Recent Advances in the Synthesis of 2-Pyrones

The present review summarizes the recent progresses in the synthesis of 2-pyrones and the application to the synthesis of marine natural products. Especially, much attention was placed on the transition metal catalyzed synthetic methodologies in this review.


Introduction
Pyrones constitute a family of six-membered unsaturated cyclic compounds containing an oxygen atom. In view of chemical motifs, γ-pyrone is the vinylogous form of α-pyrone (instead of α-pyrone, the term "2-pyrone" will be used hereafter), which possesses a lactone. As a result, these ring systems share similar chemical properties ( Figure 1) [1][2][3]. 2-pyrone is extremely prevalent in numerous natural products isolated from plants, animals, marine organisms, bacteria, fungi, and insects that exhibit a broad range of biological activities, such as antifungal, antibiotic, cytotoxic, neurotoxic and phytotoxic( Figure 2) [4]. Moreover, 2-pyrone can OPEN ACCESS serve as a versatile building block for the synthesis of key intermediates in synthetic organic chemistry as well as in medicinal chemistry due to the existence of functional groups, such as conjugated diene and the ester group. Thus, development of a highly efficient synthetic method affording substituted 2-pyrones under mild conditions has been one of considerable attention in organic chemistry.
For all its importance in organic chemistry and medicinal chemistry, it was not until recently that various transition metal-catalyzed methods for the efficient synthesis of 2-pyrone have been developed and thus we were able to have a clear understanding of the exact nature and the unique chemical behavior of 2-pyrone. The present review will be concerned with the recent advances in the synthesis of 2-pyrones with a special emphasis on metal-catalyzed methods, but other significant methods will be covered as well as the synthesis of complex marine natural products.

Palladium-Catalyzed Synthesis of 2-Pyrones
Larock and co-workers demonstrated a consecutive two-step approach to 2-pyrones employing a Sonogashira coupling reaction to prepare (Z)-2-alken-4-ynoates, followed by electrophilic cyclization (Scheme 1) [19]. Although in some cases this protocol affords 5-membered lactones or mixtures of 5-and 6-membered lactones, it is compatible with various alkynyl esters bearing diverse functional groups and readily provides the anticipated 2-pyrones. Further treatment of the products with electrophiles such as ICl, I2, PhSeCl, p-O2NC6H4SCl, and HI affords the corresponding substituted 2-pyrones. Especially, iodo-2-pyrone would be a key intermediate in synthesis of more complex molecules (Scheme 1).

Scheme 2. Synthesis of difluorinated 2-pyrones involving Sonogashira alkynylation.
The proposed catalytic cycle suggests that the iodoacid (4) reacts with the alkyne in the presence of Pd(0) to produce the enynoic acid (C) (Figure 3). Regenerated Pd(0) species in the first cycle is again oxidized into Pd(II) by an acid moiety HX (X could be I-, Cl-) in the reaction. In the second catalytic cycle, 2-pyrone is formed by the cyclization of the enynoic acid under the catalysis of Pd(II), followed by reductive elimination generating the Pd(0). Pal and co-worker further extended the scope of the coupling-cyclization strategy to the regioselective synthesis of 2-pyrone fused with a pyrazol moiety (8) (Scheme 3) [21]. This method proceeds via Pd/C-mediated tandem C-C and C-O bond formation between the 5-iodopyrazole-4-carboxylic acid (7) and a terminal alkyne to afford pyrano [4,3-c]pyrazol-4(1H)-one (8) in a single pot.
The actual catalyst in this process is a Pd(0) complex, which is generated by the reduction of Pd(OAc)2 ( Figure 4). In the proposed mechanism, the vinylic (or aromatic) iodide (13) is added to Pd(0) oxidatively and the allenyl-tributyltin (16) reagent would be cross-coupled with the vinylic iodide (13) to afford the corresponding 3-allenylpropenoic acid (C) by transmetallation and reductive elimination. The allene moiety is further activated by complexation with Pd(II) and undergoes intramolecular 6-exo-dig nucleophilic attack by the carboxylic group. At the end of the catalytic cycle, 2-pyrone (18) is formed while Pd(II) is regenerated to enter into a new reaction cycle. 2-Pyrone synthesis by a direct coupling of a functional vinylstannane to an acyl chloride is an intriguing example developed by Parrain and co-workers (Scheme 6) [24]. This annulation most probably proceeds via a Stille reaction/cyclization sequence in good yields.
In view of the reaction mechanism, this annulation follows the typical palladium-catalyzed coupling sequence involving (1) reduction of Pd(II) to the actual catalyst Pd(0); (2) oxidative addition of the halide or triflate to Pd(0) (A); (3) vinylpalladium coordination to the alkyne and subsequent insertion to form a vinylpalladium complex (B); (4) formation of a seven-membered palladacyclic complex (C) via attack of the carbonyl oxygen on the vinylpalladium complex (C); and (5) reductive elimination to regenerate the Pd(0) catalyst ( Figure 6). In some cases, the significant problem in the synthesis of 2-pyrone via a cyclization of a carboxylic acid ester on an alkyne is the selectivity between 5-exo-dig and 6-endo-dig cyclization. In this regard, catalytic system based upon N-heterocyclic carbenes (NHC) developed by Almqvist and co-workers is rewarding in favor of the 6-endo-dig product (Scheme 9) [27]. In the reaction, selection of an appropriate Lewis acid is as much important as a catalyst. For example, addition of BF3.Et2O as a Lewis acid additive in replacement of TFA affords complete 6-endo-dig selectivity in the Pd-NHC catalyzed reaction.
The substituted tricyclic 2-pyrones were synthesized in outstanding yields from the corresponding internal acetylenes. This was proven to work excellently for alkyl, cycloalkyl, aryl, and heteroaryl substituted acetylenes. Jiang and co-workers reported a highly efficient strategy for the synthesis of 2-pyrones and pyridones via Pd-catalyzed oxidative annulations between acrylic derivatives and internal alkynes with high regioselectivity (Scheme 10) [28]. This process is attractive and practical because O2 (1 atm) is used as a stoichiometric oxidant and only H2O is generated as the only byproduct under mild conditions. Scheme 10. Pd-catalyzed oxidative annulations between acrylic derivatives and internal alkynes.
The coordination and ligand exchange of the acrylic derivative (32) with Pd(II) are involved in the initial step of the Pd-catalyzed oxidative annulation to provide X-Pd intermediate (B). After exo coordination of 31 and insertion of the diarylethyne molecule into B forms the vinyl-palladium complex (C), the intramolecular Heck-type reaction occurs to provide the alkyl-palladium species (D). Then, 2-pyrone (33) and Pd(0) would be released by β-hydride elimination and the molecular oxygen under the assistance of Cu(II) would regenerate the catalyst by oxidation of Pd(0) to Pd(II) to complete the catalytic cycle ( Figure 7).

Gold-Catalyzed Cyclo-Isomerization Strategy
Due to the alkynophilic character with high functional group compatibility and many other advantages, gold catalysis has been indeed at the center of rapid development during the past decade. Recently, a highly regioselective synthesis of pyrano [3,4-b]indol-1(9H)-ones (35) via gold(III) chloride catalyzed cyclo-isomerization of 3-ethynyl-indole-2-carboxylic acid (34) was achieved in good to excellent yields by Perumal and co-workers (Scheme 11) [29].
In the reaction, either alkyl substitution at the nitrogen or an electron releasing substituent in the aryl ring is advantageous because this reaction proceeds at a short reaction time and provides the expected 2-pyrone in higher yields. These observations might be explained that formation of a gold complex becomes easy when the electron density of the triple bond increases. Scheme 11. Gold-catalyzed cyclo-isomerization of 3-ethynyl-indole-2-carboxylic acid (34).
An excellent addition to this reaction category is the sequential alkyne activation of readily available allenyl propiolates by a gold(I) catalyst, [(Ph3P)AuCl]/AgSbF6 developed by the Schreiber group (Scheme 12) [30]. An intermediate oxocarbenium ion formed by a 6-endo-dig cyclization induced by the activation of the alkyne converts into distinct products by two pathways: H elimination or Friedel-Crafts-type addition of electron-rich aromatic and heteroaromatic derivatives (Scheme 12). In pathway A, elimination would afford a vinyl 2-pyrone (37) while pathway B, a Friedel-Crafts-type reaction with electron-rich aromatic and heteroaromatic compounds such as indole, furan, and benzofuran would provide a nucleophile adduct (38) (Scheme 12).

Scheme 12.
A sequential alkyne activation of allenyl propiolates by a gold(I) catalyst.
Pale and co-workers developed a two-step procedure to substituted 2-pyrones catalyzed by a gold(I) catalyst (Scheme 13) [31]. This reaction proceeds through an unprecedented rearrangement of β-alkynylpropiolactones (39) to furnish 2-pyrones (40) in a high overall yield.

Scheme 13. 2-Pyrones from unprecedented rearrangement of β-alkynylpropiolactones (39).
In a proposed mechanism, cationic pyrone gold intermediate (D) would be formed from both σ-and π-Au complexes (A) and (B) ( Figure 8). This is possible through either a 1,3-oxygen shift or Hashmi-type cyclization from A and through cyclization of C from B. Elimination and subsequent protodeauration of the intermediate (D) would then provide the corresponding 2-pyrones (40). Side products, such as the enyne 41 and the acid 42, also support σ-coordination at the β-lactone carbonyl. In the course of a selective synthesis of the unusually sensitive cyclophanic 2-pyrone neurymenolide A (51), Fürstner and co-workers revisited the gold chemistry [32].
It is proposed that the ready cleavage of the tert-butyl group off of putative intermediate is critical for the release of the 2-pyrone ring. Later, this new method along with a ring closing alkyne metathesis (RCAM) was successfully applied to the efficient total synthesis of neurymenolide A (46) as key transformations ( Figure 9).
An inseparable mixture of β-keto ester (52) and its tautomer (53) was used as a model system for this transformation. Reaction screening with various catalysts revealed that [Bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)-gold(I) in a 4:1 mixture of AcOH/MeCN at room temperature provided 54 in 73% yield. Consequently, the synthesis of violapyrone C (58) was accomplished in 22% overall yield using the Gold(I)-catalyzed intramolecular 6-endo-dig cyclization of tert-butyl ynoates as the key reaction (Scheme 16).
Schreiber and co-workers reported that a sequential alkyne activation of terminal alkynes and propiolic acids by gold(I) catalysts furnishes 2-pyrones (Scheme 17) [34]. This novel cascade reaction involving propiolic acids give rise to 2-pyrones with different substitution patterns.

Scheme 17.
A novel cascade reaction involving propiolic acids to 2-pyrones with a gold catalyst.
This reaction probably begins with addition of the carboxylic acid to the β-position of the propiolic acid (60) providing vinyl ester (B) (Figure 10). In the next step, cationic gold(I) further activates B to generate oxocarbenium (C). The acyl group is transferred to the C-Au bond of C to simultaneously regenerate the gold(I) catalyst. Carboxylic acid E initiates the 6-endo-dig cyclization onto the activated alkyne and enolization affords 4-hydroxy 2-pyrone (63). Later they found that the 3-unsubstituted 2-pyrones can be synthesized in good yields by using maleic acid in place of acrylic acid in their studies on the rhodium-catalyzed dehydrogenative coupling of carboxylic acids using the same catalytic system [36].
Interestingly, internal alkynes prefer homocyclization, and therefore, the better choice for the reaction would be the cyclization of internal alkyne and terminal alkyne combination.  Ryu and co-workers developed a ruthenium-catalyzed carbonylative [3 + 2 + 1] cycloaddition, using silylacetylenes, α,β-unsaturated ketones, and CO to provide a new method for the synthesis of tetrasubstituted 2-pyrones (Scheme 21) [39]. In this reaction, the carbonyl group and α-carbon of vinyl ketones are combined as a three-atom assembling unit.
The ruthenium carbonyl complex generates a ruthenium hydride species with an amine-HI salt or water. This intermediate reacts with methyl vinyl ketone to give a ruthenium enolate ( Figure 13). Next a vinyl ruthenium complex is generated via carboruthenation of the enolate to silylacetylene. This intermediate then undergoes CO insertion to provide an acyl ruthenium complex. Cyclization, followed by β-hydride elimination would give the 2-pyrone and regenerate the ruthenium hydride species.

Phosphine-Catalyzed Synthesis of 2-Pyrones
One-step phosphine-catalyzed annulation between aldehydes (85) and ethyl allenoate (86) to form 6-substituted 2-pyrones (87) was reported by Kwon and co-workers (Scheme 24) [42]. The reaction can be explained by clear discussion of the E/Z-isomerism of the zwitterion formed by the addition of a phosphine to the allenoate (Figure 15). Equilibrium shifts toward the E-isomeric zwitterion sterically demanding trialkylphosphines and lead to the formation of 6-substituted 2-pyrones.

Scheme 27.
Application of Baylis-Hillman reaction to the synthesis of 2-pyrone.

Ring Expansion Strategy
Liebeskind and co-workers found that the addition of a lithiated O-silylated cyanohydrin to a cyclobutenedione (99) with subsequent intramolecular 1,4-silyl migration and displacement of cyanide generates in situ a 4-acylcyclobutenone, which undergoes spontaneous ring expansion to a substituted 2-pyrone (100) in good to excellent yield (Scheme 28) [46].

Scheme 28. Synthesis of 2-pyrones employing a lithiated O-silylated cyanohydrin.
The facile ring expansion of the 4-acylcyclobutenone at or below room temperature is a unique feature of this reaction since heating at temperatures in excess of 100 °C is required in most ring expansions of 4-aryl-or 4-vinylcyclobutenones ( Figure 16). Substituted 3,4-dimethyl-2-pyrones (102) were prepared in good yields by treatment of 3-carboethoxyethylidene cyclobutanols with various bases (Scheme 29) [47]. Jung and co-workers proposed a mechanism involving ring opening of the metal alkoxide (A) to give the carbanion (B), which undergoes proton transfer to give the more stable carbanion (C) and double bond isomerization to give the enolate (D) to form the pyrone ring (102) via attack on the ester.

Scheme 29.
A ring opening of the metal alkoxide (A) to 2-pyrones.
Although δ-lactone (106) was the major component of the crude products, this was converted into 2-pyrone (107) in silica gel TLC chromatography purification.
It is of note that ketene (122) undergoes 1,3-shift of chlorine, which was determined by 13 C NMR experiment ( Figure 20). Thus, the chlorine atom interchanges between two carbonyl groups and also these ketenes can exist as a mixture of two conformers, such as s-cis (A) and s-trans (B). The reaction completed by nucleophilic attack of the OH group of the enol form (D) at the acyl carbonyl position of the ketene, followed by ring closure. Usachev and co-workers developed a convenient synthesis of a series of 2-pyrones with a CF3 group at the 6-position and aryl group at position 4, from readily available aryl-4,4,4-trifluorobutane-1,3-diones (125), PCl5, and sodium diethyl malonate (126) (Scheme 37) [56].
The experimentally proven mechanism describes that the reaction is initiated by the magnesium chloride-mediated conversion of glycidic ester (129) to keto ester (A) (Figure 21). Subsequently, elimination of acetone via keto-enol tautomerism results in formation of intermediate D. At this stage, the reaction proceeds in two different plausible pathways. For example, nucleophilic addition of hydroxyl group to ester carbonyl carbon (pathway A) would provide 4-chloro-3-hydroxy-2-pyrone (130) after elimination of MeOH. In contrast, nucleophilic attack at keto carbonyl position (pathway B) would furnish 3-chloro-2-hydroxy-2,5-dihydrofuran-2-carboxylate (F). Later, Baran and co-workers applied this method to the total synthesis of (±)-haouamine A (137) on the premise that a cyclohexadiene from the pyrone-alkyne Diels-Alder reaction can serve as a viable precursor since it can release CO2 to undergo subsequent aromatization (Scheme 39) [58].

Scheme 39. Total synthesis of haouamine A (137).
In consequence, the total synthesis of the structurally complex haouamine A (137) was realized in eight steps from readily available indanone (131) via the unprecedented chemistry specifically tailored for a pyrone-assisted stitching of the bent aromatic ring.

Synthetic Application of 3,5-Dibromo-2-Pyrone
Due to the outstanding stereochemical outcome in the Diels-Alder cycloadditions, substituted 2-pyrones have been extensively used as key intermediates in the synthesis of complex natural products. Especially, brominated 2-pyrones are attractive ambident dienes as they can react with both electron poor and rich dienophiles via normal-and inverse-electron-demand Diels-Alder cycloadditions with good stereocontrol. The dual reactivity of brominated 2-pyrones is resulted from the fact that the bromine atom at 3-or 5-position on the 2-pyrone ring can either withdraw or donate electron density to the diene moiety of the 2-pyrone ring. However, despite the versatility and usefulness of brominated 2-pyrones, their synthetic application has been hampered by the limited accessibility.
Later, the investigation further extended to cycloadditions with highly sterically hindered cycloalkenyl enol ethers to provide a series of tricyclolactones, which was unprecedented in the past (145, Scheme 42) [63]. With regard to the stereochemical outcome of the cycloadditions, mostly endo-products were prepared with cyclic enol ethers up to seven-membered ring systems while exo-product was produced in moderate selectivity.
The resulting cycloadducts (144) from the previously described Diels-Alder cycloaddition reactions were further transformed into corresponding bicarbocyclic skeletons or aromatic compounds (Scheme 45). For example, the two bromine groups on the resulting cycloadducts can be independently manipulated to produce more complex bicyclolactones (159, 160, Scheme 45). Thus, selective debromination under typical Bu3SnH/AIBN condition and subsequent reductive lactone ring opening reaction with LAH provided the corresponding ester (161), and the direct opening of the lactone bridge with NaOMe was accompanied with a concomitant 1,4-elimination and subsequent aromatization to provide the aromatic compounds (162, Scheme 45) [61].

Conclusions
Over the past two decades, we have witnessed great strides in our understanding of 2-pyrone chemistry. In a synthetic point of view, the development of new methodology for the efficient synthesis of 2-pyrones has been at the center of much attention in the field of organic synthesis. As a result, a range of synthetic methodologies have been developed so far and they are categorized into several classes, including (1) metal-catalyzed synthesis of 2-pyrones; (2) synthesis of 2-pyrones using an organo catalyst; (3) phosphine-catalyzed synthesis of 2-pyrones; (4) synthesis of 2-pyrones via iodolactonization; (5) synthesis of 2-pyrones via Baylis-Hillman reaction; (6) synthesis of 2-pyrones via ring expansion strategy; (7) synthesis of 2-pyrones via base-promoted condensation; (8) synthesis of 2-pyrones via rearrangement-cyclization strategy, etc. Additionally, the chemistry of 3,5-dibromo-2-pyrone (143) and 4-bromo-6-methyl-2-pyrone (173) has been well established by the pioneering works of Cho and Fairlamb and it is currently at the stage to provide useful tools for the synthesis of complex natural products.