Boron Homologation - Princeton...
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B R Boron Homologation Zhe Dong MacMillan Research Group Group Meeting Feb 14th, 2019 LG B R Boron Enabled Assembly Line synthesis
Transcript of Boron Homologation - Princeton...
BR
Boron Homologation
Zhe DongMacMillan Research Group
Group MeetingFeb 14th, 2019
LG
B
R
Boron Enabled Assembly Line synthesis
Continuous Carbon Chiral Center Synthesis
��Quick access to starting materials
��Reactivity: overcoming the steric bulk
��Selectivity: facile synthesis of all 4 enantiomersUnsolved Problem
Lucas, E. L.; Jarvo, E. R. Nat. Rev. Chem. 2017, 1, 65.
��Stereospecific or Stereoconvergent?
Chiral Metal CatalysisM
M = Li, Mg, Zn, B, Sn
Br+ Stereoconvergent?
No asymmetric reportNo access to all 4 enantiomers
Continuous Carbon Chiral Center Synthesis
��Quick access to starting materials
��Reactivity: overcoming the steric bulk
��Selectivity: facile synthesis of all 4 enantiomersUnsolved Problem
Lucas, E. L.; Jarvo, E. R. Nat. Rev. Chem. 2017, 1, 65.
��Stereospecific or Stereoconvergent?
Racemic Metal CatalysisM
M = Li, Mg, Zn, B, Sn
Br+ Stereospecific
No good way to generate chiral nucleophileMatch and mismatch issue
Continuous Carbon Chiral Center Synthesis
��Quick access to starting materials
��Reactivity: overcoming the steric bulk
��Selectivity: facile synthesis of all 4 enantiomersUnsolved Problem
Leonori D.; Aggarwal V.K. Acc. Chem. Res., 2014, 47, 3174
��Stereospecific Reaction without Catalysis
One Step from chiral alcohol
[B]+
Solve all the mentioned issues in both seactivity/ selectivity
Problem: functional group tolerance/ low temperature
Li OCb
[B]
Boron 1,2-Metallate Rerrangments
O N
O
OCb
Me Me
Me
Me
Boron Homologation via 1,2-Metallate Rerrangments
Non-Catalyzed Boron Homologation
Catalyzed Boron Homologation
Matteson Homologation
Zweifel Olefination
Aggarwal Homologation
Assembly Line Synthesis
Heteroatom Issue
Real-World Application
Double Electron Transfer Initiated Reaction
Single Electron Transfer Initiated Reaction
Matteson Homologation: Reaction Discovery
Cl3CB
BrO-nBu
O-nBu
+ MgBrEt2O/THF = 1 :1
Cl3CB
O-nBu
O-nBu
More hindered group easier to migrate: More Bulky, More Reactive
Cl3CB
Br
O-nBunBu-O
Scope and Conditions
MgBr MgBr
Me
Me
MgBrMeMe
Me
MgBr
Me
25◦C 22h 91% IY
25◦C 2h 80% IY
-70◦C 2h 63% IY
25◦C 22h 90% IY
Matteson, D. S.; Mah, R. W. H. J. Am. Chem. Soc. 1963, 85, 2599.
α-Chlorol-alkyl Lithium Reagents for Homologation
BO
O+ THF - 100◦C to 25◦C B
Cl
LiCl
Cl
O
OB O
O
Cl
B
Cl
O
O
B
Cl
O
OB
Cl
O
O
Me
EtEt
Me
MeMe B
Cl
O
O
Ph
B
Cl
O
OMe
Me
MeMe
B
Cl
O
OMe
Me
MeMe
B
Cl
O
OMeO2C
3B
Cl
O
OEt
OBn
80% IY 77% IY 78% IY 84% IY
81% IY 90% IY
MeMe
MeMe
87% IY 67% IY
Cl
DCM + n-BuLi
0.90 equiv
Matteson, D. S.; Majumdar, D. J. Am. Chem. Soc. 1980, 102, 7588.
Matteson Homologation: Iterative Version
B
Br
O
O
+ M Type I : Form SN2BO
O
BO
O
Cy
Cy + M Type II: HomologationBr
BO
OCy
Cy
MBrB
O
OCy
Cy
BO
O
Cy
Cy MBr
MBr
BO
O
Cy
Cy
lterative Synthesis
Chiral Diol as Auxiliary for Diastereoselective Homologation
BO
O+ THF - 100◦C to 25◦C B
Cl
LiCl
Cl
O
ORR
R
RR
R
MgBr
BO
OR
R
R
MeMe
OO
Me
BPh B
O
O RL
RS
R
LiCl
Cl
BO
ORL
RS
R
Cl
PhMeMgBr
BO
ORL
RS
R
Me
Ph
LiCl
Cl
BO
ORL
RS
R
Me
Ph BO
O
RL
RS
R
Me
PhMeMgBr
Me
90% IY for 5 steps97% ee. 9:1 d.r.
BO
O
RL
RS
R
Me
PhCl
OHMe
PhMe
THF -20◦C to 25◦C
NaBO3
1.00 equiv
Matteson, D. S.; Ray, R. J. Am. Chem. Soc. 1980, 102, 7590.
Chiral Diol as Auxiliary : Painful Access to Diastereomer
Ph BO
O RL
RS
R
LiCl
Cl
MeMgBrB
O
ORL
RS
R
Me
Ph
OHMe
PhMe
5 steps in one potPh B
O
O RL
RS
RWithout work-up OH
Me
PhMe
???Ph BO
O RL
RS
R
HN
CO2H CO2H
B
Me
PhNO
O
O
O
HO
HORL
RS
R
BO
ORL
RS
R
Me
Ph
LiCl
Cl
BO
ORL
RS
R
Me
Ph BO
O
RL
RS
R
Me
PhMeMgBr
Me
93% IY for 3 steps100% ee. 15:1 d.r.
BO
O
RL
RS
R
Me
PhCl
OHMe
PhMe
NaBO3
1. BCl3
2.
94% IY 94% ee
1. HCl
2.75% IY100% ee
79% IY
Matteson, D. S.; Ray, R. J. Am. Chem. Soc. 1980, 102, 7590.
Chiral Diol as Auxiliary : Improvement on Selectivity
B O
O
ClCl
R
R
ZnCl
ClBO
O+ THF - 100◦C to 25◦C B
Cl
LiCl
Cl
O
ORR
R
RR
R
1.12 equiv
55 mol% ZnCl2
[B]
Cl
Me [B]
Cl
[B]
Cl
Et [B]
Cl
PhMe
Me
61% IY90% es
30% IY88% es
75% IY92.5% es
57% IY74% es
W/O ZnCl2
86% IY98.5% es
89% IY99.5% es
99% IY99.5% es
83% IY95.7% es
W ZnCl2
Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. J. Am. Chem. Soc. 1986, 108, 810.Matteson, D. S.; Sadhu, K. M. J. Am. Chem. Soc. 1983, 105, 2077.
Matteson Homologation: State of Art
BO
OCyTrO
CyLi
Cl
Cl1.
2. NaOBn
LiCl
Cl3. Li
Cl
Cl5. Li
Cl
Cl7.
4. MeMgBr 6. NaH 8. Allyl-MgCl
BO
OCy
Cy
Me
OBnTrO
38% IYPurification Purification
HO
Cy
Cy
HO
Easy to install
Easy to deprotect/switch
MeB
O
OCy
Cy NucLiR X 6B
O
OCy
Cy
MeCl
Me
OPMBOBn
Et
45% IY for 12 chemical step
HN OO
O
O
ON
NNH
MeN
OOH
Me
PhMe O
O
Me
O
Me
Me
Me
Et Me MeMe
Lagunamide AMatteson, D. S.; Soundararajan, R.; Ho, O. C.; Gatzweiler, W. Organometallics 1996, 15, 152.Gorges, J.; Kazmaier, U. Org. Lett. 2018, 20, 2033.
Zweifel Olefination: Reaction Discovery
+ B HTHF
BI2 / NaOH
THF/H2O, r.t.
BI OH
B
IOH
OHEt
Et
Me
75% IY99:1 Z/E
70% IY85:15 Z/E
BBrCN , DCM
then NaOH (aq)
BBr CN
B
BrCN
Anti-Elimination
Syn-Elimination
Et Et
69% IY96:4 E/Z
75% IY98:2 E/Z
Me
MeMe
1,2-Shift
Zweifel, G.; Arzoumanian, H.; Whitney, C. C. J. Am. Chem. Soc. 1967, 89, 3652.Zweifel, G.; Fisher, R. P.; Snow, J. T.; Whitney, C. C. J. Am. Chem. Soc. 1972, 94, 6560.
Zweifel Olefination: State of Art
BpinBr
1. t-BuLi
2.
3. I2, NaOMe
Bpin
1. t-BuLi
2.
3. PhSeCl4. m-CPBA
B
SePh
O
O
O MeMe
MeMe
Excellent Syn Elimination
BO
OMeMe
MeMe
High Reactive Olefin
B
I
O
OMe
Me
MeMe
OMe
MeMe
Me
OMe83% IY 100% es
96:4 E/Z
Me
Me
OMe
95% IY 100% es
> 98:2 Z/E
Me
Armstrong, R. J.; García-Ruiz, C.; Myers, E. L.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2017, 56, 786.
Zweifel Olefination: State of Art
BpinBr
1. t-BuLi
2.
3. I2, NaOMe
Bpin
1. t-BuLi
2.
3. PhSeCl4. m-CPBA
B
SePh
O
O
O MeMe
MeMe
Excellent Syn Elimination
BO
OMeMe
MeMe
High Reactive Olefin
B
I
O
OMe
Me
MeMe
OMe
Armstrong, R. J.; García-Ruiz, C.; Myers, E. L.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2017, 56, 786.
52% IY > 20:1 d.r.
98:2 Z/E45% IY > 20:1 d.r.
98:2 Z/E
TBDPSOMe
Me
OTBS
MeOPMB
Me
TBDPSOMe
OTBS
Me MeOPMB
Me
Aggarwal Homologation: Accidental Discovery?
S
O
BF4
LiHMDS
THF 5◦C
S
O
BEt3/O2. then H2O2
THF 5◦CEt
OH
75% IY
98% ee
S
O
H H H
Si Face Blocked
BEt3 S
O
H H HBEt Et
Et1,2-Shift
Et
BEt2H[O]
Et
OH
Proposed Mechanism
Aggarwal, V. K.; Fang, G. Y.; Schmidt, A. T. J. Am. Chem. Soc. 2005, 127, 1642.
Aggarwal Homologation: New Leaving Group
OCb
HSHR
O
O
NiPr2
Li
HR
N NsBuLi + (–)-Sparteine
Et2O –78 °C
Bpin
MgBr2 O
O
NiPr2
Bpin
HRBpinHR
Me Ph
OH
iPr Ph
OH
Ph
OHMeMe
TBSO Ph
OH
Ph
OH
Ph Et
OH
Ph iPr
OH
Ph Et
NHBn
Ph
H2O2/NaOH work up
BCl3/BnN3 work up
70% IY 94% ee
70% IY 96% ee
64% IY 96% ee
73% IY 96% ee
94% IY 94% ee
91% IY 96% ee
81% IY 96% ee
63% IY 96% ee
N N
H
H
(-)-Sparteine
Stymiest, J. L.; Dutheuil, G.; Mahmood, A.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2007, 46, 7491.
Aggarwal Homologation: Reagent Controlled Chiralty Transfer
N N
H
H
(–)-Sparteine
H
H
N N
(+)-Sparteine
Not AvailableUsed to be Widely Available
H
Me N N
(+)-Sparteine Surrogate
Not Widely Commercial Available
Stymiest, J. L.; Dutheuil, G.; Mahmood, A.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2007, 46, 7491.
Aggarwal Homologation: Reagent Controlled Chiralty Transfer
Ph(CH2)2 OCbsBuLi + (–)-sp
then Et-Bpin Ph(CH2)2 Et
Bpin
78% IY
96% ee
sBuLi + (+)-sps
then Et-BpinPh(CH2)2 Et
Bpin
78% IY
94% ee
Me OCb
Li•(–)-sp
Ph(CH2)2 Et
Me OCb
Li•(+)-sps
HO Me
Ph(CH2)2 Et
HO Me63% IY
94:6 d.r.
82% IY
96:4 d.r.
Me OCb
Li•(–)-sp
Ph(CH2)2 Et
HO Me64% IY
94:6 d.r.
Me OCb
Li•(+)-sps
Ph(CH2)2 Et
HO Me63% IY
90:10 d.r.
Stymiest, J. L.; Dutheuil, G.; Mahmood, A.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2007, 46, 7491.
Transfer Alcohol Chirality to C-B bond
Ar Me O
O
NiPr2
LiMe
Ar
sBuLi
Et2O –78 °C
Bpin
Ph Me
H2O2/NaOH work up
95% IY 100% es
80% IY 94% es
98% IY 84% es
97% IY 96% es
85% IY 96% es
95% IY 100% es
94% IY 98% es
OCb
O
O
NiPr2
BpinMe
ArBpin
Me
Ar45 °C
OHEt
Ph Me
OHiPr
OHEt
Me
OHEt
MeO
92% IY 96% es
Me
OHEt
Cl
Ph Me
OH
Ph Me
OH
Ph Me
OHO
> 98% ee
Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature 2008, 456, 778.
Transfer Alcohol Chirality to C-B bond
Ar Me O
O
NiPr2
LiMe
Ar
sBuLi
Et2O –78 °C
BEt3
Ph Me
H2O2/NaOH work up
91% IY 100% es
91% IY 96% es
90% IY 90% es
87% IY 92% es
OCb
OCbMe
Ar BpinMe
Ar45 °C
OHEt
Ph Me
OHiPr
OHEt
Me
OHEt
MeO
87% IY 90% es
Me
OHEt
Cl
> 98% eeB
Et EtEt
Inversion
From iPr-9-BBN
Inversion only happen when carbon-anion is benzylic
Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature 2008, 456, 778.
From Benzylic Alcohol to Normal Secondary Alcohol
BpinR1
R2O
O
NiPr2
BpinR1
R2
Ar R1
sBuLi
Et2O –78 °C
OCbBpin
R1
OCb
R
R1
OCb
R
Alkyl R1
OCb sBuLi
MeOD Alkyl R1
DCbO
AcidIc C-H Bond
D <10%
More Electron-Withdraw
New leaving group required
Me
Me
Me
Me
MeMe
O
O
R2
R1
Comformationally Stable Anion
D 92%
OTIB
Installation:Me
OHEt
TIBOH,PPh3, DIAD
Me
OTIBEt
Pulis, A. P.; Aggarwal, V. K. J. Am. Chem. Soc. 2012, 134, 7570.
Partridge, B. M.; Chausset-Boissarie, L.; Burns, M.; Pulis, A. P.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2012, 51, 11795.
Alkyl R1
OTIB sBuLi
MeOD Alkyl R1
DTIBO
From Benzylic Alcohol to Normal Secondary Alcohol
BpinR1
Alkyl
sBuLi
CPME –50 °C
B
Alkyl R1
OTIB
O
O
MeMe
B[neo] 50 °C
Me
80% IY 100% es
OHEtBn
Me
74% IY 100% es
OHiPrBn
Me
OHBn
NF
Me
OHBn
Me
Me
OHBn
78% IY 100% es
73% IY 100% es
73% IY 100% es
Me
72% IY 100% es
OHEt
Me
OHEtTHPO
56% IY 93%brsm 98% es
Et
40% IY 78%brsm 100% es
OHEtBn
Pulis, A. P.; Blair, D. J.; Torres, E.; Aggarwal, V. K. J. Am. Chem. Soc. 2013, 135, 16054.
O
MeMe
MeMe
X = Cl 7I% X = Br 83%
X = Cl 20% X = Br 5%
LiCHCl2 then [O]
THF –78 °C to r.t.B
Ph MeEt
OO
MeMe Me
Me
Ph MeEt
O68% IY 100% es
From Tertiary Boronic Acid to Quaternary Carbon Center
LiCH2X
THF –78 °C
1,2-Shift then [O]
r.t.
Quaternary Carbon + Methylene
B
Ph MeEt
Ph MeEt
BOO
Me
MeMe
Me
XH
HPh Me
Et
OH
Ph MeEt
BOO
Me
MeMe
Me
HH
X
C-Migration
O-Migration
OO
MeMe Me
Me
1,2-Shift then [O]
r.t. B
Ph MeEt
O
Sonawane, R. P.; Jheengut, V.; Rabalakos, C.; Larouche-Gauthier, R.; Scott, H. K.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2011, 50, 3760.
From Tertiary Boronic Acid to Quaternary Carbon Center
THF –78 °C
1,2-Shift then [O]
Slow
Quaternary Carbon + Methine
Bpin
Ph MeEt
Ph MeEt
Bpin
OCbMe
H Ph MeEt
OHMe OCb
Li•(–)sp MeH
Bpin
OCbMe
H Ph MeEt
Li•(–)sp
Ph EtMe
Li•(–)sp
Ph EtMe
Bpin
OCbMe
H
1,2-Shift then [O]
Ph EtMe
OHMeH
dr = 88 : 12
Racemic dr = 2 : 1
NO
MeMe
O
OMe
OCbx
sBuLi + (–)-sp
then SnMe3Cl Me OCbX
SnMe3
90% ee 96% ee (Recryst)
sBuLi + (+)-sps
then Et-BpinMe OCbX
SnMe3
88% ee 94% ee (Recryst)
Slow
Blair, D. J.; Fletcher, C. J.; Wheelhouse, K. M. P.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2014, 53, 5552.
Ph
Me OH
70% IY d.r. > 97:3
Ph
Me OH
76% IY d.r. > 99:1
From Tertiary Boronic Acid to Quaternary Carbon Center
THF –78 °C
1,2-Shift then [O]
THF Reflux
Quaternary Carbon + Methine
Bpin
Ph MeEt
Ph MeEt
Bpin
OCbMe
HPh Me
Et
OHMe OCbX
LiMeH
Ph EtMe
Li Allyl-Br quench
Ph EtMe
Ph
Me OH
78% IY d.r. = 99:1
Ph
Me OH
73% IY d.r. = 98:2
EtMe
EtMe
MeEt
MeEt
Bpin
Ph MeEt
Me OCbX
Li
then allylBr
Me OCbX
Li
then allylBr
then allyBr
Me OCbX
Li
then allyBr
Me OCbX
LiPh EtMe
Bpin
Ph EtMe
H
Blair, D. J.; Fletcher, C. J.; Wheelhouse, K. M. P.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2014, 53, 5552.
From Tertiary Boronic Acid to Quaternary Carbon Center
THF –78 °C
1,2-Shift then [O]
THF Reflux
Quaternary Carbon + Quaternary Carbon
Bpin
Me MeMe
Me MeMe
Bpin
OCbPh
Me
Me MeMe
OHPhMePh Me
LiCbO
Me MeMe
BOO
Me
MeMe
Me
OMe
Ph
O
NMe
Me
MeMe
Too Hindered to form
Reduced Steric Hinderance
More Positve Boron Center
tBuBMe2
Me MeMe
BMeMe
OMe
Ph
O
N
MeMe
Me
Me
Bpin
Me MeMe
2.0 equiv MeMgBr
Et2O, r.t. 20 min
BMe2
Me MeMe Purified by Distillation
Watson, C. G.; Balanta, A.; Elford, T. G.; Essafi, S.; Harvey, J. N.; Aggarwal, V. K. J. Am. Chem. Soc. 2014, 136, 17370.
Ar Me O
O
NiPr2
LiMe
Ar
sBuLi
Et2O –78 °C
BMe2
OCb
OCbMe
ArBMe2
Me
Arr.t.
> 98% eeB
MeMe
Inversion
From Tertiary Boronic Acid to Quaternary Carbon Center
Quaternary Carbon + Quaternary Carbon
Selective MigrationtBu > iPr >> Me
64% IY d.r. = 99:1> 99% ee
BMe2
Me Me
Ph Me
LiCbO
Ph
MePh Me
LiCbO
Ph Me
LiCbO
MeMe
BMe2
Ph
MeMe
MePh
Me OH
56% IY d.r. = 99:1> 99% eePh
MeMe
MePh
HO Me
Watson, C. G.; Balanta, A.; Elford, T. G.; Essafi, S.; Harvey, J. N.; Aggarwal, V. K. J. Am. Chem. Soc. 2014, 136, 17370.
Ar Me O
O
NiPr2
LiMe
Ar
sBuLi
Et2O –78 °C
BMe2
OCb
OCbMe
ArBMe2
Me
Arr.t.
> 98% eeB
MeMe
Inversion
From Tertiary Boronic Acid to Quaternary Carbon Center
Quaternary Carbon + Quaternary Carbon
Selective MigrationtBu > iPr >> Me
Watson, C. G.; Balanta, A.; Elford, T. G.; Essafi, S.; Harvey, J. N.; Aggarwal, V. K. J. Am. Chem. Soc. 2014, 136, 17370.
56% IY d.r. = 98:2> 99% ee
Ar Me
LiCbO
Ar
MeEt Ph Me
LiCbO
BMe2
Ar
MeEt
Ph MeO
BO
MeMe
Et
MeMgBr Ph Me
LiCbO
Ph
MeHO
One Pot Ar= pOMeC6H4
Drug Candidate Synthesis
N
NH2N
Me
N O
NNN
O
N Me
MeSN2
Suzuki
Oxazole Synthesis
N
NH2N
BO
OMe
Me
MeMe Me
N
NH2
OHBr
NNH
HO
OO
NClMe
Me
Me
OBr
H
Chiral Separation
Senanayake, C. H. et al. Org. Lett. 2014, 16, 4360.
Drug Candidate Synthesis
Me
OBr
H Matteson HomologationB
Me
BrO
O
MeMe
MeMe Aggarwal Homologation
Me
Br
BOO
MeMeMe
MeLiCbO
Route 1 Deprotonation vs Li-Halogen Exchange
BrB
OO
MeMeMe
Me
Me
LiCbO
Route 2 Me Migration is problem
MeB
OO
MeMeMe
Me
4-Br-C6H4
LiTIBO
Route 3 Chiral Alcohol is hard to access
Cheap Chiral Alcohol
Senanayake, C. H. et al. Org. Lett. 2014, 16, 4360.Senanayake, C. H. et al. J. Org. Chem. 2015, 80, 1651.
Drug Candidate Synthesis
B
Me
BrO
O
MeMe
MeMeAggarwal HomologationMe
Br
BOO
MeMeMe
MeLiCbO
Me
Br
OCbAlkyl-Li
Me
Li
OCb
Me
Br
LiCbO
excess
Me
Br
OCbAlkyl-Li
BOO
MeMeMe
Me
+
Cryogenic ConditionsMe
Br
LiCbO
-10 °C BOO
MeMeMe
Me
Alkyl
Me
Br
OCb
+
Senanayake, C. H. et al. Org. Lett. 2014, 16, 4360.Senanayake, C. H. et al. J. Org. Chem. 2015, 80, 1651.
Pre-mix
Drug Candidate Synthesis
B
Me
BrO
O
MeMe
MeMeAggarwal HomologationMe
Br
BOO
MeMeMe
MeLiCbO
excess
Senanayake, C. H. et al. Org. Lett. 2014, 16, 4360.Senanayake, C. H. et al. J. Org. Chem. 2015, 80, 1651.
Me
Br
OCbLDA
Me
Br
LiCbO
Me
Br
OCb
BOO
MeMeMe
Me
+
Cryogenic ConditionsMe
Br
LiCbO
CMPE -10 °C to 0 °C
Epimerization occurs before full conversion
1.2 equiv1.0 equiv99.9% ee
1.2 equiv LDA B
Me
BrO
O
MeMe
MeMe
99% Y on 24kg scale98.6% ee
Pre-mix
Drug Candidate Synthesis
Me
Br
OCb
BOO
MeMeMe
Me
+CMPE -10 °C to 0 °C
1.2 equiv1.0 equiv99.9% ee
1.2 equiv LDA B
Me
BrO
O
MeMe
MeMe
99% Y on 24kg scale98.6% ee
Pre-mix
Me
Br
BpinCbO 1,2-Shift
Fast
B
Me
BrO
O
MeMe
MeMe
Me
Br
LiCbO Bpin
Me
BrMe
Br
CbOB
Me
BrO
O
MeMe
MeMe
+
1,2-Shift
SlowBy-product
Senanayake, C. H. et al. Org. Lett. 2014, 16, 4360.Senanayake, C. H. et al. J. Org. Chem. 2015, 80, 1651.
B
Me
BrO
O
MeMe
MeMe
CMPE -15 °C
1.5 equiv LDAMe
Br
LDA addtion time
2.0 equiv DCM
then H2O2
O
Yield
< 1min
35 min
93%
25%
Drug Candidate Synthesis
Problem : Muliple Homologation:
ClBpin
Me
Br
Bpin
Me
Br
1,2-Shift
Fast
Cl
Li
ClCl
Me
BrCl
BpinClCl
Li
Me
BrCl
Bpin
Cl
Senanayake, C. H. et al. J. Org. Chem. 2015, 80, 1651.
B
Me
BrO
O
MeMe
MeMe
THF/1,4-Dioxane -45 °C to r.t
1.5 equiv LDA Me
Br
2.0 equiv DCM
then H2O2
O
Drug Candidate Synthesis
What is the trick?
ClCl
Li-45 °C
Bpin
Me
BrDCM
LDA Bpin
Me
Br ClCl
+ClCl
Li
Excess
-25 °CBpin
Me
Br ClCl
Inert
ClCl
Li
Fast Decomposion
Cl
Cl
> -15 °C
Bpin
Me
Br ClCl
1,2-Shift
Fast
Me
BrCl
Bpin
Senanayake, C. H. et al. J. Org. Chem. 2015, 80, 1651.
94 %Y
Programmable Temperature Enabled Assemble Line Synthesis
MROB
O
O BO
O MRO
MRO
BO
O
Auto Synthesis with Reagent Controlled Chirality
MeMe
MeMe
MeMe
MeMe
Working Hypothesis:
BO
O
MeMe
MeMe
MeMe
MeMe
Burns, M.; Essafi, S.; Bame, J. R.; Bull, S. P.; Webster, M. P.; Balieu, S.; Dale, J. W.; Butts, C. P.; Harvey, J. N.; Aggarwal, V. K. Nature 2014, 513, 183
Programmable Temperature Enabled Assemble Line Synthesis
MROB
O
O BO
O MRO
MRO
BO
O
Auto Synthesis with Reagent Controlled Chirality
MeMe
MeMe
MeMe
MeMe
Working Hypothesis:Li
TIBO
- 78 °C 0.5 hB
O
O
MeMe
MeMe
OBIT
1.3 eq
LiTIBO
- 42 °C 1h
BO
O
MeMe
MeMe
OBITr.t. 1 h
MeMe
MeMe
Burns, M.; Essafi, S.; Bame, J. R.; Bull, S. P.; Webster, M. P.; Balieu, S.; Dale, J. W.; Butts, C. P.; Harvey, J. N.; Aggarwal, V. K. Nature 2014, 513, 183
BO
OMe
Me
MeMe
Programmable Temperature Enabled Assemble Line Synthesis
Working Hypothesis:Li
TIBO
- 78 °C 0.5 hB
O
O
MeMe
MeMe
OBIT
1.3 eq
LiTIBO
- 42 °C 1h
BO
O
MeMe
MeMe
OBITr.t. 1 h
Burns, M.; Essafi, S.; Bame, J. R.; Bull, S. P.; Webster, M. P.; Balieu, S.; Dale, J. W.; Butts, C. P.; Harvey, J. N.; Aggarwal, V. K. Nature 2014, 513, 183
BO
OMe
Me
MeMe
High Purity Reagents:
O
OMesBuLi + (–)-sp
then SnMe3Cl Me OTIB
SnMe3
82% ee 99.8% ee (Recryst)
sBuLi + (+)-sps
then Et-BpinMe OTIB
SnMe3
79% ee
99.8% ee (Recryst)
Me Me
Me
Me
Me
Me
Programmable Temperature Enabled Assemble Line Synthesis
Burns, M.; Essafi, S.; Bame, J. R.; Bull, S. P.; Webster, M. P.; Balieu, S.; Dale, J. W.; Butts, C. P.; Harvey, J. N.; Aggarwal, V. K. Nature 2014, 513, 183
State of Art:
Bpin
MeMe Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
OHMe
Me
Me
Me
Me
Me
Me
Me
Me
Me
58% IY> 99:1 d.r.
+ 8 C+ 9 C+ 10 C
1972
Aq\Work Up Aq\Work Up H2O2\Work Up
Ph
Ph
Programmable Temperature Enabled Assemble Line Synthesis
Burns, M.; Essafi, S.; Bame, J. R.; Bull, S. P.; Webster, M. P.; Balieu, S.; Dale, J. W.; Butts, C. P.; Harvey, J. N.; Aggarwal, V. K. Nature 2014, 513, 183
Bpin
MeMe Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
OHMe
Me
Me
Me
Me
Me
Me
Me
Me
Me
44% IY> 99:1 d.r.
+ 8 C+ 9 C+ 10 C
1945
Aq\Work Up Aq\Work Up H2O2\Work Up
State of Art:
Ph
Ph
Programmable Temperature Enabled Assemble Line Synthesis
Burns, M.; Essafi, S.; Bame, J. R.; Bull, S. P.; Webster, M. P.; Balieu, S.; Dale, J. W.; Butts, C. P.; Harvey, J. N.; Aggarwal, V. K. Nature 2014, 513, 183
State of Art:
Bpin
MeMe Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
Me Li
OTIB
OHMe
Me
Me
Me
Me
Me
Me
Me
Me
Me
45% IY> 99:1 d.r.
+ 8 C+ 9 C+ 10 C
0973
Aq\Work Up Aq\Work Up H2O2\Work Up
From Hydrocarbon to Polypropionates
HO2CC15H31
Me Me Me Me Me Me Me Me
OH
O
OH OH OH OH OH OH OH
Me Me Me Me Me Me Me
(+)- Hydroxyphthioceranic acid
H
Me
Anti-AntiPolyketides Fragments
Why Oxygen is difficult?
Conformation Stability
TBSO Li
OTIBBpin
OTBS
Me
BpinOTBS
Me OTBS
OTIB R
OTBS
MBpin
OTBS
RBpin
OTBS
Me OPG
OTIBR
Me Bpin
OTBS
OTIB
Bootwicha, T.; Feilner, J. M.; Myers, E. L.; Aggarwal, V. K. Nat. Chem. 2017, 9, 896.
Using Si Atom Instead of Oxygen
NOMe
SiMe Me
Cl
Li SiRSiSN
OMe
SiMe Me
Cl
Li
Et2O –78 °C to r.t.B
77% IY
95:5 d.r.
79% IY
95:5 d.r.
O
O
MeMe
MeMe
SiS
Bpin
[SiS]
Bpin
SiMeMe
NOMe
Bpin
[SiS]
Bn
tBuO2CBpin
[SiR]
Bn
tBuO2CBpin
[SiS]
NBpin
[SiS]
NBoc
BpinMe
[SiS]
71% IY
≥ 98:2 d.r.
79% IY
92:8 d.r.
71% IY
91:9 d.r.
Bootwicha, T.; Feilner, J. M.; Myers, E. L.; Aggarwal, V. K. Nat. Chem. 2017, 9, 896.
Using Si Atom Instead of Oxygen
NOMe
SiMe Me
Cl
Li SiRSiSN
OMe
SiMe Me
Cl
Li
Et2O –78 °C to r.t.B
77% IY
95:5 d.r.
79% IY
95:5 d.r.
O
O
MeMe
MeMe
SiS
Bpin
[SiS]
Bpin
SiMeMe
NOMe
Bpin
[SiS]
Bn
tBuO2CBpin
[SiR]
Bn
tBuO2CBpin
[SiS]
NBpin
[SiS]
NBoc
BpinMe
[SiS]
71% IY
≥ 98:2 d.r.
79% IY
92:8 d.r.
71% IY
91:9 d.r.
Bootwicha, T.; Feilner, J. M.; Myers, E. L.; Aggarwal, V. K. Nat. Chem. 2017, 9, 896.
Transfer Si Atom to Oxygen
MeCN/MeOH = 1: 1 r.t.SiMe
MeN
OMe
N
NIr
N
N
F F
F
FCF3
F3C
t-Bu
t-Bu
2 mol% [Ir]1.5 equiv Methyl Acrylate
SiOMe
MeMe
75%-80% Y
Urea•H2O2
KF, KHCO3
THF, MeOHBpin
BpinOH
OH
SiMeMe
Bpin
N
OMe+ No Reaction
SiOMe
MeMe
Bpin
Bn
Bn
Me
Me
+
SiOMe
MeMe
Bn
Me
[SiR]
Bpin
80% IYd.r. = 94 : 6
NOMe
SiMe Me
Cl
Li
NOMe
SiMe Me
Cl
Li
Bootwicha, T.; Feilner, J. M.; Myers, E. L.; Aggarwal, V. K. Nat. Chem. 2017, 9, 896.
34 w Blue LED
Transfer Si Atom to Oxygen : Proposed Mechanism
MeCN/MeOH = 1: 1 r.t.
34 w Blue LED
SiMeMe
NOMe
2 mol% [Ir]1.5 equiv Methyl Acrylate
SiOMe
MeMe
75%-80% YBpin
Bpin
CatalyticPhotoredox
Cycle
reductant
*IrIII
oxidant
SETSET
IrIII
IrII
SiMeMe
NOMe
R
+ •MeOH
SiMe
Me
R
OMeH+
SiMeMe
NOMe
R
NOMe
CO2Me
SET
NOMe
MeO2C
Bootwicha, T.; Feilner, J. M.; Myers, E. L.; Aggarwal, V. K. Nat. Chem. 2017, 9, 896.
Iterative Assembly Line Synthesis of Polypropionate
BpinSiS Ir
Li
MeTIBOMeS
MeS
ClLi C
BpinSiMe2OMe
Me
SiR Ir MeS C
Bpin
SiMe2
Me Me
SiMe2OMeMeO
[O]
OH
OH
Me Me
OH
38% IY > 95:5 d.r.
Bn BpinSiR Ir C x 3
BpinSiMe2OMe
Bn3
SiR Ir
26% IY > 95:5 d.r.
Li
then I2/MeONa
[O]
Bn
OH OH OH OH
29% IY > 95:5 d.r.
Bootwicha, T.; Feilner, J. M.; Myers, E. L.; Aggarwal, V. K. Nat. Chem. 2017, 9, 896.
Merging Pd Catalysis with Boron-1,2-Shift
B +
OTf 1 mol% Pd(OAc)2
1.5 mol% L*
THF 60 °C 14 h
H2O2/NaOH OH FePh
NMe2Ph
NMe2
Ar2P
PAr2
Me
OMe
Me
Ar =
Chiral Ligand
Pd(0)
ArOTf
Ar-PdII-OTf
BR
Ar-PdII
BneoR
Bneo
RPdII-Ar
Bneo
RAr
Cationic PdII is the Key
O
OMe
Me
O
OMe
Me
Zhang, L.; Lovinger, G. J.; Edelstein, E. K.; Szymaniak, A. A.; Chierchia, M. P.; Morken, J. P. Science 2016, 351, 70.
Merging Pd Catalysis with Boron-1,2-Shift
+
OTf 1 mol% Pd(OAc)2
1.5 mol% L*
THF 60 °C 14 h
H2O2/NaOH OH FePh
NMe2Ph
NMe2
Ar2P
PAr2
Me
OMe
Me
Ar =
Chiral Ligand
83% IY
94% es
68% IY
92% ee
73% IY
90% ee
41% IY
80% ee
B O
OMe
Me
Ph
OH
Ph
OH
CHOPh
OH
Ph
OH
CO2Me
80% IY
90% ee
OHPh OH
PhTMS
OHPh
NMe
OHPhMeO
MeOOMe
48% IY
76% ee
86% IY
90% ee
77% IY
88% ee
Zhang, L.; Lovinger, G. J.; Edelstein, E. K.; Szymaniak, A. A.; Chierchia, M. P.; Morken, J. P. Science 2016, 351, 70.
Merging Pd Catalysis with Boron-1,2-Shift
3 mol% Pd(dba)23.6 mol% dippf
MeTHF 40 °C 14 h
Fe(iPr)2P
P(iPr)2dippf
B O
O
MeMe
MeMe
Bpin
Ar
Bpin
SO
Me
1. 1.3 equiv t-BuLi
2.
1.3 equiv1.0 equiv
1.2 equiv Ar-OTf
Pd(0)
ArOTf
Ar-PdII-OTf
Ar-PdII
Cationic PdII is the Key
BpinR
H
BR
HOO
MeMeMe
Me
RBpin
PdII-Ar
RBpin
ArBr
N.R.
Fawcett, A.; Biberger, T.; Aggarwal, V. K. Nat. Chem. 2019, 11, 117.
Merging Pd Catalysis with Boron-1,2-Shift
3 mol% Pd(dba)23.6 mol% dippf
MeTHF 40 °C 14 h
Fe(iPr)2P
P(iPr)2dippf
B O
O
MeMe
MeMe
Bpin
Ar
Bpin
SO
Me
1. 1.3 equiv t-BuLi
2.
1.3 equiv1.0 equiv
1.2 equiv Ar-OTf
Pd(0)
ArOTf
Ar-PdII-OTf
Ar-PdII
Cationic PdII is the Key
BpinR
H
BR
HOO
MeMeMe
Me
RBpin
PdII-Ar
RBpin
ArBr
N.R.
Fawcett, A.; Biberger, T.; Aggarwal, V. K. Nat. Chem. 2019, 11, 117.
Merging Pd Catalysis with Boron-1,2-Shift
3 mol% Pd(dba)23.6 mol% dippf
MeTHF 40 °C 14 h
Fe(iPr)2P
P(iPr)2dippf
B
40% IY
>98:2 d.r.
77% IY 100% es
>98:2 d.r.
76% IY
>98:2 d.r.
52% IY
>98:2 d.r.
O
O
MeMe
MeMe
Bpin
Ar
Bpin
SO
Me
1. 1.3 equiv t-BuLi
2.
1.3 equiv1.0 equiv
1.2 equiv Ar-OTf
Bpin
Ph
tBuO2C Bpin
PhMe
PMP
Bpin
Ph
Ph
Bpin
PhBocN
CyBpin
Bpin
CyBpin
N
CyBpin
BrCy
Bpin
58% IY
>98:2 d.r.
74% IY >98:2 d.r.
62% IY
>98:2 d.r.
78% IY
>98:2 d.r.
Fawcett, A.; Biberger, T.; Aggarwal, V. K. Nat. Chem. 2019, 11, 117.
Merging Racical Reaction with Boron-1,2-Shift
BOO
MeMe Me
Me
Li
Et2O, 0 °C to r.t.B
OO
MeMe Me
Me5 mol% BEt3
MeCN 80 °C 24 h
5.0 equiv Rf-I
then NaOH, H2O2
Rf OH
Rf I
Rf
BOO
MeMe Me
Me
Rf
BOO
MeMe Me
Me
Rf I
BOO
MeMe Me
Me
Rf
B OO
MeMe
MeMe
Rf
1,2-Shift
F F
Me
F F
FF
FFF
F
FF
Atom Transfer
I
Kischkewitz, M.; Okamoto, K.; Mück-Lichtenfeld, C.; Studer, A. Science 2017, 355, 936.
Merging Racical Reaction with Boron-1,2-Shift
BOO
MeMe Me
Me
Li
Et2O, 0 °C to r.t.B
OO
MeMe Me
Me5 mol% BEt3
MeCN 80 °C 24 h
5.0 equiv Rf-I
then NaOH, H2O2
Rf OH
Rf I
BOO
MeMe Me
Me
Rf
F F
FF
I
Kischkewitz, M.; Okamoto, K.; Mück-Lichtenfeld, C.; Studer, A. Science 2017, 355, 936.
68% IY 65% IY 65% IY 36% IY 1:1 d.r.
Ph
OHC4F9 Ph
OHC4F9
Et
OHC10F21
Me
OHC4F9Et
Me
77% IY
O
Me
O
Et
61% IY
Ph
OH
MeCN Ph
OHCF3
41% IYWith Togni I
58% IY
O
Me
O
Et
FF
Merging Racical Reaction with Boron-1,2-Shift
BOO
MeMe Me
Me
Li
Et2O, 0 °C to r.t.B
OO
MeMe Me
Me
DMI r.t. 16 h
1.5 equiv EWG-CH2I
then NaOH, H2O2
Bpin
34W Blue LED
EWG
Silvi, M.; Sandford, C.; Aggarwal, V. K. J. Am. Chem. Soc. 2017, 139, 5736.
O
PhI
O
Ph
BOO
MeMe Me
Me
O
Ph
BOO
MeMe Me
MeI
O
PhI
SET
BOO
MeMe Me
Me
O
Ph+
B OO
MeMe
MeMe
O
Ph
1,2-Shift
Merging Racical Reaction with Boron-1,2-Shift
BOO
MeMe Me
Me
Li
Et2O, 0 °C to r.t.B
OO
MeMe Me
Me
DMI r.t. 16 h
1.5 equiv EWG-CH2I
then NaOH, H2O2
Bpin
34W Blue LED
EWG
81% IY 88% IY 88% IY 74% IY
Ph
B
Me
65% IY 69% IY 70% IYWith 1 mol% Ru[bpy]3Cl2
68% IY
OO
MeMe Me
Me
Ph
O
B
Me
OO
MeMe Me
Me
Ph
O
Me
Me
B
Me
OO
MeMe Me
Me
Ph
O
Me
MeMe
B
Me
OO
MeMe Me
Me
Ph
OEt
Ph
BOO
MeMe Me
Me
Ph
O
B
Me
OO
MeMe Me
Me
EtCF3
B
Me
OO
MeMe Me
Me
EtCO2Et
CO2Et
Ph
BOO
MeMe Me
Me
CO2Et
FF
With 1 mol% Ru[bpy]3Cl2
Silvi, M.; Sandford, C.; Aggarwal, V. K. J. Am. Chem. Soc. 2017, 139, 5736.
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