Preparation of (3S,4S)-1-Benzhydryl-3-[(5R)-1′-hydroxyethyl]-4-acyl-2-azetidinones from (2R,3R)-Epoxybutyramide Precursors

Deng, Biwei; Demillequand, Marc; Laurent, Mathieu Y.; Touillaux, Roland; Belmans, Marc; Kemps, Luc; Cérésiat, Marcel; Marchand‐Brynaert, Jacqueline

doi:10.1016/s0040-4020(00)00196-4

Cited by 18 publications

(14 citation statements)

References 25 publications

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“…Recently, we became interested in the synthesis of novel precursors of carbapenems [3,4]. Our strategy involved the use of a benzhydryl moiety as N-protecting group of the azetidinone ring, instead of the habitual p-anisyl substituent [2] which requires large quantities of ceric ammonium nitrate (CAN), a highly toxic reagent, for deprotection.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of N-[1',1'-(diphenyl)-hydroxymethyl]-3(S)-[1'(R)- hydroxyethyl]-4(S)-(t-butyl-oxomethyl)-azetidin-2-one, C23H27NO4, an unexpectedly stable intermediate in the photochemical cleavage of N-benzhydryl protecting group

Tinant¹,

Laurent²,

Cérésiat³

et al. 2003

Zeitschrift Für Kristallographie - New Crystal Structures

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Source of material Starting from N-(diphenyl-methyl)-3(S)-[1¢(R)-hydroxyethyl]-4(S)-(t-butyl-oxomethyl)-azetidin-2-one [3], after treatment at 293 K with N-bromosuccinimide (1.2 equiv.) in CH 2Cl2-H2O mixture (5:1) under irradiation (white light) in the presence of a catalytic amount of molecular bromine (0.1 equiv.), we could isolate the titled compound (crude) as a yellowish oil. A typical signal at 87.4 ppm in 13 C NMR spectroscopy indicated the presence of an O,N-hemi-aminal motif (N-C-OH) [6]. The compound was crystallized by slow evaporation from a CH 2Cl2 solution. Experimental detailsAll the H atoms of the CH 2, CH3 and aromatic groups were calculated. Those of the CH and OH were located by difference Fourier maps. The H atoms were refined with a common isotropic temperature factor (U iso = 0.120(4) Å 2 ). Discussion -[1¢,1¢-(diphenyl)-hydroxymethyl]-3(S)-[1¢(R)-hydroxyethyl]-4(S)-(t-butyl-oxomethyl)-azetidin-2-one was surprisingly stable and required the addition of a strong acid (p-Tos-OH, 1 equiv.) to release benzophenone. X-ray diffraction analysis of a monocrystal confirmed unambiguously the O,N-hemi-aminal structure of the title compound. This structure was initially proposed on the basis of 1 H and 13 C NMR data only [6]. Only 4 structures of azetidin-2-one with the N-hemi-aminal motif have been reported [7][8][9][10]11]. In all these molecules the C-N (mean value 1.432 Å) and C-OH (mean value 1.390 Å) bond lengths are shorter than those observed in the title compound, 1.472(5) Å and 1.418(5) Å respectively. This is probably the result of the steric constraint on the C atom resulting from the substitution by two phenyl rings. There are two intermolecular hydrogen bonds with the following geometry

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Section: Discussionmentioning

confidence: 99%

Crystal structure of N-[1',1'-(diphenyl)-hydroxymethyl]-3(S)-[1'(R)- hydroxyethyl]-4(S)-(t-butyl-oxomethyl)-azetidin-2-one, C23H27NO4, an unexpectedly stable intermediate in the photochemical cleavage of N-benzhydryl protecting group

Tinant¹,

Laurent²,

Cérésiat³

et al. 2003

Zeitschrift Für Kristallographie - New Crystal Structures

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“…The next step of our synthesis of 1 was the cyclization of the epoxybutyramide precursors to azetidinones 12-15 under basic conditions [Scheme 1, step (b)]: the carbanion formed by abstraction of a hydrogen atom α to the COR group could attack the epoxide moiety intramolecularly. Both the nucleophilic and electrophilic parts of the reagents being ambident functions, four cyclized products could be formed in principle: [10] the azetidinones A (enolate C-alkylation at the C2 atom of the epoxide ring), the 5,6-dehydromorpholin-3-ones B (enolate O-alkylation at the C2 atom of the epoxide ring), the 4,5,6,7-tetrahydro-4-azaoxepin-5-ones C (enolate O-alkylation at the C3 atom of the epoxide ring) and the pyrrolidin-2-ones D (enolate C-alkylation at the C2 atom of the epoxide ring). Experimentally, three products, A, B and C, were isolated and carefully identified, with ratios depending on the nature of the Nprotecting group (PG), the nature of the R substituent and the experimental conditions ( Table 3).…”

Section: Resultsmentioning

confidence: 99%

“…[8] We therefore decided to revisit Hanessian's synthesis, but replacing the N-(p-methoxyphenyl) (PMP) substituent with an N-benzhydryl or N-(p,pЈ-dimethoxy)-benzhydryl group, which should enable deprotection by hydrogenation or acidic hydrolysis. [9] What was expected to be a trivial structural modification proved to bring major changes in the chemical reactivity and selectivity of the C3-C4 cyclization key step with it, [10] so the experimental conditions and the nature of the substituent R were adapted. Other surprises, however, also arose from the deprotection step [11] and the Baeyer-Villiger oxidation.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of (1′R,3S,4S)‐3‐[1′‐(tert‐Butyldimethylsilyloxy)ethyl]‐ 4‐(cyclopropylcarbonyloxy)azetidin‐2‐one

Laurent

Cérésiat²,

Marchand‐Brynaert

2006

Eur J Org Chem

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The novel carbapenem precursor 1e has been synthesized from L‐threonine, cyclopropyl methyl ketone and benzhydrylamine (for the introduction of the azetidinone N‐protecting group). Two independently prepared building blocks – sodium (2R,3R)‐2,3‐epoxybutyrate as a mixed salt with NaBr (2b) and N‐(benzhydryl)aminomethyl cyclopropyl ketone (4e) – were coupled to give (2R,3R)‐N‐(benzhydryl)‐N‐(2‐cyclopropyl‐2‐oxoethyl)‐2,3‐epoxybutyramide (8e). This key intermediate gave a regio‐ and stereoselective C3–C4 ring closure on LiHMDS treatment in THF at 0 °C to yield(1′R,3S,4S)‐4‐cyclopropylcarbonyl‐1‐diphenylmethyl‐3‐(1‐hydroxyethyl)azetidin‐2‐one (13e). N‐Deprotection of 13e was performed by photochemical bromination and subsequent hydrolysis. The resulting (1′R,3S,4S)‐4‐(cyclopropylcarbonyl)‐3‐(1‐hydroxyethyl)azetidin‐2‐one (23e) reacted in a Baeyer–Villiger oxidation with a total control of the regioselectivity (due to the poor migratory aptitude of the cyclopropyl group) to furnish (1′R,3S,4S)‐3‐(1‐hydroxyethyl)‐4‐(cyclopropylcarbonyloxy)azetidin‐2‐one (24e), subsequent O‐silylation achieving the total synthesis of 1e (title compound).(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

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“…This was experimentally confirmed. However, the O-alkylation products were still formed in low yields [2], A careful column-chromatography allowed the separation of the side-products and their analysis by NMR [2]. The structure of the titled compound was fully confirmed by the X-ray diffraction analysis of crystals formed by slow evaporation from a solution of ethanol; it is a single …”

Section: Source Of Materialsmentioning

confidence: 99%

“…)-ds-2,3-epoxy-butyramide with lithium carbonate in dimethylformamide at 372 Κ [2]. The desired ß-lactam was formed in medium yield, and accompanied with side-products resulting from intramolecular O-alkylation processes [3].…”

Section: Source Of Materialsmentioning

confidence: 99%

Crystal structure of (6R ,7S)-N-benzhydryl-6-hydroxy-7-methyl- 2-tert-butyl-4,5,6,7-tetrahydro-4-aza-oxepin-5-one, C23H27NO3

Tinant¹,

Declercq²,

Cérésiat³

et al. 2001

Zeitschrift Für Kristallographie - New Crystal Structures

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026stereoisomer as the result of a stereocontrolled SNi reaction. Such acyclization process is allowed by the Baldwin's rules [5], but the occurrence of seven-membered rings from intramolecular epoxide ring-opening appears rather low [3,6,7]. DiscussionThe 7-membered ring adopted a very distorded conformation characterized by a pseudo twofold axis passing through C7 and the midpoint of the C3-N4 bond: AC 2 (C7) = 18.5° but also by a mirror plane through C6 and the midpoint of the double bond AC S = 23.

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Preparation of (3S,4S)-1-Benzhydryl-3-[(5R)-1′-hydroxyethyl]-4-acyl-2-azetidinones from (2R,3R)-Epoxybutyramide Precursors

Cited by 18 publications

References 25 publications

Crystal structure of N-[1',1'-(diphenyl)-hydroxymethyl]-3(S)-[1'(R)- hydroxyethyl]-4(S)-(t-butyl-oxomethyl)-azetidin-2-one, C23H27NO4, an unexpectedly stable intermediate in the photochemical cleavage of N-benzhydryl protecting group

Crystal structure of N-[1',1'-(diphenyl)-hydroxymethyl]-3(S)-[1'(R)- hydroxyethyl]-4(S)-(t-butyl-oxomethyl)-azetidin-2-one, C23H27NO4, an unexpectedly stable intermediate in the photochemical cleavage of N-benzhydryl protecting group

Synthesis of (1′R,3S,4S)‐3‐[1′‐(tert‐Butyldimethylsilyloxy)ethyl]‐ 4‐(cyclopropylcarbonyloxy)azetidin‐2‐one

Crystal structure of (6R ,7S)-N-benzhydryl-6-hydroxy-7-methyl- 2-tert-butyl-4,5,6,7-tetrahydro-4-aza-oxepin-5-one, C23H27NO3

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