Volume 2021, Issue 14 p. 2099-2102
Communication
Open Access

A General Stereocontrolled Synthesis of Opines through Asymmetric Pd-Catalyzed N-Allylation of Amino Acid Esters

Dominik Albat

Dominik Albat

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln, Germany

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Dr. Jörg-Martin Neudörfl

Dr. Jörg-Martin Neudörfl

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln, Germany

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Prof. Dr. Hans-Günther Schmalz

Corresponding Author

Prof. Dr. Hans-Günther Schmalz

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln, Germany

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First published: 16 March 2021
Citations: 5

Dedicated to Günter Helmchen.

Graphical Abstract

A palladium catalyst prepared in situ from a tartrate-derived C2-symmetric diphosphane enables the highly stereoselective N-allylation of amino acid esters. The products are efficiently converted into natural and unnatural opines, which are of relevance due to their biological properties.

Abstract

A stereo-divergent synthesis of natural and unnatural opines in stereochemically pure form is based on the direct palladium-catalyzed N-allylation of α-amino acid esters (up to 97 % ee or 99 : 1 d.r.) using methyl (E)-2-penten-4-yl carbonate in the presence of only 1 mol% of a catalyst, prepared in-situ from the C2-symmetric diphosphine iPr-MediPhos and [Pd(allyl)Cl]2. Selected target compounds (incl. a derivative of the drug enalapril) were efficiently obtained from the N-allylated intermediates by oxidative cleavage (ozonolysis) of the allylic C=C bond under temporary N-Boc-protection.

The so-called opines form a class of peptide-related compounds which are structurally characterized by the unique feature that two α-amino acids are fused in such a fashion that they share a common alpha nitrogen atom. In nature, such compounds are synthesized through reductive amination from an amino acid and an α-keto acid by means of specific NAD(P)H dehydrogenases.1 The two most prominent types of opines are N2-(1-D-carboxyethyl) amino acids such as octopine (1) derived from pyruvate, and N2-(1,3-D-dicarboxypropyl) amino acids such as nopaline (2), which are biosynthetically formed from an α-amino acid and α-ketoglutarate (Figure 1).2

Details are in the caption following the image

Molecular structure of selected opines.

The biological role of opines in organisms is versatile. One prominent example are agrobacteria which undergo a unique parasitic relationship with injured plants by transferring a specific tDNA into the genome of the plant to induce an excessive growth of the affected cells (plant tumor) and the expression of enzymes that produce opines such as 1 or 2.3 While these unusual metabolites cannot be catabolized by the plant itself, they serve the agrobacteria as a food source, both for carbon and nitrogen.4 As another interesting biological mechanism, certain gram-negative bacteria such as pathogenic Pseudomonas aeruginosa and Staphylococcus aureus exploit the outstanding metallophoric properties of staphylopine (3) and pseudopalin (4) to acquire essential transition metals within a host cell.5 These opines are released by the bacteria to form metal complexes which are then transferred back into the bacteria by specific transporter proteins.5 Therefore, such opines are also of interest for the development of new antibiotics acting as molecular “trojan horses”.6

Due to their fascinating biological function and potential for the development of new pharmaceuticals,7 opines represent an interesting challenge for stereoselective chemical synthesis. Early approaches toward opines were based on the N-alkylation of α-amino acids either through nucleophilic substitution using racemic8 or non-racemic9 electrophiles or by reductive amination employing α-ketoesters.10 In the latter case significant degrees of diastereoselectivity were observed, however, only one of the two possible diastereomers could be prepared.10b

In principle, asymmetric allylic amination (Tsuji-Trost) reactions, catalyzed either by palladium11 or iridium,12 offer an interesting option for the set-up of amino-substituted chirality centers under configurational control. However, the use of amino acid derivatives in such reactions is often associated with unsatisfying selectivities, and few applications have been reported.13 Recently, we succeeded in developing a powerful protocol for the Pd-catalyzed asymmetric N-allylation of α-amino acid esters employing a new class of chiral diphosphane ligands.14 More precisely, we found that our previously developed tartrate-derived C2-symmetric MediPhos ligands,15 such as (R,R)-L1* (Figure 2), allowed the direct asymmetric N-allylation of N-unprotected amino acid esters with outstanding levels of stereocontrol. Despite their architectural relationship with the broadly established Trost ligand L2*,16 our ligands proved to be clearly superior not only in terms of stereo-induction but also by exhibiting a strong ligand acceleration. In fact, the catalysts generated in-situ from L1* using [Pd(allyl)Cl]2 as a metal source were found to be much more active than the corresponding L2*-derived catalysts, allowing to reduce the catalyst loading.14

Details are in the caption following the image

Structure of the C2-symmetric iPr-MediPhos ligand L1* in comparison to the Trost ligand L2*.

Against this background we reasoned that our method for the asymmetric N-allylation of amino acid esters should open a general and stereo-divergent entry towards opines (5) as outlined in Scheme 1, provided that the oxidative cleavage of the allylation products (6) can be efficiently performed. While we had previously used only the carbonate rac-8 (with R=Et) to demonstrate the N-allylation protocol, we were interested in adapting the methodology also to other carbonates, especially employing rac-8 a (R=Me) formally as a pyruvate equivalent (see above) to access N2-(1-carboxyethyl) amino acids (5, R=Me) in both diastereomeric series. Noteworthy, while this work was in progress, Lei and coworkers reported a synthesis of pseudopaline (4) via Pd-catalyzed allylation of an N-nosylated amino acid ester employing methyl cyclopentenyl carbonate in the presence of a chiral ligand of type L2*.6

Details are in the caption following the image

A strategy for the stereo-divergent synthesis of opines based on Pd-catalyzed asymmetric N-allylation.

We started our investigation with the Pd-catalyzed asymmetric allylation of simple (N-unprotected) glycine esters employing the carbonate rac-8 a and (R,R)-L1* as a most promising chiral ligand.14 The results, summarized in Table 1, indicate that the desired allylic amines of type 9 were formed with good to excellent enantioselectivity in all cases, depending on the reaction conditions. Using glycine tert-butyl ester (7 a) at a concentration of 2.00 M full consumption of rac-8 a was already observed after one hour at 25 °C (entry 1), however, the enantioselectivity (72 % ee) was somewhat disappointing. Dilution of the catalytic system led to longer reaction times but also to an increase of the enantiomeric excess (entries 2 and 3). We then asked ourselves whether the commercially available hydrochloride salts 7 b or 7 c, respectively, could be employed as a more practical alternative to the volatile glycine ester 7 a. This could indeed be achieved by simply adding equimolar amounts of NEt3 to the reaction system (entries 4 to 10). Under optimized conditions (entry 11) the methyl ester 9 c was obtained with an enantioselectivity of 97 % ee after 15 h in the presence of 2 mol% of the in-situ formed Pd catalyst. The expected (R)-configuration of the product 9 c14 was confirmed after conversion to the diester 12 by comparison of the molecular rotation with an L-alanine-derived reference sample. Noteworthy, the enantioselectivity proved to be time-independent, and the reactions were usually run overnight to ensure full conversion (15–22 h).

Table 1. Optimization of the asymmetric N-allylation of glycine esters employing the chiral ligand (R,R)-L1*.[a]

image

Entry

Amine

Conc[b] [mol/l]

Conversion[c] [%]

ee[d] [%]

1

7 a

2.00

100

72

2

7 a

1.00

100

78

3

7 a

0.50

100

85

4

7 b

2.00

100

75

5

7 b

1.00

100

82

6

7 b

0.50

100

84

7

7 c

2.00

100

90

8

7 c

1.00

100

91

9

7 c

0.50

100

94

10

7 c

0.25

45[e]

97

11[f]

7 c

0.25

100

97

  • [a] Reactions were performed on a 0.7 mmol scale using either 7 a (1.3 eq) or 7 b/c in the presence of Et3N (1.3 eq). [b] Concentration of rac-8 a. [c] Conversion of rac-8 a (GC-MS). [d] Enantiomeric excess of 9 determined by GC on a chiral stationary phase; configurational assignments are based on rotary values given in the literature for compound 12. [e] Conversion after 22 h. [f] 1 mol% of [Pd(allyl)Cl]2 and 2.6 mol% of L1* were used.

The transformation of the N-allylation product 9 c into strombine (13) as a most simple opine was achieved as shown in Scheme 2. For the crucial oxidative cleavage of the C=C double bond we applied the ozonolysis protocol of Marshall,17 which leads directly to the methyl ester. However, the amine function had to be protected as a Boc derivative (10) to avoid complete decomposition of the material during the oxidation step. The diester 11 was finally deprotected to afford strombine (13, isolated as the hydrochloride salt) in 60 % overall yield from 9 c.

Details are in the caption following the image

Enantioselective synthesis of strombine. Reagents and conditions: a) see Table 1, entry 11; b) Boc2O, NaHCO3, dioxane/H2O (1 : 1), r.t., 12 h; c) O3, NaOH (2.5 M in MeOH), CH2Cl2, −78 °C, 1 h; d) TMSOTf, CH2Cl2, 0 °C, 1 h; e) LiOH, H2O, r.t., 4 d, then HCl.

Having elaborated reliable conditions both for the asymmetric N-allylation of glycine esters (Table 1) and the oxidative cleavage of the olefin (Scheme 2), we next investigated the application of the protocols to the diastereoselective synthesis of opines derived from chiral amino acids. Much to our satisfaction, the N-allylation of the alanine, phenylalanine and glutamic acid derivatives 7 df with rac-8 a proceeded smoothly under the proven conditions to afford the expected products 14, 15 and 16, respectively, with excellent diastereoselectivity (Scheme 3). A small matched/mismatched effect was observed, and the (R,S)-diastereomers were formed with superior selectivity in the presence of the chiral ligand (R,R)-L2*. In most cases, the main product was isolated as a pure diastereomer after flash chromatography. The expected relative configuration of the phenylalanine-derived compound (R,S)-15 was secured by X-ray crystal structure analysis of its N-Boc-protected derivative (Figure 3).

Details are in the caption following the image

Diastereoselective N-allylation of different (S)-α-amino acid esters.

Details are in the caption following the image

Structure of (R,S)-Boc-15 in the crystalline state.19

To complete the synthesis of selected opines, the N-allylated products (R,S)-14, (R,S)-15 und (R,S)-16 were further transformed under the proven conditions (Scheme 4). Marshall ozonolysis of the N-Boc protected derivatives of (R,S)-14 and (R,S)-15 afforded 17 and 18, respectively, from which the diastereomercially pure opines 19 (alanopine)18 and 20 were obtained through deprotection in about 50 % overall yield (four steps). Similarly, (R,S)-16 was converted to the triester 21.

Details are in the caption following the image

Conversion of the allylation products 14–16 into N2-(1-d-carboxyethyl) amino acids (alanopine derivatives). Reagents and conditions: a) Boc2O (5–10 equiv, neat), 80 °C, 13–16 h; b) O3, NaOH (2.5 M in MeOH), CH2Cl2, −78 °C, 1 h; c) TMSOTf, CH2Cl2, 0 °C, 20–45 min; d) LiOH, MeOH/H2O, r.t., 1–4 d, then HCl.

Finally, to probe the generality of the method in a slightly different context, we employed the allylic carbonate rac-2320 to N-allylate the dipeptide ester 22 (Scheme 5). By using either (R,R)-L1* or (S,S)-L1* both diastereomers of 24 were obtained with virtually complete diastereoselectivity according to NMR analysis of the crude product. The supposedly (S)-configurated product 24, obtained in 58 % yield in the presence of (S,S)-L1* as a chiral ligand, was then further converted by N-Boc protection and ozonolysis under the Marshall conditions (O3, NaOH in EtOH). Instead of the expected ester, however, the aldehyde was obtained in this case, which was converted by Pinnick oxidation into the acid 25 which represents a derivative of the prominent drug enalapril.7

Details are in the caption following the image

Synthesis of a protected derivative of enalapril. Reagents and conditions: a) [Pd(allyl)Cl]2 (2 mol%), (S,S)-L1* (4.3 mol%), THF, 25 °C, 14 h, r.t.; b) Boc2O (8 equiv, neat), 80 °C, 15 h (86 %); c) O3, NaOH (1.5 M in EtOH), CH2Cl2, −78 °C, 1 h (70 %); d) NaClO2, NaH2PO4.H2O, 2-methyl-2-butene, tBuOH/H2O, r.t., 16 h (50 %).

In conclusion, we have demonstrated the usefulness of the asymmetric Pd-catalyzed N-allylation of amino acid esters using the highly active and selective MediPhos ligand L1*. We are optimistic, that the developed protocol for the stereo-controlled conversion of amino acids into N-(1-carboxyalkyl) derivatives will find future application also in other laboratories.

Acknowledgements

The University of Cologne and the German Federal Ministry of Education and Research (Project 16GW0187 “EnVision”) are gratefully acknowledged for financial support. Open access funding enabled and organized by Projekt DEAL.

    Conflict of interest

    The authors declare no conflict of interest.