Synthesis of the (+)‐C26–C40 Domain of the Azaspiracids by a Novel Double Intramolecular Hetero‐Michael Addition Strategy

Abstract

The azaspiracid natural products (AZA 1 ± 5, ) are causative agents of human poisonings associated with the consumption of shellfish that were first recognized in the Netherlands in 1995. [1] Originally isolated from the mussel Mytilus edulis cultivated in Killary Harbor, Ireland, the azaspiracids have since been detected in a growing range of aquatic organisms and geographical locations. Physiological aspects of azaspiracid poisoning (AZP) are distinct from those of other known shellfish intoxications. These include delayed onset and prolonged duration of acute symptoms, and necrosis of the intestine, thymus, and liver. Hence, the azaspiracids represent an emerging new class of environmental toxins with serious economic and human health consequences. As a result there is an urgent need of authentic samples for continued environmental monitoring.Structurally, the azaspiracids are complex w-amino acids that contain within their 40-carbon backbone an unprecedented array of polycyclic, spiro-fused ring systems. Among the members of this class reported to date, minor variations in skeletal substitution occur within the C1 ± C25 domain, but the C26 ± C40 portion remains constant. The relative stereochemistries within the C6 ± C25 and C28 ± C40 domains of the azaspiracids have been assigned, but neither the stereochemical relationship between these two regions, nor the absolute stereochemistry of either has been established. These factors molecular architectures in electronic devices in which the well-defined character of p-conjugated oligomers is combined with the material properties of polymers Experimental SectionBOPVUP: Under an argon atmosphere, diisocytosine compound 2 (0.03 g, 0.07 mmol) was dissolved in anhydrous pyridine (5 mL) and heated to 90 8C. A solution of OPV-isocyanate 1 (0.20 g, 0.15 mmol) in anhydrous pyridine (10 mL) was added and the reaction mixture was stirred overnight at 90 8C. The solution was subsequently cooled to room temperature and the pyridine was removed by evaporation under vacuum. The residue was purified by column chromatography (silica gel, ethyl acetate then CH 2 Cl 2 to remove impurities and finally CH 2 Cl 2 /MeOH (97/3, v/v) to collect the desired product) to afford BOPVUP as an orange solid (95 mg; 45 % yield). UV/Vis (CHCl 3 ): l max (e) 432 nm (258 000 m À1 cm À1 ); (m), 963 (s), 916 (w), 850 (m); MALDI-TOF MS (M r 3062.62) m/z: 3063.29; elemental analysis calcd (%) for C 196 H 306 N 8 O 18 (M r 3062.[1] For examples see:

Synthesis of the Southern FGHI Ring System of Azaspiracid‐1 and Investigation into the Controlling Elements of C28‐ and C36‐Ketalization

“…The outlined approach represents the shortest route to the FGHI ring system reported to date 2e. 3e,g,p In addition, we have demonstrated that careful selection of conditions for the ketalization steps allows control over the stereochemical outcome of the reaction. Completion of the total synthesis of azaspiracid‐1 ( 1 ) will be reported in due course.…”

“…Aldol reaction of ketone 32 and aldehyde 34 gave the coupled adduct 35 in excellent yield as a single diastereomer. On the basis of precedent from us and others,2e, 3e,g we suspected that the C34 stereochemistry was once again incorrect. Fortunately, after removal of the TMS group at C33 and mixed ketal formation at C36, we were able to cleanly invert the C34 stereochemistry using Martin's modified Mitsunobu conditions 12.…”

“…CSA, MeOH) led to extensive decomposition. Interestingly, treatment of 46 with Yb(OTf) 3 2e, 3e,g,p in PhMe led to rapid formation (30 min, room temperature) of a single new product 47 . Careful analysis by 2D NMR spectroscopy revealed that 47 possessed the undesired stereochemistry at C36.…”