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Literature Report 2014-01-07Huang, W.-X. checker: Chen, Z.-P.
Enantiospecific Total Synthesis of N-Methylwelwitindolinone D Isonitriley
Garg, N. K. et al. Angew Chem Int Ed 2013 52 12422Angew. Chem. Int. Ed. 2013, 52, 12422.
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ContentsContents
1 Introduction of the Corresponding Author1. Introduction of the Corresponding Author
2. Introduction of Welwitindolinones
3. Total Synthesis of Welwitindolinone D by Garg Group
4. Total Synthesis of Welwitindolinone D by Rawl Group4. Total Synthesis of Welwitindolinone D by Rawl Group
5. Summary
2
1 Introduction of the Corresponding Author1. Introduction of the Corresponding Author
B.S., New York University (2000, Marc Walters)
Ph.D., California Institute of Technology (2005, Brian Stoltz)
NIH postdoctoral scholar (2005-2007, Larry Overman)
Joined the faculty at UCLA (2007)
Research: total synthesis of natural products, transition-
metal catalyzed cross-coupling
Neil K. Garg
3
2. Introduction of Representative Welwitindolinones
1 D i l t d f Fi h ll i l d Fi h ll j
4
1. D was isolated from Fischerella muscicola and Fischerella major;2. Biological activities: antifungal effects, microtubule depolymerization.
Figure 2 Structural Analysis of Welwitindolinone D IsonitrileFigure 2. Structural Analysis of Welwitindolinone D Isonitrile
1. Oxindole-fused bicyclo[4.3.1] framework;
2. Five stereocenters, two quaternary carbons;
3. A heavily substituted cyclohexyl ring;
4. An ether linkage between C3 and C14.
5
3. Total Synthesis of Welwitindolinone D by Garg Group
Scheme 1. Retrosynthetic Analysis of 1
6
Scheme 2. Total Synthesis of 1
Me
OPivMe
K2CO3, MeOHBr
Me
OHMe
+
H
O Me
Me
6
NMe
OH OTBS
O Me
Me
7 8
Me
MeI2, MeOH
Me
O
H
Br54% yield, 2 steps
TBSCl, imidazole,DMAP, Bu4NI, DMF
90% yield Me
Me
Me
O
H
Br
NMe
9
Br
NMe
Br
10
TBSO
O Me
Me
MeH
HNaNH2 (10.5 equiv.)t-BuOH (3.5 equiv.)
46% i ldO
Me
Me OTBS
+
NMe
O Me
5
46% yieldratio:6/12 = 2.5:1
NMe
Me
11
7
5 11
Scheme 3. Elaboration of 5 to Keto Oxindole 3
TBSO
Me
MeH
H
1. NBS, CH2Cl2; NaHCO32. HCl, EtOH, 80 oC
HO
Me
MeH
H
TBSCl, imidazole,DMAP, Bu4NI, DMF
NMe
O MeH
5NMe
O MeH
12
O
H83% yield, 2 steps 92% yield
OTBSMe
H
D
MH
H N
5 12TBSO
Me
MeH 1. LiAlD4, THF, -78 to 0 oC
2 Cl CC(O)NCO K CO MeOH
NMe
O
OO
Me
MeH
H2N
NM
O Me
MeH
O
H
2. Cl3CC(O)NCO, K2CO3, MeOH
quantitative yield, 2 steps
OTBSMe
HN
D
MH
4Me13
AgOTf, PhI(OAc)2,bathophenanthroline
1. HCl, EtOH2 D M ti N HCO
OMe
HN
D
MH
PhPhNMe
O
OHN
OMe
MeH
bathophenanthroline 2. Dess-Matin, NaHCO3
quantitative yield, 2 steps
NMe
O
OHN
OMe
MeH
70% yield
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N Nbathophenanthroline
Me14
Me3
Scheme 4 Unexpected Formation of Cyclobutane 17
OMeOMe
Scheme 4. Unexpected Formation of Cyclobutane 17
CuBr2, THF
71% yield
OMe
OHN
O
D
Me
MeH
H
BrOMe
OHN
O
D
Me
MeH
H
H
NaH, air, THF
97% yield71% yield
NMe
O
Me
15
NMe
O
Me
3
97% yield
OMe
OHN
D
MeH
BrMe
MeH
O OHD
O
NMe
O
OO Me NMeMe
N
O
OH
16 17
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Table 1: Conversion of 15 to Acetate 18 and Cyclized Product 2
Entry Conditions Conversion to products
18 (%) 2 (%)
1 Mn(OAc)3 (4.0 eq.), AcOH, 80 oC 74 0
2 Mn(OAc)3 (4.0 eq.), AcOH, 150 oC 2 53
3Mn(OAc)3 (4.0 eq.), AcOH, 150 oC;
K2CO3, MeOH, H2O, 70 oC0 56
10
Scheme 5. Double C–H Functionalization of Substrate 3 to Install theTetrahydrofuran Ringy g
11
Scheme 6. Completion of (+)-1
OOMe
OOHN
O
D
Me Me
LiAlH4, THF
OHMe
OOHN
O
D
Me Me
1. Ba(OH)2, H2O2. IBX, TFA, DMSO
O
O Me
Me
MeH
NH2
O
92% yield 66% yield 2 steps
NMe
O
O Me
2
NMe
O
O Me
19
NMe
O
O
Me
20
92% yield 66% yield, 2 steps
2 19 20
O
MeH
O
MeH
Burgess reagent, THF, Benzene
O
O
Me
MeCN
OHCO2H, Ac2O
O
O
Me
MeOHCNH
O
77% yield, 2 stepsTHF, 0 oC to rt
NMe
(+)-1
NMe
21
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4. Total Synthesis of Welwitindolinone D by Rawal Group
Scheme 1. Retrosynthetic Analysis of 1
13
Rawal, V. H. et al. J. Am. Chem. Soc. 2011, 133, 5798.
Scheme 2. Synthesis of Cyclization Precursor 4
14
Scheme 3. Synthesis of Pentacycle 13
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S h 4 S th i f N M th l l iti d li D I it il (1)Scheme 4. Synthesis of N-Methylwelwitindolinone D Isonitrile (1)
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5 S5. Summary
O
Lewis acid-mediatedalkylative coupling
Rawal group in 2011:1 fi t t t l th i
O
O Me
Me
MeH
CN
OOxime rearrangement
1. first total synthesis;2. 14 steps, 4.8% overall yield.N
Me
O
(±)-1Pd-catalyzedenolate arylation
OMe
enolate arylation
Garg group in 2013:1. enantiospecific total synthesis;2. 17 steps, 2.8% overall yield.
O
O
Me
Me
MeH
CN
OAg-promoted nitrene
insertion
p yNMe
O
(-)-1IndolyneCyclization
I2-promoted addition
17
The welwitindolinone family of natural products has attractedThe welwitindolinone family of natural products has attracted
tremendous attention from the synthetic community over the past two
decades Interest in these compounds stems from their promisingdecades. Interest in these compounds stems from their promising
biological profiles, in addition to their compact, yet daunting structures.
Synthetic efforts toward the welwitindolinones have led to at least tenSy t et c e o ts to a d t e e t do o es a e ed to at east te
methods for building the bicyclo[4.3.1] core that is common to most of
these natural products. However, the sheer difficulty associated with late-p y
stage manipulations has plagued most synthetic routes and only a few
completed syntheses have been reported in recent years.
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In summary, we have completed the enantiospecific total synthesis of
N-methylwelwitindolinone D isonitrile. Several unexpected hurdles,y p ,
including the formation of the unusual cyclobutane-containing compound
17 were overcome en route to the natural product. Our total synthesis
features a double C-H functionalization of keto oxindole 3 to introduce the
tetrahydrofuran ring of 1 and is achieved in 17 steps from readily available
carvone derivative 6.
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Burgess Reagent 由氯磺酰异氰酸酯与甲醇和三乙胺在苯中反应制取：
Burgess Reagent 脱水机理：
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Mechanism of Ioximes to Isothiocyanatesy
R C NOH
H
NCS R C NOH
Cl
Et3NR C N O
R N
SO
NH2R N C S +
H N NH
OH2N NH2
S
H2NNH2 H2N NH2
Kim, J. N. et al. Tetrahedron Lett. 1997, 38, 1597.
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Mechanism for Desulfurization of the Isothiocyanate
Mukaiyama, T. et al. Bull. Chem. Soc. Jpn. 1965, 38, 858.
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