asymmetric henry and aza-henry reactions 010604...asymmetric henry and aza-henry reactions d.j....
TRANSCRIPT
Asymmetric Henry and Aza-Henry Reactions
D.J. Osborn III
Drugs and Sugars
HO
HO
HN
OH
OHArbutamine
Coronary Heart Disease
HCl
O
O
HN
OH
NSO2
AmprenavirHIV Protease Inhibitor
NH2
O
ON
OH
HO
H
H
Lycorine
HN
MethylamphetamineADHD
O
O
HN
MDMASeratonin Release
MescalineSeratonin Release
NH2MeO
MeO
MeO
OH
OH
HO
HO OH
OH
Substituted Inositols
Recent Approaches to Selectivity• Chiral Ligands
– Shibasaki's Bimetallic Lanthanide/Lithium System– Trost's Zn/Chiral Phenol System– Lin's Zn/β-Amino Alcohol System– Jorgensens's Cu/BOX System– Evans' Cu/BOX System
• Chiral Quaternary Ammonium Salts– Corey– Maruoka
• Chiral Organic Catalysts– Takemoto's Chiral Thioureas– Johnston's Chiral Proton
• Dendrizymes– Smith – Cossio
Henry Reaction – General Mechanism
R
NO2HH
pKa = ~9
R
HH
N OO
:B
PlanarNitronate
R
N OO
H N ORH O
:B
BH
Control Nitronate Geometry and Reactivity to gain Selectivity
PyramidalNitronate
H
OH
NO O
R'
NO
O
R' H
O H
HB
- B:R
NO
O
R' H
HHOR
R
Control Approach and TS for Selectivity
Henry Reaction – Selectivity
RL
RMRS
OH
H
OH
NO O
R'
NO
O
R' H
O H
HB
- B:R
NO
O
R' H
HHOR
R
Control Approach and TS for Selectivity
N
O
MOH
O
RH
N
O
MOH
O
RR
R
H
N
O
MOH
O
RH
N
O
MOH
O
RR
R
H
syn
antiH
CO Me
H
H
H
MeH
OH
Re face
Si face
O2N
CH2
NO2
HC
O Me
H
H
H
RH
OH
Re face
Si face
CH2
NO2
O2N
Henry Reaction – General Mechanism
H
OH
NO O
R'
NO
O
R' H
O H
HB
- B:R
NO
O
R' H
HHOR
R
Control Approach and TS for Selectivity
pKa = ~9
R
HH
N OO
:B
PlanarNitronate
R
N OO
H N ORH O
:B
BH
Control Nitronate Geometry and Reactivity to gain Selectivity
PyramidalNitronate
R
NO2HH
RN
O
OHO
R1 H
B:
RN
O
O
R'OH BH++
Elimination can be a problem
Aza-Henry Reaction – General Mechanism
H
N
R'
NO2HH
B
R'
NH H N
O
O
R'
- BHO
O
+R
PG
+ BH
PlanarNitronate
PyramidalNitronate
R H
N
H
N
R'
NO
OHB
RN
O
OHN
R1H
PG
PGH
H
H
PG
- :BH
NO O
R'
Bimetallic - Shibasaki
Sasai, H.; Tokunga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org. Chem., 1995, 60, 7388
Aldehyde Nitroalkane Time (h) Temp. (oC) Yield (%) Syn / Anti ee (%)
H
ONO2
75 -20 70 89:11 93
NO2138 -40 85 93:7 95
HO
NO2
111 -40 97 92:8 97
H
O
HO
NO2
93 -40 96 92:8 95
H
O
R'+ Cat. (3.3 mol%)
THFR''
NO2
R'R''
NO2
OH
+R'
R''
OH
NO2
OH
OH
C
C
C
C
Et3Si
Et3Si
(R)-6,6'-Disubstituted BINOL
Best Selectivity
Bimetallic - Shibasaki
Sasai, H.; Tokunga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org. Chem., 1995, 60, 7388
LaOO O
O
O
O
Li
Li
Li
R
R
R
R
R
R
H
O
R
R'
N
H H
O
R
H
N
R' R
H
OR'
N
H R
H
O
H
N
R' H
O
R
O
O O
O
O
O
O
O
H
R'
N
H
O
R
R'
H
N
O
O
O
O
La
Li
La
Li
La La
Li Li
Li Li
syn anti
anti
anti
syn
syn
Steric Repulsions are Minimized
Bimetallic - Shibasaki
Sasai, H.; Tokunga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org. Chem., 1995, 60, 7388
Nu
O H
HC
O R
H
H
HC
O R
H
H
H
R HNu
OH
H
R H
Nu
OH
Nu
O HH
HR
H
HR
Nu-
Nu-Re face
Si face
Re face
Si face
LaOO O
O
O
O
Li
Li
Li
R
R
R
R
R
R
Bimetallic - Shibasaki
Sasai, H.; Tokunga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org. Chem., 1995, 60, 7388
LaOO O
O
O
O
Li
Li
Li
R
R
R
R
R
R
LaOOO
O
O
O
Li
Li
Li
LaO
OOO
O
O
Li
LiLi
R'R
NO2
OH
R
NO2
OHN
O
R LaO
OOO
O
O
Li
Li LiO
H
NO
R
OH
R'
R'CHO
Zinc Based - Trost
Trost, B. M.; Yeh, V. S. C. Angew. Chem.-Int. Edit. 2002, 41, 861
H
O+ CH3NO2
2 (mol%)4-A MS
solvent, T,24 h
OH
NO2
10
10
10
10
10
2
2
10
6
5
5
5
5
5
5
5
2.5
5
5
-20
-20
-20
-20
-20
-78 then -20
-78 then -20
-78 then -20
THF:dioxane, 4:1
69
68
68
75
20
17
75
44
70
78
85
57
51
55
86
85
85
86
CH3NO2(equiv)
Catalyst(mol%)
T (oC) Solvent % Yield % ee
THF
THF
toluene
THF
THF
THF
Et2O
CH2Cl2
CH3
N N
OPhPh
O PhPh
O
Zn Zn
Et
2
Zinc Based - Trost
Trost, B. M.; Yeh, V. S. C. Angew. Chem.-Int. Edit. 2002, 41, 861
CH3
N N
OPhPh
O PhPh
O
Zn Zn
Et
2
R H
OCH3NO2+
2 (5 mol%), ZnEt2 (2 equiv.)
THF, -78 then -35 oC24 h
RNO2
OH
R Yield (%) ee (%)
Ph
BnO
75
59
58
88
90
56
85
84
88
93
92
86
84 87
Zinc Based - Trost
Trost, B. M.; Yeh, V. S. C. Angew. Chem.-Int. Edit. 2002, 41, 861
CH3
N N
OPhPh
O PhPh
O
Zn Zn
Et
2
R H
OCH3NO2+
2 (5 mol%), ZnEt2 (2 equiv.)
THF, -78 then -35 oC24 h
RNO2
OH
R Yield (%) ee (%)
75
71
69
79
91
93
78
90
MeO
MeO
N
Boc
Zinc Based - Trost
Trost, B. M.; Yeh, V. S. C. Angew. Chem.-Int. Edit. 2002, 41, 861
CH3
N N
OPhPh
O PhPh
O
Zn Zn
Et
CH3
N N
OPhPh
O PhPh
O
Zn Zn
O
NO
CH3NO2 CH3CH3
CH3
N N
OPhPh
O PhPh
O
Zn Zn
O
NO
O H
R
CH3
N N
OPhPh
O PhPh
OZn Zn
ONO2
RH
CH3
N N
OPhPh
O PhPh
O
Zn Zn
O
NO
ONO2
RH
HONO2
RH
CH3NO2
R H
O
Zinc Based - Lin
Zhong, Y. W.; Tian, P.; Lin, G. Q. Tetrahedron: Asymmetry 2004, 15, 771
H
H
4a
OH
NH
Ph
OH
HN Ph
H
H OH HN Ph
NH
PhHO
4b
H
H OH HN Ph
NH
PhHO
5
5 mol% Ligand, ZnEt2
THF
Time Yield (%) ee (%)
10
10
7
7
9
8
87
81
93
77
59
90
38
12
25
46
38
52
Ligand : ZnEt2
1 : 3
1 : 3
1 : 5
1 : 2
1 : 1
1 : 2
Ligand
4b
5
4b
4b
4b
4a
8 75 591 : 24b
CH3NO2+
Temperature
0 oC
0 oC
0 oC
0 oC
0 oC
-25 oC
-25 oC
O
H
OH
NO2
Zinc Based - Lin
Zhong, Y. W.; Tian, P.; Lin, G. Q. Tetrahedron: Asymmetry 2004, 15, 771
R H
OCH3NO2+
4a (10 mol%), ZnEt2 (2 equiv.)
THF, -25 oC RNO2
OH
R Time Yield (%) ee (%)
Ph
Ph
8
11
10
12
20
20
90
74
90
82
50
40
52
37
66
67
69
74
H
H
4a
OH
NH
Ph
OH
HN Ph
Zinc Based - Lin
Zhong, Y. W.; Tian, P.; Lin, G. Q. Tetrahedron: Asymmetry 2004, 15, 771
R Time Yield (%) ee (%)
MeO
OMe
8
36
42
23
80
81
73
75
33
25
21
49
R H
OCH3NO2+
4a (10 mol%), ZnEt2 (2 equiv.)
THF, -25 oC RNO2
OH
H
H
4a
OH
NH
Ph
OH
HN Ph
Copper Based - Jorgensen
N
O
N
O
tBu tBuMXn
N
O
N
O
Ph
Ph Ph
PhMXn
N
O
N
O
Ph PhMXn
N
O
N
O
Ph
Ph Ph
PhMXn
N
O
N
O
Ph PhMXn
P
PCuClO4
TolTol
TolTol
Copper Based - Jorgensen
Knudsen, K. R.; Risgaarc, T.; Nishiwaki, N.; Gothelf, K. V..; Jorgensen, K. A. J. Am. Chem. Soc., 2001, 123, 5843
NTMSO O
R'
NPMP
CO2Et
+Cat. (20 mol%)
-100 oCO2N
CO2Et
R'
HN
R' Catalyst % Yield % ee erythro erythro:threo Configuration(C2,C3)
EtEtEt
Et
Et
Et
Et
Et
EtEtEtMePentylBn
(R)-4(R)-5a(R)-5b
(S)-6a
(S)-6b
(S)-6c
(S)-6d
(4R,5S)-7a(4R,5S)-7b(4R,5S)-7c(4R,5S)-7d
(S)-6a(4R,5S)-7d(4R,5S)-7a
999958
90
63
67
92
52
685494678793
161256
90
56
89
70
96
972695
>988388
1:311:17:1
3:1
5:1
18:1
6:1
6:1
10:19:1
25:15:
39:132:
(R,R)(S,S)(R,R)
(S,S)
(S,S)
(S,S)
(S,S)
(R,R)
(R,R)(R,R)(R,R)(S,S)(R,R)(R,R)
PMP
N
O
N
O
5a: MXn = Cu(I)ClO45b: MXn = Cu(I)(OTf)2
tBu tBuMXn
N
O
N
O
6a: MXn = Cu(I)ClO46b: MXn = Cu(I)PF66c: MXn = Cu(I)(OTf)26d: MXn = Cu(I)(SbF6)2
Ph PhMXn
N
O
N
O
7a: MXn = Cu(I)ClO47b: MXn = Cu(I)PF67c: MXn = Cu(I)(OTf)27d: MXn = Cu(I)(SbF6)2
Ph
Ph Ph
PhMXn
P
P
4 (R)-Tol-BINAP
CuClO4
TolTol
TolTol
Copper Based - Jorgensen
Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V..; Jorgensen, K. A. Angew. Chem. Int. Ed., 2001, 40, 2992
N
O
N
O
(S) - 4
tBu tBuMXn
N
O
N
O
Ph
Ph Ph
PhMXn
(4R, 5S) - 5
N
O
N
O
(R) - 6
Ph PhMXn
a : MXn = Cu(I)(OTf)2b : MXn = Cu(I)(SbF6)2c : MXn = Cu(I)Br2
NTMSO O
Et
NPMP
CO2Et
+Cat. , base O2N
CO2Et
R'
HN
Time (days)Catalyst % Conv. ee (syn / anti)syn / anti
1
1
1
1
1
1
1
1
1
1
1
7
1
5
4a
5a
6a
6a
6a
6b
6c
6a
6a
6a
6a
6a
6a
6a
862
85
14
26
85
69
83
40
80
43
83
86
87
87 / 70
2 / 2
94 / 85
97 / 90
97 / 83
26 / 21
93 / 86
95 / 95
97 / 91
72 / 76
96 / 86
91 / 85
95 / 79
97 / 87
95 / 5
84 / 16
92 / 8
96 / 4
97 / 3
60 / 40
95 / 5
82 / 18
95 / 5
54 / 46
95 / 5
92 / 8
93 / 7
95 / 5
PMP
Solvent
CH2Cl2CH2Cl2CH2Cl2
THF
Et2O
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2CH2Cl2
CH2Cl2CH2Cl2CH2Cl2
CH2Cl2
Mol %
20
20
20
20
20
20
20
20
20
20
20
10
20
20
Room Temperature
Copper Based - Jorgensen
Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V..; Jorgensen, K. A. Angew. Chem. Int. Ed., 2001, 40, 2992
NTMSO O
R
NPMP
CO2Et
+(R)-6a O2N
CO2Et
R'
HN
Catalyst % Yield ee (syn / anti)dr syn / anti
Et
H
Me
Me
Pentyl
Bn
Ph
81
38
61
50
52
80
59
97 / 87
87
97 / 95
99 / 98
97 / 89
95 / 88
74 / 77
95 / 5
70 / 30
73 / 27
93 / 7
95 / 5
55 / 45
PMP
Temperature (oC)
0rt
rt
0
rt
rt
rt
Et3N, rt
N
O
N
O
Ph PhCu
TfO OTf
(R) - 6a
Copper Based - Jorgensen
Risgaard, T.; Gothelf, K. V.; Jorgensen, K. A. Org. Biomol. Chem. 2003, 1, 153
NTMSO O
R' R''
O
H+
1) 6c-Cu(OTf)2 (20 mol%), TBAT, rt2) 4, Pyridine, CH2Cl2, rt
R'O
NO2R''
OPh
CF3MeO
R' R'' % Yield dr threo:erythro %ee threo
Et
Et
Et
Et
Et
Et
Pentyl
Et
Ph
p-MeOC6H4
p-NCC6H4
p-O2NC6H4
m-O2NC6H4
2-Np
Ph
(E)-Ph-CH=CH
76
34
47
63
67
34
81
44
5 : 1
3 : 1
>10 : 1
>10 : 1
>10 : 1
2.5 : 1
3 : 1
>10 : 1
65
59
40
50
45
60
43
45Cl
OPh
CF3MeO
4
TBATtetrabutylammonium
triphenylsilyldifluorosilicate
(Bu)4N Si(F)2(Ph)3
N
O
N
O
6c
Ph
Ph Ph
PhMXn
Copper Based - Jorgensen
Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V..; Jorgensen, K. A. Angew. Chem. Int. Ed., 2001, 40, 2992
Mechanism proposed by Jorgensen
NO
N
O
MeMe
CuN
O
PG
OEt
NO
N
O
MeMe
Cu O N
N
O OEt
O
R
HPG
NO
N
O
MeMe
CuO N
N
O OEt
OR
HPG
NPG
OEt
O
-2 TfO
NO2EtO
O
HN
R
PMP
R
NO2
NEt3HNEt3
NPG
OEt
O
NO
N
O
MeMe
CuOTf
OTf
Tetrahedral Cu ?
Copper Based - Jorgensen
Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V..; Jorgensen, K. A. Angew. Chem. Int. Ed., 2001, 40, 2992
My proposed alteration to Jorgensen’s Mechanism
NO
N
O
MeMe
CuN
O
PG
OEt
NO
N
O
MeMe
Cu
O N
N
O OEt
R
HPG
NO
N
O
MeMe
CuO N
N
O OEt
OR
HPG
NPG
OEt
O
-2 TfO
NO2EtO
O
HN
R
PMP
R
NO2
NEt3HNEt3
NPG
OEt
O
NO
N
O
MeMe
CuOTf
OTf
O
Should be Planar
Copper Based - Evans
Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692
N
O
N
O
L: bis(oxazoline) ligand
R' Time (h) Yield (%) ee (%)
H
O
R'+ [(L)Cu](OAc)2
EtOH, rtCH3NO2
R'NO2
OH
Ph2-MeC6H4
2-MeOC6H4
2-NOC6H4
2-ClC6H4
1-naphthyl4-FC6H4
4-ClC6H4
4-PhC6H4PhCH2CH2
i-Bu
i-Prn-Bucyclohexyl
i-Bu
2242274
15154521202448
484848
96
7672918688667073708186
868795
83
9493938991879290919092
949393
94
(R)
Copper Based - Evans
Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692
ON
CH3
O
XCuXL
L
ON
O
CH3
CuLL X
O
NCH2O
-HX
RCHO
CuLL X
O
NO
O
R
+HX
O
NO
OH
R
XCuXL
L
Cu CuLLL2
CuLL
E
Nu
CuLL Nu
E
HighestReactivity
IntermediateReactivity
LowestReactivity
CuLL
Nu
E
CuLL OAc
O
O CuLL O
O
OAc
H
R
NO
H
HCu
LL OAc
O
O
H
R
N HH
O
H R
NO
H
H
Favored by Evans
Quaternary Ammonium Salts - Corey
Corey, E. J. and Zhang, Fu-Yao, Angew. Chem. Int. Ed., 1999, 38, 1931
Bn2NH
O
tBuOCONH H
OtBuOCONH NO2
OH
Bn2N NO2
OH(10 mol%)
12.5 eq. KFTHF, -10 oC, 6h
86%
(10 mol%)
10 eq. KFCH2Cl2, -10 oC, 12h
88%
Bn2N NO2
OH
tBuOCONH NO2
OH
+
+
+
+
CH3NO2
CH3NO2
9:1
17:1
NO
N
F
NO
N
Br
Quaternary Ammonium Salts - Corey
Corey, E. J. and Zhang, Fu-Yao, Angew. Chem. Int. Ed., 1999, 38, 1931
gives syn products gives anti prodcuts
Nu-Nu-
Quaternary Ammonium Salts - Maruoka
Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 2054
N
Ar
Ar
HF2
(S,S)-1
CF3
CF3
F3C CF3
CF3
CF3
Ar =
1a 1b
ON
OSiR3
R1
H R2
O
+(S,S) - 1b (2 mol%)
THF-98 to -78 oC
1 N HCl
0 oC R1 R2
OH
NO2
Me
EtBnO(CH2)2
Et3
Me3
tBuMe2
Me3
Ph
p-MePh
p-FPh
β-Np
Ph
Ph
2
34
3
5
4
4
4
4
4
83 (74:26)
92 (92:8)90 (90:10)
94 (85:15)
45 (57:43)
92 (94:6)
94 (83:17)
88 (92:8)
94 (90:10)
70 (87:13)
33 (1R,2S)
95 (1R,2S)93 (1R,2S)
92 (1R,1S)
11 (1R,2S)
97
90
93
91
91
%ee(config.)
% Yield(anti/syn)
Time (h)R2R3R1
Quaternary Ammonium Salts - Maruoka
Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 2054
Favored Disfavored
Quaternary Ammonium Salts - Maruoka
Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 2054
R2
O HO
O
N
H
R1 N
syn
H
O R2O
O
N
H
R1 N
anti
Substituted Thioureas - Takemoto
Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625
Ar
NP(O)Ph2
ArNO2
R
HNP(O)Ph2
R
NO2+
1b (0.1 equiv.)
CH2Cl2, rt
Ar R % Yield %ee (dr)
Ph
4-MePh
4-ClPh
2-napth
2-furyl
2-pyridyl
2-thienyl
Cinnamyl
Ph
H
H
H
H
H
H
H
H
Me
87
72
76
78
85
91
57
68
83
67
63
67
70
76
68
64
65
67 (73:27)
F3C
CF3
NH
NH
S
N
1b
Substituted Thioureas - Takemoto
Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625
N N
S
N
ON
O
R HH
H HN N
S
N
ON
O
R
H H
H
H
3.416 A
Chiral Proton Catalyst - Johnston
Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418
N N
N NHH
H H
H OTf
Catalyst
Yield (%) %eedrR''R'
H
p-NO2
m-NO2
H
p-CF3O
p-Cl
m-NO2
o-NO2
p-CF3
p-NO2
H
CH3
CH3
CH3
CH3
CH3
H
H
CH3
CH3
57
61
65
69
53
59
51
62
50
60
_
_
_
14:1
19:1
17:1
11:1
7:1
19:1
7:1
60
82
95
59
81
82
89
82
84
90
H
NBoc
R' R''
NO2
HNBoc
R'
NO2
R''+
-20 oC
Cat. (10 mol%)
Dendrizyme Approach - Smith
Davis, A. V.; Driffield, M.; Smith, D. K. Org. Lett. 2001, 3, 3075
N
HN
NHNH
O
O
NHBoc
BocHN O NHBoc
NHBoc
NHBocBocHN
G1(N:)
N
HN
NHNH
O
O
NH
HN O HN
HN
NHHN
O
BocHNNHBoc
O
NHBoc
BocHN
O
BocHN
BocHN
ONHBoc
OBocHN
BocHN
BocHN
G2(N:)
Dendrizyme Approach - Smith
Davis, A. V.; Driffield, M.; Smith, D. K. Org. Lett. 2001, 3, 3075
N
HN
NHNH
O
O
NH
HN O HN
HN
NHHN
O
BocHNNHBoc
O
NHBoc
BocHN
O
BocHN
BocHN
ONHBoc
OBocHN
BocHN
BocHN
G2(N:)
N
HN
NHNH
O
O
NHBoc
BocHN O NHBoc
NHBoc
NHBocBocHN
G1(N:)
H
O+
Cat. (15 mol%)
THF
OH
Time Conversion (%) syn : anti
48
1
1
0.5
48
24
none
85
95
91
92
94
57 : 43
56 : 44
55 : 45
42 : 58
54 : 46
Catalyst
none
DIPEA
NEt3 + acetamide
G1(N:)
G2(N:)
NEt3
(10 mol%)
NO2
NO2
OH
NO2O2N O2N O2N
+
Dendrizyme Approach - Cossio
Zubia, A.; Cossio, F. P.; Morao, L. A.; Rieumont, M.; Lopez, X. J. Am. Chem. Soc. 2004, 126, 5243
N
O
O O
A0
N
O
O O
MA2
O
OO
OO
O
MA1
N
O
O O
O
OO
Dendrizyme Approach - Cossio
Zubia, A.; Cossio, F. P.; Morao, L. A.; Rieumont, M.; Lopez, X. J. Am. Chem. Soc. 2004, 126, 5243
N
O
O O
DA1
O O
O
O
O
O
DA2
N
O
O O
O O
O
O
O
O
O
oO
O
O
O
O O O O
O
O
Dendrizyme Approach - Cossio
Zubia, A.; Cossio, F. P.; Morao, L. A.; Rieumont, M.; Lopez, X. J. Am. Chem. Soc. 2004, 126, 5243
TA2
N
O
O O
O O
O
O
O
O
O
O O
O
OO
OO
O
OO
O
OO
O
O
OO
OO
OOO
O
OO
O
O
OO
N
O
O O
O O
O
O
O
O
O
O O
TA1
Dendrizyme Approach - Cossio
Zubia, A.; Cossio, F. P.; Morao, L. A.; Rieumont, M.; Lopez, X. J. Am. Chem. Soc. 2004, 126, 5243
H
O+
Cat. (15 mol%)
THF
OH
kobs (10-4s-1) syn : anti
12.11
10.85
5.53
8.25
3.70
69 : 31
67 : 33
68 : 32
66 : 34
Catalyst
A0
MA2
DA1
DA2
MA1
NO2
NO2
OH
NO2
+OH
66 : 34
1.89
1.03
67 : 33
72 : 28
TA1
TA2
Increasing Bulkiness
N
O
O O
A0
TA2
N
O
O O
O O
O
O
O
O
O
O O
O
OO
OO
O
OO
O
OO
O
O
OO
OO
OOO
O
OO
O
O
OO
C-13 Side-Chain of Taxol
Borah, J. C.; Gogoi, S.; Boruwa, J.; Kalita, B.; Barua, N. C. Tetrahedron Lett. 2004, 45, 3689
Ph
NO2
OBn+ Ph OBn
NO2
OH
(2R, 3S)
H
O
La-(R)-BINOL (10 mol%)
THF, -50 oC,80% Yield
Ph OBn
NO2
OH
(2R, 3S)
Ph OBn
NO2
OAc
Ac2O, Pyridine
93% YieldPh OH
NH2
OAc
10% Pd/CEtOH, H2, rt80% Yield
98% ee
Ph OH
NH2
OAc
Ph OH
NH2
OAc
O
Glacial Acetic AcidWater, 5 oC82% Yield
CrO3
96% ee
Ph OH
NH
OAc
O1) Benzoyl Chloride, Et3N, 0 oC
2) Et2NMe-H2O
O
Ph
Inositol Derivatives
Soengas, R. G.; Estevez, J. C.; Estevez, R. J. Org. Lett. 2003, 5, 4457
O
BnO
BnO
OH
OH
OBn
O2N
O
BnO
HO
OH
O2NO
BnO
H
O O2N OH
TBAFTHF
rt, 10 h75% Yield
O
O
O
O
O
BnO
BnO
OH
OH
OH
OBn
OBn
O2N
BnO
HO OH
CHO
OBn
OBn
O2N
BnO
HO OH
OBn
O2N
2% aq. NaCO3H
MeOHrt. 14 h
53% yield
Inositol Derivatives
Soengas, R. G.; Estevez, J. C.; Estevez, R. J. Org. Lett. 2003, 5, 4457
O
BnO
BnO
OH
OH
OH
OBn
OBn
O2N
BnO
HO OH
CHO
OBn
OBn
O2N
BnO
HO OH
OBn
O2N
CHO
OBn
NO2
BnO
HO OH
O
BnO
BnO
OH
OH
OBn
O2N
+
OH
OBn
NO2
BnO
HO OH
OBnOBn
Conclusions• Chiral Ligands
– Shibasaki's Bimetallic Lanthanide/Lithium System– Trost's Zn/Chiral Phenol System– Lin's Zn/ System– Jorgensens's Cu/BOX System– Evans' Cu/BOX System
• Chiral Quaternary Ammonium Salts– Corey– Maruoka
• Chiral Organic Catalysts– Takemoto's Chiral Thioureas– Johnston's Chiral Proton
• Dendrizymes– Smith– Cossio
Acknowledgements• Dr. Borhan• Dr. Baker• Dr. Ruby N. Ghosh• Jamie Dunn• Baker Group