Stereoselective Synthesis of (-)-PF1163A via Prins Cyclization

Abstract

A highly stereoselective and convergent total synthesis of PF1163 A is described while proving the versatility of Prins cyclization in natural product synthesis. The Prins cyclization, Yamaguchi esterification, and ring-closing metathesis reactions are the key steps utilized in the synthesis of macrolactone.

Keywords

(-)-PF1163A - 13-membered macrolactone - Prins cyclization - ring-closing metathesis

References

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5

Aldehyde 9 was prepared from (R)-citronellol in two steps in 76% overall yield as shown in Scheme  [4] .

Scheme 4

11

{(2 S ,4 R )-6-[( R )-5-(Benzyloxy)-3-methylpentyl]-tetrahydro-4-(methoxymethoxy)-2 H -pyran-2-yl} Methyl 4-Methylbenzenesulfonate (10)
To a stirred solution of alcohol 9 (1.8 g, 3.78 mmol) in anhyd CH₂Cl₂ (20 mL) at 0 ˚C were added DIPEA (1.31 mL, 7.56 mmol), DMAP (cat.) and MOMCl (0.91 g, 11.34 mmol) successively, the resulting mixture was stirred for 3 h at r.t. and then quenched by adding H₂O (10 mL) and extracted with CH₂Cl₂ (3 Ž 20 mL). The organic extracts were washed with brine (10 mL), dried over anhyd Na₂SO₄, and concentrated under reduced pressure to remove the solvent, and the crude residue was purified by column chromatography to afford the pure product 10 as a liquid (1.80 g, 92%). R _f  = 0.7 (SiO₂, 10% EtOAc in hexane); clear oil; R _f  = 0.5 (EtOAc-hexane, 3:7). [α]_D ^²0 -2.6 (c 1.15, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 7.82-7.76 (m, 2 H), 7.38-7.22 (m, 7 H), 4.66 (s, 2 H), 4.49 (s, 2 H), 4.14-3.92 (m, 2 H), 3.73-3.61 (m, 1 H), 3.59-3.43 (m, 3 H), 3.35 (s, 3 H), 3.25-3.14 (m, 1 H), 2.43 (s, 3 H), 1.98-1.88 (dd, 2 H, J = 9.4, 2.8 Hz), 1.78-1.01 (m, 10 H), 0.87 (d, 3 H, J = 6.4 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 144.6, 138.6, 132.9, 129.7, 128.3, 127.9, 127.5, 127.4, 94.3, 76.1, 72.8, 72.5, 72.4, 72.0, 68.5, 55.2, 38.0, 36.6, 34.4, 33.1, 32.5, 29.8, 21.5, 19.5. IR (KBr): ν_max = 2922, 2852, 1456, 1362, 1037, 979 cm^-¹. ESI-MS: m/z = 521 [M⁺ + H], 543 [M⁺ + Na].
(4 S ,6 S ,9 R )-4-(Methoxymethoxy)-9-methyldodec-11-en-6-ol (16)
To a stirred soln of 15 (0.8 g, 2.15 mmol) in anhyd THF (8 mL), TBAF (4.3 mL, 4.3 mmol) was added, and the mixture was stirred at 0 ˚C for 2 h. The reaction mixture was quenched with H₂O (5 mL) and extracted with EtOAc (2 × 5 mL), and the combined organic layers washed with brine (10 mL), dried over anhyd Na₂SO₄, and concentrated under reduced pressure to remove the solvent. The crude residue was then purified by column chromatography on silica gel (EtOAc-hexane, 1:9) to afford 16 as a white solid; yield 0.46 g (83%); clear oil; R _f  = 0.4 (EtOAc-hexane, 2:8); [α]_D ^²0 +12.1 (c 0.9, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 5.85-5.70 (m, 1 H), 5.05-4.94 (m, 2 H), 4.76-4.62 (m, 2 H), 3.90-3.76 (m, 2 H), 3.40 (s, 2 H), 2.13-2.02 (m, 1 H), 1.96-1.84 (m, 1 H), 1.68-1.08 (m, 10 H), 0.99-0.84 (m, 6 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 137.5, 115.5, 96.2, 75.9, 68.2, 55.8, 41.2, 41.1, 37.0, 34.9, 32.9, 32.4, 19.4, 18.7, 14.1. IR (KBr): ν_max = 3453, 2930, 1459, 1376, 1038, 911 cm^-¹. ESI-MS: m/z = 281 [M⁺ + Na].
(2 S )-(4 S ,6 S ,9 R )-4-(Methoxymethoxy)-9-methyldodec-11-en-6-yl 3-{4-[2-(benzyloxy)ethoxy]phenyl}-2-( N -Methylbut-3-enamido) Propanoate (19)
To a stirred solution of N-Boc-deprotected amine (200 mg, 0.35 mmol) in anhyd CH₂Cl₂ (12 mL) was added carboxylic acid fragment B (33 mg, 0.38 mmol) and then HOBt (4 mg, 0.035 mmol) followed by EDCI (201 mg, 1.05 mmol). The reaction was stirred for 6 h at r.t., quenched with HCl (1 N, 15 mL), and diluted with Et₂O (20 mL). The aqueous layer was extracted with Et₂O (20 mL), and the resulting solution washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc-hexane, 3:7) to afford diene 2 as a colorless oil (160 mg, 75%). R _f  = 0.4 (EtOAc-hexane, 3:7); [α]_D ^²0 -9.3 (c 0.5,CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 7.36-7.23 (m, 5 H), 7.11-7.01 (m, 2 H), 6.86-6.77 (m, 2 H), 5.85-5.65 (m, 2 H), 5.35-5.27 (m, 1 H), 5.11-4.90 (m, 4 H), 4.64-4.44 (m, 4 H), 4.13-4.06 (m, 2 H), 3.82-3.76 (m, 2 H), 3.51-3.39 (m, 1 H), 3.36-3.18 (m, 4 H), 3.14-2.86 (m, 4 H), 2.82 (s, 3 H), 2.10-1.96 (m, 1 H), 1.94-1.80 (m, 1 H), 1.67-1.19 (m, 11 H), 0.95-0.82 (m, 6 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 171.1, 169.5, 157.6, 137.1, 131.0, 129.8, 129.1, 128.4, 127.7, 117.7, 115.9, 114.9, 114.6, 96.2, 74.5, 73.4, 72.8, 68.5, 67.3, 57.8, 55.8, 41.3, 39.2, 38.9, 37.4, 33.9, 32.7, 32.3, 31.6, 29.8, 19.4, 18.2, 14.3. IR (KBr): ν_max = 2924, 2856, 1650, 1243, 1046 cm^-¹. ESI-MS: m/z = 660 [M⁺ + Na].
(3 S ,10 R ,13 S )-3-[4-(2-hydroxyethoxy)benzyl]-13- S -2-(methoxymethoxy)pentyl-4,10-dimethyl-1-oxa-4-azacyclotridecane-2,5-dione (21)
To solution of compound 20 (0.200 g, 0.328 mmol) in EtOAc (10 mL) was added Pd/C 10% (50 mg) and the mixture stirred under H₂ atmosphere for 7 h. After completion, the reaction mass was filtered through Celite, and the solvent was removed under reduced pressure to give crude product 21. Purification using column chromatog-raphy on silica gel (hexane-EtOAc, 4:1) gave pure product as a colorless solid (0.145 g, 85% yield); [α]_D ^²5 -48.5 (c 0.5, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 7.22-7.07 (m, 2 H), 6.83 (d, 2 H, J = 8.5 Hz), 5.13-5.02 (m, 1 H), 4.66-4.39 (m, 2 H), 4.08-4.02 (m, 2 H), 3.97-3.90 (m, 2 H), 3.35 (s, 3 H), 3.23-3.11 (t, 1 H, J = 11.1 Hz), 3.07-2.91 (m, 3 H), 2.88-2.57 (m, 1 H), 2.26-2.07 (m, 1 H), 1.72-1.08 (m, 19 H), 0.92-0.89 (m, 2 H), 0.85 (t, 3 H, J = 6.8 Hz), 0.81 (d, 3 H, J = 6.2 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 169.9, 130.2, 129.9, 114.8, 114.5, 75.4, 72.2, 69.0, 61.45, 55.7, 55.5, 39.0, 38.7, 37.3, 33.5, 33.3, 31.5, 30.1, 29.6, 25.1, 24.1, 20.5, 17.9, 14.2. IR (film): ν = 3437 (OH), 2926, 2869, 1728, 1636, 1512, 1247, 1038 cm^-¹. ESI-MS: m/z = 544 [M + Na]⁺.
(3 S ,10 R ,13 S )-3-[4-(2-hydroxyethoxy)benzyl]-13-[( S )-2-hydroxy pentyl]-4,10-dimethyl-1-oxa-4-azacyclotridecane-2,5-dione [PF1163 A(1)] To a stirred solution of 21 (0.02 g, 0.03 mmol) in anhyd TFA-CH₂Cl₂ (1:5, 2 mL) was added at 0 ˚C, and the reaction mixture was stirred for 2 h at r.t. The reaction mixture was quenched with NaHCO₃ (1 mL) and extracted with CH₂Cl₂ (2 × 2 mL), and the combined organic layers were washed with brine (2 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc-hexane, 3:7) to afford 1 as a colorless oil (13 mg, 75%). R _f  = 0.4 (EtOAc-hexane, 7:3); [α]_D ^²0 -88.5 (c 1.0, MeOH). ^¹H NMR (200 MHz, CDCl₃):
δ = 7.20-7.03 (m, 2 H), 6.84-6.75 (m, 2 H), 5.82-5.66 (m, 1 H), 5.14-4.91 (m, 1 H), 4.01 (s, 1 H), 3.90 (s, 1 H), 3.53-3.27 (m, 2 H), 3.01-2.80 (m, 3 H), 2.78-2.52 (m, 1 H), 2.38-2.24 (m, 1 H), 1.76-1.02 (m, 22 H), 0.91 (t, J = 7.8 Hz, 3 H), 0.82 (d, J = 7.8 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 173.9, 171.7, 157.4, 130.3, 128.8, 114.5, 73.2, 69.1, 66.6, 61.3, 56.0, 49.4, 42.1, 39.0, 33.9, 33.2, 29.7, 24.1, 20.7, 19.0, 14.0. IR (KBr): ν_max = 3429, 2924, 2856, 1728, 1632, 1511, 1459, 1247 cm^-¹. ESI-HRMS: m/z [M + Na]⁺ calcd for C₂₇H₄₃O₆NNa: 500.2988; found: 500.2979.