total synthesis of (±)-alopecuridine and its biomimetic ...ccc.chem.pitt.edu/wipf/current...
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Eric E. Buck Current Literature
April 9, 2011
Total Synthesis of (±)-Alopecuridine and Its Biomimetic Transformation into (±)-Sieboldine A
Zhang, X.-M.; Tu, Y.-Q.; Zhang, F.-M.; Shao, H.; Meng, X . Angew. Chem. Int. Ed. 2011, 50, ASAP
OMe
O
O
NOH
H
sieboldine A
MeO
NOH
HO
alopecuridine
Eric Buck @ Wipf Group Page 1 of 13 4/16/2011
Isolation and Background!
Ayer, W. A.; Altenkirk, B.; Valverde-Lopez, S.; Douglas, B.; Raffauf, R. F.; Wiesbach, J. A. Can. J. Chem. 1968, 46, 15-20 Ayer, W. A.; Altenkirk, B.; Fukazawa, Y. Tetrahedron 1974, 30, 4213-4214
• Alopecuridine was isolated from L. alopecuroides (foxtail club moss).
• There are 38 species in the genus Lycopodiella, which are found all over the world.
• There is no known biological data associated with alopecuridine.
MeO
NOH
HO
alopecuridine
Eric Buck @ Wipf Group Page 2 of 13 4/16/2011
Isolation and Background!
Hirasawa, Y.; Morita, H.; Shiro, M.; Kobayashi, J. Org. Lett. 2003, 5, 3991-3993
• Sieboldine A was isolated from the club moss L. sieboldii collected in Kagoshima.
• Inhibits acetylcholinesterase (IC50 = 2.0 µM) and is cytotoxic against murine lymphoma L1210 cells (IC50 = 5.1 µg/mL. (Below: Lycopodium Cernuum)
OMe
O
O
NOH
H
sieboldine A
Eric Buck @ Wipf Group Page 3 of 13 4/16/2011
Overmanʼs Synthesis of (+)-Sieboldine A!
Canham, S. M.; France, D. F.; Overman, L. E. J. Am. Chem. Soc. 2010, 132, 7876-7877
OO
OPhOTBDPS
OTESMe
OTES7 steps 1) Swern [O], 86%
2) N2=C(COMe)PO(OMe)2, K2CO3, MeOH, 90%
OPhOTBDPS
OTESMe
(t-Bu)2P(o-biphenyl)AuCl, AgSbF6
1.1 equiv i-PrOH, CH2Cl2
OTESHPhO
OTES+Au
Me
R
OTESHPhO
Me
AuO
Me OPh
OTBDPS
78%
Eric Buck @ Wipf Group Page 4 of 13 4/16/2011
Overmanʼs Synthesis of (+)-Sieboldine A!
Canham, S. M.; France, D. F.; Overman, L. E. J. Am. Chem. Soc. 2010, 132, 7876-7877
OMe OPh
OTBDPS
1) Ozonolysis; Me2S; DBU 86%
2) 10 mol% Eu(fod)3, ethyl vinyl ether, 86%
Me
OTBDPS
O OEt
3) DIBAL-H
HO
DMDO; BF3•OEt2, EtSH
53%Me
OTBDPS
OOH
O SEtO
MeO
O
NOH
H
sieboldine A
6 steps
20 steps, 5.5 %
Eric Buck @ Wipf Group Page 5 of 13 4/16/2011
Kobayashiʼs Proposed Biomimetic Pathway for Sieboldine A !
Hirasawa, Y.; Morita, H.; Shiro, M.; Kobayashi, J. Org. Lett. 2003, 5, 3991-3993
Eric Buck @ Wipf Group Page 6 of 13 4/16/2011
Title Paper: Retrosynthesis!
Zhang, X.-M.; Tu, Y.-Q.; Zhang, F.-M.; Shao, H.; Meng, X . Angew. Chem. Int. Ed. 2011, 50, ASAP
OMe
O
O
NOH
H
sieboldine A
BiomimeticOxidation Me
O
NOH
HO
alopecuridine
MeOOH
O
HN
alopecuridine
MeOHOH
BocN
MOMOSmI2-Mediated
PinacolCoupling
Me
BocN
MOMO O
CHO
Me O OH
NBoc
SemipinacolRearrengement
I
Me
+
NBoc
O
Eric Buck @ Wipf Group Page 7 of 13 4/16/2011
Title Paper: Synthesis of Intermediates!
Zhang, X.-M.; Tu, Y.-Q.; Zhang, F.-M.; Shao, H.; Meng, X . Angew. Chem. Int. Ed. 2011, 50, ASAP
I
Me
O 1) NaBH4, CeCl3•7 H2O, MeOH
2) Ac2O, Et3N, DMAP, DCM,97% over 2 steps
I
Me
OAc Me3Si
BF3•OEt2, DCE, 58 oC
I
Me
75%
NBoc
O
NBoc
O
d.r. = 3:1
1) N2CHCOOEt, BF3•OEt2,Et2O, -30 oC, 55%
2) aq K2CO3, THF, reflux, 75%
Eric Buck @ Wipf Group Page 8 of 13 4/16/2011
Title Paper: Addition and Epoxidation!
Zhang, X.-M.; Tu, Y.-Q.; Zhang, F.-M.; Shao, H.; Meng, X . Angew. Chem. Int. Ed. 2011, 50, ASAP
I
Med.r. = 3:1
NBoc
O
BA
1) t-BuLi, CeCl3; B, -78 oC
2) m-CPBA, NaHCO3, DCM, 0 oC+ Me O OH
NBoc
3.5:1
66% over 2 steps
NBoc
OHMe
NBoc
OHMe
MeBocN
HO
inseparable diastereoisomers
[O][O]
Eric Buck @ Wipf Group Page 9 of 13 4/16/2011
Title Paper: Semipinacol and Pinacol Rearrangement!
Zhang, X.-M.; Tu, Y.-Q.; Zhang, F.-M.; Shao, H.; Meng, X . Angew. Chem. Int. Ed. 2011, 50, ASAP
Me O OH
NBoc
BF3•OEt2 (2 equiv)
Et2O, -30 to -15 oCMe
HO
BocN
O
45%
1) MOMCl2) O3; PPh3
86% over 2 steps
Me
CHOMOMO
BocN
O MeMOMO
NBoc
O
OH
SmI2
HMPA, SmI2THF, 0 oC
MeHO
BocN
OH
OH
60%
Eric Buck @ Wipf Group Page 10 of 13 4/16/2011
Title Paper: End Game Synthesis of Alopecuridine!
Zhang, X.-M.; Tu, Y.-Q.; Zhang, F.-M.; Shao, H.; Meng, X . Angew. Chem. Int. Ed. 2011, 50, ASAP
MeMOMO
BocN
OH
OH 1) 6 N HCl
2) Boc2O (80% over 2 steps)
3) TPAP, NMO, 55%
Me
BocN
O
OHO
TFA; NaHCO3
96%
O
+HNOH
HO
alopecuridine•TFA
CF3COO-
13 steps, 10.5% yield
Eric Buck @ Wipf Group Page 11 of 13 4/16/2011
Title Paper: Biomimetic Transformation of Alopecuridine !
Zhang, X.-M.; Tu, Y.-Q.; Zhang, F.-M.; Shao, H.; Meng, X . Angew. Chem. Int. Ed. 2011, 50, ASAP
MeO
+HNOH
HO
alopecuridine•TFA
CF3COO-O
MeO
O
NOH
H
sieboldine A (15 steps, 6.3%)
1) m-CPBA, DCM
2) HgO, MeOH, 35 oC60% over 2 steps
MeO
NOH
HO
OO
MeO
N
OH
OH
OMe
O
N
OH
O
[O]
Eric Buck @ Wipf Group Page 12 of 13 4/16/2011
Summary!
• Overman completed the first synthesis of (+)-sieboldine A in 20 steps (5.5% overall yield) with a key Au(I)-catalyzed cyclization and subsequent pinacol rearrangement.
• The Tu group finished the first synthesis of (±)-alopecuridine in 13 steps (10.5% overall yield) utilizing a key semipinacol rearrangement to install the 9-membered ring and a pinacol rearrangement to install the 5-membered ring.
• (±)-Sieboldine A was completed in 2 additional steps from (±)-alopecuridine via an oxidative rearrangement that also validated Kobayashi’s proposed biosynthesis.
• A natural sample of alopecuridine is no longer available and no known NMR spectroscopic data has been reported (crystal structure of acylated alopecuridine is reported). The author’s NMR data is similar to fawcettimine hydrobromide.
MeO
NOH
HO
alopecuridine
MeO
NH
HO
fawcettimine
Eric Buck @ Wipf Group Page 13 of 13 4/16/2011
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