2H
OH
OHOH
OH
OHOHO
Me
MeHO
Me
O O MeOH
NH2HOamphotericin B
OO
OH
H
HO
OH
OH O NH2
O
discodermolide
O
O OOH
HO
O
N
S
epothilone A
OMe
OO
N
OMe MeMeO
MeOH
H
H
O
HO
O
Me
Me
OH
MeO
H
O
FK506
Strategies for StereocontrolledSynthesis
Asymmetric SynthesisReaction or sequence that selectively creates one ormore stereogenic elements by reaction at heterotopicfaces, atoms, or groups in the substrate(s)
Reading on Stereochemical Principles
Carey and Sundberg "Advanced Organic Chemistry" Part A (2000) Chapters 2 and 3
E. L. Eliel and S. H. Wilen
"Stereochemistry of Organic
Compounds" (1994)
5.511 TextGawley and Aube
Strategies for StereocontrolledSynthesis
Thermodynamic Control Strategies
Kinetic Control Strategies
Strategies for the Synthesis of Acyclic Target Molecules: Chirality Transfer Case Study: Prostaglandins from Sugars
(Stork)
Strategies for StereocontrolledSynthesis
Thermodynamic control strategies What determines the relative E of stereoisomers Tactics for establishing thermodynamic control
Kinetic control strategies Substrate control strategies Reagent control strategies Dynamic kinetic resolution
Strategies for StereocontrolledSynthesis
Thermodynamic Control Relative energy of diastereomers determines outcome of reaction
A X Y
or
AX
Y
9 : 1 = 90 : 1025 : 1 = 96 : 449 : 1 = 98 : 2
ΔGxy0.5 kcal/mol 70:301.0 kcal/mol 84:161.5 kcal/mol 92:82.0 kcal/mol 97:3
Strategies for StereocontrolledSynthesis
Kinetic Control Ratio of products determined by relative energy of diastereomeric transition states
A
X
Y
k1
k2
Strategies for StereocontrolledSynthesis
Thermodynamic control strategies What determines the relative E of stereoisomers Tactics for establishing thermodynamic control
O
O OOH
HO
O
N
S
epothilone A
Strategies for StereocontrolledSynthesis
Thermodynamic Control Relative energy of diastereomers determines outcome of reaction
I. What determines the relative energy of stereoisomers? De-stabilizing Non-bonded Repulsion
Stabilizing Non-covalent Interactions
Stereoelectronic Effects
Deviation from optimal geometry for orbital overlap (angle strain)
Destabilizing torsional interactions
Stabilizing secondary orbital interactions Dipole-dipole interactions
Strategies for StereocontrolledSynthesis
Tactics for Establishing Thermodynamic Control
Case Study #1 Cycloreversion
O O
O
O
O
O
O
OO
O
O
O
+
endo exo
+
Herndon et al. J. Org. Chem. 1978, 43, 518
Room temperature
40 °C, 24-48 h
100 : 0
0 : 100ΔΔG‡ = 3.8 kcal/mol activation barrier lower for endo
ΔG = 1.9 kcal/mol exo more stable
Strategies for StereocontrolledSynthesis
Tactics for Establishing Thermodynamic ControlCase Study #2 Equilibration via Enolates I
G. Stork et al. J. Am. Chem. Soc. 1976, 98, 1583
O
CO2H
HO
PGA2
O
CO2R
RO
H
RO2C
CO2R
RO
H
RO2C
1) KOt-Bu THF, rt2) NaOH, H2O !
H
R2R1
H
O
Strategies for StereocontrolledSynthesis
Tactics for Establishing Thermodynamic ControlCase Study #3 Equilibration via Enolates II
G. Solladie et al. Tetrahedron Lett. 1987, 28, 797
H OR
O
OH OH
H OR
O
OH OH
available via Solladie chemistry
H OR
O
OH OH
H OR
O
OH OH
acetone
cat. TsOH
O O
OHC
OR
Strategies for StereocontrolledSynthesis
Tactics for Establishing Thermodynamic ControlCase Study #3 Equilibration via Enolates II
G. Solladie et al. Tetrahedron Lett. 1987, 28, 797
H OR
O
OH OH
H OR
O
OH OH
available via Solladie chemistry
H OR
O
OH OH
aq HCltarget
H OR
O
OH OH
acetone
cat. TsOHO
O
CHO
OR
O
O
OR
OHC
K2CO3MeOH
Strategies for StereocontrolledSynthesis
Tactics for Establishing Thermodynamic ControlCase Study #4 Equilibration via Ionization
R. L. Danheiser et al. J. Am. Chem. Soc. 2003, 125, 4970
TsN
N
CN
toluene 85 °C 15 h
CH3CN 120 °C 18 h
TsN
N
H
CN
Heat
CH3 CH3
TsN
N
H
CN
CH3
+
63 37
0 100
N
N
HCN
TsN
N
H
CN
CH3
Ts
CH3
Strategies for StereocontrolledSynthesis
Tactics for Establishing Thermodynamic ControlCase Study #5 Spiroketals - “Spontaneous Assembly”
Review on chemistry of spiroketals: K. F. Albizati et al. Chem. Rev. 1989, 89, 1617D. A. Evans et al. J. Am. Chem. Soc. 1979, 101, 6789S. L. Schreiber et al. J. Org. Chem. 1991, 56, 6255
O
O
OHO
1
2
3
6
OSiR3
OSiR3
O O OEtO
1 23
4
56
C-1 to C-9 Fragment of6-Deoxyerythronolide B CSA, MeOH, CCl4
Heat
87:13
90%
OH
O
OHO
*
*
*