Leinamycin

DNA alkylation has the potential to yield a time-dependent spectrum of adducts, in which initially formed kinetically favored lesions give way to the thermodynamically favored adducts over time. Reversible alkylation has been observed at several of the nucleophilic sites in DNA, including N3A (CC-1065,7, Scheme 8.10, duocarmycin, 8)," " NIA (qui-none methide, 9)," N7G (leinamycin, Schane 8.11, aflatoxin Bj epoxide, 10 and quinone methide, 9),57.ii4.ii8 (quinone methide, 9)," and bPG (ecteinascidin 743,11)." The bidentate Nl/ISPG adduct of malondialdehyde also forms reversibly. ... 

Reaction of thiolates with the l,2-dithiolan-3-one 1-oxide heterocycle of leinamycin generates the snlfenate intermediate Cyclization of this sulfenate onto... 

A more complex structure is that of leinamycin 45 (Scheme 15), a material with potent cytotoxic and antitumor properties, isolated from a Streptomyces sp. A 1,2 dithiolane-3-one ring is spiro fused to a complex macrolactam96 (and references therein). Leinamycin has the remarkable ability to cleave DNA. In brief, leinamycin reacts with a thiol and, after a profound rearrangement, forms an episulfonium ion. This ion alkylates the N7 position of guanosine residues in double stranded DNA an unstable adduct is depurinated by hydrolysis of the glycosidic bond between the alkylated base and a deoxyribose residue. Some structurally less complex l,2-dithiolane-3-one 1-oxides have a similar DNA cleaving ability.97... 

A synthesis of the functional core of the antibiotic leinamycin consisted of several steps, one of them being the preparation of an alkyl-substituted thietanone in moderate yield by cyclization of 2-mercapto propionic acid derivatives in isobutyl chloroformate and in the presence of triethylamine (Scheme 20) <2003T833, 2003PS1163>. 

A similar intramolecular Wittig-Horner reaction provides a key 5,6-dihydropyran-2-one 880 intermediate during synthetic studies towards leinamycin. The choice of base, lithium tert-butylate (/-BuOLi), is vital for the high yield observed due to the importance of the lithium cation for smooth deprotonation of the phosphonoacetate, the first time this base is documented during a Wittig-Horner olefination (Equation 353) <2005T7481>. 

Although some examples have previously shown the feasibility of this reaction, very few studies have been reported recently. The isolation of a new antibiotic, leinamycin, featuring a novel dithioperoxyester S-oxide moiety, led Pattenden and Shuker [249] to a strategy based upon the [2+2] cycloaddition of a thioketone and a ketene. The expected 4-membered ring thio-lactone was obtained, albeit in modest yield, very probably due to the low thermal stability of thioacetone. The product could be transformed into a model dithiolane oxide. 

By these reactions, optically active 1,2-diol units can be positioned efficiently on the desired carbon skeletons. Recently, the above methodologies have been successfully utilized for the stereoselective syntheses of natural and unnatural poly-oxy compounds such as monosaccharides, leinamycin, paclitaxel (Taxol ), and a part of rapamycin. ... 

Tang GL, Cheng YQ, Shen B. Leinamycin biosynthesis revealing unprecedented architectural complexity for a hybrid polyketide synthase and nonribosomal peptide synthetase. Chem. Biol. 2004 11 33-45. 

A recent study on the reactivity of the parent benzo-l,2-dithiolan-3-one 1-oxide 79a (R = R = H) and o- and /i-substituted derivatives 79b-g with -propyl thiol in acetone/water mixture (7/3) was prompted (Table 5) by the observation that the DNA-cleaving activity and antitumor activity of leinamycin 5 depends, in part <2005JOC6968>, on initial thiol attack on its l,3-dioxo-l,2-dithiolane functionality. Experimental results have proved that the presence of chlorine as an electron acceptor in the /i ra-position relative to the sulfmyl sulfur S-1 of precursor 79e and ortho-substituents with lone electron pairs in the case of precursors 79b and 79d are responsible for increased product formation of polysulfanes 80 and 81. A rationale in terms of substituent effects, operating through-space and through-bond of the intermediates a and b, respectively, was suggested. In other words, the reaction is favored by ortho-substituents with lone pair electrons next to the dithiolanone-oxide (S-1) reaction center or a decrease of the electron density at the /i ra-position. 

An efficient approach to the synthesis of l,2-dithiolan-3-one 1-oxide, which is the bioactive moiety of macrolactam-type antiobiotic leinamycin 5, involves the sequence of reactions shown in Scheme 49 <2004TL4307, 2006JME5626>. 

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