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