View
0
Download
0
Category
Preview:
Citation preview
Asymmetric NucleophilicCatalysis
Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 2003, 125, 4166-4173Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368-
13369
Me Ph
HOH R O R
OO
Chiral catalyst Me Ph
HOH
Me Ph
HO R
O
NOR2
R1
OX
O
Chiral catalystX = alkyl, OR
NO
O
R2
R1
O
X
Nucleophilic Catalysis: The BasicsReactions Catalyzed by Nucleophiles
Ph OH
OC
Ph
Me CatalystPh O
O
H Ph
Me
Addition of alcohols to ketenes:
Acylation of alcohols to anhydrides:
Ph
OH
Me Me
O
O Me
O Catalyst
Ph
O
Me
Me
O
Rearrangement of O-acylated enolates:
NO
Me
O
Me
Me
O
CatalystN
O
Me
O
Me
O
Me
Nucleophilic Catalysis: The BasicsAcylation of Alcohols
Me
O
O
O
Me Ph
OH
Me
UncatalyzedSlow
Ph
O
Me
Me
O
N
NMe Me
N
N
Me
O
Much strongeracylating agent
O Me
O
Catalyzed Fast
Ph
OH
Me
Fu, G. C. Acc. Chem. Res. 2000, 33, 412-420
DMAP
Nucleophilic Catalysis: The BasicsSteglich Rearrangement
O
NR R
O
O
X5-acyloxyoxazole N
N
N
N
XO
O
NR R
O
O
NR R
O
O X
N
N
DMAP
This can also be done with pyridine asthe catalyst, but it takes 24 hrs at 100 oCversus a few minutes at room temp.
Hofle, G.; Steglich, W.; Vorbruggen, H. Angew Chem., Int. Ed. Engl. 1978, 17, 569
x = Me, OR
Kinetic Resolutions: Theory
ln[(1-c)(1-ee)]ln[(1-c)(1+ee)]
s = =kfast-reacting enantiomerkslow-reacting enantiomer
s = selectivityc = conversion c = 1 – A + B
A0 + B0
ee = %ee of recovered substrate
A = amt. of fast-reacting enantiomer @ time TB = amt. of slow-reacting enantiomer @ time T
A0 = initial amt. of fast-reacting enantiomerB0 = intial amt. of slow-reacting enantiomer
Kinetic resolutions are the best way for getting extremely enantioenriched compounds, usually utilizing an enzyme to preferentially react away one enantiomer of the substrate, leaving behind the other enantiomer of the substrate.
Chen, C.; Fujimoto, Y., Girdaukas, G., Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294Equation was numerically solved by Clark, C. T. using a TI-85 graphing calculator
%ee of unreacted substrate
0
10
20
30
40
50
60
70
80
90
100
0 20 40 60 80 100
% Conversion
% e
e
s = 3
s = 5
s = 10
s = 25
s = 100
%ee of product
0
10
20
30
40
50
60
70
80
90
100
0 20 40 60 80 100
% Conversion
% e
e
s = 3
s = 5
s = 10
s = 25
s = 100
Kinetic Resolutions: Theory Pt. 2
ln(1-c*(1+ee))ln(1-c*(1-ee))
s = =kfast-reacting enantiomerkslow-reacting enantiomer
s = selectivityc = conversion c = 1 – A + B
A0 + B0
ee = %ee of product
A = amt. of fast-reacting enantiomer @ time TB = amt. of slow-reacting enantiomer @ time T
A0 = initial amt. of fast-reacting enantiomerB0 = intial amt. of slow-reacting enantiomer
What about the other half of what you have? What is the %ee of the product at a given percentconversion with a known value of s?
Chen, C.; Fujimoto, Y., Girdaukas, G., Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294Equation was numerically solved by Clark, C. T. using a TI-85 graphing calculator
Enantioselective Acylations with Chiral Phosphines:Early Work with Non-Enzymes
(CH2)n
OHOH
OH
PhPh
HO
entry substrate catalyst anhydride %ee 5(conv.)
selectivity (s) 1a n=01b n=1
2
1b1b1b1b1a
22222
PhCH(OH)tBu
346a6b6a
36a46a6b6a
Ac2OAc2OAc2OAc2OAc2O
Ac2OAc2OBz2OBz2OBz2O
3-ClBz2O
9 (40)11 (60)65 (66)42 (80)52 (10)
50 (40)27 (22)22 (31)68 (84)58 (70)81 (25)
1.21.34.52.63.2
2.91.21.65.54.7
12-15
12345
67891011
+
5-10 mol%catalystO
R O R
OOH
RL RS
O
RL RS
OH
RL RS+
R
meso substrates
chiral phosphines:
CH2Cl2
Me Me
Ph2P PPh2PPh PPh
R
R
6a, R = Me6b, R = Et
3 4
Vedejs, E.; Daugulis, O.; Diver, T. S. J. Org. Chem. 1996, 61, 430-431.
perdeuterated Ac2Ogive monoacetate without loss of deuterium: no ketene mechanism operative
5 1
This was the largest s value for a non-enzyme at the time
O
Enantioselective Acylations with Chiral Phosphines:An Improved Catalyst
A selectivity of 12 – 15 is good, but can it be improved?Yes!
New catalysts:
P
Me MeH
H
Ph
Me
P
Me MeH
HMe
Me
Me
P
Me MeH
HMe
Me
Me Me
MeMe
Me
1 2
3
Retrosyntheses of catalysts:
P
Me MeH
H
Ar
MeO
SO2
OH
Me
MeMeH
ArPH2
Me
MeOH
HH
OHMe
MeMe
OLi
MeO
O
OTfH
OO
Me
Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 2003, 125, 4166
Enolate Alkylations Using Lactate Triflates
MeMe
OLi
MeO
O
OTfH
OO
Me
MeO
O
OTfH
OO
Me
MeO
OEt
OTfH
OLiHMe
MeEtO2C
MeH
OTf
OLiHMe
Me
MeCO2EtH
Favored Disfavored due tolone-pair repulsion
–55 oC
OTf
Me
MeOH
HHMe
Me
MeOH
HHMe
10-15 : 1 d.r.
How do you access the minor diastereomer? Use a cryptand-like ester
MeMe
OLiOH
Me
Me
Me H
OTfO
OO
LiOMe Me
MeOH
HHMe
Me
MeOH
HHMe
1 : 6-10 d.r.
LAH52%
OH OH
LAH30-40%
OH OH
–55 oCToluene
Continued Synthesis of Phosphine Catalysts
Me
MeOH
HHMe
OH
SOCl2
OSO
OH
Me
MeMeHCCl4
reflux
RuCl3 3H2ONaIO4
MeCN, CCl4,H2O, 60%
OSO2
OH
Me
MeMeH
PhPHLiTHF SO3Li
OH
Me
MeMeH
HPPh
BuLiSO3Li
OH
Me
MeMeH
LiPPh
P
Me MeH
H
Ph
Me
P
Me MeH
H
Ph
Me
BH3 THF85%
P
Me MeH
H
PhBH3
Me
P
Me MeH
H
Ph
Me
BH3
36:1 d.r.
PyrrolideneP
Me MeH
H
Ph
Me
Acylation of Alcohols Using Phenyl Catalyst
670.1(–40o)t-BuPhPh
10.1Mei-Pri-Pr
16Mec-C3H5i-Pr
724Me2-naphthylPh
130.1i-PrPhi-Pr
160.6t-BuPhMe
250.02t-BuPh1-naphthyl
241t-BuPhPh
sRelative rateR2R1Anhydride R
R1 R2
OH
R O R
O OP
Me MeH
H
Ph
MeR1 R2
O R
O
Toluene, r.t. R1 R2
OH
Syntheses of Other Phosphine Catalysts
OSO2
OH
Me
MeMeH
ArPHLiTHF SO3Li
OH
Me
MeMeH
HPAr
BuLi
P
Me MeH
H
Ar
Me
P
Me MeH
H
Ar
Me
BH3 THF85%
P
Me MeH
H
ArBH3
Me
P
Me MeH
H
Ar
Me
BH3 PyrrolideneP
Me MeH
H
Ar
Me
2 Ar= 3,5-Me2C6H33 Ar= 3,5-t-Bu2C6H3
2 = 43:13 = 91:1
Evaluation of Me2Ph-PBO
sSolventR2R1Anhydride R
12Heptanei-BuPhi-Bu
14Heptanei-PrPhi-Bu
14TolueneMe2-naphthyli-Bu
8.1Toluenet-BuPhPh
R1 R2
OH
R O R
O O
R1 R2
O R
OP
Me MeH
HMe
Me
MeR1 R2
OH
Evaluation of t-Bu2Ph-PBO
390tol/–40 °CMe2,4,6-Me3C6H2i-Pr
220 (328)tol/–40 °CMe2,4,6-Me3C6H2i-Pr
15tol/RTMe2,4,6-Me3C6H2i-Pr
55 (60)hept/–40 °Cn-BuPhi-Pr
18hept/RTn-BuPhi-Pr
17tol/RTMe2-naphthyli-Pr
99 (117)hept/–40 °Ci-PrPhi-Pr
20hept/RTi-PrPhi-Pr
10tol/RTt-BuPhPh
sSolvent/TempR2R1Anhydride R
R1 R2
OH
R O R
O O
R1 R2
O R
OP
Me MeH
HMe
t-Bu
t-BuR1 R2
OH
Summary of Acylations Using PBO Catalysts
• Phosphabicylooctane catalysts can be effectively used for a number ofkinetic resolutions of benzylic alcohols.
• Separation of enantiomers of these catalysts is not exceptionallydifficult, done through use of lactate esters and recrystallizations
• Enantioselectivities are exceptional, with values of s = 380• Selectivites high enough to warrant correction for %ee of catalyst• Synthesis is quite air-sensitive at parts, yields of the alkylations are low,
and the catalyst must be stored as the borane complex, due tointerconversion of diastereomers at phosporus
• The full paper only covered the use of a few catalysts• Will this replace using enzymes for kinetic resolutions? Not yet, I think
Chiral Nucleophilic Pyridine Catalysts:Background
NMe2N
DMAPTwo mirror plane
NMe2NR
H
One mirror plane
NMe2NR
H
MLn
No mirror planesa "planar-chiral" DMAP
NMe2N *R
Substitution with a chiralgroup will also make a chiral
DMAP
Fu's Catalysts:Vedejs' Catalyst
R R
R R
R
N
Me2N
Fe
N
R R
R R
R
FeCH2OTES
N
NMe Me
H
OAcCAr3
Greg Fu was the first person to use these types ofcatalysts for catalytic enantioselective work
Acylations Catalyzed by Planar-Chiral DMAP Analogs
+
racemic
O
Me O Me
OOH
Ph Me
OAc
Ph Me
OH
Ph Me+2 mol% cat
NEt3
1 2Ph Ph
Ph Ph
Ph
N
Me2N
Fe
catalyst
entry % conv.after 1 h
solvent, rt
selectivity
12345
solvent
DMFCH3CNCH2Cl2acetone
THF
6101484
3.43.67.08.79.6
Desymmetrizations:
MeMe
MeMe
OH OH
MeMe
MeMe
OH OH
MeMe
MeMe
OAc OAc
1% cat, Ac2O
NEt3, 0 °Ct-amyl alcohol
98% ee43%
99% ee39%
+
6789
EtOActolueneEt2Ot-amyl alcohol
613838
11111327
entry % conv.after 1 h selectivitysolvent
MeMe
MeMe
OH OH
MeMe
MeMe
OH OAc
99% ee91%
1% cat, Ac2O
NEt3, 0 °Ct-amyl alcohol
racemic
meso
Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794-2795.
Synthesis of a New Chiral Nucleophilic Catalyst
N
NMe Me
Br2, K2CO3
N
NMe Me
Br
Ph3CCOOH LAH Ph3CCH2OH TPAP, NMO63% Ph3CCHO
t-BuLi
N
NMe Me
LiPh3CCHO
Ac2O58%
N
NMe Me
H
CPh3OAc
N
NMe Me
H
CPh3OAc
Groziak, M. P.; Melcher, L. M. Heterocycles, 1987, 26, 2905.
Me MeCH2SO3H
O1.
in toluene2. NaOH3. Repeat
N
NMe Me
H
CPh3OAc
Ab initio geometry of acyl pyridinium
2096PBOBnPh5895DMAPPhPh9287PBOBniBu9190DMAPPhiBu9091PBOBnallyl9190DMAPPhallyl9090PBOBnBn9599DMAPPhBn8988PBOBnMe9195DMAPPhMe
% ee% yieldcatalystR’R
Comparison of Pyridine Catalyst and t-Bu2Ph-PBO Catalyst
N
OMeO
OCO2R'
RN
OMeO
O
RCO2R'
1 mol % (R)-DMAP catalystor 10 mol % PBO, t-amyl
alcohol, 0 oC, 12h
Substrate Scope for the Chiral Nucleophilic Pyridine Catalyzed Steglich Rearrangement
O
Me
MeOO OPh
O10 mol% (S)-DMAP
THF, 23 oC, 24h OMeO
O O
Me
MeOO
MeCO2Ph
PhO2C
83% yield90% ee
7% yield80% ee
O
Me
O OPh
O1 mol% (S)-DMAP
Et2O, 23 oCO
O
MeO
OPh
92% yield92% ee
O
Ph
O OCH2CCl3
O20 mol% (S)-DMAP
CH2Cl2, –40 oC OO
PhO
OCH2CCl3
92% yield86% ee
NCO2Ph
Ph
O OPh
O
10 mol% (S)-DMAPt-amyl alcohol, 40 oC N
CO2Ph
O
PhOPh
O
93% yield86% ee
Summary of Vedejs’ Nucleophilic Asymmetric Catalysts
• Four new asymmetric nucleophilic catalysts have been synthesized andevaluated by the Vedejs group
• Catalysts are straightforward to make in moderate yields• t-Bu2Ph-PBO and the chiral pyridine catalyst both show high
enantioselectivities when catalyzing a Steglich rearrangement• PBO catalysts have exceptional s values for kinetic resolutions of
benzylic alcohols, and, based on Fu’s research, Vedejs’ chiral pyridinecatalyst could also work well in this reaction
Recommended