The fight against infectious disease rages on as scientists continue their struggle to overcome the emergence of drug resistance through new discoveries in chemistry and biology. [1] The recent discovery of platensimycin (1, Scheme 1) by a Merck research team is a beautiful illustration of how natural products chemistry combined with modern biological techniques can lead to important developments in the search for new antibiotics. [2] Platensimycin (1) was identified by highthroughput screening and RNA silencing technologies as a potent and selective inhibitor of the b-ketoacyl-(acyl-carrierprotein) synthase (FabF). Flexible synthetic routes to platensimycin may be particularly useful in accessing novel analogues that may prove superior to the natural product with regard to its pharmacological properties. [3] Herein we report a new synthetic strategy that leads from the readily available and inexpensive (R)-(À)-carvone ( 7) to the tetracyclic enone 2-a convenient precursor to platensimycin (1).
Scheme 1 outlines, in retrosynthetic format, the overall plan for the construction of the required enone 2 starting from (R)-(À)-carvone (7). Thus, enone 2 was expected to arise from tricyclic ketone 3, whose connection to bicyclic keto aldehyde 4 could be recognized through a retro-anionic or radical 1,4addition reaction. The origins of 4 were then traced to hydroxy keto acetal 5 by standard functional-group manipulations. Finally, 5 was envisioned to arise from enone 6 through a radical-based ring closure, with the latter intermediate being readily traced back to (R)-(À)-carvone (7) through a retro-Grignard reaction.
According to the synthetic blueprint, the synthesis of 2 began from (R)-(À)-carvone (7, Scheme 2). Thus, 1,2-addition of Grignard reagent 8 to (À)-carvone (7) under Luche conditions (CeCl 3 ) [4] led to the corresponding tertiary alcohol, which was directly oxidized (PCC) without further purification to afford enone 6 in 90 % yield for the two steps. Intramolecular radical cyclization within the substituted carvone 6 with concomitant construction of the C8 quaternary center was accomplished through application of the sequential oxymercuration/reductive-alkylation methodology pioneered by Giese. [5] In this instance, treatment of 6 with Hg(OAc) 2 resulted in selective Markovnikov oxymercuration of the geminal disubstituted alkene. The intermediate organomercurial species was then reduced with NaBH 4 , presumably leading to the corresponding primary radical, which underwent 1,4-addition onto the enone system, thereby furnishing a mixture (ca. 1:1) of exo (5 a) and endo (5 b, existing predominantly as its hemiketal form 5 b'; 5 b'/5 b ca. 6:1) alcohols in 61 % yield. Dehydration of a mixture of 5 a + 5 b/5 b' with Martins sulfurane [6a,b] led to exocyclic alkene 9, [6c] which was subjected to a regioselective silyl enol ether formation (TMSI, HMDS) followed by an electrophilic quench with PhSeCl, and subsequent oxidative elimination (H 2 O 2 ) to give enone 10 in 36 % yield from 5 a + 5 b/5 b'. Finally, unveiling of the dioxane-masked aldehyde in 10 was achieved under micro-Scheme 1. Structure and retrosynthetic analysis of (À)-platensimycin (1).