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The Lupin Alkaloids Ian Bass Seiple 10/11/2006

Lupin alkaloids baran

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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