Patent Application: US-31877702-A

Abstract:
this invention provides a total synthesis of merrillactone and merrilactone analogues for use as neurotrophic agents in the treatment of neurodegenerative diseases . the invention also provides intermediates for use in the synthesis of merrilactone and its analogues .

Description:
in one embodiment , this invention provides a compound having the structure wherein z is o or & gt ; n — x , where x is h , straight or branched substituted or unsubstituted alkyl , alkenyl or alkynyl , or acyl , carbamoyl , cycloalkyl , aryl , heterocycloalkyl , heteroaryl , aralkyl , amino , alkyl amino , or dialkyl amino ; wherein each of r 1 and r 2 is h or r 1 and r 2 together are ═ o ; wherein each of r 3 and r 4 is h or r 3 and r 4 together are ═ o ; wherein each of r 5 and r 6 is , independently , h , alkyl , aralkyl , or aryl ; wherein each of r 7 and r 8 is , independently , h or or 14 , where r 14 is alkyl or — c ( o )— r 15 , where r 15 is h , — ch 2 r 16 , — chr 16 r 16 , — cr 16 r 17 r 16 , — or 16 , alkenyl or alkynyl , cycloalkyl , aryl , heterocycloalkyl , heteroaryl , aralkyl , amino , alkyl amino , or dialkyl amino , wherein each r 16 is straight or branched , substituted or unsubstituted alkyl , alkenyl or alkynyl , cycloalkyl , aryl , heterocycloalkyl , heteroaryl , aralkyl , or amino ; and wherein r 17 is straight or branched , unsubstituted alkyl , alkenyl or alkynyl , cycloalkyl , aryl , heterocycloalkyl , heteroaryl , aralkyl , or amino , wherein each of r 9 and r 10 is , independently , h , alkyl , oh , or or 13 , where r 13 is an alkyl , an acyl , or an amide , or r 9 and r 10 together are ═ ch 2 , wherein if one of r 7 or r 8 and one of r 9 or r 10 is absent , a double bond is formed as indicated by the broken line ; and wherein each of r 11 and r 12 is , independently , h , oh , or or 13 , where r 13 is an alkyl , an acyl , or an amide , or r 11 and r 12 together are ═ o , in another embodiment of the compound z is & gt ; n — x , where x is h , straight or branched substituted or unsubstituted alkyl , alkenyl or alkynyl , or acyl , carbamoyl , cycloalkyl , aryl , heterocycloalkyl , heteroaryl , aralkyl , amino , alkyl amino , or dialkyl amino . in yet another embodiment of the compound z is o or & gt ; n — x , where x is h , straight or branched alkyl , alkenyl or alkynyl , or acyl , carbamoyl , cycloalkyl , aryl , heterocycloalkyl , heteroaryl , aralkyl , amino , alkyl amino , or dialkyl amino ; wherein each of r 1 and r 2 is h or r 1 and r 2 together are ═ o ; wherein each of r 3 and r 4 is h or r 3 and r 4 together are ═ o ; wherein each of r 5 and r 6 is , independently , h , alkyl , or aralkyl ; wherein each of r 7 and r 8 is , independently , h or or 14 , where r 14 is alkyl or — c ( o )— r 15 , where r 15 is h , — ch 2 r 16 , — chr 16 r 16 , — cr 16 r 17 r 16 , — or 16 , cycloalkyl , aryl , or aralkyl , wherein each r 16 is alkyl , cycloalkyl , or aryl , aralkyl ; and wherein r 17 is alkyl , cycloalkyl , aryl , or aralkyl , wherein each of r 9 and r 10 is , independently , h , alkyl , oh , or or 13 , where r 13 is an alkyl , an acyl , or an amide , or r 9 and r 10 together are ═ ch 2 , wherein if one of r 7 or r 8 and one of r 9 or r 10 is absent , a double bond is formed as indicated by the broken line ; and wherein each of r 11 and r 12 is , independently , h , oh , or or 13 , where r 13 is an alkyl , an acyl , or an amide , or r 11 and r 12 together are ═ o , wherein each of r 1 and r 2 is h , or r 1 and r 2 together are ═ o ; wherein each of r 3 and r 4 is h , or r 3 and r 4 together are ═ o ; wherein each of r 5 and r 6 is , independently , h , alkyl , aralkyl , or aryl ; wherein each of r 7 and r 8 is , independently , h or or 14 , where r 14 is alkyl or — c ( o )— r 15 , where r 15 is h , — ch 2 r 16 , — chr 16 r 16 , — cr 16 r 17 r 16 , — or 16 , alkenyl or alkynyl , cycloalkyl , aryl , heterocycloalkyl , heteroaryl , aralkyl , amino , alkyl amino , or dialkyl amino , wherein each r 16 is straight or branched , substituted or unsubstituted alkyl , alkenyl or alkynyl , cycloalkyl , aryl , heterocycloalkyl , heteroaryl , aralkyl , or amino ; and wherein r 17 is straight or branched , unsubstituted alkyl , alkenyl or alkynyl , cycloalkyl , aryl , heterocycloalkyl , heteroaryl , aralkyl , or amino ; and wherein r 9 is h , alkyl , oh , or or 13 , where r 13 is an alkyl , an acyl , or an amide . in this embodiment , r 9 may be h , alkyl or or 13 , where r 13 is an alkyl , an acyl , or an amide . also disclosed is a compound wherein r 1 and r 2 together are ═ o ; wherein each of r 3 and r 4 is h ; wherein each of r 5 and r 6 is , independently , h , alkyl , or aralkyl ; wherein each of r 7 and r 8 is , independently , h or or 14 , where r 14 is alkyl or — c ( o )— r 15 , where r 15 is h , — ch 2 r 16 , — chr 16 r 16 , — cr 16 r 17 r 16 , — or 16 , alkenyl or alkynyl , cycloalkyl , aryl , heterocycloalkyl , heteroaryl , aralkyl , amino , alkyl amino , or dialkyl amino , wherein each r 16 is straight or branched , substituted or unsubstituted alkyl , alkenyl or alkynyl , cycloalkyl , aryl , heterocycloalkyl , heteroaryl , aralkyl , or amino ; and wherein r 17 is straight or branched , unsubstituted alkyl , alkenyl or alkynyl , cycloalkyl , aryl , heterocycloalkyl , heteroaryl , aralkyl , or amino ; and in yet another embodiment , the invention provides a compound having the structure wherein z is o or & gt ; n — x , where x is h , straight or branched substituted or unsubstituted alkyl , alkenyl or alkynyl , or acyl , carbamoyl , cycloalkyl , aryl , heterocycloalkyl , heteroaryl , aralkyl , amino , alkyl amino , or dialkyl amino ; wherein each of r 1 and r 2 is h or r 1 and r 2 together are ═ o ; wherein each of r 3 and r 4 is h or r 3 and r 4 together are ═ o ; wherein each of r 5 and r 6 is , independently , alkyl , aralkyl , or aryl ; and in a further embodiment , this invention provides a compound having the structure wherein each of ra , ra ′, rb , and rb ′ is independently h , alkyl , alkenyl , alkynyl , acyl , or carbamoyl , or either ra and rb or ra ′ and rb ′ together with the carbons to which they are attached form a substituted or unsubstituted five or six member ring ; and wherein each of rc and rc ′ is , independently , h , oh or or , wherein r is alkyl , acyl or q , where q is a silyl protecting group , or both rc and rc ′ together are ═ o . this invention also provides a process for forming a cyclic ring in the compound so as to produce the compound having the structure wherein each of ra , ra ′, rb , and rb ′ is independently h , alkyl , alkenyl , alkynyl , acyl , or carbamoyl , or either ra and rb or ra ′ and rb ′ together with the carbons to which they are attached form a substituted or unsubstituted five or six member ring ; and wherein each of rc and rc ′ is , independently , h , oh or or , wherein r is alkyl , acyl or q , where q is a silyl protecting group , or both rc and rc ′ together are ═ o , with bu 3 snh or tris -( trimethyl silyl )- silane (( tms ) 3 sih ) and a free radical initiator so as to thereby produce the compound . where each of r ′ and r ″ is independently alkyl , alkenyl , alkynyl , acyl , or carbamoyl , or r ′ and r ″ together form a substituted or unsubstituted five or six member ring , with bu 3 snh or tris -( trimethyl silyl )- silane (( tms ) 3 sih ) and a free radical initiator so as to thereby produce the compound . with bu 3 snh or tris -( trimethyl silyl )- silane (( tms ) 3 sih ) and a free radical initiator so as to thereby produce the compound . with bu 3 snh and albn so as to thereby produce the compound . this invention also provides a process for synthesizing a compound having the structure where q is a silyl protecting group , with a compound having the structure at a temperature of from about 140 ° c . to 230 ° c . to produce a compound having the structure b ) reacting the compound of step a ) with meona to produce c ) treating both products of step b ) with clco 2 me to produce d ) treating both products , of step c ) with nabh 4 to produce e ) treating the products of step d ) with lioh to produce f ) treating the product of step e ) with o 3 followed by bn 2 nh * tfa to produce g ) treating the product of step f ) with nabh 4 to produce h ) treating the product of step g ) with mec ( oet ) 3 to produce i ) treating the product of step h ) lioh and i 2 and to produce j ) treating the product of step i ) with allylsnbu 3 to produce k ) treating the product of step j ) with lhmds , tmscl and phsecl , and then with phsebr and mecn to produce l ) treating the product of step k ) with o 3 , ch 2 cl 2 and 1 - hexene to produce m ) treating the product of step l ) with bu 3 snh and albn to produce n ) treating the product of step m ) with tsoh to produce o ) treating the product of step n ) with mcpba or a dimethyldioxirane to produce p ) treating the product of step o ) with an acid to produce the compound . at a temperature of from about 160 ° c . to 180 ° c . to produce a compound having the structure b ) reacting the compound of step a ) with meona and meoh to produce c ) treating both products of step b ) with clco 2 me in thf to produce d ) treating both products of step c ) with nabh 4 and meoh to produce e ) treating the products of step d ) with aqueous lioh to produce f ) treating the product of step e ) first with o 3 and pph 3 , and then with bn 2 nh * tfa in benzene to produce g ) treating the product of step f ) with nabh 4 and ch 2 cl 2 in meoh to produce h ) treating the product of step g ) with mec ( oet ) 3 and pivoh to produce i ) treating the product of step h ) first with aqueous lioh and meoh , and then with i 2 and nahco 3 in thf to produce j ) treating the product of step i ) with allylsnbu 3 , albn and phh to produce k ) treating the product of step j ) first with lhmds , tmsci and phsecl , and then with phsebr and mecn to produce l ) treating the product of step k ) first with o 3 , ch 2 cl 2 and 1 - hexene , and then with phh , net 3 under reflux conditions to produce m ) treating the product of step l ) with bu 3 snh and albn , and phh to produce n ) treating the product of step m ) with aqueous tsoh and phh under reflux conditions to produce o ) treating the product of step n ) with mcpba and ch 2 cl 2 to produce p ) treating the product of step o ) with aqueous tsoh and ch 2 cl 2 to produce the compound . tfa = trifluoroacetic acid thf = tetrahydrofuran bn 2 nh . tfa = dibenzylammonium trifluoroacetate lhmds = lithium hexamethyldisilazide tbs = tert - butyldimethylsilyl pivoh = pivalic acid aibn = azobis -( isobutyronitrile ) phh = benzene mecn = acetonitrile meoh = methanol mcpba = meta - chloroperbenzoic acid tsoh = para - toluenesulfonic acid the invention further contemplates the use of prodrugs which are converted in vivo to the therapeutic compounds of the invention ( see , e . g ., r . b . silverman , 1992 , “ the organic chemistry of drug design and drug action ”, academic press , chapter 8 , the entire contents of which are hereby incorporated by reference ). such prodrugs can be used to alter the biodistribution ( e . g ., to allow compounds which would not typically enter the reactive site of the protease ) or the pharmacokinetics of the therapeutic compound . certain embodiments of the disclosed compounds can contain a basic functional group , such as amino or alkylamino , and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids , or contain an acidic functional group and are thus capable of forming pharmaceutically acceptable salts with bases . the term “ pharmaceutically acceptable salts ” in this respect , refers to the relatively non - toxic , inorganic and organic acid or base addition salts of compounds of the present invention . these salts can be prepared in situ during the final isolation and purification of the compounds of the invention , or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base , and isolating the salt thus formed . representative salts include the hydrobromide , hydrochloride , sulfate , bisulfate , phosphate , nitrate , acetate , valerate , oleate , palmitate , stearate , laurate , benzoate , lactate , phosphate , tosylate , citrate , maleate , fumarate , succinate , tartrate , napthylate , mesylate , glucoheptonate , lactobionate , and laurylsulphonate salts and the like . ( see , e . g ., berge et al . ( 1977 ) “ pharmaceutical salts ”, j . pharm . sci . 66 : 1 – 19 ). it will be noted that the structure of some of the compounds of this invention includes asymmetric carbon atoms and thus occur as racemates and racemic mixtures , single enantiomers , diastereomeric mixtures and individual diastereomers . all such isomeric forms of these compounds are expressly included in this invention . each stereogenic carbon may be of the r or s configuration . it is to be understood accordingly that the isomers arising from such asymmetry ( e . g ., all enantiomers and diastereomers ) are included within the scope of this invention , unless indicated otherwise . such isomers can be obtained in substantially pure form by classical separation techniques and / or by stereochemically controlled synthesis . compounds discussed above , such a merrilactone a , promote the maintenance and growth of neurons both in vivo and in vitro and promote neurite outgrowth in fetal rat cortical neurons . based on their chemical and structural similarities to merrilactone a , such activity of the disclosed compounds is not expected . furthermore , the activity of the disclosed compounds both in vivo and in vitro can be determined by using published test procedures . the challenge of creating the densely oxygenated , highly compact architecture of merrilactone a in the laboratory added to the attractiveness of the project . one of the provocative features of the target system is the presence of an oxetane linkage bridging the β - faces of c7 and c1 . we envisioned the possibility that such an oxetane might arise by payne - like rearrangement of α - epoxide 2 . it was further conjectured that isomerization of exo - olefin 3 followed by epoxidation would lead to 2 . a critical step en route to 3 might be a free radical cyclization 6 of a substrate of type 4 , enabling formation of a new quaternary center in a densely substituted environment . it was further anticipated that suitable two - fold oxidation of 5 might provide the required complementary functionality of 4 . this line of reasoning invited a proposal that overall “ allyl - lactonization ” could be used to convert 6 to 5 . recognition of the γ , δ - unsaturated acid character of 6 called to mind the possibility of reaching this intermediate by claisen rearrangement via 7 . preparation of 7 was to be achieved through a ring cleavage - reclosure sequence from 8 . the latter structure , in turn , was suggestive of a diels - alder based construction . however , the prospects of a direct cycloaddition between 9 and 10 to reach 8 were not promising . even uncongested butenolides are not particularly powerful dienophiles . the presence of the two methyl groups , creating a tetrasubstituted “ dienophilic ” double bond , was likely to preclude such a cycloaddition . hence , we sought to compensate for the expected steric impediment through recourse to a more reactive dienophile substructure ( cf . 12 ). the development of a scheme which , in effect , circumvents the inertness of 10 was a key challenge to our prospectus . the reaction of 2 , 3 - dimethylmaleic anhydride ( 12 ) 7 and 11 8 occurred under the conditions shown , to afford 13 in 74 % yield . we next turned to regioselective reduction of the c14 carbonyl group ( future merrilactone a numbering ). attempted reductions with conventional borohydride reagents led to complex mixtures . this lack of selectivity necessitated a somewhat awkward , but high yielding , circumvention . it was established that ring opening of 13 with sodium methoxide proceeded smoothly . treatment of the resulting salts ( 14 and 15 ) with clco 2 me in thf afforded mixed anhydrides 16 and 17 . remarkably , exposure of this mixture to the action of nabh 4 and methanol 9 led to clean reduction of 17 while leaving 16 unchanged . ( the inertness of the c12 carbonyl in 16 may be due to its axial orientation .) subsequent addition of lithium hydroxide to the mixture afforded compounds 18 and 20 , easily separable by a simple extraction . treatment of 18 with libhet 3 11 also afforded 20 . the regioconvergence of this scheme obviated any need for chromatographic separation of intermediates and afforded 20 in 78 % overall yield from 13 . the stage was now set for the ring cleavage - reclosure sequence ( cf . 8 → 7 in retrosynthesis plan ). ozonolysis of 20 followed by reductive workup , as shown , led to a dialdehyde , which on aldol condensation using corey &# 39 ; s conditions 12 afforded the cyclodehydrated product 21 in high yield . following reduction 13 of the aldehyde function , allylic alcohol 22 was in hand . the next stage called for claisen rearrangement to reach 23 . the most advantageous way to achieve this result proved to be via the johnson orthoester protocol . 14 the mixture of esters ( 23 / 24 ˜ 1 . 8 : 1 ) thus produced was hydrolyzed , and the resultant acids subjected to iodolactonization . two crystalline and chromatographically separable iodolactones , 25 and 26 , were obtained in 35 and 59 % yields , respectively . chain extension of the required “ anti - backbone ” isomer 26 was accomplished ( 75 % yield ) by the elegant c - allylation method of keck . 15 as noted above , ( cf . 5 → 4 in the retrosynthesis ) oxidation at two sites would be required to complete the setting for the proposed key cyclization step ( cf . 4 → 3 ). an efficient sequence to deal with potentially awkward functional group management issues in advancing beyond 27 was developed . thus , selenenylation at c10 was accomplished via an intermediate silyl ketene acetal . with this subgoal achieved , bromoselenenylation of the terminal vinyl group of 27 was conducted according to methodology introduced some years ago by rauscher . 16 concurrent oxidative deselenation afforded the desired 29 . the setting for testing the key free radical cyclization was at hand . our initial concerns that the steric congestion at the sp 2 center at c9 might lead to the competitive reduction of the vinylic radical , fortunately , proved groundless . in the event , treatment of 29 under the standard conditions 6a afforded a 90 % yield of 30 . isomerization of the exo methylene group in 30 envisioned at the planning stage was accomplished concurrently with liberation of the c7 β - alcohol . while hydroxyl groups have often been used to direct epoxidation with peracids in a syn sense , 17 in the case at hand the congested nature of the β - face of the c1 – c2 double bond is such that epoxidation occurs primarily ( 3 . 5 : 1 ) from its α - face ( see compound 2 ). 18 in the final step of the synthesis , merrilactone a is produced by an acid - induced homo - payne rearrangement ( see 2 → 1 ). the spectroscopic properties of 31 , 2 , and 1 were in complete accord with the published data . 5b further confirmation came from the identity of the nmr spectra of synthetic (±)− 1 with those of natural merrilactone a . in summary , a total synthesis of merrilactone a has been accomplished . the first generation route described above provides , for the first time , ample material for extensive preclinical evaluations of merrilactone a . the chemistry developed to date ( 20 steps , 10 . 7 % overall yield ) is amenable to scale - up to multigram levels . moreover , the use of dimethylmaleic anhydride ( 12 ) as a dienophile leading to the incorporation of two angular methyl groups has broad potential implications which warrant follow - up . all reactions were carried out under an argon atmosphere . tetrahydrofuran , diethyl ether , and dichloromethane were purified by passing through solvent columns . 10 other solvents were obtained commercially and were used as received . 1 -( t - butyldimethylsilyloxy )- 1 , 3 - butadiene was prepared according to a literature procedure . all other reagents were reagent grade and purified where necessary . reactions were monitored by thin layer chromatography ( tlc ) using em science 60f silica gel plates . flash column chromatography was performed over scientific adsorbents inc . silica gel ( 32 – 63 μm ). melting points were measured on a thomas hoover capillary melting point apparatus and are uncorrected . 1 h nmr and 13 c nmr spectra were recorded on bruker - spectrospin spectrometers . the chemical shifts are reported as δ values ( ppm ) relative to tms . infrared spectra were recorded on a perkin - elmer paragon 1000 ft - ir spectrophotometer ( nacl plates , film ). low - resolution mass spectral analyses were performed on a jeol lc / ms system using chemical ionization . diels - alder adduct 13 . a flask containing a mixture of 2 , 3 - dimethylmaleic anhydride ( 2 . 520 g , 20 . 0 mmol ), 1 -( t - butyldimethylsilyloxy )- 1 , 3 - butadiene ( 5 . 53 g , 30 . 0 mmol ), symm - collidine ( 150 mg ), methylene blue ( 5 mg ), and mesitylene ( 6 . 2 ml ) was purged with argon several times and stirred under reflux in an oil bath at 165 ° c . for 2 . 5 days . the solvents were removed by kugelrohr distillation at 100 ° c ., and the residue was purified by flash chromatography ( hexanes / etoac 19 : 1 ) to afford 4 . 604 g ( 74 % yield ) of the product which crystallized upon standing . 1 h nmr ( cdcl 3 , 400 mhz ): δ − 0 . 03 ( s , 3h ), 0 . 01 ( s , 3h ), 0 . 79 ( s , 9h ), 1 . 16 ( s , 3h ), 1 . 31 ( s , 3h ), 2 . 00 ( dd , j = 21 , j = 4 , 1h ), 2 . 99 ( d , j = 21 , 1h ), 4 . 13 ( d , j = 5 . 7 , 1h ), 5 . 96 ( m , 2h ); 13 c nmr ( cdcl 3 , 100 mhz ): − 5 . 6 , − 4 . 4 , 14 . 7 , 17 . 7 , 25 . 3 , 25 . 6 , 30 . 0 , 44 . 2 , 53 . 9 , 70 . 2 , 126 . 9 , 130 . 1 , 175 . 4 , 176 . 7 ; ir ( nacl , cm − 1 ): 1784 s , 1852 m ( anhydride c ═ o ); ms found : 311 . 1 ( m + 1 ), calc . 310 . 16 ; mp 62 – 63 ° c . lactone 20 . part a . a stirring mixture of diels - alder adduct 13 ( 1 . 240 g , 4 . 00 mmol ) and dry methanol ( 10 ml ) was treated at rt with 25 % methanolic solution of meona ( 0 . 92 ml , 4 . 02 mmol ). after 15 minutes , the mixture was rotary evaporated , and the residue was coevaporated twice with benzene to dryness . the resulting viscous oil was dissolved in thf ( 10 ml ), the solution was cooled in an ice bath and treated with clco 2 me ( 0 . 400 ml , 5 . 18 mmol ). after 20 minutes , the mixture was cooled to − 78 ° c ., and solid nabh 4 ( 400 mg , 10 . 57 mmol ) was added , followed by dropwise addition of dry meoh ( 1 . 60 ml ). the mixture was allowed to warm up to − 35 ° c ., quenched with saturated aqueous ammonium chloride ( 6 ml ), warmed to rt , diluted with water , and extracted twice with et 2 o . the aqueous phase was acidified to ph 3 – 4 with 1 m hcl and extracted twice with et 2 o . the combined ethereal extract was evaporated , the residue dissolved in thf ( 12 ml ), and stirred vigorously with aqueous lioh ( 4 ml , 5 %) for 1 . 5 hours . the mixture was diluted with water and extracted 3 times with hexanes . the hexane extract ( containing almost pure lactone 20 ) was washed twice with 1 m naoh , then brine , dried with na 2 so 4 , and set aside . part b . the combined alkaline aqueous phase from the previous step was acidified with 1 m hcl and extracted 3 times with et 2 o . the ethereal solution was dried over mgso 4 , rotary evaporated , and the residue was coevaporated with benzene . the resulting crude half - ester 18 ( 758 mg , 2 . 21 mmol ) was cooled in an ice bath and treated with libhet 3 ( 1m in thf , 12 ml ). after stirring overnight at rt , the mixture was cooled again in an ice bath , quenched with 1 m naoh ( 8 ml ), and then carefully treated with 10 % h 2 o 2 ( 18 ml ) added in several portions to avoid excessive heating . after stirring for 0 . 5 hour , the solution was acidified with 1 m hcl to ph 5 – 6 and extracted with et 2 o twice . the viscous residue on the bottom of the flask was shaken vigorously with 1 m hcl and et 2 o until completely dissolved . the resulting two - phase mixture was combined with the aqueous phase , acidified to ph 5 – 6 again , and extracted with ether twice . the combined ethereal extract was washed with brine once , dried over mgso 4 , rotary evaporated , redissolved in 10 ml of ch 2 cl 2 , and treated with tfa ( 0 . 04 ml ). after 3 days , this mixture was combined with the previously obtained hexane solution of lactone 20 , evaporated , and subjected to flash chromatography ( hexanes / etoac 19 : 1 ) to afford 925 mg ( 78 % yield ) of the product as colorless oil which crystallized upon standing . 1 h nmr ( cdcl 3 , 500 mhz ): δ 0 . 05 ( s , 3h ), 0 . 08 ( s , 3h ), 0 . 86 ( s , 9h ), 1 . 06 ( s , 3h ), 1 . 09 ( s , 3h ), 2 . 00 ( ddd , j = 19 . 3 , j = 1 . 9 , j = 1 . 0 , 1h ), 2 . 14 ( ddd , j = 19 . 3 , j = 2 . 1 , j = 1 . 6 , 1h ), 3 . 73 ( d , j = 7 . 6 , 1h ), 3 . 97 ( d , j = 4 . 7 , 1h ), 4 . 32 ( d , j = 7 . 6 , 1h ), 5 . 76 – 5 . 83 ( m , 2h ); 13 c nmr ( cdcl 3 , 100 mhz ): − 5 . 4 , − 4 . 1 , 16 . 2 , 17 . 7 , 25 . 6 , 26 . 2 , 30 . 7 , 39 . 2 , 50 . 1 , 70 . 0 , 75 . 4 , 126 . 4 , 126 . 7 , 179 . 6 ; ir ( nacl , cm − 1 ): 1777s ( c ═ o ); ms found : 297 . 1 ( m + 1 ), calc . 296 . 18 ; mp 44 – 44 . 5 ° c . unsaturated aldehyde 21 . a solution of lactone 20 ( 592 mg , 2 mmol ) in a mixture of dry ch 2 cl 2 ( 20 ml ) and dry meoh ( 20 ml ) was ozonated at − 78 ° c . until blue color appeared , then purged with oxygen until colorless , treated with pph 3 ( 630 mg , 2 . 4 mmol , added in 6 ml of ch 2 cl 2 ), and allowed to warm up to rt . the solvents were removed by rotary evaporation , the residue was coevaporated with benzene and dissolved in benzene ( 40 ml ). dibenzylammonium trifluoroacetate ( 124 mg , 0 . 4 mmol ) was added , and the resulting solution was stirred at 63 ° c . for 9 hours . the solvent was evaporated , and the residue was chromatographed ( hexanes / ethyl acetate 9 : 1 ) to afford 580 mg ( 94 % yield ) of the product as colorless oil which crystallized upon standing . 1 h nmr ( cdcl 3 , 400 mhz ): δ 0 . 12 ( s , 3h ), 0 . 15 ( s , 3h ), 0 . 90 ( s , 9h ), 1 . 25 ( s , 3h ), 1 . 33 ( s , 3h ), 4 . 04 ( d , j = 9 . 2 , 1h ), 4 . 26 ( d , j = 9 . 2 , 1h ), 4 . 61 ( d , j = 2 . 2 , 1h ), 6 . 62 ( d , j = 2 . 2 , 1h ), 9 . 82 ( s , 1h ); 13 c nmr ( cdcl 3 , 100 mhz ): − 5 . 1 , − 4 . 7 , 16 . 3 , 17 . 5 , 18 . 0 , 25 . 6 , 53 . 2 , 57 . 4 , 75 . 8 , 82 . 9 , 132 . 9 , 149 . 3 , 149 . 6 , 176 . 1 , 189 . 8 ; ir ( nacl , cm − 1 ): 1688 s ( aldehyde c ═ o ), 1778 s ( lactone c ═ o ); ms found : 311 . 1 ( m + 1 ), calc . 310 . 16 ; mp 57 – 57 . 5 ° c . allylic alcohol 22 . solid nabh 4 ( 130 mg , 3 . 44 mmol ) was added to a solution of aldehyde 21 ( 536 mg , 1 . 73 mmol ) in ch 2 cl 2 ( 28 ml ) stirring at − 78 ° c ., followed by slow addition of methanol ( 12 ml ). the mixture was allowed to warm slowly to rt and then quenched by careful addition of saturated aqueous nh 4 cl ( 5 ml ), then diluted with water , and extracted 3 times with ch 2 cl 2 . the organic extract was washed once with brine , dried over na 2 so 4 and rotary evaporated . the resulting colorless oil contained 1 % of ch 2 cl 2 by 1 h nmr , but otherwise was completely pure ( 593 mg , quant . yield ). the oil crystallized after prolonged standing . 1 h nmr ( cdcl 3 , d 2 o , 500 mhz ): δ 0 . 07 ( s , 3h ), 0 . 09 ( s , 3h ), 0 . 87 ( s , 9h ), 1 . 16 ( s , 3h ), 1 . 18 ( s , 3h ), 4 . 03 ( d , j = 8 . 7 , 1h ), 4 . 15 ( d , j = 14 . 0 , 1h ), 4 . 21 ( d , j = 8 . 7 , 1h ), 4 . 28 ( d , j = 14 . 0 , 1h ), 4 . 30 ( d , j = 0 . 8 , 1h ), 5 . 59 ( d , j = 0 . 8 , 1h ); 13 c nmr ( cdcl 3 , 100 mhz ): − 5 . 1 , − 4 . 6 , 16 . 3 , 17 . 4 , 18 . 0 , 25 . 7 , 54 . 6 , 58 . 7 , 59 . 5 , 78 . 9 , 83 . 1 , 126 . 2 , 150 . 6 , 177 . 3 ; ir ( nacl , cm − 1 ): 1757 s ( c ═ o ), 3436 br ( o — h ); ms found : 313 . 1 ( m + 1 ), calc . 312 . 18 ; mp 71 . 5 – 72 . 5 ° c . claisen esters 23 and 24 . a mixture of allylic alcohol 22 ( 593 mg , 1 . 87 mmol ), pivalic acid ( 75 mg , 0 . 74 mmol ), freshly distilled triethyl orthoacetate ( 5 . 5 ml , 30 mmol ), and mesitylene ( 5 . 5 ml ) was stirred in an oil bath at 135 – 140 ° c . in a flask equipped with a short - path distillation head under a slow flow of argon , adding 75 mg of pivalic acid every 2 hours and monitoring the progress of the reaction by 1 h nmr . after 12 hrs , 2 ml of triethyl orthoacetate was added and the heating was continued overnight . nmr analysis indicated ca . 95 % conversion . the mixture was cooled to rt , the solvents were removed by kugelrohr distillation at 100 ° c ., and the residue was purified by flash chromatography ( hexanes / etoac 14 : 1 ) to afford 658 mg ( 92 % yield ) of the product as a mixture of diastereomers ( 23 / 24 = 1 . 8 : 1 ). 1 h nmr ( cdcl 3 , 400 mhz ): δ − 0 . 03 ( s , 1 . 65h ), 0 . 08 ( app s , 4 . 65h ), 0 . 11 ( s , 3h ), 0 . 86 ( s , 4 . 95h ), 0 . 88 ( s , 9h ), 1 . 18 ( s , 3h ), 1 . 19 ( s , 3h ), 1 . 23 – 1 . 30 ( m , 7 . 95h ), 2 . 46 ( dd , j = 15 . 8 , j = 7 . 4 , 1h ), 2 . 53 ( m , 1 . 1h ), 2 . 58 ( dd , j = 15 . 8 , j 6 . 5 , 1h ), 3 . 05 ( m , 1h ), 3 . 24 ( m , 0 . 55h ), 3 . 88 ( d , j = 8 . 7 , 1h ), 3 . 90 ( d , j = 4 . 1 , 1h ), 3 . 94 ( d , j = 8 . 2 , 0 . 55h ), 4 . 13 – 4 . 19 ( m , 5 . 2h ), 4 . 85 ( d , j = 3 , 0 . 55h ), 4 . 91 ( d , j = 3 , 0 . 55h ), 5 . 00 ( d , j = 2 . 2 , 1h ), 5 . 03 ( d , j = 2 . 2 , 1h ); ir ( nacl , cm − 1 ): 1736s ( ester c ═ o ), 1777 s ( lactone c ═ o ); ms found : 383 . 2 ( m + 1 ), calc . 382 . 22 . iodolactones 25 and 26 . part a : hydrolysis . the diastereomeric mixture of esters 23 and 24 ( 569 mg , 1 . 49 mmol ) was stirred with a solution of lioh ( 200 mg ) in a mixture of meoh ( 6 ml ) and water ( 2 ml ) at rt for 12 hrs , diluted with water , acidified with 1 m hcl to ph 2 – 3 , and extracted 3 times with ch 2 cl 2 . the organic extract was washed with brine , dried over na 2 so 4 , and rotary evaporated . the residue ( ca . 0 . 55 g ) was used directly in the next step . 1 h nmr ( cdcl 3 , 400 mhz ): δ 0 . 01 ( s , 1 . 65h ), 0 . 08 ( s , 3h ), 0 . 09 ( s , 1 . 65h ), 0 . 11 ( s , 3h ), 0 . 87 ( s , 4 . 95h ), 0 . 89 ( s , 9h ), 1 . 18 ( s , 3h ), 1 . 20 ( s , 3h ), 1 . 23 ( s , 1 . 65h ), 1 . 25 ( s , 1 . 65h ), 2 . 53 ( dd , j = 16 . 2 , j = 7 . 3 , 1h ), 2 . 61 ( m , obscured by 2 . 64dd , 1 . 1h ), 2 . 64 ( dd , j = 16 . 2 , j = 6 . 6 , 1h ), 3 . 06 ( m , 1h ), 3 . 23 ( m , 0 . 55h ), 3 . 88 ( d , j = 4 . 0 , 1h ), 3 . 89 ( d , j = 8 . 6 , 1h ), 3 . 95 ( d , j = 8 . 2 , 0 . 55h ), 4 . 15 ( d , j = 8 . 2 , 0 . 55h ), 4 . 16 ( d , obscured by 4 . 19d , 0 . 55h ), 4 . 19 ( d , j = 8 . 6 , 1h ), 4 . 90 ( d , j = 2 . 9 , 0 . 55h ), 4 . 95 ( d , j = 2 . 9 , 0 . 55h ), 5 . 04 ( d , j = 2 . 2 , 1h ), 5 . 06 ( d , j = 2 . 2 , 1h ), cooh not observed ; ir ( nacl , cm − 1 ): 1711s ( acid c ═ o ), 1774s , br ( lactone c ═ o ), 3000 – 3500br ( coo — h ); ms found : 355 . 1 ( m + 1 ), calc . 354 . 19 . part b : iodolactonization . to a solution of the mixture of carboxylic acids 23a and 23b ( 0 . 55 g , see above ) in 3 ml of thf , was added 7 . 5 ml of saturated aqueous nahco 3 . the mixture was cooled in an ice bath , treated with a solution of i 2 ( 1 . 143 g , 4 . 5 mmol ) in 12 ml of thf , protected from light , and stirred at rt for 12 hrs . excess i 2 was quenched by addition of aqueous na 2 so 3 , the mixture was diluted with water and extracted 3 times with ch 2 cl 2 . the organic extract was washed with brine , dried over na 2 so 4 , and rotary evaporated . the mixture of products crystallized spontaneously . the crude product was taken up in ch 2 cl 2 and preadsorbed on silica gel . column chromatography ( hexanes / etoac 7 : 1 , then 3 : 1 ) gave incomplete separation . the mixed fractions were chromatographed again . combined yield of the desired iodolactone 26 was 421 mg ( 59 % based on the ester mixture ). additionally , 250 mg of the epimeric iodolactone 25 ( 35 % yield ) was obtained . 26 ( major iodolactone ): 1 h nmr ( cdcl 3 , 400 mhz ): δ 0 . 08 ( app s , 6h ), 0 . 89 ( s , 9h ), 1 . 17 ( s , 3h ), 1 . 24 ( s , 3h ), 2 . 45 ( dd , j = 19 . 3 , j = 2 . 4 , 1h ), 2 . 79 ( dd , j = 11 . 5 , j = 2 . 4 , 1h ), 3 . 33 ( d , j = 11 . 1 , 1h ), 3 . 36 ( dd , partly obscured by 3 . 33d , j = 19 . 3 , j = 11 . 5 , 1h ), 3 . 57 ( d , j = 11 . 1 , 1h ), 3 . 82 ( s , 1h ), 3 . 89 ( d , j = 8 . 4 , 1h ), 4 . 31 ( d , j = 8 . 4 , 1h ); 13 c nmr ( cdcl 3 , 100 mhz ): − 5 . 3 , − 4 . 9 , 7 . 8 , 15 . 8 , 16 . 2 , 17 . 7 , 25 . 6 , 37 . 3 , 55 . 9 , 57 . 1 , 61 . 2 , 72 . 4 , 87 . 9 , 95 . 5 , 174 . 1 , 176 . 3 ; ir ( nacl , cm − 1 ): 1777s ( c ═ o ); ms found : 481 . 0 ( m + 1 ), calc . 480 . 08 ; mp 213 – 214 ° c . 25 ( minor iodolactone ): 1 h nmr ( cdcl 3 , 400 mhz ): δ 0 . 06 ( s , 3h ), 0 . 10 ( s , 3h ), 0 . 91 ( s , 9h ), 1 . 20 ( s , 3h ), 1 . 23 ( s , 3h ), 2 . 78 – 2 . 89 ( m , 2h ), 3 . 06 ( m , 1h ), 3 . 25 ( d , j = 11 . 1 , 1h ), 3 . 73 ( d , j = 11 . 1 , 1h ), 3 . 85 ( d , j = 9 . 4 , 1h ), 4 . 00 ( d , j = 7 . 2 , 1h ), 4 . 27 ( d , j = 9 . 4 , 1h ); 13 c nmr ( cdcl 3 , 100 mhz ): − 5 . 0 , − 4 . 5 , 14 . 5 , 15 . 7 , 17 . 2 , 17 . 8 , 25 . 7 , 30 . 9 , 50 . 0 , 55 . 9 , 61 . 3 , 73 . 7 , 78 . 3 , 93 . 4 , 175 . 4 , 176 . 0 ; ir ( nacl , cm − 1 ): 1774s ( c ═ o ); ms found : 481 . 0 ( m + 1 ), calc . 480 . 08 ; mp 216 – 217 ° c . keck product 27 . iodolactone 26 ( 421 mg , 0 . 876 mmol ), allyltributyltin ( 1 . 36 ml , 4 . 39 mmol ), aibn ( 14 mg , 0 . 085 mmol ), and benzene ( 4 . 4 ml ) were added into a flask equipped with a reflux condenser and a magnetic stirring bar , the mixture was degassed using the freeze - pump - thaw technique ( 3 – 4 cycles ) and immersed into an oil bath kept at 85 ° c . after 3 hours , another 14 mg of aibn was added , and the heating was continued for an additional 1 . 5 hours . the mixture was cooled , the solvent was rotary evaporated , and the residue was diluted with 1 ml of ch 2 cl 2 ( to prevent crystallization ) and chromatographed ( hexanes / etoac 7 : 1 ) to afford the crystalline product contaminated with bu 3 snbr . the impurities were removed by washing the crystals with hexanes , evaporating the washings , and washing the crystalline residue with hexanes again , and so on until evaporation gave mostly oil . the pure product thus obtained weighed 258 mg ( 75 % yield ). 1 h nmr ( cdcl 3 , 500 mhz ): δ 0 . 06 ( s , 3h ), 0 . 07 ( s , 3h ), 0 . 88 ( s , 9h ), 1 . 17 ( s , 3h ), 1 . 23 ( s , 3h ), 1 . 56 ( m , 1h ), 1 . 98 ( m , 1h ), 2 . 05 ( m , 1h ), 2 . 17 ( m , 1h ), 2 . 54 ( dd , j = 8 . 8 , j = 1 . 5 , 1h ), 2 . 71 ( d , j = 10 . 9 , 1h ), 3 . 00 ( dd , j = 18 . 8 , j = 10 . 9 , 1h ), 3 . 78 ( s , 1h ), 3 . 87 ( d , j = 8 . 6 , 1h ), 4 . 21 ( d , j = 8 . 6 , 1h ), 5 . 05 ( d , j = 10 . 2 , 1h ), 5 . 10 ( dd , j = 17 . 2 , j = 1 . 2 , 1h ), 5 . 77 ( d , j = 10 . 3 , 1h ), 5 . 80 ( m , 1h ); 13 c nmr ( cdcl 3 , 100 mhz ): − 5 . 2 , − 4 . 8 , 16 . 2 , 16 . 4 , 17 . 8 , 25 . 6 , 27 . 7 , 33 . 9 , 36 . 5 , 54 . 0 , 58 . 0 , 60 . 3 , 72 . 5 , 89 . 0 , 98 . 3 , 116 . 1 , 136 . 5 , 174 . 6 , 176 . 6 ; ir ( nacl , cm − 1 ): 1779s ( c ═ o ); ms found : 395 . 2 ( m + 1 ), calc . 394 . 22 ; mp 154 – 155 ° c . cyclization precursor 29 . to a solution of 27 ( 258 mg , 0 . 654 mmol ) in 12 ml of thf stirring at − 78 ° c . was added lhmds ( 1 m in thf , 0 . 75 ml ). after 0 . 5 hour , tmscl ( 100 μl , 0 . 788 mmol ) was added . the mixture was stirred for 0 . 5 hour at − 78 ° c ., then for 0 . 5 hour at rt , cooled to − 78 ° c . and treated with phsecl ( 142 mg , 0 . 741 mmol ) in 9 ml of thf . the mixture was allowed to warm to rt over 1 . 5 hours , diluted with water , and extracted with et 2 o 3 times . the ethereal extract was dried over mgso 4 , rotary evaporated , the residue was diluted with ch 2 cl 2 , and evaporated again . the crude selenide was dissolved in 7 ml of dry mecn and treated with a solution of phsebr until brownish color persisted ( ca . 6 ml of solution prepared from 119 mg of ( phse ) 2 , 0 . 38 ml of 2m br 2 in chcl 3 , and 6 . 6 ml of mecn ) at rt . after 0 . 5 hour , the mixture was evaporated at 25 ° c . by stirring under vacuum , the residue redissolved in 20 ml of ch 2 cl 2 , and ozonated at − 78 ° c . until blue color persisted . the cold mixture was treated with 3 ml of 1 - hexene and then added in several portions to a boiling solution of 2 ml of net 3 in 80 ml of benzene . after the addition was complete , the mixture was refluxed for 0 . 5 hour , evaporated to dryness , and the residue was chromatographed ( hexanes / etoac 4 : 1 ) to afford 237 mg ( 77 % yield ) of the white crystalline product . 1 h nmr ( cdcl 3 , 400 mhz ): δ 0 . 17 ( s , 3h ), 0 . 19 ( s , 3h ), 0 . 90 ( s , 9h ), 0 . 91 ( s , 3h ), 1 . 20 ( s , 3h ), 2 . 18 – 2 . 26 ( m , 1h ), 2 . 32 – 2 . 49 ( m , 3h ), 3 . 93 ( d , j = 10 . 2 , 1h ), 4 . 36 ( s , 1h ), 4 . 68 ( d , j = 10 . 2 , 1h ), 5 . 42 ( d , j = 2 . 0 , 1h ), 5 . 57 ( dd , j = 1 . 0 , j = 0 . 8 , 1h ), 5 . 93 ( s , 1h ); 13 c nmr ( cdcl 3 , 100 mhz ): − 5 . 2 , − 5 . 0 , 16 . 2 , 18 . 4 , 25 . 8 , 32 . 4 , 35 . 5 , 49 . 7 , 59 . 7 , 71 . 7 , 73 . 9 , 94 . 7 , 114 . 3 , 117 . 4 , 132 . 1 , 171 . 4 , 171 . 9 , 175 . 6 ; ir ( nacl , cm − 1 ): 1765s ( c ═ o ); ms found : 471 . 0 ( m + 1 ), calc . 470 . 11 ; mp 145 – 146 . 5 ° c . exo olefin 30 . a solution of 29 ( 237 mg , 0 . 492 mmol ), bu 3 snh ( 270 μl , 0 . 985 mmol ), and aibn ( 8 mg , 0 . 049 mmol ) in 50 ml of benzene was degassed using the freeze - pump - thaw technique ( 3 cycles ) and heated under reflux in an oil bath at 85 ° c . after 2 . 5 hrs , 8 mg of aibn was added and the heating was continued for 1 . 5 hrs . the mixture was evaporated , and the residue was chromatographed ( hexanes / etoac 7 : 1 ) to afford 185 mg of the white crystalline product still containing tributyltin impurities . the latter were removed by washing the crystals with hexanes ( 3 × 3 ml ), evaporating the washings , and washing the crystalline residue with hexanes again , and so on until evaporation gave mostly oil . the product thus obtained was pure by 1 h nmr and weighed 177 mg ( 90 % yield ). 1 h nmr ( cdcl 3 , 400 mhz ): δ 0 . 01 ( s , 3h ), 0 . 06 ( s , 3h ), 0 . 86 ( s , 9h ), 1 . 22 ( s , 3h ), 1 . 24 ( s , 3h ), 1 . 76 ( m , 1h ), 2 . 14 ( m , 1h ), 2 . 61 ( m , 2h ), 2 . 79 ( d , j = 19 . 2 , 1h ), 3 . 03 ( d , j = 19 . 2 , 1h ), 3 . 89 ( d , j = 8 . 4 , 1h ), 4 . 01 ( s , 1h ), 4 . 43 ( d , j = 8 . 4 , 1h ), 4 . 95 ( app s , 1h ), 5 . 25 ( dd , j = 1 . 9 , j = 1 . 7 , 1h ); 13 c nmr ( cdcl 3 , 100 mhz ): − 4 . 4 , − 3 . 4 , 16 . 7 , 17 . 7 , 17 . 9 , 25 . 8 , 33 . 8 , 37 . 6 , 43 . 6 , 56 . 8 , 62 . 5 , 66 . 3 , 72 . 4 , 89 . 2 , 106 . 2 , 112 . 2 , 152 . 9 , 174 . 5 , 177 . 0 ; ir ( nacl , cm − 1 ): 1778 s ( c ═ o ); ms found : 393 . 1 ( m + 1 ), calc . 392 . 20 ; mp 175 – 175 . 5 ° c . alcohol 31 . a mixture of 30 ( 177 mg , 0 . 451 mmol ), tsoh . h 2 o ( 343 mg , 1 . 80 mmol ), and benzene ( 17 ml ) was heated under reflux for 3 hours in an oil bath at 90 ° c ., then cooled , diluted with et 2 o , and washed with aqueous nahco 3 . the aqueous wash was extracted with ch 2 cl 2 3 times , the combined organic phase was dried over na 2 so 4 , rotary evaporated , and chromatographed ( ch 2 cl 2 / etoac 5 : 1 ) to afford 123 mg ( 98 %) of the product . 1 h nmr ( cdcl 3 , 300 mhz ): δ 1 . 19 ( s , 3h ), 1 . 23 ( s , 3h ), 1 . 82 ( d , j = 1 . 5 , 3h ), 1 . 82 ( m , 2h ), 2 . 66 ( d , j = 19 . 1 , 1h ), 2 . 85 ( d , j = 19 . 1 , 1h ), 3 . 75 ( d , j = 6 . 0 , 1h ), 3 . 95 ( d , j = 8 . 7 , 1h ), 4 . 16 ( d , j = 6 . 0 , 1h ), 4 . 22 ( d , j = 8 . 7 , 1h ), 5 . 37 ( m , j = 32 1 . 5 , 1h ), 13 c nmr ( cdcl 3 , 75 mhz ): 15 . 0 , 15 . 7 , 16 . 7 , 39 . 9 , 41 . 0 , 55 . 5 , 62 . 5 , 69 . 8 , 73 . 8 , 86 . 3 , 104 . 6 , 124 . 6 , 141 . 5 , 175 . 4 , 179 . 0 ; 1 h nmr ( cd 3 od , 400 mhz ): 1 . 15 ( s , 3h ), 1 . 19 ( d , j = 0 . 8 , 3h ), 1 . 79 ( ddd , j = 2 . 4 , j = 2 . 1 , j = 1 . 5 , 3h ), 2 . 35 ( ddq , j = 18 . 4 , j = 2 . 4 , j = 2 . 4 , 1h ), 2 . 55 ( ddq , j = 18 . 4 , j = 2 . 1 , j = 2 . 1 , 1h ), 2 . 77 ( d , j = 19 . 3 , 1h ), 2 . 87 ( d , j = 19 . 3 , 1h ), 3 . 97 ( d , j = 8 . 6 , 1h ), 4 . 08 ( s , 1h ), 4 . 16 ( d , j = 8 . 6 , j = 0 . 8 , 1h ), 5 . 33 ( ddq , j = 2 . 4 , j = 2 . 1 , j = 1 . 5 , 1h ); 67 13 c nmr ( cd 3 od , 100 mhz ): 15 . 1 , 16 . 1 , 16 . 9 , 40 . 6 , 41 . 9 , 57 . 0 , 64 . 0 , 71 . 5 , 74 . 4 , 87 . 1 , 106 . 5 , 125 . 1 , 143 . 8 , 177 . 9 , 180 . 2 ; ir ( nacl , cm − 1 ): 1770 s ( c ═ o ), 3462 br ( o — h ); ms found : 279 . 1 ( m + 1 ), calc . 278 . 12 ; mp 189 – 190 ° c . ( softens at 175 ° c ). our 1 h and 13 c nmr data for spectra recorded in cd 3 od match those reported by fukuyama et al . 5b for cdcl 3 ( probably due to a typographical error ). epoxides 2 and 2a . the procedure of fukuyama et al . 5b was essentially followed . a solution of alcohol 30 ( 123 mg , 0 . 442 mmol ) and mcpba ( 180 mg , 1 . 04 mmol ) in 12 ml of ch 2 cl 2 was left for 2 days at rt . the mixture was treated with saturated aqueous na 2 so 3 and aqueous nahco 3 , and extracted 3 times with ch 2 cl 2 . the extract was washed with brine , dried over na 2 so 4 , and rotary evaporated . the crude product ( 133 mg , quant .) consisted of a 3 . 5 : 1 mixture of epoxides 2 and 2a . the mixture was used directly in the next step , since column chromatography ( chcl 3 / meoh 5b or ch 2 cl 2 / acoet ) did not result in efficient separation of the epimers . the pure major epoxide 2 could be obtained by two recrystallizations from etoac / hexanes . major epoxide 2 : 1 h nmr ( cd 3 od , 400 mhz ): δ 1 . 11 ( s , 3h ), 1 . 16 ( s , 3h ), 1 . 54 ( s , 3h ), 2 . 07 ( d , j = 16 . 2 , 1h ), 2 . 25 ( dd , j = 16 . 2 , j = 1 . 6 , 1h ), 2 . 58 ( d , j = 19 . 1 , 1h ), 3 . 00 ( d , j = 19 . 1 , 1h ), 3 . 66 ( d , j = 1 . 6 , 1h ), 3 . 93 ( d , j = 8 . 5 , 1h ), 4 . 12 ( s , 1h ), 4 . 47 ( d , j = 8 . 5 , 1h ); 13 c nmr ( cd 3 od , 100 mhz ): 16 . 1 , 16 . 6 , 17 . 9 , 37 . 3 , 38 . 6 , 57 . 3 , 64 . 8 , 67 . 4 , 69 . 4 , 71 . 7 , 75 . 8 , 83 . 9 , 108 . 3 , 177 . 4 , 180 . 2 ; ir ( nacl , cm − 1 ): 1772 s ( c ═ o ), 3410 br ( o — h ); ms found : 295 . 0 ( m + 1 ), calc . 294 . 11 ; mp 249 . 5 – 250 ° c . (±)- merrilactone a ( 1 ). the procedure of fukuyama et al . 5b was essentially followed . the mixture of epoxides 2 and 2a ( 133 mg ) was stirred with tsoh . h 2 o ( 80 mg , 0 . 42 mmol ) in 25 ml of ch 2 cl 2 for 1 day at rt . the tsoh . h 2 o was filtered off and washed 3 times with ch 2 cl 2 . the crude product was adsorbed on silica gel ( ca . 0 . 5 g ) and chromatographed ( ch 2 cl 2 / acoet 4 : 1 , then 2 : 1 , then 1 : 1 ) to give 14 mg ( 11 % from alcohol 30 ) of somewhat impure minor epoxide 2a followed by (±)- merrilactone a ( 92 mg , 71 % from alcohol 30 ). minor epoxide 2a : 1 h nmr ( cd 3 od , 300 mhz ): δ 1 . 10 ( s , 3h ), 1 . 13 ( d , j = 0 . 7 , 3h ), 1 . 49 ( s , 3h ), 1 . 93 ( dd , j = 16 . 2 , j = 2 . 2 , 1h ), 2 . 39 ( d , j = 16 . 2 , 1h ), 2 . 82 ( d , j = 19 . 0 , 1h ), 3 . 28 ( d , j = 19 . 0 , 1h ), 3 . 40 ( d , j = 2 . 2 , 1h ), 3 . 74 ( d , j = 9 . 0 , 1h ), 4 . 14 ( s , 1h ), 5 . 20 ( d , j = 9 . 0 , 1h ); 13 c nmr ( cd 3 od , 75 mhz ): 16 . 0 , 17 . 0 , 17 . 8 , 37 . 4 , 41 . 7 , 64 . 2 , 65 . 5 , 68 . 0 , 73 . 4 , 88 . 0 , 107 . 4 , 176 . 6 , 180 . 2 ; ir ( nacl , cm − 1 ): 1772 s ( c ═ o ), 3450 br ( o — h ); ms found : 295 . 0 ( m + 1 ), calc . 294 . 11 ; merrilactone a : 1 h nmr ( cd 3 od , 400 mhz ): δ 1 . 08 ( s , 3h ), 1 . 23 ( s , 3h ), 1 . 48 ( s , 3h ), 2 . 28 ( dd , j = 15 . 4 , j = 1 . 5 , 1h ), 2 . 68 ( d , j = 19 . 4 , 1h ), 2 . 70 ( d , j = 5 . 2 , 1h ), 2 . 73 ( d , j = 5 . 2 , 1h ), 2 . 90 ( d , j = 19 . 4 , 1h ), 3 . 94 ( dd , j = 5 . 2 , j = 1 . 5 , 1h ), 4 . 01 ( d , j = 10 . 1 , 1h ), 4 . 59 ( d , j = 10 . 1 , 1h ), 4 . 73 ( s , 1h ); 13 c nmr ( cd 3 od , 75 mhz ): 16 . 0 , 17 . 4 , 17 . 4 , 32 . 2 , 43 . 9 , 58 . 5 , 61 . 2 , 66 . 0 , 75 . 5 , 79 . 9 , 90 . 3 , 96 . 2 , 107 . 3 , 177 . 7 , 179 . 3 ; ir ( nacl , cm − 1 ): 1761 s ( c ═ o ), 3450 br ( o — h ); ms found : 295 . 0 ( m + 1 ), calc . 294 . 11 ; mp 233 . 5 – 234 . 5 ° c . 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