C-GLYCOSIDIC ADRIAMYCIN ANALOGS

Abstract: A new procedure for preparing the C.1-2,4-pentadienyl derivatives of 2-deoxyhexopyranoses, as well as a new procedure for allylation of daunosamine. These methods are particularly useful for the preparation of intermediates in the synthesis of adriamycin C-glycosidic analogs which are useful anti-tumor agents. These methods provide the first enabling disclosure of methods to prepare these desired adriamycin and anthrocyclinone C-glycosidic analogs.

Description: C-GLYCOSIDIC ADRIAMYCIN ANALOGS Acknowledgement of Government Support This work was supported by PHS Grant CA32250, awarded by the National Cancer Institute, DHHS. Technical Field This invention concerns synthetic methods in the preparation of desired organic compounds. More particularly, the invention concerns general methods which can be used specifically for the preparation of intermediates in the synthesis of C-glycosidic adriamycin and araetantrone analogs which will have useful anti-tumor activity. Background Art Among the plethora of chemotherapeutic agents in use at this time for the treatment of solid tumors, metastatic conditions, and leukemiaβ, adriamycin and its analogs are among the most prominent. Adriamycin is a commercial name for doxorubicin. which is a polycyclic naphthacene-baβed glycoside of the deoxyamino sugar, daunosamine. A class of similar compounds, which are also glycoβides of daunosamine, but which contain polycyclic systems related to anthracene, is represented by ametantrone and mitoxantrone. This class also has powerful anti-tumor activity. It has been suggested that the C-glycoside analogs of these anti-tumor compounds might have some advantageous properties in connection with their therapeutic use. It is known that adriamycin and its analogs are inactivated by de-glycoβidation. It is expected that though the C-glycoside analogs would be resistant to this degradation, aβ they are isoβteric to compoundβ of known anti-tumor activity, they should be effective in analogous therapeutic ways. Acton, E. M. , et al. Carbohydrate Research (1981) 92:235-245 suggested a synthetic pathway for the preparation of such C-glycosidic analogs, but the reaction pathway suggested has since been shown not to yield the expected products. Therefore, although the goal was stated, the means for attaining it have not been available in the art. The present invention provides a general means for obtaining essential intermediates in the production of the desired C-glycosides. It is also of general use in obtaining pentadienyl and acetaldehyde derivatives of 2-deoxypyranoβe sugars. Disclosure of the Invention This invention enables the production of Cl (2,4-pentadienyl)glycosides of a 2-deoxypyranose. and. in particular, these derivatives of daunosamine. The method is useful for preparing the acetaldehyde derivatives as well. The resulting pentadienyl derivatives are useful as intermediates because they can then be linked to appropriate polycyclic systems using a Diels-Αlder reaction and converted to desired C-glycosidic adriamycin analogs using standard means known in the art. The acetaldehyde derivatives are useful as substrates for Wittig type reactions to obtain related pentadienyl derivatives. Thus, the methods of the invention provide the first enabling disclosure directed to these C-glycosides. In one aspect, the invention relates to a method for preparing C.l-(2,4-pentadiene) derivatives of 2-deoxypyranose sugars. This method is applicable to the preparation of such derivatives of daunosamine. It compriβeβ treating the 2-deoxypyranose, which has a leaving group at Cl. with a- l-trimethylsilyl-2,4- pentadiene in the presence of a Lewis acid. In another aspect, the invention relates to a method for the preparation of Cl acetaldehyde derivatives of 2-deoxypyranoβes, in particular, of daunosamine. using an analogous process to obtain the Cl allyl derivatives, and then subjecting these to ozonolysis. In other aspects, the invention relates to the intermediates so prepared and to the target compounds to which these intermediates are converted. Thus, the invention relates to compounds of the formula: OH wherein X is O or NH; Y is H or OHe: with the proviso that if X-NH. Y must be OMe; R is COCH , COCH OH. CHOHCH... CHOHCH 2 OH. H. 1-3C alkyl. 1-2C terminal hydroxyalkyl or the 2-7C alkyl or aryl organic acid esters or 1-6C alkyl ethers thereof; or 13-ketimine (such as hydrazones and oximeβ) derivatives of COCH. or COCH.OH; at least one of R2 and R3 is H, and the other is OH or OCH,; and A and B are each independently H or alkyl (1-6C). or A and B taken together are orpholino. thiomorpholino, or piperidinyl. optionally mono or di substituted by CN. The compounds of formula (1) are useful as anti-tumor agents. Another aspect of the invention relates to compounds of the formula: wherein R, R , R , A and B are as above-defined, and H is H or OH. These compounds of formula (2) are also useful anti-tumor agents. Other aspects of the invention relate to intermediates in the reactions converting the new products of the novel chemical synthesis methods of the invention to the compounds of formulas (1) and (2). Thus, in still another aspect, the invention relates to compounds of the formula: NHP wherein Y is as above-defined; P is a protecting group, such as acetyl, trichloroacetyl, or, optimally trifluoroacetyl; R. is H o -a protecting group, such as acyl (1-4C), or optionally substituted aroyl (6-15C); and Q is H, alkyl (1-3C), OMe. OEt, -OCH-CH-OMe, -O-tetrahydropyranyl, Br, or COOMe. The compounds of formula (3) result from modifying a polycyclic ring system which results from the Diels-Alder condensation of the appropriate pentadienyl glycosides with the appropriate anthracene tetrone analogs. This polycyclic ring system is contained in the compounds of formula (4): In still another aspect, the invention relates to the compounds of formula (4) wherein Q. P, Y and R are as above-defined; and wherein the dotted line at Z indicates either a TΓ bond or an epoxide ring. In still another aspect, the invention relates to compounds of formula (5) which are intermediates analogous to those of formula (4) but which result from Diels-Alder condensation with a naphthalene analog. The compound of formula (5) have the structure: NHP wherein P, Q, R and W are as above-defined. In still other aspects, the invention relates o compounds of the formulas: NHP NHP wherein P, Q and R are as set forth above. Compounds of the formula (6) where Q is H, CH., OHe, OEt, -OCH CH.OMe, or -O-tetrahydropyranyl, and the compound of formula (7) are obtainable as the direct substitution products in the pentadienylation or allylation method of the invention. Compound (8) is the ozonolysis product of compound (7). Compounds of formula (6) wherein Q is as above, and also wherein Q is ethyl, propyl, isopropyl, Br, or COOMe. are obtainable by a Wittig reaction using the compound of formula (8). Modes of Carrying Out the Invention A. Definitions and General Parameters As used herein, "alkyl" is defined as a straight or branched chain hydrocarbon subβtituent having the designated number of carbon atoms; alkoxy is -OR wherein R is alkyl as above-defined; acyl is R- 9C- wherein R is alkyl as above defined. "Aryl" refers to a subβtituent containing a benzene ring which is linked to the substituted compound referred to either directly, or through a lower alkyl (1-4C) chain. Aryl substituents are. therefore, exemplified by phenyl. phenylethyl, 2-phenyl-2- ethylpropyl, and the like. Aroyl is Arc- wherein Ar is aryl as above defined. The alkyl or aryl substituents (including those which constitute the alkyl portion of alkoxy or acyl or the aryl portion of aroyl) referred to herein may. if so designated, optionally be substituted by one to three substituents selected from the group consisting of hydroxy, alkoxy (1-4C), carbonyl (C«0), carbalkoxy (COOR, wherein R is alkyl) or CN. Substitutions may also include multiple substitution by halo such as fluoro. chloro, bromo, or iodo. In the case of aryl substituents these optional substituents may also include alkyl (1-4C) and nitro. A 2-deoxy hexopyranose (or other substrate) which is "activated", for example, in the 1-position is "activated" by the presence of a good leaving group in that position. The daunosamine sugars may conveniently be activated in the 1-poβition by esterifying the -OH with an aroyl group, especially p-nitrobenzoyl. It will be noted that the compounds claimed herein contain a number of chiral centers. Where the depiction of such chiral centers is ambiguous, it is understood that either configuration comes within the denoted species of the formula. The ordinary conventions of projection formulas are used where configuration is specified. If it is desired to separate the compounds into forms which are represented by only one configuration, this is possible using standard techniques for the separation of organic chemicals, such as recrystallization, chromatography. thin layer chromatography. and the like. All of the compounds of the invention contain daunosamine or a protected form, βterβoisomer, or derivative of daunosamine. Thus compounds of the invention contain configurations at the daunosamine chiral centers which are already fixed, and all of the,permutations of the remaining chiral centers will generate compounds which are diastereomers with respect to each other, permitting standard separation techniques to be used. It should be noted that in the compounds of formula (1), which represent end-products of pharmaceutical applicability, the hydroxyl and methylene bridge on ring A occupy chiral carbons. The compounds of the invention include all of the stereoisomers, although those which are isoβteres of the adriamycin series are preferred. Those compounds which are direct products of Diels-Alder addition (formulas (4) and (5)) under most conditions contain the methylene link from ring A to daunosamine and the two cis hydrogens at the A/B ring fusion on opposite sides of the ring. When performed under optimum conditions the substitution which leads to the formation of the pentadienyl glycosides or allyl glycosides is stereoselective in accord with results predicted by the anomeric effect, enhanced in some cases by participation of an O-acyl or O-aroyl group at C-4. To the extent that βtereoselectivity is not realized, the desired stereoiβoroer may be separated using standard separation techniques. B. General Reactions and Modes of Preparation B.l. Summary At the heart of the invention is an effective, and, optimally, stereoselective method for forming the Cl glycosides of 2-deoxy-hexopyranoβeβ. The method comprises treating the substrate 2-deoxy-hexopyranose with l-trimethylsilyl-2.4-pentadiene or 1-trimethyl- βilyl-2-propene to obtain the corresponding Cl-(2,4- pentadienyl) or Cl allyl glycoβide respectively. Either of these glycosides may be converted to the corresponding pyranoβyl acetaldehyde by ozonolysis. The products of the reactions which represent the methods of the invention are particularly important when the pyranose substrate is daunosamine (i.e., 2,3,6- trideoxy-3-amino-L-lyxohexopyranoβe). The pentadienyl products are capable of reacting with suitable dieneophileβ included in polycyclic naphthalene or anthracene based systems to obtain C glycosides of anthracene or naphthacene polycyclic systems, respectively. These products are readily convertible to adriamycin or ametantrone/mitoxantrone analogs with anti-tumor activity. The allyl glycoside products are primarily useful by virtue of their ability to be converted to the corresponding acetaldehyde derivatives which can then be used as substrates for Wittig type reactions to obtain pentadienyl glycosides that bear a greater variety of Q substituents than are obtainable directly using a tri ethylsilyl pentadiene. In short, the methods of the invention offer both a general method for forming Cl allyl or pentadienyl substituted 2-deoxy-hexopyranoses, and a method specifically for obtaining intermediates in the synthesis of compounds with anti-tumor activity. The routes made possible to obtain these compounds are set forth in schematic form in reaction scheme 1. adriamycin analogs -13- If the pentadienyl daunosamine is obtained directly (left route). Q must be H. methyl. OMe. OEt. -OCH-CH-OMe. or -O-tetrahydropyranyl and the product compound of formula (1) or (2) will be limited accordingly. R in the compounds formula (1) or (2) thus produced must be H or methyl, or embodiments of R obtainable by addition to an A-ring carbonyl, as further described below. Additional embodiments of R may be obtained, however, by use of the Wittig reaction with the daunosaminyl acetaldehyde of formula (8) (right hand • route) . The resulting C-glycosidic analogs of the adriamycin group are then used in a manner similar to that disclosed with respect to the adriamycin group per se, as, for example, set forth in U.S. patent 4.464,529 issued 7 August 1984 to the same assignee, and incorporated herein by reference. The C-glycosidic ametantrones/mitoxantrones are used as described by Wallace, R. E.. et al, Cancer Res (1979) 39.:1570; (1980) 4_:1427 incorporated herein by reference. B.2. Allylation Pentadienylation Reactions In the most general terms, a 2-deoxyhexo- pyranose sugar substrate "activated"—i.e.. containing a suitable leaving group, at position 1 is treated with either allyl trimethylsilane. 2.4-pentadienyl trimethylsilane or the corresponding 2-methoxy-. 2-ethoxy-. 2-methyl-, 2-(2-methoxy)ethoxy- or 2-tetrahydropyranoxy- derivatives of 2.4-pentadienyl trimethylsilane in the presence of a Lewis acid. The trimethylsilane starting materials are available by synthesis using known methods. Any available allyl or pentadienyl trimethylsilane compound can be used and the foregoing are listed as among those previously synthesized. The substrate sugar is a 2-deoxyhexopyranoβe having a suitable leaving group at position 1. Such leaving groups include aroyl substituents such as benzoyl. toluoyl, or p-nitrobenzoyl or may be fluoro. However, the p-nitrobenzoyl leaving group iβ extremely successful, and the reaction is optimally stereo¬ selective when this leaving group is used. Alternative leaving groups may result in loss of stereoselectivity. Accordingly, the p-nitrobenzoyl leaving group is highly preferred and it is, indeed, pointless to utilize others as the p-nitrobenzoyl derivative is quite easily made, and is entirely satisfactory. The α p-nitrobenzoyl (pNB) derivative of daunosamine, for example, yields almost exclusively the α glycoβylated product. The remaining substituents on the pyranose ring may influence the stereoselectivity; in particular an acyl or aroyl group in the 4 position of daunosamine aids in the formation of the α derivative. The substrate sugar may be any 2-deoxyhexo- pyranose and may have additional deoxy positions, as well as amino substitutions. That is. positions 3, 4, and 6 may each be, independently, OH as in the basic pyranose structure, deoxy, or deoxyamino. wherein the hydroxy and amino groups may occupy either of the two possible chiral configurations. If amino groups are present, they must be protected by suitable protecting groups such as acyl or aroyl. A particularly useful protecting group is trifluoroacetyl. This group iβ entirely successful, easily attached, easily removed when desired, and quite effective. While alternate protecting groups could, in principle, be used, as was the case with the pNB derivative of the Cl hydxoxyl, there is no particular point in seeking alternatives in the face of this success. Hydroxyl groups are desirably, but not necessarily protected as well. Suitable protecting groups include benzoyl, pNB, and other acyl or aroyl esters. pNB appears particularly satisfactory for this purpose. A particularly preferred substrate, because of the utility of the products, is a protected daunosamine, e.g. , l,4-di-0-p-nitrobenzσyl-2.3,6-trideoxy-3- trifluoroacetamido-α-L-lyxo-hexopyranoβe. The reaction is conducted in the presence of a Lewis acid such as TiCl. or Me.SiOSO-CF.. and most preferably in the presence of boron trifluoride etherate. The reaction is carried out by preparing a mixture of the pyranose and silane reagents in the presence of a moderately -polar aprotic organic solvent such as, for example, acetonitrile, ether, or tetra- hydrofuran, preferably acetonitrile. The Lewis acid, for example, boron trifluoride in ether solution is added slowly to the mixture, preferably dropwise. The reaction iβ allowed to increase in temperature to approximately room temperature and stirred for sufficient time to allow ~he reaction to go substantially to completion, usually around 2-4 hr. The product iβ isolated from the reaction mixture using ordinary means, such as extraction into an inert organic solvent from aqueous base, followed by evaporation of solvent, and subjected to subsequent standard purification techniques. The reaction conditions are quite mild and straightforward, and depending on the stereochemistry of the ring, and 'the nature of the leaving group, a high yield of the desired α product (i.e.. the α glycoβide) is obtained. B.3. Alternative Method to Form the Cl Pentadienyl Glycosides An alternate approach to prepare the Cl pentadienyl daunoβamineβ of formula (6) takeβ advantage of the formation of the corresponding allyl glycoside. prepared as in TB.2. The allyl compound is converted by standard ozonolyβiβ procedures to the 2-daunosaminoyl acetaldehyde derivative, as in reaction scheme 2, which is then converted to the correβponding pentadienyl derivative by a standard Wittig reaction using a compound of the formula CH2«C-CH2Br wherein Q is as Q above-defined. Reaction Scheme 2 The reβulting pentadienyl glycoβides may be used in the Diels-Alder reaction of IB.4. B.4. Diels-Alder Reactions When daunosamine or its derivatives are used as βubβtrateβ for the pentadienylation reactions of the invention as decribed in IB.2 or in the conversion sequence of IB.3, the resulting Cl-(2.4-pentadienyl)- glycoβideβ can be converted, by Diels-Alder reaction with suitable polycyclic systems, to intermediates in the formation of adriamycin analogs or the correβponding ametantrones. The carbohydrate substrate for the Diels-Alder reaction is an N-protected 2,3,6-trideoxy-3-amino-α- L-lyxohexopyranoside having the Cl pentadienyl substitution. The amino group may be protected by any suitable acylating agent such as and preferably, for example, trifluoroacetyl. This amino group may then, βubβequently, be. converted to alternative N-derivatives as will be described below. in the Diels-Alder, and subsequent reactions the 4-hydroxy group of the daunosamine may be in the free hydroxyl form, or may be eβterified by reaction with suitable carboxylic acid derivatives to give the acyl or aroyl or substituted aroyl ester. The ester group may later be removed by standard hydrolysis procedures. The dienophile used for the Diels-Alder reaction in preparing the useful intermediateβ to the adriamycin or ametantrone analogs iβ generally a polycyclic dione or tetrone. and the product is a naphthacene or anthracene derivative. For the anthracene (ametantrone analog) products, a useful dieneophile is 5,8-dihydroxy-l,4--naphthaquinone. For adriamycin analogs, useful dieneophile substrates are compounds of the formula: wherein Y and Z are as above-defined. The Diels-Alder reaction shown in scheme 3 iβ performed in the presence of an inert aprotic βolvent such as, for example, toluene. The reaction is carried out under an inert atmosphere such as nitrogen, at a temperature range of about 60°C-100°C, preferably about 80°C-85°C for approximately several hours. The product is isolated using routine procedures. Reaction Scheme 3 The 4-hydroxyl is shown as unprotected; however in a preferred embodiment a pNB group would be used for this purpose. The linking methylene in the product is on the opposite side of the ring from the hydrogens of the A/B ring bridge (this reβulting from the endo reaction); thus the representations in Reaction Scheme 3 are of diaβtereomeric pairs which may be separated using standard chromatographic techniques. B.5. Conversion to Target Compounds For the ametantrone analogs, the Diels-Alder products are directly convertible to the target compounds of formula (2) by modifying the A ring subβtituent Q to obtain the desired R, if necessary. followed by aromatization of the A ring. For the adriamycin analogs, preliminary modification of the B and C rings may be required prior to adding the elements of wate *r to the A ring double bond. B.5.a. Adriamycin Analogs The Diels-Alder products of TB.4 which will lead to the target compoundβ of the formula (1) may be βeparated into desired βtereoiβomers at any convenient stage of the following reactions. The first steps of the conversion to the target compounds result in enolization of the carbonyl moieties of ring B to a hydroquinone. This iβ a one-step reaction if Z iβ a rt bond, but a three-step reaction if Z represents an epoxide. Where Z represents an epoxide, the compound of formula (4) iβ first reduced to the correβponding alkene in a two βtep reaction using, first sodium dithionite to aromatize the C ring, followed by treating with lead tetraacetate to give the desired alkene. This alkene is, .of course, the direct product of the Diels-Alder reaction when Z is a TΓ bond. The alkene iβ then treated with acid in the presence of a polar solvent and in an inert atmosphere at approximately room temperature for sufficient time to permit the desired enolization to take place. This time iβ usually 2-6 hr, roughly around 4 hr. The desired product of formula (3) is accompanied by a side product of formula (11) as shown in reaction scheme 4. The compound of formula (11) may also have useful anti-tumor activity when modified by removal of protecting groups as described in % B.6 below. 10 Reaction c eme The protecting group for the amino. which iβ. ideally, trifluoroacetyl iβ still present. The hydroxyl at poβition 4 will, under most conditions also retain the protecting group which was present through the previous reactions, although the 4-poβition is shown here with a free OH. The remaining steps to obtain the desired target compounds depend on the nature of Q and the nature of R. Where Q is identical to the desired R in the target compound, the conversion iβ simplified accordingly. (It should be apparent that Q and R are only identical if Q is H or alkyl (1-3C).) The compoundβ of formula (3) then need only to be further modified by addition of the elements of water to the ring A double bond, and by removal of the TFA protecting group to obtain the embodiments of the compoundβ of 2 3 formula (1) wherein R is H, R is OH; and A and B are both hydrogen. Further modification of R 2, R3, A and B may also be effected as described in T B.6. Similarly, removal of protecting groups from the βide products of formula (11) results in analogous compounds with anti-tumor activity. The addition to the A ring π bond will be conducted in a manner dependent on the nature of Q. If Q is H in formula (3) this will be done with a regioβelective agent such as a bulky alkyl borane, preferably 9-BBN under conditions suitable for this reagent (see, for example, Brown, H. C , et al, J Am Chem Soc (1977) 9_£:3427). The addition reβultβ in a compound which differβ from a compound of formula (1) wherein R iβ H only in requiring the removal of protecting groups, and optional modification of the sugar substituents, as described in T B.6. For those embodiments of formula (3) wherein Q is alkyl (1-3C). hydration of the double bond will be carried out uβing customary reagents for the addition of the elements of water. (If Q is COOMe, the same procedure is followed as for ■ alkyl, but the resultant product of the hydration must then be reduced with, for example, a metal hydride to obtain the correβponding alcohol - i.e. R « CH-OH. which could optionally be esterifled or converted to the ether. Compounds of formula (1) which result include, for example. 3-hydroxymethyl-l,2,3,4-tetrahydro-5,12-dihydroxy-l- [(2,3,6-trideoxy-3-amino-α-L-lyxo-hexopyranosyl)methy1] naphthacene-6,ll-dione. 3-butanoylmethyl-l,2,3,4-tetrahydro-5,12-dihydroxy-l- [(2,3,6-trideoxy-3-amino-α-L-lyxo-hexopyranoβyl)methyl] naphthacene-6.11-dione, and 3-butoxymethyl-l,2,3,4-tetrahydro-5,12-dihydroxy-l- [(2,3,6-trideoxy-3-amino- -L-lyxo- ^ hexopyranoβyl)methyl]' naphthacene-6,11-dione. ) For the remaining cases wherein R iβ not identical with Q, the appropriate hydration product iβ used to obtain an intermediate with a carbonyl group in the A ring. If Q is H, the hydration product iβ oxidized using a relatively mild oxidizing agent, such as dimethyl βulfoxide/dicyclohexylcarbodiimide or pyridinium chlorochromate under neutral conditions to obtain the corresponding ketone. If Q iβ a leaving group βuch as Br or OMe, no oxidation is necessary. An acetylide is then added to the ketone as shown in reaction scheme 5, and the product converted to the desired embodiments of R. [ 0 ] dns dns (10) Reaction Scheme 5 The ketone iβ treated with a sodium or lithium acetylide, or the correβponding magneβium bromide acetylide and hydrated in the preβence of mercuric oxide to obtain the addition product βhown in reaction βcheme 5 as formula (10). Modifications of the acyl. roup to obtain the various alternate embodiments of R in formula (1) employ conversions known in the art. The compound of formula (10) may, itself, be deprotected and modified as desired according to the procedureβ set forth in t B.6 to obtain embodiments of the formula (1) wherein R is COCH.. βuch as. for example, 3-acetyl-l.2.3,4-tetrahydro-5,12-dihydroxy-l- [(2.3,6-trideoxy-3-amino-α-L-lyxo-hexopyranosyl)methyl] naphthacene-6,11-dione. The acyl may also be reduced to the correβponding alcohol, thus providing an intermediate for conversion by deprotection and modification procedures to compounds of formula (1) wherein R is CHOHCH-, such as 3-(l-hydroxyethyl)-l,2,3,4-tetrahydro- 5,12-dihydroxy-l-[(2,3,6-trideoxy-3-araino-α-L-lyxo- hexopyranosyl)methyl]naphthacene-6,11-dione. This may optionally be followed by derivatization to the eβter or. ether. Reaction with bromine at the α carbon of the acyl βubβtituent permits formation of embodiments wherein R contains a terminal hydroxy or ester or ether derivative thereof. By treating the compound of formula (10) with bromine, followed by substitution of the bro o subβtituent in baβe. compoundβ of the formula (1) are obtained wherein R iβ COCH.OH, βuch as 3-(2-hydroxyacetyl)-1,2.3,4-tetrahydro-5.12-dihydroxy- l-[(2,3,6-trideoxy-3-araino-α-L-lyxo-hexopyranoβyl) methyl]naphthacene-6,11-dione. The intermediates bearing the -COCH.OH βubβtituent may be used to obtain various additional embodiments of R. In one conversion, the carbonyl is reduced to the alcohol, by treating with an appropriate metal hydride, to obtain compounds suitable for deprotection and modification to the various compounds of formula (1) wherein R is CHOHCH.OH, such as 3-(1.2-dihydroxyeth l)-l,2,3,4-tetrahydro-5.12-dihydroxy- l-[(2,3,6-trideoxy-3-amino-α-L-lyxo-hexopyranoβyl) methyl]naphthacene-6,11-dione. Alternatively, the carbony1 may be reduced to the methylene, leaving intact the terminal hydroxy. thus permitting conversion to compoundβ of formula (1) wherein R iβ CH-CH.OH, and their correβponding esters and ethers. Exemplary of βuch compoundβ iβ 3-(2-hydroxyethyl)-l,2,3.4-tetrahydro- 5,12-dihydroxy-l-[(2,3,6-trideoxy-3-amino-α-L-lyxo- hexopyranoβyl)methyl]naphthacene-6,11-dione. Intermediates, or compoundβ of the formula (1) wherein R iβ COCH. or COCH.OH may also be converted to the coresponding ketime derivativeβ by reaction with the appropriate amine, hydroxylamine or hydrazine. Thus, these compounds may be formed by reaction with compoundβ of the formula KNH_ wherein iβ OH or NHS, wherein S iβ an alkyl or aryl βubβtituent. The foregoing conversions are summarized in reaction scheme 6. dns Reaction Scheme 6 B.5.b. Ametantrone Analogβ The compoundβ of the invention of formula (2) which are ametantrone analogβ may be prepared from the intermediate obtained by Diels-Alder reaction without preliminary modification of the polycyclic system. The final step will be aromatization of the A ring as βhown in reaction βcheme 7. (2) Reaction Scheme 7 If Q is identical to R. which is'possible if Q iβ H or alkyl (1-3C), or convertible to R. which iβ the case if Q is COOMe. this iβ the only step (other than deprotection and sugar group modification) required. If, however. Q is not the same as or convertible to Q, . the reaction βhown in βcheme 7 must be preceded by a series of reactions to obtain the desired embodiment. This iβ done by preparing the compound of formula (5) wherein Q is H or a leaving group, and conducting procedureβ preciβely analogouβ to thoβe βet forth in f B.5.a, i.e. addition of the elements of water to the TΓ bond, oxidation, if necessary, to the ketone, addition of acetylide to the ketone. and modifiation of the reβulting acetyl βubβtituent. The coversions are precisely those shown for the adriamycin analogs in reaction βcheme 6. Aromatization of the A ring (which does not. in this case, contain a π bond) is the final βtep in modification of the polycyclic system and iβ conducted by a modification of the conditions βhown in reaction βcheme 7. B.6. Protective Group Removal and Sugar Modification For compounds of either formula (1) or (2), the protecting TFA group from the 3-amino position iβ removed, and, if desired, replaced by suitable βubβtituentβ to obtain the embodimentβ of formula (1) or (2) wherein A and B are as defined. These conversions have been set forth in some detail in U.S. Patent 4.035,566; U.S. Patent 4,301,277; and U.S. Patent 4.464,529; as well as U.S. Serial No. 598.016. filed April 14, 1984, and assigned to the βame assignee, all incorporated herein by reference. Modification of the ring system so as to obtain _C->NH iβ possible in those embodiments wherein Y iβ OMe, as described in U.S. 4,109,076 incorporated herein by reference, similarly, the hydroxyl group at position 4 may be methylated, or may be reduced to form the 4-deoxy sugar by means known in the art. Examples The following examples are intended to illustrate but not to limit the invention. Example 1 Preparation of l-(2.3.6-Trideoxy-4-0-p-nitrobenzoyl-3-trifluoroacetamido- α-L-lyxo-hexopyranosyl)-2-propene. The procedure was similar to that disclosed by Kozikowski, et al. Tetrahedron Lett (1983) 24:1563. 541 mg (1.00 mmoles) of 1.4-di-O-p-nitro- benzoyl-2,3,6-trideoxy-3-trifluoroacetaroido-α-L-lyxo- hexopyranoβe; 505 mg (4.00 mmoles) of allytrimethylβilane; and 157 mg (1.10 mmoles) of boron trifluoride etherate were used. The boron trifluoride was added dropwise to a cold mixture of pyranose and silane in 20 ml of acetonitrile, protected from moisture in an ice bath. The reaction mixture allowed to reach room temperature, and stirred at room temperature for 3 hr. The reaction waβ diluted with 50 ml of βaturated sodium bicarbonate and extracted with 3 x 30 ml of ethyl ether. The ether waβ dried over MgSO.. filtered and evaporated to dryneββ. The oily residue. 420 mg (101\). waβ chromatographed on βilica gel 2 x [20 cm x 20 cm x 2 mm] with 25* EtOAc/hexane and gave R--0.4. Elution yielded 350 mg (94*) of foam. This reβidue was crystallized from 25 ml Et-O/hexanβ (1/6) to give 350 mg (84*) l-(2,3,6-trideoxy-4-0-p-nitrobenzoyl-3- trifluoroacetamido-α-L-lyxo-hexopyranosyl)-2-propene; ; p 138-139*C HPLC silica gel chromatography using 1% isopropanol/hexane gave 100* one isomer. Analysiβ waβ con β i β tent with C..H.β F 3 N 2 0 6 and NMR was consistent with the expected allyl pryanose. Example 2 Preparation of (2.3.6-Trideoχy-4-O ι -p-nitrobenzoyl-3- trifluoroacetamido-α-L-lyxo-hexopyranoβyl)acetaldehyde 208 mg (0.500 mmoles) of the pyranoβyl propene from Example 1 was dissolved in 25 ml McCl_ and chilled to -78 β C (dry ice acetone bath). O, was bubbled through (from a 0_ generator) until a permanent blue color appeared. The blue solution was stirred at -78 β C for 4 hr. The excess 0_ was removed by bubbling argon into the reaction mixture, and 1 ml of dimethyl sulfide added at -78°C to destroy the ozonide intermediate. The reaction was allowed to reach room temperature; TLC showed the presence of intermediate (two spots) but no aldehyde. MeOH (1 ml) waβ added and the aldehyde slowly began to form, as followed by TLC After 3 days stirring, and addition of 5 ml MeOH. most intermediate was converted to aldehyde. The solution was evaporated to dryneβs to yield 190 mg (91*) of (2.3,6-trideoxy-4-0-p-nitrobenzoyl-3-trifluoroacetamido- α-L-lyxo-hexopyranoβyl)acetaldehyde. The residue waβ chromatographed on 20 x 20 cm x 2 mm thick βilica gel plate and developed with 50* EtOAc/hexane. The product waβ eluted with ethylacetate to give 158 mg of aldehyde. The identity of product with the expected aldehyde waβ confirmed by mass βpectroβcopy (m/e-418) and by NMR. Examole 3 Preparation of (E)-l-(2.3.6-Trideoxy-4-0-p- nitrobenzoyl ' -3-trifluoroacetamido-α-L- lyχo-hexopyranoβyl)-2.4-pentadiene The procedure waβ similar to that of ozikowski, et al (supra). 2.80 g (5.17 mmoles) of 1.4-di-O-p- nitrobenzoyl-2.3.6-trideoxy-3-trifluoroacetamido- α(β)-L-lyxo-hexopyranose (α/fi ratio of 1/4); 3.15 g (20.7 mmoles) of (E)-(2,4- pentadienyl)-trimethylsilane; and 0.970 g (6.21 mmoles) of boron trifluoride: etherate were used. The boron trifluoride was added dropwise to a mixture of the pyranose and silane in 100 ml of acetonitrile, protected from moisture in an ice bath. The reaction was allowed to reach room temperature, and then stirred at room temperature for 3 hr. The reaction mixture was diluted with 250 ml of βaturated sodium bicarbonate and extreacted with 3 x 100 ml of ethyl * ether. The ether waβ dried over MgSO 4., filtered, and evaporated to dryneβs to yield 2.6 g of (E)-l-(2,3,6- trideoxy-4-0-p-nitrobenzoyl-3-trifluoroacetamido-α- L-lyxo-hexopyrano8yl)-2,4-pentadiene (114*) as an oil. The residue was placed on a silica gel column and developed with 10* ethyl acetate/hexane to obtain 1.82 g (85*) of pure product. A small sample of the material from the silica gel was purified on thick layer silica gel with 25* EtOAc/hexane. The R £ was 0.4. and the spot, which was eluted with CHC1 3 , showed 100* purity on HPLC Elemental analysis of this sample was consistent with C 2Q H 21 F 3 N 2 0 6 and NMR (400 MHz). Examole 4 Preparation of (E)-l-_2.3.6-Trideoχy-3-trifluoro- acetamido-α-L-lyχo-hexopyranoβyl)-2.4-pentadiene (Removal of p-nitrobenzoyl from position 4) 0.700 g (1.58 mmoles) of the pentadienyl pyranose prepared in Example 3 was mixed with 10 ml of diisopropyl amine and 50 ml of methanol and stirred at room temperature for 18 hr. The solution was evaporated to dryneββ. The residue was placed on two 20 x 20 cm x 2 mm βilica gel thick plates and developed with (1/1) hexane/ethylacetate.. R f «0.33. The eluate (ethyl acetate) contained 380 mg (82*) of foam, which waβ crystallized from 30 ml of hexane to give 359 mg (77*) of (E)-l-(2,3.6-trideoxy-3-trifluoroacetaraido-α-L- lyxo-hexopyranoβyl)-2,4-pentadiene, mp 111-112*C Analysis was consistent with 13 H 18 F 3 N0 3 and tnβ NMR (300 MHz) matched that expected for the desired product. Example 5 (The Diels-Alder Reaction Step) Preparation of 5a.lla-Epoχy-1.4.4a.5a.lla.l2a-hexahvdro- 1-r (2.3.6-trideoχy-4-benzoyl-3-trifluoroacetamido-α- L-lyxo-hexopyranosyl)-methyl]-naphthacene-5.6.11.12- tetrone A. The procedure was similar to that of Chandler, et al. J Chem Soc Perkin I (1980) 1007. The pentadienyl pyranose from Example 4 was first benzoylated at the 4 position. Benzoyl chloride was added to a solution of 150 mg (0.511 mmoles) pyranose in 25 ml of dry pyridine. with magnetic stirring, in an ice bath and protected from moisture. The mixture was brought to room temperature, heated to 45°C for 4 hr and then stirred at room temperature for 18 hr. The -35- βolution was poured into 100 ml ice water and extracted ith 2 x 50 ml CHC1 3 . The CHC1 3 waβ washed with 50 ml 1 N HCl. 50 ml βaturated NaHC0 3 and 50 ml H 2 0. The CHC1 3 waβ then dried over MgSO., filtered and 5 evaporated to dryneβs to yield 210 mg (103*) of a syrup. This residue was chromatographed on a 20 x 20 cm x 2 mm thick silica gel plate with 25* EtOAc/hexane and gave R f ~ 0.45. The eluted (EtOAc) product was 182 mg which remained a gum on "recrystallization" with 10 Et.O/hexane or MeOH/H.O. The IR showed no OH and good benzoyl carbonyl peaks and the NMR was consistent with the expected product. A mixture of 170 mg (0.427 mmoles) of the above product gum and 120 mg (0.472 mmoles) of 4a.9a-epoxy- 15 4a.9a-dihydro-anthracene-1.4.9,10-tetrone in 10 ml of toluene was heated at 90-95*C for 4 hr under N_. The reaction mixture waβ cooled. 10 ml of hexane added, and the mixture chilled and filtered to give 235 mg of brown solid. The mass spectrum showed m/e, 651 an -NMR (90 20 MHz) shows two C.'s at 1.15 (d) and 1.16 (d). J g -«6 Hz, indicating the. preβence of the two expected dia- βtereomerβ of 5a,lla-epoxy-l,4,4a,5a,lla.l2a-hexahydro- l-[(2,3,6-trideoxy-4-benzoyl-3-trifluoroacetamido- -L- lyxo-hexopyrano8yl)-methyl]-naphthacene-5,6,ll,12-tetrone 25 in equal amounts. The C proton peaks at 5.26 and 5.29 were two broad singlets indicating the presence of pyranose sugar. B. In an analogous manner, but using instead of the 4-O-benzoyl lyxo-hexopyranose derivative, the 30 4-OH and 4-O-p-nitrobenzoyl derivativeβ, reβpectively, there were prepared: the 4-hydroxy analog of the compound of fA: 5a,lla-epoxy-1,4,4a,5a,lla,12a- hexahydro-2-[(2,3,6-trideoxy-3-trifluoroacetamido-α- L-lyxo-hexopyranoβyl)-methyl]-naphthacene-5,6,ll.12- tetrone; and the 4-O-p-nitrobenzoyl analog of the compound of YA: 5a, la-epoxy-1,4.4a.5a.11a.12a- hexahydro-2-[(2.3,6-tridβoxy-4-0-p-nitrobenzoyl- 3-trifluoroacetamido-α-L-lyxo-hexopyranosyl)-methyl]- naphthacene-5.6,11,12-tetrone The 4-hydroxy analog gave two peaks of equal amounts of diastereoraers on C-18 HPLC using a 0.1 M NaH 2 P0 4 /CH 3 CN gradient. HR-MS showed m/e 547.1452 (calc for C 2_,7_H2_4.F3,NO8_ - 547.1454); NMR gave Co. protons at 1.22(d) and 1.25(d) J- ,»6.4 Hz. The 4-O-p-nitrobenzoyl analog gave a mp of 160-210 (dec) and m/e«696. Example 6 Conversions of the Polycyclic Systems (Steps in Obtaining Intermediates of Formula (3)) The Diels-Alder product from the condensation of the epoxyanthracene system was converted to a compound of formula (3) in a three step process that includes a two step conversion of the epoxide to the corresponding alkene (Tβ A and B), followed by aromatization of the B ring. A. Reduction to the Naphthacene Dione A.l. A sample of 220 mg (0.338 mmoles) of the product of Example 5. ΪA in 5 ml of MeOH was reduced to the hydroquinone with 178 mg (1.10 mmoles) of sodium dithionite in 2 ml H_0. The sodium dithionite solution was added dropwise, to the stirred MeOH solution of the tetrone. After 5 hr, one drop of 1 N HCl was added (pH of βolution 3-4), and the reaction . mixture waβ diluted with 25 ml H_0 and extracted with 25 ml CHC1 . The CHC1 was washed with saturated NaHC0 3 solution. The CHC1. was then dried over MgSO.. filtered and evaporated to dryness to give 130 mg (61*) of 1,4.4a,12a-tetrahydro-6,11-dihydroxy-l- [ (2,3, 6-trideoxy-4-0-benzoyl-3-trifluoroacetamido-α-L- lyxo-hexopyranoβyl)methyl]-naphthacene-5.12-dione. The. residue was chromatographed on 2 x (20 x 20 cm x 2 mm) βilica gel plateβ, developed with 25* EtOAc/hexane and gave a broad band at 0.2 to 0.5 R. which waβ eluted with EtOAc. The 74 mg (35*) of the product waβ eluted and showed an MS peak at 635. The NMR (90 MHz) showed two C 6 '8 at 0.81 (d) and 1.16 (d). A.2. In an analogouβ manner, but uβing the 4-hydroxy analog prepared in Example 5, IB there waβ prepared 1,4,4a, 12a-tetrahydro-6, 11-dihydroxy-l- [ (2,3,6-trideoxy-3-trifluoroacetamido-α-L-lyxo- hexopyranoβyl)methyl]-naphthacene-5, 12-dione. This product gave the two expected diastereomers on C-18 ■ HPLC, 0.1 M NaH 2 P0 4 /CH 3 CN gradient; HR-MS gave m/e 533.1670 (calc for C__H,-F_NO_«533.1661) ; NMR Z7 26 3 7 (90 M Hz) showed two Co. protons; 1.34(d) and 0.86(d); B. Conversion to the Alkene Sixty mg (0.0941 mmoles) of the product from YA.l of this Example was treated with 55 mg (0.124 mmoles) of lead tetraacetate. The solution (pink) waβ stirred for 3 hr. The reaction was diluted with 25 ml CHCl. and washed with 20 ml of saturated NaHC0 3 βolution. The CHCl. waβ dried over MgSO., filtered and evaporated to dryness to yield 40 mg (67*) red-brown foam, mostly 1,4,4a,12a-tetrahydro-l-[ (2,3,6-trideoxy-4- 0-benzoyl-3-trifluoroacetamido-α-L-lyxo-hexopyranoβyl)- methyl]-naphthacene-5,6, 11,12-tetrone. NMR (90 MHz) -38- βhowed no phenolic OH and two Co, protons at 0.95 (d) and 1.18 (d); J _«6.1 Hz. indicating two compoundβ. Two c protonβ giving broad singlets at 5.18 and ' 5.27 indicate the pyranose sugar; the mass spectrum showed a m/e-635. C Enollzation of the B Ring Twenty mg (0.198 mmoles) of trimethylamine in 2 ml methanol under N_ was added to 35 mg (0.0551 mmoles) of the product of IB of this Example, in 5 ml MeOH. The βolution waβ βtirred 4 hr at room temperature and then evaporated to dryness. Upo redisβolving in 5 ml of MeOH a red solid precipitated to give 5 mg (14*) of a βide product having an aromatized A ring, of formula (11) 5,12-dihydroxy-l-[(2.3,6-tredeoxy- 4-0-benzoyl-3-trifluoroacetamido-α-L-lyxo-hexo- pyranosyl)methyl]-naphthacene-6,11-dione (as indicated by m/.e«633). This βide product can be further treated to remove protecting groups to give target compoundβ analogouβ to the adriamycin compoundβ of the invention, which also have anti-tumor activity. The filtrate waβ evaporated, and the residue was subjected to thick layer silica gel chromatography and 5 mg of the desired product of formula (3), 1,4-dihydro-5.12-dihyroxy-2-[(2,3.6-trideoxy-4-0- benzoyl-3-trifluoroacetamido-α-L-lyxo-hexopyransoyl)- ethyl]-naphthacene-6.11-dione (as indicated by m/e«635) was recovered by elution of the material at R f -0.5. Example 7 Preparation of 1.4-Dihydro-2.12-dihydroχy-l-f (2.3.6- trideoχy-3-trifluoroacetamido-α-L-lyxo-hexo- pyranosyDmethyll-naphthacene-6.11-dione A. (Alternate Diels-Alder Condensation) In a manner analogous to that of Example 5. 60 mg (0.204 mraoleβ) of (E)-l-(2.3,6-trideoxy-3-trifluoro- acetamido-α-L-lyxo-hexopyranoβyl)-2.4-pentadiene was mixed with 50 g (0.21 mmole) of anthracene-1.4,9,10- tetrone in 10 ml toluene and the mixture was heated under N_ at 90-100*0 for 18 hr. Ten ml of hexane waβ added and the mixture chilled, and the solid was filtered to give 132 mg (122*) of a mixture containing the desired compound, 1,4,4a,12a-tetrahydro-l-[ (2,3,6- trideoxy-3-trifluoroacetamide-α-L-lyxo-hexo- pyranos 1) eth l]-naphthacene-5,6.11,12-tetrone. NMR showed a mixture of desired product and compound made by internal Diels-Alder reaction with positions 4a and 9a of the tetrone. As the desired product is unstable to silica gel, it was subjected to aromatization as set forth below without further purification. B. (Enolization of the B Ring) The procedure was based on Beilstein'β Handbuch der Organiβchen Chemie. 4th ed., 6 3rd βuppl. p 5608. 0.204 mmoles of l,4,4a,12a-tetrahydro-l-[(2,3,6- trideoxy-3-trifluoroacetamldo-α-L-lyxo-hexo- pyranosyl)methyl]-naphthacene-5,6, 11,12-tetrone (~ 50* pure) as prepared in 1A was dissolved in 10 methanol and 0.2 ml of methanol saturated with HCl added under an argon atmosphere. A red solid formed. After 4 hr, the mixture was filtered, to give 12 mg (11*) of a solid which contained the desired product 1.4-dihydro- 5,12-dihydroxy-l-[(2,3,6-trideoxy-3-trifluoroaceta ido- α-L-lyxo-hexopyranoβyl)methyl]-naphthacene-6.11-dione which βhowed a 9:1 isomer ratio on HPLC. To obtain additional product, filtrate was evaporated to dryness and the residue taken up in 10 ml MeOH and again evaporated to dryness to give 100 mg (92*) of a residue which was chromatographed on a thick silica gel plate 20 x 20 cm x 2 mm and developed by 50* EtOAc/hexane. The eluted 16 mg (15*) of red orange foam waβ subjected to HPLC and showed a mixture of desired products in a 3/5 ratio and a trace of the side product aromatized A ring isomer of formula (11). NMR on the chromatographed sample gave C_ protons 0.84(d) & 1.11(d); J «6 Hz; phenolic OH 13.68 and 13.46. Example 8 Preparation of 1.4.4a.9a-tetrahydro-l-_ (2.3.6- trideoχy-4-0-p-nitrobenzoyl-3-trifluoroacetamido- α-L-lyχo-hexo-pyranoβyl)me hyπ-anthracene-9.10-dione A. Ninety mg (0.203 mmoles) of (E)-l-(2.3.6- trideoxy-4-0-p-nitrobenzoyl-3-trifluoroacetamido-α-L- lyxo-hexopyranoβyl)-2,4-pentadiene and 22.0 mg (0.140 mmoles) of 1,4 naphthoquinone were mixed in 10 ml toluene and the mixture was heated under N at 80-88°C for 4 hr. The reaction was chilled to 0°C and filtered to give 55 mg (65*) l,4,4a,9a-tetrahydro-l-[(2,3,6- trideoxy-4-0-p-nitrobenzoyl-3-trifluoroacetamido- -L- lyxo-hexo-pyranoβyl)methyl]-anthracene-9,10-dione in impure form. NMR gave 2 C 6 protons 1.03(d) and 1.17(d); J_ _»6.0 Hz in approximately equal amounts, and two C protons 5.22 and 5.34 as broad singlets indicating pyranose sugar. B. In an analogous manner, the free 4-hydroxy pyranose analog of the 4-p-nitrobenzoyl pyranose tetrahydroanthraquinone derivative of fA waβ prepared uβing 60 mg (0.204 mmoles) of (E)-l-(2,3,6-trihydroxy-3-trifluoroacetamido-α-L-lyxo- hexopyranoβyl) 2,4-pentadiene and 33 mg (0.208 mmoles) of 1.4-naphthoquinone as starting materials. Eighty-five mg (92*) of a tan solid containing the two isomerβ of 1.4,4a,9a-tetrahydro- l-[(2,3,6-trihydroxy-3-trifluoroacetamido-α-L-lyxo- hexopyranoβe)methyl]anthracene-9,10-dione waβ obtained. HR-MS gave 451.1604 ( calc for C 2 3 H 24 F 3 N0 5" 451.1606); NMR gave C g protons 1.25(d) and 1.14(d), J- ,-6.0. Example 9 Preparation of l-_ (2.3.6-trideoχy-4-Q-p-nitrobenzoyl-3- trlfluoroacetamido-α-L-lyχo-hexopyranoyl)methyl-9.1Q- anthraguinone A. Twenty-five mg (0.042 mmoles) of the product of Example .8, VA and 25 mg (0.247 mmoles) triethyl amine were mixed in 5 ml toluene and the mixture was stirred for 4 hr at 80-8θ°C. The solution was evaporated to dryness. The residue was taken up in 10 ml toluene and again evaporated to dryness. The residue was diββolved in 3 ml MeOH and water added to the cloud point (~ 3 ml). The mixture waβ heated to clear βolution and then chilled overnight. The solid was filtered to give 20 mg (80*) l-[(2,3,6-trideoxy- 4-0-e-nitrobenzoyl-3-trifluoro-acetamido-α-L-lyxo- hexopyranoyl)raethyl-9,10-anthraquinone; mp 253-256°C The mass spectrum gave m/e of 596 and analysis C 3 . 0 H 23 F 3 N 2 0 8 « 0.5 H 2 0 was as follows: C 59.51; H 3.99; N 4.63; (calc); C 59.56; H 3.84; N 4.60; (found). B. In an anologous manner. l-[(2,3.6-trideoxy- 3-trifluoroacetamido-α-L-lyxo-hexopyranosyl)methyl]- 9.10-anthraquinone waβ prepared uβing the product of Example 8. IB. The desired anthraquinone. formed in 71* yield had an mp 288-292*C. a mass spectrum m/e-447; analyβiβ C 23 H 2Q F 3 N0 5 gave C 61.74; H 4.51; N 3.13 (calc); C 61.91; H 4.79; N 3.18 (found). NMR (90 MHz) Co proton 1.23(d); J. o,o, 6.6 Hz, linker CH 3.69(d). Example 10 Removal of TFA -The TFA waβ removed from the product of Example 9, -IB to give l-[(2,3,6-trideoxy-3-amino-α-L-lyxo- hexopyranoβyl)methyl]-9,10-anthraquinone as follows: 50 mg (0.112 mmoleβ) of l-[(2.3,6-trideoxy-3-trifluoro acetamido-α-L-lyxo-hexopyranosy1)methyl]-9,10- anthraquinonβ were mixed with 1 ml N butyl amine in 15 ml MeOH. The mixture waβ refluxed for 3 days, and the reaction followed by TLC Starting material has R f 0.9 and product has R f 0.4. The βolution waβ evaporated to dryness. The residue was purified on thick silica gel plate, developed with 25* MeOH/CHCl.. The eluted product was dissolved in 3 ml MeOH and 1 ml CC1 (hot) filtered, and then chilled. A gel formed and was βlowly filtered until the gel dried on the filter to give 17 mg (44*) of l-[(2,3,6-trideoxy- 3-amino-α-L-lyxo-hexopyranoβyl)methyl]-9,10-anthra- quinone mp > 280 β C #C-18 HPLC 0.1 N aH 2 P0 4 /CH 3 CN βhowed 100* of one peak.

Claims: Cla ims 1. A method of preparing C pentadienyl derivatives of a 2-deoxyhexopyranoβe which comprises treating l-poβition-activated-2-deoxyhexopyranose, with a l-trimethylsilyl-2,4-pentadiene compound in the preβence of a Lewie acid. 2. The method of claim 1 wherein the 1-poβition-activated 2-deoxyhexopyranoβe has a O-p-nitrobenzoyl group at the 1-poβition. 3. The method of claim 1 wherein the 1-position-activated 2-deoxyhexopyranose is a l-O-p-nitrobenzoyl derivative of daunosamine. 4. The method of claim 3 wherein the 1-position-activated 2-deoxyhexopyranose is 1,4-di-O-p- nitro-benzoyl-2,3,6-trideoxy-3-trifluoroacetamido-α-L- lyxo-hexopyranose. 5. A method for preparing a compound of the formula: wherein Q is H, CH 3> OMe. OEt, -OCH 2 CH 2 OMe, or -O-tetrahydropyranyl; R 4 iβ H, acyl(l-4C), or optionally substituted aroyl (6-15C); and P is a protecting group; which method comprises treating a compound of the formula: NHP wherein R. and P are as above-defined and pNB iβ p-nitrobenzoyl, with a compound of the formula Q Me SiCH C-CHCH»CH 2 where Q iβ as above defined, in the presence of a Lewis acid. 6. A method for preparing a 2-deoxyhexo- pyranosyl acetaldehyde which comprises treating a 1-poβition-activated 2-deoxyhexopyranose with l-trimethylβilyl-2-propene in the preβence of a Lewie acid, to obtain a Cl allyl intermediate, followed by treating said intermediate with ozone. 7. The method of claim 6 wherein the 1-position-activated 2-deoxyhexopyranose has a O-p-nitrobenzoyl group in the 1-position. 8. The method of claim 6 wherein the 1-position-activated 2-deoxyhexopyranose is a 1-O-p-nitrobenzoyl derivative of daunosamine. 9. The method of claim 8 wherein the 1-position-activated 2-deoxyhexopyranose is 1,4-di-O-p-nitro-benzoyl-2,3.6-trideoxy-3- trifluoroacetamido-α-L-lyxo-hexopyranose. 10. A compound of the formula: OH wherein X is O or NH; Y is H or OMe; with the proviso that if X-NH. must be OMe; R is COCH 3 . COCH 2 OH. CHOHCH 3 . CHOHCH OH. H. 1-3C alkyl. 1-2C terminal hydroxyalkyl or the 2-7C alkyl or aryl organic acid esters or 1-6C alkyl ethers thereof; or CNKCH, or CNKCH 2 OH. wherein K is OH or NHS, where S is aryl or alkyl; at least one of R 2 and R3 iβ H, and the other iβ OH or OCH 3 ; and A and B iβ each independently H or alkyl (1-6C), or A and B taken together are morpholino, thiomorpholino, or piperidinyl, optionally mono or di substituted by CN. 11. A compound of the formula: w o W is H or OH; R iβ COCH 3 . COCH 2 OH. CHOHCH-,. CHOHCH 2 OH. H. 1-3C alkyl. 1-2C terminal hydroxyalkyl or .the 2-7C alkyl or aryl organic acid esters or 1-6C alkyl ethers thereof; or CNKCH 3 or CNKCH.,OH. wherein K iβ OH or NHS. where S iβ aryl or alkyl; 2 3 at least one of R and R iβ H. and the other is OH or OCH_; and A and B is each independently H or alkyl (1-6C), or A and B taken together are morpholino. thiomorpholino, or piperidinyl, optionally mono or di substituted by CN. 12. A compound of the formula: NHP Y is H or OMe; R 4 is H, acyl (1-4C), or optionally substituted aroyl (6-15C); and P is a protecting group; and Q is H. alkyl (1-3C). OMe. OEt. -OCH-CH-OMe, -0-tetrahydropyranyl, Br. or COOMe. 13. A compound of the formula: Y is H or OMe; Z is a IT bond or epoxide; R 4 is H, acyl (1-4C), or optionally substituted aroyl (6-15C); P is a protecting group; and Q is H. alkyl (1-3C). OMe, OEt. -OCΕLCH-OMe. -O-tetrahydropyranyl, Br, or COOMe. 14. A compound of the formula: NHP w is H or OH: R_ is H, acyl (1-4C), or optionally 4 substituted aroyl (6-15C ) ; P is a protecting -group; Q is H. alkyl (1-3C). OMe. OEt. - O CH 2 CH 2 OMe, -O-tetrahydropyranyl, Br, or CO O Me. 15. A compound of the formula: NHP R_ is H. acyl (1-4C). or optionally 4 substituted aroyl (6-15C); P is a protecting group; and Q is H. alkyl (1-3C). OMe. OEt. -OCH 2 CH 2 OMe, -O-tetrahydropyranyl. Br. or COOMe. 16. A compound of the formula: (11) R is COCH 3 . COCH 2 OH, CHOHCH j . CHOHCH 2 OH. H. 1-3C alkyl, 1-2C terminal hydroxyalkyl or the 2-7C alkyl or aryl organic acid esters or 1-6C alkyl ethers thereof; or CNKCH 3 or CNKCH.,OH. wherein K is OH or NHS, where S is aryl or alkyl; at least one of R 2 and R3 is H. and the other is OH or OCH_; and A and B is each independently H or alkyl (1-6C). or A and B taken together are morpholino, thiomorpholino, or piperidinyl, optionally mono or di substituted by CN.

Inventors: ACTON EDWARD M, RYAN KENNETH J, TRACY MICHAEL, ACTON, EDWARD, M., RYAN, KENNETH, J., TRACY, MICHAEL
Applicants: STANFORD RES INST INT, SRI INTERNATIONAL
Application year: 1985
Main classification: C07D307
IPC codes: C07D309, C07H15