Total Synthesis of (-)-Pepluanol B: Conformational Control of the Eight-Membered Ring System.

1. Total Synthesis of (-)-Pepluanol B: Conformational
Control of the Eight-Membered Ring System
Highlight
 Pd- catalyzed bicyclic formation
 Ley-Griffith oxidation
 Swern oxidation
 Rh-catalyzed double bond isomerization
 Eschenmoser Methenylation
 RCM reaction
 Cyclopropanation
Zhang, J., Liu, M., Wu, C., Zhao, G., Chen, P., Zhou, L., … She, X. (2020). Total Synthesis of
(‐)‐Pepluanol B: Conformational Control of the Eight‐Membered Ring System. Angewandte
Chemie.
1
Abraham Dilnesa
Addis Ababa University

2. Introduction
 Euphorbia genus:
– have been used in traditional herbal medicines:
skin ulcers and warts, as well as cancer tumors and
intestinal parasites.
– provided a large number of significant diterpenoids.
Euphorbia diterpenoids :
– attracted widespread attention from both chemical and
biological communities.
– polycyclic molecular archetectures.
– Bioactivities : antitumor, multidrug-resistance reversing
(MDR), antiviral and anti-inflammatory properties.
2

3. Euphorbia peplus
Euphorbia peplus
 Herbaceous annual growing to about
a foot high.
 It is a small, branched, upright plant
with pale green foliage and stems.
 Traditionally used to treat asthma and
psoriasis.
 Five novel biogenetically related
diterpenoids have been successively
isolated from this plant b/n 2016-2018 .
3

4. Cont.
.
Figure 1. Structures and synthetic progress of Euphorbia diterpenoids 1-5.
 effectively inhibitory actions on the kv 1.3 potassium channel ,
responsible for treatment of intractable diseases such as asthma,
type-1 diabetes, multiple sclerosis, and psoriasis.
Me
O
H
H
Me
Me
H
Me
O
H H
OMe
OMe
Me
Pepluacetal (1)
Me
O
Me
Me
H
HH
Me
OH
H
O
Me
Pepluanol A (2)
H
Me
Me
H
OH
Me
O
Me
O H
H
Me
11
9
7
5
17
3
1
15
13
Pepluanol B (3)
this work
O
OH
OH
Me
O
Me
Me
O
Me
Me
Me
Me
Pepluanol C (4)
Me
Me
Me
H
H
H
OH
O OH
OH
Me
Me
H
Pepluanol D (5)
7
7
8
10
7
4

5.  has the best IC50 value of 9.50 μM
 Fused [5-5-8-3] tetracyclic framework.
 Six stereogenic centers and one quaternary center.
 Stereoselective construction of the eight membered
ring system was critical.
O H
Me
Me
Me
H
H
O
H
Me H
HO
R
13
14
15






Fig. Structure of (-)-Pepluanol B
(-)-Pepluanol B
5

6. O H
Me
Pepluanol B (3)
Me
Me
H
H
O
H
Me H
HO
R
PMBO H
Me
6
HO
HO
Me
Me
H
H
PMBO H
Me
TMSO
14
15
OH
8
PMBO H
Me
7
HO
TMSO
OH
HO
H
H
10
late-stage
functionalization
stereoselective
cyclopropanation
ring closing
metathesis
O
9
MgBr
Scheme 1. Retrosynthetic analysis of (-)-Pepluanol B
6

7. O
PMBO H
H
a. NaH, PMBCl, TBAI
b. (COCl)2, DMSO, Et3N
80% over 2 steps
11
c. LDA, TMSCl
d. [(CH3)2NCH2]+
l-
e. CH3I, Al2O3 (basic)
65% over 3 steps
O
PMBO H
H
a. 5%Pd(OAc)2, Pd(OAc)4
HOAc,1.5 d, rt
b. NaOH, MeOH
rt, 5 h
70% over 2 steps
OH
HO
H
H
(±)-10
12
Total synthesis of (±)-pepluanol B.
7

8. H
H
H
Pd
trans
addition H
H
Pd
H
OAc
H
Pd OAc
cis- addition
H
H
OAc-
SN2
OAc
H
H
H
OAc
H
H
H
OAc
OAc
OAc
OAc
Pd(IV)
OAc
AcO
H
H
Pd- catalyzed diacylated bicyclo formation
8

9. OSiMe3
N
I
O
N
+ SiMeI
Me I
O
N
I
H
O
Eschenmoser methylenation
Eschenmoser's salt
Al2O3
9

10. O
PMBO H
H
O
PMBO H
H
f. 5 mol% RhCl3.3H2O
86%
13
O
PMBO H
g. LDA, 9, -780
C
30 min
h. Et3N, TMSOTF
00
C, 30 min.
78% over 2 steps
O
9
TMSO
14
15
i. CeCl3, AllylMgBr
72%
PMBO H
Me
TMSO
14
15
OH
8
EtOH and CH2Cl2
110 0
C , 25 min
3 h , rt
12
7
O
H
Ce
Cl
Cl
Cl
Mg
Br
10

11. RhCl3 + EtOH Rh
H
OEt
Cl
+ Cl2
Homolytic
spilte
O
O
Rh
H
OEt
H
O
Rh
OEt
H
O
Cl
Cl
-hydride
elimination
insertion
O
Rh
H
OEt
Cl
-complex
reductive
elmination
Rh-catalyzed double bond isomerization
11

12. PMBO H
Me
TMSO
14
15
OH
8
j. 5 mol% Grubbs 2nd
CH2Cl2, reflux, 3 h.
88% PMBO H
Me
7
HO
TMSO
PMBO H
Me
6
HO
HO
k. TEBAC, CHBr3
NaOH, 78%
i. Me3CuLi2, MeI
m. TBAF, THF
Me
Me
H
H
PMBO H
Me
20
Me
Me
H
O
H
O
H
a. NBS, pyridine
then DMP
95%
Br
HO
Br
Ru
Cl
Cl
PCy3
N N
Ph
2nd Generation Grubbs Catalyst
N
Cl
benzyltriethylammonium
chloride
12

13. HO-
H CBr3
C
Br
Br
Br
C
Br
Br
C
Br
Br
C
Br
Br
C
Me
Me
Cu
Me
Me
Li
insertion
Cyclopropanation reaction
13

14. PMBO H
Me
20
Me
Me
H
H
O
H
O
H
PMBO H
Me
21
Me
Me
H
H
O
H
O
H
b. LDA, MeI, 72%
Br
Me H
f. Zn-Cu, EtOH
O H
Me
24
Me
Me
H
O
H
Me H
HO
Br
R
O H
Me
23
Me
Me
H
O
H
O
H
Br
Me H
R
c. DDQ, CH2Cl2
d. TPAP, NMO
45%, for 2 steps
Sat. aq. NH4Cl
93%
14

15. O H
Me
()-Pepluanol B (3)
Me
Me
H
H
O
H
Me H
HO
Me
h. 20 mol% RhCl3.3H2O
EtOH, 1000
C, 2 h
60% brsm
R
g. TMMN, Ac2O, DMF
95 0
C
O H
Me
25
Me
Me
H
H
O
H
Me H
HO
O H
Me
24
Me
Me
H
O
H
Me H
HO
96%
15
N N
TMMN = tetramethylmethylenediamine.

16. N N
O
O O
N N
O
N +
N
O
O
O
O
O
N
H
O
+
+

16

17. OH
HO
H
H
(±)-10
OH
HO
H
H
(+)-10
50 g scale
44% yield
99.6% ee
lipase PS
vinyl acetate,
TBME
15 days
18 steps
O H
Me
(-)-24
Me
Me
H
O
H
Me H
HO
O H
Me
(-)-Pepluanol B
Me
Me
H
H
O
H
Me H
HO
Me
R
2 steps
94% ee
PS =Pseudomonas cepacia
TBME =tert-butyl methyl ether
Scheme 5. Enantioselective synthesis of (-)-pepluanol B.
17

18. Conclusion
 (±)- Pepluanol B was accomplished in 20 steps
(3.0% overall yield).
 Highly stereoselective C-C bond are formed
through :
• sterically hindered aldol reaction,
• nucleophilic Grignard reagent addition,
• RCM reaction,
• cyclopropanation reaction.
 Less protecting group used.
18

19. Thank You!!!
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