Synthesis 2019; 51(04): 976-984
DOI: 10.1055/s-0037-1610304
paper
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Fmoc- and Boc-Protected (2S,5S)- and (2R,5R)-5-Aminomethylprolines

Amelie L. Bartuschat
,
Nina Hegmann
,
Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Friedrich- Alexander-Universität Erlangen-Nürnberg, Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany   Email: markus.heinrich@fau.de
› Author Affiliations
Deutsche Forschungsgemeinschaft HE5413/6-1
Further Information

Publication History

Received: 11 September 2018

Accepted: 17 September 2018

Publication Date:
25 October 2018 (eFirst)

Abstract

The proline derivatives (2S,5S)dmamPro, (2S,5S)N-Boc-amPro and (2R,5R)dmamPro are useful building blocks for peptides since they allow conformational fixation of peptidyl–CO–N-prolyl bonds in the unusual cis conformation. The stereoselective syntheses of these dimethylaminomethyl-prolines is achieved from literature-known precursors with overall yields of 23% [over 8 steps for (2S,5S)dmamPro], 33% [over 9 steps for (2S,5S)N-Boc-amPro] and 12% [over 8 steps for (2R,5R)dmamPro]. The applicability of (2S,5S)N-Boc-amPro in peptide synthesis is demonstrated through the preparation of an Fmoc-Val-amPro-OMe dipeptide.

Supporting Information

 
  • References

  • 1 Brandts JF. Halvorson HR. Brennan M. Biochemistry 1975; 14: 4953
  • 2 Andreotti AH. Biochemistry 2003; 42: 9515
  • 3 Eckert BS. Schmid F.-X. BioSpectrum 2006; 3
  • 4 Shoulders MD. Raines RT. Annu. Rev. Biochem. 2009; 78: 929
  • 5 Dorman DE. Bovey FA. J. Org. Chem. 1973; 38: 2379
  • 6 Cheng HN. Bovey FA. Biopolymers 1977; 16: 1465
  • 7 Fischer S. Dunbrack RL. Karplus M. J. Am. Chem. Soc. 1994; 116: 11931
  • 8 For a review article, see: Mothes C. Caumes C. Guez A. Boullet H. Gendrineau T. Darses S. Delsuc N. Moumné R. Oswald B. Lequin O. Karoyan P. Molecules 2013; 18: 2307

    • For syntheses of 3-substituted proline derivatives, see:
    • 9a Perni RB. Farmer LJ. Cottrell KM. Court JJ. Courtney LF. Deininger DD. Gates CA. Harbeson SL. Kim JL. Lin C. Lin K. Luong Y.-P. Maxwell JP. Murcko MA. Pitlik J. Rao BG. Schairer WC. Tung RD. Van Drie JH. Wilson K. Thomson JA. Bioorg. Med. Chem. Lett. 2004; 14: 1939
    • 9b Beausoleil E. Sharma R. Michnick SW. Lubell WD. J. Org. Chem. 1998; 63: 6572
    • 9c Hodges JA. Raines RT. J. Am. Chem. Soc. 2005; 127: 15923
    • 9d Jenkins CL. Bretscher LE. Guzei IA. Raines RT. J. Am. Chem. Soc. 2003; 125: 6422
    • 9e Caumes C. Delsuc N. Azza RB. Correia I. Chemla F. Ferreira F. Carlier L. Luna AP. Moumne R. Lequin O. Karoyan P. New J. Chem. 2013; 37: 1312

      For syntheses of 4-substituted proline derivatives, see:
    • 10a Doi M. Nishi Y. Kiritoshi N. Iwata T. Nago M. Nakano H. Uchiyama S. Nakazawa T. Wakamiya T. Kobayashi Y. Tetrahedron 2002; 58: 8453
    • 10b Demange L. Ménez A. Dugave C. Tetrahedron Lett. 1998; 39: 1169
    • 10c Pandey AK. Ganguly HK. Yap GP. A. Zondlo NJ. Org. Biomol. Chem. 2016; 14: 2327
    • 10d Owens NW. Stetefeld J. Lattová E. Schweizer F. J. Am. Chem. Soc. 2010; 132: 5036
    • 10e Klein LL. Li L. Chen H.-J. Curty CB. DeGoey DA. Grampovnik DJ. Leone CL. Thomas SA. Yeung CM. Funk KW. Kishore V. Lundell EO. Wodka D. Meulbroek JA. Alder JD. Nilius AM. Lartey PA. Plattner JJ. Bioorg. Med. Chem. 2000; 8: 1677
    • 10f Jiang J. Yang L. Jin Q. Ma W. Moroder L. Dong S. Chem. Eur. J. 2013; 19: 17679
    • 10g Zhang Z. Aerschot AV. Hendrix C. Busson R. David F. Sandra P. Herdewijn P. Tetrahedron 2000; 56: 2513
    • 10h Zondlo N. Pandey A. Tressler C. WO2014127052A1, 2014
    • 11a Holmgren SK. Taylor KM. Bretscher LE. Raines RT. Nature 1998; 392: 666
    • 11b Kotch FW. Guzei IA. Raines RT. J. Am. Chem. Soc. 2008; 130: 2952
    • 11c Erdmann RS. Wennemers H. Angew. Chem. Int. Ed. 2011; 50: 6835
    • 11d Shoulders MD. Guzei IA. Raines RT. Biopolymers 2008; 89: 443
    • 11e Shoulders MD. Hodges JA. Raines RT. J. Am. Chem. Soc. 2006; 128: 8112
    • 11f DeRider ML. Wilkens SJ. Waddell MJ. Bretscher LE. Weinhold F. Raines RT. Markley JL. J. Am. Chem. Soc. 2002; 124: 2497
    • 11g Jenkins CL. McCloskey AI. Guzei IA. Eberhardt ES. Raines RT. Biopolymers 2005; 80: 1
    • 11h Siebler C. Erdmann RS. Wennemers H. Angew. Chem. Int. Ed. 2014; 53: 10340
    • 11i Erdmann RS. Wennemers H. J. Am. Chem. Soc. 2010; 132: 13957
    • 12a Golbik R. Yu C. Weyher-Stingl E. Huber R. Moroder L. Budisa N. Schiene-Fischer C. Biochemistry 2005; 44: 16026
    • 12b Boulègue C. Milbradt AG. Renner C. Moroder L. J. Mol. Biol. 2006; 358: 846
    • 12c Steiner T. Hess P. Bae JH. Wiltschi B. Moroder L. Budisa N. PLoS ONE 2008; 3: e1680
    • 12d Heindl C. Hübner H. Gmeiner P. Tetrahedron: Asymmetry 2003; 14: 3153
    • 12e Renner C. Alefelder S. Bae JH. Budisa N. Huber R. Moroder L. Angew. Chem. Int. Ed. 2001; 40: 923
    • 12f Cadamuro SA. Reichold R. Kusebauch U. Musiol H.-J. Renner C. Tavan P. Moroder L. Angew. Chem. Int. Ed. 2008; 47: 2143
    • 12g Kuemin M. Nagel YA. Schweizer S. Monnard FW. Ochsenfeld C. Wennemers H. Angew. Chem. Int. Ed. 2010; 49: 6324
    • 12h Naduthambi D. Zondlo NJ. J. Am. Chem. Soc. 2006; 128: 12430
    • 13a Teixidó M. Zurita E. Mendieta L. Oller-Salvia B. Prades R. Tarragó T. Giralt E. Biopolymers 2013; 100: 662
    • 13b Talbot A. Maltais R. Kenmogne LC. Roy J. Poirier D. Steroids 2016; 107: 55
  • 14 Nagaike F. Onuma Y. Kanazawa C. Hojo H. Ueki A. Nakahara Y. Nakahara Y. Org. Lett. 2006; 8: 4465
  • 15 Johannesson P. Lindeberg G. Tong W. Gogoll A. Synnergren B. Nyberg F. Karlén A. Hallberg A. J. Med. Chem. 1999; 42: 4524
    • 16a Sunilkumar G. Nagamani D. Argade NP. Ganesh KN. Synthesis 2003; 2304
    • 16b Kamijo S. Hoshikawa T. Inoue M. Org. Lett. 2011; 13: 5928
  • 17 Beausoleil E. Lubell WD. J. Am. Chem. Soc. 1996; 118: 12902
    • 18a Magaard VW. Sanchez RM. Bean JW. Moore ML. Tetrahedron Lett. 1993; 34: 381
    • 18b Alonso De Diego SA. Muñoz P. González-Muñiz R. Herranz R. Martín-Martínez M. Cenarruzabeitia E. Frechilla D. Del Río J. Luisa Jimeno M. Teresa García-López M. Bioorg. Med. Chem. Lett. 2005; 15: 2279
    • 19a Melis C. Bussi G. Lummis SC. R. Molteni C. J. Phys. Chem. B 2009; 113: 12148
    • 19b Rodríguez I. Calaza MI. Cativiela C. Eur. J. Org. Chem. 2013; 1093
    • 19c Hinderaker MP. Raines RT. Protein Sci. 2003; 12: 1188
  • 20 For related, ring-annulated derivatives, see: Aillard B. Kilburn JD. Blaydes JP. Tizzard GJ. Findlow S. Werner JM. Bloodworth S. Org. Biomol. Chem. 2015; 13: 4562
    • 21a An SS. A. Lester CC. Peng J.-L. Li Y.-J. Rothwarf DM. Welker E. Thannhauser TW. Zhang LS. Tam JP. Scheraga HA. J. Am. Chem. Soc. 1999; 121: 11558
    • 21b Arnold U. Hinderaker MP. Köditz J. Golbik R. Ulbrich-Hofmann R. Raines RT. J. Am. Chem. Soc. 2003; 125: 7500
  • 22 Bartuschat AL. Wicht K. Heinrich MR. Angew. Chem. Int. Ed. 2015; 54: 10294

    • For alternative effects leading to the conformational fixation of amide bonds, see:
    • 23a Gorske BC. Bastian BL. Geske GD. Blackwell HE. J. Am. Chem. Soc. 2007; 129: 8928
    • 23b Gorske BC. Stringer JR. Bastian BL. Fowler SA. Blackwell HE. J. Am. Chem. Soc. 2009; 45: 16555
    • 23c Caumes C. Roy O. Faure S. Taillefumier C. J. Am. Chem. Soc. 2012; 134: 9553
    • 23d Szekely T. Caumes C. Roya O. Faure S. Taillefumier C. C. R. Chim. 2013; 16: 318
    • 23e Moure A. Sanclimens G. Bujons J. Masip I. Alvarez-Larena A. Pérez-Payá E. Alfonso I. Messeguer A. Chem. Eur. J. 2011; 17: 7927
    • 23f Stringer JR. Crapster JA. Guzei IA. Blackwell HE. J. Org. Chem. 2010; 75: 6068
    • 23g Yamasaki R. Tanatani A. Azumaya I. Saito S. Yamaguchi K. Kagechika H. Org. Lett. 2003; 5: 1265
    • 23h See also ref. 11a.

      For related synthetic routes, see:
    • 24a Kajino H. Nihei S. Ikeuchi Y. Miyamoto H. Numagami E. EP2103619A1, 2009
    • 24b Jain S. Sujatha K. Krishna KV. R. Roy R. Singh J. Anand N. Tetrahedron 1992; 48: 4985
    • 25a Watson HA. O’Neill BT. J. Org. Chem. 1990; 55: 2950
    • 25b Yamamoto Y. Hoshino J. Fujimoto Y. Ohmoto J. Sawada S. Synthesis 1993; 298
    • 25c Aggarwal VK. Sandrinelli F. Charmant JP. H. Tetrahedron: Asymmetry 2002; 13: 87
  • 26 Gu Q. Jiang L.-X. Yuan K. Zhang L. Wu X.-Y. Synth. Commun. 2008; 38: 4198
    • 27a Brown HC. Choi YM. Narasimhan S. J. Org. Chem. 1982; 47: 3153
    • 27b Lehmann L. Friebe M. Brumby T. Sülzle D. Platzek J. 2004 WO 2004087656
    • 27c Burkholder TP. Fuchs PL. J. Am. Chem. Soc. 1990; 112: 9601
  • 28 Roeske RW. Weitl FL. Prasad KU. Thompson RM. J. Org. Chem. 1976; 41: 1260
  • 29 Dubowchik GM. Firestone RA. Tetrahedron Lett. 1996; 37: 6465
  • 30 The optical purity of the Boc-protected derivative 17a was determined by chiral HPLC using two different solvent systems.