Development of a New Nonsugar-Based Strategy for the Synthesis of the Hydroxylated Indolizidinone Skeleton

Abstract

The diastereocontrolled formation of the polyhydroxylated indolizidinone skeleton from linear alkynylamides is achieved by the sequential combination of two key cyclization steps. In particular, a PIFA-mediated intramolecular alkyne amidation reaction affords the 5-alkenoylpyrrolidinone skeleton, whereas a subsequent Ru-catalyzed ring-closing-metathesis protocol assembles the bicyclic indolizidine framework. Manipulation of the ketone carbonyl group, developed in the former cyclization step under controlled reductive conditions, and oxidation of the C6-C7 double bond, generated in the latter one under Upjohn conditions, fix the 6,7,8-trihydroxy groups in a complete diastereoselective manner.

Key words

hypervalent iodine - PIFA - alkynylamides - metathesis - indolizidinones

References and Notes

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13

The selection of the E/Z mixture of 3 was made on the basis of economic reasons with respect to both expensive isolated stereoisomers. Moreover, it was anticipated that an E/Z mixture of (±)-6 should render the same compound after the ring-closing-metathesis step. All these compounds (4-6) were prepared as E/Z isomers and no effort to isolate them was attempted.

20

A combination of NOESY, selective COSY, and HMBC experiments were carried out to establish the stereochemical relationships in compounds (±)-12a,b and (±)-13a. From these results, the relative stereochemistry in (±)-11a,b was inferred.

21

Representative Procedure for the PIFA-Mediated Heterocyclization: Synthesis of( rac )- N -Allyl-5-(3-phenylacryloyl)pyrrolidin-2-one [(±)-10]
A solution of alkynylamide 9 (885 mg, 3.7 mmol) in CF₃CH₂OH (30 mL) was stirred at 0 ˚C, and a solution of PIFA (2.3 g, 5.5 mmol) in 25 mL of the same solvent was added dropwise. The reaction mixture was stirred at that temperature for 2 h. For the workup, aq Na₂CO₃ (20%, 30 mL) was added, and the mixture was extracted with CH₂Cl₂ (2 × 40 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and the solvent evaporated. Purification of the crude by flash chromatography (EtOAc) gave pyrrolidinone as a chromatographically pure yellowish oil (74%). Following the representative procedure, pyrrolidinone (±)-10 was obtained from 9 (74%) and purified by flash chromatography (EtOAc) as a yellowish oil. ^¹H NMR (300 MHz, CDCl₃): δ = 7.70 (d, J = 15.8 Hz, 1 H), 7.54-7.39 (m, 5 H), 6.76 (d, J = 15.8 Hz, 1 H), 5.75-5.62 (m, 1 H), 5.15-5.08 (m, 2 H), 4.53-4.41 (m, 2 H), 3.46-3.38 (m, 1 H), 2.48-2.33 (m, 3 H), 2.00-1.93 (m, 1 H) ppm. ^¹³C NMR (300 MHz, CDCl₃): δ = 197.2, 175.2, 145.2, 133.9, 132.1, 131.2, 129.1, 128.6, 121.4, 118.8, 63.7, 44.5, 29.6, 21.4 ppm. IR: ν = 1692, 1609 (CO) cm^-¹. HRMS: m/z calcd for C₁₆H₁₇NO₂˙H⁺: 256.1338; found: 256.1335.
Representative Procedure for the L-Selectride Reductive Step: Synthesis of rac -(5 R ,1′ R )- N -Allyl-5-(1-hydroxy-3-phenylallyl)pyrrolidin-2-one [(±)-11a]
A solution of L-Selectride^® (1.8 mL, 1.0 M in THF) was added dropwise to a cold (-78 ˚C) solution of pyrrolidinone (±)-10 (230 mg, 0.9 mmol) in 4.5 mL of the same solvent. After 30 min, the temperature was raised to r.t. and 2 mL of an aq solution of NaOH (10%) was added. The whole mixture was extracted with CH₂Cl₂ (3 × 10 mL), the combined organic layers were dried over Na₂SO₄, and the solvent evaporated. Purification of the crude by flash chromatography (EtOAc) gave pyrrolidinone (±)-11a as a chromatographically pure yellowish oil (70%). ^¹H NMR (300 MHz, CDCl₃): δ = 7.30-7.17 (m, 5 H), 6.59 (d, J = 15.9 Hz, 1 H), 6.10 (dd, J = 15.9, 6.0 Hz, 1 H), 5.72-5.65 (m, 1 H), 5.14 (d, J = 4.5 Hz, 1 H), 5.10 (s, 1 H), 4.39-4.25 (m, 2 H), 3.76-3.64 (m, 2 H), 2.88 (br s, 1 H), 2.36-1.98 (m, 4 H) ppm. ^¹³C NMR (300 MHz, CDCl₃): δ = 175.9, 136.2, 132.8, 132.3, 128.7, 128.0, 127.5, 126.5, 117.8, 73.4, 61.6, 44.7, 30.2, 20.5 ppm. IR: ν = 3374, 1670 cm^-¹. HRMS: m/z calcd for C₁₆H₁₉NO₂˙H⁺: 258.1494; found: 258.1507.
Representative Procedure for the Dihydroxylation Step: Synthesis of rac -(6 S ,7 S ,8 S ,9 R )-6,7,8-Trihydroxyhexahydroindolizidin-3-one [(±)-13a] K₂OsO₄˙2H₂O (7 mg, 0.015 mmol) and N-methyl-morpholine-N-oxide (70 mg, 0.6 mmol) were sequentially added to 2 mL of an acetone-H₂O (1:1) solution of indolizidinone (±)-12a (50 mg, 0.3 mmol). The mixture was stirred at r.t. for 18 h, and then filtered through Celite. The volatiles were eliminated, and the residue was column chromatographed (EtOAc) to render trihydroxyindolizi-dinone (±)-13a as a colorless oil (93%). ^¹H NMR (300 MHz, MeOD): δ = 5.48 (d, J = 3.7 Hz, 1 H), 3.94-3.64 (m, 3 H), 2.49-2.29 (m, 2 H), 2.11-1.87 (m, 4 H) ppm. ^¹³C NMR (300 MHz, MeOD): δ = 177.5, 74.5, 68.2, 65.0, 57.2, 35.2, 32.5, 19.6 ppm. IR: ν = 3408, 1660 cm^-¹. HRMS: m/z calcd for C₈H₁₃NO₄˙H⁺: 188.0923; found: 188.0915.