Synthesis of enantiomerically pure (S)-methanocarbaribo uracil nucleoside derivatives for use as antiviral agents and P2Y receptor ligands

Article abstract of DOI:10.1021/jo801224j

(Chemical Equation Presented) We have developed an approach toward enantiomerically pure (S)-methanocarba ribonucleosides based on several functional group transformations on a sensitive bicyclo[3.1.0]-hexane system. D-Ribose was transformed into methanocarba alcohol 3 followed by conversion of the OH group to a nitrile with inversion of configuration at C4. The nitrile group was subsequently reduced in two stages to the 5′-hydroxymethyl group. An ester group appended to a tertiary carbon (Cl) was transformed to an amino group as a nucleobase precursor.

Full text of DOI:10.1021/jo801224j

SCHEME 1
Synthesis of Enantiomerically Pure
(S)-Methanocarbaribo Uracil Nucleoside
Derivatives for Use as Antiviral Agents and P2Y
Receptor Ligands
Artem Melman,†,‡ Minghong Zhong,§ Victor E. Marquez,*,§
and Kenneth A. Jacobson*,‡
Department of Chemistry and Biomolecular Science,
Clarkson UniVersity, Potsdam, New York 13699, Molecular
Recognition Section, Laboratory of Bioorganic Chemistry,
National Institute of Diabetes and DigestiVe and Kidney
Diseases, National Institutes of Health, Bethesda, Maryland
20892, and Laboratory of Medicinal Chemistry, Center for
Cancer Research, NCI-Frederick, NIH,
osteosarcoma cells without the toxicity of its North counterpart.2
In the study of the GPCRs (G protein-coupled receptors) that
respond to extracellular nucleosides (adenosine receptors) and
nucleotides (P2Y receptors), the preference for a North (N) or
South (S) ribose conformation depends on the receptor
subtype.1,3-5 The P2Y6 receptor for UDP prefers the (S)-
methanocarba analogue of dUDP, which is more potent than
the corresponding 2′-deoxyriboside, dUDP. This knowledge is
now being used to design additional nucleotide analogues having
enhanced potency and selectivity for a given receptor subtype.
(N)-Methanocarba analogues of 2′-deoxyadenosine 3′,5′-bis-
phosphates constitute the most potent and selective antagonists
of the P2Y1 receptor, which have potential as antithrombotic
agents.5,6
Frederick, Maryland 21702
kajacobs@helix.nih.goV; marquezV@mail.nih.goV
ReceiVed June 6, 2008
Synthetic methods for methanocarba nucleosides have un-
dergone refinement based on carbene cyclopropanation, me-
tathesis, and other reactions.7-10 However, only the racemic
form of (S)-methanocarba ribonucleosides has so far been
reported.9 Our approach toward enantiomerically pure (S)-
methanocarbanucleoside 1 (Scheme 1) was based on a previ-
ously published synthesis of (N)-methanocarba-based agonists
of the A3 adenosine receptor.11 The synthesis of the North
template started from L-ribose and involved as a key intermedi-
ate compound 2. A closer look at its enantiomer 3 and the target
(S)-methanocarba derivative 1 revealed a similar carbocyclic
skeleton possessing an identical configuration of the two OH
groups at positions 2 and 3. Enantiomer 3 can be therefore
We have developed an approach toward enantiomerically
pure (S)-methanocarba ribonucleosides based on several
functional group transformations on a sensitive bicyclo[3.1.0]-
hexane system. D-Ribose was transformed into methanocarba
alcohol 3 followed by conversion of the OH group to a nitrile
with inversion of configuration at C4. The nitrile group was
subsequently reduced in two stages to the 5′-hydroxymethyl
group. An ester group appended to a tertiary carbon (C1)
was transformed to an amino group as a nucleobase
precursor.
(3) Kim, H. S.; Ravi, R. G.; Marquez, V. E.; Maddileti, S.; Wihlborg, A.-
K.; Erlinge, D.; Malmsjo¨, M.; Boyer, J. L.; Harden, T. K.; Jacobson, K. A. J. Med.
Chem. 2002, 45, 208–218.
(4) Costanzi, S.; Joshi, B. V.; Maddileti, S.; Mamedova, L.; Gonzalez-Moa,
M.; Marquez, V. E.; Harden, T. K.; Jacobson, K. A. J. Med. Chem. 2005, 48,
8108–8111.
(5) Kim, H. S.; Ohno, M.; Xu, B.; Kim, H. O.; Choi, Y.; Ji, X. D.; Maddileti,
S.; Marquez, V. E.; Harden, T. K.; Jacobson, K. A. J. Med. Chem. 2003, 46,
4974–4987.
(6) Hechler, B.; Nonne, C.; Roh, E. J.; Cattaneo, M.; Cazenave, J. P.; Lanza,
F.; Jacobson, K. A.; Gachet, C. J. Pharm. Exp. Therap. 2006, 316, 556–563.
(7) Lee, K.; Cass, C.; Jacobson, K. A. Org. Lett. 2001, 3, 597–599.
(8) Gallos, J. K.; Koftis, T. V.; Massen, Z. S.; Dellios, C. C.; Mourtzinos,
I. T.; Coutouli-Argyropoulou, E.; Koumbis, A. E. Tetrahedron 2002, 58, 8043–
8053.
Recent studies of the SAR of nucleosides and nucleotides as
antiviral agents and receptor ligands have reported that confor-
mational constraint of the ribose ring of such ligands allows
the identification of preferred conformations of the normally
freely interconverting sugar ring. Use of the methanocarba
bicyclo[3.1.0]hexane ring system, which can be fixed in a North
(N) or South (S) rigid envelope conformation,1 as a ribose
substitute has greatly aided these studies. For example, (S)-
methanocarbathymidine specifically inhibits the growth of
herpes simplex virus type 1 thymidine kinase-transduced
(9) Shin, K. J.; Moon, H. R.; George, C.; Marquez, V. E. J. Org. Chem.
2000, 65, 2172–2178.
(10) Lee, J. A.; Kim, H. O.; Tosh, D. K.; Moon, H. R.; Kim, S.; Jeong, L. S.
Org. Lett. 2006, 8, 5081–5083.
† Clarkson University.
‡ National Institute of Diabetes and Digestive and Kidney Diseases.
§ NCI-Frederick.
(1) Marquez, V. E.; Siddiqui, M. A.; Ezzitouni, A.; Russ, P.; Wang, J.;
Wagner, R. W.; Matteucci, M. D. J. Med. Chem. 1996, 39, 3739–3747.
(2) Schelling, P.; Claus, M. T.; Johnert, R.; Marquez, V. E.; Schulz, G. E.;
Scapozza, L. J. Biol. Chem. 2004, 279, 32832–32838.
(11) (a) Tchilibon, S.; Joshi, B. V.; Kim, S. K.; Duong, H. T.; Gao, Z. G.;
Jacobson, K. A. J. Med. Chem. 2005, 48, 1745–1758. (b) Joshi, B. V.; Moon,
H. R.; Fettinger, J. C.; Marquez, V. E.; Jacobson, K. A. J. Org. Chem. 2005,
70, 439–447.
10.1021/jo801224j CCC: $40.75
Published on Web 09/24/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8085–8088 8085

SCHEME 2
SCHEME 3
SCHEME 4
converted into the target (S)-methanocarbanucleotide 1 through
(a) replacement of the C4 hydroxyl with a CH2OH group
accompanied by inversion of configuration at C4 and (b)
conversion of the ester group into a 2,4-pyrimidinedione ring.
Our initial synthetic plan (Scheme 1) involved conversion
of alcohol 3 into alcohol 4 through substitution with a one-
carbon nucleophile synthon. Subsequent transformations of
alcohol 4 included converting the ester function into a primary
amino group followed by final assembly of the uracil ring.
Preparation of alcohol 6 (Scheme 2) from D-ribose followed
a published procedure for the synthesis of its enantiomer12 and
was accomplished in 6% overall yield.13 Subsequent acid-
catalyzed rearrangement of alcohol 6 provided a 60:40 equi-
librium mixture of alcohols 3 and 6 that could not be separated
chromatographically. The equilibrium mixture was enriched to
a ratio of 80:20 by the selective crystallization of alcohol 6,
leading to further enhancement to a ratio of 90:10 through
recrystallization. The resulting mixture of alcohols 3 and 6 was
converted into the corresponding triflates 7 and 8, which could
be separated chromatographically. However, due to instability
of triflates 7 and 8 all subsequent experiments were done with
the mixture without purification.
isomers could be subjected to nucleophilic substitution to
provide nitrile 11 as the only isomer in 63% yield.14
Our original synthetic plan involved hydrolysis of the ester
group in nitrile 11 followed by a Curtius rearrangement.
However, basic hydrolysis of nitrile 11 with NaOH in
MeOH-H2O (Scheme 3) resulted in formation of either ethyl
4-cyanobenzoate or 4-cyanobenzoic acid rather than the expected
plain hydrolysis of the carboxylic group. The same outcome
was observed with other reagents commonly used for basic
hydrolysis, such as H2O-Et3N or K2CO3.
Since (N)-methanocarba derivatives are generally stable to
bases, the observed transformation is undoubtedly related to the
presence of an acidic proton at the R-position to the cyano group.
The most probable mechanism of the rearrangement involves
C4 deprotonation followed by ring-opening of the cyclopropane
ring driven by the strain of the bicyclo[3.1.0]hexane system and
aromatization of the resulting carbanion through sequential
ꢀ-eliminations to give ethyl 4-cyanobenzoate 14.
A first attempt at substitution with a one-carbon nucleophilic
synthon involved reaction of triflate 8 with 2-lithio 1,3-dithiane
(Scheme 2). Although triflate 8 was found to be unstable under
the reaction conditions the nucleophilic substitution provided
the desired dithiane 9 in 35% yield. The reaction proceeded
with inversion of configuration at C4, as evidenced by a change
in the coupling constants J3,4 and J4,5 from 6 Hz to 0 in the 1H
NMR spectrum. Subsequent mercury perchlorate-assisted hy-
drolysis of dithiane 9 resulted in aldehyde 10 in low yield, most
probably due to the instability of the compound. Final reduction
of aldehyde 10 with NaBH4 provided target alcohol 4.
Since the overall yield of alcohol 4 by this method was low,
we tried an alternative one-carbon nucleophilic synthon. Nu-
cleophilic substitution in triflate 8 with sodium cyanide (Scheme
2) provided the nitrile 11, although in only 40% yield; however,
replacement of sodium cyanide with lithium cyanide resulted
in improved yield. Furthermore, we found that separation of
triflates 8 and 7 was not necessary, and a 90:10 mixture of these
We surmised that the undesired transformation could be
avoided by decreasing the acidity of the R-proton at C4. This
can be most easily accomplished through a reduction of the
cyano group to obtain a CH2OH group. However, reduction of
the cyano group of the nitrile was complicated since complex
hydrides that are most commonly used for such transformations
are incompatible with the ester functionality of nitrile 11. This
problem was solved through the catalytic hydrogenation of
nitrile 11 (Scheme 4). Although catalytic hydrogenation of
nitriles is most commonly used for the preparation of amines,15
we found that the reaction could be stopped at the stage of
aldehyde 10. Conducting the hydrogenation in a MeOH-H2O-
AcOH solution resulted in rapid hydrolysis of the initially
formed imine 15, thus preventing its further reduction. The
resulting unstable aldehyde 10 was immediately reduced with
NaBH4 to yield alcohol 4 in 55% overall yield.
TBDPS protection of alcohol 4 produced silyl ether 16, which
was hydrolyzed into acid 17 (Scheme 4). Acid 17 was converted
into the corresponding azide 18 through formation of a mixed
(12) Joshi, B. V.; Melman, A.; Mackman, R. L.; Jacobson, K. A. Nucleosides,
Nucleotides, & Nucleic Acids 2008, 27, 279–291.
(13) All intermediate compounds possessed spectral data identical with those
published in ref 12.
(14) Triflate 7 presumably does not produce the corresponding nitrile.
(15) Hudlicky, M. Reductions in Organic Chemistry; American Chemical
Society: Washington, DC, 1984; pp 239-240.
8086 J. Org. Chem. Vol. 73, No. 20, 2008

SCHEME 5
mL), H2O (1.5 mL), and HOAc (0.5 mL) was treated with 10%
Pd/C (20 mg). The flask was filled with hydrogen and stirred for
2 h at room temperature. The mixture of unreacted nitrile 11 and
aldehyde 10 was filtered, and the filtrate was evaporated at room
temperature. The residue was dissolved in EtOAc (30 mL), washed
with satd NaHCO3-H2O solution until CO2 evolution ceased, dried
(Na2SO4), and evaporated at room temperature. The residue was
purified by flash chromatography (20% to 30% EtOAc-hexane)
to afford the crude aldehyde, which was dissolved in MeOH (5
mL) and treated with NaBH4 (20 mg, 0.5 mmol), followed by
acetone (1 mL) after 10 min). The reaction mixture was evaporated
and the residue was dissolved in EtOAc (20 mL), washed with
brine (3 mL), dried (Na2SO4), and evaporated. The residue was
purified by flash chromatography (20 to 30% EtOAc-hexane) to
afford the title compound as a colorless oil (0.14 g, 0.55 mmol,
55%). [R]20D -18.35 (c 0.60, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 5.36 (d, 1H, J ) 6.6 Hz), 4.59 (d, 1H, J ) 6.9 Hz), 4.15 (m,
2H), 3.66 (br m, 2H), 2.37 (t, 1H, J ) 6.0 Hz), 1.99 (dd, 1H, J )
6.0, 9.3 Hz), 1.49 (s, 3H), 1.42 (t, 1H, J ) 5.2 Hz), 1.29 (s, 3H),
1.25 (t, 3H, J ) 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 172.8,
110.0, 85.0, 80.5, 64.6, 60.9, 46.8, 37.6, 35,5, 26.2, 24.1, 19.6, 14.2.
(1S,2S,5S,3R,4R)-1-Ethoxycarbonyl-4-[(tert-butyldiphenylsily-
loxy)g, 3.1 mmol) and imidazole (0.10 g, 1.5 mmol) in DMF
methyl]-2,3-O-isopropylidene-2,3-dihydroxybicyclo[3.1.0]hexane (16).
To a stirred solution of alcohol 4 (0.80 g, 3.1 mmol) and imidazole
(0.10 g, 1.5 mmol) in DMF (3 mL) was added neat tert-
butyldiphenylchlorosilane (1.26 g, 4.5 mmol) followed by the
dropwise addition of triethylamine (0.81 g, 8 mmol). The reaction
mixture was stirred for 14 h at room temperature, diluted with 20%
EtOAc-hexane (50 mL), washed with water (2 × 20 mL) and
brine, dried (Na2SO4), and evaporated. The residue was purified
by flash chromatography (0% to 20% EtOAc-hexane) to give silyl
anhydride followed by reaction with sodium azide. Thermal
rearrangement of azide 18 was conducted in the presence of
benzyl alcohol and resulted in the Cbz-protected amine 19,
which was deprotected by hydrogenation to afford amine 20
(Scheme 5).
Building of the uracil ring from amine 20 followed a
previously described procedure for the syntheses of chiral 2′-
deoxyribo versions of (S)-methanocarbanucleosides.16 Reaction
of the amine 20 with an 3-ethoxyacryloyl isocyanate16 afforded
the urea 21 in 70% yield. Cyclization of 21 with ethanolic HCl
resulted in the concomitant removal of the acetal and TBDPS
protection of the hydroxyl groups, to yield the target (S)-
methanocarba nucleoside 1 in 21% yield from compound 21.
In conclusion, we have developed an approach toward
enantiomerically pure (S)-methanocarba nucleosides based on
functionalgrouptransformationonasensitivebicyclo[3.1.0]hexane
system. These derivatives are now suitable for detailed studies
in biological systems.
ether 16 as a colorless oil (1.05 g, 2.1 mmol, 69%); [R]20 -45.8
D
(c 0.98, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.64 (m, 4H), 7.42
(m, 6H), 5.37 (d, 1H, J ) 7.2 Hz), 4.57 (d, 1H, J ) 7.2 Hz), 4.13
(m, 2H), 3.65 (br. m, 2H), 2.35 (t, 1H, J ) 4.8 Hz), 2.07 (dd, 1H,
J ) 6.0, 9.6 Hz), 1.50 (s, 3H), 1.41 (t, 1H, J ) 5.1 Hz), 1.29 (s,
3H), 1.24 (t, 3H, J ) 7.2 Hz), 1.05 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 172.9, 135.7, 133.1, 129.9, 127.8, 110.9, 85.5, 80.9, 65.9,
60.9, 46.7, 38.1, 36.2, 26.9, 26.3, 24.2, 19.9, 19.2, 14.3.
Experimental Section
(1S,2S,5S,3R,4R)-1-Ethoxycarbonyl-4-cyano-2,3-O-isopropylidene-
2,3-dihydroxybicyclo[3.1.0] hexane (11). A solution of alcohol 3
(0.97 g, 4 mmol) and pyridine (0.35 g, 4.4 mmol) in CH2Cl2 (8.8
mL) at 0 °C was treated dropwise over a period of 2 min with a
solution of trifluoromethanesulfonic anhydride (1.24 g, 4.4 mmol)
in CH2Cl2 (8.8 mL). The reaction mixture was stirred at 0 °C for
10 min more after the addition was completed, and hexane (25
mL) was added. After 5 min the resulting suspension was filtered
through a pad of silica gel and the silica gel was washed with a
30% EtOAc-hexane mixture (100 mL). The combined organic
filtrates were evaporated at room temperature, the resulting residue
of the triflate was dissolved in dry CH2Cl2 (2 mL) at 0 °C, and a
0.5 M solution of lithium cyanide in DMF (7.8 mL) was added to
the solution. The reaction mixture was stirred at 0 °C for 30 min,
dissolved in a 50% EtOAc-hexane mixture (50 mL), washed with
water (2 × 10 mL) and brine (1 × 10 mL), dried (Na2SO4), and
evaporated. The residue was purified by flash chromatography (10%
(1S,2S,5S,3R,4R)-4-[(tert-Butyldiphenylsilyloxy)methyl]-2,3-O-
isopropylidene-2,3-dihydroxybicyclo[3.1.0]hexane-1-carboxylic Acid
(17). A solution of silyl ether 16 (1.0 g, 2 mmol) in methanol (50
mL) was treated with 6 M NaOH (4 mL) and stirred under reflux
for 2 h, evaporated, neutralized with conc HCl, and extracted with
CH2Cl2 (3 × 30 mL). The combined organic extracts were dried
(Na2SO4) and evaporated, and the residue was purified by flash
chromatography (10% to 50% EtOAc-hexane) to afford 17 as a
colorless oil (0.71 g, 1.5 mmol, 76%); [R]20D -51.5 (c 0.80, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.62 (m, 4H), 7.39 (m, 6H), 5.32
(d, 1H, J ) 7.2 Hz), 4.53 (d, 1H, J ) 7.2 Hz), 3.65 (br m, 2H),
2.38 (t, 1H, J ) 4.8 Hz), 2.15 (m, 1H), 1.60 (m, 1H), 1.50 (s, 3H),
1.29 (s, 3H), 1.27 (t, 3H, J ) 7.2 Hz), 1.05 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 179.8, 135.7, 133.1, 129.9, 127.9, 111.1, 85.2, 80.4,
65.8, 46.8, 37.8, 36.9, 26.9, 26.3, 24.2, 20.7, 19.2.
(1S,2S,5S,3R,4R)-1-Azidocarbonyl-4-[(tert-butyldiphenylsily-
loxy)methyl]-2,3-O-isopropylidene-2,3-dihydroxybicyclo[3.1.0]hex-
ane (18). A solution of acid 17 (0.70 g, 1.5 mmol) and N,N-
diisopropylethylamine (0.20 g, 1.6 mmol) in acetone (15 mL) at
room temperature was treated with neat diphenylchlorophosphate
(0.43 g, 1.6 mmol). The reaction mixture was stirred for 30 min
followed by treatment with aqueous sodium azide (0.13 g in 2 mL,
2 mmol). The reaction mixture was stirred for 30 min and
evaporated at room temperature, then the residue was partitioned
between water (10 mL) and CH2Cl2 (50 mL). The organic layer
was dried (Na2SO4) and evaporated, and the residue was purified
by flash chromatography (10 to 30% EtOAc-hexane) to afford the
to 20% EtOAc-hexane) to afford 11 as colorless oil (0.63 g, 2.5
1
mmol, 63%); [R]20 -77.9 (c 1.82, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 5.54 (d, 1H, J ) 6.9 Hz), 4.90 (d, 1H, J ) 6.9 Hz), 4.20
(m, 2H), 3.18 (s, 1H), 2.40 (dd, 1H, J ) 5.7, 9.6 Hz), 1.67 (dd,
1H, J ) 5.4, 9.3 Hz), 1.50 (s, 3H), 1.42 (t, 1H, J ) 5.4 Hz), 1.30
(s, 3H), 1.29 (t, 3H, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ
170.9, 119.1, 112.9, 85.7, 80.7, 61.5, 35.6, 34.8, 26.0, 24.2, 19.3,
14.2.
(1S,2S,5S,3R,4R)-1-Ethoxycarbonyl-2,3-O-isopropylidene-2,3-di-
hydroxy-4-(hydroxymethyl)bicyclo[3.1.0]hexanecarboxylate (4).
Method A. A solution of nitrile 11 (0.25 g, 1 mmol) in MeOH (3
title compound as a colorless oil (0.67 g, 0.13 mmol, 88%); [R]20
D
(16) Ezzitouni, A.; Marquez, V. E. J. Chem. Soc., Perkin Trans. 1 1997,
1073–1078.
1
-63.0 (c 0.48, CHCl3); H NMR (300 MHz, CDCl3) δ 7.63 (m,
J. Org. Chem. Vol. 73, No. 20, 2008 8087

4H), 7.35 (m, 6H), 5.21 (d, 1H, J ) 6.3 Hz), 4.45 (d, 1H, J ) 7.2
Hz), 3.59 (d, 2H, J ) 4.2 Hz), 2.29 (t, 1H, J ) 4.2 Hz), 2.10 (m,
1H), 1.56 (m, 1H), 1.50 (m, 1H), 1.41 (s, 3H), 1.20 (s, 3H), 0.99
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 179.4, 135.7, 133.1, 130.0,
127.9, 111.2, 85.4, 80.4, 65.8, 46.2, 41.1, 38.3, 26.9, 26.3, 24.2,
21.9, 19.3.
evaporated for reaction with amine 20. The evaporated aliquot was
dissolved in CH2Cl2 (2 mL) and added to a precooled (-78 °C)
solution of amine 20 (0.20 g, 0.46 mmol). The reaction mixture
was allowed to warm to room temperature and stirred for 14 h.
The reaction mixture was evaporated and the residue was purified
by flash chromatography to afford the title urea as a pale yellow
1
N-{(1S,2S,5S,3R,4R)-1-Benzyloxycarbamino}-4-[(tert-butyldiphenyl-
silyloxy)methyl]-2,3-O-isopropylidene-2,3-dihydroxybicyclo[3.1.0]hex-
ane (19). A solution of azidoketone 18 (0.67 g, 1.3 mmol) and benzyl
alcohol (1 mL) in toluene (20 mL) was refluxed for 5 h. The reaction
mixture was evaporated, then the residue was twice purified by
flash chromatography (5% methanol-chloroform, then 30%
oil (0.20 g, 0.34 mmol, 74%); [R]20 -32.7 (c 0.44, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 9.09 (s, 1H, 8.92 (s, 1H), 7.66 (m,
4H), 7.57 (d, 1H, J ) 12.0 Hz), 7.36 (m, 6H), 5.16 (d, 1H, J ) 12
Hz), 5.05 (d, 1H, J ) 7.2 Hz), 4.43 (d, 1H, J ) 7.2 Hz), 3.82 (m,
4H), 2.34 (t, 1H, J ) 7.8 Hz), 1.67 (dd, 1H, J ) 4.8, 9.0 Hz), 1.50
(s, 3H), 1.23 (m, 7H), 1.05 (s, 9H); 13C (75 MHz, CDCl3) δ 167.4,
163.0, 155.1, 135.6, 133.8, 129.7, 127.7, 110.9, 97.8, 83.8, 83.5,
67.6, 65.3, 47.9, 45.2, 31.4, 27.0, 26.3, 24.1, 19.4, 17.4, 14.5.
EtOAc-hexane) to afford title compound as a colorless oil (0.54
1
g, 1.1 mmol, 69%); [R]20 -24.7 (c 1.08, CHCl3); H NMR (300
D
MHz, CDCl3) δ 7.78 (br d, 4H), 7.37 (m, 11H), 5.32 (br s, 1H),
5.18 (br s, 2H), 5.05 (br d, 1H, J ) 5 Hz), 4.57 (br d, 1H, J ) 6
Hz), 3.97 (br s, 2H), 2.42 (br t, 1H, J ) 6.6 Hz), 1.72 (m, 1H),
1.60 (s, 3H), 1.29 (s, 3H), 1.43 (s, 3H), 1.19 (s, 9H), 1.08 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 159.1, 156.2, 136.6, 135.8, 135.7,
129.8, 127.9, 128.2, 128.6, 133.8, 111.0, 84.1, 83.4, 66.6, 65.3,
47.7, 46.0, 31.4, 27.0, 26.3, 24.2, 19.4, 17.7.
1-[(1S,2S,5S,3R,4R)-2,3-Dihydroxy-4-(hydroxymethyl)bicyclo[3.1.0]-
hexyl]-1,3-dihydropyrimidine-2,4-dione (1). A solution of urea 21
(0.20 g, 0.34 mmol) in ethanol (3 mL) was added conc HCl (0.1
mL). The reaction mixture was refluxed for 5 h, then evaporated.
The residue was purified by flash chromatography (0 to 20%
MeOH-chloroform) to afford compound as amorphous solid (18
1
mg, 0.071 mmol, 21%); [R]20 -51.6 (c 0.64, MeOH); H NMR
D
(1S,2S,5S,3R,4R)-1-Amino-4-[(tert-butyldiphenylsilyloxy)methyl]-
2,3-O-isopropylidene-2,3-dihydroxybicyclo[3.1.0] hexane (20). A solu-
tion of benzyl carbamate 19 (0.63 g, 1.1 mmol) in methanol (5
mL) was stirred under hydrogen in the presence of 10% Pd on
carbon (50 mg) for 2 h at atmospheric pressure. The reaction
mixture was filtered and the residue was evaporated to afford the
(300 MHz, CD3OD) δ 7.50 (d, 1H, J ) 7.5 Hz), 5.59 (d, 1H, J )
8.1 Hz), 4.43 (d, 1H, J ) 6.6 Hz), 3.83 (d, 1H, J ) 6.6 Hz), 3.60
(m, 2H), 2.07 (t, 1H, J ) 4.8 Hz), 1.60-1.70-1 (m, 2H), 0.90 (m,
1H); 13C NMR (75 MHz, CD3OD) δ 184.9, 151.1, 105.3, 78.8,
76.0, 67.7, 56.2, 54.3, 29.4, 18.5, 13.5.
title compound as a colorless oil (0.42 g, 0.96 mmol, 87%); [R]20
D
Acknowledgment. We thank Dr. Dina M. Sigano for optical
rotation measurements and Drs. James A. Kelley, Christopher
Lai, and Dilip Tosh for high-resolution mass spectral measure-
ments. This research was supported in part by the Intramural
Research Programs of the National Institutes of Health, NIDDK
and the Center for Cancer Research, National Cancer Institute
at Frederick.
1
-22.9 (c 0.68, CHCl3); H NMR (300 MHz, CDCl3) δ 7.66 (m,
4H), 7.42 (m, 6H), 4.68 (d, 1H, J ) 7.5 Hz), 4.48 (d, 1H, J ) 7.5
Hz), 3.68 (m, 2H, J ) 4.2 Hz), 2.17 (t, 1H, J ) 4.2 Hz), 1.6 (m,
1H), 1.49 (s, 3H), 1.36 (m, 1H), 1.25 (s, 3H), 1.09 (s, 9H), 0.97 (t,
1H, J ) 4.2 Hz); 13C NMR (75 MHz, CDCl3) δ 135.7, 133.4, 129.9,
127.8, 88.5, 84.7, 66.4, 48.5, 47.0, 32.0, 27.1, 26.9, 26.4, 24.4, 19.4,
18.1.
(1S,2S,3R,4R)-1-(3-Ethoxyacryloyl)aminocarbamoyl-4-[(tert-butyl-
diphenylsilyloxy]-2,3-O-isopropylidene-2,3-dihydroxybicyclo[3.1.0]hex-
ane (21). To a solution of 3-ethoxyacrylic acid (2 mmol) in CH2Cl2
(1 mL) was added neat oxalyl chloride (2 mmol) and DMF (0.02
g). The reaction mixture was stirred for 30 min, then was evaporated
at room temperature. The residue was dissolved in toluene (5 mL)
and stirred with silver cyanate (4 mmol) for 4 h. The resulting
solution was filtered, and a 1.25 mL aliquot of the solution was
Supporting Information Available: General experimental
details, procedures for the synthesis of compounds 9, 10, and 4
(method B) and 1H and 13C NMR spectra and HRMS measure-
ments of all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO801224J
8088 J. Org. Chem. Vol. 73, No. 20, 2008