Expedient Synthesis of the Proposed Structure of Cryptoconcatone H Exploiting Hidden Symmetry

Abstract

Synthesis of the originally assigned structure of the styryl tetrahydropyranol-dihydropyranone natural product cryptoconcatone H from C ₂-symmetric (±)-1,8-nonadiene-4,6-diol is reported. Desymmetrization by Mitsunobu reaction with crotonic acid established the requisite inter-ring stereochemical relationship and was followed by a highly diastereoselective Re₂O₇-catalyzed Prins cyclization with cinnamaldehyde to construct the 2,4,6-cis-tetrahydropyranol ring. Ring-closing metathesis resulted in formation of the dihydropyranone ring and completed the synthesis in three steps and 32% overall yield. The brevity of the synthesis is the result of the recognition of hidden, inter-ring symmetry in the target and the ensuing choice of an appropriately symmetric diol as our starting material.

Key words

cryptoconcatone H - total synthesis - hidden symmetry - Mitsunobu reaction - Prins cyclization - ring-closing metathesis

Publication History

Received: 14 September 2022

Accepted after revision: 04 November 2022

Accepted Manuscript online:
04 November 2022

Article published online:
30 November 2022

• References and Notes

• 1a Yang B.-Y, Kong L.-Y, Wang X.-B, Zhang Y.-M, Li R.-J, Yang M.-H, Luo J.-G. J. Nat. Prod. 2016; 79: 196
• 1b Yang B.-Y, Shi Y.-M, Luo J.-G, Kong L.-Y. Nat. Prod. Res. 2017; 31: 1409
• 2a Della-Felice F, Sarotti AM, Pilli RA. J. Org. Chem. 2017; 82: 9191
• 2b Della-Felice F, de Assis FF, Sarotti AM, Pilli RA. Synthesis 2019; 51: 1545
• 3 Csókás D, Bates RW. Synlett 2019; 30: 178
• 4 For a recent review of the utility of symmetry as a tool in natural product synthesis, see: Álvarez LC, Gaviria MA, Kim SL, Vogel TR, Schindler CS. Synthesis 2021; 53: in press DOI: 10.1055/a-1702-5062.
• 5 Samoshin VV, Gremyachinskiy DE, Smith LL, Bliznets IV, Gross PH. Tetrahedron Lett. 2002; 43: 6329
• 6 Walleser P, Brückner R. Eur. J. Org. Chem. 2014; 3210
• 7a Yadav JS, Subba Reddy BV, Mahesh Kumar G, Murthy CV. S. R. Tetrahedron Lett. 2001; 42: 89
• 7b Yadav JS, Subba Reddy BV, Sekhar KC, Gunasekar D. Synthesis 2001; 885
• 7c Sreedhar B, Swapna V, Sridhar C, Saileela D, Sunitha A. Synth. Commun. 2005; 35: 1117
• 7d Yadav JS, Subba Reddy BV, Narayana Kumar GG. K. S, Aravind S. Synthesis 2008; 395
• 7e Tadpetch K, Rychnovsky SD. Org. Lett. 2008; 10: 4839
• 8 The assignment of 12 as the 2,4,6-cis-tetrahydropyranol was based on the typically observed stereochemical outcome of Prins reactions and later confirmed by comparison of NMR data of 1.
• 9 The primary focus of ref. 7e is the study of the catalytic activity of O₃ReOSiPh₃ in Prins cyclizations. Only a single example of the use of Re₂O₇ is presented.
• 10 Preparation of Tetrahydropyranol 12To a solution of alcohol 11(61.0 mg, 0.27 mmol) and cinnamaldehyde (44 μL, 0.35 mmol) in hexanes (2.4 mL) and CH₂Cl₂ (0.3 mL) at room temperature was added Re₂O₇ (13.1 mg, 0.027 mmol). The reaction mixture was stirred for 5 h, at which time TLC analysis indicated complete consumption of starting material. The solvent was removed in vacuo to give a black oil. Purification by silica gel flash column chromatography (2:1 hexanes/EtOAc) provided 61.6 mg (64%) of 12 as a yellow oil.Analytical Data for 12 ¹H NMR (400 MHz, CDCl₃): δ = 7.35 (br d, J = 7.2 Hz, 2 H), 7.28 (t, J = 7.2 Hz, 2 H), 7.21 (tt, J = 7.2, 1.7 Hz, 1 H), 6.92 (dq, J = 15.4, 6.9 Hz, 1 H), 6.55 (d, J = 16.0 Hz, 1 H), 6.17 (dd, J = 16.0, 5.9 Hz, 1 H), 5.81 (dq, J = 15.4, 1.7 Hz, 1 H), 5.76 (ddt, J = 17.2, 10.2, 7.0 Hz, 1 H), 5.18 (dtd, J = 9.8, 6.1, 4.0 Hz, 1 H), 5.11–5.05 (m, 2 H), 3.93 (ddt, J = 11.4, 6.0, 1.5 Hz, 1 H), 3.83 (tt, J = 11.0, 4.5 Hz, 1 H), 3.53–3.47 (m, 1 H), 2.42–2.31 (m, 3 H), 2.06–1.97 (m, 3 H), 1.77 (dd, J= 6.9, 1.7 Hz, 3 H), 1.72 (ddd, J = 14.4, 5.8, 4.0 Hz, 1 H), 1.35 (q, J = 11.3 Hz, 1 H), 1.20 (q, J = 11.3 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 166.3, 144.8, 136.9, 133.6, 130.6, 129.6, 128.6, 127.7, 126.6, 123.1, 118.1, 76.1, 73.2, 70.5, 68.0, 41.1, 40.9, 40.1, 39.2, 18.0. IR (thin film): 3406, 2943, 2916, 2850, 1714, 1655, 1495, 1444, 1361, 1310, 1292, 1266, 1184, 1102, 1068, 1016, 998, 914, 837, 746, 732, 693 cm^–1. HRMS (ESI): m/z calcd for C₂₂H₂₈O₄Na [M + Na⁺]: 379.1885; found: 379.1895.
• 11 For a recent review on the use of Re₂O₇ as a catalyst in organic synthesis, see: Floreancig PE. Synlett 2021; 32: 1406
• 12 Ghosh AK, Capiello J, Shin D. Tetrahedron Lett. 1998; 39: 4651
• 13 Others have observed similar cross-metathesis products in attempted RCM reactions of crotonates. For example, see ref. 6.
• 14 Preparation of Dihydropyranone 1To a solution of 12 (53.3 mg, 0.15 mmol) in CH₂Cl₂ (15 mL) at room temperature was added Grubbs second-generation catalyst (2.5 mg, 0.003 mmol). The reaction was heated to reflux for 1 h, at which time TLC analysis indicated complete consumption of starting material. After cooling to room temperature, the crude reaction mixture was concentrated in vacuo. Purification by silica gel flash column chromatography (EtOAc) gave 35.8 mg (97% pure, 74% yield) of 1as viscous pale yellow oil.Analytical Data for 1 ¹H NMR (400 MHz, CDCl₃): δ = 7.38 (br d, J = 7.2 Hz, 2 H), 7.31 (t, J = 7.2 Hz, 2 H), 7.23 (tt, J = 7.2, 1.8 Hz, 1 H), 6.89 (ddd,J = 9.7, 5.9, 2.6 Hz, 1 H), 6.57 (d, J = 16.0 Hz, 1 H), 6.19 (dd, J = 16.0, 5.9 Hz, 1 H), 6.02 (br dd, J = 9.8, 2.5 Hz, 1 H), 4.67 (dtd, J = 11.4, 6.0, 4.5 Hz, 1 H), 4.00 (ddt, J = 11.2, 5.8, 1.5 Hz, 1 H), 3.90 (tt, J = 11.0, 4.6 Hz, 1 H), 3.74–3.68 (m, 1 H), 2.49 (ddt, J = 18.4, 11.4, 2.6 Hz, 1 H), 2.40 (br ddd, J = 18.4, 5.7, 4.3 Hz, 1 H), 2.21–2.14 (m, 2 H), 2.09 (ddt, J = 12.3, 4.5, 2.0 Hz, 1 H), 2.03 (ddt, J = 12.3, 4.5, 2.0 Hz, 1 H), 1.88 (dt, J= 14.4, 5.6 Hz, 1 H), 1.37 (q, J = 11.3 Hz, 1 H), 1.30 (q, J = 11.3 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 164.7, 145.7, 136.7, 130.4, 129.5, 128.6, 127.8, 126.6, 121.2, 76.1, 75.1, 71.5, 67.8, 41.1, 40.6, 40.5, 29.3. IR (thin film): 3405, 2921, 2850, 2849, 1698, 1494, 1448, 1390, 1312, 1251, 1188, 1153, 1069, 1037, 969, 814, 750, 734, 696 cm^–1. HRMS (ESI): m/z calcd for C₁₉H₂₃O₄ [M + H⁺]: 315.1596; found: 315.1591.