asymmetric radical reactionsaug 30, 2018 · chiral lewis acid-mediated reactions 12 cyclization...
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Asymmetric Radical Reactions
Zhen Liu 08/30/2018
Contents
– Introduction
– Reactions Using Chiral Auxiliary
– Chiral Lewis Acid-Mediated Reactions
– Transition Metal-Catalyzed Reactions
– Reactions Using Chiral Organocatalysts
– Miscellaneous
2
Contents
3
– Introduction
– Reactions Using Chiral Auxiliary
– Chiral Lewis Acid-Mediated Reactions
– Transition Metal-Catalyzed Reactions
– Reactions Using Chiral Organocatalysts
– Miscellaneous
Introduction–Radical Chemistry
4
R1 R2•
Radical
Features:• Very reactive• Nearly planar (slight pyramidal)
HMe
EtClH2C
(+)-1
Cl2
hυCl
MeEt
ClH2C
(±)-2
CHOMe
Et
(–)-3
DTBP
H
MeEt
(±)-4
iPr iPrΔ
Parsons, A. F. An Introduction to Free Radical Chemistry, Oxford: Blackwell Science 2000.
Radicals Stability:
R2
R3
R1 >R2
R1> R1 hyperconjugation effect
E
RadicalSOMO
π*
n (long pair)
NucleophilicElectrophilic
ORR1
R2
R
O
Brown, H. C. et. al. J. Am. Chem. Soc. 1940, 62, 3435.
Doering, W. von E. et. al. J. Am. Chem. Soc. 1952, 74, 3000.
Introduction–Radical Chemistry
5
Sibi, M. P. et. al. Chem, Rev. 2003, 103, 3263.
RadicalPrecursor
InitiationRadical-1 Radical-2 Neutral
SpeciesPropagation Termination
ChainProcess
The Fate of Radicals
Atom Transfer
Addtion to Neutral Molecule
Fragmentation
Coupling
104–108 dm3•mol–1•s–1
104–108 dm3•mol–1•s–1
105–109 s–1
109 dm3•mol–1•s–1
One example:
Et
Me HBr
DTBP Et
Me Br
Mechanism:
tBuO OtBu hυ or Δ2 tBuO
tBuO H Br tBuOH + Brinitiationsteps
Et
Me + BrEt
Me Br
Et
Me Br H BrEt
Me Br + Br
propagationsteps
Br Br Br2
Et
Me Br BrEt
Me BrBr
terminationsteps
Common radical initiators:
N
CN
Me MeN Me
CN
Me
AIBN
RO OR Et3B
Contents
– Introduction
– Reactions Using Chiral Auxiliary
– Chiral Lewis Acid-Mediated Reactions
– Transition Metal-Catalyzed Reactions
– Reactions Using Chiral Organocatalysts
– Miscellaneous
6
Reactions Using Chiral Auxiliary
7
Porter, N. A. et. al. J. Am. Chem. Soc. 1989, 111, 8311.
Giese, B. et. al. J. Am. Chem. Soc. 1990, 112, 6741.
N NO
O
Porter, Giese and Lindner, 1989
N NO
OtBu
+ N NO
OtBu
tBuHgCl
NaBH4, 25 ºC
40 1:
N NO
O
Giese, 1990
N NO
OtBu
+ N NO
OtBu
tBuHgCl
NaBD4, 25 ºC
13 1:
tBu
D D
NO
OX
NO
OX
Favored Unfavored
vs.
Reactions Using Chiral Auxiliary
8
Naito, T. et. al. J. Org Chem. 2000, 65, 176.
Entry RI Yield (%) d.r.
1
2
3
EtI
iPrI
tBuI
80
80
83
95:5
96:4
>98:2
NS
ONOBn
O
O
R
RAttack from si face is preferred
A
NS
O
NOBnO
O
B
NS
OO
O
C
NOBn
NS
OO
O
D
BnON
NSO2
O
H
NOBn
Naito, 2000
RI (5 eq.), BF3•Et2O (2 eq.)Bu3SnH (2.5 eq.), BEt3 (5 eq.)
DCM, –78 ºCN
SO2
O
R
NHOBn
NSO2
O
iPr
NHOBn Mo(CO)6 (0.7 eq.)
H2O/MeCN, refluxN
SO2
O
iPr
NH2 1N LiOH
THFHO
O
iPr
NH2
D-Valine55% over 4 steps
Reactions Using Chiral Auxiliary
9Sibi, M. P. et. al. J. Org. Chem. 2002, 67, 1738.
N
O
Sibi, 2002
iPrI (10 eq.), Sm(OTf)3 (1 eq.)Bu3SnH (6 eq.), BEt3 (3 eq.)
O2, DCM/THF, –78 ºC
N
O
CO2Et
iPr
CO2EtO O
O O
Ph
Ph
Ph
Ph
95%, d.r. = 29:1
NO
CO2EtO
O
PhPh
Sm OTfTfO OTf iPr
iPr
x
N
OSm(OTf)3 (1 eq.)
Bu3SnH (6 eq.), BEt3 (3 eq.)
O2, DCM/THF, –78 ºCN
OCO2Et CO2EtO O
O O
Ph
Ph
Ph
Ph
Br OMe
(10 eq.)OMe
NaHMDS, THF
I OMe
N
O
CO2EtO
O
Ph
Ph
OMe
OMe
LiOH, H2O2 HO
O
CO2Et
OMe
OMe
50%
88%
1. BH3/THF, –15 ºC
2. PPTS, reflux3. BBr3 (4 eq.)
OO
HOHO
69% for three steps
(–)-Enterolactone
71%
Contents
– Introduction
– Reactions Using Chiral Auxiliary
– Chiral Lewis Acid-Mediated Reactions
– Transition Metal-Catalyzed Reactions
– Reactions Using Chiral Organocatalysts
– Miscellaneous
10
Chiral Lewis Acid-Mediated Reactions
11
Murakata, M. et. al. Tetrahedron1999, 55, 10295.
Hydrogen Atom Transfer
O O
IR
O O
HR
NN
BnO
OBn
(S)-L1
MgI2/Et2OBu3SnH, DCM, –78 ºC
5a, R = CH2OMe 5b, R = CH2OEt5c, R = CH2OBn 5d, R = Me
Entry Substrate Yield (%) ee (%)1234
5a5b5c5d
88 62 (R)84 65 (R)89 58 (R)78 30 (S)
Sibi, M. P. et. al. Angew. Chem. Int. Ed. 2001, 40,1293.
Conjugate Radical Reaction
HN
O
2-Naph CO2MeHN
O
2-Naph CO2Me
R
Mg(ClO4)2/L2 (1.3 eq.)RX, BEt3/O2
Bu3SnH, DCM, –78 ºC
O
N N
O
L2
Entry Yield (%) ee (%)1234
76 8071 6572 85 (R)62 83 (R)
5 54 27 (R)
RXAcBrMeOCH2BrEtIiPrItBuI
Chiral Lewis Acid-Mediated Reactions
12
Cyclization Reaction
O O
OEt
Me Me
BrMe
O
MeCO2Et
Br MeMe
Mg(ClO4)2 (1 eq.)
BEt3,toluene, 4Å MS, –78 ºC
MeMeO
N N
O
tBu tBuL3 (1.1 eq.)
MeMeO
N N
O
tBu tBuMgO O
EtOMe
MeMe
67% (94% ee)
Allylation Reaction
MX2, BEt3/O2DCM, –78 ºC
N
O
BrR1
O
O+ Z N
O
R1O
O+ Z–Br
R2R2
O
N N
O
R3 R3
Entry Yield (%) ee (%)1234
84 42 (S)65 60 (S)
5
R1
MeMe
R2
MeMe
R3
PhPh
MX2 Z(R, R)(R, R)
Config.
Zn(OTf)2 SnBu3Zn(OTf)2 Si(OEt)3
88 90 (R)tBu Me Ph (R, R) Zn(OTf)2 SiMe386 68 (S)tBu Me Ph (R, R) MgI2 SiMe365 88 (R)tBu -(CH2)2- tBu (S, S) MgI2 SiMe3
MX
X ON
ONN
OMe
Me
O
O
H
H
R
R
MX
OON
XNMe
Me
O
O
H
H
R
R
H
NO
H
vs.tBu
tBu
Porter, N. A. et. al. J. Org. Chem. 1997, 62, 6702.
Yang, D. et. al. J. Am. Chem. Soc. 2001, 123, 8612.
Chiral Lewis Acid-Mediated Reactions
13Yoon, T. P. et. al. Science 2014, 344, 392.
Sibi, M. P. et. al. J. Org. Chem. 2001, 123, 9472.
Addition-Trapping Reaction
N
O
PhO
O+ SnBu3 N
O
PhO
O R O
N N
O
L2
MgI2/L2 (30 mol%)RI, BEt3/O2
DCM, –78 ºC
R = iPr, 93%, 37:1 d.r., 93% eeR = tBu, 84%, 99:1 d.r., 97% ee
Cycloaddition Reaction
Ph
O
Me+
Me
O
Me
O O
Ph Me
Me
O O
Ph Me
Eu(OTf)3 (10 mol%)L4 (20 mol%)
[Ru(bpy)3Cl2] (5 mol%)iPr2NEt, MeCN, rt., hυ
Eu(OTf)3 (10 mol%)L5 (30 mol%)
[Ru(bpy)3Cl2] (5 mol%)iPr2NEt, MeCN, rt., hυ
trans-6 (92% ee)71%, 7:1 d.r.
cis-6 (95% ee)78%, 4.5:1 d.r.
ON
Me Me
OH O NHnBuL4
NaBH4
ONH
Me Me
OH O NHnBuL5
Ph
O
Me
*LnM
Ph
O
Me
*LnM
Me
O[2+2]
trans-6 or cis-6
e–
Ru(bpy)32+*
Ru(bpy)32+ Ru(bpy)3+
iPr2NEthυ
Chiral Lewis Acid-Mediated Reactions
14Meggers, E. et. al. Nature 2014, 515, 100.
N
NR2
OR1
+ Br EWG N
NR2
O
R1EWG
Λ-Ir (2 mol%)Na2HPO4 (1.1 eq.)
visible light, 40 ºC
N
NMe
O
Ph
NO2
NO2
N
NMe
O
Me
CN
NO2
N
NiPr
O
Ph
97%, 99% ee 87%, 97% ee
O
Br
86%, 91% ee
NIrN
StBu
NCMeNCMe
StBu
Λ-Ir
+
PF6–
7 8 9
Meggers, 2014
N
NMe
OR Λ-Ir N
NMe
OR
[Ir]
N
NMe
OR
[Ir]
N
NMe
OR
[Ir]
EWG
N
NMe
OR
[Ir]
EWG
AsymmetricCatalysis
7
9 PS
PS+
PS*
PhtoredoxCatalysis
Visible light
SET
Br EWG
Br EWG•–
SET
EWGBr–
Contents
– Introduction
– Reactions Using Chiral Auxiliary
– Chiral Lewis Acid-Mediated Reactions
– Transition Metal-Catalyzed Reactions
– Reactions Using Chiral Organocatalysts
– Miscellaneous
15
Transition Metal-Catalyzed Reactions
16Fu, G. C. et. al. Science 2016, 351, 681.
Fu, G. C. et. al. J. Am. Chem. Soc. 2005, 127, 4594.
Fu, G. C. et. al. Science 2016, 354, 1265.
Cross-Coupling Reactions
NPh
BnO
Br
R1 + R2 ZnX
racemic
NiCl2•glyme (10 mol%)(R)-(iPr)-Pybox (13 mol%)
DMI/THF, 0 ºCNPh
BnO
R2
R1
up to 96% eeup to 90% yield
NN
OO
NiPr iPr(R)-(iPr)-Pybox
R1
X
Bpin
NiCl2•glyme (10 mol%)(S, S)-L6 (13 mol%)
R2ZnBr (1.8 eq.)
DMA/THF, 0 ºC
R1
R2
Bpin
(S, S)-L6 (Ar = o-tolyl)
Ar Ar
MeHN NHMe
up to 95% eeup to 86% yield
racemic
R2N
O
R1
Cl +
racemic(1.2 eq.)
cat. CuCl/(S)-L7hυ (blue LED)
LiOtBu (1.5 eq.)toluene, –40 ºC
up to 99% eeup to 98% yield
R2HN
X R2N
O
R1
NR2
X(S)-L7
P Ph
Transition Metal-Catalyzed Reactions
17Liu, G. et. al. J. Am. Chem. Soc. 2016, 138, 15547.
Buchwald, S. L. et. al. Angew. Chem. Int. Ed. 2013, 52, 12655.
Buchwald, S. L. et. al. J. Am. Chem. Soc. 2015, 137, 8069.
Alkene Difunctionalization Reactions
HO
O
Arn
n = 1, 2
+I
O
CF3
O Cu(MeCN)4PF6 (7.5 mol%)(S, S)-L3 (7.5 mol%)
MTBE, rt.
OOAr
CF3n
MeMeO
N N
O
tBu tBuL3up to 83% ee
up to 88% yield
HO
O
Rn
n = 1, 2
R'•, Cu(MeCN)4PF6/L3 OOR
R'n
OOR
N3n
OOAr
SO2Phn
OOAr
Ar'n
PhI(OAc)2, TMSN3 Ag2CO3, TsCl DTBP, Ar'N2BF4
+I
O
CF3
Cu(MeCN)4PF6 (1 mol%)L2 (1.5 mol%), TMSCN
MeCN, rt.
Me Me
ArAr
CNCF3
O
N N
O
L2up to 99% ee
Transition Metal-Catalyzed Reactions
18
Liu, G. et. al. Science 2016, 353, 6303.
C–H Functionalization
Ar R
cat. CuOAc/L*TMSCN (2–3 eq.)
NFSI (1.5 eq.)C6H6, rt., N2
Ar R
CNR2R2
O
N N
O
R3 R3L*
NC
71%, –97% ee
NC
73%, 97% ee
N3
N
CN
SO2Ph
Cl
76%, 98% ee
NC
80%, 96% ee
S
NPh
N2
MeO2C
O2S NO2
Cat-1 (2 mol%)Benzene, rt.
92%, 96:4 d.r.O2S
MeO2C
NO2
N2
MeO2C
O2S Ar
Cat-1 [Co]MeO2C
O2S Ar
H-abstraction [Co]MeO2C
O2S ArSubstitution
O2S
MeO2C Ar
NN
N NCo
iPr iPr
iPr iPr
NHO
H
H
tBu
NHO
HH
tBu
HN
HNO
OH
H
H
H
tBu
tBu
Cat-1
Zhang, X. P. et. al. Chem. Sci. 2015, 6, 1219.
Contents
– Introduction
– Reactions Using Chiral Auxiliary
– Chiral Lewis Acid-Mediated Reactions
– Transition Metal-Catalyzed Reactions
– Reactions Using Chiral Organocatalysts
– Miscellaneous
19
Reactions Using Chiral Organocatalysts
20
HN
O
I HN
O H
81%, 84% ee
Bu3SnH, BEt3, toluene, –78 ºC
NH
OMeMe
Me
N
O
(2.5 eq.)N
OMeMe
Me
N
O
H O
NH H SnBu3
Hydrogen-bonding Organocatalysts
NHOMe
Me
Me N
O
OPh
NH
O
N
toluene, –40 ºC, hυ
PET catalyst (30 mol%)
NH
O
NN
OMe
Me
Me NO
HOPh
H
N
OH
N
64%, 70% ee
Ph
ONNMe2
HO NHNMe2Ph
O
OP
O
OH
SiPh3
SiPh3
(10 mol%)
90%, 92% ee
[Ir(ppy)2(dtbpy)]PF6 (2 mol%)dioxane, rt., hυ
NH
EtO2C CO2EtH H
Me Me
PhO H
NNMe2
O PO O
O*
Bach, T. et. al. Angew. Chem. Int. Ed. 2004, 43, 5849.
Bach, T. et. al. Nature 2005, 436, 1139.
Knowles, R. R. et. al. J. Am. Chem. Soc. 2013, 135, 17735.
Reactions Using Chiral Organocatalysts
21
Jang, D. O. et. al. Chem. Commun. 2006, 5045.
HO
O
H
NOBn
RI (5 eq.), QP (2 eq.)BEt3 (0.5 eq.)/O2
DCM/H2O, rt.HO
O
R
NHOBn
Entry RI Yield (%) R:S
1
2
3
nOctI
iPrI
tBuI
50
83
60
40:60
21:79
1:>99
HO
O
H
NOBn
RI (5 eq.), QDP (2 eq.)BEt3 (0.5 eq.)/O2
DCM/H2O, rt.HO
O
R
NHOBn
Entry RI Yield (%) R:S
1
2
3
nOctI
iPrI
tBuI
50
83
60
58:42
62:38
>99:1
OH
OMe
N
NHH2PO2
Quinine, QP
OH
OMe
N
NH
H2PO2Quinidine, QDP
Chiral Brønsted Acids
OH
OMe
N
NH
H2PO2
O N
HO H
O
•R
Si-face attack
Reactions Using Chiral Organocatalysts
22
Chiral Amine Catalysts–SOMO Activation
R H
O+
R'SiMe3
RH
OR'
CAN (2 eq.), NaHCO3
DME, –20 ºC
NH
NO Me
tBuPh
•CF3COOH
(20 mol%)
70–88%, 87–95% ee
H
O
Me NH
NO Me
tBuPh
IP ≈ 9.8 eV IP ≈ 8.8 eV
N
NO Me
tBuPh
MeIP ≈ 7.2 eV
N
NO Me
tBuPh
MeSOMO-activated
NH
NO Me
tBuPh
N
NO Me
tBuPh
R
N
NO Me
tBuPh
R
N
NO Me
tBuPh
R
N
NO Me
tBuPh
RMe3Si
N
NO Me
tBuPh
RMe3Si
RH
O
RH
O
H
CANoxidation
CANoxidation
SiMe3
N
NO Me
tBuPh
R
MacMillan, D. W. C. et. al. Science 2007, 316, 582.
Reactions Using Chiral Organocatalysts
23
Chiral Amine Catalysts–SOMO Activation
R H
O+
RH
OON
FeCl3, NaNO2, O2
NH
NO Me
Me
Ph (20 mol%)49–78%, up to 90% ee
NO
Me
R H
O+
55–92%, 86–96% eeNH
NO Me
tBuPh (20 mol%)
R'
OTMS
RH
OR'
O
CAN (2 eq.), DTBP, H2OAcetone, –20 ºC
R H
O+
61–93%, 89–96% eeNH
NO Me
tBuPh (20 mol%)
R'R
H
OR'
KF3B
CAN (2 eq.), NaHCO3, H2ODME, –50 ºC
Sibi, M. P. et. al. J. Am. Chem. Soc. 2007, 129, 4124.
MacMillan, D. W. C. et. al. J. Am. Chem. Soc. 2007, 129, 7004.
MacMillan, D. W. C. et. al. J. Am. Chem. Soc. 2008, 130, 398.
Reactions Using Chiral Organocatalysts
24
Merge Photoredox with Organocatalysis
H
OnBu + Br Ph
O Fluorescent lightOrganocatalyst, Ru(bpy)3Cl2
2,6-lutidine, DMF, rt.H
OPh
Hex O
84%, 96% ee
RuN
N
NN
N
N
2+
2Cl–
Ru(bpy)3Cl2
NH
NO Me
Me tBu
Organocatalyst
•HOTf
NH
NO Me
Me tBu
N
NO Me
Me tBu
R
RH
O
N
NO Me
tBu Me
R O
Ph
N
NO Me
tBu Me
R O
Ph
H
OPh
R O
Ru(bpy)32+*
Ru(bpy)32+
Ru(bpy)3+hυ
Si-face open
Br–
Br Ph
O Ph
O
Ph
O
MacMillan, D. W. C. et. al. Science 2008, 322, 77.
Reactions Using Chiral Organocatalysts
25
H
OR +
Ir(ppy)2(dtb-bpy)PF6 (0.5 mol%)
2,6-lutidine, DMF, –20 ºCH
OCF3
R
90–99% ee
NH
NO Me
Me tBu•TFA
(20 mol%)
CF3I
H
OR +
fac-Ir(ppy)3 (0.5 mol%)
2,6-lutidine, DMSO, rt.H
O
R
87–97% ee
(20 mol%)NH
NO Me
Bn Me•HOTf
Br Ar Ar
MacMillan, D. W. C. et. al. J. Am. Chem. Soc. 2009, 131, 10875.
MacMillan, D. W. C. et. al. J. Am. Chem. Soc. 2010, 132, 13600.
Contents
– Introduction
– Reactions Using Chiral Auxiliary
– Chiral Lewis Acid-Mediated Reactions
– Transition Metal-Catalyzed Reactions
– Reactions Using Chiral Organocatalysts
– Miscellaneous
26
Chiral Organotin Hydride or Chiral Thiols
27
Maruoka, K. et. al. Nature Chem. 2014, 6, 702.
Br
O
OEt
O
OEt
lewis acid (1 eq.)stannane (1.1 eq.)
9-BBN, toluene, –78 ºC
75%, 96% ee
NMn
N
O OCl tBu
tButBu
tBu
NMe2
SnH(men)2
men =
CO2BnCO2Bn
+ tBuOCO2Bn
CO2BntBuO
OH SH
Me
SitBu(4-CF3C6H4)2
R
R
R = 10-Bu-9-anthryl(3 mol%)
Benzoyl peroxide, toluene, rt., hυ
95%, 95:5 d.r., 86% ee
OH S
Me
Si
R
RtBu
Ar Ar
OtBu
BnO2C
BnO2C
Chiral Organotin Hydride
Chiral Thiol
Schiesser, C. H. et. al. Chem. Commun. 1999, 1665.
Solid-State Photochemistry
28
Scheffer, J. R.; Trotter, J. et. al. J. Am. Chem. Soc. 1986, 108, 5648.
iPrO2C
CO2iPr
hυ, solidCO2iPriPrO2C
P212121 (chiral) 95% ee
SN Bn
H PhH
P21 (chiral)
hυ, solid
SN Bn
PhH
NS Bn
HPh
81% ee, 100% conv.
Phtochemistry in Chiral Crystals
Sakamoto, M. et. al. J. Am. Chem. Soc. 1996, 118, 10664.
Enzyme-catalyzed Reactions
29
Hyster, T. K. et. al. Nature 2016, 540, 414.
Biocatalysis
O
O
nBr
R
Racemic
O
O
n
R O
O
n
R
RasADH (1 mol%)NADP+ (1 mol%)
GDH-105, glucose, TRISGlycerol, DMSO
460 nm hυ, rt.
LKADH (0.25 mol%)NADP+ (0.4 mol%)
kPi, iPrOH, DMSO460 nm hυ, rt.
O
O
O
OF
O
O
Me
O
O
Ph
Ras-ADH47%, e.r. 97/3
LKADH91%, e.r. 2/98
Ras-ADH79%, e.r. 3/97
LKADH56%, e.r. 4/96
Ras-ADH29%, e.r. 80/20
LKADH80%, e.r. 4/96
Ras-ADH82%, e.r. 81/19
LKADH74%, e.r. 9/91
N
NN
NNH2
O
OHOH
OP
O
P
OO
O OO N
O
OHOH
NH2
O
NAD+
Acknowledgements
30