Total synthesis (±)-Hongoquercin A (1), the racemate of an antibacterial been confirmed by X-ray analysis of its ethyl ester (±)-10. Synthesis of the naturally occurring (+)-hongoquercin A from fungal metabolite, has been synthesized starting from geranylacetone (2) and ethyl orsellinate (ethyl 2,4-(-)-sclareol (11) established its configuration as depicted in 1. dihydroxy-6-methylbenzoate, 5). The structure (±)-1 has
In 1998, Roll et al. isolated hongoquercin A (1) from an unidentified terrestrial fungus as an antibacterial antibiotic against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. [1] They proposed the structure 1, i.e. a sesquiterpene coupled with orsellinic acid, for hongoquercin A, including its relative configuration, mainly on the basis of its NMR analysis. [1] Its absolute configuration, however, remained unknown. We became interested in establishing the absolute configuration of the naturally occurring (ϩ)-hongoquercin A (1) through its synthesis. This paper describes (i) the synthesis of (±)-1, the structure of which was unequivocally established by X-ray analysis of the corresponding ethyl ester (±)-10, and (ii) the synthesis of (ϩ)-1 from (Ϫ)-sclareol (11), the absolute configuration of which is known. The latter work clarified the absolute configuration of (ϩ)-1 as depicted.
Our retrosynthetic analysis of 1 is shown in Scheme 1. As in the case of the synthesis of (±)-K-76 [2] [3] and natural (Ϫ)-K-76, [4] the target molecule 1 can be dissected into the sesquiterpene part A and the orsellinic acid part B, coupling of which would afford the precursor for the closure of the tetrahydropyran C-ring of 1. Building block A is a known compound, [5] while B may readily be prepared from the Scheme 1. Retrosynthetic analysis of hongoquercin A commercially available ethyl orsellinate (ethyl 2,4-dihydroxy-6-methylbenzoate, 5).
(5). Iodination of 5 with benzyltrimethylammonium di-Scheme 2 summarizes our synthesis of (±)-hongoquercin chloroiodate [6] furnished the 3-iodo derivative 6, the phe-A (1). Geranylacetone (2) was converted into the known nolic hydroxy groups of which were protected as bis(2-trialcohol (±)-3 according to Mori and Koga [5] in 15% overall methylsilylethyloxy)methoxy (bisSEM) ether functionalities yield (5 steps). Treatment of (±)-3 with phosphorus tribroto give 7 ( ϭ B). mide afforded the corresponding bromide (±)-4, [5] the ses-Prior to the successful coupling of (±)-4 with 7, various quiterpene part (A) of hongoquercin A (1). Preparation of attempts were made to find suitable conditions for coupling the phenolic acid part B ( ϭ 7) started from ethyl orsellinate of the sesquiterpene part with the phenolic acid part. We first attempted to use a Stille reaction [7] between the allyl-[ ]