Carboxy lactones, preparation

Almotriptan has also been synthesized via decarboxylation of the carboxylic acid intermediate 65, but a detailed preparation of 65 was not provided in the patent literature (Scheme 22)." The patent indicates that the carboxy indole 65 was prepared according to the method of Gonzalez.°° Thus, (2-oxo-tetrahydro-3-furanyl)-glyoxylic acid ethyl ester (62) was heated in aqueous H2SO4 to give 2-oxo-5-hydroxypentanoic acid in situ, which was treated with hydrazine 59 to produce hydrazone 63. Fischer cyclization of 63 using HCl gas in DMF gave the lactone 64, which was converted to carboxylic acid 65. Decarboxylation of 65 was catalyzed by cuprous oxide in quinoline at 190 °C to afford almotriptan (5)." ... 

The procedure is a detailed description of the Austin and Howard preparation. The mechanism presumably Involves anchimeric assistance of the carboxy group in decomposition of an intermediate diazonium 1on, leading to a labile o-lactone ... 

Ozonation of 2-Carboxy-4-nitro-N,N-dimethylaniline (I). The amine (2.10 grams, 10 mmoles) was dissolved in the appropriate solvents (200 ml methanol, ethyl acetate, or methylene chloride) and ozonized at 0°C with equimolar amounts of ozone quantitative absorption occurred. Near the end of the ozonation time, a precipitate formed. In ozonations in methanol this substance was identical with lactone III mp 176°-177°C, prepared according to Villiger (10). In the other solvents the insoluble product was the demethylated starting material, mp 265°-268°C (dec.) reported mp 263°-264°C (11). The mother liquor was evaporated, and the two compounds were separated by fractional crystallization. The results are shown in Table I. 

An interesting route to a-carboxy-8-lactones (81) and a-methylenelactones (80), based on hydrolysis of Knoevenagel products (79) of Meldrum s acid with cyclic aliphatic ketones (78), has been developed (Scheme 14). Reduction of 5-methylene derivatives of Meldrum s acid has been performed catalyti-caiiyi30 or by use of LAH. Imidoylation reaction of Meldrum s acid and subsequent solvolysis of the resulting (82) yields -enamino esters (83) in good yields.Flash vacuum pyrolysis of alkylidene derivatives of Meldrum s acid can be used to prepare methylene ketenes (84), a class of compounds difficult to prepare by conventional methods. By this procedure, methylene ketenes are obtained from aromatic aldehydes and ketones and from aliphatic ketones in only two steps. Intramolecular trapping of the methylene ketene obtained from the ketone (85) has been used successfully in the synthesis of the naphthol (86). ... 

Adam and his co-workers have shown that sterically congested E-olefins are conveniently prepared by the lactone route shown in Scheme 7. Stereocontrol is achieved because a-lithiocarboxylates condense with aldehydes and ketones to give -hydroxy acids of predominantly r/ireo-configuration once formed, dehydrative cyclization is straightforward because the bulky substituents force the carboxy and hydroxy groups into juxtaposition. 

In an early application, the aqueous Diels-Alder reaction of diene carboxy-lates was used to effect a very concise synthesis of the vemolepin precursor 5.2 [60]. This compound had previously been prepared by Schlessinger via another route in 11 steps from ethyl crotonate [61]. Reaction of the substituted methacrolein 5.3 with sodium ( )-3,5-hexadienoate (5.4) in water proceeded at 50 C to give the Diels-Alder endo adduct 5.5 along with a minor amount of the exo adduct (not shown) quantitatively in a ratio of 10/1 (Scheme 1.4). Sodium borohydride was added directly to this reaction mixture to produce the 6-hydroxycarboxylate 5.6, which lactonized spontaneously upon acidic workup. This one-pot operation resulted in the isolation of vemolepin AB-ring... 

The bromo-alkoxylation route for the synthesis of crown ethers (6,189 5,178) has been adapted to allow the preparation of substituted mono- and di-thia-crown systems (Scheme 49). Once again, one of these sequences uses the cyclization that is effected by a sulphonyl chloride and a base, as does a recently reported preparation of oxo-crown ethers e.g. Scheme 50 for the mono-oxo-series. Studies here imply activation of the carboxy- rather than of the alkoxy-terminus by the sulphonyl chloride. The ester functions reduce the complexing ability of these macrocycles with respect to normal crown ethers. The reduction of oxo-crowns to cyclic ethers, rather than to the diols that might be expected from reduction of a lactone, by LiAlHi has been studied the crown system seems to be necessary, and the involvement of lithium complexes has been suggested. 

When copolymers are prepared by ring opening polymerization of chiral monomers such as cyclic ethers and thioethers, lactones, lactams, N-carboxy anhydrides, etc., the chirality of the monomers is often retained in the repeating groups incorporated into the copolymers. A few stereoregular copolymers prepared this way have been analyzed by nmr spectroscopy, but much remains to be done in this area. 

A simplified synthesis relies on the potential to protect difunctional compounds as cyclic derivatives. For example, 1,2-diols are masked as cyclic acetals (Section 24-8), hydroxy acids as lactones (Section 19-9), amino acids as lactams (Section 19-10), and dicarboxylic acids as anhydrides (Section 19-8). The last two possibilities merit consideration as applied to Asp. However, direct lactam formation can be quickly ruled out because of the complications of ring strain (although /3-lactams have been used in the preparation of aspartame). This problem is absent with respect to dehydration to the five-membered ring anhydride. Because anhydrides are activated carboxylic acid derivatives (Section 20-3), the Asp anhydride can be coupled directly with Phe-OCHa without the help of added DCC. Nucleophilic attack of the amino end of Phe-OCHs occurs preferentially at the desired position, albeit not completely so 19% of the product derives from peptide-bond formation at the /3-carboxy group of Asp. 

At this point, some alternative methods are worthy of mention for the synthesis of polydepsipeptides. The copolymerization of lactones and amino acid carboxy-anhydrides using stannous octanoate as catalyst affords random polydepsipeptides, and is an attractive way to prepare polymers with pendant functional groups [42]. In addition, the ROP of amino acid N-carboxyanhydrides and lactic acid anhydrosulfite affords polymers the structure of which may be either random or blocky-like , depending on the catalyst/initiator system used [43, 44). 

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