Synthesis of Pyrrolidinols by Radical Additions to Carbonyls Groups ^†

Abstract

Radical cyclizations represent powerful synthetic strategies for the assembling of heterocycles. Most radical cyclizations are based on the addition to C C double or triple bonds. On the contrary, the addition to C O double bonds is rarely reported, since it proceeds reversibly due to the formation of thermodynamically unfavorable alkoxy radicals. Herein we report our attempts to construct substituted pyrrolidin-3-ols by tin-mediated radical cyclization of 5-phenylseleno-3-aza-pentanals. These rings are widely represented in natural products and drug candidates with various biological activities.

1. Introduction

Radical cyclizations are considered effective procedures for the assembling of five membered heterocycles [1,2] with useful applications in the stereoselective synthesis of natural and/or biologically active compounds. Often, the cyclization occurs via an intramolecular addition of a carbon-centered radical to C C double bonds. Arylselenides have been widely employed as radical precursors in tin hydride-mediated reactions due to the high synthetic accessibility, the good functional group tolerance, and the easy homolytic cleavage of the weak C Se bond [3,4]. In fact, even if the phenylselenyl groups can be removed by Bu₃Sn at rates comparable to those of a bromine,they are more stable to most synthetic transformations and can be introduced in the molecule early in the synthetic sequence. Scheme 1 shows examples of synthesis of tetrahydrofurans [5,6,7] and pyrrolidines [8,9,10] starting from 3-oxa or 3-aza-5-hexenyl radicals, via a 5-exo-trig cyclization paths.

Good yields, excellent regioselectivity, and a poor to good level of diastereocontrol were observed depending on the structure of the starting compounds, the nature of hydrogen donor, the type of protecting group, and the presence of Lewis acids (path a and b). Other cyclizations involve intramolecular radical addition to conjugated alkenes or allenes [11,12]. On the contrary, radical cyclizations by addition to other multiple bonds i.e., C O bonds is less common [13]. Even if the addition of the carbon radical to a carbonyl group is faster than that to a carbon carbon double bond, it is not easy to trap the alkoxy cyclic radical. In fact β-scission reactions can occur, generating more stable open chain intermediates. At this purpose, a few years ago, we reported the stereoselective synthesis of tetrahydrofuran-3-ols by means of a tin-mediated radical cyclization of 5-phenylseleno-3-oxa-pentanals (Scheme 1, path c) [14]. As a continuation of this work,and part of our studies in the use of selenium reagents for the synthesis of heterocycles of biological interest [15,16,17,18], we now report our attempts to construct pyrrolidin-3-ols using 5-phenylseleno-3-aza-pentanals as radical precursors (Scheme 1, path d). 3-Hydroxylated pyrrolidines were identified in several natural products and compounds of pharmaceutical interest. Representative examples are reported in Figure 1: the bioactive metabolite of Kainic acid I, isolated from the red alga Digenea simplex [19], the (+)-Preussin (II) isolated from fermentation broths of Aspergillus ochraceus and Preussia sp., with antibiotic and cytotoxic activities against different human tumor cell lines [20], and the Asciminib (III) [21],an allosteric ABL 1 Tyrosine kinase inhibitor clinical candidate for the treatment of chronic myelogenous leukemia, are reported.

2. Results and Discussion

The synthesis of the radical precursor 4 was obtained in three steps starting from the N-Tosyl-2-benzylaziridine 1 (Scheme 2), adapting literature procedures [8,14]. The highly regioselective ring opening of the aziridine 1 by the nucleophilic species, generated in situ by diphenyl diselenide and NaBH₄ in ethanol,afforded the selenide 2 in excellent yield.

Then, the alkylation of the nitrogen atom was carried out in the presence of methyl bromoacetate to furnish the intermediate 3 in good yield. The partial reduction of ester 3 to aldehyde 4 was performed in excellent yield with DIBAL-H. This compound was then submitted to the radical cyclization by treatment, with a slight excess of tributyltin hydride, in the presence of a catalytic amount of AIBN in refluxing benzene. Pyrrolidin-3-ols 5 and 6 were obtainedin a modest yield as a mixture 62:38 of the cis and trans isomers. The two diastereoisomers were separated by medium pressure column chromatography. The stereochemical attribution was made by Nuclear Overhauser Effect Spectroscopy (NOESY) experiments (Figure 2).

Observation of the NOE crosspeak in the 2D NOESY spectrum indicated the spatial proximity of the C–3 and C–5 methine hydrogens of the major diastereomer 5. The cross peak is absent in the minor isomer 6 as expected for a trans 3,5-disubstituted pyrrolidine.

Further experiments were carried out in order to optimize the yields. We explored several conditions varying the amount of Bu₃SnH, the nature of the H-donor (Ph₃SnH), and the solvent. Unfortunately, no improvement was obtained.

The procedure was also applied to the synthesis of 5-phenyl substituted 3-pyrridinols (Scheme 3).

In this case the ring opening of the aziridine 7 was performed with PhSeSi(Me)₃ generated in situ from diphenyl diselenide, NaH, and trimethylsilyl chloride under reflux. The β-amino selenide 8 isolated by medium pressure chromatography was obtained in 64% yield. A total of 30% of the regioisomer was also recovered. This reaction proceeds with better yield and regioselectivity than those obtained in similar processes carried out with other nucleophilic selenium species. Successively, the usual alkylation followed by the partial reduction of the ester 9 gave the aldehyde 10. The radical cyclization carried out using Bu₃SnH and AIBN lead to the mixture of compounds 11 and 12 with a slight preference for the cis isomer (58:42 after column chromatography). The mixture of the 3-pyrrolidinols was separated by medium pressure chromatography and structurally attributed by NOESY experiments.

3. Conclusions

The synthesis of 3-hydroxylated pyrrolidines via intramolecular addition of carbon radicals to aldehydes has been carried out. Radicals derived from 4 and 10 undergo 5-exo-trig-cyclizations to afford mixtures of cis and trans 5-substituted-pyrrolidin-3-ols in poorer yields than those observed in similar cyclizations to tetrahydrofuranols. Further investigations with selenium reagents for the synthesis of biologically active pyrrolidine derivatives are currently underway.