Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1994-05-13
1998-05-26
Kight, John
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 41, 549 63, C07H 1924
Patent
active
057567069
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to diastereoselective processes for preparing optically active cis-nucleosides and nucleoside analogues and derivatives. The novel processes of this invention allow the stereo-controlled synthesis of a given enantiomer of a desired cis-nucleoside or nucleoside analogue or derivative in high optical purity. This invention also relates to novel intermediates useful in the processes of this invention.
BACKGROUND OF THE INVENTION
Nucleosides and their analogues and derivatives are an important class of therapeutic agents. For example, a number of nucleosides have shown antiviral activity against retroviruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and human T-lymphotropic virus (HTLV) (PCT publication WO 89/04662 and European Patent publication 0349242 A2). Among the nucleosides shown to have antiviral activity are 3'-azido-3'-deoxythymidine (AZT) and 2'3'-dideoxycytidine (DDC).
Most nucleosides and nucleoside analogues and derivatives contain at least two chiral centers (shown as * in formula (A)), and exist in the form of two pairs of optical isomers (i.e., two in the cis-configuration and two in the trans- configuration). However, generally only the cis-isoiners exhibit useful biological activity. ##STR1## Different enantiomeric forms of the same cis-nucleoside may, however, have very different antiviral activities. M.M. Mansuri et al., "Preparation Of The Geometric Isomers Of DI)C, DDA, D4C and D4T As Potential Anti-HIV Agents", Bioorg.Med.Chem. Lett., 1 (1), pp. 65-68 (1991). Therefore, a general and economically attractive stereoselective synthesis of the enantiomers of the biologically active cis-nucleosides is an important goal.
Many of the known processes for producing optically active nucleosides and their analogues and derivatives modify naturally occurring (i.e., optically active) nucleosides by altering the base or by altering the sugar via reductive procedures such as deoxygenation or radical initiated reductions. C.K. Chu et al., "General Synthesis Of 2 ', 3'-Dideoxynucleosides And 2'1,3'-Didehydro-2 ', 3'-Dideoxynucleos J.Org.Chem., 54, pp. 2217-2225 (1989). These transformations involve multiple steps, including protection and deprotection and usually result in low yields. Moreover, they begin with and maintain the optical activity of the starting nucleoside. Thus, the nucleosides produced by these processes are limited to specific analogues of the enantiomeric form of the naturally occurring nucleoside. In addition, these procedures require the availability of the naturally occurring nucleoside, often an expensive starting material.
Other known processes for producing optically active nucleosides rely on conventional glycosylation procedures to add the sugar to the base. These procedures invariably give anomeric mixtures of cis- and trans-isomers which require tedious separation and result in lower yields of the desired biologically active cis-nucleoside. Improved glycosylation methods designed to yield only the cis-nucleoside require addition of a 2'- or 3'-substituent to the sugar. Because the 2'- or 3'-substituent is only useful in controlling cis-nucleoside synthesis in one configuration (when the 2' or 3' substituent is trans- to the 4' substituent), multiple steps are required to introduce this substituent in the proper configuration. The 2'- or 3'-substituent must then be removed after glycosylation, requiring additional steps. L. Wilson and D. Liotta, "A General Method For Controlling Stereochemistry In The Synthesis Of 2'-Deoxyribose Nucleosides", Tetrahedron Lett., 31, pp. 1815-1818 (1990). Furthermore, to obtain an optically pure nucleoside product, the starting sugar must be optically pure. This also requires a series of time-consuming syntheses and purification steps.
SUMMARY OF THE INVENTION
The present invention overcomes the difficulties and shortcomings of the prior art and provides processes for producing optically active cis-nucleosides and nucleoside analogues and derivatives of formula
REFERENCES:
patent: 4231945 (1980-11-01), McCombie
patent: 4383114 (1983-05-01), Vince
patent: 4882316 (1989-11-01), Lambert et al.
patent: 5204466 (1993-04-01), Liotta et al.
patent: 5210085 (1993-05-01), Liotta et al.
Lukevics et al., Nucleosides Synthesis--Organosilicon Methods, Ellis Norwood, New York, NY, 1991.
Tann et al., "Fluorocarbohydrates in Synthesis. An Efficient Synthesis of 1-(2-Deoxy-2-fluoro-.beta.-D-arabinofuranosyl)5-iodouracil (.beta.-FIAU) and 1-(2-Deoxy-2-fluoro-.beta.-D-arabinofuranosyl)thymine (.beta.-FMAU)," J. Organic Chem., 50(19), 3644-3647 (Sep. 20, 1985).
Brodfuehrer et al., "A Stereocontrolled Synthesis of 1,3,5-Tri-O-benzoyl-.alpha.-D-ribofuranose," J. Organic Chem., 50(14), 2597-2598 (Jul. 12, 1985).
Goodman, "Chemical Syntheses and Transformations of Nucleosides," in Basic Principles in Nucleic Acid Chemistry, vol. 1, Academic Press, New York, 1974, pp. 106-110.
March, Advanced Organic Chemistry, McGraw-Hill Book Co., New York, 1968, pp. 896-897.
M. Fieser, Reagents for Organic Synthesis, vol. 8, Wiley-Interscience, New York, 1980, pp. 261-263.
M. Fieser, Reagents for Organic Synthesis, vol. 12, Wiley-Interscience, New York, 1986, pp. 543-547.
Aggarwal et al. "Synthesis and Biological Evaluation of Prodrugs of Zidovudine", J. Med. Chem., vol. 33, pp. 1505-1510 (1990).
Beres et al., "Stereospecific Synthesis And Antiviral Properties of Different Enantiomerically Pure Carbocyclic 2'-Deoxyribonucleoside Analogues Derived From Common Chiral Pools: (+)-(1R,5S)-and(-)-(1S, 1353-1360 (1990).
Chu et al., "An Efficient Total Synthesis of 3'-Azido-3'-Deoxythymidine (AZT) and 3'-Azido-2', 3'-dideoxyuridine (AZDDU. CS-87) From D-Mannitol", Tetrahedron Lett., vol. 29 (42), pp. 5349-5352 (1988).
Chu et al., "General Synthesis of 2',3'-Dideoxynucleosides And 2',3'-Didehydro-2',3'-Dideoxynucleosides", J. Org. Chem., vol. 54, pp. 2217-2225 (1989).
Choi, et al., "In Situ Complexation Directs the Stereochemistry of N-Glycosylation in the Synthesis of Oxathiolanyl and Dioxolanyl Nucleoside Analogues", J.Am. Chem. Soc., vol. 113, pp. 9377-9379 (1991).
Chu et al., "Synthesis And Structure-Activity Relationships Of 6-Substituted 2',3'-Dideoxypurine Nucleosides As Potential Anti-human Immunodeficiency Virus Agents", J. Med. Chem., vol. 33, pp. 1553-1561 (1990).
Chu et al., "A Highly Stereoselective Glycosylation of 2-(Phenylselenenyl)-2,3-Dideoxyribose Derivative With Thymine: Synthesis Of 3'-Deoxy-2',3'-Didehydrothymidine And 3'-Deoxythymidine", J. Org. Chem., vol. 55, pp. 1418-1420 (1990).
Chu et al., "Asymmetric Synthesis of Enantiomerically Pure (-)-(1'R,4'R)-Dioxolane-Thymine And Its Anti-HIV Activity", Tetrahedron Lett., vol. 32(31), pp. 3791-3794 (1991).
Evans, et al. "Divergent Asymmetric Syntheses of Dioxolane Nucleoside Analogues", Tetrahedron: Asymmetry, vol. 4(11), pp. 2319-2322 (1993).
Farina and Benigni, "A New Synthesis Of 2',3'-Dideoxynucleosides For AIDS Chemotherapy", Tetrahedron Lett., vol. 29(11), pp. 1239-1242 (1988).
Gosselin et al., "Systematic Synthesis And Biological Evaluation of .alpha.-and .beta.-D-Lyxofuranosyl Nucleosides Of The Five Naturally Occurring Nucleic Acid Bases", J. Med. Chem., vol. 30, pp. 982-991 (1987).
Herdewijn et al., "3'-Substituted 2',3'-Dideoxynucleoside Analogues as Potential Anti-HIV (HTLV-III/LAV) Agents", J. Med. Chem., vol. 30, pp. 1270-1278 (1987).
Huryn et al., "Synthesis Of Iso-ddA, Member Of a Novel Class Of Anti-HIV Agents", Tetrahedron Lett., vol. 30(46), pp. 6259-6262 (1989).
Huryn et al., "Synthesis of Iso-ddA, Member Of A Novel Class Of Anti-HIV Agents-Dioxolane-T. A New 2'3'-Dideoxynucleoside Prototype With In Vitro Activity Against HIV", Chemtracts-Organic Chemistry, vol. 3, pp. 249-251 (1990).
Jeong et al., "Asymmetric Synthesis and Biological Evaluation of .beta.-L-(2R,5S)-and .alpha.-L-(2R,5R)-1,3-Oxathiolane-Pyrimidine and -Purine Nucleosides as Potential Anti-HIV Agents", J. Med. Chem., vol. 36(2), pp. 181-195 (1993).
Kim, et al., "1,3-Dioxolanyl Purine Nucleosides (2R,4R) and
Mansour Tarek
Tse Allan H. L.
Biochem Pharma Inc.
Crane L. Eric
Haley, Jr. James F.
Kight John
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