Stereoselective synthesis of the C14-C26 fragment of the cytotoxic macrolide FD-891

A stereoselective synthesis of the C₁₄-C₂₆ fragment of the naturally occurring, cytotoxic macrolide FD-891, is described. Asymmetric Evans aldol reactions and aldehyde Brown allylations are key steps of the synthesis.     

Stereoselective synthesis of the cytotoxic macrolide aspergillide B

A total, stereoselective synthesis of the cytotoxic macrolide aspergillide B has been performed. A cross metathesis and a C-glycosidation via a Mukaiyama-type aldol reaction were key features of the synthesis. The macrocyclic lactone ring was created by means of the Yamaguchi procedure.     

The total synthesis and biological properties of the cytotoxic macrolide FD-891 and its non-natural (Z)-C12 isomer

A total, stereoselective synthesis of the naturally occurring, cytotoxic macrolide FD-891 and of its non-natural (Z)-C12 isomer is described. Three fragments of the main carbon chain were stereoselectively prepared by using asymmetric aldol and allylation reactions as the key steps. The molecule was then assembled by using two Julia-Kocienski olefinations to connect the three fragments and a Yamaguchi reaction to close the macrolactone ring. Some specific biological properties (cytotoxicity, binding to tubulin) have been determined for both macrolides. The E configuration of the C12-C13 olefinic bond seems to be an important feature in determining the cytotoxicity but the precise biological mechanism of the latter still remains to be cleared.     

Enantioselective total synthesis of FD-891

The enantioselective synthesis of FD-891 has been achieved with a longest linear sequence of 21 steps. The synthetic strategy involves the use of aldol additions of a chlorotitanium enolate of N-acylthiazolidinethiones as the key reaction to establish 6 of the 10 stereogenic centers. A key cross-metathesis and a late-stage Julia olefination serve to assemble three key subunits.     

Stereostructure of a novel cytotoxic 18-membered macrolactone antibiotic FD-891

The absolute stereochemistry of FD-891, a novel cytotoxic 18-membered macrolactone antibiotic, was determined by a synthetic approach as well as X-ray diffraction of degradative derivatives. The absolute configuration of FD-891 turned out to be as shown above. The stable conformer of FD-891 was also discussed with respect to biological activity by comparison with the structurally related concanamycin A on the bases of molecular mechanics calculations. [structure: see text]     

Stereoselective synthesis of the phorboxazole A macrolide by ring-closing metathesis

[Structure: see text] Described is a regio- and stereoselective ring-closing metathesis (RCM) to form the C2-C3 alkene of the macrolide-containing domain of phorboxazole A. This work demonstrates a dramatic effect of reaction solvent on RCM product (E/Z)-selectivity. This process offers an alternative assembly of the macrolide-containing domain of phorboxazole A, one of the most potent anticancer agents known.     

Stereoselective total synthesis of antitumor macrolide (+)-rhizoxin D

[structure: see text] A convergent, stereoselective total synthesis of the macrolide antitumor agent rhizoxin D is described. (+)-DIPCl-promoted asymmetric aldol reaction, Evans-Tishchenko 1,3-diol synthesis, modified Julia coupling, and Horner-Wadsworth-Emmons reactions are featured.     

Stereoselective synthesis of the monomeric unit of actin binding macrolide rhizopodin

An efficient, scalable, and stereocontrolled synthesis of the entire carbon framework of an actin binding dimeric macrolide rhizopodin has been accomplished in its protected form. The key features of our synthesis include a titanium catalyzed anti acetal aldol reaction, a substrate controlled diastereoslelective prenyl stannylation, a Mukaiyama aldol reaction, an indium mediated diastereoselective propargylation, and an advanced stage Stille coupling reaction.     

Stereoselective total synthesis of cytotoxic sporiolide A

A simple and highly efficient stereoselective total synthesis of cytotoxic agent sporiolide A has been achieved starting from d-mannitol; the strategy of synthesis utilizes stereoselective zinc-mediated allylation, aldol coupling and ring-closing metathesis as key steps.     

Stereoselective synthesis of cytotoxic anhydrophytosphingosine pachastrissamine [jaspine B

A practical stereoselective synthesis of cytotoxic anhydrophytosphingosine pachastrissamine (jaspine B) was achieved in 48% overall yield from D-(-)-tartaric acid. Key features of the sequence include the diastereoselective formation of a tetrol with three contiguous chiral centers, which was further elaborated to pachastrissamine. The synthetic route is operationally simple, diastereoselective and is amenable for the synthesis of a number of analogues of pachastrissamine.     

Stereoselective total synthesis of the cytotoxic lactone (−)-spicigerolide

A highly stereoselective synthesis of the naturally occurring lactone (−)-spicigerolide has been achieved utilizing OsO₄-catalyzed dihydroxylation, CBS, Lindlar’s reductions, Still-Gennari, and Grignard reactions as the key reaction steps.     

A divergent approach to apoptolidin and FD-891: asymmetric preparation of a common intermediate

Biologically active Apoptolidin and FD-891 have structural similarity in their macrocyclic cores. Asymmetric preparation of a common intermediate in the total synthesis of these two macrolides is presented. A modified Masuyama Sn-allylation was employed to control the relative stereochemistry in the synthesis of the intermediate.     

Stereoselective total synthesis of arenastatin A, a spongean cytotoxic depsipeptide

A highly stereoselective total synthesis of arenastatin A, an extremely potent cytotoxic cyclic depsipeptide from marine sponge, was developed. The desired 7,8-β-epoxide in arenastatin A was constructed by asymmetric sulfur ylide-mediated epoxidation in good yield and highly stereoselective manner.     

Stereoselective synthesis of both tetrahydropyran rings of the antitumor macrolide, (-)-lasonolide A

Stereoselective syntheses of both functionalized tetrahydropyran subunits of (-)-lasonolide A are described. These tetrahydropyran rings were constructed using catalytic asymmetric hetero Diels-Alder reactions as the key steps. The C22 quaternary stereocenter present in the upper tetrahydropyran ring was constructed by a stereoselective alkylation, and the C9 hydroxy stereochemistry of the bottom tetrahydropyran was constructed by a stereoselective epoxidation followed by a regioselective epoxide opening reaction.     

A concise stereoselective formal total synthesis of the cytotoxic macrolide (+)-Neopeltolide via Prins cyclization

A convergent and highly stereoselective formal total synthesis of the naturally occurring, cytotoxic 14-membered macrolide neopeltolide has been achieved via two Prins cyclizations.     

Stereoselective synthesis of cytotoxic anhydrophytosphingosine pachastrissamine (jaspine B) from D-xylose

The first naturally occurring anhydrophytosphingosine, pachastrissamine (jaspine B), a marine compound cytotoxic toward P388, A549, HT29, and MEL28 cell lines at IC(50) = 0.01 microg/mL level, has been stereoselectively synthesized from D-xylose in 10 linear steps with 25.7% overall yield.     

Stereoselective synthesis of premisakinolide A, the monomeric counterpart of the marine 40-membered dimeric macrolide misakinolide A

[structure: see text] The first synthesis of premisakinolide A, the monomeric counterpart of misakinolide A, the marine 40-membered macrolide displaying potent activity against a variety of human carcinoma cell lines, has been reported. The strategy was highlighted by a crucial coupling of a tetrahydropyran fragment and an alkynylaluminum reagent having a polypropionate chain, the highly stereoselective cross aldol reaction of segment A and segment B, and the stereospecific construction of the polypropionate structure based on original acyclic stereocontrol.     

Total synthesis of cytotoxic macrolide amphidinolide B1 and the proposed structure of amphidinolide B2

The first enantioselective total syntheses of cytotoxic macrolide amphidinolide B1 and the proposed structure for amphidinolide B2 have been accomplished. Key features of the syntheses include a diastereoselective aldol condensation, a spontaneous Wadsworth-Emmons macrocyclization and a directed epoxidation/elimination sequence.     

Enantioselective synthesis of aurisides A and B, cytotoxic macrolide glycosides of marine origin

The enantioselective synthesis of aurisides A and B, macrolide glycosides of marine origin, was achieved by a convergent approach. The C1-C9 segment 4 was prepared from (R)-pantolactone, and the C10-C17 segment 14 was synthesized from (R)-glycidyl trityl ether. The Nozaki-Hiyama-Kishi reaction between 4 and 14 and subsequent reactions gave seco acid 10, which was converted into the aglycon (3) of aurisides by construction of the 14-membered lactone and bromine-substituted conjugated diene. The glycosylation reaction of the aglycon provided aurisides A and B.