Synthesis of Adamantylglycine Using a Diastereoselective Grignard-to-Nitrone Addition

Abstract

In contrast to amino acids with a bulky substituent like tert-leucine, adamantylglycine has so far received little attention. Here, a new, practical synthesis of adamantylglycine is described. This is based on a highly diastereoselective addition of adamantyl Grignard reagent to 2,3-O-cyclohexylideneglyceraldehyde N-benzylnitrone, mediated by the Lewis acid diethylaluminum chloride. Adamantylglycine is obtained from the nitrone in 6 steps and 28% yield as a crystalline hydrochloride with 0.5 methanol incorporated.

Key words

glyceraldehyde - chiral nitrone - Grignard addition - electrophilic glycine equivalent - crystal structure

References

• For overviews with numerous examples of applications, see:
• 1a Risch N. Arend M. In Houben-Weyl, Methoden der Organischen Chemie   4th ed., Vol. E21b:  Helmchen G. Hoffmann RW. Mulzer J. Schaumann E. Thieme; Stuttgart: 1995.  p.1833 
• 1b Principles and Applications of Asymmetric Synthesis   Lin G.-Q. Li Y.-M. Chan ASC. Wiley-Interscience; New York: 2001. 
• 1c Asymmetric Synthesis of Natural Products   Koskinen A. Wiley; Chichester: 1993. 
• 1d Asymmetric Synthesis - The Essentials   Christmann M. Bräse S. Wiley-VCH; Weinheim: 2007. 
• 2a Chemistry and Biochemistry of the Amino Acids   Barrett GC. Chapman and Hall; London: 1985. 
• 2b Scott JW. In Asymmetric Synthesis   Vol. 4:  Morrison JD. Scott JW. Academic Press; Orlando: 1984.  p.1 
• 2c Asymmetric Synthesis: Construction of Chiral Molecules Using Amino Acids   Coppola GM. Schuster HF. Wiley; New York: 1987. 
• 3a Chiral Auxiliaries and Ligands in Asymmetric Synthesis   Seyden-Penne J. Wiley; New York: 1995. 
• 3b Evans DA. In Asymmetric Synthesis   Vol. 3B:  Morrison JD. Academic Press; Orlando: 1984.  p.1 
• 3c Meyers AI. Lutomski KA. In Asymmetric Synthesis   Vol. 3B:  Morrison JD. Academic Press; Orlando: 1984.  p.213 
• 3d Enders D. In Asymmetric Synthesis   Vol. 3B:  Morrison JD. Academic Press; Orlando: 1984.  p.275 
• 3e Job A. Janeck CF. Bettray W. Peters R. Enders D. Tetrahedron: Asymmetry  2002,  58:  2253 
• 4a Kagan HB. In Asymmetric Synthesis   Vol. 5:  Morrison JD. Academic Press; Orlando: 1985.  p.1 
• 4b Wang D.-H. Engle KM. Shi B.-F. Yu JQ. Science  2010,  327:  315 
• See, e.g.:
• 5a Longbottom DA. Franckevicius V. Ley SV. Chimia  2007,  61:  247 
• 5b Seayad J. List B. Org. Biomol. Chem.  2005,  3:  719 
• For uses of tert-leucine and tert-leucinol, see:
• 6a Tomioka K. Koga K. In Asymmetric Synthesis   Vol. 2A:  Morrison JD. Academic Press; New York: 1983.  p.201 
• 6b Guével A.-C. In Encyclopedia of Reagents for Organic Synthesis   Vol. 5:  Paquette LA. Wiley; Chichester: 1995.  p.2961 
• 6c Bolm C. Kasyan A. Drauz K. Günther K. Raabe G. Angew. Chem. Int. Ed.  2000,  39:  2288 ; Angew. Chem. 2000, 112, 2374 (including references to tert-sila-leucine)
• 7 Mahadik GS. Hitchcock SR. Tetrahedron: Asymmetry  2010,  21:  33 
• 8a Do KQ. Tanei P. Gavierel M. Schwyzer R. Helv. Chim. Acta  1979,  62:  956 
• 8b Belokon YN. Maleyev VI. Vitt SV. Ryzhov MG. Kondrashov YD. Golubev SN. Vauchskii YP. Kazika AI. Novikova MI. Krasutski PA. Yurchenko AG. Dubchak IL. Shklover VE. Struchkov YT. Bakhmutov VI. Belikov VM. J. Chem. Soc., Dalton Trans.  1985,  17 
• 8c Gálvez N. Moreno-Mañas M. Vallribera A. Molins E. Cabrero A. Tetrahedron Lett.  1996,  37:  6197 
• 8d Gálvez N. Moreno-Mañas M. Padros I. Sebastian RM. Serra N. Vallribera A. Polyhedron  1995,  14:  1397 
• 8e Clariana J. Garsía-Granda S. Gotor V. Gutiérrez-Fernández A. Luna A. Moreno-Mañas M. Vallribera A. Tetrahedron: Asymmetry  2000,  11:  4549 
• 8f Augeri DJ. Robl JA. Betebenner DA. Magnin DR. Khanna A. Robertson JG. Wang A. Simpkins LA. Taunk P. Huang Q. Han S.-P. Abboa-Offei B. Cap M. Xin L. Tao L. Tozzo E. Welzel GE. Egan DM. Marcinkeviciene J. Chang SY. Biller SA. Kirby MS. Parker RA. Hamann LG. J. Med. Chem.  2005,  48:  5025 
• 9 Yield of 1˙HCl 2.3% after 6 steps from 1-adamantane carboxaldehyde: Hasegawa M. Taniyama D. Tomioka K. Tetrahedron  2000,  56:  10153 
• 10 cf.: Use of adamantylglycinol for respective oxazoline ligands: Villhauer EB. Brinkman JA. Naderi GB. Burkey BF. Dunning BE. Prasad K. Mangold BL. Russell ME. Hughes TE. J. Med. Chem.  2003,  46:  2774 
• 11 Wanka L. Cabrele C. Vanejews M. Schreiner PR. Eur. J. Org. Chem.  2007,  1474 
• 12 Aldrich PE. Hermann EC. Meier WE. Paulshock M. Prichard WW. Snyder JA. Watts JC. J. Med. Chem.  1971,  14:  535 
• 13 Rosenthal K. Sokol MS. Ingram RL. Subramanian R. Fort RC. Antimicrob. Agents Chemother.  1982,  22:  1031 
• For pioneering work concerning RM additions to 2,3-O-isopropylidene gylceraldehyde imines, see:
• 14a Yoshimura J. Sato T. J. Am. Chem. Soc.  1964,  86:  3858 
• 14b Ohgo Y. Yoshimura J. Sato T. Bull. Chem. Soc. Jpn.  1969,  42:  728 
• 14c See also: Carcano M. Nicotra F. Panza L. Russo G. Chem. Commun.  1989,  297 
• 15 Bloch R. Chem. Rev.  1998,  98:  1407 
• 16 Franz T. Hein M. Veith U. Jäger V. Peters E.-M. Peters K. von Schnering HG. Angew. Chem., Int. Ed. Engl.  1994,  33:  1298 ; Angew. Chem. 1994, 106, 1308
• 17a Veith U. Leurs S. Jäger V. Chem. Commun.  1996,  329 
• 17b Meunier N. Veith U. Jäger V. Chem. Commun.  1996,  331 
• 18a Veith U. Schwardt O. Jäger V. Synlett  1996,  1181 
• 18b Schwardt O. Veith U. Gaspard C. Jäger V. Synthesis  1999,  1473 
• 19 Li F. Schwardt O. Jäger V. Synthesis  2006,  2173 ; and references cited therein
• For basic work on such nitrone additions, see:
• 20a Dondoni A. Franco S. Merchan FL. Merino P. Tejero T. Tetrahedron Lett.  1993,  34:  5475 
• 20b Merino P. Castillo E. Merchan FL. Tejero T. Tetrahedron: Asymmetry  1997,  8:  1725 
• 20c Merino P. Anoro S. Castillo E. Merchan F. Tejero T. Tetrahedron: Asymmetry  1996,  7:  1887 
• 20d Merino P. Castillo E. Franco S. Merchan FL. Tejero T. Tetrahedron  1998,  54:  12301 
• 20e Merino P. Castillo E. Franco S. Merchan FL. Tejero T. J. Org. Chem.  1998,  63:  2371 
• 20f Schade W. Reissig H.-U. Synlett  1999,  632 
• 20g Merino P. C. R. Chim.  2005,  8:  775 
• 20h cf.: Portolés R. Murga J. Falomir E. Carda M. Uriel S. Marco JA. Synlett  2002,  711 
• 21a Li F. Ph.D. Dissertation   University of Stuttgart; Germany: 2007. 
• 21b cf.: Jäger V. Bierer L. Dong H.-Q. Palmer A. Shaw D. Frey W. J. Heterocycl. Chem.  2000,  37:  455 
• 21c Palmer AM. Jäger V. Synlett  2000,  1405 
• 21d Palmer AM. Jäger V. Eur. J. Org. Chem.  2001,  1293 
• 21e Palmer AM. Jäger V. Eur. J. Org. Chem.  2001,  2547 
• 22 For ‘asymmetric derivatization of glycines’ and ‘glycine cations’, see: Williams RM. Synthesis of Optically Active α-Amino Acids   Pergamon Press; Oxford: 1989.  p.95 
• 23 Methods for the Oxidation of Organic Compounds   Haines AH. Academic Press; London: 1988. 
• 24a Zimmermann PJ. Blanarikova I. Jäger V. Angew. Chem. Int. Ed.  2000,  39:  910 , Angew. Chem. 2000, 112, 936
• 24b Zimmermann PJ. Lee J.-Y. Blanarikova I. Endermann R. Häbich D. Jäger V. Eur. J. Org. Chem.  2005,  3450 
• 24c Lee J.-Y. Schiffer G. Jäger V. Org. Lett.  2005,  7:  2317 
• 24d Henneböhle M. Le Roy P.-Y. Hein M. Ehrler R. Jäger V. Z. Naturforsch., B  2004,  59:  451 
• 25a Hubschwerlen C. Schmid G. Helv. Chim. Acta  1993,  66:  2206 
• 25b Hubschwerlen C. Synthesis  1986,  962 
• 25c Krämer B. Franz T. Picasso S. Pruschek P. Jäger V. Synlett  1997,  295 
• 25d Palomo C. Aizpurua JM. García JM. Galarza R. Legido M. Urchegui R. Román P. Luque A. Server-Carrió J. Linden A. J. Org. Chem.  1997,  62:  2070 
• 26 Yurchenko AG. Fedorenko TV. Zh. Org. Khim.  1987,  23:  970 ; Chem. Abstr. 1988, 108, 204255y
• 27 Dondoni A. Franco S. Junquera F. Merchan F. Merino P. Tejero T. Synth. Commun.  1994,  24:  2537 
• 28 cf.: Use in isoxazolidine reductions: DeShong P. Dicken CM. Leginus JM. Whittle RR. J. Am. Chem. Soc.  1984,  106:  5598 
• 29 Rundel W. In Houben-Weyl, Methoden der Organischen Chemie   4th ed., Vol. X/4:  Müller E. Thieme; Stuttgart: 1968.  p.309 
• 30 Frey W. Baskakova A. Jäger V. Z. Kristallogr. - New Cryst. Struct.  2009,  224:  27 
• 31a Yin H. Franck RW. Chen S.-L. Quigley GJ. Todardo L. J. Org. Chem.  1992,  57:  644 
• 31b Menzel A. Ph.D. Dissertation   University of Stuttgart; Germany: 2000. 
• 32 Kocienski PJ. Protecting Groups   Thieme; Stuttgart: 1994.  p.95 
• 33 Frey W. Baskakova A. Menzel A. Jäger V. Z. Kristallogr. - New Cryst. Struct.  2010,  225:  245 
• 34 Frey W. Baskakova A. Jäger V. Z. Kristallogr. - New Cryst. Struct.  2010,  225:  247 
• 35a Kraus GA. Roth B. J. Org. Chem.  1980,  45:  4825 
• 35b Lindgren BO. Hilsson T. Acta Chem. Scand.  1973,  27:  888 
• 38 Liu K.-C. Shelton BR. Howe RK. J. Org. Chem.  1980,  45:  3916 
• 39a Maskill H. Jencks WP. J. Am. Chem. Soc.  1987,  109:  2062 
• 39b Borch RF. Bernstein MD. Durst HD. J. Am. Chem. Soc.  1971,  93:  2897 
• 40a Schmid CR. Bryant JD. Dowlatzedah M. Philips JL. Prather DE. Schantz RD. Sear NL. Vianco CS. J. Org. Chem.  1991,  56:  4056 
• 40b Chittenden GJF. Carbohydr. Res.  1980,  84:  350 
• 41a Sheldrick GM. SHELXS-97. Program for the Solution of Crystal Structures   University of Göttingen; Germany: 1997. 
• 41b Sheldrick GM. SHELXL-97. Program for the Refinement of Crystal Structures   University of Göttingen; Germany: 1997. 
• 41c Sheldrick GM. SHELXTL-Plus. Structure Determination Software Suite   Release 4.1. Siemens Analytical Systems Inc.; Madison: 1991. 
• 42 cf.: Veith U. Diploma Thesis   University of Würzburg; Germany: 1991. 
• 43 Canas-Rodriguez A. Ruiz-Poveda SG. Coronel-Borges LA. Carbohydr. Res.  1987,  159:  217 
• 44 Basel Y. Hassner A. J. Org. Chem.  2000,  65:  6368 

36

Crystallographic data for adamantylglycine 1˙HCl˙(0.5MeOH) have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-770794. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or e-mail: [e-mail]].

37

The presence of MeOH in crystalline 1˙HCl has apparently been overlooked in earlier work.^8,9