05 Conformational Anal 2

Acyclic Conformational Analysis-2
D. A. Evans
http://www.courses.fas.harvard.edu/colgsas/1063
Chem 206
! Problems of the Day:

Can you predict the stereochemical outcome of this reaction?
O
Chemistry 206
OTs
Me
EtO
Advanced Organic Chemistry
n-C4H9
OLi
LiNR2
Me
EtO
n-C4H9
OTs
98:2
Lecture Number 5
D. Kim & Co-workers, Tetrahedron Lett. 1986, 27, 943.
Acyclic Conformational Analysis-2
OH
Introduction to Allylic Strain
CH2OBn
O
Me
Me
B2H6
H2O2
"
"
O
Me
CH2OBn
Me
diastereoselection 8:1
! Reading Assignment for week

A. Carey & Sundberg: Part A; Chapters 2 & 3
R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 2000, 39, 2054-2070
Conformation Design of Open-Chain Compounds (handout)
Y. Kishi & Co-workers, J. Am. Chem. Soc. 1979, 101, 259.
Me
Me
R. W. Hoffmann, Chem. Rev. 1989, 89, 1841-1860

Allylic 1-3-Strain as a Controlling Element in Stereoselective Transformations
(handout)
Me
PhNCO
Et3N
"
Me
"
O
N
NO2
only one isomer
A. Kozikowski & Co-workers, Tetrahedron Lett. 1982, 23, 2081.
D. A. Evans
Wednesday,
September 27, 2006
We call this
Allylic Strain
D. A. Evans
Chem 206
Acyclic Conformational Analysis: Allylic Strain
The Definition of Allylic Strain
Can you predict the stereochemical outcome of this reaction?

F. Johnson, Chem. Rev. 1968, 68, 375; Allylic Strain in Six-Membered Rings
R. W. Hoffmann, Chem. Rev. 1989, 89, 1841-1860 (handout)
Allylic 1-3-Strain as a Controlling Element in Stereoselective Transformations
OTs
Houk, Hoffmann JACS 1991, 113, 5006

R2
Consider the illustrated general structure

where X & Y are permutations of C, N, and O:
R3
EtO
3
Y
OLi
Me
LiNR2
R1
n-C4H9
R small
! Relevant enolate
R3
R2
R1
N
R large
R2
R1
N
R +
R large
R small
R small
Olefin
R large
R2
R1
N
O +
R small
Imine
In the above examples, the resident allylic stereocenter (!) and its associated
substituents frequently impart a pronounced bias towards reactions occuring at
the pi-bond.
Nonbonding interactions between the allylic

substituents (Rlarge, Rsmall) & substituents at
the 2- & 3-positions play a critical role in
defining the stereochemical course of such
reactions
A(1,2)
R2
R3
Y
2
(CH2)4OTs
TsO(H2C)4
Me
A1
R large
R small
interaction
OR
OR
Me
Bu
OLi
Bu
C
H
Bu
Me
OLi
H
Me
OR
TsO(H2C)4
C
Bu
OLi
Bu
C
Bu
OR
OLi
OR
Me
H
Me
HO
O
R
OBn
Hg(OAc)2
NaBH4
HO Me
R
OBn
M. Isobe & Co-workers, Tetrahedron Lett. 1985, 26, 5199.
(CH2)4OTs
A2
B2
C2
Representative Reactions controlled by Allylic Strain Interactions

HO
(CH2)4OTs
OR
C
C
OLi
C1 H
B1
H
Me
H
C
critical conformations
A(1,3)
interaction
R1
major
R large
Nitrone
Me
1
n-C4H9
R small
Imonium ion
98:2
EtO
conformations
R1
n-C4H9
Typical examples:
R2
Me
EtO
R large
X
2
OTs
EtO2C
Me
minor
n-C4H9
OLi
(CH2)4OTs
D. A. Evans
O
OTs
Me
EtO
LiNR2
n-C4H9
Me
LiNR2
MeI
Me3Si
R-substituent
diastereoselection
R = Me
R = Et
87:13
80:20
R = CHMe2
40:60
Me
n-C4H9
H
Ph
Ph
O
OBn
LiNR2
Me
H
CO2Me
95% yield
Me
OH
"one isomer"
Br
H
CO2Me
one isomer at C2
I. Fleming & Co-workers, Chem. Commun. 1986, 1198.
RO2C
H
OBn diastereoselection 90:10 at C3
Me3Si
MeCHO
71% yield
MeO
LiNR2
Me3Si
RO2C
major diastereomer opposite

to that shown

Y. Yamamoto & Co-workers, Chem. Commun. 1984, 904.
MeO
OMe
EtO
Me3Si
OMe
Ph
OM
NH4Cl
O
EtO
Ph
EtO
n-C4H9
n-C4H9
Chem 206
Allylic Strain & Enolate Diastereoface Selection
Bn
G. Stork & Co-workers, Tetrahedron Lett. 1987, 28, 2088.
Me
Sn(OTf)2
Bn
RCHO
Boc
S
N
Boc
R
91-95%
S diastereoselection >95%
OH
T. Mukaiyama & Co-workers, Chem. Letters 1986, 637
TBSOCH2
Me CH2
Me CH2
LiNR2
MeI
TBSOCH2
"one isomer"
Me H
H
CO2Me
Me
OMe
86%
PhMe2Si
OEt
MeI
PhMe2Si
OEt
Me
MeS
MeS
Me
O
OMe diastereoselection 99:1
MeS
Me
K. Koga & Co-workers, Tetrahedron Letters 1985, 26, 3031.
I
CO2Et
OM
MeI
H
CO2Me
T. Money & Co-workers, Chem. Commun. 1986, 288.
Ph(MeS)2CLi
R = Me: diastereoselection 99:1

R = Ph: diastereoselection 97:3
OLi
R
O-t-Bu
KOt-Bu
THF -78 C
CO2Et
R = H: one isomer
CO2-t-Bu R = Me: > 15 :1

H
Y. Yamaguchi & Co-workers, Tetrahedron Letters 1985, 26,1723.
D. A. Evans
Chem 206
Allylic Strain & Olefin Hydroboration
! The basic process
Hydroborations dominated by A(1,3) Strain

S
S
H
OH
H2B
C
R
B2H6
OMe
OMe OH
B2H6
Me
Me
OH
Me
A
CH2
Me3C
Oxidant
Ratio, A:E
MCPBA
69:31
JOC, 1967, 32, 1363
BH3, H2O2
34:66
JOC, 1970, 35, 2654
Y. Kishi & Co-workers, J. Am. Chem. Soc. 1979, 101, 259.
Reference
OH
BnO
OH
Me
Me
B2H6
BnO
H2O2
Me
OH
Me
R2BH
major diastereomer
OH
RM
Me
R
R
control elements
H
H
RM
A(1,3) allylic strain

Steric effects; RL vs RM
Staggered transition states
Me
Me
Me
ThexylBH2,
Me
C
CH2OR
OH
TrO
OTr
OH
R2BH
Me
RL
H2O2
OH
TrO
H
H
RM
H
OH
OH
OH
Diastereoselection;
5:1
Me
Me
ThexylBH2,
Me
CH2OR
Me
OH
OH
OH
OTr
OH
OH
OH
OH
OTr
Diastereoselection;
Me
RL
OTr
then BH3 TrO
Me
R
See Houk, Tetrahedron 1984, 40, 2257
Me
Me
major diastereomer
OH
RM
Me
Me
TrO
then BH3
RL
Me
Me
C. H. Heathcock et. al. Tetrahedron Lett 1984 25 243.
RL
H2O2
Me
Diastereoselection = 3:1
OH
RL
OH
Me
! Acyclic hydroboration can be controlled by A(1,3) interactions:
RM
OH
H2O2
Me
Me
RL
Me
Me
Me
RM
CH2OBn
H2O2
Me
Me
CH2OBn
4: 1
Still, W.C.; Barrish, J. C. J. Am. Chem. Soc. 1983, 105, 2487.
OH
D. A. Evans
Consider the resonance structures of an amide:
O
R3
Chem 206
Allylic Strain & Amide Conformation
R1
R3
R1
C
N
+
R2
R3
R large
X
2
The selection of amide protecting group may be done with the knowledge that
altered conformational preferences may result:
R1
R small
A(1,3) interactions between the "allylic substituent" and the R1 moiety will
strongly influence the torsion angle between N & C1.
Me
C
N
Me
R C
R C
Ph
Favored
O
N
C
O
H
strongly favored
H
H
Me
N
R C
Me
O
R C
H
N
Me
Me
strongly favored
HCO2H
D. Hart, JACS 1980, 102, 397
O
Me
N
H
N
+ R
OM
base
favored
O
Me
Ph O
diastereoselection >95%
N
H
Me
L
H
(Z)-Enolate
H
H
O
H
N
Me L
OM
base
disfavored
O
H
N
Ph
H
H
HOCO
As a result, amides afford (Z) enolates under all conditions
" Problem: Predict the stereochemical outcome of this cyclization.

OH
A(1,3) interaction between the C2 & amide

C
R
substituents will strongly influence the torsion
N
angle between C1 & C2.
R
R
Quick, J. Org. Chem. 1978, 43, 2705
published X-ray structure of this amide shows chair

Me diaxial conformation
H R
Me
Disfavored
A(1,3)
Chow
Can. J. Chem. 1968, 46, 2821
N
+
! conformations of cyclic amides

C
Disfavored
Me
Favored for
R = COR
Favored
Me
Favored for
R = H, alkyl
identify HOMO-LUMO pair
N
Me L
N
Me
(E)-Enolate
D. A. Evans
Polypropionate Biosynthesis: The Acylation Event
A(1,3) Strain and Chiral Enolate Design

O
Me
O
N
O
LDA
O
Me
or NaNTMS2
Bn
enolization selectivity
>100:1
Bn
Me
N
H
JACS. 1982,104, 1737.

O
Me
SR
SR
Me
Me
Li
O
Et
O
!
Me
Cl
O
Me
Me
R
with M. Ennis JACS 1984, 106, 1154.
Diastereoselection ~ 97 : 3
El
N
Me
L
L
N
H
Me
Me
O
El
N
L
L
Why does'nt the acylation product rapidy epimerize at the exocyclic

stereocenter??
R
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
O
Me
H
N
R
R
favored
These allylic strain attributes are an integral part of the design criteria of
chiral amide and imide-based enolate systems
O
O
Me
Reduction
First laboratory analogue of the acylation event
! In the enolate alkylation process product epimerization is a serious

problem. Allylic strain suppresses product enolization through the
intervention of allylic strain
O
El
CO2
SR
Me
Bn
OH
SR
El
favored
enolization geometry
Acylation
O
N
HO
El(+)
Chem 206
Allylic Strain & Amide Conformation
CH2OH
Me
O
O
N
N
Bn
Evans
Tetr Lett. 1977, 29, 2495
Evans
JACS 1982,104, 1737.
Me
Me
N
Me
OH
Myers
JACS 1997, 119, 6496
X-ray structure
O
R
N
Me
R
R
Discodermolide
D. A. Evans
Chem 206
hinge
Me
O H
Me
Me
16
HO
O
Me
Me
Me
Me
17
Me
OH
OH
NH2
O
OH
- immunosuppressive activity
- potent microtubule-stabilizing agent
(antitumor activity similar to that of taxol)
The epimers at C16 and C17 have no or almost no biological activity.
The conformation about C16 and C17 is critical to discodermolide's biological activity.
S. L. Schreiber et al. JACS 1996, 118, 11061.
D. A. Evans
Conformational Analysis - Discodermolide X-ray 1

Me
HO
O H
Me
Me
Me
Me
Me
OH
Me
Me
OH
OH
NH2
O
Chem 206
Conformational Analysis - Discodermolide X-ray 2
D. A. Evans
Me
HO
O
O H
Me
Me
Me
16
Me
Me
Me
Me
OH
OH
NH2
O
OH
16
Chem 206

05 Conformational Anal 2

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Acyclic Conformational Analysis-2

! Problems of the Day:

Advanced Organic Chemistry

Acyclic Conformational Analysis-2

Introduction to Allylic Strain

! Reading Assignment for week

Y. Kishi & Co-workers, J. Am. Chem. Soc. 1979, 101, 259.

R. W. Hoffmann, Chem. Rev. 1989, 89, 1841-1860

only one isomer

A. Kozikowski & Co-workers, Tetrahedron Lett. 1982, 23, 2081.

Acyclic Conformational Analysis: Allylic Strain

The Definition of Allylic Strain

Can you predict the stereochemical outcome of this reaction?

Houk, Hoffmann JACS 1991, 113, 5006

Consider the illustrated general structure

Nonbonding interactions between the allylic

Representative Reactions controlled by Allylic Strain Interactions

I. Fleming & Co-workers, Chem. Commun. 1986, 1198.

OBn diastereoselection 90:10 at C3

major diastereomer opposite

I. Fleming & Co-workers, Chem. Commun. 1985, 318.

D. Kim & Co-workers, Tetrahedron Lett. 1986, 27, 943.

Allylic Strain & Enolate Diastereoface Selection

G. Stork & Co-workers, Tetrahedron Lett. 1987, 28, 2088.

T. Mukaiyama & Co-workers, Chem. Letters 1986, 637

K. Koga & Co-workers, Tetrahedron Letters 1985, 26, 3031.

T. Money & Co-workers, Chem. Commun. 1986, 288.

R = Me: diastereoselection 99:1

I. Fleming & Co-workers, Chem. Commun. 1984, 28.

CO2-t-Bu R = Me: > 15 :1

Y. Yamaguchi & Co-workers, Tetrahedron Letters 1985, 26,1723.

Allylic Strain & Olefin Hydroboration

! The basic process

Hydroborations dominated by A(1,3) Strain

JOC, 1967, 32, 1363

JOC, 1970, 35, 2654

Y. Kishi & Co-workers, J. Am. Chem. Soc. 1979, 101, 259.

A(1,3) allylic strain

then BH3 TrO

See Houk, Tetrahedron 1984, 40, 2257

C. H. Heathcock et. al. Tetrahedron Lett 1984 25 243.

! Acyclic hydroboration can be controlled by A(1,3) interactions:

Still, W.C.; Barrish, J. C. J. Am. Chem. Soc. 1983, 105, 2487.

Allylic Strain & Amide Conformation

D. Hart, JACS 1980, 102, 397

As a result, amides afford (Z) enolates under all conditions

" Problem: Predict the stereochemical outcome of this cyclization.

A(1,3) interaction between the C2 & amide

Quick, J. Org. Chem. 1978, 43, 2705

published X-ray structure of this amide shows chair

! conformations of cyclic amides

identify HOMO-LUMO pair

Polypropionate Biosynthesis: The Acylation Event

A(1,3) Strain and Chiral Enolate Design

JACS. 1982,104, 1737.

with M. Ennis JACS 1984, 106, 1154.

Why does'nt the acylation product rapidy epimerize at the exocyclic

While conformers B and C meet the stereoelectronic requirement for

First laboratory analogue of the acylation event

! In the enolate alkylation process product epimerization is a serious

Allylic Strain & Amide Conformation

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 1