14-membered macrolactone

A convergent total synthesis of 15-membered macrolactone, (-)-amphidinolide P was reported by D.R. Williams and coworkers.In their approach, they utilized the Sakurai aiiyiation to introduce the C7 hydroxyl group and the homoallylic side chain. The transformation was effected by BF3-OEt2 at -78 °C to provide the homoallylic alcohol as a 2 1 mixture of diastereomers. The desired alcohol proved to be the major diastereomer, as it resulted from the Felkin-Ahn controlled addition of the allylsilane to the aldehyde. The minor diastereomer was converted into the desired stereoisomer via a Mitsunobu reaction. 

Reducing Antibacterial Effects of 14- and 15-Membered Macrolactone Macrolides... 

Nicolaou et al. were the first to report the successful use of RCM to prepare the 16-membered macrolactone nucleus of the epothilones and present a strategy for their total synthesis based on this reaction. The approach involved formation of the C12,C13 olefin and is outlined in Scheme 2 [12,13]. 

Erythromycin A (Figure 8.2, 1) is a clinically important antibiotic produced by Saccharopolispora erythraea. It consists of a 14-membered macrolactone ring to... 

The DesVll desosaminyl transferase naturally transfers D-desosamine to both 12- and 14-membered macrolactones, which is an example of inherent flexibility towards the acceptor aglycone. This unusual property of DesVll has been exploited to generate novel macrolide derivatives that differ in size of the macrolactone ring and in their oxygenation/reduction state. A Streptomyces lividans strain in which the genes involved in the biosynthesis and transfer of D-desosamine were... 

The disaccharide fragment of tricolorin A 110, which is a 19-membered macrolactone, was synthesized by efficient RCM of terminal diene 108 to give 109 and its hydrogenation in 77% yield [39]. The presence of sugar groups as a polar relay substituent, its proper distance to the alkene groups, and low steric hindrance close to the double bonds are decisive parameters for the efficient RCM of 108. 

Figure 9 Precursor-directed biosynthesis. A block in the 6-dEB pathway was created by a Cys— Ala mutation in the active site of the KS of module 1. Feeding diketides with different a and j substitutions resulted in the 6-dEB analogs in which the starter unit or first extender unit was modified. The stereochemistry of an unsaturated triketide dictated whether it was incorporated into module 2 or 3, leading to either a 14-membered or 16-membered macrolactone. See Sec. VI.C for details.

Besides conformational disarming, one-pot methods also benefit from building blocks that are electronically disarmed. Biao Yu and coworkers utilized this effect in the one-pot assembly of the 19-membered macrolactone-containing tricolorin A (16) (Scheme 6.3) [13, 14], The key design of their synthesis is the chemoselective activation and coupling of the perbenzylated donor 7 to the bis-acyl-containing disarmed bifunctional acceptor 12. The subsequent glycosylation of macrolactone 14 in the same flask formed the protected tricolorin A15 in 43% overall yield, which was deprotected to provide tricolorin A (16). 

For the cyclization to the 16-membered macrolactone structure of epothilones C and D (= desoxyepothilones A and B, resp. [26]), three different strategies have been used successfully so far (1) Ring-closing olefin metathesis (RCM) between C12 and Cl3. RCM is a comparably new method in total synthesis and underwent enor-... 

A formal total synthesis of oximidine II was achieved by G.A. Molander et al., using an intramoiecuiar Suzuki-type cross-coupiing between an alkenyl potassium trifluoroborate and an alkenyl bromide to construct the highly strained, polyunsaturated 12-membered macrolactone core of the natural product. " The stability of potassium trifluoroborates was exploited in order to establish the best conditions for the macrocyclization. 

INOC was successfully employed in the total synthesis of the 16-membered macrolactone (+)-macrosphelide B 53. Interestingly, the cycloaddition of nitrile oxide generated in situ from 51 was more stereoselective in dioxane than in CH2CI2 (dr 10 1 vs 2 1). The major isomer was then converted into 53 by reductive N-0 bond cleavage, dehydration and MEM deprotection <05OL3159>. 

Isolated from a Bahamian collection of L. majuscula, caylobolide (73) is a unique 36-membered macrolactone that shows cytotoxicity to human colon cancer cell line HCT-166. Caylobolide contains a 1,3,5-triol and a repeating 1,5-diol within the macrocycle. The 1,5-diol had not been reported before the isolation of caylobolide and points to a unique biosynthetic pathway. Additionally, this compound is interesting because of its being atypical of the metabolites usually isolated from cyanobacteria. The 1,5-diol repeat is likely produced from PKS modules that catalyze full reduction of the /1-ketone alternating with those that simply reduce the /1-ketone to an... 

Amphidinolides R (17) and S (18) are minor congeners of amphidinolide J (9). The structure of amphidi-nolide R (17) was assigned as a regioisomer of amphidinolide J (9) having a 14-membered macrolactone ring, since treatment of amphidinolide J (9) and amphidinolide R (17) with sodium methoxide yielded an identical linear methyl ester. On the other hand, amphidinolide S (18) was concluded to be the 9-didehydro form of amphidinolide J (9) by spectroscopic data. ... 

Avermectins and milbemycins are naturally occurring 16-membered macrolactones that show a broad spectrum of anthelmintic and pesticidal activity with relatively low toxicity to both humans and animals. The milbemycins differ from the avermectins primarily in the lack of a disaccharide moiety and oxygen functionality at Cl3,... 

Attempts at altering polyketide chain length have resulted in a number of abridged lactones. By repositioning the thioester domain in DEBS to the C-terminal end of module 5, a 12-membered macrolactone analog of 10-deoxymethynolide, the aglycon precursor to methymycin, was produced [28],... 

The resorcylic acid lactones (RALs) are a family of benzannulated macrolides, which are produced by a variety of fungi and show versatile biological activities (6). According to their name, they consist structurally of a partially substituted p-resorcylic acid scaffold, which is linked to a 12- or 14-membered macrolactone moiety. Selected members of this group are shown in Fig. 9.1. 

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