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
The total synthesis of 1-O-methyllateriflorone (2) is described. The construction of the cage-like domain of the molecule involved a biomimetic Claisen/Diels-Alder cascade, whereas the novel spiroxalactone framework was generated by an intramolecular Michael reaction within precursor 16a involving the carboxylate residue as the nucleophile. This finding might bear on the biosynthetic pathway by which nature forms lateriflorone. Described herein is also an interesting cascade sequence involving facile 6 pi electrocyclizations which leads to complex benzopyran systems. The biological evaluation of a small library of lateriflorone analogues and related systems establishing the first SAR within this class of compounds is also included. Among the most active compounds against tumor cells are 2, 16b, 56, 58, and 59.
An efficient strategy has been established for the enantiodivergent synthesis of natural product inspired compounds embodying both tropane and pyrrolidine natural product fragments. This strategy includes the enantioselective kinetic resolution of racemic tropanes by means of a copper(I)-catalyzed [3+2] cycloaddition and allows the preparation of two enantiopure products in a one-pot reaction in high yield and with high diastereo- and enantioselectivity by using one chiral catalyst.
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