Acyclic Conformational Analysis: Allylic StrainD. A. Evans Chem 206

R. W. Hoffmann, Chem. Rev. 1989, 89, 1841-1860 (handout)Allylic 1-3-Strain as a Controlling Element in Stereoselective Transformations

F. Johnson, Chem. Rev. 1968, 68, 375; Allylic Strain in Six-Membered Rings

Consider the illustrated general structure where X & Y are permutations of C, N, and O:

The Definition of Allylic Strain

R large

YR1

X

R2

R3

R small

12

3

Houk, Hoffmann JACS 1991, 113, 5006

In the above examples, the resident allylic stereocenter (!) and its associated substituents frequently impart a pronounced bias towards reactions occuring at the pi-bond.

Typical examples:

!!!!

Nitrone

++

Olefin Imine Imonium ion

R small

R largeR3

R2 R1R1

N

R2

R large

R small R small

RN

R2 R1

R large R large

R1

N

R2

O

R small

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(1,3)interaction

A(1,2)interaction

3

2 1

R small

R3X

YR2 R1

R large

diastereoselection 10:1

M. Isobe & Co-workers, Tetrahedron Lett. 1985, 26, 5199.

Representative Reactions controlled by Allylic Strain Interactions

O

Me

HOH

R

OBn OBn

RH

HO

Me

O

HO

Hg(OAc)2

NaBH4

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

98:2

EtOMe

O

n-C4H9

OTs

H

Can you predict the stereochemical outcome of this reaction?

EtOMe

OLi

n-C4H9

OTs

H

1 2+LiNR2

C

HBu

(CH2)4OTs

COLi

ORMeC

H

Bu

TsO(H2C)4C

OLi

ORMe C

H

Bu(CH2)4OTs

COLi

ORMe

C

H Bu

(CH2)4OTs

COLi

ORMe C

H

Bu

(CH2)4OTs

COLi

ORMeC

TsO(H2C)4

H

Bu

COLi

ORMe

Hn-C4H9

EtO2CMe

2

Hn-C4H9

OMe

EtO1

critical conformations

! Relevant enolate conformations major

minor

A1 B1 C1

A2 B2 C2

Allylic Strain & Enolate Diastereoface SelectionD. A. Evans Chem 206

R = Ph: diastereoselection 97:3

R = 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

CO2Me

Me

RO2CO

O

H H

OO

RO2C

Me

CO2Me

EtOMe

O

n-C4H9

OTs

H Hn-C4H9

OMe

EtO

Br

H

EtO

H

CH2

EtO

O

CO2Me

MeTBSOCH2

H

CH2

H

TBSOCH2

Me

CO2Me

Me

n-C4H9H

MeO

n-C4H9H

Me

PhMe2Si OEt

R OOMR

OEtPhMe2Si

MeI

LiNR2

LiNR2

LiNR2

MeI

LiNR2

MeI

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

R = Me: > 15 :1

R = H: one isomer

THF -78 C

diastereoselection 90:10 at C3one isomer at C2

71% yield

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

MeCHO

MeI

Ph(MeS)2CLi

86%

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 shown

40:60

80:20

87:13

R = CHMe2

R = Et

R = Me

R-substituent diastereoselection

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

R

Me3Si OMe

Ph O

N

OMPh

OMeMe3Si

R

N

Me O S

N

Boc

N SBnBn

S

Boc

S OMe

OHR

H

OMe

OMe

MeSMeS

Me

Me3Si

MeS

OBn

Ph O OPh

OBnMe3Si

Me

H

O

OMeMe

OH

H

HCO2Et

CO2-t-Bu

OLi

O-t-BuCO2Et

I

R

R

KOt-Bu

LiNR2

RCHO

Sn(OTf)2

NH4Cl

Allylic Strain & Olefin HydroborationD. A. Evans Chem 206

BH3, H2O2 34:66 JOC, 1970, 35, 2654

JOC, 1967, 32, 136369:31MCPBA

ReferenceRatio, A:EOxidant

E

! The basic process

C C

R

R

R

R

BH

H

H

S

CR

R

CR

R

B

S

H

HH

C

H

C

H2B

R

R

R

R

Me3C

H

CH2

A

Staggered transition states

Steric effects; RL vs RM

A(1,3) allylic straincontrol elements

See Houk, Tetrahedron 1984, 40, 2257

major diastereomer

major diastereomer

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

RLOH

RM Me MeRM

OHRL

OH

RL

RM H

CH C

Me

CH2OR

HB

OH

RLOH

RM MeRMOH

MeRL

RR

B

RR

H

C C

Me

CH2OR

H

HRM

RL

R2BH

H2O2

H2O2

R2BH

Diastereoselection = 3:1

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

diastereoselection 12:1

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

diastereoselection 8:1

Hydroborations dominated by A(1,3) Strain

MeMe

CH2OBnO

OH

OCH2OBn

Me Me

Me

OH MeMe

O

OMe

O

Me Me

OMe

Me

OH

OH

OH

BnO OH

Me Me Me MeMeMe

OHBnOH2O2

B2H6

B2H6

H2O2

H2O2

B2H6

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

Diastereoselection; 4: 1

ThexylBH2,

then BH3

ThexylBH2,

then BH3

Diastereoselection; 5 : 1OTr

OH

TrO

TrO OTr

OH

Me

Me

OH

MeMe

OH

Me

OH

OH

Me

OH

Me

TrO OTrOH

MeMe

TrO

OH

Me

OH

Me

OH

Me

OH

OTr

Allylic Strain & Amide ConformationD. A. Evans Chem 206

A(1,3) interactions between the "allylic substituent" and the R1 moiety will strongly influence the torsion angle between N & C1.

1+

1

12

3Consider the resonance structures of an amide:

R large

YR1

X

R2

R3

R small

R

R3N

CO R1

RR

CR1

N

O

R3

R

Me

MeN

CO Me

Me

ChowCan. J. Chem. 1968, 46, 2821

strongly favored

! conformations of cyclic amides

+

strongly favored

NC

O

RN

C

R

R H

R HCR

O

N

R

N

O

C

O

R

Me

HMeCR

O

N

HH

Me

Me

H

A(1,3)

!

!

D. Hart, JACS 1980, 102, 397

diastereoselection >95%

" 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

N MeMe

Ph

O O

O

N

O

HHOCO

PhPh

OH

O

N

HCO2H

DisfavoredFavored

Favored forR = COR

Favored forR = H, alkyl

The selection of amide protecting group may be done with the knowledge that altered conformational preferences may result:

N

R

OH

H H

HO

N

R

N

H

H

O

RH

O

HN

R

N

HO

C

Disfavored

O

RH H

O

HN

C

O

R

Favored

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

+

C

RN

O

R

CR

C

H

Me

NR

O

R

O N

R

R

L

L

H

C

Me

R

NL

LO

H

H

C

H

NL

LO

Me

H

C

H

H

O NL

L

Me

MeN

L

OM

NL

OM

L

L

Me

H

H

identify HOMO-LUMO pair

Allylic Strain & Amide ConformationD. A. Evans Chem 206

El(+)JACS. 1982,104, 1737.

LDA

or NaNTMS2enolization selectivity

>100:1

MO O

N OMe

BnBn

Me

O

N O

O

A(1,3) Strain and Chiral Enolate Design

Bn

Me

O

N O

O

El

favoredenolization geometry

C

H

NL

L

O

Me

H

! In the enolate alkylation process product epimerization is a serious problem. Allylic strain suppresses product enolization through the

intervention of allylic strain

C

H

NL

L

O

Me

El

C

H

NL

L

O

Me ElC

H

NL

L

O

MeEl

A CB

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

Bn

Me

O

N O

O

Evans JACS 1982,104, 1737.

EvansTetr Lett. 1977, 29, 2495

CH2OHO

MeN

MeN

O

Me

Me

OH

Myers JACS 1997, 119, 6496

Polypropionate Biosynthesis: The Acylation Event

Acylation Reduction

CO2O

HO

Me

SR

O

O

R SRR SR

O

Me

O

R SR

OH

Me

O

First laboratory analogue of the acylation event

N O

OO

R

Me

O

R

O

N O

O

Me

Li

Et Cl

O

Me

Diastereoselection ~ 97 : 3with M. Ennis JACS 1984, 106, 1154.

!

O NR

RC

R

Me H

O NR

RC

H

R Me

favored

X-ray structure

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

D. A. Evans Chem 206

OMe

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.

General Texts

Conformational Analysis - Discodermolide X-ray 1D. A. Evans Chem 206

OMe

Me

OH

Me

O

HO

Me

OH

Me

Me

O

Me

OH

Me

O

NH2H

General Texts

Conformational Analysis - Discodermolide X-ray 2D. A. Evans Chem 206

OMe

Me

OH

Me

O

HO

Me

OH

Me

Me

O

Me

OH

Me

O

NH2H

16

16

Evans, Kim, Breit Chem 206Conformational Analysis: Cyclic Systems-2

eq

ax ax

eq

ax

eq

eqax

Cyclobutane

! = 28

! Eclipsing torsional strain overrides increased bond angle strain by puckering.

! Ring barrier to inversion is 1.45 kcal/mol.

145-155

(MM2)

! !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.

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

HH H

H

HH

H

H

HH H

H

H

H

H

H

H

H

H

H

Cyclopentane

C2 Half-ChairCsEnvelope

! 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.

! Since there is no "natural" conformation of cyclopentane, the ring conforms to minimize interactions of any substituents present.

HH

HH

CsEnvelope

H

H

H

H

HH

H

! A single substituent prefers the equatorial position of the flap of the envelope (barrier ca. 3.4 kcal/mol, R = CH3).

HH H

H

H

H

H

HH

X

X

! 1,2 Disubstitution prefers trans for steric/torsional reasons (alkyl groups) and dipole reasons (polar groups).

CsEnvelope

X

! A carbonyl or methylene prefers the planar position of the half-chair (barrier 1.15 kcal/mol for cyclopentanone).

Me

Me ! 1,3 Alkyl Disubstitution: Cis-1,3-dimethyl cyclopentane 0.5 kcal/mol more stable than trans.

H

(MM2)

Evans, Kim, Breit Chem 206Conformational Analysis: Cyclic Systems-3

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.

H

HH

H OH

OH

H

HH

H

k6k6

k5= 23

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

Examples:

O

H

H

H

H

H

H

H

H

OHk5

NaBH4

NaBH4

HH

O

O OH

O NaBH4

Problem: Rationalize the regioselectivity of the following reduction

Stork, JACS, 1979, 7107.

O O O Ohydrolyzes

13 times faster than

O

OEt

OO

OEt

OH

95.5:4.5 keto:enol 76:24 enol:keto

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

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

O O OTBSO O

XO

Me

O

O

Me

OX

MeMe MeMe

12

182227

Me

Me

X = CMe2

"Total Synthesis of the Antifungal Macrolide Antibiotic (+)-Roxaticin," Evans, D. A.; Connell, B. T.

J. Am. Chem. Soc., 2003, 125, 10899-10905

O O OTBSO O

XO

Me

O

O

Me

OX12

182227

Me

Me

PPTS, rt, MeOH.

OH OH OH OH OH

HOMe2CH

Me

O

O

Me

OH2

12

16

2227

X = C(CH2)4

PPTS, rt, MeOH.63%

Evans, Breit Chem 206Conformational Analysis: Cyclic Systems-4

R

R

Monosubstituted Cyclohexanes: A Values

Keq!G = RTlnKeq

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

! 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

H

H

C

C

Me

H

HH

C

H

H Me

H

H

Me

H

H

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

H HH HMe

H HMe

Me MeMe

Me

1.74 1.80 2.15 5.0AValue

H H H H

The "relative size" of a substituent and the associated A-value may not correlate. For example, consider the CMe3 and SiMe3 substituents. While the SiMe3substituent has a larger covalent radius, it has a smaller A-value:

CMe

Me

Me

4.5-5.0

SiMe

MeMe

H H

2.5

SnMe

Me

Me

H

1.1AValue

Can you explain these observations?

! The impact of double bonds on A-values:

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

R

H

H

R

R = Me

substituentA-value

(cyclohexane)

0.8 1.74

R = OMe 0.8 0.6

R = OAc 0.6 0.71

!"G

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 Chem 206Conformational Analysis: Cyclic Systems-5

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

Me

H

O

H

Me

O

Impact of Trigonal Carbon

!G = 1.36 kcal/molversus 1.74 for cyclohexane

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

Me

H

H

Me

!G = 1.56 kcal/molversus 1.74 for cyclohexane

O O

Me3C Me3C

base epimerization

CHMe2

H

H

CHMe2

!G = 0.59 kcal/molversus 2.15 for cyclohexane

O O

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

CMe3

H

H

CMe3

!G = 1.62 kcal/mol versus 5.0 for cyclohexane

O O

Me3C

Me3C

Me3C

Me3C

base epimerization

base epimerization

Me

Me

Me

Me

Me

Me

Me

Me

Polysubstituted Cyclohexane A Values

1,4 Disubstitution: A Values are roughly additive.

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

!G = 0 kcal/mol

! As long as the substituents on the ring do not interact in either conformation, their A-values are roughly additive

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

!G = A(Me) A(X)

X

H

Me

H

Me H

XH

H

X

Me

H

Me X

HH

The new interaction!

The cis Isomer

For X = MeH

Me

Me

H

Me Me

HH

H

H

+ 3.7

+ 0.88+ 0.88

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

Evans, Breit Chem 206Conformational Analysis: Cyclic Systems-6

Let's now consider geminal substitution

!G = A(Ph) A(Me)

Me

Ph

Me

Ph

The prediction:

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

Observed: !G = 0.32 kcal/mol

Me

Me

MeMe

Let's now consider vicinal substitution

!G = 1 gauche butane 2A(Me)The prediction:

!G = +0.88 2(1.74) = +2.6 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 1: HH

H

H

OH

OH

H MeMe

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.

H

Me

Me

Case 2:

H

H

HH

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

diastereoselection 89:11

EtO EtO

O

n-C4H9H

MeO

n-C4H9H

Problem:Can you rationalize the stereochemical outcome of this reaction?

LiNR2

MeI

Evans, Breit Chem 206Conformational Analysis: Cyclic Systems-7

Heteroatom-Substituted 6-Membered Rings

Me

H !"G = 1.74 kcal/mol

H

Me

Reference:

! 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).

O

Me

H !"G = 2.86 kcal/molO

H

Me

H

(1)

N

Me

H !"G = 2.5 kcal/molN

H

MeH H

H

(4)

O

Me

H !"G = 2.86 kcal/molO

H

Me

O

Me

H !"G = 1.43 kcal/molO

H

Me

O

Me

H !"G = 1.95 kcal/molO

H

Me

H

(1)

(2)

(3)

N

Me

H !"G = 2.5 kcal/molN

H

Me

N

Me

H !"G = 1.6 kcal/molN

H

Me

N

Me

H !"G = 1.9 kcal/molN

H

Me

H H

H H

H H

H

(4)

(5)

(6)

A-Values for N-Substituents in Piperidine

N

H

!G = 0.36 kcal/molN H

The Reference:

N

Me

!G = 3.0 kcal/molN Me

! Hydrogen is "bigger" than the Nlone Pair.

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

Evans, Breit Chem 206Conformational Analysis: Bicyclic Ring Systems

H

H

2.4 kcal/mol 0 Relative !G

rigid

Decalin Ring System (6/6)

mobile

H

H

H

H

Let's identify the destabilizing gauche butane interactions in the cis isomer

H

H

1

2

3

4

Gauche-butane interactions

C1 ! C2

C1 ! C3

C4 ! C3

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

Estimate the energy difference between the two methyl-decalins shown below.

Me

H

Me

H

Hydrindane Ring System (6/5)

H

H

H

H

flexible rigid

!G = 0.5 kcal/mol (at 23 C)!G = 0.0 kcal/mol (at ~200 C)

! 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

H

H

favored

!G = +6.4 kcal/mol

H

H

HMe

HH

H

H

HMe

HH

R R

A/B CisA/B Trans

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

DC

BA BC D

A

Evans, Breit Chem 206Conformational Analysis: Axial vs Equatorial Reactivity

Different reactivity for axial and equatorial substituents

! Acetylation with Ac2O/Py

OH

OH

k rel 1 0.13

Me3C OH Me3C

OH

1 0.27

Axial substituents are more hindered, thus less reactive in many transformations

H

H

H

H

k rel

CO2H

CO2H

1 0.04

Me3C CO2H Me3C

CO2H

1 0.05

! Acid-catalyzed esterification

H

H

H

H

k rel

k rel

! Ester Saponification

Me3C CO2Et Me3C

CO2Et

20 1

H

H

k rel

! SN2 Reactions (Displacement with PhS)

Me3C OTs Me3C

OTs

1 31

H

H

k rel

The axial diastereomer is not always slower reacting:

! Alcohol Oxidation with Cr(6+)

Me3C OH Me3C

OH

1 3.2

H

H

k rel

OH

1 3.36

H

k rel

Me

Me

MeH

OHMe

Me

Me

The rate-determining step is breakdown of the chromate ester. This is an apparent case of strain acceleration

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