Harnessing Glycal-Epoxide Rearrangements: The Generation of the AB, EF, and IJ Rings of Adriatoxin Clement Osei Akoto and Prof. Jon D. Rainier* Department of Chemistry, University of Utah 315 South 1400 East Salt Lake City, UT 84112-085 [email protected]; [email protected] O O O O O O O O O O N aO 3 SO H H H H H Me Me Me H H Me O SO 3 Na OH H H A E G J OH H H H H H H H H H Me A driatoxin (A TX ) N aO 3 SO B C D F H I Synthetic Studies of Adriatoxin: Synthetic Studies of Adriatoxin: O O O O O O O O O O N aO 3 SO H H H H H Me Me Me H H Me OH H H H H H H H H H Me O H H Me OH N aO 3 SO A B C D E F G H I J K 5 8 11 14 17 21 24 29 32 35 38 41 44 Y essotoxin (Y TX ) Adriatoxin, an analog of yessotoxin (sulphated polyether toxin), was isolated from the digestive glands of mussels Mytilus galloprovincialis by Cimminiello and co- workers in 1997. 1 It and its analogs exhibit potent neurotoxic action on cultured cerebellar neurons, they induce a two-fold increase in cytosolic calcium, they display potent cytotoxic activities against human tumor cell lines, and they induce caspase activation and cause apoptotic changes. 2 1 1 st st Generation Retro-Synthetic Analysis of Adriatoxin: Generation Retro-Synthetic Analysis of Adriatoxin: O O O O O O O O O O N aO 3 SO N aO 3 SO H H H H H Me Me Me H H Me O SO 3 Na OH H H A B C D E F G H I J OH H H H H H H H H H Me O O PO PO H H H A B H H OH HO O O OH H Me Me E F H H H PO PO O O H Me OMe OP H H I J OP H H + + O OH HO OH D -2-deoxyribose HO H om opropagylalcohol O OAc OAc OAc D-glucaltriacetate Our convergent 1 st generation retro-synthetic strategy involves the coupling of the AB, EF and IJ ring subunits, which can be synthesized from D-2-deoxyribose, homopropagyl alcohol and D-glucal respectively. Synthesis of the AB Ring Subunit of Adriatoxin: Synthesis of the AB Ring Subunit of Adriatoxin: The A-ring was synthesized from D-2-deoxyribose in 6 steps having utilized our olefin metathesis, carbonyl olefination protocol. DMDO epoxidation followed by treatment with MgCl 2 gave a ketone intermediate resulting from a stereoselective 1,2-hydride migration. Reduction, followed by cyclization and oxidation led to the AB ring core as a mixture of isomers. Oxidation, DBU equilibration and reduction of the resulting ketone gave the AB subunit as a single product. 3 Synthetic Studies of the IJ Ring Subunit of Adriatoxin: Synthetic Studies of the IJ Ring Subunit of Adriatoxin: The synthesis of IJ ring subunit commenced from the functionalized I ring. Swern oxidation followed by MeLi addition provided the desired tertiary alcohol in 7 : 1 diastereomeric ratio. Subsequent vinylation followed by RCM led to the IJ ring framework. m-CPBA epoxidation in methanol followed by acetylation led to the IJ ring core. Inversion of the C32 stereocenter to that required for the synthesis of adriatoxin was achieved via hydrogenolysis and then oxidation of the resulting alcohol. Reduction of the resulting ketone with L-Selectride and acetylation gave the IJ-ring subunit. 3 1 1 st st Generation Synthetic Studies of the EF Subunit of Adriatoxin: Generation Synthetic Studies of the EF Subunit of Adriatoxin: BPSO OH L -D IPT, Ti(O i Pr) 4 t-BuO O H , 4A M S, CH 2 Cl 2 , -30 o C , 30h, 85% , 88% ee BPSO OH O Ti(O i Pr) 4 , PhM e, O H , 70% 120 o C , 6h 1. TsC l, Py, D M AP, 2. K 2 CO 3 , M eOH, 50% (2 steps) O O BPSO C uC N , TH F, CH 2 =C H M gBr, O BPSO HO -78 o C -(-40 o C )-0 o C, 2h, 80% 1.NaH , M eI, TH F 2.''R u'', PhM e, 60 o C, 60% (2 steps) O BPSO H M eO H R h(PPh 3 ) 3 Cl, DABCO, EtO H :H 2 O (9.5:0.5) 40% O BPSO H M eO H 1)D M DO , C H 2 Cl 2 2) M gBr, TH F, 90% , O BPSO H M eO H OH E Ac 2 O , D M AP, Et 3 N, CH 2 Cl 2 R T, 1 h, 90% O BPSO H M eO H OAc E J 19,20 = 9.5 H z J 19,18 = 9.5 H z J 19,18` = 3.5 H z 20 19 18 d.r = ~10:1 OH BPSO OH O Starting from the allylic alcohol the acyclic diene was synthesized in 6 steps. Ring closing metathesis followed by isomerization with Wilkinsons catalyst resulted in the desired 7-membered ring formation. DMDO oxidation followed by allyl grignard addition gave the desired E ring framework in 10 : 1 diastereoselectivity. 2 2 nd nd Generation Retro-Synthetic Analysis of Adriatoxin: Generation Retro-Synthetic Analysis of Adriatoxin: The more convergent 2 nd generation retro-synthetic analysis involves the formation of the EF subunit from D-mannitol, followed by the coupling of the 3 subunits (AB, EF and IJ rings) to generate Adriatoxin. 2 2 nd nd Generation Synthesis of the EF Subunit of Adriatoxin: Generation Synthesis of the EF Subunit of Adriatoxin: Starting from the acetonide protected D-glyceraldehyde, the E ring system can be synthesized in 5 steps using our olefin metathesis, carbonyl olefination protocol. Further 7 steps will lead to the EF ring core via our optimized glycal Claisen rearrangement protocol. 3 Further 9 steps will lead to complete functionalization of the EF subunit which will then be carried forward for coupling. Coupling and End-Game of Adriatoxin: Coupling and End-Game of Adriatoxin: Successful coupling of the AB and EF subunits gave the ABEF ring core in 82% yield. Followed by our olefin metathesis, carbonyl olefination reaction, and subsequent DMDO oxidation and reductive cyclization will give the fully functionalized ABCDEF ring. Coupling of the IJ-ring, followed by sulfonation and global deprotection will give the natural product adriatoxin. References References 1.) Ciminiello, P.; Fattorusso, E.; Forino, M.; Magno, S.; Poletti, R.; Satake, M.; Viviani, R.; Yasumoto, T. Toxicon 1997, 35, 177–183. 2.(a) Gomez, A. P.; Gutierrez, A. F.; Novelli, A.; Franco, J. M.; Paz, B.; Sanchez, M. T. F. Toxicological Sciences 2006, 90 (1), 168. (b) Konishi, M.; Yang, X.; Li, B.; Fairchild, C. R.; Shimizu Y. J. Nat Prod. 2004, 67, 1309. (c.) Malaguti, C.; Ciminiello, P.; Fattorusso, E.; Rossini, G. P. Toxicol. In Vitro 2002, 16, 357–363. (d) Leira, F.; Alvarez, C.; Vieites, J. M.; Vieytes, M. R.; Botana, L. M. Toxicol. In Vitro 2002, 16, 23- 31. 3.) Osei Akoto, C.; Rainier, J. D. Angew. Chem. Int. Ed. 2008, 47, 8055. Acknowledgments Acknowledgments Dr. Charles Mayne (NMR) Dr. Jim Miller (Mass Spec.) University of Utah Department of Chemistry Pfitzer Global Research and Development (PGRD) 1.H 2 , Pd(O H) 2 /C, EtO A c, 90% 2. SO 3 . Py, Et 3 N, DM SO , DCM , 90% O ( t Bu) 2 Si O O H H H Me O OAc OMe I J O Ac 2 O , D M AP, Et 3 N, CH 2 Cl 2 O ( t Bu) 2 Si O O H H H Me O OAc OMe I J OAc O ( t Bu) 2 Si O O OBn H H OH H 1.(CO Cl) 2 , D M SO , Et 3 N , C H 2 Cl 2 , 2.M eLi, PhM e, -90 o C, I O ( t Bu) 2 Si O O OBn H H OH H Me (d.r = 7:1), O ( t Bu) 2 Si O O OBn H H H Me O m -C PBA , M eOH , 2."R u", RT, 1h, 60% (2 steps) -63 o C-R T, 2h 75% dr = 5.5:1 O ( t Bu) 2 Si O O OBn H H H Me O OH OMe I J 36 1,3 J H 36 = 3.4, 3.6 H z Ac 2 O , D M AP, Et 3 N, CH 2 Cl 2 R T, 1 h, 96% O ( t Bu) 2 Si O O OBn H H H Me O OAc OMe I J 35 36 37 1,3 J H 36 = 2.7, 3.3 H z 80% (2 steps) 1.H g(CF 3 O 2 C) 2 , OEt L-Selectride, 2 eqs. TH F, -78 o C, 90% O ( t Bu) 2 Si O O H H H Me O OAc OMe I J OH (> 10:1) J* = 3.4 H z 96% 32 32 O O H H H A B H H Me OH TBSO O O OH H Me Me E H H H HO 2 C TESO O O H Me OMe OAc H H I J OBn H H + + F O O Ph O O O O O O O O O O N aO 3 SO H H H H H Me Me Me H H Me O SO 3 Na OH H H A E G J OH H H H H H H H H H Me A driatoxin (A TX ) N aO 3 SO B C D F H I 1 4 8 14 18 25 29 35 37 O O H H O H Me O Me O Ph E F OMe 22 23 19 HO OH OH OH OH OH D -Mannitol O O H H O Ph O O OH H Me E 19 20 O O O H CH 2 CHCH 2 CH 2 Br, M g, Et 2 O , rt-(-78 o C) ZnCl 2 , -90 o C , Et 2 O, 87% (2 steps), d.r.= 6:1 O O OH 1. PPTS, M eO H reflux, 24h, 89% O O OH H H DCC, DM AP, CH 2 Cl 2 , R T, 24h 2. PhC H (OM e) 2 , C SA , R T, 82% Ph O OH O O O H H O Ph O O H H O Ph TiC l 4 , TM EDA, TH F/DCM , Zn, PbC l 2, CH 3 CHBr 2, 60 o C , 75 m in., 65% O O O O O O 1. D M DO , C H 2 Cl 2 ; D IBA L-H , C H 2 Cl 2 , -78 o C, 80% 2. SO 3 . Py, Et 3 N, DM SO , DCM , 85% O O H H O Ph O O O H E 1.M eM gBr, -78 o C PhM e (d.r.=5:1), 92% 2.PPTS, PhC l,Py, 135 o C, 75% 2. A llyl-Br, N aH , TBA I, D M F, 0 o C-65 o C, 85% 1. m -C PBA , M eOH , -78 o C -R T, 2h, 88% O O H H O H Me O Me O Ph E F O O H H O H Me O Ph E F OMe PPTS, PhM e, Py, 100-120 o C, 92% , d.r.= >10:1 O O H H O H Me O O Ph Me 1. N aBH 4 , M eO H 94% 2. PM BBr, K H, TBA I, D M F, 86% E F O O H H O H Me O O PM B Ph Me H E F 21 22 J 21,22 = 4.4 H z J 21,22 = 12.2 H z 3 2 1 1` 2` 3` O O H H O H Me O O Ph E [3,3]C laisen R earrangem ent F [3,3] 2. TBSC l, D M F, im idazole, 50 o C, 85% 3. C SA , M eO H , 93% HO TBSO H H O H Me O O PM B Me H E F 1. TsC l, Et 3 N, CH 2 Cl 2 , 94% 2. NaCN, DM F, 60 o C, 96% 3. iBu 2 AlH , C H 2 Cl 2 , -78 o C, 4. NaClO 2 , t BuO H , N aH 2 PO 4 , H 2 O , 2-M e-2-butene, TH F, (65% , 2 steps) 1. C SA , M eO H , 93% HO 2 C TBSO H H O H Me O O PM B Me H E F O O O O Ph Me H H H OH H H B A E HO 2 C PM BO H H O Me H O Me O PM B H F TESO O H H H Me O OBn OMe OBn I J + O O O O Ph Me H H H O H H B A O E HO H H O Me H O Me O PM B H F O O O O Ph Me H H H O H H B A E O H H O Me H O Me OH H F C D H H Y am aguchi esterification 1. R CM 2. D M DO, D IBA L-H coupling Adriatoxin 3. R eductive cyclization Cl 3 C 6 H 2 CO C l, TH F, Et 3 N; DM A P, PhM e, (82% ) O OH HO OH D -2-deoxyribose 1. Ph 3 PM eBr, t -BuO K , 2. PhC H (OM e) 2 , C SA , 60% (2 steps) 3. (C O Cl) 2 , D M SO , Et 3 N , -78 o C, 4. M eM gBr, Et 2 O, -78 o C, 60% (2 steps) O O Ph Me OH H DCC, DM AP, DCM , R T, 24h M eO OMe O OH 80% TiC l 4 , TM EDA, TH F/DCM , Zn, PbC l 2, CH 3 CHBr 2, 50 o C , 60 m in., 60% O O O Me H O Ph OMe M eO O O Ph Me H O OMe OMe A DM DO , C H 2 Cl 2 , M eM gBr 1. N aBH 4 , M eO H 90% or DM DO , C H 2 Cl 2 , M gBr 2 . Et 2 O O O Ph Me H O OMe OMe O H DM DO , C H 2 Cl 2 , TH F, M gC l 2 , 75% O O Ph Me H O OMe OMe O H J 19,20 = 10.3 H z J 19,18 = 10.7 H z J 19,18` = 5.4 H z 20 19 18 O O Ph Me H O OMe OMe OAc H H O O Ph Me H O H H O 1)D M DO , C H 2 Cl 2 2) M gBr, THF, O O Ph Me H O H H O OH A B 2. PPTS, PhC l, Py, 135 o C, 90% 2.3:1 m ixture ofisom ers 1.(CO Cl) 2 , D M SO , Et 3 N , -78 o C 2. D BU , equilibration O O Ph Me H O H H O A B H A A A B O O Ph Me H O H H O OH A B H H O N aBH 4 , M eO H 60% (3 steps)