The Amphidinolide T-Series

Transcription

1 How a Total ynthesis Evolves ver Time The Amphidinolide T-eries H Jason M. tevens 12/06/2006

2 Amphidinolide Natural Products Isolated in 2000 from marine dinoflagellates of the genus Amphidinium living in symbiosis with kinowan acoel flatworm Amphiscolops Have exhibited significant antitumor properties and cytotoxicity against a variety of NCI tumor cell lines as well as human carcinoma KB cells Consist of highly oxygenated, stereochemically rich macrolactones ranging from 12 to 29 atoms with various degrees of unsaturation.

3 Total ynthesis of the T-eries Amphidinolides T1 and T3-5 have been synthesized to date The first total synthesis of T4 was reported by Fürstner in 2002 and T1, T3, T4, and T5 in The total synthesis of Amphidinolide T1 was first reported by Ghosh in The Jamison group reported the syntheses of Amphidinolide T1 and T4 in 2004 and In 2006 the Zhao group reported the total synthesis of Amphidinolide T3 The library of the total synthesis of other Amphidinolides continues to grow steadily

4 A Glance at the T-eries H H H H H H

5 Fürstner s Retrosynthesis TB H I Mukaiyama Reaction Negishi Acyl Chloride Coupling H 2 Cl Ring Closing tathesis Fürstner, A.; Aïssa, C.; Ragot, J. Angew. Chem. 2002, 114, Fürstner, A.; Aïssa, C.; Ragot, J. J. Am. Chem. oc. 2003, 125,

6 Assembly of the Mukaiyama ubstrates 1. DIBAL-H, Toluene, -95 o C 2. (-)-Ipc 2 B-allyl, Et 2, -100 o C H 1. KCN, DM 2. DIBAL-H, CH 2 Cl 2, -78 o C 3. 2 H, CaCl 2, CH 2 Cl 2, 0 o C Ts 70% over 2 steps Ts 78% over 3 steps H- is Commercially Available 2 H N Bu 2 BTf, Et 3 N 90% H N 5 steps 60% MM TB TB

7 Mukaiyama electivity MM 2 ncl 4, CH 2 Cl 2, -78 o C Then silyl enol ether 86% TB Nu Nucleophile attacks from the inside due to stereoelectronics JAC 1999, 121, 12208

8 Negishi Coupling Partners H tbu [((R)-Binap)-RuCl 2 ] 2 (NEt 3 ) catalyst H 2, H, 95 o C tbu 84% H EDCI, DMAP, CH 2 Cl 2 93% tbu Cl 2 steps Quant. MM 1a.L-electride gives -H down - 72% 1b. LAH (5 eq) LiI (10 eq) gives -H up - 70% TBDP MM TB 2. KHMD, TBDPCl, THF - 77% 3. p-tsh, H - 75% 4. P 3, I 2, Imidazole, toluene - 80% I

9 Negishi Acyl Chloride Coupling TBDP MM I Cl THF is cleaved under these conditions 1. Zn/Cu Couple, TMCl Toluene, DMA 2. Pd 2 (dba) 3 cat., P(2-furyl) 3 cat., 40-50% TBDP MM H MM H ZnI MM TBDP H I TBDP MM TBDP MM TBDP MM ZnI

10 lefin Issues MM MM TBDP TBDP 1. Grubbs Catalyst, CH 2 Cl 2, reflux* 2. H 2 (1 atm), Pd/C, EtAc 2 steps 74% MM TBDP CH 2 Br 2, TiCl 4 P 3 =CH 2 THF H or quant H Nysteds Reagent 65% BrZn ZnBr Zn MM Nysted's Reagent Peterson lefination - complete failure

11 Endgame MM TBDP ilyl Deprotection xidize MM Deprotection H T1 MM Deprotection xidize ilyl Deprotection H H K 2 C 3, H H T3 T4 T5

12 What we learned The Mukaiyama reaction is an efficient method of building the molecule up from the furan Protecting groups, if not chosen carefully, may alter the desired conformations of advanced intermediates and produce unfavorable reactivity The Negishi coupling is probably not the best coupling reaction lefination is problematic after generation of the macrolactone ynthesizing the Northern Hemisphere of the molecule with differentiable protecting groups provides a template for synthesis of 4 of 5 T-Amphidinolides H

13 Ghosh s Retrosynthesis 2 Mukaiyama Reaction TB Bn H TB Br Latent lefin Ring Closing tathesis Yamaguchi Ghosh, A. K.; Liu, C. J. Am. Chem. oc. 2003, 125, 2374

14 Building the Furan NHTs H 1. TiCl 4, i-pr 2 NEt; 90% 2. LAH, THF, r.t.; 91% H H 1. Li, TrisCl, THF -78 o C - rt; 86% 2. NaCN, DM 80 o C; 95% 3. aq. HCl, H rt; 98% Bn Bn DIBAL-H, -78 o C, then TM(CH 2 ) 2 H, p-tsh Mg 4, r.t. Bn 91% 3 i Bn N H HN Bn Bn Bn

15 Mukaiyama Precursor 3 i Bn 1. H 2, Pd/C, EtAc 2. (ClC) 2, DM, Et 3 N 3. 3 P=CH 2, THF 82%over 3 steps 3 i Grubbs Cat 40 o C CH 2 Cl 2 96% Bn N 3 i 2 Bn N 1. H 2, Pd/C, EtAc 2. BnH, n-buli 3. H 2, CaCl 2 CH 2 Cl 2, rt 79% 3 steps Bn

16 ilyl Enol Ether Construction NHTs H 1. TiCl 4, i-pr 2 NEt 2. TIPTf, i-prnet 2 0 o C 3. DIBAL-H, -40 o C 4. I 2, P 3, Imidazole, rt I TIP TB H t-buli, Et 2, -78 o C - rt Bn 76% over 4 steps Bn 80% Pr TB H TIP Bn 1. TPAP, NM, rt 2. Cp 2 Ti 2, THF 80 o C 84% over 2 steps Pr TB TIP Bn 1. Li/NH 3-33 o C, THF 2. LAH, THF, rt 3. NB, 0 o C - rt no yield for PG removal 82% 2 steps H TB Br 1. TPAP, NM, rt 2. MgBr -78 o C - rt 3. TPAP, NM, rt 4. LiHMD, TBCl, HMPA -78 o C - rt no yield reported for ox. or grignard addition TB TB Br

17 Endgame Br Br TB 2 Bn TB Pr DTBMP, AlCl 3, -35 o C 73% TB Pr Bn t-bu N DTBMP t-bu 1. HF-pyr, pyr 2. H 2, Pd/C 3. 2,4,6-(Cl 3 )CCl i-pr 2 NEt, then DMAP toluene 4. Zn, NH 4 Cl, EtH, 80 o C H 38% over 4 steps no yield reported for hydrog.

18 Improvements? The olefin was protected in this synthesis although it seems the protection wasn t very effective The furan was used as the foundation for building up the molecule and its construction was more concise RCM was an effective means of coupling for generation of the side chain prior to the macrocyclization Yamaguchi conditions provided to be an effective means of completing the synthesis H

19 Jamison Retrosynthesis Aldehyde Alkyne Coupling H Aldehyde Epoxide Coupling

20 Lactone Precursor Bu 3 n 5 steps Ac 25% (CH 2 ) 4 TB Et 2 BF 3, CH 2 Cl 2-78 o C - rt (CH 2 ) 4 H H TB 88%, > 95:5 dr I, cat CuI, cat. Pd(P 3 ) 4 pyrrolidine 98% (CH 2 ) 4 H I 2, P 3, imidazole 73% (CH 2 ) 4 I N H H 1. LDA, LiCl 2. NaH, t-buh, H 89% over 2 steps

21 Epoxide-Alkyne Coupling N 1. LDA, THF; CCCH 2 Br 2. LAH, THF 3. TBCl, imidazole, DMF 70% over 3 steps TB Ni(CD) 2 (10 mol%) Bu 3 P (20 mol%) Et 3 B TB H Pr 81% yield.99% dr Jamison, T.F.; Molinaro, C. J. Am. Chem. oc. 2003, 125, 8076

22 TB Pr H DCC 4-PPY 72% > 95:5 dr Endgame TB H 1. TBAF 2. DMP 80% over 2 steps H H Ni(cod) 2 (20 mol%) PBu 3 (40 mol%) Et 3 B, toluene 44% 31% > 10:1 dr H H H 1. TBTf, 2,6-lut 2. 3, 2 3. CH 2 I 2, Zn, ZrCl 4, PbCl 2 4. HF-pyr 25% over 4 steps H Colby, E. A.; Jamison, T. F. J. rg. Chem. 2003, 68, 156

23 Key teps in the T4 ynthesis CBr 4,P Br 3 Br Li, TMCl 3 i Ni(0) L N Ni R L N Ni R L N Ni BEt 2 Ni H L N Ni L N BEt BEt 2 2 R R R 1 R R R R 1 1 H R 1 H C 2 H T4

24 Improvements? Demonstrated that the molecule can tolerate a fair amount of manipulation during the late stages The conformation of the molecule in the late stages can terminate both internal and external means of stereocontrol elective oxidative cleavage can be a useful means of protection H

25 Zhao s Retrosynthesis 1,3-Dithiane Addition H H Bn TB Macrolactonization Deng, L.; Huang, X.; Zhao, G. J. rg. Chem. 2006, 71, 4625.

26 Building the Furan NH 2 H 2 C C 2 H D-Glutamic acid Tr LDA, I, -78 o C 81% 11:1 dr Tr 1. LAH, THF 2. TBCl, Imidazole, DMF 0 o C 3. Ac 2, DMAP, Et 3 N 4. TBAF 5. DMP, CH 2 Cl 2 86% over 5 steps Tr Ac (R,R)-,2-diamino-1,2-diphenylethanebis(sulfonamide), BBr 3, CH 2 Cl 2, then allyltributylstannane rt 6h, then -CH -78 o C 2 h 85%, dr > 99:1 Tr Ac H 1. TsCl, pyr, rt 2. KH, diglyme, glycol, 40 o C 3. BH 3 2, THF then 30% H 2 2, NaH 4. I 2, P 3, imidazole, THF 99%, 99%, 83%, 95% Tr I 2 Bn 1. n-buli, HMPA, THF, -78 o C then R-I 2. Na-Hg, EtH 80% over 2 steps Tr Bn

27 Generating the Aldehyde Tr H 1. 80% HAc 2. P 3, I 2, imidazole, THF 3. 1,3-dithiane, THF/HMPA then R-H 4. NaHC 3, CH 3 I, CH 3 CN-H 2 (4:1) rt 16 h 95% 95%, 91%, 83%, 95% Bn Bn R H P 3 I I R H 3 P I I - I - P + 3 I - RI 3 P R

28 Umpoles Everywhere! Et H C 2 1. [(R)-BINAP-RuCl 2 ](DMF) H 2, H, 20 atm, 100 o C 2. TBCl, imidazole, DMF 3. DIBAL-H, CH 2 Cl 2, -78 o C 4. H(CH 2 ) 3 H, BF 3 Et 2 all steps ~92% 1. i-prnet 2, BMCl 2. LAH 3. P 3, I 2, imidazole 90% over 3 steps BM TB I t-buli, HMPA, THF, -78 o C Thiane then iodide 83% BM TB BM TB 1. I 2, NaHC 3, acetone/h 2 (5:1) 0 o C 2. Cp 2 Ti 2, toluene 110 o C 82%, 86% BM TB 1. Li/NH 3, THF, -78 o C 2. DMP, CH 2 Cl 2 3. ZnCl 2, 3 i(ch 2 ) 3 i 3 Et 2, 0 o C - rt TB 99%, 95%, 92%

29 Back to Asymmetric Reductions H Bn TB 1. t-buli, HMPA/THF (1:9) 2. DMP, NaHC 3, CH 2 Cl 2 80% 1:1.7 dr, 90% TB Bn NaBH 4 - No selectivity L- electride - N.R. LiBH 4-88%down CB Red. - 68% up H TB isolated yields TB Bn Bn

30 Endgame H 1. Ac 2, DMAP, pyridine 2. DDQ, CH 2 Cl 2 /H 2 (10:1), 30 h Ac TB 92%, 95% TB Bn H 1. PCC, NaAc, CH 2 Cl 2, 4 A M 0 o C 2. AgN 3, NaH, THF, H 2, 0 o C 3. HF-pyr THF, rt 4. LiH, H/H 2 (5:1) 40 o C 96%, 81%, 94%, 95% H H H 1. 2,4,6-Cl 3 CCl, i-prnet 2 45 o C then DMAP, toluene 2. I(CF 3 C 2 H) 2, H/H 2 (10:1) 15 o C 66%, 82% H

31 Improvements? The olefin was installed early to prevent future problems and carried through successfully The furan was again used as a foundation for building the molecule although it was prepared in a different way The macrolactonization that was demonstrated by Ghosh was effectively used The current synthesis provides a template for preparation of future amphidinolides H

32 Final Thoughts After several total syntheses the reactivity has been sufficiently investigated f the four syntheses each has its own highlights and drawbacks with the best synthesis probably as a blend of each The broad scope and report by Fürstner provided future researchers a template to follow and improve upon The evolution is apparent in that each subsequent synthesis drew upon what was learned from previous efforts to continuously improve how the target molecule is prepared