Total Synthesis of (−)‐Platensimycin by Advancing Oxocarbenium‐ and Iminium‐Mediated Catalytic Methods

Abstract

(-)-Platensimycin is a potent inhibitor of fatty acid synthase that holds promise in the treatment of metabolic disorders (e.g., diabetes and "fatty liver") and pathogenic infections (e.g., those caused by drug-resistant bacteria). Herein, we describe its total synthesis through a four-step preparation of the aromatic amine fragment and an improved stereocontrolled assembly of the ketolide fragment, (-)-platensic acid. Key synthetic advances include 1) a modified Lieben haloform reaction to directly convert an aryl methyl ketone into its methyl ester within 30 seconds, 2) an experimentally improved dialkylation protocol to form platensic acid, 3) a sterically controlled chemo- and diastereoselective organocatalytic conjugate reduction of a spiro-cyclized cyclohexadienone by using the trifluoroacetic acid salt of α-amino di-tert-butyl malonate, 4) a tetrabutylammonium fluoride promoted spiro-alkylative para dearomatization of a free phenol to assemble the cagelike ketolide core with the moderate leaving-group ability of an early tosylate intermediate, and 5) a bismuth(III)-catalyzed Friedel-Crafts cyclization of a free lactol, with LiClO4 as an additive to liberate a more active oxocarbenium perchlorate species and suppress the Lewis basicity of the sulfonyloxy group. The longest linear sequence is 21 steps with an overall yield of 3.8 % from commercially available eugenol.

Organocatalyzed Synthesis of [3.2.1] Bicyclooctanes

“…Many efforts have been devoted to the synthesis of its cage-like ketolide core. The work of Eey and Lear [4], which can be considered a base-promoted alkylation, uses DBU 3 , DIPEA 6 , and TBAF 7 as bases (Scheme 3). The best result was obtained with 6 and xylene as solvent.…”

“…Gelsemine has attracted considerable attention since its discovery due to its specific antinociception in chronic pain [1,2]. In the same manner, platensimycin possesses a potent and broad-spectrum Gram-positive antibacterial activity, with no cross-resistance to an array of major antibiotic-resistant microbes and has been synthesized several times [3,4]. Vitisinol D, which has not been synthesized in enantiomeric form and only one racemic total synthesis has been described [5], presents antithrombotic properties [6], and finally compounds that are inhibitors of phenylethanolamine N -methyltransferase as PNMT inhibitor [7] are shown in Figure 1.…”

Total synthesis of natural products using hypervalent iodine reagents

“…In 2010, we proposed an asymmetric formal synthesis of (−)-platensimycin 25 (Beaulieu et al, 2010 , 2011 ), a natural antibiotic isolated from a strain of Streptomyces platensis by Wang and Soisson in 2006 and acting as a FabF inhibitor (Wang et al, 2006 ). The intriguing structure and bioactivity of this compound have evoked a great deal of interest in the synthetic arena (Nicolaou et al, 2006 , 2007a , b , 2008 , 2009a ; Lalic and Corey, 2007 ; Li et al, 2007 ; Tiefenbacher and Mulzer, 2007 , 2008 ; Zou et al, 2007 ; Kim et al, 2008 ; Matsuo et al, 2008 ; Ghosh and Xi, 2009 ; McGrath et al, 2009 ; Yun et al, 2009 ; Eey and Lear, 2010 , 2014 ; Palanichamy and Kaliappan, 2010 ; Tiefenbacher et al, 2010 ; Xing et al, 2010 ; Hirai and Nakada, 2011 ; Ueda et al, 2011 ; Zheng et al, 2011 ; Horii et al, 2013 ). As illustrated in Figure 4 , we targeted structure 24 , an advanced intermediate in Nicolaou's synthesis (Nicolaou et al, 2009b ) containing the main tetracyclic core of (−)-platensimycin.…”

A stepwise lactol carbocyclisation to bridged ethers via a keto–acetal cascade

“…Bridged ethers are found in numerous natural products, [1][2][3][4][5][6][7] including the potent anti-cancer agent englerin A (Scheme 1). 2,5,6 Recently, oxabicyclo natural products containing the benzo-8-oxabicyclo[3.2.1]octane core (Figure 1) have been identified as Gram-positive antibiotics, anti-parasitic agents and anti-cancer agents, 1,2 adding further incentive to access such bridged systems.…”

“…Bridged ethers are found in numerous natural products, [1][2][3][4][5][6][7] including the potent anti-cancer agent englerin A (Scheme 1). 2,5,6 Recently, oxabicyclo natural products containing the benzo-8-oxabicyclo[3.2.1]octane core (Figure 1) have been identified as Gram-positive antibiotics, anti-parasitic agents and anti-cancer agents, 1,2 adding further incentive to access such bridged systems. Accordingly, general methods of constructing polysubstituted O-bridged systems with control of stereochemistry are valuable in the synthesis of natural products and new scaffolds for medicinal chemistry.…”