The Lupin Alkaloids Ian Bass Seiple 10/11/2006 Baran Group Meeting I.B. Seiple The Lupin Alkaloids 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 7 4 6 8 3 N 9 1 2 10 Baran Group Meeting I.B. Seiple The Lupin Alkaloids 10/11/2006 H H HO HO NHAc NR NH NH H H H N N N H H N N N O O O (-)-Cytisine (R = H) (-)-Lupinine (+)-Epilupinine Lusitanine (many alkylated Angustifoline Albine derivatives) O O H H H N N H N H H N N N N N H H N N H N N H H H O OH (-)-Sparteine Aphylline Aphyllidine (+)-Lupanine Retamine (+)-aloperine O OH H H H O N N N N N N H H O Baptifoline Multiflorine Camoensidine O O O O O N N N N N H H H H H H H H H H H H H H H H H H H N N N N N (+)-Matrine (-)-Sophocarpine (-)-Sophoridine (-)-Sophoramine (+)-Allomatrine Baran Group Meeting I.B. Seiple The Lupin Alkaloids 10/11/2006 Biosynthesis NH2 NH2 O CO2H Decarboxylation H' ! H H H ! NH+ + NH NH2 NH2 NH2 NH NH L-lysine O O + O NH2 H NH [O], condensation H H H N+ H N N+ N NH O H H H + H- delivery N N W. M. Golebiewski, I. D. Spenser, Can. J. Chem., 1988, 66, 1734 N+ N H H (-)-sparteine HO reduction H N (-)-Lupinine Baran Group Meeting I.B. Seiple The Lupin Alkaloids 10/11/2006 OH 1. LiAlH OH Br 4 OH rt to reflux, Et EtO2C CO2Et Na, xylenes, reflux O 2. H , Pd/C EtO2C 2 2 N Vibramixer (41%) Bn (82%) Bn K2CO3 (28%) N N NH2 (after two distillations) O HO O HIO4, pH = 5 O H H buffer, rt LiAlH4, Et2O H N N N epilupinine paraformaldehyde acetic acid Hg(OAc)2, acetic acid reflux, K CO N+ O N acetone N O 2 3 O N N reflux H HCl multiple xtalizations N+ (13%) N KOH, diethylene glycol hydrazine hydrate, 75 ºC to 200 ºC N N (±)-sparteine E. E. van Tamelen and R. L. Foltz, J. Am. Chem. Soc. 1969, 91 (26), 7372-7377 Baran Group Meeting I.B. Seiple The Lupin Alkaloids 10/11/2006 BnO BnO BnO formaldehyde (37% aq) BnO BnO H2 (50 psi), Pd/C, 28 h, 65 ºC (82%) H LiAlH4, THF, 0 ºC H H HCl, EtOH (100%) + O H N N 2 N N NH2 Lupinine 1 (separable) 1.6 BnO P. A. Grieco and D. T. Parker, J. Org. Chem. 1988, 53, 3325-3330 H2 (50 psi), Pd/C, HCl, EtOH (100%) H N Epilupinine LDA, THF, Tol Tol Tol LDA, THF O S O S O S CeCl3 • H H O -20 to -10 ºC (92%) I I 7 H O O 2 + S S N Tol O N Tol -78 to rt, 29 h (62%) N NaBH4 N N MeOH 30% 58% 1. LiAlH , THF LDA, THF Tol Tol 4 OH O S O S Et2O, 0 ºC, 3 h (88%) ethylcyano- H CO Et H CO Et H formate 2 2 2. Raney-Ni, EtOH (90%) + Also, Al-Hg removal of the sulfer was attempted before reduction, resulting in a -78 to rt, 2 h N N N 1:3.6 ratio, with a slightly reduced yield. 11% 84% (+)-epilupinine It is also important to note that starting with 1. LiAlH , THF OH the enantiomer of the menthyl sulfinate 4 yields (-)-lupinine as the major product in Et2O, 0 ºC, 3 h (88%) H 2. Raney-Ni, EtOH (90%) similar ratios. N (-)-lupinine D. H. Hua et al, Synthesis, 1991, 970-974 Baran Group Meeting I.B. Seiple The Lupin Alkaloids 10/11/2006 1. (SOCl)2, DMSO, Et3N, (91%) 2. (-)-B-methoxydiisopinocampheylborane, OAc OMs OAc OH allyltrimethylsilane, Et2O, -78 ºC, then H OAc N3 1. PPh3, THF, then H2O (66%) NaOH, H2O2 (76%) H 2. acryloyl chloride, Et3N, 3. MsCl, Et3N, CH2Cl2 (99%) NaN3, DMF, 80 ºC CH2Cl2 (89%) N N N Cbz Cbz Cbz O O 1. NaOH, THF (98%) O Grubb's catalyst 2. MsCl, Et N OAc HN 3 H CH2Cl2, reflux (79%) OAc HN CH2Cl2 (67%) OMs HN NaH, THF, rt (89%) H H N N N Cbz Cbz Cbz O O O N DDQ, dioxane N N H reflux (50%) 6 N HCl, reflux (78%) Silvani et al, Org. Lett., 2004, 6 (4), 493-496 H H H H H H N N N H Cbz Cbz (-)-Cytisine 1. Dess-Martin 1. (COCl)2, DMSO, Et3N, Me3Si CH2OH CH2Cl2, rt CH2OAc CH2Cl2, -65 ºC to rt CH2OAc SiMe3 1. DCC, HOBt, MeCN, rt 2. KMnO , ButOH-phosphate 62% aldehyde 4 2. NaOH, MeOH, rt 26% cyclized product buffer (pH 7.2) HN N N O N Cbz 2. K CO , MeOH Cbz Cbz 83% 2 3 90% H2N O OH OH Cbz H H HO N 10% Pd-C, Et3N-THF (2:8) Cbz N H Cbz N H2, 10% Pd-C, EtOH TFA, 0 ºC N 120 ºC, sealed tube, 8 h N N N SiMe3 72% N 65% (-)-Virgilidone D. Lesma et al., Eur. J. Org. Chem., 2001, 1377 Baran Group Meeting I.B. Seiple The Lupin Alkaloids 10/11/2006 1. (Boc)2O, Et3N, CH2Cl2 (quant.) LiHMDS, N-(5-chloro-2-pyridyl)triflimide HO 2. (COCl)2, DMSO, Et3N, CH2Cl2 O TfO -40 to rt (91%) THF, -78 ºC to -20 ºC (89%) CO2Me CO2Me CO2Me N N N H Boc Boc Pd(PPh3)4, LiCl, CuI 2-tributylstannyl-6-methoxypyridine 1. H2, Pd/C, MeOH, rt (quant.) THF, 65 ºC (88%) 2. TFA, CH2Cl2, 0 ºC (quant.) MeO N MeO N CO2Me CO2Me NH N Boc 1. NaH, MeI or BnBr, THF-HMPA 0 ºC to rt (quant.) SmI2, THF-HMPA 2. LDA, ClCO2Et, THF MeOH, 0 ºC to rt (78%) -78 ºC (quant.) CO2Et LiAlH4, THF, 0 ºC to rt (96% total) MeO N MeO N N O N O H R OH OH OH OH TMSCl, NaI, MeCN, reflux MeO N + MeO N O N + O N H H (R = Me) N N N N R R Me Me 50% 46% 83% quant. (-)-jussiaeiine A (R = Me) (-)-kuraramine (-)-isokuraramine O O H , Pd(OH) , MsCl, Et N, CH Cl 2 2 3 2 2 (R = Bn) N ammonium formate N T. Honda et al, J. Org. Chem. 2005, 70, 499-504 0 ºC, then toluene MeOH, reflux (81%) reflux (89%) H H H H N N Bn H (+)-cytisine Baran Group Meeting I.B. Seiple The Lupin Alkaloids 10/11/2006 Bn Br- N N (Bu3Sn)2, BnPd(Ph3P)2Cl 1. LiAlH4, Et2O Br N DMF 130 ºC 2. BnBr, MeCN CO Me N 2 40 - 50% N 70 - 80% Br CO2Me N OH OMe OMe O'Neil, B. T. et. al. Org. Lett. 2000, 2, 4201 OMe H (1 atm), PtO 1. BnBr, MeCN 76% 2 2 100% O 2. Na2S2O4 MeOH/Et3N 85:15 trans:cis N O Bn Bn N N H2 (1 atm), PtO2 MeOH 1. LiHMDS, THF, 0 ºC 100% CO2Me 2. ClP(O)(OEt)2, THF, -78 to 20 ºC 82% N 4:1 trans:cis N OH OMe OMe OPO(OEt)2 N 1. MeSO2Cl, Et3N, CH2Cl2 O 2. PhMe, reflux 58% 3. H2, Pd(OH)2, NH4HCO2, MeOH P(OAc)2 (2.5 mol %) 57% P(o-tol)3 (5 mol %) Coe, J. W. Org. Lett. 2000, 2, 4205 Et3N (5 eq), MeCN, 60 ºC 1. Me NO•2H O, OsO (cat.) 3 2 4 NH 2. NaIO4, EtOH-H2O (3:1) 3. H (50 psi), Pd(OH) , aq. NH OH MnO2, C6H6, 80 ºC 2 2 4 N N N 74% 48% over 3 steps O O O (±)-Cytisine Baran Group Meeting I.B. Seiple The Lupin Alkaloids 10/11/2006 1. HSiCl3, [(allyl)PdCl]2 1. Ethylene glycol, TsOH H , Pd/C, Pd(OH) O O 2 2 O (-)-S-MOP 2. LDA, BnO(CH2)3CHO Zn(N ) •2pyr, DEAD, PPh 3 2 3 H 2. H O , KI, KHCO 3. MsCl O O 2 2 3 OBn (78%) N3 3. Swern O 4. DBU O O (64%) BocNHOBoc, TFA, 4Å MS, then O 1. Lawesson's reagent TiCl4 2. Raney Ni K2CO3, DMF NaHCO3 N N N (62%) 3.