Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling

The synthesis of the polyketide section present in the potently cytotoxic marine cyclodepsipeptide jasplakinolide and related natural products, geodiamolides and seragamides, is reported. The key step is a Negishi cross coupling of (R)-(3-methoxy-2-methyl-3-oxopropyl)zinc(II) bromide and an (E)-iodoalkene that was synthesized via an aluminium ester enolate attack at (R)-propylene oxide. The overall synthesis comprises nine steps with an overall yield of 21%. It proved to be possible to liberate the free 8-hydroxynonenoic acid and to couple it with a protected tripeptide composed of L-alanine, N,O-dimethyl-D-iodotyrosine, and TIPS-protected L-threonine, which occurs as partial structure of seragamide A. The tripeptide section of seragamide A was assembled by solution-phase synthesis and an open-chain analogue of the natural product was obtained.

Alkaloid Synthesis: Indolizidine 223AB (Cha), Lepadiformine (Kim), Kainic Acid (Fukuyama), Gephyrotoxin (Smith), Premarineosin A (Reynolds)

Jin Kun Cha of Wayne State University prepared (Org. Lett. 2014, 16, 6208) the allene 1 by SN2′ coupling of a cyclopropanol with a propargylic tosylate. Silver-mediated cyclization converted 1 into 2, that was reduced with diimide to the Dendrobates alka­loid indolizidine 223AB 3. Sanghee Kim of Seoul National University observed (Chem. Eur. J. 2014, 20, 17433) high diastereoselectivity in the Ireland–Claisen rearrangement of 4 to 5. The acid 5 was the key intermediate for the synthesis of the tunicate alkaloid lepadiformine 6. Tohru Fukuyama of Nagoya University also used (Eur. J. Org. Chem. 2014, 4823) an ester enolate Claisen rearrangement to set the relative and absolute configuration of 7. Pd-catalyzed cyclization then led to 8, that was carried on to the excitatory amino acid receptor agonist kainic acid 9. Gephyrotoxin 12 was so named because it incorporates structural elements from two different classes of the Dendrobates alkaloids. Martin D. Smith of the University of Oxford envisioned (Angew. Chem. Int. Ed. 2014, 53, 13826) the cascade cyclization of deprotected 10 to give, after reduction, the ketone 11. Zhen Yang of the Peking University Shenzhen Graduate School showed (Chem. Eur. J. 2014, 20, 12881) that the Rh carbene derived from 13 readily cyclized to an imine. The facial selectivity of the addition of the Grignard reagent 14 to that imine depended on the temperature of the reaction. At room temperature, 15 was formed. At low temperature, the other diastereomer predominated. Ring-closing metathesis was used for the elaboration of 15 to the Stemona alkaloid tuberostemospiroline 16. Kevin A. Reynolds of Portland State University prepared (J. Org. Chem. 2014, 79, 11674) 19 by condensation of the pyrrole 17 with the aldehyde 18. The biosyn­thetic enzyme, that they had overexpressed, oxidized 19 to the antimalarial alkaloid permarineosin A 20.

Organocatalyzed C–C Ring Construction: The Carreira Synthesis of (+)-Crotogoudin

Kazuaki Kudo of the University of Tokyo developed (Org. Lett. 2013, 15, 4964) a peptide catalyst for the enantioselective construction of 3 by the addition of 2 to 1. Thorsten Bach of the Technische Universität München devised (Science 2013, 342, 840; J. Am. Chem. Soc. 2013, 135, 14948) a Lewis acid organocatalyst for the photo­cyclization of 4 to 5. Albert Moyano of the Universitat de Barcelona effected (Eur. J. Org. Chem. 2013, 3103) enantioselective conjugate addition of 7 to 6 to give the cyclopentane 8. Daniel Romo of Texas A&M optimized (Nature Chem. 2013, 5, 1049) the addition of 9 to 10 to give the β-lactone 11. Kamal Kumar and Herbert Waldmann of the Technische Universität Dortmund found (Angew. Chem. Int. Ed. 2013, 52, 9576) that the addition of 12 to 13 followed by Bayer–Villiger oxidation and deacylation delivered 14 in high ee. David W. Lupton of Monash University opened (Angew. Chem. Int. Ed. 2013, 52, 9149) the cyclopropane of 15 in situ, leading to an ester enolate that added to 16 to give 17. Jeffrey S. Johnson of the University of North Carolina used (Chem. Sci. 2013, 4, 2828) an organocatalyst to mediate the addition of the prochiral 18 to 19, leading to 20. M. Belén Cid of the Universidad Autónoma de Madrid added (J. Org. Chem. 2013, 78, 10737) the nitroalkane 22 to the unsaturated aldehyde 21, leading, after intramolecular Julia-Kocienski addition, to the cyclohexene 23. Additions that pro­ceed in high ee with cyclopentenone and cyclohexenone are often not as selective with cycloheptenone 24. Wei Wang of the University of New Mexico and Wenhu Duan of the Shanghai Institute of Materia Medica observed (Tetrahedron Lett. 2013, 54, 3791) that addition of nitromethane and of nitroethane to 24 were both highly effective. Strategies have been developed for applying organocatalysis to the assembly of polycarbacyclic ring systems. Sanzhong Luo of the Beijing National Laboratory for Molecule Sciences uncovered (Synthesis 2013, 45, 1939) a simple amine that effi­ciently catalyzed the Robinson annulation of 26 with 27 to give 28.