Diynes enantioselective cycloaddition

Axially chiral A/-aryl-2-pyridone 55 was obtained by the reaction of a,w-diyne 7 with o-substituted aryl isocyanate (Scheme 5.19) [34]. BINAP was an efficient ligand for enantioselective cycloaddition to give axial chirality. 

It is used for preparing cationic COD-Rh complexes with phosphine ligands for enantioselective [2+2+2] cycloaddition of unsymmetrical diynes with styrene and noibomene derivatives to yield bi- and tetra-cyclic products with good ( 50%) to very good (>90%) enantiomeric enrichment [Shibata et al. Tetrahedron 63 12853 2007], for hydrogenation [Nagel et al. Chem Ber 119 3326 1986, Ojima et al. Tetrahedron 45 6901 1989, Sawamura et al. J Am Chem Soc 117 9602 1995], and for hydrosilylation [Takeuchi et al. J Org Chem 60 3045 1995]. 

Enantioselective intermolecular [2-F2-F2] cycloadditions of 1,6-diynes with a,fS-unsaturated carbonyl compounds are valuable methods for the synthesis of chiral cyclohexadienes in a single step [36]. The intramolecular Diels-Alder reaction (IMDA) is known to be a powerful strategy for the construction of complex multicyclic skeletons [37]. Tanaka reported an efficient enantioselective domino intermolecular [2-F2-F2]/IMDA cycioaddition reaction occurring between 1,6-diyne 106 and amide-linked 1,5-diene 107 bearing two sterically and/or electronically... 

In this reaction, both triple bonds in 1,6-diynes 100 and one of the prochiral alkynes in the phosphine oxides 101 react enantioselectively in a Rh-catalysed [2- -2-h2] cycloaddition, generating an aromatic ring attached to the newly... 

Rhodium(I)-catalysed 2 + 2 + 2-cycloadditions of ene-allene (96) with allene (97) yielded trans-fused hydrindanes (98) and decalins with high regio- and stereo-selectivities (Scheme 31). A Ni-phosphine complex catalysed the 2 + 2 + 2- (g) cycloaddition of diynes with substituted ketenes to produce 2,4-cyclohexadienones in high yields. No decarbonylation products were observed. The chiral A-heterocyclic carbene-catalysed enantioselective 2 + 2 + 2-cycloaddition of ketenes with CS2 produced l,3-oxatian-6-ones in good yields and with high enantioselectivities. 2" ... 

Guitian et al. also reported the first cocycUzation of arynes with alkynes such as dimethyl acetyl-enedicarboxylate (DMAD) leading to phenanthrenes 101 or naphthalenes 102. The selectivity of the process can be tuned by an appropriate choice of the catalyst (Schane 12.52) [90]. These authors have also described the first enantioselective version of this process, using a Pd-(BINAP) complex as catalyst, although the nonracemic 9,12-dimethoxypentahelicene 103 was isolated in a modest yield but with reasonable ee (Scheme 12.52) [91]. Diynes can also participate in [2+2+2] cycloaddition with arynes as demonstrated by Mori et al. in the total synthesis of taiwanins C and E 104a and b (Scheme 12.52) [92]. 

The transition metal-catalyzed [2+2+2] cycloaddition has been applied to the atroposelective biaryl synthesis. The first example is the chiral cobalt(I) complex-catalyzed [2+2+2] cycloaddition of aryl-diynes with nitriles to produce axially chiral arylpyridines [19a]. Subsequently, the enantioselective synthesis of axially chiral biaryl phosphine oxides has also been achieved (Scheme 21.16) [19b]. 

The apphcation of the rhodinm(l)-catalyzed double [2+2+2] cycloaddition approach to the synthesis of symmetric biaryl diphosphoms compounds was first accomplished in the reactions of l,4-bis(diphenylphosphinoyl)bnta-l,3-diyne with terminal diynes to give achiral biaryl bisphosphine oxides [23a]. Cj-Symmetric axially chiral biaryl diphosphonates were obtained with perfect enantioselectivity by using a phosphonate-substituted 1,3-bntadiyne and internal 1,6-diynes (Scheme 21.19) [23b]. Axially chiral biaryl dicarboxylates were also obtained by this method [23b]. 

Anilides, bearing a sterically demanding orfho-substituent, are known to exist as atropisomers due to a high rotational barrier around aryl-nitrogen single bond. The cationic rhodium(I)/xyl-BINAP complex-catalyzed enantioselective [2+2+2] cycloaddition of 1,6-diynes with trimethylsilylynamides afforded axiaUy chiral anilides with good to excellent enantioselectivity (Scheme 21.21) [25]. 

The high-yielding and highly enantioselective synthesis of carba[10]paracyclophanes has been achieved by the cationic rhodium(I)/(S,S)-BDPP complex-catalyzed [2+2+2] cycloaddition of cyclic diynes with terminal monoynes (Scheme 21.22) [26]. 

Takeuchi and coworkers reported an iridium-catalyzed cycloaddition of a,o -diynes and nitriles to give pyridines in 2012 [57]. With [Ir (cod)Cl]2/DPPF or BINAP as the catalytic system, pyridines were formed effectively (Scheme 3.24). A wide range of nitriles (aliphatic and aromatic nitriles) can be applied and reacted smoothly with Q ,a -diynes to give the pyridines. In the case of unsymmetrical diyne bearing two different internal alkyne moieties, high regioselectivity can be achieved which can be explained by the different reactivities of the a-position in iridacyclopentadiene. Terpyridine and quinquepyridine were prepared as well. [Ir(cod)Cl]2/chiral diphosphine catalyst can be applied to enantioselective synthesis. Kinetic resolution of the racemic... 

Cyclization of alkynes also involves nickel-alkyne intermediates, and bis(alkyne)nickel species have been proposed as intermediates in the catalytic cyclization of diynes with m situ generated benzynes to give naphthalene derivatives, as shown in Scheme 2. A related, intermolecular [2+2+2]-cycloaddition of an alkene and two alkynes is also catalyzed by iu situ generated Ni(0) species the use of chiral, monodentate oxazoline ligands renders this process enantioselective (Scheme 3). ... 

The Rh(I)/dppf complex-catalysed 2-i-2-i-2-cycloaddition of oximes and diynes formed substituted pyridines in moderate to good yields (88%), under mild conditions. A one-pot procedure has been developed using aldehydes.The Ni-catalysed 2 -I-2 -I-2-cycloaddition of isocyanates (117) with 1,3-dienes (118) in MeCN produced 6-substituted dihydropyrimidine 2,4-diones (119). A key intermediate in this reaction is a five-membered azanickelacyclic species (Scheme 35). " The enantioselective cationic Rh(I)-catalysed 2-i-2-i-2-cycloaddition of diynes and isocyanates formed axially chiral pyridones with high ees (82%). The unique source of chirality is provided by a system containing [Rh(cod)Cl]2, l,4-bis(diphenylphosphino)butane, and the silver phosphate salt Ag(5)-TRIP. " " The Rh-catalysed 2-I-2-I-2-cycloaddition of diynes to sulfonimines in DCE, at r.t. to 80 °C, yielded 1,2-dihydropyridines in good yields (54-86%) and enantioselectivity (61-96%... 

Shibata, T., Kawachi, A., Ogawa, M., Kuwata, Y., Tsuchikama, K., Endo, K. (2007). Rhodium-catalyzed enantioselective [2+2+2] cycloaddition of diynes with unfunctionalized aUcenes. Tetrahedron, 63, 12853-12859. 

Shibata and coworkers have developed a Rh-catalyzed, highly enantioselective [2 + 2-1-2] cycloaddition of 1,6-diynes 33 and alkenes using an optimized rhodium catalyst (Scheme 9.9) [18], Without any additive other than the catalyst, the use of cjt -methylene cyclic ketones 34 or lactones 35 as activated alkenes allowed access to chiral spirocyclic structures 36. Interestingly, an impressive regioselectivity along with good enantioselectivity were observed when a dissymmetric 1,6-diyne was used in the process. 

Tsuchikama, K., Kuwata, Y., Shibata, T. (2006). Highly enantioselective construction of a chiral spirocyclic structure by the [2-1-2-1-2] cycloaddition of diynes and exo-methylene cyclic compounds. Journal of American Chemical Society 128, 13686-13687. 

The synthesis of chiral racemic atropisomeric pyridines by cobalt-catalyzed [2 + 2 + 2] cycloaddition between diynes and nitriles was reported in 2006 by Hrdina et al. using standard CpCo catalysts [CpCo(CO)2, CpCo(C2H4)2, CpCo(COD)] [34], On the other hand, chiral complexes of type II were used by Gutnov et al. in 2004 [35] and by Hapke et al. in 2010 [36] for the synthesis of enantiomerically enriched atropisomers of 2-arylpyridines (Scheme 1.18). This topic is described in detail in Chapter 9. It is noteworthy that the 2004 paper contains the first examples of asymmetric cobalt-catalyzed [2 - - 2 - - 2] cycloadditions. At that time, it had been preceded by only three articles dealing with asymmetric nickel-catalyzed transformations [37]. Then enantioselective metal-catalyzed [2 -i- 2 - - 2] cycloadditions gained popularity, mostly with iridium- and rhodium-based catalysts, as shown in Chapter 9. 

A cationic rhodium(I)/Solphos complex catalyzed regio- and enantioselective one-pot [2 -I- 2 -I- 2] cycloaddition/transesteriflcation of 1,6-diynes, possessing the alkoxy-carbonyl group at an alkyne terminus, with tertiary propargylic alcohols to give chiral 3,3-disubstituted phthalides (Scheme 4.49) [52]. 

The cationic rhodium(I)/axially chiral biaryl diphosphine complex catalyzed the enantioselective desymmetrization of symmetric dialkynylphosphine oxides via rhodium-catalyzed [2- -2-1-2] cycloaddition with 1,6-diynes to give / -stereogenic alkynylphosphine oxides (Scheme 4.50) [53]. This method was also applied to... 

The enantioselective desymmetrization of substituted malononitriles via cationic rhodium(I)/axially chiral biaryl bisphosphine-catalyzed [2 + 2 + 2] cycloaddition with a 1,6-diyne proceeded at room temperature to give enantio-enriched bicycUc pyridines in good yields with moderate ee values (Scheme 4.66) [55],... 

A limited number of examples of enantioselective [2 - - 2 - - 2] cycloaddition to give axially and central carbon chiral pyridine have been reported [23,30]. However, [2 -I- 2 -I- 2] cycloaddition to give a chiral pyridine by the kinetic resolution of racemic nitriles has not been reported (Scheme 5.17). The reaction of a, co-diyne 7 with racemic secondary nitrile in the presence of a catalytic amount of [Ir(cod)Cl]2/(/ )-Segphos gave chiral pyridine 47 in 75% yield with 80% ee. 

Shibata et al. disclosed the reaction of branched triynes in which a 1,6-diyne moiety and alkyne are connected by a rigid 2-aminophenyl tether. An intramolecular [2 + 2 + 2] cycloaddition gave tripodal cyclophanes in high yield with excellent ee (Scheme 8.18) [13a]. It is noteworthy that the [15]cyclophane skeleton (n = 10) can be constructed efficiently without racemization. This is the first example of the enantioselective synthesis of tripodal cyclophanes. 

The enantioselective synthesis of axially chiral hydroxy carboxylic acid derivatives 42 was accomplished by the cationic rhodium(I)/BINAP complex-catalyzed [2 + 2 + 2] cycloaddition of a,w-diynes 40 with 2-alkoxynaphthalene-derived alkynyl esters 41 with high yields and ee values (Scheme 9.15) [17],... 

The enantioselective double [2-f 2-1-2] cycloaddition reactions of 1,3-diynes with two molecules of 1,6-diynes were also developed. The enantioselective double [2+ 2-I-2] cycloaddition of electron-rich 1,3-diynes 53 with two molecules of... 

Axially chiral pyridines as well as axially chiral pyridones could be synthesized via rhodium-catalyzed enantioselective [2 + 2 + 2] cycloaddition. The reaction of 1,6-diyne 68 with ethyl cyanoformate (69) in the presence of the cationic rhodium(I)/Segphos catalyst furnished axially chiral arylpyridine 70 as a single regioi-somer with excellent ee value (Scheme 9.25) [19],... 

The enantioselective synthesis of axially chiral P—N ligands was also accomplished by rhodium-catalyzed [2 + 2+-2] cycloaddition. The reactions of 1,6-diynes 75 with diphenylphosphinoyl-substituted isoquinolinyl acetylenes 76 furnished diphenylphosphinoyl-substituted axially chiral 1-arylisoquinolines 77 with high yields and ee values (Scheme 9.28) [23], The new diphenylphosphinoyl-substituted axially chiral 1-arylisoquinoline 77 (Z = NTs, R = Me) was derivatized to the corresponding axially chiral P—N ligand 78 and isoquinoline A-oxide 79 without racemization, which could be used in the rhodium-catalyzed hydroboration and Lewis base-catalyzed allylation, respectively [23],... 

A promising one-step route via rhodium-catalyzed double [2-I-2-1-2] cycloaddition was described for the synthesis of tetra-ort/70-substituted axially chiral diaryls from the diyne and tetrayne substrates produced from available alkynes [66]. Enantioselective syntheses of both C2 symmetric and asymmetric tetra-ort/ o-substituted axially chiral diaryls 2.72 and 2.75 through the rhodium-catalyzed [2-I-2-I-2] double cycloaddition of either 2.70 or 2.73 to the diyne 2.71 or tetrayne 2.74, respectively, gave products with ee 99% (Scheme 2.26) [66]. 

Table 2.5 shows the results of [2- -2-l2] cycloaddition reactions involving oxygen-, nitrogen- and ethylene-linked tetraynes 2.78. Here the cycloaddition involves two 1,6- or 1,7-diyne molecules linked with a 1,4-naphthalene spacer [61, 68]. The pentaaryl-substituted compounds with four consecutive axial chiralities were isolated, possessing almost absolute enantioselectivity. 

The ynamides are multipurpose synthetic blocks that are very promising reactants in light of this methodology [72, 73]. Tanaka has carried out the enantioselective synthesis of axially chiral anilides by the rhodium-catalyzed [2-I-2-I-2] cycloaddition of 1,6-diynes 2.93 to trimethylsilyly-namides 2.94 to form the corresponding axially chiral anilides 2.95 with high enantioselectivity. The anilide yield depends on the substituents in the ynamide (Scheme 2.33) [74]. 

Scheme 2.33 Rhodium-catalyzed enantioselective [2-1-2-1-2] cycloaddition of 1,6-diynes with ynamides.

Scheme 2.54 Rhodium-catalyzed enantioselective [24-24-2] cycloaddition reactions of 1-alkynylphosphine oxides with 1,6-diynes.

A practical method for the synthesis of axially chiral biaryl monophosphine oxides was developed by Tanaka and coworkers [104]. Enantioselective [24-24-2] cycloaddition of 1-alkynylphosphine 2-naphthol derivatives 2.157 with 1,6-diyne 2.156 in the presence of cationic rhodium catalyst including (R)-H8-binap (i.e., (R)-(4-)-2,2 -bis(diphenylphosphino)-5,5, 6,6, 7,7, 8,8 -octahydro-l,l -binaphthyl) leads to axially chiral phosphine oxides 2.158 in high yields and high enantioselectivity (Scheme 2.54)... 

The [24-24-2] cycloaddition was also used to synthesize biaryl diphosphines (Scheme 2.56) [107]. A double [2- -2- -2] cycloaddition of l,4-bis(diphenylphosphino)buta-l,3-diyne 2.162 to diyne 2.161 in the presence of cationic Rh(I) and Ag/binap as a catalyst afforded biaryl diphosphine oxides 2.163 in high yield and with excellent enantioselectivity. Reduction with trichlorosilane/phosphite led to the corresponding... 

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