Enantioselective Total Synthesis of (-)-Acetylaranotin, a - - PowerPoint PPT Presentation

Julian A. Codelli, Angela L. A. Puchlopek, and Sarah E. Reisman*

• JACS. ASAP. Oct. 24, 2011

DOI: 10.1021/ja209354e Christopher Rosenker Wipf Group - Current Literature November 12, 2011

Enantioselective Total Synthesis of (-)-Acetylaranotin, a Dihydrooxepine Epidithiodiketopiperazine

O N N O AcO H O O H OAc

S S

18 steps Ot-Bu O O H Ph NH2 CO2Et commercially available starting materials acetylaranotin

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Epidithiodiketopiperazine natural products

Epidithiokiketopiperazines (ETP) are a broad collection of fungal metabolites that contain at least 14 different core structures.

• Biosynthetically arise by the joining of two amino acids which are further

functionalized via oxidative pathways

• Subset contains a 7-membered dihydrooxepine ring

Biological activity of dihydrooxepine containing ETPs include inhibition of viral RNA polymerase and antiproliferative/apoptotic activity against human cancer cells.

Gardiner, D. M.; Waring, P.; Howlett, B. J. Microbiology 2005, 151, 1021. Codelli, J. A.; Puchlopek, A. L. A.; Reisman, S. E. J. Am. Chem. Soc. 2011, DOI: 10.1021/ja209354e.

O N N O AcO H O O H OAc

S S

O N N O H O O H

S S

O HO Ph O O Ph O N N H O O

S S

O O O OH MeO OMe (!)-acetylaranotin (+)-MPC1001B (!)-emethallicin A N N O O

S S

H HO (!)-gliotoxin OH

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Biosynthetic proposal of gliotoxin and aranotin type natural products

Neuss, N.; Boeck, L. D.; Brannon, D. R.; Cline, J. C.; DeLong, D. C.; Gorman, M.; Huckstep, L. L.; Lively, D. H.; Mabe, J.; Marsh, M. M.; Molloy, B. B.; Nagarajan, R.; Nelson, J. D.; Stark, W. M. Antimicrob. Agents Chemother. 1968, 213. Gardiner, D. M.; Waring, P.; Howlett, B. J. Microbiology 2005, 151, 1021.

The biosynthesis of gliotoxin and aranotin type natural products is hypothesized to occur via an epoxidized benzene ring.

HN O HN O [O] O N O OHH O HN O O HN O O [O] O OH N O H gliotoxin type aranotin type ring expansion

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Synthetic Methodologies to from Oxepines

SO2 SO2 O 10-3 mmHg 580 °C (55%) O HCO3H (39%) O O O TMS LiHMDS; AcO2 -70 °C (70%) OAc O TMS CCl4, 135 °C 12 h (94%) O TMS OAc

Cadogan, Gosney & Co-workers: Cope rearrangement using a highly strained epoxycyclobutane. White & Co-workers: Cope rearrangement of cis-divinyl epoxide.

Aitken, R. A.; Cadogan, J. I. G.; Gosney, I.; Hamill, B. J.; McLaughlin, L. M. J. Chem. Soc.; Chem. Comm. 1982, 1164. Clark, D. L.; Chou, W.-N.; White, J. B. J. Org. Chem. 1990, 55, 3975. Chris Rosenker @ Wipf Group Page 4 of 16 12/29/2011

Synthetic Methodologies to from Oxepines

Snapper & Leyhane: Thermal fragmentation of highly strained epoxides provides functionalized oxepines.

Leyhane, A. J.; Snapper, M. L. Org. Lett. 2006, 8, 5183.

O O H CO2Me H m-CPBA CH2Cl2 (93%) O H CO2Me H O H H 200 °C, 2 h BHT, PhH [0.01 M] O O CO2Me H O O CO2Me H 35% 36% O O CO2Me H O O CO2Me H O H H H H O O H H H H O O H H H CO2Me CO2Me CO2Me H a b

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Synthetic Methodologies to from Oxepines

Vargas & Co-workers: Isolated oxepine during structural elucidation of sesquiterpene hydroperoxide.

Lu, T.; Vargas, D.; Fischer, N. H. Phytochemistry 1993, 34, 737. Goodman, R.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 9392. Goodman, R. M. Ph.D. Thesis, Harvard University, May 1998.

H O O Ph OH Ac2O, pyridine (31%) H O O Ph OAc O OH O O Ac H Pyr: H O O Ph OAc O

Kishi & Goodman: Criegee rearrangement of allylic hydroperoxides to form an Aranotin type precursor.

N BzBr H TBDPSO HOO

• 1. (p-NO2Bz)2O, DMAP

(5 mol%), -45 to -20 °C

• 2. BF3·Et2O (47 mol%)
• 40 to -20 °C, 6 h

(45% over two steps) O N TBDPSO H BzBr p-NO2BzO O N TBDPSO H BzBr 0.45 torr 150 to 250 °C (70%) N BzBr H TBDPSO O O O p-NO2Ph

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Synthetic Methodologies to from Oxepines

Bräse & Co-workers: Enol-ether RCM on an unprotected allylic alcohol.

Fustero, S.; Sáchez-Roselló, M.; Jiménez, D.; Sanz-Cervera, J. F.; del Pozo, C.; Aceña, J. L. J. Org. Chem. 2006, 71, 2706. Gross, U.; Nieger, M.; Bräse, S. Chem.-Eur. J. 2010, 16, 11624.

O Ph O Ph Grubbs II toluene, reflux (60%) O Grubbs II toluene, reflux O O 23% 46% N CO2t-Bu H Boc OH TBSO [Ir(cod)Cl]2 (10 mol%) NaHCO3, vinyl acetate toluene, 100 °C (95%, E:Z;8:2) N CO2t-Bu H Boc O TBSO Grubbs II, Grubbs-Hoveyda, Schrock catalysts O N CO2t-Bu TBSO H Boc

• 1. TBAF, THF (87%)
• 2. Grubbs II (20 mol%)

toluene, 110 °C (quant.) O N CO2t-Bu HO H Boc H H

Fustero & Co-workers: Tandem RCM-olefin isomerization methodology.

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Synthetic Methodologies to from Oxepines

Peng, J.; Clive, D. L. J. Org. Lett. 2007, 9, 2939. Peng, J.; Clive, D. L. J. J. Org. Chem. 2009, 74, 513.

Clive & Peng: Acid-induced cyclicization of pendant alcohol onto a vinylogous amide.

N N H O O S O SiMe3 HO SePh MEMO (MeO)2CH(NMe2) THF (70% brsm) N N H O O S O SiMe3 MEMO NMe2 SePh HO TFA, toluene 50 °C (77%) N N O O S O SiMe3 O MEMO H PhSe NaIO4, THF-H2O (39%) N N O O S O SiMe3 O MEMO H O N N H O O

S S

O O O OH MeO OMe (+)-MPC1001B

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Synthetic Methodologies to from Oxepines

Alcázar, E.; Pletcher, J. M.; McDonald, F. E. Org. Lett. 2004, 6, 3877. Koo, B.; McDonald, F. E. Org. Lett. 2007, 9, 1737. Liu, P. N.; Su, F. H.; Wen, T. B.; Sung, H. H. Y.; Williams, I. D.; Jia, G. Chem.-Eur. J. 2010, 16, 7889. Varela-Fernández, A.; García-Yebra, C.; Varela, J. A.; Esteruelas, M. A.; Saá, C. Angew. Chem. Int., Ed. 2010, 49, 4278.

McDonald & Co-workers W-cat cycloisomerization

H OH HO O O

• 1. cat. W(CO)6, Et3N

THF, h!, 55 °C

• 2. Ac2O, DMAP

O O O AcO 61-82% H OH HO O O 1. Et3N, THF, 60 °C

• 2. Ac2O, Et3N, DMAP

O O O AcO W(CO)5 MeO 82%

Jia & Co-workers Ru-cat cylcoisomerization

Ru O O N N N PPh2

THF, 80 °C HO H O 91%

R4 OH H R1 R2 R3 O R1 R2 R3 R4 [CpOs(py)3]PF6 pyridine, 90 °C 56-68%

Esteruelas, Saá & Co-workers Os-cat cylcoisomerization

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Reisman Group Retrosynthetic Analysis

Codelli, J. A.; Puchlopek, A. L. A.; Reisman, S. E. J. Am. Chem. Soc. 2011, DOI: 10.1021/ja209354e.

O N N O AcO H O O H OAc

S S

(!)-acetylaranotin O N N O HO H O O H OH H H O N CO2Et TBSO H Teoc N CO2Et Teoc H TBSO H H H O N H CO2Et H H Ot-Bu O Ph H O Ph NH2 CO2Et O Ot-Bu metal-catalyzed cycloisomerization catalytic asymmetric (1,3)-dipolar cycloaddition commercially available starting materials

(-)-acetylaranotin was isolated over 40 years ago and had not yet been synthesized

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Catalytic asymmetric (1,3)-dipolar cycloaddition

Codelli, J. A.; Puchlopek, A. L. A.; Reisman, S. E. J. Am. Chem. Soc. 2011, DOI: 10.1021/ja209354e. Kim, H. Y.; Shih, H.-J.; Knabe, W. E.; Oh, K. Angew. Chem., Int. Ed.. 2009, 48, 7420.

Ph N CO2Et t-BuO2C

• 1. CuI (10 mol %)

brucin-OL (10 mol %) DBU (10 mol %) (50%, 96% ee)

• 2. TFA, Et3SiH, CH2Cl2 (77%)

N H HO2C Ph CO2Et ·TFA >98% ee N N O OMe OMe O H H H H (!)-brucine $3.34/g (Aldrich) OsO4, NMO acetone, t-BuOH H2O N N O OMe OMe O H H H H HO OH H 95% brucin-OL N N O OMe OMe O H H H H O O H Cu N OEt Ph O t-BuO H O

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Synthesis of Acetylaranotin

Codelli, J. A.; Puchlopek, A. L. A.; Reisman, S. E. J. Am. Chem. Soc. 2011, DOI: 10.1021/ja209354e.

N H HO2C Ph CO2Et ·TFA

• 1. Teoc-OSu, Et3N

H2O/dioxane (83%)

• 2. O3, CH2Cl2, !78 °C;

then DMS (93%) N CO2Et O O HO H H Teoc

O O TMS Teoc:

THF, !78 to 0 °C; N CO2Et O O H H Teoc MgBr N CO2Et HO O H H Teoc HO NaBH4, EtOH (86%) N CO2Et H Teoc OH HO

• 1. TBSOTf, 2,6-lutidine

CH2Cl2, 0 °C (85%)

• 2. AcOH, THF, H2O

(3:1:1) (79%) N CO2Et H Teoc OH TBSO DMP, pyr, CH2Cl2 (93%) N CO2Et H Teoc O TBSO H then PPh3, DIAD CH2Cl2, 0 °C (76%)

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Synthesis of Acetylaranotin: dihydrooxepine formation

Codelli, J. A.; Puchlopek, A. L. A.; Reisman, S. E. J. Am. Chem. Soc. 2011, DOI: 10.1021/ja209354e.

NCS, CH2Cl2 pyrrolidine·TFA; NaBH4, EtOH (93%) N CO2Et H Teoc O TBSO H O N CO2Et TBSO H Teoc Conditions [Rh(cod)Cl]2, [Rh(cod)(MeCN)2]BF4, CpRuCl[(4-FC6H4)3P]2 (CO)5W=C(OMe)Me, AuCl, Pd(OAc)2, CuI, AgOTf w/ and w/o ligands and additives Conditions N CO2Et H Teoc OH TBSO Cl [Rh(cod)Cl]2 (5 mol %) (4-FC6H4)3P (60 mol %) DMF, 85 °C (88%) O N CO2Et TBSO H Teoc Cl LiCl, Li2CO3, DMF 100 °C (53%) O N CO2Et TBSO H Teoc desilylation O N H CO2Et TBSO H mixture of mono- & bis-desilylated products

• 1. TBAF, THF, 0 °C (84%)
• 2. LiCl, Li2CO3, DMF

100 °C (65%) A A

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Synthesis of Acetylaranotin

Codelli, J. A.; Puchlopek, A. L. A.; Reisman, S. E. J. Am. Chem. Soc. 2011, DOI: 10.1021/ja209354e.

O N H CO2Et TBSO H LiOH, MeOH O N H CO2H TBSO H O N N O TBSO H O O H OTBS H H O N CO2Et TBSO H Teoc Me3SnOH, DCE, 80 °C (90%) O N CO2H TBSO H Teoc A A, BOP-Cl Et3N, DMF (87%) O N N O TBSO H O H OTBS H CO2Et P O N N O O O O Cl BOP-Cl Dimerization Teoc

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TBAF·(t-BuOH)4 MeCN, 70 °C N2 atm (76%) O N N O HO H O O H OH H H TBAF·(t-BuOH)4 MeCN, 70 °C air (50%) O N N O HO H O O H OH HO OH NaHMDS, THF; S8, NaHMDS; then NaHMDS (40%) O N N O HO H O O H OH

S4

• 1. AcCl, DMAP

CH2Cl2 (70%) 2. (100 equiv) Et3N, MeCN; then O2 (45%) HS SH O N N O AcO H O O H OAc

S S

O N N O TBSO H O H OTBS H CO2Et Teoc

Synthesis of Acetylaranotin

Codelli, J. A.; Puchlopek, A. L. A.; Reisman, S. E. J. Am. Chem. Soc. 2011, DOI: 10.1021/ja209354e.

(-)-acetylaranotin (18 steps, 0.45%, from ethylglycinate)

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Conclusion

• Completed the first total synthesis of (-)-acetylaranotin in

18 steps (~0.45 % yield)

• Synthetic highlights include:
• Rhodium-catalyzed cycloisomerization/chloride elimination to provide

dihydrooxepine

• Azomethine ylide (1,3)-dipolar cycloaddition gave stereoselective access

to functionalized pyrrolidine

• Complete retention of steroechemistry during epitetrathiodiketo-

piperazine formation

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