polyprenylated acylphloroglucinol 
 ( ppap ) natural products including 
 nemorosone , clusianone , and hyperforin are structurally complex molecules 
 having promising chemotherapeutic properties ( figure 1 ) . ppaps 
 are highly regarded for their biological activities which include anticancer , antiviral , and 
 antibacterial properties . bottlenecks 
 toward their applications in disease treatment are stability issues , synthetic challenges , and promiscuous biological activity . thus , medicinal chemistry and biological evaluation of novel analogs 
 within the ppap family are of high interest but have been underdeveloped . with these challenges in mind , we sought to develop a route that 
 was both chemically efficient and applicable to diversity - oriented 
 synthesis ( dos ) . representative ppap natural 
 products . as expertly penned by mulzer in 
 a recent review , there are numerous tactics 
 to render a given synthesis 
 efficient including biosynthetic considerations . by considering a 
 biosynthetic hypothesis for a natural product , often innate reactivity can be exploited , ideally resulting in an efficient synthetic strategy . 
 in the case of ppaps , the molecules are presumed to be derived from 
 three building blocks : a desoxyhumulone substrate such as 1 and two additional prenyl cation equivalents which react distinctly 
 to assemble the bicyclo[3.3.1]nonane core via ( a ) dearomative prenylation 
 and ( b ) alkene - intercepted prenylation ( scheme 1 ) . union of the prenyl fragments with 
 the phloroglucinol at either the 2- and 4-positions or the 4- and 
 6-positions yields nemorosone ( arbitrary absolute configuration shown ) 
 or clusianone , respectively . generally speaking , this isomeric difference 
 is referred to as  type a  and  type b  
 throughout this family . ppap through union of the phloroglucinol core to a geranyl fragment 
 ( dearomatization ) and a prenyl cation ( cascade bicyclo[3.3.1]nonane 
 assembly ) . although the biosynthesis is efficient and complexity generating , 
 it has yet to be realized in a laboratory setting . we hypothesized that 
 pd - catalyzed dearomative conjunctive allylic 
 annulation ( dcaa ) of desoxyhumulones 1 and 2-methylene-1,3-propanediol 
 derivative 2 would serve as an efficient biosynthesis - inspired , 
 diversity - oriented strategy to access a plethora of ppap analogs 3 possessing many of the essential structural features for 
 bioactivity ( scheme 2 ) . such an approach to ppap core structures would take advantage of 
 biosynthetic , innate reactivity ( phloroglucinol dearomatization , 
 allylic alkylation ) and utilize the predictably reactive reagent 2 which has been utilized extensively in conjunctive bond - forming 
 processes . herein , we report our initial 
 discoveries enabling the rapid construction of diverse ppap analogs 
 for biological evaluation through this modular and step - economic sequence . in order to realize a diversity - oriented approach 
 to ppap - type 
 structures , it was necessary to establish a modular , scalable , and 
 robust route to allyl - desoxyhumulone scaffolds 1 . the 
 synthesis of allyl desoxyhumulone 1a , a common intermediate 
 en route to the natural products plukenetione a , 7-epi - nemorosone , and ( )-clusianone ( scheme 3a ) , has been achieved 
 by direct c - allylation of 2-acylphloroglucinol 4a with 
 allyl bromide in low yield due to overalkylation or by selective o - allylation then claisen rearrangement 
 requiring temperatures exceeding 200 c ( scheme 3b ) . generally speaking , allylated phenols 5 can be accessed 
 through high - temperature ( > 200 c ) or lewis acid promoted 
 -allyl 
 phenyl ether claisen rearrangements ( scheme 4 ) . due to the sensitivity of acylphloroglucinols 
 and desoxyhumulones , we wondered if a relatively low - temperature and 
 neutral formal allyl phenyl ether claisen rearrangement could be achieved 
 via pd(0)-catalysis . as shown in scheme 5 , 
 we envisioned access to desoxyhumulones via pd - catalyzed decarboxylative 
 allylation ( dca ) which should controllably 
 generate diallyl phenyl ether7a in accord with the site - specificity of the dca process . claisen 
 rearrangement under mild conditions via allyl phenyl ether ionization and concomitant c - allylation to provide product 1a ( scheme 5 ) . percent 
 conversion as determined 
 by h nmr analysis . to examine the possibility for a mild pd - catalyzed double decarboxylative 
 allylation / claisen rearrangement sequence yielding desoxyhumulones 1 , we prepared the requisite starting material 6a in > 95% yield from 2-benzoylphloroglucinol 4a and 
 allyl 
 chloroformate . excitingly , we found that 
 a highly efficient reaction of 6a to the desired product 1a occurred using 1 mol % pd(pph3)4 in 
 cyclohexane ( cyh ) at 75 c for 2h ( table 1 , entry 1 ) . of note , reaction for 5 min under the same conditions 
 resulted in complete conversion to the o - allylated byproduct 7a confirming its intermediacy en route to product 1a . regarding other solvents , ch2cl2 and thf 
 yielded only o - allylated products ( table 1 , 
 entries 3 and 4 ) , whereas toluene was also found to be a competent 
 solvent for desoxyhumulone scaffold synthesis ( table 1 , entry 5 ) . to confirm that pd(pph3)4 is involved in 
 the mild allyl aryl ether claisen rearrangement , we prepared 7a via dca of 6a and resubjected it to the reaction 
 conditions sans the palladium catalyst . upon addition of the palladium catalyst under the optimized 
 conditions ( cyclohexane , 75 c ) , conversion to 1a commences ( scheme 6 ) . regarding the scope of allyl - desoxyhumulone 
 synthesis via double 
 dca / formal claisen rearrangement , phloroglucinols with a variety of 
 2-acyl groups were found to be compatible coupling partners ( scheme 7a ) . for example , desoxyhumulones 1a1d having 2-benzoyl- , acetyl- , isobutyryl- , 
 and isovaleroyl groups were prepared . internal allylic substitution 
 proceeded as desired to afford products 1e and 1f ; however , terminally substituted allylic coupling partners 
 ( e.g. , cinnamyl and prenyl ) afforded complex mixtures . excitingly , the reaction could be extended to 
 related aromatic starting materials such as resorcinol 1 g and orcinols 1h1j . importantly , 
 a variety of large - scale ( gram  multigram scale ) reactions were 
 performed for each of the compatible scaffolds identified ( phloroglucinols 1a / d , resorcinol 1 g , and orcinol 1h ) . all multigram scale reactions were successful with reduced catalyst 
 loading ( 0.25 mol % pd(pph3)4 ) at an increased 
 concentration ( 0.5 m in cyclohexane ) . to broaden substrate scope and further enhance the diversity of ppap analogs for our investigation , 
 we also removed the o - methyl group on 1a , 1b , and 1d with bbr3 to access 
 the unprotected variants 1k1 m ( scheme 7b ) . in addition to the synthesis 
 of desoxyhumulones 1a1 m via dca / formal 
 claisen rearrangement , we 
 also investigated the synthesis of related scaffolds ( scheme 8) . interestingly , we found that the mono - allyl phenyl carbonate 8a only underwent dca to provide 
 allyl phenyl ether 8b under the optimized conditions 
 and did not undergo formal allyl phenyl ether -claisen rearrangement 
 regardless of the reaction duration ( scheme 8a ) . in addition , the double dca / claisen rearrangement was extended 
 to the chrysin - derived flavone scaffold 9a under slightly 
 modified conditions ( scheme 8b ) . from the commercially 
 available flavone chrysin , we prepared 6,8-diallylchrysin1n without silica gel chromatography 
 in 99% yield over the two - step sequence via intermediate 9a . with a variety of desoxyhumulone scaffolds 1a1j in hand , many of which were prepared 
 in multigram quantities , 
 we next turned to the development of the key dearomative conjunctive 
 allylic annulation ( dcaa ) to provide a diversified set of ppap analogs . 
 using the model coupling reaction between 1a and 2 , we began our quest for the optimal pd catalyst , solvent , 
 and reaction conditions ( table 2 ) . mono - methyl allyl desoxyhumulone 1a was chosen 
 as an initial scaffold as it was thought , based on our previous studies , that the methyl ether would direct the annulation 
 to the 2- and 4-positions of the substrate (  type a we ultimately identified two standard conditions 
 ( a and b , table 2 , entries 1 and 2 ) that were 
 utilized throughout 
 our studies to construct ppap analogs . standard conditions a ( pd(pph3)4 , cyclohexane ) were found to be highly solvent 
 dependent as related conditions in dce , toluene , and thf did not produce 
 the desired product ( table 2 , entries 35 ) . standard conditions b ( pd / binap ) appeared to be more tolerant to solvent 
 choice , though reaction times were found to be significantly longer 
 in lower boiling solvents such as cyclohexane and thf ( table 2 , entries 6 and 7 ) . standard conditions 
 a. standard conditions b. 2 mol % 
 pd2dba3 , 4 mol % rac - binap , 
 premixed in reaction solvent 
 for 10 min , . determined 
 by h nmrof 
 the crude reaction mixture . interestingly , using either the methylated ( 1a1f , scheme 7a ) or the nonmethylated 
 ( 1k1 m , scheme 7b ) desoxyhumulone scaffolds , either  type a  or type 
 b  ppap structures could be selectively prepared ( schemes 9 and 10 , respectively ) . o - methyldesoxyhumulones 1a1f reacted under standard conditions a ( table 2 , entry 1 ) to yield  type a  ppap analogs 3a3f in excellent yields ( scheme 9a ) . the reaction tolerated both allyl ( 3a3d ) and -methylallyl ( 3e and 3f ) substitution at c4 and c6 . type 
 b  annulation adducts 3k3 m under modified conditions via regioselective cyclization at the 
 more nucleophilic c4 and c6 positions ( scheme 10a ) . we discovered that increased reaction 
 times , lower temperatures , and larger catalyst ( pd2dba3/binap ) loadings were required for successful cyclization 
 to the  type b  core as low yields were obtained using 
 standard conditions a or b. as one possible explanation , the nucleophilic 
 phenolate moiety at c5 may bind to binary palladium(0 ) more effectively 
 than binap resulting in loss of catalytic activity . pleasingly , our general purification procedure developed 
 for dearomatized phloroglucinols and ppap derivatives allowed access to bicyclo[3.3.1]nonanes 3k3 m along with their potassium salts in high yields without the use of silica gel chromatography ( scheme 10a ) . moreover , using the 
 grubbs second - generation catalyst , we could 
 also conveniently access prenylated analogs of both type a 
 and b  ppaps 3 as shown for prenylated variants 3ca ( scheme 9b ) and 3ma ( scheme 10b ) in excellent yields . all products 3 led to selective prenylation of the monosubstituted allyl 
 groups leaving the exo - methylene intact . removal of the methyl enol ether could be accomplished 
 in good yield revealing the vinylogous acid functionality commonly 
 found in ppap natural products ( scheme 9b ) . we opted to store the vinylogous acid 3ca as its dicyclohexyl 
 ammonium salt , and the  type b scaffolds 3k3 m were stored as potassium salts due to their enhanced stability and shelf life . we also found that alkyl substitution at c4 and c6 
 was important 
 for success of the dcaa reaction ( scheme 11 ) . while the standard allyl - desoxyhumulone 1a underwent 
 clean reaction under the optimized conditions to afford 3a , neither the proteo-(4a ) or the chlorinated ( 10a ) variants reacted with conjunctive reagent 2 under standard conditions a or b , likely due to a combination of 
 steric and electronic influences . from the successful studies on allyl - desoxyhumulones 1a1f ( scheme 9 ) and 1k1 m ( scheme 10 ) , we reasoned that other scaffolds bearing at least a resorcinol 
 oxygenation pattern , an acyl group , and alkyl substituents at c4 and 
 c6 should also undergo the desired dcaa process . we proceeded to test 
 our hypothesis by further broadening our investigation to construct 
 a diverse set of resorcinol- and orcinol - derived ppap analogs via 
 dcaa ( scheme 12 ) . excitingly , we discovered 
 that resorcinol derivative 1 g and orcinol derivatives 1h1j yielded ppap 
 analogs 3g3j lacking a vinylogous 
 acid moiety ( scheme 12 , eqs 1 and 2 ) . moreover , 
 the structure of dcaa product 3h was unequivocally determined 
 by x - ray crystallography ( figure 2 ) . pyranone heterocycle 3n ( scheme 12 , eq 3 ) , likely resulting from 
 enhanced nucleophilicity of the unprotected phenol moiety positioned para to the acyl group in 1n ( cf . dcaa adduct 3n is structurally 
 similar to the anticancer ppap natural products oblongifolins f and 
 g. next , starting from allylated methyl 
 atratate ( 11a ) , available in 1-step from methyl atratate , 
 an inexpensive flavoring molecule ( $0.25/g ) , dcaa yielded two - separable products having  type 
 a the mixture likely 
 arises from the intermediate anion reacting through either major- 
 or minor - contributing resonance structures , which can be reasoned 
 by the fact that keto - stabilized allyl anions prefer to react at the 
 most - stabilized position . finally , lupulone 
 derivative 12a yielded a ppap analog bearing gem - diallyl substitution ( scheme 12 , eq 5 ) . x - ray crystal structure of analog 3h . in conclusion , we have achieved a biosynthesis - inspired , 
 diversity - oriented 
 synthesis approach to both  type a and b  ppap analogs . 
 through the use of two consecutive pd - catalyzed reactions , double 
 dca / claisen rearrangement and a dcaa , we can rapidly prepare ppap 
 molecules for biological evaluation . the reaction is applicable to 
 a number of electron - rich aromatic substrates bearing a resorcinol 
 or phloroglucinol substitution pattern . further studies including 
 construction of highly diverse ppap - inspired chemical libraries for 
 biological studies and development of asymmetric dcaa are currently 
 in progress and will be reported in due course .