Upload
others
View
7
Download
0
Embed Size (px)
Citation preview
A1,3 Strain and the Anomeric Effect
Michael Shaghafi Chem. Topics Feb. 6, 2012
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+
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:
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 %
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 %
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 %
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
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
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.
A1,3 Control in Cycloadditions: A Classical Example
Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1880.
Roush: Total Synthesis of Spinosyn A
Winbush, S. M.; Mergott, D.J.; Roush, W. R. J. Org. Chem. 2008, 73, 1818–1829.
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.
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 %
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)!
Barbas Carbohydrate Synthesis: Model for Diastereoselectivity
Uehara, H.; Imashiro, R.; Hernandez-Torres, G.; Barbas III, C. F. PNAS, 2010, 107, 20672–20677.
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.
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
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:
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 %
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
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
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!
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