Lupin Alkaloid

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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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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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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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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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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Lupin Alkaloid