Synthesis of dehydro derivatives of cycloheximide and inactone

Article abstract of DOI:10.1023/A:1012586621401

Catalytic hydrogenation of 3-chloro-2-(2,6-dioxopiperidin-4-ylacetyl)-2-cyclohexenones over palladium catalyst leads to formation of dehydrocycloheximide derivatives. Reduction of the same compounds with Zn-Ag yields dehydroinactone derivatives.

Full text of DOI:10.1023/A:1012586621401

Russian Journal of Organic Chemistry, Vol. 37, No. 5, 2001, pp. 724 728. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 5, 2001,
pp. 762 765.
Original Russian Text Copyright
2001 by Buravskaya, Lakhvich.
Synthesis of Dehydro Derivatives of Cycloheximide
and Inactone
T. N. Buravskaya and F. A. Lakhvich
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus,
ul. Akad. Kuprevicha 5, korp. 2, Minsk, 220141 Belarus
e-mail: prostan@ns.iboch.ac.by
Received June 21, 2000
Abstract Catalytic hydrogenation of 3-chloro-2-(2,6-dioxopiperidin-4-ylacetyl)-2-cyclohexenones over
palladium catalyst leads to formation of dehydrocycloheximide derivatives. Reduction of the same compounds
with Zn Ag yields dehydroinactone derivatives.
Glutarimide antibiotics cycloheximide (I) [1] and
inactone (II) [2] were isolated from Streptomyces
griseus. The synthesis of cycloheximide was described
previously [3].
ketone fragment being retained. Such modifications
are important for preparation of new physiologically
active substances from both natural antibiotics having
a
-tricarbonyl moiety [6] and numerous derivatives
of synthetic -triketones exhibiting a wide spectrum
of pesticide activity [7]. On the other hand, the trans-
formation of compounds III VI into glutarimide anti-
biotics like cycloheximide, inactone, streptovitacins,
and their analogs implies selective modification of the
-tricarbonyl system. It is known [8] that catalytic
hydrogenation of cyclohexane-based -triketones is
not selective: It usually gives mixtures of products
formed by reduction of one carbonyl group in the ring
or in the side chain. Therefore, we examined different
ways of reduction of diketones VII X [4, 9]. Diketone
X was a mixture of cis and trans isomers at a ratio of
1 : 3. The catalytic hydrogenation of compounds
VII X over 30% Pd/BaSO4 resulted in reduction of
of the C C bond and hydrodechlorination to afford
-diketones XI XIV (Scheme 1). Compounds XI,
XII, and XIII are analogs of dehydrocycloheximide
(XIV), differing by the number and position of methyl
groups in the cyclohexene ring. Compound XIV was
obtained previously by oxidation of cycloheximide (I)
or by the total synthesis [3]. The structure of -di-
ketones XI XIV is confirmed by the spectral data.
In the preceding publications [4, 5] we proposed
schemes for the synthesis of some analogs of glutar-
imide antibiotics from cyclic triacylmethanes having
a glutarimide fragment in the side chain. We described
modifications of the -tricarbonyl system in com-
pounds III VI, which are 6-oxo derivatives of
dehydrocycloheximide and its 4,4-dimethyl, 4-methyl,
and 3,5-bisnormethyl analogs, through regioselective
transformation of one carbonyl group into enamino,
the degree of oxidation of carbon atoms in the -tri-
Compound XIII shows in the 1H NMR spectrum
signals from the cyclohexane fragment: a singlet from
two geminal methyl groups at 1.0 ppm and signals
from methylene protons at 1.46, 2.17, and 2.30 ppm,
and a complete set of signals from the glutarimide
moiety. The spectra of XI and XII also contained
signals from both structural fragments. It should be
noted that all signals in the spectra of XI XIII appear
III, R1 = R2 = H; IV, R1 = H, R2 = CH3; V, R1 = R2 = CH3.
1070-4280/01/3705-0724$25.00 2001 MAIK Nauka/Interperiodica

SYNTHESIS OF DEHYDRO DERIVATIVES OF CYCLOHEXIMIDE AND INACTONE
725
Scheme 1.
VII, XI, XV, R1 = R2 = H; VIII, XII, XVI, R1 = H, R2 = CH3; IX, XIII, XVII, R1 = R2 = CH3.
0.1 to 0.35 ppm upfield relative to those observed for
initial -triketones III V. This pattern is explained by
weaker deshielding effect of the -dicarbonyl system
as compared to -tricarbonyl.
VII IX. Products XI XIII were formed from com-
pounds VII IX in 82 96% yield in 1 2 days at room
temperature. The reaction with diketone X required
heating for 5 days at 40 45 C, and the yield of XIV
was 73%. Obviously, the presence of methyl groups
in positions 3 and 5 of the cyclohexane ring hinders
adsorption of the substrate on the catalyst surface.
-Diketones XI XIV exist in the enol form which
is stabilized by strong intramolecular hydrogen bond.
1
This follows from the presence in their H NMR
spectra of a downfield signal in the region 15.6
16.1 ppm, which belongs to the chelated hydroxy
proton. In addition, a positive test for enolic hydroxy
group was obtained on treatment with a solution of
iron(III) chloride. In the IR spectra absorption bands
from conjugated C C and C O bonds were present
at 1616 and 1690 cm , respectively. According to the
data of [10], 2-acylcyclohexanones XI XIV are likely
to exist as endo-enol tautomers A.
With the goal of comparing spectroscopic param-
eters we have synthesized -diketone XIV by oxida-
tion of cycloheximide I. The product had trans-
arranged methyl groups (trans-XIV). Its 1H NMR
spectrum contained two doublets from the methyl
protons at 1.05 and 1.25 ppm and a downfield signal
at 15.7 ppm from the chelated hydroxy proton. The
methylene protons on C4 gave a multiplet signal at
1.53 ppm. In the 1H NMR spectrum of product XIV
obtained by hydrogenation of diketone X we observed
two doublets of the methyl groups, which are typical
1
Under the same conditions the hydrogenation of
diketone X was more difficult than the reduction of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 5 2001

726
BURAVSKAYA, LAKHVICH
of their trans arrangement, and one more doublet at
1.20 ppm; the intensity ratio of the doublets located
at 1.05, 1.20, and 1.25 ppm was about 2:1:1. This
means that the reduction product is a mixture of cis
and trans isomers at a ratio of 1:1. The doublet at
1.20 ppm belongs to the 3-CH3 group of the cis
isomer of XIV. The upfield doublets from the 5-CH3
groups in cis-XIV and trans-XIV coincide with
each other (in both isomers the 5-methyl group is
equatorial); therefore, the signal at 1.05 ppm has
a double intensity. Signals from methyl groups that
are not contiguous to the carbonyl group appear
separately, for they have different configurations. The
C5-methylene group ( 2.07 ppm), and singlets from
the C3H2 protons and geminal methyl groups at 2.33
and 1.13 ppm, respectively). These data are well
consistent with those published in [12].
An analogous treatment of chlorodiketones VII,
VIII, and X led to formation of mixture of the corre-
sponding enediones (dehydroinactone XVIII and its
analogs XV and XVI) and -diketones XI, XII, and
XIV. Compound XVIII was a mixture of cis and
1
trans isomers. This follows from the H NMR spec-
trum which contained two signals from the olefinic
proton ( 5.28 and 5.31 ppm) and signals from the
C4H2 groups of both isomers, , ppm: 1.38 m (1H)
and 1.78 m (1H) (cis isomer, axial and equatorial
protons); 1.64 m (2H, trans isomer).
1
observed pattern is similar to the H NMR spectra of
the corresponding -triketones [11]: the difference
between the chemical shifts of the methyl protons in
the trans isomer is larger than in the cis isomer: 0.20
and 0.15 ppm, respectively. In the downfield region of
the spectrum there were two signals from the chelated
hydroxy proton at 15.68 and 16.08 ppm, which also
indicate the presence of a mixture of two isomers. The
product of hydrogenation of compound X showed in
the spectrum both C4-methylene proton signal of
EXPERIMENTAL
The IR spectra were recorded on a UR-20 spec-
trometer. The UV spectra were measured on a Specord
1
UV-Vis spectrophotometer in alcohol. The H NMR
spectra were obtained on a Bruker WM-360 instru-
ment (360 MHz) using tetramethylsilane as internal
reference. The melting points were determined on
a Koefler device.
2-(2,6-Dioxopiperidin-4-ylacetyl)cyclohexanones
XI XIV. Diketone VII X, 0.001 mol, in 10 ml of
tetrahydrofuran was hydrogenated over 100 mg of
30% Pd/BaSO4. The catalyst was separated, the sol-
vent was removed from the filtrate, and the residue
was recrystallized from ether or acetone.
trans-2,4-Dimethyl-6-(2,6-dioxopiperidin-4-yl-
acetyl)cyclohexanone (XIV). A solution of 200 mg
of CrO3 in 10 ml of glacial acetic acid was added to
a solution of 200 mg of cycloheximide (I) in 10 ml
of glacial acetic acid. The mixture was stirred for
3 h at 5 10 C, diluted with 50 ml of ice water, and
extracted with chloroform. The extract was dried over
magnesium sulfate, the solvent was distilled off,
and the residue was recrystallized from methylene
chloride ethanol. Yield 170 mg.
2-(2,6-Dioxopiperidin-4-ylacetyl)-2-cyclohexen-
ones XV XVIII. To 1 g of zinc dust we added 5 ml
of 10% hydrochloric acid, and the resulting suspen-
sion was shaken periodically. After a few minutes,
the solution was separated by decanting, the remain-
ing zinc was washed with acetone (2 5 ml) and ether
(5 ml), a suspension of 35 mg of silver acetate in 5 ml
of boiling acetic acid was added, and the mixture was
stirred for 1 min. The solution was separated by
decanting, and the dark zinc silver mixture was
washed with acetic acid (5 ml), ether (4 5 ml), and
trans-XIV at
1.53 ppm (with a halved intensity)
and a multiplet at 1.71 ppm, typical of the equatorial
methylene proton at C4 in the cis isomer of XIV.
The signal from the axial proton of the same isomer
appears at
1.25 ppm.
Thus we have shown that catalytic hydrogenation
of diketone X results in formation of dehydrocyclo-
heximide (XIV) as a mixture of cis and trans isomers
and that compounds VII IX give rise to products
XI XIII. These compounds can also be used as
precursors of cycloheximide (I) and its analogs.
The reduction of diketone IX with a Zn Ag couple
yields dehydroinactone isomer XVII (Scheme 1).
According to the data of [12, 13], such reactions are
carried out in methanol at room temperature and are
accompanied by heat evolution. Taking into account
poor solubility of compound IX in methanol, we
performed the reaction in a mixture of methanol with
tetrahydrofuran, and the reaction mixture was heated
under reflux with stirring. As a result, we obtained
two products, compound XVII and -diketone XIII
at a ratio of 1:2. Compound XVII is likely to exist
in the enedione form. It gave a negative test for enolic
hydroxyl with a solution of iron(III) chloride. Its
structure is also confirmed by the UV and IR spectral
data. In the IR spectrum we observed absorption
1
bands at 1555 and 1680 cm , which are characteristic
of conjugated C C and C O bonds, respectively.
1
The H NMR spectrum contained a signal from vinyl
proton at 6.43 ppm, a two-proton doublet from the
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SYNTHESIS OF DEHYDRO DERIVATIVES OF CYCLOHEXIMIDE AND INACTONE
727
Yields, melting points, and IR and 1H NMR spectra of glutarimide derivatives XI XVIII
Comp.
no.
Yield,
%
1
mp,
C
IR spectrum, , cm
1H NMR spectrum (CDCl3), , ppm (J, Hz)
XI
91
96
134 136
1615, 1695, 1710, 1725, 1.69 s (4H), 2.30 s (2H), 2.40 t (4H, 7.8), 2.47 d (2H,
3100, 3200 (KBr) 6), 2.78 s (2H), 2.83 s (1H), 8.18 s (1H), 15.68 s (1H)
XII
168.5 170.5 1625, 1690, 1700, 1725, 1.0 d (3H, 6), 1.25 s (2H), 1.78 m (2H), 1.96 2.07 m
3100, 3200 (KBr)
(1H), 2.26 2.52 m (6H), 2.80 m (3H), 8.1 s (1H),
15.64 s (1H)
XIII
82
73
136.5 139 1615, 1690, 1705, 1720, 1.00 s (6H), 1.46 t (2H, 6.6), 2.17 s (2H), 2.30 t (2H,
3090, 3183 (KBr)
6.6), 2.37 q (2H, 9), 2.49 d (2H, 6), 2.79 s (2H),
2.84 s (1H), 8.25 s (1H), 15.61 s (1H)
XIVa
165 169
170 173
1610, 1690, 1705, 1730, 1.05 d (3H, 6), 1.20 d (1.5H, 7.2), 1.25 d (1.5H, 7.2),
3090, 3200 (KBr)
1.53 m (2H), 1.71 m (H), 1.87 m (2H), 2.38 m (3H),
2.53 m (3H), 2.78 s (2H), 2.83 s (1H), 8.07 s (1H),
15.68 s (0.5H), 16.08 s (0.5H)
XIVb
89
1625, 1690, 1710, 1730, 1.05 d (3H, 6), 1.25 d (3H, 7.2), 1.53 m (2H), 1.87 m
3100, 3200 (KBr);
1580, 1612, 1710,
1730, 3380 (CHCl3)
(2H), 2.38 m (3H), 2.53 m (3H), 2.78 s (2H), 2.83 s
(1H), 8.36 s (1H), 15.70 s (1H)
XVc
42
50
128 130
163 165
1580, 1675, 1705, 1730, 2.36 m (6H), 2.43 d (2H, 6.6), 2.51 d (2H, 6.6), 2.76 m
3100, 3230 (film) (3H), 5.36 s (1H), 8.43 s (1H)
XVId
1565, 1675, 1720, 1740, 1.10 d (3H, 6.6), 1.45 t (2H, 7.2), 1.75 m (2H), 1.92 m
3100, 3210, (CCl4)
(1H), 2.17 2.66 m (4H), 2.79 m (3H), 5.97 s (1H),
8.07 s (1H)
XVIIe
18
34
190 193
170 173
1555, 1680, 1705, 1725, 1.13 s (6H), 2.07 d (2H, 6), 2.33 s (2H), 2.66 s (2H),
3100, 3220 (CHCl3)
2.73 d (2H, 6), 2.79 d (2H, 4.8), 2.84 s (1H), 6.43 s
(1H), 7.86 s (1H)
XVIIIf
1600, 1660, 1715, 1740, 1.08 1.31 m (6H), 1.38 m (H), 1.64 m (2H), 1.78 m (1H),
3100, 3230 (CCl4)
2.08 m (2H), 2.25 2.48 m (4H), 2.69 m (3H), 5.28 s
(0.5H), 5.31 s (0.5H), 8.00 s (1H)
a
b
c
d
e
f
Mixture of cis and trans isomers at a ratio of 1:1.
trans Isomer; UV spectrum, max, nm ( ): 293 (9655).
-Diketone XI was also obtained (42%).
-Diketone XII was also obtained (21%).
UV spectrum, max, nm ( ): 239 (4670). -Diketone XIII was also obtained (40%).
Ratio of cis and trans isomers 1:1. -Diketone XIV was also obtained (20%).
methanol (5 ml). A solution of 0.001 mol of com-
pound VII X in 5 ml of THF was added to the moist
Zn Ag mixture, and the resulting mixture was heated
for 2 6 h at 30 40 C under vigorous stirring. The
precipitate was filtered off and washed with THF. The
filtrate was evaporated, the residue was treated with
a mixture of ether (or chloroform) and 10% hydro-
chloric acid, and the aqueous phase was extracted with
the corresponding solvent (5 10 ml). The combined
extracts were washed and dried over MgSO4, the sol-
vent was removed, and the residue was recrystallized
from acetone and was subjected to chromatography
on silica gel to isolate -diketones XI XIV and
enediones XV XVIII.
REFERENCES
1. Whiffen, A.J., Bohonas, N., and Emerson, R.L.,
J. Bacteriol., 1946, vol. 52, no. 4, pp. 610 616.
2. Preud’Homme, J. and Dubost, M., Handbook of
14th Int. Congr. on Pure and Applied Chemistry,
Zurich, 1955, p. 382.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 5 2001

728
BURAVSKAYA, LAKHVICH
3. Johnson, F., Starkovsky, N.A., Paton, A.C., and
Carlson, A.A., J. Am. Chem. Soc., 1966, vol. 88,
no. 1, pp. 149 159.
Akhrem, A.A., Chem. Rev., 1999, vol. 99, no. 4,
pp. 1047 1065.
8. Smith, H., J. Chem. Soc., 1953, no. 3, pp. 803 810.
4. Lakhvich, F.A., Buravskaya, T.N., and Akhrem, A.A.,
9. Akhrem, A.A., Lakhvich, F.A., Budai, S.I., Khlebni-
kova, T.S., and Shcherbakova, T.N., Dokl. Akad.
Nauk SSSR, 1976, vol. 226, no. 6, pp. 1326 1329.
Khim. Prirodn. Soedin., 1993, no. 4, pp. 598 601.
5. Buravskaya, T.N. and Lakhvich, F.A., Russ. J. Org.
Chem., 1996, vol. 32, no. 7, pp. 969 975; Burav-
skaya, T.N. and Lakhvich, F.A., Russ. J. Org. Chem.,
1998, vol. 34, no. 2, pp. 250 252.
10. Jones, R.A. and Stokes, M.J., Tetrahedron, 1984,
vol. 40, no. 6, pp. 1051 1060.
11. Lakhvich, F.A., Buravskaya, T.N., and Akh-
rem, A.A., Vestsi Akad. Nauk Belarusi, Ser. Khim.
Navuk, 1992, no. 2, pp. 77 83.
6. Garmaise, D.L., Chu, D.T.W., Bernstein, E., and
Inaba, M., J. Med. Chem., 1979, vol. 22, no. 5,
pp. 559 564; Lakhvich, F.A. and Khlebnikova, T.S.,
Vestsi Akad. Navuk Belarusi, Ser. Khim. Navuk, 1996,
no. 4, pp. 101 119.
12. Akhrem, A.A., Lakhvich, F.A., and Pyrko, A.N.,
Zh. Org. Khim., 1983, vol. 19, no. 11, pp. 2322
2328; Clark, R.D. and Heathcock, C.H., J. Org.
Chem., 1976, vol. 41, no. 4, pp. 636 643.
7. Lakhvich, F.A., Lis, L.G., Rubinov, D.B., Rubino-
va, I.L., Kurbako, V.Z., and Bykhovets, A.I., Vestsi
Akad. Navuk BSSR, Ser. Khim. Navuk, 1989, no. 1,
pp. 51 58; Rubinov, D.B., Rubinova, I.L., and
13. Novak, L., Baan, G., Marasfalvi, J., and Szantay, Cs.,
Chem. Ber., 1980, vol. 113, no. 9, pp. 2939 2949.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 5 2001