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8/18/2019 Lupin Alkaloid
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The Lupin Alkaloids
Ian Bass Seiple
10/11/2006
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The Lupin AlkaloidsI.B. SeipleBaran Group Meeting
10/11/2006
Lupin• Grain legume, high in protein, commonly used for livestock feed in Europe, Africa, Australia, and Asia• Also used in cereals, baby formula, pasta, soups and salads in the United States (22 states, 42,000 pounds/year)
• Seeds used in traditional Chinese medicine• Has been cultivated for over 2000 years• Over 500 species of the genus Lupinus known• In its raw form, the mildly toxic lupin alkaloids present in the plants causes a bitter taste, and are used as a defensive mechanism against herbivores• Alkaloids are commonly removed (or reduced) by soaking the raw seeds in water prior to use• In the 1920's, German plant breeders produced the first alkaloid-free, "sweet" lupin
Lupin Alkaloids - Biological Properties
• (-)-Cytisine has been identified as a selective partial nicotinic receptor agonist (nicotinic acetylcholine recepters are affected by Parkinson's and Alzheimer's diseases) (Nicotine is a full agonist at neuronal nAChR's, and has additional undesirable biological effects)
• Alkaloid extracts from Lupinus species have recently shown antimicrobial activity• L. albus showed inhibitory effects on Gram negative bacteria• L. varius and L. densiflorus strongly inhibited Gram positive bacteria• Many known lupin alkaloids show significant antifungal activity• matrine has shown antiulcerogenic and anticancer activities.
N
1
2
3
4
5
6
7
8
9
10
Quinolizidine Core Structure
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The Lupin AlkaloidsI.B. SeipleBaran Group Meeting
10/11/2006
Biosynthesis
NH2
CO2H
NH2
H
L-lysine
Decarboxylation
NH2
H'
NH2
HNH2
O
HNH+ NH
NH
NH+
NH
NH2[O], condensation
N+
O
N
ONH+
N+
O
HN
N+
N+H
H
H H H
H
H
H- delivery
N
NH
H
(-)-sparteine
W. M. Golebiewski, I. D. Spenser, Can. J. Chem., 1988, 66, 1734
reduction
N
HO
(-)-Lupinine
H
O
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The Lupin AlkaloidsI.B. SeipleBaran Group Meeting
10/11/2006
EtO2CBr
NH2
N
CO2EtEtO2Crt to reflux, Et2
K2CO3 (28%)(after two distillations)
Na, xylenes, reflux
Vibramixer (41%) BnN
OOH 1. LiAlH4
2. H2, Pd/C
(82%)
HIO4, pH = 5buffer, rt
HN
O
N
O
LiAlH4, Et2O
N
HO
epilupinine
H H
NH HCl
paraformaldehydeacetic acidacetone
refluxmultiple xtalizations(13%)
N O
N
N+ O
N+
N
N
O
N
N
Hg(OAc)2, acetic acidreflux, K2CO3
KOH, diethylene glycolhydrazine hydrate, 75 ºCto 200 ºC
(±)-sparteine E. E. van Tamelen and R. L. Foltz, J. Am. Chem. Soc. 1969, 91 (26), 7372-7377
BnN
OHOH
O
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The Lupin AlkaloidsI.B. Seiple Baran Group Meeting10/11/2006
N
Br
OMe
N
Br CO2Me
(Bu3Sn)2, BnPd(Ph3P)2ClDMF 130 ºC
N
CO2Me
N
OMe
40 - 50%
1. LiAlH4, Et2O2. BnBr, MeCN
70 - 80%
N
N
OMe
Bn
OH
Br-
N
N
OMe
Bn
OH
H2 (1 atm), PtO2MeOH/Et3N
100%85:15 trans:cis
1. BnBr, MeCN2. Na2S2O4
82%4:1 trans:cis
N
CO2Me
N
OMe
Bn
H2 (1 atm), PtO2MeOH
76%
(±)-Cytisine
1. MeSO2Cl, Et3N, CH2Cl22. PhMe, reflux3. H2, Pd(OH)2, NH4HCO2, MeOH
58%
N
O
N
O
O
NH
1. LiHMDS, THF, 0 ºC2. ClP(O)(OEt)2, THF, -78 to 20 ºC100%
N
OPO(OEt)2
O
P(OAc)2 (2.5 mol %)P(o-tol)3 (5 mol %)Et3N (5 eq), MeCN, 60 ºC
N
O
57%
MnO2, C6H6, 80 ºC
N
O
74%
1. Me3NO•2H2O, OsO4 (cat.)2. NaIO4, EtOH-H2O (3:1)3. H2 (50 psi), Pd(OH)2, aq. NH4OH
48% over 3 steps
O'Neil, B. T. et. al. Org. Lett. 2000, 2 , 4201
Coe, J. W. Org. Lett. 2000, 2 , 4205
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The Lupin AlkaloidsI.B. SeipleBaran Group Meeting
10/11/2006
1. HSiCl3, [(allyl)PdCl]2 (-)-S -MOP
2. H2O2, KI, KHCO33. Swern
O
O
1. Ethylene glycol, TsOH2. LDA, BnO(CH2)3CHO
3. MsCl4. DBU(64%)
O
OBnO
O
H2, Pd/C, Pd(OH)2Zn(N3)2•2pyr, DEAD, PPh3
(78%)
O
N3 OO
H
TiCl4
O
N
O
(62%)
1. Lawesson's reagent2. Raney Ni
3. LDA, I(CH2)4Cl4. NaI, acetone(76%)
O
N
Cl
BocNHOBoc,K2CO3, DMF
(95%)O
N
N
BocO
Boc
TFA, 4Å MS, thenNaHCO3
(74 - 98%)
N+
N
-O
hv (254 nm)benzene
(76%)
NN
O
LiAlH4, THF, reflux
(95%)
NN
(+)-sparteine
Note: by starting with the othernorbornadione enantiomer, (-)-sparteine could also besynthesized, but it iscommercially available.
15.7% overall
J. Aube´ et al., Org. Lett., 2002, 4 (15), 2577-2579
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The Lupin AlkaloidsI.B. Seiple Baran Group Meeting
10/11/2006
BnN
CO2Et
1. LHMDS, EtOCH2Cl, THF -78 ºC to rt, 87%2. KOtBu, THF, -78 ºC
84% BnN
CO2Et
1. MeCO2tBu, LDA, THF, -78 ºC 68%2. 10% Pd/C, H2 (1 atm), 100%
3. AcOH, toluene, reflux, 73% N
O
CO2Et
H
1. LiAlH4, THF
2. PBr3, toluene
70%
N
O
BrH
2-pyridone, K2CO3, Bu4NBrtoluene, reflux
66%
N
O
N
HO
LDA (2 eq), THF, rt, 3 h
44%
N
O
H
N
H
O
MnO2, CH2Cl2
70%
N
O
HN
O
BH3•THF, 0 ºC to rt
85%
N
HN
O
(±)-anagyrine
BocN
CO2Me
LHMDS, (EtO2C)2C=CH2THF, -78 to rt
79%
BocN
CO2Me
EtO2C
EtO2C
1. TFA, CH2Cl2, THF, 0 ºC, 100%2. AcOH, toluene, reflux, 89%3. NaCl, H2O, DMSO, 130 ºC 72 h, 72%
N
O
CO2Me
H
Gallagher, T.; Gray, D. Angew. Chem. Int. Ed. 2006, 45 , 2419-2423
as above
N
HN
O
(±)-thermopsine
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The Lupin AlkaloidsI.B. SeipleBaran Group Meeting
10/11/2006
N
O
O
acrylonitrile, base N
O
O
CN NC
Pd/C, AcOH, 50 psi
N
N
O
d,l- matrine
H
NO
OCN 1. LiAlH4, Et2O, rt
2. glutaric anhydride, CHCl33. Ac2O, CHCl3, reflux
(56% total)
NO
O
N
O
O
L-Selectride, CH2Cl2, -30 ºCthen MeSO3H, CHCl3 rt 20 h(46% total)
N
N
O
H
O
O
1. 33% H2SO42. L-Selectride
3. 1,1'-thiocarbonyldi- imidazole, ClCH2CH2Cl4. Bu3SnH, xylene reflux
N
N
O
d,l- matrine
H
(23% overall)Jen Chen, J. Chem. Soc.,Chem. Comm. 1986, 905-907
L. Mandell et al , J. Am. Chem. Soc. 1963, 85 , 2683-2684
O
OEt O O
OEt benzene, reflux, -H2O
H2NCO2Et
N
O
CO2EtCO2Et
1.
2. Adam's cat., 2000 psi EtOH, acetic acid3. 100 ºC, neat (lactamization)
1. NaH, benzene, reflux2. acetic acid, reflux
N
O
O
(55%)
(65%)
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