Enantiopure 2-substituted glyceraldehyde derivatives by Aza-Claisen rearrangement or C-alkylation of enamines

Organic Letters

Volumn 10, Issue 20, 2008, Pages 4537-4540

  Bridgwood, Katy L ^a   Tzschucke, C Christoph ^a   O'Brien, Matthew ^a   Wittrock, Sven ^a   Goodman, Jonathan M ^a   Davies, John E ^a   Logan, Angus W J ^a   Hüttl, Matthias R M ^a   Ley, Steven V ^a  

^a Department of Chemistry ^*  (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 61349120769     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol8018242     Document Type: Article

References (48)

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40. 1H NMR spectroscopy through the observation of an nOe between the exocyclic enamine proton and the methylene group of the dioxane ring. This assignment was subsequently confirmed by the crystal structure of the corresponding N-(2-methylallyl)enammonium bromide ent-4b (see Supporting Information).
41. 2, piperidine, 100 °C: dr 4:1, 120 °C: dr 4:1.
42. The stereochemistry of the major components from 6b and 6c was determined by analogy to 6a.
43. 6c was isolated as a 6:1 inseparable mixture of diastereomers at the allylic centere: see Supporting Information for full experimental details and spectra.
44. The enammonium salt of 4b was isolated and subsequently subjected to rearrangement conditions, which gave identical results to the one-pot procedure. This provides strong evidence for an N-alkylation/[3,3]-rearrangement process and not direct C-alkylation. Additionally, no reaction was observed in the case of 4d. If the direct C-alkylation process was operative, we would expect some product formation.
45. Jaguar (version 7.0) was used (Schrodinger LLC: New York, 2007) and the 6-31G* basis set (Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular Orbital Theory; Wiley: New York, 1986) with the the B3LYP functional: Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.
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47. 2. This long bond appears to be a feature of the aza-Claisen reaction.
48. Enamine 7 can have an almost planar nitrogen atom, with good overlap between the nitrogen lone pair and the double bond π-orbitals, but at the cost of steric interactions between the isopropyl groups and the rest of the molecule. Twisting around the C-N bond reduces the steric interactions, but reduces the lone pair double bond overlap. The energy change for this rotation is small (less than 1 kcal/mol) until the lone pair is at about 45° to the double bond, when the energy increases rapidly. The most reactive conformation, with the lone pair perfectly aligned with the double bond orbitals, is similar in energy to the minimum energy conformation.