Heterocyclic analogs of prostaglandins: I. Synthesis of 3-alkyl(aralkyl)-2,5-dihydrofuran-2-ones as synthons for 11-deoxy-10- oxaprostanoids

Article abstract of DOI:10.1023/B:RUJO.0000003193.75790.de

3-Acyl(arylmethyleneacyl)tetronic acids were synthesized. Selective hydrogenation of the carbonyl group in the acyl fragment and reduction of the conjugated double bond afforded in high yield the corresponding 3-alkyl(aralkyl) derivatives possessing eithe

Full text of DOI:10.1023/B:RUJO.0000003193.75790.de

Russian Journal of Organic Chemistry, Vol. 39, No. 7, 2003, pp. 998 1009. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 7, 2003,
pp. 1060 1072.
Original Russian Text Copyright
2003 by Pashkovskii, Katok, Khlebnikova, Koroleva, Lakhvich.
Heterocyclic Analogs of Prostaglandins: I. Synthesis
of 3-Alkyl(Aralkyl)-2,5-dihydrofuran-2-ones as Synthons
for 11-Deoxy-10-oxaprostanoids
F. S. Pashkovskii, Ya. M. Katok, T. S. Khlebnikova,
E. V. Koroleva, and F. A. Lakhvich
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus,
ul. Akademika Kuprevicha 5/2, Minsk, 220141 Belarus
e-mail: evk@ns.iboch.bas-net.by
Received March 1, 2002
Abstract 3-Acyl(arylmethyleneacyl)tetronic acids were synthesized. Selective hydrogenation of the carbonyl
group in the acyl fragment and reduction of the conjugated double bond afforded in high yield the correspond-
ing 3-alkyl(aralkyl) derivatives possessing either natural or modified prostaglandin -chain. Reduction of the
conjugated double bond in vinylogous 3-alkyl(aralkyl)tetronic acid amides with sodium cyanotrihydridoborate
gave a mixture of stereoisomeric -amino lactones which underwent retro-Michael elimination of the amine
residue, leading to 3-alkyl(aralkyl)-2,5-dihydrofuran-2-ones. The latter can be regarded as synthons for
11-deoxy-10-oxaprostanoids.
2,5-Dihydrofuran-2-one (2-buten-4-olide) system is
a structural fragment of a series of natural compounds,
such as acetogenins [1], muconolactones [2], leptos-
faerin [3], and strigol [4], which exhibit antibiotic,
cytotoxic, antitumor, antimalarial, immunosuppres-
sive, pesticide, and other kinds of biological activity
[5]. 2-Buten-4-olides turned out to be convenient
intermediate products in the synthesis of natural com-
pounds and their analogs having a -butyrolactone
moiety [6], including biologically active prostaglandin
heteroanalogs, 10-oxaprostanoids [7]. Therefore,
development of efficient procedures for the prepara-
tion of 2,5-dihydrofuran-2-ones is important from the
practical viewpoint.
The present communication describes a new syn-
thesis of 3-alkyl(aralkyl)-2,5-dihydrofuran-2-ones as
synthons for biologically active 10-oxaprostanoids.
As starting compounds we used 3-acyl(arylmethylene-
Scheme 1.
I, R = H; II, R = Me; III, R = Et; IV, R = COOMe; V, VIII, R = H, R = Et; VI, IX, R = H, R = COOMe;
VII, X, R = Me, R = COOMe.
1070-4280/03/3907-0998$25.00 2003 MAIK Nauka/Interperiodica

HETEROCYCLIC ANALOGS OF PROSTAGLANDINS: I.
999
Scheme 2.
III, XII, XIV, XVI, XVIII, R = Me, R = Et; IV, X, XIII, XV, XVII, R = Me, R = COOMe.
acyl)tetronic acids. 3-Acyltetronic acids VIII X were
prepared by the procedure reported in [8]. O-Acylation
of tetronic and 5-methyltetronic acid triethylammo-
nium salts I and II [9] with caprylic acid (III) or
pimelic acid monomethyl ester (IV) in the presence
of N,N -dicyclohexylcarbodiimide (DCC), followed
by isomerization of intermediate O-acyl derivatives
V VII under catalysis by 4-dimethylaminopyridine
(DMAP), gave 3-acyltetrahydrofuran-2,4-diones VIII
X in 85 90% yield (Scheme 1).
Compound X and acyltetronic acid XVIII were
also synthesized by an alternative method, according
to which the heterocycic -dicarbonyl fragment is
built up in the final stage [10]. Acylation of Mel-
drum’s acid (XI) with caprylic acid (III) or pimelic
acid monomethyl ester (IV) in the presence of
a catalytic amount of 4-dimethylaminopyridine and
1.2 equiv of DCC in methylene chloride gave acidic
-tricarbonyl compounds XII and XIII, respectively.
The latter were treated with 0.5 equiv of acetone in
boiling toluene to obtain their neutral synthetic
equivalents XIV and XV. Thermolysis of XIV and
XV leads to the same -keto ketene intermediates A
as those formed by thermolysis of XII and XIII.
Unlike -tricarbonyl precursors XII and XIII, com-
pounds XIV and XV can readily be purified by
chromatography on aluminum oxide. Heating of XIV
and XV with an equimolar amount of ethyl lactate in
boiling toluene afforded -substituted acetoacetic acid
esters XVI and XVII in high yield. The latter under-
went Dieckmann cyclization by the action of tetra-
butylammonium fluoride [11] to give target 3-acyl-
tetronic acids X and XVIII in 73 and 81% yield,
respectively (Scheme 2).
With the goal of obtaining precursors of 1,5-inter-
phenylene heteroprostanoids, 3-acetyltetronic acids
XIX and XX were brought into condensation with
methyl 4-formylbenzoate under conditions analogous
to those described by us previously [12]. As a result,
we obtained arylmethyleneacyl derivatives XXI and
XXII in high yield (Scheme 3). It should be noted
that, unlike condensation of 3-acetyltetronic acids
Scheme 3.
XIX, XXI, R = H; XX, XXII, R = Me.
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PASHKOVSKII et al.
1
Table 1. Yields, melting points, IR, H NMR, and mass spectra, and elemental analyses of 3-acyltetronic acids VIII X,
XVIII, XXI, and XXII
Found, %
Calculated, %
Mass spec-
trum, m/z
[M+]
Comp.
no.
Yield, %
mp, C (solvent)
Formula
C
H
C
H
VIII
IX
X
XVIII
XXI
XXII
90
87
67 69 (ether hexane)
42 44 (ether hexane)
63.74
56.23
58.10
65.10
7.95
6.38
6.75
8.44
4.19
4.65
C12H18O4
C12H16O6
C13H18O6
C13H20O4
C15H12O6
C16H14O6
63.70
56.24
57.77
64.98
62.50
63.57
8.02
6.30
6.71
8.39
4.20
4.67
226
256
270
240
288
302
85,a 73b
81b
39 41 (ether)
171 172 (ethyl acetate) 62.54
163 166 (ether)
75
72
63.69
Comp.
no.
1
IR spectrum, , cm
1H NMR spectrum, , ppm (J, Hz)
VIII
1620, 1668, 1700 sh, 1755 sh, 1780 0.90 t (3H, CH3, J = 6.5), 1.16 1.50 m (8H, 4CH2), 1.72 quint
[2H, CH2CH2(CO), J = 7.5], 2.92 t and 2.94 t [2H, (CO)CH2,
J = 7.5], 4.58 s and 4.68 s (2H, CH2, ring), 7.78 9.02 br.s (1H,
OH, enol)
IX
1605 sh, 1615, 1665, 1695, 1740,
1780
1.34 1.56 m (2H, CH2), 1.56 1.84 m (4H, 2CH2), 2.34 t (2H,
CH2CO2Me, J = 7.2), 2.93 t and 2.96 t [2H, (CO)CH2, J = 7.2],
3.69 s (3H, CO2CH3), 4.58 s and 4.70 s (2H, CH2, ring),
9.89 br.s (1H, OH, enol)
X
1615, 1670, 1700, 1740, 1780
1.34 1.56 m (2H, CH2), 1.53 d (3H, CHCH3, J = 7.0), 1.56
1.84 m (4H, 2CH2), 2.34 t (2H, CH2CO2Me, J = 7.2), 2.93 t
and 2.96 t [2H, (CO)CH2, J = 7.2], 3.69 s (3H, CO2CH3),
4.80 m (1H, CHCH3), 9.89 br.s (1H, OH, enol)
XVIII
XXI
XXII
1595 sh, 1620, 1675, 1685 sh, 1760 0.90 t (3H, CH3, J = 6.5), 1.18 1.46 m (8H, 4CH2), 1.53 d (3H,
CHCH3, J = 7.0), 1.71 quint [2H, C(O)CH2CH2, J = 7.5],
2.92 t [2H, C(O)CH2, J = 7.5], 4.80 m (1H, CHCH3), 9.38 br.s
(1H, OH, enol)
1565, 1585, 1640, 1705, 1730, 1770
3.95 s (3H, CO2CH3), 4.63 s and 4.70 s (2H, CH2, heteroring),
7.77 d (2H, Harom, J = 8.0), 7.81 d and 7.86 d (1H, CH,
Jtrans = 16.0), 8.04 d and 8.06 d (1H, CH , Jtrans = 16.0),
8.12 d (2H, Harom, J = 8.0)
1580, 1600, 1650, 1698, 1745
1.58 d (3H, CHCH3, J = 7.0), 3.96 s (3H, CO2CH3), 4.78 q and
4.86 q (1H, CHCH3, J = 7.0), 7.77 d (2H, Harom, J = 8.0),
7.84 d and 7.87 d (1H, CH, Jtrans = 16.0), 8.04 d and 8.06 d
(1H, CH , Jtrans = 16.0), 8.12 d (2H, Harom, J = 8.0), 9.50 br.s
(1H, OH, enol)
a
By acylation of tetronic acid.
By cyclization of -substituted acetoacetic acid ethyl ester.
b
XIX and XX with 4-formylbenzoic acid (which is
characterized by a low yield because of a poor solubil-
ity of 4-formylbenzoic acid [12]), the use of the corre-
sponding methyl ester considerably increases the yield
of arylmethyleneacyl derivatives and facilitates their
isolation and purification.
The transition to the corresponding -dicarbonyl
derivatives, 3-alkyl(aralkyl)tetronic acids implies
chemoselective hydrogenation of the carbonyl group
in the acyl substituent of cyclic -tricarbonyl pre-
cursors. We tried to effect this transformation in three
ways (a c). Ionic hydrogenation of -tricarbonyl
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HETEROCYCLIC ANALOGS OF PROSTAGLANDINS: I.
1001
Scheme 4.
VIII, XXIII, R = H, R = C7H15; IX, XXIV, R = H, R = (CH2)5COOMe; XXV, R = H, R = (CH2)5COOH; XXI, R = H, R =
(E)-CH CHC6H4COOMe-p; XXVIII, R = H, R = (CH2)2C6H4COOMe-p; X, XXVI, R = Me, R = (CH2)5COOMe; XVIII,
XXVII, R = Me, R = C7H15; XXII, R = Me, R = (E)-CH CHC6H4CO2Me-p; XXIX, R = Me, R = (CH2)2C6H4COOMe-p.
compounds VIII, IX, XXI, and XXII by the action
of triethylsilane in trifluoroacetic acid [13] in the
presence of a catalytic amount of LiClO4 (a) gave
-dicarbonyl compounds XXIII, XXIV, XXVIII, and
XXIX in high yield. Only the yield of XXVII was
63%, presumably due to loss of the product during
washing of the reaction mixture with hexane to
remove silanes (the product is appreciably soluble
in hexane).
tion from the aqueous phase with organic solvents.
The isolation of oily products is also easy: here,
preliminary removal of THF is not necessary. Thus
we have proposed a general and efficient procedure
for the synthesis of cyclic -alkyl- -dicarbonyl
compounds [15]. The application of this procedure to
-tricarbonyl compounds VIII, XVIII, XXI, and
XXII afforded products XXIII and XXVII XXIX
in 91 97% yield (Scheme 4).
It should be noted that the ester group attached to
the aromatic ring in compounds XXI and XXII is
stable under conditions of procedure (c), while the
ester group in compound IX is readily hydrolyzed to
give acid XXV as the major product. We have found
that replacement of tetrahydrofuran by methanol leads
to considerable increase in the yield of target -di-
carbonyl compound XXIV. Nevertheless, the optimal
procedure for the preparation of ester XXIV is (a)
with the use of triethylsilane in trifluoroacetic acid,
which rules out hydrolysis of the ester group during
the reduction.
Wide synthetic potential of cyclic -dicarbonyl
compounds originates from versatile chemical reac-
tions involving the ketomethylene fragment. The
selectivity of these reactions can be governed by the
use of -dicarbonyl compounds per se or derivatives
of their enol forms.
We then focused on the preparation of enol deriva-
tives of alkyl-substituted tetronic acids and develop-
ment of effective ways of their transformation into
2-buten-4-olides. A classical procedure for the syn-
thesis of , -unsaturated cyclic ketones from cyclic
-diketones includes conversion of the latter into
vinyl enol ethers and selective reduction of the con-
jugated carbonyl group therein with diisobutylalu-
minum hydride at low temperature ( 78 C) [16].
Subsequent treatment of the reaction mixture results
in decomposition of -hydroxy ketones to enones via
elimination of water.
Selective hydrogenation of the acyl carbonyl group
in tricarbonyl compounds VIII, X, XVIII, XXI, and
XXII was also performed according to procedure (b)
which was proposed for acyl derivatives of Meldrum’s
acid, 5-acylbarbituric acid, dehydroacetic acid, and
3-acyl-4-hydroxycoumarins. It includes reduction of
the above substrates with sodium cyanotrihydrido-
borate [14]. We have found that this procedure is
applicable to preparation of 3-alkyltetronic acids from
-tricarbonyl precursors. In the reaction with aryl-
methyleneacyl derivatives, as well as in ionic hydro-
genation, the reduction involved the entire enone
fragment of the arylmethyleneacyl substituent. The
procedure turned out to be inconvenient from the
experimental viewpoint because of difficulties in
the isolation of products from the reaction mixtures
containing high-boiling acetic acid which readily
dissolves organic compounds. Following method (b),
the yields of -alkyl- -dicarbonyl compounds XXIII
and XXVI XXIX were 65 80%.
Our experiments showed that the reduction of
cyclic -tricarbonyl compounds of the cyclopentane,
cyclohexane, tetronic acid, and -pyrone series with
cyanotrihydridoborate (c) is more efficient when it
is performed in the system THF 2 N aqueous HCl. In
this case, the procedure for isolation of products from
the reaction mixture is considerably simplified, so that
the yield increases. Removal of THF under reduced
pressure results in almost complete crystallization of
the target -dicarbonyl compounds from aqueous
solution containing inorganic components; an addi-
tional amount of the product can be isolated by extrac-
Taking into account the known possibility for
regioselective synthesis of enol ethers at the lactone
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 7 2003

1002
PASHKOVSKII et al.
Scheme 5.
carbonyl group of 3-alkyltetronic acids by the action
of Meerwein salts [17], we tried to apply this proce-
dure to the preparation of butenolides. Theoretically,
reduction of the ketone carbonyl group in enol ethers,
followed by treatment of the reaction mixture with
water, could lead to formation of -hydroxylactones
which could then be converted into 2-buten-4-olides
through elimination of water (Scheme 5).
In order to verify the feasibility of the above
approach, 3-(6-methoxycarbonylhexyl)tetronic acid
(XXIV) and 5-methyl-3-octyltetronic acid (XXVII)
were converted into enol ethers XXX and XXXI,
respectively, by the action of triethyloxonium tetra-
fluoroborate. Enol ethers XXX and XXXI were
reduced with diisobutylaluminum hydride in diethyl
ether at 78 C, and subsequent treatment of the reac-
tion mixtures with water gave desired butenolides
XXXII and XXXIII (Scheme 6). However, the yield
of XXXIII was as low as 28%, and the yield of
XXXII was even smaller (12%) as a result of
an appreciable contribution of reduction of the side-
chain ester group. Our attempts to raise the yield of
the target product through variation of the solvent,
temperature, and way of addition of the reducing
agent were unsuccessful.
reduction of the conjugated double bond in enamino
derivatives of 3-alkyltetronic acids with subsequent
retro-Michael elimination of the amine residue from
the -aminolactones thus formed [18]. By heating of
3-alkyltetronic acids XXIII, XXIV, and XXVI
XXVIII with pyrrolidine in boiling toluene we ob-
tained the corresponding enamino lactones XXXIV
XXXVIII in 80 90% yield. The yield of sterically
hindered enamino lactone XXXIX ranged from 50 to
60%. Prolonged boiling of the reaction mixture and
addition of p-toluenesulfonic acid as catalyst did not
result in appreciable increase of the yield of XXXIX.
The conjugated double bond in XXXIV XXXIX
was smoothly reduced by the action of sodium cyano-
trihydridoborate on a solution of the substrate in
2 N methanolic hydrogen chloride at room tempera-
ture. After evaporation of methanol, treatment of the
reaction mixture with aqueous alkali gave -amino-
lactones XL XLV as mixtures of diastereoisomers.
Unlike enamino derivatives of tetronic acids, the
double bond in enamino derivatives of carbocyclic
-dicarbonyl compounds is quite resistant to reduction
under analogous conditions [19].
We have found that the resulting -aminolactones
undergo partial retro-Michael elimination of the pyr-
rolidine moiety to afford 2,5-dihydrofuran-2-ones
during chromatographic purification on silica gel. In
order to accelerate the transformation of aminolac-
tones into butenolides, compounds XL XLV were
heated in boiling toluene in the presence of silica gel.
Under these conditions, butenolides XXXII, XXXIII,
Therefore, we examined another approach to
butenolides through enamino derivatives of 3-alkyl-
substituted tetronic acids (enaminolactones) and
developed a convenient three-step procedure for the
synthesis of 3-alkyl- and 3,5-dialkyl-substituted
2,5-dihydrofuran-2-ones. The procedure consists of
Scheme 6.
XXIV, XXX, XXXII, R = H, R = (CH2)5COOMe; XXVII, XXXI, XXXIII, R = Me, R = C7H15.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 7 2003

HETEROCYCLIC ANALOGS OF PROSTAGLANDINS: I.
1003
Scheme 7.
XXIII, XXXIV, XL, XLVI, R = H, R = C7H15; XXIV, XXXII, XXXV, XLI, R = H, R = (CH2)5COOMe; XXVIII, XXXVIII,
XLIV, XLVIII, R = H, R = (CH2)2C6H4COOMe-4; XXVI, XXXVI, XLII, XLVII, R = Me, R = (CH2)5COOMe; XXVII,
XXXIII, XXXVII, XLIII, R = Me, R = C7H15; XXIX, XXXIX, XLV, XLIX, R = Me, R = (CH2)2C6H4COOMe-4.
and XLVI XLIX were formed in 55 65% yield
(calculated on enamino lactones XXXIV XXXIX)
(Scheme 7). It is important that the yield of the target
butenolides does not decrease when crude aminolac-
tones XL XLV are used (obtained after primary
treatment of the reaction mixture). Unlike diisobutyl-
aluminum hydride, sodium cyanotrihydridoborate as
reducing agent ensures considerably higher yields
of the target products and conservation of the ester
moiety.
Thus, using 3-acyltetronic acids as starting com-
pounds, we have developed a four-step procedure for
the synthesis of 3-alkyl- and 3,5-dialkyl-substituted
2,5-dihydrofuran-2-ones. The products, butenolides
XXXII, XXXIII, and XLVI XLIX are convenient
synthons for biologically active 11-deoxy-10-oxa-
prostanoids.
was added under stirring at 0 C to a suspension of
9 mmol of tetronic acid I or II in anhydrous CH2Cl2.
To the resulting homogeneous solution we added in
succession 0.36 g (2.97 mmol) of 4-dimethylamino-
pyridine, 1.56 ml (9.9 mmol) of caprylic acid (III) or
1.72 g (9.9 mmol) of pimelic acid monomethyl ester
(IV), and (in portions) 2.22 g (10.8 mmol) of dicyclo-
hexylcarbodiimide. The mixture was stirred for
10 min at 0 C, the cooling bath was removed, and
the mixture was stirred for 15 h at room temperature.
The precipitate of N,N -dicyclohexylurea was filtered
off and washed with ethyl acetate. The filtrate was
combined with the washings and evaporated, 80 ml
of diethyl ether and 25 ml of 1.5 N hydrochloric acid
were added to the residue, and the mixture was shaken
in a separatory funnel. The aqueous phase was
removed, and the organic phase was washed with
20 ml of 1.5 N hydrochloric acid and 20 ml of water
and dried over MgSO4. The solvent was evaporated,
and the residue was subjected to column chromatog-
raphy on silica gel using hexane ether as eluent
(gradient elution). The product was recrystallized from
appropriate solvent. The yields, melting points and
spectral and analytical data of compounds VIII X are
given in Table 1.
EXPERIMENTAL
The melting points were determined on a Boetius
device. The 1H NMR spectra were measured on
a Bruker AC-200 spectrometer (200 MHz) from solu-
tions in CDCl3 containing TMS as internal reference.
The IR spectra were recorded on a UR-20 instrument
from samples prepared as thin films or KBr pellets.
The mass spectra (70 eV) were run on a Varian MAT-
311 mass spectrometer. The progress of reactions and
the purity of products were monitored by TLC on
6-Substituted 2,2-dimethyl-4H-1,3-dioxin-4-ones
XIV and XV. Triethylamine, 3 ml (21.6 mmol), was
added dropwise under stirring at 0 C to a solution of
2.59 g (18 mmol) of 2,2-dimethyl-1,3-dioxane-4,6-di-
one (XI) in dry chloroform. To the resulting mixture
we added 0.73 g (6 mmol) of 4-dimethylaminopyri-
dine and (dropwise) a solution of 2.84 ml (18 mmol)
of caprylic acid (III) or 3.13 g (18 mmol) of pimelic
acid monomethyl ester (IV) in 15 ml of chloroform.
Silufol UV-254 plates. Silica gel 100/160
m
(Czechia) and aluminum oxide were used for column
chromatography.
Acylation of tetronic acids I and II with car-
boxylic acids. Triethylamine, 1.38 ml (9.9 mmol),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 7 2003

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PASHKOVSKII et al.
1
Table 2. Yields, melting points, IR, H NMR, and mass spectra, and elemental analyses of 3-alkyltetronic acids XXIII
XXVII, XXVIII,a and XXIXa
Found, %
Calculated, %
Mass spec-
trum, m/z
[M+]
Comp.
no.
Yield, %
(method)
mp, C (solvent)
104 107 (ether)
Formula
C12H20O3
C12H18O5
C
H
C
H
XXIII
XXIV
91 (a),
65 (b),b
93 (c)
88 (a),
37 (b),
79 (c)c
60 (c)
80 (b)e
63 (a),
77 (b),e
94 (c)
67.91
9.56
67.89
9.50
212
76 78 (ether hexane)
59.35
7.46
59.49
7.49
242
XXVd
XXVI
XXVII
125 128 (ether)
57.89
60.70
68.94
7.06
7.97
9.76
C11H16O5
C13H20O5
C13H22O3
57.88
60.92
68.99
7.07
7.87
9.80
228
256
226
63.5 65f (hexane)
Comp.
no.
1
IR spectrum, , cm
1H NMR spectrum, , ppm (J, Hz)
XXIII
1410, 1455, 1465, 1605 1665, 1720, 0.87 t (3H, CH3, J = 6.5), 1.10 1.38 m (10H, 5CH2), 1.38
2720
1.58 m (2H, CH2), 2.21 t (2H, CH2, J = 7.5), 4.70 s (2H, CH2,
ring)
XXIV
1410, 1440, 1645 br, 1735, 2715
1.34 m (4H, 2CH2), 1.50 quint (2H, CH2, J = 7.2), 1.62 quint
(2H, CH2CH2CO2Me, J = 7.2), 2.20 t (2H, 3-CH2, J = 7.2),
2.33 t (2H, CH2CO2Me, J = 7.2), 3.68 s (3H, CO2CH3),
4.66 s (2H, CH2, ring)
XXVd
XXVI
1420, 1475, 1580 sh, 1610 1660, 1715, 1.34 m (4H, 2CH2), 1.54 1.81 m (4H, 2CH2), 2.43 t (2H, CH2,
2715 J = 7.5), 2.47 t (2H, CH2, J = 7.5), 4.83 s (2H, CH2, ring)
1410, 1440, 1635 br, 1680, 1720, 1740, 1.34 m (4H, 2CH2), 1.50 d (3H, CHCH3, J = 6.5), 1.50 m (2H,
2715
CH2), 1.62 quint (2H, CH2CH2CO2Me, J = 7.2), 2.20 t (2H,
3-CH2, J = 7.2), 2.33 t (2H, CH2CO2Me, J = 7.2), 3.68 s (3H,
CO2CH3), 4.85 q (1H, CHCH3, J = 6.5)
XXVII
1410, 1480, 1635 br, 1725, 2400 2800
0.88 t (3H, CH3, J = 6.5), 1.13 1.39 m (10H, 5CH2), 1.39
1.62 m (2H, CH2), 1.51 d (3H, CHCH3, J = 6.5), 2.20 t (2H,
3-CH2, J = 7.5), 4.85 q (1H, CHCH3, J = 6.5)
a
The spectral parameters of compounds XXVIII [yield 97% (a), 76% (b),b 97% (c); mp 161 163 C (from ethyl acetate)] and XXIX
[yield 89% (a), 71% (b),b 91% (c); mp 115 117 C (from ether hexane)] are fully consistent with our previous data [12].
Isolated by crystallization from dilute aqueous solutions of acetic acid.
Yield of the reduction product upon replacement of THF by methanol.
The 1H NMR spectrum of XXV was recorded in pyridine-d5.
b
c
d
e
f
Isolated by column chromatography after evaporation of acetic acid under reduced pressure.
Melting point of a sample prepared by method (c).
Dicyclohexylcarbodiimide, 4.45 g (21.6 mmol), was
then added in portions, the cooling bath was removed,
and the mixture was stirred for 15 h at room tempera-
ture. The precipitate of N,N -dicyclohexylurea was
filtered off and washed with chloroform. The filtrate
was combined with the washings and evaporated, and
150 ml of diethyl ether and 50 ml of 1.5 N hydro-
chloric acid were added to the residue. The mixture
was shaken in a separatory funnel, the aqueous phase
was separated, and the organic phase was washed with
50 ml of 5% hydrochloric acid and 50 ml of water
and dried over Na2SO4. The solvent was removed
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HETEROCYCLIC ANALOGS OF PROSTAGLANDINS: I.
1005
Table 3. Yields, IR, 1H NMR, and mass spectra, and elemental analyses of 3-alkyl(aralkyl)-substituted 2,5-dihydrofuran-
2-ones XXXII, XXXIII, and XLVI XLIX
Found, %
Calculated,
C
%
Compound
no.
Mass spectrum,
Yield, %
Formula
m/z [M+]
C
H
H
XXXII
XXXIII
XLVI
12,a 58b
28,a 63b
63.65
74.34
73.39
65.14
69.22
70.02
7.99
10.51
10.25
8.37
C12H18O4
C13H22O2
C12H20O2
C13H20O4
C15H16O4
C16H18O4
63.70
74.24
73.43
64.98
69.22
70.06
8.02
10.54
10.27
8.39
226
210
196
240
260
274
65
55
62
56
XLVII
XLVIIIc
XLIXd
6.16
6.20
6.57
6.61
Comp.
no.
1
IR spectrum, , cm
1H NMR spectrum, , ppm (J, Hz)
XXXII
XXXIII
XLVI
1445, 1460, 1660, 1745, 1760
1460, 1470, 1665, 1765
1470, 1665, 1765
1.33 m (4H, 2CH2), 1.49-1.66 m (4H, 2CH2), 2.26 t.q (2H,
3
4
5
3-CH2, J = 7.5, J = J = 1.7), 2.28 t (2H, CH2CO2Me, J =
3
5
7.5), 3.64 s (3H, CO2CH3), 4.75 q (2H, OCH2, ring, J = J =
1.7), 7.09 quint (1H, 4-H, 3J = 4J = 1.7)
0.89 t (3H, CH3, J = 6.0), 1.15 1.38 m (10H, 5CH2), 1.42 d (3H,
CHCH3, J = 7.0), 1.56 quint (2H, CH2, J = 7.5), 2.28 br.t
3
3
(2H, 3-CH2, J = 7.5), 5.02 q.d (1H, CHCH3, J1 = 7.0, J2 =
1.5), 7.01 q (1H, 4-H, 3J = 4J = 1.5)
0.89 t (3H, CH3, J = 6.5), 1.10 1.48 m (10H, 5CH2), 1.58 quint
3
4
(2H, CH2, J = 7.0), 2.31 t.d (2H, 3-CH2, J = 7.5, J = 1.5),
3
5
4.79 q (2H, OCH2, ring, J = J = 1.5), 7.11 quint (1H, 4-H,
3J = 4J = 1.5)
XLVII
1465, 1660, 1740, 1760
1.33 m (4H, 2CH2), 1.38 d (3H, CHCH3, J = 7.0), 1.48 1.68 m
3
4
5
(4H, 2CH2), 2.24 t.t (2H, 3-CH2, J = 7.5, J = J = 1.5),
2.29 t (2H, CH2CO2Me, J = 7.5), 3.65 s (3H, CO2CH3),
3
3
5
4.98 q.t (1H, CHCH3, J1 = 7.0, J2 = J = 1.5), 6.98 q (1H,
4-H, 3J = 4J = 1.5)
XLVIIIc
XLIXd
1435, 1465, 1620, 1665, 1720, 1763
1443, 1465, 1620, 1665, 1730, 1765
1.94 quint (2H, CH2CH2Ar, J = 7.5), 2.36 t.d [2H, CH2(CH2)2Ar,
4
3J = 7.5, J = 1.8], 2.74 t (2H, CH2Ar, J = 7.5), 3.92 s (3H,
3
5
CO2CH3), 4.78 q (2H, OCH2, ring, J = J = 1.8), 7.14 quint
3
4
(1H, 4-H, J = J = 1.8), 7.27 d (2H, Harom, J = 8.0), 7.98 d
(2H, Harom, J = 8.0)
1.40 d (3H, CHCH3, J = 7.0), 1.92 quint (2H, CH2CH2Ar, J =
7.5), 2.33 br.t [2H, CH2(CH2)2Ar, J = 7.5], 2.74 t (2H,
CH2Ar, J = 7.5), 3.91 s (3H, CO2CH3), 5.01 q.d (1H, CHCH3,
3
3
4
3J1 = 7.0, J2 = 1.5), 7.03 q (1H, 4-H, J = J = 1.5), 7.26 d
(2H, Harom, J = 8.0), 7.97 d (2H, Harom, J = 8.0)
a
b
c
By reduction of tetronic acid enol ethers with diisobutylaluminum hydride.
By reduction of enamino lactones with sodium cyanotrihydridoborate.
mp 54.5 56 C (from ether).
d
mp 36 37 C (from ether hexane).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 7 2003

1006
PASHKOVSKII et al.
1
Table 4. Yields, IR, H NMR, and mass spectra, and elemental analyses of 4-(1-pyrrolidinyl)-2,5-dihydrofuran-2-ones
XXXIV XXXIX
Found, %
H
Calculated,
H
%
Comp.
no.
Mass spectrum,
Yield, %
Formula
m/z [M+]
C
N
C
N
XXXIV
XXXV
90
84
72.27
64.94
66.12
72.90
69.37
69.97
10.15
8.49
8.81
10.49
7.03
7.34
5.14
4.65
4.54
5.03
4.15
4.01
C16H27NO2
C16H25NO4
C17H27NO4
C17H29NO2
C19H23NO4
C20H25NO4
72.41
65.06
65.99
73.07
69.28
69.95
10.25
8.53
8.79
10.46
7.04
7.34
5.28
4.74
4.53
5.01
4.25
4.08
265
295
309
279
329
343
XXXVI
XXXVII
XXXVIII
XXXIX
89
82
80
50 60
Comp.
no.
1
IR spectrum, , cm
1H NMR spectrum, , ppm (J, Hz)
XXXIV
1450, 1460, 1475 sh, 1615, 1640, 1730 0.88 t (3H, CH3, J = 6.5), 1.15 1.53 m (12H, 6CH2), 2.00 m
(4H, 2CH2, pyrrolidine), 2.31 t (2H, CH2, J = 7.5), 3.46 m
(4H, 2CH2, pyrrolidine), 4.54 s (2H, CH2, butenolide)
XXXV
1450, 1465, 1640, 1745
1.21 1.52 m (6H, 3CH2), 1.62 m (2H, CH2), 2.00 m (4H, 2CH2,
pyrrolidine), 2.31 t (4H, CH2CO2Me, 3-CH2, J = 7.2), 3.46 m
(4H, 2CH2, pyrrolidine), 3.66 s (3H, CO2CH3), 4.56 s (2H,
CH2, butenolide)
XXXVI
1435, 1460, 1625, 1740
1.20 1.54 m (6H, 3CH2), 1.48 d (3H, CHCH3, J = 6.5), 1.54
1.76 m (2H, CH2), 1.82 2.14 m (4H, 2CH2, pyrrolidine),
2.32 t (4H, CH2CO2Me, 3-CH2, J = 7.5), 3.50 m (4H, 2CH2,
pyrrolidine), 3.67 s (3H, CO2CH3), 4.80 q (1H, CHCH3,
J = 6.5)
XXXVII
1435, 1460, 1630, 1740
0.89 t (3H, CH3, J = 6.5), 1.22 1.41 m (12H, 6CH2), 1.49 d (3H,
CHCH3, J = 6.5), 1.85 2.13 m (4H, 2CH2, pyrrolidine), 2.33 t
(2H, 3-CH2, J = 7.5), 3.51 m (4H, 2CH2, pyrrolidine), 4.82 q
(1H, CHCH3, J = 6.5)
XXXVIII 1450, 1460, 1625, 1635, 1725 sh, 1735 1.82 quint (2H, CH2CH2Ar, J = 7.5), 1.93 m (4H, 2CH2, pyrroli-
dine), 2.37 t [2H, CH2(CH2)2Ar, J = 7.5], 2.72 t (2H, CH2Ar,
J = 7.5), 3.33 m (4H, 2CH2, pyrrolidine), 3.90 s (3H,
CO2CH3), 4.52 s (2H, OCH2, ring), 7.26 d (2H, Harom, J =
8.0), 7.94 d (2H, Harom, J = 8.0)
XXXIX
1440, 1460, 1620, 1730
1.46 d (3H, CHCH3, J = 6.5), 1.69 2.04 m (6H, CH2CH2Ar,
2CH2, pyrrolidine), 2.38 t [2H, CH2(CH2)2Ar, J = 7.5], 2.72 t
(2H, CH2Ar, J = 7.5), 3.38 m (4H, 2CH2, pyrrolidine), 3.90 s
(3H, CO2CH3), 4.78 q (1H, CHCH3, J = 6.5), 7.26 d (2H,
Harom, J = 8.0), 7.95 d (2H, Harom, J = 8.0)
under reduced pressure, the oily residue (acylated
Meldrum’s acid XII or XIII) was dissolved in 25 ml
of toluene, and 0.66 ml (9 mmol) of acetone was
added. The mixture was heated for 1.5 h under reflux
and was concentrated under reduced pressure. The
residue was purified by column chromatography
on aluminum oxide using hexane ether as eluent
(gradient elution). The products were pale yellow oily
substances.
6-Heptyl-2,2-dimethyl-4H-1,3-dioxin-4-one
1
(XIV). Yield 71%. H NMR spectrum, , ppm: 0.89 t
(3H, CH3, J = 6.5 Hz), 1.22 1.40 m (8H, 4CH2),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 7 2003

HETEROCYCLIC ANALOGS OF PROSTAGLANDINS: I.
1007
1.45 1.62 m (2H, CH2), 1.69 s (6H, 2-CH3), 2.22 t
solvent was removed under reduced pressure, and
40 ml of 10% hydrochloric acid was added to the
residue. The aqueous phase was extracted with ether
(5 25 ml). The combined extracts were dried over
Na2SO4 and evaporated, and the residue was purified
by column chromatography on silica gel using
hexane ether as eluent (gradient elution).
The yields, melting points, and spectral data of
compounds X and XVIII thus obtained are given
in Table 1.
(2H, CH2C C, J = 7.5 Hz), 5.23 s (1H, 5-H). IR spe-
1
ctrum, , cm : 1635, 1735.
2,2-Dimethyl-6-(5-methoxycarbonylpentyl)-4H-
1
1,3-dioxin-4-one (XV). Yield 67%. H NMR spec-
trum, , ppm: 1.33 1.45 m (2H, CH2), 1.48 1.72 m
(4H, 2CH2), 1.69 s (6H, 2-CH3), 2.23 t (2H, CH2,
J = 7.5 Hz), 2.33 t (2H, CH2CO2Me, J = 7.5 Hz),
3.68 s (3H, CO2CH3), 5.24 s (1H, 5-H). IR spectrum,
1
, cm : 1640, 1735, 1745.
Condensation of 3-acetyltetronic acids XIX and
XX with methyl 4-formylbenzoate. 3-Acetyltetronic
acids XIX and XX were prepared by the procedure
described in [20]. A 20-mmol portion of compound
XIX or XX was dissolved in 40 ml of dry benzene,
and 2.96 ml (30 mmol) of piperidine and 2.95 g
(18 mmol) of methyl 4-formylbenzoate were added.
The mixture was heated for 5 h under reflux in a flask
equipped with a Dean Stark trap, and was left to
stand overnight at room temperature. The solvent was
distilled off under reduced pressure, and the residue
was treated with 1 N hydrochloric acid to pH 2. The
crystals of condensation product were filtered off,
washed with some amount of 1 N hydrochloric acid
and with water, dried in air, and recrystallized. The
yields, melting points, and spectral data of compounds
XXI and XXII thus obtained are given in Table 1.
3-Alkyl-substituted tetronic acids XXIII XXIX
(Table 2). a. Reduction of 3-acyltetronic acids with
triethylsilane in trifluoroacetic acid. To a solution
of 1 mmol of -tricarbonyl compound in 5 ml of tri-
fluoroacetic acid containing 1% of lithium perchlorate
we added in portions 0.48 ml (3 mmol, in the reduc-
tion of 3-acyltetronic acids) or 0.64 ml (4 mmol, in
the reduction of arylmethyleneacyltetronic acids) of
triethylsilane, and the mixture was left overnight at
room temperature. The solvent was distilled off under
reduced pressure, and the residue was cooled and
washed with several portions of cold hexane. After
solidification, the cryctalline product was transferred
to a filter, washed with water, dried in air, and recrys-
tallized. Oily products were purified by column
chromatography on silica gel using hexane ether as
eluent (gradient elution).
Thermolysis of 6-substituted 2,2-dimethyl-4H-
1,3-dioxin-4-ones XIV and XV with ethyl lactate in
toluene. A mixture of 12.8 mmol of compound XIV
or XV and 1.46 ml (12.8 mmol) of ethyl lactate in
50 ml of toluene was heated for 1.5 h under reflux.
The solvent was removed under reduced pressure, and
the residue was purified by column chromatography
on silica gel using hexane ether as eluent (gradient
elution). The products were pale yellow oily sub-
stances.
1-Ethoxycarbonylethyl 3-oxodecanoate (XVI).
Yield 92%. 1H NMR spectrum, , ppm (enol-to-
ketone ratio 1:6.5): 0.90 t (3H + 3/6.5H, CH3, J =
6.5 Hz), 1.16 1.42 m (11H + 11/6.5H, 4CH2
+
CO2CH2CH3), 1.51 d (3H + 3/6.5H, CHCH3, J =
7.0 Hz), 1.61 m (2H + 2/6.5H, CH2), 2.22 t [2/6.5H,
C(OH)CH2, J = 7.5 Hz], 2.60 t [2H, C(O)CH2, J =
7.5 Hz], 3.52 s [2H, C(O)CH2C(O)O], 4.23 q (2H +
2/6.5H, CO2CH2CH3, J = 7.0 Hz), 5.11 s [1/6.5H,
C(OH) CHC(O)O], 5.14 q (1H + 1/6.5H, CHCH3,
J = 7.0 Hz), 11.82 s (1/6.5H, OH, enol). IR spectrum,
1
, cm : 1640, 1670, 1730, 1760.
1-Ethoxycarbonylethyl 8-methoxycarbonyl-3-
oxooctanoate (XVII). Yield 90%. 1H NMR spectrum,
, ppm (enol-to-ketone ratio 1:6): 1.30 t (3H + 3/6H,
CO2CH2CH3, J = 7.0 Hz), 1.33 1.45 m (2H + 2/6H,
CH2), 1.53 d (3H + 3/6H, CHCH3, J = 7.0 Hz), 1.56
1.76 m (4H + 4/6H, 2CH2), 2.32 t [2H + 4/6H,
CH2CO2Me (enol + ketone), C(OH)CH2, J =
7.2 Hz], 2.62 t [2H, C(O)CH2, J = 7.0 Hz], 3.52 s
[2H, C(O)CH2C(O)O], 3.67 s (3H + 3/6H, CO2CH3),
4.22 q (2H + 2/6H, CO2CH2CH3, J = 7.0 Hz), 5.10 s
[1/6H, C(OH) CHC(O)O], 5.14 q (1H + 1/6H,
CHCH3, J = 7.0 Hz), 11.82 s (1/6H, OH, enol). IR
b. Reduction of 3-acyltetronic acids with sodium
cyanotrihydridoborate in acetic acid. To a solution
of 10 mmol of -tricarbonyl compound in 15 ml of
glacial acetic acid we added in portions under stirring
at 0 C 1.26 g (20 mmol) of sodium cyanotrihydrido-
borate. When the entire amount of the reducing agent
was added, the cooling bath was removed, and the
mixture was stirred for 5 h at room temperature. If
the product was a crystalline substance, the mixture
1
spectrum, , cm : 1640, 1670, 1730 sh, 1755.
Dieckmann cyclization of thermolysis products
XVI and XVII by the action of tetrabutylammo-
nium fluoride in THF. To 11.5 mmol of compound
XVI or XVII we added under argon 25 ml of a 1 M
solution of tetrabutylammonium fluoride (25 mmol)
in THF, and the mixture was stirred at room tempera-
ture. When the reaction was complete (TLC), the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 7 2003

1008
PASHKOVSKII et al.
was poured onto ice (in a beaker), the overall volume
was adjusted to 60 ml, and the mixture was acidified
with 2 ml of concentrated hydrochloric acid. The
mixture was cooled for several hours, and the product
was filtered off, washed with water, dried in air, and
purified by recrystallization. If the product was an oily
substance, acetic acid was removed under reduced
pressure, 50 ml of 1 N hydrochloric acid was added
to the residue, and the mixture was extracted with
chloroform. The extracts were dried over Na2SO4,
filtered, and evaporated, and the residue was purified
by column chromatography on silica gel using
hexane ether as eluent (gradient elution).
c. Reduction of 3-acyltetronic acids with sodium
cyanotrihydridoborate in the system THF 2 N hydro-
chloric acid. To a solution of 1 mmol of -tricarbonyl
compound in 6 ml of THF we added under stirring
5 ml of 2 N hydrochloric acid. In some cases, the
initial compound partially precipitated from the solu-
tion. To the resulting mixture (solution or suspension)
we added under stirring in portions 0.16 g (2.5 mmol,
in the reduction of 3-acyltetronic acids) or 0.22 g
(3.5 mmol, in the reduction of 3-arylmethyleneacyl-
tetronic acids) of sodium cyanotrihydridoborate. The
mixture was stirred until the reaction was complete
(TLC). By the end of the process, the mixture divided
into two layers containing no solid species. The
organic phase was separated, and the aqueous phase
was estracted with ether or chloroform. The extracts
were combined with the organic phase, dried over
Na2SO4, and evaporated. Oily products were purified
by column chromatography on silica gel. Poorly
soluble crystalline products were isolated from the
aqueous phase after evaporation of THF under reduced
pressure. An additional amount was isolated from the
aqueous phase by extraction with chloroform. Portions
of the products isolated by filtration and extraction
were combined and finally purified by recrystalliza-
tion from appropriate solvent.
5-Ethoxy-4-(6-methoxycarbonylhexyl)-2,3-di-
hydrofuran-3-one (XXX). Yield 81%. 1H NMR
spectrum, , ppm: 1.20 1.38 m (4H, 2CH2), 1.38
1.52 m (2H, CH2), 1.44 t (3H, OCH2CH3, J =
7.0 Hz), 1.61 quint (2H, CH2CH2CO2CH3, J =
7.0 Hz), 2.07 t (2H, CH2, J = 7.0 Hz), 2.30 t (2H,
CH2CO2CH3, J = 7.5 Hz), 3.66 s (3H, CO2CH3),
4.44 q (2H, OCH2CH3, J = 7.0 Hz), 4.53 s [2H,
1
OCH2C(O), ring]. IR spectrum, , cm : 1620, 1710,
1745. Mass spectrum, m/z: 270 [M+].
5-Ethoxy-2-methyl-4-octyl-2,3-dihydrofuran-3-
1
one (XXXI). Yield 89%. H NMR spectrum, , ppm:
0.88 t (3H, CH3, J = 6.5 Hz), 1.18 1.33 m (10H,
5CH2), 1.36 1.52 m (2H, CH2), 1.42 t (3H, OCH2-
CH3, J = 7.0 Hz), 1.48 d (3H, CHCH3, J = 7.0 Hz),
2.06 t (2H, CH2, J = 7.5 Hz), 4.42 q (2H, OCH2CH3,
J = 7.0 Hz), 4.60 q (1H, CHCH3, J = 7.0 Hz). IR
1
spectrum, , cm : 1615, 1705. Mass spectrum, m/z:
254 [M+].
Reduction of 4-alkyl-5-ethoxy-2,3-dihydrofuran-
3-ones XXX and XXXI with diisobutylaluminum
hydride. To a mixture of 1 mmol of enol ether XXX
or XXXI and diethyl ether we added at 78 C under
argon 1.5 ml of a 1 M solution of diisobutylaluminum
hydride in hexane (1.5 mmol). The mixture was
stirred at 78 C until the initial compound disap-
peared completely (TLC), 1.5 ml of water was added
at that temperature, and the mixture was allowed to
warm up to room temperature. To the resulting sus-
pension we added 50 ml of ether, and the mixture
was dried over MgSO4. The drying agent was filtered
off, the filtrate was evaporated, and the residue was
purified by column chromatography on silica gel
(hexane ether, gradient elution). The yields and spec-
tral parameters of compounds XXXII and XXXIII
are given in Table 3.
4-(1-Pyrrolidinyl)-2,5-dihydrofuran-2-ones
XXXIV XXXIX. Pyrrolidine, 1 ml (12 mmol), was
added dropwise under stirring to a suspension of
10 mmol of appropriate 3-alkyltetronic acid in 30 ml
of toluene. The resulting mixture containing pyrroli-
dinium salt of -dicarbonyl compound was heated for
5 8 h under reflux in a flask equipped with a Dean
Stark trap (to remove liberated water). The mixture
was filtered, the solvent was distilled under reduced
pressure, and the residue was purified by column
chromatography on silica gel using chloroform as
eluent. Enamino lactones XXXIV XXXIX were
isolated as viscous oily substances. Their yields and
spectral parameters are given in Table 4.
O-Alkylation of 3-alkyltetronic acids XXIV and
XXVII with triethyloxonium tetrafluoroborate. To
a solution of 2.5 mmol of 3-alkyltetronic acid XXIV
or XXVII in 30 ml of methylene chloride we added
under stirring 1.42 g (7.5 mmol) of triethyloxonium
tetrafluoroborate. When the reaction was complete
(TLC), the mixture was passed through a layer of
silica gel using chloroform as eluent. The eluate was
evaporated under reduced pressure, and the residue
was subjected to chromatography in a short column
charged with aluminum oxide using ether hexane as
eluent. The corresponding enol ethers were isolated
as mobile oily substances.
2,5-Dihydrofuran-2-ones XXXII, XXXIII, and
XLVI XLIX. To a solution of 1 mmol of enamino
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HETEROCYCLIC ANALOGS OF PROSTAGLANDINS: I.
1009
lactone XXXIV XXXIX in 5 ml of methanol we
added under stirring 0.5 mg of Methyl Orange and
then several drops of a 6 N solution of HCl in
methanol until the mixture turned bright red. Sodium
cyanotrihydridoborate, 0.15 g (2.4 mmol), was added
in portions, and a 6 N methanolic solution of HCl was
added dropwise at such a rate that the bright red color
of the mixture was maintained. The progress of the
reaction was monitored by the rate of HCl absorption
and by TLC. The solvent was removed under reduced
pressure, 5 ml of water and 15 ml of diethyl ether
were added to the residue, and a 1 N aqueous solution
of sodium hydroxide was then added dropwise until
the aqueous phase turned yellow. The organic phase
was separated, and the aqueous phase was extracted
with ether (2 10 ml). The extracts were combined
with the aqueous phase and evaporated to dryness to
obtain aminolactones XL XLV as mixtures of dia-
stereoisomers. Crude products XL XLV were heated
for 6 12 h in 10 ml of boiling toluene in the presence
of 2 g of silica gel (until the initial compounds were
completely converted into the corresponding buten-
olides, according to TLC). The mixture was filtered
from silica gel, and the precipitate was washed with
toluene (2 10 ml). The filtrate was combined with
the washings and evaporated under reduced pressure.
The residue was purified by column chromatography
on silica gel using hexane ether as eluent (gradient
elution). The yields and spectral parameters of com-
pounds XXXII, XXXIII, and XLVI XLIX are given
in Table 3.
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This study was financially supported by the Inter-
national Science Foundation (grant no. INTAS-97-
0084) and by the Byelorussian Republican Foundation
for Basic Research (project no. Kh01-121).
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