A Short Diastereo- and Enantioselective Synthesis of cis-4,5-Disubstituted Oxazolidin-2-ones

Abstract

The asymmetric synthesis of cis-4,5-disubstituted oxazolidin-2-ones is described. Following a four step reaction sequence of α-alkylation, 1,2-addition with subsequent carbamate protection, cyclization and concluding with cleavage of the auxiliary the title compounds are obtained in moderate yields and in excellent diastereo- and enantiomeric excesses (de = 88 - > 96%, ee > 96%).

Key words

asymmetric synthesis - hydrazones - nucleophilic addition - α-alkylation - oxazolidinones

References

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8

By nucleophilic addition to α-amino carbonyl compounds, α-amino acids, α-hydroxy imines, or ring opening of epoxides and aziridines.

9

By aldol-type reaction of an anion α to nitrogen with a carbonyl compound or pinacol-type reaction of imino- or oximino compounds with a carbonyl compound.

10

Sequential addition of the heteroatoms to olefins leads to trans product. Simultanous introduction gives cis product.

11

Most common method is the addition of an amino equivalent (azide or carbamate) to oxygen containing substrates.

18

General Procedure of α-Alkylation of Glycol Aldehyde SAMP-hydrazone 6: A solution of 6 (10 mmol) in anhyd THF (5 mL) was slowly added to a solution of 2.0 equiv LDA (freshly prepared from n-butyllithium and diisopropylamine) in anhyd THF (20 mL) at -78 °C. After being stirred at that temperature for 15 h, methyl iodide (30 mmol) was added at -100 °C. The solution was stirred for 1 h at that temperature and then allowed to warm up to r.t. within 20 h. The reaction mixture was quenched with sat. NH₄Cl solution (15 mL). The aq portion was extracted with Et₂O (3 × 10 mL), and the combined organic layers were washed with sat. NaCl solution, dried over anhyd Na₂SO₄ and concentrated in vacuo. After the isomer ratio was determined, flash column chromatography of the residue on silica gel eluting with pentane-Et₂O gave 7a.

21

Same configuration of the generated stereogenic center as in 7a-d, but change of priority ranking leads to (R)-nomenclature.

22

Typical Procedure of 1,2-Addition to Glycol Aldehyde SAMP-hydrazone, Cyclization and N,N-Cleavage to Oxazolidin-2-ones: A solution of t-butyllithium (1.6 M) in hexane (9.6 mmol) was slowly added to a solution of 7a (4.8 mmol) in anhyd THF (24 mL) at -100 °C. In case of freshly prepared RLi reagent (entry 6, 7) the hydrazone solution was added. The solution was stirred for 15 h and allowed to warm up to -30 °C. After cooling down to -78 °C MOCCl (48 mmol) was rapidly added. After being stirred at that temperature for 15 h, the reaction mixture was quenched with sat. NaHCO₃ solution (15 mL). The aq portion was extracted with Et₂O (3 × 15 mL), the combined organic layers were washed with brine, dried over anhyd Na₂SO₄ and concentrated in vacuo. After filtration through silicia gel washing with pentane-Et₂O the crude product was dissolved in dry THF (15 mL) and TBAF (1 M) in THF (14.4 mmol) was added at r.t. After being stirred for 4 d at that temperature, the reaction mixture was concentrated in vacuo at 35 °C. The residue was filtered through silica gel washing with pentane-Et₂O. The crude product was dissolved in THF (15 mL) and added to a solution of Li (48 mmol) in NH₃ (125 mL) at -78 °C. The solution was allowed to warm up to -33 °C. After being stirred at the temperature for 40 min, the reaction mixture was quenched with NH₄Cl (2.5 g). NH₃ was removed at r.t. and the residue was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were washed with brine and dried over anhyd Na₂SO₄ and concentrated in vacuo. After the isomer ratio was determined, flash column chromatography of the residue on silica gel eluting with pentane-Et₂O gave the desired product 10b.

23

For some examples higher temperature of up to 35 °C was necessary to reduce the reaction time.

26

Up to > 98% de according to ref. [13] .

27

Major diastereomer isolated by flash chromatography. Relative configuration of the two generated centers at the oxazolidinone ring towards the configurationally known auxiliary (S")-center gives the absolute configuration of 9a.