D. A. Evans
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 Houk, Hoffmann JACS 1991, 113 , 5006 R2
Consider the illustrated general structure where X & Y are permutations of C, N, and O:
R3
!
R3
R1 N
R large
!
R2 R large
R small
R small Olefin
N R +
R1 !
N O +
OTs Me
EtO
1
n-C4H9
H
O
1 !
Relevant enolate conformations
Me
major H
R large
R small Nitrone
A(1,3) interaction R2 3 R1 Nonbonding interactions between the allylic Y substituents (Rlarge, Rsmall) & substituents substituents at X R large the 2- & 3-positions play a critical role in R3 2 1 defining the stereochemical course of such R small reactions A(1,2) interaction
(CH2)4OTs TsO(H2C)4 Me A1
C
H C
OR
OR Me Bu
OLi
Bu
C
C H
Bu Me
OLi
B1
C1
Me
HO O
R OBn
Hg(OAc)2 NaBH4
HO Me
H
O
R OBn
diastereoselection diastereoselecti on 10:1
M. Isobe & Co-workers, Tetrahedron Lett . 1985, 26 , 5199.
(CH2)4OTs OR C C OLi H
critical conformation conformations s H
H Me
OR Me TsO(H2C)4
C
C Bu
OLi
Bu C
C
Bu OR OLi
OR Me
C
H
(CH2)4OTs
A2
B2
C2
Representative Representati ve Reactions controlled by Allylic Strain Interactions H
2
98:2
H
EtO 1
n-C4H9
In the above examples, the resident allyli c stereocenter ( !) and its associated substituents frequently impart a pronounced bias towards reactions occuring at the pi-bond.
HO
+
R large
!
–
Imonium ion
LiNR2
R1
R small
Imine
OLi
Me
n-C4H9
X 2
R2 R large
OTs
R1
R small R2
R1
O EtO
3 Y
Typical examples: R2
Chem 206
Acyclic Conformational Conformational Analysis: Analysis: Allylic Strain Strain
EtO2C
Me
2
minor n-C4H9
H
C
OLi (CH2)4OTs
O
O
OTs Me
EtO
MeI
D. Kim & Co-workers,
diastereoselection 89:11
R
R-substituent
diastereoselection
R = Me R = Et
87:13 80:20
R = CHMe 2
40:60
RO2C
Ph
Tetrahedron Lett . 1986, 27 , 943.
MeO
Ph
O LiNR2
OBn
G. Stork & Co-workers,
Me
diastereoselection 90:10 at C 3 one isomer at C 2
OH
"one isomer"
Me
H CO2Me
95% yield
OBn
I. Fleming & Co-workers, Chem. Commun . 1986, 1198.
Br H CO2Me
O
H
Me3Si
Me–CHO
O
RO2C H
LiNR2
major diastereomer opposite to that shown
H
71% yield
O
OMe
I. Fleming & Co-workers, Chem. Commun . 1985, 318. Y. Yamamoto & Co-workers, Chem. Commun . 1984, 904.
Me3Si
MeO
O
Me3Si
OMe
Me
n-C4H9
H
Me3Si R
EtO
LiNR2
Ph
OM NH4Cl
H
O
O EtO
Ph diastereoselection 98:2
n-C4H9
H
n-C4H9
Me
EtO
LiNR2
n-C4H9
Chem 206
Allylic Strain & Enolate Diastereoface Selection
D. A. Evans
Bn
O
N
Me
S N
S
R–CHO
Boc
Tetrahedron Lett . 1987, 28 , 2088.
Sn(OTf)2
Bn
H
N
S N
Boc R
91-95%
O
S
diastereoselection >95%
OH
T. Mukaiyama & Co-workers, Chem. Letters 1986, 637
TBSOCH2
Me CH2
Me CH2
O
TBSOCH2
LiNR2
Ph(MeS)2C–Li
"one isomer"
Me H
MeI
H CO2Me
Me
OMe
86%
I CO2Et
PhMe2Si
OM
O
MeI
OEt
PhMe2Si
I. Fleming & Co-workers,
Chem. Commun . 1984,
OMe
diastereoselection 99:1
Me
H
O-t-Bu °
R = Me:
diastereoselection 99:1
R = Ph:
diastereoselection 97:3
28.
OLi R
KOt-Bu THF -78 C
OEt Me
O
K. Koga & Co-workers, Tetrahedron Letters 1985, 26 , 3031.
Chem. Commun . 1986, 288.
R
Me
MeS
H CO2Me
T. Money & Co-workers,
R
Me–I
MeS MeS
CO2Et
R = H: one isomer
CO2-t-Bu R = Me: > 15 :1 H
R
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
B
H
H
H
B
OH
‡
R
R
C
R
C
R
R
C R
R
R
C
B2H6
diastereoselection 8:1
R
OMe
R
OMe
O
Me
Me
OH
Me
diastereoselection 12:1
CH2 Me3C
Y. Kishi & Co-workers, J. Am. Chem. Soc . 1979, 101, 259.
Oxidant
Ratio, A:E
MCPBA
69:31
JOC , 1967, 32 ,
1363
BH3, H2O2
34:66
JOC , 1970, 35 ,
2654
Reference
OH
E
H
BnO
OH Me
Me
B2H6
BnO
H2O2
OH
Me
Me
Acyclic hydroboration can be controlled by A(1,3) interactions:
OH Me
R2BH
major diastereomer
OH RM
Me R R
control elements
B
H H
RM
A(1,3) allylic strain Steric effects; RL vs RM Staggered transition states
H
C
Me
Me
Me
ThexylBH2,
Me CH2OR
OH
TrO
OTr
OH R2BH
Me
RL
H2O2 OH
OH RM
Me
Me
R
TrO
B
H H
C
C
RM H
OH
OH
Diastereoselection;
5:1
Me
Me
Me
CH2OR
Me
OH
OH
OH
OTr OH
OH
OH
OH
OTr Diastereoselection;
Me RL
ThexylBH2,
OTr OH
then BH3 TrO
Me R
See Houk, Tetrahedron 1984, 40 , 2257
Me
major diastereomer
Me
TrO
then BH3
C
RL
Me
Me
C. H. Heathcock et. al. Tetrahedron Lett 1984 25 243.
RL
H2O2
Me
Diastereoselection = 3:1
OH RL
RM
OH
O
A
RL
OH
B2H6 H2O2
Me
Me
RM
Me
Me
R
Me
!
CH2OBn
O
H2O2
Me
Me
C
R
C
O
H
H2B
H
H
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
C
Chem 206
Allylic Strain & Amide Conformation
R1
N
–O
R
R3
1
R1
C N +
R
R2 R3
3 Y
The selection of amide protecting group may be done with the knowledge that altered conformational preferences may result:
R1 R large
X 2
R
R small
H
A(1,3) interactions between the "allylic substituent" and the R1 moiety will strongly influence the torsion angle between N & C1.
Me
C N
O
H
H
Me
O
R
C
O
R C
N
R C
R
O
O N Ph "
Me
H
Favored
H O N
C
H
R
R
C O
H strongly favored
O
H H
Me N R C Me O
R C
H N
Me Me
H
strongly favored
Problem: Predict the stereochemical outcome of this cyclization. HOCO
O Me
!
N O
C
N H
L
R
N + R
R
‡
L
OM base favored
O Me
Ph
C
L N Me L
diastereoselection >95%
N H
Me
N
L H
L
L
‡
OM base disfavored
O H
identify HOMO-LUMO pair
O
C
L
H
H
!
N Ph
C
(Z )-Enolate
O H
H
HCO2H
D. Hart, JACS 1980, 102 , 397
2
1
H
Quick, J. Org. Chem. 1978, 43 , 2705
OH
–O
As a result, amides afford (Z) enolates under all conditions
published X-ray structure of this amide shows chair diaxial conformation
O
2
1
A(1,3) interaction between the C2 & amide C R substituents will strongly influence the torsion N angle between C1 & C2. R R
H
O
R
R O
O
Me
Disfavored
H R
N
A(1,3) Chow Can. J. Chem. 1968, 46 , 2821
H
H
R
H
N +
N
N
conformations of cyclic amides R
R
R
R
Disfavored
–O
N
H
N
Me
!
N
Favored for R = COR
O
Favored
Me
H
H
Favored for R = H, alkyl
1
R
O
O
O
1
C
L
N Me L
H
N Me
L
L
(E )-Enolate
D. A. Evans
A(1,3) Strain and Chiral Enolate Design O Me
O N
M
O LDA O
Me
Polypropionate Biosynthesis: The Acylation Event O
O
N
or NaNTMS2
Bn
enolization selectivity >100:1
O
C
Me
N H
JACS . 1982,104 , 1737. O
L
Me
O
O
!
O
Reduction
R
SR
Me
Me
First laboratory analogue of the acylation event
O
Li O
O Et
In the enolate alkylation process product epimerization is a serious problem. Allylic strain suppresses product enolization through the intervention of allylic strain
O
O
O
O !
Me
N
Cl
N
O Me
O
Me R
R
with M. Ennis JACS 1984 , 106, 1154.
Diastereoselection ~ 97 : 3
El
C
N
El
Me
L L
O
C
L
N H
Me
B
L
Me O
C
C
H
El N
L L
A
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
C
H N H
R R
favored
These allylic strain attributes are an integral part of the design criteria of chiral amide and i mide-based enolate systems O O Me
SR
O
SR
Bn
H
OH
Me
El
favored enolization geometry
R
– CO2
O
O N
L
Acylation
SR
HO
El(+)
‡
O
R
Bn
H
O
Chem 206
Allylic Strain & Amide Conformation
CH2OH
Me
O O N
O
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
C
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
O
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
O H
Me
Me
Me Me Me
OH
Me
Me OH
OH
O
NH2 O
Chem 206
Conformational Analysis - Discodermolide X-ray 2
D. A. Evans
Me
O
O H
Me
Me
Me
16
HO
Me Me Me
Me OH
OH
O
NH2 O
OH
16
Chem 206
Evans, Kim, Breit
Chem 206
Conformational Analysis: Cyclic Systems-2 Cyclobutane
145-155°
Cyclopentane
ax
ax
Eclipsing torsional strain overrides increased bond angle strain by puckering. !
eq eq ! =
28 °
eq
eq ax ax
!
Ring barrier to inversion is 1.45 kcal/mol.
H
H
H
H H
H
H H
H
H H
CsEnvelope
H
H
H
H
H
H H
H H
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 H
! A
G = 1 kcal/mol favoring R = Me equatorial
!
1,3 Disubstitution prefers cis diequatorial to for di-bromo cmpd.
trans by 0.58 kcal/mol
Disubstitution prefers for steric/torsional reasons (alkyl groups) and dipole reasons (polar groups).
Me 1,2 Disubstitution prefers trans diequatorial to by 1.3 kcal/mol for diacid (roughly equivalent to the cyclohexyl analogue.)
H H
X
X
Me
cis
H H
single substituent prefers the equatorial position of the flap of the envelope (barrier ca. 3.4 kcal/mol, R = CH3).
! 1,2 trans
!
H
H
Alkyl Disubstitution: Cis-1,3-dimethyl cyclopentane 0.5 kcal/mol more stable than trans.
! 1,3
! 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 sp 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
H
H
NaBH4
k6
H H H H
H H
H H
OH k6
H H
NaBH4
O
H
k5
H
k5
= 23
OH
H
H
Brown, H. C.; Ichikawa, K. Tetrahedron 1957, 1, 221.
Problem: Rationalize the regioselectivity of the following O O reduction O
H
O
hydrolyzes 13 times faster than NaBH4
O
H
O
O OH 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.
2
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
O
O
Me
Me
OTBSO
O
22
18
O
Me 27
Me Me O
27
Me
22
18 XO
O
X = C(CH2)4
OH
OH
OH
OH
Me
PPTS, rt, MeOH.
63%
PPTS, rt, MeOH.
OX
12
Me
<10%
O
Me O
OX
12
X = CMe2
OTBSO
Me
XO
O
O
OH
Me 27
Me2CH
22 16
O
HO 12
O
OH
2
Roxiticin
Me
O
O
hydrolyzes 13 times faster than
O
O
Conan, J-Y.; Natat, A.; Priolet, D. Bull. Soc. Chim., Fr.
1976 ,
1935.
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:
Observed:
Me
Me
Ph
!G°
= A(Ph) – A(Me)
!G°
= +2.8 – 1.7 = +1.1 kcal/mol
H
Case 1:
H
H
Me Me H
Me
The prediction:
!G° = –0.32 kcal/mol
Observed:
!G°
= 1 gauche butane – 2A(Me)
!G°
= +0.88 – 2(1.74) = +2.6 kcal/mol
!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
H
OH H OH
H
H
H
H
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
H
diastereoselection 89:11
D. Kim & Co-workers, Tetrahedron Lett . 1986, 27 , 943.
Conformational Analysis: Bicyclic Ring Systems
Evans, Breit
Chem 206
Estimate the energy difference between the two methyl-decalins shown below. Me
Me
H
H
Hydrindane Ring System (6/5) H
H
rigid
flexible
Decalin Ring System (6/6) H
H
= –0.5 kcal/mol (at 23 °C) !G° = 0.0 kcal/mol (at ~200 °C)
H
H
mobile
H !G°
rigid ! The
turnover to favor the cis fusion results from the entropic preference for the less ordered cis isomer.
H
The 5-5 Ring System H H
H
H
H
H
favored
2.4 kcal/mol
0
Relative !G°
!G°
= +6.4 kcal/mol
Let's identify the destabilizing gauche butane interactions in the cis isomer H
H
3 H
2
4
C1
C2
C1
C3
C4
1
Me
Gauche-butane interactions
"G°(est)
C3
C A
Me
H
D
C
B
H
A/B Trans
H
R
H
H
H
A
H
R
D
B
H
H
A/B Cis
= 3(0.88) = 2.64 kcal/mol Rationalize the conformational flexibility of a
A/B Trans vs. A/B Cis Steroid!