1. Passerini Reaction Revisited:
Atom-Economical Construction of
-Hydroxy--Aminoamides,
-Ketoamide Protease Inhibitors and
-Ketoamide Natural Products
J. Edward Semple, Ph.D.
Department of Medicinal Chemistry
Corvas International, Inc.
3030 Science Park Road
San Diego, CA 92121
&
Structural Bioinformatics
10929 Technology Place
San Diego, CA 92127
International Conference on Multicomponent Reactions,
Combinatorial and Related Chemistry,
Genova, Italy, April 14-16, 2003
2. Application of the Ugi 4CC to the
Total Synthesis of Furanomycin
J. E. Semple, P. C. Wang, Z. Lysenko and M. M. Joullie J. Am. Chem. Soc. 1980, 102, 7505.
M. M. Joullie, P. C. Wang and J. E. Semple J. Am. Chem. Soc. 1980, 102, 887.
OMe CHO OMe
N
O
N
H
Ph
O Ph
Me
H
OMe
NH2
O
OH
H
H H
O
OH
OH
OH
OH
OH
O
N
O
N
H
Ph
O
H
Me
Ph
Me
O
NH2
O
OH
H
Me
H H
2-Methyl-5-furfural Ugi adduct-1 (R, 2R, 5S)-
Furanomycin
-D-Glucose Ugi adduct-2 (S, 2R, 5S)-
Furanomycin
(Natural)
3. -Hydroxy--Amino Acid Natural Products
N-Benzoyl-3-phenylisoserine:
Taxol® side chain
Bestatin:
antitumor antibiotic
and immunomodulator
Amastatin:
aminopeptidase A and leucine
aminopeptidase inhibitor
N
H
OH
O
OH
O
H2N N
H
CO2H
OH
O
H2N N
H
H
N
OH
O
O
N
H
O
CO2H
CO2H
5. Conventional Synthetic Approaches to
-Hydroxy--Amino Acid Derivatives
PGNH CO2H
R1
PGNH CHO
R1
R1
CO2Me
HCl•H2N
OH
BocNH
R1
CO2Me
OH
Boc
N
H
N
H
CO2R
R1 O
OH
R1'
Pn....P 4P3P2
N
H
N
H
R1 O R1'
O
H
N
P2'-P3'-P4'-etc
O
PGNH CHO
R1 R1
CO2Me
N
H
OH
PG
1. LiOH, MeOH,
H2O, H+
2. P1' Aminoacid
coupling
PG
N
H
N
H
CO2R
R1 O
2 steps
OH
P1--Ketoamide Target
1. NaHSO3, H2O
2. KCN, KHCO3,
THF, H2O
3. HCl, reflux
4. MeOH, H+
1. Deblock P1 amine
2. Coupling rxns
3. Optionally deblock
P1' acid
4 Optionally elaborate
P1' residue, coupling
5. Deprotect side chains
6. [O]
Reprotect
amino
group:
Boc2O,
NaHCO3,
THF, H2O
R1'
1. (EtS)3CLi,
-78°, THF
2. HgCl2, HgO,
95% MeOH
1. LiOH, MeOH,
H2O, H+
2. P1' Aminoacid
coupling
-Ketoamide Targets
Modest to Poor Yields
Route A: Cyanohydrin
Route B: Orthothioformate
Compilation of stereospecific and
asymmetric approaches: H. H. Wasserman,
M. Xia, M. R. Jorgensen, E. A. Curtis
Tetrahedron Lett. 1999, 40, 6163
6. Peptides and Peptidyl P1--Ketoamides
I. Schechter and A. Berger Biochem. Biophys. Res. Commun. 1967, 27, 157
Peptide Peptidyl -Ketoamide
H
N
N
H
H
N
N
H
H
N
R4
R3O
O
O
R2
R1
O
N
H
H
N
O
OR1'
R2'
P1P2P3P4 P1
'
P2
'
S1
S4 S2
S3 S2
'
S1
'
H
N
N
H
H
N
N
H
R4
R3O
O
O
R2
R1
O
P1P2P3P4 P1
'
P2
'
S1
S4 S2
S3 S1
'
H
N
N
H
O
OR1'
R2'
S2
'
N
H
O
scissile bond serine trap
7. P1--Ketoamides: Potent Enzyme Inhibitors
Cyclotheonamides:
CtA, N-formyl
CtB, N-acetyl
Family of macrocyclic peptides incorporating
a highly reactive P1--ketoargininamide
transition state inhibitor functionality: potent
thrombin and serine protease Inhibitors.
HN
HN
N
O
NH(Ac, CHO)
O
N
H
O
NH
O
O
O
HN
HN NH2
OH
N
H
N
H
NH
H2N NH
O
N
N
H
O
O
MeO2C
O O
CVS 3040
Potent mixed FIIa/FXa inhibitor
with good OBA in rats
:
N
H
N
H
O
N
O
N
H
O2S
MeO
O
NH
HN NH2
O
N
H
N
H
O
H
N
O
O
O
O
Bn
Eurystatin A:
Novel macrocyclic ketoamide
with prolyl endopeptidase
(PEP) inhibitory activity.
HNHN
NH
OO
O
NH
O
O
P1-Ketoargininamide:
Potent thrombin inhibitor
(Corvas)
P1-Norvalinketoamide:
Calpain inhibitor
(Alkermes)
8. P1--Ketoamides: CVS 2308-99Tc Novel
Thrombus Imaging Agent
N
O
N
O
N
H
O
N
H
O
O
O
N
H
O
HN
O
N
H
H2N
O
O
N
H
N
H O
5 N
N
H
N
H
CO2H
O
O
CO2H
O
N
H
N
H
CO2H
O
O NH
O
N
H N
H
O
HO2C
OH
O CO2 H
OH
H2N NH
N
NMe2
OOH
N
O
S
Tc
NH
O
O
H
G. P. Vlasuk, T. R. Webb, D. A. Pearson
and M. M. Abelman U. S. Patent 5492895, 1996
Serine trap
9. The Passerini Reaction
N
OH
O
R1
R4
O O
N
H
O
R1R2
R1NC + R2R3CO + R4CO 2H
acyl
H+
O O
H
O
R3
R4
R2
R1 N
R3
R2
R4
O
R3
-Acyloxyamide ProductM. Passerini, Gazz. Chim. Ital. 1921, 51, 126.
M. Passerini and G. Ragni, Gazz. Chim. Ital. 1931, 61, 964.
I. Ugi et al. in Isonitrile Chemistry, I. Ugi, Ed.; Academic:
New York, 1971; Chapter 7.
A. Dömling and I. Ugi, Angew. Chem. Intl. Ed. 2000, 39, 3168.
shift
10. Passerini Reactions of -Amino Aldehydes with
TFA and Pyridine-Type Bases
PG1NH
N
OH
O
R1
CF3
O
PGNH
PGNH
O2CCF3
N
H
O
R1
H
PGNH
OH
N
H
O
R1
N
H
OH
N
H
O
R1
R3
O
N
H
N
H
O
R1
R3
O
O
H+
PGNH
OH
OH
O
R2
O
R2
R2
R2R2
R2
R2
CF3CO2H,
R1NC,
Pyridine,
CH2Cl2
acyl
shift
Hydrolytic
work-up
-Hydroxy--amino amide derivatives:
• ca. 1:1 mixture @ new hydroxy center
• retention of chirality at original centers
*
Elaboration
1. Optional sidechain
deprotection
2. Oxidation
Hydrolysis
-Ketoamide Derivatives
-Hydroxy--amino acid
"norstatine" derivatives
J. E. Semple, T. D. Owens, K. Nguyen and
O. E. Levy Organic Lett. 2000, 2, 2769.
J. E. Semple and O. E. Levy. WO 0035868 A2,
June, 2000; Priority: December 1998;
U.S. Patent 6376649 B1, April 2002.
J. E. Semple et al. Abstracts of Papers, 218th
American Chemical Society National Meeting,
New Orleans, LA, August 22-26, 1999;
ORGN-419, MEDI-240.
Passerini reaction with TFA and pyridine:
W. Lumma J. Org. Chem. 1981, 46, 3668.
TiCl4-catalyzed Passerini-type reactions:
D. Seebach et al. Chem. Ber. 1988, 121, 507;
Helv. Chim. Acta 1983, 66, 1618.
11. Passerini Reactions of -Amino Aldehydes
with TFA: Effect of Bases
Organic Base Additive pKa % Yield 3
2,6-di-t-Butyl Pyridine ~ 9 72
2,4,6-Collidine 7.4 71
2,6-Lutidine 6.6 68
Pyridine 5.2 60
N-Methylmorpholine 7.5 41
DABCO 8.2 33
4-N,N-Dimethylaminopyridine 9.7 18
N,N-Diisopropylethylamine 11 15
Fmoc
N
H
CHO CN
O
O Fmoc
N
H O
O
OH
N
H
OOrganic base,
TFA, DCM,
0 °C to RT
1 2 3
12. Passerini Reactions of -Amino Aldehydes with TFA
Variation 1: PGNHCH(R 2)CHO + R 1 NC + CF 3CO 2H = PGNHCH(R 2)CH(OH)CONHR 1
Cmpd PG Amino Acid SC R2 R1 %Yield
a Boc Cys(Me) CH2SMe CH2CO2Me 62
b Fmoc Val CH(CH3)2 CH2CO2t -Bu 68
c Fmoc Tyr(t -Bu) CH2Ph-4-(t -BuO) CH2CO2Et 69
d Boc Arg(NO2) (CH2)3NHC(=NH)NHNO 2 CH2CO2Et 38
e Fmoc Arg(Pmc) (CH2)3NHC(=NH)NHPmc CH2CH2Ph 75
f Boc Arg(NO2) (CH2)3NHC(=NH)NHNO 2 t -Bu 92
g Boc Phe CH2Ph CH2CO2Allyl 67
h Boc Phe CH2Ph t -Bu 24-71
i Cbz d -Phe CH2Ph (S )-CH(i -Bu)CO2Bn 65
j Boc ChxAla CH2Chx t -Bu 46
k Fmoc Gly H CH2CO2Allyl 77
l Fmoc Ala CH3 CH2CO2Allyl 83
m Fmoc Abu CH2CH3 CH2CO2Allyl 73
n Fmoc Val CH(CH3)2 CH2CO2Allyl 68
o Fmoc nor-Val (CH2)2CH3 CH2CO2Allyl 87
p Fmoc Leu CH2CH(CH3)2 CH2CO2Allyl 85
q Fmoc nor-Leu (CH2)3CH3 CH2CO2Allyl 69
r Fmoc Phe CH2Ph CH2CO2Allyl 67
s Fmoc Tyr(t -Bu) CH2Ph-4-(t -BuO) CH2CO2Allyl 66
t Fmoc Ser(t -Bu) CH2Ot -Bu CH2CO2Allyl 68
u Fmoc Asp(t -Bu) CH2CO2t -Bu CH2CO2Allyl 60
v Fmoc Arg(Pmc) (CH2)3NHC(=NH)NHPmc CH2CO2Allyl 76
w Fmoc Lys(Boc) (CH2)4NHBoc CH2CO2Allyl 79
x Fmoc Thr CH3(CH)Ot -Bu CH2CO2Allyl 62
y Fmoc allo -Thr CH3(CH)Ot -Bu CH2CO2Allyl 74
HCV
Inhibitor
libraries
Thrombin
and FXa
Inhibitors,
Libraries,
Bestatin
N
H
N
H
R2
OH
O
PG R1
J. E. Semple, T. D. Owens,
K. Nguyen and O. E. Levy
Organic Lett. 2000, 2, 2769.
J. E. Semple and O. E. Levy,
WO 0035868 A2, 2000; US
Patent 6376649 B1, 2002
13. Passerini TFA Protocol: Synthesis of
-Hydroxy--Amino Acid Derivatives
1. BH 3•THF,
0° to RT, 91%
2. Pyr•SO3, Et3N,
CH 2Cl2, DMSO,
0° to RT, ~quant
OH
BocNH
O
BocNH
H
OH
N
H
BocNH
O
OH
O
BocNH
O
OH
t-BuNC, TFA,
pyridine, CH 2Cl2,
0° to RT, 46%
1. 6N HCl, reflux
2. Boc2O, K 2CO 3,
dioxane, H 2O
3. NaHSO 4, H2O,
72%
A, 17 grams
OH
BocNH
OH
BocNH
NH 2
H
N
NH 2
NNO 2
OH
O
H
N NNO 2
N
HO
BocNH
OH
O
NH 2
H
N
BocNH
H
NH 2
H
N NNO 2
O
NNO 2 1. Me(MeO)NH•HCl,
CH 3CN, HOBt,
EDC, NMM,
0° to RT, 68%
2. LiAlH4, THF,
-78° to 0°
3. NaHSO 4, H2O,
-20°, 71%
t-BuNC, TFA,
pyridine, CH 2Cl2,
0° to RT, 92%
1. 6N HCl, reflux
2. Boc2O, Na 2CO 3,
dioxane, H 2O
3. NaHSO 4, H2O,
52%
B, 5 grams
BocNH
H
O
t-BuNC, TFA,
pyridine, CH 2Cl2,
0° to RT, 24% or
t-BuNC, TFA,
2,4,6-collidine, CH2Cl2,
0° to RT, 72%
OH
BocNH N
H
O
OH
BocNH OH
O
1. 6N HCl, reflux, ~quant.
2. Boc2O, NaHCO 3,
THF, H2O
3. NaHSO 4, H2O,
93%
C, 23 grams
1. Me(MeO)NH•HCl,
TBTU, HOBt, CH3CN,
RT, ~quant.
2. LiAlH4, THF,
-78° to 0°
3. NaHSO4, H2O,
-20°, 99%
BocNH
OH
O
J. E. Semple, T. D. Owens, K. Nguyen
and O. E. Levy Organic Lett. 2000, 2, 2769.
14. Concise Synthesis of Bestatin
J. E. Semple, T. D. Owens, K. Nguyen, O. E. Levy Organic Lett. 2000, 2, 2769.
J. E. Semple, T. D. Owens, K. Nguyen, O. E. Levy, 16th International Symposium for
Synthesis in Organic Chemistry, Cambridge, UK, July 19–22, 1999; P.4.
15. Passerini Reactions of -Amino Aldehydes with
Carboxylic Acids
L. Banfi, G. Guanti, R. Riva, A. Basso, E. Calcagno
Tetrahedron Lett. 2002, 43, 4067.
L. Banfi, G. Guanti, and R. Riva Chem. Commun. 2000, 985.
J. E. Semple and O. E. Levy. WO 0035868A2, June, 2000
(Priority: 12/18/98); US Patent 6376649 B1, April 2002.
J. E. Semple et al. Abstracts of Papers, 218th American
Chemical Society National Meeting, New Orleans, LA,
August 22-26, 1999; ORGN-419, MEDI-240.
J. E. Semple, T. D. Owens, K. Nguyen and O. E. Levy
16th International Symposium for Synthesis in Organic
Chemistry, Cambridge, UK, July 19–22, 1999; P.4.
O. E. Levy, K. Nguyen, T. D. Owens and J. E. Semple
Abstracts of Papers, 16th American Peptide Symposium ,
Minneapolis, MN, June 26–July 1, 1999; P-6653.
PGNH CHO PGNH
R2
NHR
O
O
R1
O
H2N
R2
NHR
O
O
R1
O
N
H
R2
NHR
O
OH
R1
O
N
H
R2
NHR
O
R1
O
O
R2
acyl migration
-Acyloxy--aminoamide:
• Ca. 1,1 mixture @ new acyloxy center.
• Retention of chirality @ *.
N
OH
O
R
R1
O
PGNH
R2
*
RNC, R1CO2H,
solvent
-PG
Cleave
acyl moiety
N
H
R2
NHR
O
OH
Ketoamide target or
advanced intermediate
PG
H+
Further
chemistry
[O]
Further
chemistry
16. Passerini Reactions: Examples of
“Atom-Economical” Synthesis
Entry PG R2 R1 R Solvent %Yield Comments
1 Boc (S)-(CH2)3NHC(NH2)=N-NO2 Fmoc-Pro CH2CO2Et EtOH 51
2 Boc (S)-(CH2)3NHC(NH2)=N-NO2 Alloc-Pro CH2CO2Et EtOH 50
3 Boc (S)-(CH2)3NHC(NH2)=N-NO2 Ac CH2CO2Et EtOH 35-48
4 Boc (S)-(CH2)3NHC(NH2)=N-NO2 Bz CH2CO2Et EtOH 57
5 Boc (S)-(CH2)3NHC(NH2)=N-NO2 Ph(CH2)2 CH2CO2Et EtOH 60-62 Thrombin inhibitors
6 Fmoc (S)-(CH2)3NHC(NH2)=N-PMC Ac CH2CO2Et CH2Cl2 76
7 Boc (S)-(CH2)3NHC(NH2)=N-NO2 Alloc-Pro Phe-Tyr(Cl2Bn)-OMe CH2Cl2 59 Cyclotheonamide
8 Boc (S)-(CH2)3NHC(NH2)=N-NO2 BnSO2-7Lac-Gly CH2CO2Et EtOH 39 CVS 1778 ketoamide
9 Fmoc (S)-(CH2)3NHC(NH2)=N-PMC Ph(3-OMe)SO2-Pdn-Gly PhEt MeOH 38 CVS 2044 ketoamide
10 Fmoc (S)-(CH2)3NHC(NH2)=N-NO2 BnSO2-d-Arg(NO2)-Sar CH2CO2Et CH2Cl2 31 FXa Inhibitor
11 Boc (S)-(CH2)3NHC(NH2)=N-NO2 PrPent-Asp(OMe)-Pro CH2CO2Allyl CH2Cl2 83 CVS 1123 ketoamide
12 Fmoc (S)-i-Pr Ac CH2CO2t-Bu CH2Cl2 84
13 Fmoc (S)-i-Pr Formyl CH2CO2t-Bu CH2Cl2 50 R1CO labile in MeOH
14 Boc (S)-i-Pr Ac CH2CO2Me CH2Cl2 66
15 Fmoc (S)-Me d-Boc-Orn(Z)- Leu-OMe CH2Cl2 73
16 Fmoc (S)-Me l-Boc-Orn(Z)- Leu-OMe CH2Cl2 75-80 Eurystatin
17 Cbz (S)-Bn Bz CH2CO2Et CH2Cl2 44
18 Fmoc (S)-Bn Bz CH2CO2Et CH2Cl2 69
19 Boc (S)-Bn Ac CH2CO2Et CH2Cl2 67
20 Cbz (S)-Bn Bz CH2CO2t-Bu MeOH 44
21 Boc (S)-(CH2)2CH3 Ac CH2CO2Me CH2Cl2 Hep C Libraries
22 Fmoc (S)-4-t-BuO-Bn BnSO2-d-Arg(NO2)-Sar CH2CO2Et CH2Cl2 31
N
H
N
H
R2
O
O
PG
R1
O
R
*
*
CO
Note: retention @ *
Thrombin inhibitors
Thrombin inhibitors
T. D. Owens and J. E. Semple Organic Lett. 2001, 3, 3301.
J. E. Semple and O. E. Levy, WO 0035868 A2, 2000;
US Patent 6376649 B1, 2002
17. Novel Application to the P1--Ketoamide
Thrombin Inhibitor CVS 2392
N
OH
N-NO2
NH2
BocNH
H
N N-NO 2
NH2
HCl•H2N N
H
CO2Et
OH
O
N
BnSO 2NH
O
O
OH
+
N
H
H
N N-NO2
NH2
O
O
N
H
OEt
1. H2, Pd/C,
HOAc, EtOH,
H2O, 40 psi,
~quant
2. Moffatt [O]
3. RP-HPLC, 61%
CVS 2392
N
BnSO 2NH
O
O
N
H
H
N N-NO2
NH2
OH
O
N
H
N
N
H
O
O
N
H
H
N NH•TFA
NH2O
N
H
OEt
O
O2S
CO2H
Ph
O
O
Boc
EDC, HOBt,
DIEA, CH3CN,
RT, 68%
OEt
O
1. NaOEt (cat), EtOH,
30 min, 0°
2. HOAc, 91%
O
+
CNCH 2CO 2Et,
CH2Cl2, 0° to RT,
4-6 days, 60-62%
3. HCl, EtOH,
0°, 10 min, ~quant.
J. E. Semple, T. D. Owens, K. Nguyen and
O. E. Levy Organic Lett. 2000, 2, 2769.
18. Tandem Passerini Reaction, N-Amino Deprotection,
Acyl Migration Strategy for P1--Ketoamide
Thrombin Inhibitor CVS 2328
N
OH
N-NO2
NH 2
BocNH
H
N N-NO2
NH 2
BocNH N
H
CO 2Et
O
O
O
H
N N-NO2
NH 2
N
H
N
H
CO2Et
OH
OO
N
O
NHBnSO2
N
O
N
H
BnSO2
H
N NH•TFA
NH 2
N
H
N
H
CO2Et
OO
N
O
N
H
O2S
O
CNCH 2CO2Et,
EtOH, 0° to RT,
4 days, 39-75%
OH
N
O
N
H
BnSO 2
1. H2, Pd/C,
HOAc, EtOH,
H 2O, 40 psi,
~quant
2. Moffatt [O]
3. RP- HPLC, 50%
1. HCl, EtOAc,
0° to RT,~quant
2. Et3N, EtOH,
pH ~8.5-9,
0° to RT, 65-90%
O
+
CVS 2328
J. E. Semple and T .D. Owens,
unpublished
19. Application to CVS 2308 -Ketoamide
CVS 2308-99Tc
Thrombus
Imaging AgentJ. E. Semple and
T. D. Owens,
unpublished
N N-NO2
NH2OH
N
H
Boc
N
H
N
O
CO2Me
O CO2H
CN
O
O
Boc
N
H
N
H
O
H
N
N-NO2
NH2
O
O
O
NH
N
O
MeO2C O
O
N
H
N
H
O
H
N
N-NO2
NH2
OH
O
O
N
H
N
O
CO2Me
O
O
N
H
N
H
O
H
N
N-NO2
NH2
O
O
N
H
N
O
CO2Me
O
O
N
NH
NHCH(Ph)2O
+ +
CH2Cl2,
0°-RT,
5 days, 83%
1. 5 N HCl, EtOAc,
0°-RT, quant.
2. 2 eq. Et 3N,
CH3CN, pH ~9,
0°-RT,
14 hrs, 82%
1. EDC, DMSO,
DCAA, toluene,
0°-RT, 1 hr, ~quant.
2. Ph 2CHNHCONHNH 2•TFA,
NaOAc, EtOH, H 2O,
reflux, 55-82%
Advanced intermediate
- 5.7 gm
20. Efficient Construction of P3-Pyridone
P1--Ketoamide CVS 3040
J. E. Semple and J. J . Cui,
unpublished
N
H
Fmoc
Fmoc
N
H
N
HO
O
O
N
ONHS
MeO
N
H
N
H
OH
O
N
O
N
H
S
MeO
O
N
H
N
H
O
O
N
O
N
H
S
MeO
O
H
N NH•TFA
NH2
N
O
N
H
S
MeO
CO2H
NC
NH
H2N N-Pmc
H
N N-Pmc
NH2
N N-Pmc
NH2OH
O
O
O
O
O
O
O
O
CH2Cl2,
0°-RT, 38%
Et2NH (10 eq.),
CH2Cl2,0° to RT,
12 hrs, 82%
1. Moffatt [O],
~quant
2. TFA, CH2Cl2,
0° to RT
3. RP-HPLC,
50-56%
+ +
CVS 3040
- 2.3 gm
21. Studies on the Total Synthesis of -
Ketoamide Natural Products
Cyclotheonamides A and B:
CtA, N-formyl derivative
CtB, N-acetyl derivative
Family of macrocyclic peptides incorporating
a reactive P1--ketoargininamide transition
state inhibitor functionality: potent thrombin and
serine protease Inhibitors.
Synthetic studies: (a) Maryanoff, B. E.; Nicolaou,
K. C. et al. J. Am. Chem. Soc. 1995, 117, 1225.
(b) Wipf, P.; Kim, H. J. Org. Chem. 1993, 58, 5592.
(c) Hagihiri, M.; Schreiber S. L. J. Am. Chem. Soc.
1992, 114, 6570.
Cyclotheonamides E2 and E3:
Wasserman, H. H. and Zhang, R.
Tetrahedron 2002, 58, 6277.
Eurystatins:
Eurystatin A: R = Me
Eurystatin B: R = Et
Novel 13-membered macrocyclic ketoamides with
prolyl endopeptidase (PEP) inhibitory activity.
Synthetic studies: (a) Wasserman, H. H.; Peterson,
A. K. J. Org. Chem. 1997, 62, 8972. (b) Schmidt, U.;
Weinbrenner, S. J. Chem. Soc. Chem. Commun.
1994, 1003.
NH
O
OH
NH
NH
O
O
O
NH
N
H
NHNH2
N
H
(Ac, CHO)
N
O
O
N
H
O O
N
H
N
H
O
O
N
H
O
R
22. Cyclotheonamides: Model Studies
Utilizing Key Passerini Protocol
O-Bn(Cl2)
BocNH CO2H
CN
N
H
FmocNH
N
H
CO 2Me
O
OBn(Cl 2)
CO 2Me
O
OBn(Cl 2)
O
BocNH N
H
H
N
NH
H2N N-NO2
O O CO2Me
OBn(Cl 2)
O
N-Alloc
1. Et2NH, CH2Cl2 ,
0° to RT
99%
2. HCO2H, Ac2O,
CH2Cl2, RT to
reflux, 79%
3. CCl3OCOCl,
NMM, -40° to 0°,
CH2Cl2, 39-79%
1. MeOH, HCl,
0° to RT,
98%
2. Fmoc-d-Phe-OH,
EDC, HOBt,
NMM, CH3CN,
RT, quant
1. HCl, MeOH,
0° to RT, quant
2. Et 3N, pH~ 8-9,
MeOH, RT,
98%, acyl shift
Alloc-Pro-OH,
Boc-Arg(NO2)-H,
CH 2Cl2 , 0° to
RT, 2 days, 59%
Ct A/B: N(10) through C(17)
model compound
- 550 mg
HN
HN
N
O
NH(Ac, CHO)
O
N
H
O
NH
O
O
O
HN
HN NH2
OH
O
N
H
N
H
H
N
NH
H2N N-NO 2
OH O CO 2Me
OBn(Cl 2)
O
N
O
O
T. D. Owens, J. E. Semple Organic Lett. 2001, 3, 3301.
J. E. Semple, 219th American Chemical Society National
Meeting, San Francisco, CA March 26-30, 2000; ORGN.667.
CtA/B
23. Total Synthesis of Eurystatin A
T. D. Owens, G. L. Araldi, R. F. Nutt and J. E. Semple Tetrahedron Lett. 2001, 42, 6271
24. Passerini Reactions with -Aminoaldehyde
Derivatives: Summary
TFA-Pyridine Conditions:
• Efficient, concise, high-yielding synthesis of -hydroxy-amino amides and
-hydroxy--amino acid derivatives.
• Scalable, up to 65-75 gms.
Protocols Utilizing Carboxylic Acids:
• Atom-economical synthesis of relatively complex -acyloxycarboxamides.
• Orthogonal amino deprotection-acyl migration reactions occur under very mild
conditions and directly deliver complex -hydroxy--acylamino amides.
• Scalable, up to 17-20 gms.
Stereochemistry:
• ca. 1:1 to 3:1 mixture at newly created -hydroxy center.
• Retention of stereochemical integrity at other chiral centers.
Applications:
• -Hydroxy-amino amides and -hydroxy--amino acid derivatives.
• Peptidyl and peptidomimetic -ketoamide serine and cysteine protease inhibitors.
• Natural products featuring -ketoamide moieties.
25. Acknowledgements
Timothy D. Owens, Ph.D.
Nathaniel K. Minami
Odile E. Levy, Ph.D.
Gian-Luca Araldi, Ph.D.
Jean J. Cui, Ph.D.
Daniel V. Siev
Khanh Nguyen
Ruth F. Nutt, Ph.D.
Terence K. Brunck, Ph.D.
Prof. M. M. Joullie (PENN)