A synthetic and in silico study on the highly regioselective Diels-Alder reaction of the polyenic antifungal antibiotics natamycin and flavofungin

The tetraenic macrolide antibiotic natamycin and the pentaenic macrolide flavofungin gave monoadducts on Diels-Alder reaction with 4-phenyl-1,2,4-triazoline-3,5-dione. The regioselectivity of the reaction as well as the conformation of the products was studied using theoretical calculations.     

A total synthesis of the antitumour macrolide rhizoxin D

An enantioselective synthesis of rhizoxin D, isolated from the plant pathogenic fungus Rhizopus chinensis, is described. The overall strategy is based on elaboration of the delta-lactone-substituted vinyl stannane and the phosphonate-substituted vinyl iodide, followed by their coupling to the core 16-membered macrolide via a sequential intermolecular Horner-Wadsworth-Emmons olefination, leading to (50), and by an intramolecular Stille reaction. The triene oxazole-containing side chain in rhizoxin D is then introduced using the phosphine oxide in an E-selective Horner-Wittig reaction with the macrolide aldehyde.     

Rapid entry into the cryptophycin core via an acyl-beta-lactam macrolactonization: total synthesis of cryptophycin-24

[see structure]. An efficient, concise approach to the macrolide core of the cryptophycins, potent antimitotic agents, has been achieved. The reaction sequence features a novel macrolactonization utilizing a reactive acyl-beta-lactam intermediate that incorporates the beta-amino acid moiety within the 16-membered macrolide core. This highly modular approach, which allows for multiple alterations throughout the structure, was successfully applied to the total synthesis of cryptophycin-24.     

Total synthesis of aigialomycin D

[reaction: see text] The first total synthesis of resorcinylic macrolide aigialomycin D was described. The resorcinylic moiety was constructed by a highly efficient Diels-Alder reaction using a disiloxydiene and a 14-membered "ynolide" as the dienophile synthesized by ring-forming olefin metathesis.     

Synthesis of new 14-membered macrolide antibiotics via a novel ring contraction metathesis

[reaction: see text] A novel ring opening ring closing metathesis (ROM-RCM) was demonstrated for cyclic conjugated dienes, effecting the excision of a C(2)H(2) unit and a net ring contraction. Applying the ring contraction metathesis, new 14-membered ring macrolide antibiotics were synthesized in a single step from existing 16-membered ring macrolides. This new class of macrolide antibiotics will provide access to new therapeutics for the treatment of macrolide-resistant bacterial infections.     

Total synthesis of pikromycin

The total synthesis of pikromycin (6), the first isolated macrolide antibiotic, was achieved. The target macrolide was retrosynthetically divided into two parts, pikronolide (6a) (aglycon) and D-desosamine. The aglycon was synthesized using key reactions such as an asymmetric aldol reaction, Yamaguchi esterification, and ring-closing metathesis. The aglycon was coupled successfully with the trichloroacetimidate derivative of D-desosamine under Lewis acidic conditions to afford pikromycin. Narbomycin (5) was also synthesized from narbonolide (5a) under identical conditions.     

Total synthesis of the marine macrolide (+)-neopeltolide

A concise total synthesis of the antiproliferative macrolide (+)-neopeltolide has been completed, utilising a Jacobsen hetero Diels-Alder reaction to install the trisubstituted tetrahydropyran ring.     

First stereoselective total synthesis of antibiotic macrolide Berkeleylactone F

The first stereoselective total synthesis of antibiotic macrolide Berkeleylactone F is described. The synthetic sequence notably features Sharpless kinetic resolution to access chiral epoxide followed by its regioselective ring-opening reaction, Sharpless asymmetric reaction and ring-closing metathesis.     

Synthesis and stereochemical elucidation of a 14-membered ring phosphonate

[structure: see text]. We report the synthesis and stereochemical elucidation of a 14-membered ring phosphonate. The key step in the synthesis of the macrolide phosphonate was the cyclization of the acyclic precursor using the Mitsunobu reaction, a mild reaction for the preparation of mixed phosphonates.     

4 + 2]-annulations of chiral organosilanes: Application to the total synthesis of leucascandrolide A

Complete details of an asymmetric synthesis of leucascandrolide A (1) are described. The synthesis highlights the use of two diastereoselective [4 + 2]-annulations for the assembly of the functionalized bispyranyl macrolide 3. An efficient assembly and union of the oxazole-containing side chain 4 with macrolide 3 was carried out using a Mitsunobu reaction. A convergent route to the oxazole side chain was developed using a Sonogashira cross-coupling between 2-trifloyloxazole 16 and alkyne 17, which allowed for the installation of the C9'-C10' (Z)-olefin.     

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.     

Total synthesis of aspercyclide C

The first total synthesis of (+)-aspercyclide C (1) is reported using a kinetically controlled RCM reaction to form the 11-membered, unsaturated lactone ring of this bioactive diaryl ether macrolide.     

Asymmetric synthesis of the polyol subunit of the macrolide antibiotic, ossamycin

An asymmetric synthesis of the C1-C16 polyol subunit of the macrolide antibiotic, ossamycin, has been achieved through stepwise carbon-chain elongation reaction from d-glucose.     

Synthetic studies toward pondaplin: total synthesis of pondaplin analogues

Syntheses of synthetic analogues of pondaplin 1 have been achieved. Final macrolide construction was accomplished using a Keck macrolactonization reaction.     

Synthetic studies toward potent cytostatic macrolide rhizopodin: stereoselective synthesis of the C16-C28 fragment

A stereoselective synthesis of the C16-C28 fragment of cytostatic C₂-symmetric macrolide rhizopodin is described. Enantioselective addition of a chiral thiazolidinethione derived titanium enolate to acetal, Evans’ aldol reaction, Horner-Wadsworth-Emmons reaction, and Mukaiyama aldol reaction were applied as key steps.     

Formal total synthesis of cyanolide A

Formal total synthesis of cyanolide A, aglycosidic dimeric macrolide is accomplished. The key reactions involved are asymmetric acetate aldol reaction, CBS reduction, and Shiina's lactonization.     

Total Synthesis of (−)-Bafilomycin A1: Application of Diastereoselective Crotylboration and Methyl Ketone Aldol Reactions

A careful orchestration of protecting groups is an essential requirement for the total synthesis of the macrolide antibiotic bafilomycin A₁ ( 1 ). Key steps were the Suzuki cross-coupling reaction of two advanced, suitably protected intermediates prior to closure of the macrocycle, as well as a highly stereoselective methyl ketone aldol reaction.     

Stereoselective synthesis of the cytotoxic macrolide FD-891

[reaction: see text] A total synthesis of the naturally occurring, cytotoxic macrolide FD-891 is described. Three fragments were first stereoselectively constructed using mainly asymmetric aldol and allylation reactions. The complete framework was then assembled using two Julia-Kocienski olefinations to connect the three fragments and a Yamaguchi reaction to close the macrolactone ring.     

Synthetic studies on goniodomin A: convergent assembly of the C15-C36 segment via palladium-catalyzed organostannane-thioester coupling

A stereocontrolled convergent synthesis of the C15-C36 segment of goniodomin A, a potent anti-angiogenic marine polyether macrolide, has been achieved using Stille-type cross-coupling reaction of a vinylstannane and a thioester as a key segment assembly process.     

Synthetic studies toward the construction of the cis-decalin portion of superstolides A and B. Application of a sequential double michael reaction and an anionic oxy-Cope rearrangement

A highly convergent strategy for the asymmetric synthesis of the cis-decalin portion of the antitumor macrolide superstolide A was developed. The key reactions in our approach involve a sequential double Michael reaction and an anionic oxy-Cope rearrangement.