Download - A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Transcript
Page 1: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

A1,3 Strain and the Anomeric Effect

Michael Shaghafi Chem. Topics Feb. 6, 2012

Page 2: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Introduction: Definition of A1,3 Strain

HH

R

Rotation about σ-bond between α-stereocenter and olefin is associated with an energetic cost (steric/van der Waals interaction).

RLRm

RmH

R

HRL

RLH

R

RmH

1

3

3 3

1 1

RLH

R

HRm

HH

R

RmRL

3

1

Rotation about allylic stereocenterto a lower energy confirmation = A1,3 strain minimization.

H

H

R

Rm

RL 1

3

Confirmational preferences based upon minimization of A1,3

strain can differentiate diastereofacial faces of pro-chiral nucleophiles and electrophiles (i.e. π-bonds).

- Can lead to diastereoselective reactions if significant differences in steric bulk are realized between R, Rm, and RL.

E+

E+

Page 3: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Energy Differences Upon Sigma-Bond Rotation

Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1880.

H

CH3CH3

H H

CH3H

CH3

0 kcal/mol + 0.73 kcal/mol

ab initio calculations: MP2-6-31G (Houk)

H

H

CH3CH3

> + 2.0 kcal/mol

Mono-substituted olefins:

CH3

CH3CH3

H CH3

CH3H

CH3

0 kcal/mol + > 4.0 kcal/mol

CH3

H

CH3CH3

> + 3.44 kcal/mol

Z-substituted olefins:

Page 4: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

A Warm-Up: Hydroboration

Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1880.

CH3

HPhMe2Si

Me

OH

ds = 50 %

HPhMe2Si

Me

CH3

OHds = 95 %

CH3

HPhMe2Si

Me 1. BH3

2. [O]

HPhMe2Si

Me

CH3

1. BH3

2. [O]

CH3

HH3C

(CH2)7=

1. BH3

2. [O]

CH3

HH3C

OH

ds = 90 %

Page 5: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Diastereoselective Epoxidation of Olefins: A Classical Case

Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1880.

OH

OPh

HO O

O

Cl

H

OBn

OH

m-CPBA

OBnm-CPBAOH

OBnm-CPBAOH

OBnm-CPBAOH

SiMe3

OBn

OH

Ods = > 97 %

OBn OOH ds = > 96 %

OBn OOH ds = 60 %

OBn OOH

SiMe3

ds = > 95 %

Page 6: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Diastereoselective Epoxidation of Olefins: Allylic Silanes and Siloxyethers

Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1880.

OR3Si

OOH

Ar

SiMe2Ph

PhMe2Si

m-CPBA

m-CPBA

PhMe2Si O PhMe2Si O+

61 : 39

PhMe2Si O PhMe2Si O+

> 95 : 5

R

t-BuMe2SiO m-CPBAOH R

t-BuMe2SiO

OHO

Ti(Oi-Pr)4t-BuOOH

R

t-BuMe2SiO

OHO

Rt-BuMe2SiO

O

H

Minimized A1,3 Strain

OH O

ArOH

mCPBACoordination

No Coordination:Attack from less hindered face

ds = > 94 %

ds = > 90 %

Page 7: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Classical Synthetic Example: Kishi’s Total Synthesis of Monensin

Schmid, G.; Fukuyama, T.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 260–262.

Ar

OEt

HC3H5

H

HOH2C

Ar

OEt

HC3H5

H

HOH2C

O

mCPBA, NaHCO3DCM, rt

quant., sole productOAr

H Et OHH

steps

OArH Et OH

HO

ArH Et O

H

H Br

NBS, MeCN

rt

57 %

Single Diastereomer

OArH Et OH

H

H

Br

Page 8: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Diastereoselective Epoxidation of Olefins: A Recent Application to Library Synthesis

Coombs, T.C.; Lushington, G. H.; Douglas, J.; Aube, J. Angew. Chem. Int. Ed. 2011, 50, 2734–2737.

NH

HH

ArN

ArH

OOR

1,3-diaxial minimization A1,3 minimization

Page 9: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Diastereoselective Epoxidation of Olefins: A Recent Application to Library Synthesis

Coombs, T.C.; Lushington, G. H.; Douglas, J.; Aube, J. Angew. Chem. Int. Ed. 2011, 50, 2734–2737.

Page 10: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

A1,3 Control in Cycloadditions: A Classical Example

Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1880.

Page 11: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Roush: Total Synthesis of Spinosyn A

Winbush, S. M.; Mergott, D.J.; Roush, W. R. J. Org. Chem. 2008, 73, 1818–1829.

Page 12: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

A1,3 Control in Cycloadditions: Roush Synthesis of Spinosyn A

Winbush, S. M.; Mergott, D.J.; Roush, W. R. J. Org. Chem. 2008, 73, 1818–1829.

Page 13: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

A1,3 and Control in Addition to Nitrones

Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1880.

N O

OHC5H11

t-BuMe2SiOCH3

N O

OHC5H11

t-BuMe2SiOCH3

AcOH

THF, –100 ºCds = > 95 %

N O

OHC5H11

LiOCH3

N O

OHC5H11

HOCH3

AcOH

THF, –100 ºCds = 80 %

N O

OHR

PhSeCH3

N O

OHR

PhSeCH3

AcOH

THF, –100 ºC

R = Me, ds = 91 %

= n-Bu, ds = 95 % = Ph, ds = 80 %

NH3C

OH

NO

H3C

H

Intramolecular [3+2] Only product

55 %

Page 14: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Barbas Carbohydrate Synthesis: Asymmetric Organocatalytic Michael-Henry Reactions

Uehara, H.; Imashiro, R.; Hernandez-Torres, G.; Barbas III, C. F. PNAS, 2010, 107, 20672– 20677.

d.r. (6 + 5:7) = usually > 10:1; 36 % to 76 % yield (2 steps)!

Page 15: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Barbas Carbohydrate Synthesis: Model for Diastereoselectivity

Uehara, H.; Imashiro, R.; Hernandez-Torres, G.; Barbas III, C. F. PNAS, 2010, 107, 20672–20677.

Page 16: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Introduction: The Anomeric Effect

Kirby, A. J. Oxford Chemistry Primers: Stereoelectronic Effects 1996, Oxford University Press.!

OHO

HO

HOHO

OHOR

OHO

HOHO

ORβ-glucopyranose

βα

α-glucopyranose

R = H 64 36:

R = Me 33 : 67

H

R

H

H

RHH

OR

H

OHH

RHH

Steric Preference:

Contra-Steric Preference: Anomeric Effect = Electrostatic Effect

R = alkyl

R = polar group - i.e. OMe, Halogen, OAc, etc.

Page 17: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Introduction: The Anomeric Effect

Kirby, A. J. Oxford Chemistry Primers: Stereoelectronic Effects 1996, Oxford University Press.!

OBzOBzO

OBzX O

OBz

XBzO

OBzX = F, Cl, Br

Ph

OBz =

OAcO

AcO

AcOAcO

OAcOR

OAcO

AcOAcO

ORβ-glucopyranose

βα

α-glucopyranose

R = OAc 14 86:

R = Cl 6 : 94

Page 18: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Explaining the Anomeric Effect: Electrostatics

OHH

X

nO σ*C–X OXH

σ*C–XσC–C

σ*C–Br

nO

ΔΕσ*C–Clσ*C–F

σ*C–X

ΔΕ

σC–C

Just considering electrostatics:

Page 19: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

The Anomeric Effect is General and Predictable: Kishi’s Monesin Total Synthesis

Kishi, Y. et. al. J. Am. Chem. Soc. 1979, 101, 262–263.

O

HO

Me O Me

HO2CMe

Me

Me

HO O

OH Et H

Me

H

Me

HHO CH2OH

Me

O

OOH

MeR1

R2 Me

From Degradation Studies followed by X-rayMonensin

Spiroketalization

Aldol Reaction

O X

Y

OHMe

Hn-C6H13

1:1 ratio of anomers 1:2

CSA

DCM, rtO

HOMeMe

n-C6H13

HOBn

Me

HO10% Pd/C

CH3OH, AcOHrt 1 X = O, Y = CH2

2 X = CH2, Y = O

O X

Y

OHMe

Hn-C6H13

Only 1 (anomeric)

OBn

HO

MeHO Me

HO2C

Me

Me

Me

HO O

OH Et H

Me

H

Me

HHO CH2OH

MeO

as above Monensin53 %

Page 20: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Roush: Toward the Total Synthesis of Integramycin

Sun, H.; Abbott, J. R.; Roush, W. R. Org. Lett. 2011, 13, 2734–2737.

-  A1,3 minimization controls π-bond facial selectivity ! in the iodonium formation. !-  Also formation of the doubly anomeric conformation! should drive the equilibrium!

OO

Me

H

Me

TIPSO

OTIPS

Me

I

Iodoketalization OHO

Me

Me

TIPSO

OTIPS

Me

NIS

Page 21: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Stereoselectivity in Glycosidic Bond Formation: Radical Reactions

Abe, H.; Shuto, S.; Matsuda, A. J. Am. Chem. Soc. 2001, 123, 11870–11882.

OOPg

(PgO)n

OOPg

(PgO)n

X = D, CH2CH2CN, n-BuSnC3H6

Xα-selectivity dominates

OR

AcOAcO

OAcnO SOMO

SOMO σ*C2

(anomeric stabilization)Studies by Giese

Studies by RenaudS

t-BuO

SePh

Bu3SnD, AIBN

Benzene, reflux

St-Bu

O

D SnBu3

St-Bu

O

St-Bu

O

D

Radical Cieplack Effect

Page 22: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Conformationally Locking in α-Glycosylation: α-Selective Substrates

Abe, H.; Shuto, S.; Matsuda, A. J. Am. Chem. Soc. 2001, 123, 11870–11882.

OAcO SePh

AcO

20

OSePh

21

OO

OMe

OMe(α/β) = 1:1

Acceptor: A = n-Bu3SnD, B = n-Bu3SnC3H5!

Page 23: A Strain and the Anomeric Effect - Faculty WebsitesA1,3 Strain and the Anomeric Effect Michael Shaghafi Chem. Topics Feb. 6, 2012 . Introduction: Definition of A1,3 Strain H H R ...

Conformationally Locking in β-Glycosylation: β-Selective Substrates

Abe, H.; Shuto, S.; Matsuda, A. J. Am. Chem. Soc. 2001, 123, 11870–11882.

O

O OBPh

OH SePh

11

O

OTIPSSePh

OTIPSOTIPS

12