c  h functionalization 
 logic is rapidly permeating the way 
 organic chemists approach synthesis and deconstruct target molecules . 
 with methodological advances developing at an increasing pace ,
new 
 disconnections and strategies once thought impossible are now available 
 for consideration during synthesis planning . while these methods have 
 sporadically been utilized to great effect for decades ,
only recently 
 have these strategies been formalized and articulated as an efficient 
 and effective means to construct molecules of interest . in comparison 
 to traditional prefunctionalization approaches , there are inherent 
 benefits to using c
 h bonds as latent functional groups in 
 terms of redox , atom , and step economy .
furthermore , many issues of 
 chemoselectivity are frequently mitigated by simply removing the functional 
 groups from the equation altogether .
c  h functionalization 
 methods are particularly compelling from a strategic standpoint because 
 they can challenge preconceived notions in order to provide solutions 
 to longstanding problems in organic chemistry .
stereocontrolled synthesis of complex cyclobutanes is one 
 such 
 problem that was identified while surveying the wide diversity of 
 cyclobutane - containing natural products that have been reported in 
 the literature .
common among all of these cyclobutanes , with 
 the exception of tripartilactam ( 4 ) , is that they are pseudodimeric ; they are composed of two 
 similar , but distinct , olefin precursors .
for instance , the piperarborenines 
 ( 1 and 2 ) have differing degrees of oxidation 
 on the aryl rings , with one ring containing two methoxy substituents 
 and the other possessing three . the dictazoles 
 ( 5 and 6 ) , anthocertotonic acid ( 3 ) , and pipercyclobutanamide a ( 8) , on the other hand , 
 are fully unsymmetrical with four different substituents on the cyclobutane 
 ring .
additionally , a wide variety of 
 cyclobutane stereochemistries are observed , furthering the difficulty 
 of general strategies for their construction .
complex cyclobutane natural 
 products . with increasing interest apparent 
 in the fields of medicinal chemistry , 
 polymer , and material science , a dearth of methods for the construction 
 of cyclobutanes has been revealed , particularly in comparison to its 
 smaller and larger homologues .
the most 
 commonly considered and direct approach to cyclobutane synthesis is 
 through a [ 2 + 2 ] photocycloaddition .
while 
 this strategy has proven useful in many intramolecular contexts and 
 homodimerizations , the successful heterodimerization 
 of two olefins is highly dependent upon the proper steric and electronic 
 properties of the monomers .
additionally , the resulting stereochemistry 
 is largely at the mercy of the substrates chosen . for the heterodimerization 
 of two similar monomers
, a photochemical approach could be highly 
 inefficient , as illustrated in figure 2 .
this 
 first issue , presuming a photocycloaddition reaction is viable , is 
 one of statistics .
since the two monomers are effectively identical 
 in terms of steric and electronic parameters , there is likely no preference 
 for heterodimerization over homodimerization .
the orientation of the 
 olefin monomers during the dimerization is another point of consideration , 
 since both head - to - head and head - to - tail modes of cyclization are 
 possible .
when these factors are combined with facile e / z isomerism of the starting materials under photochemical 
 conditions , a potentially very complex mixture of dimeric products 
 could arise that presumably would be very challenging to purify . further 
 supporting this line of reasoning
, the homodimerization of methyl cinnamate in the presence of bf3et2o leads to 8 of the 11 possible isomeric cyclobutane products .
potential products of a hypothetical photochemical [ 2 
 + 2 ] heterodimerzation 
 reaction .
partial solutions to this problem 
 have emerged from solid - state 
 photochemistry , template - directed photochemistry , and photoredox catalysis . 
 as shown in figure 3a , seminal studies on topochemistry 
 by schmidt demonstrated that direct irradiation of different crystal 
 polymorphs of cinnamic acid ( 9 ) in the solid state leads 
 to different cyclobutane dimers .
the  
 polymorph leads to -truxillic acid ( 10 ) , while 
 the  form gives exclusively -truxinic acid ( 11 ) .
this chemistry was the basis for the syntheses of the symmetrical 
 cyclobutane dimers dipiperamide a and incarvillateine .
notably , the  polymorph of cinnamic acid is photoinert 
 due to improper olefin spacing and alignment in the solid state .
this 
 strategy is not well suited for heterodimerizations , however , since 
 a 1:1 cocrystallization and precise packing of the two different olefins 
 in the crystal lattice would be required , a challenging crystal engineering 
 problem that has only been observed in highly biased systems .
template - directed photochemistry has also seen 
 success in controlling the stereo- and regiochemistry of [ 2 + 2 ] reactions 
 by placing two olefins in close proximity through molecular imprinting , supramolecular encapsulation , or other noncovalent interactions ( e.g. , hydrogen bonding ) . while this approach has allowed the controlled dimerization of several 
 cinnamic derivatives that are otherwise unreactive ,
recently , impressive progress has been made using visible 
 light photoredox catalysis for highly efficient and stereoselective 
 dimerization of olefins , including reports of controlled heterodimerization 
 by yoon and co - workers ( figure 3b ) .
currently , these methods are limited to aryl 
 enone ( e.g. , 12 ) or an electron - rich styrene ( e.g. , 15 ) substrate for productive cyclization and only generate 
 head - to - head adducts .
direct ring - closing strategies 
 are entropically disfavored and are frequently low yielding , even 
 for simple substrates .
ketene cycloaddition 
 is one of the most useful methods for cyclobutane synthesis , due to 
 the high levels of regio- and stereoselectivity frequently observed 
 and a variety of methods for ketene formation , though the product 
 always results in a cyclobutanone .
examples of 
 ( a ) solid - state photochemistry and ( b ) photoredox - catalyzed 
 [ 2 + 2 ] cycloadditions .
cyclobutane natural products also have proven to be challenging 
 to properly elucidate using standard spectroscopic methods , particularly 
 nmr .
numerous stereochemical and constitutional 
 errors have been made in the literature when attempting to determine 
 the structure of cyclobutane - containing natural products .
these misinterpretations likely derive from 
 the fluxional nature of the cyclobutane ring system that rapidly undergoes 
 ring flipping , resulting in unpredictable nmr chemical shifts that 
 have been described as  rather erratic  .
proton coupling constants , which 
 are routinely used as a diagnostic stereochemical tool in other cyclic 
 systems , are widely varied for cyclobutanes , with cis and trans vicinal coupling ranging 4.611.5 
 and 2.010.7 hz , respectively . in combination with the frequently observed long - range jh , h coupling across the ring , compounds 
 of mistaken identity are frequently proposed . from the viewpoint of 
 structural confirmation
, a direct dimerization strategy would be at 
 a disadvantage , since the true structure would likely not be challenged 
 if the spectral and physical data matched those which were reported . 

reassignments are generally reliant upon x - ray crystallography , chemical synthesis , and , more recently , 
 computational methods . since the majority 
 of cyclobutane - containing natural products
have not been evaluated 
 by one of these means , it stands to reason that many of the structures 
 suggested in the literature are in fact incorrect .
while many 
 terpene - derived cyclobutanes are produced through cationic 
 polyolefin cyclization , the role of enzymes in the production of many 
 cyclobutane dimers is unclear .
the marine 
 natural products dictazole a ( 5 ) , dictazole b ( 6 ) , and sceptrin ( 19 ) are isolated from deep - sea 
 sponges where very little sunlight penetrates , making a purely photochemical 
 [ 2 + 2 ] pathway improbable .
furthermore , sceptrin ( 19 ) is isolated as an enantiopure molecule , almost certainly implying 
 enzymatic intervention .
a recent report 
 by molinski demonstrated the production of benzosceptrin c from its 
 monomer , oroidin , using a  metabiosynthetic  approach 
 with cell - free enzyme extracts .
this 
 oxidative dimerization , proposed to occur through a series of single - electron - transfer 
 events , suggests that a similar enzymatic pathway is operative for 
 the conversion of hymenidin ( 18 ) to sceptrin ( 19 ) ( figure 4 ) .
additional support for this 
 arises from the reluctance of hymenidin ( 18 ) and aplysinopsin 
 ( 21 ) to undergo photochemical [ 2 + 2 ] reactions .
the piperine cyclobutane natural products ( 2325 ) , on the other hand , are isolated from pepper plants and 
 are necessarily exposed to light . these molecules are isolated as 
 racemic mixtures and could be produced by unselective photochemical 
 [ 2 + 2 ] photocycloaddition reactions , as a variety of dimeric products 
 with differing stereochemical patterns have been isolated .
curiously , the intermolecular [ 2 + 2 ] photocycloaddition 
 of these monomers is highly inefficient ; therefore , additional templating 
 or intervention within the plant cell has been proposed .
[ 4 + 2 ] adducts , such as ageliferin 
 ( 20 ) , dictazoline 
 c ( 22 ) , and chabamide ( 25 ) , are also isolated 
 alongside the cyclobutane dimers .
hymenidin ( 18 ) and 
 aplysinopsin ( 21 ) also do not engage in diels 
piperine ( 23 ) can undergo thermal dimerization to chabamide ( 25 ) , but forcing conditions are required ( > 130 c ) and the 
 reaction 
 is unselective . an alternate biosynthetic 
 hypothesis for formation of these [ 4 + 2 ]
dimers has been proposed 
 by our group , in which a vinyl cyclobutane rearrangement ( vcb ) gives 
 the six - membered - ring natural products from the respective cyclobutane 
 dimers .
experimental support for this pathway has been provided by 
 the direct conversion of sceptrin ( 19 ) into ageliferin 
 ( 20 ) and the epimeric nagelamide e in 50% and 28% yields , 
 respectively , after microwave irradiation in water at 200 c .
williams also suggested this as a possible pathway 
 for the biogenesis of dictazoline c ( 22 ) on the basis 
 of preliminary experiments with naturally isolated dictazole a ( 5 ) .
taking 
 into account the limitations of regio- and stereocontrol 
 of a direct dimerization strategy , an unconventional retrosynthesis 
 of unsymmetrical cyclobutane dimers was considered using c 
common among many of the cyclobutane natural products shown in figure 1 is a carbonyl group attached directly to the cyclobutane 
 ring .
this led us to consider a general cyclobutane strategy in which 
 the carbonyl is viewed as a latent directing group for c 
this would permit the direct installation of the 
 desired functionality in a facially controlled manner , guided by the 
 preexisting stereocenter .
if two c  h functionalization reactions 
 could be employed sequentially , the synthetic challenge of pseudosymmetry 
 and stereochemistry would be greatly simplified . while c 
h 
 functionalization of cyclopropanes had received some attention at 
 the time , examples of direct cyclobutane 
 functionalization were limited to a harsh magnesiation procedure described 
 by eaton and co - workers .
h bonds in the literature 
 were generally limited , but a seminal report by daugulis and co - workers 
 in 2005 appeared promising ( figure 5a ) . employing an aminoquinoline directing group , 

a wide variety of methylene c  h bonds could be arylated under 
 palladium ( ii / iv ) catalysis . furthermore , the only cyclic substrate 
 examined , cyclohexane 26 , delivered the bis - arylated 
 product 27 in 61% yield as the all - syn isomer . to test the competence of four - membered rings in this methodology , 
 cyclobutane 28 was prepared and subjected to the reaction 
 conditions with iodobenzene .
encouragingly , this substrate outperformed 
 any of the examples described in the original report , giving the bis - phenylated 
 cyclobutane 29 in 97% isolated yield and as a single 
 diastereomer .
additionally , the palladium loading could be lowered 
 to 1 mol % , making this one of the most efficient sp c 
h 
 functionalization reaction reported to date using a pd ( ii / iv ) manifold . following this initial proof of concept ,
studies were directed 
 toward two potential problems : sequential cross - coupling reactions 
 and the scope of coupling partners . in order to access the unsymmetrical 
 cyclobutane targets in figure 1 , the c  h 
 functionalization reactions would need to be performed sequentially 
 in a controlled manner . to test the viability of a monofunctionalization , 
 the phenylation reaction was repeated with 1 equiv of iodobenzene 
 ( figure 5b ) . a statistical mixture ( 1:1.5:1 ) 
 of starting material 28 ,
monoarylated cyclobutane 30 , and bis - arylated cyclobutane 29 resulted , 
 implying that the rate of the second arylation is nearly identical 
 with that of the first arylation . while this was initially discouraging , 
 we were hopeful that the issue could be overcome through alteration 
 of the reaction conditions or substrate control on a more functionalized 
 system .
( b ) statistical 
 arylation of 28 with 1 equiv of iodobenzene . to test the generality of the c  h cross - coupling 
 reaction , 

other coupling partners were explored and the scope was found to be 
 broad ( scheme 1 ) .
electron - rich arenes , such 
 as those found in the piperarborenine natural products ( 1 and 2 ) , performed excellently to give 31 and 32 in 98% and 96% yield , respectively .
two n - tosylated indoles were introduced onto the cyclobutane 
 ring in 92% yield , encouraging potential access to the dictazole natural 
 products ( 5 and 6 ) . additionally , the c  h 
 olefination reaction needed for pipercyclobutanamide a ( 8) was successful in the daugulis chemistry , with iodostyrene giving 34 in 77% yield .
even the bis - dienoate 35 could 
 be prepared using this strategy , introducing a substructure found 
 in tripartilactam ( 4 ) . finally , alkynylation proved facile 
 according to chatani s protocol to give 36 in 
 83% yield , which could serve as an alternate 
 entry to the dictazole natural products through a larock indole synthesis . 
 with these preliminary results ,
efforts were directed toward the total 
 synthesis of the dictazole and piperarborenine families of natural 
 products .
reagents and conditions : ( a ) 
 5 mol % of pd(oac)2 , 80 c , 5 h. reagents and conditions : 10 mol % 
 of pd(oac)2 , 80 c , 12 h. reagents and conditions : 5 mol % of pd(oac)2 , licl ( 3 equiv ) , 100 c , 12 h. the structure of dictazole 
 a ( 5 ) offers a number of difficulties for synthesis ; 
 the most notable is the four contiguous stereocenters around the congested 
 cyclobutane core , two of which are quaternary spiroiminoimidazolidinone 
 rings .
furthermore , each of the substituents 
 is unique , as only one of the indoles is brominated and a single spiro 
 ring bears methyl groups . to add to this challenge
, the spiro stereocenter 
 at c-3 could not be determined by standard spectroscopic means and 
 its relative configuration is unknown . applying the cyclobutane c 
h 
 functionalization strategy , a retrosynthesis of dictazole a ( 5 ) was devised ( figure 6 ) .
the spiroiminoimidazolidinone 
 rings were first deconstructed ; one could arise through strecker type 
 chemistry ( further disconnected to a protected alcohol ) and another 
 from an aminoquinoline amide , leading back to intermediate 37 .
two sequential c  h arylation reactions with appropriate 
 3-iodoindoles would remove two of the stereocenters and lead back 
 to symmetrical cyclobutane 38 .
notably , the bromide present 
 on one of the indoles in dictazole a ( 5 ) should be tolerated 
 in the arylation chemistry , since it proceeds through a palladium 
 ( ii / iv ) catalytic cycle .
finally , the 
 quaternary amino - amide stereocenter at c-1 could arise from an ugi 
 four - component coupling of cyclobutanone 40 , 8-isocyanoquinoline 39 , methylamine , and a suitable carboxylic acid .
retrosynthesis of dictazole a ( 5 ) employing 
 c  h 
 arylation and an ugi reaction . to test the viability of this approach ,
( benzyloxy)cyclobutanone 42 was prepared by thermal [ 2 + 2 ] cycloaddition of benzyl 
 vinyl ether ( 41 ) and in situ formed dichloroketene following 
 poisson s one - pot procedure in 
 50% yield ( scheme 2 ) .
unfortunately , it was 
 wholly ineffective in the ugi reaction under a variety of reaction 
 conditions explored , despite ample precedent for the use of cyclobutanones 
 in ugi reactions .
interestingly , the 
 side reactions were determined to be direct addition reactions of 
 isonitrile 39 with the carboxylic acid or an alcoholic 
 solvent to give dearomatized benzimidazoles ( 45 ) .
while 
 the pivalic acid adduct 45c could be observed by crude h nmr , it was not isolable and hydrolyzed to 45a , which was characterized by x - ray crystallography .
these bizarre 
 addition reactions can be rationalized by considering the cyclized 
 zwitterionic isomer 44 , wherein a deprotonation / addition 
 mechanism would generate the observed products . during the exploration of an ugi strategy ,
a model study 
 was also 
 under investigation to examine the effect of quaternary -amino 
 substituents in the daugulis c  h arylation reaction .
a series of substrates were synthesized from 
 commercially available ethyl 1-amino-1-cyclobutanecarboxylate ( see 
 the experimental section for preparations ) . 

surprisingly , these proved to have highly deleterious effects on the 
 c  h arylation chemistry .
azide 46a and cbz - protected 
 amine 46b gave no detectable arylated products on reaction 
 with iodoindole 47 , simply decomposing or remaining unreactive 
 after prolonged heating , respectively ( table 1 ) .
phthalimide - derived 46c required heating to 130 c 
 to initiate the reaction and was accompanied by nonspecific decomposition , 
 yielding only 14% of bis - indolated 48c with full consumption 
 of the starting material .
this lowered reactivity was attributed to 
 the coordinating nature of the nitrogen substituents , generating an 
 unreactive chelate with the directing group and preventing cyclometalation .
ester - derived cyclobutane 46d was 
 examined next , since it is less coordinating and could be converted 
 to the requisite amine through a curtius rearrangement . while this 
 substrate was also significantly less reactive than the parent cyclobutane 28 , it performed the arylation chemistry at much lower temperature 
 ( 90 c ) than phthalimide 46c and the mass balance 
 was largely unreacted starting material .
therefore , a 1,1-cyclobutanedicarboxylate 
 derivative was targeted for the second - generation approach to dictazole 
 a ( 5 ) .
a diastereoselective 
 synthesis of the c  h activation precursor 
 began following a report from merck for the preparation of cyclobutane 
 hydroxy acids that is scalable and employs inexpensive starting materials . in this reaction ,
the dianion of 4-methoxyphenylacetic 
 acid ( 49 ) was treated with epichlorohydrin in a double - alkylation 
 reaction to deliver hydroxy acid 50 as a single diastereomer 
 ( scheme 3 ) .
the observed relative stereochemistry 
 can be rationalized by invoking a magnesium chelate that templates 
 the final ring - closing alkylation .
fischer esterification and alcohol 
 protection with tbscl generated cyclobutane 51 in 55% 
 yield over the three steps .
the electron - rich methoxyarene was selected 
 in anticipation of the ruthenium tetroxide catalyzed arene degradation , 
 which gave acid 52 in 70% yield .
notably , performing 
 the reaction in the absence of acetonitrile and at dilute concentrations 
 were necessary to avoid overoxidation of the tbs alcohol to the corresponding 
 cyclobutanone . with the key cyclobutane substrate 52 prepared , studies 
 on the c  h functionalization chemistry commenced .
two directing 
 groups developed by daugulis and co - workers , 8-aminoquinoline ( 53a ) and o - thioanisidine ( 53b ) , were tested in the arylation reaction and were coupled to the 
 carboxylic acid with edc to give 54a and 54b in 75% and 84% yields , respectively ( scheme 4 ) .
similar to the case for 46d , aminoquinoline 54a was found to be poorly suited for 
 the direct arylation chemistry , delivering bis - indolated cyclobutane 55a in 21% yield ( unoptimized ) with primarily starting material 
 remaining .
the thioanisidine 54b , on the other hand , 
 performed better . under the same reaction conditions ,
this was especially peculiar , because the thioanisidine - derived directing 
 group was reported to generally be less reactive toward methylene 
 c  h bonds in comparison to the aminoquinoline directing group .
this observation , combined with the significant 
 effect of  substitution , highlights the subtle geometric factors 
 at play in the c  h functionalization chemistry . temporarily bypassing the problem of sequential arylation 
 of the 
 two different indoles ,
attention was directed at removal of the directing 
 groups for the construction of the guanidine - containing spirocycle . 

removal of the directing group proved to be very challenging , since 
 the inherently strong amide bond is quite sterically hindered after 
 introduction of the indoles .
many conditions explored for amide deprotection 
 met with failure , and even hydrolysis 
 of the ester in 55a for a curtius rearrangement resulted 
 in primarily decarboxylation of the generated acid .
the difficulty 
 in removal of the amide - based directing groups is consistent with 
 previous studies by chen and co - workers , in which considerable functional 
 group manipulation was required to cleave the aminoquinoline auxiliary . recognizing the need for a new directing 
 group that could be more 
 easily deprotected , we considered an imide - based strategy .
since picolinamide 
 was reported to be a competent directing group by daugulis in his 
 2005 communication , a picolinimide - based directing 
 group seemed logical .
imides in general 
 are much more susceptible to hydrolysis than amides , and this would 
 give a second , less hindered carbonyl group for reaction and removal . 
 to test this hypothesis , picolinimide 57 was prepared 
 via the pentafluorophenyl ester
according to the andrus protocol in 
 79% yield over two steps ( scheme 5 ) .
gratifyingly , this directing group was found 
 to be competent in the c  h arylation chemistry , giving the 
 bis - indolated imide 58 along with the corresponding palladium 
 complex pd(58)2 ( confirmed by x - ray crystallography ) . 

as anticipated , the imide motif was found to be much more easily cleaved 
 than then traditional amide - based systems . treating the mixture of 58 and pd(58)2 with a dcm/2-propanol 
 solution saturated with ammonia in the presence of catalytic scandium 

while it was possible to separate 58 from its palladium complex , it was more convenient to subject both 
 to the ammonolysis , as they converge to the same product .
the acetate 
 derivative of 60 was prepared in an analogous fashion 
 ( see the experimental section for details ) 
 but strangely proved unsuccessful in the c  h arylation chemistry 
 under the same reaction conditions .
it is possible that the inductive 
 effect of the acetate influences the efficiency of the reaction or 
 the larger tbs ether locks the ring into a more favorable geometry 
 for c  h insertion and cross - coupling . with the successful deprotection of the picolinimide directing 
 group ,
this ring required regioselective methylation , 
 attempts were made to prepare substrates that would allow for selective 
 alkylation , through either a hydantoin or an appropriately protected 
 spiroguanidine .
hydantoin 63 was the expected product 
 from a curtius rearrangement of 59 , since the primary 
 amide could intramolecularly collapse onto the intermediate isocyanate 
 ( scheme 6 ) .
unexpectedly , hydantoin 63 was isolated as the minor product ( 23% yield ) and aminonitrile 62 was isolated as the major product ( 69% yield ) when the 
 carboxylic acid was treated with excess diphenylphosphoryl azide ( dppa ) . 

this suggests that the hindered primary amide dehydrates competitively 
 with the rearrangement of the intermediate acyl azide under the reaction 
 conditions .
interested in moving forward , we alkylated hydantoin 63 with methyl iodide to give 64 in 80% yield , 
 but conversion of the carbonyl to the imino group of 65 through activation with meerwein s salt or lawesson s 
 reagent met with failure . reconsidering the strategy , 
 we turned our attention to the major 
 product of the curtius reaction , aminonitrile 62 , as 
 an intermediate to carry forward .
bergs 
 hydantoin synthesis was envisioned in which an isocyanate would replace 
 carbon dioxide to directly generate the desired heterocycle . in this 
 reaction , 62 was treated with tosyl isocyanate and heated 
 in ethanol to produce the undesired spirocycle 66 .
the 
 true identity of the product was initially uncertain because of the 
 ambiguous spectroscopic and mass spectrometry ( ms ) data ( scheme 7 ) .
spirocycle 66 could be dimethylated 
 with methyl iodide to give 67 , which also appeared to 
 be in agreement with the desired ring system ( e.g. , 65 ) . during this time , however , crystals were obtained of 66 , and the aza - bucherer 
bergs reaction was demonstrated to 
 be unsuccessful through x - ray crystallographic analysis . instead of 
 the desired oxygen closure ,
the nitrogen of urea 72 cyclized 
 onto the nitrile to give intermediate 73 , which underwent 
 additional sulfonyl migration to produce the observed product 66 .
still interested in utilizing aminonitrile 62 , we 
 were successful in hydrating amide 69 using parkin s 
 platinum catalyst ( 68 ) , tolerating the free primary amine 
 ( scheme 7 ) . unfortunately , 
 this amine was reluctant to react with a number of electrophiles for 
 spirocycle synthesis ( isothioureas , cyanogen bromide , bis(methylthio)methylenesulfonamides , 
 etc . ) even when combined with a range of bases and salt additives 
 ( ag , hg , etc . ) .
recalling the facile reaction 
 of 62 with tosyl isocyanate , amide 69 was 
 also found to react to give urea 71 .
dehydration of this 
 urea was expected to generate a carbodiimide that would cyclize to 
 the desired product ( 70 ) , but treatment with burgess 
 reagent gave 66 as the exclusive product in 67% yield 
 for the two steps .
again , the hindered primary amide was surprisingly 
 susceptible to dehydration , leading to intermediate 72 . given the unforeseen difficulty in constructing the requisite 
 spirocycles , 
 efforts at this time were directed to a separate set of pseudodimeric 
 cyclobutane natural products , the piperarborenines , whose synthesis 
 was being explored concurrently . despite the initial challenges in 
 the synthesis of dictazole a ( 5 ) , further efforts are 
 aimed at construction of the spirocycles at an earlier stage in the 
 synthesis and application of knowledge gained during the piperarborenine 
 projects for sequential introduction of the differentiated indole 
 substituents .
contemporaneous with the dictazole studies , efforts were 
 also being directed toward the synthesis of stereoisomeric piperarborenines 
 b ( 1 ) and d ( 2 ) .
the central challenge associated 
 with the piperarborenine natural products is the controlled , sequential 
 installation of the two different aryl rings on the cyclobutane core . 

piperarborenine b ( 1 ) has a cis , trans , cis relative configuration with the 
 two aryl substituents on opposite sides of the cyclobutane ring , whereas 
 the arenes are on the same face of the cyclobutane in the trans , trans , trans piperarborenine d ( 2 ) ( figure 7 ) . continuing with our 
 general c
 h functionalization strategy , we viewed the dihydropyridone 
 motif as a latent directing group for c  h arylation and devised 
 a divergent strategy from the all - cis cyclobutane 74 .
from this intermediate , piperarborenine b ( 1 ) could be prepared by an epimerization at c-1 , directed c 
h 
 arylation , and further functional group manipulations to install the 
 imide side chains .
alternatively , piperarborenine d ( 2 ) could be accessed by performing a c  h arylation directly 
 on 74 , followed by epimerization of both c-1 and c-3 
 stereocenters .
the divergent intermediate 74 was envisioned 
 arising from a desymmetrizing monoarylation reaction of a cyclobutanedicarboxylate 
 derived from 75 .
while the 1,3-cyclobutanedicarboxylate 75 appears to be quite simple , the shortest synthesis reported 
 in the literature was eight steps in 20% overall yield starting from 
 pentaerythritol ( 76 ) .
viewing 
 this route unsuitable for our needs , we envisioned a new synthesis 
 of 1,3-cyclobutanedicarboxylates starting from methyl coumalate ( 78 ) .
inspired by corey s 
 seminal work on pyrone photochemistry 
 and more recent studies by maulide and co - workers , we selected methyl 
 coumalate ( 78 ) as a potential starting material to solve 
 the 1,3-cyclobutanedicarboxylate problem . upon irradiation with ultraviolet light , methyl coumalate ( 78 )
was reported to undergo a successful photochemical 4 
 electrocyclization reaction to generate photopyrone 77 .
this intermediate was attractive , 
 since only two reductions would be needed to arrive at the desired 
 cyclobutane monocarboxylic acid 75 . in practice , it was 
 found that the intermediate photopyrone 77 is quite reactive , 
 rapidly decomposing when treated with acid / base and thermally reverting 
 back to the parent coumalate along with nonspecific decomposition . 

consistent with earlier reports by corey , hydrogenation of photopyrone 77 with palladium on carbon resulted in varying mixtures of 
 -lactone 79 and the desired acid 75 ( scheme 8) .
resubjection of -lactone 79 to the reaction 
 conditions did not result in further reduction , implying that the 
 c  o bond must be reduced first to produce 75 . 

gratifyingly , switching the heterogeneous catalyst to platinum on 
 carbon consistently gave the monoacid 75 as the sole 
 product and diastereomer observed by h nmr .
furthermore , 
 both the 4 electrocyclization and the hydrogenation reactions 
 could be performed with dcm as the solvent , allowing the sequence 
 to be further telescoped to an edc coupling with o - thioanisidine ( 53b ) , giving 80 in 61% 
 yield in a single operation from methyl coumalate ( 78 ) . with the cyclobutanedicarboxylate problem resolved , 
 studies commenced 
 toward the development of a desymmetrizing c  h monoarylation 
 reaction of cyclobutane 80 with 3,4,5-trimethoxyiodobenzene 
 ( 81 ) .
preliminary results were promising , with the conditions 
 originally reported by daugulis and co - workers ( 6 equiv of ari , no 
 solvent , 110 c ) giving the desired monoarylated cyclobutane 82 in 30% isolated yield ( table 2 , 
 entry 1 ) . since the carboxylate ligands on the palladium are proposed 
 to be directly involved in the c  h cleavage event , it was reasoned 
 that a bulkier carboxylate could hinder the second cyclometalation 
 event and the production of doubly arylated 83 . indeed , 
 pivalic acid in combination with tert - butyl alcohol 
 as a solvent proved to be effective ( entry 2 ) , though the overall 
 conversion of the reaction was also lowered .
further screening of solvents revealed that trifluoroethanol ( tfe ) 
 improved the reaction , permitting the temperature and catalyst loading 
 to be lowered slightly , but more of the overarylation byproduct 83 was produced ( entry 3 ) .
switching the solvent to hexafluoro-2-propanol 
 ( hfip ) maintained the accelerating effects of tfe but almost fully 
 suppressed the second arylation , possibly due to the increased steric 
 bulk . with these optimized conditions ,
monoarylated cyclobutane 82 was obtained in 65% isolated yield , though the conversion 
 dropped slightly when the reaction was scaled up , leading to a 52% 
 yield on a gram scale .
additionally , the beneficial effects of fluorinated 
 alcoholic solvents on c  h activation reactions has been reported 
 in other palladium - catalyzed systems since the disclosure of this 
 work . in order to access piperarborenine b ( 1 ) ,
a selective 
 inversion of the directing group stereocenter at c-1 was needed , followed 
 by a second c  h arylation reaction .
while the epimerization 
 of the amide is energetically favorable to create a trans relationship to the aryl ring , the issue is complicated by the presence 
 of the also epimerizable ester moiety at c-3 .
since inversion of both 
 of the stereocenters is the most thermodynamically favorable result , 
 initial experiments were stopped at incomplete conversion of the starting 
 material to observe the selectivity of the initial epimerization . 
 upon screening various bases , c-3 epimer 85 and double 
 epimer 86 were observed , along with an unexpected transannular 
 cyclization to form imide 87 ( table 3 ) .
sodium methoxide in meoh / thf showed very little selectivity , 
 resulting in roughly equal quantities of 84 and 85 ( entry 1 ) .
the hindered amine base dbu showed some selectivity 
 for c-1 epimerization ( 3/1 ) , though more forceful reaction conditions 
 were required .
interestingly , a counterion effect was observed with 
 hindered alkoxide bases ( entries 3 and 4 ) .
potassium tert - butoxide slightly favored ester epimer 85 , while lithium tert - butoxide favored c-1 epimer 84 .
extending 
 the reaction time of entry 3 to 24 h resulted in nearly full conversion 
 to 86 , as anticipated .
encouraged by the lithium tert - butoxide result , the solvent was changed to toluene 
 ( entry 5 ) .
this slowed the reaction rate ( 15% conversion in 24 h ) 
 but only the desired 84 was detectable in the crude h nmr , in addition to starting material .
further optimization 
 of temperature , concentration , and reaction time resulted in entry 
 6 , which minimized undesired side reactions while maintaining high 
 conversion of starting material to give 84 in 79% yield . 

the origins of selectivity in this system are uncertain and are currently 
 under investigation .
completion of the piperarborenine b ( 1 ) synthesis 
 is shown in scheme 9a . a second , directed c 
h 
 arylation reaction with 3,4-dimethoxyiodobenzene ( 88 ) 
 provided 89 in 46% yield .
the reaction conditions developed 
 for c  h monoarylation of 80 proved ineffective 
 for this reaction , but performing the reaction in tert - butyl alcohol at high reaction concentrations ( 1 m ) gave acceptable 
 results .
attempts to further conversion of the reaction by raising 
 the temperature to 110 c resulted in the production of tris- 
 and tetraarylated cyclobutanes ( tentatively assigned by h nmr and lc - ms ) in small quantities , along with significant decomposition . 
 with the second c 
h arylation secured , all that remained to 
 complete piperarborenine b ( 1 ) was the conversion of 
 the directing group and ester moieties to dihydropyridone imides . 

this could also prove problematic , since methods for direct amide 
 bond cleavage are generally very harsh , requiring strong acid or base 
 and heat .
this is further complicated by the stereochemical lability 
 of the ester and amide functionalities .
while 1,2-trans relationships in cyclobutanes are energetically favored over cis relationships , the 1,3-cis and trans orientations are nearly thermoneutral 
 ( 0.1 kcal / mol difference for dimethyl 1,3-cyclobutanedicarboxylate ) .
kibayashi and co - workers observed this problem 
 during the synthesis of the natural product dipiperamide a , wherein 
 hydrolysis of 93 with barium hydroxide resulted in equal 
 amounts of the two inseparable epimers 94 and 95 ( scheme 9b ) .
fortunately , the two - step deprotection strategy developed by grieco 
 and evans allowed for retention of the carefully constructed stereotetrad . in this reaction , dmap - catalyzed carbamoylation with boc anhydride 
 generated 90 in 90% yield , with x - ray crystallographic 
 analysis confirming the presumed stereochemistry .
warming 90 in the presence of lithium hydroperoxide resulted in the hydrolysis 
 of both the amide directing group and the methyl ester in 83% yield . 

bis - acid 91 was converted to the corresponding bis - acid 
 chloride and heated with dihydropyridone 92 to give piperarborenine 
 b ( 1 ) in 77% isolated yield , which matched the spectral 
 and experimental data reported in the isolation paper . the use of 
 4  molecular sieves as an acid scavenger was uniquely effective 
 for this reaction , with traditional bases resulting in low yields 
 and significant formation of byproducts ( possibly resulting from epimerization 
 and ketene generation ) .
initial attempts to synthesize piperarborenine d ( 2 ) focused on the resubjection of 82 to the c 
unfortunately , this consistently resulted in low yields ( < 20% ) 
 and significant decomposition .
the presence of the methyl ester substituent 
 on the same face as the directing group and aryl ring , which was critical 
 for monoarylation , presumably hindered the second reaction .
taking 
 this into consideration , we hypothesized that epimerization of the 
 ester stereocenter ( c-3 ) would alleviate this issue .
previous epimerization 
 studies ( vide supra ) suggested that thermodynamically controlled conditions 
 would not deliver epimer 85 selectively ; therefore , an 
 alternative approach was devised . treating 82 with 2.2 
 equiv of khmds and quenching
the resulting dianion with ammonium chloride , 
 delivered c-3 epimer 85 in 6580% yield as the 
 only observable product .
initial amide n  h 
 deprotonation allows for exclusive formation of ester enolate 98 as a result of charge separation .
when this dianion was 
 quenched with ammonium chloride , the c-3 epimer was produced as a 
 single diastereomer .
the somewhat low and ranging yield of this transformation 
 results from the rapid decomposition of intermediate dianion 98 , along with a sluggish second deprotonation at reduced 
 temperatures . in agreement with the proposed blocking role of the 
 methyl ester ,
notably , the combination of hfip and 
 pivalic acid again proved superior to all other reaction conditions 
 examined and delivered the bis - arylated 99 in 81% yield 
 ( scheme 11 ) .
refluxing 99 in an 
 ethanolic solution of sodium hydroxide effected epimerization at c-1 , 
 hydrolysis of the amide directing group , and hydrolysis of the methyl 
 ester to produce the bis - acid in 86% yield .
conversion to the bis - acid 
 chloride and heating according to the piperarborenine b protocol gave 
 piperarborenine d ( 2 ) , which did not match the spectroscopic data from the original isolation report .
examination of the isolation data revealed a 
 number of inconsistencies  particularly the number of unique 
 peaks in the c nmr for a compound containing a v plane of symmetry .
further analysis led to the consideration 
 of a head - to - head type dimer ( 100 ) for piperarborenine 
 d that was more consistent with the data provided , and this structure 
 was confirmed through synthesis using an intramolecular photocycloaddition 
 strategy .
after the successful synthesis of the piperarborenine natural 
 products , we were interested in extending our general c  h functionalization 
 strategy to more complex members of the family , and pipercyclobutanamide 
 a ( 8) was selected to further explore the cyclobutane 
 c  h olefination chemistry . additionally , 
 if this c  h functionalization strategy could be coupled to 
 a vinylcyclobutane rearrangement , access to unsymmetrical [ 4 + 2 ] 
 adducts in the natural product family could also be possible .
the general synthetic strategy is analogous 
 to the approach used for the piperarborenines , involving controlled , 
 sequential c  h functionalizations and epimerizations .
the appropriate c  h functionalization precursor ( 101 ) was prepared using the methodology developed in the piperarborenine 
 syntheses .
methyl coumalate ( 78 ) was reacted in a telescoped sequence involving photochemical electrocyclization , 
 hydrogenation , and edc coupling to 8-aminoquinoline ( 53a ) to give 101 in 54% yield 
 ( scheme 12 ) .
a mono - olefination reaction was 
 initially examined with iodostyrene 102 as the coupling 
 partner , but the reaction surprisingly gave the tetrasubstituted all - cis cyclobutane 103 in 50% yield .
x - ray crystallographic 
 analysis confirmed that no epimerizations took place during the course 
 of the reaction and the highly strained cyclobutane was successfully 
 obtained .
this is in direct contrast to the arylation chemistry , in 
 which only small quantities of 96 could be produced . 
 taking this result into consideration
, we reversed the order of synthetic 
 operations with a c  h monoarylation reaction performed first , 
 followed by the olefination .
while the hfip solvent that was critical 
 in the monoarylation of 80 was ineffective due to the 
 intolerance of methylenedioxy aryl iodide 104 , the pivalic 
 acid additive still proved beneficial and delivered 105 in 54% yield .
recalling the facile formation of all - cis - cyclobutane 103 , we directly olefinated monoarylated 105 with iodostyrene 106 to give the tetrasubstituted 
 cyclobutane 107 in 59% yield , without needing to epimerize 
 the c-3 ester stereocenter . from cyclobutane 107 ,
two epimerization events 
 were 
 needed to obtain the relative stereochemistry found in pipercyclobutanamide 
 a ( 8) . this transformation was expected to occur easily , 
 due to the thermodynamically favorable release of strain leading to 
 the all - trans isomer , as well as previous experience 
 during the synthesis of the proposed structure of piperarborenine 
 d ( 2 ) ( vide supra ) .
addition of sodium methoxide to a 
 thf solution of 107 at room temperature rapidly epimerized 
 the c-1 stereocenter , and warming the reaction mixture to 45 c 
 inverted the c-3 methyl ester stereocenter ( scheme 13 ) .
an aqueous solution of sodium hydroxide was added at the 
 end of the reaction to give acid 108 .
treatment of the 
 crude carboxylic acid with excess dibal transformed the aminoquinoline 
 directing group into an aldehyde , providing the proper oxidation state 
 required for pipercyclobutanamide a ( 8) . the free carboxylic 
 acid was intentionally used in the reaction to preserve this oxidation 
 state , with the initially generated aluminum carboxylate protecting 
 the functional group from further reduction .
reductions of secondary 
 amides to aldehydes with dibal have scarcely been reported , and the 
 success of this case is due to the chelating aminoquinoline amide 
 and the pendant carboxylate .
this is 
 supported by the complete failure of the reaction when more coordinating 
 solvents , such as thf , were employed .
the structure of pipercyclobutanamide 
 a ( 8) was completed by peptide coupling of aldehyde 109 with piperidine ( 4045% overall yield from 107 ) and olefination following ando s protocol for cis - selective unsaturated amide synthesis in 80% isolated 
 yield . unfortunately , the h and c nmr data of 8 did not match the 
 data reported for the natural product .
contemporaneous 
 with our work , the tang group also synthesized the proposed structure 
 of pipercyclobutanamide a ( 8) and discovered that the 
 data reported by the isolation chemists were identical with those 
 of the [ 4 + 2 ] adduct chabamide ( 25 ) , thereby revising 
 its structure ( scheme 13 ) . while the proposed structure of pipercyclobutanamide a 
 ( 8) proved to be incorrect , we were still interested 
 in the possibility 
 of vinylcyclobutane rearrangements to test the biogenetic hypothesis 
 and give stereocontrolled access to the unsymmetrical cyclohexene 
 derived natural products . to test this possibility
, the symmetrical 
 bis - olefinated cyclobutane 34 was suspended in water 
 and heated to 200 c for 5 min in a microwave reactor , the conditions 
 developed for the conversion of sceptrin ( 19 ) to ageliferin 
 ( 20 ) ( scheme 14 ) .
while the starting 
 material cleanly transformed into a new compound , it was identified 
 as epimer 112 .
this result was further confirmed by treatment 
 of 34 with potassium tert - butoxide to 
 give the same compound .
curious if the electron - rich styrenes present 
 in the piperine family would be more amenable to vinylcyclobutane 
 rearrangement , we also subjected the proposed structure of pipercyclobutanamide 
 a ( 8) to the microwave conditions . in this case , only 
 starting material was recovered and even the cis - olefin 
 stereochemistry remained intact .
both of these compounds also failed 
 to give any of the desired cyclohexene isomers when reacted with the 
 radical cation salt tris(p - bromophenyl)aminium hexachloroantimonate .
in 
 conclusion , the use of c  h functionalization logic to 
 tackle unaddressed problems in organic chemistry has provided an expedient 
 and broadly applicable solution to the construction of stereochemically 
 complex cyclobutanes . in addition to 
 the successful synthesis and structural revision of the piperarborenine 
 natural products ( 1 , 2 , 8) , 
 a number of general discoveries were also made en route . during the 
 investigations toward the dictazoles ( 5 , 6 ) , a scalable ,
diastereocontrolled synthesis of 1,1-cyclobutanedicarboxylates 
 was devised , the surprising reactivity of 8-isocyanoquinoines was 
 unveiled , and a new , easily removable picolinimide directing group 
 for the c  h functionalization chemistry was invented . the piperarborenines 
 ( 1 , 2 , 8) led to the development 
 of a new , one - step route to cis-1,3-cyclobutanedicarboxylates , 
 divergent access to multiple cyclobutane stereoisomers through controlled 
 epimerization reactions , and a reductive conversion of the 8-aminoquinoline 
 amide directing group to an aldehyde under mild conditions . with this 
 case study as additional support for the utility of c  h disconnections 
 in synthesis ,
h bonds can be used 
 as latent functional groups in synthesis planning , inevitably leading 
 to the generation of new , useful methodologies and discoveries .
all reactions were carried out under 
 an argon atmosphere with dry solvents using anhydrous conditions unless 
 otherwise stated .
dry diethyl ether ( et2o ) , dichloromethane 
 ( ch2cl2 ) , acetonitrile ( ch3cn ) , toluene 
 ( phme ) , n , n - dimethylformamide ( dmf ) , 
 tetrahydrofuran ( thf ) , methanol ( meoh ) , and triethylamine ( et3n ) were obtained by passing these previously degassed solvents 
 through activated alumina columns .
reagents were purchased at the 
 highest commercial quality and used without further purification , 
 unless otherwise stated .
reactions were monitored 
 by thin - layer chromatography ( tlc ) carried out on 0.25 mm e. merck 
 silica gel plates ( 60f-254 ) using uv light as the visualizing agent , 
 as well as one of the following mixtures as a developing agent followed 
 by heating of the tlc plate : anisaldehyde , phosphomolybdic acid , ceric 
 ammonium molybdate , or potassium permanganate .
e. merck silica gel 
 ( 60 , particle size 0.0430.063 mm ) was used for flash column 
 chromatography .
preparative thin - layer chromatography ( ptlc ) separations 
 were carried out on 0.25 or 0.5 mm e. merck silica gel plates ( 60f-254 ) . 

nmr spectra were recorded on 600 , 500 , and 400 mhz instruments and 
 calibrated using residual undeuterated solvent as an internal reference 
 ( chcl3 at 7.26 ppm for h nmr and 77.16 ppm 
 for c nmr ) .
the following abbreviations ( or combinations 
 thereof ) are used to explain the multiplicities : s , singlet ; d , doublet ; 
 t , triplet ; q , quartet ; m , multiplet ; b , broad .
high - resolution mass 
 spectra ( hrms ) were recorded on an lc / msd tof time - of - flight mass 
 spectrometer by electrospray ionization time - of - flight reflectron 
 experiments .
cyclobutanecarbonyl chloride ( 2.47 g , 20.8 mmol , 
 1 equiv ) in dcm ( 50 ml ) was added dropwise to a vigorously stirred 
 biphasic solution of 8-aminoquinoline ( 3.00 g , 20.8 mmol ) in dcm / saturated 
 aqueous sodium bicarbonate ( 50 ml/100 ml ) at room temperature .
the 
 reaction mixture was stirred for 3 h , and the layers were separated , 
 extracted with dcm ( 2  50 ml ) , washed with brine , and dried 
 over sodium sulfate .
after filtration and concentration , the product 
 was filtered through a silica plug ( 3% et2o in dcm ) to 
 give 28 ( 4.58 g , 97% ) as a colorless oil that slowly 
 crystallizes upon standing : white crystalline solid ( 5354 
 c ) : rf = 0.45 ( silica gel , 3/1 hexanes / etoac ) ; 
 hrms ( m / z ) calcd for c14h14n2o ( [ m + h ] ) 227.1184 , found 
 227.1188 ; ir ( film ) max 3351 , 2942 , 1680 , 1521 , 
 1484 , 1323 , 790 cm ; h nmr ( 500 mhz , 
 cdcl3 )  9.73 ( br s , 1 h ) , 8.80 ( dd , j = 7.6 , 1.4 hz , 1 h ) , 8.75 ( dd , j = 4.2 , 1.7 hz , 
 1 h ) , 8.09 ( dd , j = 8.3 , 1.7 hz , 1 h ) , 7.49 ( t , j = 7.9 hz , 1 h ) , 7.43 ( dd , j = 8.3 , 1.4 
 hz , 1 h ) , 7.38 ( dd , j = 8.2 , 4.2 hz , 1 h ) , 3.37 ( p , j = 8.5 hz , 1 h ) , 2.542.41 ( m , 2 h ) , 2.352.19 
 ( m , 2 h ) , 2.091.99 ( m , 1 h ) , 1.991.89 ( m , 1 h ) ; c nmr ( cdcl3 , 126 mhz )  173.7 , 148.1 , 138.4 , 
 136.3 , 134.6 , 127.9 , 127.4 , 121.5 , 121.3 , 116.3 , 41.4 , 25.5 , 18.2 . 28 ( 226 mg , 1.00 mmol ) , pd(oac)2 ( 2.25 mg , 0.01 mmol , 0.01 equiv ) , silver acetate ( 500 mg , 
 3.0 mmol , 3 equiv ) , and iodobenzene ( 334 l , 3.0 mmol , 3 equiv ) 
 were placed in a sealed tube , and toluene ( 3.3 ml ) was added under 
 ambient conditions .
the tube was sealed and placed in an 80 c 
 oil bath for 24 h. the reaction mixture was cooled to room temperature , 
 diluted with dcm ( 5 ml ) , filtered through a pad of celite , and concentrated . 

the resulting yellow solid was purified by silica gel chromatography 
 ( 1020% etoac in hexanes ) to give 29 ( 368 mg , 
 97% ) as a white crystalline solid ( 137138 c ) : rf = 0.4 ( silica gel , 3/1 hexanes / etoac ) ; hrms 
 ( m / z ) calcd for c26h22n2o ( [ m + h ] ) 379.1810 , found 379.1809 ; 
 ir ( film ) max br 3354 , 3025 , 1686 , 1518 , 1483 , 1322 , 
 1159 , 695 cm ; h nmr ( 500 mhz , cdcl3 ) :  9.55 ( s , 1 h ) , 8.73 ( dd , j = 4.2 , 
 1.7 hz , 1 h ) , 8.33 ( dd , j = 7.3 , 1.7 hz , 1 h ) , 8.01 
 ( dd , j = 8.3 , 1.7 hz , 1 h ) , 7.39 ( d , j = 7.3 hz , 4 h ) , 7.35 ( dd , j = 8.2 , 4.2 hz , 1 h ) , 
 7.327.27 ( m , 2 h ) , 7.25 ( t , j = 7.8 hz , 4 
 h ) , 7.137.09 ( m , 2 h ) , 4.19 ( td , j = 8.2 , 
 3.2 hz , 1 h ) , 4.10 ( dt , j = 11.7 , 8.2 hz , 2 h ) , 3.60 
 ( td , j = 11.3 , 10.1 hz , 1 h ) , 2.77 ( dtd , j = 10.1 , 7.9 , 3.2 hz , 1 h ) ; c nmr ( cdcl3 , 126 mhz )  168.9 , 147.8 , 140.7 , 138.2 , 136.1 , 134.2 , 
 128.1 , 127.7 , 127.2 , 127.0 , 126.1 , 121.3 , 121.0 , 116.4 , 54.6 , 39.1 , 
 29.9 . 28 ( 50 mg , 0.221 mmol ) , pd(oac)2 ( 2.5 mg , 
 0.011 mmol , 0.05 equiv ) , silver acetate ( 111 mg , 0.66 mmol , 3 equiv ) , 
 and 3,4-methylenedioxyiodobenzene ( 164 mg , 0.66 mmol , 3 equiv ) were 
 placed in a sealed tube and toluene ( 740 l ) was added under 
 ambient conditions .
the tube was sealed and placed into an 80 c 
 oil bath for 5 h. the reaction mixture was cooled to room temperature , 
 diluted with dcm ( 2 ml ) , filtered through a pad of celite , and concentrated . 

the resulting orange solid was purified by silica gel chromatography 
 ( 1/1/4 to 1/1/3 dcm / et2o / hexanes ) to give 31 ( 96.5 mg , 98% ) as a white crystalline solid ( 182183 c ) : rf = 0.2 ( silica gel , 3/1 hexanes / etoac ) ; hrms 
 ( m / z ) calcd for c28h23n2o5 ( [ m + h ] ) 467.1607 , 
 found 467.1607 ; ir ( film ) max br 3351 , 2889 , 1683 , 
 1519 , 1483 , 1236 , 1035 , 931 cm ; h 
 nmr ( 400 mhz , cdcl3 )  9.50 ( s , 1 h ) , 8.72 ( dd , j = 4.2 , 1.7 hz , 1 h ) , 8.39 ( dd , j = 6.7 , 
 2.3 hz , 1 h ) , 8.03 ( dd , j = 8.3 , 1.7 hz , 1 h ) , 7.397.28 
 ( m , 3 h ) , 6.84 ( d , j = 1.7 hz , 2 h ) , 6.78 ( ddd , j = 8.0 , 1.8 , 0.8 hz , 2 h ) , 6.65 ( d , j = 
 8.0 hz , 2 h ) , 5.78 ( dd , j = 9.2 , 1.5 hz , 4 h ) , 4.04 
 ( td , j = 8.0 , 3.3 hz , 1 h ) , 3.973.87 ( m , 
 2 h ) , 3.37 ( q , j = 11.2 hz , 1 h ) , 2.65 ( dtd , j = 9.9 , 7.8 , 3.3 hz , 1 h ) ; c nmr ( cdcl3 , 101 mhz )  169.0 , 147.9 , 147.5 , 145.9 , 138.3 , 136.2 , 
 134.5 , 134.3 , 127.8 , 127.3 , 121.4 , 121.1 , 120.1 , 116.5 , 108.0 , 107.8 , 
 100.7 , 54.8 , 38.9 , 30.7 . this compound was prepared analogously 
 to 31 , only employing 3,4,5-trimethoxyiodobenzene ( 195 
 mg ) , and purified by silica gel chromatography ( 2/2/3 to 2/2/1 dcm / et2o / hexanes ) to give 32 ( 118.2 mg , 96% ) as a pale 
 yellow foam : rf = 0.2 ( silica gel , 1/1 
 hexanes / etoac ) ; hrms ( m / z ) calcd 
 for c32h34n2o7 ( [ m + h ] ) 559.2444 , found 559.2444 ; ir ( film ) max br 3349 , 2937 , 1686 , 1587 , 1520 , 1236 , 1123 , 1006 , 826 cm ; h nmr ( 500 mhz , cdcl3 )  9.56 ( s , 
 1 h ) , 8.67 ( dd , j = 4.3 , 1.7 hz , 1 h ) , 8.41 ( dd , j = 7.4 , 1.6 hz , 1 h ) , 8.04 ( dd , j = 8.3 , 
 1.7 hz , 1 h ) , 7.397.28 ( m , 3 h ) , 6.51 ( s , 4 h ) , 4.12 ( td , j = 8.1 , 3.2 hz , 1 h ) , 3.96 ( dt , j = 11.2 , 
 8.0 hz , 2 h ) , 3.69 ( s , 12 h ) , 3.64 ( s , 6 h ) , 3.36 ( q , j = 11.1 hz , 1 h ) , 2.75 ( dtd , j = 9.7 , 7.9 , 3.2 hz , 
 1 h ) ; c nmr ( cdcl3 , 126 mhz )  169.1 , 
 152.9 , 147.8 , 138.1 , 136.5 , 136.3 , 136.2 , 134.1 , 127.7 , 127.2 , 121.4 , 
 121.2 , 116.3 , 103.8 , 60.6 , 55.9 , 54.3 , 39.1 , 31.1 .
this compound was prepared analogously 
 to 31 , only 
 employing n - tosyl-3-iodoindole ( 263 mg ) , and purified by silica gel chromatography ( 1/1/3 
 to 3/3/4 dcm / et2o / hexanes ) to give 33 ( 156.1 
 mg , 92% ) as light yellow crystals .
crystals suitable for x - ray diffraction 
 were obtained from etoac : pale yellow crystals ( 185187 c ) ; rf = 0.1 ( silica gel , 3/1 hexanes / etoac ) ; hrms 
 ( m / z ) calcd for c44h36n4o5s2 ( [ m + h ] ) 765.2205 , found 765.2198 ; ir ( film ) max br 3346 , 
 2940 , 1680 , 1520 , 1362 , 1170 , 1124 , 736 cm ; h nmr ( 400 mhz , cdcl3 )  9.57 ( s , 1 h ) , 8.70 
 ( dd , j = 4.3 , 1.7 hz , 1 h ) , 8.47 ( dd , j = 7.1 , 2.0 hz , 1 h ) , 8.05 ( dd , j = 8.3 , 1.7 hz , 
 1 h ) , 7.847.77 ( m , 2 h ) , 7.73 ( s , 2 h ) , 7.587.54
( m , 
 2 h ) , 7.52 ( d , j = 8.4 hz , 4 h ) , 7.447.33 
 ( m , 3 h ) , 7.227.11 ( m , 4 h ) , 6.82 ( d , j = 
 8.0 hz , 4 h ) , 4.284.10 ( m , 3 h ) , 3.613.48 ( m , 1 h ) , 
 2.992.87 ( m , 1 h ) , 2.13 ( s , 6 h ) ; c nmr ( cdcl3 , 101 mhz )  168.7 , 148.2 , 144.2 , 138.1 , 136.0 , 135.2 , 
 134.9 , 134.2 , 130.6 , 129.6 , 127.7 , 127.1 , 126.6 , 125.0 , 124.4 , 123.0 , 
 121.6 , 121.4 , 121.1 , 119.3 , 116.2 , 113.6 , 53.8 , 33.1 , 31.9 , 21.4 . 28 ( 46 mg , 0.20 mmol ) , pd(oac)2 ( 4.6 mg , 0.02 mmol , 
 0.10 equiv ) , silver acetate ( 100 mg
, 0.60 mmol , 3 equiv ) , and iodostyrene 
 ( 138 mg , 0.60 mmol , 3 equiv ) were placed in a sealed tube , and toluene 
 ( 1 ml ) was added under ambient conditions .
the tube was sealed and 
 placed in an 80 c oil bath for 12 h. the reaction mixture was 
 cooled to room temperature , diluted with dcm ( 2 ml ) , filtered through 
 a pad of celite , and concentrated .
the resulting orange solid was 
 purified by silica gel chromatography ( 10% etoac in hexanes ) to give 34 ( 66.2 mg , 77% ) as pale yellow needles ( 128129 c ) : rf = 0.45 ( silica gel , 3/1 hexanes / etoac ) ; hrms 
 ( m / z ) calcd for c30h26n2o ( [ m + h ] ) 431.2123 , found 431.2125 ; 
 ir ( film ) max br 3349 , 2934 , 1677 , 1519 , 1483 , 1322 , 
 968 , 748 , 692 cm ; h nmr ( 400 mhz , 
 cdcl3 )  9.76 ( s , 1 h ) , 8.87 ( dd , j = 7.6 , 1.4 hz , 1 h ) , 8.61 ( dd , j = 4.2 , 1.7 hz , 
 1 h ) , 8.07 ( dd , j = 8.3 , 1.7 hz , 1 h ) , 7.52 ( t , j = 7.9 hz , 1 h ) , 7.45 ( dd , j = 8.3 , 1.4 
 hz , 1 h ) , 7.387.31 ( m , 5 h ) , 7.277.21 ( m , 4 h ) , 7.197.12 
 ( m , 2 h ) , 6.69 ( dd , j = 15.8 , 8.3 hz , 2 h ) , 6.52 
 ( d , j = 15.9 hz , 2 h ) , 3.75 ( td , j = 8.3 , 3.0 hz , 1 h ) , 3.48 ( dqd , j = 10.4 , 8.2 , 
 0.9 hz , 2 h ) , 2.87 ( q , j = 10.6 hz , 1 h ) , 2.53 ( dtd , j = 10.9 , 8.1 , 2.9 hz , 1 h ) ; c nmr ( cdcl3 , 101 mhz )  170.3 , 148.0 , 138.5 , 137.5 , 136.3 , 134.5 , 
 131.2 , 130.2 , 128.4 , 127.9 , 127.4 , 127.1 , 126.4 , 121.5 , 121.5 , 116.7 , 
 53.2 , 38.6 , 34.0
. 28 ( 90 mg , 0.40 mmol ) , pd(oac)2 ( 8.9 mg , 
 0.04 mmol , 0.10 equiv ) , silver acetate ( 199 mg , 1.20 mmol , 3 equiv ) 
 and vinyl iodide ( 301 mg , 1.20 mmol , 
 3 equiv ) were placed in a sealed tube , and toluene ( 1.32 ml ) was added 
 under ambient conditions . the tube was sealed and placed in an 80 
 c oil bath for 12 h. the reaction mixture was cooled to room 
 temperature , diluted with dcm ( 3 ml ) , filtered through a pad of celite , 
 and concentrated .
the resulting orange oil was purified by silica 
 gel chromatography ( 1530% etoac in hexanes ) to give 35 ( 146.5 mg , 78% ) as a pale yellow foam : rf = 0.55 ( silica gel , 1/1 hexanes / etoac ) ; hrms ( m / z ) calcd for c28h30n2o5 ( [ m + h ] ) 475.2233 , found 
 475.2234 ; ir ( film ) max br 3347 , 2948 , 1713 , 1621 , 
 1523 , 1285 , 1169 cm ; h nmr ( 400 mhz , 
 cdcl3 )  9.64 ( s , 1 h ) , 8.78 ( dd , j = 7.5 , 1.5 hz , 1 h ) , 8.69 ( dd , j = 4.2 , 1.7 hz , 
 1 h ) , 8.08 ( dd , j = 8.3 , 1.7 hz , 1 h ) , 7.50 ( dd , j = 8.3 , 7.5 hz , 1 h ) , 7.45 ( dd , j = 8.3 , 
 1.5 hz , 1 h ) , 7.37 ( dd , j = 8.3 , 4.2 hz , 1 h ) , 7.23 
 ( dd , j = 15.7 , 0.7 hz , 2 h ) , 6.25 ( d , j = 8.4 hz , 2 h ) , 5.69 ( d , j = 15.6 hz , 2 h ) , 3.783.69 
 ( m , 1 h ) , 3.64 ( s , 6 h ) , 3.683.55 ( m , 2 h ) , 2.63 ( q , j = 10.4 hz , 1 h ) , 2.51 ( dtd , j = 10.8 , 
 8.3 , 2.9 hz , 1 h ) , 1.77 ( d , j = 1.2 hz , 6 h ) ; c nmr ( cdcl3 , 101 mhz )  169.6 , 167.8 , 149.4 , 
 148.1 , 141.5 , 138.4 , 136.5 , 134.2 , 133.7 , 128.0 , 127.5 , 121.8 , 121.7 , 
 116.8 , 116.1 , 53.1 , 51.5 , 35.3 , 34.4 , 12.7 . 28 ( 200 mg , 0.884 mmol ) , pd(oac)2 ( 10.0 mg , 0.045 mmol , 0.05 equiv ) , silver acetate ( 443 mg , 
 2.65 mmol , 3 equiv ) , lithium chloride ( 112 mg , 2.64 mmol , 3 equiv ) , 
 and tips - bromoacetylene ( 693 mg , 2.65 
 mmol , 3 equiv ) were placed in a sealed tube , and toluene ( 1.76 ml ) 
 was added under ambient conditions .
the tube was flushed with argon , 
 sealed , and placed in a 100 c oil bath for 12 h. the reaction 
 mixture was cooled to room temperature , diluted with dcm ( 3 ml ) , filtered 
 through a pad of celite , and concentrated .
the resulting orange oil 
 was purified by silica gel chromatography ( 2.57% et2o in hexanes ) to give 36 ( 430 mg , 83% ) as a light yellow 
 oil that crystallized upon standing : light yellow crystalline solid 
 ( 6163 c ) ; rf = 0.7 ( silica 
 gel , 3/1 hexanes / etoac ) ; hrms ( m / z ) calcd for c36h54n2osi2 ( [ m + h ] ) 587.3853 , found 587.3857 ; ir ( film ) max br 3355 , 2942 , 2864 , 2159 , 1698 , 1524 , 882 , 675 cm ; h nmr ( 400 mhz , cdcl3 )  
 10.01 ( s , 1 h ) , 8.90 ( dd , j = 7.5 , 1.6 hz , 1 h ) , 
 8.77 ( dd , j = 4.2 , 1.7 hz , 1 h ) , 8.13 ( dd , j = 8.3 , 1.7 hz , 1 h ) , 7.537.44 ( m , 2 h ) , 7.41 ( dd , j = 8.2 , 4.2 hz , 1 h ) , 3.68 ( td , j = 8.5 , 
 3.5 hz , 1 h ) , 3.41 ( dt , j = 11.1 , 8.4 hz , 2 h ) , 3.06 
 ( q , j = 11.0 hz , 1 h ) , 2.70 ( dtd , j = 10.5 , 8.4 , 3.0 hz , 1 h ) , 0.850.75 ( m , 42 h ) ; c nmr ( cdcl3 , 101 mhz )  167.5 , 148.0 , 138.8 , 136.2 , 
 135.0 , 127.8 , 127.5 , 121.3 , 121.1 , 117.1 , 106.7 , 84.0 , 52.8 , 36.2 , 
 26.6 , 18.5 , 11.2 . to 
 benzyl vinyl ether ( 2.50 g. 18.6 mmol , 1 equiv ) in dry diethyl ether 
 ( 300 ml ) at room temperature
was added zn  cu ( 18.27 g , 279 
 mmol , 15 equiv ) , followed by trichloroacetyl chloride ( 5.30 ml , 46.5 
 mmol , 2.5 equiv ) dropwise over 3 h. a saturated solution of ammonium 
 chloride in methanol ( 250 ml ) was added , and the mixture was refluxed 
 for 30 min .
the crude reaction product was partitioned between diethyl ether ( 200 
 ml ) and water ( 200 ml ) , the layers were separated , and the aqueous 
 layer was extracted with diethyl ether ( 2  75 ml ) . the combined 
 organics were washed with brine ( 150 ml ) and dried over na2so4 .
after filtration and concentration , the crude product 
 was purified by column chromatography ( 10% et2o in hexanes ) 
 to give 42 ( 1.65 g , 50% ) as a colorless oil with spectroscopic 
 data that matched those previously reported .
triethylamine 
 ( 1.0 ml , 7.17 mmol , 2.5 equiv ) was added to a solution of 8-formamidoquinoline 
 ( 500 mg , 2.9 mmol ) in dcm ( 4 ml ) at room temperature in a two - neck 
 flask equipped with a reflux condenser .
a toluene solution of phosgene 
 ( 1.9 m , 1.83 ml , 3.48 mmol , 1.2 equiv ) was added dropwise , and the 
 exothermic reaction was allowed to reflux gently .
after the mixture 
 was cooled to room temperature , ammonia gas was bubbled through the 
 solution to quench any unreacted phosgene and then the mixture was 
 purged with nitrogen . the black reaction mixture was diluted with 
 dcm ( 4 ml ) and filtered through celite .
the black filtrate was concentrated , 
 and et2o ( 4 ml ) was added .
the soluble portion was filtered 
 through celite again , washing with et2o ( 3  3 ml ) . 

trituration of this material with hexanes ( 3  2 ml ) left 
 the desired isonitrile 39 ( 285 mg , 64% ) as a light yellow 
 solid ( > 75 c , decomp ) : rf = 0.5 
 ( silica gel , 1/1 hexanes / etoac ) [ reactive ; spot is from the resulting 
 formamide ] ; hrms ( m / z ) n / a , unstable ; 
 ir ( film ) max 3047 , 2127 , 1682 , 1596 , 1498 , 1389 , 
 826 , 762 cm ; h nmr ( 400 mhz , cdcl3 )  9.06 ( dd , j = 4.2 , 1.7 hz , 1 h ) , 
 8.20 ( dd , j = 8.4 , 1.7 hz , 1 h ) , 7.87 ( dd , j = 8.3 , 1.3 hz , 1 h ) , 7.79 ( dd , j = 7.5 , 
 1.4 hz , 1 h ) , 7.577.47 ( m , 2 h ) ; c nmr ( cdcl3 , 101 mhz )  152.0 , 142.8 , 136.4 , 129.5 , 128.8 , 127.8 , 
 125.9 , 122.7 , 77.5 , 77.2 , 76.8 .
methanol ( 0.5 ml ) was added 
 to a solution of 39 ( 40 mg , 0.26 mmol ) in dcm ( 0.5 ml ) 
 at room temperature .
after 4 h , the mixture was concentrated and purified 
 directly by column chromatography ( 2550% etoac in hexanes ) 
 to give methanol adduct 45b ( 25.3 mg , 52% ) as a light 
 yellow oil : rf = 0.2 ( silica gel , 1/1 
 hexanes / etoac ) ; hrms ( m / z ) calcd 
 for c11h10n2o ( [ m + h ] ) 187.0871 , found 187.0875 ; ir ( film ) max br 3373 , 
 2931 , 1477 , 1340 , 1192 , 1062 , 803 , 740 cm ; h nmr ( 500 mhz , cdcl3 )  8.21 ( s , 1h ) , 7.74 
 ( d , j = 8.1 hz , 1h ) , 7.27 ( dd , j = 15.3 , 8.0 hz , 1h ) , 7.19 ( d , j = 7.2 hz , 1h ) , 
 7.10 ( dd , j = 9.8 , 1.1 hz , 1h ) , 6.66 ( dd , j = 3.6 , 1.1 hz , 1h ) , 5.91 ( dd , j = 9.8 , 
 3.6 hz , 1h ) , 3.01 ( s , 3h ) ; c nmr ( cdcl3 , 126 
 mhz )  141.6 , 140.2 , 130.9 , 128.1 , 123.1 , 122.0 , 121.0 , 120.2 , 
 117.5 , 80.4 , 50.3 .
potassium carbonate ( 960 mg , 6.96 mmol , 2.5 equiv ) , 
 copper sulfate 
 ( 7 mg , 0.028 mmol , 0.01 equiv ) , and the diazo transfer agent s2 ( 700 mg , 3.34 mmol , 1.2 equiv ) were successively added 
 to a solution of commercially available ethyl 1-amino-1-cyclobutanecarboxylate 
 monohydrochloride ( s1 ; 500 mg , 2.78 mmol ) in methanol 
 ( 14 ml ) at room temperature . after 24 h , the mixture was concentrated , 
 dissolved in etoac ( 20 ml ) , washed with 1 n aqueous hcl ( 10 ml ) and 
 brine , and dried over sodium sulfate . after concentration
, the crude 
 product was purified by column chromatography ( 25% et2o 
 in hexanes ) to give s3 ( 324 mg , 78% ) as a colorless oil 
 with spectral data which matched those reported ( contained 20% of inconsequential methyl ester from concomitant 
 transesterification during the reaction ) .
lithium hydroxide hydrate ( 131 mg , 3.12 
 mmol , 2 equiv ) was added to a solution of azido ester s3 ( 265 mg , 1.57 mmol ) in thf / h2o ( 10 ml , 3/1 v / v ) .
the 
 reaction mixture was stirred vigorously for 24 h and quenched with 
 3 n aqueous hcl ( 2 ml ) .
the mixture was separated and extracted with 
 etoac ( 3  5 ml ) , and the extract was washed with brine ( 10 ml ) 
 and dried over sodium sulfate .
after concentration , azido acid s4 ( 230 mg , 99% ) was isolated as a colorless oil : rf = 0.15 ( silica gel , 3/1 hexanes / etoac ) ; hrms 
 ( m / z ) calcd for c5h7n3o2 ( [ m  h ] ) 140.0465 , found 140.0464 ; ir ( film ) max br 3001 , 
 2100 , 1706 , 1416 , 1248 cm ; h nmr ( 400 
 mhz , cdcl3 )  2.732.61 ( m , 1h ) , 2.412.26 
 ( m , 1h ) , 2.161.96 ( m , 1h ) .
c nmr ( cdcl3 , 101 mhz )  178.6 , 64.8 , 31.2 , 14.7 . 8-aminoquinoline 
 ( 260 mg , 1.8 mmol , 1.2 equiv ) was added to a solution of s4 ( 211 mg , 1.5 mmol ) in dcm ( 15 ml ) cooled to 0 c , followed 
 by t3p ( 50 wt % in etoac , 1.34 ml , 2.25 mmol , 1.5 equiv ) and triethylamine 
 ( 0.42 ml , 3 mmol , 2 equiv ) .
the reaction mixture was warmed to room 
 temperature and stirred for 24 h. saturated sodium bicarbonate solution 
 ( 10 ml ) was added , and the biphasic reaction mixture was separated 
 and extracted with dcm ( 2  10 ml ) , and the extract was washed 
 with brine ( 10 ml ) and dried over sodium sulfate . after filtration 
 and concentration , the crude product was purified by silica gel chromatography 
 ( 05% etoac in hexanes ) to give 46a ( 370 mg , 92% ) 
 as a colorless oil : rf = 0.6 ( silica gel , 
 3/1 hexanes / etoac ) ; hrms ( m / z ) calcd 
 for c14h13n5o ( [ m + h ] ) 268.1198 , found 268.1201 ; ir ( film ) max br 3328 , 
 2107 , 1681 , 1523 , 1485 , 1257 , 790 cm ; h nmr ( 400 mhz , cdcl3 )  10.65 ( br s , 1 h ) , 8.84 
 ( dd , j = 4.2 , 1.7 hz , 1 h ) , 8.79 ( dd , j = 6.7 , 2.3 hz , 1 h ) , 8.12 ( dd , j = 8.3 , 1.7 hz , 
 1 h ) , 7.557.47 ( m , 2 h ) , 7.42 ( dd , j = 8.3 , 
 4.2 hz , 1 h ) , 2.912.77 ( m , 2 h ) , 2.542.42 ( m , 2 h ) , 
 2.322.17 ( m , 1 h ) , 2.142.00 ( m , 1 h ) ; c nmr ( cdcl3 , 101 mhz )  169.9 , 148.6 , 138.9 , 136.3 , 
 134.0 , 128.0 , 127.2 , 122.1 , 121.7 , 116.6 , 66.6 , 31.5 , 14.8 . triphenylphosphine 
 ( 367 mg , 1.4 mmol , 1.2 equiv ) was added to a solution of 46a ( 312 mg , 1.17 mmol ) in dioxane / h2o ( 11 ml , 10/1 v / v ) 
 at room temperature .
a reflux condenser was attached to the flask , 
 and the reaction mixture was placed in an oil bath preheated to 110 
 c for 36 h. after it was cooled to room temperature , the reaction 
 mixture was acidified with 1 n aqueous hcl ( 5 ml ) and extracted with 
 etoac ( 3  15 ml ) .
n aqueous 
 naoh ( 5 ml ) , saturated with nacl , extracted with etoac ( 3  25 
 ml ) , and dried over sodium sulfate . after filtration and concentration , 
 the crude yellow oil was purified by silica gel chromatography ( 50100% 
 etoac in hexanes ) to give s5 ( 257 mg , 91% ) as a colorless 
 oil : rf = 0.4 ( silica gel , 1/1 hexanes / etoac ) ; 
 hrms ( m / z ) calcd for c14h15n3o ( [ m + h ] ) 242.1293 , found 
 242.1294 ; ir ( film ) max br 3291 , 2935 , 1671 , 1513 , 
 1482 , 1324 , 790 cm ; h nmr ( 400 mhz , 
 cdcl3 )  8.84 ( dd , j = 7.6 , 1.5 
 hz , 1 h ) , 8.80 ( dd , j = 4.2 , 1.7 hz , 1 h ) , 8.06 ( dd , j = 8.3 , 1.7 hz , 1 h ) , 7.48 ( t , j = 7.9 
 hz , 1 h ) , 7.42 ( dd , j = 8.2 , 1.4 hz , 1 h ) , 7.36 ( dd , j = 8.3 , 4.2 hz , 1 h ) , 2.992.70 ( m , 2 h ) , 2.201.84 
 ( m , 6 h ) ; c nmr ( cdcl3 , 101 mhz )  175.0 , 
 148.5 , 139.1 , 136.2 , 134.7 , 128.0 , 127.3 , 121.5 , 121.4 , 116.1 , 60.0 , 
 35.3 , 14.3 .
cbzcl 
 ( 88 
 l , 0.62 mmol , 1.2 equiv ) was added dropwise to a vigorously 
 stirred biphasic solution of s5 ( 124 mg , 0.52 mmol ) in 
 dcm / saturated aqueous sodium bicarbonate ( 7.5 ml , 2/1 v / v ) at room 
 temperature .
the reaction mixture was stirred for 2.5 h , the phases 
 were separated and extracted with dcm ( 2  5 ml ) , and the extract 
 was washed with brine and dried over sodium sulfate . after filtration 
 and concentration , the crude yellow foam was filtered through a plug 
 of silica gel ( 50% etoac in hexanes ) to give 46b ( 188 
 mg , 97% ) as a white foam : rf = 0.15 ( silica 
 gel , 3/1 hexanes / etoac ) ; hrms ( m / z ) calcd for c22h21n3o ( [ m + h ] ) 376.1661 , found 376.1663 ; ir ( film ) max br 3326 , 2951 , 1688 , 1525 , 1486 , 1256 cm ; h nmr ( 500 mhz , cdcl3 ; major rotamer )  10.68 
 ( br s , 1 h ) , 8.83 ( br d , j = 7.7 hz , 1 h ) , 8.66 ( s , 
 1 h ) , 8.08 ( d , j = 8.0 hz , 1 h ) , 7.50 ( t , j = 7.9 hz , 1 h ) , 7.45 ( dd , j = 8.3 , 1.5 
 hz , 1 h ) , 7.397.29 ( m , 3 h ) , 7.297.21 ( m , 2 h ) , 7.136.79 
 ( br m , 1 h ) , 6.15 ( br s , 1 h ) , 5.14 ( s , 2 h ) , 2.89 ( app s , 2 h ) , 2.241.91 
 ( m , 4 h ) ; c nmr ( cdcl3 , 126 mhz ; major rotamer ) 
  172.0 , 155.1 , 148.2 , 138.8 , 136.1 , 134.4 , 128.5 , 128.0 , 127.9 , 
 127.4 , 127.3 , 126.9 , 121.6 , 121.5 , 116.4 , 66.8 , 60.4 , 31.6 , 15.4 .
triethylamine 
 ( 212 l , 1.5 mmol , 3 equiv ) was added to a solution of s5 ( 122 mg , 0.51 mmol ) in toluene ( 2.5 ml ) at room temperature , 
 followed by phthalic anhydride ( 150 mg , 1 mmol , 2 equiv ) .
the reaction 
 mixture was placed in an oil bath preheated to 110 c for 20 
 h. after the mixture was cooled to room temperature , saturated sodium 
 bicarbonate solution ( 1 ml ) was added , the reaction mixture was extracted 
 with etoac ( 3  3 ml ) , and the extract was washed with brine 
 and dried over sodium sulfate . after filtration and concentration , 
 the crude product was purified using column chromatography ( 50% etoac 
 in hexanes ) to give 46c ( 90 mg , 48% ) as colorless crystals 
 ( 188190 c ) .
( note : the low yield likely due to crystallization 
 of the product during chromatographic purification . ) : rf = 0.15 ( silica gel , 3/1 hexanes / etoac ) ; hrms ( m / z ) calcd for c22h17n3o3 ( [ m + h ] ) 372.1348 , found 
 372.1350 ; ir ( film ) max 3342 , 1774 , 1715 , 1687 , 
 1530 , 1374 , 719 cm ; h nmr ( 400 mhz , 
 cdcl3 )  10.66 ( br s , 1 h ) , 8.72 ( dd , j = 6.7 , 2.3 hz , 1 h ) , 8.66 ( dd , j = 4.3 , 1.7 hz , 
 1 h ) , 8.08 ( dd , j = 8.3 , 1.7 hz , 1 h ) , 7.83 ( dd , j = 5.5 , 3.1 hz , 2 h ) , 7.69 ( dd , j = 5.5 , 
 3.1 hz , 2 h ) , 7.527.41 ( m , 2 h ) , 7.36 ( dd , j = 8.3 , 4.2 hz , 1 h ) , 3.19 ( ddt , j = 13.5 , 8.0 , 
 2.5 hz , 2 h ) , 3.072.94 ( m , 2 h ) , 2.522.35 ( m , 1 h ) , 
 2.222.09 ( m , 1 h ) ; c nmr ( cdcl3 , 101 
 mhz )  169.7 , 168.1 , 148.4 , 138.7 , 136.2 , 134.3 , 134.1 , 132.2 , 
 127.8 , 127.2 , 123.3 , 121.9 , 121.6 , 116.6 , 62.0 , 32.0 , 18.0 .
dimethyl cyclobutanedicarboxylate 
 ( 3.50 g , 20.33 mmol ) 
 was dissolved in meoh ( 150 ml ) and cooled to 0 c .
an aqueous 
 solution of naoh ( 813 mg in 150 ml h2o ) was then added 
 dropwise over 30 min .
the reaction mixture was slowly warmed to room 
 temperature and stirred for 12 h. the meoh was removed in vacuo , and 
 the resulting aqueous solution was washed with et2o ( 100 
 ml ) . the resulting aqueous phase was acidified with 3 n aqueous hcl 
 ( 10 ml ) and extracted with etoac ( 100 ml , 2  50 ml ) .
the combined 
 organics were washed with brine ( 100 ml ) , dried over sodium sulfate , 
 and concentrated to give s6 ( 3.00 g , 93% ) as a colorless 
 oil : rf = 0.1 ( silica gel , 3/1 hexanes / etoac ) ; 
 hrms ( m / z ) calcd for c7h10nao4 ( [ m + h ] ) 181.0477 , found 
 181.0478 ; ir ( film ) max br 3504 , 2956 , 1705 , 1281 , 
 1202 ,
1138 , 688 cm ; h nmr ( 400 mhz , 
 cdcl3 )  3.77 ( s , 1h ) , 2.59 ( t , j = 8.1 hz , 1h ) , 2.081.95 ( m , 1h ) ; c nmr ( cdcl3 , 101 mhz )  177.9 , 172.2 , 100.1 , 52.9 , 52.6 , 29.0 , 
 16.3 .
8-aminoquinoline 
 ( 260 mg , 1.8 mmol , 1.2 equiv ) was added to a solution of s6 ( 237 mg , 1.5 mmol ) in dcm ( 15 ml ) cooled to 0 c , followed 
 by t3p ( 50 wt % in etoac , 1.34 ml , 2.25 mmol , 1.5 equiv ) and triethylamine 
 ( 0.42 ml , 3 mmol ) .
the reaction mixture was warmed to room temperature 
 and stirred for 24 h. saturated sodium bicarbonate solution ( 10 ml ) 
 was added , and the biphasic reaction mixture was separated , extracted 
 with dcm ( 2  10 ml ) , washed with brine ( 10 ml ) , and dried over 
 sodium sulfate . after filtration and concentration , the crude product 
 was purified by silica gel chromatography ( 1/1/8 to 1/1/6 dcm / et2o / hexanes ) to give 46d ( 409 mg , 90% ) as a pale 
 yellow oil : rf = 0.35 ( silica gel , 3/1 
 hexanes / etoac ) ; hrms ( m / z ) calcd 
 for c16h16n2o3 ( [ m + h ] ) 285.1239 , found 285.1244 ; ir ( film ) max br 3319 , 2952 , 1735 , 1680 , 1525 , 1484 , 1326 , 825 , 790 cm ; h nmr ( 400 mhz , cdcl3 )  10.42 ( br 
 s , 1 h ) , 8.82 ( dd , j = 4.2 , 1.7 hz , 1 h ) , 8.77 ( dd , j = 7.2 , 1.8 hz , 1 h ) , 8.13 ( dd , j = 8.3 , 
 1.7 hz , 1 h ) , 7.587.47 ( m , 2 h ) , 7.43 ( dd , j = 8.3 , 4.2 hz , 1 h ) , 3.83 ( s , 3 h ) , 2.882.78 ( m , 2 h ) , 2.772.68 
 ( m , 2 h ) , 2.05 ( p , j = 8.0 hz , 2 h ) ; c nmr ( cdcl3 , 101 mhz )  173.7 , 168.9 , 148.5 , 138.8 , 
 136.3 , 134.6 , 128.0 , 127.4 , 121.8 , 121.7 , 116.6 , 54.9 , 53.0 , 29.6 , 
 16.3 .
46c ( 37.1 mg , 0.10 mmol ) , 
 pd(oac)2 ( 3.4 mg , 1.5 mol , 0.15 equiv ) , silver acetate 
 ( 50 mg , 0.30 
 mmol , 3 equiv ) , and n - tosyl-3-iodoindole ( 47 ; 119 mg , 0.30 mmol , 3 equiv ) were placed in a sealed tube , and toluene 
 ( 200 l , 0.5 m ) was added under ambient conditions .
the tube 
 was sealed and placed in an oil bath preheated to 130 c for 
 24 h. the reaction mixture was cooled to room temperature , diluted 
 with dcm ( 1 ml ) , filtered through a pad of celite , and concentrated . 

the resulting dark red oil was purified by silica gel chromatography 
 ( 1/1/6 to 1/1/3 dcm / et2o / hexanes ) to give 48c ( 12.9 mg , 14% ) as colorless crystals ( > 175 c , decomp ) : rf = 0.4 ( silica gel , 1/1 hexanes / etoac ) ; hrms 
 ( m / z ) calcd for c52h39n5o7s2 ( [ m + h ] ) 910.2369 , found 910.2355 ; ir ( film ) max 3334 , 
 1777 , 1720 , 1682 , 1527 , 1364 , 1170 , 906 , 719 cm ; h nmr ( 600 mhz , cdcl3 )  10.26 ( br 
 s , 1 h ) , 8.73 ( dd , j = 7.5 , 1.4 hz , 1 h ) , 8.02 ( dd , j = 8.3 , 1.7 hz , 1 h ) , 7.967.86 ( m , 6 h ) , 7.81 ( td , j = 5.3 , 2.1 hz , 2 h ) , 7.67 ( dd , j = 4.2 , 
 1.7 hz , 1 h ) , 7.647.58 ( m , 2 h ) ,
7.577.45 ( m , 6 h ) , 
 7.287.18 ( m , 4 h ) , 7.14 ( dd , j = 8.3 , 4.2 
 hz , 1 h ) , 6.796.71 ( m , 4 h ) , 4.91 ( ddd , j = 10.8 , 9.6 , 1.1 hz , 2 h ) , 3.21 ( td , j = 11.2 , 
 10.4 , 6.7 hz , 2 h ) , 2.09 ( s , 6 h ) ; c nmr ( cdcl3 , 151 mhz ) : 168.1 , 165.4 , 147.9 , 144.2 , 138.3 , 135.9 , 135.3 , 134.7 , 
 134.5 , 133.6 , 132.0 , 131.2 , 129.5 , 127.7 , 127.5 , 126.8 , 126.4 , 124.3 , 
 123.8 , 123.0 , 121.9 , 121.5 , 120.3 , 120.2 , 116.6 , 113.6 , 73.4 , 39.1 , 
 33.8 , 21.5 .
46d ( 30 mg , 0.106 mmol ) , pd(oac)2 ( 3.6 mg , 
 1.6 mol , 0.15 equiv ) , silver carbonate ( 44 mg , 0.16 mmol , 1.5 
 equiv ) , and n - tosyl-3-iodoindole ( 47 ; 119 mg , 0.30 mmol , 3 equiv ) were placed in a sealed tube , and toluene 
 ( 200 l , 0.5 m ) was added under ambient conditions . the tube 
 was sealed and placed in an oil bath preheated to 90 c for 24 
 h. the reaction mixture was cooled to room temperature , diluted with 
 dcm ( 1 ml ) , filtered through a pad of celite , and concentrated .
the 
 resulting yellow oil was purified by silica gel chromatography ( 30% 
 etoac in hexanes ) to give 48d ( 18.3 mg , 21% ) as a white 
 crystalline solid , along with recovered 46d ( 18.7 mg , 
 62% ) : white crystalline solid ( 150155 c ) ; rf = 0.5 ( silica gel , 1/1 hexanes / etoac ) ; hrms ( m / z ) calcd for c46h38n4o7s2 ( [ m + h ] ) 823.2260 , 
 found 823.2266 ; ir ( film ) max 3294 , 1730 , 1673 , 
 1529 , 1359 , 1170 , 904 , 726 cm ; h nmr 
 ( 400 mhz , cdcl3 )  10.25 ( s , 1 h ) , 8.46 ( d , j = 6.8 hz , 1 h ) , 8.39 ( dd , j = 4.4 , 1.7 
 hz , 1 h ) , 8.03 ( d , j = 8.5 hz , 1 h ) , 7.887.70 
 ( m , 6 h ) , 7.48 ( d , j = 8.1 hz , 4 h ) , 7.477.37 
 ( m , 2 h ) , 7.317.14 ( m , 5 h ) , 6.77 ( d , j = 
 7.9 hz , 4 h ) , 4.47 ( dd , j = 11.7 , 8.1 hz , 2 h ) , 4.05 
 ( s , 3 h ) , 3.45 ( q , j = 11.3 hz , 1 h ) , 2.90 ( q , j = 9.1 hz , 1 h ) , 2.11 ( s , 6 h ) ; c nmr ( cdcl3 , 101 mhz )  173.1 , 164.6 , 148.5 , 144.4 , 138.4 , 135.9 , 
 135.1 , 134.9 , 134.0 , 130.8 , 129.6 , 127.8 , 127.1 , 126.7 , 126.0 , 124.6 , 
 123.2 , 121.7 , 121.7 , 120.3 , 119.9 , 116.6 , 113.4 , 67.2 , 53.1 , 36.6 , 
 30.1 , 21.5 . 4-methoxyphenylacetic acid ( 49 ; 2.00 g , 12.0 mmol ) 
 was dissolved in dry thf ( 3 ml ) and added dropwise to a solution of 
 isopropylmagnesium chloride in thf ( 2 m , 13.2 ml , 26.4 mmol , 2.2 equiv ) 
 dropwise , keeping the internal temperature below 50 c .
the reaction 
 mixture turned heterogeneous during the addition and was stirred for 
 30 min at room temperature .
epichlorohydrin ( 1.7 ml , 21.6 mmol , 1.8 
 equiv ) was added dropwise , keeping the internal temperature below 
 35 c , and the mixture was stirred at room temperature for 45 
 min . during the addition the solution homogenizes . a solution of isopropylmagnesium 
 chloride ( 2 m in thf , 12 ml , 24 mmol , 2 equiv ) was added to the reaction 
 mixture , which was then warmed to 60 c overnight ( 14 h ) .
the 
 reaction mixture was carefully quenched with 3 n aqueous hcl ( 20 ml ) , 
 keeping the internal temperature below 35 c .
the resulting biphasic 
 solution was separated and extracted with etoac ( 2  50 ml ) . 

the combined organics were washed with 1 n aqueous naoh ( 2  
 25 ml ) , and the combined aqueous layer was acidified with 3 n aqueous 
 hcl and extracted with etoac ( 3  25 ml ) .
the combined organic 
 layers were washed with brine ( 25 ml ) , dried over na2so4 , and concentrated to give the crude hydroxy acid 50 ( 2.16 g ) as a white solid that was used directly in the next reaction . 
 to a solution of the crude hydroxy acid in meoh ( 20 ml )
was added 
 concentrated sulfuric acid ( 54 l , 1 mmol ) , and the mixture 
 was warmed to 60 c for 12 h. the reaction mixture was cooled 
 to room temperature and neutralized with saturated sodium bicarbonate 
 solution ( 2 ml ) , and the meoh was removed in vacuo .
the resulting 
 mixture was diluted with etoac ( 50 ml ) , washed with brine ( 25 ml ) , 
 dried over na2so4 , and concentrated to give 
 the crude methyl ester ( 2.16 g ) , which was used directly in the next 
 step .
this material could be further purified using silica gel chromatography 
 ( 3060% et2o in hexanes ) for characterization to 
 give the methyl ester s7 as colorless crystals ( mp 6465 
 c ) : rf = 0.4 ( silica gel , 1/1 hexanes / etoac ) ; 
 hrms ( m / z ) calcd for c13h16o4 ( [ m + h ] ) 237.1127 , found 
 237.1131 ; ir ( film ) max br 3419 , 2950 , 1727 , 1511 , 
 1250 , 1130 , 1031 , 832 cm ; h nmr ( 400 
 mhz , cdcl3 )  7.327.21 ( m , 2 h ) , 6.906.83 
 ( m , 2 h ) , 4.16 ( apparent p , j = 6.9 hz , 1 h ) , 3.79 
 ( s , 3 h ) , 3.62 ( s , 3 h ) , 2.972.82 ( m , 2 h ) , 2.722.61 
 ( m , 2 h ) , 2.56 ( br s , 1 h ) ; c nmr ( cdcl3 , 
 101 mhz )  176.4 , 158.5 , 133.3 , 128.1 , 113.9 , 62.7 , 55.4 , 52.6 , 
 44.0 , 42.8 .
tbscl ( 2.17 g , 14.4 mmol , 1.5 equiv ) was 
 added to a solution of crude s7 ( 2.27 g , ca .
9.6 mmol ) 
 in dry dcm ( 35 ml ) at room temperature , followed by imidazole ( 3.27 
 g , 48 mmol , 5 equiv ) .
this mixture was stirred at room temperature 
 for 30 min and quenched with meoh ( 1 ml ) .
the reaction mixture was 
 diluted with dcm ( 50 ml ) , washed with 1 n aqueous hcl ( 50 ml ) and 
 brine ( 50 ml ) , and dried over na2so4 .
after 
 filtration and concentration , the crude product was purified by column 
 chromatography ( 020% et2o in hexanes ) to give 51 ( 2.34 g , 56% for three steps ) as colorless crystals ( mp 
 6365 c ) : rf = 0.6 ( silica 
 gel , 3/1 hexanes / etoac ) ; hrms ( m / z ) calcd for c19h30o4si ( [ m + h ] ) 351.1992 , found 351.1987 ; ir ( film ) max 2952 , 1732 , 1512 , 1251 , 1145 , 1053 , 833 cm ; h nmr ( 400 mhz , cdcl3 )  7.367.29 
 ( m , 2 h ) , 6.936.86 ( m , 2 h ) , 4.10 ( apparent p , j = 7.2 hz , 1 h ) , 3.80 ( s , 3 h ) , 3.61 ( s , 3 h ) , 2.85 ( ddt , j = 8.9 , 6.9 , 2.4 hz , 2 h ) , 2.68 ( ddt , j = 10.1 , 7.5 , 2.4 hz , 2 h ) , 0.88 ( s , 9 h ) , 0.02 ( s , 6 h ) ; c nmr ( cdcl3 , 101 mhz )  175.9 , 175.8 , 158.6 , 133.3 , 
 128.2 , 113.9 , 62.3 , 55.3 , 52.3 , 43.6 , 43.2 , 25.9 , 18.0 , 4.7 . sodium periodate ( 31.5 g , 147.3 mmol , 
 15 equiv ) was added to a vigorously stirred biphasic solution of 51 ( 3.44 g , 9.82 mmol ) in etoac / h2o ( 390 ml/1.15 
 l ) at 4 c .
ruthenium oxide hydrate ( 148 mg , 0.98 mmol , 0.1 equiv ) 
 was added in a single portion , and the light yellow mixture was slowly 
 warmed to room temperature and stirred for 14 h. the resulting black 
 mixture was separated and extracted with etoac ( 2  200 ml ) . 

the combined organics were washed with a brine / saturated sodium sulfite 
 solution ( 200 ml , 10/1 v / v ) , dried over na2so4 and concentrated .
the crude product was filtered through a plug 
 of silica gel ( with etoac as eluent ) to give 52 ( 1.97 
 g , 70% ) as a semicrystalline waxy solid .
( the yield of this reaction 
 at different scales has varied between 62 and 70% ; larger scales were 
 generally higher yielding . ) : rf = 0.5 
 ( silica gel , etoac ) ; hrms ( m / z ) 
 calcd for c13h24o5si ( [ m  
 h ] ) 287.1320 , found 287.1328 ; ir ( film ) max br 3418 , 2955 , 1712 , 1251 , 1135 , 1048 , 835 cm ; h nmr ( 400 mhz , cdcl3 )  4.40 ( apparent 
 p , j = 7.3 hz , 1 h ) , 3.78 ( s , 3 h ) , 2.85 ( ddd , j = 9.9 , 7.1 , 2.8 hz , 2 h ) , 2.53 ( ddd , j = 10.1 , 7.5 , 2.8 hz , 2 h ) , 0.87 ( s , 9 h ) , 0.04 ( s , 6 h ) ; c nmr ( cdcl3 , 101 mhz )  177.9 , 171.4 , 62.0 , 53.0 , 
 45.8 , 41.1 , 25.9 , 18.0 , 4.7 .
8-aminoquinoline ( 180 mg , 1.25 mmol , 1.2 
 equiv ) was added to a solution of 52 ( 300 mg , 1.04 mmol ) 
 in dcm ( 5.2 ml ) cooled to 0 c , followed by edc ( 210 mg , 1.35 
 mmol , 1.3 equiv ) .
the reaction mixture was warmed to room temperature 
 and stirred for 24 h. saturated sodium bicarbonate solution ( 10 ml ) 
 was added , and the biphasic reaction mixture was separated , extracted 
 with dcm ( 2  5 ml ) , washed with brine ( 5 ml ) , and dried over 
 sodium sulfate . after filtration and concentration , the crude product 
 was purified by silica gel chromatography ( 5% etoac in hexanes ) to 
 give 54a ( 315 mg , 76% ) as a pale yellow oil : rf = 0.55 ( silica gel , 3/1 hexanes / etoac ) ; hrms 
 ( m / z ) calcd for c22h30n2o4si ( [ m + h ] ) 415.2053 , 
 found 415.2052 ; ir ( film ) max br 3318 , 2952 , 1740 , 
 1686 , 1527 , 1145 , 1064 , 825 , 776 cm ; h nmr ( 400 mhz , cdcl3 )  10.63 ( br s , 1 h ) , 8.84 
 ( dd , j = 4.2 , 1.7 hz , 1 h ) , 8.75 ( dd , j = 6.5 , 2.5 hz , 1 h ) , 8.15 ( dd , j = 8.4 , 1.7 hz , 
 1 h ) , 7.587.50 ( m , 2 h ) , 7.45 ( dd , j = 8.3 , 
 4.2 hz , 1 h ) , 4.43 ( p , j = 7.2 hz , 1 h ) , 3.84 ( s , 
 3 h ) , 3.09 ( ddt , j = 9.2 , 7.1 , 2.3 hz , 2 h ) , 2.64 
 ( ddd , j = 9.9 , 7.1 , 2.9 hz , 2 h ) , 0.88 ( s , 9 h ) , 
 0.05 ( s , 6 h ) ; c nmr ( cdcl3 , 101 mhz )  
 173.1 , 168.5 , 148.6 , 138.8 , 136.4 , 134.6 , 128.1 , 127.4 , 122.0 , 121.8 , 
 116.7 , 62.2 , 53.1 , 47.8 , 41.7 , 25.9 , 18.1 , 4.7 . 54a ( 58.8 mg , 0.142 mmol ) , pd(oac)2 ( 3.2 mg , 14.2 mol , 0.10 equiv ) , silver acetate ( 71 mg , 0.425 
 mmol , 3 equiv ) , and n - tosyl-3-iodoindole ( 169 mg , 
 0.425 mmol , 3 equiv ) were placed in a sealed tube , and toluene ( 280 
 l , 0.5 m ) was added under ambient conditions .
the tube was 
 sealed and placed in a 110 c oil bath for 24 h. the reaction 
 mixture was cooled to room temperature , diluted with dcm ( 1 ml ) , filtered 
 through a pad of celite , and concentrated .
the resulting orange oil 
 was purified by silica gel chromatography ( 1/1/8 to 1/1/4 dcm / et2o / hexanes ) to give 55a as a yellow foam ( 29.0 
 mg , 21% yield ) : rf = 0.6 ( silica gel , 
 1/1 hexanes / etoac ) ; hrms ( m / z ) calcd 
 for c52h52n4o8s2si ( [ m + h ] ) 953.3074 , found 953.3076 ; ir ( film ) max br 3314 , 2927 , 1736 , 1676 , 1369 , 1174 , 1126 , 747 cm ; h nmr ( 400 mhz , cdcl3 )  
 10.59 ( s , 1h ) , 8.79 ( dd , j = 7.3 , 1.7 hz , 1h ) , 8.56 
 ( dd , j = 4.3 , 1.7 hz , 1h ) , 8.10 ( dd , j = 8.3 , 1.7 hz , 1h ) , 7.88 ( d , j = 0.8 hz , 2h ) , 7.887.84 
 ( m , 1h ) , 7.767.69 ( m , 2h ) , 7.607.47 ( m , 7h ) , 7.35 
 ( dd , j = 8.3 , 4.2 hz , 1h ) , 7.267.20 ( m , 5h ) , 
 6.756.69 ( m , 4h ) , 5.51 ( t , j = 8.2 hz , 1h ) , 
 4.20 ( dd , j = 8.1 , 0.9 hz , 2h ) , 4.04 ( s , 3h ) , 2.04 
 ( s , 6h ) , 0.74 ( s , 8h ) , 0.14 ( s , 5h ) ; c nmr ( cdcl3 , 126 mhz )  172.7 , 164.8 , 148.5 , 144.4 , 138.6 , 136.1 , 
 135.2 , 134.8 , 134.4 , 131.4 , 129.6 , 127.9 , 127.5 , 126.8 , 126.4 , 124.6 , 
 123.2 , 122.0 , 121.7 , 119.9 , 118.0 , 116.8 , 113.6 , 73.1 , 60.4 , 53.3 , 
 48.2 , 25.8 , 21.4 , 17.9 , 4.4 .
2-(methylthio)aniline 
 ( 40 l , 0.32 mmol , 1.2 equiv ) was added to a solution of 52 ( 77.1 mg , 0.267 mmol ) in dcm ( 1.35 ml ) cooled to 0 c , 
 followed by edc ( 66.5 mg , 0.35 mmol , 1.3 equiv ) .
the reaction mixture 
 was warmed to room temperature and stirred for 24 h. saturated sodium 
 bicarbonate solution ( 1 ml ) was added , and the biphasic reaction mixture 
 was separated , extracted with dcm ( 2  1 ml ) , washed with brine 
 ( 2 ml ) , and dried over sodium sulfate . after filtration and concentration , 
 the crude product was purified by silica gel chromatography ( 5% etoac 
 in hexanes ) to give 54b ( 92.1 mg , 84% ) as a pale yellow 
 oil : rf = 0.6 ( silica gel , 3/1 hexanes / etoac ) ; 
 hrms ( m / z ) calcd for c20h31no4ssi ( [ m + h ] ) 410.1821 , found 
 410.1827 ; ir ( film ) max br 3315 , 2953 , 1720 , 1692 , 
 1580 , 1514 , 1434 , 1147 , 1064 , 836 cm ; h nmr ( 400 mhz , cdcl3 )  9.18 ( br s , 1 h ) , 8.30 
 ( d , j = 8.2 hz , 1 h ) , 7.47 ( dd , j = 7.9 , 1.6 hz , 1 h ) , 7.30 ( t , j = 7.8 hz , 1 h ) , 
 7.08 ( t , j = 7.6 hz , 1 h ) , 4.39 ( p , j = 7.2 hz , 1 h ) , 3.82 ( s , 3 h ) , 3.00 ( ddd , j = 9.9 , 
 7.1 , 3.0 hz , 2 h ) , 2.58 ( ddd , j = 12.7 , 6.0 , 2.5 
 hz , 2 h ) , 2.37 ( s , 3 h ) , 0.88 ( s , 9 h ) , 0.04 ( s , 6 h ) ; c nmr ( cdcl3 , 101 mhz )  173.3 , 168.1 , 138.2 , 132.8 , 
 128.8 , 126.1 , 124.7 , 120.8 , 62.1 , 53.1 , 47.4 , 41.7 , 25.9 , 18.7 , 18.0 , 
 4.8 . 54b ( 65 mg , 0.159 mmol ) , pd(oac)2 ( 3.6 mg , 1.6 mol , 0.10 equiv ) , silver carbonate ( 66 mg , 0.24 
 mmol , 1.5 equiv ) , and n - tosyl-3-iodoindole ( 144 mg , 
 0.48 mmol , 3 equiv ) were placed in a sealed tube , and toluene ( 320 
 l , 0.5 m ) was added under ambient conditions . the tube was 
 sealed and placed in a 110 c oil bath for 24 h. the reaction 
 mixture was cooled to room temperature , diluted with dcm ( 1 ml ) , filtered 
 through a pad of celite , and concentrated .
the resulting dark red 
 oil was purified by silica gel chromatography ( 20/5/75 dcm / et2o / hexanes ) to give 55b ( 77.3 mg , 51% yield ) as 
 a yellow foam : rf = 0.6 ( silica gel , 1/1 
 hexanes / etoac ) ; hrms ( m / z ) calcd 
 for c50h53n3o8s3si ( [ m + h ] ) 948.2842 , found 948.2841 ; ir ( film ) max br 3309 , 2927 , 1716 , 1678 , 1172 , 735 cm ; h nmr ( 400 mhz , cdcl3 )  9.24 ( br 
 s , 1 h ) , 8.10 ( dd , j = 8.6 , 1.4 hz , 1 h ) , 7.957.89 
 ( m , 2 h ) , 7.84 ( d , j = 0.8 hz , 2 h ) , 7.727.59 
 ( m , 6 h ) , 7.357.21 ( m , 6 h ) , 7.04 ( td , j = 
 7.5 , 1.4 hz , 1 h ) , 6.916.83 ( m , 4 h ) , 5.45 ( t , j = 8.1 hz , 1 h ) , 4.18 ( dd , j = 8.1 , 0.9 hz , 2 h ) , 
 3.99 ( s , 3 h ) , 2.23 ( s , 6 h ) , 1.02 ( s , 3 h ) , 0.75 ( s , 9 h ) , 0.12 
 ( s , 6 h ) ; c nmr ( cdcl3 , 101 mhz )  173.1 , 
 164.1 , 144.7 , 138.5 , 135.2 , 134.7 , 133.9 , 131.1 , 129.8 , 129.2 , 126.9 , 
 126.3 , 126.0 , 124.7 , 124.5 , 123.2 , 121.2 , 119.9 , 117.6 , 113.5 , 72.2 , 
 59.7 , 53.5 , 48.3 , 25.8 , 21.6 , 17.9 , 16.9 , 4.3 .
acid 52 ( 1.00 g , 3.47 
 mmol ) was dissolved in dry dcm 
 ( 17.5 ml ) and cooled to 0 c in an ice bath .
pentafluorophenol 
 ( 958 mg , 5.2 mmol , 1.5 equiv ) , triethylamine ( 1.45 ml , 10.4 mmol , 
 3 equiv ) , and hatu ( 1.58 g , 4.16 mmol , 1.1 equiv ) were added sequentially , 
 and the reaction mixture was warmed to room temperature .
after 15 
 h , the reaction mixture was diluted with dcm ( 15 ml ) and quenched 
 with 1 n aqueous hcl ( 15 ml ) .
the biphasic mixture was separated , 
 washed with brine ( 15 ml ) , and dried over na2so4 .
after filtration and concentration , the crude product was purified 
 by column chromatography ( 2550% dcm in hexanes ) to give s9 ( 1.30 g , 83% ) as a colorless oil : rf = 0.7 ( silica gel , 3/1 hexanes / etoac ) ; hrms ( m / z ) calcd for c19h23f5o5si ( [ m + h ] ) 454.1313 , found 454.1322 ; 
 ir ( film ) max 2956 , 1789 , 1749 , 1518 , 1244 , 1054 , 
 994 , 835 , 777 cm ; h nmr ( 400 mhz , 
 cdcl3 )  4.38 ( apparent p , j = 7.5 
 hz , 1 h ) , 3.81 ( s , 3 h ) , 2.96 ( m , 2 h ) , 2.65 ( m , 2 h ) , 0.88 ( s , 9 
 h ) , 0.05 ( s , 6 h ) ; c nmr ( cdcl3 , 101 mhz ) 
  170.0 , 168.4 , 62.0 , 53.2 , 45.9 , 41.2 , 25.8 , 18.0 , 4.8 .
s9 ( 1.27 g , 2.80 mmol ) was 
 dissolved in dry thf ( 14 ml ) and cooled to 4 c in a cold room . 

picolinamide ( 678 mg , 5.6 mmol , 2 equiv ) was added to the cooled reaction 
 mixture , followed by potassium tert - butoxide solution 
 in thf ( 2.0 m , 3.5 ml , 7 mmol , 2.5 equiv ) . after 30 min , the reaction 
 was quenched with saturated aqueous ammonium chloride ( 3 ml ) .
the 
 biphasic mixture was diluted with etoac ( 30 ml ) , washed with brine 
 ( 15 ml ) , and dried over na2so4 .
after filtration 
 and concentration , the crude product was purified by column chromatography 
 ( 1025% etoac in hexanes ) to give 57 ( 1.05 g , 
 95% ) as colorless crystals ( mp 8385 c ) : rf = 0.25 ( silica gel , 3/1 hexanes / etoac ) ; hrms ( m / z ) calcd for c19h28n2o5si ( [ m + h ] ) 393.1846 , found 
 393.1845 ; ir ( film ) max br 3324 , 2952 , 1750 , 1725 , 
 1698 , 1478 , 1267 , 1062 , 837 cm ; h 
 nmr ( 400 mhz , cdcl3 )  10.78 ( br s , 1 h ) , 8.61 ( ddd , j = 4.8 , 1.7 , 0.9 hz , 1 h ) , 8.18 ( dt , j = 7.9 , 1.1 hz , 1 h ) , 7.89 ( td , j = 7.7 , 1.7 hz , 
 1 h ) , 7.53 ( ddd , j = 7.6 , 4.8 , 1.2 hz , 1 h ) , 4.20 
 ( tt , j = 8.0 , 7.1 hz , 1 h ) , 3.70 ( s , 3 h ) , 2.90 ( ddt , j = 9.7 , 7.3 , 2.6 hz , 2 h ) , 2.61 ( ddt , j = 12.6 , 8.2 , 2.8 hz , 2 h ) , 0.83 ( s , 9 h ) , 0.01 ( s , 6 h ) ; c nmr ( cdcl3 , 101 mhz )  171.6 , 170.9 , 162.4 , 
 148.5 , 147.7 , 138.0 , 127.8 , 123.3 , 62.0 , 52.8 , 48.3 , 40.5 , 25.8 , 18.0 , 
 4.8 .
57 ( 710 mg , 1.81 mmol ) , pd(oac)2 ( 60.9 
 mg , 0.27 mmol , 0.15 equiv ) , silver pivalate ( 1.13 g , 5.41 mmol , 3 
 equiv ) , and n - tosyl-3-iodoindole ( 2.88 g , 7.24 mmol , 
 4 equiv ) were placed in a sealed tube , and toluene ( 3.6 ml , 0.5 m ) 
 was added under ambient conditions . the tube was sealed and placed 
 in a 120 c oil bath for 24 h. the reaction mixture was cooled 
 to room temperature , diluted with dcm ( 10 ml ) , filtered through a 
 pad of celite , and concentrated .
the resulting dark red oil was purified 
 by silica gel chromatography ( 1/1/6 to 1/1/2 dcm / et2o / hexanes ) 
 to give an orange solid which , upon washing three times with cold 
 et2o ( 20 ml , 10 ml , 10 ml ) , gave a white powder ( 942 mg ) 
 containing a 5/1 mixture of 58 and pd(58)2 ( 55% combined yield ) , which was used directly in the 
 next reaction .
58 could be separated from its palladium 
 complex for characterization by silica gel chromatography ( 4/6 etoac / hexanes ) : 
 colorless crystals ( mp 197200 c ) ; rf = 0.5 ( silica gel , 1/1 hexanes / etoac ) ; hrms ( m / z ) calcd for c49h50n4o9s2si ( [ m + h ] ) 931.2867 , 
 found 931.2850 ; ir ( film ) max 3301 , 2954 , 1757 , 
 1738 , 1473 , 1368 , 1173 , 1126 , 745 cm ; h nmr ( 400 mhz , cdcl3 )  8.26 ( ddd , j = 4.8 , 1.6 , 0.9 hz , 1 h ) , 7.927.84 ( m , 3 h ) , 7.79 ( d , j = 0.9 hz , 2 h ) , 7.787.74 ( m , 4 h ) , 7.72 ( dd , j = 7.7 , 1.7 hz , 1 h ) , 7.677.62 ( m , 2 h ) , 7.34 ( ddd , j = 7.6 , 4.8 , 1.2 hz , 1 h ) , 7.277.21 ( m , 4 h ) , 7.15 
 ( dd , j = 8.4 , 0.9 hz , 4 h ) , 5.34 ( t , j = 8.3 hz , 1 h ) , 4.21 ( dd , j = 8.4 , 0.9 hz , 2 h ) , 
 3.95 ( s , 3h ) , 2.23 ( s , 6h ) , 0.72 ( s , 9 h ) , 0.15 ( s , 6 h ) ; c nmr ( cdcl3 , 101 mhz )  172.0 , 165.6 , 161.2 , 
 148.2 , 147.9 , 144.7 , 137.5 , 135.3 , 134.8 , 131.0 , 130.0 , 127.3 , 127.1 , 
 126.1 , 124.7 , 123.2 , 122.8 , 119.9 , 117.2 , 113.6 , 71.6 , 59.9 , 53.4 , 
 48.5 , 25.7 , 21.6 , 17.8 , 4.4 .
the mixture of 58 and pd(58)2 from the previous step ( 942 mg , 1.00 mmol ) was added to a saturated 
 ammonia solution of dcm/2-propanol ( 20 ml , 1/4 v / v ) [ saturated by 
 bubbling ammonia gas through the solvent mixture for 5 min ] .
scandium 
 triflate ( 24.6 mg , 0.05 mmol , 0.05 equiv ) was added , the flask was 
 capped , and the reaction mixture was stirred at room temperature for 
 24 h. nitrogen was bubbled though the reaction mixture to purge the 
 excess ammonia , and the mixture was concentrated .
purification with 
 silica gel chromatography ( 30% etoac in hexanes ) gave 59 ( 794 mg , 53% for 2 steps ) as a white foam : rf = 0.15 ( silica gel , 3/1 hexanes / etoac ) ; hrms ( m / z ) calcd for c43h48n3o8s2si ( [ m + h ] ) 826.2652 , 
 found 826.2649 ; ir ( film ) max 3472 , 2954 , 1733 , 
 1679 , 1447 , 1366 , 1173 , 1123 , 683 cm ; h nmr ( 400 mhz , cdcl3 )  7.99 ( d , j = 8.2 hz , 2 h ) , 7.80 ( d , j = 8.3 hz , 4 h ) , 7.71 
 ( s , 2 h ) , 7.60 ( d , j = 7.7 hz , 2 h ) , 7.30 ( t , j = 7.3 hz , 2 h ) , 7.24 ( d , j = 7.3 hz , 
 2 h ) , 7.20 ( d , j = 8.2 hz , 4 h ) , 6.24 ( br s , 1 h ) , 
 5.26 ( t , j = 8.0 hz , 1 h ) , 4.99 ( br s , 1 h ) , 4.06 
 ( d , j = 8.2 hz , 2 h ) , 3.90 ( s , 3 h ) , 2.31 ( s , 6 h ) , 
 0.72 ( s , 9 h ) , 0.20 ( s , 6 h ) ; c nmr ( cdcl3 , 101 mhz )  173.3 , 167.8 , 144.9 , 135.4 , 134.9 , 131.1 , 
 129.9 , 127.1 , 126.1 , 124.7 , 123.2 , 119.8 , 118.0 , 113.8 , 72.2 , 58.3 , 
 53.3 , 47.9 , 25.7 , 21.6 , 17.8 , 4.4 . triethylamine 
 ( 450 l , 3.23 mmol , 1.5 equiv ) was added to a solution of s7 ( 505 mg , 2.14 mmol ) in dcm ( 20 ml ) cooled to 0 c 
 in an ice bath , followed by acetic anhydride ( 300 l , 3.23 mmol , 
 1.5 equiv ) and dmap ( 14 mg , 0.11 mmol , 0.05 equiv ) .
the reaction was 
 mixture was stirred at 0 c for 2 h and then was quenched with 
 saturated aqueous sodium bicarbonate ( 10 ml ) .
the biphasic reaction 
 mixture was separated , extracted with dcm ( 2  10 ml ) , washed 
 with 1 n aqueous hcl ( 10 ml ) , washed with brine ( 20 ml ) , and dried 
 over sodium sulfate .
after filtration and concentration , the crude 
 product was purified by silica gel chromatography ( 25% et2o in hexanes ) to give s7 ( 552 mg , 93% ) as a colorless 
 oil : rf = 0.35 ( silica gel , 3/1 hexanes / etoac ) ; 
 hrms ( m / z ) calcd for c15h18o5 ( [ m + h ] ) 279.1232 , found 
 279.1231 ; ir ( film ) max 2953 , 1727 , 1512 , 1229 , 
 1030 , 832 cm ; h nmr ( 400 mhz , cdcl3 )  7.337.27 ( m , 2 h ) , 6.926.84 ( m , 
 2 h ) , 4.86 ( p , j = 7.2 hz , 1 h ) , 3.80 ( s , 3 h ) , 3.63 
 ( s , 3 h ) , 3.042.91 ( m , 2 h ) , 2.882.75 ( m , 2 h ) , 2.03 
 ( s , 3 h ) ; c nmr ( cdcl3 , 101 mhz )  175.5 , 
 170.6 , 158.8 , 132.6 , 128.1 , 114.0 , 64.5 , 55.4 , 52.6 , 45.1 , 39.7 , 21.1 .
sodium 
 periodate ( 3.8 g , 17.7 mmol , 10 equiv ) was added to a vigorously stirred 
 biphasic solution of s8 ( 493 mg , 1.77 mmol ) in etoac / mecn / h2o ( 9 ml/9 ml/30 ml ) cooled to 0 c in an ice bath .
ruthenium 
 oxide hydrate ( 13.4 mg , 0.09 mmol , 0.05 equiv ) was added in a single 
 portion , and the light yellow mixture was vigorously stirred for 20 
 h , while being slowly warmed to room temperature .
the resulting black 
 mixture was separated and extracted with etoac ( 2  20 ml ) .
the 
 combined organics were washed with a brine / saturated sodium sulfite 
 solution ( 200 ml , 10/1 v / v ) , dried over na2so4 , and concentrated to give a crude acid that was used directly in 
 the next reaction without further purification ( h nmr 
 ( 400 mhz , cdcl3 )  5.11 ( p , j = 
 7.6 hz , 1h ) , 3.79 ( s , 3h ) , 3.222.92 ( m , 2h ) , 2.802.60 
 ( m , 2h ) , 2.04 ( s , 3h ) ) .
oxalyl chloride ( 182 l , 2.12 mmol , 
 1.2 equiv ) was added dropwise to a solution of the acid ( ca .
1.77 
 mmol ) in dcm ( 10 ml ) containing 1 drop of dmf . after the reaction 
 mixture
was stirred at room temperature for 4 h , toluene was added 
 ( 5 ml ) and the solvent concentrated to give the crude acid chloride . 

this material was dissolved in toluene , and 2-picolinamide ( 325 mg , 
 2.66 mmol , 1.5 equiv ) was added , followed by 4  molecular sieves 
 ( 1.7 g ) .
the heterogeneous reaction mixture was heated to 90 c 
 for 16 h , and then the reaction mixture was filtered through celite , 
 concentrated , and purified by column chromatography ( 2540% 
 etoac in hexanes ) to give 60 ( 251 mg , 44% for two steps ) 
 as colorless crystals ( mp 138139 c ) : rf = 0.25 ( silica gel , 1/1 hexanes / etoac ) ; hrms ( m / z ) calcd for c15h16n2o6 ( [ m + h ] ) 321.1087 , found 
 321.1095 ; ir ( film ) max br 3319 , 1735 , 1726 , 1698 , 
 1481 , 1234 , 1044 , 747 cm ; h nmr ( 400 
 mhz , cdcl3 )  10.70 ( s , 1 h ) , 8.61 ( ddd , j = 4.8 , 1.7 , 0.9 hz , 1 h ) , 8.16 ( dt , j = 7.9 , 1.1 hz , 1 h ) , 7.89 ( td , j = 7.7 , 1.7 hz , 
 1 h ) , 7.53 ( ddd , j = 7.6 , 4.8 , 1.2 hz , 1 h ) , 4.91 
 ( p , j = 7.7 hz , 1 h ) , 3.71 ( s , 3 h ) , 3.06 ( ddt , j = 9.6 , 7.7 , 2.4 hz , 2 h ) , 2.76 ( ddt , j = 10.7 , 7.8 , 2.6 hz , 2 h ) , 2.02 ( s , 3 h ) ; c nmr ( cdcl3 , 126 mhz )  171.2 , 170.4 , 170.4 , 162.6 , 148.6 , 147.5 , 
 138.0 , 127.9 , 123.3 , 63.7 , 53.0 , 49.4 , 36.8 , 20.9 .
59 ( 400 mg , 0.484 mmol ) was dissolved 
 in thf ( 4.8 ml ) , and h2o ( 1.6 ml ) was added , followed by 
 lithium hydroxide hydrate ( 102 mg , 2.43 mmol , 5 equiv ) .
the biphasic 
 reaction mixture was stirred vigorously for 12 h and quenched with 
 1 n aqueous hcl ( 3 ml ) .
the layers were separated and extracted with 
 etoac ( 4  5 ml ) , and the extract was washed with brine ( 10 ml ) , 
 dried over sodium sulfate , filtered , and concentrated to give the 
 carboxylic acid ( 388 mg , 99% ) as a white foam , which was dissolved 
 in dry dcm ( 4.8 ml ) and cooled to 0 c .
triethylamine ( 0.27 ml , 
 1.94 mmol , 4 equiv ) was added , followed by diphenylphosphoryl azide 
 ( 0.42 ml , 1.94 mmol , 4 equiv ) .
the reaction mixture was slowly warmed 
 to room temperature and stirred for 24 h. the reaction mixture was 
 then heated to 50 c for 6 h and quenched with saturated aqueous 
 sodium bicarbonate ( 5 ml ) .
the layers were separated and extracted 
 with dcm ( 2  3 ml ) .
the combined organics were washed with brine 
 ( 5 ml ) and dried over sodium sulfate .
after filtration and concentration , 
 the crude product was purified by column chromatography ( 2550% 
 etoac in hexanes ) to give aminonitrile 62 ( 257 mg , 69% ) 
 as a white foam and hydantoin 63 ( 91 mg , 23% ) as a white 
 solid .
62 : white foam ; rf = 0.25 ( silica gel , 3/1 hexanes / etoac ) ; hrms ( m / z ) calcd for c41h44n4o5s2sina ( [ m + na ] ) 787.2420 , 
 found 787.2421 ; ir ( film ) max 2928 , 1597 , 1447 , 
 1368 , 1174 , 1129 , 746 cm ; h nmr ( 400 
 mhz , cdcl3 ) : 8.02 ( dt , j = 8.3 , 0.9 hz , 
 2 h ) , 7.85 ( d , j = 8.4 hz , 4 h ) , 7.807.79 
 ( m , 2 h ) , 7.63 ( ddd , j = 7.9 , 1.3 , 0.7 hz , 2 h ) , 
 7.397.33 ( m , 2 h ) , 7.317.25 ( m , 2 h ) , 7.257.20 
 ( m , 4 h ) , 4.57 ( t , j = 8.3 hz , 1 h ) , 3.66 ( dd , j = 8.4 , 0.9 hz , 2 h ) , 2.33 ( s , 6 h ) , 0.76 ( s , 9 h ) , 0.12 
 ( s , 6 h ) ; c nmr ( cdcl3 , 101 mhz )  145.1 , 
 135.1 , 135.1 , 130.6 , 130.0 , 127.2 , 125.4 , 124.2 , 123.6 , 119.6 , 119.4 , 
 118.0 , 114.0 , 77.5 , 77.2 , 76.8 , 69.6 , 58.2 , 52.2 , 25.7 , 21.7 , 17.8 , 
 4.4 .
63 : white solid ( > 180 c , 
 decomp ) ; rf = 0.4 ( silica gel , 1/1 hexanes / etoac ) ; 
 hrms ( m / z ) calcd for c42h44n4o7s2sina ( [ m + na ] ) 831.2318 , found 831.2332 ; ir ( film ) max br 3358 , 
 2928 , 1727 , 1367 , 1173 , 1127 , 745 cm ; h nmr ( 400 mhz , 1/1 meod / cdcl3 )  7.91 ( d , j = 8.3 hz , 2 h ) , 7.74 ( d , j = 8.4 hz , 
 4 h ) , 7.65 ( d , j = 0.9 hz , 2 h ) , 7.54 ( ddd , j = 7.9 , 1.2 , 0.7 hz , 2 h ) , 7.28 ( ddd , j = 8.4 , 7.3 , 1.3 hz , 2 h ) , 7.257.16 ( m , 6 h ) , 5.02 ( t , j = 8.1 hz , 1 h ) , 3.88 ( dd , j = 8.1 , 1.0 
 hz , 2 h ) , 2.30 ( s , 6 h ) , 0.73 ( s , 9 h ) , 0.11 ( s , 6 h ) ; c nmr ( 1/1 meod / cdcl3 , 101 mhz )  173.5 , 
 157.8 , 145.8 , 135.4 , 135.3 , 131.2 , 130.4 , 127.3 , 125.5 , 125.3 , 124.0 , 
 119.7 , 117.7 , 114.1 , 68.9 , 67.3 , 50.3 , 25.8 , 21.6 , 18.1 , 4.2 .
63 ( 119 mg , 0.147 mmol ) was dissolved 
 in dry dmf ( 1.5 ml ) , and potassium carbonate ( 122 mg , 0.88 mmol , 6 
 equiv ) was added , followed by methyl iodide ( 37 l , 0.59 mmol , 
 4 equiv ) .
after 2 h , the reaction mixture was quenched with saturated aqueous 
 ammonium chloride ( 1 ml ) and stirred for 30 min .
the reaction mixture 
 was concentrated and taken up in etoac ( 2 ml)/brine ( 2 ml ) .
the biphasic 
 mixture was separated and extracted with etoac ( 2  2 ml ) , and 
 the extract was dried over sodium sulfate . after filtration and concentration , 
 the crude product was purified by column chromatography ( 25% etoac 
 in hexanes ) to give 64 ( 98 mg , 80% ) as a white foam : rf = 0.6 ( silica gel , 1/1 hexanes / etoac ) ; hrms 
 ( m / z ) calcd for c44h48n4o7s2si ( [ m + h ] ) 837.2812 , found 837.2827 ; ir ( film ) max 2929 , 
 1768 , 1711 , 1446 , 1368 , 1173 , 1126 , 742 cm ; h nmr ( 500 mhz , cdcl3 )  8.00 ( d , j = 8.1 hz , 2 h ) , 7.79 ( d , j = 8.4 hz , 
 4 h ) , 7.68 ( d , j = 0.8 hz , 2 h ) , 7.357.28 
 ( m , 4 h ) , 7.257.19 ( m , 6 h ) , 5.13 ( t , j = 
 7.9 hz , 1 h ) , 3.89 ( d , j = 7.9 hz , 2 h ) , 3.36 ( s , 
 3 h ) , 2.42 ( s , 3 h ) , 2.33 ( s , 6 h ) , 0.76 ( s , 9 h ) , 0.10 ( s , 
 6 h ) ; c nmr ( cdcl3 , 126 mhz )  170.3 , 
 155.8 , 145.0 , 135.3 , 134.9 , 130.5 , 129.9 , 127.1 , 125.4 , 125.1 , 123.6 , 
 118.5 , 116.3 , 114.0 , 69.5 , 68.9 , 25.7 , 25.3 , 24.3 , 21.7 , 17.8 , 4.4 .
62 ( 120 mg , 0.157 mmol ) was dissolved in dioxane ( 500 
 l ) , and h2o ( 125 l ) was added , followed by 
 parkin s catalyst ( 13.5 mg , 0.031 mmol , 0.2 equiv ) .
the reaction 
 mixture was heated to 80 c for 24 h. the reaction mixture was 
 cooled to room temperature and diluted with etoac ( 1 ml ) .
the layers 
 were separated and extracted with etoac ( 3  1 ml ) , and the extract 
 was washed with brine ( 2 ml ) and dried over sodium sulfate .
after 
 filtration and concentration , the crude product was purified by column 
 chromatography ( 1525% etoac in hexanes ) to give 69 ( 77 mg , 63% ) as a pale yellow foam : rf = 0.55 ( silica gel , 1/1 hexanes / etoac ) ; hrms ( m / z ) calcd for c41h47n4o6s2si ( [ m + h ] ) 783.2706 , 
 found 783.2707 ; ir ( film ) max br 3453 , br 3380 , 
 2928 , 1681 , 1447 , 1366 , 1172 , 1126 cm ; h nmr ( 400 mhz , cdcl3 )  7.98 ( d , j = 8.2 hz , 2 h ) , 7.78 ( d , j = 8.4 hz , 4 h ) , 7.66 
 ( s , 2 h ) , 7.62 ( d , j = 7.3 hz , 2 h ) , 7.29 ( ddd , j = 8.4 , 7.2 , 1.3 hz , 2 h ) , 7.257.17 ( m , 6 h ) , 6.49 
 ( br s , 1 h ) , 5.01 ( t , j = 7.8 hz , 1 h ) , 4.86 ( br 
 s , 1 h ) , 3.47 ( d , j = 8.5 hz , 2 h ) , 2.31 ( s , 6 h ) , 
 0.72 ( s , 9 h ) , 0.20 ( s , 6 h ) ; c nmr ( cdcl3 , 101 mhz )  173.0 , 144.8 , 135.3 , 134.9 , 131.6 , 129.8 , 
 127.0 , 125.1 , 124.6 , 123.2 , 119.5 , 118.5 , 113.8 , 69.6 , 64.3 , 54.7 , 
 25.8 , 21.6 , 17.8 , 4.4 .
69 ( 90 mg , 0.115 mmol ) was 
 dissolved in thf ( 2.3 ml ) , and tosyl isocyanate ( 21 l , 0.138 
 mmol , 1.2 equiv ) was added at room temperature . after the reaction 
 mixture was stirred for 30 min , the reaction mixture was quenched 
 with aqueous ammonium hydroxide ( 2 ml ) .
the layers were separated 
 and extracted with etoac ( 3  2 ml ) , and the extract was washed 
 with brine ( 2 ml ) and dried over sodium sulfate .
after filtration 
 and concentration , the crude 71 ( 91.1 mg ) was obtained 
 as a pale yellow foam and was used directly in the following reaction . 

burgess reagent ( 7 mg , 0.03 mmol ) was added to a heterogeneous solution 
 of crude 71 ( 10 mg , 0.010 mmol ) in dcm ( 200 l ) . 
 the reaction mixture was warmed to 50 c for 2 h ( mixture turns 
 homogeneous after 15 min ) .
after concentration , the crude product 
 was purified directly by column chromatography ( 2% acetone in dcm ) 
 to give 66 ( 8.2 mg , 67% , two steps ) as a white solid 
 that is very sparingly soluble when purified , preventing nmr analysis . 

colorless 
 crystals serendipitously formed from slow evaporation of a dilute 
 tlc sample in wet dcm to further confirm the structure : colorless 
 crystals ( > 200 c , decomp ) ; rf = 
 0.5 ( silica gel , 1/1 hexanes / etoac ) ; hrms ( m / z ) calcd for c49h51n5o8s3si ( [ m + h ] ) 962.2747 , found 962.2734 ; 
 ir ( film ) max br 3532 , br 3395 , 2928 , 1771 , 1636 , 
 1358 , 1172 , 670 cm ; potassium carbonate ( 6.9 mg , 0.05 mmol , 
 6 equiv ) was added to a solution of 66 ( 8.0 mg , 8.3 mol ) 
 in dmf ( 100 l ) , followed by methyl iodide ( 2.0 l , 3.2 
 mol , 4 equiv ) .
the reaction mixture was quenched 
 with saturated aqueous ammonium chloride ( 200 l ) and stirred 
 for 30 min .
the reaction mixture was concentrated and taken up in 
 etoac ( 1 ml)/brine ( 1 ml ) . the mixture was separated and extracted 
 with etoac ( 2  1 ml ) and dried over sodium sulfate . after filtration 
 and concentration , the crude product was purified by column chromatography 
 ( 20% etoac in hexanes ) to give 67 ( 7.8 mg , 95% ) as a 
 white foam .
alternate procedure : tosyl isocyanate ( 12 l , 0.08 
 mmol , 1.25 equiv ) was added to a solution of 62 ( 50 mg , 
 0.065 mmol ) in thf ( 1.3 ml ) at room temperature .
the reaction mixture 
 was concentrated after 15 min and dissolved in absolute ethanol ( 1.3 
 ml ) .
this reaction mixture was heated to 70 c for 14 h , and 
 then the solvent was evaporated to give crude 66 .
potassium 
 carbonate ( 54 mg , 0.39 mmol , 6 equiv ) was added to a solution of crude 66 in dmf ( 650 l ) , followed by methyl iodide ( 16.3 
 l , 0.26 mmol , 4 equiv ) .
after 2 h , the reaction mixture was quenched 
 with saturated aqueous ammonium chloride ( 500 l ) and stirred 
 for 30 min .
the reaction mixture was concentrated and taken up in 
 etoac ( 2 ml)/brine ( 2 ml ) .
the mixture was separated and extracted 
 with etoac ( 2  2 ml ) and dried over sodium sulfate .
after filtration 
 and concentration , the crude product was purified by column chromatography 
 ( 20% etoac in hexanes ) to give 67 ( 47.2 mg , 73% over 
 2 steps ) as a white foam : rf = 0.6 ( silica 
 gel , 1/1 hexanes / etoac ) ; hrms ( m / z ) calcd for c51h55n5o8s3si ( [ m + h ] ) 990.3060 , found 990.3071 ; ir 
 ( film ) max 2927 , 1764 , 1627 , 1447 , 1370 , 1173 , 776 , 
 669 cm ; h nmr ( 400 mhz , cdcl3 )  8.09 ( d , j = 8.3 hz , 2 h ) , 7.95 ( d , j = 8.4 hz , 2 h ) , 7.90 ( d , j = 8.4 hz , 
 4 h ) , 7.53 ( d , j = 8.0 hz , 2 h ) , 7.49 ( s , 2 h ) , 7.32 
 ( ddd , j = 8.4 , 5.5 , 2.9 hz , 2 h ) , 7.257.17 
 ( m , 8 h ) , 4.74 ( t , j = 8.1 hz , 1 h ) , 3.92 ( dd , j = 8.2 , 1.0 hz , 2 h ) , 3.41 ( s , 3 h ) , 3.30 ( s , 3 h ) , 2.52 
 ( s , 3 h ) , 2.33 ( s , 6 h ) , 0.67 ( s , 9 h ) , 0.36 ( s , 6 h ) ; c nmr ( cdcl3 , 126 mhz )  158.9 , 154.9 , 145.2 , 
 143.5 , 139.8 , 135.2 , 134.7 , 130.5 , 130.1 , 130.1 , 127.4 , 126.9 , 125.2 , 
 125.1 , 123.6 , 118.4 , 115.4 , 114.1 , 69.5 , 68.1 , 48.2 , 30.8 , 26.1 , 25.7 , 
 21.7 , 21.7 , 17.8 , 4.9 . a flask containing 82 ( 1.60 
 g , 3.59 mmol ) was evacuated and back - filled with argon . toluene ( 12 
 ml ) was added , followed by 3.59 ml of a 1.0 m solution of liotbu in 
 hexanes ( 3.59 mmol , 1.0 equiv ) . the resulting suspension was warmed 
 to 50 c for 36 h. the reaction mixture was cooled to room temperature 
 and quenched with saturated aqueous nahco3 ( 15 ml ) .
the 
 mixture was separated , washed with brine ( 20 ml ) , dried over sodium 
 sulfate , and concentrated in vacuo .
the resulting oil was purified 
 by silica gel chromatography ( 12.5/12.5/75 to 15/15/70 dcm / et2o / hexanes ) to give 87 ( 110 mg , 7% ) as a crystalline 
 solid ( mp 200205 c ) .
x - ray - quality crystals were obtained 
 by crystallization from chcl3/et2o : rf = 0.5 ( silica gel , 3/1 hexanes : etoac ) ; hrms 
 ( m / z ) calcd for c22h23no5s ( [ m + h ] ) 414.1375 , found 414.1380 ; 
 ir ( film ) max 2936 , 1728 , 1639 , 1586 , 1519 , 1235 , 
 1124 , 814 , 747 ; h nmr ( 600 mhz , cdcl3 )  
 7.31 ( ddd , j = 8.4 , 7.2 , 1.4 hz , 1 h ) , 7.28 ( dd , j = 8.0 , 1.7 hz , 1 h ) , 7.02 ( ddd , j = 7.8 , 
 7.1 , 1.7 hz , 1 h ) , 6.38 ( d , j = 0.9 hz , 2 h ) , 5.89 
 ( dd , j = 7.8 , 1.3 hz , 1 h ) , 4.20 ( tt , j = 6.0 , 1.1 hz , 1 h ) , 3.85 ( s , 3 h ) , 3.79 ( s , 6 h ) , 3.76 ( t , j = 5.8 hz , 2 h ) , 2.83 ( d , j = 9.7 hz , 
 1 h ) , 2.68 ( dt , j = 9.6 , 5.6 hz , 1 h ) , 2.41 ( s , 3 
 h ) ; c nmr ( cdcl3 , 151 mhz )  173.8 , 
 153.6 , 138.1 , 137.2 , 133.5 , 131.2 , 129.9 , 129.0 , 127.0 , 126.2 , 103.1 , 
 61.1 , 56.3 , 48.1 , 47.1 , 30.2 , 15.7 .
34 ( 221 mg , 0.513 mmol ) was dissolved in dry thf ( 5 
 ml ) , and 
 a toluene solution of potassium tert - butoxide was 
 added ( 1.7 m , 300 l , 0.51 mmol , 1 equiv ) at room temperature . 

the reaction mixture was warmed to 45 c for 30 min , quenched 
 with saturated aqueous sodium bicarbonate solution ( 3 ml ) , and extracted 
 with etoac ( 2  5 ml ) , and the extract was washed with brine 
 ( 5 ml ) and dried over sodium sulfate .
after filtration , concentration , 
 and purification by a silica plug ( dcm ) , epimer 112 ( 212 
 mg , 96% ) was obtained as a white solid ( mp 136139 c ) : rf = 0.7 ( silica gel , 3/1 hexanes / etoac ) ; hrms 
 ( m / z ) calcd for c30h26n2o ( [ m + h ] ) 431.2123 , found 431.2125 ; 
 ir ( film ) max br 3349 , 2934 , 1677 , 1519 , 1483 , 1322 , 
 968 , 748 , 692 cm ; h nmr ( 400 mhz , 
 cdcl3 )  9.92 ( s , 1 h ) , 8.85 ( dd , j = 7.6 , 1.4 hz , 1 h ) , 8.46 ( dd , j = 4.2 , 1.7 hz , 
 1 h ) , 8.10 ( dd , j = 8.3 , 1.7 hz , 1 h ) , 7.54 ( t , j = 7.9 hz , 1 h ) , 7.517.43 ( m , 5 h ) , 7.397.31 
 ( m , 5 h ) , 7.297.22 ( m , 2 h ) , 6.62 ( d , j = 
 15.9 hz , 2 h ) , 6.46 ( dd , j = 15.9 , 7.2 hz , 2 h ) , 
 3.43 ( p , j = 8.5 hz , 2 h ) , 3.14 ( t , j = 9.4 hz , 1 h ) , 2.53 ( dt , j = 10.5 , 7.8 hz , 1 h ) , 
 2.03 ( q , j = 10.2 hz , 1 h ) ; c nmr ( cdcl3 , 101 mhz )  171.4 , 148.2 , 138.4 , 137.3 , 136.2 , 134.6 , 
 132.1 , 132.1 , 130.6 , 130.6 , 128.6 , 128.6 , 127.9 , 127.4 , 127.4 , 126.4 , 
 126.4 , 121.6 , 121.5 , 116.4 , 54.1 , 38.7 , 38.7 , 31.5 . expermental 
 data for compounds 1 , 2 , 8086 , 8991 , 
 and 99111 can be found in refs ( 50 ) and ( 53 ) .
 the 
 application of c  h functionalization logic to target - oriented 
 synthesis provides an exciting new venue for the development of new 
 and useful strategies in organic chemistry . in this article , c  
 h 
 functionalization reactions are explored as an alternative approach 
 to access pseudodimeric cyclobutane natural products , such as the 
 dictazole and the piperarborenine families . 
 the use of these strategies 
 in a variety of complex settings highlights the subtle geometric , 
 steric , and electronic effects at play in the auxiliary guided c  
 h 
 functionalization of cyclobutanes . 
Introduction
Results and Discussion
Conclusion
Experimental Section