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Synlett 2004(1): 49-52  
DOI: 10.1055/s-2003-43362
LETTER
© Georg Thieme Verlag Stuttgart · New York

A New Strategy for the Diastereoselective Synthesis of Polyfunctionalized Pyrrolidines

Andrew S. Davis, Nicole J. Gates, Karl B. Lindsay, Minyan Tang, Stephen G. Pyne*
Department of Chemistry, University of Wollongong, Wollongong, New South Wales, 2522, Australia
Fax: +61(2)42214287; e-Mail: Stephen_Pyne@uow.edu.au ;
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Publication History

Received 26 August 2003
Publication Date:
26 November 2003 (online)

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Abstract

This paper describes a new strategy for the synthesis of polyfunctionalized pyrrolidines via the ring-closing metathesis ­reaction of substituted 3-allyl-4-vinyl-2-oxazolindones and sub­sequent diastereoselective cis-dihydroxylation of the resulting ­pyrrolo[1,2-c]oxazol-3-ones.

Key words

oxazolindones - pyrrolidines - ring-closing metathesis - dihydroxylation

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Data for compound 2a: MS (CI+): m/z (%) = 126(100). HRMS (CI+) calcd for C6H8NO2: 126.05549 [M + 1]. Found: 126.05520. 1H NMR (300 MHz, CDCl3): δ = 3.82 (1 H, ddq, J = 15.5, 4.4 and 1.5 Hz, H5a), 4.26 (1 H, dd, J = 8.5 and 5.0 Hz, H7a), 4.38 (1 H, ddt, J = 15.5, 2.9, 2.1 Hz, H5b), 4.62 (1 H, t, J = 8.8 Hz, H4a), 4.74 (1 H, m, H4b), 5.93, 6.06 (2 × 1 H, m, H6 and H7). 13C NMR (75 MHz, CDCl3): δ = 54.6 (t, C5), 64.5 (d, C7a), 68.6 (t, C4), 128.9, 130.6 (d, C6 and C7), 163.2 (s, C2).

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Typical RCM Reaction Procedure: The oxazolidinone 1b (165 mg, 0.483 mmol) was dissolved in freshly distilled and dried CH2Cl2 (120 mL), then Grubbs I catalyst (80 mg, 0.097 mmol) was added. The mixture was heated at reflux under a N2 atmosphere for 20 h then cooled, before all volatiles were removed in vacuo to give an oil. The pure product 2b was obtained by column chromatography (increasing polarity from 30% to 60% EtOAc in petroleum ether as eluant) as a clear oil (110 mg, 0.347 mmol, 72%). Compound 2b: [α]D 30 -33.8 (c 0.89, CHCl3). MS (CI+): m/z (%) = 316(21) [M - 1], 318(8) [M + 1]. HRMS (CI+) calcd for C18H22NO4: 316.15220 [M - 1]. Found: 316.15472. 1H NMR (300 MHz, CDCl3): δ = 1.40-2.00 (6 H, m, H7, H8, H9), 3.44 (2 H, t, J = 6.3 Hz, H10), 3.77 (3 H, s, H16), 3.72-3.82 (1 H, m, H2), 4.22-4.38 (3 H, m, H2, H5), 4.40 (2 H, s, H11), 5.78-5.85 (1 H, m, H3), 5.95-6.02 (1 H, m, H4), 6.85 (2 H, dt, J = 8.7, 2.7 Hz, H14), 7.23 (2 H, dt, J = 8.7, 2.7 Hz, H13). 13C NMR (75 MHz, CDCl3): δ = 21.3 (t, C8), 29.2, 34.9 (t, C7, C9), 54.4 (t, C5), 55.1 (q, C16), 69.3 (t, C10), 70.3 (d, C2), 72.4 (t, C11), 81.8 (d, C6), 113.6 (d, C14), 128.5 (d, C3), 129.1 (d, C13), 1 30.4 (s, C12), 130.5 (d, C4), 159.0 (s, C15), 162.5 (s, C17).

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Compounds 1a (R = Ph) and 1c were prepared by conversion of their corresponding 2-amino alcohols to their N-Boc derivatives [(Boc)2O, Et3N] followed by cyclization to the oxazolidinone with NaH, THF and at r.t. These starting 2-amino alcohols were prepared via the Petasis reaction [10] of trans-2-phenylvinylboronic acid, allyl amine and either 2-hydroxylacetaldehyde dimer or d-xylose, respectively. All other substrates were prepared from the aminolysis of their corresponding chiral vinyl epoxides with the corresponding allylamine, [1] [2] followed by oxazolidinone formation as described above or by using triphosgene/triethylamine.

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Synthesis of 13 and 14: To a solution of 2a (50 mg, 0.400 mmol) in acetone (2.4 mL) and H2O (1.6 mL) was added 4-methylmorphilone-N-oxide (103 mg, 0.880 mmol) followed by potassium osmate dihydrate (7.4 mg, 0.020 mmol). The mixture was stirred at r.t. in a sealed flask for 24 h, then all volatiles were evaporated in vacuo to give a dark oil. The pure product was obtained by column chromatography using gradient elution with increasing polarity from 5% to 15% MeOH in CH2Cl2. This gave compound 13 (48 mg, 0.306 mmol, 76%) as a white crystalline solid. Mp 124-128 °C(dec) (Et2O). MS (CI+): m/z (%) = 160(100). HRMS (CI+) calcd for C6H10NO4: 160.06098 [M + 1]. Found: 160.06067. 1H NMR (500 MHz, D2O): δ = 3.24 (1 H, dd, J = 11.1, 8.1 Hz), 3.59 (1 H, dd, J = 11.1, 8.1 Hz), 4.09 (1 H, t, J = 3.0 Hz), 4.19-4.24 (1 H, m), 4.57-4.63 (3 H, m). 13C NMR (75 MHz, D2O): δ = 49.4 (t), 62.2 (d), 65.0 (t), 71.3 (d), 73.9 (d), 164.8 (s).
To a solution of 13 (50 mg, 0.314 mmol)in absolute EtOH (4 mL) was added NaOH (126 mg, 3.14 mmol). The mixture was heated at reflux for 1 d, followed by evaporation of all volatiles in vacuo to give a brown oil. Pure 14 was obtained by ion exchange chromatography as a white crystalline solid (40 mg, 0.300 mmol, 96%). Mp 140 °C(dec). Ion exchange chromatography was performed using Dowex 50WX8-100 acidic cation exchange resin, packed by the slurry method in a 5 mm diameter column. The compound was applied as its HCl salt dissolved in distilled H2O. After washing with H2O (100 mL) the compound was eluted from the resin using 14% aq NH3 solution. Compound 14 had identical spectral data to that described in the literature for this compound. [12]