D. A.

Evans

Chem 206

Acyclic Conformational Analysis: Allylic Strain

The Definition of Allylic Strain

Can you predict the stereochemical outcome of this reaction?

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

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

diastereoselection 10:1
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

diastereoselection 89:11

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

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

Y. Yamamoto & Co-workers, Chem. Commun. 1984, 904.

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

MeO

OMe

EtO

Me3Si

OMe

Ph

OM
NH4Cl

diastereoselection 98:2

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

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

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

diastereoselection 8:1

OMe

OMe OH

B2H6
Me

Me

OH

Me

diastereoselection 12:1

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

Evans, Kim, Breit

Chem 206

Conformational Analysis: Cyclic Systems-2

Cyclobutane

145-155

Cyclopentane
H

H
ax

ax
eq
eq

! = 28

eq

eq
ax
ax

! Eclipsing torsional strain overrides

increased bond angle strain by puckering.
! Ring barrier to inversion is 1.45 kcal/mol.

H
H

H
H

H H

CsEnvelope

H
H

H
H

H H

H
H

H
H

CsEnvelope

C2 Half-Chair

! Two lowest energy conformations (10 envelope and 10 half chair conformations
Cs favored by only 0.5 kcal/mol) in rapid conformational flux (pseudorotation)
which causes the molecule to appear to have a single out-of-plane atom "bulge"
which rotates about the ring.

(MM2)

! Since there is no "natural" conformation of cyclopentane, the ring conforms to

minimize interactions of any substituents present.

H
H

CsEnvelope
(MM2)

H
H

! !G = 1 kcal/mol favoring R = Me equatorial

! 1,3 Disubstitution prefers cis diequatorial to
trans by 0.58 kcal/mol for di-bromo cmpd.

H H

! A single substituent prefers the equatorial position of the flap of the envelope
(barrier ca. 3.4 kcal/mol, R = CH3).
! 1,2 Disubstitution prefers
trans for steric/torsional
reasons (alkyl groups) and
dipole reasons (polar groups).

Me
Me
! 1,2 Disubstitution prefers trans diequatorial to
cis by 1.3 kcal/mol for diacid (roughly equivalent
to the cyclohexyl analogue.)

H H

! 1,3 Alkyl Disubstitution: Cis-1,3-dimethyl

cyclopentane 0.5 kcal/mol more stable than trans.

! A carbonyl or methylene prefers the planar position of

the half-chair (barrier 1.15 kcal/mol for cyclopentanone).
X

Conformational Analysis: Cyclic Systems-3

Evans, Kim, Breit

Methylenecyclopentane and Cyclopentene

Strain trends:
>

>

! Decrease in eclipsing strain

more than compensates for the
increase in angle strain.

Relative to cyclohexane derivatives, those of cyclopentane prefer an sp2

center in the ring to minimize eclipsing interactions.

"Reactions will proceed in such a manner as to favor the formation or retention

of an exo double bond in the 5-ring and to avoid the formation or retention of
the exo double bond in the 6-ring systems." Brown, H. C., Brewster, J. H.;
Shechter, H. J. Am. Chem. Soc. 1954, 76, 467.

Examples:

H
O

NaBH4

k6

H
H
H H

H
H

OH

k6
= 23
k5

H
H H

NaBH4

k5

OH

Brown, H. C.; Ichikawa, K. Tetrahedron 1957, 1, 221.

Problem: Rationalize the regioselectivity of the following

O
O reduction
O

hydrolyzes
13 times faster than
NaBH4

OH
O
Conan, J-Y.; Natat, A.; Priolet, D. Bull. Soc. Chim., Fr. 1976, 1935.
O

Stork, JACS, 1979,

OH 7107.
O

O
OEt

95.5:4.5 keto:enol

OEt

76:24 enol:keto

Brown, H. C., Brewster, J. H.; Shechter, H. JACS 1954, 76, 467.

Chem 206

"Total Synthesis of the Antifungal Macrolide Antibiotic (+)-Roxaticin," Evans, D. A.; Connell, B. T.
J. Am. Chem. Soc., 2003, 125, 10899-10905

Me

Me

Me

Me

OTBSO

22

18

Me
27

Me
Me
O

27

Me

22

18

XO

X = C(CH2)4

OH

OH

OH

OH

Me

PPTS, rt, MeOH.

63%

PPTS, rt, MeOH.

OX

12

Me

<10%

Me
O

OX

12

X = CMe2

OTBSO

Me

XO

OH

Me
27

Me2CH

22
16

HO
12

OH

Roxiticin

Me

hydrolyzes
13 times faster than

Conan, J-Y.; Natat, A.; Priolet, D. Bull. Soc. Chim., Fr. 1976, 1935.

Conformational Analysis: Cyclic Systems-4

Evans, Breit

Monosubstituted Cyclohexanes: A Values

R

!G = RTlnKeq

! Meaxial has 2 gauche butane interactions more than Meequatorial.

Expected destabilization: ! 2(0.88) kcal/mol = ~1.8 kcal/mol;
Observed: 1.74 kcal/mol
Me

Me
C

Me
H
C

H
H

H
R

A Values depend on the relative size of the particular substituent.

Keq

Chem 206

Me
H

AValue

Me
Me

1.74

Me
Me

Me

1.80

2.15

5.0

The "relative size" of a substituent and the associated A-value may not correlate.
For example, consider the CMe3 and SiMe3 substituents. While the SiMe3
substituent has a larger covalent radius, it has a smaller A-value:

! The A Value, or -!G, is the preference of the substituent for the

equatorial position.

Me

Me
C Me

Me

Me

AValue

Me
Si Me

4.5-5.0

Me
Sn Me
H

2.5

1.1

Can you explain these observations?

! The impact of double bonds on A-values:

Lambert, Accts. Chem. Res. 1987, 20, 454
R

H
H

substituent

!"G

R = Me
R = OMe
R = OAc

0.8
0.8
0.6

A-value
(cyclohexane)
1.74
0.6
0.71

The Me substituent appears to respond strictly to the decrease in nonbonding

interactions in axial conformer. With the more polar substituents, electrostatic
effects due to the trigonal ring carbon offset the decreased steric environment.

Evans, Breit

Conformational Analysis: Cyclic Systems-5

Impact of Trigonal Carbon

Polysubstituted Cyclohexane A Values

! Let's now compare look at the carbonyl analog in the 3-position

Me

H
H

Me

Chem 206

! As long as the substituents on the ring do not interact in either

conformation, their A-values are roughly additive
1,4 Disubstitution: A Values are roughly additive.

Me

!G = 1.36 kcal/mol
versus 1.74 for cyclohexane

Me

Me

!G = 0 kcal/mol

Me
Me

! Let's now compare look at the carbonyl analog in the 2-position

Me
Me3C

base
epimerization
H

Me
Me

!G = 2(1.74) = 3.48 kcal/mol

Me

Me3C
O

!G = 1.56 kcal/mol
versus 1.74 for cyclohexane

1,3 Disubstitution: A Values are only additive in the trans diastereomer

X

However, the larger alkyl groups do not follow the expected trend.
Can you explain? (see Eliel, page 732)
CHMe2

base
epimerization

H
Me3C

Me3C

Me3C

Me

CHMe2

Me

Me

The new interaction!

For X = Me
H
CMe3

Me3C
O

!G = 1.62 kcal/mol
versus 5.0 for cyclohexane

!G = A(Me) A(X)

Me

The cis Isomer

!G = 0.59 kcal/mol
versus 2.15 for cyclohexane
base
epimerization

CMe3

Me

H
Me

Me

+ 0.88

H
Me

Me

!G = 2(.9) + 1(+3.7)= 5.5 kcal/mol

+ 3.7

+ 0.88

Conformational Analysis: Cyclic Systems-6

Evans, Breit

Let's now consider geminal substitution

Chem 206

Let's now consider vicinal substitution

Me

Ph

The prediction:

Me

Me

Ph

Case 1:

!G = A(Ph) A(Me)

Me
Me H

Me

The prediction:

!G = +2.8 1.7 = +1.1 kcal/mol

Observed:

!G = 1 gauche butane 2A(Me)

!G = +0.88 2(1.74) = +2.6 kcal/mol

!G = 0.32 kcal/mol
Observed:

!G = +2.74 kcal/mol

If the added gauche butane destabilization in the di-equatorial

conformer had not been added, the estimate would have been off.

Case 2:
Me
Me

OH
H
OH

Me
Me

The conformer which places the isopropyl group equatorial is much more
strongly preferred than would be suggested by A- Values. This is due to
a syn pentane OH/Me interaction.
Problem:
Can you rationalize the stereochemical outcome of this reaction?
O

O
EtO
n-C4H9

LiNR2
MeI
H

Me

EtO
n-C4H9

diastereoselection 89:11
D. Kim & Co-workers, Tetrahedron Lett. 1986, 27, 943.

Conformational Analysis: Cyclic Systems-7

Evans, Breit

Heteroatom-Substituted 6-Membered Rings

! A-values at the 2-position in both the O & N heterocycles are larger than
expected. This is due to the shorter CO (1.43 ), and CN (1.47 ) bond
lengths relative to carbon (CC; 1.53 ). The combination of bond length and
bond angle change increases the indicated 1,3-diaxial interaction (see eq 1, 4).

Reference:

Me

A-Values for N-Substituents in Piperidine

H
N

The Reference:
N

!G = 0.36 kcal/mol

Me

!G = 3.0 kcal/mol

Me

Chem 206

!"G = 1.74 kcal/mol

Me

! Hydrogen is "bigger" than the Nlone Pair.

Me

(1)

Me

!"G = 2.86 kcal/mol

Me
Me
H

!"G = 1.43 kcal/mol

!"G = 2.5 kcal/mol

Me

!"G = 1.95 kcal/mol

Me

!"G = 2.5 kcal/mol

Me

!"G = 1.6 kcal/mol

Me

!"G = 1.9 kcal/mol

O
Me
Me

H
O

(2)
(4)

H
H

H
H
H

Me

(3)

! The A-value of Nsubstituents is slightly larger than the corresponding

cyclohexane value. Rationalize

H
H

Me

(4)
N

Me

H
H

(5)

H
Me

(6) H N

H
H

Conformational Analysis: Bicyclic Ring Systems

Evans, Breit

Chem 206

Estimate the energy difference between the two methyl-decalins

shown below.
Me

Me

Hydrindane Ring System (6/5)

H

rigid

flexible

Decalin Ring System (6/6)

H

!G = 0.5 kcal/mol (at 23 C)

!G = 0.0 kcal/mol (at ~200 C)

mobile

rigid
! The turnover to favor the cis fusion results from the entropic preference for the
less ordered cis isomer.

The 5-5 Ring System

H
H

favored

2.4 kcal/mol

Relative !G

!G = +6.4 kcal/mol
Let's identify the destabilizing gauche butane interactions in the cis isomer
H

3
H

4
1

Me

Gauche-butane interactions
C1 ! C2
C1 ! C3
C4 ! C3

H
C

Me

A/B Trans

A/B Cis

"G(est) = 3(0.88) = 2.64 kcal/mol

Rationalize the conformational flexibility of a A/B Trans vs. A/B Cis Steroid!

Conformational Analysis: Axial vs Equatorial Reactivity

Evans, Breit

Different reactivity for axial and equatorial substituents

! SN2 Reactions (Displacement with PhS)

Axial substituents are more hindered, thus less reactive in many

transformations

Me3C

0.13
H

OH

Me3C

OH

The axial diastereomer is not always slower reacting:

! Alcohol Oxidation with Cr(6+)

0.27

! Acid-catalyzed esterification

CO2H
CO2H

Me3C

CO2Et

H
CO2Et

20

k rel

3.2
H

Me
OH

Me

OH

Me

H
Me

3.36

The rate-determining step is breakdown of the chromate ester. This is an

apparent case of strain acceleration

0.05

! Ester Saponification

k rel

Me

0.04
H

Me3C

Me

Me3C

CO2H
CO2H

Me3C

OH

k rel

OH

H
Me3C

k rel

31

k rel

OH
OH

Me3C

Me3C

OTs

k rel
H

k rel

OTs

! Acetylation with Ac2O/Py

k rel

Chem 206

Me3C

For a more detailed discussion of this topic see:

Eliel, E. L., S. H. Wilen, et al. (1994). Stereochemistry of Organic
Compounds pp 720-726