Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide
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1 61.7 g prepared in 39 steps 43 chemists worked on the project which lasted 20 months Chris Wipf Group 1 3/27/04
2 carbon linear polypropionate chain containing stereocenters (6 hydroxyl and 7 methyl) and 3 cis double bonds triply repeated stereotriad at C 2-4, C and C Five academic research groups have reported total syntheses numerous (at least 26) fragment syntheses also published review: Paterson,.; Florence, G. J. Eur. J. rg. Chem. 2003, 2193 isolated (9 mg) from extracts of the marine sponge Discodermia dissoluta "all discodermolide used for late preclinical research and development activities as well as for the ongoing clinical research trial has been supplied by total synthesis." the most potent known microtubule-stabilizing agent known undergoing phase clinical trials (Novartis) potent inhibitor of tumor cell growth in vitro (including paclitaxel- and epothilone-resistant cells), and in mouse models Chris Wipf Group 2 3/27/04
3 ung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, steps (24 steps longest linear sequence) 4.5% overall yield (9 mg prepared) (Acetylenic) Nozaki-Kishi alkylation (2x) PhS C Br + + PMB C 2 ipr B C 2 ipr C 2 "Roche Ester" C + or B C 2 ipr C 2 ipr Roush et al JACS 6348 arried, S. S.; Yang, G.; Strawn, M. A.; Myles, D. C. J. rg. Chem. 1997, 62, steps <<1% overall yield (3 mg prepared) Disconections as above but lefinic Nozaki-Kishi and mono-alkylation of ethyl ketone (not bis-alkylation of methyl ketone) Chris Wipf Group 3 3/27/04
4 Smith, A. B.; Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.; Qiu, Y.; Arimoto,.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 2000, 122, steps (24 steps longest linear sequence) 6% overall yield (1.04 g prepared) Wittig Negishi Coupling C + + PMB N C 2 Witting salt required 12.8 kbar ( psi), 14 days to form; Witting rxn: 59-69% yld, 15-24:1 Z/E fix: Smith, A. B.; Freeze, S.; Brouard,.; irose, T. rg. Lett. 2003, 5, 4405 MM group in place of - no pressure needed for Wittig salt formation but Wittig rxn: 51%, 4:1 Z/E Chris Wipf Group 4 3/27/04
5 Marshall, J. A.; Johns, B. A. J. rg. Chem. 1998, 63, steps (29 steps longest linear sequence) 2.2% overall yield (8 mg prepared) lithiated alkyne addition Suzuki C + + MM PMB TES PG + C SnBu 3 C 2 R Paterson,.; Delgado,.; Florence, G. J.; Lyothier,.; Scott, J. P.; Sereinig, N. rg. Lett. 2003, 5, 35 2 nd generation approach 35 steps (24 steps longest linear sequence) 5.1% overall yield Lithium Aldol Boron Aldol 2 C C C 2 Ar + + C PMB PMB PMB PMB C Chris Wipf Group 5 3/27/04
6 C steps 5 steps PMB N steps 1 ()NC steps PMB steps 3 steps C Chris Wipf Group 6 3/27/04
7 kg C 2 PMB N CCl equiv cat. PPTS, C 2 Cl 2 /cyclohexane quant. PMB 67 kg C 2 Ph xs LiB 4 TF/Et quant. PMB 50 kg cat. TEMP, 1.3 equiv NaCl KBr, KC 3, C 2 Cl 2, 2 PMB C 29 kg [unstable oil] N 1.1 equiv 1.6 equiv n-bu 2 BTf, 1.8 equiv Et 3 N, C 2 Cl % PMB 19 kg [solid] Ph N 1. Li, 2 2,, 2 ; Cl, toluene PMB 2 N Ph 1. Cl, C 2 Cl 2 / 2 PMB N equiv (R)-PhC(C 3 ), toluene 84% 19 kg [solid] equiv N--piperidine, 1.00 equiv i-buccl, C 2 Cl 2 ; 1.25 equiv N Cl, 1.30 equiv N--piperidine 80% 29 kg 77% purity Chris Wipf Group 7 3/27/04
8 ()NC PMB 25 kg N 1.2 equiv -Tf PMB 1.3 equiv 2,6-lutidine, toluene 90% 30 kg (in 2 portions using 150 kg Si 2 each!) 1. 0 psi 2, wet Pd/C, t-bu N 2. cat. TEMP, 2 equiv Ph(Ac) 2 C 2.3 kg N 1.2 equiv MgBr C 2 Cl kg N S 3 pyridine Et 3 N/DMS/C 2 Cl 2 73% (4 steps) 5 1 N 0.94 kg Chris Wipf Group 8 3/27/04
9 PMB 7 PMB 14 kg N 1.5 equiv Red-Al toluene 68% PMB C 8.3 kg 1.4 equiv NaMDS, 1.6 equiv Ph 3 PC()C 3 PMB TF 31% (15:1 Z/E) kg PMB major side-product Chris Wipf Group 9 3/27/04
10 PMB 18 kg N 1.5 equiv DDQ 4A MS, toluene 50% 6.9 kg [solid] N Ph N 1.6 equiv Ph 1.6 equiv LiAl 4 TF 91% 1.5 kg [solid] C 1.7 equiv n-bu 2 BTf, 2.0 equiv Et 3 N, C 2 Cl 2 85% N 2.1 kg [unstable solid] 1.7 equiv -Tf 1.9 equiv 2,6-lutidine, toluene quant. Ph N 2.5 equiv LiB 4 TF/Et 56% 2.9 kg Chris Wipf Group 10 3/27/ kg 1.6 equiv 2, 1.6 equiv PPh equiv imidazole, toluene/cn 90% 3.1 kg [light-sensitive oil]
11 equiv t-buli, TF/hexane equiv 9-BBN 1.6 kg 1.4 equiv PMB PMB 4.6 equiv DBAL 1.1 kg 1.0 equiv 5 mol% Pd(dppf)Cl 2, 3.5 equiv Cs 2 C 3, DMF/ 2 73% fi Marshall 1.3 kg [solid] toluene 92% PMB 1.8 kg 2.4 equiv S 3 pyridine 3.2 equiv Et 3 N, DMS/C 2 Cl 2 93% PMB 1.5 kg C PMB 4.3 equiv CrCl 2, TF 5.6 equiv C 2 =CC(Br)TMS; K, / 2 81% fi Paterson PMB 2.9 equiv DDQ PMB C 2 Cl 2 88% 1.3 kg 0.79 kg [foam] Chris Wipf Group 11 3/27/04
12 1.5 equiv Ph(Ac) 2, cat. TEMP C C 2 Cl 2, trace 2 1 equiv (CF 3 C 2 ) 2 P()C 2 C 2, 1 equiv NaMDS, 18-crown-6, toluene 78%, Z/E = 30:! 0.78 kg 2 C 1.5 equiv Cl 3 CCNC, C 2 Cl 2 ; K 2 C 3, quant. 2 C 5 equiv DBAL C 2 Cl 2, -78 C, 1 h 0.62 kg 0.79 kg [foam] 1.2 equiv Ph(Ac) 2, cat. TEMP C 2 Cl 2, trace 2 rt, 90 min 80% C 0.65 kg [foam] Chris Wipf Group 12 3/27/04
13 ()NC C 0.94 kg (2.8 mol) C ()(N()) Mol. Wt.: g (0.97 mol) C N 5 () 2 Mol. Wt.: (+)-discodermolide C N 8 Mol. Wt.: ()NC 234 g 6.6 equiv equiv (+)-DP-Cl, 6.6 equiv Et 3 N, Et equiv (71 g) Aldehyde 63% (dr ~ 4:1) ()NC 67 g [foam] xs [ 4 N]B(Ac) 3 Ac/TF 73% ()NC 76 g [foam] 3 N Cl, 61% (+)-discodermolide 28 g [foam] recrystallize 65 g from CN/ 2 Æ 61.7 g (monohydrate) Chris Wipf Group 3/27/04
14 60 g, 39 steps, 17 chromatographic purifications, 20 months, 43 chemists "The end game is far from ideal... The arduous of the final aldol coupling product is clearly not practical to move into production..." "The success of this project... sends a positive message to... the synthetic academic community... that: 'your work need not just be of academic interest' and it may be worth taking a few risks." "The option of optimizing the present synthesis further or replacing it with a better one is a topic of our ongoing studies..." "We anticipate that our new third-generation approach will further simplify the synthesis and reduce the cost of the clinical material." A. B. Smith Smith 2 nd generation approach: 34 steps (24 longest linear sequence), 6% overall yield Novartis-Smith-Paterson approach: 39 steps (26 longest linear sequence), 0.65% overall yield Chris Wipf Group 14 3/27/04
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