enantioselective total synthesis of (-) …ccc.chem.pitt.edu/wipf/current...

Julian A. Codelli, Angela L. A. Puchlopek, and Sarah E. Reisman*JACS. ASAP. Oct. 24, 2011DOI: 10.1021/ja209354e

Christopher RosenkerWipf Group - Current Literature

November 12, 2011

Enantioselective Total Synthesis of (-)-Acetylaranotin, aDihydrooxepine Epidithiodiketopiperazine

O

NN

O

AcO HO

OH OAcS S

18 steps

Ot-BuO

O

H

Ph NH2

CO2Et

commercially availablestarting materials acetylaranotin

Chris Rosenker @ Wipf Group of 16 12/29/2011

Epidithiodiketopiperazine natural products

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

•Biosynthetically arise by the joining of two amino acids which are furtherfunctionalized via oxidative pathways

•Subset contains a 7-membered dihydrooxepine ring

Biological activity of dihydrooxepine containing ETPs include inhibition of viral RNApolymerase 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

NN

O

AcO HO

OH OAcS S

O

NNO H

O

OHS SO

HO Ph

OO

Ph

O

NN

HO

OS S

O

OO

OH

MeOOMe

(!)-acetylaranotin(+)-MPC1001B

(!)-emethallicin A

NNO

OS SHHO

(!)-gliotoxinOH


Biosynthetic proposal of gliotoxin andaranotin 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 hypothesizedto occur via an epoxidized benzene ring.

HN

O

HN

O[O]

O

N

O

OHH

O

HN

OO

HN

O

O

[O]O

OH

N

O

H

gliotoxin type

aranotin type

ring expansion


Synthetic Methodologies to from Oxepines

SO2 SO2O10-3 mmHg

580 °C (55%)

OHCO3H

(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.



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

CO2MeHm-CPBA

CH2Cl2 (93%)O

H

CO2MeH

O

H

H

200 °C, 2 h

BHT, PhH[0.01 M]

OO

CO2MeH

OO

CO2MeH

35% 36%

O

O CO2MeH

O

O CO2MeH

O

H H HH

OO

H H HH

O O

H H H

CO2Me CO2Me

CO2Me

H

a

b


Synthetic Methodologies to from OxepinesVargas & 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.

HO

O

Ph

OHAc2O, pyridine

(31%)HO

O

Ph

OAc

OOH

OO Ac

HPyr:

HO

O

Ph

OAc

O

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

NBzBr

HTBDPSO

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

NTBDPSO H

BzBr

p-NO2BzO O

NTBDPSO H

BzBr

0.45 torr

150 to 250 °C(70%)

NBzBr

HTBDPSO

OO

Op-NO2Ph



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.

OPh OPhGrubbs II

toluene, reflux(60%)

O Grubbs II

toluene, reflux

O O

23% 46%

N CO2t-BuH

Boc

OH

TBSO

[Ir(cod)Cl]2 (10 mol%)NaHCO3, vinyl acetate

toluene, 100 °C(95%, E:Z;8:2) N CO2t-Bu

HBoc

O

TBSO

Grubbs II, Grubbs-Hoveyda,Schrock catalysts

O

N CO2t-BuTBSO H

Boc

1. TBAF, THF (87%)

2. Grubbs II (20 mol%) toluene, 110 °C (quant.)

O

N CO2t-BuHO H

Boc

H

H

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



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.

NN

HO

OSO

SiMe3

HO SePh

MEMO

(MeO)2CH(NMe2)

THF (70% brsm) NN

HO

OS

OSiMe3

MEMO

NMe2

SePhHO

TFA, toluene

50 °C (77%)

NNO

OS

OSiMe3O

MEMO HPhSe

NaIO4, THF-H2O

(39%) NNO

OS

OSiMe3O

MEMO H

O

NN

HO

OS S

O

OO

OH

MeOOMe

(+)-MPC1001B



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-workersW-cat cycloisomerization

HOHHO

O O

1. cat. W(CO)6, Et3N THF, h!, 55 °C

2. Ac2O, DMAP

O

O O

AcO

61-82%

HOHHO

O O

1. Et3N, THF, 60 °C

2. Ac2O, Et3N, DMAP

O

O O

AcO

W(CO)5

MeO

82%

Jia & Co-workersRu-cat cylcoisomerization

Ru

OO

N

N

N

PPh2

THF, 80 °CHO

HO

91%

R4

OH

HR1

R2

R3

OR1

R2

R3 R4

[CpOs(py)3]PF6

pyridine, 90 °C

56-68%

Esteruelas, Saá & Co-workersOs-cat cylcoisomerization


Reisman Group Retrosynthetic Analysis

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

O

NN

O

AcO HO

OH OAcS S

(!)-acetylaranotin

O

NN

O

HO HO

OH OH

H

H O

N CO2EtTBSO H

Teoc

N CO2Et

TeocHTBSO

H HH

O

NH

CO2EtH

HOt-Bu

O

Ph

H

O

Ph

NH2

CO2Et

OOt-Bu

metal-catalyzedcycloisomerization

catalytic asymmetric(1,3)-dipolar cycloaddition

commercially availablestarting materials

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


Catalytic asymmetric (1,3)-dipolarcycloaddition

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%) NH

HO2C

Ph CO2Et

·TFA>98% ee

N

NO OMe

OMe

OH H

HH

(!)-brucine$3.34/g (Aldrich)

OsO4, NMOacetone, t-BuOH

H2O

N

NO OMe

OMe

OH H

HH

HO OHH

95%brucin-OL

N

NO OMe

OMe

OH H

HH

O OH

Cu

N OEtPh Ot-BuO

H O


Synthesis of Acetylaranotin


NH

HO2C

Ph CO2Et

·TFA

1. Teoc-OSu, Et3N H2O/dioxane (83%)

2. O3, CH2Cl2, !78 °C; then DMS (93%)

N CO2EtO

O

HO H

H

Teoc

O O TMSTeoc:

THF, !78 to 0 °C;

N CO2EtO

O

H

H

Teoc

MgBr

N CO2Et

HOO

H

H

Teoc

HO

NaBH4, EtOH

(86%) N CO2EtH

Teoc

OH

HO

1. TBSOTf, 2,6-lutidine CH2Cl2, 0 °C (85%)

2. AcOH, THF, H2O (3:1:1) (79%)

N CO2EtH

Teoc

OH

TBSO

DMP, pyr, CH2Cl2 (93%)

N CO2EtH

Teoc

O

TBSO

H

then PPh3, DIADCH2Cl2, 0 °C (76%)


Synthesis of Acetylaranotin: dihydrooxepineformation


NCS, CH2Cl2pyrrolidine·TFA;

NaBH4, EtOH (93%)

N CO2EtH

Teoc

O

TBSO

H O

N CO2EtTBSO 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, AgOTfw/ and w/o ligands and additives

Conditions

N CO2EtH

Teoc

OH

TBSO

Cl [Rh(cod)Cl]2 (5 mol %)(4-FC6H4)3P (60 mol %)

DMF, 85 °C (88%)

O

N CO2EtTBSO H

Teoc

Cl

LiCl, Li2CO3, DMF100 °C (53%)

O

N CO2EtTBSO H

Teoc

desilylationO

NH

CO2EtTBSO H

mixture ofmono- & bis-desilylated

products

1. TBAF, THF, 0 °C (84%)

2. LiCl, Li2CO3, DMF 100 °C (65%)

A

A




O

NH

CO2EtTBSO H

LiOH, MeOHO

NH

CO2HTBSO H

O

NN

O

TBSO HO

OH OTBS

H

H

O

N CO2EtTBSO H

Teoc

Me3SnOH, DCE, 80 °C(90%)

O

N CO2HTBSO H

Teoc

A

A, BOP-ClEt3N, DMF

(87%)

O

N

N

O

TBSO H

OH OTBS

H

CO2Et

PO

N N OO

O O

Cl

BOP-Cl

Dimerization

Teoc


TBAF·(t-BuOH)4MeCN, 70 °C

N2 atm (76%)

O

NN

O

HO HO

OH OH

H

H TBAF·(t-BuOH)4MeCN, 70 °C

air (50%)

O

NN

O

HO HO

OH OH

HO

OH

NaHMDS, THF;S8, NaHMDS;then NaHMDS

(40%)

O

NN

O

HO HO

OH OHS4

1. AcCl, DMAP CH2Cl2 (70%)

2. (100 equiv) Et3N, MeCN; then O2 (45%)

HS SH

O

NN

O

AcO HO

OH OAcS S

O

N

N

O

TBSO H

OH OTBS

H

CO2EtTeoc



(-)-acetylaranotin

(18 steps, 0.45%, fromethylglycinate)


Conclusion

•Completed the first total synthesis of (-)-acetylaranotin in18 steps (~0.45 % yield)

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

•Azomethine ylide (1,3)-dipolar cycloaddition gave stereoselective accessto functionalized pyrrolidine

•Complete retention of steroechemistry during epitetrathiodiketo-piperazine formation


enantioselective total synthesis of (-) …ccc.chem.pitt.edu/wipf/current...

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