applications of radical reactions in asymmetric …...brandon meyers michigan state university...
TRANSCRIPT
Applications of Radical Reactionsin Asymmetric Synthesis
Brandon MeyersMichigan State UniversityDepartment of Chemistry
November 19, 2008
Outline
• Introduction– Importance of radical reactions– Challenges of stereochemistry
• Methods employed to achieve asymmetriccontrol– Chiral Auxiliary– Chiral Acid– Organocatalysis
General Bond Forming Conditions
• Acidic (Cationic)
• Basic (Anionic)
• Neutral (Radical)
n
-HF3B!O
H
HF3B!OH
I
H
HHHO
H
HH
HO IHO
H
HH
! !
INa Na
H3C Br H3C Br
Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic Chemistry. Oxford: University Press. 2001
Reversal of Reactivity
Giese, B.; Tetrahedron, 1985, 41, 4025
OLDA
O
OBu3SnHO
Br
LDA!H
Bu3Sn!Br
nucleophilic carbanion
electrophilicradicalAIBN
I
Homolytic
Cleavage
Heterolytic
CleavageI
I
electrophilic carbocation
nucleophilicradical
Radicals Stabilized by ElectronDonating Groups
Parsons, A.F. An Introduction to Free Radical Chemistry, Oxford: Blackwell Science, 2000, p. 40
O
R
O
R
Energ
y nonbondinglone pairs
RadicalSOMO
Nucleophilic Radical
Radicals Stabilized by ElectronWithdrawing Groups
O
Energ
y
!
Ononbondinglone pairs
O !"RadicalSOMO
Parsons, A.F. An Introduction to Free Radical Chemistry, Oxford: Blackwell Science, 2000, p. 40
O
H
H !!
Electrophilic Radical
Early Problems of Stereochemistry
• Synthesis of Sativene & Capocamphene
Br
O
Bu3SnH
PhCO3tBu, h!
benzene
X X
X = O (37%)X = CH2 - Sativene
X = O (25%)X = CH2 - Capocamphene
Bakuzis, P.; Campos, O.O.S.; Bakuzis, M.L.F. J. Org. Chem., 1976, 41, 3261
Methods for Asymmetric Control
Chiral Auxiliary, XC
Chiral Acid, AC
Organocatalysis
XC
O
N
R1
ORXC
OHN OR
R1
*
O
AC
R
R1 O
AC
R
R1
*
N
N
R
O
R1!LGO
R
R1*H
Sultam & Oxazolidinone Auxiliaries
Dipole-dipolecontrol
Lewis acid chelation
S
N H
R'O
O
O O
N
O
OMR'
H
RR* *
Dipole-Dipole Chiral Auxiliary
Naito, T; Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K. J. Org. Chem., 2000, 65, 176-185
S
NHMeO
O
H
NOBn
1.0 eq. Me3Al
Cl(CH2)2Cl
reflux
O
H
NOBn
SO2
N
90% yield
O
O
(1R)-(+)-2,10-camphorsultam0.67 eq.glyoxylic
oxime ether
O
H
NOBn
SO2
N
5.0 eq. R-I, CH2Cl22.5 eq. Bu3SnH
2.0 eq. BF3·OEt25.0 eq. Et3B, -78 ˚C
O
R
NHOBn
SO2
N
Mechanism
Bu3Sn I!R Bu3Sn!I R
O
NOBn
S
N
O
OR
O
NHOBn
S
N
O
OR
HSnBu3
ONOBn
S
N
O
OR
O
NOBn
S
N
O
OR
Substrate Scope
O
H
NOBn
SO2
N
5.0 eq. R-I, CH2Cl22.5 eq. Bu3SnH
2.0 eq. BF3·OEt25.0 eq. Et3B, -78 ˚C
O
R
NHOBn
SO2
N
1
Entry RI Product
Isolated
Yield (%) dr of 1
1 i-Pr-I 1a 80 096 : 4
2 Et-I 1b 80 095 : 5
3 t-Bu-I 1c 83 >98 : 2
4 i-Bu-I 1d 83 097 : 3
5 c-Hex-I 1e 86 096 : 4
Naito, T; Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K. J. Org. Chem., 2000, 65, 176-185
Preferred Site of Addition
Naito, T; Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K. J. Org. Chem., 2000, 65, 176-185
anti, s-cis
anti, s-trans syn, s-cis syn, s-trans
Note: =O O
ONOBn
S
N
O
O
R
R
O
NOBnS
N
O
O
S
N
O
O
NOBn
OS
N
O
O
O
BnON
Reduction of Oxime Ether andRemoval of Chiral Auxiliary
Naito, T; Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K. J. Org. Chem., 2000, 65, 176-185
O
R
NHOBn
SO2
N 0.7 eq. Mo(CO)6
H2O, MeCN, reflux
O
R
NH2
SO2
N
1 N LiOH-THF (1:4)O
R
NH2HO
R = i-Pr, 88% yield
Synthesis of D-Valine
R = i-Pr, 88% yield
O
R
NH2
SO2
N
55% overall yield, 4 steps
Lewis Acid Chelationto Chiral Auxiliary
Sibi, M.P.; Liu, P.; Ji, J.; Hajra, S.; Chen, J.-X. J. Org. Chem., 2002, 67, 1738-1745
HO CO2Et
O 1. (COCl)2, THF
2.
n-BuLi, -78 ˚C
CO2Et
O
87% yield, two steps
HN
OO
Ph
Ph
NO
O
Ph
Ph
CO2Et
O i-Pr!I (10 eq)
Sm(OTf)3 (1.0 eq)
Bu3SnH (6.0 eq)
Et3B (3.0 eq), O2
CH2Cl2/THF (4:1), -78 ˚C
95% yielddr = 29:1
NO
O
Ph
Ph
N CO2Et
O
O
O
Ph
Ph
Stereoselective Model
Sibi, M.P.; Liu, P.; Ji, J.; Hajra, S.; Chen, J.-X. J. Org. Chem., 2002, 67, 1738-1745
Activates !"carbon to imidecarbonyl
BlocksSi-face
N CO2Et
O
O
O
PhPh
Sm
OTf
OTfTfO
i-Pr
i-Pr
O
OOH
OH
Synthetic Application:(−)-Enterolactone
• Previous Synthesis:– Chenevert, R.; et al. 7 steps, 35%
yield• Key Step: Enzyme-catalyzed
esterification
Chenevert, R.; Mohammadi-Ziarani, G.; Caron, D.; Dasser, M.; Can. J. Chem., 1999, 77, 223
Sibi, M.P.; Liu, P.; Ji, J.; Hajra, S.; Chen, J.-X. J. Org. Chem., 2002, 67, 1738-1745
Lewis Acid Chelationto Chiral Auxiliary
N CO2Et
O Et
O
O
Ph
Ph
17% yield
BEt3 O2 Et2BOO Et
CO2Et
O
Sm(OTf)3 (1.0 eq)
Bu3SnH (6.0 eq)
Et3B (3.0 eq), O2
CH2Cl2/THF (4:1), -78 ˚C
OCH3Br
71% yield
NO
O
Ph
Ph
N CO2Et
O
O
O
Ph
Ph
OMe
(10 eq)
Total Synthesis of (–)-Enterolactone
Sibi, M.P.; Liu, P.; Ji, J.; Hajra, S.; Chen, J.-X. J. Org. Chem., 2002, 67, 1738-1745
N CO2Et
O
O
O
Ph
Ph
OMe
3-OMeC6H4-CH2I
NaHMDS, THF
-78 ˚C to -54 ˚C N CO2Et
O
O
O
OMe
PhPh
OMe
LiOH
H2O2 HO CO2Et
O
OMe
OMe
1.1.5 eq. BH3/THF
-15 ˚C
2. PPTS, reflux
50% yield 88% yield
O
OOMe
OMe
78% yield,two steps
4.0 eq. BBr3
0 ˚C to -18 ˚C
O
OOH
OH
88% yield
1
Methods for Asymmetric Control
Chiral Auxiliary, XC
Chiral Acid, AC
Organocatalysis
N
N
R
O
R1!LGO
R
R1*H
XC
O
N
R1
ORXC
OHN OR
R1
*
O
AC
R
R1 O
AC
R
R1
*
Types of Chiral Acids
• Lewis Acids
• Brønsted Acid
N
H H N
OH
OCH3
H2PO2
Quinine, QP
N
OO
N
MgI2
O
N N
O
Ph PhMgBr2
Chiral Lewis Acid Chelation
Naito, T; Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K. J. Org. Chem., 2000, 65, 176-185
O
H
NOBn
SO2
N
5.0 eq. R-I, CH2Cl22.5 eq. Bu3SnH
2.0 eq. BF3·OEt25.0 eq. Et3B, -78 ˚C
O
R
NHOBn
SO2
N
R = i-Pr 80% yield, dr = 96:4
MeONOBn
O
H
O
N N
O
Ph PhMgBr2
i-Pr-I, Bu3SnHBEt3, -78 ˚C
MeONHOBn
O
97% yield, 52% ee
Model for Selectivity
Naito, T; Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K. J. Org. Chem., 2000, 65, 176-185
Re-face open
R
N
Mg
N
O
O
N
OMeH
O
BnO
Cho, D.K.; Jang, D.O. Chem. Commun., 2006, 5045-5047
Chiral Brønsted Acids
• Quaternary Ammonium Salts ofHypophosphorous Acid
N
H H N
OH
OCH3
N
HHN
OH
OCH3
H2PO2
H2PO2
Quinine, QP Quinidine, QDP
Entry RI Product
Isolated
Yield (%)
2a Yield
(%)
er of 2
R : S
1 i-Pr-I 2b 83 7 21 : 79
2 c-Hex-I 2c 80 10 21 : 79
3 t-Bu-I 2d 60 30 01 : >99
4 1-Ad-I 2e 45 35 01 : >99
5 n-Oct-I 2f 50 25 40 : 60
Cho, D.K.; Jang, D.O. Chem. Commun., 2006, 5045-5047
Quinine Results
N
H H N
OH
OCH3
H2PO2
Quinine, QP
HO
O
H
NOBn
2 eq. QP, 5 eq. R-I0.5 eq. BEt3, O2
CH2Cl2/H2O (1:1)4 h, rt
HO
O
R
NHOBnHO
O
Et
NHOBn
1 2 2a
Entry RI Product
Isolated
Yield (%)
2a Yield
(%)
er of 2
R : S
1 i-Pr-I 2b 82 10 >62 : 38
2 c-Hex-I 2c 82 9 >72 : 28
3 t-Bu-I 2d 62 27 >99 : 1
4 1-Ad-I 2e 47 37 >99 : 1
5 n-Oct-I 2f 48 30 >58 : 42
Cho, D.K.; Jang, D.O. Chem. Commun., 2006, 5045-5047
Quinidine Results
N
HHN
OH
OCH3
H2PO2
Quinidine, QDP
HO
O
H
NOBn
2 eq. QDP, 5 eq. R-I0.5 eq. BEt3, O2
CH2Cl2/H2O (1:1)4 h, rt
HO
O
R
NHOBnHO
O
Et
NHOBn
1 2 2a
Model for Enantioselectivity
• Quinine versus Quinidine
Cho, D.K.; Jang, D.O. Chem. Commun., 2006, 5045-5047
N
H H N
OH
OCH3
H
NO
HO
O
R
Si-faceopen
H2PO2 N
HHN
OH
OCH3
H2PO2
H
N O
OH
O
R
Re-faceopen
Sibi, M.P.; Lee, S.; Lim, C.J.; Kim, S.; Subramaniam, R.; Zimmerman, J. Org. Lett., 2006, 8, 4311-4313
O
N N
O
Ph Ph
Mg(NTf2)2
Chiral Lewis Acid
HO
O
Ph I
66% yield, 75% ee
HO
O
Ph
0.3 eq. Chiral L.A.
2.0 eq. Bu3SnH
3.0 eq. Et3B/O2
CH2Cl2, -78 0C, 24 h
Conjugate Radical Addition
• Enantioselective addition to α'-hydroxy enone
Scope of α'-Hydroxy Enone andAlkyl Halide Substrates
Sibi, M.P.; Lee, S.; Lim, C.J.; Kim, S.; Subramaniam, R.; Zimmerman, J. Org. Lett., 2006, 8, 4311-4313
Entry R1 R2 Product
Isolated
Yield (%) ee (%)
1 CH2CH2Ph t-Bu 1a 66 75
2 CH2CH2Ph i-Pr 1b 85 68
3 CH2CH2Ph n-Pr 1c 63 72
4 CH2CH2Ph Et 1d 87 72
5 Ph t-Bu 2a 90 78
6 Ph i-Pr 2b 78 78
7 Ph n-Pr 2c 68 86
8 Ph Et 2d 82 80
HO
O
R1
0.3 eq. Chiral L.A.
2.0 eq. Bu3SnH
3.0 eq. Et3B/O2
CH2Cl2, -78 0C, 24 h
HO
O
R1
R2
5.0 eq. R2-I
1 R = CH2CH2Ph2 R = Ph
1a-d
2a-d
O
N N
O
Ph PhMg(NTf2)2
Chiral Lewis Acid
Model for Enantioselectivity
Sibi, M.P.; Lee, S.; Lim, C.J.; Kim, S.; Subramaniam, R.; Zimmerman, J. Org. Lett., 2006, 8, 4311-4313
X=NTf2
MgN
N
O
O
O
X
O
X
H
R1
R2
Re-faceopen
Synthetic Application: (+)-Ricciocarpin A
Agapiou, K.; Krishe, M. Org. Lett., 2003, 5, 1737-1740
O
O
O
H
H
Ricciocarpin A
• Previous Synthesis:– Krishe, M.; Agapiou, K.– 6 steps, 14% yield– Key step: Michael
cycloisomerization(+)-
Radical Conjugate Addition
Sibi, M.P.; He, L. Org. Lett., 2004, 6, 1749-1752
N
O
O
N
NO
OO
OBn
Mg
R
N
O
O
O
OBn
N
OO
N
MgI2
BrCl
5.0 eq. Et3B / O2, -78 ˚C
N
O
O
O
OBn
Cl
5.0 eq. Bu3SnH
5.0 eq.84% yield, 97% ee
O
O
O
H
H
Ricciocarpin A
Preparation of AldehydeIntermediate
Sibi, M.P.; He, L. Org. Lett., 2004, 6, 1749-1752
Sm(OTf)3CH3OH
MeO
O
OBn
Cl
NaIAcetone
98%
LiHMDS-78 ˚C to rt
97%
OMe
O
H
H
OBn
1. Pd(OH)2/H2, Hex/EtOAc, -10 ˚C
2. TEMPO, KBr, NaOCl, std. NaHCO3, 0 ˚COMe
O
H
H
CHO76% over two steps
N
O
O
O
OBn
Cl
OMe
O
HOBn
I
95%
O
O
O
H
H
Ricciocarpin A
Synthesis of Ricciocarpin A
Sibi, M.P.; He, L. Org. Lett., 2004, 6, 1749-1752
OMe
O
H
H
CHO
O
(i-PrO)3Ti
Solvent, -78 ˚C2.0 eq. s-BuLi
O
OH
H
O
Ricciocarpin A
O
OH
H
O
2.0 eq.
41% overall yield
85%
5.7 : 1
Methods for Asymmetric Control
Chiral Auxiliary, XC
Chiral Acid, AC
Organocatalysis
XC
O
N
R1
ORXC
OHN OR
R1
*
O
AC
R
R1 O
AC
R
R1
*
N
N
R
O
R1!LGO
R
R1*H
MacMillan Enamine Chemistry
Beeson, T.D.; Mastracchio, A.; Hong, J.B.; Ashton, K.; MacMillan, D.W.C. Science, 2007, 316, 582-585
NH
N
O
R1 R2
Me
H
O
R
N
N
O
R1 R2
Me
R
N
N
O
R1 R2
Me
R
SET
N
N
O
R1 R2
Me
R
N
N
O
R1 R2
Me
R
TMS O
R
*H
Previous Organocatalytic Research
• Iminium & Enamine Organocatalysis
Beeson, T.D.; Mastracchio, A.; Hong, J.B.; Ashton, K.; MacMillan, D.W.C. Science, 2007, 316, 582-585
NH
H
O
R N
R
-H2O -2 e-
N
R
Enamine ActivationHOMO catalysis
Iminium ActivationLUMO catalysis
aldehyde amine catalyst
“These two modes of catalyst activation haveprovided more than 60 asymmetric metricmethodologies over the past 7 years.”
- Dr. David MacMillan
Hypothesis - SOMO Activation
Beeson, T.D.; Mastracchio, A.; Hong, J.B.; Ashton, K.; MacMillan, D.W.C. Science, 2007, 316, 582-585
NH
H
O
N
Et
N
Et
SET
Butanal
IP = 9.8 eV
Pyrrolidine
IP = 8.8 eV
Enamine
IP = 7.2 eV
Et
SOMO-activated
N
N
O Me
Ph
N
N
O Me
Ph
Hypothesis - Enantioselectivity
• Density Functional Theory Model ofImidazolidinone Catalyst
Beeson, T.D.; Mastracchio, A.; Hong, J.B.; Ashton, K.; MacMillan, D.W.C. Science, 2007, 316, 582-585
N
N
O Me
Ph
Applications of SOMO-Organocatalysis
• α-Substitution of Aldehydes– Allylation − Enolation
– Oxyamination − Alkylation
– Vinylation
H
O
R R1
*
α-Allylation of Aldehydes
• General Reaction
Beeson, T.D.; Mastracchio, A.; Hong, J.B.; Ashton, K.; MacMillan, D.W.C. Science, 2007, 316, 582-585
CAN = Ceric Ammonium Nitrate
(NH4)2Ce(NO3)6
H
O
R
R1
SiMe3 NH
NO
Ph
CAN (2.5 equiv.)
NaHCO3, 24 hDME, -20 ˚C
H
O
R
R1
aldehyde2.5 equiv.allylsilane 20 mol% cat. 1 product
CF3COOH
Beeson, T.D.; Mastracchio, A.; Hong, J.B.; Ashton, K.; MacMillan, D.W.C. Science, 2007, 316, 582-585
H
O
81% yield, 91% ee
H
O
75% yield, 92% ee
H
O
O
72% yield, 87% ee
H
O
OBz
72% yield, 95% ee
H
O
75% yield, 94% ee
H
O
70% yield, 93% ee
NBoc
Organocatalytic Allylation:Scope of Aldehyde Substrate
H
O
R SiMe3 H
O
R20 mol%
CAN (2.5 eq.), -20 ˚C
NaHCO3, DME, 24 h
NH
NO
Ph
TFA
Organocatalytic Allylation:Scope of Allylsilane Substrate
Beeson, T.D.; Mastracchio, A.; Hong, J.B.; Ashton, K.; MacMillan, D.W.C. Science, 2007, 316, 582-585
H
O
C6H13
88% yield, 91% ee
H
O
C6H13
77% yield, 88% ee
Ph
H
O
C6H13
87% yield, 90% ee
H
O
C6H13
81% yield, 90% ee
Ph CO2Et
H
O
C6H13 SiMe3H
O
RR1
R1
20 mol%NH
NO
Ph
TFA
CAN (2.5 eq.), -20 ˚C
NaHCO3, DME, 24 h
α-Heteroarylation &Olefin Cyclization of Aldehydes
Beeson, T.D.; Mastracchio, A.; Hong, J.B.; Ashton, K.; MacMillan, D.W.C. Science, 2007, 316, 582-585
H
O
C6H13 N
Boc
H
O
NBoc 85% yield
84% ee
H
O 20 mol%
CAN (2.5 eq.), -10 ˚C
LiCl, THF, 24 h
85% yield
dr >8:1
95% ee
H
O
Cl
NH
NO
Ph
TFA
20 mol%
CAN (2.5 eq.), -20 ˚C
NaHCO3, DME, 24 h
NH
NO
Ph
TFA
+
Mechanistic Investigation
Beeson, T.D.; Mastracchio, A.; Hong, J.B.; Ashton, K.; MacMillan, D.W.C. Science, 2007, 316, 582-585
H
N
C6H13
OMe
Ph
2.5 equiv.
H
N
C6H13Ph
OMe
N
N
O
Bn t-Bu
O
Bn t-Bu
H
N
C6H13Ph
OMe
NO
Bn t-Bu
radical
cation
Mechanistic Investigation
Beeson, T.D.; Mastracchio, A.; Hong, J.B.; Ashton, K.; MacMillan, D.W.C. Science, 2007, 316, 582-585
H
O
C6H13
OMe
Ph
ONO2
65% yield
H
O
C6H13
Ph
OMe
ONO2
H
N
C6H13H
N
C6H13
OMe
Ph
Ph
OMe
N N
O O
Bn t-BuBn t-Bu
H
N
C6H13
Ph
OMe
NO
Bn t-Bu
not observed
H
N
C6H13Ph
OMe
NO
Bn t-Bu
radical
cation
Applications of SOMO-Organocatalysis
• α-Substitution of Aldehydes– Allylation − Enolation
– Oxyamination − Alkylation
– Vinylation
H
O
R R1
*
H
O
R
O
N
Sibi, M.P.; Hasegawa, M. J. Am. Chem. Soc., 2007, 129, 4124-4125
α-Oxyamination of Aldehydes
H
O
N
O
1. Catalyst,
Cp2FeBF4
2. NaBH4, rt4.0 eq.
H
OH
Ph Ph
O
Zn(OAc)2
H
OH
Ph
OH
enantioselective1,2-diol synthesis
N
Sibi, M.P.; Hasegawa, M. J. Am. Chem. Soc., 2007, 129, 4124-4125
Catalyst Optimization
Entry Catalyst mol % time, h
Isolated
Yield (%) ee (%)
1 none 24 79
2 1 100 1 61
3 2 100 1 63 76
4 2 20 1 78 64
5 3 20 1 87 80
6 4 20 1 71 -3
NH
CO2HNH
NH
N
O
Ph
NH
N
O
Ph
HOTf
HBF4
1 2
3 4
H
O
N
O
1. Catalyst, THF (1.0 M), rt
1.0 eq. Cp2FeBF4
2. 2.0 eq. NaBH4, rt
4.0 eq.
H
OH
Ph Ph
OTEMP
Scope of Aldehydes
Sibi, M.P.; Hasegawa, M. J. Am. Chem. Soc., 2007, 129, 4124-4125
Entry R Temp, ˚C time, h
Isolated
Yield (%) ee (%)
1 C6H5 r.t. 2 74 32
2 C6H5CH2 r.t. 2 80 71
3 -10 24 68 82
4 C6H5CH2CH2 r.t. 2 78 60
5 -10 24 64 84
6 4-MeO-C6H4CH2CH2 r.t. 2 77 81
7 -10 24 64 86
8 4-NO2-C6H4CH2CH2 r.t. 2 74 75
9 -10 24 75 82
10 (CH3)2CH r.t. 24 74 0
HR
O
N
O
1. 20 mol% 3, DMF (1.0 M)
0.1 eq. FeCl3, 0.3 eq. NaNO2
temp., time
2. 2.0 eq. NaBH4, rt
4.0 eq.
HR
OH
OTEMP
NH
N
O
PhHBF4
3
Model for Enantioselectivity
Sibi, M.P.; Hasegawa, M. J. Am. Chem. Soc., 2007, 129, 4124-4125
N
NO
PhN
NO
Si-faceopen
Applications of SOMO-Organocatalysis
• α-Substitution of Aldehydes– Allylation − Vinylation
– Oxyamination − Alkylation
– Enolation
H
O
R R1
*
H
O
R
O
N
H
O
R
R1
O
*
α-Enolation of Aldehydes
Jang, H.Y.; Hong, J.B.; MacMillan, D.W.C. J. Am. Chem. Soc., 2007, 129, 7004-7005
Importance of Reaction:
H
O
R
OTMS
R1H
O
R
R1
O
!-substituted1,4-dicarbonyl
One step reaction to form umpolung polarity without going through anionic mechanism
Organocatalytic Enolation:Scope of Aldehyde Substrate
Jang, H.Y.; Hong, J.B.; MacMillan, D.W.C. J. Am. Chem. Soc., 2007, 129, 7004-7005
H
O
ROTMS
PhH
O
R
Ph
O
20 mol%
CAN (2 eq.), DTBP (2 eq.)
acetone, H2O, 24 h, -20˚C
NH
NO
Ph
TFA
H
O
hexyl
Ph 85% yield
90% eeO
H
O
Ph
O7
H
O
Ph
O
H
O
Ph
O
92% yield
92% ee
74% yield
93% ee
77% yield
91% ee
H
O
Ph
O
OBn
2
71% yield
90% ee
H
O
Ph
O
NBoc
84% yield
95% ee
Organocatalytic Enolation:Scope of Enolsilane Substrate
Jang, H.Y.; Hong, J.B.; MacMillan, D.W.C. J. Am. Chem. Soc., 2007, 129, 7004-7005
t-Bu
OTBS
H
O
hexyl
t-Bu
O
74% yield
96% ee
OTBS
t-BuH
O
hexyl O
55% yield
92% ee
Enolsilane Product Enolsilane Product
H
O
hexylOSiR3
R1 H
O
hexyl
R1
O
20 mol%
CAN (2 eq.), DTBP (2 eq.)
DME, H2O, 24 h, -20˚C
NH
NO
Ph
TFA
H
O
hexyl
77% yield
92% eeO
O
H
O
hexyl
77% yield
92% eeO
OTMS
O
OTMS
Applications of SOMO-Organocatalysis
• α-Substitution of Aldehydes– Allylation − Vinylation
– Oxyamination − Alkylation
– Enolation
H
O
R R1
*
H
O
R
R1
O
*
H
O
R
R1
H
O
R
O
N
Kim, H.; MacMillan, D.W.C. J. Am. Chem. Soc., 2008, 130, 398-399
H
O
R H
O
R
R1
20 mol%NH
N
O
Ph
TFA
KF3BR1
enantioenriched!-vinyl aldehyde
aldehyde vinyl-BF3K
Organocatalytic α-Vinylation ofAldehydes
Importance of Reaction:
Form β,γ-unsaturated aldehydes without olefin transpostion
Organocatalytic Vinylation ofAldehydes
H
O
R H
O
R
R1
20 mol%NH
N
O
Ph
TFA
KF3BR1
enantioenriched!-vinyl aldehyde
aldehyde vinyl-BF3K
BF3K
R1
N
NO
R
N
N
O
Ph
R
KF3B
R1
- 1 e-N
N
O
Ph
R
KF3B
R1
Kim, H.; MacMillan, D.W.C. J. Am. Chem. Soc., 2008, 130, 398-399
Organocatalytic Vinylation:Scope of Aldehyde Substrate
Kim, H.; MacMillan, D.W.C. J. Am. Chem. Soc., 2008, 130, 398-399
H
O
RH
O
R
Ph20 mol%
CAN (2.5 eq.), -50 ˚C
NaHCO3, DME, H2O, 24 h
NH
NO
Ph
TFA
KF3BPh
H
O
Me
Ph 72% yield
94% eeH
O
Ph
4
H
O
Ph
H
O
Ph
78% yield
95% ee
82% yield
96% ee
79% yield
93% ee
H
O
Ph
OBn
2
78% yield
93% ee
H
O
Ph
NBoc
76% yield
96% ee
Et
Organocatalytic Vinylation:Scope of Vinyl Trifluoroborate Salt
Kim, H.; MacMillan, D.W.C. J. Am. Chem. Soc., 2008, 130, 398-399
H
O
hexylH
O
hexyl
R
R1
20 mol%
CAN (2.5 eq.), -50 ˚C
NaHCO3, DME, H2O, 24 h
NH
NO
Ph
TFA
KF3BR
R1
R1 = H, Me
H
O
hexyl Me
78% yield
95% eeH
O
hexyl
81% yield
94% ee
H
O
hexyl
77% yield
95% ee
Cl
H
O
hexyl
61% yield
95% ee
OMe
H
O
hexyl
82% yield
89% ee6
H
O
hexyl
84% yield
90% ee
Applications of SOMO-Organocatalysis
• α-Substitution of Aldehydes– Allylation − Enolation
– Oxyamination − Alkylation
– Vinylation
H
O
R R1
*
H
O
R
R1
O
*
H
O
R
R1
H
O
R
O
N
H
O
R
R1
R2
O
**
α-Alkylation of Aldehydes
Nicewicz, D.A.; MacMillan, D.W.C. Science, 2008, 322, 77-80
H
O
RR2
O
Br
R1
H
O
R
R2
O
R1
aldehyderacemic
!-bromocarbonyl
enantioenriched!-alkylated
"-ketoaldehyde
NH
N
MeO
MeMe
Me
Me
TfOH
Ru2+
N
N
N N
N N
Photoredox CatalystOrganocatalyst
Organocatalysis
Photoredox Catalysis
Catalytic Cycles
Nicewicz, D.A.; MacMillan, D.W.C. Science, 2008, 322, 77-80
N
N
R
t-Bu
O
NH
N
t-Bu
O
H
O
R
catalyst 6aldehyde 7
8Organocatalytic
Cycle
N
N
R
OH3C
Si-faceopen5
R1
ON
N
t-Bu
O
R
R1
9
Ru(bpy)3+ (3)
reductant
*Ru(bpy)32+ (2)
oxidant
Ru(bpy)32+
photoredox catalyst 1
PhotoredoxCatalyticCycle
SET
Br!
R1(O)C Br
4
photon source
5
R1
O
SET
N
N
R
t-Bu
O
R1
10
H R1
O
R
11
Organocatalytic Alkylation:Scope of Aldehyde Substrate
Nicewicz, D.A.; MacMillan, D.W.C. Science, 2008, 322, 77-80
H
O
hexyl
93% yield
90% eeH CO2Et
O
4
H CO2Et
O
H CO2Et
O
86% yield
90% ee
83% yield
95% ee
92% yield
90% ee
H CO2Et
O
63% yield
93% ee
H CO2Et
O
NBoc
66% yield
91% ee
Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
H
O
R
EtO
O
Br
O
OEt
NH
NMeO
MeMe
MeMe
TFA20 mol%
H
O
R
CO2Et
CO2Et
0.5 mol% Ru(bpy)3Cl2 2.0 eq 2,6-lutidine, DMFfluorescent light, 23 ˚C2.0 eq.
Organocatalytic Alkylation:Scope of α-Bromocarbonyl Substrate
Nicewicz, D.A.; MacMillan, D.W.C. Science, 2008, 322, 77-80
H
O
Hex
R
Br
O
R1
NH
NMeO
MeMe
MeMe
TFA20 mol%
0.5 mol% Ru(bpy)3Cl2 2.0 eq 2,6-lutidine, DMFfluorescent light, 23 ˚C
H
O
Hex
R
R1
O
2.0 eq.
H
O
Hex O
80% yield
92% ee
H
O
Hex
84% yield
96% ee
H
O
Hex
84% yield
95% ee
NO2
H
O
Hex
87% yield
96% ee
OMe
H
O
Hex
CO2Et 80% yield
88% ee
O
Hex
70% yield
5:1 dr, 99% ee
O
O
O
CH2CF3 CO2Et
t-BuO2C
OO
To Sum Up…
• Asymmetric control is difficult in radicalsynthesis– Fast reactivity– “Planar” structure
• Methods that have been used to controlasymmetry– Chiral Auxiliary– Chiral Acid Chelation– Organocatalysis
Acknowledgements
• Dr. Jetze Tepe• Dr. Babak Borhan• Group Membes: Brandon, Chris, Daljinder,
Jason, Mike, Rahman, Samantha, Thu,Amanda
• Arvind, Camille, Carmin