Christopher D. ThomasScheidt Research Group
Short Lit PresentationMarch 28, 2011
Asymmetric Catalysis via ChiralAlkali Metal Phosphate Complexes
O
P
O O
O M
Ar2
Ar2n
Ph
Ph
O
O
PO
OM
O
OP
Ph
Ph
O
O
** *
Asymmetric Chiral Brønsted CatalysisPromoted via BINOL-Derived Phosphoric Acids
R1
N
HO
OR3
OTMS
H
R2 R1
HN
CO2R3
R2
HO
R1
HN
CO2R3
R2
HO
syn/anti = 87:13-100:0ee = 81-96%
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566-1568.
10 mol%cat.
-78 ºCPhMe24 h
R1
NBoc
H
2 mol% cat.
CH2Cl2rt, 1 h
O O
R1
NHBoc
Ac
Ac
*
isolated yields 93-99%ee = 90-98%
Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356-5357.
O
P
OH
O
O
*
X
X
X = H, Ph
Me Me
Me
NO2OMe
BINOLDerivedOrgano-Catalysts
Gridnev, I. D.; Kouchi, M.; Sorimachi, K.; Terada, M.Tetrahedron Lett. 2007, 48, 497-500.
H-Bond interaction assists facial preferenceof incoming nucleophilic addition to imine.
Which Is the Actual Catalyst: Chiral Phosphoric Acid or Chiral Calcium Phosphate?
Ar1 H
NBoc
R1
O
R3
O
R2
Ar1
BocHN
R1
O
R2
R3O
Ar1
BocHN
R1
O
R3O
O
P
O O
O M
Ar2
Ar2
n
M = H
M = Ca
(0.5-5 mol%)
CH2Cl2 or toluene
R1, R3 = alkyl, SAr; R2 = H, alkyl
Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew. Chem. Int. Ed. 2010, 49, 3823-3826.
Biosketch of Prof. Dr. Kazuaki Ishihara
Born in Aichi, Japan on April 26, 1963 (Age 47).Education
• 1981-1985: Bachelors of Engineering, Dept. of Applied Chemistry, School of Engineering, Nagoya Univ. (H. Yamamoto)• 1985-1987: Master of Engineering, Dept. of Applied Chemistry, School of Engineering, Nagoya Univ. (H. Yamamoto)• 1987-1991: Doctor of Engineering, Dept. of Applied Chemistry, School of Engineering, Nagoya Univ. (H. Yamamoto)
Career• 1991-1992: Postdoctoral Fellow under E.J. Corey• 1992-1994: Assistant Professor, Nagoya Univ., Department of Applied Chemistry• 1994-1997: Assistant Professor, Nagoya Univ., Department of Biotechnology• 1997-2001: Associate Professor, Nagoya Univ., Research Center of Waste and Emission Management• 2001-2002: Associate Professor, Nagoya Univ., Department of Biotechnology• 2002-present: Full Professor, Nagoya Univ., Department of Biotechnology
CV is 33 pages long, last updated 12/29/10My CV is 4 pages long, last updated 2/21/11
Metal Contaminants in Phosphoric Acids
OPh H2O2
O
O
P
O
OH
*
(10 mol%)
CHCl3, -40 ºC
O O
Ph
yield = 65%, ee = 88%Washed w/4N HCl: yield = 99%, ee = 88%
Xu, S.; Wang, Z.; Zhang, X.; Ding, K. Angew. Chem. Int. Ed. 2008, 47, 2840-2843.
O
O
P
O
NH
*
OMe
OMe
S
O
CF3
O
Ca
Phosphoramide complexes showed a 2:1ratio of phosphoramide:calcium.
Rueping, M.; Theissman, T.; Kuenkel, A.; Koenigs, R. M.Angew. Chem. Int. Ed. 2008, 47, 6798-6801.
Did not believe Ca-complexes were catalyzing reactionin the presence of acid.
Hypothesis: Alkali Metals Could Activate 1,3-Dicarbonyls More Effective Than Their Acids?
O
O
P
O
O
*
(2-5 mol%)
Ph
NBoc
H
O O
solvent, 1 h
M
Ar
Ar
n
Ph
NHBoc
Ac
Ac
*
cat-A: Ar =
cat-B: Ar =
Entry
123456789
10
Catalyst
cat-Acat-Acat-Acat-Acat-Acat-Acat-Acat-Bcat-Bcat-B
M
LiNaMgCaSrHHHH
Ca
Purifcation of Cat.
nonenonenonenonenone
on Silica Gelwashed w/HClwashed w/HClwashed w/HCl
none
Solvent
DCMDCMDCMDCMDCMDCMDCMDCMPhMeDCM
T (ºC)
rtrtrtrtrtrtrtrt
-30rt
Yield
99%88%
>99%>99%>99%86%88%
>99%>99%93%
ee (config)
11% (S)9% (S)
43% (R)92% (R)59% (R)92% (R)27% (S)49% (S)93% (S)30% (S)
• Alkali salts prepared by mixing the free acid with 0.5 equiv. of Li(OiPr), NaOMe, Mg(OtBu)2, Ca(OiPr)2 and Sr(OiPr)2.
• HCl washes conducted with 2M HCl and extracted with EtOAc.
Ca-Phosphate Mediated Mannich-Type Reaction
O
O
P
O
O
*
(2.5 mol%)
Ar
NBoc
H
O
S(2,6-xyl)
O
solvent, 1 h
Ca
Ar
Ar
n
Ar
NH
*
Ar =
Boc
Me
O
S(2,6-xyl)O1.1 equiv.
Ar =
>99% yield98% ee
(0.5 mol%)
>99% yield94% ee
Me
>94% yield92% ee
MeO
>90% yield90% ee
Cl
>99% yield91% ee
Br
>88% yield97% ee
>99% yield96% ee
S
Evidence for Ca-Phosphate Complex andProposed Transition State
• Salt generated in situ and detected by FAB-HRMS (m/z for [Ca[1a]2]+ calc: 1543.3736, found: 1543.3749).• Oligomeric structure postulated based on 31P NMR in CD2Cl2 showed a broad peak at 0.05 ppm.• After adding substrates to the in situ generated catalyst, 31P NMR showed a sharp singlet at 4.55 ppm suggesting a monomeric structure of Ca[1a]2.• Other potential active catalysts ruled out such as:
- Ca[1a] salt- Ca-free acid (2.02 ppm)- Ca-enolate
• Transition state proposed:- Half-piped groove formed around Ca-center - Pronucleophile is activated by Brønsted basic P=O moiety- Aldimine activated by Lewis acidic Ca-center- re-face attack favored resulting in R productsO
O
P
O
O
*
Ca
Ar
Ar
2
Ar =
Ca[1a]2
Chiral Calcium VAPOL Phosphate Mediated Asymmetric Chlorination and Michael Reactions of 3-
Substituted Oxindoles
NBoc
O
R1
R2
NCl
O
O
Me
O
NBoc
O
R2R1
Cl
ee up to >99%
NBoc
O
R2R1 Me
O
ee up to 95%
Ph
Ph
O
O
PO
OCa
O
OP
Ph
Ph
O
O
Ca[P1]2
Zheng, W.; Zhang, Z.; Kaplan, M. J.; Antilla, J. C. J. Am. Chem. Soc. 2011, 133, 3339-3341.
Biosketch of Jon C. Antilla, Ph.D.
Education• 1995: Bachelors of Science, Dept. of Chemistry, Northern Michigan University, cum laude• 1995-2000: Ph.D., University of Chicago under William D. WulffThesis: “Catalytic Asymmetric Aziridnation”
Career• 2000-2003: NIH Postdoctoral Fellow under Stephen L. Buchwald, Cu-Catalyzed N-arylation of azoles and coupling of amines with arylboronic acids.• 2003-2005: Assistant Professor, The University of Mississippi• 2005-2010: Assistant Professor, The University of South Florida• 2010-present: Associate Professor, The University of South Florida• 2009: Visiting Professor at the University of Le Havre, Le Havre, France• Member of: Moffitt Cancer Center, The Center for Molecular Diversity in Drug Design, Discovery, and Delivery, and Florida Center of Excellence for Biomolecular Identification and Targeted Therapeutics
Optimization Studies on Catalytic Chlorinationof 3-Phenyloxindole
NBoc
O
Ph
NBoc
O
Ph Cl
Ph
Ph
O
O
PO
O
NCS, 5 mol% cat.
solvent, rt, 1 h
M
n
Entry
123456789
101112131415
M
No Cat.HHHHHHH
NaK
MgCaSrBaCa
Purification
n/aon Silicaon Silicaon Silicaon Silicaon Silicaon Silica
w/HClnonenonenonenonenonenonenone
Solvent
PhMePhMeDCM
EtOAcPhH
i-PrOAci-PrOAci-PrOAci-PrOAci-PrOAci-PrOAci-PrOAci-PrOAci-PrOAci-PrOAc
Yield
<20%99%99%99%99%99%99%99%99%99%99%99%99%99%99%
ee
n/a51%48%50%60%80%90%
0%6%0%
37%91%86%
9%94%
(S)-VAPOL-Phosphate
Proposed Transition State
Entry 15: NCS added as a 0.12 Msolution in i-PrOAc
Substrate Scope for Asymmetric Chlorination
NBoc
O
R1
NBoc
O
R1Cl
(S)-Ca[VAPOL-PO4]2
NCS, i-PrOAc, rt, 30 min
R2R2
NBoc
O
Cl
99% yield94% ee
NBoc
O
Cl
99% yield93% ee
NBoc
O
Cl
99% yield96% ee
NBoc
O
Cl
99% yield>99% ee
NBoc
O
Cl
99% yield90% ee
NBoc
O
Cl
99% yield93% ee
NCO2Me
O
Cl
99% yield97% ee
NBoc
O
Me Cl
99% yield62% ee
NBoc
O
Cl
99% yield98% ee
NBoc
O
Cl
99% yield92% ee
NBoc
O
Cl
99% yield97% ee
NBoc
O
Cl
99% yield87% ee
Me F
MeO F
Me
F
Me
F F
F
Asymmetric Michael Reaction Catalyzed by(S)-Ca(VAPOL-PO4)2
NBoc
O
R1
NBoc
O
R1(S)-Ca[VAPOL-PO4]22.5 mol%
i-PrOAc, 0 ºC
R2R2
Me
O
Me
O
NBoc
O
Me
O
NBoc
O
Me
O
NBoc
O
Me
O
NBoc
O
Me
O
F
Me
23 h, 97% yield90% ee
22 h, 96% yield95% ee
34 h, 96% yield95% ee
34 h, 96% yield90% ee
(3.0 eq)
Chiral Magnesium BINOL Phosphate-Catalyzed Phosphination of Imines: Access to Enantioenriched
alpha-Amino Phosphine Oxides
O
O
P
O
O Mg
R
R
n
R
NR'
Ph2P(O)Hcatalyst: Mg(1a)2
R PPh2
HN
O
R'
R' =Ph
Ph
or
ee up to 96% ee up to 99%
R = 9-anthryl
Mg(1a)2
Ingle, G. K.; Liang, Y.; Mormino, M. G.; Li, G.; Fronczek, F. R.; Antilla, J. C. Org. Lett., 2011, ASAP
Optimization of Enantioselective Addition of Diphenylphosphine Oxide to N-Benzhydryl Imine
O
O
P
O
O M
R
R
n
R
NPh2P(O)H
catalyst
R PPh2
HN
O
Ph
Ph
solvent, rt, 12 h
Ph
Ph
cat-A: R =
cat-B: R =
cat-C: R =
SiPh3
entry
123456789
catalyst (loading)
cat-B (10 mol%)cat-C (10 mol%)cat-A (10 mol%)cat-A (10 mol%)
Na-cat-A (10 mol%)Ca-cat-A (5 mol%)Mg-cat-A (5 mol%)
Mg-cat-A (2.5 mol%)cat-A (10 mol%)
purification
on Silicaon Silicaon Silicaon Silica
nonenonenonenone
washed w/HCl
yield
68%61%72%97%56%96%95%92%87%
ee
0%38%82%91%55%91%93%80%80%
1.2 equiv. 1.0 equiv.
Scope of N-Benzhydryl Imine Substrates
O
O
P
O
O Mg
R
R
n
R
NPh2P(O)H
cat-A (5 mol%)
R PPh2
HN
O
Ph
Ph
CH3CN, rt, 12 h
Ph
Ph
cat-A: R =
1.2 equiv. 1.0 equiv.
entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
R
Ph
p-OMePh
o-MePh
m-MePh
p-FPh
p-BrPh
p-NO2Ph
1-Naph
2-Furyl
c-C6H11
i-Pr
n-Pr
n-Bu
Ph-(CH2CH2)
yield
95%
95%
96%
95%
95%
97%
97%
95%
93%
96%
92%
88%
65%
73%
ee
93%
90%
89%
92%
90%
92%
95%
96%
91%
91%
86%
62%
52%
48%
When (cat-A)2Ca used, a 96% yield
and 81% ee was obtained.
Changing Imine Protecting Group
O
O
P
O
O Mg
R
R
n
R
NPh2P(O)H
cat-A (5 mol%)
CH3CN, rt, 12 h
cat-A: R =
2.0 equiv. 1.0 equiv.
entry
1
2
3
4
5
6
7
8
9
R
Ph
p-OMePh
o-MePh
p-FPh
2-Furyl
i-Pr
n-Pr
n-Bu
Ph-(CH2CH2)
yield
90%
92%
92%
95%
98%
72%
73%
84%
86%
ee
99%
92%
96%
16%
87%
85%
80%
74%
93%
Entry 1: When (cat-A)2Ca used, a 95% yield
and 90% ee was obtained.
When cat-A was washed with HCl a 90% yield
and 79% ee was obtained.
PPh2
NH
R
O
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