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

7
6

1
2

10

The Lupin Alkaloids

I.B. Seiple

HO

HO

(-)-Lupinine

(+)-Epilupinine

OH
N

Albine

H
N

OH

(+)-Lupanine

Retamine

Aphyllidine

Aphylline

(-)-Sparteine
O

Angustifoline

NH

(-)-Cytisine (R = H)
(many alkylated
derivatives)

Lusitanine

NH

NR

NHAc

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Baptifoline

Multiflorine

O
N

O
N

H
H

Camoensidine

H
H

(+)-Matrine

H
H

H
H

(-)-Sophocarpine

H
H

H
H

(-)-Sophoridine

(-)-Sophoramine

H
H

(+)-Allomatrine

N
H H

(+)-aloperine

The Lupin Alkaloids

I.B. Seiple

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10/11/2006

Biosynthesis
NH2
CO2H
H
NH2

Decarboxylation

NH2
H'
H
NH2

NH

NH+

NH2

NH

L-lysine
O
NH2
H
NH
H
N+

N+

[O], condensation

N+

NH+

H- delivery

O
H
H
N

N+

H
H
N

W. M. Golebiewski, I. D. Spenser, Can. J. Chem., 1988, 66, 1734

(-)-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)

LiAlH4, Et2O

H
N

O
Bn
N

OH

1. LiAlH4
2. H2, Pd/C

OH
OH

(82%)

Bn
N

HO

O
O

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10/11/2006

epilupinine

paraformaldehyde
acetic acid
acetone
N
H HCl

Hg(OAc)2, acetic acid

reflux, K2CO3

N+

O
N

reflux
multiple xtalizations
(13%)

KOH, diethylene glycol

hydrazine hydrate, 75 C
to 200 C

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 C

formaldehyde (37% aq)

28 h, 65 C (82%)

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BnO

BnO

H2 (50 psi), Pd/C,

HCl, EtOH (100%)

BnO
H

H2N

Lupinine

NH2

(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 C (92%)
S

Tol
O S
CO2Et
H

O
S

O S
I

Tol -78 to rt, 29 h (62%)

1. LiAlH , THF

4
Tol
Et2O, 0 C, 3 h (88%)
O S
CO2Et 2. Raney-Ni, EtOH (90%)
H

+
N

11%

84%

Tol

CeCl3
7 H2O
NaBH4
MeOH

O S
H

Tol

O S
H

Tol

+
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.

(+)-epilupinine
1. LiAlH4, THF
Et2O, 0 C, 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 C, then
NaOH, H2O2 (76%)
3. MsCl, Et3N, CH2Cl2 (99%)

OH

OAc

Grubb's catalyst
CH2Cl2, reflux (79%)

HN
H

OAc

O
N

DDQ, dioxane
reflux (50%)

Cbz

Cbz

CH2OAc

CH2OAc SiMe
3

90%

Cbz

TFA, 0 C
72%

N
OH

H
N

Silvani et al, Org. Lett., 2004, 6 (4), 493-496

H

(-)-Cytisine

OH

N
H

1. (COCl)2, DMSO, Et3N,

CH2Cl2, -65 C to rt
2. KMnO4, ButOH-phosphate
buffer (pH 7.2)

Cbz

NaH, THF, rt (89%)

HN
H

Cbz

H
N

OMs

6 N HCl, reflux (78%)

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

N3

Cbz

NaN3, DMF, 80 C

SiMe3

OAc

Cbz

Cbz

HO

OMs

OAc

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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%

Cbz

2. K2CO3, MeOH

10% Pd-C, Et3N-THF (2:8)

120 C, sealed tube, 8 h

N
N

D. Lesma et al., Eur. J. Org. Chem., 2001, 1377

Cbz

H2, 10% Pd-C, EtOH

65%
(-)-Virgilidone

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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LiHMDS, N-(5-chloro-2-pyridyl)triflimide
THF, -78 C to -20 C (89%)

TfO
CO2Me

N
H

Boc

Pd(PPh3)4, LiCl, CuI

2-tributylstannyl-6-methoxypyridine
THF, 65 C (88%)

Boc

1. H2, Pd/C, MeOH, rt (quant.)

2. TFA, CH2Cl2, 0 C (quant.)
N

MeO

CO2Me

MeO

N
Boc

1. NaH, MeI or BnBr, THF-HMPA

0 C to rt (quant.)
2. LDA, ClCO2Et, THF
-78 C (quant.)

SmI2, THF-HMPA
MeOH, 0 C to rt (78%)
MeO

MeO

N
N
H

CO2Et

OH

CO2Me
NH

N
R

LiAlH4, THF, 0 C to rt (96% total)

OH

OH

OH

TMSCl, NaI, MeCN, reflux

MeO

MeO

N
R

N
R

50%

(R = Me)

46%
O

(R = Bn)
H

H
N
Bn

N
H
N
Me

83%

quant.

(-)-kuraramine

(-)-isokuraramine

H2, Pd(OH)2,
ammonium formate
MeOH, reflux (81%)

+
N
Me

(-)-jussiaeiine A (R = Me)
MsCl, Et3N, CH2Cl2
0 C, 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

(Bu3Sn)2, BnPd(Ph3P)2Cl
DMF 130 C

1. LiAlH4, Et2O
2. BnBr, MeCN
CO2Me

Br

CO2Me

40 - 50%

70 - 80%

OMe

O'Neil, B. T. et. al. Org. Lett. 2000, 2, 4201

OMe

OH

OMe

1. BnBr, MeCN
2. Na2S2O4

H2 (1 atm), PtO2
MeOH/Et3N

76%

100%
85:15 trans:cis

N
O

Bn

Bn

100%

1. LiHMDS, THF, 0 C
2. ClP(O)(OEt)2, THF, -78 to 20 C

H2 (1 atm), PtO2
MeOH
CO2Me

82%
4:1 trans:cis

OMe

OH

OMe

OPO(OEt)2
N

1. MeSO2Cl, Et3N, CH2Cl2

2. PhMe, reflux
3. H2, Pd(OH)2, NH4HCO2, MeOH

P(OAc)2 (2.5 mol %)

P(o-tol)3 (5 mol %)
Et3N (5 eq), MeCN, 60 C

57%

Coe, J. W. Org. Lett. 2000, 2, 4205

1. Me3NO2H2O, OsO4 (cat.)
2. NaIO4, EtOH-H2O (3:1)
3. H2 (50 psi), Pd(OH)2, aq. NH4OH

MnO2, C6H6, 80 C
N
O

58%

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

2. H2O2, KI, KHCO3

3. Swern

TiCl4

(62%)

3. MsCl
O 4. DBU
(64%)

1. Lawesson's reagent
2. Raney Ni

H2, Pd/C, Pd(OH)2

Zn(N3)22pyr, DEAD, PPh3

O
OBn

O
O

BocNHOBoc,
K2CO3, DMF

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(78%)

N3

O
O

TFA, 4 MS, then

NaHCO3

(95%)

3. LDA, I(CH2)4Cl
O 4. NaI, acetone
(76%)

(74 - 98%)

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 C to rt, 87%
2. KOtBu, THF, -78 C
84%

BnN

1. MeCO2tBu, LDA, THF, -78 C 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

70%

CO2Et
O

2-pyridone, K2CO3, Bu4NBr

toluene, reflux

N
O

66%
H

LDA (2 eq), THF, rt, 3 h

44%

MnO2, CH2Cl2

70%
H

Br

N
O
N
N

BH3THF, 0 C to rt
N

85%

O
H

()-thermopsine

()-anagyrine

BocN

LHMDS, (EtO2C)2C=CH2
THF, -78 to rt

BocN

as above
1. TFA, CH2Cl2, THF, 0 C, 100%
2. AcOH, toluene, reflux, 89%
3. NaCl, H2O, DMSO, 130 C 72 h, 72%

EtO2C
CO2Me

79%

EtO2C

CO2Me

Gallagher, T.; Gray, D. Angew. Chem. Int. Ed. 2006, 45, 2419-2423

O
N

CO2Me

The Lupin Alkaloids

I.B. Seiple

OEt

O
OEt

CO2Et
1. H2N
benzene, reflux, -H2O

O
N

Pd/C, AcOH, 50 psi

O
CN NC

2. Adam's cat., 2000 psi

(55%)
EtOH, acetic acid
CO2Et
3. 100 C, neat (lactamization)
CO2Et
(65%)

acrylonitrile, base

1. NaH, benzene, reflux

2. acetic acid, reflux

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L. Mandell et al, J. Am. Chem. Soc. 1963, 85, 2683-2684

d,l-matrine

CN

O
O

1. LiAlH4, Et2O, rt
2. glutaric anhydride, CHCl3
3. Ac2O, CHCl3, reflux

L-Selectride, CH2Cl2, -30 C

then MeSO3H, CHCl3 rt 20 h
(46% total)

O
N

O O

(56% total)
N

1. 33% H2SO4
2. L-Selectride

H
O

Jen Chen, J. Chem. Soc.,Chem. Comm. 1986, 905-907

3. 1,1'-thiocarbonyldiimidazole, ClCH2CH2Cl
4. Bu3SnH, xylene reflux

d,l-matrine
(23% overall)

The Lupin Alkaloids

I.B. Seiple

MeO2C

CO2Me

CO2Me

Na+

C
N

CO2Me
NH

(86%)

MeO2C

1. Et3N,

2. B(OH)3
toluene, reflux
(100%)

MeO2C
O
N
H

2. EtOCSSK, acetone
(72%)

N
H

EtO

N
H

MeO2C
O

CO2Me

TFA, CH2Cl2
CO2tBu

(90%)

CO2Me

N
H

CO2H

MeO2C
O

MeO2C
O

(COCl)2, CH2Cl2;
N-hydroxy-4-methylthiazolinethione,
Et3N; tert-dodecanethiol, Chx,
AIBN, reflux
H

(56%)

O
CO2tBu

CO2Me

MeO2C
O

1. BH3Me2S, THF
H

N
H

2. 2 M HCl, reflux
(85%)

N
E

N
O

MeO2C
O
N

Propogation

CO2Me
S

OEt

CO2tBu S

N
O

()-matrine

CO2Me

CO2tBu

CO2Me

MeO2C
CO2Me

H
CO2tBu

MeO2C

CO2Me

to

benzene, then
2-propanol, heat
(27% total)

S. Z. Zard et al, Angew. Chem. Int. Ed. 1998, 37 (8), 1128-1131

MeO2C
O

CO2tBu

lauroyl peroxide

CO2tBu 1. ClCH2COCl, Et N
3

(90%)

CO2Me

CO2Me

CO2tBu
CO2tBu H2, Pd/C

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N
O