1222
J. Org. Chem. 2000, 65, 1222-1224
Asymmetric Synthesis of a C-3 Substituted Pipecolic Acid
Scheme 1
Andrew J. Souers and Jonathan A. Ellman* University of California at Berkeley, Department of Chemistry, Berkeley, California 94720 Received August 13, 1999
The design and synthesis of conformationally constrained amino acids has attracted considerable attention from the synthetic and medicinal chemistry communities.1 The replacement of constrained amino acids for natural amino acids in both peptides and peptidomimetics is a proven strategy for probing the structural requirements of receptor-bound ligand conformations,2 increasing potency of receptor-ligand interactions,3 and imparting proteolytic stability.4 In the course of our ongoing peptidomimetic efforts, we required access to enantiomerically and diastereomerically enriched pipecolic acid derivatives with substitution5 at the C-3 position.6 For our purposes, it was important not only that the compound be suitable for incorporation into solid-phase synthesis but also that a “functional handle” be present for postsynthetic modification. Based upon a recent report by Piscopio,7 we designed and synthesized the novel amino acid 1 through a modular and efficient route that is highly amenable to analogue synthesis. We envisioned the cyclic amino acid 1 coming from the N-allylated amino acid 7 via sequential ring closing metathesis and hydrogenation (Scheme 1). This densely functionalized amino acid would be accessed by the 3,3 Claisen rearrangement of chiral ester 5, which is derived from chiral allylic alcohol 4 (Scheme 2) and N-Boc glycine. As illustrated in Scheme 2, the synthesis was initiated by Wittig condensation of known aldehyde 28 and the ylide of acetonyltriphenylphosphonium chloride. Refluxing the reaction solution for 24 h in 3:1 dioxane/H2O afforded the R,β-unsaturated ketone 3 in 73% yield. As expected, only the E-alkene isomer was detected by proton NMR spectroscopy. Asymmetric reduction of this ketone with (S)-2-methyl-CBS-oxazaborolidene9 and (1) For recent reviews, see: (a) Gibson, S. E.; Thomas, N.; Guillo, N.; Tozer, M. J. Tetrahedron. 1999, 55, 585-615. (b) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699-1720. (c) Duthaler, R. O. Tetrahedron 1994, 50, 1539-1650. (2) (a) Tellier, F.; Archer, F.; Brabet, I.; Pin, J.-P.; Azerad, R. Bioorg. Med. Chem. 1998, 6, 195-208. (b) Charette, A. B.; Cote, B. J. Am. Chem. Soc. 1995, 117, 12721-12732. (3) Holladay, M. W.; Lin, C. W.; May, C. S.; Garvey, D. S.; Witte, D.; Miller, T. R.; Wolfram, C. A. W.; Nadzan, A. M. J. Med. Chem. 1991, 34, 455-457. (4) Ogawa, T.; Yoshitomi, H.; Kodama, H.; Waki, M.; Stammer, C.; Shimohgashi, Y. FEBS. Lett. 1989, 250, 227. (5) Swarbrick, M. E.; Gosselin, F.; Lubell, W. D. J. Org. Chem. 1999, 64, 1993-2002 and ref 18 therein. (6) (a) Murray, P. J.; Starkey, I. D. Tetrahedron Lett. 1996, 37, 1875-1878. (b) Christie, B. D.; Rappoport, H. J. Org. Chem. 1985, 50, 1239-1246. (c) Angle, S. R.; Arnaiz, D. O. Tetrahedron Lett. 1989, 30, 515-518 and references therein. (7) (a) Miller, J. F.; Termin, A.; Koch, K.; Piscopio, A. D. J. Org. Chem. 1998, 63, 3158-3159. (b) For related work, see: Burke, S. D.; Ng, R. A.; Morrison, J. A.; Alberti, M. J. J. Org. Chem. 1998, 63, 31603161. (8) Ikeda, Y.; Uka, J.; Ikeda, N.; Yamamoto, H. Tetrahedron. 1987, 43, 731-741. (9) (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. Engl. 1998, 37, 1986-2012.
Scheme 2a
a Key: (a) acetonyltriphenylphosphonium chloride (1.2 equiv), Na2CO3 (1.2 equiv), 3:1 dioxane/H2O, reflux, 24 h; (b) catecholborane (1.98 equiv), CBS-(S)-oxazaborolidene (0.14 equiv), toluene, -78 °C; (c) N-Boc-Gly (1.2 equiv), DMAP (0.4 equiv), DIC (1.2 equiv), CH2Cl2; (d) LDA (3 equiv), THF, -20 °C f -78 °C then ZnCl2/THF (1.2 equiv) -78 °C f rt, 10 h.
catecholborane afforded the (R)-allylic alcohol 4 in 94% yield and 88% ee as determined by HPLC analysis of the corresponding Mosher esters.10 The absolute configuration was inferred from ample literature precedent.11 After coupling alcohol 4 with N-Boc-Gly to afford ester 5, we employed a modified version of the Kazmaier 3,3 Claisen rearrangement procedure to set the two contiguous stereocenters of amino acid 6.12 Under the optimized conditions (see the Experimental Section), the rearrangement proceeded from the zinc-chelated Z-ester enolate to afford acid 6 in 85-90% yield. A single diastereomer was observed by HPLC and NMR analysis. On the basis of the literature precedent of Kazmaier12 and Bartlett,13 acid 6 was assigned as the syn diastereomer with E-alkene stereochemistry as would be expected from a chair transition state. We then turned our attention to the selective electrophilic allylation of the Boc-nitrogen in the presence of the carboxylic acid moiety (Scheme 3). Although several different conditions have appeared in the literature,14 the best reported yield for the allylation of a Boc-protected amino acid was 50%. It was found that allylation using allyl iodide and NaH in THF over several days proceeded in 62-68% yield on a multigram scale, with starting (10) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512519. (11) For reductions of related R,β-unsaturated ketones, see: Lo¨gers, M.; Overman, L. E.; Welmaker, G. S. J. Am. Chem. Soc. 1995, 117, 9139-9150. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C. P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925-7926. (c) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1995, 36, 9153-9156. (d) Wipf, P.; Lim, S. Chimia 1996, 50, 157-167. (12) Kazmaier, U. Angew. Chem., Int. Ed. Engl. 1994, 33, 998-999. (b) Kazmaier, U.; Krebs, A. Angew. Chem. Int. Ed. Engl. 1995, 34, 2012-2014. (c) Kazmaier, U.; Maier, S. Tetrahedron. 1996, 52, 941954. (13) Bartlett, P. A.; Barstow, J. F. J. Org. Chem. 1982, 47, 39333941. (b) Bartlett, P. A.; Tanzella, D. J.; Barstow, J. F. Tetrahedron Lett. 1982, 23, 619-622.
10.1021/jo991293l CCC: $19.00 © 2000 American Chemical Society Published on Web 02/03/2000
Notes
J. Org. Chem., Vol. 65, No. 4, 2000 1223 Scheme 3a
a Key: (a) allyl iodide (1.5 equiv), NaH (3 equiv), THF, 0 °C f rt, 72 h; (b) Grubbs cat. (0.05 equiv), CH2Cl2; (c) 10% Pt/C, H2, EtOAc, 50 psi, 16 h.
material accounting for the remaining mass. Attempts to accelerate the reaction rate by elevating the reaction temperature or by use of a more polar solvent, such as DMF, resulted in appreciable amounts of O-alkylation. No epimerization was detected in either the recovered starting material or product as determined by HPLC analysis. The densely functionalized amino acid 7 was then subjected to ring closing metathesis conditions using Grubb’s phosphorylidine catalyst [RuCl2(dCHPh)(PCy3)2].15 Although the reaction proceeded cleanly, column chromatography was insufficient to completely remove catalyst-derived impurities. The unpurified material was therefore directly submitted to the hydrogenation reaction at 50 psi H2 with 10% Pt/C. After filtration over Celite, pure amino acid 1 was obtained in 86% overall yield for the two steps. Two experiments were performed to rigorously establish the diastereomeric and enantiomeric purity of the final pipecolic acid 1. First, acid 1 was converted to the methyl ester by diazomethane treatment. Upon subjection to base, an approximately 1:1 ratio of the methyl ester of 1 and the corresponding epimer were obtained as determined by HPLC-MS. HPLC analysis of the methyl ester of 1 clearly established that, to the limits of detection (
