An improved synthesis of piperazino-piperidine based CCR5 antagonists with flexible variation on pharmacophore sites

Article abstract of DOI:10.1016/j.tet.2004.11.057

An improved and efficient synthetic route towards piperidino-piperazine based CCR5 antagonists was developed. The new approach was flexible for introducing various substituents in the pharmacophore sites via Grignard reagent addition and reductive amination. l-Amino acids were used as a chiral pool to introduce and then induce the desired stereochemistries, meanwhile rendering the variable substitution. The efficient construction of the piperazino-piperidine nucleus was achieved in a highly convergent manner with a key building block of N¹-Boc-4-substituent-4-aminopiperidine, exhibiting significant advantages in terms of concise synthetic route and environmental-friendly reagents over the previously described stepwise synthesis, in which a modified Strecker reaction was involved with highly toxic reagents such as diethylaluminum cyanide.

Full text of DOI:10.1016/j.tet.2004.11.057

Tetrahedron 61 (2005) 1281–1288
An improved synthesis of piperazino-piperidine based CCR5
antagonists with flexible variation on pharmacophore sites
*
Xiao-Hua Jiang, Yan-Li Song, Dong-Zhi Feng and Ya-Qiu Long
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, CAS,
555 Zuchongzhi Road, Shanghai 201203, China
Received 8 July 2004; revised 10 November 2004; accepted 11 November 2004
Available online 8 December 2004
Abstract—An improved and efficient synthetic route towards piperidino-piperazine based CCR5 antagonists was developed. The new
approach was flexible for introducing various substituents in the pharmacophore sites via Grignard reagent addition and reductive amination.
L-Amino acids were used as a chiral pool to introduce and then induce the desired stereochemistries, meanwhile rendering the variable
substitution. The efficient construction of the piperazino-piperidine nucleus was achieved in a highly convergent manner with a key building
block of N1-Boc-4-substituent-4-aminopiperidine, exhibiting significant advantages in terms of concise synthetic route and environmental-
friendly reagents over the previously described stepwise synthesis, in which a modified Strecker reaction was involved with highly toxic
reagents such as diethylaluminum cyanide.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
by compounds in Figure 1. The SAR investigation in the
two series has disclosed that the 1-N-substituents and 2(S)-
substituents in the piperazine ring as well as the 4-substi-
tution at the phenyl group are important pharmacophore
elements determining the potency and selectivity.6–8 The
methyl group at the 4-position of the piperidine ring
enhanced the binding potency by 3–7 fold relative to its
des-methylation counterparts. However, the three important
sites in the pharmacophore were inaccessible through
previously reported synthetic methodology, and the intro-
duction of the methyl group at the 4-position of the
piperidine ring involved a highly toxic reagent of diethyl-
aluminum cyanide.6,7
Human immunodeficiency virus type 1 (HIV-1) is the
etiological agent of acquired immunodeficiency syndrome
(AIDS). Currently HIV-1 reverse transcriptase and protease
inhibitors are available for the treatment of AIDS, and the
highly active antiretroviral therapy has been very effective
in bringing down the viral load; however, emergence of
multi-drug resistant viral strains and intolerance to available
agents can complicate the response to the treatment.
Recently, CCR5, a co-receptor essential for HIV-1 recog-
nition and entry into CD4C macrophages and T-cells1 but
not essential for human functions2 has emerged as a highly
validated target for antiviral therapy.3 The blockade of viral
entry with small molecules targeting the CCR5 co-receptor
could represent a new class of anti HIV-1 agent.3,4 A proof
of concept for this approach has been provided by Sch-C
and Sch-D, two CCR5 antagonists as HIV-1 entry inhibitors
under clinical trials (Fig. 1).5
To enable further structural optimization and pharmaco-
logical study of the promising piperazine-core compounds,
we sought a facile and practical synthesis of the structurally
diverse piperazino-piperidine analogs. In this paper, we
report a versatile synthetic approach which provides
potential for the variation of the pharmacophore elements
without using highly toxic and flammable reagent such as
diethylaluminum cyanide employed by the Schering–
Plough’s modified Strecker reaction.
Among an impressive number of structurally diverse,
small-molecule CCR5 inhibitors reported so far,4–11 piper-
idine- and piperazine-based compounds disclosed by
Schering–Plough Research Institute are an attractive and
promising class of potent CCR5 antagonists, as exemplified
2. Results and discussion
Keywords: Piperazino-piperidine nucleus; CCR5 antagonist; Reductive
amination; Chiral pool; 4-Substituent-4-aminopiperidine.
* Corresponding author. Tel.: C86 21 50806600; fax: C86 21 50806876;
e-mail: yqlong@mail.shcnc.ac.cn
As part of our program to further refine compounds in the
piperazino-piperidine family for improved potency and
higher selectivity, we developed a concise and convenient
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.057

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X.-H. Jiang et al. / Tetrahedron 61 (2005) 1281–1288
Figure 1. Piperidine- and piperazine-based CCR5 antagonists.
synthetic approach (Scheme 1) to afford structurally diverse
piperidino-piperazine containing compounds typified by the
general structure of 1, in which the 1-N-substituents and
2(S)-substituents in the piperazine ring as well as the group
at the 4-position of the piperidine can be varied readily. Our
improved methodology provides a general access to a
variety of piperazino-piperidine amide analogs for further
pharmacological study as HIV-1 entry inhibitors.
Accordingly, the adjacent asymmetric center of the 1-N-
substituent (S-configuration is preferred) could be installed
via asymmetric induction by the reductive amination of the
aryl methyl ketone with the L-amino acid. Our experiments
showed that the asymmetric induction effect is dependent on
the structure of the side chain of L-amino acid. Under our
reaction conditions, the dr value [the diastereomeric ratio of
(1S,2S) over (1R,2S)] varied in the range of 50–72% with
the 2S-methyl group being the best one. The resulting
diastereoisomers were easily separated by flash silica gel
chromatography (for 4b, its following chloroacetylated
products were more easy to separate by column chroma-
tography). The stereochemistry of the synthetic 4a was
Following an early finding that the chirality of piperazine
2-substituent requires (S)-configuration for effective CCR5
binding,7 we envisioned that this stereochemistry could be
introduced using natural amino acids as a chiral pool, which
also renders the structural variation of 2-substituent.
1
determined by the comparison of H NMR data with the
Scheme 1. A general procedure to synthesize various piperazino-piperidine based CCR5 antagonists.

X.-H. Jiang et al. / Tetrahedron 61 (2005) 1281–1288
1283
literature.12 The less polar diastereomer was found to be
(1S,2S)-configured, and the more polar counterpart was the
(1R,2S)-configured. The configuration of the resulting
diastereoisomers [(1S,2S)-4 and (1R,2S)-4] was further
confirmed in the case of compound 4c, by synthesizing an
authentic sample according to the literature method,6 which
was identified to correspond to the less polar fraction of the
diastereomer pair generated by the reductive amination.
Therefore, the established guideline could be applied to the
determination of the absolute configuration of the 1N-
substituent of the piperazine ring produced by the asym-
metric induction of the adjacent L-amino acid.
potent and orally active CCR5 antagonist as HIV-1 entry
inhibitor developed by Schering–Plough Research Institute,
was accomplished in excellent yield using 1N-Boc-4-
methyl-4-aminopiperidine as a smart building block.
Compared to previously reported procedure, the newly
developed methodology provides us with a facile and
practical access to structurally diverse piperazino-piperidine
compounds for the elaboration of effective inhibitors of
HIV-1 cell entry.
3. Conclusions
In summary, we developed an improved and efficient
procedure to prepare various piperidino-piperazine based
CCR5 antagonists. Starting from commercially available
4-substituted-benzaldehyde, the nucleophilic addition of the
Grignard reagent followed by Jone’s oxidation afforded the
aryl alkyl ketone. Reductive amination of the aryl alkyl
ketone with L-amino acid introduced the desired chirality
and the substitution at the 2(S)-position of the piperazine
ring. Subsequently the efficient and concise synthesis of the
piperazino-piperidine nucleus was achieved in a highly
convergent manner with a key building block of 1N-Boc-4-
substituted-4-amino-piperidine, devoid of using highly
toxic reagents employed by previously described stepwise
synthetic approach. The improved methodology was
versatile and flexible for introducing various substituents
in the key positions of the pharmacophore, thus potentially
benefits the SAR studies of piperazino-piperidine com-
pounds as HIV-1 entry inhibitors.
The general synthetic method for the preparation of
structurally diverse piperidino-piperazine amides is
depicted in Scheme 1. Nucleophilic addition of alkyl-
magnesium reagent to commercially available 4-trifluoro-
methylbenzaldehyde followed by Jone’s oxidation afforded
ketone 3, possessing the various R1 substituents. Reductive
amination of the ketone 3 with various L-amino acid
produced diastereoisomers which were easily separated by
flash silica gel chromatography to afford the desired
(1S,2S)-amine 4, introducing a variable group of R2. The
secondary amine was then reacted with 2-chloroacetyl
chloride to yield the corresponding (2-chloroacetyl)-amino-
acetic acid methyl ester 5, which was converted to the
desired aryl diketopiperazino-piperidine 7 by treatment with
4-substituent-4-amino-piperidine-1-N-Boc 6, allowing the
introduction of an alkyl or aryl group (R3) at the 4-position
of the piperidine. The key building blocks 6 were
conveniently prepared according to our recently developed
efficient methodology employing isonipecotate as a starting
material and Curtius rearrangement as a key step.13 Boc
removal of 7 with trifluoroacetic acid followed by reduction
with NaBH4 in the presence of boron trifluoride etherate
gave the aryl piperazino-piperidine analogs 8. The coupling
of the resulting free amine with the desired aromatic acids
proceeded under standard conditions to furnish the desired
products 1.
4. Experimental
4.1. General
All reactions were performed under nitrogen atmosphere
with flame-dried glassware. Solvents were distilled and
dried according to standard procedures. H NMR spectra
1
Notably, our approach employed the 4-substituent-4-amino-
piperidine-1-N-Boc 6 as a building block to construct the
piperazino-piperidine scaffold in a highly convergent
manner. The reactivity was affected by the substituent at
the 4-position of the 4-amino-piperidine. When N1-Boc-4-
aminopiperidine 6a is used, the cyclization was readily
accomplished in one step with high yield (compounds
7a–c), while the mono-substituted intermediate was isolated
and continued the intramolecular lactamization in a
different reaction condition (with refluxing toluene and
catalytic 2-pyridinol)14 when N1-Boc-4-methyl-4-amino-
piperidine 6b is used (compound 7d). In both cases, no
racemization was observed. Our developed methodology is
devoid of using highly toxic and flammable reagent such as
diethylaluminum cyanide employed by the Schering–
Plough’s modified Strecker reaction, and provides potential
for convenient introduction of various substituents at the
important 4-position of the piperidine ring.
were recorded on a Varian 300-MHz or 400-MHz
spectrometer. 13C NMR spectra were recorded on a Varian
Mercury VX 400-MHz spectrometer. Melting points
(uncorrected) were determined on a Buchi-510 capillary
apparatus. Specific rotations (uncorrected) were determined
in a Perkin–Elmer 241 polarimeter. Elemental analysis were
determined to be within G0.4% of the theoretical values for
elements C, H and N. IR spectra were recorded on a DTGS
spectrometer in KBr pellets. Low and high-resolution mass
spectra were determined on Finnigan MAT-95 mass
spectrometer. TLC was performed on 0.25 mm HSGF 254
silica gel plates. All final products were characterized by
NMR, IR, MS and elemental analysis or high resolution
mass spectra.
4.1.1. 1-(4-Trifluoromethyl-phenyl)-ethanol (2).15 Mag-
nesium turnings (0.631 g, 25.0 mmol) were placed into a dry
three-neck flask, equipped with an addition funnel and
condenser. Anhydrous ether (10 mL) was added to cover the
turnings. To initiate the reaction, about 2 mL of a solution of
CH3I (1.6 mL, 25.0 mmol) and 16.0 mL of anhydrous ether
were added. After formation of bubbles at the surface of the
turnings, the remaining CH3I–ether solution was added
Using this improved methodology, we efficiently syn-
thesized a series of piperazino-piperidine amide analogs
1a–d with a variety of 2-substituents on the piperazine ring.
The concise synthesis of compound 1d (Sch-350634), a

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X.-H. Jiang et al. / Tetrahedron 61 (2005) 1281–1288
dropwise (at a ratio to maintain a moderate reflux). After the
addition, the mixture was stirred at room temperature for
45 min. To the above ethereal Grignard reagent (11.0 mL),
a,a,a-trifluro-p-tolualdehyde (1.68 mL, 12.26 mmol) in
15.0 mL of anhydrous ether was added with constant
agitation at 0 8C under N2. The mixture was refluxed for
1.5 h, then poured into a cold aqueous ammonium chloride
solution. The aqueous layer was extracted with Et2O, the
combined Et2O extracts were washed with saturated
aqueous Na2S2O3 and brine, then dried over Na2SO4- and
evaporated under vacuum. The residue was purified by
chromatography using petroleum ether/etherZ10:1 to
afford compound 2 (3.145 g, 100%) as yellow oil. 1H
NMR (400 MHz, CDCl3): d 7.60 (d, 2H, JZ8.2 Hz); 7.48
(d, 2H, JZ8.1 Hz); 4.96 (q, 1H, JZ6.4 Hz); 2.03 (s, 1H);
1.50 (d, 1H, JZ6.4 Hz).
(d, 2H, JZ8.1 Hz); 7.44 (d, 2H, JZ8.1 Hz); 3.87 (q, 1H,
JZ6.6 Hz); 3.61 (s, 3H); 3.34 (q, 1H, JZ6.9 Hz); 1.93 (br,
1H); 1.36 (d, 3H, JZ6.6 Hz); 1.29 (d, 3H, JZ7.0 Hz). 13C
NMR (400 MHz, CDCl3): d 175.50, 148.97, 129.21,
126.95(!2), 125.23(!2), 125.19, 55.41, 53.81, 51.48,
22.95, 18.46. IR (KBr) n: 3330, 2977, 1739, 1619, 1454,
1326, 1201, 1162, 1124, 1068, 1016, 844 cmK1
.
4.1.4. 3-Methyl-2-[1-(4-trifluoromethyl-phenyl)-ethyl-
amino]-butyric acid methyl ester (4b). The solution of
L-valine methyl ester hydrochloride (1.10 g, 6.57 mmol) in
dry 1,2-dichloroethane (25.0 mL) was treated with sequen-
tial 40-(trifluoromethyl)-acetophenone (1.12 g, 5.98 mmol)
and sodium triacetoxyborohydride (1.77 g, 8.37 mmol) in a
similar way to the preparation of 4a. The residue was
purified by chromatography using petroleum ether/
EtOAcZ10:1 as eluent to give compound 4b (0.91 g,
yield 50.0%) as colorless oil (mixture of two diastereo-
4.1.2. 1-(4-Trifluoromethyl-phenyl)-ethanone (3).16
A
solution of CrO3 (26.72 g, 267.2 mmol) in 23.0 mL of
concentrated sulfuric acid was diluted with water to a
volume of 100 mL to afford 2.672 N Jone’s reagent. To a
solution of compound 2 (3.314 g, 17.25 mmol) in 50 mL of
acetone at 0 8C was added Jone’s reagent (13.11 mL)
dropwise with stirring. The resulting orange solution was
stirred at 0 8C for 0.5 h. The cooling bath was removed and
2-propanol was added dropwise, whereupon a green
precipitate formed immediately. The mixture was stirred
at room temperature for 20 min and filtered through celite.
The flask and the celite pad was washed with acetone and
the solvent was removed, the yellow oil was purified by
flash chromatography on silica gel eluted with petroleum
ether/etherZ10:1 to obtain compound 3 (2.588 g, 82.2%) as
white solid. 1H NMR (400 MHz, CDCl3): d 8.07 (d, 2H, JZ
8.0 Hz); 7.60 (d, 2H, JZ8.0 Hz); 2.67 (s, 3H).
1
isomers). H NMR (400 MHz, CDCl3): d 7.57–7.42 (m,
9.44H); 3.75 (q, 1.36H, JZ6.5 Hz); 3.71 (s, 3H); 3.67 (q,
1H, JZ6.6 Hz); 3.57 (s, 4.08H); 3.06 (d, 1.36H, JZ6.2 Hz);
2.70 (d, 1H, JZ6.2 Hz); 1.92–1.79 (m, 4.72H); 1.32 (d, 1H,
JZ6.5 Hz); 1.31 (d, 1.36H, JZ6.6 Hz); 0.94 (d, 4.08H, JZ
6.7 Hz); 0.93 (d, 4.08H, JZ6.7 Hz); 0.91 (d, 3H, JZ
6.7 Hz); 0.87 (d, 3H, JZ6.7 Hz). 13C NMR (400 MHz,
CDCl3): d 175.90, 175.20, 149.50, 149.10, 129.25, 127.32,
127.18, 125.29, 64.79, 56.74, 56.64, 51.2, 51.33, 31.65,
25.43, 22.61, 19.42, 19.03, 18.63, 18.38. IR (KBr) n: 3446,
2996, 1735, 1619, 1469, 1419, 1324, 1199, 1162, 1126,
1066, 1018, 844, 781, 609 cmK1. EI-MS (m/z, %): 302
(MCK1); 260 (20.0); 228 (8.0); 173 (100.0); 153 (37.0).
4.1.5. 3-Phenyl-2-[1-(4-trifluoromethyl-phenyl)-ethyl-
amino]-propionic acid methyl ester (4c). The solution of
L-phenylalanine methyl ester hydrochloride (2.588 g,
12.0 mmol) in0 30.0 mL of dry 1,2-dichloroethane was
treated with 4 -(trifluoromethyl) -acetophenone (1.871 g,
10.0 mmol) and sodium triacetoxyborohydride (3.179 g,
15.0 mmol) in a similar way to the preparation of 4a. The
purification from chromatography using petroleum ether/
EtOAc (12:1) gives compound 4c (1.342 g, yield 37%) as
glassy solid. [a]D20ZK49.7 (cZ1.6, CDCl3). 1H NMR
(400 MHz, CDCl3): d 7.45 (d, 2H, JZ8.0 Hz); 7.31–7.26
(m, 3H); 7.17 (d, 2H, JZ8.0 Hz); 7.12–7.10 (m, 2H); 3.74
(q, 1H, JZ6.4 Hz); 3.68 (s, 3H); 3.19 (dd, 1H, JZ8.0,
6.0 Hz); 2.93 (dd, 1H, JZ13.2, 5.6 Hz); 2.81 (dd, 1H, JZ
13.2, 8.0 Hz); 1.92 (br, 1H); 1.29 (d, 3H, JZ6.4 Hz). 13C
NMR (400 MHz, CDCl3): d 175.42, 149.03, 137.32, 129.33
(!3), 128.26 (!2), 127.03 (!2), 126.65 (!2), 125.26,
122.38, 60.49, 56.35, 51.69, 40.09, 25.22. EI-MS (m/z, %):
351 (MC, 0.1); 332 (1.0); 292 (18.0); 260 (66.0); 173
(100.0). IR (KBr): 3346, 2928 (m), 1736, 1618, 1327, 1140,
4.1.3. 2-[1-(4-Trifluoromethyl-phenyl)-ethylamino]-pro-
pionic acid methyl ester (4a). To the solution of L-alanine
methyl ester hydrochloride (1.023 g, 6.41 mmol) in dry 1,2-
dichloroethane (15 mL) was added Et3N (1.117 mL,
6.41 mmol). After stirring at room temperature for 0.5 h,
40-(trifluoromethyl)acetophenone (1.0 g, 5.34 mmol) was
added, then the reaction mixture was treated with sodium
triacetoxyborohydride (2.266 g, 10.69 mmol) and HOAc
(0.61 mL, 10.69 mmol). The mixture was stirred at room
temperature for 22 h. The reaction was quenched with
saturated NaHCO3 and extracted with Et2O. The organic
layers were washed with saturated NaHCO3 and brine, dried
over Na2SO4. The solvent was removed under vacuum. The
residue was purified by chromatography using petroleum
ether/etherZ10:1 to give compound 4a (0.788 g, yield
54.2%) as colorless oil. [a]2D0ZK113.6 (cZ0.8, CHCl3). 1H
NMR (400 MHz, CDCl3): d 7.57 (d, 2H, JZ8.1 Hz); 7.45
(d, 2H, JZ8.1 Hz); 3.80 (q, 1H, JZ6.6 Hz); 3.72 (s, 3H);
3.06 (q, 1H, JZ7.0 Hz); 1.38 (d, 3H, JZ6.6 Hz); 1.25 (d,
3H, JZ7.0 Hz). 13C NMR (400 MHz, CDCl3): d 176.42,
149.25, 129.64, 126.98 (!2), 125.19 (!2), 122.79, 56.25,
54.13, 51.42, 24.92, 19.43. IR (KBr) n: 3334, 2975, 1737,
1619, 1452, 1419, 1324, 1203, 1164, 1124, 1066, 1016,
844 cmK1. EI-MS (m/z, %): 274 (MCK1, 1.0); 260 (7.0);
216 (100.0); 173 (99.0); 153 (37.0).
1067, 702 cmK1
.
The (1R,2S) isomer, colorless oil in yield of 30%. [a]2D0Z
1
C44.3 (cZ0.7, CDCl3). H NMR (400 MHz, CDCl3): d
7.56 (d, 2H, JZ8.1 Hz); 7.40 (d, 2H, JZ8.1 Hz); 7.31–7.15
(m, 5H); 3.79 (q, 1H, JZ6.5 Hz); 3.52 (t, 1H, JZ6.7 Hz);
2.95 (d, 2H, JZ6.7 Hz); 1.90 (br, 1H); 1.28 (d, 2H, JZ
6.6 Hz). 13C NMR (400 MHz, CDCl3): d 174.20, 148.60,
137.00, 129.31, 129.17, 128.43, 128.27 (!2), 127.24 (!2),
127.05, 126.79, 125.38, 122.80, 60.59, 56.32, 51.62, 39.38,
The (1R, 2S) isomer is colorless oil, yield 17.0%. [a]2D0Z
C9.5 (cZ1.1, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.57

X.-H. Jiang et al. / Tetrahedron 61 (2005) 1281–1288
1285
23.00. EI-MS (m/z, %): 332 (MCK19, 2.0); 292 (19.0); 260
(85.0); 173 (100.0); 153 (11.0); 91 (8.0).
1653, 1456 (m), 1327, 1167, 1122, 1070, 847, 754,
704 cmK1
.
4.1.6. 2-{(2-Chloro-acetyl)-[1-(4-trifluoromethyl-phenyl)-
ethyl]-amino}-propionic acid methyl ester (5a). The
secondary amine 4a (0.479 g, 1.74 mmol) was dissolved
in 1,2-dichloroethane (15.0 mL), chloroacetyl chloride
(2.78 mL, 34.8 mmol) was added to the above solution at
room temperature. The mixture was stirred under refluxing
for 3 h. Both the solvent and chloroacetyl chloride was
removed under vacuum. The remaining yellow syrup was
purified by chromatography using petroleum ether/EtOAc
(3.5:1) to give compound 5a (0.589 g, yield 96.0%) as
glassy solid. [a]D20ZK105 (cZ0.6, CHCl3). 1H NMR
(400 MHz, CDCl3): d 7.70–7.60 (m, 4H); 5.28 (q, 1H, JZ
7.2 Hz); 4.19 (qAB, 2H, JZ12.4 Hz); 3.57 (s, 3H); 3.49 (q,
1H, JZ7.2 Hz); 1.77 (d, 3H, JZ7.2 Hz); 1.56 (d, 3H, JZ
7.2 Hz). 13C NMR (400 MHz, CDCl3): d 170.30, 165.30,
142.24, 130.31, 128.23 (!2), 125.31 (!2), 122.53, 56.03,
52.60, 52.12, 41.45, 18.76, 15.93. EI-MS (m/z, %): 353
(MCC2, 0.3); 351 (MC, 1.0); 274 (28.0); 266 (12.0); 264
(36.0); 173 (100.0); 153 (14.0). IR (KBr): 3467, 3037, 2958,
4.1.9. 4-{3-Methyl-2,5-dioxo-4-[1-(4-trifluoromethyl-
phenyl)-ethyl]-piperazin-1-yl}-piperidine-1-carboxylic
acid tert-butyl ester (7a). The compound 5a (0.8 g,
2.28 mmol), N1-Boc-4-aminopiperidine 6a (0.5 g,
2.5 mmol) and Et3N (0.35 mL) in CH3OH (10 mL) were
refluxed overnight and the solvent was removed under
reduced pressure. The residue was purified by chromatog-
raphy using petroleum ether/EtOAcZ1:1 to give compound
7a (0.644 g, yield 59%) as white solid. [a]2D0ZK42.0 (cZ
1
1.0, CHCl3). H NMR (400 MHz, CDCl3): d 7.60 (d, 2H,
JZ8.2 Hz); 7.35 (d, 2H, JZ8.3 Hz); 5.83 (q, 1H, JZ
7.1 Hz); 4.47–4.41 (m, 1H); 4.24–4.21 (m, 2H); 3.90 (s,
2H); 3.75 (q, 1H, JZ7.1 Hz); 2.78–2.75 (m, 2H); 1.65 (d,
3H, JZ7.1 Hz); 1.70–1.48 (m, 4H); 1.47 (d, 3H, JZ
7.1 Hz); 1.46 (s, 9H). 13C NMR (400 MHz, CDCl3): d
167.69, 164.82, 154.46, 143.40, 130.24, 127.21 (!2),
125.88, 125.20, 122.50, 79.95, 53.51, 51.57, 50.67, 45.04,
42.94 (!2), 28.59 (!2), 28.38 (!3), 19.45, 17.64. EI-MS
(m/z, %): 484 (MCC1, 1.0); 483 (MC, 7.0); 427 (24.0); 410
(20.0); 301 (13.0); 173 (12.0); 82 (100). IR (KBr): 3431,
1741, 1633, 1437, 1329, 1240, 1121, 1068, 841, 613 cmK1
.
2982, 1676, 1659, 1443, 1327, 1142 cmK1
.
4.1.7. 2-{(2-Chloro-acetyl)-[1-(4-trifluoromethyl-phenyl)-
ethyl]-amino}-3-methyl-butyric acid methyl ester (5b).
Compound 5b was prepared from 4b according to the same
procedure as 5a. The residue was chromatographed using
petroleum ether/EtOAcZ7:1 to separate the diastereo-
isomers (0.797 g, total yield 84.0%, each isomer in yield
of w42%). The less polar isomer 5b is colorless oil.
[a]2D0ZK84.4 (cZ2.4, CHCl3). 1H NMR (300 MHz,
CDCl3): d 7.56–7.39 (m, 4H); 5.31 (br, 1H); 4.29–3.81
(m, 3H); 3.39 (s, 3H); 2.55–2.38 (m, 1H); 1.76 (d, 3H, JZ
6.6 Hz); 1.02 (d, 6H, JZ6.3 Hz). EI-MS (m/z, %): 381
(MCC2, 2.0); 379 (MC, 6.0); 362 (3.0); 360 (9.0); 322
(1.3); 320 (3.9); 264 (20.0); 173 (100.0). IR (KBr): 3450
2989, 2974, 2881, 1734, 1714, 1651, 1452 (m), 1335, 1165,
1121, 1273, 1120, 849, 613 cmK1. HRMS (EI) calcd for
C17H21ClF3NO3 379.1162, found 379.1157.
4.1.10. 4-{3-Isopropyl-2,5-dioxo-4-[1-(4-trifluoromethyl-
phenyl)-ethyl]-piperazin-1-yl}-piperidine-1-carboxylic
acid tert-butyl ester (7b). The compound 5b (0.527 g,
1.39 mmol), N1-Boc-4-aminopiperidine 6a (0.2 g,
1.67 mmol) and DIPEA (0.44 mL, 2.51 mmol) in CH3CN
(10 mL) were refluxed overnight and the solvent was
removed under reduced pressure. The residue was purified
by chromatography using petroleum ether/EtOAcZ1:1 to
give the compound 7b as white solid in yield of 42.3%.
[a]2D0ZK16.8 (cZ1.0, CHCl3). 1H NMR (400 MHz,
CDCl3): d 7.59 (d, 2H, JZ8.0 Hz); 7.37 (d, 2H, JZ
8.0 Hz); 5.57–5.51 (m, 1H); 4.53–4.45 (m, 1H); 4.18 (brs,
2H); 3.95 (d, 1H, JZ17.6 Hz); 3.82 (d, 1H, JZ17.6 Hz);
3.56 (d, 1H, JZ7.2 Hz); 2.21–2.12 (m, 1H); 1.85–1.71 (m,
2H); 1.65 (d, 3H, JZ7.2 Hz); 1.59–1.48 (m, 4H); 1.46 (s,
9H); 1.04 (d, 3H, JZ6.8 Hz); 0.96 (d, 3H, JZ6.8 Hz). 13C
NMR (400 MHz, CDCl3): d 165.01, 164.44, 154.46, 143.51,
130.12, 127.46 (!2), 125.81, 125.77, 122.57, 79.90, 64.01,
54.28, 50.72, 45.68, 33.99, 28.81 (!2), 28.34 (!3), 28.08
(!2), 20.42, 18.14, 16.86. EI-MS m/z: 511 (MC).
The more polar isomer: [a]2D0ZK23.5 (cZ1.1, CHCl3). 1H
NMR (300 MHz, CDCl3): d 7.66–7.57 (m, 4H); 5.33–5.31
(m, 1H); 4.34–4.13 (m, 2H); 3.80–3.72 (m, 3H); 3.40–3.37
(m, 1H); 2.42–2.25 (m, 1H); 1.71–1.63 (brd, 3H); 0.98–0.20
(m, 6H). EI-MS (m/z, %): 381 (MCC2, 3.0); 379 (MC,
9.0); 362 (4.0); 360 (12.0); 322 (2.0); 320 (6.0); 264 (30.0);
173 (100.0).
The more polar isomer (1R,2S)-5b was analogously
converted to the corresponding (1R,2S)-7b as white solid
in yield of 48%. [a]2D0ZC55.1 (cZ5.1, EtOAc). H NMR
1
4.1.8. 2-{(2-Chloro-acetyl)-[1-(4-trifluoromethyl-phenyl)-
ethyl]-amino}-3-phenyl-propionic acid methyl ester (5c).
Compound 5c was prepared analogously to 5a. The
purification by chromatography using petroleum ether/
EtOAcZ6:1 afforded compound 5c (0.553 g, yield 90.0%)
(400 MHz, CDCl3): d 7.55 (d, 2H, JZ8.4 Hz); 7.49 (d, 2H,
JZ8.4 Hz); 5.35 (br, 1H); 4.56–4.44 (m, 1H); 4.18 (brs,
1H); 3.91 (d, 1H, JZ17.2 Hz); 3.89 (d, 1H, JZ4.0 Hz); 3.74
(d, 1H, JZ17.2 Hz); 2.74 (br, 2H); 1.70 (d, 3H, JZ7.2 Hz);
1.53 (br, 4H); 1.49 (s, 9H); 0.87 (d, 3H, JZ6.8 Hz); 0.79 (d,
3H, JZ6.8 Hz). 13C NMR (400 MHz, CDCl3): d 164.91,
164.35, 154.37, 143.43, 130.04, 127.65, 127.39, 125.73,
125.12, 122.41, 79.81, 63.93, 54.20, 50.64, 45.60, 33.92,
28.75 (!2), 28.26 (!3), 28.01 (!2), 20.34, 18.07, 16.88.
IR (KBr): 3315, 2974, 2247, 1662, 1126, 1072, 1016, 922,
733 cmK1. EI-MS (m/z, %): 511 (MC), 455 (26.0); 438
(18.0); 369 (8.0); 173 (25.0); 82 (100); 57 (50.00). HREI-
MS calcd for C26H36F3N3O4 511.2658, found 511.2668.
1
as glassy solid. [a]D20ZK72.6 (cZ0.8, CDCl3). H NMR
(400 MHz, CDCl3): d 7.59 (d, 2H, JZ8.2 Hz); 7.45 (d, 2H,
JZ8.1 Hz); 7.36–7.21 (m, 5H); 5.10 (q, 1H, JZ7.0 Hz);
4.28–4.13 (m, 2H); 3.70–3.67 (m, 1H); 3.58–3.53 (m, 1H);
3.51 (s, 3H); 1.12 (d, 3H, JZ7.0 Hz). EI-MS (m/z, %): 429
(MCC2, 2.0); 427 (MC, 6.0); 410 (1.0); 408 (3.0); 350
(12.0); 336 (6.0); 292 (14.0); 260 (39.0); 196 (16.0); 173
(40.0); 162 (100.0); 91 (20.0). IR (film): 2953 (m), 1740,

1286
X.-H. Jiang et al. / Tetrahedron 61 (2005) 1281–1288
4.1.11. 4-{3-Benzyl-2,5-dioxo-4-[1-(4-trifluoromethyl-
phenyl)-ethyl]-piperazin-1-yl}-piperidine-1-carboxylic
acid tert-butyl ester (7c). The compound 7c was prepared
from 5c and 6a according to the same procedure as 7b. The
residue was purified by chromatography using petroleum
ether/EtOAcZ1:1 to give compound 7c (0.436 g, yield
7a (0.242 g, 0.5 mmol) was dissolved in methylene chloride
(2.5 mL) and trifluoroacetic acid (5 mL) was added. The
mixture was stirred at room temperature for 2 h. After
removing the solvent and trifluoroacetic acid under reduced
pressure, 2 N NaOH was added and extractive work up with
EtOAc. The organic layer was washed with saturated
NaHCO3, brine and dried over Na2SO4. The solvent was
removed under vacuum to give (S)-4-((S)-1-(4-trifluro-
methyl)phenyl)- ethyl-3-methyl)-1-(piperidin-4-yl)pipera-
zine-2,5-dione, which was used directly for next step
without purification.
1
83%) as white foam. [a]2D0ZK42.0 (cZ1.0, CHCl3). H
NMR (400 MHz, CDCl3): d 7.62 (d, 2H, JZ8.3 Hz); 7.40
(d, 2H, JZ8.0 Hz); 7.33–7.29 (m, 3H); 7.15 (d, 2H, JZ
6.8 Hz); 5.92 (q, 1H, JZ7.4 Hz); 4.45–4.38 (m, 1H); 4.15–
4.09 (m, 2H); 4.03 (t, 1H, JZ4.2 Hz); 3.32 (d, 1H, JZ
17.1 Hz); 3.27 (dd, 1H, JZ13.9, 3.6 Hz); 3.12 (dd, 1H, JZ
14.0, 4.7 Hz); 2.74–2.67 (m, 2H); 2.12 (d, 1H, JZ16.8 Hz);
1.85 (d, 1H, JZ7.2 Hz); 1.46–1.37 (m, 3H); 1.43 (s, 9H);
1.10–1.06 (m, 1H). 13C NMR (400 MHz, CDCl3): d 165.85,
165.66, 154.31, 143.41, 134.56, 130.45, 130.12 (!2),
128.77 (!2), 127.88, 127.45 (!2), 125.88, 125.09, 122.39,
79.8, 58.82, 52.59, 50.52, 44.37, 42.78, 39.87 (!2), 28.26
(!3), 27.96 (!2), 18.26. EI-MS (m/z, %): 559 (MC, 2.0),
503 (9.0), 486 (5.0), 459 (10.0), 368 (6.0), 285 (4.0), 173
(58.0), 91 (20.0), 82 (100.0). IR (KBr): 3442, 2978, 2933,
1691, 1662, 1427, 1327, 1167, 1124, 1072 cmK1. HREI-MS
calcd for C30H36F3N3O4 559.2658, found 559.2671.
The crude diketopiperzaine (0.192 g, 0.5 mmol) prepared
above was dissolved in dimethoxy ethane (5 mL) and
sodium borohydride (0.189 g, 5.0 mmol), boron trifluoride
etherate (0.38 mL, 3.0 mmol) were added to the solution.
The mixture was stirred under reflux for 3 h and then cooled
to 0 8C. Methanol (6 mL) and concentrated hydrogen
chloride (3.6 mL) were added successively to the mixture
and stirred for 15 min at room temperature, then refluxed for
45 min. The mixture was concentrated, and basified with
6 N sodium hydroxide, then extracted with EtOAc. The
combined organic layers were washed with brine and dried
over Na2SO4. The solvent was removed under vacuum to
give the compound 8a as glassy solid. Used for next step
without further purification.
4.1.12. 4-Methyl-4-{3-methyl-2,5-dioxo-4-[1-(4-trifluoro-
methyl-phenyl)-ethyl]-piperazin-1-yl}-piperidine-1-car-
boxylic acid tert-butyl ester (7d). Compound 5c (0.221 g,
0.63 mmol), N1-Boc-4-amino-4-methyl-piperidine 6b
(0.148 g, 0.69 mmol) in CH3CN (5.0 mL) was refluxed
overnight and the solvent was removed under reduced
pressure. The residue was purified by chromatography using
petroleum ether/EtOAc 1:1 as eluent to give the mono-
substituted intermediate (0.265 g, yield 80.0%) as colorless
4.1.14. 2-Isopropyl-4-piperidin-4-yl-1-[1-(4-trifluoro-
methyl-phenyl)-ethyl]-piperazine (8b). The preparation
of 8b is similar to that of 8a.
4.1.15.
2-Benzyl-4-piperidin-4-yl-1-[1-(4-trifluoro-
methyl-phenyl)-ethyl]-piperazine (8c). The preparation
of 8c is also similar to that of 8a.
1
oil. [a]2D0ZC80 (cZ1.65, CHCl3). H NMR (400 MHz,
CDCl3): d 7.64 (AB, 2H, JABZ8.3 Hz); 7.60 (AB, 2H, JAB
Z
8.3 Hz); 5.19 (q, 1H, JZ6.9 Hz); 3.56 (s, 3H); 3.52–3.40 (m,
7H); 1.97 (br, 1H, D2O exchangeable); 1.71 (d, 3H, JZ
6.9 Hz); 1.55 (d, 3H, JZ6.9 Hz); 1.49–1.47 (m, 2H); 1.44 (s,
9H); 1.08 (s, 3H). EI-MS (m/z, %): 529 (MC, 3.0); 428 (6.0);
301 (23.0); 256 (21.0); 188 (56.0); 171 (100.0); 127 (62.0).
4.1.16. 2-Methyl-4-(4-methyl-piperidin-4-yl)-1-[1-(4-tri-
fluoromethyl-phenyl)-ethyl] -piperazine (8d). Prepared
analogously to 8a. Used directly for next step without
further purification.
The mono-substituted intermediate (0.309 g, 0.58 mmol)
and 2-hydroxy-pyridine (0.05 g, 0.43 mmol) were dissolved
in dry toluene (1.5 mL) and stirred at 90 8C for 6 h. After
removing the solvent, the residue was purified by chroma-
tography using PE/EtOAc (1:1) as eluent to give compound
7d as white solid (0.244 g, yield 84%). [a]2D0ZK16.3 (cZ
4.1.17. (2,4-Dimethyl-1-oxy-pyridin-3-yl)-(4-{3-methyl-
4-[1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-
piperidin-1-yl)-methanone (1a).17 The crude piperidine 8a
(0.178 g, 0.5 mmol) was dissolved in methylene chloride
(2 mL) and treated with 2,4-dimethylnicotinic acid-N-oxide
(0.1 g, 0.6 mmol), EDCI (0.144 g, 0.75 mmol), HOBT
(0.101 g, 0.75 mmol) and DIPEA (0.175 mL). The mixture
was stirred at room temperature overnight and the solvent
was removed under reduced pressure. The residue was
purified by chromatography using CH2Cl2/CH3OH (30:1) to
give the compound 1a (0.1 g, 37.0% overall yield of three
1
1.2, CHCl3). H NMR (400 MHz, CDCl3): d 7.60 (d, 2H,
JZ8.0 Hz); 7.36 (d, 2H, JZ8.0 Hz); 5.82 (q, 1H, JZ
7.2 Hz); 4.06 (d, 1H, JZ12.8 Hz); 3.91 (d, 1H, JZ12.8 Hz);
3.64 (q, 1H, JZ7.2 Hz); 3.59–3.48 (m, 2H); 3.26–3.11 (m,
2H); 2.44–2.39 (m, 1H); 2.26–2.21 (m, 1H); 1.79–1.68 (m,
2H); 1.66–1.62 (m, 3H); 1.48 (d, 3H, JZ7.2 Hz); 1.47 (s,
9H); 1.36 (s, 3H). 13C NMR (400 MHz, CDCl3): d 169.51,
164.75, 154.58, 143.47, 130.38, 128.16 (!2), 125.60,
125.15, 122.32, 79.69, 58.85, 54.83, 50.64, 46.48 (!2),
40.13, 35.43, 35.20, 28.32 (!3), 21.77, 18.06, 15.93. EI-
MS (m/z, %): 497 (MC); 441 (56.0); 424 (11.0); 301 (23.0);
173 (18.0); 96 (100); 57 (43.0). IR (KBr): 3400, 2980, 2862,
1
steps) as white foam. [a]2D0ZC12.1 (cZ1.0, CHCl3). H
NMR (400 MHz, CDCl3): d 8.16 (d, 1H, JZ6.3 Hz); 7.58–
7.51 (m, 4H); 7.00 (dd, 1H, JZ6.3, 3.6 Hz); 4.76 (brt, 1H);
4.11 (brs, 1H); 3.55 (brd, 1H); 3.04–2.75 (m, 4H); 2.58–2.56
(m, 1H); 2.44 (d, 3H, JZ19.5 Hz); 2.31–2.22 (m, 5H); 2.15
(d, 3H, JZ19.5 Hz); 2.04–2.00 (m, 1H); 1.80–1.76 (m, 2H);
1.54–1.48 (m, 1H); 1.29 (d, 3H, JZ6.6 Hz); 1.14 (dd, 3H,
JZ6.0, 1.5 Hz). ESI-MS (m/z, %): 505 (MCC1, 100). EI-
MS (m/z, %): 504 (MC, 0.85); 487 (40.0); 426 (51.0); 314
(41.0); 246 (44.0); 173 (31.0); 134 (100). HREI-MS calcd
for C27H35N4O2F3: 504.2712, found, 504.2719.
1684, 1653, 1414, 1327, 1140, 1173 cmK1
.
4.1.13. 2-Methyl-4-piperidin-4-yl-1-[1-(4-trifluoro-
methyl-phenyl)-ethyl]-piperazine (8a). The compound

X.-H. Jiang et al. / Tetrahedron 61 (2005) 1281–1288
1287
4.1.18. (2,4-Dimethyl-1-oxy-pyridin-3-yl)-(4-{3-isopro-
pyl-4-[1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-
yl}-piperidin-1-yl)-methanone (1b). Prepared from the
crude piperidine 8b in a similar manner to 1a. Chromato-
graphy purification using CH2Cl2/CH3OH (30:1) afforded
1b as white foam in an overall yield of 68.0%. [a]2D0Z
4.1.20. (2,4-Dimethyl-1-oxy-pyridin-3-yl)-(4-methyl-4-
{3-methyl-4-[1-(4-trifluoromethyl-phenyl)-ethyl]-piper-
azin-1-yl}-piperidin-1-yl)-methanone (1d).6,7 Compound
1d was synthesized from the crude piperidine 8d
analogously to 1a. The residue was purified by chromato-
graphy (CH2Cl2/CH3OHZ30:1) to give compound 1d
(0.085 g, three steps in 64% yield) as white gum.
[a]2D0ZC9.1 (cZ0.9, CHCl3). 1H NMR (300 MHz,
CDCl3): d 8.16 (d, 1H, JZ6.6 Hz); 7.58–7.50 (m, 4H);
7.00 (d, 1H, JZ6.9 Hz); 4.22 (brt, 1H); 3.98 (brs, 1H); 3.45–
3.36 (m, 2H); 3.01–2.96 (m, 2H); 2.67–2.57 (m, 1H); 2.46
(d, 3H, JZ9.9 Hz); 2.41–2.24 (m, 4H); 2.26 (d, 3H, JZ
9.0 Hz); 2.03–1.95 (brt, 1H); 1.76–1.70 (m, 2H); 1.46–1.34
(m, 3H); 1.29 (d, 3H, JZ6.9 Hz); 1.14 (d, 3H, JZ6.3 Hz);
0.93 (s, 3H). ESI-MS (m/z, %): 519 (MCCH, 100.0), 541
(MCCNa, 37.0).
1
K15.6 (cZ0.70, CHCl3). H NMR (400 MHz, CDCl3): d
8.17 (d, 2H, JZ6.8 Hz); 7.57 (m, 4H); 7.01 (dd, 1H, J1Z
4.0 Hz, J2Z6.8 Hz); 4.78 (m, 1H); 4.34 (q, 1H, JZ6.8 Hz);
3.39 (m, 1H); 3.02–2.82 (m, 3H); 2.72–2.53 (m, 2H); 2.44
(d, 3H, JZ25.2 Hz); 2.38–2.33 (m, 1H) 2.15–2.05 (m, 3H);
2.25 (d, 3H, JZ25.2 Hz); 2.10–1.99 (m, 2H); 1.57–1.45 (m,
1H); 1.30 (d, 3H, JZ6.8 Hz); 1.26–1.24 (m, 2H); 0.97 (m,
6H). 13C NMR (400 MHz, CDCl3): d 164.63, 148.52,
145.08, 138.41, 134.70, 132.88, 132.67, 128.67, 127.85
(!2), 124.87 (!3), 61.77, 61.10, 52.83, 48.86, 45.60,
44.12, 40.69, 29.64, 29.00, 27.80, 26.14, 19.93, 18.34,
15.92, 15.39, 14.95. ESI-MS (m/z, %): 533 (MCC1,
100%).
Acknowledgements
Similarly the diastereoisomer (1R,2S)-1b was synthesized
from (1R,2S)-8b in yield of 66.0% as white foam. [a]2D0Z
C17.9 (cZ0.7, CHCl3). H NMR (300 MHz, CDCl3): d
Financial supports from Shanghai Municipal Committee of
Science and Technology (02QB14056 and 03DZ19219) and
the Chinese Academy of Sciences (STZ-01-27 and KSCX1-
SW-11) were greatly appreciated.
1
8.17 (d, 2H, JZ6.0 Hz); 7.55 (d, 2H, JZ7.8 Hz); 7.34 (d,
2H, JZ7.8 Hz); 7.00 (d, 1H, JZ6.0 Hz); 4.80–4.70 (m,
1H); 4.31 (q, 1H, JZ6.0 Hz); 3.40–3.34 (m, 1H); 3.02–2.80
(m, 3H); 2.69–2.61 (m, 2H); 2.51–2.49 (m, 1H); 2.43 (d, 3H,
JZ18.0 Hz); 2.34–2.20 (m, 4H); 2.23 (d, 3H, JZ18.0 Hz);
2.10–1.99 (m, 2H); 1.81–1.74 (m, 1H); 1.47–1.38 (m, 2H),
1.38 (d, 3H, JZ6.0 Hz); 1.00–0.96 (m, 3H); 0.92 (d, 3H,
JZ6.9 Hz). 13C NMR (400 MHz, CDCl3): d 164.60,
145.90, 145.01, 138.36, 134.67, 132.74, 128.96, 128.13
(!2), 125.48, 124.93, 124.78, 122.78, 61.60, 60.29, 54.62,
47.54, 45.40, 44.55, 40.54, 29.60, 28.40, 27.20, 26.24,
19.80, 18.29, 17.14, 15.34, 14.90. IR (film): 3421, 2960,
2869, 1639, 1450, 1326, 1122 cmK1. ESI-MS (m/z, %): 533
(MCC1, 100%). HR-ESIMS calcd for C29H39O2N4F3CH:
533.3103, found: 533.3098.
References and notes
1. For a review on chemokines and chemokine receptors, see
Cascieri, M. A.; Springer, M. S. Curr. Opin. Chem. Biol. 2000,
4, 420–427.
2. Liu, R.; Paxton, W. A.; Choe, S.; Ceradini, D.; Martin, S. R.;
Horuk, R.; MacDonald, M. E.; Stuhlmann, H.; Koup, R. A.;
Landau, N. R. Cell 1996, 86, 367–377.
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Today 2000, 5, 183–194. (b) Schwarz, M. K.; Wells, T. N. C.
Nat. Rev. Drug Discov. 2002, 1, 347–358.
4.1.19. (4-{3-Benzyl-4-[1-(4-trifluoromethyl-phenyl)-
ethyl]-piperazin-1-yl}-piperidin-1-yl)-(2,4-dimethyl-1-
oxy-pyridin-3-yl)-methanone (1c). Prepared from the
crude piperidine 8c analogously to 1a. The residue was
purified by chromatography using CH2Cl2/CH3OH (30:1) to
give the compound 1c (0.305 g, three steps in yield of
4. For a review on small molecule antagonists of CCR5 as HIV-1
inhibitors, see Kazmierski, W.; Bifulco, N.; Yang, H.; Boone,
L.; DeAnda, F.; Watson, C.; Kenakin, T. Bioorg. Med. Chem.
2003, 11, 2663–2676.
5. Borman, S. Promising Drugs. In Chemical and Engineering
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1
54.0%) as white foam. [a]2D0ZC6.1 (cZ0.9, CHCl3). H
6. 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, 3343–3346 and references cited
therein.
NMR (400 MHz, CDCl3): d 8.17 (d, 1H, JZ6.4 Hz); 7.57
(d, 2H, JZ8.0 Hz); 7.52 (d, 2H, JZ8.4 Hz); 7.34–7.29 (m,
2H); 7.25–7.17 (m, 3H); 7.18 (t, 2H, JZ7.6 Hz); 4.77 (t, 1H,
JZ13.6 Hz); 3.98–3.96 (m, 1H); 3.36 (d, 1H, JZ9.6 Hz);
3.26–3.24 (m,1H); 3.02–2.80 (m, 4H); 2.51–2.32 (m, 7H);
2.42 (d, 3H, JZ22.4 Hz); 2.22 (d, 3H, JZ24.4 Hz); 1.97–
1.92 (m, 1H); 1.84 (s, 1H); 1.74–1.71 (m, 1H); 1.41 (d, 3H,
JZ6.4 Hz); 1.46–1.40 (m, 1H). 13C NMR (400 MHz,
CDCl3): d 164.57, 149.97, 144.99, 140.11, 138.34, 134.69,
132.78, 129.08 (!2), 128.78, 128.41 (!2), 127.59 (!2),
125.96, 125.53, 125.17, 124.93, 124.77, 122.82, 61.27,
58.67, 56.68, 49.63, 45.57, 45.03, 40.74, 29.50, 28.44,
27.90, 18.27, 15.30, 14.88. IR (KBr): 3423, 2926 (m),
1637, 1450, 1325, 1283, 1161, 1121, 1067, 845, 744,
702 cmK1. ESI-MS (m/z, %): 581 (MCC1, 100%).
HREI-MS calcd for C33H39N4O2F3CH: 581.3103, found
581.3110.
7. Tagat, J. R.; McCombie, S. W.; Steensma, R. W.; Lin, S.-I.;
Nazareno, D. V.; Baroudy, B. M.; Vantuno, N.; Xu, S.; Liu, J.
Bioorg. Med. Chem. Lett. 2001, 11, 2143–2146.
8. Palani, A.; Shapiro, S.; Josien, H.; Bara, T.; Clader, J. W.;
Greenlee, W. J.; Cox, K.; Strizki, J. M.; Baroudy, B. M.
J. Med. Chem. 2002, 45, 3143–3160.
9. 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, 3137–3141.
10. Debnath, A. K. J. Med. Chem., 2003, 46, 4501–4515.
11. Lynch, C. L.; Hale, J. J.; Budhu, R. J.; Gentry, A. L.; Finke,

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