http://www.courses.fas.harvard.edu/~chem206/
EtO Me
O
n-C4H9
OTs
H
EtO Me
OLi
n-C4H9
OTs
H
C
HBu
(CH2)4OTs
C OLiORMeC
H
Bu
TsO(H2C)4 C
OLi
ORMe
C
H
Bu (CH2)4OTs
C OLiORMe
C
H Bu
(CH2)4OTs
C OLiORMe C
H
Bu
(CH2)4OTs
C OLiORMeC
TsO(H2C)4
H
Bu
C OLiORMe
Hn-C4H9
EtO2C Me
Hn-C4H9
O Me
EtO
A1 B1 C1
A2 B2 C2
LiNR2
Chem 206D. A. Evans
Carl A. Morales Friday, September 27, 2002
Chemistry 206
Advanced Organic Chemistry
Lecture Number 5
Acyclic Conformational Analysis-2
a73 Conformations of Simple Olefinic Substrates
a73 Introduction to Allylic Strain
a73 Introduction to Allylic Strain-2: Amides and Enolates
a73 Reading Assignment for week
Acyclic Conformational Analysis-2
A. Carey & Sundberg: Part A; Chapters 2 & 3
R. W. Hoffmann, Chem. Rev. 1989, 89, 1841-1860Allylic 1-3-Strain as a Controlling Element in Stereoselective Transformations
R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 2000, 39, 2054-2070Conformation Design of Open-Chain Compounds
F. Weinhold, Angew. Science 2001, 411, 539-541"A New Twist on Molecular Shape"
98:2
Can you predict the stereochemical outcome of this reaction?
a73 Problems of the Day: (To be discussed)
2
1
critical conformations
1 2+
a73 Relevant enolate
conformations major
minor
~ 3.1 ~ 3.7 ~3.9 ~ 7.6
Estimates of In-Plane 1,2 &1,3-Dimethyl Eclipsing Interactions
Me Me MeMe Me MeMeMe
Hierarchy of Vicinal Eclipsing Interactions
δ E kcal mol -1+1.0
+1.4+3.1C C
X Y
HH H H
X Y
H HH Me
Me Me
Useful Destabilizing Interactions to Remember
It may be concluded that in-plane 1,3(Me?Me) interactions are Ca +4 kcal/mol while 1,2(Me?Me)
interactions are destabliizing by Ca +3 kcal/mol.
minimized structure
Chem 206D. A. Evans
Stabilized Eclipsed Conformations in Simple OlefinsD. A. Evans Chem 206
Butane versus 1-Butene
eclipsed conformationstaggered conformation
? G° = +4 kcal mol-1
MeC
H
C H H MeH Me H
HH H
Me
eclipsed conformationstaggered conformation
? G° = –0.8.3 kcal mol-1
Me
CC H H CH2CH2
HH
Me
+1.33kcal
+1.32 kcal
+0.49 kcal
Φ = 180
Φ = 120
Φ = 50
Φ = 0
Φ = 180Φ = 0
The Torsional Energy Profile
Conforms to ab initio (3-21G) values:Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035.
H CH C H
H
HH C
H C H
H H
H CH C HH
H
Me Me
HH
C HCHH
Me Me
Simple olefins exhibit unusal conformational properties relative to their saturated counterparts a73 The Propylene Barrier C
H
CH2
H
H
H
CH CH2
Heclipsed conformation
staggered conformation
+2.0 kcal/mol
a73 Acetaldehyde exhibits a similar conformational bias
O
HHH H
O
MeHH H
O
HMeH H
O
MeMeH H
The low-energy conformation in each of above cases is eclisped
H Me
H H HH
109° H CH
2
H HH
120°Propane versus Propene
Hybridilzation change opens up the C–C–C bond angle
K. Wiberg, JACS 1985, 107, 5035-5041
X C H
H
H
H repulsive interaction between pi–C–X & σ–C–H
X C H
H
H
K. Houk, JACS 1987, 109, 6591-6600
New destabilizing effect
H
H
0
1
2
3
4
5
-180 -90 0 90 180
0
1
2
3
4
5
-180 -90 0 90 180
CH C HH
OH
H H
CH C HH
Me
H H
C HCHH
Me
H
H Me
H
H C HC
H
H
Me
H
H
CH C HH
Me
H
H
CH C HH
HO
H
H
C HCHH
OH
H
HC
H C H
H
HO
H
H
C HCHH
OH
H
H
C HCHH
ΦΦ
Φ = 180Φ = 0
Φ = 0
Φ = 60
Φ = 120
Φ = 180
+1.18 kcal
+0.37 kcal
+2.00kcal
+1.33kcal
+1.32 kcal
+0.49 kcal
Φ = 180
Φ = 120
Φ = 50
Φ = 0
Φ = 180Φ = 0
E (kca
l/mol)
The Torsional Energy ProfileThe Torsional Energy Profile
Chem 206Evans, Duffy, & Ripin Conformational Barriers to Rotation: Olefin A-1,2 Interactions
(Deg)
E (kca
l/mol)
2-propen-1-ol1-butene
Conforms to ab initio (3-21G) values:Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035.
(Deg)
0
1
2
3
4
5
-180 -90 0 90 180
0
1
2
3
4
5
-180 -90 0 90 180
Chem 206Evans, Duffy, & Ripin Conformational Barriers to Rotation: Olefin A-1,2 Interactions-2
(Deg)
2-methyl-1-butene
E (kca
l/mol
)
+2.68kcal
+1.39 kcal
+0.06 kcal
Φ = 180
Φ = 110
Φ = 50
Φ = 0
Φ = 180Φ = 0
The Torsional Energy Profile
(Deg)
2-methyl-2-propen-1-ol
E (kca
l/mol
)
The Torsional Energy Profile
Φ = 0 Φ = 180
Φ = 0
Φ = 60
Φ = 120
Φ = 180
+0.21 kcal
+1.16 kcal
+2.01kcal
H CH C Me
H
H
H CH C MeH H
H CH
Me
H H
C MeCHH
C MeH
H
Me
Me
HH
C MeCHH
Me
Me
H CH C Me
HH
OH
OH
HO
H CH HC MeH
OH
HO
H
HC MeC
HH
HH C MeCHH
H
H C MeCH
H
Φ Φ
0
1
2
3
4
5
-180 -90 0 90 180
0
1
2
3
4
5
-180 -90 0 90 180
Values calculated using MM2 (molecular mechanics) force fieldsvia the Macromodel multiconformation search. Review: Hoffman, R. W. Chem. Rev. 1989, 89, 1841.
(Z)-2-buten-1-ol(Z)-2-pentene
(Deg) (Deg)
Chem 206Evans, Duffy, & Ripin Conformational Barriers to Rotation: Olefin A-1,3 Interactions
E (kca
l/mol
)
E (kca
l/mol
)
+0.86kcal
+1.44 kcal
Φ = 180
Φ = 120
Φ = 0
Φ = 180Φ = 0
The Torsional Energy ProfileThe Torsional Energy Profile
Φ = 0 Φ = 180
Φ = 0
Φ = 90
Φ = 180+3.88 kcal
+0.52kcal
H CMe C H
H
H
H CMe
Me
H H
C HCMeH H
CMe C HHH
OH
C HH
H
HO
OH
HH
C HCMeH
OH
Me
H CMe C HH H
Me
Me
H
HC HC
MeH
H
H C HCMe
H
Φ
Φ
0
1
2
3
4
5
-180 -90 0 90 180
60 °
2.7 kcal/mol
Lowest energy conformer
30 °
+0.66
+4.68
+0.40 kcal+0.34
Φ = -80
Φ = 0
Φ = 80
E (kca
l/mol)
+2.72
Φ = 150
Φ = 110
Φ = -140
Φ = 180Φ = 0
The Torsional Energy Profile
Chem 206Evans, Duffy, & Ripin Conformational Barriers to Rotation: Olefin A-1,3 Interactions-2
(Z)-2-hydroxy-3-pentene
Rotate clockwise
(Deg)
30 °
Lowest energy conformer
100 °
100 °
4.6 kcal/mol
0.3-0.4 kcal/mol
H CMe C HH OH
Me
H CMe C HHHO
H CMe
H CMe C H
HHO
Me
C H
H
HO Me
Me
OHH C HC
MeH
Me
HMe
OH
C HCMeH
H CMe C HH
HO
Me
Me
OH
MeOH
H Me
C HCMeH
H
Me
H C
Me C HMe
H
OH
CHMe CH OH H
HO
Me
C HCMeH
OH
MeMe
H
Me
H C
CH CHO
Me
OH
H
Me
C MeH
H
A(1,3) interaction 4.0 kcal/mol
A(1,2) interaction 2.7 kcal/mol (MM2)
3
2 1R
small
R3 X
YR2 R1 R
large*
Φ
D. A. Evans Chem 206
O Me
Me OH Me
O
HO
Me OH
Me
Me
O
Me
OH
Me
O
NH2H
16
17
hinge
- immunosuppressive activity- potent microtubule-stabilizing agent
(antitumor activity similar to that of taxol)
The conformation about C16 and C17 is critical to discodermolide's biological activity.
Discodermolide
The epimers at C16 and C17 have no or almost no biological activity.
S. L. Schreiber et al. JACS 1996, 118, 11061.
Conformational Analysis - Discodermolide X-ray 1D. A. Evans Chem 206
O Me
Me
OH
Me
O
HO
Me
OH
Me
Me
O
Me
OH
Me
O
NH2H
Conformational Analysis - Discodermolide X-ray 2D. A. Evans Chem 206
O Me
Me OH Me
O
HO
Me OH
Me
Me
O
Me
OH
Me
O
NH2H
16
16
R
C R1
N
O
R3
R1
Me
Me N
CO Me
Me
N
HO
CO
RH
R large
Y R1
X
R2
R3
R small
NC
O
R
H
R
R
R3 N
C–O R1
R+
N
C
R
R–O
+ HCR
O
N
R
MeCRO
N
HHMe
NC
O
R
Me
H
Me
H
N MeMe
Ph
O O
O
N
R
O H
H H
HO
N
R
C
N R
–O
R
R
R
+
C
R N
O
R
R
R
C
H
Me H
O N LL
C
MeH
H
O N LL
C
HMe
H
O N L
L
C
H
H Me
O N
L
L
Me N
L
OM
L
H
N L
OM
LMe
HN
O
HHOCO
PhPh
OH
O
N
N
H
H
O
R H
O
HN
R
H
O
HN
C
O
R
HCO2H
?
?
base
base
(Z)-Enolate
disfavored
favored
(E)-Enolate
As a result, amides afford (Z) enolates under all conditions
A(1,3) interaction between the C2 & amide substituents will strongly influence the torsion
angle between C1 & C2.
1 221
DisfavoredFavored
Favored forR = CORFavored for
R = H, alkyl
The selection of amide protecting group may be done with the knowledge that altered conformational preferences may result:
Allylic Strain & Amide ConformationD. A. Evans Chem 206
a54
a54
D. Hart, JACS 1980, 102, 397
diastereoselection >95%
a73 Problem: Predict the stereochemical outcome of this cyclization.
published X-ray structure of this amide shows chairdiaxial conformation
Quick, J. Org. Chem. 1978, 43, 2705
ChowCan. J. Chem. 1968, 46, 2821
strongly favored
a73 conformations of cyclic amides
strongly favored
A(1,3) interactions between the "allylic substituent" and the R1 moiety will strongly influence the torsion angle between N & C1.
1
12
3Consider the resonance structures of an amide:
Disfavored Favored
A(1,3)
identify HOMO-LUMO pair
O N RRC
R
Me H
O N RRC
H
R Me
MO O
N OMe
BnBn
Me
O
N O
O
Bn
Me
O
N O
O
El
C
HMe
H
O N L
L
C
HMe
El
O N L
L C
H
Me El
O N L
L
C
H
MeEl
O N L
L
A CB
Bn
Me
O
N O
O
CH2OHO
Me N Me N
O
Me
Me
OH
O
HO
Me
SR
O
O
R SR R SR
O
Me
O
R SR
OH
Me
O
N O
OO
Me
O
Me
O
N O
O
Me
Li
Et Cl
O
Allylic Strain & Amide ConformationD. A. Evans Chem 206
El(+) JACS. 1982,104, 1737.
LDA
or NaNTMS2 enolization selectivity >100:1
A(1,3) Strain and Chiral Enolate Design
?
favoredenolization geometry
a73 In the enolate alkylation process product epimerization is a serious problem. Allylic strain suppresses product enolization through the
intervention of allylic strain
While conformers B and C meet the stereoelectronic requirement for enolization, they are much higher in energy than conformer A. Further, as
deprotonation is initiated, A(1,3) destabilization contributes significantly to reducing the kinetic acidity of the system
These allylic strain attributes are an integral part of the design criteria of chiral amide and imide-based enolate systems
Evans JACS 1982,104, 1737.EvansTetr Lett. 1977, 29, 2495 Myers JACS 1997, 119, 6496
Polypropionate Biosynthesis: The Acylation Event
Acylation Reduction
– CO2
First laboratory analogue of the acylation event
Diastereoselection ~ 97 : 3
favored
X-ray structure
with M. Ennis JACS 1984, 106, 1154.
Why does'nt the acylation product rapidy epimerize at the exocyclic stereocenter??
a70
Allylic Strain & Enolate Diastereoface SelectionD. A. Evans Chem 206
Y. Yamaguchi & Co-workers, Tetrahedron Letters 1985, 26,1723.
R = Me: > 15 :1R = H: one isomerTHF -78 °C
diastereoselection 90:10 at C3one isomer at C
271% yield
I. Fleming & Co-workers, Chem. Commun. 1986, 1198.
Me–CHO
Me–IPh(MeS)2C–Li86% diastereoselection 99:1
K. Koga & Co-workers, Tetrahedron Letters 1985, 26, 3031.
T. Mukaiyama & Co-workers, Chem. Letters 1986, 637
diastereoselection >95%
91-95%
Y. Yamamoto & Co-workers, Chem. Commun. 1984, 904.
major diastereomer opposite to that shown40:60
80:2087:13R = CHMe
2
R = EtR = Me
R-substituent diastereoselection
I. Fleming & Co-workers, Chem. Commun. 1985, 318.
R = Ph: diastereoselection 97:3R = Me: diastereoselection 99:1
I. Fleming & Co-workers, Chem. Commun. 1984, 28.
D. Kim & Co-workers, Tetrahedron Lett. 1986, 27, 943.
diastereoselection 98:2
G. Stork & Co-workers, Tetrahedron Lett. 1987, 28, 2088.
"one isomer"
95% yield
"one isomer"
T. Money & Co-workers, Chem. Commun. 1986, 288.
diastereoselection 89:11
RMe3Si OMe
Ph O
N
OMPh
OMeMe3Si R
N
Me O S
NBoc N SBnBn SBoc
S OMe
OHR
H
OMe
OMeMeSMeS
Me
Me3Si
MeS
OBn
Ph O OPh
OBnMe3Si
Me
H
O
OMeMe
OH
H
H CO2Et
CO2-t-Bu
OLi
O-t-BuCO2Et
I
R
R
CO2Me
MeRO
2C O
O
H H
O ORO
2C
Me
CO2Me
EtO Me
O
n-C4H9
OTs
H Hn-C4H9
O Me
EtO
Br H
EtO
H
CH2
EtO
O
CO2Me
MeTBSOCH
2H
CH2
H
TBSOCH2 Me
CO2Me
Me
n-C4H9 H
MeO
n-C4H9 H
MePhMe2Si OEt
R OOMR
OEtPhMe2Si
KOt-Bu
LiNR2
R–CHOSn(OTf)2
NH4Cl
MeI
LiNR2
LiNR2
LiNR2MeI
LiNR2MeI