total synthesis of epicoccin g - ccc.chem.pitt.educcc.chem.pitt.edu/wipf/current...

K. C. Nicoalou, Sotirios Totokotsopoulos, Denis Giguère,Ya-Ping Sun, and David Sarlah

JACS. ASAP. May 6, 2011DOI: 10.102/ja2032635

Christopher RosenkerWipf Group - Current Literature

May 21, 2011

Total Synthesis of Epicoccin G

Chris Rosenker@ Wipf Group of 16 5/30/2011

Biological activities and clinical use ofdiketopiperazines

Huang, R.; Zhou, X.; Xu, T.; Yang, X.; Liu, Y. Chem. Biodivers. 2010. 7. 2809.Martins, M. B.; Carvalho, I. Tetrahedron 2007. 63. 9923.Mack, D. J.;Brichacek, M.; Plichta, A.; Njardrson J. T. “Top 200 Pharmaceutical Products by Worldwide Sales in 2009”

http://cbc.arizona.edu/njardarson/group/sites/default/files/Top200PharmaceuticalProductsByWorldwideSalesin2009.pdfImage from http://www.mannkindcorp.com/Collateral/Documents/English-US/101LR-TechnosphereTechTeaser-01.19.11.pdf

124 DKP’s have been isolated from marine sourcesup to 2008. A subclass includes dithio substitution.

Exhibit interesting bioactivities including:• plant-growth promotion• antimicrobial activity• quorum-sensing signaling (used by groups oforganisms to coordinate behavior)• antitumor activity• antiviral activity• inhibition against aflatoxin production

HNNH

O

OR2

R1 H

HNH2OH

OR1 H dimerization

NN

NH

H O

O

OO

Cialis (Tadalafil)Ranked 61st in 2009 ($1.6 billion)treatment of erectile dysfunction(phosphodiesterase 5 inhibitor)

HNNH

HN

O

HOOCO

ONH

O

COOH

Technosphere® technologyPart of formulation for inhaledinsulin marketed by MannKind

Biosynthetically derived by the dimerization ofamino acids


Synthesis of diketopiperazine natural products

Williams, R. M.; Rastetter, W. H. J. Org. Chem. 1980. 45. 2625.

NN

O

OCHO

MeSS

SSCPh3

1. NaBH4, THF, i-PrOH2. KI3, pyridine

NN

O

O

OHS

S

2:1; anti:syn (±)-hyalodendrin29%

NN

O

O OH

HMeSCl, Et3N

THF, -100 °C NN

O

O

CHOSMe

1. Li(t-BuO)3AlH2. TBDMSCl, Im

3. LDA; then MeSSMe, -78 °C

NN

O

OSMe

MeS

OTBDMS

1. LDA; then BnBr2. HCl

NN

O

O

MeS

SMeOH

61% over 4 steps

(±)-gliovictin85%

(alkylation >9:1 dr)

Rastetter and Williams: Sulfenylation strategy and epidithiodiketopiperazine formation during the synthesis of (±)-gliovictin and (±)-hyalodendrin.



Miknis, G. F.; Williams, R. M. J. Am. Chem. Soc. 1993. 115. 536.

Williams and Miknis: Interesting diketopiperazine formation strategy and disulfide formationfor the synthesis of (±)-aspirochlorine.

AcO

Cl

O O

NOBN

NHO OMe NBS, CHCl3

rt AcO

Cl

O

N

N

O

OMeO

OBNBrH

OBN-o-NO2Bn 67%

steps

AcO

Cl

O

NH

N

O

OMeO

AcS

SAcMeONH2, CSA

AcO

Cl

O

NH

N

O

OMeO

SS

H

H

(±)-aspirochlorine20-34%

mixture of diastereomers



Kim, J.; Ashenhurst, J. A.; Movassaghi, M. Science 2009. 324. 238.

First total synthesis of dimeric epidithiodiketopiperazine alkaloid

NHBoc

HN

O

CO2Me

N

1. TFA; then morpholine

2. Br23. MeI

NN

NPhO2S SO2Ph

Br

H O

O

49% over 4 steps

1. CoCl(PPh3)3 (46%)2. Py2AgMnO4 (63%)

3. TBSCl, PPY (55%)4. Na(Hg) (87%) N

N

NH

H O

ONN

HNHO

O

TBSO

OTBS

OHHO

K2CS3, TFA

NN

NH

H O

O

S

S SNN

HNHO

O

S

SS

56%

ethanolamine; then

KI3, pyridineN

N

NH

H O

O

SS

NN

HNHO

O

SS

(+)-11,11'-dideoxyverticillin A62%

Movassaghi and co-workers: Biosynthetically inspired approach to (+)-11,11’-dideoxyverticillin A


Epicoccin G isolation and structural assignment

Guo, H.; Sun, B.; Gao, H.; Chen, X.; Liu, S.; Yao, X.; Liu, X.; Che, Y. J. Nat. Prod. 2009. 72. 2115.Wang, J.; Ding, G.; Fang, L.; Dai, J.; Yu, S.; Wang, Y.; Chen, X.; Ma, S.; Qu, J.; Xu, S.; Du, D. J. Nat. Prod. 2010. 73. 1240.Image copied from http://website.nbm-mnb.ca/mycologywebpages/NaturalHistoryOfFungi/Hyphomycetes.html

X-ray structure of epicoccin GIsolated by two groups from epicoccum nigrum

(endophytic fungus) in China

Structure and relative stereochemistry wasdetermined by HRMS, 1H, 13C, and 2-D NMR;absolute configuration determined by Mosher esteranalysis and single crystal X-ray crystallography

Groups report identical characterization data exceptfor [α]D of +69.0 (c = 0.17, MeOH) and -141.5 (c =0.1, MeOH)

Reported as epicoccin G and ent-epicoccin G but hadthe same structure

33 g of crude extract provided 91 mg of epicoccin G

NN

O

O

MeS

SMe

H

H

O

OH

HO

OH

H

epicoccin G


Selected dithiodiketopiperazines

Nicolaou, K. C.; Totokotsopoulos, S.; Giguère, D.; Sun, Y.; Sarlah, D. J. Am. Chem. Soc. 2011, DOI: 10.1021/ja203263

NN

O

O2 3

4 5

6

78

92'3'

4'5'

6'

7' 8'

9'

NN

O

O

MeS

SMe

H

H

O

OH

HO

OH

H

epicoccin GEpicoccum nigrum (endophytic fugus)anti-HIV IC50: 13.5 µM (C8166 cells)

NN

O

O

MeS

SMe

H

H

O

OH

HO

OH

H

8,8'-epi-ent-rostratin B

NN

O

O

H

H

O

OH

HO

OH

H

rostratin BExserohilum rostratum (marine-derived fungus)

human colon carcinoma IC50: 1.9 µM (HTC-116)

SS

NN

O

O

H

H

O

OH

HO

OH

HS

S

exserohiloneExserohilum holmii (endophytic fungus)

suspected antibactrial and antifungal activity

SciFinder: Substructure search of 6-5-6-5-6 diketopiperazine core gives 40 structures8 references (6 isolation papers, 2 synthetic methodologies)


Retrosynthetic analysis of epicoccin G

Nicolaou, K. C.; Totokotsopoulos, S.; Giguère, D.; Sun, Y.; Sarlah, D. J. Am. Chem. Soc. 2011, DOI: 10.1021/ja2032635

NN

O

O

MeS

SMe

H

H

O

OH

HO

OH

H

epicoccin G

NN

O

O

MeS

SMe

H

H

O

OH

HO

OH

H[H]

NN

O

O

MeS

SMe

H

HH

HKornblum - DeLaMarerearrangement

OO

OO

NN

O

O

H

H

H

HH

H

sulfenylation/photooxygenation

dimerization

NBoc

CO2Me

H

HO

oxidativecyclization

HO NHBoc

CO2H

N-Boc tyrosine3.25 $/g (NovaBioChem)


Kornblum-DeLaMare rearrangement“The base catalyzed decompostion of a dialkyl peroxide”

Journal of the American Chemical Society, 1951Nathan Kornblum and Harold E. DeLaMare (Purdue University)

Mechanistic considerations

O ONH

25 °C, 80 hO

HO

79% 25%PGH2

OO

OH

C5H11

HO

O

R

R

O

HO

R

R

PGE2

PGD2COOH

Important key step in the biosynthesisof prostaglandins

OO

H

Et3NO

O HEt3N NEt3

OH

O

not an intermediatein the rearrangement reaction

O OMe2N H

OHOMe2N

B

OOMe2N

H

base

O-Ocleavage

O OHB

Kornblum, N.; DeLaMare, H. E. J. Am. Chem. Soc. 1951. 73. 880.Frimer, A. A. Chem. Rev. 1979. 79. 359.Kelly, D. R.; Bansal, H.; Morgan, J. J. G. Tetrahedron Let. 2007. 43. 9331.Staben, S. T.; Linghu, X.; Toste, F. D. J. Am. Chem. Soc. 2006. 128. 12658.

First enantioselective Kornblum-DeLaMare rearrangement utilized Meso-endoperoxides

and chiral cinchona alkaloids

OO

deMeQDAcCH2Cl2, rt

n

N

O

OAcN

O O

H

H

76-99% yield50-99% ee

n = 1-3

O

OH

n

n

small

large


HO NHCbz

CO2H PhI(OAc)2MeCN/i-PrOH (3:1)

NCbz

CO2Me

OH

HO

O

OO

NHCbzH

42% (50 g scale)99% ee

3 M KOH/H2O-20 °C, 10 min

80% yield97% ee

Oxidative cyclization of tyrosine

Wipf, P.; Kim, Y. Tetrahedron Lett. 1992. 33, 5477.Pierce, J. G.; Kasi, D.; Fushimi, M.; Cuzzupe, A.; Wipf, P. J. Org. Chem. 2008. 73. 7807.Nicolaou, K. C.; Totokotsopoulos, S.; Giguère, D.; Sun, Y.; Sarlah, D. J. Am. Chem. Soc. 2011, DOI: 10.1021/ja2032635Avogadro: an open-source molecular builder and visualization tool. Version 1.03. http://avogadro.openmolecules.net/

~1 kcal/mol difference in energy;Only one cyclization product observed;Intramolecular hydrogen bonding may

account for selectivity

Observed

Not-observed

Optimized “racemization free”large scale preparation

HO NHBoc

CO2H 1. PhI(OAc)2, MeOH2. NaHCO3, MeOH, rt

NBoc

CO2Me

OH

HO

51%over two steps

(Wipf yield)

O

OO

NHBocH

BocN

CO2MeO H

OHnot observed


Synthesis of epicoccin G

Nicolaou, K. C.; Totokotsopoulos, S.; Giguère, D.; Sun, Y.; Sarlah, D. J. Am. Chem. Soc. 2011, DOI: 10.1021/ja2032635Wipf, P.; Kim, Y. Tetrahedron Lett. 1992. 33, 5477.

HO NHBoc

CO2H1. PhI(OAc)2, MeOH2. NaHCO3, MeOH, rt

NBoc

CO2Me

OH

HO

1. Ac2O, Et3N, DMAP, CH2Cl2 0 °C to rt, 4 h

2. Zn, AcOH, MeOH, 65 °C, 0.5 h3. DBU, PhMe, 65 °C, 3 h

51%over two steps

(Wipf yield)

NBoc

CO2Me

H

HO

NaBH4, CeCl3•7H2OMeOH, -78-0 °C, 1 h

NBoc

CO2Me

H

HHO51%

over three steps 92%

TFA, CH2Cl2 (1:1)0-25 °C, 0.5 h

NH

CO2Me

H

HHO

99%

LiOH (aq), THF (5:1), 0-25 °C, 3 h

NBoc

CO2H

H

HHO

99%

O

OO

NHBocH



Nicolaou, K. C.; Totokotsopoulos, S.; Giguère, D.; Sun, Y.; Sarlah, D. J. Am. Chem. Soc. 2011, DOI: 10.1021/ja2032635Avogadro: an open-source molecular builder and visualization tool. Version 1.03. http://avogadro.openmolecules.net/

NH

CO2Me

H

HHO

NBoc

CO2H

H

HHO

BOP-Cl, Et3N, CH2Cl20-25 °C, 15 h

NBoc

H

HHO

O

NOH

H

H

OOMe86%

TFA, CH2Cl20-25 °C, 15 h;

then Et3N, CH2Cl20-25 °C, 15 h

NN

O

O

H

H

H

H

HO

OHH

H

(CF3CO)2O, Et3N, DMAP

MeCN, -40-25 °C, 1 h

77%over two steps

NN

O

O

H

H

H

H

F3COCO

OCOCF3

H

H

69%

Pd(PPh3)4, K2CO3, dioxane

65 °C, 0.5 h

NN

O

O

H

H

H

H

H

H

90%




no trans sulfenylation observed;suggesting intramolecular delivery

NN

O

O

H

H

H

H

H

H

S8, NaHMDS, THF, 25 °C1 min; then A, 1 min; then

NaHMDS, 25 °C, 0.5 h

A

NN

O

O

H

H

H

H

SSnS

SSnS

n = 0-6NaBH4, THF:MeOH (1:1)0-25 °C, 0.75 h; then MeI

25 °C, 15 h

NN

O

O

H

H

H

H

MeS

SMe

24%

NN

O

O

H

H

H

H

MeS

SMe

34%(from A)

NaBH4, THF:MeOH (1:1)0-25 °C, 0.75 h; then aq KI3

25 °C, 10 min

NN

O

O

H

HH

HS

S

32% and23% 2,2'-epi

(from A)NaBH4, THF:MeOH (1:1)0-25 °C, 0.75 h; then MeI

25 °C, 15 h (65%)H

H




N

HN

N

NH

Ph Ph

PhPh

TPP

NN

O

O

H

H

H

H

MeS

SMe

O2, TPP, CH2Cl2, 400 WPhilips-MH400/U sun lamp

-45 °C, 40 min; then DBU-45-0 °C, 1 h

NN

O

O

MeS

SMe

H

HH

H

OO

OOH

H

B

B

NN

O

O

H

H

H

H

MeS

SMe

O

OH

O

HO

52%

H2, Pd(OH)2/C, MeOH25 °C, 1 h

NN

O

O

H

H

H

H

MeS

SMe

O

OH

O

HO

86%epicoccin G

[!]D -141.0 (c = 0.10, MeOH)

H

H


Synthesis of 8,8’-epi-ent-rostratin B


NN

O

O

H

HH

HS

S

O2, TPP, CH2Cl2, 400 WPhilips-MH400/U sun lamp

0 °C, 2 h; then Et3N0-25 °C, 3 h

55%

[CuH(PPh3)]6, benzene25 °C, 0.5 h; then

aq. KI3, 25 °C, 10 min

82%

8,8'-epi-ent-rostratin B

NN

O

O

H

HH

HS

SOO

OO

NN

O

O

H

HH

HS

S

O

OH

HO

O NN

O

O

H

HH

HS

S

O

OH

HO

O


Conclusions

• Key steps include:

• Oxidative cyclization of tyrosine for starting material synthesis

• Two-directional, intramolecular sulfenylation

• Photooxygenation - Kornblum-DeLaMare rearrangement

• Synthesis of Epicoccin G in 18 steps from N-Boc tyrosine(longest linear sequence) with a 2.9% yield (from Wipf indoline).

• Synthesis of 8,8’-epi-ent-rostratin B in 19 steps from N-Boctyrosine (longest linear sequence) with a 2.0% yield (from Wipfindoline).
