the lupin alkaloids - scripps research institute · pdf filei.b. seiple the lupin alkaloids...
Post on 05-Feb-2018
237 Views
Preview:
TRANSCRIPT
The Lupin Alkaloids
Ian Bass Seiple10/11/2006
The Lupin AlkaloidsI.B. Seiple Baran Group Meeting10/11/2006
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.
N1
2
3
4
5
6
7
8
9
10
Quinolizidine Core Structure
The Lupin AlkaloidsI.B. SeipleBaran Group Meeting
10/11/2006
N
N
O
H
H
(+)-Lupanine
N
NH
H
O
Multiflorine
N
NH
H
(-)-Sparteine
N
N
O
H
H
H
HN
N
O
H
H
H
H
(-)-Sophoridine
N
N
O
H
H
H
H
(-)-Sophocarpine(+)-Matrine
N
N
O
H
H
H
(-)-Sophoramine
N NH
H
H
(+)-aloperine
N
HO
(-)-Lupinine
N
NH
O
H
H
Angustifoline
N
NH
O
H
H
Albine
N
NH
H
Aphylline
O
N
NH
Aphyllidine
O
N
NH
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 alkylatedderivatives)
The Lupin AlkaloidsI.B. SeipleBaran Group Meeting
10/11/2006
Biosynthesis
NH2
CO2HNH2
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
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
The Lupin AlkaloidsI.B. SeipleBaran 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 OS
Tol
O
LDA, THF-20 to -10 ºC (92%)
NS
Tol
O
N
STol
OLDA, THF,
-78 to rt, 29 h (62%)
I I
N
STol
O
N
STol
O
+
30% 58%
H HCeCl3 • 7 H2O
NaBH4MeOH
LDA, THFethylcyano-formate
-78 to rt, 2 hN
STol
O
N
STol
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
The Lupin AlkaloidsI.B. SeipleBaran 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
OMsOAcH
NaN3, DMF, 80 ºC
N
Cbz
N3OAcH
1. PPh3, THF, then H2O (66%)2. acryloyl chloride, Et3N, CH2Cl2 (89%)
N
Cbz
OAcH
HN
O
Grubb's catalyst CH2Cl2, reflux (79%)
N
Cbz
OAcH
HN
O
N
Cbz
OMsH
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, dioxanereflux (50%) 6 N HCl, reflux (78%)
NH
N
O
H H
(-)-Cytisine
Silvani et al, Org. Lett., 2004, 6 (4), 493-496
NCbz
CH2OAc
OH
1. (COCl)2, DMSO, Et3N,
CH2Cl2, -65 ºC to rt
2. KMnO4, ButOH-phosphate
buffer (pH 7.2)
90%
NCbz
CH2OAc
OH
O
SiMe3
H2N
1. DCC, HOBt, MeCN, rt2. NaOH, MeOH, rt
83%
NCbz
CH2OH
O
HN
Me3Si
1. Dess-Martin CH2Cl2, rt
62% aldehyde26% cyclized product
2. K2CO3, MeOH
N
NCbz
HO
SiMe3
TFA, 0 ºC
72% N
NCbzH
10% Pd-C, Et3N-THF (2:8)120 ºC, sealed tube, 8 h
N
NCbz
N
NH H
H2, 10% Pd-C, EtOH
65%(-)-Virgilidone
D. Lesma et al., Eur. J. Org. Chem., 2001, 1377
The Lupin AlkaloidsI.B. SeipleBaran Group Meeting
10/11/2006
NH
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)triflimideTHF, -78 ºC to -20 ºC (89%)
N
Boc
CO2Me
TfO
Pd(PPh3)4, LiCl, CuI2-tributylstannyl-6-methoxypyridineTHF, 65 ºC (88%)
N
Boc
CO2MeNMeO
1. H2, Pd/C, MeOH, rt (quant.)2. TFA, CH2Cl2, 0 ºC (quant.)
NH
CO2MeNMeO
SmI2, THF-HMPAMeOH, 0 ºC to rt (78%)
NH
O
NMeO
1. NaH, MeI or BnBr, THF-HMPA 0 ºC to rt (quant.)2. LDA, ClCO2Et, THF -78 ºC (quant.)
NR
O
NMeOCO2Et LiAlH4, THF, 0 ºC to rt (96% total)
NR
NMeO
OH
50%
NR
NMeO
OH
+
46%
(-)-jussiaeiine A (R = Me)
NMe
NH
O
OH
NMe
NH
O
OH
+
83% quant.
(-)-kuraramine (-)-isokuraramine
TMSCl, NaI, MeCN, reflux
(R = Me)
(R = Bn)MsCl, Et3N, CH2Cl20 ºC, then toluenereflux (89%)
NBn
N
O
H H
H2, Pd(OH)2,ammonium formateMeOH, reflux (81%)
NH
N
O
H H
(+)-cytisine
T. Honda et al, J. Org. Chem. 2005, 70, 499-504
The Lupin AlkaloidsI.B. SeipleBaran Group Meeting
10/11/2006
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
The Lupin AlkaloidsI.B. Seiple Baran Group Meeting10/11/2006
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 O
O
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 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
The Lupin AlkaloidsI.B. SeipleBaran 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, THF2. PBr3, toluene
70%
N
O
Br
H
2-pyridone, K2CO3, Bu4NBrtoluene, reflux
66%
N
O
N
HO
LDA (2 eq), THF, rt, 3 h
44%
N
O
HN
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
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%)
The Lupin AlkaloidsI.B. SeipleBaran Group Meeting
10/11/2006
N
C
O CO2MeMeO2C
Na+
(86%) NH
OCO2Me
CO2Me 1. Et3N,
O
2. B(OH)3 toluene, reflux(100%)
N
O
MeO2CCO2Me
N
CO2tBu H2, Pd/C
(90%)NH
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
CO2tBuH
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
MeO2CCO2Me
N
N
O
O
MeO2CCO2Me
E
N
N
O
O
MeO2CCO2Me
CO2tBu
N
N
O
O
MeO2CCO2Me
CO2tBu
S
S
OEt
Propogation
top related