Chemoenzymatic synthesis of a 1,2,3-triazolo- δ-lactone derivative

Introduction

Lactones are widely distributed in nature and play important roles in living organisms. The γ- and δ-lactones are the most common naturally occurring lactones. They are highly stable and show antimicrobial and cytotoxic activities [1, 2].

The chemistry of 1,2,3-triazole derivatives has gained interest over the past few years due to their wide range of applications in chemical, biological, medicinal, and materials science. The Huisgen 1,3-dipolar cycloaddition of azides and alkynes is the most efficient pathway for the synthesis of substituted 1,2,3-triazoles as chemotherapeutic agents [3–5], synthetic intermediates for bioactive compounds, agrochemicals, optical brighteners, photostabilizers, anticorrosive agents, and metal chelators [6–9]. The extraordinary stability toward metabolic transformations and aromatic nature of the triazole ring, along with its high dipole moment and H-bonding capability, makes it an important functionality as a connecting group [10–13].

The synthesis of compounds containing both δ-lactone and triazole rings attracts some interest because they are expected to possess important biological activities [14–18]. Moreover, the correlation between chirality and biological activity has become important in the pharmaceutical science [19]. Many applications have been focused on the chiral resolution of racemic substrates as the catalytic access to enantiomerically enriched chiral building blocks in organic syntheses [20].

We report here the enzymatic resolution of a 2-thienyl-substituted homoallylic alcohol and the synthesis of highly enantiomerically enriched 1,2,3-triazolo-δ-lactone derivative (+)-6.

Results and discussion

The key substrate rac-1 was synthesized by the addition of allylmagnesium bromide to the commercially available 2-thienylcarbaldehyde [21] (Scheme 1).

Scheme 1

The racemate rac-1 was resolved by treatment with enzymes to produce the enantiomerically enriched homoallylic alcohol (S)-(-)-1 and the ester (R)-(+)-2 (Scheme 1). The enantiomeric resolution reactions were performed using various lipases with a 1:1 substrate/enzyme ratio and vinyl acetate as an acyl donor and solvent at 30°C.

The results of the enzymatic resolution of rac-1 using Lipozyme, Novozyme 435, and Candida rugosa lipase (CRL) are summarized in Table 1. Lipozyme and Novozyme 435 gave good enantioselectivities varying between 74% and 95% ee. The enzyme CRL was not an adequate lipase for this resolution. Function c in Table 1 shows the velocity of the transformation of each enantiomer. The dimensionless enantiomeric ratio E can serve as a convenient measure of the enantioselectivity of an enzymatic resolution. Function E can be mathematically linked to the conversion c of the reaction and the optical purities of substrate and product, as indicated in Table 1. The value of E can be regarded as good in the range of 15–30 and excellent when it exceeds 30. According to these analyses, Lipozyme shows good and Novozyme 435 excellent selectivities.

The absolute configuration of alcohol (-)-1 was determined as S and that for ester (+)-2 as R, by comparing the specific rotations with the literature values [22, 23].

The treatment of homoallyl ester (R)-(+)-2 with m-chloroperoxybenzoic acid yielded the oxirane (+)-3 (Scheme 2). Epoxide (+)-3 was subjected to the reaction with NaN₃, which yielded vicinal azidoalcohol (+)-4. A 1,3-dipolar cycloaddition reaction of (+)-4 with diethyl acetylenedicarboxylate afforded a 1,2,3-triazole derivative (+)-5. Finally, intramolecular cyclization of (+)-5 by treatment with dibutyltin oxide yielded the target 1,2,3-triazolo-δ-lactone (+)-6 [14].

Scheme 2

 

Conclusions

2-Thienyl-substituted allyl alcohol rac-1 was successfully resolved by treatment with Lipozyme with high enantioselectivity (95% ee). The resultant enantiopure ester (R)-(+)-2 was transformed into 1,2,3-triazolo-δ-lactone (+)-6 in excellent yield.

Experimental

The ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded in CDCl₃ on a Bruker Spectrospin Advance DPX 400 spectrometer. Optical rotations were measured in a 10-cm cell using a Rudolph Research, Autopol III polarimeter. HPLC measurements were performed with a Thermo Separation Products P1500-SN-4000-UV2000 instrument, using a Chiralcel OJ-H analytical column (250×4.60 mm). HRMS spectra were recorded on an Agilent Technologies 6224 Accurate-Mass TOF LC/MS at the National Nanotechnology Research Center of Bilkent University (UNAM). Melting point was measured by Stuart SMP3 instrument. Flash column chromatography was performed on silica gel (60-mesh; Merck). The reactions were monitored by thin-layer chromatography (TLC) using Merck 0.2-mm silica gel 60 F₂₅₄ analytical aluminum plates, visualized by UV light and polymolybden phosphoric acid in ethanol. All extracts were dried over anhydrous magnesium sulfate and solutions were concentrated under reduced pressure by using a rotary evaporator. Lipozyme and CRL were purchased from Aldrich and Novozyme 435 was donated by Novo Nordisk AS, Bagsverd, Denmark.