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Article

Highly Efficient and Mild Gold (I) Catalyzed Synthesis of 3,8-Diarylidene-2,7-dioxaspiro[4.4]nonane-1,6-diones

by
Antonia Iazzetti
1,
Dario Allevi
1,
Andrea Calcaterra
2,*,
Giancarlo Fabrizi
2,
Antonella Goggiamani
2,
Giulia Mazzoccanti
2,
Alessio Sferrazza
2,†,
Rosanna Verdiglione
2 and
Valeria Vergine
2
1
Dipartimento di Scienze Biotecnologiche di Base Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Campus di Roma, Largo Francesco Vito 1, 00168 Rome, Italy
2
Department of Chemistry and Technology of Drugs, Sapienza-University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
*
Author to whom correspondence should be addressed.
†
Alessio Sferrazza is Currently a Research Scientist at IRBM S.p.A., Medicinal Chemistry Department, Via Pontina km 30, n. 600, 00071 Pomezia, Italy.
Molecules 2023, 28(1), 300; https://doi.org/10.3390/molecules28010300
Submission received: 13 December 2022 / Revised: 23 December 2022 / Accepted: 27 December 2022 / Published: 30 December 2022
(This article belongs to the Special Issue New Therapeutic Tools against MDR Tumors: Discovery, Synthesis and Evaluation of Bioactive Compounds)
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Abstract

:
The gold-catalyzed cyclization of 2,2-bis(3-arylprop-2-yn1-yl)malonic acid has been proposed as an efficient approach to substituted 3,8-dibenzyl-2,7-dioxaspiro[4.4]nonane-1,6-diones. The reaction proceeds smoothly in mild reaction conditions to give the desired products in quantitative yields in the presence of variously substituted starting materials. In addition, the synthesis of γ-arylidene spirobislactone bearing different substituents on the two aromatic rings has been achieved. This kind of compound could be of great interest in pharmaceutical science given the widespread presence of this scaffold in bioactive natural and synthetic products.

1. Introduction

3,8-dibenzyl-2,7-dioxaspiro[4.4]nonane-1,6-diones are molecules endowed with a complex γ-benzyl-spirobis-γ-lactone scaffold, which gained a great interest from researchers due to their biological activity and appealing conformational features, which include the presence of an element of chirality, namely a stereocenter or a chirality axis. A great number of unique bioactive natural products are endowed with a spirolactone moiety [1]. Among these, some compounds contain a spirobislactone unit or a very similar moiety, as α- and β-levantenolides, biyouyanagin A and B, hyperolactones A and C, clionamide D, longianone (Figure 1) [2]. Moreover, some natural products isolated from Carpesium abrotanoides bearing a similar γ-dilactones scaffold, namely dicarabrol A, dicarabrone C, and dipulchellin A (Figure 1), showed promising biological activities, including anti-inflammatory, antitumor, antiplasmodial, and bactericidal effects [3]. In 2007 a patent reported, among the others, a compound bearing a spirodilactone moiety (Figure 1) with antiviral activity against Flaviviridae family of viruses, in particular HCV [4]. More recently, a granted patent describes the preparation and use of spirobislactones as useful crosslink reagents for the synthesis of polymeric materials to be employed in coating processes for automotive applications [5]. Considering the preparation of spirobislactones, the first synthetic routes have been established by simple methods, using multistep synthesis that includes the cyclization of the two spirolactone rings in separate reaction steps, with low overall yields [6,7,8,9].
Roland et al. reported in 1963 the preparation of spirolactones by the reaction of dibromomalononitrile with two equivalents of ethylene, followed by acid hydrolysis [10]. Kotha et al. afforded spirobislactone scaffold by treating diethyl diallylmalonate with sulfuric acid [11]. The diseleno-derivative of spirobislactone was obtained by a Japanese group as a mixture of diastereoisomers by treating diethyl diallylmalonate with phenylselenyl chloride [12,13]. Maldemy et al. reported the cyclization of malonate derivatives with iodine(III) reagents to afford the spirobislactone [14]. The use of acid, base, and metal catalysis played a key role in the synthetic access to spirobislactones. Bronsted acids as triflic acid or concentrated sulfuric acid have been used in the dilactonization of tert-butyl diallylmalonate [15], and diethyl diallylmalonate, respectively [11]. Fairlamb et al. discovered that the treatment of dimethyl diallylmalonate with the Lewis acid SbF5 generated from HSbF6 during a Pd catalyzed cycloisomerization of 1,6-dienes, afforded instead of the desired monocyclized product a mixture of stereoisomer of the dimethyl spirobislactone [16]. Only one example in literature reported the use of polymer-supported bases like PS-DMAP or PS-BEMP to catalyze the spirodilactonization of phenyl glycidyl ether with dimethyl malonate, in a solvent-free reaction [17]. The use of metal catalysts is without any doubt highly efficient for the spirodilactonization process, starting from acyclic precursors. In 1980s two different groups reported an oxidative spirodilactonization reaction of malonic acid in presence of an alkene catalyzed by Mn(III) acetate [18,19,20]. Copper (II) or silver (I) triflates were used by Adrio et al. [21] and Yang et al. [22], respectively, to afford dilactonization of diallymalonic acid to the spirobislactone scaffold, by intramolecular addition of carboxylic acid to the olefin moiety, which selectively led to a spiro-γ-bislactone.
Recently, the use of gold (I) catalysts for the activation of C-C triple bond opened new horizons for the construction of complex molecular scaffolds [23], including for the synthetic access to spirobislactones starting from dipropargylmalonate derivatives. As shown by the wide range of substrate and product scope reported by a recent review [23], gold(I)-catalyzed activation of alkynes is a consolidated method for the construction of molecular complexity. The first examples of gold(I) activation of alkynes were reported by Teles [24] and Tanaka [25], demonstrating the potential of gold(I) in organic synthesis. Currently, gold(I) complexes are the most efficient catalysts for the electrophilic activation of alkynes, and the formation of new carbon−carbon or carbon−heteroatom bonds can be achieved by using different nucleophiles [26,27,28]. Au(I) complexes usually are linear and two-coordinate, as highlighted by a significant number of alkyne-gold complexes that have been characterized and studied in solution or theoretically. Generally, the most effective catalysts for the activation of alkynes are complexes [LAuL′]X or [LAuX], which contain weakly coordinating neutral (L′) or anionic ligand (X−). These complexes can enter catalytic cycles by ligand (often a nitrile) exchange with the unsaturated substrate. Gold(I) complexes selectively activate π-bonds of alkynes in complex way, which has been explained by relativistic effects. Generally, the nucleophilic Markovnikov attack to η2-[AuL]+-activated alkynes 1 forms trans-alkenyl-gold complexes 2 as intermediates (Scheme 1) [23].
In this field, we recently investigated the gold-catalyzed intramolecular hydroarylation reaction of N-ethoxycarbonyl-N-propargylanilines as effective tool for the preparation of 4-substituted-1,2-dihydroquinolines [29], and the synthesis of polycyclic chromene cores through gold (I)-catalyzed intramolecular hydroarylation reaction [30]. Based on these studies, we evaluated the possibility to obtain a gold (I) synthetic approach to spirobislactones. This class of compounds exhibit remarkable features which justify a continue efforts in the development of synthetic procedures to access them. Additionally, at the best of our knowledge, only few examples of gold(I) catalysis successfully employed for the preparation of spirobislactones have been reported in literature. In 2013, Chiarucci et al. reported the synthesis of γ-vinylbutyrolactones by intramolecular oxaallylic alkylation with alcohols. Starting from dimethyl 2,2-bis((E)-4-hydroxybut-2-en-1-yl)malonate they afforded the corresponding γ-methylenespirobislactone by using IMesAuCl/AgOTf as catalyst [31]. A similar γ,γ′-dibenzylspirobislactone was obtained by Zhu et al. by gold-catalyzed homogeneous oxidative carboheterofunctionalization of diallylmalonic acid, in the presence of phenylboronic acid, SIMesAuCl as catalytst, and selectfluor as an oxidant [32]. Gold nanoparticles stabilized by PEG-tagged imidazolium salts have also been used as recyclable catalysts for the cycloisomerization of γ-alkynoic acids into enol-lactones, among the other products, a γ,γ-divinylspirobislactone was obtained starting from dipropargylmalonic acid [33].
Finally, spirobislactones could be prepared as single enantiomers by using chiral Au(I) complexes, as recently reported by Lin et al. [34]. The application of phosphine-nitrogen chiral ligands and related gold (I) complexes used as catalytic systems for the asymmetric reactions have been patented in Chine from the same group [35].
In this paper are reported the results of our studies that led to the development of a method for the synthesis of spirolactones 5 starting from substituted dialkynylmalonic acids 4 (Scheme 2).

2. Results and Discussion

To start our work, we decided to investigated the Au-catalyzed cyclization of 2,2-bis(arylprop-2-ynyl)malonic acids 4 affording 3,8-diarylidene-2,7-dioxaspiro[4.4]nonane-1,6-diones 5 (Table 1). Our preliminary experiments to establish the best reaction conditions for the conversion of 2,2-bis(3-phenylprop-2-ynyl)malonic acid 4a into the corresponding spirolactone 5a are reported in the following Table 1. No cyclization was observed in presence of palladium catalyst or in presence of Au(III) (Table 1, entry 1,2). In contrast, the use of an electrophilic complex of Au(I) with the Buchwald’s sterically bulky biaryl phosphine ligand JohnPhos and acetonitrile as catalyst (Figure 2), led the formation of the desired product in quantitative yields, and in very mild conditions (Table 1, entry 5). Indeed, the best results were obtained at room temperature, very likely due to the decrease of decomposition reactions.
The reaction scope was investigated by using other 2,2-bis(3-arylprop-2-ynyl)malonic acids (4) (Table 2) in the same conditions optimized for substrate 4a. 2,2-bis(3-arylprop-2-ynyl)malonic acids 4 used for these studies were prepared by alkylation of diethyl malonate 6 with propargyl bromide, followed by two Sonogashira cross-coupling with two different aryl halides. Then, the hydrolysis of functionalized diethyl malonate completes the sequences for the preparation of symmetrical or unsymmetrical substrates 4 to be investigated in the gold-catalyzed spirodilactonization reaction (Scheme 3). Since the substituted malonic acid 4a was obtained in a quantitative yield from the last step, the hydrolysis reaction of the other esters 8 was then performed in sequence with the Au (I)-promoted cyclization (Table 2), without isolating the acids 4.
Under the optimized reaction conditions several derivatives bearing a variety of useful functional groups have been prepared and obtained in a quantitative yield. The synthesized compounds are summarized in Table 2.

3. Materials and Methods

3.1. General Experimental Procedures

Melting points were recorded with a Büchi melting point B-545 and are not corrected. 1H and 13C NMR spectra have been acquired with a Bruker Avance 400 spectrometer operating at 400.13 and 100.6 MHz, respectively, at 300 K in DMSO-d6, using 5 mm diameter glass tubes. Chemical shifts were expressed in ppm and coupling constants (J) in hertz (Hz), approximated to 0.1 Hz. The residual solvent peak was used as an internal reference for 1H and 13C NMR spectra. Data for 1H NMR are reported as follows: chemical shift, multiplicity (br = broad, ovrlp = overlapped, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet), coupling constant, integral. Spectra were processed with the program MestReNova version 6.0.2–5475, FT and zero filling at 64 K. High-resolution (HR) mass spectra were obtained using a Thermo Fischer Exactive mass spectrometer equipped with an ESI source and an Orbitrap analyzer: capillary temperature 275 °C, spray voltage 3.5 kV, sheath gas (N2) 10 arbitrary units, capillary voltage 65 V, tube lens 125 V. Analytical TLC was performed using 0.25 mm Fluka F254 silica gel. The compounds on TLC were revealed by quenching fluorescence (at 254 or 365 nm) using a 4W UV lamp. Otherwise, TLC plates were stained with p-anisaldehyde acidic solution in EtOH or a 10% solution of phosphomolybdic acid in EtOH and heated (T = 120 °C). The product mixture purifications were carried out with silica column chromatography using Fluka 60 Å silica gel (0063–0200 mm, 70–230 mesh). Flash chromatography was performed using 200−400 mesh silica gel. Commercially available reagents and solvents were supplied by Sigma-Aldrich (St. Louis, MI, USA) and used without further purification.

3.2. Procedure for the Screening of Optimal Catalyst, Temperature and Additive for the Gold (I)-Catalyzed Synthesis of 3,8-Dimethylene-2,7-dioxaspiro[4.4]nonane-1,6-diones 5

In a 5 mL Carousel Tube Reactor (Radley Discovery Technology) containing a magnetic stirring bar Au(I) catalyst (0.02 mmol) was dissolved in 1.0 mL of CH2Cl2. Then, 2,2-di(prop-2-ynyl)malonic acid (0.5 mmol) was added and the reaction mixture was stirred for a time ranging from 0.5 to 24 h at a temperature ranging from room temperature to 100 °C. After this time, n-hexane was added to the reaction mixture and then it was centrifuged. The precipitate was separated from the liquid layer to obtain 3,8-dimethylene-2,7-dioxaspiro[4.4]nonane-1,6-dione.

3.3. Procedures for the Synthesis of Stating Materials

Diethyl 2,2-di(prop-2-yl)malonate (7) has been synthetized according to known procedures and their characterization data match our own in all respects [36,37].
diethyl 2,2-di(prop-2-yn-1-yl)malonate (7): colorless oil, 83%. 1H NMR (400 MHz, CDCl3) δ 4.21 (q, J = 7.1 Hz, 4H), 2.96 (d, J = 2.6 Hz, 4H), 2.01 (m, 2H), 1.24 (t, J = 7.1 Hz, 6H). 13C NMR (CDCl3): δ 168.7, 78.5, 71.8, 62.2, 56.4, 22.6, 14.1.

3.4. Typical Procedure for the Preparation of 2,2-Bis(3-phenylprop-2-yn-1-yl)malonate (8a)

Compounds 8a, b, c, f, g, h, i, j, k, l, n have been prepared according to the typical procedure described below, by using suitable aryl iodides.
A flask equipped with a magnetic stirring bar was charged with PdCl2(PPh3)2 (42 mg, 0.06 mmol, 0.02 equiv.) and CuI (22.8 mg, 0.12 mmol, 0.04 equiv.) dissolved in diisopropylamine (12 mL) and N,N-dimethylformamide (6 mL). The resultant solution was stirred under nitrogen at room temperature for 10 min before adding iodobenzene (1346 mg, 736 μL, 6.6 mmol, 2.2 equiv.) and diethyl 2,2-di(prop-2-yn-1-yl)malonate (7) (709 mg, 3.0 mmol, 1.0 equiv.) and stirred for 4 h at room temperature. After this time, the reaction mixture was diluted with Et2O and washed with a saturated NH4Cl solution, HCl 2 N, and with brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 (25–40 μm), eluting with an 80/20 (v/v) n-hexane/AcOEt mixture to obtain 1106 mg (90% yield) of diethyl 2,2-bis(3-phenylprop-2-yn-1-yl)malonate 8a.

3.5. Typical Procedure for the Preparation of Diethyl 2-(3-(3-methoxyphenyl)prop-2-yn-1-yl)-2-(3-phenylprop-2-yn-1-yl)malonate (8d)

Compounds 8d, e, m were prepared according to the typical procedure described below, by using suitable aryl iodides.
A flask equipped with a magnetic stirring bar was charged with a solution of PdCl2(PPh3)2 (42 mg, 0.06 mmol, 0.02 equiv.) and CuI (22.8 mg, 0.12 mmol, 0.04 equiv.) in diisopropylamine (12 mL) and N,N-dimethylformamide (6 mL), iodobenzene (673 mg, 368 μL, 3.3 mmol, 1.1 equiv.) and diethyl 2,2-di(prop-2-yn-1-yl)malonate (7) (709 mg, 3.0 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature under argon for 4 h before adding 1-iodo-3-methoxybenzene (772 mg, 3.3 mmol, 1.1 equiv.). After 6 h, the mixture was diluted with Et2O and washed with a saturated NH4Cl solution, HCl 2 N, and with brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 (25–40 μm), eluting with an 80/20 (v/v) n-hexane/AcOEt mixture to obtain 628 mg (50% yield) of 2-(3-(3-methoxyphenyl)prop-2-yn-1-yl)-2-(3-phenylprop-2-yn-1-yl)malonate (8d).
diethyl 2,2-bis(3-phenylprop-2-yn-1-yl)malonate (8a): yellow pale oil. 1H NMR (400 MHz, CDCl3) δ 7.44–7.37 (m, 4H), 7.30 (m, 6H), 4.30 (q, J = 7.1 Hz, 4H), 3.30 (s, 4H), 1.31 (t, J = 7.1 Hz, 8H). 13C NMR (101 MHz, CDCl3) δ 169.0, 131.8, 128.3, 128.1, 123.2, 84.2, 83.8, 62.1, 57.2, 23.8, 14.2.
diethyl 2,2-bis(3-(4-methoxyphenyl)prop-2-yn-1-yl)malonate (8c): yellow pale oil. 1H NMR (CDCl3): δ 7.33 (d, J = 8.3 Hz, 4H), 6.82 (d, J = 8.3 Hz, 4H), 4.28 (q, J = 7.0 Hz, 4H), 3.81 (s, 6H), 3.25 (s, 4H), 1.30 (t, J = 7.0 Hz, 6H). 13C NMR (CDCl3): δ 169.2, 159.4, 133.1, 115.4, 113.9, 83.5, 82.7, 62.0, 57.3, 55.4, 23.8, 14.2.
diethyl 2-(3-(4-methoxyphenyl)prop-2-yn-1-yl)-2-(3-phenylprop-2-yn-1-yl)malonate (8d): yellow pale oil. 1H NMR (CDCl3): δ 7.45–7.36 (m, 2H), 7.31 (m, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.01 (d, J = 7.4 Hz, 1H), 6.94 (br s, 1H), 6.87 (m, 1H), 4.30 (q, J = 7.1 Hz, 4H), 3.81 (s, 3H), 3.29 (s, 4H), 1.31 (t, J = 7.2 Hz, 6H). 13C NMR (CDCl3): δ 169.0, 159.4, 131.8, 129.4, 128.3, 128.1, 124.4, 124.3, 123.2, 116.7, 114.6, 84.2, 84.1, 83.8, 83.7, 62.1, 57.2, 55.3, 29.8, 23.8, 14.2.
diethyl 2,2-bis(3-(4-methylphenyl)prop-2-yn-1-yl)malonate (8f): yellow pale oil. 1H NMR (400 MHz, CDCl3): δ 7.30 (d, J = 8.0 Hz, 4H), 7.10 (d, J = 7.8 Hz, 4H), 4.29 (q, J = 7.1 Hz, 4H), 3.28 (s, 4H), 2.35 (s, 6H), 1.30 (t, J = 7.1 Hz, 6H). 13C NMR (CDCl3): δ 169.0, 138.1, 131.6, 129.0, 120.2, 83.8, 83.5, 62.0, 60.4, 57.3, 23.8, 21.5, 14.2.
diethyl 2,2-bis(3-(naphthalen-1-yl)prop-2-yn-1-yl)malonate (8g): yellow pale oil. 1H NMR (CDCl3): δ 8.34 (d, J = 8.2 Hz, 2H), 7.82 (dd, J = 12.2, 8.2 Hz, 6H), 7.65 (d, J = 7.0 Hz, 2H), 7.60–7.46 (m, 6H), 7.40 (t, J = 7.7 Hz, 2H), 4.33 (q, J = 7.1 Hz, 4H), 3.54 (s, 4H), 1.31 (t, J = 7.1 Hz, 6H). 13C NMR (CDCl3): δ 169.3, 133.6, 133.3, 130.7, 128.6, 128.4, 126.9, 126.5, 126.4, 125.3, 121.0, 89.2, 82.0, 62.3, 57.3, 24.5, 14.3.
diethyl 2,2-bis(3-(4-bromo-3-fluorophenyl)prop-2-yn-1-yl)malonate (8i): yellow pale oil. 1H NMR (CDCl3): δ 7.47 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 9.1 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.23 (s, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3): δ 168.8, 160.0, 157.5, 133.5, 128.7, 128.7, 124.2, 124.1, 119.7, 119.5, 109.6, 109.4, 86.3, 82.1, 62.3, 56.9, 23.9, 14.3.
diethyl 2,2-bis(3-(4-chlorophenyl)prop-2-yn-1-yl)malonate (8j): yellow pale oil. 1H NMR (CDCl3): δ 7.32 (d, J = 8.6 Hz, 4H), 7.29–7.23 (m, 4H), 4.29 (q, J = 7.1 Hz, 4H), 3.25 (s, 4H), 1.30 (t, J = 7.1 Hz, 6H). 13C NMR (CDCl3): δ 168.9, 134.2, 133.0, 128.7, 121.7, 85.3, 82.8, 62.2, 57.1, 23.9, 14.2.
diethyl 2,2-bis(3-(4-bromophenyl)prop-2-yn-1-yl)malonate (8k): yellow pale oil. 1H NMR (CDCl3): δ 7.43 (d, J = 8.2 Hz, 4H), 7.26 (t, J = 8.8 Hz, 4H), 4.28 (q, J = 7.1 Hz, 4H), 3.25 (s, 4H), 1.29 (t, J = 7.0 Hz, 6H). 13C NMR (CDCl3): δ 168.9, 139.2, 133.6, 133.2, 131.6, 122.4, 122.1, 85.5, 82.9, 62.2, 57.0, 23.9, 14.2.
diethyl 2,2-bis(3-(2-methyl-5-nitrophenyl)prop-2-yn-1-yl)malonate (8l): yellow pale oil. 1H NMR (CDCl3): δ 8.18 (d, J = 1.8 Hz, 2H), 8.02 (dd, J = 8.4, 1.9 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 4.28 (q, J = 7.1 Hz, 4H), 3.34 (s, 4H), 2.49 (s, 6H), 1.29 (t, J = 7.1 Hz, 6H). 13C NMR (CDCl3): δ 168.7, 147.8, 146.1, 130.3, 127.0, 124.4, 122.9, 90.6, 80.8, 62.4, 56.7, 24.1, 21.1, 14.2.
diethyl 2-(3-(4-chlorophenyl)prop-2-yn-1-yl)-2-(3-(4-methoxyphenyl)prop-2-yn-1-yl)malonate (8m): yellow pale oil. 1H NMR (CDCl3): δ 7.30 (d, J = 3.6 Hz, 2H), 7.28 (d, J = 3.6 Hz, 3H), 7.23 (d, J = 8.5 Hz, 3H), 6.78 (d, J = 8.7 Hz, 2H), 4.25 (q, J = 7.1 Hz, 4H), 3.77 (s, 3H), 3.22 (d, J = 9.1 Hz, 4H), 1.32–1.19 (J = 7.1 Hz, 6H). 13C NMR (CDCl3): δ 169.0, 159.5, 134.1, 133.1, 133.0, 128.6, 121.8, 115.3, 113.9, 85.5, 83.7, 82.7, 82.5, 62.1, 57.2, 55.3, 23.9, 23.8, 14.2.
diethyl 2,2-bis(3-(2-methoxyphenyl)prop-2-yn-1-yl)malonate (8n): yellow pale oil. 1H NMR (CDCl3): δ 7.33 (dd, J = 7.5, 1.4 Hz, 2H), 7.25–7.20 (m, 2H), 6.86–6.81 (m, 4H), 4.24 (q, J = 7.1 Hz, 4H), 3.83 (s, 6H), 3.33 (s, 4H), 1.26 (t, J = 7.1 Hz, 6H). 13C NMR (CDCl3): δ 169.1, 160.2, 133.8, 129.4, 120.4, 112.7, 110.8, 88.7, 79.9, 62.0, 57.5, 55.8, 24.1, 14.2.

3.6. General Procedure for the Synthesis of 3,8-Dimethylenespiro[4.4]nonane-1,6-diones (5)

In a 10 mL round bottom flask, 2,2 disubstituted diethyl malonate (8) (0.5 mmol) was dissolved in 2 mL of EtOH and 1 mL of NaOH 2N was added. The reaction mixture was heated at reflux and stirred for one hour. After cooling, the reaction mixture was acidified with conc. HCl, diluted with Et2O, and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was used without further purification in the next step. In a 5 mL Carousel Tube Reactor (Radley Discovery Technology) containing a magnetic stirring bar JohnPhos Au(MeCN)SbF6 catalyst (0.02 mmol) was dissolved at room temperature in 1.0 mL of CH2Cl2. Then, 2,2-disubstituted malonic acid (0.5 mmol) was added and the reaction mixture was stirred for 1 h at room temperature. After this time, n-hexane was added to the reaction mixture and then it was centrifuged. The precipitate was separated from the liquid layer to obtain 3,8-dimethylene-2,7-dioxaspiro[4.4]nonane-1,6-dione or the corresponding substituted derivative in 96–100% yield.
3,8-dibenzylidene-2,7-dioxaspiro[4.4]nonane-1,6-dione (5a):1H NMR (DMSO): δ 7.52 (s, 2H), 7.38 (d, J = 6.2 Hz, 2H), 7.25 (s, 1H), 5.87 (s, 1H), 3.63 (d, J = 16.3 Hz, 1H), 3.37 (d, J = 22.0 Hz, 2H). 13C NMR (DMSO): δ 171.8, 146.0, 133.6, 128.6, 128.1, 126.9, 104.5, 36.4. HRMS (ESI Orbitrap) m/z 333.11245 [M + H]+ (calcd for C21H17O4+, 333.11214), 355.09397 [M + Na]+ (calcd for C21H16O4Na+, 355.09408).
3,8-dimethylene-2,7-dioxaspiro[4.4]nonane-1,6-dione (5b): white solid; mp: 60–61 °C. 1H NMR (DMSO): δ 4.82 (m, 2H), 4.54 (br s, 2H), 3.41 (d, J = 17.3 Hz, 2H), 3.14 (d, J = 17.3 Hz, 2H); 13C NMR (DMSO): δ 168.6, 131.7, 128.2, 62.1, 56.8, 36.1. HRMS (ESI Orbitrap) m/z 181.04937 [M + H]+ (calcd for C9H9O4+, 181.04954), 203.03167 [M + Na]+ (calcd for C9H8O4Na+, 203.03148).
3,8-bis(4-methoxybenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5c): white solid; mp: 50–51 °C. 1H NMR (DMSO): δ 7.26 (t, J = 8.0 Hz, 2H), 7.10–7.05 (m, 4H), 6.80 (dd, J1,2 = 6.0 Hz, J2,3 = 2.0 Hz, 2H), 5.81 (s, 2H), 5.73 (s, 1H), 3.73 (s, 6H), 3.58 (d, J = 17.6 Hz, 2H), 3.32 (d, J = 17.6 Hz, 2H); 13C NMR (DMSO): δ 172.2, 159.8, 146.6, 135.3, 130.1, 121.1, 114.2, 112.7, 104.9, 55.5, 50.6, 36.9. HRMS (ESI Orbitrap) m/z 393.13553 [M + H]+ (calcd for C23H21O6+, 393.13326), 415.11464 [M + Na]+ (calcd for C23H20NaO6+, 415.11521).
3-benzylidene-8-(3-methoxybenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5d): white solid; mp: 40–41 °C. 1H NMR (DMSO): δ 7.53 (d, J = 7.2 Hz, 2H), 7.39–7.25 (m, 4H), 7.13–7.08 (m, 2H), 6.84 (d, J = 7.2 Hz, 1H), 5.87–5.85 (m, 2H), 3.76 (s, 3H), 3.62 (d, J = 17.2 Hz, 2H), 3.37 (d, J = 17.2 Hz, 2H); 13C NMR (DMSO): δ 172.2, 159.8, 146.6, 146.4, 135.3, 134.0, 130.1, 129.1, 128.6, 127.3, 121.1, 114.3, 112.7, 105.0, 104.9, 55.5, 50.6, 36.9. HRMS (ESI Orbitrap) m/z 363.12143 [M + H]+ (calcd for C22H19O5+, 363.12270), 385.10529 [M + Na]+ (calcd for C22H18NaO5+, 385.10464).
3-(4-acetylbenzylidene)-8-benzylidene-2,7-dioxaspiro[4.4]nonane-1,6-dione (5e): white solid; mp: 45–46 °C. 1H NMR (DMSO): δ 7.97 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 7.2 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.24 (t, J = 7.6 Hz, 1H), 5.98 (s, 1H), 5.88 (s, 1H), 3.69–3.61 (m, 2H), 3.43–3.35 (m, 4H); 13C NMR (DMSO): δ 197.7, 172.2, 172.1, 148.9, 146.4, 138.8, 135.3, 134.0, 129.1, 129.1, 128.6, 127.3, 105.0, 104.2, 50.6, 37.1, 36.9, 27.1. HRMS (ESI Orbitrap) m/z 375.12211 [M + H]+ (calcd for C23H19O5+, 375.12270), 397.10425 [M + Na]+ (calcd for C23H18NaO5+, 397.10464).
3,8-bis(4-methylbenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5f): white solid; mp: 55–56 °C. 1H NMR (DMSO): δ 7.42 (d, J = 7.8 Hz, 4H), 7.19 (d, J = 7.2 Hz, 4H), 5.81 (s, 2H), 3.60 (d, J = 16.8 Hz, 2H), 3.36 (d, J = 16.8 Hz, 2H), 2.30 (s, 6H); 13C NMR (DMSO): δ 172.3, 145.6, 136.6, 131.2, 129.6, 128.5, 104.9, 50.7, 36.9, 21.2. HRMS (ESI Orbitrap) m/z 361.14517 [M + H]+ (calcd for C23H21O4+, 361.14344), 383.12479 [M + Na]+ (calcd for C23H20NaO4+, 383.12538).
3,8-bis(naphthalen-1-ylmethylene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5g): white solid; mp: 45–46 °C. 1H NMR (DMSO): δ 8.20 (d, J = 7.6 Hz, 2H), 7.96 (d, J = 7.4 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 7.1 Hz, 1H), 7.57 (m, 6H), 6.61 (s, 1H), 3.80 (d, J = 17.2 Hz, 1H), 3.55 (d, J = 17.2 Hz, 1H); 13C NMR (DMSO): δ 172.4, 147.9, 133.8, 131.1, 130.4, 128.9 127.8, 127.1, 126.7, 126.4, 126.0, 124.6, 101.7, 51.3, 36.9. HRMS (ESI Orbitrap) m/z 433.14383 [M + H]+ (calcd for C29H21O4+, 433.14344), 455.12643 [M + Na]+ (calcd for C29H20NaO4+, 455.12538).
3,8-bis(3-methoxybenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5h): white solid; mp: 65–66 °C. 1H NMR (DMSO): δ 7.30 (t, J = 8.0 Hz, 2H), 7.13 (d, J = 7.7 Hz, 2H), 7.09 (s, 2H), 6.88–6.82 (m, 2H), 5.85 (s, 2H), 3.77 (s, 3H) 3.62 (d, J = 17.4 Hz, 2H), 3.37 (d, J = 17.4 Hz, 2H); 13C NMR (DMSO): δ 172.2, 159.8, 146.6, 135.3, 130.1, 121.1, 114.3, 112.8, 104.9, 55.5, 50.6, 36.9. HRMS (ESI Orbitrap) m/z 393,13415 [M + H]+ (calcd for C23H21O6+, 393,13326), 415.11583 [M + Na]+ (calcd for C23H20NaO6+, 415.11521).
3,8-bis(4-bromo-3-fluorobenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5i): white solid; mp: 65–66 °C. 1H NMR (DMSO): δ 7.72 (t, J = 8.0 Hz, 2H), 7.46 (d, J = 10.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 5.92 (s, 2H), 3.64 (d, J = 17.6 Hz, 2H), 3.38 (d, J = 17.6 Hz, 2H); 13C NMR (DMSO): δ 171.8, 159.9, 157.5, 148.4, 136.0, 135.9, 134.1, 126.2, 116.2, 116.0, 106.4, 106.2, 103.1, 50.5, 36.9. HRMS (ESI Orbitrap) m/z 524.91356 [M + H]+ (calcd for C21H13Br2F2O4+, 524.91432), 546.89517 [M + Na]+ (calcd for C21H12Br2F2NaO4+, 546.89626).
3,8-bis(4-chlorobenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5j): white solid; mp: 65–66 °C. 1H NMR (DMSO): δ 7.51 (d, J = 7.6 Hz, 4H), 7.41 (d, J = 7.6 Hz, 4H), 5.86 (m, 2H), 3.59 (d, J = 17.2 Hz, 2H), 3.34 (d, J = 17.2 Hz, 2H); 13C NMR (DMSO): δ 172.0, 147.2, 133.0, 131.7, 130.2, 129.1, 103.8, 50.6, 36.9. HRMS (ESI Orbitrap) m/z 401.03474 [M + H]+ (calcd for C21H15Cl2O4+, 401.03419), 423.01581 [M + Na]+ (calcd for C21H14Cl2NaO4+, 423.01614).
3,8-bis(4-bromobenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5k): white solid; mp: 67–68 °C. 1H NMR (DMSO): δ 7.58 (d, J = 8.4 Hz, 4H), 7.48 (d, J = 8.4 Hz, 4H), 5.88 (s, 2H), 3.62 (d, J = 18.0 Hz, 2H), 3.35 (d, J = 18.0 Hz, 2H); 13C NMR (DMSO): δ 172.0, 147.3, 133.3, 132.0, 130.5, 120.2, 103.9, 50.6, 36.9. HRMS (ESI Orbitrap) m/z 488.93451 [M + H]+ (calcd for C21H15Br2O4+, 488.93316), 510.91493 [M + Na]+ (calcd for C21H14Br2NaO4+, 510.91511).
3,8-bis(2-methyl-5-nitrobenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5l): white solid; mp: 57–58 °C. 1H NMR (DMSO): δ 8.46 (d, J = 2.4 Hz, 2H), 8.03 (dd, J1,2 = 6.0 Hz, J2,3 = 2.4 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 6.09 (s,2H), 3.75 (d, J = 18.0 Hz, 2H), 3.46 (d, J = 18.0 Hz, 2H), 2.45 (s, 6H); 13C NMR (DMSO): δ 171.9, 149.0, 146.4, 144.2, 134.1, 131.8, 123.2, 122.0, 100.9, 50.9, 37.0, 20.4. HRMS (ESI Orbitrap) m/z 451.11426 [M + H]+ (calcd for C23H19N2O8+, 451.11359), 473.09627 [M + Na]+ (calcd for C23H18N2NaO8+, 473.09554).
3-(4-chlorobenzylidene)-8-(4-methoxybenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5m): white solid; mp: 55–56 °C. 1H NMR (DMSO): δ 7.54 (d, J = 8.4 Hz, 2H), 7.46 (t, J = 7.2 Hz, 4H), 6.95 (d, J = 8.8 Hz, 2H), 5.89 (s,1H), 5.80 (s, 1H), 3.76 (s, 3H), 3.60 (d, J = 18.0 Hz, 2H), 3.46 (d, J = 18.0 Hz, 2H); 13C NMR (DMSO): δ 171.7, 171.6, 158.1, 146.7, 144.0, 132.5, 131.1, 129.7, 129.4, 128.6, 126.1, 125.7, 114.1, 114.0, 104.2, 103.4, 103.3, 97.3, 55.1, 50.2, 36.5, 36.3. HRMS (ESI Orbitrap) m/z 397.08365 [M + H]+ (calcd C22H18ClO5+, 397.08373), 419.06529 [M + Na]+ (calcd for C22H17ClNaO5+, 419.06567).
3,8-bis(2-methoxybenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5n): white solid; mp: 61–62 °C. 1H NMR (DMSO): δ 7.69 (dd, J = 7.8, 1.4 Hz, 2H), 7.29–7.22 (m, 2H), 7.03 (d, J = 8.3 Hz, 2H), 6.99 (t, J = 7.8 Hz, 2H), 6.04 (s, 2H), 3.82 (s, 6H), 3.67 (dd, J = 17.3, 1.6 Hz, 2H), 3.38 (dd, J = 17.3, 1.6 Hz, 2H). 13C NMR (DMSO): δ 172.3, 156.0, 146.3, 129.4, 128.8, 122.2, 120.9, 111.5, 98.9, 56.0, 50.8, 37.1. HRMS (ESI Orbitrap) m/z 393.13428 [M + H]+ (calcd for C23H21O6+, 393.13326), 415.11581 [M + Na]+ (calcd for C23H20NaO6+, 415.11521).

4. Conclusions

The activation of alkynes by gold(I) complexes is a versatile tool for the selective functionalization of C-C triple bond with several nucleophiles, including heteroatoms. The intramolecular version of this reaction leads to cyclic or heterocyclic intermediates, that are useful for the synthesis of high value pharmaceutically relevant compounds. We demonstrated that functionalized symmetric or unsymmetric biarylacetylenic malonic acids may be efficiently cyclized under extremely mild conditions at room temperature in presence of JohnPhosAu(MeCN)SbF6 catalyst, and without any additives. The corresponding γ-arylmethylene-spirobislactones were isolated in excellent yields (96–100%). This process constitutes an easy and efficient access to highly valuable building blocks of natural products or biologically active compounds. The high reactivity of gold(I) catalyst towards the activation of C-C triple bond, associated with very mild reactions conditions would allow further synthesis of lactones.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28010300/s1, Figure S1: 1H NMR of 3,8-dibenzylidene-2,7-dioxaspiro[4.4]nonane-1,6-dione (5a); Figure S2: 13C NMR of 3,8-dibenzylidene-2,7-dioxaspiro[4.4]nonane-1,6-dione (5a); Figure S3: 1H NMR of 3,8-dimethylene-2,7-dioxaspiro[4.4]nonane-1,6-dione (5b); Figure S4: 13C NMR of 3,8-dimethylene-2,7-dioxaspiro[4.4]nonane-1,6-dione (5b); Figure S5: 1H NMR of 3,8-bis(4-methoxybenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5c); Figure S6: 13C NMR of 3,8-bis(4-methoxybenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5c); Figure S7: 1H NMR of 3-benzylidene-8-(3-methoxybenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5d); Figure S8: 13C NMR of 3-benzylidene-8-(3-methoxybenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5d); Figure S9: 1H NMR of 3-(4-acetylbenzylidene)-8-benzylidene-2,7-dioxaspiro[4.4]nonane-1,6-dione (5e); Figure S10: 13C NMR of 3-(4-acetylbenzylidene)-8-benzylidene-2,7-dioxaspiro[4.4]nonane-1,6-dione (5e); Figure S11: 1H NMR of 3,8-bis(4-methylbenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5f); Figure S12: 13C NMR of 3,8-bis(4-methylbenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5f); Figure S13: 1H NMR of 3,8-bis(naphthalen-1-ylmethylene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5g); Figure S14: 1H NMR of 3,8-bis(naphthalen-1-ylmethylene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5g); Figure S15: 1H NMR of 3,8-bis(3-methoxybenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5h); Figure S16: 13C NMR of 3,8-bis(3-methoxybenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5h); Figure S17: 1H NMR of 3,8-bis(4-bromo-3-fluorobenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5i); Figure S18: 13C NMR of 3,8-bis(4-bromo-3-fluorobenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5i); Figure S19: 1H NMR of 3,8-bis(4-chlorobenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5j); Figure S20: 13C NMR of 3,8-bis(4-chlorobenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5j); Figure S21: 1H NMR of 3,8-bis(4-bromobenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5k); Figure S22: 13C NMR of 3,8-bis(4-bromobenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5k); Figure S23: 1H NMR of 3,8-bis(2-methyl-5-nitrobenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5l); Figure S24. 13C NMR of 3,8-bis(2-methyl-5-nitrobenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5l); Figure S25: 1H NMR of 3-(4-chlorobenzylidene)-8-(4-methoxybenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5m); Figure S26: 13C NMR of 3-(4-chlorobenzylidene)-8-(4-methoxybenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5m); Figure S27: 1H NMR of 3,8-bis(2-methoxybenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5n); Figure S28: 1H NMR of 3,8-bis(2-methoxybenzylidene)-2,7-dioxaspiro[4.4]nonane-1,6-dione (5n).

Author Contributions

A.I.: writing, editing and revision. D.A.: synthesis of compounds. A.C.: conceptualization, methodology, writing and editing the draft. G.F. and A.G.: conceptualization, methodology, revision, and advice. G.M. and V.V.: chromatography and compound purification. A.I., A.S. and R.V.: synthesis of compounds and NMR. G.F. funding acquisition. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the MIUR (Ministry of Education University and Research) under Grant number 2017SXBSX4 (PRIN project 2017, “Targeting Hedgehog pathway: virtual screening identification and sustainable synthesis of novel Smo and Gli inhibitors and their pharmacological drug delivery strategies for improved therapeutic effects in tumors”); MIUR under the Excellence Departments Grant to the Department of Chemistry and Technology of Drugs, and Sapienza University of Rome under Grant “Progetti Ateneo 2019”.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data is contained within the article or supplementary material.

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 28 00300 g001 550
Figure 1. Bioactive natural and synthetic products containing spirobislactone moiety or similar scaffold.
Figure 1. Bioactive natural and synthetic products containing spirobislactone moiety or similar scaffold.
Molecules 28 00300 g001
Molecules 28 00300 sch001 550
Scheme 1. Activation of alkynes by electrophilic Au(I) complexes and nucleophilic addition to the C-C triple bond. A labile ligand (L′) is exchanged with the alkyne, forming a π-complex (2), followed by the anti-addition of a nucleophile to the η2-[AuL]+-activated alkyne (2).
Scheme 1. Activation of alkynes by electrophilic Au(I) complexes and nucleophilic addition to the C-C triple bond. A labile ligand (L′) is exchanged with the alkyne, forming a π-complex (2), followed by the anti-addition of a nucleophile to the η2-[AuL]+-activated alkyne (2).
Molecules 28 00300 sch001
Molecules 28 00300 sch002 550
Scheme 2. Work hypothesis.
Scheme 2. Work hypothesis.
Molecules 28 00300 sch002
Molecules 28 00300 g002 550
Figure 2. Chemical structure of JohnPhosAu(MeCN)SbF6 catalyst.
Figure 2. Chemical structure of JohnPhosAu(MeCN)SbF6 catalyst.
Molecules 28 00300 g002
Molecules 28 00300 sch003 550
Scheme 3. Synthesis of symmetrical or unsymmetrical diethyl diarylalkynylmalonates 8 and diarylalkynylmalonic acids 4.
Scheme 3. Synthesis of symmetrical or unsymmetrical diethyl diarylalkynylmalonates 8 and diarylalkynylmalonic acids 4.
Molecules 28 00300 sch003
Table
Table 1. Screening for the best catalyst and reaction conditions for the spirodilactonization to γ-arylmethylene-spirobislactones 5: cyclization of 2,2-bis(3-phenylprop-2-yn-1-yl)malonic acid 4a to 3,8-benzylidene-2,7-dioxaspiro[4.4]nonane-1,6-diones 5a a,b.
Table 1. Screening for the best catalyst and reaction conditions for the spirodilactonization to γ-arylmethylene-spirobislactones 5: cyclization of 2,2-bis(3-phenylprop-2-yn-1-yl)malonic acid 4a to 3,8-benzylidene-2,7-dioxaspiro[4.4]nonane-1,6-diones 5a a,b.
Molecules 28 00300 i001
EntryCatalystBaseSolventT (°C)t (h)Yield 5a (%)
1PdCl2(CH3CN)2K2CO3 cMeCN8024-
2NaAuCl4-EtOH10012-
3JohnPhosAu
(MeCN)SbF6		-DCM80190
4JohnPhosAu
(MeCN)SbF6 d		-DCM40199
5JohnPhosAu
(MeCN)SbF6 d		-DCMrt1100
a Reactions were carried out on a 0.5 mmol scale in 2.0 mL of solvent using 0.05 equiv. of catalyst. b Yields are given for isolated compounds. c 2.0 equiv. of base were used. d 0.02 equiv of catalyst were used.
Table
Table 2. Substrate scope for the gold(I)-catalyzed spirodilactonization to γ-arylidenespirobislactones 5 a,b.
Table 2. Substrate scope for the gold(I)-catalyzed spirodilactonization to γ-arylidenespirobislactones 5 a,b.
Molecules 28 00300 i002
EntryAr1Ar2t (h)Yield of 5 (%)
1PhPh15a 100
2HH15b 100
34-OCH3-C6H4-4-OCH3-C6H4-0.55c 96
43-OCH3-C6H4-Ph-15d 98
5Ph-4-COCH3-C6H4-0.55e 99
64-CH3-C6H44-CH3-C6H4-15f 98
71-naphtyl1-naphtyl15g 100
83-OCH3-C6H4-3-OCH3-C6H4-15h 97
94-Br-3-F-C6H3-4-Br-3-F-C6H2-0.55i 100
104-Cl-C6H4-4-Cl-C6H4-15j 100
114-Br-C6H4-4-Br-C6H4-15k 99
122-CH3,5-NO2-C6H3-2-CH3,5-NO2-C6H3-15l 98
134-Cl-C6H4-4-OCH3-C6H4-15m 97
142-OCH3-C6H4-2-OCH3-C6H4-15n 98
a Reactions were carried out on a 0.5 mmol scale in 2.0 mL of CH2Cl2 using 0.02 equiv. of catalyst at rt, under air. b Yields are given for isolated compounds.
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MDPI and ACS Style

Iazzetti, A.; Allevi, D.; Calcaterra, A.; Fabrizi, G.; Goggiamani, A.; Mazzoccanti, G.; Sferrazza, A.; Verdiglione, R.; Vergine, V. Highly Efficient and Mild Gold (I) Catalyzed Synthesis of 3,8-Diarylidene-2,7-dioxaspiro[4.4]nonane-1,6-diones. Molecules 2023, 28, 300. https://doi.org/10.3390/molecules28010300

AMA Style

Iazzetti A, Allevi D, Calcaterra A, Fabrizi G, Goggiamani A, Mazzoccanti G, Sferrazza A, Verdiglione R, Vergine V. Highly Efficient and Mild Gold (I) Catalyzed Synthesis of 3,8-Diarylidene-2,7-dioxaspiro[4.4]nonane-1,6-diones. Molecules. 2023; 28(1):300. https://doi.org/10.3390/molecules28010300

Chicago/Turabian Style

Iazzetti, Antonia, Dario Allevi, Andrea Calcaterra, Giancarlo Fabrizi, Antonella Goggiamani, Giulia Mazzoccanti, Alessio Sferrazza, Rosanna Verdiglione, and Valeria Vergine. 2023. "Highly Efficient and Mild Gold (I) Catalyzed Synthesis of 3,8-Diarylidene-2,7-dioxaspiro[4.4]nonane-1,6-diones" Molecules 28, no. 1: 300. https://doi.org/10.3390/molecules28010300

APA Style

Iazzetti, A., Allevi, D., Calcaterra, A., Fabrizi, G., Goggiamani, A., Mazzoccanti, G., Sferrazza, A., Verdiglione, R., & Vergine, V. (2023). Highly Efficient and Mild Gold (I) Catalyzed Synthesis of 3,8-Diarylidene-2,7-dioxaspiro[4.4]nonane-1,6-diones. Molecules, 28(1), 300. https://doi.org/10.3390/molecules28010300

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