while it is remarkable 
 to consider the sheer wealth and architectural 
 diversity of natural products that can be produced from a relatively 
 small set of starting materials , equally striking is the number of 
 structures within that collection that can be envisioned to arise 
 via the union of a secondary metabolite with itself . indeed , by some 
 estimates , between 15 and 20% of all natural products likely include 
 a dimerization process at some point in their biogenesis .
this analysis includes materials with obvious 
 symmetry , such as sceptrin ( 1 , scheme 1 ) , compounds with equivalent halves 
 but non - symmetric unions , such as complanadine a ( 2 ) , and materials whose symmetry has been partially 
 erased through subsequent structural modifications like oxidation 
 or decarboxylation , such as cp-225,917 ( 3 ) .
given the significant energy invested in the 
 creation of any natural product , the ubiquity of such dimers is logical , 
 since dimerization enables rapid access to additional molecular scaffolds 
 without invoking entirely new biosynthetic pathways . indeed , with 
 their distinct three - dimensional shapes and functional group presentations , 
 these new materials may well afford evolutionary advantages to the 
 producing species .
dimer linkages are colored 
 in purple . considering only those dimeric 
 natural products that possess obvious 
 monomer symmetry ( i.e. , those that have not undergone extensive modifications , 
 such as 3 ) , nature appears to deploy two general strategies 
 to access such materials .
the first and most typical approach forges 
 the dimer in a final synthetic operation from fully functionalized 
 monomers .
such processes can range from the simple and direct construction 
 of a single connecting bond to far more complex bond - forming unions , 
 such as that postulated for the conversion of sorbicillin ( 4 ) into trichodimerol ( 5 ) through a series of michael 
 reactions and ketalizations . in the second 
 dimerization approach ,
monomer union occurs at an earlier stage , with 
 subsequent tandem modifications of each half leading to the final 
 structure ( as in 6  7  8 and 10  11  12 ) . during the past several 
 decades ,
synthetic chemists have become 
 particularly skilled at utilizing both of these bio - inspired strategies 
 to access dimeric materials from monomers .
the first strategy is the most appealing from a retrosynthetic standpoint , 
 especially if it directly replicates nature s synthesis . in practice ,
though , it often requires extensive 
 screening of conditions to achieve success and sometimes affords only 
 modest yields of final product .
the second approach has provided the 
 opportunity for further creativity , as dimers distinct from those 
 deployed by nature can also be elaborated in tandem sequences to the 
 final target .
this concept was , to the best of our knowledge , first 
 demonstrated by stork in the synthesis of -onocerin ( 8) in four steps from 9 , and used more recently to great effect by a number of groups , including boger in his approach to 12 .
it also arguably constitutes the only 
 general solution for dimer synthesis when direct , final - step dimerization 
 can not be achieved , whether due to challenges in target patterning , 
 monomer reactivity , and/or the absence of suitable enzymes to achieve 
 the needed bond constructions . yet , despite their respective advantages , 
 these two approaches also share a potential limitation : the key step 
 linking the monomeric materials typically possesses a single reactive 
 course .
thus , if the needed bond(s ) and/or stereocenter(s ) are 
 improperly established in this operation , it is exceedingly difficult 
 to overcome such results .
such issues arose during our efforts 
 to synthesize the coccinellid 
 family of alkaloids , materials secreted by numerous species of ladybugs 
 as defensive compounds when provoked and 
 viewed by some as potential commercial insecticides , particularly 
 for the control of aphid pest populations .
figure 1 provides the structures of eight 
 of the nine monomers within this class ( 1421 ) , tricyclic architectures differing in ring junction stereochemistry , 
 oxidation state , and olefin placement .
structures 
 of the coccinellid class of alkaloids : unique monomeric 
 and dimeric frameworks .
in addition to these materials , several larger and more complex 
 compounds are known wherein half of their framework possesses these 
 monomer cores , such as chilocorine a ( 22 ) , as well as two other species that structurally 
 reflect the dimeric combination of these cores in the form of psylloborine 
 a ( 23 ) and isopsylloborine 
 a ( 24 ) .
the sole distinction 
 between these latter two natural products is ring - junction enamine 
 isomerism within their fused , highly congested , and stereochemically 
 rich frameworks . to date , the monomeric members have elicited significant 
 synthetic interest , with several approaches based on both classical 
 and modern bond constructions affording every tricycle drawn in figure 1 .
intriguingly , however , it is 
 only within the past year that the first asymmetric synthesis of any 
 of these members has been accomplished .
equally surprising , no work toward any higher - order structure has 
 been reported , nor has any mechanistic hypothesis been advanced to 
 account for dimer formation in nature .
to date , that work has identified a single common synthetic 
 intermediate capable of rapidly affording every monomer drawn in figure 1 .
it has also led to 
 a biosynthetic proposal for the formation of both psylloborine 
 a ( 23 ) and isopsylloborine a ( 24 ) , 
 one that , when reduced to practice , resulted in a non - natural , regioisomeric 
 dimer .
this unexpected result , coupled with observations from other 
 instances where incorrect dimeric unions have occurred in biomimetic 
 constructions , has led to the development of a unique , non - biomimetic 
 strategy for complex dimer synthesis .
as will be described in the 
 ensuing sections , this alternate strategy has afforded rapid syntheses 
 of both psylloborine a ( 23 ) and isopsylloborine 
 a ( 24 ) through sequences involving some of the most complex 
 condensation / michael / mannich cascade chemistry yet 
 reported .
significantly , this approach 
 can likely be applied to other challenging dimerizations and may , 
 in certain cases , be as efficient and powerful as an overall synthetic 
 design .
given the absence of any proposal for how either psylloborine 
 a ( 23 ) or isopsylloborine a ( 24 ) might 
 arise in nature , we began by pondering mechanistic pathways that could 
 account for their formation from the known tricyclic coccinellid alkaloids . 

the idea that ultimately proved the most attractive is shown in scheme 2 and was inspired by a key structural observation 
 among the monomers depicted in figure 1 .
namely , 
 although three of those monomers ( 1416 ) have a stable n - oxide counterpart ( 1921 , drawn below its respective precursor ) , propyleine 
 and isopropyleine ( 17 and 18 , a 1:3 
 equilibrating mixture in solution , respectively ) do not .
thus , perhaps the n - oxides of 17 and/or 18 are unstable and , if generated ( 25 ) , convert to a reactive electrophilic species such 
 as 26 .
if this material 
 was formed in the presence of a molecule of propyleine ( 17 ) , then perhaps it could undergo the sequence of events 
 shown in scheme 2 , involving a vinylogous mannich 
 reaction , proton transfer , mannich reaction , and terminating proton 
 loss to generate dimers 23 and/or 24 . in total , this proposed direct , 
 final - stage dimerization sequence 
 would form two new c 
the main assumption of this analysis , at least in terms of a successful 
 laboratory execution , is that pre - existing chirality within the monomers 
 could dictate the facial presentation of the reacting partners ( i.e. , 
 enzymatic intervention would not be required ) .
equally critical , but 
 unclear , were ( 1 ) whether one or both dimeric products would result 
 from such a pathway , and ( 2 ) whether only propyleine ( 17 ) would be the active nucleophile , or if its equilibrating 
 and more dominant enamine isomer , isopropyleine ( 18 ) , could participate in addition to , or instead of , 17 . despite these concerns ,
the overall attractiveness of such 
 a dimerization 
 process prompted us to test its viability .
thus , we set out to develop 
 synthetic pathways to access 17/18 as well 
 as 26 .
scheme 3 provides a retrosynthetic approach that we hoped could ultimately 
 address the synthetic challenges posed by the nucleophilic and 
 electrophilic partners needed to test our proposed dimerization 
 sequence .
as indicated , our goal was to prepare bicyclic intermediate 30 through an intramolecular condensation between the deprotected 
 amine variant of 31 and its neighboring carbonyl .
then , 
 if its thermodynamically favored trisubstituted enamine could be isomerized 
 to its less stable , exocyclic counterpart and intramolecularly displace 
 a suitably disposed leaving group , propyleine ( 17 ) would result alongside its equilibrating enamine isomer , isopropyleine 
 ( 18 ) .
although isomerization to the exocyclic enamine 
 isomer is clearly disfavored , we believed the final ring formation 
 would be an energetically downhill and essentially irreversible process 
 that would enable the reaction to be driven to completion .
worth 
 noting is that this sequence , while not fully biomimetic , is certainly 
 bio - inspired as a disubstituted piperidine undergoing enamine condensation 
 and subsequent attack on an intramolecular electrophile has 
 been proposed to account for the biosynthetic formation of several 
 monomeric alkaloids in this class .
indeed , 
 as shown in the lower half of scheme 3 , braekman 
 and co - workers demonstrated that polyketo - myristic acid ( formed from 
 stearic acid through enzymatic oxidations ) is the biosynthetic precursor 
 to coccinelline ( 19 ) via the proposed intermediacy of 33 , a compound containing a 10-membered ring ; the intervening steps listed above each arrow are one proposal 
 for how these net transformations might specifically occur .
our proposed 
 synthesis of 17/18 is based on a similar , 
 but differently ordered , set of chemical events involving no individual 
 ring size greater than six , in which a disubstituted piperidine ( 34 ) becomes the tricyclic system through an enamine condensation 
 and a terminating c  c bond formation driven by nucleophilic 
 attack of the enamine moiety .
assuming success in our proposed synthetic operations 
 leading to 17/18 , attempts to generate electrophile 26 in situ through n - oxide 
 formation would then begin . as an alternative approach to access 26
, we also considered a de novo preparation 
 from 32 , again proposing enamine equilibration and subsequent 
 c  c bond formation to close the final ring of its tricyclic 
 framework .
given that this proposed key starting material ( 31 ) possesses three reactive domains ( highlighted in blue , 
 green , and orange ) with sufficiently distinct and tunable electrophilic 
 and nucleophilic properties , we also questioned whether every 
 other monomer configuration ( i.e. , 1416 and 1921 ) within the class could 
 be accessed from the same entry point . if so , then a near - universal , family - level solution for the coccinellid 
 alkaloids would exist , with enantioselective syntheses of all 
 monomeric members possessing optical activity being achieved , some 
 for the first time . based on this plan ,
our first objective 
 was to devise an 
 efficient synthesis of our key , common building block ( 31 ) .
as shown in scheme 4 , we ultimately developed 
 two different routes to accomplish that goal , both starting from the 
 commercially available n - boc-(s)-()-piperidine-2-ethanol 
 ( 36 ) .
this material was chosen because it possessed a 
 key chiral center that we anticipated would readily encode the remaining 
 stereochemical information into the final target .
our 
 first route began with silylation of the alcohol and was followed 
 by a copper - mediated allylation with branched bromide 37 , itself available in two steps from 
 propargyl alcohol ( see supporting information for synthesis ) .
these operations led to trans - disposed 
 intermediate 38 in 84% overall yield and with > 19:1 
 diastereoselectivity 
 based on h nmr analysis .
with 
 all of the carbons of the final target already in place , only functional 
 group manipulations and redox adjustments remained .
these events began 
 by conversion of 38 into enone 39 through 
 a modestly yielding and sometimes capricious wacker oxidation ( 41% 
 yield ) promoted by pdcl2(phcn)2 in dmf / h2o at 60 c , followed by a nearly quantitative base - induced 
 ( naoh ) olefin isomerization ; these transformations afforded the new 
 alkene with 4:1 selectivity which we assume to have the structure 
 shown , though we never explicitly confirmed the process as being e - dominant .
next , we hoped to set the methyl stereocenter 
 of the target through a diastereoselective reduction .
this step 
 ultimately proved to be the most challenging of the sequence , with 
 repeated attempts at substrate - directed hydrogenation using wilkinson s 
 or crabtree s catalysts affording either no diastereoselection 
 or preference for the undesired methyl epimer on 39 or 
 its deconjugated enone precursor .
fortunately , use of yamamoto s 
 bulky lewis acid , aluminum tris(2,6-diphenylphenoxide ) ( atph ) , in tandem with l - selectride afforded the desired 
 stereocenter with a 15:1 diastereomeric ratio ( dr ) and in 75% 
 yield .
a final desilylation using tbaf 
 in thf at 25 c then delivered the desired building block ( 31 ) in a sequence that was just seven steps overall ( including 
 the two - step preparation of 37 ) .
reagents and conditions : ( a ) 
 tbdpscl ( 1.05 equiv ) , imidazole ( 2.0 equiv ) , ch2cl2 , 25 c , 19 h ; ( b ) s - buli ( 1.5 equiv ) , 
 tmeda ( 1.6 equiv ) , et2o , 78 to 45 c , 
 1 h ; cucn2licl ( 1.5 equiv ) , 78 c , 1 h ; 37 ( 3.0 equiv ) , 78 to 25 c , 4 h , 84% over two steps ; 
 ( c ) pdcl2(phcn)2 ( 0.1 equiv ) , cucl ( 1.0 equiv ) , 
 dmf / h2o ( 10/1 ) , o2 , 60 c , 6 h , 41% ; ( d ) 
 naoh ( 2.0 equiv ) , i - proh , 25 c , 1 h , 100% ; 
 ( e ) atph ( 1.5 equiv ) , ch2cl2 , 0 c , 20 
 min ; l - selectride ( 2.0 equiv ) , 78 c , 1 h , 75% , 15:1 
 dr ; ( f ) tbaf ( 2.0 equiv ) , thf , 25 c , 2 h , 91% ; ( g ) tbscl ( 1.1 
 equiv ) , imidazole ( 2.0 equiv ) , ch2cl2 , 25 c , 
 19 h ; ( h ) same as step b but with 40 ( 5.0 equiv ) instead 
 of 37 , 92% ; ( i ) k2oso42h2o ( 0.005 equiv ) , naio4 ( 4.0 equiv ) , 2,6-lutidine 
 ( 2.0 equiv ) , 1,4-dioxane / h2o ( 3/1 ) , 25 c , 24 h ; ( j ) 42 ( 2.2 equiv ) , thf , 78 c , 2.5 h ; ( k ) k2oso42h2o ( 0.005 equiv ) , naio4 ( 4.0 equiv ) , 2,6-lutidine ( 2.0 equiv ) , 1,4-dioxane / h2o ( 3/1 ) , 25 c , 16 h , 95% ; ( l ) tfaa ( 5.0 equiv ) , pyridine 
 ( 15 equiv ) , 4-dmap ( 0.1 equiv ) , ch2cl2 , 0 c , 
 1.5 h ; ( m ) dbu ( 1.5 equiv ) , ch2cl2 , 0 to 25 
 c , 1.5 h , 80% ( n ) atph ( 1.5 equiv ) , ch2cl2 , 0 c , 30 min ; l - selectride ( 2.0 equiv ) , 78 c , 
 1 h ; 1 m hcl ( 10 equiv ) , meoh , 25 c , 1 h , 79% . concurrent with these efforts , especially in light of 
 the low - yielding 
 wacker oxidation step , we developed an additional sequence to 31 .
though slightly longer at eight steps , it proved to be 
 operationally simpler and higher yielding overall .
it began similarly 
 from 36 , with a two - step sequence of silyl protection 
 of the alcohol ( this time as a tbs ether ) and a copper - mediated addition 
 using allylic bromide 40 that proceeded in 92% overall 
 yield .
subsequent oxidative cleavage of the new alkene , mediated by 
 k2oso4 and naio4 , afforded methyl ketone 41 .
the remaining carbon 
 atoms of the target were then installed via nucleophilic addition 
 of grignard reagent 42 , with a second oxidative cleavage 
 then generating the ketone within 43 in 95% yield over 
 three steps .
formation of the desired enone was accomplished via trifluoroacetate 
 formation and dbu - induced elimination in 80% yield over two steps . 

finally , this transformation was followed by the same facially selective 
 hydride delivery , with a terminating in situ deprotection 
 upon quenching of the -reduction product with hcl , completing 
 the synthesis of 31 in 79% yield and in 8:1 dr .
worth noting is that both routes contributed substantively to the 
 delivery of material for subsequent studies , with each being performed 
 on relatively large scales .
indeed , the first route was able to deliver 
 2.68 g of 31 in a single campaign , while the second afforded 
 3.02 g of this key intermediate .
with compound 31 in hand , our efforts to synthesize 
 the monomeric members of the coccinellid class began in earnest
. starting 
 with propyleine and isopropyleine ( 17 and 18 , scheme 5 ) , we first converted the 
 alcohol within 31 to a reactive bromide ( 44 ) through the intermediacy of its n - deprotected 
 tfa salt ( tfa ; pbr3 , one - pot operation ) .
we then dissolved 
 this material ( 44 ) in i - proh and treated 
 it with et3n in hopes that its enamine could be isomerized 
 to its less stable , exocyclic counterpart ( 45 ) as noted 
 earlier , thereby inducing a terminating cyclization .
pleasingly , this 
 conjecture proved true , affording ( )-propyleine ( 17 ) and ( )-isopropyleine ( 18 ) as 
 an equilibrating 1:3 mixture in 43% yield .
this nine - step sequence 
 ( using the step count of the shorter route to 31 ) is 
 the first asymmetric solution for these targets and the shortest route 
 to date .
in addition , the levorotatory rotation of the final 
 synthetic materials matched that of the natural isolates , confirming 
 the absolute configuration of these compounds for the first time as 
 based on the initial assignment of 36 ( cf .
reagents and conditions : ( a ) 
 tfa / ch2cl2 ( 1:1 ) , 0 c , 1 h ; solvent removal , 
 pbr3 ( 5.0 equiv ) , et2o , 70 c , 5 h ; ( b ) 
 et3n ( 1.0 equiv ) , i - proh ( cat . ) , ch2cl2 , 25 c , 13 h , 43% yield over two steps ; 
 ( c ) nabh(oac)3 ( 5.0 equiv ) , ch2cl2 , 0 c , 3 h , 80% , 3.7:1 dr ; ( d ) bzonhmehcl ( 1.0 equiv ) , 
 dmso , 25 c , 2 d , 62% ; ( e ) tfa / ch2cl2 ( 1:1 ) , 
 0 c , 1 h ; concentrate , pbr3 ( 5.0 equiv ) , et2o , 70 c , 5 h ; ( f ) et3n ( 0.77 equiv ) , i - proh ( 0.91 equiv ) , ch2cl2 , 40 c , 4 h ; 
 concentrate , aq naoh ( 10 equiv ) , meoh , 65 c , 6 h , 46% over two 
 steps , 1:1.2 dr , recyclable . from here , subsequent 
 reduction of a portion of these natural products 
 with nabh(oac)3 led to a 3.7:1 mixture of precoccinelline 
 ( 14 ) and hippodamine ( 15 , scheme 5 ) . due to the trans - ring fusions 
 of these materials , it was difficult to predict the outcome of this 
 reaction a priori .
however , given the observed facial 
 bias , we presume that if the top ring ( as drawn in the two - dimensional 
 depiction of 46 ) were to adopt a twist - boat orientation , 
 as indicated by the three - dimensional representation of imine 46 in scheme 5 , then hydride delivery 
 from the bottom face would appear to be preferred , forming precoccinelline 
 ( 14 ) .
if true , then hippodamine ( 15 ) would 
 have resulted from hydride delivery onto the other side of the structure . 

presumably , delivery from the top face , forming hippodamine , forces 
 the methyl group into an unfavorable 1,3-diaxial relationship with 
 the incoming hydride in the transition state , whereas delivery from 
 the opposite face produces no such interaction . from the standpoint 
 of synthesis ,
however , as precoccinelline ( 14 ) 
 has previously been readily converted into its n - oxide 
 congener coccinelline ( 19 , cf .
figure 1 ) , its preparation allowed us 
 to claim a formal synthesis of this oxidized monomer as well .
alternatively , -oxidation of common intermediate 31 with bzonhmehcl , followed by 
 the same general steps already described ( tfa ; pbr3 in 
 one pot then et3n , i - proh ; naoh ) generated 
 oxidized skeleton 48 by way of 47 as a mixture 
 of recyclable diastereomers about the new , highlighted chiral center .
this compound ( 48 ) has previously been advanced by 
 mueller to hippodamine and hippocasine ( 15 and 16 , respectively ) as well as their n - oxides 
 ( 20 and 21 , cf .
figure 1 ) , thus completing total and/or 
 formal syntheses of all eight monomers drawn in scheme 1 , all starting from a single starting material ( i.e. , 31 ) . with syntheses of our targeted monomers complete , 
 our attention 
 now turned to dimerization .
although our proposed nucleophilic 
 partner was already available from the synthesis of propyleine 
 and isopropyleine ( 17 and 18 ) , efforts 
 to generate a reactive electrophile directly from these materials 
 through n - oxidation were unsuccessful .
as such , we 
 sought an alternate and potentially more controlled path to the needed 
 electrophilic dimerization precursor in the form of cross - conjugated 
 diene 49 ( scheme 6 ) .
our hope 
 was that , upon exposure to an appropriate proton source , iminium electrophile 26 ( schemes 2 and 7 ) could be generated in situ , and then we 
 could expose that species to the appropriate nucleophilic partners . 

our initial route to access this compound sought to dehydrate 51 , itself readily prepared from 31 in just two 
 steps via oxidation and a one - pot tfa - promoted deprotection / condensation / mannich 
 reaction sequence .
unfortunately , no conditions were found that could 
 reliably afford 49 from this intermediate . as such , an 
 alternate , slightly longer four - step pathway was developed as shown 
 in the lower half of scheme 6 .
the key operation was the final step involving dibal - h - mediated 
 reduction of vinylogous amide 53 .
this step proceeded 
 in 45% conversion ( based on crude h nmr of samples 
 accounting for full mass recovery ) to afford 49 along 
 with the -reduced counterpart of 53 .
as this critical 
 compound proved unstable and difficult to purify , it was carried forward 
 directly into dimerization studies once formed .
reagents and conditions : 
 ( a ) 
 ( cocl)2 ( 1.6 equiv ) , dmso ( 3.2 equiv ) , et3n 
 ( 6.0 equiv ) , ch2cl2 , 78 to 0 c , 
 90 min , 94% ; ( b ) tfa / ch2cl2 ( 1/1 ) , 0 c , 
 1 h , carried forward crude ; ( c ) ruo2xh2o ( 0.10 equiv ) , naio4 ( 4.0 equiv ) , acetone / h2o ( 1:1 ) , 0 c , 90 min , 77% ; ( d ) p - nitrophenol 
 ( 1.2 equiv ) , dcc ( 1.2 equiv ) , 4-dmap ( 0.10 equiv ) , 25 c , 20 
 h ; filter , solvent removal , tfa / ch2cl2 ( 1:1 ) , 
 0 c , 1 h ; ( e ) i - proh ( cat . ) , ch2cl2 , 40 c , 18 h , 31% over two steps ; ( f ) dibal - h 
 ( 2.5 equiv ) , thf/1,4-dioxane ( 4:1 ) , 25 c , 4 min .
following extensive experimentation with acid source and 
 solvent , 
 we found that electrophile 26 ( scheme 7 ) could be obtained when 49 was taken up in cd2cl2 ( to enable 
 close monitoring by nmr analysis ) and exposed to tfa at 25 c . 

when propyleine and isopropyleine ( 17 and 18 ) were then added as a cd2cl2 solution 
 to this electrophile 2 min later , a new dimeric material was 
 formed over the course of 2 h in 21% overall yield from 53 .
unfortunately , this material did not match the spectral data for 
 either 23 or 24 .
extensive nmr analysis ( h , c , cosy , tocsy , 
 noesy , hsqc , and hmbc ; see supporting information for full details ) ultimately revealed that this dimer was non - natural , 
 resulting from incorrect regiocontrol in the union of the two 
 building blocks , as noted by the highlighted carbons within their 
 frameworks . this result meant that isopropyleine ( 18 ) , not propyleine ( 17 ) , served as the nucleophilic 
 partner .
we have elected to give this new dimeric material , compound 54 , the name  psylloborine b  , should 
 it ever prove to be a natural isolate .
reagents and conditions : ( a ) 
 tfa ( 1.0 equiv based on vinylogous amide 53 ) , 25 c , 
 2 min ; 17 and 18 ( 1:3 , 1.07 equiv combined 
 based on vinylogous amide 53 ) , 25 c , 2 h , 21% over 
 two steps .
as indicated in figure 2 , extensive molecular 
 modeling employing hand - held model kits has provided a rationale as 
 to why this outcome may have occurred .
critically , we believe it is 
 the result of kinetic control based on the stereoelectronic 
 and conformational demands of the lone desymmetrizing methyl group 
 within nucleophiles 17 and 18 , not 
 the ratio of these two components in solution . in theory , there are 
 a total of four possible reactive pathways : either propyleine 
 or isopropyleine serving as a nucleophile ( with the nucleophilic 
 carbons colored to match that of scheme 7 ) , 
 with approach of the electrophile occurring from either the 
 top or bottom face .
these possibilities are drawn in figure 2 as transition states a  d , all viewed from the perspective of looking down the c 
n 
 bond of the enamine , with the nitrogen atom located behind the circle 
 of the newman projection .
possible basis for the observed dimerization 
 result based on transition - state 
 models for electrophile addition ( i.e. , 26 ) using 
 either the propyleine ( 17 ) or isopropyleine 
 ( 18 ) enamines as nucleophile . based on the analysis provided earlier in the context of 
 scheme 2 , the requisite pathway to psylloborine 
 a 
 ( 23 ) or isopsylloborine a ( 24 ) would 
 require nucleophilic attack by propyleine ( transition 
 states a and/or b ) . in transition state a
, a favorable pseudochair - like transition state can be achieved , 
 but it incurs a significant steric penalty by requiring the incoming 
 electrophile to approach syn to the pendant 
 methyl group . in transition state b , addition from the 
 bottom face is now anti to the pendant methyl group , 
 but it seems to require a pseudoboat - like orientation to proceed , 
 with a number of destabilizing flagpole and eclipsing interactions 
 resulting as indicated . by contrast , when isopropyleine ( 18 ) is the enamine nucleophile ( transition states c and d ) , there are no proximal substituents 
 that can destabilize the approach of the electrophile as in 
 pathway a or b. therefore , the lowest energy 
 pathway is likely to proceed through these transition states , and 
 thus 54 results . given this experimental outcome , a new synthetic 
 approach was needed for psylloborine a ( 23 ) and/or 
 isopsylloborine a ( 24 ) .
ultimately , it was careful 
 consideration of this , as well as other cases where direct dimerization 
 had also failed , which led to the revised 
 retrosynthesis as drawn in scheme 8 .
this analysis 
 is based on a conceptually different approach for dimer synthesis 
 from those posited within the confines of scheme 1 and centered on the long - established principle that intramolecular 
 linking can potentially overcome those factors governing intermolecular 
 reactivity .
specifically , rather than 
 combine advanced materials in a final step or merge simpler materials 
 earlier and then elaborate in tandem , instead ( 1 ) link two simpler precursors at an appropriate site to 
 ensure proper regiocontrol and ( 2 ) embed enough chiral information 
 and reactivity within the overall structure to establish the remaining 
 rings and stereocenters as well as forge any remaining bonds 
 between the two halves .
intramolecular 
 dimerization ,  and compound 59 was designed for 
 the coccinellid alkaloids on the basis of its general concepts , outfitted 
 with one of the requisite dimer linkages ( highlighted in purple in 
 scheme 8) that could not be forged from direct , 
 advanced monomer coupling . from here , two cascades were envisioned 
 to forge the remaining rings , stereocenters , and final dimeric 
 linkage needed to complete the targets .
initiation of the first cascade 
 required the ability to differentiate selectively between the protecting 
 groups on the two piperidine rings in 59 to reach 58 via a condensation and michael closure .
the second cascade 
 would utilize an added electron - withdrawing group ( ewg , colored in 
 blue ) on one of the pendant methyl groups of the final target to dictate 
 the correct order of bond constructions through condensation , enamine - based 
 michael attack to form the tricyclic ring system , and a terminating 
 mannich ring - closure to complete the carbon framework .
collectively , 
 these two cascades would forge five new bonds , five new rings , and 
 four stereogenic centers , assuming again that pre - existing chirality 
 within 59 could govern the incorporation of the remaining 
 chiral elements . if successful , then a terminating excision of the 
 ewg in cascade product 57 would complete the synthesis 
 of 23 and/or 24 . on initial inspection
, this approach appears contrary 
 to the general 
 tenets of retrosynthetic analysis , since 
 an arguably more complex precursor and set of terminating events are 
 required than those needed for the two dimerization strategies presented 
 in scheme 1 . however , given the failure of 
 direct dimerization and the likely inapplicability of tandem elaboration 
 to a non - symmetric dimer , we required a distinct strategy .
one potential 
 and logical benefit of this new approach is that the final stitching 
 operations appear to take advantage of biosynthetic efficiency through 
 the use of cascades that resemble nature s synthesis of the 
 monomeric frameworks . indeed ,
apart from the linkage within 59 , the portions of this material colored in scheme 8 match very closely the analogous portions of structures 55 and 56 , moving only one bond colored in black 
 and changing the positioning and identity of the functional groups 
 colored in blue .
moreover , we anticipated that this synthetic sequence 
 would not be much longer than the failed direct dimerization strategy . 
 indeed , key test substrate 59 was expected to readily 
 arise from a horner 
wadsworth  emmons 
 coupling between phosphonate 60 , a material we anticipated 
 could be readily synthesized , and aldehyde 50 , the oxidized 
 version of our key common intermediate for monomer synthesis which 
 was already available on gram scale ( cf .
, the incorporation of 
 this group would be attempted once most of 59 had been 
 assembled to afford opportunities to probe different variants as needed 
 to successfully induce the designed cascades . as shown in scheme 9 , the key elements of 
 this new  dimerization  precursor were indeed synthesized 
 quite readily , starting once again from piperidine 36 , the same material used earlier to commence our monomer syntheses . 

its core elements closely mirror the synthetic pathways described 
 earlier in the context of scheme 4 , differing 
 only in terms of the fragments coupled , and thus will not be discussed 
 in detail ( scheme 9 ) .
pleasingly , after phosphonate 60 was accessed in just six steps from 36 , the 
 masamune  roush variant of the horner  wadsworth  emmons 
 reaction ( licl , i - pr2net in ch3cn at 25 c ) coupled it with aldehyde 50 to afford 65 , with the previously inaccessible intermolecular dimerization 
 linkage now in place ( highlighted in purple in scheme 9 ) .
reagents and conditions : ( a ) 
 tbscl ( 1.1 equiv ) , imidazole ( 2.0 equiv ) , ch2cl2 , 25 c , 19 h ; ( b ) sec - buli ( 1.5 equiv ) , tmeda 
 ( 1.6 equiv ) , et2o , 78 to 45 c , 1 
 h ; cucn2licl ( 1.5 equiv ) , 78 c , 1 h ; allyl bromide 
 ( 5.0 equiv ) , 78 to 25 c , 2 h , 91% over two steps ; ( c ) 
 k2oso42h2o ( 0.005 equiv ) , naio4 ( 4.0 equiv ) , 2,6-lutidine ( 2.0 equiv ) , 1,4-dioxane / h2o ( 3/1 ) , 25 c , 2.5 h ; ( d ) 62 ( 1.22 equiv ) , 
 ch2cl2 , 25 c , 14 h , 84% over two steps ; 

( e ) pd / c ( 10% , 0.06 equiv ) , h2 , meoh / etoac ( 3/1 ) , 78 
 to 25 c , 20 h , 97% ; ( f ) 64 ( 2.0 equiv ) , thf , 78 
 to 45 c , 1.5 h , 87% ; ( g ) licl ( 4.0 equiv ) , i - pr2net ( 2.0 equiv ) , 25 c , 30 min ; 50 ( 1.0 equiv ) , 25 c , 4 h ; hcl ( 6.0 equiv ) , meoh , 0 c , 
 25 min , 79% . from here ,
treatment of 65 ( scheme 10 ) with tfa at 78 
 c differentiated the two boc - protected 
 piperidine ring systems by taking advantage of neighboring group participation , 
 selectively transforming the upper ring boc group ( as drawn ) into 
 a base - labile carbamate through cyclization onto the enone while leaving 
 the lower ring boc group intact . although this operation afforded 
 no stereocontrol at the highlighted center within 66 , that outcome was of no consequence , as this chiral center would 
 be subsequently destroyed .
the synthesis of the key precursor ( in 
 protected form as 66 ) was then completed by oxidizing 
 the alcohol and performing a horner  wadsworth 
emmons 
 coupling with an aryl sulfone - containing phosphonate [ either ph- , 
 3,5-(cf3)2ph- , or 4-no2ph- , vide infra ] .
pleasingly , 
 treatment of all three of these variants of 66 with 1,1,3,3-tetramethylguanidine 
 ( tmg ) in a 9:1 mixture of toluene / i - proh effected 
 the desired reaction sequence of carbamate cleavage , enone regeneration , 
 condensation , enamine equilibration to the exocyclic isomer , and a 
 terminating michael addition . however , despite the high control in 
 bond construction events , the highlighted chiral center within 68 was generated in a 1:1.2 dr favoring the undesired , undrawn 
 epimer .
exploration of various conditions revealed that this outcome 
 could not be improved , with several alternatives affording inferior 
 stereoselection .
while not optimal , it was certainly an improvement 
 on the direct dimerization approach where that center could not be 
 forged correctly to any degree .
reagents and conditions : ( a ) 
 10% v / v tfa in ch2cl2 ( 10 equiv ) , ch2cl2 , 78 c , 2 h , 89% , 2:1 dr ; ( b ) oxalyl 
 chloride ( 1.6 equiv ) , dmso ( 3.2 equiv ) , et3n ( 6.0 equiv ) , 
 78 c , 30 min ; 0 c , 1 h ; ( c ) phosphonate ( ar = 
 3,5-(cf3)2c6h3 , 1.0 equiv ) , 
 licl ( 2.0 equiv ) , i - pr2net ( 2.0 equiv ) , 
 ch3cn , 25 c , 30 min ; substrate ( 1.0 equiv ) , ch3cn , 25 c , 2 h , 67% over two steps ( all ensuing yields 
 are for when ar = 3,5-(cf3)2c6h3 ) ; ( d ) tmg ( 1.0 equiv ) , toluene / i - proh ( 9:1 ) , 
 25 c , 5.5 h , 1:1.2 dr ; ( e ) tfa / ch2cl2 , 
 0 c , 1 h ; ( f ) c6d6 , 65 c , 3 h , 15% 
 yield over three steps ( 79% yield per transformation ) ; ( g ) 5 wt % 
 na / hg ( 276 equiv ) , i - proh , 25 c , 30 min , 46% ; 
 ( h ) tfa ( 2.0 equiv ) , clch2ch2cl , 75 c , 
 30 min , 75% . pressing forward with 
 both diastereomers ( as they could not be 
 separated at this stage when the ewg was an aryl sulfone ) , treatment 
 of 68 with tfa in ch2cl2 at 0 c 
 for 1 h removed the remaining boc group to unveil the free amine needed 
 to initiate the second cascade .
subsequent dissolution in benzene - d6 ( to monitor the reaction ) and heating at 65 
 c then initiated that cascade sequence : condensation to 69 , michael closure to 70 , and a terminating 
 mannich reaction to complete the synthesis of 72 . as 
 long as the aryl sulfone was sufficiently electron - deficient [ i.e. , 
 ar = 3,5-(cf3)2ph- or 4-no2ph- ] , 
 these operations proceeded in the order designed
however , when the 
 unsubstituted phenyl sulfone was used , a large portion of the material 
 appeared to undergo mannich reaction prior to michael addition to 
 afford materials believed to have structure 71 . despite various attempts , these compounds
thus , the more electron - withdrawing 
 aryl sulfones seem to have enabled the sequence to succeed by ensuring 
 that michael reaction preceded mannich closure . taken together , 
 these two cascade events arguably constitute the 
 most complex use of condensation / michael / mannich chemistry 
 yet described , given that they involve a total of seven distinct chemical 
 events that forged three c 
n bonds , five 
 rings , and four stereocenters ; the overall yield obtained for 
 the 3,5-(cf3)2ph variant , at 15% , reflects a 
 throughput of 79% per chemical transformation .
finally , exposure of 
 the 3,5-(cf3)2ph derivative of 72 to na / hg amalgam transformed it into 
 psylloborine a ( 23 ) , a material identical in all 
 respects to the natural isolate , thereby completing the first total 
 synthesis of this molecule as well as that of any dimeric coccinellid 
 alkaloid . as a final experiment ,
heating 
 this material with tfa in clch2ch2cl at 75 c 
 afforded isopsylloborine a ( 24 ) , completing the 
 first total synthesis of this dimer as well as establishing 23 as a viable biosynthetic precursor to 24 . in total , the route to 23 required 
 16 linear steps , only four steps more than the original direct dimerization 
 approach that failed to deliver the target , thus highlighting the 
 efficiency of this alternate dimerization strategy .
finally , 
 it is worth noting that while only the 3,5-(cf3)2phso2- group afforded complete success for 
 the entire sequence , ewgs other than sulfones were also probed for 
 the final cascades . as shown in scheme 11 , 
 use of the same sequence with a simple methyl ketone ( i.e. , 73 , x = me ) proceeded in similar overall yield ( 79% per transformation 
 for the steps shown ;
see supporting information ) to generate the full heptacyclic core of the dimeric coccinellid 
 alkaloids ( 74 ) .
however , no approach could be discovered 
 to convert the methyl ketone to the final pendant methyl of the target 
 natural products .
by contrast , use of a simple methyl ester ( i.e. , 73 , x = ome ) , a far easier group to potentially remove , arrested 
 at compound 75 with mannich closure preceding michael 
 addition in the second cascade , just as a simple vinyl phenyl sulfone 
 had putatively done ( 69  71 , ar = ph ) .
reagents and conditions : ( a ) 
 tfa / ch2cl2 , 0 c , 1 h ; ( b ) tmg ( 2.0 equiv ) , i - proh , 25 c , 1 h ; ( c ) i - proh , 60 
 c , 2.5 h , 38% yield over three steps ; ( d ) tfa / ch2cl2 , 0 c , 1 h ; ( e ) i - proh , 80 c , 
 2 h , 56% yield over two steps .
scheme 12 provides a possible graphical 
 explanation for sequence arrest , with steric clashing likely being 
 the basis for the failed terminating ring - closure .
collectively , these findings reveal overall that , while 
 there is some flexibility in the groups that can allow the key elements 
 of this cascade chemistry to proceed , careful control of electronics 
 is required to fully orchestrate the designed sequences .
in 
 summary , a concise synthesis of ten members of the coccinellid 
 family of alkaloids has been accomplished in both total and formal 
 format , all starting from a single , common intermediate .
key components 
 of the developed chemistry include the use of several cascade - based 
 bond constructions involving finely tuned and highly reactive intermediates 
 coupled with a new synthetic logic for the formation of dimeric natural 
 products where biomimetic , direct dimerization approaches have failed 
 to control regio- and stereoselectivity .
we anticipate that 
 this unique design for dimerization is applicable to a number of other 
 natural product compound classes , foremost of which may be the myrmicarin 
 alkaloids for which available approaches have failed .
work is ongoing 
 to verify that assertion , as are biochemical studies of the synthesized 
 materials and efforts to prepare other molecules in the class .
 although dimeric 
 natural products can often be synthesized in the 
 laboratory by directly merging advanced monomers , these approaches 
 sometimes fail , leading instead to non - natural architectures via incorrect 
 unions . 
 such a situation arose during our studies of the coccinellid 
 alkaloids , when attempts to directly dimerize nature s presumed 
 monomeric precursors in a putative biomimetic sequence afforded only 
 a non - natural analogue through improper regiocontrol . 
 herein , 
 we outline a unique strategy for dimer formation that obviates these 
 difficulties , one which rapidly constructs the coccinellid dimers 
 psylloborine a and isopsylloborine a through a terminating 
 sequence of two reaction cascades that generate five bonds , five rings , 
 and four stereocenters . 
 in addition , a common synthetic intermediate 
 is identified which allows for the rapid , asymmetric formal or complete 
 total syntheses of eight monomeric members of the class . 
Introduction
Results and Discussion
Conclusion