Enantioselective Synthesis of 8-<i>epi</i>-Xanthatin and Biological Evaluation of Xanthanolides and Their Derivatives

Abstract

An enantioselective synthesis of 8-epi-xanthatin (9) has been accomplished starting from the bicyclic lactone 3, which has been used for the synthesis of other xanthanolides, sundiversifolide (4) and diversifolide (5), through a synthetic route without the use of a selenium species. Additionally we have evaluated antimicrobial activities of five natural xanthanolides and their derivatives. Although the synthetic xanthanolides did not show any activity against methicillin-resistant Staphylococcus aureus (MRSA), some of the synthetic intermediates did exhibit moderate antimicrobial activities.Key words xanthanolide; enantioselective synthesis; antimicrobial activity; methicillin-resistant Staphylococcus aureus Multidrug-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) continue to pose clinical challenges. 1,2) Recently the emergence of community-acquired MRSA has compounded the problem 3,4) and focused increased attention on efforts to develop new anti-MRSA drugs.In 1997, Sato et al. 5) reported that xanthatin (7), a member of the xanthanolides, 6) a sesquiterpene family possessing the characteristic oxabicyclo[5.3.0] decene core as its common basic carbon framework, exhibited potent anti-MRSA activity with an MIC value of 7.8 µg/mL. Xanthanolide sesquiterpenes were isolated from Helianthus annuus L. or Xanthium sp. and divided into two groups according to the configuration of their cis-and trans-ring junctions. Representative examples of the cis-fused xanthanolides are the sundiversifolide (4), 7-10,11) the diversifolide (5) 10,12) and the 8-epi-xanthatin (9) 11,13,14) ; xanthatin (7) 11,15) and 11α,13-dihydroxanthatin (8) belong to the trans series. 11,16) They are known for their wide variety of interesting allelopathic, 17) cytotoxic, 18) anti-leishmanial, 19) and anti-MRSA activity.5) As part of our ongoing program directed towards the synthesis of xanthanolides, we have established an efficient access to both cis-and trans-xanthanolides starting from the bicyclic lactone 2 with a cis ring juncture, which can be prepared from the Evans aldol adduct 1 as the common key intermediate in an optically pure form, and have achieved the total synthesis of four xanthanolides, 4, 5, 6 and 7. In this report we describe an enantioselective synthesis of 8-epi-xanthatin (9) starting from 3, which is the intermediate for 4 and 5, and the biological evaluation of the compound library including the five xanthanolides and their derivatives (Chart 1).8-epi-Xanthatin (9), commonly isolated from the extracts of the aerial parts of various species in the genus Xanthium, has also been obtained upon elimination of acetic acid from xanthumin (8-epi-2-acetoxy-3-hydroxanthatin). It has been shown Note * To whom correspondence should be addressed. e-mail: shishido@ph.tokushima-u.ac.jp 12) total synthesis of 1. In our previous synthesis of xanthatin (7), 15) which possesses a similar basic carbon framework and functionalities except for the stereochemistry on the ring junction, we employed two types of syn...

Xanthanolides in Xanthium L.: Structures, Synthesis and Bioactivity

“…In the same year, Martin et al, reported the first total synthesis of the (+)-8-epi-xanthatin starting from the commercially available ester in 14 steps with overall yield of 5.5% [ 86 ]. In 2008, Shishido et al, completed the enantioselective total synthesis of xanthatin by the construction of the vinyl functionality at C1 and the exo-methylene at C11 via the syn-elimination of selenoxides from an optically pure cis-fused bicyclic lactone, and then, they reported an enantioselective total synthesis of 8-epi-xanthatin ( 2 ) by developing a synthetic route without the stoichiometric selenium reagents in 2012 [ 87 , 88 ]. In 2012, Tang et al, developed a method to synthesize the enantiopure γ-butyrolactones via a controllable Wagner–Meerwein-type dyotropic rearrangement of cis-β-lactones and successfully applied it to prepare a number of xanthanolides [ 89 ].…”

Advances in the Total Synthesis of Xanthanolide‐Type Sesquiterpenoids

“…In 2012, Shishido et al. reported the enantioselective synthesis of 8‐ epi ‐xanthatin ( 2 ) based on the above chemistry . Starting from key intermediate 87 , diene 99 was obtained through sequential deprotection, an Appel reaction, and a base‐promoted β‐elimination reaction.…”

Natural sesquiterpenoids

“…273 Known xanthanolides have been found in Inula sericophylla 439 and Xanthium sibiricum. 386 An enantioselective synthesis of 8-epi-xanthatin has been described, 440 whilst syntheses of this lactone and other xanthanolides have been achieved using a controllable dyotropic rearrangement of cis-blactones. 441 The activity of xanthatin on gastric carcinoma cells 442 and lung cancer cells 443 has been investigated.…”