nakadomarin a - University of Illinois, UC · PDF file2,5%Pd-C AcOEt. A, B, C, D Tetracyclic...
21
-
Upload
phunghuong -
Category
Documents
-
view
216 -
download
1
Transcript of nakadomarin a - University of Illinois, UC · PDF file2,5%Pd-C AcOEt. A, B, C, D Tetracyclic...
Nakadomarin A
A BC
D
E
F
• Cytotoxicity against murine lymphoma L1210 cells (IC50 1.3 μg/mL)• Inhibitory activity against cyclin dependent kinase 4 (IC50 9.9 μg/mL)• Antifungal activity against Trichophyton mentagrophytes (MIC 23 μg/mL)• Antibiotic activity against Gram‐positive bacterium Corynebacterium xerosis (MIC 11 μg/mL)
Kobayashi, J.; Watanabe, D.; Kawasaki, N.; Tsuda, M. J. Org. Chem. 1997, 62, 9239. KCG
Proposed Biosynthesis
N
N
N
N
NNN N
HH
(-)-Keramaphidin B
N N
HH
N
HCHO
NH
N
N
OH
H OH
Ircinal A
Diels-Alder
retro-MannichN
N
HH
OH
HO
N
N
OHOH
H
Mannich N
N
OHO
H
N
N
H
OH
OH
N
N
H
O
Nakadomarin A
Kobayashi, J.; Watanabe, D.; Kawasaki, N.; Tsuda, M. J. Org. Chem. 1997, 62, 9239.Baldwin, J.E.; Whitehead, R.C. Tetrahedron Lett. 1992, 33, 2059. KCG
Selective Hydrogenation Model Study
N
H HH
H
Bs
RNOBoc
H HH
NOENBs
N
O
HH BocH H
NOE
SGBNagata, T.; Nishida, A.; Nakagawa, M. Tetrahedron Lett. 2001, 42, 8345-8349.
NBs
O
NBoc
NBs
O
NBoc
NBs
O
NBoc
H2, 5% Pd-CAcOEt
A, B, C, D Tetracyclic Core Construction
Nagata, T.; Nakagawa, M.; Nishida, A. J. Am. Chem. Soc. 2003, 125, 7484-7485. SGB
Nakadomarin A : Rings E and F
NO
N
AcO
H
BsO
NO
N
AcO
H
BsO
1) NaNapthalene
2) 5-hexenoic acidWSC.HClHOBt
77% 2 steps
MMPhPh
MPh
M
MRed-AlToluene, reflux
86%
N N
RuClCl
PCy2Ph
MesMes
CH2Cl2, 50oC
20 mol%
70%
Nagata, T.; Nakagawa, M.; Nishida, A. J. Am. Chem. Soc. 2003, 125, 7484-7485. BW
Retrosynthesis
HN
NH
H
HN
NH
H O
HN
H
NHHN
H
NH2
O
HN
O
ONH
MeMe
OTBS
OMe
DSPOno, K.; Nakagawa, M.; Nishida, A. Angew. Chem. Int. Ed. 2004, 43, 2020.
Furan Formation
HNNBsO
H
OTBDPS
HNNBsO
H
OTBDPS
TMSO
OTMSO2, Halogen lamp,
Rose Bengal, DCM/MeOH
quant. adducts (1.2:1)
BEUOno, K.; Nakagawa, M.; Nishida, A. Angew. Chem. Int. Ed. 2004, 43, 2020.
Ring Closing Metathesis
Bu3SnH
AIBN
BocO
N
H
O
DSOno, K.; Nakagawa, M.; Nishida, A. Angew. Chem. Int. Ed. 2004, 43, 2020.
Kerr’s Retrosynthesis
Young, I.S.; Kerr, M.A. J. Am. Chem. Soc. 2007, 129, 1465. ID
Pyrrolidines via Nitrone/Cyclopropane Homo [3+2] Dipolar Cycloaddition
Young, I.S.; Kerr, M.A. Angew. Chem. Int. Ed. 2003, 42, 3023. Young, I.S.; Williams, J.L.; Kerr, M.A. Org. Lett. 2005, 7, 953. ID
Kerr’s Total Synthesis
MeO
NH OBn
CO2MeCO2Me
O
OH
O
TBDPSO
NO
Br
OBn
O CO2Me
OTBDPS
O
OBn
CO2Me
1. SmI22. MsCl3. tBuOH
O CO2Me
OTBDPSCO2Me
N
OBn
OOBn
1. NiCl2, NaBH4, Na2CO32. LiAlH43. MsCl
4. TBDPSO NH2
5
O
OTBDPS
N
OBn
OOBn
N
OTBDPS
2 cycles of deprotection,oxidation, HWE, and RCM
NO
NO MeOO
AlO
OMeH H
E/Z = 5:3Inseparable
Na
NO
N
(+) - Nakadomarin A and inseparable E isomer
Young. I. S.; Kerr. M. A. J. Am. Chem. Soc. 2007, 129, 1465-1469. TMA
Completion of the Synthesis of Nakadomarin A
Young. I. S.; Kerr. M. A. J. Am. Chem. Soc. 2007, 129, 1465-1469. SJL
Zhai’s Synthesis
2
2
2
2
EMWDeng, H.; Yang, X.; Tong, Z.; Li, Z.; Zhai, H. Org. Lett. 2008, 10, 1791.
EMWDeng, H.; Yang, X.; Tong, Z.; Li, Z.; Zhai, H. Org. Lett. 2008, 10, 1791.
Zhai’s Synthesis
Williams’ Retrosynthesis
Ahrendt, K.A.; Williams, R.M. Org. Lett. 2004, 6, 4539. PW
Azomethine Ylide [1,3]-Dipolar Cycloaddition
Ahrendt, K.A.; Williams, R.M. Org. Lett. 2004, 6, 4539. PW
7 8 9
3A Mol sieves
Funk’s Retro- and Forward Synthesis
Stereochemistry confirmed by X‐Ray Structure
DMKNilson, M.G.; Funk, R.L. Org. Lett. 2006, 8, 3833.
Stereochemical Rational
O
H
O
O
OMeNMe
NBoc
N
NMe
O
OOMe
O
Ot-BuO
Sc
O
t-BuON
NMe
O
OOMe
O
Sc
NMe O Sc
O
OMe
N
t-BuO
O
O
H
ON
N
H
Ot-Bu
O
OOMeSc
O
Me
MeN
O H OMe
O
N
HO
OOt-Bu
H
synclinal anticlinal
Sc(OTf)3
StericElectrostatic
(Racemic)
DMKNilson, M.G.; Funk, R.L. Org. Lett. 2006, 8, 3833.
Evaluation of Approaches
EPG
Deng, Yang, Tong, Li and Zhai, Org. Lett. 2008
NH
OPh
Ph
O+ H
O
OO
MeMe
N
O
Boc
+35%
N
OPh
PhN
O O
H
Me Me
O Boc
O
H
21.5%(5 steps)
7.5% overallN
N
H
O
O
Boc
CO2Me
Probably app. 10 steps;Potentially two low yieldingtransition metal steps,better than 7.6% overall?
(-)-nakadomarin A
Highly simplifyingtransformation
N
ONMeO2C
TsH
BOC
OP
3
1) Reduction
2) Wittig
N
ON
TsH
BOC
OP
3
ent-(+)-nakadomarin A
Nishida's intermediate
10 steps
O
I
change starting material:
OP
3
O
Ivs.
9 steps8.8% overall
7.6%
15 steps shorterthan Nishida, same
overall yield
Ahrendt and Williams, Org. Lett. 2004
Evaluation of Approaches
EPG
Nilson and Funk, Org. Lett. 2006
