Enantioselective synthesis of SNAP-7941: Chiral dihydropyrimidone inhibitor of MCH1-R

Article abstract of DOI:10.1021/jo801463j

(Chemical Equation Presented) An enantioselective synthesis of SNAP-7941, a potent melanin concentrating hormone receptor antagonist, was achieved by using two organocatalytic methods. The first method utilized to synthesize the enantioenriched dihydropyrimidone core was the Cinchona alkaloid-catalyzed Mannich reaction of β-keto esters to acylimines and the second was the chiral phosphoric acid-catalyzed Biginelli reaction. Completion of the synthesis was accomplished via selective urea formation at the N3 position of the dihydropyrimidone with the 3-(4-phenylpiperidin-1-yl)propylamine side chain fragment. The synthesis of SNAP-7921 highlights the utility of asymmetric organocatalytic methods in the construction of an important class of chiral heterocycles.

Full text of DOI:10.1021/jo801463j

Enantioselective Synthesis of SNAP-7941: Chiral Dihydropyrimidone
Inhibitor of MCH1-R
Jennifer M. Goss and Scott E. Schaus*
Department of Chemistry, Life Science and Engineering Building, Boston UniVersity,
24 Cummington Street, Boston, Massachusetts 02215
seschaus@bu.edu
ReceiVed July 3, 2008
An enantioselective synthesis of SNAP-7941, a potent melanin concentrating hormone receptor antagonist,
was achieved by using two organocatalytic methods. The first method utilized to synthesize the
enantioenriched dihydropyrimidone core was the Cinchona alkaloid-catalyzed Mannich reaction of ꢀ-keto
esters to acylimines and the second was the chiral phosphoric acid-catalyzed Biginelli reaction. Completion
of the synthesis was accomplished via selective urea formation at the N3 position of the dihydropyrimidone
with the 3-(4-phenylpiperidin-1-yl)propylamine side chain fragment. The synthesis of SNAP-7921
highlights the utility of asymmetric organocatalytic methods in the construction of an important class of
chiral heterocycles.
Introduction
hormone receptor (MCH1-R) antagonists (Figure 1).6 In most
cases only one enantiomeric form of the heterocycle is often
determined to be biologically active.7 While racemic DHPMs
are easily constructed via the Biginelli reaction, a 3-component
condensation reaction of ureas, ꢀ-keto esters, and aldehydes,8
a limited number of asymmetric methods exist to access the
Dihydropyrimidones (DHPMs) are a class of heterocyclic
compounds1 that possess wide ranging biological activity2 such
as calcium channel modulators,3 antihypertensive agents,4
mitotic kinesin Eg5 inhibitors,5 and melanin concentrating
* Author to whom correspondence should be addressed. Phone: 01-617-353-
2489. Fax: 01-617-353-6466.
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10.1021/jo801463j CCC: $40.75
Published on Web 09/04/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7651–7656 7651

Goss and Schaus
SCHEME 1. Retrosynthetic Analysis of SNAP-7941
FIGURE 1. Biologically Active DHPMs.
chiral heterocycle in high enantiomeric purity. Early approaches
include chemical resolution,9 enzymatic synthesis,10 and chiral
Yb-11 or Ce/In-complex12 catalyzed Biginelli reactions. More
recently, asymmetric organocatalytic approaches have emerged
as effective methods to construct enantioenriched DHPMs. We
developed the asymmetric Mannich reaction13 of ꢀ-ketoesters
to acylimines catalyzed by the Cinchona alkaloids as a way to
construct chiral DHPM heterocycles.14 Subsequent to our initial
communication, Gong and co-workers reported the first asym-
metric organocatalytic Biginelli reaction catalyzed by a BINOL-
derived chiral phosphoric acid catalyst, yielding chiral DHPMs
in high enantiomeric ratios.15 These methods could be readily
applied to asymmetric synthesis due to the accessibility of the
reagents and catalysts, as well as the useful levels of enanti-
oselectivity.
SCHEME 2. Synthesis of DHPMs via Asymmetric Mannich
Reaction
SNAP-7941 is a chiral DHPM identified as a small molecule
inhibitor of MCH1-R in a G protein-coupled receptor (GPCR)
biased library screening. Inhibition of MCH1-R promotes weight
loss in obese rats, and decreases anxiety and depression in both
guinea pigs and rats, as shown in social interaction studies.6
SNAP-7941 exhibits a Kd of 0.18 nM with specific binding of
98% in COS-7 cells expressing human MCH1-R. However,
synthesis of SNAP-7941 in enantioenriched form relies on a
chiral separation of the racemic dihydropyrimidone synthon.16
In an effort to synthesize chiral DHPMs and apply these methods
toward the synthesis of a relevant target, SNAP-7941, we
investigated using both the Cinchona alkaloid-catalyzed asym-
metric Mannich reaction and the chiral phosphoric acid-
catalyzed Biginelli reaction as the key enantioselective step in
the synthesis. Our goal was to illustrate the utility of both the
asymmetric Mannich reaction and the asymmetric Biginelli
reaction in the synthesis of SNAP-7941.
SNAP-7941 consists of two main structural components, a
chiral DHPM and a 3-(4-phenylpiperidin-1-yl)propylamine side
chain linked as a urea (Scheme 1). The two approaches to the
chiral DHPM require different building blocks to construct the
amine stereocenter. The Cinchona alkaloid-catalyzed asym-
metric Mannich addition of methoxy methylacetoacetate to
N-alloc-3,4-difluorophenyl aldimine results in the amine precur-
sor that is ultimately converted to the heterocycle with micro-
wave irradiation.17 The chiral phosphoric acid-catalyzed mul-
ticomponent Biginelli reaction results in direct formation of the
chiral DHPM. Both methods proved to be equally effective in
accessing the desired heterocycle for the synthesis of enan-
tioenriched SNAP-7941.
(10) Schnell, B.; Strauss, U. T.; Verdino, P.; Faber, K.; Kappe, C. O.
Tetrahedron: Asymmetry 2000, 11, 1449–1453.
(11) Huang, Y.; Yang, F.; Zhu, C. J. Am. Chem. Soc. 2005, 127, 16386–
16387.
(12) Munoz-Muniz, O.; Juarisiti, E. ARKIVOC 2003, 11, 16–26.
(13) For reviews see: (a) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99,
1069–1094. (b) Denmark, S.; Nicaise, J.-C. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yammamoto, H., Eds.; Springer: Berlin,
Germany, 1999; Vol. 2, p 954. (c) Benaglia, M.; Cinquini, M.; Cozzi, F. Eur. J.
Org. Chem. 2000, 4, 563–572. (d) Co´rdova, A. Acc. Chem. Res. 2004, 37, 102–
112. (e) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 35, 5797–5815.
(14) (a) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc.
2005, 127, 11256–11257. (b) Lou, S.; Dai, P.; Schaus, S. E. J. Org. Chem. 2007,
72, 9998–10008.
Results and Discussion
(15) Chen, X.-H.; Yu, X.-Y.; Liu, H.; Cun, L.-F.; Gong, L.-Z. J. Am. Chem.
Soc. 2006, 128, 14802–14803.
(16) Lagu, B. PCT Int. Appl. WO 2002006245 A1, 2002.
Synthesis of SNAP-7941 DHPM Core via the Mannich
Reaction. Synthesis of the SNAP-7941 DHPM using the
7652 J. Org. Chem. Vol. 73, No. 19, 2008

EnantioselectiVe Synthesis of SNAP-7941
TABLE 1. Asymmetric Mannich Reactions with
SCHEME 3. DHPM Formation from Mannich Adduct
N-Alloc-3,4-difluorophenyliminea
entry
catalyst
ketoester
% yieldb
erc
1
2
3
4
5
5
5
8a
8b
8b
8b
8b
72
68
77
88
89
71:29
91:9
85:15
93:7
7
5d
5e
93.5:6.5
a Reactions were run with imine 9 (1.00 mmol), ꢀ-ketoesters 8a and
8b (3.00 mmol), and catalyst (0.10 mmol) in CH2Cl2 (10 mL) at -35
°C for 24 h, followed by flash chromatography on silica gel. b Yield of
isolated product. c Determined by chiral HPLC analysis. d Reaction run
at -50 °C with 0.20 mmol of catalyst in CH2Cl2 (5 mL). e Reaction run
at -50 °C with 0.20 mmol of catalyst in CH2Cl2 (10 mL).
observed in the absence of a C4 substituent on the ꢀ-ketoester
(Table 1, entry 2). Mannich addition of methylacetoacetate 8b
catalyzed by cinchonine proceeded in moderate yield and good
enantiomeric ratio (Table 1, entry 2). The addition with
methylacetoacetate 8b was further optimized by increasing
catalyst loading to 20 mol % while reducing the reaction
temperature, to afford the desired chiral amine 10b in high yield
with an enantiomeric ratio of 93.5:6.5 (Table 1, entry 5). While
the additions of methylacetoacetate 8b to acylimine 9 provided
enantioenriched Mannich products, we investigated a method
utilizing R,R-allylcarbamate-3,4-difluorophenyl sulfone and
generating the corresponding acylimine in situ. The R-amido
sulfones are bench stable and easily synthesized,19 and we have
previously illustrated the utility of the R-amido sulfones in the
asymmetric Mannich reaction.14b
Addition of C4 methoxy substituted ꢀ-ketoester 8a to
R-amido sulfone 11 again provided the Mannich adduct 10a in
low yields and moderate enantioselectivities (Table 1, entries 1
and 2). We hypothesized that the C4 substituent plays a crucial
role. The observed decrease in reactivity may be attributed to a
disruption of hydrogen bonding nature between the catalyst and
the ꢀ-ketoester, as additions with methoxy methylacetoacetate
8a generally provided lower yields and selectivities when
compared to the unsubstituted methylacetoacetate 8b. To
determine whether the change in reactivity and selectivity was
a steric or electronic effect, the Mannich reaction with C4 methyl
substituted ꢀ-ketoester 8c was examined. Mannich addition of
8c to R-amido sulfone 11 catalyzed by cinchonine did not
significantly decrease selectivity or yield (Table 2, entry 5). We
reasoned that an intramolecular hydrogen bond of the tautomer
alcohol and the C4 methoxy substituent of 8a interrupts the
hydrogen-bonding nature. To overcome the low selectivity, we
sought to synthesize the DHPM core with ꢀ-ketoester 8b and
install the methoxy substituent at a later stage. Best results were
obtained for the Mannich reaction of ꢀ-ketoester 8b and R,R-
allylcarbamate-3,4-difluorophenyl sulfone 11 catalyzed by cin-
chonine, providing chiral amine 10b in high yield and high
enantiomeric ratio (Table 2, entry 3).
TABLE 2. Asymmetric Mannich Reactions with
r,r-Allylcarbamate-3,4-difluorophenyl Sulfonea
entry
catalyst
ketoester
% yieldb
erc
1
2
3
4
5
5
7
5
7
5
8a
8a
8b
8b
8c
67
81
95
67
98
78:22
82:18
94:6
85:15
89:11
a Reactions were run with amido sulfone 11 (1.00 mmol), ꢀ-ketoesters
8a-c (3.00 mmol), and catalyst (0.10 mmol) in CH2Cl2 (10 mL) and
Na2CO3 in brine (10 mL) at -15 °C for 24 h, followed by flash
chromatography on silica gel. b Yield of isolated product. c Determined
by chiral HPLC analysis.
asymmetric Mannich reaction required the addition of a ꢀ-ke-
toester to an acylimine, followed by urea formation and
subsequent ring closure (Scheme 2). On the basis of our previous
work, cinchonine would be the preferred catalyst for the
asymmetric Mannich reaction; however, additional catalysts
were evaluated in the reaction including other Cinchona
alkaloids and thiourea Cinchona alkaloid derived catalyst 7.18
A catalyst screen was conducted to identify the optimal catalyst
for the reaction.
Low yield and selectivity was observed for the asymmetric
Mannich addition of methoxy methylacetoacetate 8a to N-alloc-
3,4-difluorophenylimine 9 catalyzed by cinchonine 5 (Table 1,
entry 1). We suspected that the C4 methoxy substituent was
problematic as better reaction rates and selectivities were
Conversion of the chiral imine to the desired enantioenriched
DHPM proceeded via a two-step process. Exposure of Mannich
adduct 10b to a catalytic amount of Pd(PPh3)4, an excess of
trimethylsilyl isocyanate, and 3,5-dimethylbarbituric acid as an
allyl scavenger affords the desired silyl urea (Scheme 3).
(17) (a) Stadler, A.; Kappe, C. O. J. Comb. Chem. 2001, 3, 624–630. (b)
Wannberg, J.; Dallinger, D.; Kappe, C. O.; Larhed, M. J. Comb. Chem. 2005,
7, 574–583. (c) Wang, X.; Quan, Z.; Wang, F.; Wang, M.; Zhang, Z.; Li, Z.
Synth. Commun. 2006, 36, 451–456. (d) Dallinger, D.; Kappe, C. O. Nature
Protoc. 2007, 2, 1713–1721. (e) Banik, B. K.; Reddy, A. T.; Datta, A.;
Mukhupadhyay, C. Tetrahedron Lett. 2007, 48, 7392–7394.
(18) Vakulya, B.; Varga, S.; Csampai, A.; Soo´s, T. Org. Lett. 2005, 7, 1967–
1969.
(19) (a) Petrini, M. Chem. ReV. 2005, 105, 3949–3977. (b) Messinger, P.
Pharmazie 1976, 31, 16–18.
J. Org. Chem. Vol. 73, No. 19, 2008 7653

Goss and Schaus
SCHEME 4. Synthesis of the C4 Methoxy-Substituted
DHPM
SCHEME 5. Synthesis of 3-(4-Phenylpiperidin-1-yl)propy-
lamine Side Chain
TABLE 3. Asymmetric Biginelli Reaction Catalyzed by Chiral
Binapthol-Derived Phosphoric Acida
Ph(CH3)3NBr3, providing DHPM 13 in equally high yield.
Installation of the methoxy substituent proceeded through
nucleophilic substitution with sodium methoxide. Use of either
microwave or thermal conditions provided the heterocyclic core
of SNAP-7941 14 in 85% yield with retention of enantioen-
richment.
Synthesis of the DHPM Core via the Asymmetric Bigi-
nelli Reaction. The asymmetric Biginelli reaction catalyzed by
BINOL-derived phosphoric acids was also investigated to
produce the desired SNAP-7941 DHPM core. Use of methoxy
methylacetoacetate 8a in the multicomponent reaction provided
DHPM 14 in low yield and enantioselectivity (Table 3, entry
1). This observation is again attributed to an unfavorable
hydrogen-bonding nature as the use of methylacetoacetate 8b
greatly improved yield and selectivity (Table 3, entries 2 and
3). Optimal reaction conditions were achieved with a limiting
amount of urea and an excess of both aldehyde and methylac-
etoacetate (Table 3, entries 4, 5, and 6). DHPM 12 was
synthesized in 96% yield with 94.5:5.5 er, utilizing 3,3′-
diphenyl-substituted BINOL-derived phosphoric acid catalyst
17b. The Biginelli product was recrystallized and functionalized
via the previously described bromination and methanolysis
procedures to provide the enantioenriched SNAP-7941 core.
entry
15:8:16
catalyst
ketoester
% yieldb
erc
1
2
3
4
1.0:5.0:2.0
1.2:5.0:1.0
1.2:5.0:2.0
1.0:5.0:2.0
1.0:5.0:2.0
1.0:5.0:2.0
17b
17a
17b
17b
17c
17b
8a
8b
8b
8b
8b
8b
27
50
42
96
65
27
64.5:35.5
63:37
83:17
94.5:5.5
77.5:22.5
64.5:35.5
5
6d
a Reactions were run with urea 15, phosphoric acid catalysts 17a-c (0.02
mmol), aldehyde 16 in CH2Cl2 (3 mL) for 2 h. ꢀ-Ketoesters 8a and 8b
(1.00 mmol) were added, and the mixture was stirred at room temperature
for 6 days, and subsequently purified by flash chromatography on silica gel.
b Yield of isolated product. c Determined by chiral HPLC analysis. d The
reaction was run at 0.5 M.
Synthesis of 3-(4-Phenylpiperidin-1-yl)propylamine Side
Chain. Piperidine 18 and boronic acid 19 were synthesized
according to previously reported literature procedures.21 Suzuki
coupling of 18 and 19 provided the desired piperidinyl amide
20 in 51% yield. Subsequent hydrogenation followed by acid
deprotection of 20 afforded the piperidinyl phenyl acetamide
hydrochloride salt 22 in 86% overall yield. Nucleophilic
substitution of N-Boc propyl bromide 2319 with piperidinyl
hydrochloride salt 22 yielded the Boc protected amide side chain
24. Deprotection of the Boc group with TFA and subsequent
pH adjustment afforded the desired amine 25 (Scheme 5).
Synthesis of SNAP-7941. Synthesis of N-substituted DHPM
carbamate 26 via addition of p-nitrophenyl chloroformate was
achieved in 70% yield (Scheme 6). The urea moiety of SNAP-
7941 was constructed via addition of piperidine side chain 25
to N-substituted DHPM carbamate 26. Optimal yield and
Formation of the heterocycle proceeds without purification of
the silyl urea with subsequent ring closure under acidic
conditions. The desired DHPM was achieved in 80% yield with
retention of stereochemistry (Scheme 3). The heterocycle was
purified by recrystallization to provide DHPM 12 in an
enantiomeric ratio of >99:1.
Installation of the C4 methoxy substituent proceeded through
bromination and subsequent methanolysis of DHPM 12. Mono-
bromination of the C4 methyl of the DHPM was achieved in
high yield by using a solid supported brominating agent reported
by Kappe and co-workers (Scheme 4).20 The monobrominated
DHPM was also synthesized by using brominating reagent
(20) Khanetsky, B.; Dallinger, D.; Kappe, C. O. J. Comb. Chem. 2004, 6,
884–892.
7654 J. Org. Chem. Vol. 73, No. 19, 2008

EnantioselectiVe Synthesis of SNAP-7941
SCHEME 6. Synthesis of SNAP-7941
trimethylsilyl isocyanate (0.346 g, 3.00 mmol), and THF (10 mL).
The solution containing the 10b and 3,5-dimethylbarbituic acid was
transferred via cannula to the palladium and isocyanate mixture.
The reaction mixture was stirred for 4 h. The solution was then
concentrated under reduced pressure, and a solution of 75% acetic
acid in ethanol (3 mL) was added. The solution was transferred to
a 10 mL microwave tube, and irradiated for 3 min at 30 °C. The
reaction mixture was concentrated under reduced pressure and the
resulting residue was purified by flash chromatography over silica
gel (elution with 80% to 100% EtOAc in hexanes) to afford the
dihydropyrimidone reaction product as a white solid.
General Procedure for the Chiral Phosphoric Acid-Catalyzed
Asymmetric Biginelli Reaction. An oven-dried 10-mL round-
bottomed flask equipped with stir bar was charged with urea 15
(0.012 g, 0.20 mmol), phosphoric acid catalyst (17a-c) (0.02
mmol), 3,4-difluorobenzaldehyde (16) (44 µL, 0.40 mmol), and
CH2Cl2 (3 mL). The flask was sealed with a Teflon cap (caplug),
and the solution was stirred for 2 h at room temperature. The
dicarbonyl compound (8a, 8b) (1.0 mmol) was slowly added, and
the solution was stirred for 6 days. Silica gel was added to the
reaction mixture, and the mixture was concentrated under reduced
pressure. The resulting solid was purified by flash chromatography
over silica gel (with 80-100% EtOAc in hexanes) to afford the
Biginelli reaction products as white solids.
Synthesis of SNAP-7941. A solution of 25 (0.050 g, 0.10 mmol),
24 (0.083 g, 0.30 mmol), DIPEA (0.078, 0.60 mmol), and anhydrous
CH2Cl2 (3 mL) was stirred at room temperature under argon
atmosphere for 24 h. The mixture was concentrated and the resulting
residue was purified by flash chromatography over silica gel (elution
with 1-5% methanol in ethyl acetate) to provide the desired final
compound as a yellow oil.
reaction time was obtained with Hu¨nig’s base, providing the
enantioenriched form of SNAP-7941 in 90% yield.
Conclusion
We have developed two organocatalytic enantioselective
approaches to SNAP-7941 that focus on the synthesis of the
chiral dihydropyrimidone core. The asymmetric Mannich reac-
tion catalyzed by Cinchona alkaloids and the asymmetric
Biginelli reaction catalyzed by chiral phosphoric acids were
equally effective at producing the desired heterocycle. The
additional steps required by the Mannich route are offset by
the time required for the enantioselective Biginelli reaction.
Despite the progress to date, some challenges still remain.
However, these approaches are the first highly enantioselective
routes to this important class of biologically and pharmaceuti-
cally relevant compounds. The development of effective syn-
thetic approaches will hopefully facilitate future efforts to
characterize the activity and biological properties of these chiral
heterocycles.
Characterization Data for Selected Compounds: (a) 2-[(R)-
Allyloxycarbonylamino-3,4-diflurophenylmethyl)-3-oxo-4-me-
thoxybutyric Acid Methyl Ester (10a). Clear viscous oil (0.25 g,
67% yield). 1H NMR (CDCl3, 400 MHz, both diastereomers
reported): δ 7.10 (m, 8H), 6.41 (d, J ) 9.2 Hz, 1H), 6.33 (d, J )
8.8 Hz, 1H), 5.86 (m, 2H), 5.53 (m, 1H), 5.43 (m, 1H), 5.30 (s,
1H), 5.27 (s, 1H), 5.23 (s, 1H), 5.20 (s, 1H), 4.50 (d, J ) 5.6 Hz,
4H), 4.32 (m, 2H), 4.08 (dd, J ) 7.2, 6.8 Hz, 2H), 3.87 (dd, J )
14.8, 6.0 Hz, 2H), 3.69 (s, 3H), 3.62 (s, 3H), 3.44 (s, 3H), 3.29 (s,
3H). 13C NMR (CDCl3, 75.0 MHz, both diastereomers reported):
δ 204.5, 202.2, 171.4, 169.0, 167.4, 156.0, 155.8, 151.7, 149.3 (d,
Experimental Section
General Procedure for Asymmetric Mannich Reaction of
r-Amido Sulfones. To an oven-dried 50-mL round-bottomed flask
equipped with a stir bar was added R-amido sulfone 11 (0.40 g,
1.00 mmol), (+)-cinchonine (0.029 g, 0.10 mmol), and CH2Cl2 (10
mL). The solution was cooled to -15 °C. The dicarbonyl compound
(8a-c) (3.00 mmol) and 10 mL of a solution of Na2CO3/NaCl were
sequentially added dropwise. The reaction was stirred for 24 h at
-15 °C and then diluted with CH2Cl2 (20 mL) and H2O (20 mL).
The organic layer was quickly separated, and the aqueous phase
was extracted with CH2Cl2 (2 × 20 mL). The organic layers were
combined, dried over sodium sulfate, filtered, and concentrated
under reduced pressure. The resulting residue was purified by flash
chromatography over silica gel (elution with 30% to 40% ethyl
acetate in hexanes) to afford the Mannich reaction products as white
solids.
General Procedure for Conversion from Mannich Adduct
to Dihydropyrimidone. To an oven-dried 50-mL round-bottomed
flask equipped with stir bar was added 10b (0.34 g, 1.00 mmol),
3,5-dimethylbarbituric acid (0.156 g, 1.00 mmol), and THF (10
mL). To another oven-dried 50-mL round-bottomed flask equipped
with stir bar was added Pd(PPh3)4 (0.060 g, 0.050 mmol),
2
1JCF ) 212.0 Hz), 136.9, 132.7, 122.8 (d, JCF ) 80.0 Hz), 117.8
2
2
(d, JCF ) 60.0 Hz), 116.1 (d, JCF ) 72.0 Hz), 66.3, 60.1, 59.6,
57.5, 53.4, 53.2, 52.8, 51.9. IR (thin film, cm-1): 3425, 2956, 1722,
1612, 1519, 1503, 1437, 1345, 1284, 1222, 1118, 1059. High
resolution mass spectrum m/z 394.1095 [(M + Na+) calcd for
C17H19NO6NaF2+: 394.1078]. [R]23 -28.7 (c 4.0, CHCl3). 78:22
D
er; HPLC analysis, tr major (of single diastereomer) 9.7 min, tr
minor (of single diastereomer) 11.2 min [ChiralcelAD column,
hexanes:IPA 90:10, 1.0 mL/min].
(b) 2-[(R)-Allyloxycarbonylamino-3,4-diflurophenylmethyl)-
3-oxo-butyric Acid Methyl Ester (10b). White solid (0.97 g, 97%
yield). Mp: 97-100 °C. 1H NMR (CDCl3, 400 MHz, both
diastereomers reported): δ 7.12 (m, 6H), 6.99 (s, 2H), 6.41 (d, J )
8.8 Hz, 1H), 6.25 (d, J ) 9.2 Hz, 1H), 5.85 (m, 2H), 5.47 (m, 1H),
5.37 (dd, J ) 6.8, 2.0 Hz, 1H), 5.21 (m, 5H), 4.49 (d, J ) 1.6 Hz,
4H), 4.00 (d, J ) 5.6 Hz, 1H), 3.94 (d, J ) 4.0 Hz, 1H), 3.68 (s,
3H), 3.66 (s, 3H), 2.23 (s, 3H), 2.00 (s, 3H). 13C NMR (CDCl3,
75.0 MHz, both diastereomers reported): δ 202.0, 199.6, 170.5,
1
168.2, 166.6, 155.0, 154.8, 150.6 (d, JCF ) 220.0 Hz), 148.1 (d,
1JCF ) 220.0 Hz), 131.8, 121.6 (d, 2JCF ) 24.0 Hz), 117.2 (d, 2JCF
) 44.0 Hz), 115.2 (d, 2JCF ) 72.0 Hz), 65.4, 63.0, 59.7, 52.1, 51.7,
30.0, 29.5, 22.0. IR (thin film, cm-1): 3423, 2996, 1720, 1649, 1612,
1519, 1503, 1437, 1363, 1284, 1219, 1147, 1119, 1061. High
resolution mass spectrum m/z 364.0954 [(M + Na+) calcd for
(21) (a) Mizuno, T.; Fukamatsu, T.; Takeuchi, M.; Shinkai, S. J. Chem. Soc.,
Perkin Trans. 1 2000, 407–413. (b) Cowart, M.; Latshaw, S. P.; Bhatia, P.;
Daanen, J. F.; Rohde, J.; Nelson, S. L.; Patel, M.; Kolasa, T.; Nakane, M.; Uchic,
M. E.; Miller, L. N.; Terranova, M. A.; Chang, R.; Donnelly-Roberts, D. L.;
Namovic, M. T.; Hollingsworth, P. R.; Martino, B. R.; Lynch, J. J.; Sullivan,
J. P.; Hsieh, G. C.; Moreland, R. B.; Brioni, J. D.; Stewart, A. O. J. Med. Chem.
2004, 47, 3853–3864.
C16H17NO5NaF2+: 364.0972]. [R]23 -32.4 (c 4.0, CHCl3). 94:6
D
er; HPLC analysis, tr major (of single diastereomer) 23.7 min, tr
J. Org. Chem. Vol. 73, No. 19, 2008 7655

Goss and Schaus
minor (of single diastereomer) 31.9 min [ChiralcelAD-H column,
hexanes:IPA 95:5, 1.0 mL/min].
16.0 Hz, 2H). 13C NMR (CDCl3, 75.0 MHz): δ 171.5, 169.2, 153.9,
152.6, 149.2, 146.5, 144.6, 139.0, 137.7, 129.5, 123.3, 122.8, 118.0,
117.8 (d, 2JCF ) 68.0 Hz), 116.6 (d, 2JCF ) 72.0 Hz), 101.7, 68.3,
59.5, 55.5, 53.6, 53.5, 52.1, 40.9, 38.6, 30.6, 25.0, 24.9, 21.4. IR
(thin film, cm-1): 3291, 2950, 2501, 1713, 1647, 1409, 1517, 1436,
1394, 1313, 1280, 1219, 1117, 1083, 964, 912. [R]23D +130 (c 2.0,
CHCl3).
(c) (S)-Methyl-4-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (12). White solid (0.254 g,
1
90% yield). Mp: 204-206 °C. H NMR (DMSO, 400 MHz): δ
4
9.31 (s, 1H), 7.82 (s, 1H), 7.35 (d and ddCF, J ) 6.4 Hz, JCF
)
)
8.4 Hz, 4JCF ) 10.8 Hz, 1H), 7.20 (d and ddCF, J ) 6.0 Hz, 4JCF
4
8.0 Hz, JCF ) 10.8 Hz, 1H), 7.07 (m, 1H), 5.15 (d, J ) 3.6 Hz,
Acknowledgment. The authors acknowledge CEM Corpora-
tion (Matthew, NC) for microwave instrumentation and Symyx,
Inc. (Santa Clara, CA) for chemical reaction planning software.
The authors thank ChemAxon (Budapest, Hungary), Molinspi-
ration Cheminformatics (Slovak Republic), and OpenEye Sci-
entific Software (Santa Fe, NM) for academic software support.
This research was supported by a gift from Amgen, Inc. and
the NIH (R01 GM078240).
1H), 3.52 (s, 3H), 2.25 (s, 3H). 13C NMR (DMSO, 75.0 MHz): δ
1
2
165.9, 152.2, 149.7, 147.9 (d, JCF ) 236.3 Hz), 142.6 (d, JCF
)
2
2
16.0 Hz), 123.1, 117.8 (d, JCF ) 68.3 Hz), 115.5 (d, JCF ) 68.0
Hz), 98.5, 53.3, 51.1, 18.3. IR (thin film, cm-1): 3328, 2922, 2850,
1696, 1645, 1516, 1434, 1279, 1228, 1093. High resolution mass
+
spectrum m/z 283.0912 [(M + H+) calcd for C13H13N2O3F2
:
283.0894]. [R]23D +10.0 (c 2.0, CHCl3). >99:1 er HPLC analysis,
tr minor 18.2 min, tr major 27.0 min [ChiralcelOD column, hexanes:
IPA 95:5, 1.0 mL/min].
(d) SNAP-7941 (1). Yellow oil (0.055 g, 0.090 mmol). 1H NMR
(CDCl3, 400 MHz): δ 8.90 (s, 1H), 8.11 (s, 1H), 7.79 (s, 1H), 7.50
(d, J ) 8.00 Hz, 1H), 7.26 (s, 1H), 7.20 (s, 1H), 7.13 (m, 2H),
7.02 (m, 2H), 6.84 (d, J ) 8.00 Hz, 1H), 6.56 (s, 1H), 4.61 (s,
2H), 3.65 (s, 3H), 3.42 (s, 3H), 3.31 (m, 3H), 2.82 (m, 2H), 2.54
(m, 2H), 2.18 (m, 2H), 2.12 (s, 3H), 1.99 (m, 4H), 1.83 (d, J )
Supporting Information Available: Experimental proce-
dures, characterization data, and chiral chromatographic analysis.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO801463J
7656 J. Org. Chem. Vol. 73, No. 19, 2008