Studies towards the Synthesis of Leiodolide A

Abstract

Two dienes comprising the complete heavy-atom framework of the macrocyclic core of the marine macrolide leiodolide A were prepared by esterification of an appropriate carboxylic acid and two alcohol building blocks. The latter were obtained in a stereoselective fashion from (R)-citronellal via a Crimmins-type aldol reaction, oxidative double bond cleavage, and efficient oxazole formation as the key transformations. The possible ring-closing metathesis (RCM) based macrocyclization of the dienes was investigated under different conditions. None of the cyclized product was obtained in any of these experiments, thus indicating that RCM between C6 and C7 may not be a viable strategy for the total synthesis of leiodolide A.

Key words

leiodolide - natural product - oxazole - ring-closing metathesis - total synthesis

• References and Notes

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• 10 Preparation of Aldol Product 16 To a cooled (–78 °C) solution of (4R,5S)-3-(2-(benzyloxy)acetyl)-4-methyl-5-phenyloxazolidin-2-one (3.33 g, 10.2 mmol, 1.00 equiv) in CH₂Cl₂ (100 mL) was added TiCl₄ (1.17 mL, 10.7 mmol, 1.05 equiv) dropwise (immediate very intense yellow coloration), and the mixture was stirred for 15 min. Then Hünig’s base (99.5%, 1.97 mL, 11.3 mmol, 1.10 equiv) was added dropwise, and the dark-colored solution was stirred for 80 min at –78 °C. After addition of N-methyl-2-pyrrolidinone (0.98 mL, 10.2 mmol, 1.00 equiv) at –78 °C, the mixture was stirred for additional 10 min followed by the addition of (R)-(+)-citronellal (13, 3.70 mL, 20.4 mmol, 2.0 equiv). The dark-colored reaction mixture was stirred for 3.5 h at –78 °C and then allowed to warm to 0 °C over a period of 20 min. The reaction was quenched at 0 °C with 100 mL half-saturated aq NH₄Cl. The organic layer was separated, and the aqueous layer was extracted with CH₂Cl₂ (3 × 75 mL). The combined organic extracts were washed with sat. aq NaCl (100 mL), then dried over Na₂SO₄, and concentrated to yield a yellow oil. Purification of this material by flash chromatography (hexane–EtOAc, 5:1 → 3:1 → 2:1) afforded the desired aldol product as a viscous, colorless oil (3.24 g, 66%) and a mixture of undesired diastereomers (489 mg, 10%, dr = 12:3:1; ratio of all diastereoisomers formed in the reaction = 128:12:3:1). R_f = 0.44 (hexane–EtOAc 2:1); R_f = 0.13 (hexane–EtOAc, 5:1); [α]_D ²³ +45.8° (c 0.919, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.28 (m, 10 H), 5.72 (d, J = 7.1 Hz, 1 H), 5.14–5.09 (m, 1 H), 5.11 (d, J = 2.3 Hz, 1 H), 4.77 (quint, J = 6.8 Hz, 1 H), 4.72 (d, J = 11.4 Hz, 1 H), 4.50 (d, J = 11.4 Hz, 1 H), 4.09–4.01 (br m, 1 H), 2.16 (br d, J = 9.0 Hz, 1 H), 2.06–1.92 (m, 2 H), 1.78 (ddd, J = 13.6, 9.9, 4.3 Hz, 1 H), 1.73–1.66 (m, 1 H), 1.68 (s, 3 H), 1.60 (s, 3 H), 1.41–1.16 (m, 3 H), 0.92 (d, J = 6.7 Hz, 3 H), 0.90 (d, J = 6.7 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.7, 153.2, 137.2, 133.1, 131.3, 129.0, 128.9 (2 C), 128.6 (2 C), 128.6 (2 C), 128.3, 125.7 (2 C), 124.9, 80.6, 79.9, 73.2, 70.7, 55.5, 41.4, 37.9, 28.9, 25.8, 25.6, 19.1, 17.8, 14.5. IR (film): 3475 (w, br, 3600–3250), 2962 (w), 2925 (w), 1778 (s), 1709 (m), 1455 (m), 1342 (s), 1198 (s), 1147 (m), 1121 (s), 1030 (m). ESI-HRMS: m/z calcd for C₂₉H₃₇NNaO₅ [M + Na]⁺: 502.2564; found: 502.2558.
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The synthesis of aldol product 22 has been described previously:
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• 21 Preparation of Ester 5 To a solution of carboxylic acid 7 (9.30 mg, 0.0344 mmol, 2.14 equiv) and Et₃N (0.011 mL, 0.0764 mmol, 4.75 equiv) in THF (0.5 mL) was added 2,4,6-trichlorobenzoyl chloride (9.0 μL, 0.0573 mmol, 3.56 equiv) dropwise. The reaction mixture was stirred for 50 min, then a solution of alcohol 9 (6.40 mg, 0.0161 mmol, 1.00 equiv) in toluene (0.5 mL) and 4-dimethylaminopyridine (Aldrich 99%, 8.00 mg, 0.0650 mmol, 4.04 equiv) were added; a suspension formed immediately after the addition of DMAP. The resultant white/grey suspension was stirred at r.t. for 24 h, when the reaction was quenched with sat. aq NaHCO₃ (3 mL), which was followed by the addition of EtOAc (4 mL). The organic layer was separated and the aqueous solution was extracted with EtOAc (2 × 4 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc–hexane, 1:10) to afford ester 5 as an oil (4.4 mg, 42%). R_f = 0.31 (hexane–EtOAc, 10:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.43 (s, 1 H), 5.78–5.73 (m, 1 H), 5.71 (br t, J = 2.7 Hz, 1 H), 5.63 (t, J = 7.0, 1 H), 5.25 (dt, J = 17.1, 1.8 Hz, 1 H), 5.07 (dt, J = 10.4, 1.8 Hz, 1 H), 5.03 (br t, J = 1.5 Hz, 1 H), 4.51 (br d, J = 4.7 Hz, 1 H), 4.23 (dd, J = 10.1, 1.6 Hz, 1 H), 4.09–3.97 (m, 2 H), 3.40 (s, 3 H), 3.26–3.22 (m, 1 H), 3.08 (d, J = 7.0 Hz, 1 H), 2.84–2.70 (m, 2 H), 1.99 (br t, J = 1.1 Hz, 3 H), 1.84–1.75 (m, 1 H), 1.73–1.60 (m, 2 H), 1.56 (d, J = 2.8 Hz, 3 H), 1.44–1.39 (m, 2 H), 1.32–1.26 (m, 1 H), 0.94 (d, J = 6.3 Hz, 3 H), 0.893 (s, 9 H), 0.886 (s, 9 H), 0.08 (s, 6 H), 0.04 (s, 3 H), 0.02 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.0, 165.2, 160.6, 141.7, 140.0, 133.6, 133.6, 116.9, 114.2, 112.8, 80.7, 78.5, 70.2, 66.1, 58.5, 36.3, 35.1, 33.6, 29.5, 26.1, 26.0 (3 C), 25.9 (3 C), 19.9, 18.9, 18.5, 18.2, 12.0, –4.4, –4.6, –4.7, –4.8.
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• 25 Reactions were carried out with 0.5 mg or 1 mg of dienes 5 or 6 at concentrations <0.004 M in DCE or toluene at reflux temperature for several hours. No conversion was observed at r.t. Conversion was assessed by TLC and MS (ESI⁺). Diene 5 was only investigated with the Grubbs II and the Hoveyda–Grubbs II catalysts.
• 26 While we were primarily interested in the behavior of the O-protected dienes 5 and 6 (in light of the strategy depicted in Scheme 1), we have also prepared small quantities of the free parent compounds by treatment of 5 and 6 with HF-pyridine. In orienting experiments with these materials on an analytical scale we could not detect any cyclized product; in fact, the free alcohols seemed to be highly prone to decomposition under RCM conditions, although definitive conclusions are not possible, due to the small scale of the reactions.