5,6-dihydropyran-2-ones lactonization

Some dihydropyran-2-ones are natural products and mass spectrometry has proved to be a useful tool in structure elucidation. For example, massoilactone (147), which is secreted by formicine ants, was characterized by its mass spectrum. On electron impact, the alkyl group is readily cleaved generating an ion at m/e 97 (68AJC2819). This process parallels the behaviour of other simple lactones. 

The indirect dehydrogenation to pyranones has received rather more attention. The allylic bromination of 5,6-dihydropyran-2-one by NBS, followed by the elimination of hydrogen bromide, is described in detail and offers the attractions of mild conditions and easy isolation of the product (770S(56)49). A similar approach was used to synthesize the steroidal pyran-2-ones from the fully saturated lactone (354), with a combination of dehydrogenation and dehydrobromination to achieve oxidation (64MI22400). 

Titanium(IV) chloride is used as the catalyst in a Knoevenagel reaction between various 2,2-disubstituted 3-hydroxypropanals and malonic acid or its esters. The products are substituted dihydropyran-2-ones (536) (79LA751). The reaction, which occurs cleanly and in good yield, utilizes an excess of the titanium halide and is thought to involve a cyclic complex which undergoes an ester exchange to a lactone complex (Scheme 198). 

The dianion derived from but-2-ynoic acid reacts with aldehydes to give 5-hydroxyalk-2-ynoates (539). Partial reduction over a Lindlar catalyst and acid-catalyzed cyclization of the resulting enoate gives the dihydropyran-2-one (78LA337). The route is exemplified by the synthesis of the naturally occurring massoia lactone (Scheme 200). In previous work (46JCS954) the hydroxyalkynoic acids themselves, obtained from epoxides and acetylene, were used. 

One of the most reactive 1,3-dicarbonyl compounds used in the domino-Knoevenagel-hetero-Diels-Alder reaction is N,N-dimethyl barbituric acid 2. It has been shown that the fairly stable products can easily been transformed into other compounds via a reduction of the urea moiety with DIBAL-H [20]. Thus, reaction of 30 with DIBAL-H at 78 °C led to 46, which can be hydrolyzed to give 47 (Scheme 5.9). In a similar way, 48 was transformed into 50 via 49 and 12 to 52 via 51. The obtained compounds containing a lactone and an amide moiety can again be further transformed using DIBAL-H followed by an elimination. In this way, dihydropyran 54 is obtained from 50 via 53 as one example. 

Recently, Mukaiyama and co-workers prepared cinchona alkaloid-derived chiral quaternary ammonium phenoxide-phenol complex 23 and used it as an efficient organocatalyst for the tandem Michael addition and lactonization between oc,f-unsaturated ketones and a ketene silyl acetal 24 derived from phenyl isobutyrate. This approach permits the highly enantioselective synthesis of a series of 3,4-dihydropyran-2-ones (25), as shown in Scheme 4.11 [17]. 

The conjugate addition of diethylzinc to 5,6-dihydropyran-2-one 37 to give lactone 38 in 92% ee is a rare successful example of the use of the bridged bi-sphosphoramidite 39 developed by Chan (Scheme 5) [30]. 

Scheme 7.80 Asymmetric synthesis of 3,4-dihydropyran-2-ones by cascade Mukaiyama Michael/lactonization.

The lactonization of MBH derivatives to give 3-arylidene-3,4-dihydropyran-2-one derivatives has been realized by treatment with TFAA in CH2CI2 at room temperature.As shown in Scheme 4.102, ot-arylidene-8-lactones 317 were obtained in 50 83% yields. Subsequent oxidation of 317 with PCC afforded the desired a-pyrones 318 in 51-64% yields. By application of this synthetic strategy, tricyclic compound 320, previously reported by Basavaiah and Satyanarayana, " and bicyclic compound 319 could be prepared from easily available MBH adducts. 

Substituted derivatives of 5,6-dihydro-a-pyrones (dihydropyran-2-ones or more specifically 2H-dihydropyran-2-ones) occur widely in nature, particularly in plants and bacteria. They possess an a,P-unsaturated-5-lactone ring (1) with an alkyl, alkenyl or aryl substituent at C-6 and occasionally a varied substitution pattern around the ring. Many of these compounds are biologically active, exhibiting phytotoxi-... 

Mukaiyama et al. have productively employed chiral quaternary ammonium phe-noxides derived from Cinchona alkaloids as catalysts in a new and efficient method for the preparation of optically active 3,4-dihydropyran-2-one derivates via tandem Mukaiyama-Michael addition/lactonization between a, 3-unsaturated ketones and the silyl enolate derived from phenyl isobutyrate (Scheme 2.51) [150]. In this... 

In a paper that described a detailed preparation of air-stable cinchona alkaloid-derived chiral quaternary ammonium phenoxides, the Mukaiyama group also used these to enantioselectively prepare 3,4-dihydropyran-2-ones 160 [85]. A low loading of organocatalyst 159 at low temperatures, in a series of solvents, resulted in the formation of the optically active lactone products in high yields with excellent control of enantio- and diastereoselectivity. This process was proposed to go through a phenoxide-ion-catalyzed domino Michael addition and lactonization catalytic cycle as illustrated below. Many variations of the ketene silyl acetals and a, -unsaturated ketones were combined in this domino process (Scheme 7.32). Earlier,... 

When similar initiators were employed in the polymerization of 6,8-dioxa-bicyclo[3.2.1]octan-7-one (2) macrocyclic oligomers containing alternating tetrahydropyran and ester units resulted at low temperatures. At higher temperatures the lactone homopolymer was formed. The mechanism of polymerization of 2,3-dihydropyran derivatives (3) depended on the nature of the substituents, with low molecular weight polymers being formed in all cases studied. ... 

Lactone rings are a structural feature ofmany natural products [1]. Most particularly, those bearing a 5,6-dihydropyran-2-one moiety (see general structure 1, Figure 2.1) are relatively common in various types of natural sources [2]. Because of their manifold biological properties (Section 2.4), these compounds are of marked interest not only from a chemical but also from a pharmacological perspective. 

Formation of 5.6-dihydropyran-2-ones via lactonization of a 5-hydroxy acid... 

The transition-metal-catalyzed olefin metathesis is a still recent, but already well-established, development, which has evolved toward a highly useful synthetic tool [27]. The ring-closing variant of this reaction ]ring-closing metathesis (RCM)] has proved to be very suitable for the preparation of carbo- and heterocycles of any ring size, except for those that are strained ]28, 29]. In the case of 5,6-dihydropyran-2-ones, RCM of homoaUyl acrylates has very often been used for the direct creation of this heterocyclic system, most particularly in the past decade (Figure 2.4). Allyl esters of fi,y-unsaturated acids may also be subjected to RCM with the formation of P,y-unsaturated 8-lactones, which can be easily isomerized by acid or base catalysis to their a,fi-unsaturated counterparts ]6, 30-39]. 

An approach of a completely different type is the very recently pubhshed ruthenium-catalyzed reaction of allyHc chlorides with imsaturated acids, which yields an allyhc unsaturated ester via an enantioselective substitution. If the acidic component is a fS,y-unsaturated acid, an allyl fS,y-unsaturated ester is obtained, RCM of which affords an unsaturated S-lactone. The primary product is a P,y-unsaturated S-lactone (3,6-dihydropyran-2-one), but addition of isopropanol to the solvent stimulates migration of the double bond with the formation of the 5,6-dihydropyran-2-one (Scheme 2.25) [60]. The authors demonstrated the apphcability of their method to the preparation of natural products with the synthesis of (R)-massoialactone in 56% overall yield and 90% enantiomeric excess [39dj. 

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