Full text of DOI:10.1016/S0040-4020(01)01191-7

TETRAHEDRON
Pergamon
Tetrahedron 58 /2002) 967±974
Synthetic approaches to ꢀ^)-c-4-amino-r-1,c-2,t-3-cyclo-
pentanetrimethanol: a precursor of higher homologues
of xylo-carbocyclic nucleosides
p
Marõa Jose Figueira, Olga CaamanÄo, Franco Fernandez, Xerardo Garcõa-Mera
Â
and Marcos Daniel Garcõa
Â
Â
Â
Â
 Â
Departamento de Quõmica Organica, Facultad de Farmacia, Universidad de Santiago de Compostela,
E-15782 Santiago de Compostela, Spain
Received 9 October 2001; revised 28 November 2001; accepted 30 November 2001
AbstractÐAminoalcohol 3, a compound of interest for the synthesis of carbocyclic analogs of nucleosides, was prepared from
/^)-/2endo,3exo)bicyclo[2.2.1]hept-5-ene-2,3-dimethanol. In the key step, oxidative degradation of a carboxamide was ef®ciently achieved
by treatment of amidoester 10 with lead tetraacetate in tert-butanol. q 2002 Published by Elsevier Science Ltd.
1.Introduction
been prepared and subjected to more or less extensive
evaluation of their biological activity.8±12 Both antiviral
and antitumoural activities have been found among those
with xylo con®guration.13,14
A number of nucleosides and nucleoside analogs are known
to be potent selective inhibitors of the replication of HIV-1,
HSV-2, HBV and/or HCMV in vitro and in vivo, and some
now constitute the basis of clinically important therapies.1
One major class of modi®ed nucleosides comprises the
carbocyclic nucleosides,2 in which the furan ring is replaced
by a carbocycle. Arysteromycin /1), a natural member of
this family obtained from Streptomyces citricolor,3 is highly
toxic to cell cultures,4 is active against vaccinia virus5 and
inhibits AdoHcy hydrolase with a Ki of 5 nM.6 Abacavir /2)7
is a synthetic cyclopentenoid nucleoside with great anti-
HIV activity that is used clinically to treat AIDS and
AIDS-related complex.
In view of the above, and of the fact that there are also
biologically active nucleoside analogs that have a hydroxy-
methyl group directly bound to the carbocycle,15 we have
embarked on the development of versatile methods for the
synthesis of series of higher homologues of carbocyclic
nucleosides. Here we describe a convenient synthesis of
the aminotriol 3, a key intermediate in the preparation of
higher homologues of xylo-carbocyclic nucleosides such as
4 /Fig. 1).
Given the above precedents, a large number of carbocyclic
nucleoside derivatives of pentane, with pseudosugar con-
®gurations matching those of all the pentofuranoses, have
2.Discussion
Direct retrosynthetic analysis led to the choice of
Figure 1.
Keywords: xylo-carbocyclic nucleosides; oxidative degradation; aminoalcohol.
0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020/01)01191-7

968
M. J. Figueira et al. / Tetrahedron 58,2002) 967±974
O
O
HO
OH
OH
OH
OBz
a
b
OBz
OBz
BzO
6
5
7
c
O
O
O
O
O
HO
NH2
d
OBz
OBz
BzO
BzO
9
e
8
O
O
O
O
MeO
MeO
NH2
HN Boc
HO
NH2·HCl
g
f
OBz
OBz
OH
HO
BzO
BzO
14
10
15·HCl
i
h
HO
HO
AcO
HN Boc
NH2
OH
OH
j
NH
AcO
HO
HO
O
17
3
16
Scheme 1. /a) BzCl, pyridine, rt, 48 h; /b) KMnO4, AcOH, Aliquat 336, benzene, rt, 5 h; /c) Ac2O, re¯ux, 24 h; /d) NH3 gas, THF, 08C, 45 min; /e) MeOH,
p-TsOH; /f) Pb/OAc)4, t-BuOH, Et3N, re¯ux, 2 h; /g) 12N HCl, AcOH, re¯ux, 12 h; /h) LiAlH4, THF, re¯ux, 6.5 h; /i) 1.5 M DIBAL-H in toluene, 2758C,
2.5 h; /j) 2N HCl, MeOH, re¯ux, 4 h; then Amberlite IRA-400 /OH), MeOH.
/^)-/2endo,3exo)-bicyclo[2.2.1]hept-5-eno-2,3-dimethanol
/5) as starting material. This compound is easily obtained by
LiAlH4 reduction of the product of the Diels±Alder reaction
between diethyl fumarate and cyclopentadiene,16 and oxi-
dative cleavage of its double bond, followed by modi®-
cation of the resulting carboxy groups, would lead to a
®nal product with the desired con®guration.
a high selectivity that is attributed to the two carbonyl
groups being associated with different degrees of steric
hindrance to nucleophilic attack, the neighboring benzoyl-
oxymethyl group being cis to the carbonyl in one case and
trans in the other /the reactive carbonyl was assumed to be
the one with the trans benzoyloxymethyl) /Fig. 2).
Oxidative degradation of the carbamoyl group of 9 under
classical Hofmann conditions afforded an intractable
mixture that NMR studies showed to include the products
of partial deprotection of the hydroxymethyl groups. Treat-
ment of the ester 10 with HTIB in acetonitrile,17 followed by
4N NaOH, likewise led to a complex mixture, from which
only a 12% yield of the aminoester 11 was isolated; while
treatment of 10 with lead tetraacetate in re¯uxing acetic
acid18,19 gave an even smaller yield of the acetamide
ester 12 /9%, although 35% of the starting material was
The route actually followed is shown in Scheme 1 /in which
all compounds represent racemic mixtures). Diol 5 was
protected as its bis-benzoate /6), which afforded the
dicarboxylic acid 7 when subjected to oxidative ring-
opening with potassium permanganate in CH2Cl2/AcOH
in the presence of Aliquat 336. Heating 7 in re¯uxing acetic
anhydride gave the cyclic anhydride 8 in excellent yield.
Gaseous ammonia treatment of a solution of 8 in dry THF
at 0±58C then afforded the carbamoylcarboxylic acid 9 with
O
O
O
MeO
MeO
HO
NH2
NHAc
HN Boc
OBz
OBz
OBz
BzO
BzO
BzO
11
12
13
Figure 2.

M. J. Figueira et al. / Tetrahedron 58,2002) 967±974
969
Figure 3. X-Ray crystallographic structure of 14.
recovered). However, treatment of 9 with lead tetraacetate
in tert-butyl alcohol, with triethylamine as catalyst, gave the
N-Boc derivative 13 as the only product in 59% yield, and
application of the same procedure to the ester 10 afforded a
93% yield of the corresponding ester 14, the structure of
which was con®rmed by an X-ray diffractometric study of
a single crystal /Fig. 3).20 Though obtained from a racemic
solution, this crystal was composed solely of molecules with
1S con®guration. Their structure con®rmed that in step 8!9
it was the carbonyl trans to its neighboring OBz that was
reactive, and also that no epimerization processes occurred
under the reaction conditions used to arrive at 14.
ing solid was acetylated, chromatographic fractionation of
the products affording the carbamate 18 and the formamide
19 in 4 and 18% yield, respectively. However, reduction of
14 with DIBAL±H23 directly gave 59% yield of 17. Finally,
the Boc group was removed with re¯uxing HCl /2N in
methanol), and the resulting solution of 3´HCl was passed
through a basic ion-exchange resin /Amberlite IRA-400
/OH)) to obtain the free aminoalcohol 3 /Fig. 4).
3.Experimental
3.1. General
Transformation of 14 into 3 requires both the reduction of
the ester group and deprotection of the nitrogen. Depro-
tection by acid hydrolysis gave the hydrochloride form of
an amino acid /15´HCl), which after reduction with excess
LiAlH4 in re¯uxing THF was treated with water /just
suf®cient to destroy the excess LiAlH4), concentrated to
dryness, and then treated with acetic anhydride and pyri-
dine.21 These post-reduction steps were carried out under
the assumption that the reduction product was 3, and were
aimed at obtaining a peracetylated product that would be
more easily isolatable than this aminopolyol, but in the
event only the lactam 16 was isolated, in 82% yield. This
is not the ®rst time we have obtained bicyclic lactams upon
LiAlH4 treatment of cis-1,3-disubstituted cyclopentanes
with a sterically hindered carbonyl.19
Silica gel /230 mesh) was purchased from Merck. All other
chemicals used were of reagent grade and were obtained
from Aldrich Chemical Co. Melting points were measured
in a Reichert Ko¯er Thermopan and are uncorrected. Infra-
red spectra were recorded in a Perkin±Elmer 1640 FTIR
1
spectrophotometer. H NMR spectra /300 MHz) and 13C
NMR spectra /75.47 MHz) were recorded in a Bruker
AMX 300 spectrometer, using TMS as internal standard
/chemical shifts in d values, J in Hz). Mass spectra were
recorded on a Kratos MS-59 spectrometer. Flash chroma-
tography was performed on silica gel /Merck 60, 230±240
mesh) and analytical TCL on pre-coated silica gel plates
/Merck 60 F254, 0.25 mm). X-Ray diffraction data were
collected in an Enraf Nonius CAD4 automatic diffracto-
meter using the program CAD4-EXPRESS.
In view of the above, we decided to reduce the ester group
before removal of Boc. Selective reduction of 14 with
LiBH4,22 followed by conventional work-up, afforded just
a 25% yield of the tris/hydroxymethyl)carbamate 17,
although the total yield of compounds readily convertible
to 3 increased to 47% when the aqueous phase obtained
during work-up was concentrated to dryness and the result-
3.1.1. ꢀ^)-ꢀ2endo,3exo)-Bicyclo[2.2.1]hept-5-en-2,3-di-
methanol dibenzoate ꢀ6). Benzoyl chloride /11.39 mL,
97.76 mmol) was added dropwise under argon, over 20
min, to a solution of diol 5 /6.16 g, 39.94 mmol) in dry
pyridine /46 mL). The reaction mixture was stirred at
room temperature for 48 h, cooled to 5±108C, brought to
strongly basic pH with aqueous 2N NaOH, and extracted
with Et2O /2£150 mL). The pooled organic phases were
washed with H2O and dried /Na2SO4) and the solvent was
removed in vacuo, leaving 6 as a colorless oily residue
/14.04 g, 97%). IR /®lm): 2967, 1718, 1450, 1314, 1271,
H
AcO
NHBoc
AcO
NH
OAc
AcO
O
OAc
AcO
1
1111, 709 cm21. H NMR /CDCl3) d: 8.09±8.04 [m, 4H,
18
19
2£/20-H160-H)]; 7.59±7.56 /m, 2H, 2£40-H); 7.55±7.41
[m, 4H, 20/30-H150-H)]; 6.32 /dd, 1H, Jˆ5.67, 3.13 Hz,
Figure 4.

970
M. J. Figueira et al. / Tetrahedron 58,2002) 967±974
HCvCH); 6.15 /dd, 1H, Jˆ5.67, 2.85 Hz, HCvCH); 4.50
/dd, 1H, Jˆ10.93, 6.54 Hz, CHHOBz); 4.34 /dd, 1H,
Jˆ10.93, 8.59 Hz, CHHOBz); 4.19 /dd, 1H, Jˆ10.79,
6.84 Hz, CHHOBz); 4.07 /dd, 1H, Jˆ10.79, 8.94 Hz,
and 63.43 /2£CH2OBz); 46.29 and 45.31 /C11C3);
44.39 and 42.09 /C41C5); 32.19 /C2). Anal. calcd for
C23H20O7 /408.40): C, 67.74; H, 4.94. Found: C, 67.89; H,
5.13.
Â
Â
CHHOBz); 3.01 /s, 1H, 1-H o 4-H); 2.83 /s, 1H, 4-H o 1-
H); 2.30±2.22 /m, 1H, 2exo-H); 1.63±1.55 /m, 3H, 3endo-
H17-H2). 13C NMR /CDCl3) d: 167.00 and 166.89 /20CO);
138.33 and 134.55 /CvC); 133.39 and 133.33 /20C40);
130.69 and 130.62 /20C10); 130.01 and 130.00
[2£/C201C60)]; 128.82 and 128.80 [2£/C301C50)]; 68.62
and 68.33 /2£CH2OBz); 46.72 /C7); 44.93 and 44.61
/C11C4); 43.46 and 42.97 /C21C3). EIMS m/z /%): 362
/M, 4); 175 /34); 105 /100); 77 /60); 66 /37); 51 /14). Anal.
calcd for C23H22O4 /362.42): C, 76.22; H, 6.12. Found: C,
76.42; H, 6.35.
3.1.4. ꢀ^)-c-2,t-3-Bisꢀbenzoyloxymethyl)-c-4-carbamoyl-
r-1-cyclopentanecarboxylic acid ꢀ9). A stream of gaseous
NH3 was passed for 45 min over a solution of 8 /5.68 g,
13.91 mmol) in dry THF /150 mL) in an ice bath. The
resulting suspension was concentrated dryness, and the
brownish solid residue /6.05 g) was taken up in water
/150 mL), cooled to 08C and acidi®ed with 2N HCl
/5 mL). Compound 9 was precipitated as a solid that was
®ltered out, dried to constant weight /5.74 g) and recrystal-
lized from EtOH /4.72 g, 80%). Mp 168±1708C. IR /KBr):
3478, 3204, 2962, 1715, 1643, 1602, 1584, 1452, 1315,
3.1.2. ꢀ^)-c-4,t-5-Bisꢀbenzoyloxymethyl)-r-1,c-3-cyclo-
pentanedicarboxylic acid ꢀ7). A solution of 6 /5.00 g,
13.80 mmol) in benzene /210 mL) was added dropwise to
a vigorously stirred solution of KMnO4 /6.65 g, 42.1 mmol),
Aliquat 336 /1.00 g, 2.49 mmol) and AcOH /1.53 mL) in
water /210 mL) at 0±58C. The mixture was stirred at room
temperature for 5 h, cooled to 5±108C, treated dropwise
with a solution of Na2S2O5 /8.00 g, 42.03 mmol) in the
least possible quantity of water, and acidi®ed with 2N
H2SO4 /30 mL). The aqueous phase was extracted with
Et2O, this extract was pooled with the organic phase, and
this combined organic phase was washed with saturated
Na2CO3 solution until the washings were basic. This basic
extract was acidi®ed with 2N H2SO4 and kept at 08C for
12 h, and the resulting precipitate was ®ltered out. Crystal-
lization from toluene afforded 7 as a white solid /4.64 g,
79%). Mp 134±1358C. IR /KBr): 2964, 1713, 1490, 1451,
1270, 1208, 1118, 1071, 1024, 709 cm21 1H NMR
.
/DMSO-d6) d: 12.36 /bs 1H, D2O exch., CO2H); 7.96±
7.93 [m, 4H, 2£/20-H160-H)]; 7.66±7.60 /m, 2H,
2£40-H); 7.50±7.44 [m, 5H, 4H after D2O /2£/30-H150-
H)1NHH)]; 6.93 /bs, 1H, D2O exch., NHH); 4.33 /dd,
4H, Jˆ12.00, 4.52 Hz, 2£CH2OBz); 3.13±3.04 /m, 1H);
2.62±2.54 /m, 3H); 2.15±1.90 /m, 2H). 13C NMR
/DMSO-d6) d: 175.38 /CO2H); 174.57 /CONH2); 166.05
and 166.00 /2£PhCO); 133.63 /2£C40); 130.03 and
129.96 /2£C10); 129.61 and 129.57 [2£/C201C60)];
129.03 and 128.97 [2£/C301C50)]; 66.57 and 65.06 /2£
CH2OBz); 45.91, 45.20 and 44.51 /C11C21C4); 42.31
/C3); 33.22 /C5). EIMS m/z /%): 198 /3); 182 /3); 181
/4); 138 /8); 123 /4); 122 /8); 106 /8); 105 /100); 93 /6);
91 /4); 84 /5); 79 /8); 78 /5); 77 /42); 66 /7); 51 /10). Anal.
calcd for C23H23NO7 /425.46): C, 64.93; H, 5.45; N, 3.29.
Found: C, 65.20; O, 5.67; N, 3.45.
1
1313, 1298, 1271, 1116, 711 cm21. H NMR /CDCl3) d:
9.99 /bs, 2H, D2O exch., 2£CO2H); 7.99±7.95 [m, 4H,
2£/20-H160-H)]; 7.56±7.47 /m, 2H, 2£40-H); 7.43±7.34
[m, 4H, 2£/30-H150-H)]; 4.54±4.41 /m, 4H, 2£CH2OBz);
3.13±3.06 /m, 1H); 2.91±2.80 /m, 2H); 2.74±2.65 /m, 1H);
2.46±2.36 /m, 1H); 2.30±2.20 /m, 1H). 13C NMR /CDCl3):
180.15 and 179.41 /2£CO2H); 166.82 and 166.67 /2£
COPh); 133.62 and 133.53 /2£C40); 130.07 and 129.99
[2£/C201C60)]; 130.02 /2£C10); 128.89 and 128.83
[2£/C301C50)]; 65.86 and 64.51 /2£CH2OBz); 46.04 and
45.67 /C11C3); 44.35 and 44.09 /C41C5); 32.19 /C2).
Anal. calcd for C23H22O8 /426.42): C, 64.78; H, 5.20.
Found: C, 65.01; H, 5.44.
3.1.5. Methyl ꢀ^)-c-2,t-3-bisꢀbenzoyloxymethyl)-c-4-
carbamoyl-r-1-cyclopentanecarboxylate ꢀ10). A solution
of 9 /1.86 g, 4.37 mmol) in dry MeOH /126 mL) was
re¯uxed for 24 h in the presence of a catalytic amount of
p-TsOH acid /0.05 g, 0.26 mmol). After removal of MeOH,
the resulting brownish solid residue /2.04 g) was fraction-
ated by column chromatography using 1:2 hexane/AcOEt as
eluent, and the fractions containing the product were
concentrated to dryness, affording 10 /1.70 g, 89%) as a
colorless oil that crystallized upon cooling. Mp 81±838C
/Et2O/AcOEt). IR /KBr): 3403, 3144, 2951, 1736, 1721,
1
1699, 1684, 1451, 1316, 1274, 1181, 1115, 708 cm21. H
NMR /CDCl3) d: 8.01±7.97 [m, 4H, 2£/20-H160-H)];
7.58±7.52 /m, 2H, 2£40-H); 7.44±7.38 [m, 4H, 4£/30-
H150-H)]; 6.50 /bs, 1H, D2O exch., NHH); 5.51 /bs, 1H,
D2O exch., NHH); 4.59 /dd, 1H, Jˆ11.55, 4.64 Hz,
2-CHHOBz); 4.48 /d, 2H, Jˆ5.70 Hz, 3-CH2OBz); 4.43
/dd, 1H, Jˆ11.55, 4.84 Hz, 2-CHHOBz); 3.59 /s, 3H,
CH3); 3.14±3.11 /m, 1H); 2.82±2.65 /m, 3H); 2.43±2.41
/m, 1H); 2.31±2.26 /m, 1H). 13C NMR /CDCl3) d: 176.09
/CO2CH3); 174.83 /CONH2); 167.19 and 166.62 /2£PhCO);
133.69 and 133.54 /2£C40); 130.04 [2£/C201C60)]; 129.98
/2£C10); 128.90 and 128.85 [2£/C301C50)]; 65.59 and
64.38 /2£CH2OBz); 52.41 /OCH3); 48.01 /C1); 45.83
/C4); 45.77 /C2); 44.33 /C3); 32.69 /C5). EIMS m/z /%):
439 /1, M1); 334 /3); 318 /1); 317 /2); 195 /7); 152 /17);
106 /7); 105 /100); 93 /6); 77 /36). Anal. calcd for
C24H25NO7 /439.46): C, 65.59; H, 5.73. Found: C, 65.74;
H, 5.90.
3.1.3. ꢀ^)-c-4,t-5-Bisꢀbenzoyloxymethyl)-r-1,c-3-cyclo-
pentanedicarboxylium anhydride ꢀ8). A solution of 7
/5.95 g, 13.95 mmol) in Ac2O /35 mL) was re¯uxed for
24 h. Removal of excess Ac2O by codistillation with dry
toluene at reduced pressure afforded solid 8 /5.66 g, 99%).
Mp 164±1658C. IR /KBr): 1814, 1765, 1712, 1277, 1122,
1000, 990, 708 cm21 1H NMR /CDCl3) d: 8.05±8.02
.
[m, 4H, 2£/20-H160-H)]; 7.63±7.55 /m, 2H, 2£40-H);
7.50±7.44 [m, 4H, 2£/30-H150-H)]; 4.58±4.51 /m, 2H,
CH2OBz); 4.50±4.38 /m, 2H, CH2OBz); 3.47 /s, 1H);
3.31 /d, 1H, Jˆ3.85 Hz); 2.74±2.66 /m, 2H); 2.38±2.32
/m, 1H); 2.22±2.10 /m, 1H). 13C NMR /CDCl3) d: 168.65
and 167.83 /OC±O±CO); 166.67 and 166.53 /2£PhCO);
134.06 and 133.90 /2£C40); 133.63 and 133.54 /2£C10);
130.17, 130.07, 129.98 and 129.50 [2£/C201C60)];
129.10, 129.02, 128.89 and 128.83 [2£/C301C50)]; 65.83

M. J. Figueira et al. / Tetrahedron 58,2002) 967±974
971
3.1.6. Methyl ꢀ^)-c-2,t-3-bisꢀbenzoyloxymethyl)-c-4-amino-
r-1-cyclopentanecarboxylate ꢀ11). A solution of 10
/0.47 g, 1.07 mmol) in CH3CN /5.4 mL) was treated under
argon with a suspension of HTIB /0.62 g, 1.07 mmol) in
CH3CN /5.4 mL). The mixture was stirred at room tempera-
ture for 10 min, re¯uxed for 24 h, allowed to cool, ®ltered,
and concentrated under reduced pressure. The resulting
residue was treated with 0.4N NaOH /3£10 mL), and this
solution was stirred and extracted with CH2Cl2 /3£25 mL).
The pooled organic phases were dried over Na2SO4, and
evaporation of the solvent under reduced pressure yielded
0.5 g of an oily product that was fractionated by column
chromatography using 1:1, 1:1.5, 1:2 and 0:1 hexane/
AcOEt mixtures as successive eluents. Removal of the
solvent under reduced pressure from the fractions eluted
with AcOEt gave 0.19 g of a yellowish oil that upon further
chromatography with 30:1±1:1 CH2Cl2/MeOH mixtures as
successive eluents afforded compound 11 /70 mg, 12%) in
the last few fractions. IR /®lm): 2952, 1718, 1316, 1274,
C60)]; 128.85 and128.80 [2£/C301C50)]; 65.33 and 64.29
/2£CH2OBz); 52.45 /C4); 51.76 /CH3O); 47.94 /C1); 45.07
and 44.59 /C21C3); 35.95 /C5); 23.82 /CH3CO). EIMS m/z
/%): 453 /0.1, M1); 288 /3); 210 /3); 209 /14); 167 /12); 166
/12); 150 /29); 106 /10); 105 /100); 77 /33). Anal. calcd for
C25H27NO7 /453.48): C, 66.21; H, 6.00; N, 3.09. Found: C,
66.33; H, 6.14; N, 3.19.
3.1.8. ꢀ^)-c-2,t-3-Bisꢀbenzoyloxymethyl)-c-4-tert-butoxy-
carbonylamino-r-1-cyclopentanecarboxylic acid ꢀ13).
Lead tetraacetate /0.55 g, 1.23 mmol) was added under
argon to a suspension of carbamoyl acid 9 /0.42 g, 1.00
mmol) in dry t-BuOH /5 mL). The reaction mixture was
heated to 708C, dry Et3N /0.4 mL) was added dropwise,
and this mixture was re¯uxed for 7 h. Removal of the
solvents under vacuum left a solid residue /0.70 g) that
was fractionated by column chromatography using 25:1
CH2Cl2/MeOH as eluent. Concentration of the fractions
containing 13 to dryness left 0.29 g /59%) of a white
solid. Mp 144±1468C, after grinding and washing with
CH2Cl2. IR /KBr): 2974, 1761, 1711, 1685, 1514, 1394,
1
1177, 1111, 1069, 710 cm21. H NMR /CDCl3) d: 8.01±
7.97 [m, 4H, 2£/20-H160-H)]; 7.57±7.52 /m, 2H, 2£40-H);
7.44±7.38 [m, 4H, 2£/30-H150-H)]; 4.60±4.40 /m, 4H,
2£CH2OBz); 3.57 /s, 3H, CH3O); 3.33 /q, 1H, Jˆ7.97 Hz,
4-H); 3.16 /bs, 2H D2O exch., NH2); 3.09 /q, 1H, Jˆ
7.86 Hz, 1-H); 2.68±2.62 /m, 1H); 2.36±2.17 /m, 2H);
2.04±1.99 /m, 1H). 13C NMR /CDCl3) d: 175.38
/COOCH3); 166.88 and 166.60 /2£PhCO); 133.57 and
133.55 /2£C40); 130.09 /2£C10); 130.03 and 129.96
[2£/C201/C60)]; 128.88 and 128.85 [2£/C301C50)];
64.70 and 64.51 /2£CH2OBz); 54.59 /C4); 52.42 /CH3O);
49.42 /C1); 44.14 and 43.51 /C21C3); 37.51 /C5). EIMS
m/z /%): 347 /3); 346 /14); 330 /6); 167 /9); 122 /5); 108
/12); 106 /9); 105 /100); 96 /5); 94 /5); 91 /5); 83 /5); 79 /5);
78 /5); 77 /51); 51 /7). Anal. calcd for C23H25NO6 /411.45):
C, 67.14; H, 6.12; N, 3.40. Found: C, 67.33; H, 6.31; N,
3.51.
1
1367, 1282, 1166, 1118, 715 cm21. H NMR /DMSO-d6)
d: 12.31 /bs, 1H, D2O exch., CO2H); 7.94±7.92 [m, 4H,
2£/20-H160-H)]; 7.66±7.60 /m, 2H, 2£40-H); 7.50±7.43
[m, 4H, 2£/30-H150-H)]; 7.09 /d, 1H, D2O exch., Jˆ
7.97 Hz, NH); 4.37±4.25 /m, 4H, 2£CH2OBz); 3.82±3.76
/m, 1H, 4-H); 3.07±2.98 /m, 1H, 1-H); 2.61±2.58 /m, 1H);
2.20±2.18 /m, 1H); 2.08±2.04 /m, 1H); 1.95±1.87 /m, 1H);
1.33 [s, 9H, C/CH3)3]. 13C NMR /DMSO-d6) d: 174.50
/CO2H); 165.71 and 165.68 /2£PhCO); 153.31 /N±CO±
O); 133.29 /2£C40); 129.73 and 129.61 /2£C10); 129.34
and 129.22 [2£/C201C60)]; 128.71 and 128.62 [2£/C301
C50)]; 77.70 [C/CH3)3]; 65.26 and 64.67 /2£CH2OBz);
52.17 /C4); 46.26 /C1); 42.18 /C3); 38.69 /C2); 34. 48
/C5); 28.21 [C/CH3)3]. EIMS m/z /%): 274 /10); 197 /15);
154 /21); 153 /37); 152 /70); 149 /23); 122 /10); 108 /12);
106 /11); 105 /100); 97 /11); 77 /35); 69 /12); 58 /18); 57
/42). Anal. calcd for C27H31NO8 /497.54): C, 65.18; H, 6.28;
N, 2.82. Found: C, 65.40; H, 6.37; N, 2.99.
3.1.7. Methyl ꢀ^)-c-2,t-3-bisꢀbenzoyloxymethyl)-c-4-
acetamido-r-1-cyclopentanecarboxylate ꢀ12). A suspen-
sion of 10 /1.00 g, 2.27 mmol) and Pb/OAc)4 /1.24 g, 2.79
mmol) in AcOH /6 mL) was re¯uxed for 2 h. Removal of
AcOH by distillation at reduced pressure left a dark brown
residue that was dissolved in water /25 mL). After addition
of CH2Cl2 /25 mL), neutralization of this solution with
saturated NaHCO3 precipitated a solid that was ®ltered
out and washed with CH2Cl2. The organic phase was
removed from the ®ltrate, the aqueous phase was extracted
with CH2Cl2 /2£25 mL), and the pooled organic phases
were dried over Na2SO4. Removal of the solvent left a resi-
due /0.70 g) that was fractionated by column chroma-
tography using 60:1 CH2Cl2/MeOH as eluent. The ®rst
fractions eluted afforded 12 /90 mg, 9%) as a colorless oil,
and the following fractions unaltered 10 /0.35 g). Com-
pound 12: IR /®lm): 3383, 1717, 1654, 1451, 1272, 1176,
3.1.9. Methyl ꢀ^)-c-2,t-3-bisꢀbenzoyloxymethyl)-c-4-tert-
butoxycarbonylamino-r-1-cyclopentanecarboxylate ꢀ14).
Lead tetraacetate /1.46 g, 3.30 mmol) was added under
argon to a solution of carbamoyl ester 10 /1.18 g, 2.69
mmol) in t-BuOH /7 mL). The mixture was heated to
708C, Et3N /1.06 mL, 3.28 mmol) was added dropwise,
and the resulting suspension was re¯uxed for 2 h, ®ltered
while warm, and concentrated in vacuo, affording 1.82 g of
a yellowish solid that was fractionated by column chroma-
tography using 2:1 hexane/AcOEt /10£50 mL followed by
15£100 mL) as eluent. Concentration of fractions 7±25 to
dryness yielded solid carbamate 14 /1.26 g, 92%). An
analytical sample was obtained by recrystallization from
AcOEt/Et2O. Mp 149±1508C. IR /KBr): 3377, 2973,
1727, 1703, 1514, 1452, 1370, 1320, 1277, 1205, 1164,
1
1113, 711 cm21. H NMR /CDCl3) d: 8.02±7.94 [m, 4H,
1
2£/20-H160-H)]; 7.56±7.48 /m, 2H, 2£40-H); 7.43±7.34
[m, 4H, 2£/30-H150-H)]; 6.56 /d, 1H, D2O exch., Jˆ
8.84 Hz, NH); 4.57±4.36 [m, 5H, /2£CH2OBz14-H)];
3.54 /s, 3H, CH3O); 3.16±3.09 /m, 1H, 1-H); 2.65±2.55
/m, 1H); 2.41±2.31 /m, 2H); 1.95 /s, 3H, CH3CO); 1.92±
1.86 /m, 1H). 13C NMR /CDCl3) d: 176.10 /CO±O); 169.98
/CO±N); 166.76 and 166.53 /2£PhCO); 133.56 and 133.48
/2£C40); 130.18 /2£C10); 129.99 and 129.96 [2£/C201
1123, 712 cm21. H NMR /CDCl3) d: 8.00±7.96 [m, 4H,
2£/20-H160-H)]; 7.58±7.51 /m, 2H, 2£40-H); 7.45±7.37
[m, 4H, 2£/30-H150-H)]; 5.25 /d, 1H, D2O exch.,
Jˆ8.57 Hz, NH); 4.57 /dd, 1H, Jˆ11.43, 4.44 Hz,
CHHOBz); 4.52±4.41 /m, 2H, CH2OBz); 4.41 /dd, 1H,
Jˆ11.43, 5.71 Hz, CHHOBz); 4.22±4.17 /m, 1H, 4-H);
3.57 /s, 3H, CH3O); 3.11 /dt, 1H, Jˆ7.72, 5.55 Hz, 1-H);
2.66±2.56 /m, 1H); 2.43±2.33 /m, 2H); 1.97±1.89 /m,

972
M. J. Figueira et al. / Tetrahedron 58,2002) 967±974
1H); 1.42 [s, 9H, C/CH3)3]. 13C NMR /CDCl3) d: 175.62
/CO2CH3); 166.79 and 166.56 /2£PhCO); 155.88 /CONH);
133.53 and 133.43 /2£C40); 130.26 /2£C10); 130.02
[2£/C201C60)]; 128.82 [2£/C301C50)]; 79.83 [C/CH3)3];
65.23 and 64.41 /2£CH2OBz); 53.25 /C4); 52.37 /CH3O);
47.95 /C1); 44.59 and 43.96 /C21C3); 36.17 /C5); 28.78
[C/CH3)3]. EIMS m/z /%): 288 /6); 211 /9); 167 /14); 152
/9); 108 /23); 106 /10); 105 /100); 77 /30); 57 /25). Anal.
calcd for C28H33NO8 /511. 65): C, 65.74; H, 6.50; N, 2.74.
Found: C, 65.91; H, 6.66; N, 2.81.
EIMS m/z /%): 255 /4, M1); 212 /M±COCH3, 15); 196
/14); 177 /25); 170 /25); 154 /94); 153 /88); 152 /100);
150 /58); 140 /27); 136 /57); 126 /20); 123 /23); 108
/40); 100 /27); 94 /32); 92 /40); 91 /33); 82 /40); 79 /27);
69 /34); 60 /40); 58 /35). Anal. calcd for C12H17NO5
/255.27): C, 56.46; H, 6.71; N, 5.49. Found: C, 56.59; H,
6.88; N, 5.56.
3.1.12. Reduction of 14: preparation of tert-butyl ꢀ^)-N-
[t-2,c-3,c-4-trisꢀhydroxymethyl)-r-1-cyclopentyl]carba-
mate ꢀ17), ꢀ^)-c-4-tert-butoxycarbonylamino-r-1,t-2,c-3-
cyclopentyltrimethyl triacetate ꢀ18) and ꢀ^)-c-4-formyl-
amino-r-1,t-2,c-3-cyclopentyltrimethyl triacetate ꢀ19).
Method A. LiBH4 /0.67 g, 30.8 mmol) was suspended in
dry THF /150 mL) and re¯uxed under argon for 1 h. A
solution of 14 /1.50 g, 2.93 mmol) in dry THF /20 mL)
was added dropwise, re¯uxing was continued for 4 h,
MeOH /15 mL) and water /3 mL) were added, and re¯uxing
was continued for another 30 min. The organic solvents
were removed under reduced pressure and the resulting
solid residue was dissolved in water /75 mL). This solution
was extracted with AcOEt /4£74 mL), and the pooled
organic extracts were dried over Na2SO4 and concentrated
to dryness in vacuo, yielding 0.80 g of a solid that was
fractionated by column chromatography using, succes-
sively, 1:1, 1:2 and 1:4 hexane/AcOEt, AcOEt and 3:1
AcOEt/MeOH as eluents. Removal of the solvent from the
last fractions eluted left the trihydroxycarbamate 17 /0.20 g,
25%) as a colorless oil. IR /®lm): 3387, 2926, 2247, 1654,
3.1.10. ꢀ^)-c-4-Amino-c-2,t-3-bisꢀhydroxymethyl)-r-1-
cyclopentanecarboxylic acid hydrochloride ꢀ15´HCl). A
solution of 14 /0.50 g, 0.98 mmol) in a mixture of AcOH
/6.3 mL) and 12N HCl /4.2 mL) was re¯uxed for 12 h, and
removal of the solvents in vacuo by successive coevapo-
rations with toluene afforded 0.38 g of a solid residue that
was recrystallized from EtOH/Et2O and identi®ed as 15´HCl
/0.10 g; 49%). Mp 228±2298C. IR /KBr): 3236, 2951, 2920,
1741, 1174, 1024, 988 cm21. 1H NMR /DMSO-d6) d: 8.17
/bs, 3H, D2O exch., NH31); 5.02 /bs, 1H, D2O exch., OH);
4.32 and 4.22 /part AB system ABX, 2H, Jˆ9.25, 6.53,
1.12 Hz, 2-CH2); 3.62 and 3.57 /part AB system ABX,
2H, Jˆ11.30, 5.26, 4.86 Hz, 3-CH2, reduces to a doublet
upon treating the sample with D2O, Jˆ5.50 Hz); 3.32 /q,
1H, Jˆ9.55 Hz, 4-H); 3.08 /dt, 1H, Jˆ5.63, 10.02 Hz, 1-H);
2.77±2.69 /m, 1H, 3-H); 2.52±2.41 /m, 1H); 1.92±1.84 /m,
1H); 1.81±1.72 /m, 1H). 13C NMR /DMSO-d6) d: 180.21
/CO2H); 70.68 and 59.44 /2£CH2OH); 52.98 /C4); 50.00
/C3); 41.54 and 40.93 /C11C2); 32.31 /C5).
1
1560, 1363, 914 cm21. H NMR /CDCl3) d: 5.07 /d, 1H,
D2O exch., Jˆ8.31 Hz, NH); 4.15 /bs, 3H, D2O exch., 3£
OH); 3.79±3.59 /m, 7H, 3£CH2OH11-H); 2.28±2.22 /m,
1H); 2.17±2.02 /m, 2H); 1.64±1.53 /m, 1H); 1.43 [s, 9H,
C/CH3)3]; 1.40±1.29 /m, 1H). 13C NMR /CDCl3) d: 156.73
/NCOO); 79.87 [C/CH3)3]; 62.63 /2£CH2OH); 61.71
/CH2OH); 52.62 /C1); 51.47 /C2); 43.90 /C3); 40.31
/C4); 34.55 /C5); 28.35 [C/CH3)3]. Anal. calcd for
C13H25NO5 /275.34): C, 56.71; H, 9.15; N, 5.09. Found:
C, 56.88; H, 9.28; N, 5.19.
3.1.11. ꢀ^)-ꢀ5endo,6exo)-5,6-Bisꢀacetoxymethyl)-2-aza-
bicyclo-[2.2.1]-heptan-3-one ꢀ16). 15´HCl /60 mg, 0.29
mmol) was added under argon in one dose to a suspension
of LiAlH4 /20 mg, 0.53 mmol) in dry THF /4 mL) at 08C,
and the mixture was stirred at this temperature for 15 min,
re¯uxed for 6.5 h, and cooled again to 08C. Water was
added, and removal of the solvents by successive coevapo-
rations with toluene under reduced pressure left a white
solid that was taken up in 10 mL of Ac2O. After addition
of pyridine /10 mL) and stirring under argon at room
temperature for 24 h this mixture was concentrated to
dryness, the residue was taken up in 25 mL of NaHCO3,
the resulting mixture was extracted with CH2Cl2 /3£
25 mL), and the pooled organic phases were dried over
Na2SO4. Evaporation of the solvent in vacuo left a brown
oil /70 mg) that was fractionated by column chroma-
tography using, successively, 1:3 hexane/AcOEt, 1:4
hexane/AcOEt, AcOEt and MeOH as eluents. Lactam 16
was isolated as a white solid /60 mg, 82%) from the
fractions eluted with MeOH, and was recrystallized from
hexane/AcOEt. Mp 155.5±1578C. IR /KBr): 3340, 2949,
The aqueous phases obtained above during the extraction
with AcOEt were pooled and concentrated to dryness, and
the resulting solid residue was taken up in Ac2O /40 mL).
After addition of pyridine /40 mL), this solution was stirred
for 30 h, the solvents were removed under reduced pressure,
and the brown residue so obtained was taken up in NaHCO3
/50 mL). This solution was extracted with AcOEt /2£
50 mL), and the pooled organic phases were dried over
Na2SO4 and concentrated, affording 0.20 g of an oil that
was fractionated by column chromatography on silica gel
using 1:5 hexane/AcOEt /3£10 mL) and AcOEt /10£
10 mL) as successive eluents. Carbamate 18 /0.05 g, 4%)
was isolated from the fractions eluted with hexane/AcOEt,
and formamide 19 /0.17 g, 18%) from those eluted with
AcOEt.
1
1766, 1729, 1648, 1541, 1252, 1175, 1046 cm21. H NMR
/CDCl3) d: 5.64 /d, 1H, D2O exch., Jˆ7.66 Hz, NH); 4.42
/dd, 1H, Jˆ9.69, 6.52 Hz, CHHOAc); 4.30±4.24 /m, 3H,
CHHOAc1CH2OAc); 4.07 /dd, 1H, Jˆ11.55, 6.79 Hz,
1-H); 3.04 /dt, 1H, Jˆ5.00, 9.75 Hz, 4-H); 2.79±2.71 /m,
1H); 2.61 /ddd, 1H, Jˆ13.89, 10.01, 8.36 Hz); 2.07 /s, 3H,
CH3CO); 2.02±1.92 /m, 1H); 1.97 /s, 3H, CH3CO); 1.81
/ddd, 1H, Jˆ13.91, 8.55, 5.10 Hz). 13C NMR /CDCl3) d:
179.95 /CONH); 170.75 and 170.09 /2£CH3CO); 70.84 and
63.97 /2£CH2OAc); 52.77 /C1); 49.40 /C4); 42.43 and
41.40 /C51C6); 34.15 /C7); 23.27 and 20.81 /2£CH3CO).
Compound 18: transparent oil. IR /®lm): 3628, 3362, 2972,
1
1684, 1506, 1456, 1243, 1034 cm21. H NMR /CDCl3) d:
4.58 /bs, 1H, D2O exch., NH); 4.21 /dd, 1H, Jˆ11.14,
4.48 Hz, CHHOAc); 4.12±4.06 /m, 5H, CHHOAc12£
CH2OAc); 3.85±3.76 /m, 1H, 1-H); 2.41±2.35 /m, 1H);
2.27±2.20 /m, 2H); 2.05 /s, 9H, 3£CH3CO); 1.85±1.83
/m, 1H); 1.43 [s, 9H, C/CH3)3]; 1.40±1.32 /m, 1H). 13C

M. J. Figueira et al. / Tetrahedron 58,2002) 967±974
973
1
NMR /CDCl3) d: 171.39, 171.29 and 171.21 /3£CH3CO);
155.79 /NCOO); 80.38 [C/CH3)3]; 65.36, 64.86 and 64.63
/3£CH2OAc); 53.50 /C1); 48.50 /C2); 40.96 /C3); 37.99
/C4); 36.33 /C5); 28.76 [C/CH3)3]; 21.32 /3£CH3CO).
EIMS m/z /%): 328 /3); 241 /15); 240 /100); 225
/23); 224 /14); 182 /13); 180 /36); 165 /55); 164
/28); 122 /26); 121 /25); 120 /29); 108 /22); 105
/17); 93 /13); 57 /63). Anal. calcd for C19H31NO8
/401.45): C, 56.84; H, 7.78; N, 3.49. Found: C, 57.06;
H, 7.92; N, 3.59.
/®lm): 3356, 1458, 1027 cm21. H NMR /DMSO-d6) d:
3.54±3.33 /m, 6H, 3£CH2OH); 2.84±2.76 /m, 1H, 4-H);
2.07±2.00 /m, 1H); 1.85±1.76 /m, 2H); 1.33±1.24 /m,
1H); 1.10±1.00 /m, 1H). 13C NMR /DMSO-d6) d: 64.04,
62.28 and 61.95 /3£CH2OH); 54.98 /C4); 53.84 /C3); 45.59
/C2); 41.72 /C1); 39.39 /C5). Anal. calcd for C8H17NO3
/175.23): C, 54.84; H, 9.78; N, 7.99. Found: C, 55.05; H,
9.96; N, 8.12.
Acknowledgements
Compound 19: colorless oil. IR /®lm): 3648, 3362, 2959,
1
1734, 1654, 1541, 1458, 1388, 1242, 1034 cm21. H NMR
The authors thank the Spanish Ministry of Education and
Science /MEC-DGICYT) and the Xunta de Galicia for
®nancial support under project PB94-0617 and XUGA
20309B98, respectively.
/CDCl3) d: 8.14 /s, 1H, NCHO); 6.25 /bs, 1H, D2O exch.,
NH); 4.21 /dd, 1H, Jˆ11.41, 4.92 Hz, CHHOAc); 4.18±
4.05 /m, 6H, CHHOAc12£CH2OAc14-H); 2.46±2.44
/m, 1H); 2.32±2.23 /m, 2H); 2.05 /s, 9H, 3£CH3CO);
2.03±1.94 /m, 1H); 1.43±1.39 /m, 1H). 13C NMR
/CDCl3) d: 171.41, 171.36 and 171.25 /3£CH3CO);
161.30 /NCHO); 65.17, 64.63 and 64.37 /3£CH2OAc);
50.75 /C4); 48.11 /C3); 41.25 /C2); 38.38 /C1); 35.82
/C5); 21.33, 21.28 and 21.23 /3£CH3CO). EIMS m/z
/%): 286 /0.1, M2COCH3); 269 /2); 226 /7); 149
/63); 136 /37); 122 /28); 121 /31); 120 /20); 109
/22); 108 /23); 105 /31); 104 /100); 94 /18); 93 /36);
91 /40); 81 /25); 79 /36); 69 /28). Anal. calcd for
C15H23NO7 /329.35): C, 54.70; H, 7.04; N, 4.25.
Found: C, 54.98; H, 7.21; N, 4.44.
References
1. /a) De Clercq, E. Clin. Microbiol. Rev. 1995, 200±239.
/b) Kolb, M. V. Prog. Drug Res. 1997, 48, 195±232.
/c) Colacino, J. M.; Staschke, K. A. Prog. Drug Res. 1998,
50, 259±322.
2. For recent reviews on CANs: /a) Zhu, X.-F. Nucleosides,
Nucleotides Nucleic Acids 2000, 19, 651±690. /b) Marquez,
V. E. Adv. Antiviral Drugs Des. 1996, 2, 89±146.
/c) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.;
Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994,
50, 10611±10670. /d) Borthwick, A. D.; Biggadike, K.
Tetrahedron 1992, 48, 571±623.
Method B. A solution of 14 /0.94 g, 1.84 mmol) in dry
toluene /25 mL) was slowly added under argon to a com-
mercial 1.5 M solution of DIBAL-H in toluene /14 mL,
21 mmol) at 2758C. This mixture was stirred for 2.5 h at
2758C, 10:1 toluene/MeOH /11 mL), MeOH /2 mL) and
water /10 mL) were successively added at the same
temperature, and when the resulting mixture had reached
room temperature the solid formed was ®ltered out and
washed with AcOEt /150 mL). The pooled ®ltrates were
dried over Na2SO4, and removal of the solvents under
reduced pressure left an oily residue /0.63 g) that was frac-
tionated by column chromatography using 1:2 hexane/
AcOEt followed by AcOEt as eluents. Concentration in
vacuo of the fractions containing product yielded 17
/0.30 g, 59%) as a colorless oil identical to that obtained
by method A.
3. /a) Kusaka, T.; Yamamoto, H.; Shibata, M.; Muroi, M.; Kishi,
T. K. J. Antibiot. 1968, 21, 255±263. /b) Shealy, Y. F.;
Clayton, J. D. J. Am. Chem. Soc. 1966, 88, 3885±3887.
/c) Boyer, S. J.; Leahy, J. W. J. Org. Chem. 1997, 62,
3976±3980.
4. Shealy, Y. F.; Clayton, J. D. J. Pharm. Sci. 1973, 62, 858±859.
5. Houston, D. M.; Dolence, E. K.; Keller, B. T.; Patel-Thombre,
U.; Borchardt, R. T. J. Med. Chem. 1985, 28, 471±477.
6. Guranowski, A.; Montgomery, J. A.; Cantoni, G. L.; Chiang,
P. K. Biochemistry 1981, 20, 110±115.
7. /a) Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61,
4192±4193. /b) Daluge, S. M.; Good, S. S.; Faletto, M. B.;
Miller, W. H.; Wayne, H.; St. Clair, M. H.; Boone, L. R.;
Tisdale, M.; Parry, N. R.; Reardon, J. E.; Dornsife, R. E.;
Averett, D. R. R.; Krenitsky, T. A. Antimicrob. Agents
Chemother. 1997, 41, 1082±1093. /c) Faletto, M. B.; Miller,
W. H.; Garvey, E. P.; St. Clair, M. H.; Daluge, S. M.; Good,
S. S. Antimicrob. Agents Chemother. 1997, 41, 1099±1107.
/d) Foster, R. H.; Faulds, D. Drugs 1998, 729±736.
8. Shealy, Y. F.; Clayton, J. D. J. Pharm. Sci. 1973, 62, 1432±
1434.
3.1.13. ꢀ^)-c-4-Amino-r-1,c-2,t-3-cyclopentanetrimethanol
ꢀ3). A solution of 17 /150 mg, 0.54 mmol) in MeOH /4 mL)
and 2N HCl /4 mL) was re¯uxed for 4 h. Removal of the
solvents by successive coevaporations with toluene and
EtOH then yielded 3´HCl as a dense yellowish oil /0.15 g).
1H NMR /DMSO-d6), d: 7.93 /b s, 3H, DO exch., NH3 );
1
2
4.89 /bs, 2H, D2O exch., 2£OH); 4.35 /t, 1H, D2O exch.,
9. Vince, R.; Daluge, S. J. Med. Chem. 1977, 20, 612±613.
10. Shealy, Y. F.; O'Dell, C. A.; Shannon, W. M.; Arnett, G.
J. Med. Chem. 1983, 26, 156±161.
Jˆ5.05 Hz, OH); 3.67±3.38 /m, 6H, 3£CH2OH); 3.26±3.19
/m, 1H, 4-H); 2.15±1.91 /m, 2H); 1.90±1.71 /m, 2H); 1.49±
1.40 /m, 1H).
11. Shealy, Y. F.; Clayton, J.; Arnett, G.; Shannon, W. M. J. Med.
Chem. 1984, 27, 670±674.
A solution of 0.14 g of this oil in MeOH /2.5 mL) was
loaded on a column of Amberlite IRA-400 /Cl2) /4.7 mL)
in water /previously activated with 33 mL of 1N NaOH),
and was eluted with MeOH /30 mL). Concentration in
vacuo of the alkaline solution so obtained yielded amino-
alcohol 3 as a dense ochre-colored oil /93 mg, 98%). IR
12. Peterson, M. L.; Vince, R. J. Med. Chem. 1990, 33, 1214±
1219.
13. Vince, R.; Brownell, J.; Daluge, S. J. Med. Chem. 1984, 27,
1358±1360.
14. Vince, R.; Turakhia, R. H.; Shannon, W. M.; Arnett, G. J. Med.
Chem. 1987, 30, 2026±2030.

974
M. J. Figueira et al. / Tetrahedron 58,2002) 967±974
15. /a) Nishiyama, Y.; Yamamoto, N.; Yamada, Y.; Daikoku, T.;
Ichikawa, Y.-I.; Takahashi, T. J. Antibiot. 1989, 42, 1854±
1859. /b) Norbeck, D. W.; Kern, E.; Hayashi, S.; Rosenbrook,
W.; Sham, H.; Herrin, T.; Plattner, J. J.; Erickson, J.; Clement,
J.; Swanson, R.; Shipkowitz, N.; Hardy, D.; Marsh, K.; Arnett,
G.; Shannon, W.; Broder, S.; Mitsuya, H. J. Med. Chem. 1990,
33, 1281±1285. /c) Smee, D. F.; Barnett, B. B.; Sidwell, R. W.;
Reist, E. J.; Holy, A. Antiviral Res. 1995, 26, 1. /d) Yang,
H. R.; Drain, R. L.; Franco, C. A.; Clark, J. M. Antiviral
Res. 1996, 29, 233±241. /e) Tenney, D. J.; Yamanaka, G.;
Voss, S. M.; Cianci, C. W.; Tuomari, A. V.; Sheaffer, A. K.;
Alam, M.; Colonno, R. J. Antimicrob. Agents Chemother.
1997, 41, 2680±2685.
18. Handa, S.; Earlam, G. J.; Geary, P. J.; Hawes, J. E.; Phillips,
G. T.; Pryce, R. J.; Ryback, G.; Shears, J. H. J. Chem. Soc.
Perkin Trans. 1 1994, 1885±1886.
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19. Nieto, M. I.; Blanco, J. M.; CaamanÄo, O.; Fernandez, F.;
Â
Gomez, G. Tetrahedron 1998, 54, 7819±7830.
20. The crystallographic data of 14 have been deposited at
Cambridge Crystallographic Data Centre as supplementary
publication No. 14 CCDC 171793. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK.
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21. Figueira, M. J.; Blanco, J. M.; CaamanÄo, O.; Fernandez, F.;
Â
Â
Garcõa-Mera, X.; Lopez, C. Synthesis 2000, 1459±1463.
22. Soai, K.; Ookawa, A. J. Org. Chem. 1986, 51, 4000±4005.
23. Csuk, R.; von Scholz, V. Tetrahedron 1994, 50, 10431±
10442.
16. Naemura, K.; Nakazuki, M. Bull. Chem. Soc. Jpn 1973, 46,
888±892.
17. /a) Lazbin, I. M.; Koser, G. F. J. Org. Chem. 1987, 52, 476±
477. /b) Vasudevan, A.; Koser, G. F. J. Org. Chem. 1988, 53,
5158±5160.