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, theThe western fragment 3 was prepared in a few stepssteps, as shownillustrated in Scheme 1. Therefore,Initially, the commercially available Grignard reagent 8 was reacted with iodineiodine, yieldingresulting in the formation of compound 9. Subsequently, compound 9which was directly coupled with compound 10 under copper catalysis to afford the dialkyne 11. The central alkyne moiety was then reduced byusing LiAlH4, (with the reduction directed by the primary alcohol),alcohol group. Stannylation and then stannylation andTBS protection gavewere performed, leading to the formation of compound 12 in good to excellent yield and diastereoselectivity. FinalFinally, the synthesis of the final fragment 3 was synthesized byinvolved Pd/Cu Cu-catalyzed cross-coupling and a subsequent oxidation tostep.
Scheme 1: Synthesis of western fragment 3.
Synthesis of Eastern Fragment 6
The synthesis of the eastern fragment 6 neededinvolved 15a steps15-step route starting from commercially available compounds 13 and 14, as showndepicted in Scheme 2. The authors firstinitially describeemployed the coupling of 13 and 14 by iridium-catalysedcatalyzed allylation developed by M. Krische and co-workers.workers Forto facilitate the coupling of 13 and 14. To achieve the stereoselective synthesis of tetrahydrofuranestetrahydrofuranes, likesuch as compound 16, they successfully employed a cobalt-catalysedcatalyzed oxidative Mukaiyama Mukaiyama-type cyclization iscyclization, a powerful method alreadypreviously usedutilized 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 ofSubsequently, the free alcohol was oxidized, followed by Weinreb amide ester synthesis and treatment with a Grignard reagentreagent, deliveringleading to the formation of compound 17. The authors notedemphasized thatthe treatmentnecessity of treating the compound with DBU wasto necessary for theachieve complete conjugation of the double bond with the ketone.ketone Diastereoselectivemoiety. The diastereoselective reduction and protection steps then yieldedprovided compound 18 in excellent yield. A two-step protocol was employed to convert compound 18 to the diol 19 was then applied which was, followed by the temporary formation of an epoxide formationand andsubsequent opening of the epoxide openingto toyield the terminal alkene 20. FinalFinally, late-stage modificationsmodifications, likeincluding protection/iodination to yield compound 21, and deprotectionsubsequent deprotection, were necessary to provideobtain the eastern fragment 6.
Scheme 2: Synthesis of eastern fragment 6.
Synthesis of Central Fragment 7
The synthesis of the central fragment 7 was again accomplishedachieved in a modular mannermanner, as shownillustrated in Schemes 3 and 4. Firstly,Initially, the two main fragmentsfragments, 25 and 28, were synthesized (see Scheme 3), whichand were thensubsequently coupled towith fragment 7 (see Scheme 4). In detaildetail, glucose 22 wasunderwent diprotecteddiprotection, followed by a two-step process of oxidation and oxidized/cleavedcleavage, toresulting in compound 23 in two steps. Then. Grignard addition and subsequent oxidation deliveredsteps yielded alkynone 24. NoyoriBy employing a Noyori-type reductionreduction, selectively gaveprotected compound 25 was obtained after TBS protection. The othersecond fragmentfragment, 28, was synthesized in a four four-step protocol starting from compound 26. includingThe synthesis included stereoselective reduction, chemoselective acid reduction, TBS protectionprotection, and saponification.
Scheme 3: Synthesis of intermediates 25 and 28.
With fragments 25 and 28 in hand, the acid and the free alcohol moieties were coupled bythrough Steglich esterificationesterification. andSubsequent alkyne reduction gaveresulted in the formation of compound 29 in excellent yieldyield, as shown in Scheme 4. The ester group of compound 29 was then transformed into thean alkenealkene, which then undergounderwent metathesis to yield compound 30 inwith 47%a total yield.yield of 47%. To further advance the synthesis, Fürstner et al al.then decided to reduce the double bondbond, andleading to the formation of compound 31 was achieved after deprotection. Oxidation of compound 31 to the dicarbonyl was followed by Wittig olefination, reductionreduction, and TBS protectionprotection, toresulting in the formation of compound 32. Then,The next steps involved the partial cleavage of the PMP group was partially cleaved and Swern oxidationoxidation, gaveyielding aldehyde 33. Subsequently, aldehyde 33which was then propargylated and transformed into the final central fragment 7 inthrough threea steps.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 concentratedfocused 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 bythrough a [Pd] cross-coupling.coupling reaction. Then a gold-catalyzed cycloisomerization of compound 5 gaveresulted in the formation of compound 35 in situ. whichUpon addition of PPTS, compound 35 further reacted to yield the spiro compound 36 after the addition of PPTS. Then. TBS protection of the secondary alcohol and deprotection of the primary alcohol waswere necessary steps for the followingsubsequent Sharpless epoxidation. ThenFollowing this, the Appel reaction with iodine gavewas employed, leading to the formation of compound 4. In the final three steps, compound 4 was first coupled with deprotonated compound 3. ThenThen, the sulfonate group was removedreductively reductivelyremoved, and global deprotection finallyultimately gaveyielded 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 revisedachieved the structurestructural revision of prorocentin but also highlightsshowcased up-to-datethe utilization of state-of-the-art chemical transformations,transformations. isAdditionally, furthermorethe accompaniedproject byprovided extensivecomprehensive analytical datasets, andoffering thereforesignificant hasbenefits an overall benefit forto the total synthesis community. In contrast toUnlike many short-step terpene syntheses fromseen thein lastrecent years, this project alsoserves isas a showcaseremarkable example of a successful multi-step synthesis notthat afraidfearlessly oftackles 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)