10.1002/anie.201806742
Angewandte Chemie International Edition
COMMUNICATION
constructed (20–23). Evaluation of 2-naphthyl electrophile scope
(Figure 3) revealed the tolerance of acetylene units (27),
pinacolboronic esters (28), nitriles (29), acrylates (30) and Lewis
basic N-heterocycles (31). Extension to 1-naphthyl electrophiles
(32–34) as well as regioisomeric benzothiophene (35) and
benzofuran (36) heterobenzylic electrophiles was also
possible.14 While π-extended electrophiles functioned effectively,
simple monocyclic benzylic phosphates are unreactive,
presumably due to the aforementioned energy required for
dearomatization.[2-6] Pfp-esters derived from alkyl acetic acids
are also unreactive within this cooperative catalysis framework.
reaction. This is complementary to the ligand-centered
enantiocontrol typical of Pd-catalysis, and further demonstrates
the potential of cooperative catalysis to address challenges in
reactivity and stereocontrol that are be beyond single catalysts.
Our current efforts are directed toward the union of monocyclic
benzyl electrophiles with C1-ammonium enolates and will be
reported in due course.
Acknowledgements
We gratefully acknowledge Indiana University and the National
Institutes of Health (R01GM121573) for generous financial
support. We thank Dr. Maren Pink and Dr. Chun-Hsing Chen
(IU) for X-ray crystallography. This project was partially
supported by the IU Vice Provost for Research through the
Research Equipment Fund.
Our interest in this process stems not only from the well-
documented challenges associated with enantioselective
catalysis via cationic π-(benzyl)Pd intermediates, but also from
the potential of such reactions to address the synthesis of
therapeutically-relevant chiral molecules. Here we demonstrate
the utility of this method toward the synthesis of the thrombin
inhibitor DX-9065A (41),[15] a selective inhibitor of the coagulant
enzyme activated factor X (FXa).[16] Ethyl ester 40 is a key
intermediate en route to 41 and was previously prepared as a
1:1 diastereomeric mixture at the ester-bearing stereocenter;
crystallization provided 41 as a single diastereomer.[14] We
envisioned the stereocontrolled preparation of 39 (and thence
40) using the method described here. In the event, direct
alkylation of ester 37 with benzylic phosphate 38 gave 39 in 83%
isolated yield as a single diastereomer demonstrating complete
catalyst-control over stereoinduction (Scheme 1). Thereafter,
transesterification gave the key ethyl ester 40 in quantitative
yield.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: benzylation • palladium • cooperative catalysis •
Lewis base • enantioselective
[1]
For reviews, see: (a) J. Tsuji, Tetrahedron 2015, 71, 6330–6348; (b) B.
M. Trost, Tetrahedron 2015, 71, 5708–5733; (c) J. D. Weaver, A.Recio,
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2921–2944; (f) B. M. Trost, D. L. Van Vranken, Chem. Rev. 1996, 96,
395–422.
(S)-BTM (20 mol%)
O
OPfp
XantphosPd G3 (10 mol%)
iPr2NEt (1.1 equiv.)
toluene, rt, 24 h
O
OPfp
H
[2]
[3]
For a review describing the reactivity of transition metal η3-benzyl
complexes, see: B. M. Trost, L. C. Czabaniuk, Angew. Chem. Int. Ed.
2014, 53, 2826–2851; Angew. Chem. 2014, 126, 2868–2895. For a
review of Pd-catalyzed benzylic alkylation using (hetereo)benzylic
electrophiles, see: (b) J. Le Bras, J. Muzart, Eur. J. Org. Chem. 2016,
2565–2593.
N
O
O
H
37
er >99:1
39
H
83%, dr >20:1
er >99:1
N
OP(O)(OPh)2
38
N
N
Boc
Boc
EtOH
DMAP (2 mol%)
iPr2NEt, THF, rt
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O
OH
O
OEt
H
H
HN
2 steps
N
NH2
O
H
O
41
40
H
DX-9065a
99%, dr >20:1
er >99:1
N
N
HN
Boc
Me
Scheme 1. Synthesis of DX-9065a.
[4]
(a) J.-Y. Legros, A. Boutros, J.-C. Fiaud, M. Toffano, J. Mol. Catal. A
2003, 196, 21–25; (b) J.-Y. Legros, M. Toffano, J.-C. Fiaud
Tetrahedron 1995, 51, 3235–3246.
In conclusion, we have demonstrated the first example of an
enantioselective Pd-catalyzed benzylic alkylation of acyclic ester
nucleophiles. Critical to the success of this reaction was (i)
identification of the uniquely effective phosphate nucleofuge,
and (ii) the cooperative action of a Lewis base catalyst, which
governs the in situ production of stereo-defined C1-ammonium
enolate nucleophiles as well as the enantioselectivity of the
[5]
[6]
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132, 15534–15536.
[7]
Nickel catalyzed methods permit asymmetric benzylic alkylations using
organometallic nucleophiles. For selected examples, see: (a) B. L. H.
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