Synthesis of γ,δ-Didehydrohomoglutamates by the Phosphine-Catalyzed γ-Addition Reaction to Acetylenic Esters

Abstract

The design and synthesis of new nonproteinogenic R-amino acids is an area of current interest. 1 In particular, γ,δ-unsaturated R-amino acids have attracted attention due to their presence in natural products 2 and their usefulness as synthetic intermediates in the preparation of other R-amino acid derivatives, 3 as well as their pharmacological interest. 4 Phosphines are known to impart electrophilic character to the γ-carbon of acetylenic esters (Trost reaction). 5 This reaction has been used for C-C bond formation at carbon C-4 of ethyl 2-butynoate (1) by using carbon pronucleophiles with active hydrogen atoms. 5b Therefore, glycines that possessed an enhanced acidity of the R-CH on the basis of a suitably masked nitrogen atom (2, 3) could serve satisfactorily as pronucleophiles in the Trost reaction. Their reaction with 1 should afford the N-protected γ,δ-didehydrohomoglutamates 4, which are difficult to prepare by previously reported procedures 6 (Scheme 1). Results and DiscussionAt the onset of our study, glycine imines 2 were chosen as the pronucleophilic counterpart. 7 Heating alkyne 1 with an equimolecular ammount of 2a (R 1 ) H, R 2 , R 3 ) Ph) with 1 in toluene solution with a catalytic ammount of triphenylphosphine (5% mol) in the presence of an acetic acid-sodium acetate buffer (50% mol) 5a resulted in the recovery of the starting material together with (E)-ethyl 4-acetoxy-2-butenoate (40%). 8 The same result was obtained when the bis(methylthiomethylene)glycinate 2b (R 1 ) H, R 2 , R 3 ) SMe) or the aldimine 7,9 2c (R 1 ) H, R 2 ) p-Cl-C 6 H 4 , R 3 ) H) were used as pronucleophiles.Next, more basic reaction conditions were tested. Thus, the acetic acid-sodium acetate buffer previously used was replaced by t BuOH-KO t Bu (50% mol), which should guarantee 10 the deprotonation of glycinates 2. However, instead of the corresponding γ,δ-didehydrohomoglumates 4, the R, -didehydroglutamates 5 (Scheme 2) were the only products obtained. The results are given in Table 1.It has to be pointed out that compounds 5 were not formed in the absence of Ph 3 P and that the Michael addition of the potassium enolate of 2b with 1 in THF solution did only take place in the presence of a crown ether. 11 Therefore, the formation of the R, -didehydroglutamates 5 must be accounted for by the protonation (1) For recent references, see: (a) Burgess, K.; Ho, K.-K.; Pettit, B. M. J. Am. Chem. Soc. 1995, 117, 54. (b) Obrecht, D.; Altorfer, M.; Lehmann, C.; Schönholzer, P.; Mü ller, K. For some leading references on the most relevant methods for the synthesis of γ,δ-unsaturated amino acids, see the following. (i) Ene reaction of sulfonylimines: Yao, S.; Fang, X.; Jørgensen, K. A. J. Chem. Soc., Chem. Commun. 1998, 2547. (ii) Allylation of electrophilic glycines: Roos, E. C.; Mooiweer, H. H.; Hiemstra, H.; Speckam, W. C.; Kaptein, B.; Boesten, W. H. J.; Kamphuis, J. and references cited therein. (7) For pKa data of glycine aldimines and ketimines, see: O'Donnell, M. J.; Bennett, W. D.; Jacobsen, W. N.; Ma, Y.; Huffman, J. C. Tet...

Lewis Base Catalysis in Organic Synthesis

“…The nucleophilic attack by an external reagent at the g position of XXVIII is an interesting possibility because it represents a 4 umpolung reactivity of the starting alkynoate. [123] In the case of alcohols, [124] amines, [125] carboxylic acids, [126] malonates, [127] glycine imines, and nitroalkanes, [128] g addition to XXXV or XXXVI occurs to give products 84 or 85, respectively (Scheme 29). [129] The g addition of bifunctional reagents such as diols, diamines, and amino thiols leads to novel methods for the phosphane-catalyzed synthesis of thiazoles, dihydrofurans, and a variety of other heterocycles.…”

Lewis‐Base‐Katalyse in der organischen Synthese

“…Eine interessante Möglichkeit ist der nucleophile Angriff durch ein externes Reagens an der gPosition von XXVIII, da dies der a 4 -Reaktivitätsumpolung des ursprünglichen Alkinoats entspricht. [123] Alkohole, [124] Amine, [125] Carbonsäuren, [126] Malonate, [127] Glycinimine und Nitroalkane [128] reagieren unter g-Addition an XXXV oder XXXVI zu den Produkten 84 bzw. 85 (Schema 29).…”

Organocatalytic transformations of alkynals, alkynones, propriolates, and related electron-deficient alkynes

“…Alvarez-Ibarra and co-workers described the g-addition of nitroacetates to ethyl 2-alkynoates 86 using modified Trost conditions. 43 Thus, the use of more basic buffer (t-BuOH-KOt-Bu) allowed the formation of a,a-disubstituted nitroacetates 90 in good yields (Scheme 39). The authors synthesized a series of homoglutamate derivatives by reduction of the nitro group on 90.…”