A Novel, One-Pot Ring Expansion of Cyclobutanones. Syntheses of Carbovir and Aristeromycin

Article abstract of DOI:10.1021/jo9919759

A novel, one-pot ring-expansion procedure was developed using Me₃S(O)I, NaH, and Sc(OTf)₃. The scope and limitations were briefly examined, and a tentative mechanism was proposed. Application of the methodology to known cyclobutanone 1 provided the corresponding cyclopentanone, which was successfully advanced to (+)-carbovir and (+)-aristeromycin.

Full text of DOI:10.1021/jo9919759

J . Org. Chem. 2000, 65, 1865-1872
1865
A Novel, On e-P ot Rin g Exp a n sion of Cyclobu ta n on es. Syn th eses of
Ca r bovir a n d Ar ister om ycin
Brian Brown and Louis S. Hegedus*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
Received December 28, 1999
A novel, one-pot ring-expansion procedure was developed using Me3S(O)I, NaH, and Sc(OTf)3. The
scope and limitations were briefly examined, and a tentative mechanism was proposed. Application
of the methodology to known cyclobutanone 1 provided the corresponding cyclopentanone, which
was successfully advanced to (+)-carbovir and (+)-aristeromycin.
In tr od u ction
An efficient synthesis of optically active R-alkyl-R-
alkoxycyclobutanones via the photolytic reaction of chro-
mium carbene complexes with optically active ene-
carbamates has been developed in these laboratories.1
These underwent clean Baeyer-Villiger oxidation to
butyrolactones with retention of configuration of the
migrating quaternary center. This chemistry was used
to synthesize (+)-tetrahydrocerulenin,2 (+)-cerulenin,3
optically active spiroketals,4 as well as a template for the
synthesis of nucleoside analogues.5 Cyclobutanone 1 was
converted to (-)-cyclobut-A,6 a carbocyclic analogue of
oxetanocin A having potent antiviral activity and good
metabolic stability7 (eq 1). Five-membered carbocyclic
nucleoside analogues are also of current interest for
similar reasons of high antiviral activity and metabolic
stability and have recently been the focus of substantial
synthetic efforts.8 Since cyclobutanones are known to
undergo carbocyclic ring expansion to cyclopentanones
under a variety of conditions,9 the chemistry in eq 1 offers
a potential synthetic approach to carbocyclic nucleoside
analogues such as carbovir and aristeromycin, provided
the expansion occurs with the desired regioselectivity.
Below are presented studies addressing the develop-
ment of novel carbocyclic ring expansion methodology and
its application to the synthesis of carbovir and aristero-
mycin.
Resu lts a n d Discu ssion
Diazomethane methodology offers a simple, one-step
procedure for the ring expansion of cyclobutanones to
cyclopentanones.10 With unsymmetrical cyclobutanones,
migration of the less-substituted R-carbon is generally
favored, but regioselectivity is dependent on many other
factors, and predictions are difficult. Treatment of trisub-
stituted cyclobutanone 1 with diazomethane resulted in
efficient ring expansion to cyclopentanones 2 and 3 in a
3:1 ratio, with the undesired regioisomer 2 (migration of
the less substituted carbon) predominating. R-Deoxygen-
ation with SmI2, to produce disubstituted cyclobutanone
4, followed by treatment with diazomethane produced
cyclopentanones 5 and 6, again in good yield, but with
little regioselectivity (eq 2). Use of TMSCHN2, with and
without use of Lewis acid additives, also failed to provide
the desired compounds. Thus, attention was turned from
diazoalkanes in search of more effective reagents for the
desired ring expansion.
(1) (a) Hegedus, L. S.; Bates, R. W.; So¨derberg, B. C. J . Am. Chem.
Soc. 1991, 113, 923. (b) Riches, A. G.; Wernersbach, L. A.; Hegedus,
L. S. J . Org. Chem. 1998, 63, 4691. (c) For a review of photochemical
reactions of chromium carbene complexes, see: Hegedus, L. S.
Tetrahedron 1997, 53, 4105.
(2) Miller, M. W.; Hegedus, L. S. J . Org. Chem. 1993, 58, 6779.
(3) Kedar, T. E.; Miller, M. W.; Hegedus, L. S. J . Org. Chem. 1996,
61, 6121.
(4) Bueno, A. B.; Hegedus, L. S. J . Org. Chem. 1998, 63, 684.
(5) (a) Reed, A. D.; Hegedus, L. S. Organometallics 1997, 16, 2313.
(b) Reed, A. D.; Hegedus, L. S. J . Org. Chem. 1995, 60, 3787. (c)
Umbricht, G.; Hellman, M. D.; Hegedus, L. S. J . Org. Chem. 1998, 63,
5173.
(6) Brown, B.; Hegedus, L. S. J . Org. Chem. 1998, 63, 8012.
(7) Norbeck, D. W.; Kern, E.; Hayashi, S.; Rosenbrook, W.; Sham,
H.; Herrin, T.; Plattner, J . J .; Erikson, J .; Clement, J .; Swanson, R.;
Shipkowitz, N.; Hardy, D.; Marsh, K.; Arnett, G.; Shannon, W.; Broder,
S.; Matsuya, H. J . Med. Chem. 1990, 33, 1281.
A variety of sulfur-stabilized anions have been used
to mediate carbocyclic ring expansions.10 Specifically,
(8) For a review see: Crimmins, M. T. Tetrahedron 1998, 54, 9229.
(9) For a review see: (a) Bellus, D.; Ernst, B. Angew. Chem., Int.
Ed. Engl. 1987, 27, 797. (b) Lee-Ruff, E. New Synthetic Pathways from
Cyclobutanones. In Advances in Strain in Organic Chemistry; Halton,
B., Ed.; J AI Press: Greenwich, CT, 1991; Vol. 1.
(10) Wong, H. C. N. In Houben-Weyl Methods of Organic Chemistry;
de Meijere, A., Ed.; Georg Thieme Verlag: Stuttgart, Germany, 1997;
Vol. E17e, pp 495-521.
10.1021/jo9919759 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/02/2000

1866 J . Org. Chem., Vol. 65, No. 6, 2000
Brown and Hegedus
Trost has added substituted R-lithiomethyl phenyl sul-
fones to cyclic ketones to form intermediate alkoxides,
sion along with elimination of ethanol to produce cyclo-
pentenone 9 as the sole regioisomer, but in poor yield
(eq 4).
In an attempt to shorten this route, and patterned after
Trost’s Lewis acid-induced rearrangements mentioned
above, Et3Al was added to the reaction of cyclobutanone
1 with dimethylsulfoxonium methylide to promote ring
expansion over epoxidation. This novel, one-pot procedure
did form the ring-expanded products, solely of the desired
regiochemistry, although in modest yield and selectivity.
In experiments to gain insight into this reaction, the
isolated epoxide 8 was treated with Et3Al in DMF, which
provided only recovered starting material. This indicated
that the reaction was not simply a Lewis acid-catalyzed
rearrangement of an epoxide intermediate. When NaI
(concomitantly generated with the ylide in the reaction
of Me3S(O)I with NaH) was included in the experiment
above, the ring expansion products were again observed.
Iodohydrin 10 was also found when the corresponding
2-methoxy-2-methylcyclobutanone was treated under the
same conditions. Therefore, the reaction is believed to
occur via epoxidation, followed by Lewis acid-catalyzed
iodohydrin formation, and rearrangement to the cyclo-
pentyl compounds. Other experiments demonstrated the
requirement for DMSO (generated in the epoxide forma-
tion) in effecting smooth rearrangement. Its exact func-
tion, however, is still not understood, and further mecha-
nistic studies will be required.
which were rearranged under Lewis acidic conditions to
ring-expanded products.12a Additionally, Gadwood has
employed a similar method using methyl o-chlorophenyl-
sulfoxide anions, where the intermediate alcohol was
isolated and rearranged using KH.12b Subjecting cyclo-
butanone 1 to similar conditions resulted in the formation
of the intermediate cyclobutanols 7. However, attempted
ring expansions under basic or acidic conditions failed
to provide the desired cyclopentanone products, either
returning starting materials or leading to decomposition
depending on the reaction conditions (eq 3).
The scope of this one-pot ring expansion of trisubsti-
tuted cyclobutanones was briefly examined (Table 1). In
all cases, the yields were modest, and alkoxide elimina-
tion was noted. With some substrates rearrangement
was incomplete, and varying amounts of epoxide were
obtained.
Because both the starting cyclobutanones and the
product cyclopentanones were somewhat unstable to
acidic conditions, and due to the incompatibility of Et3-
Al with DMF, a milder Lewis acid was sought. In recent
years, lanthanide triflates have come to the fore as highly
reactive yet selective Lewis acids with a high tolerance
for a range of functional groups.14 Replacing Et3Al with
scandium triflate greatly improved the reaction, provid-
ing higher yields, no recovered epoxide, and little if any
alkoxide elimination (Table 1). Furthermore, the reaction
proceeds with complete selectivity favoring only the
desired regioisomer. The procedure proved fairly general
within the limited range of substrates examined. How-
ever, one important exception should be noted. With
Cyclobutanones have also been converted to cyclo-
pentanones in a two-step process involving conversion
to the spiro epoxides by reaction with a sulfur ylide
followed by treatment with lithium iodide.13 Treatment
of cyclobutanone 1 with dimethylsulfonium methylide
resulted in extensive decomposition, presumably by
initial enolization, with no formation of the desired
epoxide. In contrast, the less basic dimethylsulfoxonium
methylide produced the desired spiro epoxide 8 as a
single diastereomer in fair yield, with the stereochemistry
being determined by X-ray analysis. Treatment of 8 with
lithium iodide and triethylamine resulted in ring expan-
(11) Molander, G. A. Org. React. 1994, 46, 211.
(12) (a) Trost, B. M.; Mikhail, G. K. J . Am. Chem. Soc. 1987, 109,
4124. (b) Gadwood, R. C.; Mallick, I. M.; DeWinter, A. J . J . Org. Chem.
1987, 52, 2, 774.
(14) For an overview, see: Lanthanides: Chemistry and Uses in
Organic Synthesis; Kobayashi, S., Ed.; Springer: New York, 1999.
(13) Trost, B. M.; Latimer, H. J . Org. Chem. 1978, 43, 1031.

Syntheses of Carbovir and Aristeromycin
J . Org. Chem., Vol. 65, No. 6, 2000 1867
Ta ble 1
methodology and the previously mentioned ring-expan-
sion procedure are shown in Scheme 1. The syntheses
were optimized using racemic material and repeated with
the corresponding optically active compounds.
Cyclobutanone 1 was prepared in excellent yield as a
single diastereoisomer by the previously reported5c pho-
tolysis of the chromium carbene complex with the ene
carbamate19 shown in Scheme 1. Ring expansion, followed
by elimination of ethanol, led to cyclopentenone 9 in good
yield. Reduction of the enone was best achieved by
hydrogenation. Using palladium on carbon as a catalyst
offered little (3:2) facial selectivity. Since these diastereo-
mers, which were difficult to separate, become enantio-
meric in the following oxazolidinone elimination step,
attention was turned to other catalysts to increase
selectivity. It was anticipated that the oxazolidinone
could be used to direct hydrogenation from the R-face
with a cationic Rh or Ir catalyst.20 However, only poor
selectivity was observed under these conditions, with
Crabtree’s catalyst21 and [Rh(COD)dppb]BF4 each pro-
viding an approximately 2:1 ratio of trans/cis products
in CH2Cl2. Interestingly, use of a coordinating solvent led
to much greater selectivity, but now favored attack from
the â-face. Thus, the use of [Rh(COD)dppb]BF4 in DMF
gave a 12:1 ratio of trans/cis products, affording 16 in
77% isolated yield.
Elimination of the oxazolidinone (which could be
recovered in 96% yield) with LDA followed by reduction
of the cyclopentenone with DIBAL occurred primarily
(7:1 dr) from the face opposite the benzyloxymethyl
group to give cis-cyclopentenol 17.22 Sodium borohydride/
cerium(III) chloride was less selective (4:1 dr). Treatment
of 17 with ethyl chloroformate gave allylic carbonate 18,
the key intermediate for the synthesis of both carbovir
and aristeromycin, in high yield and 98% ee (Chiralcel
OD HPLC analysis). Palladium-catalyzed amination of
carbonate 18 with 2-amino-6-chloropurine proceeded in
good yield, giving 63% of 19 (96% ee by Chiralcel OD
HPLC analysis), along with 20% of the N7 isomer,23
which was easily separated. Debenzylation (BCl3) of 19,
followed by conversion of the chloropurine to guanine,
completed the synthesis of (+)-carbovir.
a
Conditions: (A) 3 equiv of Et3Al, 25 °C, 9 h; (B) 0.25 equiv of
Sc(OTf)3, 50 °C, 5 h. Isolated yields of 12/13. c Material ac-
b
d
companied by 10% epoxide. Only epoxide (46%) was obtained.
e Elimination occurred during purification. The crude material was
96:4 12:13.
R-deoxygenated substrates, none of the desired products
were obtained. In the case of 4 and 14, only oxazolidinone
and benzyl alcohol, respectively, were recovered. Reaction
of 15 under these conditions returned only a low yield of
starting material. Presumably, the starting materials
enolize and decompose through either the cyclobutene or
cyclobutenone, as with similar 3-heterosubstituted cyclo-
butanones bearing R-protons.15
Palladium-catalyzed coupling of carbonate 18 with
adenine gave a 3.5:1 mixture of N9:N7 regioisomers, pro-
viding 21 in 65% isolated yield. Cis-dihydroxylation of
compounds of this type proceed with limited facial bias.24
In some systems, the use of RuO4 has overcome this
problem,25 while in others varying the solvent used for
osmylations has provided high stereoselectivity.26 Initial
attempts to dihydroxylate 21 by catalytic osmylation
proceeded with almost no selectivity and generally
With this new ring-expansion methodology in hand,
attention was turned to its use in the synthesis of carbo-
cyclic nucleoside analogues. Some carbocyclic nucleosides,
including aristeromycin16 and carbovir17 (eq 1), display
impressive antiviral activity. A wide range of enantio-
selective synthetic approaches to these cyclopentyl nucleo-
sides have been developed,8 among which the palladium-
catalyzed desymmetrization of meso-cyclopent-2-en-1,4-
biscarbonates18 has proven broadly useful. The syntheses
of carbovir and aristeromycin utilizing both palladium
(18) Trost, B. M.; Madsen, R.; Guile, S. G.; Elia, A. E. H. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1569.
(19) Akiba, T.; Tamura, O.; Terashima, S. Org. Synth. 1998, 75, 45.
(20) For
a review of substrate directed hydrogenations, see:
Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem Rev. 1993, 93, 1307
and references therein.
(21) Crabtree, R. H.; Davis, M. W. Organometallics 1983, 2, 681.
(22) For an efficient synthesis of unprotected 17, see: Hodgson, D.
M.; Witherington, J .; Moloney, B. A. J . Chem. Soc., Perkin Trans. 1
1994, 3373.
(23) The same yield and N9/N7 ratio had been observed in the
closely related coupling of the dicarbonate of 18. See: Nokami, J .;
Matsumura, H.; Nakashima, K.; Shibata, S. Chem. Lett. 1994, 1071.
(24) For some rationalizations of OsO4 selectivity, see: (a) Katagiri,
N.; Ito, Y,; Kitano, K.; Toyota, A.; Kaneko, C. Chem. Pharm. Bull. 1994,
42, 2653. (b) Poli, G. Tetrahedron Lett. 1989, 30, 7385.
(25) Mulvihill, M. J .; Miller, M. J . Tetrahedron 1998, 54, 6605.
(26) Tokoro, Y.; Kobayashi, Y. Chem. Commun. 1999, 807.
(15) Seebach, D. In Houben-Weyl Methoden der Organischen Chemie;
Muller, E., Ed.; Georg Thieme Verlag: Stuttgart, Germany, 1971; Vol.
IV, pp 192-196.
(16) Kusaka, T.; Yamamoto, H.; Shibata, M.; Muroi, M.; Kishi, T.;
Mizuno, K. J . Antibiot. 1968, 34, 359.
(17) Vince, R.; Hua, M. J . Med. Chem. 1990, 33, 17.

1868 J . Org. Chem., Vol. 65, No. 6, 2000
Brown and Hegedus
Sch em e 1
Ta ble 2
compd
conditions
24a :b
compd
conditions
K2OsO4, NMO
THF/H2O (30:1), 10 °C
OsO4, NMO, THF/H2O (30:1), 10 °C
AD Mix-R
t-BuOH/H2O
23a :b
21
K2OsO4, NMO
1.1:1.0
22
1.0:1.6
acetone/MeOH/H2O
K2OsO4, NMO, MeCN/THF/t-BuOH/H2O
AD Mix-R
1.1:1.0
1.0:4.0
1.2:1.0
1.0:2.4
t-BuOH/H2O
AD Mix-â
1.0:3.3
1.0:1.8
AD Mix-â
1.0:1.4
t-BuOH/H2O
t-BuOH/H2O
OsO4 (1.1 equiv), CH2Cl2, 25 °C
OsO4 (1.1 equiv), DMF, -15 °C
2.3:1.0 (81%)
favored the undesired all-cis compound (Table 2). Trost
reported a 2.4:1 ratio of trans/cis diols by catalytic
osmylation of 22 in THF/H2O.27 Therefore, 21 was depro-
tected with BCl3 to afford alcohol 22. Unfortunately, in
our hands dihydroxylation of 22 under these conditions
provided only a 1.2:1 ratio favoring aristeromycin over
its 2′,3′-bis-epimer. Further examination of reaction
conditions, however, did provide aristeromycin as the
major isomer in an improved 2.3:1 ratio through the use
of 1.2 equiv of OsO4 in DMF, delivering the racemic target
compound in 55% isolated yield (the nonracemic run
yielded 43% of (+)-aristeromycin).
The nonracemic syntheses followed similarly to the
racemic series, except that (+)-aristeromycin (94% ee by
Chiralpak AD analysis of its 3′,5′-(1,1,3,3-tetraisopropyl-
disiloxane) derivative of 23a ) remained contaminated
with 10% of an unidentified impurity.
Although this study provided the inactive enantiomers
of these analogues, it detailed a method for the formation
of “unnatural” L-nucleosides. Analogues of this configur-
ation are becoming increasingly important, since a num-
ber of these derivatives are more potent and less toxic
than their D-counterparts,28 and relatively few ap-
proaches toward these compounds have been described.29
(28) Schinazi, R. F.; Chu, C. K.; Peck, A.; McMillan, A.; Mathis, R.;
Cannon, D.; J eong, L. S.; Beach, J . W.; Choi, W. B.; Yeola, S.; Liotta,
D. C. Antimicrob. Agents Chemother. 1992, 36, 672.
(27) Trost, B. M.; Li, L.; Guile, S. D. J . Am. Chem. Soc. 1992, 114,
8745.

Syntheses of Carbovir and Aristeromycin
J . Org. Chem., Vol. 65, No. 6, 2000 1869
chromatographic purification (20% EtOAc/Hex) provided cyclo-
pentanone 5 (31.6 mg, 0.072 mmol, 31%) as a clear gum and
6 (47.2 mg, 0.107 mmol, 46%) as a white solid. 5: 1H NMR δ
7.37-7.25 (m, 5H), 7.12-7.03 (m, 6H), 6.95-6.85 (m, 4H), 5.59
(d, J ) 8.0 Hz, 1H), 5.03 (d, J ) 8.0 Hz, 1H), 4.44-4.34 (m,
3H), 3.77-3.72 (m, 2H), 2.92 (m, 1H), 2.32 (m, 1H), 2.16-2.02
(m, 2H), 1.67-1.55 (m, 1H); 13C NMR δ 213.2, 158.0, 137.8,
135.7, 134.3, 128.5, 128.4, 128.3, 128.2, 127.9, 127.8, 127.7,
126.0, 80.0, 73.6, 67.8, 63.7, 55.9, 51.4, 37.4, 25.4; IR (film)
1746 cm-1; mp 129-130 °C. Anal. Calcd for C28H27NO4: C,
76.16; H, 6.18; N, 3.17. Found: C, 76.40; H, 6.36; N, 3.17. 6:
1H NMR δ 7.40-7.26 (m, 5H), 7.09-7.03 (m, 6H), 6.91-6.83
(m, 4H), 5.58 (d, J ) 8.0 Hz, 1H), 5.00 (d, J ) 8.0 Hz, 1H),
4.50 (d, J ) 11.7 Hz, 1H), 4.45 (d, J ) 11.7 Hz, 1H), 4.43-
4.33 (m, 1H), 3.63-3.59 (m, 2H), 2.87 (m, 1H), 2.53 (dd, J )
8.4, 18.3 Hz, 1H), 2.38 (dd, J ) 7.7, 18.3 Hz, 1H), 2.10 (dd,
J ) 9.9, 18.7 Hz, 1H), 1.98 (ddd, J ) 1.9, 11.0, 18.7 Hz, 1H);
13C NMR δ 212.6, 158.1, 137.7, 135.3, 134.1, 128.6, 128.4,
128.3, 127.9, 127.8, 127.6, 126.1, 126.0, 80.1, 73.6, 71.1, 63.4,
54.9, 42.7, 41.0, 39.9; IR (film) 1748 cm-1; mp 125-126 °C.
Anal. Calcd for C28H27NO4: C, 76.16; H, 6.18; N, 3.17. Found:
C, 76.08; H, 6.26; N, 3.17.
Exp er im en ta l Section
Gen er a l Meth od s. Compounds 4,6 11a ,30 11b,31 11c,30 and
11e30 were prepared by the published methods. THF was
distilled from sodium-benzophenone ketyl; CH2Cl2, DMF, and
Et3N were distilled from CaH2. 1H NMR (300 MHz) and 13C
NMR (75 MHz) were recorded in CDCl3 except where noted,
and chemical shifts are given in ppm relative to Me4Si (0 ppm,
1H), CDCl3 (77.0 ppm, 13C). Column chromatography was
performed with ICN 32-63 nm, 60 Å silica gel using flash
column techniques. Elemental analyses were performed by
M-H-W Laboratories, Phoenix, AZ. All reactions were per-
formed under an atmosphere of Ar unless otherwise noted.
Cyclobu ta n on e 1. A solution of (benzyloxymethyl)(ethoxy)-
pentacarbonylchromium (9.29 g, 24.7 mmol) and (4S,5R)-
oxazolidinone 1 (10.0 g, 37.7 mmol) in CH2Cl2 (82 mL,
degassed) in a Pyrex pressure tube was placed under CO (∼80
psi), cooled to -35 °C, and irradiated with a 450 W Hg-vapor
lamp for 6 days. Concentration of the crude reaction mixture
followed by removal of Cr(CO)6 by sublimation gave 15.9 g of
a light green solid. Purification by flash chromatography (80%
Hex/CH2Cl2 to 25% EtOAc/Hex gradient elution) provided 2.82
g of recovered oxazolidinone 1 (10.6 mmol) as a white solid
and cyclobutanone 1 (8.13 g, 17.2 mmol, 70%) as a white
foam: 1H NMR δ 7.38-7.50 (m, 5H), 6.97-7.10 (m, 6H), 6.74-
6.80 (m, 2H), 6.54 (br s, 2H), 5.59 (d, J ) 7.5 Hz, 1H), 5.03 (d,
J ) 7.5 Hz, 1H), 4.81 (t, J ) 10.2 Hz, 1H), 4.70 (d, J ) 11.1
Hz, 1H), 4.55 (d, J ) 11.1 Hz, 1H), 4.06 (d, J ) 9.0 Hz, 1H),
3.7 (d, J ) 9.0 Hz, 1H), 3.75 (m, 2H), 2.71 (dd, J ) 18, 9.6 Hz,
1H), 2.45 (dd, J ) 10.6, 18 Hz, 1H), 1.23 (t, J ) 7.0 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 206.4, 158.5, 137.2, 135.5, 133.6,
128.7, 128.3, 128.1, 128.0, 127.9, 127.7, 126.7, 125.9, 97.7, 80.3,
Cyclobu ta n ol 7a . Following the method of Trost,12b BuLi
(1.6 M/Hex, 0.153 mL, 0.242 mmol) was added dropwise to a
-78 °C solution of PhSO2Me (38 mg, 0.242 mmol) in THF (1.2
mL) and stirred for 20 min. A solution of 1 (103 mg, 0.218
mmol) in THF (1.0 mL) was added dropwise and stirred for
5.5 h. The reaction was quenched with saturated NH4Cl (10
mL) and extracted with CH2Cl2. The organic extract was dried
(Na2SO4) and concentrated to give 137 mg of white foam. Flash
chromatography provided 7a as a white solid (75.0 mg, 0.122
mmol, 56%): 1H NMR δ 7.87 (d, J ) 7.1 Hz, 2H), 7.65-7.35
(m, 8H), 7.11-6.91 (m, 6H), 6.83-6.71 (m, 2H), 6.52 (br s, 2H),
5.52 (d, J ) 7.4 Hz, 1H), 4.99 (d, J ) 7.4 Hz, 1H), 4.69 (d, J )
11.3 Hz, 1H), 4.63 (d, J ) 11.3 Hz, 1H), 4.22 (t, J ) 10.1 Hz,
1H), 4.04 (d, J ) 10.4 Hz, 1H), 3.95 (d, J ) 10.4 Hz, 1H), 3.91
(br s, 1H), 3.85 (dd, J ) 7.0, 8.8 Hz, 1H) 3.60-3.46 (m, 2H),
3.39 (d, J ) 13.1 Hz, 1H), 2.42 (dd, J ) 9.9, 13.1 Hz, 1H), 1.73
(br t, J ) 11 Hz, 1H), 1.15 (t, J ) 7.0 Hz, 3H); 13C NMR δ
158.1, 141.2, 136.9, 135.6, 133.6, 133.5, 129.1, 128.9, 128.5,
128.2, 128.0, 127.8, 126.0, 87.5, 80.4, 74.5, 73.5, 68.2, 64.6, 60.6,
74.4, 69.0, 64.8, 61.6, 48.0, 46.1, 15.6; IR (film) 1791, 1752 cm-1
[R]D +42.4 (c 1.0, CHCl3).
;
Cyclopen tan on es 2/3. Freshly prepared CH2N2 was bubbled
through a 0 °C solution of cyclobutanone 1 (39.0 mg, 0.0827
mmol) in 1:1 THF/DMF (1.4 mL), and the yellow solution was
allowed to stand for 2.5 h. Evaporation and flash chromato-
graphic purification (20-33% EtOAc/Hex gradient elution)
provided cyclopentanones 2 (23.7 mg, 0.0488 mmol, 59%) and
3 (8.2 mg, 0.017 mmol, 20%) as clear films. 2: 1H NMR δ 7.43-
7.34 (m, 5H), 7.15-6.95 (m, 7H), 6.85-6.77 (m, 3H), 5.57 (d,
7.2 Hz, 1H), 4.99 (d, J ) 7.2 Hz, 1H), 4.95 (dd, J ) 7.8, 11.1
Hz, 1H), 4.64 (d, J ) 11.7 Hz, 1H), 4.47 (d, J ) 11.7 Hz, 1H),
3.98 (d, J ) 9.0 Hz, 1H), 3.81 (quin, J ) 6.9 Hz, 1H), 3.73 (d,
J ) 9.3 Hz, 1H), 3.32 (quin, J ) 6.9 Hz, 1H), 2.32 (ddd, J )
2.4, 9.0, 19.5 Hz, 1H), 2.08 (dt, J ) 9.9, 19.5 Hz, 1H), 1.78 (m,
1H), 1.62 (m, 1H), 1.20 (t, J ) 6.9 Hz, 3H); 13C NMR δ 215.0,
158.6, 136.9, 136.4, 133.6, 128.7, 128.3, 128.1, 127.9, 127.7,
126.1, 84.1, 80.6, 74.6, 71.7, 64.1, 59.9, 54.7, 36.7, 22.3, 15.5;
59.8, 50.2, 34.8, 15.8; IR (film) 3484, 1746 cm-1
.
Cyclobu tan ol 7b. Following Gadwood’s general procedure,12c
LDA (0.72 M/THF, Hex, 0.19 mL, 0.14 mmol) was added
dropwise to a -78 °C solution of o-chlorophenyl methyl-
sulfoxide (25 mg, 0.14 mmol) in THF (0.75 mL) and stirred
for 15 min. A solution of 1 (57 mg, 0.12 mmol) in THF (0.40
mL) was added dropwise, stirred at -78 °C for 10 min, and
allowed to warm to room temperature. The mixture was
diluted with saturated NH4Cl (10 mL) and extracted with CH2-
Cl2. The organic extract was washed with brine, dried (MgSO4),
and concentrated to give 61 mg of a milky gum. Gadwood
reports using the crude product directly. However, the follow-
ing reaction failed and 7b was isolated after flash chromatog-
raphy (30-50% EtOAc/Hex) of the reaction mixture as a yellow
gum (12.3 mg): 1H NMR δ 7.95-7.84 (m, 1H), 7.61-7.33 (m,
8H), 7.17-7.00 (m, 6H), 6.83-6.71 (m, 2H), 6.63 (br s, 2H),
5.53 (d, J ) 7.5 Hz, 1H), 5.03 (d, J ) 7.5 Hz, 1H), 4.50 (s, 2H),
4.47 (br s, 1H), 4.29 (t, J ) 10.2 Hz, 1H), 4.10 (d, J ) 10.8 Hz,
1H), 4.04 (d, J ) 10.8 Hz, 1H), 3.85 (dq, J ) 7.0, 9.0 Hz, 1H),
3.62 (dq, J ) 7.1, 9.0 Hz, 1H), 3.38 (d, J ) 13.8 Hz, 1H), 2.97
(dd, J ) 2.0, 13.8 Hz, 1H), 2.31 (dd, J ) 9.7, 12.6 Hz, 1H),
1.88 (ddd, J ) 2.0, 10.5, 12.6 Hz, 1H), 1.12 (t, J ) 7.0 Hz, 3H);
13C NMR δ 158.1, 141.6, 137.4, 136.1, 133.7, 132.3, 129.9,
129.6, 128.8, 128.3, 127.9, 126.1, 125.9, 87.5, 80.3, 74.9, 74.5,
IR (film) 1751 cm-1; mp 181-183 °C. Anal. Calcd for C30H31
-
NO5: C, 74.21; H, 6.43; N, 2.88. Found: C, 74.17; H, 6.49; N,
2.86. 3: 1H NMR δ 7.45-7.33 (m, 6H), 7.15-6.97 (m, 7H),
6.75-6.70 (m, 2H), 5.51 (d, J ) 7.3 Hz, 1H), 4.98 (dd, J ) 7.6,
8.5 Hz, 1H), 4.71 (d, J ) 7.3 Hz, 1H), 4.66 (d, J ) 11.4 Hz,
1H), 4.56 (d, J ) 11.4 Hz, 1H), 4.05 (d, J ) 9.5 Hz, 1H), 3.70-
3.67 (m, 2H), 3.55 (quin, J ) 7.0 Hz, 1H), 2.70 (dd, J ) 1.0,
18.6 Hz, 1H), 2.57 (d, J ) 18.6 Hz, 1H), 2.23 (dd, J ) 8.5, 18.2
Hz, 1H), 2.08 (ddd, J ) 1.0, 7.6, 18.2 Hz, 1H), 1.18 (t, J ) 6.9,
3H); 13C NMR δ 211.5, 158.6, 137.0, 135.9, 133.5, 128.8, 128.3,
128.2, 127.9, 126.0, 83.7, 80.4, 74.4, 71.8, 63.8, 58.6, 55.3, 44.9,
40.8, 15.8; IR (film) 1748 cm-1; mp 145-147 °C; HRMS m/z
(M + H) calcd 486.2280, obsd 486.2281.
Alternatively, 3 was prepared in 73% from cyclobutanone
1 using the ring-expansion procedure described below.
Cyclopen tan on es 5/6. Freshly prepared CH2N2 was bubbled
through a 0 °C solution of cyclobutanone 4 (98.9 mg, 0.231
mmol) in THF (1 mL), and the yellow solution was allowed to
stand overnight with gradual warming. Evaporation and flash
68.6, 64.5, 60.9, 59.3, 50.6, 35.1, 15.9; IR (film) 3319, 1748 cm-1
.
Ep oxid e 8. A suspension of Me3S(O)I (101 mg, 0.457 mmol)
and NaH (60 wt % in mineral oil, 18.4 mg, 0.460 mmol) in
DMF (2.5 mL) was stirred for 10 min and cooled to 0 °C. A
solution of 1 (202 mg, 0.43 mmol) in DMF (2.0 mL) was added
dropwise, and the mixture was stirred for 2.5 h and allowed
to warm slightly, at which time the bath was removed. After
another 20 h, the mixture was diluted with H2O (10 mL) and
extracted with CH2Cl2. The organic phase was washed with
brine (10 mL), dried (Na2SO4), and concentrated to give 0.35
(29) For
a synthesis of L-carbocyclic nucleosides starting from
D-glucose, see: Wang, P.; Agrofoglio, L. A.; Chu, C. K. Tetrahedron
Lett. 1997, 38, 4207.
(30) Reeder, L. M.; Hegedus, L. S. J . Org. Chem. 1999, 64, 3306.
(31) Soderburg, B. C.; Hegedus, L. S.; Sierra, M. A. J . Am. Chem.
Soc. 1990, 112, 4364.

1870 J . Org. Chem., Vol. 65, No. 6, 2000
Brown and Hegedus
g of brown oil. Flash chromatography (CH2Cl2 to 1% MeOH/
CH2Cl2) provided 0.131 g of 8 as a white solid (0.270 mmol,
63%): 1H NMR δ 7.55-7.35 (m, 5H), 7.10-6.93 (m, 6H), 6.79-
6.71 (m, 2H), 6.51 (br s, 2H), 5.55 (d, J ) 7.5 Hz, 1H), 5.10 (d,
J ) 7.5 Hz, 1H), 4.78 (d, H)11.0 Hz, 1H), 4.65 (d, J ) 11.0
Hz, 1H), 4.63 (t, J ) 10.2 Hz, 1H), 4.00 (d, J ) 10.0 Hz, 1H),
3.86 (dq, J ) 7.1, 8.7 Hz, 1H), 3.76 (d, J ) 10.0 Hz, 1H), 3.75
(dq, J ) 7.0, 8.7 Hz, 1H), 2.95 (d, J ) 5.4 Hz, 1H), 2.63 (d,
J ) 5.4 Hz, 1H), 2.12 (dd, J ) 10.2, 12.9 Hz, 1H), 1.82 (dd,
J ) 10.0, 12.9 Hz, 1H), 1.20 (t, J ) 7.0 Hz, 3H); 13C NMR δ
158.2, 138.0, 136.3, 133.9, 128.7, 128.1, 127.8, 126.8, 126.0,
86.8, 80.3, 74.5, 69.2, 64.5, 60.5, 49.7, 49.0, 29.9, 15.9; IR (film)
1750 cm-1; mp 134-136 °C.
Cyclobu ta n on e 11d . According to the published general
procedure,30 a solution of pentacarbonyl[(methyl)(methoxy)-
carbene]chromium(0) (0.500 g, 2.00 mmol) and cis-4,5-di-
phenyl-3-vinyl-2-oxazolidinone (0.796 g, 3.00 mmol) in CH2-
Cl2 (20 mL, degassed) was placed under CO (80 psi) and
irradiated (450 W Hg vapor lamp) for 6.5 h at 35 °C. The
mixture was concentrated, triturated with MeOH, and filtered
to remove Cr(CO)6. Purification of the crude tan solid by flash
chromatography (2% EtOAc/CH2Cl2) afforded 11d as a white
solid (0.329 g, 0.937 mmol, 47%): 1H NMR δ 7.17-7.04 (m,
6H), 7.03-6.95 (m, 2H), 6.89-6.80 (m, 2H), 5.93 (d, J ) 7.4
Hz, 1H), 5.10 (d, J ) 7.4 Hz, 1H), 4.54 (t, J ) 9.8 Hz, 1H),
3.40 (s, 3H), 2.92 (dd, J ) 9.3, 18.1 Hz, 1H), 2.58 (dd, J )
10.2, 18.1 Hz, 1H), 1.53 (s, 3H); 13C NMR δ 205.9, 158.2, 134.5,
133.5, 128.6, 128.2, 127.9, 127.1, 126.0, 96.1, 80.2, 65.8, 52.8,
48.5, 43.5, 14.5; IR (film) 1789, 1738 cm-1; mp 186-187 °C.
Anal. Calcd for C21H21NO4: C, 71.78; H, 6.02; N, 3.99. Found:
C, 71.46; H, 6.15; N, 3.85.
Cyclob u t a n on e 11f. A solution of pentacarbonyl[(tetra-
hydrofuran-2-yl)carbene]chromium (0)32 (1.09 g, 4.15 mmol)
and cis-4,5-diphenyl-3-vinyl-2-oxazolidinone (1.65 g, 6.23 mmol)
in CH2Cl2 (20 mL, degassed) was treated as above for 2 days.
Workup and flash chromatographic purification (30 to 40%
EtOAc/Hex gradient elution) provided 11f as a white solid
(0.732 g, 2.01 mmol, 49%): 1H NMR δ 7.15-7.09 (m, 6H),
7.03-6.97 (m, 2H), 6.90-6.85 (m, 2H), 5.96 (d, J ) 7.6 Hz,
1H), 5.06 (d, J ) 7.6 Hz, 1H), 4.31 (t, J ) 9.9 Hz, 1H), 3.99
(dd, J ) 7.0, 13.5 Hz, 1H), 3.86 (dd, J ) 7.7, 13.5 Hz, 1H),
3.06 (dd, J ) 9.5, 17.6 Hz, 1H), 2.61 (dd, J ) 9.9, 17.6 Hz,
1H), 2.30-2.11 (m, 2H), 2.07-1.94 (m, 2H); 13C NMR δ 207.8,
157.8, 134.4, 133.7, 128.7, 128.5, 128.1, 128.0, 127.4, 125.9,
99.4, 80.1, 70.1, 66.4, 51.5, 43.4, 28.4, 25.9; IR (film) 1792, 1745
cm-1; mp 194-195 °C. Anal. Calcd for C22H21NO4: C, 72.71;
H, 5.82; N, 3.85. Found: C, 72.83; H, 5.80; N, 3.87.
Gen er a l P r oced u r e for th e Rin g Exp a n sion of Cyclo-
bu ta n on es. A suspension of NaH (60 wt %, 1.2 mmol) and
Me3S(O)I (1.3 mmol) in DMF (5 mL) was stirred for 30 min at
room temperature and cooled to 0 °C. A solution of cyclo-
butanone in DMF (5 mL) was added slowly (5-30 min). The
ice bath was removed, and the mixture was stirred for 15 min.
Solid Sc(OTf)3 (0.25 mmol) was added to the reaction and
allowed to react for 10 min, at which point the mixture was
heated to 50 °C for 4-5 h. The mixture was diluted with H2O
(40 mL) and extracted with Et2O. The combined organic layers
were wasched with brine, dried (Na2SO4), and concentrated
to give a yellow solid. Purification by flash chromatography
gave the desired products.
13C NMR δ 205.2, 175.7, 137.5, 132.0, 128.5, 128.0, 127.8, 78.7,
72.1, 42.3, 16.2; IR (film) 1712 cm-1
.
Cyclop en ta n on e 12b/Cyclop en ten on e 13b. From cyclo-
butanone 11b (42.1 mg, 0.221 mmol), flash chromatography
(8-12% EtOAc/Hex gradient elution) afforded 12b (32.1 mg,
0.157 mmol, 71%) as a clear oil and 13b as a clear film (3.5
mg, 0.020 mmol, 9%). 12b: 1H NMR δ 7.36-7.22 (m, 3H),
7.21-7.15 (m, 2H), 3.62 (dd, J ) 6.6, 8.4 Hz, 1H), 3.28 (s, 3H),
2.87 (ddd, J ) 1.1, 8.6, 18.3 Hz, 1H), 2.59 (dd, J ) 6.2, 18.3
Hz, 1H), 2.55 (d, J ) 18.0 Hz, 1H), 2.42 (dd, J ) 1.1, 18.0 Hz,
1H), 1.01 (s, 3H); 13C NMR δ 216.2, 139.9, 128.4, 128.1, 127.3,
127.0, 83.1, 50.4, 50.0, 48.8, 43.1, 19.1; IR (film) 1744 cm-1
;
HRMS m/z (M + H) calcd 204.1150, obsd 204.1150. 13b: 1H
NMR δ 7.37-7.22 (m, 3H), 7.14-7.09 (m, 2H), 6.09 (m, 1H),
3.90 (d, J ) 7.0 Hz, 1H), 2.93 (dd, J ) 7.3, 18.7 Hz, 1H), 2.40
(dd, J ) 2.2, 18.7 Hz, 1H), 1.91 (s, 3H); 13C NMR δ 208.9, 180.1,
141.2, 131.2, 129.0, 127.2, 50.6, 45.7, 17.6; IR (film) 1710 cm-1
;
HRMS m/z (M + H) calcd 173.0966, obsd 173.0964.
Cyclop en ta n on e 12c. From cyclobutanone 11c (45.3 mg,
0.206 mmol), flash chromatography (15 to 33% EtOAc/Hex
gradient elution) afforded 12c (31.6 mg, 0.135 mmol, 66%) as
a clear oil: 1H NMR δ 7.10 (d, J ) 8.8 Hz, 2H), 6.86 (d, J )
8.8 Hz, 2H), 3.80 (s, 3H), 3.57 (t, J ) 7.7 Hz, 1H), 3.28 (s, 3H),
2.85 (dd, J ) 8.8, 18.7 Hz, 1H), 2.54 (dd, J ) 7.7, 18.7 Hz,
1H), 2.53 (d, J ) 19.1 Hz, 1H), 2.41 (dd, J ) 1.1, 19.1 Hz, 1H),
1.01 (s, 3H); 13C NMR δ 216.3, 158.5, 131.9, 129.0, 113.7, 83.1,
55.2, 50.5, 49.2, 48.8, 43.3, 19.0; IR (film) 1743 cm-1
.
Cyclop en ten on e 13c: 1H NMR δ 7.04 (d, J ) 8.5 Hz, 2H),
6.86 (d, J ) 8.5 Hz, 2H), 6.03 (m, 1H), 3.86 (d, J ) 6.9 Hz,
1H), 3.80 (s, 3H), 2.91 (dd, J ) 7.0, 18.7 Hz, 1H), 2.37 (dd,
J ) 2.2, 18.7 Hz, 1H), 1.90 (s, 3H); 13C NMR δ 209.1, 180.4,
158.7, 133.1, 131.0, 128.2, 114.3, 55.2, 49.9, 45.8, 17.6; IR (film)
1706 cm-1; mp 98-99 °C.
Cyclop en ta n on e 12d . From cyclobutanone 11d (44.4 mg,
0.126 mmol), flash chromatography (35% EtOAc/Hex) afforded
12d (36.6 mg, 0.100 mmol, 79%) as a white solid: 1H NMR δ
7.15-7.06 (m, 6H), 6.99-6.92 (m, 2H), 6.86-6.79 (m, 2H), 5.84
(d, J ) 7.4 Hz, 1H), 4.86 (d, J ) 7.4 Hz, 1H), 4.55 (dd, J ) 5.3,
9.0 Hz, 1H), 3.22 (s, 3H), 2.55 (m, 2H), 2.48 (dd, J ) 9.0, 19.0
Hz, 1H), 2.09 (dd, J ) 5.3, 19.0 Hz, 1H), 1.48 (s, 3H); 13C NMR
δ 212.6, 158.4, 135.0, 133.6, 128.8, 128.5, 128.1, 128.0, 127.9,
127.4, 126.2, 126.1, 126.0, 83.4, 80.3, 65.4, 57.1, 50.3, 48.8, 40.7,
18.5; IR (film) 1743 cm-1; mp 186-188 °C. Anal. Calcd for
C
22H23NO4: C, 72.31; H, 6.34; N, 3.83. Found: C, 72.10; H,
6.21; N, 3.83.
Cyclop en ten on e 13d : 1H NMR δ 7.15-7.05 (m, 6H), 7.00-
6.94 (m, 2H), 6.92-6.83 (m, 2H), 6.11 (m, 1H), 5.86 (d, J ) 8.0
Hz, 1H), 4.88 (m, 1H), 4.81 (d, J ) 8.0 Hz, 1H), 2.50 (dd, J )
7.4, 18.3 hz, 1H), 2.23 (s, 3H), 2.12 (dd, J ) 2.9, 18.3 Hz, 1H);
13C NMR δ 203.9, 173.1, 157.7, 134.7, 133.9, 133.4, 128.6,
128.3, 128.0, 127.7, 125.9, 80.3, 63.5, 56.7, 39.4, 16.6; IR (film)
1752, 1710 cm-1; mp 163-166 °C. Anal. Calcd for C21H19NO3:
C, 75.66; H, 5.74; N, 4.20. Found: C, 75.74; H, 5.87; N, 4.09.
Cyclop en ta n on e 12e. From cyclobutanone 11e (42.9 mg,
0.278 mmol), flash chromatography (7% EtOAc/Hex gradient
elution) afforded 12e (31.6 mg, 0.188 mmol, 68%) as a clear
oil: 1H NMR δ 3.20 (s, 3H), 2.82 (td, J ) 3.3, 9.8 Hz, 1H), 2.70
(m, 1H), 2.44 (dt, J ) 1.8, 18.3 Hz, 1H), 2.22 (d, J ) 18.3 Hz,
1H), 2.10-1.94 (m, 1H), 1.94-1.81 (m, 1H), 1.78-1.62 (m, 2H),
1.62-1.45 (m, 1H), 1.34 (s, 3H), 1.29-1.10 (m, 1H); 13C NMR
δ 221.3, 80.7, 52.3, 51.4, 49.4, 46.6, 29.7, 29.2, 26.9, 18.8; IR
(film) 1741 cm-1; HRMS m/z (M + H) calcd 168.1150, obsd
168.1151.
Cyclop en ta n on e 12a . From cyclobutanone 11a (42.1 mg,
0.191 mmol), flash chromatography (15% EtOAc/Hex) afforded
12a (29.0 mg, 0.124 mmol, 65%) as a clear oil: 1H NMR δ
7.39-7.30 (m, 5H), 4.61 (d, J ) 11.9 Hz, 1H), 4.50 (d, J ) 11.9
Hz, 1H), 3.98 (m, 1H), 3.21 (s, 3H), 2.61 (dd, J ) 5.5, 18.3 Hz,
1H), 2.47-2.31 (m, 3H), 1.43 (s, 3H); 13C NMR δ 215.0, 137.9,
128.4, 127.7, 127.6, 82.9, 80.9, 71.5, 50.0, 47.1, 42.8, 16.8; IR
(film) 1748 cm-1; HRMS m/z (M + H) calcd 234.1256, obsd
234.1254.
Cyclop en ta n on e 12f/Cyclop en ten on e 13f. From cyclo-
butanone 11f (44.7 mg, 0.123 mmol), flash chromatography
(30% EtOAc/Hex to 5% MeOH/CH2Cl2 gradient elution) af-
forded 12f (25.0 mg, 0.0662 mmol, 54%) and 13f (12.5 mg,
0.0312 mmol, 25%) as white solids. 12f: 1H NMR δ 7.15-7.05
(m, 6H), 6.99-6.92 (m, 2H), 6.87-6.77 (m, 2H), 5.83 (d, J )
7.7 Hz, 1H), 4.81 (d, J ) 7.7 Hz, 1H), 4.45 (dd, J ) 2.2, 8.6 Hz,
1H), 3.83 (m, 2H), 2.70 (d, J ) 19.0 Hz, 1H), 2.68 (dd, J ) 8.5,
19.0 Hz, 1H), 2.45 (d, J ) 19.0 Hz, 1H), 2.35-2.25 (m, 1H),
2.20-1.92 (m, 4H); 13C NMR δ 213.3, 158.4, 134.8, 133.6, 128.8,
128.5, 128.1, 128.0, 127.4, 125.9, 89.6, 80.3, 67.8, 65.2, 58.5,
49.2, 41.7, 31.1, 25.9; IR (film) 1735 cm-1; mp 184-186 °C.
Cyclop en ten on e 13a : 1H NMR δ 7.39-7.30 (m, 5H), 5.99
(s, 1H), 4.67 (d, J ) 11.7 Hz, 1H), 4.54 (m, 2H), 2.67 (dd, J )
5.9, 18.0 Hz, 1H), 2.39 (dd, J ) 2.2, 18.0 Hz, 1H), 2.16 (s, 3H);
(32) Betschart, C.; Hegedus, L. S. J . Am. Chem. Soc. 1992, 114, 5010.

Syntheses of Carbovir and Aristeromycin
J . Org. Chem., Vol. 65, No. 6, 2000 1871
Anal. Calcd for C23H23NO4: C, 73.19; H, 6.14; N, 3.71. Found:
C, 72.91; H, 6.02; N, 3.76. 13f: 1H NMR δ 7.15-7.05 (m, 6H),
7.01-6.93 (m, 2H), 6.90-6.83 (m, 2H), 6.13 (m, 1H), 5.90 (d,
J ) 8.0 Hz, 1H), 5.01 (m, 1H), 4.81 (d, J ) 8.0 Hz, 1H), 3.78
(t, J ) 5.8 Hz, 2H), 2.76 (m, 1H), 2.54-2.41 (m, 2H), 2.11 (dd,
J ) 3.3, 18.7 Hz, 1H), 2.02-1.87 (m, 4H); 13C NMR δ 203.9,
177.2, 158.0, 134.8, 133.7, 132.0, 128.8, 128.6, 128.0, 127.7,
125.9, 80.5, 63.2, 61.3, 55.7, 39.2, 29.7, 26.4; IR (film) 3448,
1749, 1716, 1687 cm-1; mp 127-129 °C.
3414, 1712 cm-1; HRMS m/z (M + H) calcd 205.1236, obsd
205.1229; [R]24 -34.2 (c 1.0, CH2Cl2).
D
Ca r bon a te 18. Ethyl chloroformate (0.10 mL, 1.0 mmol)
was added to a solution of cyclopentanol 17 (55.4 mg, 0.271
mmol) and pyridine (0.11 mL, 1.4 mmol) in CH2Cl2 (2.5 mL).
The mixture was stirred for 20 min, quenched with saturated
NaHCO3 (7 mL), and extracted with CH2Cl2. The combined
organic layers were dried (Na2SO4) and concentrated to give
a yellow oil. Purification by flash chromatography (5% EtOAc/
Hex) afforded 18 as a clear oil (65.5 mg, 0.237 mmol, 87%):
1H NMR δ 7.37-7.24 (m, 5H), 6.10 (m, 1H), 5.90 (dt, J ) 1.8,
5.5 Hz, 1H), 5.58 (m, 1H), 4.51 (s, 2H), 4.18 (q, J ) 6.9 Hz,
2H), 3.42 (dq, J ) 7.4, 9.2 Hz, 2H), 2.94 (m, 1H), 2.51 (dt, J )
8.0, 14.3 Hz, 1H), 1.64 (dt, J ) 4.4, 14.3 Hz, 1H), 1.30 (t, J )
7.1 Hz, 3H); 13C NMR δ 154.8, 138.8, 138.3, 130.0, 128.4, 127.5,
Cyclop en ten on e 9. Following the general procedure, cyclo-
butanone 1 (0.500 g, 1.06 mmol) was ring-expanded to provide
the cyclopentanone 3 as a white solid (0.375 g, 0.772 mmol,
73%) and cyclopentenone 9 as a clear film (15.6 mg, 0.0355
mmol, 3.3%). To a solution of 3 in THF (2.2 mL) and MeOH
(4.5 mL) was added Li2CO3 (71 mg, 0.96 mmol). The resulting
suspension was stirred for 2.5 h. It was then diluted with
saturated NH4Cl (15 mL) and extracted with CH2Cl2. The
combined organic layers were dried (Na2SO4) and concentrated
to give a yellow gum. Flash chromatographic purification (33%
EtOAc/Hex) provided cyclopentenone 9 as a white foam (0.327
g, 0.744 mmol, 96%; 0.343 g, 0.780 mmol, 74% over two
steps): 1H NMR δ 7.45-7.30 (m, 5H), 7.15-7.00 (m, 6H), 6.90-
6.75 (m, 4H), 6.37 (m, 1H), 5.56 (d, J ) 8.2 Hz, 1H), 5.09 (m,
1H), 4.73 (d, J ) 8.2 Hz, 1H), 4.68 (AB, J ) 11.9 Hz, 2H), 4.43
(AB, J ) 16.5 Hz, 2H), 2.49 (dd, J ) 7.2, 18.7 Hz, 1H), 2.10
(dd, J ) 3.0, 18.7 Hz, 1H); 13C NMR δ 203.4, 172.0, 157.8,
137.0, 134.8, 133.8, 133.0, 128.8, 128.6, 128.2, 127.9, 127.6,
125.9, 80.2, 73.6, 67.2, 63.2, 54.2, 39.3; IR (film) 1754, 1718,
82.9, 74.2, 73.1, 63.7, 44.9, 33.4, 14.2; IR (film) 1739 cm-1; [R]24
-1.3 (c 1.0, CHCl3).
D
P u r in e 19. A -40 °C suspension of carbonate 18 (29.0 mg,
0.105 mmol), 2-amino-6-chloropurine (19.5 mg, 0.115 mmol),
and Pd(PPh3)4 (12.0 mg, 0.0104 mmol) in DMF (1.0 mL) was
stirred for 3.5 h, allowing it to warm slowly to 10 °C.
Concentration and flash chromatographic purification (1.5-
3% MeOH/CH2Cl2 gradient elution) gave 19 containing a ∼10%
impurity as a clear film (23.6 mg, 0.663 mmol, 63%), which
was taken on without further purification: 1H NMR δ 7.89 (s,
1H), 7.37-7.24 (m, 5H), 6.19 (dt, J ) 1.9, 5.6 Hz, 1H), 5.85
(dt, J ) 2.2, 5.6 Hz, 1H), 5.58 (m, 1H), 5.16 (br s, 2H), 4.52 (s,
2H), 3.48 (m, 2H), 3.10 (m, 1H), 2.80 (dt, J ) 8.8, 14.2 Hz,
1H), 1.70 (dt, J ) 5.5, 14.2 Hz, 1H); 13C NMR δ 158.8, 153.4,
151.0, 141.0, 139.1, 137.8, 132.1, 129.0, 128.5, 127.7, 125.5,
1632 cm-1; mp 123-125 °C; [R]24 38.0 (c 1.0, CHCl3). Anal.
D
Calcd for C28H25NO4: C, 76.52; H, 5.73; N, 3.19. Found: C,
76.47; H, 5.46; N, 3.13.
73.2, 72.3, 59.2, 45.6, 34.9; IR (film) 3319, 1608, 1561 cm-1
.
Cyclop en ta n on e 16. A solution of cyclopentenone 9 (0.206
mg, 0.468 mmol) and [Rh(COD)dppb]BF4 (31 mg, 0.043 mmol)
in DMF (3.0 mL) was stirred under H2 (80 psi) for 5.5 h, at
which point more catalyst was added (30 mg). The black
solution was stirred for an additional 13 h and then evaporated
to give a black gum. Flash chromatographic (25% EtOAc/Hex)
purification provided impure 16 as a white foam (0.190 g).
Recrystallization (EtOAc/Hex/MeOH) afforded pure 16 (0.139
g) as a white solid. Preparative HPLC purification (97:3 10%
CH2Cl2/Hex/i-PrOH, 10 mL/min) of the mother liquor gave an
additional 19.2 mg of 16 as a white solid (0.158 mg total, 0.359
mmol, 77%): 1H NMR δ 7.50-7.35 (m, 4H), 7.10-7.00 (m, 6H),
6.90-6.81 (m, 3H), 6.80-6.55 (br s, 2H), 5.49 (d, J ) 7.7 Hz,
1H), 4.77 (d, J ) 7.7 Hz, 1H), 4.69 (d, J ) 12.0 Hz, 1H), 4.61
(m, 1H), 4.47 (d, J ) 12.0 Hz, 1H), 4.00 (dd, J ) 2.6, 9.5 Hz,
1H), 3.59 (dd, J ) 3.2, 9.5 Hz, 1H), 3.05 (m, 1H), 2.53-2.25
(m, 3H), 1.83 (dd, J ) 9.2, 17.0 Hz, 1H); 13C NMR δ 213.7,
158.2, 137.7, 135.5, 133.7, 128.7, 128.4, 128.2, 128.0, 126.0,
Ca r bovir (20). A solution of BCl3 (1 M in CH2Cl2, 1.0 mL,
1.0 mmol) was added dropwise to a -78 °C solution of purine
19 (mg, mmol) in CH2Cl2 (0.50 mL). The resultant mixture
was stirred at -78 °C for 2 min and then allowed to warm
with stirring over 40 min. Methanol (3 mL) was added, and
the mixture was concentrated. This was repeated twice,
followed by the addition of a saturated 0 °C solution of NH3
in MeOH (2 mL). Concentration of the solution gave a tan
solid, which was purified by flash chromatography (3% MeOH/
CH2Cl2) to provide the corresponding free alchohol as a clear
gum (22.0 mg, 0.0853 mmol, 83%): 1H NMR (DMSO) δ 7.88
(s, 1H), 6.17 (dt, J ) 2.2, 5.5 Hz, 1H), 5.82 (dt, J ) 2.2, 5.5 Hz,
1H), 5.53 (m, 1H), 5.09 (br s, 2H), 3.89 (dd, J ) 4.0, 10.7 Hz,
1H), 3.76 (dd, J ) 3.7, 10.7 Hz, 1H), 3.36 (br s, 1H), 3.13 (m,
1H), 2.83 (dt, J ) 9.6, 14.0 Hz, 1H), 2.03 (dt, J ) 5.5, 14.0 Hz,
1H); 13C NMR (DMSO) δ 158.5, 152.9, 151.4, 141.8, 138.9,
129.7, 125.7, 64.7, 60.9, 47.6, 32.9; IR (film) 3319, 1612, 1562
cm-1; HRMS m/z (M + H) calcd 266.0809, obsd 266.0802; [R]24
D
80.5, 74.1, 70.1, 64.6, 53.4, 41.5, 41.3, 38.5; IR (film) 1745 cm-1
mp 138-139 °C; [R]24 1.3 (c 1.0, CH2Cl2). Anal. Calcd for
;
74.8 (c 0.84, MeOH).
D
Combined portions of the alcohol (57.2 mg, 0.215 mmol) were
heated to 100 °C in 0.5 N NaOH (2 mL) for 3.5 h. Adsorption
of the crude mixture onto Florisil, followed by purification by
flash chromatography (15% MeOH/CH2Cl2), afforded carbovir
(20) as a white solid (38.2 mg, 0.185 mmol, 72%): 1H NMR
(DMSO) δ 10.53 (br s, 1H), 7.57 (s, 1H), 6.43 (br s, 2H), 6.10
(dt, J ) 2.0, 5.8 Hz, 1H), 5.85 (dt, J ) 2.0, 5.8 Hz, 1H), 5.32
(m, 1H), 4.71 (t, J ) 5.4 Hz, 1H), 3.42 (t, J ) 5.4 Hz, 1H), 2.84
(m, 1H), 2.57 (dt, J ) 8.6, 13.9 Hz, 1H), 1.55 (dt, J ) 5.4, 13.9
Hz, 1H); 13C NMR (DMSO) δ 156.9, 153.6, 150.7, 138.2, 134.9,
C
28H27NO4: C, 76.17; H, 6.16; N, 3.17. Found: C, 75.91; H,
5.93; N, 3.16.
Cyclop en ten ol 17. To a 0 °C solution of cyclopentanone
16 (0.241 g, 0.547 mmol) in THF (5.0 mL) was added dropwise
a solution LDA (0.87 M in THF/Hex, 0.31 mL, 0.27 mmol).
The reaction mixture was stirred 15 min, diluted with satu-
rated NH4Cl (7 mL), and extracted with CH2Cl2. The combined
organic layers were washed with brine, dried (Na2SO4), and
concentrated to give a white solid, which was dissolved in THF
(4.0 mL) and cooled to -78 °C. To this solution was added
dropwise a solution of DIBAL (1 M in THF, 1.30 mL, 1.30
mmol), and the resultant solution was stirred for 2 h, allowing
it to slowly warm to 0 °C. The reaction mixture was quenched
with 1 N HCl (15 mL) and stirred for 5 min, after which it
was extracted with EtOAc. The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated to give
a white solid. Purification by flash chromatography (20%
EtOAc/Hex) gave 17 as a clear oil (55.4 mg, 0.271 mmol,
50%): 1H NMR δ 7.37-7.25 (m, 5H), 5.95 (dt, J ) 2.0, 5.5 Hz,
1H), 5.82 (dd, J ) 2.6, 5.5 Hz, 1H), 4.62 (d, J ) 6.5 Hz, 1H),
4.55 (d, J ) 11.9 Hz, 1H), 4.52 (d, J ) 11.9 Hz, 1H), 3.47 (m,
2H), 2.85 (m, 1H), 2.69 (br s, 1H), 2.32 (ddd, J ) 7.0, 8.6, 13.9
Hz, 1H), 1.57 (dt, J ) 1.9, 13.9 Hz, 1H); 13C NMR δ 137.6,
135.1, 135.0, 128.4, 127.8, 75.8, 73.4, 71.4, 44.6, 37.3; IR (film)
129.7, 116.6, 64.0, 58.4, 47.7, 34.3; IR (film) 3326, 1691 cm-1
;
mp 235-239 °C dec; HRMS m/z (M + H) calcd 248.1147, obsd
248.1147; [R]24D 60.3 (c 0.4, MeOH) [lit.33 mp 210-220 °C, dec;
[R]24 59.5 (c 0.4, MeOH)].
D
P u r in e 21. A suspension of carbonate 18 (53.2 mg, 0.193
mmol), adenine (38.7 mg, 0.286 mmol), and Pd(PPh3)4 (30.1
mg, 0.0260 mmol) in DMF (2 mL) was stirred at room
temperature for 90 min. The mixture was concentrated and
purified by flash chromatography (3% MeOH/CH2Cl2) to afford
21 as a white foam (40.1 mg, 0.125 mmol, 65%): 1H NMR δ
8.37 (s, 1H), 7.90 (s, 1H), 7.37-7.25 (m, 5H), 6.20 (dt, J ) 1.9,
(33) Evans, C. T.; Roberts, S. M.; Shoberu, K. A.; Sutherland, A. G.
J . Chem. Soc., Perkin Trans I 1992, 589.

1872 J . Org. Chem., Vol. 65, No. 6, 2000
Brown and Hegedus
5.6 Hz, 1H), 6.00 (br s, 2H), 5.89 (dt, J ) 2.0, 5.6 Hz, 1H),
5.75 (m, 1H), 4.52 (s, 2H), 3.50 (m, 2H), 3.12 (m, 1H), 2.86 (dt,
J ) 8.8, 14.0 Hz, 1H), 1.73 (dt, J ) 5.5, 14.0 Hz, 1H); 13C NMR
δ 155.5, 152.7, 149.7, 139.0, 138.8, 137.9, 129.4, 128.4, 128.1,
127.6, 119.7, 73.2, 72.5, 59.2, 45.6, 35.3; IR (film) 3318, 1648,
of diastereomers (NMR). Purification by preparative HPLC
(95:5 to 80:20 H2O/MeOH gradient elution over 55 min)
provided (()-aristeromycin (23a ) as a clear film, which was
crytallized (MeOH/EtOAc) to give a white solid (13.7 mg,
0.0516 mmol, 55%), and (()-2′,3′-bis-epi-aristeromycin (23b)
as a clear film (6.6 mg, 0.025 mmol, 26%). 23a : 1H NMR
(DMSO) δ 8.20 (s, 1H), 8.12 (s, 1H), 7.18 (br s, 2H), 4.98 (d,
J ) 5.9 Hz, 1H), 4.82-4.64 (m, 3H), 4.34 (m, 1H), 3.84 (m,
1H), 3.47 (m, 1H), 3.17 (d, J ) 4.3 Hz, 1H), 2.23 (dt, J ) 8.7,
12.5 Hz, 1H), 2.04 (m, 1H), 1.72 (m, 1H); 13C NMR (DMSO) δ
155.9, 152.1, 149.7, 140.1, 74.6, 71.7, 63.0, 59.3, 45.3, 29.3; IR
(film) 3329, 3207, 1648, 1603 cm-1; mp (() 228-231 °C dec
[lit.34 mp 238-242 °C]; HRMS m/z (M + H) calcd 266.1253,
obsd 266.1249.
1598 cm-1; mp 147-149 °C; [R]24 39 (c 0.81, CHCl3). Anal.
D
Calcd for C18H19N5O: C, 67.27; H, 5.96; N, 21.79. Found: C,
67.41; H, 5.84; N, 22.00.
Alcoh ol 22. A solution of BCl3 (1 M in CH2Cl2, 0.80 mL,
0.80 mmol) was added dropwise to a solution of purine 21 (36.5
mg, 0.101 mmol) in CH2Cl2 (0.90 mL) at -78 °C. The resulting
mixture was stirred at -78 °C for 15 min and then allowed to
warm with stirring over 20 min. Methanol (2 mL) was added,
and the mixture was concentrated. This was repeated twice,
followed by the addition of a solution of NH3 in MeOH
(saturated at 0 °C, 2 mL). Concentration of the solution gave
a tan solid, which was purified by flash chromatography (7%
MeOH/CH2Cl2) to provide alchohol 22 containing a ∼15%
impurity as a clear gum, which was used without further
purification (15.0 mg, 0.0649 mmol, 64%). A portion of (()-22
was recrystallized (MeOH/EtOAc) to provide analytically pure
material: 1H NMR (DMSO) δ 8.13 (s, 1H), 8.04 (s, 1H), 7.20
(br s, 2H), 6.13 (dt, J ) 1.8, 5.5 Hz, 1H), 5.91 (m, 1H), 5.58
(m, 1H), 4.74 (t, J ) 5.1 Hz, 1H), 3.46 (t, J ) 5.1 Hz, 2H), 2.90
(m, 1H), 2.67 (dt, J ) 8.7, 13.7 Hz, 1H), 1.65 (dt, J ) 5.5, 13.7
Hz, 1H); 13C NMR (DMSO) δ 155.9, 152.3, 149.2, 138.7, 138.3,
129.7, 118.9, 63.9, 59.0, 47.7, 34.2; IR (film) 3172, 1672, 1648,
1604, 1575 cm-1; mp (() 183-186 °C. Anal. Calcd for
(+)-Aristeromycin (23a ) was prepared as above using
(+)-22 (9.5 mg, 0.041 mmol) and OsO4 (12.8 mg, 0.050 mmol)
to afford (+)-23a , contaminated with a 10% unidentified
impurity (4.7 mg, 0.018 mmol, 43%): [R]24 31 (c 0.2, DMF)
D
[lit.35 [R]23 51 (c 0.3, DMF)].
D
Ack n ow led gm en t. Support for this research under
Grant No. GM26178 from the National Institutes of
General Medical Sciences (Public Health Service) is
gratefully acknowledged. Mass spectra were obtained
on instruments supported by the National Institutes of
Health shared instrumentation grant GM49631.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 7a ,b, 8, 12c, 13a ,c,f, and 18 and an
ORTEP diagram from the X-ray crystal structure of 8. This
information is available free of charge via the Internet at
http://pubs.acs.org.
C
11H13N5O: C, 57.13; H, 5.67; N, 30.28. Found: C, 57.27; H,
5.81; N, 30.43.
Ar ist er om ycin (23a ). To a -10 °C solution of (()-22
(21.8 mg, 0.0943 mmol) in DMF (1.5 mL) was added OsO4
(26.7 mg, 0.103 mmol), and the resultant solution was allowed
to stand for 36 h at -15 °C. The mixture was then diluted
with MeOH (0.5 mL), quenched with saturated aqueous
NaHSO3 (0.5 mL), and stirred for 20 min. The suspension was
filtered through Celite, diluted with MeOH, and filtered again
to give 30 mg of a clear gum, determined to be a 2.3:1 mixture
J O9919759
(34) Shealy, Y. F.; Clayton, J . D. J . Am. Chem. Soc. 1966, 88, 3885.
(35) Secrist, J . A. III; Montgomery, J . A.; Shealy, Y. F.; O’Dell,
C. A.; Clayton, S. J . J . Med. Chem. 1987, 30, 746.