Post on 07-Oct-2020
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
.
.