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Total Synthesis of Talatisamine (M. Inoue, 2020)

Talatisamine (1, see Figure 1) is a highly oxidized hexacyclic alkaloid. Isolated already almost 50 years ago from aconitum species published in Tetrahedron, the natural product was until now only once synthesized by Karel Wiesner et al. in the early 70s. In a recently published study, the Masayuki Inoue (井上将行) group from the University of Tokyo are now able to describe a second access to this alkaloid in the journal Angewandte Chemie. From a retrosynthetic view, the Inoue group decided to use the already examined strategy from Wiesner et al. to introduce the five-membered ring starting from enone 2. The 5,6,7-tricyclic ring system in the western part of the molecule from 2 should be available from a 6,6,6-tricyclic system by rearrangement. This tricyclic system itself should be available from 4 by intramolecular Diels Alder reaction. The Diels Alder precursor 4 should be synthesized from 5 and 6 by organometallic addition.


Figure 1. Retrosynthetic analysis for the total synthesis of talatisamine (1) by M. Inoue.

Coupling of fragments 5 and 6

For the synthesis of fragment 6, the Inoue group started with enone 7 with a 1,4 silylation followed by alpha acylation to 8 as shown in Scheme 1. Then another acylation gave a diester, which was subjected to a double Mannich reaction to form the desired 6,6-bicyclic ring system 9 in 39% from enone 7. However, the diastereoselectivity stayed low (2.5:1). In the next step, Fleming Tamao oxidation successfully introduced the secondary alcohol. Under the acidic conditions, retro aldol reaction led to the equilibration of the diastereomer (8:1). The alcohol was then protected as TBS ether 6 in 48% yield over 3 steps from 9. Using a common organometallic strategy alkyne 5 was coupled in 85% yield, but disappointing diastereoselectivity (dr 1:1). However, Barton McCombie deoxygenation slightly led to an improvement of the dr to 2.4:1.


Scheme 1. Coupling of fragments 5 and 6.

Intramolecular Diels Alder reaction

After deoxygenation to 11 (see Scheme 2), the alkyne was fully reduced and the more accessible ester was converted into the methyl ether 12 by reduction and methylation. Note that the authors were able to separate the diastereomers at this stage. Then silyl ether deprotection was followed by methylation. Then the reduction of the second ester was followed by oxidation to the aldehyde 14 in 73% yield over 2 steps. Tebbe olefination gave the terminal alkene, which was followed by MOM deprotection and bromination of the phenol to 15. The introduction of the bromide was essential for the following Diels Alder reaction.


Scheme 2. Further functionalization of fragment 11.

With fragment 15 in hand, the Inoue group was now able to examine the intramolecular Diels Alder reaction as shown in Scheme 3. First, the phenolic system had to be oxidized to the quinone 4 using PIDA and HCl for amine protection. Under thermal conditions Diels Alder cyclization gave 3 in 89% with regioselectivity from 2.2 to 1 (other isomer not shown), however, dimerization could be prevented by aforementioned bromination. The bromide could then successfully been removed in the next step and the ketone was reduced to the alcohol and converted into the triflate 16. The following Wagner-Meerwein rearrangement was induced by high temperatures and the usage of DBU to get in situ intermediate 17 which was oxidized to enone 2 in 83% yield. Enolization and oxidation in a vinylogous Rubottom oxidation were followed by Swern oxidation to access diketone 18.


Scheme 3. Intramolecular Diels Alder reaction and rearrangement.

Completion of total synthesis

In the last steps, ketone 18 was first transformed into the hydrazone followed by Luche reduction. Then reduction to diimine by catecholborane triggered the isomerization of the double bond to get alkene 19 in 44% yield from 18 as shown in Scheme 4. The free alcohol was then transformed into the methyl ether which was followed by acidic ketal cleavage and reduction to Wiesner's intermediate 20. However, reproduction of the literature-known procedure was challenging and talatisamine 1 was synthesized in only 29% yield after an extensive screening of reaction conditions. 


Scheme 4. Completion of the total synthesis of talatisamine (1).

In total, the Inoue group was able to report a new access to this highly complex natural product in 33 steps from enone 7. In their key steps, they were able to construct the polycyclic system by an intramolecular Diels Alder reaction and a Meerwein-Wagner rearrangement.

Published in: D. Kamakura, H. Todoroki, D. Urabe, K. Hagiwara, M. Inoue Angewandte Chemie Int. Ed. 2020, 59, 479-486. doi: 10.1002/anie.201912737