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Bioinspired and Concise Synthesis of(±)-Stemoamide
Yan Wang, Lili, Zhu, Yuying Zhang, Ran Hong*Angew. Chem. Int. Ed. 2011, ASAP
DOI: 10.1002/anie201005833
Stemoamide
1R. A. Pili, M. C. F. de Oliveira, Nat. Prod. Rep. 2000, 17, 117 - 127.
N
O
O
O Me
H
HH
stemoamide
Stemona Tuberosa
• Class of alkaloids isolated from stemonaceae species (around 100 compounds known).• Used in chinese an japanese traditionnal medicines for the treatment of respiratory
deseases (Asthma, tuberculosis, bronchitis).• However, the biological activities of the plants could not be associated with any of the
stemona alkaloids.• Stemoamide, isolated in 1992, is a simple member of the family: many reported
syntheses.
Stemona Alkaloids
2R. A. Pili, M. C. F. de Oliveira, Nat. Prod. Rep. 2000, 17, 117 - 127.C. Seger, K. Mereiter, E. Katenegger, T. Pacher, H. Greger, O. Hofer, Chem. Biodiversity 2004, 1, 265 - 279.
N
O
O
O Me
H
HH N
O
stemoamide
N
O
N
O
O
O
Et
H
H
H
Me
H
H
stenine
N
O
O
N
O
O
Me
Me
H
H
HH
H
O
parvistemoline
N
O
NO
O
OMe
Me
O
O
Me
stenonamide
NO
H
O
O
Me
OH
N
O
tuberostemospironine
Common feature : perhydroazaazulene core
Stemona Alkaloids
2R. A. Pili, M. C. F. de Oliveira, Nat. Prod. Rep. 2000, 17, 117 - 127.C. Seger, K. Mereiter, E. Katenegger, T. Pacher, H. Greger, O. Hofer, Chem. Biodiversity 2004, 1, 265 - 279.
N
O
O
O Me
H
HH N
O
stemoamide
N
O
N
O
O
O
Et
H
H
H
Me
H
H
stenine
N
O
O
N
O
O
Me
Me
H
H
HH
H
O
parvistemoline
N
O
NO
O
OMe
Me
O
O
Me
stenonamide
NO
H
O
O
Me
OH
N
O
tuberostemospironine
Common feature : perhydroazaazulene core
Spermidine Biosynthesis
3
H2NNH2
CO2Hornithine
-CO2H2N
NH2
putrescine
N N
N
NO
HO OH
SH2N
HO2CNH2
S-Adenosyl Methionine (SAM)
-CO2SH2N
Ado
SH2N
Ado H2NNH2
H2N NH
NH2
spermidine
+ AdoS
spermidine putrescine+
homospermidine
NH
NH2H2N + H2N NH2
Proposed Biosynthesis
4
NH
NH2H2N NH
O O
N
O
Mannich
N
O
homospermidine
[Ox]
H2N NH
NH2N
O
spermidine
N
O
PPO
N N
[Ox]
N
O
O
O
stemoamide
C. Seger, K. Mereiter, E. Katenegger, T. Pacher, H. Greger, O. Hofer, Chem. Biodiversity 2004, 1, 265 - 279.
Known pyrrolizidinebiosynthesis
Alternative Biosynthetic Origin
5
NO
H
O
O
Me
OH
N
O
tuberostemospironine
H. Greger, J. Schinnerl, S. Vajrodaya, L. Brecker, O. Hofer, J. Nat. Prod. 2009, 72, 1708 - 1711.
Already isolated from Pandanaceae familyRecently found in Stemonaceae.Isoprene unit proposed to arise from leucine.N
HO O
O O
pandanamines
Acid/base work-up
N
O
O
OO
Among other alkaloids
First Synthesis
6D. R. Williams, J. P. Reddy, G. S. Amato, Tetrahedron Lett. 1994, 35, 6417 - 6420.
N
O
O
O Me
H
HH
stemoamide
CO2Me
TBSOOBn
N3
TBSO
THF/H2O refluxCHOTBSO
12 stepsTBSO
OBn
TBSOH H
H
NH
O
1) H2, Pd/C
2) MsCl, pyr.
TBSOOMs
TBSOH
H
NH
O
NaH, THF
87 %
71 %3 steps
TBSO
TBSOH
N O
1) HF.NEt3
2) Dess-Martin TBSO
OH
N O
TBAF
O
HOH
NO
H H
H
H
PCC(–)-stemoamide
59 % 3 steps80 %
PPh3
Jacobi Approach
7
N
O
O
O Me
H
HH
stemoamide
P. A. Jacobi, K. Lee, J. Am. Chem. Soc. 1997, 119, 3409 - 3410.P. A. Jacobi, K. Lee, J. Am. Chem. Soc. 2000, 122, 4295 - 4303.
NHHO2C
O
L-pyroglutamic acid
1) SOCl2, MeOH
2) NaBH4NH
OHO
OEt
H+NH
OO
OEt
83 % 93 %
Cl
O
ClMe-ala P2O5
NH
O
ClO
OMe N
O
ClMeO
80 % (2 steps)
NH
OO
OEt
1) NaH
2) TsOH/ MeOH N
O NMeO
OH
O
55 %
1) Swern ox.
N2 PO(OMe)22)
3) MeIN
O NMeO
O
21 % (3 steps)
Pb: methylation at the pseudobenzylic position
Diels-Alder / retro Diels-Alder
8P. A. Jacobi, K. Lee, J. Am. Chem. Soc. 1997, 119, 3409 - 3410.P. A. Jacobi, K. Lee, J. Am. Chem. Soc. 2000, 122, 4295 - 4303.
N
O NMeO
O
C6H4(Et)2
182 °C
N
N
OMeO
-MeCN
O
N
OH
O
MeO
H
H+ N
O
O
O
H
H
50 - 55 % gram scale
NiCl2, NaBH4 N
O
O
O
H
H
N
O
O
O
H
H
H H
73 % 15 %
+
Cycloaddition believed to proceed via electron transfer: oxazole radical cation poordiene (reverse demand D. A). Supported by oxidised by-products and beneficial effectof benzoquinone on large scale.
N
O
O
O Me
H
HH
stemoamide
Miscellaneous Routes
9N. Bogliotti, P. I. Dalko, J. Cossy, J. Org. Chem. 2006, 71, 9528 - 9531.
O
OMe
N
O
H
O1) NaBH4
2)PhSH, TsOH
O
OMe
N
O
H
PhS Bu3SnHAIBN
62 %
N
O
O
O Me
H
HH
epi-stemoamide74 %
O
CO2Et
O
I
OTHF
DLP, C6H6
O
O
OTHF
CO2Et
H
HI
65 %
1) NaN3
DMF, 80 °C O
O
OTHF
CO2Et
H
HN3
O
O
OTHF
CO2Et
H
+
1) H2, Pd/C
2) TsOH, MeOH3) MsCl, Et3N
ONH
H
OMs
O
O
H 36 % (4 steps)d.r. 1:1
S. K. Khim, A. G. Schultz, J. Org. Chem. 2004, 69, 7734 - 7736.
N
O
O
O Me
H
HH
stemoamide
Bates Synthesis
10R. W. Bates, S. Sridhar, Synlett, 2009, 12, 1979 - 1981.
N
OHC
Br O
42 % from succinimide (4 steps)
In, AcOH (2 equiv.)THF/H2O N
.H
HO
O
82 %, d.r. 16:1
1) Ru3(CO)12, Et3N CO (100 psi), 100 °C2) NiCl2, NaBH4
N
O
O
O Me
H
HH
stemoamide45 % recryst.
(2 steps)
R
R'
"Ru(CO)x"
R'
.
O
[Ru]
H
CO
R
R'
.
O
O[Ru]
H
[Ru]
O
O
R R'
.HO
R
R'O
O
R
N
O
O
O Me
H
HH
stemoamide
Hong Retrosynthesis
11Yan Wang, Lili, Zhu, Yuying Zhang, Ran Hong, Angew. Chem. Int. Ed. 2011, ASAP
N
O
O
O Me
H
HH
stemoamide
N
O
TMS
RO
N
O
O
O Me
H
HH
stemoamide
N
.
HO
O
H
Br CHO
TMSHN
O
O
+ +
11Yan Wang, Lili, Zhu, Yuying Zhang, Ran Hong, Angew. Chem. Int. Ed. 2011, ASAP
N
O
O
O Me
H
HH
stemoamide
First Trials
Br CHOTMS
1) n-BuLi, THF, -78 °C
then
2) TBSCl, DBU, DCM, rt
TMS
Br
TBSO
77 % (2 steps)
1) K2CO3 (2 equiv.)
succinimide (2 equiv.) TBSO
N
O
EtO
2) Lindlar/ H2
3) NaBH4, EtOH
TMS
TBSO
N
O
EtO
TMS
BF3.OEt2 or TFA
CH2Cl2, 0°C
N
O
OH
93 % (3 steps)
79 %
Key Step
11Yan Wang, Lili, Zhu, Yuying Zhang, Ran Hong, Angew. Chem. Int. Ed. 2011, ASAP
N
O
O
O Me
H
HH
stemoamide
TMS
Br
TBSO
1) K2CO3 (2 equiv.)
succinimide (2 equiv.)
TBSO
N
O
EtO
2) NaBH4, EtOH
SnCl4
CH2Cl2, rt NO
Cl
56 %
SnCl4
CH2Cl2, low T N
.
O
33 %
93 % (2 steps)
TBSO
TMS
TBSO
N
O
EtO
TMS
FeCl3 (1 equiv.)
C5H8, 0°C N
.
O
86 % (d.r. 3:1)
TBSO
HTMS
TBSON
H
O
Hvia
H
Carbonylation
11Yan Wang, Lili, Zhu, Yuying Zhang, Ran Hong, Angew. Chem. Int. Ed. 2011, ASAP
N
O
O
O Me
H
HH
stemoamide
N
.
O
d.r. 3:1
TBSO
HTBAF, THF
96 %
N
.
O
d.r. 3:1
HO
H Ru3(CO)12, CO (10 atm)
Et3N (100 °C) NO
O
H
O
H
81 %Only 1 dia. observed
HN
O
H-[Ru]-O H
H-[Ru]-ON
O
H H
N
.
O
O
[Ru]H2
[Ru]H2
NO
O
H
O
H
NiCl2. NaBH4
MeOH, rt NO
O
H
O
H
stemoamide
H
Kinetic Resolution
11Yan Wang, Lili, Zhu, Yuying Zhang, Ran Hong, Angew. Chem. Int. Ed. 2011, ASAP
N
O
O
O Me
H
HH
stemoamide
NHO
HO
H
Ag+
N
O
H
Ag+
HO
H
NH
OHO
H
Ag+
NO
HO
H
1) fast
2) H+
N
O
H
Slow
2) H+ O
H
N
.
O
d.r. 3:1
HO
H
AgNO3 (0.8 equiv.)CaCO3 (0.8 equiv.)
Acetone/H2O N
.
O
HO
H
64 % (d.r. 50 : 1)
NO
O
H
+
36 % (d.r. 1 : 2)
H
Conclusions
11Yan Wang, Lili, Zhu, Yuying Zhang, Ran Hong, Angew. Chem. Int. Ed. 2011, ASAP
N
O
O
O Me
H
HH
stemoamide
Shortest racemic synthesis: 37 % overall yield (8 steps)
Still, poor diastereoselectivity of the key step.
Carbonylation leads eventually to one diastereoisomer: fine forracemic synthesis.
For an hypothetic chiral synthesis, necessity of an additionnal kineticresolution.
Easy access to enantioenriched starting material by Carreiraasymmetric propargylation.
Why not included? Further issues? Allenic alcohol is proposed to beepimerised, what about allenic amide?
N
.
O
HO
H
![synthesis 2009.ppt [Kompatibilitätsmodus] · 2014. 9. 12. · Repertory 9 Boericke, O.E.; Repertory 10 Phatak S R Concise Repertory of Homeopathic MedicinesPhatak, S.R. Concise Repertory](https://img.pdfslide.net/doc/110x75/6101267bf420fa2e6342d053/synthesis-2009ppt-kompatibilittsmodus-2014-9-12-repertory-9-boericke.jpg)
