WO1990000173A1

WO1990000173A1 - 4'-deoxy-2'-halo-anthracycline antibiotics, methods for their use, and intermediates and methods for synthesis thereof

Info

Publication number: WO1990000173A1
Application number: PCT/US1989/002524
Authority: WO
Inventors: Waldemar Priebe; Nouri Meamati-M; Roman Perez-Solar
Original assignee: Board Of Regents, The University Of Texas System
Priority date: 1988-06-27
Filing date: 1989-06-09
Publication date: 1990-01-11
Also published as: AU3774389A

Abstract

4'-Deoxy-2'-halo-anthracycline antibiotics (I) are disclosed, as well as compositions including such antibiotics, and methods for their use in inhibiting neoplastic cell growth. Also disclosed are synthetic methods and intermediates which are useful in preparing such anthracyclines, as well as other previously unaccessible 4'-deoxy-2'-halo-3'-hydroxy anthracycline antibiotics, where R1 is selected from the group consisting of CH¿3? and CH2OH, where R?2¿ is selected from the group consisting of H and acyl having the formula -COR3 where R3 is selected from the group consisting of aliphatic and aromatic hydrocarbons having 1-18 carbons, and where X is selected from the group consisting of F, Cl, Br, and I.

Description

4' -Deoxy-2' -halo-Anthracycline

Antibiotics, Methods for Their Use, and

Intermediates and Methods for Synthesis Thereof

The present invention relates to anthracycline antibiotics, the synthesis of such compounds, and methods of using such compounds and formulations thereof in antitumor therapy.

Anthracycline antibiotics such as doxorubicin and daunorubicin are known to have antineoplastic activity. However, these compounds and many of their derivatives have serious side effects, such as cardiotoxicity, which severely restrict the dosage and the frequency with which they can be administered, and thus limit their overall effectiveness. There is a long standing need for analogs which will have higher activity and lower toxicity, as well as a broader spectrum of antitumor activity, than the previously known compounds. Research in the area of anthracyclines has often encountered difficulty in synthesizing new compounds which might have desirable activity. Therefore, there is also a longstanding need for new synthetic schemes and chemical intermediates which will aid in the preparation of potential antitumor agents. The present invention includes compounds which have the formula

R is selected from the group consisting of CH₃ and CH₂OH, while R² is selected from the group consisting of H and acyl groups having the formula -COR³. R³ is selected from the group consisting of aliphatic and aromatic

hydrocarbons having 1-18 carbons. X is selected from the group consisting of fluorine, chlorine, bromine, and iodine.

The present invention also concerns compositions which include a pharmaceutically effective amount of a compound in accordance with the above formula and a pharmaceutically acceptable carrier.

These antibiotic compounds and compositions have been found to have antitumor activity, and are believed to be useful in methods of inhibiting neoplastic cell growth in a host. Such methods involve administering to the host a effective amount of a compound or composition in

accordance with the present invention. Particular compounds in accordance with the present invention have been shown to have high activity and low toxicity. The present invention also concerns synthetic method and chemical intermediates which are useful in the preparation of antibiotic compounds in accordance with the present invention. In one embodiment, a useful

intermediate is a 6-deoxy-glycal having at the C-3

position a substituent having the formula OZ¹. Z¹ is selected from the group consisting of H, acyl having the formula -COR³ and silyl having the formula -Si(R⁴)₂R⁵. R³ is selected from the group consisting of aliphatic and aromatic hydrocarbons having 1-18 carbons. For example,

R³ can suitably be -(CH₂)_nCH₃ where n is 0-17. R⁴ is selected from the group consisting of aliphatic and aromatic hydrocarbons having 1-10 carbons. R⁵ is selected from the group consisting of aliphatic and aromatic hydrocarbons having 1-18 carbons, preferably 1-12 carbons. Intermediates in accordance with the present

invention can be prepared by a method which includes the steps of :

(a) blocking the hydroxyl group at the C-3 position of a 6-deoxy-glycal selected from the group consisting of L-rhamnal and L-fucal, so that the C-3 substituent will be

OSi(R⁴)₂R⁵, where R⁴ is selected from the group consisting of aliphatic and aromatic hydrocarbons having 1-10 carbons and where

R⁵ is selected from the group consisting of aliphatic and aromatic hydrocarbons having

1-18 carbons; (b) derivatizing the product of step (a) at the

hydroxyl group at the C-4 position so that the C-4 substituent will be -OCSR⁶, where R⁶ is any group that will not prevent deoxygenation at the C-4 position; (c) deoxygenating the product of step (b) at the C-4 position by reacting it with tributyltin hydride. One synthetic method of the present invention for preparing a 4'-deoxy-2-halo anthracycline includes the steps of:

(a) coupling an anthracyclinone with a 3-O-acetyl4-deoxy-glycal, and

(b) reacting the product of step (a) with a base to remove the 3'-O-acetyl group. Suitable glycals include 3-O-acetyl-4-deoxy-L-rhamnal and 3-O-tert-butyldimethylsilyl-4-deoxy-L-rhamnal. Suitable bases include methoxide anions.

One synthetic method of the present invention for preparing a 4'-deoxy-2'-halo anthracycline includes the steps of:

(a) coupling a 14-blocked anthracyclinone with a 3-O-acetyl-4-deoxy-L-rhamnal in the presence of a N-halosuccinimide,

(b) reacting the product of step (a) with a base to remove the 3'-O-acetyl group, and (c) deblocking the anthracycline at the C-14 position.

"14-blocked anthracyclinone" means an anthracyclinon moiety which has been substituted at the C-14 position with a group which will be stable while the 3'-acetyl group is removed and then can be unblocked in a good yield. The 14-blocked anthracyclinone can suitably be a 14-O-silylated adriamycinone.

Alternatively, step (a) can be accomplished by coupling a 14-blocked anthracyclinone with a 1,2-dihalo-3-O-acetyl-4-deoxy-L-hexopyranosyl in the presence of a salt of a heavy metal selected from the group consisting of Hg, Ag, and Cd. The 1,2-dihalogenated substrate can be provided by reacting a 3-O-acetyl-4-deoxy-L-glycal with an appropriate halogen.

Another synthetic method in accordance with the present invention includes the steps of (a) coupling a 14-O-silylated anthracyclinone with a 3-O-acetyl-4-deoxy-L-glycal in the presence of Niodosuccinimide,

(b) reacting the product of step (a) with a

methoxide anion to remove the 3'-O-acetyl group, and

(c) reacting the product of step (b) with a fluoride anion to remove the silyl group. Another synthetic method for preparing a 4'-deoxy-2'-halo anthracycline compound in accordance with the present invention includes the steps of (a) reacting daunomycinone with 3-O-acetyl-4-deoxy-L-rhamnal, and (b) reacting the product of step (a) with a base to remove the 3'-O-acetyl group. Step (a) is preferably carried out by reacting daunomycinone with 3-O-acetyl-4-deoxy-L-rhamnal in the presence of N-iodosuccinimide.

The intermediates and synthetic methods described and claimed in this patent, which have been found to give high yield, are useful for synthesizing the anthracyclinn compounds described above, as well as for synthesis of other previously unaccessible 4'-deoxy-3'-hydroxy antibiotics which are substituted at C-2'. Figures 1, 2, and 3 show synthetic schemes for preparation of compounds in accordance with the present invention.

Specific anthracyclines in accordance with the present invention include the following two examples:

In addition to H, other suitable R² substituents include -CO(CH₂)_nCH₃, where n is 0-17, preferably 0-6.

Specific embodiments of intermediates in accordance with the present invention have the following formulae:

R⁶ can be any substituent that will not prevent

deoxygenation at the C-4 position, such as a thioalkyl, imidazoyl, or phenoxy group. Suitable R⁶ substituents include H, Me, Ph, SMe, CH₂CH₂Ph, CHCHPh, C₆H₃(OMe)₂, C₆H₄SO₂, C₆H₄NO₂, and C₆H₄OMe. (Throughout this patent, well known abbreviations are used such as Me for methyl, Ph for phenyl, Ac for acetyl, and t-Bu for tert-butyl.) Z¹ is as described before. Suitable Z¹ substituents include Ac, SiMe₂t-Bu, and SiPh₂t-Bu.

In one embodiment of the methods of synthesizing 4'-deoxy-2'-halo anthracyclines, the product of step (a) has the formula

where X is selected from the group consisting of F, Cl, Br, and I, where R⁴ is selected from the group consisting of aliphatic and aromatic hydrocarbons having from 1-10 carbons, and where R⁵ is selected from the group

consisting of aliphatic and aromatic hydrocarbons having from 1-18 carbons. As a specific example, such a method can include the steps of (a) reacting a compound having the formula

with 3-O-acetyl-4-deoxy-L-rhamnal and N-iodosuccinimide, thereby producing

(b) reacting the product of step (a) with sodium methoxide to remove the 3'-O-acetyl group, and (c) reacting the product of step (b) with a fluoride anion to desilylate the hydroxyl group at C-14. The fluoride anion can suitably be provided by tetrabutyl ammonium fluoride. Example 1

The synthesis described below is represented in Figure 1. 1.5-Anhvdro-2,6-dideoxγ-L-arabino-hex-1-enitol (compound 2 , L-rhamnal) To a solution of 3,4-di-O-acetyl-L-rhamnal (compound 1; Pfanstiehl Labs, Inc.) (57 g, 0.266 mole) in absolute methanol (500 ml) was added with stirring anion-exchange resin (8.5 g, Amberlite IRN-78, OH-form). The solution was monitored with TLC (hexane-ethyl acetate 2:1) until completion of the reaction (18 hours). The mixture was filtered and then evaporated under diminished pressure. The product was compound 2 (Rf 0.09, hexane-ethyl acetate 2:1), which was crystalized upon evaporation of solvent to give 34.5 g (100%).

3-O-tert-Butγldimethylsilyl-L-rhamnal (compound 3a )

To a solution of compound 2 (34.5 g, 0.265 mol) and imidazole (45 g, 0.663 mol) in N,N-dimethylformamide (150 ml) was added with stirring t-butylchlorodimethyl silane (43.9 g, 0.292 mol). The solution was stirred at room temperature until complete disappearance of the substrate (2 hours). The mixture was then poured into water (300 ml) and extracted with hexane (800 ml x 3). The organic extract was combined and washed with water (500 ml), dried over sodium sulfate and evaporated. The resulting oil (63 g) was used in the next step as a mixture containing additionally compounds 3b (3,4-di-O-tert-butyldimethylsilyl-L-rhamnal) (1.5%) and 3c (4-O-tertbutyldimethylsilyl-L-rhamnal) (3%).

3-O-tert-Butyldimethylsilyl-4-O-(methylthio) thiocarbonylL-rhamnal (compound 4)

To a solution in dry oxalane (600 ml) containing compound 3a (63 g, 0.258 mol), and a minute amount of compounds 3b and 3c, and imidazole (63 mg) under argon, was added sodium hydride (15.5 g, 0.387 mol, 60%

dispersion in mineral oil). After stirring for 2 hours at room temperature, carbon disulfide (58.9 g, 0.774 mol) was added and stirring continued for two more hours after which iodomethane (64.8 g, 0.456 mol) was added and stirring was continued overnight. Then glacial acetic acid (13 ml) was added slowly to destroy the excess of sodium hydride. Solvent was removed and ether (400 ml) was added and the mixture was washed with 5% NaHCO₃ (150 ml) and water (150 ml x 2). The organic extract was dried over sodium sulfate, filtered and evaporated. The resulting oil (84 g), was used in the next step as a mixture of a major product Rf 0.8 and a minor product Rf 0.88 (hexanetoluene 4:3). ¹³C-NMR δ :215.5(C=S), 143.5(C-1),

102.8(C-2), 82.8(C-4), 72.4(C-5), 66.1(C-3), 25.6(Me₃CSi), 19.2(CH₃S), 17.9(CH₃CSi), 16.6(C-6). 3-O-tert-Butyldimethylsilyl-4-deoxy-L-rhamnal (compound 5)

To a solution of compound 4 (84 g, 0.251 mol) in anhydrous toluene (500 ml) under argon was added AIBN (2,2'-azobisisobutyronitrile) (4.2 g) and tributyltin hydride (87.7 g, 0.301 mol). The solution was stirred at 90°C until complete disappearance of the substrate (45 min.). The solvent was then removed and the product was chromatographed with hexane-toluene (10:1). Compound 5

13

was obtained as an oil (48.8 g, 85.0% yield). C-NMR δ: 144.3(C-1), 105.9(C-2), 71.0(C-5), 63.6(C-3), 39.9(C-4), 25.8(Me₃CSi), 20.9(C-6), 18.1(Me₃CSi), -4.62(Me₂Si).

Figure 1 also shows an alternate synthetic scheme for preparing compound 5, starting with 3,4-di-O-acetyl-Lfucal instead of 3,4-di-O-acetyl-L-rhamnal.

3-O-Acetyl-4-deoxy-L—rhamnal (compound 6.

Compound 5 (34.5 g, 0.151 mol) was dissolved in oxalane (300 ml), dichloromethane (150 ml), pyridine (10 ml), and tetrabutylammonium fluoride (0.23 mol, 223 ml of a 1M solution in oxalane) was added. The solution was stirred at room temperature until complete disappearance of the substrate (48 hours). Sodium sulfate (anhydrous) was added and the mixture was stirred for an additional 20 minutes and then filtered and evaporated. Pyridine (100 ml) was added followed by acetic anhydride (21.6 g, 0.21 mol) and stirring was continued at room temperature for 4 more hours. Dichloromethane (300 ml) was then added and the mixture was washed with 0.1N HC1 (100 ml), 5% NaHCO₃ (100 ml), and water (3 x 100 ml). The organic layer was dried over sodium sulfate, filtered and evaporated.

Compound 6 was obtained as an oil (21.15g, 89.8%). 13_C- NMR δ: 170.7(C=0), 146.6(C-1), 100.7(C-2), 70.7(C-5),

65.6(C-3), 35.1(C-4), 21.0(OAc), 20.5(C-6).

Example 2

The synthesis described below is represented in

Figure 2.

7-O-(3-O-acetyl-2-iodo-2,4,6-trideoxy-α-L-lyxohexopyranosyl)daunomycinone (compound 7)

To a solution of daunomycinone (DNM in figure 2; 100 mg, 0.25 mmol) and 3-O-acetyl-4-deoxy-L-rhamnal (compound 6; 58 mg, 0.37 mmol) in dry acetonitrile (2.0 ml) and oxolane (1 ml) at 0°C was added with stirring Niodosuccinimide (NIS; 83 mg, 0.37 mmol). The resulting mixture was stirred for 15 minutes at 0°C and then after 12 hours at 25°C an additional 0.5 equivalent (41 mg, 0.18 mmol) of 3-O-acetyl-4-deoxy-L-rhamnal (compound 6) and 0.5 equivalent (29 mg, 0.18 mmol) of N-iodosuccinimide were added, and the mixture was stirred until disappearance of the substrate (24 hours) on TLC (toluene-acetone, 4:1). Dichloromethane (20 ml) was added and the resulting solution was washed with 10% aqueous sodium thiosulfate (2 x 15 ml) and then water (3 x 20 ml). The extract was dried with sodium sulfate, filtered, and evaporated. Red solid residue was prepurified by crystalization from dichloromethane-hexane. TLC (toluene-acetone, 20:1) revealed the presence of a major (Rf 0.16) and a minor (Rf 0.24) product which were subsequently separated by column chromatography on silica gel (10 g) with toluene-acetone 20:1. Compound 7 precipitated from a solution of ethyl ether-dichloromethane upon addition of hexane; yield 130 mg (75%).

Analysis: Calculated for C₂₉H₂₉IO₁₁ (680.4): C 51.19, H 4.29

Found: C 50.95, H 4.36

Additionally, compound 8 (7-O-(3-O-acetyl-2-iodo- 2,4,6-trideoxy-β-L-lyxo-hexopyranosyl) daunomycinone) was isolated as a minor product; yield 10 mg (5.7%); mp 126¬

128°C.

7-O-(2-iodo-2.4,6-trideoxy-α-L-lyxo-hexopyranosyl) daunomycinone (compound 9)

A solution of compound 7 (40 mg, 0.058 mmol) in methanol (5.0 ml) was treated with 0.5 M solution of sodium methoxide in methanol (0.35 ml). After 40 min. of stirring at room temperature the reaction was completed. Dry ice was added and the mixture was diluted with

dichloromethane (100 ml) and washed with water (50 ml x 3), dried (sodium sulfate), filtered, and evaporated. TLC showed one spot having Rf 0.15 (toluene-acetone, 8:1). The product, compound 9, was crystallized from

dichloromethane and ethyl ether; yield 25 mg (66%); mp 145-148°C. Example 3

The synthesis described below is represented in

Figure 3.

7-O-(3-Q-Acetyl-2-iodo-2,4,6-trideoxy-α-L-lyxohexopyranosyl,-14-O-tert-butyldimethylsilyladriamycinone (compound 12) Compound 11 was prepared from daunomycinone (compound 10) using generally the same procedure described by Horton et al, J. Antibiotics 37(8), 853-858 (1984). To a

solution of compound 11 (250 mg, 0.473 mmol) and 3-O-acetyl-4-deoxy-L-rhamnal (compound 6, 110 mg, 0.71 mmol) in dry acetonitrile (4.0 ml) and oxolane (2.0 ml) at 0°C was added with stirring N-iodosuccinimide (160 mg, 0.71 mmol). The resulting mixture was stirred for 15 minutes at 0°C and after 12 hours at 25°C an additional 0.5 equivalent (125 mg, 0.24 mmol) of 3-O-acetyl-4-deoxy-Lrhamnal (compound 6) and 0.5 equivalent (80 mg, 0.35 mmol) of N-iodosuccinimide were added, and the mixture was stirred until disappearance of the substrate (24 hours) on TLC (toluene-acetone, 8:1). A work-up similar to that described above for compound 7 gave, after column

chromatography (toluene-acetone 40:1), as a major product, compound 12 with a yield of 330 mg (86%). Further

purification of compound 12 by crystallization afforded 285 mg of red crystals (74% ; mp 145-150°C).

Analysis : Calculated for C₃₅ H₄₃IO₁₂ Si . H₂O ( 828.7 ) : C 50.68 , H 5.43

Found : C 50.70 , H 5.29

14-O-tert-Butyldimethylsilyl-7-O- ( 2-iodo-2 , 4.6-trideoxy-α-L-lvxo-hexopyranosyl ) adriamycinone ( compound 13) To a solution of compound 12 (200 mg, 0.246 mmol) in methanol (10.0 ml) was added with stirring 0.5M sodium methoxide in methanol (1.5 ml). After 90 minutes, the reaction was terminated by adding dry ice. The mixture was then diluted with dichloromethane (100 ml) and washed with water (50 ml x 3), dried with sodium sulfate, filtered, and evaporated (170 mg, 89.6%). TLC showed one spot having Rf 0.25 (toluene-acetone. 8:1). The product was then crystallized from dichloromethane and hexane to give analytically pure compound 13; yield 150 mg (79%).

7-O-(2-Iodo-2,4,6-trideoxy-α-L-lyxo-hexopyranosyl) adriamycinone (compound 14) To a solution of compound 13 (110 mg, 0.143 mmol) in oxolane (10 ml), dichloromethane (4 ml), and pyridine (0.07 ml), was added with stirring tetrabutylammonium fluoride (0.25 ml of a IM solution in oxolane). After completion of the reaction (TLC, toluene-acetone, 4:1) in 20 minutes, the mixture was diluted with dichloromethane (150 ml) and washed with 0.1N HCl(50 ml), 5% aqueous NaHCO₃ (50 ml) and water (50 ml x 3). The organic layer was dried (sodium sulfate) and the residue after

evaporation was purified by dissolving in oxolanedichloromethane and precipitating by addition of ethyl ether. The solid was washed with ether and dried to afford pure compound 14; yield 62 mg (70%); mp 155-160°C.

Example 4

The antitumor activity of compounds 9 and 14 was tested against L-1210 murine leukemia in vivo. L-1210 cells (1 million) were inoculated intraperitoneally on da 0 to BDF1 mice. Groups of 6 mice each were used. Result were expressed as % T/C (median survival of treated animals: median survival of control animals x 100).

Results obtained are shown below:

Dose

Compound mg/kg % T/C

9. 6.25 128

1122..55 142

25 142

14 6.25 185

12.5 214

25 300

Doxorubicin 10 200

Compound 14 appeared to be significantly more active and less toxic than doxorubicin. * * *

Compositions in accordance with the present invention can include a pharmaceutically effective amount of one or more of the novel antibiotic compounds and a

pharmaceutically acceptable carrier. The compositions can also contain solubility-enhancing agents such as DMSO or the commercial surfactants Tween 20, Tween 80, Cremophor, or Klucel. Alternatively, the active compounds might be formulated in a fatty emulsion, encapsulated in liposomes or polymeric drug carriers.

Methods in accordance with the present invention comprise administering to a host an effective amount of the compounds or compositions described above. The administering step is preferably parenteral and by

intravenous, intraarterial, intramuscular, intralymphatic. intraperitoneal, subcutaneous, intrapleural or intrathecal injection or by topical application or oral dosage. Such administration is preferably repeated on a timed schedule until tumor regression or disappearance has been achieved and may be used in conjunction with other forms of tumor therapy such as surgery or chemotherapy with different agents.

The description and examples given in this patent are intended to illustrate the present invention. They are not intended to be an exhaustive list of all possible specific embodiments of the present invention. Those skilled in the art will recognize that modifications could be made to the specific embodiments listed here which would still be within the scope of the present invention.

Claims

CLAIMS :

1. A compound which has the formula

where R¹ is selected from the group consisting of CH₃ and CH₂OH, where R² is selected from the group consisting of H and acyl having the formula -COR³ where R³ is selected from the group consisting of aliphatic and aromatic hydrocarbons having 1-18 carbons, and where X is selected from the group consisting of F, Cl, Br, and I.

2. The compound of Claim 1, where R³ is -(CH₂)_nCH₃ where n is from 0-6.

3. A compound which has the formula

4. A compound which has the formula

5. A composition including a pharmaceutically effective amount of a compound which has the formula

and a pharmaceutically acceptable carrier, where R¹ is selected from the group consisting of CH₃ and CH₂OH, where R² is selected from the group consisting of H and acyl having the formula -COR³, where R³ is selected from the group consisting of aliphatic and aromatic hydrocarbons having 1-18 carbons, and where X is selected from the group consisting of F, Cl, Br, and I.

6. The composition of claim 5, where R³ is -(CH₂)_nCH₃ where n is from 0-6.

7. A composition including a pharmaceutically effective amount of a compound which has the formula

and a pharmaceutically acceptable carrier.

8. A composition including a pharmaceutically effective amount of a compound which has the formula

and a pharmaceutically acceptable carrier.

9. A method of inhibiting neoplastic cell growth in a host, including the step of administering to the host an effective amount of a compound having the formula

where R¹ is selected from the group consisting of CH₃ and

CH₂OH, where R² is selected from the group consisting of H and acyl having the formula -COR³ , where R³ is selected from the group consisting of aliphatic and aromatic hydrocarbons having 1-18 carbons, and where X is selected from the group consisting of F, Cl, Br, and I.

10. The method of claim 9, where R³ is -(CH₂)_nCH₃ where n is 0-6.

11. A method of inhibiting neoplastic cell growth in a host, including the step of administering to the host an effective amount of a compound having the formula

12. A method of inhibiting neoplastic cell growth in a host, including the step of administering to the host an effective amount of a compound having the formula

13. A 6-deoxy-glycal having at the C-3 position a

substituent OZ¹, where Z¹ is selected from the group consisting of H, -COR³ and -Sι(R⁴)₂R⁵ where R⁴ is selected from the group consisting of aliphatic and aromatic hydrocarbons having 1-10 carbons, and where R³ and R⁵ are separately selected from the group consisting of aliphatic and aromatic hydrocarbons having 1-18 carbons.

14. A compound having the formula

where R⁶ is any substituent that will not prevent

deoxygenation at the C-4 position, where Z¹ is selected from the group consisting of H, -COR³ and -Si(R⁴)₂R⁵, where R⁴ is selected from the group consisting of

aliphatic and aromatic hydrocarbons having 1-10 carbons, and where R³ and R⁵ are separately selected from the group consisting of aliphatic and aromatic hydrocarbons having 1-18 carbons.

15. The compound of claim 14, where R⁶ is selected from the group consisting of thioalkyl, imidazoyl, and phenoxy.

16. The compound of claim 14, where R⁶ is -SMe.

17. The compound of claim 14, where Z¹ is -SiMe₂t-Bu.

18. The compound of claim 14, where Z¹ is -SiPh₂t-Bu.

19. A compound having the formula

where R⁶ is any substituent that will not prevent

aliphatic or aromatic hydrocarbons having 1-10 carbons, and where R³ and R⁵ are separately selected from the group consisting of aliphatic or aromatic hydrocarbons having

1-18 carbons.

20. The compound of claim 21, where R⁶ is selected from the group consisting of thioalkyl, imidazoyl, and phenoxy.

21. The compound of claim 19, where R⁶ is -SMe.

22. The compound of claim 19, where Z₁ is -SiMe₂t-Bu.

23. The compound of claim 19, where Z₁ is -SiPh₂t-Bu.

24. A compound having the formula

25. A compound having the formula

26. A compound having the formula

where Z¹ is selected from the group consisting of H, -COR³ and -Sι(R⁴)₂R⁵, where R⁴ is selected from the group consisting of aliphatic or aromatic hydrocarbons having 1-10, carbons and where R³ and R⁵ are separately selected from the group consisting of aliphatic or aromatic

hydrocarbons having 1-18 carbons.

27. A compound having the formula

28. A compound having the formula

29. A method of preparing a 4'-deoxy-2'-halo-3-hydroxy anthracycline compound, including the steps of:

(a) coupling an anthracyclinone with a 3-O-acetyl- 4-deoxy-glycal; and

(b) reacting the product of step (a) with a base to remove the 3'-O-acetyl group.

30. A method of preparing a 4'-deoxy-2'-halo

anthracycline compound, including the steps of: (a) coupling a 14-blocked anthracyclinone with a 3- O-acetyl-4-deoxy-L-rhamnal in the presence of a N-halosuccinimide;

(b) reacting the product of step (a) with a base to remove the 3'-O-acetyl group; and

(c) deblocking the anthracycline at the C-14

position.

31. The method of claim 30, where the 14-blocked

anthracyclinone is a 14-O-silylated adriamycinone.

32. A method of preparing a 4'-deoxy-2'-halo

anthracycline compound, including the steps of:

(a) coupling a 14-O-silylated anthracyclinone with a

3-O-acetyl-4-deoxy-L-rhamnal in the

presence of N-iodosuccinimide;

(c) reacting the product of step (b) with a fluoride anion to remove the silyl group.

33. The method of claim 32, where the 14-O-silylated anthracylinone is a 14-O-silylated adriamycinone.

34. The method of claim 32, where the product of step (a) has the formula

where X is selected from the group consisting of F, Cl, Br, and I, where R⁴ is selected from the group consisting of aliphatic and aromatic hydrocarbons having 1-10 carbons, and where R⁵ is selected from the group

consisting of aliphatic and aromatic hydrocarbons having 1-18 carbons.

35. A method of preparing a 4'-deoxy-2'-iodo

anthracycline compound, including the steps of:

(a) reacting a compound having the formula

with 3-O-acetyl-4-deoxy-L-rhamnal and Niodosuccinimide, thereby producing

(b) reacting the product of step (a) with a

methoxide anion to remove the 3'-acetyl group; and

(c) reacting the product of step (b) with a fluoride anion to desilylate the hydroxyl group at C-14.

36. The method of claim 35, where the fluoride anion is provided by tetrabutylammonium fluoride.

37. A method of preparing a 4'-deoxy-2'-halo-3'-hydroxy anthracycline compound, including the steps of:

(a) reacting daunomycinone with a 3-O-acetyl-4- deoxy-L-glycal; and

(b) reacting the product of step (a) with a base to remove the 3'-acetyl group.

38. The method of claim 36, where the glycal is 3-O-acetyl-4-deoxy-L-rhamnal.

39. A method of preparing a 4'-deoxy-2'-halo-3'-hydroxy anthracycline compound, including the steps of: (a) reacting daunomycinone with 3-O-acetyl-4-deoxy¬

L-rhamnal and N-iodosuccinimide; and

(b) reacting the product of step (a) with a

methoxide anion to remove the 3'-acetyl group.

40. A method of preparing a 4'-deoxy-glycal, including the steps of:

-OSi(R⁴)₂R⁵, where R⁴ is selected from the group consisting of aliphatic and aromatic hydrocarbons having 1-10, carbons and where R⁵ is selected from the group consisting of aliphatic and aromatic hydrocarbons having 1-18 carbons;

(b) derivatizing the product of step (a) at the

hydroxyl group at the C-4 position so that the C-4 substituent will be -OCSR⁶, where R⁶ is any group that will not prevent deoxygenation at the C-4 position;

(c) deoxygenating the product of step (b) at the C-4 position by reacting it with tributyltin hydride.

41. The method of claim 40, where R⁶ is selected from the group consisting of thioalkyl, imidazoyl, and phenoxy.

42. The method of claim 39, where R⁶ is selected from the group consisting of H, Me, Ph, SMe, CH₂CH₂Ph, CHCHPh, C₆H₃(OMe)₂, C₆H₄SO₂, C₆H₄NO₂, and C₆H₄OMe.