Of pironetin

Kondoh, M., Usui, T., Kobayashi, S., et al. (1998). Cell cycle arrest and antitumor activity of pironetin and its derivatives. Cancer Lett, 126, 29-32. 

ABSTRACT Discodermolide and pironetin are two immunosuppressive agents with antitumor activity. The isolation, structure elucidation, biological activity are reported as well as the synthetic routes to these two compounds. Five syntheses of discodermolide and seven syntheses of pironetin are described. 

There are many cancer therapeutic agents, which inhibit the metaphase progression. So, the in vivo antitumor activity of pironetin in... 

Table 2 Antitumour activity of pironetin againt P388...

The structure of pironetin was determined to be (5/ ,6/ )-5-ethyl-5,6-dihydro-6[(jE )-(2/ ,35,4/ ,55)-2-hydroxy-4-methoxy-3,5-dimethyl-7-nonenyl]-2H-pyran-2-one by FAB-MS, H and 13C NMR, COSY, COLOC, DEPT, IR, X-ray crystallographic analyses and adapted Mosher s method to determined the absolute configuration [74]. The biosynthesis of pironetin appeared to involve assembly of acetate, propionate and butyrate precursors. Four fermentation experiments were carried out in order to determine the biosynthetic origin of the carbon skeleton and oxygen atoms of pironetin. [1-13C] Acetate, [2-13C]acetate, [1,2-13C] acetate, [l-13C]propionate, [l-1 C]butyrate and L-[methyl-I3C]methionine were led separately to Streptomyces sp. culture and pironetin was isolated and purified. Analysis of pironetin by 13C NMR showed that pironetin was derived from four acetate units, two propionate units, one butyrate unit and one methyl unit of methionine [78] (Fig. 4). 

Not only the interesting activities but also the unique and simple structure make pironetin and its derivatives attractive synthetic targets and seven total synthesis of pironetin have been reported. 

Gurjar et al. have developed two strategies, which could be adapted for the preparation of pironetin and of its analogues. The key steps in Gurjar s syntheses, to control the stereogenic centers, are the regioselective opening of epoxides obtained by a Sharpless epoxidation and an Evans aldol condensation. 

In 1997, Chida et al. presented a convergent synthesis of (-)-pironetin starting from L-quebrachitol 131 and L-malic acid. The acyclic portion of (-)-pironetin possessing four contiguous chiral centers were constructed stereoselectively from L-quebrachitol and the 2-pyrane moiety was prepared from L-malic acid. In this synthesis, the nucleophilic addition of a dithiane to epoxide is a strategic key step. 

In 1998 [102], Kitahara et al. reported also a convergent total synthesis of (-)-pironetin by using three chiral buiding blocks the (lS,5S,6R)-5-hydroxy-bicyclo[4.1.0]heptan-2-one, a dithiane and an epoxide. As in the previous synthesis, the nucleophilic addition of the dithiane to the epoxide... 

Keck et al. have used the lactone annulation procedure developed in their laboratory to install the lactone moiety by reaction of the lithium enolate of methylacetate with a (3-acetoxy aldehyde [108]. The other key steps include a diastereoselective Lewis acid mediated (Z)-crotylstannane aldehyde addition, a highly selective Lewis acid promoted Mukaiyama aldol reaction and an arari-selective Sml2 reduction of a p-hydroxyketone. The preparation of the C8-C15 fragment of (-)-pironetin started with the chelation-controlled addition of (Z)-crotyl tri-n-butylstannane to the (3-benzyloxy-aldehyde 153 in the presence of TiCU [109] to give the... 

The synthesis of (-)pironetin began with the known (S)-acyloxazolidone. Asymmetric aldol addition of the boron enolate of A with aldehyde 165 gave the syrc-aldol adduct 166 with an excellent... 

This synthesis required 18 steps from A and the overall yield in (-)pironetin is 11 %. This synthesis is probably one of the shortest approaches of pironetin. 

C.U. Sodium Periodate In section 3.7.A.ii, a mixture of osmium tetroxide and periodic acid oxidatively cleaved alkenes. Sodium periodate can cleave diols directly. In the Chida et al. synthesis of pironetin, for example, 371 was cleaved to dialdehyde 372 using an aqueous acetone solution of NalOq. l Sodium periodate in dichloromethane, in the presence of sodium bicarbonate, has also been used.5l9... 

The Nysted reagent (696) 2 jg commercially available, and it reacts with aldehydes or ketones in the presence of BF3 etherate to give an alkene. Reaction with 2-phenylpropanal, for example, gave an 82% yield of 697.5 3 The Takai reactionist uses MeCHl2 in the presence of CrCl2 to generate the alkene. An example is taken from Chida s synthesis of pironetin in which aldehyde 698 was converted to 699 in 74% yield as an 11 1 mixture of (ElZ) isomers.iSS... 

Scheme 10.19. Chiral template-based retrosynthesis of pironetin (226).

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