yessotoxin ( 1 , ytx ) , a disulfated polycyclic ether natural product was first reported in 1987 by murate , yasumoto , and co - workers from the digestive gland of the scallop patinopecten yessoensis ( figure 1 ) . it was subsequently discovered that ytx is produced by the dinoflagellates protoceratium reticulatum , lingulodinium polyedrum , and gonyaulax spinifera . ytx is acutely toxic to mice when administered intraperitoneally ( ld50 = 286 g / kg ) but not orally ( up to 54 mg / kg ) . the bioactivity of ytx ranges from modulating cytosolic calcium homeostasis , disrupting the degradation pathway of e - cadherin , inducing apoptotic cell death through the activation of caspases , to inducing lysosomal damage . adriatoxin ( 2 , atx ) , a trisulfated analogue of ytx , was first isolated in 1998 from the digestive gland of the mussel mytilus galloprovincialis collected in the adriatic sea . structurally , ytx and atx share the same a - j ring system , with ytx bearing an additional pyran ( k - ring in ytx ) and a hydrophobic side chain . both compounds have attracted considerable interest from the organic synthesis community because of their challenging structures and intriguing properties . we have previously reported the syntheses of the ab , ef , and ij ring systems of atx . our approach to the total synthesis of marine polycyclic ether natural products has largely focused on a convergent strategy that is centered around an olefinic - ester cyclization reaction that pairs cyclic ether subunits and leads to the generation of two additional rings . herein , we describe our convergent synthesis of the abcdef and fghi ring systems of ytx and atx ( 3 and 4 ) . the synthesis of the ab bicyclic coupling precursor is depicted in scheme 1 . from known tricyclic substrate 5 , tbs ether formation and ozonolysis gave 7 after conversion of the aldehyde into the corresponding carboxylic acid . outlined in scheme 2 is our synthesis of the ef bicyclic coupling precursor . from tricycle 8 , pmb ether formation , ozonolysis and reduction of a single flask conversion of the 1 alcohol in 10 into the corresponding triflate and the 2 alcohol into the corresponding tbs ether gave 11 . displacement of the triflate in 11 by lithium trimethylsilylacetylide and removal of the tbs group afforded 12 . partial hydrogenation provided ef coupling precursor 13 . with 7 and 13 in hand , esterification using yamaguchi s conditions gave 14 ( scheme 3 ) . when subjected to our modified takai - utimoto reaction conditions , 14 underwent a smooth olefinic ester cyclization to afford d ring cyclic enol ether 15 as the only product in 50% yield . based on our inability to isolate by - products , we believe that the modest yield was due to the instability of 15 and not the inefficiency of the reaction . treatment of 15 with dmdo followed by reduction of the resulting epoxide with ibu2alh generated secondary alcohol 16 in 60% yield as a 3:1 mixture of diastereomers . the stereochemistry at c12 and c13 in 16 was established using h nmr and the j value between c12 and c13 following the conversion of 16 into the corresponding acetate 17 ( tyx and atx numbering ) . oxidation of the mixture of diastereomers to ketone 18 followed by removal of the tbs group afforded hemiketal 19 . treatment of 19 with zn(otf)2 and etsh gave the corresponding o , s - mixed ketal as a single diastereomer with concomitant removal of the benzylidene and the pmb groups . the c2 and c4 hydroxyl groups of triol 20 were selectively converted into cyclic silylene 21 . when 21 was subjected to ph3snh and aibn in refluxing toluene , the o , s - mixed ketal was reduced to give 3 containing the a - f ring system of both ytx and atx . having completed the synthesis of the a - f ring system , we turned our attention to the f - i subunit . depicted in scheme 4 is the synthesis of the f - ring coupling precursor 30 . from known alcohol 22 , acetylation followed by olefinic ester cyclization gave cyclic enol ether 24 . the c19 angular methyl group helped to direct a stereoselective epoxidation of 24 with mcpba . in situ the treatment of 25 with ppts , pyridine , and heat initiated a claisen rearrangement giving ketone 26 as a single diastereomer . the stereochemistry of the newly installed angular methyl group was confirmed through the indicated noe correlations . reduction of the ketone and pmb ether formation afforded 27 . while the extension of the propenyl side chain in 27 into the pentenyl side chain present in 29 was relatively inefficient , it could be carried out on a reasonable scale . removal of the benzylidene and pmb groups followed by selective c-18 , c-20 pmb acetal formation provide the f - ring coupling precursor 30 . the i - ring subunit 39 was synthesized according to the route outlined in scheme 5 . from the previously reported alcohol 31 , tertiary alcohol formation , removal of pmb group and oxidation gave 32 . hydroboration and oxidative work - up provided the 1 alcohol while simultaneously removing the tms group to give 34 . the coupling of 36 with lithium acetylide gave 37 after removal of the silyl protecting groups . tes ether formation and partial hydrogenation of the alkyne followed by ozonolysis and oxidation afforded the i - ring coupling precursor 39 . yamaguchi esterification using alcohol 30 and acid 39 gave ester 40 ( scheme 6 ) . olefinic - ester cyclization gave eight - membered g - ring cyclic enol ether 41 in 40% yield . we are unaware of any other reports of eight - membered cyclic enol ether formation using either olefinic - ester cyclization or olefinic enol ether cyclization conditions . having access to 41 , we next examined the incorporation of the h - ring and the c-26 methyl group ( scheme 7 ) . the oxidation of 41 with dmdo was followed by the in situ reduction of the resulting epoxide with ibu2alh giving secondary alcohol 43 as a single diastereomer . the incorporation of the c-26 methyl group was accomplished through alkylation of the enolate from 44 to give 45 . reductive cyclization of the tes - protected hydroxy ketone 45 using tmsotf and et3sih resulted in the generation of the g - ring . interestingly , when a benzylidene acetal rather than a p - methoxy benzylidene actal was used as the protecting group on the f - ring , it could not be cleanly removed under the reductive cyclization conditions , giving instead a mixture of benzyl protected alcohols . we were able to ascertain the relative stereochemistry of 4 using the indicated noe enhancements . in summary , we have achieved the convergent syntheses of both the abcdef and fghi ring system of ytx and atx using our olefinic ester cyclization strategy . we have also demonstrated that eight - membered cyclic enol ethers can be generated using an olefinic ester cyclization reaction . further studies towards the total syntheses of ytx and atx are currently in progress in our laboratory . nmr spectra were recorded on varian inova-400 mhz , varian inova-500 mhz or varian vxr-500 mhz spectrometers . chemical shifts were reported in  , parts per million ( ppm ) , relative to benzene ( 7.16 ) , chloroform ( 7.27 ) , or dichloromethane ( 5.32 ) as internal standards . coupling constants , j , were reported in hertz ( hz ) and refer to apparent peak multiplicities and not true coupling constants . mass spectra were recorded at the mass spectrometry facility at the department of chemistry of the university of utah at salt lake city on a finnigan mat 95 mass spectrometer . optical rotations were obtained on a perkin - elmer model 343 polarimerter ( na d line ) using a microcell with 1 dm path length . solvents were purified according to the guidelines in purification of common laboratory chemicals ( perrin , armarego , and perrin : oxford , 1966 ) . dichloromethane , 2,6-lutidine , triethylamine , tmeda , chlorobenzene and pyridine were distilled from cah2 . tetrahydrofuran and diethyl ether were dried from the sodium ketyl of benzophenone and distilled before use . zinc dust ( < 10 m , aldrich ) was activated by washing with 5% hydrochloric acid , h2o , methanol , and ether and dried in vacuo overnight . all other reagents were used without further purification . unless otherwise noted , all reactions were performed under a nitrogen atmosphere in flame - dried glassware using standard syringe , cannula , and septa apparatus . layer chromatography ( tlc ) was performed on silica gel plates ( 0.25 mm ) precoated with a fluorescent indicator . flash chromatography was performed using 4063 m silica gel ( 200  400 mesh ) . ( ( ( 2r,4ar,5as,7r,8s,9ar,10as)-8-allyl-4a - methyl-2-phenyloctahydro-4h - pyrano[2,3:5,6]pyrano[3,2-d]dioxin-7-yl)oxy)(tert - butyl)dimethylsilane ( 6 ) . to a solution of 5 ( 25 mg , 0.072 mmol ) and 2,6-lutidine ( 25 l , 0.22 mmol ) in ch2cl2 ( 10 ml ) the reaction mixture was stirred for 2 h after which the reaction was quenched with sat . the aqueous phase was extracted with ch2cl2 ( 3  5 ml ) and the extracts were combined , dried ( na2so4 ) , and concentrated . flash chromatography ( 8:1 hexanes : ethyl acetate ) provided 30 mg of 6 ( 90% ) as a colorless oil . rf 0.60 ( 5:1 hexanes : ethyl acetate ) ; [ ]d = 48.9 ( c = 0.47 , thf ) ; h nmr ( 500 mhz , c6d6 )  7.60 ( d , j = 7.3 hz , 2h ) , 7.19 ( t , j = 7.3 hz , 2h ) , 7.13 ( t , j = 7.3 hz , 1h ) , 6.14 ( dddd , j = 17.1 , 10.2 , 6.8 , 6.8 hz , 1h ) , 5.40 ( s , 1h ) , 5.22 ( bd , j = 17.1 hz , 1h ) , 5.13 ( bd , j = 10.2 hz , 1h ) , 3.92 ( d , j = 10.0 hz , 1h ) , 3.53 ( d , j = 10.0 hz , 1h ) , 3.47 ( ddd , j = 10.7 , 7.3 , 4.9 hz , 1h ) , 3.38 ( ddd , j = 10.2 , 9.3 , 3.4 hz , 1h ) , 3.35 ( dd , j = 12.5 , 3.5 hz , 1h ) , 3.26 ( ddd , j = 8.8 , 8.8 , 2.9 hz , 1h ) , 2.94 ( ddd , j = 10.2 , 9.8 , 4.9 hz , 1h ) , 2.752.69 ( m , 1h ) , 2.35 ( ddd , j = 7.3 , 7.3 , 7.3 hz , 1h ) , 2.31 ( ddd , j = 11.7 , 4.4 , 4.4 hz , 1h ) , 2.19 ( ddd , j = 11.2 , 4.4 , 4.4 hz , 1h ) , 1.88 ( ddd , j = 11.2 , 11.2 , 11.2 hz , 1h ) , 1.43 ( s , 3h ) , 0.93 ( s , 9h ) , 0.01 ( s , 3h ) , 0.01 ( s , 3h ) ; c nmr ( 125 mhz , c6d6 )  138.5 , 135.3 , 128.8 , 128.2 , 126.7 , 116.8 , 102.8 , 82.6 , 79.9 , 78.2 , 76.4 , 70.3 , 69.9 , 69.6 , 40.1 , 36.4 , 30.9 , 25.8 , 18.0 , 15.2 , 4.0 , 4.8 ; ir ( neat ) 2955 , 2933 , 2859 , 1463 , 1380 , 1331 , 1254 , 1092 cm ; esi / ms ( m / z ) calcd for c26h41o5si 461.3 ( m+h ) , found 461.3 . 2-((2r,4ar,5as,7r,8s,9ar,10as)-7-((tert - butyldimethylsilyl)oxy)-4a - methyl-2-phenyloctahydro-4h - pyrano[2,3:5,6]pyrano[3,2-d]dioxin-8-yl)acetic acid ( 7 ) . o3 was bubbled through a solution of 6 ( 30 mg , 0.065 mmol ) in ch2cl2 ( 20 ml ) at 78 c until the reaction was a light blue color . excess o3 was purged from the reaction mixture by bubbling n2 through it until the light blue color completely faded away . triphenylphosphine ( 51 mg , 0.19 mmol ) was then added and the reaction mixture was allowed to slowly warm to rt . flash chromatography ( 50:1 to 5:1 hexanes : ethyl acetate ) provided the corresponding aldehyde ( 28 mg , 92% ) as a colorless oil . to a solution of aldehyde obtained above ( 28 mg , 0.061 mmol ) in thf ( 3 ml ) was successively added tbuoh ( 3 ml ) , h2o ( 3 ml ) , 2-me-2-butene ( 0.6 ml ) , nah2po4 ( 36 mg , 0.30 mmol ) and naclo2 ( 27 mg , 0.30 mmol ) . the resulting mixture was stirred at rt for 2 h after which the reaction was quenched with h2o ( 3 ml ) . the reaction mixture was extracted with ethyl acetate ( 3  5 ml ) and the organic extracts were combined , dried ( na2so4 ) and concentrated . flash chromatography ( gradient of 1:1 hexanes : ethyl acetate to ethyl acetate ) provided acid 7 ( 19 mg , 67% ) as a colorless oil . rf 0.30 ( 2:1 hexanes : ethyl acetate ) ; [ ]d = 52.2 ( c = 0.39 , thf ) ; h nmr ( 500 mhz , cd2cl2 )  7.517.47 ( m , 2h ) , 7.417.37 ( m , 3h ) , 5.58 ( s , 1h ) , 3.92 ( d , j = 10.2 hz , 1h ) , 3.693.60 ( m , 3h ) , 3.55 ( ddd , j = 10.7 , 9.3 , 4.9 hz , 1h ) , 3.48 ( ddd , j = 11.2 , 9.3 , 3.9 hz , 1h ) , 3.22 ( ddd , j = 11.2 , 9.8 , 4.4 hz , 1h ) , 2.89 ( dd , j = 15.6 , 2.9 hz , 1h ) , 2.42 ( dd , j = 15.6 , 9.3 hz , 1h ) , 2.27 ( ddd , j = 11.7 , 4.4 , 4.4 hz , 1h ) , 2.20 ( ddd , j = 11.2 , 4.4 , 4.4 hz , 1h ) , 1.78 ( ddd , j = 11.7 , 11.7 , 11.7 hz , 1h ) , 1.53 ( ddd , j = 11.7 , 11.7 , 11.7 hz , 1h ) , 1.52 ( s , 3h ) , 0.92 ( s , 9h ) , 0.14 ( s , 3h ) , 0.13 ( s , 3h ) ; c nmr ( 125 mhz , cd2cl2 )  177.2 , 138.1 , 129.2 , 128.4 , 126.5 , 103.1 , 79.8 , 79.6 , 78.2 , 76.4 , 70.3 , 70.0 , 69.3 , 39.5 , 37.7 , 30.6 , 25.7 , 17.9 , 15.1 , 4.1 , 4.9 ; ir ( neat ) 3259 , 2954 , 2861 , 1714 , 1463 , 1377 , 1256 , 1093 cm ; esi / ms ( m / z ) calcd for c25h37o7si 477.3 ( mh ) , found 477.4 . 2-((2r,4ar,5as,7r,8s,9ar,11as)-7-((4-methoxybenzyl)oxy)-8,9a - dimethyl-2-phenyldecahydro - dioxino[5,4-b]pyrano[2,3-f]oxepin-8-yl)ethan-1-ol ( 9 ) . to a solution of 8 ( 28 mg , 0.075 mmol ) in thf ( 5 ml ) at rt was added kh ( 30 mg 30% dispersion in mineral oil , 0.23 mmol ) . after being allowed to stir for 10 min . , dmpu ( 4.5 l , 0.038 mmol ) , pmbbr ( 54 l , 0.38 mmol ) and a catalytic amount of tbai were added to the reaction mixture . after stirring overnight , nh4cl ( aq . , 5 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  5 ml ) and the combined organic extracts were dried ( na2so4 ) , and concentrated . flash chromatography ( 10:1 hexanes : ethyl acetate ) gave a colorless oil which was used in the next step without further purification . o3 was bubbled through a solution of the pmb ether from the procedure outlined above in ch2cl2 ( 20 ml ) at 78 c until the reaction mixture was a light blue color . excess o3 was purged from the reaction mixture by bubbling n2 through it until the light blue color completely faded ( ca . triphenylphosphine ( 59 mg , 0.23 mmol ) was then added and the reaction mixture was allowed to slowly warm to rt . after stirring for 12 h , the resulting solution was concentrated under reduced pressure . flash chromatography ( 50:1 to 5:1 hexanes : ethyl acetate ) provided the corresponding aldehyde as a colorless oil . to a solution of the aldehyde obtained above in meoh ( 5 ml ) at 0 c was added nabh4 ( 8.5 mg , 0.23 mmol ) . the reaction mixture was stirred for 2 h after which the reaction was quenched with acetone ( 3 ml ) . the mixture was concentrated and the residue was purified using flash chromatography ( 4:1 hexanes : ethyl acetate ) to give 9 as a colorless oil ( 28 mg , 74% over 3 steps ) . rf 0.50 ( 2:1 hexanes : ethyl acetate ) ; [ ]d = 15.5 ( c = 0.45 , thf ) ; h nmr ( 500 mhz , cd2cl2 )  7.547.51 ( m , 2h ) , 7.447.38 ( m , 3h ) , 7.29 ( d , j = 8.8 hz , 2h ) , 6.94 ( d , j = 8.3 hz , 2h ) , 5.45 ( s , 1h ) , 4.64 ( d , j = 11.2 hz , 1h ) , 4.41 ( d , j = 11.2 hz , 1h ) , 4.33 ( dd , j = 10.2 , 4.9 hz , 1h ) , 3.83 ( s , 3h ) , 3.843.78 ( partially obscured m , 1h ) , 3.61 ( dd , j = 10.3 , 10.3 hz , 1h ) , 3.54 ( ddd , j = 9.8 , 9.8 , 4.9 hz , 1h ) , 3.50 ( dd , j = 11.7 , 4.4 hz , 1h ) , 3.37 ( dd , j = 12.2 , 3.4 hz , 1h ) , 3.15 ( br s , 1h ) , 2.302.17 ( m , 2h ) , 1.961.85 ( m , 4h ) , 1.79 ( ddd , j = 12.2 , 12.2 , 12.2 hz , 1h ) , 1.74 ( ddd , j = 14.7 , 7.8 , 3.9 hz , 1h ) , 1.34 ( s , 3h ) , 1.33 ( s , 3h ) ; c nmr ( 125 mhz , cd2cl2 )  159.6 , 138.3 , 130.7 , 129.5 , 129.1 , 128.4 , 126.4 , 113.9 , 100.9 , 83.2 , 80.4 , 79.2 , 78.9 , 78.1 , 74.8 , 70.8 , 69.7 , 59.3 , 55.5 , 43.5 , 39.5 , 28.7 , 28.5 , 21.9 , 21.0 ; ir ( neat ) 3448 , 2946 , 2870 , 1613 , 1513 , 1458 , 1377 , 1248 , 1096 cm ; esi / ms ( m / z ) calcd for c29h38o7na 521.2 ( m+na ) , found 521.3 . to a solution of 9 ( 0.126 g , 0.253 mmol ) in thf ( 5 ml ) at rt was added tbuok ( 0.50 ml of 1.0 m solution in thf , 0.50 mmol ) . bnbr ( 0.12 ml , 1.01 mmol ) was added slowly and the reaction mixture was stirred for 3 h before the reaction was quenched with sat . nh4cl ( aq . , 5 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  5 ml ) and the combined organic extracts were dried ( na2so4 ) , and concentrated . the residue from above was dissolved in meoh ( 15 ml ) and the mixture was cooled to 0 c . csa ( 15 mg , 0.065 mmol ) was added and the reaction mixture was allowed to slowly warm to rt . the aqueous phase was extracted with ethyl acetate ( 3  10 ml ) and the combined organic extracts were dried ( na2so4 ) , and concentrated . flash chromatography ( 1:1 hexanes : ethyl acetate ) gave 10 as a colorless oil ( 0.112 g , 89% over 2 steps ) . rf 0.60 ( ethyl acetate ) ; [ ]d = 19.0 ( c = 0.51 , thf ) ; h nmr ( 500 mhz , cd2cl2 )  7.407.30 ( m , 5h ) , 7.28 ( d , j = 8.3 hz , 2h ) , 6.90 ( d , j = 8.8 hz , 2h ) , 4.59 ( d , j = 11.2 hz , 1h ) , 4.48 ( s , 2h ) , 4.38 ( d , j = 10.7 hz , 1h ) , 3.87 ( br d , j = 5.5 hz , 1h ) , 3.82 ( s , 3h ) , 3.71 ( br s , 1h ) , 3.643.60 ( m , 2h ) , 3.553.48 ( m , 3h ) , 3.44 ( dd , j = 11.2 , 4.2 hz , 1h ) , 2.70 ( br s , 2h ) , 2.17 ( ddd , j = 11.7 , 3.9 , 3.9 hz , 1h ) , 1.951.76 ( m , 4h ) , 1.761.65 ( m , 2h ) , 1.54 ( ddd , j = 13.7 , 6.3 , 2.2 hz , 1h ) , 1.27 ( s , 6h ) ; c nmr ( 125 mhz , cd2cl2 )  159.4 , 139.2 , 131.1 , 129.4 , 128.5 , 127.9 , 127.6 , 113.9 , 85.7 , 79.6 , 79.3 , 76.5 , 75.5 , 73.0 , 71.7 , 70.8 , 66.7 , 64.5 , 55.4 , 41.7 , 36.2 , 28.8 , 27.9 , 22.3 , 20.2 ; ir ( neat ) 3383 , 2929 , 2870 , 1613 , 1455 , 1375 , 1248 , 1090 cm ; esi / ms ( m / z ) calcd for c29h40o7na 523.3 ( m+na ) , found 523.3 . to a solution of 10 ( 0.112 g , 0.224 mmol ) and 2,6-lutidine ( 0.104 ml , 0.893 mmol ) in ch2cl2 ( 20 ml ) at 78 c was added trifluoromethanesulfonic anhydride ( 40.0 l , 0.234 mmol ) . after 30 min tbsotf ( 77.0 l , 0.335 mmol ) was added to the reaction mixture . the reaction mixture was allowed to warm slowly to rt before it was quenched with sat . nahco3 ( aq . , 10 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  10 ml ) . the combined organic phase was dried ( na2so4 ) and concentrated to give a yellow oil . the oil was dissolved in a 10:1 mixture of hexanes : ethyl acetate , filtered through a plug of silica gel ( 10:1 ) , and concentrated . to a solution of trimethylsilylacetylene ( 0.168 ml , 1.19 mmol ) in thf ( 10 ml ) at 0 c was added nbuli ( 0.474 ml of 2.50 m solution in hexanes , 1.19 mmol ) . the reaction mixture was stirred at 0 c for 30 min and then cooled to 78 c . a solution of 11 obtained from above and hmpa ( 0.207 ml , 1.19 mmol ) in thf ( 5 ml ) was transferred via cannula into the acetylide containing reaction mixture . the reaction mixture was stirred for 2 h after which the reaction was quenched with sat . nh4cl ( aq . , 10 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  10 ml ) . the combined organic phase was dried ( na2so4 ) and concentrated to give a dark brown oil which was taken up in thf ( 10 ml ) . to the resulting solution was added tbaf ( 1.12 ml of 1.0 m solution in thf , 1.12 mmol ) and the mixture was stirred at rt overnight before the reaction was quenched with sat . nh4cl ( aq . , 10 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  10 ml ) , the organic phases were combined , dried ( na2so4 ) , and concentrated . flash chromatography ( 4:1 hexanes : ethyl acetate ) gave 12 as a colorless oil ( 85.7 mg , 75% 3 steps ) . rf 0.50 ( 2:1 hexanes : ethyl acetate ) ; [ ]d = 21.6 ( c = 0.42 , thf ) ; h nmr ( 500 mhz , cd2cl2 )  7.407.28 ( m , 5h ) , 7.27 ( d , j = 8.8 hz , 2h ) , 6.90 ( d , j = 8.3 hz , 2h ) , 4.58 ( d , j = 10.8 hz , 1h ) , 4.48 ( s , 2h ) , 4.38 ( d , j = 11.2 hz , 1h ) , 4.08 ( br s , 1h ) , 3.81 ( s , 3h ) , 3.79 ( partially obscured ddd , j = 7.3 , 5.4 , 1.5 hz , 1h ) , 3.633.59 ( m , 2h ) , 3.52 ( dd , j = 12.2 , 4.2 hz , 1h ) , 3.42 ( dd , j = 11.7 , 3.9 hz , 1h ) , 3.41 ( ddd , j = 16.6 , 5.4 , 2.4 hz , 1h ) , 2.33 ( ddd , j = 17.1 , 7.8 , 2.7 hz , 1h ) , 2.182.10 ( partially obscured m , 1h ) , 2.13 ( ddd , j = 12.2 , 3.9 , 3.9 hz , 1h ) , 2.10 ( t , j = 2.4 hz , 1h ) , 1.941.75 ( m , 5h ) , 1.68 ( ddd , j = 12.2 , 12.2 , 12.2 hz , 1h ) , 1.51 ( ddd , j = 13.2 , 5.9 , 2.9 hz , 1h ) , 1.25 ( s , 6h ) ; c nmr ( 125 mhz , cd2cl2 )  159.4 , 139.3 , 131.2 , 129.4 , 128.5 , 127.8 , 127.6 , 113.8 , 83.3 , 81.2 , 79.5 , 78.5 , 76.5 , 75.4 , 73.3 , 73.0 , 70.8 , 70.1 , 66.7 , 55.4 , 41.7 , 35.9 , 28.7 , 26.7 , 24.6 , 22.2 , 20.1 ; ir ( neat ) 3419 , 2929 , 2869 , 2339 , 1613 , 1454 , 1374 , 1248 , 1089 cm ; esi / ms ( m / z ) calcd for c31h40o6na 531.3 ( m+na ) , found 531.3 . ( 2s,3r,4as,6r,7s,9ar)-6-allyl-2-(2-(benzyloxy)ethyl)-3-((4-methoxybenzyl)oxy)-2,9a - dimethyloctahydro-2h - pyrano[3,2-b]oxepin-7-ol ( 13 ) to a solution of 12 ( 85.7 mg , 0.169 mmol ) in ethyl acetate ( 10 ml ) was added quinoline ( 10 l , 0.08 mmol ) and lindlar s pd catalyst ( 10 mg ) . the mixture was stirred under 1 h2 ( 1 atm ) for 2 h before it was passed through a celite plug with ethyl acetate . the filtrate was concentrated and flash chromatography ( 4:1 hexanes : ethyl acetate ) gave 13 as a colorless oil ( 78.8 mg , 92% ) . rf 0.55 ( 2:1 hexanes : ethyl acetate ) ; [ ]d = 14.9 ( c = 0.43 , thf ) ; h nmr ( 500 mhz , cd2cl2 )  7.387.28 ( m , 5h ) , 7.26 ( d , j = 8.8 hz , 2h ) , 6.90 ( d , j = 8.3 hz , 2h ) , 5.89 ( dddd , j = 17.1 , 10.3 , 6.8 , 6.8 hz , 1h ) , 5.145.07 ( m , 2h ) , 4.58 ( d , j = 11.2 hz , 1h ) , 4.47 ( s , 2h ) , 4.37 ( d , j = 11.2 hz , 1h ) , 3.89 ( br d , j = 5.9 hz , 1h ) , 3.80 ( s , 3h ) , 3.68 ( ddd , j = 6.4 , 6.4 , 1.4 hz , 1h ) , 3.623.58 ( m , 2h ) , 3.47 ( dd , j = 12.2 , 4.2 hz , 1h ) , 3.41 ( dd , j = 11.7 , 3.9 hz , 1h ) , 2.272.15 ( m , 2h ) , 2.10 ( ddd , j = 12.2 , 4.4 , 3.9 hz , 1h ) , 1.931.80 ( m , 4h ) , 1.781.69 ( m , 2h ) , 1.65 ( ddd , j = 12.2 , 12.2 , 12.2 hz , 1h ) , 1.49 ( ddd , j = 13.2 , 5.3 , 2.7 hz , 1h ) , 1.24 ( s , 6h ) ; c nmr ( 125 mhz , cd2cl2 )  159.4 , 139.3 , 135.4 , 131.2 , 129.4 , 128.5 , 127.8 , 127.5 , 116.9 , 113.8 , 84.7 , 79.6 , 78.5 , 76.5 , 75.4 , 73.7 , 72.9 , 70.7 , 66.7 , 55.4 , 41.7 , 39.4 , 35.9 , 28.8 , 26.7 , 22.3 , 20.1 ; ir ( neat ) 3423 , 2929 , 1613 , 1513 , 1454 , 1374 , 1248 , 1087 cm ; esi / ms ( m / z ) calcd for c31h42o6na 533.3 ( m+na ) , found 533.3 . to a solution of acid 7 ( 36.0 mg , 0.0753 mmol ) in thf ( 8 ml ) was added triethylamine ( 45.9 l , 0.330 mmol ) and 2,4,6-trichlorobenzoyl chloride ( 35.3 l , 0.223 mmol ) . the reaction mixture was heated to 40 c and stirred for 2 h before being concentrated . a solution of alcohol 13 ( 36.8 mg , 0.0722 mmol ) in toluene ( 10 ml ) was transferred via cannula to the resulting residue . dmap ( 42.3 mg , 0.347 mmol ) was then added and the reaction mixture was heated at 40 c for 2 h after which the reaction was quenched with sat . nahco3 ( aq . , 10 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  10 ml ) and the organic extracts were combined , dried ( na2so4 ) and concentrated . flash chromatography ( 10:1 hexanes : ethyl acetate ) provided ester 14 ( 67.8 mg , 97% ) as a colorless oil . rf 0.25 ( 5:1 hexanes : ethyl acetate ) ; [ ]d = 14.8 ( c = 0.30 , thf ) ; h nmr ( 500 mhz , cd2cl2 )  7.467.43 ( m , 2h ) , 7.387.34 ( m , 7h ) , 7.327.27 ( m , 1h ) , 7.22 ( d , j = 8.3 hz , 2h ) , 6.86 ( d , j = 8.8 hz , 2h ) , 5.88 ( dddd , j = 17.1 , 10.3 , 6.8 , 6.8 hz , 1h ) , 5.52 ( s , 1h ) , 5.13 ( dd , j = 18.1 , 1.0 hz , 1h ) , 5.09 ( d , j = 10.7 hz , 1h ) , 4.99 ( d , j = 6.3 hz , 1h ) , 4.57 ( d , j = 10.7 hz , 1h ) , 4.49 ( d , j = 11.7 hz , 1h ) , 4.45 ( d , j = 11.7 hz , 1h ) , 4.36 ( d , j = 10.7 hz , 1h ) , 3.89 ( d , j = 10.3 hz , 1h ) , 3.79 ( s , 3h ) , 3.75 ( dd , j = 6.2 , 6.2 hz , 1h ) , 3.723.58 ( m , 5h ) , 3.55 ( ddd , j = 9.8 , 9.8 , 4.4 hz , 1h ) , 3.48 ( partially obscured ddd , j = 10.8 , 9.3 , 3.9 hz , 1h ) , 3.44 ( partially obscured dd , j = 11.7 , 4.4 hz , 1h ) , 3.36 ( dd , j = 12.2 , 3.9 hz , 1h ) , 3.19 ( ddd , j = 10.7 , 9.3 , 4.4 hz , 1h ) , 2.87 ( dd , j = 14.9 , 2.7 hz , 1h ) , 2.39 ( dd , j = 14.9 , 9.5 hz , 1h ) , 2.312.23 ( m , 3h ) , 2.16 ( ddd , j = 11.2 , 3.9 , 3.9 hz , 1h ) , 2.12 ( ddd , j = 12.2 , 3.9 , 3.9 hz , 1h ) , 1.971.64 ( m , 8h ) , 1.591.48 ( m , 1h ) , 1.50 ( s , 3h ) , 1.25 ( s , 3h ) , 1.24 ( s , 3h ) , 0.92 ( s , 9h ) , 0.13 ( s , 3h ) , 0.11 ( s , 3h ) ; c nmr ( 125 mhz , cd2cl2 )  170.8 , 159.4 , 139.3 , 138.0 , 134.8 , 131.1 , 129.3 , 129.2 , 128.5 , 128.4 , 127.8 , 127.6 , 126.6 , 117.2 , 113.8 , 103.1 , 82.6 , 80.5 , 80.1 , 79.9 , 78.9 , 78.2 , 77.1 , 76.3 , 76.2 , 75.4 , 73.0 , 71.0 , 70.4 , 70.0 , 69.4 , 66.8 , 55.4 , 42.0 , 39.6 , 39.2 , 38.3 , 36.6 , 30.7 , 28.9 , 25.8 , 23.6 , 22.0 , 19.8 , 18.0 , 15.1 , 4.1 , 4.8 ; ir ( neat ) 2932 , 2859 , 1735 , 1613 , 1514 , 1456 , 1378 , 1250 , 1092 cm ; esi / ms ( m / z ) calcd for c56h78o12sina 993.5 ( m+na ) , found 993.5 . to a solution of ticl4 ( 0.245 ml , 2.23 mmol ) in ch2cl2 ( 15 ml ) at 0 c was added thf ( 1.18 ml , 13.4 mmol ) dropwise . to the resulting yellow solution was added tmeda ( 2.03 ml , 13.4 mmol ) dropwise ; the solution turned to a red - brown color . the ice bath was then removed and the mixture was allowed to warm for 15 min . activated zn dust ( 330 mg , 5.08 mmol ) and pbcl2 ( 74.0 mg , 0.266 mmol ) were then added . the resulting mixture went through a series of color changes from brown to green to purple and finally to blue - green over the course of 35 min . to the slurry was transferred a solution of ester 14 ( 67.8 mg , 0.0699 mmol ) and ch3chbr2 ( 0.200 ml , 2.23 mmol ) in ch2cl2 ( 5 ml ) via cannula . the reaction mixture was then heated to reflux for 30 min before it was cooled to 0 c . k2co3 ( aq . , 1.0 ml ) for 30 min and filtering the mixture . concentration and flash chromatography ( 10:1 hexanes : ethyl acetate ) gave 15 as a colorless oil ( 32.9 mg , 50% ) . rf 0.20 ( 5:1 hexanes : ethyl acetate ) ; [ ]d = 40.3 ( c = 0.29 , thf ) ; h nmr ( 500 mhz , cd2cl2 )  7.487.45 ( m , 2h ) , 7.407.32 ( m , 7h ) , 7.307.26 ( m , 1h ) , 7.24 ( d , j = 8.3 hz , 2h ) , 6.86 ( d , j = 8.8 hz , 2h ) , 5.56 ( s , 1h ) , 4.56 ( d , j = 11.2 hz , 1h ) , 4.52 ( br d , j = 3.4 hz , 1h ) , 4.47 ( d , j = 11.7 hz , 1h ) , 4.42 ( d , j = 11.7 hz , 1h ) , 4.37 ( d , j = 11.2 hz , 1h ) , 3.90 ( d , j = 10.2 hz , 1h ) , 3.78 ( s , 3h ) , 3.673.60 ( m , 2h ) , 3.603.52 ( m , 2h ) , 3.503.40 ( m , 5h ) , 3.37 ( dd , j = 12.2 , 3.9 hz , 1h ) , 3.31 ( ddd , j = 9.3 , 9.3 , 2.0 hz , 1h ) , 3.12 ( ddd , j = 11.2 , 9.3 , 4.4 hz , 1h ) , 2.54 ( d , j = 15.1 hz , 1h ) , 2.28 ( br d , j = 16.6 hz , 1h ) , 2.21 ( ddd , j = 11.2 , 4.4 , 4.4 hz , 1h ) , 2.16 ( ddd , j = 11.7 , 3.9 , 3.9 hz , 1h ) , 2.13 ( ddd , j = 12.2 , 3.9 , 3.9 hz , 1h ) , 2.051.66 ( m , 10h ) , 1.50 ( s , 3h ) , 1.47 ( ddd , j = 10.7 , 10.7 , 10.7 hz , 1h ) , 1.24 ( s , 3h ) , 1.19 ( s , 3h ) , 0.90 ( s , 9h ) , 0.10 ( s , 3h ) , 0.09 ( s , 3h ) ; c nmr ( 125 mhz , cd2cl2 )  159.4 , 151.6 , 139.3 , 138.1 , 131.1 , 129.4 , 129.2 , 128.5 , 128.4 , 1279 , 127.6 , 126.5 , 113.8 , 103.0 , 94.8 , 80.6 , 80.0 , 79.9 , 79.7 , 79.1 , 78.8 , 78.0 , 77.0 , 76.4 , 75.6 , 73.0 , 70.8 , 70.7 , 69.9 , 69.5 , 66.5 , 55.4 , 41.9 , 40.0 , 39.9 , 35.9 , 30.7 , 29.7 , 29.4 , 28.8 , 25.8 , 23.5 , 22.5 , 18.0 , 15.1 , 4.1 , 4.8 ; ir ( neat ) 2933 , 2859 , 1651 , 1513 , 1458 , 1377 , 1250 , 1093 cm ; esi / ms ( m / z ) calcd for c55h76o11sina 963.5 ( m+na ) , found 963.6 . to a solution of 15 ( 28.6 mg , 0.0304 mmol ) in ch2cl2 ( 5 ml ) at 78 c was added a solution of dimethyl dioxirane ( 0.61 ml of 0.10 m solution in ch2cl2 , 0.061 mmol ) dropwise . the resulting residue was dissolved in ch2cl2 ( 5 ml ) and cooled to 78 c . to this was added a solution of dibalh ( 0.304 ml of 1.0 m solution in thf , 0.30 mmol ) . after stirring for 2 h , nh4cl ( aq . , 3 ml ) and allowed to warm to rt . a solution of sat . potassium sodium tartrate solution ( aq , 10 ml ) was added and the resulting mixture was stirred for 30 min . the aqueous phase was extracted with ch2cl2 ( 3  10 ml ) and the combined organic phase was dried ( na2so4 ) and concentrated . flash chromatography ( 5:1 hexanes : ethyl acetate ) provided major alcohol 16 ( 17.5 mg , 60% ) and minor alochol ( 6.1 mg , 21% ) both as colorless oil . to a solution of 16 ( 17.5 mg , 0.0183 mmol ) in ch2cl2 ( 5 ml ) was added activated 4 ms ( 20 mg ) , nmo ( 21.4 mg , 0.183 mmol ) and tpap ( 1 mg , 0.003 mmol ) . flash chromatography ( 5:1 hexanes : ethyl acetate ) gave ketone 18 as a colorless oil ( 17.4 mg , 100% ) . rf 0.55 ( 3:1 hexanes : ethyl acetate ) ; [ ]d = 42.0 ( c = 0.10 , thf ) ; h nmr ( 500 mhz , c6d6 )  7.60 ( d , j = 7.8 hz , 2h ) , 7.33 ( d , j = 7.8 hz , 2h ) , 7.267.06 ( m , 9h ) , 6.79 ( d , j = 7.8 hz , 2h ) , 5.39 ( s , 1h ) , 4.44 ( d , j = 11.2 hz , 1h ) , 4.41 ( d , j = 11.2 hz , 1h ) , 4.36 ( d , j = 11.7 hz , 1h ) , 4.25 ( d , j = 11.2 hz , 1h ) , 4.08 ( dd , j = 7.3 , 3.4 hz , 1h ) , 3.92 ( d , j = 10.2 hz , 1h ) , 3.783.70 ( m , 2h ) , 3.663.60 ( m , 1h ) , 3.563.50 ( partially obscured m , 1h ) , 3.53 ( partially obscured d , j = 10.2 hz , 1h ) , 3.453.25 ( m , 4h ) , 3.28 ( s , 3h ) , 3.16 ( ddd , j = 8.3 , 8.3 , 4.4 hz , 1h ) , 3.083.00 ( m , 2h ) , 2.97 ( dd , j = 15.6 , 6.4 hz , 1h ) , 2.76 ( ddd , j = 13.2 , 7.8 , 2.4 hz , 1h ) , 2.362.22 ( m , 3h ) , 2.162.00 ( m , 4h ) , 2.001.88 ( m , 2h ) , 1.861.62 ( m , 6h ) , 1.43 ( s , 3h ) , 1.33 ( s , 3h ) , 1.18 ( s , 3h ) , 0.98 ( s , 9h ) , 0.06 ( s , 3h ) , 0.02 ( s , 3h ) ; c nmr ( 125 mhz , c6d6 )  205.1 , 159.6 , 139.4 , 138.4 , 131.0 , 129.2 , 128.9 , 128.4 , 128.2 , 127.4 , 126.7 , 114.0 , 102.8 , 81.0 , 80.2 , 80.1 , 79.8 , 79.5 , 79.4 , 78.9 , 78.3 , 76.9 , 76.4 , 75.7 , 73.0 , 71.7 , 70.6 , 69.9 , 69.5 , 66.5 , 54.6 , 46.1 , 42.2 , 40.2 , 39.6 , 36.7 , 33.3 , 31.0 , 30.1 , 29.2 , 28.8 , 25.8 , 24.8 , 22.8 , 22.6 , 18.0 , 15.1 , 4.1 , 4.8 ; ir ( neat ) 2931 , 2858 , 1727 , 1513 , 1460 , 1377 , 1250 , 1092 cm ; esi / ms ( m / z ) calcd for c55h78o12sik 995.5 ( m+k ) , found 995.5 . to a solution of 16 ( 25.6 mg , 0.0267 mmol ) in ch2cl2 ( 8 ml ) was added et3n ( 37.2 l , 0.267 mmol ) , ac2o ( 12.6 l , 0.133 mmol ) , and dmap ( 3.3 mg , 0.027 mmol ) . the reaction mixture was stirred for 2 h before the reaction was quenched with sat . after separation the aqueous phase was extracted with ch2cl2 ( 3  5 ml ) and the combined organic phase was dried ( na2so4 ) and concentrated . flash chromatography ( 5:1 hexanes : ethyl acetate ) provided 17 as a colorless oil ( 21.7 mg , 81% ) . rf 0.60 ( 3:1 hexanes : ethyl acetate ) ; [ ]d = 24.9 ( c = 0.24 , thf ) ; h nmr ( 500 mhz , c6d6 )  7.60 ( d , j = 7.3 hz , 2h ) , 7.33 ( d , j = 7.3 hz , 2h ) , 7.247.08 ( m , 8h ) , 6.79 ( d , j = 7.8 hz , 2h ) , 5.39 ( s , 1h ) , 4.99 ( ddd , j = 10.7 , 10.7 , 4.4 hz , 1h ) , 4.52 ( d , j = 11.2 hz , 1h ) , 4.42 ( d , j = 11.2 hz , 1h ) , 4.37 ( d , j = 13.2 hz , 1h ) , 4.34 ( d , j = 12.2 hz , 1h ) , 3.92 ( d , j = 9.8 hz , 1h ) , 3.76 ( dd , j = 15.6 , 7.3 hz , 1h ) , 3.683.50 ( m , 6h ) , 3.503.37 ( m , 2h ) , 3.30 ( s , 3h ) , 3.203.01 ( m , 4h ) , 2.77 ( ddd , j = 11.7 , 4.4 , 4.4 hz , 1h ) , 2.44 ( ddd , j = 12.2 , 3.9 , 3.9 hz , 1h ) , 2.382.30 ( m , 2h ) , 2.162.02 ( m , 3h ) , 2.021.94 ( m , 2h ) , 1.90 ( ddd , j = 11.7 , 11.7 , 11.7 hz , 1h ) , 1.851.76 ( m , 3h ) , 1.75 ( s , 3h ) , 1.721.53 ( m , 3h ) , 1.45 ( s , 3h ) , 1.32 ( s , 3h ) , 1.20 ( s , 3h ) , 0.98 ( s , 9h ) , 0.09 ( s , 3h ) , 0.03 ( s , 3h ) ; c nmr ( 125 mhz , c6d6 )  169.2 , 159.6 , 139.4 , 138.5 , 131.2 , 129.3 , 128.8 , 128.4 , 128.2 , 127.4 , 126.7 , 114.0 , 102.8 , 81.5 , 81.1 , 79.9 , 79.7 , 79.3 , 79.1 , 78.3 , 77.0 , 76.4 , 75.7 , 73.0 , 71.1 , 70.6 , 69.9 , 69.6 , 66.6 , 54.7 , 42.2 , 40.4 , 39.8 , 37.7 , 34.5 , 30.9 , 30.1 , 29.5 , 29.0 , 25.9 , 22.7 , 22.6 , 20.7 , 18.0 , 15.2 , 3.9 , 4.6 ; ir ( neat ) 2931 , 2858 , 1740 , 1614 , 1513 , 1458 , 1375 , 1245 , 1090 cm ; esi / ms ( m / z ) calcd for c57h80o13sina 1023.5 ( m+na ) , found 1023.5 . ( 2r,4ar,5as,6ar,7as,8ar,9as,11r,12s,13ar,15as,16ar,17as,18ar,19as)-12-(2-(benzyloxy)ethyl)-11-((4-methoxybenzyl)oxy)-4a,12,13a - trimethyl-2-phenylicosahydro - dioxino[4,5:5,6]pyrano[2,3:5,6]pyrano[2,3:5,6]pyrano[2,3:5,6]pyrano[3,2-b]pyrano[2,3-f]oxepin-7a(4h)-ol ( 19 ) . to a solution of 18 ( 17.7 mg , 0.0185 mmol ) in thf ( 10 ml ) at 0 c was slowly added hfpy ( 0.60 ml , 33 mmol ) . the reaction mixture was allowed to warm to rt and stirred for 2 d before it was quenched with sat . nahco3 ( aq . , 50 ml ) . the aqueous phase was extracted with ethyl acetate ( 3  10 ml ) and the combined organic phase was dried ( na2so4 ) and concentrated . flash chromatography ( 2:1 hexanes : ethyl acetate ) provided 19 as a colorless oil ( 15.5 mg , 99% ) . rf 0.35 ( 2:1 hexanes : ethyl acetate ) ; [ ]d = 15.8 ( c = 0.22 , thf ) ; h nmr ( 500 mhz , cd2cl2 )  7.487.45 ( m , 2h ) , 7.397.24 ( m , 8h ) , 7.23 ( d , j = 8.3 hz , 2h ) , 6.86 ( d , j = 8.3 hz , 2h ) , 5.56 ( s , 1h ) , 4.55 ( d , j = 11.2 hz , 1h ) , 4.45 ( d , j = 11.7 hz , 1h ) , 4.41 ( d , j = 12.2 hz , 1h ) , 4.36 ( d , j = 10.7 hz , 1h ) , 4.08 ( br d , j = 6.8 hz , 1h ) , 3.92 ( d , j = 9.8 hz , 1h ) , 3.803.74 ( m , 1h ) , 3.78 ( s , 3h ) , 3.683.62 ( m , 2h ) , 3.593.44 ( m , 4h ) , 3.42 ( partially obscured dd , j = 11.7 , 4.4 hz , 1h ) , 3.333.27 ( m , 1h ) , 3.22 ( ddd , j = 11.7 , 2.4 , 1.5 hz , 1h ) , 3.17 ( ddd , j = 12.7 , 9.3 , 3.4 hz , 1h ) , 3.13 ( ddd , j = 11.2 , 9.3 , 3.9 hz , 1h ) , 2.232.00 ( m , 4h ) , 1.931.88 ( m , 2h ) , 1.861.73 ( m , 3h ) , 1.731.65 ( m , 2h ) , 1.631.52 ( m , 2h ) , 1.50 ( s , 3h ) , 1.45 ( ddd , j = 11.7 , 11.7 , 11.7 hz , 1h ) , 1.411.25 ( m , 2h ) , 1.22 ( s , 3h ) , 1.18 ( s , 3h ) , 1.161.95 ( m , 1h ) ; c nmr ( 125 mhz , cd2cl2 )  138.0 , 131.0 , 129.3 , 129.2 , 128.4 , 127.8 , 127.5 , 126.5 , 113.8 , 103.0 , 93.9 , 82.2 , 81.9 , 79.8 , 79.6 , 79.3 , 78.6 , 77.6 , 77.0 , 76.3 , 75.6 , 72.9 , 70.8 , 70.2 , 68.9 , 66.5 , 55.4 , 49.2 , 43.2 , 41.8 , 39.7 , 35.3 , 34.1 , 30.6 , 30.2 , 29.2 , 28.8 , 25.8 , 25.2 , 22.4 , 22.2 , 15.0 ; ir ( neat ) 3323 , 3055 , 2927 , 1624 , 1433 , 1265 , 1113 cm ; esi / ms ( m / z ) calcd for c49h62o12na 865.4 ( m+na ) , found 865.4 . to a solution of 19 ( 15.9 mg , 0.0189 mmol ) in ch2cl2 ( 6 ml ) and etsh ( 2 ml ) was added zn(otf)2 ( 140 mg , 0.385 mmol ) . the reaction mixture was heated to reflux and stirred for 12 h before it was cooled to rt and the reaction quenched with sat . nahco3 ( aq . , 5 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  5 ml ) and the combined organic phase was dried ( na2so4 ) and concentrated . flash chromatography ( 20:1 dichloromethane : methanol ) provided triol 20 as a colorless oil . to the solution of the triol obtained above in dmf ( 10 ml ) at 20 c the reaction mixture was stirred at 20 c for 1 h before pyridine ( 6.2 ml , 0.077 mmol ) was added . the mixture was stirred for another 5 min and the reaction was quenched with sat . nahco3 ( aq . , 10 ml ) . the aqueous phase was extracted with et2o ( 3  10 ml ) and the combined organic phase was dried ( na2so4 ) and concentrated . flash chromatography ( 3:1 hexanes : ethyl acetate ) provided a colorless oil which was taken on to the next transformation without additional purification . to a solution of the colorless oil obtained above in toluene ( 10 ml ) was added ph3snh ( 200 mg , 0.570 mmol ) . the reaction mixture was heated to reflux and aibn ( 0.0046 m solution in toluene , 2.0 ml , 9.2 mol ) was added via syringe pump over 2 h. the mixture was then cooled to rt and solvent was removed under reduced pressure . flash chromatography ( 2:1 hexanes : ethyl acetate ) provided 3 as a colorless oil ( 7.3 mg , 51% 3 steps ) . rf 0.20 ( 2:1 hexanes : ethyl acetate ) ; [ ]d = 7.6 ( c = 0.10 , thf ) ; h nmr ( 500 mhz , cd2cl2 )  7.397.27 ( m , 5h ) , 4.50 ( s , 2h ) , 4.07 ( dd , j = 12.2 , 4.4 hz , 1h ) , 3.88 ( d , j = 10.2 hz , 1h ) , 3.75 ( d , j = 10.2 hz , 1h ) , 3.59 ( dd , j = 6.4 , 4.4 hz , 1h ) , 3.54 ( dd , j = 12.2 , 3.9 hz , 1h ) , 3.403.35 ( m , 1h ) , 3.33 ( dd , j = 11.7 , 3.9 hz , 1h ) , 3.26 ( ddd , j = 10.8 , 9.3 , 4.4 hz , 1h ) , 3.19 ( ddd , j = 12.7 , 8.8 , 4.4 hz , 1h ) , 3.132.95 ( m , 6h ) , 2.322.24 ( m , 2h ) , 2.182.10 ( m , 2h ) , 2.001.68 ( m , 10h ) , 1.65 ( ddd , j = 11.7 , 11.7 , 11.7 hz , 1h ) , 1.42 ( s , 3h ) , 1.411.34 ( m , 1h ) , 1.23 ( s , 3h ) , 1.16 ( s , 3h ) , 1.10 ( s , 9h ) , 1.03 ( s , 9h ) ; c nmr ( 125 mhz , cd2cl2 )  138.4 , 129.0 , 128.4 , 128.4 , 81.9 , 81.4 , 80.4 , 78.6 , 77.8 , 77.7 , 77.6 , 77.4 , 76.8 , 75.0 , 74.9 , 74.3 , 73.7 , 73.2 , 69.8 , 67.1 , 43.8 , 40.5 , 37.4 , 35.9 , 35.7 , 34.0 , 32.3 , 29.9 , 29.3 , 28.0 , 23.9 , 20.4 , 20.1 , 15.6 ; ir ( neat ) 3417 , 2925 , 2855 , 1652 , 1457 , 1375 , 1080 cm ; fab / ms ( m / z ) calcd for c42h66o10siag 865.3476 ( m+ag ) , found 865.3475 . to a solution of 22 ( 1.24 g , 5.30 mmol ) in ch2cl2 ( 25 ml ) was added et3n ( 3.70 ml , 26.6 mmol ) , ac2o ( 1.50 ml , 15.6 mmol ) , and dmap ( 0.646 g , 5.30 mmol ) . the resulting mixture was stirred for 2 h before the reaction was quenched with sat . nahco3 ( aq . , 20 ml ) . the phases were separated and the aqueous phase was extracted with ch2cl2 ( 3  20 ml ) . flash chromatography ( 5:1 hexanes : ethyl acetate ) provided 23 as a colorless oil ( 1.15 g , 79% ) . rf 0.60 ( 4:1 hexanes : ethyl acetate ) ; [ ]d = 71.2 ( c = 0.32 , thf ) ; h nmr ( 500 mhz , c6d6 )  7.59 ( d , j = 7.3 hz , 2h ) , 7.18 ( t , j = 7.3 hz , 2h ) , 7.12 ( t , j = 7.3 hz , 1h ) , 5.96 ( dddd , j = 17.6 , 10.3 , 7.3 , 6.3 hz , 1h ) , 5.34 ( s , 1h ) , 5.14 ( d , j = 17.1 hz , 1h ) , 5.08 ( d , j = 10.3 hz , 1h ) , 4.99 ( d , j = 10.7 hz , 1h ) , 3.73 ( dd , j = 10.1 , 2.7 hz , 1h ) , 3.64 ( d , j = 10.7 hz , 1h ) , 2.402.33 ( m , 1h ) , 2.292.21 ( m , 1h ) , 1.69 ( s , 3h ) , 1.56 ( s , 3h ) ; c nmr ( 125 mhz , c6d6 )  168.8 , 138.5 , 135.2 , 128.8 , 128.2 , 126.5 , 116.8 , 101.7 , 81.6 , 75.7 , 74.2 , 33.5 , 21.1 , 16.1 ; ir ( neat ) 2985 , 2859 , 1737 , 1643 , 1452 , 1367 , 1237 , 1099 cm ; esi / ms ( m / z ) calcd for c16h20o4na 299.1 ( m+na ) , found 299.1 . ( 2r,4ar,8as)-4a,6-dimethyl-2-phenyl-4,4a,8,8a - tetrahydropyrano[3,2-d]dioxine ( 24 ) . to a solution of ticl4 ( 7.37 ml , 67.2 mmol ) in ch2cl2 ( 440 ml ) at 0 c was added thf ( 35.5 ml , 0.404 mol ) dropwise . to the resulting yellow solution the ice bath was removed and the mixture was allowed to stir for 15 min after which activated zn dust ( 9.83 g , 0.151 mol ) and pbcl2 ( 2.22 g , 7.98 mmol ) were added . the resulting mixture went through a series of color changes from brown to green to purple and finally to blue - green over the course of 10 min . to the resulting slurry was transferred a solution of ester 23 ( 1.16 g , 4.20 mmol ) and ch3chbr2 ( 6.02 ml , 67.2 mmol ) in ch2cl2 ( 20 ml ) via cannula . the reaction mixture was then heated to reflux for 2 h before it was cooled to 0 c . k2co3 ( aq . , 50 ml ) . the resulting mixture was stirred for 30 min , filtered and the filtrate was concentrated . flash chromatography ( 15:1 hexanes : ethyl acetate ) gave 24 as a colorless oil ( 0.949 g , 92% ) . rf 0.70 ( 5:1 hexanes : ethyl acetate ) ; [ ]d = + 23.0 ( c = 0.43 , thf ) ; h nmr ( 500 mhz , c6d6 )  7.52 ( d , j = 7.3 hz , 2h ) , 7.17 ( t , j = 7.3 hz , 2h ) , 7.12 ( t , j = 7.3 hz , 1h ) , 5.37 ( s , 1h ) , 4.22 ( d , j = 4.4 hz , 1h ) , 3.94 ( d , j = 9.8 hz , 1h ) , 3.65 ( dd , j = 10.7 , 6.4 hz , 1h ) , 3.60 ( d , j = 10.3 hz , 1h ) , 2.121.98 ( m , 2h ) , 1.61 ( s , 3h ) , 1.34 ( s , 3h ) ; c nmr ( 125 mhz , c6d6 )  148.5 , 138.5 , 128.8 , 128.1 , 126.6 , 102.3 , 92.9 , 77.1 , 75.7 , 69.6 , 24.0 , 19.9 , 15.3 ; ir ( neat ) 2921 , 2859 , 1673 , 1453 , 1378 , 1312 , 1150 , 1093 cm ; esi / ms ( m / z ) calcd for c15h18o3na 269.1 ( m+na ) , found 269.1 . ( 2r,4ar,6s,8as)-6-allyl-4a,6-dimethyl-2-phenyltetrahydropyrano[3,2-d]dioxin-7(6h)-one ( 26 ) . to a solution of 24 ( 0.576 g , 2.34 mmol ) in meoh ( 30 ml ) at 78 c the reaction mixture was slowly warmed up to 0 c , at which point sat . the mixure was extracted with ch2cl2 ( 3  15 ml ) and the combined organic extracts were dried ( na2so4 ) and concentrated . flash chromatography ( 3:1 hexanes : ethyl acetate ) provided a white solid ( 0.550 g , 80% ) which was used in the next transformaiton without additional purification . to a solution of the material obtained above in thf ( 30 ml ) was added nah ( 88.0 mg , 3.67 mmol ) , allyl bromide ( 0.800 ml , 9.19 mmol ) , and tbai ( 50.0 mg , 0.135 mmol ) . nh4cl ( aq . , 20 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  15 ml ) and the organic extracts were combined , dried ( na2so4 ) and concentrated . the resulting residue was passed through a short silica gel plug ( 5:1 hexanes : ethyl acetate ) and concentrated to give a colorless oil 25 which was taken into the subsequent transformation without additional purification . to the colorless oil obtained above in toluene ( 50 ml ) was added pyridine ( 7.40 ml , 91.6 mmol ) and ppts ( 2.76 g , 11.0 mmol ) . the resulting reaction mixture was heated to reflux for 16 h. the mixture was cooled to rt and the reaction was quenched with sat . nahco3 ( aq . , 30 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  20 ml ) and the combined organic extracts were dried ( na2so4 ) and concentrated . flash chromatography ( 5:1 hexanes : ethyl acetate ) provided 26 ( 0.409 g , 72% 2 steps ) . rf 0.70 ( 3:1 hexanes : ethyl acetate ) ; [ ]d = + 11.2 ( c = 0.43 , thf ) ; h nmr ( 500 mhz , c6d6 )  7.50 ( d , j = 7.3 hz , 2h ) , 7.20 ( t , j = 7.3 hz , 2h ) , 7.14 ( t , j = 7.3 hz , 1h ) , 5.77 ( dddd , j = 17.6 , 10.3 , 7.3 , 7.3 hz , 1h ) , 5.31 ( s , 1h ) , 5.03 ( d , j = 10.3 hz , 1h ) , 4.99 ( d , j = 17.6 hz , 1h ) , 3.85 ( d , j = 10.3 hz , 1h ) , 3.81 ( dd , j = 12.2 , 7.0 hz , 1h ) , 3.47 ( d , j = 10.3 hz , 1h ) , 2.61 ( dd , j = 18.6 , 6.8 hz , 1h ) , 2.41 ( dd , j = 18.6 , 11.7 hz , 1h ) , 2.30 ( dd , j = 13.2 , 7.5 hz , 1h ) , 2.14 ( dd , j = 13.7 , 7.5 hz , 1h ) , 1.25 ( s , 3h ) , 1.19 ( s , 3h ) ; c nmr ( 100 mhz , c6d6 )  208.8 , 138.1 , 133.0 , 128.9 , 128.2 , 126.5 , 119.1 , 101.8 , 83.8 , 76.3 , 68.3 , 46.4 , 39.4 , 26.5 , 17.1 ; ir ( neat ) 2982 , 2865 , 1716 , 1521 , 1456 , 1372 , 1143 , 1114 cm ; esi / ms ( m / z ) calcd for c18h22o4na 325.2 ( m+na ) , found 325.1 . summary of cosy spectrum for 26 proton at 5.77 ppm ( c-25 ) shows cross peaks with protons at 5.03 ppm ( c-26 ) , 4.99 ppm ( c-26 ) , 2.30 ppm ( c-24 ) and 2.14 ( c-24 ) . proton at 3.85 ppm ( c-18 ) shows cross peaks with proton at 3.47 ppm ( c-18 ) . proton at 3.81 ppm ( c-20 ) shows cross peaks with protons at 2.61 ppm ( c-21 ) and 2.41 ppm ( c-21 ) . proton at 2.61 ppm ( c-21 ) shows cross peaks with proton at 2.41 ppm ( c-21 ) . proton at 2.30 ppm ( c-24 ) shows cross peaks with proton at 2.14 ppm ( c-24 ) . summary of 1d noe spectrum for 26 irradiation at 1.25 ppm ( c-23 methyl ) resulted in enhancement at 1.19 ppm ( c-19 methyl ) and 2.30 ppm ( c-24 ) and 2.14 ppm ( c-24 ) . ( 2r,4ar,6s,7r,8as)-6-allyl-7-((4-methoxybenzyl)oxy)-4a,6-dimethyl-2-phenylhexahydropyrano[3,2-d]dioxine ( 27 ) . to a solution of 26 ( 378 mg , 1.25 mmol ) in meoh ( 25 ml ) at 0 c was added nabh4 ( 190 mg , 5.0 mmol ) . the reaction was quenched with acetone ( 10 ml ) after the reaction mixture had stirred for 2 . the solvent was then removed under reduced pressure and the residue was purified using flash chromatography ( 3:1 hexanes : ethyl acetate ) to give the corresponding alcohol as a colorless oil ( 382 mg , 100% ) . to a solution of the alcohol obtained above ( 382 mg , 1.25 mmol ) in thf ( 20 ml ) at 0 c was added nah ( 82.4 mg , 3.43 mmol ) , pmbbr ( 0.82 ml , 5.69 mmol ) , hmpa ( 0.220 ml , 1.15 mmol ) , and tbai ( 50 mg , 0.135 mmol ) . the reaction mixture was stirred at rt for 12 h before the reaction was quenched with sat . nh4cl ( aq . , 20 ml ) . the mixure was extracted with ch2cl2 ( 3  15 ml ) and the combined organic extracts were dried ( na2so4 ) and concentrated . flash chromatography ( 10:1 hexanes : ethyl acetate ) gave 27 as a colorless oil ( 442 mg , 83% ) . rf 0.55 ( 5:1 hexanes : ethyl acetate ) ; [ ]d = 32.8 ( c = 0.30 , thf ) ; h nmr ( 500 mhz , c6d6 )  7.64 ( d , j = 7.8 hz , 2h ) , 7.277.12 ( m , 5h ) , 6.82 ( d , j = 7.8 hz , 2h ) , 6.07 ( dddd , j = 17.1 , 9.8 , 7.3 , 7.3 hz , 1h ) , 5.39 ( s , 1h ) , 5.14 ( dd , j = 9.8 , 1.3 hz , 1h ) , 5.04 ( dd , j = 17.6 , 1.0 hz , 1h ) , 4.44 ( d , j = 11.2 hz , 1h ) , 4.24 ( d , j = 11.7 hz , 1h ) , 3.85 ( d , j = 9.7 hz , 1h ) , 3.44 ( dd , j = 11.2 , 4.4 hz , 1h ) , 3.40 ( d , j = 9.7 hz , 1h ) , 3.32 ( s , 3h ) , 3.23 ( dd , j = 12.7 , 3.4 hz , 1h ) , 2.46 ( dd , j = 13.7 , 6.4 hz , 1h ) , 2.33 ( dd , j = 14.2 , 7.8 hz , 1h ) , 2.18 ( ddd , j = 11.7 , 3.9 , 3.9 hz , 1h ) , 1.85 ( ddd , j = 11.7 , 11.7 , 11.7 hz , 1h ) , 1.53 ( s , 3h ) , 1.34 ( s , 3h ) ; c nmr ( 125 mhz , c6d6 )  159.7 , 138.7 , 135.0 , 130.8 , 129.3 , 129.3 , 128.8 , 128.2 , 126.7 , 117.4 , 114.0 , 102.7 , 80.6 , 78.6 , 77.7 , 76.9 , 71.5 , 70.3 , 68.9 , 54.7 , 46.6 , 26.8 , 23.3 , 19.1 ; ir ( neat ) 2947 , 2864 , 1611 , 1512 , 1461 , 1376 , 1247 , 1144 , 1086 cm ; esi / ms ( m / z ) calcd for c26h32o5na 447.2 ( m+na ) , found 447.2 . ( 2r,4ar,6s,7r,8as)-6-(but-3-en-1-yl)-7-((4-methoxybenzyl)oxy)-4a,6-dimethyl-2-phenylhexahydropyrano[3,2-d]dioxine ( 28 ) . to a solution of 27 ( 0.245 g , 0.578 mmol ) in thf ( 15 ml ) at 0 c was added bh3dms ( 0.87 ml of 2.0 m solution in thf , 1.7 mmol ) . after stirring for 2 h h2o ( 1.0 ml ) , naoh ( 2.0 ml of 3.0 m aq . the combined organic extracts were dried ( na2so4 ) and concentrated . to the product obtained above in ch2cl2 ( 15 ml ) was added 4 ms ( 0.60 g ) , nmo ( 0.680 g , 5.78 mmol ) , and tpap ( 5 mg , 14.2 mol ) . the resulting mixture was stirred at rt for 2 h and then concentrated . the residue was filtered through a short slica gel plug ( 5:1 hexanes : ethyl acetate ) to give the crude aldehyde . to a slurry of methyltriphenylphosphonium bromide ( 1.03 g , 2.88 mmol ) in thf ( 10 ml ) was added tbuok ( 2.9 ml of 1.0 m solution in thf , 2.9 mmol ) . after stirring at rt for 30 min , the resulting solution was transferred to a solution of the crude aldehyde from above in thf ( 10 ml ) . after 2 h the reaction was quenched with nh4cl ( aq . , 10 ml ) . flash chromatography ( 10:1 hexanes : ethyl acetate ) gave 28 as a colorless oil ( 0.154 g , 61% for 3 steps ) . rf 0.60 ( 5:1 hexanes : ethyl acetate ) ; [ ]d = 55.4 ( c = 0.37 , thf ) ; h nmr ( 500 mhz , c6d6 )  7.64 ( d , j = 7.3 hz , 2h ) , 7.22 ( t , j = 7.3 hz , 2h ) , 7.187.12 ( m , 3h ) , 6.81 ( d , j = 8.3 hz , 2h ) , 5.85 ( dddd , j = 17.1 , 10.2 , 6.8 , 6.3 hz , 1h ) , 5.42 ( s , 1h ) , 5.09 ( dd , j = 17.1 , 1.5 hz , 1h ) , 5.00 ( dd , j = 10.2 , 1.5 hz , 1h ) , 4.44 ( d , j = 11.2 hz , 1h ) , 4.20 ( d , j = 11.7 hz , 1h ) , 3.84 ( d , j = 9.8 hz , 1h ) , 3.39 ( d , j = 10.8 hz , 1h ) , 3.36 ( dd , j = 11.2 , 4.9 hz , 1h ) , 3.31 ( s , 3h ) , 3.24 ( dd , j = 12.2 , 3.4 hz , 1h ) , 2.242.12 ( m , 3h ) , 1.86 ( ddd , j = 11.7 , 11.7 , 11.7 hz , 1h ) , 1.81 ( ddd , j = 13.2 , 11.2 , 5.4 hz , 1h ) , 1.64 ( ddd , j = 13.7 , 11.2 , 5.4 hz , 1h ) , 1.53 ( s , 3h ) , 1.33 ( s , 3h ) ; c nmr ( 125 mhz , c6d6 )  160.2 , 140.0 , 139.2 , 131.1 , 129.9 , 129.3 , 128.7 , 127.2 , 114.6 , 114.5 , 103.2 , 81.3 , 79.5 , 77.9 , 77.5 , 70.7 , 69.3 , 55.2 , 42.1 , 28.3 , 27.1 , 23.5 , 19.6 ; ir ( neat ) 2943 , 2863 , 1639 , 1513 , 1460 , 1375 , 1248 , 1086 cm ; esi / ms ( m / z ) calcd for c27h34o5k 477.2 ( m+k ) , found 477.2 . ( 2r,4ar,6s,7r,8as)-7-((4-methoxybenzyl)oxy)-4a,6-dimethyl-6-(pent-4-en-1-yl)-2-phenylhexahydropyrano[3,2-d]dioxine ( 29 ) . to a solution of 28 ( 74.6 mg , 0.170 mmol ) in thf ( 5 ml ) at 0 c was added bh3dms ( 0.340 ml of 2.0 m solution in thf , 0.680 mmol ) . the reaction mixture was stirred for 2 before it was quenched with h2o ( 1.0 ml ) , naoh ( 1.0 ml of 3.0 m aq . the combined organic phase was dried ( na2so4 ) and concentrated . to the crude product obtained from above in ch2cl2 ( 10 ml ) was added 4 ms ( 0.20 g ) , nmo ( 0.200 g , 1.71 mmol ) , and tpap ( 2.0 mg , 5.7 mol ) . after stirring for 2 h the resulting residue was filtered through a short silica gel plug ( 5:1 hexanes : ethyl acetate ) to give the crude aldehyde . to a slurry of methyltriphenylphosphonium bromide ( 300 . mg , 0.840 mmol ) in thf ( 5 ml ) was added tbuok ( 0.84 ml of 1.0 m solution in thf , 0.84 mmol ) . after stirring at rt for 30 min , the solution was transferred to a solution of the crude aldehyde from above in thf ( 5 ml ) . the reaction mixture was stirred for an additional 2 h before the reaction was quenched with nh4cl ( aq . , 10 ml ) . flash chromatography ( 15:1 hexanes : ethyl acetate ) gave 29 as a colorless oil ( 42.1 mg , 55% for 3 steps ) . rf 0.60 ( 5:1 hexanes : ethyl acetate ) ; [ ]d = 24.2 ( c = 0.24 , thf ) ; h nmr ( 500 mhz , c6d6 )  7.66 ( d , j = 7.3 hz , 2h ) , 7.22 ( t , j = 7.3 hz , 2h ) , 7.207.12 ( m , 3h ) , 6.82 ( d , j = 8.8 hz , 2h ) , 5.83 ( dddd , j = 16.6 , 9.8 , 6.3 , 6.3 hz , 1h ) , 5.41 ( s , 1h ) , 5.08 ( dd , j = 17.1 , 1.5 hz , 1h ) , 5.02 ( d , j = 10.2 hz , 1h ) , 4.46 ( d , j = 11.7 hz , 1h ) , 4.20 ( d , j = 11.7 hz , 1h ) , 3.85 ( d , j = 9.8 hz , 1h ) , 3.40 ( d , j = 10.3 hz , 1h ) , 3.37 ( dd , j = 11.2 , 4.9 hz , 1h ) , 3.31 ( s , 3h ) , 3.25 ( dd , j = 12.2 , 3.4 hz , 1h ) , 2.20 ( ddd , j = 9.7 , 3.9 , 3.9 hz , 1h ) , 2.021.96 ( m , 3h ) , 1.88 ( ddd , j = 11.7 , 11.7 , 11.7 hz , 1h ) , 1.731.66 ( m , 1h ) , 1.55 ( s , 3h ) , 1.551.45 ( m , 3h ) , 1.35 ( s , 3h ) ; c nmr ( 125 mhz , c6d6 )  159.7 , 139.1 , 138.7 , 130.7 , 129.5 , 128.9 , 128.2 , 126.7 , 114.5 , 114.0 , 102.7 , 80.8 , 78.9 , 77.7 , 77.1 , 70.2 , 68.8 , 54.7 , 42.0 , 34.6 , 26.6 , 23.1 , 22.6 , 19.2 ; ir ( neat ) 2943 , 2864 , 1639 , 1513 , 1461 , 1375 , 1248 , 1086 cm ; esi / ms ( m / z ) calcd for c28h36o5na 475.3 ( m+na ) , found 475.2 . ( 2r,4ar,6s,7r,8as)-2-(4-methoxyphenyl)-4a,6-dimethyl-6-(pent-4-en-1-yl)hexahydropyrano[3,2-d]dioxin-7-ol ( 30 ) . to a solution of 29 ( 42.1 mg , 93.1 mol ) in meoh ( 5 ml ) at 0 c was added csa ( 6.5 mg , 28 mol ) . the reaction mixture was warmed to rt and stirred for 5 h before the reaction was quenched with sat . nahco3 ( aq . , 5 ml ) . the aqueous phase was extracted with ethyl acetate ( 3  5 ml ) . flash chromatography ( 3:1 hexanes : ethyl acetate ) gave the corresponding diol as a colorless oil ( 29.3 mg , 86% ) . to a solution of the diol obtained above in ch2cl2 ( 4.5 ml ) was added ph 7 buffer ( 0.5 ml ) and ddq ( 36.5 mg , 0.161 mmol ) . the reaction mixture was stirred at rt for 2 h before h2o ( 5 ml ) was added . the aqueous phase was extracted with ethyl acetate ( 3  5 ml ) and the combined organic extracts were dried ( na2so4 ) , and concentrated . flash chromatography ( 2:1 hexanes : ethyl acetate ) gave the corresponding triol as a colorless oil ( 18.9 mg , 96% ) . to a solution of the triol obtained from the procedure outlined in the previous paragraph in ch2cl2 ( 5 ml ) was added anisaldehyde dimethylacetal ( 19.8 l , 0.116 mmol ) and csa ( 9.0 mg , 39 mol ) . the reaction mixture was stirred at rt overnight before the reaction was quenched with nahco3 ( aq . , 5 ml ) . the aqueous phase was extracted with ethyl acetate ( 3  5 ml ) and the combined organic extracts were dried ( na2so4 ) , and concentrated . flash chromatography ( 3:1 hexanes : ethyl acetate ) gave 30 as a colorless oil ( 24.8 mg , 88% ) . rf 0.25 ( 3:1 hexanes : ethyl acetate ) ; [ ]d = 9.3 ( c = 0.15 , thf ) ; h nmr ( 500 mhz , c6d6 )  7.57 ( d , j = 8.3 hz , 2h ) , 6.83 ( d , j = 8.3 hz , 2h ) , 5.84 ( dddd , j = 17.1 , 10.3 , 6.8 , 6.8 hz , 1h ) , 5.42 ( s , 1h ) , 5.08 ( d , j = 17.6 hz , 1h ) , 5.02 ( d , j = 10.3 hz , 1h ) , 3.86 ( d , j = 9.8 hz , 1h ) , 3.42 ( d , j = 9.8 hz , 1h ) , 3.38 ( dd , j = 12.2 , 4.9 hz , 1h ) , 3.303.26 ( partially obscured m , 1h ) , 3.26 ( s , 3h ) , 2.052.00 ( m , 2h ) , 1.87 ( ddd , j = 11.2 , 4.4 , 4.4 hz , 1h ) , 1.80 ( ddd , j = 11.7 , 11.7 , 11.7 hz , 1h ) , 1.641.58 ( m , 2h ) , 1.51 ( s , 3h ) , 1.531.41 ( m , 2h ) , 1.15 ( s , 3h ) ; c nmr ( 125 mhz , c6d6 )  160.9 , 139.6 , 131.6 , 128.5 , 115.1 , 114.2 , 103.3 , 81.3 , 78.6 , 77.5 , 73.7 , 69.4 , 55.1 , 42.6 , 35.1 , 31.4 , 23.1 , 22.2 , 19.6 ; ir ( neat ) 3483 , 2943 , 2867 , 1615 , 1517 , 1465 , 1377 , 1250 , 1069 cm ; esi / ms ( m / z ) calcd for c21h30o5na 385.2 ( m+na ) , found 385.2 . ( 4ar,6s,7s,8ar)-6-allyl-7-hydroxy-7-methyltetrahydropyrano[3,2-d]dioxasilin-8(4h)-one ( 32 ) . to a solution of ( cocl)2 ( 0.53 ml , 6.2 mmol ) in ch2cl2 ( 40 ml ) at 78 c was added a solution of 31 ( 1.90 g , 4.08 mmol ) in ch2cl2 ( 10 ml ) via cannula . after stirring at 78 c for 45 min , et3n ( 2.28 ml , 16.4 mmol ) nh4cl ( aq . , 50 ml ) and allowed to warm to rt . the aqueous phase was extracted with ch2cl2 ( 3  50 ml ) and the combined organic extracts were dried ( na2so4 ) and concentrated . flash chromatography ( 20:1 hexanes : ethyl acetate ) provided the corresponding ketone ( 1.85 g , 98% ) as a colorless oil . to a solution of the ketone obtained from the protocol outlined in the previous paragraph ( 1.80 g , 4.17 mmol ) in 80 ml toluene at 90 c was added meli ( 18 ml of 1.6 m in diethyl ether , 29 mmol ) dropwise . after stirring the reaction mixture for 1 h at 90 c , nh4cl ( aq . , 50 ml ) and allowed to warm to rt . the aqueous phase was extracted with ch2cl2 ( 3  20 ml ) and the combined organic extracts were dried ( na2so4 ) and concentrated . flash chromatography ( 20:1 hexanes : ethyl acetate ) provided the corresponding tertiary alcohol ( 1.56 g , 84% ) as a colorless oil . to a solution of the tertiary alcohol from above ( 0.80 g , 1.67 mmol ) in ch2cl2 ( 27 ml ) was added ph 7 buffer ( 3 ml ) and ddq ( 0.76 g , 3.4 mmol ) . the reaction mixture was stirred at rt for 2 h before h2o ( 20 ml ) was added . the aqueous phase was extracted with ethyl acetate ( 3  15 ml ) and the combined organic extracts were dried ( na2so4 ) , and concentrated . flash chromatography ( 2:1 hexanes : ethyl acetate ) gave the corresponding diol as a colorless oil ( 0.57 g , 95% ) . to a solution of the diol from above ( 0.11 g , 0.31 mmol ) in a mixture of ch2cl2 ( 6 ml ) and dmso ( 3 ml ) were added et3n ( 0.21 ml , 1.65 mmol ) and so3py ( 0.24 g , 1.65 mmol ) . the reaction mixture was stirred for 3 h at rt before the reaction was quenched with h2o ( 10 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  5 ml ) and the combined organic extracts were dried ( na2so4 ) , and concentrated . flash chromatography ( 10:1 hexanes : ethyl acetate ) gave 32 as a colorless oil ( 0.10 g , 91% ) . rf 0.60 ( 5:1 hexanes : ethyl acetate ) ; [ ]d = 54.2 ( c = 0.57 , thf ) ; h nmr ( 500 mhz , cdcl3 )  5.72 ( dddd , j = 17.0 , 10.0 , 6.6 , 6.6 hz , 1h ) , 4.98 ( dd , j = 17.0 , 1.3 hz , 1h ) , 4.93 ( d , j = 10.0 hz , 1h ) , 4.56 ( d , j = 9.7 hz , 1h ) , 4.14 ( dd , j = 10.2 , 4.6 hz , 1h ) , 3.98 ( s , 1h ) , 3.89 ( dd , j = 10.1 , 10.1 hz , 1h ) , 3.34 ( ddd , j = 9.8 , 9.8 , 4.6 hz , 1h ) , 3.18 ( dd , j = 9.9 , 2.1 hz , 1h ) , 2.32 ( dd , j = 14.4 , 7.1 hz , 1h ) , 2.13 ( ddd , j = 16.1 , 9.8 , 6.4 hz , 1h ) , 1.22 ( s , 3h ) , 0.93 ( s , 9h ) , 0.87 ( s , 9h ) ; c nmr ( 125 mhz , cdcl3 )  206.4 , 134.8 , 117.2 , 85.9 , 78.4 , 77.9 , 77.7 , 66.9 , 32.9 , 27.4 , 27.1 , 22.8 , 20.2 , 19.9 ; ir ( neat ) 3482 , 2937 , 2863 , 1736 , 1473 , 1390 , 1162 , 1112 cm ; esi / ms ( m / z ) calcd for c18h32o5sina 379.2 ( m+na ) , found 379.2 . ( 4ar,6s,7r,8r,8as)-6-(3-hydroxypropyl)-7-methylhexahydropyrano[3,2-d]dioxasiline-7,8-diol ( 34 ) . to a solution of 32 ( 1.56 g , 4.38 mmol ) in ch2cl2 ( 40 ml ) at 0 c was added 2,6-lutidine ( 3.10 ml , 26.6 mmol ) and tmsotf ( 2.38 ml , 13.3 mmol ) . the reaction mixture was allowed to slowly warm up to rt over 2 h before it was quenched with h2o ( 20 ml ) . flash chromatography ( 20:1 hexanes : ethyl acetate)gave the tms ether as a colorless oil ( 1.90 g , 100% ) . to a solution of tms ether ( 1.90 g , 4.44 mmol ) in thf ( 40 ml ) at 78 c was added l - selectride ( 6.7 ml of 1.0 m solution in thf , 6.7 mmol ) . the reaction mixture was allowed to slowly warm to rt over 2 h before the reaction was quenched with sat . nh4cl ( aq . , 20 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  10 ml ) . the resulting residue was passed through a plug of silica gel ( 10:1 hexanes : ethyl acetate ) and concentrated giving a colorless oil that was used in the subsequente transformation without additional purification . to a solution of the colorless oil obtained from the above procedure in thf ( 15 ml ) at 0 c was added bh3dms ( 2.0 m solution in thf , 11 ml , 22 mmol ) . solution ) were added after 2 h. the reaction mixture was warmed to rt and stirred overnight . flash chromatography gave 34 as a colorless oil ( 1.17 g , 70% over 2 steps ) . rf 0.35 ( 1:1 hexanes : ethyl acetate ) ; [ ]d = 39.3 ( c = 0.29 , thf ) ; h nmr ( 500 mhz , cdcl3 )  4.10 ( dd , j = 9.5 , 4.6 hz , 1h ) , 3.78 ( dd , j = 9.3 , 2.7 hz , 1h ) , 3.73 ( dd , j = 10.2 , 10.2 hz , 1h ) , 3.713.63 ( m , 2h ) , 3.583.53 ( m , 2h ) , 3.43 ( d , j = 10.2 hz , 1h ) , 3.40 ( br s , 1h ) , 3.16 ( br s , 1h ) , 3.07 ( br s , 1h ) , 1.76 ( ddd , j = 14.2 , 7.1 , 7.1 hz , 1h ) , 1.711.62 ( m , 1h ) , 1.601.50 ( m , 1h ) , 1.291.21 ( m , 1h ) , 1.08 ( s , 3h ) , 0.98 ( s , 9h ) , 0.95 ( s , 9h ) ; c nmr ( 125 mhz , cdcl3 )  78.9 , 75.8 , 74.3 , 71.8 , 70.9 , 67.0 , 62.5 , 30.1 , 27.6 , 27.4 , 24.6 , 22.9 , 20.4 , 18.8 ; ir ( neat ) 3414 , 2936 , 2893 , 2862 , 1472 , 1393 , 1157 , 1102 cm ; esi / ms ( m / z ) calcd for c18h36o6sina 399.2 ( m+na ) , found 399.3 . ( 2r,3r,4r,5s,6s)-4,5-bis(benzyloxy)-6-(3-(benzyloxy)propyl)-2-(hydroxymethyl)-5-methyltetrahydro-2h - pyran-3-ol ( 35 ) . to a solution of 34 ( 1.17 g , 3.11 mmol ) in thf ( 40 ml ) was added kh ( 3.0 g of 30% dispersion in mineral oil , 22 mmol ) . the mixture was stirred at rt for 30 min and then cooled to 0 c . to the resulting mixture the reaction mixture was warmed to rt and stirred overnight before the reaction was quenched with sat . nh4cl ( aq . , 20 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  20 ml ) . the combined organic extracts were dried ( na2so4 ) and concentrated to give a yellow oil which was taken to the next step without additional purification . to the residue from above in thf ( 20 ml ) at 0 c was added hfpy ( 1.0 ml , 55 mmol ) . the resulting reaction mixture was allowed to warm up to rt overnight . nahco3 ( aq . , 20 ml ) and the aqueous phase was extracted with ethyl acetate ( 3  20 ml ) . flash chromatography ( 1:1 hexanes : ethyl acetate ) provided diol 35 ( 0.98 g , 61% over 2 steps ) as a colorless oil . rf 0.40 ( 1:1 hexanes : ethyl acetate ) ; [ ]d = 31.4 ( c = 0.18 , thf ) ; h nmr ( 500 mhz , cdcl3 )  7.507.35 ( m , 15h ) , 5.02 ( d , j = 11.2 hz , 1h ) , 4.80 ( d , j = 11.2 hz , 1h ) , 4.72 ( d , j = 11.5 hz , 1h ) , 4.66 ( d , j = 11.5 hz , 1h ) , 4.62 ( s , 2h ) , 4.08 ( d , j = 3.9 hz , 1h ) , 3.98 ( d , j = 10.2 hz , 1h ) , 3.95 ( partially obscured br d , j = 14.6 hz , 1h ) , 3.883.76 ( m , 2h ) , 3.70 ( ddd , j = 10.0 , 3.4 , 3.4 hz , 1h ) , 3.663.62 ( m , 2h ) , 3.143.04 ( m , 2h ) , 2.101.98 ( m , 2h ) , 1.901.78 ( m , 1h ) , 1.601.48 ( m , 1h ) , 1.38 ( s , 3h ) ; c nmr ( 125 mhz , cdcl3 )  139.2 , 139.1 , 139.0 , 128.8 , 128.7 , 128.0 , 127.9 , 127.8 , 127.7 , 127.3 , 81.2 , 78.1 , 76.9 , 76.8 , 75.4 , 73.1 , 70.8 , 68.0 , 63.9 , 63.2 , 27.3 , 25.3 , 16.6 ; ir ( neat ) 3421 , 2930 , 2874 , 1496 , 1454 , 1380 , 1210 , 1106 cm ; esi / ms ( m / z ) calcd for c31h38o6na 529.3 ( m+na ) , found 529.3 . ( 2r,3r,4r,5s,6s)-4,5-bis(benzyloxy)-6-(3-(benzyloxy)propyl)-5-methyl-2-(prop-2-yn-1-yl)tetrahydro-2h - pyran-3-ol ( 37 ) . to a solution of 35 ( 0.57 g , 1.13 mmol ) and 2,6-lutidine ( 0.495 ml , 4.25 mmol ) in ch2cl2 ( 20 ml ) at 78 c was added trifluoromethanesulfonic anhydride ( 0.192 ml , 0.114 mmol ) . after stirring for 30 min tesotf ( 0.288 ml , 0.127 mmol ) was added to the reaction mixture . after warming to rt nahco3 ( aq . , 10 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  10 ml ) . the combined organic extracts were dried ( na2so4 ) and concentrated to give a yellow oil . the oil was passed through a short plug of silica gel ( 10:1 hexanes : ethyl acetate ) and concentrated to give triflate 36 . to a solution of trimethylsilylacetylene ( 0.690 ml , 4.88 mmol ) in thf ( 20 ml ) at 0 c was added nbuli ( 1.94 ml of 2.5 m solution in hexanes , 4.85 mmol ) . the reaction mixture was stirred for 30 min and then cooled to 78 c . to the resulting solution of acetylide was added a solution of 36 and hmpa ( 0.900 ml , 5.17 mmol ) in thf ( 10 ml ) via cannula . nh4cl ( aq . , 10 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  10 ml ) . the combined organic extracts were dried ( na2so4 ) and concentrated to give a dark brown oil which was taken up in thf ( 15 ml ) . to the solution was added tbaf ( 4.90 ml of 1.0 m solution in thf , 4.90 mmol ) and the mixture was stirred at rt overnight before it was quenched with sat . nh4cl ( aq . , 10 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  10 ml ) . flash chromatography ( 4:1 hexanes : ethyl acetate ) gave 37 as a colorless oil ( 0.34 g , 59% over 3 steps ) . rf 0.20 ( 4:1 hexanes : ethyl acetate ) ; [ ]d = 21.6 ( c = 0.45 , thf ) ; h nmr ( 500 mhz , cdcl3 )  7.427.27 ( m , 15h ) , 5.01 ( d , j = 11.0 hz , 1h ) , 4.72 ( d , j = 11.5 hz , 1h ) , 4.65 ( d , j = 11.5 hz , 1h ) , 4.56 ( s , 2h ) , 4.54 ( d , j = 11.5 hz , 1h ) , 4.02 ( d , j = 1.7 hz , 1h ) , 3.85 ( d , j = 9.8 hz , 1h ) , 3.643.58 ( m , 4h ) , 2.67 ( ddd , j = 17.1 , 2.4 , 2.4 hz , 1h ) , 2.47 ( ddd , j = 17.1 , 5.9 , 2.7 hz , 1h ) , 2.302.23 ( m , 1h ) , 2.01 ( t , j = 2.7 hz , 1h ) , 2.001.90 ( m , 2h ) , 1.811.70 ( m , 1h ) , 1.501.40 ( m , 1h ) , 1.34 ( s , 3h ) ; c nmr ( 125 mhz , cdcl3 )  139.1 , 138.9 , 138.7 , 128.8 , 128.6 , 128.5 , 128.2 , 128.0 , 127.8 , 127.6 , 127.5 , 127.1 , 81.3 , 81.2 , 78.3 , 77.0 , 75.5 , 75.2 , 73.0 , 70.8 , 69.9 , 64.0 , 27.1 , 25.1 , 22.4 , 16.2 ; ir ( neat ) 3420 , 2928 , 2873 , 2119 , 1606 , 1496 , 1454 , 1378 , 1209 , 1104 cm ; esi / ms ( m / z ) calcd for c33h38o5k 553.3 ( m+k ) , found 553.2 . ( ( ( 2r,3r,4r,5s,6s)-2-allyl-4,5-bis(benzyloxy)-6-(3-(benzyloxy)propyl)-5-methyltetrahydro-2h - pyran-3-yl)oxy)triethylsilane ( 38 ) . to a solution of 37 ( 600 mg , 1.17 mmol ) in ch2cl2 ( 20 ml ) at 0 c was added 2,6-lutidine ( 0.272 ml , 2.34 mmol ) and tesotf ( 0.343 ml , 1.52 mmol ) . the reaction mixture was allowed to slowly warm to rt over 3 h before the reaction was quenched with sat . nahco3 ( aq . , 10 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  10 ml ) and the combined organic extracts were dried ( na2so4 ) and concentrated . flash chromatography ( 5:1 hexanes : ethyl acetate ) provided the corresponding tes ether ( 732 mg , 100% ) as a colorless oil . to a solution of the tes ether obtained from above in ethyl acetate ( 30 ml ) was added quinoline ( 70 l , 0.59 mmol ) and lindlar s pd catalyst ( 50 mg ) . the reaction mixture was stirred h2 ( 1 atm ) for 2 h before being passed through a celite plug using ethyl acetate . the filtrate was concentrated and flash chromatography ( 10:1 hexanes : ethyl acetate ) gave 38 as a colorless oil ( 638 mg , 87% ) . rf 0.50 ( 15:2 hexanes : ethyl acetate ) ; [ ]d = + 1.2 ( c = 0.45 , thf ) ; h nmr ( 500 mhz , c6d6 )  7.44 ( d , j = 7.3 hz , 2h ) , 7.33 ( d , j = 7.3 hz , 2h ) , 7.28 ( d , j = 7.3 hz , 2h ) , 7.207.04 ( m , 9h ) , 6.08 ( dddd , j = 17.1 , 11.2 , 6.8 , 6.8 hz , 1h ) , 5.19 ( dd , j = 17.1 , 1.9 hz , 1h ) , 5.11 ( d , j = 6.8 hz , 1h ) , 5.08 ( dd , j = 8.8 , 1.9 hz , 1h ) , 4.68 ( d , j = 11.2 hz , 1h ) , 4.42 ( d , j = 10.7 hz , 1h ) , 4.38 ( d , j = 11.3 hz , 1h ) , 4.29 ( s , 2h ) , 4.054.00 ( m , 2h ) , 3.82 ( d , j = 2.4 hz , 1h ) , 3.61 ( dd , j = 9.3 , 2.0 hz , 1h ) , 3.393.31 ( m , 2h ) , 2.68 ( dd , j = 13.2 , 6.8 hz , 1h ) , 2.24 ( ddd , j = 15.6 , 7.8 , 7.8 hz , 1h ) , 2.061.95 ( m , 2h ) , 1.701.60 ( m , 1h ) , 1.561.48 ( m , 1h ) , 1.19 ( s , 3h ) , 1.00 ( t , j = 7.8 hz , 9h ) , 0.64 ( q , j = 7.8 hz , 6h ) , 0.30 ( s , 3h ) ; c nmr ( 125 mhz , c6d6 )  140.3 , 140.1 , 139.9 , 136.2 , 128.9 , 128.8 , 128.8 , 128.0 , 127.9 , 127.8 , 127.8 , 127.7 , 117.0 , 83.0 , 78.0 , 77.7 , 76.4 , 76.0 , 74.7 , 73.1 , 71.1 , 63.9 , 37.3 , 27.7 , 26.0 , 17.7 , 7.7 , 5.9 ; ir ( neat ) 2955 , 2876 , 1454 , 1379 , 1239 , 1107 , 1027 cm ; esi / ms ( m / z ) calcd for c39h54o5sina 653.4 ( m+na ) , found 653.4 . 2-((2r,3r,4r,5s,6s)-4,5-bis(benzyloxy)-6-(3-(benzyloxy)propyl)-5-methyl-3-((triethylsilyl)oxy)tetrahydro-2h - pyran-2-yl)acetic acid ( 38 ) . o3 was bubbled through a solution of 38 ( 638 mg , 1.01 mmol ) in ch2cl2 ( 60 ml ) at 78 c until the reaction mixture remained light blue in color . the excess o3 was purged from the reaction mixture by bubbling n2 through it until the light blue color completely dissipated ( ca . triphenylphosphine ( 1.33 g , 5.08 mmol ) was then added and the mixture was allowed to slowly warm to rt . flash chromatography ( 50:1 to 5:1 hexanes : ethyl acetate ) provided the aldehyde ( 600 . mg , 0.949 mmol ) in thf ( 10 ml ) at 0 c was added tbuoh ( 10 ml ) , h2o ( 10 ml ) , 2-me-2-butene ( 2.0 ml ) , nah2po4 ( 570 mg , 0.475 mmol ) and naclo2 ( 430 mg , 0.48 mmol ) . the resulting mixture was extracted with ethyl acetate ( 3  15 ml ) and the organic extracts were combined , dried ( na2so4 ) and concentrated . flash chromatography ( 1:1 hexanes : ethyl acetate to ethyl acetate ) provided acid 39 ( 615 mg , 100% ) as a colorless oil . rf 0.50 ( 2:1 hexanes : ethyl acetate ) ; [ ]d = 9.4 ( c = 0.27 , thf ) ; h nmr ( 500 mhz , c6d6 )  11.7 ( br s , 1h ) , 7.44 ( d , j = 7.8 hz , 2h ) , 7.32 ( d , j = 7.8 hz , 2h ) , 7.29 ( d , j = 7.4 hz , 2h ) , 7.197.03 ( m , 9h ) , 5.09 ( d , j = 11.2 hz , 1h ) , 4.65 ( d , j = 11.2 hz , 1h ) , 4.52 ( ddd , j = 8.8 , 8.8 , 3.4 hz , 1h ) , 4.41 ( d , j = 11.2 hz , 1h ) , 4.37 ( d , j = 11.2 hz , 1h ) , 4.31 ( s , 2h ) , 4.11 ( d , j = 10.7 hz , 1h ) , 3.82 ( d , j = 2.0 hz , 1h ) , 3.73 ( dd , j = 9.2 , 2.0 hz , 1h ) , 3.403.32 ( m , 2h ) , 2.86 ( dd , j = 15.4 , 3.2 hz , 1h ) , 2.54 ( dd , j = 15.4 , 9.0 hz , 1h ) , 2.021.92 ( m , 2h ) , 1.721.62 ( m , 1h ) , 1.50 ( ddd , j = 9.3 , 9.3 , 9.3 hz , 1h ) , 1.16 ( s , 3h ) , 0.96 ( t , j = 7.8 hz , 9h ) , 0.58 ( q , j = 7.8 hz , 6h ) ; c nmr ( 125 mhz , c6d6 )  178.3 , 140.1 , 140.0 , 139.9 , 128.9 , 128.8 , 128.8 , 128.1 , 127.9 , 127.8 , 127.8 , 127.7 , 82.8 , 78.0 , 77.9 , 76.0 , 73.8 , 73.8 , 73.0 , 70.8 , 63.9 , 38.2 , 27.4 , 25.7 , 17.6 , 7.6 , 5.7 ; ir ( neat ) 3330 , 2956 , 2877 , 1713 , 1454 , 1241 , 1111 cm ; esi / ms ( m / z ) calcd for c38h52o7sina 671.4 ( m+na ) , found 671.3 . ( 2r,4ar,6s,7r,8as)-2-(4-methoxyphenyl)-4a,6-dimethyl-6-(pent-4-en-1-yl)hexahydropyrano[3,2-d]dioxin-7-yl 2-((2r,3r,4r,5s,6s)-4,5-bis(benzyloxy)-6-(3-(benzyloxy)propyl)-5-methyl-3-((triethylsilyl)oxy)tetrahydro-2h - pyran-2-yl)acetate ( 40 ) . to a solution of acid 39 ( 53.4 mg , 82.2 mol ) in thf ( 8 ml ) was added triethylamine ( 0.100 ml , 0.719 mmol ) and 2,4,6-trichlorobenzoyl chloride ( 77.0 l , 0.493 mmol ) . the reaction mixture was heated at 40 c for 2 h before the solvent was removed in vacuo . to the resulting residue was transfered a solution of alcohol 30 ( 24.8 mg , 68.5 mol ) in toluene ( 8 ml ) followed by dmap ( 0.100 g , 0.820 mmol ) . the resulting reaction mixture was heated at 40 c for 2 h and then the reaction was quenched with sat . nahco3 ( aq . , 10 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  10 ml ) , the organic extracts were combined , dried ( na2so4 ) and concentrated . flash chromatography ( 10:1 hexanes : ethyl acetate ) provided ester 40 ( 57.4 mg , 84% ) as a colorless oil . rf 0.70 ( 4:1 hexanes : ethyl acetate ) ; [ ]d = 26.2 ( c = 0.29 , thf ) ; h nmr ( 500 mhz , c6d6 )  7.55 ( d , j = 8.8 hz , 2h ) , 7.44 ( d , j = 7.3 hz , 2h ) , 7.35 ( d , j = 7.3 hz , 2h ) , 7.29 ( d , j = 7.8 hz , 2h ) , 7.207.05 ( m , 9h ) , 6.82 ( d , j = 8.3 hz , 2h ) , 5.84 ( dddd , j = 17.1 , 10.3 , 6.8 , 6.8 hz , 1h ) , 5.32 ( s , 1h ) , 5.22 ( dd , j = 11.2 , 4.9 hz , 1h ) , 5.11 ( d , j = 11.2 hz , 1h ) , 5.08 ( dd , j = 15.6 , 1.5 hz , 1h ) , 5.02 ( dd , j = 10.3 , 1.0 hz , 1h ) , 4.68 ( d , j = 11.2 hz , 1h ) , 4.49 ( ddd , j = 10.3 , 7.3 , 3.4 hz , 1h ) , 4.43 ( d , j = 11.2 hz , 1h ) , 4.38 ( d , j = 11.2 hz , 1h ) , 4.33 ( s , 2h ) , 4.13 ( d , j = 9.8 hz , 1h ) , 3.99 ( dd , j = 9.8 , 2.0 hz , 1h ) , 3.88 ( d , j = 2.0 hz , 1h ) , 3.80 ( d , j = 9.8 hz , 1h ) , 3.423.34 ( m , 3h ) , 3.27 ( s , 3h ) , 3.283.24 ( partially obscured m , 1h ) , 2.86 ( dd , j = 14.7 , 3.4 hz , 1h ) , 2.62 ( dd , j = 14.7 , 7.3 hz , 1h ) , 2.29 ( ddd , j = 11.2 , 4.4 , 3.9 hz , 1h ) , 2.081.96 ( m , 5h ) , 1.801.55 ( m , 6h ) , 1.49 ( s , 3h ) , 1.30 ( s , 3h ) , 1.22 ( s , 3h ) , 1.00 ( t , j = 8.3 hz , 9h ) , 0.67 ( q , j = 7.8 hz , 3h ) , 0.66 ( q , j = 8.3 hz , 3h ) ; c nmr ( 125 mhz , c6d6 )  170.7 , 160.8 , 140.2 , 140.0 , 139.8 , 139.5 , 131.6 , 128.9 , 128.8 , 128.8 , 128.5 , 128.0 , 127.9 , 127.9 , 127.9 , 127.8 , 127.7 , 115.1 , 114.1 , 103.1 , 82.6 , 80.5 , 78.1 , 78.0 , 77.3 , 77.1 , 76.0 , 74.3 , 74.0 , 73.2 , 73.0 , 71.0 , 69.5 , 63.9 , 55.1 , 42.4 , 37.8 , 34.9 , 30.5 , 28.2 , 27.8 , 26.1 , 23.6 , 23.0 , 19.5 , 17.6 , 7.6 , 5.8 ; ir ( neat ) 2954 , 2876 , 1741 , 1496 , 1379 , 1249 , 1106 cm ; esi / ms ( m / z ) calcd for c59h80o11sina 1015.6 ( m+na ) , found 1015.5 . ( 2r,3r,4r,5s,6s)-4,5-bis(benzyloxy)-6-(3-(benzyloxy)propyl)-2-(((2r,4ar,5as,11ar,12as , z)-2-(4-methoxyphenyl)-4a,5a - dimethyl-4a,5a,6,7,8,11a,12,12a - octahydro-4h - dioxino[4,5:5,6]pyrano[3,2-b]oxocin-10-yl)methyl)-5-methyltetrahydro-2h - pyran-3-ol ( 41 ) . to a solution of ticl4 ( 0.230 ml , 2.09 mmol ) in ch2cl2 ( 13 ml ) at 0 c was added thf ( 1.10 ml , 12.5 mmol ) dropwise . tmeda ( 1.90 ml , 12.5 mmol ) was added dropwise to the resulting yellow solution . activated zn dust ( 304 mg , 4.68 mmol ) and pbcl2 ( 69.0 mg , 0.248 mmol ) were added after the red - brown reaction mixture had stirred for 15 min . the resulting slurry went through a series of color changes from brown to green to purple and finally to blue - green over the course of 35 min . a solution of ester 40 ( 32.3 mg , 32.5 mol ) and ch3chbr2 ( 0.190 ml , 2.12 mmol ) in ch2cl2 ( 3 ml ) was transferred to the reaction mixture via cannula . the reaction mixture was then heated to reflux for 2 h before it was cooled to 0 c and the reaction was quenched with sat . k2co3 ( aq . , 1.0 ml ) . after stirring for 30 min at 0 c the filtrate was concentrated and flash chromatography ( 10:1 hexanes : ethyl acetate ) gave 41 as a colorless oil ( 12.5 mg , 40% ) . rf 0.55 ( 5:1 hexanes : ethyl acetate ) ; [ ]d = 14.1 ( c = 0.28 , thf ) ; h nmr ( 500 mhz , c6d6 )  7.61 ( d , j = 8.8 hz , 2h ) , 7.50 ( d , j = 7.3 hz , 2h ) , 7.38 ( d , j = 7.3 hz , 2h ) , 7.30 ( d , j = 7.3 hz , 2h ) , 7.217.06 ( m , 9h ) , 6.83 ( d , j = 8.3 hz , 2h ) , 5.48 ( s , 1h ) , 5.16 ( d , j = 11.2 hz , 1h ) , 4.90 ( dd , j = 8.3 , 2.9 hz , 1h ) , 4.71 ( d , j = 11.2 hz , 1h ) , 4.47 ( d , j = 11.2 hz , 1h ) , 4.41 ( d , j = 11.2 hz , 1h ) , 4.31 ( s , 2h ) , 4.14 ( d , j = 9.8 hz , 1h ) , 3.98 ( dd , j = 9.8 , 4.9 hz , 1h ) , 3.89 ( d , j = 6.8 hz , 1h ) , 3.88 ( s , 1h ) , 3.69 ( dd , j = 9.8 , 2.2 hz , 1h ) , 3.48 ( d , j = 9.8 hz , 1h ) , 3.443.38 ( m , 2h ) , 3.27 ( s , 3h ) , 3.283.22 ( partially obscured m , 1h ) , 2.91 ( d , j = 14.6 hz , 1h ) , 2.301.97 ( m , 8h ) , 1.841.70 ( m , 2h ) , 1.691.56 ( m , 3h ) , 1.55 ( s , 3h ) , 1.36 ( s , 3h ) , 1.24 ( s , 3h ) , 1.01 ( t , j = 7.8 hz , 9h ) , 0.64 ( q , j = 7.8 hz , 6h ) ; c nmr ( 100 mhz , c6d6 )  160.8 , 155.7 , 140.3 , 140.1 , 140.0 , 131.8 , 128.9 , 128.8 , 128.5 , 128.0 , 127.9 , 127.9 , 127.8 , 127.7 , 114.1 , 108.1 , 103.2 , 84.0 , 83.1 , 81.3 , 78.5 , 78.0 , 77.9 , 77.8 , 76.1 , 74.9 , 74.5 , 73.1 , 71.1 , 69.4 , 63.9 , 55.1 , 46.3 , 40.2 , 33.6 , 31.0 , 30.5 , 28.5 , 27.8 , 25.9 , 28.5 , 27.8 , 25.9 , 22.4 , 22.1 , 19.8 , 17.8 , 7.6 , 5.8 ; ir ( neat ) 2928 , 2876 , 1615 , 1496 , 1378 , 1250 , 1108 cm ; esi / ms ( m / z ) calcd for c58h78o10sik 1001.6 ( m+k ) , found 1001.5 . to a solution of 41 ( 19.7 mg , 20.4 mol ) in ch2cl2 ( 5 ml ) at 78 c was added a solution of dimethyl dioxirane ( 0.42 ml of 0.10 m solution in ch2cl2 , 0.042 mmol ) dropwise . the reaction mixture was warmed to 0 c and the solvent was removed in vacuo . the residue was dissolved in ch2cl2 ( 5 ml ) and the reaction mixture was cooled to 78 c and a solution of i - bu2alh ( 0.21 ml of 1.0 m solution in thf , 0.21 mmol ) was added . after stirring for 2 h at 78 c , nh4cl ( aq . , 3 ml ) and allowed to warm to rt . a solution of saturated potassium sodium tartrate ( 10 ml ) was added and the mixture was stirred violently for 30 min . the aqueous phase was extracted with ch2cl2 ( 3  10 ml ) and the combined organic extracts were dried ( na2so4 ) and concentrated to give alcohol 43 . to a solution of the alcohol obtained from above in ch2cl2 ( 5 ml ) was added activated 4 ms ( 20 mg ) , nmo ( 25.0 mg , 0.213 mmol ) and tpap ( 1 mg , 0.003 mmol ) . flash chromatography ( 5:1 hexanes : ethyl acetate ) gave ketone 44 as a colorless oil ( 12.2 mg , 61% 2 steps ) . rf 0.55 ( 3:1 hexanes : ethyl acetate ) ; [ ]d = 20.2 ( c = 0.18 , thf ) ; h nmr ( 500 mhz , c6d6 )  7.58 ( d , j = 8.8 hz , 2h ) , 7.46 ( d , j = 7.3 hz , 2h ) , 7.36 ( d , j = 7.8 hz , 2h ) , 7.30 ( d , j = 7.8 hz , 2h ) , 7.217.06 ( m , 9h ) , 6.83 ( d , j = 8.3 hz , 2h ) , 5.36 ( s , 1h ) , 5.08 ( d , j = 11.2 hz , 1h ) , 4.70 ( d , j = 11.2 hz , 1h ) , 4.50 ( dd , j = 9.3 , 6.3 hz , 1h ) , 4.44 ( d , j = 11.2 hz , 1h ) , 4.40 ( d , j = 11.2 hz , 1h ) , 4.32 ( s , 2h ) , 4.12 ( ddd , j = 9.8 , 6.8 , 2.9 hz , 1h ) , 4.09 ( dd , j = 10.3 , 1.5 hz , 1h ) , 3.85 ( d , j = 2.0 hz , 1h ) , 3.81 ( d , j = 9.8 hz , 1h ) , 3.79 ( dd , j = 9.8 , 2.4 hz , 1h ) , 3.443.33 ( m , 4h ) , 3.27 ( s , 3h ) , 3.14 ( dd , j = 12.2 , 3.0 hz , 1h ) , 2.87 ( ddd , j = 14.2 , 7.8 , 4.9 hz , 1h ) , 2.312.06 ( m , 5h ) , 2.041.94 ( m , 3h ) , 1.841.70 ( m , 2h ) , 1.641.54 ( m , 3h ) , 1.52 ( s , 3h ) , 1.34 ( s , 3h ) , 1.24 ( s , 3h ) , 1.03 ( t , j = 7.8 hz , 9h ) , 0.69 ( q , j = 7.8 hz , 6h ) ; c nmr ( 100 mhz , c6d6 )  213.9 , 160.9 , 140.2 , 140.1 , 139.9 , 131.6 , 128.9 , 128.8 , 128.5 , 128.0 , 127.9 , 127.9 , 127.8 , 127.7 , 114.1 , 103.1 , 85.4 , 83.3 , 82.9 , 81.4 , 78.0 , 77.9 , 77.4 , 76.0 , 73.9 , 73.2 , 73.2 , 71.1 , 69.7 , 63.9 , 55.1 , 44.0 , 40.2 , 35.4 , 28.9 , 27.8 , 26.0 , 21.5 , 21.1 , 20.2 , 17.6 , 7.6 , 5.9 ; ir ( neat ) 2934 , 2876 , 1704 , 1616 , 1496 , 1378 , 1249 , 1105 cm ; esi / ms ( m / z ) calcd for c58h78o11sik 1017.6 ( m+k ) , found 1017.5 . summary of cosy spectrum for 44 proton at 4.50 ppm ( c-28 ) shows cross peaks with proton at 2.28 ppm ( c-29 ) . proton at 4.12 ppm ( c-30 ) shows cross peaks with proton at 3.79 ppm ( c-31 ) . proton at 4.09 ppm ( c-34 ) shows cross peaks with protons at 1.62 ppm ( c-35 ) . proton at 3.81 ppm ( c-18 ) shows cross peaks with proton at 3.40 ppm ( c-18 ) . proton at 2.06 ppm ( c-21 ) shows cross peaks with proton at 3.36 ppm ( c-22 ) and 3.14 ( c-20 ) . summary of 1d noe spectrum for 44 irradiation at 4.50 ppm ( c-28 ) resulted in enhancement at 3.36 ppm ( c-22 ) . irradiation at 3.14 ppm ( c-20 ) resulted in enhancement at 5.36 ppm ( c - a ) , 3.40 ppm ( c-18 ) , and 3.36 ppm ( c-22 ) . to a solution of 44 ( 5.0 mg , 5.1 mol ) in thf ( 4 ml ) at 78 c was added lihmds ( 0.102 ml of 1.0 m solution in thf , 0.10 mmol ) . after 10 min , mei ( 16 l , 0.254 mmol ) was added and the reaction mixture was allowed to slowly warm up to 22 c before the reaction was quenched with nh4cl ( aq . , 5 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  5 ml ) and the combined organic extracts were dried ( na2so4 ) and concentrated . flash chromatography ( 5:1 hexanes : ethyl acetate ) provided 45 ( 4.7 mg , 93% ) as a colorless oil . [ a]d = 22.3 ( c = 0.14 , thf ) ; h nmr ( 400 mhz , cd2cl2 )  7.36 ( d , j = 8.8 hz , 2h ) , 7.327.19 ( m , 15h ) , 6.87 ( d , j = 8.3 hz , 2h ) , 5.44 ( s , 1h ) , 4.96 ( d , j = 10.7 hz , 1h ) , 4.58 ( d , j = 11.2 hz , 1h ) , 4.54 ( d , j = 11.2 hz , 1h ) , 4.48 ( d , j = 11.2 hz , 1h ) , 4.46 ( s , 2h ) , 4.32 ( dd , j = 9.8 , 5.9 hz , 1h ) , 3.85 ( d , j = 1.5 hz , 1h ) , 3.79 ( s , 3h ) , 3.74 ( d , j = 9.8 hz , 1h ) , 3.683.52 ( m , 3h ) , 3.523.40 ( m , 5h ) , 2.99 ( ddd , j = 7.8 , 7.8 , 7.8 hz , 1h ) , 2.602.49 ( m , 1h ) , 2.352.19 ( m , 2h ) , 2.13 ( ddd , j = 11.7 , 3.9 , 3.9 hz , 1h ) , 1.951.50 ( m , 8h ) , 1.50 ( s , 3h ) , 1.36 ( s , 3h ) , 1.28 ( s , 3h ) , 1.20 ( d , j = 7.3 hz , 3h ) , 1.03 ( t , j = 7.8 hz , 9h ) , 0.71 ( q , j = 7.8 hz , 6h ) ; c nmr ( 100 mhz , c6d6 )  214.2 , 160.4 , 139.6 , 139.5 , 131.1 , 128.4 , 128.3 , 128.0 , 127.5 , 127.4 , 127.3 , 127.2 , 113.6 , 102.6 , 85.4 , 83.5 , 82.4 , 80.5 , 77.4 , 77.4 , 77.0 , 76.9 , 75.5 , 74.8 , 73.1 , 72.6 , 70.5 , 69.2 , 63.4 , 57.6 , 54.6 , 49.9 , 44.7 , 35.8 , 30.0 , 29.2 , 28.4 , 27.3 , 25.5 , 21.6 , 21.3 , 19.4 , 17.2 , 7.1 , 5.3 ; ir ( neat ) 2956 , 2876 , 1718 , 1616 , 1496 , 1377 , 1249 , 1104 cm ; esi / ms ( m / z ) calcd for c59h80o11sina 1015.6 ( m+na ) , found 1015.5 . ( 2s,3r,4as,7s,7ar,8ar,9r,10s,11s,12ar,13as,14ar)-9,10-bis(benzyloxy)-11-(3-(benzyloxy)propyl)-3-(hydroxymethyl)-3,4a,7,10-tetramethylhexadecahydropyrano[3,2-b]pyrano[2,3:5,6]pyrano[2,3-g]oxocin-2-ol ( 4 ) . to a solution of 45 ( 4.7 mg , 4.7 mol ) in ch2cl2 ( 3 ml ) at 78 c were added et3sih ( 76 l , 0.47 mmol ) and tmsotf ( 8.6 l , 47.0 mol ) . after stirring for 1 h , the reaction mixture was slowly warmed to 50 c , at which temperature the reaction was quenched with nahco3 ( aq . , 5 ml ) . the aqueous phase was extracted with ch2cl2 ( 3  5 ml ) and the combined organic extracts were dried ( na2so4 ) and concentrated . flash chromatography ( 2:1 hexanes : ethyl acetate ) provided 4 ( 2.8 mg , 80% ) as a colorless oil . rf 0.45 ( 1:1 hexanes : ethyl acetate ) ; [ ]d = 1.1 ( c = 0.05 , thf ) ; h nmr ( 500 mhz , cd2cl2 )  7.407.20 ( m , 15h ) , 4.96 ( d , j = 11.2 hz , 1h ) , 4.56 ( d , j = 11.2 hz , 1h ) , 4.45 ( d , j = 11.2 hz , 1h ) , 4.43 ( s , 2h ) , 4.40 ( d , j = 11.2 hz , 1h ) , 4.04 ( d , j = 2.0 hz , 1h ) , 3.82 ( br d , j = 11.7 hz , 1h ) , 3.713.64 ( m , 2h ) , 3.493.46 ( m , 2h ) , 3.413.35 ( m , 2h ) , 3.29 ( d , j = 10.7 hz , 1h ) , 3.22 ( ddd , j = 11.7 , 8.8 , 4.4 hz , 1h ) , 3.12 ( dd , j = 9.8 , 2.0 hz , 1h ) , 2.76 ( dd , j = 9.3 , 9.3 hz , 1h ) , 2.30 ( ddd , j = 11.2 , 4.4 , 4.4 hz , 1h ) , 2.062.00 ( m , 2h ) , 1.96 ( ddd , j = 10.7 , 4.4 , 4.4 hz , 1h ) , 1.951.35 ( m , 11h ) , 1.28 ( s , 3h ) , 1.22 ( s , 3h ) , 1.14 ( s , 3h ) , 1.08 ( d , j = 6.8 hz , 3h ) ; c nmr ( 100 mhz , c6d6 )  140.1 , 128.9 , 128.8 , 128.0 , 127.9 , 127.8 , 127.7 , 88.1 , 86.2 , 83.8 , 80.8 , 78.8 , 78.7 , 77.7 , 77.2 , 76.6 , 75.0 , 73.2 , 71.1 , 71.0 , 69.1 , 68.7 , 63.8 , 46.3 , 40.7 , 40.0 , 33.9 , 32.1 , 30.5 , 27.9 , 26.0 , 22.7 , 20.3 , 18.8 , 17.9 ; ir ( neat ) 3500 , 3028 , 2925 , 1599 , 1494 , 1451 , 1264 , 1077 cm ; esi / ms ( m / z ) calcd for c45h60o9k 783.4 ( m+k ) , found 783.3 . summary of cosy spectrum for 4 proton at 4.04 ppm ( c-32 ) shows cross peaks with proton at 3.12 ppm ( c-31 ) . proton at 3.12 ppm ( c-31 ) shows cross peaks with proton at 3.66 ppm ( c-30 ) . proton at 1.08 ppm ( c-26 methyl ) shows cross peaks with protons at 1.70 ppm ( c-26 ) . proton at 1.70 ppm ( c-26 ) shows cross peaks with proton at 2.76 ppm ( c-27 ) . proton at 2.76 ppm ( c-27 ) shows cross peaks with proton at 3.22 ppm ( c-28 ) . proton at 3.22 ppm ( c-28 ) shows cross peaks with protons at 2.30 ppm ( c-29 ) and 1.50 ppm ( c-29 ) . protons at 2.30 ppm ( c-29 ) and 1.50 ppm ( c-29 ) both show cross peaks with proton at 3.66 ppm ( c-30 ) . summary of 1d noe spectrum for 4 irradiation at 3.22 ppm ( c-28 ) resulted in enhancement at 3.66 ppm ( c-30 ) , 3.40 ppm ( c-22 ) , 2.30 ppm ( c-29 ) , and 1.70 ppm ( c-26 ) . irradiation at 2.76 ppm ( c-27 ) resulted in enhancement at 3.12 ppm ( c-31 ) , 1.50 ppm ( c-29 ) , and 1.08 ppm ( c-26 methyl ) .
yessotoxin and adriatoxin are members of the polycyclic ether family of marine natural products . outlined in this article 
 is our synthetic approach to two subunits of these targets . 
 central to our strategy is a coupling sequence that employs an olefinic - ester cyclization reaction . 
 as outlined , this sequence was used in two coupling sequences . 
 first it was used to merge the a , b- and e , f - bicyclic precursors and in the process generate the c , d - rings . 
 second it was used to couple the f- and i - rings while building the eight - membered g - ring and subsequently the h - ring pyran .