Enaminone‐Based Synthesis of Dipodazine Derivatives

Abstract

A series of racemic dipodazine analogues 9 were prepared in 22 -80% yield from (3Z,6RS)-3-[(dimethylamino)methylidene]-6-methyl-1-(phenylmethyl)piperazine-2,5-dione (7) (Scheme 1), which was prepared in four steps from (RS)-alanine methyl ester hydrochloride. The preparation of nonracemic 7 from (S)-alanine methyl ester hydrochloride failed, since the introduction of the enamino functionality at position 3 of the precursor 6 was accompanied by almost complete racemization.Introduction. -Many marine natural products with potent pharmacological activities contain an indole nucleus [1]. Such indole derivatives are, e.g., aplysinopsins (1; Fig. 1), which have attracted considerable interest due to their cytotoxicity towards cancer cells and their ability to affect neurotransmitters [2]. Recently, the nortopsentins and meridianins (2), another series of indole alkaloids with interesting antitumor properties, have been isolated from the sponge Spongosorites ruetzleri, and from tunicate Aplidium meridianum [3]. Structurally, the meridianins comprise a brominated and/ or hydroxylated indole nucleus bearing a 2-aminopyrimidine substituent at the 3-position [4], and they are potent inhibitors of several protein kinases [5]. Other interesting biologically active indole alkaloids are 1) tryptophan-dehydrobutyrine diketopiperazine (TDD; 3) [6], a fungal metabolite isolated from Streptomyces spectabilis and Streptomyces sp. M1513-bF5; 2) barettin (4) [7], isolated from the marine sponge Geodia barretti, a diketopiperazine condensation product of 6-bromodehydrotryptophan and arginine; as well as 3) dipodazine (5) [8], a diketopiperazine derivative composed of dehydrotryptophan and glycine, which has been isolated from Penicillium dipodomyis and meat-associated P. nalgiovese. The syntheses of compounds 3 -5 and their analogues include condensation of 1H-indole-3-carbaldehyde with piperazine-2,5-dione derivatives as the key-step [6 -8].Alkyl 3-(dimethylamino)propenoates and related enaminones have been recently used as building blocks for the preparation of dehydro-alanine derivatives and many heterocyclic systems such as fused pyridines, pyrimidines, pyranones, and other compounds, including some natural products (e.g., indole alkaloids) and their synthetic analogues [9]. Various chiral analogues of 3-(dimethylamino)propenoates have also been prepared from commercially available, enantiomerically pure starting materials such as a-amino acids and (+)-camphor, and were employed as key intermediates and reagents in the synthesis of 1) functionalized heterocycles, e.g., 3-heteroarylalanine derivatives and related compounds, 2) heterocyclic analogues of dipeptides, and 3) terpene-func-

(S)-N-Benzyl-3(6)-methylpiperazine-2,5-diones as chiral solvating agents for N-acylamino acid esters

“…Scheme 1). [16][17][18][19] Then, 1 H NMR spectra of the valine ester (RS)-5b and the leucine ester (RS)-5d were taken in CDCl 3 in the presence of (S)-1c (1c:5b,d = 1:1, c = 0.073 M) at 29°C, 0°C, and À20°C. To our disappointment, no splitting of the NH signals or any other signals was observed in these spectra (Fig.…”

“…Both (S)-1-Benzyl-6-methylpiperazine-2,5-dione (S)-1a [16][17][18][19] and (S)-1-benzyl-3-methylpiperazine-2,5-dione (S)-1b 15 were prepared from (S)-alanine methyl ester hydrochloride (S)-2 following literature procedures. Similarly, the model amino acid derivatives (RS)-5a-5l were prepared in two steps according to known general protocols 20,21 from the corresponding racemic aamino acids: D,L-alanine (RS)-6a, D,L-valine (RS)-6b, D,L-norvaline (RS)-6c, D,L-leucine (RS)-6d, D,L-b-phenylalanine (RS)-6e, D,L-aphenylglycine (RS)-6f, D,L-methionine (RS)-6g, D,L-aspartic acid (RS)-6h, D,L-glutamic acid (RS)-6i, D,L-serine (RS)-6j, D,L-histidine (RS)-6k, and D,L-tryptophan (RS)-6l.…”

“…This compound was prepared from (S)-alanine methyl ester hydrochloride (S)-2 and pentafluorobenzaldehyde following the literature procedure for the preparation of its analogue (S)-1a 12,16 via reductive benzylation 17 (2?3c), chloroacetylation 18 (3?4c), and cyclization with ammonia 19 (3?1c).…”

Synthesis of spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3-amines via stereoselective cycloadditions of trimethylenemethane to (1S,3EZ,4R)-3-arylimino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones

“…[11][12][13][14][15][16][17][18][19][20][21][22] Within this context, (+)-camphor derived enaminones were used in the stereoselective synthesis of 3-( [1,2,4]triazolo [4,3-x]azin-3-yl)-(+)-camphors and their analogues; [23][24][25] the synthesis of terpene functionalized pyrazoles; 26 coupling reactions with amines 27 and Grignard reagents, 28 in the preparation and reductions of (1R,4E,5S)-4-oximino-1,8,8-trimethyl-2-oxabicyclo[3.2.1]-octan-3-one; 29 in 1,3-dipolar cycloaddition reactions of a-alkylidene-(+)-camphors and analogues 30 and (+)-camphor derived pyrazolidin-3-ones; 31 and in the preparation of b-campholenolactone derivatives. 32 In continuation of this work, we herein report the acid-catalyzed transformations of (1S)-(+)-camphorquinone 1 with anilines 2a-e into 3-iminocamphor derivatives 3a-e, stereoselective 1,3-dipolar cycloadditions of trimethylenemethane 4 to dipolarophiles 3a-e, and further reductions of the so formed spiro cycloadducts 5 and 6 into novel non-racemic amines 8a,b; diamines 8c,d, 9d, 10d; and aminoalcohol 11d.…”

Transformations of Methyl 2-[(E)-2-(Dimethylamino)-1-(methoxycarbonyl)ethenyl]-1-methyl-1H-indole-3-carboxylate

“…These versatile reagents have been used for the preparation of various heterocyclic systems [12] and natural products and their analogues such as 3-substituted indoles, dipodazines [14], aplysinopsins [15], and meridianins [16], or employed in combinatorial syntheses of heterocycles and N-acyldehydroalanine esters [17]. Here, we present an efficient synthesis of the 2-heteroaryl-substituted novel indoles 1 -3 (Scheme) 1 ).…”