Note: Descriptions are shown in the official language in which they were submitted.
23~
This invention relates to the pr~paration of certain racemic or
optically active lactone diol derivatives, namely the racemic or optically
active lactone diol derivatives o:E the structural formula I
O--C~
~ ~I)
R10~ CH2 H
wherein,
R represents acyl, hydrocarbon optionally containing also oxygen in the
claim or silyl.
Thus, this invention provides for a process for preparing a racemic
or optically active lactone diol derivative of the structural formula I
~0
O--C
~ (I)
Rl`'o CH2-OH
wherein
Rl represents acyl, hydrocarbon optionally containing also oxygen in the chain
or silyl, which process comprises:
~a) reacting a racemic or optically active lactone diol of the structural
formula II O-~C~
. ~
~II)
.~'`~
HO CH2-H
with a trialkyl-silyl derivative of the structural formula IIII)
, .
., . -- 1 --
~;
`
~3~38
R2 Si R (III)
,~
,~
wherein
R2, R3 and R4 each represent alkyl, and
xl represents chloride, bromine or iodine or dialkyl-amino, then acylating the
compound of the structural formula IV
~O--C~
~ ~IV)
HO CH2-OR
initally obtained,
wherein
R5 represents -SiR2R3R4, with a compound of structural formula (V)
- o
R6 .C ~x2 (V)
or formula ~1
R7 - N = C = (VI)
wherein
R6 represents alkyl, aryl, substituted aryl or aralkyl,
R7 represents alkyl, aryl or substituted aryl, and
X represents chlorine or iodine
and deblocking the primary hydroxyl of the lactone derivative of the structural
formula VII O- C
~ (VII)
R O CH2 OR
''
~: .
thus obtained
wherein,
R8 represents R6 -C0- or R7 -NH-C0- by acid hydrolysis; or
(b) acylating the racemic or optically active lactone diol of the structural
formula II with an ~cid halogenide of the structural formula V, reacting the
compound of the structural formula IV, initially obtai.ned wherein R5 represents
R6 -C0-, with a trialkyl silyl derivative of the structural formula III, then
deblocking the primary hydroxyl group of the lactone derivative of the structural
formula VIII ~0 C\
~ " (VIII)
9 '"" ~ 8
R 0 CH2-R
thus obtained,
wherein
R8 represents R6 -C0- and
R9 represents -SiR R3R ,
by solvolysis carried out under alkaline condltions, or
~c) reacting the racemic or optically active lactone diol of the structural
formula II with a benzyl halogenide of the structural formula IX
~ CH2 - X3 (IX)
wherein
X3 represents chlorine, bromine or iodine, reacting the compound of the struct-
ural formula IV, initally obtained,
wherein
R5 represents ben~yl~
with a trialkyl-silyl derivative of the structural formula III, or with an
,
"
, .
~3~23~3
acid halogenide of the structural formula V, and then deblocking the primary
hydroxyl of the lactone diol derivatives of the structural formula X
O--C~
~"' (X)
R10'`"" C~12-Rll
thus obtained J
wherein
Rll represents benzyl, benzyloxy-carbonyl, trichloro-ethoxy-carbonyl, and
R10 represents R6 -C0-, or -SiR2R3R4 by catalytic hydrogenation or with nascent
hydrogen.
According to a preferred embodiment of process variant
~a) the secondary hydroxyl can be protected by aroyl, carbamoyl, preferably
by p phenyl benzoyl, benzoyl, actyl, p phenyl, phenylcarbamoyl and the primer
hydroxyl may be deblocked with acetic acid at a temperature no* exceeding 50C.
According to a preferred embodiment of process variant
~b) primaryhydroxyl is protected by alkanoyl or aroyl, preferably by benzoyl
or acetyl, and the secunder hydroxyl by alkoxy-dialkyl-methyl such as methoxy-
dimethyl methyl or ethoxy-methyl-methyl, and the primaryhyroxyl is solvolysed
in a lower alkanol, in the presence of a base, preferably of potassium carbonate.
According to a preferred embodiment of process variant
~c) primaryhydroxyl is protected by benzyl, benzyloxy-carbonyl, or
trichloroethoxy-carbonyl, and the secunder hydroxyl by phenyl-benzoyl, benzoyl,
tetrahydropyranyl or silyl substituted by three identical or different Cl 6
alkyls. The primaryhydroxyl is deblocked by catalytic dehydrogenation
achieved by nascent hydrogen generated from an acid by zinc, in the presence
of a palladium catalyst under a hydrogen pressure of 3 atm.
: .
~3~3~
Among the entermediates employed in this invention are, for example
3,3a~,4,5,6,6a~-hexahydro-2-oxo-4~-trimethylsilyl-oxymethyl-5~-hydroxy-2H-
cyclopenta[b]furane and 3,3a~,4,5,6,6a~-hexahydro-2-oxo-4~-trityloxymethyl-5~-
hydroxy-2~1-cyclopenta[b]-furane which are novel compounds.
There are a lot of methods known in the art for the total synthesis
of various prostaglandine analoges. In the known synthesis methods the way
elaborated by E.J. Corey et al. takes a prominent part as regarding its ability
to solve stereochemical problems, universality and importance [J. Amer. Chem.
Soc., 91, 5675 /1969/, ibid: 929 397 /1970/, ibid: 93, 1490 /1961/]. This
method fUlfills also the requirements of the industrial production. The aimed
product of the Corey synthesis is PGF2~9 which can be easily transformed into
other pharmaceutically important natural prostaglandines, thus for example into
PGEl, PGE2, PGEl , and PGEl~. The key-intermediate of the synthesis is the
"Corey aldehyde" - wherein Rl represents p-phenyl-benzoyl or p-phenyl-carbamoyl-in which the four asymmetric carbon atoms have the same absolute and relative
configuration as those of the PGF2~, and which contains both free or marked
carbonyl functions serving for the preparation of the side-chains during the
reaction, and the p-phenyl-benzoyl or p-phenyl-phenyl-carbamoyl hydroxyl-
protecting groups, which are to control the stereoselective reduction of the
C15-keto group. [J. Amer. Chem Soc. 9~, 8616 /1972/]. According to the
synthesis "~orey aldehyde" and the other acyloxy lactone aldehydes of the
structural formula XI ~z
O--C
~ (XI)
`
R 0CH0
are prepared by oxydating acyloxy-lactones of the structural formula I~ wherein
R represents acyl. The preparation of the compounds of the structural formula
~,
:, :
: :
~ ,
,
1~3~38
I in this way, however, is extremely complicated, due to the high number
of the reaction steps, and to the fact that the reagents are expensive and
difficult to obtain.
Some other synthesis methods for the preparation of the compounds
of the structural formula XI, I or of the compounds having similar field
of application are to cope with similar difficulties ~See for example J. Amer.
Soc., 95, 6853 /1973/, J.C.S. Perkin I. 2796 /1973/). We have surprisingly
found that the compounds of the structural formula I may be prepared by
selective acylation of the racemic or optically active lactone diol of the
structural formula II [~ II or ~ II].
Lactone diol of the structural formula II is a very convenient
starting material, since it is readily available when prepared according to
the cheap four-step synthesis disclosed in Tetrahedron Letters 4639-42 ~1976),
using cyclopentadiene as starting substance. It should be noted that some
representatives of the compounds of the structural formula I, for example
the compound in which Rl is acetyl, can be prepared by partial deacetylation
of the lactone diol diacetate of the structural formula XII
O--C~O
(XII)
R10` CH2-R
wherein
20R and R each represent acetyl,
this method, however, can not be extended to the preparation of the compounds
of the structural formula I in general, and the acyl-migration taking place
during the reaction has unfavourable consequences. It has been found that
the primaryhydroxyl of the racemic or optically active lactone diol of the
structural formula II can be subjected to a selective blocking reaction using
. , , , ~ .
; ~'~ ,,
.
~3~%3~3
various suitable reagents, and then the compound of the structural formula
IV, initially obtainedJ in which R5 is a blocking group, can be protected on
its free hydroxyl by any kind of acyl, for example p-phenyl-benzoyl, p-phenyl-
phenyl-carbamoyl or of hydrocarbon, for e~ample tetrahydropyranyl. Finally
the blocking group of the primaryhydroxyl is splitted off without attacking
the ether or ester bond on the secondaryhydroxyl.
For the selective treatment of the primary and secondary hydroxyl
of the compound of the structural formula II there is already a method known
in the art [J. ~mer. Chem. Soc. 93 1491 /1971/], wherein as a bottom-note,
without any experimental details the following procedure is suggested for
solving the problem:
The primaryhydroxyl of the lactone diol of the structural formula
~-)-II is subjected to a selective trichloro-acetylating reaction, the second-
aryhydroxyl of the hydroxyl-lactone trichloroacetate of the struc~ural formula
IV obtained, wherein RS is trichloro-acetyl, is subseqently protected by
tetrahydropyranyl, and then compound of the structural formula ~If obtained
in the second step, in which Rl is tetrahydropyranyl and R5 is trichloroacetyl,
is subjected to a saponification reaction. Thus tetrahydropyranyloxy-lactone-
alcohol is obtained, which compound is within the scope o the structural
formula I, and in which Rl represents tetrahydropyranyl.
The selective blocking of the primaryhydroxyl in the lactone diol
is the decisive reaction step of our synthesis. Blocking can be achieved by
various reactions, thus by acylation, alkylation and silylation. The regio-
selectivity of the above reactions, however, is the function of the acylating,
alkylating and silyla~ing agents applied and of the reaction conditions.
Generally the reaction results also in the production of secunder mono-acyl,
mono-alkyl and mono-silyl side-products, which are~ however, easy to separate
from the corresponding primarymain-products by column chromatography.
~ ':
..' -
~ - 7 -
~L~3~
What has been said above concerning the regioselectivity of the
blocking reaction holds in respect of the acylating reactions carried out
with 1 mole equivalent of acetic anhydride, acetyl chloride, benzoyl chloride
or p-phenyl-benzoyl chloride in the presence of a base. The acylating reaction
carried out by trichloroacetyl chloride did not prove to be absolutely
regioselective, either, the aimed primarymono-acyl product was, however, easy
to isolate by column chromatography in all of the above-mentioned cases.
Results obtained when etherifying the compound of the structural
formula II were very similar. Thus, for example reacting the above compound
with 1 mole equivalent of benzyl chloride mono-primarybenzylether of the
structural formula IV, wherein R5 is benzyl, was obtained as a main product,
together with the mono-secondary-benzyl ether of the structural formula I,
wherein Rl represents benzyl, and with a small amount of the dibenzyl ether
of the structural formula XII, wherein Rl and R5 each reprasent benzyl. ~
The case is similar when silylating the compound of the structural
formula II with 1 mole equivalent of trimethylchloride sylane, in the presence
of a base. Neither at 0C nor at room temperature could we achieve a 100%
selectivity in pyridine-dichloromethane solvent mixture and at 30-40%
completion of the reaction bothmono-sil,y~l ethers and the di-silyl ether were
detected.
We have surprisingly found that with certain reagents under certain
reaction conditions near 100% regioselectivity could be achieved for the
blocking reaction of the primaryhydroxyl of the compound of the structural
formula II. Thus silylating the racemic or optically active compound of the
structural formula II with 1.0 to 1.1 mole equivalent of trimethylsilyl diethyl
amine [Acta Chem. Acad. Sci. Hung., 58, 189 /1968/~ in acetonitrile at 0C,
the reaction proceeds smoothly in some minutes, resulting in the mono-primary-
silyl ether of the structural formula IV, in which R5 represents trimethyl
,
3~3
silyl, besides mono-primary-silyl ether traces, which can be detected only
chromatographically.
It should be noted that using 2 to 2.5 equivalents of the above
reagent also the di-silyl ether can be produced in 30 to ~5 minutes.
Among the alkylating agents triphenyl-methyl chloride was found
to be able to procluce a similarregio5elective reaction. When carrying out
the tritylating reaction in pyridine, at room temperature, the crystalline
mono-primary-triethyl ether of the structural formula IV, in which R5 is
trityl, is obtained practically quantitatively.
The free secondaryhydroxyl of the compounds of the structural
formula IV can be subjected to acylation or alkylation. The compounds of
the structural formula IV preferably used in prostaglandine synthesis can be
acylated in a manner known per se using a p-phenyl-benzoyl chloride or p-
phenyl-isocyanate as acylating agents9 but also the tetrahydropyranyl ether
of these compounds can be prepared employing 3,4-2H-dihydropyrane. Thus
products of the structural formula XII are obtained, in which Rl and R5
represent different acyl, alkyl or silyl groups.
In the last step of our synthesis the primaryhydroxyl is deblocked
by methods known per se. Care must be taken, however, that the reagents
applied should not attack on the ester or other bond on the secondaryhydroxyl.
Trimethylsilyl and trityl are easily removable by hydrolysis effected under
mild acid conditi~n, with heating. This last reaction step can be carried
out also simultaneously with the separa*ion step following the acylation of
the secondaryhydroxyl.
Should the primaryhydroxyl be blocked by acyl, for example acetyl
or benzoyl, it is advisable to protect the secondaryhydroxyl by a protecting
group resistant to a mild alkaline hydrolysis, thus for example by an ether
type group, preferably by tetrahydropyranyl. When proceeding according to
~:~3~23~3
this method, the compounds of the structural formula XII, wherein Rl is
hydrocarbon, for example tetrahydropyranyl or benzyl and R5 represents acyl,
are treated with sodium alcoholate in an alcoholic medium, and thus compounds
of the structural formula I are prepared.
The following Examples illustrate but do not limit the product
and process of the present invention.
Example 1
(-)-3,3a~,4,5,6,6a~-hexahydro-4~-benzoyloxymethyl-5~-hydroxy -2H-
cyclopentano[b]furane-2-on 354 mg (2moles) of levorotatory lactone diol of
the structural formula II are dissolved in the mixture of 2 ml of dry pyridine
and 10 ml of dichloro methane, the mixture is ice-cooled to 0C and the
solution o~ 295 g ~2.1 mmoles) of benzoyl chloride in 5 ml of dichloro
methane i5 added gradually. The proceedings of the reaction is followed by
t.l.c. ~fter two hours the following spots are to be observed: spots corres-
ponding to a small amount of the starting material, and to traces of the
secondary monobenzoate (Rf = 0.34, ethyl acetate), respectively, but the
main spot is to be found at Rf = 0.60 ~ethyl acetate), which corresponds to
the primer monobenzoate. The reaction mixture is diluted with 30 ml of
dichloromethane and is poured into 30 ml of 7% equeous sulfuric acid solution
under ice-cooling, washed with 10 ml of 2.5% aqueous sodium bicarbonate
solution and dried over magnesium sulfate. The solvent is then evaporated
whereupon 550 mg of a colourless oil is obtained, which is chromatographed
on 60 g of silica gel and eluated in 2:1 to 1:1 benzoyl-ethyl acetate solvent
mixture, using the gradient eluating technique. Evaporating the fractions
containing the main product 399 mg (72%) of the title monobenzoate are
obtained which proved to be uniform according to the t.l.c. measurements.
[~]23 = -22 (c = 1.37, ethyl acetate)
IR: 3400, 3010, 2920, 1770, 1710, 1600, 1590, 1450, 1265,1200, 1165, 1110,
- 10 -
-, .
,
1065, 1030, 710 cm~l.
Example 2
(~)-3,3a~,4,5,6,6a~-hexahydro-4~-acetoxymethyl-5a-hydroxy-2H-
cyclopentano[b]furane-2-on
~ ollowing the procedure set forth in the Example 1 but using 214.2 mg
(2.1 mmoles) of acetic anhydride as acylating agent, 452 mg of a crude product
are obtained, subjecting this product to column chromatography as described
in the Example 1, 124 mg (58%) of the title primer monoacetate are obtained.
t.l.c. (on "Kieselgel nach Stahl"plate): Rf = 0.10 (benzene ethyl acetate 1:1);
0.42 (ethyl acetate); 0.61 ~ethyl acetate - methanol 6:1).
Example 3
~ +)-3,3a~,4,5,6,6a~-hexahydro-4~-benzyloxymethyl-5a-hydroxy-2H-
cyclopentano[b]furane-2-on
320 mg ~1.86 mmoles) of racemic lactone diol of the structural
formula II are dissolved in 25 ml of acetone and 350 mg ~2.05 mmoles) of
benzyl bromide and 290 mg of potassium carbonate are added. The reaction
mixture is stirred at room temperature for 8 to 10 hours and the reaction is
followed by t.l.c. The main spot is to be observed at Rf = 0.46 ~GF254
"Kiselgel nach Stahl" plate, ethyl acetate) which corresponds to the primer
benzyl ether main product. The solvent is then evaporated, the residue taken
up in ethyl acetate, washed subsequently wi-th water and brine, dried over
magnesium sulfate and chromatographed on a chromatographic column made of
60 g of silica gel. The eluation is carried out with 2:1 to 1:1 mixture of
benzene and ethyl acetate using the conventional gradient eluating technique.
The fractions containing the main product are pooled and evaporated to give
the title compound in form of a pale-yellow oil.
IR: 3400 ~-OH), 1760 ~-CO-lactone), 1080 ~-CO-), 700, 7~0 ~-CH-) cm 1.
' ';~
~,~3~3~
Example 4
(+)-3,3a~,4,5,6,6a~-hexahydro-4~-benzoyloxymethyl-5~-tetrahydro-
pyranyloxy-211-cyclopentano[b]furane-2-on
230 mg (0.83 mmoles) of levorotatory lactone diol primer monobenzoate
of the general formula IV, in which R5 is benzoyl, are dissolved in 5 ml of
dry benzene, 0.5 ml (5.5 mmoles) of 3,4-2H-dihydropyrane and 1 drop of
phosphorous oxychloride are added. According ~o the t.l.c. measurements the
reaction is completed within one hour. Thereafter four drops of triethyl
amine and 5 ml of pentane are added and after 1 to 2 hours the resulted downy
precipitate is filtered off. Upon removing the solvent on a rotatory evaporator
under vacuo, 300 mg (100%) of the title compound is obtained as a colourless
oil having the following physical characteristics:
Rf = 0.33 (on a GF254 "Kieselgel nach Stahl" plate, with benzene-ethyl acetate
3~
IR: 3010, 2910, 2850, 1770, 1710, 1600, 1260, 1160, 1110, 1070, 1030, 1010,
910, 710 cm~l.
Example 5
(-)-3,3a~,4,5,6,6a~-hexahydro-4~-hydroxymethyl-5~-tetrahydropyranyloxy-
2H~cyclopentano[b]furane-2-on
300 mg (0.83 mmoles) of levor~atory lactone diol derivative of the
structural formula XII, in which Rl represents tetrahydropyranyl and R5
represents benzoyl are dissolved in 5 ml of dry methanol and 2 ml of 0.5 M
methanolic solution of sodium methoxide are added.
According to the t.l.c. measurement the debenzoylating reac*ion is
completed in 50 minutes. 1 ml of 1 M methanolic solution of acetic acid is
then added and the solvent is removed on a rotatory evaporator, in vacuo.
The residue is dissolved in 15 ml. of ethyl acetate and the solution is
subsequently washed with 3 ml of 5% sodium carbona~e solution, 2-fold 3 ml of
- 12 -
,' '. ~
~o~3~3~
water and 3 ml of brine, dried over sodium sulfate and evaporated. 201 mg (96%)
of the title ~-) lactone diol secunder tetrahydropyranyl ether are obtained.
Physical properties: [N]D = -30.7 ~1 (c = 0.9~, methanol).
IR (max.): 3420, 2910, 1850, 1760, 1345, 1165, 1120, 1110, 1070, 1030, 1010 cm
Rf = 0.20 (ethyl acetate), 0.~3 (6:1 ethyl acetate - methanol on a GR254
"Kieselgel nach Stahl" plate.
_ mple 6
(-)-3,3a~-4,5,6,6a~-hexahydro-4~-hydroxymethyl-5~-benzoyloxy-2H-
cyclopentano~b]furane-2On
172 mg (l~noles) of levorotatory lactone diol of the structural formula
II are dissolved in 5 ml of acetonitrile and 1.1 ml of 1 M solution of trimethyl
silyl-diethyl-amine in acetonitrile and added dropwise, at room temperature,
with stirring in 1 to 2 minutes. According to the t.l.c. measurement (benzene-
ethyl acetate 1:1) the reaction is completed in 10 minutes. The main spot
is found a~ Rf=0.36, but an other spot at Rf = 0.69 shows that also bis-silyl
ether traces are present. The solvent and ~he formed diethyl amine is removed
on a rotatory evaporator, under pressure of 12 to 15 torr, and at a temperature
not exceeding 30C. The res~due i5 257 mg of a yellowish oil which is then
dissolved in 5 ml of dichloro methane and the solution added to the mixture
of 1 ml of dry pyridine and 162 mg ~1.15 mmoIes) of ben~oyl chloride at 0C
in 5 to 6 minutes. Af~er two hours of stirring the reaction mixture is poured
into 10 ml of a 40% aqueous acetic acid solution, the container is washed
out with 2 to 3 ml of dichloro methane, which is added to the reaction mixture,
and then the mixture is allowed to stir for 30 to 35 minutes or shaken in a
separating fumlel very intensively. The phases are separated, the aqueous
phase is extracted with four 10 ml portions of dichloro methane and the combined
organic extracts are washed to neutral in small portions, with 5% solution of
sodium carbonate, and then dried over magnesium sulfate. Upon removing the
- 13 -
. . .
~3~23~
solvent 240 mg of the title compound remain in form of a colourless oil,
which can be turned into crystalline form upon stirring with a glass-stick.
After recrystallization from the mixture of ethyl aceta~e and hexane 210 mg
~76%) of lactone diol secunder-mono-benzoate are obtained, melting at 117 to
118C. [u] ~max): 3450, 2920, 1770, 1710, 1600, 1580, 1540, 1270, 1200, 1165,
1110, 1090, 1070, 1030, 710 cm 1,
Example 7
~ -)-3,3a~,4,5,6,6a~-hexahydro-4~-hydroxymethyl-5~-~p-phenyl-
benzoyloxy)-2H-cyclopentano[b]furane-2-on
The procedure set forth in the Example 6 is followed till the
addition of the acylating agent. In the present Example the solution of 249 mg
~1.15 mmoles) of p-phenyl-benzoyl chloride in 2 ml of pyridine are added
dropwise to the solution of the mono-primer-silyl ether in dichloro methane,
at room temperature, in 5 to 6 minutes. The mixture is stirred for two hours
and the proceedings of the reaction is controlled by t.l.c. The reaction
mixture is then poured into 10 ml of a 40% aqueous solution of acetic acid,
the container is washed with 2 to 3 ml of dichloro methane, which are then
added to the reaction mixture. The mixture is vigorously stirred for 30-35
minutes, or is shaken in a separating funnel. After separating the phases
the combined organic extracts are washed to neutral with 5% aqueous sodium
carbonate solution, and are dried over magnesium sulfate. After removing the
solvent 360 mg of a colourless oil are obtained, which are then recrystallized
from the mixture of dichloro methane and hexane, giving 301 mg ~85%) of the
title compound. The physical characteristics of the title compound are:
[~]D5 = -88.7~ (c=l.0, chloroform).
NMR (CDCL3): 7.0 to 8.0 (m, 7H, aromatic protons), 6.2 (m, 2H, aromatic protons),
4.85 (m, lH, -CH-0-), 4.5 (t, lH, -CH-0-), 1.85 to 2.7 (m, 9H).
- 14 -
. . .
~.~3~
Example 8
(-)-3,3a~,4,5,6,6a~-hexahydro-4~-hydroxymethyl-5~-(p-phenyl-
phenylcarbamoyloxy)-2H-cyclopentano[b]furane-2-on
The procedure set forth in the Example is followed till preparing
the mono-primary-silyl ether. The obtained oil is taken up in 10 ml of dry
tetrahydro furane and 223.2 g (1.2 mmoles) of p-phenyl-phenyl-isocyanate and
121 mg of triethyl amine are added subsequently. The reaction mixture is
then stirred at room temperature for 5 hours, controlling the proceedings of
the reaction by t.l.c. measurement. The obtained reaction mixture is poured
into 10 ml of 40% aqueous acetic acid solution, the container is washed out
with 2 to 3 ml of dichloro methane, and the washings being added to the
reaction mixture it is stirred vigorously for 30 to 25 minutes. The phases
are separated, the aqueous layer is extracted with four 10 ml portions of
dichloro methane and the combined organic extracts are washed to neutral with
5% aqueous sodium carbonate solution, in small portions. The residue is
dried over magnesium sulfate, the solvent is removed, 350 mg of a colourless
oil are obtained. Recrystallization from the mixture of dichloromethane
and hexane yields 295 mg of the title compound. Rf = 0.35 (ethyl acetate -
hexane, on a GF254 "Kieselgel nach Stahl" plate).
Example 9
(-)-3, 3a~,4,5,6,6a~-hexahydro-4~-trityloxymethyl-5~-hydroxy-2H-
cyclopentene[b]furane-2-on
303 mg (1.76 mmoles) of levorotatory lactone diol of the structural
formula II are dissolved in 2 ml of dry pyridine and 502 mg (1.8 mmoles) of
trityl chloride are added in one portion. The resulted orange solution is
stirred for 20 to 40 hours, and thereafter 30 ml of 1 N ice-cooled hydrochloric
acid 20 ml of ethyl acetate are added subsequently. The organic layer is
separated, subsequently washed with 5 ml of 5% sodium bicarbonate solution
,j
,~
~.
:
; . , , ~:
::
z~
and 5 ml of brine and dried over sodium sulfate. The solvent is distilled
off in vacuo on a rotatory evaporator and the obtained solid is taken up
in 6 ml of ethyl acetate. Upon the addition of 7 to 15 ml of petrol ether
a crystalline substance is obtained, whicll is identified as the title compound.
Yield: 668 mg ~91.5%). Physical characteristics: Rf = 0.71 (ethyl acetate),
Rf = 0.58 (benzene-ethyl acetate 1:1) both on a GF254 "Kieselgel nach Stahl"
plate.
Melting point: 108 to 109C.
[~]D = -14.3 10.5 ~c 1.79, methanol)
Example 10
(-)-3,3a~,4,5,6,6a~-hexahydro-4~-hydroxymethyl-5~-(p-phenyl-
benzoyloxy)-2H-cyclopentano[b~furane-2-on
414 mg (1 mmoles) of the compound of the structural formula IV,
in which R represents a trityl group, are dissolved in 6 ml of dichloro
methane and 249 mg (1.15 mmoles) of p-phenyl-benzoyl chloride in 2 ml of
dry pyridine are added dropwise to the solution. The reaction mixture is stir-
red for two hours, whereas the proceedings of the reaction is followed by
t.l.c. The reaction mixture is then poured into 10 ml of 80% aqueous acetic
acid solution, the container is washed out wi~h 2 to 3 ml of dichloro methane
and the mixture is stirred for 30 to 35 minutes at 60C. The organic and
aqueous layers are separa~ed, the aqueous phase is extracted with four 10 ml
portions of dichloro methane, and the combined organic solutions are washed
to neutral with 5% sodium carbonate solution in small portions, and dried
over magnesium sulfate. Upon removing the solvent 372 mg of a colourless
oil are obtained. Recrystallization from the mixture of dichloro methane
and hexane yields 303 mg of the title compound (87%) as a crystalline solid,
which was found to be identical with the crystals obtained in Example 7.
- 16 -
~' ' -
~3~
Example 11
~ -)-3,3a~,4,5,6,6a~-hexahydro-4~-trimethylsilyloxy-methyl-5~-
hydroxy-2H-cyclopentano[b]furane-2-on
167 mg (0.97 mmoles) of the levorotatory compound of the structural
formula II are dissolved in 5 ml of acetonitrile at room temperature, and
1 ml of 1 M solution of trimethyl-silyl-diethylamine in acetonitrile are added
with stirring. After a reaction period of 20 minutes the solvent is evaporated.
250 mg of a pale-yellow oil are obtained. Recrystallization from 1 ml of ether
with addition of 3 to 5 ml of hexane yeilds 193 mg ~81.5%) of the title com-
pound.
Melting point: 48.5 to 49.5 C [~]D = -26.9 ~c = 0.9 aceto nitrile)
R~ = 0.70 ~ethyl acetate, 0.36 ~benzene - ethyl acetate 1:1).
It should be noted that the product may be recrystallized also
from the mixture of benzene and hexane.
- 17 _
.i
