(R)-3,3,6-Trimethyl-3,3a,4,5-tetrahydro-1H-cyclopenta[c]furan

Abstract

(R)-3,3,6-trimethyl-3,3a,4,5-tetrahydro-1H-cyclopenta[c]furan was obtained by the acid cyclization of the alcohol (S)-(2-methyl-5-(prop-1-en-2-yl)cyclopent-1-en-1-yl)methanol, which, in turn, is obtained from (R)-limonene. The structure of the new compound was established using NMR spectroscopy (¹H, ¹³C, COSY, HSQC, and HMBC spectra) and high-resolution mass spectrometry. The chemical shifts of the proton and carbon atoms were calculated at the DFT level with a high correlation between the calculated and experimental values.

1. Introduction

Natural products are frequently used as construction blocks for the synthesis of more complex structures. This is especially true when chirality is an issue since many easily found natural products are chiral.

Limonene 1 (Figure 1) is commonly used in this context since both enantiomers can be easily obtained.

Compound 2 (Figure 1) and its enantiomer have been used as an intermediate in synthetic procedures for the last 50 years. Most of their uses have been in the synthesis of terpenoids [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16], although other types of compounds have also been prepared from 2 [17].

The preparation of compound 2 is usually carried out from limonene, as shown in Scheme 1. Limonene is converted to the keto aldehyde 5 either directly by ozonolysis [8] or by the sequence of epoxidation, the opening of the epoxide, and the oxidative cleavage of the corresponding diol [18]. Compound 5 is then subjected to an intramolecular aldol cyclization using piperidine acetate to give compound 6, which comes from the attack of the aldehyde enolate onto the ketone [19]. The reduction of the aldehyde of 6 under Luche conditions gives alcohol 2 [8].

In some cases, other synthetic routes have been used for the preparation of 2; however, these routes are more complex [2,3,7,17,20,21].

During an ongoing project in our laboratories, we used compound 2 as an intermediate. Thus, its synthesis was carried out starting from (R)-(+)-limonene and using the ozonolysis route; no problems occurred. All the intermediate compounds and the prepared alcohol 2 presented spectroscopic data identical to the published data. Working with small amounts to test the following reactions, we observed that a sample left in an NMR tube in CDCl₃ started to change spontaneously into a new compound (see Figure S1). However, another sample dissolved in CDCl₃ treated with base was completely stable for several days. Since the transformation appears to be derived from the acidity of the deuterated solvent, we decided to study this transformation, which could diminish the yield in any reaction using 2 in acidic environments.

2. Results and Discussion

The new compound was completely formed after several hours, and it was assigned as structure 7 following its spectroscopic study. Thus, the ¹H-NMR spectra showed large differences with the starting compound 2. The vinylic protons of the isopropenyl moiety were absent and now, two singlets integrating for 3H each could be found at 0.99 ppm and 1.3 ppm, indicating methyl groups on sp³ carbons. Another singlet, integrating for 3H, was found at 1.65 ppm, indicating a methyl group on an sp² carbon. The polarity of the new compound according to TLC (Rf = 0.45, 90:10 hex:EtOAc) was also different from that of the starting alcohol 2 (Rf = 0.16, 90:10 hex:EtOAc). These changes prompted us to further analyze the new compound. To that end, more spectroscopic data were collected.

The ¹³C-NMR spectra showed the same number of carbons as in compound 2. The signals included two vinylic quaternary carbons and a quaternary carbon next to a heteroatom. Also, three methyl groups and three methylene groups could be observed from the DEPT-90 and DEPT-135 spectra. The HSQC spectrum showed the presence of two diastereotopic CH₂ groups and confirmed the rest of the observations from the monodimensional spectra. The COSY spectrum showed the coupling between the proton of the CH and one of the CH₂ groups with diastereotopic protons, as well as the coupling between this and the other diastereotopic CH₂ (Figure 2). Also, the long-range couplings shown in Figure 2 were visible. An HMBC spectrum also showed the expected correlations, including those of the quaternary carbons on compound 7 (Figure 2). The HRMS spectrum indicated that the composition of the new compound is C₁₀H₁₆O.

From the data collected, it seems plausible that the new compound was formed by an intramolecular hydroalkoxylation reaction in which the OH on compound 2 attacks the protonated double bond of the isopropenyl moiety in an exo-trig fashion according to Baldwin’s rules, leading to the formation of a tetrahydrofuran ring. This gives rise to compound 7 (Scheme 2). This compound has not been reported previously in the scientific literature.

This type of cyclization is well known in the literature. When the substitution pattern is favourable, such as in our case, in which the Markovnikov protonation of the double bond results in a highly stabilized intermediate, Brønsted acids have been used [22,23]. However, in other substitution patterns, these reactions are commonly carried out using other catalysts, usually metal triflates [24].

To confirm our results, a few drops of chloroform saturated with HCl gas were added to a sample of 2 dissolved in chloroform. Following the reaction via TLC, it was observed that the transformation of 2 into 7 took place in a short time. Thus, this reaction may occur easily in acidic environments.

Compound 7 proved to be quite unstable, and it was difficult to purify since it decomposed easily.

To introduce another confirmation of the proposed structure of 7, we carried out the computation of the ¹H-NMR and ¹³C-NMR chemical shifts at the DFT level.

The GIAO method [25], as implemented in ORCA 6.0.0 [26], was used. The calculation on the optimized structure of 7 (Figure 3) was carried out using the B3LYP functional together with the PCSSEG-2 basis set. The solvent (CHCl₃) was simulated using the CPCM method. As a reference, TMS, computed at the same level, was used. The calculation on both nuclei resulted in a very good correlation between the computed values and the experimental ones (R² = 0.9984 for the proton spectrum and R² = 0.9996 for the carbon spectrum), thus giving further proof of the proposed structure. The details of the calculations are included as Supplementary Materials.

3. Experimental

3.1. General Experimental

All solvents and reagents were purified using standard techniques or used as supplied from commercial sources. Reactions under standard conditions were monitored by thin-layer chromatography (TLC) on silica gel 60 F254 plates. Silica gel (200–300 mesh) was used for column chromatography. NMR spectra were recorded in CDCl₃, at 500 MHz for 1H NMR and 125 MHz for 13C NMR on a Bruker Avance instrument. Chemical shifts are given in (δ) parts per million and coupling constants (J) are given in Hz. ¹H- and ¹³C-spectra were referenced using the solvent signal as an internal standard. The data are reported as follows: s = singlet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, and bs = broad singlet. High-resolution mass spectral analysis (HRMS) data were obtained using a VG AutoSpec spectrometer via electrospray ionization (ESI).

3.2. (R)-3,3,6-Trimethyl-3,3a,4,5-tetrahydro-1H-cyclopenta[c]furan (7)

To a stirred solution of 2 (15 mg, 0,10 mmol) in chloroform (10 mL) were added 5 drops of chloroform saturated with hydrogen chloride. The reaction was checked using TLC and when the starting material was completely consumed, the solvent was evaporated at low temperature and the residue was purified using flash chromatography (95:5 hex:EtOAc), giving the title compound 7 (12 mg, 80%). ¹H NMR (500 MHz, CDCl₃) δ 4.16 (bs, 2H), 3.05 (bs, 1H), 2.77 (bs, 1H), 2.45 (dd, J = 15.5, 10.0 Hz, 1H), 1.87 (dt, J = 12.6, 7.7 Hz, 1H), 1.65 (s, 3H), 1.49 (m, 1H), 1.29 (s, 3H), 0.99 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 142.3, 128.2, 79.7, 62.2, 61.5, 43.4, 27.7, 24.9, 21.8, 14.4. HRMS (ESI-TOF) m/z: (M + Na)⁺ C₁₀H₁₆NaO calcd. 175.1099, found 175.1106.