Download The Anomeric Effect and more Lecture notes Chemistry in PDF only on Docsity!
Baran Group Meeting Paul^ Krawczuk
The Anomeric Effect
Wednesday, November 9 , 2005
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.
O O
OR
OR
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.
Y Y
X
X
R
X
H
R
R
H
X
R
one gauche interaction
two gauche interactions
- OR has an axial preferecne in a C 1 substituted tetrahydropyran
C
S
N
O
I
Br Cl F
Electronegativites of Relavant Atoms
Historical Aspects of the Anomeric Effect
First observed in 1955 by J.T. Edward and in 1958 by R.U. Lemieux.
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.
R R
O
O
R R
alkyl substituted cyclohexanes prefer equitorial orientation over axial
alkyl substituted tetrahydropyrans show this same preference
O
H
HO
H
HO
H
OH
OH
H
H
OH
O
H
HO
H
HO
H
H
OH
H
OH
OH
the anomeric carbon of the most abundant natural sugar, D-glucopyranose, also prefers an equtorial orientation. (^36) % : 64 %
ratio of preference gives us some insight that something is different
O
H
HO
H
HO
H
OMe
OH H
H
OH
O
H
HO
H
HO
H
H
OH H
OMe
OH
conversion into a methyl ether at the anomeric carbon produces a different
result from the above
67 % : 33 %
different from reigning cyclohexane conformational analysis model
O
H
AcO
H
AcO
H
OAc
OAc
H
H
OAc
O
H
AcO
H
AcO
H
H
OAc
H
OAc
OAc
O
H
AcO
H
AcO
H
Cl
OAc H
H
OAc
O
H
AcO
H
AcO
H
H
OAc H
Cl
OAc
substitution with more electronegative
groups changes the observed ratio to a
greater extent
preferred by generalized anomeric effect
!!G o
anomeric effect (stabilization) = " !G
o (heterocycle)
- " !G
o (steric)
For the anomeric stabilization to effect the conformation at all it must
be more stabalizing then the sum of all of the steric factors
electronic factor
steric factor
O O
Me Me
Me
OMe
H
H
Me
H
OMe
H
O O
Me Me
Linear Example: often referred to as the gauche effect
Franck, R.W., Tetrahedron, 1983 , 39 , 3251.
Further Reading: G.R.J. Thatcher (ed.), T he Anomeric Effect and Related Stereolectronic Effects. ACS Symposium Series # 539 , 1993. Review: Juaristi, E., Cuevas, G., Tetrahedron, 1992 , 48 ( 24 ), 5019 - 5087.
~ 1. 5 kcal
Paul Krawczuk Baran Group Meeting
Most widely accepted explanation for the anomeric effect:
O O (^) O
OR
OR
hyperconjugation resonace form stabalizes axial conformation
Closer Examination of Orbitals:
O
stabalizing 2 electron interaction
HOMO: non-bonding (nOxygen)
LUMO: anti-bonding (!*C-O)
O
OR
Further Evidence:
O
O
Cl
Cl e^ a
bond lenght: increased in the axial C-Cl bond ( 1. 819 Å)
versus the equatorial C-Cl bond ( 1. 7181 Å)
O
O
a
e
axial bond also observed to be longer then
equitorial bond in this constrained case
OR
39 Å
43 Å
observed bond length for bond 2 is shorter then typical O-C bond and longer for bond 1
H
OR
antiperiplanar representation
This model is referd to as
Antiperiplanar Lone Pair
Hypothesis or ALPH
Other Explanations:
Dipole Stabilization: Opposing dipoles are stabalizing relative to aligned dipoles
O
O
OR
OR
Electrostatic Repulsion: Decreased electrostatic interactions are favored
destabalizing dipole interaction
H
OR
OR
H
destabalizing interaction of electronegative atom gauche with two lone pairs
destabalizing interaction of electronegative atom gauche with only one lone pair favored
Sovent also plays a role : Increase in anomeric
stabilization associated with low solvent dipole
O O
OMe
OMe
Solvent CCl 4 benzene CHCl 3 acetone MeOH MeCN H 2 O
Dipole
- 2
- 3
- 7
- 7
- 6
- 5
- 5
% axial 83 82 71 72 69 68 52
Net Anomeric Effect probably due to a combination of factors
Lemieux, R.U., et al. Can. J. Chem. 1969 , 47 , 4427.
Romers, C., et al. Topics Stereochem., 1969 , 4 , 39.
Baran Group Meeting Paul^ Krawczuk
Spiroketals: found in many natural products
structural conformations that depend on the anomeric effect
HO OH
O cat. acid
O
O
stereochemistry?
O
O O
O
O
O
O
2 anomeric effects^ O (most stable)
1 anomeric effect
no anomeric effects (least stable)
1 anomeric effect
General considerations for spiroketal ring systems. Actual outcome will also be dependent on substituents
O
H
H
OH
OMe
PTSA (cat.) MeOH
O
H
H
OH
kinetic conditions
thermodynamic conditions
O
H
H
O
H
high energy twist-boat conformation required for Bürgi-Dunitz angle
O
H
H
HO
H
H
kinetic pathway thermodynamic pathway
O
H
H
O
H
O
H
H
O
H
45 : 55
100 : 0
e
a
a
e
Anomeric Control of Product Distribution:
G.R.J. Thatcher (ed.), T he Anomeric Effect and Related Stereolectronic Effects. ACS Symposium Series # 539 , 1993.
The Reverse Anomeric Effect: Fact or Fiction?
O
NR 3
O
NR 3
Preference for equatorial position with positively charged-electronegative substituents
O
NR 3
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
NR 3 interesting exception:
O
N
Me
O
N
Me
Ratcliffe, A.J. Fraser-Reid, B. J .Chem. Soc. Perkin Trans. 1 1990 , 747 - 750.
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.
C. L. Perrin, Tetrahedron, 1995 , 51 , 11901.
Baran Group Meeting Paul^ Krawczuk
From: Perron, F., Albizati, K.F. Chem.Rev. 1989 , 89 , 1617 - 1661
Brief Sampling of Simple Spiroketal Natural Products:
Non-Anomeric spiroketal:
Agric. Biol. Chem., 1986. 50 , 2693.
Org. Lett., 2004 , 6 ( 21 ), 3849 - 3852.
O
Baran Group Meeting Paul^ Krawczuk
O
spirolides B and D
OH
OTES
TBDPSO
PhI(OAc) 2
I 2 , h! O O
OR
TBDPSO
HF, py
R=TES
R=H
PhI(OAc) 2
I 2 , h!
O
O
TBDPSO O
4 diastereomers 1 : 1 : 1 : 1 pTSA, CH 2 Cl 2 3 : 1 : 0. 9 : 0
Brimble, M. A. Molecules. 2004 , 9 , 394 - 404
S
S
THPO Br Br
t-BuLi (^) HgO, BF S 3 • OEt 2
S
THPO
S
S
OH
CH 2 Cl 2
O O
O
COOMe
LDA
I(CH 2 ) 4 OTBS
O
COOMe
LiI, 2 , 6 - lutidene
O
1 ) Li(CH 2 ) 4 OTBS, 74 %
2 ) POCl 3 , py
O 3
PPh 3
PPTS
Sequence 1 :
Sequence 2 :
O
O O O
O
O
35 % two steps
common intermediate
"trans" (^) "cis"
2 anomeric effects major product
4 anomeric effects strongly disfavored due to dipole repulsion
- 85 : 1 to 3. 35 : 1 depending on solvent
Synthesis of Spirotekals:
McGarvey, G.J., Stepanian, M.W. Tet. Lett., 1996 , 37 ( 31 ), 5461 - 5466.
O
OMe
O
O
h! O
OMe
O
O
Norrish type II
O
OMe
O
HO
Photochemical Cyclization:
O
OMe
HO
a
O
O
OMe
HO
HO
O
pTSA O
O
O
HO
O
h!
O
O
HO
O
OH O
O
HO
O
OH
isomerize to anomerically stabalized isomer
cat. Acid
Cottier, L.; Descotes, G. Tetrahedron 1985 , 41 ( 2 ), 409.
1 , 5 hydrogen abstraction
Azaspiracid:
incorrect structure originally targeted and synthesized (^) correct structure as compared to natural product
both forms show anomeric stabalization
key spiroketal step:
O
O (^) O
OTES OTBDPS
H
H
O
S S
O
O TMSOTf
O OTBDPS H
O H
O O
S S
HO
H
H
° C
Iodine(III) mediated radical cyclization to Spiroacetals:
Nicolaou, K.C., et al. Angew. Chem. Int. Ed. 2004 , 43 , 4318 - 4324.
OH
OH
O O
OH OR
O O
OR
OR
OR
OR
OR
THPO
Paul Krawczuk Baran Group Meeting
Examples of Spiroketal Tethering:
Olefin Metathesis
O
OH
OMe
OTBDPS
OBn
OH
Tf 2 NH
O
O
OMe
OTBDPS
OBn
100 %!
Grubbs Gen- 1 10 mol %
O
O
OMe
OTBDPS
OBn
will be applied to the synthesis of spirastrellolide A
Liu, J., Hsung, R. P., Org. Lett. 2005 , 7 ( 11 ), 2273 - 3376.
Diels Alder
BnO OBn
OTBS
O
PPTS
CH 2 Cl 2
HO
OTBS
OBn
OBn
OTBS
O
O
TBSO
1 ) TBAF 2 ) TBSCL, imidazole 3 ) TPAP, NMO
66 % three steps
OBn
OBn
O
O
TBSO
O
LHMDS
N
MeI K 2 CO 3
OBn
OBn
O
O
TBSO
O CH 2 Cl 2
OBn
OBn
O O
TBSO
O
ZnCl 2
only diastereomer
H
o^ o
R o LA
axial axial
favored transition state leading to product
endo-boat-boat w/ two anomeric effects
o^ o
R
R
o
H
H
Wang, J., Hsung, R. P., Ghosh, S.K. Org. Lett. 2005 , 6 ( 12 ), 1939 - 1942.
Pauson-Khand
Co 2 (CO) 8
Me 3 NO
O
O
OAc
Co 2 (CO) 8
Me 3 NO
O
O
OAc
O
° C
° C H
undergoes facile elimination
anti
undergoes slow elimination
O
O
OAc
O
H
O
O
OAc
O
O
O
E
A
axial
probable transition state two anomeric effects and two chair conformations
side reaction
side reaction
O
O
O
O
O
O
O O
OAc
Co 2 (CO) 8
Me 3 NO
100 ° C
O
O
OAc
O
O (^) O
AcO
Co 2 (CO) 8
Me 3 NO
100 ° C
R
O
O
OAc
R
H
H
O
R=Me 63 % R=Et 50 %
Ghosh, S.K., Hsung, R.P., Liu, J. J. Am. Chem. Soc. 2005 , 127 , 8260 - 8261.
O (^) O
OP
anomeric control dominates stereochemical outcome even if substituent is forced into axial position
[cis:trans] [ 95 :< 5 ]
[cis:trans] [< 5 : 95 ]
O O
AcO
Co 2 (CO) 8
Me 3 NO
100 ° C
R
O
O
OAc
R
O
R=Me 49 % R=Et 40 %
Co 2 (CO) 8
Me 3 NO
100 ° C
5 membered ring:
O
O
OP
H
O
finally able to force selectivity with bulky silyl group - sterics beat anomeric effect
P=TES [cis:trans] [ 36 : 64 ] P=TBS [cis:trans] [ 10 : 90 ] P=TBDPS [cis:trans] [< 5 : 95 ]
O
O
H
OP
equitorial
