The catalytic asymmetric addition of alkyl- and aryl-zinc reagents to an isoxazole aldehyde

Abstract

Nucleophilic addition of alkyl-and aryl zinc reagents to a C(4) functionalized isoxazolyl aldehyde proceeded effectively with high enantioselectivity (85-94% e.e.). The amino alcohol catalyst (S)-2-piperidinyl-1,1,2-triphenyl ethanol (10) afforded the (R)-product 2b, as established by x-ray crystallography.Functionalized isoxazoles represent an extremely important class of compounds in the synthesis of therapeutically relevant molecules. 1 The recent report of Myers on the asymmetric addition of zinc reagents to an isoxazole aldehyde, 2 prompts this description of our own studies on an analogous C-4 functionalized system. 3 Since the landmark report of the selective glutamate receptor ligand AMPA (Chart 1), 4 the Krogsgaard-Larsen group has continued to uncover groundbreaking sub-type selectivity, exemplified by the recent observation of GluR1 selectivity of the 2-Benzyl-tetrazole (2-Bn-Tet) analog of AMPA. 5,6 In order to expand upon our previously reported catalytic asymmetric synthesis of isoxazole containing glutamate analogs, 7-9 we came to examine the nature of asymmetric addition of carbon-based nucleophiles to isoxazolyl aldehyde 1 for the synthesis of novel ACPA analogues, 3.Numerous methods exist for the nucleophilic addition of alkyl and aryl groups to aldehydes. The use of zinc-based reagents was chosen based on (1) The abundance of chiral catalysts which afford the products in high yield and high enantiomeric excesses (ee's); (2) The availability of a wide variety of alkyl and aryl substituents on zinc (either commercially, or via a single synthetic step); and (3) The rate of the uncatalysed (racemic) reaction is most often near zero in the absence of a catalyst, theoretically leading to very high ee's.Results from alkyl zinc additions to isoxazolyl aldehyde 1 are summarized in Table 1. The proof of concept for this series of reactions was initially examined with Et 2 Zn as nucleophile and a BINOL/Ti(OiPr) 4 co-catalysts system developed by Walsh, 10 et al. This system was chosen due to the wide variety of functional groups tolerated as well as the consistently high yields and high ee's of products formed. Unfortunately, repeated attempts at nucleophilic addition to 1 using this method failed completely. The product from aqueous workup following © 2008 Elsevier Ltd. All rights reserved. *Corresponding author. Tel.: 406-243-4132; fax: 406-243-5228; e-mail: Nicholas.natale@umontana.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the reaction appears to have...

Isoxazole analogues bind the System xc- transporter: Structure–activity relationship and pharmacophore model

“…The amino acid analogues of AMPA were prepared using synthetic methodology previously described by our laboratory, with the exception of MOM- and BOM-ACPA, 7b and 7e respectively, which were prepared from the known 5-hydroxymethylene acetal 18, via a straightforward Williamson ether synthesis, and carried forward to the amino acids using our previously described sequence 19.…”

“…Amino acids, racemic ACPA ((±)- 7 ) 45, (±)- 8 (S)-ACPA, ((−)-7) , 7d, 7g, 7f 19, 7a and (S,S)- 7c 18 were prepared using methods previously described by our laboratories, and full experimental details have been published. (S)-MOM-ACPA ( 7b ) and BOM-ACPA ( 7e ) 46 were prepared from 12 via the known 5-hydroxyl-methyl acetal 18 using the amino acid synthesis sequence previously described 19.…”

Preparation of chiral isoxazole carbinols via catalytic asymmetric Corey-Bakshi-Shibata reduction.

“…Spectroscopic data were identical with those of racemic 3a. 12 HPLC separation on a chiral stationary phase (Chiracel AS column, 254 nm detector, 1 ml/min, 30:1 hexanes: EtOH) showed that the product had a 43% enantiomeric excess. 3-methyl-isoxazol-4-yl]-1,4-dihydropyridine-3,5-dicarboxylate 3i.…”

“…11,12 Over fifty attempts employing chiral bis-oxazolines, 13 Shibasaki's lanthanum BINOL, 14 Jacobsen's salen aluminum catalyst, 15 and Sparteine, 16 in the lateral metalation reaction failed to produce a significant enantio-enrichment of the product. We sought an alternate route which would provide synthetically useful results, and now report that the use of the Corey-Bakshi-Shibata (CBS) 17 reduction on isoxazolyl ketones produces chiral isoxazolyl carbinols in uniformly excellent chemical yields with high enantiocontrol in many cases.…”

“…The absolute configuration of (S)-3a was established by comparison of optical rotation to (R)-3a established by single crystal X-ray diffractometry using anomalous scattering techniques on a derived chloro-phenylisoxazolo [3,4-d]pyridazinone as previously described. 12 The absolute configuration of (S)-3j, produced by reduction with (R)-…”