Asymmetric Heteroatom Conjugate Additions David Favor Evans Group Seminar R 2 R 1 O R 3 X H R 2 R 1 O X * R 3 I. a) Diastereoselective Oxygen Nucleophiles b) Enantioselective Oxygen Nucleophiles II. a) Diastereoselective Nitrogen Nucleophiles b) Enantioselective Nitrogen Nucleophiles III. a) Diastereoselective Sulfur Nucleophiles b) Enantioselective Sulfur Nucleophiles IV. a) Diastereoselective Chlorine Additions H 3/10/00 01-Favor Title 7/28/00 1:41 PM
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Asymmetric Heteroatom Conjugate AdditionsDavid Favor
Evans Group Seminar
R2 R1
OR3 X
H
R2 R1
OX
*
R3
I. a) Diastereoselective Oxygen Nucleophilesb) Enantioselective Oxygen Nucleophiles
II. a) Diastereoselective Nitrogen Nucleophilesb) Enantioselective Nitrogen Nucleophiles
III. a) Diastereoselective Sulfur Nucleophilesb) Enantioselective Sulfur Nucleophiles
IV. a) Diastereoselective Chlorine Additions
H
3/10/00
01-Favor Title 7/28/00 1:41 PM
O
Asymmetric Alkoxide Addition to a γγγγ-Chiral Enone
OMe
O
O
O
1 equiv NaOR, 3 M in ROH
-50 °C, 1 h
>85% yield
OMe
O
O
O
OMe
O
O
O
+
85 : 15 = Z : E
Mulzer, J.; Kappert, M.; Gottfried, H.; Jibril, I. Angew. Chem. Int. Ed. Engl. 1984, 23, 704.
OR OR
Alcohol
MeOH
MeOH
MeOH
EtOH
BnOH
dr (a:b)
60:40
91:9
95:5
86:14
76:24
time (min)
6
6
60
60
120
a bT (°C)
25
-50
-78
-50
-10
H
O
H
CO2R
MeMe
02-Favor OD-Mulzer 3/8/00 4:31 PM
H
Diastereoselective Benzylalcohol Additions to δδδδ-Subtituted-αααα,ββββ-unsaturated Esters
MeN
O
O
Me
Ph
Cbz
MeN
O
O
Me
Ph
CbzOBnPhCH2ONa or PhCH2OLi
2:1 PhCH2OH/THF, -50 °C, 18 h
98% yielddr = >95 : 5
BnON
O
O
Me
Ph
Cbz
BnON
O
O
Me
Ph
CbzOBnPhCH2OK, 2:1 PhCH2OH/THF -30 °C, 60 h 80% yield
dr = >95 : 5
O
H N
Ph
Me
Cbz
H
ROC
Nu
Bernardi, A.; Cardani, S.; Scolastico, C.; Villa, R. Tetrahedron 1990, 46, 1987.
Insensitivity to counterion implies a non-chelated mechanism.
dicyclohexyl-18-crown-6
or
PhCH2OK, PhCH2OH
-5 °C, 24 h
35% yield
03-Favor OD-Scolastico 3/8/00 4:31 PM
Diastereoselective Benzyloxymercuration of γγγγ-Alkyl-δδδδ-hydroxy-αααα,ββββ-unsaturated Esters
MeCO2Me
O
MeCO2Me
O
MeCO2Me
OH
1) 2.5 equiv BnOH, 1.3 equiv Hg(OAc)2cat. 70% HClO4, CH2Cl2, 24 h, rt
2) pH 7 work up
3) 1 equiv NaBH4, THF, pH 8 buffer, 0 °C
Me
BnO
BnO
Me
MeCO2Me
O
MeCO2Me
O
Me
BnO
BnO
OBn
OBn
O
Me
Me OBn
O
dr = 57 : 43, 73% yield
dr = 93 : 7, 66% yield
dr = >98 : 2, 60% yield
Thaisrivongs, S.; Seebach, D. J. Am. Chem. Soc. 1983, 105, 7407.
same conditions as above
same conditions as above
Hg
H
O
MeH
Me
Ph
CO2Me
OAc
BnOH
H
04-Favor OD-Seebach 3/10/00 11:41 AM
Enantioselective Epoxidation of αααα,,,,ββββ-Enones Utilizing Polyamino Acids Catalysts
O
Itsuno, S.; Sakakura, M.; Ito, K. J. Org. Chem. 1990, 55, 6047.
O
O
O
O
O
O
Cl
O2NOMe
MeO
OEt
Cl
OMe
Julia, S.; Masana, J.; Vega, J. C. Angew. Chem. Int. Ed. Engl. 1980, 19, 929.
First example of the use of polyamino acid for enantioselective epoxidation:
For a review of polyamino acid mediated epoxidations see:Ebrahim, S.; Wills, M. Tetrahedron: Asymm 1997, 8, 3163.Pu, L. Tetrahedron: Asymm 1998, 9, 1457.
cross-linked polystyrene with grafted with polyleucine (n = 32)H2O2-NaOH, PhCH3
99
90
76
90
83
99
87
98
89
56
89
56
98
83
%ee %yield
Reaction conditions:
R R
O
R R
OO
05-Favor OE-Itsuno 3/10/00 10:32 AM
Enantioselective Epoxidation of αααα,,,,ββββ-EnonesN
Et
N O
Ph
Br-
R
O
X -40 °C, 12h
8 M aq. KOCl10 mol% catalyst
PhCH3
+R
O
X
O
Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1, 1287.
X
H
F
H
F
H
H
H
%ee
93
98
94
91
94
95
93
% yield
96
93
90
90
85
70
87
R
Ph
Ph
p-NO2Ph
pentyl
C6H11
p-MeOPh
β-Napht
+
Catalyst
8 more substrates reported
5 equiv
First example: Helder, R.; Hummel, J. C.; Laane, R. W.; Wiering, J. S.; Wynberg, H. Tetrahedron Lett. 1976, 1831.
H
06-Favor OE-Corey-I 3/8/00 4:33 PM
Enantioselective Epoxidation of αααα,,,,ββββ-Enones
Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1, 1287.
Stereochemical Rational
Front Back
O
R
R = Me 76% ee
R = Ph 61% ee
07-Favor OE-Corey-II 3/6/00 5:47 PM
Asymmetric Addition of Benzylamine to Menthylcrotonate Derivatives
R
O
OPhCH2NH2, rt
15 kbar, MeOH
R=
Ph
p-PhOPh
β-Napht
%de
60
95
99
% yield
85
90
5024 h
d'Angelo, J.; Maddaluno, J. J. Am. Chem. Soc. 1986, 108, 8112.Mezrhab, B.; Dumas, F.; d'Angelo, J.; Riche, C. J. Org. Chem. 1994, 59, 500.
Me
R
O
O
MeBnHN
s-cis,syns-trans,syn
O Me
O
O
O
Me
Gas phase calculations indicated that methyl acrylate prefers the s-cis,syn conformation. (Loncharich, R. J.; Schwartz, T. R.; Houk, K. N. J. Am. Chem. Soc. 1987, 109, 14.)
The dipole moment of the s-trans,syn and the s-cis,syn crononates are 2.55 and 1.65 D respectively. (George, W. O.; Hassid, D. V. J. Chem. Soc., Perkin Trans. 2 1972, 4, 400.)
Polar, protic solvents are required. Reactions fail in THF and CH2Cl2.
Favored Unfavored
08-Favor ND-d'Angelo 3/8/00 4:40 PM
Diastereoselective Additions of O-Benzylhydroxylamine to Unsaturated Amides
NMeN R
O O
Amoroso, R.; Cardillo, G.; Sabitino, P.; Tomasini, C.; Trere, A. J. Org. Chem. 1993, 58, 5615.
PhMe
Lewis acid, CH2Cl2;
1.2 equiv BnONH2
R
Me
Pr
Me
Me
Pr
Pr
dr (a:b)
80:20
77:23
19:81
20:80
13:87
11:89
% yield
80
90
65
70
81
83
Lewis acid
TiCl4
TiCl4
AlCl(Me)2
AlCl(Me)2
AlCl(Me)2
AlCl(Me)2
NMeN R
O O
PhMe
+
NHOBn
NMeN R
O O
PhMe
NHOBn
a b
Nonchelate product
Chelate product Evans Diels-Alder Conditions J. Am. Chem. Soc. 1988, 110, 1238.
-78 °C
1.0 eq
1.0 eq
1.4 eq
2.0 eq
1.4 eq
2.0 eq
09-Favor ND-Cardillo 3/8/00 4:39 PM
Ph
O
%de % yield
Yamamoto, Y.; Asao, N.; Uyehara, T. J. Am. Chem. Soc. 1992, 114, 5427.
Rχ Ph
O [Bn(TMS)N]2CuLi
THF, -78 °C
Napt
O N
SO2
Rχ Ph
O NHBn
72 74 9080 95 78
%de % yield %de % yield
Ph
O
N
SO2
1) [Bn(TMS)N]2CuLi
THF, -78 °C2) CH3CHO
Me Ph
OTBS
CO2Rχ
NHBn
3) TBSCl
99% de, 71% yield
1) LAH
2) Et3SiCl3) (Boc2)O
Me Ph
OTBS NH(Boc)Bn
OTES
1) AcOH
2) Swern [O]3) NaClO2
NaH2PO4
Me Ph
OTBS
CO2H
NHBn
NBn
MePh
O
H H
OTBS
N+Me
Cl
2)
1) TFA
36% yield
68% yield 65% yield
Asymmetric Addition of Amines to Crotonate Derivatives: Three Component ββββ-Lactam Synthesis
10-Favor ND-Yamamoto 3/8/00 4:52 PM
Asymmetric Addition of 1,1'-Binaphthylamine to Crotonates
NH
1) 1.5 equiv BuLi, DME, -63 °C
2)
t-BuO R
O
1.5 equiv
1 equiv
N
t-BuO R
O
Hawkins, J. M.; Fu, G. C. J. Org. Chem. 1986, 51, 2820.
R=
Me
Hept
i-Bu
i-Pr
dr
66:1
53:1
69:1
34:1
% yield
83
80
74
96
Hawkins, J. M.; Lewis, T. A. J. Org. Chem. 1992, 57, 2114.
NH
1) 1.1 equiv BuLi, DME, -63 °C
2)
t-BuO Me
O
1.1 equiv
1 equiv
N
t-BuO Me
O2) MeI
71% yield, ds 65:2:2:1
Hawkins, J. M.; Lewis, T. A. J. Org. Chem. 1994, 59, 649.
NaphtNapht
H
Me
MeO O
H
+0.5-3.6 kcal
Napht Napht
H
Me
OMeO
H
0 kcalHouk et al. J. Org. Chem. 1988, 53, 3880.
MM2 calculation
11-Favor ND-Hawkins 3/10/00 10:14 AM
Asymmetric Addition of Lithiated αααα-Methylbenzylamide Derivates to Crotonates
Davies, S. G.; Ichihara, O. Tetrahedron: Asymm. 1991, 3, 183.
RO Me
O
R
Me
Bn
t-Bu
%de
95
95
>99
% yield
85
88
82
+ AmineTHF, -78 °C
15 minRO Me
O NR R
Ph NLi
Me
Ph Ph NLi
Me
Ph
Me
Ph NLi
Me
OMe
OMe%de
>99
98
>99
% yield
57
23 (at 0 °C)
27
%de
95
96
>99
% yield
68
74
83
THF, -78 °C
15 min
Ph NLi
Me
Ph
90 % yield
2 equiv
Ph
Me
PhN
Ph-p-OBnPh-p-OBn MeO2C
MeO2CMeO2C THF, -78 °C
15 min
Ph NLi
Me
OMe
OMe
96% de
Ph
Me
ArN
MeO2C
Removal:H2, Pd(OH)2
Removal:CAM or DDQ
Davies, S. G.; Ichihara, O. Tetrahedron Lett. 1998, 3, 6045.
78% yield>99% de
12-Favor ND-Davies-I 3/8/00 4:40 PM
Calculated Stereochemical Model for Addition of Lithiated αααα-Methylbenzylamide Derivates to Crotonates
Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asymm. 1994, 5, 1999.
t-Bu O
PhOH
H
N BC
A
PhD
Ph
N HH
Me
PhH
Ph
N HH
Ph
MePh
H
N HH
Ph
HPh
Me
N HH
Ph
HMe
Ph
Energy: 0 kJ mol-1 +11 kJ mol-1 +12 kJ mol-1 +17 kJ mol-1
CHEM-X modelling package was used (Chemical Design Limited, Chepping Norton, UK).
A B C D
2Å "The conformational reorganization which occurs as the amide approaches the ester bears striking resemblence to the wings of a butterfly in flight which, as it alights on a leaf, assumes a parallel orientation."
13-Favor ND-Davies-II 3/10/00 2:48 PM
t-BuO
O
Ph NM
Me
Ph
Ph
Me
Ph
RO
O N
t-BuO
OPh
Me
Ph
RO
O N
MeIMe
Tandem Asymmetric Addition of αααα-Methylbenzylamide/Alkylation to Crotonates
Bunnage, M. E.; Davies, S. G.; Goodwin, C. J.; Walters, I. A. S. Tetrahedron Asymm. 1994, 5, 35.
+ THF, -78 °C
15 h
4 equiv
+THF, -78 °C
15 h;
19 : 1 syn : anti
M
Li
Mg
%de
95
>95
% yield
92
78
t (h)
1
15
Ph NM
Me
Ph
4 equivM
Li
Mg
%de
30
90
% yield
78
73
14-Favor ND-Davies-III 3/10/00 10:29 AM
t-BuO
O
Ph NLi
Me
Ph
Ph
Me
Ph
RO
O N
Me
MeI
Tandem Asymmetric Addition of αααα-Methylbenzylamide to Crotonates
t-BuO
O
Ph NLi
Me
Ph
Ph
Me
Ph
RO R
O N
N
SO2
O
R
OH
Davies, S. G.; Garrido, N. M.; Ichihara, O.; Walters, I. A. S. Chem. Comm 1993, 1153.
+THF, -78 °C; MeI
4 equiv
condition A:
1) THF, -78 °C, quenchcondition B:
2) LDA, THF, -78 °C;condition
A
B
%de
30
94
% yield
78
70
+ THF, -78 °C;
4 equiv
R
Ph
Bn
%de
92
91
% yield
86
63
anti:syn
22:1
>25:1
Bunnage, M. E.; Davies, S. G.; Goodwin, C. J. Synlett 1993, 731.Bunnage, M. E.; Davies, S. G.; Goodwin, C. J. Perkin Trans. 1 1993, 1375.
Z-enolate
E-enolate
15-Favor ND-Davies-IV 3/10/00 10:29 AM
Asymmetric Addition of Lithiated αααα-Methylbenzylamide Derivates to Crotonates
Ph NLi
Me
Pht-BuO
O
+
Ph
Me
Ph
t-BuO
O N
t-Bu t-Bu
OH2) THF, 0 °C -> RT
6 d
Ph
Me
Ph
t-BuO
O N
solvent
THF/PhCH3
THF
%de
71
>98
% yield
85
65
T(°C)
-78
-95
>98% de, 75% yield
Ph NLi
Me
Pht-BuO
O
+
Ph
Me
Ph
t-BuO
O N
t-Bu t-Bu
OH2)
Ph
Me
Ph
t-BuO
O N1) solvent, -78 -> -30 °C
solvent
THF/PhCH3
THF
%de
>95
>95
% yield
70
70
T(°C)
-78
-95
>97% de, 97% yield
Davies, S. G.; Ichihara, O.; Lenior, I.; Walters, I. A. S. J. Chem. Soc., Perkin Trans. 1 1994, 1411.
1.5 equiv
1.5 equiv
8.5 equiv t-BuOH3.8 equiv KHMDS
THF, 0 °C -> RT
6 d
8.5 equiv t-BuOH3.8 equiv KHMDS
1) solvent, -78 -> -30 °C
16-Favor ND-Davies-V 3/1/00 10:08 PM
Asymmetric Addition of Amines to Crotonate Derivatives: Three Component ββββ-Lactam Synthesis
Asao, N.; Tsukada, N.; Yamamoto, Y. Chem. Comm. 1993, 1660.
NH
MePh
O
H H
OTBS
t-BuO
O
+THF, -78 °C
15 minPh N
Li
Me
Ph
Ph
Me
PhPh
t-BuO
O
Ph
N
one isomer observed
98 % yield
Ph
Me
Ph
Me
OH
Ph
N
COt-Bu
1) 3 equiv LDA, 0 °C
2) 3 equiv boron reagent, -78 °C
3) CH3CHO, -78 °C
addative
none
Bu3B
Et3B
(BuO)3B
(MeO)3B
dr
78:22
81:19
86:14
75:25
91:9
% yield
100
72
82
82
89
Ph
Me
Ph
Me
OH
Ph
N
COt-Bu
1) TBSCl, imid
2) Pd(OH)2/C, H2
54% yield
Me
OTBS
Ph
NH2
COt-Bu
1) TFA, CH2Cl2
2) PPh3, CH3CNN S S N
55% yield
17-Favor ND-YamamotoI 2/28/00 11:54 AM
Asymmetric Addition of TMS-SAMP to Unsaturated Esters
R2O R1
O
R
Me
Me
t-Bu
t-Bu
%de
95
95
98
97
% yield
48
40
32
67
NOMeNH
Me3Si
+
R2O R1
O
NOMeNH
1.3 equiv
1.3 equiv BuLi, THF, -78 °C;
SiO2, EtOAc
R
Me
Pr
i-Pr
C11H23
1 2
Raney-Ni/H2
H2O, 60-75 °C
~75-85% yield
HO R1
O NH2
Enders, D.; Wahl, H.; Bettray, W. Angew. Chem. Int. Ed. Engl. 1995, 34, 455.
TMS-SAMP
(S)-2-methoxymethyl-1-trimethylsilylpyrrolidine
R
ROO
NONSi
MeLiMe
Me
Me
N
O
N Si
Me
Me
Me
Me
Li
Stereochemical Rational
si-face
re-face
Enders, D.; Wiedemann, J. Liebigs Ann. Recueil 1997, 699.
18-Favor ND-Enders-I 3/8/00 4:47 PM
Tandem Asymmetric Addition of TMS-SAMP/Alkylation of Unsaturated Esters
t-BuO R1
O
NOMeNH
Me3Si
+
t-BuO R1
O
NOMeNH
1.3 equiv
Raney-Ni/H2
H2O, 60-75 °C
~63-87% yield
HO R1
O NH2
Enders, D.; Bettray, W.; Raabe, G.; Runsink, J. Synthesis 1994, 1322.
TMS-SAMP
Br
MeI
EtI
C4H9I
Electrophile %yield
56
26
51
34
64
52
67
%de
77
76
>96
>96
>96
>96
>96
E
Et
Et
Et
Ph
Ph
Ph
R
I OTMS
PhCH2Br
Ph PhCH2Br
2) 3 equiv HMPAelectrophile, -78 °C
1) 1.3 equiv BuLi, THF, -78 °C, 15h
E
19-Favor ND-Enders-II 3/8/00 4:48 PM
t-BuO
O
t-BuO
O
n
0
1
2
3
4
%de
-
-
>96
>96
>96
% yield
NR
NR
64
54
38
Enders, D.; Wiedemann, J. Liebigs Ann. Recueil 1997, 699.
1.3 equiv
1) THF, -78 °C
Xn
n - 2
2) HMPA, -78 °C
3) SiO2, EtOAc
X
Br
Br
Br
Br
I
N
OMeHN
+N
OMeNLiMe3Si
t-BuO
O n
2
3
4
%de
>96
>96
>96
% yield
43
58
581.3 equiv
1) THF, -78 °C
Xn
2) SiO2, EtOAc
X
Cl
Cl
Br
+N
OMeNLiMe3Si
t-BuO
O
n - 2
NOMe
N
3) K2CO3, MeOH
EtOAc, ∆
Tandem Asymmetric Addition of TMS-SAMP/Cyclization of Unsaturated Esters
20-Favor ND-Enders-III 3/8/00 4:49 PM
Asymmetric Addition of Lithiated Amines to Chiral Naphthyloxazolines
Shimano, S.; Meyers, A., I. J. Am. Chem. Soc. 1994, 116, 6437.Shimano, S.; Meyers, A., I. J. Org. Chem. 1995, 60, 7445.
NO
1.5 equiv amine
1) 1 equiv HMPA, THF-78 -> -50 °C
2) electrophile, -78 °C+
N
O
E
NR2
LiN
LiN
LiN
LiN
H
LiN
NLi
NLiO
O
Br
MeI
MeI
MeI
MeI
MeI
MeI
MeI
BrPh
Electrophile %yield
94
93
NR
NR
NR
95
92
67
96
dr
98.5 : 1.5
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
NR
NR
NR
NO H
LiN
R
R
H
EX
O
PMe3N
NMe3
Stereochemical Model
NMe3
21-Favor ND-Meyers-I 3/8/00 4:49 PM
Asymmetric Addition of Lithiated Amines to Chiral Naphthyloxazolines
Shimano, S.; Meyers, A., I. J. Am. Chem. Soc. 1994, 116, 6437.Shimano, S.; Meyers, A., I. J. Org. Chem. 1995, 60, 7445.
N
O
1.5 equiv amine
1) 1 equiv HMPA, THF-78 -> -50 °C
2) MeI, -78 °C+
LiN
LiN
NLi
NLiO
O
H
MeO
H
H
H
H
N
O
Me
NR2
X X
Me3SiLiN
SiMe3
NLi
N
O
Me
N
OO
1) conc. HCl, 0 ~ 20 °C
2) NaOH in H2O-BuNH2
145 °C, sealed tube
72% yield
OH
O
Me
NH2
%yield
91
90
NR
94
94
94
dr
97.5 : 2.5
>99 : 1
>99 : 1
NR
>99 : 1
>99 : 1
X
22-Favor ND-Meyers-II 3/8/00 4:50 PM
Asymmetric Additions of αααα-Methylbenzyl Hydroxylamine to Unsaturated Esters
MeO R
O
Baldwin, S. W.; Aube, J. Tetrahedron Lett. 1987, 28, 179.
benzene, K2CO3
∆, 1 equiv MeOH
+
αααα ββββ
ratio(αααα:ββββ)
80:20
86:14
82:18
80:20
69:31
70:30
% yield
91
22
80
74
54
65
R
Me*
Me (cis)
Pr
i-Pr
Ph
CH2CO2Me
1) H2, Pd/C
2) KHSO4, MsCl
3) Na/NH3
N
R
O H
39-91% yieldNH
Ph
HMe
HO
+
Stereochemical rational
MeO
R
O
N
Ph
HMe
OH
H
N
Ph
H
MeO
H
H
favored
unfavored
*αααα:ββββ ratios of other solvents: hexanes (90:10) ether (70:30) diglyme (65:35)
Ph
HMe
NO
O R
Ph
HMe
NO
O R
23-Favor ND-Baldwin 3/8/00 4:35 PM
Diastereoselective Alkylations of ββββ-Aminoesters
MeO Me
O
Seebach, D.; Estermann, H. Tet. Lett. 1987, 28, 3103.
R
HN
O
Ph2 equiv LDA
THF, -78 °C; Electrophile
MeO Me
O HN
O
Ph
E R2
Electrophile
CH3I
CH3CH2I
CH2=CHCH2Br
C6H5CH2Br
C6H5CH2Br
dr
4:1
16:1
31:1
36:1
99:1
% yield
50
73
70-90
70-90
80
R=
H
H
H
H
Me
MeO Me
O
R
N
Ph
OLi
E+
Li
24-Favor ND-Seebach 3/10/00 9:49 AM
NO Me
O O
O
O O
O
PhPh
Ph Ph
Ti(OTf)2
NO Me
O O NHOBn10 mol% catalyst, PhCH3
1.5 equiv H2NOBn, 0 °C
NO R
O O
NO R
O O NHOBn10 mol% catalyst, PhCH3
1.5 equiv H2NOBn, rt
28% ee, 100% conversion
R= Pr 35% ee, 94% conversion
R= Ph 42% ee, 69% conversion
Falborg, L.; Jorgensen, K. L. J. Chem. Soc., Perkin Trans. 1 1996, 2823.
optimal catalyst
EnantioselectiveO-Benzylhydroxylamine Additions to Unsaturated Imides
25-Favor NE-Jorgensen 3/7/00 10:56 PM
EnantioselectiveO-Benzylhydroxylamine Additions to Enones
N R
O
NMe
Me
MgBr2, H2NOBn (1.1 equiv)
Ligand, CH2Cl2, -60°C, ~20 h
R
% ee
92
92
90
95
87
83
30 mol%
% yield
80
74
53
80
76
24
% ee
88
88
70
90
67
NR
% yield
87
84
57
85
56
NR
10 mol%
N R
O
NMe
Me
NHOBn
Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 1998, 120, 6615.
HN R
O NHOBn
OBn
+
MgI2, Zn(OTf)2, Mg(OTf)2, ZnBr2, and Sn(OTf)2 all gave lower yields and/or selectivity.
N Me
O
O
Oligand, Lewis acid, H2NOBn
% ee
28
41
100 mol%
% yield
81
74
% ee
65
42
% yield
98
94
30mol%
N Me
O
O
O NHOBn
% ee
96
92
90
96
83
78
100 mol%
% yield
62
56
39
62
41
21
Lewis acid
MgBr2
MgI2
CH2Cl2, -60°C, ~20 h
N
R
O NMe
Me
O O
N NMg
favored unfavored
Stereochemical Rational
Me
Et
C6H11
Bn
i-Pr
Ph
26-Favor NE-Sibi 3/8/00 4:53 PM
Enantioselective Hydrazoic Acid Additions to Unsaturated Amides
Ph NH
R
O O
R= % ee
96
97
95
95
58
95
96
97
% yield
96
97
97
98
60
97
93
99
Me
Et
i-Pr
Ph
Ph
n-Pr
OBn
t-Bu
10 mol% catalyst, -40 °C
PhCH3/CH2Cl2, 24 h Ph NH
R
O O N36.6 equiv HN3
O
N
tBu
tBu O
Al
N
tBu
tBuMe
Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959.
H
H
N
N
O
OAl
R
O
COArHN
Catalyst:
O N Me
O O
HN3 O N Me
O O N35 mol% cat, rt
PhCH3, 48 h+
50% conv.34% ee
Disfavored
Favored
Stereochemical Rational
27-Favor NE-Jacobsen 3/7/00 10:51 PM
Diastereoselective Thiolphenol Additions to Unsaturated Imides
NO R
O O
T(°C)
-50
-30
0
0
% yield
98
95
91
96
RχN R
O SPh0.1 equiv PhSLi
10 equiv PhSH
THF, -50 °C
RχN R
O SPh
RχN R
O SPh
RχN R
O SPh
Me Me Me MeMe
R=
E-Me
Z-Me
E-Ph
Z-Ph
A
>89
3
8
8
A B C D
B
<1
4
2
1
C
4
<1
45
22
D
6
>92
45
69
Miyata, O.; Shinada, T.; Nimomiya, I.; Naito, T. Tetrahedron Lett. 1991, 32, 3519.
Miyata, O.; Shinada, T.; Nimomiya, I.; Naito, T. Tetrahedron 1997, 53, 2421.
PhSLi
Stereochemical Rational
NO
OMe Me
Me
O
Me
28-Favor SD-Naito-I 3/10/00 12:18 PM
Diastereoselective Thiolphenol Additions to Unsaturated Amides: Formal Synthesis of (+)-Diltiazem
NO
O O
Miyata, O.; Shinada, T.; Nimomiya, I.; Naito, T. Tetrahedron Lett. 1991, 32, 3519.
OMEMOMe
SLi
NH2
SH
NH2
3 equiv
1.5 equiv
THF, -40 °C
NO
O O
OMEMOMe
S
H2N
78% yield
1) Me3Al, CH2Cl2, ∆
NH
S
O
OH
OMe
N
S
O
OAc
OMe
2) TiCl483% yield
Me2N
Yakugaku Zasshi1973, 93, 729.
Miyata, O.; Shinada, T.; Nimomiya, I.; Naito, T. Tetrahedron 1997, 53, 2421.
(+)-Diltiazem: A potent vasodilating agent and calcium channel blocker.
E:Z ratio= 4:1syn:anti ratio= 82:18
97% yield
29-Favor SD-Naito-II 3/8/00 4:54 PM
Wu, M.-J.; Wu, C.-C.; Tseng, T.-C. J. Org. Chem. 1994, 59, 7188.
R1
O
N
SO2
Asymmetric Addition of Thiols to N-Enoylsultams
Catalyst
Et3N
Et2AlCl
BF3•Et2O
TiCl4
10 mol%LiSCH2CO2Me
ratio(αααα:ββββ)
50:50
70:30
-
80:20
50:50
% yield
65
51
NR
96
86
T(°C)
-78
25
25
-78
-50*
t(h)
2
5
75
3
5
Thiol (R2SH)+
5 equiv
*THF used
CH2Cl2R
O SR2
R
O SR2
+
αααα ββββ
Thiol (R2)
CH3COSH
HSCH2CH2CO2Me
PhCH2SH
PhSH
o-(CO2Me)PhSH
HSCH2CO2Me
ratio(αααα:ββββ)
86:14
89:11
65:35
60:40
99:1
87:13
% yield
56
89
79
98
67
72
T(°C)
25
-78
-78
25
-78
-78
t(h)
24
6
48
24
3
24
R1
Me
Me
Me
Me
Me
Ph
1.5 equiv TiCl4R = MeThiol = HSCH2CO2Me
Rχ Rχ
30-Favor SD-Wu 3/10/00 10:33 AM
Diastereoselective Thiolphenol Additions to Unsaturated Amides
NO R
O O
OCPh3
% de
86
96
89
98
70
% yield
90
91
71
90
64
SLi0.08 equiv
1 equiv Mg(ClO4)2CH3CH2CN, -78 °C
1-3 h
SH
+
6 equiv
NO R
O O
OCPh3
SPh
Tomioka, K.; Muraoka, A.; Kanai, M. J. Org. Chem. 1995, 60, 6188.
R
Me
i-Pr
Bu
Ph
CO2Me
31-Favor SD-Tomioka 3/8/00 4:55 PM
Nishimura, K.; Ono, M.; Nagoka, Y.; Tomioka, K. J. Am. Chem. Soc. 1997, 119, 12974.
R
H
Me
i-Pr
t-Bu
TMS
%yield
99
93
99
99
97
t (h)
3
2
2
1
1
%ee
71
79
85
90
88
Me2N
Ph Ph
O
MeO
MeCO2Me
HS
R
+
0.1 equiv
0.08 equiv 2-R-PhSH
toluene, -20 °C
3 equiv
MeCO2Me
S
R
+
Enantioselective Arylthiolate Additions to αααα,ββββ-Unsaturated Esters
MeO
Ph Ph
OMeN
N
6% ee, 92% yield 15% ee, 86% yield
Other attempted ligands:
LiS
N Nn
Li N
N
N
SMe
Banister, A. J.; Clegg, W.; Gill, W. J. Chem. Soc., Chem. Comm 1987, 850.
monomericpolymeric
32-Favor SE-Tomioka 3/8/00 4:58 PM
Enantioselective Arylthiolate Additions to αααα,ββββ-Unsaturated Esters
Nishimura, K.; Ono, M.; Nagoka, Y.; Tomioka, K. J. Am. Chem. Soc. 1997, 119, 12974.
R
Me
Et
i-Bu
Ph
Bn
%yield
99
99
93
78
98
t (min)
120 (at -78 °C)
18
30
72 (at -40 °C)
30
%ee
97
93
94
70
95
Me2N
Ph Ph
O
OMe
RCO2Me
HS
TMS
+
0.08 equiv
toluene/hexanes (1:1), -60 °C3 equiv
RCO2Me
S
TMS
+
Li
2-TMSPhS
CO2Me
CO2Me
96 cis 82 33
92 trans 10 33
83 84 60 (at -20 °C)
33-Favor SE-Tomioka-II 3/4/00 10:04 PM
Enantioselective Thiol Additions to Cyclic Enones
O
LaO O
O
O
Na
ONa
Na
O O
O O
O
R1
n
R2 SH10 mol% catalyst
PhCH3:THF (60:1)
-40 °C
O
n R1
SR2
Enone
n = 2, R1 = H
n = 2, R1 = H
n = 2, R1 = H
n = 1, R1 = H
n = 3, R1 = H
n = 2, R1 = Me
% ee
84
681,2
90
56
83
85
% yield
93
87
86
94
87
56
SH
SH
CH2SH
CH2SH
CH2SH
Thiol (R2SH)
+
time (h)
0.3
0.3
14
4
41 (20 mol% cat)
43 (20 mol% cat, -20 °C)
Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 4043.
1 2% ee was observed in THF2 AlLi(binapht)2,
GaNa(binapht)2, LaLi3(binapht)3, LaK3(binapht)3, Labinapht,
29% ee 3% ee
10% ee
39% ee
22% ee
EtO
O
CH2SH 56 41
CH2SH
NA
*
Catalyst
*
*
*
34-Favor SE-Shibasaki 3/8/00 4:58 PM
Enantioselective Thiol Additions to Enones
O
LaO O
O
O
Na
ONa
NaR SH
Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 4043.
O
LaO OH
O
O
Na
O
Na
Na-S
R
O
O
LaO OH
O
O
Na
O
Na
Na-S
R
O
SR
O
SR
O *
*
*
*
*
*
*
*
+
R = 2.9%(R)-LSB
2.423 Å2.425 Å
La O
35-Favor SE-Shibasaki-II 3/8/00 9:08 AM
Catalytic Asymmetric Protonations in Michael Additions of Thiols to Enones
EtS
O
R
SH
t-Bu
+ EtS
O
R
10 mol% catalyst
CH2Cl2, -78 °C
Metal
La
Sm
Sm
Sm
Sm
Sm
%ee
88
93
88
90
87
84
% yield
90
86
89
78
89
98
R
Me
Me
Me
i-Pr
Bn
Ph
Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 4043.
2 mol% cat, 10 mmol scale
O
LaO O
O
O
Na
ONa
Na
O O
O O
*
Catalyst
*
*
*
S
t-Bu
36-Favor SE-Shibasaki-III 3/10/00 9:53 AM
Enantioselective Thiol Additions to Unsaturated Imides
O
ON N
O
Ph Ph
NO Me
O O
NO Me
O O SAr R
Ph*
o-Tolyl
Mesityl
β-Napht
α-Napht
%ee
94
95
96
91
55
% yield
84
99
36
88
92
Kanemasa, S.; Oderaotoshi, Y.; Wada, E. J. Am. Chem. Soc. 1999, 121, 8112.
NMe2 NMe210 mol%
ZnI2, Zn(OTf)2, Mg(ClO4)2, andZn(ClO4)2•6H2O, and Sn(OTf)2 all gave satisfactory catalytic activity with poor enantioselictivity.
Perchlorates of Cu(II), Fe(II), and Mn(II) showed only low catalytic activity.
Anhydrous catalyst gave no ee.
%ee
80
89
95
87
87
% yield
quant
82
84
94
73
THF, no proton sponge, 24 h, rt
CH2Cl2/THF (10:1), 96 h, 0 °C
*in CH2Cl2 only afforded 79% ee, 81% yield
Ligand:
10 mol% each ligand, Ni(ClO4)2•6H2O
1.1 equiv
RSH +
37-Favor SE-Kanemasa 3/8/00 4:57 PM
Enantioselective Thiol Additions to Unsaturated Imides
NO Me
O O
NO Me
O O SAr10 mol% each ligand, metal salt
Kanemasa, S.; Oderaotoshi, Y.; Wada, E. J. Am. Chem. Soc. 1999, 121, 8112.
SH
+
1.1 equiv
O
ON N
O
Ph Ph
Ligand:
38-Favor SE-Kanemasa-II 3/7/00 11:28 PM
Conjugate Addition of Chlorine to αααα,ββββ-Unsaturated Chiral Amides
NNH
R
O O
%de
32
66
10
78
60
48
% yield
50
86
72
54
50
29
Kishikawa, K.; Furusawa, A.; Kohmoto, S.; Yamamoto, M.; Yamada, K. J. Org. Chem. 1993, 58, 7296.
1 equiv TiCl4
PhCH3, rt, 1h
R
Me
Et
Pr
Me
Et
Pr
Ar =
Ph
Ph
Ph
1-Napht
1-Napht
1-Napht
NNH
R
O O Cl
Me
ON
Rχ
NH
H
Me
Ti
Cl Cl
ClCl
OOH
Me
ON
Rχ
NH
HMe
Ti
ClCl
Cl Cl
O OH
+
+
+
+
Author's Stereochemical Rational
favored unfavored
39-Favor ClD-Kishikawa 3/7/00 9:06 PM
Bu
Conjugate Addition of Chlorine to αααα,ββββ-Unsaturated Chiral Imides
NO R2
O O
dr
50:50
75:25
83:17
86:14
92:8
>99:1
>99:1
% yield
30
98
80
90
98
80
80
Cardillo, G.; Di Martino, E.; Gentilucci, L.; Tamasini, C.; Tomasoni, L. Tetrahedron: Asymm. 1995, 6, 1957.
NH
R1R1
3 equiv Lewis acid
-78 °C, CH2Cl2
Lower yields (20-30%) were obtained with 1 equiv of Lewis acid with the same diastereoselectivity.
R2
Me
Me
Me
Me
Me
n-Pr
n-Pr
R1
H
Me
n-Pr
n-Bu
n-Bu
n-Bu
n-Bu
Lewis acid
BCl2-i-OPr
BCl2-i-OPr
BCl2-i-OPr
BCl2-i-OPr
BCl2-OMe
BCl2-i-OPr
BCl2-OMe
NO R2
O O
NH
R1R1
Cl
imide hydrolysis: LiOH/H2O2 80% yield
NO
O
OR2
HN Bu
BCl
OPrCl
si face favored
re face unfavored
Stereochemical Rational
40-Favor ClD-Caridillo 3/6/00 6:40 PM
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