Reductive condensation between β-keto esters and aldehydes: Preparation of novel carbon-linked dihydropyrone inhibitors of hepatitis C virus polymerase

Article abstract of DOI:10.1055/s-0030-1258276

The route for the preparation of carbon-linked pyrone libraries involving an optimized one-step reductive condensation between active methylene compounds and aldehydes is described. The initial synthesis of these analogues utilizing conventional alkylatio

Full text of DOI:10.1055/s-0030-1258276

PAPER
4015
Reductive Condensation between b-Keto Esters and Aldehydes: Preparation
of Novel Carbon-Linked Dihydropyrone Inhibitors of Hepatitis C Virus
Polymerase
C
arbon-Linked Dihydr
a
opyrone In
r
hibitor
s
o
f
Hepatitis
C
V
irus Poly
A
merase ngelica Linton,* Javier Gonzalez, Hui Li, John Tatlock, Tanya Jewell, Sarah Johnson, Matt Drowns,
Leena Patel, Julie Blazel, Martha Ornelas
Pfizer Global Research & Development, 10770 Science Center Drive, San Diego, CA 92121, USA
Fax +1(858)6788156; E-mail: angelica.linton@pfizer.com
Received 9 July 2010; revised 31 August 2010
permeability. Experimental pKa measurements of the sul-
Abstract: The route for the preparation of carbon-linked pyrone li-
braries involving an optimized one-step reductive condensation be-
tween active methylene compounds and aldehydes is described. The
initial synthesis of these analogues utilizing conventional alkylation
fur-linked compounds were shown to have a pKa ~3–5 (2,
Figure 1, exp. pKa = 3.41), indicating that the compound
is isosterically similar to most carboxylic acids. In order
methods proved to be unsuitable for singleton or library application. to ensure cellular permeation, further modifications were
The chemistry was not only low-yielding but presented serious pu-
necessary to achieve desired potency in the cell-based rep-
rification challenges. The optimized route reported herein utilizes a
licon assay. Knowing that the enol moiety within the di-
Lewis base-borane complex that acts in situ first as a catalyst for the
hydropyrone central core was critical for enzyme potency,
condensation, then as a mild reducing agent to cleanly yield the de-
we envisioned a way to modulate the pKa by replacing the
sired product in a one-pot reaction.
sulfur with a methylene linker. The strategy towards low-
Key words: Knoevenagel condensation, C–C bond formation,
ering the ionization state of target molecules by reducing
HCV polymerase inhibitor, dihydropyrone, amine-borane reagents
the acidity of the pyrone in order to improve the perme-
ability of this series of compounds led to the discovery of
carbon-linked dihydropyrones (C-linked dihydropyrones,
Hepatitis C virus (HCV) continues to be a major public
Figure 1, e.g., compound 3, IC50 = 0.02 mM, EC50 = 0.33
health problem worldwide.1 Although this area of re-
mM). The experimental pKa of these carbon-linked com-
search has been the subject of intensive investigation for
the past 20 years, these efforts have yielded relatively few
pounds was ~5–6 (e.g., compound 3, Figure 1, pKa = 6).
marketed drugs, each with their own liabilities. There is
C pocket
an ongoing need for new therapies utilizing alternate
mechanistic approaches.2
OH
B pocket
S
Development of HCV NS5B polymerase inhibitors, par-
ticularly those which bind to allosteric sites, has gained in-
O
O
NH2
creasing interest.3 We have reported previously the
identification of a novel class of non-nucleoside HCV
NS5B polymerase inhibitors from high-throughput
screening (Figure 1, compound 1, IC50 = 0.93 mM, geno-
type 1b).4 Moreover, we described how our team was able
to achieve low nanomolar activity in an enzymatic assay
against the truncated genotype 1b HCV NS5B D21 poly-
merase with sulfur-linked dihydropyrone analogues (S-
linked dihydropyrones, Figure 1, e.g., compound 2,
IC50 = 0.04 mM and EC50 = 3.25 mM).4,5 This class of
compounds, although potent in the enzymatic assay (IC50)
only demonstrated moderate antiviral activity in the cell-
based replicon assay (EC50) at micromolar concentrations.
Additionally the S-linked analogue demonstrated poor ab-
sorption after oral dosing (2.5% absorbed) in rat pharma-
cokinetic evaluation.6
HO
A pocket
1
OH
S
N
N
N
O
O
N
MeO
Cl
2
OH
N
N
N
It was reasoned that the acidity of the dihydropyrone was
responsible for the large EC50/IC50 ratio due to poor cell
O
O
N
MeO
Cl
3
SYNTHESIS 2010, No. 23, pp 4015–4020
Advanced online publication: 30.09.2010
x
x.
x
x
.
2
0
1
0
Figure 1 Progression of dihydropyrones as HCV polymerase inhi-
bitors
DOI: 10.1055/s-0030-1258276; Art ID: M05010SS
© Georg Thieme Verlag Stuttgart · New York

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M. A. Linton et al.
PAPER
Although the chemistry to obtain the S-linked analogues ous reduction of the resultant benzylidene Meldrum’s acid
proved to be straightforward and was suitable for library has been reported.10
production,5 the preparation of the C-linked analogues
Hrubowchak and Smith were able to induce a reductive
demonstrated to be quite challenging (Scheme 1). The
alkylation of Meldrum’s acid using a dimethylamine-
carbon-linked C fragment analogues were originally pre-
borane complex.11 Additionally, Feeney and co-workers
pared from 4, employing an enolate formation under basic
utilized amine-borane complexes for the reductive meth-
conditions followed by nucleophilic displacement of het-
ylation of amino groups in several proteins, concluding
erobenzylic and other alkyl halides under Finkelstein con-
that dimethylaminoborane is a slightly weaker reducing
ditions. However, these reactions were very low yielding
agent compared to sodium cyanoborohydride although
(0–20%), and separation of the desired product from the
less toxic.12 In a comparison that included the various bo-
undesired O-alkylated and bis-alkylated side products
rane complexes, pyridine-borane was found to be slightly
was inefficient.
stronger than sodium cyanoborohydride.
A safe, easy to handle and mild reducing agent to perform
under neutral conditions, selective towards functionalities
R3
that could be present in our complex scaffold such as es-
O
O
O
O
ters, nitriles, olefins, etc., as well as applicable to library
production and large-scale manufacturing was desired.
After careful examination of the physical and chemical
properties of the commercially available amine-borane re-
agents we decided to investigate the reaction with dimeth-
ylaminoborane.13 The reagent has a reasonable thermal
stability, is soluble in water and a variety of other
solvents14 and can be hydrolyzed via acidic aqueous ex-
traction all of which make it suitable for synthetic proce-
dures. Dimethylaminoborane can also be stored at
ambient temperature for long periods of time without sig-
nificant deterioration.15 To our satisfaction, the novel
method involving the reductive alkylation of intermediate
4 with commercially available aldehydes in the presence
of dimethylaminoborane (BH3·NHMe2) complex, result-
ed in exclusive carbon alkylation in 30–70% yields.
Hence, the scope of the reaction was explored further.
R1
R2
O
O
i
R1
R2
5
4
Scheme 1 Preparation of carbon-linked pyrones via alkylation un-
der basic conditions. Reagents and conditions: (i) XCH2R3, NaI,
Na2CO3, H2O–DME (1:1), 80 °C, 5 h, yield: 0–20%.
The main objective as described in this paper was to de-
velop a simple, safe, environmentally friendly, and inex-
pensive procedure for the synthesis of the C-linked
dihydropyrones.
The reaction of active methylene compounds with alde-
hydes in the presence of chlorotrimethylsilane/sodium io-
dide/acetonitrile reagent has been previously reported.7
Although the reaction worked well with aryl aldehydes,
use of aliphatic primary aldehydes or isobutyraldehyde af-
forded alkylidenation products or dihydrofurans. Jursic
and Stevens reported a very efficient two-step preparative
procedure for the synthesis of 5-alkyl and 5-benzylbarbi-
turic acids derivatives via the reduction of alkylidine in-
termediates with zinc in acetic acid.8 It has also been
reported that the condensation of barbituric acid deriva-
tives with aromatic aldehydes is a simple and straightfor-
ward procedure.9 The reaction of aryl aldehydes with
Meldrum’s acid in the presence of formic acid and trieth-
ylammonium formate (TEAF) followed by the spontane-
Our initial study focused first on the reactivity of dihydro-
pyrones towards various aldehydes with the A and B frag-
ments fixed as a cyclopentane and as a 4-isopropoxy-3-
chlorophenyl, respectively (Compound 6a, Scheme 2).16
The first screening tested the initial reaction conditions
between the dihydropyrone 6a (R1 = i-Pr) and four ali-
phatic aldehydes and one ketone (Table 1). The best
yields were obtained by mixing stoichiometric amounts of
the two reactants and the borane complex in a 3:1
CH2Cl2–MeOH solution (0.5 M final concentration) and
stirring together at room temperature overnight. Use of
C pocket
R2
R3
O
B fragment
B pocket
O
O
O
O
O
i
R1O
R1O
Cl
6a
Cl
A pocket
7
A fragment
R1 = i-Pr
R1 = i-Pr
Scheme 2 Reductive condensation of 6-{2-[3-chloro-4-(propan-2-yloxy)phenyl]ethyl}-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (6a,
R1 = i-Pr) with alkyl aldehydes and a ketone. Reagents and conditions: (i) R2R3CO, BH3·NHMe2, CH2Cl2–MeOH (3:1).
Synthesis 2010, No. 23, 4015–4020 © Thieme Stuttgart · New York

PAPER
Carbon-Linked Dihydropyrone Inhibitors of Hepatitis C Virus Polymerase
4017
an additional 16 hours at room temperature, followed by
an acidic quench to pH 3 to destroy any residual borane.
Table 1 Reductive Condensation of Active Methylene Dihydropy-
rone 6a (R1 = i-Pr) with Alkyl Aldehydes and a Ketone
In another experiment, pyrones 6a (R = i-Pr) and 6b (R =
Me) were combined with several aryl aldehydes
(Table 2). Results indicated that the best yields were ob-
tained when the temperature was raised to 40 °C after ad-
dition of the borane reagent. Heating above 40 °C was
found to be detrimental to the reaction. Maintaining a
slightly elevated, but still mild temperature helped to op-
timize the reaction with aryl aldehydes.
Entry
R2
R3
H
Product
7a
Yield (%)a
1
2
3
4
5
H
50
40
49
50
30
Me
Et
H
7b
H
7c
i-Pr
Me
H
7d
Me
7e
Next, the stability of various functional groups on the B
pocket substituent under this reaction conditions was ex-
plored (Scheme 3). We selected the most potent C frag-
a The compounds were purified by preparative HPLC.
ment:
5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-
Table 2 Reductive Condensation of Active Methylene Dihydropy-
rones 6a (R1 = i-Pr) and 6b (R1 = Me) with Alkyl Aldehydes and Ke-
tones
carbaldehyde, based on the replicon based assay (EC50)6
and combined it with dihydropyrones incorporating a
large variety of functional groups at the B pockets substit-
uent. An array containing ethers, ketones, esters, acetals,
nitriles, alcohols, and amines is shown in Table 3 indicat-
ing that the reaction conditions are quite mild and are
compatible with various functionalities.
R2
O
O
O
R1
O
Cl
8
N
N
N
Entry
1
R1
R2
Product Yield (%)
H
O
N
N
N
O
O
O
O
Me
N
N
O
i-Pr
N
8a
8b
60
55
O
Ar
i
Ar
N
10
Me
9
N
N
2
Me
Scheme 3 Reductive condensation of aryl-6-cyclopentyldihydropy-
ran-2,4-diones 9 with 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-
2-carbaldehyde. Reagents and conditions: (i) BH3·NH Me2, CH2Cl2–
MeOH (3:1), 35–40 °C.
Cl
Me
N
3
4
Me
Me
8c
63
57
Table 3 Reductive Condensation of Aryl-6-cyclopentyldihydropy-
ran-2,4-diones 9
N
CN
Entry
Ar
Product
Yield (%)
8d
O
1
10a
35
5
6
Me
8e
8f
50
40
N
N
N
HO
OMe
N
N
N
2
10b
37
O
O
O
N
i-Pr
Cl
N
3
4
10c
10d
57
42
MeO
HO
CH2Cl2 as a co-solvent was necessary owing to the poor
solubility of the pyrone in pure methanol. Experiments
were performed to determine the optimal order of addi-
tion. Results indicated that the best yields were obtained
from stirring the reactants together overnight at room tem-
perature, then adding the borane complex and stirring for
F
Cl
Synthesis 2010, No. 23, 4015–4020 © Thieme Stuttgart · New York

4018
M. A. Linton et al.
PAPER
1H NMR (DMSO-d6): d = 1.14 (d, J = 6.30 Hz, 6 H), 1.40–1.53 (m,
8 H), 1.70–1.75 (m, 2 H), 1.95–1.98 (m, 1 H), 2.35–2.44 (m, 8 H),
3.19 (s, 2 H), 3.57 (d, J = 16 Hz, 1 H), 3.69 (d, J = 16 Hz, 1 H),
4.41–4.47 (m, 1 H), 6.91–6.93 (s, 1 H), 7.00–7.07 (m, 2 H), 7.10 (d,
J = 2.00 Hz, 1 H), 10.70 (br s, 1 H).
Table 3 Reductive Condensation of Aryl-6-cyclopentyldihydropy-
ran-2,4-diones 9 (continued)
Entry
5
Ar
Product
Yield (%)
20
MS (ESI): m/z = 540.2 [M + H]+.
10e
N
S
OMe
Anal. Calcd for C29H35N4O4: C, 64.61; H, 6.54; N, 10.39. Found: C,
64.30; H, 6.81; N, 10.35.
Targeted Library Protocol for the Reductive Condensation Re-
action between Active Methylene Compounds with Aldehydes;
General Procedure
6
7
8
10f
10g
10h
66
60
35
HN
O
O
The reactions were carried out in 10 × 75 mm test tubes, each
equipped with a 3 × 6 mm stir bar. Solutions of pyrone 917 were pre-
pared in CH2Cl2 (0.2 M, reactant A). Solutions of the aldehydes
were prepared in MeOH (0.1 M, reactant B, which should be freshly
prepared before use). A solution of Me2NH·BH3 (dimethylamino-
borane reagent) in MeOH (1.0 M) and a 1 M solution of aq HCl
were also prepared. Using an Eppendorf pipette reactant A (400 mL,
0.08 mmol) was placed into the appropriate test tubes. The tubes
were placed in a SpeedVacTM and the CH2Cl2 was evaporated in
vacuo for 2 h. The reactant A in the tubes was the reconstituted with
MeOH (400 mL). Using a Rainin pipette, reactant B (840 mL, 0.08
mmol, 1.05 equiv) was delivered in the appropriate tubes. The tubes
were then placed in an AlasynTM block and the reaction mixtures
were heated at 40 °C and stirred for 16 h. Using a Rainin pipette, the
borane reagent solution (84 mL, 0.08 mmol, 1.05 equiv) was deliv-
ered to the tubes and once again the tubes were placed in the
AlasynTM block and the reaction mixtures were heated at 40 °C and
stirred for an additional 16 h. 1 M aq HCl (125 mL) was delivered to
each of the tubes and they were stirred/shaken for 20 min at r.t. The
volatiles were removed in vacuo using the Speed-Vac.TM The resid-
ual of the tubes was dissolved in DMSO (1.340 mL) and purified by
preparative HPLC.
NC
Cl
O
O
N
It is worth noting that the preformed alkylidine intermedi-
ates studied in this investigation were not reduced by the
addition of dimethylaminoborane.
In conclusion, we have demonstrated that the preparation
of carbon-linked pyrone analogues can be achieved utiliz-
ing a one-step reductive condensation between active
methylene compounds and alkyl and aryl aldehydes em-
ploying dimethylaminoborane reagent, which acts first as
a catalyst of the Knovenagel condensation then as a mild
reducing agent to produce a clean desired product in one
pot. This chemistry was used for the preparation of single
compounds or the parallel synthesis of compound librar-
ies, as well as enabling the preparation of kilogram-scale
batches for animal studies.17
6-{2-[3-Chloro-4-(propan-2-yloxy)phenyl]ethyl}-6-cyclopentyl-
4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one (7a)
1H NMR (400 MHz, CDCl3): d = 7.10–7.20 (m, 1 H), 6.90–7.02 (m,
1 H), 6.74–6.90 (m, 1 H), 4.28–4.61 (m, 1 H), 2.96–3.44 (m, 1 H),
2.39–2.81 (m, 4 H), 1.43–2.36 (m, 12 H), 1.32–1.39 (m, 6 H), 1.02–
1.15 (m, 2 H).
MS (APCI): m/z = 393.30 [M + H]+.
All reactions were performed in septum-sealed flasks under a slight
positive pressure of argon unless otherwise noted. All starting ma-
terials and chemical reagents were purchased from commercial sup-
pliers and used without further purification, unless otherwise
6-{2-[3-Chloro-4-(propan-2-yloxy)phenyl]ethyl}-6-cyclopentyl-
3-ethyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one (7b)
1H NMR (400 MHz, CDCl3): d = 0.87–1.03 (m, 3 H), 1.35 (s, 3 H),
1.37 (s, 3 H), 1.39–2.43 (m, 13 H), 2.49–2.86 (m, 4 H), 3.12–3.30
(m, 1 H), 4.40–4.62 (m, 1 H), 6.86 (d, J = 8.59 Hz, 1 H), 6.92–6.99
(m, 1 H), 7.14 (s, 1 H).
1
indicated. H NMR spectra were recorded on a Bruker instrument
operating at 300 MHz or 400 MHz and are obtained as DMSO-d6 or
CDCl3 solutions (reported in ppm), using CDCl3 as the reference
standard (7.26 ppm) or DMSO-d6 (2.49 ppm). Other NMR solvents
were used as needed. The mass spectra were obtained using LC/MS
or APCI. The inhibitors were prepared as racemates.
MS (APCI): m/z = 407.20 [M + H]+.
6-{2-[3-Chloro-4-(propan-2-yloxy)phenyl]ethyl}-6-cyclopentyl-
4-hydroxy-3-propyl-5,6-dihydro-2H-pyran-2-one (7c)
1H NMR (400 MHz, CDCl3): d = 0.91–0.99 (m, 22 H), 1.33–1.39
(m, 6 H), 3.12–3.29 (m, 1 H) 4.45–4.56 (m, 1 H), 6.81–6.92 (m, 1
H), 6.93–7.06 (m, 1 H), 7.08–7.23 (m, 1 H).
Reductive Condensation Reaction between Active Methylene
Compounds with Aldehydes; Compound 8f; Typical Procedure
5,7-Dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde17
(0.39 g, 2.20 mmol) was added to a solution of 6-{2-[3-chloro-4-
(propan-2-yloxy)phenyl]ethyl}-6-cyclopentyldihydro-2H-pyran-
2,4(3H)-dione (6a;16 0.71 g, 1.87 mmol) in MeOH–CH2Cl2 (3:1, 4
mL). The reaction mixture was stirred for 15 hours at r.t. and then
treated with BH3·NHMe2 (0.13 g, 2.20 mmol) and the temperature
was increased to 40 °C. After 15 h, the reaction mixture was
quenched with 1 N aq HCl (4 mL) and extracted with CH2Cl2 con-
taining 10% MeOH (2 × 50 mL). The combined organic layers were
concentrated and purified by preparative HPLC to give the title
compound as a white solid; yield: 0.40 g (40%).
MS (APCI): m/z = 421.20 [M + H]+.
6-{2-[3-Chloro-4-(propan-2-yloxy)phenyl]ethyl}-6-cyclopentyl-
4-hydroxy-3-(2-methylpropyl)-5,6-dihydro-2H-pyran-2-one
(7d)
1H NMR (400 MHz, CDCl3): d = 0.86–1.03 (m, 6 H), 1.34–1.41 (m,
6 H), 1.42–3.29 (m, 19 H) 4.46–4.56 (m, 1 H), 6.82–6.92 (m, 1 H),
6.93–6.99 (m, 1 H), 7.08–7.24 (m, 1 H).
MS (APCI): m/z = 435.30 [M + H]+.
Synthesis 2010, No. 23, 4015–4020 © Thieme Stuttgart · New York

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Carbon-Linked Dihydropyrone Inhibitors of Hepatitis C Virus Polymerase
4019
6-{2-[3-Chloro-4-(propan-2-yloxy)phenyl]ethyl}-6-cyclopentyl-
4-hydroxy-3-(propan-2-yl)-5,6-dihydro-2H-pyran-2-one (7e)
1H NMR (400 MHz, CDCl3): d = 6.64–7.26 (m, 3 H), 4.41–4.60 (m,
1 H), 3.00–3.25 (m, 1 H), 1.48–2.87 (m, 15 H), 1.29–1.40 (m, 6 H),
1.02–1.19 (m, 6 H).
6-[2-(5-Acetyl-4-hydroxy-2-methoxyphenyl)ethyl]-6-cyclopen-
tyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)meth-
yl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one (10a)
1H NMR (300 MHz, DMSO-d6): d = 1.34–1.66 (m, 8 H), 1.80–2.06
(m, 3 H), 2.32–2.49 (m, 12 H), 2.65 (d, J = 17 Hz, 1 H), 3.57–3.72
(m, 6 H), 6.31 (s, 1 H), 6.90 (s, 1 H), 7.46 (s, 1 H), 12.52 (s, 1 H).
MS (APCI): m/z = 421.40 [M + H]+.
MS (ESI): m/z = 535.20 [M + H]+.
6-{2-[3-Chloro-4-(propan-2-yloxy)phenyl]ethyl}-6-cyclopentyl-
4-hydroxy-3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-5,6-di-
hydro-2H-pyran-2-one (8a)
Anal. Calcd For C29H34N4O6·0.25H2O: C, 64.61; H, 6.45; N, 10.39.
Found: C, 64.57; H, 6.39; N, 10.22.
1H NMR (DMSO-d6): d = 0.90–1.36 (m, 14 H), 1.54–1.61 (m, 2 H),
2.20–2.39 (m, 3 H), 2.57–2.73 (m, 4 H), 4.10 (s, 3 H), 4.44–4.49 (m,
1 H), 6.49–6.48 (m, 7 H), 13.50 (br s, 1 H).
6-{2-[3-Chloro-4-(2-methyl-1,3-dioxolan-2-yl)phenyl]ethyl}-6-
cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-
yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one (10b)
1H NMR (400 MHz, DMSO-d6): d = 1.50–1.70 (m, 9 H), 2.20–2.22
(m, 2 H), 2.49–2.90 (m, 10 H), 3.39 (s, 3 H), 3.70–3.74 (m, 2 H),
3.78 (d, J = 16 Hz, 1 H), 3.90 (d, J = 16 Hz, 1 H), 4.04–4.07 (m, 2
H), 7.13 (s, 1 H), 7.32 (s, 1 H), 7.36 (d, J = 8 Hz, 1 H), 7.61 (d, J = 8
Hz, 1 H), 10.90 (s, 1 H).
MS (ESI): m/z = 524.20 [M + H]+.
Anal. Calcd for C30H35ClN4O4: C, 68.89; H, 6.74; N, 5.36. Found:
C, 69.11; H, 6.73; N, 5.36.
6-[2-(3-Chloro-4-methoxyphenyl)ethyl]-3-[(4-chloro-1-methyl-
1H-pyrazol-3-yl)methyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-
2H-pyran-2-one (8b)
MS (ESI): m/z = 567.20 [M + H]+.
Anal. Calcd for C30H35ClN4O5: C, 63.54; H, 6.22; N, 9.88. Found:
C, 63.27; H, 6.27; N, 9.56.
1H NMR (DMSO-d6): d = 1.50–1.71 (m, 8 H), 2.01–2.05 (m, 2 H),
2.39–2.41 (m, 1 H), 2.49–2.57 (m, 2 H), 2.74 (d, J = 16 Hz, 1 H),
3.18 (d, J = 5.30 Hz, 1 H), 3.39 (d, J = 16.00 Hz, 1 H), 3.47 (d,
J = 16 Hz, 1 H), 3.60 (s, 3 H), 3.83 (s, 3 H), 7.05 (d, J = 8.30 Hz, 1
H), 7.11 (dd, J = 8.30, 2.00 Hz, 1 H), 7.23 (d, J = 2.00 Hz, 1 H), 7.76
(s, 1 H), 10.64 (s, 1 H).
Methyl 4-(2-{2-Cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-
a]pyrimidin-2-yl)methyl]-4,6-dioxotetrahydro-2H-pyran-2-
yl}ethyl)-2-fluorobenzoate (10c)
1H NMR (300 MHz, CDCl3): d = 1.25–1.85 (m, 8 H), 2.01–1.10 (m,
3 H), 2.58–2.80 (m, 10 H), 3.10 (t, J = 12.57 Hz, 1 H), 3.88 (s, 3 H),
6.91 (d, J = 2.57 Hz, 1 H), 6.99 (s, 1 H), 7.15 (d, J = 1.58 Hz, 1 H),
7.92 (m, H).
MS (ESI): m/z = 479.20 [M + H]+.
Anal. Calcd for C24H28Cl2N2O4: C, 60.13; H, 5.89; N, 5.84. Found:
C, 59.94; H, 5.95; N, 5.69.
MS (ESI): m/z = 523.20 [M + H]+.
6-[2-(3-Chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-[(1-
methyl-1H-imidazol-2-yl)methyl]dihydro-2H-pyran-2,4(3H)-
dione (8c)
Anal. Calcd for C28H31FN4O5: C, 64.36; H, 5.98; N, 10.72. Found:
C, 64.50; H, 5.40; N, 10.70.
1H NMR (CDCl3): d = 1.44– 1.70 (br m, 8 H), 2.00 (m, 2 H), 2.20
(m, 3 H), 2.30 (m, 2 H), 2.99 (m, 2 H), 3.01 (m, 2 H), 3.46 (s, 3 H),
3.78 (m, 1 H), 3.89 (s, 3 H), 6.72 (d, J = 2.15 Hz, 1 H), 6.83, (d,
J = 2.15 Hz, 1 H), 6.90 (s, 1 H), 7.14 (d, J = 3.07 Hz, 1 H), 7.24 (d,
J = 3.06 Hz, 1 H).
6-{2-[3-Chloro-4-(2-hydroxypropan-2-yl)phenyl]ethyl}-6-cy-
clopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-
yl)methyl]-4-hydroxytetrahydro-2H-pyran-2-one (10d)
1H NMR (300 MHz, CDCl3): d = 1.55 (s, 1 H), 1.64–1.71 (m, 12 H),
1.94–2.03 (m, 2 H), 2.30–2.43 (m, 2 H), 2.50 (d, J = 17.90 Hz, 2 H),
2.58–2.64 (m, 2 H), 2.64–2.72 (m, 5 H), 2.78 (s, 3 H), 4.07 (s, 2 H),
6.83 (s, 1 H), 6.98–7.04 (m, 1 H), 7.11 (d, J = 1.13 Hz, 1 H), 7.50
(d, J = 8.10 Hz, 1 H).
MS (ESI): m/z = 445.20 [M + H]+.
Anal. Calcd for C25H31ClN2O3: C, 67.78; H, 7.05; N, 6.32. Found:
C, 67.48; H, 7.25; N, 6.37.
MS (ESI): m/z = 561.00 [M + Na]+.
3-({6-[2-(3-Chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hy-
droxy-2-oxo-5,6-dihydro-2H-pyran-3-yl}methyl)benzonitrile
(8d)
Anal. Calcd for C29H35ClN4O4·1.5AcOH: C, 61.09; H, 6.57; N,
8.91. Found: C, 61.22; H, 6.50; N, 8.65.
1H NMR (CDCl3): d = 1.43–1.86 (br m, 8 H), 2.02 (m, 2 H), 2.29
(m, 1 H), 2.44–3.02 (m, 7 H), 3.95 (s, 3 H), 6.88–7.91 (m, 7 H).
6-Cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-
2-yl)methyl]-6-[2-(2-ethyl-5-methoxypyridin-4-yl)ethyl]-4-hy-
droxy-5,6-dihydro-2H-pyran-2-one (10e)
MS (ESI): m/z = 511.20 [M + H]+.
1H NMR (400 MHz, DMSO-d6): d = 0.94 (t, J = 7.58 Hz, 3 H),
1.19–1.53 (m, 8 H), 1.83 (m, 1 H), 1.91 (m, 1 H), 2.20 (m, 4 H),
2.29–2.37 (m, 6 H), 2.43 (q, J = 7.58 Hz, 2 H), 2.59 (d, J = 17.2 Hz,
1 H), 3.50 (d, J = 16.2 Hz, 1 H), 3.56 (s, 3 H), 3.61 (d, J = 16.2 Hz,
1 H), 6.83 (s, 1 H), 6.85 (s, 1 H), 7.88 (s, 1 H), 10.82 (s, 1 H).
Anal. Calcd for C27H28ClNO4: C, 69.59; H, 6.06; N, 3.01. Found: C,
69.67; H, 6.14; N, 3.13.
6-[2-(3-Chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-3-[(5,7-
dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hy-
droxy-5,6-dihydro-2H-pyran-2-one (8e)
MS (ESI): m/z = 506.20 [M + H]+.
1H NMR (CDCl3): d = 1.37–1.85 (br m, 8 H), 1.98 (m, 2 H), 2.37
(m, 1 H), 2.49–2.80 (m, 11 H), 3.86 (s, 3 H), 4.05 (d, J = 15.60 Hz,
1 H), 4.12 (d, J = 15.60 Hz, 1 H), 6.81 (d, J = 8.60 Hz, 1 H), 6.85 (s,
1 H), 7.00 (d, J = 8.60 Hz, 1 H), 7.12 (s, 1 H).
Anal. Calcd for C28H35N5O4×0.5AcOH: C, 65.03; H, 6.96; N, 13.08.
Found: C, 65.15; H,7.05; N, 12.79.
N-{(1R)-1-[4-(2-{2-Cyclopentyl-5-[(5,7 dimethyl[1,2,4]triazo-
lo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-
2H-pyran-2-yl}ethyl)phenyl]ethyl}ethanesulfonamide (10f)
1H NMR (300 MHz, DMSO-d6): d = 1.07 (t, J = 7.30 Hz, 3 H), 1.40
(d, J = 6.90 Hz, 3 H), 1.50–1.80 (m, 9 H), 2.11–2.16 (m, 2 H), 2.48–
2.59 (m, 7 H), 2.78–2.83 (m, 3 H), 3.71 (d, J = 16 Hz, 1 H), 3.85 (d,
MS (ESI): m/z = 466.20 [M + H]+.
Anal. Calcd for C27H31ClN4O4: C, 63.46; H, 6.11; N, 10.96. Found:
C, 63.23; H, 6.27; N, 10.74.
Synthesis 2010, No. 23, 4015–4020 © Thieme Stuttgart · New York

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M. A. Linton et al.
PAPER
J = 16 Hz, 1 H), 4.03 (t, J = 14, 7.30 Hz, 2 H), 4.39–4.45 (m, 1 H),
7.06 (s, 1 H), 7.21–7.31 (m, 4 H), 7.66 (d, J = 8.30 Hz, 1 H), 10.90
(s, 1 H).
MS (ESI): m/z = 582.20 [M + H]+.
References
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No. 164: http://www.who.int/mediacentre/factsheets/fs164/
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Dragovich, P.; Jewell, T.; Prins, T.; Zhou, R.; Blazel, J.;
Parge, H.; Love, R.; Hickey, M.; Doan, C.; Shi, S.; Duggal,
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Jewell, T.; Prins, T.; Zhou, R.; Blazel, J.; Ornelas, M.;
Truesdale, L.; Moore, M.; Rahavendran, S. V.; Parge, H.;
Love, R.; Hickey, M.; Doan, C.; Shi, S.; Duggal, R.; Lewis,
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Document in preparation.
Anal. Calcd for C30H39N5O5S: C, 61.94; H, 6.76; N, 12.04. Found:
C, 61.80; H, 6.87; N, 12.20.
2-[2-Chloro-4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazo-
lo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-
2H-pyran-2-yl}ethyl)phenyl]-2-methylpropanenitrile (10g)
IR (neat): 2243, 2355, 1666, 1625, 1543, 1390 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.39–1.64 (m, 8 H), 1.67 (s, 6
H), 2.01–2.05 (m, 2 H), 2.36–2.46 (m, 7 H), 2.51–2.57 (m, 2 H),
2.69 (d, J = 17 Hz, 2 H), 3.61 (d, J = 16 Hz, 1 H), 3.72 (d, J = 16 Hz,
1 H), 6.94 (s, 1 H), 7.25 (s, 1 H), 7.28 (s, 1 H), 7.35 (d, J = 8 Hz, 1
H), 10.75 (s, 1 H).
MS (ESI): m/z = 548.20 [M + H]+.
(6) Li, H.; Linton, A.; Tatlock, J.; Gonzalez, J.; Borchardt, A.;
Abreo, M.; Jewell, T.; Patel, L.; Drowns, M.; Ludlum, S.;
Goble, M.; Yang, M.; Blazel, J.; Rahavendran, R.; Skor, H.;
Shi, S.; Lewis, C.; Fuhrman, S. J. Med. Chem. 2007, 50, 396.
(7) Sakai, T.; Miyata, K.; Tsuboi, S.; Utaka, M. Bull. Chem. Soc.
Jpn. 1989, 62, 4072.
(8) Jursic, B.; Stevens, E. Tetrahedron. Lett. 2003, 44, 2203.
(9) Jursic, B. S. J. Heterocycl. Chem. 2001, 38, 655.
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(11) Hrubowchak, D. M.; Smith, F. X. Tetrahedron Lett. 1983,
24, 4951.
Anal. Calcd for C30H34ClN5O3×1H2O: C, 63.65; H, 6.41; N, 12.37.
Found: C, 63.60; H, 6.30; N, 12.21.
6-Cyclopentyl-6-(2-{4-[(3,5-dimethylisoxazol-4 yl)meth-
oxy]phenyl}ethyl)-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimi-
din-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one (10h)
1H NMR (DMSO-d6): d = 1.39–1.72 (br m, 8 H), 2.19 (m, 2 H), 2.21
(s, 3 H), 2.39 (s, 3 H), 2.47–2.70 (m, 10 H), 2.81 (d, J = 17.50 Hz,
1 H), 3.71 (d, J = 16.10 Hz, 1 H), 3.85 (d, J = 16.20 Hz, 1 H), 7.04
(s, 1 H), 7.27 (d, J = 8.10 Hz, 2 H), 7.36 (d, J = 8.10 Hz, 2 H), 10.98
(s, 1 H).
(12) Cabacungan, J. C.; Ahmed, A. I.; Feeney, R. F. Anal.
Biochem. 1982, 124, 272.
MS (ESI): m/z = 570.20 [M + H]+.
Anal. Calcd for C31H35N5O4·0.6H2O: C, 67.39; H, 6.61; N, 12.68.
Found: C, 67.39; H, 6.52, N, 12.45.
(13) Weast, R. C.; Astle, M. J. CRC Handbook of Chemistry and
Physics, 62nd ed; CRC Press: Boca Raton, 1981.
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(15) Amine borane bulletin, Callery Chemical Company:
http://www.scribd.com/doc/30133102/
Acknowledgment
Boron%E2%80%93Nitrogen-Compounds-Organic.
(16) Gonzalez, J.; Jewell, T.; Li, H.; Linton, A.; Tatlock, J.,
(Pfizer Inc., USA), PCT Int. Appl. WO 2006018725, 2006.
(17) Camp, D.; Matthews, C. F.; Neville, S. T.; Rouns, M.; Scott,
R. W.; Truong, Y. Org. Process Res. Dev. 2006, 10, 814.
The authors would like to thank Dr. Martin Edwards, Dr. Robert
Kania, and Dr. Alex Guo for their support and helpful discussions.
We also thank Dr. William Farrell, Christy Aurigemma, Jack
Barrett, and Phuong Tran for their assistance in the HPLC purifica-
tion.
Synthesis 2010, No. 23, 4015–4020 © Thieme Stuttgart · New York