Page 129 - Read Online

Page 2 of 10 Xu et al. Chem Synth 2023;3:17 https://dx.doi.org/10.20517/cs.2022.35

intrinsic reactivity or selectivity issues associated with mono-activated reactants, acyl transfer strategy
utilizes the acyl group as a transient activating group to produce bis-activated reactants [Scheme 1A]. Such a
chemical event involves a reaction cascade of X-Y bond formation, intramolecular cyclization, and the
retro-Claisen reaction, where the challenging mono-activated function could be implemented formally. In
this context, several catalytic asymmetric acyl transfer methods have been developed based on nucleophile
activation [Scheme 1B]. For example, Mondal, Song et al. developed the asymmetric cascade Michael/acyl
transfer reactions of α-nitroketones and 1,3-diketones using bifunctional organocatalysts [3-11] . Rodriguez and
Luo reported the secondary or primary amine-catalyzed acyl transfer reactions [12-16] . Very recently, Yi et al.
have established an elegant iridium-catalyzed asymmetric cascade allylation/acyl transfer reaction for the
[17]
synthesis of enantiomerically enriched 3-hydroxymethyl pentenal units . Besides, using acyl transfer,
Zhou, Yang et al. prepared the medium-sized-ring lactams from cyclobutanone β-ketoamides [18-21] . Despite
these achievements via nucleophile activation, acyl transfer via electrophile activation remains far less
developed [Scheme 1C]. As far as we know, there was only one example from the Pan group, where
nitroenone was used as an electrophilic acyl transfer reagent in catalytic asymmetric Friedel-Crafts and
[22]
Michael reactions . Therefore, the development of new catalytic asymmetric acyl transfer methods via
electrophile activation is highly desired.

Our group has a long-standing interest in developing facile protocols for synthesizing biologically important
molecules. Recently, we have discovered that α-hydroxy-1-indanones could serve as a valid synthon in
cyclization reactions with activated Michael acceptors via chiral dinuclear zinc catalysis [23,24] . Along this line,
we envisioned that dinuclear zinc-catalyzed asymmetric acyl transfer reaction between α-hydroxy-1-
indanones 1 and nitroenones 2 was feasible via less-explored electrophile activation mechanism, generating
thereby the protected cyclic tertiary α-hydroxyketones 3 in an enantioselective, step- and atom-economic
manner. As illustrated in Scheme 2, the reaction cascade was triggered by dinuclear zinc-catalyzed Michael
reaction [25,26] , which led to the intermediate Int-1. The subsequent intramolecular cyclization/retro-Claisen
reaction resulted in the acyl transfer product 3. However, therein lie several synthetic organic chemistry
challenges to this reaction proposal, which include: the enantioselective formation of the tetrasubstituted
stereocenter, the side-formations of potential interruption product hemiketal Int-2 and dehydration
product dihydrofuran 4. Herein, we introduce a highly enantioselective acyl transfer protocol via under-
exploited electrophile activation by making use of dinuclear zinc-catalyzed Michael/cyclization/retro-
Claisen reaction cascade, which led to a step- and atom-economic access to a variety of protected cyclic
tertiary α-hydroxyketones in good yields with excellent enantioselectivities.

EXPERIMENTAL
Under a nitrogen atmosphere, a solution of diethylzinc (20 μL, 1.0 M in hexane, 0.02 mmol) was added
dropwise to a solution of L4 (0.01 mmol, 9.6 mg) in MeCN (2 mL). After the mixture was stirred for 30 min
o
at 30 C, 1a (0.2 mmol, 29.6 mg) and 2a (0.2 mmol, 50.6 mg) were added. The reaction mixture was stirred
for 48 h at the same temperature. The reaction was quenched with HCl solution (1 M, 2 mL), and the
organic layer was extracted with CH Cl (3 × 5 mL). The combined organic layer was washed with brine and
2
2
dried over Na SO . The solvent was removed under reduced pressure by using a rotary evaporator. The
2
4
residue was purified by flash chromatography with petroleum ether/ethyl acetate (4:1) to afford the desired
chiral product 3a.
RESULTS AND DISCUSSION
The model reaction between α-hydroxy-1-indanone 1a and 2-nitro-1,3-diphenylprop-2-en-1-one 2a was
initially performed in the presence of 10 mol % of dinuclear zinc catalyst in situ generated from 10 mol % of
ligand L1 and 20 mol % of ZnEt in tetrahydrofuran (THF) at 30 C oC Figure 1. The desired product 3a was
o
2