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Paul KrawczukBaran Group MeetingThe 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 conformationsabout the bond C–Y in the system X–C–Y–C where X and Y are heteroatomshaving nonbonding electron pairs, commonly at least one of whichis nitrogen, oxygen, sulfur or fluorine.
Y Y
X
X
R
X
H
R
R
H
X
R
one gaucheinteraction
two gaucheinteractions
-OR has an axial preferecne in a C1 substituted tetrahydropyran
CS NOIBrClF
2.52.53.03.52.52.83.04.0
Electronegativitesof 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
OO
R
R
alkyl substituted cyclohexanes prefer equitorial orientation over axial
alkyl substituted tetrahydropyrans show this same preference
O
H
HO
H
HO
H
OHOH
HH
OH
O
H
HO
H
HO
H
HOH
HOH
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
OMeOH
HH
OH
O
H
HO
H
HO
H
HOH
HOMe
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
OAcOAc
HH
OAc
O
H
AcO
H
AcO
H
HOAc
HOAc
OAc
86% : 14%
O
H
AcO
H
AcO
H
ClOAc
HH
OAc
O
H
AcO
H
AcO
H
HOAc
HCl
OAc
94% : 6%
substitution with more electronegative groups changes the observed ratio to a greater extent
preferred by generalized anomeric effect
!!Goanomeric effect (stabilization) = " !Go(heterocycle) - " !Go
(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
OOMe Me
Me
OMe
H
H
Me
H
OMe
H
OO
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.), The 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 KrawczukBaran Group MeetingThe Anomeric Effect
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 aebond lenght: increased in the axial C-Cl bond (1.819Å)versus the equatorial C-Cl bond (1.7181Å)
O
O
a
eaxial bond also observed to be longer then equitorial bond in this constrained case
OR
1.39 Å
1.43 Å
observed bond length for bond 2 is shorter then typical O-C bondand longer for bond 1
1
2
H
OR
antiperiplanarrepresentation
This model is referd to as Antiperiplanar Lone Pair Hypothesis or ALPH
Other Explanations:
Dipole Stabilization: Opposing dipoles are stabalizing relative to aligned dipoles
OO
OR
OR
Electrostatic Repulsion: Decreased electrostatic interactions are favored
destabalizingdipole 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
SolventCCl4benzeneCHCl3acetoneMeOHMeCNH2O
Dipole2.22.34.7
20.732.637.578.5
% axial83827172696852
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.
O
Paul KrawczukBaran Group MeetingThe Anomeric Effect
The Exo-Anomeric Effect:
Anomeric Effect of Radicals:
O
H
AcO
H
AcO
H
OAcH
H
OAc
O
H
AcO
H
AcO
H
OAcH
H
OAc
X
Bu3SnD
O
H
AcO
H
AcO
H
OAcH
X
OAc
H
Bu3SnO
H
AcO
H
AcO
H
OAcH
H
OAc
O
H
AcO
H
AcO
H
OAcH
H
OAc
D
Major Product
98:2
-20oC
-20oC
Giese, B., Dupuis, J., Tetrahedron Lett., 1983, 25, 1349.
O
OH
O
O
CH3 viewhere
H
O
O
H
same orbital overlap with exocyclic oxygen observed as stabalizing resonance form
O
H
O
also can be stabalizing with equitorial substituents
endo anomeric effect is the dominant stabalizing interaction with axial substituents, the exo anomeric effect is stronger with equitorial subsitutents
minor contribution to overall resonancerelative to endo anomeric effect
viewhere
H
O
CH3
O
H
O
Anomeric Effect=(exo-AEeq)-(exo-AEax+endo-AEax)
Praly, J. P., Lemieux, R.U., Can. J. Chem. 1987, 65, 213.
endo anomeric effect is absent in the equitorial conform so this term is zero
Bu3Sn
Effect is observed in dioxanes and dithianes:
O
O
S
S
X
X
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
S
X
Effect is observed in tetrahydrothiopyran:
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 very minimal with amine nitrogens:
amine nitrogen not electronegative enough to produce a significant anomeric effect on tetrahydropyran
O
NH2
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
Effects at sp2 centers:
R O
O
R
R
O
O R
R O
O
R R O
O
R
increased barrier of rotation due to stabalizing interaction
Paul KrawczukBaran Group MeetingThe Anomeric Effect
Spiroketals: found in many natural products
structural conformations that depend on the anomeric effect
HO OH
O cat.acid
O
Ostereochemistry?
O
OO
O
O
O
O
O2 anomeric effects(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
kineticconditions
thermodynamicconditions
O
H
H
O
H
high energy twist-boatconformation requiredfor 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.), The Anomeric Effect and Related Stereolectronic Effects. ACS Symposium Series #539, 1993.
The Reverse Anomeric Effect: Fact or Fiction?
O
NR3
O
NR3
Preference for equatorial position with positively charged-electronegative substituents
O
NR3
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
NR3 interesting exception:O
N
Me
O
NMe
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, 1617-1661Brimble, M.A., Furkert, D.P. Current Organic Chemistry, 2003, 7, 1461-1484.
C. L. Perrin, Tetrahedron, 1995, 51, 11901.
Paul KrawczukBaran Group MeetingThe Anomeric Effect
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.
Me Me
Me
Paul KrawczukBaran Group MeetingThe Anomeric Effect
O OMePhH H
HOTMS
MeOHTEA
O OMePhH H
HOMeOH
HCl
O OMePhH H
HO
O
HPh
OMe
OTMS
How can we use the anomeric effect?
anomeric control of axial OMe
Danishefsky, S. Langer, M. J. Org. Chem. 1985, 50, 3674-3676.
O
H
BnO
H
BnO
H
OBnH
OBn
Ratcliffe, A.J. Fraser-Reid, B. J .Chem. Soc. Perkin Trans. 1 1990 747-750.
O
NBS
MeCN
O
OH
ClO
H
BnO
H
BnO
H
OBnH
OBn
RN O
Cl
68% from ! anomer64% from " anomer
pure " and ! anomers usedNaOMe
R=Ac
R=H
O
O
O
OH
OTIPS
MeEt
H
H H
H
O MeOMe
OMeOMe
OAc
O
O
O
O
OR
MeEt
H
H H
H
O MeOMe
OMeOMe
(+)-Lepicidin A:
":! 17:1controlled by anomeric effect
H+, cat. Ph3CClO4
R=TIPS
R=H
HF, CH3CN
O
Ag-ZeoliteCH2Cl2
O
O
O
O
O
MeEt
H
H H
H
O MeOMe
OMeOMe
MeNFmoc
Br
OMe
NFmoc
":! 6:1anomeric effectgives undesired productEvans, D. A.; Black W. C. J. Am. Chem. Soc. 1993,115, 4497-4513.
Discaccharide from Apoptolidin:
O
SPh
OH
MeO
TBSOMe SF3N(Et)2 O
MeO
TBSOMe
PhSF
O
Me
OH
Me
SPh
OBnOH
SnCl2
O
MeO
TBSOMe
PhS O
Me
O
Me
SPh
OBnOR
" < !
bulky SPh groups used to discourage anomeric control of product
O
MeO
TBSOMe
PhS O
Me
O
SPh
OBnOTES
87%
! desired isomer
69%
100%
R=H
R=TESTESOTf
Ra-Ni O
MeO
TBSOMe
O
Me
O
OHOTES
SF3N(Et)2
100%
O
MeO
TBSOMe
O
Me
O
FOTES":! 15:1
used in glycosylation
92%
Nicolaou, K.C. et. al. J. Am. Chem. Soc. 2001, 125, 15433-15442.
OH OMe
5% PdCl2CO, MeOH
CuCl
25oC, 25hrsO
OMeCOOMe
H
OH OMe
5% PdCl2CO, MeOH
CuCl
25oC, 25hrsO OMe
COOMeH
only " isomer
>95 " isomer
HOR
Pd
O
HOR
Pd
whereas:
OH
5% PdCl2CO, MeOH
CuCl
25oC, 25hrsO
MeCOOMe
H
1:1
Semmelhack, M.F., et al. Pure & Appl. Chem., 1990, 62(10), 2035-2040.
O
O
Paul KrawczukBaran Group MeetingThe Anomeric Effect
O
spirolides B and D
OH
OTES
TBDPSO
PhI(OAc)2
I2, h!O
O
OR
TBDPSO
HF, pyR=TES
R=H
PhI(OAc)2
I2, h!
O
OOTBDPSO
**
4 diastereomers 1 : 1 : 1 : 1pTSA, CH2Cl2
3: 1 : 0.9 : 0
Brimble, M. A. Molecules. 2004, 9, 394-404
90%
S
STHPO BrBr
t-BuLi HgO, BF3•OEt2S
S
THPO
S
S
OH
CH2Cl2OO
O
COOMeLDA
I(CH2)4OTBS
O
COOMe
LiI, 2,6-lutidene
O
"
1) Li(CH2)4OTBS, 74%
2) POCl3, py
O3
PPh3
PPTS
Sequence 1:
Sequence 2:
OO
OOO
O
89%40%
35% two steps
commonintermediate
64%
34%58%
"trans" "cis"
2 anomeric effectsmajor product
4 anomeric effectsstrongly disfavored due to dipole repulsion
1.85:1 to 3.35:1depending 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
OHO
O
HO
O
OH
isomerizeto 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
OTBDPSOTES
H
H
O
SS
O
O TMSOTf
O OTBDPS
H
HO
OO
S S
HO
H
H
89%-90°C
Iodine(III) mediated radical cyclization to Spiroacetals:
Nicolaou, K.C., et al. Angew. Chem. Int. Ed. 2004, 43, 4318-4324.
OH
OH
OO
OHOR
OO
OR
OR
OR
OR
OR
THPO
Paul KrawczukBaran Group MeetingThe Anomeric Effect
Examples of Spiroketal Tethering:
Olefin Metathesis
O
OH
OMe
OTBDPS
OBn
OH
Tf2NH
O
O
OMe
OTBDPS
OBn
100% !
Grubbs Gen-110 mol %
95% 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
CH2Cl2
89 %
79%
HO
OTBS
OBn
OBn
OTBS
O
O
TBSO
1) TBAF2) TBSCL, imidazole3) TPAP, NMO
66% three steps
OBn
OBn
O
O
TBSO
O
LHMDS
N
MeIK2CO3
1)
2)
OBn
OBn
O
O
TBSO
O CH2Cl2
OBn
OBn
OO
TBSO
O
ZnCl2
only diastereomer
H-78oC-R.T.
oo
R o
LA
axial axial
favored transition state leading to product
endo-boat-boatw/ two anomeric effects
oo
R
R
o
H
H
Wang, J., Hsung, R. P., Ghosh, S.K. Org. Lett. 2005, 6(12), 1939-1942.
Pauson-Khand
Co2(CO)8
Me3NO
O
O
OAc
Co2(CO)8
Me3NO
O
O
OAc
O
100°C
100°CH
undergoesfacile elimination
anti
undergoesslow elimination
O
O
OAc
O
H
O
O
OAc
O
O
O
E
A
axial
probable transition statetwo anomeric effects andtwo chair conformations
91%
90%
side reaction
side reaction
O
OO
O
OO
O O
OAc
Co2(CO)8
Me3NO
100°C
OO
OAc
O
O O
AcO
78%
Co2(CO)8
Me3NO
100°C
RO
O
OAcR
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
Co2(CO)8
Me3NO
100°C
RO
O
OAcR
O
R=Me 49%R=Et 40%
Co2(CO)8
Me3NO
100°C
5 membered ring:
OO
OPH
O
finally able to force selectivity with bulky silyl group - sterics beat anomeric effect
40% P=TES [cis:trans] [36:64] P=TBS [cis:trans] [10:90]P=TBDPS [cis:trans] [< 5:95]
OO
H
OP
equitorial