Asymmetric Synthesis of 4′-Quaternary 2′-Deoxy-3′- and -4′-epi-β-C- and -N-Nucleosides

Abstract

A versatile and efficient route to both enantiomers of 4′-quaternary 2′-deoxy-3′- and -4′-epi-β-C- and -N-nucleosides is described. The asymmetric synthesis involves the SAMP/RAMP-­hydrazone α-alkylation methodology and diastereoselective nucleophilic 1,2-additions. Manipulation of the substituents in the anomeric position leads to the thermodynamically more stable β-anomers of excellent diastereo- and enantiomeric purity (>99% de and ee).

Key words

nucleoside analogues - asymmetric synthesis - hydrazones - quaternary stereocentres - diastereoselective reduction

References

• 1a Nomura M. Shuto S. Tanaka M. Sasaki T. Mori S. Shigeta S. Matsuda A. J. Med. Chem.  1999,  42:  2901 
• 1b Shuto S. Kanazaki M. Ichikawa S. Minakawa N. Matsuda A. J. Org. Chem.  1998,  63:  746 
• 1c Waga T. Ohuri H. Meguro H. Nucleosides Nucleotides  1996,  15:  287 
• 1d O-Yang C. Wu HY. Fraser-Smith EB. Walker KAM. Tetrahedron Lett.  1992,  33:  37 
• 1e O-Yang C. Kurz W. Eugui EM. McRoberts MJ. Verheyden JPH. Kurz LJ. Walker KAM. Tetrahedron Lett.  1992,  33:  41 
• 1f Rangam G. Rudinger NZ. Müller HM. Marx A. Synthesis  2005,  1467 
• 1g Kohgo S. Yamada K. Kitano K. Iwai Y. Sakata S. Ashida N. Hayakawa H. Nameki D. Kodama E. Matsuoka M. Mitsuya H. Ohrui H. Nucleosides, Nucleotides Nucleic Acids  2004,  23:  671 
• 2 Marx A. Summerer D. Synlett  2004,  217 
• 3 Kool ET. Annu. Rev. Biochem.  2002,  71:  191 
• For an overview, see:
• 4a Perspectives in Nucleoside and Nucleic Acid Chemistry   Kisakürek MV. Rosemeyer H. VHCA; Zürich: 2000. 
• For a review on aza nucleosides, see:
• 4b Yokoyama M. Momotake A. Synthesis  1999,  1541 
• For a review on thio nucleosides, see:
• 4c Yokoyama M. Synthesis  2000,  1637 
• 4d Alho MAM. Errea MI. Sguerra VL. D’Accorso NB. Talarico LB. Garcia CC. Damonte EB. J. Heterocycl. Chem.  2005,  42:  979 
• 5 Vorbrüggen H. Ruh-Pohlenz C. Org. React.  2000,  55:  1 
• 6 Brotschi C. Häberli A. Leumann CJ. Angew. Chem. Int. Ed.  2001,  40:  3012 ; Angew. Chem. 2001, 113, 3101
• 7 For a review on C-nucleosides, see: Wu Q. Simons C. Synthesis  2004,  1533 
• 8 Hess MT. Schwitter U. Petretta M. Giese B. Naegli H. Biochemistry  1997,  36:  2332 
• 9 Enders D. Hieronymi A. Ridder A. Synlett  2005,  2391 
• 10 For a review, see: Enders D. Voith M. Lenzen A. Angew. Chem. Int. Ed.  2005,  44:  1304 
• For reviews, see:
• 11a Job A. Janeck CF. Bettray W. Peters R. Enders D. Tetrahedron  2002,  58:  2253 
• On hydrazone cleavage, see:
• 11b Enders D. Wortmann L. Peters R. Acc. Chem. Res.  2000,  33:  157 
• 13 Imamoto T. Tawarayama Y. Sugiura Y. Mita T. Hatanaka Y. Yokoyama M. J. Org. Chem.  1984,  49:  3904 
• 14 Evans DA. Chapman KT. Carreira EM. J. Am. Chem. Soc.  1988,  110:  3560 
• 15a Sugimura H. Osumi K. Yamazaki T. Yamaya T. Tetrahedron Lett.  1991,  32:  1813 
• 15b Sujino K. Sugimura H. Synlett  1992,  553 
• 15c Nicolaou KC. Seitz SP. Papahatjis DP. J. Am. Chem. Soc.  1983,  105:  2430 
• 16 Enders D. Breuer I. Drosdow E. Synthesis  2005,  3239 

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