total synthesis of maoecrystal v: yy - · pdf file19 diterpenoid...
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Literature Report
Total Synthesis of Maoecrystal V:
Literature Report
y yEarly-Stage of C-H Functionalization and Lactone
Assembly by Radical CyclizationAssembly by Radical Cyclization
Reporter: Ji YueChecker: Chen MuwanggDate: 2013/12/02
Zakarian, A. et al. J. Am. Chem. Soc. 2013, 135, 14552.
University of Californiaat Santa Barbara
ContentContent
Introduction1
Retrosynthesis of Maoecrystal V2
Synthesis of Maoecrystal V3 y y
Summary4 Summary4
IntroductionIntroduction
Isodon species
Isolated and characterized by Sun and coworkers in 2004 Remarkably selective cytotoxicity against HeLa cells (IC = 20
毛萼香茶菜
Remarkably selective cytotoxicity against HeLa cells (IC50 = 20 ng/mL); Cisplatin (IC50 = 990 ng/mL).
Sun, H.-D. et al. Org. Lett. 2004, 6, 4327.
IntroductionIntroduction
17
AD
23
1615
13 9 10
B
CE 45
8
18
19
13
12
11
9
14
10
6 19
711 14 6
C19 Diterpenoid Compact pentacyclic system Compact pentacyclic system Six stereocenters (two all-carbon) Three contiguous quaternary stereocenters
IntroductionIntroductionYang’s Synthesis
OAcOAc
The model reaction of dearomatic-Diels-Alder reaction
O O
OO
PhCH3
130 oC
OOAc
AC
D E
O Pb(OAc)4AcOH
92%
O
O
OA
130 C
O OO
3 5
C
HOO
92%
OO
OAc
PhCH3
130 oC
OAcO
2
O
O130 oC
O OO
4 6
Yang, Z. et al. Org. Lett. 2009, 11, 4770.
Introductiont oduct o
Yang’s Synthesis：The first total synthesis of ()-maoecrystal V
OAc OAcE
O
OOH
OO
O
OA B
C
DEPb2(OAc)4AcOH, 0 oC
PhMe145 oC
O OA
E
O O O OC
36% yield
a b c
Yang, Z. et al. J. Am. Chem. Soc. 2010, 132, 16745.
IntroductionIntroduction
Danishefsky’s Synthesis
IMDA
Danishefsky s Synthesis
O O
SO2PhIMDA
O O
SO2Ph
i j
O O O-face
OH
O
HO
m-CPBA
O
HOO
O
O
p-TsOH
-face
OH
H
O O O O O Ok l m
Danishefsky, S.-J. et al. J. Am. Chem. Soc. 2012, 134, 18860.
Constuction of Bicyclic [2.2.2] octane viaan IMDA Reactionan IMDA Reaction
IMDA: Intramolecular Diels-Alder reaction
OOEt
EtOCl
O
O
IMDA: Intramolecular Diels Alder reaction
O
i-Pr2NEtDMAP
73% yield O
EtO
O
BHT, o-DCB
98% yield
Cl O
O
EtO
EtOO O
O
O Cl O O
O
OOEt
EtO
Oe gOH
EtO
EtO
Et3N, DMAP
82% yield
SCl
O
OEtO
OSO
60% yield
BHT, i-Pr2NEtd O
O
EtO
EtOO
S O
O
OS
OO
f h
O
Zakarian, A. et al. Org. Lett. 2011, 13, 1080.
Retrosynthesis of Maoecrystal VRetrosynthesis of Maoecrystal V
Zakarian, A. et al. J. Am. Chem. Soc. 2013, 135, 14552.
An Early Installation of Dihydrobenzofuran IntermediateIntermediate
mechanism
An IMDA ReactionAn IMDA Reaction
Mechanism
Lactone Assembly by Radical CyclizationLactone Assembly by Radical Cyclization
Lactone Assembly by Radical CyclizationLactone Assembly by Radical CyclizationO OBn OPMB
t Bu SnH
O
O
t-Bu3SnHAIBN orACHN or
V70O OBn OPMB
O OBn OPMB
23O
O OBn
O
O
S O18
O
OO
O
O OBnO
(Me3Si)3SiHAIBN, PhH55% yield
PhSe OD
E BC
19OO
24
O OBn OPMB O OBn OPMB O OBn OPMBt b
O
OO
O
O
O
O OBn OPMB
step astep b
H
O
OO OO
Synthesis of Maoecrystal VSynthesis of Maoecrystal V
SummarySummary
Y ' M th d
O
OAc
Yang's Method
OOAc
WesselyIMDA
O
O
O
O
O
OO
OH
O OO
WesselyOxidation
OO
Danishefsky's Method
O O
O
2
3 5
1617
12
1315
10 9
O
IMDA
( )-Maoecrystal V (1)
O O
O3
4
5 121411
7
86
O O
SO2PhIMDA
O O
SO2Ph
( )-Maoecrystal V (1)
SummarySummary
Among many known ent-kauranoids, maoecrystal V stands outfor its atypical molecular architecture in this class of natural
d t I l t d d h t i d b S d k iproducts. Isolated and characterized by Sun and co-workers in2004, this unique C19 diterpenoid displayed potent (IC50 = 20ng/mL) and remarkably selective cytotoxicity against HeLang/mL) and remarkably selective cytotoxicity against HeLacells. The pentacyclic framework of maoecrystal V integratesthree contiguous quaternary stereocenters (two all-carbon), abicyclo[2.2.2]octan-2-one subunit, and a strained centraltetrahydrofuran flanked by trans-fused six-membered rings.Collectively these structural characteristics amount to anCollectively, these structural characteristics amount to anexquisite challenge for chemical synthesis. Numerousresearch groups initiated programs directed at thesynthesis of maoecrystal V, identifying the construction of thequaternary stereogenic centers as one of the maint t i l d d l i ff ti l tistrategic goals and developing many effective solutions.
The successful completion of the first total synthesis oft l V i i f t d b Y dmaoecrystal V in racemic form, reported by Yang and co-
workers in 2010, relied on a concise strategy centered on anintramolecular Diels−Alder reaction (IMDA). The reactionintramolecular Diels Alder reaction (IMDA). The reactionenables a rapid assembly of the bicyclooctanone andtetrahydrofuran ring systems in one event, albeit with lowfacial selectivity for the diene counterpart. The second of thetwo completed total syntheses of (±)-maoecrystal V reportedto date was described by Peng and Danishefsky in 2012 Otherto date was described by Peng and Danishefsky in 2012. Otherresearch groups have also developed creative and efficientapproaches based on IMDA chemistry that is envisioned toprecede tetrahydrofuran formation.
In closing, a concise total synthesis of maoecrystal V has beenaccomplished (24 steps 1 5% overall yield from sesamol) Theaccomplished (24 steps, ∼1.5% overall yield from sesamol). Thestrategic focus on the central strained tetrahydrofuran ringresulted in an initial disassembly of the lactone ring to ay gpolycyclic enol ether. The enol ether was constructed by anIMDA reaction of a tethered CH2=CH2 equivalent with a 2,4-
l h di f t bt i d b id ticyclohexadienone fragment obtained by oxidativedearomatization of a dihydrobenzofuran intermediate. Thisintermediate, in turn, was prepared by an effective Rhodium-intermediate, in turn, was prepared by an effective Rhodiumcatalyzed C−H functionalization reaction which can potentiallybe modified to access enantioenriched products using chiralRhodium catalysts.
An IMDA ReactionAn IMDA Reaction
95% yield
OO
OBn
OH
OBnOH
EtO OHCH3MgBr
12 13
y
O OPMB O OPMB
Hydrolysis
MeMgBrMg
X
OM X OBO
OOMg
O OPMB
EtOOMgX
OBn
OMgX
OBn
B k
O OPMB O OPMB
Back
E E EEH
HN2
Rh2(OAc)2
EH
HN2
Rh - N2
EH
HRh
HMe H
Me HMe
EH
EH
EH H
HMe
Rh
H
HMe
Rh
H
HMe
RhE
MeMe
b kback