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J Am Chem Soc. Author manuscript; available in PMC 2019 August 22.
Published in final edited form as:
J Am Chem Soc. 2018 August 22; 140(33): 10593–10601. doi:10.1021/jacs.8b06699.
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 Wasa*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, United States
Abstract
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Catalytic transformations of α-amino C–H bonds to afford valuable enantiomerically enriched αsubstituted 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 α,β-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 β-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.
Graphical Abstract
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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
*
Corresponding Author: wasa@bc.edu.
‡Author Contributions
M.S. and J. Z. C. contributed equally to this paper.
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.
Notes
The authors declare no competing financial interest.
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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 reactions between unactivated substrates is
an important and largely unresolved problem in enantioselective catalysis.
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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 α-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 α,β-unsaturated molecules to afford β-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 Nalkylamines 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 α,β-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 β-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
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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 hydrogenbond 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 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 α,β-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 Mannichtype 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 α,β-unsaturated compounds. Thus, under redox-neutral conditions and
without the need for a precious metal salt,25 we would synthesize α-substituted amines 3,
entities that are difficult to access by “direct” Mannich strategies. Many of the reported
methods for β-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 α-amino radical,26 an iminium ion,27–30 an αhalo, an α-hydroxyl or an α-metalated species.31–35 Catalytic stereoselective α-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.
RESULTS AND DISCUSSION
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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 β-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 nonpolar aromatic hydrocarbon, 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,
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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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A variety of α,β-unsaturated carbonyl compounds and related electrophiles may be used in
reaction with N-arylpyrrolidine 1a to generate the corresponding α-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 α-quaternary carbon center,
in 97% yield. Dimethyl 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).
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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-MethoxyN,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 β-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 Narylpyrrolidine (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(4phenyl-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
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(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)3activated VII, the latter of which might suffer from severe steric repulsion between the gemdimethyl 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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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 3trifluoromethylphenyl-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., π–cation, π–π
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 Nacryloyloxazolidinones 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%
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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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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 βamino ester (5a), β-amino acid (5b), and β-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 Nalkylamines, 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-4,4dimethyloxazolidin-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 2,6dimethylaryl 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-Hsubstituted 3w (89:11 e.r. (3w-anti) and 93:7 e.r. (3w-syn)). Sterically encumbered N,N,Ntrialkylamines could also react with 2r to afford 4i (52% yield, 88:12 er) and 4j (46% yield,
96:4 er).
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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 (ΔG = 20.6 and 21.1 kcal/mol respectively), whereas XI and
XII generate enantiomers of the major diastereomer (ΔG = 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).
CONCLUSIONS
In brief, we have designed an efficient and diastereo- and enantioselective C–C bond
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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 α,β-unsaturated compounds, can be adjusted. Accordingly, enhancements in
both the efficiency and stereoselectivity of C–C bond forming reactions between amines and
α,β-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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Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
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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37. 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.
38. Phipps RJ; Hamilton GL; Toste FD Nat. Chem 2012, 4, 603–614. [PubMed: 22824891]
39. Brak K; Jacobsen EN Angew. Chem., Int. Ed 2013, 52, 534–561.
40. The absolute configuration of the minor diastereomer was determined as (R)-N-((R)-2-hydroxy-1phenylethyl)-2-((S)-1-(4-methoxy-2,6-dimethylphenyl)pyrrolidin-2-yl)propanamide. See the
Supplementary Information for further details.
41. Yang L; Adam C; Nichol GS; Cockroft SL Nat. Chem 2013, 5, 1006–1010. [PubMed: 24256863]
42. Pollice R; Bot M; Kobylianskii IJ; Shenderovich I; Chen P J. Am. Chem. Soc 2017, 139, 13126–
13140. [PubMed: 28823152]
J Am Chem Soc. Author manuscript; available in PMC 2019 August 22.
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Figure 1. Structures and reactivity of cooperative catalysts.
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(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 α,β-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 βamino carbonyl compounds atom economically and under redox neutral conditions.
J Am Chem Soc. Author manuscript; available in PMC 2019 August 22.
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Figure 2. Coupling of N-alkylamines and α,β-unsaturated compounds through B(C6F5)3catalyzed hydride abstraction.
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The values correspond to yields of isolated and purified products. Diastereomeric ratio (d.r.)
values were determined by analysis of the unpurified product mixture through analysis of 1H
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.
J Am Chem Soc. Author manuscript; available in PMC 2019 August 22.
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Figure 3. The effect of chiral Lewis acid co-catalysts on enantioselective coupling of an Nalkylamine and N-acryloyloxazolidinones.
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(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.
J Am Chem Soc. Author manuscript; available in PMC 2019 August 22.
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Figure 4. The influence of different PyBOX ligand and oxazolidinone substituents.
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(a) Notable improvements in reaction efficiency and stereoselectivity were observed with
halophenyl-substituted PyBOX ligands. (b) β-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 β-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.
J Am Chem Soc. Author manuscript; available in PMC 2019 August 22.
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Figure 5. Synthesis of chiral α-substituted amines.
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(a) As demonstrated through preparation of β-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 β-amino ester, a β-amino alcohol and a β-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 β-amino amides. For 3v
and 4f–4h, diastereomers were isolated by silica gel chromatography and then converted into
β-amino esters (5) that were determined to be enantiomerically pure.
J Am Chem Soc. Author manuscript; available in PMC 2019 August 22.
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Figure 6. Stereochemical models to account for the observed sense of stereoselectivity.
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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; ΔΔEdisp =
ΔΔE(PBE0-D3BJ) – ΔΔE(PBE0).
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J Am Chem Soc. Author manuscript; available in PMC 2019 August 22.
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Table 1.
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Evaluation of Reaction Parameters
entry
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a
Lewis acid
a,b
(mol%)
solvent
reaction time
(h)
yield (%), anti:syn
3a
yield (%)
3b
1
B(C6F5)3
5.0
CH2CI2
12
>95, 2.3:1
<5
2
B(C6F5)3
5.0
Et2O
12
94, 2.3:1
<5
3
B(C6F5)3
5.0
THF
12
26, 1.9:1
<5
4
B(C6F5)3
5.0
Toluene
12
81, 2.4:1
5
5
B(C6F5)3
5.0
Benzene
12
>95, 2.4:1
<5
6
B(C6F5)3
5.0
Benzene
0.5
>95, 2.4:1
<5
7
B(C6F5)3
2.5
Benzene
48
84, 1.7:1
<5
8
none
0
Benzene
12
0
0
9
BF3•OEt2
5.0
Benzene
12
0
0
10
BPh3
5.0
Benzene
12
0
0
Conditions: 1-(4-Methoxy-2,6-dimethylphenyl)pyrrolidine (0.2 mmol), methyl acrylate (0.3 mmol), Lewis acid, solvent (0.3 mL), under N2,
22 °C.
b
Yields were determined by 1H NMR analysis of unpurified product mixtures with mesitylene as the internal standard. See the Supporting
Information for details.
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J Am Chem Soc. Author manuscript; available in PMC 2019 August 22.