Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 2: Discovery of potent, selective, and orally bioavailable compounds

Article abstract of DOI:10.1016/j.bmcl.2003.12.005

Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent

Full text of DOI:10.1016/j.bmcl.2003.12.005

Bioorganic & Medicinal Chemistry Letters 14 (2004) 941–945
Antagonists of human CCR5 receptor containing
4-(pyrazolyl)piperidine side chains. Part 2: Discovery of potent,
selective, and orally bioavailable compounds
Dong-Ming Shen,a,* Min Shu,a Christopher A. Willoughby,a Shrenik Shah,a
Christopher L. Lynch,a Jeffrey J. Hale,a Sander G. Mills,a Kevin T. Chapman,a
Lorraine Malkowitz,b Martin S. Springer,b Sandra L. Gould,b Julie A. DeMartino,b
Salvatore J. Siciliano,b Kathy Lyons,a James V. Pivnichny,a Gloria Y. Kwei,c
Anthony Carella,d Gwen Carver,d Karen Holmes,d William A. Schleif,d
Renee Danzeisen,d Daria Hazuda,d Joseph Kessler,d Janet Lineberger,d
d
Michael D. Millerd andEmilio A. Emini
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
bDepartment of Immunology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
cDepartment of Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
dDepartment of Antiviral Research, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA
Received2 September 2003; revised24 November 2003; accepted2 December 2003
Dedicated to Professor Orville L. Chapman on the occasion of his 71st birthday
Abstract—Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded
the isopropyl compound 9. This compoundis a potent CCR5 antagonist showing goodin vitro antiviral activity against HIV-1, an
excellent selectivity profile, andgoodoral bioavailability in three animal species. During this investigation, a new methodfor the
preparation of a-(pyrrolidin-1-yl)-a,a-dialkyl acetic acid from a pyrrolidine and a-bromo-a,a-dialkyl acetic acid using silver triflate
was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of
a-(pyrrolidin-1-yl)acetic acid was also uncovered.
# 2004 Elsevier Ltd. All rights reserved.
The discovery that the chemokine receptor CCR5 is a
co-receptor with CD4 for HIV-1 cell entry has sparked
widespread interest in small molecule CCR5 antagonists
as potential agents for the treatment andprevention of
HIV-1 infection.1ꢀ12 Previous reports from these
laboratories have described 1-amino-2-aryl-4-(piperidin-
2ꢀ7
1-yl)butanes,1,2,12 1,3,4-trisubstitutedpyrroliindes,
andrelatedcompounds
11
as potent CCR5 antagonists.
Some of these displayed very good antiviral
activity against HIV-1 in vitro andreasonable oral
bioavailability in animal species.
In the preceding paper, the incorporation of a hetero-
aryl ring into the piperidine side-chain in the 1,3,4-tri-
substituted pyrrolidine series afforded compounds such
as 1 with potent CCR5 binding and in vitro antiviral
activities.13 However, this and related compounds did not
have the requiredpharmacokinetic profile or off-target
Keywords: CCR5 antagonist; HIV-1; Antiviral; Pyrazole.
* Corresponding author. Tel.: +1-732-594-7303; fax: +1-732-594-
8080; e-mail: dongming_shen@merck.com
0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.12.005

942
D.-M. Shen et al. / Bioorg. Med. Chem. Lett. 14 (2004) 941–945
selectivity for further development. Herein we detail our
continued SAR studies in this series leading to potent,
selective, andorally bioavailable compounds.
improvements in the PK profile andsome restoration of
antiviral activity. The sensitivity of the PK profile to the
substitutions at these positions was most dramatically
illustratedby the comparison of 9 and 10. The addition
of a single methylene group anddeletion of a fluorine
increasedthe clearance of compound 10 by almost 20-fold
comparedto compound 9.
Results from some related4-(4-fluorophenyl)piperidines
such as 2 and 3 have shown that the nature of the alkyl
group attachedto the acetic acidportion of the mole-
cule can have a profoundeffect on their pharmaco-
kinetic (PK) profiles.4 For example, the isopropyl
compound 3 is bioavailable in several animal species
although its CCR5 binding and antiviral activities were
modest. In contrast, cyclohexyl compound 2 showed
similar PK profile in the rat as 1.14 This result inspired
us to prepare a set of alkyl derivatives of 1 at that posi-
tion. These compounds were prepared using the meth-
ods reported previously.5,13 Since a 3-fluorophenyl
moiety was one of the few replacements of the phenyl
group on the pyrrolidine that preserve CCR5 binding
activity,4 analogues having this 3-fluorophenyl were also
prepared( Table 1).
Due to its improvedPK profile andantiviral activity in
the HeLa assay, compound 9 was investigatedin more
detail. In an HIV-1 infectivity inhibition assay, using
peripheral bloodmononuclear cells against the BAL-1
strain (the PBMC assay),17 it gave an average IC95 of
22ꢁ16 nM (n=26). The decreases in clearance of com-
pounds 8 and 9 comparedto other in Table 1 parallel a
decline in their volumes of distribution (Vdss). There-
fore, it may be attributedto increases in plasma protein
binding. Indeed, compound 9 was 99.90% and99.96%
protein boundin human andrat plasma, respectively.
Therefore, the PBMC assays were repeatedin the pre-
sence of 50% normal human serum. Under these more
stringent conditions, 9 gave IC95 of 350ꢁ320 nM
(n=14). The other four compounds in Table 1 showed
higher activity in the PBMC assay, indicating that larger
alkyl groups enhance potency in this crucial measure of
antiviral activity.
Our results showedthat the simple addition of a fluor-
ine on compound 1 to give 4 did not consistently affect
its activity or pharmacokinetic profile. The cycloalkyl-
methylene compounds 5 and 6 possessedsimilar activity
andPK profiles as 1. Replacing the cyclohexyl in 1 with
an isobutyl as in 7 resultedin some improvements in the
Clp andAUC values, but with about a 10-foldloss of
antiviral activity in the cell culture HIV-1 infectivity
assay using HeLa cells (HeLa assay). More dramatic
improvements in PK were observedwhen the isopropyl
group was introduced in compound 8. However, there
was a further loss of antiviral activity. Adding a fluorine
to compound 8 afforded 9 andproudcedfurther
In addition to its excellent binding activity on the CCR5
receptor, our leadcompound 1 also showedmultiple
submicromolar activities against other targets including
the L-type Ca2+ channel where it showedan IC 50 of 225
nM. To our surprise, compound 9 was very selective,
showing no activity (IC50 or Ki>10,000 nM) in the
L-type Ca2+ channel or on a panel of about 150 other
Table 1. CCR5 binding affinity, antiviral activity, and pharmacokinetic profile in the rat of pyrazole compounds with various alkylacetic acids
CompdCCR5
R=
HeLa
IC90 (nM)c
Clp,
(mL/min/kg)
AUCNpo
(mM h/dose)
Vdss
(L/kg)
t1/2, h
F
(%)
PBMC
IC95 (nM)f
PBMC
IC95 50%
NHS (nM)
IC50 (nM)a
.
X=
1
4
5
6
7
8
9
10
c-Hex
c-Hex
c-Bu-CH2
c-Pr-CH2
i-Bu
i-Pr
i-Pr
c-Bu
H
F
F
1.2, 2.0b
1.6
1.2
0.4,0.4
0.4
0.4
0.4
3.7
11
3.7
3.7
64
84
46e
81e
43
12.6e
3.2
60e
0.02
0.01
0.05
0.03
0.13
0.45
1.1
3.4
3.9
1.4
1.2
2.1
0.50
0.28
1.0
0.82
0.83
0.71
0.25
1.2
5.6
1.4
1.0
4.1
3
7.3
8.1
17
17
11
11
<8 (n=2)
NDd
<8, 31
NDd
<0.8 (n=3)
<8
<8
35ꢁ44 (n=4)
F
1.2
31
125
H
H
F
2.9b
2.8b
1.5
NDd
NDd
22ꢁ16 (n=26)
350ꢁ320 (n=14)
H
1.6
0.06
NDd
NDd
a IC50’s reportedare averages of triplicate measurements whose standarderrors were normally <15% in a given assay. Assay to assay variability was
within ꢁ2-fold based on a standard compound. Unless otherwise noted, data from displacement of [125I]-labeledMIP-1 a from the CCR5 receptor
expressedon CHO cell membranes. See ref 3 footnote 20 for assay protocol.
b Data from GP120-membrane assay. See ref 15 for assay protocol.
c Cell culture infectivity assay by HIV-1 in HeLa cells. See ref 16 for assay conditions.
d Not determined.
e All compounds were dosed at 0.5 mpk IV and 2.0 mpk po. These compounds were dosed as a mixture of five compounds. Mixture dosing can inflate
AUCpo and %F compared to single dosing; increases of 2- to 3-fold were common for compounds discussed here. Values of Clp usually did not change
significantly in cases where comparisons are available.
f
Inhibition of HIV-1 infectivity in human donor PBMCs over a 7-day period. Results under the heading of 50% NHS were obtained in the presence of
50% normal human serum. See ref 17 for assay protocol.

D.-M. Shen et al. / Bioorg. Med. Chem. Lett. 14 (2004) 941–945
943
receptors andenzymes (data not shown). Compound
was also a true antagonist without any agonist activity
basedon a microphysiometer assay. At 1 and10 mM,
it showed0% of the initial response of MIP-1 a at its
EC50 (1–2 nM).
9
of 11a or b resultedin no change. No intermediates were
observedby HPLC during the transformation of 9 to
12.19 Although a number of other reagents, such as Ph-
18
I(OAc)2,20 H2O2/H2SO4/100ꢂC,21 anodic oxidation,22
3+
andMn
complexes,23 are known to decarboxylate
similar amino acids, this Pd/C/air method offer simpli-
city andpotential chemoselectivity. Reacting 12 with
isomeric triflates 13a and b afforded compounds 20 and
21, respectively, after hydrogenolysis (Scheme 1).
It was clear from the data presented in Table 1 that only
minor structural changes couldbe toleratedin 9 without
jeopardizing its PK profile. Therefore, additional close
analogues of 9 were investigatedin an effort to improve
antiviral activity while preserving its PK profile (Table
The displacement of triflates by pyrrolidine during the
preparation of compound 22 requiredthe use of the
purifiedtriflate in DMF at 50 ꢂC versus DCM at room
temperature for less sterically hindered cases. The
methodusedto couple the triflate andpyrroliidne
2). Compound 23 was preparedusing the methosd
5,13
reportedearlier.
Synthesis of compounds 20 and 21
took advantage of our observation of a novel dealk-
ylation process. During the catalytic hydrogenolysis of
benzyl or p-methoxybenzyl (PMB) esters such as 11 to
generate compounds such as 1 or 9, exposure of the reac-
tion mixtures to air for any length of time before the Pd/C
catalyst was filteredresultedin the rapidformation of a
side-product. This side-product was identified as pyrro-
lidine 12. Exposing the reaction mixture to air for a few
hours after finishing hydrogenolysis without filtering
out the catalyst resultedin complete conversion to 12.
Alternatively, stirring methanol solutions of 1 or 9 in
the presence of Pd/C catalyst and air gave 12 as the only
product by HPLC. No hydrogen pretreatment was
requiredfor this reaction to proceed. Similar treatment
described before was not suitable for the introduction of
dialkyl acetate groups as required in 24 and 25.
Although there were several reports for preparing simi-
lar compounds,24ꢀ26 they failedin our case. After con-
siderable experimentation, a method was found for the
preparation of this type of compoundas shown in
Scheme 2.27 Diazotization of a-methylvaline in the pre-
sence of hydrobromic acid and potassium bromide gave
bromo acid 14 in a low yield.28 Side-products included
the corresponding hydroxy acid and trimethyl acrylic
acidand2-isopropyl acrylic acidfrom elimination. The
bromo acid 14 hydrolyzes partially on silica gel. There-
fore, a semi-crude mixture containing about 50% 14
was usedin the next step. Slow adition of a THF
solution of silver triflate to a mixture of 14, excess pyr-
rolidine 15,29 andfour equivalents of DIEA in THF
followedby quenching with KBr gave a mixture of
isomeric silyl compounds. The mixture was desilylated
during purification on preparative HPLC using MeCN
andwater with 0.1% TFA. The alcohols 16 were con-
vertedto PMB esters 17. The isomeric PMB esters can
be separatedon silica gel. They were convertedto iso-
meric aldehydes 18a and 18b separately using Swern
oxidation. Reductive amination with pyrazolylpiper-
idine 1913 anddebenzylation gave the final compounds
24 and 25. The identity of 24 and 25 were assigned
basedon comparison of proton NMR of 18a and 18b
with those of the corresponding isopropyl compounds
(the aldehyde precursor to 11b andits diastereomer).
Scheme 1. Reagents: (a) H2, Pd/C, MeOH; (b) Pd/C, exposure to air,
MeOH; (c) DIEA, MeCN, rt.
Scheme 2. Reagents: (a) NaNO2, KBr, HBr, H2O, 5%; (b) AgOTf, 4 equiv DIEA, THF, rt; (c) preparative RP-HPLC (MeCN/H2O/0.1%
trifluoroacetic acid), 60%; (d) 4-methoxybenzyl chloride, Cs2CO3, DMF, rt, 52%; (e) oxalyl chloride, dimethyl sulfoxide, Et3N, dichloromethane,
ꢀ78 ꢂC to rt, 88–100%; (f) NaBH(OAc)3, DIEA, 1,2-dichloroethane; (g) 96% formic acid, rt, 71–89% (two steps).

944
D.-M. Shen et al. / Bioorg. Med. Chem. Lett. 14 (2004) 941–945
Table 2. CCR5 binding affinity, antiviral activity, and pharmacokinetic profile in the rat of compound 9 analogues
CompdCCR5
R=
HeLa
IC90, (nM)b
Clp,
(mL/min/kg)
AUCNpo
(mM h/dose)
,
Vdss
(L/kg)
t1/2
(h)
F
(%)
IC50, (nM)a
.
R0=
20
21
22
23
24
25
(S)-s-Bu
(R)-s-Bu
t-Bu
3-Pentyl
i-Pr
Me
H
H
H
H
Me
i-Pr
0.8
0.9
0.8
0.9
1.6
5.5
<0.14
0.4
<0.14
0.4
300
25
0.16
ND
3.7
0.80
ND
0.62
0.64
ND
0.24
0.49
ND
0.43
0.54
ND
0.79
0.59
ND
0.74
13
ND
71
52
ND
21
NDc
5.7d
19d
NDc
10
>300
a See footnote a of Table 1.
b See ref 16 for assay conditions.
c Not determined.
d See footnote e of Table 1.
Addition of a methyl group to the isopropyl region of 9
afforded compounds 20–22 with goodCCR5 binding
affinity andantiviral activity as measuredin the HeLa
assay (Table 2). Compound 23, with the addition of two
methyl groups, conformedto the same trend. However,
only the t-Bu compound 22 showedimprovements in its
PK profile in the rat over 9, especially in oral AUCN.
Modifications leading to a,a-dialkyl analogues 24 and 25
yielded a considerable loss of antiviral activity and some
deterioration in the rat PK profile of 25 comparedto 9.
in the rat was not realizedin the dog. When 9 was dosed
at 10 mpk po in the rat, it showeda significant increase
in dose-normalized AUC and %F to 3.14 and 31.7%,
respectively, comparedwith 1.05 and10.6% at 2 mpk.
That suggestedthat its oral bioavailability might
improve at higher doses in larger animals as well.
In summary, modifications in the a-alkyl acetic acid
region andadition of a 3-fluoro substitution to the
phenyl group on pyrrolidine in our lead pyrazole com-
pound 1 have resultedin the isopropyl compound 9. It
is a potent CCR5 antagonist with goodin vitro antiviral
activity against HIV-1, excellent selectivity versus a
large panel of receptors, enzymes, transporters andion
channels, andoral bioavailability in several animal spe-
cies. During this investigation, a new methodfor the
introduction of a-(pyrrolidin-1-yl) group onto a,a-di-
alkylacetic acidvia the bromo acidwas discovered. A
novel Pd-mediated N-dealkylation of a-(pyrrolidin-1-
yl)acetic acid was also uncovered. Additional SAR
studies focusing on the benzyl portion of compound 9
andits analogues will be the subject of our next report.
Compound 22 showedan IC of <8 nM in the HIV-1
95
PBMC infectivity inhibition assay (n=3). In the pre-
sence of 50% normal human serum, its IC95 was 40ꢁ28
nM (n=3). Therefore, addition of the methyl group to 9
restoredantiviral activity of 22 back to the level of our
initial leadcompound 1. However, its selectivity profile
was not as goodas compound 9. For example, 22 had
an IC50 of 3.5 mM at the type 2 Na+ channel.
Basedon their overall properties, compounds 9 and 22
were further evaluatedin dog andrhesus monkey for
their pharmacokinetic profiles (Table 3). Unfortunately,
the improvement of the PK profile of 22 over 9 observed
Acknowledgements
Table 3. Pharmacokinetic profiles of CCR5 antagonists 9 and 22 in
dog and rhesus monkeya
The authors wouldlike to thank Dr. G. R. Kieczy-
kowski, Mr. J. F. Leone andMr. F. Wong for synthetic
assistance andDrs. C. G. Caldwell andP. E. Finke for
reviewing the manuscript. D.-M.S. wouldlike to thank
Professor Barry M. Trost for a very enlightening
discussion concerning possible mechanisms for the
conversion of 9 to 12.
Compd
9
22
13
1.0
0.50
0.64
Dog
Clp (mL/min/kg)
.
3.5
1.9
0.61
3.4
AUCNpo (mM h/dose)
Vdss (L/kg)
t1/2 (h)
F (%)
20
44
Monkey
Clp (mL/min/kg)
.
20
0.08
1.2
1.3
4.7
AUCNpo (mM h/dose)
Vdss (L/kg)
References and notes
t1/2 (h)
F (%)
1. Finke, P. E.; Oates, B.; Mills, S. G.; MacCoss, M.;
Malkowitz, L.; Springer, M. S.; Gould, S. L.; DeMartino,
J. A.; Carella, A.; Carver, G.; Holmes, K.; Danzeisen, R.;
a Compounds were dosed at 0.5 mpk iv and 2.0 mpk po. Compound 22
was not testedin monkey.

D.-M. Shen et al. / Bioorg. Med. Chem. Lett. 14 (2004) 941–945
945
Hazuda, D.; Kessler, J.; Lineberger, J.; Miller, M.;
Schlief, W. A.; Emini, E. A. Bioorg. Med. Chem. Lett.
2001, 11, 2475 andreferences citedtherein.
13. Shen, D.-M.; Shu, M.; Mills, S. G.; Chapman, K. T.;
Malkowitz, L.; Springer, M. S.; Gould, S. L.; DeMartino,
J. A.; Siciliano, S. J.; Kwei, G. Y.; Carella, A.; Carver, G.;
Holmes, K.; Schleif, W. A.; Danzeisen, R.; Hazuda, D.;
Kessler, J.; Lineberger, J.; Miller, M. D.; Emini, E. A.
Bioorg. Med. Chem. Lett. 2004, 14, preceding paper in this
issue. doi:10.1016/j.bmcl.2003.12.004.
14. This trendwas not always observed. In the related4-(3-
phenylpropyl)piperidine series, the isopropyl compound
has similar pharmacokinetic profile as the cyclohexyl
compound with diminished CCR5 binding and antiviral
activities (ref 5).
15. Siciliano, S. J.; Kuhmann, S. E.; Weng, Y.; Madani, N.;
Springer, M. S.; Lineberger, J. E.; Danzeisen, R.; Miller,
M. D.; Kavanaugh, M. P.; DeMartino, J. A.; Kabat, D. J.
Biol. Chem. 1999, 274, 1905.
16. Hazuda, D. J.; Felock, P.; Witmer, M.; Wolfe, A.;
Stillmock, K.; Grobler, J. A.; Espeseth, A.; Gabryelski, L.;
Schleif, W.; Blau, C.; Miller, M. D. Science 2000, 287, 646.
17. Saag, M. S.; Emini, E. A.; Laskin, O. L.; Douglas, J.;
Lapidus, W. I.; Schleif, W. A.; Whitley, R. J.; Hildebrand,
C.; Byrnes, V. W.; Kappes, J. C.; Anderson, K. W.; Massari,
F. E.; Shaw, G. M. New Engl. J. Med. 1993, 329, 1065.
18. See note 20 of ref 3 for assay protocol.
19. We have not studied the mechanism or scope of this trans-
formation, although it appears to be general to compounds
reportedhere. During a discussion with Prof. Barry M.
Trost, he suggesteda Pd-mediatedoxidative decarboxyla-
tion of compounds such as 1 and 9 to an iminium inter-
mediate followed by hydrolysis as a possible pathway.
20. Boto, A.; Hernandez, R.; Suarez, E. J. Org. Chem. 2000,
65, 4930 andreferences citedtherein.
21. Barsukov, A. V.; Yaroshenko, G. F.; Lastovskii, R. P.;
Dyatlova, N. M. J. Gen. Chem. USSR (Engl. Transl.)
1983, 53, 1109.
22. Hashiguchi, S.; Maeda, Y.; Kishimoto, S.; Ochiai, M.
Heterocycles 1986, 24, 2273.
2. Willoughby, C. W.; Berk, S. C.; Rosauer, K. G.;
Delgrado, S.; Chapman, K. T.; Gould, S. L.; Springer,
M. S.; Malkowitz, L.; Schlief, W. A.; Hazuda, D.; Miller,
M.; Kessler, J.; Danzeisen, R.; Holmes, K.; Lineberger, J.;
Carella, A.; Carver, G.; Emini, E. A. Bioorg. Med. Chem.
Lett. 2001, 11, 3137.
3. Hale, J. J.; Budhu, R. J.; Mills, S. G.; MacCoss, M.;
Malkowitz, L.; Siciliano, S.; Gould, S. L.; DeMartino, J. A.;
Springer, M. S. Bioorg. Med. Chem. Lett. 2001, 11, 1437.
4. Hale, J. J.; Budhu, R. J.; Holson, E. B.; Finke, P. E.;
Oates, B.; Mills, S. G.; MacCoss, M.; Gould, S. L.;
DeMartino, J. A.; Springer, M. S.; Siciliano, S.;
Malkowitz, L.; Schlief, W. A.; Hazuda, D.; Miller, M.;
Kessler, J.; Danzeisen, R.; Holmes, K.; Lineberger, J.;
Carella, A.; Carver, G.; Emini, E. A. Bioorg. Med. Chem.
Lett. 2001, 11, 2741.
5. Lynch, C. L.; Hale, J. J.; Budhu, R. J.; Gentry, A. L.;
Mills, S. G.; Chapman, K. T.; MacCoss, M.; Malkowitz,
L.; Springer, M. S.; Gould, S. L.; DeMartino, J. A.;
Siciliano, S. J.; Cascieri, M. A.; Carella, A.; Carver, G.;
Holmes, K.; Schlief, W. A.; Danzeisen, R.; Hazuda, D.;
Kessler, J.; Lineberger, J.; Miller, M.; Emini, E. A.
Bioorg. Med. Chem. Lett. 2002, 12, 3001 andreferences
citedtherein.
6. Willoughby, C. W.; Rosauer, K. G.; Hale, J. J.; Budhu,
R. J.; Mills, S. G.; Chapman, K. T.; MacCoss, M.;
Malkowitz, L.; Springer, M. S.; Gould, S. L.; DeMartino,
J. A.; Siciliano, S. J.; Cascieri, M. A.; Carella, A.; Carver,
G.; Holmes, K.; Schlief, W. A.; Danzeisen, R.; Hazuda,
D.; Kessler, J.; Lineberger, J.; Miller, M.; Emini, E. A.
Bioorg. Med. Chem. Lett. 2003, 13, 427.
7. Lynch, C. L.; Willoughby, C. W.; Hale, J. J.; Holson,
E. J.; Budhu, R. J.; Gentry, A. L.; Rosauer, K. G.;
Caldwell, C. G.; Chen, P.; Mills, S. G.; MacCoss, M.;
Berk, S.; Chen, L.; Chapman, K. T.; Malkowitz, L.;
Springer, M. S.; Gould, S. L.; DeMartino, J. A.; Siciliano,
S. J.; Cascieri, M. A.; Carella, A.; Carver, G.; Holmes, K.;
Schlief, W. A.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Emini, E. A. Bioorg. Med.
Chem. Lett. 2003, 13, 119.
23. Gangopadhyay, S.; Ali, M.; Saha, S. K.; Banerjee, P. J.
Chem. Soc., Dalton Trans. 1991, 2729.
24. Carrell, D. P.; Cragoe, E. J. WO 9640104, 1996.
25. Guziec, F. S. J.; Torres, F. F. J. Org. Chem. 1993, 58, 1604.
26. Kahovec, L.; Hohlrausch, K. W. F. Monatsh. Chem.
1943, 74, 104.
8. Baba, M.; Nishimura, O.; Kanzaki, N.; Okamoto, M.;
Sawada, H.; Iizawa, Y.; Shiraishi, M.; Aramaki, Y.;
Okonogi, K.; Ogawa, Y.; Meguro, K.; Fujino, M. Proc.
Natl. Acad. Sci. U.S.A. 1999, 96, 5698.
9. Tagat, J. R.; Steensma, R. W.; McCombie, S. W.; Nazareno,
D. V.; Lin, S.-I.; Neustadt, B. R.; Cox, K.; Xu, S.;
Wojcik, L.; Murray, M. G.; Vantuno, N.; Baroudy, B. M.;
Strizki, J. M. J. Med. Chem. 2001, 44, 3343 andreferences
citedtherein.
10. For a review, see: Kazmierski, W.; Bifulco, N.; Yang, H.;
Boone, L.; DeAnda, F.; Watson, C.; Kenakin, T. Bioorg.
Med. Chem. 2003, 11, 2663.
11. Lynch, C. L.; Gentry, A. L.; Hale, J. J.; Mills, S. G.;
MacCoss, M.; Malkowitz, L.; Springer, M. S.; Gould,
S. L.; DeMartino, J. A.; Siciliano, S. J.; Cascieri, M. A.;
Doss, G.; Carella, A.; Carver, G.; Holmes, K.; Schlief,
W. A.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Emini, E. A. Bioorg. Med.
Chem. Lett. 2002, 12, 677.
27. As a model reaction, simultaneous slow addition (syringe
pump) of THF solutions of 1.1 equivalents each of silver
triflate andcommercially available 2-bromo-isobutyric
acidto pyrrolidine 15 in the presence of 4 equiv of DIEA
followedby HPLC purification (MeCN/H 2O, 0.1% TFA)
with concurrent loss of the silyl group gave 72% of alco-
hol product and 16% of a side product having two units
of isobutyric acidincorporated. For another application
of this reaction, see Zhang, F., et al. Bioorg. Med. Chem.
Lett. 2003, 13, 2573. Slow addition of silver triflate or the
bromo acidalone gave 60 and65% of the desiredpro-
duct, respectively. Ag2O/toluene with or without sonica-
tion gave much lower conversions. Silver trifluoroacetate
gave similar results as silver triflate.
12. Kim, D.; Wang, L.; Caldwell, C. G.; Chen, P.; Finke,
P. E.; Oates, B.; MacCoss, M.; Mills, S. G.; Malkowitz,
L.; Gould, S. L.; DeMartino, J. A.; Springer, M. S.;
Hazuda, D.; Miller, M.; Kessler, J.; Danzeisen, R.;
Carver, G.; Carella, A.; Holmes, K.; Lineberger, J.;
Schlief, W. A.; Emini, E. A. Bioorg. Med. Chem. Lett.
2001, 11, 3099 and3103.
28. Petit, Y.; Larcheveque, M. Org. Synth. 1997, 75, 37.
29. About 2-foldexcess of 15 was usedto minimize the
bis-alkylation product discussed in footnote 27 above.