Transcript Asymmetric Synthesis of b,g-Substituted Glutamic Acids

Asymmetric Synthesis of b,gSubstituted Glutamic Acids
Hruby, V. J., and Guoxia Han
Department of Chemistry
University of Arizona
Introduction
The Importance of Glutamic Acid:
a-MSH:
Ac-Ser-Tyr-Ser-Met-Glu5-His-Phe-Arg-Trp-Gly-LysPro-Val-NH2
SRIF:
Ser-Ala-Asn-Ser-Asn-Pro-Ala-Met-Ala-Pro-ArgGlu12-Arg-Lys-Ala-Gly-Cys-Lys-Asn-Phe-Phe-TrpLys-Thr-Phe-Thr-Ser-Cys-OH
Why Side Chain Substitution?
Constrained amino acids
Constrained peptides
Receptor selective and potent ligands
Retrosynthetic Pathway A
R2
R1
ROOC
COOH
COOH
COOR'
NH2
HO
NPG
COOH
NH2
OHC
COOR'
NPG
HO
COOH
R'OH
HCl (gas)
NH2
HO
COOR'
NH2
Boc2O
Na2CO3
Dioxane/H2O
HO
COOR'
NBoc2
CH3CN
DMAP
Boc2O
PCC
PDC
Swern
Dess Martin
N.R.
HO
COOR'
NHBoc
Retrosynthetic Route B
R2
R1
COOH
COOH
NH2
ROOC
COOH
COOR'
NPG
COOH
NH2
Me
COOMe
Me
COOMe
NHPf
+
MeOOC
O
O
N
Pf
LiCuMe2
RT
LiCuMe2
COOMe
OMe
HO
N
Pf
NHPf
LiCuMe2
TMSCl
o
-78 C
MeOOC
N
-78 oC
COOMe
Pf
M. M. Paz and F. J. Sardina, J. O. C., 1993, 58, pp6990-5.
COOMe
Retrosynthetic Route C
R2
R2
COOH
R1
O
O
R1
COOH
O
O
N
NH2
H
N
H
OR'
O
O
O
O
N
H
OH
OR'
N
PG
OR'
O
O
N
H
OH
O
R'OH/HCl
or
DCC/DMAP/R'OH
(R' = Et or iPr)
O
N
H
OR'
Boc2O
DMAP
MeCN
O
O
N
Boc
OR'
PhSe
O
O
N
Boc
LHMDS
PhSeCl
OR'
PhSe
SePh
O
O
N
Boc
PhSe
OR'
O
O
N
Boc
OR'
H2O2
H2O2
A few products
O
O
N
PG
OR'
PhSe
SePh
O
N
Boc
COO
O
N
Boc
COO
H
O
O
O
N
Boc
O
O
N
H
OMe
OR'
NaBH4
MeOH
or
EtOH
N
Boc
O
N
H
OH
OPG
TBDMSCl
Imidazole
DMF
O
N
OTBDMS
H
Boc2O
DMAP
MeCN
R1
O
N
Boc
OTBDMS
R1MgBr
CuX
20%
O
1. LHMDS
PhSeCl
2. H2O2
N
Boc
O
OTBDMS
N
Boc
OTBDMS
R1 = Me, Ph
R1MgBr
CuX
O
R1
HN
Boc
OTBDMS
Me
R1
O
Boc
+
Me
R1
H
LHMDS
MeI
N
R1
O
OTBDMS
N
O
OTBDMS
Boc
N
OH
H
[O]
Me
R1
O
Me
O
OH
H2N
Hydrolysis
O
O
OH
R1
N
H
OH
O
N
Bn
O
N
Boc
OTBDMS
O
N
Cbz
O
N
H
OTBDMS
BuLi/BnBr
or
NaH/BnBr
O
O
N
Cbz
OH
OTBDMS
N
Bn
O
O
OTBDMS
OTBDMS
N
H
OCbz
LiBH4/TMSCl
THF
O
N
Cbz
OH
TBDMSCl
Imidazole
DMF
O
N
Cbz
OTBDMS
Recent Work
O
O
O
O
MgBr
O
N
Boc
24%
OTBDPS
O
N
Boc
OTBDPS
O
O
O
O
MgBr
O
CuBr
N
Ts
OTBDPS
71%
O
N
Ts
OTBDPS
J. Cossy, M. Cases and D. G. Pardo, Synlett, 1998, pp507-9.
Just in…
Me
O
MeMgBr-Et2O
CuBr-Me2S-THF
N
Boc
OTBDMS
0 oC to RT
Ar
O
N
Boc
OTBDMS
PG: Cbz, Bn, Ts, etc.
O
Future Plan
N
PG
PG': t-Bu, TBDPS, etc.
OPG'
R2
R1
O
O
N
H
R2
R2
R1
OH
R2
R1
COOH
O
O
N
H
OH
N
N
OH
H
R2
R1
O
N
H
OH
H
OH
Acknowledgements
Dr. Victor J. Hruby
Dr. Jon Rainier
Dr. Koert
Hans-Dieter Arndt
NIH and USPHS
ACS Medicinal Division
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