Synthesis of ketone analogues of prolyl and pipecolyl ester FKBP12 ligands

Article abstract of DOI:10.1021/jm0200456

The recently discovered small-molecule ligands for the peptidyl and prolyl isomerases (PPIase) of FKBP12 have been shown to possess powerful neuroprotective and neuroregenerative effects. Ketone analogues of the prolyl and pipecolyl esters, which mimic on

Full text of DOI:10.1021/jm0200456

3558
J . Med. Chem. 2002, 45, 3558-3568
Syn th esis of Keton e An a logu es of P r olyl a n d P ip ecolyl Ester F KBP 12 Liga n d s
Yong-Qian Wu,* Douglas E. Wilkinson, David Limburg, J ia-He Li, Hansjorg Sauer, Doug Ross, Shi Liang,
Dawn Spicer, Heather Valentine, Mike Fuller, Hong Guo, Pam Howorth, Raj Soni, Yi Chen,
J oseph P. Steiner, and Gregory S. Hamilton
Department of Research, Guilford Pharmaceuticals, Inc., 6611 Tributary Street, Baltimore, Maryland 21224
Received J anuary 29, 2002
The recently discovered small-molecule ligands for the peptidyl and prolyl isomerases (PPIase)
of FKBP12 have been shown to possess powerful neuroprotective and neuroregenerative effects.
Ketone analogues of the prolyl and pipecolyl esters, which mimic only the FKBP binding domain
portion of FK506, are proposed and an efficient synthetic strategy is presented in this report,
along with the preliminary results of in vitro and in vivo biological studies.
In tr od u ction
metabolically stable ligands, we now report the synthe-
sis and biological evaluation of a series of ketone
analogues of 1, such as compound 5h (Figure 1).
FKBP12 is one of the best-characterized members of
the class of proteins called immunophilins. It serves as
a cellular receptor for the important immunosuppres-
sant drug FK506.1,2 FKBP12 is also known to have
peptidyl and prolyl isomerase (PPIase, or rotamase)
enzyme activity, catalyzing the interconversion of cis
and trans rotamers of amide bonds in proline-containing
peptide and protein substrates.3 PPIases have been
found to play critical roles in a variety of biological
processes other than immunosuppresion, including pro-
tein trafficking and regulation of neurite outgrowth.4
Ch em istr y
Syntheses of prolyl and pipecolyl ketones are rela-
tively uncommon in the literature. In our ongoing
structural probe of novel FKBP inhibitors, the ketone
analogues were found to be the most challenging
synthetically.
A retrosynthetic examination of target compounds
such as 5h (shown in Figure 2), analogue of 1, initially
suggested the synthesis should start by formation of the
ketone through various alkylaryl Grignard reagents
(method A). This would allow extensive SAR around
both the alkyl (chain length) and aryl portions of the
molecule. After exploring the two most popular electro-
philes used in the literature for synthesizing ketones
via Grignard reactions, we have determined that the
Weinreb amide electrophile17 gave the best yield and
the cleanest reaction for the proline derivatives while
the 2-pyridine carbothiolate18 was preferred for the
pipecolyl ring series. Therefore, as shown in Scheme 1,
addition of Grignard reagents to the commercially
available Weinreb amide derivative of Boc-proline 2
yielded intermediate ketones 3. Deprotection of the Boc
group using TFA followed by acylation with methyl
chlorooxoacetate provided the desired oxamate inter-
mediates 4. Reaction with various Grignard reagents
at -78 °C resulted in highly selective addition at the
more electrophilic carbonyl of the ketoamide moiety,
yielding the desired products 5 (see Table 1). Similarly,
as shown in Scheme 2, the pipecolyl derivatives 11 (see
Table 1) were synthesized starting from commercially
available L-Boc-pipecolic acid 6. As a side note, several
other electrophiles including the prolinal were explored.
The aldehyde was advantageous when sterically hin-
dered and less reactive Grignard reagents were used;
however, an extra oxidation step was required to convert
the resultant alcohol to the ketone.
FK506 possesses two distinct binding domains:
a
FKBP12 binding domain and an “effector domain”,
which mediates interaction of the drug-immunophilin
complex with the secondary protein target calcineurin
(Figure 1). Inhibition of calcineurin by the FK506-
FKBP12 complexes, not blocking the catalytic rotamase
activity, is the mechanistic basis for the observed
immunosuppressant effects of FK506.5 Recently, FKBP12
has been found to be present in nearly 50-fold higher
concentration in the central nervous system compared
to the immune system.6 It was subsequently found that
FK506 mimicked the effects of trophic factors such as
nerve growth factor in vitro, promoting neurite out-
growth in neuronal cultures at picomolar concentra-
tions.7 In vivo, FK506 promoted regeneration and repair
of damaged facial8 and sciatic nerves9 in rats, suggesting
therapeutic utility for FKBP12 ligands in treating
neurological disorders.4,10,11
We reported previously that small-molecule ligands,
such as GPI 1046 (Figure 1, 1), for FKBP12 possess
powerful neuroprotective and neuroregenerative proper-
ties in vitro and in vivo.10,11 The neurotrophic effects of
these compounds are independent of the immunosup-
pressive pathways because they lack the “effector
domain” of FK506. Previously, work by ourselves and
other groups exploring the SAR of small molecules that
mimic only the FKBP binding domain portion of FK506
has focused on esters, thioesters, and amides of proline
and pipecolic acid.12-16 As part of our program exploring
various classes of FKBP12 ligands and seeking more
Although method A was successful for the synthesis
of several simple phenyl alkyl ketone analogues, we soon
encountered several problems and limitations with this
approach. First, there were a limited number of com-
mercially available Grignard reagents, requiring syn-
* To whom correspondence should be addressed. Phone: 410-631-
6823. Fax: 410-631-6848. E-mail: wuy@guilfordpharm.com.
10.1021/jm0200456 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/09/2002

Synthesis of Ketone Analogues
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3559
F igu r e 1. FK506 and small-molecule mimetics of the FKBP12 binding domain.
coupling product. To improve the yield of the desired
terminal coupling product, we explored several different
factors that may influence the product ratio, including
palladium catalysts, phosphine ligands, solvents, and
temperatures. We found that the recently reported
bulky phosphine ligand 3223 could significantly suppress
F igu r e 2. Synthetic approaches for the ketone compounds
exemplified by 5h .
thesis of the desired organometallic reagent from either
an alcohol or halide for each compound. For instance,
phenylbutyl Grignard 14 was obtained in two steps from
the corresponding alcohol 12, as shown in Scheme 3a.
Second, in many cases obtaining the halide precursors,
like the one for compound 5g as shown in Scheme 3b,
required a long and tedious synthesis. Alkyne 15,
reacting with 16, was converted to 17 via palladium-
mediated carbon-carbon coupling, followed by trans-
formation of the alcohol to bromide 18. Several attempts
to make the corresponding Grignard 19 failed. Hence,
20 was obtained by saturation of the triple bond via
hydrogenation, followed by benzyl protection of the
phenolic alcohol. Finally, 21 was converted to the
Grignard 22. As shown in Scheme 3c, once again, we
were unable to transform 4-bromobutylpyridine 23 into
its Grignard 24, which was needed for 5h . Thus, it
appeared that method A was not a practical and efficient
route to obtain compounds needed particularly for SAR
in the aryl region.
We therefore developed an alternative route based on
bond dissection “B” in our retrosynthetic analysis
(Figure 2). This route, shown in Scheme 4, proceeded
through a common intermediate (28 in Scheme 4) from
which the final products could be made in the last step
of the synthesis using various aromatic/heterocyclic
halides through a Heck coupling.19,20 As shown in
Scheme 4, addition of the commercial Grignard reagent
3-butenylmagnesium bromide to the Boc-proline Wein-
reb amide of 2 yielded ketone intermediate 25. Further
elaboration via similar chemistry shown in Scheme 1
yielded 28. Compound 28, containing a terminal alkene,
was subjected to a facile palladium-catalyzed coupling
with various aromatic/heterocyclic halides, and the final
products 5g,h were obtained following the hydrogena-
tion reaction.
the formation of the internal coupling product, and the
desired product could be easily purified from the side
product (<5%) by either silica chromatography or re-
crystallization. General application of this improved
method will be the subject of a future publication.24
Diketopipecolic acid 33 was available in our labora-
tory from earlier work, and taking advantage of it as a
starting material further shortened the synthesis. Com-
pound 33 was converted to the carbothiolate 34, and
35 was obtained after 34 was treated with a Grignard
reagent made from the commercially available precursor
1-bromo-5-(trimethylsilyl)-4-pentyne (Scheme 6). The
silyl protecting group on the terminal alkyne was
removed to give 36, which could be subsequently coupled
to the aryl/heterocyclic group. It was interesting to note
that the diketo moiety, hindered by the 1,1-dimethyl-
propyl or tert-butyl groups, showed remarkable resis-
tance and remained intact even in the presence of excess
Grignard reagent up to 0 °C. Further elaboration from
36 as described above resulted in the desired final
product 11e (see Table 1). 34 could also be converted to
11d directly by treating it with the 5-phenylpentylmag-
nesium bromide.
In contrast, reaction of Grignards with the proline
analogue of 38 or 39 led to significant addition to the
amide carbonyl of the diketo moiety to yield 40 without
producing appreciable amounts of the desired product
41 (Scheme 7). The fact that the prolylcarbonyl position
was quite hindered25 might explain partially the reac-
tivity differences between the prolyl and pipecolyl series.
When standard Heck reaction conditions were used,
a significant amount (25-35%) of internal coupling side
product 31 was produced from the reaction of 28 and
3-bromopyridine (Scheme 5). This was consistent with
previous literature reports.21,22 The internal coupling
product compromised the yield and purification process,
since it has a slightly lower Rf value than the terminal
Biologica l Resu lts a n d Discu ssion
Inhibition of the rotamase activity of FKBP-12 by test
compounds was assayed as described previously,13 and
apparent Ki’s were obtained and used as measures of
relative ligand binding affinities. The compounds de-

3560 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Wu et al.
Sch em e 1a
a
Reagents and conditions: (a) RMgX, THF, 0 °C; (b) 50% TFA, CH2Cl2; (c) methyl chlorooxoacetate, TEA, CH2Cl2, 0 °C; (d) R′MgX,
THF, -78 °C, 3 h.
(R)-tartrate salt from Oxford Asymmetry. Analytical thin-layer
chromatography was carried out using Merck DC-F254 pre-
coated silica gel plates. Flash chromatography was performed
using Kieselgel 60 (230-400 mesh) silica gel. 1H and 13C NMR
spectra were recorded on either a Varian 300 MHz or a Bruker
400 MHz instrument. Chemical shifts are reported in parts
per million (ppm). Mass spectral analyses were performed by
Oneida Research Services, Whitesboro, NY. Elemental analy-
ses were determined by Atlantic Microlab, Norcross, GA, and
are within (0.4% of the calculated values unless otherwise
noted.
scribed are mimetics of the FKBP binding domain of
FK506 (Figure 1) and, as expected, retain good affinity
for FKBP12. In vitro results of compounds are shown
in Table 1, and their inhibition constants range from
low nanomolar to low micromolar values. By way of
comparison, the ketone compounds were generally
several-fold less potent as FKBP12 inhibitors than the
corresponding esters or thioesters; however, they were
generally an order of magnitude more potent than
amides in this regard. The neurotrophic properties of
these ketones were evaluated in an in vivo model of
neurodegeneration. Parkinson’s disease is a serious
neurodegenerative disorder resulting from degeneration
of the nigrostriatal dopaminergic pathway and subse-
quent decrease in dopaminergic transmission.26 N-Meth-
yl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neu-
rotoxin that selectively destroys dopaminergic neurons.27
MPTP lesioning of dopaminergic neurons in mice was
used to test the effectiveness of our compounds as an
animal model of Parkinson’s disease as described previ-
ously.8 The data in Table 1 (both concurrent and post-
MPTP) are shown as percent recovery of striatal dopam-
inergic innervation relative to MPTP-treated animals
not receiving test drugs. Our studies indicated that
these compounds were effective in restoring striatal
innervation when administered orally at 10 mg/kg dose
after lesioning with MPTP and they were as potent and
efficacious as their ester/thioester amide analogues12,15,16
in this mouse model. For example, compound 5h regen-
erated striatal dopaminergic terminals post-MPTP-
lesioning in a bell-shaped dose-response curve (Figure
3). It produced significant effects at doses as low as 0.1
mg/kg and regenerated 45% recovery somewhere be-
tween 0.4 and 1.0 mg/kg. The maximum recovery
(around 50%) was consistent with what we had typically
observed for many of our other compounds, such as 1.
However, compound 5h was about 10-fold more potent
(peak at 0.4 mg/kg) than 1.
2(S)-(4-P h en ylbu tyr yl)p yr r olid in e-1-ca r boxylic Acid
ter t-Bu tyl Ester (3f). 2(S)-(Methoxymethylcarbamoyl)pyrro-
lidine-1-carboxylic acid tert-butyl ester 2 (2.0 g, 7.74 mmol)
was dissolved in anhydrous THF (10 mL), cooled to 0 °C, and
treated with freshly prepared 4-phenylbutylmagnesium bro-
mide 14 (2.1 equiv). The reaction mixture was stirred at 0 °C
for 1 h and at room temperature overnight. The reaction
mixture was quenched with 2 × 50 mL of 1 N HCl and water.
The resulting mixture was extracted with 2 × 100 mL of
EtOAc. The organic phase was dried, concentrated, and
purified on a silica gel column (25% EtOAc/hexane) to provide
1.33 g (54%) of the desired product.
1H NMR (CDCl3, 300
MHz): δ 1.28 (s, 9H); 1.66-1.87 (m, 6H); 2.32-2.42 (m, 2H);
2.49-2.52 (m, 2H); 3.32-3.51 (m, 2H); 4.12 (dd, 1H, J ) 3.5,
7.0 Hz); 7.04-7.19 (m, 5H). TLC: Rf ) 0.48 (25% EtOAc/
hexane).
2(S)-Oxo-[2-(4-ph en ylbu tyr yl)pyr r olidin -1-yl]acetic Acid
Meth yl Ester (4f). A mixture of 2(S)-(4-phenylbutyryl)-
pyrrolidine-1-carboxylic acid tert-butyl ester 3f (1.33 g, 4.19
mmol) and trifluoroacetic acid (0.98 mL, 12.57 mmol) in
methylene chloride (5 mL) was stirred overnight at room
temperature. The reaction mixture was evaporated in vacuo
to yield a thick oil and was used directly for the next step
without purification.
A mixture of above product 2(S)-4-phenyl-1-pyrrolidin-2-yl-
butan-1-one and triethylamine (4.05 g, 40.0 mmol) was dis-
solved in methylene chloride (20 mL) and stirred at 0 °C for
15 min. Methyl chlorooxoacetate (0.44 g, 4.61 mmol) was added
dropwise, and the mixture was stirred for an additional 2 h
at 0 °C. The reaction mixture was washed with water. The
organic phase was dried, concentrated, and purified on a silica
gel column (50% EtOAc/hexane) to yield a yellow oil, 0.56 g
(44%). 1H NMR (CDCl3, 300 MHz): δ 1.66-1.87 (m, 4H); 2.32-
2.42 (m, 2H); 2.49-2.67 (m, 4H); 3.62-3.78 (m, 2H); 3.82 (s,
3H); 4.68 (d, 1H, J ) 6.8 Hz); 7.19-7.31 (m, 5H). TLC: Rf )
0.40 (50% EtOAc/hexane).
2(S)-3,3-Dim eth yl-1-[2-(4-p h en ylbu tyr yl)p yr r olid in -1-
yl]bu ta n e-1,2-d ion e (5f). 2(S)-Oxo-[2-(4-phenylbutyryl)pyr-
rolidin-1-yl]acetic acid methyl ester 4f (0.56 g, 1.8 mmol) was
dissolved in anhydrous THF (10 mL), cooled to -78 °C, and
treated with 1,1-dimethylethylmagnesium chloride (1.0 M, 2.04
mL). The reaction mixture was allowed to stir for 3 h. The
reaction mixture was washed with saturated ammonium
chloride. The organic phase was dried, concentrated, and
purified on a silica gel column (25% EtOAc/hexane) to provide
0.44 g (72%) of the desired product as a clear oil. HPLC
analysis using a chiral column indicated a sharp single peak
(>95%, retention time of 5.65 min), suggesting 5f is a single
stereoisomer. 1H NMR (CDCl3, 300 MHz): δ 1.30 (s, 9H); 2.14-
2.19 (m, 1H); 2.46-2.70 (m, 4H); 3.46 (dd, 1H, J ) 6.5, 6.7,
10.4 Hz); 3.54 (dt, 1H, J ) 7.1, 10.3 Hz); 4.59 (dd, 1H, J ) 4.6,
Con clu sion s
We have developed an efficient synthetic approach to
the synthesis of (N-glyoxyl)prolyl and pipecolyl ketone
compounds, and we believe they are the first reported
examples of ketone compounds as FKBP12 ligands. Our
biological results suggest that they are potent neu-
rotrophic agents with potential therapeutic utility in
treating degenerative disorders of the nervous system,
such as Parkinson’s disease.
Exp er im en ta l Section
Gen er a l Meth od s. All commercially available starting
materials and solvents were reagent grade. Anhydrous tet-
rahydrofuran (THF) and diethyl ether were used as obtained
from Sigma-Aldrich Inc. (S)-Pipecolic acid was obtained as the

Synthesis of Ketone Analogues
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3561
Ta ble 1. Structures, Methods, and Preliminary in Vitro and in Vivo Data for N-Glyoxylprolyl and Pipecolyl Ketones

3562 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Ta ble 1 (Continued)
Wu et al.
a
Values of kinetic constants are the means of at least three independent estimations. Standard deviations were generally lower than
b
15%. Reference 14.
4.8 Hz); 7.19-7.30 (m, 5H). 13C NMR (CDCl3, 400 MHz): δ
208.4, 207.7, 165.6, 141.9, 128.9, 128.7, 126.4, 64.2, 47.8, 43.5,
39.6, 35.3, 28.2, 26.6, 25.1, 22.7, Anal. Calcd for C20H27NO3:
C, 72.92; H, 8.26; N, 4.25; O, 14.57. Found: C, 73.05; H, 8.34;
N, 4.31. TLC: Rf ) 0.52 (25% EtOAc/hexane).
2(S)-3,3-Dim et h yl-1-(2-p en t a n oylp yr r olid in -1-yl)p en -
t a n e-1,2-d ion e (5a ). 1H NMR (CDCl3, 300 MHz): δ 0.87-
0.91 (m, 6H); 1.11 (s, 3H); 1.18 (s, 3H); 1.20-2.0 (m, 10H); 2.52
(t, 2H, J ) 7.2 Hz); 3.45-3.62 (m, 2H); 4.56 (m, 1H). 13C NMR
(CDCl3, 400 MHz): δ 208.6, 207.4, 165.5, 64.2, 47.7, 40.1, 32.3,
28.1, 25.6, 25.0, 24.1, 23.4, 22.6, 14.2, 9.2. Anal. Calcd for
0.87 (t, 3H, J ) 7.5 Hz); 1.22 (s, 3H); 1.25 (s, 3H); 1.67 (m,
4H); 1.70-2.33 (m, 6H); 2.61 (t, 2H, J ) 7.1 Hz); 3.52 (m, 2H);
4.17 (t, 2H, J ) 6.2 Hz); 4.52 (m, 1H); 7.16-7.49 (m, 5H). 13C
NMR (CDCl3, 400 MHz): δ 208.6, 207.5, 165.5, 142.8, 128.6,
128.5, 126.0, 64.3, 47.7, 43.0, 40.1, 36.2, 32.3, 28.1, 25.6, 25.0,
24.1, 22.8, 9.2. Anal. Calcd for C22H31NO3: C, 73.91; H, 8.74;
N, 3.92; O, 13.43. Found: C, 73.48; H, 8.35; N, 3.69. TLC: Rf
) 0.80 (10% CH2Cl2/EtOAc).
2(S)-1-Cycloh exyl-2-[2-(5-p h en ylp en ta n oyl)p yr r olid in -
1-yl]eth a n e-1,2-d ion e (5c). 1H NMR (CDCl3, 300 MHz): δ
1.0-1.40 (m, 6H); 1.56-2.20 (m, 12H); 2.61 (t, 2H, J ) 7.2
Hz); 3.60-3.90 (m, 2H); 4.16 (t, 2H, J ) 6.9 Hz); 4.48 (m, 1H);
4.85 (m, 1H); 7.14-7.28 (m, 5H). 13C NMR (CDCl3, 400 MHz):
δ 208.2, 203.3, 164.2, 142.5, 128.8, 128.7, 126.1, 65.1, 48.2, 46.4,
40.3, 36.1, 31.3, 28.5, 27.9, 26.2, 25.9, 23.3, 22.3. Anal. Calcd
C
16H27NO3: C, 66.59; H, 9.71; N, 4.85; O, 17.06. Found: C,
66.59; H, 9.61; N, 4.70. TLC: Rf ) 0.60 (10% CH2Cl2/EtOAc).
2(S)-3,3-Dim eth yl-1-[2-(5-p h en ylp en ta n oyl)p yr r olid in -
1
1-yl]p en ta n e-1,2-d ion e (5b). H NMR (CDCl3, 300 MHz): δ

Synthesis of Ketone Analogues
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3563
Sch em e 2a
7.26-7.30 (m, 1H); 7.59-7.62 (m, 1H); 7.71-7.77 (m, 1H); 8.63
(br s, 1H). TLC: Rf ) 0.56 (40% EtOAc/hexane).
2-(4-P h en ylbu tyr yl)p ip er id in e-1-ca r boxylic Acid ter t-
Bu tyl Ester (8b). 2-(Pyridin-2-ylsulfanylcarbonyl)piperidine-
1-carboxylic acid tert-butyl ester 7 (2.0 g, 7.74 mmol) was
dissolved in anhydrous THF (10 mL), cooled to 0 °C, and
treated with freshly prepared 3-phenylpropylmagnesium bro-
mide (2.1 equiv). The reaction mixture was stirred at 0 °C for
1 h and at room temperature overnight. The reaction mixture
was quenched with 2 × 50 mL of water. The resulting mixture
was extracted with 2 × 100 mL of EtOAc. The organic phase
was dried, concentrated, and purified on a silica gel column
(10% EtOAc/hexane) to provide 0.92 g (69%) of the desired
product. 1H NMR (CDCl3, 300 MHz): δ 1.15-1.36 (m, 2H);
1.42 (s, 9H); 1.66-1.87 (m, 4H); 1.87-1.93 (m, 2H); 2.39-2.44
(m, 2H); 2.56-2.61 (m, 2H); 2.82 (m, 1H); 4.06-4.11 (m, 1H);
4.52 (br s, 1H); 7.04-7.19 (m, 5H). TLC: Rf ) 0.48 (25%
EtOAc/hexane).
4-P h en yl-1-p ip er id in -2-yl-bu ta n -1-on e (9b). A mixture
of 2-(4-phenylbutyryl)piperidine-1-carboxylic acid tert-butyl 8b
(0.92 g, 2.78 mmol) and trifluoroacetic acid (0.65 mL, 8.34
mmol) in methylene chloride (5 mL) was stirred overnight at
room temperature. The reaction mixture was evaporated in
vacuo to yield a thick oil used directly for the next step without
purification.
Oxo-[2-(4-p h en ylb u t yr yl)p ip er id in -1-yl]a cet ic Acid
Meth yl Ester (10b). A mixture of 4-phenyl-1-piperidin-2-yl-
butan-1-one 9b (0.65 g, 2.78 mmol) and triethylamine (1.16 g,
11.5 mmol) was dissolved in methylene chloride (20 mL) and
stirred at 0 °C for 15 min. Methyl chlorooxoacetate (0.38 g,
3.06 mmol) was added dropwise, and the mixture was stirred
for an additional 2 h at 0 °C. The reaction mixture was washed
with water. The organic phase was dried, concentrated, and
purified on a silica gel column (25% EtOAc/hexane) to yield
clear oil, 0.77 g (88%). 1H NMR (CDCl3, 300 MHz): δ 1.45-
1.91 (m, 6H); 1.93-1.99 (m, 2H); 2.36-2.43 (m, 2H); 2.52-
2.62 (m, 2H); 2.84 (m, 1H); 3.84 (s, 3H); 3.91-3.96 (m, 1H);
5.10 (d, 1H, J ) 7.5 Hz); 7.18-7.30 (m, 5H). TLC: Rf ) 0.48
(25% EtOAc/hexane).
2(S)-3,3-Dim et h yl-1-[2-(4-p h en ylb u t yr yl)p ip er id in -1-
yl]p en ta n e-1,2-d ion e (11b). Oxo-[2-(4-phenylbutyryl)piperi-
din-1-yl]acetic acid methyl ester 10b (0.77 g, 2.43 mmol) was
dissolved in anhydrous THF (15 mL), cooled to -78 °C, and
treated with 1,1-dimethylpropylmagnesium chloride (1.0 M,
2.7 mL). The reaction mixture was allowed to stir for 3 h. The
reaction mixture was washed with saturated ammonium
chloride. The organic phase was dried, concentrated, and
purified on a silica gel column (25% EtOAc/hexane) to provide
0.67 g (77%) of the desired product as a clear oil. 1H NMR
(CDCl3, 300 MHz): δ 0.90 (t, 3H, J ) 7.5); 1.21 (s, 3H); 1.24
(s, 3H); 1.31-1.78 (m, 7H); 1.94 (t, 2H, J ) 7.3 Hz); 2.23 (br d,
1H, J ) 13.5 Hz); 2.48 (t, 2H, J ) 7.3 Hz); 2.63 (t, 2H, J ) 8.1
Hz); 3.15 (dt, 1H, J ) 12.5, 13.0 Hz); 3.37 (br d, 1H, J ) 13.1
Hz); 5.10 (d, 1H, J ) 5.3 Hz); 7.16-7.29 (m, 5H). 13C NMR
(CDCl3, 400 MHz): δ 210.9, 208.1, 170.7, 144.6, 131.6, 129.2,
126.4, 60.8, 49.9, 47.6, 41.5, 38.2, 35.6, 28.1, 27.1, 26.8, 26.3,
23.5, 9.2. Anal. Calcd for C22H31NO3: C, 73.92; H, 8.74; N, 3.92;
O, 13.43. Found: C, 74.03; H, 8.80; N, 3.94. TLC: Rf ) 0.55
(25% EtOAc/hexane).
a
Reagents and conditions: (a) PySSPy, TPP, MeCN, reflux or
PySH, DCC, DMAP, CH2Cl2; (b) RMgX, THF, 0 °C; (c) 50% TFA,
CH2Cl2; (d) methyl chlorooxoacetate, TEA, CH2Cl2, 0 °C; (e) R′MgX,
THF, -78 °C, 3 h.
for C23H31NO3: C, 74.76; H, 8.46; N, 3.79; O, 12.99. Found:
C, 74.78; H, 8.56; N, 3.70. TLC: Rf ) 0.68 (25% EtOAc/hexane).
2(S)-1-P h en yl-2-[2-(5-p h en ylp en ta n oyl)p yr r olid in -1-yl]-
eth a n e-1,2-d ion e (5d ). 1H NMR (CDCl3, 300 MHz): δ 1.69
(m, 4H); 1.70-2.20 (m, 4H); 2.63 (m, 2H); 3.71 (m, 2H); 4.19
(t, 2H, J ) 7.2 Hz); 4.61 (m, 1H); 7.13-7.56 (m, 10H). 13C NMR
(CDCl3, 400 MHz): δ 208.3, 197.6, 166.9, 141.9, 138.9, 132.4,
129.6, 129.3, 128.9, 128.8, 126.4, 60.0, 47.3, 39.5, 36.1, 29.1,
24.8, 23.2, 21.2. Anal. Calcd for C23H25NO3: C, 73.53; H, 6.71;
N, 3.73; O, 13.21. Found: C, 73.48; H, 6.58; N, 3.13. TLC: Rf
) 0.80 (10% CH2Cl2/EtOAc).
2(S)-1-3,3-Dim et h yl-1-((2S)-2-{5-[2,3,5,6-t et r a flu or o-4-
(tr iflu or om eth yl)p h en yl]p en ta n oyl}-1-p yr r olid in yl)-1,2-
p en ta n ed ion e (5e). 1H NMR (CDCl3, 300 MHz): δ 0.88 (t,
3H, J ) 7.5 Hz); 1.24 (s, 3H); 1.27 (s, 3H); 1.54-2.22 (m, 10H);
2.55 (m, 2H); 2.79 (m, 2H); 3.50 (m, 2H); 4.55 (m, 1H). 13C NMR
(CDCl3, 400 MHz): δ 206.5, 206.0, 164.1, 146.2.0, 144.5, 142.4,
124.1, 100.3, 62.9, 45.9, 38.4, 33.2, 29.6, 27.2, 26.8, 23.8, 22.6,
22.0, 21.5, 21.0, 7.9. Anal. Calcd for C23H36NO3F7: C, 55.53;
H, 5.27; N, 2.82. Found: C, 55.62; H, 5.32; N, 2.79. TLC: Rf )
0.70 (25% EtOAc/hexane).
2(S)-1-{2-[5,5-Bis-(4-flu or oph en yl)pen tan oyl]pyr r olidin -
1-yl}-3,3-d im eth ylp en ta n e-1,2-d ion e (5i). 1H NMR (CDCl3,
300 MHz): δ 0.87 (t, 3H, J ) 7.5 Hz); 1.21 (s, 3H); 1.24 (s,
3H); 1.44-2.10 (m, 8H); 2.48 (m, 2H); 3.44-3.66 (m, 3H); 3.88
(t, 2H, J ) 7.6 Hz); 4.53 (dd, 1H, J ) 4.8, 8.7 Hz); 6.96 (d, 4H,
J ) 8.3 Hz); 7.17 (d, 4H, J ) 8.3 Hz). 13C NMR (CDCl3, 400
MHz): δ 208.9, 208.6, 167.1, 159.3, 141.4, 132.4, 119.6, 63.7,
47.5, 43.2, 40.5, 39.0, 37.8, 29.1, 24.6, 23.8, 23.2, 21.3, 9.2. Anal.
Calcd for C28H33NO3F2: C, 71.62; H, 7.08; N, 2.98; O, 10.22;
F, 8.09. Found: C, 71.53; H, 7.09; N, 2.92. TLC: Rf ) 0.5 (25%
EtOAc/hexane).
2(S)-3,3-Dim eth yl-1-[2-(6-p h en ylh exa n oyl)p yr r olid in -
1-yl]p en ta n e-1,2-d ion e (5j). H NMR (CDCl3, 300 MHz): δ
1
0.87-0.92 (m, 3H); 1.16-1.40 (m, 8H); 1.60-1.71 (m, 6H);
1.73-2.06 (m, 5H); 2.56-2.66 (m, 3H); 3.47-3.55 (m, 2H);
4.58-4.62 (m, 1H); 7.18-7.20 (br, s, 3H); 7.27-7.32 (br s, 2H).
13C NMR (CDCl3, 400 MHz): δ 208.6, 207.9, 165.4, 142.9,
128.8, 128.6, 126.0, 64.3, 47.8, 40.4, 36.1, 33.5, 31.6, 29.1, 28.2,
24.4, 24.1, 23.5, 23.4, 22.5, 9.35. Anal. Calcd for C23H33NO3:
C, 74.36; H, 8.95; N, 3.77; O, 12.92. Found: C, 74.14; H, 8.94;
N, 3.75. TLC: Rf ) 0.35 (25% EtOAc/hexane).
2-(P yr id in -2-ylsu lfa n ylca r bon yl)p ip er id in e-1-ca r boxy-
lic Acid ter t-Bu tyl Ester (7). A mixture of piperidine-1,2-
dicarboxylic acid 1-tert-butyl ester 6 (3.0 g, 13.14 mmol), N,N′-
dicyclohexylcarbodiimide (4.07 g, 19.71 mmol), 2-mercapto-
pyridine (1.75 g, 15.77 mmol), and 4-(dimethylamino)pyridine
(0.1 g) was dissolved in methylene chloride (120 mL) and
stirred overnight. The reaction mixture was filtered through
Celite and concentrated to a yellow oil. The oil was purified
on a silica gel column (40% EtOAc/hexane) to yield 3.0 g (71%)
2(S)-3,3-Dim eth yl-1-(2-pen tan oylpiper idin -1-yl)pen tan e-
1,2-d ion e (11a ). 1H NMR (CDCl3, 300 MHz): δ 0.86 (t, 3H, J
) 7.5 Hz); 1.15 (s, 3H); 1.18 (s, 3H); 1.11-1.72 (m, 11H); 2.19
(br, d, 1H, J ) 13.5 Hz); 2.40 (t, 2H, J ) 7.3 Hz); 3.09 (dt, 1H,
J ) 3.2, 12.4 Hz); 3.33 (br d, 1H, J ) 13.9 Hz); 5.05 (d, 1H, J
) 5.6 Hz). 13C NMR (CDCl3, 400 MHz): δ 208.5, 208.3, 167.8,
62.9, 47.0, 44.8, 39.2, 33.1, 25.8, 25.5, 24.3, 23.9, 23.5, 22.7,
14.2, 9.1. Anal. Calcd for C17H29NO3: C, 69.12; H, 9.89; N, 4.74;
O, 16.25. Found: C, 68.99; H, 9.83; N, 4.69. TLC: Rf ) 0.83
(25% EtOAc/hexane).
2(S)-3,3-Dim eth yl-1-[2-(5-p h en ylp en ta n oyl)p ip er id in -
1-yl]p en ta n e-1,2-d ion e (11c). 1H NMR (CDCl3, 300 MHz):
δ 0.86 (t, 3H, J ) 7.5 Hz); 1.18 (s, 3H); 1.21 (s, 3H); 1.24-1.75
(m, 11H); 2.20 (br, d, 1H, J ) 15.4 Hz); 2.76-2.79 (m, 2H);
2.89 (dd, 2H, J ) 2.2, 8.8 Hz); 3.02 (dt, 1H, J ) 12.8, 13.1 Hz);
1
of the desired product. H NMR (CDCl3, 300 MHz): δ 1.15-
1.48 (m, 2H); 1.51 (s, 9H); 1.60-1.80 (m, 4H); 2.29-2.35 (m,
2H); 301-3.11 (m, 1H); 4.05-4.2 (m, 1H); 4.65 (br, s, 1H);

3564 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Wu et al.
Sch em e 3a
a
Reagents and conditions: (a) CBr4, TPP, CH2Cl2; (b) Mg, THF or ether, reflux; (c) (PPh3)2PdCl2, CuI, TEA, CH2Cl2; (d) 10% Pd/C, H2,
EtOH; (e) benzyl bromide.
Sch em e 4a
a
Reagents and conditions: (a) BrMgCH2CH2CHCH2, THF, 0 °C; (b) 50% TFA, CH2Cl2; (c) methyl chlorooxoacetate, TEA, CH2Cl2; (d)
ClMgC(CH3)2CH2CH3, THF, -78 °C; (e) 3-bromopyridine or 4-benzyloxybromobenzene, Pd(OAc)2, CuI, tri(orthotolyl)phosphine, TEA,
CH2Cl2; (f) 10% Pd/C, H2, EtOH.
Sch em e 5a
a
Reagents and conditions: (a) 3-bromopyridine, Pd(OAc)2, CuI, tri(orthotolyl)phosphine, TEA, CH2Cl2; (b) 3-bromopyridine, Pd(OAc)2,
32, TEA, CH2Cl2.
3.33 (br d, 1H, J ) 13.2 Hz); 5.08 (d, 1H, J ) 5.6 Hz); 7.14-
7.27 (m, 5H). 13C NMR (CDCl3, 400 MHz): δ 208.3, 208.1,
167.8, 142.5, 128.8, 128.7, 126.2, 57.9, 47.0, 44.7, 39.3, 36.1,
32.9, 31.2, 25.5, 25.3, 24.3, 23.9, 23.5, 9.2. Anal. Calcd for
23H33NO3: C, 74.36; H, 8.95; N, 3.77; O, 12.92. Found: C,
74.30; H, 8.93; N, 3.81. TLC: Rf ) 0.48 (25% EtOAc/hexane).
C

Synthesis of Ketone Analogues
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3565
Sch em e 6a
a
Reagents and conditions: (a) PySH, DCC, DMAP, CH2Cl2; (b) BrMg(CH2)3CCSi(CH3)3, THF; or BrMg(CH2)5Ph; (c) excess tBAF, THF;
(d) 3-iodopyridine, (PPh3)2PdCl2, CuI, TEA, CH2Cl2; (e) 10% Pd/C, H2, EtOH.
Sch em e 7a
a
Reagents and conditions: (a) BrMg(CH2)3CCSi(CH3)3, THF.
2(S)-3,3-Dim eth yl-1-[2-(6-p h en ylh exa n oyl)p ip er id in -1-
yl]bu ta n e-1,2-d ion e (11f). 1H NMR (CDCl3, 300 MHz): δ 1.28
(s, 9H); 1.31-1.43 (m, 2H); 1.57-1.75 (m, 9H); 2.27 (br, d, 1H,
J ) 13.7 Hz); 2.45 (t, 2H, J ) 7.4 Hz); 2.60 (t, 2H, J ) 7.4 Hz);
3.19 (dt, 1H, J ) 3.2, 12.4 Hz); 3.35 (br, d, 1H, J ) 13.2 Hz);
5.11 (d, 1H, J ) 13.2 Hz); 7.15-7.26 (m, 5H). 13C NMR (CDCl3,
400 MHz): δ 208.7, 208.3, 167.9, 142.9, 128.8, 128.7, 126.1,
57.9, 47.1, 44.9, 43.4, 39.5, 36.1, 31.6, 29.1, 26.6, 25.5, 23.6,
21.2. Anal. Calcd for C23H33NO3: C, 74.36; H, 8.95; N, 3.77;
O, 12.92. Found: C, 74.39; H, 8.89; N, 3.85. TLC: Rf ) 0.79
(20% EtOAc/hexane).
4-(4-Ben zyloxyp h en yl)bu t-3-yn -1-ol (17). A mixture of
but-3-yn-1-ol 15 (9.1 g, 128.35 mmol), 4-(4-benzyloxyphenyl)
iodide 16 (43.79 g, 141.2 mmol), and triethylamine (16.88 g,
166.86 mmol) was dissolved in methylene chloride (350 mL)
and stirred for 5 min at room temperature. Pd (cat.) (8.98 g,
12.8 mmol) and copper iodide (1.85 g, 9.7 0 mmol) was added
F igu r e 3. Dose-Rresponse curve of compound 5h in the post-
MPTP model.
to the reaction mixture and stirred for an additional hour. The
mixture was refluxed at 50 °C overnight. The organic phase
was concentrated and purified on a silica gel column (25-50%
2(S)-3,3-Dim eth yl-1-[2-(6-p h en ylh exa n oyl)p ip er id in -1-
yl]p en ta n e-1,2-d ion e (11d ). H NMR (CDCl3, 300 MHz): δ
1
EtOAc/hexane) to provide 19.08 g (59%) of the desired product
1
as a brown solid. H NMR (CDCl3, 400 MHz): δ 2.69 (t, 2H, J
0.89 (t, 3H, J ) 7.5 Hz); 1.22 (s, 3H); 1.24 (s, 3H); 1.32-1.78
(m, 13H); 2.21 (br, d, 1H, J ) 13.5 Hz); 2.48 (t, 2H, J ) 6.7
Hz); 2.64 (t, 2H, J ) 7.0 Hz); 3.17 (dt, 1H, J ) 12.6, 12.9 Hz);
3.38 (br d, 1H, J ) 13.2 Hz); 5.10 (d, 1H, J ) 5.5 Hz); 7.15-
7.30 (m, 5H). 13C NMR (CDCl3, 400 MHz): δ 208.4, 208.3,
167.8, 142.9, 128.8, 128.7, 126.1, 57.9, 47.1, 44.8, 39.5, 36.1,
32.9, 31.6, 29.2, 24.4, 23.9, 23.6, 23.5, 21.2, 9.18. Anal. Calcd
for C24H35NO3: C, 74.77; H, 9.15; N, 3.63; O, 12.45. Found:
C, 74.80; H, 9.12; N, 3.61. TLC: Rf ) 0.42 (25% EtOAc/hexane).
) 4.0 Hz); 3.81 (t, 2H, J ) 4.0 Hz); 5.07 (s, 2H); 7.36-7.45 (m,
9H). TLC: Rf ) 0.5 (50% EtOAc/hexane).
4-(4-Ben zyloxyp h en yl)bu t-3-yn yl Br om id e (18). A mix-
ture of 4-(4-benzyloxyphenyl)-but-3-yn-1-ol 17 (19.08 g, 75.62
mmol) and carbon tetrabromide (30.09 g, 90.74 mmol) was
dissolved in methylene chloride (400 mL) and cooled to 0 °C.
Triphenylphosphine (23.8 g, 90.74 mmol) was added slowly
in small portions. After being stirred for 1 h at 0 °C, the

3566 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Wu et al.
reaction mixture was warmed to room temperature and stirred
overnight. The reaction mixture was concentrated and purified
on a silica gel column (5-30% EtOAc/hexane) to yield an
orange solid, 21.8 g (92%). 1H NMR (CDCl3, 400 MHz): δ 2.98
(t, 2H, J ) 4.0 Hz); 3.54 (t, 2H, J ) 4.0 Hz); 5.09 (s, 2H); 7.28-
7.45 (m, 9H). TLC: Rf ) 0.45 (30% EtOAc/hexane).
4-(4-Br om obu t-1-yn yl)p h en ol (20). A mixture of 4-(4-
benzyloxyphenyl)-but-3-ynl bromide 18 (21.8 g, 69.16 mmol)
and 10 wt % palladium on carbon (6.0 g) was suspended in
methanol (200 mL) and shaken on a Parr apparatus under
hydrogen (50 psi) overnight. The reaction mixture was filtered
through Celite and concentrated to a brown oil (14 g). The oil
was used without further purification.
3H); 4.95-5.10 (m, 3H); 5.75-5.85 (m, 1H). TLC: Rf ) 0.2
(40% EtOAc/hexane).
2(S)-3,3-Dim et h yl-1-(2-p en t -4-en oylp yr r olid in yl)p en -
ta n e-1,2-d ion e (28). A solution of oxamate 27 (21.0 g, 88
mmol) in 150 mL of THF was cooled to -78 °C, under nitrogen,
and treated with 200 mL (180 mmol) of 0.9 M 3,3-dimethyl-
propylmagnesium chloride. After the mixture was stirred for
2.5 h, TLC indicated that the reaction was complete. It was
quenched with 300 mL of saturated NH4Cl followed by 200
mL of EtOAc. The layers were separated, and the aqueous
layer was extracted once more with 300 mL of EtOAc. The
combined organic layers were dried over MgSO4, filtered, and
concentrated, and the product was purified on silica gel with
20% EtOAc in hexane to obtain 28 as a light-yellow oil, 21.0 g
(85%). 1H NMR (CDCl3, 400 MHz): δ 0.87 (t, 3H, J ) 7.5 Hz);
1.21 (s, 6H); 1.64-1.95 (m, 5H); 2.14-2.18 (m, 1H); 2.32-2.40
(m, 2H); 2.60-2.72 (m, 2H); 3.47-3.62 (m, 2H); 4.57-4.61 (m,
1H); 4.97-5.07 (m, 2H); 5.78-5.84 (m, 1H). TLC: Rf ) 0.7
(2:3 EtOAc/hexane).
(4-Ben zyloxyp h en yl)bu tyl Br om id e (21). 4-(4-Bromo-
but-1-ynyl)phenol 20 (14.0 g, 65.47 mmol) was dissolved in
methylene chloride (200 mL). Benzyl bromide (12.3 g, 72.01
mmol) was added dropwise via a syringe and allowed to stir
at room temperature for 1 h. The reaction mixture was warmed
to reflux (50 °C) and stirred overnight. After cooling to room
temperature, the reaction mixture was washed with water.
The organic phase was dried, concentrated, and purified on a
silica gel column (5-10% EtOAc/hexane) to yield the desired
product as a yellow oil, 13.32 g (64%). 1H NMR (CDCl3, 400
MHz): δ 1.75-1.83 (m, 2H); 1.89-1.96 (m, 2H); 2.63 (t, 2H, J
) 7.5 Hz); 3.46 (t, 2H, J ) 6.5 Hz); 5.09 (s, 2H); 6.96 (d, 2H, J
) 9.0 Hz); 7.14 (d, 2H, J ) 9.0 Hz); 7.35-7.49 (m, 5H). TLC:
Rf ) 0.8 (5% EtOAc/hexane).
(4-Ben zyloxyp h en yl)bu tylm a gn esiu m Br om id e (22).
Magnesium turnings (1.52 g, 62.59 mmol) was stirred over-
night under an inert atmosphere. (4-Benzyloxyphenyl)butyl
bromide 21 (13.32 g, 41.72 mmol) and an iodine crystal were
dissolved in anhydrous THF (40 mL) and added to the stirring
magnesium slowly until initiation occurred. Continuous ad-
dition was allowed to sustain the reaction, at which time the
reaction mixture was refluxed for an additional 2 h. The result
was used directly for the next step.
2(S)-3,3-Dim eth yl-1-[2-(5-(3-p yr id yl)p en t-4-en oyl)p yr -
r olid in yl]p en ta n e-1,2-d ion e (29). To a solution of olefin 28
(500 mg, 1.78 mmol) in 7 mL of Et3N was added 3-bromopy-
ridine (310 mg, 1.96 mmol), palladium(II) acetate (20 mg, 0.09
mmol), and tri(orthotolyl)phosphine (108 mg, 0.36 mmol), and
the mixture was refluxed overnight. The mixture was concen-
trated, and the products were purified on a silica gel column,
eluting with a gradient from 50% EtOAc in hexane to 75%
EtOAc to obtain 29 as a light-brown oil, 480 mg (75%). 1H NMR
(CDCl3, 400 MHz): δ 0.87 (t, 3H, J ) 7.5 Hz); 1.21 (s, 6H);
1.62-2.02 (m, 6H); 2.12-2.23 (m, 1H); 2.50-2.61 (m, 2H);
2.66-2.88 (m, 2H); 3.42-3.59 (m, 2H); 4.60-4.63 (m, 1H);
6.23-6.32 (m, 1H); 6.41 (d, 1H, J ) 15.9 Hz); 7.19-7.23 (m,
1H); 7.65 (dt, 1H, J ) 8.0, 2.0 Hz); 8.43 (dd, 1H, J ) 4.5, 2.0
Hz); 8.54 (d, 1H, J ) 2.0 Hz). TLC: Rf ) 0.5 (80% EtOAc/
hexane).
2(S)-3,3-Dim eth yl-1-[2-(5-(3-p yr id yl)p en ta n oyl)p yr r o-
lid in yl]p en ta n e-1,2-d ion e (5h ). Platinum oxide (12 mg) was
added to a solution of 29 (300 mg, 0.84 mmol) in methanol (8
mL). The mixture was hydrogenated at 1 atm for 2.5 h and
was then filtered through Celite and concentrated. Eluting
through a short bed of silica gel (100% EtOAc) furnished
analytically pure material, 260 mg (87%). HPLC analysis using
a chiral column indicated a sharp single peak (>95%, retention
ter t-Bu tyl 2-P en t-4-en oylp yr r olid in eca r boxyla te (25).
To a solution of 3-propenylmagnesium bromide (97 mL of a
0.5 M solution; 48.4 mmol) in THF (15 mL), cooled to 0 °C
and under a nitrogen atmosphere, was added dropwise with
stirring a solution of tert-butyl 2-(N-methoxy-N-methylcar-
bamoyl)pyrrolidinecarboxylate 2 (5.0 g, 19.4 mmol) in 15 mL
of THF. The mixture was stirred overnight while slowly
warming to room temperature. The reaction was quenched by
the addition of 80 mL of saturated NH4Cl followed by 50 mL
of ethyl acetate and 20 mL of water. The layers were
separated, and the aqueous layer was extracted with 2 × 100
mL of EtOAc. The combined organic layers were dried over
MgSO4, filtered, and concentrated, and the crude product was
purified on a silica gel column with 10% EtOAc in hexane to
obtain the olefin 25 as a clear oil, 4.30 g (88%). 1H NMR
(CDCl3, 400 MHz): δ 1.41 (s, 9H); 1.78-1.91 (m, 3H); 2.07-
2.22 (m, 1H); 2.30-2.37 (m, 2H); 2.45-2.62 (m, 2H); 3.40-
3.58 (m, 2H); 4.22-4.25 (m, 1H); 4.95-5.07 (m, 2H); 5.75-
5.86 (m, 1H). TLC: Rf ) 0.7 (33% EtOAc/hexane).
1
time of 8.65 min), suggesting 5h is a single stereoisomer. H
NMR (CDCl3, 400 MHz): δ 0.87 (t, 3H, J ) 7.5 Hz); 1.21 (s,
6H); 1.61-1.66 (m, 4H); 1.68-1.72 (m, 2H); 1.77-1.80 (m, 1H);
1.94-1.99 (m, 2H); 2.13-2.16 (m, 1H); 2.50-2.56 (m, 1H);
2.60-2.66 (m, 2H); 3.47-3.50 (m, 1H); 3.52-3.55 (m, 1H); 4.57
(dd, 1H, J ) 8.8, 4.8 Hz); 7.18-7.22 (m, 1H); 7.49 (d, 1H, J )
7.8 Hz); 8.42-8.46 (m, 2H). 13C NMR (CDCl3, 400 MHz): δ
208.2, 207.6, 165.4, 150.0, 147.5, 137.8, 136.4, 123.7, 64.2, 47.3,
40.0, 38.1, 33.2, 33.1, 30.9, 28.2, 24.3, 23.4, 23.0, 9.3. Anal.
Calcd for C21H30N2O3: C, 70.36; H, 8.44; N, 7.81. Found: C,
70.15; H, 8.54; N, 7.76. TLC: Rf ) 0.30 (4:1 EtOAc/hexane).
Note: The final hydrogenation step may be done using 10%
Pd/C and hydrogenating for 5 h at 60 psi. Ethanol or ethyl
acetate may be used instead of methanol.
Meth yl 2-Oxo-2-(2-pen t-4-en oylpyr r olidin yl)acetate (27).
Trifluoroacetic acid (65.7 g, 576 mmol) was added dropwise to
a solution of 24.3 g (96 mmol) of 25 in 45 mL of methylene
chloride, and the mixture was cooled to 0 °C. After being
stirred for 4 h, the mixture was concentrated in vacuo to
remove TFA. The residue was dissolved in 800 mL of meth-
ylene chloride and treated with triethylamine (20 g, 198 mmol)
while stirring and cooling the mixture in an ice bath. Methyl
oxalyl chloride (13.5 g, 106 mmol) was added as a solution in
40 mL of methylene chloride in 10 mL portions each followed
by 5 mL of Et3N. After the addition, a final 10 mL portion of
Et3N was added and the mixture was stirred overnight. It was
concentrated, treated with 100 mL of 1:1 EtOAc/hexane and
filtered to remove solids, and the concentrated residue was
purified on silica gel, eluting with 1:1 hexane/EtOAc to obtain
2(S)-3,3-Dim eth yl-1-(2-{5-[4-(p h en ylm eth oxy)p h en yl]-
p en t-4-en oyl}p yr r olid in yl)p en ta n e-1,2-d ion e (30). A solu-
tion of 3,3-dimethyl-1-(2-pent-4-enoylpyrrolidinyl)pentane-1,2-
dione 28 (1.73 g, 6.20 mmol), 4-benzyloxybromobenzene (1.80
g, 6.83 mmol), palladium(II) acetate (70 mg, 0.31 mmol), and
tri(orthotolyl)phosphine (380 mg, 1.24 mmol) in triethylamine
(23 mL) was refluxed overnight. The mixture was concentrated
in vacuo and purified on a silica gel column, eluting with a
gradient from 10% EtOAc/hexane to 20% EtOAc/hexane to
obtain 1.72 g (60%) of 30 as a yellow oil. 1H NMR (CDCl3, 400
MHz): δ 0.87 (t, 3H, J ) 7.5 Hz); 1.24 (s, 6H); 1.60-2.00 (m,
5H); 2.10-2.33 (m, 1H); 2.40-2.60 (m, 2H); 2.62-2.82 (m, 2H);
3.38-3.62 (m, 2H); 4.61 (q, 1H, J ) 4.5 Hz); 5.05 (s, 2H); 6.05
(dt, 1H, J ) 16.0, 4.5 Hz); 6.36 (d, 1H, J ) 16.0 Hz); 6.90 (d,
2H, J ) 8.5 Hz); 7.25 (d, 2H, J ) 8.5); 7.28-7.46 (m, 5H).
TLC: Rf ) 0.7 (50% EtOAc/hexane).
1
oxamate 2 as a brownish oil, 18.80 g (82%). H NMR (CDCl3,
400 MHz): δ 1.77-1.92 (m, 2H); 1.94-2.05 (m, 2H); 2.30-
2.40 (m, 2H); 2.55-2.75 (m, 2H); 3.65-3.75 (m, 2H); 3.79 (s,

Synthesis of Ketone Analogues
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3567
2(S)-3,3-Dim eth yl-1-{2-[5-(4-h ydr oxyph en yl)pen tan oyl]-
p yr r olid in yl}p en ta n e-1,2-d ion e (5g). A mixture of 1.63 g
(3.53 mmol) of 30 and 400 mg of 10% Pd/C in 100 mL of EtOAc
was hydrogenated at 50 psi overnight. The mixture was
filtered through Celite, concentrated, and chromatographed
1.11 (s, 3H); 1.22-1.76 (m, 9H); 2.12-2.21 (m, 3H); 2.46-2.50
(m, 1H); 2.98-3.10 (m, 1H); 3.25 (br, d, 1H, J ) 13.0 Hz); 4.98
(d, 1H, J ) 5.5 Hz); 7.09-7.12 (m, 1H); 7.54-7.58 (m, 1H);
8.36 (br s, 1H); 8.49 (br s, 1H). TLC: Rf ) 0.52 (60% EtOAc/
hexane).
1
(25% EtOAc/hexane) to obtain 800 mg (61%) of 5g. H NMR
2(S)-3,3-Dim eth yl-1-[2-(6-p yr id in -3-yl-h exa n oyl)p ip er i-
d in -1-yl]p en ta n e-1,2-d ion e (11e). A mixture of 2(S)-3,3-
dimethyl-1-[2-(6-pyridin-3-yl-hex-5-ynoyl)piperidin-1-yl]pentane-
1,2-dione 37 (0.61 g, 1.59 mmol) and platinum oxide (0.1 g,
0.44 mmol) was suspended in methanol (5 mL). The reaction
mixture was placed under a hydrogen atmosphere (1 atm) and
was stirred overnight. It was filtered through Celite, concen-
trated, and purified on a silica gel column, eluting with 50%
EtOAc/hexane to yield 0.45 g (73%) of the desired product as
a clear oil. 1H NMR (CDCl3, 400 MHz): δ 0.89 (br s, 2H); 1.21
(s, 3H); 1.24 (s, 3H); 1.28-1.74 (m, 13H); 2.27 (br d, 1H, J )
13.0 Hz); 2.63 (t, 2H, J ) 7.7 Hz); 3.22 (m, 1H); 3.40 (br, d,
1H, J ) 12.8 Hz); 4.16 (t, 2H, J ) 6.4 Hz); 5.22 (d, 1H, J ) 5.4
Hz); 7.26 (m, 1H); 7.51 (d, 1H, J ) 7.7 Hz); 8.45 (s, 2H). 13C
NMR (CDCl3, 400 MHz) δ 208.4, 208.3, 167.7, 150.5, 147.5,
138.1, 136.4, 124.3, 58.0, 47.1, 44.7, 39.5, 36.1, 32.9, 31.6, 29.1,
25.5, 24.3, 23.9, 23.5, 21.2, 9.2. Anal. Calcd for C23H34N2O3‚
0.6H2O: C, 69.52; H, 8.93; N, 7.05; O, 14.50. Found: C, 69.33;
H, 8.62; N, 7.17. TLC: Rf ) 0.52 (60% EtOAc/hexane).
(CDCl3, 400 MHz): δ 0.87 (t, 3H, J ) 7.50 Hz); 1.21 (s, 6H);
1.49-1.72 (m, 4H); 1.74-1.86 (m, 2H); 1.87-1.98 (m, 2H);
2.10-2.21 (m, 1H); 2.46-2.63 (m, 4H); 3.43-3.68 (m, 3H); 4.59
(q, 1H, J ) 4.5 Hz); 6.72 (d, 2H, J ) 8.40 Hz); 7.03(d, 2H, J )
13
8.40 Hz). C NMR (CDCl3, 400 MHz): δ 208.7, 208.5, 165.9,
154.3, 132.4, 129.6, 116.6, 62.1, 47.1, 41.5, 37.8, 35.7, 31.6, 29.1,
24.6, 23.8, 23.5, 21.6, 9.1. Anal. Calcd for C22H31NO4: C, 70.75;
H, 8.37; N, 3.75. Found: C, 70.64; H, 8.44; N, 3.65. TLC: Rf )
0.45 (75% hexane/EtOAc).
2(S)-1-(3,3-Dim eth yl-2-oxop en ta n oyl)p ip er id in e-2-ca r -
both ioic Acid P yr id in -2-yl Ester (34). A mixture of 2(S)-
1-(3,3-dimethyl-2-oxopentanoyl)piperidine-2-carboxylic acid 33
(6.3 g, 24.7 mmol), N,N′-dicyclohexylcarbodiimide (7.6 g, 37.0
mmol), 2-mercaptopyridine (3.02 g, 27.2 mmol), and 4-(dim-
ethylamino)pyridine (0.91 g, 7.41 mmol) was suspended in
methylene chloride (300 mL) and stirred at room temperature
overnight. The reaction mixture was filtered through Celite,
and the organic phase was concentrated in vacuo to yield a
clear oil. The oil was purified on a silica gel column (25-35%
EtOAc/hexane) to provide 8 g (83%) of the desired product as
Refer en ces
1
a yellow solid. H NMR (CDCl3, 400 MHz): δ 0.92 (t, 3H, J )
(1) Harding, M. W.; Galat, A.; Uehling, D. E.; Schreiber, S. L. A
7.5 Hz); 1.26 (s, 3H); 1.31 (s, 3H); 1.66-1.84 (m, 7H); 2.45-
2.48 (m, 1H); 3.34-3.41 (m, 1H); 3.46-3.50 (m, 1H); 5.50 (d,
1H, J ) 5.5 Hz); 7.34 (dd, 1H, J ) 1.0, 7.5 Hz); 7.61 (d, 1H, J
) 8.0 Hz); 7.78 (dt, 1H, J ) 2.0, 8.0 Hz); 8.66-8.68 (m, 1H).
TLC: Rf ) 0.65 (10% EtOAc/hexane).
receptor for the immunosuppressant FK506 is
a cis-trans
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2(S)-3,3-Dim eth yl-1-[2-(6-tr im eth ylsilan yl-h ex-5-yn oyl)-
piper idin -1-yl]pen tan e-1,2-dion e (35). 2(S)-1-(3,3-Dimethyl-
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34 (1.5 g, 4.30 mmol) was dissolved in anhydrous THF (20 mL),
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mixture was allowed to stir for 4 h. The reaction mixture was
washed with saturated ammonium chloride. The organic phase
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(25% EtOAc/hexane) to provide 1.35 g (83%) of desired product
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1
as a clear oil. H NMR (CDCl3, 400 MHz): δ 0.75 (t, 3H, J )
7.5 Hz); 1.08 (s, 3H); 1.11 (s, 3H); 1.22-1.76 (m, 9H); 2.12-
2.21 (m, 3H); 2.46-2.50 (m, 1H); 2.98-3.10 (m, 1H); 3.25 (br
d, 1H, J ) 13.0 Hz); 4.98 (d, 1H, J ) 5.5 Hz). TLC: Rf ) 0.65
(10% EtOAc/hexane).
2(S)-1-(2-Hex-5-yn oylp ip er id in -1-yl)-3,3-d im eth ylp en -
ta n e-1,2-d ion e (36). 2(S)-3,3-Dimethyl-1-[2-(6-trimethylsila-
nyl-hex-5-ynoyl)piperidin-1-yl]pentane-1,2-dione 35 (0.5 g, 1.32
mmol) was dissolved in anhydrous THF (5 mL), cooled to -78
°C, and treated with tetrabutylammonium fluoride (1.0 M, 6.6
mL). The reaction mixture was allowed to stir for 2 h. The
reaction mixture was diluted with EtOAc (100 mL) and washed
with water. The organic phase was dried, concentrated, and
purified on a silica gel column (25% EtOAc/hexane) to provide
0.3 g (75%) of the desired product as a clear oil. 1H NMR
(CDCl3, 400 MHz): δ 0.75 (t, 3H, J ) 7.5 Hz); 1.08 (s, 3H);
1.11 (s, 3H); 1.22-1.76 (m, 10H); 2.12-2.21 (m, 3H); 2.46-
2.50 (m, 1H); 2.98-3.10 (m, 1H); 3.25 (br d, 1H, J ) 13.0 Hz);
4.98 (d, 1H, J ) 5.5 Hz). TLC: Rf ) 0.45 (10% EtOAc/hexane).
2(S)-3,3-Dim eth yl-1-[2-(6-p yr id in -3-yl-h ex-5-yn oyl)p ip -
er id in -1-yl]p en ta n e-1,2-d ion e (37). A mixture of 2(S)-1-(2-
hex-5-ynoylpiperidin-1-yl)-3,3-dimethylpentane-1,2-dione 36
(0.85 g, 2.78 mmol), 3-iodopyridine (0.63 g, 3.06 mmol), and
triethylamine (0.37 g, 3.64 mmol) was dissolved in methylene
chloride (25 mL) and allowed to stir for 5 min at room
temperature. (PPh3)2PdCl2 (0.2 g, 0.28 mmol) and copper iodide
(0.04 g, 0.21 mmol) were added to the reaction mixture and
stirred for an additional hour. The mixture was refluxed at
50 °C overnight. The organic phase was concentrated and
purified on a silica gel column (60% EtOAc/hexane) to provide
0.6 g (61%) of the desired product as a yellow oil. 1H NMR
(CDCl3, 400 MHz): δ 0.75 (t, 3H, J ) 7.5 Hz); 1.08 (s, 3H);

3568 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
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