total synthesis of epicoccin g - ccc/upcmld
TRANSCRIPT
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 Page 1 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
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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.
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Synthesis of diketopiperazine natural products
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
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Synthesis of diketopiperazine natural products
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
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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
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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)
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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)
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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
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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
Chris Rosenker@ Wipf Group Page 10 of 16 5/30/2011
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
Chris Rosenker@ Wipf Group Page 11 of 16 5/30/2011
Synthesis of epicoccin G
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%
Chris Rosenker@ Wipf Group Page 12 of 16 5/30/2011
Synthesis of epicoccin G
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/
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
Chris Rosenker@ Wipf Group Page 13 of 16 5/30/2011
Synthesis of epicoccin G
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/
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
Chris Rosenker@ Wipf Group Page 14 of 16 5/30/2011
Synthesis of 8,8’-epi-ent-rostratin B
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/
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
Chris Rosenker@ Wipf Group Page 15 of 16 5/30/2011
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).
Chris Rosenker@ Wipf Group Page 16 of 16 5/30/2011