Concise Total Synthesis of Crambescin B Methyl Ester

Abstract

In this study, a concise total synthesis of crambescin B methyl ester, a cyclic guanidine alkaloid, has been achieved. The key aspects of this new approach include (1) A Mannich reaction between an α-amidosulfone and a β-keto ester to construct the main scaffold, and (2) acid-catalyzed dehydrative cyclization, leading to an enol ether in a highly stereoselective manner. This synthetic approach is nine steps shorter than our previously published method.

Key words

total synthesis - guanidine alkaloids - alkaloids - voltage-gated sodium channels - Mannich reaction - crambescin B

Publication History

Received: 07 November 2024

Accepted after revision: 09 December 2024

Accepted Manuscript online:
09 December 2024

Article published online:
08 January 2025

• References and Notes

• 1a Berlinck RG. S, Braekman JC, Daloze D, Hallenga K, Ottinger R, Bruno I, Riccio R. Tetrahedron Lett. 1990; 31: 6531
• 1b Jares-Erijman EA, Ingrum AA, Sun F, Rinehart KL. J. Nat. Prod. 1993; 56: 2186
• 1c Bondu S, Genta-Jouve G, Leirós M, Vale C, Guigonis J.-M, Botana LM, Thomas OP. RSC Adv. 2012; 2: 2828

For the structural revision and the first total synthesis of racemic crambescin B analogues, see:
• 2a Snider BB, Shi Z. J. Org. Chem. 1992; 57: 2526
• 2b Snider BB, Shi Z. J. Org. Chem. 1993; 58: 3828

For reviews on VGSCs in basic and therapeutic research, see:
• 3a Catterall WA. J. Physiol. (Oxford U. K.) 2012; 590: 2577
• 3b Bagal SK, Brown AD, Cox PJ, Omoto K, Owen RM, Pryde DC, Sidders B, Skerratt SE, Stevens EB, Storer RI, Swain NA. J. Med. Chem. 2013; 56: 593
• 3c Bagal SK, Chapman ML, Marron BE, Prime R, Storer RI, Swain NA. Bioorg. Med. Chem. Lett. 2014; 24: 3690
• 3d de la Lera Ruiz M, Kraus RL. J. Med. Chem. 2015; 58: 7093
• 4a Nakazaki A, Ishikawa Y, Sawayama Y, Yotsu-Yamashita M, Nishikawa T. Org. Biomol. Chem. 2014; 12: 53
• 4b Nakazaki A, Nakane Y, Ishikawa Y, Yotsu-Yamashita M, Nishikawa T. Org. Biomol. Chem. 2016; 14: 5304
• 4c Tsukamoto T, Chiba Y, Nakazaki A, Ishikawa Y, Nakane Y, Cho Y, Yotsu-Yamashita M, Nishikawa T, Wakamori M, Konoki K. Bioorg. Med. Chem. Lett. 2017; 27: 1247
• 4d Nakazaki A, Mouri S, Nakane Y, Ishikawa Y, Yotsu-Yamashita M, Nishikawa T. Heterocycles 2022; 105: 343
• 4e Yonekura Y, Konno M, Ozaki T, Nakazaki A. Eur. J. Org. Chem. 2024; 27: e202400176
• 5a Sawayama Y, Nishikawa T. Synlett 2011; 651
• 5b Sawayama Y, Nishikawa T. Angew. Chem. Int. Ed. 2011; 50: 7176
• 5c Sawayama Y, Nishikawa T. Yuki Gosei Kagaku Kyokaishi 2012; 70: 1178

For a recent review, see:
• 6a Gimeno MC, Herrera RP. Eur. J. Org. Chem. 2020; 1057
• 6b Tillman AL, Yeb J, Dixon DJ. Chem. Commun. 2006; 1191
• 6c Lou S, Dai P, Schaus SE. J. Org. Chem. 2007; 72: 9998
• 6d Neuvonen AJ, Pihko PM. Org. Lett. 2014; 16: 5152
• 7 Moody CJ, Shah P. J. Chem. Soc., Perkin Trans. 1 1988; 1407
• 8 Fesenko AA, Shutalev AD. Tetrahedron 2015; 71: 9528
• 9 Mannich Adduct 10 This compound was synthesized according to the reported procedure.⁸ A solution of β-keto ester 9 (490 mg, 1.79 mmol) in anhyd THF (3.0 mL) was added to a suspension of a 60% dispersion of NaH in mineral oil (42 mg, 1.8 mmol) in anhyd THF (1.5 mL) at 0 °C, and the resulting mixture was stirred at 0 °C for 25 min. A solution of the α-amidosulfone 5 (740 mg, 1.61 mmol) in anhyd THF (3.0 mL) was then added, and the mixture was stirred at r.t. for 20 h. The reaction was then quenched with sat. aq NH₄Cl. EtOAc (30 mL) was added, and the resulting mixture was partitioned. The organic layer was washed with H₂O (3 × 15 mL) then dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash column chromatography [neutral silica gel, hexane–EtOAc (9:1 to 3:1)] to give a pale-yellow oil; yield: 840 mg (88%; dr = 54:46 as determined by ¹H NMR analysis). IR (film): 1717, 1507, 1254, 1097 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.03 (s, 6 H, CH₃ of TBS), 0.85–0.91 (m, 12 H, t-Bu of TBS, CH₃ ), 1.15–1.40 [m, 18 H, –CH₂(CH₂ )₉CH₃], 1.41–1.65 [m, 2 H, –CH₂ (CH₂)₉CH₃], 1.67–1.85 (m, 2 H, –CH₂CH₂ CH₂–), 2.63 [t, J = 7 Hz, 2 H, –CH₂C(=O)CH₂ –], 3.34–3.62 (m, 2 H, –CH₂ OTBS), 3.72 (s, 3 H, –OCH₃ ), 3.77 [d, J = 5.5 Hz, 1 H, –C(=O)CHC(=O)–], 4.22 (m, 1 H, –HNCHCH–), 5.07 [s, 2 H, –C(=O)OCH₂ Ph], 5.49 [br d, J = 10 Hz, 0.46 H, –C(=O)NH–], 5.68 [br d, J = 10 Hz, 0.54 H, –C(=O)NH–], 7.27–7.38 (m, 5 H, Ph). ¹³C NMR (100 MHz, CDCl₃): δ = –5.2, 14.3, 18.4, 22.8, 26.1, 26.6, 29.3, 29.5, 29.6, 29.7, 29.8, 32.1, 33.4, 40.0, 51.4, 52.7, 60.8, 61.9, 66.7, 128.1, 128.2, 128.6, 136.8, 156.0, 168.9, 205.6. HRMS (ESI, positive): m/z [M + Na]⁺ calcd for C₃₃H₅₇NNaO₆Si: 614.3847; found: 614.3833.
• 10 Snider reported that the related cyclization of an N-guanylated system provided a 1:1 mixture of E- and Z-isomers: see ref. 2b.
• 11a Bergeron RJ, McManis JS. J. Org. Chem. 1987; 52: 1700
• 11b Kim KS, Qian L. Tetrahedron Lett. 1993; 34: 7677
• 12 Bernatowicz MS, Wu Y, Matsueda GR. Tetrahedron Lett. 1993; 34: 3389
• 13 For a related method for preventing the formation of HCHO using EtOH instead of MeOH, see: Benoiton NL. Int. J. Pept. Protein Res. 1993; 41: 611