A. A. Greenfield et al. / Tetrahedron Letters 44 (2003) 2729–2732
2731
completion the reaction mixture was quenched with
water, treated with acid or base followed by extraction
with ethyl acetate and evaporation of solvents. The
crude material was purified by flash chromatography
(eluent ethyl acetate–hexane). Typical conversions
>95%, yield >80%.
Design and optimization of a selective and efficient
oxidation methodology turned out to be rather chal-
lenging. Two successful approaches were explored: (a)
CrO3–MeCN system that provided sufficient conversion
in the majority of cases, and (b) tetrapropylammonium
perruthenate (TPAP)–N-methyl morpholine N-oxide
(NMMO) traditionally used for selective alcohol–alde-
hyde conversion,10,11 which we found to be extremely
useful for alcohol–acid transformation. Due to better
reproducibility, universal nature and facile isolation,
the latter system was adopted. Adequate yields of target
acids (8) were obtained when performing the oxidations
in acetonitrile at ambient conditions and prolonged
reaction times.
Oxidation. To a stirred at room temperature solution of
alcohol (7) (1 mmol) in 5–10 ml MeCN was added
N-methylmorpholine-N-oxide (2 equiv., 2 mmol) and
tetrapropylammonium perruthenate (10 mol%). The
progress of the reaction was monitored by TLC. After
completion the mixture was quenched with water or 2N
HCl. Excess of sodium bisulphite is added and the
mixture stirred for 10 min. After typical work-up (dilu-
tion with water and acid or base followed by extrac-
tion) and evaporation of solvents the residue was
purified by flash chromatography (eluent ethyl acetate–
methanol) or preparative thin layer chromatography.
Typical conversions >95%, yields were in a range 30–
70%.
All intermediates and products synthesized in the
course of this study have been isolated, purified and
fully characterized. Comprehensive characterization
data are available.12
In summary, we have established a convenient and
potentially universal synthetic methodology amenable
for a rapid synthesis of a series of highly functionalized
and diversified terphenyls. Utilization of a hydroxy-
ethoxy function serving as both protecting group and a
precursor of oxyacetic fragment allowed us to minimize
the overall number of synthetic steps. A powerful, yet
synthetically simple procedure of conversion of alcohols
into acids based on catalytic tetrapropylammonium
perruthenate oxidation allowed us to use a uniform
protocol for all target compounds and may serve as a
useful expansion of this efficient methodology. The
biological effects of these compounds will be reported
elsewhere.
References
1. Mayer, S. C.; Caufield, C. E.; Gundersen, E. G.; Katz, A.
H.; Moxham, C. M.; Seestaller-Wehr, L. M.; Taylor, J.
R.; and Xu, W. Design and synthesis of novel terphenyl
PTPase 1B inhibitors for the treatment of type II dia-
betes, Part I: The application of modeling investigations.
Abstracts of Papers, 219th National Meeting of the Amer-
ican Chemical Society, 2000; American Chemical Society;
San Francisco, CA; MEDI-247.
2. Greenfield, A. A.; Butera, J. A.; Caufield, C. E.;
Graceffa, R. F.; Gundersen, E. G.; Havran, L. M.;
Lennox, J. R.; Mayer, S. C.; Moxham, C. M.; Seestaller-
Wehr, L. M.; Taylor, J. R. Design and synthesis of novel
terphenyl PTPase 1B inhibitors for the treatment of type
II diabetes, Part II: The application of matrix approach.
Abstracts of Papers, 219th National Meeting of the Amer-
ican Chemical Society, 2000; American Chemical Society;
San Francisco, CA; MEDI-248.
3. Gundersen, E. G.; Butera, J. A.; Caufield, C. E.;
Graceffa, R. F.; Greenfield, A. A.; Havran, L. M.;
Lennox, J. R.; Mayer, S. C.; Morris, K. M.; Moxham, C.
M.; Seestaller-Wehr, L. M.; and Taylor, J. R. Design and
synthesis of novel terphenyl PTPase 1B inhibitors for the
treatment of type II diabetes, Part III: Tailpiece modifica-
tions. Abstracts of Papers, 219th National Meeting of the
American Chemical Society, 2000; American Chemical
Society; San Francisco, CA; MEDI-249.
The general procedures are presented below.
Arylation. To a stirred solution of K2CO3 (3 mmol, 1.5
ml of 2 M solution) were added 10–15 ml of dioxane, 1
mmol of substrate (3) and 1.1–1.2 mmol of aryl boronic
acid. The reaction flask was purged with nitrogen and
1–3 mol% of PdCl2(DPPF) was added to the mixture.
After stirring at room temperature for 0.5–1 h the
temperature was raised to 50–60°C. The progress of the
reaction was monitored by TLC. After typical work-up
(dilution with water and acid or base followed by
extraction) and evaporation of solvents the residue was
placed onto flash column (eluent ethyl acetate–hexane)
and quickly eluted to remove Pd residue. Typical con-
versions >95%, ratio monoaryl:bisaryl=2-4:1.
4. Havran, L. M.; Butera, J. A.; Caufield, C. E.; Graceffa,
R. F.; Greenfield, A. A.; Gundersen, E. G.; Mayer, S. C.;
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PTPase 1B inhibitors for the treatment of type II dia-
betes, Part IV: Headpiece modifications. Abstracts of
Papers, 219th National Meeting of the American Chemical
Society, 2000; American Chemical Society; San Fran-
cisco, CA; MEDI-250.
Amidation. To a stirred cooled (below −20°C) solution
of ester (4) or (5) (1 mmol) in 5–10 ml THF was added
solution of an appropriate lithiated amine (see Fig. 1)
in THF (below 0°C). Ideally, 2 equiv. is required for
secondary amines and 3 equiv. for primary amines. The
progress of the reaction was monitored by TLC. The
reaction is instantaneous at room temperature, yet to
avoid any complications it is recommended to mix the
reagents at low temperature (−40°C) and allow the
mixture to warm up. An excess of metallated amine is
usually required to offset extra amounts of water. After
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