Recent Advances in Inverse-Electron-Demand Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes

This review is an endeavor to highlight the progress in the inverse-electron-demand hetero-Diels–Alder reactions of 1-oxa-1,3-butadienes in recent years. The huge number of examples of 1-oxadienes cycloadditions found in the literature clearly demonstrates the incessant importance of this transformation in pyran ring synthesis. This type of reaction is today one of the most important methods for the synthesis of dihydropyrans which are the key building blocks in structuring of carbohydrate and other natural products. Two different modes, inter- and intramolecular, of inverse-electron-demand hetero-Diels–Alder reactions of 1-oxadienes are discussed. The domino Knoevenagel hetero-Diels–Alder reactions are also described. In recent years the use of chiral Lewis acids, chiral organocatalysts, new optically active heterodienes or dienophiles have provided enormous progress in asymmetric synthesis. Solvent-free and aqueous hetero-Diels–Alder reactions of 1-oxabutadienes were also investigated. The reactivity of reactants, selectivity of cycloadditions, and chemical stability in aqueous solutions and under physiological conditions were taken into account to show the potential application of the described reactions in bioorthogonal chemistry. New bioorthogonal ligation by click inverse-electron-demand hetero-Diels–Alder cycloaddition of in situ-generated 1-oxa-1,3-butadienes and vinyl ethers was developed. It seems that some of the hetero-Diels–Alder reactions described in this review can be applied in bioorthogonal chemistry because they are selective, non-toxic, and can function in biological conditions taking into account pH, an aqueous environment, and temperature.


Introduction
Cycloaddition reactions provide quick and economic methods for the construction of monocyclic, polycyclic and heterocyclic systems. The use of hetero-substituted diene and dienophiles is important for the application of Diels-Alder cycloadditions towards natural and biologically active product synthesis. Dihydro-and tetrahydropyran derivatives are prevalent structural subunits in a variety of natural compounds, including carbohydrates, pheromones, alkaloids, iridoids and polyether antibiotics [1][2][3][4][5][6][7][8]. The abundance of carbohydrates in living cells is a reason for the development of new synthetic procedures for the preparation of natural and unnatural sugars. There are two synthetic routes leading to dihydropyran derivatives via [4 ? 2] cycloadditions. The first one is the [4 ? 2] cycloaddition of the carbonyl group of aldehydes or ketones, acting as heterodienophiles, with electronrich 1,3-butadienes [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. The second route is the hetero-Diels-Alder (HDA) reactions of electron-deficient a,b-unsaturated carbonyl compounds, representing an 1-oxa-1,3-butadiene system, with electron-rich alkenes. Excellent diastereoselectivity is a characteristic feature of heterocycloaddition of many substituted a,bunsaturated carbonyl compounds. The HDA reactions of oxabutadienes also show a high regioselectivity. These reactions have been classified as cycloadditions with inverse-electron-demand [24]. The reviews on this topic have already been published but they cover the literature until only 1997 [1][2][3][4][5][6][7][8]24]. The most comprehensive one was written by Tietze and Kettschau in Topics in Current Chemistry in 1997 [2]. The presented review is an endeavor to highlight the progress in the HDA reactions with inverse-electron-demand of 1-oxa-1,3butadienes after the year 2000. The reactivity of a,b-unsaturated carbonyl compounds in HDA reactions is low and the reactions must be conducted at high temperature [25][26][27] or under high pressure [28][29][30]. The use of enol ethers as dienophiles with electron-donating groups improves the cycloadditions but high temperature is needed and diastereoselectivity of these reactions is still low. Aza-substituted dienophiles have been used more rarely than their oxygenated counterparts in the HDA reactions of 1-oxa-1,3-butadienes. Enamines can participate in these reactions, providing entry to highly complex molecules [31][32][33]. The reactivity of 1-oxa-1,3-butadiene can be enhanced by introducing electron-withdrawing substituents [34][35][36][37][38][39]. Presence of an electron-withdrawing group in the 1-oxadiene system lowers the lowest energy unoccupied molecular orbital (LUMO) energy level which then can more easily overlap with the highest energy unoccupied molecular orbital (HOMO) orbital of the dienophile. Tietze et al. calculated the influence of various substituents on the energy of LUMO orbitals in 4-N-acetylamino-1-oxa-1,3-butadienes using semiempirical methods [40]. It was found that the energy depends on the type and position of a substituent in the 1-oxadiene system. The cyano and trifluoromethyl groups in the 3 position were found to have the highest influence on reactivity of 1-oxa-1,3butadienes in cycloadditions with enol ethers. In addition to the effect of the substituents in the heterodiene, Lewis acid catalysts, such as ZnCl 2 , TiCl 4 , SnCl 4 , EtAlCl 2 , Me 2 AlCl, LiClO 4 , Mg(ClO 4 ) 2 , Eu(fod) 3 , Yb(fod) 3 , accelerate the HDA reactions [41][42][43][44][45][46][47][48][49][50][51][52][53]. The choice of the Lewis acid also has influence on the stereoselectivity of cycloadditions because this catalyst is involved in an endo or an exo-transition structure and steric interactions are important for stereochemistry.
Inverse-electron-demand HDA reaction between a,b-unsaturated carbonyl compounds and electron-rich alkenes gives an enantioselective approach to chiral dihydropyrans which are precursors for the synthesis of carbohydrate derivatives. To obtain optically active carbohydrate derivatives by the HDA approach, either a chiral transformation via the use of a chiral auxiliary or a catalytic enantioselective reaction is necessary [50][51][52][53]. Two different modes of inverse-electron-demand HDA reactions of 1-oxa-1,3-butadienes are discussed in this paper: inter-and intramolecular mode. The geometry of the transition structures of HDA reactions influences the diastereoselectivity of cycloadditions. There are four different transition states for HDA reactions of 1-oxa-1,3-butadienes, according to an endoor exo-orientation of the dienophile and an (E)-or (Z)-configuration of the 1-oxa-1,3-butadiene [2]. The four transition structures for inter-and intramolecular HDA reactions providing the two diastereomers cis and trans are showed in Figs. 1 and 2. The orientation of the dienophile-vinyl ether, with the alkoxy group being close to the oxygen atom in the heterodiene is called endo (Fig. 1) [2]. The opposite is called exo. For intramolecular HDA reactions of 1-oxa-1,3-butadienes, the orientation with the chain connecting the heterodiene and dienophile lying close to the heterodiene is called endo (Figure 2) [2]. The cis-adduct can be formed by an endo-E or exo-Z orientation. The trans-adduct is obtained by either an exo-E or endo-Z transition state (Figs. 1, 2).
Tietze et al. extensively described the domino Knoevenagel hetero-Diels-Alder reactions of unsaturated aromatic and aliphatic aldehydes with different 1,3dicarbonyl compounds for the synthesis of heterocycles with a pyran ring [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68]. In the intramolecular mode, the 1-oxa-1,3-butadienes are prepared in situ by a Knoevenagel condensation of aldehydes bearing the dienophile moiety. This method has a broad scope since a multitude of different aldehydes and 1,3dicarbonyl compounds can be used. Different examples of inter-and intramolecular HDA reactions of 1-oxa-1,3butadienes described in literature after the year 2000 are discussed below. The usefulness of HDA reactions of oxadienes is connected with the number of bonds which are formed in one sequence and with the fact that complex molecules can be obtained by this method. Thus, the HDA reactions of a,b-unsaturated carbonyl compounds are atom economic and they allow for regio-, diastereo-and enantioselective synthesis of multifunctional pyran derivatives from relatively simple compounds. Therefore, these cycloadditions can be potentially applied in bioorthogonal chemistry.
Another interesting example of HDA reaction of 1-oxa-1,3-butadienes with vinyl ethers was described by Klahn and Kirsch [75]. They examined dehydrogenation of b-oxonitriles 8 by treatment with o-iodoxybenzoic acid (IBX) at room temperature (Scheme 2). Products of the dehydrogenation-unsaturated counterparts 10 can react in situ, undergoing rapid HDA reactions with enol ethers 9 to produce polyfunctionalized dihydropyrans 11. Cycloadducts 11 were generated in moderate to good yields and with excellent cis-diastereoselectivity (up to [99:1).
The scope of intermolecular HDA reactions of 1-oxa-1,3-butadienes with inverse-electron-demand was expanded to cycloadditions with enecarbamate [78].    [79,80]. The amino aldehydes 32 were treated with the 1,3-dicarbonyl components 34 and benzoyl enol ethers 33 in toluene in the presence of catalytic amounts of EDDA and trimethyl orthoformate as dehydrating agent in an ultrasonic bath. The domino reaction sequence of Knoevenagel, HDA reaction, and hydrogenation allows rapid access to a number of N-heterocycles of different ring sizes and with different substituents in a betaine 37.
Radi et al. described a protocol for the multicomponent microwave-assisted organocatalytic domino Knoevenagel HDA reaction for the synthesis of substituted 2,3-dihydropyran[2,3-c]pyrazoles [81]. The reported procedure can be used for the fast generation of pyran [2,3-c]pyrazoles with potential anti-tuberculosis activity.
A mixture of pyrazolone 38, aldehyde 40 and 10 equiv of ethyl-vinyl ether 39 was MW irradiated and heated at 110°C in the presence of the appropriate organocatalyst A-F (Scheme 7). The best results were obtained in the presence of diaryl-prolinols B and C. In the absence of the catalyst the reaction did not start at all. Using the catalyst B and t-BuOH as the solvent, the authors obtained the cycloadducts 41 and 42 in yields (56 and 12 %, respectively) and improved diastereoisomeric ratio (4:1) in comparison to the results previously obtained.
Inverse-electron-demand HDA reaction of 1-oxa-1,3-butadienes was used in synthesis of the fused uracils-pyrano[2,3-d]pyrimidine-2,4-diones [82]. This group of uracils, as a fused heterobicyclic system, constitutes an important contribution in medicinal chemistry and a wide variety of attractive pharmacological effects has been attributed to them [83]. First, it was examined that 5-arylidene-N,Ndimethylbarbituric acids 43 undergo smooth HDA reactions with enol ethers 44 to afford cis-47 and trans-48 diastereoisomers of 7-alkoxy-5-aryl-2H-pyrano[2,3d]pyrimidine-2,4-diones in excellent yields (84-95 %; Scheme 8). Cycloadducts 47 with cis-configurations were the major products. Next, three-component one-pot created by a trans-diaxial-elimination of the appropriate alcohol were also obtained in these reactions. The advantages of these reactions are: the excellent yields, short reactions times, and the fact that cycloadditions do not require drastic conditions, but can be carried out at room temperature. The described reactions give easy and rapid access to both cis-47 as trans-48 diastereoisomers of uracils and pure diastereoisomers can be very easily isolated by column chromatography. Also, solvent-free HDA reactions of 5-arylidene derivatives of barbituric acids 50 with ethyl vinyl ether 51 were investigated at room temperature and pyrano[2,3d]pyrimidines 52 and 53 were obtained in excellent yields (Scheme 9) [84]. Threecomponent one-pot syntheses of fused uracils were performed in aqueous suspensions. ''On water'' reactions of barbituric acids 50, aldehydes 54, and ethyl vinyl ether 51 where carried out at ambient temperature, whereas the one-pot synthesis with barbituric acids 50, aldehydes 54, and styrene or N-vinyl-2oxazolidinone 56 required the heating of aqueous suspensions at 60°C (Scheme 9). Formation of the unexpected side products 55 can be explained as the result of three-component reactions of barbituric acids and acetaldehyde which were produced from reaction of etyl vinyl ether and water, and ethyl vinyl ether 51. Described ''on water'' cycloadditions were characterized by higher diastereoselectivity in contrast to reactions carried out in homogenous organic media (dichloromethane, toluene, Scheme 9). They allowed the cis adducts 57 to be obtained preferentially or exclusively. Green methods presented in this study avoid the use of catalysts, the heating of reaction mixtures for long time at high temperature, and the use of organic solvents.

Catalytic Hetero-Diels-Alder Reactions of 1-Oxa-1,3-Butadienes with Achiral Lewis Acids
It was mentioned in the Introduction that Lewis acids accelerate the HDA reactions of 1-oxa-1,3-butadienes [41][42][43][44][45][46][47][48][49][50][51][52][53]. Lewis acids can also improve regioselectivity and diastereoselectivity of these reactions. The example of catalytic HDA reaction are cycloadditions of a-keto-b,c-unsaturated phosphonates 58 and 65 with cycloalkenes: cyclopentadiene 59, cyclohexadiene 62, dihydrofuran, and dihydropyran 66, described by Hanessian and Compain (Scheme 10) [85]. The reactions led to the formation of the hetero-Diels-Alder products 60, 63 and 67 in addition to the normally expected Diels-Alder cycloadducts 61 and 64. Hetero-Diels-Alder cycloadducts with the endo product as the major isomer were the main products in the presence of SnCl 4 as a Lewis acid. The effect of substituents on stereochemistry of these reactions can be explained by considering steric interactions in the transition state. Increasing the bulk of the ester moiety lowered the ratio of hetero to normal Diels-Alder products while geminal substitution favored the product formed by HDA reaction. In the reactions of dialkyl a-  [86]. The solid-phase sequence allowed an unprecedented reuse of the catalyst in the presence of excess dienophile in solution. Also, attempts with ethyl vinyl ether as an achiral dienophile gave positive results.
Gong et al. examined asymmetric inverse-electron-demand HDA reaction of trisubstituted chiral enol ether 75 derived from (R)-mandelic acid (Scheme 12) [87]. Chiral 1,2,3,5-substituted tetrahydropyrans were synthesized by a three-step sequence with a remarkable and unprecedented endo and facial stereocontrol. The key step involved the Eu(fod) 3 -catalyzed HDA reaction of a trisubstituted chiral enol ether 75 and an activated heterodiene 74. The stereoselective hydrogenation of the heteroadducts 1-alkoxydihydropyrans 76 was optimized by using Pd on charcoal and diisopropylethylamine, leading to a unique isomer [87].
A complete reversal of facial differentiation was achieved by using a different Lewis acid, leading to the stereoselective formation of either endo-a 79 or endo-b 80 adducts. The endo-a adduct 79 was obtained with using Eu(fod) 3 as the catalyst and endo-b adducts 80 was the main product if the promoter was SnCl 4 (Scheme 13) [88,89].

Enantioselective Approach: Catalytic Enantioselective Hetero-Diels-Alder
Reactions of 1-Oxa-1,3-Butadienes with Chiral Lewis Acids The catalytic enantioselective HDA reactions of 1-oxa-1,3-butadienes with chiral Lewis acids were widely explored reactions. The chiral bisoxazoline copper(II) complexes have been shown to be effective catalysts for inverse-electron-demand HDA reactions.  A highly enantioselective approach for the synthesis of optically active carbohydrate derivatives by inverse-electron-demand HDA reaction of a,b-unsaturated carbonyl compounds with electron-rich alkenes catalyzed by combination of chiral bisoxazolines and Cu(OTf) 2 as the Lewis acid was also presented by Jorgensen et al. [91]. The reaction of unsaturated a-keto esters 89 and 92 with vinyl ether 90 and various types of cis-disubstituted alkenes 93 proceeded in good yield, high diastereoselectivity, and excellent enantioselectivity (Scheme 15). The potential of the reaction was demonstrated by the synthesis of optically active carbohydrates such as spiro-carbohydrates, an ethyl b-D-mannoside tetraacetate, and acetal-protected C-2-branched carbohydrates [91].
Catalytic enantioselective HDA reaction of 1-oxa-1,3-butadiene with inverseelectron-demand was used in synthesis of the marine neurotoxin-(?)-azaspiracid [92]. Cycloaddition between two components of the HDA reaction 95 and 96 proceeded readily using 2 mol% loadings of the hydrated copper complex 97 (Scheme 16). Catalyst 97 was dehydrated with molecular sieves prior to use. Diethyl ether was the optimal solvent for this HDA reaction (97 % ee, dr 94:6). The desired cycloadduct 98 was isolated in 84 % yield as a single isomer.
The tridentate (Schiff base) chromium complex has been identified as a highly diastereoselective and enantioselective catalyst in HDA reactions between aldehydes and mono-oxygenated 1,3-diene derivatives [93]. Jacobsen et al. examined if use of this chiral catalyst can be evaluated for the reactions of conjugated aldehydes [94]. The inverse-electron-demand HDA reactions of crotonaldehyde and the wide range of a,b-unsaturated aldehydes 99 bearing b substituents and vinyl ether 100   Usage of solvents generally resulted in significantly lower enantioselectivity in the cycloaddition. As the steric bulk of the alkyl group of dienophile was increased, the selectivity and reactivity decreased. The optimal dienophile was ethyl vinyl ether. In the solid state, catalyst 101 exists as a dimeric structure, bridged through a single water molecule and bearing one terminal water ligand on each chromium center. Opening of a coordination site by dissociation of the terminal water molecule for complexation of the aldehyde substrate explains the important role of molecular sieves in these reactions [95,96].
Asymmetric inverse-electron-demand HDA reaction of 1-oxa-1,3-butadienes was a key step in synthesis of several members of the bioactive styryllactone family [97]  The high yield and enantioselectivity of the reactions was restored (up to 95 % yield and 95 % ee). The ester alkyl group of b,c-unsaturated a-ketoesters 111 has almost no influence on either the reactivity or enantioselectivity. Similarly, the substituent on the phenyl ring of the enones 111 has minimal effects on the reactivity and the asymmetric induction of these reactions. b,c-Unsaturated aketophosphonates 111 may also be applied in these reactions if a higher loading of the precatalyst modules (10 mol%) is used. The authors proposed a plausible transition state on the basis of the product 116 stereochemistry and the MDO structure [103]. They showed that the aldehyde 112 reacts with the OHIC moiety of the MDO to form an (E)-enamine. Next, the thiourea moiety of the MDO forms   hydrogen bonds with the enone 111 and directs to enamine from the front. The attack of the enone 111 onto the Re face of the enamine in an endo transition state leads to the formation of the observed (4S, 5R)-product 116.

Enantioselective Approach: Hetero-Diels-Alder Reactions of 1-Oxa-1,3-Butadienes with Chiral Auxiliaries
Inverse-electron-demand HDA reaction between 1-oxa-1,3-butadienes and electronrich alkenes represents one of the most direct approaches for the synthesis of optically active carbohydrate derivatives. To obtain optically active dihydropyrans derivatives by the HDA approach, either a catalytic enantioselective reaction or a chiral transformation via the use of a chiral auxiliary is necessary. The enantioselective HDA reaction requires chiral 1-oxa-1,3-butadienes or optically active alkene. The HDA reaction of the a,b-unsaturated ketone 118 prepared in situ from protected D-xylose 117 was used as the key step for the synthesis of a C10 higher carbon sugar 119 in a one-pot multi-step route (Scheme 21) [104]. Two molecules of a,b-unsaturated ketone 118 undergo the HDA reaction affording the 10 carbon sugar 119. Reduction and catalytic hydrogenation of cycloadduct 119 gave stereoselectively a single product 121 in an excellent yield.
Recently, it was shown that fused uracils, such as pyrano[2,3-d]pyrimidines with an aryl substituent at carbon C(5) in the ring system can be efficiently synthesized by HDA reactions of 5-arylidene derivatives of barbituric acids with vinyl ethers [82]. To increase the potential pharmacological activity of the fused uracil, a sugar moiety can be introduced instead of an aryl group at the C(5) position of pyrano[2,3-d]pyrimidine. Therefore, 5-ylidene barbituric acids bearing the carbohydrate substituent were constructed. A convenient and efficient procedure for the preparation of fused uracils containing a sugar moiety was described [105]. The reaction sequence was: Knoevenagel condensation of unprotected sugars and barbituric acid in water, acetylation of C-glycosides and HDA reaction.  In the field of pericyclic reactions, the development of new cycloreactants is a continuous challenge. Dimedone enamines were applied as new dienophiles in HDA reactions with inverse-electron-demand of 1-oxa-1,3-butadienes [106]. Cycloadditions of barbituric acid 5-ylidene alditols 132, representing a 1-oxa-1,3-butadiene system, with dimedone enamines 133 were performed in dichloromethane at room temperature for 3 days, and fused uracils-chromeno [ proton nuclear magnetic resonance ( 1 H NMR) and two-dimensional (2D) NMR spectra allowed for the determination that cycloadducts 134 exist in solution as a mixture of the neutral form 134 NF and dipolar ion 134 DI. The prepared fused uracils, possessing both amine and enol functional groups, share amphiprotic properties and are zwitterions in solid state. Important for biological interaction, groups such as different sugar moieties, enol moieties and different amino groups can be introduced into fused uracil systems by this simple HDA reaction. It was also shown that different alkenes can be used as dienophiles towards barbituric acid 5-ylidene alditols 132; for example, styrene or 1-amino-2-thiocarbamoyl-cyclopent-1-ene [106]. The application of stereoselective inverse-electron-demand HDA reaction of 1-oxa-1,3-dienes and chiral allenamides in natural product synthesis was described by Song et al. [107]. They used this reaction as a key step in synthesis of the C1-C9 subunit of (?)-zincophorin (Scheme 25).
Cis-fused cycloadducts are the main products in intramolecular HDA reactions of oxabutadienes obtained from aromatic aldehydes [54,55]. Reactions of oxabutadienes derived from aliphatic aldehydes result in the trans-fused cycloadducts [56,57]. In recent years, intramolecular HDA reactions of 1-oxa-1,3-butadienes have been used widely in numerous reactions in organic synthesis due to their economical and stereo-controlled nature. These reactions allow the formation of two or more rings at once, avoiding sequential chemical transformations. Therefore, the scope of the intramolecular HDA reactions of 1-oxadienes was expanded recently. The influence of an electron-withdrawing group at C-3 in 1-oxa-1,3-butadienes on the intramolecular HDA reaction was studied. First, the influence of cyano, carbonyl, and ethoxycarbonyl groups was examined [108]. Next, it was demonstrated that . Cis-fused 2H-pyran derivatives 143 were the major products. An increase of the reactivity and a decrease of the diastereoselectivity of the HDA reactions were observed in order: PhS derivative, PhSO 2 derivative and compounds containing PhSO group [108,109].
The most widely used 1-oxa-1,3-butadienes in intramolecular HDA reactions are usually those where the double bond is placed between the symmetrical 1,3-dicarbonyl compounds. Shanmugasundaram et al. studied the heterocycloaddition in which the alkene part was flanked by a keto carbonyl and a lactone carbonyl [110]. The reactions of 4-hydroxy coumarin and its benzo-analogues 144 with O-prenylated aromatic aldehydes 145 were examined (Scheme 27). Pyrano fused polycyclic compounds 147 and 148 were prepared with a high degree of chemoselectivity by the application of microwave irradiation. These reactions offers an easy access to pyrano[3,2c]coumarin 147 which is a structural element of many natural products.
Chemoselectivity was achieved with the reduction in reaction time because the cycloadducts 147 and 148 formed in the ratios ranging from 79:21-95:5 when the reactions were carried out under microwave irradiation for 10-150 s. Reactions of unsymmetrical 1,3-diones 144 with citronellal were also described [110].
Surprising formation of a 2,3-dihydro-4H-pyran containing 14-membered macrocycle 151 by sequential olefin cross metathesis and a highly regiospecific intramolecular HDA reaction of 1-oxa-1,3-dienes was described by Prasad and Kumar (Scheme 28) [111]. They studied the reaction of a hydroxydienone 149 derived from tartaric acid with Grubbs' second generation catalyst. Presence of the unprotected hydroxyl group in the hydroxyenone led to the formation of macrocycle 151. Protection of the hydroxyl group resulted in the ring-closing metathesis product 150.
The authors made the experiment to show that obtaining macrocycle 151 involves the formation of intermediate 155. Lewis acid catalysts were used in this new type of transformation. Wada et al. examined the catalytic asymmetric tandem transetherification-intramolecular HDA reaction of methyl (E)-4-methoxy-2-oxo-3-butenoate 157 with d,e-unsaturated alcohols 158 (Scheme 29) [113]. The optically active catalyst derived from the (S,S)-tert-Bu-bis(oxazoline) and Cu(SbF 6 ) 2 in presence of molecular sieves was a highly effective Lewis acid catalyst. The trans-fused hydropyranopyran derivatives 160 were prepared in yields up to 83 % and with high enantiomeric excess up to 98 %. In order to prevent the acid-induced cyclization, molecular sieves were used as a dehydratation agent. Yadav et al. presented the synthesis of carbohydrate analogues, cis-fused chiral polyoxygenated (tricyclic, tetracyclic, and pentacyclic) heterocycles by domino Knoevenagel intramolecular HDA reactions [114]. The O-prenyl derivative of a sugar aldehyde 161 derived from D-glucose underwent reactions with 1,3-diones 162, 164, 166 and 168 in presence of sodium acetate in acetic acid at 80°C (Scheme 30). The reactions were highly stereoselective affording exclusively cis-fused furopyranopyrans 163, 165, 167 and 169 in 70-82 % yields. The authors suggested that the cycloadditions proceeded in a concerted manner via an endo-E-syn transition state.

Catalytic Intramolecular HDA Reaction of 1-Oxa-1,3-Butadienes and Alkynes
Due to the lower reactivity of alkynes in comparison to the corresponding alkenes, no HDA reaction of 1-oxa-1,3-butadienes with alkynes has been reported.  carried out in the presence of CuI (40 mol%) and water as the solvent and tetracyclic uracils 175 were prepared in 70-84 % yields. The authors explained that the initial step of cycloaddition was probably the formation of a p-complex with CuI since copper(I) salts can act as a p-electrophilic Lewis acid. This complexation of alkyne increases activity toward an 1-oxa-1,3-butadiene system (Scheme 31).
The major advantage of this reaction is the fact that pentacyclic indole derivatives 188 can be isolated by filtration from the reaction mixture. This method also has advantages such as the use of commercially available, non-toxic and inexpensive ZnO as catalyst, low loading of catalyst, and high yields of products.
Balalaie   [123]. Pentacyclic heterocycles 196 and 197 were formed by a catalyst-free method in good yields and with high regio-and stereo-selectivity. Aldehydes 193 underwent the Knoevenagel condensation with 4-hydroxydithiocoumarin 194 in water at reflux to give the intermediates 195 in which two different heterodiene fragments were presented. The thiocarbonyl group of the thioester 195 reacted as heterodiene. The cycloadducts were obtained as a mixture of cis-and trans-isomers. The authors observed the influence of the substituent R 2 on reaction diastereoselectivity. The trans-isomer 196 was the main product for some reactions whereas for others, the products 197 were formed with the predominance of the cis-isomers (Scheme 35).
The importance of quinoline and its fused derivatives prompted Baruah  containing a dienophile moiety [124]. Baruah and Bhuyan also studied the HDA reactions for other 1-oxa-1,3butadienes (Scheme 37) [124]. These compounds possessing diene and dienophile moieties were prepared from aldehydes 209 by treatment with N-allyl methyl amine 210 in presence of K 2 CO 3 . Obtained products 211 on treatment with 212 or 213 in presence of piperidine in water at room temperature afforded the cycloadducts 214 or 215 in 52-70 % yields. Parmar  3 Application of Inverse-Electron-Demand Hetero-Diels-Alder Reactions of 1-Oxa-1,3-Butadienes in Bioorthogonal Chemistry For chemical biologists, discovering new reactions which can expand the toolbox of bioorthogonal chemistry is a current challenge. Development of new orthogonal methods for labeling in the biosystems is still continued, although effective bioorthogonal reactions such as copper-free click chemistry have been developed [126]. Reactions which can be used in bioorthogonal click chemistry should meet the requirements: high reactivity and selectivity of reagent functional groups, chemical stability in aqueous solutions in vivo, biocompatibility and high reaction rate under physiological conditions [127][128][129][130]. Bioorthogonal ligations have been widely used in biomedical research since they can selective labels of biomolecules in living systems. Some of inverse-electron-demand HDA reactions 1-oxa-1,3butadienes developed in recent years fulfill the criteria of click chemistry compiled by Sharpless [131,132] and, in the future, can be used as bioorthogonal cycloaddition. There is only one example in the literature of application of inverse-electron-demand HDA reactions of 1-oxa-1,3-butadienes in bioorthogonal chemistry. Lei et al. described a new bioorthogonal ligation by click HDA cycloaddition of in situ-generated o-quinolinone quinone methides and vinyl thioethers [133]. High selectivity and the fact that this cycloaddition can proceed smoothly under aqueous conditions make it suitable for bioorthogonal chemistry. o-Quinone methides represent an 1-oxa-1,3-butadiene system which can undergo quick and selective inverse-electron-demand HDA cycloadditions. It is important that generation of the o-quinone methides can't be conducted in harsh reaction conditions because it could be harmful for the organism cells. HDA cycloadditions of photochemically generated o-naphthoquinone methides 222 with vinyl ethers or enamines 223 as dienophiles were described by Arumugam and Popik (Scheme 39) [134][135][136]. They used ultraviolet (UV) light to generate 1-oxa-1,3-butadienes 222.
Li et al. optimized both reaction partners to make the reaction suitable for bioorthogonal ligation [133]. Introduction of more electronegative nitrogen into a heterodiene system 221 improved its reactivity and hydrophilicity (Scheme 40). As dienophile was used small and chemically stable in vivo vinyl thioether 227. o-Quinolinone quinine methide 226 was prepared from 8-(hydroxymehyl)-2methylquinolin-7-ol 225 without use of catalyst and UV light. Cycloreactants 226 Li et al. proved that HDA cycloaddition of o-quinolinone quinine methide 226 and vinyl thioether 227 can be utilized for labeling of multiple biomolecules in complex living systems when it is combined with other methods [137]. When cycloreactants 225 and 227 were combined with 5,6-didehydro-11,12-didehydrodibenzo[a,e]cyclooctene 229 and (azidomethyl)benzene 230 in a mixture of H 2 O/CH 3 CN at 37°C, only products 228 and 231 were obtained, and no cross reaction products were prepared (Scheme 41). 1,3-Dipolar cycloaddition of azide 230 and alkyne 229 is widely used in bioorthogonal ligation as strain-promoted azide alkyne cycloaddition (SPAAC). The results indicated that these two ligations proceeded simultaneously without interfering with each other.
It seems that some of the HDA reactions described in Chapter 2 can be used in bioorthogonal chemistry in the future because they are selective, non-toxic, and can function in biological conditions taking into account pH, an aqueous environment, and temperature.

Conclusion
This review article is an effort to summarize recent developments in inverseelectron-demand HDA reactions of 1-oxa-1,3-butadienes. Some of the papers related to the inverse-electron-demand HDA reactions of 1-oxa-1,3-butadienes found in the literature clearly demonstrate the importance of this transformation which opened up efficient and creative routes to different natural products containing six-membered oxygen ring systems. This type of cycloaddition is today one of the most important methods for the synthesis of dihydropyrans which are the key building blocks in carbohydrate derivative synthesis. Especially, the domino Knoevenagel HDA reactions have been frequently applied for the synthesis of natural products. The main advantage of the inverse-electron-demand HDA reaction of oxabutadienes is formation of dihydropyran derivatives with up to three stereogenic centers in one step from simple achiral precursors. This transformation characterizes the huge diversity, excellent efficiency, high regioselectivity, diastereoselectivity, and enantioselectivity observed in many cases. In recent years, the use of chiral Lewis acids, chiral organocatalysts, new heterodienes, or new dienophiles have given enormous progress. Recently, HDA reactions of 1-oxabutadienes conducted without a solvent or in water were developed and the results suggested that the presented green methods may displace other methods that use various organic solvents and that are performed at high temperature. Application of inverse-electron-demand HDA reactions of 1-oxa-1,3-butadienes in bioorthogonal chemistry is still challenging because there is only one example of this bioorthogonal cycloaddition in the literature. The author of this review sincerely hopes that this article will stimulate future research in bioorthogonal inverse- electron-demand cycloaddition of 1-oxa-1,3-butadienes and will encourage scientists to design novel bioorthogonal ligations.