Boron Homologation

LG R

B B
R

Boron Enabled Assembly Line synthesis

Zhe Dong
MacMillan Research Group
Group Meeting
Feb 14th, 2019
 Continuous Carbon Chiral Center Synthesis

Quick access to starting materials

Reactivity: overcoming the steric bulk

Unsolved Problem Selectivity: facile synthesis of all 4 enantiomers

Stereospecific or Stereoconvergent?

Br
+ Chiral Metal Catalysis
Stereoconvergent?
M

M = Li, Mg, Zn, B, Sn

No asymmetric report
No access to all 4 enantiomers

Lucas, E. L.; Jarvo, E. R. Nat. Rev. Chem. 2017, 1, 65.

 Continuous Carbon Chiral Center Synthesis

Quick access to starting materials

Reactivity: overcoming the steric bulk

Unsolved Problem Selectivity: facile synthesis of all 4 enantiomers

Stereospecific or Stereoconvergent?

Br
+ Racemic Metal Catalysis
Stereospecific
M

M = Li, Mg, Zn, B, Sn

No good way to generate chiral nucleophile

Match and mismatch issue

Lucas, E. L.; Jarvo, E. R. Nat. Rev. Chem. 2017, 1, 65.

 Continuous Carbon Chiral Center Synthesis

Quick access to starting materials

Reactivity: overcoming the steric bulk

Unsolved Problem Selectivity: facile synthesis of all 4 enantiomers

Stereospecific Reaction without Catalysis

[B]
+ Boron 1,2-Metallate Rerrangments
Li OCb

One Step from chiral alcohol [B]

Me Me Solve all the mentioned issues in both seactivity/ selectivity

O N Me Problem: functional group tolerance/ low temperature

O Me
OCb

Leonori D.; Aggarwal V.K. Acc. Chem. Res., 2014, 47, 3174
Boron Homologation via 1,2-Metallate Rerrangments

Non-Catalyzed Boron Homologation

Matteson Homologation

Zweifel Olefination

Aggarwal Homologation

Real-World Application

Assembly Line Synthesis

Heteroatom Issue

Catalyzed Boron Homologation

Double Electron Transfer Initiated Reaction

Single Electron Transfer Initiated Reaction

 Matteson Homologation: Reaction Discovery

O-nBu O-nBu
nBu-O O-nBu
B B
Cl3C + MgBr Cl3C O-nBu B
O-nBu
Et2O/THF = 1 :1 Cl3C
Br
Br

Scope and Conditions

MgBr MgBr MgBr MgBr

Me Me Me
Me

Me
Me

25◦C 22h 25◦C 22h 25◦C 2h -70◦C 2h

90% IY 91% IY 80% IY 63% IY

More hindered group easier to migrate: More Bulky, More Reactive

Matteson, D. S.; Mah, R. W. H. J. Am. Chem. Soc. 1963, 85, 2599.

 α-Chlorol-alkyl Lithium Reagents for Homologation

O O
O Cl
B B O
B + Li THF - 100◦C to 25◦C O
O Cl Cl
Cl Cl
0.90 equiv

DCM + n-BuLi

O
O Et O Me O
Me B
Et B B B Ph O
O Me O Me O
Cl
Cl Cl Cl

80% IY 77% IY 78% IY 84% IY

Me Me Me
Me Me Me
OBn O O O O
Me Me Me
Et B B B MeO2C B
O Me O Me O Me O
3
Cl Cl Cl Cl

81% IY 90% IY 87% IY 67% IY

Matteson, D. S.; Majumdar, D. J. Am. Chem. Soc. 1980, 102, 7588.

 Matteson Homologation: Iterative Version

O
O
B
B + M O Type I : Form SN2
O
Br

Cy

O
O
B Cy + M B Type II: Homologation
Cy
O
Br O

Cy

Cy
Cy
O
O
M M M Cy
O Cy B
B Br B Br Br O
Cy O
O

Cy

lterative Synthesis
 Chiral Diol as Auxiliary for Diastereoselective Homologation

R
R R
R R
Cl MgBr O
O R O
+ Li B R
B THF - 100◦C to 25◦C B R
THF -20◦C to 25◦C O
O Cl O
R
Cl
1.00 equiv

Me Me
Cl RS RS
RL RL
RS Li O Me
O
O RL Cl MeMgBr
Ph B R R
Ph B Ph B O
O O O
O B
R Cl Me

RS Cl
RL Cl Me Me
O Li
Ph O RS Ph O RS Ph
R Cl B MeMgBr B NaBO3
Ph B OH
O RL RL
Me O Me O Me
Me
R R
90% IY for 5 steps
97% ee. 9:1 d.r.

Matteson, D. S.; Ray, R. J. Am. Chem. Soc. 1980, 102, 7590.

 Chiral Diol as Auxiliary : Painful Access to Diastereomer

RS Me RS Me
O RL 5 steps in one pot O RL
Ph ??? Ph
Ph B OH Ph B OH
Without work-up
O O
R Me R Me

O RS
Cl RS
RL RL
RS Li O
O O
O RL Cl MeMgBr 1. BCl3 N 1. HCl
R Ph B Ph B R
Ph B Ph B
O O
H O RS
O N HO
R Me Me RL Me
2. O 2.
94% IY CO2H CO2H 75% IY 79% IY
HO R
94% ee 100% ee

RS Cl
RL Cl Me Me
O Li
Ph O RS Ph O RS Ph
R Cl B MeMgBr B NaBO3
Ph B OH
O RL RL
Me O Me O Me
Me
R R
93% IY for 3 steps
100% ee. 15:1 d.r.

Matteson, D. S.; Ray, R. J. Am. Chem. Soc. 1980, 102, 7590.

 Chiral Diol as Auxiliary : Improvement on Selectivity

R
R
R R
O Cl 55 mol% ZnCl2 O O R
R
+ Li R
B THF - 100◦C to 25◦C B B O Cl
O Cl O
R Cl Zn
Cl Cl
1.12 equiv Cl

Me [B] Et [B] Me [B] [B]

Ph

Cl Cl Me Cl Cl

W/O ZnCl2 57% IY 61% IY 30% IY 75% IY

74% es 90% es 88% es 92.5% es

W ZnCl2 83% IY 86% IY 89% IY 99% IY

95.7% es 98.5% es 99.5% es 99.5% es

Matteson, D. S.; Sadhu, K. M. J. Am. Chem. Soc. 1983, 105, 2077.

Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. J. Am. Chem. Soc. 1986, 108, 810.
 Matteson Homologation: State of Art

Cy
Cy Cl Cl Cl Cl
1. Li 3. Li 5. Li 7. Li OBn O
O Cy
Cl Cl Cl Cl TrO B
TrO B Cy O
O
2. NaOBn 4. MeMgBr 6. NaH 8. Allyl-MgCl Me

Purification Purification 38% IY

HO Cy

HO Cy

Easy to install

Easy to deprotect/switch Ph
Me O
Me N O
Cy N N
H
Et Me O Me O N Me
Cy O Me
LiR Nuc X6 Cy
B
O Me O HN O
O OH O O
B Cy
O OBn OPMB Cl
Me Me
O Me
45% IY for 12 chemical step Et Me Me Me

Lagunamide A
Matteson, 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

I2 / NaOH
+ B H B
THF THF/H2O, r.t.

1,2-Shift Anti-Elimination
Me
I
I OH OH
Et B
Et B OH

75% IY 70% IY
99:1 Z/E 85:15 Z/E

BrCN , DCM Me Me
B
then NaOH (aq)

Me
Syn-Elimination

Br Et Et
Br CN CN
B
B 69% IY 75% IY
96:4 E/Z 98:2 E/Z

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

1. t-BuLi 1. t-BuLi
Br
2. Bpin 2. Bpin

3. PhSeCl 3. I2, NaOMe

4. m-CPBA

Ph
Me
Se O Me
Me I Me
Me
O O O
Me Me Me
B B B
Me O Me O Me
O OMe
Me

Excellent Syn Elimination High Reactive Olefin

Me Me Me

Me
Me Me
OMe OMe
95% IY 100% es 83% IY 100% es
> 98:2 Z/E 96:4 E/Z

Armstrong, R. J.; García-Ruiz, C.; Myers, E. L.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2017, 56, 786.
 Zweifel Olefination: State of Art

1. t-BuLi 1. t-BuLi
Br
2. Bpin 2. Bpin

3. PhSeCl 3. I2, NaOMe

4. m-CPBA

Ph
Me
Se O Me
Me I Me
Me
O O O
Me Me Me
B B B
Me O Me O Me
O OMe
Me

Excellent Syn Elimination High Reactive Olefin

OTBS OTBS

Me TBDPSO OPMB
TBDPSO
Me Me Me Me Me Me
OPMB
Me
52% IY > 20:1 d.r.
45% IY > 20:1 d.r.
98:2 Z/E
98:2 Z/E

Armstrong, R. J.; García-Ruiz, C.; Myers, E. L.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2017, 56, 786.
 Aggarwal Homologation: Accidental Discovery?

BEt3/O2. OH
S LiHMDS S then H2O2
Et
THF 5 ◦C THF 5◦C
O O
BF4
75% IY
98% ee

Proposed Mechanism

H Et
H H H Et
H H OH
B Et H BEt2
BEt3 1,2-Shift [O]
S S Et
Et

O O

Si Face Blocked

Aggarwal, V. K.; Fang, G. Y.; Schmidt, A. T. J. Am. Chem. Soc. 2005, 127, 1642.
 Aggarwal Homologation: New Leaving Group

HR HS N N
sBuLi + (–)-Sparteine Bpin
Li O Bpin O
OCb Et2O –78 °C
MgBr2 O NiPr2 Bpin
O NiPr2 HR HR
HR
H2O2/NaOH work up

OH OH Me Me OH OH

Me Ph iPr Ph TBSO Ph Ph

70% IY 70% IY 64% IY 73% IY

H
94% ee 96% ee 96% ee 96% ee

N N

H
OH OH NHBn
OH (-)-Sparteine
Ph Et Ph iPr Ph Et
Ph Ph

BCl3/BnN3 work up
94% IY 91% IY 81% IY 63% IY
94% ee 96% ee 96% ee 96% ee

Stymiest, J. L.; Dutheuil, G.; Mahmood, A.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2007, 46, 7491.
 Aggarwal Homologation: Reagent Controlled Chiralty Transfer

H H
H

N N Me N N
N N

H
H
(–)-Sparteine (+)-Sparteine (+)-Sparteine Surrogate

Used to be Widely Available Not Available 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

HO Me HO Me
64% IY 82% IY
94:6 d.r. 96:4 d.r.
Ph(CH2)2 Et Ph(CH2)2 Et

Li•(–)-sp Li•(–)-sp

Me OCb Me OCb

Bpin sBuLi + (+)-sps sBuLi + (–)-sp Bpin

Ph(CH2)2 OCb
Ph(CH2)2 Et then Et-Bpin then Et-Bpin Ph(CH2)2 Et
78% IY 78% IY

94% ee 96% ee

Li•(+)-sps Li•(+)-sps

Me OCb Me OCb

HO Me HO Me
63% IY 63% IY
90:10 d.r. 94:6 d.r.
Ph(CH2)2 Et Ph(CH2)2 Et

Stymiest, J. L.; Dutheuil, G.; Mahmood, A.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2007, 46, 7491.
 Transfer Alcohol Chirality to C-B bond

OCb Li O Bpin
sBuLi Me Bpin O Me
Ar Me Et2O –78 °C O NiPr 2 Me Bpin
Ar 45 °C Ar
O NiPr2
Ar
> 98% ee
H2O2/NaOH work up

Et OH Et OH Et OH
Et OH
Me Me
Ph Me
MeO Cl

95% IY 98% IY 97% IY 92% IY

100% es 84% es 96% es 96% es

iPr OH OH OH O OH

Ph Me Ph Me Ph Me Ph Me

80% IY 85% IY 95% IY 94% IY

94% es 96% es 100% es 98% es

Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature 2008, 456, 778.
 Transfer Alcohol Chirality to C-B bond

OCb Li O Me
sBuLi Inversion
Me OCb Me
Ar Me Ar
Et2O –78 °C O NiPr 2 45 °C Bpin
Ar B Ar
Et Et
> 98% ee BEt3 Et
H2O2/NaOH work up

Et OH Et OH Et OH
Et OH
Me Me
Ph Me
MeO Cl

91% IY 90% IY 87% IY 87% IY

100% es 90% es 92% es 90% es

iPr OH
Inversion only happen when carbon-anion is benzylic
Ph Me

91% IY
96% es

From iPr-9-BBN

Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature 2008, 456, 778.
 From Benzylic Alcohol to Normal Secondary Alcohol

OCb OCb OCb

sBuLi Bpin Bpin O
Ar R1 R1 R1 R1 R1
Et2O –78 °C Bpin
R O NiPr2 R2
R2
R

AcidIc C-H Bond

Me Me

OCb CbO D
sBuLi Me Me
Alkyl R1
Alkyl R1 MeOD O

D <10%
R1 O
New leaving group required Me Me
R2 OTIB

OTIB TIBO D
sBuLi More Electron-Withdraw
Alkyl R1 Comformationally Stable Anion
Alkyl R1 MeOD

D 92%

OH TIBOH, OTIB
Installation: Et PPh3, DIAD Et
Me Me

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.
 From Benzylic Alcohol to Normal Secondary Alcohol

O
Me
B
OTIB sBuLi Me R1
O
Bpin
Alkyl R1 CPME –50 °C B[neo] 50 °C Alkyl

Me
Et OH iPr OH OH OH
Bn Bn Bn Bn
Me Me Me Me

74% IY 78% IY 73% IY

80% IY
100% es 100% es 100% es
100% es

N
F
OH Et OH Et OH Et OH
Bn THPO Bn
Me Me Me Et

73% IY 72% IY 56% IY 93%brsm 40% IY 78%brsm

100% es 100% es 98% es 100% es

Pulis, A. P.; Blair, D. J.; Torres, E.; Aggarwal, V. K. J. Am. Chem. Soc. 2013, 135, 16054.
 From Tertiary Boronic Acid to Quaternary Carbon Center

Quaternary Carbon + Methylene

Me
X
Me OH
H O Me 1,2-Shift then [O]
B O Me
Me Me H Et
Me Me r.t. Ph
Et Me
Ph
Me
O O X = Cl 7I%
B LiCH2X C-Migration X = Br 83%
Et
Ph THF –78 °C
Me Me Me
Me Me
H
Me O Me
H O Me 1,2-Shift then [O]
B O Me O
X r.t. B
Et
Ph Et
Me Ph
Me
O-Migration
X = Cl 20%
X = Br 5%
Me Me
Me Me
O
LiCHCl2 then [O] 68% IY
O O
B Et 100% es
THF –78 °C to r.t. Ph
Et Me
Ph
Me

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

Quaternary Carbon + Methine

Li•(–)sp Me
OCb OH
Bpin 1,2-Shift then [O] H
Me OCb Me
Bpin Et
Et H Slow
Ph THF –78 °C Ph
Me Et Me
Ph
Me

OCb Li•(–)sp Li•(–)sp dr = 88 : 12

Me Et Me Racemic dr = 2 : 1
Bpin Ph Ph
H Me Et

Slow
OCb Me
OH
1,2-Shift then [O] H
Me
Bpin Me
H
Ph
Me Et
Ph
Et

O
SnMe3
SnMe3 sBuLi + (–)-sp
sBuLi + (+)-sps Me O N
O then SnMe3Cl Me OCbX
Me OCbX then Et-Bpin Me
Me 90% ee
88% ee 96% ee (Recryst)
94% ee (Recryst)
OCbx

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

Quaternary Carbon + Methine

Li
OCb Me
OH
Bpin Me Li Me 1,2-Shift then [O] H
OCbX Allyl-Br quench
Bpin
Et Me H Et
Ph THF –78 °C Ph Et THF Reflux Ph
Me Et Ph Me
Me
H
Me Me
Ph Ph
Et Et

Li Li
Me OH Me OH
76% IY 78% IY
Me OCbX Me OCbX
Me d.r. > 99:1 Et d.r. = 99:1
Bpin then allyBr Ph Ph then allylBr Bpin
Et Me
Me Et
Ph Li Li Ph
Et Me
Me OH Me OH
Me OCbX 70% IY 73% IY Me OCbX
Me d.r. > 97:3 Et d.r. = 98:2 then allylBr
then allyBr Ph Ph
Et Me

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

Quaternary Carbon + Quaternary Carbon

CbO Li OCb
Ph
Ph OH
Bpin Ph Me Bpin 1,2-Shift then [O] Me
Me
Me Me Me
Me THF –78 °C Me Me
Me Me THF Reflux Me

Me O Me
O
Me
Me
Me N O N
Me O Me
Me O Me
Me Me Me
B O Me
Me Ph B Me Me
Me Ph
Me Me
Me Me
Me

Too Hindered to form tBuBMe2

Reduced Steric Hinderance

More Positve Boron Center

Bpin
2.0 equiv MeMgBr BMe2
Me Purified by Distillation
Me Me
Me Et2O, r.t. 20 min Me
Me

Watson, C. G.; Balanta, A.; Elford, T. G.; Essafi, S.; Harvey, J. N.; Aggarwal, V. K. J. Am. Chem. Soc. 2014, 136, 17370.
 From Tertiary Boronic Acid to Quaternary Carbon Center

Quaternary Carbon + Quaternary Carbon

OCb Li O Me
sBuLi Inversion
Me OCb
Ar Me
Ar Me Et2O –78 °C O NiPr2
Ar B r.t. BMe2
Ar
Me
> 98% ee BMe2 Me Selective Migration
tBu > iPr >> Me

Me
CbO Li 64% IY
Me Me
d.r. = 99:1
Me Ph Me Ph
CbO Li Ph > 99% ee
Me Me
BMe2 Ph Me Me OH
Ph BMe2
Me Me

CbO Li
Me
Ph Me 56% IY
Me Me
d.r. = 99:1
Ph
Ph > 99% ee
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.
 From Tertiary Boronic Acid to Quaternary Carbon Center

Quaternary Carbon + Quaternary Carbon

OCb Li O Me
sBuLi Inversion
Me OCb
Ar Me
Ar Me Et2O –78 °C O NiPr2
Ar B r.t. BMe2
Ar
Me
> 98% ee BMe2 Me Selective Migration
tBu > iPr >> Me

Me Me
CbO Li CbO Li CbO Li Et Me HO Me
56% IY
Ar Me MeMgBr Et Me Ph Me Ph Me Ar Ph d.r. = 98:2
O O
B Ar BMe2 Ph Me
> 99% ee
Et
One Pot Ar= pOMeC6H4

Watson, C. G.; Balanta, A.; Elford, T. G.; Essafi, S.; Harvey, J. N.; Aggarwal, V. K. J. Am. Chem. Soc. 2014, 136, 17370.
 Drug Candidate Synthesis

SN2
Me
Me N
Me
Suzuki
N N
O
N
N O
N
Oxazole Synthesis
H 2N N

Me
Me O
Me O
O Me HO Me Cl
B NH2
O Me N
N N
N N Me
H 2N N Br OH H

Me
H

O
Br

Chiral Separation

Senanayake, C. H. et al. Org. Lett. 2014, 16, 4360.

 Drug Candidate Synthesis

Me Me
H Matteson Homologation O Aggarwal Homologation
B Me

O O Me
Br Br
Me
Me

Me Me
CbO Li Me Me

Route 1 Me O O Deprotonation vs Li-Halogen Exchange

B
Br Cheap Chiral Alcohol

Me Me
CbO Li Me Me

Route 2 O O Me Migration is problem

B
Br
Me

Me Me
TIBO Li Me Me

Route 3 Me O O Chiral Alcohol is hard to access

B
4-Br-C6H4

Senanayake, C. H. et al. Org. Lett. 2014, 16, 4360.

Senanayake, C. H. et al. J. Org. Chem. 2015, 80, 1651.
 Drug Candidate Synthesis

Me Me
CbO Li Me Me Me

Me O O Aggarwal Homologation O Me
B
B
O Me
Br Br
Me
Me
excess

OCb OCb CbO Li Li

CbO
Alkyl-Li
Me Me Me Me
Cryogenic Conditions
Br Li Br Br

Me Me Me Me
Me Me OCb Me Me OCb
Alkyl-Li
O O + Me O O + Me
B -10 °C B
Br Alkyl Br

Pre-mix

Senanayake, C. H. et al. Org. Lett. 2014, 16, 4360.

Senanayake, C. H. et al. J. Org. Chem. 2015, 80, 1651.
 Drug Candidate Synthesis

Me Me
CbO Li Me Me Me

Me O O Aggarwal Homologation O Me
B
B
O Me
Br Br
Me
Me
excess

OCb CbO Li CbO Li

LDA
Me Me Me
Cryogenic Conditions
Br Br Br

Epimerization occurs before full conversion

Me Me
Me Me OCb Me
1.2 equiv LDA O Me
O O + Me B
B Me
CMPE -10 °C to 0 °C O
Br Br
Me
Me
1.0 equiv
1.2 equiv 99% Y on 24kg scale
99.9% ee
98.6% ee
Pre-mix

Senanayake, C. H. et al. Org. Lett. 2014, 16, 4360.

Senanayake, C. H. et al. J. Org. Chem. 2015, 80, 1651.
 Drug Candidate Synthesis

Me Me
Me Me OCb Me
1.2 equiv LDA O Me
O O + Me B
B Me
CMPE -10 °C to 0 °C O
Br Br
Me
Me
1.0 equiv
1.2 equiv 99% Y on 24kg scale
99.9% ee
98.6% ee
Pre-mix

Me
CbO Bpin 1,2-Shift O
B Me
Me Me
Fast O
Br
Me
Br Me

Me

Me Bpin
CbO Li 1,2-Shift
O Me
B Me By-product
CbO
Me
+ Me Br
Slow
O
Br
Me Br
Me

Br

Senanayake, C. H. et al. Org. Lett. 2014, 16, 4360.

Senanayake, C. H. et al. J. Org. Chem. 2015, 80, 1651.
 Drug Candidate Synthesis

Me
Me
1.5 equiv LDA O
O Me
B 2.0 equiv DCM
O Me
CMPE -15 °C Br
Br
Me
Me then H2O2

LDA addtion time Yield

< 1min 93%
35 min 25%

Problem : Muliple Homologation:

Li
Li
Me Me Me Cl Cl Me Cl
Cl Cl 1,2-Shift
Bpin
Bpin Bpin Bpin
Fast
Cl Cl
Br Br Cl Cl Br Br

Senanayake, C. H. et al. J. Org. Chem. 2015, 80, 1651.

 Drug Candidate Synthesis

Me Me
1.5 equiv LDA
O Me O
B 2.0 equiv DCM
O Me
THF/1,4-Dioxane -45 °C to r.t
Br Br
Me
Me then H2O2

94 %Y

What is the trick? Me

Bpin
Me
Li Li
LDA Br Bpin
-45 °C DCM +
Cl Cl Cl Cl
Br Cl Cl
Excess

Me

Bpin Li Cl
-25 °C
Br Cl Cl Cl Cl Cl

Inert Fast Decomposion

Me
> -15 °C Me
1,2-Shift
Bpin Bpin
Fast
Br Cl Cl Cl
Br

Senanayake, C. H. et al. J. Org. Chem. 2015, 80, 1651.

 Programmable Temperature Enabled Assemble Line Synthesis

Me
Me Me
Me
O Me
O Me
M M M
O B Me
B Me RO B Me RO O
O RO
O Me
Me
Me

Auto Synthesis with Reagent Controlled Chirality

Working Hypothesis:

O Me
B
O Me
Me
Me

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

Me
Me Me
Me
O Me
O Me
M M M
O B Me
B Me RO B Me RO O
O RO
O Me
Me
Me

Auto Synthesis with Reagent Controlled Chirality

Working Hypothesis: Me
1.3 eq Li Me
O
TIBO
B Me Li
O Me
- 78 °C 0.5 h TIBO
OBIT
Me
Me
O - 42 °C 1h
Me
B Me
O
Me
Me
O
B Me
O Me
r.t. 1 h
OBIT

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

High Purity Reagents:

Me Me
O
SnMe3
SnMe3 sBuLi + (–)-sp
sBuLi + (+)-sps Me O
then SnMe3Cl Me OTIB
Me OTIB then Et-Bpin Me Me
82% ee
79% ee
Me Me 99.8% ee (Recryst)
99.8% ee (Recryst)

Working Hypothesis: Me
1.3 eq Li Me
O
TIBO
B Me Li
O Me
- 78 °C 0.5 h TIBO
OBIT
Me
Me
O - 42 °C 1h
Me
B Me
O
Me
Me
O
B Me
O Me
r.t. 1 h
OBIT

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

State of Art:

Aq\Work Up Aq\Work Up H2O2\Work Up

OTIB OTIB
OTIB OTIB OTIB
Me
Me Li Me Li
Me Li Me Li Me Li
Bpin
OTIB OTIB OTIB
OTIB
Ph
Me Li Me Li Me Li
Me Li

Me Me Me Me Me
+8C 1
OH 58% IY
+9C 97
> 99:1 d.r.
+ 10 C 2
Me Me Me Me Me
Ph

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

State of Art:

Aq\Work Up Aq\Work Up H2O2\Work Up

OTIB OTIB
OTIB OTIB OTIB
Me
Me Li Me Li
Me Li Me Li Me Li
Bpin
OTIB OTIB OTIB
OTIB
Ph
Me Li Me Li Me Li
Me Li

Me Me Me Me Me
+8C 1
OH 44% IY
+9C 94
> 99:1 d.r.
+ 10 C 5
Me Me Me Me Me
Ph

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

State of Art:

Aq\Work Up Aq\Work Up H2O2\Work Up

OTIB OTIB
OTIB OTIB OTIB
Me
Me Li Me Li
Me Li Me Li Me Li
Bpin
OTIB OTIB OTIB
OTIB

Me Li Me Li Me Li
Me Li

Me Me Me Me Me
+8C 0
OH 45% IY
+9C 97
> 99:1 d.r.
+ 10 C 3
Me Me Me Me Me

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
 From Hydrocarbon to Polypropionates

Me Me Me Me Me Me Me Me
C15H31
HO2C

(+)- Hydroxyphthioceranic acid OH

Me
OH OH OH OH OH OH OH

O
H
Me Me Me Me Me Me Me
Polyketides Fragments Anti-Anti

Why Oxygen is difficult?

OTBS OTIB OTBS OTBS OTBS

Bpin Bpin
TBSO Li OTIB
R Bpin
Me Conformation Stability Me M
OTBS

OTBS
Bpin Bpin OTIB
R OTIB Me
R
Me OTBS
OPG

Bootwicha, T.; Feilner, J. M.; Myers, E. L.; Aggarwal, V. K. Nat. Chem. 2017, 9, 896.
 Using Si Atom Instead of Oxygen

OMe OMe
N Li N Li
SiS SiR
Si Cl Si Cl
Me Me Me Me

N
Me Me OMe
SiS [SiS] Me Si
Me O
B
Me Et2O –78 °C to r.t. Bpin Bpin
O
Me

[SiS] [SiS] [SiS] [SiR]

[SiS]
tBuO C tBuO C
2 2
Bpin Bpin Bpin Bpin
N Bpin
N Boc
Me
Bn Bn

79% IY 71% IY 71% IY 77% IY 79% IY

92:8 d.r. 91:9 d.r. ≥ 98:2 d.r. 95:5 d.r. 95:5 d.r.

Bootwicha, T.; Feilner, J. M.; Myers, E. L.; Aggarwal, V. K. Nat. Chem. 2017, 9, 896.
 Using Si Atom Instead of Oxygen

OMe OMe
N Li N Li
SiS SiR
Si Cl Si Cl
Me Me Me Me

N
Me Me OMe
SiS [SiS] Me Si
Me O
B
Me Et2O –78 °C to r.t. Bpin Bpin
O
Me

[SiS] [SiS] [SiS] [SiR]

[SiS]
tBuO C tBuO C
2 2
Bpin Bpin Bpin Bpin
N Bpin
N Boc
Me
Bn Bn

79% IY 71% IY 71% IY 77% IY 79% IY

92:8 d.r. 91:9 d.r. ≥ 98:2 d.r. 95:5 d.r. 95:5 d.r.

Bootwicha, T.; Feilner, J. M.; Myers, E. L.; Aggarwal, V. K. Nat. Chem. 2017, 9, 896.
 Transfer Si Atom to Oxygen

Me OMe
N 2 mol% [Ir]
Me Si OH
Me OMe 1.5 equiv Methyl Acrylate Urea•H2O2
Me Si Bpin OH
Bpin MeCN/MeOH = 1: 1 r.t. KF, KHCO3
34 w Blue LED 75%-80% Y THF, MeOH

F F

Me OMe t-Bu
Me Si N N Li
+ No Reaction N N
Bn Bpin OMe Ir CF3
Si Cl F
Me Me N
Me
N
t-Bu

Me OMe F
F3C
Me OMe
Me Si [SiR]
Me Si OMe
N Li Bn
+ Bpin
Bn Bpin
Si Cl Me
Me 80% IY
Me Me
d.r. = 94 : 6

Bootwicha, T.; Feilner, J. M.; Myers, E. L.; Aggarwal, V. K. Nat. Chem. 2017, 9, 896.
 Transfer Si Atom to Oxygen : Proposed Mechanism

Me OMe
N 2 mol% [Ir]
Me Si
Me OMe 1.5 equiv Methyl Acrylate
Me Si Bpin
MeCN/MeOH = 1: 1 r.t.
Bpin
34 w Blue LED 75%-80% Y

*IrIII
oxidant IrIII
Photoredox
MeOH Catalytic
+•
Cycle
N
Me OMe
Me OMe Me Si
SET SET
H+ Si
Me R
R IrII
reductant

N
CO2Me OMe
N Me
N Me Si
OMe
SET OMe
MeO2C R

Bootwicha, T.; Feilner, J. M.; Myers, E. L.; Aggarwal, V. K. Nat. Chem. 2017, 9, 896.
 Iterative Assembly Line Synthesis of Polypropionate

MeO
SiS Ir MeS SiMe2OMe SiR Ir MeS SiMe2 SiMe2OMe
C
Bpin Bpin
Bpin
Me Me Me

[O]
Li
MeS
Li Cl C
TIBO Me
OH OH

OH
Me Me

38% IY > 95:5 d.r.

SiR Ir C x3 SiMe2OMe Li
SiR Ir [O] OH OH OH OH
Bn Bpin Bn Bpin
3
then I2/MeONa
26% IY > 95:5 d.r. Bn

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

Me Ph Me
Me OTf 1 mol% Pd(OAc)2 Ar2P Fe
O OH
1.5 mol% L* H2O2/NaOH NMe2 Ar = OMe
B + Ph
O
PAr2
THF 60 °C 14 h Me
NMe2
Chiral Ligand

Bneo ArOTf
Ar Pd(0)
R

Me
Bneo
Cationic PdII is the Key Ar-PdII-OTf Me
O
PdII-Ar
R B
O
R

Ar-PdII

Bneo
R

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

Me Ph Me
OTf 1 mol% Pd(OAc)2 Ar2P Fe
Me
O OH
1.5 mol% L* H2O2/NaOH NMe2 Ar = OMe
+ Ph
B
O PAr2
THF 60 °C 14 h Me
NMe2
Chiral Ligand

OH OH
OH OH
Ph Ph
Ph Ph CHO
CO2Me

83% IY 68% IY 73% IY 41% IY

94% es 92% ee 90% ee 80% ee

OH
OH OH
MeO Ph
OH Ph
Ph
TMS Ph
N MeO
Me
OMe

80% IY 48% IY 86% IY 77% IY

90% ee 76% ee 90% ee 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
O Me Me
1. 1.3 equiv t-BuLi 3 mol% Pd(dba)2
Ar
S O Me 3.6 mol% dippf (iPr)2P Fe
2. Bpin B Me 1.2 equiv Ar-OTf
O
Me Bpin
1.0 equiv MeTHF 40 °C 14 h P(iPr)2
1.3 equiv dippf

Br
Ar
N.R.
ArOTf
R
Pd(0)
Bpin

PdII-Ar
Cationic PdII is the Key Ar-PdII-OTf
R H
Bpin Bpin
R
Me Me
Me
Me
H
O O
B
Ar-PdII
R

Fawcett, A.; Biberger, T.; Aggarwal, V. K. Nat. Chem. 2019, 11, 117.
 Merging Pd Catalysis with Boron-1,2-Shift
O Me Me
1. 1.3 equiv t-BuLi 3 mol% Pd(dba)2
Ar
S O Me 3.6 mol% dippf (iPr)2P Fe
2. Bpin B Me 1.2 equiv Ar-OTf
O
Me Bpin
1.0 equiv MeTHF 40 °C 14 h P(iPr)2
1.3 equiv dippf

Br
Ar
N.R.
ArOTf
R
Pd(0)
Bpin

PdII-Ar
Cationic PdII is the Key Ar-PdII-OTf
R H
Bpin Bpin
R
Me Me
Me
Me
H
O O
B
Ar-PdII
R

Fawcett, A.; Biberger, T.; Aggarwal, V. K. Nat. Chem. 2019, 11, 117.
 Merging Pd Catalysis with Boron-1,2-Shift
O Me Me
1. 1.3 equiv t-BuLi 3 mol% Pd(dba)2
Ar
S O Me 3.6 mol% dippf (iPr)2P Fe
2. Bpin B Me 1.2 equiv Ar-OTf
O
Me Bpin
1.0 equiv MeTHF 40 °C 14 h P(iPr)2
1.3 equiv dippf

Bpin

N
Br
Cy Cy Cy Cy
Bpin Bpin Bpin Bpin

58% IY 74% IY 62% IY 78% IY

>98:2 d.r. >98:2 d.r. >98:2 d.r. >98:2 d.r.

Ph
Ph Ph Ph
Me
Ph Bpin BocN
tBuO C
2 Bpin Bpin Bpin
PMP

40% IY 77% IY 100% es 76% IY 52% IY

>98:2 d.r. >98:2 d.r. >98:2 d.r. >98:2 d.r.

Fawcett, A.; Biberger, T.; Aggarwal, V. K. Nat. Chem. 2019, 11, 117.
 Merging Racical Reaction with Boron-1,2-Shift

Me Me Me Me
Me Me Me
Me 5 mol% BEt3 Rf OH
Li O O 5.0 equiv Rf-I
O O
B B
Et2O, 0 °C to r.t. MeCN 80 °C 24 h
then NaOH, H2O2

Rf I

F F

Me

Me Me
Me Me
F Me Me
F F Me Me
O O F
Rf B Rf
O O
B
I
Me Me
Me
Atom Transfer
F O Me
F 1,2-Shift Me Me
Rf B O Me Me

F F
O O
Rf I Rf B

F F

Kischkewitz, M.; Okamoto, K.; Mück-Lichtenfeld, C.; Studer, A. Science 2017, 355, 936.
 Merging Racical Reaction with Boron-1,2-Shift

Me Me Me Me
Me Me Me
Me 5 mol% BEt3 Rf OH
Li O O 5.0 equiv Rf-I
O O
B B
Et2O, 0 °C to r.t. MeCN 80 °C 24 h
then NaOH, H2O2

OH
OH OH OH
Et C4F9
C4F9 C4F9 C10F21
Ph Ph Et
Me Me
Me Me
Me Me
F F
68% IY O IY O
65% 65% IY 36% IY
Rf B
1:1 d.r.
I
O O
OH OH
O O F
CF3
F Ph CN Ph
Me
Et Me Et Me

Rf I

77% IY 58% IY F F 61% IY 41% IY

With Togni I

Kischkewitz, M.; Okamoto, K.; Mück-Lichtenfeld, C.; Studer, A. Science 2017, 355, 936.
 Merging Racical Reaction with Boron-1,2-Shift

Me Me Me Me
EWG
Me Me Me
Me Bpin
1.5 equiv EWG-CH2I
Li O O
O O
B B
DMI r.t. 16 h
Et2O, 0 °C to r.t. 34W Blue LED
then NaOH, H2O2

O
I
Ph

Me Me
Me Me I O
Me Me
O Me Me
O O Ph
B
+ O O
Ph B
Me Me
Me
SET
O O Me
1,2-Shift Me Me
B O Me Me
Ph O O
O O
I B
Ph
Ph

Silvi, M.; Sandford, C.; Aggarwal, V. K. J. Am. Chem. Soc. 2017, 139, 5736.
 Merging Racical Reaction with Boron-1,2-Shift

Me Me Me Me
EWG
Me Me Me
Me Bpin
1.5 equiv EWG-CH2I
Li O O
O O
B B
DMI r.t. 16 h
Et2O, 0 °C to r.t. 34W Blue LED
then NaOH, H2O2

Me Me Me Me Me Me Me Me
Me Me Me Me Me Me Me Me

O O O O O O O O
B B B B
Me Me
Ph Ph Ph Ph
Ph Me
Me Et Me Me Me
O Me Me
O O O

81% IY 88% IY 88% IY 74% IY

Me Me Me Me Me Me Me Me
Me Me Me Me Me Me Me Me

O O O O O O O O
B B B F F B CO2Et
Ph
Ph CF3 Ph CO2Et CO2Et
Et Me Et Me
O

65% IY 68% IY 69% IY 70% IY

With 1 mol% Ru[bpy]3Cl2 With 1 mol% Ru[bpy]3Cl2

Silvi, M.; Sandford, C.; Aggarwal, V. K. J. Am. Chem. Soc. 2017, 139, 5736.