Scalable Synthesis of Amaryllidaceae Isocarbostyril Alkaloids from Enantiomerically Pure 7-Azabicyclo[2.2.1]heptanone Scaffold: Total Synthesis of (+)-7-Deoxypancratistatin

Ganesh Pandey; Rushil Fernandes; Debasis Dey

doi:10.1055/s-0036-1591022

Synlett, Inhaltsverzeichnis

Synlett 2018; 29(06): 805-809
DOI: 10.1055/s-0036-1591022

letter

Scalable Synthesis of Amaryllidaceae Isocarbostyril Alkaloids from Enantiomerically Pure 7-Azabicyclo[2.2.1]heptanone Scaffold: Total Synthesis of (+)-7-Deoxypancratistatin

Autoren

Ganesh Pandey*

Molecular Synthesis Laboratory, Centre of Biomedical Research, Sanjay Gandhi Post Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow 226014 (U.P.), India eMail: gp.pandey@cbmr.res.in
Rushil Fernandes

Molecular Synthesis Laboratory, Centre of Biomedical Research, Sanjay Gandhi Post Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow 226014 (U.P.), India eMail: gp.pandey@cbmr.res.in
Debasis Dey

Molecular Synthesis Laboratory, Centre of Biomedical Research, Sanjay Gandhi Post Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow 226014 (U.P.), India eMail: gp.pandey@cbmr.res.in

Abstract

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Abstract

A conceptually new and scalable strategy (ten linear steps, 13.9% overall yield) has been developed to synthesize (+)-7-deoxypancratistatin from optically pure 7-azabicyclo[2.2.1]heptanone scaffold. The crucial trans-B–C ring junction was fixed at an early stage of the synthesis by exploiting the rigid bicyclic structural framework of the starting precursor. Stereoselective installation of hydroxyl groups around the perimeter of the cyclohexenyl C-ring involved sequential epoxidation–phenylselenylation–oxydeselenylation sequence followed by dihydroxylation. The most attractive feature of this synthesis is the use of a protection–deprotection step only at the penultimate step making the protocol very efficient and atom economical.

Key words

asymmetric synthesis - natural products - antitumor agents - total synthesis - alkaloids

Volltext

Referenzen

References and Notes

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14 tert-Butyl [(1S, 2R)-2-(benzo[d][1,3]dioxol-5-yl)cyclohex-3-en-1-yl]carbamate (6) Sodium naphthalenide (Na-Nap) was prepared by taking naphthalene (706 mg, 5.51 mmol, 3 equiv) in dry, degassed THF (40 mL) and adding freshly cut sodium (633 mg, 27.5 mmol, 15 equiv) and stirring at r.t. for 3 h. The dark green Na-Nap solution was then transferred via syringe to a dry, argon-filled round-bottom flask and cooled while stirring to –78 °C. A solution of 9 (840 mg, 1.84 mmol, 1.0 equiv) in 20 mL dry THF (freshly distilled from benzophenone ketyl) was added dropwise into the cooled Na-Nap solution. After addition was complete, the reaction was quenched by adding sat. aq NH₄Cl solution and warmed to r.t.. The two layers were separated, and the aqueous layer was diluted with water and extracted with EtOAc (3 × 20 mL). The combined organic layer was dried with anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/ EtOAc, 9:1) to yield 6 (512 mg, 88%) as a crystalline white solid. mp 124–128 °C; [α]_D ^24.7 + 106.5 (c 0.51 in MeOH). IR (KBr): 3356, 2929, 1685, 1529, 1247, 1173, 1042 cm^–1. ¹H NMR (800 MHz, CDCl₃): δ = 6.79–6.69 (m, 3 H), 5.95–5.87 (m, 3 H), 5.62 (d, J = 8.53 Hz, 1 H), 4.64 (br s, 1 H), 3.70 (br s, 1 H), 3.23 (br s, 1 H), 2.26–2.20 (m, 1 H), 2.19–2.12 (m, 1 H), 1.93–1.87 (m, 1 H), 1.62–1.56 (m, 1 H), 1.40 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 155.2, 147.5, 146.1, 136.7, 128.2, 127.8, 121.5, 108.7, 107.9, 100.7, 79.0, 52.4, 47.8, 28.3, 25.7, 23.1. HRMS (ESI): m/z calcd for [C₁₈H₂₃NO₄ + Na⁺]: 340.1519; found: 340.1519.
15 tert-Butyl [(1S, 2R, 3S, 6R)-2-(benzo[d][1,3]dioxol-5-yl)-7-oxabicyclo[4.1.0]heptan-3-yl]carbamate (10) To a stirred solution of 6 (500 mg, 1.58 mmol, 1.0 equiv) in CH₂Cl₂ at r.t. was added m-CPBA (882 mg, 3.94 mmol, 2.5 equiv). After stirring for 1 h at that temperature, the reaction mixture was cooled in an ice bath and quenched by the addition of sat. aq NaHCO₃, and stirring vigorously until the pink color completely disappeared. This was diluted with CH₂Cl₂, washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by flash column chromatography (hexane/ EtOAc, 5:1) to obtain major isomer 10 (394 mg, 75%) as a white solid. mp 165–169 °C. [α]_D ^24.5 + 54.2 (c 0.24 in MeOH). IR (CHCl₃): 2545, 1686, 1578, 1415 cm^–1. ¹H NMR (800 MHz,CDCl₃): δ = 6.79 (d, J = 8.03 Hz, 1 H), 6.76 (s, 1 H), 6.74 (d, J = 7.53 Hz, 1 H), 5.96 (dd, J = 1.4, 6.52 Hz, 2 H), 4.72 (br s, 1 H), 3.56 (br s, 1 H), 3.33 (br s, 1 H), 3.19 (br s, 1 H), 2.98–2.89 (m, 1 H), 2.23 (d, J = 15.06 Hz, 1 H), 2.07–2.00 (m, 1 H), 1.71–1.65 (m, 1 H), 1.48–1.40 (m, 1 H), 1.36 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 155.0, 147.8, 146.5, 134.5, 121.4, 108.6, 108.3, 101.0, 79.2, 56.1, 52.4, 51.5, 47.2, 29.7, 28.3, 22.7. HRMS (ESI): m/z calcd for [C₁₈H₂₃NO₅ + Na⁺]: 356.1468; found: 356.1470.
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