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

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

Boronic Ester

Boranes

ü Mild organic Lewis acids

ü Mitigated reactivity profile

ü Stability, easy of handling

Boronic Ester

Boranes

ü Low toxicity

ü Degradation into boric acid

ü “Green” compounds

Boronic Ester

Boranes

ü Low toxicity

ü Degradation into boric acid

ü “Green” compounds

Attractive class of synthetic intermediates

Boronic Ester

Boranes

Versatile Intermediates

R O BOR

ORR OH

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

NHCbzB2pin2

PdCl2(dppf) (3 mol%)KOAc, DMSO, 80 ºC

OB2pin2

BpinOMe

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

3) 5% aq. HCl80%

iPr2NO

NHCbzB2pin2

PdCl2(dppf) (3 mol%)KOAc, DMSO, 80 ºC

OB2pin2

BpinOMe

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

(3 mol%)

C6H6, 80 ºC, 16 hBrBr

B2pin2Ni(COD)2 (10 mol%)

PCy3 (20 mol%)

HCO2Na (3 equiv)Toluene, 95-120 ºC

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

3) 5% aq. HCl80%

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

Linaphthalene

THF6 h, −45 ºC

NBNAr Ar

MeOTfNBNAr Ar

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

N NMes

Ar = Mes

20% dbu, B2pin2MeOH/THF, 22 ºC, 14 h

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

pinBBpinOR

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

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

B2pin2, THF, 0 ºC, 23 h Me Bu

98% ee 96% ee

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

iPrX-Ray

LCu Ot-Bu B2pin2pentane91%

LCu Bpin

LCu O Bpin

COB2pin2

pinB O Bpin

O LCu Ot-Bu

B2pin2C6H6, 22 h, rt

Bpin88%

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

LCu Bpin

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

B2pin2MeOH ( 2 equiv)

95% OPh2P PPh2

DPEphos

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

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

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

MeOHMe

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

MeCuCl/xantphos (5 mol%)

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

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

EtBpin

HCuCl (5 mol%)

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

NaOt-Bu (20 mol%)B2pin2, MeOH

THF, rt, 5 h

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

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

94%, 90% ee

FePh2PHMePCy2

(R)-(S)-Josiphos

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

94%, 90% ee

FePh2PHMePCy2

(R)-(S)-Josiphos

OCO2MeCuOt-Bu/L* (5 mol%)

B2pin2THF, 0 ºC, 48 h

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

94%, 90% ee

FePh2PHMePCy2

(R)-(S)-Josiphos

OCO2MeCuOt-Bu/L* (5 mol%)

B2pin2THF, 0 ºC, 48 h

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

PhBpin

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

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

2008, 47, 145

LCu Bpin

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

R Bpin

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

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

BpinBocHNSN2

SN2’

1,2-addition1,4-addition

Insertion

Our Inspiration

R1 Bpin

sp3-Boron stereocenters

Difunctionalization of !-bonds

Our Inspiration

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

R2E R1

LCu Bpin

L*Cu Bpin

OpinBO

OEtR1 N

O OEtH

L*Cu Bpin

α-Amino boronates

Unpublished results

LCu BpinR1 R2 R1 R2

L*Cu Bpin

R R R R

L*Cu Bpin

Vinyl Boronates

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

R1 HMe Bpin

R1 HLCu Bpin

Where it all began

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

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

1,4-diols in NatureOH

RC5H11

OH1% HClO4

BpinR1

R2 R4R3

LCu Bpin

First Experiments

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

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

THF, -20 ˚C

anti78% dr = 94:6

(±)BnO

unstable

LCu Bpinantiaddition

R2R1 O

R1 O R2

(trans, E)

(cis, E)

(cis, Z)

(trans, Z)

Scope of the AdditionCuCl /xantphos (10 mol%)

NaOt-Bu (30% mol), B2pin2

THF, -20 ˚C

C7H15O

R1 OR3

R2 R2R1

Me Z/E : 93/7

OOtrans

Scope of the AdditionCuCl /xantphos (10 mol%)

NaOt-Bu (30% mol), B2pin2

THF, -20 ˚C

C7H15O

R1 OR3

R2 R2R1

Me Z/E : 93/7

OOtrans

78% dr = 94:6syn

75% dr = 97:3

80% dr = 94:6

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

Scope of the Addition

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

C7H15O

(±) (±)

C7H15O

OTBDPS C7H15O

OTBDPS

C7H15 OTBDPS

OHC7H15 OTBDPS

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

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

THF, -20 ˚C

R1 OR3

R2 R2R1

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

Me BnOOTES

One pot

Orthogonally protected triols

Me BnOOTES

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

R2 CuL

R3 Bpin

LCuO R2R4

R3 Bpin

pinBO R2R4

R3 Bpin

LCu-Bpin

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

Copper-Catalyzed Carboboration of AlkynesSingle regio-

and stereoisomer

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

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

Functionalization of the C-B bond

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

Cyclopropyl Amino-Boronic Esters

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

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

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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