Syntheses of Enantiopure 3,4-Diamino-1-Substituted Pyrrolidines

Abstract

A convenient and general route to enantiopure 3,4-diamino-1-substituted pyrrolidines has been devised. 1-Alkyl, 1-alkanoyl, 1-cycloalkyl and 1-aryl-3,4-diaminopyrrolidines of the (3R,4R)-configurations have all been prepared, the cycloalkyl and (mono)aryl being novel derivatives. A previous difficulty in the synthesis of such compounds is the observation that dimesylates undergo two-fold displacement with sodium azide in very poor yields (<10%), if at all. However, use of lithium azide permits satisfactory yields of the diazides 5 and hence the corresponding diamines 6 and their derivatives, and avoids the generation and use of hydrazoic acid, as previously required in a Mitsunobu procedure.

Key words

enantioselective synthesis - pyrrolidines - vicinal diamines - two-fold inversions - lithium azide

References

• 1a Tomioka K. Synthesis  1990,  541 
• 1b Togni A. Venanzi LM. Angew. Chem., Int. Ed. Engl.  1994,  33:  497 
• 1c Scheurer A. Mosset P. Saalfrank RW. Tetrahedron: Asymmetry  1997,  8:  1243 
• 1d Akester J. Cui J. Fraenkel G. J. Org. Chem.  1997,  62:  431 
• 2 Yoshioka M. Kawakita T. Ohno M. Tetrahedron Lett.  1989,  30:  1657 
• 3 Ludovic J. Rouden J. Maddaluno J. Lasne M.-C. J. Org. Chem.  2004,  69:  8893 
• 4a Lohray BB. Baskaran S. Rao BS. Mallesham B. Bharath KSN. Reddy BY. Venkateswarlu S. Sadhukhan AK. Kumar MS. Sarnaik HM. Bioorg. Med. Chem. Lett.  1998,  525 
• 4b Grey J. Dyck B. Rowbottom MW. Tamiya J. Vickers TD. Zhang MZ. Zhao LR. Heise CE. Schwarz D. Saunders J. Goodfellow VS. Bioorg. Med. Chem. Lett.  2005,  999 
• 5 Flinois K. Yuan Y. Bastide C. Harrison-Marchand A. Maddaluno J. Tetrahedron  2002,  58:  4707 
• 6 Alexopoulos K. Fatseas P. Melissari E. Vlahakos D. Roumelioti P. Mavromoustakos T. Mihailescu S. Paredes-Carbajal MC. Mascher D. Matsoukas J. J. Med. Chem.  2004,  47:  3338 
• 7 Sturm PA. Cory M. Henry DW. McCall JW. Ziegler JB. J. Med. Chem.  1977,  20:  1333 
• 8a Löwik DWPM. Weingarten MD. Broekema M. Brouwer AJ. Still WC. Angew. Chem. Int. Ed.  1998,  37:  1846 
• 8b Ryan K. Still WC. Bioorg. Med. Chem. Lett.  1999,  9:  2673 
• 8c Iorio EJ. Still WC. Bioorg. Med. Chem. Lett.  1999,  9:  2145 
• 9 Trost BM. Pan Z. Zambrano J. Kujat C. Angew. Chem. Int. Ed.  2002,  41:  4691 
• 10 Brouwer AJ. van der Linden HJ. Liskamp RMJ. J. Org. Chem.  2000,  65:  1750 
• 11 Han B. Wang Z.-J. Jaun B. Krishnamurthy R. Eschenmoser A. Org. Lett.  2003,  5:  2071 
• 12 Skarzewski J. Gupta A. Tetrahedron: Asymmetry  1997,  8:  1861 
• 13 Shriner RL. Furrow CL. Org. Synth.  1955,  35:  49 
• 14 Prasad ASB. Kanth JVB. Periasamy M. Tetrahedron  1992,  48:  4623 
• 15 Marson CM. Melling RC. J. Org. Chem.  2005,  70:  9771 
• 17 Nagel U. Kinzel E. Andrade J. Prescher G. Chem. Ber.  1986,  119:  3326 
• 18 Larson ER. Raphael RA. J. Chem. Soc., Perkin Trans. 1  1982,  521 
• 19 Rottlander M. Palmer N. Knochel P. Synlett  1996,  573 
• 20 Bourson J. Oliveros L. J. Organomet. Chem.  1982,  77:  229 
• 21 Hoffman-Bang N. Acta Chem. Scand.  1957,  11:  581 
• 22 Vaultier M. Knouzi N. Carrie R. Tetrahedron Lett.  1983,  24:  763 
• 23 Bhattacharjee MN. Chaudhuri MK. Ghosh SK. Hiese Z. Roy N. J. Chem. Soc., Dalton Trans.  1983,  2561 

16

For displacement of a fluoro substituent on a quinolone ring by N,N′-bis-Boc derivatives of (3R,4R)-3,4-diamino-
pyrrolidine, see reference 3.