A gas chromatography/mass spectrometry method using selected ion monitoring with negative ion detection and methane chemical ionization was employed to quantitate a marker for bacterial peptidoglycan, D-alanine, in mammalian tissues. D-Alanine originating from bacterial peptidoglycan was obscured by substantial amounts of D-alanine generated by racemization from L-alanine present in tissue protein. To overcome this problem, samples were enzymatically treated and hydrolyzed in deuterated hydrochloric acid. Newly formed D-alanine derived from protein was labeled with deuterium and bacterial D-alanine remained unlabeled, enabling differentiation by the molecular weight increase. Butyl heptafluorobutyryl derivatives of the D- and L-amino acids were separated on a fused silica capillary column coated with Chirasil-val. The amounts of bacterial D-alanine found in livers of arthritic rats were consistent with previously reported levels of other carbohydrate-derived markers for bacterial peptidoglycan-polysaccharide complexes.
Organocopper conjugate addition to a,b-unsaturated carbonyl systems represents an important area for organic synthesis.2) To overcome difficulties encountered with 1,4-addition to unsaturated aldehydes and esters due to competing 1,2-addition and to unsaturated amides owing to low reactivity of the C-C double bond in their carbonyl compounds, Lewis acid-and trimethylsilyl halide-mediated organocopper reagents have been devised. Moreover, to enhance the reactivity of the organocopper reagents, various types of reagents including the higher-order cuprates have also been developed.Asymmetric organocopper-conjugate addition reactions have been carried out by the use of 1) chiral auxiliaries in either the copper reagent or the a,b-unsaturated carbonyl compound, 2) chiral ligands, 3) a chiral catalyst, or 4) a chiral solvent. Compared with other asymmetric additions of cuprates, methods employing a conjugate acceptor with a chiral auxiliary are most reliable and promising in view of high performance because selectivities in the reactions by other methods are dependent on a large number of factors, including substrate and cuprate structure, solvent, 3) and the presence of added salts. Asymmetric conjugate addition of organometallic species to a,b-unsaturated enone with a chirally sulfinylated auxiliary has been developed by Posner et al.4) who reported highly stereoselective 1,4-additions of Grignard reagents with or without a Lewis acid, and organocuprates. On the other hand, studies of asymmetric organocopper-conjugate additions using a,b-unsaturated amides are not common since the amides are essentially inert toward organometallic reagents 5) unless another activating group is introduced in these molecules. To circumvent the low reactivity of the C-C double bond in these amides, activated amides (X*ϭchiral auxiliary, XϭC, N, O) such as the N-enoyl lactams 6) (A, B) and the N-enoyl sultams 7) (C), or the use of trimethylsilyl chloride (TMSCl) as an additive for the amide (D) 8) have been devised to date. In the course of our studies on asymmetric reactions using chiral sulfoxides, we recently reported the highly diastereoselective Diels-Alder reaction of a,b-unsaturated amides 1 and 2, which are obtained, respectively, from a chiral sulfinyl auxiliary 3 and (E)-cinnamoyl-and crotonoyl chloride. 9) Encouraged by the excellent results with both the reactivity and the diastereoselectivity of 1 in the cycloaddition, we were intrigued by the conjugate addition of an organocopper reagent to these amides. To evaluate the reactivity and selectivity in organocopper-conjugate addition, we planned the reaction using the a,b-unsaturated amides. Here we describe the diastereoselective conjugate addition of organocopper reagents to 1 and 2 with a remote chiral auxiliary 3. 10)First, we undertook the conjugate addition of methylcopper and dimethyl cuprate derived from methyllithium and copper(I) iodide to cinnamide 1 (Chart 1). The results are December 2001 Chem. Pharm. Bull. 49(12) 1609-1614 (2001) 1609 * To whom correspondenc...
The alkylation by allyl halides of the intermediate enolate, prepared in situ by conjugate addition of di-p-tolylcuprate to chiral (p-tolylsulfinyl)pyrrolyl cinnamoyl amide, gave the (2R,3R)-adducts as the major products with 81% to 94% de's. Methanolysis of the products afforded the corresponding methyl esters, together with efficient recovery of the chiral sulfinyl auxiliary without loss of optical purity.Recently we reported that the asymmetric conjugate addition to an a,b-unsaturated amide 1 by arylcopper reagents (ArCu and Ar 2 Cu) proceeds smoothly to afford major 1,4-addition product 2 with high diastereoselectivity (2 vs. 3). 1 The major adduct 2 obtained was transformed into the corresponding ester 4, together with efficient recovery of the chiral auxiliary 6 (Scheme 1). Encouraged by the results in the addition reaction of 1, we were intrigued by alkylation of the intermediate enolate 7 via a tandem reaction sequence, which enables the construction of two adjacent chiral centers in an one-pot operation.To date, the alkylation protocol of intermediate enolates, prepared in situ by a conjugate addition of a copper reagent, culminated in the synthesis of a number of biologically important natural products. 2 Most studies on the asymmetric tandem reactions have dealt with chiral gsubstituted cyclic alkenones usually possessing a rigid framework, which provides a fixed transition structure. For example, the utilization of 4-alkoxy substituted cyclopentenones as starting material and bulky copper reagents resulted in highly diastereoselective tandem reactions. 2 The use of such a sterically bulky cuprate bearing the dimethyl(phenyl)silyl group is also effective for the alkylation. 3 Trapping of the intermediate enolates, generated by conjugate addition, with a 'small group' such as formaldehyde often resulted in the formation of nearly an equal amount of diastereoisomers. 4,5 The stereoselective introduction of an electrophile at C(2) position could thus be governed by the steric and stereoelectronic nature of the substituent and/or the organocuprate. 6Compared to the vast amount of work with cyclopentenone derivatives, little work has been done with the a,b-unsaturated ester and amide functionalities due to their low reactivity. Snieckus et al. 7 reported an elegant tandem reaction of a,b-unsaturated amides, and obtained the tandem products in good yields as an undefined mixture of diastereoisomers.Herein we report the asymmetric tandem conjugate addition-alkylation of a,b-unsaturated amide 1. Since we had already demonstrated that aryl copper reagents, prepared from the Grignard reagent and copper(I) iodide, are effective for the conjugate addition to the amide 1 (up to 95% de), we used the p-tolylcopper reagent (p-Tol 2 Cu·Mg-Br·MgBrI) as an organocuprate in the tandem reaction.Our initial investigation centered on deuterium incorporation at C(2) position of 1 by trapping the metal enolate 7. According to the procedure we previously established, 1 the 1,4-addition of 1 was carried out with 3 equivalents ...
Asymmetric conjugate additions of arylcopper reagents, derived from aryl Grignard reagents and copper(I) iodide, to a chiral sulfinyl pyrrolyl a,b-unsaturated enones have been achieved.Organocopper conjugate addition to a,b-unsaturated carbonyl systems represents an important area for organic synthesis. 1 Owing to low reactivity of the C-C double bond in carbonyl compounds such as unsaturated esters, the Lewis acid-and trimethylsilyl halide-mediated conjugate additions have been reported. Morever, to enhance the reactivity of organocopper reagents, various types of the reagents including the higher order cuprates have also been developed. Generally, organocopper reagents are less reactive 2 toward a,b-unsaturated amides than the corresponding aldehydes, ketones and esters. The asymmetric version of this reaction has extensively been studied by the use of chirally functionalized activated amides such as N-enoyloxazolidinones 1 , N-enoyllactams 3 and N-enoylsultams. 4To date, most asymmetric conjugate additions using chiral sulfoxides as a chiral auxiliary have dealt with a-sulfinyla,b-unsaturated enones as a Michael-type acceptor. 5 Major reasons for this are the belief that the sulfinyl oxygen and enone carbonyl should coordinate tightly with a metal species in an organometallic reagent, resulting in a conformationally rigid chelate, and the higher reactivity of enone carbonyls compared to ester and amide carbonyls. Compared to these reactions, less progress has been made in conjugate additions to chiral sulfoxides that possess a reaction site remote from the sulfinyl auxiliary. 6Recently we reported the asymmetric Diels-Alder reaction of an a,b-unsaturated amide 1. 7 Encouraged by the excellent results with both the reactivity and the diastereoselectivity of 1 in the cycloaddition, our interest lay on the organocopper-conjugate addition to 1. The aim of this work is to show the highly diastereoselective conjugate addition of organocopper reagents to 1 having a remote chiral sulfinyl auxiliary.Initially, we undertook the conjugate addition to 1a by alkyl-and dialkyl cuprates derived from the corresponding alkyllithiums and copper(I) iodide. The results are summarized in the Table. Attempts to perform the conjugate addition with methyllithium and copper(I) iodide gave no desired product, accompanied by considerable amounts of sulfinyl pyrrole 2 during the reaction. This impasse was not improved by the use of other organolithium reagents, or with the addition of a Lewis acid such as boron trifluoride or trimethylsilyl halide under some reaction conditions. We next turned to the use of Grignard reagents instead of lithium reagents because the higher selectivity was observed using organomagnesium species of more coordinating ability than organolithiums. As a result, the organocuprates generated from Grignard reagents afford better results in diastereoselectivity and yield than the use of the cuprates obtained from organolithiums. 3In contrast to the results with organolithium reagents, the copper reagents generated f...
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