Spiro Compounds. Группа авторов
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fashion. Several β‐dicarbonyl substrates 162 bearing different alkyl chains and both electron‐withdrawing and electron‐donating groups on the aryl ring of the methyleneindolinone 1 and the nitrosoarene 163 are well tolerated (31–94% yields, >20 : 1 dr and 95–99% ee). Also, various electron‐withdrawing groups (R4) at the methylene position afforded the desired products with high stereocontrol. Control experiments pointed out the importance of the Boc group as a hydrogen‐bond acceptor for activating the methyleneindolinones. The proposed mechanism is depicted in Scheme 3.15; enolization of acetylacetone promoted by the tertiary amine group of the bifunctional catalyst is followed by N‐selective addition to nitrosobenzene under basic conditions. The resulting ketimine is deprotonated and the methyleneindolinone is activated by the same catalyst to promote the intermolecular Michael addition. The final irreversible Mannich‐type cyclization proceeds smoothly to afford the enantioenriched spiranic products 160.
Scheme 3.15 Bifunctional squaramide‐catalyzed synthesis of enantioenriched spirocyclic oxindoles via ketimine intermediates with multiple active sites.
Source: Modified from Sun et al. [27].
Wang, Hong, and coworkers reported the first stereoselective 1,3‐dipolar cycloaddition reaction between azlactones 172 and methyleneindolinones 1 catalyzed by chiral phosphoric acids (Scheme 3.16) [28]. The methodology gives access to highly substituted 3,3‐pyrrolidonyl spirooxindole scaffolds 173, which are present in a number of natural products. The authors take advantage of the high versatility of azlactones, which under the effect of Brønsted acids can form N‐protonated 1,3‐dipoles. The dipole reacts with the methyleneindolinone 1 wherein the hydroxyl proton and the phosphoryl oxygen of the chiral phosphoric acid form double H‐bond interactions with both substrates, channeling the reaction in an enatioselective manner. The substituents on the binol backbone of the catalysts have a significant influence on the reaction enantiocontrol, where the bulkier catalyst 174 gave the best results. A wide variety of substitution patterns and functional groups on both substrates are well tolerated, affording the products 173 with good to excellent yields, diastereo‐ and enantioselectivities.
Scheme 3.16 Chiral phosphoric acid‐catalyzed enantioselective 1,3‐dipolar cycloaddition between methyleneindolinones and azlactones.
Source: Modified from Zhang et al. [28].
3.3.2 Organocatalytic [4+2] Cycloaddition Strategies to Construct Spiro Compounds
In 2016, Jørgensen and coworkers reported the asymmetric synthesis of spiroindenes 182 containing up to four contiguous stereocenters via trienamine catalysis (Scheme 3.17) [29]. The reaction between benzofulvenes 183 and 2,4‐dienals 184 catalyzed by the diphenylprolinol silyl ether catalyst 138 and ortho‐fluorobenzoic acid (o‐FBA) as additive furnish the indenes spiro‐fused to cyclohexene compounds 182 through a formal [4+2] cycloaddition. A range of differently substituted spiroindene compounds was formed efficiently in high yields (66–98%) and excellent stereoselectivities (6 : 1–>20 : 1 dr and 79–99% ee). The authors proposed that the all‐E‐configured trienamine intermediate reacts with the benzofulvene via an endo transition state where charge stabilization between the nitrile group and the enamine moiety could be a significant factor for the catalytic performance and the observed stereoselectivity. Finally, the Michael acceptor present in products 182 was demonstrated to facilitate further intramolecular cyclizations to yield complex polycyclic products. Thus, reduction of the aldehyde moiety to the alcohol or reductive amination with benzylamine triggered the intramolecular oxa‐ or aza‐Michael additions to yield the tetracyclic spirocompounds 192 and 193 as a single diastereoisomer in 58 and 54% yield, respectively.
The same group reported the first asymmetric organocatalyzed [4+2]‐cycloaddition reaction via a tetraenamine intermediate 194a–b for the construction of highly functionalized spirocyclic oxindoles 195 (Scheme 3.18) [30]. The reaction between 2‐(cyclohepta‐1,3,5‐trien‐1‐yl)acetaldehyde 196 and 3‐alkyliden oxindoles 197 in the presence of diphenylprolinol silyl ether catalyst 198 forms a wide range of spiranic products in high stereoselectivities (86 : 14–>95 : 5 dr and 68–95% ee) containing a highly functionalized six‐membered ring with an annulated seven‐membered ring. Mechanistic investigations suggested a stepwise mechanism via tetraenamine formation, conjugate addition, catalyst hydrolysis, and a final cyclization/isomerization sequence. Although the s‐trans conformer of the nucleophilic enamine 194a was detected by NMR spectroscopy, the authors proposed that the reactive intermediate is the enamine 194b, based on computational studies as well as the stereochemical outcome of the reaction.
Scheme 3.17 Stereoselective synthesis of spiroindene via trienamine catalysis with benzofulvenes.
Source: Modified from Donslund et al. [29].
In 2014, Connon and coworkers developed the first catalytic asymmetric Tamura [4+2] cycloaddition reaction for the construction of spiro compounds 206 (Scheme 3.19) [31]. Alkylidene oxindoles 203 react with enolizable anhydrides 204 by means of a quinine‐derived squaramide bifunctional catalyst 205 to generate the densely functionalized spirooxindoles 206 bearing three contiguous stereocenters with excellent enantiocontrol (89%–>99% ee). The methodology tolerates a wide range of enolizable anhydrides and alkylidene oxindoles with different stereoelectronic requirements. Interestingly, using 20 mol% of the organocatalyst at −50 °C, the kinetic diastereomer 213 can be isolated in 98% ee. Thus, by simply changing the reaction temperature is possible to switch the stereoselectivity of the process, an important approach in target‐oriented synthesis.
Scheme 3.18 Organocatalytic [4+2] addition reactions via tetraenamine intermediate.
Source: Modified from Stiller et al. [30].
In 2017, Yang and coworkers designed a sulphonamide‐based H‐bond donor organocatalyst derived from L‐pyroglutamic acid, a cheap chiral feedstock available in both