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Synlett 2003(5): 0671-0674
DOI: 10.1055/s-2003-38347
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Straightforward Synthesis of N-Hydroxy Peptides

Pascal Maire, Véronique Blandin, Monique Lopez, Yannick Vallée*
LEDSS, UMR CNRS-Université Joseph Fourier, BP 53, 38041 Grenoble Cedex 9, France
Fax: +33(4)76635983; e-Mail: Syrca.Ledss@ujf-grenoble.fr;
Further Information

Publication History

Received 30 January 2003
Publication Date:
28 March 2003 (online)

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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

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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).