CA1131622A - Intermediates for the synthesis of (.sup. )-4- demethoxydaunorubicin - Google Patents

Abstract

INTERMEDIATES FOR THE SYNTHESIS OF

Abstract of the Disclosure The present invention encompasses novel inter-mediates having the following structural formulas:

(?) wherein X is hydrogen, methoxy, or hydroxy;

(?) wherein X is hydrogen, methoxy, or hydroxy; and (?) wherein X is hydrogen, methoxy, or hydroxy.
Compounds of the present invention are useful in synthesizing (?)-4-demethoxydaunorubicin, daunorubicin, adriamycin, and carminomycin which are potent antitumor agents.

Description

~3~6~

The present invention encompasses novel inter-mediates which are useful in preparing 4-demethoxy-daunorubicin, daunorubicin, and adriamycin which are potent antitumor agents. The process is advantageous in that it is more amenable to large scale production of this class of antitumor agent.
4-Demethoxydaunorubicin is a glycosiae formed from a tetracyclic aglycone, (~)-4-demethoxydaunomycinone, ~n~ a~ amino sugar, daunosamine. Daunorubicin is a glyco-side formed from daunomycinone and daunos~m;ne. Adriamycin is a glycoside formed from adriamycinone and daunos~m;ne.
The synthesis of 4-demethoxydaunorubicin which is an analog of the known antibiotic daunorubicin is aescribed in ~.S. Patent No. 4 r 046,878 and F. Arcamone, et.
al., CANCER TREATMENT REPORTS, 60 (7~:829-834 (1976) which also include experimental data showing its utility as a potent antitumor compound. Antitumor activity of (~)-4-demethoxydaunorubicin is also described in A. DiMarco, et.
al., CANCER TREATMENT REPORTS, 61 ~5):8g3-894 (1977~.
Other prior art related to the synthesis of daunomycinone, daunorubicin, adriamycinone, and aariamycin by methods which differ from the present invention is aescribed in C. M.
Wong, et. al., CAN. J. CHEM., 51:466-467 (1973); A.S.
~ende, et.al., J. AM. CHEM. SOC., 98:1967-1969 (1~76);

`
. . ~, T. ~. Smith, et.al., J. AM. CHEM. SOC., 98:1969-1971 ~19763;
A. S. Rende, et.al., TETRAHEDRON LETTERS, 40:3537-3540 (1977); F. Arcamone, et.al., C~IM. IND. (MILAN), 51:834 (1969~, and U.S~ Patent No. 3,803,124.
The present invention differs from the prior art in that it utilizes novel trimethylsilyl or trialkyl~ilyl I !
intermediates to afford a proces~ which is more efficient and more amenable to large scale production.
It is the object of this invention to provide certain novel intermediates which are useful in the prepa-ration of 4-demethoxydau~orubicin, daunorubicin, and adriamyci~. These novel intermediates are converted into (+)-4-demethoxydaunomycinone or daunomycinone by means of the pxocesses illustrate~ in Schemes A a~d B. (~)-4-Demethoxydaunomycinone may then be converted in~o 4-demethoxydaunomycin by methods described in ~.S. Patent No. 4,046,878. Daunomycinone may be used to prepare daunorubicin and adriamycin by methods described in Acton, et.al., J. MED~ CHEM. 17:659-660 (1974)~

Scheme A

OH ~

HC 9 C ~C~ C~3 1. BuLi (C~3)3SiC --C - C~ -CH3

2. (C~3)3~iCl (I) 3. ~+ ~II) ¦ ~2 Pd~B~S04 quinoline '\ ~. , ;

(III) ~3~

C - CH ~ H
/ 3 <
C=C 1. CrO3 /C=C\
(CH3)3Si ~ 2. H(C 3)3 CH -CH3 (IV) ~III) ~

¦ isopropenylacetate ~1, EI+
RO ¦VI) .
\C=C/ ~

(V) X O O .

+) ~ ~ OR ~ OR

pa/Baso~ ~
X O O H Si(C~3)3 X O~ k si(c~3)3 (VI) tYlI) . . .
~ HCl-MeOH
., O~ O H
(~ ~ ( ) O~ O H OCH .
trifluoro- ~ \ ./ 3 acetic acid l~
1 7 ~ HzO ~ ~ ~ ~ J OC~
X 9H O H Si(CH333 I T ~ ~
(IX) X OH ~ Si (CH3)3.
(VIII) HC -- CMgBx /

~+~f--cn ~ / c_c~

~,~J ` ~0~ Pb ~OAc) 4 ~ ` OH
X OHO H Si (CH3) 3 XOO H Si (CH3) 3 (X) ¦ (XI ) i sopropenyl acetate isopropenyl \ H~ acetate ~ ~OA ~ C----C~

CCH3 ~'J OCCE13 X 0~1 0 H S i ~CE13) 3 X O ~ Si(CH )3 (XII) ~XIII) 3 KOAc--HOAC
~1 ~ ~ .
O OCCE~3 O O~
~p_f ~",y C _C}I

OCC~E3 ta~e ~,J OCCH"
X OO~I Si(C~3)3 ~ X O O~ Si (C~I3~3 (XI~13 .

¦ Pb~OAc)4 . ¦ Pb(OAc)4 ~¦~ ,1 AcO~

~J~; OCC~3 1~ ollc~3 (XV~) X O OH OCCH3 I aniline ¦ anl ine ~¦~H20 ~ H20 (XVII) ~5- (XXI) ~3~

(~CII3 (+"~ 7 ~ 33 (XVII) 3 (XXI) OCCH3 methanol ¦ H20 sopropanol Ol O
~ CCH3 ~Cl I3 l' r [~ ~ J 0~3 X OH OH X O OH O
(XVIII~ (XIX) (+)-4-demethoxydaunomycinonP HO

(+)-daunomyeinone,or 4-demethoxydaunorubiein earmi~omyeinone daunorubiein~ or R = alkyl having 1-4 carbon atoms earminomycin I
acyl havi~g 1~5 carbon atoms trialkylsilyl wherein the alkyl radical has 1-4 carbon atoms.
X = hydrogen, methoxy, or hydroxy.

~3~2 Scheme B
lcl~2 OCH3 ~ C -OCH3 CH2- C ~ OH
X OH H Si(CR3)3X OH a si ~CH3)3 (IX) (XXII) sopropanol ~ / ' (+) ~ O H OH O H R
p~rOpenyl ~ CCH3 aceta~e OCCH3 ~+~ ~ ~ ~
X OH O H Si(CH3)3 X OH ~ Si(CH3)3 (XXIY) (XXIII) ¦ Pb~OAc3~ .
HOAc \ ~ . ~

O O ~ 11 ' O

(+~ 3 ~O~c- ~ 3 (XXV) (XXVI) 1 3 3 isopropenyl a$etate ~ / ~ ' .

~7~ (XXVII ) C3 ~OAc ~ 33 ~ OCC~3 X O O~ Si(CH3)3 (XXVIII) (XXVII) X = ~ydrogen, methoxy, or hydroxy.

In a typical example, wherein R is acetyloxy and X is hydrogen, 3-butyne-2-ol (I) is reacted with butyl lithium and chlorotrimethylsilane and then with acid to give 4-(trimethylsilyl)-3-butyn-3-ol (II) which is hydrogenated S in the presence of quinoline and benzene with palladium on barium sulfate as catalyst to give Ci5-4- (trimethyl-silyl)-3-buten-2-ol (III). cis-4-(Trimethylsilyl)-3-buten-2-ol (III) is treated with Jones Reagent ( a solutio~
of chromic acid and sulfuri.c acid in water) at a temperature below 10C and the product is equilibrated with acid to gi~e trans-4-(trimethylsilyl~-3-buten-2-one (IV). The preparation of this compound has been previously described lR. A. Fe~ix, et. al. J. ORG. CHEM. 37, 2323 (1972), and ~.G. Brook, CAM. J. CHEM. 51, 2024 (1973~. trans-4-(Trimethylsilyl)-3-bUten-2-One tIV) is reacted wi~h isopropenyl acetate in the presence of ac-d to gi~e trans-2-(acetyloxy)-4-(trimethylsilyl)-1~3-butadiene (V). trans-2-(~cetyloxy)-4-(trimethylsilyl~-1,3-butadiene (V) is reacted with qulnizarin-quinone to produce (~)-3-(acetyloxy)-1,4,4a~,12a~-tetra-hydro-la-(trime~hylsilyl)-5,6,11,12-naphthacenetetrone (VI). .
The reaction is typically carried out at a temperature of 45-50C. over a period of 96 hours. Chemical reduction or hydrogenation of (+)-3-(acetyloxy)-1,4~4a~,12a~-tetrahydro-

3~3~

la-ttrLmethylsilyl)-5,6,11,12-naphthacenetetrone ~VI) usins palladium on barium sulfate as catalyst provides (+)-3-(acetyloxy)-1,4,4a~,12a~-tetrahydro-6,11-dihydroxy~
(trLmethylsilyl)-5,12-naphthacenedione ~VII) which is refluxed with methanol and hydrochloric acid to give ~+)-1,2,3,4,4a~,12a~-hexahydro-6,11-dihydroxy-3,3-dimethoxy-l-~trimethylsilyl)--5,12-naphthacenedlone (VIII) which i8 .
then reacted with trifluoroacetic acid and water to yield (~)-3,~,4a~,12a~-tetrahydro-6,11-dihydroxy la-krimethyl-sily~r2,5,12(1~)-naphthacenetrione (IX). (+~-3,4,4ag,12ag-tetrahydro-6,11-dihydroxy-la-(trimethylsilyl~-2,5,12~
naphthacenetrione (IX) is con~erted to (~)-3-ethynyl-1,2,3,

4,4a~,12a~-hexahydro-3~,6,11-trihydroxy-la-(trimethyl-silyl)-5,12-naphthacenedione (X) via a Grignard reaction.
Compound X is stirred with isopropenyl acetate and acid for 20 hours at room temperature to give (~)-3~-(acetyloxy~-3-ethynyl-1,2,3,4,4a~,12a~-hexahydro-6,11-dihydrOxY-la-(trimethylsilyl)-5,12-naphthacenedione (XII) which is then oxidized with lead tetraacetate to provide ~ 3~-(acetyloxy~-3-ethynyl-1,2,3,4,4a~12a~-hexahydro-la-(trime~h~lsilyl)-

5,6,11,12-naphthacenetetrone (XIII~. Alternately, compound X is oxidized with lead tPtraacetate to yield (~-3-. .
ethynyl-1,2,3,4,4a~,12a~-hexahydro-3~ hydroxy-la-(trimethyl-silyl3-5,6,11,12-naphthacenetetrone (XI~ which is then heated with isopropenylacetate and acid to provide XIII.
Heating XIII with potassium acetate and acetic acid yielas tr~ns~ 9-(acetyloxy)-9-ethynyl-7,8,9,lO~tetrahydro-6,11-dihydroxy-l-(trimethyl~ilyl)-5,12-naphthacenedione (XIV) ._ which is heated with isopropenyl acetate and acid to give trans~ 9,11-bis(acetyloxy)-9-ethynyl-7 t 8,9,10-tetrahydrQ-_9:

~L13~

6-hydroxy-7-(trimethylsilyl)-5,12-naphthacenedione (XV).
When XV is allowed to react with lead tetraacetate the trimethylsilyl group i5 replaced ~y an acetyloxy group to give ClS- (+) -7,9,11-tris(acetyloxy)-9-ethynyl-7,8,9,10-tetrahydro 6-hydroxy-5,12~naph~1acenedione (XVI) which when refluxed with mercuric chloride, aniline and water affords ClS- (~) -9-acet~1-7,9,11-tris(acetylox~7,8,9,10-tetrahydro-6-hydroxy-5,12-naphthacenedione (XVII). ~ydrolYsis _.
of th~ acetyloxy group~ by reacting cis-tf)-9-acetyl-7,9,11-tris(acetyloxy)-7,8,g,10-tetrahydro-6-hydroxy-5,12-naphthacenedione (XVII) with methanol and hydrochloric acid gives (+)-4-demethoxyaaunomycinone (XVIII).
In an alternate route, XIV is reacted with lead . _ _ .. . _ . _ _ _ _ _ . _ ... .. _ . . . _ .. . . . . . ....
tetraacetate and Potas.sium fluoride in acetic acid then r~uced to give ClS- (+)-7,9-bis (acetyloxy~-9-ethynyl-7,8,9,10- -tetrahydro-6,11-dihydroxy-5,12-naphthacenedione ~XX).
~ This reaction has the advantage of being stereospecific for the cis configuration so that it is not necessary to sepa-.
rate the cis is~mer by chr~matographic methods. X~ is reacted with mercuric chloride, aniline and water to gi~e ClS (+) -9-acetyl-7,9-bis(acetyloxy)-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-naphthacenedione ~XXI) which is then refluxed with isopropanol, water r and hydrochloric acid to gi~e XVIII.
(f ~ -4-demethoxydaunomycinone (XVIII) is converted to (+)-4-demethoxydaunorubicin (XIX) by methods deF.cribed in U.S. Patent No~ 4,046,878.
~hen X is a methoxy group the final product i~
(+)-daunomycinone which may be converted to th~ Xnown antitumor agent daunorubicin by methods described in ~.A. Acton, et.al., ~.- MED~ CEEM. 17 (6~, 659 660 ~1974).

Scheme B illustrates an alternate route for converting (+)-3,4,4a~,12a~-tetrahydro-6,11-dihydroxy-lx-~trimethylsilyl)-2,5,12(1H)-naphthacenetrione (IX) into CiS- (+) -9-acetyl-7,9~ tris(acetyloxy)~7,8,9,10-tetrahydro-6-hydroxy-5,12-naphthacenedione (XVII). Methylvinyl ether is treated with tertiary butyl lithium in tetrahydro-furan and the product is allowed to react with (~)-3,4,4aB, 12a~-tetrahydro-6,11-dihydroxy-1-(trimethylsilyl)-2,5,12 ~l~I)-naphthacenetrione (IX) to pxoauce (~-1,2,3,4,4a~,12aB-hexahydro-3~,6,11-trihydroxy-3-(1-methoxyethenyl)-la-~trimethylsilyl)-5,12-naphthacenedione`~XXII) which is hydrolyzed in aqueous isopropanol in the presence of hydrochloric acid to provide (+)-3-acetyl-1,2,3,4,4a~,12a~-hexahydro-3~,6,11-trihyaroxy-1~-(trimethylsilyl)-5,12-naphthacenedione (XXIII). Mixing XXIII with isopropenyl ace~ate i~ the presence of acid and stirring at room temperature for 72 hours yields (~-3-acetyl-3~-(acetyloxy)-2,3,4,5,5a~,12aB-hexahydro-6,11-dihydroxy-1~-(trimethyl-silyl)-5rl2-naphthacenedione (XXIV~ which is reacted with lead tetraacetate in acetic acid to give (f) -3-acetyl-3 ~-(acetyloxy~-1,2,3,4,4a~,12a~-hexahydro-la-(trimethylsilyl)-5,6,11,12-naphthacenetetrone (XXV). Warming XXV with potassium acetate in acetic acid gives trans~ 9-acetyl-9-(acetyloxy)-7,8,9,10-tetrahydro-6,11-dihydroxy-

7-(trimethylsilyl)-5,12-naphthaconedione (XXVI). ~eating XXVI with isopropenyl acetate in the presence of acid pro~ides trans-~+)-9-acetyl-9,11-bis-(acetyloxy)-7,8,9,10-tetrahydro-6-hydroxy-7-(trimethylsilyl)~5,12-naphthacene-dione (XXYII) which i5 allowed to react with lead tetra~
acetate in acetic acid for 2 hours at room temperature to ~L13~2 give cis-(+)-9-acetyl-7,9,11-tris(acetyloxy)-7,8,9,10-tetr~hydro-6-hydroxy-5,12-naphthacenedione (XXvIII).
Those skilled in the art will recognize that other trialkylsilyl groups may be substituted for the trimethylsilyl group in the compounds of Scheme A and Scheme B by using conventional preparation techniques.
Thus the present invention encompasses inter-mediates of the formula ~+~

X OH O H Si(CH3)3 wherein X is hydrogen, methoxy, or hydroxy, intermediatës . . .... . . .._ of the formula O O H _ +)/ ~ follC~3 X O O ~ Si(C~I3)3 wherein X is hydrogen~ methoxy, or hydroxy, a~d ïnter-mediates of the formula (+~ ~`OCC~

X 0~ (C~)3 wherein X is hydrogen, methoxy, or hydroxy.
The following examples describe in detail the preparation of compounds utilizing the process of the present invention. It will be apparent to those skilled in the art that many modifications, both of materials and methods, may be practiced wlthout departing from the purpose and intent of this disclosure. Throughout the examples hereinafter set forth temperature~ are gi~en in , degrees Centigrade (C~, and relative amounts in parts by weight and parts by volume is specified. The relationship between parts by weight and parts by volume is the 3ame as that existing ~etween grams and milliliters.
The Roman numerals used in the examples correspond to those used to describe compounds of Schemes A ~nd B
5 wherein X is hydrogen and R is acetyloxy.
EX~MPLE 1 A solution of 107.1 parts by weight of 3-butyne-2- ¦
ol (I~ m 1000 parts by volume of dry ethyl ether is chillsd to -50C. (internal temperature) and 1390 parts ~y volume of 2.17 M n-butyl lithium in hexane is added over a 2 hour period.
The internal temperature is allowed to rea~h 10C. during the latter p~rt of the addition to facilitate ~tirring. The mixture is then cooled again to -30C (internal) and 400 parts by volume of chlorotrimethylsilane in 200 parts by volume of ethyl ether is added ov~r a 15 minute period. The mixture is allowed to warm slowly to room temperature overnight~ After a brief period of re~ ux the mixtur~ i~ again cooled to 25C.
and 100 parts by volume o~ water is added causing the internal temperatuxe to rise to 37Co Aft6r stirriny for 1 hour, more ~L3~6~

water is added. The organic layer is separated and washea with 5~ aqueous hydrochloric acid and water. The solution is dried over sodium sulfate, then concentrated to approx;~tely 400 parts by volume. After adding 500 parts per volume of methanol and 200 part~ per volume of 5% hydrochloric acid the solution is stirred at room temperature for one hour then diluted with lO00 parts per volume of water and extracted with ether.
The ether extract is washed with water, dried over sodium sulfate and roncentrated to afford 4-(trimethylsilyl)-3--butyn-2-ol (II~ which distills at 49 50C/0.25 mm and has .he following structural formula C~3 ~

CH3 ~ C C CH - C~3 C~3 ... .

A solution of 94.15 parts by weight of 4~(trimet~yl-silyl)-3-butyn-2--ol (II) in 940 parts by volume of ~enzene and 4.7 parts by volume of quinoline is hydrogè~ated at a constant pressure of 2 p,s~i. in the presence of 9.4 parts by weight , of 5% paIladium on barium sulfate until one equivalent of hydrogen is consumed. The catalyst is removed and the solu-tion is washed twice with 100 parts p~r volume of 5%~aqueous 2~ hydrochloric acid and then wi~h water~ AftPr drying over sodium suIfate, ~he solvent is removed and the residue is distilled at 33-39C/0.3 mm to gi~e CiS-4- (trimPthylsilyl)-3-buten-2-ol (III) which has the following structural formula:

H

(C~3)3Si / \ C / - C~

EX~MPLE 3 -A solution of 174.6 parts by weight of cis-4-(trimethylsilyl)-3-buten-2-ol (III) in 2000 parts by ~olume of a~etone is chilled to -10C ~nd treated slowly with an excess (350 parts by volume) of Jone~ Reagent (a solution of chromic acid and sulfuric acid in water) while keeping the internal temperature beiow 10 C. The resulting pre-cipitate is allowed to settle and ~he supernatant is decanted and concentrated on a rotary ~vaporator ak 25C~ to remove much of the acetone . The precipitate is dissolved in water and the solution is extracted with ethyl ether. The ether extract is added to the acetone residue and the combined solutio~s are washed with water, then with 5% aqueous hydro-chloric acid, and again with water. The ether extract is then dried over sodium sulfate and the ether removed ~y vacuum distillation. The residue is taken up in 500 parts by ~olume of isopropanol and 20 parts by volume of concentra-ted agueous hydrochlori~ acid is added. The mixture is stored at room temperature ~or 18 hours then diluted wi~h 1000 parts ~y ~ol~me of benzene and washed repeatealy wi~h water. The washes are extracted with 500 parts-by volume of b~nzene and dried over sOaium sulfate to yiela ran_-4-(tri-methylsilyl)-3-buten-2-one (IY~ which has a boiling point of 165-169C~ and is represented by khe followiny structural formula 1~3~Z~ ~
ll / c~3 \C
\~
(~H3)3Si A mixture of 1.40 parts by weight of p-toluene sulfonic acid monohydrate and 100 part~ by volum2 of ~enzene is distilled through a 15 cm. Vigreaux column until 7~
parts per volume of distillate i8 collected. 100 Parts per volume isopropenylacetate i8 added to the reactio~
vessel and distillation i5 resumed until the boiling point reaches 92C. After cooling to room temperature, 18.6 ~parts by weight of trans-4-(trimethylsilyl?-3-buten-2-one (IV) is added to the reaction ~essel. The mixture is heated and distilled slowly with the,temperature at the ~ottom of the col~mn maintained at 85C. for 20 hours. The reaction mix- g ture is cooled then flash distilled, and the product is redistilled at 35-37 & /0~ mm to yield trans-2-(acetyloxy)-4-(trim~thylsilyl)-1,3-butadiene (V) which has the followi~g structural formula EI2C~

f - ~ - C C~3 C - H
~_f Si(CH3)3 ~ solution of 2~.9 parts by weight of 1,4,9,10-anthracenetetrone in 800 parts ~y volume of benzene i~ heated and about 50 parts by volume are removed by distillation.
S The remaining solution is then cooled under nitrogen to an internal tempera~ure of 50C. and 18.0 parts ~y weight of trans 2-(acetyloxy) 4-ttrimethYlsilyl)-1,3-butaaiene (V) are added. The mixtuxe is maintained at 45-50C. for 96 hours and then allowed to cool to room temperature with con-tinued stirring overnight. 100 Paxts by volume of cyclo-hexane i5 added and the mixture i5 chilled. The resulting solid is collected and washed with banzene then dried. The - product is recrystallized from benzene to give (~)-3-(ace-tyloxy)-1,4,4a~,12a~-tetrahydro-la (trLmethyls;lyl)-5,6,11,12-naphthacenetetrone (VI) which melts at 197-200C. and has the :
following structural formula ol .
~+) o O Si(C~3)3 EXAMPLæ 6 A solution of 19~3 parts by weight of (+~-3-(acetyloxy)-1,4,4a~,12a~-tetrahydro-la-(trLmethylsilyl)-5,6,11,12-naphthacenetetron~ (~I) in 1300 parts by w lume of tetrahydrofuran is hydrogenated over 1.93 parts by weight of 5% palladium on barium sulfate at a constant pressure of 2 p.s.i. for Z 1/2 houxs. rhe catalyst is removed and the Z
filtrate concentrated to a small vol~e which i~ digested in 400 parts by volume of ethyl acetate. The resulting product is recrystallized from ben~ene-cyclohexane to give (+)-3-(acetyloxy)-1,4,4a~,12a~-tetrahydro-6,11-dihydrQxy-la-(trimethylsilyl)-5,12-naphtAacenedione (VII) which melts at 217-225C ~decomposition) and has the following structural form~la O~ o ~ i(CH3)3 A suspensio~ of 18.14 parts by weight of (+)-3-(acetyloxy~-1,4,4a~,12a~-tetrahyaro-6,11-dihydroxy-la-(trimethylsilyl)-5,12-naphthacenedione (VII) in 800 parts by volume of methanol, plus 10 parts by volume of concentrated hydrochloric acid is re~luxed with vigorous stirring for 4 hours, then chilled well, filteredr ana rinsed with cold methanol. The crude solid is recrystallized from methylene chloride-methanol to give (+)-1,2,3,4,4a~,12a~-hexahydro- ~
6,11-dihydroxy-3~3-dimethoxy-1~-(trimethylsilyl)-5,12-naphthaceneaione ~VIII) which me-ts at 210-211C. and is represented by the following structural formula ~+) ~ OC~3 OH ~ Si(CR3)3 To a solution of 15.16 parts ~y weight of t )-1,2,3,4,4aR,12a~-hexahydro-6,11-dihydroxy-3,3-dimethoxy-lo-(trimethylsilyl~-5,12-naphthacenedione ~VIII) in 100 parts by volume of trifluoroacetic acid ~nder nitroge~ ~s .:
added 20 parts by volume of water over a period of 1 hour, causing the solution to changa from brown to pale yellow, with the formati~n of a solid yellow ma55. 100 Parts by volume of water is added with mixing, and the solid i~ col- :
lected, washed with water, and dried. Recrystallization from benzene ethyl ether gives (+)-3,4,4a~,12a~-tetrahydro-6,11 dihydroxy-4a-~trLmethylsilyl)-2,5,12(1~)-naphthacenetrione which melts at 204-207C (soft at 192C) and ha~ the following structural formula 0~ 0 t+) ~ f . O~ o ~ Si(~3)3 Purified acetylene i~ bubbled into a dry ice-cooled flask containing 150 parts per volume of fre~hly distilled tetrahydrofuran. After an increase of about 100 parts per volume i~ noted, 50 parts per volume of 2.53M
ethyl magnesium bromide in ether is added over a 10 minute ~eriod. The mixture is allowed to warm to 10C., with acetylene still bubbling, then i3 cooled to -30C. A
solution of 11.5 part~ by weight of (+)-3,4,4a~,12a~-tetrahydro-6,11-dihydroxy la-(trimethylsilyl)-2~5~l2(~
naphthacenetrione (IX) in a total of 450 parts per volume tetrahydrofuran is added with stirring. The mixture is held at -20C. for 30 minut~s, then the temperature is allowed to rise to 0C. and held there for another 30 minutes.
50 Parts per volume of cold ~aturated ammonium chloride is added, followed by 150 parts per volume of 50% aqueous ~Cl, and then 300 paxts per volume of water and nitrogen is bubbled through the mixture overnight. The solid which separates is ~iltered, washed with water, and dried. 12.6 Parts by weight of the solid is dissolved Ln methylene chloride, the ~olution - is concentr~ted to about 75 parts per volume, and 150 parts per volume of cyclohexane is added. The resulting precipi-tate is recovered by filtration and recrystallized from ethyl ether-hexane to give (+)-3-ethynyl-1,2,3,4,4a~,12a~-h~xahydro-3~6~ trihydroxy-la-(trimethylsilyl)-5~12-naphthacenedione ~X) which melts at 206-208C. and has the following structural form~la:

., .

O~ O H

(t) ~ ~ O~

OH O H Si(CH3)3 Concentration o~ the mother liquors and recrystal-lization of the precipitate from benzene-cyclohexane gives (+)=3-ethynyl-1,2,3,4,4a~,12a~-hexahydro-3a,6,11-trihydroxy-la-(trimethylsilyl)-5,12-naphthacenedione which melts at 229-231C. and has the following structural formula (O ~`C-CI~

o~ o ~ Si(C~3)3 Chromatography of the mother liquors (dr~ column 60 parts by weight of neutral ~ acid, 100-200 mesh developed with ethylacetate-benzene~ gives partial separa-tion of the above compounds. The first eluate is recrystal-lized from methylene chloride-cyclohexa~e to give (~)-3-ethynyl-1,2,3,4,4a~,12a~-hexahydro-3~,6,11-trihydroxy-la-.(trimethylsilyl)-5,12-naphthacenedione (X~ which melts at 204-206C. The later fractions are recrystallized from henzene-cyclohexane to give ( )-3-ethynyl 1,2,3,4,4ae,12a~-hexahydro-3a,6,11-~rihydroxy-1~-(trimethylsilyl)-5,12-naphthacenedione which melts at 229-231C.

To a ~uspen3ion of 12.26 parts by weight of (~)-3-ethyny~ 2~3~4~4a~rl2a~-hexahydro-3~t6~ll-trihydroxy-la-(trimethylsilyl~-~,12-naphthacenedione (X) in 100 parts per volume cf acetic acid is added 16.5 parts by weight of approximately 85% lead tetraacetate. The solution is allowed to stand for 30 minutes at room temperature, then 100 parts per vol~me of water is added slowly with vigorous stirring.
The mixture is chilled and filtered. The solid collected on the filter is washed with water and dried under high vacuum to give (+)-3-ethynyl-1,2,~,4,4a~,12a ~hexahydro-3 ~hydroxy-lo-~trimethylsilyl)-5,6,11,12-naphthacenetetrone ~XI) which melt~ at 183-187C. and has the following structural formula ~+) ~ o~

O O H Si~CH3)3 EX~?LE 11 1~ To a suspension of 1.0 part per weight of (~-3-ethynyl-lt~,3,4,4a~,12a~-hexahydro-3~,6,11~trihydroxy-la- (trimethylsilyl)-5,12-naphthacenedio~e (X) in 15 parts per Yolume of isopropenyl acetate i~ added 0 7 05 part ~y weight of p-toluenesulfonic acid hydrate. The mixtura is stirred at room temperature for 20 hours~ then concentrated under a stre~m of nitrogen to about S parts per volume. Ater adding 20 parts per volu`~ e~hyl ether, the solid which forms is collected a~d washed with ether. The crude .

.~ ~ 3~

product is recrystallized from methylene chloride-ethyl ether to yield (+)-3~-(acetyloxy)-3-ethynyl-1,2,3,4,4a~,12ag-hexahydro-6,11-dihyslroxy-la-(trimethylsilyl)-5,12-naphtha-cenad~one (XII) melting at 211-213C. and having the following S struc~ural ormula (+, ~ ~oGc~3 OH O ~ Si(CH333 The combined mother liquors are concentra~ed to a small volume, passed through a 10 parts per weight neutral sil;c~ acid column in methylene chloride and crystallized.
Recrystalliz~tion from benzene-cyclohexane gives a sample :
of the above product, ha~i~g a melting point of 213-214C.

EXAMPLE 12 .
(A3 A suspensio~ of lsO . 26 parts by weight o (~) 3-ethynyl-1,2,3;4,4a~,12a~-hexahyS~ro-3~-hydroxy~
Strimethylsilyl)-5,6~11,12-naphthacenetetrone lXI3 and 0.075 part by weight o p-toluenesulfonic acid hydrate in 50 parts by volume of is~propenyl acetate is heated fs3r 3 hours in a 60~ water ba~h (solutlon is not complete but the solid bes-omes lighter in color3. The mixture is coolesd to room temperature over a two-hour period, then diluted with 50 ~, 2~ parts by volume of ethyl e~her. The crude-solid is collected~ ¦
washed with ethyl e~her and recry~tallized from me~hylene chloride-e~hyl ether to yield (~)-3~-5acetylo~y)-3-ethynyl-1,2,3,4,4aB,12aB-hexahydro-la-(trimethylsilyl)-5,6,11,12- :

naphthacen~tetrone (XIII) which melts at 206-208C.
(decomposition) and ha~ ~he following structural formula:

1~
0 0 H Si (CH3)3 (B) To a suspen~ion of 0.67 part by weight of (+) 3~-(acetyloxy)-3-ethynyl-1,2,3,4,4a~,12a ~hexahydro-6~ aihydroxy-lor(trimethyl~ilyl~-5~l2-naphthacenedione (XII) in 10 parts per volume of acetic acid is added 1.O
part by weight of approximately ~5% lead tetraacetate, causing the yellow solid to dissol~e and a pink solid to precipitate.
The mixture is allowed to stand for 30 minutes, then 2S
parts per volume of water is added. The solid is collected, washed with water, and dried. ~ecrystallization from methy-lene chloride-ethyl e~her gi~es (~3-3g-~acetyloxy)-3-ethynyl-1,2,3,4,4a~,12a~-hexahydro-la-(trimethylsilyl)-5,6,11,12-.
naphthacenetetrone (XIII~ which melts at 213-215C. (decom-position) and has the following s~ructural formula:

O O EI ~ ~EI

(+) ~ ~ ~ `OIlC~3 O O H Si(C~3)3 -~4-EXAMPLE:_ 13 To a solution of 4.6 parts by weight of (~-3 ~(acetyloxy)-3-ethynyl-1,2,3,4,4aB,12aB-hexahydro-la-(trimethylsilyl)-5,6,11,12-naphthacenetetrone (XIII) in 50 part~ per volume of acetic acid at 95C. is added 5 parts by volume of acetic acid saturated with potassium ace-tate. The mixture i held at 95~C for 3 hours, then allowed to cool to room temperature and diluted wi~h S parts per volume of water. The solid is removed by filtration, washed with water, and dried. ~ecrystallization from methyle~e chloride-ethyl ether gives trans-(~)-9-(acetyloxy~-9-ethynyl-7,8,9,10-tetrahydro-6,11-dihydroxy-7-(trimethyl-silyl)-5,12-naphthacenedione (XIV) which melts at 204-206C. and has the following structural formula O q~` C_C~ ~

(+) ~ ~ `OIlC~3 O 0~ Si(CH3)3 EXA~PLE 14 - A suspension of 20.02 parts by wQight of trans-~ 9-(acetytoxy)-9-ethynyl-7,8/9,10-tetrahydr~-6,11-dihydroxy-7-~trimethylsilyl)-5,12-naph~hacenedione (XIV) and 1.0 part by weight of p-toluenesulfonic acid monohydrate in 200 parts by volume of isopropenyl acetate is heated under a 20 centimeter Vigreaux column and slowly distilled at 60-80C. for 3 hours, then at 80-95C. for 1 hour until about 30 parts per volume of distillate is collected.

~3~2~

The contents of the reaction vessel are cooled to room temperature, with the formation of a thick solid. The reaction mixture is diluted with 50 parts per ~olume of ethyl ether and chilled, and the solid is collected and washed with ethyl ether. Recrystallization from methylene chloride-ether gives trans-(~)-9,11-bis~acetyloxy)-9-ethynyl-7,8,9,10-tetrahydro-6-hydroxy-7-(trimethylsilyl)-5,12-naphthacenedione (XV) which melts at 181-182C. and haR the following structural ¦
formula1l ¦

~+)~ OIlC~3 O OH Si(C~33 The combined mother liquor~ are stripped of most of the ether, diluted with methylene chloride, washed with water and dried over sodium sulfate. After concentrating ~ -to dryness, the residue is chromatographed on a dry column of 60 parts of neutral sili~ acid, 100-200 mesh. ~The material is dissolved in benzene~ ~hen developed with 200 parts per volume of benzene, 1%, 2%, and 5% e~hyl acetate in benzene and the fractions ar~ collected by color bands).
~he first fractio~ is crystallized from methylene chloride-ether to yield ~he ~tarting material.
The second fraction is crystallized from methylene chloride-ethyl ether to yield trans-(~3-9,11-bis(acetyloxy~-9-ethynyl-7,8,9,10-tetrahydro-6-hydroxy-7-(trImethylsilyl)-5,12-naphthacenedione (XV~ melting at 179-182C. and having Z~

the following structural formula Il , o OCC~13 ~+) ~ J OCCH3 0 OH S i (CH3 ) 3 li, The third fraction is crystallized from ethyl ether-hexane to yield trans-t~)-6,9,11-tristacetyloxy)-9- ' ethynyl-7,8,9,10-tetrahydro~7-(trimethylsilyl)-5,12- ' naphthacenedione which melts at 205-207C. and has the following .
structural formula o .
Il I
o O~C~3 (+~ ~ ~ CE~

o OC~3 Si(C~3~3 ~XANPLE 15 To a solution of 14.3 parts by weight of dried lead tetraacetate in 500 parts by volwme of acetic acid -~
i~ adaed 1.0 part by volume of water followed by 14~65 parts by weight of trans~ -g,ll-bis(acetyloxy)-9-eth.ynyl-7,8,g;10-tetrahydro-6-hydroxy-7-~trimethylsilyl)-5,12-~aphthacene-dione (XV)~ The mixture is stirred at room temperature for 4 hours, then hea$ed to 40C. for a~out 30 mi~ute~ until solution is complete. The solutio~ is held at room tempera-ture for 2 hours, then 1.0 part per volume of water is addedand stirring is conti~ued for another 2 hours. 50 Parts per volume of water is added, and the solution is stirred over-night while rem~ining at room temperature. The resulting precipitate is collected, washed with 90% acetic acid and digested in 200 parts per ~olume of hot acetic acid.
50 Parts per volume of water i5 added and the solution is cooled. The resulting solid is collected, washedwith water, dried and chromatographed on 80 parts by weight of neutral s~ic acid, 100-200 mesh develop~ng with 5% ethyl acetate in methylene chloride. The major ~raction is crystallized from benzene-cyclohexane to give cis-(+)-7,9,11-tri~(ace-tyloxy)-9-ethynyl-7,8,9,10-tetrahydro-6-hydroxy-5,12-naphtha-cenedione ~XVI3 which meits at 233-235C. (decomposition) and has the following structural formula I ~CC~3 C _ CH

( ~+) ~ ~ ) OCC~3 O O~ OCC~3 The various acetic acid mother liquors are con-centrated to about 100 parts by volume and diluted with 200 parts by volume of water. The crude solîd which results is filtered, washed with water, dried and chromatographed as be~ore. The main fraction when crystallized from benzene-cyclohexane gives a mixture of isomers melting at 220-~24C
tdecompositio~) consisting of about 4n% of cis-(~-7~9,11-tris(acetyloxy)-9-eth~nyl-7,8,9,10-tetrahydro-S-hyaroxy-5,12-naphthacenedione (XVI3 ha~ing the following structural fo~mula -~8-~3~
B

l ~CCH3 C _CH

~3 O o~ OCCH3 i and about 60~ o~ trans-(+)-7,9,11-tris(acetyloxy)-9-ethynyl-7,8,9,10-tetrahydro-6-hydroxy-5,12-naphthacenedione having the following structural formula:

O OCCH

(+) ~ ~ ~ OCC~3 O OH OCC~3 ~he filtrates and minor (s~ower~ fractions from chromatograms are combined and re-chromatographed on 60 parts by weight of neutral silic acid 100-200 mesh devel-oping wi~h 600 pprts by volume of 5% ethyl acetate in benzene, foiïowed by 200 parts by volume of 1~ ac~tate i~ benzene, then 200 parts ~y volume of 20%- e~hyl~acetate in benzene.
, ., , . .. ,, . _ , _ . . . . . . . ..
The first fraction is crystallized ~rom benzene-cyclohexane to yield a mixture of the above cis and trans isomers melting at 224~230C~ (decomposition).
The second fraction i~ crystallized from benzene-ethyl ether to gi~e CiS~ 9,ll-bis(acetyloxy)-9-ethynyl-7,8,9,19-tetrahydro-6,7-dihydroxy-5,12-naphthacenedione which melts at 233-235C. (decomposition) and has the following structural formula: .

z ~CC~3 C -C~

~+) ~ ~ C~3 O OH O~

The third fraction is crystallized from benzene to give CiS~ 7,11-bis(acetyloxy)-9-ethynyl-7,8,9,10-tetrahydro-6,9-dihydroxy-S,12-naphthacenedione which melts at 224-226C. and has the following structural formula o ~1 (+) O O~ O~C~3 .
A mixture of 0.4 part by weight of cis-~+)-7,9,11-tris(ace~yloxy~-9-ethynyl-7,8,9,10-tetrahydro-6-hyaroxy-5,12-naphthacenedione [XVI3, 0~58 part by weight of mercuric chloride, 0.10 part by volume of aniline, 24 p~rts by volume of benzene and 4.8 parts by volume of water is refluxed with vigorous stirring for 5 hours. The resulting suspension is `filtered to yield a mercuric complex of the product which is suspended in 300 parts by ~olume of methylene chlori~e.
Hydrogen sulfide is bubbled through the suspension. The mercuric sulfide which forms is removed by filtratio~.and the filtrate is concentrated to dryness~ The residue is ~3~

chromatographed on a 10 parts by weight neutral silicic acid 100-200 mesh column developed with 5~ ethyl acetate i~ methylene chloride. The main fraction is crystallized from benzene-ethyl ether to yield cis~ 9-acetyl-7,9,11-tris(acetyloxy)-7,8,9,.10-tetrahydro-6-hydroxy-5,12-naphtha-cenedione (XVII) which melts at 220-~23C. and ha5 the fol-lowing structural ~ormula +) ~ 1 ~C~3 A suspension of 0.156 part by weight of CiS- t+)-9-acetyl-7,9,11-tris~acetyloxy)-7,8,9,10-tetrahydro-6-hydroxy-5,12-naphthacenedione (XVII) in 40 parts by ~olume of methanol, 10 parts by ~olume of water and 1 part by volume o~ concentrated aqueous hydrochloric acid is refluxed for 40 hoursO The resulting monohydrate which precipitates as red crystals is removed by filtration. The anhydrous form of the product is obtained by reflu~ing a sample of ~he monohydrate in be~zene under a De~n-Stark trap~ The resulting solution is filtered and the filtrate is concentrated to yield a small residue. The residue is diluted with ethyl ether and the resulting solid is collected by filtration to give CiS- (~) -9-acetyl-7,8,9,10-te~rahydro-6.,7,9,ll-tetra-hydroxy-5,12-naphthacenedione (XVIIX) also kno~n as (~

~3~ 2 4-demethoxydaunomyci~one which melts at 194-196C and has the following structural formula o (+)' ~ C 3 O OH O~

EXAMPI2 1~
A suspe~sion of 1.5 parts by weight of trans-~+)-9-(acetyloxy)-9-ethynyl-7,8,9,10-tetrahyaro-6,11-aihydroxy-7-(trimethylsilyl)-5,12-naphthacenedione (XIV) and 3.1 p æ ts by weight of lead tetraacetate in 25 parts by volume o~
acetic acid is stirred fox 3 hours (until all the red solid dissolves~ Addition of 0.9 part by weight of potassium fluo-ride gives a thick white preci~;~itate llead II fluoride).
The mixture is stirred for 18 hours at room temperature then diluted wi~h 200 parts by volume of methylene ~hlorideu The white precipitat~ is removed by filtration. To the filtrate is added 1 part by weight of sodium bisulfite, then 100 par~s by volume of water is added slowly with stirring.
The organic layer is separated and washed with water and dried over sodium sulfate. After ~he solvent is removed, the residue is triturated with ethyl ether then recrystallized rom methylene chloride-ethyl ether to yield cis~ 7,9-bis-(acetyloxy~-9-ethynyl-7,8,g,10-tetrah~dro-6,11-dihydroxy-5,12-naphthacenedione lXX) which melts at 2S5-266C. and has the following structural formula q OH C--C~I
(+, ~ J ~ ~l`ollc~3 O OH OCC~I3 The combined mother liquors are chromatographed on ~0 parts by weight of neutral s~ acid, develo~ with 1% ethyl acetate in methylene chloride. The first ~raction eluted is crystallized from methylene chloride-ethyl ether to yield the above product.
The second fraction is crystallized from methylene chloride-e~hyl ether to yield Ci5~ )-9- (acetyloxy~-9~
ethynyl-7,8,9,10-tetrahydro-6,7,11-trihydroxy-5,12-naphtha-cenedione which melts at 245-248C. and has the following structural formula o OEI
(+, r~ ~f~ ~ 3 O OH O~
The ~hird fraction is evaporated to provide crude cis-~+~-7-(acetyloxy)-9-ethynyl-7,8,9,10-tetrahydro-6,9,11-trihydroxy-5,12-naph~hacenedione which has the following structural formula ~3~
~-CII

o OH O I I CH3 A suspensio~ of 1~066 parts by weight of CiS- (+) 7,9-bis~acetyloxy)-9-ethynyl-7,8,9,10-tetrahydro-6,11- .
dihydroxy-5,12-naphthace~edione (XX) and 1.50 parts by weigh~
of mercuric chloride in 0.26 part by volume of aniline, 8~0 parts hy volume of waterr and gO.Q parts by volume of ben~
zene is refluxed with vigorous stirring for 12 hours and then allowed to cool to room temperature.
The solid i5 collected by filtxation. The organic layer of the filtrate is separated and evaporated to dryness.
The residue is combined with the solid and suspended iR 800 ,parts by vol~me of methylene chlorideO 50 Parts by volume o~ 10% aqueous hydrochloric acid is added and ~he mixture is stirred until solutio~ i~ completeO The me~hyle~e chlori~e layer is separated~ treated wi~h hydrogen sulfide a~d filtered.
The filtrate is concentrated and the residue is crystallized .
from me~hyle~e chloride-ethyl ether to giYe CiS~ 9 acetyl-7~9-bis(acetyloxy)-7,8,9,10-tetrahydro-6,11-dihyaroxy-5,12-naphthacenediQne (XXI) which melts at 243-245C. and has the following structural formula .

~+) ~ ~ CC~3 O O~ OCC~3 A suspension of 0.082 parts by weight of Ci-~
9-acetyl-7,g-bis(acetyloxy)-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-naphthacenedione ~XXI) in 40 parts by volume of iso-S propanol, 5 parts ~y volume of water, and 1 part by volume o~
concentrated hydrochloric acid is refluxed for 4~ hours, then diluted with 10 parts by volume of water and distilled until about 20 part~ by volume remain in the reaction vessel. The mixture is allowed to cool and the solid which forms is . 10 collected, washed with water, and ~ried then rearystallized from benze~e-ethyl ether tv give cis (+)-9-acetyl-7,8,9,10-tetrahydro-6,7,9,11-tetrahydroxy-5,12-naphthacanedione (XVIII) which melts at lg7-200C ana has the following ~tructural formula ~+) O ~ OlEI

. ExAMoeLE_21 Substituting 5-methoxy-1,4,9,lO-anthracenetetrone for the 1,4,9,10-anthracenetetrone in Example 5 and sub- .

st~ntially repeating pr~cedures described in Examples 5 through 20 gives Ci6- (+) -9-acetyl-4-methoxy-7,8,9,10-tetrahydxo-6,7,9,11-tetrahydroxy-5,12-naphthacenedione also known as (~)-daunomycinone which has the following structural formula ~1 r~
OC~3 V O~ O~

A solution of 0.7 part by weight of methyl vinyl ether in 12 parts ~y volume of dry tetrahydrofuran is cooled to -55C and three parts by volume of 1.8M tertiary butyl lithium in pentane is added. The resulting suspension is allowed to warm until solution is complete and is then added to a cold ~-30C) solution of 0.382 part by weight of (+)-3,4,4a~,12aB-tetrahydro-6,11-dihydroxy-1-~rime~hyl-silyl)-2,5,12(1}~)-naphthacenetrione (IX) in 20 ml o:E dry tetrahydro~uran. The reaction mixture is allowed to warm slowly to about 0C and is poured onto 200 ml of 20~ a~ueous ammonium chloride solution. The mixture is extracted wi~h me~hylene chloride and the extracts are washed with water and dried over sodium sulfate. Removal of solvents leaves a brown oil which is crude (~-1,2,3,4,4a~,12a~-hexahydro-3~,6,11-trihydroxy-3-51-methoxyethenyl)-la-(trLmethylsilyl)-5,12-naphthacenedione (XXII) which has the following structural formula ~31~

ll~2 OH O ~ C ~ OCH3 o~

OH O H Si~CH3)3 This crude material is dissolved in 40 ml of isopropanol and 10 m7 of 0.lN hydrochloric acid is added. After stirring for 1 hour at room temperature, the mixture is diluted with water and the crude product is collected and dri~d. Chromato- ¦-graphic purification on neutral ~l~ic acid developing with 10% ethyl acetate in benzene produces a main fraction consis-ting of about 70% of (~)-3-acetyl-1,2,3,4~4a~,12a~-hexahydro-3~,6,11-trihydroxy-la-(trimethylsilyl)-5,12-naphthacenedione ~XXIII) which has ~he following structural formula ~ C~3 ~+, ~ ~['` ~' .

o~ o ~ Si(C~3~3 and about 30% of (+)-3-acetyl-lt2,3,4,4a~,12a~-hexahydro-3,6,11-~rihydroxy-la-~trimethylsilyl)-5,12-naphthacenedione which has the following structural formula (+) ~ ~ 3 `' OH O ~ Si~C~3)3 ~ 3~,2~

EY~MPLE 23 A suspension of 0.130 part by weight of crude (+~-3-acetyi-1,2,3,4,4a gf 12a~-hexahydro-3~,6,11-trihy~roxy-la-(tr~methylsilyl)-5,12-naphthacenedione ~XXIII) in 10 parts by volume of isopropenyl acetate and 0.060 part by weight of ~-toluenesulfonic acid monohydrate is stirred for 72 hours at room temperature, with solution gradually occurring. Fol-lowing the addition of 0.100 part by weight of sodium bicar-bonate the mixture is diluted with water and extracted with methylene chloride. The extract is evaporated to dryn~ss and the residue is purified by chromatography on neutral silicic acid developing with 2% ethyl a~etate in benzene. The main raction is crystallized from methylene chloride ethyl ether to yield (+)-3-acetyl-3~-~acetyloxy~-1,2,3,4,4a~,12a~-hexahydro-6,11-dihydroxy-la (trimethylsilyl)-5,12-naphtha-cenedione (XXI~) which melts at 238-242~C. and has the fol-lowing structural formula ~+) ~ /OIlC~3 011 0 ~I Si ~C~I3) 3 .

The mo~her liquors contain additional ~mounts of this compound mixe~ with the isomexic (+)-3-acetyl 3a-~acetyloxy~-1,2,3,4, 4a~,12a~-hexahydro-6,11-dihydroxy-la-(trimethylsilyl)-5,12-naphthacenedione which hss the following structural formuls:

OH O ~ CCH

(+) ~ ollC~3 OH O H Si(C~3)3 I

To a suspension of 0~340 par~ by weight of (~)-3-acetyl-3~-(acetyloxy)-1,2,3,4,4aB,12a~-hexahydro-6,11-dihydroxy-la-(trimethylsilyl)-5,1~-naphthaceneaione (XXIV3 in 10 parts by volume of acetic acid is added 0.500 part by weight o~ lead tetraacetate. The mixture is stirred vigoro~ly for 30 minutes during which tim~ the yellow solid dissolves and a pink solid ~eparates. After diluting the mixture with 10 parts by volume o~ water the solid is collected, washed with water and dried to yield crude ( )-3-acetyl-3~-(ace~yloxy)-1,2,3,4,4a~,12aB-hexahydro-la-(trimethylsilyl)-5g6~11,12- ~
naphthacenetetrone (XXV) which has the following structural formula . II
/l ~

O O Si(C~3)3 To this material is added 10 parts by volume of acetic acid, the mixture is heated to 90~. and 1 part by volume of a satuxated solution of potassium acetate in acetic acid is added. After 3 hours at 90~C. ~he mixture is allowed to cool ~3~i2~

and is dtluted with 10 parts by volume of water. ~he solid i~ collected, washed with water and dried to yield crude trans-(+)-~-acetyl-9-(acetyloxy)-7,8,9,10-tetrahydro-6,11-dihy~roxy-7-ttrLmethyl~ilyl)-5,12-naphthacened~one (XXVI) S which has the following structural formula (+) ~li r-~ ` /`` olc33 O 0~ Si(CH3)3 This material together with O.001 part by weight of p-toluene-sulfo~ic acid monohydrate is heated in 25 parts by volume of isopropenyl acetate with ~low distillation of about 10 :
parts by volume over a 4 hour period. The mixture is cooled to room temperature a~d O.100 part by weight of sodium bicar-bonate is added followed by 20 parts by volume of water. The resulting suspension is extracted with methyle~e chloride.
After chromatographic purification on neutral s~c acid developing with 1% ethyl acet~ in methylene chloride, the mai~ fraction on tA turation with ethyl ether gives trans-(+) g-acetyl-9,11-bis(acetyloxy)-7,8,9,10-tetrahydro-6- ¦
hydro~y-7- ttrLmethy~silyl)-5,12-naphthacenedione ~XXYII3 whi~h has the following structural formula '~X li ~J'~ I

0 0~ SitCH ) ~.~L L3~

To a solution of 1.0 part by weight of .lead tetra-acetate in ~5 parts by volume of acetic acid is added 0.5 part by vo~ume of water and 0.32 part by weight of trans-l+)-9-acetyl-9,11-bi~acetyloxy)~7,8,g,10-tetrahydro-6-hydroxy-7-(trimethylsilyl)-5,12-naphthacenedione (XXVII).
After 2 hours at room temperature ~he reaction i8 complete and the mixture is diluted with 250 parts by volume of water.
The resulting precipitate is collected, washed with water and dried. The solid is extracted with methylene chloride flltering to remove the lead oxides. The solution is concentratsd to a small volume and diluted with ethyl ether to give a solid which is recrystallized from methylene chloride-ethyl ether to yield pure Ci5- (+) -9-acetyl-7,9,11-tris(acetyloxy)-7,8,9,10-tetrahydro-6-hydroxy-5,12-naphthacenedione (XXVIII) which melts at 220-223C. and ha-~ the following structural formula o o8cH f~

(+~ ~ ~3 Chromatographic separation of the mother liquors on neutral s~ acid developing wi~h 10~ ethyl acetate in benzene gives two main fractionsO The first ~raction consists of a mixture containing about 25% of the above compound with about 75%
of trans~ 9-acetyl-7,9,11-tris(acetyloxy)-7,8~9,10-_ tetranydro-6-hydroxy-5,12-naphthacenedione which has ths followi~g structural formula .

~3~
C~3 O OH OCC~3 The second fraction consists of an approximately equal mixture of cis- and trans-~+)-9-acetyl-9,11-bis(acetyloxy)-7,8,9,10- -tetrahydro-6,7-dihydroxy-5,12-naphthacenedione which have the following structural formulas O O
O OICCH3 OCC~
(+) ~ ~OClc}~3 O ~ OEI :-~+) ~ 3 O ~ 0~ ' :
~ EXa~PLE 26 A round bottom flask containing a ma~etic stirxing bar is charged with 25 parts by volume of anhydrous ethanol~
Argon is bubbled through the stirred solvent for 1 hour.
The Rolvent is then refluxed for 1 houx ~nder an argon abmosphere ~3~

and cooled to room temperature. 0.1 Part by weight of (+)-3-(acetyloxy)-1,4,4a~,12a~-tetrahydro-6,11-dihydroxy-~ -~trimethylsllyl)-5,12 naphthacenedione (VII) is added to the flask producing a yellow heterogeneous mixture which is S cooled to 0C. in an ice bath. 0.34 Parts by volume methyl-magnesium bromide in ethyl_ether_(2.15M) i~ syring~d into the _ stirred reaction mixture. After 45 minutes at 0C. the homo-geneous orange solution is poured into a mixture of SO parts by volume o 2% acetic acid and 50 parts by volume of methylene chloride. The methylene chloride phase is separated and the aqueous phase extracted twice with 50 parts by volume of methylene chloride. The combined organic extracts are dried over anhydrous disodium sulfate, filtered and stripped on a rotary evaporator to give (~)-3,4,4a~12a~-tetrahy~ro-6,11-dihydroxy-la1~rimethylsily~-2,5,12~ naphthacenetrione (IX) whish has the following structural formula (+1 ~

Si(C~3)3 EXAMæLE 27 Substituting 5-hydroxy-1,4,g,10-anthracenetetrone for the 1,4,9,10-an~hracenetetrone in Example 5 and substan-tially repeating procedures described in Examples S through 20 gives cis-(+)-9-acet~1-4-hydroxy-7 r 8,9,10-tetrahydro~6,7,9,11-~43-~L~3~

tetrahydroxy-5,12-naphthacenedione also known as ~)-carmino-mycinone which has the following structural fonmula O Q~ CCH3 '+

OH O OH O~

Claims (3)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound of the formula (XIII):

(?) (XIII) wherein X is hydrogen, methoxy, or hydroxy, which comprises either a) oxidation of a compound of the formula (XII):

(?) (XII) with lead tetra-acetate, or b) heating a compound of the formula (XI):

(?) (XI) with isopropenyl acetate and acid.

2. The process as in claim 1 wherein the compound thus prepared is (?)-3.beta.-(Acetyloxy)-3-ethynyl-1,2,3,4,4a.beta.,12a.beta.-hexahydro-1.alpha.-(trimethylsilyl)-5,6,11,12-naphthacenetetrone.

3. The process as in claim 1 wherein the compound thus prepared is (?)-3.beta.-(Acetyloxy)-3-ethynyl-1,2,3,4,4a.beta.,12a.beta.-hexahydro-1.alpha.-(trimethylsilyl)-10-methoxy-5,6,11,12-naphtha-cenetetrone.

4. A compound of the formula (XIII):

(?) (XIII) wherein X is hydrogen, methoxy, or hydroxy, whenever pre-pared by the process as claimed in claim 1.

5. A compound of the formula as defined in claim 4 which is (?)-3.beta.-(Acetyloxy)-3-ethynyl-1,2,3,4,4a.beta.,12a.beta.-hexahydro-1.alpha.-(trimethylsilyl)-5,6,11,12-naphthacenetetrone, whenever prepared by the process as claimed in claim 2.

6. A compound of the formula as defined in claim 4 which is (?)-3.beta.-(Acetyloxy)-3-ethynyl-1,2,3,4,4a.beta.,12a.beta.-hexahydro-1.alpha.-(trimethylsilyl)-10-methoxy-5,6,11,12-naphtha-cenetetrone, whenever prepared by the process as claimed in

claim 3.