1.3.1 Biomimetic Wagner-Meerwein Approaches to Aconitine Core The Wagner-Meerwein rearrangement of a [2.2.2]-bicyclooctane which comprises the C and D rings of the C20 atisine and denudatine scaffolds to the [3.2.1]-bicyclooctane characteristic of the C18-and C19-diterpenoid alkaloids has inspired biomimetic approaches in many of the total syntheses reported to date. Targeting a [2.2.2]-bicyclooctane as an intermediate in the synthesis of C18- and C19-diterpenoid alkaloids has two main strategic advantages. Firstly, it allows for the divergent synthesis of two families of natural products via a late stage diversification of the carbon skeleton. Secondly, the [2.2.2]-bicyclooctane structural motif is a classic keying element for retrosynthetic disconnection via a Diels-Alder cycloaddition, one of the most well studied transformations in organic chemistry. Wiesner’s synthesis of talatisamine (1) employing such an approach represents the first total synthesis of a C19-diterpenoid alkaloid.
Me NEt OH
OPP C7-C17 bond
formation C20 atisine-type
(22) Me
NEt
C20 denudatine-type (23) Me
NEt
7 17 7
17
oxidation 8
10 9
8 9
10
NEt
HO H OH Oxidation Me
NEt
HO H OH
O OH
OPP OH
9 8 10
C19 aconitine-type (26) N
HO
OH
HO OH Et
A E F B
C
D
O HO A
E F
B C D
25
Wagner- Meerwein
+ (-OH) 24
Scheme 1.1 Wiesner’s synthesis of the atisine core.
Wiesner’s route to talatisamine is summarized here (Schemes 1.1 and 1.2). Beginning from tetracyclic arene 27, prepared in 21 steps, Birch reduction followed by N-acetylation affords enone 28 upon treatment with acid. [2 + 2] photocycloaddition with ketene affords cyclobutane 29. Ketalization of 29 with ethylene glycol followed by oxidative-cleavage of the cyclobutane exo-methylene and subsequent ketone reduction gives cyclobutanol 30. Treatment with acid effects retro-aldol/aldol cascade to give the less strained cyclohexane isomer 32, forming the atisine core. In seven further steps, they access a [2.2.2]-bicyclooctane with a tosylate leaving group suitable for the desired rearrangement. Treatment with tetramethylguanidine in DMSO at high temperature forms the rearranged product as a mixture of alkenes after deprotonation of the resulting tertiary carbocation. To complete the core, the C7–C17 bond was formed by an aza-Prins reaction upon oxidation of the amine.
NMs MeO OMe
OMe
NAc MeO OMe
O 3. HCl, MeOH
1. Na/NH3
2. Ac2O
hυ
•
NAc MeO OMe
O
NAc MeO OMe
X OH 3. NaBH4
1. HO(CH2)2OH 2. OsO4, NaIO4
HCl NAc
MeO OMe
O OH NAc
MeO OMe
X OMe TsO
7 steps
28 29
NAc MeO OMe
O O
X = ethylene ketal
X = ethylene ketal
31 30 33 32
27
atisine core
Scheme 1.2 Wiesner’s synthesis of talatisamine (1).
In a later synthesis of the C19-diterpenoid alkaloid 13-desoxydelphonine (39), Wiesner and coworkers sought to rearrange the denudatine core, where the C7–C17 bond is already in place (Scheme 1.3).19 Starting from ortho-quinone mono-ketal 34, Diels-Alder cycloaddition with benzyl vinyl ether followed by global reduction with Zn and acetic acid affords the denudatine core in 35. This can be elaborated in 12 steps to the substrate for the Wagner- Meerwein rearrangement, which procedes smoothly to deliver the aconitine core in excellent yield. This product can be advanced in 4 steps to 13-desoxydelphonine.
NAc MeO OMe
X OMe TsO
NAc
OMe MeO OMe
O O DMSO
180 °C NH Me2N NMe2
+
40% yield 40% yield
3 steps NEt
OMe MeO OMe
HO Hg(OAc)2
H2O 40% yield NEt
HO OMe HO MeO OMe
NAc MeO OMe
O
O OMe
NAc MeO OMe
O
O OMe
NEt
OMe MeO OMe
HO X = ethylene ketal
36 37 38
39 talatisamine (1) 40
17 7
xx
33 atisine core
Scheme 1.3 Wiesner’s synthesis of 13-desoxydelphonine (39).
The Sarpong lab has utilized this strategy for the synthesis of a variety of diterpenoid alkaloid carbon skeletons, including the aconitine-type C19-diterpenoid alkaloids (Scheme 1.4).20,21 In their elegant 2015 synthesis of liljestrandinine (3), they employ an intramolecular Diels-Alder cycloaddition of an ortho-quinone monoketal with a pendant olefin to build the [2.2.2]-bridged C/D-bicycle 42. This intramolecular approach also provides an efficient way to form the central B-ring. In short order, they elaborate 42 to an alkyl triflate, which serves as the substrate for the Wagner-Meerwein rearrangement. Similar approaches have been used by the Fukuyama and Inoue labs in their syntheses of C19-diterpenoid alkaloids.22,23
MeO OMeONMe
MeO
O R
O O
O 34 R = H, Br (2:1)
NMe
HO OMe HO MeO OMe
MeO
1. OBn 2. Zn, AcOH
N N DMSO/o-xylene
180 °C 89% yield 4 steps
OMe
OMe ONMe MeO
MeO O 13-desoxydelphonine O
(39)
12 steps
35
37 NMe OMe
O O
MeO OBn Diels-Alder MeO
MeO OMeNMe
Br X O
X = ethylene ketal MeO
OMe denudatine core
36
38
Scheme 1.4 Sarpong’s synthesis of liljestrandinine (3).
1.3.2 Gin’s Synthesis of Neofinaconitine (60) Scheme 1.5 Gin’s approach to aconitine core.
Gin and coworkers used a different approach to the C/D-bicycle in their synthesis of the C18-diterpenoid alkaloid neofinaconitine (60, Schemes 1.5 and 1.6).24 They assemble the [3.2.1]-bicycle directly via a Diels-Alder reaction between a cyclopentadiene derived from 46 and cyclopropane dienophile (47). Prior to the work presented in subsequent chapters, this is
NCO2Me
MOMO OMe
NCO2Me
MeO OMe
OTf OMOM MeO
H2O NCO2Me
OMe
MOMO HO NEt MeO
OMe
HO HO MeO
liljestrandinine (3)
4 steps DBU
DMSO 120 °C Wagner–Meerwein
rearrangement OMe
NCO2Me
MOMO MeO
MeO OMe
NCO2Me
O MeO MeO
MeO 1. 2N HCl
2. PIDA 98% yield
(2 steps)
150 °C
77% yield
NCO2Me
MeO OMe
OMe O denudatine framework
MeO
4 Steps
45 44 43
42 41
40
O
MeO
+
Et3N TBSOTf
0 °C
OMe OTIPS TBSO
8 steps
MeO Br TBSO
TIPSO [6 steps]
1.6 : 1 rr
+
EtN O
Br CO2Me
MeO EtN O
Br
CO2Me
H O
O Tf2NH H
CH2Cl2
75% yield N
O
MeO O
CO2Me O
BrEt 17 11
3 steps Diels–Alder
MeO
N O
Br
CO2Me
H
OH
O Et
NEt
MeO MeO2C
HO O
O
Br 11
17
11 17 Diels–Alder
Mannich Cyclization 46
47
48 49 50
51 52
53 54
the only example of a total synthesis of a C18- or C19-diterpenoid alkaloid which does not involve a Wagner-Meerwein rearrangement to form the C/D-bicycle. Upon elaboration of 48 to diene 49, they perform a fragment coupling Diels-Alder with dienophile 50 to form the A- ring of the natural product. Intramolecular Mannich reaction forms the A/E/F-tricycle of the natural product and afforded the unexpected product 54 after intramolecular oxy-Michael.
Scheme 1.6 Completion of C18-diterpenoid alkaloid neofinaconitine (60).
To break the unnecessary C–O bond of the enol ether 54, allylic oxidation and mesylate formation enabled elimination to bis-enone 59 (Scheme 1.6). The final bond of the natural product core is forged using a Giese addition of a C7-radical to the D-ring enone to give 59.
This intermediate is elaborated to the C18-diterpenoid alkaloid neofinaconitine (60) in 11 further steps.