Straightforward Synthesis of N-Hydroxy Peptides

Abstract

N-Hydroxy dipeptides are readily synthesized by reduction of the corresponding oximes. The two diastereomers obtained are easily separated by flash chromatography. They can be coupled with a third amino acid moiety - without protection of the hydroxyl group - to give N-hydroxy tripeptides.

Key words

N-hydroxy peptides - oximes - reduction - hydroxyl­amines - N-/O-acylation

References

• For reviews see:
• 1a Ottenheijm HCJ. Herscheid JDM. Chem. Rev.  1986,  86:  697 
• 1b Marraud M. Vanderesse R. In Houben-Weyl, Methods of Organic Chemistry   4th ed., Vol. E22c:  Goodman M. Thieme; Stuttgart: 2002. 
• 2a Isolation and structure determination: Umezawa K. Nakazawa K. Ikeda Y. Naganawa H. Kondo S. J. Org. Chem.  1999,  64:  3034 
• 2b Biosynthesis of polyoxypeptin A: Umezawa K. Ikeda Y. Kawase O. Naganawa H. Kondo S. J. Chem. Soc., Perkin Trans. 1  2001,  1550 
• 3a Garrouste P. Pawlowski M. Tonnaire T. Sicsic S. Dumy P. de Rosny E. Reboud-Ravaux M. Fulcrand P. Martinez J. Eur. J. Med. Chem.  1998,  33:  423 
• 3b Marastoni M. Bazzaro M. Salvadori S. Bortolotti F. Tomatis R. Bioorg. Med. Chem.  2001,  9:  939 
• 4a Dupont V. Lecoq A. Mangeot J.-P. Aubry A. Boussard G. Marraud M. J. Am. Chem. Soc.  1993,  115:  8898 
• 4b Takeuchi Y. Marshall GR. J. Am. Chem. Soc.  1998,  120:  5363 
• Selected examples:
• 5a Akiyama M. Katoh A. Mutsui Y. Watanabe Y. Umemoto K. Chem. Lett.  1996,  915 
• 5b Hara Y. Akiyama M. J. Am. Chem. Soc.  2001,  123:  7247 
• 6 Kolosa T. Chimiak A. Tetrahedron  1977,  33:  3285 
• Formation of the N-benzyloxy amide link is very sensitive to steric hindrance and generally requires strong acylating systems such as HATU {N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethan-aminium hexafluorophosphate} see:
• 7a Akiyama M. Iesaki K. Katoh A. Shimizu K. J. Chem. Soc., Perkin Trans. 1  1986,  851 
• 7b Bianco A. Zabel C. Walden P. Jung G. J. Peptide Sci.  1998,  4:  471 
• 8a Nucleophilic substitution on α-bromo acid: Kolasa T. Chimiak A. Tetrahedron  1974,  30:  3591 
• 8b Use of α-hydroxy acid via the triflate derivative: Feenstra RW. Stokkingreef EHM. Nivard RJF. Ottenheijm HCJ. Tetrahedron  1988,  44:  5583 
• 8c Under Mitsunobu conditions: Hanessian S. Yang R.-Y. Synlett  1995,  633 
• 8d Oxyamination of N-acylsultam enolate: Oppolzer W. Tamura O. Deerberg J. Helv. Chim. Acta  1992,  75:  1965 
• 8e Oxidation of α-amino acid derivatives: Grundke G. Keese W. Rimpler M. Synthesis  1987,  1115 
• 8f See also: Feenstra RW. Stokkingreef EHM. Reichwein AM. Lousberg WBH. Ottenheijm HCJ. Tetrahedron  1990,  46:  1745 
• 8g See also: Detomaso A. Curci R. Tetrahedron Lett.  2001,  42:  755 
• 9 Ottenheijm HCJ. de Man JHM. Synthesis  1975,  163 
• 11 Tijhuis MW. Herscheid JDM. Ottenheijm HCJ. Synthesis  1980,  890 
• 12 Reduction of 2h with sodium cyanoborohydride was also inefficient
• 19a Preparation of DMTMM: Kunishima M. Kawachi C. Morita J. Terao K. Iwasaki F. Tani S. Tetrahedron  1999,  55:  13159 
• 19b Use in the synthesis of hydroxamates: De Luca L. Giacomelli G. Taddei M. J. Org. Chem.  2001,  66:  2534 
• 20a Reaction of N-alkyl hydroxylamine with mixed anhydrides of amino acids: Nakonieczna L. Chimiak A. Synthesis  1987,  418 
• 20b Acylation of optically active N-hydroxy Leucine methyl ester with simple acyl chlorides: Jin Y. Kim DH. Tetrahedron: Asymmetry  1997,  8:  3699 

10

The two oxime isomers are separated by liquid chromatography. No difference in diastereoselectivity was observed in their reduction so that they were used as a mixture.

13

All new compounds gave spectroscopic and analytical data in agreement with the assigned structures. Selected example: N-hydroxy dipeptide (S,S)-3b: [α]_D ²⁵ -3.8 (c 2.26, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.08 (d, ³ J = 9.6 Hz, 1 H, CONH), 5.46 (br, 2 H, NHOH), 4.61 (dd, ³ J = 9.6 and 4.8 Hz, H, CHα Val), 4.21 (m, 2 H, OCH ₂CH₃), 3.66 (q, ³ J = 7.1 Hz, 1 H, CHα Ala), 2.23 (m, 1 H, CH-i-Pr), 1.29 (t, ³ J = 7.0 Hz, 3 H, OCH₂CH ₃), 1.26 (d, ³ J = 7.1 Hz, 3 H, CH ₃ Ala), 0.97 (d, ³ J = 6.9 Hz, 3 H, CH ₃-i-Pr), 0.91 (d, ³ J = 6.9 Hz, 3 H, CH ₃-i-Pr). ¹³C NMR (75.5 MHz, CDCl₃): δ = 174.0, 172.8, 62.2, 61.6, 56.7, 31.2, 19.2, 17.7, 15.6, 14.3. MS (CI): m/z = 233 (100, M + H⁺), 187 (60), 159 (53). IR (KBr,
cm^-1): 3323 (m), 3254 (w), 2977 (m), 1738 (s), 1663 (s), 1541 (s).

14

Typical example: reduction of 9.33 mmol of 2b gave after flash chromatography (silica gel; CH₂Cl₂-MeOH, 97:3) 3.82 mmol of the first diastereomer, 0.53 mmol of a 1:1 mixture (estimated from ¹H NMR) and 3.69 mmol of the second diastereomer.

15

See ref. 1 and references therein.

16

Compound (S,S,S)-4 {Fmoc-Ala₁Ψ[CO(NOH)]Ala₂Val₃-OEt}: [α]_D ²⁵ -12.7 (c 1.28, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 8.94 (s, 1 H, OH), 7.73 (d, ³ J = 7.4 Hz, 2 H, CHar Fmoc), 7.58 (d, ³ J = 7.4 Hz, 2 H, CHar Fmoc), 7.37 (dd, ³ J = 7.4 and 7.4Hz, 2 H, CHar Fmoc), 7.27 (dd, ³ J = 7.4 and 7.4 Hz, 1 H, CHar Fmoc), 7.27 (dd, ³ J = 7.4 and 7.4 Hz, 1 H, CHar Fmoc), 7.16 (br d, ³ J = 8.7 Hz, 1 H, NH Val₃), 5.96 (d, ³ J = 7.0 Hz, 1 H, NH Ala₁), 5.29 (q, ³ J = 7.0 Hz, 1 H, CHα Ala₂), 4.97 (dq, ³ J = 7.0 and 6.8 Hz, 1 H, CHα Ala₁), 4.50 (dd, ³ J = 8.7 and 4.9 Hz, 1 H, CHα Val₃), 4.38-4.27 (m, 2 H, CHH and CH Fmoc), 4.23-4.16 (m, 1 H, CHH Fmoc), 4.17 (q, ³ J = 7.1 Hz, 2 H, OCH ₂CH₃), 2.21-2.09 (m, 1 H, CH-i-Pr Val₃), 1.49 (d, ³ J = 7.0 Hz, 3 H, CH ₃ Ala₂), 1.42 (d, ³ J = 6.8 Hz, 3 H, CH ₃ Ala₁), 1.23 (t, ³ J = 7.1 Hz, 3 H, OCH₂CH ₃), 0.91 (d, ³ J = 6.9 Hz, 3 H, CH ₃-i-Pr Val₃), 0.88 (d, ³ J = 6.9 Hz, 3 H, CH ₃-i-Pr Val₃). ¹³C NMR (50 MHz, CDCl₃): δ = 172.8, 172.3, 171.7, 156.4, 143.9, 141.4, 127.8, 127.2, 125.3, 120.1, 67.4, 61.6, 57.3, 54.3, 47.2, 47.2, 31.5, 19.0, 18.2, 17.8, 14.5, 14.3. MS (CI): m/z = 543 (27, M + NH₄ ⁺) 304 (100), 179 (69). IR (KBr, cm^-1): 3316 (s br), 2964 (m), 1734 (s), 1701 (s), 1641 (s), 1533 (s), 1450 (s).

17

Selected ¹H NMR data (250 MHz, CDCl₃) for compound 5: δ = 7.42 (br d, ³ J = 4.5 Hz, 1 H, -NH-O-CO-), 3.73 [qd, ³ J = 6.9 and 4.5 Hz, 1 H, -CH(CH₃)-NH-O(CO)-].

18

Abbreviations: DCC, dicyclohexylcarbodiimide; HOBt, 1-hydroxybenzotriazole; EDCI, 1-ethyl-3-(3′-dimethyl-aminopropyl)carbodiimide; BOP, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-phosphate; DMTMM, 4-(4, 6-dimethoxy[1,3,5]triazin-2-yl)-4-methyl-morpholinium chloride.

21

Running the reaction in CDCl₃ in a NMR tube with 3 equiv of pyridine indicates that with 0.7 equiv of TMSCl two exchanging products are first visible. After the addition of an excess TMSCl (up to 2.2 equiv), only one product remains. This is in agreement with previous findings (see ref. 20a).