New anthracyclinones and their production

A new compound of the formula ##STR1## wherein R.sup.1 is a hydrogen atom, a hydroxyl group or an alkoxyl group of 1-4 carbon atoms and R.sup.2 is an ethyl group or acetyl group is now provided, which is an intermediate compound useful for synthesis of antitumor anthracyclines. This new anthracycline is produced by cyclization of a new compound of the formula ##STR2## wherein R.sup.1 is as defined above and TMS denotes a trimethylsilyl group, followed by decarboxylation of the cyclization product.

SUMMARY OF THE INVENTION 
This invention relates to a new anthracycline compound and also to a 
process for the production of this new compound. 
BACKGROUND OF THE INVENTION 
Anthracycline antibiotics are useful as antitumor agent and are generally 
produced by fermentation. For low cost production of anthracyclines, 
syntheses of the aglycone moiety of the anthracycline compound, 
anthracyclinone, has also been attempted (see Arcamone "Topics in 
Antibiotic Chemistry" Vol. 2, pages 99-239 (1978) and Terashima "Journal 
of Synthetic Organic Chemistry, Japan" 40, 20 (1982)). 
The present inventor has now found that when a naphthoquinone or juglone 
and a furan diene compound of the formula (III) shown later are employed 
as the starting material and condensed, the regiospecific Diels-Alder 
condensation readily proceeds, that the adduct product so obtained from 
the Diels-Alder reaction can be converted into an acetal compound by the 
reaction with L-(+)-2,3-butanediol, and that when this acetal compound is 
condensed with 1-(trimethylsilyl)-2-butanone or 
3-methyl-1-(trimethylsilyl)-3-butene-2-on, followed by cyclization of the 
resultant aldol condensation product, the anthracyclinone skelton can be 
constructed under stereochemical control. Thus, the present inventor has 
now first succeeded in achieving practical asymmetric syntheses of the new 
anthracycline compound of the formula (I) and also anthracyclinone of 
formula (A) shown below. On the basis of these new findings, this 
invention has been accomplished. 
DETAILED DESCRIPTION OF THE INVENTION 
According to a first aspect of this invention, therefore, there is 
provided, as the new compound useful as an intermediate for synthesis of 
antitumor anthracyclines, a compound represented by the general formula 
(I) 
##STR3## 
wherein R.sup.1 denotes a hydrogen atom, a hydroxyl group or an alkoxyl 
group of 1-4 carbon atoms and R.sup.2 denotes an ethyl group or an acetyl 
group. 
According to a second aspect of this invention, there is provided a process 
for the production of the compound of the general formula 
##STR4## 
wherein R.sup.1 and R.sup.2 are as defined above, which comprises the 
steps of: 
(a) cyclizing the compound of the formula 
##STR5## 
wherein R.sup.1 and R.sup.2 are as defined above and TMS denotes a 
trimethylsilyl group by treating with a base in an organic solvent to 
produce the compound of the formula 
##STR6## 
wherein R.sup.1, R.sup.2 and TMS are as defined above, and 
(bi) decarboxylating the compound of the formula (I') by treating with a 
tetra-alkyl ammonium fluoride or hydrogen fluoride in an organic solvent 
to produce the desired compound of the formula (I). 
According to a third aspect of this invention, there is provided a process 
for the production of the compound of the formula (I) 
##STR7## 
wherein R.sup.1 and R.sup.2 are as defined above, which comprises the 
consecutive steps of: 
(i) subjecting a compound of the formula (III) 
##STR8## 
wherein TMS denotes a trimethylsilyl group, and a compound of the formula 
(IV) 
##STR9## 
wherein R.sup.3 is a hydrogen atom or a hydroxyl group and X is a bromo 
group or a hydrogen atom to Diels-Alder condensation either in the 
presence of 4,4'-thiobis(6-t-butyl-3-methylphenol) as a radical scavenger 
and an acid acceptor when the group X of the compound (IV) denotes a bromo 
group, or in the presence of a catalyst when the group X of the compound 
(IV) denotes a hydrogen atom, to produce the compound of the formula (Va) 
##STR10## 
wherein R.sup.3 and TMS are as defined above, 
(ii) oxidizing the compound of the formula (Va) in the presence of a base 
to produce the compound of the formula (V) 
##STR11## 
wherein R.sup.3 and TMS are as defined above, 
(iii) optionally alkylating the group (R.sup.3) of the compound of the 
formula (V) where R.sup.3 denotes a hydroxyl group, by reacting with an 
alkyl iodide of 1-4 carbon atoms in an organic solvent to produce the 
compound of the formula (VI) 
##STR12## 
wherein R.sup.4 is an alkyl group of 1-4 carbon atoms and TMS is as 
defined above, 
(iv) ozonolyzing the compound of the formula (VIa) 
##STR13## 
wherein R.sup.1 is a hydrogen atom, a hydroxyl group or an alkoxyl group 
of 1-4 carbon atoms as defined above and TMS is as defined above [the 
compound of the formula (VIa) generically representing both the compound 
of the above formula (V) and the compound of the above formula (VI)], 
thereby to give the aldehyde compound of the formula (VIb) 
##STR14## 
wherein R.sup.1 and TMS are as defined above, 
(v) reacting the aldehyde compound of the formula (VIb) with 
L-(+)-2,3-butanediol in an inert organic solvent in the presence of an 
acid catalyst to produce an acetal compound of the formula (VII) 
##STR15## 
wherein R.sup.1 and TMS are as defined above, 
(vi) either condensing the acetal compound of the formula (VII) and 
1-(trimethylsilyl)-2-butanone of the formula (VIII) 
##STR16## 
wherein TMS is a trimethylsilyl group to produce a compound of the formula 
(II') 
##STR17## 
wherein R.sup.1 and TMS are as defined above; or condensing the acetal 
compound of the formula (VII) and 3-methyl-1-(trimethylsilyl)-3-buten-2-on 
of the formula (IX) 
##STR18## 
wherein TMS is as defined above to produce a compound of the formula (II") 
##STR19## 
wherein R.sup.1 and TMS are as defined above, followed by ozonolyzing the 
compound of the formula (II") to produce a compound of the formula (II'") 
##STR20## 
wherein R.sup.1 and TMS are as defined above, 
(vii) cyclizing a compound of the formula (II) 
##STR21## 
wherein R.sup.1 is as defined above and R.sup.2 is an ethyl group or an 
acetyl group [the compound of the formula (II) generically representing 
both the compound of the formula (II') and the compound of the formula 
(II'")] by the treatment with a base in an anhydrous organic solvent to 
produce a compound of the formula (I') 
##STR22## 
wherein R.sup.1, R.sup.2 and TMS are as defined above, and 
(viii) decarboxylating the cyclization product of the formula (I') by 
treating with a tetraalkyl ammonium fluoride or hydrogen fluoride in an 
organic solvent to produce the desired compound of the formula (I). 
The production of the new compound of the formula (I) of this invention by 
the process according to the third aspect of this invention is now 
depicted schematically by the following reaction scheme in which it is 
shown that the preparation of the compound of the formula (II) where 
R.sup.2 denotes an ethyl group and the preparation of the compound of the 
formula (II) where R.sup.2 denotes an acetyl group proceed in part through 
different routes via the different compounds of the formulae (II') and 
(II'"). 
##STR23## 
In the above reaction scheme, the substituent R.sup.3 denotes a hydrogen 
atom or a hydroxyl group, X denotes a hydrogen atom or a bromine atom, TMS 
denotes a trimethylsilyl group, R.sup.1 denotes a hydrogen atom, a 
hydroxyl group or an alkoxyl group of 1-4 carbon atoms, R.sup.4 denotes an 
alkyl group of 1-4 carbon atoms, and R.sup.2 denotes an ethyl group or an 
acetyl group in the concerned compounds. 
The new compound of the formula (I) according to this invention can be 
converted into an anthracyclinone compound of the formula (A) 
##STR24## 
wherein R.sup.1 and R.sup.2 are as defined above, when it is treated with 
an acid, especially trifluoroacetic acid. 
The process of this invention is now described in detail with reference to 
each stage shown in the above reaction scheme. 
Stage A: In this stage, principally, the compound (III) is condensed with 
the naphthoquinone compound (IV) (corresponding to the step (i) of the 
third aspect process of this invention). The reaction conditions employed 
for this Diels-Alder reaction are depending on the nature of ths 
substituent X of the compound (IV) used as the starting material. Thus, 
when X is a bromo group in the compound (IV), the condensation of the 
compound (III) and the compound (IV) may be carried out under thermal 
conditions by heating at a refluxing temperature of the solvent employed. 
An inert organic solvent such as aromatic hydrocarbons, for example, 
benzene, toluene, xylene may suitably by employed in this reaction. The 
reaction is effected in the presence of an acid acceptor such as strontium 
carbonate for the purpose of preventing degradation of the reactants and 
in the presence of 4,4'-thiobis(6-t-butyl-3-methylphenol) as radical 
scavenger for causing the reaction to proceed smoothly. When X is a 
hydrogen atom in the compound (IV), the reaction can be carried out not 
only under thermal condition by heating as described above but also can be 
effected under the radical cation condition. This reaction under the 
radical cation conditions may be carried out in an inert organic solvent 
at a reaction temperature of -20.degree. C. to 0.degree. C. In order to 
promote the radical cation reaction, it is desirable that the reaction is 
effected in the presence of a catalyst such as 
tris(p-bromophenyl)ammoniumyl hexachloroantimonate [(p-BrC.sub.6 
H.sub.4).sub.3 N.sup.+ SbCl.sub.6.sup.- ]. 
By the Diels-Alder reaction, there is produced the compound of the formula 
##STR25## 
wherein R.sup.1 and TMS are as defined above. This compound may be 
employed in a next reaction step without purification. 
After the end of the Diels-Alder condensation, the crude product so 
obtained containing the compound (Va) is then oxidized with air or oxygen 
gas in a second step (corresponding to the step (ii) of the third aspect 
process of this invention) in such a manner that the compound (Va) in 
solution in an inert organic solvent such as chloroform is treated with 
air or oxygen gas in the presence of a base, for example, an alkylamine, 
preferably di-isopropylethylamine. In this way, there is produced the 
compound of the formula (V) shown in the reaction scheme. 
Stage A-1: In this stage, the alkylation is effected to convert the 
compound (V) where the substituent R.sup.3 is a hydroxyl group, into the 
compound (VI) where the hydroxyl group has been replaced by an alkoxyl 
group. The alkylation can be effected in by usual method in an organic 
solvent such as chloroform and dichloromethane using an alkyl iodide as 
the alkylating reagent and preferably in the presence of silver oxide as 
an acid acceptor (corresponding to the optional step (iii) of the third 
aspect process of this invention). 
Stage B: In this stage, the compound (V) or the compound (VI) [generically 
represented by the compound of the formula (VIa) mentioned before in 
respect of the third aspect process of this invention] is firstly 
ozonolyzed (corresponding to the step (iv) of the third aspect process of 
this invention) to produce an aldehyde compound of the formula 
##STR26## 
wherein R.sup.1 and TMS are as defined above. The ozonolysis of the 
compound (V) can be carried out by passage of ozone gas through a solution 
of the compound (V) in an organic solvent such as halogenated 
hydrocarbons, preferably methylene chloride, chloroform, carbon 
tetrachloride and the like at a low temperature, preferably in the 
vicinity of -78.degree. C. After the ozonolysis was completed, the 
reaction mixture can be treated in an usual manner, for example, by 
purging with nitrogen, so that the excess of ozone can be removed from the 
reaction mixture. The aldehyde product so obtained can be utilized as such 
in a next step without purification. 
In the next step, the aldehyde compound (VIb) is reacted with 
L-(+)-2,3-butanediol to produce the acetal compound (VII) (corresponding 
to the step (v) of the third aspect process of this invention). 
The reaction of the aldehyde compound (VIb) with the butanediol can be 
carried out by refluxing a mixture of the aldehyde compound and the 
butanediol in an inert organic solvent such as dry toluene under stream of 
an unreactive gas such as nitrogen gas, argon gas and the like. The 
reaction may suitably be effected in the presence of an acid catalyst such 
as pyridinium p-toluenesulfonate and the like. The acetal compound (VII) 
so obtained can be isolated from the reaction mixture by chromatography 
and then purified by recrystallization from methanol. The acetal compound 
(VII) is usually obtained as yellow-colored needles. 
In a further step, the acetal compound (VII) is condensed with a 
(trimethylsilyl)methylketone compound of the formula (VIII) or (IX). This 
aldol condensation step is necessary to be effected using different 
procedures and different reaction conditions, dependently upon the nature 
of the substituent R.sup.2 which is to be provided in the final compound 
(I) of this invention, as described below in more details. 
Stage C-1: When the substituent R.sup.2 of the final product (I) of this 
invention is to be ethyl, the aldol condensation step of reacting the 
acetal compound (VII) with 1-(trimethylsilyl)-2-butanone [(CH.sub.3).sub.3 
Si--CH.sub.2 --CO--CH.sub.2 CH.sub.3 ], that is, the compound (VIII) is 
effected as said further step (corresponding to a first alternative 
procedure of the step (vi) of the third aspect process of this invention) 
to produce the compound (II'). This reaction can be carried out in an 
anhydrous organic solvent such as dry acetonitrile, tetrahydrofuran (THF) 
and the like at a low temperature from -20.degree. C. to -13.degree. C. 
and in the presence of a Lewis acid such as tin tetrachloride as catalyst. 
The reaction may suitably be carried out under stream of an unreactive gas 
such as argon in order to prevent degradation of the reactants. 
In this aldol condensation reaction, there is byformed, in addition to the 
desired compound (II'), some quantity of its stereo isomer of the formula 
##STR27## 
wherein R.sup.1 and TMS are as defined above. For isolation and 
purification of the desired compound (II'), therefore, the aldol 
condensation products may be chromatographed on silica gel developed with 
chloroform-ethyl acetate as eluent, followed by recrystallization from 
hexane, affording the compound (II') as desired. 
Stage C-2: When the substituent R.sup.2 of the final product (I) is to be 
acetyl, the aldol condensation step of reacting the acetal compound (VII) 
with 3-methyl-1-(trimethylsilyl)-3-buten-2-on, that is, the compound (IX) 
is effected as said further step (corresponding to a second alternative 
procedure of the step (vi) of the third aspect process of this invention) 
to produce the compound (II"). This reaction can be carried out in an 
organic solvent such as toluene, acetonitrile, THF and the like at a low 
temperature, preferably in the vicinity of -78.degree. C. and generally at 
a temperature of -30.degree. C. to -80.degree. C. and in the presence of a 
Lewis acid such as boron trifluoride and the like as catalyst. 
This aldol condensation reaction gives the compound of the formula 
##STR28## 
wherein R.sup.1 and TMS are as defined above, together with its stereo 
isomer of the formula. 
##STR29## 
wherein R.sup.1 and TMS are as defined above. The resulting aldol 
condensation products comprising the compound (II") and its stereo isomer 
in mixture may be used as such in the next, ozonolysis step without 
separation of the compound (II") from its isomer. 
The above-mentioned aldol condensation step for producing the compound 
(II") is followed by a step of ozonolyzing this compound in an organic 
solvent such as methanol, dichloromethane and the like at a low 
temperature, preferably of -78.degree. C. so that the compound of the 
formula (II'") shown in the reaction scheme is formed. For this purpose, 
ozone gas may conveniently by passed into a solution of the compound (II") 
in an appropriate solvent. The reaction solution is then treated in an 
usual manner, for example, by purging with nitrogen gas, so that the 
excess of ozone is removed therefrom. The reaction solution is then 
evaporated in vacuo to give the residue containing the compound (II'") 
which may then be isolated and purified by chromatography on silica gel 
developed with benzene-ethyl acetate as eluent, affording the compound 
(II'"), usually as a yellow syrup. 
The compounds of the formula (II') and the compound of the formula (II'") 
obtained as above are new compounds which are not described in any printed 
publications. 
Stage D: In this stage, the compound (II') or the compound (II'") produced 
as above (generically represented by the compound (II) shown hereinbefore 
in respect of the second or third aspect process of this invention) is 
cyclized (corresponding to the step (a) of the second aspect process or to 
the step (vii) of the third aspect process of this invention). For this 
purpose, the cyclization reaction may be carried out by treating the 
compound (II) with a base such as DBN (namely, 
1,5-diazabicyclo-[4.3.0]nonene-5) or DBU (namely, 
[1.8]diazabicyclo-[5.4.0]undec-7-ene) in an anhydrous organic solvent such 
as dry THF at ambient temperature. This reaction may desirably be effected 
under stream of nitrogen gas in order to prevent degradation of the 
cyclization product. By this cyclization, there is formed the compound of 
the formula (I") shown in the reaction scheme. 
In this cyclization step, there is by-formed, in addition of the compound 
(I"), its stereo isomer of the formula 
##STR30## 
wherein R.sup.1 and TMS are as defined above,. The compound (I") may be 
isolated from its stereo isomer (I'") by chromatography on silica gel 
developed with benzeneethyl acetate (5:2), if necessary. If desired, 
however, the products from this cyclization step may be used as such in 
the next, decarboxylation step without separation of the compound (I") 
from the compound (I'"). 
Stage E: In this stage, the compound (I') [including the compounds (I") and 
(I'")] produced as above is decarboxylated to remove the 
(trimethylsilyl)ethoxycarbonyl group (--CO.sub.2 CH.sub.2 CH.sub.2 TMS) 
(corresponding to the step (b) of the second aspect process or to the step 
(viii) of the third aspect process of this invention). This 
decarboxylation reaction may be carried out by treating the compound (I') 
with a solution of a tetra-alkyl ammonium fluoride, especially 
tetra-n-butyl ammonium fluoride or hydrogen fluoride in an inert organic 
solvent such as dry THF or DMF at ambient temperature or a low 
temperature. This reaction may suitably be carried out under stream of 
nitrogen gas in order to prevent degradation of the decarboxylated 
product. By this reaction, there is produced the desired compound of the 
formula (I) shown in the reaction scheme. 
The new compound (I) produced as above according to this invention can be 
converted into an anthracyclinone compound of the formula (A) shown 
hereinbefore when it is treated with an acid such as trifluoroacetic acid 
at a low temperature (see Examples 17-22 given later). When certain sugar 
moiety is condensed with the 7-position of the anthracyclinone compound 
(A) by a known method, the product obtained is potentially useful 
antibiotics having antitumor activity such as daunomycins. 
In the process depicted in the foregoing reaction scheme, a naphthoquinone 
or juglone compound such as the compound (IV) is condensed with the diene 
compound (III) under the Diels-Alder reaction conditions (in Stage A of 
the reaction scheme), when the condensation reaction proceeds 
regiospecifically so that the diene compound (III) is combined in the 
resultant condensation product in such direction as observed with the 
compound (V). Further, when the aldehyde compound (VIb) is reacted with 
L-(+)-2,3-butanediol (in Stage B of the reaction scheme), there is formed 
the acetal compound of the formula (VII). Furthermore, when this acetal 
compound (VII) is reacted with a silylketone (VIII) or (IX) such as ethyl 
(trimethylsilyl) methyl ketone (in Stage C-1 or C-2 of the reaction 
scheme), the aldol condensation takes place under a high stereochemical 
control to afford the compound having the desired chirarity as shown by 
the formula (II') or (II"). These facts are now firstly discovered by the 
present inventor. These new reactions are associated in an ingenious way 
to provide the new processes of this invention which achieved first 
practical asymmetric syntheses of anthracyclinones in a high optical 
purity. 
The process of this invention is now illustrated with reference to Examples 
1-4; Examples 5-6; Examples 7-8; Examples 9-10; Examples 11-14 and 
Examples 15-16.

EXAMPLE 1 
Synthesis of 
4-[2'-(trimethylsilyl)ethoxycarbonylmethyl]-8-hydroxy-anthraquinofuran 
The titled compound having formula (V') given below was synthesized through 
the following route which corresponds to Stage A of the reaction scheme 
hereinbefore shown. 
##STR31## 
(a) Bromojuglone compound (IV') (3.48 g, 13.8 mmol), the furan diene 
compound (III), i.e. 2-(trimethylsilyl)-ethyl ester of 3-furyl-vinylacetic 
acid (9.24 g; approx. 2 molar equivalents), strontium carbonate (4.47 g, 
30.27 mmol) and 4,4'-thiobis(6-t-butyl-3-methylphenol) (10 mg) as radical 
scavenger were added to benzene (350 ml), and the mixture was refluxed 
under azeotropic distillation for 23 hours to effect Diels-Alder 
condensation (corresponding to the step (i) of the third aspect process of 
this invention). 
The reaction solution was passed through a Celite bed to remove the 
precipitated inorganic salts. The Celite bed was then washed with 
methylene chloride. The reaction solution was combined with the methylene 
chloride washings and then concentrated in vacuo to leave a red-black 
residue. The residue was purified by silica gel column chromatography with 
elution first with benzene to elute the starting compound and then with 
benzene-ethyl acetate (95:5) to elute the product, i.e. compound (Va-1), 
which was separated as a red solid (44.1 g; 76%). This was used for the 
next step without purification. 
(b) The crude dihydrobenzofuran compound (Va-1) so obtained (4.22 g, 10 
mmol) and diisopropylethylamine (3.47 ml, 20 mmol) were added to 
chloroform (347 ml), and the mixture was stirred at room temperature for 
17 hours to effect air-oxidation (corresponding to the step (ii) of the 
third aspect process of this invention) and then concentrated in vacuo to 
leave yellow-black residue. The residue was dissolved in chloroform and 
the solution was chromatographed in silica gel column (silica gel G: 300 
ml) with elution first with chloroform and then with benzene-ethyl acetate 
(3:2) to yield the crude product as yellow-brown solid (3.59 g; 85.5%). 
This was purified by recrystallization from a mixture of methylene 
chloride and methanol to afford the pure, titled benzofuran compound (V') 
as yellow-brown plates with m.p. 168.degree.-169.degree. C. 
EXAMPLE 2 
Synthesis of 
(1'S,2'S)-2-[carbo-(2-trimethylsilyl)ethoxymethyl]-3-[1',2'-dimethyl-ethyl 
enedioxymethyl]-4,5-dihydroxyanthraquinone 
The titled compound (VII') was synthesized through the following route 
which corresponds to Stage B of the reaction scheme. 
##STR32## 
(a) Compound (V') (420 mg, 1 mmol) obtained in Example 1 above was 
dissolved in anhydrous methylene chloride (200 ml) and the solution was 
cooled to -78.degree. C. Into the solution were introduced first ozone for 
10 minute to effect ozonolysis (corresponding to the step (iv) of the 
third aspect process of this invention), and then nitrogen gas at 
-78.degree. C. for 40 minutes and dimethyl sulfide (20 ml) was added to 
remove the excess ozone. The mixture was warmed to room temperature, the 
reaction solution was stirred at room temperature for further 1 hour and 
then concentrated in vacuo to yield the aldehyde compound (VIb-1) as 
yellow-brown crystals. This was used for the next step without 
purification. 
(b) The crude aldehyde compound (VIb-1) thus obtained and 
L-(+)-2,3-butandiol (225 mg, 2.5 mmol; 0.5 molar equivalents) were added 
to dry toluene (40 ml), and the mixture was refluxed for 4 hours under 
nitrogen gas in the presence of a catalytic amount of pyridinium 
p-toluenesulfonate (75 mg, 0.3 mmol; 0.3 molar equivalents) to conduct the 
condensation reaction (corresponding to the step (v) of the third aspect 
process of this invention). The reaction solution was concentrated in 
vacuo and the resulting residue was purified by preparative silica gel 
thin layer chroamtography with elution with benzene-ethyl acetate (10:1) 
to yield the titled compound (VII') (423 mg; 85% from compound V') as 
yellow crystals. This was purified by recrystallization from methanol to 
yield pure acetal compound (VII') as yellow needles, m.p. 
118.degree.-119.degree. C. 
EXAMPLE 3 
Synthesis of 
(1'R,1"S,2"S)-2-[carbo(2-trimethylsilyl)ethoxy]methyl-3-[1'-(2"-hydroxy-1" 
-methyl)propyloxy-3'-oxo]pentyl-4,5-dihydroxyanthraquinone 
The titled compound (IIa) was synthesized by the following step which 
corresponds to Stage C-1 of the reaction scheme. 
##STR33## 
Compound (VII') (49.8 mg, 0.1 mmol) obtained in Example 2 above and 
ethyl-(trimethylsilyl)methylketone (VIII) [i.e. 
1-(trimethylsilyl)-2-butanone] (288 mg, 2 mmol; 20 molar equivalents) were 
dissolved in anhydrous acetonitrile (15 ml), and to the solution was added 
at -20.degree. C. a solution of stannic chloride (SnCl.sub.4) (108 mg, 0.3 
mmol, 3 molar equivalents, freshly distilled) in anhydrous methylene 
chloride (0.5 ml) dropwise over 15 minutes. The reaction mixture was 
further stirred at a temperature of -20.degree. C.--13.degree. C. for 1.5 
hours to conduct the aldol condensation (corresponding to a first 
alternative procedure of the step (vi) of the third aspect process of this 
invention). Then, saturated aqueous sodium carbonate (3.5 ml) was added to 
the reaction mixture at -20.degree. C. The reaction mixture was warmed to 
room temperature and was extracted with methylene chloride. The combined 
organic extract was dried over anhydrous sodium sulfate and concentrated 
in vacuo. The oily residue was purified by preparative silica gel thin 
layer chromatography with elution with chloroform-ethyl acetate (20:1) to 
yield compound (IIa) (49.6 mg; 87%) and compound (IIb) (2.81 mg; 5.0%). 
Compound (IIa) was purified by recrystallization from hexane as yellow fine 
plates, m.p. 81.degree.-83.degree. C. 
EXAMPLE 4 
Synthesis of (8S, 
trans)-8-ethyl-10-[2'(S)-hydroxy-1'(S)-methylpropyloxy]-7,8,9,10-tetrahydr 
o-1,8,11-trihydroxy-5,12-naphthacenedione 
(a) Keto-ester compound (1) (40.05 mg, 0.07 mmol) which has the formula: 
##STR34## 
wherein TMS is trimethylsilyl group (which was prepared in Example 3 and 
mentioned as compound IIa) was dissolved in anhydrous tetrahydrofuran (12 
ml), and to the solution was added 1,5-diazabicyclo[4,3,0]nonene-5 (DNB) 
(26.8 mg, 0.211 mmol; 5 molar equivalents) in one portion at room 
temperature under nitrogen gas. The mixture was stirred for 6 hours to 
conduct the cyclization reaction (corresponding to Stage D of the flow 
sheet and also to the step (vii) of the third aspect process of this 
invention), after which 1N hydrochloric acid (0.35 ml) and ethylether (70 
ml) were added successively. The ether extract was washed with saturated 
aqueous sodium chloride, dried over anhydrous sodium sulfate and 
concentrated in vacuo to yield an oily residue. The residue was purified 
by preparative this layer chromatography on silica gel with elution with 
benzene-ethyl acetate (5:2 by volume) to afford compound (2) (29.28 mg; 
73%) together with compound (3) (4.76 mg; 11.9%) with m.p. 
187.degree.-189.degree. C. 
##STR35## 
Compound (2) was purified by recrystallization from methanol, as orange 
plates, m.p. 117.degree.-118.degree. C.; [.alpha.].sub.D -230.degree. (c 
0.053, chloroform-methanol (1:I)). 
(b) To a solution of compound (2) (28.05 mg, 0.05 mmol) in anhydrous 
tetrahydrofuran (3 ml) was added dropwise 1M solution of 
tetra-n-butylammonium fluoride in tetrahydrofuran (400 .mu.l, 0.4 mmol) at 
room temperature under nitrogen gas, and the mixture was stirred for 6 
hours to effect the decarboxylation reaction (corresponding to Stage E of 
the flow sheet and also to the step (viii) of the third aspect process of 
this invention). The reaction solution, after the addition of 1N 
hydrochloric acid (400 .mu.l), was diluted with methylene chloride and 
dried by passage through a short cotton column. The dried solution was 
concentrated in vacuo and the residue was purified by preparation silica 
gel-thin layer chromatography with elution with benzene-ethyl acetate 
(5:2) to afford the titled compound (4) (15.69 mg; 75%). 
##STR36## 
Compound (4) was purified by recrystallization from hexane-benzene to give 
yellow crystals with m.p. 139.degree.-141.degree. C. and [.alpha.].sub.D 
-113.degree. (c 0.053, chloroform-methanol (1:1)). 
Compound (4) was also obtained from the minor compound (3) in comparable 
yield. For preparative purposes, it was possible to carry out the 
transformation of compound (1) to compound (4) without isolation and 
separation of the compounds (2) and (3) in about 65-70% overall yield. 
EXAMPLE 5 
Synthesis of (1'R,1"S,2"S)-2-[carbo(2-trimethylsilyl) 
ethoxymethyl]-3-[1'-(2"-hydroxy-1"-methyl)propyl-3',4'-dioxopentyl]-4,5-di 
hydroanthraquinone 
The titled compound of formula (IIf) was synthesized through the following 
route which corresponds to Stage C-2 of the reaction scheme. 
##STR37## 
(a) Acetal compound (VII') (99.6 mg, 0.2 mmol) obtained in Example 2 above 
and 2-propenyl-(trimethylsilyl)-methylketone (IX) [namely, 
3-methyl-1-(trimethylsilyl)-3-buten-2-on] (368 .mu.l, 4 mmol; 20 molar 
equivalents) were dissolved in dry toluene (40 ml), and the solution was 
cooled to -78.degree. C., followed by dropwise addition of saturated 
solution of boron trifluoride in dry toluene (32 ml) (prepared at 
-78.degree. C.) over 2 hours, during which there occurred the aldol 
condensation reaction (corresponding to a second alterative procedure of 
the step (vi) of the third aspect process of this invention). To the 
resulting deep red solution was added saturated aqueous sodium hydrogen 
carbonate (14 ml) at -78.degree. C. and the reaction mixture was warmed to 
room temperature. The reaction mixture was extracted with methylene 
chloride, and the extract was dried over anhydrous sodium sulfate and 
concentrated in vacuo. The brown oily residue was purified by preparative 
silica gel thin layer chromatography with elution with benzene-ethyl 
acetate (10:1) to give a yellow oily mixture of compound (IId) and 
compound (IIe) (95.92 mg; 82.4%). 
The oily mixture (95.92 mg; 0.165 mmol) was dissolved in methanol (96 ml) 
and the solution was cooled to -78.degree. C., and ozone was introduced 
into the solution at -78.degree. C. over 5 minutes (corresponding to the 
oxidation step in the second alternative procedure of the step (vi) of the 
third aspect process of this invention), and then nitrogen gas was bubbled 
thereinto at -78.degree. C. over 40 minutes to remove the excess ozone. 
Then, dimethyl sulfide (1.65 ml) was added to the reaction mixture at 
-78.degree. C. and the reaction mixture was warmed to room temperature and 
stirred for further 1 hour. The solvent was distilled off in vacuo to 
leave a brown oily residue. This was purified by preparative silica gel 
thin layer chromatography with elution with benzene-ethyl acetate (10:1) 
to yield the tilted compound (IIf) (72.35 mg; 75.2%) and compound (IIg) 
(5.71 mg; 6%) as yellow oil. 
EXAMPLE 6 
Synthesis of 
(8S-trans)-8-acetyl-10-[2'(S)-hydroxy-1"(S)-methylpropyloxy]-7,8,9,10-tetr 
ahydro-1,8,11-trihydroxy-5,12-naphthacenedione 
(a) .alpha.-Diketone compound (5) (72.4 mg, 0.12 mmol) of the formula: 
##STR38## 
wherein TMS is trimethylsilyl and Me is methyl (which was prepared in 
Example 5 and mentioned as compound IIf) was dissolved in anhydrous 
tetrahydrofuran (12.4 ml), and DBN (76.9 mg, 0.62 mmol; 5 molar 
equivalents) was added in one portion to the solution at room temperature. 
The resulting violet solution was stirred for 10 minutes to effect the 
cyclization reaction (the step (vii) of the third aspect process of this 
invention), after which 1N hydrochloric acid (0.62 ml) was added and the 
reaction mixture was diluted with methylene chloride. The reaction mixture 
was dried by passing through a cotton column. After the solvent was 
distilled off, the residual yellow solid was purified by preparative 
silica gel thin layer chromatography with elution with chloroform-ethyl 
acetate (20:1) to yield yellow solid compound (6) (44.2 mg; 61%) and 
compound (7) (17.4 mg; 24%) of the formulae: 
##STR39## 
Compound (6) was recrystallized from a mixture of benzene and hexane to 
give yellow plates, m.p. 108.degree.-109.degree. C. and [.alpha.].sub.D 
-26.degree. (c 0.10, chloroform-methanol (1:1)). 
Compound (7) was recrystallized similarly from a mixture of benzene and 
hexane to give yellow-orange powder, m.p. 167.degree.-170.degree. C. 
(b) Cyclic ketone compound (6) prepared in step (a) (71.4 mg, 0.122 mmol) 
was dissolved in dry N,N-dimethylformamide (8 ml), and to the solution was 
added a 1M solution of tetra-n-butyl ammonium fluoride (n-Bu.sub.4 NF) in 
tetrahydrofuran (0.98 ml, 0.98 mmol; 8 molar equivalents) dropwise over 5 
minutes at room temperature. The violet-colored mixture was stirred for 6 
hours to effect the decarboxylation reaction (the step (viii) of the third 
step process of this invention), after which 1N hydrochloric acid (0.98 
ml) was added and the reaction mixture was diluted with methylene 
chloride. The reaction was dried by passing through a cotton column. The 
dried solution was concentrated in vacuo and the residual yellow solid was 
purified by preparative silica gel-thin layer chromatography eluting with 
benzene-ethyl acetate (1:1) to afford compound (8) (42.6 mg; 78.8%) as 
yellow crystals. 
##STR40## 
Compound (8) was recrystallized from a mixture of benzene and hexane to 
give the pure 11-deoxy compound as yellow powder with m.p. 
138.degree.-140.degree. C. and [.alpha.].sub.D -49.degree. (c 0.10, 
chloroform-methanol (1:1)). 
Compound (8) was also prepared from compound (7) [a stereoisomer of 
compound (6)] in the same manner as above in a yield of 61%. Compound (8) 
was obtained from compound (5) in overall yield of 65% without isolation 
and separation of the intermediate compounds. 
EXAMPLE 7 
(a) Synthesis of 
4-[carbo(2'-trimethylsilyl)ethoxymethyl]-8-methoxyanthraquinofuran (VI') 
Compound (VI') was synthesized by the following step which corresponds to 
Stage A-1 of the reaction scheme. 
##STR41## 
The benzofuran compound (V') (1.05 g, 2.5 mmol) obtained in Example 1 
above, silver oxide (Ag.sub.2 O) (8.69 g, 37.5 mmol; 15 molar equivalents) 
and methyl iodide (35.5 g, 0.25 mol; 100 molar equivalents) were admixed 
with chloroform (250 ml), and the mixture was heated to 50.degree. C. 
under nitrogen gas with stirring for 64 hours to conduct the methylation 
reaction (corresponding to optional alkylation step (iii) of the third 
aspect process of this invention). 
The reaction solution was passed through a Celite bed to remove the 
precipitated inorganic materials. The Celite bed and the inorganic 
precipitate were washed with methylene chloride. The reaction solution 
having passed through the Celite bed was combined with the methylene 
chloride washings, and the combined solution was concentrated in vacuo. 
The residue was purified by preparative thin layer chromatography with 
elution with benzene-ethyl acetate (5:2) to yield the titled compound 
(VI') (990 mg; 91.3%) as yellow solid. This was purified by 
recrystallization from methanol to yield compound (VI') as yellow powder, 
m.p. 124.degree.-124.5.degree. C. 
(b) Synthesis of 
(1'S,2'S)-2-[carbo-(trimethylsilyl)ethoxymethyl]-3-[1',2'-dimethylethylene 
dioxymethyl]-4-hydroxy-5-methoxyanthraquinone (VII') 
##STR42## 
Compound (VI') obtained in step (a) above was treated in the same manner as 
in Example 2 to yield the titled compound (VII"). 
(c) Synthesis of 
(1'R,1"S,2"S)-2-[carbo(2-trimethylsilyl)ethoxymethyl]-3-[1'-(2"-hydroxy-1" 
-methyl)propyloxy-3'-oxopentyl]-4-hydroxy-5-methoxyanthraquinone (IIh) 
##STR43## 
Compound (VII") obtained in step (b) above was treated in the same manner 
as in Example 3 to yield the titled compound (IIh). 
EXAMPLE 8 
Synthesis of 
(8S,trans)-8-ethyl-10-[2'(S)-hydroxy-1'(S)-methylpropyloxy]-7,8,9,10-tetra 
hydro-8,11-dihydroxy-1-methoxy-5,12-naphthacenedione 
##STR44## 
Keto-ester compound (9) (which was prepared in Example 7 and mentioned as 
compound IIh) was treated in the same manner as in Example 4 (a) and (b) 
to yield the titled compound (10) in a yield comparable to that in Example 
4. 
pmr (80 MHz): .delta.1.0-2.0 (m, 8-CH.sub.2, CH.sub.3 and 1'-CH.sub.3, 
2'-CH.sub.3), 4.27 (s, 3H, OCH.sub.3), 5.48 (t, 1H, 10-H); 7.5-8.1 (m, 4H, 
2-H, 3-H, 4-H and 6-H). 
EXAMPLE 9 
Synthesis of 
(1'R,1"S,2"S)-2-[carbo(2-trimethylsilyl)ethoxymethyl]-3-[1'-(2"-hydroxy-1" 
-methyl)propyloxy-3',4'-dioxopentyl]-4-hydroxy-5-methoxyanthraquinone (IIi) 
##STR45## 
Compound (VII') obtained in step (b) of Example 7 was treated in the same 
manner as in Example 5 to yield the titled compound (IIi). 
EXAMPLE 10 
Synthesis of 
(8S,trans)-8-acetyl-10-[2'(S)-hydroxy-1'(S)-methylpropyloxy]-7,8,9,10-tetr 
ahydro-8,11-dihydroxy-5,12-naphthacenedione 
##STR46## 
Keto-ester compound (11) (which was prepared in Example 9 and mentioned as 
compound IIi) was treated in the same manner as in Example 6 (a) and (b) 
to afford the titled compound (12) in a yield comparable to that in 
Example 6. 
pmr (80 MHz): .delta.0.75-1.25 (m, 1'-CH.sub.3 and 2'-CH.sub.3), 2.35 (s, 
3H, 14-CH.sub.3), 4.17 (s, 3H, OCH.sub.3), 5.40 (t, 1H, 10-H), 7.3-7.8 (m, 
4H, 2-H, 3-H, 4-H and 6-H). 
EXAMPLE 11 
Synthesis of 4-[2'-(trimethylsilyl)ethoxycarbonylmethyl]anthraquinofuran 
(V") 
Compound (V") was synthesized through the following route which corresponds 
to Stage A of the reaction scheme. 
##STR47## 
(a) Naphthoquinone of formula (IV") (316 mg, 2.02 mmol) and a furandiene 
compound of formula (III) (0.83 g, 50 mmol) were dissolved in toluene (10 
ml), and the solution was cooled to -20.degree. C., followed by addition 
of tris(D-bromophenyl)ammoniumyl hexachloroantimonate[(p-BrC.sub.6 
H.sub.4).sub.3 NSbCl.sub.6 ] (82 mg, 0.01 mmol) in one portion with 
stirring under nitrogen. The mixture was stirred at -20.degree. C. for 10 
minutes and then warmed to 0.degree. C. After stirring for 15 minutes, an 
additional amount (0.16 g, 10 mmol) of the furandiene compound (III) was 
added to the mixture at 0.degree. C. and the stirring was continued for 
further 15 minutes at 0.degree. C. and then at room temperature for 
further 15 minutes to complete the desired Diels-Alder reaction 
(corresponding to the step (i) of the third aspect process of this 
invention). The reaction mixture was filtered through a pad of Celite and 
the Celite pad was washed with ether. The filtrate was combined with the 
ether washings, and the combined solution was concentrated in vacuo to 
afford a crude product. This was purified by silica gel column 
chromatography with elution with 5% ethyl acetate-benzene, affording 
compound (Va-2) as an orange solid (497 mg; 76%). 
(b) The adduct compound (Va-2) (497 mg, 1.53 mmol) was dissolved in 
chloroform (50 ml) and diisopropylethylamine (0.50 ml, 2.9 mmol) was added 
to the solution. The reaction mixture was stirred under air atmosphere at 
room temperature for 16 hours for oxidation (corresponding to the step 
(ii) of the third aspect process of this invention) and concentrated in 
vacuo. The crude product recovered as residue was purified by silica gel 
column chromatography with elution with 10% ethyl acetate-benzene, 
affording 425 mg of compound (V") (425 mg; 86%). 
EXAMPLE 12 
Synthesis of 
(1'S,2'S)-2-[carbo(2-trimethylsilyl)ethoxymethyl]-3-[1',2'-dimethylethylen 
edioxymethyl]-4-hydroxyanthraquinone (VII"') 
Compound (VII"') was synthesized by the following step which corresponds to 
Stage B of the reaction scheme. 
##STR48## 
Compound (V") obtained in step (b) of Example 11 was treated in the same 
manner as in Example 2 to yield the titled compound (VII"'). 
EXAMPLE 13 
Synthesis of 
(1'R,1"S,2"S)-2-[carbo(2-trimethylsilyl)ethoxymethyl]-3-[1'-(2"-hydroxy-1" 
-methyl)propyloxy-3'-oxopentyl]-4-hydroxyanthraquinone (IIj) 
Compound (IIj) was synthesized by the following step which corresponds to 
Stage C-1 of the reaction scheme. 
##STR49## 
Compound (VII"') obtained in Example 12 above was treated in the same 
manner as in Example 3 to yield the titled compound (IIj). 
EXAMPLE 14 
Synthesis of 
(8S,trans)-8-ethyl-10-[(2'(S)-hydroxy-1'(S)-methyl)-propyloxy]-7,8,9,10-te 
trahydro-8,11-dihydroxy-5,12-naphthacenedione 
##STR50## 
Keto-ester compound (13) (which was prepared in Example 13 and mentioned as 
compound IIj) was treated in the same manner as in Example 4 (a) and (b) 
to yield the titled compound (14) in a yield comparable to that in Example 
4. 
pmr (80 MHz): .delta., 1.04-1.23 (m, 6H, 8--CH.sub.2 CH.sub.3 and 
1'-CH.sub.3, 2'-CH.sub.3), 3.46 (t, 1H, 10-H), 7.54 (s, 1H, 6-H), 7.6-8.3 
(m, 4H, 1-H, 2-H, 3-H and 4-H). 
EXAMPLE 15 
Synthesis of 
(1'R,1"S,2"S)-2-[carbo(2-trimethylsilyl)ethoxymethyl]-3-[1'-(2"-hydroxy-1" 
-methyl)propyloxy-3',4'-dioxopentyl]-4-hydroxyanthraquinone (IIk) 
##STR51## 
Acetal compound (VII"') obtained in Example 12 was treated in the same 
manner as in Example 5 to afford the titled compound (IIk). 
EXAMPLE 16 
Synthesis of 
(8S,trans)-8-acetyl-10-[2'(S)-hydroxy-1'(S)-methylpropyloxy]-7,8,9,10-tetr 
ahydro-8,11-dihydroxy-5,12-naphthacenedione 
##STR52## 
Keto-ester compound (15) (which was prepared in Example 15 and mentioned as 
compound IIk) was treated in the same manner as in Example 6 (a) and (b) 
to yield compound (16) in a yield similar to that in Example 6. 
pmr (80 MHz): .delta., 1.10 and 1.20 (both d, 3H, 1'-CH.sub.3 and 
2'-CH.sub.3), 2.38 (s, 3H, 14-CH.sub.3), 3.46 (t, 1H, 10-H), 7.65 (s, 1H, 
6-H), 7.7-8.3 (m, 4H, 1-H, 2-H, 3-H and 4-H). 
The following Examples 17-22 illustrates that the compounds obtained by the 
process of this invention may be converted into daunomycinone derivatives. 
EXAMPLE 17 
Synthesis of 4-demethyl-11-deoxy-13-deoxo-daunomycinone (A-1) 
##STR53## 
To compound (4) (38.4 mg, 0.090 mmol) obtained in step (b) of Example 4 was 
added trifluoroacetic acid (3 ml) dropwise over 2 minutes with cooling to 
-78.degree. C. under argon gas. The cooling bath was warmed to 10.degree. 
C. over 3 hours and the mixture was stirred for further 1.7 hours and then 
concentrated in vacuo. The residue was dissolved in acetone (7 ml) and a 
5% aqueous sodium hydrogen carbonate (3 ml) (freshly prepared) was added 
thereto. The mixture was stirred for 1 hour, diluted with water (16 ml) 
and then extracted with dichloromethane three times. The organic layers so 
separated were combined, dried over anhydrous sodium sulfate and 
concentrated in vacuo to leave a crude product. 
The crude product was purified by preparative thin layer chromatography 
with twice elution with 12% ethyl acetate-benzene to afford the desired 
product in a pure state (27.0 mg; 8.5%). This was further purified by 
recrystallization from hot benzene to yield compound (A-1) as red crystals 
with m.p. 189.degree.-191.degree. C. and [.alpha.].sub.D +148.degree. (c 
0.10, chloroform-methanol (1:1)). 
EXAMPLE 18 
Synthesis of 4-demethyl-11-deoxy-daunomycinone (A-2) 
##STR54## 
Compound (8) obtained in step (b) of Example 6 was treated with 
trifluoroacetic acid in the same manner as in Example 17 above to afford 
the titled compound (A-2) in a yield comparable to that obtained in 
Example 13. m.p. 173.degree.-176.degree. C.; [.alpha.].sub.D +195.degree. 
(c 0.10, chloroform-methanol (1:1)). 
EXAMPLE 19 
Synthesis of 11-deoxy-13-deoxo-daunomycinone (A-3) 
##STR55## 
Compound (10) obtained in Example 8 above was treated with trifluoroacetic 
acid at -78.degree. C. in the same manner as in Example 17 to afford the 
titled compound (A-3) in a yield comparable to that obtained in Example 
17. m.p. 213.degree.-216.degree. C.; [.alpha.].sub.D +132.degree. (c 0.10, 
chloroform-methanol (1:1)). 
EXAMPLE 20 
Synthesis of 11-deoxy-daunomycinone (A-4) 
##STR56## 
Compound (12) obtained in Example 10 was treated with trifluoroacetic acid 
in the same manner as in Example 17 to afford the titled compound (A-4) in 
a yield comparable to that obtained in Example 17. m.p. 
215.degree.-219.degree. C.; [.alpha.].sub.D +174.degree. (c 0.10, 
chloroform-methanol (1:1)). 
EXAMPLE 21 
Synthesis of 4-demethoxy-11-deoxy-13-deoxo-daunomycinone (A-5) 
##STR57## 
Compound (14) obtained in Example 14 was treated with trifluoroacetic acid 
at -78.degree. C. in the same manner as in Example 17 to afford the titled 
compound (A-5) in a yield comparable to that obtained in Example 17. m.p. 
186.degree.-188.degree. C.; [.alpha.].sub.D +81.degree. (c 0.10, 
chloroform-methanol (1:1)). 
EXAMPLE 22 
Synthesis of 4-demethoxy-11-deoxy-daunomycinone (A-6) 
##STR58## 
Compound (16) obtained in Example 16 was treated in the same manner as in 
Example 17 to yield the titled compound (A-6) in a yield comparable to 
that obtained in Example 17. m.p. 201.degree.-213.degree. C.; 
[.alpha.].sub.D +124.degree. (c 0.10, chloroform-methanol (1:1)). 
The following Examples 23-24 illustrate the preparation of the starting 
materials for use in the process of this invention. 
EXAMPLE 23 
Synthesis of furan diene of the formula 
##STR59## 
(a) Preparation of furyl methyl ketone 
##STR60## 
3-Furoic acid (25.0 g, 0.233 mmol) was dissolved in dry ether (1.1 l), and 
to the solution was added a solution of 1.42M methyllithium (0.51 mol) in 
ether (370 ml) dropwise over 55 minutes at 0.degree. C., with stirring 
under nitrogen. The reaction mixture was stirred at room temperature for 
10 hours and then poured into ice-cold 1N hydrochloric acid (1 l) under 
good stirring. The ether layer was separated and the water layer was 
extracted with ether. The combined ether layers were washed first with 1N 
sodium hydroxide (134 ml) and then with saturated aqueous sodium chloride 
(200 ml.times.2), dried over anhydrous sodium sulfate and concentrated in 
vacuo at ca. 5.degree. C. and then briefly at room temperature. 
The crude product (23.25 g; 92%) thus obtained was used for the next step 
without purification. 
A pure sample was obtained by sublimation (40.degree. C. at 20 mmHg) as 
colorless needles, m.p. 51.degree.-51.5.degree. C. 
(b) Preparation of .beta.-(trimethylsilyl)ethyl ester of bromoacetic acid 
EQU TMS-CH.sub.2 CH.sub.2 OH.fwdarw.TMS-CH.sub.2 CH.sub.2 O-CO-CH.sub.2 Br 
.beta.-Trimethylsilylethanol (49.5 g, 0.42 mol) and N,N-dimethylaniline 
(53.3 g, 0.44 mol) were dissolved in anhydrous methylene chloride (250 
ml), and to the ice-cold solution was added dropwise bromoacetyl bromide 
(89 g, 0.44 mol) over 30 minutes, at 0.degree. C. with stirring under 
nitrogen gas. The reaction solution was stirred at room temperature for 1 
hour, diluted with methylene chloride (300 ml), washed successively with 
1N hydrochloric acid (100 ml.times.5), saturated aqueous sodium hydrogen 
carbonate (100 ml.times.3) and saturated aqueous sodium chloride (100 ml) 
once and dried over anhydrous sodium sulfate. 
The dried mixture was evaporated in vacuo to remove the solvent and the 
residue was distilled in vacuo to give the desired compound (95.67 g; 
95.3%) as colorless oil with b.p. 82.degree.-84.degree. C. at 3 mmHg. 
(c) Preparation of phosphonate compound of formula (a) 
EQU TMS-CH.sub.2 -CH.sub.2 O-CO-CH.sub.2 Br.fwdarw.TMS-CH.sub.2 CH.sub.2 
-O-CO-CH.sub.2 -P(O)(OEt).sub.2 (a) 
To triethyl phosphite (34.7 g, 0.209 mol) was added dropwise over 1 hour at 
70.degree. C. the bromoacetic acid ester (50 g, 0.209 mol) obtained in the 
above step (b). Then, the reaction mixture was slowly heated to 
170.degree. C., and the resulting ethyl bromide was removed by 
distillation. After heating at that temperature for 16 hours, the reaction 
solution was distilled in vacuo to afford compound (a) (59.1 g; 95.4%) as 
colorless oil with b.p. 141.degree.-145.degree. C. at 2 mmHg. 
(d) Preparation of compound (b) 
##STR61## 
Sodium hydride (6.14 g, 0.154 mol) (newly washed with anhydrous hexane) was 
suspended in anhydrous tetrahydrofuran, and to the suspension was added 
dropwise the phosphonate compound of formula (a) (47.40 g, 0.16 mol) 
obtained in the above step (c) at room temperature over 30 minutes. A 
clear solution was formed, and after 40 minutes, the crude furyl methyl 
ketone (14.68 g, 0.134 mol) obtained in the above step (a) in the form of 
a solution in anhydrous tetrahydrofuran (200 ml) was added dropwise to 
said clear solution over 25 minutes at room temperature. The reaction 
mixture was further stirred at room temperature for 1 hour and then heated 
to 50.degree. C. for 2 hours. After cooling to room temperature, water 
(830 ml) was added dropwise to the cooled reaction mixture and the aqueous 
layer formed was extracted with ether. The combined ether extracts were 
washed with water and then with saturated aqueous sodium chloride, dried 
over anhydrous sodium sulfate. The dried solution was concentrated in 
vacuo to leave a brown oil. This was purified by silica gel G-column 
chromatography using hexane-ethyl acetate (20:1) as eluent to afford 
compound (b) (24.58 g; 73%) as a colorless oil. 
(e) Preparation of compound (c) which corresponds to compound (III') 
##STR62## 
To a solution of anhydrous diisopropylamine (29.55 g, 0.293 mol) in 
anhydrous tetrahydrofuran (440 ml) was added a 2.35M solution of 
n-butyllithium (0.146 mol) in hexane (62.3 ml) dropwise over 1 hour, at 
0.degree. C. with stirring under nitrogen. The stirring was continued at 
that temperature for further 20 minutes. The reaction mixture was cooled 
to -78.degree. C., to which was added a solution of compound (b) obtained 
in the above step (d) in the form of the conjugated ester (24.58 g, 0.0975 
mol) in anhydrous tetrahydrofuran (50 ml) dropwise over 20 minutes. After 
the completion of the addition, the mixture was further stirred for 25 
minutes. Then, phenol (15.5 g, 0.166 mol) was added in one portion to the 
reaction mixture at -78.degree. C. under nitrogen gas and the mixture was 
stirred for 15 minutes, after which saturated aqueous ammonium chloride 
(540 ml) was added at a stroke and the reaction mixture was warmed to room 
temperature. Subsequently, water (150 ml) and ether (500 ml) were added to 
the reaction mixture. The organic layer was separated and the water layer 
was extracted with ether. The organic layer was combined with the ether 
extracts, washed with 1N aqueous sodium hydroxide (655 ml) and then with 
saturated aqueous sodium chloride, and dried over anhydrous sodium 
sulfate. The organic solution was concentrated in vacuo, and the residue 
was purified by passing through a short column of silica gel to yield a 
3:1 mixture (23.65 g) of the de-conjugated ester of formula (c) and 
conjugated ester of formula (b). This mixture was used for the Diels-Alder 
reaction in step (a) of Example 1 given hereinbefore. 
EXAMPLE 24 
Synthesis of 2-propenyl-(trimethylsilyl)methyl ketone of formula (f) which 
was used in step (a) of Example 5 
##STR63## 
Lithium (750 mg, 107 mmol) and trimethylsilylmethyl chloride (6.6 ml, 47.28 
mmol) were added to dry pentane and the mixture was heated to 100.degree. 
C. for 4.5 hours under nitrogen gas. The resulting violet mixture 
containing compound (e) was cooled to 0.degree. C., to which was added 
dropwise a solution of methyl methacrylate of formula (d) (2.5 ml, 23.64 
mmol) in dry pentane (5 ml) over 15 minutes at 0.degree. C. After stirring 
at 0.degree. C. for 15 minutes, the mixture was further stirred at room 
temperature for 2 hours. The reaction mixture was then poured into ice 
water (15 ml), followed by extraction with ether. The ether extract was 
dried over anhydrous sodium sulfate and concentrated in vacuo to yield a 
crude product (3.73 g) as yellow oil. This crude product was purified by 
distillation in vacuo to afford the desired product of formula (f), i.e. 
the compound (IX) hereinbefore given, in the form of a colorless oil (1.9 
g; 40%) with b.p. 72.degree. C. at 1.5 mmHg.