Second-generation Synthesis Research Articles

First- and second-generation total synthesis of ciguatoxin CTX3C.

More than 20,000 people suffer annually from ciguatera seafood poisoning in subtropical and tropical regions. The extremely low content of the causative neurotoxins, designated as ciguatoxins, in fish has hampered isolation, detailed biological studies, and preparation of anti-ciguatoxin antibodies for detecting these toxins. Furthermore, the large (3 nm in length) and complex molecular structure of ciguatoxins has impeded chemists from completing their total synthesis. In this article, the full details of studies leading to the total synthesis of ciguatoxin CTX3C are provided. The key elements of the first-generation approach include O,O-acetal formation from the right and left wing fragments, conversion from O,O-acetal to O,S-acetal, a radical reaction to cyclize the G ring, a ring-closing metathesis reaction to close the F ring, and final removal of the 2-naphtylmethyl protective groups. Subsequent studies provided a second-generation total synthesis, which is more concise and results in a higher yield. Second-generation synthesis was accomplished by using a direct method of constructing the key intermediate O,S-acetal from alpha-chlorosulfide and a secondary alcohol. These syntheses ensure a practical supply of ciguatoxin for biological applications.

Second-generation synthesis of protected phosphonothiodifluoromethylene analogues of nucleoside-3′-phosphates

A practical, eight-step synthesis of the key intermediate 14 in 19% overall yield from α- d-xylose is described. The preparation can be carried out on multi-gram scale and involves the use of the organomagnesium reagent 2d . The capability of derivative 14 to be transformed into the title compounds is examplified by the preparation of 15 . Additionally, X-ray crystallography of intermediate 12 provided the first structural data on difluorophosphonothioates.

A second-generation synthesis of the C1-C28 portion of the altohyrtins (spongistatins).

A practical second-generation synthesis of an advanced intermediate in our total synthesis of altohyrtin C (spongistatin 2) has been developed. A new approach to the C1-C15 (AB) portion features a vinyllithium addition to an aldehyde followed by a palladium-catalyzed allylic reduction to install the troublesome C13-C15 segment. Our general approach to the C16-C28 (CD) spiroketal has been retained, but some improvements have been made. Most notably, the kinetically controlled CD-spiroketalization reaction now proceeds in high yield with excellent diastereoselection. This new strategy uses the anti-aldol coupling used in our first-generation synthesis to join AB and CD fragments. A total of 9.6 g of intermediate 57 has been produced using this improved route.

Second-generation synthesis of the polypropionate subunit of callystatin A based on regioselective internal alkyne hydrostannation.

[formula: see text] An improved route to the polypropionate segment of callystatin A is described in which the efficient directed hydrostannation of an internal alkyne and subsequent iodinolysis provides a key vinylic iodide intermediate.

ChemInform Abstract: A Second-Generation Synthesis of Polypyrrolinone Nonpeptidomimetics: Prelude to the Synthesis of Polypyrrolinones on Solid Support.

A second-generation asymmetric synthesis of polypyrrolinones (3) has been achieved exploiting scalemic α-aminolactones (1) as building blocks. Imine formation between an appropriate lactone (1) and aldehyde (2), followed in turn by pyrrolinone ring construction promoted by KHMDS in the presence of 18-crown-6 and modified Swern oxidation furnished pyrrolinone aldehyde 3. This iterative, efficient three-step protocol paves the way for the synthesis of polypyrrolinones on solid support.

Progress in the Synthesis of OPC-15161: Easy Access to Dioxygenated Pyrazine N-Oxide Structure

An improved synthetic route to OPC-15161 (1), a novel inhibitor of superoxide anion generation, is described. Choice of the protecting group is the key to the second-generation synthesis. Usefulness of the 2-cyanoethyl (CE)-protecting group in our process research is emphasized in comparison with that of other protecting groups. This process can be carried out in four steps with 40% overall yield from tryptophan methyl ester, which also opens a general route for the preparation of the related 5-alkoxypyrazin-2(1H)-one 4-oxides.

A second-generation synthesis of polypyrrolinone nonpeptidomimetics: prelude to the synthesis of polypyrrolinones on solid support.

[reaction: see text] A second-generation asymmetric synthesis of polypyrrolinones (3) has been achieved exploiting scalemic alpha-aminolactones (1) as building blocks. Imine formation between an appropriate lactone (1) and aldehyde (2), followed in turn by pyrrolinone ring construction promoted by KHMDS in the presence of 18-crown-6 and modified Swern oxidation furnished pyrrolinone aldehyde 3. This iterative, efficient three-step protocol paves the way for the synthesis of polypyrrolinones on solid support.

Total Syntheses of (−)-Lycoricidine, (+)-Lycoricidine, and (+)-Narciclasine via 6-exo Cyclizations of Substituted Vinyl Radicals with Oxime Ethers

The development of an approach to the total synthesis of the title alkaloids is described. The approach utilizes as the key strategic element a stereoselective 6-exo radical cyclization of a vinyl radical to an O-benzyloxime radical acceptor group. The vinyl radical was itself generated by regioselective addition of phenylthiyl radical to a disubstituted alkyne. The regiochemical issues of such additions, which result in different outcomes with tri-n-butylstannyl radicals and phenylthiyl radicals, are discussed. The first such synthesis described, that of (−)-lycoricidine, proceeded in 14 steps and 11% overall yield from 10 and served to develop the radical chemistry required. A second-generation synthesis, this time of the natural (+) enantiomer, was developed using insights gleaned from the first study and proved much more efficient, providing the target alkaloid in nine steps and 44% overall yield. This approach was then employed in the more demanding case of (+)-narciclasine. Several problems arising ...

Toward the second-generation synthesis of zaragozic acids: Construction of the 2,8-dioxabicyclo[3.2.1]octane core system via tandem carbonyl ylide Formation and 1,3-dipolar cycloaddition sequence

A highly efficient construction of the 2,8-dioxabicyclo[3.2.1]octane core structure of zaragozic acids, inhibitors of the enzyme squalene synthase, has been achieved by exploiting the sequence of rhodium(II)-mediated intramolecular carbonyl ylide formation from an α-diazo ester and stereocontrolled 1,3-dipolar cycloaddition with (E)-3-hexene-2,5-dione.

A second-generation synthesis of scalemic 3,5,5-trisubstituted pyrrolin-4-ones: Incorporation of functionalized amino acid side-chains

To access mimics of peptidal β-strands ( 1), scalemic 3,5,5-trisubstituted pyrrolin-4-ones bearing the tyrosine, serine, and lysine side-chains have been generated via cyclization of metalated imino esters and deprotection. The functionalized imino esters were prepared by asymmetric alkylation of a common oxazolidinone precursor ( 2) derived from L-prenylglycine.

Studies on tumor promoters. 9. A second-generation synthesis of phorbol

Studies on tumor promoters. 9. A second-generation synthesis of phorbol

Indole diterpene synthetic studies. 5. Development of a unified synthetic strategy; a stereocontrolled, second-generation synthesis of (-)-paspaline

Cette synthese procede par une conversion en 9 etapes de la cetone(+) de Wieland-Miescher en l'ethyleneacetal d'une desahydro, benzo [e] indenedione-1,7. Ce compose doit etre un intermediaire utile pour la synthese d'autres membres de cette famille d'alcaloides diterpeniques tremorgeniques indoliques