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Page 2 of 6 Sayed et al. Chem Synth 2023;3:20 https://dx.doi.org/10.20517/cs.2023.05

hydride-mediated allylic alkylation of enolizable carbonyl compounds with readily available allenes, alkynes
or 1,3-dienes as the unconventional allylating reagents has recently emerged as a promising protocol for the
3
3
[1-3]
stereoselective construction of Csp -Csp bonds with high efficiency . Due to their less enolizability and
weak nucleophilicity, simple esters remain challenging substrates for these coupling reactions. Additionally,
the strategy of metal/organo combined catalysis has recently emerged as one of the wide-ranging disciplines
[4-7]
and powerful tools in asymmetric synthesis . Considering the recent achievements of chiral Lewis base
catalysis in catalytic asymmetric α-functionalization of esters through a “rebound” mechanism [8-13] , the
cooperative combination of chiral Lewis bases and metal hydride catalysis may offer great opportunities to
the aforementioned chemistry. Recently, the groups of Snaddon and Zi have made remarkable progress in
this area through palladium and chiral Lewis base cooperative catalysis [14-16] .

In 2022, Snaddon described an enantioselective α-alkylation of esters 1 with oxyallenes 2 enabled by Pd/
chiral isothiourea cooperative catalysis [Scheme 1]. In this procedure, the isothiourea catalyst is believed
[14]
to first react with the pentafluorophenyl (Pfp) ester 2 to liberate PfpO anion and generate an
-
acylammonium ion (Int-1), which is intercepted by the Pd catalyst to afford the C1-ammonium enolate
(Int-2) and a palladium hydride species. Then nucleophilic intermediate (Int-2) synergistically combines
with O-substituted π(allyl)-Pd intermediate (Int-3) generated through the hydropalladation of the terminal
-
π-bond of allene 2 to give acylammonium (Int-4). Nucleophilic attack of the PfpO anion to (Int-4) releases
the Lewis base catalyst and delivers product 3. The designed catalytic system enabled a broad reaction scope
with excellent enantioselectivities and high anti- selectivity, which is arduous to access via classical aldol
reactions due to the undesired retro-aldol fragmentation. Furthermore, the products 3 could be readily
converted to enantiomerically pure 1,2-amino alcohols in good overall yield through a two-step NH
3
[11]
aminolysis and Hofmann rearrangement sequence .

Simultaneously, Zi, Tang and co-workers independently developed a stereodivergent coupling of
alkoxylallenes 2 with pentafluorophenyl esters 1 through the combined catalysis of a chiral Lewis base and a
chiral palladium catalyst [Scheme 2]. Through the combination of (S)-L1-Pd and (S)-LB-1, anti-4 could
[15]
be obtained with up to > 99% ee and > 20:1 dr. Instead, (R)-L2-Pd and (S)-LB-1 together rendered the
reaction highly syn-selective with excellent enantioselectivities. In this way, all four possible stereoisomers
could be obtained from a given pair of substrates through a rational selection of the corresponding catalysts.
Notably, DFT studies suggested a protonative hydropalladation pathway rather than a Pd hydride migratory
insertion occurred during the formation of the π-allyl Pd species.

Very recently, Zi group contributed another stereodivergent protocol by describing the diastereodivergent
alkylation of 1,3-dienes 5 with pentafluorophenyl esters employing Pd/chiral Lewis base cooperative
catalysis, providing structurally important 6 in high yields with excellent selectivities [Scheme 3]. The
[16]
absolute and relative stereochemistry of the product could be selected via a judicious choice of palladium
and isothiourea combinations. Under the optimized conditions, a variety of 1,3-dienes with an aryl or
heteroaryl substituent, as well as a broad scope of pentafluorophenyl acetates 1, were successfully tolerated
in this transformation. As a synthetic utility of this protocol, the coupling products were converted through
the transformation of the pentafluorophenyl group to alcohols, esters, and amides with two adjacent chiral
centers with high levels of diastereo- and enantio- selectivity. Moreover, based on the current protocol, a
concise synthesis of the analgesic tapentadol 9 could be realized with an overall yield of 47% in eight steps.

In summary, the groups of Snaddon and Zi have established several impressive protocols describing highly
stereoselective α-alkylation of esters employing simple allenes and dienes via palladium hydride/chiral Lewis
base catalysis. These are the few examples that successfully combine the chemistry of metal hydride-