Dong XINGMarch 9th 2016

Metal Carbene-Involved C-H Functionalization--New Pathways and Synthetic Applications

Guangbin Dong Group Meeting @ UT Austin

Metal Carbene-Involved C-H Functionalization

The C‐H activation/C‐C formation proceeds in a single step through a three‐centered hydride transfer‐like transition state with a small activation energy

Sp3 C-H Functionalization

Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181

This concerted three‐centered transition state allows efficient asymmetric control by chiral metal catalysts

Metal Carbene-Involved C-H Functionalization

Aromatic sp2 C-H Functionalization

Competitive Buchner Ring Expansion

Metal Carbene-Involved C-H Functionalization

N N2

CO2Me

Br

+Rh2(S-DOSP)4

NCO2Me

Br N

MeO2C

Br24%64% ee

36%0% ee

+

The zwitterionic intermediate‐involving pathway makes it difficult to achieve asymmetric control by chiral metal catalysts

Davies, H. M. L.; Jin, Q. Org. Lett. 2004, 6, 1769

Aromatic sp2 C-H Functionalization

Ye, B.; Cramer, N. Angew. Chem. Int. Ed. 2014, 53, 7896Racemic version reported by Rovis: Hyster, T. K.; Ruhl, K. E.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 5364

Directing Group-Assisted Enantioselective Aromatic C-H Functionalization

via “CMD” Mechanism

Plausible mode for the enantioselectivity

Scope of the diazo compounds

Enantioselective C(sp2)-H Insertion of Aniline Derivatives with Diazo Cpds

Xu, B.; Li, M.-L.; Zuo, X.-D.; Zhu, S.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2015, 137, 8700

Xu, B.; Li, M.-L.; Zuo, X.-D.; Zhu, S.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2015, 137, 8700

Proposed Pathway for this transformation

Xu, B.; Li, M.-L.; Zuo, X.-D.; Zhu, S.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2015, 137, 8700

Mechanism Studies

Substrate Scope

Scope of Diazo Cpds Scope of Aniline Substrates

Xu, B.; Li, M.-L.; Zuo, X.-D.; Zhu, S.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2015, 137, 8700

R1N2

CO2R2

1,2-proton transfer

R1CO2R2

Xpath a

X

M

R1 CO2R2

HX

H

R1

OM

OR2

active zwitterionic intermediate

Zhang, J. et al JACS, 2014, 136, 6904Shi, X. et al ACIE, 2014, 53, 9817Zhou, Q,-L et al JACS, 2015, 137, 8700

H

X +

R1M

CO2R2

metal catalyst

path b

electrophilictrapping

chiral co-cat.

R1

X

CO2R2

Benzylic QuaternaryCarbon Center

X

Our Design—Electrophilic Interception of the Zwitterionic Intermediate

Precedent—Using Indole & N‐Phenyl Diazoamide as Zwitterionic Precursor

13

Jia, S.; Xing, D.*; Zhang, D.; Hu, W.* Angew. Chem. Int. Ed., 2014, 53, 13098Synfacts, 2014, 10(11), 1171

Using Imine as the Electophile & Rh&Chiral PPA Co-Cat. System

Substrate Scope-1

entry 3 Ar1/Ar2 4 yield (%)b drc ee (%)d

1 3a p-Cl-C6H4/Ph 4a 74 91:9 99

2 3b p-Br-C6H4/Ph 4b 68 92:8 98

3 3c p-F-C6H4/Ph 4c 67 91:9 99

4 3d p-CF3-C6H4/Ph 4d 68 87:13 98

5 3e 3,4-Cl2-C6H3/Ph 4e 73 95:5 90

6 3f Ph/Ph 4f 57 88:12 96

7 3g p-Me-C6H4/Ph 4g 43 82:18 98

8 3h p-F-C6H4/p-Cl-C6H4 4h 68 86:14 99

9 3i p-Cl-C6H4/p-Br-C6H4 4i 57 85:15 99

10 3j Ph/m-Br--C6H4 4j 56 80:20 97

4k84%

90:10 dr; 99% ee

4l83%

90:10 dr; 99% ee

4m71%

91:9 dr; 99% ee

4n79%

92:8 dr; 98% ee

4o40%

78:22 dr; 97% ee

4t74%

91:9 dr; 98% ee

4p71%

95:5 dr; 99% ee

4u55%

88:12 dr; 99% ee

4v73%

90:10 dr; 99% ee

MeO2C

HN

p-F-C6H4

Z2N Ph

p-Cl-C6H4 MeO2C

HN

p-F-C6H4

Z2N Ph

p-Br-C6H4 MeO2C

HN

p-F-C6H4

Z2N Ph

p-Me-C6H4 MeO2C

HN

p-F-C6H4

Z2N Ph

m-OMe-C6H4

EtO2C

HN

p-F-C6H4

Z2N Ph

Ph

MeO2C

HN

p-Br-C6H4

N Ph

Ph

Et

Bn

MeO2C

HN

p-Br-C6H4

N Ph

Ph

Me

Z

MeO2C

HN

p-Br-C6H4

N Ph

Ph

Et

CO2Et

MeO2C

HN

p-Br-C6H4

Bn2N Ph

Ph

4s68%

90:10 dr; 98% ee

MeO2C

HN

p-Br-C6H4

N Ph

Ph

Me

Bn

4q58%

95:5 dr; 99% ee

MeO2C

HN

Ph

Bn2N Ph

Ph4r

51%95:5 dr; 97% ee

MeO2C

HN

p-Me-C6H4

Bn2N Ph

Ph

Substrate Scope-2

Control Expt. & Intermolecular KIE

Control Experiment

Intermolecular KIE

Proposed Transition State

NO

Z

Pg1

NPg2

Z: carbon substituent

NH

NN

HN O

OH

Me

(+)-gliocladin C

ONH

NN

HN O

OH

Me

(+)-bionectin A, R = H(+)-gliocladine C, R = Me (+)-leptosin D, R = i-Pr(+)-T988A, R = CH2OH(+)-bionectin B, R = CH(OH)Me

OH

SS

RNH

NN

HN O

OH

Me

(+)-gliocladin A, R = OH(+)-gliocladin B, R = H

R

SMe

SMe

“Electrophilic Trapping” Protocol for Synthesis of Mixed 3,3’-Bisoxindoles

NN

NN

Me

MeH

H

Me

Me

N NMeHMe

(-)-idiospermuline

NN

NNH

H

Me

Me

HNNH

O

O

O

O

Bn

Bn

(+)-WIN 64821

NH

N

N

HNH

H

NN

O

O

O

O

R

R

R = Me, (+)-dideoxyverticillinR = CH2OH, (+)-chaetocin

SS

SSMe

Me

NH

N

N

HN

Me

MeH

H

(-)-Chimonanthine

NO

Pg

N2

ElectrophileNPg

2

HN

O

Z

Pg1

NPg2

Z: carbon substituent

“Electrophilic Trapping” Protocol for Synthesis of Mixed 3,3’-Bisoxindoles

via

N

N

[Rh]

O

R1

R2

N

N

O[Rh]

R1

R2

zwitterionic intermediate

Xing, D.*; Jing, C.; Li, X.; Qiu, H.; Hu, W.* Org. Lett. 2013, 15, 3578.

Synfacts, 2013, 9(10), 1078

Using Ethyl Glyoxylate as the Electrophile

Xing, D.*; Jing, C.; Li, X.; Qiu, H.; Hu, W.* Org. Lett. 2013, 15, 3578.

Synfacts, 2013, 9(10), 1078

Synthetic Applications

Jing, C.; Xing, D.*; Wang, C.; Hu, W.* Tetrahedron 2015, 71, 3597

Using Formaldehyde as Electrophile

oxonium ylide

NR

O

Rh OH2

Using Formaldehyde as Electrophile

NR1

O

N2

R2

HCHO (aq)+

ArNH2

Rh2(OAc)4NR1

OR2

ArHNOH

H2ONR1

OR2

HOOH

Rh2(OAc)4

21 examples42 - 98% yields

14 examples26 - 74% yields

Wang, C.; Xing, D.*; Wang, D.; Wu, X.; Hu, W.* J. Org. Chem. 2014, 79, 3908

Using in situ Generated Iminoester as the Electrophile

Rh(II) (1 mol%)

chiral PPA(5 mol%)

ArNH2

60 - 92% yieldup to >20:1 drup to 99% eeN

O

R2

N2

N

N HN

CO2EtO

R1

R2

CO2Et

O

CH2Cl2

+NR1 +

1

2 5

Ar

Jing, C.; Xing, D.*; Hu, W.* Org. Lett. 2015, 17, 4336

Using in situ Generated Iminoester as the ElectrophileControl Experiment

Gong, L.-Z. et al Angew. Chem. Int. Ed. 2014, 53, 10763.

NO

NBn

RNH2

Br

O

CO2EtH

3b 4N

N HN

CO2EtO

Bn

R

BrRh2(OAc)4(2 mol%)

(S)-6j (5 mol%)4 Å MSxylene25 oC

7a (R = Boc)7r (R = Bn)

1 h:5b (R = Boc): 13% yield, >95:5 d.r., 14% ee5r ( R= Bn): < 5%20 h:5b (R = Boc): 92% yield, >95:5 d.r., 67% ee5r ( R= Bn): 12% yield, >95:5 d.r., 57% ee

As a comparation, Gong’s similar work follows a stepwise pathway

Metal-Free Synthesis of 3-Aryloxindoles

Zhai, C.;. Xing, D.*; Jing, C.; Zhou, J.; Wang, C.; Wang, D.; Hu, W.* Org. Lett. 2014, 16, 2934

N2N

N2

O

R NO

R

H Ar

Friedel-Craftsalkylation

N

Ar

O

R

diazonium ion

H N HN

NH

O

F

MeO

Cl

BMS-204352

F3C

MaxiPostTM

Metal-Free Synthesis of 3-Halooxindoles

N

O

N2 NBS(1.0 equiv)

CH2Cl20 oC

NO

Br

+

1a 2a 3a

N

O

Br

95%2a:3a = 93:7

N

O

N2 NXS(1.0 equiv)

CH2Cl20 oC

NO

X

+

1a 2 3

N

O

X

95%2a:3a = >95:5

X = Cl, I

Unpublished results

Proposed [4+1] Cycloaddition of 3-Diazoxindole

NMe

NMeO

O

Cl

NH

NMeO

O

NMeO

MeO

O2N

anti-tumor acetylcholinesterase(AChE) inhibitory

NH

NO

anti-bacterial

OS

Cl

NH

NO

SO2N

anti-tubercular

Cl

Cl

MeN

O

ClCl

O CuL

CO2Ar

R1 R2

via

Son, S.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 1046

Son, S.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 1046

Zhou, J.‐L.; Wang, L.‐J.; Xu, H.; Sun, X.‐L.; Tang, Y. ACS Cat. 2013, 3, 685

NO

R1

OR3

R5R4

Failed Substrates:

All attempts for the synthesis of dihydrofuran-spirooxindole failed

Development for the synthesis of 2-pyrrolin-spirooxindole

Our designed strategy for spirooxindole synthesis

Entry Cat. (mol%) solvent T (°C) Yield (%)b Drc

1 Rh2(OAc)4 (2) CH2Cl2 40 64 > 95:5

2 Rh2(OAc)4 (2) CHCl3 40 51 > 95:5

3 Rh2(OAc)4 (2) toluene 40 73 > 95:5

4 Rh2(OAc)4 (2) EtOAc 40 60 > 95:5

5 Rh2(OAc)4 (2) toluene 60 55 > 95:5

6 Rh2(OAc)4 (2) toluene 15 77 > 95:5

7 d Rh2(OAc)4 (2) toluene 15 68 > 95:5

8 Cu(OTf)2 (10) CH2Cl2 40 43 > 95:5

9 CuPF6(MeCN)4(10) CH2Cl2 40 48 > 95:5

Unpublished Results

NMe

NO

PhPMP

CO2Me

NMe

NO

PhPMP

CO2Me

F

NMe

NO

PhPMP

CO2Me

Cl

NMe

NO

PhPMP

CO2Me

Br

NMe

NO

PhPMP

CO2Me

Me

NMe

NO

PhPMP

CO2Me

MeO

NBn

NO

PhPMP

CO2Me

NBoc

NO

PhPMP

CO2Me

NCbz

NO

PhPMP

CO2Me

NMe

NOPMP

CO2MeF

NMe

NOPMP

CO2MeCl

NMe

NOPMP

CO2MeBr

NMe

NOPMP

CO2Me

NMe

NOPMP

CO2MeO2N

NMe

NOPMP

CO2MeMe

NMe

NOPMP

CO2MeS

NMe

NO Br

CO2Me

Br

O2N

3a, 77% 3b, 65% 3c, 70% 3d, 63% 3e, 71%

3f, 87% 3g, 49% 3h, 85% 3i, 81% 3j, 76%

3k, 84% 3l, 62% 3m, 90% 3n, 79% 3o, 61%

3p, 52% 3q, 96%

Me

Unpublished Results

3h

Et3SiH, TFADCM, 78 °C

N

NO

PhPMP

CO2Me

Boc

K2CO3, DME/H2O

refluxNH

NO

PhPMP

CO2Me

N

NPh

PMP

CO2Me

Boc

98%

73%

4, dr > 95:5 65, dr > 95:5

LiBH4

87%

NBS, Et3SiH

DCM, 0 °CN

NO

PhPMP

Boc

BrOMe

HO

N

NO

PhPMP

CO2Me

Boc

HO

N

NO

PhPMP

CO2Me

Boc

m-CPBA

DCM, 40 °C65%

7 8, dr > 95:5

THF, 0 °C

78%

OH

Unpublished Results

Initial Biological Evaluations

HCT116 (p53 wild‐type)HCT116 (p53 knock out)SASJ‐1 (p53 wild‐type)

PTP1BAurora AXBP1 splicingNFkB pathwaySirt1HDAC6

Collaborators: Prof. Jia Li’s Group from National Center for Drug Screening of China

Initial Biological Evaluations

39

HCT116 (p53 wild-type & knock out)

Initial p53‐MDM2 interaction inhibiting

Entry Cpd IC50 (uM)HCT116 (wt)

IC50 (uM)HCT116 (ko)

1 001 27.4 32.42 018 8.9 21.13 002 19.9 14.14 004 26.8 31.55 003 19.9 21.36 006 35.4 10.97 010 17.7 21.48 022 30.1 11.19 011 27.7 26.410 020 3.0 11.3

Entry Cpd IC50 (uM)HCT116 (wt)

IC50 (uM)HCT116 (ko)

11 008 26.9 >10012 009 5.7 21.813 021 37 2914 007 17 2515 017 23 5016 012 85 1917 013 15.5 >10018 016 26 1519 022 14.5 25.620 023 16 >100

40

Entry Cpd IC50 (uM)HCT116 (wt)

IC50 (uM)HCT116 (ko)

1 301 16 > 1002 302 25 2003 303 23 604 304 27 675 305 26 246 306 12 307 307 21 348 308 14 259 309 17 25

Entry Cpd IC50 (uM)HCT116 (wt)

IC50 (uM)HCT116 (ko)

10 310 1.6 3211 311 15 1212 312 24 20013 313 16 >10014 314 20 >10015 315 21 2416 316 8.4 16.517 317 6.5 1918 318 16 >10019 319 12 >100

HCT116 (p53 wild-type & knock out)

Initial p53‐MDM2 interaction inhibiting

N

N HN

CO2RO

R4

R3

Ar

R1

R2

series 3(19 cpds)

41

A549（Lung cancer cell line）

Antitumor activity‐1

Entry Cpd IC50 (uM)1 001 27.42 018 8.93 002 19.94 004 26.85 003 19.96 006 35.47 010 17.78 022 30.19 011 27.7

10 020 3.0

Entry Cpd IC50 (uM)11 008 26.412 009 6.413 021 64.514 007 8.815 017 20.216 012 15.217 013 4.318 016 20.819 022 24.520 023 12.5

5 out of 23 cpds: IC50

42

HCT116 (colon cancer cell line)

3 out of 19 cpds: IC50

43

SASJ-1 (plasma cancer cell line)

7 out of 21 cpds: Inh% @10 M > 85%

Entry Cpd Inhibition@10 M

1 WCJ001 44.09 2 WCJ002 29.64 3 WCJ003 12.09 4 WCJ004 24.34 5 WCJ005 9.34 6 WCJ006 19.75 7 WCJ007 92.65 8 WCJ008 62.01 9 WCJ009 87.74 10 WCJ010 52.60

Entry Cpd Inhibition@10 M

11 WCJ011 98.09 12 WCJ012 94.85 13 WCJ013 96.10 14 WCJ014 32.69 15 WCJ015 94.22 16 WCJ016 50.60 17 WCJ017 41.59 18 WCJ018 93.54 19 WCJ019 78.89 20 WCJ020 16.14 21 WCJ021 20.65

Antitumor activity‐3

44

Entry Cpd IC50 (M)1 WCJ007 >10 2 WCJ009 >10 3 WCJ011 4.14

Entry Cpd IC50 (M)4 WCJ012 >10 5 WCJ013 4.75 6 WCJ015 >10 7 WCJ018 1.76

Antitumor activity‐3

SASJ-1 (plasma cancer cell line)

Thanks for Your Attention!