syntheses(of(xanthofulvin(and(vinaxanthone ...ccc.chem.pitt.edu/wipf/current...
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Syntheses of Xanthofulvin and Vinaxanthone, Natural Products Enabling Spinal Cord Regenera?on�
Abram Axelrod, Anders M. Eliasen, MaDhew R. Chin, Katherine Zlotkowski, and Dionicio Siegel* Angew. Chem. Int. Ed. 2013, 52, 3421 –3424 �
Feng Zhang @ Wipf Group Page 1 of 12 04/20/2013�
Feng Zhang Wipf Group Current Literature
April 20, 2013 �
O
HO2CHO
HO
O
OMe
Me
OH
O
O CO2HOH
OH O
HO2CHO
HO
O
OMe
O
Me
O
O CO2HOH
OH
xantofulvin (1) vinaxanthone (2)
Introduc?on�
• The failure of neurons in the central nervous system (CNS) to undergo regeneraGon following injury accounts for the permanent and debilitaGng effects that accompany spinal cord injury, for which there is no cure.
• Gene therapy, biologics, and stem-‐cell-‐based approaches have received considerable aOenGon in promoGng CNS regeneraGon
• The delivery of drugs directly into the spinal cavity through spinal injecGon can expedite small-‐molecule-‐based drug development.
• Moreover, a variety of hydrogels and other polymers for conGnuous drug delivery, developed specifically for spinal cord therapy, when coupled with a validated small molecule will provide a unique and promising plaTorm for therapeuGc development.
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Scanning electron micrograph of Penicillium sp. SPF-‐3059 �
O
HO2CHO
HO
O
OMe
Me
OH
O
O CO2HOH
OH O
HO2CHO
HO
O
OMe
O
Me
O
O CO2HOH
OH
xantofulvin (1) vinaxanthone (2)
Tetrahedron Le2. 1991, 32, 4737 – 4740; An?biot. 2003, 56, 610 – 616. Sumitomo Kagaku 2005, 1–8; Nat. Med. 2006, 12, 1380 – 1389. �
Strongly block the effects of the inhibitor of axonal regeneraGon semaphorin3A (Sema3A) with no observable cytotoxicity at concentraGons above 1000 Gmes the effecGve dose. Animal studies of xanthofulvin have demonstrated remarkable effects aYer complete spinal cord transecGon. �
Feng Zhang @ Wipf Group Page 4 of 12 04/20/2013�
Synthesis of 5,6-‐dehydropolivione (11) �
O
O
O
1. PivCl, DMAP, iPr2NEt2. TBSOTf, TEA
69% two steps
OTBSO
OPiv
tBuO2CMe
O
THF, rt, 96%
tBuO2C
PivO OTBSO
Me
O
+CO2tBu
PivO OTBSO
O Me
> 20 : 1
HCl/THF76%
tBuO2C
HO OTBS
Me
OPivO MOMCl, iPr2NEt
72%
tBuO2C
MOMO OTBS
Me
OPivO Me2NCH(OMe)2
DME, 85 °C, 62%
tBuO2C
MOMO OH
OPivO
NMe2
O
O
O
Me
OH
OMeMe
toluene, 110 °C, 42%
tBuO2C
MOMO
PivO96%
O
O OH
Me
O HO2C
HO
HO
O
O OH
Me
O
3 4 5 6
7 (acetophenone) 8 9 (enaminone)
10 (triketone) 11 (5,6-dehydropolivione)
BCl3
Proposed dimeriza?on of 5,6-‐dehydropolivione (11) genera?ng vinaxanthone (2) �
HO2C
HO
HO
O
O OH
Me
O
HO2C
HO
HO
O
O O
Me
OH
HO2C
HO
HO
O
O OH
Me
O
Me
O
OH
O
HO2COH
OH
O
β eliminationMichael addition
HO2C
HO
HO
OH
O O
Me
O
O
Me
O
chromone condensation -H2O
HO2C
HO
HO
O
O
Me
O
OO
Me
O
O
HO2COH
OH
tautomerization
HO2C
HO
HO
O
O
Me
O
HOO
Me
O
O
HO2COH
OH
6π electrocyclization
HO2C
HO
HO
O
O
Me
O
O
O
HO2COH
OH
OH
Me O
β eliminationO
HO2CHO
HO
O
OMe
O
Me
O
O CO2HOH
OH
vinaxanthone (2)
+
HO2C
HO
HO
OH
O O
Me
O
MeO
O
O
CO2HOH
OH
O
O
O
HO2COH
OH
chromone condensation -H2O
HO2C
HO
HO
O
O O
MeOO
Me
O
O CO2HOH
OH
tautomerization
HO2C
HO
HO
O
O O
OHMeO
Me
O
O CO2HOH
OH
6π electrocyclization
HO2C
HO
HO
O
O O
OH O
O CO2HOH
OH
MeO
Meβ elimination
HO2C
HO
HO
O
O O
Me O
O CO2HOH
OH
MeO
2',3'-dehydroxanthofulvin
11
HO2C
HO
HO
O
O OH
Me
OH2O, 55 °C
61% O
HO2CHO
HO
O
OMe
O
Me
O
O CO2HOH
OH
vinaxanthone (2)
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Proposed reac?on of Polivione with 5,6-‐Dehydropolivione �
HO2C
HO
HO
O
O OH
Me
O
11HO2C
HO
HO
O
O O
Me
OH
HO2C
HO
HO
O
O OH
Me
O
Me
O
OH
O
HO2COH
OH
O
β eliminationMichael addition
HO2C
HO
HO
OH
O O
Me
O
O
Me
O
chromone condensation -H2O
HO2C
HO
HO
O
O
Me
O
OO
Me
O
O
HO2COH
OH
tautomerization
HO2C
HO
HO
O
O
Me
O
HOO
Me
O
O
HO2COH
OH
6π electrocyclization
HO2C
HO
HO
O
O
Me
O
O
O
HO2COH
OH
OH
Me O
β eliminationO
HO2CHO
HO
O
OMe
O
Me
O
O CO2HOH
OH
+
HO2C
HO
HO
OH
O O
Me
O
MeO
O
O
CO2HOH
OH
O
O
O
HO2COH
OH
chromone condensation -H2O
HO2C
HO
HO
O
O O
MeOO
Me
O
O CO2HOH
OH
tautomerization
HO2C
HO
HO
O
O O
OHMeO
Me
O
O CO2HOH
OH
6π electrocyclization
HO2C
HO
HO
O
O O
OH O
O CO2HOH
OH
MeO
Meβ elimination
HO2C
HO
HO
O
O OH
Me O
O CO2HOH
OH
MeO
xanthofulvin (1)
tautomerization
hemiketal formation
O
HO2CHO
HO
O
OMe
O
HO Me
O
CO2HOH
OH
411J
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Synthesis of intermediate 15�
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tBuO2C
MOMO OH
OPivO
NMe2
9 (enaminone)
I2, CHCl3, rt60%
tBuO2C
MOMO
PivO
12 (iodochromone)
O
OI
OH
MePdCl2(PPh3)2, CuI, iPr2NH
64%
tBuO2C
MOMO
PivO
13
O
OOH
Me
PDC
DCM, rt, 56%
tBuO2C
MOMO
PivO
14 (ynone)
O
OO
Me
NaH, -78 °C, 83%
Me OMe
O OtBuO2C
MOMO
PivO
O
O
OR
O
OMe
Me
R = Me 15
R = H 16
NaOH, 87%
pentasubstituted arene
Proposed mechamism of ynone (14) genera?ng intermediate (15) �
Feng Zhang @ Wipf Group Page 8 of 12 04/20/2013�
tBuO2C
MOMO
PivO
O
O
14
Me
O
OMe
OH
tBuO2C
MOMO
PivO
O
O
OMe
O
MeOH
β eliminationMichael addition
tBuO2C
MOMO
PivO
OH
O
MeO
OMe
O
6-exo-dig
tBuO2C
MOMO
PivO
O
O
OMe
O
MeOO
Me
tautomerization6π electrocyclization
β elimination
Me
O
Me
O
Me
O
H+
H
H+
tBuO2C
MOMO
PivO
O
O
OMe
O
MeOO
Me
tBuO2C
MOMO
PivO
O
O
OMe
O
MeOH
tBuO2C
MOMO
PivO
O
O
OMe
O
Me
OMe OMe
15
Comple?on of the synthesis of xanthofulvin (1) �
Feng Zhang @ Wipf Group Page 9 of 12 04/20/2013�
tBuO2C
MOMO
PivO
O
O
OH
O
Me
OMe
16
tBuO2C
MOMO
PivO
OH
O
+NMe2
9 (enaminone)
HBTU, iPr2NEt, DMF88%
tBuO2C
MOMO
PivO
O
O
O
O
Me
OMe
O
Me2N
OMOMOPiv
CO2tBu
tBuO2C
MOMO
PivO
O
O O
Me
OMe
O
O
NMe2
CO2tBuOPiv
OMOM
pyr.HClMeCN, 65 °C
68%
tBuO2C
MOMO
PivO
O
O O
Me
OMe
O
O CO2tBuOPiv
OMOM
17
18 (diketone) 19
1. NaBH3CN
2. BCl3, DMF89% two steps
O
HO2CHO
HO
O
OMe
Me
OH
O
O CO2HOH
OH
xantofulvin (1)
Outgrowth of GFP-‐labled cholinergic neurons in vivo in C. elegans a]er treatment with dibutyryl cAMP, xanthofulvin, and vinaxanthone. �
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Control: 0.2% DMSO in M9 buffer�
Conclusions
• The first report of the total synthesis of natural product xanthofulvin.
• The steps for total synthesis of vinaxanthone are shorter than previous medthods
• A highly regioselecGve Diels–Alder reacGon of an ynone ester.
• Tandem reacGon sequences for the formaGon of vinaxanthone from 5,6-‐dehydropolivione.
• An HBTU-‐mediated coupling of carboxylic acid derivaGve and ortho hydroxy enaminone with subsequent O-‐to-‐C transfer, bringing two funcGonalized fragments together
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Thanks!�
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