Synthesis of (+)-neplanocin A from a chromium-carbene complex-derived optically active butenolide

Full text of DOI:10.1021/jo000154x

4200
J . Org. Chem. 2000, 65, 4200-4203
pure form in overall ≈60% yield (from chromium hexac-
Syn th esis of (+)-Nep la n ocin A fr om a
arbonyl and R-benzyloxymethyl acetyl chloride), by start-
ing with the appropriate enantiomer of the phenyl
glycine-derived chiral auxiliary.10 Butenolide 4 has struc-
tural features (the double bond that might be cis hy-
droxylated and a leaving group geminal to the ring
oxygen) that make it an attractive precursor to neplano-
cin A, utilizing the above phosphonate anion/intra-
molecular ylide process. Studies to convert 4 to neplano-
cin A are described below.
Ch r om iu m -Ca r ben e Com p lex-Der ived
Op tica lly Active Bu ten olid e
L. S. Hegedus and L. Geisler
Department of Chemistry, Colorado State University,
Fort Collins, Colorado 80523
Received February 3, 2000
In tr od u ction
(-)-Neplanocin A (1)1 is a cyclopentenyl analogue of
adenosine with potent antitumor and antiviral activity
and is a powerful inhibitor of S-adenosylhomocysteine
hydrolase.2 A number of asymmetric syntheses of nepl-
anocin A have been reported.3 Several rely on chemo-
enzymic processes to provide optically active intermedi-
ates,4 while others start with optically active materials
from the “chiral pool” such as D-ribonolactone,5 D-ribose,6
or L-tartaric acid.7 Optically active cyclopentenone 2 is a
key intermediate in the synthesis of a number of car-
bocyclic nucleosides, in addition to neplanocin A.3 It has
been synthesized from ribonolactone by ring opening of
the lactone with the lithium anion of dimethyl meth-
ylphosphonate, followed by oxidation of the released
γ-hydroxy group and Wadsworth-Emmons cyclization
onto the thus-formed ketone.5 With ribonolactone, this
multistep process suffered from modest yields and partial
racemization. However, with simpler lactones (e.g., 3)
having an alkoxide leaving group geminal to the lactone
ring oxygen, this ring opening/cyclization occurred in a
one-pot, cascade process without detectable racemization,
providing an efficient approach to neplanocin analogues.8
Recently, an efficient synthesis of optically active
butenolide 4, a potential precursor to nucleoside ana-
logues, has been reported from these laboratories.9 Both
enantiomers are equally available in enantiomerically
Resu lts a n d Discu ssion
cis-Hydroxylation of (()-4 with potassium permanga-
nate/dicyclohexano-18-crown-6 produced a single cis diol
in 72% yield at 70% conversion (50% isolated yield of 5).
The use of sodium periodate in the presence of a catalytic
amount of ruthenium(III) chloride11 produced a 3:1
mixture of cis diols in overall 65% yield, at 80% conver-
sion (40% and 12% isolated yields of diastereomers of 5,
respectively). The major diol from the periodate oxidation
corresponded to the product from the permanganate
oxidation (Scheme 1). Attempts to establish the stereo-
chemistry of these diols using NOESY measurements
failed, as is often the case in five-membered ring systems.
COSY established that the proton â to the carbonyl group
for the major diastereomer appeared at δ 4.6 while the
R proton appeared at δ 4.31. The situation was reversed
for the minor isomer, with the â proton appearing at δ
4.32 and the R proton at δ 4.62. The â proton of both
isomers showed a substantial NOE interaction with the
CH2OBn group, making stereochemical assignments
impossible.
(1) (a) Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi,
M.; Otani, M. J . Antibiot. 1981, 34, 359. (b) Hayashi, M.; Yaginuma,
S.; Yoshioka, H.; Nakatsu, K. J . Antibiot. 1981, 34, 675.
(2) Borchardt, R. T.; Keller, B. T.; Patel-Thombre, U. J . Biol. Chem.
1984, 259, 4353.
(3) For general reviews of carbocyclic nucleoside syntheses, see: (a)
Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571. (b)
Crimmins, M. T. Tetrahedron 1998, 54, 9229. For a recent asymmetric
synthesis involving Pd-catalyzed desymmetrization, see: Trost, B. M.;
Madsen, R.; Guile, S. D. Tetrahedron Lett. 1997, 38, 1707.
(4) (a) Arita, M.; Adachi, K.; Ito, Y.; Sawai, H.; Ohno, M. J . Am.
Chem. Soc. 1983, 105, 4049. (b) Medich, J . R.; Kunnen, K. B.; J ohnson,
C. R. Tetrahedron Lett. 1987, 28, 4131. (c) Yoshida, N.; Kamikubo, T.;
Ogasawara, K. Tetrahedron Lett. 1998, 39, 4677. (d) Deardorff, D. R.;
Shambayati, S.; Miles, D. C.; Heerding, D. J . Org. Chem. 1988, 53,
3614. (e) Hill, J . M.; Hutchinson, E. J .; LeGrand, D. M.; Stanley, M.;
Thorpe, A. J .; Turner, N. J . J . Chem. Soc., Perkin Trans. 1 1994, 1483.
(5) (a) Marquez, V. E.; Lim, M.-I.; Tseng, C. K-H.; Markovac, A.;
Priest, M. A.; Khan, M. S.; Kaskar, B. J . Org. Chem. 1988, 53, 5709.
(b) Marquez, V. E.; Lim, M., III; Markovac, A.; Priest, M. A. Nucleic
Acid Chem. 1991, 252.
(6) (a) Borcherding, D. R.; Scholtz, S. A.; Borchardt, R. T. J . Org.
Chem. 1987, 52, 5457. (b) Ohira, S.; Sawamoto, T.; Yamamoto, M.
Tetrahedron Lett. 1995, 36, 1537.
(7) Bestmann, H. J .; Roth, D. Angew. Chem., Int. Ed. Engl. 1990,
29, 99.
(8) Ali, S. M.; Ramesh, K.; Borchart, R. T. Tetrahedron Lett. 1990,
31, 1509.
The major isomer was thought to be that from attack
of the R face of the butenolide, resulting in the stereo-
isomer required for conversion to neplanocin A, on the
basis of previous studies with simpler analogues.12
However when the cis diol from (-)-4 was carried through
the synthetic sequence in Scheme 1, (+)-neplanocin A was
produced rather than the expected (-) enantiomer. Since
(10) The chiral ene carbamate was made in one step and 78% yield
from phenyl glycinol and (ethoxy)(methyl)carbene chromium penta-
carbonyl. The chiral oxazolidinone auxiliary was recovered in >80%
yield in the elimination step generating enone 4. Miller, M.; Hegedus,
L. S. J . Org. Chem. 1993, 58, 6779.
(9) (a) Reed, A. D.; Hegedus, L. S. Organometallics 1997, 16, 2313.
(b) For an updated procedure, see: Brown, B.; Hegedus, L. S. J . Org.
Chem. 2000, 65, 1865.
(11) Shing, T. K. M.; Tai, V. W-F.; Tam, E. K. Angew. Chem., Int.
Ed. Engl. 1994, 33, 2312.
(12) Reed, A. D.; Hegedus, L. S. J . Org. Chem. 1995, 60, 3787.
10.1021/jo000154x CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/01/2000

Notes
J . Org. Chem., Vol. 65, No. 13, 2000 4201
Sch em e 1
it is the cis-hydroxylation step that sets all of the stereo
centers, the major diol resulted from cis-hydroxylation
of the â-face of the butenolide, the face opposite the
alkoxy group. To confirm that the major diol was indeed
5-â and not 5-R, it was converted to its acetonide, which
had an [R]D of +8° (c ) 0.06, CHCl3), in comparison to
the reported [R]D of -7.2° (c ) 1.1, CHCl3) reported for
the R-isomer.5 (-)-Neplanocin A should be available by
the same chemistry by starting with the (+) enantiomer
of 4, which is readily available from S-phenyl glycine.10
NaBH4/CeCl35 occurred exclusively from the face opposite
the protected diol, giving 8 in virtually quantitative yield.
A number of approaches for the direct introduction of
adenine into allylic alcohols such as 8 have been reported.
Mitsunobu coupling4c seemed the most direct approach.
However, at room temperature in THF, no reaction
occurred, perhaps because of the very low solubility of
adenine in the reaction medium. Heating to 100 °C in a
pressure tube resulted in extensive decomposition.
Similarly, conversion of alcohol 8 to the tosylate6 met
with limited success because of difficulty in the separa-
tion from excess tosyl chloride and the intolerance of the
next step to tosyl chloride. In contrast, mesylation of 813
proceeded in excellent yield without complications. Cou-
pling of 9 (adenine/K2CO3/18-crown-6)13 took place in 54%
yield accompanied by small amounts (∼4%) of the N-7
isomer, results comparable to other reported direct
couplings with adenine.5,9b Removal of the two protecting
groups in a single step with BCl35 in 41% yield completed
this synthesis of (+)-neplanocin A. The natural enanti-
omer should be available by this same route from (+)-4.
Since cyclopentenone 7 has served as the key intermedi-
ate in the synthesis of a number of carbocyclic nucleoside
analogues,3 its asymmetric synthesis by this route may
streamline syntheses of these compounds as well.
The synthesis of (+)-neplanocin A from (-)-4 is out-
lined in Scheme 1. cis-Hydroxylation of (-)-4 (KMnO4/
dicyclohexano-18-crown-6) proceeded in only 50% yield,
somewhat lower than that observed with the model
butenolide (having a butyl group in place of the benzyl-
oxymethyl group).12 In this case, the formation of diol 5-â
is in competition with the decomposition of both buteno-
lide 4 and diol 5-â under the reaction conditions. The
reaction was monitored and quenched when the undes-
ired side products began to form, making it possible to
recycle 4. Care was also required to prevent hydrolysis
of the lactone during the acid hydrolysis of the manga-
nate ester.
For synthetic purposes, protection as the cyclohex-
anone ketal 6 was more efficient than conversion to the
acetonide. Treatment of 6 with the lithium salt of
dimethyl methylphosphonate produced cyclopentenone 7
in good yield in the one-pot lactone ring-opening, in-
tramolecular Wadsworth-Emmons process. This step
was quite sensitive to reaction conditions. It was critical
that the phosphonate anion be completely consumed in
the ring lactone-opening step prior to formation of any
of the enone 7, since this compound can also react with
the phosphonate anion. Reduction of ketone 7 with
Exp er im en ta l Section
Gen er a l Meth od s. THF was distilled from sodium-benzo-
phenone ketyl, and CH2Cl2, DMF, and Et3N were distilled from
CaH2. Commercially available reagents were used as received
except as indicated, and the dimethyl methylphosphonate was
stored in a desiccator. 1H NMR, NOE, COSY (300 MHz), 13C
(13) Medich, J . R.; Kunnen, K. B.; J ohnson, C. R. Tetrahedron Lett.
1987, 28, 4131.

4202 J . Org. Chem., Vol. 65, No. 13, 2000
Notes
NMR (75 MHz), and HSQC (400 1H MHz) spectra were recorded
in CDCl3 unless otherwise noted, and chemical shifts are given
in ppm relative to CDCl3 (7.24 ppm). Column chromatography
was performed with ICN 32-66 nm, 60 Å silica gel using flash
column techniques. Elemental analyses were performed by
M-H-W Laboratories, Phoenix, AZ. FAB-High-Resolution Mass
Spectrometry (HRMS) was obtained with a Fisons VG AutoSpec
mass spectrometer with a Cs ion gun, m-nitrobenzyl alcohol was
used for the matrix, and the resolution was set to 10,000. All
reactions were performed in flame-dried glassware under an
atmosphere of Ar unless otherwise noted.
(4S,5S)-3-Ben zyloxym eth yl-4,5-O-cycloh exylid en e-cyclo-
p en t-2-en on e (7). Following the general procedure of Borcherd-
ing et al.,6 a two-necked flask was flame-dried and charged with
freshly distilled dimethyl methylphosphonate (37 µL, 0.35 mmol)
and 2.2 mL of THF. The solution was cooled to -78 °C with an
acetone/dry ice bath, and n-butyllithium (0.2 mL, 0.35 mmol)
was added down the sidearm of the flask, to precool the solution,
via syringe over a 15 min period. The solution was stirred for
an additional 15 min after the addition was complete. Protected
diol 7 (125 mg, 0.345 mmol), dissolved in a minimal amount of
THF, was added down the sidearm via syringe. The solution was
stirred at -78 °C for 2.5 h. The acetone/dry ice bath was
removed, and the solution was warmed to room temperature (∼1
h). The solution was partitioned between Et2O and brine. The
organic layer was separated, and the aqueous layer was ex-
tracted with Et2O. The combined etheral layers were dried over
MgSO4, filtered, and concentrated by rotary evaporation. The
crude oil was purified by flash column chromatography (25:1 f
10:1 hex/EtOAc gradient elution) to yield enone 7 as a yellow
oil (56 mg, 0.18 mmol, 52%) and some recovered starting
(3S,4R,5R)-5-Ben zyloxym eth yl-5-eth oxy-3,4-d ih yd r oxy-
d ih yd r o-fu r a n -2-on e (5-â). (-)-5-Benzyloxymethyl-5-ethoxy-
5H-furan-2-one (4)9 (0.900 g, 3.62 mmol) was dissolved in 30 mL
of CH2Cl2, and cis-dicyclohexano-18-crown-6 (0.135 g, 0.362
mmol) was added. The solution was cooled to -40 °C in a dry
ice/acetonitrile bath, and KMnO4 (0.744 g, 4.71 mmol) was added
in five portions over 45 min. The mixture was stirred at -40 °C
until side products were visible (ca. 2-3 h) by TLC (silica gel,
hex/ETOAc, 3:1). Solid NaHSO3, H2O, and two drops of 1 M H2-
SO4 were added, and the mixture was transferred to a separatory
funnel. The mixture was shaken vigorously and additional solid
NaHSO3 was added until the solution decolorized upon shaking.
The organic layer was separated, and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were dried
over MgSO4, filtered, and concentrated. The crude yellow oil was
purified by flash column chromatography (5:1 f 3:1 hex/Et2O
f 100% Et2O gradient elution) to yield diol 5-â as a clear oil
(0.514 g, 1.82 mmol, 50%) and recovered butenolide 4 (0.256 g).
material 6 (17.5 mg). 7: [R]25 +7° (c ) 0.855, EtOH); 1H NMR
D
δ 7.38 (m, 5H), 6.16 (m, 1H), 5.05 (d, J ) 5.7 Hz, 1H), 4.64 (d, J
) 11.7 Hz, 1H), 4.60 (d, J ) 12.0 Hz, 1H), 4.50 (dd, J ) 1.8 Hz,
J ) 17.4 Hz, 1H), 4.46 (d, J ) 6.0 Hz, 1H), 4.33 (dd, J ) 1.2 Hz,
J ) 17.7 Hz, 1H), 1.58 (m, 10H); 13C NMR δ 201.7, 173.9, 137.1,
128.5, 128.3, 128.0, 127.6, 116.2, 77.6, 77.4, 73.3, 67.6, 37.3, 35.8,
25.0, 23.9, 23.6; IR (neat) 1724 cm-1; FAB-HRMS calcd for
C19H22O4 (M + H) 315.1596, found 315.1600. Anal. Calcd for
C
19H22O4: C, 72.56; H, 7.05. Found: C, 72.32; H, 6.91.
5-â: [R]25 -17° (c ) 1.83, EtOH); 1H NMR δ 7.35 (m, 5H), 4.63
(1R,4S,5R)-3-Ben zyloxym et h yl-4,5-O-cycloh exylid en e-
D
(m, 1H), 4.60 (s, 2H), 4.29 (dd, J ) 2.7 Hz, J ) 4.8 Hz, 2H), 3.87
(d, J ) 11.1 Hz, 1H), 3.75 (d, J ) 10.8 Hz, 1H), 3.63 (q, J ) 7.1
Hz, 2H), 2.93 (m, 2H), 1.15 (t, J ) 7.1 Hz, 3H); 13C NMR δ 175.4,
136.9, 128.5, 128.1, 128.0, 107.4, 73.7, 71.9, 69.4, 64.2, 59.1, 15.3;
IR (neat) 3421, 1793 cm-1; FAB-HRMS calcd for C14H18O6 (M
+ H) 283.1182, found 283.1174.
cyclop en t-2-en ol (8). Enone 7 (67 mg, 0.21 mmol) was dissolved
in 0.2 mL of MeOH (stored over 3 Å molecular sieves). The
solution was cooled to 0 °C, and CeCl3‚7H2O (66.7 mg, 0.179
mmol) was added. NaBH4 (12.1 mg, 0.32 mmol) was added in
three portions, and the reaction was stirred at 0 °C for 10 min.
Glacial acetic acid was added via syringe until pH ∼5, brine was
added, and the mixture was extracted with Et2O. The combined
etheral layers were dried over MgSO4, filtered, and concentrated
by rotary evaporation. The crude oil was purified by flash column
chromatography (25:1 hex/EtOAc gradient elution) to yield
5-Ben zyloxym eth yl-5-eth oxy-3,4-d ih yd r oxy-d ih yd r o-fu -
r a n -2-on e (5-r a n d 5-â). (-)-Butenolide 4 (52.5 mg, 0.211
mmol) was dissolved in 2 mL of ETOAc and 2 mL of CH3CN,
and the mixture was cooled to 0 °C. RuCl3‚xH2O (3.1 mg, 0.015
mmol) and NaIO4 (67.8 mg, 0.317 mmol) were dissolved in 0.75
mL of H2O and added to the butenolide solution via syringe.
The reaction was stirred vigorously for 5 min and then poured
into saturated aqueous Na2S2O3. The organic layer was extracted
with ETOAc, combined, dried over MgSO4, filtered, and concen-
trated. The crude brown residue was purified by flash column
chromatography (4:1-3:1 hex/ETOAc gradient elution) to yield
diol 5-R (7 mg, 0.02 mmol, 12%) and 5-â (24 mg, 0.085 mmol,
40%) as clear oils and recovered butenolide 4 (11 mg). 5-r: 1H
NMR (400 MHz) δ 7.31 (m, 5H), 4.61 (m, 1H), 4.57 (d, J ) 12.4
Hz, 1H), 4.49 (d, J ) 11.6 Hz, 1H), 4.30 (d, J ) 5.6 Hz, 1H), 3.90
(m, 1H), 3.73 (d, J ) 9.6 Hz, 1H), 3.68 (m, 1H), 3.66 (d, J ) 10.4
Hz, 1H), 3.17 (s, 1H), 2.96 (d, J ) 8.4 Hz, 1H), 1.24 (t, J ) 7.2,
3H); 13C NMR δ 174.0, 136.4, 128.7, 128.3, 128.0, 127.8, 103.6,
74.0, 70.8, 70.2, 69.5, 61.0, 15.4.
(3S,4R,5R)-5-Ben zyloxym eth yl-5-eth oxy-3,4-O-cycloh ex-
ylid en e-d ih yd r o-fu r a n -2-on e (6). A flask, equipped with
reflux condensor and Soxhlet extractor containing 4 Å molecular
sieves, was charged with diol 5 (27 mg, 0.096 mmol) and 8 mL
of benzene. The solution was warmed to reflux, and then a few
crystals of TsOH were added. The mixture was kept at reflux
for until no starting material was present (∼30 min) by TLC
(silica gel, hex/ETOAc, 4:1). The mixture was cooled to room
temperature and quenched with saturated aqueous Na2CO3. The
separated organic layer was washed with saturated aqueous Na2-
CO3 and water. The organic layer was then dried over MgSO4,
filtered, and concentrated by rotary evaporation. The crude oil
(37 mg) was purified by flash column chromatography (25:1 hex/
alcohol 8 as a clear film (64 mg, 0.20 mmol, 96%): [R]25 -28°
D
(c ) 1.69, EtOH); 1H NMR δ 7.28 (m, 5H), 5.77 (s, 1H), 4.95 (d,
J ) 5.4 Hz, 1H), 4.73 (t, J ) 5.4 Hz, 1H), 4.54 (m, 2H), 4.13 (s,
2H), 2.76 (d, J ) 9.9 Hz, 1H) 1.58 (m, 10H); 13C NMR δ 173.8,
137.3, 128.3, 127.8, 115.2, 106.4, 78.9, 75.5, 73.6, 64.2, 59.0, 36.5,
35.7, 24.7, 23.8, 23.7, 15.2; IR (neat) 3540 cm-1; FAB-HRMS
calcd for C19H24O4 (M + H) 317.1753, found 317.1740.
(1R,4S,5R)-Meth a n esu lfon ic Acid 3-Ben zyloxym eth yl-
4,5-O-cycloh exylid en e-cyclop en t-2-en yl Ester (9). Alcohol
8 (40 mg, 0.126 mmol) was dissolved in 3 mL of CH2Cl2 and
cooled to 0 °C. NEt3 (0.02 mL, 0.164 mmol) and then MsCl (0.01
mL, 0.164 mmol) were added via syringe. The reaction was
stirred at 0 °C for 10 min and quenched with water. The aqueous
layer was separated and extracted with CH2Cl2. The combined
organic layers were washed with saturated aqueous NaHCO3,
dried over MgSO4, and concentrated by rotary evaporation. The
crude oil was purified by flash column chromatography (4:1 hex/
EtOAc) to yield mesylate 9 as a clear oil (43 mg, 0.109 mmol,
86%): [R]25 +15° (c ) 1.96, EtOH); 1H NMR (400 MHz) δ 7.30
D
(m, 5H), 5.78 (d, J ) 0.8 Hz, 1H), 5.39 (dd, J ) 2.0 Hz, J ) 5.2
Hz, 1H), 4.94 (d, J ) 5.6 Hz, 1H), 4.89 (t, J ) 5.4 Hz, 1H), 4.57
(d, J ) 12.0 Hz, 1H), 4.54 (d, J ) 12.0 Hz, 1H), 4.20 (d, J ) 14.0
Hz, 1H), 4.15 (d, J ) 14.4 Hz, 1H), 3.12 (s, 3H), 1.54 (m, 10H);
13C NMR (400 MHz) δ 147.3, 137.7, 128.4, 127.8, 127.6, 125.0,
114.2, 82.6, 80.9, 76.8, 73.0, 66.1, 39.0, 37.1, 36.4, 24.9, 23.9; IR
(neat) 1350, 1175 cm-1; FAB-HRMS calcd for C20H26O6S (M+)
394.1450, found 394.1438.
(1S,4S,5R)-9-(3-Ben zyloxym eth yl-4,5-O-cycloh exylid en e-
cyclop en t-2-en yl)-9H-p u r in -6-yla m in e (10). K2CO3 (36.4 mg,
0.264 mmol) and 18-crown-6 (34.8 mg, 0.132 mmol) were
dissolved in 1.8 mL of DMF. Adenine (35.6 mg, 0.264 mmol) was
added, and the solution was stirred for 10 min. Mesylate 9 (52
mg, 0.13 mmol), dissolved in a minimal amount of DMF, was
added dropwise to the solution. The solution was warmed to ∼70
°C for 18 h and then cooled to room temperature. The DMF was
removed by rotary evaporation. The resulting tan residue was
dissolved in CH2Cl2, filtered through Celite to remove any solid
ETOAc) to yield protected diol 6 as a clear oil (30 mg, 0.083
1
mmol, 86%): [R]25 -15° (c ) 1.38, EtOH); H NMR δ 7.30 (m,
D
5H), 4.87 (d, J ) 4.8 Hz, 1H), 4.65 (d, J ) 12.3 Hz, 1H), 4.60 (d,
J ) 12.6 Hz, 1H), 4.56 (d, J ) 5.1 Hz, 1H), 3.84 (d, J ) 10.8 Hz,
1H), 3.71 (d, J ) 10.5 Hz, 1H), 3.68 (m, 2H), 1.57 (m, 10H), 1.16
(t, J ) 6.9 Hz, 3H); 13C NMR δ 173.8, 137.3, 128.3, 127.8, 115.1,
106.4, 78.9, 75.5, 73.6, 64.2, 59.0, 36.5, 35.6, 24.7, 23.8, 15.2; IR
(neat) 1801 cm-1; FAB-HRMS calcd for C20H26O6 (M + H)
363.1808, found 363.1804.

Notes
J . Org. Chem., Vol. 65, No. 13, 2000 4203
particles, and concentrated. The resulting yellow oil was purified
by flash column chromatography (6:1 hex/ETOAc f 100% CH2-
Cl2 f 3% MeOH/CH2Cl2 gradient elution) to first yield a clear
oil, which was triturated with CH2Cl2 to remove any inorganic
impurities. Concentration of the triturating solvent gave 10 as
was repeated twice more, followed by the addition of a solution
of NH3 in MeOH (1 mL, saturated at 0 °C), which was
concentrated to provide a white solid. The crude solid was
purified by flash column chromatography (10% EtOH/CH2Cl2
f 20% MeOH/CH2Cl2 gradient elution) to provide a white solid,
which was triturated with ETOH to remove any inorganic
impurities. Concentration of the triturating solvent gave (+)-1
as a white solid (4.9 mg, 0.0186 mmol, 41%): [R]D +35° (c )
a clear oil (31 mg, 0.072 mmol, 54%): [R]25 +102° (c ) 1.34,
D
1
EtOH); H NMR δ 8.34 (s, 1H), 7.64 (s, 1H), 7.31 (m, 5H), 6.07
(bs, 2H), 5.78 (s, 1H), 5.55 (s, 1H), 5.38 (d, J ) 4.2 Hz, 1H), 4.70
(d, J ) 4.5 Hz, 1H), 4.63 (d, J ) 9.3 Hz, 1H), 4.54 (d, J ) 18.3
Hz, 1H), 4.50 (d, J ) 18.6 Hz, 1H), 4.24 (d, J ) 11.4 Hz, 1H),
1.59 (m, 10H); 13C NMR (400 MHz) δ 155.3, 152.7, 149.8, 149.6,
138.9, 137.8, 128.4, 127.8, 127.6, 122.8, 120.1, 113.4, 83.9, 83.6,
72.9, 66.5, 64.7, 37.2, 35.6, 24.9, 24.0, 23.6; IR (neat) 3319, 3156,
1648, 1596 cm-1; FAB-HRMS calcd for C24H27N5O3 (M + H)
434.2192, found 434.2195. The column then gave the N-7 isomer
(2 mg, 0.005 mmol, 4%): 1H NMR δ 8.49 (s, 1H), 7.85 (s, 1H),
7.34 (m, 5H), 6.02 (s, 1H), 5.76 (s, 1H), 5.53 (d, J ) 1.5 Hz, 1H),
5.25 (d, J ) 14.7 Hz, 1H), 4.72 (d, J ) 6.0 Hz, 1H), 4.65 (s, 2H),
4.31 (d, J ) 15.0 Hz, 1H), 4.26 (d, J ) 15.0 Hz, 1H), 1.65 (m,
10H).
1
0.5, H2O). The H, 13C, and mass spectra of this compound were
identical to those previously reported.5a
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 5-R, 5-â, 6, 7, 8, 9, 10, N-7 isomer of
10, and 1; DEPT 13C NMR spectra for compounds 5-â and 5-R;
1
NOE spectra for compounds 5-â and 5-R; H-13C 2D (HSQC)
spectra for compounds 5-â and 5-R; 1H-1H 2D (COSY) spectra
for compounds 5-â and 5-R (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(+)-Nep la n ocin A (1). Protected (+)-neplanocin A 10 (20 mg,
0.0461 mmol) was dissolved in 0.5 mL of CH2Cl2, and the
mixture was cooled to -78 °C. BCl3 (0.5 mL, 0.461 mmol) was
added slowly via syringe down the side of the flask to precool
the solution. The mixture was stirred until no starting material
was observed (∼10 min) by TLC (silica gel, 10% MeOH in CH2-
Cl2). The solution was warmed to room temperature, quenched
with MeOH, and concentrated. MeOH (2 mL) was added, and
the solution was concentrated. This addition/evaporation process
Ack n ow led gm en t. Support for this research under
grant GM54524 from the National Institutes of General
Medical Sciences (Public Health Service) is gratefully
acknowledged. Mass spectra were obtained on instru-
ments supported by the National Institutes of Health
shared instrumentation grant GM49631.
J O000154X