Page 111 - Read Online

Page 4 of 20 Wang et al. Chem Synth 2023;3:12 https://dx.doi.org/10.20517/cs.2023.01

Figure 3. Asymmetric N-H bond insertion reaction by α-carbonyl sulfonium ylides. This figure is used with permission from the
American Chemical Society [43] .

insertion reaction with condition C or D, generating the desired α-amino esters 5 in excellent results (50%-
69% yields, 78%-95% ee).

Moreover, the authors also investigated the possible mechanism. The mechanistic studies revealed that the
reaction undergoes a protonation-amination sequence and the enantioselectivity is controlled by dynamic
kinetic resolution in the amination step, rather than the initial protonation . In the proposed mechanism
[43]
[Figure 4], the chiral phosphoric acid enables the protonation of sulfonium ylide 1 that is in resonance with
the enolate mixture of Z/E-isomers 6, to give an intermediate mixture of (S)-7 and (R)-7 that pair with
chiral phosphate anion. Subsequent amine substitution by 2 delivers the desired chiral α-amino product 3
and simultaneously releases the chiral phosphoric acid catalyst. Indeed, intermediate 7 is in the catalyst
resting state and permits sufficient epimerization of the labile tertiary stereocenter in (S)-7 and (R)-7. Thus,
the enantioselectivity is controlled during amination by pseudo dynamic kinetic resolution of the
intermediate mixture of (S)-7 and (R)-7. In addition, phosphate ester 8 as a by-product could be found in
the catalytic mixture but is unable to react with amine 2 due to its inactiveness.

Asymmetric cyclization reaction of sulfonium ylides
Intermolecular cycloaddition is one of the most essential and powerful tools for the construction of cyclic
skeletons. Indeed, since the significant breakthrough of asymmetric organocatalysis in the early 2000s [26-29] ,
organocatalyzed enantioselective cycloaddition reactions involving sulfonium ylides have been widely
explored for the synthesis of diverse cyclic compounds. In this section, we divide the organocatalyzed
asymmetric transformations of sulfonium ylides into two categories: cyclopropanation and [4 + 1]
cyclization reaction for simplicity.

Organocatalyzed asymmetric cyclopropanation
Since cyclopropanation of sulfonium ylides with electron-deficient olefins was developed by Corey and
[13]
Chaykovsky in 1965 , the research on the corresponding asymmetric version has been devoted continuous
[20]
attention from chemists, and many great achievements have been made in this aspect . The first
enantioselective organocatalytic cyclopropanation was achieved by means of iminium activation in 2005
[Figure 5] . In this work, MacMillan and coworker chose chiral 2-carboxylic acid dihydroindole C5 as the
[44]
catalyst to activate α,β-unsaturated aldehydes 9 for generating iminium ion intermediates11. Due to the
existence of the attractive electrostatic interactions of sulfonium cation and carboxylate anion, the Si face of
the sulfonium ylide approaches the Re face of the iminium ion through the transition state 12 to give the
intermediate 13. And then, an intramolecular cyclization gives chiral cyclopropane products 10 in good
yields (63%-85%) with high diastereo- and enantioselectivities (6:1-72:1 dr and 89%-96% ee) [Figure 5]. In