06 Conformational Anal 3

7/29/2019 06 Conformational Anal 3

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Chem 206D. A. Evans

D. A. Evans

Friday,

September 30, 2005

http://www.courses.fas.harvard.edu/~chem206/

! Reading Assignment for week

A. Carey & Sundberg: Part A; Chapter 3

Conformational Analysis: Part3

Chemistry 206

Advanced Organic Chemistry

Lecture Number 6

Conformational Analysis-3

! Conformational Analysis of C4! C6 Rings

Three Types of Strain:

Prelog Strain: van der Waals interactions

Baeyer Strain: bond angle distortion away from the idealPitzer Strain: torsional rotation about a sigma bond

Baeyer Strain for selected ring sizes

size of ring Ht of Combustion(kcal/mol)

Total Strain(kcal/mol)

Strain per CH2(kcal.mol)

"angle strain"deviation from 10928'

3456789

101112131415

499.8656.1793.5944.8

1108.31269.21429.61586.81743.11893.42051.92206.12363.5

27.526.36.20.16.29.7

12.612.411.34.15.21.91.9

9.176.581.240.020.891.211.401.241.020.340.400.140.13

2444'944'044'

-516'

Eliel, E. L., Wilen, S. H. Stereochemistry of Organic CompoundsChapter 11, John Wiley & Sons, 1994.

! Baeyer "angle strain" is calculated from the deviation of the

planarbond angles from the ideal tetrahedral bond angle.

! Discrepancies between calculated strain/CH2 and the "anglestrain" results from puckering to minimize van der Waals oreclipsing torsional strain between vicinal hydrogens.

Conformational Analysis of Cyclic Systems

de Meijere, "Bonding Properties of Cyclopropane & their ChemicalCharacteristics"

Angew Chem. Int. Ed.1979, 18, 809-826 (pdf)

Eliel & Wilen, "Stereochemistry of Organic Compounds, "Chapter 11,Configuration and Conformation of Cyclic Molecules, Wiley, 1994

Ribeiro & Rittner, "The Role of Hyperconjugation in the Conformational Analysis of

Methylcyclohexane and Methylheterocyclohexanes"J. Org. Chem., 2003, 68, 6780-6787 (handout)

HH

O

O OH

ONaBH4

Problem: Rationalize the regioselectivity of the following reduction

Stork, JACS, 1979, 7107.


2/13

Cyclopropane: Bonding, Conformation, Carbonium Ion StabilizationEvans, Kim, Breit Chem 206

H

H

H

H

Cyclopropane

!Necessarily planar.!Subtituents are therefore eclipsed.!Disubstitution prefers to be trans.

! = 3080 cm-1

" = 120

!Almost sp2, not sp3

Nonbonding

Walsh Model for Strained Rings:

!Rather than! and !* c-c bonds, cyclopropane has sp2 and p-typeorbitals instead.

H

H

side view

!1 (bonding)

! (antibonding) ! (antibonding)

" (antibonding)

" (bonding) " (bonding)

3

de Meijere, "Bonding Properties of Cyclopropane & their Chemical Characteristics"Angew Chem. Int. Ed.1979, 18, 809-826 (handout)

de Meijere, A.; Wessjohann, L. "Tailoring the Reactivity of Small Ring BuildingBlocks for Organic Synthesis." Synlett1990 , 20. (pdf)

Carbocation Stabilization via Cyclopropylgroups

C

A rotational barrier of about13.7 kcal/mol is observed in

following example:H

Me

MeNMR in super acids

!(CH3) = 2.6 and 3.2 ppm


3/13

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

eq

ax ax

eq

ax

eq

eq

ax

Cyclobutane

! = 28

!Eclipsing torsional strain overridesincreased 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 cisdiequatorial totransby 0.58 kcal/mol for di-bromo cmpd.

!1,2 Disubstitution prefers transdiequatorial tocisby 1.3 kcal/mol for diacid (roughly equivalentto the cyclohexyl analogue.)

H

H 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 conformationsCs 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 tominimize 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 preferstrans for steric/torsionalreasons (alkyl groups) anddipole reasons (polar groups).

CsEnvelope

X

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

Me

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

H

(MM2)


4/13

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

Methylenecyclopentane and Cyclopentene

Strain trends:

> >

! Decrease in eclipsing strainmore than compensates for the

increase in angle strain.

Relative to cyclohexane derivatives, those of cyclopentane prefer an sp2center in the ring to minimize eclipsing interactions.

!

"Reactions will proceed in such a manner as to favor the formation or retentionof 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. Tetrahedron1957, 1, 221.

Examples:

O

H

H

H

H

H

H

H

H

OHk5

NaBH4

NaBH4

O OO O

hydrolyzes13 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. JACS1954

, 76, 467.

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


5/13

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%


6/13

3

1

7

55

71

3

HO R

OH

O

OH

CO2H

CO2H

OHOH

OH

OCO2HHO

HO2C

HO2C

OH

ROO

HO

H

Zaragozic Acid C Synthesis

CH2Cl2:THF78 C

5

73

1

7

53

MgBr

H

OCO2

tBu

O

tBuO2C

O

OBn

TBSO Ph

HO

OBn

OTBS Ph

H

OCO2

tBu

O

tBuO2C

3

7

51

91%

OBn

OTBS

tBuO2C

OOH

OCO2

tBu

O

tBuO2C

7

51

3

OBn

OTBS

O

H

O

O

O

CO2tButBuO2C

H

3 steps

76%

86%

3 steps

Chelate Control

0:10:1 CH2Cl2:TFA:H2O, 18 h

1

7O

O

CO2tButBuO2C

H OO O

tBuO2C

OTBS

O

Ph

Me

2 steps

70%Me

OPMB

BnLi

5

O

O

Ph

Me

O

O

CO2tButBuO2C

H OtBuO2C

OTBS

Me

OR

Bn

OH

4'

3

1

7

5

Zaragozic acid C

O

O

Ph

OAc

MeO

H

OH

HO2CHO2C

HOCO2H

Ph O

Me

94%

R = PMB R = Ac (89%)

65%

J. Leighton, J. Barrow

JACS1994, 116, 12111-12112


7/13


8/13


9/13


10/13

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-equatorialconformer 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 morestrongly preferred than would be suggested by A-Values. This is due toa 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


11/13


12/13

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! C2C1! C3C4! C3

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

Estimate the energy difference between the two methyl-decalinsshown 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 cisfusion results from the entropic preference for theless ordered cisisomer.

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 Transvs. A/B CisSteroid!

DC

BA BC D

A


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