Total Synthesis of Tronocarpine (K. Namba, 2021)

Tronocarpine (1, see Figure 1) is a pentacyclic alkaloid isolated from the plant species Tabernaemontana corymbosa two decades ago by T.-S. Kam, K.-M. Sim and T.-M. Lim from the University of Malaya (Malaysia). In 2020, the first enantioselective total synthesis was reported by F.S. Han and coworkers, which delivered 1 in 20 steps from commercially available substrates. Now, the research group of Kosuke Namba from the Tokushima University (Japan) was able to report a second synthetic report aiming for a more concise total synthesis of this alkaloid. As shown in Figure 1, tronocarpine (1) should be available from 2 by late-stage functionalization. In their key step 2 should be available from 3 in a one-pot reaction. During this tandem cyclization, two C-N bonds and one C-C bond should be established in a highly diastereoselective fashion including one quarternary center. The indole 3 itself should be available from literature-known compounds 4 and 5.

Figure 1. Retrosynthetic analysis for the total synthesis of tronocarpine (1).

Synthesis of cyclization precursor 3

For the construction of the indole moiety 4 and 5 (see Scheme 1) were chosen by the Namba group, which are both available in one step by literature-known procedures. The addition of tributylphosphine led to the formal 1,4-addition of dicarbonyl enolate 4 to unsaturated system 5 (for details see Tetrahedron 2005), then indole was introduced under reductive conditions yielding in 6 as a diastereomeric and enantiomeric mixture. This was followed by reductive coupling with 7 and azide formation to 8 in 56% resp. 93% yield. Reduction of the most accessible ester to the aldehyde was with 52% yield surprisingly selective and followed by the formation of the silyl enol ether. The enolate was then directly subjected to acetaldehyde in a Mukaiyama aldol reaction yielding in 3 in 35% yield. The authors noted, that they also were able to isolate side products because of hemiaminal and acetal formation (25%). These side products were easily transformed into 3 using amberlyst 15.

Scheme 1. Synthesis of key fragment 3 in 5 steps from 4 and 5.

Tandem cyclization and completion of the total synthesis

As shown in Scheme 2, the pentacyclic core structure of tronocarpine (1) was established in a single pot reaction from precursor 3 in 70% yield. First, the addition of a soft base at 0°C led to the formation of unsaturated aldehyde 9 by elimination. Then at higher temperatures, enolate formation and attack of the aldehyde led to aldol product 10 as a diastereomeric mixture (alcohol and double bond). In the next transformation, amide formation was observed to deliver intermediate 11. The addition of Pd under H₂ atmosphere led to the second lactam formation. Finally, the addition of base yielded in the diastereomeric pure product 2 by retro-aldol/aldol equilibration. With 2 in hand, the synthesis of alkaloid 1 was finished by 1,3 rearrangement of the hydroxy group and reductive opening of the lactam to 12 (61%) and final oxidation and aminal formation to 1 in 89%.

Scheme 2. Tandem cyclization and completion of the total synthesis of tronocarpine (1).

For an enantioselective version of this total synthesis, racemic 6 could be separated into the enantiomers by enzymatic resolution (not shown). In total, the Namba group described a new short total synthesis of the alkaloid 1 featuring unique access to the pentacyclic core skeleton by an impressive one-pot tandem cyclization. With this key step, they were able to synthesize 1 in only 9 steps from commercially available material.

Published in: A. Nakayama, T. Nakamura, T. Zaima, S. Fujimoto, S. Karanjit, K. Namba Angewandte Chemie Int. Ed. 2021, 60, 635-639. doi: 10.1002/anie.202009966