Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2023 Sep 21;145(39):21197–21202. doi: 10.1021/jacs.3c08410

Total Synthesis of Njaoamine C by Concurrent Macrocycle Formation

Thomas Varlet 1, Sören Portmann 1, Alois Fürstner 1,*
PMCID: PMC10557140  PMID: 37734001

Abstract

graphic file with name ja3c08410_0006.jpg

In conceptual terms, the first total synthesis of the cytotoxic marine natural product njaoamine C differs from all known approaches toward related alkaloids of the manzamine superfamily in that both macrocyclic rings enveloping the diazatricyclic core are concomitantly formed; this goal was reached by double ring closing alkyne metathesis (dRCAM). The success of this maneuver does not merely reflect a favorable preorientation of the four alkyne chains that need to be concatenated in the proper pairwise manner but is also the outcome of dynamic covalent chemistry involving error correction by the chosen “canopy” molybdenum alkylidyne catalyst. The end game downstream of dRCAM capitalizes on the striking chemoselectivity of palladium-catalyzed hydrostannation, which selects for (hetero)arylalkynes even in the presence of sterically much more accessible dialkylalkynes or alkenes; for this preference, the method complements the classical repertoire of hydrometalation and semireduction reactions.

The final attempt made by Baldwin and co-workers to emulate the proposed biosynthesis of keramaphidin B (rac-1) as the parent member of the manzamine alkaloid estate1−3 consisted of an intermolecular hetero-Diels–Alder reaction of the dihydropyridinium salt 4 to access tetraene 5, which was then exposed to Grubbs catalyst 9 in the hope of enforcing the formation of both enveloping macrocycles in one pot (Scheme 1).4 This venturous plan was met with little success in that no more than 1–2% of 1 was obtained together with 10–20% of the monocyclized compound 6, even though the ring closing metathesis (RCM) reaction was performed under very high dilution.4 The corresponding bis-hydrochloride salt 5·2HCl was also tested to rule out that catalyst deactivation by the free amines was liable, but the yield of 1 was even lower in this case. Attempts to close the missing 13-membered ring by resubjecting 6 (or a derived salt) to 9 or 10 were to no avail either, resulting mainly in decomposition of the substrate.4

Scheme 1. Prior Art (Top) and Retrosynthetic Analysis of Njaoamine C (Bottom).

Scheme 1

Open in a new tab

Prompted by this poor outcome, we had deliberately based our initial foray toward this family of polycyclic marine alkaloids on a strategy involving two consecutive macrocyclization events. In the end, different variants of this blueprint turned out to be successful, allowing us to reach keramaphidin B ((+)-1), ingenamine A, nominal and actual xestocyclamine A, epi-tetrahydrohalicyclamine B, and nominal njaoamine I ((+)-2)5 (the structure of this natural product was found to be wrong and had to be corrected during our endeavor).6−8 Somewhat surprisingly, even sequences involving two consecutive metathesis events proved viable and high yielding (ring closing alkyne metathesis (RCAM)/RCM or RCAM/RCAM).7 The fact that no ene/yne or yne/yne crossover was observed in these cases piqued our curiosity and led us to reconsider the possibility of concurrent formation of both signature macrocycles.9,10 Indeed, tetra-yne 7 afforded product 8 in 35% yield when treated with an alkyne metathesis catalyst generated in situ from 11 and 12, despite the presence of two basic sites in 7 that might quench the activity of the high-valent molybdenum alkylidyne.7,11 If one considers that the cores of tetra-ene 5 and tetra-yne 7 feature, in geometric terms, the same 1,4-etheno-bridged 2,7-diazadecaline scaffold, this outcome represents a significant advance over the Baldwin precedent,4 even though a substantial amount (ca. 17%) of a second isomer of unknown constitution was also formed.7 The price to pay was the high catalyst loading (60 mol %), which caused problems during product isolation. In the end, however, this lead finding was not pursued any further, as we saw at the time no good way to elaborate 8 into nominal njaoamine I (2), which would mandate selective semireduction of the sterically very hindered and deactivated C31–C32 triple bond flanking the quinoline while keeping the exposed C38–C39 alkyne inscribed into the 17-membered ring intact.7

This selectivity issue downstream of the double ring closing alkyne metathesis (dRCAM) event might vanish if one were to chase the sister compound njaoamine C (3) comprising a smaller A-ring, which is an equipotent cytotoxic agent of unknown absolute configuration derived from a Reniera sponge collected off the Tanzania coastline.12 In this case, 2-fold Lindlar-type reduction13 of a diyne of type A formed by dRCAM from tetrayne B should pave the way to this unconquered bioactive target of considerable architectural splendor. For this tantalizing outlook, it seemed worthwhile to study the projected dRCAM in more detail, in the hope of improving its efficiency by suppressing isomer formation and optimizing the catalyst loading.14−16 The latter goal, however, is arguably nontrivial because njaoamine C (3) comprises a hydroxyquinoline ring (instead of the ordinary quinoline in 2), which is a powerful chelating ligand for most transition metal reagents and catalysts. As outlined below, we ultimately managed to meet these criteria and were able to complete the first total synthesis of (−)-3; as a gratifying spin-off, even a practical solution was found for the chemoselectivity issue that had previously compelled us not to pursue the dRCAM strategy en route to nominal njaoamine I (2).

For the assembly of an appropriate tetra-yne substrate for the envisaged dRCAM strategy, it sufficed to adapt the blueprint underlying our previous studies (Scheme 2). Specifically, compounds 14 and 16 were prepared on a multigram scale from commercial 13 and 15, respectively, by minor adaptation of the published procedures (for details, see the Supporting Information).7 When treated with tBuOLi in tetrahydrofuran (THF) at low temperature, these building blocks engage in an exquisitely selective Michael/Michael reaction cascade to afford the tricyclic product 17 in 66% yield on a gram scale after reintroduction of the −NBoc group prior to workup; it is the C23-OTBS group (njaoamine numbering) in 16 that relays stereochemical information onto the five newly formed chiral centers. The elaboration of 17 to 19 also followed our prior work;7 as expected, it proved straightforward, high yielding, and scalable. The C23-OH group, which had been quintessential for the assembly process, was then removed by conversion into a chloromethylsulfonate followed by base-induced elimination;17,18 the resulting cyclic enamide 20 was best reduced with NaBH3CN in neat formic acid to give 21 in high overall yield.19,20

Scheme 2. Diazatricyclic Core.

Scheme 2

Open in a new tab

The scales shown in this and the following schemes refer to the single largest batch.

We had originally planned to access the required hydroxyquinoline building block by regioselective C–H borylation/oxidation of the quinoline fragment 22 previously used en route to njaoamine I.7 This shortcut had been inspired by a literature report describing iridium-catalyzed C8-selective C–H borylations of quinolines with the aid of a silica-supported phosphine ligand.21 When applied to 22, however, alcohol 23 formed by reduction of the ketone was the only discernible product in the crude mixture (Scheme 3).22 Therefore we pursued a de novo synthesis starting from commercial 7-benzyloxyindole 24. This compound was readily elaborated into the tryptamine derivative 26 without the need to purify any intermediate compound by flash chromatography.23 Oxidative ring cleavage with NaIO4 followed by N-deformylation with HCl/MeOH afforded 27, which reacted with 28 in a Dieckmann-type condensation to give hydroxyquinoline 29 in good yield.24 The derived triflate 30(25) was cross coupled with the alkylborane generated from alkene 31 and 9-H-9-BBN; while optimizing this step, NaOAc was identified as a particularly effective (though apparently underutilized) promoter for the alkyl-Suzuki–Miyaura reaction.26 The benzyl ether in 32 inherited from the commercial substrate had to be swapped for a Boc-group27 prior to installation of the nonterminal alkyne, which was accomplished in almost quantitative yield by enol triflate formation/elimination at low temperature.28 Routine protecting group management followed by oxidation of the primary alcohol then furnished aldehyde 34 in readiness for attachment to the core.29

Scheme 3. Hydroxyquinoline Segment.

Scheme 3

Open in a new tab

The methyl carbamate of 21 was then cleaved off with L-Selectride, and the resulting amine subjected to reductive amination with 34 to give tetra-yne 35 in well reproducible 58% yield (Scheme 4).30 With copious material in hand, the stage was set for the decisive dRCAM step. Rather than employing the two-component system 11/12,11 we resorted to the “canopy catalyst” series for alkyne metathesis, as they are structurally well-defined entities of exquisite performance for reasons that are well understood by now.31−36 Complex 40a as the lead member combines high reactivity with a remarkable tolerance toward functional groups, including numerous basic sites.31,37 Indeed, 40a converted tetra-yne 35 by dRCAM into diyne 36 as the only detectable product (1H NMR) in ≤1 h of reaction time. After brief optimization, we settled on the use of 20 mol % of 40a in toluene (2 mM) at 60 °C38 in the presence of MS 5 Å as a 2-butyne sequestering agent;39,40 under these conditions, 36 was isolated in 91% yield. Prior to workup, however, one must make sure that the catalyst is completely removed by filtration through a plug of silica; otherwise, the product (partly) decomposes upon evaporation of the solvent. Cycloalkyne formation is hence reversible, and ring opening is obviously so facile that it can ruin the outcome.

Scheme 4. Completion of the Total Synthesis.

Scheme 4

Open in a new tab

Interestingly, the use of 40a was mandatory; even the only slightly more encumbered sibling 40b(41) proved much less adequate in that it furnished a mixture, of which the desired product 36 is only a minor constituent (≈ 10%). LC-MS and 1H NMR indicate the presence of several monomeric compounds with only one macrocycle closed; other components are dimeric in nature (for details, see the Supporting Information). Details apart, this product distribution implies that tetra-yne 35 does not transform straight away into 36; rather, it is first engaged in more random inter- as well as intramolecular alkyne metathesis reactions. Because of the lower activity of 40b, the initial product distribution does not evolve much with time, whereas 40a is capable of reopening cycloalkynes once formed and also likely able to cleave dimeric species. Indeed, when 40a (30 mol %) was added to the mixture, the desired product 36 accumulated and could be isolated in 58% yield.42 These observations imply that the selective formation of 36 is not solely reflecting a favorable geometric preorientation of the four alkyne side chains branching off the tricyclic core of 35, since other ways of connecting the termini are possible. For the successful formation of 36, dynamic covalent chemistry (DCC) must come into play,43 in that the catalyst corrects initial mistakes by scrambling of the mixture and hence gives the target compound the chance to accumulate. While DCC employing alkyne metathesis has gained prominence in material science,14,44 the current example is arguably the first advanced incarnation in the realm of natural product total synthesis.45

The ease of the dRCAM reaction stood in sharp contrast to the difficulties with the supposedly trivial semireduction of diyne 36.13 Despite considerable experimentation, we were incapable of reducing both triple bonds concomitantly to the corresponding Z-alkenes. The shielded C31–C32 alkyne invariably became reduced only after the exposed C35–C36 triple bond had been fully saturated to furnish product 37; otherwise, it remained untouched to give enyne 38. Confronted with this impasse, several alternative strategies were contemplated.46 In the end, we opted for metal-catalyzed hydrostannation, which is common for alkynes but infrequent for alkenes devoid of steering substituents.47,48 Indeed, only the shielded triple bond of 38 was engaged in a palladium-catalyzed hydrostannation, whereas the exposed olefin remained untouched. Although this chemoselectivity pattern is not unprecedented,48,49 the outcome is striking if one considers that palladium-catalyzed hydrogenation saturates the alkene before the alkyne starts to react. Compound 39 was formed essentially as a single alkenylstannane regioisomer.50 The amide group of 39 was reduced to the corresponding amine with Dibal-H in Et2O; under these conditions, the carbonate group was also cleaved off of the hydroxyquinoline, but the heterocyclic ring itself remained untouched. Subsequent treatment with HCl in 1,4-dioxane at 60 °C entailed concomitant protodestannation51 and cleavage of the second Boc group. The spectroscopic data of synthetic njaoamine C (−)-3 thus formed were in excellent agreement with those reported in the literature, but the [α]D is of opposite sign;12 our sample hence represents the enantiomer of the natural product (for details, see the Supporting Information).

The “reversed” chemoselectivity profile of the palladium-catalyzed hydrostannation manifested in the selective formation of 39 carries even further. An early literature report had shown that 4-octyne remained largely unchanged under conditions where PhC≡CMe reacted well.49,52 This somewhat hidden information on what seems to be differential reactivity of substantial measure worked in our favor (Scheme 5). Specifically, the remaining sample of tetra-yne 7 from our previous study on njaoamine I was resubjected to dRCAM with 40a (25 mol %) as the catalyst to furnish product 8 in a significantly improved yield of 59%.7 Gratifyingly, it was the shielded triple bond branching off the quinoline ring that had resisted all previous attempts at selective manipulation, which succumbed to palladium-catalyzed hydrostannation, whereas the exposed dialkylalkyne within the 17-membered ring remained unchanged. Subsequent protodestannation of 41 gave 42 in an unoptimized 30% yield, which potentially connects to njaoamine I (2) by amide reduction.53

Scheme 5. Route to Nominal Njaoamine I Revisited.

Scheme 5

Open in a new tab

These case studies allowed us to conclude that concomitant dRCAM is an emanation of dynamic covalent chemistry, which in turn is the fruit of ever more powerful alkyne metathesis catalysts; it constitutes a conceptually new strategy for the synthesis of polycyclic targets, even if of low overall symmetry. It gains its full potential when combined with chemoselective downstream functionalization reactions, which allow one or the other triple bond of a diyne to be addressed at will. Ongoing work in our group explores further possibilities along these lines.

Acknowledgments

Generous financial support by the Max-Planck Society is gratefully acknowledged. We thank Dr. C. Farès and S. Tobegen for help with numerous NMR analyses, and R. Leichtweiß and S. Klimmek for excellent HPLC service (all at MPI).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c08410.

  • Experimental Section including characterization data (PDF)

  • NMR spectra of new compounds (PDF)

Open access funded by Max Planck Society.

The authors declare no competing financial interest.

Supplementary Material

ja3c08410_si_001.pdf (2MB, pdf)
ja3c08410_si_002.pdf (16.5MB, pdf)

References

  1. Baldwin J. E.; Whitehead R. C. On the Biosynthesis of Manzamines. Tetrahedron Lett. 1992, 33, 2059–2062. 10.1016/0040-4039(92)88141-Q. [DOI] [Google Scholar]
  2. For an overview of the many synthetic approaches to alkaloids of this biosynthetic pedigree, see the following and literature cited therein:; Cheng B.; Reyes J. Recent Progress on the Total Syntheses of Macrocyclic Diamine Alkaloids. Nat. Prod. Rep. 2020, 37, 322–337. 10.1039/C9NP00031C. [DOI] [PubMed] [Google Scholar]
  3. For a recent study toward keramaphidin B, see:; Mehta M. M.; Gonzalez J. A. M.; Bachman J. L.; Garg N. K. Cyclic Allene Approach to the Manzamine Alkaloid Keramaphidin B. Org. Lett. 2023, 25, 5553. 10.1021/acs.orglett.3c01489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baldwin J. E.; Claridge T. D. W.; Culshaw A. J.; Heupel F. A.; Lee V.; Spring D. R.; Whitehead R. C. Studies on the Biomimetic Synthesis of the Manzamine Alkaloids. Chem. - Eur. J. 1999, 5, 3154–3161. . [DOI] [Google Scholar]
  5. For the isolation and initial structure assignment of njaoamine I, see:; Urda C.; Pérez M.; Rodríguez J.; Fernández R.; Jiménez C.; Cuevas C. Njaoamine I, a cytotoxic polycyclic alkaloid from the Haplosclerida sponge Haliclona (Reniera) sp. Tetrahedron Lett. 2018, 59 (26), 2577–2580. 10.1016/j.tetlet.2018.05.059. [DOI] [Google Scholar]
  6. Meng Z.; Fürstner A. Total Synthesis Provides Strong Evidence: Xestocyclamine A is the Enantiomer of Ingenamine. J. Am. Chem. Soc. 2020, 142 (27), 11703–11708. 10.1021/jacs.0c05347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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 (35), 14402–14414. 10.1021/jacs.1c07955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dalling A. G.; Späth G.; Fürstner A. Total Synthesis of the Tetracyclic Pyridinium Alkaloid epi-Tetradehydrohalicyclamine B. Angew. Chem., Int. Ed. 2022, 61 (41), e202209651 10.1002/anie.202209651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. For a related case, in which no ene/yne crossover was observed while closing the peripheral rings, see:; Toma T.; Kita Y.; Fukuyama T. Total Synthesis of (+)-Manzamine A. J. Am. Chem. Soc. 2010, 132 (30), 10233–10235. 10.1021/ja103721s. [DOI] [PubMed] [Google Scholar]
  10. Fürstner A. Lessons from Natural Product Total Synthesis: Macrocyclization and Postcyclization Strategies. Acc. Chem. Res. 2021, 54 (4), 861–874. 10.1021/acs.accounts.0c00759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. For the catalyst system, see:; Schaubach S.; Gebauer K.; Ungeheuer F.; Hoffmeister L.; Ilg M. K.; Wirtz C.; Fürstner A. A Two-Component Alkyne Metathesis Catalyst System with an Improved Substrate Scope and Functional Group Tolerance: Development and Applications to Natural Product Synthesis. Chem.—Eur. J. 2016, 22 (25), 8494–8507. 10.1002/chem.201601163. [DOI] [PubMed] [Google Scholar]
  12. Reyes F.; Fernández R.; Urda C.; Francesch A.; Bueno S.; de Eguilior C.; Cuevas C. Njaoamines A–F, new cytotoxic polycyclic alkaloids from the haplosclerid sponge Reniera sp. Tetrahedron 2007, 63 (11), 2432–2438. 10.1016/j.tet.2007.01.013. [DOI] [Google Scholar]
  13. Oger C.; Balas L.; Durand T.; Galano J.-M. Are Alkyne Reductions Chemo-, Regio-, and Stereoselective Enough To Provide Pure (Z)-Olefins in Polyfunctionalized Bioactive Molecules?. Chem. Rev. 2013, 113 (3), 1313–1350. 10.1021/cr3001753. [DOI] [PubMed] [Google Scholar]
  14. Fürstner A. The Ascent of Alkyne Metathesis to Strategy-Level Status. J. Am. Chem. Soc. 2021, 143 (38), 15538–15555. 10.1021/jacs.1c08040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fürstner A. Alkyne Metathesis on the Rise. Angew. Chem., Int. Ed. 2013, 52 (10), 2794–2819. 10.1002/anie.201204513. [DOI] [PubMed] [Google Scholar]
  16. Lee D.; Volchkov I.; Yun S. Y. Alkyne Metathesis. Org. React. 2020, 102, 613–931. 10.1002/0471264180.or102.02. [DOI] [Google Scholar]
  17. In our synthesis of nominal njaoamine I, we had used Martin sulfurane for the analogous elimination; in the present case, however, the product co-eluted with the Ph2SO resulting from this reagent, which made product isolation difficult.
  18. Shimizu T.; Ohzeki T.; Hiramoto K.; Hori N.; Nakata T. Chloromethanesulfonate as an Efficient Leaving Group: Rearrangement of the Carbon-Carbon Bond and Conversion of Alcohols into Azides and Nitriles. Synthesis 1999, 1999 (08), 1373–1385. 10.1055/s-1999-3541. [DOI] [Google Scholar]
  19. Previously, we used NaBH3CN in CH2Cl2 with TFA as promoter; the use of neat HCOOH, however, proved more robust and higher yielding.
  20. Ainscow R. B.; Brettle R.; Shibib S. M. The reduction of tertiary N-styrylenamides. J. Chem. Soc., Perkin Trans. 1 1985, 1781–1786. 10.1039/p19850001781. [DOI] [Google Scholar]
  21. Konishi S.; Kawamorita S.; Iwai T.; Steel P. G.; Marder T. B.; Sawamura M. Site-Selective C-H Borylation of Quinolines at the C8 Position Catalyzed by a Silica-Supported Phosphane–Iridium System. Chem. Asian J. 2014, 9 (2), 434–438. 10.1002/asia.201301423. [DOI] [PubMed] [Google Scholar]
  22. As expected, the classical catalyst system of [Ir(cod)(OMe)]2/4,4′-dtbpy resulted in selective borylation at the C6 position of the quinoline; for details see the Supporting Information. For the methodology, see:Mkhalid I. A. I.; Barnard J. H.; Marder T. B.; Murphy J. M.; Hartwig J. F. C–H Activation for the Construction of C–B Bonds. Chem. Rev. 2010, 110 (2), 890–931. 10.1021/cr900206p. [DOI] [PubMed] [Google Scholar]
  23. Ueda H.; Satoh H.; Matsumoto K.; Sugimoto K.; Fukuyama T.; Tokuyama H. Total Synthesis of (+)-Haplophytine. Angew. Chem., Int. Ed. 2009, 48 (41), 7600–7603. 10.1002/anie.200902192. [DOI] [PubMed] [Google Scholar]
  24. Sasakura K.; Sugasawa T. Simple Synthesis of Pyrrolo[3,4-c]-Quinoline-3-Ones and Pyrrolo[3,4-c]Quinoline-3,4-Diones. Synth. Commun. 1987, 17 (6), 741–753. 10.1080/00397918708075749. [DOI] [Google Scholar]
  25. The reaction required careful control to prevent competing formation of the enol triflate.
  26. Chemler S. R.; Trauner D.; Danishefsky S. J. The B-Alkyl Suzuki-Miyauria Cross-Coupling Reaction: Development, Mechanistic Studies, and Applications in Natural Product Synthesis. Angew. Chem., Int. Ed. 2001, 40, 4544–4568. . [DOI] [PubMed] [Google Scholar]
  27. The use of N-methylimidazole was instrumental in order to keep the ketone function intact; for precedent, see:; Basel Y.; Hassner A. Di-tert-butyl Dicarbonate and 4-(Dimethylamino)pyridine Revisited. Their Reactions with Amines and Alcohols1. J. Org. Chem. 2000, 65 (20), 6368–6380. 10.1021/jo000257f. [DOI] [PubMed] [Google Scholar]
  28. Brummond K. M.; Gesenberg K. D.; Kent J. L.; Kerekes A. D. A new method for the preparation of alkynes from vinyl triflates. Tetrahedron Lett. 1998, 39 (47), 8613–8616. 10.1016/S0040-4039(98)01928-5. [DOI] [Google Scholar]
  29. Parikh J. R.; Doering W. v. E. Sulfur trioxide in the oxidation of alcohols by dimethyl sulfoxide. J. Am. Chem. Soc. 1967, 89 (21), 5505–5507. 10.1021/ja00997a067. [DOI] [Google Scholar]
  30. Abdel-Magid A. F.; Carson K. G.; Harris B. D.; Maryanoff C. A.; Shah R. D. Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures. J. Org. Chem. 1996, 61, 3849–3862. 10.1021/jo960057x. [DOI] [PubMed] [Google Scholar]
  31. 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 (25), 11279–11294. 10.1021/jacs.0c04742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 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]
  33. Thompson R. R.; Rotella M. E.; Du P.; Zhou X.; Fronczek F. R.; Kumar R.; Gutierrez O.; Lee S. Siloxide Podand Ligand Scaffold for Molybdenum-Catalyzed Alkyne Metathesis and Isolation of a Dynamic Metallatetrahedrane Intermediate. Organometallics 2019, 38, 4054–4059. 10.1021/acs.organomet.9b00430. [DOI] [Google Scholar]
  34. Haack A.; Hillenbrand J.; Leutzsch M.; van Gastel M.; Neese F.; Fürstner A. Productive Alkyne Metathesis with “Canopy Catalysts” Mandates Pseudorotation. J. Am. Chem. Soc. 2021, 143, 5643–5648. 10.1021/jacs.1c01404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Haack A.; Hillenbrand J.; van Gastel M.; Fürstner A.; Neese F. Spectroscopic and Theoretical Study on Siloxy-Based Molybdenum and Tungsten Alkylidyne Catalysts for Alkyne Metathesis. ACS Catal. 2021, 11, 9086–9101. 10.1021/acscatal.1c01587. [DOI] [Google Scholar]
  36. Berkson Z. J.; Lätsch L.; Hillenbrand J.; Fürstner A.; Copéret C. Classifying and Understanding the Reactivities of Mo-Based Alkyne Metathesis Catalysts from 95Mo NMR Chemical Shift Descriptors. J. Am. Chem. Soc. 2022, 144 (33), 15020–15025. 10.1021/jacs.2c06252. [DOI] [PubMed] [Google Scholar]
  37. For other advanced applications that illustrate this aspect, see ref (7) and the following:; a 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]; b Tang J.; Li W.; Chiu T.-Y.; Martinez-Pena 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.. A Scalable Total Synthesis of Portimine A and B Reveals the Basis of Their Potent and Selective Anti-cancer Activity. Nature 2023; 10.1038/s41586-023-06535-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. The reaction proceeded well even at ambient temperature, although somewhat more slowly (ca. 2 h).
  39. Complex 40a is the most active but the thermally least stable member of the “canopy series”; this fact impacts on any attempt at optimizing the catalyst loading. For a study into the decomposition pathways, see ref (41).
  40. For the use of molecular sieves as a butyne-sequestering agent, see:; a 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]; b Heppekausen J.; Stade R.; Kondoh A.; Seidel G.; Goddard R.; Fürstner A. Optimized Synthesis, Structural Investigations, Ligand Tuning and Synthetic Evaluation of Silyloxy-Based Alkyne Metathesis Catalysts. Chem. - Eur. J. 2012, 18, 10281–10299. 10.1002/chem.201200621. [DOI] [PubMed] [Google Scholar]
  41. Hillenbrand J.; Korber J. N.; Leutzsch M.; Nöthling N.; Fürstner A. Canopy Catalysts for Alkyne Metathesis: Investigations into a Bimolecular Decomposition Pathway and the Stability of the Podand Cap. Chem.—Eur. J. 2021, 27 (56), 14025–14033. 10.1002/chem.202102080. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. The lower yield is mainly due to difficulties in separating the large amounts of ligands derived from the two catalysts (combined loading of 60%) in the crude material.
  43. Rowan S. J.; Cantrill S. J.; Cousins G. R. L.; Sanders J. K. M.; Stoddart J. F. Dynamic Covalent Chemistry. Angew. Chem., Int. Ed. 2002, 41 (6), 898–952. . [DOI] [PubMed] [Google Scholar]
  44. Huang S.; Lei Z.; Jin Y.; Zhang W. By-design molecular architectures via alkyne metathesis. Chem. Sci. 2021, 12, 9591–9606. 10.1039/D1SC01881G. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. On rare occasions, we had previously observed that dimeric (oligomeric) species are formed that might eventually convert into cyclic monomers; compare:; a Lehr K.; Fürstner A. An efficient route to the musk odorant (R,Z)-5-muscenone via base-metal-catalysis. Tetrahedron 2012, 68 (37), 7695–7700. 10.1016/j.tet.2012.05.085. [DOI] [Google Scholar]; b Schaubach S.; Michigami K.; Fürstner A. Hydroxyl-Assisted trans-Reduction of 1,3-Enynes: Application to the Formal Synthesis of (+)-Aspicilin. Synthesis 2016, 49 (01), 202–208. 10.1055/s-0035-1562381. [DOI] [Google Scholar]
  46. In addition to numerous attempts at selective semihydrogenation using various poisoned and unpoisoned catalysts, hydroboration/protodeborylation as well as the use of activated metals (Zn*, TaCl5/Zn) were unsuccessful.
  47. Smith N. D.; Mancuso J.; Lautens M. Metal-Catalyzed Hydrostannations. Chem. Rev. 2000, 100 (8), 3257–3282. 10.1021/cr9902695. [DOI] [PubMed] [Google Scholar]
  48. Alami M.; Hamze A.; Provot O. Hydrostannation of Alkynes. ACS Catal. 2019, 9 (4), 3437–3466. 10.1021/acscatal.9b00482. [DOI] [Google Scholar]
  49. Likewise, the dialkylalkyne moiety in 36 hardly reacted even when a large excess of Bu3SnH was used; see the Supporting Information. Therefore double-hydrostannation of diyne 36 followed by exhaustive protodestannation was no competitive alternative. This barely documented (see ref (52)) differential in reactivity between aryl and alkyl alkynes toward Pd-catalyzed hydrostannation is enabling (see Scheme 5) and currently subject to more systematic study.
  50. Polar substituents exert directing effects on metal-catalyzed hydrostannation reactions; see refs (47) and (48). Although it cannot be excluded that the lateral −NHBoc group is involved in the regioselective formation of alkenylstannane 39, the electronic bias of the C31–C32 triple bond in 38 is likely the dominant factor since PhC≡CMe—under the same reaction conditions—also affords a single regioisomer with the Bu3Sn– group residing adjacent to the phenyl ring; see ref (52).
  51. The Bu3Sn– group in 39 is an exquisite handle for late-stage diversification that may allow the pharmacophore to be mapped in more detail; compare:; a Rummelt S. M.; Preindl J.; Sommer H.; Fürstner A. Selective Formation of a Trisubstituted Alkene Motif by trans-Hydrostannation/Stille Coupling: Application to the Total Synthesis and Late-Stage Modification of 5,6-Dihydrocineromycin. B. Angew. Chem. Int. Ed. 2015, 54 (21), 6241–6245. 10.1002/anie.201501608. [DOI] [PubMed] [Google Scholar]; b Meng Z.; Souillart L.; Monks B.; Huwyler N.; Herrmann J.; Müller R.; Fürstner A. A “Motif-Oriented” Total Synthesis of Nannocystin Ax. Preparation and Biological Assessment of Analogues. J. Org. Chem. 2018, 83 (13), 6977–6994. 10.1021/acs.joc.7b02871. [DOI] [PubMed] [Google Scholar]
  52. Zhang H. X.; Guibe F.; Balavoine G. Palladium- and molybdenum-catalyzed hydrostannation of alkynes. A novel access to regio- and stereodefined vinylstannanes. J. Org. Chem. 1990, 55 (6), 1857–1867. 10.1021/jo00293a035. [DOI] [Google Scholar]
  53. Because of the small amount of material, this reduction has not been carried out. However, ref (7) shows the selective reduction of a closely related amide in the presence of an alkyne.

Associated Data

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

Supplementary Materials

ja3c08410_si_001.pdf (2MB, pdf)
ja3c08410_si_002.pdf (16.5MB, pdf)

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

RESOURCES