Towards Synthesis of Simplified Analogues of Pateamine A

<p>Pateamine A (22) is a natural product that was isolated from a marine sponge inhabiting the coast of New Zealand. It exhibits potent inhibition of protein synthesis and nonsense-mediated mRNA decay through binding with eIF4A isoforms. Due to the scarcity of pateamine A (22) in the natural source and the low yield of total synthesis of pateamine A, it is necessary to prepare structurally simplified analogues which would allow further research on structure-activity relationships (SAR) of pateamine A (22). Based on the structure-activity relationship studies reported by Romo and co-workers, a simplified triazole analogue 182 lacking methyl groups was synthesized by Hemi Cumming, a previous Ph.D. student who studied at Victoria University of Wellington. The antiproliferative activity of this analogue was found to be significantly lower than that of pateamine A, suggesting that the thiazole embedded within the molecule or the excised methyl groups are crucial for its potency. Therefore, to further explore the necessary features for its selective activity for eIF4A isoforms, new thiazole analogues 183 – 186 and triazole analogues (10S)-and (10R)-analogue 187 were targeted in this project. The preparation of the thiazole-containing macrocyclic core of analogues 183 and 184 was achieved. It features: (1) gold-catalysed thiazole formation through coupling between an alkyne fragment and a thioamide fragment; (2) preparation of the Z,E-dienoate moiety by base-induced ring-opening of a δ-substituted-α, β-unsaturated lactone; and (3) a modified Mukaiyama macrolactonisation. The synthesis of the triazole-containing macrocyclic core of (10S)-analogue 187 was completed. It features: (1) a copper-catalysed triazole formation through 1,3-dipolar cycloaddition between an alkyne fragment and an azide fragment; (2) preparation of the Z,E-dienoate moiety by base-induced ring-opening of δ-substituted-α, β-unsaturated lactone; and (3) a modified Mukaiyama macrolactonisation. Studies on the preparation of a side-chain fragment with suitable functionalities to allow coupling with the various macrocycles through olefination reactions were also conducted. The attachment of the side-chain fragment onto the macrocyclic cores for the synthesis of the targeted analogues 183 and 184 and (10S)-analogue 187 will be investigated in future work. These experimental results will inform the synthesis of new generation analogues to further study the key structures required for effective binding to the protein target eIF4A and selectivity between isoforms.</p>

Towards Synthesis of Simplified Analogues of Pateamine A

<p>Pateamine A (22) is a natural product that was isolated from a marine sponge inhabiting the coast of New Zealand. It exhibits potent inhibition of protein synthesis and nonsense-mediated mRNA decay through binding with eIF4A isoforms. Due to the scarcity of pateamine A (22) in the natural source and the low yield of total synthesis of pateamine A, it is necessary to prepare structurally simplified analogues which would allow further research on structure-activity relationships (SAR) of pateamine A (22). Based on the structure-activity relationship studies reported by Romo and co-workers, a simplified triazole analogue 182 lacking methyl groups was synthesized by Hemi Cumming, a previous Ph.D. student who studied at Victoria University of Wellington. The antiproliferative activity of this analogue was found to be significantly lower than that of pateamine A, suggesting that the thiazole embedded within the molecule or the excised methyl groups are crucial for its potency. Therefore, to further explore the necessary features for its selective activity for eIF4A isoforms, new thiazole analogues 183 – 186 and triazole analogues (10S)-and (10R)-analogue 187 were targeted in this project. The preparation of the thiazole-containing macrocyclic core of analogues 183 and 184 was achieved. It features: (1) gold-catalysed thiazole formation through coupling between an alkyne fragment and a thioamide fragment; (2) preparation of the Z,E-dienoate moiety by base-induced ring-opening of a δ-substituted-α, β-unsaturated lactone; and (3) a modified Mukaiyama macrolactonisation. The synthesis of the triazole-containing macrocyclic core of (10S)-analogue 187 was completed. It features: (1) a copper-catalysed triazole formation through 1,3-dipolar cycloaddition between an alkyne fragment and an azide fragment; (2) preparation of the Z,E-dienoate moiety by base-induced ring-opening of δ-substituted-α, β-unsaturated lactone; and (3) a modified Mukaiyama macrolactonisation. Studies on the preparation of a side-chain fragment with suitable functionalities to allow coupling with the various macrocycles through olefination reactions were also conducted. The attachment of the side-chain fragment onto the macrocyclic cores for the synthesis of the targeted analogues 183 and 184 and (10S)-analogue 187 will be investigated in future work. These experimental results will inform the synthesis of new generation analogues to further study the key structures required for effective binding to the protein target eIF4A and selectivity between isoforms.</p>

Total synthesis of (R)-Argentilactone and (R)-Goniothalamin using a Free Radical Photoredox Approach to α,β-Unsaturated δ-Lactones.

α,β-Unsaturated δ-lactones are structural motifs found in diverse pharmacologically active natural products. In fact, the unsaturated lactone is often responsible for the biological activity. Herein, we report a new approach for the syntheses of (R)-argentilactone and (R)-goniothalamin based on a photoredox intermolecular iodolactonization mediated by a photoredox process. This new approach, already employed in our research group, stands as a new methodology to achieve several natural products containing α,β-unsaturated δ-lactones.

A multifunctional divergent scaffold to access the formal syntheses of various sesquiterpenoids

A new divergent scaffold for the synthesis of various sesquiterpenoids in furan and α,β-unsaturated lactone oxidation states was developed through a novel, concise and scalable route.

Alkylated Stereogenic Centers: The Jia Synthesis of (−)-Goniomitine

John W. Wong of Pfizer and Kurt Faber of the University of Graz used (Adv. Synth. Catal. 2014, 356, 1878) a wild-type enzyme to reduce the nitrile 1 to 2 in high ee. Takafumi Yamagami of Mitsubishi Tanabe Pharma described (Org. Process Res. Dev. 2014, 18, 437) the practical diastereoselective coupling of the racemic acid 3 with the inexpensive pantolactone 4 to give, via the ketene, the ester 5 in high de. Takeshi Ohkuma of Hokkaido University devised (Org. Lett. 2014, 16, 808) a Ru/Li catalyst for the enantioselective addition of in situ generated HCN to an N-acyl pyrrole 6 to give 7 in high ee. Yujiro Hayashi of Tohoku University found (Chem. Lett. 2014, 43, 556) that an aldehyde 8 could be condensed with formalin, leading in high ee to the masked aldehyde 9. Stephen P. Fletcher of the University of Oxford prepared (Org. Lett. 2014, 16, 3288) the lactone 12 in high ee by adding an alkyl zirconocene, prepared from the alkene 11, to the unsaturated lactone 10. In a remarkable display of catalyst control, Masakatsu Shibasaki of the Institute of Microbial Chemistry and Shigeki Matsunaga of the University of Tokyo opened (J. Am. Chem. Soc. 2014, 136, 9190) the racemic aziridine 13 with malonate 14 using a bimetallic catalyst. One enantiomer of the aziridine was converted specifically to the branched product 15 in high ee. The other enantiomer of the aziridine was converted to the regioisomeric opening product. Kimberly S. Peterson of the University of North Carolina at Greensboro used (J. Org. Chem. 2014, 79, 2303) an enantiomerically-pure organophosphate to selec­tively deprotect the bis ester 16, leading to 17. Chunling Fu of Zhejiang University and Shengming Ma of the Shanghai Institute of Organic Chemistry showed (Chem. Commun. 2014, 50, 4445) that an organocatalyst could mediate the brominative oxi­dation of 18 to 19. The ee of the product was easily improved via selective crystalliza­tion of the derived dinitrophenylhydrazone. James P. Morken of Boston College developed (Org. Lett. 2014, 16, 2096) condi­tions for the allylation of an allylic acetate such as 20 with 21, to deliver the coupled product 22 with high maintenance of ee.

Abstract 90: Inimitable Ouabain: The Endogenous Circulating Cardiotonic Steroid that Singularly Stimulates Sodium Potassium Pump Activity at Low Doses

Rationale: Cardiotonic steroids (CTS), such as digoxin, have been used to treat heart failure (HF) for over 200 years. They inhibit the sodium-potassium pump (NKP), and increase cardiac contractility by inhibiting efflux of sodium through the pump (“digitalis hypothesis”). CTS possess three structural components: a saturated/unsaturated lactone ring, steroid core, and sugar moiety, each of which may be involved in NKP inhibition/stimulation. It is now known that inhibition of the NKP in patients with HF increases mortality, and all major beneficial treatments increase its activity. Endogenous circulating CTS such as ouabain are generally thought to inhibit the NKP, despite studies sporadically reporting ouabain-induced pump stimulation. This study aims to identify whether ouabain-induced pump stimulation occurs, and if so, which structural components are involved in causing pump stimulation. Methods & Results: Cardiac myocytes were isolated from male New Zealand White rabbits, placed in a Tyrode’s solution, and whole-cell patch clamped. They were exposed to 0-30nM ouabain, 0-50nM dihydroouabain (ouabain with a saturated lactone ring) or 0-500nM ouabagenin (ouabain lacking a sugar moiety) for 1 min, followed by a potassium-free solution, with the difference in current yielding the NKP current. Compared to the 0.47±0.05 pA/pF Tyrode’s solution control (n=11), 5nM ouabain significantly increased NKP current to 0.69±0.09 pA/pF ( P <0.05, n=6). Exposure to dihydroouabain or ouabagenin did not significantly change NKP current in the studied concentration range. Cell viability assays carried out on the breast cancer cell line MCF7, which have an NKP structure extremely similar to that of cardiomyocytes, showed significantly elevated viability above control values (n=2) following 24h treatment with 0-9nM ouabain; maximum viability was 116±5% at 0.28nM ( P <0.05, n=4). A significant change in viability was not observed for ouabagenin or digoxin in the same concentration range. Conclusion: Low-dose ouabain uniquely stimulates NKP activity. Low-dose dihydroouabain and ouabagenin do not, suggesting that a sugar moiety and unsaturated lactone ring are required for pump stimulation. Ouabain in its unaltered form may be a potential treatment for HF.