Synthesis of the C′D′E′F′ Domain of Maitotoxin

Abstract

A devised biomimetic strategy toward the C′D′E′F′ domain (6) of maitotoxin (1) led to hydroxy triepoxide 8 as a postulated polyepoxide precursor. However, all attempts to induce the desired cascade to form the targeted compound through a zip-type reaction under neutral or acidic conditions failed, prompting adoption of a linear stepwise approach to 6. The successful synthetic strategy for the synthesis of the C′D′E′F′ domain of maitotoxin commenced from furfuryl alcohol (11), proceeded through F′ ring building block 15, and involved two regio-and stereoselective intramolecular hydroxy epoxide openings and a stereoselective SmI 2 -mediated ring closure to forge rings C′, E′, and D′, respectively. 13 C NMR spectroscopic analysis of the synthesized domain (6) and comparisons with previous results confirmed the original structural assignment of this region of maitotoxin. X-Ray crystallographic analysis of 6 provided unambiguous proof of its structure.

Maitotoxin: An Inspiration for Synthesis

“…Oxidation of these hydroxy furan products, either with NBS or m CPBA, induces Achmatowicz rearrangement to yield the expanded ring systems 64 , from which the hydroxyl group can be excised conveniently through reduction with Et 3 SiH and BF 3 •OEt 2 , generating 6-membered cyclic ether enones 65 , and thence a variety of other tetrahydropyran derivatives. This methodology has been applied already to the construction of several maitotoxin ring systems, including the building blocks shown in Scheme 11b ( 66 – 71 ), [40–43] in multigram quantities.…”

“…[43] This sequence employed a Noyori reduction/Achmatowicz rearrangement [38,39] ( 84 → 69 ), two intramolecular hydroxy epoxide openings [12] ( 69 → 117 and 120 → 121 ) and a ketyl radical conjugate addition to an α,β-unsaturated ester facilitated by SmI 2 [48] ( 118 → 119 ). As seen in Scheme 18b, the 13 C NMR chemical shifts of synthetic C′D′E′F′ domain 122 were in excellent agreement with those of maitotoxin corresponding to the same carbons, with the exception of the edge carbons.…”

“…Crystalline 122 yielded to X-ray crystallographic analysis, which revealed its interesting concavity, apparently caused by the three congested methyl groups as shown in Figure 5. [43] …”

“…[51–63] The scarcity of maitotoxin, however, prevents its full biological investigation and hampers the identification of its target and the complete elucidation of its mechanism of action. On the other hand, synthetic studies inspired by the molecule of maitotoxin culminated in the synthesis of several of its polycyclic frameworks, including the ABCDEFG ( 102 ), [42] GHIJKLMNO ( 95 ), [41] QRSTU ( 109 ), [46] WXYZA′ ( 116 ), [47] and C′D′E′F′ ( 122 ) [43] domains (see Figure 7). The availability of these synthetic materials allowed re-confirmation of the originally assigned structure of maitotoxin, which had been challenged, in the meantime, and provided the foundation for further developments in the field.…”

Following the Lead from Nature: Divergent Pathways in Natural Product Synthesis and Diversity‐Oriented Synthesis

“…The synthesis provided rapid access to divergent synthetic branch points, affording a collection of analogues in addition to the natural products themselves (Scheme 1). [31][32][33] The intermolecular version of the key PEDA reaction had also been used by Nicolaou's group to access hybocarpone. [34] These syntheses provided the opportunity and impetus to fully investigate the generality and the scope of this photocyclisation in addition to delivering the first example of intramolecular PEDA with an all-carbon side-chain.…”