Career-in-Review: Neil K. Garg

Zhen Liu 01/07/2016

Prof. Neil K. Garg

1996–2000 New York University (Sc. B.)

2000–2005 Caltech (Ph. D.)Supervisor: Brian M. Stoltz

2005–2007 UC Irvine (Postdoc)Supervisor: Larry E. Overman

2007–2012 Assistant Professor (UCLA)

2012–2013 Associate Professor (UCLA)

2013–present Full Professor (UCLA)

Selected Awards 2010 Thieme Chemistry Journal Award2010 NSF CAREER Award2015 Arthur C. Cope Scholar Award2016 Tetrahedron Young Investigator Award……

Contents

– Aryne Chemistry

– Interrupted Fischer Indolization

– Metal-Catalyzed Cross-Coupling Reactions

– Summary and Outlook

3

Contents

– Aryne Chemistry

– Interrupted Fischer Indolization

– Metal-Catalyzed Cross-Coupling Reactions

– Summary and Outlook

4

Aryne Chemistry

5

Benzyne Electrophilic Character

Hoffmann, R.; Imamura, A.; Hehre, W. J. J. Am. Chem. Soc. 1968, 90, 1499.

Aryne Chemistry

6

Goetz, A. E.; Bronner, S. M.; Cisneros, J. D.; Melamed, J. M.; Paton, R. S.; Houk, K. N.; Garg, N. K. Angew. Chem. Int. Ed. 2012, 51, 2758.

Three Categories

Aryne Chemistry

7Bronner, S. M.; Garg, N. K. J. Org. Chem. 2009, 74, 8842.

X strong base TMSOTf

F

OH iPrN=C=O O NHiPr

O

i. TMEDA, TBSOTf

ii. TMEDA, nBuLi

O N

OTBS

iPr

LiN N

TMSClacidic workup

O NHiPr

OTMS

DBU, Et2NH OH

TMS

PhNTf2

66%

OTf

TMS

Himeshima, Y.; Sonada, T.; Kobayashi, H. Chem. Lett. 1983, 1211.

Cl

HO

TMS

TMSO

nBuLi, then Tf2O

86%

Kobayashi, 1983

TMS

TfO

8

Selected Examples

entry trapping agent products yield (ratio)

Me

OH

N3 Bn

NMe

65%

1

2

3

NMe

O

Me

+

NMe

O

Me

80%(3:1)

NMe

+

NNNBn

NMe

NNN

Bn

86%(2.4:1)

Bronner, S. M.; Bahnck, K. B.; Garg, N. K. Org. Lett. 2009, 11, 1007.

Aryne Chemistry

NH

BnO

NMe

HO iPrN=C=ONMe

OHN

OiPr

i. TMEDA, TBSOTf

ii. TMEDA, nBuLiNMe

OHN

OiPr

TMSDBU, Et2NH

then PhNTf2 NMe

TfOTMS

i. NaH, MeI

ii. H2, Pd/C94%, 2 steps

90%

84% 88%

F

NMe

9

Aryne Chemistry

Bronner, S. M.; Bahnck, K. B.; Garg, N. K. Org. Lett. 2009, 11, 1007.

NH

BnO

NMe

HO iPrN=C=ONMe

OHN

OiPr

i. TMEDA, TBSOTf

ii. TMEDA, nBuLiNMe

OHN

OiPr

TMSDBU, Et2NH

then PhNTf2 NMe

TfOTMS

i. NaH, MeI

ii. H2, Pd/C94%, 2 steps

90%

84% 88%

F

NMe

NMe

OHN

OiPr

DBU, Et2NH

then PhNTf2 NMe

TfO

88%TMS TMS

NMe

OO

TBAF92%

CsF73%

NH2

NMe

HN

NMeN

H

+ (3:1)

Aryne Chemistry—Aryne Distortion Model

10

Im, G-Y. J.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong, P. H.-Y.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2010, 132, 17933.

11

Medina, J. M.; Mackey, J. L.; Garg, N. K.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 15798.

Aryne Chemistry—Aryne Distortion Model

12

Goetz, A. E.; Garg, N. K. Nat. Chem. 2013, 5, 54.

Aryne Chemistry

N

XTMS

OTf

N

XCsFTrapping

agent N

X R

Selected Examples

entry trapping agent products yield (ratio)

HN

N

1

2

+

X = H1.9:1(77%)

X = Br1:5.8(64%)

N

+N

O

MeN

XNMe

N

NMe

X

Ph

tBu

O

X

PhtBu

N

ONtBu X = H

1.9:1(76%)

X = Br1:3.3(60%)

X

Ph

N

TMSOTf

N

CsFTrapping

agent N

R

entry trapping agent products yield (ratio)

HN

N

3

4

+

X = H1.9:1(77%)

X = OSO2NMe2>15:1(64%)

MeN

NMe

Ph

tBu

O

X = H1.9:1(76%)

X = OSO2NMe210.7:1(61%)

X X X

X N

NMe

X

N

+N

O

X

PhtBu

N

ONtBu

X

Ph

Cycloalkyne Chemistry

13

Medina, J. M.; McMahon, T. C.; Jiménez-Osés, G.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2014, 136, 14706.

OTf

TMS

OTf

TMS

CsFTrappingagent

X

Y

CsFTrappingagent

X

Y

N

OTf

TMS

CsFTrappingagent

N N

X

YCbz Cbz Cbz

orN

Nuc

Cbz

McMahon, T. C.; Medina, J. M.; Yang, Y.-F.; Simmons, B. J.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2015, 137, 4082.

14

Cycloalkyne Chemistry

McMahon, T. C.; Medina, J. M.; Yang, Y.-F.; Simmons, B. J.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2015, 137, 4082.

entry trapping agent products yield (ratio)

N

2

3

99%(>20:1)

N

+N

OPh

tBu

O

PhtBu

Cbz

tBu

PhON

N

84%(12.7:1)

N

OTf

TMS

CsFTrapping

agentN

X

YCbz Cbz

orN

Nuc

Cbz

1 78%(>20:1)

Selected Examples

N NHN

N

Cbz

N

NH

O

N

N

Cbz

O

Cbz

15

Applications of Aryne Chemistry

NMe

OO

SCNH

MeMe

MeCl

NMe

OO

CNH

MeMe

MeO

O

(–)-N-methylwelwitindolinoneC isothiocyanate

N-methylwelwitindolinoneD isonitrile

NH

NO

HNMe

MeMe OH

(–)-indolactam V

NMe

OO

SCNH

MeMe

MeCl

(–)-N-methylwelwitindolinoneB isothiocyanate

NH

MeMe

OH

Me Me

tubingensin A

NH

NO

HNMe

MeMe OH

(–)-pendolmycin (–)-lyngbyatoxin AMeMe

NH

NO

HNMe

MeMe OH

Me

MeMe(–)-teleocidin A-2

NH

NO

HNMe

MeMe OH

Me

MeMe

J. Am. Chem. Soc. 2011, 133, 15797. Angew. Chem. Int. Ed. 2013, 52,12422. J. Am. Chem. Soc. 2014, 136, 14710. J. Am. Chem. Soc. 2014, 136, 3036.

J. Am. Chem. Soc. 2011, 133, 3832. Chem. Sci. 2014, 5, 2184. Chem. Sci. 2014, 5, 2184. Chem. Sci. 2014, 5, 2184.

(–)-N-Methylwelwitindolinone C Isothiocyanate—Retrosynthetic Analysis

16

Huters, A. D.; Quasdorf, K. W.; Styduhar, E. D.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 15797.

NMe

OO

SCNH

MeMe

MeCl

(–)-N-methylwelwitindolinoneC isothiocyanate

NMe

OO

HH

MeMe

MeCl

NMe

OH

H

MeMe

MeRO

NMe

O

H

MeMe

MeRO

NMe

BrO

Me

Me

ORMe

Late-StageBridgehead

Functionalization

IndolyneCyclization

NMe

Br O

OHMe

MeMe

17

Huters, A. D.; Quasdorf, K. W.; Styduhar, E. D.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 15797.

(–)-N-Methylwelwitindolinone C Isothiocyanate—Total Synthesis

OMe

Me(S)-carvone

MgBr

CuBr•SMe2

O

Me

Me

OPivMe

80%C2

i. K2CO3, MeOH

ii. I2,

NMe

Br

54%, 2 stepsNMe

Br

C3

O

Me

Me

OPiv

C1

Me

O

Me

Me

OPiv

C1

Me

TBSCl, imidazoleO

OHMe

MeMe

NMe

Br O

OTBSMe

MeMe

C4

90%

46%

NaNH2

NMe

OH

H

MeMe

MeOTBS

+

NMe

OMeMe

Me OTBS

2.5 : 1

C5 C6

18

(–)-N-Methylwelwitindolinone C Isothiocyanate—Total Synthesis

Huters, A. D.; Quasdorf, K. W.; Styduhar, E. D.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 15797.

NMe

OH

H

MeMe

MeOTBS

C5

i. TBAFii. Dess–Martin [O]

95%, 2 stepsNMe

OH

H

MeMe

MeO

C7

74%, 2 stepsNMe

OH

H

MeMe

Me

C8

SnMe3

75%

CuCl2

NMe

OH

H

MeMe

Me

C9

Cl

i. NBSii. HCl, 80 °C

89%, 2 stepsNMe

OH

H

MeMe

Me

C10

Cl

OH

i. KHMDS; –78 °C, Comins' reagentii. (Me3Sn)2, Pd(PPh3)4, LiCl

i. iBu2AlHii. Cl3C(O)NCO; K2CO3, MeOH

86%, 2 steps NMe

MeMe

C11

O

H

ClMe

HHOH2N

O33% yield +

25% recovered C10

AgOTf, PhI(OAc)2 bathophenanthroline

NMe

MeMe

C12

O

H

ClMe

HOO

HN

i. Ba(OH)2•8H2O

48%, 2 steps NMe

OH2N

H

MeMe

Me

C13

Cl

OH

77%DMAP, 90 °C

NMe

OO

SCNH

MeMe

MeCl

(–)-N-methylwelwitindolinoneC isothiocyanate

N O

S

O N

ii. IBX, TFA

– Aryne Chemistry

– Interrupted Fischer Indolization

– Metal-Catalyzed Cross-Coupling Reactions

– Summary and Outlook

19

Contents

Fischer Indole Synthesis

20

Fischer, E.; Jourdan, F. Chem. Ber. 1883, 16, 2241.

NH

NH2+ O

R1

R2 H+R1

R2

NH

Fischer, 1883

NH

N

R1R2

H+

NH

NH

R1R2

NHNH

R1R2

H+

NH2

R1R2

NH2NH2

HR1

NH2

R2

R1

R2

NH

– H+

– NH3

Interrupted Fischer Indolization

21

NR

NH2+ H2O, AcOH

R'XHO

R''R'

NR

X

R''

H

X = O, NTs

XHO

R''H+n

O

R'' n

H

XH

Boal, B. W.; Schammel, A. W.; Garg, N. K. Org. Lett. 2009, 11, 3458.

HXR''

NH2

H

– NH3

NH2

NH

HNH3

R'' HX

NH

R'' HX

R' R' R'NR

X

R''

H

n

NH2NH2

HXR''R''

NHNH

HXR''

NNH

HXH+ H+

R'

n nn

nn

R'R'R'

22

NMe

NMeO

O

HNPh

H

Me

(+)-phenserineAlzheimer's therapeutic

NH

NTsH

NO

O

Br

tetracyclic indoline coreof perophoramidine

NHN

Br

Cl

Cl

NMeN

perophoramidine

HN

NOHC

CO2Me

MeO

H

H

(±)-Aspidophylline A

HN

N

CO2Me

MeO

H

H

Picrinine

N

N

CO2Me

Me

H

H

Strictamine

Applications of Interrupted Fischer Indolization

J. Org. Chem. 2012, 77, 725. Org. Lett. 2012, 14, 4556.

J. Am. Chem. Soc. 2011, 133, 8877. J. Am. Chem. Soc. 2014, 136, 4504. J. Am. Chem. Soc. 2014, 136, 4504.

(±)-Aspidophylline A—Retrosynthetic Analysis

23

Zu, L.; Ben, W. B.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 8877.

HN

NOHC

CO2Me

MeO

H

H

(±)-Aspidophylline A

HN NH2

+O

RNH

H MeH CO2Me

HO

CO2Me

RNRO

ROX

MeRNH

H MeCO2Me

RORO

RN

OO

CO2HCO2H

Late-Stage Interrupted Fischer Indolization

Heck Cyclization

24

TsNH

H MeCO2Me

O

O

TsNH

H MeH CO2Me

HO

HN

NTs

CO2Me

MeO

H

Hphenylhydrazinevarious acids

A9

A10A12

(±)-Aspidophylline A—Total Synthesis

NBn

BnO

O

O OO

PhMe, reflux

BnN

BnOO

O

O

OHH

BnN

OO

HN

MeOO

MeO

CO2Me

NHTsMeO

MeO

CO2Me

TsNMeO

MeOI

Me TsNH

H MeCO2Me

MeOMeO

TsNH

H MeCO2Me

OTsNH

H MeCO2Me

O

Cu2O, H2O

150 °C, microwave

i. HC(OCH3)3, heat p-TsOH, MeOH

ii. Na, NH3

i. nBuLi, TsClii. K2CO3, MeOH

IMeBr

Pd(PPh3)4

MeCN, 70 °C

dr 8:1

i. FeCl3•6H2O

ii. In, EtOH, 90 °C aq. NH4Cl

50–69% 87%, 2 steps

90%, 2 steps70%

95–99%

90%

i. LiHMDS, DMPUii. allyl iodide

AI A2 A3 A4

A5

A4

A6 A7

A8 A9

75%

NMe

MeMe MeMe

25

TsNH

H MeCO2Me

O

TsNH

H MeCO2Me

O

PivO N

NTs

CO2Me

MePivO

H

Hphenylhydrazine

various acids

A9

A11A13

(±)-Aspidophylline A—Total Synthesis

NBn

BnO

O

O OO

PhMe, reflux

BnN

BnOO

O

O

OHH

BnN

OO

HN

MeOO

MeO

CO2Me

NHTsMeO

MeO

CO2Me

TsNMeO

MeOI

Me TsNH

H MeCO2Me

MeOMeO

TsNH

H MeCO2Me

OTsNH

H MeCO2Me

O

Cu2O, H2O

150 °C, microwave

i. HC(OCH3)3, heat p-TsOH, MeOH

ii. Na, NH3

i. nBuLi, TsClii. K2CO3, MeOH

IMeBr

Pd(PPh3)4

MeCN, 70 °C

dr 8:1

i. FeCl3•6H2O

ii. In, EtOH, 90 °C aq. NH4Cl

50–69% 87%, 2 steps

90%, 2 steps70%

95–99%

90%

i. LiHMDS, DMPUii. allyl iodide

AI A2 A3 A4

A5

A4

A6 A7

A8 A9

75%

NMe

MeMe MeMe

26

(±)-Aspidophylline A—Total Synthesis

HN

NOHC

CO2Me

MeO

H

H

(±)-Aspidophylline A

TsNH

H MeCO2Me

O

A9

NaBH4

TsNH

H MeCO2Me

A14

HO

98%

i. OsO4, NaIO4

ii. NaBH4

83%, 2 steps

TsNH

H MeCO2Me

A15

HO

HO

i. H2SO4

ii. Dess–Martin [O]

76%, 2 steps

TsNH

H Me

A16

O

O O

TFA

HN NH2

N

NTs

Me

H

H

A17 (not isolated)O

O

HN

NTs

CO2Me

MeO

H

H

A12

K2CO3

70%(one pot, from A16)

i. Mg, NH4Cl

ii. formic acid, DIC, DMAP

68%, 2 steps

– Aryne Chemistry

– Interrupted Fischer Indolization

– Metal-Catalyzed Cross-Coupling Reactions

– Summary and Outlook

27

Contents

C–O Bond Activation

28

Quasdorf, K. W.; Tian, X.; Garg, N. K. J. Am. Chem. Soc. 2008, 130, 14422.

ORtransition

metal catalyst MORL

LR' R'M' Ar Ar

R'

C-C Bond Formation

Quasdorf, K. W.; Riener, M.; Petrova, K. V.; Garg, N. K. J. Am. Chem. Soc. 2009, 131, 17748.

Ar OPivB(OH)2

R+Ar

RNiCl2(PCy3)2, K3PO4

Ar1 OR +NiCl2(PCy3)2, K3PO4

Ar2 B(OH)2 Ar1 Ar2

R = C(O)NEt2, CO2tBu, SO2NMe2

toluene, heat, 24 h

toluene, heat, 24 h

Traditionally difficult when anything other than OTf

29

Quasdorf, K. W.; Antoft-Finch, A.; Liu, P.; Silberstein, A. L.; Komaromi, A.; Blackburn, T.; Ramgren, S. D.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 6352.

O NMe2

O

C–O Bond Activation

30

Quasdorf, K. W.; Antoft-Finch, A.; Liu, P.; Silberstein, A. L.; Komaromi, A.; Blackburn, T.; Ramgren, S. D.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 6352.

C–O Bond Activation

31

Ramgren, S. D.; Silberstein, A. L.; Yang, Y.; Garg, N. K. Angew. Chem. Int. Ed. 2011, 50, 2171.

Mesganaw, T.; Silberstein, A. L.; Ramgren, S. D.; Fine Nathel, N. F.; Hong, Xin; Liu, P.; Garg, N. K. Chem. Sci. 2011, 2, 1766.

Hie, L.; Ramgren, S. D.; Mesganaw, T.; Garg, N. K. Org. Lett. 2012, 14, 4182.Fine Nathel, N. F.; Kim, J.; Hie, L.; Jiang, X. Y.; Garg, N. K. ACS Catal. 2014, 4, 3289.

OSO2NMe2R + HN R'

R''

[Ni(cod)2]SIPr•HClNaOtBu

dioxane, heat

NR

R'

R''

OCONEt2R + HN R'

R''

[Ni(cod)2]SIPr•HClNaOtBu

dioxane, heat

NR

R'

R''

X + HN R'

R''

NiCl2(DME)SIPr•HCl

NaOtBu, Ph–B(pin)2-Me-THF, heat

(Het)Ar Ar(Het) NR'

R''

X = Cl or OSO2NMe2green solvent

C–O Bond Activation

N NiPr

iPr

iPr

iPr

Cl

SIPr•HCl

32

Mesganaw, T.; Fine Nathel, N. F.; Garg, N. K. Org. Lett. 2012, 14, 2918.

OC(O)NEt2 toluene, heat(Het)Ar (Het)Ar1 H

NiCl2(PCy3)TMDSO, K3PO4 O SiSi Me

Me

Me

Me

H HTMDSO

R'OC(O)NEt2

X

carbamate-directedfunctionalization reductive cleavage

of carbamates

R'OC(O)NEt2 cine substitution

R'

X X = C(O)R, Alkyl, Silyl ......

C–O Bond Activation

33

Hie, L.; Fine Nathel, N. F.; Shah, T. K.; Baker, E. L.; Hong, X.; Yang, Y.-F.; Liu P.; Houk, K. N.; Garg, N. K. Nature 2015, 524, 79.

Weires, N. A.; Baker, E. L.; Garg, N. K. Nat. Chem. 2016, 8, 75.

Ar N

OR2

R1

R1, R2 ≠ H

+ HO R

[Ni(cod)2]SIPr

toluene, heat Ar OR

O+ HN R2

R1

(Het)Ar1 N

OR

Boc+

(Het)Ar2 [Ni(cod)2]SIPr

K3PO4, H2Otoluene, heat

(Het)Ar1 (Het)Ar2

O+ HN R

Boc

B(OH)2

or

(Het)Ar2 B(pin)

R = Me or Bn

C–N Bond Activation

34

[Ni(cod)2], SIPrK3PO4, H2Otoluene, heat

N

O

N

OBn

H Boc

Bn

O

(pin)B

O

N

OBn

HO

[Ni(cod)2], SIPr, toluene, heat

O

O

O

O

Me

MeMei. Boc2O, DMAP, CH3CN, rt.A

C

OH

Me

MeMe

(–)-mentholB

NH

O

O

O

Me

Me MeBni. Boc2O, DMAP, CH3CN, rt.ii. A, [Ni(cod)2], SIPr, K3PO4

H2O, toluene, heat

ii. B, [Ni(cod)2], SIPrtoluene, heat

C–N Bond Activation

35

C–N Bond Activation

Other Metal-catalyzed Coupling Reactions

36

Mesganaw, T.; Im, G-Y. J.; Garg, N. K. J. Org. Chem. 2013, 78, 3391.

Silberstein, A. L.; Ramgren, S. D.; Garg, N. K. Org. Lett. 2012, 14, 3796.

Ramgren, S. D.; Hie, L.; Ye, Y.; Garg, N. K. Org. Lett. 2013, 15, 3950.

Ramgren, S. D.; Garg, N. K. Org. Lett. 2014, 16, 824.

OAc

Pd(OAc)2PPh3 resin, Et3N

EtCN, 105 °C

diphenylhexatriene

• gram scale• useful compound (fluorescent probes)

ROR' FeCl2

SIMes•HCl

DCM-THF+ ClMg alkyl R

alkyl

R' = OCONEt2 or OSO2NMe2

NNMesMes

Cl

SIMes•HCl

X +NiCl2(PCy3)2

K3PO42-Me-THF or tamyl alcohol

heat(Het)Ar1 (Het)Ar1

X = Br, I, Cl or OSO2NMe2 green solvent

(Het)Ar2 B(OH)2 (Het)Ar2

X +Pd(PPh3)4

KFDCM, heat

(Het)Ar

X = Br, I or OTf

O

MeTMS

O

Me(Het)Ar

Summary

37

– Aryne Chemistry • Aryne Distortion Model• Alkaloid Total Synthesis (e.g., (–)-N-methylwelwitindolinone C Isothiocyanate)

– Interrupted Fischer Indolization • Methodology Development• Alkaloid Total Synthesis (e.g., (±)-Aspidophylline A)

– Metal-catalyzed Cross Coupling Reactions • C–O Bond Activation• C–N Bond Activation

Outlook and Possible Future Directions

38

• Total Synthesis and Drug Development

• Develop Ni(II)-Catalyzed C–N Bond Activation Reactions

• Kinetic Study of the C–N Bond Activation Reactions

• Photoredox Chemistry

Acknowledgements

• Keary

• All Group members

39