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

molecules

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

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; [email protected] (I.E.T.); [email protected] (R.B.); [email protected] (D.D.); [email protected] (N.M.G.) 2 Departamento de Ciencias Farmacéuticas, Facultad de Farmacia, CIETUS, IBSAL, University of Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain * Correspondence: [email protected]; Tel.: +34-923-294400 † These authors have contributed equally to this work.

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.

Keywords: Diels–Alder; dienes; aldehydes; chiral compounds; synthesis

1. Introduction Citation: Tobal, I.E.; Bautista, R.; One of the reactions that is in the heart of every organic chemist is the Diels–Alder Diez, D.; Garrido, N.M.; García- reaction [1]. Dienes are one of the essential components to form the adduct. The reactivity of García, P. 1,3-Cyclohexadien-1-Als: these compounds in the Diels–Alder reaction varies with electron-withdrawing or donating Synthesis, Reactivity and Bioactivities. groups and with conformation restriction as they are part of a cyclic system. Molecules 2021, 26, 1772. https:// A very special building block is the 1,3-cyclohexadien-1-al. This scaffold is present in doi.org/10.3390/molecules26061772 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 Academic Editor: Paolo Quadrelli oil of Crocus sativus L. (saffron) [4], or citral dimer 3, which has been isolated from marine

Received: 19 February 2021 bryozoan Flustra foliacea [5]. Some other examples are compound 5, extracted from black Accepted: 12 March 2021 cardamom (Amomum tsao-ko)[6]; compound 6, which is obtained from the fungus Botrytis Published: 22 March 2021 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

Publisher’s Note: MDPI stays neutral compound 4 have been obtained [9] (Figure1). In particular, safranal 2 can be considered a with regard to jurisdictional claims in reference compound containing the 1,3-cyclohexadiene-1-al scaffold showing interesting published maps and institutional afﬁl- bioactivities, from neuroprotection [10] to anticancer effects [11]. In this review, aromatic iations. aldehydes were not considered due to the different nature of benzaldehydes and related

Molecules 2020, 25,aromatic x FOR PEER REVIEW derivatives in terms of obtention and reactivity. 2 of 33

Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ Figure 1. Cont. 4.0/).

Molecules 2021, 26, 1772. https://doi.org/10.3390/molecules26061772 https://www.mdpi.com/journal/molecules

Figure 1. Natural and synthetic compounds with 1,3-cyclohexadien-1-al scaffold.

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.

Figure 2. Summary of methodologies for the obtention of 1,3-cyclohexadien-1-als. The corresponding bibliography is shown in blue numbers.

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FigureFigure 1. Natural Natural1. Natural and and and synthetic synthetic synthetic compounds compounds with with 1,3 1,3-cyclohexadien-1-al -1,3cyclohexadien-1-al-cyclohexadien-1-al scaffold. scaffold.

2. Synthesis Synthesis2. Synthesis of of of1,3-Cyclohexadien-1-Al 1,3-Cyclohexadien-1-Al 1,3-Cyclohexadien-1-Al Scaffold Scaffold ThereThere are are limited limited methodologies methodologies applied applied to toafford afford 1,3-cyclohexadien-1-al 1,3-cyclohexadien-1-al scaffold. scaffold. scaffold. Among them, organocatalytic methods are the more versatile ones, creating the 1,3- AmongAmong them, them, organocatalytic organocatalytic methods methods are are the the mo more versatilere versatile ones, ones, creating creating the the 1,3-cyclo- 1,3-cyclo- cyclohexadienal scaffold through one-pot reactions compared with other methodologies hexadienalhexadienal scaffold scaffold through through one-pot one-pot reaction reactions compareds compared with with other other methodologies methodologies using using using Lewis acids or formylating agents where the reactant already shows the cyclic LewisLewis acids acids or orformylating formylating agents agents where where the the reactant reactant already already shows shows the the cyclic cyclic 1,3-diene 1,3-diene 1,3-diene or at least the cyclic system. or orat leastat least the the cyclic cyclic system. system. Herein, we review the reported methodologies applied to the synthesis of 1,3-cyclohex- Herein,Herein, we we review review the the reported reported methodolog methodologiesies applied applied to theto the synthesis synthesis of 1,3-cyclo-of 1,3-cyclo- adien-1-als. The described methods can be classiﬁed as aldol-type condensations, pericyclic hexadien-1-als.hexadien-1-als. The The described described methods methods can can be beclassified classified as aldol-typeas aldol-type condensations, condensations, per- per- cyclizations, functional group interconversions and transformations, and organometallic icyclicicyclic cyclizations, cyclizations, functional functional group group interconversions interconversions and and transformations, transformations, and and organo- organo- and organocatalyzed reactions. The general accessibility to this scaffold by the different metallicmetallic and and organocatalyzed organocatalyzed reactions. reactions. The The general general accessibility accessibility to tothis this scaffold scaffold by bythe the methodologies is shown in Figure2. differentdifferent methodologies methodologies is shownis shown in Figurein Figure 2. 2.

FigureFigure 2. Summary2. Summary of methodologiesof methodologies for for thethe the obtentionobtention obtention ofof 1,3-cyclohexadien-1-als.1,3-cyclof 1,3-cyclohexadien-1-als.ohexadien-1-als. The The correspondingcorresp correspondingonding bibliography bibliography is is shown in blue numbers. shownshown in bluein blue numbers. numbers.

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] (Scheme1). 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 Molecules 2020,, 25,, xx FORFOR PEERPEER REVIEWREVIEW 3 of 33

2.1. Functional Group Interconversions and Isomerizations The simple functional group interconversions can be a pathway for the obtention of γ 1,3-cyclohexadienals, as in the case ofof thethe semisynthesissemisynthesis ofof safranalsafranal 2 startingstarting fromfrom γ-py--pyronene 8 [12] (Scheme 1). The epoxidation of 8 results in a mixture of mono and diepoxide Molecules 2021, 26, 1772 ronene 88 [12][12] (Scheme(Scheme 1).1). TheThe epoxidationepoxidation ofof 8 resultsresults inin aa mixturemixture ofof monomono andand diepoxidediepoxide3 of 32 derivatives. The isolated exocyclic epoxide 9 (36%)(36%) isis transformedtransformed inin twotwo stepssteps intointo safra-safranal 2.. Firstly,Firstly, halogenationhalogenation ofof doubledouble boundbound conductsconducts toto 10 quantitatively and then a one- pot reaction consisting in the dibromo elimination and epoxide-opening, allowing the ob- thetentiontention obtention ofof thethe of 1,3-diene1,3-diene the 1,3-diene system,system, system, whereinwherein wherein thethe hydroxyl the hydroxyl group group of the of intermediate the intermediate is oxi- is oxidized,dized, resulting resulting in safranal in safranal 2 inin2 ingoodgood good yield.yield. yield.

SchemeScheme 1.1. SemisynthesisSemisynthesis ofof safranalsafranal 22...

OtherOther semisynthesissemisynthesis ofof safranalsafranal 22 startsstarts fromfrom αα-cyclocitronitrile-cyclocitronitrile-cyclocitronitrile andandand takestakestakes placeplaceplace ininin threethreethree steps:steps:steps: oxidation,oxidation,oxidation, elimination,elimination,elimination, andandand reductionrereduction [[13]13] (Scheme(Scheme2 ).2).. The TheThe epoxidation epoxidationepoxidation and andand epoxideepoxide openingopening by by base base conducts conducts to to the the hydroxyderivative hydroxyderivative12 ,12 which,, whichwhich can cancan be eliminatedbebe eliminatedeliminated by protonationby protonation with withp-toluensulfonic p-toluensulfonic-toluensulfonic acid (TsOH)acidacid (TsOH)(TsOH) to afford toto affordafford13. The 13 reduction.. TheThe reductionreduction of cyano ofof groupcyanocyano withgroup diisobutyl with diisobutyl aluminium aluminium hydride hydride (DIBAL-H) (DIBAL-H) results inresults safranal in safranal2. 2..

SchemeScheme 2.2. SynthesisSynthesis ofof safranalsafranal 22 fromfromfrom α α-cyclocitronitrile.-cyclocitronitrile.-cyclocitronitrile.

TheThe transformation of of botrydial botrydial 14 14 intointointo itsits derivativederivative its derivative botrydienalbotrydienal botrydienal 6 (Scheme(Scheme6 (Scheme 3)3) cancan3 bebe) cantriggeredtriggered be triggered underunder FetizonFetizon under Fetizon conditionsconditions conditions withwith aa withququantitative a quantitative yield, as yield, described as described by Durán- by DurPatrónán-Patr et al.ó n[14]. et al. [14].

Scheme 3. Transformation of botrydial 14 into botrydienal 6 by reaction with Ag2CO3. SchemeScheme 3.3. TransformationTransformation ofof botrydialbotrydial14 14into intointo botrydienal botrydienalbotrydienal6 6by bybyreaction reactionreactionwith withwith Ag AgAg222COCO333... αββεε ζ StartingStarting from α,,β, ,,ε,,,ζ,-unconjugated-unconjugated-unconjugated dienalsdienals dienals suchsuch such asas 15 as,, the15the, unconjugatedunconjugated the unconjugated doubledouble double bondbond β γ α β γ δ bondcan be can isomerized be isomerized to form to the form corresponding the corresponding α,,β,,γ,,δ-unsaturated-unsaturated, , , -unsaturated aldehydealdehyde aldehyde ((16)) usingusing ( 16ze-ze-) usingolite-NaY zeolite-NaY in dry conditions in dry conditions (Scheme (Scheme4). Longer4). reaction Longer periods reaction conduct periods the conduct aromatiza- the aromatizationtiontion products,products, products, althoughalthough althoughthisthis cacan be this easily can controlled be easily controlled [15]. [15].

Scheme 4. Isomerization of dienal 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 (Scheme5 ). The transformation takes place in two steps. Firstly, oxidation and then C2H4 addition Molecules 2020, 25, x FOR PEER REVIEW 4 of 33

Scheme 4. Isomerization of dienal 15.

2.2. Oxidation Molecules 2021, 26, 1772 4 of 32 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 silicasilica molecularmolecular sievessieves showingshowing zeolite-zeolite-ββ topologytopology containingcontaining LewisLewis acidacid centers (Zr-β or Sn- β).). Despite Despite the the obtention obtention of of 1919 being possible by using both catalysts, when Sn-Sn-ββ is used instead of Zr-β, 19 isis obtained obtained with higher yields [[16,17].16,17]. Low molecular weight 1,3-cyclohexadienals1,3-cyclohexadienals have have special special relevance relevance in in perfumery, perfumery, with with some some terpene terpene deriva- de- tivesrivatives being being of interest, of interest, such such as safranalas safranal2 and 2 and analogues. analogues. In In this this regard, regard, thethe conversionconversion of thujone (waste product in forest industry) into different derivatives has been studied, obtaining safranal 2 and analogues [[18].18].

Scheme 5. Synthesis of terephthalic derivatives from biomass.

2.3. Vilsmeier–Haack Formylation When the reactant presents the appropriateappropriate enic system, the VilsmeierVilsmeier reactionreaction cancan afford the 1,3-cyclohexadien-1-al1,3-cyclohexadien-1-al scaffold. Among several examples, it can bebe foundfound thatthat 20 22 24 28 the application to tetracyclic triterpenic derivatives 20,, 22–24,, and 28 [19–23][19–23] can be transformed into their corresponding derivatives 21, 25–27, and 29 with moderate or good yields formed into their corresponding derivatives 21, 25–27, and 29 with moderate or good (Scheme6). Equivalent conditions with POCl 3 in the presence of N-formylmorpholine yields (Scheme 6). Equivalent conditions with POCl3 in the presence of N-formylmorpho- as formylating agent can be used. Such is the case of the transformation of 30 to di- line as formylating agent can be used. Such is the case of the transformation of 30 to dienal enal 31, although lower yield is attained since hydroxyderivative 32 is detected as a by- 31, although lower yield is attained since hydroxyderivative 32 is detected as a by-product product [24]. Heterocyclic compounds such as 33 can be transformed into the correspond- [24]. Heterocyclic compounds such as 33 can be transformed into the corresponding het- ing heterocyclohexa-1,3-dienals (34) under Vilsmeier–Haack conditions (Scheme6)[25]. erocyclohexa-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 (Scheme7). 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 (Scheme8). 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 Scheme9[ 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].

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Scheme 6. Synthesis of cyclohexandienals under Vilsmeier–Haack reaction conditions.

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 SchemegeneratedScheme 6. 6.Synthesis Synthesiswith significant of cyclohexandienalsof cyclohexandienals yields. under under Vilsmeier–Haack Vilsmeier–Haack reaction reaction conditions. conditions.

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.

SchemeScheme 7. 7.Carvone Carvone35 35formylation formylation under under Vilsmeier–Haack Vilsmeier–Haack conditions. conditions.

Scheme 7. Carvone 35 formylation under Vilsmeier–Haack conditions.

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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]. Scheme 8. Formylation reaction in the synthetic preparation of cyclohexadienal motif. Such a transformation is shown below in the reactivity section. Molecules 2020, 25, x FOR PEER REVIEW 6 of 33 2.4. Aldol-type Reactions and Horner Olefinations TheOther 1,3-cyclohexadienal formylating agents scaffold such as canDMSO also can be alsoobtained be used, as startinga result from of glutaraldehyde the corre- Molecules 2021, 26, 1772 self-assemblysponding conjugated via intramolecular enol (Scheme aldol 8). The reacti 1,3-cyclohexadienalon polimerization, obtained as shownhas been in used 6Scheme of 32as 9 [27,28].a precursor Through of diazocinethis intramolecular steroid derivatives aldol reaction, through eight-member1,3-cyclohexadienal ring formation compound [26]. sub- stitutedSuch ain transformation C-3 can be obtained. is shown below in the reactivity section.

Scheme 8. Formylation reaction in the synthetic preparation of cyclohexadienal motif.

2.4. Aldol-type Reactions and Horner Olefinations Scheme 9. Self-dimerization of glutaraldehyde 43. 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 Aldol reaction and condensation of α,β-aldehydes can be performed in self-conden- [27,28]. Through this intramolecular aldol reaction, 1,3-cyclohexadienal compound sub- sation or cross-condensation modality.The self-condensation of all-E-retinal 45 can be per- SchemestitutedScheme 8.8.in FormylationFormylation C-3 can be reactionreactionobtained. inin thethe syntheticsynthetic preparationpreparation ofof cyclohexadienalcyclohexadienal motif.motif. formed in the presence of sodium hydride (Scheme 10) [29]. The enolate intermediate re- acts2.4. with Aldol-type the starting Reactions aldehyde and Horner and Olefinations cyclizes, forming the 1,3-cyclohexadien-1-al scaffold 48. In theThe enolate 1,3-cyclohexadienal intermediate, scaffold the β-methyl can also groupbe obtained holds as the a resultnegative of glutaraldehyde charge and reacts at theself-assembly conjugated via position intramolecular of the aldolaldehyde reacti inon apolimerization, process where as the shown Z/E inconfiguration Scheme 9 of double[27,28]. bound Through is not this determinant, intramolecular allowing aldol reaction, in any case 1,3-cyclohexadienal the condensation compound and formation sub- of dienal.Schemestituted 9. in Self-dimerization C-3 can be obtained. of glutaraldehyde 4343..

β Starting aldehydesAldol reaction and condensation of α, -aldehydes Self-condensation can be products 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 re-

acts withCHO the starting aldehyde and cyclizes, formingOHC the 1,3-cyclohexadien-1-al scaffold 48Scheme. In the 9. enolateSelf-dimerization intermediate, of glutaraldehyde the β-methyl 43 . group holds the negative charge and reacts at the conjugated position of the aldehyde in a process where the Z/E configuration of 45 β doubleAldol bound reaction is not anddeterminant, condensation allowing of α, in-aldehydes any case 48the can condensation be performed and in formationself-conden- of dienal.sation or cross-condensation modality.The self-condensation80 % of all-E-retinal 45 can be performed in the presence of sodium hydride (Scheme 10) [29]. The enolate intermediate re- Starting aldehydesacts with the starting aldehyde and cyclizes Self-condensation, forming the 1,3-cyclohexadien-1-al products scaffold CHO48. In the enolate intermediate,NaH the β-methyl OHCgroup holds the negative charge and reacts at the conjugated position of the aldehyde in a process where the Z/E configuration of double boundCHO is not determinant, allowing inOHC any case the condensation and formation of 46 H 49 dienal. 80 % 45 O 48 Starting aldehydes Self-condensation products Molecules 2020, 25, x FOR PEER REVIEW 80 % 7 of 33 CHO CHO Similar results are obtained with senecialdehyde 47, self-condensation reaction pro- O 47 CHOmoted byCHO alkali [30]. InNaH this case, a global yieldOHCOHC of 80% is obtained, and compounds 50–52 50 are obtained in a ratio 2:3:5 (Scheme 11). Cyclodimerization also occurs when crotonalde- 75 % 45 hyde is treated with solid base catalysts of metal oxides49 and silica. In this case, the ob- 46 H 48 SchemeScheme 10. 10.Self-condensationSelf-condensation of of αα,β,β-aldehydes-aldehydes in thethe formation formation of of 1,3-cyclohexadien-1-al 1,3-cyclohexadien-1-al80 % units. units. tained diene can evolve by dehydrogenation and aromatization80 % [31]. O CHO CHO OHC CHO NaH 47 O 50 46 H 7549 % 80 % Scheme 10. Self-condensation of α,β-aldehydesO in the formation of 1,3-cyclohexadien-1-al units. CHO CHO SchemeScheme 11.11. Self-condensationSelf-condensation ofof senecialdehydesenecialdehyde 4747in in thethe formationformation ofof 1,3-cyclohexadien-1-al1,3-cyclohexadien-1-al50 50.. 47 O 50 TrimethylsilylTrimethylsilyl andand acetateacetate enolderivativesenolderivatives53 53serve serve asas startingstarting materialmaterial forfor obtainingobtaining 75 % 1,3-cyclohexadien-1-als1,3-cyclohexadien-1-als throughthrough thethe lithiumlithium enolateenolate formationformation (Scheme(Scheme 12 12).). IntermediateIntermediate β Scheme 10. Self-condensation5454 cancan be be accessed accessed of α, via -aldehydesvia metalation metalation in the of 53of formation 53with with MeLi. of MeLi. 1,3-cyclohexadien-1-al The The subsequent subsequent addition units. addition of a conjugatedof a conju- aldehydegated aldehyde47 or 51 47yields or 51 1,3-cyclohexadienalsyields 1,3-cyclohexadienals50 or 55 50, respectively. or 55, respectively. In this manner, In this manner, lithium enolateslithium enolates are a versatile are a versatile tool in tool organic in organi synthesis,c synthesis, allowing allowing for the for cross-condensationthe cross-condensation between two different unsaturated aldehydes, opening the possibilities among the non-chiral condensation methodology [32].

Scheme 12. Cross-condensation of unsaturated aldehydes in the formation of 1,3-cyclohexadien-1- als.

The aldol reaction between aldehyde 46 and its enolate formed in presence of potas- sium 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 ni- triles 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.

Scheme 13. Self-condensation of α,β-unsaturated aldehyde 46 in the formation of 1,3-cyclohexadien-1-al 49.

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

Molecules 2020, 25, x FOR PEER REVIEW 7 of 33 Molecules 2020, 25, x FOR PEER REVIEW 7 of 33 Similar results are obtained with senecialdehyde 47, self-condensation reaction pro- motedSimilar by alkali results [30]. are In thisobtained case, witha global senecialdehyde yield of 80% 47is obtained,, self-condensation and compounds reaction 50–52 pro- aremoted obtained by alkali in a [30]. ratio In 2:3:5 this (Schemecase, a global 11). Cy yieldclodimerization of 80% is obtained, also occurs and compoundswhen crotonalde- 50–52 hydeare obtained is treated in awith ratio solid 2:3:5 base(Scheme catalysts 11). Cy ofclodimerization metal oxides and also silica. occurs In whenthis case, crotonalde- the ob- tainedhyde is diene treated can with evolve solid by basedehydrogenation catalysts of metal and aromatization oxides and silica. [31]. In this case, the obtained diene can evolve by dehydrogenation and aromatization [31].

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. Trimethylsilyl and acetate enolderivatives 53 serve as starting material for obtaining 1,3-cyclohexadien-1-alsTrimethylsilyl and throughacetate enolderivatives the lithium enolate 53 serve formation as starting (Scheme material 12). forIntermediate obtaining 541,3-cyclohexadien-1-als can be accessed via metalationthrough the of lithium 53 with en MeLi.olate formationThe subsequent (Scheme addition 12). Intermediate of a conju- Molecules 2021, 26, 1772 7 of 32 gated54 can aldehyde be accessed 47 or via 51 metalation yields 1,3-cyclohexadienals of 53 with MeLi. 50The or subsequent55, respectively. addition In this of manner,a conju- lithiumgated aldehyde enolates 47 are or a 51 versatile yields 1,3-cyclohexadienalstool in organic synthesis, 50 or allowing 55, respectively. for the cross-condensa- In this manner, tionlithium between enolates two are different a versatile unsaturated tool in organi aldechydes, synthesis, opening allowing the possibilitiesfor the cross-condensa- among the betweennon-chiraltion between two condensation differenttwo different unsaturated methodology unsaturated aldehydes, [32]. alde hydes, opening opening the possibilities the possibilities among among the non- the chiralnon-chiral condensation condensation methodology methodology [32]. [32].

Scheme 12. Cross-condensation of unsaturated aldehydes in the formation of 1,3-cyclohexadien-1- SchemealSchemes. 12.12. Cross-condensationCross-condensation of of unsaturated unsaturated aldehydes aldehydes in in the the formation formation of 1,3-cyclohexadien-1-als.of 1,3-cyclohexadien-1- als. TheThe aldolaldol reactionreaction betweenbetween aldehyde 46 and its enolate formed in presence of potas- siumsiumThe terttert -butoxidealdol-butoxide reaction ((tt--BuOK)BuOK) between leadsleads aldehyde toto thethe 46 dimericdimeric and its intermediate intermediateenolate formed thatthat in ininpresence acidicacidic mediumofmedium potas- evolvesevolvessium tert to-butoxide form the the ( t-self-condensation self-condensationBuOK) leads to productthe product dimeric 4949 (Scheme (Schemeintermediate 13) 13 )[[33]. that33 ].α ,inβα-Unsaturated ,βacidic-Unsaturated medium ni- nitrilestrilesevolves produce produceto form analogue analoguethe self-condensation condensation condensation mechan product mechanism,ism, 49 giving(Scheme giving the 13)the corresponding [33]. corresponding α,β-Unsaturated 2-amino-1,3- 2-amino- ni- 1,3-cyclohexadien-1-carbonitrilecyclohexadien-1-carbonitriletriles produce analogue condensation scaffold; scaffold; mechanthese these deism, derivativesrivatives giving can the can becorresponding be easily easily converted converted 2-amino-1,3- to theirtheir correspondingcorrespondingcyclohexadien-1-carbonitrile aldehydes.aldehydes. scaffold; these derivatives can be easily converted to their corresponding aldehydes.

SchemeScheme 13.13. Self-condensation ofofα α,β,β-unsaturated-unsaturated aldehyde aldehyde46 46in in the the formation formation of of 1,3-cyclohexadien- 1,3-cyclohexa- 1-aldien-1-alScheme49. 13. 49 .Self-condensation of α,β-unsaturated aldehyde 46 in the formation of 1,3-cyclohexadien-1-al 49. StudyingStudying thethe reactivity reactivity of ethylof ethyl 4-(diethoxyphosphinyl)-3-oxobutanoate 4-(diethoxyphosphinyl)-3-oxobutanoate56 with 56 enalswith Molecules 2020, 25, x FOR PEER REVIEW(Schemeenals Studying (Scheme 14), one 14),the ﬁnds onereactivity thatfinds after that of conjugatedethylafter conjug4-(diethoxyphosphinyl)-3-oxobutanoate Michaelated Michael addition addition to the to corresponding the corresponding 56 8 enalwith of 33 andenalenals subsequentand (Scheme subsequent 14), Horner one Horner finds reaction thatreaction over after theover conjug free the carbonylated free Michael carbonyl compound, addition compound, the to formationthe the corresponding formation of cyclic of compoundscyclicenal and compounds subsequent such assuch dienalHorner as dienal50 reaction(22%) 50 (22%) andover the andthe major freethe major carbonyl product, product, compound, the directthe direct Hornerthe Hornerformation reaction reac- of producttion product57 (53%), 57 (53%), occurs occurs [34]. The[34]. strong The strong basic basic medium medium allows allows for the for self-condensation the self-condensa- of crotonaldehydetion of crotonaldehyde [35]. [35].

Scheme 14. Michael andand Horner–Wadsworth–EmmonsHorner–Wadsworth–Emmons reactions reactions in thein the synthesis synthesis of cyclohexadienal of cyclohexadi-50. enal 50. Starting from linear starting materials, the cyclization to form six-membered rings can beStarting performed from in linear two stepsstarting through materials, Horner the oleﬁnation cyclization of toα ,formβ-unsaturated six-membered aldehydes rings andcan be Michael performed addition in two to thesteps resulting through unsaturated Horner olefination system (Schemeof α,β-unsaturated 15). Ester aldehydes reduction yieldsand Michael the 1,3-cyclohexadienal addition to the resulting scaffold, unsatu whereinrated relative system conﬁguration (Scheme 15). can Ester becontrolled reduction byyields using the different 1,3-cyclohexadienal bases for the scaffold, conjugated wherein addition. relative This configuration methodology can has be been controlled used in theby using total synthesisdifferent bases of natural for the products conjugated containing addition. 1,3-cyclohexadien-1-al This methodology has scaffolds been used such in asthe ( ±total)-cis synthesis/trans-2,3,3a,7a-tetrahydro-1 of natural productsH containing-indene-4-carbaldehyde 1,3-cyclohexadien-1-al61 and 63 scaffoldsthat have such been 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].

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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].

Scheme 14. Michael and Horner–Wadsworth–Emmons reactions in the synthesis of cyclohexadienal 50.

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 Molecules 2021, 26, 1772 8 of 32 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 preparedapplied for starting obtaining from 1,3-cyclohexadienals aldehyde 58 and the due ylide to their of 59 interest[6]. Similar as intermediates methodology of pol- has beenysubstituted applied aromatic for obtaining compounds, 1,3-cyclohexadienals as indicated in due the to preparation their interest of as 67 intermediates from 64 and of65 polysubstituted(Scheme 15) [36]. aromatic The use compounds, of chiral phosphines as indicated in this in the reaction preparation opens ofthe67 possibilityfrom 64 and of 65asymmetric(Scheme 15synthesis)[36]. The for use this of scaffold, chiral phosphines as exemplified in this in reaction the preparation opens the of possibility 71 from of68 asymmetricusing phosphine synthesis derivative for this scaffold,C, obtaining as exempliﬁed good enantiomeric in the preparation excess (ee) of 71 andfrom moderate68 using phosphineyield [16]. derivative C, obtaining good enantiomeric excess (ee) and moderate yield [16].

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COOR CHO Ph3P COOR p-BrPh 1) DIBAL-H p-BrPh CsCO 2) DMP Br 64 3 98 % 92 % p-BrPh Ph Ph 2 steps Ph 66 67 O 65

COOR CHO L P COOR 3 Ph 1) DIBAL-H Ph CsCO3 Br 68 2) DMP 62 % (83 %ee) 83 % Ph Ph Ph 2 steps Ph

O 70 71 69

Chiral phosphines (PL3):

PPh2 MeO PPh2 MeO PAr2 MeO PAr'2 MeO PPh2 MeO PAr2 MeO PAr'2 PPh2

ACDB (S)-BINAP

OMe tBu Ar: Ar':

OMe tBu SchemeScheme 15.15. MichaelMichael andand Horner–Wadsworth–Emmons Horner–Wadsworth–Emmons reactions reactions in in the the synthesis synthesis of cyclohexadienals.of cyclohexadienals. 2.5. Pericyclic Reactions: Diels–Alder and Electrocyclizations 2.5. PericyclicThe Diels–Alder Reactions: reaction Diels–Alder is the and most Electrocyclizations important and versatile reaction in synthetic organicThe chemistry Diels–Alder for preparingreaction is six-membered the most impo rings.rtant Theand 1,3-cyclohexadien-1-al versatile reaction in synthetic scaffold canorganic be afforded chemistry via for Diels–Alder preparing six-membered reaction by cycloaddition rings. The 1,3-cyclohexadien-1-al followed by base-promoted 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.

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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 Molecules 2020, 25, x FOR PEER REVIEWbenzaldehyde derivative. 10 of 33

SchemeScheme 16. 16.Diels–Alder Diels–Alder reactions reactions towards towards the synthesis the synthesis of 1,3-cyclohexadien-1-al of 1,3-cyclohexadien-1-al scaffold. scaffold.

Another example of Diels–Alder cycloaddition wherein a high regioselectivity is 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 actsreached as a regioselective thanks to the assistant sulfur-containing as well as a good diene leaving is shown group in once Scheme the adduct 17 [40,41]. is formed, The sulfide yieldingacts as a theregioselective 1,3-cyclohexadienal. assistant Theas well reaction as a good of the leaving diene 85 groupwith once acroleine the adduct86 yields is formed, theyielding typical the mono-olefin 1,3-cyclohexadiena adduct of thel. The Diels–Alder reaction reaction of the diene that after 85 with elimination acroleine of allylic 86 yields the ethylsulfidetypical mono-olefin group yields adduct 1,3-cyclohexadienal of the Diels–Alder88. The reaction can that be after catalyzed elimination by ZnBr 2of, allylic ◦ ◦ allowingethylsulfide a lower group activation yields energy 1,3-cyclohexadienal and thus heating 88 at 60. TheC insteadreaction of can 100 beC. Thecatalyzed reaction by ZnBr2, ◦ canallowing be even a carriedlower outactivation at 20 C whenenergy LiClO and4 /Etthus2O heating is added at as 60 catalyst, °C instead but higher of 100 reaction °C. The reac- times are needed. tion can be even carried out at 20 °C when LiClO4/Et2O is added as catalyst, but higher reaction times are needed.

Scheme 17. Diels–Alder reaction towards the synthesis of 1,3-cyclohexadien-1-al scaffold.

The Lewis acid- or Brønsted acid-catalyzed Diels–Alder reaction between cinnamal- dehyde 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 trifluo- ride ethyl etherate BF3·OEt2, LiClO4, TiCl4, and catalytic TsOH (0.2 equivalents) proved most efficient [42].

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Scheme 16. Diels–Alder reactions towards the synthesis of 1,3-cyclohexadien-1-al scaffold.

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, Molecules 2021, 26, 1772 allowing a lower activation energy and thus heating at 60 °C instead of 100 °C. The10 reac- of 32 tion can be even carried out at 20 °C when LiClO4/Et2O is added as catalyst, but higher reaction times are needed.

SchemeScheme 17.17. Diels–Alder reaction towardstowards thethe synthesissynthesis ofof 1,3-cyclohexadien-1-al1,3-cyclohexadien-1-al scaffold.scaffold.

The Lewis acid- or Brønsted acid-catalyzed Diels–Alder reaction between cinnamalde- hydeThe90 and Lewis different acid- or enamines Brønsted89 acid-catalyzedresulted in 1,3-cyclohexadienal Diels–Alder reaction substituted between incinnamal- 5 and 6 positionsdehyde 90 (Scheme and different 18). Among enamines the Lewis 89 resulted and Brønsted in 1,3-cyclohexadienal acids used, TsOH, substituted boron triﬂuoride in 5 and ethyl6 positions etherate (Scheme BF3·OEt 18).2, LiClOAmong4, the TiCl Lewis4, and and catalytic Brønsted TsOH acids (0.2 used, equivalents) TsOH, boron proved trifluo- most Molecules 2020, 25, x FOR PEER REVIEWefﬁcientride ethyl [42 etherate]. BF3·OEt2, LiClO4, TiCl4, and catalytic TsOH (0.2 equivalents) proved11 of 33 most efficient [42].

SchemeScheme 18.18. Diels–Alder reaction towardstowards thethe synthesissynthesis ofof 1,3-cyclohexadien-1-al1,3-cyclohexadien-1-al scaffold.scaffold.

ByBy usingusing thethe Diels–AlderDiels–Alder reactionreaction toto formform thethe 1,3-cyclohexadienal,1,3-cyclohexadienal, oneone cancan employemploy otherother startingstarting materialsmaterials suchsuch asas 2,2-bis(trifluoromethyl)-ethylene-1,1-dicarbonitrile2,2-bis(trifluoromethyl)-ethylene-1,1-dicarbonitrile 92,92, aa veryvery strongstrong dienophiledienophile (Scheme(Scheme 1919))[ [43].43]. However,However, threethree transformationtransformation stepssteps areare neededneeded toto formform thethe 1,3-cyclohexadienal1,3-cyclohexadienal fromfrom adductadduct 9494.. TheThe firstfirst step,step, thethe Diels–AlderDiels–Alder reactionreaction betweenbetween thethe dicarbonitriledicarbonitrile 92 andand thethe dienediene 9393 occursoccurs inin anan excellentexcellent yieldyield (90%)(90%) andand cancan bebe improved upup toto 97%97% whenwhen 9393 isis inin excessexcess andand increasingincreasing reactionreaction time.time. TheThe eliminationelimination ofof a nitrile group inin 94 isis carriedcarried outout byby reactionreaction withwith NaOHNaOH inin aqueousaqueous ethanol,ethanol, resultingresulting inin 95 (97% yield). yield). The The formation formation of of diene diene 9696 fromfrom 95 95takestakes place place in two in two steps: steps: allylic allylic bro- brominationmination with with N-bromosuccinimideN-bromosuccinimide (NBS) (NBS) and and elimination elimination reaction reaction with with triethylaminetriethylamine (Et(Et33N). The bromination is a criticalcritical stepstep whereinwherein monobrominationmonobromination must bebe controlled,controlled, showingshowing moderatemoderate conversion over these two steps (63%) andand lowlow yieldyield (32%).(32%). Finally, reductionreduction ofof nitrilenitrile 9696 withwith DIBAL-HDIBAL-H givesgives bis-trifluoromethyl-1,3-cyclohexadienalbis-trifluoromethyl-1,3-cyclohexadienal 9797 inin moderatemoderate yield.yield.

SchemeScheme 19.19. Diels–Alder reaction towardstowards thethe synthesissynthesis ofof hexaﬂuorinatedhexafluorinated safranalsafranal 9797..

OtherOther dienes derived from vinamidinium saltssalts areare versatileversatile intermediatesintermediates toto performperform Diels–AlderDiels–Alder reactionsreactions (Scheme (Scheme 20 20))[44 [44].]. For For example, example, starting starting from from the previouslythe previously prepared pre- vinamidiniumpared vinamidinium salt 101 salt, reaction 101, reaction with acrylaldehyde with acrylaldehyde results results in cyclohexadiene in cyclohexadiene102. These 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.

Scheme 20. Diels–Alder reaction of vinamidium salts and unsaturated aldehydes.

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

Molecules 2020, 25, x FOR PEER REVIEW 11 of 33

Scheme 18. Diels–Alder reaction towards the synthesis of 1,3-cyclohexadien-1-al scaffold.

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.

Scheme 19. Diels–Alder reaction towards the synthesis of hexafluorinated safranal 97.

Molecules 2021, 26, 1772Other dienes derived from vinamidinium salts are versatile intermediates to perform 11 of 32 Diels–Alder reactions (Scheme 20) [44]. For example, starting from the previously prepared vinamidinium salt 101, reaction with acrylaldehyde results in cyclohexadiene 102. These vinamidiniumvinamidinium salt diene salt precursors diene precursors are prepared are prepared in three in three steps, steps, starting starting from from un- unsaturated saturated methylketonesmethylketones such suchas 98 as by98 reactionby reaction with with a asecondary secondary amine,amine, pyrrolidine pyrrolidine in this in case. The this case. The resultingresulting enamine enamine 99 isis tautomerizedtautomerized to theto the iminium iminium salt 94 salt, and 94 then, and a secondthen a equivalent second equivalentof of secondary secondary amine amine is added is added to form to form the vinamidinium the vinamidinium salt 101 salt. 101.

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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. Scheme 20. SchemeDiels–Alder 20. Diels–Alder reaction of reaction vinamidium of vinamidium salts and salts unsaturated and unsaturated aldehydes. aldehydes.

Starting from linear trienes, Lewis acid-catalyzed electrocyclizations form the 1,3- Molecules 2020, 25, xStarting FOR PEER from REVIEW linear trienes, Lewis acid-catalyzed electrocyclizations form the 1,3-cy- 12 of 33 cyclohexadiene-1-carbaldehyde fragment (Scheme 21)[45]. The Z/E conﬁguration of clohexadiene-1-carbaldehydedoublebonds as bonds well fragment as wellthe presence as (Scheme the presence of large 21) of[45].substituents large The substituents Z/ Ein configuration 5 positi inon 5 position are key of doublepoints are key in points terms inof termsestablishing of establishing the energy the barrier energy for barrier the electrocyclization for the electrocyclization to occur. to occur.

Scheme 21. Synthesis and thermal cyclization of hexatrienes 106 and 109; CuTC = copper(I) thio- Schemephene-2-carboxylate.Scheme 21. SynthesisSynthesis and and thermal thermal cyc cyclizationlization of hexatrienes of hexatrienes 106 and106 109and; CuTC109; CuTC= copper(I) = copper(I) thio- thiophene-2-carboxylate.phene-2-carboxylate. Organoruthenium complexes can yield 1,3-cyclohexadienal scaffold through a 6e-π Organoruthenium complexes can yield 1,3-cyclohexadienal scaffold through a 6e-ππ electrocyclizationOrganoruthenium (Scheme complexes 22). can The yield re 1,3-cyclohexadienalaction takes place scaffold between through a 1,6-diyne a 6e- 110 and acro- electrocyclizationelectrocyclization (Scheme 22).22). The The reaction reaction takes takes place place between between a 1,6-diyne a 1,6-diyne 110 and110 acro-and acroleineleine [46]. [46]. [ 46 ].

Scheme 22. Ruthenium catalyzed electrocyclization in the preparation of 1,3-cyclohexadienal scaffold. SchemeScheme 22. 22.Ruthenium Ruthenium catalyzed catalyzed electrocyclization electrocyclization in the preparation in the of preparation 1,3-cyclohexadienal of 1,3-cyclohexadienal scaffold. scaffold.2.6. Organometallic Synthetic Procedures According to the reaction conditions reported by Corey et al. [47], γ,δ-unsaturated 2.6.esters Organometallic can be used as Syntheticprecursors Procedures of 1,3-cyclohexadien-1-als (Scheme 23). The transfor- mationAccording of 113 into to intermediate the reaction 116 conditionsby reaction withreported the previously by Corey prepared et al. [47],bis(di- γ,δ-unsaturated estersmethylaluminium)-1,3-propanethiol can be used as precursors followed of 1,3-cy by aclohexadien-1-als two-step reaction of (Schemelithium diiso- 23). The transfor- propylamide/hexamethylphosphoramide (LDA/HMPTA) anion formation and addition mationof methanol of for113 quenching into intermediate leads to the desired 116 by product reaction 1 in goodwith yield. 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.

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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.

Scheme 21. Synthesis and thermal cyclization of hexatrienes 106 and 109; CuTC = copper(I) thiophene-2-carboxylate.

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].

Molecules 2021, 26, 1772 12 of 32 Scheme 22. Ruthenium catalyzed electrocyclization in the preparation of 1,3-cyclohexadienal scaffold.

2.6.2.6. OrganometallicOrganometallic SyntheticSynthetic ProceduresProcedures AccordingAccording toto the the reaction reaction conditions conditions reported reported by by Corey Corey et al.et [al.47 ],[47],γ,δ -unsaturatedγ,δ-unsaturated es- tersesters can can be usedbe used as precursors as precursors of 1,3-cyclohexadien-1-als of 1,3-cyclohexadien-1-als (Scheme (Scheme 23). The 23). transformation The transfor- of 113mationinto intermediateof 113 into intermediate116 by reaction 116 with by the reaction previously with prepared the previously bis(dimethylaluminium)- prepared bis(di- 1,3-propanethiolmethylaluminium)-1,3-propanethiol followed by a two-step followed reaction by of lithiuma two-step diisopropylamide/hexamethyl- reaction of lithium diiso- phosphoramidepropylamide/hexamethylphosphoramide (LDA/HMPTA) anion formation (LDA/HMPTA) and addition anion of methanolformation for and quenching addition leadsof methanol to the desired for quenching product leads1 in good to the yield. desired product 1 in good yield.

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SchemeScheme 23.23. Employment ofof organoaluminiumorganoaluminium reagentreagent inin thethe synthesissynthesis ofof cyclohexadienalcyclohexadienal1 1..

AnAn organometallicorganometallic method method using using Cr(CO) Cr(CO)3 complex3 complex and and benzaldehyde benzaldehyde consisting consisting of itsof dearomatizationits dearomatization and and chemoselective chemoselective nucleophile nucleophile addition addition has been has reported been reported (Scheme (Scheme 24)[48] . Starting24) [48]. from Starting benzaldehyde, from benzaldehyde, preparation of preparation the corresponding of the phenylmethanimine–tricarbo- corresponding phenylme- nylchromiumthanimine–tricarbonylchromium complex 117 is performed. complex 117 Addition is performed. of a nucleophile Addition isof followeda nucleophile in the is formationfollowed in of the anionic formation cyclohexadienyl of anionic complex cyclohexadienyl118 that iscomplex trapped 118 with that different is trapped bromides, with providingdifferent bromides, at the end theproviding 1,3-cyclohexadienal at the end the substituted 1,3-cyclohexadienal in 5 and 6 positions. substituted Different in 5 and ratio 6 ofpositions. products Different119 and ratio120 is of obtained products depending 119 and 120 on is the obtained R1 and depending R2 groups. on Compound the R1 and119 R2 isgroups. preferentially Compound formed 119 whenis preferentially R1 is a phenyl formed group, when while R1 is cyclohexadienal a phenyl group,120 whileis formed cyclo- 2 selectivelyhexadienal when120 is R formedis an allylselectively or propargyl when R group.2 is an allyl or propargyl group.

SchemeScheme 24.24. Cr(CO)33 complex-mediated dearomatization in the synthesis of cyclohexadienals.

InIn thesethese complexes,complexes, 117117,, thethe imineimine group,group, actsacts asas anan auxiliaryauxiliary thatthat directsdirects RR11 toto thethe orthoortho positionposition viavia lithium–nitrogenlithium–nitrogen interactioninteraction (Scheme(Scheme 25 25).). ExternalExternal chiralchiral ligandsligands cancan bebe addedadded toto thethe reactionreaction inin orderorder toto induceinduce stereoselectivitystereoselectivity inin thethe productproduct [[49],49], showingshowing thethe highesthighest enantioselectivitiesenantioselectivities when PhLiPhLi isis usedused asas nucleophile.nucleophile. TheThe externalexternal ligandligand formsforms anan oligomericoligomeric entityentity withwith thethe nucleophilenucleophile actingacting asas aa bridgebridge insteadinstead ofof aa simplesimple chelatingchelating process.process.

Scheme 25. Cr(CO)3 complex-mediated dearomatization in the presence of chiral ligands.

A selection of nitrogen-containing precursors that can be used to form the corresponding tricarbonylchromium complex is shown in Scheme 26 [48–51]. 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.

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Scheme 23. Employment of organoaluminium reagent in the synthesis of cyclohexadienal 1.

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.

Scheme 24. Cr(CO)3 complex-mediated dearomatization in the synthesis of cyclohexadienals.

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 Molecules 2021, 26, 1772 highest enantioselectivities when PhLi is used as nucleophile. The external ligand forms 13 of 32 an oligomeric entity with the nucleophile acting as a bridge instead of a simple chelating process.

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.

AA selection selection of of nitrogen-containing nitrogen-containing precursors precursors that that can can be beused used to toform form the the corre- correspond- ingsponding tricarbonylchromium tricarbonylchromium complex complex is shownis shown in in Scheme Scheme 26 26[ [48–51].48–51]. These These precursors precursors can be can be prepared using the corresponding amine (R-NH2) and the benzaldehyde unit. prepared using the corresponding amine (R-NH2) and the benzaldehyde unit. When the When the nitrogen-containing precursor is optically pure, the reaction shows high dia- nitrogen-containing precursor is optically pure, the reaction shows high diastereoselectivity stereoselectivity in the addition of nucleophiles in an asymmetric manner (up to 98% dia- in the addition of nucleophiles in an asymmetric4 manner (up to 98% diatereomeric excess, tereomeric excess, de), as4 in the case of R . Molecules 2020, 25, x FOR PEER REVIEWde), as in the case of R . 14 of 33

Molecules 2020, 25, x FOR PEER REVIEW 14 of 33

Scheme 26. Selection of Cr(CO)3 complexes used in dearomatization reactions for the preparation Scheme 26. Selection of Cr(CO)3 complexes used in dearomatization reactions for the preparation of of cyclohexadienals. cyclohexadienals.Scheme 26. Selection of Cr(CO)3 complexes used in dearomatization reactions for the preparation of cyclohexadienals. The tricarbonylchromium-mediated dearomatization is a useful tool to access substi- The tricarbonylchromium-mediated dearomatization is a useful tool to access substituted cyclohexadienals. It has been used to synthesize acetoxytubipofuran, as a reacemic tuted cyclohexadienals.The tricarbonylchromium-mediated It has been used to synthesize dearomatization acetoxytubipofuran, is a useful as tool a reacemic to access substi- mixture [52] and also as the two separated enantiomers [51]. The natural product, isolated mixture [52] andtuted also cyclohexadienals. as the two separated It has enantiomersbeen used to synthesize [51]. The acetoxytubipofuran, natural product, isolated as a reacemic from Tubipora musica,mixture is an[52] eudesmane and also as marinethe two sesquite separatedrpene enantiomers that has been[51]. Thesynthesized natural product, isolated from Tubipora musica, is an eudesmane marine sesquiterpene that has been synthesized from dienal (S,S)-from126 andTubipora (R,R)- musica,126 as iskey an intermediates, eudesmane marine which sesquite in turnrpene have beenthat has pre- been synthesized from dienal (S,S)-126 and (R,R)-126 as key intermediates, which in turn have been prepared pared according fromto the dienal synthetic (S,S)- pathway126 and described (R,R)-126 in as Scheme key intermediates, 27. which in turn have been pre- according to thepared synthetic according pathway to the describedsynthetic pathway in Scheme described 27. in Scheme 27.

Scheme 27. Cr(CO)3 complex-mediated dearomatization in the synthesis of cyclohexadienals towards acetoxytubipofuran. Scheme 27. Cr(CO)Scheme3 complex-mediated 27. Cr(CO)3 complex-mediated dearomatization dearomatization in the synthesis in the synthesis of cyclohexadienals of cyclohexadienals to- to- wards acetoxytubipofuran. wards2.7. Organocatalytic acetoxytubipofuran. Methodologies The access to2.7. chiral Organocatalytic 1,3-cyclohexadienals Methodologies can be accomplished by using organocatal- β ysis. This methodologyThe is aaccess versatile to chiral method 1,3-cy thatclohexadienals uses as starting can materials be accomplished an α, -unsatu- by using organocatal- β β rated aldehyde andysis. a Thisα, -unsaturated methodology aldehyde is a versatile with method a methyl that or uses methylene as starting group materials in . an α,β-unsatu- A high number ratedof proline aldehyde derivatives and a αhave,β-unsaturated been used aldehyde as organocatalysts with a methyl (129 –or139 methylene), as group in β. shown in SchemeA 28 high [53]. number Two different of proline mechan derivativesisms have have been been proposed: used as (4 organocatalysts+ 2) cycload- (129–139), as dition or Michaelshown addition in Schemeand cyclization 28 [53]. Two[53]. different mechanisms have been proposed: (4 + 2) cycloaddition or Michael addition and cyclization [53].

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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) Molecules 2020, 25, x FOR PEER REVIEWcycloaddition or Michael addition and cyclization [53]. 15 of 33

SchemeScheme 28.28. OrganocatalyzedOrganocatalyzed synthesissynthesis ofof 1,3-cyclohexadien-1-als1,3-cyclohexadien-1-als fromfrom citralcitral51 51..

TheThe ﬁrstfirst useuse ofof prolineproline asas aa catalystcatalyst beginsbegins withwith itsits applicationapplication inin thethe biomimeticbiomimetic cyclizationcyclization ofof citral,citral, synthesizingsynthesizing unsaturatedunsaturated aldehydesaldehydes (Scheme(Scheme 2929))[ [54,55].54,55]. However,However, thethe speciﬁcspecific useuse ofof prolineproline toto synthesizesynthesize 1,3-cyclohexadienals1,3-cyclohexadienals occurredoccurred inin 19921992 [[56],56], wherewhere thethe reactionreaction ofof thisthis aminoacidaminoacid withwith differentdifferentα α,β,β-unsaturated-unsaturated aldehydesaldehydes promotedpromoted theirtheir self-condensation.self-condensation. The good enantiomericenantiomeric excessexcess (up toto 65%)65%) resultedresulted inin aa deepeningdeepening ofof thethe researchresearch onon thethe useuse ofof prolineproline asas organocatalystorganocatalyst asas wellwell asas thethe developmentdevelopment ofof prolineproline analoguesanalogues withwith improved improved catalytic catalytic properties. properties. L-proline L-proline is usedis used in excessin excess in these in these reactions reac- andtions the and self-condensation the self-condensation product product is always is always detected. detected. When When other other proline proline derivatives deriva- cis suchtives assuch 4-hydroxy-L-proline, as 4-hydroxy-L-proline, D-proline, D-proline, and and-4-hydroxy-D-proline cis-4-hydroxy-D-proline are used, are used, the self- the assembly of the aldehydes is observed; however, this self-condensation product of citral is self-assembly of the aldehydes is observed; however, this self-condensation product of not observed when Trp, His, Arg, Gly, or ILeu are used as catalysts for citral dimerization. citral is not observed when Trp, His, Arg, Gly, or ILeu are used as catalysts for citral di- This condensation takes place through Schiff-base formation as a synthetic inter- merization. mediate that reacts with other equivalents of α,β-unsaturated aldehyde yielding the This condensation takes place through Schiff-base formation as a synthetic interme- 1,3-cyclohexadien-1-al core. However, sometimes the intermediate Schiff-base is stable diate that reacts with other equivalents of α,β-unsaturated aldehyde yielding the 1,3-cy- enough and can be isolated, as in the case of the corresponding Schiff-base of L-proline clohexadien-1-al core. However, sometimes the intermediate Schiff-base is stable enough and retinal [53]. and can be isolated, as in the case of the corresponding Schiff-base of L-proline and retinal In this sense, even when cross-condensation is performed, the autocondensation reac- [53]. tion should be considered as a possible background reaction. In the case of the use of citral, In this sense, even when cross-condensation is performed, the autocondensation re- there is frequently the presence of the citral homodimer among the reaction products [57,58], asaction well should as in organocatalyzed be considered as cycloaddition a possible ba inckground multicomponent reaction. reactions In the case [59 ].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].

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Scheme 29. Organocatalytic self-condensation of α,β-unsaturated aldehydes towards 1,3-cyclohex- Scheme 29. OrganocatalyticScheme 29. Organocatalyticadien-1-al self-condensation compounds. self-condensation of α, β-unsaturated of α,β-unsaturated aldehydes towards aldehydes 1,3-cyclohexadien-1-al towards 1,3-cyclohex- compounds. adien-1-al compounds. Among the different organocatalysts,organocatalysts, thethe aminocatalystsaminocatalysts proline,proline, MacMillan’sMacMillan’s 138138 oror Among the139139 different,, andand Hayashi-Jorgensen’sHayashi-Jorgensen’s organocatalysts, the 137137 aminocatalysts [[60]60] catalystscatalysts cancan proline, promotepromote MacMillan’s MichaelMichael additionaddition 138 or byby iminiumiminium 139, and Hayashi-Jorgensen’ssalt formation withwith 137 thethe [60] acceptoracceptor catalysts enal.enal. can OnOnpromote the other Michael hand, addition a carbonyl by donoriminium cancan bebe activated salt formationby with forming the acceptor the enamine enal. On by the addition other hand, of the a organocatalyst carbonyl donor and can ensuing be activated Michael addition. by forming theThus,Thus, enamine iminium by addition salt-enamine of the formationorganocatalyst turns and out ensuing to be key Michael in these addition. organocatalytic path- Thus, iminiumwaysways salt-enamine (Scheme 30).30formation). Aldehydes Aldehydes turns such suchout toas as becrotonal crotonaldehyde key indehyde these organocatalytic reacts reacts with with L-proline L-proline path- through through a [3 a ways (Scheme[+3 30).3] + cycloaddition, 3 ]Aldehydes cycloaddition, such but but aswhen crotonal when other otherdehyde α,βα-unsaturated,β-unsaturated reacts with aldehydes L-proline aldehydes with through with β-substituentsβ-substituents a [3 react react in + 3] cycloaddition,inthe the same but same when conditions, conditions, other αthe,β the-unsaturated observed observed product aldehydes product is the is with the (4 + (4 β2)-substituents + adduct 2) adduct [61]. [ 61react The]. The inmechanistic mechanistic ex- the same conditions,explanationplanation the suggests observed suggests that product that increasing increasing is the the (4 the +steric 2) steric adduct hindrance hindrance [61]. Thein inβ -positionmechanisticβ-position of these ofex- these series series of al- of planation suggestsaldehydesdehydes that eases increasing eases the the indirect indirect the steric Mannich Mannich hindrance reaction reaction in β pathway-position pathway andof and these (4 (4 + series2) 2) adducts of al- instead ofof thethe dehydes eases[3[3 the ++ 3] indirect cycloaddition Mannich products reaction when pathway carboncarbon and 33 isis(4 moremore+ 2) adducts accessible.accessible. instead of the [3 + 3] cycloaddition products when carbon 3 is more accessible.

Scheme 30. Organocatalyst-mediatedOrganocatalyst-mediated cycloaddition cycloaddition of ofα,βα-unsaturated,β-unsaturated aldehydes aldehydes towards towards 1,3- 1,3- Scheme 30. Organocatalyst-mediatedcyclohexadien-1-al compounds.compounds. cycloaddition of α,β-unsaturated aldehydes towards 1,3- cyclohexadien-1-al compounds. The reactionreaction of of different different aldehydes aldehydes in thein the presence presence of L-proline of L-proline yields yields the correspond- the corre- The reactioningsponding (4 of + different 2) (4 adducts, + 2) adducts,aldehydes and results and in results the are shownpresence are show in Tableofn L-proline in1 Table[ 61]. 1 Pyrrolidineyields [61]. Pyrrolidine the corre- can also can be also a good be a sponding (4 +catalystgood 2) adducts, catalyst for the and for (4 results the + 2) (4 cycloaddition +are 2) showcycloadditionn in [ 62Table], where [6 12], [61]. where a widePyrrolidine a scopewide isscope can given. also is given. Subsequentbe a Subsequent arom- good catalyst atizationfor the (4 of + 2) the cycloaddition diene adducts [62], by where reaction a wide with scope DDQ oris given. MnO2 Subsequentgives the benzaldehyde

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2 aromatizationaromatization ofof thethe dienediene adducts adducts byby reaction reaction withwith DDQDDQ oror MnO MnO2 givesgives thethe benzalde- benzalde- derivatives,hydehyde derivatives, derivatives, providing, providing, providing, in this in in way,this this way, way, a good a a good good methodology methodology methodology for controlledforfor controlled controlled substitution substitution substitution of benzaldehyde derivatives. ofof benzaldehyde benzaldehyde derivatives. derivatives.

α β TableTable 1. 1. Examples ExamplesExamples of of cyclohexadienals cyclohexadienals obtained obtained obtained in in inthe the the (4 (4 (4+ + 2) +2) cycloaddition 2)cycloaddition cycloaddition of of α α of,β,β-unsaturated-unsaturated, -unsaturated aldehydesaldehydes mediated mediated by by L-proline. L-proline.

1 2 3 4 Compound R1 R2 R3 R4 % Yield (ee) CompoundCompound R1 R R R2 RR 3 R R4 % Yield% Yield (ee)(ee) 5050 MeMe HH H H Me Me 82 82 (--) (--) 50 Me H H Me 82 (–) 2 150150 HH ααOAcOAc ααCHCH2OAcOAc HH 68 68 (94) (94) 150 H αOAc αCH2OAc H 68 (94) 151 151151 HHHH HH ααPhαPhPh HH H 61 61 (63) (63) 61 (63) 152 152152 MeMeMe HH H ααPhαPhPh HH H 72 72 (32) (32) 72 (32) 153 153153 MeMeMe HH H ααPhαPhPh HH H 78 78 (56) (56) 78 (56) 154 154 MeMe H H ααEtEt H H 71 (--) 71 (–) 155 154 MeMe H H αEtαMe H H 71 (--) 82 (41) 155155 MeMe HH ααMeMe HH 82 82 (41) (41)

WatanabeWatanabe et et al.al. al. synthesizedsynthesized synthesized a a highhigh high numbernumber number ofof of 1,3-cyclohexadienal1,3-cyclohexadienal 1,3-cyclohexadienal derivativesderivatives derivatives withwith with differentdifferent substitutionsubstitution degreesdegrees usingusing prolineproline asas organocatalyst organocatalystorganocatalyst (Scheme (Scheme(Scheme 31 31)31))[ [63].63[63].]. By ByBy this thisthis procedure, the homodimerization product can be observed in a variety of yields (5 to procedure,procedure, the the homodimerization homodimerization product product can can be be observed observed in in a a va varietyriety of of yields yields (5 (5 to to 75%), 75%), 75%), and moderate ee (36 to 72%) are observed, depending on the combination of donor– andand moderate moderate ee ee (36 (36 to to 72%) 72%) are are observed, observed, depending depending on on the the combination combination of of donor–ac- donor–ac- acceptor aldehydes. ceptorceptor aldehydes. aldehydes.

α β SchemeScheme 31. 31.31. Examples ExamplesExamples of of cyclohexadienals cyclohexadienals of cyclohexadienals obtained obtained obtained in in L-proline-mediated L-proline-mediated in L-proline-mediated reaction reaction reaction of of α α,β,β-unsatu--unsatu- of , - unsaturatedratedrated aldehydes. aldehydes. aldehydes.

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TheThe optimizationoptimization ofof thethe reactionreaction consistsconsists ofof pre-formingpre-formingpre-forming thethe iminiumiminiumiminium saltsalt ofofof donordonordonor aldehyde-prolinealdehyde-proline andand thenthen then additionaddition addition ofof of acceptoracceptor acceptor aldehyde,aldehyde, aldehyde, minimizingminimizing minimizing inin thisthis in this wayway way thethe for- thefor- formationmationmation ofof the ofthe the homo-dimmer.homo-dimmer. homo-dimmer. IntramolecularIntramolecular organocatalyzed organocatalyzed cycloaddition cycloaddition has has been been screened screenedscreened in inin a a variety variety of of cin- cin- namaldehydenamaldehyde derivatives,derivatives, obtainingobtaining dihydrodibenzofuransdihydrodibdihydrodibenzofuransenzofurans withwith goodgood enantioselectivityenantioselectivityenantioselectivity andand yieldsyields (Scheme(Scheme 3232)32))[ [64].[64].64].

SchemeScheme 32.32. IntramolecularIntramolecular organocatalyticorganocatalytic formationformationformation ofofof cyclohexadienalcyclohexadienalcyclohexadienal unit.unit.unit.

AA formalformal formal eliminativeeliminative eliminative (4(4 (4++ 2)2) + cycloadditioncycloaddition 2) cycloaddition cancan bebe can performed,performed, be performed, startingstarting starting fromfrom aa γγ-enoliz- from-enoliz- a β γableable-enolizable αα,,ββ-unsaturated-unsaturatedα,β-unsaturated carbonylcarbonyl compoundcompound carbonyl compound (diene(diene)) andand (diene) anan enalenal and (dienophile)(dienophile) an enal (dienophile) (Scheme(Scheme 33)33) ([65].[65].Scheme TheThe33 additionaddition)[65] . of Theof anan addition organocatalystorganocatalyst of an organocatalyst allowsallows forfor aa diastereoselectiondiastereoselection allows for a diastereoselection inin thethe cycloadditioncycloaddition in thethroughthrough cycloaddition thethe formationformation through ofof thethe the Schiff-base.Schiff-base. formation ofAfterAfter the screening Schiff-base.screening thethe After reactionreaction screening conditionsconditions the reac- andand tiondemonstratingdemonstrating conditions thethe and generalgeneral demonstrating applicabilityapplicability the of generalof ththee (4(4 applicability++ 2)2) eliminativeeliminative of thecycloaddition,cycloaddition, (4 + 2) eliminative oneone cancan cycloaddition,applyapply thethe procedureprocedure one can toto steroi applysteroid-basedd-based the procedure dicyanodicyano to substrates.substrates. steroid-based dicyano substrates.

SchemeScheme 33.33. Organocatalyst-mediatedOrganocatalyst-mediated cycloadditioncycloaddition forfor thethe synthesissynthesis ofofof cyclohexadienalcyclohexadienalcyclohexadienal core. core.core.

TheThe samesamesame methodology methodologymethodology has hashas been beenbeen applied appliedapplied to thetoto thethe synthesis synthesissynthesis of chiral ofof chiralchiral 1,3-cyclohexadienals, 1,3-cyclohexadi-1,3-cyclohexadi- where a high diastereoselection has been reported, showing up to a 85:15 diastereomeric enals,enals, wherewhere aa highhigh diastereoselectiondiastereoselection hashas beenbeen reported,reported, showingshowing upup toto aa 85:1585:15 diastere-diastere- ratio and moderate to good yield (Scheme 34)[66]. omericomeric ratioratio andand moderatemoderate toto goodgood yieldyield (Scheme(Scheme 34)34) [66].[66].

SchemeScheme 34.34. Organocatalytic-mediatedOrganocatalytic-mediated synthesissynthesis ofof chiralchiral 1,3-cyclohexadienals.1,3-cyclohexadienals. β ItIt isis importantimportantimportant tototo highlighthighlighthighlight thethethe relevancerelevancerelevance ofofof thethethe βββ-substitution-substitution-substitution inin donordonor aldehyde,aldehyde,aldehyde, whenwhen insteadinstead ofof aa methylmethyl group,group, thethe conjugatedconjugated unsaturationunsaturation isis an an exocyclic exocyclic double double bond, bond, andand thethe reactivityreactivity forfor thethethe cyclohexadienecyclohexadienecyclohexadiene formationformformationation decreases,decreases,decreases, signiﬁcantlysignificantlysignificantly reducingreducingreducing thethethe reactionreaction yield.yield. However,However, However, inin in thisthis this case,case, case, twotwo two chirchir chiralalal centerscenters centers areare generatedgenerated are generated inin thethe in reactionreaction the reaction prod-prod- productuctuct withwith with excellentexcellent excellent diasterediastere diastereoselectivityoselectivityoselectivity (Scheme(Scheme (Scheme 35).35). 35).

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SchemeScheme 35. 35. Organocatalytic-mediated Organocatalytic-mediated synthesis of of chiral chiral 1,3-cyclohexadienal 1,3-cyclohexadienal 179 . 179. SchemeScheme 35.35. Organocatalytic-mediatedOrganocatalytic-mediated synthesissynthesis ofof chiralchiral 1,3-cyclohexadienal1,3-cyclohexadienal179 179.. ThisThis organocatalytic organocatalytic process process is a veryvery useful useful tool tool that that can can be beapplied applied to one-pot to one-pot reac- reac- ThisThis organocatalytic process process is is a avery very useful useful tool tool that that can can be applied be applied to one-pot to one-pot reactionstions where where successive successive cycloadditions cycloadditions areare produc produced.ed. Saktura Saktura et al.et al.reported reported this thisreaction reaction reactionstions where where successive successive cycloadditions cycloadditions are produc are produced.ed. Saktura Saktura et al. reported et al. reported this reaction this cascade of uracil and conjugated aldehydes where the 1,3-cyclohexadienal is synthesized cascadereactioncascade of ofuracil cascade uracil and and of uracilconjugated conjugated and conjugated aldehydesaldehydes aldehydeswhere where the the 1,3-cyclohexadienal where 1,3-cyclohexadienal the 1,3-cyclohexadienal is synthesized is synthesized is in situ as the synthetic equivalent, the enamine 182 (Scheme 36) [67]. The enamine 182 in in situsynthesizedin situ as asthe the synthetic in synthetic situ as equivalent, theequivalent, synthetic the equivalent, enamineenamine 182 the182 (Scheme enamine (Scheme 36)182 36) [67].(Scheme [67]. The The enamine 36 )[enamine67]. 182 The in 182 in basic media reacts again with the other equivalent of the conjugated aldehyde 181 to form basicenaminebasic media media182 reacts reactsin basicagain again media with with the reactsthe otherother again equivalentequivalent with the of of otherthe the conjugated conjugated equivalent aldehyde of aldehyde the conjugated181 to181 form to form bicyclo [2.2.2]octane 183. bicycloaldehydebicyclo [2.2.2]octane [2.2.2]octane181 to form 183 183 bicyclo. . [2.2.2]octane 183.

Scheme 36. Organocatalytic-mediated synthesis of cyclodienal and subsequent reaction with con- Scheme 36. Organocatalytic-mediated synthesis of cyclodienal and subsequent reaction with conjugated aldehyde 181. Scheme 36. Organocatalytic-mediatedSchemejugated 36. aldehyde Organocatalytic-mediated synthesis 181.of cyclodienal and synthesis subsequent of cyclodienal reaction with and conjugated subsequent aldehyde reaction181. with conjugated aldehyde 181. Other examples of 1,3-cyclohexadien-1-als obtained as synthetic intermediates can be OtherOther examples of 1,3-cyclohexadien-1-als 1,3-cyclohexadien-1-als obtained obtained as as synthetic synthetic intermediates intermediates can can be befound found in the in thework work of Jorgensen, of Jorgensen, who who synthe synthesizedsized tetrahydroisochrom tetrahydroisochromenesenes starting starting from foundOther in examples the work ofof Jorgensen,1,3-cyclohexadien-1-als who synthesized obtained tetrahydroisochrom as syntheticenes intermediates starting from can be fromoxadendralenes oxadendralenes (Scheme (Scheme 37) [68]. 37)[ In68 ].the In aim the aimof obtaining of obtaining the tetrahydroisochromene the tetrahydroisochromene de- oxadendralenes (Scheme 37) [68]. In the aim of obtaining the tetrahydroisochromene de- foundderivativesrivatives in the in work a in three-component a three-component of Jorgensen, reaction, who reaction, synthe research researchsized first tetrahydroisochrom ﬁrstaccomplished accomplished screening screeningenes the starting reaction the re- from rivatives in a three-component reaction, research first accomplished screening the reaction oxadendralenesactionconditions conditions to obtain (Scheme to obtaindienal 37) dienal186 [68].. Good 186In the. yield Good aim and yield of diastereoselectivityobtaining and diastereoselectivity the tetrahydroisochromene is obtained is obtained in the re- in de- conditions to obtain dienal 186. Good yield and diastereoselectivity is obtained in the re- rivativestheaction reaction inof aldehydea three-component of aldehyde 184 and184 185and reaction, in the185 presencein research the presence of organocatalyst first of accomplished organocatalyst S-137, screeningobtainingS-137, obtaining the the oxa- reaction action of aldehyde 184 and 185 in the presence of organocatalyst S-137, obtaining the oxa- conditionsthedendralene oxadendralene to obtainintermediate dienal intermediate (Scheme 186. Good (Scheme 37). yieldOnce 37 ).thisand Once reaction diastereoselectivity this reactionis viable, is the viable, next is obtained thestep next involves stepin the re- dendralene intermediate (Scheme 37). Once this reaction is viable, the next step involves involvesthe reaction the with reaction vinyl with ether vinyl 187. ether The cyclization187. The cyclization occurs in the occurs presence in the of presence a co-catalyst of a actionthe ofreaction aldehyde with 184 vinyl and ether 185 187 in .the The presence cyclization of occursorganocatalyst in the presence S-137 ,of obtaining a co-catalyst the oxa- co-catalystsuch as Eu(fod) such3as (10 Eu(fod) mol %),3 (10 resulting mol %), in resulting the desired in the tetrahydrochromene desired tetrahydrochromene 188. 188. dendralenesuch as Eu(fod) intermediate3 (10 mol (Scheme%), resulting 37). in Once the desired this reaction tetrahydrochromene is viable, the 188 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.

SchemeScheme 37.37. Synthesis ofof cyclohexadienalcyclohexadienal compoundscompounds andand subsequentsubsequent cycloadditioncycloaddition reaction.reaction. Scheme 37. Synthesis of cyclohexadienal compounds and subsequent cycloaddition reaction. 3. Reactivity of 1,3-Cyclohexadien-1-Als 3. Reactivity of 1,3-Cyclohexadien-1-Als Scheme 37. Synthesis of cyclohexadienal compounds and subsequent cycloaddition reaction.

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

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Molecules 2020, 25, x FOR PEER REVIEWThe 1,3-cyclohexadien-1-carboxaldehyde unit is a highly functionalized small20 mole- of 33 The 1,3-cyclohexadien-1-carboxaldehyde unit is a highly functionalized small mole- 3.cule Reactivity with high of potential 1,3-Cyclohexadien-1-Als as building block, and as such it has been used widely for the cule with high potential as building block, and as such it has been used widely for the constructionTheThe 1,3-cyclohexadien-1-carboxaldehyde 1,3-cyclohexadien-1-carboxaldehyde of a great variety of compounds. unit Reactivityunit is ais highly a highly of functionalizedthe functionalized functional small groups small molecule mole- in the construction of a great variety of compounds. Reactivity of the functional groups in the withscaffoldcule high with has potential beenhigh harnessed,potential as building as and building block, a great and block, deal as such andof transformations itas has such been it has used been involve widely used typical for widely the reactions construc- for the scaffold has been harnessed, and a great deal of transformations involve typical reactions tionof theconstruction of double a great bond variety of a functional great of compounds. variety group, of compounds. Reactivityaldehyde functional of Reactivity the functional group,of the groups functionaland the in α the ,βgroups-unsaturated scaffold in the has of the double bond functional group, aldehyde functional group, and the α,β-unsaturated beenaldehydescaffold harnessed, system. has been and Several harnessed, a great examples deal and of a transformations greatof each deal of of these transformations involve three typicaltypes involve of reactions reactivity typical of theare reactions doubleshown aldehyde system. Several examples of each of these three types of reactivity are shown bondbelow.of the functional double bond group, functional aldehyde group, functional aldehyde group, functional and thegroup,α,β and-unsaturated the α,β-unsaturated aldehyde system.below.aldehyde Several system. examples Several of examples each of these of each three of typesthese ofthree reactivity types of are reactivity shown below.are shown 3.1.below. Reactions Involving Double Bond(s) 3.1. Reactions Involving Double Bond(s) 1,3-Cyclohexadien-1-carboxaldehyde 1 was considered as a starting material in the 3.1.1,3-Cyclohexadien-1-carboxaldehyde Reactions Involving Double Bond(s) 11 was considered as a starting material in the total 1,3-Cyclohexadien-1-carboxaldehydesynthesis of fumagillol 190 [69,70], in whichwas the considered first step as implies a starting dihydroxylation material in the of total synthesissynthesis1,3-Cyclohexadien-1-carboxaldehyde ofof fumagillolfumagillol 190 [[69,70],69,70], inin whichwhich 1 was the theconsidered ﬁrstfirst stepstep as impliesimplies a starting dihydroxylationdihydroxylation material in the ofof the more electron rich γ,δ-double bond (Scheme 38). the total moremore synthesis electronelectron of richrich fumagillol γγ,,δδ-double-double 190 bond[69,70],bond (Scheme(Scheme in which 3838). the). first step implies dihydroxylation of the more electron rich γ,δ-double bond (Scheme 38).

Scheme 38. Dihydroxilation of 1,3-cyclohexadien-1-carboxaldehyde in the total synthesis of fum- Scheme 38. DihydroxilationDihydroxilation of of1,3-cyclohexadien-1-carboxaldehyde 1,3-cyclohexadien-1-carboxaldehyde in the in total the synthesis total synthesis of fum- of agillolScheme 190. 38. Dihydroxilation of 1,3-cyclohexadien-1-carboxaldehyde in the total synthesis of fum- fumagillolagillolagillol 190 190. 190. . Dihydroxylation reaction of cyclohexadienal 150 (Scheme 39) to diol 192 was also Dihydroxylation reaction of cyclohexadienal 150 (Scheme 3939)) to dioldiol 192192 waswas alsoalso consideredDihydroxylation in the total synthesis reaction ofof (+) cyclohexadienal palitantin [71], 150 a natural (Scheme compound 39) to diol with 192 antifungalwas also considered in the total total synthesis synthesis of of (+) (+) palitan palitantintin [71], [71 ],a anatural natural compound compound with with antifungal antifun- [72]considered and antibiotic in the activities total synthesis [73]. ofThe (+) cyclohexadienepalitantin [71], a naturalcarboxaldehyde compound intermediate with antifungal 150 gal[72] [ 72and] and antibiotic antibiotic activities activities [73]. [73 ].The The cyclohexadiene cyclohexadiene carboxaldehyde carboxaldehyde intermediate intermediate 150150 was[72] obtained and antibiotic by self-dimerizacion activities [73]. ofThe (E )-4-acetoxycrotonaldehydecyclohexadiene carboxaldehyde 191 inintermediate the presence 150 of waswas obtainedobtained byby self-dimerizacionself-dimerizacion ofof ((EE)-4-acetoxycrotonaldehyde)-4-acetoxycrotonaldehyde 191 inin thethe presencepresence ofof L-prolinewas obtained [71]. by self-dimerizacion of (E)-4-acetoxycrotonaldehyde 191 in the presence of L-prolineL-proline [[71].71 [71].].

SchemeScheme 39. 39.Dihydroxilation Dihydroxilation of of cyclohexadienal cyclohexadienal 150 150 inin in thethe the totaltotal total synthesissynthesissynthesis ofof (+)-palitantin(+)-palitantin 193 193. . Scheme 39. Dihydroxilation of cyclohexadienal 150 in the total synthesis of (+)-palitantin 193. TheThe preparation preparation of of hexafluorinatedhexafluorinated hexafluorinated safranal safranal 9797 hashas been been achieved byby HaasHaas et et al. al. The preparation of hexafluorinated safranal 97 has been achieved by Haas et al. (Scheme(Scheme 4040) )[40) [43].43 [43].]. Hydrogenation Hydrogenation of of the the C3–C4 C3–C4 double double bondbond inin suchsuch a a compound compound in inin the thethe (Scheme 40) [43]. Hydrogenation of the C3–C4 double bond in such a compound in the presencepresence of palladiumof palladium on on charcoal charcoal catalyst catalyst le led ledd to to another another hexafluori hexafluorinatedhexafluorinated naturalnatural product, product, presence of palladium on charcoal catalyst led to another hexafluorinated natural product, 7,7,7,8,8,8-hexafluoro-7,7,7,8,8,8-hexafluoro-7,7,7,8,8,8-hexafluoro-ββ-cyclocitralβ-cyclocitral 194 194.. . 7,7,7,8,8,8-hexafluoro-β-cyclocitral 194.

Scheme 40. Hydrogenation of hexafluorinated safranal 97. Scheme 40. Hydrogenation of hexaﬂuorinatedhexafluorinated safranal 9797.. Scheme 40. Hydrogenation of hexafluorinated safranal 97. Trost et al. recently presented an interesting study about the catalytic palladium ox- Trost et al. recently recently presented presented an an interest interestinging study study about about the the catalytic catalytic palladium palladium ox- yallyTrost cycloaddition et al. recently reaction presented with anconjugated interesting dienes study [74], about wherein the catalytic 1,3-cyclohexadiene-1- palladium ox- oxyallyyally cycloaddition cycloaddition reaction reaction with with conjugated conjugated dienes dienes [74], [74], wherein wherein 1,3-cyclohexadiene-1- 1,3-cyclohexadiene-1- yallycarboxaldehyde cycloaddition was reaction also tested, with givingconjugated the corresponding dienes [74], whereinbicyclic tetrahydrofuran 1,3-cyclohexadiene-1- prod- carboxaldehyde waswas alsoalso tested, tested, giving giving the the corresponding corresponding bicyclic bicyclic tetrahydrofuran tetrahydrofuran product prod- carboxaldehydeuct 196 with extraordinary was also tested, chemoselectivity giving the corresponding (Scheme 41). Thisbicyclic shows tetrahydrofuran once more the prod-ver- 196uct 196with with extraordinary extraordinary chemoselectivity chemoselectivity (Scheme (Sch 41eme). This 41). showsThis shows once moreonce themore versatility the ver- uct satility196 with of extraordinarythe cyclohexadienal chemoselectivity unit, which (Schcan beeme involved 41). This in shows many oncedifferent more transfor- the ver- ofsatility the cyclohexadienal of the cyclohexadienal unit, which unit, can which be involved can be ininvolved many different in many transformations. different transfor- satilitymations. of the cyclohexadienal unit, which can be involved in many different transformations. mations.

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Scheme 41. Oxyallyl cycloaddition reaction with cyclohexadienal. SchemeScheme 41.41. OxyallylOxyallyl cycloaddition cycloaddition reaction reaction withwith cyclohexadienal.cyclohexadienal. Tricarbonyl iron complex of 1,3-cyclohexadiene-1-carboxaldehyde 1 has been pre- TricarbonylTricarbonyl iron ironiron complex complexcomplex of ofof 1,3-cyclohexadiene-1-carboxaldehyde 1,3-cyclohexadiene-1-carboxaldehyde1,3-cyclohexadiene-1-carboxaldehyde1 has 11 beenhashas beenbeen prepared pre-prepared in a photochemical reaction with iron pentacarbonyl (Scheme 42) [75]. Such com- paredinpared a photochemical inin aa photochemicalphotochemical reaction reactionreaction with iron withwith pentacarbonyl ironiron pentacarbonylpentacarbonyl (Scheme (Scheme(Scheme 42)[75]. 42)42) Such [75].[75]. complex SuchSuch com-com-197 plex 197 was synthesized in the route to structurally constrained tricarbonyl (trans-penta- wasplexplex synthesized197197 waswas synthesizedsynthesized in the route inin thethe to routeroute structurally toto structurallystructurally constrained constrainedconstrained tricarbonyl tricarbonyltricarbonyl (trans-pentadienyl) ((transtrans-penta--pentadienyl) iron cations 199 to study acid catalyzed rearrangements. dienyl)irondienyl) cations ironiron 199cationscationsto study 199199 toto acid studystudy catalyzed acidacid catalyzedcatalyzed rearrangements. rearrangements.rearrangements.

Scheme 42. Formation of tricarbonyl iron complex of 1,3-cyclohexadiene-1-carboxaldehyde 1. SchemeScheme 42.42. FormationFormation of of tricarbonyl tricarbonyl iron iron complexcomplex ofof 1,3-cyclohexadiene-1-carboxaldehyde1,3-cyclohexadiene-1-carboxaldehyde 111... Aromatization of cyclohexadienals has been used to prepare aromatic aldehydes AromatizationAromatization of of cyclohexadienalscyclohexadienals has has been been usedused toto prepareprepare aromaticaromaticaromatic aldehydesaldehydesaldehydes (Scheme 43) [76]. Oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) al- (Scheme(Scheme 4343)43))[ 76[76].[76].]. Oxidation OxidationOxidation with withwith 2,3-dichloro-5,6-dicyano-1,4-benzoquinone 2,3-dichloro-5,6-dicyano-1,4-benzoquinone2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (DDQ)(DDQ) allows al-allows for the aromatization reaction with moderate to high yields. lowsforlows the forfor aromatization thethe aromatizationaromatization reaction reactionreaction with moderatewithwith moderatemoderate to high toto yields. highhigh yields.yields.

Scheme 43. Aromatization reaction of cyclohexadienals. SchemeScheme 43.43. AromatizationAromatization reactionreaction ofof cyclohexadienals.cyclohexadienals. Phenyl-substitutedPhenyl-substituted cyclohexadienalscyclohexadienals 200200 werewere foundfound toto spontaneouslyspontaneously aromatizearomatize inin Phenyl-substitutedPhenyl-substituted cyclohexadienalscyclohexadienals 200200 werewere foundfound toto spontaneouslyspontaneously aromatizearomatize inin lowlow conversionconversion ofof 5–15%5-15% in a periodperiod ofof oneone toto severalseveral daysdays [[63].63]. However,However, aromatizationaromatization lowlow conversionconversion ofof 5-15%5-15% inin aa periodperiod ofof oneone toto severalseveral daysdays [63].[63]. However,However, aromatizationaromatization couldcould alsoalso bebe performedperformed inin quantitativequantitative yieldsyields byby reactionreaction withwith potassiumpotassium permanganatepermanganate couldcould alsoalso bebe performedperformed inin quantitativequantitative yielyieldsds byby reactionreaction withwith potassiumpotassium permanganatepermanganate (Scheme(Scheme 44).44). Those Those aromatic aromatic compounds compounds 201201 couldcould find ﬁnd use useas fluorescent as ﬂuorescent probes probes to iden- to (Scheme(Scheme 44).44). ThoseThose aromaticaromatic compoundscompounds 201201 couldcould findfind useuse asas fluorescentfluorescent probesprobes toto iden-iden- identifytify the protein the protein binding binding partner partner of a ofparticular a particular cyclohexadienal cyclohexadienal in studies in studies of such of suchcom- tifytify thethe proteinprotein bindingbinding partnerpartner ofof aa particularparticular cyclohexadienalcyclohexadienal inin studiesstudies ofof suchsuch com-com- compoundspounds to activate to activate neurite neurite outgrowth outgrowth activity activity [63]. [ The63]. cy Theclohexadienal cyclohexadienal core core200 was200 wasgen- poundspounds toto activateactivate neuriteneurite outgrowthoutgrowth acactivitytivity [63].[63]. TheThe cycyclohexadienalclohexadienal corecore 200200 waswas gen-gen- generatederated by a by cross-cond a cross-condensationensation reaction reaction of α,β of-unsaturatedα,β-unsaturated aldehydes aldehydes mediated mediated by L-pro- by eratederated byby aa cross-condcross-condensationensation reactionreaction ofof αα,,ββ-unsaturated-unsaturated aldehydesaldehydes mediatedmediated byby L-pro-L-pro- L-prolineline (Scheme (Scheme 44). 44). lineline (Scheme(Scheme 44).44).

SchemeScheme 44.44. AromatizationAromatization reactionreaction ofof phenyl-substitutedphenyl-substituted cyclohexadienals.cyclohexadienals. SchemeScheme 44.44. AromatizationAromatization reactionreaction ofof phenylphenyl-substituted-substituted cyclohexadienals.cyclohexadienals. InIn lineline withwith this,this, thethe aboveabove reactionreaction sequencesequence ofof organocatalyticorganocatalytic synthesissynthesis of the cy- InIn lineline withwith this,this, thethe aboveabove reactionreaction sequensequencece ofof organocatalyticorganocatalytic synthesissynthesis ofof thethe cy-cy- clohexadieneclohexadiene carboxaldehydecarboxaldehyde unitunit andand subsequentsubsequent oxidationoxidation reactionreaction hashas beenbeen usedused asas aa clohexadieneclohexadiene carboxaldehydecarboxaldehyde unitunit andand subsequesubsequentnt oxidationoxidation reactionreaction hashas beenbeen usedused asas aa fair strategy for the preparation of multi-substituted aromatic aldehydes [62]. Scheme 45 fairfair strategystrategy forfor thethe preparationpreparation ofof multi-substitutedmulti-substituted aromaticaromatic aldehydesaldehydes [62].[62]. SchemeScheme 4545

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Molecules 2020, 25, x FOR PEER REVIEW 22 of 33 Molecules 2020,, 25,, xx FORFOR PEERPEER REVIEWREVIEW 22 of 33 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- depictsdepicts a (4 + 2) 2) and and (3 (3 + + 3) 3) cycloaddition cycloaddition of of α,αβ,-unsaturatedβ-unsaturated aldehydes aldehydes mediated mediated by byL- proline 131 or pyrrolide 129/acetic acid (AcOH) to afford the cyclohexadiene carboxalde- L-prolineproline 131131 oror pyrrolide pyrrolide 129129/acetic/acetic acid acid (AcOH) (AcOH) to to afford afford the the cyclohexadiene cyclohexadiene carboxalde- carboxalde- hyde intermediate that was not isolated and spontaneously oxidize or directly submitted hydehyde intermediateintermediate thatthat waswas notnot isolatedisolated andand spontaneouslyspontaneously oxidizeoxidize oror directlydirectly submittedsubmitted to oxidation reaction conditions with MnO2 or DDQ for the formation of the aromatic toto oxidationoxidation reactionreaction conditionsconditions withwith MnOMnO22 or DDQ for thethe formationformation ofof thethe aromaticaromatic compound [62]. compoundcompound [[62].62].

Scheme 45. Organocatalytic synthesis of cyclohexadienals/oxidation reaction in the synthesis of SchemeScheme 45.45. OrganocatalyticOrganocatalytic synthesis synthesis of of cyclohexadienals cyclohexadienals/oxidation/oxidation reaction reaction in inthe the synthesis synthesis of of aromatic aldehydes. aromaticaromatic aldehydes.aldehydes. In the following example (Scheme 46), pentasubstituted aromatic compounds are In thethe followingfollowing exampleexample (Scheme(Scheme 4646),), pentasubstitutedpentasubstituted aromaticaromatic compoundscompounds areare prepared under the above mentioned reaction sequence via intermediate cyclohexadiene preparedprepared underunder thethe aboveabove mentionedmentioned reactionreaction sequencesequence viavia intermediateintermediate cyclohexadienecyclohexadiene carboxaldehyde 202 that was oxidized with atmospheric air appealing, therefore, in this carboxaldehydecarboxaldehyde 202 thatthat waswas oxidizedoxidized withwith atmosphericatmospheric airair appealing,appealing, therefore,therefore, inin thisthis case, under environmentally friendly reaction conditions [77]. Intermediate cyclohexadi- case,case, underunder environmentallyenvironmentally friendlyfriendly reactionreaction conditionsconditions [[77].77]. Intermediate cyclohexadi-cyclohexadienal 202 is formed via a Michael type cascade reaction mediated by organocatalyst 137. enalenal 202202 isis formedformed viavia aa MichaelMichael typetype cascadecascade reactionreaction mediatedmediated byby organocatalystorganocatalyst 137137..

Scheme 46. Organocatalytic synthesis of cyclohexadienals/aromatization reaction in the synthesis SchemeScheme 46.46. Organocatalytic synthesissynthesis of of cyclohexadienals/aromatization cyclohexadienals/aromatization reaction reaction in in the the synthesis synthesis of of pentasubstituted aromatic compounds. pentasubstitutedof pentasubstituted aromatic aromatic compounds. compounds. 3.2. Reactions Involving the Aldehyde Functional Group 3.2.3.2. Reactions Involving the Aldehyde FunctionalFunctional GroupGroup Oxidation of the aldehyde group in 1,3-cyclohexadien-1-carboxaldehyde to the car- OxidationOxidation ofof thethe aldehydealdehyde groupgroup inin 1,3-cyclohexadien-1-carboxaldehyde1,3-cyclohexadien-1-carboxaldehyde to the carboxylic acid has been achieved with silver hydroxide prepared in situ (Scheme 47) [78]. boxylicboxylic acid has beenbeen achievedachieved with silver hydroxide prepared in situ (Scheme 47)47)[ [78].78]. Compound 203 was used in the cycloaddition reaction with 4-N-methyl-1,2,4-triazolin- CompoundCompound 203203was was used used in in the the cycloaddition cycloaddition reaction reaction with with 4-N 4--methyl-1,2,4-triazolin-3,5-N-methyl-1,2,4-triazolin- 3,5-dione 204. dione3,5-dione204 .204.

SchemeScheme 47.47. OxidationOxidation ofof 1,3-cyclohexadien-1-carboxaldehyde1,3-cyclohexadien-1-carboxaldehyde toto carboxyliccarboxylic acidacid203 203.. Scheme 47. Oxidation of 1,3-cyclohexadien-1-carboxaldehyde to carboxylic acid 203.. ReductionReduction reactions of of the the aldehyde aldehyde group group in inthe the cyclohexadienal cyclohexadienal core core have have also been also Reduction reactions of the aldehyde group in the cyclohexadienal core have also been beendescribed. described. In this Inmanner, this manner, the natural the product natural safranal product 2 safranalwas converted2 was to converted the correspond- to the described. In this manner, the natural product safranal 2 was converted to the correspond- correspondinging alcohol 206alcohol in near 206quantitativein near quantitative yield with LiAlH yield with4 (Scheme LiAlH 48)4 (Scheme [79]. The 48 resultant)[79]. The al- ing alcohol 206 in near quantitative yield with LiAlH4 (Scheme 48) [79]. The resultant al- resultantcohol 206 alcohol was submitted206 was to submitted a photooxygenation to a photooxygenation reaction for reaction the formation for the of formation endoperox- of cohol 206 was submitted to a photooxygenation reaction for the formation of endoperox- endoperoxideide 207 in a chemoselective207 in a chemoselective singlet oxygen singlet (4 oxygen + 2) cycloaddition (4 + 2) cycloaddition reaction. reaction.That transfor- That ide 207 in a chemoselective singlet oxygen (4 + 2) cycloaddition reaction. That transfor- transformationmation was also was assayed also assayeddirectly directlyon safranal on safranalcompound compound 2. However,2. However, the desired the endoper- desired mation was also assayed directly on safranal compound 2. However, the desired endoper- endoperoxideoxide 208 turned208 outturned to decompose out to decompose in this case. in this case. oxide 208 turned out to decompose in this case.

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Scheme 48. Reduction of safranal 2 to alcohol 206. SchemeScheme 48.48. ReductionReduction ofof safranalsafranal 22 toto alcoholalcohol 206206..

SchemeReduction 48. Reduction of the of safranal aldehyde 2 to alcohol group 206 in. natural aldehydes 61 and 63 has been performed ReductionReduction ofof thethe aldehydealdehyde groupgroup inin naturalnatural aldehydesaldehydes 6161 andand 6363 hashas beenbeen performedperformed with the aim of confirming the structure of such natural compounds (Scheme 49) [6]. Al- withwith the aim of of confirming conﬁrming the the structure structure of of such such natural natural compounds compounds (Scheme (Scheme 49) 49[6].)[ Al-6]. AldehydedehydeReduction 6363 presentpresent of the inaldehyde in black black cardamomgroup cardamom in natural has has aldehydesbeen been fo foundund 61 andto to produce produce63 has been a a trigeminal performed effect inin withdehyde the aim63 present of confirming in black the structurecardamom of suchhas beennatural fo compoundsund to produce (Scheme a trigeminal 49) [6]. Al- effect in the mouth. dehydethe mouth. 63 present in black cardamom has been found to produce a trigeminal effect in the mouth.

Scheme 49. Reduction of naturalnatural aldehydes 61 and 63 toto thethe correspondingcorresponding alcohols.alcohols. Scheme 49. 49. Reduction Reduction of naof turalnatural aldehydes aldehydes 61 and 61 63 and to the63 tocorresponding the corresponding alcohols. alcohols. The greatgreat versatilityversatility ofof the the cyclohexadiene cyclohexadiene carboxaldehyde carboxaldehyde moiety moiety is demonstratedis demonstrated in TheThe great great versatility versatility of theof thecyclohexadiene cyclohexadiene carboxaldehyde carboxaldehyde moiety moietyis demonstrated is demonstrated thein the utilization utilization of suchof such scaffold scaffold in thein the total total synthesis synthesis of manyof many varied varied compounds. compounds. That That is inin thethe utilization utilization of ofsuch such scaffold scaffold in the in totalthe totalsynthesis synthesis of many of variedmany compounds.varied compounds. That That theis the case case of theof the citotoxic citotoxic compound compound acetoxytubipofuran acetoxytubipofuran (Scheme (Scheme 50). The50). strategyThe strategy followed fol- isis thethe case case of of the the citotoxic citotoxic compound compound acet oxytubipofuranacetoxytubipofuran (Scheme (Scheme 50). The 50). strategy The strategyfol- fol- forlowed its synthesisfor its synthesis implies implies a tricarbonyl a tricarbonyl chromium-mediate chromium-mediate dearomatization dearomatization to access to access the lowedlowed for for its its synthesis synthesis implies implies a tricarbonyl a tricarbonyl chromium-mediate chromium-mediate dearomatization dearomatization to access to access substitutedthe substituted cyclohexadiene cyclohexadiene carboxaldehyde carboxaldehyde compound compound126 [51 126]. Further [51]. Further transformations transfor- thethe substitutedsubstituted cyclohexadiene cyclohexadiene carboxaldehyde carboxaldehyde compound compound 126 [51]. 126 Further [51]. Furthertransfor- transfor- tomations the ﬁnal to to the the acetoxytubipofuran final final acetoxytubipofuran acetoxytubipofuran are followed.are followed.are followed. Among Among Among them, them, reduction reductionthem, reduction of of the the al- aldehydeof the al- moietymations in to the the cyclohexadienal final acetoxytubipofuran core is performed are followed. with Among NaBH them,in the reduction presence ofof CeClthe aldehyde moiety moiety in in the the cyclohexadienal cyclohexadienal core coreis performed is performed with NaBH with4 4 NaBHin the 4presence in the presence of of3 (Schemedehyde moiety50). in the cyclohexadienal core is performed with NaBH4 in the presence of CeCl33 (Scheme (Scheme 50). 50). CeCl3 (Scheme 50).

Scheme 50. Reduction of the aldehyde moiety in the 1,3-cyclohexadien-1-al core in the total synthesis

of acetoxytubipofuran.

Molecules 2020, 25, x FOR PEER REVIEW 24 of 33 Molecules 2020, 25, x FOR PEER REVIEW 24 of 33 Molecules 2021, 26, 1772 23 of 32 Scheme 50. Reduction of the aldehyde moiety in the 1,3-cyclohexadien-1-al core in the total syn- thesisthesis ofof acetoxytubipofuran.acetoxytubipofuran.

TheThe synthesissynthesis of ( −)-drimenol)-drimenol)-drimenol hashas has alsoalso also beenbeen been achievedachieved achieved byby by meansmeans means ofof of aa reduction areduction reduction reac-reac- re- actiontiontion ofof of thethe the correspondingcorresponding corresponding cyclohexadienecyclohexadiene cyclohexadiene caca carboxaldehyderboxaldehyde derivative derivative (Scheme (Scheme 51)51)[ [80].80]. SuchSuch reductionreduction reactionreaction unexpectedlyunexpectedly involvedinvolved thethe wholewholeα α,β,,β---γγ,,δ,δ-unsaturated-unsaturated-unsaturated aldehydealdehydealdehyde system.system. ( (−−)-Drimenol,)-Drimenol,)-Drimenol, inin in turn,turn, turn, hashas has beenbeen been usedused used asas asststarting starting material material in the in thesynthesis synthesis of (− of)-)- (polygodial−)-polygodial [81] [and81] and (−)-warburganal)-warburganal (−)-warburganal [82][82] (Scheme [(Scheme82] (Scheme 51).51). 51).

SchemeScheme 51.51. ReductionReduction ofof thethe cyclohexadienalcyclohexadienal corecore inin thethe synthesissynthesis ofof ((−−)-drimenol.)-drimenol.

AnotherAnother typicaltypical reaction reaction of theof aldehydethe aldehy functionalde functional group is thegroup Horner–Wadsworth– is the Horner– EmmonsWadsworth–Emmons coupling with coupling phosphonates with phosphonat [13]. Such transformationes [13]. Such transformation was the choice was for thethe conversionchoice for the of safranalconversion2 to of 3,4-didehydroretinal safranal 2 toto 3,4-didehydroretinal3,4-didehydroretinal45 involving two 45 consecutive involvinginvolving two phosphonatetwo consecu-consecu- couplingtivetive phosphonatephosphonate reactions couplingcoupling and reductions reactionsreactions (Scheme andand reductionsreductions 52). (Scheme(Scheme 52).52).

SchemeScheme 52.52. Horner–Wadsworth–EmmonsHorner–Wadsworth–Emmons reactionreaction ofof safranal.safranal.

ReactionReaction ofof thethe aldehydealdehyde groupgroup withwith organometallicorganometallic compoundscompounds hashas beenbeen usedused forfor β thethethe construction construction ofof of miscellaneousmiscellaneous miscellaneous structuresstructures structures... ThisThis This isis thethe isthe casecase case ofof thethe of preparationpreparation the preparation ofof β-dam--dam- of - damascenone,ascenone, wherein wherein safranal safranal 2 waswas2 was reactedreacted reacted withwith with thethe the correspondingcorresponding Grignard reagentreagentreagent (Scheme(Scheme 5353))[ [18].18]. SubsequentSubsequent oxidationoxidation withwith MnOMnO22 produced β-damascenone. Isomeriza- (Scheme 53) [18]. Subsequent oxidation with MnO2 produced β-damascenone. Isomeriza- tion of the double bond on the side chain can be accomplished with para-toluensulfonic tiontion ofof thethe doubledouble bondbond onon thethe siside chain can be accomplished with para-toluensulfonic-toluensulfonic acid to obtain β-damascenone in higher yield (Scheme 53). acid to obtain β-damascenone-damascenone inin higherhigher yieldyield (Scheme(Scheme 53).53).

SchemeScheme 53.53. ReactionReaction ofof safranalsafranal withwithth aaa GrignardGrignardGrignard reagent.reagent.reagent.

SchemeScheme 5454 showsshows thethe reactionreaction ofof cyclohexadienecyclohexadiene carboxaldehydecarboxaldehyde unitunit withwith anotheranother Grignard reagent bearing a silicon group [83]. Grignard reagent bearing a silicon group [83].

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Molecules 2021, 26, 1772 24 of 32 MoleculesMolecules 2020 2020, ,25 25, ,x x FOR FOR PEER PEER REVIEW REVIEWScheme 54. Reaction of cyclohexadiene carboxaldehyde unit with a Grignard2525 reagent. of of 33 33 Molecules 2020, 25, x FOR PEER REVIEW 25 of 33 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].

SchemeScheme 54.54. ReactionReaction ofof cyclohexadienecyclohexadiene carboxaldecarboxaldehydehyde unitunit withwith aa GrignardGrignard reagent.reagent. Scheme 54.54. Reaction of cyclohexadiene carboxaldehydecarboxaldehyde unitunit withwith aa GrignardGrignard reagent.reagent. InIn thethe synthesissynthesis ofof tritiumtritium labelledlabelled 9-9-ciscis-retinoic-retinoic acidacid 213213 (Scheme(Scheme 55),55), aa keykey reactionreaction ofof thetheInIn cyclohexadienal cyclohexadienal thethe synthesissynthesis of of tritium coretritiumcore withwith labelled labelled anan organolithiumorganolithium 9- 9-ciscis-retinoic-retinoic acidreagentreagent acid213 213 was(Schemewas (Scheme usedused 55 in in),55), the athe key a initialkeyinitial reaction reaction stagesstages of the[84].of[84]. the cyclohexadienal cyclohexadienal core core with with an organolithiuman organolithium reagent reagent was was used used in the in initial the initial stages stages [84]. [84].

Scheme 55. Reaction of safranal 2 with an organolithium reagent.

The aldehyde functional group has been harnessed in intramolecular (macro)cyclization reactions. Such is the case of the preparation of diazecine derivatives by intramolec-

ular Schiff-base formation in the presence of boric acid (Scheme 56) [26]. SchemeScheme 55.55. Reaction Reaction ofof safranalsafranal 2 2 withwith anan organolithiumorganolithium reagent. reagent.reagent. Scheme 55. Reaction of safranal 2 with an organolithium reagent. TheThe aldehyde aldehydealdehyde functional functionalfunctional group group group has hashas been beenbeen harnessed ha harnessedrnessed in inin intramolecular intramolecularintramolecular (macro)cyclization (macro)cycliza-(macro)cycliza- reactions.tiontion reactions.Thereactions. aldehyde Such SuchSuch is the functional isis case thethe casecase of thegroup ofof preparation thethe has prepprep beenarationaration ha ofrnessed diazecine ofof diazecinediazecine in intramolecular derivatives derivativesderivatives by (macro)cycliza- intramolecular byby intramolec-intramolec- Schiff-baseulartionular reactions.Schiff-baseSchiff-base formation Such formationformation is in the the case inin presence thethe of pres presthe ence ofprepence boric arationofof boricboric acid of(Scheme acidacid diazecine (Scheme(Scheme 56)[ derivatives26 56)56)]. [26].[26]. by intramolecular Schiff-base formation in the presence of boric acid (Scheme 56) [26].

Scheme 56. Intramolecular cyclization in the preparation of diazecine derivatives.

SchemeSchemeThe 56.56. IntramolecularIntramolecularsynthesis of cyclizationcyclizationcyclization diterpenoid ininin the thethe preparation prpreunicellaneeparationeparation of ofof diazecine diazecinediazecine skeletons derivatives. derivatives.derivatives. 219 incorporating 1,3-cyclohexa- Schemediene 56.moiety Intramolecular is shown cyclization in Scheme in the pr eparation57, wherei of diazecinen a key derivatives. step is the intramolecular pinacol TheThe synthesis synthesissynthesis of ofof diterpenoid diterpenoidditerpenoid eunicellane eunicellaneeunicellane skeletons skeletonsskeletons219 219219incorporating incorporatingincorporating 1,3-cyclohexadiene 1,3-cyclohexa-1,3-cyclohexa- macrocyclization reaction induced by low valent titanium under McMurry conditions moietydienedieneThe moietymoiety is synthesis shown isis shown inshown of Scheme diterpenoid inin Scheme Scheme57, wherein eunicellane 57,57, whereiwherei a key stepnskeletonsn aa key iskey the stepstep 219 intramolecular is isincorporating thethe intramolecularintramolecular pinacol 1,3-cyclohexa- macrocy- pinacolpinacol clizationmacrocyclizationdiene[85].macrocyclization moiety reaction is shown inducedreactionreaction in by inducedSchemeinduced low valent 57, byby whereilowlow titanium valentvalentn a underkey titaniumtitanium step McMurry is under underthe intramolecular conditions McMurryMcMurry [ 85conditionsconditions]. pinacol [85].macrocyclization[85]. reaction induced by low valent titanium under McMurry conditions [85].

SchemeScheme 57.57. IntramolecularIntramolecular macrocyclizationmacrocyclization inin thethe preparationpreparation ofof eunicellaneeunicellane skeletons.skeletons. SchemeScheme 57. 57.Intramolecular Intramolecular macrocyclization macrocyclization in the preparation in the preparation of eunicellane of skeletons. eunicellane skeletons. Scheme 57. Intramolecular macrocyclization in the preparation of eunicellane skeletons. AnotherAnother exampleexample ofof utilizationutilization ofof thethe aldehydealdehyaldehydede groupgroupgroup ofofof thethethe cyclohexadienalcyclohexadienalcyclohexadienal corecorecore in inin intramolecularintramolecularintramolecularAnotherAnother example macrocyclization macrocyclizationmacrocyclization example of utilization of utilization reaction reactionreaction of the is isis aldehy shown shofshown ownthede in ininaldehy group Scheme SchemeScheme ofde 58 58the58 [group [86]. 86[86]. cyclohexadienal]. In InIn thisof thisthis the case,case, cyclohexadienal reactionreaction core in core in ofintramolecularintramolecularof thethe aldehydealdehyde macrocyclization withwith macrocyclization thethe inin situ-preparedsitu-prepared reaction reaction organolithiumisorganolithium shown is in sh Schemeown reagentreagentreagent in58 Scheme[86].was waswas accomplishedIn accomplishedaccomplished this 58 case, [86]. reaction Inusing usingusing this case, reaction highofofhigh the the dilutiondilution aldehyde aldehyde conditionsconditions with with the inin inthe thethesitu-preparedthe in presencepresencepresence situ-prepared of ofof organolithium CeCl CeClCeCl333.. organolithium reagent was reagent accomplished was accomplishedusing using high dilution conditions in the presence of CeCl3. high dilution conditions in the presence of CeCl3.

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SchemeSchemeScheme 58. Intramolecular 58. 58.58.Intramolecular Intramolecular Intramolecular macrocyclization macrocyclization macrocyclization macrocyclization in in cyclohexadienal cyclohexadienalin incyclohexadienal cyclohexadienal derivative.derivative derivative derivative 3.3.3.3. ReactionsReactions Involving Involving the theα ,αβ,-Unsaturatedβ-Unsaturated Aldehyde Aldehyde System System 3.3. Reactions3.3. Reactions Involving Involving the α ,theβ-Unsaturated α,β-Unsaturated Aldehyde Aldehyde System System ReactivityReactivity ofof the theα α,β,β-unsaturated-unsaturated aldehyde aldehyde system system has ha beens been utilized utilized in in the the prepa- prepara- ReactivityReactivity of the of α the,β-unsaturated α,β-unsaturated aldehyde aldehyde system system has been has beenutilized utilized in the in prepara- the prepara- rationtion of of highly highly elaborated elaborated compounds. compounds. As As an anexample, example, reaction reaction of cyclohexadienal of cyclohexadienal deriva- tion oftion highly of highly elaborated elaborated compounds. compounds. As an As example, an example, reaction reaction of cyclohexadienal of cyclohexadienal deriva- deriva- derivativetive 74 with74 anwith organocuprate an organocuprate is shown is shown in Scheme in Scheme 59, yielding59, yielding mainly mainly the the1,4-addition 1,4- tive 74addition with an product organocuprate [37]. is shown in Scheme 59, yielding mainly the 1,4-addition producttive 74 with [37]. an organocuprate is shown in Scheme 59, yielding mainly the 1,4-addition productproduct [37]. [37].

Scheme 59. Organocuprate addition in cyclohexadienal derivative 74. SchemeSchemeScheme 59. Organocuprate 59. 59.Organocuprate Organocuprate addition addition addition in incyclohexadienal cyclohexadienal in cyclohexadienal derivative derivative74 74. . 74. The α,β-unsaturated aldehyde system in 222 can participate in an inverse electron The α,β-unsaturated aldehyde system in 222 can participate in an inverse electron Thedemand αThe,β-unsaturated hetero-Diels–Alderα,β-unsaturated aldehyde aldehyde reaction system system with in 222 ain canvinylether 222 participate can participate 223 into anform in inverse an tetrahydroiso- inverse electron electron demand hetero-Diels–Alder reaction with a vinylether 223 to form tetrahydroisochromene demandchromene hetero-Diels–Alder 224, presenting reactionfive continuous with astereoce vinylethernters (Scheme223 to 60)form [68]. tetrahydroiso- Such transfor- 224demand, presenting hetero-Diels–Alder ﬁve continuous stereocentersreaction with (Scheme a vinylether 60)[68]. Such 223 transformation to form tetrahydroiso- has mation has been achieved by means of the Lewis acid catalyst Eu(fod)3 [fod = 6,6,7,7,8,8,8- chromenebeenchromene achieved 224, presenting224 by, presenting means five of the continuousfive Lewis continuous acid catalyststereoce stereoce Eu(fod)nters nters(Scheme[fod (Scheme = 6,6,7,7,8,8,8-heptaﬂuoro- 60) [68]. 60) Such[68]. Suchtransfor- transfor- heptafluoro-2,2-dimethyl-3,5-octadienoate). In fact, the3 reaction is carried out in a one-pot mation2,2-dimethyl-3,5-octadienoate).mation has been has beenachieved achieved by means by means In of fact, the of theLewis the reaction Lewis acid iscatalystacid carried catalyst Eu(fod) out inEu(fod) a3 [fod one-pot3 =[fod 6,6,7,7,8,8,8- fashion = 6,6,7,7,8,8,8- heptafluoro-2,2-dimethyl-3,5-octadienoate).whereinfashionheptafluoro-2,2-dimethyl-3,5-octadienoate). organocatalyticwherein organocatalytic annulation annulation with formation In fa wict, Inth thefa offormationct, thereaction the cyclohexadiene reaction of is thecarried iscyclohexadiene carried dicarboxalde-out in out a one-pot in dicar-a one-pot fashionhydeboxaldehydefashion wherein222 whereinis followed organocatalytic 222 isorganocatalytic followed by the hetero-Diels–Alder annulationby the annulation hetero-Diels–Alder with reactionwiformationth formation by reaction of addition the of cyclohexadieneby the of addition thecyclohexadiene vinyl of etherthe dicar- vinyl dicar- boxaldehydeandetherboxaldehyde the and Lewis 222 the is acidLewis222 followed catalystis acidfollowed catalystby that the shouldby hetero-Diels–Alderthat the beshouldhetero-Diels–Alder compatible be compatible with reaction the reaction with previous by the addition by previous organocatalytic addition of organocat-the of vinyl the vinyl alytic reaction conditions. etherreaction etherand the and conditions. Lewis the Lewis acid catalystacid catalyst that should that should be compatible be compatible with withthe previous the previous organocat- organocat- alyticalytic reaction reaction conditions. conditions.

SchemeScheme 60. 60.Inverse Inverse electron electron demand demand hetero-Diels–Alder hetero-Diels–Alder reaction reaction of cyclohexadienal of cyclohexadienal derivative derivative222. 222. Such a reaction concept has been extended further to achieve the sequential organocat- SchemeScheme 60. Inverse 60. Inverse electron electron demand demand hetero-Diels–Alder hetero-Diels–Alder reaction reaction of cyclohexadienal of cyclohexadienal derivative derivative alytic annulation reaction forming intermediate 222 and the subsequent cycloaddition reac- 222. 222. Such a reaction concept has been extended further to achieve the sequential organo- 225 tioncatalytic with aannulation different aldehyde reaction forming(Scheme intermediate 61)[68]. In both222 and cases, the tetrahydroisochromenes subsequent cycloaddition 224 are formed in good yields and excellent stereoselectivities, and the great versatility of Suchreaction Sucha reaction with a reaction a conceptdifferent concept has aldehyde been has beenextended 225 extended(Scheme further 61)further to [68]. achieve to In achieve both the cases,sequential the sequential tetrahydroiso- organo- organo- the cyclohexadienal core is highlighted. catalyticchromenescatalytic annulation annulation 224 arereaction formed reaction forming in goodforming intermediate yields intermediate and excelle 222 and 222nt stereoselectivities,the and subsequent the subsequent cycloaddition and cycloaddition the great reactionversatilityreaction with witha of different the a cyclohexadienaldifferent aldehyde aldehyde 225 core (Scheme 225is highlighted. (Scheme 61) [68]. 61) [68].In both In bothcases, cases, tetrahydroiso- tetrahydroiso- chromeneschromenes 224 are 224 formed are formed in good in goodyields yields and excelleand excellent stereoselectivities,nt stereoselectivities, and theand great the great versatilityversatility of the of cyclohexadienal the cyclohexadienal core iscore highlighted. is highlighted.

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Scheme 61. Cycloaddition reaction of cyclohexadienal derivative 222. Scheme 61. Cycloaddition reaction of cyclohexadienal derivativederivative 222222.. 4. Biological Activities of 1,3-Cyclohexadien-1-Carboxaldehyde 4. Biological Activities of 1,3-Cyclohexadien-1-Carboxaldehyde A variety of bioactivities have been reported for compounds containing the 1,3-cy- A variety of of bioactivities bioactivities have have been been repo reportedrted for for compounds compounds containing containing the the 1,3-cy- 1,3- clohexadienal scaffold: neuroprotective, anti-inflammatory, antibacterial, anticancer, cycyclohexadienalclohexadienal scaffold: scaffold: neuroprotective, neuroprotective, anti-inflammatory, anti-inflammatory, antibacterial, antibacterial, anticancer, anticancer, cy- cytotoxic,totoxic, and and phytotoxic. phytotoxic. totoxic, and phytotoxic. ApartApart fromfrom the the organoleptic organoleptic properties properties of ofVitis Vitis vinifera viniferathat that in partin part could could be due be due to 1,3- to Apart from the organoleptic properties of Vitis vinifera that in part could be due to cyclohexadien-1-carboxaldehyde,1,3-cyclohexadien-1-carboxaldehyde, the main the main biological biological properties properties of this of class this of class compounds of com- 1,3-cyclohexadien-1-carboxaldehyde, the main biological properties of this class of com- havepounds been have studied been instudied saffron. in Thesaffron. saffron The aqueous saffron extractaqueous inhibits extract the inhibits chemically the chemically induced pounds have been studied in saffron. The saffron aqueous extract inhibits the chemically gastricinduced cancer gastric progression cancer progression in the Wistar inalbino the Wistar rat [87 albino–89]. Safranal rat [87–89].2, which Safranal is present 2, which in the is induced gastric cancer progression in the Wistar albino rat [87–89]. Safranal 2, which is flowerspresent ofinCrocus the flowers sativus ofL., Crocus has been sativus studied L., has profusely, been studied and manyprofusely, biological and many activities biological have present in the flowers of Crocus sativus L., has been studied profusely, and many biological beenactivities found have for it.been Safranal found2 forhas it. been Safranal proved 2 has to be been a neuroprotective proved to be a andneuroprotective anti-inflamatory and activities have been found for it. Safranal 2 has been proved to be a neuroprotective and agentanti-inflamatory [90–99]. Recently, agent [90–99]. Prof. Watanabe Recently, and Prof colleagues. Watanabe have and been colleagues involved have in the been study in- anti-inflamatory agent [90–99]. Recently, Prof. Watanabe and colleagues have been in- ofvolved substituted in the study heterodimeric of substituted compounds heterodi generatedmeric compounds by proline-mediated generated by condensation proline-medi- of volved in the study of substituted heterodimeric compounds generated by proline-medi- αated,β-unsaturated condensation aldehydes of α,β-unsaturated [53] (Figure aldehydes3). [53] (Figure 3). ated condensation of α,β-unsaturated aldehydes [53] (Figure 3).

FigureFigure 3.3. HeterodimericHeterodimeric and and dimeric dimeric 1,3-cyclohexadien-1-als 1,3-cyclohexadien-1-als (226 (–226–237237) and) examplesand examples biologically biologically active. Figure 3. Heterodimeric and dimeric 1,3-cyclohexadien-1-als (226–237) and examples biologically active. active.

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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 ableProf. to stimulate Watanabe neurite and colleaguesoutgrowth, evaluated while homodimer the library 232 of supported compounds the fordevelopment their ability of to stimulateneural extensions. neurite outgrowth It is interesting in a PC12to highlight assay [that63]. the Two same heterodimers, compound 230230 togetherand 231 with, were μ able233 to–235 stimulate demonstrated neurite complete outgrowth, inhibition while of homodimer cell growth 232at 1 supportedg/mL against the Jurkats, development a hu- ofman neural T cell extensions. leukemia It cell is interesting line. Two tocompounds, highlight that236 and the same237, were compound reasonably230 togetheractive μ withagainst233– Bacillus235 demonstrated subtilis, with complete MIC values inhibition within the ofcell 10–25 growth g/mL at range. 1µg/mL against Jurkats, a humanRecent T cell studies leukemia with cell Crocus line. sativus Two compounds,L. (saffron) extract236 and as237 well, were as its reasonably main constitu- active againstents—crocin,Bacillus crocetin, subtilis, withand safranal MIC values 2—show within interesting the 10–25 anticancerµg/mL range. properties (Table 2). However,Recent studiesmore studies with Crocusare needed sativus in orderL. (saffron) to evaluate extract the as real well single as its effect main of constituents— each component, as in the combined treatment they may act synergistically against malignant cells. crocin, crocetin, and safranal 2—show interesting anticancer properties (Table2). However, The in vitro results for safranal 2 showed a positive effect in leukemia and breast cancer more studies are needed in order to evaluate the real single effect of each component, and is a promising agent for treatment, prevention, and combined therapy for liver cancer as in the combined treatment they may act synergistically against malignant cells. The [11]. in vitro results for safranal 2 showed a positive effect in leukemia and breast cancer and is The 1,3-cyclohexadienals such as safranal 2 are the direct precursors of endoperox- a promising agent for treatment, prevention, and combined therapy for liver cancer [11]. ides such as 208 that show antimalarial activity [15,79].

TableTable 2. 2.Biological Biological activities activities of of 1,3-cyclohexadien-1-als 1,3-cyclohexadien-1-als ( 2,, 66,, 77,, 3636, ,208208, ,233233).).

CompoundCompound ActivityActivity Test Test Reference Reference Anticancer, antioxidant, neuroprotective, anti-in- 2 Anticancer, antioxidant, In vitro [11,87–99] 2 neuroprotective,flammatory In vitro [11,87–99] 6 Cytotoxic,anti-inﬂammatory phytotoxic, antibiotic In vitro [7,14,100] 7 6 Cytotoxic,Antibacterial, phytotoxic, antifu antibioticngal In vitroIn vitro [7,[8]14 ,100] 367 Antibacterial,Cytotoxic antifungal In vitroIn vitro [101] [8] 20836 AntimalaricCytotoxic In vitro [15,79] [101 ] 233208 AntimalaricAntibacterial In vitro [102] [15,79 ] 233 Antibacterial In vitro [102] Compound 6, when compared with Botrydial as a reference compound for phytotox- icityThe and 1,3-cyclohexadienals antibiotic activity, showed such as safranalslightly less2 are activity the direct for precursorsthese bioassays of endoperoxides [7,14,100]. suchHowever, as 208 that6 is more show active antimalarial than other activity structurally [15,79].-related Botrydial derivatives; thus, the 1,5-dialdehydeCompound moiety6, when seems compared to be fundamental with Botrydial for askeeping a reference Botrydial compound activity for[7]. phyto-The toxicitystructure-activity and antibiotic relationship activity, studies showed for slightly Botrydial less analogues activity for showed these that bioassays the higher [7,14 Mi-,100]. However,chael acceptor6 is more capacity, active the than lower other antibiotic structurally-related and phytotoxicicty Botrydial activities. derivatives; thus, the 1,5-dialdehydeThe use of moiety Indian seemsfungi of to Parmelia be fundamental genus as a for food keeping supplement, Botrydial aimed activity the study [7]. of The Parmelia perlata crude extracts, showed antimicrobial and antifungal activity. Among the structure-activity relationship studies for Botrydial analogues showed that the higher isolated compounds from Parmelia perlata extracts, 7 is present, showing potent antibacte- Michael acceptor capacity, the lower antibiotic and phytotoxicicty activities. rial activity and moderate antifungal activity compared with the other compounds iso- The use of Indian fungi of Parmelia genus as a food supplement, aimed the study of lated from the extract [8]. 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]. Molecules 2021, 26, 1772 28 of 32

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.

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