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. 2023 Nov 15;145(47):25533–25537. doi: 10.1021/jacs.3c10212

Total Synthesis of Aleutianamine

Hao Yu 1, Zachary P Sercel 1, Samir P Rezgui 1, Jonathan Farhi 1, Scott C Virgil 1, Brian M Stoltz 1,*
PMCID: PMC10690800  PMID: 37967164

Abstract

graphic file with name ja3c10212_0007.jpg

Aleutianamine is a recently isolated pyrroloiminoquinone natural product that displays potent and selective biological activity toward human pancreatic cancer cells with an IC50 of 25 nM against PANC-1, making it a potential candidate for therapeutic development. We report a synthetic approach to aleutianamine wherein the unique [3.3.1] ring system and tertiary sulfide of this alkaloid were constructed via a novel palladium-catalyzed dearomative thiophene functionalization. Other highlights of the synthesis include a palladium-catalyzed decarboxylative pinacol-type rearrangement of an allylic carbonate to install a ketone and a late-stage oxidative amination. This concise and convergent strategy will enable access to analogues of aleutianamine and further investigation of the biological activity of this unique natural product.

Cancer-related illnesses are the second leading cause of death in the United States behind only heart disease.1 Pancreatic cancer is the third leading cause of cancer death and is projected to be the second deadliest cancer by 2040, exemplified by a dismal 12% five year survival rate for patients with the disease.2,3 These alarming statistics can be attributed to difficulties in early disease detection, the lack of common genetic mutations associated with the disease, and overall ineffective treatment options.4 Despite advances in new therapeutics for pancreatic cancer,5,6 patient survival has only marginally increased in the past several decades.

Historically, natural products have contributed significantly toward drug discovery and novel therapeutics, particularly in the areas of cancer and infectious disease.7 Indeed, several of the state-of-the-art therapies for pancreatic cancer are natural products or natural product derivatives.3 Aleutianamine (1), isolated in 2019 by Hamann and co-workers, is a marine-derived alkaloid that possesses potent and selective cytotoxicity toward solid tumor cell lines.8 Most notably, it displays 25 nM IC50 against the human pancreatic adenocarcinoma cell line PANC-1. This potency is over 160 times greater than that of the FDA-approved chemotherapeutic agent gemcitabine, demonstrating the therapeutic potential of the natural product.9

Aleutianamine (1) belongs to the pyrroloiminoquinone alkaloid family of natural products defined by their conserved central planar, tricyclic ring system. These natural products have received significant attention from the synthetic community due to their complex molecular frameworks and broad biological activites.10 Structurally, aleutianamine (1) possesses a unique heptacyclic ring system which consists of a pyrroloiminoquinone unit, a bridged azabicyclo[3.3.1]nonane ring system substituted with a congested tertiary alkyl sulfide and an alkenyl bromide, and another bridging thioaminal linkage (Figure 1A). The multibridged ring system of the natural product bears three stereocenters and is highly strained due to extensive unsaturation. The congested sulfide, the potentially labile thioaminal moiety, and the remote alkenyl bromide represent considerable synthetic challenges.

Figure 1.

Figure 1

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(A) Aleutianamine and the proposed biosynthesis from related alkaloids. (B) Retrosynthetic logic. (C) Key transformation for the proposed strategy.

Aleutianamine (1) is proposed to arise biosynthetically from either makaluvamine F (2) or discorhabdin B (3) (Figure 1A).8 Recently, Tokuyama accomplished the first total synthesis of aleutianamine (1) by a biomimetic approach wherein a discorhabdin B analog underwent a cationic rearrangement to produce the ring system of aleutianamine (1), supporting the proposed biosynthetic pathway (see Supporting Information (SI)).11

We devised an alternative nonbiomimetic approach centered around formation of the bridging [3.3.1] ring system followed by late-stage arene oxidation, a strategy that is unique in comparison to previous pyrroloiminoquinone syntheses (Figure 1B). The dearomative arylation of a thiophene was envisioned as a key transformation to enable this strategy, as this reaction would construct the bridging [3.3.1] ring system and congested tertiary bridgehead sulfide in a single synthetic step (Figure 1C). We were inspired by previous reports of dearomative phenol cross-couplings, but the analogous transformation of thiophenes has yet to be reported.12

Retrosynthetically, oxidation state adjustment and cleavage of the aryl C–N bond of aleutianamine (1) would lead back to thiolactone 8 (Scheme 1). This intermediate would arise from partially saturated thiolactone 9 by installation of vinyl bromide. Retrosynthetic cleavage of the Csp2–Csp3 bond of the [3.3.1] ring system by the proposed dearomative arylation simplifies the target to aryl bromide 10, which could be rapidly prepared in a convergent fashion from tryptamine 11 and aminothiophene 12.

Scheme 1. Retrosynthetic Analysis.

Scheme 1

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Our studies commenced with the Fischer indole synthesis of tryptophol 14 from known arylhydrazine 13(13) and dihydrofuran (Scheme 2A).14 A three-step sequence involving a Mitsunobu reaction with DPPA, subsequent N-tosylation, and Staudinger reduction yielded protected tryptamine 11. Finally, intramolecular Buchwald–Hartwig amination provided tricyclic aniline 15.15 The synthesis of thiophene coupling fragment 12 (Scheme 2B) began with aminothiophene 16, which was prepared in one step from 1,4-cyclohexanedione monoethylene ketal via Gewald aminothiophene synthesis.16 Saponification and decarboxylation served to remove the ester group, and the resulting amine was readily protected as the trifluoroacetamide. Subsequent ketal cleavage afforded the ketothiophene coupling partner 12.

Scheme 2. (A) Synthesis of Tricyclic Aniline 15; (B) Synthesis of Aminothiophene 12.

Scheme 2

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Coupling of tricyclic aniline 15 with ketothiophene 12 was achieved by employing indium hydride mediated reductive amination conditions developed by Yang17 (Scheme 3). Subsequent bromination yielded the cyclization precursor 10. To our delight, treatment of bromoaniline 10 with Pd(dba)2 and XPhos in the presence of base led to the desired dearomative cyclization with concomitant cleavage of the trifluoroacetamide to yield free thioimidate 17.18 In addition to completing the carbon skeleton of aleutianamine (1) and assembling the tertiary alkyl sulfide, this reaction constitutes the first dearomative arylation of a thiophene derivative to date. The product of this coupling (17) was then N-tosylated to provide thioimidate 18—the N-tosyl group proved critical for further functionalization, as free thioimidate 17 was recalcitrant to hydrolysis and other electron-withdrawing groups were excessively labile. To circumvent the challenging purification of free thioimidate 17, the dearomative arylation and tosylation steps were telescoped to provide an improved yield of tosyl thioimidate 18 on multigram scale.

Scheme 3. Synthesis of Thioimidate 18 via Novel Thiophene Dearomatization.

Scheme 3

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Subjection of intermediate 18 to aqueous alkaline conditions led to the hydrolysis of the tosyl thioimidate, yielding thiobutenolide 9 (Scheme 4). While a variety of standard conditions failed to promote vinylogous desaturation of this intermediate (9), soft enolization with TBSOTf afforded an intermediate silyl ketene thioacetal that was treated with DDQ to provide diene 19, the structure of which was confirmed by X-ray crystallography. Reasoning that the electronics of diene 19 would promote bromination at the undesired C1 position, we opted to delay the installation of the alkenyl bromide until the final stage of the synthesis. Thus, DIBAL reduction of the thiolactone smoothly provided thiolactol 20. Treatment with CAN oxidized the arene to the desired pyrroloiminoquinone 21, and addition of aqueous ammonia effected amination and aerobic oxidation to deliver pyrroloiminoquinone 22.19 Finally, the addition of TFA led to dehydrative cyclization to yield thioaminal 23, which bears the full ring system of aleutianamine (1). Unfortunately, direct bromination of N-tosyl des-bromoaleutianamine (23) was unsuccessful in our hands; all surveyed bromination conditions led to decomposition or undesired regioselectivity.

Scheme 4. Synthesis of N-Tosyl des-Bromoaleutianamine (23) and Failed Late-Stage Bromination Attempts.

Scheme 4

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To circumvent the unsuccessful late-stage bromination, we attempted to increase the oxidation state at C2 on diene 19, which would provide a functional handle for bromination. However, the incorporation of a suitable functional handle proved to be a significant challenge. Installation of a ketone or an equivalent thereof at the C2 position was attempted by allylic oxidation, thia-Michael addition and Pummerer Rearrangement, and organosilane or organoborane 1,6-addition (see SI). Additionally, incorporation of an oxidation handle into aminothiophene coupling fragment 12 proved unsuccessful. Ultimately, ketone installation was achieved via an unconventional sequence. Beginning with diene 19, γ,δ-dihydroxylation with OsO4 provided diol 25, which was readily advanced to carbonate 26 (Scheme 5). Treatment with Pd(0) and dppe led to a decarboxylative pinacol-type rearrangement, presumably via putative π-allyl Pd(II) intermediate 27, which could undergo decarboxylation to afford 28, and subsequent β-hydride elimination and tautomerization to afford the desired ketone 29. To the best of our knowledge, this represents the first palladium-catalyzed decarboxylative pinacol-type rearrangement of allylic carbonates.20 Conversion to enol triflate 30 was followed by Shirakawa and Hayashi’s Ru-catalyzed triflate–halogen exchange to provide desired alkenyl bromide 8.21 Finally, in an analogous fashion to the synthesis of des-bromo compound 23, 1,2-reduction with DIBAL followed by oxidative amination and cyclization yielded penultimate intermediate 24, and tosyl group cleavage with NaOMe afforded aleutianamine (1) in a longest linear sequence of 20 steps.22

Scheme 5. Completion of the Total Synthesis of Aleutianamine (1).

Scheme 5

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This total synthesis represents a nonbiomimetic synthetic approach to aleutianamine (1). Key to the synthetic approach were the Pd-catalyzed intramolecular dearomative arylation of an aminothiophene, ketone installation by the Pd-catalyzed pinacol-type rearrangement of a cyclic carbonate, and late-stage arene oxidative amination. Efforts to prepare analogues of aleutianamine with related sequences and to establish a structure–activity relationship against biologically relevant cancer cell lines are ongoing.

Acknowledgments

The authors gratefully acknowledge Caltech, the NSF (CHE-2247315), and the Heritage Medical Research Investigators Program for financial support. Z.P.S. and S.P.R. thank the NSF GRFP for predoctoral fellowships. Dr. Mike Takase (Caltech) and Dr. Mona Shahgholi (Caltech) are thanked for assistance with X-ray crystallography and mass spectrometry, respectively. Dr. David VanderVelde (Caltech) is acknowledged for NMR instrumentation.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c10212.

  • Experimental procedures, spectroscopic data (1H NMR, 13C NMR, IR, HRMS), and crystallographic data (PDF)

Author Contributions

‡ H.Y. and Z.P.S. contributed equally

The authors declare no competing financial interest.

Supplementary Material

ja3c10212_si_001.pdf (3.6MB, pdf)

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Associated Data

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

Supplementary Materials

ja3c10212_si_001.pdf (3.6MB, pdf)

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