Synthesis of 2‐Hydroxy‐1,4‐oxazin‐3‐ones through Ring Transformation of 3‐Hydroxy‐4‐(1,2‐dihydroxyethyl)‐β‐lactams and a Study of Their Reactivity

Abstract

The reactivity of 3-hydroxy-4-(1,2-dihydroxyethyl)-β-lactams with regard to the oxidant sodium periodate was evaluated, unexpectedly resulting in the exclusive formation of new 2-hydroxy-1,4-oxazin-3-ones through a C3C4 bond cleavage of the intermediate 4-formyl-3-hydroxy-β-lactams followed by a ring expansion. This peculiar transformation stands in sharp contrast with the known NaIO(4)-mediated oxidation of 3-alkoxy- and 3-phenoxy-4-(1,2-dihydroxyethyl)-β-lactams, which exclusively leads to the corresponding 4-formyl-β-lactams without a subsequent ring enlargement. In addition, this new class of functionalized oxazin-3-ones was further evaluated for its potential use as building blocks in the synthesis of a variety of differently substituted oxazin-3-ones, morpholin-3-ones and pyrazinones. Furthermore, additional insights into the mechanism and the factors governing this new ring-expansion reaction were provided by means of density functional theory calculations.

A nitrilase-mediated entry to 4-carboxymethyl-β-lactams from chemically prepared 4-(cyanomethyl)azetidin-2-ones

“…of methoxy-, benzyloxy-or phenoxyacetyl chloride 5a-c in the presence of an excess of triethylamine as a base. [42][43][44][45] The optically pure b-lactams 6a-c were prepared in 85-89% yield and with high diastereomeric ratios of (90/10)-(95/5), favoring the expected relative cis-conguration as conrmed by the 1 H NMR (CDCl 3 ) spectra. Indeed, the vicinal coupling constants between the protons on the 3-and 4-position of the b-lactam rings in compounds 6a-c ranged between 5.0 and 5.5 Hz (CDCl 3 ), indicating a cis-relationship according to literature values.…”

“…In that respect, (E)-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methylidene]amines 4a,b were prepared in 88-90% yield via condensation of primary amines 3a,b with (R)-glyceraldehyde acetonide 2, obtained via periodate-induced oxidative cleavage of commercially available 1,2:5,6-di-O-isopropylidene-D-mannitol 1 in a quantitative way according to a literature procedure (Scheme 1). 41,42 The obtained imines 4a,b were subsequently used as substrates in the Staudinger synthesis of (3R,4S)-3-alkoxy/aryloxy-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-b-lactams 6a-c by using 1.3 equiv. of methoxy-, benzyloxy-or phenoxyacetyl chloride 5a-c in the presence of an excess of triethylamine as a base.…”

“…Indeed, the vicinal coupling constants between the protons on the 3-and 4-position of the b-lactam rings in compounds 6a-c ranged between 5.0 and 5.5 Hz (CDCl 3 ), indicating a cis-relationship according to literature values. 44,46 Next, b-lactams 6a-c were easily converted into the corresponding 4-hydroxymethyl-b-lactam key intermediates 7a-c in 82-96% yield via a three-step approach, including (i) p-toluenesulphonic acid-mediated hydrolysis in a THF/water mixture (1/1) under reux conditions for 4-6 hours, 42,44,45,47 (ii) subsequent oxidation using sodium periodate in the presence of sodium bicarbonate and stirring in dichloromethane for 2-16 hours at room temperature, [43][44][45]47 and (iii) selective reduction by means of two molar equiv. of sodium borohydride in methanol under reux for 1-2 hours.…”

Ring Expansions of β-Lactams and β-(thio)lactones

“…The reactivity of 3-hydroxy-4-(1,2-dihydroxyethyl)-β-lactams 84 with sodium periodate has been evaluated, giving the exclusive formation of 2-hydroxy-1,4-oxazin-3-ones 85 in good to excellent yields (Scheme 29) [33]. This behavior is in sharp contrast with the NaIO 4 -mediated oxidation of 3-alkoxy-and 3-phenoxy-4-(1,2-dihydroxyethyl)-β-lactams, which exclusively leads to the corresponding 4-formyl-β-lactam derivatives under the same reaction conditions.…”

Deployment of Small-Ring Azaheterocycles as Building Blocks for the Synthesis of Organofluorine Compounds

“…41 To that end, β-lactams 164 were converted into 2-hydroxy-1,4-oxazin-3-ones 165 through a peculiar NaIO 4 -induced ring transformation. Selective deoxyfluorination of 1,4-oxazin-3-ones 165 was achieved upon treatment with Morph-DAST (morpholinosulfur trifluoride), affording 2-fluoro-1,4-oxazin-3-ones 166.…”