Deconstructive fluorination of cyclic aminesJose Roque, Yusuke Kuroda, Lucas T. Göttemann, Richmond Sarpong

Sarpong Research Group, College of Chemistry, University of California, Berkeley, CA, USA 94720

NR

F

NBz

NBz

NHBz

2b: 45%2c: 39% 2d: 70%*

2h: 49%

2f: 33%

NR

NBz

NBz

NBz

NBz

NHBz

2e: 40%

F

NHBz

F

NBz

R R

NBz

F

2i: 59%

NBz

Me Me

NHBz

F

NBz

H

HH

H

NBz

2o: 46%

NMe

2p: 81% 2q: 56%

NMe

O O

2g: 67%

NBz

NBz

MeMe Me

NBz

NHPiv

2r: 43%

NPiv

O

O

F

F

F

n n

Me

2t: 22%

2s: 28%

NBz

CO2H

NBz

HO2C

NHBz

FF

NHBz

FF

1b: R = Ac1c: R = Boc1d: R = Piv

1e

1f

1g

1h

1l

1j: R = Me1k: R = Et

1m

1i

2m: 43%

2l: 50% (1:1 dr)

2j: 81%2k: 85%

1o

1p: n = 11q: n = 2

1r

1s

1t

MeO2C MeO2C O

O

O

F

O

F

NHBz

F

NBz

MeO2C MeO2C

2n: 68%1n

O

O

O

Substrate Scope

NBz

NBz

F

OH NBz

FF

1110 12

NBz

O

FF

mechanistically driven reaction design

O

12a: 76%

F+

H2O

[Ag], F+

NBz

O

FF

Me

12b: 54%

NBz

12c: 61%

O

FF

AgBF4 (0.25 equiv)

acetone:H2O (1:1)rt, 15 h

10

Catalytic gem-Difluorination of Enamides

NBz

F

O

NBz

OH NBz

O

NHBz

F

BzHN

[Ox] thendecarboxylative

fluorination

O

Path B

Path A

radicalring-opening

B C

DSelectfluor

N

O

H NF

NF

H

PhthN

O

H PhthNF

N

O

OH NF

D 2a

7 8

9 6

6

H

CHO

Bz

BzBz

H

BzBz

H

NBz1a

AgBF4 (4 equiv)

acetone:H2O (1:9)40 °C, 1 h

55%

AgBF4 (4 equiv)

acetone:H2O (1:9)40 °C, 1 h

70%

AgBF4 (4 equiv)

acetone:H2O (1:9)40 °C, 1 h

23%

AgBF4 (4 equiv)

acetone:H2O (1:9)rt, 16 h54%

Possible Mechanisms for Ring Opening

NBz

NBz

OH

H2O

A B

1a

Ag(ll) + 5

Ag(l)

N1aAg(l)

Ph O

Selectfluor

NN

Cl

2BF4Ag(ll) +

Ag(l)5

(1)

F

(2)

NN

F

Cl2BF4

Selectfluor(1 equiv)

AgBF4 (1 equiv)

acetone:H2O (1:9)40 °C, 1 h

NN

F

ClBF4

–

1) No consumption of Selectfluor when treated with equimolar amount of AgBF42) Line broadening in the 1H NMR suggests the formation of a paramagnetic Ag(II) complex.3) Downfield shifts of 1a observed upon addition of AgBF4 suggests binding of Amide to Ag(I)

Proposed Mechanism for Oxidation Step

ON

R NR

E

NR

NR

OH

NR

O

E+

A B C

1st stage:α-oxidation

2nd stage:radical ring-opening

H2O

[Ag]E+ source

deconstructive functionalization

[Ag]

cyclic amines as latent radical synthons

[Ag]

NR

OH

B

NR

O

B

NR

NR

A

(1) Silver mediated oxidation - Uknown

(3) Over-oxidation of hemiaminal

NR

NR

OH

A B

H2O

(2) Transition metal compatible with aqueous media

Reaction Design Challenges:

Strategy and Design

NN

F

Cl2BF4

Selectfluor(4 equiv)

NBz

NBz

FOAgBF4 (4 equiv)

acetone:H2O (1:9)40 °C, 1 h

entry yield (%)*

123456

81†

4200

5152

variation from the standard conditions

noneAgNO3 instead of AgBF4

no [Ag]NFSI instead of SelectfluorMeCN instead of acetone

AgBF4 (50 mol%)

1a 2a

* Yield by 1H NMR integration using Ph3CH as an internal standard. † Isolated yield.

+

Reaction Development

N

value-added bond construction

RNR

F

OCsp3–F bond formation

1) Tune lipophilicity 2) Influence on pKa

3) Conformational tuning4) Increased metabolic stability

H2N Fn

R

novel fluorinated building blocks

NH

HN

OO

FR

complex/late-stage chemical diversification

NR

Challenges:- Unstrained ring system- Saturated heterocycle

NH

F

paroxetine

HO

HO

O

H

H

N Me

morphine

NH

peptide

O

O

- Cyclic amines are found in drugs, agrochemicals, natural products, and peptides.

- Piperidine is the most encountered heterocycle in U.S. FDA approved drugs.

NH

NH

OMe

O

OMe

OMe

troxipide

NH

Me

coniine

NH

N

NH

Me O H2N

N

O

H

H

NC

saxagliptin

N H

HNO

HO2C

Me

HOMe

alvimopan

anabasine ritalin

HN

ONH

O

R

OR

O

R

N MeH

O

epimythrine

Application of Deconstructive Functionalization

HNBz

HN

OMe Me

O

OMe

F

NBz

HN

OMe Me

O

OMe HNBz

HN

OMe Me

NH

O Me

O

OMe

F

NBz

HN

OOMe

O

Me Me

O

3a 4a

4d

4c

76%

50% (25% RSM)

39% (25% RSM)

NOMe

OO

Me

NHBz

HNOMe

OO

Me

NHBz

F

3b 4b

AgBF4 (4 equiv)

acetone:H2O (1:9)rt, 15 h

38% (40% RSM)

AgBF4 (4 equiv)

acetone:H2O (1:9)rt, 15 h

Peptide Diversification

Carbon–Carbon Bond Cleavage

(well established)

functional groupdiversity

(elusive)

skeletaldiversity

FG

C(sp2)–C(sp2) bond cleavage

(well established)

OO

olefin metathesis ozonolysis

C(sp3)–C(sp3) bond cleavage

Not readily available

(elusive)

M

[M]

O[M]

O

[M]

β-carbon fragmentationC–C activation

M

σ*

MC–CM

MC C

C–C Bond80–110 kcal/mol

C–M Bond20–70 kcal/mol

Ring Strain27 kcal/mol

Kinetic barrier Thermodynamic considerations

Acknowledgements and References1) Hoveyda, A.H.; Zhugralin, A.R. Nature 2007, 450, 243–251. 2) Vougioukalakis, G.C.; Grubbs, R.H. Chem. Rev. 2010, 110, 1746-1787. 3) Vitaku, E.; Smith, D.T.; Njardason, J.T. J. Med. Chem. 2014, 57, 10257-10274. 4) Sun, H.;Tawa,G.; Wallqvist, A. Drug Discov.Today 2012,17, 310–324. 5) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320–330. 6) Roque, J. B.; Kuroda, Y.; Göttemann, L. T.; Sarpong, R. Science 2018, 361, 171–174. 7) Roque, J. B.; Kuroda, Y.; Göttemann, L. T.; Sarpong, R. Nature 2018, 564, 244–248.Prof.

Richmond SarpongDr.

Yusuke Kuroda Lucas Göttemann

HNPiv

OPh

O

C-O bond formation

HNPiv

NC

C-C bond formation

HNPiv

MeS

C-S bond formation

HNPiv

N3

C-N bond formation

N

O

tBu

Cyclization

Peptide Diversification:

NPiv

CO2H

NHPiv

O

O

NBz

NBz

1) [Ag]2) Base

89% over two steps(94%)*

1) [Ag]NBS

44%

one chromatography event1a 13

1514

Ring Contraction

Skeletal Remodeling

HNHN

Piv O

R

NH

O

CO2Me

Me

MeMe

1) [Ag], NCS2) NucN

Piv

Other Directions: Deconstructive Diversification

.

.