Topics in Current Chemistry (2020) 378:16
1 3
et al. extended this cooperative Lewis base/palladium process to the enantioselective α-benzylation of esters (Scheme 21) [30]. Under standard BTM/PdXantphos G3
conditions, various α-benzylated pentafluorophenyl esters could be prepared in good
yields and with excellent levels of stereoselectivity. Unfortunately, this protocol is
restricted to π-extended electrophiles. The use of diphenylphosphate as the leaving group was critical to high reactivity and high enantioselectivity. The synthetic
utility of the process was demonstrated in the synthesis of the thrombin inhibitor
DX-9065a.
To further interrogate the modularity of this process, Snaddon et al. moved to
assess the reactivity of somewhat less common electron-withdrawing carbonylsubstituted π(allyl)Pd
+
electrophiles [31]. When using BTM/XantphosPd G3 conditions, ester-substituted electrophiles performed well; however, amide-substituted
electrophiles unexpectedly afforded mixtures of alkene isomers. Employing the preformed Pd(P(2-thienyl) 3 ) 3 complex as the palladium catalyst gave exceptional alkene E-selectivity. Furthermore, this new catalyst combination proved to be general
and accommodated a wide range of electron-withdrawing groups on the electrophile
including aldehydes, ketones, amides, esters, thioesters, and nitriles (Scheme 22).
Having established modular control over various electrophile classes via the Pdcatalyst, Snaddon et al. have extended their investigations to include pyrrole acetic
acid nucleophiles (Scheme 23) [32]. The efficiency of the reaction was independent
OPfp
O
N
H
R 1
X
(i) [Pd] (5 mol%)
(R)-BTM (20 mol%)
iPr 2 EtN (1.25 equiv.)
THF, rt; then NH 3 (g)
(ii) PIFA (2.0 equiv.)
R 2 OH, 60 °C
NH
OR 3
O
via isocyanate:
NH
OMe
O
80%, 86% ee
[Pd]: XantphosPdG3
NH
OMe
O
MeO
62%, 90% ee
[Pd]: Pd(P(2-thienyl) 3 ) 3
NH
Bn
OMe
O
MeO
79%, 88% ee
[Pd]: Pd(P(2-thienyl) 3 ) 3
NH
O t Bu
O
56%, 90% ee
[Pd]: XantphosPdG3
R 1
R 1
N
O
OMe
Me
Selected Examples:
Towards Sertraline:
HN
O t Bu
O
HN
O t Bu
O
SiMe 2 Bn
Cl
Cl
NHMe
Cl
Cl
Sertraline
O
X = OMs, OCO 2
t Bu
R 2
R 2
R 2
30 Examples
O
OMe
53%, 82% ee
[Pd]: Pd(P(2-furyl) 3 ) 3
Cl
Cl
I
Pd 2 (dba) 3 (2.5 mol%)
n Bu 4 NF, H 2 O
THF, 0 °C to rt
70%, 82% ee
Scheme 24 Formation of enantioenriched homoallylic amines by Snaddon
Reprinted from the journal
120
1 3
et al. extended this cooperative Lewis base/palladium process to the enantioselective α-benzylation of esters (Scheme 21) [30]. Under standard BTM/PdXantphos G3
conditions, various α-benzylated pentafluorophenyl esters could be prepared in good
yields and with excellent levels of stereoselectivity. Unfortunately, this protocol is
restricted to π-extended electrophiles. The use of diphenylphosphate as the leaving group was critical to high reactivity and high enantioselectivity. The synthetic
utility of the process was demonstrated in the synthesis of the thrombin inhibitor
DX-9065a.
To further interrogate the modularity of this process, Snaddon et al. moved to
assess the reactivity of somewhat less common electron-withdrawing carbonylsubstituted π(allyl)Pd
+
electrophiles [31]. When using BTM/XantphosPd G3 conditions, ester-substituted electrophiles performed well; however, amide-substituted
electrophiles unexpectedly afforded mixtures of alkene isomers. Employing the preformed Pd(P(2-thienyl) 3 ) 3 complex as the palladium catalyst gave exceptional alkene E-selectivity. Furthermore, this new catalyst combination proved to be general
and accommodated a wide range of electron-withdrawing groups on the electrophile
including aldehydes, ketones, amides, esters, thioesters, and nitriles (Scheme 22).
Having established modular control over various electrophile classes via the Pdcatalyst, Snaddon et al. have extended their investigations to include pyrrole acetic
acid nucleophiles (Scheme 23) [32]. The efficiency of the reaction was independent
OPfp
O
N
H
R 1
X
(i) [Pd] (5 mol%)
(R)-BTM (20 mol%)
iPr 2 EtN (1.25 equiv.)
THF, rt; then NH 3 (g)
(ii) PIFA (2.0 equiv.)
R 2 OH, 60 °C
NH
OR 3
O
via isocyanate:
NH
OMe
O
80%, 86% ee
[Pd]: XantphosPdG3
NH
OMe
O
MeO
62%, 90% ee
[Pd]: Pd(P(2-thienyl) 3 ) 3
NH
Bn
OMe
O
MeO
79%, 88% ee
[Pd]: Pd(P(2-thienyl) 3 ) 3
NH
O t Bu
O
56%, 90% ee
[Pd]: XantphosPdG3
R 1
R 1
N
O
OMe
Me
Selected Examples:
Towards Sertraline:
HN
O t Bu
O
HN
O t Bu
O
SiMe 2 Bn
Cl
Cl
NHMe
Cl
Cl
Sertraline
O
X = OMs, OCO 2
t Bu
R 2
R 2
R 2
30 Examples
O
OMe
53%, 82% ee
[Pd]: Pd(P(2-furyl) 3 ) 3
Cl
Cl
I
Pd 2 (dba) 3 (2.5 mol%)
n Bu 4 NF, H 2 O
THF, 0 °C to rt
70%, 82% ee
Scheme 24 Formation of enantioenriched homoallylic amines by Snaddon
Reprinted from the journal
120