Synthesis of Atisine-type Alkaloids · 2020. 8. 28. · 2 Education: 1980–1984 B.S., Shandong...
Transcript of Synthesis of Atisine-type Alkaloids · 2020. 8. 28. · 2 Education: 1980–1984 B.S., Shandong...
Synthesis of Atisine-type Alkaloids
Literature Report III
Reporter Checker
Date
: Yang Zhao : Zhou-Hao Zhu : 2018-7-16
Ma, D. et al. Angew. Chem. Int. Ed. 2018, 57, 6676 Baran, P. S. et al. J. Am. Chem. Soc. 2014, 136, 12592
2
Education: 1980–1984 B.S., Shandong University
1984–1989 Ph.D., Shanghai Institute of Organic Chemistry (Xiyan Lu)
1990–1994 Postdoc., University of Pittsburgh and Mayo Clinic, U.S.A.
1995– now Prof., Shanghai Institute of Organic Chemistry
Research: Total synthesis of complex natural products
New synthetic methodologies: Copper-catalyzed coupling
reactions; Asymmetric Michael additions, Henry reaction;
Intramolecular Dearomative Oxidative Coupling
Biochemistry
CV of Prof. Dawei Ma
Contents
3
1
2
Introduction
3
4
Semisynthesis of (-)-Isoatisine
Summary
Total Syntheses of Azitine
Introduction
4
N
OHMe
N
Me
hetisine-type
nominine
hetidine-type
HOO
(-)-spirafine III
atisine-type
N
OHMe
(-)-isoatisine
N
OHMe
azitine
O
C20 diterpenoid alkaloids
Introduction
Atisine-type diterpenoid alkaloids isolated from Aconitum
Folk medicine for the treatments of rheumatism and neuralgia
Bicycle[2,2,2]octane system with the attached allylic alcohol
5
N
OHMe
O
(-)-Isoatisine Aconitum
Yao, B.-H. et al. J. Pharm. Anal. 2011, 1, 57 Baran, P. S. et al. J. Am. Chem. Soc. 2014, 136, 12592
N
OHMe
O
Me
MeMe
O
OAc
Me
Me
OHHO O
(-)-Steviol
Hofmann-Löffler-Freytag Reaction
Me
Me
NH
P(O)(OEt)2 OH4
20
NH
P(O)(OEt)2
Mukaiyama Oxidation/Fragmentation
7
(-)-Isoatisine
2020
Retrosynthetic Analysis
6
Barton-McCombie Deoxygenation Reaction
R OH
Y X
S
Base
O Y
S
R
thioxoester
AIBN, PhCH3reflux
(n-Bu)3SnHR H
Initiation step:
N
CN
Me
MeN
CN
Me
Me heatMe
CN
Me
2 + N2
(n-Bu)3Sn MeCN
Me(n-Bu)3Sn+Me
CN
MeH
Propagation step:
O Y
S
R
Sn(n-Bu)3
RO Y
SSn(n-Bu)3
R
S
YO
Sn(n-Bu)3
H Sn(n-Bu)3 R H + Sn(n-Bu)3
H
7
X = Cl, imidazolyl; Y=SMe, imidazolyl, OPh, OMe; R-OH = 1o, 2o or 3o alcohol
Hofmann-Löffler-Freytag Reaction
R1N
R2
XN
R1
HR2
NR1
R2
Base
-HX
∆ or hv orradical initiator
X
R1N
R2
X
H
acidic or neutralor weakly basic
medium
HN
XR2
R1
∆ or hv orradical initiator
HN
R1
X
R2H- X
HN
R1
H
R2
1,5-Habstraction
N
HR2
R1
alkyl radical
H
+ XHN
R1
H
R2X
δ-halogenated amine
:B
-BH
:N
R1
HR2
X- X
NH
R1R2
:BH
-BHN
R1
R2
8
X = Cl, Br, I
80%
1 2
Me
Me
HO O
EDCl, HOBt,NH4OH
Me
Me
H2N O
LiAlH4Me
Me
H2N94%
Me
Me
NH
P(O)(OEt)2
P(OEt)2(O)Cl,DIPEA
93% Me
Me
NH
P(O)(OEt)2
Co(acac)2, Et3SiH, O2
59%
O
MeO
OH OH OH
OH
Me
MeMe
O
OHNH
P(O)(OEt)2
Ac2O, Et3N,DMAP
90%
Amberlyst® 15
87%
Me
MeMe
O
OAcNH
P(O)(OEt)2
47%Me
OAcMe
OH
MeNH
P(O)(OEt)2
NaBH4
3
4 5
6 7 8
Mukaiyama Oxidation/Fragmentation
20
Necessary directing group for C20 C-H activation
Semisynthesis of (-)-Isoatisine
9
N
OHMe
O
1) thio CDI2) (TMS)3SiH, AIBN
85%Me
OAcMe
OH
MeNH
P(O)(OEt)28
Me
OAcMe
MeNH
P(O)(OEt)29
OHMe
Me
O 11H I
PIDA, I2, 90-W sunlamp
OAcMe
MeN
P(O)(OEt)210
I
thenK2CO3, MeOH
71%
Martin's Sulfurane
91%
Me
O 12H I
SeO2, tBuOOH
63%
Me
O 13H I
OH
95%
Me
N
(-)-isotisine
OH
O
+Me
N
OH
O
epi-minor
NH2HO
Barton-McCombiedeoxygenation
Hofmann-Löffler-Freytag reaction
Selective C20 C-H activation
(C6H5)2S
OC(CF3)2C6H5
OC(CF3)2C6H5
6
2
2013
20
10
Semisynthesis of (-)-Isoatisine
N
OHMe
O
Introduction
11
Ma, D. et al. Angew. Chem. Int. Ed. 2018, 57, 6676
Atisine-type
N
OHMe
(-)-Isoatisine
N
OHMe
Azitine
O
Me
Me
OHHO O
(-)-Steviol
CN
O
α,β-Unsaturated nitrile
CN CN
MeO
O
CNOMe
OH
OAc
CN
OH
OTBS
MeO
ClMg
a) Oxidative Dearomatizationb) Diels-Alder Cycloaddition
Chelation-ControlledConjugate Addition
OAc CN
OMe
OH
Reductive Cyclization
N
OHMe
Azitine
14
6
62 8
+
CN
O1
Retrosynthetic Analysis
12
Luche Reduction
13
R1 R2
ONaBH4, CeCl3,
ROH
R1 R2
OH
B
H
H H
H
+ [BH3(OR)]Ce3+
[BH2(OR)2] ROH
B
H
RO ORH
OR2
R1
H OR
Ce3+
OR2
R1
H ROH OHR2
R1
HRO
- H2
Both acyclic and cyclic enones are reduced to corresponding allylic alcohols
Chelation-Controlled Conjugate Addition
14
R1 CN
OH
tBuMgClR2MgX OR1
CMgN MgX2
R2
OR1
Mg
R2
H
CN
MgX2
R3X R1 CN
OH
R2
R3
R1 CN
OH
R1 CN
OH
R2
R3
tBuMgCl, R2MgX
then R3X
γ-hydroxy group in an α,β-unsaturated nitrile could promote the conjugate addition by chelation to the Grignard reagent
Steward, O. W. et al. Angew. Chem. Int. Ed. 2004, 43, 1126
Swern Oxidation
15
R1 R2 R1 R2
OOH (COCl)2 or TFAA, DMSO then Et3N
S OMe
Me(COCl)2
S OMe
MeCl
O
O
Cl
S ClMe
MeCO, CO2
Cl-
R1 R2
OH
S OMe
Me
H
R1
R2
B
SMe2
R1 R2
O
1o or 2o alcohols
Low temperature/Solvent
Van Leusen Reaction
16
OR2
R1 Me SO2CH2N=C
tBuOK
O
NC
TosCH2N C TosCHN C
OR2
R1
O
N
R1
R2H
Tos
R1
R2H
Tos
O
N
R1
R2
Tos H
R1
R2 Tos
NO
H
-TosC N
O
H
RO
R2
R1
C NR2
R1 O
H
OR
C NR2
R1-HCOOR R1
R2
H
C N
tBuOK
H
R1
R2
H
C N
5-endo-dig
I
II
III
Van Leusen, A. M. et al. J. Org. Chem. 1977, 42, 3115
97%
1 2
NaBH4, CeCl3MeOH tBuMgCl then 8
CN
O Mg
3
CN
O
CN
OH
OMe
OTBS
OAc CN
4
OMe
OTBS
O
then AcClthen
NaBH4, MeOH
61% OAc CN
5
OMe
OTBS
OH
OAc CN
6
OMe
OH
Matin's sulfuranethen TBAF
74%
PIDA, MeOHNaHCO3 then
toluene, 105 oC
88%
7
Luche ReductionChelation-Controlled Conjugate Addition
(C6H5)2S
OC(CF3)2C6H5
OC(CF3)2C6H5
OAc CN
OOMe
OMe
Total Syntheses of Azitine
17
N
OHMe
N
OHMe
OTBS
OMe
HO
SOCl2, pyridine
81%
OTBS
OMe
Cl
Mg, 90 oC
OTBS
OMe
ClMg
18 19 8
Preparation of Grignard Reagent 8
18
CN13
O
ONC
CN14
O
O
CN
Me
TosMic, tBuOKtBuOH
LDA, MeI
68% for 2 steps15
O
OMe
NH NH
7OAc CN
OOMe
OMe
9OAc CN
O (CH2OH)2
OAc CNO
O
Dibal-H
OH CNO
O (COCl)2, DMSOthen Et3N
CN12
OO
O
10
11
SmI2 (4 eq.)
LAH
88% for 4 stepsS
O O
MeN C
Van Leusen Reaction
Swern Oxidation
4
4
4
19
Total Syntheses of Azitine
N
OHMe
15
O
OMe
NH NH
Li/NH3(l)
16
O
OMe
NH NHLi
e-path b
path a
path a
19 24% yield (2 steps)
O
OMe
N
O
OMe
NH
NHLi
path b
O
OMe
NH NH
O
OMe
N
17
18
20
46% yield (2 steps)further
reduction
THF/iPrOH
19 : 20 = 1 : 2
20
Total Syntheses of Azitine
TsOH, Acetone/H2OO
OMe
N 20
Me
N 22
Me
Nazitine
91% for 2 steps
SeO2, TBHP
56%
OH
Me
N 21
O PPh3MeBr, nBuLi
21
Total Syntheses of Azitine
Summary
22
CN CN
MeO
OCNOMe
OH
OAc
N
OHMe
Azitine
CN
O
N
OHMe
O
Me
MeMe
O
OAcMe
Me
OHHO O
(-)-Steviol
Me
Me
NH
P(O)(OEt)2 OH
20 NH
P(O)(OEt)2
(-)-Isoatisine
4
10
Semisynthesis of (-)-Isoatisine
Total Syntheses of Azitine
Baran, P. S. et al. J. Am. Chem. Soc. 2014, 136, 12592
Ma, D. et al. Angew. Chem. Int. Ed. 2018, 57, 6676
Summary
17 steps, 5.4% overall yield Chelation-trigged conjugate addition Oxidative dearomatization/ Diels-Alder cycloaddition Reduction of a dinitrile intermediate
23
N
OHMe
O
(-)-Isoatisine
N
OHMe
Azitine
13 steps, 4.6% overall yield Mukaiyama oxidation/fragmentation Hofmann-Löffler-Freytag reaction (Suárez modification)
Semisynthesis of (-)-Isoatisine
Total Syntheses of Azitine
Baran, P. S. et al. J. Am. Chem. Soc. 2014, 136, 12592
Ma, D. et al. Angew. Chem. Int. Ed. 2018, 57, 6676
The First Paragraph
24
Owing to their caged and polycyclic ring systems, the C20 diterpenoid
alkaloids are recognized among the most architecturally complex natural
products, and have elicited considerable interest from the synthetic
community over the past several decades. These synthetic campaigns
culminated in the completion of formal and total syntheses of a subset of C20
diterpenoid alkaloids, namely nominine, atisine, isoatisine and so on.
However, most of these synthetic routes require a large number of steps
and are restricted to a very particular structure. There is plenty of room for
developing more concise total syntheses towards atisine- and hetidine-type
alkaloids. Herein, we report a short and efficient approach for the assembly
of a tetracyclic dinitrile compound. By making use of this common
intermediate, we achieved the first total synthesis of azitine, an anti-
leishmanial atisine-type diterpenoid alkaloid that was first isolated from
Consolida hellespontica.
25
In conclusion, we have described a unified approach towards the
atisane-type C20 diterpenoid alkaloids, as exemplified by the first total
syntheses of azitine. The syntheses feature a number of key
transformations, including a) chelation-triggered conjugate addition to
control the contiguous three stereogenic centers in the cyclohexane unit,
b) oxidative dearomatization/Diels–Alder cycloaddition to forge the crucial
bicyclo[2.2.2]octane moiety with a free cyano group at the C20 position, c)
reduction of a dinitrile intermediate to form an N-heterocycle with the
correct oxidation state at the C20 position. If other Grignard reagents with
functional groups at C6/C7 and functionalized α,β-unsaturated nitriles were
employed in the chelation-controlled conjugate addition, it should be facile
to assembly other functionalized diterpenoid alkaloids. Thus the present
synthetic strategy provides a reliable and efficient approach for diverse
syntheses of diterpenoid alkaloids and their analogues.
The Last Paragraph
Acknowledgement
26
27
Mukaiyama Hydration
R
RH
L2Co3+
L2Co2+
RH
O2
RH
OL2Co2+
RH
OO
L2Co3+
L2Co3+ H
Et3SiH
RH
OOSiEt3 L2Co2+
O2, Et3SiHRH
OH
O
From Fan-Jie Meng
Allylic Hydroxylation of Alkenes with SeO2
28
R1 R2
HSeO O
R1 R2
SeHO O
R1 R2
OSe
OH
R1 R2
OH
ene [2,3]-sigmatropic
R1 R2 R1 R2
OHSeO2
R1
O
MeO OMe
SmI2R2R1
O
MeO OMe
R2MeOH
R1
OH
MeO OMe
R2
SmI2R1
OH
MeO OMe
R2R1
OH
OMe
R2
R1
O
OMe
R2SmI2
R1
O
OMe
R2MeOH
R1
OH
OMe
R2
SmI2R1
OH
OMe
R2
R1
OH
R2R1
O
R2
29
Removal of Two Methoxyl Group with SmI2