Next Article in Journal
Flavone-Rich Fractions and Extracts from Oroxylum indicum and Their Antibacterial Activities against Clinically Isolated Zoonotic Bacteria and Free Radical Scavenging Effects
Next Article in Special Issue
Synthesis and Modeling of Ezetimibe Analogues
Previous Article in Journal
Solvent-Controlled Self-Assembled Oligopyrrolic Receptor
Previous Article in Special Issue
Intramolecular Nicholas Reaction Enables the Stereoselective Synthesis of Strained Cyclooctynes
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 26
Issue 6
10.3390/molecules26061772
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

1,3-Cyclohexadien-1-Als: Synthesis, Reactivity and Bioactivities

by
Ignacio E. Tobal
1,†,
Rocío Bautista
1,†,
David Diez
1,
Narciso M. Garrido
1 and
Pilar García-García
2,*
1
Departamento de Química Orgánica, Facultad de Ciencias Químicas, University of Salamanca, Plaza de los Caídos 1–5, 37008 Salamanca, Spain
2
Departamento de Ciencias Farmacéuticas, Facultad de Farmacia, CIETUS, IBSAL, University of Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain
*
Author to whom correspondence should be addressed.
†
These authors have contributed equally to this work.
Molecules 2021, 26(6), 1772; https://doi.org/10.3390/molecules26061772
Submission received: 19 February 2021 / Revised: 9 March 2021 / Accepted: 12 March 2021 / Published: 22 March 2021
(This article belongs to the Special Issue New Synthetic Methods for Organic Compounds)
Browse Figures
Versions Notes

Abstract

:
In synthetic organic chemistry, there are very useful basic compounds known as building blocks. One of the main reactions wherein they are applied for the synthesis of complex molecules is the Diels–Alder cycloaddition. This reaction is between a diene and a dienophile. Among the most important dienes are the cyclic dienes, as they facilitate the reaction. This review considers the synthesis and reactivity of one of these dienes with special characteristics—it is cyclic and has an electron withdrawing group. This building block has been used for the synthesis of biologically active compounds and is present in natural compounds with interesting properties.

Graphical Abstract

1. Introduction

One of the reactions that is in the heart of every organic chemist is the Diels–Alder reaction [1]. Dienes are one of the essential components to form the adduct. The reactivity of these compounds in the Diels–Alder reaction varies with electron-withdrawing or donating groups and with conformation restriction as they are part of a cyclic system.
A very special building block is the 1,3-cyclohexadien-1-al. This scaffold is present in natural products isolated from several plants [2,3], such as 2,6,6-trimethyl-1,3-cyclohexadien-1-carboxaldehyde known as safranal 2 that is the main constituent of the essential volatile oil of Crocus sativus L. (saffron) [4], or citral dimer 3, which has been isolated from marine bryozoan Flustra foliacea [5]. Some other examples are compound 5, extracted from black cardamom (Amomum tsao-ko) [6]; compound 6, which is obtained from the fungus Botrytis cinerea [7]; and compound 7 from an Indian fungi Parmelia perlata of Parmelia genus [8], which is used as a food supplement. Moreover several synthetic chiral structures such as compound 4 have been obtained [9] (Figure 1). In particular, safranal 2 can be considered a reference compound containing the 1,3-cyclohexadiene-1-al scaffold showing interesting bioactivities, from neuroprotection [10] to anticancer effects [11]. In this review, aromatic aldehydes were not considered due to the different nature of benzaldehydes and related aromatic derivatives in terms of obtention and reactivity.

2. Synthesis of 1,3-Cyclohexadien-1-Al Scaffold

There are limited methodologies applied to afford 1,3-cyclohexadien-1-al scaffold. Among them, organocatalytic methods are the more versatile ones, creating the 1,3-cyclohexadienal scaffold through one-pot reactions compared with other methodologies using Lewis acids or formylating agents where the reactant already shows the cyclic 1,3-diene or at least the cyclic system.
Herein, we review the reported methodologies applied to the synthesis of 1,3-cyclohexadien-1-als. The described methods can be classified as aldol-type condensations, pericyclic cyclizations, functional group interconversions and transformations, and organometallic and organocatalyzed reactions. The general accessibility to this scaffold by the different methodologies is shown in Figure 2.

2.1. Functional Group Interconversions and Isomerizations

The simple functional group interconversions can be a pathway for the obtention of 1,3-cyclohexadienals, as in the case of the semisynthesis of safranal 2 starting from γ-pyronene 8 [12] (Scheme 1). The epoxidation of 8 results in a mixture of mono and diepoxide derivatives. The isolated exocyclic epoxide 9 (36%) is transformed in two steps into safranal 2. Firstly, halogenation of double bound conducts to 10 quantitatively and then a one-pot reaction consisting in the dibromo elimination and epoxide-opening, allowing the obtention of the 1,3-diene system, wherein the hydroxyl group of the intermediate is oxidized, resulting in safranal 2 in good yield.
Other semisynthesis of safranal 2 starts from α-cyclocitronitrile and takes place in three steps: oxidation, elimination, and reduction [13] (Scheme 2). The epoxidation and epoxide opening by base conducts to the hydroxyderivative 12, which can be eliminated by protonation with p-toluensulfonic acid (TsOH) to afford 13. The reduction of cyano group with diisobutyl aluminium hydride (DIBAL-H) results in safranal 2.
The transformation of botrydial 14 into its derivative botrydienal 6 (Scheme 3) can be triggered under Fetizon conditions with a quantitative yield, as described by Durán-Patrón et al. [14].
Starting from α,β,ε,ζ-unconjugated dienals such as 15, the unconjugated double bond can be isomerized to form the corresponding α,β,γ,δ-unsaturated aldehyde (16) using zeolite-NaY in dry conditions (Scheme 4). Longer reaction periods conduct the aromatization products, although this can be easily controlled [15].

2.2. Oxidation

Using the furfural derivative 17 from a renewable source for its conversion into terephthalic acid, one can obtain the intermediate 18 and the dienic side-product 19 (Scheme 5). The transformation takes place in two steps. Firstly, oxidation and then C2H4 addition catalyzed by silica molecular sieves showing zeolite-β topology containing Lewis acid centers (Zr-β or Sn-β). Despite the obtention of 19 being possible by using both catalysts, when Sn-β is used instead of Zr-β, 19 is obtained with higher yields [16,17]. Low molecular weight 1,3-cyclohexadienals have special relevance in perfumery, with some terpene derivatives being of interest, such as safranal 2 and analogues. In this regard, the conversion of thujone (waste product in forest industry) into different derivatives has been studied, obtaining safranal 2 and analogues [18].

2.3. Vilsmeier–Haack Formylation

When the reactant presents the appropriate enic system, the Vilsmeier reaction can afford the 1,3-cyclohexadien-1-al scaffold. Among several examples, it can be found that the application to tetracyclic triterpenic derivatives 20, 22–24, and 28 [19,20,21,22,23] can be transformed into their corresponding derivatives 21, 25–27, and 29 with moderate or good yields (Scheme 6). Equivalent conditions with POCl3 in the presence of N-formylmorpholine as formylating agent can be used. Such is the case of the transformation of 30 to dienal 31, although lower yield is attained since hydroxyderivative 32 is detected as a by-product [24]. Heterocyclic compounds such as 33 can be transformed into the corresponding heterocyclohexa-1,3-dienals (34) under Vilsmeier–Haack conditions (Scheme 6) [25].
Vilsmeier reaction conditions applied to carvone 35 affords the corresponding 2-chloro-1,3-cyclohexadienal derivative 36 (Scheme 7). However, these reaction conditions show poor yield in the obtention of this product, since two by-products (37 and 38) are generated with significant yields.
Other formylating agents such as DMSO can also be used, starting from the corresponding conjugated enol (Scheme 8). The 1,3-cyclohexadienal obtained has been used as a precursor of diazocine steroid derivatives through eight-member ring formation [26]. Such a transformation is shown below in the reactivity section.

2.4. Aldol-Type Reactions and Horner Olefinations

The 1,3-cyclohexadienal scaffold can also be obtained as a result of glutaraldehyde self-assembly via intramolecular aldol reaction polimerization, as shown in Scheme 9 [27,28]. Through this intramolecular aldol reaction, 1,3-cyclohexadienal compound substituted in C-3 can be obtained.
Aldol reaction and condensation of α,β-aldehydes can be performed in self-condensation or cross-condensation modality.The self-condensation of all-E-retinal 45 can be performed in the presence of sodium hydride (Scheme 10) [29]. The enolate intermediate reacts with the starting aldehyde and cyclizes, forming the 1,3-cyclohexadien-1-al scaffold 48. In the enolate intermediate, the β-methyl group holds the negative charge and reacts at the conjugated position of the aldehyde in a process where the Z/E configuration of double bound is not determinant, allowing in any case the condensation and formation of dienal.
Similar results are obtained with senecialdehyde 47, self-condensation reaction promoted by alkali [30]. In this case, a global yield of 80% is obtained, and compounds 50–52 are obtained in a ratio 2:3:5 (Scheme 11). Cyclodimerization also occurs when crotonaldehyde is treated with solid base catalysts of metal oxides and silica. In this case, the obtained diene can evolve by dehydrogenation and aromatization [31].
Trimethylsilyl and acetate enolderivatives 53 serve as starting material for obtaining 1,3-cyclohexadien-1-als through the lithium enolate formation (Scheme 12). Intermediate 54 can be accessed via metalation of 53 with MeLi. The subsequent addition of a conjugated aldehyde 47 or 51 yields 1,3-cyclohexadienals 50 or 55, respectively. In this manner, lithium enolates are a versatile tool in organic synthesis, allowing for the cross-condensation between two different unsaturated aldehydes, opening the possibilities among the non-chiral condensation methodology [32].
The aldol reaction between aldehyde 46 and its enolate formed in presence of potassium tert-butoxide (t-BuOK) leads to the dimeric intermediate that in acidic medium evolves to form the self-condensation product 49 (Scheme 13) [33]. α,β-Unsaturated nitriles produce analogue condensation mechanism, giving the corresponding 2-amino-1,3-cyclohexadien-1-carbonitrile scaffold; these derivatives can be easily converted to their corresponding aldehydes.
Studying the reactivity of ethyl 4-(diethoxyphosphinyl)-3-oxobutanoate 56 with enals (Scheme 14), one finds that after conjugated Michael addition to the corresponding enal and subsequent Horner reaction over the free carbonyl compound, the formation of cyclic compounds such as dienal 50 (22%) and the major product, the direct Horner reaction product 57 (53%), occurs [34]. The strong basic medium allows for the self-condensation of crotonaldehyde [35].
Starting from linear starting materials, the cyclization to form six-membered rings can be performed in two steps through Horner olefination of α,β-unsaturated aldehydes and Michael addition to the resulting unsaturated system (Scheme 15). Ester reduction yields the 1,3-cyclohexadienal scaffold, wherein relative configuration can be controlled by using different bases for the conjugated addition. This methodology has been used in the total synthesis of natural products containing 1,3-cyclohexadien-1-al scaffolds such as (±)-cis/trans-2,3,3a,7a-tetrahydro-1H-indene-4-carbaldehyde 61 and 63 that have been prepared starting from aldehyde 58 and the ylide of 59 [6]. Similar methodology has been applied for obtaining 1,3-cyclohexadienals due to their interest as intermediates of polysubstituted aromatic compounds, as indicated in the preparation of 67 from 64 and 65 (Scheme 15) [36]. The use of chiral phosphines in this reaction opens the possibility of asymmetric synthesis for this scaffold, as exemplified in the preparation of 71 from 68 using phosphine derivative C, obtaining good enantiomeric excess (ee) and moderate yield [16].

2.5. Pericyclic Reactions: Diels–Alder and Electrocyclizations

The Diels–Alder reaction is the most important and versatile reaction in synthetic organic chemistry for preparing six-membered rings. The 1,3-cyclohexadien-1-al scaffold can be afforded via Diels–Alder reaction by cycloaddition followed by base-promoted β-elimination. For example, intramolecular Diels–Alder reaction of 72 catalysed by a Lewis acid produces the adduct intermediate 73, which can be transformed in the corresponding dienal 74 by elimination reaction (Scheme 16) [37]. Other alternatives for the obtention of 1,3-cyclohexadienal after a Diels–Alder reaction consist of the presence of a good leaving group positioned on the allylic position of the reaction adduct. Starting from the alkylthioenolate 75 [38], by treatment with acrolein, the adduct 76 is formed in low yield, resulting as major product the dienal 77 (60% yield), which could be obtained in higher yield by augmenting the reaction time. When the Diels–Alder reaction is performed with 2-(4-chlorophenylseleno)-2-butenal 78 as dienophile [39], the oxidative deselenylation (with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)) of intermediate 80 conducts to the desired 1,3-cyclohexadienal (81–84) with excellent yields (Scheme 16). However, this oxidation must be carefully controlled, as DDQ can aromatize the ring obtaining the benzaldehyde derivative.
Another example of Diels–Alder cycloaddition wherein a high regioselectivity is reached thanks to the sulfur-containing diene is shown in Scheme 17 [40,41]. The sulfide acts as a regioselective assistant as well as a good leaving group once the adduct is formed, yielding the 1,3-cyclohexadienal. The reaction of the diene 85 with acroleine 86 yields the typical mono-olefin adduct of the Diels–Alder reaction that after elimination of allylic ethylsulfide group yields 1,3-cyclohexadienal 88. The reaction can be catalyzed by ZnBr2, allowing a lower activation energy and thus heating at 60 °C instead of 100 °C. The reaction can be even carried out at 20 °C when LiClO4/Et2O is added as catalyst, but higher reaction times are needed.
The Lewis acid- or Brønsted acid-catalyzed Diels–Alder reaction between cinnamaldehyde 90 and different enamines 89 resulted in 1,3-cyclohexadienal substituted in 5 and 6 positions (Scheme 18). Among the Lewis and Brønsted acids used, TsOH, boron trifluoride ethyl etherate BF3·OEt2, LiClO4, TiCl4, and catalytic TsOH (0.2 equivalents) proved most efficient [42].
By using the Diels–Alder reaction to form the 1,3-cyclohexadienal, one can employ other starting materials such as 2,2-bis(trifluoromethyl)-ethylene-1,1-dicarbonitrile 92, a very strong dienophile (Scheme 19) [43]. However, three transformation steps are needed to form the 1,3-cyclohexadienal from adduct 94. The first step, the Diels–Alder reaction between the dicarbonitrile 92 and the diene 93 occurs in an excellent yield (90%) and can be improved up to 97% when 93 is in excess and increasing reaction time. The elimination of a nitrile group in 94 is carried out by reaction with NaOH in aqueous ethanol, resulting in 95 (97% yield). The formation of diene 96 from 95 takes place in two steps: allylic bromination with N-bromosuccinimide (NBS) and elimination reaction with triethylamine (Et3N). The bromination is a critical step wherein monobromination must be controlled, showing moderate conversion over these two steps (63%) and low yield (32%). Finally, reduction of nitrile 96 with DIBAL-H gives bis-trifluoromethyl-1,3-cyclohexadienal 97 in moderate yield.
Other dienes derived from vinamidinium salts are versatile intermediates to perform Diels–Alder reactions (Scheme 20) [44]. For example, starting from the previously prepared vinamidinium salt 101, reaction with acrylaldehyde results in cyclohexadiene 102. These vinamidinium salt diene precursors are prepared in three steps, starting from unsaturated methylketones such as 98 by reaction with a secondary amine, pyrrolidine in this case. The resulting enamine 99 is tautomerized to the iminium salt 94, and then a second equivalent of secondary amine is added to form the vinamidinium salt 101.
Starting from linear trienes, Lewis acid-catalyzed electrocyclizations form the 1,3-cyclohexadiene-1-carbaldehyde fragment (Scheme 21) [45]. The Z/E configuration of double bonds as well as the presence of large substituents in 5 position are key points in terms of establishing the energy barrier for the electrocyclization to occur.
Organoruthenium complexes can yield 1,3-cyclohexadienal scaffold through a 6e-π electrocyclization (Scheme 22). The reaction takes place between a 1,6-diyne 110 and acroleine [46].

2.6. Organometallic Synthetic Procedures

According to the reaction conditions reported by Corey et al. [47], γ,δ-unsaturated esters can be used as precursors of 1,3-cyclohexadien-1-als (Scheme 23). The transformation of 113 into intermediate 116 by reaction with the previously prepared bis(dimethylaluminium)-1,3-propanethiol followed by a two-step reaction of lithium diisopropylamide/hexamethylphosphoramide (LDA/HMPTA) anion formation and addition of methanol for quenching leads to the desired product 1 in good yield.
An organometallic method using Cr(CO)3 complex and benzaldehyde consisting of its dearomatization and chemoselective nucleophile addition has been reported (Scheme 24) [48]. Starting from benzaldehyde, preparation of the corresponding phenylmethanimine–tricarbonylchromium complex 117 is performed. Addition of a nucleophile is followed in the formation of anionic cyclohexadienyl complex 118 that is trapped with different bromides, providing at the end the 1,3-cyclohexadienal substituted in 5 and 6 positions. Different ratio of products 119 and 120 is obtained depending on the R1 and R2 groups. Compound 119 is preferentially formed when R1 is a phenyl group, while cyclohexadienal 120 is formed selectively when R2 is an allyl or propargyl group.
In these complexes, 117, the imine group, acts as an auxiliary that directs R1 to the ortho position via lithium–nitrogen interaction (Scheme 25). External chiral ligands can be added to the reaction in order to induce stereoselectivity in the product [49], showing the highest enantioselectivities when PhLi is used as nucleophile. The external ligand forms an oligomeric entity with the nucleophile acting as a bridge instead of a simple chelating process.
A selection of nitrogen-containing precursors that can be used to form the corresponding tricarbonylchromium complex is shown in Scheme 26 [48,49,50,51]. These precursors can be prepared using the corresponding amine (R-NH2) and the benzaldehyde unit. When the nitrogen-containing precursor is optically pure, the reaction shows high diastereoselectivity in the addition of nucleophiles in an asymmetric manner (up to 98% diatereomeric excess, de), as in the case of R4.
The tricarbonylchromium-mediated dearomatization is a useful tool to access substituted cyclohexadienals. It has been used to synthesize acetoxytubipofuran, as a reacemic mixture [52] and also as the two separated enantiomers [51]. The natural product, isolated from Tubipora musica, is an eudesmane marine sesquiterpene that has been synthesized from dienal (S,S)-126 and (R,R)-126 as key intermediates, which in turn have been prepared according to the synthetic pathway described in Scheme 27.

2.7. Organocatalytic Methodologies

The access to chiral 1,3-cyclohexadienals can be accomplished by using organocatalysis. This methodology is a versatile method that uses as starting materials an α,β-unsaturated aldehyde and a α,β-unsaturated aldehyde with a methyl or methylene group in β. A high number of proline derivatives have been used as organocatalysts (129–139), as shown in Scheme 28 [53]. Two different mechanisms have been proposed: (4 + 2) cycloaddition or Michael addition and cyclization [53].
The first use of proline as a catalyst begins with its application in the biomimetic cyclization of citral, synthesizing unsaturated aldehydes (Scheme 29) [54,55]. However, the specific use of proline to synthesize 1,3-cyclohexadienals occurred in 1992 [56], where the reaction of this aminoacid with different α,β-unsaturated aldehydes promoted their self-condensation. The good enantiomeric excess (up to 65%) resulted in a deepening of the research on the use of proline as organocatalyst as well as the development of proline analogues with improved catalytic properties. L-proline is used in excess in these reactions and the self-condensation product is always detected. When other proline derivatives such as 4-hydroxy-L-proline, D-proline, and cis-4-hydroxy-D-proline are used, the self-assembly of the aldehydes is observed; however, this self-condensation product of citral is not observed when Trp, His, Arg, Gly, or ILeu are used as catalysts for citral dimerization.
This condensation takes place through Schiff-base formation as a synthetic intermediate that reacts with other equivalents of α,β-unsaturated aldehyde yielding the 1,3-cyclohexadien-1-al core. However, sometimes the intermediate Schiff-base is stable enough and can be isolated, as in the case of the corresponding Schiff-base of L-proline and retinal [53].
In this sense, even when cross-condensation is performed, the autocondensation reaction should be considered as a possible background reaction. In the case of the use of citral, there is frequently the presence of the citral homodimer among the reaction products [57,58], as well as in organocatalyzed cycloaddition in multicomponent reactions [59].
Among the different organocatalysts, the aminocatalysts proline, MacMillan’s 138 or 139, and Hayashi-Jorgensen’s 137 [60] catalysts can promote Michael addition by iminium salt formation with the acceptor enal. On the other hand, a carbonyl donor can be activated by forming the enamine by addition of the organocatalyst and ensuing Michael addition. Thus, iminium salt-enamine formation turns out to be key in these organocatalytic pathways (Scheme 30). Aldehydes such as crotonaldehyde reacts with L-proline through a [3 + 3] cycloaddition, but when other α,β-unsaturated aldehydes with β-substituents react in the same conditions, the observed product is the (4 + 2) adduct [61]. The mechanistic explanation suggests that increasing the steric hindrance in β-position of these series of aldehydes eases the indirect Mannich reaction pathway and (4 + 2) adducts instead of the [3 + 3] cycloaddition products when carbon 3 is more accessible.
The reaction of different aldehydes in the presence of L-proline yields the corresponding (4 + 2) adducts, and results are shown in Table 1 [61]. Pyrrolidine can also be a good catalyst for the (4 + 2) cycloaddition [62], where a wide scope is given. Subsequent aromatization of the diene adducts by reaction with DDQ or MnO2 gives the benzaldehyde derivatives, providing, in this way, a good methodology for controlled substitution of benzaldehyde derivatives.
Watanabe et al. synthesized a high number of 1,3-cyclohexadienal derivatives with different substitution degrees using proline as organocatalyst (Scheme 31) [63]. By this procedure, the homodimerization product can be observed in a variety of yields (5 to 75%), and moderate ee (36 to 72%) are observed, depending on the combination of donor–acceptor aldehydes.
The optimization of the reaction consists of pre-forming the iminium salt of donor aldehyde-proline and then addition of acceptor aldehyde, minimizing in this way the formation of the homo-dimmer.
Intramolecular organocatalyzed cycloaddition has been screened in a variety of cinnamaldehyde derivatives, obtaining dihydrodibenzofurans with good enantioselectivity and yields (Scheme 32) [64].
A formal eliminative (4 + 2) cycloaddition can be performed, starting from a γ-enolizable α,β-unsaturated carbonyl compound (diene) and an enal (dienophile) (Scheme 33) [65]. The addition of an organocatalyst allows for a diastereoselection in the cycloaddition through the formation of the Schiff-base. After screening the reaction conditions and demonstrating the general applicability of the (4 + 2) eliminative cycloaddition, one can apply the procedure to steroid-based dicyano substrates.
The same methodology has been applied to the synthesis of chiral 1,3-cyclohexadienals, where a high diastereoselection has been reported, showing up to a 85:15 diastereomeric ratio and moderate to good yield (Scheme 34) [66].
It is important to highlight the relevance of the β-substitution in donor aldehyde, when instead of a methyl group, the conjugated unsaturation is an exocyclic double bond, and the reactivity for the cyclohexadiene formation decreases, significantly reducing the reaction yield. However, in this case, two chiral centers are generated in the reaction product with excellent diastereoselectivity (Scheme 35).
This organocatalytic process is a very useful tool that can be applied to one-pot reactions where successive cycloadditions are produced. Saktura et al. reported this reaction cascade of uracil and conjugated aldehydes where the 1,3-cyclohexadienal is synthesized in situ as the synthetic equivalent, the enamine 182 (Scheme 36) [67]. The enamine 182 in basic media reacts again with the other equivalent of the conjugated aldehyde 181 to form bicyclo [2.2.2]octane 183.
Other examples of 1,3-cyclohexadien-1-als obtained as synthetic intermediates can be found in the work of Jorgensen, who synthesized tetrahydroisochromenes starting from oxadendralenes (Scheme 37) [68]. In the aim of obtaining the tetrahydroisochromene derivatives in a three-component reaction, research first accomplished screening the reaction conditions to obtain dienal 186. Good yield and diastereoselectivity is obtained in the reaction of aldehyde 184 and 185 in the presence of organocatalyst S-137, obtaining the oxadendralene intermediate (Scheme 37). Once this reaction is viable, the next step involves the reaction with vinyl ether 187. The cyclization occurs in the presence of a co-catalyst such as Eu(fod)3 (10 mol %), resulting in the desired tetrahydrochromene 188.

3. Reactivity of 1,3-Cyclohexadien-1-Als

The 1,3-cyclohexadien-1-carboxaldehyde unit is a highly functionalized small molecule with high potential as building block, and as such it has been used widely for the construction of a great variety of compounds. Reactivity of the functional groups in the scaffold has been harnessed, and a great deal of transformations involve typical reactions of the double bond functional group, aldehyde functional group, and the α,β-unsaturated aldehyde system. Several examples of each of these three types of reactivity are shown below.

3.1. Reactions Involving Double Bond(s)

1,3-Cyclohexadien-1-carboxaldehyde 1 was considered as a starting material in the total synthesis of fumagillol 190 [69,70], in which the first step implies dihydroxylation of the more electron rich γ,δ-double bond (Scheme 38).
Dihydroxylation reaction of cyclohexadienal 150 (Scheme 39) to diol 192 was also considered in the total synthesis of (+) palitantin [71], a natural compound with antifungal [72] and antibiotic activities [73]. The cyclohexadiene carboxaldehyde intermediate 150 was obtained by self-dimerizacion of (E)-4-acetoxycrotonaldehyde 191 in the presence of L-proline [71].
The preparation of hexafluorinated safranal 97 has been achieved by Haas et al. (Scheme 40) [43]. Hydrogenation of the C3–C4 double bond in such a compound in the presence of palladium on charcoal catalyst led to another hexafluorinated natural product, 7,7,7,8,8,8-hexafluoro-β-cyclocitral 194.
Trost et al. recently presented an interesting study about the catalytic palladium oxyally cycloaddition reaction with conjugated dienes [74], wherein 1,3-cyclohexadiene-1-carboxaldehyde was also tested, giving the corresponding bicyclic tetrahydrofuran product 196 with extraordinary chemoselectivity (Scheme 41). This shows once more the versatility of the cyclohexadienal unit, which can be involved in many different transformations.
Tricarbonyl iron complex of 1,3-cyclohexadiene-1-carboxaldehyde 1 has been prepared in a photochemical reaction with iron pentacarbonyl (Scheme 42) [75]. Such complex 197 was synthesized in the route to structurally constrained tricarbonyl (trans-pentadienyl) iron cations 199 to study acid catalyzed rearrangements.
Aromatization of cyclohexadienals has been used to prepare aromatic aldehydes (Scheme 43) [76]. Oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) allows for the aromatization reaction with moderate to high yields.
Phenyl-substituted cyclohexadienals 200 were found to spontaneously aromatize in low conversion of 5–15% in a period of one to several days [63]. However, aromatization could also be performed in quantitative yields by reaction with potassium permanganate (Scheme 44). Those aromatic compounds 201 could find use as fluorescent probes to identify the protein binding partner of a particular cyclohexadienal in studies of such compounds to activate neurite outgrowth activity [63]. The cyclohexadienal core 200 was generated by a cross-condensation reaction of α,β-unsaturated aldehydes mediated by L-proline (Scheme 44).
In line with this, the above reaction sequence of organocatalytic synthesis of the cyclohexadiene carboxaldehyde unit and subsequent oxidation reaction has been used as a fair strategy for the preparation of multi-substituted aromatic aldehydes [62]. Scheme 45 depicts a (4 + 2) and (3 + 3) cycloaddition of α,β-unsaturated aldehydes mediated by L-proline 131 or pyrrolide 129/acetic acid (AcOH) to afford the cyclohexadiene carboxaldehyde intermediate that was not isolated and spontaneously oxidize or directly submitted to oxidation reaction conditions with MnO2 or DDQ for the formation of the aromatic compound [62].
In the following example (Scheme 46), pentasubstituted aromatic compounds are prepared under the above mentioned reaction sequence via intermediate cyclohexadiene carboxaldehyde 202 that was oxidized with atmospheric air appealing, therefore, in this case, under environmentally friendly reaction conditions [77]. Intermediate cyclohexadienal 202 is formed via a Michael type cascade reaction mediated by organocatalyst 137.

3.2. Reactions Involving the Aldehyde Functional Group

Oxidation of the aldehyde group in 1,3-cyclohexadien-1-carboxaldehyde to the carboxylic acid has been achieved with silver hydroxide prepared in situ (Scheme 47) [78]. Compound 203 was used in the cycloaddition reaction with 4-N-methyl-1,2,4-triazolin-3,5-dione 204.
Reduction reactions of the aldehyde group in the cyclohexadienal core have also been described. In this manner, the natural product safranal 2 was converted to the corresponding alcohol 206 in near quantitative yield with LiAlH4 (Scheme 48) [79]. The resultant alcohol 206 was submitted to a photooxygenation reaction for the formation of endoperoxide 207 in a chemoselective singlet oxygen (4 + 2) cycloaddition reaction. That transformation was also assayed directly on safranal compound 2. However, the desired endoperoxide 208 turned out to decompose in this case.
Reduction of the aldehyde group in natural aldehydes 61 and 63 has been performed with the aim of confirming the structure of such natural compounds (Scheme 49) [6]. Aldehyde 63 present in black cardamom has been found to produce a trigeminal effect in the mouth.
The great versatility of the cyclohexadiene carboxaldehyde moiety is demonstrated in the utilization of such scaffold in the total synthesis of many varied compounds. That is the case of the citotoxic compound acetoxytubipofuran (Scheme 50). The strategy followed for its synthesis implies a tricarbonyl chromium-mediate dearomatization to access the substituted cyclohexadiene carboxaldehyde compound 126 [51]. Further transformations to the final acetoxytubipofuran are followed. Among them, reduction of the aldehyde moiety in the cyclohexadienal core is performed with NaBH4 in the presence of CeCl3 (Scheme 50).
The synthesis of (−)-drimenol has also been achieved by means of a reduction reaction of the corresponding cyclohexadiene carboxaldehyde derivative (Scheme 51) [80]. Such reduction reaction unexpectedly involved the whole α,β-γ,δ-unsaturated aldehyde system. (−)-Drimenol, in turn, has been used as starting material in the synthesis of (−)-polygodial [81] and (−)-warburganal [82] (Scheme 51).
Another typical reaction of the aldehyde functional group is the Horner–Wadsworth–Emmons coupling with phosphonates [13]. Such transformation was the choice for the conversion of safranal 2 to 3,4-didehydroretinal 45 involving two consecutive phosphonate coupling reactions and reductions (Scheme 52).
Reaction of the aldehyde group with organometallic compounds has been used for the construction of miscellaneous structures. This is the case of the preparation of β-damascenone, wherein safranal 2 was reacted with the corresponding Grignard reagent (Scheme 53) [18]. Subsequent oxidation with MnO2 produced β-damascenone. Isomerization of the double bond on the side chain can be accomplished with para-toluensulfonic acid to obtain β-damascenone in higher yield (Scheme 53).
Scheme 54 shows the reaction of cyclohexadiene carboxaldehyde unit with another Grignard reagent bearing a silicon group [83].
In the synthesis of tritium labelled 9-cis-retinoic acid 213 (Scheme 55), a key reaction of the cyclohexadienal core with an organolithium reagent was used in the initial stages [84].
The aldehyde functional group has been harnessed in intramolecular (macro)cyclization reactions. Such is the case of the preparation of diazecine derivatives by intramolecular Schiff-base formation in the presence of boric acid (Scheme 56) [26].
The synthesis of diterpenoid eunicellane skeletons 219 incorporating 1,3-cyclohexadiene moiety is shown in Scheme 57, wherein a key step is the intramolecular pinacol macrocyclization reaction induced by low valent titanium under McMurry conditions [85].
Another example of utilization of the aldehyde group of the cyclohexadienal core in intramolecular macrocyclization reaction is shown in Scheme 58 [86]. In this case, reaction of the aldehyde with the in situ-prepared organolithium reagent was accomplished using high dilution conditions in the presence of CeCl3.

3.3. Reactions Involving the α,β-Unsaturated Aldehyde System

Reactivity of the α,β-unsaturated aldehyde system has been utilized in the preparation of highly elaborated compounds. As an example, reaction of cyclohexadienal derivative 74 with an organocuprate is shown in Scheme 59, yielding mainly the 1,4-addition product [37].
The α,β-unsaturated aldehyde system in 222 can participate in an inverse electron demand hetero-Diels–Alder reaction with a vinylether 223 to form tetrahydroisochromene 224, presenting five continuous stereocenters (Scheme 60) [68]. Such transformation has been achieved by means of the Lewis acid catalyst Eu(fod)3 [fod = 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octadienoate). In fact, the reaction is carried out in a one-pot fashion wherein organocatalytic annulation with formation of the cyclohexadiene dicarboxaldehyde 222 is followed by the hetero-Diels–Alder reaction by addition of the vinyl ether and the Lewis acid catalyst that should be compatible with the previous organocatalytic reaction conditions.
Such a reaction concept has been extended further to achieve the sequential organocatalytic annulation reaction forming intermediate 222 and the subsequent cycloaddition reaction with a different aldehyde 225 (Scheme 61) [68]. In both cases, tetrahydroisochromenes 224 are formed in good yields and excellent stereoselectivities, and the great versatility of the cyclohexadienal core is highlighted.

4. Biological Activities of 1,3-Cyclohexadien-1-Carboxaldehyde

A variety of bioactivities have been reported for compounds containing the 1,3-cyclohexadienal scaffold: neuroprotective, anti-inflammatory, antibacterial, anticancer, cytotoxic, and phytotoxic.
Apart from the organoleptic properties of Vitis vinifera that in part could be due to 1,3-cyclohexadien-1-carboxaldehyde, the main biological properties of this class of compounds have been studied in saffron. The saffron aqueous extract inhibits the chemically induced gastric cancer progression in the Wistar albino rat [87,88,89]. Safranal 2, which is present in the flowers of Crocus sativus L., has been studied profusely, and many biological activities have been found for it. Safranal 2 has been proved to be a neuroprotective and anti-inflamatory agent [90,91,92,93,94,95,96,97,98,99]. Recently, Prof. Watanabe and colleagues have been involved in the study of substituted heterodimeric compounds generated by proline-mediated condensation of α,β-unsaturated aldehydes [53] (Figure 3).
Prof. Watanabe and colleagues evaluated the library of compounds for their ability to stimulate neurite outgrowth in a PC12 assay [63]. Two heterodimers, 230 and 231, were able to stimulate neurite outgrowth, while homodimer 232 supported the development of neural extensions. It is interesting to highlight that the same compound 230 together with 233–235 demonstrated complete inhibition of cell growth at 1μg/mL against Jurkats, a human T cell leukemia cell line. Two compounds, 236 and 237, were reasonably active against Bacillus subtilis, with MIC values within the 10–25 μg/mL range.
Recent studies with Crocus sativus L. (saffron) extract as well as its main constituents—crocin, crocetin, and safranal 2—show interesting anticancer properties (Table 2). However, more studies are needed in order to evaluate the real single effect of each component, as in the combined treatment they may act synergistically against malignant cells. The in vitro results for safranal 2 showed a positive effect in leukemia and breast cancer and is a promising agent for treatment, prevention, and combined therapy for liver cancer [11].
The 1,3-cyclohexadienals such as safranal 2 are the direct precursors of endoperoxides such as 208 that show antimalarial activity [15,79].
Compound 6, when compared with Botrydial as a reference compound for phytotoxicity and antibiotic activity, showed slightly less activity for these bioassays [7,14,100]. However, 6 is more active than other structurally-related Botrydial derivatives; thus, the 1,5-dialdehyde moiety seems to be fundamental for keeping Botrydial activity [7]. The structure-activity relationship studies for Botrydial analogues showed that the higher Michael acceptor capacity, the lower antibiotic and phytotoxicicty activities.
The use of Indian fungi of Parmelia genus as a food supplement, aimed the study of Parmelia perlata crude extracts, showed antimicrobial and antifungal activity. Among the isolated compounds from Parmelia perlata extracts, 7 is present, showing potent antibacterial activity and moderate antifungal activity compared with the other compounds isolated from the extract [8].
The in vitro assays of compound 36, which was evaluated on human keratinocyte NCT 2544 cell line and three different in vitro studies, showed higher cytotoxicity compared with its corresponding aromatized analogue. Cyclohexadienal 36 shows similar IC50 values compared with SDS (sodium dodecyl sulfate), IC50 = 0.12 mM and IC50 = 0.13 mM, respectively, and thus it can be considered a strong irritant [101].
Cyclohexadienal 238 shows potent antibiotic activity against methicillin-susceptible, methicillin-resistant, and tetracycline-resistant Staphilococcus aureus (MSSA, MRSA, and TRSA, respectively). The bactericidal activities (MBCs) were lower due to the oxygen bearing substituent proximal to C-3 [102].

5. Conclusions

The 1,3-cyclohexadien-1-al scaffold is a naturally occurring fragment with special interest due to its presence in safranal (Crocus sativus) or citral dimer (Flustra foliacea) with antioxidant, neuroprotective, and antiinflamatory bioactivities. Different synthetic 1,3-cyclohexadien-1-als have also shown important biological activities such as cytotoxic, phytotoxic, antibiotic, and activator of neurite outgrowth. In this manner, the synthesis of new 1,3-cyclohexadien-1-als is of interest in medicinal chemistry as a potential source of bioactive compounds.
The different synthetic methodologies that have been used to obtain this scaffold are functional group interconversion, isomerization, Vilsmeier–Haack formylation, aldol-type and Horner reactions, organometallic reactions and organocatalysis-mediated transformations. Among them, the methods affording chiral 1,3-cyclohexadienal are pericyclic reactions, organometallic, chiral phosphine Horner reactions, and organocatalytic procedures. The latter organocatalytic methodologies have been the most widely used for this purpose.
Furthermore, a great versatility has been shown for the 1,3-cyclohexadien-1-carbaldehyde unit as building block with its participation in many different reactions for the construction of a great variety of compounds.
In summary, this manuscript shows the importance of the 1,3-cyclohexadien-1-als in organic synthesis, not only as building blocks but also in their biological activities as key compounds of interest in medicinal chemistry.

Author Contributions

D.D. designed the manuscript, and I.E.T., R.B., N.M.G., and P.G.-G. wrote the manuscript and made considerations to it. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Junta de Castilla y León, grant number SA076P20, UIC021” FEDER funds and University of Salamanca (Programa I. Programa de financiación de grupos de investigación, 2020 and Modalidad C2, 2021). The financial support is gratefully acknowledged. IET thanks the FSE (European Social Fund) and Junta de Castilla y León for his grant.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Diels, O.; Alder, K. Syntheses in the hydroaromatic series. I. Addition of “diene” hydrocarbons. Justus Liebigs Ann. Chem. 1928, 460, 98–122. [Google Scholar] [CrossRef]
  2. Griesser, M.; Weingart, G.; Schoedl-Hummel, K.; Neumann, N.; Becker, M.; Varmuza, K.; Liebner, F.; Schuhmacher, R.; Forneck, A. Severe drought stress is affecting selected primary metabolites, polyphenols, and volatile metabolites in grapevine leaves (Vitis vinifera cv. Pinot noir). Plant Physiol. Biochem. 2015, 88, 17–26. [Google Scholar] [CrossRef] [PubMed]
  3. Mastelić, J.; Jerković, I.; Mesić, M. Volatile constituents from flowers, leaves, bark and wood of Prunus mahaleb L. Flavour Fragr. J. 2006, 21, 306–313. [Google Scholar] [CrossRef]
  4. Tarantilis, P.A.; Tsoupras, G.; Polissiou, M. Determination of saffron (Crocus sativus L.) components in crude plant extract using high-performance liquid chromatography-UV-visible photodiode-array detection-mass spectrometry. J. Chromatogr. A 1995, 699, 107–118. [Google Scholar] [CrossRef]
  5. Peters, L.; Wright, A.D.; Krick, A.; König, G.M. Variation of brominated indoles and terpenoids within single and different colonies of the marine bryozoan Flustra foliacea. J. Chem. Ecol. 2004, 30, 1165–1181. [Google Scholar] [CrossRef] [PubMed]
  6. Starkenmann, C.; Mayenzet, F.; Brauchli, R.; Wunsche, L.; Vial, C. Structure Elucidation of a Pungent Compound in Black Cardamom: Amomum Tsao-Ko Crevost Et Lemarié (Zingiberaceae). J. Agric. Food Chem. 2007, 55, 10902–10907. [Google Scholar]
  7. Reino, J.L.; Durán-Patrón, R.; Segura, I.; Hernández-Galán, R.; Riese, H.H.; Collado, I.G. Chemical transformations on botryane skeleton. Effect on the cytotoxic activity. J. Nat. Prod. 2003, 66, 344–349. [Google Scholar] [CrossRef] [PubMed]
  8. Thippeswamy, B.; Sushma, N.; Naveenkumar, K. Evaluation of antimicrobial property of lichen-Parmelia perlata. Afr. J. Pharm. Pharmacol. 2013, 7, 1242–1250. [Google Scholar]
  9. Jacques, B.; Eloi, A.; Chavarot-Kerlidou, M.; Rose-Munch, F.; Rose, E.; Gérard, H.; Herson, P. Unprecedented (η5-Formylcyclohexadienyl)Mn(CO)3 Complexes: Synthesis, Structural and Theoretical Characterizations, and Resolution of the Planar Chirality. Organometallics 2008, 27, 2505–2517. [Google Scholar]
  10. Papandreou, M.A.; Kanakis, C.D.; Polissiou, M.G.; Efthimiopoulos, S.; Cordopatis, P.; Margarity, M.; Lamari, F.N. Inhibitory activity on amyloid-β aggregation and antioxidant properties of Crocus sativus stigmas extract and its crocin constituents. J. Agric. Food Chem. 2006, 54, 8762–8768. [Google Scholar] [CrossRef]
  11. Lambrianidou, A.; Koutsougianni, F.; Papapostolou, I.; Dimas, K. Recent Advances on the Anticancer Properties of Saffron (Crocus sativus L.) and Its Major Constituents. Molecules 2021, 26, 86. [Google Scholar] [CrossRef] [PubMed]
  12. Boulin, B.; Arreguy-San Miguel, B.; Delmond, B. Le γ-Pyronène: Synthon d’Accès au Safranal et Précurseur d’Intermédiaires de Synthèse de la Forskoline et du Strigol. Tetrahedron 1998, 54, 2753–2762. [Google Scholar] [CrossRef]
  13. van Wijk, A.A.C.; van de Weerd, M.B.; Lugtenburg, J. Synthetic Scheme for the Preparation of 13C-Labeled 3,4-Didehydro-Retinal, 3-Hydroxyretinal, and 4-Hydroxyretinal up to Uniform 13C-Enrichment. Eur. J. Org. Chem. 2003, 2003, 863–868. [Google Scholar] [CrossRef]
  14. Durán-Patrón, R.; Hernández-Galán, R.; Rebordinos, L.G.; Cantoral, J.M.; Collado, I.G. Structure-activity relationships of new phytotoxic metabolites with the botryane skeleton from Botrytis cinerea. Tetrahedron 1999, 55, 2389–2400. [Google Scholar] [CrossRef]
  15. Emmanuel Hatzakis, I.O.; Bogdan, A. Solaja and Manolis Stratakis Synthesis of Novel Polar Derivatives of the Antimalarial Endoperoxides Ascaridole and Dihydroascaridole. ARKIVOC 2007, 8, 124–135. [Google Scholar]
  16. Pacheco, J.J.; Davis, M.E. Synthesis of terephthalic acid via Diels-Alder reactions with ethylene and oxidized variants of 5-hydroxymethylfurfural. Proc. Natl. Acad. Sci. USA 2014, 111, 8363–8367. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Pacheco, J.J.; Labinger, J.A.; Sessions, A.L.; Davis, M.E. Route to Renewable PET: Reaction Pathways and Energetics of Diels–Alder and Dehydrative Aromatization Reactions Between Ethylene and Biomass-Derived Furans Catalyzed by Lewis Acid Molecular Sieves. ACS Catal. 2015, 5, 5904–5913. [Google Scholar] [CrossRef]
  18. Kutney, J.P.; Gunning, P.J.; Clewley, R.G.; Somerville, J.; Rettig, S.J. The chemistry of thujone. XVI. Versatile and efficient routes to safronitrile, β-cyclogeranonitrile, β-cyclocitral, damascones, and their analogues. Can. J. Chem. 1992, 70, 2094–2114. [Google Scholar] [CrossRef] [Green Version]
  19. Gogoi, J.; Bezbaruah, P.; Saikia, P.; Goswami, J.; Gogoi, P.; Boruah, R.C. Synthesis of a novel class of steroidal tetrazolo[1,5-a]pyridines via intramolecular 1,3-dipolar cycloadditions. Tetrahedron Lett. 2012, 53, 1497–1500. [Google Scholar] [CrossRef]
  20. Jones, G.; Stanforth, S.P. The Vilsmeier Reaction of Non-Aromatic Compounds. In Organic Reactions; Overman, L.E., Ed.; Willey: Hoboken, NJ, USA, 2004; Volume 56, pp. 355–686. [Google Scholar]
  21. Laurent, H.; Wiechert, R. Synthesis and reactions of 3-chlor-2-formyl-steroids. Chem. Ber. 1968, 101, 2393–2403. [Google Scholar] [CrossRef]
  22. Consomi, A.; Mancini, F.; Pallini, U.; Patelli, B.; Sciaki, R. Reactions of dienamines and dienol ethers. Gazz. Chim. Ital. 1970, 100, 244. [Google Scholar]
  23. Laurent, H.; Schulz, G.; Wiechert, R. Notiz über die Darstellung von 7-Chlor-2-formyl-Δ2.4.6-steroiden. Chem. Ber. 1966, 99, 3057–3059. [Google Scholar] [CrossRef]
  24. Katritzky, A.R.; Marson, C.M.; Wang, Z. Reactions of alkyl-substituted 2-cyclohexen-1-ones with Vilsmeier reagents. J. Org. Chem. 1987, 52, 2730–2734. [Google Scholar] [CrossRef]
  25. Escher, I.; Glorius, F. Science of Synthesis; Thieme Chemistry; Georg Thieme Verlag KG Stuttgart: Stuttgart, Germany, 2007; Volume 25, p. 711. [Google Scholar]
  26. Lauro, F.-V.; Francisco, D.C.; Marcela, R.-N.; Virginia, M.-A.; Elodia, G.-C.; Eduardo, P.G.; Lenin, H.; Maria, L.-R.; Alondra, L.-J.; Jhair, C.-T. Design and Synthesis of two Steroid-diazocine derivatives. Heterocycl. Lett. 2018, 8, 745–753. [Google Scholar]
  27. Migneault, I.; Dartiguenave, C.; Bertrand, M.J.; Waldron, K.C. Glutaraldehyde: Behavior in aqueous solution, reaction with proteins, and application to enzyme crosslinking. BioTechniques 2004, 37, 798–802. [Google Scholar] [CrossRef]
  28. Zhang, H.; Fei, J.; Yan, X.; Wang, A.; Li, J. Enzyme-Responsive Release of Doxorubicin from Monodisperse Dipeptide-Based Nanocarriers for Highly Efficient Cancer Treatment In Vitro. Adv. Funct. Mater. 2015, 25, 1193–1204. [Google Scholar] [CrossRef]
  29. Verdegem, P.J.E.; Monnee, M.C.F.; Mulder, P.P.J.; Lugtenburg, J. Condensation of all-E-retinal. Tetrahedron Lett. 1997, 38, 5355–5358. [Google Scholar] [CrossRef]
  30. Dyakonova, I.A.; Cherkaev, G.V.; Erman, M.B. Alkali-catalysed Self-condensation of 3-Methylbut-2-enal: Formation of Novel Rosoxide Dehydro Analogue. Mendeleev Commun. 1994, 4, 88. [Google Scholar] [CrossRef]
  31. Kurokawa, H.; Yanai, M.; Ohshima, M.-A.; Miura, H. Cyclodimerization of crotonaldehyde to form cyclohexadienecarbaldehydes and tolaldehydes over solid base catalysts. React. Kinet. Mech. Catal. 2012, 105, 401–412. [Google Scholar] [CrossRef]
  32. Duhamel, L.; Guillemont, J.; Poirier, J.-M.; Chabardes, P. A new prenylation method using the lithium enolate of prenal. Reaction with aldehydes and α,β-unsaturated aldehydes. Tetrahedron Lett. 1991, 32, 4495–4498. [Google Scholar] [CrossRef]
  33. Valla, A.; Andriamialisoa, Z.; Labia, R. Synthesis of new cyclic retinoids via base induced self-condensation of C-13, C-14 and C-15 units. Tetrahedron Lett. 2000, 41, 3359–3362. [Google Scholar] [CrossRef]
  34. Moorhoff, C.M.; Schneider, D.F. Comments on the reaction of ethyl 4-(diethoxyphosphinyl)-3-oxobutanoate and related phosphonate esters with enals. Tetrahedron Lett. 1987, 28, 559–562. [Google Scholar] [CrossRef]
  35. Moorhoff, C.M.; Schneider, D.F. Condensation of ethyl and methyl 4-(triphenylphosphoranylidine)-3-oxobutanoate with enals. Tetrahedron Lett. 1987, 28, 4721–4724. [Google Scholar] [CrossRef]
  36. Ye, L.-W.; Han, X.; Sun, X.-L.; Tang, Y. Tandem Michael addition/ylide olefination reaction for the synthesis of highly functionalized cyclohexadiene derivatives. Tetrahedron 2008, 64, 8149–8154. [Google Scholar] [CrossRef]
  37. Marshall, J.A.; Audia, J.E.; Shearer, B.G. Conjugate addition of organocuprates to trans-4a,5,6,7,8,8a-hexahydronaphthalene-1-carboxaldehydes. Synthesis of a chlorothricin degradation product. J. Org. Chem. 1986, 51, 1730–1735. [Google Scholar] [CrossRef]
  38. De Groot, A.; Jansen, B.J.M. Diels-Alder Reaction of Exocyclic Sulfur-Substituted 1,3-Dienes. Synthesis 1978, 1978, 52–53. [Google Scholar] [CrossRef]
  39. Kenji, U.; Kunikazu, T.; Sigeru, T. 2-(4-Chlorophenylseleno)-2-butenal as a New Dienophile for Diels-Alder Reaction. Bull. Chem. Soc. Jpn. 1983, 56, 2867–2868. [Google Scholar] [CrossRef]
  40. Skowroriska, A.; Dybowski, P.; Koprowski, M.; Krawczyk, E. The Diels-Alder Reactions of (Z)-1,2-Diheterosubstituted-1,3-Dienes. Sulfur as a Regiochemical Control. Tetrahedron Lett. 1995, 36, 8133–8136. [Google Scholar] [CrossRef]
  41. Koprowski, M.; Skowrońska, A.; Główka, M.L.; Fruziński, A. Fully regio- and endo-stereoselective synthesis of new polycyclic allylic sulfides via a Diels–Alder reaction. Synthetically useful transformations of these sulfides. Tetrahedron 2007, 63, 1211–1228. [Google Scholar] [CrossRef]
  42. Kotschy, A.; Hajós, G.; Timári, G.; Messmer, A.; Schantl, J.G. “Ionic Diels-Alder Reaction” of Hetaryldienamines. Heterocycl. Commun. 1997, 3, 449. [Google Scholar] [CrossRef]
  43. Brandt, K.; Haas, A.; Hardt, T.; Mayer-Figge, H.; Merz, K.; Wallmichrath, T. Synthesis of geminal-bis(trifluoromethyl)-substituted dienes, heterodienes, 7,7,7,8,8,8-hexafluoro-β-cyclocitral and -safranal. J. Fluor. Chem. 1999, 97, 115–125. [Google Scholar] [CrossRef]
  44. Zhou, S.; Sánchez-Larios, E.; Gravel, M. Scalable Synthesis of Highly Reactive 1,3-Diamino Dienes from Vinamidinium Salts and Their Use in Diels–Alder Reactions. J. Org. Chem. 2012, 77, 3576–3582. [Google Scholar] [CrossRef]
  45. Bishop, L.M.; Roberson, R.E.; Bergman, R.G.; Trauner, D. On the Development of Catalytic Carba-6π Electrocyclizations. Synthesis 2010, 2010, 2233–2244. [Google Scholar] [CrossRef] [Green Version]
  46. Varela, J.A.; Rubín, S.G.; González-Rodríguez, C.; Castedo, L.; Saá, C. A New Ru-Catalyzed Cascade Reaction Forming Polycyclic Cyclohexadienes from 1,6-Diynes and Alkenes. J. Am. Chem. Soc. 2006, 128, 9262–9263. [Google Scholar] [CrossRef]
  47. Corey, E.J.; Kozikowski, A.P. Bis(dimethylaluminum) 1,3-propanedithiolate–a useful reagent in the conversion of esters to unsaturated aldehydes and ketones. Tetrahedron Lett. 1975, 16, 925–928. [Google Scholar] [CrossRef]
  48. Kuendig, E.P.; Ripa, A.; Liu, R.; Bernardinelli, G. Arenes to Substituted Cyclohexadienes: Nucleophile/Electrophile Additions across an Arene Double Bond. J. Org. Chem. 1994, 59, 4773–4783. [Google Scholar] [CrossRef]
  49. Amurrio, D.; Khan, K.; Kündig, E.P. Asymmetric Addition of Organolithium Reagents to Prochiral Arene Tricarbonylchromium Complexes. J. Org. Chem. 1996, 61, 2258–2259. [Google Scholar] [CrossRef]
  50. Bernardinelli, G.; Gillet, S.; Kündig, E.P.; Liu, R.; Ripa, A.; Saudan, L. Diastereoselective Transformation of Arenes into Highly Enantiomerically Enriched Substituted Cyclohexadienes. Synthesis 2001, 2001, 2040–2054. [Google Scholar] [CrossRef]
  51. Kündig, E.P.; Cannas, R.; Laxmisha, M.; Ronggang, L.; Tchertchian, S. Chromium-Mediated Asymmetric Synthesis of Both Enantiomers of Acetoxytubipofuran. J. Am. Chem. Soc. 2003, 125, 5642–5643. [Google Scholar] [CrossRef] [PubMed]
  52. Kündig, E.P.; Laxmisha, M.S.; Cannas, R.; Tchertchian, S.; Ronggang, L. Chromium-Mediated Dearomatization: Application to the Synthesis of Racemic 15-Acetoxytubipofuran and Asymmetric Synthesis of Both Enantiomers. Helv. Chim. Acta 2005, 88, 1063–1080. [Google Scholar] [CrossRef]
  53. Bench, B.J.; Liu, C.; Evett, C.R.; Watanabe, C.M.H. Proline Promoted Synthesis of Ring-Fused Homodimers:  Self-Condensation of α,β-Unsaturated Aldehydes. J. Org. Chem. 2006, 71, 9458–9463. [Google Scholar] [CrossRef]
  54. Yamada, S.-I.; Shibasaki, M.; Terashima, S. A biogenetic-type asymmetric cyclization syntheses of optically active α-cyclocitral and trans-α-damascone. Tetrahedron Lett. 1973, 14, 381–384. [Google Scholar] [CrossRef]
  55. Yamada, S.-I.; Shibasaki, M.; Terashima, S. A new biogenetic-type cyclization of citral to α-cyclocitral via an enamine. Tetrahedron Lett. 1973, 14, 377–380. [Google Scholar] [CrossRef]
  56. Asato, A.E.; Watanabe, C.; Li, X.-Y.; Liu, R.S.H. The proline and β-lactoglobulin mediated asymmetric self-condensation of β-ionylideneacetaldehyde, retinal and related compounds. Tetrahedron Lett. 1992, 33, 3105–3108. [Google Scholar] [CrossRef]
  57. Paduraru, M.P.; Wilson, P.D. Synthesis of the Polycyclic Ring Systems of Artocarpol A and D. Org. Lett. 2003, 5, 4911–4913. [Google Scholar] [CrossRef] [PubMed]
  58. Peña, J.; Moro, R.F.; Basabe, P.; Marcos, I.S.; Díez, D. Solvent free l-proline-catalysed domino Knoevenagel/6π-electrocyclization for the synthesis of highly functionalised 2H-pyrans. RSC Adv. 2012, 2, 8041–8049. [Google Scholar] [CrossRef]
  59. Weber, A.K.; Schachtner, J.; Fichtler, R.; Leermann, T.M.; Neudörfl, J.M.; Jacobi von Wangelin, A. Modular synthesis of cyclic cis- and trans-1,2-diamine derivatives. Org. Biomol. Chem. 2014, 12, 5267–5277. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Hayashi, Y.; Kawamoto, Y.; Honda, M.; Okamura, D.; Umemiya, S.; Noguchi, Y.; Mukaiyama, T.; Sato, I. Diphenylprolinol Silyl Ether Catalyzed Asymmetric Michael Reaction of Nitroalkanes and β,β-Disubstituted α,β-Unsaturated Aldehydes for the Construction of All-Carbon Quaternary Stereogenic Centers. Chem. A Eur. J. 2014, 20, 12072–12082. [Google Scholar] [CrossRef]
  61. Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Liao, J.-H. Enantioselective Organocatalytic Formal [3 + 3]-Cycloaddition of α,β-Unsaturated Aldehydes and Application to the Asymmetric Synthesis of (−)-Isopulegol Hydrate and (−)-Cubebaol. Org. Lett. 2006, 8, 2217–2220. [Google Scholar] [CrossRef] [PubMed]
  62. Hong, B.-C.; Tseng, H.-C.; Chen, S.-H. Synthesis of aromatic aldehydes by organocatalytic [4+2] and [3+3] cycloaddition of α,β-unsaturated aldehydes. Tetrahedron 2007, 63, 2840–2850. [Google Scholar] [CrossRef]
  63. Bench, B.J.; Tichy, S.E.; Perez, L.M.; Benson, J.; Watanabe, C.M.H. Synthesis and cellular effects of cycloterpenals: Cyclohexadienal-based activators of neurite outgrowth. Bioorganic Med. Chem. 2008, 16, 7573–7581. [Google Scholar] [CrossRef]
  64. Wang, Z.-Y.; Wong, W.-T.; Yang, D. Organocatalyzed Asymmetric Synthesis of Dihydrodibenzofurans Based on a Dienamine Process. Org. Lett. 2013, 15, 4980–4983. [Google Scholar] [CrossRef]
  65. Brindani, N.; Rassu, G.; Dell’Amico, L.; Zambrano, V.; Pinna, L.; Curti, C.; Sartori, A.; Battistini, L.; Casiraghi, G.; Pelosi, G.; et al. Organocatalytic, Asymmetric Eliminative [4+2] Cycloaddition of Allylidene Malononitriles with Enals: Rapid Entry to Cyclohexadiene-Embedding Linear and Angular Polycycles. Angew. Chem. Int. Ed. 2015, 54, 7386–7390. [Google Scholar] [CrossRef]
  66. Urosa, A.; Tobal, I.E.; de la Granja, Á.P.; Capitán, M.C.; Moro, R.; Marcos, I.S.; Garrido, N.M.; Sanz, F.; Calle, E.; Díez, D. Diastereoselective synthesis of chiral 1,3-cyclohexadienals. PLoS ONE 2018, 13, e0192113. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Saktura, M.; Frankowski, S.; Joachim, B.; Albrecht, Ł. Aminocatalytic Synthesis of Uracil Derivatives Bearing a Bicyclo[2.2.2]octane Scaffold via a Doubly Cycloadditive Reaction Cascade. Synthesis 2020. [Google Scholar] [CrossRef]
  68. Hammer, N.; Leth, L.A.; Stiller, J.; Jensen, M.E.; Jørgensen, K.A. Oxadendralenes in asymmetric organocatalysis for the construction of tetrahydroisochromenes. Chem. Sci. 2016, 7, 3649–3657. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Vosburg, D.A.; Weiler, S.; Sorensen, E.J. A Concise Synthesis of Fumagillol. Angew. Chem. Int. Ed. 1999, 38, 971–974. [Google Scholar] [CrossRef]
  70. Vosburg, D.A.; Weiler, S.; Sorensen, E.J. Concise stereocontrolled routes to fumagillol, fumagillin, and TNP-470. Chirality 2003, 15, 156–166. [Google Scholar] [CrossRef] [PubMed]
  71. Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Huang, G.-F.; Su, C.-F.; Liao, J.-H. Organocatalytic Asymmetric Robinson Annulation of α,β-Unsaturated Aldehydes:  Applications to the Total Synthesis of (+)-Palitantin. J. Org. Chem. 2008, 73, 2480. [Google Scholar] [CrossRef] [Green Version]
  72. Yamaji, K.; Fukushi, Y.; Hashidoko, Y.; Yoshida, T.; Tahara, S. Characterization of Antifungal Metabolites Produced by Penicillium Species Isolated from Seeds of Picea glehnii. J. Chem. Ecol. 1999, 25, 1643–1653. [Google Scholar] [CrossRef]
  73. Curtis, P.J.; Hemming, H.G.; Smith, W.K. Frequentin; an antibiotic produced by some strains of Penicillium frequentans Westling. Nature 1951, 167, 557–558. [Google Scholar] [CrossRef]
  74. Trost, B.M.; Huang, Z.; Murhade, G.M. Catalytic palladium-oxyallyl cycloaddition. Science 2018, 362, 564. [Google Scholar] [CrossRef] [Green Version]
  75. Jablonski, C.R.; Sorensen, T.S. Acid Catalyzed Rearrangements of Structurally Constrained Tricarbonyl(trans-pentadienyl)iron Cations. Can. J. Chem. 1974, 52, 2085–2097. [Google Scholar] [CrossRef] [Green Version]
  76. Adams, J.; Belley, M. New methods of formation of meta-substituted aromatic compounds. J. Org. Chem. 1986, 51, 3878–3881. [Google Scholar] [CrossRef]
  77. Peng, F.; Zhao, Q.; Huang, W.; Liu, S.-J.; Zhong, Y.-J.; Mao, Q.; Zhang, N.; He, G.; Han, B. Amine-catalyzed and functional group-controlled chemo- and regioselective synthesis of multi-functionalized CF3-benzene via a metal-free process. Green Chem. 2019, 21, 6179–6186. [Google Scholar] [CrossRef]
  78. Hennig, A.; Schwarzlose, T.; Nau, W.M. Bridgehead carboxy-substituted 2,3-diazabicyclo[2.2.2]oct-2-enes: Synthesis, fluorescent properties, and host-guest complexation. Arkivoc 2007, 8, 341–357. [Google Scholar] [CrossRef] [Green Version]
  79. Griesbeck, A.G.; de Kiff, A.; Neudörfl, J.M.; Sillner, S. Singlet oxygen addition to cyclo-1,3-hexadienes from natural sources and from organocatalytic enal dimerization. Arkivoc 2015, 3, 101–110. [Google Scholar] [CrossRef]
  80. Lagnel, B.M.F.; Morin, C.; De Groot, A. Synthesis of drimanes from (+)-larixol. Synthesis 2000, 13, 1907–1916. [Google Scholar] [CrossRef]
  81. Razmilic, I.; López, J.; Sierra, J. An Alternative Partial Synthesis of (-)-Polygodial. Synth. Commun. 1987, 17, 95–103. [Google Scholar] [CrossRef]
  82. Oyarzún, M.L.; Cortés, M.; Sierra, J. Synthesis of (-)-DRIM-7-ENE-9α, 11, 12 Triol. The Direct Precursor of (-)-Warburganal. Synth. Commun. 1982, 12, 951–958. [Google Scholar] [CrossRef]
  83. Denmark, S.E.; Hite, G.A. Silicon-Directed Nazarov Cyclizations. Part VI. The anomalous cyclization of vinyl dienyl ketones. Helv. Chim. Acta 1988, 71, 195–208. [Google Scholar] [CrossRef]
  84. Bennani, Y.L.; Boehm, M.F. Syntheses of High Specific Activity 2,3- and 3,4-[3H]2-9-cis-Retinoic Acid. J. Org. Chem. 1995, 60, 1195–1200. [Google Scholar] [CrossRef]
  85. Frichert, A.; Jones, P.G.; Lindel, T. Synthesis of eunicellane-type bicycles embedding a 1,3-cyclohexadiene moiety. Beilstein J. Org. Chem. 2018, 14, 2461–2467. [Google Scholar] [CrossRef]
  86. Semmelhack, M.F.; Sarpong, R.; Bergman, J.; Ho, D.M. Evaluation of alkene isomerization as a trigger for enediyne activation. Tetrahedron Lett. 2002, 43, 541–544. [Google Scholar] [CrossRef]
  87. Dogra, A.; Kotwal, P.; Gour, A.; Bhatt, S.; Singh, G.; Mukherjee, D.; Nandi, U. Description of Druglike Properties of Safranal and Its Chemistry behind Low Oral Exposure. ACS Omega 2020, 5, 9885–9891. [Google Scholar] [CrossRef] [Green Version]
  88. Rezaee, R.; Hosseinzadeh, H. Safranal: From an aromatic natural product to a rewarding pharmacological agent. Iran. J. Basic Med. Sci. 2013, 16, 12. [Google Scholar] [PubMed]
  89. Melnyk, J.P.; Wang, S.; Marcone, M.F. Chemical and biological properties of the world’s most expensive spice: Saffron. Food Res. Int. 2010, 43, 1981–1989. [Google Scholar] [CrossRef]
  90. Sadeghnia, H.R.; Shaterzadeh, H.; Forouzanfar, F.; Hosseinzadeh, H. Neuroprotective effect of safranal, an active ingredient of Crocus sativus, in a rat model of transient cerebral ischemia. Folia Neuropathol. 2017, 55, 206–213. [Google Scholar] [CrossRef] [PubMed]
  91. Zhang, C.; Ma, J.; Fan, L.; Zou, Y.; Dang, X.; Wang, K.; Song, J. Neuroprotective effects of safranal in a rat model of traumatic injury to the spinal cord by anti-apoptotic, anti-inflammatory and edema-attenuating. Tissue Cell 2015, 47, 291–300. [Google Scholar] [CrossRef]
  92. Ali, M.S.; Al-Lohedan, H.A. Experimental and computational investigation on the molecular interactions of safranal with bovine serum albumin: Binding and anti-amyloidogenic efficacy of ligand. J. Mol. Liq. 2019, 278, 385–393. [Google Scholar] [CrossRef]
  93. Bharti, S.; Golechha, M.; Kumari, S.; Siddiqui, K.M.; Arya, D.S. Akt/GSK-3β/eNOS phosphorylation arbitrates safranal-induced myocardial protection against ischemia–reperfusion injury in rats. Eur. J. Nutr. 2012, 51, 719–727. [Google Scholar] [CrossRef]
  94. Hosseinzadeh, H.; Sadeghnia, H.R. Safranal, a constituent of Crocus sativus (saffron), attenuated cerebral ischemia induced oxidative damage in rat hippocampus. J. Pharm. Pharm. Sci. 2005, 8, 394–399. [Google Scholar] [PubMed]
  95. Sadeghnia, H.R.; Kamkar, M.; Assadpour, E.; Boroushaki, M.T.; Ghorbani, A. Protective effect of safranal, a constituent of Crocus sativus, on quinolinic acid-induced oxidative damage in rat hippocampus. Iran. J. Basic Med. Sci. 2013, 16, 73. [Google Scholar]
  96. Samarghandian, S.; Azimi-Nezhad, M.; Samini, F. Preventive effect of safranal against oxidative damage in aged male rat brain. Exp. Anim. 2015, 64, 65–71. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Zhu, K.-J.; Yang, J.-S. Anti-allodynia effect of safranal on neuropathic pain induced by spinal nerve transection in rat. Int. J. Clin. Exp. Med. 2014, 7, 4990. [Google Scholar] [PubMed]
  98. Fukui, H.; Toyoshima, K.; Komaki, R. Psychological and neuroendocrinological effects of odor of saffron (Crocus sativus). Phytomedicine 2011, 18, 726–730. [Google Scholar] [CrossRef]
  99. Hosseinzadeh, H.; Younesi, H.M. Antinociceptive and anti-inflammatory effects of Crocus sativus L. stigma and petal extracts in mice. Bmc Pharmacol. 2002, 2, 7. [Google Scholar]
  100. Colmenares, A.; Aleu, J.; Duran-Patron, R.; Collado, I.; Hernandez-Galan, R. The putative role of botrydial and related metabolites in the infection mechanism of Botrytis cinerea. J. Chem. Ecol. 2002, 28, 997–1005. [Google Scholar] [CrossRef]
  101. Anzaldi, M.; Sottofattori, E.; Dusatti, F.; Ferro, M.; Pani, M.; Balbi, A. Synthesis of ionones and carvone analogues: Olfactory properties and preliminary toxicity assays. Eur. J. Med. Chem. 2000, 35, 797–803. [Google Scholar] [CrossRef]
  102. Socha, A.M.; LaPlante, K.L.; Rowley, D.C. New bisanthraquinone antibiotics and semi-synthetic derivatives with potent activity against clinical Staphylococcus aureus and Enterococcus faecium isolates. Bioorganic Med. Chem. 2006, 14, 8446–8454. [Google Scholar] [CrossRef]
Molecules 26 01772 g001 550
Figure 1. Natural and synthetic compounds with 1,3-cyclohexadien-1-al scaffold.
Figure 1. Natural and synthetic compounds with 1,3-cyclohexadien-1-al scaffold.
Molecules 26 01772 g001
Molecules 26 01772 g002 550
Figure 2. Summary of methodologies for the obtention of 1,3-cyclohexadien-1-als. The corresponding bibliography is shown in blue numbers.
Figure 2. Summary of methodologies for the obtention of 1,3-cyclohexadien-1-als. The corresponding bibliography is shown in blue numbers.
Molecules 26 01772 g002
Molecules 26 01772 sch001 550
Scheme 1. Semisynthesis of safranal 2.
Scheme 1. Semisynthesis of safranal 2.
Molecules 26 01772 sch001
Molecules 26 01772 sch002 550
Scheme 2. Synthesis of safranal 2 from α-cyclocitronitrile.
Scheme 2. Synthesis of safranal 2 from α-cyclocitronitrile.
Molecules 26 01772 sch002
Molecules 26 01772 sch003 550
Scheme 3. Transformation of botrydial 14 into botrydienal 6 by reaction with Ag2CO3.
Scheme 3. Transformation of botrydial 14 into botrydienal 6 by reaction with Ag2CO3.
Molecules 26 01772 sch003
Molecules 26 01772 sch004 550
Scheme 4. Isomerization of dienal 15.
Scheme 4. Isomerization of dienal 15.
Molecules 26 01772 sch004
Molecules 26 01772 sch005 550
Scheme 5. Synthesis of terephthalic derivatives from biomass.
Scheme 5. Synthesis of terephthalic derivatives from biomass.
Molecules 26 01772 sch005
Molecules 26 01772 sch006 550
Scheme 6. Synthesis of cyclohexandienals under Vilsmeier–Haack reaction conditions.
Scheme 6. Synthesis of cyclohexandienals under Vilsmeier–Haack reaction conditions.
Molecules 26 01772 sch006
Molecules 26 01772 sch007 550
Scheme 7. Carvone 35 formylation under Vilsmeier–Haack conditions.
Scheme 7. Carvone 35 formylation under Vilsmeier–Haack conditions.
Molecules 26 01772 sch007
Molecules 26 01772 sch008 550
Scheme 8. Formylation reaction in the synthetic preparation of cyclohexadienal motif.
Scheme 8. Formylation reaction in the synthetic preparation of cyclohexadienal motif.
Molecules 26 01772 sch008
Molecules 26 01772 sch009 550
Scheme 9. Self-dimerization of glutaraldehyde 43.
Scheme 9. Self-dimerization of glutaraldehyde 43.
Molecules 26 01772 sch009
Molecules 26 01772 sch010 550
Scheme 10. Self-condensation of α,β-aldehydes in the formation of 1,3-cyclohexadien-1-al units.
Scheme 10. Self-condensation of α,β-aldehydes in the formation of 1,3-cyclohexadien-1-al units.
Molecules 26 01772 sch010
Molecules 26 01772 sch011 550
Scheme 11. Self-condensation of senecialdehyde 47 in the formation of 1,3-cyclohexadien-1-al 50.
Scheme 11. Self-condensation of senecialdehyde 47 in the formation of 1,3-cyclohexadien-1-al 50.
Molecules 26 01772 sch011
Molecules 26 01772 sch012 550
Scheme 12. Cross-condensation of unsaturated aldehydes in the formation of 1,3-cyclohexadien-1-als.
Scheme 12. Cross-condensation of unsaturated aldehydes in the formation of 1,3-cyclohexadien-1-als.
Molecules 26 01772 sch012
Molecules 26 01772 sch013 550
Scheme 13. Self-condensation of α,β-unsaturated aldehyde 46 in the formation of 1,3-cyclohexadien-1-al 49.
Scheme 13. Self-condensation of α,β-unsaturated aldehyde 46 in the formation of 1,3-cyclohexadien-1-al 49.
Molecules 26 01772 sch013
Molecules 26 01772 sch014 550
Scheme 14. Michael and Horner–Wadsworth–Emmons reactions in the synthesis of cyclohexadienal 50.
Scheme 14. Michael and Horner–Wadsworth–Emmons reactions in the synthesis of cyclohexadienal 50.
Molecules 26 01772 sch014
Molecules 26 01772 sch015a 550Molecules 26 01772 sch015b 550
Scheme 15. Michael and Horner–Wadsworth–Emmons reactions in the synthesis of cyclohexadienals.
Scheme 15. Michael and Horner–Wadsworth–Emmons reactions in the synthesis of cyclohexadienals.
Molecules 26 01772 sch015aMolecules 26 01772 sch015b
Molecules 26 01772 sch016 550
Scheme 16. Diels–Alder reactions towards the synthesis of 1,3-cyclohexadien-1-al scaffold.
Scheme 16. Diels–Alder reactions towards the synthesis of 1,3-cyclohexadien-1-al scaffold.
Molecules 26 01772 sch016
Molecules 26 01772 sch017 550
Scheme 17. Diels–Alder reaction towards the synthesis of 1,3-cyclohexadien-1-al scaffold.
Scheme 17. Diels–Alder reaction towards the synthesis of 1,3-cyclohexadien-1-al scaffold.
Molecules 26 01772 sch017
Molecules 26 01772 sch018 550
Scheme 18. Diels–Alder reaction towards the synthesis of 1,3-cyclohexadien-1-al scaffold.
Scheme 18. Diels–Alder reaction towards the synthesis of 1,3-cyclohexadien-1-al scaffold.
Molecules 26 01772 sch018
Molecules 26 01772 sch019 550
Scheme 19. Diels–Alder reaction towards the synthesis of hexafluorinated safranal 97.
Scheme 19. Diels–Alder reaction towards the synthesis of hexafluorinated safranal 97.
Molecules 26 01772 sch019
Molecules 26 01772 sch020 550
Scheme 20. Diels–Alder reaction of vinamidium salts and unsaturated aldehydes.
Scheme 20. Diels–Alder reaction of vinamidium salts and unsaturated aldehydes.
Molecules 26 01772 sch020
Molecules 26 01772 sch021 550
Scheme 21. Synthesis and thermal cyclization of hexatrienes 106 and 109; CuTC = copper(I) thiophene-2-carboxylate.
Scheme 21. Synthesis and thermal cyclization of hexatrienes 106 and 109; CuTC = copper(I) thiophene-2-carboxylate.
Molecules 26 01772 sch021
Molecules 26 01772 sch022 550
Scheme 22. Ruthenium catalyzed electrocyclization in the preparation of 1,3-cyclohexadienal scaffold.
Scheme 22. Ruthenium catalyzed electrocyclization in the preparation of 1,3-cyclohexadienal scaffold.
Molecules 26 01772 sch022
Molecules 26 01772 sch023 550
Scheme 23. Employment of organoaluminium reagent in the synthesis of cyclohexadienal 1.
Scheme 23. Employment of organoaluminium reagent in the synthesis of cyclohexadienal 1.
Molecules 26 01772 sch023
Molecules 26 01772 sch024 550
Scheme 24. Cr(CO)3 complex-mediated dearomatization in the synthesis of cyclohexadienals.
Scheme 24. Cr(CO)3 complex-mediated dearomatization in the synthesis of cyclohexadienals.
Molecules 26 01772 sch024
Molecules 26 01772 sch025 550
Scheme 25. Cr(CO)3 complex-mediated dearomatization in the presence of chiral ligands.
Scheme 25. Cr(CO)3 complex-mediated dearomatization in the presence of chiral ligands.
Molecules 26 01772 sch025
Molecules 26 01772 sch026 550
Scheme 26. Selection of Cr(CO)3 complexes used in dearomatization reactions for the preparation of cyclohexadienals.
Scheme 26. Selection of Cr(CO)3 complexes used in dearomatization reactions for the preparation of cyclohexadienals.
Molecules 26 01772 sch026
Molecules 26 01772 sch027 550
Scheme 27. Cr(CO)3 complex-mediated dearomatization in the synthesis of cyclohexadienals towards acetoxytubipofuran.
Scheme 27. Cr(CO)3 complex-mediated dearomatization in the synthesis of cyclohexadienals towards acetoxytubipofuran.
Molecules 26 01772 sch027
Molecules 26 01772 sch028 550
Scheme 28. Organocatalyzed synthesis of 1,3-cyclohexadien-1-als from citral 51.
Scheme 28. Organocatalyzed synthesis of 1,3-cyclohexadien-1-als from citral 51.
Molecules 26 01772 sch028
Molecules 26 01772 sch029 550
Scheme 29. Organocatalytic self-condensation of α,β-unsaturated aldehydes towards 1,3-cyclohexadien-1-al compounds.
Scheme 29. Organocatalytic self-condensation of α,β-unsaturated aldehydes towards 1,3-cyclohexadien-1-al compounds.
Molecules 26 01772 sch029
Molecules 26 01772 sch030 550
Scheme 30. Organocatalyst-mediated cycloaddition of α,β-unsaturated aldehydes towards 1,3-cyclohexadien-1-al compounds.
Scheme 30. Organocatalyst-mediated cycloaddition of α,β-unsaturated aldehydes towards 1,3-cyclohexadien-1-al compounds.
Molecules 26 01772 sch030
Molecules 26 01772 sch031 550
Scheme 31. Examples of cyclohexadienals obtained in L-proline-mediated reaction of α,β-unsaturated aldehydes.
Scheme 31. Examples of cyclohexadienals obtained in L-proline-mediated reaction of α,β-unsaturated aldehydes.
Molecules 26 01772 sch031
Molecules 26 01772 sch032 550
Scheme 32. Intramolecular organocatalytic formation of cyclohexadienal unit.
Scheme 32. Intramolecular organocatalytic formation of cyclohexadienal unit.
Molecules 26 01772 sch032
Molecules 26 01772 sch033 550
Scheme 33. Organocatalyst-mediated cycloaddition for the synthesis of cyclohexadienal core.
Scheme 33. Organocatalyst-mediated cycloaddition for the synthesis of cyclohexadienal core.
Molecules 26 01772 sch033
Molecules 26 01772 sch034 550
Scheme 34. Organocatalytic-mediated synthesis of chiral 1,3-cyclohexadienals.
Scheme 34. Organocatalytic-mediated synthesis of chiral 1,3-cyclohexadienals.
Molecules 26 01772 sch034
Molecules 26 01772 sch035 550
Scheme 35. Organocatalytic-mediated synthesis of chiral 1,3-cyclohexadienal 179.
Scheme 35. Organocatalytic-mediated synthesis of chiral 1,3-cyclohexadienal 179.
Molecules 26 01772 sch035
Molecules 26 01772 sch036 550
Scheme 36. Organocatalytic-mediated synthesis of cyclodienal and subsequent reaction with conjugated aldehyde 181.
Scheme 36. Organocatalytic-mediated synthesis of cyclodienal and subsequent reaction with conjugated aldehyde 181.
Molecules 26 01772 sch036
Molecules 26 01772 sch037 550
Scheme 37. Synthesis of cyclohexadienal compounds and subsequent cycloaddition reaction.
Scheme 37. Synthesis of cyclohexadienal compounds and subsequent cycloaddition reaction.
Molecules 26 01772 sch037
Molecules 26 01772 sch038 550
Scheme 38. Dihydroxilation of 1,3-cyclohexadien-1-carboxaldehyde in the total synthesis of fumagillol 190.
Scheme 38. Dihydroxilation of 1,3-cyclohexadien-1-carboxaldehyde in the total synthesis of fumagillol 190.
Molecules 26 01772 sch038
Molecules 26 01772 sch039 550
Scheme 39. Dihydroxilation of cyclohexadienal 150 in the total synthesis of (+)-palitantin 193.
Scheme 39. Dihydroxilation of cyclohexadienal 150 in the total synthesis of (+)-palitantin 193.
Molecules 26 01772 sch039
Molecules 26 01772 sch040 550
Scheme 40. Hydrogenation of hexafluorinated safranal 97.
Scheme 40. Hydrogenation of hexafluorinated safranal 97.
Molecules 26 01772 sch040
Molecules 26 01772 sch041 550
Scheme 41. Oxyallyl cycloaddition reaction with cyclohexadienal.
Scheme 41. Oxyallyl cycloaddition reaction with cyclohexadienal.
Molecules 26 01772 sch041
Molecules 26 01772 sch042 550
Scheme 42. Formation of tricarbonyl iron complex of 1,3-cyclohexadiene-1-carboxaldehyde 1.
Scheme 42. Formation of tricarbonyl iron complex of 1,3-cyclohexadiene-1-carboxaldehyde 1.
Molecules 26 01772 sch042
Molecules 26 01772 sch043 550
Scheme 43. Aromatization reaction of cyclohexadienals.
Scheme 43. Aromatization reaction of cyclohexadienals.
Molecules 26 01772 sch043
Molecules 26 01772 sch044 550
Scheme 44. Aromatization reaction of phenyl-substituted cyclohexadienals.
Scheme 44. Aromatization reaction of phenyl-substituted cyclohexadienals.
Molecules 26 01772 sch044
Molecules 26 01772 sch045 550
Scheme 45. Organocatalytic synthesis of cyclohexadienals/oxidation reaction in the synthesis of aromatic aldehydes.
Scheme 45. Organocatalytic synthesis of cyclohexadienals/oxidation reaction in the synthesis of aromatic aldehydes.
Molecules 26 01772 sch045
Molecules 26 01772 sch046 550
Scheme 46. Organocatalytic synthesis of cyclohexadienals/aromatization reaction in the synthesis of pentasubstituted aromatic compounds.
Scheme 46. Organocatalytic synthesis of cyclohexadienals/aromatization reaction in the synthesis of pentasubstituted aromatic compounds.
Molecules 26 01772 sch046
Molecules 26 01772 sch047 550
Scheme 47. Oxidation of 1,3-cyclohexadien-1-carboxaldehyde to carboxylic acid 203.
Scheme 47. Oxidation of 1,3-cyclohexadien-1-carboxaldehyde to carboxylic acid 203.
Molecules 26 01772 sch047
Molecules 26 01772 sch048 550
Scheme 48. Reduction of safranal 2 to alcohol 206.
Scheme 48. Reduction of safranal 2 to alcohol 206.
Molecules 26 01772 sch048
Molecules 26 01772 sch049 550
Scheme 49. Reduction of natural aldehydes 61 and 63 to the corresponding alcohols.
Scheme 49. Reduction of natural aldehydes 61 and 63 to the corresponding alcohols.
Molecules 26 01772 sch049
Molecules 26 01772 sch050 550
Scheme 50. Reduction of the aldehyde moiety in the 1,3-cyclohexadien-1-al core in the total synthesis of acetoxytubipofuran.
Scheme 50. Reduction of the aldehyde moiety in the 1,3-cyclohexadien-1-al core in the total synthesis of acetoxytubipofuran.
Molecules 26 01772 sch050
Molecules 26 01772 sch051 550
Scheme 51. Reduction of the cyclohexadienal core in the synthesis of (−)-drimenol.
Scheme 51. Reduction of the cyclohexadienal core in the synthesis of (−)-drimenol.
Molecules 26 01772 sch051
Molecules 26 01772 sch052 550
Scheme 52. Horner–Wadsworth–Emmons reaction of safranal.
Scheme 52. Horner–Wadsworth–Emmons reaction of safranal.
Molecules 26 01772 sch052
Molecules 26 01772 sch053 550
Scheme 53. Reaction of safranal with a Grignard reagent.
Scheme 53. Reaction of safranal with a Grignard reagent.
Molecules 26 01772 sch053
Molecules 26 01772 sch054 550
Scheme 54. Reaction of cyclohexadiene carboxaldehyde unit with a Grignard reagent.
Scheme 54. Reaction of cyclohexadiene carboxaldehyde unit with a Grignard reagent.
Molecules 26 01772 sch054
Molecules 26 01772 sch055 550
Scheme 55. Reaction of safranal 2 with an organolithium reagent.
Scheme 55. Reaction of safranal 2 with an organolithium reagent.
Molecules 26 01772 sch055
Molecules 26 01772 sch056 550
Scheme 56. Intramolecular cyclization in the preparation of diazecine derivatives.
Scheme 56. Intramolecular cyclization in the preparation of diazecine derivatives.
Molecules 26 01772 sch056
Molecules 26 01772 sch057 550
Scheme 57. Intramolecular macrocyclization in the preparation of eunicellane skeletons.
Scheme 57. Intramolecular macrocyclization in the preparation of eunicellane skeletons.
Molecules 26 01772 sch057
Molecules 26 01772 sch058 550
Scheme 58. Intramolecular macrocyclization in cyclohexadienal derivative.
Scheme 58. Intramolecular macrocyclization in cyclohexadienal derivative.
Molecules 26 01772 sch058
Molecules 26 01772 sch059 550
Scheme 59. Organocuprate addition in cyclohexadienal derivative 74.
Scheme 59. Organocuprate addition in cyclohexadienal derivative 74.
Molecules 26 01772 sch059
Molecules 26 01772 sch060 550
Scheme 60. Inverse electron demand hetero-Diels–Alder reaction of cyclohexadienal derivative 222.
Scheme 60. Inverse electron demand hetero-Diels–Alder reaction of cyclohexadienal derivative 222.
Molecules 26 01772 sch060
Molecules 26 01772 sch061 550
Scheme 61. Cycloaddition reaction of cyclohexadienal derivative 222.
Scheme 61. Cycloaddition reaction of cyclohexadienal derivative 222.
Molecules 26 01772 sch061
Molecules 26 01772 g003 550
Figure 3. Heterodimeric and dimeric 1,3-cyclohexadien-1-als (226–237) and examples biologically active.
Figure 3. Heterodimeric and dimeric 1,3-cyclohexadien-1-als (226–237) and examples biologically active.
Molecules 26 01772 g003
Table
Table 1. Examples of cyclohexadienals obtained in the (4 + 2) cycloaddition of α,β-unsaturated aldehydes mediated by L-proline.
Table 1. Examples of cyclohexadienals obtained in the (4 + 2) cycloaddition of α,β-unsaturated aldehydes mediated by L-proline.
Molecules 26 01772 i001
CompoundR1R2R3R4% Yield (ee)
50MeHHMe82 (--)
150HαOAcαCH2OAcH68 (94)
151HHαPhH61 (63)
152MeHαPhH72 (32)
153MeHαPhH78 (56)
154MeHαEtH71 (--)
155MeHαMeH82 (41)
Table
Table 2. Biological activities of 1,3-cyclohexadien-1-als (2, 6, 7, 36, 208, 233).
Table 2. Biological activities of 1,3-cyclohexadien-1-als (2, 6, 7, 36, 208, 233).
Molecules 26 01772 i002
CompoundActivityTestReference
2Anticancer, antioxidant, neuroprotective, anti-inflammatoryIn vitro[11,87,88,89,90,91,92,93,94,95,96,97,98,99]
6Cytotoxic, phytotoxic, antibioticIn vitro[7,14,100]
7Antibacterial, antifungalIn vitro[8]
36CytotoxicIn vitro[101]
208Antimalaric [15,79]
233AntibacterialIn vitro[102]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Tobal, I.E.; Bautista, R.; Diez, D.; Garrido, N.M.; García-García, P. 1,3-Cyclohexadien-1-Als: Synthesis, Reactivity and Bioactivities. Molecules 2021, 26, 1772. https://doi.org/10.3390/molecules26061772

AMA Style

Tobal IE, Bautista R, Diez D, Garrido NM, García-García P. 1,3-Cyclohexadien-1-Als: Synthesis, Reactivity and Bioactivities. Molecules. 2021; 26(6):1772. https://doi.org/10.3390/molecules26061772

Chicago/Turabian Style

Tobal, Ignacio E., Rocío Bautista, David Diez, Narciso M. Garrido, and Pilar García-García. 2021. "1,3-Cyclohexadien-1-Als: Synthesis, Reactivity and Bioactivities" Molecules 26, no. 6: 1772. https://doi.org/10.3390/molecules26061772

Article Metrics

Back to TopTop