Catalytic Asymmetric Synthesis of Unprotected β2-Amino Acids

Article abstract of DOI:10.1021/jacs.1c00249

We report here a scalable, catalytic one-pot approach to enantiopure and unmodified β2-amino acids. A newly developed confined imidodiphosphorimidate (IDPi) catalyzes a broadly applicable reaction of diverse bis-silyl ketene acetals with a silylated aminomethyl ether, followed by hydrolytic workup, to give free β2-amino acids in high yields, purity, and enantioselectivity. Importantly, both aromatic and aliphatic β2-amino acids can be obtained using this method. Mechanistic studies are consistent with the aminomethylation to proceed via silylium-based asymmetric counteranion-directed catalysis (Si-ACDC) and a transition state to explain the enantioselectivity is suggested on the basis of density functional theory calculation.

Full text of DOI:10.1021/jacs.1c00249

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Catalytic Asymmetric Synthesis of Unprotected β2‑Amino Acids
Chendan Zhu, Francesca Mandrelli, Hui Zhou, Rajat Maji, and Benjamin List*
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ABSTRACT: We report here a scalable, catalytic one-pot approach to enantiopure and unmodified β2-amino acids. A newly
developed confined imidodiphosphorimidate (IDPi) catalyzes a broadly applicable reaction of diverse bis-silyl ketene acetals with a
silylated aminomethyl ether, followed by hydrolytic workup, to give free β2-amino acids in high yields, purity, and enantioselectivity.
Importantly, both aromatic and aliphatic β2-amino acids can be obtained using this method. Mechanistic studies are consistent with
the aminomethylation to proceed via silylium-based asymmetric counteranion-directed catalysis (Si-ACDC) and a transition state to
explain the enantioselectivity is suggested on the basis of density functional theory calculation.
mong the various classes of amino acids, β2-amino acids
Ahold a particularly prominent place and occur in an
increasing number of pharmaceuticals, natural products, and
drug candidates.1−11 However, while chemists, in recent years,
have delivered several methods toward the asymmetric
synthesis of β2-amino acids,12−39 catalytic approaches that
directly deliver the free, unmodified amino acid, without
requiring separate redox- or protecting group manipulations, to
our knowledge, have not yet been developed. Our inspirational
blueprint to address this challenge is a hypothetical chiral acid
catalyzed direct three-component-Mannich reaction of carbox-
ylic acids with formaldehyde and ammonia (eq 1).
to apply this approach to a TMSX*-catalyzed reaction of bis-
SKAs with a silylated aminomethyl ether, followed by
hydrolytic workup and extraction, which should deliver the
free, unmodified β2-amino acids and enable a simple catalyst
HX* recovery (eq 2, X*− = enaniopure counteranion). Here
we report on the realization of this concept with a general and
highly enantioselective imidodiphosphorimidate (IDPi) cata-
lyzed Mukaiyama Mannich-type reaction that delivers free β2-
amino acids with either aromatic or aliphatic substituents.
We chose α-benzyl bis-SKA 1a as our model substrate and
commercially available α-aminomethyl ether 2a as methylene
imine equivalent to initiate our studies (Table 1). An initial
catalyst exploration revealed that moderately acidic Brønsted
acids, such as chiral phosphoric acids (CPAs),67,68 even upon
warming, did not give any of the desired product, while
imidodiphosphoric (IDP)69 acids promoted the reaction at 0
°C to give racemic product (see the Supporting Information).
In contrast, the much more acidic IDPi catalysts provided both
sufficient reactivity and promising enantioselectivity (at −40
°C in toluene). Among our IDPi libraries, spirocyclopentyl-3-
fluorenyl substituted catalysts 3 turned out to be particularly
promising in terms of reactivity and enantioselectivity.
Extending the perfluoroalkyl sulfonyl chains in the inner core
further increased the enantioselectivity (entries 1−4). With
catalyst 3d, temperature and solvent were further optimized.
Lowering the temperature to −60 °C led to a slight increase in
enantioselectivity (entry 5). Importantly, with pentane as the
solvent instead of toluene, the enantiomeric ratio significantly
increased (entry 6). Furthermore, we tested IDPi catalysts 3e−
g, possessing an additional substituent at the fluorenyl group
(entries 7−10). Ultimately, we identified the tert-butyl
Unfortunately, except with malonic acid derivatives and
nonenantioselectively so,40,41 such a “dream-reaction” has not
yet been realized, arguably due to the current inability of
chemists to catalytically enolize carboxylic acids.42−44 An
attractive, even though less direct alternative would be a
Mukaiyama-style reaction of preformed bis-silyl ketene acetals
(bis-SKAs) with a formaldehyde imine equivalent. While this
transformation has been described in a nonenantioselective
fashion,45 asymmetric versions are entirely unknown. Encour-
aged by our recent studies on silylium-based asymmetric
counteranion-directed catalysis (Si-ACDC),46−66 we envisaged
Received: January 8, 2021
Published: March 1, 2021
© 2021 The Authors. Published by
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https://dx.doi.org/10.1021/jacs.1c00249
J. Am. Chem. Soc. 2021, 143, 3312−3317
3312

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a
heteroaromatic groups, such as 1k with naphthyl and 1l
bearing a thiophenyl substituent, were well tolerated, affording
the aminomethylation products 4k and 4l in excellent yield
and e.r..
Table 1. Reaction Development
Directly aryl-substituted bis-SKAs 1m−q were also exam-
ined and proved to be slightly less reactive, requiring 3 mol %
of catalyst 3h to furnish the corresponding products in
moderate to good yields and excellent enantioselectivities.
The scope of this transformation also includes simple,
aliphatic β2-amino acids. For example, bis-SKAs 1r−u, which
were generated from propionic acid, butyric acid, valeric acid,
and hexanoic acid, respectively, reacted smoothly, where the
enantioselectivities increased with longer alkyl chains.
Branched and cyclic alkyl groups (4v−x) and a methoxy-
(4y) and an olefin-substituted alkyl chain (4z) were all
tolerated and provided the desired products in good to
excellent yields and enantioselectivity. Interestingly, the
enantiopure bis-SKA 1A and its enantiomer ent-1A reacted
to products 4A and 4B in good yields and, in both cases,
featuring excellent and catalyst-controlled diastereoselectivity.
Limitations of our method include the use of bis-silyl ketene
acetals derived from α,α-disubstituted carboxylic acids and of
C-substituted imine sources, which display reduced reactivity
and lead to lower diastereoselectivity and enantioselectivity
(see the Supporting Information).
The absolute configuration of our obtained β2-amino acids
was determined from X-ray crystallographic analysis of
products 4h, 4i, and 4j. Furthermore, bromoalkyl substituted
bis-SKA 1C gave γ-aminobutyric acid uptake inhibitor (S)-
(+)-nipecotic acid70 5 in a one-pot operation in 84% yield and
97:3 e.r. when treating the initial reaction product with
triethylamine. The absolute configuration of amino acid 5 was
determined by converting it to the corresponding benzamide 6,
crystals of which were subjected to an X-ray crystallographic
a
Reactions were conducted on a 0.02 mmol scale: 1a:2 = 1.2:1.
b
1
Yields were determined by H NMR using mesitylene as internal
c
standard. After simplified workup, enantiomeric ratios (e.r.) were
measured by HPLC. See the Supporting Information for further
information.
1
analysis. H NMR investigation of the crude reaction mixture
revealed the existence of silylated product 4C, confirming that
cyclization occurs only upon base treatment. In fact, oligomers
were detected with concomitant formation of a small amount
of compound 5 if the reaction mixture was treated with only
water. Instead, treatment with benzoyl chloride and aqueous
potassium carbonate enabled the access to the corresponding
α-amidomethylated δ-valerolactone 7.
The practicality of our method was illustrated with two
scale-up experiments, involving an extremely concise product
purification and catalyst recovery. Using 1 mol % of catalyst
3h, 12 mmol of bis-SKA 1a and 10 mmol of imine precursor
2a gave 1.77 g of the free β2-amino acid 4a in 99% isolated
yield with an e.r. of 95.5:4.5. The workup of the reaction
mixture included a simple extraction with water and washing
with dichloromethane without further purification. Gratify-
ingly, catalyst 3h could be easily recovered in 96% yield from
the organic phase via flash chromatography and acidification.
Similarly, 2.84 g of the aliphatic free β2-amino acid 4u was
obtained in 98% isolated yield with an e.r. of 95:5 from 20
mmol of reagent 2a using only 0.5 mol % of catalyst 3h, which
was recovered in 95% yield from the organic phase after flash
chromatography and acidification.
substituted IDPi catalyst 3h as the optimal one, giving an e.r. of
96:4 in almost quantitative yield (entry 10).
We also studied the effect of the aminomethyl source on the
conversion and stereochemical outcome (entries 11−14).
Different ethers 2 with varying leaving groups were examined.
Interestingly, while the alkoxy group had only an insignificant
effect on the enantiocontrol, isopropyl ether 2c gave only poor
conversion at −60 °C (entries 10−12). These results are
consistent with the absence of the leaving group of ether 2 in
the enantiodetermining step and point toward an efficient
association of the bis(silyl)iminium ion with the IDPi anion.
This hypothesis could indeed be validated with a remarkably
broad scope of both aromatic and aliphatic bis-SKAs (Table
2). Various free β2-amino acids with electronically and
sterically diverse substituents were obtained in excellent yields
and enantioselectivities. For example, bis-SKAs 1a−c with
different methylene tether lengths between a phenyl group and
carboxylic acid functionality afforded the desired products in
similar excellent yields and enantioselectivities. Similarly, either
electron-neutral or electron-donating groups at the β-phenyl
ring of the bis-SKA gave the corresponding free β2-amino acids
in >90% yields with around 95:5 e.r. (4d−e). Notably, β2-
amino acids with electron-withdrawing groups (F, CF3, Cl),
either at the ortho-, meta-, or para-position of the β-phenyl ring
were generated in >90% yield with higher enantioselectivities
(>97:3 e.r.) (4f−j). Other substrates with aromatic and
Optionally, the crude products can be readily derivatized in
situ into a variety of synthetically useful building blocks such as
the corresponding N-Boc- or N-Fmoc-protected β2-amino
acids 8 and 9 by treating the reaction mixture with an
appropriate derivatization reagent.
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a
Table 2. Substrate Scope
a
Reactions were conducted on a 0.2 mmol scale: 1:2a = 1.2:1. Isolated yields with e.r. measured by HPLC. For derivatization, see Supporting
b
c
Information. e.r. measured by HPLC after derivatization. 3 mol % 3h. BzCl, benzoyl chloride; DCM, dichloromethane; TEA, triethylamine.
On the basis of the observation that the alkyl group of ethers
2 had an insignificant effect on the enantioselectivity (Table 1,
entries 11−14), coupled with literature results,45,58−66 we
envision a catalytic cycle as shown in Figure 1a. Accordingly,
the reaction commences with the in situ silylation of the IDPi
catalyst 3 by bis-SKA 1 to furnish the N-silylated catalyst I
and/or its diastereomeric O−Si-silatropomers.58−66 α-Amino-
methyl ether 2 then reacts with catalyst I, generating the
methylene iminium ion-IDPi anion pair II, simultaneously
liberating TMSOMe.45 Subsequently, bis-SKA 1 reacts with
the cationic methylene iminium ion in the anionic catalyst
pocket to give ion pair III. Intra-ion-pair silyl transfer from the
cationic product back onto its counteranion then furnishes the
silylated product IV and re-establishes the silylated catalyst I.
Finally, hydrolytic workup and extraction of the reaction
mixture delivers the free β2-amino acid 4. On the basis of a
detailed conformational search and subsequent Density
Functional Theory (DFT) optimization of ion pair II, we
tentatively propose a sterical hindrance-based selectivity model
(Figure 1b), where re-facial addition of bis-SKA 1 to methylene
iminium-IDPi anion pair II leads to the observed enantiomer
(see the Supporting Information).
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Accession Codes
CCDC 2056835−2056839 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Benjamin List − Max-Planck-Institut fu
45470 Mulheim an der Ruhr, Germany; orcid.org/0000-
0002-9804-599X; Email: list@kofo.mpg.de
̈
r Kohlenforschung,
̈
Authors
Chendan Zhu − Max-Planck-Institut fu
45470 Mulheim an der Ruhr, Germany
Francesca Mandrelli − Max-Planck-Institut fu
Kohlenforschung, 45470 Mulheim an der Ruhr, Germany
Hui Zhou − Max-Planck-Institut fur Kohlenforschung, 45470
Mulheim an der Ruhr, Germany
Rajat Maji − Max-Planck-Institut fu
Mulheim an der Ruhr, Germany; orcid.org/0000-0003-
2614-1795
̈
r Kohlenforschung,
̈
̈
r
̈
̈
̈
̈
r Kohlenforschung, 45470
̈
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00249
Notes
The authors declare the following competing financial
interest(s): We have a patent on the catalyst class.
Figure 1. (a) Proposed catalytic cycle. (b) Suggested re-facial
approach of the SKA onto the DFT optimized iminium-IDPi ion pair
II.
ACKNOWLEDGMENTS
■
We thank the generous support from the Max Planck Society,
the Deutsche Forschungsgemeinschaft (DFG, German Re-
search Foundation, Leibniz Award to B.L.) and under
Germany’s Excellence Strategy (EXC 2033-390677874-RE-
SOLV), the European Research Council (ERC, European
Union’s Horizon 2020 research and innovation program “C−
H Acids for Organic Synthesis, CHAOS” Advanced Grant
Agreement No. 694228), and the Horizon 2020 Marie
Sklodowska-Curie Postdoctoral Fellowship (to R.M., Grant
agreement No. 897130). The authors thank Benjamin
Mitschke for his help during the preparation of this manuscript
and several members of the group for crowd reviewing. We
also thank the technicians of our group and the members of
our NMR, MS, and chromatography groups for their excellent
service.
We have developed a traceless and scalable approach to
enantiopure free β2-amino acids via catalytic asymmetric
aminomethylation of bis-silyl ketene acetals. A variety of
aromatic and aliphatic bis-SKAs from carboxylic acids with
diverse electronics and sterics were tolerated in this trans-
formation and provided the corresponding amino acids in
excellent yields and enantioselectivities. The purification
process is extremely simple and concise and enables catalyst
recovery. We conducted control experiments that are
consistent with a mechanism that proceeds via Si-ACDC,
while preliminary computational studies suggest steric effects
to cause the observed enantioselectivity. As IDPi catalysts are
currently being commercialized, the methodology reported
here may facilitate the synthesis of pharmaceuticals, natural
products, and peptidic foldamers.
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c00249.
Experimental details and analytical data for all new
compounds, crystallographic data for compounds 4h, 4i,
and 4j, HPLC traces, NMR spectra, computational
studies, optimized structures, and Cartesian coordinates
(PDF)
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J. Am. Chem. Soc. 2021, 143, 3312−3317