Baran lab Group Meeting Yuzuru Kanda Classics in Semisynthesis 5/13/17
Semi(-)synthesis is; (Total) syntheses cannot clearly be classified to total/semi synthesis A synthesis which uses complex natural products (isolated or cultured) as the but we can "score" the synthesis by how "semisynthetic" it is. starting material to synthesize other target molecules. This is C-C bond Non spontaneous HO O AcO O (Redox) + + OH semisynthesis OH formation/cleavage stereo inversion Me Me NHBzO Me Me 1– X (overall yield) 1. TESCl Me Me steps HO 2. Ac2O Ph O Me 3. side chain Me O OH O Good semisynthesis Good semisyntheses are not H 4. HF H - least redox manipulation HO OAc HO OAc necessarily good and interesting OBz OBz - least stereocenter inversion total synthesis Baccatin III N Taxol - least C-C bond formation/cleavage Erythromycin - other criterias for good syntheses N NH2 (least step counts, high yield, high ee, atom economy etc...) 1. NH2OH N 2. 2-MeOpropene O Me * no penalty for esterifications, heteroatom alkylations, PG manipulations 3. Me2SO4 O Me O 4. H+, Na S O * nothing to do with complexity change, mass change, atom incorporation ratio 2 2 4 N OMe Me Me O Redox C-C Inv step yield score NMe HO OMe Me Me 2 Taxol 0 0 0 4 80% 80 HO OH O O O Me Clarithromycin 0 0 0 4 58% 58 Me Me NMe2 HO Paeonisuffrone 6 1 0 10 6.7% 2.0 O Me Me Solithromycin O O O O CN 104650166 Jolkinolide B 8 2 0 11 10% 0.9 Me Me F Nature 2016, 533, 338. Cyclopamine 7 5 0 20 1% 0.4 O O OMe Clarithromycin HN Me Me Me J. Antibiot. 1984, 37, 187. little lot Me H Me OH Me Ti(III)-Promoted Radical Cyclization of Epoxy Enones. Me O Total Synthesis of (+)-Paeonisuffrone. (JOC. 2009, 74, 1798.) O O Me O O Total synthesis Me H Me Is this Jolkinolide B semisynthesis? O OH O Me Synthesis. 2014, 46, 2574 Me H H Cyclopamine OH HO ACIE. 2009, 48, 7911. Other GMs to be refered Carvone O ? semisynthesis (Green, 2012), Vindoline (Mitsos, 2004), Me Paeonisuffrone Delphinine (Ambhaikar, 2004), Shikimic acid (Ambhaikar, 2005), semisynthesis Classic terpene syntheses (Maimone, 2005), Tetracycline (Lin, 2005), Morphine/ Codeine (Li, 2005) , Limonoids (Renata, 2011), Borderline between total/semi syntheses are very vague and arbitral Creativity from the Chiral Pool: Carvone (Rosen, 2012), opinions of semisynthesis advantages of semisynthesis Pentacyclic Triterpenes (Michaudel, 2013), Creativity from the Chiral Pool: Sugar Edition (Martinez, 2014), - cheating!!! - buying chiral centers Steroids (See, 2014), - step inefficient (PG, redox) - buying oxidations states Highlights in Peptide and Protein Synthesis (Malins, 2016), - chemistry is limited by the SM - less C-C/X bond formations Creativity from the Chiral Pool: Amino acids (deGruyter, 2017) Baran lab Group Meeting Yuzuru Kanda Classics in Semisynthesis 5/13/17
Me R O Me OH O MeN HO O Me O O R O OMe N O N O N OH N N MeO O O N HN Me Me H Camptothecin; O N N Cl NR OH OH HO 1. NH R = H HO 2 O Me 2 O Me Me Et O Irinotecan HO butylaldehyde, Me N 2. Rifampicin OH OH US 6723849 O Me H Me H2N OL. 2004, 6, 3921. FeSO4, CN 101481377 Me N H O /H SO N O US 8546573 OH NEt 2 2 2 4 2 NMe K252c Rifamycin SV; R = H CHO H OH OH N O N N 20th century O H H Me N O O COOH Me O N N Me O MsO OMs HO H N N O O COOMe H O Me 1. ClCOAr Me HO Me OMe O O MeO Cephalotaxine OMe 2. HBr OTf MeOOC OH N N MeN R BzCl 21st century homoharringtonine CN 102304132. Staurosporine; R = H O Midostaurin; R= BzCl ClCOAr TL. 1999, 40, 2931. O OH 1. thioCDI H OTBS LY333531 NMe2 2. MeI N O Me 1. NaOMe OPRD. 2002, 6, 471. O Me 2. Et3N•3HF H O O N O N BF3•Et2O, N TMSketene, N N O O O KF TBSO H TBSO H Me O O Me Me N N MeO Me OMe Me OMe O fradcarbazole A NMe O O Me Tet. 2015, 71, 7990. MeN N O OH O TFA MeO S OH NH O MeN S 3 NH N N H Baran lab Group Meeting Yuzuru Kanda Classics in Semisynthesis 5/13/17 OMe OMe Me RuCl [(R)-DRBM-Segphos](DMF) Me 2 2 HO Me MOMO Me H H2, MeOH, Et3N H Me Me O H OH H H H H H Me Me HOOC HOOC NMe NMe H H Me N N Artemisinic acid MeO H 4 step O H 1. EtOCOCl O CN PG manipulation O CN 2. TPP, air, hν, TFA NH NH cyanosafracin B NH2 NHBoc O O Me 7 steps Me Me OMe Me HOO H PG Me MOMO Me 5 steps O O O PG HOO H O H OHC Me H OMe O Me EtO O Me O HO H NMe MOMO Me Me N O H O OH H EtO H O H Me Me H O O O CN Me NaNO2, NH2 NMe H2O EtO O 2/3 steps OH N H OMe O H Me PG Me Me MOMO Me O CN H H H H NH Me Me O H OH H NHBoc O Me O O O O NMe Me Pt-650 O O O O OMe OH HCl H N Me Artemisinin MeOH Me Artemether O H Jorumycin synthesis from OPRD. 2014, 18, 417. OPRD. 2012, 16, 764. O CN Safracin B OPRD. 2007, 11, 336. O SFm Eur. J. Org. Chem. 2017, 975. KBH4, Me Tf2O, DMSO; iPr EtN; tBuOH; HO CaCl2, MeOH H H 2 O NHTroc Me (CH3N)2C=NtBu; OMe Me Me Ac O NH O 2 NHTroc OMe MeO HO Me H H O H H O Me O O Me MOMO Me H O O AcO S H O Me O H O O O AcO S H Me O O OMe O O O H NMe H 1. H2O O Me H NMe N Me 2. Et3N, Me HO O H succinic anhydride Artesunate N US 6677463 O O H O OH ET-743 OL. 2000, 2, 2545. O CN Baran lab Group Meeting Yuzuru Kanda Classics in Semisynthesis 5/13/17
N MeO OMe 1. DBU NH2 NH2 2. TBSCl O OH N Bekanamycin O 1. (4'', 6'' protect) N OTBS H H2N OH OH 2. TsCl (N protect) H O O 3. Zn, NaI (deOxy) O HO H2N N H O 1. LDA; MeO N BF •Et O 3 2 HO OH O 2. HF•py 1. H2O2 3. Cs CO NH2 R2 2 3 strychnine 2.TFAA; H NHBoc NHBoc NHTs NHTs KOH N H O O 1. AcOH O 2. Na, NH3 N O N O 3. Boc2O O H2N OH TsHN OH O O O O 1. DBU HO BocHN O TsHN Me N H 2. Ac2O N H OH H 3. HBr H HO OH O OH N 4. NaBH CN N O 3 O NHBoc NHTs
H PhthN OH 1. AcOH Me H 2. Na, NH Sungucine N H N H O 1. COOH 3 Chem. Eur. J. 2. TFA 3. PtO2, H2 Strychnogucine B 3. N H 2016, 22, 11593. O O 2 4 4. Pt2O, H2 Tabersonine R = H Chem. Phar. Bull. NH2 NH2 1. HNO3 N 1987, 35, 2136. NH2 2. Zn Me NH O N Vinblastine 2 CN 101575354 R Leurosidine NH2 NH2 Me H O 1. Ac2O HO MeO O H2N OH H 2. NBS Catharanthine N O O Ac COOMe O HO H N N 3. BuONO O N 2 H OH H COOMe 4. CuI, NaOMe N O O HO OH Dibekacin Me HO H2N NH2 N H Me MeO OAc HO OH Arbekacin N NH2 H Me COOMe CN 101575354 OAc Catharanthine Vindoline HO N Vincristine Me HO COOMe JACS. 2009, 131, 4904. J. Chem. Soc. Perkin trans. I. 1987, 155. Vindorosine J. Chem. Soc. Chem. Commun. 1984, 909. Baran lab Group Meeting Yuzuru Kanda Classics in Semisynthesis 5/13/17
1. BrCN O O 1. BnCl, NaI, K CO NMe O NR' 2. KOH O OH 2 3 OH OBn 2. BnCl, NaI, KOH 1. Me R' = Me H 3. KOH 2. H2 HO OH BnO OBn O O MeO MeO OMe 3. RMgX OMe HO O BnO HO Thebaine H H H OH Ellagic acid O Bn-HHDP (rac); O Me R no epimerization AcOH reflux or even NEET N O Ph O S 1. RBr O O OH Ph 2. KOtBu, O CuCl , O O C H SH O O 2 OH R = O 5 11 HO nBuNH2 O HO O O O Thienorphine OMe HO 1. sugar, DCC H O Syn. Commun. 2005, 35, 701. OH single 2. H2, Pd/C H HO atropisomer! HO R = tBu; Buprenorphine Me R US 8981097 OHHO OH OH 1:1 atropisomer OPRD. 2015, 19, 957 OH HO OH MeSO - OH O 4 HO HO O Me OH 1. phosphate buffer N O Cl 1. LAH O 2. H2, Pd/C N O O 2. Me2SO4 OH OH O O O O 1. KOH Coptisine chloride 2. mCPBA O OH O OH HO O HO OH Me HO OH OH HO N O O 5-O-desgalloylepipunicacortein HO O J. Org. Chem. 1998. 63, 24. O O Chem. Eur. J. 2012, 18, 9063. H Me O O N Chem. Commun. 2011, 47, 1628. HO O O O O HO O O 1. NaBH O O O 4 HO OH R O 2. H SO /AcOH HO O O H 2 4 O 1. DCC OH HO O H Me HO 2. H , Pd/C HO Chelamidine R = OH N 2 1. HCO H O2N OH Chelidonine R = H 3 single 2. KOH + HO OH CL. 1986, 739. BF3•Et2O, O atropisomer! Bn-HDDP (rac) OH Et3SiH H Pedunculagin O Eur. J. Org. Chem. 2003, 2128 Baran lab Group Meeting Yuzuru Kanda Classics in Semisynthesis 5/13/17
+ COOEt Me Me 1. H OH Me COOH O O 2. [O] Me O Me Me H OH H Roche process Hecogenin Me O 3. Ac2O Me H 4. NaBH Me H O HO OH O NH2 4 H H OH Me NHAc H H Shikimic acid Oseltamivir HO R O H Me AcO OH Me Me O Ph Me O Me H Me 1. Me3SI, NaH Pb(OAc) O EtO P COOEt COOEt 4 N Ph O 2. BF3•Et2O Me H H EtO OSiPh2Me O Me R = O Me H TsCl, py CHO Me HCOOH Me H H air Cs CO ; AcHN 2 3 O NO2 AcO AcHN PhCl EtOH AcO H NO Me NHAc H NO2 2 Me H HN H2N COOtBu Me COOEt Me Me TolSH Me Zn, 1. KCN, Me Oseltamivir Me TolS 2. NaH, DMSO NH3; TMSCl H N K CO Bz Me H 2 One-pot 2 3 O COOEt Me H N AcHN Veratramine No evaporation O NH2 Me O2N STol H TL. 1964, 33, 2281. No solvent exchange Me NHAc 36% Me HO JACS. 1967, 89, 4521. Chem. Eur. J., 52, 17789-17800 (2013) H2N COOtBu Me H H NR + Me Me Me H OH OMe O Me O OMe OMe H NCb N 1. NaOH O N Et2Zn, z H 2. MeI H H OAc MeO OMe Me (ArO)2P(O)OH, MeO Me H Me H CH2I2; MsOH Me 3. KMnO4 OMe OH H H H H H CbzCl; Condelphine 1. BBr3•SMe2 R'O PivCl PivO 2. CrO3, H2SO4 R, R' = H; cyclopamine Me Me 3. H2SO4 R = Cbz, R' = Piv OH H OMe O N Me Me NH2 O H OH O Cl OMe OMe NH2 O N H O H OMe Me H OMe Me Neofinaconitine HO OMe O O H H JACS. 2013, 135, 14313. S Me N IPI-926 H Baran lab Group Meeting Yuzuru Kanda Classics in Semisynthesis 5/13/17
Me Me OH Me Me O 1. mCPBA hydrocortisone NaBH4; O 2. TMSOTf; PPh3AuOTf, DBU, Me NaIO ; Me HO OH 4 mCPBA Oleanolic acid BF3•Et2O TsOH O Me H 3. NaIO4; CH2N2 Me Me H Me H Me Me H COOH O H H OAc OBn O O O O HO O Me O HO O Me Me Me Me Me BnO O BnO OBn Me O H OAc Me Me Me O H 1. BnBr I2 OHC 2. Jones H H nBu MeOOC MeOOC 3. NH2OH•HCl O O Me Me H Me Me OBz Me 1. NaOMe O I 2. LiAlH(OtBu)3; O Me O H Me O H HO BzCl HO O O N O HO O H O H Me Me Me Me MeOOC H O Chem. Eur. J. HO O 1. Na PdCl , HO OH 2010, 16, 1871. O 2 4 HO OH 1. mCPBA; CSA NaOAc, AcOH O OH O HCl OH OH OBz 2. Ac2O O Me 2. Me NBH(OAc) ; Me OBz 4 3 O Me O Me DDQ O 3. MeI Me H MeO O H AcO Me Me Me 4. MsCl O N O H ClPd Me H O O 3. py; Pb(OAc) ; NaBH O 4 4 Me Me H 1. OsO4 72% (3 steps) HO 2. (MeO) CMe O 2 2 3. DBU, Me NCH(OMe) ; Me O 2 2 HCl; PCC HO O OBz O O HO O Me AcO Me AcO Me OH N Me Me HO O JACS. 2008, MeO MeO H MeO Me AcO Me HO OH O HO 130, 5872. OH O O OH O 1. Et NH H O OH Me H 2 HO Me O 2. DBN; HCl O O O O O Me Me H COOH O BnO O OH O O Wortmannin O 3. Et2NH; TL. 1996, 37, 6141. Me K2CO3, MeOH; Lobatoside E HCl HO OH OH 4. Ac2O Me OBn OH 5. PCC