Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide

HO H O O OH O O

OH NH2

• 61.7 g prepared in 39 steps • 43 chemists worked on the project which lasted 20 months

Chris Kendall @ Wipf Group 1 3/27/04 Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide

8 HO 22 H O O OH O O 1 5 13 OH NH2 OH

• 24 carbon linear polypropionate chain containing 13 stereocenters (6 hydroxyl and 7 methyl) and 3 cis double bonds • triply repeated stereotriad at C2-4, C12-10 and C18-20

• Five academic research groups have reported total syntheses • numerous (at least 26) fragment syntheses also published • review: Paterson, I.; Florence, G. J. Eur. J. Org. 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 I clinical trials (Novartis) • potent inhibitor of tumor cell growth in vitro (including paclitaxel- and epothilone-resistant cells), and in mouse models

Chris Kendall @ Wipf Group 2 3/27/04 Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054

• 36 steps (24 steps longest linear sequence) • 4.5% overall yield (9 mg prepared)

(Acetylenic) Nozaki-Kishi alkylation (2x) CHO I H HO PhS O Br + + H O O OH O O O OPMB OTBS OH NH2 OTBS OH

CO2iPr O B CO2iPr O TBSO TBSO

CHO + or OTBS TBSO OH OH OH CO2iPr O B CO2iPr O HO CO2Me Roush et al. "Roche Ester" 1990 JACS 6348

Harried, S. S.; Yang, G.; Strawn, M. A.; Myles, D. C. J. Org. Chem. 1997, 62, 6098

• 27 steps • <<1% overall yield (3 mg prepared) • Disconections as above but Olefinic Nozaki-Kishi and mono-alkylation of ethyl ketone (not bis-alkylation of methyl ketone)

Chris Kendall @ Wipf Group 3 3/27/04 Smith III, A. B.; Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 2000, 122, 8654

• 37 steps (24 steps longest linear sequence) • 6% overall yield (1.04 g prepared)

Wittig Negishi Coupling I TBSO CHO HO TBSO H I TBSO O O H O O O O OH O O + +

OH NH2 OH OTBS OH OMe

OMe PMBO N Me OH O

HO CO2Me

• Witting salt required 12.8 kBar (185 000 psi), 14 days to form; Witting rxn: 59-69% yld, 15-24:1 Z/E

• fix: Smith III, A. B.; Freeze, S.; Brouard, I.; Hirose, T. Org. Lett. 2003, 5, 4405 • MOM group in place of TBS - no pressure needed for Wittig salt formation but Wittig rxn: 51%, 4:1 Z/E

Chris Kendall @ Wipf Group 4 3/27/04 Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885

• 39 steps (29 steps longest linear sequence) • 2.2% overall yield (8 mg prepared)

lithiated alkyne Suzuki addition CHO HO TBSO I H O O OH O O + + I

OH NH2 O O OMOM PMBO OTES OH PMP

SnBu3 PGO + CHO H CH2OR

Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.; Scott, J. P.; Sereinig, N. Org. Lett. 2003, 5, 35

• 2nd generation approach • 35 steps (24 steps longest linear sequence) • 5.1% overall yield Lithium Aldol

CO2Ar HO MeO2C CHO O + + O O OH O O OHC OTBS OPMB OH NH2 OTBS Boron OH Aldol

PMBO PMBO OH PMBO CHO Chris Kendall @ Wipf Group 5O OH 3/27/04 Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide

HO CO2Me

6 + 2 steps

5 steps Me 6 + 1 steps PMBO N OMe OH O

1 O MeO(Me)NOC 5 I 3 + 1 steps 21 15 TBSO O O OTBS PMP PMBO 7 I

13 OTBS 11 + 1 steps

3 steps

7 15 OHC 21 O O O HO 13 TBS 7 15 21 OTBS NH2 H O O OH O O 1 5 13 OH NH2 OH

Chris Kendall @ Wipf Group 6 3/27/04 Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide

NH 8 HO 22 1.0 equiv PMBO CCl H 3 O O OH O O HO PMBO 1 5 13 CO2Me cat. PPTS, CO2Me OH NH2 CH2Cl2/cyclohexane 33 kg quant. 67 kg OH [oil]

O 1.1 equiv N cat. TEMPO, Ph O xs LiBH4 1.3 equiv NaOCl O PMBO O PMBO OH PMBO N THF/EtOH KBr, KHCO3, CHO 1.6 equiv n-Bu2BOTf, quant. CH Cl , H O 1.8 equiv Et N, CH Cl 50 kg 2 2 2 29 kg 3 2 2 OH O O 46 - 55% [oil] [unstable oil] 19 kg [solid]

1. LiOH, H2O2, MeOH, H2O; HCl, toluene 1. HCl, CH Cl /H O Me PMBO OH • H N Ph 2 2 2 PMBO N 2 OMe 2. 1.05 equiv (R)-PhCH(CH3)NH2, OH O 2. 1.05 equiv N-Me-piperidine, OH O toluene 1.00 equiv i-BuOCOCl, 84% 19 kg CH2Cl2; 29 kg [solid] 1.25 equiv MeONHMe•HCl, [oil] 1.30 equiv N-Me-piperidine 77% purity 80%

Chris Kendall @ Wipf Group 7 3/27/04 Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide

8 HO 22 H 1 O O O OH O O MeO(Me)NOC 5 1 5 13 OH NH2

OTBS OH

1. 130 psi H2, Me 1.2 equiv TBS-OTf Me wet Pd/C, t-BuOH PMBO N PMBO N OMe OMe 1.3 equiv 2,6-lutidine, 2. cat. TEMPO, OH O TBSO O toluene 2 equiv PhI(OAc)2 25 kg 90% 30 kg [oil] chromatography (in 2 portions using 150 kg SiO2 each!)

Me Me Me 1.2 equiv MeMgBr N SO •pyridine 5 1 N N OMe 3 OMe OHC OMe OH O O O O O TBSO O CH2Cl2 Et3N/DMSO/CH2Cl2 TBS 73% (4 steps) TBS 2.3 kg 1.6 kg 0.94 kg [oil] [oil] [oil] chromatography

Chris Kendall @ Wipf Group 8 3/27/04 Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide

8 HO 22 H O O OH O O 1 5 13 OH NH2 OH

PMBO 7 I

13 OTBS

Me 1.5 equiv Red-Al PMBO N PMBO OMe CHO toluene TBSO O OTBS 68% 14 kg 8.3 kg [oil] chromatography

1.4 equiv NaHMDS, I 1.6 equiv Ph3PCH(I)CH3 O PMBO PMBO THF 7 13 OTBS TBSO 31% (15:1 Z/E) 1.08 kg major side-product [oil] chromatography

Chris Kendall @ Wipf Group 9 3/27/04 Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide

I 21 15 TBSO O O

PMP Me Me 1.5 equiv DDQ N PMBO N OMe OMe 4A MS, toluene O O O OH O 50% 8 PMP HO 22 18 kg H 6.9 kg O O OH O O [solid] 1 5 13 OH NH2

OH Ph

O 1.6 equiv Ph N O 1.6 equiv LiAlH4 CHO O O 1.7 equiv TBS-OTf N O O THF 1.7 equiv n-Bu2BOTf, 1.9 equiv 2,6-lutidine, O O OH O O 91% PMP 2.0 equiv Et3N, CH2Cl2 toluene 85% PMP quant. 1.5 kg [solid] 2.1 kg [unstable solid]

1.6 equiv I2, OH I O 2.5 equiv LiBH4 1.6 equiv PPh3 N THF/EtOH O O O O O O O 3.2 equiv imidazole, O O O O TBS TBS 56% PMP toluene/MeCN PMP TBS PMP 90% 2.0 kg 3.1 kg 2.9 kg [oil] [light-sensitive oil] [oil] chromatography chromatography Chris Kendall @ Wipf Group 10 3/27/04 Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide

I 1. 2.8 equiv t-BuLi, THF/hexane

TBSO O O 2. 1.6 equiv 9-MeOBBN PMP

1.6 kg 1.4 equiv PMBO PMBO I 4.6 equiv DIBAL O O O 5 mol% Pd(dppf)Cl2, toluene OTBS TBS 3.5 equiv Cs2CO3, OTBS PMP 92% DMF/H O 1.1 kg 2 73% 1.3 kg 1.0 equiv ﬁ Marshall ‹ [solid]

4.3 equiv CrCl2, THF PMBO PMBO 2.4 equiv SO3•pyridine CHO 5.6 equiv CH2=CHCH(Br)TMS; O O OH O OPMB 3.2 equiv Et3N, KOH, MeOH/H2O TBS TBS 81% OTBS PMP DMSO/CH2Cl2 OTBS 93% ﬁ Paterson 1.8 kg 1.5 kg [oil] [oil] chromatography chromatography

PMBO 2.9 equiv DDQ HO

O OPMB CH2Cl2 O OH TBS 88% TBS OTBS OTBS

1.3 kg 0.79 kg [oil] [foam] chromatography chromatography

Chris Kendall @ Wipf Group 11 3/27/04 Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide

1.5 equiv PhI(OAc)2, 1 equiv (CF3CH2O)2P(O)CH2CO2Me, HO cat. TEMPO 1 equiv NaHMDS, OHC

O OH CH2Cl2, trace H2O O OH 18-crown-6, toluene TBS TBS 78%, Z/E = 30:! OTBS OTBS

0.78 kg

1.5 equiv Cl3CCONCO, CH2Cl2; 5 equiv DIBAL MeO2C MeO2C O O O O OH K2CO3, MeOH CH2Cl2, TBS quant. TBS -78 °C, 1 h OTBS OTBS NH2

0.62 kg 0.79 kg [oil] [foam] chromatography

1.2 equiv PhI(OAc)2, HO cat. TEMPO OHC O O O CH2Cl2, trace H2O O O O TBS rt, 90 min TBS OTBS NH2 OTBS NH 80% 2 0.65 kg [foam] chromatography

Chris Kendall @ Wipf Group 12 3/27/04 Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide

O HO MeO(Me)NOC OHC H O O O O O OH O O TBS OH NH OTBS OTBS NH2 2

0.94 kg (2.8 mol) 647 g (0.97 mol) OH C8H12O3(TBS)(N(Me)OMe) C25H39NO5(TBS)2 (+)-discodermolide Mol. Wt.: 331.5 Mol. Wt.: 664.1 C33H55NO8 Mol. Wt.: 593.8

O 1. 5.4 equiv (+)-DIP-Cl, HO MeO(Me)NOC 6.6 equiv Et3N, Et2O O O O O MeO(Me)NOC 2. 1.0 equiv (71 g) Aldehyde TBS OTBS NH OTBS 63% (dr ~ 4:1) 2 234 g OTBS 6.6 equiv 67 g [foam] chromatography

HO xs [Me4N]B(OAc)3H 3 N HCl, MeOH HO O O O (+)-discodermolide MeO(Me)NOC AcOH/THF TBS 61% 73% OTBS NH2 28 g OTBS [foam] chromatography 76 g [foam] recrystallize chromatography 65 g from MeCN/H2O Æ 61.7 g (monohydrate) Chris Kendall @ Wipf Group 13 3/27/04 Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide

HO H O O OH O O

OH NH2 OH

• 60 g, 39 steps, 17 chromatographic purifications, 20 months, 43 chemists

• "The end game is far from ideal ... The arduous chromatography 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 III

• Smith III 2nd 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 Kendall @ Wipf Group 14 3/27/04