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.

The total syntheses of the cytotoxin marine natural product floresolide B (1) and its Delta(6,7)-Z isomer (2) have been achieved through an olefin metathesis-based strategy.

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).

[reaction: see text] Quantum mechanical calculations demonstrate that the second step of a Claisen-Diels-Alder reaction cascade controls regioselectivity that gives advanced intermediates for the synthesis of gambogin and 1-O-methyllateriflorone.

The first copper-catalyzed enantioselective [4 + 1] annulation of yne-allylic esters with 1,3-dicarbonyl compounds was realized through an elegant remote stereocontrol strategy. The very remote ε regioselective nucleophilic substitution was developed by employing a novel chiral copper-vinylvinylidene species from the new C4 synthon yne-allylic esters. Thus, greatly diverse spirocycles were obtained with ample scope and excellent levels of chemo-, regio-, and enantioselectivities. Moreover, detailed mechanistic studies suggest an yne-allylic substitution and Conia-ene cascade pathway on the remote stereochemical induction progress.

A highly enantioselective copper-catalyzed vinylogous propargylic substitution has been developed. Aromatic and aliphatic propargylic esters react smoothly with substituted coumarins under mild reaction conditions to give the desired products with excellent yields and enantioselectivities. Subsequent single-step transformations enable the synthesis of a wide range of multifunctional and diverse compounds, and allow the efficient combination of different natural product fragments. Investigation of the obtained compound collection in cell-based assays monitoring changes in phenotype led to the discovery of a novel class of autophagy inhibitors.