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T1 - Total synthesis of Brevetoxin A

A total synthesis of brevetoxin A is reported. Two tetracyclic coupling partners, prepared from previously reported advanced fragments, were effectively united via a Horner—Wittig olefination. The resulting octacycle was progressed to substrates that were explored for reductive etherification, the success of which led to a penultimate tetraol intermediate. The tetraol was converted to the natural product through an expeditious selective oxidative process, followed by methylenation.

N2 - Brevetoxin B was isolated from the red tide organism Karenia brevis in 1981 as the first example of marine polycyclic ethers. This compound shows potent neurotoxicity, by binding to sodium channels, causing massive fish kills and human health problems. Since further biological studies are hampered by the limited availability from nature, chemical synthesis has been the sole realistic way to obtain sufficient amounts of brevetoxin B. Moreover, the huge molecular architecture is a particularly attractive target for synthetic chemists. In this account, we describe the highly convergent total synthesis of brevetoxin B based on our methodology, including intramolecular allylation and subsequent ring-closing metathesis.

Two previous syntheses of Brevetoxin B have been described by Nicolaou et al.

T1 - Total synthesis of brevetoxin B

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The planned approach for the total synthesis of brevetoxin A focused on a versatile endgame that would exploit the selective manipulation of tetraol 2 (), which would derive from mixed methyl ketal 3 via stereoselective reductive etherification. Ketal 3 would be obtained through the stereoselective Horner—Wittig coupling of phosphine oxide 5 and aldehyde 6. This route was attractive not only because it allowed for optimal convergence by simplifying the natural product into two halves of similar complexity, but also because it found precedent in the strategy previously reported by Nicolaou. Further, it was reasoned that the dithioketal moiety of aldehyde 6 could serve as a stabilized precursor to mixed ketal 3, or lead to sulfone 4 in the event that formation or reductive etherification of mixed ketal 3 proved problematic. The Horner—Wittig coupling partners 5 and 6 would be obtained from advanced fragments 7 and 8, respectively. The BCDE fragment 7 and GHIJ subunit 8 had been previously prepared in significant quantities through similar highly convergent [X+2+X] strategies based on a Horner—Wadsworth—Emmons coupling of the B and E ring units (and the G and J subunits) and subsequent construction of the central CD and HI rings.

Total synthesis of brevetoxin B — Okayama University

The synthetic challenge posed by brevetoxin A reflectsthe high complexity of its molecular structure: 10 oxygen atoms and achain of 44 carbon atoms are woven into a polycyclic macromolecule thatincludes 10 rings (containing between 5 and 9 atoms) and 22 stereogeniccentres.

Here we describe thesuccessful incorporation of methods that were specifically developed forthe construction of these rings, into an overall strategy for the totalsynthesis of brevetoxin A in its naturally occurring form.

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FULL TEXT Abstract: A total synthesis of brevetoxin A is reported


Total synthesis of brevetoxin A - SAO/NASA ADS

The exquisite structures of marine polycyclic ether natural products have captured the imagination of synthetic chemists for over two decades. The structures of the polyether ladder toxins characteristically contain a linear series of trans fused ether rings of varying sizes from five to nine members with assorted methyl and hydroxyl substituents appended. As novel technologies for the convergent preparation of these targets have emerged, a number of total syntheses of the ladder toxins have been completed. The structure of brevetoxin A (1), a representative member of this class, was first elucidated in 1986 by Shimizu, and co-workers by X-ray analysis and independently determined by Nakanishi through spectroscopic studies. Brevetoxin A (1) contains ten rings (including five-, six-, seven-, eight, and nine-membered oxacycles) fused in a linear array adorned by 22 tetrahedral stereocenters. A metabolite of Karenia brevis, brevetoxin A is a toxic component of the infamous red tide phenomenon, which has been responsible for massive fish kills as well as neurotoxic shellfish poisoning and bronchial irritation in humans. The potent activity of brevetoxin A is attributed to strong binding to the α subunit of the voltage-sensitive sodium ion channels effecting an increase in the mean channel open time and inhibiting channel inactivation. To date, the landmark total synthesis reported by Nicolaou stands as the only completed synthesis of this intriguing target.

Total synthesis of brevetoxin B. | Sigma-Aldrich

AB - Brevetoxin B was isolated from the red tide organism Karenia brevis in 1981 as the first example of marine polycyclic ethers. This compound shows potent neurotoxicity, by binding to sodium channels, causing massive fish kills and human health problems. Since further biological studies are hampered by the limited availability from nature, chemical synthesis has been the sole realistic way to obtain sufficient amounts of brevetoxin B. Moreover, the huge molecular architecture is a particularly attractive target for synthetic chemists. In this account, we describe the highly convergent total synthesis of brevetoxin B based on our methodology, including intramolecular allylation and subsequent ring-closing metathesis.

The convergent total synthesis of brevetoxin B (1) has been achieved

Brevetoxin A is a decacyclic ladder toxin that possesses five-,six-, seven-, eight-, and nine-membered oxacycles, as well as 22 tetrahedral stereocenters. Herein, we describe a unified approach to the B, E, G, and J rings predicated upon a ring-closing metathesis strategy from the corresponding dienes. The enolate technologies developed in our laboratory allowed access to the precursor acyclic dienes for the B, E, and G medium ring ethers. The strategies developed for the syntheses of these four monocycles ultimately provided multigram quantities of each of the rings, supporting our efforts toward the convergent completion of brevetoxin A.

Convergent synthesis of the F–K ring segment of brevetoxin B

Brevetoxin B was isolated from the red tide organism Karenia brevis in 1981 as the first example of marine polycyclic ethers. This compound shows potent neurotoxicity, by binding to sodium channels, causing massive fish kills and human health problems. Since further biological studies are hampered by the limited availability from nature, chemical synthesis has been the sole realistic way to obtain sufficient amounts of brevetoxin B. Moreover, the huge molecular architecture is a particularly attractive target for synthetic chemists. In this account, we describe the highly convergent total synthesis of brevetoxin B based on our methodology, including intramolecular allylation and subsequent ring-closing metathesis.

Total synthesis of brevetoxin B (RSC Publishing)

Borrowing from precedent in the Nicolaou synthesis, attention was turned to the reductive etherification of sulfone 4 rather than the ketal 3 in an attempt to increase the lability of the leaving group at C27., Removal of the MOP acetal from olefin 14 () under acidic conditions followed by treatment of the hydroxy-dithioketal with AgClO4 provided the cyclic mixed S,O-ketal 18. Upon obtaining sulfone 4 via oxidation with m-CPBA, reductive etherification with concomitant removal of the PMB protecting groups was readily accomplished, furnishing diol 16 in 85% yield.

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