Total Synthesis of 1‐O‐Methyllateriflorone

Abstract

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).

Methyl 3,3,7,7,9-pentamethyl-1,5-dioxaspiro[5.5]undec-8-ene-8-carboxylate

“…The sixmembered 1,3-dioxane fragment is in the chair conformation and the cyclohexene fragment is in a distorted half-chair conformation. A similar spirocyclic framework to that forming the skeleton of (I) is also found in two other crystal structures (Kosela et al, 1999;Nicolaou et al, 2003). However, in both of these structures the ring framework is only a small part of a larger molecule.…”

Towards a Total Synthesis of the New Anticancer Agent Mensacarcin: Synthesis of the Carbocyclic Core

“…Methods for carrying out this transformation include oxidation by using ceric ammonium nitrate (CAN), [16] hypervalent iodine reagents [20] or anodic methods. [21] Initial efforts in this area have been fruitful with the successful CAN oxidation of compound rac-20.…”

Constructing molecular complexity and diversity: total synthesis of natural products of biological and medicinal importance

“…Our biomimetic strategy toward this 1- O -methyllateriflorone first called upon a tandem sequence of reactions that would deploy, starting from a prochiral substrate, a Claisen rearrangement in order to set the stage for an intramolecular Diels-Alder reaction that was destined to cast the molecule’s cage-type structural unit. 173 Following accomplishment of this task, the spiroxalactone motif was secured after an initial ester-based union of the two domains of the molecule through a delicate series of steps that included activation of a phenolic substrate with phenyliodonium bis-trifluoroacetate in methanol, an oxidative process that left a superfluous methoxy group within the product. This undesired moiety was concurrently removed under the acidic conditions subsequently employed to induce the formation of the required spirocyclization.…”