nucleophilic boron: new opportunities for carbon-boron bond ......• access to...

Nucleophilic Boron: New Opportunities for

Carbon-Boron Bond Formation

Mariola Tortosa

Boronic Esters in Synthetic Chemistry

R BOR

OR

Hall, D. In Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine; Wiley-VCH:Weinheim, 2011.

Boronic Ester


R BOR

OR


R BR

R

Boronic Ester

Boranes


R BOR

OR

ü Mild organic Lewis acids

ü Mitigated reactivity profile

ü Stability, easy of handling


R BR

R

Boronic Ester

Boranes


R BOR

OR




ü Low toxicity

ü Degradation into boric acid

ü “Green” compounds


R BR

R

Boronic Ester

Boranes


R BOR

OR




ü Low toxicity

ü Degradation into boric acid

ü “Green” compounds

Attractive class of synthetic intermediates


R BR

R

Boronic Ester

Boranes


Versatile Intermediates


Versatile Intermediates

R BOR

OR

HO O

BOR

ORR

OHO

R O BOR

ORR OH

H2O

Suzuki- Miyaura Coupling

Nobel Prize 2010

X = halogen, triflate


Cozaar®(Merck)

Pageant®(BASF)

Dolobid®(Merck)

Catalysis for the Preparation of Boronic Esters

Snieckus et al. Tetrahedron Lett. 1985, 49, 5997BOH

OH1) s-BuLi, TMEDA, −78 ºC2) B(OMe)3

3) 5% aq. HCl80%

iPr2NO

iPr2NO


MeO

O

IOMe

NHCbzB2pin2

PdCl2(dppf) (3 mol%)KOAc, DMSO, 80 ºC

B BO

OO

OB2pin2

MeO

O

BpinOMe

NHCbz

95%

Snieckus et al. Tetrahedron Lett. 1985, 49, 5997

a) Miyaura et al. J. Org. Chem. 1995, 60, 7508b) Danishefsky et al. Angew. Chem. Int. Ed. 2001, 40, 1967

BOH


3) 5% aq. HCl80%

iPr2NO

iPr2NO


MeO

O

IOMe

NHCbzB2pin2

PdCl2(dppf) (3 mol%)KOAc, DMSO, 80 ºC

B BO

OO

OB2pin2

MeO

O

BpinOMe

NHCbz

95%

MeO

H

MeO

Bpin

B2pin21/2 [IrCl(COD)]2/bpy

(3 mol%)

C6H6, 80 ºC, 16 hBrBr

OMe

O

OtBu

B2pin2Ni(COD)2 (10 mol%)

PCy3 (20 mol%)

HCO2Na (3 equiv)Toluene, 95-120 ºC

Bpin

O

OtBu

Snieckus et al. Tetrahedron Lett. 1985, 49, 5997

a) Miyaura et al. J. Org. Chem. 1995, 60, 7508b) Danishefsky et al. Angew. Chem. Int. Ed. 2001, 40, 1967

Hartwig et. al. J. Am. Chem. Soc. 2002, 124, 390 Martin et al. J. Am. Chem. Soc. 2015, 137, 6754

BOH


3) 5% aq. HCl80%

iPr2NO

iPr2NO

Boronic Esters in Biomedicine and Materials

New Drugs

Velcade®

New Drugs Covalent Organic Frameworks

Radiotherapy

Velcade®


New Drugs Covalent Organic Frameworks

Bond Formation

Radiotherapy

Velcade®


Classical C-B bond formation

Electrophilic Boron

Limited C-BBond Formation

Carbon-Boron Bond Formation

Classical C-B bond formation

Electrophilic Boron

Limited C-BBond Formation

NucleophilicBoron

ElectrophilicBoron

Nucleophilic Boron

Unprecedented

C-B bond formation

Nucleophilic Boron: Boryllithium

Nozaki, K. et al. Science 2006, 314, 113Nozaki, K. et al. J. Am. Chem. Soc. 2008, 130, 16069

N NAr ArAr = 2,6-(i-Pr)2C6H3

1) Mg2) BBr3 N

BNAr Ar

Br56%NBNAr Ar

Li

Linaphthalene

THF6 h, −45 ºC

NBNAr Ar

Li

NBNAr Ar

Me

MeOTfNBNAr Ar

Ph OH

PhCHO

85%40%

Nucleophilic Boron: Lewis Base Activation

Hoveyda, A. H. et al. J. Am. Chem. Soc. 2009, 131, 7253Fernández, E. et al. Angew. Chem. Int. Ed. 2010, 49, 5130Bo, C.; Fernández E. et al. Angew. Chem. Int. Ed. 2011, 50, 7158

LB = Lewis Base (NHC, RO-)Formal sp2 boron nucleophilesMetal-free conditions

Nucleophilic Boron: Lewis Base Activation

Hoveyda, A. H. et al. J. Am. Chem. Soc. 2009, 131, 7253Fernández, E. et al. Angew. Chem. Int. Ed. 2010, 49, 5130Bo, C.; Fernández E. et al. Angew. Chem. Int. Ed. 2011, 50, 7158

LB = Lewis Base (NHC, RO-)Formal sp2 boron nucleophilesMetal-free conditions

MeO

O

Ph

N NMes

Ph Ph

iPr

Ar

Ar = Mes

5%

20% dbu, B2pin2MeOH/THF, 22 ºC, 14 h

87%

MeO

O

Ph

Bpin

er = 98:2

Hoveyda, A. H. et al. J. Am. Chem. Soc. 2012, 134, 8277

Hosomi, A. et al. Tetrahedron Lett. 2000, 41, 6821Miyaura, N. et al. J. Organomet. Chem. 2001, 625, 47

Formal boron nucleophile

Nucleophilic Boron: Copper-Catalysis

LCu BpinLCuB2pin2

LCuOR

pinBBpinOR

Reviews: a) Westcott, S. A.; Marder, T. B. et al. Chem Rev. 2016, 116, 9091. b) Yoshida, H. ACS Catal. 2016, 6, 1799


Me Bu

O

O

MeOCu(Ot-Bu) (10 mol%)xantphos (10 mol%)

B2pin2, THF, 0 ºC, 23 h Me Bu

Bpin

98% ee 96% ee

Ito, H.; Sawamura, M. et al. J. Am. Chem. Soc. 2005, 127, 16034

N N

Cu

Bpin

iPr

iPr

iPr

iPrX-Ray

LCu Ot-Bu B2pin2pentane91%

LCu Bpin

LCu O Bpin

CO2

COB2pin2

pinB O Bpin

Ph H

O LCu Ot-Bu

B2pin2C6H6, 22 h, rt

Ph

OBpin

Bpin88%

Sadighi, J. P. et al. J. Am. Chem. Soc. 2005, 127, 17196J. Am. Chem. Soc. 2006, 128, 11036

LCu Bpin


Me

O

OEt

CuCl/DPEphos (3 mol%)NaOt-Bu (9 mol%)

B2pin2MeOH ( 2 equiv)

Me

O

OEt

pinB

95% OPh2P PPh2

DPEphos

Yun, J. et al. Org. Lett. 2006, 8, 4887


Me

O

OEt

CuCl/DPEphos (3 mol%)NaOt-Bu (9 mol%)


Me

O

OEt

pinB

95% OPh2P PPh2

DPEphos

Yun, J. et al. Org. Lett. 2006, 8, 4887

LCuCl NaOt-Bu+ LCuOt-Bu

LCu-Bpin

B2pin2

LCuOMe

B2pin2

pinBOMe

pinBOt-Bu

Me

O

OEt

Me

O

OEt

pinB

CuLMe

OCuL

OEt

pinB

MeOHMe

O

OEt

pinB

H


Hoveyda, A. H. et al. J. Am. Chem. Soc. 2011, 133, 7859

MeCuCl/xantphos (5 mol%)

KOt-Bu (50 mol%)B2pin2, MeOH (2 equiv)

Bpin

Me

H

Sawamura, M. et al. Angew. Chem. Int. Ed. 2011, 50, 2778

BocHNMesN NMes

CuCl1 mol%

NaOt-Bu (1 mol%)B2pin2, MeOH (1.5 equiv)

toluene, −50 ºC, 9 h

BocHNBpin

αH

EtBpin

Et

HCuCl (5 mol%)

P(p-tolyl)3 (6 mol%)

NaOt-Bu (20 mol%)B2pin2, MeOH

THF, rt, 5 h

β

Yun, J. et al. Chem. Commun. 2011, 47, 2943


Me

O

OEt

CuCl (3 mol%), L* (4 mol%)NaOt-Bu (3 mol%)


Me

O

OEt

pinB

94%, 90% ee

FePh2PHMePCy2

(R)-(S)-Josiphos

L*

Yun, J. et al. Angew. Chem. Int. Ed. 2008, 47, 145


Me

O

OEt



Me

O

OEt

pinB

94%, 90% ee

FePh2PHMePCy2

(R)-(S)-Josiphos

L*

Me

OCO2MeCuOt-Bu/L* (5 mol%)

B2pin2THF, 0 ºC, 48 h

Me

Bpin

N

N P

P

Me

t-Bu

t-Bu

Me

L*

(R,R)-QuinoxP*75%, 95% ee




Me

O

OEt



Me

O

OEt

pinB

94%, 90% ee

FePh2PHMePCy2

(R)-(S)-Josiphos

L*

Me

OCO2MeCuOt-Bu/L* (5 mol%)

B2pin2THF, 0 ºC, 48 h

Me

Bpin

N

N P

P

Me

t-Bu

t-Bu

Me

L*

(R,R)-QuinoxP*75%, 95% ee

Ph

Me

PhBpin

Me

N N

Ph Ph

Ph

SOO

O-

CuCl/L* (7.5 mol%)NaOt-Bu (80 mol%)

B2pin2MeOH (2 equiv)−50 ºC, 48 h L*

95%, 88% ee



Hoveyda, A. H. et al. Angew. Chem. Int. Ed. 2011, 50, 7079

Copper-Catalyzed Borylations

R

O

Ph

pinB

Yun et al. Angew. Chem. Int. Ed.

2008, 47, 145

LCu Bpin

Sadighi et al. J. Am. Chem. Soc. 2006, 128, 11036 R

OBpin

Bpin

Ar

O

HR H

NSO

R Bpin

HNSO

Ellman et al. J. Am. Chem. Soc. 2008, 130, 6910

R

R

OCO2MeBpin

Ito et al. J. Am. Chem. Soc. 2007, 129, 14856

Marder et alAngew. Chem. Int. Ed.

2012, 51, 528

Hoveyda et al. J. Am. Chem. Soc. 2011, 133, 7859

R Ph

O

Br

Bpin

BocHN

BpinBocHNSN2

SN2’

1,2-addition1,4-addition

Insertion

Our Inspiration

R1 R2

Bpin

*

R1 Bpin

sp3-Boron stereocenters

Difunctionalization of !-bonds

Our Contribution

Angew. Chem. Int. Ed. 2011, 50, 3950

1,4-Diols

J. Am. Chem. Soc. 2014, 136, 15833

Cyclopropyl and CyclobutylBoronates

Diaryl methanes

Angew. Chem. Int. Ed. 2016, 55, 6969

ACS Catal. 2016, 6, 442Chem. Comm. 2015, 51, 17684

R1O

R2E R1

OHR2

Bpin

LCu Bpin

OR R

OHR R

Bpin

L*Cu Bpin

R1 NH

OpinBO

OEtR1 N

O

O OEtH

L*Cu Bpin

α-Amino boronates

Unpublished results

LCu BpinR1 R2 R1 R2

pinB

L*Cu Bpin

R R R R

Bpin

L*Cu Bpin

Vinyl Boronates

J. Am. Chem. Soc. 2012, 134, 15165

R1 HMe Bpin

R1 HLCu Bpin

MeI

Where it all began

OH

OH

O

O

OH

R

O

HO

OOH

O

OHHO

HO

O OHOH

Nigricanoside A, R = Nigricanoside B, R =

Andersen R. J. et al. J. Am. Chem. Soc. 2007, 129, 5822

Diastereoselective Synthesis of 1,4-Diols

Symmetric Diols Non-Symmetric Diols

Two Chiral Sources

OH

OH

OH

OHRR

R

O

R

O

RO

R1

O

R2

OH

H

O

EWGR2

OHR1

OH

R1 H

OR2

OH

symmetric diols non-symmetric diols

+

+

Formal Stereocontrolled Hydrolysis of Vinyl Oxiranes

• Access to primary, secondary and tertiary diols

• Access to syn and anti diols

• Access to orthogonally protected 1,4-diols

Conrow, R. E. Org. Lett. 2006, 8, 2441

Formal StereocontrolledHydrolysis

O[O]

HO H

1,4-diols in NatureOH

OH

C5H11

OOH

RC5H11

OH

OHR

OH1% HClO4

1:1

R1O

R4

R2

R3

OH

BpinR1

R2 R4R3

OP

OHR1

R2 R4R3

LCu Bpin

[O]

First Experiments

Angew. Chem. Int. Ed. 2011, 50, 3950

trans

CuCl /xantphos (10 mol%)NaOt-Bu (30% mol), B2pin2

THF, -20 ˚C

KHCO3

H2O2

BnOO

MeE

BnOOH

Me

OH

anti78% dr = 94:6

(±)BnO

OHMe

Bpin

unstable

(±)

LCu Bpinantiaddition

R2R1 O

R1 O R2

O R2

R2O

R1

R1

R1

OHR2

OH

R1

OHR2

OH

(trans, E)

(cis, E)

(cis, Z)

(trans, Z)

anti

syn

Scope of the AdditionCuCl /xantphos (10 mol%)

NaOt-Bu (30% mol), B2pin2

THF, -20 ˚C

C7H15O

ZPh

O

R1 OR3

OHR3

Bpin2

[O]

R2 R2R1

OHR3

OHR2

R1

BnOO

Me Z/E : 93/7

OOtrans

EZ

cis

Scope of the AdditionCuCl /xantphos (10 mol%)

NaOt-Bu (30% mol), B2pin2

THF, -20 ˚C

C7H15O

ZPh

O

R1 OR3

OHR3

Bpin2

[O]

R2 R2R1

OHR3

OHR2

R1

BnOO

Me Z/E : 93/7

OOtrans

EZ

cis

BnOOH

Me

OH

anti

C7H15

OH

OH

78% dr = 94:6syn

75% dr = 97:3

Ph

OH

OH

syn

80% dr = 94:6

OH

OH

OH

OH

80% dr = 100:0 80% dr = 100:0syn anti

Scope of the Addition

Ph

OHOH

OH

OH

OH

HO

75%

60% dr = 100:0 70% dr = 96:4

PhO

O O

C7H15O

Me

Me

OHOH

C7H15

MeMe

47%

(±) (±)

C7H15O

OTBDPS C7H15O

OTBDPS

C7H15 OTBDPS

OH

OHC7H15 OTBDPS

OH

OH

70% dr = 78:22 71% dr = 91:9

CuCl /xantphos (10 mol%)NaOt-Bu (30% mol), B2pin2

THF, -20 ˚C

R1 OR3

OHR3

Bpin2

[O]

R2 R2R1

OHR3

OHR2

R1

Silyloxy Boronates and Orthogonally Protected Diols

1) CuCl (10 mol%)/ligand (10 mol%) NaOt-Bu (30% mol), 1.2 equiv B2pin2 -20 ˚C, THF, 3 h

2) TESCl, imidazole3) KHCO3, H2O2

BnOO

Me BnOOTES

Me

OH

One pot

Orthogonally protected triols

62%

BnOO

Me BnOOTES

Me

B(pin)1) CuCl (10 mol%)/ligand (10 mol%) NaOt-Bu (30% mol), 1.2 equiv B2pin2 -20 ˚C, THF, 3 h

2) TESCl, imidazole 80% anti:syn = 94:6

stable!

One pot

Proposed Mechanism

Angew. Chem. Int. Ed. 2011, 50, 3950

LCuCl NaOt-Bu+ LCuOt-Bu

R1O

R4

R2

R3

R1O

R4

R2 CuL

R3 Bpin

R1

LCuO R2R4

R3 Bpin

R1

pinBO R2R4

R3 Bpin

LCu-Bpin

B2pin2

B2pin2

Trisubstituted Methyl-Branched Alkenes

unstable

Synthesis of Cis Methyl-Branched Vinyl Boronates

Copper-Catalyzed Hydro- and Carboboration of Alkynes

Hoveyda et al J. Am. Chem. Soc. 2011, 133, 7859Yun et al Chem. Comm. 2011, 47, 2943Sawamura et al Angew. Chem. Int. Ed. 2011, 50, 2778

LCu Bpin

LCu Bpin

Copper-Catalyzed Hydro- and Carboboration of Alkynes

Hoveyda et al J. Am. Chem. Soc. 2011, 133, 7859Yun et al Chem. Comm. 2011, 47, 2943Sawamura et al Angew. Chem. Int. Ed. 2011, 50, 2778

LCu Bpin

LCu Bpin

LCu Bpin

LCu Bpin

Copper-Catalyzed Carboboration of AlkynesSingle regio-

and stereoisomer

J. Am. Chem. Soc. 2012, 134, 15165

Copper-Catalyzed Carboboration of Alkynes

Synthesis of Trisubstituted Alkenes

J. Am. Chem. Soc. 2012, 134, 15165Yoshida et al. Org. Lett. 2013, 15, 952Cazin et al. ACS Catal. 2014, 4, 1564Kanai et al. J. Am. Chem. Soc. 2016, 138, 7528

Tranylcypromine

Milnacipran

Cyclopropanes in Drugs

Tranylcypromine

Milnacipran

Cyclopropanes in Drugs

Chiral Cyclopropylboronates: Deng et al Angew. Chem. Int. Ed. 1998, 37, 2845Gevorgyan et al, J. Am. Chem. Soc. 2003, 125, 7198;Ito et al, J. Am. Chem. Soc. 2010, 132, 11440

Copper-Catalyzed Desymmetrization

Diastereoselectivity?

Enantioselectivity?

Non-coordinating groups

R1 R2 R1 R2LCu Bpin

? pinB

(a) Liu, X.; Fox, J. M. J. Am. Chem. Soc. 2006, 128, 5600. (b) Simaan, S.; Masarwa, A.; Bertus, P.; Marek, I. Angew.Chem. Int. Ed. 2006, 45, 3963. (c) Yang, Z.; Xie, X.; Fox, J. M. Angew. Chem. Int. Ed. 2006, 45, 3960. (d) Masarwa, A.;Stanger, A.; Marek, I. Angew. Chem, Int. Ed. 2007, 46, 8039. (e) Tarwade, V.; Liu, X.; Yan, N.; Fox, J. M. J. Am. Chem.Soc. 2009, 131, 5382. (f) Simaan, S.; Masarwa, A.; Zahor, E.; Stanger, A.; Bertus, P.; Marek, I. Chem. Eur. J. 2009, 15,8449.

*

Copper-Catalyzed Desymmetrization

Diastereoselectivity?

Enantioselectivity?

Non-coordinating groups

R1 R2 R1 R2LCu Bpin

? pinB

Challenges:

(a) Liu, X.; Fox, J. M. J. Am. Chem. Soc. 2006, 128, 5600. (b) Simaan, S.; Masarwa, A.; Bertus, P.; Marek, I.Angew. Chem. Int. Ed. 2006, 45, 3963. (c) Yang, Z.; Xie, X.; Fox, J. M. Angew. Chem. Int. Ed. 2006, 45, 3960. (d)Masarwa, A.; Stanger, A.; Marek, I. Angew. Chem, Int. Ed. 2007, 46, 8039. (e) Tarwade, V.; Liu, X.; Yan, N.; Fox,J. M. J. Am. Chem. Soc. 2009, 131, 5382. (f) Simaan, S.; Masarwa, A.; Zahor, E.; Stanger, A.; Bertus, P.; Marek,I. Chem. Eur. J. 2009, 15, 8449.

First Problem: Dimer Formation

Screening Chiral Ligands

J. Am. Chem. Soc. 2014, 136, 15833

Scope of the Reaction

68%dr ≥ 98:2, er = 95:5

61%dr = 97:3, er = 96:4

62%dr = 97:3, er = 95:5

53%dr = 98:2, er = 96:4

70%dr = 95:5, er = 93:7

43%dr ≥ 98:2, er = 92:8

52%dr ≥ 98:2, er = 97:3

60%dr ≥ 98:2, er = 92:8

73%dr = 98:2, er = 91:9

56%dr = 98:2, er = 93:7

MeOD

54%dr = 81:19, er = 96:4

50%dr = 80:20, er = 98:2

Functionalization of the C-B bond

J. Am. Chem. Soc. 2014, 136, 15833

Cyclopropyl Amino-Boronic Esters

J. Am. Chem. Soc. 2014, 136, 15833

Cyclobutyl Boronates

• Novel desymmetrization

• First catalytic approach

• Synthetic handle for derivatization





Matteson et al, Org. Lett. 1999, 1, 379 Bach, T. et al J. Am. Chem. Soc. 2013,135, 14948


rigid sp3 scaffold

> three dimensionality

Template for Drug Discovery




Matteson et al, Org. Lett. 1999, 1, 379 Bach, T. et al J. Am. Chem. Soc. 2013,135, 14948


meso


Angew. Chem. Int. Ed. 2016, 55, 6969

meso

Cyclobutyl Boronates: Versatile Intermediates

Angew. Chem. Int. Ed. 2016, 55, 6969

New areas of chemical space

Valuable syntheticintermediates

Novel boron containing molecules

BORON INNOVATION

nucleophilic boron: new opportunities for carbon-boron bond ......• access to...

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