The document discusses lupin alkaloids, which are mildly toxic compounds found in lupin plants. It provides details on the chemical structures and properties of various lupin alkaloids such as cytisine. It also describes recent research that has focused on synthesizing lupin alkaloids like cytisine through organic reactions in order to study their biological activities and potential applications.

1. The Lupin Alkaloids
Ian Bass Seiple
10/11/2006

2. The Lupin AlkaloidsI.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.
N
1
2
3
4
5
6
7
8
9
10
Quinolizidine Core Structure

3. The Lupin AlkaloidsI.B. Seiple
Baran Group Meeting
10/11/2006
N
N
O
H
H
(+)-Lupanine
N
N
H
H
O
Multiflorine
N
N
H
H
(-)-Sparteine
N
N
O
H
H
H
H
N
N
O
H
H
H
H
(-)-Sophoridine
N
N
O
H
H
H
H
(-)-Sophocarpine(+)-Matrine
N
N
O
H
H
H
(-)-Sophoramine
N N
H
H
H
(+)-aloperine
N
HO
(-)-Lupinine
N
NH
O
H
H
Angustifoline
N
NH
O
H
H
Albine
N
N
H
H
Aphylline
O
N
N
H
Aphyllidine
O
N
N
H
O OH
N
N
O
H
H
CamoensidineBaptifoline
N
NHAc
H
Lusitanine
N
N
OH
H
H
Retamine
H
N
HO
(+)-Epilupinine
H
N
N
O
H
H
H
H
(+)-Allomatrine
N
NR
O
(-)-Cytisine (R = H)
(many alkylated
derivatives)

4. The Lupin AlkaloidsI.B. Seiple
Baran Group Meeting
10/11/2006
Biosynthesis
NH2
CO2H
NH2
H
L-lysine
Decarboxylation
NH2
H'
NH2
H
NH2
O
H
NH+ NH
NH
NH+
NH
!
!
NH2
[O], condensation
N+
O
N
O
NH+
N+
O
H
N
N+
N+
H
H
H H H
H
H
H- delivery
N
N
H
H
(-)-sparteine
W. M. Golebiewski, I. D. Spenser, Can. J. Chem., 1988, 66, 1734
reduction
N
HO
(-)-Lupinine
H
O

5. The Lupin AlkaloidsI.B. Seiple
Baran Group Meeting
10/11/2006
EtO2C
Br
NH2
N
CO2EtEtO2Crt to reflux, Et2
K2CO3 (28%)
(after two distillations)
Na, xylenes, reflux
Vibramixer (41%) Bn
N
O
OH 1. LiAlH4
2. H2, Pd/C
(82%)
HIO4, pH = 5
buffer, rt
H
N
O
N
O
LiAlH4, Et2O
N
HO
epilupinine
H H
N
H HCl
paraformaldehyde
acetic acid
acetone
reflux
multiple xtalizations
(13%)
N O
N
N+ O
N+
N
N
O
N
N
Hg(OAc)2, acetic acid
reflux, K2CO3
KOH, diethylene glycol
hydrazine hydrate, 75 ºC
to 200 ºC
(±)-sparteine E. E. van Tamelen and R. L. Foltz, J. Am. Chem. Soc. 1969, 91 (26), 7372-7377
Bn
N
OH
OH
O

6. The Lupin AlkaloidsI.B. Seiple
Baran Group Meeting
10/11/2006
BnO
NH2
O
LiAlH4, THF, 0 ºC
BnO
H2N
formaldehyde (37% aq)
28 h, 65 ºC (82%)
BnO
N
BnO
N
H H
+
1 1.6
H2 (50 psi), Pd/C,
HCl, EtOH (100%)
BnO
N
H
BnO
N
H
Lupinine
Epilupinine
H2 (50 psi), Pd/C,
HCl, EtOH (100%)
P. A. Grieco and D. T. Parker, J. Org. Chem. 1988, 53, 3325-3330
(separable)
N O
S
Tol
O
LDA, THF
-20 to -10 ºC (92%)
N
S
Tol
O
N
S
Tol
O
LDA, THF,
-78 to rt, 29 h (62%)
I I
N
S
Tol
O
N
S
Tol
O
+
30% 58%
H HCeCl3 •
7 H2O
NaBH4
MeOH
LDA, THF
ethylcyano-
formate
-78 to rt, 2 h N
S
Tol
O
N
S
Tol
O
+
11% 84%
H HCO2Et CO2Et
1. LiAlH4, THF
Et2O, 0 ºC, 3 h (88%)
2. Raney-Ni, EtOH (90%)
N
H
OH
(+)-epilupinine
1. LiAlH4, THF
Et2O, 0 ºC, 3 h (88%)
2. Raney-Ni, EtOH (90%)
N
H
OH
(-)-lupinine
Also, Al-Hg removal of the sulfer was
attempted before reduction, resulting in a
1:3.6 ratio, with a slightly reduced yield.
It is also important to note that starting with
the enantiomer of the menthyl sulfinate
yields (-)-lupinine as the major product in
similar ratios.
D. H. Hua et al, Synthesis, 1991, 970-974

7. The Lupin AlkaloidsI.B. Seiple
Baran Group Meeting
10/11/2006
N
Cbz
OHOAc
1. (SOCl)2, DMSO, Et3N, (91%)
2. (-)-B-methoxydiisopinocampheylborane,
allyltrimethylsilane, Et2O, -78 ºC, then
NaOH, H2O2 (76%)
3. MsCl, Et3N, CH2Cl2 (99%)
N
Cbz
OMsOAc
H
NaN3, DMF, 80 ºC
N
Cbz
N3OAc
H
1. PPh3, THF, then H2O (66%)
2. acryloyl chloride, Et3N,
CH2Cl2 (89%)
N
Cbz
OAc
H
HN
O
Grubb's catalyst
CH2Cl2, reflux (79%)
N
Cbz
OAc
H
HN
O
N
Cbz
OMs
H
HN
O1. NaOH, THF (98%)
2. MsCl, Et3N
CH2Cl2 (67%)
N
N
O
Cbz
H H
H
NaH, THF, rt (89%)
N
N
O
Cbz
H H
DDQ, dioxane
reflux (50%) 6 N HCl, reflux (78%)
N
H
N
O
H H
(-)-Cytisine
Silvani et al, Org. Lett., 2004, 6 (4), 493-496
N
Cbz
CH2OAc
OH
1. (COCl)2, DMSO, Et3N,
CH2Cl2, -65 ºC to rt
2. KMnO4, ButOH-phosphate
buffer (pH 7.2)
90%
N
Cbz
CH2OAc
OH
O
SiMe3
H2N
1. DCC, HOBt, MeCN, rt
2. NaOH, MeOH, rt
83%
N
Cbz
CH2OH
O
HN
Me3Si
1. Dess-Martin
CH2Cl2, rt
62% aldehyde
26% cyclized product
2. K2CO3, MeOH
N
N
Cbz
HO
SiMe3
TFA, 0 ºC
72% N
N
CbzH
10% Pd-C, Et3N-THF (2:8)
120 ºC, sealed tube, 8 h
N
N
Cbz
N
N
H H
H2, 10% Pd-C, EtOH
65%
(-)-Virgilidone
D. Lesma et al., Eur. J. Org. Chem., 2001, 1377

8. The Lupin AlkaloidsI.B. Seiple
Baran Group Meeting
10/11/2006
N
H
CO2Me
HO
1. (Boc)2O, Et3N, CH2Cl2 (quant.)
2. (COCl)2, DMSO, Et3N, CH2Cl2
-40 to rt (91%)
N
Boc
CO2Me
O LiHMDS, N-(5-chloro-2-pyridyl)triflimide
THF, -78 ºC to -20 ºC (89%)
N
Boc
CO2Me
TfO
Pd(PPh3)4, LiCl, CuI
2-tributylstannyl-6-methoxypyridine
THF, 65 ºC (88%)
N
Boc
CO2MeNMeO
1. H2, Pd/C, MeOH, rt (quant.)
2. TFA, CH2Cl2, 0 ºC (quant.)
NH
CO2MeNMeO
SmI2, THF-HMPA
MeOH, 0 ºC to rt (78%)
N
H
O
NMeO
1. NaH, MeI or BnBr, THF-HMPA
0 ºC to rt (quant.)
2. LDA, ClCO2Et, THF
-78 ºC (quant.)
N
R
O
NMeO
CO2Et LiAlH4, THF, 0 ºC to rt (96% total)
N
R
NMeO
OH
50%
N
R
NMeO
OH
+
46%
(-)-jussiaeiine A (R = Me)
N
Me
N
H
O
OH
N
Me
N
H
O
OH
+
83% quant.
(-)-kuraramine (-)-isokuraramine
TMSCl, NaI, MeCN, reflux
(R = Me)
(R = Bn)MsCl, Et3N, CH2Cl2
0 ºC, then toluene
reflux (89%)
N
Bn
N
O
H H
H2, Pd(OH)2,
ammonium formate
MeOH, reflux (81%)
N
H
N
O
H H
(+)-cytisine
T. Honda et al, J. Org. Chem. 2005, 70, 499-504

9. The Lupin AlkaloidsI.B. Seiple
Baran Group Meeting
10/11/2006
N
Br
OMe
N
Br CO2Me
(Bu3Sn)2, BnPd(Ph3P)2Cl
DMF 130 ºC
N
CO2Me
N
OMe
40 - 50%
1. LiAlH4, Et2O
2. BnBr, MeCN
70 - 80%
N
N
OMe
Bn
OH
Br-
N
N
OMe
Bn
OH
H2 (1 atm), PtO2
MeOH/Et3N
100%
85:15 trans:cis
1. BnBr, MeCN
2. Na2S2O4
82%
4:1 trans:cis
N
CO2Me
N
OMe
Bn
H2 (1 atm), PtO2
MeOH
76%
(±)-Cytisine
1. MeSO2Cl, Et3N, CH2Cl2
2. PhMe, reflux
3. H2, Pd(OH)2, NH4HCO2, MeOH
58%
N
O
N
O
O
NH
1. LiHMDS, THF, 0 ºC
2. 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

10. The Lupin AlkaloidsI.B. Seiple
Baran Group Meeting
10/11/2006
1. HSiCl3, [(allyl)PdCl]2
(-)-S-MOP
2. H2O2, KI, KHCO3
3. Swern
O
O
1. Ethylene glycol, TsOH
2. LDA, BnO(CH2)3CHO
3. MsCl
4. DBU
(64%)
O
OBn
O
O
H2, Pd/C, Pd(OH)2
Zn(N3)2•2pyr, DEAD, PPh3
(78%)
O
N3
O
O
H
TiCl4
O
N
O
(62%)
1. Lawesson's reagent
2. Raney Ni
3. LDA, I(CH2)4Cl
4. NaI, acetone
(76%)
O
N
Cl
BocNHOBoc,
K2CO3, DMF
(95%)
O
N
N
BocO
Boc
TFA, 4Å MS, then
NaHCO3
(74 - 98%)
N+
N
-
O
hv (254 nm)
benzene
(76%)
N
N
O
LiAlH4, THF, reflux
(95%)
N
N
(+)-sparteine
Note: by starting with the other
norbornadione enantiomer, (-)-
sparteine could also be
synthesized, but it is
commercially available.
15.7% overall
J. Aube´ et al., Org. Lett., 2002, 4 (15), 2577-2579

11. 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
Br
H
2-pyridone, K2CO3, Bu4NBr
toluene, reflux
66%
N
O
N
H
O
LDA (2 eq), THF, rt, 3 h
44%
N
O
H
N
H
O
MnO2, CH2Cl2
70%
N
O
H
N
O
BH3•THF, 0 ºC to rt
85%
N
H
N
O
(±)-anagyrine
BocN
CO2Me
LHMDS, (EtO2C)2C=CH2
THF, -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
H
N
O
(±)-thermopsine

12. The Lupin AlkaloidsI.B. Seiple
Baran 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
N
O
O
CN 1. LiAlH4, Et2O, rt
2. glutaric anhydride, CHCl3
3. Ac2O, CHCl3, reflux
(56% total)
N
O
O
N
O
O
L-Selectride, CH2Cl2, -30 ºC
then MeSO3H, CHCl3 rt 20 h
(46% total)
N
N
O
H
O
O
1. 33% H2SO4
2. L-Selectride
3. 1,1'-thiocarbonyldi-
imidazole, ClCH2CH2Cl
4. 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
H2N
CO2Et
N
O
CO2Et
CO2Et
1.
2. Adam's cat., 2000 psi
EtOH, acetic acid
3. 100 ºC, neat (lactamization)
1. NaH, benzene, reflux
2. acetic acid, reflux
N
O
O
(55%)
(65%)

13. The Lupin AlkaloidsI.B. Seiple
Baran Group Meeting
10/11/2006
N
C
O CO2MeMeO2C
Na+
(86%) NH
O
CO2Me
CO2Me 1. Et3N,
O
2. B(OH)3
toluene, reflux
(100%)
N
O
MeO2C
CO2Me
N
CO2tBu H2, Pd/C
(90%)
N
H
CO2tBu 1. ClCH2COCl, Et3N
2. EtOCSSK, acetone
(72%)
N
CO2tBu
O
S
SEtO
lauroyl peroxide
benzene, then
2-propanol, heat
(27% total)
N
N
O
H
MeO2C CO2Me
H CO2tBu
N
N
O
H
MeO2C CO2Me
CO2tBu
H
3
to
1
S. Z. Zard et al, Angew. Chem. Int. Ed. 1998, 37 (8), 1128-1131
N
N
O
H
MeO2C CO2Me
H CO2tBu
N
N
O
H
MeO2C CO2Me
H CO2H
TFA, CH2Cl2
(COCl)2, CH2Cl2;
N-hydroxy-4-methylthiazolinethione,
Et3N; tert-dodecanethiol, Chx,
AIBN, reflux
N
N
O
H
MeO2C CO2Me
H H
1. BH3•Me2S, THF
2. 2 M HCl, reflux
(85%)
N
N
O
HH H
O
O
O O O
(90%) (56%)
(±)-matrine
N
CO2tBu
O
N
O
MeO2C
CO2Me
N
N
O
O
MeO2C
CO2Me
E
N
N
O
O
MeO2C
CO2Me
CO2tBu
N
N
O
O
MeO2C
CO2Me
CO2tBu
S
S
OEt
Propogation