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. 2018 Aug 8;14:2082-2089.
doi: 10.3762/bjoc.14.182. eCollection 2018.

D-Fructose-based Spiro-Fused PHOX Ligands: Synthesis and Application in Enantioselective Allylic Alkylation

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Free PMC article

D-Fructose-based Spiro-Fused PHOX Ligands: Synthesis and Application in Enantioselective Allylic Alkylation

Michael R Imrich et al. Beilstein J Org Chem. .
Free PMC article

Abstract

Phosphinooxazoline (PHOX) ligands are an important class of ligands in asymmetric catalysis. We synthesized ten novel D-fructose-derived spiro-fused PHOX ligands with different steric and electronic demand. The application of two of them was tested in asymmetric allylic alkylation. The ligands are prepared in two steps from readily available 1,2-O-isopropylidene protected β-D-fructopyranoses by the BF3·OEt2-promoted Ritter reaction with 2-bromobenzonitrile to construct the oxazoline moiety followed by Ullmann coupling of the resulting aryl bromides with diphenylphosphine. Both steps proceeded mostly in good to high yields (57-86% for the Ritter reaction and 35-89% for the Ullmann coupling). The Ritter reaction gave two anomers, which could be separated by column chromatography. The prepared ligands showed promising results (er of up to 84:16) in Tsuji-Trost reactions with diphenylallyl acetate as model substrate.

Keywords: Fürst–Plattner rule; Ritter reaction; Tsuji–Trost reaction; Ullmann coupling; oxazoline.

Figures

Figure 1
Figure 1
General structure of PHOX ligands 1 and structures of annulated glucosamine-based PHOX and PyOx ligands 2 and 3 and spiro-fused PyOx and PHOX ligands 4 and 5.
Scheme 1
Scheme 1
Preparation of 1,2-isopropylidene-protected D-fructose derivatives with different substitution pattern at positions 3, 4 and 5. PG: protective group, X: leaving group.
Scheme 2
Scheme 2
Activation of 7 to oxocarbenium ion 9 in the Ritter reaction.
Scheme 3
Scheme 3
Zemplén deacetylation of 10i.
Figure 2
Figure 2
Molecular structure of 10j. Ellipsoids are given at the 50% probability level. Grey = carbon, red = oxygen, white = hydrogen, purple = nitrogen, orange = bromine.
Scheme 4
Scheme 4
Benzylation of 10j to give 10b.
Scheme 5
Scheme 5
Plausible mechanism of the Ritter reaction. For better clarity C-2 is not shown in conformers 9a and 9b.
Scheme 6
Scheme 6
Neighboring group participation of ester protective groups. For better clarity C-2 is not shown in conformers 9a and 9c.
Scheme 7
Scheme 7
Pd catalyzed Tsuji–Trost reation. BSA: N,O-bis(trimethylsilyl)acetamide, DMM: dimethyl malonate.

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