C-H Functionalization of Amines via Alkene-Derived Nucleophiles through Cooperative Action of Chiral and Achiral Lewis Acid Catalysts: Applications in Enantioselective Synthesis

Article abstract of DOI:10.1021/jacs.8b06699

Catalytic transformations of α-amino C-H bonds to afford valuable enantiomerically enriched α-substituted amines, entities that are prevalent in pharmaceuticals and bioactive natural products, have been developed. Typically, such processes are carried out

Full text of DOI:10.1021/jacs.8b06699

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Article
C–H Functionalization of Amines via Alkene-Derived Nucleophiles
through Cooperative Action of Chiral and Achiral Lewis
Acid Catalysts: Applications in Enantioselective Synthesis
ming shang, Jessica Zee Chan, Min Cao, Yejin Chang, Qifan
Wang, Brennan Cook, Sebastian Torker, and Masayuki Wasa
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b06699 • Publication Date (Web): 25 Jul 2018
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C–H Functionalization of Amines via Alkene-Derived Nucleophiles
through Cooperative Action of Chiral and Achiral Lewis Acid
Catalysts: Applications in Enantioselective Synthesis
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Ming Shang,‡ Jessica Z. Chan,‡ Min Cao, Yejin Chang, Qifan Wang, Brennan Cook,
Sebastian Torker and Masayuki Wasa1*
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Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
ABSTRACT: Catalytic transformations of -amino C–H bonds to afford valuable
enantiomerically enriched -substituted amines, entities that are prevalent in pharmaceuticals
and bioactive natural products, have been developed. Typically, such processes are carried out
under oxidative conditions, and require precious metal-based catalysts. Here, we disclose a
strategy for enantioselective union of N-alkylamines and ,-unsaturated compounds, performed
under redox-neutral conditions, and promoted through concerted action of seemingly competitive
Lewis acids, B(C6F5)3 and a chiral Mg–PyBOX complex. Thus, a wide variety of -amino
carbonyl compounds may be synthesized, with complete atom economy, through stereoselective
reaction of an in situ generated enantiomerically enriched Mg-enolate and an appropriate
electrophile.
INTRODUCTION
Cooperative catalysts (e.g., Fig. 1a, A1–A4), which are capable of two distinct and
simultaneous functions, can doubly activate substrate molecules.1-6 One advantage of this
strategy in catalysis is the considerable rate enhancement that can become available as a result of
increased proximity of the reacting substrates. Cooperative acid/base enantioselective catalysis
has previously been applied to the development of reactions between in situ generated, acid-
activated electrophiles and base-activated nucleophiles. The wasteful pre-activation step may
thus be obviated.1-6 Nevertheless, notable shortcomings remain unaddressed. For instance, self-
quenching might occur in a mixture that contains an electrophile, a nucleophile, together with an
acid and a base catalyst. One way to circumvent acid–base complexation is by avoiding a
combination that exhibits high affinity (i.e., hard–hard or soft–soft pairing). However, this latter
approach has thus far been limited to cases in which weakly to moderately acidic and/or basic
promoters are involved, where only highly acid- or base-sensitive substrates can be used.
Development of potent and unquenchable cooperative two-catalyst systems that facilitate
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reactions between unactivated substrates is an important and largely unresolved problem in
enantioselective catalysis.
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Figure 1. Structures and reactivity of cooperative catalysts. (a) Previously reported examples of
cooperative acid/acid catalysts involve structurally and/or functionally disparate acidic promoters. (b)
Intramolecular hydride transfer occurs within a frustrated Lewis pair complex to afford zwitterionic iminium
ions. (c) Enantioselective coupling of N-alkylamines and ,-unsaturated compounds by cooperative acid/acid
catalysis. (d) A possible mechanism might involve enantio- and diastereoselective C–C bond formation
between iminium ion and chiral enolate, generated in situ by cooperative functions of a chiral and an achiral
Lewis acid catalyst. The reaction affords -amino carbonyl compounds atom economically and under redox
neutral conditions.
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The application of frustrated Lewis pairs (FLPs), consisting of hindered and
electronically disparate Lewis acids and Lewis bases, has recently emerged as an attractive
strategy for overcoming mutual quenching. An unquenched acid/base pair may thus be utilized
for synergistic activation of otherwise unreactive molecules such as H2 and CO2.7-9 Furthermore,
FLPs that are comprised of a boron-based Lewis acid and a Lewis basic amine substrate, and
contain easily accessible -hydrogens (e.g., B; Fig. 1b), have been shown to engage in Lewis
acid-mediated hydride abstraction. Such processes produce an iminium cation and a borohydride
anion (C),10-13 the latter of which might then react with a carbonyl-containing species to afford
D.10 A related investigation illustrates that the presence of stoichiometric amounts of B(C6F5)3
can lead to C–C bond forming reactions between N-alkylamines and ,-unsaturated molecules
to afford -amino carbonyl compounds.13 Still, engagement of iminium ions formed by
organoboron-catalyzed hydride abstraction from amines in the context of a catalytic
transformation has been confined to dehydrogenation of N-containing heterocycles.14,15 To the
best of our knowledge, such strategies are yet to be successfully applied to catalytic C–C bond
forming transformations.16,17 One way to address this problem would be by designing a catalyst
that can abstract a hydride from an amine substrate, mediate enantioselective C–C bond
formation, and regenerate the active Lewis pair without significant deactivation due to the
presence of a Lewis basic moiety.
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While contemplating how to design a catalytic process for stereoselective coupling of N-
alkylamines and carbon-based nucleophiles, we envisioned utilizing two potent Lewis acid
catalysts for accomplishing separate tasks (Fig. 1c-d). We imagined that B(C6F5)3 could receive a
hydride from amine 1, generating a borohydride and an iminium ion (I). Concurrently, a chiral
Lewis acid co-catalyst would activate the ,-unsaturated substrate (e.g., 2) to facilitate
reduction by the aforementioned borohydride (III), furnishing the corresponding chiral enolate
(IV). An ensuing stereoselective reaction between the iminium ion and the enantiomerically
enriched enolate would deliver a -amino carbonyl product (3). One key advantage of the
approach would be that efficiency and stereoselectivity might be optimized through evaluation of
pairs of readily accessible Lewis acids and chiral ligands. Accordingly, a central design principle
is that the untethered Lewis acid catalysts must perform their separate tasks without any
overlapping of their function, as otherwise, stereoselectivity would suffer (due to reaction
facilitated by the achiral component).18 Enantioselective transformations promoted by the shared
action of two different metal complexes,1-5,19 as well as Brønsted acid and organometallic
complexes20,21 or hydrogen-bond donors22 are known (e.g., Fig. 1a, A1–A4). However, in
contrast to what we aimed to accomplish, in the previous approaches, the Lewis acidic promoters
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were structurally and/or functionally disparate, translating to minimal overlay in their modes of
action; namely, their simultaneous presence did not pose a complication. Here, we report that
functionally similar B(C6F5)3 and a chiral Lewis acid co-catalyst can operate in concert to
promote enantioselective coupling of N-alkylamines and various ,-unsaturated compounds.
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The plan outlined above is distinct from the traditional “direct” Mannich-type reactions,
where Lewis acid and Brønsted base catalysts cooperate to generate first an enolate, and then
promote its addition to an aldimine, which has already been prepared through a separate
operation.4,5,23,24 There are a small number of reported examples regarding direct Mannich-type
reactions that involve esters, amides or thioesters; deprotonation is more difficult in these
instances, because of diminished acidity (pKa in the range of 25–30). We sought to generate the
requisite electrophilic and the nucleophilic species in situ from readily available N-alkylamines
and ,-unsaturated compounds. Thus, under redox-neutral conditions and without the need for a
precious metal salt,25 we would synthesize -substituted amines 3, entities that are difficult to
access by “direct” Mannich strategies. Many of the reported methods for -amino C–H
functionalization rely on transition metal-based catalysts (e.g., Fe-, Cu-, Ru-, Rh-, Pd-, Ir-, Pt-
based), and, often, demand oxidative conditions.26-36 These catalyst systems may either forge C–
C bonds directly,36 or first convert a substrate amine into a more active intermediate, such as an
-amino radical,26 an iminium ion,27-30 an -halo, an -hydroxyl or an -metalated species.31-35
Catalytic stereoselective -amino C–H functionalization has been investigated as well.27,29,30,34,36
However, the development of non-precious metal-based methods that complements the existing
stereoselective techniques represents a compelling problem.
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RESULTS AND DISCUSSION
To begin, we set out to identify an appropriate combination of an acidic catalyst and an
amine substrate that would allow for efficient hydride abstraction (as opposed to formation of a
stable acid–base adduct). We first probed the ability of B(C6F5)3 to catalyze the reaction between
N-aryl pyrrolidine (1a) and methyl acrylate (2a), affording -amino ester 3a (Table 1; see the
Supplementary Information for data regarding screening of N-substituents). In this representative
process, a single Lewis acid B(C6F5)3 would be responsible for activation of the amine as well as
the Michael acceptor (Fig. 1d, M–L* = B(C6F5)3). Treatment of 1a and 2a with 5.0 mol%
B(C6F5)3 in CH2Cl2 at 22 °C for 12 hours afforded 3a in >95% yield as a separable mixture of
diastereomers (entry 1, anti:syn = 2.3:1); there was less than 5% of the di-substituted product
(3b). With Et2O and THF as the solvent, 3a was formed in 94% and 26% yield, respectively
(entries 2–3). When the reaction was carried out in a relatively non-polar aromatic hydrocarbon,
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such as toluene and benzene, 3a was obtained in 81% and >95% yield (entries 4–5); in benzene,
3a was isolated in >95% yield in just 30 minutes (entry 6). At lower loading of B(C6F5)3 (2.5
mol%), longer reaction time was needed (48 h, 3a in 84% yield; entry 7).37 None of the desired
product was formed in the absence of B(C6F5)3 (entry 8), or when the less hindered BF3•OEt2 or
the less acidic BPh3 were used (entries 9–10). The latter findings support the notion that highly
acidic B(C6F5)3 together with sterically demanding and electron-rich N-alkylamines represent the
most effective combination.
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Table 1. Evaluation of Reaction Parametersa,b
aConditions: 1-(4-Methoxy-2,6-dimethylphenyl)pyrrolidine (0.2 mmol), methyl acrylate (0.3 mmol), Lewis
b
1
acid, solvent (0.3 mL), under N2, 22 °C. Yields were determined by H NMR analysis of unpurified product
mixtures with mesitylene as the internal standard. See the Supporting Information for details.
A variety of ,-unsaturated carbonyl compounds and related electrophiles may be used
in reaction with N-arylpyrrolidine 1a to generate the corresponding -substituted amines (3a–3k,
Fig. 2). Reaction with methyl acrylate (2a) and benzyl acrylate (2c) afforded 3a and 3c in 97%
and 91% yield, respectively. Whereas isopropyl acrylate (2d) gave 3d in 78% yield, no product
was obtained with tert-butyl acrylate; this decline in efficiency probably arises from inferior
ability of B(C6F5)3 in coordinating with the more sterically encumbered acrylates.
Transformation with the less electrophilic thioacrylate (2e) gave 3e (53% yield), and acrylonitrile
(2f) proved to be a viable starting material, furnishing 3f in 50% yield. Reaction with methyl
methacrylate (2g) gave 3g, containing an -quaternary carbon center, in 97% yield. Dimethyl
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acetylenedicarboxylate (2h) was converted in situ to an allenolate nucleophile, which reacted
with 1a-derived iminium ion to deliver 3h in 52% yield as a separable mixture of E and Z
isomers (1:1.6). Transformations with N-phenylmaleimide (2i), trans-fumaronitrile (2j), and (E)-
β-nitrostyrene (2k) furnished 3i–3k (84% to >95% yield).
R1
R2
R4
N
R1
R3
R2
H
B(C6F5)3
5.0 or 10 mol%
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EWG
N
EWG
R5
R4
R3
H
+
R5
CH2Cl2 or C6H6, 22 or 70 °C
12 24 or 48 h
1
2
3, 4
O
O
O
O
N
Ar
N
N
Ar
N
Ar
OBn
Oi-Pr
SPh
OMe
Ar
H
H
H
H
3a, 97% yield*
2.3:1 anti:syn
3d, 78% yield*
2.1:1 anti:syn
3e, 53% yield*
1.8:1 anti:syn
3c, 91% yield*
2.5:1 anti:syn
O
O
NPh
O
CN
N
Ar
H
N
Ar
N
Ar
OMe
OMe
N
Ar
OMe
Me
H
H
H
O
O
3f, 50% yield†
1.3:1 anti:syn
3i, 99% yield*
4.5:1 anti:syn
3h, 52% yield*
E:Z = 1:1.6
3g, 97% yield*
Me
TBSO
Me
O
O
CN
N
NO2
N
N
Ar
N
Ar
Ar
OMe
OMe
Ar
H
CN
H
Ph
H
H
3j, 92% yield†
1.2:1 anti:syn
3k, 84% yield†
1.2:1 anti:syn
3l, 95% yield*
3.0:1 anti:syn
3m, 82% yield*
6.9:5.9:3.0:1 d.r.
O
O
Me
O
O
Me
Me
N
Ar
OBn
N
NPh
N
Ar
N
Ar
OMe
OMe
H
H
Me
H
H
O
Me
4a, 91% yield†
3p, 62% yield†
3n, 63% yield*
10:1 anti:syn
3o, 66% yield*
2.0:1 anti:syn
OTBS
O
Ph
Ph
O
H
O
Me
O
Me
Me
Me
Me
Me
Me
Me
N
OBn
N
OMe
N
OBn
N
OBn
Me
Ph
Me
Me
H
H
Me
Ph
Me
Me H
4d, 91% yield†
(R,S):(R,R) = 1.5:1
4b, 85% yield†
4c, 91% yield†
4e, 95% yield†
Figure 2. Coupling of N-alkylamines and ,-unsaturated compounds through B(C6F5)3-catalyzed
hydride abstraction. The values correspond to yields of isolated and purified products. Diastereomeric ratio
1
(d.r.) values were determined by analysis of the unpurified product mixture through analysis of H NMR
spectra. *5.0 mol% of B(C6F5)3 was used. †10 mol% of B(C6F5)3 was used. See the Supplementary Information
for details.
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Next, we investigated reactions with cyclic and acyclic N-alkylamines. 3,3-Dimethyl-,3-
((tert-butyldimethylsilyl)oxy)-substituted N-aryl pyrrolidines (1l, 1m), N-aryl piperidine (1n) and
N-aryl azepane (1o) gave the corresponding products (3l–3o) in 63% to 95% yield. There was
efficient hydride abstraction at the N-methyl site of various amines. 4-Methoxy-N,N,2,6-
tetramethylaniline (1p) reacted with N-phenylmaleimide to afford 3p (62% yield). A series of
trialkyl-substituted amines that lack the fused N-aryl group were coupled efficiently with
acrylates, leading to the formation of 4a–4e (85%–95% yield). Reaction of (R)-N-methyl-1-
phenyl-N-((R)-1-phenylethyl)ethan-1-amine with benzyl acrylate (2c) delivered 4d as a 1.5:1
mixture of diastereomers, which were separable through silica gel chromatography, allowing us
to secure the -amino esters in enantiomerically pure form (see the Supplementary Information
for details). The less hindered N-alkylamines (e.g., N-methyl pyrrolidine) did not react with 2c,
probably due to the formation of stable B(C6F5)3–amine adducts, which may compete with Lewis
acid-catalyzed hydride abstraction.
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Having realized the single-catalyst racemic transformation based on the hydride
abstraction concept, we chose to develop an enantioselective version of the catalytic process by
employing B(C6F5)3 in combination with an appropriate chiral Lewis acid. With N-
arylpyrrolidine (1a) and 3-acryloyloxazolidin-2-one (2q) as model substrates, systematic
evaluation of Lewis acid/chiral ligand complexes was performed (Fig. 3a). In the presence of 10
mol% of B(C6F5)3 and Mg(OTf)2, various bis-oxazoline ligands were tested (12 mol%, L1–L4).
Whereas in the presence of PhBOX (L1) and DBFOX (L2) there was minimal conversion to 3q
(<10% yield), with PyBOX (L3, (S,S)-2,2'-(2,6-pyridinediyl)bis(4-phenyl-2-oxazoline)) we
obtained 3q in 35% yield, 1.1:1 anti:syn ratio, and 71:29 e.r. and 80:20 e.r. (syn and anti isomer,
respectively). There was further improvement in efficiency (3q in >95% yield) when 2,6-bis((S)-
4-(3-chlorophenyl)-4,5-dihydrooxazol-2-yl)pyridine (L4) was utilized as the chiral ligand. There
was minimal conversion to the desired product and/or low enantioselectivity with Mg(OTf)2/L4,
or when Cu(OTf), Ni(OTf)2, Zn(OTf)3, Sc(OTf)3, Mg(ClO4)2, and other Lewis acid co-catalysts
were employed in combination with various ligands (see the Supplementary Information for
details). Because B(C6F5)3 catalyzes the C–C bond forming reaction between 1a and 2q in the
absence of the chiral Mg-based co-catalyst (Fig. 3b; rac-3q, 35% yield), the presence of this
Lewis acid can engender considerable diminution in e.r. However, we subsequently discovered
that the reaction of 1a with 3-acryloyl-4,4-dimethyloxazolidin-2-one (2r), catalyzed by the
combination of B(C6F5)3 and Mg(OTf)2/L4 can deliver either diastereoisomer of 3r in high e.r.
(3r-anti and 3r-syn in 97:3 and 98:2 e.r., respectively, 88% yield; Fig. 3c). The higher
enantioselectivity probably arises from a preference for Mg-activated VIII over B(C6F5)3-
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activated VII, the latter of which might suffer from severe steric repulsion between the gem-
dimethyl group of 2r and B(C6F5)3, a contention supported by the fact that 2r does not react in
the absence of Mg(OTf)2/L4.
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(a)
O
O
O
O
B(C6F5)3, 10 mol% Mg(OTf)2
10 mol%
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N
Ar
N
N
O
+
O
N
H
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Ar
12 mol% L1–L4, CH2Cl2, 22 °C, 12 h
H
1a
2q
3q
Me Me
O
O
O
O
O
O
N
N
O
N
N
N
N
N
N
O
O
N
N
Ph
L3
L4
L1
L2
Ph
Ph
Ph
Cl
Cl
Ph
Ph
35% yield
1.1:1 anti:syn
7% yield
>95% yield
1.6:1 anti:syn
<5% yield
1.3:1 anti:syn
56:44 er (anti)
52:48 er (syn)
2.0:1 anti:syn
50:50 er (anti)
50:50 er (syn)
71:29 er (anti)
80:20 er (syn)
80:20 er (anti)
68:32 er (syn)
(b)
B(ArF)3
O
O
+
O
no co-catalyst:
B(C6F5)3
N
N
N
O
Ar
N
Ar
N
Ar
H
–
H
O
(ArF)3B
H
O
1a
rac-3q,
V
35% yield, 4.8:1 anti:syn
+
L4
Mg
B(C6F5)3
Mg(OTf)2
O
O
B(ArF)3
+
+
O
O
O
N
N
N
Ar
O
or
Ar
N
N
O
–
3q-ee, >95% yield
1.6:1 anti:syn
80:20 e.r. (anti)
68:32 e.r. (syn)
–
L4
O
(ArF)3B
H
(ArF)3B H
2q
O
VI
V
steric
repulsion
(c)
B(ArF)3
O
O
+
N
Ar
–
O
B(C6F5)3
Me
no co-catalyst:
Me
N
N
O
N
N
Ar
H
Ar
O
Me
H
(ArF)3B
H
Me
O
1a
rac-3r,
<5% yield
VII
L4
+
steric
repulsion
B(C6F5)3
O
O
Mg
B(ArF)3
+
+
N
O
Mg(OTf)2
O
O
Me
N
N
Ar
Me
O
or
Ar
N
Me
N
O
–
–
3r-ee, 88% yield
4.3:1 anti:syn
97:3 e.r. (anti)
98:2 e.r. (syn)
Me
L4
O
(ArF)3B
H
Me
(ArF)3B H
O
Me
VIII
2r
VII
Figure 3. The effect of chiral Lewis acid co-catalysts on enantioselective coupling of an N-alkylamine
and N-acryloyloxazolidinones. (a) Initial evaluation of chiral co-catalysts revealed that
Mg(OTf)2/bis(oxazoline) complexes catalyze stereoselective C–C bond formation. (b) Competing B(C6F5)3-
catalyzed racemic C–C bond forming reaction could deteriorate overall enantioselectivity. (c) The use of more
hindered N-acryloyl oxazolidinone suppresses the racemic process to achieve C–C bond formation with higher
enantioselectivity.
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With 2r as the electrophilic partner, fine-tuning of PyBOX ligands was performed (L3–
L12, Fig. 4a). With derivatives that possess a halophenyl moiety (L4, L7–L10), 3r was
generated in superior yield and stereoselectivity (compared to other alkyl- or aryl-substituted
ligands, L3, L5, L6, L11, L12). Whereas reaction with phenyl-substituted L3 gave 3r in low
yield (18%; 94:6 e.r. for anti and syn isomers), that of 3-chlorophenyl-subsituted L4 afforded 3r
in 88% yield as a 4.3:1 mixture of anti:syn isomers (97:3 and 98:2 e.r., respectively). The size
and position of the halogen substituent within the chiral catalyst can influence a reaction
outcome. With 3-fluorophenyl- (L7) or 3-bromophenyl-substituted (L8) ligands, the
transformations were moderately efficient (3r in 36% and 54% yield, respectively), but highly
enantioselective (97:3 e.r. (3r-anti) and 98:2 e.r. (3r-syn)). With 2-chlorophenyl- (L9) and 4-
chlorophenyl-substituted (L10) ligands, on the other hand, while 3r was isolated in higher yield
88% and 72%, respectively), there was some diminution in diastereo- and enantioselectivity (ca.
2:1 anti:syn, ca. 90:10 e.r. for 3r-anti). What is more, reactions performed in the presence of
meta-tolyl-substituted L11 or electron-withdrawing 3-trifluoromethylphenyl-substituted L12
were much less efficient (<20% yield). Although the precise origin of such notable effects by the
catalyst structure remains to be elucidated, the present findings suggest that non-covalent
interactions38,39 (e.g., –cation, – interactions) between ligand substituents and in situ-
generated iminium ion and/or Mg–enolate might be critical.
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With B(C6F5)3 and Mg(OTf)2/L4 as optimal catalysts, we surveyed a series of achiral and
chiral N-acryloyloxazolidinones (Fig. 4b). In contrast to dimethyl-substituted oxazolidinone 3r
was obtained in 88% yield and up to 98:2 e.r. (Fig. 3c), the less hindered 3q was generated in
>95% yield, but only in up to 80:20 e.r., presumably as a result of competing transformation
catalyzed by B(C6F5)3. Cyclohexyl-substituted 3s was obtained in anti:syn ratio of 5.6:1 (vs. 3q
(1.6:1) and 3r (4.3:1)), and enantiomerically pure N-acryloyloxazolidinones containing benzyl
(2t) or phenyl (2u-(S), 2u-(R)) moieties proved to be suitable starting materials as well. (R)-3-
Acryloyl-4-phenyloxazolidin-2-one (2u-(R)) represents the “matched” enantiomer with
Mg(OTf)2/L4 pairing to afford 3u-(R) in >95% yield and 6.8:1:0:0 d.r.; with 2u-(S), 3u-(S) was
obtained in 61% yield and 3.7:1:0:2.1 d.r. The significant impact of the chiral co-catalyst on
efficiency and stereoselectivity is evident as 3u-(R) was produced in just 14% yield and
2.5:2.5:1:1 d.r. in its absence. With B(C6F5)3 and Mg(OTf)2/L4 loadings reduced to 5.0 mol%,
3u-(R) was obtained in 93% yield (6.8:1:0:0 d.r.).
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(a)
10 mol% B(C6F5)3
O
O
O
O
10 mol% Mg(OTf)2
4
5
6
7
N
Ar
N
O
+
N
O
N
Ar
H
O
O
H
N
Me
Me
Me
Me
N
N
1a
2r
3r
R
R
12 mol%
8
CH2Cl2, 22 °C, 12 h
9
O
O
O
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O
O
N
N
N
N
N
Me
Ph
i-Pr
F
Cl
L3: 18% yield
L4: 88% yield
anti:syn 4.3:1
anti, 97:3 e.r.
syn, 98:2 e.r.
L5: 21% yield
anti:syn 4.2:1
anti, 55:45 e.r.
syn, 62:38 e.r.
L6: 71% yield
anti:syn 3.4:1
anti, 85:15 e.r.
syn, 89:11 e.r.
L7: 36% yield
anti:syn 3.5:1
anti, 97:3 e.r.
syn, 98:2 e.r.
anti:syn 3.5:1
anti, 94:6 e.r.
syn, 94:6 e.r.
O
N
O
O
N
O
N
O
N
Cl
N
Br
CF3
Me
Cl
L8: 54% yield
anti:syn 5.0:1
anti, 97:3 e.r.
syn, 98:2 e.r.
L10:
72% yield
L9: 88% yield
anti:syn 1.8:1
anti, 90:10 e.r.
syn, 97:3 e.r.
L12: 18% yield
anti:syn 3.5:1
anti, 90:10 e.r.
syn, 90:10 e.r.
L11: <10% yield
anti:syn 2.0:1
anti:syn 2.3:1
anti, 91:9 e.r.
syn, 98:2 e.r.
10 mol% B(C6F5)3
10 mol% Mg(OTf)2
(b)
O
R
O
O
O
+
N
O
N
Ar
N
O
N
Ar
H
12 mol% L4
R
H
R
R
CH2Cl2, 22 °C, 12 h
1a
2
3
O
O
O
O
O
O
O
O
N
N
Ar
N
Ar
N
O
Me
N
O
N
Ar
N
O
N
O
Ar
H
H
H
H
Me
Bn
H
3t, 66% yield
12:2.0:1:0 d.r.
3q, >95% yield
anti:syn 1.6:1
anti, 80:20 e.r.
syn, 68:32 e.r.
3r, 88% yield
3s, 79% yield
anti:syn 4.3:1
anti, 97:3 e.r.
syn, 98:2 e.r.
anti:syn 5.6:1
anti, 95:5 e.r.
syn, 98:2 e.r.
O
O
O
H
with 10 mol% B(C6F5)3 and
0 mol% Mg(OTf)2/L4:
3u-(R), 14% yield, 2.5:2.5:1:1 d.r.
O
N
Ar
N
H
O
N
N
O
(S)
Ar
(R)
H
Ph
H
Ph
with 5.0 mol% B(C6F5)3 and
5.0 mol% Mg(OTf)2/L4:
3u-(R), 93% yield, 6.8:1:0:0 d.r.
3u-(R), >95% yield
3u-(S), 61% yield
3.7:1:0:2.1 d.r.
6.8:1:0:0 d.r.
Figure 4. The influence of different PyBOX ligand and oxazolidinone substituents. (a) Notable
improvements in reaction efficiency and stereoselectivity were observed with halophenyl-substituted PyBOX
ligands. (b) -Amino amides were prepared in up to 98:2 e.r. from the achiral N-acryloyloxazolidinone. With
chiral oxazolidinones and Mg(OTf)2/L4, enantiomerically pure -amino amide 3u-(R) could be obtained after
separation of diastereomers by silica gel chromatography. Catalyst loading can be lowered to 5.0 mol%
without deterioration in yield of isolated and purified product.
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The catalytic protocol is amenable to scale-up; for instance, 5.0 mmol of 1a was
converted to 3u-(R) in 6.7:1:0:0 dr (>95% conv.; Fig. 5a). The diastereomers were separated
readily by silica gel chromatography to afford the major isomer in 1.47 g (70% yield; minor
diastereomer: 0.16 g, 8% yield). The predominant diastereomer was then converted to -amino
ester (5a), -amino acid (5b), and -amino alcohol (5c) in 64–91% yield and >99:1 er.
Furthermore, treatment of 3u-(R) with NaOMe in methanol led to the formation of 5d in 97%
yield. X-ray crystallographic analysis of 5d revealed its absolute configuration to be (R,R,R).40
The two-catalyst protocol is applicable to synthesis of a variety of N-alkylamines, affording 3v
and 4f–4h as separable mixtures of diastereomers (see the Supplementary Information for
details). After chromatographic separation, each of the diastereomers was converted into the
corresponding benzyl ester (5), and HPLC analysis showed that 3v and 4f–4h were generated in
>99:1 e.r. in either isomeric form. The presence of Mg(OTf)2/L4 was essential, as otherwise 4h
was produced in only 32% and 1:1 d.r. in its absence. Reactions of various N-substituted
pyrrolidines with 3-acryloyl-4,4-dimethyloxazolidin-2-one (2r) catalyzed by B(C6F5)3 and
Mg(OTf)2/L4 were investigated. While no desired product was obtained with N-
phenylpyrrolidine (see the Supplementary Information for details), 3w, 3x and 3y possessing the
hindered and electron-donating 2,6-dimethylaryl substituents were produced in 71, 69 and 70%
overall yield, respectively. An increase in enantioselectivity for both anti and syn diastereomers
was observed with more hindered para-t-Bu-substituted 3y (91:9 e.r. (3y-anti) and 98:2 e.r. (3y-
syn)) over para-H-substituted 3w (89:11 e.r. (3w-anti) and 93:7 e.r. (3w-syn)). Sterically
encumbered N,N,N-trialkylamines could also react with 2r to afford 4i (52% yield, 88:12 er) and
4j (46% yield, 96:4 er).
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8
(a)
(b)
5.0 mol% B(C6F5)3
O
major
diastereomer
70% yield, 1.47 g
O
H
O
H
O
5.0 mol% Mg(OTf)2
N
N
O
N
O
+
N
H
Ar
Ar
6.0 mol% L4
CH2Cl2, 22 °C, 12 h
H
Ph
Ph
minor
diastereomer
8% yield, 0.16 g
3u-(R), >95% conv.
1a, 5.0 mmol
2u-(R), 7.5 mmol
6.7:1:0:0 d.r.
O
O
9
O
O
1) H2O2, LiOH
2) AcCl, MeOH
1) H2O2, LiOH
2) CAN
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N
Ar
N
Me
Ph
O
N
H
OH
N
Ar
OMe
Me
Me
H
5b, 64% yield
>99:1 e.r.
3u-(R), major diastereomer
5a, 87% yield
>99:1 e.r.
NaOMe
MeOH
LiBH4
MeOH
Me
(R) O
(R)
N
Ar
N
OH
H
H
H
H
(R)
Me
N
Me
Me
Ph
HO
5c, 91% yield
>99:1 e.r.
MeO
5d, 97% yield
(c)
10 mol% B(C6F5)3
10 mol% Mg(OTf)2
1) H2O2
LiOH
R3
O
R
R3
O
O
R
R3
O
H
O
R1
R1
R1
H
O
N
O
N
+
N
N
O
O
N
OBn
R2
R2
2) BnBr
K2CO3
12 mol% L4
CH2Cl2, 22 °C, 12 h
R2
R
R
H
5
1
2
3, 4
Me
O
O
O
Me
O
Me
O
Me Me
N
O
H
Me
t-Bu
N
N
O
N
N
O
N
O
N
N
O
Me
i-Pr
TBSO i-Pr
Me
H
H
H
Ph
Me
Ph
Ph
Me
Ph
MeO
3v-major
4f-major
4g-major
4h-major
74% yield, >99:1 e.r.
4h-minor
58% yield, >99:1 e.r.
3v-minor
17% yield, >99:1 e.r.
47% yield, >99:1 e.r.
4f-minor
50% yield, >99:1 e.r.
4g-minor
24% yield, >99:1 e.r.
20% yield, >99:1 e.r.
10% yield, >99:1 e.r.
O
O
O
O
O
O
H
O
O
O
O
Me Me
N
N
N
t-Bu
N
O
N
O
N
O
Me
Me
Me
N
N
O
N
N
O
Me
Me
Me
Me
H
i-Pr
TBSO i-Pr
H
Me
Me
Me
H
Me
Me
Me
H
Me
Me
Me
t-Bu
Me
3x-anti
3y-anti
57% yield, 91:9 e.r.
3y-syn
3w-anti
4i
52% yield, 88:12 e.r.
4j
56% yield, 89:11 e.r.
3w-syn
15% yield, 93:7 e.r.
54% yield, 89:11 e.r.
3x-syn
15% yield, 93:7 e.r.
46% yield, 96:4 e.r.
13% yield, 98:2 e.r.
Figure 5. Synthesis of chiral -substituted amines. (a) As demonstrated through preparation of -amino
amide 3u-(R), the catalytic reactions are amenable to gram-scale operations. (b) The versatility of 3u-(R) was
demonstrated by its conversion into a -amino ester, a -amino alcohol and a -amino acid. The absolute
configuration of 3u-(R) was determined by X-ray crystallographic analysis of 5d. (c) A series of N-
alkylamines reacted with 2 to afford the corresponding -amino amides. For 3v and 4f–4h, diastereomers were
isolated by silica gel chromatography and then converted into -amino esters (5) that were determined to be
enantiomerically pure.
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We have developed a stereochemical model for reaction of the L3–Mg–enolate complex
with the in situ generated iminium ion by means of density functional theory (DFT) studies (Fig.
6). These investigations suggest that the enantiomers of the minor diastereomer are probably
formed via IX and X (G = 20.6 and 21.1 kcal/mol respectively), whereas XI and XII generate
enantiomers of the major diastereomer (G = 18.1 and 18.8 kcal/mol, respectively). High
enantioselectivity for the major as well as the minor diastereomer is due to effective blocking of
the re face of the Mg bound enolate (IX and XI). Nonetheless, we should note that highly
accurate modeling of diastereoselectivity is difficult, and depends strongly on attenuation of
dispersion interactions in solution.41,42 It is possible that modes other than IX and X might
similarly contribute to formation of the minor diastereomer (see the Supplementary Information).
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Figure 6. Stereochemical models to account for the observed sense of stereoselectivity. Stereochemical
model for reaction of L3Mgenolate complex with iminium ion; DFT studies were performed at the PBE0-
D3BJ/def2TZVPP//M06L/DF-def2SVP level of theory in CH2Cl2 (SMD solvation model). See the
Supplementary Information for details. Abbreviations: L3, PyBOX ligand; SMD, solvation model based on
density; Edisp = E(PBE0-D3BJ) – E(PBE0).
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CONCLUSIONS
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In brief, we have designed an efficient and diastereo- and enantioselective C–C bond
forming transformation by implementing the cooperative action of two non-precious metal-based
Lewis acid catalysts that possess overlapping functions. We illustrate that by proper tuning of
different features of structurally and electronically different Lewis acids and substrates, the
ability of Lewis acid catalysts to serve as a hydride acceptor from amines, or an activator of ,-
unsaturated compounds, can be adjusted. Accordingly, enhancements in both the efficiency and
stereoselectivity of C–C bond forming reactions between amines and ,-unsaturated
compounds can be attained without concomitant loss in enantioselectivity arising from any
undesirable mode of catalysis by the achiral Lewis acid component. The principles outlined
herein serve as a conceptual framework for the development of new processes that demand
separate and independently operational Lewis acidic co-catalysts whose functions might easily
overlap and the simultaneous use of which might initially seem to have a negative impact on
enantioselectivity. Studies aimed at achieving highly enantioselective C–C bond forming
reactions with a broader scope of hydride donors and pro-nucleophiles are in progress.
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ASSOCIATED CONTENT
Supporting Information Available: Experimental procedures and spectral data for all new compounds
(PDF). This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*wasa@bc.edu
Author Contributions
‡M.S. and J. Z. C. contributed equally to this paper.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
We are grateful for financial supports from the National Institutes of Health (GM-128695) and Boston
College. We are thankful to Professor Amir H. Hoveyda (BC) for helpful discussions. Dr. Juan del Pozo
del Valle, Dr. Filippo Romiti, Mr. Malte S. Mikus (BC), and Mr. Richard Y. Liu (MIT) are thanked for
their assistance with this project. We are grateful to Professor James P. Morken for a loan of PyBOX
ligands, and Dr. Bo Li for the X-ray crystallographic analysis.
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As suggested by one of the reviewers, the significant difference in reaction rate observed when the loading
of B(C6F5)3 is lowered from 5.0 mol% to 2.5 mol% suggests that the mechanism of the reaction proposed in
Figure 1d is not the complete picture. Formations of aggregates or other preorganized states requiring
multiple equivalents of B(C6F5)3 or substrate may be involved. Kinetic and spectroscopic studies carried
out using N-aryl pyrrolidine (1a) and isopropyl acrylate exhibited approximately second order dependence
with respect to B(C6F5)3 (see the Supplementary Information for details). Detailed mechanistic
investigations are being carried out.
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See
the
Supplementary Information for further details.
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