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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

The western fragment 3 was prepared in a few steps, as illustrated in Scheme 1. Initially, the commercially available Grignard reagent 8 was reacted with iodine, resulting in the formation of compound 9. Subsequently, compound 9 was coupled with compound 10 under copper catalysis to afford the dialkyne 11. The central alkyne moiety was then reduced using LiAlH4, with the reduction directed by the primary alcohol group. Stannylation and TBS protection were performed, leading to the formation of compound 12 in good to excellent yield and diastereoselectivity. Finally, the synthesis of the final fragment 3 involved Pd/Cu-catalyzed cross-coupling and a subsequent oxidation step.


Scheme 1: Synthesis of western fragment 3.

Synthesis of Eastern Fragment 6

The synthesis of the eastern fragment 6 involved a 15-step route starting from commercially available compounds 13 and 14, as depicted in Scheme 2. The authors initially employed the iridium-catalyzed allylation developed by M. Krische and co-workers to facilitate the coupling of 13 and 14. To achieve the stereoselective synthesis of tetrahydrofuranes, such as compound 16, they successfully employed a cobalt-catalyzed oxidative Mukaiyama-type cyclization, a powerful method previously utilized in total synthesis (see also Total Synthesis and Structural Revision of Amphirionin-2 (H. Fuwa, 2021)). Subsequently, the free alcohol was oxidized, followed by Weinreb amide ester synthesis and treatment with a Grignard reagent, leading to the formation of compound 17. The authors emphasized the necessity of treating the compound with DBU to achieve complete conjugation of the double bond with the ketone moiety. The diastereoselective reduction and protection steps then provided compound 18 in excellent yield. A two-step protocol was employed to convert compound 18 to the diol 19, followed by the temporary formation of an epoxide and subsequent opening of the epoxide to yield the terminal alkene 20. Finally, late-stage modifications, including protection/iodination to yield compound 21, and subsequent deprotection, were necessary to obtain the eastern fragment 6.


Scheme 2: Synthesis of eastern fragment 6.

Synthesis of Central Fragment 7

The synthesis of the central fragment 7 was achieved in a modular manner, as illustrated in Schemes 3 and 4. Initially, the two main fragments, 25 and 28, were synthesized (see Scheme 3), and subsequently coupled with fragment 7 (see Scheme 4). In detail, glucose 22 underwent diprotection, followed by a two-step process of oxidation and cleavage, resulting in compound 23. Grignard addition and subsequent oxidation steps yielded alkynone 24. By employing a Noyori-type reduction, selectively protected compound 25 was obtained after TBS protection. The second fragment, 28, was synthesized in a four-step protocol starting from compound 26. The synthesis included stereoselective reduction, chemoselective acid reduction, TBS protection, and saponification.


Scheme 3: Synthesis of intermediates 25 and 28.

With fragments 25 and 28 in hand, the acid and free alcohol moieties were coupled through Steglich esterification. Subsequent alkyne reduction resulted in the formation of compound 29 in excellent yield, as shown in Scheme 4. The ester group of compound 29 was then transformed into an alkene, which underwent metathesis to yield compound 30 with a total yield of 47%. To further advance the synthesis, Fürstner et al. decided to reduce the double bond, leading to the formation of compound 31 after deprotection. Oxidation of compound 31 to the dicarbonyl was followed by Wittig olefination, reduction, and TBS protection, resulting in the formation of compound 32. The next steps involved the partial cleavage of the PMP group and Swern oxidation, yielding aldehyde 33. Subsequently, aldehyde 33 was propargylated and transformed into the final central fragment 7 through a three-step process.


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 focused on the final steps of the total synthesis of prorocentin (1), as shown in Scheme 5. In detail, the eastern fragment 6 and central fragment 7 were coupled through a [Pd] cross-coupling reaction. Then a gold-catalyzed cycloisomerization of compound 5 resulted in the formation of compound 35 in situ. Upon addition of PPTS, compound 35 further reacted to yield the spiro compound 36. TBS protection of the secondary alcohol and deprotection of the primary alcohol were necessary steps for the subsequent Sharpless epoxidation. Following this, the Appel reaction with iodine was employed, leading to the formation of compound 4. In the final three steps, compound 4 was first coupled with deprotonated compound 3. Then, the sulfonate group was reductively removed, and global deprotection ultimately yielded prorocentin (1).


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


This impressive total synthesis project not only achieved the structural revision of prorocentin but also showcased the utilization of state-of-the-art chemical transformations. Additionally, the project provided comprehensive analytical datasets, offering significant benefits to the total synthesis community. Unlike many short-step terpene syntheses seen in recent years, this project serves as a remarkable example of a successful multi-step synthesis that fearlessly tackles 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)