Brevetoxin b HO K H Meo Me、Ho H Me HoMe、Ho G H A B C D 0 M K C. Nicolaou. 1995
Brevetoxin B K. C. Nicolaou, 1995 O O O O O O O O O O O H O O Me H H H H H H Me H H H HO H Me H H Me Me H H H Me Me A B C D E F G H I J K
EF HH Brevetoxin B is a marine neurotoxin most commonly associated with red tides Annually responsible for the deaths of thousands of marine organisms The structure of this poison was identified in 1981 by Lin, Nakanishi, and Clardy The framework consists of a single carbon chain folded into eleven fused rings Twenty three stereocenters are present in the molecule
Introduction • Brevetoxin B is a marine neurotoxin most commonly associated with Red Tides – Annually responsible for the deaths of thousands of marine organisms • The structure of this poison was identified in 1981 by Lin, Nakanishi, and Clardy. • The framework consists of a single carbon chain folded into eleven fused rings. • Twenty three stereocenters are present in the molecule O O O O O O O O O O O H O O Me H H H H H H Me H H H HO H Me H H Me Me H H H Me Me A B C D E F G H I J K
Third generation Retrosynthetic approach TBSO 1: brevetoxin B 85 EFG
Third Generation Retrosynthetic Approach O O O O O O O O O O O O O Me H H H H H H Me H H H HO H Me H H Me Me H H H Me Me A B C D E F G H I J K 1: brevetoxin B O O O O O O O O O O OTPS Me H H H H H H Me H H H TBSO H Me H H Me Me EtS H Me Me A B C D E F G I J K EtS HO 85 O O O O O O O Me H H H H H H Me H Me H H Me Me Me A OTMS PPh3 O O O H H OTBS EtS H Me I EtS H H O J K OTPS + 87 86 B C D E F G
Retrosynthetic Approach Cont OTBS ☆一8 Me OTMS E FG PPh3 C TBSo、:CHo . OH OHOHOH 99: D-mannitol 79: D-mannose
Retrosynthetic Approach Cont. O O O O O O O Me H H H H H H Me H Me H H Me Me Me A OTMS PPh3 87 B C D E F G OH OH OH OH OH OH TBSO CHO Me PivO + 99: D-mannitol 97 O O O H H OTBS EtS H Me I EtS H H O J K OTPS 86 HO O OH OH HO OH 79: D-mannose
Total Synthesis Construction of Key Intermediates 86 and 87 Meo me Me OTMS H。MeH E FG AB C OTBS 87 EtS EtS OTPS H 86
Total Synthesis Construction of Key Intermediates 86 and 87 O O O O O O O Me H H H H H H Me H Me H H Me Me Me A OTMS PPh3 87 B C D E F G O O O H H OTBS EtS H Me I EtS H H O J K OTPS 86
Construction of intermediate 86 1. Ac2O(excess), pyr, 25C 2. allyltrimethylsilane, BF3 OEt2 1.m2C=s,PhcH3110°c TMSOTf, CH3CN,0C 2. n-Bu3SnH, AIBN(cat) 3. NaoMe,MeOH,25° 5% 4.4-BuPha SiCl imid. DMF0C 79. D-mannose en 2-methoxypropene CSA(cat ),0C (82%) 1. amberlyst-15(H") MeH,60°c(72%) DMF,1009(74%) OTPS AlMe3, MgBr2 OEt2 (COCl2, DMSO, H2Ch, 78C (61% Yield of 91 enEN.0°c OTPS (100%Yed) 114 1.03,CH2Ch2-780 2cH2 CHMgBr,TFH,0° DMF. 25.C (44% Yield) TPS 2 O3, CH2Cl2,-78C (ca. 1: 1 mixture of 3. Ph3P=CHCO2I (ca. 3: 1 mixture of 25 (78% overall
Construction of Intermediate 86 HO O OH OH HO OH 79: D-mannose O OH O O H OTPS 1. Ac2O (excess), pyr., 25 oC 2. allyltrimethylsilane, BF3 OEt2 , TMSOTf, CH3CN, 0 oC 3. NaOMe, MeOH, 25 oC (75% overall) 4. t-BuPh2SiCl, imid., DMF, 0 oC; then 2-methoxypropene, CSA (cat.), 0 oC (82%) 112 1. Im2C=S, PhCH3 , 110 oC 2. n-Bu3SnH, AIBN (cat), PhCH3 , 110 oC (66% overall) O O O H OTPS 113 1. amberlyst-15 (H + ), MeOH, 60 oC (72%) 2. n-Bu2SnO, MeOH, 60 oC; then BnBr, DMF, 100 oC (74%) O HO BnO H OTPS 114 (COCl)2 , DMSO, CH2Cl2 , -78 oC; then Et3N, 0 oC (100% Yield) O H O O H OTPS M L L Ph Nu O O BnO H OTPS 115 AlMe3 , MgBr2 OEt2 , CH2Cl2 , -50 oC (61% Yield of 91) O HO H OTPS 91 Me OBn K (ca. 3:1 mixture of diastereomers) 1. O3 , CH2Cl2, -78 oC; then Me2S, Ph3P 2. CH2=CHMgBr, TFH, 0 oC (44% Yield) O HO OTPS 117 Me OBn K HO H H (ca. 1:1 mixture of diastereomers) O HO OTPS 90 Me OBn K TPSO H H CO2Me 1. t-BuPh2SiCl, imid., DMF, 25 oC 2. O3 , CH2Cl2 , -78 oC; then Me2S, Ph3P 3. Ph3P=CHCO2Me, PhH, 25 oC (78% overall)
Construction of intermediate 86 Continued NaH, THF, 25C Me0C Dibal-H(1.5 eq), C. 78 C then MeO2C O (75% overall) 89 1. Dibal-H (2.2 eq). CH2C278°c 2. mCPBA, CH2Ch2,0C 31B2邮19)多 1.(COCI)2, DMSO, CH2Ch 78C, then Et3N 2. Ph P=CHCO, Me, PhH, 25C (75% overall) MeO2C CSA(cat ) CH2CL, 25C (ca. 10: 1 mixture of epoxide stereoisomers in favor (71%) 0f119 0Bn1.0:CH2Ch78℃c 1. TBAF. THF. 25oC then Ph3P: ther 2. (COCI)2, DMsO, NaBH4MeOH,25°C then Et3N 2. 2-methoxypropene, COmE MeO2c OTPS CSA(cat ) CH2Cl2, 25C 3. Ph3P=CHCO2 M (85% overall) CH2Ch2,25°C 93% overall (Eza.4:1)
Construction of Intermediate 86 Continued O HO OTPS 90 Me OBn K TPSO H H CO2Me NaH, THF, 25 oC (92%) O OTPS 89 Me OBn K TPSO H H MeO2C O H Dibal-H (1.5 eq),CH2Cl2 , -78 oC; then Ph3P=CHCO2Me (75% overall) J O OTPS 118 Me OBn K H H O H J O TPS MeO2C 1. Dibal-H (2.2 eq), CH2Cl2 , -78 oC 2. mCPBA, CH2Cl2 , 0 oC (77% overall) O OTPS 119 Me OBn K H H O H J O TPS O HO (ca. 10:1 mixture of epoxide stereoisomers in favor of 119) 1. (COCl)2 , DMSO, CH2Cl2 , -78 oC, then Et3N 2. Ph3P=CHCO2Me, PhH, 25 oC 3. TBAF (1.2 equiv.), THF, 25 oC (75% overall) O OTPS 88 Me OBn K H H O H J HO O MeO2C O OTPS 120 Me OBn K H H O H J O MeO2C HO H I H CSA (cat.), CH2Cl2 , 25 oC (71%) 1. O3 , CH2Cl2 , -78 oC; then Ph3P; then NaBH4, MeOH, 25 oC 2. 2-methoxypropene, CSA (cat.), CH2Cl2 , 25 oC (85% overall) O OTPS 121 Me OBn K H H O H J O H I H O O O 122 Me OBn K H H O H J O H I H O O CO2Me 1. TBAF, THF, 25 oC 2. (COCl)2, DMSO, CH2Cl2, -78 oC; then Et3N 3. Ph3P=CHCO2Me, CH2Cl2, 25 oC (93% overall) (E:Z ca. 4:1)
Construction of intermediate 86 Continued 1. H2, Pd(oH), EtOAC, 25C 2. LAIH. THF. 0C (92% for steps 1 and 2) OTPS HH H 0-CO2Me 3.t-BuPh2SiCl, Et,N 4DMAP,cH2Cz,25°C 4. +-BuMe2 SIOTf, 2, 6-lutidine, (95% for steps 3 and 4) 1. CSA, CH2Cl2: MeOH (1: 1),0C 2. TBSCI,imid,DMF,0° 3. NMO, TPAP (cat ) CH3CN, 25C 1. EtSH, Zn(OTD2, CH2Cl2, 25C OTBS 2.CSA.MeOH.25℃ ES入H。、Me OTPS JK (68% overall)
O 122 Me OBn K H H O H J O H I H O O CO2Me 1. H2, Pd(OH)2, EtOAc, 25 oC 2. LAlH4 , THF, 0 oC (92% for steps 1 and 2) 3. t-BuPh2SiCl, Et3N, 4-DMAP, CH2Cl2 , 25 oC 4. t-BuMe2SiOTf, 2,6-lutidine, CH2Cl2 , 0 oC (95% for steps 3 and 4) O 124 Me OTBS K H H O H J O H I H O O OTPS 1. CSA, CH2Cl2 :MeOH (1:1), 0 oC 2. TBSCl, imid., DMF, 0 oC 3. NMO, TPAP (cat.), CH3CN, 25 oC O 125 Me OTBS K H H O H J O I H O OTPS OTBS 1. EtSH, Zn(OTf)2 , CH2Cl2 , 25 oC 2. CSA, MeOH, 25 oC 3. SO3 pyr., Et3N, DMSO, CH2Cl2 , 0 oC (68% overall) O O O H H OTBS EtS H Me I EtS H H O J K OTPS Key Intermediate 86 Construction of Intermediate 86 Continued
Construction of intermediate 87 CH2C2,-78 1.Ph P=CMeCO,Et then Et N THF80°C 2. PhCH(OMeh 2. AIMe, CH,CI,, -20C CSA, CH,CI, (75%from109) 25"C 1. TMS-imidazole 1. (-DET, Ti(Oi-Pr)4, BuOOH, CH2C2,-2℃ 2. Dibal-H CH-Ch 2.S0 DMSO -78 CH2Cl2,-78 1. TBAF THF. 25.C 2. PPTS CH-Ch. 0 to 25C 3PhP=CH2,ThHF,0℃ OTMS (73% overall 1. f-BuMe, SiCI imid DMF,50℃C 2.9-BBN. THF. 25 then naoh,HO20℃
Construction of Intermediate 87 O OH HO HO H H 1. Ph3P=CMeCO2Et THF, 80 oC 2. PhCH(OMe)2 , CSA, CH2Cl2 , 25 oC (96% overall) O O Me Ph OH H CO2Et 1. (COCl)2 , DMSO, CH2Cl2 , -78 oC; then Et3N 110: 2-deoxy-D-ribose 109 O O Ph H CO2Et 127 Me 2. AlMe3 , CH2Cl2 , -20 oC (75% from 109) Me OH 1. TMS-imidazole, CH2Cl2 , 25 oC 2. Dibal-H, CH2Cl2 , -78 oC (96% overall) O O Ph H 128 MeOTMS Me OH 1. (-)-DET, Ti(Oi-Pr)4 , t-BuOOH, CH2Cl2 , -25 oC 2. SO3 pyr., DMSO, CH2Cl2 , -78 oC 3. Ph3P=CH2 , THF, 0 oC O (73% overall) O Ph H 130 MeOTMS Me O 1. TBAF, THF, 25 oC 2. PPTS, CH2Cl2 , 0 to 25 oC (89% overall) O O Ph H 131 Me O Me H OH F 1. t-BuMe2SiCl, imid., DMF, 50 oC 2. 9-BBN, THF, 25 oC; then NaOH, H2O2 , 0 oC (88% overall) O O Ph H 132 Me O Me H OTBS F OH
Construction of intermediate 87 OH I(COCT)h, DMSO, CH2 Cl2, 1.Dba-H,CH2C2,-738"C 78°C, then Et,n 0 2. mCPBA,CHCl2,0°C CO,Et OTBS 2. Ph: P=CMeCO2Et, PhCO,H(cat ) PhH, 50 1. SO, pyr, Et N, DMSO 1.TBAF,THF,25℃C CH,Ch0C F 2. PPTS. CH,CI,.0 to 25C 2. PhaP=CH, THF.0C Ph (86% overall (81% overall) Only diasteromer observed 1.CSA(ceat.,MeOH0℃ 入oH1 KH, BnBr, THI,45℃ (95% FG 2.9-BBN,THF,25°C 2. i-BuMe, SiCl(2.5 equiv ) then Naoh,H2O2,0°C id,DMF,50°C 3.CSA(cat,MeOH,0°C 3.KH,BnB,THF,45℃ 4.(COCH, DMSO, CH2, (75% overall) 78°C, then et3N (81% for steps 2-4) F TBSO THF,0C(99%90
Construction of Intermediate 87 1. (COCl)2 , DMSO, CH2Cl2 , -78 oC; then Et3N O O Ph H 133 Me O Me H OTBS F Me CO2Et O O Ph H 132 Me O Me H OTBS F OH 1. Dibal-H, CH2Cl2 , -78 oC 2. mCPBA, CH2Cl2 , 0 oC (94% overall) O O Ph H 134 Me O Me H O F TBS OH O Me 1. SO3 pyr., Et3N, DMSO, CH2Cl2 , 0 o O C O Ph H 135 Me O Me H O F TBS O Me 1. TBAF, THF, 25 oC 2. PPTS, CH2Cl2 , 0 to 25 oC (86% overall) O O Ph H 136 Me O Me H O F OH H Me 1. KH, BnBr, THF, 45 oC 2. 9-BBN, THF, 25 oC; then NaOH, H2O2 , 0 oC G O O Ph H 137 Me O Me H O F OBn H Me G OBn 2. Ph3P=CMeCO2Et, PhCO2H (cat.), PhH, 50 oC (86% overall) 2. Ph3P=CH2 , THF, 0 oC (81% overall) 3. KH, BnBr, THF, 45 oC (75% overall) 1. CSA (cat.), MeOH, 0 oC (95%) 2. t-BuMe2SiCl (2.5 equiv.), imid., DMF, 50 oC 3. CSA (cat.), MeOH, 0 oC 4. (COCl)2 , DMSO, CH2Cl2 , -78 oC; then Et3N (81% for steps 2-4) O TBSO H 105 Me O Me H O F OBn H Me G OBn TBSO PPh3 THF, 0 oC (99%) TBSO H 139 Me O Me H O F OBn H Me G OBn TBSO Only diasteromer observed
