1/7/04 Group Meeting Thienamycin Richter First Total Synthesis (Racemic): Merck OH J. Am. Chem. Soc. 1978, 100, 313 J. Org. Chem. 1980, 45, 1130 J. Org. Chem. 1980, 45, 1135 J. Org. Chem. 1980, 45, 1142 NH2 S N O CO2H Isolation: OAc N 1. Merck, 1976 C 2. From Streptomyces cattleya O OAc SO2Cl -20 oC N O Merck & Co., Inc., U.S. Patent 3,950,357 (April 12, 1976) OAc 1. 10% Pd/C, Structure and Absolute Stereochemistry: 2. X-Ray of N-acetylthienamycin methyl ester N O O LDA, -78 2. Resistant to bacterial b-lactamase N O Me 1. BuLi, -78 oC; ClCO2PNB, 85% oC; N CH3CHO O MeO OMe BF3•Et2O 77% H OH 1. Active against gram-positive and gram-negative bacteria Na2SO3, 0 oC 42% Me N 2. MeOH, NaOMe 0-25 oC, 95% H Properties: J. Antibiotics. 1979, 32, 1 OH 40 psi H2, 100% 1. Chemical transformation and spectroscopy J. Am. Chem. Soc. 1978, 100, 6491 SO2Cl H2O, K2HPO4 O 2. H2O/HOAc, 65 oC, 82% O 3:2 (S:R) OCO2PNB OH N O OCO2PNB 1. CrO3, Py, celite H O O O R = O2N N H 1 Br2, 0 oC, Et2O/THF; SR N 2. BF3•Et2O, HSR, 46% SR H cyclohexene Et3N, DMF 87% First Total Synthesis (Racemic): Merck Asymmetric Total Synthesis: Merck J. Am. Chem. Soc. 1978, 100, 313 J. Org. Chem. 1980, 45, 1130 J. Org. Chem. 1980, 45, 1135 J. Org. Chem. 1980, 45, 1142 OCO2PNB J. Am. Chem. Soc. 1980, 102, 6161 O N OCO2PNB 9:1 DMF:H2O K2HPO4, 60% N O 1. Br2, Et2O/THF, 0 oC; Et3N, DMF, 58% CO2PNB 2. AgF, Py, 68% 3. collidine, LiI, 120 oC PNBO2C SR 2. 10% Pd/C, 23% NH2 N O O S Li N 3. NaI, acetone, D 4. TBSCl, Et3N, 50% TMS S TMS I O S -78 oC, 80% TBS 1. LDA (2 eq), -78 oC; N-acetylimidazole (2 eq), 82% OH N 2. K-Selectride, KI, RT, 87% TBS TMS S O S TBS S CO2H (±) Thienamycin 1. HgCl2, HgO, H2O/MeOH, 93% 2. H2O2, H2O/MeOH, 76% 3. carbonyl diimidazole 4. MgCH2CO2PNB, 86% 2 NH O S N OH CO2PNB 2. tBuMgCl, RT, ON; 2N HCl, NH4Cl 1. NaBH4 2. MsCl, Et3N 1. iPr2NH, DMSO O NH2 CO2Bn N OH CO2PNB O SR OCO2PNB N 1. Me3SiCl, Et3N SR PNBO2C 1. SOCl2, Py 2. nBu3P, CO2Bn CO2PNB Tol, reflux, 44% H BnO2C OCO2PNB SR PNBO2C O 1/7/04 Group Meeting Thienamycin Richter OH O CO2PNB N O 1. HCl/MeOH, 90% TBS 2. Et3N, 90% O O S N3 CO2H 1/7/04 Group Meeting Thienamycin Richter Asymmetric Total Synthesis: Merck Asymmetric Total Synthesis from Penicillin: Merck J. Am. Chem. Soc. 1980, 102, 6161 J. Am. Chem. Soc. 1981, 103, 6765 O OH N2 OH O O CO2PNB N 80 oC, 100% O 1. ClPO(OPh)2, DMAP, iPr2NEt OH CO2PNB O NHCO2PNB OTBS CO2PNB CO2Me S NH2 N O S BrCH2CO2Me 50% CO2Bn 96:4 (R:S) OTBS 1. KMnO4, Py/H2O 2. TBSCl, Et3N, DMF Cl N 3. Cl2, CCl4, 57% O O TBS O TMSO CO2H (+) Thienamycin O CO2Bn N OH N (2eq), 0 oC 55% 2NH•BH3 CO2Bn 1. "TBS" 2. tBuOK, S Pd/C, H2 S N 2. iPr2NEt, 70% HS iPr NHCO2PNB O CO2Bn MgTFA2 (5eq), Et2O; OH N H3PO4, 70% O O S CH3CHO, ZnCl2; N Rh2(OAc)4 N N 2 H S O Bn OH N2 N2 1. AgBF4, 70% 2. MeOH/H2O/HCl NH O O CO2Bn OH NH2 N O S CO2H (+) Thienamycin 3 1/7/04 Group Meeting Thienamycin Richter Racemic Total Synthesis: Merck Process Asymmetric Total Synthesis: Merck Process Tetrahedron Lett. 1980, 21, 2783 O J. Org. Chem. 1986, 51, 1498 Bz 1. BzNH2, Tol, MS EtO2C EtO2C 2. ketene, Tol 3. NaCNBH3, HOAc CO2Et NH H H Formation of chiral enamino ketone: OH H CO2Et O Ph EtO2C + 1:1 enantiomers H CO2Et NH2 O 1. HCl (conc), reflux 2. Pd(OH)2/C, 40 psi H2, HOAc OH BzOH, O HOAc, 70 oC NH2 N CO2H OTBS 1. Et3N, DCC, 60 oC NH2 H O O H N Ph H3CO OCH3 CO2CH3 CO2CH3 CO2H CO2Bz HO2C Ph 2. TBSCl, Et3N, DMF 3. Pd/C, 40 psi H2 N O TBS Ph 1. carbonyldiimidazole 2. Meldrum's acid, DMAP 3. PNBOH 4. HCl, MeOH/H2O 5. PPh3, DIAD, HCO2H 6. HCl N OH O O NH MeO2C CO2PNB CO2Me O OH NH2 N O S CO2H (±) Thienamycin 4 H 1. Not necessary to isolate after condensation step 2. Use of a catalytic amount of HOAc doubles rate of condensation, supresses byproduct formation, helps establish equilibrium 3. Once equilibrium established, introduce ketene gas and reaction is instantaneous with >95% yield. 1/7/04 Group Meeting Thienamycin Richter Asymmetric Total Synthesis: Merck Process Asymmetric Total Synthesis: Merck Process J. Org. Chem. 1986, 51, 1498 J. Org. Chem. 1986, 51, 1498 Reduction with boron reagents. Completion of Synthesis of Key Intermediate 1. Acidic borohydride reductions resulted in no stereocontrol 2. Catechol borane at -78 oC resulted in desired reduction to give: 1. Intermediate above isolated by conversion to the lactone and crystallization (>90% yield) to give pure: O Ph N MeO2C H H O O N H CO2Me CO2Me 3. Sodium cyanoborohydride reduction with acetic or propionic acid resulted in rapid reduction of the enol 4. Reduction product was <50% yield and elimination was a major competing reaction Catalytic Hydrogenation 1. Conditions: Pt/C, H3PO4 (2 eq), HOAc, RT, 90-1000 psi H2 2. Reduction proceeds from most accessible face (back) to give >60% yield of product 3. High H2 pressure supresses side product formation and enhances stereoselectivity Ph H O NH MeO2C MeO2C 5 CO2Me 2. Hydrolysis of the ester proceeded in >98% yield with concentrated HCl at 85 oC with no purification necessary 3. Remove solvent by vacuum distillation. 4. Remove the protecting group with Pd/C and H2 and crystallize the product in >90% yield. 5. Allows generation of the key intermediate below in 50% overall yield with only two purification steps OH CO2H HO2C NH2 Detailed Study of the Mitsunobu Reaction as Applied to the Synthesis of Thienamycin. Ph N Ph H H J. Am. Chem. Soc. 1988, 110, 6487 OH H CO2Me Could invert the stereocenter as above, or invert intramolecularly on the compound above. Tetrahedron Lett. 1981, 22, 913 Mitsunobu Mechanism Racemic Formal Synthesis: Grieco J. Am. Chem. Soc. 1988, 110, 6487 HCO2H PriO2C N N H N N PriO2C N N CO2iPr PriO2C ROH OTBDPS N H N N H H N O 1. BOC2O, Et3N, DMAP 2. LDA; PhSSPh Racemic Formal Synthesis: Grieco J. Am. Chem. Soc. 1984, 106, 6414 Br O O 1. 10% NaOH, 30% H2O2, 2. BF3•Et2O 78% 3. NaH, HMPA, THF, BnBr, nBu4NI, 85% OBn O O HO2C O 1. LAH 2. NaBH4, NiCl2 3. TBDPSCl, Et3N, DMAP 4. PCC, NaOAc 74% 65% O 1. TFA 2. Et3N; DCC, 84% OBn OBn 1. KMnO4, NaIO4, H2O/tBuOH, NaHCO3 OTBDPS NBOC 2. NaOMe, MeOH 3. mCPBA, -78 4. Tol, 100 oC, 73% POPh3 1. LiAlH(OMe)3, THF, -100 oC, 91% 2. DBU OBn oC RO2CH HCO2 O OTBDPS NH CO2iPr ROPPh3 CO2iPr 1. H2NOH•HCl, NaOAc 2. TsCl, DMAP, Py 80% O HCO2H HCO2 OBn CO2iPr PPh3 PPh3 PriO2C J. Am. Chem. Soc. 1984, 106, 6414 OBn CO2iPr PPh3 PriO2C 1/7/04 Group Meeting Thienamycin Richter OTBDPS NHBOC CO2H 3. nBu4NF 4. Jones, 80% 1. Pd, H2, 100% 2. carbonyldiimidazole; MgO2CCH2CO2PNB 50% OBn OH NH O O CO2PNB NH O OH NH2 N O S CO2H (±) Thienamycin 6 Asymmetric Formal Synthesis: Jacobi Asymmetric Formal Synthesis: Jacobi Making Grieco Asymmetric Nicholas Reaction J. Org. Chem. 1996, 61, 2413 1. TBDPSCl 2. PDC/DMF, 70% 3. (COCl)2, 99% OH HO nBuLi, 4. 75%, O Ph O J. Org. Chem. 1996, 61, 2413 J. Am. Chem. Soc. 1987, 109, 5749. Schreiber asymmetric Nicholas O O Ph O CH2OTBDPS Co2(CO)8 R'O N Me Co O 79%, O OBn Co MeO TMS O R OBn TMS Me DMF/TFH/H2O (3:3:1), 74% CH2OTBDPS Co OBn HO CH2OTBDPS 1. TFA 2. DCC 1. DPPA, tBuOH Nu [O] R Y CH2OTBDPS 1. nBu2BOTf, N MeO NH N TMS CH2OTBDPS TMS O TMSTf Et3N 66% O O N O CH2OTBDPS 1. Bu2BOTf, Ph Me Ph Co TMS Co (+) Thienamycin O O N OBn TMS OBn MeO CH2OTBDPS O O Co CO2H OBn O Nu LA O O NHBOC CH2OTBDPS O Y Co OBn NH Co CH2OTBDPS OBn 2. OsO4, NaIO4 71% 56% Co O O O R H+ or LiOH/H2O2 N Ph Co Y Me nBu BOTf, 2 R'O Y R NH 7 1/7/04 Group Meeting Thienamycin Richter Me CH2OTBDPS Asymmetric Formal Synthesis: Ley Asymmetric Formal Synthesis: Evans J. Chem. Soc., Chem. Commun. 1984, 494 O Me2SCH2 OMe OMe Tetrahedron Lett. 1986, 27, 4961 O OH OMe O OMe DMSO, 89% O O Fe2(CO)9 O NH2 1. TBSOTf, Lutidine, 98% O Fe(CO)3 OMe CAN N 87% O MeO 1. O3, -78 DMS 2. silica isomerization 3. K-Selectride, KI 4. Na, NH3, 75% 2. O3; DMS 3. allylMgCl, ZnCl 87% TBSO OH O 1. Me3Al, O H2NOMe 79% N OMe Ph OMe oC; O OH TBSO Ph OMe N N ZnCl2•TMEDA O 29% OH OTBS 1. MsCl, Py 2. K2CO3, 94% CO2Me OMe NH O OMe NHOMe 3. Li, NH3, 98% 4. RuO4, CH2N2, 70% O OH OH O NH2 NH2 N S N O CO2H (+) Thienamycin 8 O CH3CHO, 82% MeO O N O nBu BOTf; 2 Fe(CO)3 84% Ph 1/7/04 Group Meeting Thienamycin Richter S CO2H (+) Thienamycin NH O 1/7/04 Group Meeting Thienamycin Richter Asymmetric Formal Synthesis: Hanessian Asymmetric Formal Synthesis: Hanessian J. Am. Chem. Soc. 1985, 107, 1438 J. Org. Chem. 1990, 55, 3098 OH NH2 CO2H J. Am. Chem. Soc. 1985, 107, 1438 J. Org. Chem. 1990, 55, 3098 2. p-MeOC6H4NHCH2COCH3, MS, ClCO2iBu, N-methylmorpholine 70% O O N N anisyl CO3H OTBS O 1. K2CO3, DMF, 75% 2. TBSCl, DMF, 1. (EtO)2POCl, base 2. HSCH2CH2NHCO2PNB, OTBS O 1. NaNO2, KBr, H2SO4; NaOH O O CO2PNB 3. 51% AcOH, 78% nBu NF, 4 OH imidazole, 80% 3. CAN, 87% 89% NH N O O S CO2H (±) Thienamycin OTBS O NH O 1. CH3NO2, base, 87% 2. MsCl, Py 63% 9 O 1. lithium diallyl cuprate, 63% 2. LiHMDS, BrCH2CO2PNB 3. OsO4 4. H5IO6, 100% NO2 N O N O OTBS O OTBS CO2PNB CO2PNB 1. LiHMDS, -100 oC; PhSeCl, 71% 2. H2O2, 100% 3. O3, 100% N O NH2 CO2H NHCO2PNB OH S CO2PNB Racemic Formal Synthesis: Kametani Asymmetric Formal Synthesis: Shibasaki J. Am. Chem. Soc. 1980, 102, 2060 J. Chem. Soc., Chem. Commum. 1982, 1324 Tetrahedron Lett. 1982, 23, 2875 O N CO2Me O N 54% SO2Ph MeO PhSH H2, PtO2 OMe NH N cinchonidine O 100% MeO O CO2Me OMe OH CO2Me 2. AcOH 3. NaBH4, 90% 1. ClCO2PNB, Py, 85% OMe MeMgI NH OTBS NTBS NH O O OCO2PNB 2. HSCH2CH2NHCO2PNB 86% O NH SPh NTBS 3. Collins o 54% optical yield 4. NaBH4, -78 C OH SCH2CH2NHCO2PNB OTBS NTBS 2. PhSH, Et3N N-bromoacetamide; Na2SO3, 37% NTBS 3. mCPBA 4. BrMgCH2CCH 5. TBSCl, Et3N O 1. LDA, -78 oC; ClCO2PNB, 68% OTBS SCH2CH2NHCO2PNB 1. HCl 2. TBSCl, DMF imidazole OH O OMe O OCO2PNB 1. TBSCl, DMF, imidazole 2. LDA; CH3CHO NH 10.1% 3:2 mixture 1. ClCO2PNB, Py, 85% SPh OH NH2 OMe OMe SPh CO2PNB O O CO2PNB O OH NH2 N O OH S CO2H (±) Thienamycin 10 1/7/04 Group Meeting Thienamycin Richter NH2 N O S CO2H (+) Thienamycin Richter Thienamycin Summary of Selected Syntheses 1978, Merck Med. Chem. Racemic Total Synthesis 19 steps, ca 0.2% yield 1980, Merck Med. Chem. Asymmetric Total Synthesis 19 steps, ca 9.8% yield 1981, Merck Process. Asymmetric Total Synthesis 13 steps from Penicillin, ca 5.4% yield 1980, Merck Process. Racemic Total Synthesis 21 steps, >10% yield 1986, Merck Process. Asymmetric Total Synthesis 17 steps, >10% yield 1984, Grieco. Racemic Formal Synthesis 29 steps, ca 3.2% yield 1996, Jacobi. Asymmetric Formal Synthesis 21 steps, ca 1.8% yield 1984, Ley. Asymmetric Formal Synthesis 18 steps, ca 0.2% yield 1986, Evans. Asymmetric Formal Synthesis 20 steps, ??% yield 1990, Hanessian. Asymmetric Formal Synthesis 20 steps, ca 0.84% yield 1980, Kametani. Racemic Formal Synthesis 14 steps, 0.1% yield 1982, Shibasaki. Asymmetric Formal Synthesis 20 steps, ca 4.3% yield 11 1/7/04 Group Meeting Selected Other Synthese Not Presented 1982, Hanessian. Asymmetric Formal Synthesis Can. J. Chem. 1982, 60, 2292 1982, Shiozaki. Racemic Formal Synthesis Tetrahedron. 1982, 38, 3457 1985, Georg. Asymmetric Formal Synthesis J. Chem. Soc., Chem. Commun. 1985, 1433 1986, Fleming. Asymmetric Formal Synthesis J. Chem. Soc., Chem. Commun. 1986, 1198 1986, Buynak. Racemic Formal Synthesis J. Chem. Soc., Chem. Commun. 1986, 941 1986, Shibasaki. Formal Synthesis Chem. Pharm. Bull. 1986, 34, 1434 1987, Meyers. Asymmetric Formal Synthesis Tetrahedron Lett. 1987, 28, 5103 1987, Cainelli. Asymmetric Formal Synthesis J. Chem. Soc., Perkin Trans. I. 1987, 2637 1990, Palomo. Asymmetric Formal Synthesis J. Chem. Soc., Chem. Commun. 1990, 1390 1994, Tanimori. Racemic Formal Synthesis Heterocycles. 1994, 38, 1533 1995, Davies. Asymmetric Formal Synthesis Tetrahedron: Asymmetry. 1995, 6, 2507 2000, Tatsuta. Asymmetric Formal Synthesis J. Antibiotics. 2000, 53, 1231