The Lupin Alkaloids
Ian Bass Seiple
10/11/2006
The Lupin Alkaloids
I.B. Seiple
Baran 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.
Quinolizidine Core Structure
5
4
3
7
6
8
N
9
1
2
10
The Lupin Alkaloids
I.B. Seiple
HO
HO
H
H
H
N
N
(-)-Lupinine
(+)-Epilupinine
N
N
N
H
H
N
H
OH
N
N
H
O
H
N
H
Albine
H
N
N
H
H
N
OH
(+)-Lupanine
Retamine
N
N
H
N
O
Aphyllidine
N
N
N
N
N
H
Aphylline
(-)-Sparteine
O
H
H
O
Angustifoline
H
O
NH
N
H
O
(-)-Cytisine (R = H)
(many alkylated
derivatives)
Lusitanine
H
NH
N
O
N
O
H
H
NR
NHAc
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H
O
Baptifoline
O
Multiflorine
O
N
N
O
N
H
H
Camoensidine
H
H
(+)-Matrine
N
H
H
N
H
H
(-)-Sophocarpine
H
H
O
O
N
H
H
(-)-Sophoridine
H
N
N
H
H
N
H
(-)-Sophoramine
H
N
H
H
(+)-Allomatrine
N
H H
(+)-aloperine
The Lupin Alkaloids
I.B. Seiple
Baran Group Meeting
10/11/2006
Biosynthesis
NH2
CO2H
H
NH2
Decarboxylation
O
NH2
H'
H
NH2
H
!
NH
NH+
NH2
!
NH
L-lysine
O
NH2
H
NH
H
N+
N+
[O], condensation
H
N+
N
NH+
H- delivery
O
H
H
N
N+
O
H
H
N
H
O
H
N
W. M. Golebiewski, I. D. Spenser, Can. J. Chem., 1988, 66, 1734
H
(-)-sparteine
HO
reduction
H
N
(-)-Lupinine
NH+
The Lupin Alkaloids
I.B. Seiple
EtO2C
Br
NH2
HIO4, pH = 5
buffer, rt
rt to reflux, Et2
EtO2C
CO2Et Na, xylenes, reflux
N
Vibramixer (41%)
K2CO3 (28%)
(after two distillations)
H
LiAlH4, Et2O
H
N
O
Bn
N
OH
1. LiAlH4
2. H2, Pd/C
OH
OH
(82%)
Bn
N
HO
O
O
O
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10/11/2006
N
H
N
epilupinine
paraformaldehyde
acetic acid
acetone
N
H HCl
N
O
Hg(OAc)2, acetic acid
reflux, K2CO3
N+
N
O
N
reflux
multiple xtalizations
(13%)
N
KOH, diethylene glycol
hydrazine hydrate, 75 ºC
to 200 ºC
O
N+
N
N
(±)-sparteine
E. E. van Tamelen and R. L. Foltz, J. Am. Chem. Soc. 1969, 91 (26), 7372-7377
The Lupin Alkaloids
I.B. Seiple
BnO
BnO
LiAlH4, THF, 0 ºC
formaldehyde (37% aq)
28 h, 65 ºC (82%)
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BnO
BnO
H
H
H2 (50 psi), Pd/C,
HCl, EtOH (100%)
BnO
H
+
O
H2N
N
N
N
Lupinine
NH2
1
(separable)
1.6
H2 (50 psi), Pd/C,
HCl, EtOH (100%)
P. A. Grieco and D. T. Parker, J. Org. Chem. 1988, 53, 3325-3330
BnO
H
N
Epilupinine
O
N
Tol
LDA, THF
ethylcyanoformate
-78 to rt, 2 h
LDA, THF,
LDA, THF
-20 to -10 ºC (92%)
S
O
N
Tol
O S
CO2Et
H
I
O
S
O S
I
Tol -78 to rt, 29 h (62%)
1. LiAlH , THF
4
Tol
Et2O, 0 ºC, 3 h (88%)
O S
CO2Et 2. Raney-Ni, EtOH (90%)
H
+
N
N
11%
84%
N
Tol
CeCl3 •
7 H2O
NaBH4
MeOH
O S
H
Tol
O S
H
Tol
+
N
N
30%
58%
OH
H
Also, Al-Hg removal of the sulfer was
attempted before reduction, resulting in a
1:3.6 ratio, with a slightly reduced yield.
N
(+)-epilupinine
1. LiAlH4, THF
Et2O, 0 ºC, 3 h (88%)
2. Raney-Ni, EtOH (90%)
OH
H
N
(-)-lupinine
D. H. Hua et al, Synthesis, 1991, 970-974
It is also important to note that starting with
the enantiomer of the menthyl sulfinate
yields (-)-lupinine as the major product in
similar ratios.
The Lupin Alkaloids
I.B. Seiple
OAc
1. (SOCl)2, DMSO, Et3N, (91%)
2. (-)-B-methoxydiisopinocampheylborane,
allyltrimethylsilane, Et2O, -78 ºC, then
NaOH, H2O2 (76%)
3. MsCl, Et3N, CH2Cl2 (99%)
OH
OAc
O
Grubb's catalyst
CH2Cl2, reflux (79%)
HN
H
OAc
O
N
DDQ, dioxane
reflux (50%)
H
H
N
H
Cbz
Cbz
CH2OAc
CH2OAc SiMe
3
90%
N
Cbz
TFA, 0 ºC
72%
N
OH
H
N
H
N
Silvani et al, Org. Lett., 2004, 6 (4), 493-496
H
(-)-Cytisine
O
OH
N
N
H
1. (COCl)2, DMSO, Et3N,
CH2Cl2, -65 ºC to rt
2. KMnO4, ButOH-phosphate
buffer (pH 7.2)
Cbz
NaH, THF, rt (89%)
HN
H
Cbz
O
H
N
N
OMs
N
6 N HCl, reflux (78%)
H
N
N
HN
H
1. PPh3, THF, then H2O (66%)
2. acryloyl chloride, Et3N,
CH2Cl2 (89%)
Cbz
O
1. NaOH, THF (98%)
2. MsCl, Et3N
CH2Cl2 (67%)
Cbz
O
N3
N
N
Cbz
H
NaN3, DMF, 80 ºC
O
N
SiMe3
OAc
Cbz
Cbz
HO
OMs
N
N
OAc
H
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10/11/2006
Cbz
Me3Si
1. DCC, HOBt, MeCN, rt
2. NaOH, MeOH, rt
62% aldehyde
26% cyclized product
HN
Cbz
H2N
1. Dess-Martin
CH2Cl2, rt
CH2OH
83%
N
Cbz
2. K2CO3, MeOH
O
10% Pd-C, Et3N-THF (2:8)
120 ºC, sealed tube, 8 h
N
N
D. Lesma et al., Eur. J. Org. Chem., 2001, 1377
Cbz
H
H2, 10% Pd-C, EtOH
N
N
65%
(-)-Virgilidone
H
The Lupin Alkaloids
I.B. Seiple
1. (Boc)2O, Et3N, CH2Cl2 (quant.)
2. (COCl)2, DMSO, Et3N, CH2Cl2
-40 to rt (91%)
HO
CO2Me
O
CO2Me
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10/11/2006
LiHMDS, N-(5-chloro-2-pyridyl)triflimide
THF, -78 ºC to -20 ºC (89%)
TfO
CO2Me
N
N
H
N
Boc
Pd(PPh3)4, LiCl, CuI
2-tributylstannyl-6-methoxypyridine
THF, 65 ºC (88%)
Boc
1. H2, Pd/C, MeOH, rt (quant.)
2. TFA, CH2Cl2, 0 ºC (quant.)
N
MeO
CO2Me
N
MeO
N
Boc
1. NaH, MeI or BnBr, THF-HMPA
0 ºC to rt (quant.)
2. LDA, ClCO2Et, THF
-78 ºC (quant.)
SmI2, THF-HMPA
MeOH, 0 ºC to rt (78%)
MeO
MeO
N
N
H
CO2Et
N
O
OH
CO2Me
NH
N
R
LiAlH4, THF, 0 ºC to rt (96% total)
O
OH
OH
OH
TMSCl, NaI, MeCN, reflux
MeO
N
+
MeO
N
O
N
R
N
R
50%
(R = Me)
46%
O
(R = Bn)
H
H
N
Bn
O
N
H
N
Me
83%
quant.
(-)-kuraramine
(-)-isokuraramine
O
H2, Pd(OH)2,
ammonium formate
MeOH, reflux (81%)
N
+
N
Me
(-)-jussiaeiine A (R = Me)
MsCl, Et3N, CH2Cl2
0 ºC, then toluene
reflux (89%)
N
H
T. Honda et al, J. Org. Chem. 2005, 70, 499-504
N
H
H
N
H
(+)-cytisine
The Lupin Alkaloids
I.B. Seiple
Baran Group Meeting
10/11/2006
Br-
Bn
Br
N
(Bu3Sn)2, BnPd(Ph3P)2Cl
DMF 130 ºC
N
N
1. LiAlH4, Et2O
2. BnBr, MeCN
CO2Me
N
Br
CO2Me
40 - 50%
70 - 80%
N
OMe
O'Neil, B. T. et. al. Org. Lett. 2000, 2, 4201
OMe
OH
OMe
1. BnBr, MeCN
2. Na2S2O4
O
N
H2 (1 atm), PtO2
MeOH/Et3N
76%
100%
85:15 trans:cis
N
O
Bn
Bn
N
100%
1. LiHMDS, THF, 0 ºC
2. ClP(O)(OEt)2, THF, -78 to 20 ºC
N
H2 (1 atm), PtO2
MeOH
CO2Me
N
82%
4:1 trans:cis
OMe
N
OH
OMe
OPO(OEt)2
N
1. MeSO2Cl, Et3N, CH2Cl2
2. PhMe, reflux
3. H2, Pd(OH)2, NH4HCO2, MeOH
O
P(OAc)2 (2.5 mol %)
P(o-tol)3 (5 mol %)
Et3N (5 eq), MeCN, 60 ºC
57%
Coe, J. W. Org. Lett. 2000, 2, 4205
1. Me3NO•2H2O, OsO4 (cat.)
2. NaIO4, EtOH-H2O (3:1)
3. H2 (50 psi), Pd(OH)2, aq. NH4OH
MnO2, C6H6, 80 ºC
N
O
58%
N
74%
O
48% over 3 steps
NH
N
O
(±)-Cytisine
The Lupin Alkaloids
I.B. Seiple
1. HSiCl3, [(allyl)PdCl]2
(-)-S-MOP
1. Ethylene glycol, TsOH
2. LDA, BnO(CH2)3CHO
O
2. H2O2, KI, KHCO3
3. Swern
O
TiCl4
N
(62%)
3. MsCl
O 4. DBU
(64%)
1. Lawesson's reagent
2. Raney Ni
H2, Pd/C, Pd(OH)2
Zn(N3)2•2pyr, DEAD, PPh3
O
OBn
O
O
BocNHOBoc,
K2CO3, DMF
N
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(78%)
H
N3
O
O
TFA, 4Å MS, then
NaHCO3
N
(95%)
3. LDA, I(CH2)4Cl
O 4. NaI, acetone
(76%)
O
O
(74 - 98%)
O
N Boc
Cl
BocO
hv (254 nm)
benzene
N
-O
N+
LiAlH4, THF, reflux
N
N
(76%)
O
(95%)
N
N
(+)-sparteine
15.7% overall
J. Aube´ et al., Org. Lett., 2002, 4 (15), 2577-2579
Note: by starting with the other
norbornadione enantiomer, (-)sparteine could also be
synthesized, but it is
commercially available.
The Lupin Alkaloids
I.B. Seiple
1. LHMDS, EtOCH2Cl,
THF -78 ºC to rt, 87%
2. KOtBu, THF, -78 ºC
84%
BnN
1. MeCO2tBu, LDA, THF, -78 ºC 68%
2. 10% Pd/C, H2 (1 atm), 100%
3. AcOH, toluene, reflux, 73%
BnN
CO2Et
CO2Et
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O
N
1. LiAlH4, THF
2. PBr3, toluene
H
70%
CO2Et
O
O
O
2-pyridone, K2CO3, Bu4NBr
toluene, reflux
N
N
O
66%
H
H
LDA (2 eq), THF, rt, 3 h
44%
H
N
N
MnO2, CH2Cl2
N
70%
H
O
Br
N
O
N
N
H
N
N
BH3•THF, 0 ºC to rt
N
85%
H
O
H
(±)-thermopsine
O
O
(±)-anagyrine
BocN
LHMDS, (EtO2C)2C=CH2
THF, -78 to rt
BocN
as above
1. TFA, CH2Cl2, THF, 0 ºC, 100%
2. AcOH, toluene, reflux, 89%
3. NaCl, H2O, DMSO, 130 ºC 72 h, 72%
EtO2C
CO2Me
79%
EtO2C
CO2Me
Gallagher, T.; Gray, D. Angew. Chem. Int. Ed. 2006, 45, 2419-2423
O
N
H
CO2Me
The Lupin Alkaloids
I.B. Seiple
OEt
O
OEt
O
O
CO2Et
1. H2N
benzene, reflux, -H2O
O
O
O
N
Pd/C, AcOH, 50 psi
O
CN NC
O
N
N
2. Adam's cat., 2000 psi
(55%)
EtOH, acetic acid
CO2Et
3. 100 ºC, neat (lactamization)
CO2Et
(65%)
acrylonitrile, base
N
O
1. NaH, benzene, reflux
2. acetic acid, reflux
O
O
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N
H
L. Mandell et al, J. Am. Chem. Soc. 1963, 85, 2683-2684
N
d,l-matrine
CN
N
O
O
1. LiAlH4, Et2O, rt
2. glutaric anhydride, CHCl3
3. Ac2O, CHCl3, reflux
O
L-Selectride, CH2Cl2, -30 ºC
then MeSO3H, CHCl3 rt 20 h
(46% total)
N
O
O
N
O O
(56% total)
N
1. 33% H2SO4
2. L-Selectride
H
O
O
Jen Chen, J. Chem. Soc.,Chem. Comm. 1986, 905-907
N
O
3. 1,1'-thiocarbonyldiimidazole, ClCH2CH2Cl
4. Bu3SnH, xylene reflux
N
H
N
d,l-matrine
(23% overall)
The Lupin Alkaloids
I.B. Seiple
MeO2C
O
CO2Me
CO2Me
Na+
C
N
O
CO2Me
NH
(86%)
MeO2C
1. Et3N,
O
O
2. B(OH)3
toluene, reflux
(100%)
MeO2C
O
N
H
N
2. EtOCSSK, acetone
(72%)
N
H
EtO
S
N
H
H
MeO2C
O
CO2Me
TFA, CH2Cl2
CO2tBu
(90%)
CO2Me
N
H
H
N
CO2H
MeO2C
O
O
MeO2C
O
(COCl)2, CH2Cl2;
N-hydroxy-4-methylthiazolinethione,
Et3N; tert-dodecanethiol, Chx,
AIBN, reflux
H
(56%)
H
O
CO2tBu
CO2Me
MeO2C
O
O
1. BH3•Me2S, THF
H
N
H
2. 2 M HCl, reflux
(85%)
N
E
N
N
O
MeO2C
O
N
Propogation
CO2Me
S
OEt
CO2tBu S
N
O
H
N
N
N
H
(±)-matrine
CO2Me
CO2tBu
O
O
O
O
1
N
CO2Me
N
N
MeO2C
CO2Me
H
CO2tBu
H
O
MeO2C
CO2Me
N
N
O
to
O
benzene, then
2-propanol, heat
(27% total)
S. Z. Zard et al, Angew. Chem. Int. Ed. 1998, 37 (8), 1128-1131
MeO2C
O
CO2tBu
N
N
S
3
H
lauroyl peroxide
CO2tBu 1. ClCH2COCl, Et N
3
(90%)
N
CO2Me
CO2Me
CO2tBu
CO2tBu H2, Pd/C
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N
O