Synthetic Study on Lactonamycins, Part 2: Stereoselective Access to ABCD-Ring System

Dedicated to the memory of Prof. Hidetoshi Yamada

Abstract

Toward a stereoselective total synthesis of the lactonamycins, we recently reported an approach to the DEF-ring system. Here we report a model study for constructing the ABCD-ring system, revealing a viable approach through (1) construction of the C-ring by asymmetric benzoin cyclization, (2) introduction of an angular hydroxy group through oxidation of an isoxazolium salt, and (3) construction of the AB rings through a ring-opening/closing sequence.

Key words

natural products - total synthesis - lactonamycins - aromatic polyketides - isoxazoles - benzoin cyclization

• References and Notes

• 1 Current address: Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606–8501, Japan.
• 2a Matsumoto N, Tsuchida T, Maruyama M, Sawa R, Kinoshita N, Homma Y, Takahashi Y, Iinuma H, Naganawa H, Sawa T, Hamada M, Takeuchi T. J. Antibiot. 1996; 49: 953
• 2b Matsumoto N, Tsuchida T, Maruyama M, Kinoshita N, Homma Y, Iinuma H, Sawa T, Hamada M, Takeuchi T. J. Antibiot. 1999; 52: 269
• 3 Höltzel A, Dieter A, Schmid DG, Brown R, Goodfellow M, Beil W, Jung G, Fiedler H.-P. J. Antibiot. 2003; 56: 1058
• 4a Cox C, Danishefsky SJ. Org. Lett. 2000; 2: 3493
• 4b Cox C, Danishefsky SJ. Org. Lett. 2001; 3: 2899
• 4c Kelly TR, Xu D, Martínez G, Wang H. Org. Lett. 2002; 4: 1527
• 4d Kelly TR, Cai X, Tu B, Elliott EL, Grossmann G, Laurent P. Org. Lett. 2004; 6: 4953
• 4e Henderson DA, Collier PN, Pavé G, Rzepa P, White AJ. P, Burrows JN, Barrett AG. M. J. Org. Chem. 2006; 71: 2434
• 4f Wehlan H, Jezek E, Lebrasseur N, Pavé G, Roulland E, White AJ. P, Burrows JN, Barrett AG. M. J. Org. Chem. 2006; 71: 8151
• 4g Parsons PJ, Board J, Waters AJ, Hitchcock PB, Wakenhut F, Walter DS. Synlett 2006; 3243
• 4h Le Vézouët R, White AJ. P, Burrows JN, Barrett AG. M. Tetrahedron 2006; 62: 12252
• 4i Parsons PJ, Waters AJ, Walter DS, Board J. J. Org. Chem. 2007; 72: 1395
• 4j Watanabe K, Iwata Y, Adachi S, Nishikawa T, Yoshida Y, Kameda S, Ide M, Saikawa Y, Nakata M. J. Org. Chem. 2010; 75: 5573
• 4k Jacques SA, Patel BH, Barrett AG. M. Tetrahedron Lett. 2011; 52: 6072
• 4l Jacques SA, Michaelis S, Gebhardt B, Blum A, Lebrasseur N, Larrosa I, White AJ. P, Barrett AG. M. Eur. J. Org. Chem. 2012; 107
• 4m Dubois S, Rodier F, Blanc R, Rahmani R, Héran V, Thibonnet J, Commeiras L, Parrain J.-L. Org. Biomol. Chem. 2012; 10: 4712
• 4n Parsons PJ, Jones DR, Walsh LJ, Allen LA. T, Onwubiko A, Preece L, Board J, White AJ. P. Org. Lett. 2017; 19: 2533
• 4o Parsons PJ, Allen LA. T, Jones DR. Padgham A. C, Pryke JA, McKenna J, O’Reilly D. Synthesis 2018; 50: 84

For a review, see:
• 4p Yao Y.-L, Liu Z.-P. Curr. Org. Chem. 2016; 20: 1659
• 5a Cox CD, Siu T, Danishefsky SJ. Angew. Chem. Int. Ed. 2003; 42: 5625
• 5b Siu T, Cox CD, Danishefsky SJ. Angew. Chem. Int. Ed. 2003; 42: 5629
• 6 Tatsuta K, Tanaka H, Tsukagoshi H, Kashima T, Hosokawa S. Tetrahedron Lett. 2010; 51: 5546
• 7 Adachi S, Watanabe K, Iwata Y, Kameda S, Miyaoka Y, Onozuka M, Mitsui R, Saikawa Y, Nakata M. Angew. Chem. Int. Ed. 2013; 52: 2087
• 8a Koyama Y, Yamaguchi R, Suzuki K. Angew. Chem. Int. Ed. 2008; 47: 1084
• 8b Takada A, Hashimoto Y, Takikawa H, Hikita K, Suzuki K. Angew. Chem. Int. Ed. 2011; 50: 2297
• 8c Yamashita Y, Hirano Y, Takada A, Takikawa H, Suzuki K. Angew. Chem. Int. Ed. 2013; 52: 6658
• 8d Takikawa H, Ishikawa Y, Yoshinaga Y, Hashimoto Y, Kusumi T, Suzuki K. Bull. Chem. Soc. Jpn. 2016; 89: 941
• 8e Sato S, Sakata K, Hashimoto Y, Takikawa H, Suzuki K. Angew. Chem. Int. Ed. 2017; 56: 12608
• 8f Yamashita Y, Hirano Y, Takada A, Takikawa H, Suzuki K. Synthesis 2018; 50: 2490
• 9a Stagno D’Alcontres G. Gazz. Chim. Ital. 1950; 80: 441
• 9b Kashima C. Heterocycles 1979; 12: 1343
• 9c Baraldi PG, Barco A, Benetti S, Pollini GP, Simoni D. Synthesis 1987; 857
• 9d Kotyatkina AI, Zhabinsky VN, Khripach VA. Russ. Chem. Rev. 2001; 70: 641
• 9e Hua F, Szostak M. Adv. Synth. Catal. 2015; 357: 2583
• 9f Galenko AV, Khlebnikov AF, Novikov MS, Pakalnis VV, Rostovskii NV. Russ. Chem. Rev. 2015; 84: 335
• 10a Hashimoto Y, Takada A, Takikawa H, Suzuki K. Org. Biomol. Chem. 2012; 10: 6003
• 10b Takikawa H, Hashimoto Y, Suzuki K. Chem. Lett. 2014; 43: 1607
• 11a Hachisu Y, Bode JW, Suzuki K. J. Am. Chem. Soc. 2003; 125: 8432
• 11b Hachisu Y, Bode JW, Suzuki K. Adv. Synth. Catal. 2004; 346: 1097
• 11c Takikawa H, Hachisu Y, Bode JW, Suzuki K. Angew. Chem. Int. Ed. 2006; 45: 3492
• 11d Takikawa H, Suzuki K. Org. Lett. 2007; 9: 2713
• 12 Takikawa H, Takada A, Hikita K, Suzuki K. Angew. Chem. Int. Ed. 2008; 47: 7446
• 13a Rawling BJ. Nat. Prod. Rep. 1999; 16: 425
• 13b Thomas R. ChemBioChem 2001; 2: 612
• 13c Staunton J, Weissman KJ. Nat. Prod. Rep. 2001; 18: 380
• 13d Rix U, Fischer C, Remsing LL, Rohr J. Nat. Prod. Rep. 2002; 19: 542
• 13e Hertweck C, Luzhetskyy A, Rebets Y, Bechthold A. Nat. Prod. Rep. 2007; 24: 162
• 13f Zhou H, Li Y, Tang Y. Nat. Prod. Rep. 2010; 27: 839
• 14 Zhang X, Alemany LB, Fiedler H, Goodfellow M, Parry R. Antimicrob. Agents Chemother. 2008; 52: 574
• 15a We have established a unified approach for constructing highly functionalized naphthalenes by the effective preparation of 2-substituted 3-methoxycarbonyl-4-methoxyfurans and their regioselective cycloadditions with α-alkoxybenzynes; see: Sato S, Kawada T, Takikawa H, Suzuki K. Synlett 2017; 28: 1719
• 15b For an application to the total synthesis of tetracenemycins C and X, see ref. 8e.
• 16 Reaction of ‘acyclic’ substrate L gave a mixture of the trans-diol M (29%) and the ring-contracted product N, resulting from a retro-aldol/aldol reaction (Scheme 7). See: Takikawa H. Ph.D. Dissertation. Tokyo Institute of Technology; Japan: 2008
• 17 Takikawa H, Sato S, Seki R, Suzuki K. Chem. Lett. 2017; 46: 998
• 18 Lecornué F, Ollivier J. Org. Biomol. Chem. 2003; 1: 3600
• 19 The ¹H NMR analysis of the crude products of the reaction of 8 and 9 suggested that the cycloaddition proceeded with high, if not perfect, regioselectivity, which could be rationalized in FMO terms (Figure 3) by considering the primary orbital interaction of the nitrile oxide 8 (HOMO) and enone 9 (LUMO). See refs. 8b,d–f, and 10.
• 20 Kerr MS, Read de Alaniz J, Rovis T. J. Am. Chem. Soc. 2002; 124: 10298
• 21 The enantiomeric purity of (–)-12 was assessed by HPLC analysis on a chiral stationary phase (Daicel CHIRALPAK AD-H; see Supporting Information). Although the absolute stereochemistry of 12 was not assigned, it is sufficient to say that the related asymmetric benzoin-forming reaction gave the R-configured α-ketol O when triazolium salt 11c, related to 11b, was used as the catalyst precursor (Scheme 8); see ref. 11c.
• 22 Dibenzyl ether 13 was obtained as a single diastereomer, as confirmed by ¹H NMR analysis.
• 23 For details, see Supporting Information.
• 24 Ito Y, Hirao T, Saegusa T. J. Org. Chem. 1978; 43: 1011
• 25 A similar reaction of cyclic 2-hydroxy-1,3-diketones into ring-expanded lactones was observed in the Nicolaou synthesis of viridicatumtoxin B; see: Nicolaou KC, Hale CR. H, Nilewski C, Ioannidou HA, ElMarrouni A, Nilewski LG, Beabout K, Wang TT, Shamoo Y. J. Am. Chem. Soc. 2014; 136: 12137
• 26a Scherkenbeck J, Dietrich W, Müller D, Böttger D, Welzel P. Tetrahedron 1986; 42: 5949
• 26b Yates P, Burke PM. Can. J. Chem. 1987; 65: 1695
• 26c Arjona O, de Dios A, Plumet J, Saez B. J. Org. Chem. 1995; 60: 4932
• 26d Wu J.-D, Shia K.-S, Liu H.-J. Tetrahedron Lett. 2001; 42: 4207
• 26e Fraser CJ, Howell GP, Harrity JP. A. Org. Biomol. Chem. 2012; 10: 9058
• 27 When an acetyl group was employed for the C14a-OH protection, no ring-opened product was detected; instead the C-silylation product P was obtained in 39% yield (17% recovery) (Scheme 9).
• 28 These two steps could be carried out in one pot and, after the ring opening of 17, direct addition of PhSH and Et₃N gave 19 in 83% yield (two steps from 17), a better yield than that of the stepwise protocol (see above; 51% yield, two steps).Sulfide 19; One-Pot ProtocolEster 17 (504 mg, 0.790 mmol) was azeotropically dried with toluene and dissolved in CH₂Cl₂ (24 mL). Et₃N (1.32 mL, 9.39 mmol) and Me₃SiOTf (850 μL, 4.70 mmol) were added at 0 °C and the mixture was stirred for 17 h at rt. PhSH (160 μL, 1.57 mmol) was then added at 0 °C, and the resulting mixture was stirred for 1 h at rt. Additional portions of Et₃N (110 μL, 0.783 mmol) and PhSH (40 μL, 0.392 mmol) were added at 0 °C, and the mixture was again stirred for 1 h at rt. The reaction was quenched by adding sat. aq NaHCO₃, and the product was extracted with CH₂Cl₂ (×3). The combined organic extracts were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified chromatographically by using a Smart Flash EPCLC W-Prep 2XY system [Ultra Pack Diol-40B, hexane–EtOAc (77:23 to 56:44)] to give a yellow amorphous solid; yield: 538 mg (83%); mp 64–66 °C; R_f = 0.43 (hexane–EtOAc, 2:1).IR (ATR): 2934, 1755, 1727, 1593, 1470, 1370, 1273, 1254, 1149, 1039 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = –0.09 (s, 9 H), 2.79–2.96 (m, 3 H), 3.11 (br ddd, J = 16.8, 10.8, 3.8 Hz, 1 H), 3.80 (br d, J = 10.5 Hz, 1 H), 3.91 (s, 3 H), 4.20 (br d, J = 10.5 Hz, 1 H), 4.65 (br d, J = 9.9 Hz, 1 H), 4.75 (br d, J = 9.9 Hz, 1 H), 4.90 (br d, J = 10.2 Hz, 1 H), 4.93 (br d, J = 10.2 Hz, 1 H), 5.30 (s, 1 H), 6.96–7.11 (m, 7 H), 7.21–7.33 (m, 10 H), 7.54 (dd, J = 8.1, 7.8 Hz, 1 H), 8.17 (d, J = 17.4 Hz, 2 H), 8.31 (d, J = 17.4 Hz, 2 H). ¹³C NMR (150 MHz, CDCl₃): δ = –0.1, 27.2, 42.1, 56.4, 60.6, 67.5, 74.7, 77.8, 84.2, 92.7, 112.5, 120.8, 123.7, 125.6, 127.8, 128.1, 128.17, 128.19, 128.4, 128.5, 128.6, 128.75, 128.79, 131.3, 135.1, 135.3, 136.4, 137.5, 138.2, 140.8, 150.8, 160.3, 163.6, 188.6, 200.6. HRMS (ESI): m/z [M + Na]⁺ calcd for C₄₅H₄₅NNaO₁₀SSi: 842.2426; found: 842.2388.
• 29 The Z geometry of 20 was tentatively assigned by considering the steric disadvantage of the corresponding β-elimination of K → (E)-20 (Figure 4).
• 30 The corresponding sulfide having a benzoyl protection, rather than a p-nitrobenzoyl group, was subjected to the same sequence of reactions, giving the lower yield of 20 (60%).
• 31 By omitting the purification operation after the first step, the two-step yield of 23 from 19 was improved to 88%.
• 32a Davenport DA, Moss DB, Rhodes JE, Walsh JA. J. Org. Chem. 1969; 34: 3353
• 32b Wilson GE. Jr, Strong CJ. J. Org. Chem. 1972; 37: 2376
• 33 Stork G, Zhao K. Tetrahedron Lett. 1989; 30: 287
• 34 ¹H NMR analysis showed a single geometrical isomer. The configuration of the enol ether moiety was tentatively shown to be Z.
• 35 Acid-catalyzed conversion of 29 into 28 (CSA, MeOH, CH₂Cl₂, reflux) was unsuccessful. For related observations, see ref. 5b.