Key words
all-carbon - quaternary - stereocentres - [3+2] cycloaddition - cyclization
1
Introduction
All-carbon quaternary centres refer to stereogenic carbon centres attached to four different neighbouring carbons.[1]
[2] Such carbon centres have a special importance owing to their ubiquitous presence in natural products and to their specificity in biological systems due to their structural diversity and enhanced conformational constraints, which makes them suitable targets for protein binding. For example, spirocyclic compounds have found increased utility in drug discovery because of their three-dimensional structural uniqueness.[3] Figure [1] shows some examples of biologically active molecules containing all-carbon quaternary spiro-centres. Fredericamycin A,[4a] first isolated from Streptomyces griseus ATCC49344, is known for its potent activity against P388 mouse leukaemia, CD8F mammary tumours and B16 melanoma in vivo; whereas coleophomone D,[4b] isolated from Stachybotrys parvispora Hughes, is known for its antibacterial and antihypertensive properties. Elatol displays antibiofouling, antibacterial and antifungal properties and is also cytotoxic against HeLa and Hep-2-human carcinoma cell lines.[5a] Colletoic acid is an inhibitor of human 11β-hydroxy steroid dehydrogenase type I (11β-HSD1 inhibition is a new therapeutic approach for type I diabetes mellitus),[5b] and horsfiline, an oxindole alkaloid, is a therapeutic agent.[5c]
Figure 1 Some biologically active molecules containing all-carbon quaternary stereocentres
Given the importance of generating quaternary stereogenic carbon centres, especially as spirocyclic molecules, numerous efforts have been made for developing efficient methods for their stereocontrolled synthesis.[6]
[7]
[8]
[9]
[10]
[11] Asymmetric [3+2] cycloadditions have created a niche in organic chemistry.[12] Recently Wang and Liu catalogued all-carbon [3+2] cycloaddition methods for natural product synthesis in which they invoke the importance of the strategy to create complex scaffolds of biological interest.[13] In this review, we present selected [3+2] cycloaddition reactions that lead to formation of one or more all-carbon quaternary stereocentres reported during the period 2016–2022. These have been classified into different categories (i) based on the substrate used to generate the 1,3-dipolar species, (ii) those involving allyl-palladium intermediates, (iii) those involving phosphine-allenoate zwitterionic intermediates, and (iv) those involving radical pathways, nitrones, nitrile oxides and nitronate salts, although certain examples can be included in more than one group in this classification.
Classification based on Substrate used to Generate the 1,3-Dipole
2
Classification based on Substrate used to Generate the 1,3-Dipole
2.1
Suitably Substituted Cyclopropanes
Previous studies have shown that vinyl cyclopropanes (VCPs), when catalytically activated by palladium or by other transition metals, generate a 1,3-dipolar intermediate that can, in turn, form five-membered rings with various dipolarophiles via [3+2] cycloaddition reactions.[14] However, due to the challenges associated with the short lifetime of the intermediate in the presence of phosphine ligands, asymmetric versions of these reactions have great significance.[15] In this context, recently developed synergistic catalysis proved to be advantageous, wherein the vinyl cyclopropane is activated by a palladium catalyst while the dipolarophile is activated by a second catalyst. For instance, Jørgensen and co-workers in 2016 developed a protocol in which the activated vinyl cyclopropane reacts with the dipolarophile that is, in turn, activated by an organocatalyst. The methodology resulted in the synthesis of densely substituted cyclopentanes with up to four contiguous stereocentres in high yields and with excellent stereoselectivities. For example, vinyl cyclopropane 1 reacted with cinnamaldehyde 2 in the presence of benzoic acid in acetonitrile to yield the product 3 (Scheme [1]). Here, the vinyl cyclopropane is activated by palladium while the α,β-unsaturated aldehyde is activated as the iminium ion formed by reaction with the organocatalyst 4. More specifically, oxidative addition of Pd(0) catalyst facilitates ring opening of the vinyl cyclopropane, yielding a π-allyl palladium intermediate 5 and, in parallel, condensation of catalyst 4 and cinnamaldehyde 2 leads to the formation of the iminium ion 6. Intermediates 5 and 6 combine to generate the [3+2] cycloadduct 3.[16]
Concurrently, there were also successful efforts by Vitale and co-workers to employ iminium/enamine organocatalysis also with Pd(0) activation of vinyl cyclopropanes for the enantioselective synthesis of polysubstituted cyclopentanes by the formal [3+2] cycloaddition of vinyl cyclopropanes with enals,[17] even though generation of molecules containing all-carbon quaternary centres was not reported.
Scheme 1 Combined palladium and organocatalysis to synthesise multisubstituted cyclopentanes containing an all-carbon stereocentres
In 2020, a synergistic bimetallic catalytic system comprising palladium and rhodium catalysts was used by Du and co-workers for the enantioselective synthesis of multisubstituted spirocyclopentane oxindoles containing an all-carbon quaternary stereocentre. In this reaction, α,β-unsaturated 2-acyl imidazole 8 underwent [3+2] cycloaddition with spirovinyl cyclopropanyl-2-oxindole 7 in the presence of palladium and chiral rhodium catalysts to yield the 3-spirocyclopentane-2-oxindole derivative 9 in high yield (Scheme [2]). Here, the zwitterionic π-allyl palladium intermediate formed from 7 attacks the Re-face of the bidentate N,O-coordinated intermediate generated by the coordination of rhodium to compound 8, facilitating the formation of the product 9 as the major isomer (Scheme [2]).[18]
Scheme 2 Bimetallic catalysis to generate an all-carbon spirocentre
Enantioselective ring-openings of other suitably substituted cyclopropanes have also emerged as a powerful strategy for five-membered ring construction.[19] An intramolecular [3+2] annulation reaction of cyclopropanes was reported by Chen, Yang and co-workers in 2016 (Scheme [3]).[20] In this reaction, an amide linker was used for the annulation and TiCl4 was used as the Lewis acid. The coordination of the two carbonyl groups of substrate 10 to titanium(IV) probably facilitates the ring-opening of the cyclopropane, generating a dicarbonyl anion that, in turn, attacks the enone moiety to furnish the six-membered lactam ring and finally leads to dihydroquinolinone 11.
Scheme 3 Synthesis of dihydroquinolinones
Donor–acceptor cyclopropane 12 was used for the synthesis of pharmaceutically relevant azabicyclo[3.2.1]octane 15, bearing two all-carbon quaternary stereogenic centres at the bridgehead positions, by reduction of imine 14 and subsequent deprotection and intramolecular amidation. The imine was, in turn, synthesized by MgI2 catalysed [3+2] cycloaddition of donor–acceptor cyclopropane 12 with azadiene 13 in dichloromethane (Scheme [4]).[21]
Scheme 4 Synthesis of quaternary bridgehead stereocentres
Wang and co-workers in 2019 used the [3+2] annulation strategy to construct an all-carbon stereocentre by conducting the 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) mediated reaction of cyanocyclopropane carbonate 16 and (E)-3-aryl-2-cyano acrylate 17. The reaction takes place by the initial deprotonation of cyclopropane 16, which ring opens to form an ylide intermediate. The [3+2] annulation of the ylide to acrylate 17 leads to the cycloadduct 18 after a tautomerization step (Scheme [5]).[22]
Scheme 5 DBU-mediated [3+2] cycloaddition to construct cyclopentanes
Aminocyclopropanes have recently emerged as suitable reaction partners that can undergo annulation with alkenes and cyclopropenes under photocatalysis. In 2019, Waser and co-workers reported the [3+2] annulation reaction of cyclopropenes with cyclopropyl aniline 20 using photocatalysis. The catalyst used was 2,4,5,6-tetrakis(diphenylamino)isophthalonitrile (4DPAIPN). The transformation proved to be highly efficient, and diastereoselectivity was further improved by choosing bulky cyclopropyl aniline and difluorocyclopropenes (Scheme [6]).[23] Subsequently, in 2020, a highly diastereoselective and enantioselective [3+2] cycloaddition of cyclopropyl amine with α-alkyl styrenes was reported by Ooi and co-workers using photocatalysis to yield cyclopentanes containing all-carbon quaternary stereocentres. Here, iridium-polypyridyl complexes were used as photocatalysts and the reaction is initiated by capture of the anionic component of the photocatalyst by the cyclopropyl urea 22, generating a chiral supramolecular ion pair. Under irradiation, single electron transfer (SET) from the substrate to the excited-state cationic iridium generates a radical cation that undergoes stereoselective bond formation with the α-alkyl styrene 23 within the restrictions of the asymmetric environment created by the chiral anion.
Scheme 6 [3+2] Annulation of cyclopropene with aminocyclopropane
A representative reaction for synthesis of the cyclopentane 24 is depicted in Scheme [7].[24] The Waser group also reported the use of the amino cyclopropane monoester 25 for [3+2] annulation with suitably substituted indoles using silyl bistriflimide as catalyst (Scheme [8]). The method was successfully applied for the construction of a non-symmetrical all-carbon quaternary centre at the acceptor position of the cyclopropane in good yield and diastereoselectivity, as exemplified in Scheme [8].[25]
Scheme 7 Photocatalysed enantioselective urea-tethered cyclopentane synthesis
Construction of an all-carbon quaternary stereocentre at the α-position of aza-arenes was reported by Jiang and co-workers by synergistic photoredox and Brönsted acid catalysis. Scheme [9] shows a representative reaction of cyclopropyl aniline 20 with 2-(1-phenylvinyl)pyridine 28 that leads to 29. It was found that there were remarkable differences in enantioselectivity when using electron-withdrawing or electron-donating substituents on the aromatic ring of the 2-(1-arylvinyl)pyridine, which led to the proposition of a ternary transition state with the chiral Brönsted acid acting as the bifunctional catalyst. The chiral Brönsted acid catalyst used was an iminodiphosphoric acid that co-catalyses the reaction along with the photocatalyst, dicyanopyrazine (DPZ).[26]
Scheme 8 [3+2] Annulation of indole with aminocyclopropane
Scheme 9 Photocatalysed enantioselective pyridine tethered cyclopentane synthesis
2.2
3-Homoacyl Coumarins
Lin and co-workers have utilized the all-carbon 1,3-dipole precursor 3-homoacyl coumarin 30, in stereoselective [3+2] cycloaddition reactions in the presence of a squaramide catalyst. Initially indandione alkylidene 31 was used as the dipolarophilic partner, which led to the synthesis of coumarin/indandione fused spirocyclopentanes 32, bearing four contiguous stereocentres.[27a] Later these workers used alkylidene oxindoles as the dipolarophilic partner to yield a cycloadduct containing five contiguous stereocentres of which one is an all-carbon quaternary spirocentre.[27b] The reaction takes place via initial activation of the homoacyl coumarin 30 by deprotonation to provide a conjugate acid-base pair with H-bonding interactions. The Re-face of activated coumarin then adds to the Re-face of the alkylidene oxindole 33 to generate a Michael adduct that ultimately leads to product 34 (Scheme [10]). Lin’s group has also employed the strategy for the enantioselective synthesis of spiropyrazolone fused cyclopenta[c]chromen-4-ones.[27c] The reaction occurs by [3+2] cycloaddition of 3-homoacyl coumarin 30 with α,β-unsaturated pyrazolone 35 in the presence of a cinchona alkaloid-derived hydrogen-bonding catalyst and benzoic acid. Excellent yields of spiropyrazolones of the type 36 were obtained in a highly enantioselective manner. All these reactions are summarized in Scheme [10].
Scheme 10 Homoacyl coumarin in [3+2] cycloaddition yielding all-carbon spirocentres
2.3
Isatin-Based (Trifluoromethyl)imines
Isatin-based (trifluoromethyl)imines were reported to undergo [3+2] annulations with alkenes efficiently in the presence of metal catalysts in conjunction with organocatalysts. A Brönsted base and Lewis acid co-operatively catalysed asymmetric 1,3-dipolar cycloaddition reaction was reported to yield a series of trifluoromethyl substituted 2,3-pyrrolidinyl dispiro-oxindoles with high enantioselectivity. The reaction was initiated by deprotonation of 37 by the complex generated from the organocatalyst and Et2Zn, accompanied by release of ethane. This was followed by coordination of methylene indolinone 38 to the zinc from the less-hindered face. Michael addition followed by Mannich reaction led to an intermediate complex, from which the final product 39 was released by proton exchange and the catalytic cycle continued (Scheme [11]).[28]
Scheme 11 Zinc complex mediated all-carbon spirocentre formation
In another report, isatin-based (trifluoromethyl)imines were reported to undergo [3+2] cycloaddition with unsaturated 4-benzylidene chromanones 40 promoted by the organocatalyst DABCO. The authors could also achieve up to 69% enantiopurity for the spirooxindole-chromanone hybrid 41 using Takemoto’s bifunctional thiourea catalyst 42, via formation of an ‘exo’ transition state (Scheme [12]).[29] Concurrently Knipe and co-workers reported the use of cinchona-derived thiourea catalyst 43 for the synthesis of spiropyrrolidine oxindoles with excellent enantioselectivities. Some of the examples reported contained molecules with all-carbon quaternary stereocentres, as exemplified in the synthesis of 45 and 47 (Scheme [13]).[30]
Scheme 12 DABCO mediated all-carbon spirocentre formation
Scheme 13 Use of thiourea catalyst
2.4
Iminoesters and Isocyanoesters
Zhang and co-workers in 2017 reported a copper(I) catalysed asymmetric exo-selective [3+2] cycloaddition of β-trifluoromethyl β,β-disubstituted enone 49 with azomethine ylides (generated from glycine ketinimine 48), leading to the synthesis of chiral pyrrolidines bearing a trifluoromethylated quaternary carbon centre. The chiral ligand used in the reaction was (S)-MeO-DTBM-Biphep 53 and the copper salt used was Cu(CH3CN)4BF4 (Scheme 14). The reaction was found to be general for a wide range of enones and acyclic azomethine ylides. Moreover, the products formed could be oxidized to 3H-pyrroles using 2,3-dichloro-5,5-dicyano-1,4-benzoquinone (DDQ) and converted into N-hydroxy pyrroles and nitrones using m-CPBA in varying efficiencies.[31] Later, the same group reported the Cu(I)-Ming-Phos-catalysed enantioselective [3+2] cycloaddition of glycine ketinimine with β-trifluoromethyl enone 50, which yielded the highly functionalized pyrrolidine 52 containing an all-carbon quaternary stereocentre in 95% enantiomeric excess (Scheme [14]).[32]
Scheme 14 Copper(I) catalysed [3+2] cycloaddition for synthesis of multi-substituted pyrrolidines. Reagents and conditions: (i) Cu(CH3CN)4BF4 (5.0 mol%), Ligand (5.5 mol%), Cs2CO3 (50 mol%), THF.
Subsequently, ligand-controlled [3+2] cycloaddition of iminoesters leading to chiral pyrrolidines with adjacent or discrete quaternary stereocentres with at least one all-carbon stereocentre was reported by the same group. Scheme [15] depicts a representative reaction of α-methyl-iminoester 55 and β,β-disubstituted enone 56 in the presence of a copper catalyst and chiral ligands L1 or L2, yielding 57a or 57b as the major product, depending on the ligand. Computational studies provided insights into the regioselective control. When ligand L1 was used, the phosphorus and nitrogen atoms of the ligand remained coordinated to the Cu(I) throughout the process, yielding 57a in higher amounts, while a switch in regioselectivity was observed when L2 was used due to formation of a Cu–Oenone bond, with the amine nitrogen atom of L2 dissociating from Cu(I) centre.[33] The same group has also reported the synthesis of optically active dihydropyrroles containing an all-carbon quaternary stereocentre by copper-catalysed [3+2] cycloaddition of 56 with isocyanoesters of the type 58, and maximum yields and enantioselectivities were obtained using (R)-DTBM-Seg-Phos as catalyst. Scheme [16] shows a representative example for the synthesis of the dihydropyrrole 59.[34]
Scheme 15 Ligand-controlled [3+2] cycloaddition of iminoesters leading to chiral pyrrolidines
Scheme 16 Copper-catalyzed [3+2] for synthesis of dihydropyrrole bearing an all-carbon stereocentre. Reagents and conditions: (i) CuBF4 (CH3CN)4 (5 mol%), Ligand (5.5 mol%) (ii) K2CO3 (50 mol%), MTBE, –40 °C, 12 h.
2.5
Aldehydes and Isatins
Aldehydes and isatins are versatile substrates to generate azomethine ylides. For instance, construction of an all-carbon spiro quaternary centre was reported by Boudriga and co-workers in 2019 during the diastereoselective synthesis of dispiropyrrolo[2,1-a]isoquinoline-fused pyrrolidine-2,5-diones by [3+2] cycloaddition of the cyclic diketone-based tetrahydroisoquinolinium N-ylide. In this reaction, the azomethine ylide formed from isatin 60 and 1,2,3,4-tetrahydroisoquinoline 61 approaches the (E)-3-arylidene-1-phenyl-pyrrolidine-2,5-dione 62 in an exo-manner to yield products 63 and 64, both containing a spiro quaternary carbon centre, as depicted in Scheme [17].[35] Concurrently, Yan and co-workers reported that acetic acid can act as a catalyst to facilitate the formation of azomethine ylides from aromatic aldehydes and pyrrolidine, which, in turn, undergo [3+2] cycloaddition with 3-arylidene indolin-2-one or with 2-arylidene-1,3-indanedione to yield the corresponding functionalised pyrrolidines containing a spiro all-carbon quaternary stereocentre. In this reaction, the iminium ion 70, formed from aromatic aldehyde and pyrrolidine, undergoes a [1,3]-hydride shift yielding an enamine intermediate 72. The latter then undergoes an aldol type reaction with a second molecule of aldehyde 65 followed by dehydration and deprotonation, yielding a conjugated azomethine ylide 67 that finally participates in [3+2] cycloaddition with the alkene 68 to yield cycloadduct 69, as shown in Scheme [18].[36]
Scheme 17 Tetrahydroisoquinoline based azomethine ylide [3+2] to construct an all-carbon quaternary spirocentre
Scheme 18 Construction of an all-carbon quaternary stereocentre by acetic acid catalysis
Reaction of Allyl Palladium Intermediates
3
Reaction of Allyl Palladium Intermediates
Palladium-catalysed [3+2] cycloaddition of 5-vinyl oxazolidinones and trisubstituted alkenes using chiral ammonium–phosphine ligands was reported by Takashi and co-workers in 2016. The reaction takes place by an initial intermolecular addition of an allyl palladium species to the alkene, generating a zwitterionic intermediate. Subsequent ring closure and bond formation between the two reactive sites of the intermediate yields a product possessing three contiguous stereogenic centres, including two all-carbon quaternary centres. A phosphine ligand incorporating a quaternary ammonium halide component was used to assist Pd-halide contact. A representative reaction of oxazolidinone 73 with (E)-ethyl 2-cyano-3-phenylacrylate 74 leading to product 75 is shown in Scheme [19].[37]
Scheme 19 Synthesis of multisubstituted pyrrolidines via [3+2] cycloaddition of allyl palladium intermediates with acrylates
Nucleophilic 1,3-dipolar π-allyl palladium intermediates generated from vinyl ethylene carbonates have been found to be efficient reaction partners. For instance, synthesis of spirooxindoles with two contiguous all-carbon stereocentres was reported by Hu and co-workers by the palladium-catalysed [3+2] cycloaddition of methylene indolinone with vinyl ethylene carbonate. The reaction takes place through the initial formation of the Pd-π-allyl intermediate 79, which undergoes [3+2] cycloaddition with methylene indolinone 76 by intramolecular nucleophilic attack to yield 3,3′-tetrahydrofuryl spirooxindole 78 (Scheme [20]).[38] Recently, the 1,3-dipolar π-allyl palladium intermediate generated from vinyl ethylene carbonate was also reacted with chalcones under rhodium catalysis, leading to formation of tetrahydrofuran derivatives possessing an all-carbon quaternary stereocentre. The asymmetric bimetallic catalysis was achieved using a chiral rhodium complex catalyst along with Pd2(dba)3·CHCl3 and was demonstrated using α,β-unsaturated 2-acyl imidazole 81 and racemic phenyl vinyl carbonate 77 as cycloaddition partners. The reaction takes place by the activation of the α,β-unsaturated 2-acyl imidazole substrate 81 by the chiral rhodium complex through bidentate coordination. The zwitterionic π-allyl intermediate approaches the double bond of the rhodium complex through its Si-face. Subsequent coordination-dissociation and electron neutralization generates an intermediate that undergoes substitution with 81, releasing the target 1,2,3,4-tetrahydrofuran molecule 82 (Scheme [21]).[39]
Scheme 20 Palladium-catalyzed all-carbon spirocentre formation
Scheme 21 Synthesis of tetrahydrofuran containing an all-carbon stereocentre
Very recently, Zi and co-workers used vinyl methylene cyclic carbonates of the type 83 to generate vinyl-substituted palladium-oxyallyl species that undergo enantioselective inverse electron-demand [3+2] cycloaddition with electron-deficient nitroalkenes of type 84. A hydrogen-bond-donating ligand was used to construct the cyclopentanone 86 containing an all-carbon quaternary stereocentre in a highly stereoselective manner. The optimised ligand for achieving maximum enantiomeric excess was found to be Fe-Ur-Phos 85, which contains a urea moiety. The latter facilitates the hydrogen-bond formation between the chiral catalyst and nitro group of 84, which imparts the stereocontrol of the reaction (Scheme [22]).[40]
Scheme 22 Ferrocene-based catalyst for enantioselective cyclopentanone synthesis
Liu and co-workers recently reported cooperative catalysis mediated by a palladium catalyst and urea-tertiary amine organocatalyst for the [3+2] cycloaddition between γ-methylidene-δ-valerolactones of type 87 and β-nitrostyrene 88. The reaction occurs by the initial generation of a 1,4-dipole from 87 by oxidative addition of palladium, facilitated by CO2 release and followed by intermolecular Michael addition to the species generated from the nitro-olefin. The strong hydrogen bonding between the urea-tertiary amine catalyst 89 and the nitro-olefin helps in the Re-face attack of the zwitterionic π-allyl intermediate onto the nitro-olefin, providing good control of the stereochemistry of the all-carbon quaternary stereocentre. Subsequent intramolecular cyclisation affords the final product 90 (Scheme [23]).[41]
Scheme 23 Urea-tertiary amine catalysis. Reagents and conditions: (i) Pd2(dba)3·CHCl3 (5 mol%), Ligand (22 mol%), 89 (5 mol%), 4 Å MS, THF, –10 °C.
Reaction of Phosphine-Allenoate Zwitterionic Species
4
Reaction of Phosphine-Allenoate Zwitterionic Species
Scheme 24 [3+2] Annulation of N-tosylimines with allenoates
It is well known that phosphines can add to alkynoates and allenoates to generate zwitterions that, in turn, can undergo [3+2] cycloaddition with alkenes and alkynes.[42] Asymmetric versions of such reactions using chiral phosphine catalysts have been widely explored[43] and the strategy has been utilised for the synthesis of all-carbon quaternary stereocentres.[44] An enantioselective [3+2] annulation of α-substituted allenoates of the type 91 with β,γ-unsaturated N-tosyl imine 92 in the presence of a phosphine catalyst was reported by Lu and co-workers. The reaction resulted in the formation of cyclopentene 93, containing an all-carbon quaternary centre. The reaction takes place via initial activation of the allenoate by attack of the phosphine, generating intermediate 94 that then undergoes [3+2] annelation with the N-tosyl imine, leading to product 93 after proton shift (Scheme [24]).[45] Recently Liu and co-workers used this strategy for the regioselective synthesis of CF3-substituted quaternary carbon-centred molecules in moderate to good yields. The reaction occurs through initial nucleophilic addition of the phosphine onto the allenoate, yielding the zwitterionic intermediate 98 that undergoes α-addition to the double bond of 96 to yield the anionic intermediate 99, which, in turn, cyclises to 100. Final 1,2-proton transfer and β-elimination of the catalyst yields the target cyclopentene 97 (Scheme [25]).[46]
Scheme 25 Phosphine-catalysed cyclopentane synthesis
Scheme 26
l
-Isoleucine derived amide phosphine catalysed reaction
Yao and co-workers reported a stereoselective and enantioselective trimerization of γ-aryl-3-butynoates catalysed by l-isoleucine-derived amide phosphine to yield cyclopentenones bearing an all-carbon quaternary stereocentre. The reaction occurs by addition of the phosphine to the allenoate (formed by isomerisation of the alkyne 102) to form zwitterionic intermediate 105, which, in turn, reacts with another molecule of allenoate to yield intermediate 106 followed by intramolecular Michael addition to yield 107. After a 1,2-H shift and expulsion of the catalyst, 109 is obtained, leading eventually to the final product 104 containing an all-carbon quaternary stereocentre (Scheme [26]).[47] Very recently Takao and co-workers also utilised this strategy for the synthesis of cyclopentene molecules possessing all-carbon quaternary stereocentres using Oppolzer’s camphor sultam 113 as one of the reaction partners.[48] The camphor sultam acts as a chiral auxiliary in this reaction, which is subsequently removed by chemoselective hydrolysis using alkaline hydrogen peroxide to furnish carboxylic acid 115 in 94% yield (Scheme [27]). The high regioselectivity is probably due to the bulkiness of the camphor sultam. The authors have also applied this strategy for the formal synthesis of R-(–)-puraquinonic acid.
In another earlier report, Morita–Baylis–Hillman (MBH) carbonates were used instead of allenoates to generate zwitterionic intermediates using nucleophilic phosphines. The latter reacted with MBH carbonate 117 to yield the salt 119 that, in turn, was deprotonated by the tert-butoxide to form species 120. The dispirobisoxindole 118, containing two all-carbon quaternary stereocentres, was formed by [3+2] cycloaddition of isoindigo 116 with 120 through formation of intermediates 121 and 122 (Scheme [28]).[49]
Miscellaneous Cycloaddition Reactions
5
Miscellaneous Cycloaddition Reactions
In 2017, Li and co-workers reported that an allene-tethered electron-deficient olefin underwent intramolecular [3+2] cycloaddition in the presence of benzene thiol to yield [3.3.0]bicyclic systems containing vicinal quaternary carbon stereocentres. The intramolecular cascade reaction is initiated by an electrophilic benzene thiol radical 123, affording a thermodynamically stable tertiary radical 124, by adding to the central sp-carbon atom of the allene 121. Subsequent attack of this radical to the α,β-unsaturated double bond via a 5-exo-trig-cyclisation led to radical intermediate 125 that then underwent a 5-endo-trig-cyclisation to generate 126. The latter in the next step abstracts a hydrogen atom from the benzene thiol and is converted into the final product 122 (Scheme [29]).[50]
Scheme 27 Camphor sultam as chiral auxiliary. Reagents and conditions: (i) n-Bu3P (30 mol%), toluene, 0 °C (ii) LiOH, aq H2O2, THF/H2O, RT.
Scheme 28 Reaction of MBH carbonate in the presence of phosphine
Scheme 29 Synthesis of bicyclic [3.3.0] compounds containing vicinal all-carbon stereocentres
An intramolecular silyl-nitronate cycloaddition was reported by Veselovsky and co-workers for the enantioselective synthesis of substituted cyclopentanones containing an all-carbon quaternary stereocentre. Henry reaction of 4-methyl pentenal 127 with nitromethane in the presence of the chiral catalyst 128 yields the unsaturated nitro alcohol 129. The latter is then converted into silyl ether 130 that, when treated with 1,1,1,3,3,3-hexamethyldisilazane (HMDS), yielded cyclopentaisoxazolidinone 132 through formation of the nitronate 131 by a stereoselective intramolecular cycloaddition with trans-disposition of the OTBS substituent relative to the annulated isoxazolidinone ring. Further transformation of 132 by exposure to sodium methoxide led to ring opened oximes 134a and 134b (anti/syn ratio 12:1 by 1H NMR analysis) through nitroso tautomerism. Final deoximation of the oximes by trituration with periodic acid resulted in the cycloalkanone 135 (Scheme [30]).[51]
Scheme 30 Synthesis of cyclopentanones via intramolecular silyl-nitronate cycloaddition
A formal 1,3-dipolar cycloaddition of 3-ylidene oxindoles of the type 136 with aryl diazomethane 140 (generated from benzaldehyde 65 and tosyl hydrazine 137) was reported by Babu and co-workers in 2018.[52] In this reaction, the intermediate cycloadduct 141 underwent decomposition in the aprotic solvent to deliver 3-spirocyclopropyl-2-oxindole 138, containing an all-carbon quaternary stereocentre. It was also observed that, in the presence of protic solvent, the cycloadduct 141 tautomerizes to form 142 which, in turn, is oxidised to the corresponding spiropyrazole oxindole. The latter then undergoes spontaneous rearrangement to pyrazoloquinazolinone 139. Thus, a solvent-controlled switchable product selectivity was demonstrated, as depicted in Scheme [31].
Scheme 31 Synthesis of 3-spirocyclopropyl-2-oxindole 138 and pyrazoloquinazolinone 139
Gao and co-workers, in 2019, reported the application of a [3+2] cycloaddition strategy for the construction of the core skeleton of calyciphylline A alkaloids. Herein, nitrone-induced [3+2] cycloaddition was used for the construction of the cis-hydroindole A–C rings containing an all-carbon quaternary centre at C5. Scheme [32] shows a representative construction of the stereogenic C5 centre of an important precursor to himalensine A[53]
[54] in which a cycloheptene substrate 143 is treated with N-benzylhydroxylamine resulting in a nitrone intermediate that, on intramolecular 1,3-dipolar cycloaddition through 6-exo-cyclisation with the α,β-unsaturated ester, results in cycloadduct 144, an important precursor containing the all-carbon quaternary centre of himalensine A 145.
Scheme 32 Intramolecular nitrone-ene [3+2] cycloaddition for construction of a precursor to the himalensine alkaloids
Gao and co-workers, in 2019, reported the asymmetric total synthesis of (–)-viridin and (–)-viridiol (Figure [2]), both containing a quaternary all-carbon stereocentre at C-10. The strategy involved the synthesis of compound 146 from L-ribose, which was then transformed into the unsaturated ester 147 by ruthenium-catalysed cross-metathesis. Treatment of 147 with hydroxylamine hydrochloride generated oxime 148, which was converted into nitrile oxide 149 with chloramine-T. Subsequent intramolecular [3+2] cycloaddition generated isooxazoline 150, which, on reductive hydrogenolysis and hydrolysis, yielded ketone 151. Wittig reaction of the latter produced compound 152, which, on reaction with dimethyl hydroxylamine hydrochloride (DMHH), yielded the Weinrib amide 153. This reacted with the anion of dihydroindenol 154 to yield 155 as a mixture of diastereomers at C17 (see Figure [2]). Compound 155 was converted into the desired tetracyclic core 156, containing an all-carbon quaternary stereocentre at C10, using a metal-catalysed hydrogen atom transfer (MHAT) strategy with the help of cobalt-salen catalyst 158 and phenyl silane. Selective removal of the TES group using Dowex resin followed by oxidation with Dess–Martin periodinane (DMP) yielded compound 157, which was converted into viridin and viridiol (Scheme [33]).[55]
Figure 2 Structures of viridin and viridiol
Scheme 33 Sequential synthesis of viridiol precursor
6
Conclusion
Effective ways of constructing all-carbon stereocentres have been reported in the past five years using [3+2] cycloaddition strategies involving metal-catalysed, organocatalysed, photocatalysed, base/acid-mediated, and thermal [3+2] cycloadditions, leading to products containing one or more all-carbon stereocentres. We believe that this review along with other reviews in this period,[56]
[57]
[58]
[59]
[60]
[61] will provide insight for organic chemists wishing to construct molecules containing all-carbon quaternary stereocentres.
