Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2024 Jan 19;146(4):2345–2350. doi: 10.1021/jacs.3c13304

Total Synthesis of the Allenic Macrolide (+)-Archangiumide

Jack L Sutro 1, Alois Fürstner 1,*
PMCID: PMC10835656  PMID: 38241031

Abstract

graphic file with name ja3c13304_0005.jpg

Archangiumide is the first known macrolide natural product comprising an endocyclic allene. For the ring strain that this linear substructure might entail, it was planned to unveil the allene at a very late stage of the projected total synthesis; in actual fact, this was achieved as the last step of the longest linear sequence by using an otherwise globally deprotected substrate. This unconventional timing was made possible by a gold catalyzed rearrangement of a macrocyclic propargyl benzyl ether derivative that uses a −PMB group as latent hydride source to unveil the signature cycloallene; the protecting group therefore gains a strategic role beyond its mere safeguarding function. Although the gold catalyzed reaction per se is stereoablative, the macrocyclic frame of the target was found to impose high selectivity and a stereoconvergent character on the transformation. The required substrate was formed by ring closing alkyne metathesis (RCAM) with the aid of a new air-stable molybdenum alkylidyne catalyst.

Allenic natural products are scarce overall,1 but examples comprising an allene as part of a macrocycle are exceedingly rare. Only a single type of plant-derived germacranolide had been assigned such a substructure2 before the macrolide archangiumide (1) was disclosed in 2021.3 This unique polyketide incorporates a stereogenic allene in a 17-membered lactone, as rigorously proven by X-ray diffraction (Scheme 1A).3,4 The myxobacterium Archangium violaceum SDU8 found to produce 1 was collected in Shangdong province, China, and had been singled out by combined genome mining and NMR-based metabolomic profiling as a potential source of secondary metabolites with little structural redundancy.

Scheme 1. (A) Retrosynthetic Plan; (B) Projected Allene Formation by Gold Catalyzed Hydride Transfer; (C) Gold Catalyzed Cycloisomerization of Vinyl-allenes.

Scheme 1

Open in a new tab

While the discovery of 1 nicely confirmed this notion and represents the landmark of an essentially untapped sector of chemical space, the biological role of the compound remains obscure: 1 was assayed by the isolation team for antibacterial, antifungal, anticancer, antioxidant, and anti-inflammatory activity, but no significant effects were noticed.3 This puzzling aspect notwithstanding, archangiumide deserves attention as the prototype of a new class of secondary metabolites of microbial origin. For its linearity, an allene might well be expected to impose strain onto a macrocyclic scaffold, which, conversely, will enhance the already high reactivity of the cumulated double bonds.5,6 This seemed particularly true in the present case, where two additional E-configured alkenes and an annulated tetrahydrofuran ring cause extra rigidity and, hence, likely augment the synthetic challenge. From a strategic viewpoint, it therefore seemed prudent to unveil the allene entity at a very late stage of the projected total synthesis.7

We conjectured that the gold catalyzed rearrangement of propargyl benzyl ethers pioneered by Gagosz and co-workers might provide an adequate way to do so (Scheme 1B).8 By virtue of its high alkynophilicity,9,10 the π-acid catalyst almost certainly allows a polyunsaturated substrate of type A to be activated at the proper site;11−15 a kinetically favorable intramolecular 1,5-hydride transfer will ensue (F → I). The entropic and enthalpic gain upon release of benzaldehyde as a stable byproduct should drive the reaction forward, even if the targeted (cyclo)allene is potentially strained.

In contrast to these presumed chemical assets, the stereochemical outcome of the gold-catalyzed reaction was difficult to gauge, not least because the original report does not provide any pertinent information.8,16,17 Although a highly ordered six-membered transition state G can be envisaged that should result in chirality transfer from the propargylic center of substrate F to the chiral axis of product I upon (presumed) anti-elimination of an intermediate of type H, gold catalysts are known for their ability to racemize optically active allene derivatives; this process can be fast and facile.18 Yet, the literature also documents cases in which little or no loss of chiral information was observed on exposure of such derivatives to π-acids.19 Although a reliable forecast was therefore impossible, recourse to a chiral gold catalyst appeared to us as a potential last resort, should no other way be found to gain control over the stereochemical course of the reaction.20

Equally daunting was the fact that archangiumide is a vinylallene. On treatment with catalytic [LAu+], such compounds are known to convert into cyclopentadiene derivatives by electrocyclization via a presumed pentadienyl cation intermediate (Scheme 1C).8,21 In the present case, however, such a cycloisomerization could be disfavored by the confined macrocyclic envelope that might prevent a substrate of type A from adopting the conformation required for cyclization; moreover, the ensuing ring contraction seemed unfavorable. Beyond these plausibility arguments, there was no evidence available at the outset that the projected gold catalyzed reaction would stop at the vinylallene stage.

Although these potential issues concerned the very end game of the envisaged total synthesis, the strategic advantages of encoding the chiral allene as a macrocyclic propargyl alcohol derivative seemed to outweigh the risks. Alkynes are useful handles for fragment coupling purposes and cycloalkynes are well within reach of ring closing alkyne metathesis (RCAM).22−24 The required catalysts, most notably molybdenum alkylidynes endowed with (tripodal) silanolate ligands, hold the promise of being compatible with all functionalities present in a substrate of type B.25−28 They activate triple bonds but leave all kinds of olefins untouched, which is imperative when targeting a polyunsaturated compound such as A. Under the premise of rigorous chemical orthogonality,29 archangiumide (1) can be traced back to three very manageable building blocks, C–E, whereby fragment D corresponds to protected d-chitaric acid.

A suitable compound of this type was available on gram scale from commercial d-mannono-1,4-lactone (Scheme 2).30 The derived acetal 2 is known to react selectively at the C2-OH position with Tf2O/pyridine. Treatment of the resulting sulfonate ester 3 with MeOH in acidic medium entailed concomitant lactone opening, acetal cleavage, and cyclization of the resulting polyol to furnish compound 4.30 This product was then elaborated into aldehyde 6 in readiness for fragment coupling. It is important to note, however, that 6 proved to be unstable to storage and had to be used immediately upon preparation.

Scheme 2. Preparation of the Building Blocks.

Scheme 2

Open in a new tab

Sulfone 11 was secured by addition of propynyllithium to δ-valerolactone (7) in THF at low temperature to give the corresponding alkynylketone, which was isolated only after silylation of the primary −OH group.31 A Noyori transfer hydrogenation ensured the asymmetric reduction of the carbonyl group of 8 with excellent ee and near quantitative chemical yield;32 the plan was to engage this chiral propargylic center in the late-stage allene formation. We chose to protect the alcohol as −PMB (rather than parent benzyl) ether based on the mechanistic rationale that an electron-rich benzyl group might facilitate the gold catalyzed hydride transfer F → I via stabilization of the presumed oxocarbenium intermediate H, even though the literature does not mention any substituent effect.8 Compound 10 was then readily transformed into sulfone 11. All it took to secure the antipodal building block ent-11 was to use the enantiomeric Noyori catalyst ent-12 in the reduction step and follow the sequence from there on (for details, see the Supporting Information). With both antipodes in hand, it should be possible to clarify the so far unknown stereochemical course of the projected gold catalyzed allene formation.

For the preparation of the third building block, methyl d-lactate (13) was O-silylated and the resulting ester reduced with DIBAL-H; lithiated TMS-acetylene was then added to the aldehyde thus formed. This reaction was diastereoselective (anti/syn ≈ 8:1), high yielding, and scalable.33 Orthogonal protection of the newly formed alcohol in 14 followed by cleavage of the C-TMS group gave 15. Attempted carboalumination 15 (or partly deprotected analogues) followed by an iodine quench basically met with failure; gratifyingly though, a copper catalyzed net carboboration constituted a convenient and robust alternative that provided access to 16 in good yield and excellent selectivity.34,35 Subsequent boron/iodine exchange followed by a Sonogashira coupling36 with excess propyne at low temperature secured enyne 17 in isomerically pure form. Treatment with tosic acid in MeOH then gave the required alcohol derivative 18.

The assembly phase commenced with a modified Julia-type olefination of freshly prepared aldehyde 6 with sulfone 11 (Scheme 3). Despite the excellent track record of this transformation,37 this step required careful optimization. Specifically, LDA (rather than the more commonly used alkali hexamethyldisilazides) turned out to be the base of choice; the deprotonation of 11 had to be carried out in THF at −100 °C; a precooled (−65 °C) solution of the aldehyde in DMF was then rapidly added to the lithiated sulfone, and the resulting mixture was slowly warmed. Any excess base had to be strictly avoided and the temperature had to be rigorously controlled to prevent notable decomposition. Under these conditions, however, alkene 19 was formed in well reproducible 75% yield with a favorable isomer ratio (E/Z ≈ 6:1); the material was best purified after the saponification of the methyl ester. The resulting acid was then linked to alcohol 18 via the Yamaguchi protocol.38

Scheme 3. Completion of the Total Synthesis.

Scheme 3

Open in a new tab

In line with our expectations, macrocyclization of diyne 20 by RCAM worked well with the aid of the latest alkyne metathesis catalysts developed in our laboratory. The reaction proceeded within 30 min when the highly active “canopy catalyst” 24 was used.26,27,39,40 Although complex 25 reacted more slowly (≈2 h), this pyridine adduct has the distinct advantage that it can be handled and weighed in air;28 it is storable in a desiccator outside a glovebox for many months without noticeable decomposition. Upon dissolution in toluene, the pyridine ligand dissociates spontaneously and the active molybdenum alkylidyne is released without the need for any extra physical or chemical stimulus.28 For the ease of handling in combination with a broad functional group compatibility, 25 is deemed to mark an important advance in the field of alkyne metathesis in general.22 As the current example illustrates, 24 and 25 both selectively activated the triple bonds in 20, whereas the (conjugated) alkenes and all polar substituents, including the critically important stereogenic benzylic ether center, remained intact.

With cycloalkyne 21 in hand,41 the stage was set to test the gold catalyzed allene formation. On treatment with complex 26 (10 mol %)42 in CH2Cl2 at reflux temperature, a slow but clean formation of a single allene isomer 22 (δC = 209 ppm) was observed by NMR. Rather than trying to assign its stereostructure by spectroscopic means, global deprotection and comparison of the resulting product with archangiumide seemed to provide a faster and more conclusive answer, since the stereostructure of 1 had been unambiguously established by X-ray diffraction.3 Unfortunately, however, all our attempts to cleave the three silyl ethers in 22 resulted in rapid decomposition.43

We assumed that the increase in ring strain upon endocyclic allene formation might render this compound so sensitive. This notion was supported by the fact that the reverse order of events ultimately proved successful. Thus, cycloalkyne 21 was first treated with excess TBAF in THF; the resulting triol 23 was then exposed to 26 under the conditions described above to furnish an allene product and an equivalent of p-methoxybenzaldehyde as judged by 1H NMR. After purification of the crude material by flash chromatography, the spectral and analytical data of the synthetic sample matched those of archangiumide (1) in all respects.3 The goal was reached in 13 steps (longest linear sequence) with an overall yield of ≈3.8%; no indications argue against scale-up of the endgame, if deemed necessary.

The conceptual implications of performing the gold catalyzed reaction as the ultimate step of the entire sequence deserve comment. Since the chosen protecting group serves as a latent hydride source needed to unveil the signature cycloallene substructure of the target, the final ether cleavage gains a strategic role. The fact that the longest linear sequence was terminated by the actual key step, which followed only after an otherwise global deprotection, is highly uncommon in natural product synthesis;44 this unorthodox orchestration arguably marks an underappreciated opportunity provided by π-acid catalysis.

The exclusive formation of 1 from 23 seems to imply strict chirality transfer in the gold catalyzed step, but this conclusion could be premature. Therefore, 11-epi-20 was assembled by following the same route but using the antipodal sulfone fragment ent-11 (for details, see the Supporting Information). Once again, RCAM proceeded cleanly with the aid of the new pyridine adduct 25.28 Cleavage of the silyl groups off the resulting cycloalkyne 11-epi-21 followed by the gold catalyzed deprotective allene formation also furnished a single discrete product, although in lower yield and after a longer reaction time. Somewhat surprisingly, the recorded data once again perfectly matched those of archangiumide (1)3 and were identical to those of the sample derived from 21.

This perplexing stereoconvergence compelled us to subject the acyclic substrate 27 (96% ee), derived from one of intermediates passed through during the preparation of the sulfone building block, to the same reaction conditions (Scheme 4). In this case, the resulting allene 28 was racemic, which shows that the gold catalyzed reaction per se is stereoablative and does not transmit stereochemical information from the propargyl benzyl ether center to the incipient chiral axis of the resulting allene. The fact that archangiumide (1) was obtained as a single diastereomer, independent of whether 23 or 11-epi-23 was used as the substrate, is therefore attributed to thermodynamic control;45 it is the macrobicyclic framework decorated with six stereogenic centers and two E-alkenes that determines the stereochemical course.46 This conclusion may even bear implications for the biosynthesis of the natural product.47

Scheme 4. Control Experiment.

Scheme 4

Open in a new tab

Acknowledgments

Generous financial support by the Max-Planck-Society is gratefully acknowledged. We thank C. Wirtz for help with numerous NMR analyses, S. Klimmek and R. Leichtweiß for excellent HPLC service (all at MPI), and all analytical departments of our Institute for expert support.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c13304.

  • Experimental section including characterization data and NMR spectra of new compounds (PDF)

Open access funded by Max Planck Society.

The authors declare no competing financial interest.

Supplementary Material

ja3c13304_si_001.pdf (8.3MB, pdf)

References

  1. Hoffmann-Röder A.; Krause N. Synthesis and Properties of Allenic Natural Products and Pharmaceuticals. Angew. Chem., Int. Ed. 2004, 43, 1196–1216. 10.1002/anie.200300628. [DOI] [PubMed] [Google Scholar]
  2. This assignment was initially made with some reservation but later reiterated by the same group, see:; a Bohlmann F.; Gupta R. K.; Jakupovic J.; King R. M.; Robinson H. Natürlich vorkommende Terpen-Derivate, 292. Über das erste Sesquiterpenlacton mit einer Allengruppe aus Vernonia cotoneaster. Liebigs Ann. Chem. 1980, 1980, 1904–1906. 10.1002/jlac.198019801127. [DOI] [Google Scholar]; b Bohlmann F.; Jakupovic J.; Gupta R. K.; King R. M.; Robinson H. Allenic germacranolides, bourbonene derived lactones and other constituents from Vernonia species. Phytochemistry 1981, 20, 473–480. 10.1016/S0031-9422(00)84169-2. [DOI] [Google Scholar]; c Jakupovic J.; Schmeda-Hirschmann G.; Schuster A.; Zdero C.; Bohlmann F.; King R. M.; Robinson H.; Pickardt J. Hirsutinolides, glaucolides and sesquiterpene lactone from Vernonia species. Phytochemistry 1985, 25, 145–158. 10.1016/S0031-9422(00)94520-5. [DOI] [Google Scholar]
  3. Hu J.-Q.; Wang J.-J.; Li Y.-L.; Zhuo L.; Zhang A.; Sui H.-Y.; Li X.-J.; Shen T.; Yin Y.; Wu Z.-H.; Hu W.; Li Y.-Z.; Wu C. Combining NMR-Based Metabolic Profiling and Genome Mining for the Accelerated Discovery of Archangiumide, an Allenic Macrolide from the Myxobacterium Archangium violaceum SDU8. Org. Lett. 2021, 23, 2114–2119. 10.1021/acs.orglett.1c00265. [DOI] [PubMed] [Google Scholar]
  4. For representative examples of synthetic yet natural product-derived allenic macrolides, see:; a Liu K.; Kim H.; Ghosh P.; Akhmedov N. G.; Williams L. J. Direct Entry to Erythronolides via a Cyclic Bis[Allene]. J. Am. Chem. Soc. 2011, 133, 14968–14971. 10.1021/ja207496p. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Ghosh P.; Zhang Y.; Emge T. J.; Williams L. J. Modeling a Macrocyclic Bis[spirodiepoxide] Strategy to Erythronolide. A. Org. Lett. 2009, 11, 4402–4405. 10.1021/ol901755a. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Yu L.; Wang H.; Akhmedov N.; Williams L. J. Glycosylation of an allenic erythronolide. J. Antibiot. 2019, 72, 432–436. 10.1038/s41429-019-0156-1. [DOI] [PubMed] [Google Scholar]
  5. Yu S.; Ma S. Allenes in Catalytic Asymmetric Synthesis and Natural Product Syntheses. Angew. Chem., Int. Ed. 2012, 51, 3074–3112. 10.1002/anie.201101460. [DOI] [PubMed] [Google Scholar]
  6. Strain release from macrocyclic allenes has occasionally been used as driving force to access demanding product scaffolds. For a classical example, see:; Marshall J. A.; Sehon C. A. Total Synthesis of the Enantiomer of the Furanocembrane Rubifolide. J. Org. Chem. 1997, 62, 4313–4320. 10.1021/jo970360d. [DOI] [PubMed] [Google Scholar]
  7. For general reviews on advances in polyketide total synthesis, see the following and literature cited therein:; a Sperandio C.; Rodriguez J.; Quintard A. Catalytic strategies towards 1,3-polyol synthesis by enantioselective cascades creating multiple alcohol functions. Org. Biomol. Chem. 2020, 18, 1025–1035. 10.1039/C9OB02675D. [DOI] [PubMed] [Google Scholar]; b Friedrich R. M.; Friestad G. K. Inspirations from tetrafibricin and related polyketides: new methods and strategies for 1,5-polyol synthesis. Nat. Prod. Rep. 2020, 37, 1229–1261. 10.1039/C9NP00070D. [DOI] [PubMed] [Google Scholar]; c Liu H.; Lin S.; Jacobsen K. M.; Poulsen T. B. Chemical Syntheses and Chemical Biology of Carboxyl Polyether Ionophores: Recent Highlights. Angew. Chem., Int. Ed. 2019, 58, 13630–13642. 10.1002/anie.201812982. [DOI] [PubMed] [Google Scholar]; d Feng J.; Kasun Z. A.; Krische M. J. Enantioselective Alcohol C–H Functionalization for Polyketide Construction: Unlocking Redox-Economy and Site-Selectivity for Ideal Chemical Synthesis. J. Am. Chem. Soc. 2016, 138, 5467–5478. 10.1021/jacs.6b02019. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Dechert-Schmitt A.-M. R.; Schmitt D. C.; Gao X.; Itoh T.; Krische M. J. Polyketide construction via hydrohydroxyalkylation and related alcohol C–H functionalizations: reinventing the chemistry of carbonyl addition. Nat. Prod. Rep. 2014, 31, 504–513. 10.1039/c3np70076c. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Koskinen A. M. P.; Karisalmi K. Polyketide stereotetrads in natural products. Chem. Soc. Rev. 2005, 34, 677–690. 10.1039/b417466f. [DOI] [PubMed] [Google Scholar]
  8. Bolte B.; Odabachian Y.; Gagosz F. Gold(I)-Catalyzed Rearrangement of Propargyl Benzyl Ethers: A Practical Method for the Generation and in Situ Transformation of Substituted Allenes. J. Am. Chem. Soc. 2010, 132, 7294–7296. 10.1021/ja1020469. [DOI] [PubMed] [Google Scholar]
  9. Gorin D. J.; Toste F. D. Relativistic effects in homogeneous gold catalysis. Nature 2007, 446, 395. 10.1038/nature05592. [DOI] [PubMed] [Google Scholar]
  10. Fürstner A.; Davies P. W. Catalytic Carbophilic Activation: Catalysis by Platinum and Gold π-Acids. Angew. Chem., Int. Ed. 2007, 46, 3410–3449. 10.1002/anie.200604335. [DOI] [PubMed] [Google Scholar]
  11. Pflästerer D.; Hashmi A. S. K. Gold catalysis in total synthesis – recent achievements. Chem. Soc. Rev. 2016, 45, 1331–1367. 10.1039/C5CS00721F. [DOI] [PubMed] [Google Scholar]
  12. Zhang Y.; Luo T.; Yang Z. Strategic innovation in the total synthesis of complex natural products using gold catalysis. Nat. Prod. Rep. 2014, 31, 489–503. 10.1039/C3NP70075E. [DOI] [PubMed] [Google Scholar]
  13. Toullec P. Y.; Michelet V. Gold-Catalyzed Polycyclization Toward Natural Products Synthesis. Isr. J. Chem. 2018, 58, 578–585. 10.1002/ijch.201800002. [DOI] [Google Scholar]
  14. a Fürstner A. From Understanding to Prediction: Gold- and Platinum-Based π-Acid Catalysis for Target Oriented Synthesis. Acc. Chem. Res. 2014, 47 (3), 925–938. 10.1021/ar4001789. [DOI] [PubMed] [Google Scholar]; b Fürstner A. Gold and platinum catalysis—a convenient tool for generating molecular complexity. Chem. Soc. Rev. 2009, 38, 3208–3221. 10.1039/b816696j. [DOI] [PubMed] [Google Scholar]
  15. For natural product syntheses from our laboratory that illustrate this aspect, see:; a Chaladaj W.; Corbet M.; Fürstner A. Total Synthesis of Neurymenolide A Based on a Gold-Catalyzed Synthesis of 4-Hydroxy-2-pyrones. Angew. Chem., Int. Ed. 2012, 51, 6929–6933. 10.1002/anie.201203180. [DOI] [PubMed] [Google Scholar]; b Hoffmeister L.; Fukuda T.; Pototschnig G.; Fürstner A. Total Synthesis of an Exceptional Brominated 4-Pyrone Derivative of Algal Origin: An Exercise in Gold Catalysis and Alkyne Metathesis. Chem. - Eur. J. 2015, 21, 4529–4533. 10.1002/chem.201500437. [DOI] [PubMed] [Google Scholar]; c Benson S.; Collin M.-P.; Arlt A.; Gabor B.; Goddard R.; Fürstner A. Second-Generation Total Synthesis of Spirastrellolide F Methyl Ester: The Alkyne Route. Angew. Chem., Int. Ed. 2011, 50, 8739–8744. 10.1002/anie.201103270. [DOI] [PubMed] [Google Scholar]; d Brewitz L.; Llaveria J.; Yada A.; Fürstner A. Formal Total Synthesis of the Algal Toxin (−)-Polycavernoside. A. Chem. Eur. J. 2013, 19, 4532–4537. 10.1002/chem.201204551. [DOI] [PubMed] [Google Scholar]; e Preindl J.; Schulthoff S.; Wirtz C.; Lingnau J.; Fürstner A. Polyunsaturated C-Glycosidic 4-Hydroxy-2-Pyrone Derivatives: Total Synthesis Shows that Putative Orevactaene is Likely Identical with Epipyrone A. Angew. Chem., Int. Ed. 2017, 56, 7525–7530. 10.1002/anie.201702189. [DOI] [PubMed] [Google Scholar]; f Fürstner A. Gold Catalysis for Heterocyclic Chemistry: A Representative Case Study on Pyrone Natural Products. Angew. Chem., Int. Ed. 2018, 57, 4215–4233. 10.1002/anie.201707260. [DOI] [PubMed] [Google Scholar]
  16. Boreux A.; Lonca G. H.; Riant O.; Gagosz F. Synthesis of Trifluoromethyl-allenes by Gold-Catalyzed Rearrangement of Propargyl Benzyl Ethers. Org. Lett. 2016, 18, 5162–5165. 10.1021/acs.orglett.6b02636. [DOI] [PubMed] [Google Scholar]
  17. For an application to a nonstereogenic allene target, see:Tsukano C.; Yagita R.; Heike T.; Mohammed T. A.; Nishibayashi K.; Irie K.; Takemoto Y. Asymmetric Total Synthesis of Shagenes A and B. Angew. Chem., Int. Ed. 2021, 60, 23106–23111. 10.1002/anie.202109786. [DOI] [PubMed] [Google Scholar]
  18. a Harris R. J.; Nakafuku K.; Widenhoefer R. A. Kinetics and Mechanism of the Racemization of Aryl Allenes Catalyzed by Cationic Gold(I) Phosphine Complexes. Chem.—Eur. J. 2014, 20, 12245–12254. 10.1002/chem.201402729. [DOI] [PubMed] [Google Scholar]; b Wang Y.-M.; Kuzniewski C. N.; Rauniyar V.; Hoong C.; Toste F. D. Chiral (Acyclic Diaminocarbene)Gold(I)-Catalyzed Dynamic Kinetic Asymmetric Transformation of Propargyl Esters. J. Am. Chem. Soc. 2011, 133, 12972–12975. 10.1021/ja205068j. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Lo V. K.-Y.; Zhou C.-Y.; Wong M.-K.; Che C.-M. Silver(I)-mediated highly enantioselective synthesis of axially chiral allenes under thermal and microwave-assisted conditions. Chem. Commun. 2010, 46, 213–215. 10.1039/B914516H. [DOI] [PubMed] [Google Scholar]
  19. For pertinent examples, see:; a Lo V. K.-Y.; Wong M.-K.; Che C.-M. Gold-Catalyzed Highly Enantioselective Synthesis of Axially Chiral Allenes. Org. Lett. 2008, 10, 517–519. 10.1021/ol702970r. [DOI] [PubMed] [Google Scholar]; b Sherry B. D.; Toste F. D. Gold(I)-Catalyzed Propargyl Claisen Rearrangement. J. Am. Chem. Soc. 2004, 126, 15978–15979. 10.1021/ja044602k. [DOI] [PubMed] [Google Scholar]
  20. For an example, see:Ahlers A.; de Haro T.; Gabor B.; Fürstner A. Concise Total Synthesis of Enigmazole A. Angew. Chem., Int. Ed. 2016, 55, 1406–1411. 10.1002/anie.201510026. [DOI] [PubMed] [Google Scholar]
  21. Lee J. H.; Toste F. D. Gold(I)-Catalyzed Synthesis of Functionalized Cyclopentadienes. Angew. Chem., Int. Ed. 2007, 46, 912–914. 10.1002/anie.200604006. [DOI] [PubMed] [Google Scholar]
  22. Fürstner A. The Ascent of Alkyne Metathesis to Strategy-Level Status. J. Am. Chem. Soc. 2021, 143, 15538–15555. 10.1021/jacs.1c08040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lee D.; Volchkov I.; Yun S. Y. Alkyne Metathesis. Org. React. 2020, 102, 613–931. 10.1002/0471264180.or102.02. [DOI] [Google Scholar]
  24. Fürstner A. Alkyne Metathesis on the Rise. Angew. Chem., Int. Ed. 2013, 52, 2794–2819. 10.1002/anie.201204513. [DOI] [PubMed] [Google Scholar]
  25. Heppekausen J.; Stade R.; Goddard R.; Fürstner A. Practical New Silyloxy-Based Alkyne Metathesis Catalysts with Optimized Activity and Selectivity Profiles. J. Am. Chem. Soc. 2010, 132, 11045–11057. 10.1021/ja104800w. [DOI] [PubMed] [Google Scholar]
  26. Hillenbrand J.; Leutzsch M.; Fürstner A. Molybdenum Alkylidyne Complexes with Tripodal Silanolate Ligands. The Next Generation of Alkyne Metathesis Catalysts. Angew. Chem., Int. Ed. 2019, 58, 15690–15696. 10.1002/anie.201908571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hillenbrand J.; Leutzsch M.; Yiannakas E.; Gordon C. P.; Wille C.; Nöthling N.; Copéret C.; Fürstner A. Canopy Catalysts” for Alkyne Metathesis: Molybdenum Alkylidyne Complexes with a Tripodal Ligand Framework. J. Am. Chem. Soc. 2020, 142, 11279–11294. 10.1021/jacs.0c04742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Korber J. N.; Wille C.; Leutzsch M.; Fürstner A. From the Glovebox to the Benchtop: Air-Stable High Performance Molybdenum Alkylidyne Catalysts for Alkyne Metathesis. J. Am. Chem. Soc. 2023, 145, 26993–27009. 10.1021/jacs.3c10430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. For instructive cases that illustrate this aspect, see inter alia:; a Hickmann V.; Kondoh A.; Gabor B.; Alcarazo M.; Fürstner A. Catalysis-based and Protecting-Group-free Total Syntheses of the Marine Oxylipins Hybridalactone and the Ecklonialactones A, B, and C. J. Am. Chem. Soc. 2011, 133, 13471–13480. 10.1021/ja204027a. [DOI] [PubMed] [Google Scholar]; b Micoine K.; Fürstner A. Concise Total Synthesis of the Potent Translation and Cell Migration Inhibitor Lactimidomycin. J. Am. Chem. Soc. 2010, 132, 14064–14066. 10.1021/ja107141p. [DOI] [PubMed] [Google Scholar]; c Mailhol D.; Willwacher J.; Kausch-Busies N.; Rubitski E. E.; Sobol Z.; Schuler M.; Lam M.-H.; Musto S.; Loganzo F.; Maderna A.; Fürstner A. Synthesis, Molecular Editing, and Biological Assessment of the Potent Cytotoxin Leiodermatolide. J. Am. Chem. Soc. 2014, 136, 15719–15729. 10.1021/ja508846g. [DOI] [PubMed] [Google Scholar]; d Karier P.; Ungeheuer F.; Ahlers A.; Anderl F.; Wille C.; Fürstner A. Metathesis at an Implausible Site: A Formal Total Synthesis of Rhizoxin D. Angew. Chem., Int. Ed. 2019, 58, 248–253. 10.1002/anie.201812096. [DOI] [PubMed] [Google Scholar]
  30. Long D. D.; Smith M. D.; Martín A.; Wheatley J. R.; Watkin D. G.; Müller M.; Fleet G. W. J. Complex tetrahydrofurans from carbohydrate lactones: THF amino acids as building blocks for unnatural biopolymers. J. Chem. Soc., Perkin Trans. 2002, 1, 1982–1998. 10.1039/B111258A. [DOI] [Google Scholar]
  31. Chabala J. C.; Vincent J. E. The preparation of α,β-acetylenic ketones by condensation of lithium acetylides with lactones. Tetrahedron Lett. 1978, 19, 937–940. 10.1016/S0040-4039(01)85419-8. [DOI] [Google Scholar]
  32. Matsumura K.; Hashiguchi S.; Ikariya T.; Noyori R. Asymmetric Transfer Hydrogenation of α,β-Acetylenic Ketones. J. Am. Chem. Soc. 1997, 119, 8738–8739. 10.1021/ja971570a. [DOI] [Google Scholar]
  33. Chatterjee S.; Acharyya R. K.; Pal P.; Nanda S. Synthetic studies towards naturally occurring γ-(Z)/(E)-alkylidenebutenolides through bimetallic cascade cyclization and an adventitious photoisomerization method. Org. Biomol. Chem. 2022, 20, 2473–2499. 10.1039/D2OB00166G. [DOI] [PubMed] [Google Scholar]
  34. Alfaro R.; Parra A.; Alemán J.; García Ruano J. L.; Tortosa M. Copper(I)-Catalyzed Formal Carboboration of Alkynes: Synthesis of Tri- and Tetrasubstituted Vinylboronates. J. Am. Chem. Soc. 2012, 134, 15165–15168. 10.1021/ja307670k. [DOI] [PubMed] [Google Scholar]
  35. For an application in natural product synthesis, see:Jeanne-Julien L.; Masson G.; Astier E.; Genta-Jouve G.; Servajean V.; Beau J.-M.; Norsikian S.; Roulland E. Synthesis of a Tiacumicin B Protected Aglycone. Org. Lett. 2017, 19, 4006–4009. 10.1021/acs.orglett.7b01744. [DOI] [PubMed] [Google Scholar]
  36. Chinchilla R.; Najera C. Recent Advances in Sonogashira Reactions. Chem. Soc. Rev. 2011, 40, 5084–5121. 10.1039/c1cs15071e. [DOI] [PubMed] [Google Scholar]
  37. Aïssa C. Mechanistic Manifold and New Developments of the Julia–Kocienski Reaction. Eur. J. Org. Chem. 2009, 2009, 1831–1844. 10.1002/ejoc.200801117. [DOI] [Google Scholar]
  38. Inanaga J.; Hirata K.; Saeki H.; Katsuki T.; Yamaguchi M. A Rapid Esterification by Means of Mixed Anhydride and Its Application to Large-ring Lactonization. Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993. 10.1246/bcsj.52.1989. [DOI] [Google Scholar]
  39. For the so far most advanced applications of catalysts of this type, see ref (40) and the following:Tang J.; Li W.; Chiu T.-Y.; Martínez-Peña F.; Luo Z.; Chong C. T.; Wei Q.; Gazaniga N.; West T. J.; See Y. Y.; Lairson L. L.; Parker C. G.; Baran P. S. Synthesis of portimines reveals the basis of their anti-cancer activity. Nature 2023, 622, 507–513. 10.1038/s41586-023-06535-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. a Varlet T.; Portmann S.; Fürstner A. Total Synthesis of Njaoamine C by Concurrent Macrocycle Formation. J. Am. Chem. Soc. 2023, 145, 21197–21202. 10.1021/jacs.3c08410. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Meng Z.; Spohr S. M.; Tobegen S.; Farès C.; Fürstner A. A Unified Approach to Polycyclic Alkaloids of the Ingenamine Estate: Total Syntheses of Keramaphidin B, Ingenamine, and Nominal Njaoamine I. J. Am. Chem. Soc. 2021, 143, 14402–14414. 10.1021/jacs.1c07955. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Dalling A. G.; Späth G.; Fürstner A. Total Synthesis of the Tetracyclic Pyridinium Alkaloid epi-Tetradehydrohalicyclamine B. Angew. Chem., Int. Ed. 2022, 61, e202209651 10.1002/anie.202209651. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Yiannakas E.; Grimes M.; Whitelegge J.; Fürstner A.; Hulme A. N. An Alkyne Metathesis Based Approach to the Synthesis of the Anti-malarial Macrodiolide Samroiyotmycin A. Angew. Chem., Int. Ed. 2021, 60, 18504–18508. 10.1002/anie.202105732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. At the stage of the cycloalkyne, the minor geometric isomer derived from the Z-alkene formed in the Kocienski olefination is easily removed by flash chromatography, see the Supporting Information.
  42. Nieto-Oberhuber C.; López S.; Echavarren A. M. Intramolecular [4 + 2] Cycloadditions of 1,3-Enynes or Arylalkynes with Alkenes with Highly Reactive Cationic Phosphine Au(I) Complexes. J. Am. Chem. Soc. 2005, 127, 6178–6179. 10.1021/ja042257t. [DOI] [PubMed] [Google Scholar]
  43. The following reagents were tested: HF·pyridine in THF (with and without additional pyridine added to the mixture); TBAF in THF (with and without added HOAc (1%, v/v)); HCl (1%) in MeOH); aq. HF.
  44. For pertinent examples in which a key step terminates the longest linear sequence, see the following for leading references:; a Nicolaou K. C.; Chakraborty T. K.; Piscopio A. D.; Minowa N.; Bertinato P. Total synthesis of rapamycin. J. Am. Chem. Soc. 1993, 115, 4419–4420. 10.1021/ja00063a093. [DOI] [Google Scholar]; b Shin I.; Hong S.; Krische M. J. Total Synthesis of Swinholide A: An Exposition in Hydrogen-Mediated C–C Bond Formation. J. Am. Chem. Soc. 2016, 138, 14246–14249. 10.1021/jacs.6b10645. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Zhang Y.-A.; Yaw N.; Snyder S. A. General Synthetic Approach for the Laurencia Family of Natural Products Empowered by a Potentially Biomimetic Ring Expansion. J. Am. Chem. Soc. 2019, 141, 7776–7788. 10.1021/jacs.9b01088. [DOI] [PubMed] [Google Scholar]
  45. The course of the reaction was also followed by NMR; only one allene product was detectable even at incomplete conversion. This observation suggests that either the diasteromeric cycloallene is never formed or its isomerization is considerably faster than its formation, such that it will not accumulate in the mixture.
  46. Fürstner A. Lessons from Natural Product Total Synthesis: Macrocyclization and Postcyclization Strategies. Acc. Chem. Res. 2021, 54, 861–874. 10.1021/acs.accounts.0c00759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. It was proposed in ref (3) that allene formation precedes macrocyclization. If so, and under the proviso that the epimeric allene is not an as yet undiscovered discrete natural product, three scenarios can be envisaged: (1) the cyclization precursor contains the allene with the correct configuration; (2) both allene isomers are formed but only one can undergo ring closure because of the conformational constraints of the emerging macrocycle; (3) macrocyclization is accompanied by allene isomerization to convert a mixture of diastereomeric substrates into a single natural product.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ja3c13304_si_001.pdf (8.3MB, pdf)

Articles from Journal of the American Chemical Society are provided here courtesy of American Chemical Society

RESOURCES