Biomimetic Total Synthesis of Gambogin and Rate Acceleration of Pericyclic Reactions in Aqueous Media

Abstract

Gambogin (1, Scheme 1) has an unusual molecular architecture and exhibits cytotoxic properties against the Hela and HEL cell lines (MIC: 6.25 and 3.13 mg mL À1 , respectively). [1] Isolated from the gamboge resin of Garcina hamburyi in 1996, this naturally occurring substance provides an intriguing synthetic challenge and an opportunity for the development of new synthetic technology and biological tools. Herein we report a biomimetic [2] total synthesis of gambogin [3] and the observation of dramatic rate accelerations of the Claisen rearrangement and the Claisen/ Diels-Alder cascade reaction [4] in protic solvents, most notably in water.Our retrosynthetic plan for the molecule of gambogin (1), whose resemblance to forbesione and lateriflorone [5] influenced our thinking, is shown in Scheme 1. Thus, applying a retro-Claisen rearrangement [6] on ring A (benzopyran ring, mixture of diastereomers) unraveled the acetylenic benzenoid compound 2, which could be derived from 3 a through Oalkylation and, yet again, a Claisen rearrangement. Finally, the cagelike trioxatetracyclo[7.4.1.0 2,7 .0]tetradecane system [7] was dismantled as previously [5] to the BCD tricycle 4, whose construction from readily available starting materials was reasonably anticipated. Most significantly, the synthetic plan that emerged from this analysis offered us the opportunity to investigate the possibility of accelerating pericyclic reactions such as the Claisen and Diels-Alder reactions beyond their previously defined boundaries.The required intermediate 4 was synthesized as summarized in Scheme 2. Phloroglucinol (5) was protected with three MOM groups, and the resulting compound was brominated with NBS to afford intermediate 6 in 62 % overall yield. Lithiation of 6, followed by trapping of the generated anion with fully functionalized benzaldehyde 7 [5b, c] in diethyl ether generated bis-aromatic system 8 a in 85 % yield. However, when THF was used as the solvent in large-scale operations for solubility considerations, a spontaneous silyl group migration [8] took place, affording 8 b cleanly and in 85 % yield. Desilylation of 8 a or 8 b with TBAF and subsequent oxidation with MnO 2 furnished ketone 9 in 68 % overall yield. Ketone 9 was heated at reflux in a solution of KOH (EtOH/ H 2 O) which induced an intramolecular conjugate addition/ elimination [9] to afford tricyclic system 10. Subsequent hydrogenolysis of the two benzyl groups of 10 in THF led to the highly oxygenated xanthone 11 in 76 % overall yield. Lactolization of the catechol system of 11 through our previously reported method [5b, c] (KOtBu,[18]crown-6) failed to produce the desired lactols (12 a/12 b) in high yield. The procedure was

Total synthesis of aldehyde-containing Garcinia natural products isomorellin and gaudichaudione A

“…The reaction was then cooled to 25 C and filtered. The filtration was concentrated and the residue was purified by silica gel column chromatography (petroleum ether/ (15). To a solution of xanthone 14 (0.22 g, 0.04 mmol) in EtOAc (10 mL) was added 10% Pd/BaSO 4 (22 mg).…”

Synthesis and Anti‐tumor Evaluation of B‐ring Modified Caged Xanthone Analogues of Gambogic Acid

“…Further reduction of the alkynyl groups using Lindlar catalyst led to the precursors 12a-12d. Subsequently, application of the expected Claisen/Diels-Alder cascade reaction by heating 12a-12c in DMF [24][25][26][27] furnished caged xanthones 13a -13c, respectively, while 12d afforded forbesione (13d) and isoforbesione (13e) as isomers.…”

Polyprenylated Phloroglucinols and Xanthones

“…Studies by the Nicolaou group have shown that the Claisen/Diels-Alder reaction can be accelerated in the presence of polar solvents [119]. For instance, as depicted for the synthesis of gambogin (Scheme 12.25), the conversion of allyl ether 159 into caged structure 160a and the neo-isomer 160b was dramatically accelerated upon changing the solvent from benzene to DMF to a MeOH-water (1 : 2) mixture.…”

“…In a similar manner, the total synthesis of gambogin was achieved starting from the partially protected xanthone 157 (Scheme 12.25) [119]. This time the Claisen/Diels-Alder reaction proceeded quantitatively in refluxing MeOH-H 2 O (1 : 2) to produce the regular caged motif 160a along with its neo-isomer 160b in a 3 : 1 ratio.…”