copper-catalyzed reactions with diborons: from the beginning to recent results

Copper-CatalyzedReactionswithDiborons: FromtheBeginningtoRecentResults

HajimeIto,HokkaidoUniversity,Japan

HokkaidoUniversityinSapporoCity

HokkaidoUniversity

FacultyMembers:4000

HokkaidoUniversity

UndergraduateStudents:12000

GraduateStudents:6000

HokkaidoUniversity

FacultyMembers:4000

HokkaidoUniversity

UndergraduateStudents:12000

GraduateStudents:6000

AkiraSuzuki 2010NobelPrizeWinner

ResearchesinIto’sGroup

Cu catalysis (2000−)

Si-B/base Chemistry (2012−)

J. Am. Chem. Soc., 2012, 134, 19997; Chem. Sci. 2015, 6, 2943.

BorylationReactions

Angew. Chem., Int. Ed. 2015, 54, 8809. J. Am. Chem. Soc. 2015, 137, 420. J. Am. Chem. Soc. 2014, 136, 16515. J. Am. Chem. Soc. 2013, 135, 2635. Org. Lett. 2012, 14, 890. Angew. Chem., Int. Ed. 2011, 50, 2778. J. Am. Chem. Soc. 2010, 132, 11440. J. Am. Chem. Soc. 2010, 132, 1226 .

J. Am. Chem. Soc. 2010, 132, 5990. Angew. Chem., Int. Ed. 2010, 122, 570. Nature Chemistry 2010, 2, 972. J. Am. Chem. Soc. 2008, 130, 15774. Angew. Chem., Int. Ed. 2008, 47, 7424. J. Am. Chem. Soc. 2007, 129, 14856. J. Am. Chem. Soc. 2005, 127, 16034.

DFT calculation: J. Am. Chem. Soc. 2015, 137, 4090.

EWG(pin)B B(pin)

Cu cat.EWG

(pin)B

Ito, Hosomi Tetrahedron Lett. 2000, 40, 7807.(Ishiyama, Miyaura, Chem. Lett. 2000, 982.)

Chem. Sci., 2015, 6, 2187.

Mechano-ResponsiveMaterial

J. Am. Chem. Soc. 2008, 130, 10044.

Nature Comm. 2013, 4, 2009.

Angew. Chem., Int. Ed. 2013, 52, 12828, VIP.Chem. Sci., 2015, 6, 1491.

Chem. Sci., 2015, 6, 2187.

BoronicAcids:PreparationandApplicationsinOrganicSynthesis,MedicineandMaterials,2ndreviseded.; Hall,D.G.,Ed.;Wiley-VCH:Weinheim,2011.

B

R1 R1

H

C

R1 R1

H

HO

R1 R1

H

H2N

R1 R1

H

VersatileBuildingBlock

MajorSyntheticMethods・Hydroboration・Electrophilicreactionsofboronreagents・Pd-catalyzedreactionsofB2pin2(Miyaura’sprocedure)

OrganoboronCompounds

NopracticalnucleophilicreactionsofboronreagentsLowelectronegativityofB(2.0)makesgenerationofBaniondif@icult.

・Hydroboration

Hydroborationisnottheperfectsolution.

■Brown’sasymmetrichydroborationwithstoichiometricchiralgroup

BH2 +

H B(ipc)2 H OHoxidation

99% ee

OH+ 2

H. C. Brown (1961)

・Hydroboration

Hydroborationisnottheperfectsolution.

■Asymmetriccatalytichydroborationwaslimited.

Ph

[Rh(cod)2]BF4 (1 mol %)(R)-BINAP (1 mol %)

–78°C, 6 h

OHB

O+ Ph

B(cat)

91%, 96.2 % ee

Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 3426.!

■Brown’sasymmetrichydroborationwithstoichiometricchiralgroup

BH2 +

H B(ipc)2 H OHoxidation

99% ee

OH+ 2

H. C. Brown (1961)

・RLi,RMgXandBoronElectrophiles

RLiandRMgBrstillhavelimitations.

M R X BX

X

−MXR B

X

X

Highlybasicconditions,lowfunctionalgroupcompatibility

・RLi,RMgXandBoronElectrophiles

RLiandRMgBrstillhavelimitations.

M R X BX

X

−MXR B

X

X

Highlybasicconditions,lowfunctionalgroupcompatibility

N

Ph O N(i-Pr)2

O

(-)-sparteine

s-BuLi–78°C

Ph O N(i-Pr)2

OLi

H

N

Ph O N(i-Pr)2

OB

H

OO

Et

Et BO

O

MgBr2

PhBO

OEt

90%, 96% ee

R Li BX

■ChiralOrganoboron(Aggarwaletal)

Cu Cl +

NN

O

(DMI)(THF)

O

H SiCH3

CH3

Copper-CatalyzedHydrosilylation

no reaction

Cu Cl +

NN

O

(DMI)(THF)

O

H SiCH3

CH3


no reaction(DMI)nCu H(DMI)nCu

Cl

HSi

Cu Cl +

NN

O

(DMI)(THF)

O

H SiCH3

CH3


no reaction(DMI)nCu H(DMI)nCu

Cl

HSi

Ito, H.; Ishizuka, T.; Arimoto, K.; Miura, K.; Hosomi, A. Tetrahedron Lett. 1997, 38, 8887.

O

H Si+cat. CuCl

DMI, rt

O

H92%

H3O+CH3

CH3

Cu Cl +

NN

O

(DMI)(THF)

O

H SiCH3

CH3

Catalysis


StoichiometricReaction

OurPreliminaryCopper-CatalyzedReactions


■Hydorsilylaiton

CuCl / DMI / R3SiH:Ito, H.; Ishizuka, T.; Arimoto, K.; Miura, K.; Hosomi, A. Tetrahedron Lett. 1997, 38, 8887.

O

H Si+cat. CuCl

DMI, rt

O

H92%

H3O+CH3

CH3

CuX

SiH

Cu H

L

L

FCu(PPh3) / R3SiH: Mori, A.; Fujita, A.; Nishihara, Y.; Hiyama, T. Chem. Commun. 1997, 2159.


■Silylationwithdisilanes

Si Ph+

cat. CuOTf PBu3

DMI, rt

H3O+O

SiPh

O

SiPh

Ito, H.; Ishizuka, T.; Tateiwa, J.; Sonoda, M.; Hosomi, A. J. Am. Chem. Soc. 1998, 120, 11196.

CuX

SiSi

Cu Si

L

L

■Hydorsilylaiton

CuCl / DMI / R3SiH:Ito, H.; Ishizuka, T.; Arimoto, K.; Miura, K.; Hosomi, A. Tetrahedron Lett. 1997, 38, 8887.

O

H Si+cat. CuCl

DMI, rt

O

H92%

H3O+CH3

CH3

CuX

SiH

Cu H

L

L

FCu(PPh3) / R3SiH: Mori, A.; Fujita, A.; Nishihara, Y.; Hiyama, T. Chem. Commun. 1997, 2159.

EarlyStudiesonDiboron/CuCatalysis

CuCl/KOAc: Takahashi, K.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 982. CuX/PR3: Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron Lett. 2000, 41, 6821.

+

cat. CuX PR3

DMI, rt

H3O+

OO

BB B

O

OO

O

OO

87%

■FirstCu-CatalyzedFormalNucleophilicBorylation



+

cat. CuX PR3

DMI, rt

H3O+

OO

BB B

O

OO

O

OO

87%


CuX

BB

Cu BL

L

✔Boryl-CopperIntermediateBoronNucleophilicity LigandControlledSelectivity


Segawa, Y.; Yamashita, M.; Nozaki, K. Science 2006, 314, 113.

NNBBr

iPr

iPr iPr

iPr

NNBLi

iPr

iPr iPr

iPrLi, naphthalene

THF

■Generationof”Boryl-Anion”wasdif]icult.


+

cat. CuX PR3

DMI, rt

H3O+

OO

BB B

O

OO

O

OO

87%


CuX

BB

Cu BL

L




+

cat. CuX PR3

DMI, rt

H3O+

OO

BB B

O

OO

O

OO

87%


CuX

BB

Cu BL

L


R M X B R B

FornmalNucleophilicborylation

▶ ▶Mildreactionconditions

B CuR X R B

Umpolung

▶Catalyticasymmetricsynthesis▶

Electrophilicborylation

HighlybasicconditionsStoichiometricreaction

M R

Xantphos/Cu shows High reactivity High regio- and E/Z selectivity

Ito, H.; Kawakami, C.; Sawamura, M. J. Am. Chem. Soc. 2005, 127, 16034.

Cu(O-t-Bu)/ ligand(5 mol %)

GC yield, %

dppf

100

3744

Xantphos

Ligand E : Z a

97 : 399 : 1

96 : 4> 99 : < 197 : 3 > 99 : < 1

11 62 : 38> 99 : < 1

γ : α

dppedppp

OPPh2Ph2P

+

2.0 equiv.

OB

O

OB

O

Xantphos:

Pd(dba)2 0 57 : 43

R

OCO2Me

R

B

R = (CH2)3Ph

O O

γ

THF, rt, 3 h

BCu

OR

L

B

AllyboronSynthesis:Xantphos/Cu

S R

2.4 equiv.

Bu

B(pin)MeO2CO Bu(pin)B B(pin)+

THF, 0 °C, 40 h

10 mol% Cu(O-t-Bu)ーXantphos

88%, 97% eeγ:α = >99:1, E:Z = >99:1

97% ee


C CR2C

H R1R3

OR

HC C

B

R1R2

H

CR3H

C CR2C

H R1R3

OR

H

Cu BLL Cu B

■Cu/Xantphos:anti-SN2’reaction

AllyboronSynthesis:AsymmetricReactions

S R

2.4 equiv.

Bu

B(pin)MeO2CO Bu(pin)B B(pin)+

THF, 0 °C, 40 h

10 mol% Cu(O-t-Bu)ーXantphos

88%, 97% eeγ:α = >99:1, E:Z = >99:1

97% ee


C CR2C

H R1R3

OR

HC C

B

R1R2

H

CR3H

C CR2C

H R1R3

OR

H

Cu BLL Cu B

■Cu/Xantphos:anti-SN2’reaction

AllyboronSynthesis:AsymmetricReactions

■AsymmetricCu-catalyzedAllylboronSynthesis

Ito, H.; Ito, S.; Sasaki, Y.; Matsuura, K.; Sawamura, M. J. Am. Chem. Soc. 2007, 129, 14856.

N

N P

P

t-BuMe

t-Bu Me

(R,R)-QuinoxP*

R OCO2Me B BO

OO

O+

5 mol% Cu(O-t-Bu)/ chiral ligand

THF, 0 °C20 h R

BOO

78%, 96% eeR = PhCH2CH2


Mun, S.; Lee, J. E.; Yun, J. Org Lett. 2006, 8, 4887, Lee, J.-E.; Yun, J. Angew. Chem., Int. Ed. 2008, 47, 145.

R EWG B BO

OO

O+

cat. CuCl/Na(O-t-Bu)

chiral ligand, ROHR EWGB

OO Fe PPh2

PCy2

(R)-(S)-Josiphos*

■FirstEnantioselectiveReactionsbyYun



R EWG B BO

OO

O+



OO Fe PPh2

PCy2

(R)-(S)-Josiphos*


■FirstIsolationofBorylcopperSpecies

Efficient Homogeneous Catalysis in the Reduction of CO2 to CODavid S. Laitar, Peter Muller, and Joseph P. Sadighi*

Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts AVenue,Cambridge Massachusetts 02139

Received September 28, 2005; E-mail: [email protected]

Nature uses carbon dioxide, on a massive scale, as a one-carbonbuilding block for the synthesis of organic molecules.1 An importantpathway for the consumption of CO2 is its reduction to CO by theenzyme acetyl-CoA synthase/CO dehydrogenase (ACS-CODH).2Due to the large energy input required to generate it from CO2,CO is produced industrially from fossil fuels.3 Even with strongreducing agents, however, overcoming the OdCO bond enthalpyof 532 kJ/mol4 often presents kinetic difficulties.5,6Certain metal complexes abstract oxygen readily from CO2,7 but

the resulting metal-oxygen bonds are necessarily strong, andcatalytic turnover is rare.8 Photolytic9 and photocatalytic10 ap-proaches show promise, and synthetic electrocatalysts have achievedimpressive yields and selectivities in the reduction of CO2 to CO.11However, the chemical processes involved are obscure, making itdifficult to improve these systems by design, and CODH remainsnotably the most efficient catalyst for this reduction.12 We reportherein that a new carbene-supported copper(I) boryl complexabstracts oxygen from CO2 and undergoes subsequent turnoverreadily. Using an easily handled diboron reagent as the net oxygenacceptor,13 these key steps permit unprecedented turnover numbersand frequencies for the chemical reduction of CO2 to CO in ahomogeneous system.While exploring the chemistry of organocopper(I) complexes

supported by N-heterocyclic carbene (NHC) ligands,14 we soughtto synthesize a copper(I) boryl complex and explore its reactivitytoward CO2. Metal boryls often display distinctive reactivity,15catalyzing a number of remarkable transformations.16 AlthoughC-B bond-forming reactions have been achieved using diboroncompounds with catalytic17a or stoichiometric17b copper(I), well-defined copper boryl complexes have not been described.The known (IPr)Cu(Ot-Bu) reacts rapidly with bis(pinacolato)-

diboron (pinB-Bpin), forming a product identified as (IPr)Cu(Bpin)(1, Scheme 1) by 1H and 11B NMR spectroscopy. Diffusion ofhexane vapor into a concentrated solution of 1 in toluene, carriedout at -40 °C to avoid thermal decomposition,18 produces singlecrystals suitable for analysis by X-ray diffraction. The resultingstructure (Figure 1a) shows a monomeric, nearly linear coordinationgeometry with a Cu-B distance of 2.002(3) Å.Complex 1 reacts with CO2 under atmospheric pressure in C6D6

solution, quantitatively forming a new complex within minutes. Theresonance for 1 in the 11B NMR spectrum, a broad singlet at 41.7ppm, is replaced by a singlet at 21.8 ppm, indicative of boron boundto three oxygen atoms.19 Single crystals of this new copper complexare grown by diffusion of hexane vapor into a concentrated toluenesolution. The X-ray crystal structure (Figure 1b) reveals the productto be (IPr)Cu(OBpin) (2): The copper boryl complex abstractsoxygen from CO2, implying the release of CO as the byproduct.To confirm the formation of CO, 13C-labeled CO2 is introduced

to a resealable NMR tube containing a solution of 1 in THF-d8 at-80 °C. After 30 min of gradual warming, analysis by 11B (Figure2a) and 1H NMR spectroscopy at -40 °C indicates complete

conversion of 1 to 2. The sole labeled products visible in the 13CNMR spectrum (Figure 2b) are 13CO (δ 184 ppm) and an adduct(δ 164 ppm) formed reversibly from CO and borate 2.20Treatment of 2 in C6D6 solution with pinB-Bpin smoothly

regenerates 1, forming the stable byproduct pinB-O-Bpin,21 overa reaction time of about 20 min. The success of this turnover stepcloses a catalytic cycle for the deoxygenation of CO2. Addition ofa THF solution of (IPr)Cu(Ot-Bu) to a 100-fold excess of pinB-Bpin under an atmosphere of CO2 results in the complete conversionof pinB-Bpin to pinB-O-Bpin within 20 h at ambient temper-ature, as judged by 11B NMR analysis of an aliquot from the reactionmixture (Figure 3a). When labeled CO2 is used as the limitingreagent, in the presence of ca. 2 mol % of precatalyst 1, the 13CNMR spectrum indicates complete consumption of CO2, with COrepresenting the sole significant product (Figure 3b).In the absence of copper catalyst, under otherwise identical

conditions, no pinB-O-Bpin is detected, demonstrating that thediboron compound by itself is kinetically unable to reduce CO2 toany observable extent. Control reactions run using copper precata-lyst and pinB-Bpin in the absence of CO2 (under an atmosphere

Scheme 1 a

a Isolated yield, contains some 2 (5 mol % by 11B NMR); (b) reaction iscomplete in <10 min at ambient temp; (c) L ) IPr or ICy.

Figure 1. X-ray crystal structures, shown as 50% thermal ellipsoids, ofboryl complex 1‚C6H14 (a), and borate 2‚C7H8 (b). Hydrogen atoms (calcd)and solvent are omitted for clarity. Selected bond lengths (Å) and angles(deg), (a): Cu(1)-B(1) 2.002(3), Cu(1)-C(1) 1.937(2), C(1)-N(1) 1.363(3),C(1)-N(2) 1.363(3), C(1)-Cu(1)-B(1) 168.07(16), N(1)-C(1)-N(2)102.97(18); (b): Cu(1)-O(1) 1.8096(16), O(1)-B(1) 1.306(3), Cu(1)-C(1) 1.857(2), C(1)-N(1) 1.355(3), C(1)-N(2) 1.364(3), C(1)-Cu(1)-O(1) 174.85(10), B(1)-O(1)-Cu(1) 133.61(16), N(1)-C(1)-N(2) 103.09(18).

Published on Web 11/18/2005

17196 9 J. AM. CHEM. SOC. 2005, 127, 17196-17197 10.1021/ja0566679 CCC: $30.25 © 2005 American Chemical Society

NN

Cu

tBuOiPr

iPr

iPr

iPr

NN

CuiPr

iPr

iPr

iPr

B(pin)

(pin)B-B(pin)

Laitar, D. S.; Müller, P.; Sadighi, J. P. J. Am. Chem. Soc. 2005, 127, 17197.



R EWG B BO

OO

O+



OO Fe PPh2

PCy2

(R)-(S)-Josiphos*


■ChiralNHCLigand

Lee, Y.; Hoveyda, A. J. Am. Chem. Soc. 2009, 131, 3160.

N N

Ph Phi-Pr

i-Pr i-Pr

SO3–

Ph (pin)B B(pin)+cat.CuCl/K(O-t-Bu)

THF, –50°C, 48 h, MeOH, 2.0 equiv

+

PhB(pin)

80%, 98% ee

■FirstIsolationofBorylcopperSpecies

Efficient Homogeneous Catalysis in the Reduction of CO2 to CODavid S. Laitar, Peter Muller, and Joseph P. Sadighi*

Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts AVenue,Cambridge Massachusetts 02139

Received September 28, 2005; E-mail: [email protected]

Nature uses carbon dioxide, on a massive scale, as a one-carbonbuilding block for the synthesis of organic molecules.1 An importantpathway for the consumption of CO2 is its reduction to CO by theenzyme acetyl-CoA synthase/CO dehydrogenase (ACS-CODH).2Due to the large energy input required to generate it from CO2,CO is produced industrially from fossil fuels.3 Even with strongreducing agents, however, overcoming the OdCO bond enthalpyof 532 kJ/mol4 often presents kinetic difficulties.5,6Certain metal complexes abstract oxygen readily from CO2,7 but

the resulting metal-oxygen bonds are necessarily strong, andcatalytic turnover is rare.8 Photolytic9 and photocatalytic10 ap-proaches show promise, and synthetic electrocatalysts have achievedimpressive yields and selectivities in the reduction of CO2 to CO.11However, the chemical processes involved are obscure, making itdifficult to improve these systems by design, and CODH remainsnotably the most efficient catalyst for this reduction.12 We reportherein that a new carbene-supported copper(I) boryl complexabstracts oxygen from CO2 and undergoes subsequent turnoverreadily. Using an easily handled diboron reagent as the net oxygenacceptor,13 these key steps permit unprecedented turnover numbersand frequencies for the chemical reduction of CO2 to CO in ahomogeneous system.While exploring the chemistry of organocopper(I) complexes

supported by N-heterocyclic carbene (NHC) ligands,14 we soughtto synthesize a copper(I) boryl complex and explore its reactivitytoward CO2. Metal boryls often display distinctive reactivity,15catalyzing a number of remarkable transformations.16 AlthoughC-B bond-forming reactions have been achieved using diboroncompounds with catalytic17a or stoichiometric17b copper(I), well-defined copper boryl complexes have not been described.The known (IPr)Cu(Ot-Bu) reacts rapidly with bis(pinacolato)-

diboron (pinB-Bpin), forming a product identified as (IPr)Cu(Bpin)(1, Scheme 1) by 1H and 11B NMR spectroscopy. Diffusion ofhexane vapor into a concentrated solution of 1 in toluene, carriedout at -40 °C to avoid thermal decomposition,18 produces singlecrystals suitable for analysis by X-ray diffraction. The resultingstructure (Figure 1a) shows a monomeric, nearly linear coordinationgeometry with a Cu-B distance of 2.002(3) Å.Complex 1 reacts with CO2 under atmospheric pressure in C6D6

solution, quantitatively forming a new complex within minutes. Theresonance for 1 in the 11B NMR spectrum, a broad singlet at 41.7ppm, is replaced by a singlet at 21.8 ppm, indicative of boron boundto three oxygen atoms.19 Single crystals of this new copper complexare grown by diffusion of hexane vapor into a concentrated toluenesolution. The X-ray crystal structure (Figure 1b) reveals the productto be (IPr)Cu(OBpin) (2): The copper boryl complex abstractsoxygen from CO2, implying the release of CO as the byproduct.To confirm the formation of CO, 13C-labeled CO2 is introduced

to a resealable NMR tube containing a solution of 1 in THF-d8 at-80 °C. After 30 min of gradual warming, analysis by 11B (Figure2a) and 1H NMR spectroscopy at -40 °C indicates complete

conversion of 1 to 2. The sole labeled products visible in the 13CNMR spectrum (Figure 2b) are 13CO (δ 184 ppm) and an adduct(δ 164 ppm) formed reversibly from CO and borate 2.20Treatment of 2 in C6D6 solution with pinB-Bpin smoothly

regenerates 1, forming the stable byproduct pinB-O-Bpin,21 overa reaction time of about 20 min. The success of this turnover stepcloses a catalytic cycle for the deoxygenation of CO2. Addition ofa THF solution of (IPr)Cu(Ot-Bu) to a 100-fold excess of pinB-Bpin under an atmosphere of CO2 results in the complete conversionof pinB-Bpin to pinB-O-Bpin within 20 h at ambient temper-ature, as judged by 11B NMR analysis of an aliquot from the reactionmixture (Figure 3a). When labeled CO2 is used as the limitingreagent, in the presence of ca. 2 mol % of precatalyst 1, the 13CNMR spectrum indicates complete consumption of CO2, with COrepresenting the sole significant product (Figure 3b).In the absence of copper catalyst, under otherwise identical

conditions, no pinB-O-Bpin is detected, demonstrating that thediboron compound by itself is kinetically unable to reduce CO2 toany observable extent. Control reactions run using copper precata-lyst and pinB-Bpin in the absence of CO2 (under an atmosphere

Scheme 1 a

a Isolated yield, contains some 2 (5 mol % by 11B NMR); (b) reaction iscomplete in <10 min at ambient temp; (c) L ) IPr or ICy.

Figure 1. X-ray crystal structures, shown as 50% thermal ellipsoids, ofboryl complex 1‚C6H14 (a), and borate 2‚C7H8 (b). Hydrogen atoms (calcd)and solvent are omitted for clarity. Selected bond lengths (Å) and angles(deg), (a): Cu(1)-B(1) 2.002(3), Cu(1)-C(1) 1.937(2), C(1)-N(1) 1.363(3),C(1)-N(2) 1.363(3), C(1)-Cu(1)-B(1) 168.07(16), N(1)-C(1)-N(2)102.97(18); (b): Cu(1)-O(1) 1.8096(16), O(1)-B(1) 1.306(3), Cu(1)-C(1) 1.857(2), C(1)-N(1) 1.355(3), C(1)-N(2) 1.364(3), C(1)-Cu(1)-O(1) 174.85(10), B(1)-O(1)-Cu(1) 133.61(16), N(1)-C(1)-N(2) 103.09(18).

Published on Web 11/18/2005

17196 9 J. AM. CHEM. SOC. 2005, 127, 17196-17197 10.1021/ja0566679 CCC: $30.25 © 2005 American Chemical Society

NN

Cu

tBuOiPr

iPr

iPr

iPr

NN

CuiPr

iPr

iPr

iPr

B(pin)

(pin)B-B(pin)

Laitar, D. S.; Müller, P.; Sadighi, J. P. J. Am. Chem. Soc. 2005, 127, 17197.

Cu BO

OL

C C

C CC C

Cu Bor

C CH B

C CB

C CB

X

CuC C

BCu

X

C CB

n

Cu ORL(pin)B B(pin)

C CE B

H+orE

R X

Ar Xor

R BO

O

OC

R'R

NC

R'R

R''or

CR'R

OHBC

R'R

NHR"B

CatalysisDesign

allylic substitution

borylativecyclization

alkyl-, aryl-substitution

aldehyde, imineaddition

X X X X

XX

Cu BO

OL

C C

C CC C

Cu Bor

C CH B

C CB

C CB

X

CuC C

BCu

X

C CB

n

Cu ORL(pin)B B(pin)

C CE B

H+orE

R X

Ar Xor

R BO

O

OC

R'R

NC

R'R

R''or

CR'R

OHBC

R'R

NHR"B

CatalysisDesign





X X X X

XX

Ito, 2000–Miyaura, 2000–Yun, 2006–Marder, 2007–Molander, 2008–Kanai, 2009–Hoveyda, 2009–Santos, 2010–McQuade, 2010–Cordova, 2011–Hall, 2010–Carretero, 2011–Fernandez, 2011–Lam, 2012–

Kobayashi, 2012–Tsuji, 2012–de Vries, 2012–Ma, 2010–Zhu, 2013–Caser, 2013–Chun, 2013–Yoshida, 2014–Xiao and Fu, 2015–Feringa, 2015–Quiling, 2015–……

> 180 publications

Cu BO

OL

C C

C CC C

Cu Bor

C CH B

C CB

C CB

X

CuC C

BCu

X

C CB

n

Cu ORL(pin)B B(pin)

C CE B

H+orE

R X

Ar Xor

R BO

O

OC

R'R

NC

R'R

R''or

CR'R

OHBC

R'R

NHR"B

CatalysisDesign





X X X X

X



> 180 publications

Cu BO

OL

C C

C CC C

Cu Bor

C CH B

C CB

C CB

X

CuC C

BCu

X

C CB

n

Cu ORL(pin)B B(pin)

C CE B

H+orE

R X

Ar Xor

R BO

O

OC

R'R

NC

R'R

R''or

CR'R

OHBC

R'R

NHR"B

CatalysisDesign





X X X X



> 180 publications

Cu BO

OL

C C

C CC C

Cu Bor

C CH B

C CB

C CB

X

CuC C

BCu

X

C CB

n

Cu ORL(pin)B B(pin)

C CE B

H+orE

R X

Ar Xor

R BO

O

OC

R'R

NC

R'R

R''or

CR'R

OHBC

R'R

NHR"B

CatalysisDesign





X X X



> 180 publications

AllylicSubstitutions,Meso-andPropargyls

Ito, H.; Okura, T.; Matsuura, K.; Sawamura, M. Angew. Chem., Int. Ed. 2010, 49, 560.

RO

(pin)Bdiboron

Cu(O-t-Bu)/(R,R)-QuinoxP* (5.0 mol %)

baseH2O

iPrOCO2H

Ph

OHPhCHO (1.0 eq.)

0 °C, 18 hrt, 2 hRO- = i-PrOCO2 87%, 97% ee

dr >99:1

ORRO



RO

(pin)Bdiboron


baseH2O

iPrOCO2H

Ph

OHPhCHO (1.0 eq.)


dr >99:1

ORRO


OTIPSN

NN

N

NH2

Cl

AntiVirusDrugPrecursor

H

OTBS

CO2Me

OH

H

97% ee, >98% dsFourChiralCenters


RO

(pin)Bdiboron


baseH2O

iPrOCO2H

Ph

OHPhCHO (1.0 eq.)


dr >99:1

ORRO

CCCBu

B(pin)

MeH

74%, 97% ee

10 mol %Cu(O-t-Bu)/Xantphos

THF, 50 °C, 5 h97% ee

Me C C C Bu

OCO2Me

H

(S)

(S)

2.0 equiv.

OB

O

OB

O+

■Allenylboroncompoundswithhighee.

Ito, H.; Sasaki, Y.; Sawamura, M., J. Am. Chem. Soc. 2008, 130, 15774.


OTIPSN

NN

N

NH2

Cl

AntiVirusDrugPrecursor

H

OTBS

CO2Me

OH

H

97% ee, >98% dsFourChiralCenters

Ito, H; Kunii, S; Sawamura, M. Nature Chem. 2010, 2, 972.

Cu(O-t-Bu)(R,R)-QuinoxP*(5.0 mol %)

(pin)B B(pin)(1.5 equiv)Et2O, 24 h

OCH3Ph

racemic 98% yield97% ee

Ph

BO

O

DirectEnantio-ConvergentReaction




OCH3Ph


Ph

BO

O


OCH3Ph

CH3OPh

OCH3Ph

CH3O Phracemic

CuB

L*

CuB

L*

Ph

BO

O

anti-SN2'

syn-SN2'

■Onecatalystconvergetwosubstrateenantiomersintooneproduct enantiomer.




OCH3Ph


Ph

BO

O

PhCHO

Ph

B

CO

HPh Ph

HO

Ph

85% yield, 97% ee


OCH3Ph

CH3OPh

OCH3Ph

CH3O Phracemic

CuB

L*

CuB

L*

Ph

BO

O

anti-SN2'

syn-SN2'

■Onecatalystconvergetwosubstrateenantiomersintooneproduct enantiomer.

Cu BO

OL

C C

C CC C

Cu Bor

C CH B

C CB

C CB

X

CuC C

BCu

X

C CB

n

Cu ORL(pin)B B(pin)

C CE B

H+orE

R X

Ar Xor

R BO

O

OC

R'R

NC

R'R

R''or

CR'R

OHBC

R'R

NHR"B

CatalysisDesign





X X X

Cu BO

OL

C C

C CC C

Cu Bor

C CH B

C CB

C CB

X

CuC C

BCu

X

C CB

n

Cu ORL(pin)B B(pin)

C CE B

H+orE

R X

Ar Xor

R BO

O

OC

R'R

NC

R'R

R''or

CR'R

OHBC

R'R

NHR"B

CatalysisDesign





X X

Cu(I) cat.(pin)B–B(pin)

Cu BL

OR

RORE

RERO

RE

Cu BL B(pin)

RERE = SiR3, Arβ LCuOR+

AsymmetricBorylativeCyclizations

Cu(I) cat.(pin)B–B(pin)

Cu BL

OR

RORE

RERO

RE

Cu BL B(pin)

RERE = SiR3, Arβ LCuOR+

(pin)B B(pin)

Cu(O-t-Bu) / ligand

R XTHF, 30 °C

B(pin)

RR = R3Si, Ar, HetAr

B(pin)

NBoc

B(pin)

S

B(pin)70%, 92% ee90%, 92% ee 70%, 92% ee

X = OCO2R, OPO(OR)2

B(pin)

Me3Si

94%, 94% ee

B(pin)

BnMe2Si

83%, 94% ee

Ito, H.; Kosaka, Y.; Nonoyama, K.; Sasaki, Y.; Sawamura, M. Angew. Chem., Int. Ed. 2008, 47, 7424.Zhong, C.; Kunii, S.; Kosaka, Y.; Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010, 132, 11440.

AsymmetricBorylativeCyclizations

a The endo-cyclization product was detected (7%).

(pin)B

4 h, 86%

(pin)B

Me

Me

4 h, 90%

(pin)B

4 h, 84%

(pin)B

6 h, 87%d.r. = 1.1:1

Si(pin)BMe

Me

4 h, 74%a

5 mol % CuCl5 mol % Xantphos(pin)B-B(pin) (1.2 equiv)

K(O-t-Bu) (1.2 equiv)THF, 30 °C

nCC

Cu

(pin)B – CuBrC n

n = 1−3 n = 1−3CC

BrBr C

(pin)B

L

complex mixtureb

Br

(pin)B

4 h, 95%d.r. = 1.4:1

(pin)B

MeMe

4 h, 83%

Kubota, K.; Yamamoto, E.; Ito, H. J. Am. Chem. Soc. 2013, 135, 2635.

b The six-membered ring product was detected (4%).

BorylativeCyclizationofTerminalAlkenes

SpiroCompounds

B

B 88%

O

O

O

O

OB

OB

O

O

(1.2 equiv)

Br

Br

+

10 mol % CuCl10 mol % Xantphos

K(O-t-Bu) (2.0 equiv)THF, 30 °C, 4 h

Highexo/endoselectivity


SpiroCompounds

5 mol % CuCl / Xantphos(pin)B-B(pin) (1.2 equiv)

t-BuOK (1.2 equiv)THF, 30 °C, 4 h, 82%

B(pin)

NS

O O

NS

O O

BrBorylativecyclization


ShortSynthesisofDrugCandidate

5 mol % CuCl / Xantphos(pin)B-B(pin) (1.2 equiv)

t-BuOK (1.2 equiv)THF, 30 °C, 4 h, 82%

B(pin)

NS

O O

NS

O O

BrBorylativecyclization

1. NaBO3/4H2O THF/H2O, rt, 1 h

2. Jones Reagent acetone, 0 °C, 1 h 64% (2 steps)

C-OBondformation

Condensation

HistamineH3ReceptorLigand

O

NSO O

HO

O

NSO O

NN

NHN

HBTU, iPr2NEtDMF, rt, 2 h, 91%


ShortSynthesisofDrugCandidate

Cu BO

OL

C C

C CC C

Cu Bor

C CH B

C CB

C CB

X

CuC C

BCu

X

C CB

n

Cu ORL(pin)B B(pin)

C CE B

H+orE

R X

Ar Xor

R BO

O

OC

R'R

NC

R'R

R''or

CR'R

OHBC

R'R

NHR"B

CatalysisDesign





X X

AsymmtericMonoboryaltion

v

■FirstAsymmetric1,2-Monoborylationof1,3-Dienes

Sasaki, Y.; Zhong, C.; Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010, 132, 1226.

(pin)B (pin)B+

THF, MeOH (2.0 equiv)–40°C, 24.5h

Cu(O-t-Bu)–(R,R)-Me-DuPhos(5.0 mol %)(pin)B B(pin) (1.5 equiv)

96%, 96% ee, dr >99:1H


v



(pin)B (pin)B+



96%, 96% ee, dr >99:1H


(pin)B (pin)B 96 % eechiral Cu catalystB2(pin)2(1.5 equiv)

THF, t-BuOH (5.0 equiv)room temp.77% (dr 92:8)

chiral Cu catalystB2(pin)2(1.5 equiv)

THF, MeOH (5.0 equiv)–40°C 87% (dr 7:93)

v



(pin)B (pin)B+



96%, 96% ee, dr >99:1H

v MeMe

BuB(pin) B(pin)

BuMe

Bucat. Cu(OtBu)/diphosphine

(pin)B B(pin)THF, MeOH

cat. Cu(OtBu)/PPh3

(pin)B B(pin)THF, MeOHup to 84% ee

■Enantio-andRegioselectiveBorylationof1,3-Enynes

Sasaki, Y.; Horita, Y.; Zhong, C.; Sawamura, M.; Ito, H. Angew. Chem., Int. Edit. 2011, 50, 2778.


(pin)B (pin)B 96 % eechiral Cu catalystB2(pin)2(1.5 equiv)

THF, t-BuOH (5.0 equiv)room temp.77% (dr 92:8)

chiral Cu catalystB2(pin)2(1.5 equiv)

THF, MeOH (5.0 equiv)–40°C 87% (dr 7:93)

Cu BO

OL

C C

C CC C

Cu Bor

C CH B

C CB

C CB

X

CuC C

BCu

X

C CB

n

Cu ORL(pin)B B(pin)

C CE B

H+orE

R X

Ar Xor

R BO

O

OC

R'R

NC

R'R

R''or

CR'R

OHBC

R'R

NHR"B

CatalysisDesign





X X

Cu BO

OL

C C

C CC C

Cu Bor

C CH B

C CB

C CB

X

CuC C

BCu

X

C CB

n

Cu ORL(pin)B B(pin)

C CE B

H+orE

R X

Ar Xor

R BO

O

OC

R'R

NC

R'R

R''or

CR'R

OHBC

R'R

NHR"B

CatalysisDesign





X

BorylSubstitutionofC(sp3)−X

Br +

CuCl / Xantphos (3 mol %)K(O-t-Bu) (1.0 equiv)

THF, rtB(pin)Alkyl AlkylB B

O

OO

O

1.2 equiv

B(pin)B(pin)

4 h, 85% 5 h, 91%

B(pin)

5 h, 90%

B(pin)

44 h, 0%

B(pin)

48 h, 17%

B(pin)

5 h, 51%

B(pin)

B(pin)

24 h, 62%a

B(pin)B(pin)

30 h, 68%a

aReaction was carried out at 40°C with 15 mol % of catalyst, 2.2 equiv of B2pin2 and 2.0 equiv of base.

B(pin)

5 h, 84%

B(pin)

4 h, 92%

Alkyl X Alkyl BCu cat.

B BO

OO

O+

X = Cl, Br, I O

O

base

Alkyl MgX or LiXB(pin)

CuCl / Xantphos: Ito, H.; Kubota, K. Org. Lett. 2012, 14, 890. CuI / PPh3: Yang, C.-T.; Steel, P. G.; Marder, T. B.; Liu, L. et al. Angew. Chem., Int. Ed. 2012, 51, 528.

K. Kubota

BorylSubstitutionofC(sp3)−X

Br +

CuCl / Xantphos (3 mol %)K(O-t-Bu) (1.0 equiv)

THF, rtB(pin)Alkyl AlkylB B

O

OO

O

1.2 equiv

B(pin)B(pin)

4 h, 85% 5 h, 91%

B(pin)

5 h, 90%

B(pin)

44 h, 0%

B(pin)

48 h, 17%

B(pin)

5 h, 51%

B(pin)

B(pin)

24 h, 62%a

B(pin)B(pin)

30 h, 68%a

aReaction was carried out at 40°C with 15 mol % of catalyst, 2.2 equiv of B2pin2 and 2.0 equiv of base.

B(pin)

5 h, 84%

B(pin)

4 h, 92%

Alkyl X Alkyl BCu cat.

B BO

OO

O+

X = Cl, Br, I O

O

base

Alkyl MgX or LiXB(pin)

CuCl / Xantphos: Ito, H.; Kubota, K. Org. Lett. 2012, 14, 890. CuI / PPh3: Yang, C.-T.; Steel, P. G.; Marder, T. B.; Liu, L. et al. Angew. Chem., Int. Ed. 2012, 51, 528.

Ni catalyst: Dudnik, A. S.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 10693.

Pd catalyst: Joshi-Pangu, A.; Ma, X.; Diane, M.; Iqbal, S.; Kribs, R. J.; Huang, R.;

Wang, C.-Y.; Biscoe, M. R. J. Org. Chem. 2012, 77, 6629.

Pd, Ni catalyst: Yi, J.; Liu, J. H.; Liang, J.; Dai, J. J.; Yang, C.-T.; Fu, Y.; Liu, L.

Adv. Synth. Catal. 2012, 354, 1685.

Fe catalyst: Atack, T. C.; Lecker, R. M.; Cook, S. P. J. Am. Chem. Soc. 2014.

Zn catalyst: Bose, S. K.; Fucke, K.; Liu, L.; Steel, P. G.; Marder, T. B.

Angew. Chem., Int. Edit. 2014, 53, 1799.

◼VerySimpleReaction,andCompetitive!

K. Kubota

Cu BO

OL

C C

C CC C

Cu Bor

C CH B

C CB

C CB

X

CuC C

BCu

X

C CB

n

Cu ORL(pin)B B(pin)

C CE B

H+orE

R X

Ar Xor

R BO

O

OC

R'R

NC

R'R

R''or

CR'R

OHBC

R'R

NHR"B

CatalysisDesign





X

Cu BO

OL

C C

C CC C

Cu Bor

C CH B

C CB

C CB

X

CuC C

BCu

X

C CB

n

Cu ORL(pin)B B(pin)

C CE B

H+orE

R X

Ar Xor

R BO

O

OC

R'R

NC

R'R

R''or

CR'R

OHBC

R'R

NHR"B

CatalysisDesign





■

Latitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006, 128, 11036.

O

H1.0 mol % ICyCu(O-t-Bu)

(pin)B−B(pin), toluene

86%

O

B(pin)

B(pin)

Catalyticdiboration

(pin)B−B(pin)MeOH, toluene

O

H

1.5 mol %ICyCu(O-t-Bu) OH

B(pin)

crude product

KHF2

MeOH/H2O

OH

BF3K

81%Molander, G. A.; Wisnieski, S. R. J. Am. Chem. Soc. 2012, 134, 16856.

■ Catalyticmonoborylation

N N

ICy

Copper(I)-CatalyzedCarbonylBorylation

Enantioselectiveborylation

L*M

B C

RH

B OM

Enantioenrichedα-alkoxyalkylboronates

O

C

RH

Borylnucleophile

EnantioselectivenucleophilicborylationofaC=Odoublebondhasnoteverbeenachieved.

■


EnantioselectiveBorylationofAldehydes

R

O

B(pin)

B(pin)

R

OH

BF3K

Lowstability Lowsolubility Sadighi, J. Am. Chem. Soc. 2006 Molander, J. Am. Chem. Soc. 2012

R

O

H

L*CuCl

K(O-t-Bu)THF

(pin)B−B(pin)

R H

BHO OO

unstable

R H

BPGO OOprotection

Ourapproachforisolation

HighstabilityHighsolubility

■ NotsuitableforHPLCanalysistodetermineeevalues

✓

cf. Moore, C. M.; Medina, C. R.; Cannameia, P. C.; Mclntosh, M. L.; Ferber, C. J.; Roering, A. J.; Clark, T. B. Org. Lett. 2014, 16, 6056.

alcohol

ProtectionforHPLCAnalysis

H

B(pin)BnO

Ph H

B(pin)MeO

Ph H

B(pin)O

Ph

Ph

O

H

B(pin)O

Ph

Me2N

O

H

B(pin)Me3SiO

Ph

BnBr, NaH26%

Me3OBF428%

(PhCO)2O, DMAP20%

Me2NCOCl, pyridinecomplex mixture

Me3SiCl, imidazole64%

Ph H

O

CuCl (2 mol %)ICy⋅HCl (2 mol %)(pin)B−B(pin) (1.0 equiv)

K(O-t-Bu) (10 mol %)MeOH (2.0 equiv), THF

R H

B(pin)HO

not isolated

protection

H

B(pin)PGO

isolated yield (%)Ph

then silica gel short column

ProtectionforHPLCAnalysisK. Kubota


Ph

O

1. CuCl / L* (5 mol %) K(O-t-Bu) (10 mol %) MeOH (2.0 equiv) THF, 30 °C, 6 h

2. BnMe2SiCl, imidazole CH2Cl2, 3 h

Ph HH

BnMe2SiO B

(S)NMR yield (%)

B BO

O O

O+

1.0 equiv

OO

ChiralLigandScreening


Ph

O

1. CuCl / L* (5 mol %) K(O-t-Bu) (10 mol %) MeOH (2.0 equiv) THF, 30 °C, 6 h

2. BnMe2SiCl, imidazole CH2Cl2, 3 h

Ph HH

BnMe2SiO B

(S)NMR yield (%)

B BO

O O

O+

1.0 equiv

OO

O

O

O

O

PP

tBuOMe

tButBu

OMetBu

2

2

(R)-DTBM-SEGPHOS72%, 96% ee

O

O

O

O

PP

Me

MeMe

Me

2

2(R)-DM-SEGPHOS

71%, 32% ee(R)-SEGPHOS74%, 24% ee

O

O

O

O

PP

2

2

largersterichinderance

higherenantioselectivity

ChiralLigandScreening


coordination

σ-bondmetathesis

protonation

enantioselectiveinsertion

P

P= (R)-DTBM-SEGPHOS

DFT: Kubota, K.; Jin, M.; Ito, H. Organometallics, under revision.cf. Zhao, H.; Dang, L.; Marder, T. B.; Lin, Z. J. Am. Chem. Soc. 2008, 130, 5586.

Cu B(pin)PP

CuB(pin)

PP

O CHR

O CCu

R

B(pin)

H

PP

Cu ORPP R = OMe or

O-t-Bu

O CHR

(pin)B−B(pin)

MeOH

(pin)B−OR

A

B

C

DO CR

B(pin)

HH

Pointsnotelucidated

1.Mechanismofenantioselection

2.Effectofprotonsource

ProposedReactionMechanism

M. Jing

K. Kubota


Cu

B

P PO

HHH

Cu

B

P PO

H

HH

Ph Ph

Ph Ph

Ph

Ph Ph

Ph

Si-faceTS(favored) Re-faceTS(disfavored)

０kcal/mol +1.04kcal/mol

<

B3PW91/cc-PVDZ,RelativeGvalue(kcal/mol)at298K,1.0atm,gasphase.

Observedresult24%ee

DFT: Kubota, K.; Jin, M.; Ito, H. Organometallics, under revision.

EnantioselectionModels[(R)-SEGPHOS]

Cu

B

P PO

HHH

Cu

B

P PO

H

HH

Ar Ar

Ar Ar

Ar

Ar Ar

Ar

Si-faceTS(favored) Re-faceTS(disfavored)

０kcal/mol +1.97kcal/mol

<observedresult96%ee

Modelsfor[(R)-DTBM-SEGPHOS]

DFT: Kubota, K.; Jin, M.; Ito, H. Organometallics, under revision.B3PW91/cc-PVDZ,RelativeGvalue(kcal/mol)at298K,1.0atm,gasphase.

R

O

1. 5 mol % CuCl/ (R)-DTBM-SEGPHOS K(O-t-Bu) (10 mol %) MeOH (2.0 equiv) THF, 30 °C, 6 h

2. R3SiCl, imidazole CH2Cl2, 3 h

HB B

O

O O

O+

1.0 equiv

R H

R3SiO B

(S)isolated yield (%)

OO

B(pin)Me3SiO

H

B(pin)Me3SiO

H

B(pin)Me3SiO

H

51%, 96% ee 61%, 95% ee 84%, 95% ee 61%, 96% ee

B(pin)HO

H

B(pin)BnMe2SiO

HN

B(pin)Me3SiO

HNBoc Ts

81%, 95% ee 52%, 91% ee

B(pin)BnMe2SiO

H

69%, 90% ee

BzO

B(pin)BnMe2SiO

H

69%, 95% ee

BnO

BorylationofVariousAldehydes


H

O

H

B(pin)HOCuCl / L* (5 mol %)(pin)B−B(pin) (1.0 equiv)

K(O-t-Bu) (10 mol %)MeOH (2.0 equiv)THF (0.5 M), 30 °C, 6 h

Ph2MeSiClimidazole

CH2Cl2, 3 h

>99% conversionL* = (R)-DTBM-SEGPHOS

H

B(pin)Ph2MeSiO

22% yield99% ee

H

BF3KHOKHF2 (4.0 equiv)

MeOH/H2O, 30 min

71% yield

■ Poorstabilityoftheproducttowardsilicagelcolumn

Goodisolatedyield(71%)byconvertingintotri]luoroborate■

AromaticAldehydeCase:Unstable

CuCl / ligand (5 mol %)(pin)B−B(pin) (1.0 equiv)K(O-t-Bu) (10 mol %)MeOH (2.0 equiv)

solvent, 30 °C, 18 hthen Me3SiClimidazole, 3 h (R,S)

H

O

Me

TBSO

B(pin)

OSiMe3

Me

TBSO

(R,R)

B(pin)

OSiMe3

Me

TBSO

+

(R)

α-Stereocenter

ICy⋅HCl (2 mol %), toluene: 69%, (R,S):(R,R) = 30:70

(R)-DTBM-SEGPHOS, THF: 73%, (R,S):(R,R) = 89:11(S)-DTBM-SEGPHOS, THF: 77%, (R,S):(R,R) = 5:>95

■ Catalyst-controlledselectivityoversubstratevias

CatalystControlledReaction

For a review of Matteson homologation chemistry: Matteson, D. S. Tetrahedron 1998, 54, 10555.

cf. Sadhu, K. M.; Matteson, D. S. Organometallics 1985, 4, 1687.

Stereospeci@icC(sp3)-C(sp3)bondformation;One-carbonhomologation

Larouche-Gauthier, R.; Elfold, T. G.; Aggarval, V. K. J. Am. Chem. Soc. 2011, 133, 16794.

Ph H

B(pin)BnMe2SiO

96% ee

ClCH2Br n-BuLi

THF−78 °C→rt3 h

Ph H

BnMe2SiO B(pin)

92%, 96% ee

H2O2NaOH Ph H

HO OH

77%, 96% ee

chiral1,2-diol

chiral1,2-haloalcohol

Ph H

R3SiO Br

80%, 96% ee3,5-(CF3)2C6H3Lithen NBS, −78 °C

Usefulintermediatechiralβ-alkoxyboron

Stereospeci]icFunctionalization


H

(pin)B OSiMe3

95% ee

(S)

Benzofuran (1.2 equiv)n-BuLi (1.2 equiv)

THF, −78 °C, 1 h

NBS (1.2 equiv)

−78 °C, 1 hthen TBAF, 2 hH

Li

H

52%, 95% ee

(pin)B OSiMe3

OOH

O

(R)

Bonet, A.; Odachowski, M.; Leonori, D.; Essafi, S.; Aggarwal, V. K. Nature. Chem. 2014, 6, 584.

Stereospeci@icC(sp3)-C(sp2)bondformation;Cross-couplingwithaheteroaromaticcompound

AggarwalArylation

ChiralNHC/copper(I)complexcatalyst

HO B OO

Ph *

59%, 9% ee

HO B OO

*Ph

62%, 9% ee

HO B OO

*

no reaction

Unsuccessfulsubstrates

OB B

O

O O

O+

1.0 equiv

5 mol % CuCl / L*

NNL* =

BF4

HO B OO

*

47%, 98% ee

10 mol % K(O-t-Bu)MeOH (2.0 equiv)toluene/THF, rt, 4 h

EnantioselectiveBorylationofKetones

NH

F

O

OO

(− )-paroxetine N

N N

N

N

OPh

NH2

O ibrutinib

WAY-163909

N

NH

N

OH

(− )-preclamol

NN

Me

HMe

Me

OHN

OMe

(−)-Physostigmine

NovelBoronReagentsforAlkaloidSynthesis

N OH

(– )-preclamol

NO

Ph

PhO

O zamifenacine

ibrutinib

PyridineanditsDerivativesinHeterocyclesinNaturalProductSynthesis,Majumdar,K.C.;Chattopadhyay,S.K.,Ed.;Wiley-VCH,Weinheim,2011,Chap.8,pp.267.

NH

F

O

OO

(− )-paroxetine N

N N

N

N

OPh

NH2

O ibrutinib

WAY-163909

N

NH

N

OH

(− )-preclamol

NN

Me

HMe

Me

OHN

OMe

(−)-Physostigmine


N OH

(– )-preclamol

NO

Ph

PhO

O zamifenacine

ibrutinib


N-Heterocyclic borons

NH

BR

NH

R1

B

R

NH

F

O

OO

(− )-paroxetine N

N N

N

N

OPh

NH2

O ibrutinib

WAY-163909

N

NH

N

OH

(− )-preclamol

NN

Me

HMe

Me

OHN

OMe

(−)-Physostigmine


*LCu B

N

R3

R1

R2

NR1

R2

Novel enantioselectiveborylation

Abundant, cheap andreadily available

N OH

(– )-preclamol

NO

Ph

PhO

O zamifenacine

ibrutinib


N-Heterocyclic borons

NH

BR

NH

R1

B

R

Hydrogenation

Electrophilicallylicsubstitution

Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem. Soc. 2000, 122, 7614.

Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314.

Trost ligand

(S,S)-(R,R)-PhTRAP

FeFe

PPh2PPh2

O NH

HN O

Ph2PPPh2

2.5 mol % Pd2(dba)3CHCl37.5 mol % chiral ligand

9-BBN-C6H13 (1.05 equiv)CH2Cl2, 4 °C

NH

N+

HO

MeO

MeO

3 equiv92%, 85% ee

1.0 mol % [Rh(nbd)2]SbF61.05 mol % PhTRAP10 mol % Cs2CO3

i-PrOH, H2 (5.0 MPa)60 °C, 2 h

NAc

NAc

91%, 91% ee

AsymmetricDearomatizations

Kubota,K.;Hayama,K.;Iwamoto,H.;Ito,H.Angew.Chem.,Int.Ed.2015,30,8809.

The first enantioselective carbon-boron bond forming dearomatization by copper(I) catalysis✓Direct synthesis of chiral boryl-indolines from readily available indoles✓

N

O

OMeCbz

+ B B

2.0 equiv

O

OO

O

10 mol % Cu(O-t-Bu) / L*10 mol % Na(O-t-Bu)

t-BuOH (2.0 equiv)THF, 30 °C, 20 h

NCbz

B(pin)

OMe

O

98%, d.r. 97:393% ee

P P

Me

Me

MeMe

Me

Me

Me

Me

L* = (R,R)-xyl-BDPP

EnantioselectiveBorylativeDearomatization

Coordinationσ-Bondmetathesis

Diastereoselectiveprotonation

3,4-Additionandtoutomerization

Stericrepulsion

Cu BP

P

P

P= (R,R)-xyl-BDPP

(pin)B−(O-t-Bu)

NCbz

OOMe

Cu BPP

NCbz

O

OMeBPP

NCbz

O

OMeB

HO

HO

Cu(O-t-Bu)P

P

diboron

substrate

HO

disfavored

favored

Cu

CuP

P

A

BC

D

E

NCbz

B(pin)

OMe

OH



Coordinationσ-Bondmetathesis

Diastereoselectiveprotonation

3,4-Additionandtoutomerization

Stericrepulsion

Cu BP

P

P

P= (R,R)-xyl-BDPP

(pin)B−(O-t-Bu)

NCbz

OOMe

Cu BPP

NCbz

O

OMeBPP

NCbz

O

OMeB

HO

HO

Cu(O-t-Bu)P

P

diboron

substrate

HO

disfavored

favored

Cu

CuP

P

A

BC

D

E

NCbz

B(pin)

OMe

OH


MeOH: 94%, 94% ee d.r. 75:25

t-BuOH: 98%, 93% ee d.r. 97:3


10 mol % Cu(O-t-Bu) 10 mol % chiral ligand10 mol % Na(O-t-Bu)

N

O

OMeCbz

N

O

OMeCbz

B(pin)

0.5 mmol

+OB

OB

O

O

2.0 equiv

t-BuOH (2.0 equiv) THF, 30 °C, 18−48 h

NMR yield (%)

PP

Me

Me

Me

Me

Me

Me

Me

Me PP

P

P

MeMe

Me

Me

(R,R)-BenzP*77%, d.r. 91:9

61% ee

(R,R)-Me-Duphos71%, d.r. 97:3

37% ee

P

P

Me

tBu

tBu

MeN

N P

P

Me

tBu

tBu

Me

(R,R)-3,5-xyl-BDPP98%, d.r. 97:3

93% ee

(R,R)-BDPP98%, d.r. 89:11

74% ee

(R,R)-QuinoxP*93%, d.r. 90:10

27% ee

LigandScreening

Kubota, K.; Hayama, K. Ito, H. Angew. Chem., Int. Ed. 2015, 54, 8809.

NCbz

B(pin)

OMe

OF

93% yieldd.r. 97:3, 95% ee

NCbz

B(pin)

OMe

OCl

93% yieldd.r. 93:7, 95% ee

NCbz

B(pin)

OMe

OBr

96% yieldd.r. 97:3, 92% ee

NCbz

B(pin)

OMe

OMeO

99% yieldd.r. 97:3, 97% ee

NCbz

B(pin)

OMe

O

88% yieldd.r. 97:3, 93% ee

MeO NCbz

B(pin)

OMe

O

99% yieldd.r. 93:7, 86% ee

Br NCbz

B(pin)

OMe

O

82% yieldd.r. 83:17, 89% ee

N

O

OMeCbz

10 mol % Cu(O-t-Bu)10 mol % (R,R)-xyl-BDPPB2(pin)2 (2.0 equiv)

10 mol % Na(O-t-Bu)t-BuOH (2.0 equiv)THF, 30 °C, 4−18 h

NCbz

B(pin)

OMe

OR1

R2

R1

R2


BorylativeDearomatizationofVariousIndoles

CuCl (5 mol %)Xantphos (5 mol %)ClCO2Me (1.0 equiv)

K(O-t-Bu)/THF (1.0 equiv)MeOH (2.0 equiv), rt,

N + B B

1.2 equiv

O

OO

ON

MeO

O

BO O

detected by GC-Massdecomposed during purification

predicted structures

N

MeO

O

B O

O+Possible intermediate

NO

MeO

Cl

O

P

P

Ph Ph

Ph Ph

CuBvia

Kubota,K.;Watanabe,Y.;Hayama,K.;Ito,H.Submitted.

InitialAttemptforChiralBoryl-Piperidine

cat. Cu/L*B2(pin)2

alkoxide basealcohol

N N

RO

OClCO2R

hydridesource

N

RO

O

N

RO

O

B(pin)

B(pin)

N

RO

O

(pin)B

N

RO

O

B(pin)

*

*

*

*

Regioselective? Enantioselective?

No examples of selective borylationof conjugated dienamines

ClCO2R

NaBH4 orLiBH4

✓

✓

cat. Cu(I)/L*B2(pin)2



AlternativeStrategy:SequencialMethod

cat. Cu/L*B2(pin)2


N N

RO

OClCO2R

hydridesource

N

RO

O

N

RO

O

B(pin)

B(pin)

N

RO

O

(pin)B

N

RO

O

B(pin)

*

*

*

*

Regioselective? Enantioselective?

No examples of selective borylationof conjugated dienamines

ClCO2R

NaBH4 orLiBH4

✓

✓

cat. Cu(I)/L*B2(pin)2



Sasaki,Y.;Zhong,C.;Sawamura,M.;Ito,H.J.Am.Chem.Soc.2010,132,1226.

MeOH (2.0 equiv)THF,−20 °C, 22 h

5 mol% Cu(O-t-Bu)/(R,R)-Me-Duphos

90%, 95% ee

B(pin)

P

PMeMe

Me

Me

(R,R)-Me-Duphos

+ B B

1.5 equivO

OO

O

cf. Enantioselective monoborylation of carbocyclic dienes

10 mol %Cu(O-t-Bu)/(R,R)-Me-Duphos

MeOH (1.0 equiv)THF, –20 °C, 22 h

90%, 95% ee

P

PMeMe

Me

Me

(R,R)-Me-Duphos

AlternativeStrategy:SequencialMethod

Pyridinesto3-SubstitutedPiperidinesCuCl (5 mol %)chiral ligand (5 mol %)3 (1.2 equiv)

K(O-t-Bu) (20 mol %)MeOH (2 equiv)THF, temp., 2-4 h2a (R)-4a

NaBH4ClCO2Me

MeOH−78 °C1 h, 71%1a

NNO

MeO

NO

MeOB(pin)

P

P

Me tBu

tBu Me(R,R)-BenzP*92%, 98% ee

N

N P

P

Me tBu

tBu Me(R,R)-QuinoxP*93%, 99% ee

O

O

O

O

PPh2PPh2

(R)-SEGPHOS, <5%

P

PMeMe

Me

Me

(R,R)-Me-Duphos83%, 93% ee

PPh2PPh2

(R)-SEGPHOS, <5%

N

R1R2

NaBH4 orLiBH4

ClCO2R3

MeOH−78 °C

N

R3O

O

R1R2 5 mol % CuCl/

(R,R)-QuinoxP*B2(pin)2 (1.2 equiv)

K(O-t-Bu) (20 mol %)MeOH (2.0 equiv)THF, –10 °C, 2 h

N

R3O

O

R1R2

B(pin)

76%, 97% ee

N

BnO

OB(pin)

N

MeO

OB(pin)

93%, 99% ee

N

O

OB(pin)

88%, 98% ee

N

O

OB(pin)

90%, 97% ee

N

PhO

OB(pin)

84%, 93% ee

N

O

OB(pin)

91%, 97% ee

N

MeO

OB(pin)

86%, 92% ee

N

MeO

OB(pin)

67%, 96% ee

Me Me

N

MeO

OB(pin)

Me

no reaction

76%, 97% ee

N

N P

P

Me tBu

tBu Me

(R,R)-QuinoxP*

93%, 99% ee 88%, 98% ee 90%, 97% ee 76%, 97% ee 84%, 93% ee

91%, 97% ee 86%, 92% ee 67%, 96% ee


UnprecedentedRegio-andEnantioselective

N ClCO2MeMeOH−78 °C

N

MeO

OAr NaBH4

Ar

5 mol % CuCl/(S)-SEGPHOSB2(pin)2 (1.2 equiv)

K(O-t-Bu) (20 mol %)t-BuOH (2.0 equiv)toluene/DME0 °C, 2 h

N

MeO

O

Ar

B(pin)

(R)-SEGPHOSO

O

O

O

PPh2PPh2

(R)-SEGPHOS

5 mol % CuCl/(R)-SEGPHOSB2(pin)2 (1.2 equiv)

K(O-t-Bu) (20 mol %)t-BuOH (2.0 equiv)toluene/DME/THF(6:6:1), 0 °C, 2 h

N

MeO

OBO

O

Me

91%, d.r. 98:295% ee

N

MeO

OBO

O

OMe

82%, d.r. 96:496% ee

90%, d.r. 97:392% ee

N

MeO

OB

93%, d.r. 99:139% ee*(R,R)-QuinoxP* was used.

O

O N

MeO

OBO

O

F

91%, d.r. 96:496% ee*(S)-SEGPHOS was used.

Kubota, K.; Watanabe, Y.; Hayama, K.; Ito, H. Submitted.

Diastereo-andEnantioselectiveBorylation

(−)-ParoxetineAntidepressant drug

3. MsCl (1.5 equiv) Et3N (3.0 equiv) CH2Cl2, 0 °C→rt

1. LiCH2Cl (1.5 equiv) −78 °C→rt, 3 h2. NaBO3•4H2O (4.0 equiv), rt, 1 h

N

MeO

OBO

O

d.r. 95:596% ee

F

N

MeO

O

F

OMs

77% (3 steps)d.r. 95:5

O

O

HO

(2 equiv)

Cs2CO3 (4.0 equiv)MeCN, 90 °C, 2 hthen Pd/C, H2, 12 h

N

MeO

O

F

O

67% (2 steps)d.r. >95:5, 94% ee

O

OKOH (30 equiv)

EtOH/H2O (4:1)100 °C, 42 h

HN

F

O

61% O

O

d.r. 96:496% ee

77% (3 steps)d.r. 96:4

67% (2 steps)d.r. >95:5, 94% ee

61%

Hynes, P. S.; Stupple, P. A.; Dixon, D. J. Org. Lett. 2008, 10, 1389.

Krautwald, S.; Schafroth, M. A.; Sarlah, D.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136, 3020.

KOH (30 equiv)

EtOH/H2O (4:1)reflux, 42 h

d.r. 96:496% ee

77% (3 steps)d.r. 96:4

67% (2 steps)d.r. >95:5, 94% ee

61%

Kubota, K.; Watanabe, Y.; Hayama, K.; Ito, H. Submitted.

Diastereo-andEnantioselectiveBorylation

Cu-CatalyzedBorylationfromOurGroup

CuX/PR3: Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron Lett. 2000, 41, 6821.

+

cat. CuX PR3

DMI, rt

H3O+

OO

BB B

O

OO

O

OO

87%

Cu-CatalyzedBorylationfromOurGroup

R

BOO

J. Am. Chem. Soc. 2005J. Am. Chem. Soc. 2007

B

OR

OO

Angew. Chem., Int. Ed. 2010

BR OO

J. Am. Chem. Soc. 2010

(rac)-

R

BO

O

Angew. Chem., Int. Ed. 2008J. Am. Chem. Soc. 2010

C C CB

BuMe

H

OO


BO

O


BO

O

or

B

B

O

O

O

O


B(pin)

Org. Lett. 2012

RB

O

O

Nature Chem. 2010

Bu

BO

O


RO

BOO


B

RSi

OO

Ph Ph

Org. Lett. 2010

B(pin)HO

H


N

B(pin)

CO2R


￥Funding￥MEXT

PRESTONEXTMMCFCC

Dr. Tatsuo IshiyamaDr. Yasunori Yamamoto

Dr. Tomohiro SekiDr. Ikuo Sasaki

Dr. Eiji Yamamoto

Prof. Akira HosomiProf. Tsuneo Imamoto

Prof. Masaya Sawamura Prof. Tetsuya Taketsugu

Prof. Satoshi Maeda

Tomoko IshizukaChika KawakamiYuki KosakaShin-ichiro ItoKou MtsuuraKosuke NonoyaamTakashi Toyoda

Dr. Chongmin ZhongDr. Yusuke SasakiTakuma OkuraShun KuniiKoji KubotaTaichi OzakiYuta Takenouchi

Yuko HoritaKiyotaka IzumiRyoto KojimaHiroaki IwamotoSatoshi UkigaiDr. Ryohei Uematsu

Acknowledgements