Wednesday, November 9, 2005
The Anomeric Effect
Baran Group Meeting
Further Reading: G.R.J. Thatcher (ed.), The Anomeric Effect and Related Stereolectronic Effects. ACS
Paul Krawczuk
Anomeric Effect Defined (IUPAC):
Originally defined as the thermodynamic preference for polar groups bonded
to C-1 (the anomeric carbon of a glycopyranosyl derivative) to take up an
axial position.
Symposium Series #539, 1993.
Review: Juaristi, E., Cuevas, G., Tetrahedron, 1992, 48(24), 5019-5087.
Historical Aspects of the Anomeric Effect
First observed in 1955 by J.T. Edward and in 1958 by R.U. Lemieux.
O
Both were studying carbohydrate chemistry and noticed a preference for
alkoxy and acetyl groups to reside in the axial position. Edward proposed
that the lone pairs on the ring oxygen were contributing to the effect.
O
~1.5 kcal
OR
OR
-OR has an axial preferecne in a C1 substituted tetrahydropyran
alkyl substituted cyclohexanes prefer
equitorial orientation over axial
This effect is now considered to be a special case of a general preference
(the generalized anomeric effect) for gauche conformations
about the bond C–Y in the system X–C–Y–C where X and Y are heteroatoms
having nonbonding electron pairs, commonly at least one of which
is nitrogen, oxygen, sulfur or fluorine.
R
R
O
alkyl substituted tetrahydropyrans
show this same preference
O
R
Y
R
Y
X
H OH
the anomeric carbon of the most
abundant natural sugar,
D-glucopyranose, also prefers an
equtorial orientation.
HO
HO
HO
H
OH
OH
H
HO
HO
HO
H
36%
:
HO
HO
H
H
OH
OMe
HO
HO
67%
:
H
H
33%
H OAc
substitution with more electronegative
groups changes the observed ratio to a
greater extent
OMe
OH
H
H
H
H
OAc
OAc
86%
:
H OAc
H
H
electronic
factor
steric
factor
For the anomeric stabilization to effect the conformation at all it must
be more stabalizing then the sum of all of the steric factors
OAc
OAc
H
Linear Example:
Me
O
O
Me
O
O
Me
Me
often referred to as the
gauche effect
H OAc
HO
H
H
14%
!!Goanomeric effect (stabilization) = " !Go(heterocycle) - " !Go(steric)
Franck, R.W., Tetrahedron, 1983, 39, 3251.
HO
AcO
AcO
X
two gauche
interactions
OAc
Cl
HO
AcO
AcO
H
94%
:
6%
H
H
2.5
2.5
3.0
3.5
2.5
2.8
3.0
4.0
preferred by generalized
anomeric effect
H OAc
HO
AcO
AcO
H
HO
different from reigning cyclohexane
conformational analysis model
AcO
AcO
R
one gauche
interaction
H OH
H
H
R
R
ratio of preference gives us some
insight that something is different
conversion into a methyl ether at the
anomeric carbon produces a different
result from the above
X
R
OH
H
H
HO
C
S
N
O
I
Br
Cl
F
OH
H
64%
H OH
Electronegativites
of Relavant Atoms
X
H OH
OMe
H
H
H
Cl
OAc
H
Me
Me
H
OMe
The Anomeric Effect
Baran Group Meeting
Further Evidence:
Sovent also plays a role: Increase in anomeric
stabilization associated with low solvent dipole
O
1.39 Å
O
1.43 Å
O
O Cl e
OMe
Dipole
2.2
2.3
4.7
20.7
32.6
37.5
78.5
bond lenght: increased in the axial C-Cl bond (1.819Å)
versus the equatorial C-Cl bond (1.7181Å)
a
Cl
OMe
Solvent
CCl4
benzene
CHCl3
acetone
MeOH
MeCN
H2O
Paul Krawczuk
Romers, C., et al. Topics Stereochem., 1969, 4, 39.
% axial
83
82
71
72
69
68
52
a
e
axial bond also observed to be longer then
equitorial bond in this constrained case
O
O
Lemieux, R.U., et al. Can. J. Chem. 1969, 47, 4427.
Most widely accepted explanation for the anomeric effect:
Other Explanations:
Dipole Stabilization: Opposing dipoles are stabalizing relative to aligned dipoles
hyperconjugation resonace form
stabalizes axial conformation
O
O
O
OR
O
O
2
OR
1
OR
OR
destabalizing
dipole interaction
OR
observed bond length for bond 2 is
shorter then typical O-C bond
and longer for bond 1
Electrostatic Repulsion: Decreased electrostatic interactions are favored
Closer Examination of Orbitals:
HOMO: non-bonding (nOxygen)
H
H
OR
O
O
OR
antiperiplanar
representation
OR
LUMO: anti-bonding (!*C-O)
stabalizing 2 electron interaction
This model is referd to as
Antiperiplanar Lone Pair
Hypothesis or ALPH
H
destabalizing interaction of
electronegative atom gauche
with two lone pairs
OR
destabalizing interaction of
electronegative atom gauche
with only one lone pair
favored
Net Anomeric Effect probably due to a combination of factors
The Anomeric Effect
Baran Group Meeting
Effect is observed in tetrahydrothiopyran:
The Exo-Anomeric Effect:
O
O
H
H
H
S
same orbital overlap with
exocyclic oxygen observed as
stabalizing resonance form
O
X
O
CH3
view
here
O
O
minor contribution to overall resonance
relative to endo anomeric effect
O
O
O
view
here
X
O
O
S
S
H
H
O
X
endo anomeric effect is the dominant stabalizing
interaction with axial substituents, the exo anomeric
effect is stronger with equitorial subsitutents
CH3
O
H
Less significant contribution of anomeric effect with
tetrahydrothiopyran. However, since C-S bonds are longer
then C-C bonds 1,3-diaxial interactions are decreased and
as a result more axial isomer is seen then in the oxygen
analogs
Effect is observed in dioxanes and dithianes:
also can be stabalizing with equitorial substituents
O
Paul Krawczuk
simple extention of the tetrahydropyran case however
now there are two oxygens that take part in the
resonance structure
dithianes show an even greater preference for axial
substituents due to greater relaxation of 1,3-diaxial
interactions
Effect is very minimal with amine nitrogens:
Anomeric Effect=(exo-AEeq)-(exo-AEax+endo-AEax)
endo anomeric effect is absent in the equitorial conform so this term is zero
O
NH2
amine nitrogen not electronegative enough to produce a
significant anomeric effect on tetrahydropyran
Praly, J. P., Lemieux, R.U., Can. J. Chem. 1987, 65, 213.
Structures with N-C-X bonds where X is a strongly elcetronegative
substitutent on piperadine are not stable so the effect cannot be
studied on these systems
Anomeric Effect of Radicals:
H OAc
H OAc
H O
AcO
AcO
H
H
Bu3Sn
H
OAc
-20oC
H O
AcO
AcO
X
H
H
Bu3SnD
H
OAc
H OAc
Effects at sp2 centers:
H O
AcO
AcO
H
H
H
OAc
D
Major Product
H OAc
H
H
O
R
R
R
O
O
O
98:2
H O
AcO
AcO
R
X
OAc
H
Bu3Sn
-20oC
H OAc
R
H O
AcO
AcO
R
H
H
OAc
H
Giese, B., Dupuis, J., Tetrahedron Lett., 1983, 25, 1349.
O
O
R
O
O
R
increased barrier of rotation due to
stabalizing interaction
The Anomeric Effect
Baran Group Meeting
Paul Krawczuk
Spiroketals: found in many natural products
reviews: Perron, F., Albizati, K.F. Chem.Rev. 1989, 89, 1617-1661
Brimble, M.A., Furkert, D.P. Current Organic Chemistry, 2003, 7, 1461-1484.
Anomeric Control of Product Distribution:
structural conformations that depend on the anomeric effect
OH
H
PTSA (cat.)
MeOH
OMe
O
HO
OH
O
cat.
acid
stereochemistry?
O
O
H
O
kinetic
pathway
1 anomeric effect
O
OH
H
H
thermodynamic
pathway
O
H
H
HO
O
2 anomeric effects
(most stable)
O
O
O
H
O
H
H
no anomeric effects
(least stable)
high energy twist-boat
conformation required
for Bürgi-Dunitz angle
O
H
O
O
H
O
kinetic
conditions
a
H
1 anomeric effect
O
General considerations for spiroketal ring systems.
Actual outcome will also be dependent on substituents
H
H
O
a
H
H
e
100:0
thermodynamic
conditions
45:55
O
e
O
H
G.R.J. Thatcher (ed.), The Anomeric Effect and Related Stereolectronic Effects. ACS Symposium Series #539, 1993.
The Reverse Anomeric Effect: Fact or Fiction?
Preference for equatorial position with positively charged-electronegative substituents
O
O
NR3
NR3
O
O
NR3
NR3
C. L. Perrin, Tetrahedron, 1995, 51, 11901.
highly debated in the literature
-often the charged species studied are bulky and sterics have a greater contributioin
-dipole interactions in equitorial state are not stabalizing (evidence for this model)
-no lone pair on axial subsituent to contribute to the exo-anomeric effect
-the axial structure is weak (favored by elimination) and unlikely to exist, only the equitorial isomer is
preferred as a result
O
interesting exception:
O
N
Me
N
Me
Ratcliffe, A.J. Fraser-Reid, B. J .Chem. Soc. Perkin Trans. 1 1990, 747-750.
Baran Group Meeting
The Anomeric Effect
Brief Sampling of Simple Spiroketal Natural Products:
Non-Anomeric spiroketal:
Agric. Biol. Chem., 1986. 50, 2693.
From: Perron, F., Albizati, K.F. Chem.Rev. 1989, 89, 1617-1661
Org. Lett., 2004, 6(21), 3849-3852.
Paul Krawczuk
The Anomeric Effect
Baran Group Meeting
How can we use the anomeric effect?
OMe
Ph
O
Ph
H
H
O
H
Discaccharide from Apoptolidin:
H
Ph
MeOH
TEA
OMe
H
OTMS
H
MeOH
HCl
OTMS
Paul Krawczuk
H
Ph
O
H
OH
Me
SF3N(Et)2
O
100%
O
TBSO
MeO
H
PhS
OMe
O
Me
TBSO
MeO
O
OH
HF, CH3CN
OR
O
SPh
Me
TBSO
MeO
Ra-Ni
O
PhS
R=H
OTIPS OAc
Et
Me
O
O
O
OMe
H
O H
Me
OMe
OMe
Et
H+, cat. Ph3CClO4
87%
H
Me
O
O
H
O
H
H
H
Me
Et
NFmoc
OH
":! 17:1
controlled by
anomeric effect
Me
O
Br
O H
Me
O
Ag-Zeolite
CH2Cl2
69%
92%
Me
OMe
HO
H
H
Cl
NBS
OBn
O
pure " and ! anomers used
MeCN
O
used in glycosylation
O
Me
F
OTES
H
":! 15:1
Nicolaou, K.C. et. al. J. Am. Chem. Soc. 2001, 125, 15433-15442.
Me
OMe
OMe
O
O
OMe
Me
OMe
OMe
5% PdCl2
CO, MeOH
CuCl
OMe
25oC, 25hrs
OH
":! 6:1
anomeric effect
gives undesired product
5% PdCl2
CO, MeOH
CuCl
25oC, 25hrs
H
O
COOMe
OMe
BnO
BnO
H
H
OBn
RN
only " isomer
R
HO
O
Pd
H
COOMe
OMe
O
H OBn
HO
Me
OH
O
OH OMe
OH
Me
OTES
Me
O
BnO
BnO
TBSO
MeO
H
H
O
O
100%
O
O
O
O H
Evans, D. A.; Black W. C. J. Am. Chem. Soc. 1993,115, 4497-4513.
H OBn
NFmoc
O
SF3N(Et)2
O
O
Me
OTES
OBn
! desired isomer
OR
O "<!
O
SPh
>95 " isomer
O
R
HO
Pd
68% from ! anomer
64% from " anomer
whereas:
O
Cl
NaOMe
Ratcliffe, A.J. Fraser-Reid, B. J .Chem. Soc. Perkin Trans. 1 1990 747-750.
O
Me
F
Me
R=TIPS
Me
Me
OBn
bulky SPh groups used to discourage anomeric control of product
Danishefsky, S. Langer, M. J. Org. Chem. 1985, 50, 3674-3676.
(+)-Lepicidin A:
O
SnCl2
SPh
anomeric control of
axial OMe
H
Me
R=H
R=TES
TESOTf
TBSO
MeO
Me
OBn
PhS
Me
OMe
TBSO
MeO
O
OH
SPh
R=Ac
R=H
OH
5% PdCl2
CO, MeOH
CuCl
25oC, 25hrs
H
O
Me
COOMe
1:1
Semmelhack, M.F., et al. Pure & Appl. Chem., 1990, 62(10), 2035-2040.
The Anomeric Effect
Baran Group Meeting
Paul Krawczuk
Synthesis of Spirotekals:
THPO
Sequence 1:
Azaspiracid:
S
t-BuLi
S
THPO
S
Br
S
OH
S
Br
89%
THPO
COOMe
OR
OR
OR
OR
"
COOMe
35% two steps
OR
O3
OR
PPh3
34%
O
O
LiI, 2,6-lutidene
I(CH2)4OTBS
both forms show anomeric stabalization
40%
O
LDA
O
CH2Cl2
S
Sequence 2:
O
HgO, BF3•OEt2
OH
O
O
1) Li(CH2)4OTBS, 74%
2) POCl3, py
64%
OH
OH
PPTS
O
58%
O
incorrect structure originally targeted and synthesized
O
common
intermediate
O
O
O
"trans"
O
key spiroketal step:
1.85:1 to 3.35:1
depending on solvent
O
O
"cis"
2 anomeric effects
major product
correct structure as compared to natural product
4 anomeric effects
strongly disfavored due
to dipole repulsion
O
TMSOTf
O
S
S
OTES
O
McGarvey, G.J., Stepanian, M.W. Tet. Lett., 1996, 37(31), 5461-5466.
Photochemical Cyclization:
O
H
H
O O
HO
H
O
O
S S
-90°C
OTBDPS 89%
OTBDPS
O
H
H
H
Nicolaou, K.C., et al. Angew. Chem. Int. Ed. 2004, 43, 4318-4324.
1,5 hydrogen abstraction
Iodine(III) mediated radical cyclization to Spiroacetals:
O
HO
O
O
O
h!
O
O
O
OMe
HO
OTES
O
O
a
OMe
OMe
O
I2, h!
90%
TBDPSO
OMe
O
OH
O
O
O
OMe
HO
O
HO
pTSA
O
O
R=TES
R=H
O
HO
h!
O
O
Cottier, L.; Descotes, G. Tetrahedron 1985, 41(2), 409.
TBDPSO
HO
*
O
*
spirolides B and D
OH
O
O
O
O
OH
O
O
"
cat.
Acid
O
isomerize
to anomerically
stabalized isomer
4 diastereomers 1 : 1 : 1 : 1
3: 1 : 0.9 : 0
PhI(OAc)2
TBDPSO
HF, py
Norrish type II
HO
OR
PhI(OAc)2
pTSA, CH2Cl2
Brimble, M. A. Molecules. 2004, 9, 394-404
O
I2, h!
The Anomeric Effect
Baran Group Meeting
Examples of Spiroketal Tethering:
Pauson-Khand
Co2(CO)8
O
Olefin Metathesis
O
O
OH
OTBDPS
O
Tf2NH
89 %
OMe OBn
OAc
Grubbs Gen-1
10 mol %
OTBDPS
O
Me3NO
100°C
O
OH
Paul Krawczuk
O
91%
O
O
[cis:trans] [95:< 5]
O
OTBDPS
Co2(CO)8
O
OMe OBn
100% !
O
undergoes
slow elimination
H
OAc
O
95%
side reaction
O
OMe OBn
O
will be applied to the
synthesis of spirastrellolide A
OAc
O
Me3NO
100°C
90%
side reaction
O
O
undergoes
facile elimination
H
OAc
Liu, J., Hsung, R. P., Org. Lett. 2005, 7(11), 2273-3376.
O
O
O
anti
[cis:trans] [< 5:95]
Diels Alder
OTBS
5 membered ring:
TBSO
BnO
OBn
HO
OBn
PPTS
OTBS
OTBS
CH2Cl2
79%
O
TBSO
O
OBn
1) LHMDS
OBn
OBn
O
O
O
1) TBAF
2) TBSCL, imidazole
3) TPAP, NMO
O
OBn
OBn
2) MeI
K2CO3
O
O
O
CH2Cl2
-78oC-R.T.
Co2(CO)8
O
O
O
O R
OBn
O
H
AcO
axial
o
o
O
o
Wang, J., Hsung, R. P., Ghosh, S.K. Org. Lett. 2005, 6(12), 1939-1942.
Me3NO
100°C
R=Me 63%
R=Et 50%
O
O
Co2(CO)8
O
O
O R
R
OAc
AcO
O
O
Me3NO
100°C
R=Me 49%
R=Et 40%
Co2(CO)8
o
O
O
O
O
R
OAc
equitorial
O
axial
endo-boat-boat
w/ two anomeric effects
H
OAc
finally able to force selectivity with bulky silyl group - sterics beat anomeric effect
R
LA
o
O
H
H
o
Me3NO
100°C
78%
OAc
OBn
ZnCl2
R
R
O
O
anomeric control dominates stereochemical outcome even if substituent is forced into axial position
only diastereomer
favored transition state
leading to product
Co2(CO)8
O
O
TBSO
N
O
A
O
TBSO
probable transition state
two anomeric effects and
two chair conformations
H
E
66% three steps
O
axial
OP
Me3NO
100°C
40%
O
OP
H
H
O
OP
P=TES [cis:trans] [36:64]
P=TBS [cis:trans] [10:90]
P=TBDPS [cis:trans] [< 5:95]
Ghosh, S.K., Hsung, R.P., Liu, J. J. Am. Chem. Soc. 2005, 127, 8260-8261.