Chemoenzymatic asymmetric total synthesis of phosphodiesterase inhibitors: Preparation of a polycyclic pyrazolo[3,4-d]pyrimidine from an acylnitroso Diels-Alder cycloadduct-derived aminocyclopentenol

Article abstract of DOI:10.1021/jo0484070

(Chemical Equation Presented) Enzymatic resolution of Boc-protected 4-aminocyclopenten1-ol 4c gave both enantiomers 5c and 6c in high ee. Boc removal and separate condensation with chloropyrazolopyrimidine 18 provided elaborated 1,4-aminocyclopentenol derivatives 20 and 26, respectively. Separate treatment of 20 and 26 with Pd(0) under basic conditions induced cyclization to unsaturated polycycles 22 and 27, which, upon catalytic hydrogenation, were transformed to new cyclopentane-containing pyrazolopyrimidines 24 and 28, analogues of recently described novel phosphodiesterase inhibitors.

Full text of DOI:10.1021/jo0484070

SCHEME 1
Chemoenzymatic Asymmetric Total
Synthesis of Phosphodiesterase Inhibitors:
Preparation of a Polycyclic
Pyrazolo[3,4-d]pyrimidine from an
Acylnitroso Diels-Alder
Cycloadduct-Derived Aminocyclopentenol
May Xiao-Wu Jiang, Namal C. Warshakoon, and
Marvin J. Miller*
Department of Chemistry & Biochemistry, University of
Notre Dame, Notre Dame, Indiana 46556-5670
mmiller1@nd.edu
highlighted by several recent applications.6a,b,7 Deriva-
tives of acetate 6 are ideally suited for the introduction
of nucleophiles via palladium-mediated π-allyl chemis-
try.8 Here we report an application of enantiomerically
pure aminocyclopentenol 5 or 6 in the synthesis of
phosphodiesterase inhibitor analogues of recent interest.
Phosphodiesterases (PDE) are involved in cyclic nucleo-
tide regulation,9 and PDE inhibition as a target for
therapeutic intervention is of considerable interest.10
More specifically, the beneficial effects of inhibition of the
cGMP PDE for the treatment of cardiovascular diseases
have been notable.11 These biological properties resulted
in numerous research programs directed toward the
synthesis of PDE inhibitors and analogues thereof.12
Polycyclic guanine derivatives of the general type 7
(Figure 1) were found to be potent inhibitors of PDE1
and PDE5 in vitro and potent antihypertensive agents
in vivo.13 Polyclic pyrazolo[3,4-d] analogues of the type 8
and 9 have also been found to have similar activity.14 As
Received September 9, 2004
Enzymatic resolution of Boc-protected 4-aminocyclopenten-
1-ol 4c gave both enantiomers 5c and 6c in high ee. Boc
removal and separate condensation with chloropyrazolopy-
rimidine 18 provided elaborated 1,4-aminocyclopentenol
derivatives 20 and 26, respectively. Separate treatment of
20 and 26 with Pd(0) under basic conditions induced
cyclization to unsaturated polycycles 22 and 27, which, upon
catalytic hydrogenation, were transformed to new cyclopen-
tane-containing pyrazolopyrimidines 24 and 28, analogues
of recently described novel phosphodiesterase inhibitors.
(6) (a) Zhang, D.; Miller. M. J. J. Org. Chem. 1998, 63, 755. (b)
Zhang, D.; Su¨ling, C.; Miller. M. J. J. Org. Chem. 1998, 63, 885. (c)
Zhang, D.; Ghosh, A.; Su¨ling, C.; Miller, M. J. Tetrahedron Lett. 1996,
37, 3799.
Functionalized cyclopentane derivatives are major con-
stituents of many natural products and analogues,1 and
stereoselective syntheses of cyclopentane derivatives
have been especially important for the preparation of a
number of carbocyclic nucleosides.2 Functionalized ami-
nocyclopentenol derivatives are also potential aminogly-
cosidase inhibitors.1c,3 We have previously described an
efficient enzymatic resolution of 4-aminocyclopentol-1-
ol 44 derived from acylnitroso Diels-Alder adducts 35
(Scheme 1).
Using this process, both enantiomers of the Boc-pro-
tected 4-aminocyclopenten-1-ol 4 are available in optically
pure form by employing different enzymes. The synthetic
utility of related aminocyclopentenol derivatives has been
(7) Mulvihill, M. J.; Miller, M. J. Tetrahedron 1998, 54, 6605.
(8) (a) Trost, B. M.; Kuo. G,-H.; Benneche, T. J. Am. Chem. Soc.
1988, 110, 621. (b) Coe, D. M.; Hilpert, H.; Noble, S. A.; Peel, M. R.;
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M. R. J. Org. Chem. 1991, 56, 4990. (e) Trost, B. M.; Madsen, R.; Guile,
S. D.; Tetrahedron Lett. 1997, 38, 1707. (f) Trost, B. M.; Madsen, R.;
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Patents 1997, 7, 631.
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Chem., Int. Ed. Engl. 1982, 21, 480. (b) Olafsdottir, E. S.; Sørensen.
A. M.; Cornett, C.; Jaroszewski, J. W. J. Org. Chem. 1991, 56, 2650.
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Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571. (c)
Agrofolio, L.; Suhas, E.; Farese, A.; Condom, R.; Challend, S. R.; Earl,
R. A.; Guedj, R. Tetrahedron 1994, 50, 10611. (d) Crimmins, M. T.
Tetrahedron 1998, 54, 9229.
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1994, 59, 813. (b) King, S. B.; Ganem, B. J. J. Am. Chem. Soc. 1994,
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Buchholz, R. A.; van Aller, G.; Hamel, L. T.; Bacon, E.; Singh, B.;
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A. S.; Terret, N. K. EP 0 526 004 A1, 1993.
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alamannil, S.; Chow, J.; Cleven, R.; Cook, J.; Czarniecki, M.; Domalski,
C.; Fawzi, A.; Green, M,; Gu¨ndes, A.; Ho, G.; Laudicina, M.; Lindo,
N.; Ma, K.; Manna, M.; McKittrick, B.; Mirazai, B.; Nechuta, T.;
Neustadt, B.; Puchalski, C.; Pula, K.; Silverman, L.; Smith, A.;
Stamford, A.; Tedesco, R. P.; Tsai, H.; Tulshian, D.; Vaccaro, H.;
Watkins, R. W.; Weng, X.; Witkowski, J. T.; Xia, Y.; Zhang, H. J. Med.
Chem. 1997, 40, 2196.
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63, 3357.
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10.1021/jo0484070 CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/04/2005
2824
J. Org. Chem. 2005, 70, 2824-2827

SCHEME 3
FIGURE 1. Polycyclic guanine PDE inhibitors 7 and pyrazolo-
[3,4-d]pyrimidine analogues 8 and 9.
SCHEME 2
matographic separation, (-)-6c was determined to be
significantly optically enriched, the ee was improved from
81% to >90% with the use of the resin-bound enzyme
(ee was determined by hydrolysis of the acetate and acyl-
ation to give the corresponding Mosher ester as described
earlier4). A single recrystallization of 6c provided mul-
tigram amounts of (-)-6c in >98% ee. The chromato-
graphically separated alcohol was enriched in 5c and was
isolated in 35-45% yield. After a single recrystallization,
the compound was determined to be essentially optically
pure (>99% ee) by Mosher ester analysis.
Pyrazole 16 was prepared via a modified procedure
(Scheme 3).14 Condensation of ethyl cyanoacetate 14 with
triethyl orthoformate generated ethyl (ethoxyethylene)-
cyanoacetate 15, which was then converted to pyrazole
16 by treatment with benzylhydrazine. Condensation of
16 with phenyl isocyanate followed by base-promoted
cyclization formed intermediate 17. Compound 17 was
then converted to the desired chloride 18 by treatment
with phosphorus oxychloride.
shown in Scheme 2, we anticipated that related ana-
logues 10 could be prepared by Pd(0)-mediated cycliza-
tions of 12 to 11 followed by the reduction of the
remaining double bond. By using enzymatically resolved
compound 4, both enantiomers of 10 could be prepared
by similar methods.
Next, as shown in Scheme 4, enantiopure 5c was
converted to acetate 19. The Boc group was removed and
the resultant TFA salt of 19 was neutralized and
condensed with chloride 18 in the presence of triethyl-
amine to afford 20 in 96% yield. Our next task was to
perform the crucial palladium(0)-mediated cyclization
reaction. Gratifyingly, treatment of 20 with in situ
generated palladium(0) in THF induced formation of the
desired product, 22, under basic conditions (Table 1). It
was found that this reaction was sensitive to the base
used. When the relatively weak base NEt3 was used, the
reaction proceeded slowly, and after overnight, only 20%
of the starting material was consumed. When NaH was
used, the reaction was complete in 3 h and gave the
desired product in 79% yield. When the organic base
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-
1,3,2-diazaphosphorine, 21, was utilized, the cyclization
reaction gave the highest yield (94%) of product 22.
Compound 22 was then subjected to catalytic hydrogena-
tion. It was surprising to find that upon complete reaction
of 22, rather than the desired hydrogenated product 24,
the ring-opened product 23 was generated in 50% yield
as the only isolable product after the reaction was carried
out with Pd/C and H2. The structure of 23 was first
determined by extensive 1D and 2D NMR analysis. It
was further confirmed by synthesizing 23 through the
simple coupling reaction of cyclopentylamine 25 with
chloride 18 under conditions similar to those used to
prepare 20 (Scheme 5).
As indicated in Scheme 1, our previous publication
reported the enzymatic resolution of a number of N-
protected aminocyclopentenol 4 to provide either 5 or 6
in high ee.4 The starting material 4 for this resolution
was prepared through protection of hydroxylamine,
oxidation, and trapping of the transient nitroso interme-
diate with cyclopentadiene to produce (()-3 and N-O
bond reduction using substoichiometric (20 mol %) Mo-
(CO)6 and NaBH4 as we have also previously described.6
Although this method provided access to large amounts
of optically pure 5a and 6a, further elaboration of these
building blocks for the synthesis of complex carbocyclic
nucleosides and other highly functionalized cyclopentane-
containing compounds of interest often required the
exchange of the N-acetyl protecting group for one that
could be removed under milder conditions. Therefore, we
sought to improve the resolution of Boc-protected ami-
nocyclopentenol (()-4c which, using our reported meth-
odology,4 gave acetate (-)-6c in 81% ee (without recrys-
tallization). To develop a method that would also enable
us to recycle the enzyme, immobilized Candida antarctica
B15 was used. Racemic aminocyclopentenol (()-4c was
mixed with vinyl acetate and enzyme in wet CH2Cl2 or
heptane/CH2Cl2 for 3-4 h at room temperature providing
6c in 40-50% yield and leaving 5c unreacted. After chro-
(15) (a) CAB*, sold under the trade name CHIRAZYME L-2, C-f,
C3, Lyo by Boehringer Mannheim Corp. (b) Li, F.; Warshakoon, N. C.
Miller, M. J. J. Org. Chem. 2004, 69, 8836.
J. Org. Chem, Vol. 70, No. 7, 2005 2825

SCHEME 4
TABLE 1. Pd(0)-Catalyzed Cyclization Reaction of 20 to
22 under Basic Conditions
SCHEME 6
base
time (t)
yield of 22 (%)
NEt3
NaH
21
overnight
3 h
3 h
10 (20% conversion)
79
94
SCHEME 5
TABLE 2. Hydrogenation Reaction of Compound 22
under Different Conditions
cylic pyrazolo[3,4-d]pyrimidines in a highly efficient
manner (54% overall yield starting from optically pure
Boc-protected aminocyclopentenol 5c and 52% overall
yield from 6c). In addition to the high chemical efficiency,
this route should be compatible with peripheral variation
that will allow access to a library of compounds suitable
for biological study.
Experimental Section
conditions
product, yield (%)
Pt/C, H2
23, 50
Enzymatic Acetylations. To a solution of 4c (10 g, 50.25
mmol) in a mixture of wet heptane/dichloromethane (2.8:1, 380
mL) was added vinyl acetate (22.2 mL, 240.9 mmol). The wet
heptane was prepared by thoroughly mixing with water in a 1
L bottle, the two layers were allowed to separate, and the organic
layer was decanted and used. Resin-bound C. antarctica B lipase
(CAB*)15 (1 g) was added, and the resultant mixture was shaken
vigorously in an incubator-shaker at room temperature while
the reaction was monitored by TLC. The conversion was
complete within 3 h, although longer times had no deleterious
effect. The mixture was filtered through a filter paper to remove
the resin-bound enzyme. The enzyme was recovered and could
be used a second time of resolution of 4c. The solvent was
removed from the filtrate, and the mixture was then purified
using column chromatography (hexanes/EtOAc 10:1) to afford
5.2 g (43%) of 6c as a white solid (90% ee, determined by
hydrolysis of the acetate (K2CO3/MeOH) and derivatization with
(S)-(+)-R-methoxy-R-(trifluoromethyl)phenyl acetyl chloride for
Mosher ester analysis) The product, 6c, was recrystallized using
hexanes to afford 4.6 g of 6c as a white, crystalline solid (98%
PtO2, H2
23, 50 (90% conversion)
24, 60
H2O2, NH2NH2
The hydrogenation reaction was carried out under
different conditions, which are summarized in Table 2.
The desired selective reduction was finally achieved by
the reaction of 22 with diimide16 (HNNH, generated in
situ by reaction of aqueous hydrogen peroxide and
hydrazine in EtOH solution) to give 24 in 50-60% yield.
Starting with enantiomerically pure compound 6c, the
enantiomer of 24 also has been synthesized (Scheme 6).
Preliminary determination of phosphodiesterase (PDE1)
inhibition at a concentration of 100 µM revealed modest
activity of 26% inhibition by precursor 20 and a more
significant 71% inhibition by ring-opened product 23.
Both enantiomers of 24 and 28 showed modest PDE1
inhibition, with IC50 values of 55.8 and 41.2 µM, respec-
tively.
1
ee): [R]D ) -22.6 (c ) 0.40, CHCl3); mp ) 57-58 °C; H NMR
(300 MHz, DMSO-d6) δ 1.37 (s, 9H), 1.45 (dt, J ) 13.5, 6.0 Hz,
1H), 1.98 (s, 3H), 2.68 (dt, J ) 13.5, 7.5 Hz, 1H), 4.38 (m, 1H),
5.40 (m, 1H), 5.81 (dt, J ) 5.4, 2.1 Hz, 1H), 5.90 (m, 1H), 7.11
(d, J ) 7.5 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 20.8, 28.2,
37.6, 53.3, 77.1, 77.8, 130.9, 137.3, 154.9, 170.1; HRMS [MH+]
calcd for C12H19NO4 242.1392, found 242.1382. The unreacted
alcohol 5c was recovered in 42% yield with 98% ee after
recrystallization from hexanes/EtOAc at 0 °C: [R]D ) -69.0
In conclusion, we were able to develop a mild and
potentially general protocol for the construction of poly-
(16) (a) Liu, B.; Zhou, W. Tetrahedron 2003, 59, 3379. (b) McDonald,
F. E.; Wei, W. Org. Lett. 2002, 4, 593.
(17) (a) Hidaka, H. Asano, T. Biochim. Biophys. Acta 1976, 429, 485.
(b) Nicholson, C. D.; Chaliss, R. LA.; Shalid, M. Trends Pharmacol.
Sci. 1991, 12, 19.
2826 J. Org. Chem., Vol. 70, No. 7, 2005

(c)1.0, CHCl3); mp ) 103-104 °C. Spectral data were identical
to those previously reported.4
with H2. The reaction was monitored by TLC. Upon completion
of the reaction, the mixture was diluted with EtOAc and filtered
through a thin pad of Celite. The solvent was removed, and the
residue was purified by column chromatography eluting with
hexanes and EtOAc (1:1) to give 9.4 mg (49% yield) of a white
1-Benzyl-6-chloro-5-phenyl-1,5-dihydropyrazolo[3,4-d]-
pyrimidin-4-one (18). Compound 17 (1.1 g, 3.45 mmol)14 was
heated with POCl3 (16 mL) at reflux for 48 h. The solution was
cooled and diluted with CH2Cl2. The organic layer was washed
with saturated NaHCO3 (Caution, vigorous exotherm and gas
evolution), H2O, and brine and dried with MgSO4. After filtration
and concentration, the residue was purified by column chromo-
tagraphy eluting with hexanes/EtOAc from 10:1 to 5:1 to 3:1 to
give 0.51 g (44% yield) of a white solid: mp ) 159-161 °C; Rf )
0.65 (hexanes/EtOAc ) 1:1); 1H (300 MHz, CDCl3) δ 5.49 (s, 2H),
7.21-7.23 (m, 2H), 7.25-7.39 (m, 5H), 7.48-7.55 (m, 3H), 8.07
(s, 1H); 13C (75 MHz, CDCl3) δ 51.2, 104.3, 128.1, 128.1, 128.3,
128.7, 129.6, 129.6, 135.6, 136.0, 137.2, 148.3, 149.7, 157.2; IR
1
solid: mp ) 138-140 °C; Rf ) 0.68 (hexanes/EtOAc ) 1:4); H
(500 MHz, CDCl3) δ 1.25-1.33 (m, 2H), 1.56-1.63 (m, 4H), 2.00-
2.08 (m, 2H), 4.11 (d, J ) 6.5 Hz, 1H), 4.31, 4.32 (td, J ) 8.5,
6.5 Hz), 5.44 (s, 2H), 7.28-7.63 (m. 10H), 7.97 (s, 1H); 13C (125
MHz, CDCl3) δ 23.5, 33.0, 50.5, 53.8, 100.0, 127.7, 128.2, 128.6,
129.1, 129.8, 130.5, 134.8, 135.8, 136.8, 152.4, 152.8, 158.2; IR
(CH2Cl2, NaCl) 3000, 2987, 1554, 1223, 890 cm-1; HRMS (FAB)
calcd for C23H24N5O (M + H)+ 386.1981, found 386.1998.
(6aS,9aR)-5,6a,7,8,9,9a-Hexahydro-5-phenyl-1-(phenyl-
methyl)cyclopent[4.5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimi-
dine-4(1H)-one (24). To a solution of compound 22 (21 mg,
0.055 mmol) in ethanol (1 mL) were added 35% NH2NH2 (0.05
mL, 0.55 mmol) and 30% H2O2 (0.07 mL, 0.66 mmol) three times
at 8 h intervals. The reaction was quenched with 1 M Na2S2O3
solution, extracted with CH2Cl2, washed with brine, and dried
with NaSO4. After filtration and concentration, the residue was
purified by column chromatography eluting with hexanes and
EtOAc (1:4) to give 10 mg (50% yield) of an oil: [R]D ) -162 (c
) 1.0, CHCl3); 1H (500 MHz, CDCl3) δ 1.61-2.09 (m, 6H), 4.62-
4.64 (m, 2H), 5.38 (d, J ) 16.5 Hz, 1H), 5.64 (d, J ) 17 Hz, 1H),
7.14-7.52 (m, 10H), 7.97 (s, 1H); 13C (125 MHz, CDCl3) δ 23.1,
34.3, 35.1, 53.3, 62.6, 70.7, 99.7, 126.0, 128.4, 128.6, 128.7, 129.2,
129.5, 136.1, 136.2, 138.5, 142.5, 152.3, 157.7; IR (CH2Cl2, NaCl)
2960, 1701, 1633, 1591, 1549, 760 cm-1; HRMS (FAB) calcd for
(KBr) 3065, 1723, 1565, 1489, 1284, 1224, 1186, 1031, 712 cm-1
;
HRMS (FAB) calcd for C18H14N4O35Cl (M + H)+ 337.0856, found
337.0850.
Acetic Acid 4-(1-Benzyl-4-oxo-5-phenyl-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimidinyl-6-amino)cyclopent-2-enyl Es-
ter (20). To an ice-cold solution of 19 (50 mg, 0.21 mmol) in
CH2Cl2 (2 mL) was added trifluoroacetic acid (0.17 mL). The
mixture was stirred at 0 °C for 20 min, warmed to room
temperature, and stirred for another 1 h. The solvent was
removed by coevaporation with toluene (2 × 2 mL). The residue
was dissolved in n-BuOH (2 mL). Chloride 18 (142 mg, 0.42
mmol) was added to the solution followed by Et3N (0.26 mL, 1.89
mmol). The mixture was heated at 105 °C for 28 h under an Ar
atmosphere. After the reaction was cooled, the solvent was
removed and the residue was purified by column chromatogra-
phy eluting with hexanes/EtOAc (3:1 to 1:1) to afford 89 mg (96%
yield) of a white foam: mp ) 64 °C; Rf ) 0.65 (1:1 of hexanes/
EtOAc); [R]D ) -7.2 (c ) 1.0, CHCl3); 1H (500 MHz, CDCl3) δ
1.44 (dt, J ) 4, 14 Hz, 1H), 1.93 (s, 3H), 2.81 (q, J ) 7.5 Hz,
1H), 4.23 (d, J ) 7.5 Hz, 1H), 5.03-5.05 (m, 1H), 5.39 (s, 2H),
5.50-5.51 (m, 1H), 5.94-5.98 (m, 2H), 7.23-7.38 (m, 6H), 7.50-
7.58 (m, 4H), 7.97 (s, 1H); 13C (125 MHz, CDCl3) δ 21.0, 38.5,
50.6, 55.6, 77.2, 100.2, 127.8, 128.1, 128.6, 129.0, 129.1, 129.9,
130.6, 130.6, 133.2, 134.5, 135.9, 136.0, 136.7, 151.9, 152.4, 158.1,
C
23H22N5O (M + H)+ 384.1824, found 384.1822.
Acetic Acid 4-(1-Benzyl-4-oxo-5-phenyl-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimidinyl-6-amino)cyclopent-2-enyl Es-
ter (26, ent-20). The compound was prepared using the same
procedure employed for the synthesis of its enantiomer (20): [R]D
) +8.1 (c ) 1.0, CHCl3); 1H and 13C data were identical to those
of its enantiomer 20; HRMS (FAB) calcd for C25H24N5O3 (M +
H)+ 442.1879, found 442.1852.
(6aR,9aS)-5,6a,7,9a-Tetrahydro-5-phenyl-1-(phenyl-
methyl)cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimi-
din-4(1H)-one (27). The compound was prepared using the
same procedure employed for the synthesis of its enantiomer
(22): [R]D ) +100 (c ) 1.0, CHCl3); Rf ) 0.14 (hexanes/EtOAc
) 1:4); 1H and 13C data were identical to its enantiomer 22;
HRMS (FAB) calcd for C23H20N5O (M + H)+ 382.1668, found
382.1659.
170.3; IR (CH2Cl2, NaCl) v 2987, 1765, 1665, 1221, 880 cm-1
;
HRMS (FAB) calcd for C25H24N5O3 (M + H)+ 442.1879, found
442.1879.
(6aS,9aR)-5,6a,7,9a-Tetrahydro-5-phenyl-1-(phenyl-
methyl)cyclopent[4.5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimi-
din-4(1H)one (22). Compound 20 (31 mg, 0.07 mmol) was
dissolved in dry THF (1 mL). In a separate flask, Pd(OAc)2 (3.1
mg, 0.2 equiv) was mixed with PPh3 (18.4 mg, 1 equiv) in dry
THF (1 mL). The in situ generated Pd(0) was added to the
solution of 20, and the mixture was stirred at room temperature
for 5 min. 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhy-
dro-1,3,2-diazaphosphorine 21 (41 µL, 2 equiv) was added to the
mixture, and the reaction was stirred at room temperature for
6 h. Another portion of in situ generated Pd(0) (0.2 equiv) was
then added. After 1 h, the reaction was complete. It was then
quenched with H2O and extracted with EtOAc. The organic
phase was dried with NaSO4. After filtration and concentration,
the residue was purified by column chromatography eluting with
hexanes and EtOAc (1:1-1:4) to give 25 mg (94% yield) of an
oil: Rf ) 0.14 (hexanes/EtOAc ) 1:4); [R]D ) -99.7 (c ) 0.75,
(6aR,9aS)-5,6a,7,8,9,9a-Hexahydro-5-phenyl-1-(phenylmeth-
yl)cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(1H)-
one (28). The compound was prepared using the same procedure
employed for the synthesis of its enantiomer (24): [R]D ) +169
(c ) 0.93, CHCl3); Rf ) 0.14 (hexanes/EtOAc ) 1:4); 1H and 13
C
data were identical to its enantiomer 24; HRMS (FAB) calcd for
C23H22N5O (M + H)+ 384.1824, found 384.1830.
Acknowledgment. We thank Eli Lilly and Co. and
the NIH for the support of this research. Biological
assays were performed by MDS Pharma Services ac-
cording to literature procedures.17 We acknowledge Dr.
Jaroslav Zajicek for NMR assistance as well as Dr.
William Boggess and Nonka Sevova for mass spectro-
scopy. Special thanks are extended to Maureen Metcalf
for her assistance with this manuscript.
1
CHCl3); H (500 MHz, CDCl3) δ 2.56-2.61 (m, 1H), 2.74-2.79
(m, 1H), 4.72 (t, J ) 7 Hz, 1H), 5.23 (d, J ) 8 Hz, 1H), 5.43 (d,
J ) 17 Hz, 1H), 5.60-5.61 (m, 1H), 5.65 (d, J ) 17 Hz, 1H),
6.10-6.11 (m, 1H), 7.14-7.49 (m, 10H), 7.95 (s, 1H); 13C (125
MHz, CDCl3) δ 40.8, 53.3, 66.9, 68.1, 99.7, 125.8, 126.1, 128.4,
128.6, 128.8, 129.3, 129.5, 135.9, 136.0, 137.7, 138.5, 142.7, 151.6,
157.7; IR (CH2Cl2, NaCl) 2918, 1702, 1632, 1592, 1548, 1426,
731 cm-1; HRMS (FAB) calcd for C23H20N5O (M + H)+ 382.1668,
found 382.1651.
Note Added after ASAP Publication. The com-
pound numbers were omitted from the Table of Contents
graphic in the version published ASAP March 4, 2005.
The corrected version was published March 10, 2005.
Supporting Information Available: 1H and 13C NMR of
compounds 20, 22, 23, and 24. This material is available free
of charge via the Internet at http://pubs.acs.org.
1-Benzyl-6-cyclopentylamino-5-phenyl-1,5-dihydropyra-
zolo[3,4-d]pyrimidin-4-one (23). A solution of compound 22
(20 mg, 0.05 mmol) in methanol (5 mL) was charged with Pd/C
(10%, 6.6 mg). The mixture was stirred under a balloon filled
JO0484070
J. Org. Chem, Vol. 70, No. 7, 2005 2827