Extractives from Guttiferae. Part XXV. Synthesis of the natural 1,5-dioxygenated xanthones, dehydrocycloguanandin, guanandin, isoguanandin, and 5-hydroxy-1-methoxyxanthone

Quillinan, A. J.; Scheinmann, F.

doi:10.1039/p19720001382

Cited by 22 publications

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“…23 This alkyne 8 was then subjected to microwave conditions at 180 C to yield the cyclized material 9. Although there have been reports supporting the regiochemical outcome of this type of thermal cyclization reaction, [24][25][26][27][28] it does appear to go against conventionally held steric arguments which would Scheme 1 Retrosynthetic analysis of (À)-deguelin, featuring a late-stage oxidative alpha-arylation and a thiourea-catalyzed intramolecular cyclization. dictate that the cyclization occur in the opposite direction.…”

Section: Resultsmentioning

confidence: 99%

A concise enantioselective synthesis and cytotoxic evaluation of the anticancer rotenoid deguelin enabled by a tandem Knoevenagel/conjugate addition/decarboxylation sequence

Farmer

Scheidt

2013

Chem. Sci.

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(−)-Deguelin is a rotenoid natural product that possesses significant potential as a chemopreventive and chemotherapeutic agent. While several racemic syntheses of deguelin have been reported, a formal evaluation of the anticancer activity of both the natural and unnatural enantiomers remains lacking. We describe herein the successful application of a flexible and selective thiourea-catalyzed cyclization strategy toward the enantioselective total synthesis of deguelin, which allows access to either stereoisomer for biological studies. The synthesis was completed in six steps (longest linear) with no protecting groups. The evaluation of both enantiomers of the natural product demonstrated potent inhibition of several cancer cell lines by these compounds, but interestingly showed that the unnatural (+)-deguelin preferentially inhibited the growth of MCF-7 breast cancer and HepG2 liver carcinoma cells when compared to the natural product.

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Section: Resultsmentioning

confidence: 99%

A concise enantioselective synthesis and cytotoxic evaluation of the anticancer rotenoid deguelin enabled by a tandem Knoevenagel/conjugate addition/decarboxylation sequence

Farmer

Scheidt

2013

Chem. Sci.

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“…Heating of the latter compound in refluxing xylene induced a Claisen rearrangement, [7] furnishing, after desilylation with TBAF, benzopyran derivative 14 in 93 % overall yield. Finally, a second propargyl ether was introduced in 14; selective reduction (H 2 , Lindlar catalyst) of the acetylenic group to the corresponding olefin and Claisen rearrangement under thermal conditions provided the targeted prenylated benzopyran segment 5 in 53 % overall yield.…”

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confidence: 99%

“…With its unique spiroxalactone framework carrying a prenylated dihydrobenzoquinone moiety and a trioxatetracyclo [7.4.1.0 2,7 .0 2,11 ]tetradecane system, lateriflorone (1) represents an unusual synthetic challenge. Reported in 1999, this novel natural product [1] was isolated from the stem bark of Garcinia Lateriflora Bl (Guttiferae) collected from Indonesia, and it exhibits potent cytotoxicity against the P388 cancer cell line (ED 50 = 5.4 mg mL À1 ).…”

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confidence: 99%

Total Synthesis of 1‐O‐Methyllateriflorone

Nicolaou

Sasmal

et al. 2003

Angew Chem Int Ed

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With its unique spiroxalactone framework carrying a prenylated dihydrobenzoquinone moiety and a trioxatetracyclo [7.4.1.0 2,7 .0 2,11 ]tetradecane system, lateriflorone (1) represents an unusual synthetic challenge. Reported in 1999, this novel natural product [1] was isolated from the stem bark of Garcinia Lateriflora Bl (Guttiferae) collected from Indonesia, and it exhibits potent cytotoxicity against the P388 cancer cell line (ED 50 = 5.4 mg mL À1 ). Its seemingly fragile structure was secured by spectroscopic and X-ray crystallographic analysis. The secret of its stability, particularly at the spiroxalactonedihydroquinone junction, is probably due to the syn arrangement between the C2' proton and the C3' ester grouping which locks the leaving group in place, avoiding the belimination pathway that may lead to its rupture. The intriguing structural features of lateriflorone, coupled with its biological activity, prompted us to seek a possible pathway for its construction in the laboratory. Herein we report our findings thus far in this project, including the first total synthesis of 1-O-methyllateriflorone (2).We planned our synthesis of 1-O-methyllateriflorone (2) based on the expectation that the ester bond would be the easier bridge to forge between the two domains of the molecules. The retrosynthetic analysis began with the disconnection of the spiroxalactone moiety by rupturing its ethereal C À O bond, thus unraveling prenylated quinone 3 as a possible precursor (Scheme 1). The next rational disconnections, namely retro-aromatization of 3 and disassembly of its precursor 4 at the ester bond led to fragments 5 and 6 as suitable starting materials. Given our previous studies on forbesione, [2,3] a naturally occurring substance related to the present target, the cage ring system 6 [4] can be traced to the benzenoid compound 7. The coupling partner 5 can be obtained from a simple benzene derivative.The required prenylated 2,2'-dimethybenzopyran fragment 5 was synthesized as summarized in Scheme 2. Thus, 2,3-dihydroxybenzaldehyde (8) was selectively benzylated at the 3-position according to a literature procedure [5] to afford compound 9, which was converted into bromophenol 10 in 61 % overall yield by the following sequence: a) bromination para to the phenolic group; b) protection as a MOM ether, c) oxidation with m-CPBA; and d) cleavage of the resulting formate ester with NaHCO 3 (for abbreviations of reagents and protecting groups, see legends in schemes). Protection of the phenolic group in 10 as a TIPS ether to form 11 proceeded smoothly under standard conditions (TIPSCl, imid, 96 %). Boronation of 11 required premixing of the substrate with B(OiPr) 3 prior to addition of tBuLi in Et 2 O at À78 8C. The resulting borate derivative was then oxidized with H 2 O 2 under basic conditions (NaOH), and the resulting phenolic product was methylated to afford 12 in 76 % overall yield from 11. Scheme 1. Retrosynthetic analysis of lateriflorone (1).

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“…According to the reports, the following Claisen rearrangement‐cyclization may have two cyclization directions 14, 15, which could lead to the angular or the linear isomer. Almost equal amounts of the two isomers were prepared if the 1‐OH was exposed.…”

Section: Resultsmentioning

confidence: 99%

Efficient Total Synthesis and Biological Activities of 6‐Deoxyisojacareubin

Dai

Xing

Zhu

et al. 2013

Archiv der Pharmazie

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6-Deoxyisojacareubin was directly synthesized in a six-step route with an overall yield of about 20%. In this route, the excellent site selectivity of this Claisen rearrangement-cyclization reaction cascade was achieved by inserting a bulky p-tosyl group into the free 1-OH, and in the last step, some efficient demethylation methods were explored. Furthermore, all synthesized intermediates including 6-deoxyisojacareubin were evaluated for their inhibitory activity against the QGY-7703 cell line. Of these, compound 1 and 6-deoxyisojacareubin showed moderate activities with IC50 values of 39.61 and 9.65 µM, respectively, when compared to the positive control 5-fluorouracil with an IC50 value of 11.24 µM. Further investigation using non-radioactive detection of protein kinase C (PKC) suggested that these two compounds possessed potency in the inhibition of PKC.

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Extractives from Guttiferae. Part XXV. Synthesis of the natural 1,5-dioxygenated xanthones, dehydrocycloguanandin, guanandin, isoguanandin, and 5-hydroxy-1-methoxyxanthone

Abstract: 1 Kefereree has suggested that chemical evidence for structure (13) can be provided by vigorous oxidation to give 2,6-dimethoxybenzoic acid.

Cited by 22 publications

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A concise enantioselective synthesis and cytotoxic evaluation of the anticancer rotenoid deguelin enabled by a tandem Knoevenagel/conjugate addition/decarboxylation sequence

A concise enantioselective synthesis and cytotoxic evaluation of the anticancer rotenoid deguelin enabled by a tandem Knoevenagel/conjugate addition/decarboxylation sequence

Total Synthesis of 1‐O‐Methyllateriflorone

Efficient Total Synthesis and Biological Activities of 6‐Deoxyisojacareubin

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