The first example of macrolactonization of ω -hydroxy acids catalyzed by calcined Mg–Al hydrotalcite

Calcined Mg-Al Hydrotalcites x = 0.20, 0.27, 0.33 proved effective catalysts for the lactonization of 10, 12, 15, and 16 hydroxy acid benzotriazole esters to their correspondent macrolactones. This new methodology was used for the lactonization step in the synthesis of Sansalvamide A.


Introduction
Macrolactones 1 can be prepared indirectly in very good yields by intramolecular condensation of the ω-hydroxy acids. 2 A very practical method for macrolactonization was described by E. P. Boden and G. E. Keck, 3 who used DCC, DMAP, and DMAP•HCl to inhibit the formation of Nacylurea in the Steglich esterification. 4Recently, our group developed an efficient macrolactonization protocol using benzotriazole esters and DMAP. 5 This paper presents a new protocol based on the use of synthetic hydrotalcites [M 2+ 1-x M 3+ x (OH) 2 ] x+ [A n- x/n •mH 2 O] x-, which are hydrated aluminium-magnesium hydroxides of lamellar structure, in which the excess of positive charge, originated from the Mg 2+ to Al 3+ substitution, is compensated by carbonate anions in the interlayer space.In these compounds, also known as anionic clays, the layers are built up by condensation of MO 6 (M = Mg 2+ or Al 3+ ) octahedral as in brucite [Mg(OH) 2 ].Therefore, hydrotalcite (HT) has OH groups that are shared by three octahedral cations and point to the interlayer space. 6Calcinated hydrotalcites induce dehydration, dehydroxylation, and loss of the charge compensating anions, resulting in mixed oxides with MgO-type structures.These materials have basic properties and can be used instead of the classic base catalysts, needed for the reaction to take place, due to the following advantages: ease of separation of the products, reduction of waste streams, possible regeneration of the catalyst and low cost.These catalysts are very active and have been used for the Knovenagel condensation of aldehydes, 7 syntheses of chalcones and flavones, 8 alkylation of phenol, 9 condensation of formaldehyde and acetaldehyde, 10 selective methylation of aniline and cathecol, 11 cyanosilylation of carbonyl compounds, 12 syntheses of silylated azidohydrins, 13 etc.

Results and Discussion
As a part of our on going research program on the utilization of hydrotalcites for organic syntheses, we describe a novel and efficient lactonization procedure for ω-hydroxy acid benzotriazole esters using AlMgCO 3 -HT with different Mg 2+ /Al 3+ ratios.It is well known that the use of hydroxybenzotriazole (HOBT) avoids N-acylurea formation and generates active esters 1 and 2 (Scheme 1) in situ.Hidrotalcite is used taking into consideration that the basicity of the calcined product can be modified changing the ratio Al:(Al+Mg) ratios (x) of 0.20, 0.27 and 0.33.Hidrotalcites with these ratios were individually prepared, characterized, calcined and used.When the Aldrich Hidrotalcite was used, the lactonization was not fully accomplished.Mg-Al hydrotalcites substituted the classic DMAP base commonly used to form the corresponding macrolactone 3 and the dimer from benzotriazole esters 1 and 2. This is the first time a macrolactonization has been catalyzed by modified Mg-Al hydrotalcites.The corresponding macrolactones were formed in good yields.GC-MS analyses showed that intramolecular reactions predominated over the intermolecular ones, avoiding the formation of dimers (Table 1).I.), compared with authentic samples prepared in the laboratory or obtained as commercial products.
The M 2+ /M 3+ ions ratio can be varied within a limited range.In the case of Mg-Al HT, the lower limit is an atomic ratio of 2/1.Under this value, Al 3+ is present in a neighboring octahedral structure resulting in the formation of Al(OH) 3 .Over a ratio of 3/1, the high population of Mg in this octahedral structure can act as the nucleus in the formation of brucite.

Preparation of macrolactones, high dilution procedure
A solution of HOBT (30 mg, 0.20 mmol), EDC (38 mg, 0.20 mmol) and Hydrotalcite (200 mg) in ethanol-free chloroform (50 mL) was brought to reflux.Then a solution of ω-hydroxy acid 4 (100 mg, 0.16 mmol) in 10 mL of THF was infused via syringe pump for 18 h.After addition was completed, the syringe apparatus was removed and the reaction mixture was cooled to room temperature.The mixture was concentrated and diluted with ether (30 mL) and the hydrotalcite and urea were separated by filtration The filtrate was concentrated under reduced pressure, diluted with ethyl acetate (75 mL), washed with 10% citric acid solution (1X25 mL ), 10% K 2 CO 3 solution (1X25 mL), brine, dried over Na 2 SO 4 and concentrated under vacuum.The crude product was purified through a silica gel column chromatography (25X1.5 cm).Elution was carried out with hexane and then with 70% ethyl acetate-hexane.In this way, Sansalvamide A (5)

Figure 1 .Scheme 2 .
Figure 1.X-ray diffraction patterns of hydrotalcites Mg-Al with x = Al / (Al+Mg) = 0.20, 0.27 and 0.33 are shown; these materials show a crystalline hydrotalcite pattern, indicating the formation of these compounds.