View
0
Download
0
Category
Preview:
Citation preview
J. Am. Chem. Soc. 2017, 139, 4282Presented by: Chuan Pin Chen
CEM 852 PresentationFebruary 9, 2019
Introduction• Palhinine-type alkaloids, as members of the
Lycopodium family
Figure 1. Lycopodiaceae Plant and Known palhinine-type Lycopodium Alkaloids.
2
NR
Skeleton of Palhinine-typeLycopodium Alkaloids
Palhinine D2013 by Yu et al.Fitoterapia 2013, 91,
74
N
O
HO
HHOHN
O
HO
HH
OMe
Palhinine A2010 by Long et al.Org. Lett.
2010, 12,
3922
+
Although no activity was observed in preliminary studies, scarcity in nature precludes extensive biological evaluations of these alkaloids.
https://en.wikipedia.org/wiki/Lycopodiaceae
Challenge
3Figure 2. Designed Strategies for Assembly of the Nine-Membered Azonane Ring Embedded in the Framework of Palhinine-type Alkaloids
NR
N
O
N N
N-substitution ring-closing metathesis This work[3+2] cycloadditionInevitably twisted and transannular strain
Retrosynthesis
4
tert-Butyldimethylsilyl
(TBS) Benzyl (Bn) Oxime
Si R R
NOH
N
O
HO
HH
OMe
N
O
HO
HHOH N
O
HO
HH
ROR'
OR' N
O
H
ROR'
OR'
O
N
O
H
ROR'
OR'
HO
H
O
HR'O OR'
NO
O
HR'O OR'
HNHOH
HOTBSO
OBnTBSO
OBnO
or
palhinine A palhinine D A B
C D E F-12
chemo- andstereoselective
reduction3
reductive cleavageof N-O bond key step
regio-and stereoselective
Nitrone-olefin 3+2 cycloaddition1,3 dipolar cycloaddition
3
3
Wittigreaction
oxime formationand reduction
G-4
Synthesis of 4
5
O
Op-TsOH (1.0 equiv)
98% yield
OBr
SH
84% yield
PhSO
52% yield
OS
BnO
m-CPBA (1.05 equiv)
−78 °C to 25 °C
75% yield
NBS (1.2 equiv)CH2Cl2
NaH (1.1 equiv)
THF
NaH (1.1 equiv)I(CH2)3OBn (1.2 equiv)
DMF
0 °C, 1 h
CH2Cl2
(1.1 equiv)
reflux, 4h0 °C, 30 min
0 °C to 25 °C, 1 h
overnight
Ph
25 °C, 1.5 h
4
BnO
1 2 3
p-Toluenesulfonic acid
(p-TsOH) N-Bromosuccinimide
(NBS) Benzyl
Bn meta-Chloroperoxybenzoic
acid (m-CPBA)
SO
O OH
OO NBr
O
OOHCl
Org. Lett. 2012, 14, 3696.
I O
I(CH2)3OBn
HO OH DMF
NaH (0.1 equiv)
Br
(0.1 equiv)
CH2Cl2
PPh3 (1.05 equiv)
imidazole (1.26 equiv)rt, 24 h
rt, 24 h
HO O
Org. Lett., 2008, 10,
5497
I2 (1.05 equiv)
Synthesis of 8
6
Benzyl (Bn)
Trimethylsilyl (TMS)
4-methylmorpholine 4-oxide (NMO)
tert-Butyldimethylsilyl
(TBS) imidazole
Si
N+
O
O
Si
NHN
O
BnO
4
TMS
TiCl4 (1.2 equiv)
CH2Cl2−78 °C, 1h
82% yield
(1.5 equiv)O
BnO
(±)−5(≈
1:1 dr)
(0.1 equiv)
NMO (5.0 equiv)
K2OsO4·2H2O
THF/H2O 83% yield
25 °C, 5h25 °C, 1h
1 h
NaIO4 (5.0 equiv)
O
BnO
O(±)−6
IOTBS
CrCl2 (3.0 equiv)
(2.0 equiv)
DMFNiCl2
(0.02 equiv)
0 °C to rt, 15 h
76% yield
O
BnO
(±)−7
TBSO
(≈
1:1 dr) (≈
1:1:1:1 dr)
TBSCl (1.5 equiv)imidazole (2.0 equiv)
DMF
0 °C to rt, 1 dOH
O
BnO
(±)−8
TBSOOTBS
84% yield
(≈
1:1:1:1 dr)
Org. Lett. 2012, 14, 3696.
tert-butyldimethylsilyl 2-iodoallyl ether
7
OHCH3CN
(CH3)3SiCl (1.2 equiv)
NaI (1.2 equiv)H2O (1.0 equiv)
[(CH3)3Si]2O NaCl
rt, 1h
57% yield
+ +
Synthesis 1988, 366
OHI
OHI
OTBSI
Cl Si
https://www.synarchive.com/protecting-group/Alcohol_tert-Butyldimethylsilyl_ether
Base
Solvent
Synthesis of 12
8
O
BnO
(±)−8
TBSOOTBS
TMSOTf (2.3 equiv)NEt3
(3.5 equiv)
CH2Cl2
0 °C, 1 h
OTMS
BnO
TBSOOTBS
(±)−9
Pd(OAc)2
CH3CN
25 °C, 10 h
O
BnO
TBSOOTBS
(±)−10
TMSCl (6.0 equiv)NEt3
(6.0 equiv)
DMF
90 °C, 4 d
(≈
1:1:1:1 dr) (≈
1:1:1:1 dr) (≈
1:1:1:1 dr)
OTMS
BnO
TBSOOTBS
(±)−11
(≈
1:1 dr)
12
(≈
1:1 dr)
180 °C, 2 d
p-xylene
65% yield(2 steps)
68% yield(2 steps)
HOTBSO
OBnTBSO OTMS
BnO
TBSOOTBS
(±)−11 12
HOTBSO
OBnTBSO
Benzyl (Bn)
tert-Butyldimethylsilyl
(TBS)
Trimethylsilyl trifluoromethanesulfonate
(TMSOTf)
Si
CF3S
O
OOSi
Palladium(II) acetate (Pd(OAc)2)
Trimethylsilyl (TMS) p-xylene
Pd2+O
O-
Si
Org. Lett. 2012, 14, 3696.
Synthesis of 16
9
tert-Butyldimethylsilyl
(TBS) Benzyl (Bn)
Pyridinium p-toluenesulfonate (PPTS)
Dess–Martin periodinane
(DMP)
Si NH+
SO
O O-
IO
O
O
OO
O
O
O
J. Am. Chem. Soc. 2017, 139, 4282
H2SiF6 (30% aq. 6.0 equiv)
CH3CN
0 °C to rt
95% yield12
(≈
1:1 dr)
HOTBSO
OBnTBSO
overnight 13
(≈
1:1 dr)
HOHO
OBnHO (CH2OH)2 (20.0 equiv)
PPTS (0.1 equiv)
rt to reflux, 5 h
63% yield
14
(≈
1:1 dr)
HHO
OBnHO
OO
Dess-Martinperiodonane(2.2equiv)
NaHCO3 (5.0 equiv)H2O (2.2 equiv)
CH2Cl20 °C to rt, 30 min
15
(≈
1:1 dr)
HO
OBnO
OO
H Pd(OH)2/C (20%)
MeOH
rt to 50 °C, 45 min
quant.
H2
MgSO4 (3.2 equiv)
H
O
OO
O
HO HO
OHO
OO
H
16a (minor) 16b (major)
Synthesis of 20
10
17
(≈
1:1 dr)
H
OHHO
OOH
O
OO
O
HO HO
OHO
OO
H
16a (minor) 16b (major)
n-BuLi (2.5 equiv)
[MePPh3]+Br
(2.2 equiv)
0 °C, 30 min
then −78 °C to rt, 30 min
64% yield
THF
Dess-Martinperiodonane(1.2equiv)
NaHCO3 (2.4 equiv)CH2Cl2
rt, 30 min81% yield
18
(≈
1:1 dr)
H
OHO
OO
19
(Z/E = 1:1)
H
NHO
OO
NaOAc (4.0 equiv)
NH2OH·HCl (2.0 equiv)
EtOH/H2O
(v/v = 5:2)
rt, 30 min
99% yield
NaBH3CN (2.5 equiv)
CF3CO2H (5.0 equiv)EtOH
−40 °C, 30 min
90% yield
OH
20
H
HN
HO
OO
OH
Triphenylphosphine (PPh3)
Dess–Martin periodinane
(DMP)
Sodium acetate
(NaOAc)
P
IO
O
O
OO
O
O
O
Na+O
O-
J. Am. Chem. Soc. 2017, 139, 4282
Synthesis of 22 Building Block
11
20
H
HN
O
OO
OH HCHO (aq.) (100 equiv)
CH2Cl2rt, 12 h
21
H
NO
OO
O
22
H
O
OOo-C6H4Cl2
150 °C, 1.5 h
microwave(300 W)
N
O
H
N
O
HO
HH
OMe
palhinine Afrom 22, 23...to 26
palhinine Dfrom 22, 27 to 31
N
O
HO
HHOH
21
H
NO
OO
O
22
H
O
OO
N
O
Hor
several and differentpathways
Nitrone-olefin 3+2 cycloaddition1,3 dipolar cycloaddition
J. Am. Chem. Soc. 2017, 139, 4282
Palhinine A (the Blue Pathway)
12
Dess–Martin periodinane
(DMP)
Lithium trisiamylborohydride
(L-Selectride)
IO
O
O
OO
O
O
O
BHi-Pr
H3C
i-Pr
CH3CH3i-Pr
Li
J. Am. Chem. Soc. 2017, 139, 4282
22
H
O
OO
N
O
H
rt, 12 h
23
H
O
OO
N
O
H
Me
I
Zn (10.0 equiv)
AcOH/THF/H2O
(v/v/v = 2:1:1)
81% yield
30 °C, 8 h
24
H
O
OO
NMe
HO
Dess-Martinperiodonane(2.0 equiv)
NaHCO3 (4.0 equiv)
CH2Cl2rt, 30 min96% yield
25
H
O
OO
NMe
O
L-selectride (5.0 equiv)
−78 °C to 0 °C, 2h
THF
92% yield
26
H
O
OO
NMe
HO
2N HCl (10.0 equiv)
80 °C, 2h
89% yield
MeI (102.0 equiv)
THF
MeOH N
O
HO
HH
OMe
palhinine A
Chemo- and Stereoselective Reduction
13
Lithium trisiamylborohydride (L-Selectride)
BHi-Pr
H3C
i-Pr
CH3CH3i-Pr
Li
25
H
O
OO
NMe
O
L-selectride (5.0 equiv)
−78 °C to 0 °C, 2h
THF
92% yield
26
H
O
OO
NMe
HOO
O
HH
HH
N
Me
O
HH
HHO 3
53
5
J. Am. Chem. Soc. 2017, 139, 4282
14
Synthesis of 31 (the Red Pathway)
Dess–Martin periodinane
(DMP)
Lithium trisiamylborohydride
(L-Selectride)
p-Toluenesulfonic acid
(p-TsOH)
IO
O
O
OO
O
O
O
BHi-Pr
H3C
i-Pr
CH3CH3i-Pr
Li
SO
O OH
22
H
O
OO
N
O
HBr
(184.9 equiv)
acetonert
overnight
27
H
O
OO
N
O
H
BrZn (10.0 equiv)
AcOH/THF/H2O
(v/v/v = 2:1:1)
88% yield
30 °C, 8 h
28
H
O
OO
N
HO
Dess-Martinperiodonane(2.0 equiv)
NaHCO3 (4.0 equiv)
CH2Cl2rt, 30 min
99% yield
29
H
O
OO
N
O
L-selectride (5.0 equiv) −
78 °C to 0 °CTHF
2 h
75% yield30
H
O
OO
N
HO
p-TsOH (2.0 equiv)
60 °C
acetone/H2O
(v/v = 10:1)
31
H
O
O
N
HO
4 h
95% yield
J. Am. Chem. Soc. 2017, 139, 4282
Palhinine D (the Red Pathway)
15
31
H
O
O
N
HO
palhinine D
N
O
HO
HHOH
RuCl3 (2.0 equiv)
CH3CN/H2O
(v:v = 5:1)
64% yield
90 °C, 10 h
H
O
O
N
HON
O
HO
HHOH
J. Am. Chem. Soc. 2017, 139, 4282
Conclusion• First report on total synthesis of palhinines A and D
16
Thank You For Listening
17https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=2ahUKEwiw6sGdk6vgAhUOUt8KHYC6DLkQjxx6BAgBEAI&url=https%3A%2F%2Fdepositphotos.com%2F41441791%2Fstock-illustration-cartoon-chemist.html&psig=AOvVaw21koLy1qu0x5EKHaDb_W1s&ust=1549677893534548
~~~• ~~~
18
Details About Deprotection of N-allylamines
19Chem. Commun. 2005, 4086
To promote C=C migrations in waterChem. Eur. J. 2007, 13, 6590
Tetrahedron Lett. 2003, 44, 8693
Palhinine Related Products
20
22
H
O
OO
N
O
H
Mo(CO)6 (5.0 equiv)
CH3CN/H2O
(v/v = 9:1)
85 °C75% yield
3-epi-palhinine D
N
O
HO
HHOH
24
H
O
OO
NMe
HO N
O
HO
HH
OMe
3-epi-palhinine A
p-TsOH (2.0 equiv)
acetone/H2O
(v/v = 10:1)
98% yield
p-Toluenesulfonic acid (p-TsOH)
SO
O OH
Recommended