Synlett, Table of Contents Synlett 2021; 32(17): 1747-1750DOI: 10.1055/s-0040-1719824 letter Diastereoselective Synthesis of (3R,5R)-γ-Hydroxypiperazic Acid Taylor A. Gerrein , Yassin M. Elbatrawi , Juan R. Del Valle ∗Recommend Article Abstract Buy Article All articles of this category Abstract We report an asymmetric synthesis of the (3R,5R)-γ-hydroxypiperazic acid (γ-OHPiz) residue encountered in several bioactive nonribosomal peptides. Our strategy relies on a diastereoselective enolate hydroxylation reaction and electrophilic N-amination to provide the acyclic γ-OHPiz precursor. This orthogonally protected α-hydrazino acid intermediate is amenable to late-stage diazinane ring formation following incorporation into a peptide chain. We determined the N-terminal amide rotamer propensity of the γ-OHPiz residue and showed that the γ-OH substituent enhances trans-amide bias relative to piperazic acid. Key words Key wordsnonribosomal peptides - natural products - piperazic acid - α-hydrazino acid - oxaziridine Full Text References References and Notes 1a Vidal J. In Amino Acids, Peptides and Proteins in Organic Chemistry, Vol. 2. Hughes AB. Wiley-VCH; Weinheim: 2009: 35-92 1b Le Goff G, Ouazzani J. Bioorg. Med. Chem. 2014; 22: 6529 2a Ciufolini M, Xi N. Chem. Soc. Rev. 1998; 27: 437 2b Xi N, Alemany LB, Ciufolini MA. J. Am. Chem. Soc. 1998; 120: 80 3a Oelke AJ, France DJ, Hofmann T, Wuitschik G, Ley SV. Nat. Prod. Rep. 2011; 28: 1445 3b Handy EL, Sello JK. Peptidomimetics I,In Topics in Heterocyclic Chemistry, Vol. 48 . Dubell WD. Springer; Cham: 2015: 91-124 3c Morgan KD, Andersen RJ, Ryan KS. Nat. Prod. Rep. 2019; 36: 1628 4 Miller ED, Kauffman CA, Jensen PR, Fenical W. J. Org. Chem. 2007; 72: 323 5a Hashizume H, Sawa R, Yamashita K, Nishimura Y, Igarashi M. J. Antibiot. 2017; 70: 699 5b Igarashi M, Sawa R, Kinoshita N, Hashizume H, Nakagawa N, Homma Y, Nishimura Y, Akamatsu Y. J. Antibiot. 2008; 61: 387 6 Hale KJ, Jogiya N, Manaviazar S. Tetrahedron Lett. 1998; 39: 7163 7 Kamenecka TM, Danishefsky SJ. Angew. Chem. Int. Ed. 1998; 37: 2995 8 Depew KM, Kamenecka TM, Danishefsky SJ. Tetrahedron Lett. 2000; 41: 289 9a Ushiyama R, Yonezawa Y, Shin C.-g. Chem. Lett. 2001; 30: 1172 9b Li W, Gan J, Ma D. Org. Lett. 2009; 11: 5694 9c Kennedy JP, Lindsley CW. Tetrahedron Lett. 2010; 51: 2493 10a Makino K, Jiang H, Suzuki T, Hamada Y. Tetrahedron: Asymmetry 2006; 17: 1644 10b Kennedy JP, Brogan JT, Lindsley CW. Tetrahedron Lett. 2008; 49: 4116 11 Elbatrawi YM, Kang CW, Del Valle JR. Org. Lett. 2018; 20: 2707 12 Hanessian S, Vanasse B. Can. J. Chem. 1993; 71: 1401 13 Davis FA, Chen BC. Chem. Rev. 1992; 92: 919 14 Hanessian S, Schaum R. Tetrahedron Lett. 1997; 38: 163 15 Davis FA, Wei JH, Sheppard AC, Gubernick S. Tetrahedron Lett. 1987; 28: 5115 16a Armstrong A, Jones LH, Knight JD, Kelsey RD. Organic Lett. 2005; 7: 713 16b Kang CW, Sarnowski MP, Elbatrawi YM, Del Valle JR. J. Org. Chem. 2017; 82: 1833 17 Sarnowski MP, Kang CW, Elbatrawi YM, Wojtas L, Del Valle JR. Angew. Chem. Int. Ed. 2017; 56: 2083 18 Procedure for the Synthesis of 8 To a solution of 7 (206 mg, 565 μmol) and PPh3 (371 mg, 1.41 mmol) in 30 mL anhydrous THF was added DIAD (275 μL, 1.41 mmol) dropwise over 5 min at rt. The reaction was stirred for 3 h at 45 °C. The reaction was diluted with EtOAc and washed with brine, then dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography over silica gel (50% EtOAc/hexanes) provided Ac-(N′-Boc)-(γ-OMOM)Piz-OMe (139 mg, 401 μmol) as a colorless oil. The purified heterocycle was dissolved in 10 mL MeOH and cooled to 0 °C. Acetyl chloride (5.00 mL, 70.3 mmol) was added dropwise, and the reaction was stirred at 0 °C for 45 min. The solution was concentrated, and the resulting solid was dissolved in sat. aq. NaHCO3. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, then dried over Na2SO4, filtered, and concentrated to afford 8 as a white solid (81.1 mg, 401 μmol, 71% over 2 steps). 1H NMR (400 MHz, CDCl3): δ = 5.24 (dd, J = 6.7, 1.5 Hz, 1 H), 4.83–4.71 (m, 1 H), 3.90 (m, 1 H), 3.75 (s, 3 H), 3.00–2.88 (m, 2 H), 2.43 (d, J = 14.3 Hz, 1 H), 2.22 (s, 3 H), 2.05 (ddd, J = 14.4, 6.8, 2.4 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ = 173.6, 172.6, 62.0, 52.9, 52.7, 47.6, 32.7, 20.8. HRMS (ESI-TOF): m/z [M + H]+ calcd for C8H15N2O4: 203.1026; found: 203.1026. 19 Howard EH, Cain CF, Kang C, Del Valle JR. J. Org. Chem. 2020; 85: 1680 20 Elbatrawi YM, Pedretty KP, Giddings N, Woodcock HL, Del Valle JR. J. Org. Chem. 2020; 85: 4207 Supplementary Material Supplementary Material Supporting Information
