GRAPHIC ABSTRACT (+)-Hongoquercin A and B were synthesized from commercially available trans,trans-farnesol in 6-and 11-steps respectively using dual biomimetic strategies with polyketide aromatization and subsequent polyene functionalization from a common farnesyl-resorcylate intermediate. Key steps involve Pd(0)-catalyzed decarboxylative allylic rearrangement of a dioxinone ,-diketo-ester to a ,-diketo-dioxinone, which was readily aromatized into the corresponding resorcylate, and

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... nt polyene cyclization via enantioselective protonation or regioselective terminal alkene oxidation and cationic cyclization of enantiomerically enriched epoxide to furnish the tetracyclic natural product cores. Analogs of the hongoquercin were synthesized via halonium-induced polyene cyclizations, and the meroterpenoid could be further functionalized via saponification, hydrolytic decarboxylation, reduction and amidation reactions. Scheme 2. Thermolysis of dioxane-4,6-dione-keto dioxanones 10. RESULTS AND DISCUSSION We considered that the key meroterpenoids 13 should be available using a polyene cyclization from resorcylate 14 by enantioselective electrophilic reactions with chiral Brønsted acids (E = H), epoxidation and subsequent reaction with a Lewis acid (E = OH) or halogenations with reagents that provide halonium ion intermediates (E = Br and I) (Scheme 3). The common resorcylate intermediate 14 should be available from the cycloaromatization of ,-diketo-dioxinone 9, which could be synthesized via palladium(0)-catalyzed decarboxylative allylic rearrangement of dioxinone ,-diketo-ester 15. Dioxinone ,-diketo-ester 15 in turn should be available via C-acylation of dioxinone -keto-ester 16, which in turn is available from trapping a dioxinone-acylketene with trans,trans-farnesol (17). 10 Scheme 3. Retrosynthetic analyses of hongoquercins A (1) and B (2). Following our recently published methods, 10 thermolysis of dioxane-4,6-dione-keto dioxanone 19 at 55 o C generated the dioxinone acyl-ketene 11, which was trapped with trans,trans-farnesol (17) to provide dioxinone -keto-ester 21 (79%) (Scheme 4). Magnesium chloride mediated regioselective C-acylation of -keto-ester 21 with acetyl chloride gave dioxinone ,-diketo-ester 23, which on reaction with Pd2(dba)3 and tri(2furyl)phosphine resulted in a highly regioselective decarboxylative allylic rearrangement giving the ,-diketo dioxinone 9 and readily aromatized in situ to produce farnesyl resorcylate 14 (55% overall from 21). A geranyl substituted analog 24 was also synthesized, using the same reaction sequence, from geraniol (18) in 3 steps with an overall yield of 57%. Scheme 6. Total synthesis of (+)-hongoquercin B (2). Additional meroterpenoids analogs were prepared via epoxidation (Scheme 7) and halogenations (Scheme 8). Firstly, the geranyl-substituted resorcylate 24 was protected as its silyl ether 37 (76%) and epoxidized with the dioxirane derived from the Shi chiral ketone 38 to give epoxide 39 (69%). 18 Subsequent deprotection gave epoxide 40 (92%), which was cyclized using boron trifluoride etherate to give meroterpenoid 41 (77%, 84% ee as determined by chiral HPLC) as a single diastereoisomer. The (S)-enantiomer of meroterpenoid 41 (98% ee as determined by chiral HPLC) was obtained by recrystallization to enhance chiral purity. Secondly, we examined the halonium-induced polyene cyclization of the resorcylates to produce additional analogs (Scheme 8). 19 Reaction of the geranyl resorcylate 24 with the Snyder reagents Et2SBr·SbCl5Br (BDSB, 46) and (Et2SI)2Cl·SbCl6 (IDSI, 47) resulted in bromo-and iodo-cyclizations to produce the racemic bromomeroterpenoid 42 (64%) and racemic iodo-meroterpenoid 43 (88%) as single diastereoisomer, respectively. Racemic bromide 44 (45%, 2 : 1 dr) and racemic iodide 45 (54%, 2 : 1 dr) were also successfully synthesized from farnesyl-substituted resorcylate 14 using the BDSB 46 and IDSI 47 mediated halocyclizations. 20 Scheme 7. Synthesis of meroterpenoid 41. Scheme 8. Halocyclizations to produce meroterpenoids 42 -45. 20 The 2,2-dimethyl-1,3-benzodioxan-4-one moiety of the meroterpenoids intermediates was also used in alternative derivatization reactions (Scheme 9). Thus, reaction of the geranyl-substituted resorcylate 24 with boron trifluoride etherate at 25 o C gave the racemic meroterpenoid 48 (89%, 3 : 1 dr) and the desired pure trans-fused ring product was obtained by recrystallization from n-hexane. 21 Saponification 13 of meroterpenoid 48 gave racemic carboxylic acid 49 (69%) while hydrolytic decarboxylation gave racemic phenol 50 (97%).