Traversing Steric Limitations by Cooperative Lewis Base/Palladium Catalysis: An Enantioselective Synthesis of α-Branched Esters Using 2-Substituted Allyl Electrophiles

Article abstract of DOI:10.1002/anie.201803277

Cooperative catalysis enables the direct enantioselective α-allylation of linear prochiral esters with 2-substituted allyl electrophiles. Critical to the successful development of the method was the recognition that metal-centered reactivity and the sourc

Full text of DOI:10.1002/anie.201803277

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Accepted Article
Title: Traversing Steric Limitations via Cooperative Lewis Base/Pd
Catalysis: An Enantioselective Synthesis of α-Branched Esters
using 2-Substituted Electrophiles.
Authors: Kevin Schwarz, Colin Pearson, Gabriel Cintron-Rosado, Peng
Liu, and Thomas Neil Snaddon
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201803277
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10.1002/anie.201803277
Angewandte Chemie International Edition
COMMUNICATION
Traversing Steric Limitations via Cooperative Lewis Base/Pd
Catalysis: An Enantioselective Synthesis of α-Branched Esters
using 2-Substituted Electrophiles.
Kevin J. Schwarz,† Colin M. Pearson,† Gabriel A. Cintron-Rosado, Peng Liu,* and Thomas N.
Snaddon*
Dedication ((optional))
Abstract:
Cooperative
catalysis
enables
the
direct
mesylates was unexpected. Examination of molecular models
led us to speculate on the development of deleterious non-
bonding interactions between the 2-substitutent of the
electrophile and a pseudoaxially positioned Ph-ring of the
large Xantphos ligand (Figure 1c). This could disrupt
formation of the necessary π-complex en route to π(allyl)Pd(II)
formation. Accordingly, we posited that monodentate ligands
would relieve such interactions and re-engage the
cooperative process.
enantioselective α-allylation of linear prochiral esters using 2-
substituted allyl electrophiles. Critical to the successful
development of the method was the recognition that metal-
centered reactivity and the source of enantiocontrol are
independent. This feature is unique to simultaneous catalysis
events and permits logical tuning of the supporting ligands
without compromising enantioselectivity.
Transition metal-catalyzed allylic alkylation is
a
well-
(a) Conceptual Framework:
established and powerful method for asymmetric carbon–
carbon bond formation.[1] A hallmark of these reactions is the
high levels of enantiocontrol imparted by chiral ligands, and
implicit in their design is the ability to change the metal and/or
ligands to tune reactivity and selectivity. However, despite
significant advances numerous challenges remain, including
the ability to logically regulate metal reactivity without
compromising enantioselection. Herein, we demonstrate that
independent modulation of metal-centered reactivity and
enantiocontrol elements via cooperative catalysis can, in a
rational manner, overcome structure-based substrate
reactivity limitations during Pd-catalyzed allylic alkylation
reactions. This permits the use of 2-substituted electrophiles,
a hitherto unreactive structural class in this process.
We have embraced cooperative catalysis[2] as a general
design framework for the direct catalytic asymmetric α-
functionalization of acyclic esters (Figure 1a).[3] This construct
unites C1-ammonium enolates with transition metal
electrophiles and has addressed key challenges associated
with inter alia Lewis base turnover,[4-6] the locus of
enantiocontrol, and the preservation of enolizable
stereocenters in the products. Despite the useful substrate
scope and high efficiency of this process,[3] attempts to
accommodate substitution on the central carbon of the allyl
partner completely shut down the reaction (Figure 1b).
Although the decreased reactivity of 2-substituted allyl halides
and acetates toward oxidative ionization by Pd(0) has been
described,[7] our recovery of the highly electrophilic allyl
O
O
R1
R1
Direct α-Functionalization
alkyl, aryl, NR2, OR
OR
OR
H
H
H
=
α-Functionalized
Ester
Ester
Cooperative Catalysis:
independent modulation of reaction partners
to address limitations in reactivity and stereocontrol
O–
n+2
R1
X
L
L
+
M
+
NR3
C1-Ammonium
Enolate
Transition Metal
Electrophile
(b) 2-Substitution Inaccessible:
H
MeO
N
O
S
N
Ph
MeO
O
OMs
(S)-BTM (20 mol%)
XantphosPd G3 (5 mol%)
OPfp
+
H
OPfp
R
iPr2NEt, THF, 23 °C
H
H
R
unsuccessful when R > H
(c) This work: Hypothesis – steric interactions preclude π-complex formation when R > H
R
P
P
R
MsO
Pd
MsO
P
Pd
P
bidentate P(III)-ligand
versus
monodentate P(III)-ligand
! congested Pd-center
! significant steric interactions
in π-complex
! more accessible Pd-center
! relief of steric interactions
in π-complex
Figure 1. (a) Conceptual framework for the direct α-functionalization of
linear esters via cooperative catalysis; (b) 2-substituted electrophiles are
unreactive using previously established conditions; (c) This work: alter
ligand based modulation of Pd-reactivtiy independent of enantiocontrol.
[a]
[b]
[†]
K. J. Schwarz,† Dr. C. M. Pearson,† Prof. T. N. Snaddon
Department of Chemistry, Indiana University
800 East Kirkwood Avenue, Bloomington, IN 47405 (USA)
E-mail: tsnaddon@indiana.edu
G. A. Cintron-Rosado, Prof. P. Liu
Department of Chemistry, University of Pittsburgh
Pittsburgh, PA 15260 (USA)
While tuning metal reactivity by modification of associated
ligands is a common and effective strategy, doing so with
logical maintenance of enantiocontrol (e.g. bidentate versus
monodentate ligands) is not.[8] The postulated mechanistic
scenario upon which our cooperative catalysis is predicated
permits the separation of these two critical features.[3]
E-mail: pengliu@pitt.edu
These authors contributed equally.
Supporting information for this article is given via a link at the end of
the document.
Using our previously established conditions employing
Birman’s benzotetramisole (BTM)[9] as the Lewis base
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10.1002/anie.201803277
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COMMUNICATION
catalyst, we began by evaluating the effect of
a
periods without loss of enantioselectivity. Although Pfp and
related aryl esters can be easily derivatized without loss of
representative range of monodentate and bidentate
phosphine ligands possessing different steric and electronic
profiles (Table 1). As a control, re-evaluation of Xantphos
using this in situ catalyst formation protocol was performed.
Using this procedure, allylated product was obtained albeit in
low yield and with very poor enantioselectivity (Entry 1). As
expected, other bidentate phosphines also perform poorly
(Entries 2–4). Electron-rich monodentate phosphines were
also ineffective (Entries 5–7). Moving to tri(2-furyl)phosphine
provided the necessary reactivity and gave the allylated
product in excellent yield and with encouraging levels of
enantioselection (Entry 8). The related tri(2-thienyl)phosphine
ligand furnished the product in reproducibly higher
enantioselectivity, albeit at the expense of yield (Entry 9).
Further assessment of solvent and reaction time gave the
product in excellent yield and enantioselectivity (Entries 10–
14). Although the unique efficacy of tri(2-furyl) and tri(2-
thienyl)-phosphine ligands on reactivity is currently unknown
we expect the low steric demand and significant π-accepting
character of these ligands[10] translates to more facile
formation of Pd(0)/π-complexes as necessary progenitors to
oxidative addition.
H
N
MeO
S
N
Ph
O
MeO
(S)-BTM (20 mol%)
Pd2dba3 (5 mol%)
P(2-thienyl)3 (20 mol%)
O
R
R
+
OMs
H
OPfp
H
H
iPr2NEt (1.25 eq.)
1,4-dioxane, r.t.
R
then direct work up or amine addition
● R = OPfp: direct work up, acidic Al2O3 ● R = NR2: amine addition then Al2O3
! Direct work up
MeO
O
MeO
MeO
MeO
O
O
O
OPfp
OPfp
OPfp
OPfp
OPfp
OPfp
OPfp
H
H
H
H
1, 85%
er >99:1
2, 88%
er 95:5
3, 78%
er 96:4
4, 83%
er >99:1
Me
Me
Me
Ph
MeO
MeO
MeO
MeO
O
O
O
O
OPfp
H
H
H
H
6, 87%
er 95:5
7, 75%
er 95:5
8, 61%
er 90:10
5, 90%
er 95:5
Cl
F
Me3Si
MeO
MeO
O
O
OPfp
OPfp
H
H
9, 81%
er 92:8
10, 80%
er 96:4
F
! Nucleophile addition
Table 1. Reaction Optimization.
MeO
MeO
MeO
O
H
N
O
O
S
N
Ph
N
H
N
N
H
H
(S)-BTM (20 mol%)
Pd2dba3 (5 mol%)
PR3 (X mol%)
O
H
H
OMs
H
11, 72%
er 96:4
12, 77%
er 97:3
13, 63%
er 95:5
O
+
OPfp
OPfp
Me
F3
C
H
Me
H
H
iPr2NEt (1.25 eq)
solvent, r.t., 16 h
Me
F3C
CF3
Me
Yield [%]b
MeO
MeO
MeO
O
O
O
PR3
(mol%)
erc
Entrya
1
Solvent
THF
N
N
H
N
H
H
H
H
O
14, 80%
er 92:8
15, 69%
er 95:5
16, 73%
er 95:5
Xantphos
DPEphos
dppf
5
14
0
58:42
--
OMe
5
THF
2
MeO
MeO
5
THF
0
--
3
Cl
MeO
MeO
OH
O
H
O
dppe
5
THF
12
0
--
4
H
H
N
N
H
PCy3
10
10
10
10
10
20
20
20
20
20
THF
--
5
H
H
19, 63%
er 95:5
NBoc
17, 73%
er 96:4
18, 78%
er >99:1
x-ray
Br
Me
P(o-tolyl)3
THF
0
--
6
P(p-OMePh)3
P(2-furyl)3
THF
0
--
7
Ph
Me
THF
90
65
77
61
56
92
98e
85:15
90:10
90:10
80:20
90:10
95:5
95:5
8
Scheme 1. Electrophile Scope: Direct work up giving Pfp esters (top), and
amine addition giving amides or alcohol (bottom).
P(2-thienyl)3
P(2-thienyl)3
P(2-thienyl)3
P(2-thienyl)3
P(2-thienyl)3
P(2-thienyl)3
THF
9
10
11
12
13
14d
THF
2-MeTHF
CPME
Dioxane
Dioxane
enantioenrichment,[3,5b,11] we nonetheless sought to increase
the synthetic utility of our process further. In concert with
additional assessment of the 2-aryl substituent scope, we
have also developed an in situ amine addition protocol to
produce amides. Primary, secondary and branched amine
amines react readily to provide functionalized amides in high
yields and enantiopurity (11–18). Reduction to the
corresponding alcohol 19 using LiAlH4 was also
straightforward. Finally, we also evaluated the scope of the
Pfp ester nucleophile (Scheme 2). As expected, a range of
substitution was possible illustrating the insensitivity of the
nucleophile toward steric and electronic modification (20–31).
Significantly, α-vinyl acetic acid Pfp esters (32–33) are also
competent nucleophiles.[12]
[a] Reactions performed on a 0.1 mmol scale. [b] Yields determined by 1H
NMR by comparison with an internal standard (1,2,4,5-tetramethyl-
benzene). [c] Determined by chiral HPLC analysis. [d] 24 h reaction time.
[e] Isolated yield. Pfp = pentafluorophenyl, Ms = methanesulfonyl.
Having established effective conditions
substituted allyl mesylates were evaluated. The reaction was
remarkably general and tolerant of wide range of
a variety of 2-
a
substituents including alkyl (1–4), vinyl (5), acetylenyl (6),
halide (7–8), and aryl substitution (9–10). In each case the
product esters could be isolated and stored for prolonged
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10.1002/anie.201803277
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Th3P
PTh3
In an effort to understand the manner in which the two
Th3P
PTh3
Pd
Pd
catalytic cycles intersect we initiated
a computational
O–
Me
S
O–
S
N
Ph
+
interrogation of both the postulated enolate ligation and the
nature of stereoinduction.[13] In our original report we posited
Ph
Me
+
N
N
N
H
H
H
N
S
N
Outer-sphere Attack
TS1
∆G‡ = 12.2 kcal/mol
Inner-sphere Attack
TS2
∆G‡ = 29.8 kcal/mol
Ph
O
(S)-BTM (20 mol%)
Pd2dba3 (5 mol%)
P(2-thienyl)3 (20 mol%)
O
Me
OPfp
+
OMs
H
OPfp
H
H
iPr2NEt (1.25 eq.)
1,4-dioxane, r.t.
Me
H
Me
O
O
O
O
OPfp
OPfp
OPfp
OPfp
H
H
H
H
MeO
Me
22, 80%
er 96:4
20, 98%
er 95:5
21, 95%
er 94:6
23, 81%
er 94:6
no→σ*C-S
Me
Me
Me
Me
interaction
from (R)-BTM
Br
Me2
N
O
O
O
O
OPfp
Ph
OPfp
OPfp
OPfp
H
H
H
H
26, 84%
er 96:4
27, 75%
er 94:6
24, 91%
er 96:4
25, 82%
er 90:10
Me
Me
Me
Me
from (R)-BTM
OMe
F
MeO
MeO
MeO
O
O
O
H
O
Figure 2. DFT studies. Outer-sphere (TS1) and inner-sphere (TS2)
transition states. DFT calculations were performed at the
M06/SDD−6311+G(d,p)/SMD(THF)//B3LYP/SDD−6-31G(d) level of theory.
See SI for details.
S
OPfp
OPfp
OPfp
OPfp
H
H
H
Br
31, 96%
er 90:10
28, 86%
er 91:9
29, 80%
er 91:9
30, 88%
er 95:5
Me
Me
Me
Me
from (R)-BTM
from (R)-BTM
O
O
Me
Me
OPfp
Me
OPfp
H
H
33, 92%
er 93:7
32, 92%
er 91:9
In conclusion, we have demonstrated the separation of
enantiocontrol and metal-centered reactivity in Pd-catalyzed
allylic alkylation using linear prochiral ester nucleophiles. This
is complementary to classical ligand-only modification in Pd-
catalyzed allylic alkylation and permits a wide range of 2-
substituted allyl electrophiles to be employed in the
Me
Me
Scheme 2. Nucleophile Scope.
the intermediacy of C1-ammonium enolate-ligated π-
(allyl)Pd(II) species,[3] which was inspired by Lectka’s
stabilization of quinuclidine-derived C1-ammonium enolates
by Pd(II) and Ni(II) Lewis acids.[14] We also provided a
tentative yet predictive model for enantioselection that is
based on Smith’s model for isothiourea-derived C1-
ammonium enolate preorganization.[15] Our density functional
theory (DFT) calculations revealed that the (Z)-O-C1-
enantioselective
synthesis
of
α-branched
esters.
Electrophiles of this structural type have previously exhibited
poor reactivity. Beyond simply broadening the repertoire of
cooperative catalysis, this study documents and describes
the unique capacity of simultaneous catalysis events to
confront reactivity and stereocontrol limitations in a modular
fashion. Such flexibility is typically beyond a single catalyst.
ammonium enolate is conformationally rigid due to
a
stabilizing nO→σ*C−S interaction[16] as well as steric effects
(see SI for details). This is in line with the findings of
others[15a] and is consistent with our previously proposed
induction model in which the π-(allyl)Pd complex attacks the
less hindered face of the enolate. We then investigated both
inner- and outer-sphere nucleophile addition to the π-(allyl)Pd
complex (Figure 2).[17] The outer-sphere pathway (TS1)
requires a relatively low barrier of 12.2 kcal/mol. In contrast,
the inner-sphere addition (TS2) from an O-enolate ligated π-
(allyl)Pd complex is highly disfavored due to steric repulsion
between the C1-ammonium enolate and the ancillary ligands
on Pd. This support for an outer-sphere mechanism
reinforces the generality of our cooperative design where the
transition metal and Lewis base catalysts are fully
independent.
Acknowledgements
We gratefully acknowledge Indiana University, NIH
(R01GM121573), ACS-PRF (55734-DNI) and NSF (CHE-
1654122) 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.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: alkylation • C1-ammonium enolate • palladium •
enantioselective • Lewis base
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10.1002/anie.201803277
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COMMUNICATION
[1]
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116, 13512; (c) Chen, D.-F.; Han, Z.-Y.; Zhou, X.-L; Gong, L.-Z. Acc.
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information for further details.
[14] (a) Erb, J.; Paull, D. H.; Dudding, T.; Belding, L.; Lectka, T. J. Am.
Chem. Soc. 2011, 133, 7536–7546; (b) Paull, D. H.; Scerba, M. T.;
Alden-Danforth, E.; Widger, L. R.; Lectka, T. J. Am. Chem. Soc.
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[2]
[15] (a) West, T. H.; Walden, D. M.; Taylor, J. E.; Brueckner, A. C.;
Johnston, R. C.; Cheong, P. H.-Y.; Lloyd-Jones, G.; Smith, A. D. J.
Am. Chem. Soc. 2017, 139, 4366–4375; (b) West, T. H.; Daniels, D.
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[16] (a) Pascoe, D. J.; Ling, K. B.; Cockroft, S. L. J. Am. Chem. Soc.
2017, 139, 15160–15167; (b) For the importance of such
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2015, 58, 4383–4438.
[3]
[4]
Schwarz, K. J.; Amos, J. A.; Klein, J. C.; Do, D.; Snaddon, T. N. J.
Am. Chem. Soc. 2016, 138, 5214–5217.
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2014, 43, 6214–6226; (b) Paull, D. H.; Weatherwax, A.; Lectka, T.
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For other examples of C1-ammonium enolates in combination with
transition metal catalysis, see: (a) Spoehrle, S. S.; West, T. H.;
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139, 11895–11902; (b) Jiang, Z.; Beiger, J. J; Hartwig, J. F. J. Am.
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[17] For an instructive computational study, see: Keith, J. A.; Behenna,
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[5]
[6]
[7]
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[8]
[9]
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[12] α-Alkyl acetic acid esters are not competent in this reaction.
However, the use of α-vinyl nucleophiles would, following reduction
of the alkene, provide such products. For other examples of α-vinyl
acetic acid derived C1-ammonium enolates, see: (a) ref 5e; (b)
Arokianathar, J. N.; Frost, A. B.; Slawin, A. M. Z.; Stead, D.; Smith,
A. D. ACS. Catal. 2018, 8, 1153–1160; (c) Morrill, L. M.; Smith, S.
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1655.
[13] Thus far we have been unsuccessful in our efforts to
computationally interrogate the ligand effects on the efficiency of π-
complex formation due to the unknown role/effect of either the
nucleofuge (MsO–) or the solvent. Nonetheless, calculations reveal
little energetic difference with respect to the supporting ligand
(Xantphos versus tri(2-thienyl)phosphine) in the oxidative addition
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Two is better than one!: Cooperative
Author(s), Corresponding Author(s)*
catalysis
enables
the
direct
enantioselective α-allylation of aryl and
vinyl acetic acid esters using 2-
substituted allyl electrophiles. Critical to
the successful development of the
method was the recognition that metal-
centered reactivity and the source of
enantiocontrol are independent, which
permits logical tuning of the supporting
Page No. – Page No.
Title
ligands
without
compromising
enantioselectivity.
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