Synthesis of Optically Active Hydroxyalkyl Cycloheptatrienes: A Key Step in the Total Synthesis of 6,11-Methylene-LXB₄

Dedicated to Prof. Dr. Helmut Vorbrüggen on the occasion of his 90^th birthday

Abstract

Starting from methyl cycloheptatrienyl-1-carboxylate, 6-acylation was successfully achieved employing glutaryl chloride in the presence of AlCl₃ under controlled reaction conditions to furnish keto carboxylic acid product. After protection of this keto carboxylic acid as tert-butyl ester, reagent-controlled enantioselective reductions delivered configuration-defined methyl-6-hydroxylalkyl cycloheptatriene-1-carboxylates with up to 80% ee. Whereas simple NaBH₄ reduction of the keto carboxylic acid and subsequent lactonization afforded a methyl-6-tetrahydropyranonyl cycloheptatriene-1-carboxylate. Resolution using chiral HPLC delivered the product enantiomers with up to >99% ee Finally, ECD analyses enabled structure elucidation. The products are used as key intermediates in enantioselective 6,11-methylene-lipoxin B₄ syntheses.

Key words

lipoxin analogue - cycloheptatriene - electrophilic acylation - enantioselective reduction - chiral HPLC - ECD analysis

• References and Notes

• 1 New address: Dr. A. Nava, BASF Lampertheim GmbH, Chemiestr. 22, 68623 Lampertheim, Germany. Dr. Lars Andernach, Leibniz-Institut für Gemüse- und Zierpflanzenbau (IGZ) e.V., Theodor-Echtermeyer-Weg 1, 14979 Großbeeren, Germany.
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• 11 Most C6 acylations of methyl-cycloheptatriene-1-carboxylate B had been stopped after about 50% conversion. Always, remaining B had been recycled. The standard yields presented within the manuscript based on originally used B. Additionally, yields based on recovered starting material (brsm) are given in brackets.
• 12 For experimental details and data see the Supporting Information.
• 13 All cycloheptatriene derivatives suffer from reversible 6п-electrocyclization (norcaradiene intermediates). In the presence of nucleophiles such as chloride Michael–addition/elimination cyclopropane ring opening, etc. potentially cause the formation of regioisomeric norcaradienes and cycloheptatrienes (e.g., 1,3-diacyl, 2,7-diacyl). Longer reaction times led to the formation of further isomers.
• 14 Synthesis of Keto Acid 1 Under Ar, in a three-necked flask equipped with a reflux condenser aluminum(III) chloride (6.66 g, 49.94 mmol, 1.5 equiv) was suspended in dry CH₂Cl₂ (100 mL) and cooled in an ice-bath. Glutaryl chloride (6.37 mL, 49.94 mmol, 1.5 equiv) was added, and the mixture was stirred at 0 °C for about 1 h until complete dissolution of aluminum(III) chloride. Then, the reaction mixture was heated to reflux and methyl ester B (5.00 g, 33.29 mmol, 1.0 equiv) dissolved in dry CH₂Cl₂ (20 mL) was added. Refluxing was continued for 4 h. After cooling of the reaction mixture to –10 °C, acetic acid (15 mL) was added slowly with stirring. After 30 min, water (100 mL) was added at –10 °C, and stirring was continued for another 30 min. Then the layers were separated, and the aqueous phase was extracted with CH₂Cl₂ (3 × 50 mL). The combined organic layers were washed (brine) and dried (MgSO₄). After removal of the solvent the residue was purified via column chromatography (EtOAc/petroleum ether, 1:5 to 1:2). Yields: re-isolated methyl ester B (2.37 g, 15.78 mmol, 47%), keto carboxylic acid 1 (3.24 g, 12.26 mmol, 37% (70% brsm)), chloro keto carboxylic acid 3 (0.11 g, 0.33 mmol, 1% (2% brsm)), chloro enollactone 4 (1.47 g, 5.20 mmol, 16% (30% brsm)). 6-(1,5-Dioxo-5-hydroxypentyl)-1,3,5-cycloheptatriene 1-Carboxylic Acid Methyl Ester (1) Yellow oil; R_f = 0.31 (EtOAc/petroleum ether, 1:5).¹H NMR (300 MHz, CDCl₃): δ = 7.33–7.27 (m, 1 H, H-10), 7.18–7.13 (m, 1 H, H-8), 6.93–6.88 (m, 2 H, H-7, H-9), 3.80 (s, 3 H, H-14), 3.01 (s, 2 H, H-13), 2.86 (t, ³ J _HH= 7.1 Hz, 2 H, H-4), 2.44 (t, ³ J _HH= 7.1 Hz, 2 H, H-2), 1.99 (tt, ³ J _HH= 7.1 Hz, 2 H, H-3). ¹³C NMR (75 MHz, CDCl₃): δ = 198.0 (C-5), 178.6 (C-1), 166.0 (C-12), 133.8 (C-9), 133.6 (C-8), 133.4 (C-6), 133.2 (C-10), 132.0 (C-7), 125.6 (C-11), 52.3 (C-14), 37.2 (C-4), 32.9 (C-2), 24.7 (C-13), 19.2 (C-3). IR (neat): ν~  = 3011 (m), 2988 (m), 2947 (w), 1717 (s, br), 1589 (m), 1438 (w), 1276 (s), 1261 (s), 1038 (w), 749 (s), 703 (m), 624 (w) cm^–1. MS (FD, 5 kV/8 mA/min): m/z (%) = 264.4 (100) [M]⁺, 265.4 (57) [M + H]⁺. HRMS (ESI): m/z calcd for C₁₄H₁₆O₅Na: 287.0895; found: 287.0887. For further data, see the Supporting Information.
• 15 For data of enol ester, see the Supporting Information. Furthermore, cleavage of enol lactone 5 was run under acidic conditions (AcCl, MeOH, 50 °C) delivering 2 in 12%, enol ester of 2 in 42% yield and several isomers.
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• 18 H. C. Brown Reduction: (1̍S)-6-(5-tert-Butyloxy-5-oxo-1-hydroxypentyl)-1,3,5-cycloheptatriene 1-carboxylic acid methyl ester ((S)-7) Under Ar, to a solution of (–)-diisopinocampheylchloroborane (0.15 g, 0.47 mmol, 1.5 equiv) in dry THF (2 mL) was added ketoester 6 (0.10 g, 0.31 mmol, 1.0 equiv) in dry THF (2 mL) at –25 °C with stirring. After seven days the solvent was removed in vacuo and replaced by EtOAc (5 mL). Then, diethanolamine (0.07 g, 0.63 mmol, 2.2 equiv) was added and stirred at room temperature for 2 h in which a white precipitate formed. The solid was filtered off and washed with Et₂O. The solvent was removed in vacuo, and α-pinene could be removed in high vacuum (8 × 10^–3 mbar, 5 h). The residual crude product was purified via column chromatography (EtOAc/petroleum ether, 1:4) affording hydroxyester (S)-7 (0.02 g, 0.06 mmol, 19%) as a colorless oil. R_f = 0.20 (EtOAc/petroleum ether, 1:4). [α]_D = +11.6° (c 1.0, 25 °C, CH₂Cl₂, ee 40%). For further analytical data, see the Supporting Information.
• 19 CBS Reduction: (1̍R)-6-(5-tert-Butyloxy-5-oxo-1-hydroxypentyl)-1,3,5-cycloheptatriene 1-Carboxylic Acid Methyl Ester ((R)-7) Under Ar, (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]-oxazaborol (0.02 g, 0.07 mmol, 0.1 equiv) was dissolved in dry toluene (1 mL) and treated with borane dimethylsulfide (0.05 g, 0.63 mL, 0.84 mmol, 1.2 equiv 2 M) at 0 °C. After 1 h ketoester 6 (0.23 g, 0.70 mmol, 1.0 equiv) was added to the mixture and stirred for 5 h at 0 °C. Workup started by quenching with methanol (2 mL) and after 15 min 1 M hydrochloric acid. The aqueous layer was extracted with toluene (3 × 5 mL). The combined organic layers were washed with brine and dried over MgSO₄. The solvent was removed, and the residue was purified via column chromatography (EtOAc/petroleum ether, 1:9) affording hydroxyester (R)-7 (0.15 mg, 0.42 mmol, 67%) as a colorless oil. R_f = 0.20 (EtOAc/petroleum ether, 1:4). [α]_D –7.3° (c 1.0, 25 °C, CH₂Cl₂, ee 71%). For further analytical data, see the Supporting Information.
• 20 6-(1,5-Dihydroxy-5-oxopentyl)-1,3,5-cycloheptatriene 1-Carboxylic Acid Methyl Ester (9) The ketoacid 1 (1.03 g, 3.90 mmol, 1.0 equiv) was dissolved in methanol (60 mL) and cooled to 0 °C. Sodium borohydride (0.44 g, 11.70 mmol, 3.0 equiv) was added in small portions. The reaction stirred for 1 h at 0 °C and for 1 h at room temperature. Afterwards methanol was removed in vacuo. The residue was taken up in water and acidified with 1 M hydrochloric acid. The aqueous phase was extracted with CH₂Cl₂ (3 × 50 mL). The combined organic layers were washed with brine and dried over MgSO₄. After removal of the solvent alcohol 9 (0.82 g, 3.06 mmol, 78%) was obtained as a colorless oil. R_f = 0.18 (EtOAc/petroleum ether, 1:2). ¹H NMR (300 MHz, CD₃OD): δ = 7.22 (d, ³ J _HH = 5.9 Hz, 1 H, H-10), 6.82 (dd, ³ J _HH = 11.1 Hz, ³ J _HH = 6.0 Hz, 1 H, H-8), 6.63 (ddd, ³ J _HH = 11.1 Hz, ³ J _HH = 5.9 Hz, ⁴ J _HH = 0.8 Hz, 1 H, H-9), 6.26 (dd, ³ J _HH = 6.0 Hz, ⁴ J _HH = 0.8 Hz, 1 H, H-7), 4.21 (t, ³ J _HH = 6.4 Hz, 1 H, H-5), 3.77 (s, 3 H, H-14), 3.24 (d, ² J _HH = 13.1 Hz, 1 H, H-13̍), 2.24 (t, ³ J _HH = 7.3 Hz, 2 H, H-2), 2.16 (d, ² J _HH = 13.1 Hz, 1 H, H-13̍̍), 1.97–1.37 (m, 4 H, H-3, H-4). ¹³C NMR (100 MHz, CD₃OD): δ = 175.7 (C-1), 167.9 (C-12), 143.6 (C-6), 136.2 (C-10), 136.2 (C-8), 129.3 (C-9), 123.1 (C-7), 123.0 (C-11), 76.0 (C-5), 52.6 (C-14), 35.9 (C-4), 34.6 (C-2), 27.7 (C-13), 22.5 (C-3). IR (neat): ν~  = 3443 (b), 3024 (w), 2951 (w), 1705 (s), 1615 (w), 1542 (w), 1436 (m), 1277 (s), 1245 (m), 1212 (s), 1162 (s), 1090 (s), 1038 (m), 741 (s) cm^–1. MS (FD 5 kV/8 mA/min): m/z (%): 287.1 (100) [M+Na]⁺. HRMS-ESI C₁₄H₁₆O₅Na calcd.: 287.0887, found: 287. 0895.
• 21 6-(3,4,5,6-Tetrahydropyran-2-on-6-yl)-1,3,5-cycloheptatriene 1-Carboxylic Acid Methyl Ester (10) The alcohol 9 (0.82 g, 3.06 mmol) was dissolved in toluene (50 mL) and heated to reflux for 17 h until no alcohol could be detected (TLC). The solvent was removed in vacuo and the residue purified via column chromatography (EtOAc/petroleum ether, 1:2) to afford racemic lactone 10 (0.67 g, 2.71 mmol, 88%). The enantiomers could be separated via chiral HPLC. R_f = 0.40 (EtOAc/petroleum ether, 1:2). HPLC: racemic purification (Nucleosil 50/5, 4 × 250 mm, 2 mL/min, 133 bar) k = 2.50 (40% EtOAc/Hex), chiral HPLC: (S,S-Whelk-O1, 20 × 280, 30 mL/min, 64 bar) k _5R = 5.79, k _5S = 6.42 (15% EtOAc/Hex). [α]_D (5R enantiomer) = +72.2° (c 0.9, 25 °C, CH₂Cl₂, ee 100%), [α]_D (5S enantiomer) = –71.1° (c 1.0, 25 °C, CH₂Cl₂, ee 96%), mp 83–85 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.25 (d, ³ J _HH = 6.0 Hz, 1 H, H-10), 6.80 (dd, ³ J _HH = 11.2 Hz, ³ J _HH = 5.9 Hz, 1 H, H-8), 6.65 (ddd, ³ J _HH = 11.2 Hz, ³ J _HH = 6.0 Hz, ⁴ J _HH = 0.8 Hz, 1 H, H-9), 6.31 (d, ³ J _HH = 5.9 Hz, 1 H, H-7), 5.01–4.87 (m, 1 H, H-5), 3.78 (s, 3 H, H-14), 3.06 (d, ² J _HH = 13.5 Hz, 1 H, H-13̍), 2.73–2.45 (m, 2 H, H-2), 2.37 (d, ² J _HH = 13.5 Hz, 1 H, H-13̍̍), 2.10–1.96 (m, 1 H, H-4̍), 1.96–1.78 (m, 3 H, H-4̍̍, H-3). ¹³C NMR (100 MHz, CDCl₃): δ = 171.1 (C-1), 166.3 (C-12), 136.2 (C-6), 134.4 (C-8), 133.4 (C-10), 129.1 (C-9), 122.7 (C-7), 121.9 (C-11), 82.7 (C-5), 52.1 (C-14), 29.5 (C-2), 27.4 (C-4), 26.9 (C-13), 18.5 (C-3). IR (neat): ν~  = 3014 (w), 2951 (w), 2859 (w), 1732 (s), 1706 (s), 1538 (w), 1437 (m), 1278 (s), 1213 (s), 1162 (w), 1096 (m), 1052 (m), 933 (w), 740 (s), 627 (w), 602 (w) cm^–1. HRMS (ESI): m/z calcd for C₁₄H₁₆O₄Na: 271.0946; found: 271.0939.
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• 23 Obviously, the formation of side products from starting material and products was a slow process. Thus, short reaction times enabled to avoid the generation of rearrangement and degradation products. Disadvantage was the incomplete consumption of reactant B. However, excess of B had been recycled enabling to avoid severe loss of starting material.
• 24 The total synthesis of 6,11-methylene-lipoxine B₄ will be published in due course.