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Metal-Catalyzed Asymmetric Cross-Coupling Reactions
181215_LS_Daiki_Kamakura
Cross-Coupling Reactions Using sp3-Substrates
Choi, J.; Fu, G. C. Science, 2017, 356, 1 1
M X+
sp2-sp2 cross cpupling
sp3-sp2 cross cpupling
+ X
+ MR’’
R
R’’
R
R’’
RM
R’’
RX
sp3-sp3 cross cpupling
R’’
RM X
R’’’
R’’’’
+R‘’’
R’’’’R’’
R
Pd, Ni,….
M = BR2, ZnR, SnR3, SiR3,…; X = I, Br, Cl, OTf,….
Strategies for Asymmetric Cross-Coupling Reactions
2Choi, J.; Fu, G. C. Science, 2017, 356, 1
+ MR’’
R
R’’
RX
racemic
*M
L*
R’’
R*
if ent-L* is used,…
+ X
R’’
R
R’’
RM
*
M
L’
mechanism A(stereo retentive)
mechanism B(stereo invertive)
R’’
R*
L* = chiral ligand
L
M
chiral sunstrate
*
Contents1. Catalytic Enantioconvergent Coupling of Secondary and Tertiary Electrophiles with Olefins (Fu, 2018)
2. Enantiodivergent Pd-Catalyzed C–C Bond Formation Enabled through Ligand Parameterization (Sigman, Biscoe, 2018)
3
+ R”’MR’’
RR”’
R’’
RX
racemic
*Ni
L*
+ X
R’’
R
R’’
RM
*
Pd
L’
mechanism A(stereo retentive)
mechanism B(stereo invertive)
R’’
R*
L* = chiral ligand
L
Pd
chiral sunstrate
*
R”’’
R’’
RXR”’ +
R’’
R*
Ni
L*R”’
R”’’
Contents1. Catalytic Enantioconvergent Coupling of Secondary and Tertiary Electrophiles with Olefins (Fu, 2018)
2. Enantiodivergent Pd-Catalyzed C–C Bond Formation Enabled through Ligand Parameterization (Sigman, Biscoe, 2018)
4
+ R”’MR’’
RR”’
R’’
RX
racemic
*Ni
L*
+ X
R’’
R
R’’
RM
*
Pd
L’
mechanism A(stereo retentive)
mechanism B(stereo invertive)
R’’
R*
L* = chiral ligand
L
Pd
chiral sunstrate
*
R”’’
R’’
RXR”’ +
R’’
R*
Ni
L*R”’
R”’’
Fu’s Previous Works
5
• Enantioselective cross coupling of propargyl bromide with diphenylzinc
TMSn-Bu
Br
TMSn-Bu
PhNiIICl2•DME
L1* NO
N NOH
H H
H
L1* = (–)-indenyl-pybox
• Control of Vicinal Stereocenters through Nickel-Catalyzed Alkyl-Alkyl Cross-Coupling
DME, –20 ºC
80%, 91%ee
Ph2Zn
+
BocN Zn
2MeHN NHMe
Ar Ar
(S, S)-L2*
Ar = 1-Naphthyl
+I Ni(acac)2
(S,S)-L2*
THF/Et2O, rt
68% yield, 92%ee
CF3CF3
HNBoc
d.r. = >99 : 1
Smith, S. W.; Fu, G. C. J. Am. Che. Soc. 2008, 130, 12645.Schley, N. D.; Fu, G. C. J. Am. Che. Soc. 2014, 136, 16588.
via
TMSn-Bu
racemicd.r. = >99 : 1
racemic
Mu, X.; Shibata, Y.; Makida, Y.; Fu, G. C. Angew. Chem. Int. Ed. 2017, 56, 5821.
(NiI was an initiator)
Construction of Quaternary Carbon Center
6
R”’’M
racemic
Ni
L*
L* = chiral ligand
R’’
RXR”’
R’’
RR”’’
*R”’
• Enantioselective cross coupling of tert-haloalkane
+
It is difficult to quaternary carbon center by cross-coupling reaction
• Reported methods
Ph Br
CyMe+ ClMg
Ph
CyMeCoCl2dppp
THF, –20 ºC83%
Tsuji, T.; Yorimitsu, H.: Oshima, K. Angew. Chem. Int. Ed, 2002, 41, 4147.
Br+ (9-BBN)–Ph
NiBr2•diglymeL3
THF, –20 ºCL3
N NPh
–––> Asymmetric construction of quaternary carbon center has not been achieved.
Zultanski, S. L.; Fu, G. C. J. Am. Chem. Soc. 2013, 135, 624.
Ni-Catalyzed Reaction of sec-Bromide with Olefin
7Wang, Z.; Yin, H.; Fu, G. C. Science, 2018, 563, 379.
EtO
NHPhBr
racemic
n-Bu+
NiBr2•glyme (10 mol%)(R,R)-L3* (12 mol%)
HSi(OEt)3 (3 eq.)K3PO4•H2O (3 eq.) N N
OOPhPh Ph
Ph
Ph Ph(R,R)-L3*
2-methyl-THF–5 ºC, 40 h
EtO
NHPhH
n-Bu84%, 94%ee
variation from the “standard conditions”Entry
1
ee (%)yield
2
3
under air 66% 94%
with H2O (1.0 eq.) 78% 95%
88% 94%gram scale
<substrate scope>O
NHPhH
n-Bu
71%, 94%ee
BrEt
O
NH
CF2CF3
H
79%, 90%ee
Ph
OAc
O
Bn
64%, 96%ee
Design of Substrate
8Wang, Z.; Yin, H.; Fu, G. C. Science, 2018, 563, 379.
RO
NR’2Br
R’’
In order to reduce steric hindrance in the vicinity of the reactive site, cyclic substrate was designed.
NPh
O
Me Br
α-halo-β-lactamracemic
ter-bromide
HN
O
BrBrMe
NaOH aq.
88%
EtO
NHPhBr
racemic
n-Bu+
NiBr2•glyme (10 mol%)(R,R)-L3* (12 mol%)
HSi(OEt)3 (3 eq.)K3PO4•H2O (3 eq.) N N
OOPhPh Ph
Ph
Ph Ph(R,R)-L3*
2-methyl-THF–5 ºC, 40 h
EtO
NHPhH
n-Bu84%, 94%ee
Ni-Catalyzed Reaction of tert-Bromide with Olefin
9Wang, Z.; Yin, H.; Fu, G. C. Science, 2018, 563, 379.
N N
OOPhPh Ph
Ph
Ph Ph(R,R)-L3*
NR2
O
R1 BrR3
+NR2
O
R1
R3racemic
NPh
O
R
n-BuR1 = Me: 90%, 99%eeR1 = Et: 94%, 99%eeR1 = Bn: 85%, 98%eeR1 = i-Pr: 76%, 98%ee
NPh
O
Et
SiPh378%, 95%ee
NR
O
Et
n-BuR2 = n-Bu: 92%, 99%eeR2 = c-hex: 94%, 99%eeR2 = CHPh2: 88%, 99%eeR2 = OBn: 59%, 97%ee
NBoc
O
Me
n-Bu85%, 97%ee
NiBr2•glyme (10 mol%)(R,R)-L3* (12 mol%)
HSi(OEt)3 (3 eq.)K3PO4•H2O (3 eq.)
2-methyl-THF5 ºC, 40 h
Transformations of Obtained Compound
10
NBoc
O
Me
n-Bu85%, 97%ee
KCN, MeOH
rtMen-hex
BocHN OMe
O
77%, 97%ee
Men-hex
BocHN OH
68%, 97%ee
LiAlH4 THF, 0 ºC
THF, –40 ºC
ArMgBrMe
n-hexBocHN Ar
O
93%, 97%eeAr = p-MeOC5H4
Wang, Z.; Yin, H.; Fu, G. C. Science, 2018, 563, 379.
Initially Proposed Mechanism
11Wang, Z.; Yin, H.; Fu, G. C. Science, 2018, 563, 379.
NiBr2•glyme(R,R)-L3*N
Ph
O
Et Brn-Bu
(EtO)3Si+
NPh
O
Et
n-Bu<2% yield
R3
(EtO)3Si NR’
O
R1 NiIIL*Br
+K3PO4•H2O
NR’
O
R NiIIL*
R3
NR2
O
R1 Br
NiBr2•glyme(R,R)-L3*HSi(OEt)3
K3PO4•H2O
2-methyl-THF0ºC, 40 h
R3+
NR2
O
R1
R3racemicNi0L3
*
H–Si(OEt)3
hydrosilylation
transmetalation
• Initially proposed mechanism
• Reaction with alkylsilane
K3PO4•H2O2-methyl-THF
0ºC–––> Alkylsilane was not reaction intermediate
Mechanistic Study
12Wang, Z.; Yin, H.; Fu, G. C. Science, 2018, 563, 379.
Ni0(cod)2(R,R)-L*
n-pentane, rt
BrL*NiII
SiPh3
SiPh3
Br
+
complex A: 54%
NPh
O
Et Br
BrHNPh
O
Et
SiPh3
SiPh3+
complex A(10 mol%)
86%, 93%ee
L*NiIIBr2 + H–SiOR3 L*BrNiII–HR
H
RL*BrNi
NPh
O
Et BrNPh
O
Et
SiPh380%, 95%ee
1.2 eq.
2-Me-THF–10 ºC
• Reaction of complex A with tert-bromide
–––> complex A would be the active species of the reaction
<possible mechanism to give alkyl–NiII>
– BrSi(OEt)3
Proposed Catalytic Cycle
13Wang, Z.; Yin, H.; Fu, G. C. Science, 2018, 563, 379.
L*NiIBr
Alkyl–Br
L*BrNiII–BrAlkyl H–Si(OEt)3
Br–Si(OEt)3
L*BrNiII–H
R3
L*BrNiIIR
H
L*BrNiIIIR
H
Alkyl
NR2
O
R1 Br
NR2
O
R1
R3=
Short Summary
14Wang, Z.; Yin, H.; Fu, G. C. Science, 2018, 563, 379.
EtO
NHPhBr
racemicsec-bromide
n-Bu+
NiBr2•glyme (10 mol%)(R,R)-L3* (12 mol%)HSi(OEt)3 (3 eq.)K3PO4•H2O (3 eq.) N N
OOPhPh Ph
Ph
Ph Ph(R,R)-L3*
2-methyl-THF–5 ºC
EtO
NHPhH
n-Bu84%, 94%ee
NR2
O
R1 Br
α-halo-β-lactam
R3+
NiBr2•glyme (10 mol%)(R,R)-L3* (12 mol%)HSi(OEt)3 (3 eq.)K3PO4•H2O (3 eq.)
2-methyl-THF0 ºC
NR2
O
R1
R359–94% yield
95–99%ee
Contents1. Catalytic Enantioconvergent Coupling of Secondary and Tertiary Electrophiles with Olefins (Fu, 2018)
2. Enantiodivergent Pd-Catalyzed C–C Bond Formation Enabled through Ligand Parameterization (Sigman, Biscoe, 2018)
15
+ R”’MR’’
RR”’
R’’
RX
racemic
*Ni
L*
+ X
R’’
R
R’’
RM
*
Pd
L’
mechanism A(stereo retentive)
mechanism B(stereo invertive)
R’’
R*
L* = chiral ligand
L
Pd
chiral sunstrate
*
R”’’
R’’
RXR”’ +
R’’
R*
Ni
L*R”’
R”’’
Cross-Coupling of Chiral Boronic Esters
16
Ph Me
Bpin
+
Ar–I
Ph Me
Ar
48-86%, 84-94% es
Ph NH
Bpin
Me
O
+
Pd2(dba)3XPhos
K2CO3, H2Otoluene
Ar–Br
HN OBR2
Ph HL(Ar)PdII
Ph NH
Ar
Me
O
95%, 59%es
Pd2(dba)3
PPh3Ag2O
Imao, D,; Veronique, G.; Laberge, S.; Crudden, C. M. J. Am. Chem. Soc. 2009, 131, 5024.
88%ee
• Stereoretentive reaction
PCy2i-Pr i-Pr
i-PrXPhos
• Stereoretentive reaction
Ohmura, T.; Awano, T.; Suginome, M. J. Am. Chem. Soc. 2010, 132, 13191.87%ee
Cross-Coupling of Chiral Boronic Esters
17Wang, Z.; Yin, H.; u, G. C. Science, 2018, 563, 379.
Cl
Et Me
BF3K+
PdII NH2t-Bu3P OMs
K2CO3toluene/H2O (2 : 1)
OMe
Et Me
OMe
93% (95%es)
The factors controlling the dominant mechanism of transmetallation are not understood.
Et Me
BF3K+Ar Cl
Et Me
ArAr
Me Et
Pd/Pt-Bu3Pd/L
Li, L.; Zhao, S.; Joshi-Pangu, A.; Diane, M.; Biscoe, M. R. J. Am. Chem. Soc. 2014, 136, 14027.
(stereo invertive)
98%ee
(stereo retentive)Aim of this research:
• Development of the ligand-controlled enatiodivergent cross-coupling reaction• To reveal the factors that control the the transfer of stereochemistry
Effects of the Substituent and Ligand
18Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
Cl
Et Me
BF3K+
PdII NH2L OMs
K2CO3toluene/H2O (2 : 1)
100 ºC
Z
Et Me
Z
98%ee
Z
OMe
Me
CO2Et
CF3
CN
σpara
–0.27
–0.17
0.45
0.54
0.66
ee (L = Pt-Bu3)
–91%
–89%
–79%
–72%
–67%
L solid angle ee (Z = CO2Et)
Pt-Bu3 150º –79%
150º +4%PAd2n-Bu
PPh3 126º +12%
Pt-Bu2Ph 145º +21%
Po-tol3 153º +65%
–––> No obvious correation was observed between these results and the steric properties (solid angle).
*
Ad = adamantyl
General Scheme of Model Development
19
a A conformational search was performed for all phosphines using OPLS3 force field and low frequency- mode conformational search. Conformers within 15kcal/mol were considered for further computations. b All structures were fully optimized at the PBE0/6-31+G(d) level and frequency analysis was performed at the same level. c Multivariate model development was performed using MATLAB R2017a with forward stepwise linear regression. Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
28 ligands
conformersearch
MM a
computation
representativeset of comformers
DFT b
caluculation
individual conformer’s properties* • electronic propaties
• steric propaties
statistical analysis c
multivariate regression
ΔΔG‡ (measured)
= –RTln(x/y)propaty X
ΔΔ
G‡
(mea
sure
d)(1) (2)
ΔΔG‡ (measured)
ΔΔ
G‡
(pre
dict
ed) ΔΔG‡
(predicted) = aX + …
Reveal the factors that control the transfer of
stereochemistry
predictive statistical modelligand design
Experimental Workflow
20Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
P
1
PPh2OMeMeO
2
PCy2OMeMeO
3
4 5 6
Pt-Bu2
7Pt-Bu3
8 9PAd3
3
PPh3 PEt3 PMe3
+ other 19 phosphines
28 ligands
electronic propaties
steric propaties• percent buried volume• Sterimol values• Solid angle
* obtaine four kinds of values (min, max, Boltz, MC)with one propaty
MM, DFTcaluculation
<steric propaties>%Vbur Sterimol values
experiments
R–BF3KAr–Cl, Pd
R–Arxx%ee correlation?
• P chemical shift• P lone pair and P–C antibonding orbital energies• P partial charge• P lone pair electrostatic potential
Initial Investigations
21Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
Cl
Et Me
BF3K+
PdII NH2L OMs
K2CO3toluene/H2O (2 : 1)
100 ºC
CO2Et
Et Me
CO2Et
98%ee
L
*
P
1
ee
65%
ArPPh2
2Ar = 2, 6-di-MeOC6H3
52%
L ee
Pt-Bu2
7
Pt-Bu38
9PAd3
–68%
–79%
–93%
Epimerization via β-Hydride Elimination
22Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
PEt3 9%5
Cl
Et Me
BF3K+
PdII NH2L OMs
K2CO3toluene/H2O (2 : 1)
100 ºC
CO2Et
Et Me
CO2Et
98%ee *
L ee
PMe3 6%6
<proposed epimerized pathway>
PdIIL Ar
MeEt
PdIIL Ar
Et
PdIIL Ar
MeEt
Et Me
Ar
Et Me
Ar
epimerizedcompound
EtPdIIArL
EtAr
linear compound (undesired)
H
23Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
Enantiospecificity Trend
A correlation between enantioselectivity and Vmin was observed
only ligands providing high selectivity were further investigated (>30%ee)
P
19
PAd3
Vm i nB o l t z : M i n i m u m o f t h e
molecular electrostatic potential in the phosphorus lone pair region
A correlation between enantioselectivity and Vmin was observed
New Ligands were designed
only ligands providing high selectivity were further investigated (>30%ee)
24Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
Enantiospecificity Trend
A correlation between enantioselectivity and Vmin was observed
only ligands providing high selectivity were further investigated (>30%ee)
desired ligand
P
19
PAd3
Vm i nB o l t z : M i n i m u m o f t h e
molecular electrostatic potential in the phosphorus lone pair region
New Ligand Design
25Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
P(CF3)n
Ar2
RR
R
Ar1
electron-poor
bulky
Ar1 = 2,6-di-MeOC6H3
Ar2 =
CF3
CF3
CF3Me
10 Vmin
Bolz = –0.04011
–0.03012
–0.055
13–0.038
14 –0.029
15 –0.052
New ligand design
2
desired ligand
(as validation)
Ar1 = 2,4,6-tri-i-PrC6H2
Effects of New Ligands
26Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
Cl
Et Me
BF3K+
PdII NH2L OMs
K2CO3toluene/H2O (2 : 1)
100 ºC
CO2Et
Et Me
CO2Et
98%ee *
Ar1 = 2,6-di-MeOC6H3
Ar2 =
CF3
CF3
CF3Me
10 Vmin
Bolz = –0.04075%ee
7.4 : 1 (b: l)
11 –0.03090%ee
45 : 1 (b: l)
12 –0.05535%ee
1 : 2.1 (b: l)
13–0.03890%ee
43 : 1 (b: l)
14 –0.02990%ee
69 : 1 (b: l)
15 –0.05281%ee
(11 :1 b: l)
(as validation)
Ar1 = 2,4,6-tri-i-PrC6H2
Substrate Scope
27Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
+ conditions A or B
PdII–L (3–15mol%)PdII–L =
Ar–X
conditions A1L = 11, Cs2CO3
toluene/H2O = 1 : 1
conditions A2L = 14, K2CO3
toluene/H2O = 1 : 1
conditions BL = PAd3 (9), K2CO3toluene/H2O = 2 : 1
R1 R2
BF3K
R1 R2
Ar
*
PdII NH2L OMs
Et Me
Ph
X = Cl, conditions A290%yield, 92%es
Et Me
Ph
X = Cl, conditions B92%yield, 98%es
MeX = Cl, conditions A2
87%yield, 97%es
MeX = Cl, conditions B
90%yield, 99%es
OMe OMe
PhPh
MeX = Br, conditions A1
81%yield, 95%es
MeX = Cl, conditions B
84%yield, 91%es
PhPh
CF3 CF3
X = Cl, conditions A177%yield, 99%es
X = Cl, conditions B78%yield, 77%es
PhPh
Ph Ph
Limitation of the Reaction
28Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
+ conditions A or B
PdII–L (3–15mol%)PdII–L =
Ar–X
conditions A1L = 11, Cs2CO3
toluene/H2O = 1 : 1
conditions A2L = 14, K2CO3
toluene/H2O = 1 : 1
conditions BL = PAd3 (9), K2CO3toluene/H2O = 2 : 1
R1 R2
BF3K
R1 R2
Ar
*
MeO S MeO S
X = Cl, conditions A286%, d.r. = 30 : 1
X = Cl, conditions B65%, d.r. = 5 : 1
X = Cl, conditions A271% yield*
*conditions B results in low conversion of SM.
Ph
S
X = Br, conditions B52% yield, 95%es
Ph
S
X = Br, conditions B43% yield, 94%es
PdII NH2L OMs
Multivariate Regression Analysis
29Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
Cl
Me
BF3K+
PdII NH2L OMs
K2CO3toluene/H2O (2 : 1)
100 ºC
CO2Et
Me
CO2Et
97%ee *
Ph
Multivariate linear regression
17 training sets
+
7 varidations
Additionally, 24 ligands were tested
–90% ~ +98%eeΔΔG‡ range: 5.5 kcal/mol
Ph
omit smaller 4 ligands (B1
Boltz<4)
(10 mol%)
Results of Multivariate Linear Regression
30Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
Eσ*(P−C)ave ••• The average energy of the P−C antibonding (σ*) orbitals
ELP(P) ••• the energy of the lone pair orbital of phosphorus
9
11
PAr2OMeMeO
11Ar = 3,5-di-CF3C6H3
9
PAd3
It was found that enantioselectivity d e p e n d s o n t h e e l e c t r i c a l properties of the ligands
Proposed Reaction Mechanism
31Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
PdII NH2L OMs
PAr2OMeMeO
11Ar = 3,5-di-CF3C6H3
PAr2i-Pri-Pr
14Ar = 3,5-di-CF3C6H2
i-Pr
PdII–L =
Ar–ClPd0–L PdII
Ar
LCl
H2O, K2CO3
PdII
Ar
LHO
L = 11, 14,…
L = PAd3, Pt-Bu3,…
X2B
PdIIL
OH
ArR1
R2
X = F or OH
R1
BX3K
R2
R1HR2
BX3
X = F or OH
ClPdII(Ar)L
R1
Ar
R2
R1
Ar
R2
RBX3K RBX2
X =F or OH
H2O, K2CO3
X =F or OH
X =F or OH
R1
BX2
R2
X =F or OH
Summary
32Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
racemic
R3+
NiBr2•glyme(R,R)-L3*HSi(OEt)3K3PO4•H2O
2-methyl-THF
NR2
O
R1 Br
NR2
O
R1
R3
N N
OOPhPh Ph
Ph
Ph Ph(R,R)-L3*
R1
BF3K
R2+Ar–Cl
R1 R2
Ar
R1 R2
ArPdII–LL = PAd3
ΔΔG‡ = 1.5 + 0.62Eσ*(P-C)aveBoltz – 1.2ELP(P)
Bolz
PAr2OMeMeO
11Ar = 3,5-di-CF3C6H3
PAr2i-Pri-Pr
14Ar = 3,5-di-CF3C6H2
i-Pr
PdII–LL = 11, 14
stereo retentive
stereo invertive
33
Appendix
Branched : linear ratio
34Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
The Ratio of Branched Compounds
35Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
Preparation of Substrates
36Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
R O N(i-Pr)2
OHSHR B(pin)O
N(i-Pr)2OR
Ets-BuLi
(–)-sparteineEt2O, –78 ºC
; (pin)BEt MgBr2 reflux
Stymiest, J. L.; Dutheuil, G. D.; Mahmood, A.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2007, 46, 7491.Homologation reaction using lithiated carbamate: 140614_LS_Keiichiro_Fukushima
Et
R B(pin)
90%, 96%ee
MgBr2
R = Ph(CH2)2
Ligand Set (1)
37Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
Ligand Set (2)
38Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
Data Set
39Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
Parameters (1)
40Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
Parameters (2)
41Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
Parameters (3)
42Xhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. Science, 2018, 362, 670.
Initial Investigations
43Wang, Z.; Yin, H.; Fu, G. C. Science, 2018, 563, 379.
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