Baran Group Meeting Semi-Synthesis Jason Green

"Enantioselective Synthesis: Natural Products from Chiral Terpenes" Tse-Lok Ho

1. mCPBA hν O 2. HIO6 3. PhMgBr O OH O 4. PCC I2; OH OH t-BuOK O dihydrocarvone 5. HCO2Et O OH 6. NaIO OtBu 4 O aq. MeOH from citronellal H , Pd/C; I 2 Ph3P=CH2; O O Li0, EtNH 2 OH NC axisonitrile HO O O O Caine, D. J. Am. Chem. Soc. 1978, 100, 8030 OH OH ambruticin Ireland, R. E. J. Am. Chem. Soc. 1980, 102, 6178 OTMS TMSO hν O O + O3; HCl, AlCl3; O TMSO H OTMS O NaOH NaOH piperitone

limonene O 215 °C HO HO benzene O3; O O OH NaOH O O daucene chrysanthemic acid Ho, T. L. Synth. Commun. 1982, 12, 995 Audenaert, F. Tetrahedron 1987, 43, 5593 Baran Group Meeting Semi-Synthesis Jason Green

O O aq. NH Br 3 H H HBr; Br THF, 0 °C; H HBr; Br O t-BuOK steam Br H 2 O distillation O perillaldehyde O carvone mechanism TsO OH Al2O3; H HO C Ph3P=CH2 H 2 CHO

aromadendrene I H HO Buchi, G. J. Am. Chem. Soc. 1966, 88, 4113 sordaricin

Wallach, O. Liebigs, Ann. Chem. 1899, 305, 245 Mander, L. N. J. Org. Chem. 1991, 56, 3959

Br2; HN3 BF •OEt ; NH O 3 2 NH2 CO2H Br2; (COCl)2 C + H LAH CHO N O NaOH OH terpineol N pulegone H

O HCO2H NH 20% HCl NH NH OH H 2 N HN HN

(-)-hobartine actidine (+)-aristoteline Darbre, T. Helv. Chim. Acta 1984, 67, 1040 Wuest, J. D. J. Org. Chem. 1977, 42, 2111 Baran Group Meeting Semi-Synthesis Jason Green

0 O OH 1. Li /NH3 O O 2. H+, O O HBr; O hν (HOCH ) BF3•OEt2 2 2 O O KOH H O 3 ArCO3H

carvone NaNH 2 CO2H CO2H MeI HO podocarpic acid O O

O O H O methyl-trans-chrysanthemate grandisol

Welch, S. C. J. Org. Chem. 1977, 42, 2879 Ayer, W. A. Can. J. Chem. 1974, 52, 1352 rosenonolactone

McReadie, T. J. Chem. Soc. 1971, 317 O OH 3 O CH2Cl2 MeOH O OOH mechanism CO2Me CO2Me methyl-podocarpic acid

OAc CO2H NaIO4;

KMnO4 CO2H HO CO2Me

Cochrane, E. J. Tetrahedron Lett. 1989, 50, 7111 Baran Group Meeting Semi-Synthesis Jason Green

Merriam-Webster Dictionary 2. Degradation of a natural product. -semisynthetic 3. Redox manipulation of a natural product 1. produced by chemical alteration of a natural starting material 2. containing both chemically identified and complex natural ingredients Approaching the grey area... -What if only a small portion of the NP can be traced to the SM. IUPAC Compendium of Chemical Terminology - the Gold Book -strict rules or room for interpretation? - accepted definitions for terms in chemistry -What is the actual availability of the starting material? -1607 pages -mg/g/kg scale -no definition for semisynthesis, total synthesis, synthesis, or retrosynthesis -deplete the world supply of oceanic sponges? Wikipedia -What if you use a stoichiometric amount of a naturally derived reagent? -A type of chemical synthesis that uses compounds isolated from natural sources (e.g. plant material or bacterial or cell cultures) as starting materials. These natural biomolecules are usually large and complex Metric for comparison: molecules. This is opposed to a total synthesis where molecules are synthesized from a stepwise combination of small and cheap (usually N = M + C petrochemical) building blocks.

-Semisynthesis is usually used when the precursor molecule is too N = naturality structurally complex, or too costly or too inefficient to be produced by total (open to suggestions) synthesis.

M = mass variable = (M1/M2)*50 Definitive examples. M1 = remaining mass from the starting material M = natural product mass 1. Only source of chirality 2 -all stereocenters in the NP were in the SM -negligible mass change due to redox reactions -all stereocenters in the NP were relayed from the SM (grey?) C = complexity variable = (S1/S2)*50 S1 = number of stereocenters remaining from the starting material S = number of stereocenters in the natural product 1. NOCl O O 2 4 -inversion of stereochemistry 2. -HCl steps examples: 3. H O+ 3 (-)-limonene to (+)-carvone (-)-limonene to (+)-bilobanone O M = C H = 134 M = C H = 130 (-)-limonene (+)-carvone (+)-bilobanone 1 10 14 1 10 10 M2 = C10H14O = 150 M2 = C15H20O2 = 232 S1 = 1 S1 = 1 Royals, E. E. J. Am. Chem. Soc. 1951, 73, 5856 S2 = 1 S2 = 1 Hedge, S. G. J. Org. Chem. 1982, 47, 3148 N = 45 + 50 = 95 N = 28 + 50 = 78 Baran Group Meeting Semi-Synthesis Jason Green

X 3 Jorumycin: Total synthesis vs. degradation. Coenzym Q10: Total vs. semisynthesis n-BuLi; ZnBr ; O 2 2% Cl Pd(dppf) O I 2 I O 3 O H TMS I TMS O I 1 N I N n-BuLi; ZnBr ; O I 2 O O 2% Pd* O CN OBn O O HO 9 H N O Boc Ph solanesol 4 Ph renieramycin M (tobacco leaves, ~$7/g) TMS KOH; 24 steps 3 steps, 16% overall yield 4 steps Me3Al,Cp2ZrCl2Zr; 3 mg prepared 23 mg prepared 1, nBuLi; I2; ZnBr2; O 2% Pd*; Me Al 9 H I O 2 5 KOH; O common intermediate H Me3Al, Cp2ZrCl2 O O N O O N O Cl O Cl O OH O O OTs O O 3 mol% Williams N = O 4 mol% jorumycin Ni(PPh ) •2THF Saito N = 95 3 2 O Ni(PPh3)2•2THF O

Negishi N = 0 O 9 H Isolation: Saito, N* J. Nat. Prod. 2003, 66, 1441 Lipshutz N = 36 O 8.4 kg of sponge yielded 1.822 g of renieramycin M CoQ10 Fontana, A. Tetrahedron 2000, 56, 7305 50 g of sponge yielded 4.6 mg of jorumycin Semisynthesis: Saito, N* Tetrahedron 2004, 60, 3873 "..Synthesis of Coenzyme Q10" Negishi, E.* Org. Lett. 2002, 4, 261 Total Synthesis: Williams, R. M. JACS 2005, 127, 12684 "A Convergent Approach to Coenzyme Q" Lipshutz, B. JACS 2002, 124, 14282 Baran Group Meeting Semi-Synthesis Jason Green

OH O SO Comparative routes to the same target 3

HO tyrosine, alloleucine, arginine O O HO Cl O H H H H O N NH2 H OH H N N NH2 N N N H OH O N NH H O OH O N NH H HO O H aeruginosin 205-B

"Total Synthesis of.." aeruginosin 298-A Hanessian, S Org. Lett. 2009, 11, 4232 aeruginosin 298-B (without arginine) HO "First Total Syntheses of.." Bonjoch, J. Chem. Eur. J. 2001, 16, 3446 O H H "Total Synthesis of.. " H NH N N 2 Wipf, P. Org. Lett. 2000, 26, 4213 N H OH O N NH O H serine, alloleucine aeruginosin 298-A HO SO 3 "Enantioselective Synthesis of.." Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 11206 O H H H NH N 2 Bonjoch (298-B) 59 N N H OH O N NH Bonjoch/Wipf (298-A) 58 HO O H Trost (98B) 36 aeruginosin 98B Hanessian 11 "Total Synthesis of.." Trost, B. M. J. Am. Chem. Soc. ASAP Shibasaki (298-A) 0 Baran Group Meeting Semi-Synthesis Jason Green

(+)-epoxydictymene (-)-platensimycin lannotinidine B (-)-hispidospermidin N = 24 N = 24 N = 28 N = 20

"Total Synthesis of.." "A Chiral Pool Based Synthesis of.." "Protecting Group-Free Total "Enantioselective Total Synthesis of.." Paquette, L. A. J. Am. Chem. Nicolaou, K. C. Angew. Chem. Int. Ed. Synthesis of.." Overman, L. E.* J. Am. Chem. Soc. Soc. 1997, 119, 8438 2008, 47, 944 Yao, Z.* J. Am. Chem. Soc. 2012, 1998, 120, 4039 O 134, 12323 H OHO N HN H N N O HO H O H OH H O O O N O O O

carvone pulegone ~ $0.30/g ~ $1/g O O Cl O HO O H O NCS OH O HO B O H OH O O O N O O

O O N-methylwelwitindolinone C (+)-omphadiol HO HO Isothiocyanate N = 38 HO O N = 16 HO OH "Total Synthesis of.." D-mannose "Total Synthesis of.." Romo, D. Angew. Chem. Int. Ed. aplasmomycin Garg, N. K.* J. Am. Chem. Soc. 2011, 50, 7537 N = 52 2011, 133, 15797 "Total Synthesis of.." Corey, E. J. J. Am. Chem. Soc. 1982, 104, 6816 Baran Group Meeting Semi-Synthesis Jason Green

OH O O HO O OH PhIO O O S TMSOTf OH O OH N OH N + NH NH2 O O N 2 CH Cl OH O HO O 2 2 O OH O S 73% O OH HO O O epicoccin G tyrosines lactic acid rishirilide B N = 44 N = 2

"..Total Synthesis of Epicoccin G.." "Total Synthesis of.." Nicolaou, K. C. J. Am. Chem. Soc. 2012, 134, 17320 Pettus, T. R. R. J. Am. Chem. Soc. 2006, 128, 15625

O OH O OH O OH O N HO OH OH OH OH O OH OH O HO O O O OH HO OH OH O H hibarimicinone HO O H H H O HO HO HO prednisone cortistatin A N HO HO O + O HO O HO O OH OH N = 39 methyl α-D-glucopyranosides N = 31 "Synthesis of.." Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241 "Total Syntheses of.." Shair, M. D. J. Am. Chem. Soc. 2012, 134, 16765 natural product author N jorumycin Williams 0 CoQ10 Negishi 0 aeruginosin 298-A Shibasaki 0 rishirilide B Peus 2 aeruginosin 205-B Hanessian 11 N-methylwelwindolinine C Isothiocyanante Garg 16 hispidospermidin Overman 20 epoxydictymene Paquee Baran Group Meeting What is a Semi-Synthesis? Jason Green 24 platensimycin Nicolaou Where would you draw the line? 24 natural product author N lannonidine B jorumycin Williams 0 N ≠ 0 Yao CoQ10 Negishi 0 28 aeruginosin 298-A Shibasaki 0 N = 10 hibarimicinone rishirilide B Peus 2 Shair aeruginosin 205-B Hanessian 11 N = 50 31 N-methylwelwindolinine C Isothiocyanante Garg 16 aeruginosin 298-A hispidospermidin Overman 20 Trost epoxydictymene Paquee 24 36 platensimycin Nicolaou 24 CoQ10 lannonidine B Yao 28 Lipshutz hibarimicinone Shair 31 36 aeruginosin 298-A Trost 36 omphadiol CoQ10 Lipshutz 36 Romo omphadiol Romo 38 38 corstan A Baran 39 corstan A epicoccin G Nicolaou 44 Baran asplasmomycin Corey 52 39 aeruginosin 298-A Wipf/Bonjoch 58 epicoccin G aeruginosin 298-B Bonjoch 59 Nicolaou carvone Royals 67 44 bilabanone Hedge 78 N = Ma1 + Ca2 + X1a3 + X2a4 + ... a + a + ... = 100 asplasmomycin jorumycin Saito 95 1 2 Corey 52 step count relayed stereocenters aeruginosin 298-A redox manipulation Wipf/Bonjoch 58 aeruginosin 298-B Bonjoch 59 carvone Royals 67 nominine Cherney/Green 73(0) bilabanone Hedge 78 jorumycin Saito 95