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Stereoelectronic Control in the Formation and Cleavage of Tetrahedral
IntermediatesAntiperiplanar Lone-Pair Hypothesis and its evolution
Changyou YuanDepartment of Chemistry
Michigan State University
Outline
• Stereoelectronic control • Ozonolysis of acetals – the first generation of ALPH
• Stereoelectronic control in Hydrolysis of orthoesters and conformationally restricted acetals – the second generation of ALPH
• Ozonolysis and hydrolysis of tricyclic acetals – the third generation of ALPH
• Application of ALPH • Conclusion
Stereoelectronic control
• Definition: Control the nature of the products of a chemical reaction (or of its rate) by stereoelctronic factors.
• Specific meaning in this seminar:Control the formation and cleavage of tetrahedral intermediates of acetals, orthoesters, amidines, etc., by the proper alignment of the lone pair(s) on heteroatoms.
IUPAC Compendium of Chemical Terminology 2nd Edition (1997)
Ozonolysis of AcetalsExperimental results
R
H
OCH3
OCH3
O3
15hr, -78oC R
O
OCH3
+ CH3OH
O
O
R
H
O3
1 min, -78oCR
O
OOH
O OEt
H
O3 COOEtOH O O
No lactone observed
OAcO
AcOAcO
OAc
OCH3 1. O3
COOCH3
CH2OAc
OAc
AcO
OAc
OAc
OAcO
AcOAcO
OAcOCH3
2. Ac2O, Pyr.
P.Deslongchamps and C.Moreau. Canad. J. Chem. 1971, 49, 2465.P.Deslongchamps. C.Moreau. D.Frehel and P.Atlanti. Canad. J. Chem. 1972, 50, 3402.
Ozonolysis of Acetalsconformational analysis
Any reactive conformer must have on each oxygen atom a lone pair orbital oriented antiperiplanar to the C-H bond of the acetal function.
O
OR
H
O
O
H
OR
OR
H
1 active 2 non-active
3 active
H3CO O
H
RCH3
4 non-active
H3CO
O
HR
CH3
5 active
P.Deslongchamps P.Atlanti, D.Frehel and A.Malaval, Canad. J. Chem. 1971, 49, 2465.P.Deslongchamps. C.Lebreux and R.J.Taillefer, Canad. J. Chem. 1972, 50, 3402.
Antiperiplanar Lone-Pair Hypothesis- the first generation
• Any reactive conformer must have on each oxygen atom a lone pair orbital oriented antiperiplanar to the C-H bond of the acetal function.
YY
X
Y = O, N, S, etc.
X = H, O, etc.O
O
HA B
Why ALPH is accepted – anomeric effect
• Anomeric effect
OHO
HO
Br
OH
OH
OHO
HOOH
Br
OH
α anomer(more stable) β anomer
OHO
HOOH
OH
Br
OHO
HO
BrOH
OH
Why ALPH is accepted - E2 elimination
CH3
Cl
H
ClH
CH3
CH3
HH
Cl
H
H
KOH
alcohol
CH3
1 2
http://www.cem.msu.edu/~reusch/VirtualText/special3.htm
Intermediates in ozonolysis of Acetals
Possible ozonolysis intermediates
O
O
OR
O
O
OR
H O
OH3 4
O
O
OR
X
OR
O
OH
O
O5
P.Deslongchamps P.Atlanti, D.Frehel and A.Malaval, Canad. J. Chem. 1971, 49, 2465.P.Deslongchamps. C.Lebreux and R.J.Taillefer, Canad. J. Chem. 1972, 50, 3402.
Hydrolysis of orthoestersO OEt
OEt
O OEt
OEt
O OEt
OEt
O OEt
OEt
COOEtOH
COOEtOH
COOEtOH
COOEtOH
H+ No lactone products detected
P.Deslongchamps. C.Lebreux and R.J.Taillefer, Canad. J. Chem. 1972, 50, 3405. E.H. Cords in Progressin Physical Organic Chemistry, Vol. 4, pp 1-44. A. Streitwieser and R.W. Tafts (eds), Interscience: New York 1967.
Hydrolysis of orthoesters conformational analysis
A
O
O
OEt
Et
O
O
O
Et
O
O
O
Et
Et
Et
O
O
OEt
Et
OO
OO
Et
Et
OEt
OEt
O
O
OEt
OO
OO
Et
Et
EtO
EtO
Et
B C
D E F
G H I
P.Deslongchamps. C.Lebreux and R.J.Taillefer, Canad. J. Chem. 1972, 50, 3405. P.Deslongchamps. R.Chenevert, R.J.Taillefer, C.Moreau and J.K. Saunders. Canad. J. Chem. 1975, 53, 1601
Hydrolysis of orthoesters conformational analysis
A
O
O
O Et
Et
O
O
O
Et
Et
OO
OO
Et
Et
O Et O Et
C
E F
O
O
O H+, 24hr, no reaction
Rigid model of C
P.Deslongchamps. C.Lebreux and R.J.Taillefer, Canad. J. Chem. 1972, 50, 3405. P.Deslongchamps. R.Chenevert, R.J.Taillefer, C.Moreau and J.K. Saunders. Canad. J. Chem. 1975, 53, 1601
Hydrolysis of orthoestersReaction pathway for conformer A
A
O
O
OEt
Et
O
OEt
O
O
OEt
H
OEt
OH
O
1 2
3
P.Deslongchamps. C.Lebreux and R.J.Taillefer, Canad. J. Chem. 1972, 50, 3405. P.Deslongchamps. R.Chenevert, R.J.Taillefer, C.Moreau and J.K. Saunders. Canad. J. Chem. 1975, 53, 1601
Hydrolysis of orthoestersReaction pathway for conformer F
OO
Et
OEt
F
OH
O
O
Et
Et
OO
Et
OEt
R
H
O
OH
Et
O
O
Et
O
O
Et
HR
4
5
6
3
P.Deslongchamps. C.Lebreux and R.J.Taillefer, Canad. J. Chem. 1972, 50, 3405. P.Deslongchamps. R.Chenevert, R.J.Taillefer, C.Moreau and J.K. Saunders. Canad. J. Chem. 1975, 53, 1601
Hydrolysis of orthoestersReaction pathway for conformer E
OO
Et
OEt
E
O
OEt
OO
Et
OH
OO
Et
OH
OEt
OH
O
O
O
OH
Et
O O
8 9
10
3
11
12
P.Deslongchamps. C.Lebreux and R.J.Taillefer, Canad. J. Chem. 1972, 50, 3405. P.Deslongchamps. R.Chenevert, R.J.Taillefer, C.Moreau and J.K. Saunders. Canad. J. Chem. 1975, 53, 1601
Difference between A,F and E
OO
Et
OEt
F
A
O
O
OEt
Et
OO
Et
OEt
E
cis
trans
trans
1
4
8
O O
Et
Et
O O
R
Et
O OEt
P.Deslongchamps. C.Lebreux and R.J.Taillefer, Canad. J. Chem. 1972, 50, 3405. P.Deslongchamps. R.Chenevert, R.J.Taillefer, C.Moreau and J.K. Saunders. Canad. J. Chem. 1975, 53, 1601
Difference between A,F
A
O
O
O Et
Et
O
OEt
O
O
O Et
H
OEt
OH
O
1 2 3
OO
Et
O Et
F
OH
O
O
Et
Et
OO
Et
O Et
R
HO
OH
Et
O
O
Et
O
O
Et
HR
4
5
6
3
- EtOH
P.Deslongchamps. C.Lebreux and R.J.Taillefer, Canad. J. Chem. 1972, 50, 3405. P.Deslongchamps. R.Chenevert, R.J.Taillefer, C.Moreau and J.K. Saunders. Canad. J. Chem. 1975, 53, 1601
Stereoelectronic controlled addition of methoxide to lactonium ion
O O
O
H
H OEt
OCH3
O
H
H OCH3
OEtO
OEt
Et3OBF4
NaOMe/MeOH
i-PrOH
X COOEt
OH
14
15
16
17 18
XCOOMe
OH
19
Hydrolysis of cyclic orthoesters proceeds by loss of the axial alkoxy group. So, conformer A is the active one.
P.Deslongchamps. R.Chenevert and R.J.Taillefer, Canad. J. Chem. 1975, 53, 1601.
Stereoelectronic control in acetal FormationExperimental results
O
HOH
H
OMeO
H
H
O
HO
H
H
O
H
PTSA-MeOH, R.T. 100 : 0
PTSA-MeOH, reflux 45 : 55
+
20 21 22
N.Beaulieu, R.A. Dickinson, P. Deslongchamps. Can. J. Chem. 1980, 58, 2531.P.Deslongchamps, D.Guay, Can. J. Chem. 1985, 63, 2757.
Stereoelectronic control in acetal FormationALPH explanation
O
HOH
H
OMe
O
H
HO
H
H
O
H
H
O
H
O
H
H
O
H
O
H
H
HO
H
O
HH
H
OH
HH
chair
twist-boat
20 21
2223
24
25
100%
0%
N.Beaulieu, R.A. Dickinson, P. Deslongchamps. Can. J. Chem. 1980, 58, 2531.P.Deslongchamps, D.Guay, Can. J. Chem. 1985, 63, 2757.
Successfulness of ALPH and Challenges it faced
• Successfulness of ALPH
ALPH can predict and explain the experiment results successfully in
ozonolysis, hydrolysis and formation of Acetals and hydrolysis of
orthoesters.
• Challenges to ALPH:Can ALPH be applied to glycoside hydrolysis?
Is there some (or even trivial) amount of lactone formed under
kinetically controlled conditions in the hydrolysis of orthoester?
Apply ALPH to the hydrolysis of glycosides
O
O
OCH3
H
H
OCH3
R
R
O
OCH3
HR
H+
OR H
O H
OCH3
R
H+
O
ROH
α - glycoside
H+
chair
twist-boatβ - glycoside
H+
Based on ALPH, α glycoside should hydrolysis much faster than β glycosides.
P. Deslongchamps. In Stereoelectronic Effects in Organic Chemistry, J.E. Baldwin Ed.; Organic ChemistrySeries, Vol I; Pergamon Press: Oxford, England, 1983.
Examples where ALPH failed in its simple form
OMe
OHOH
OHOPO3H2
O
OH
HO
OH
OPO3H2
HO
Equatorial/Axial
1.9
4.1
Glycoside hydrolysis:
O
OEt
OEt
O
O
OH
O
OEtOrthoesterHydrolysis:
J.V. O’Connor and R. Barker. Carbohydr. Res. 1979, 73, 227.B.Capon, D.M. Grieve. Tetrahedron Lett 1982, 23, 4823.S. Chandrasekhar, A.J. Kirby. and R.J. Martin. J. Chem. Soc., Perkin Trans. 2, 1983, 1619.
Formation of conformationally restricted acetals
O OH
O OH
O
O
O O
1 : 1AcOH/Benzene 19hr
TFA/Benzene 2hr 1 : 0
TFA/Benzene 2hr 1 : 0
3 : 2AcOH/Benzene 19hr
( 0 kcal/mol) ( 2.4 kcal/mol)
1
2
3 4
TFA
N. Pothier, S. Goldstein, P. Deslongchamps. Helv. Chim. Acat. 1992, 75, 604.P.Deslongchamps. Pure Appl. Chem. 1993, 65, 1161.
Formation of conformationally restricted acetals- determination of the transition state
O OH
O
OH
H CH3
O
OH
H CH3
O
HO HO
O
CH3
HO O
O
H3C
OH
H3CH
O
OH
CH3
H
O
O
O
HO
O
H3C
OH
H3CH
H
H
O O
O
O
O
HO
OH
CH3
H
CH3
H
O
1
5a
5b
6 7
8 9
10
12 13 3
4
3
411
α
β
α
β
N. Pothier, S. Goldstein, P. Deslongchamps. Helv. Chim. Acat. 1992, 75, 604.P.Deslongchamps. Pure Appl. Chem. 1993, 65, 1161.
Formation of conformationally restricted acetals- determination of the transition state
O OH
O
OH
O
OH
O
HO HO
O
O O
O
OH
H3CH
O
OH O
O
O
HO
O
OH
O O
O
O
O
HO
OH
CH3
H
O
H3C
H
CH3
H
H3C
H
H3C
H3C
H
H3C
H
CH3
H
CH3
H
H3C
H
CH3
H
H+
2
14a
14b
15 16
17 18
19 20
21
3
4
3
4
22
β
α
β
α
N. Pothier, S. Goldstein, P. Deslongchamps. Helv. Chim. Acat. 1992, 75, 604.P.Deslongchamps. Pure Appl. Chem. 1993, 65, 1161.
Re–exam the stereoelectronic control in acetal formation
O
HOH
H
OMeO
H
H
O
HO
H
H
O
H
PTSA-MeOH, R.T. 100 : 0
PTSA-MeOH, reflux 45 : 55
+
23 24 25
N.Beaulieu, R.A. Dickinson, P. Deslongchamps. Can. J. Chem. 1980, 58, 2531.P.Deslongchamps, D.Guay, Can. J. Chem. 1985, 63, 2757.
Re–exam stereoelectronic control in acetal formation
O
HOH
H
OMe
O
H
HO
H
H
O
H
H
O
H
O
H
H
O
H
O
HH
H
HO
O
H
H
HO
H
O
HH
H
OHO
HH
H
OH
HH
chair
twist-boat
α
β
2324
2526
27 28
29 30
100%
0%
N.Beaulieu, R.A. Dickinson, P. Deslongchamps. Can. J. Chem. 1980, 58, 2531.P.Deslongchamps, D.Guay, Can. J. Chem. 1985, 63, 2757.
Representative 27 like and 29 like conformers
481463.3510
501483.259
501523.158
551442.957
541422.756
29 like
511012.955
491112.854
511012.853
511032.752
501062.651
27 like
Heat of formation (kcal/mol)
O•••C=O Angle(deg.)
O…C=O Distance (Å)
Data obtained from MINDO-3 calculations.
N.Beaulieu, S.Goldstein, P. Deslongchamps. Helv. Chim. Acta. 1992, 75, 604. M.L. Sinnot. Chem. Rev. 1990, 90, 1171. P.Deslongchamps, Pure App. Chem. 1993, 65, 1161.
Using the new ALPH to explain glycoside hydrolysis
O O
OCH3
H
H
OCH3R R
O
OCH3
HR
H+
OR H
HOCH3
OR H
OR
H
HOCH3
O H
OCH3
R
H+
O
H
OCH3R
H+
1 2
3
4
5
6
7
8
0.7 kcal/mol
0.45kcal/mol*
*
* 6-31G ab initio estimation.N.Beaulieu, R.A. Dickinson, P. Deslongchamps. Can. J. Chem. 1980, 58, 2531.P.Deslongchamps, D.Guay, Can. J. Chem. 1985, 63, 2757. P.Deslongchamps. In The Anomeric Effect and Associated Stereoelectronic Effects. G.R.J. Thatcher, Ed. 1993. C.W. Andrews, B.Fraser-Reid, J.P.Bowen. J. Am. Chem. Soc.1991, 113, 8293.
Hydrolysis of cyclic orthoesters – the original false experimental results
O OEt
OEt
O OEt
OEt
O OEt
OEt
O OEt
OEt
COOEtOH
COOEtOH
COOEtOH
COOEtOH
H+ No lactone product detected
P.Deslongchamps. C.Lebreux and R.J.Taillefer, Canad. J. Chem. 1972, 50, 3405. E.H. Cords in Progressin Physical Organic Chemistry, Vol. 4, pp 1-44. A. Streitwieser and R.W. Tafts (eds), Interscience: New York 1967.
Hydrolysis of cyclic orthoesters – re-examined
6 : 946
7 : 935
6 : 944
16 : 843
6 : 942
21 : 791
L%/E%Orthoester
O
OMe
OMe
OOEt
OEtO
OMe
OMe
OOMe
OMe
OOMe
OMeO
OMe
OMe
P.Deslongchamps, D.Guay, R.Chenevert. Can. J. Chem. 1985, 63, 2485. B.Capon, D.M. Grieve. Tetrahedron Lett 1982, 23, 4823.
Secondary stereoelectronic effect
Primary and secondary stereoelectronic effect in intermediates:
Y
OO
RO
O
R
R
Y
OO
R
R1
21
2R O
O
R
R
B One 2nd
stereoelectronic effect
A Two 2nd
stereoelectronic effect
The intermediates should undergo cleavage with the help of primary stereoelectronic effect and the most favored one should have themaximum number of secondary stereoelectronic effect.
P.Deslongchamps, D.Guay, R.Chenevert. Can. J. Chem. 1985, 63, 2485. P.Deslongchamps.In The Anomeric Effect and Associated Stereoelectronic Effects. G.R.J. Thatcher, Ed. 1993.
Hydrolysis of orthoesters –re-exam the rigid bicyclic systems
O
O
O Me
Me
O
O
O Me
H
OH
O
O Me
H
OH
O
O Me
H
O
O
OH
Me
O OH
HOMe O
O
H
R
R
R
R
RR
6 7 8
910 11 1294% 6%
disfavoredfavoredSteric effect:
122nd stereoelectronic effect
favoreddisfavoredEntropy Formation of 12Formation of 10
P.Deslongchamps, D.Guay, R.Chenevert. Can. J. Chem. 1985, 63, 2485. P.Deslongchmps, R. Chenevert, R.J. Taillefer. Can. J. Chem. 1975, 53, 1601. R.A. McClelland, M. Alibkai. Can. J. Chem. 1981, 59, 1169.
Hydrolysis of orthoesters – re-exam the flexible systems
OH
O
O Me
H
O
O
H
O
O
O Me
Me
O
O
O Me
H
O
O
O
H
Me
OH
O
O Me
H
O
O
H
O
O
O
H
Me
O
O
OH
Me
H
O
O
O
H
Me
O
O
OH
MeH
3 13 14
15
16
17
18
19
20
17
20
17 (84%) 20 (16%)
P.Deslongchamps, D.Guay, R.Chenevert. Can. J. Chem. 1985, 63, 2485. P.Deslongchmps, R. Chenevert, R.J. Taillefer. Can. J. Chem. 1975, 53, 1601. R.A. McClelland, M. Alibkai. Can. J. Chem. 1981, 59, 1169.
The second generation of ALPH
1st generation: Any reactive conformer must have on each oxygen atom a lone pairorbital oriented antiperiplanar to the C-H bond of the acetal function.
2nd generation:In the formation and cleavage of the tetrahedral intermediates of acetals, orthoesters, etc, it must have the help of the primary stereoelectronic effect (two antiperiplanar lone pair) and the most favored process should have maximum number of secondary stereoelectronic effect.In the determination of the possible products using ALPH, the transition states (early or late) must be considered.
Further Challenge to ALPH
Syn E2 elimination:
H
H
Br
D RO-K+
H
H
How about syn-periplanar lone pair?
O
H
O Me
Synperiplanar Lone pair- ozonolysis of tricyclic acetal
O
H
O Me
COOMe
H
H
OCOMe O
O
COOMe
H
O
1. O3 , 20min 2. Ac2O, pyridine
19% 53% 10%
1
2 3 4
S.G. Li and P. Deslongchamps. Tetra. Lett. 1993, 34, 7759.
Synperiplanar Lone pair- ozonolysis of tricyclic acetal
O
H
O Me
1
OO O
O
OMe
HOO O
O
O
O Me
O OH
OHO Me
O
COOMe
H
H
OCOMe O
O
COOMe
H
O
Esterification OxidationLactonization
2 3 4
56
7
S.G. Li and P. Deslongchamps. Tetra. Lett. 1993, 34, 7759.
Synperiplanar Lone pair- hydrolysis of tricyclic acetal
O
H
OMe
O
O
H
Me
1 8 ( 1 )( 25)
O
H
OMe
H
O
H
O
H
OH
H+
9 10 11
S.G. Li, A.J. Kirby, and P. Deslongchamps. Tetra. Lett. 1993, 34, 7757.P.V. Eikeren. J. Org. Chem. 1980, 45, 4641.
The third generation of (S)ALPH
3rd generation:
In the formation and cleavage of the tetrahedral intermediates of acetals, orthoesters, etc, it must have the help of the primary stereoelectronic effect (2 anti or 1 anti plus 1 syn periplanar lone pair) and the most favored process should have maximum number of secondary stereoelectronic effect.
In the determination of the possible products using (S)ALPH, the transition states (early or late) must be considered.
Hydrolysis of cyclic orthoesters application of (S)ALPH
O
O
O
O
O
O
OMe
Me
OMe
Ph
OMe
Me
H
H
H
H
H
H
H
H
OAc
OH
H
H
OH
OH
H
H
OBz
OH
OAc
H
H
OH
OH
H
H
OAc
Relative rates Products
2 : 1
1 : 1
Orthoesters
1
40
1680
1
2
3
4 5
6
7 8
S.G. Li, Y. L. Dory, and P. Deslongchamps. Tetrahedron, 1996, 52, 14841.
Hydrolysis of cyclic orthoesters application of (S)ALPH
16% 33% 51%
O
O
O
Me
Me
O OH O
- H+
H+
H2O - H+
H+
H2O - H+
- MeOH
OMe
O Me
OH
OO Me
O
O
Me
Me
OH
OHO
OMe
OH
OH OH OHO
Me
O
Me
H2O - H+
*
*
*
*
*
- RCOOMe
*
1
4 5 4*
9 10
11 12
S.G. Li, Y. L. Dory, and P. Deslongchamps. Tetrahedron, 1996, 52, 14841.
Hydrolysis of cyclic orthoestersapplication of (S)ALPH
O
O
O
Ph
Me
O
- H+
H+
H2O - H+
H+
OPh
O Me
OH
OO Ph
O
O
Ph
OH
OHO
Ph
*
*
*6* :100%
O
OR
RH H
H
HH
H2O
OO
H H
H
HH
H2O
2
13 like ion
14
15
13
14 like ion
S.G. Li, Y. L. Dory, and P. Deslongchamps. Tetrahedron, 1996, 52, 14841.
Hydrolysis of cyclic orthoestersapplication of (S)ALPH
OO
Me
O Me
1
OO
Me
OMe
3
Relative rate: 1 42
S.G. Li, Y. L. Dory, and P. Deslongchamps. Tetrahedron, 1996, 52, 14841.
Synthetic Application of ALPHaddition of nucleophiles to amidinium ion
N N
Ph
Nu-
solvent
NN
PhH
Nu-
NN
Ph
H
Nu-
NN
Ph
Nu
NN
PhNu
ciskinetic product
transthermodynamicproduct
AcOH or PhOH
C.L. Perrin, D.B. Yong. J. Am. Chem. Soc. 2001, 123, 4451.
Synthetic Application of ALPHaddition of nucleophiles to amidinium ion
3565DMEPhCH2MgCl
>98>98DMEPhC≡CMgBr1775PhHn-BuLi
>98>98DMSOPhC≡CMgBr1775DMEn-BuLi
>98>98DMSOHC≡CMgBr1565DMECH3Li
<280DMEPhMgBr5090THFLiAlD4
2560DMEAllylMgBr5088MeOHNaBD4
%trans
%cis
Solv-ent
Nucleopile%trans
%cis
Solv-ent
Nucleopile
C.L. Perrin, D.B. Yong. J. Am. Chem. Soc. 2001, 123, 4451.
Conclusion – a summary
• Proposed based on ozonolysis of acetals.• In 30years, it was evolved from the 1st to the 3rd
generation:Primary stereoelectronic effect plus maximum number of secondarystereoelectronic effect. Transition states (early or late) must be considered
• A useful synthetic strategy.
Acknowledgement
• Dr. Hollingsworth• Dr. Tepe• Dr. Hollingsworth group
