First Total Synthesis and Structural Revision of Prorocentin (A. Fürstner, 2023)

Prorocentin (1, as shown in Figure 1) is a complex C-35 strain polyketide that was initially reported in 2005 by Tzong-Huei Lee and his colleagues from National Taiwan University.[Org. Lett. 2005] This structurally complex compound bears an arrangement of 13 stereocenters and features a unique 6,6,6-trans-fused/spiro-linked polyether ring system. However, the bioactivity and precise configuration of this polyether remained largely unexplored.

To address these knowledge gaps and resolve potential misassignments, Alois Fürstner and co-workers (Max Planck Institut für Kohlenforschung, Mülheim a.d. Ruhr, Germany) started a challenging synthetic project which is reported in the journal JACS in 2023.[JACS 2023]

From the project's outset, the researchers suspected an incorrect assignment in one position. Through the total synthesis, they successfully elucidated the revised structure of the polyketide, providing an accurate depiction of both 1 (the actual prorocentin) and 2 (the previously proposed structure). This work not only rectifies the misassignment but also sheds new light on the fascinating architecture and potential bioactivity of this intriguing polyketide.

Figure 1: Structure of prorocentin (1) and retrosynthetic analysis by A. Fürstner.

From a retrosynthetic standpoint, the Fürstner group opted for a modular approach, employing three key fragments for the synthesis of prorocentin. In a late-stage coupling, the deprotonated sulfone 3 underwent a reaction with iodine 4. The challenging central tricyclic compound derived from 4 was accessed through a gold-catalyzed cycloisomerization of intermediate 5. The alkyne 5, in turn, was obtained through the coupling of the eastern fragment 6 with the central fragment 7. This strategic framework allowed for the synthesis of both the actual prorocentin (1) and the previously proposed structure 2. However, the focus here will primarily be on the synthesis of prorocentin (1).

Synthesis of Main Fragments

Synthesis of Western Fragment 3

First, the western fragment 3 was prepared in a few steps as shown in Scheme 1. Therefore, the commercially available Grignard 8 was reacted with iodine yielding in 9 which was directly coupled with 10 under copper catalysis to dialkyne 11. The central alkyne was reduced by LiAlH₄ (directed by the primary alcohol), and then stannylation and protection gave 12 in good to excellent yield and diastereoselectivity. Final fragment 3 was synthesized by Pd/Cu catalyzed cross-coupling and oxidation to 3.

Scheme 1: Synthesis of western fragment 3.

Synthesis of Eastern Fragment 6

The synthesis of eastern fragment 6 needed 15 steps from commercially available 13 and 14 as shown in Scheme 2. The authors first describe the coupling of 13 and 14 by iridium-catalysed allylation developed by M. Krische and co-workers. For the stereoselective synthesis of tetrahydrofuranes like 16 cobalt-catalysed oxidative Mukaiyama type cyclization is a powerful method already used in total synthesis before (see also Total Synthesis and Structural Revision of Amphirionin-2 (H. Fuwa, 2021)) and also successfully applied in this case for the synthesis of 16. Then oxidation of the free alcohol was followed by Weinreb amide ester synthesis and treatment with Grignard reagent delivering 17. The authors noted that treatment with DBU was necessary for the complete conjugation of the double bond with the ketone. Diastereoselective reduction and protection then yielded 18 in excellent yield. A two-step protocol to the diol 19 was then applied which was followed by temporary epoxide formation and epoxide opening to terminal alkene 20. Final late-stage modifications like protection/iodination to 21 and deprotection were necessary to provide eastern fragment 6.

Scheme 2: Synthesis of eastern fragment 6.

Synthesis of Central Fragment 7

The synthesis of the central fragment 7 was again accomplished in a modular manner as shown in Schemes 3 and 4. Firstly, two main fragments 25 and 28 were synthesized (see Scheme 3), which were then coupled to 7 (see Scheme 4). In detail glucose 22 was diprotected and oxidized/cleaved to 23 in two steps. Then Grignard addition and oxidation delivered alkynone 24. Noyori type reduction selectively gave 25 after TBS protection. The other fragment 28 was synthesized in a four step protocol from 26 including stereoselective reduction, chemoselective acid reduction, TBS protection and saponification.

Scheme 3: Synthesis of intermediates 25 and 28.

With 25 and 28 in hand, the acid and the free alcohol were coupled by Steglich esterification and alkyne reduction gave 29 in excellent yield as shown in Scheme 4. The ester was then transformed into the alkene which then undergo metathesis to 30 in 47% total yield. Fürstner et al then decided to reduce the double bond and 31 was achieved after deprotection. Oxidation to the dicarbonyl was followed by Wittig olefination, reduction and TBS protection to 32. Then, the PMP group was partially cleaved and Swern oxidation gave aldehyde 33 which was then propargylated and transformed into the final central fragment 7 in three steps.

Scheme 4: Coupling of intermediates 25 and 28 and synthesis of central fragment 7.

Finalization of the Total Synthesis

With all fragments in hand, Fürstner and co-workers concentrated on the final steps of the total synthesis of prorocentin (1) as shown in Scheme 5. In detail, eastern fragment 6 and central fragment 7 were coupled by [Pd] cross-coupling. Then gold-catalyzed cycloisomerization of 5 gave 35 in situ which reacted to spiro compound 36 after the addition of PPTS. Then TBS protection of the secondary alcohol and deprotection of the primary alcohol was necessary for the following Sharpless epoxidation. Then Appel reaction with iodine gave 4. In the final three steps, 4 was first coupled with deprotonated 3. Then the sulfonate was removed reductively and global deprotection finally gave prorocentin 1.

Scheme 5: Coupling of main fragments and finalization of the total synthesis of prorocentin (1) by Fürstner et al.

Conclusion

This impressive total synthesis project not only revised the structure of prorocentin but also highlights up-to-date chemical transformations, is furthermore accompanied by extensive analytical datasets, and therefore has an overall benefit for the total synthesis community. In contrast to many short-step terpene syntheses from the last years, this project also is a showcase of a successful multi-step synthesis not afraid of complex molecular structures.

Published in: R.J. Zachmann, K. Yahata, M. Holzheimer, M. Jarret, C. Wirtz, A. Fürstner Journal of American Chemical Society 2023, 10.1021/jacs.2c12529.

For another total synthesis by Fürstner et al see: Total Synthesis of Mycinolide IV and Aldgamycin N (A. Fürstner, 2021)