Asymmetric synthesis of (−)-(2R, 6R)-2,6-dimethylmorpholine

doi:10.1016/0957-4166(95)00245-K

Tetrahedron: Asymmetry

Volume 6, Issue 8, August 1995, Pages 1891-1894

https://doi.org/10.1016/0957-4166(95)00245-K Get rights and content

Abstract

The title compound was prepared efficiently by O-alkylation of (R)-ethyl lactate with the O-trifluoromethylsulphonyl derivative of (S)-ethyl lactate and further transformations of the two ester functionalities of the homochiral ether thus obtained.

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Cited by (21)

New chiral morpholine-pyrrolidine ligands affecting asymmetric selectivity in copper catalyzed Henry reaction
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These compounds are not only used as N-alkylating agents [10–12] or more in general like bases but also as versatile synthetic units in organic synthesis for the construction of agrochemicals, fungicides and bactericides [13,14]. Chiral morpholines have also been extensively used in asymmetric syntheses as both auxiliaries and ligands for synthetic organic transformation [15–19]. Moreover, six-membered ring contains a heteroatom, such as an oxygen atom in morpholine could influence its ligand catalytic properties for having an extra coordination site on the catalyst.
In this study, several chiral diamine (35, 36, 37 and 39), triamine (24 and 25), diaminol (38, 42 and 43) and triaminol ligands (29 and 30) having chiral morpholine and pyrrolidine moieties conjugated constitutes, were prepared from commercially available (S)-2-amino-2-phenylacetic acid and (S)-proline. These ligands were complexed with copper (II) salt in situ and applied to asymmetric Henry reaction. Asymmetric addition of various structurally divergent aldehydes and nitromethane in the presence of 5 mol% of chiral ligand with CuCl₂ furnished corresponding β-nitro alcohol in good yields (up to 55–79%) with good enantioselectivity (up to 89%).
Lewis acid mediated intramolecular C-O bond formation of alkanol-epoxide leading to substituted morpholine and 1,4-oxazepane derivatives: Total synthesis of (±)-Viloxazine
2016, Tetrahedron
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Moreover, there are also reports of intramolecular cyclization of alkanol epoxide using strong bases such as NaOMe,18 KOH/NaOH19 and Lewis acid like Cu(OTf)2.20 Although, many synthetic methodologies have been developed, some of them suffer from serious problems of low yields10c,11,14 strong bases,18,19 long reaction time,18 metal triflates20 and harsh reaction conditions.17a Therefore, there is a need for the protocol which facilitates the preparation in good yields, mild reaction condition and with a choice of wide variety of substrates.
Synthesis of Five-, Six-, and Seven-Membered 1,3- and 1,4-Heterocyclic Compounds via Intramolecular Hydroalkoxylation/Hydrothioalkoxylation of Alkenols/Thioalkenols
2015, Journal of Organic Chemistry
Synthesis of 2,6-disubstituted morpholines through regioselective oxiranes ring opening by tosylamide under PTC conditions
2004, Tetrahedron
Symmetric and non-symmetric 2,6-disubstituted morpholines were synthesized through regioselective nucleophilic ring opening of oxiranes with tosylamide under solid–liquid phase transfer catalysis (SL-PTC) conditions followed by cyclization of the tosylamido diols thus obtained and final deprotection of the corresponding N-tosyl morpholines. The morpholines prepared are interesting building blocks in the synthesis of pharmaceuticals and agrochemicals.
Synthesis of ether analogues derived from HUN-7293 and evaluation as inhibitors of VCAM-1 expression
2004, Bioorganic and Medicinal Chemistry Letters
The cyclic depsipeptide HUN-7293 (1) and its d-lactate analogue 2 are highly potent inhibitors of inducible cell adhesion molecule expression. We report the synthesis of ether analogues varying in stereochemistry and side chain at the former hydroxyl acid position by employing a ‘cut and paste chemistry’ methodology starting from 1. As an additional fruit of this synthetic effort, a cyclodepsipeptide featuring a tertiary amine instead of a tertiary amide between PrLEU and MALA was obtained. Results on the inhibitory profile of these compounds in assays of VCAM-1 and ICAM-1 protein expression are discussed.
Stereoselective synthesis of 2,6-disubstituted morpholines from chiral non-racemic lactams
1999, Tetrahedron Letters

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¹: Post-doctoral grant from EC (HCM programme, contract n^o, CHRXCT940501).

²: Present adress: Institut de Chimie Minérale et Analytique, BCH, Université de Lausanne, CH-1015

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CommunicationAsymmetric synthesis of (−)-(2R, 6R)-2,6-dimethylmorpholine

Abstract

Tetrahedron Lett.

J. Organomet. Chem.

Tetrahedron

Synthesis

Synlett

Synlett

Gazz. Chim. Ital.

J. Am. Chem. Soc.

Synthesis

Communication
Asymmetric synthesis of (−)-(2R, 6R)-2,6-dimethylmorpholine