Enantioselective Addition of α-Nitroesters to Alkynes

Article abstract of DOI:10.1002/anie.202014015

By using Rh–H catalysis, we couple α-nitroesters and alkynes to prepare α-amino-acid precursors. This atom-economical strategy generates two contiguous stereocenters, with high enantio- and diastereocontrol. In this transformation, the alkyne undergoes isomerization to generate a Rh^III–π-allyl electrophile, which is trapped by an α-nitroester nucleophile. A subsequent reduction with In powder transforms the allylic α-nitroesters to the corresponding α,α-disubstituted α-amino esters.

Full text of DOI:10.1002/anie.202014015

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 4599–4603
International Edition: doi.org/10.1002/anie.202014015
German Edition: doi.org/10.1002/ange.202014015
Tandem Catalysis
Enantioselective Addition of a-Nitroesters to Alkynes
Ryan T. Davison, Patrick D. Parker, Xintong Hou, Crystal P. Chung, Sara A. Augustine, and
Vy M. Dong*
Abstract: By using Rh–H catalysis, we couple a-nitroesters
and alkynes to prepare a-amino-acid precursors. This atom-
economical strategy generates two contiguous stereocenters,
with high enantio- and diastereocontrol. In this transformation,
the alkyne undergoes isomerization to generate a RhIII–p-allyl
electrophile, which is trapped by an a-nitroester nucleophile. A
subsequent reduction with In powder transforms the allylic a-
nitroesters to the corresponding a,a-disubstituted a-amino
esters.
motifs, methods for the enantio- and diastereoselective
preparation of a,a-disubstituted a-AAs bearing contiguous
stereocenters remain sought after;[6] emerging reports feature
pre-functionalized allylic partners. The direct addition of an
amino acid surrogate to a p-system represents an attractive
approach to a,a-disubstituted a-AAs. Towards this end, Zi
and co-workers exploited synergistic Pd/Cu catalysis for the
stereodivergent coupling of aldimine esters and 1,3-dienes.[7]
In a complementary approach, we propose using a Rh–
hydride (Rh–H) catalyst to couple a-nitrocarbonyls and
alkynes to generate the corresponding a-AA precursors.
This atom-economical[8] coupling exploits two simple func-
tional groups and provides rapid access to synthons for the
building blocks of life.[9]
By designing and synthesizing a-amino acids (a-AAs),
chemists have expanded the genetic code, shed light on
protein function, and enabled innovative medical applica-
tions.[1–3] The a,a-disubstituted a-AAs and related analogs
attract interest due to their metabolic stability, unique
conformations, and potent bioactivity (Figure 1).[4] Enan-
tioenriched a,a-disubstituted a-AAs are targeted by various
strategies, including phase-transfer catalysis, organocatalysis,
and transition-metal catalysis.[5] Despite an interest in these
On the basis of literature precedent,[10] we envisioned
a tandem catalytic cycle for the asymmetric coupling of a-
nitrocarbonyls 1 and alkynes 2 to yield a-AA synthons 3
(Figure 2). Wolf and Werner discovered that Rh–H com-
plexes isomerize alkynes (2) via an allene intermediate (4) to
form Rh–p-allyl species IV.[11] By using this isomerization, the
Breit laboratory achieved asymmetric and catalytic couplings
of alkynes with a wide-range of heteroatom nucleophiles to
afford branched allylic products.[12] In comparison, the
analogous coupling of alkynes with carbon nucleophiles
remains more limited, with only three asymmetric variants.[13]
We previously reported that aldehydes couple to alkynes with
high enantio- and diastereoselectivity when using a chiral Rh–
H catalyst in synergy with a chiral amine co-catalyst.[13a] Xing
and co-workers expanded this approach for the coupling of
ketones with alkynes, however, an achiral amine co-catalyst
furnishes the branched products with little to no diastereo-
control.[13c]
In related studies, we and Breit independently reported
that 1,3-dicarbonyls can couple to alkynes to generate
branched allylic carbonyl motifs.[14] Promising reactivity and
regioselectivity has been achieved. However, obtaining high
levels of enantio- and diastereoselectivity has been challeng-
Figure 1. Enantioselective addition of a-nitroesters to alkynes.
[*] R. T. Davison, Dr. P. D. Parker, X. Hou, C. P. Chung, S. A. Augustine,
Prof. Dr. V. M. Dong
Department of Chemistry, University of California, Irvine
Irvine, CA 92697 (USA)
E-mail: dongv@uci.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202014015.
Figure 2. Proposed mechanism for Rh-catalyzed allylation.
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Table 2: Survey of chiral ligands.[a]
ing. It occurred to us that a-nitrocarbonyls display compara-
ble chelation aptitude[15] and acidity (pKa = ca. 8)[16] to 1,3-
dicarbonyls. Thus, we imagined a-nitrocarbonyls would be
suitable nucleophiles for trapping Rh–p-allyl species IV. With
this design in mind, we set out to couple a-nitrocarbonyls and
alkynes with enantio- and diastereocontrol.
In preliminary studies, we discovered that various a-
nitrocarbonyls add to the commercially available alkyne 2a
(Table 1). Using a combination of [Rh(cod)Cl]2, dppf, and
diphenyl phosphate, we observe allylic a-nitroketone, a-
nitroester, and a-nitroamide products as single regioisomers
(> 20:1 rr) with moderate to high diastereoselectivity (5:1–
12:1 dr).[17] In accordance with previous reports, there is
a preference for the branched regioisomer, which bears two
contiguous stereocenters.[10a–d,12–14] Our findings complement
an enantioselective Pd-catalyzed a-nitroester allylation
reported by Ooi and co-workers.[18] In Ooiꢀs study, the use
of allylic carbonates affords linear regioisomers with one
stereocenter.
Next, we focused on an enantioselective variant for the
coupling of a-nitroesters with alkynes because the resulting
motifs are readily converted to a-AAs.[19] To identify the
appropriate chiral catalyst, we selected a-nitroester 1a and
alkyne 2a as the model substrates (Table 2). Using atropoiso-
meric bisphosphine ligands L1–L3 with a range of dihedral
angles,[20] we observe the allylic a-AA precursor 3aa with
moderate yields (45–53%) and enantioselectivities (85:15–
90:10 er). Ultimately, we found that commercial MeO-
BIPHEP ligand L6 affords 3aa in 90% yield with 97:3 er,
> 20:1 dr, and > 20:1 rr on preparative scale (1 mmol).[21,22]
This coupling relies on the use of alkynes as the unsaturated
partner instead of activated olefins, imines, propargylic
carbonates, and allylic leaving groups.[18,19] Therefore, we
explored the scope of this transformation to access unique b-
aryl-a-nitroester motifs.
[a] 1a (0.10 mmol), 2a (0.15 mmol), [Rh(cod)Cl]2 (4.0 mol%), chiral
ligand (8.0 mol%), (PhO)2P(O)OH (20 mol%), DCE (0.20 mL), 808C,
24 h. Yields determined by 1H NMR referenced to an internal standard.
[b] Isolated yield for a 1 mmol reaction.
glycine (3ba), leucine (3da), methionine (3ea), phenylalanine
(3 fa), 4-fluoro-phenylalanine (3ga), tyrosine (3ha), and
tryptophan (3ia) are generated with moderate to high yields
(34–84%) and excellent levels of enantioselectivity (ꢀ 95:5
er). The absolute configuration of 3 fa was confirmed by X-ray
crystallographic analysis.[21,22] In the case of lower yielding
substrates, we often recover a-nitroester 1.[21] The bulkier b-
branched a-nitroesters 1c and 1j do not couple to 2a to form
analogs of valine (3ca) and phenylglycine (3ja), respectively.
Alkyl-substituted esters 3ka–3na provide higher reactivity
than aryl ester 3oa. We see high levels of diastereocontrol
With this protocol, we explored the asymmetric coupling
of various a-nitroesters with 2a (Table 3). Analogs of ethyl-
À
(> 20:1 dr) for forming 3ka and 3la, which suggests the C C
bond is forged by catalyst control.
Table 1: Investigating various a-nitrocarbonyls.[a]
Table 4 captures results from our study on the addition of
1a to various alkynes 2. Aryl alkynes possessing a variety of
electronics and substitution patterns participate in the
asymmetric coupling (3ab–3al and 3ao). Alkynes bearing
halides (2b, 2c, 2h, 2i and 2l), carbonyls (2d and 2 f), and
extended p-systems (2o) transform to the corresponding
allylic a-nitroesters 3. Aryl alkynes with electron-donating
substituents (1g and 1j) display lower conversion under
standard conditions. Increasing the catalyst loading results in
improved yields of 3ag and 3aj (88% and 96%, respectively),
while maintaining high stereoselectivity (ꢀ 96:4 er and > 20:1
dr). The presence of an ortho-substituent on alkyne 2l imparts
lower reactivity (43%), presumably due to steric hindrance.
Pyridyl alkyne 2m converts to allylic a-nitroester 3am with
a higher catalyst loading. It appears that an aromatic or
heteroaromatic substituent on the alkyne is critical for
reactivity (see 3an). The absolute configuration of 3ao was
confirmed by X-ray crystallographic analysis.[21,22]
[a] 1 (0.10 mmol), 2a (0.15 mmol), [Rh(cod)Cl]2 (4.0 mol%), dppf
(8.0 mol%), (PhO)2P(O)OH (20 mol%), DCE (0.20 mL), 808C, 24 h.
Yields determined by 1H NMR referenced to an internal standard.
Cod =1,5-cyclooctadiene, dppf=1,1’-bis(diphenylphosphino)ferrocene,
DCE=1,2-dichloroethane.
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Table 3: a-Nitrocarbonyl scope.[a]
Table 4: Alkyne scope.[a]
[a] 1a (0.10 mmol), 2 (0.15 mmol), [Rh(cod)Cl]2 (4.0 mol%), MeO-
BIPHEP L6 (8.0 mol%), (PhO)2P(O)OH (20 mol%), DCE (0.20 mL),
808C, 24 h. Isolated yields. [b] [Rh(cod)Cl]2 (7.5 mol%) and L6
(15 mol%) instead of standard conditions. [c] 15:1 dr.
[a] 1 (0.10 mmol), 2a (0.15 mmol), [Rh(cod)Cl]2 (4.0 mol%), MeO-
BIPHEP L6 (8.0 mol%), (PhO)2P(O)OH (20 mol%), DCE (0.20 mL),
808C, 24 h. Isolated yields. [b] 6:1 dr. [c] Yields based on recovered
starting material (brsm): 3ea (76%), 3ga (96%), and 3ha (65%).
[d] [Rh(cod)Cl]2 (8 mol%) and L6 (16 mol%) instead of standard
conditions.
Further experiments provide support for the mechanism
depicted in Figure 2. First, we monitored a mixture of
[Rh(cod)Cl]2, MeO-BIPHEP L6, and diphenyl phosphate
Figure 3. Mechanistic studies.
1
by H NMR spectroscopy.[21] We observe a resonance in the
spectrum at À16.2 ppm. The observed resonance is consistent
with reported values for RhIII–H complexes.[23] This resonance
consumed. These results are in agreement with previous
reports that suggest maintaining a low concentration of allene
intermediate 4 slows competitive polymerization.[10i,12a,24,25]
Treating allylic a-nitroester 3aa with In powder readily
yields the corresponding a-amino ester 6 in 93% yield
[Eq. (1)]. This simple reduction allows for rapid access to a,a-
disubstituted a-amino esters that contain two contiguous
stereocenters, without stereoablation.
The use of Rh–H catalysis offers an approach to novel a-
AAs. The allylic a-AA precursors prepared contain an olefin
handle that is attractive due to its potential use for protein
modifications,[26] glycopeptide synthesis,[27] and cyclizations.[28]
1
disappears in the H NMR spectrum upon the addition of
alkyne 2a. Second, we subjected deuterated alkyne d-2a to
the standard reaction conditions (Figure 3A). We observe
deuterium scrambling into the b-, g-, and d-positions of allylic
a-nitroester d-3aa. The incorporation of hydrogen atoms at
the d-position of d-3aa supports reversible b-H elimination in
the isomerization pathway. Third, to examine the plausibility
of an allene intermediate in the catalytic cycle, we subjected
1-phenylallene (4a) to the standard conditions (Figure 3B).
We observe 3aa (14% yield) when using an excess of allene
4a. Moreover, the remaining amount of allene 4a is
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Acknowledgements
Funding provided by UC Irvine and the National Institutes of
Health (R35GM127071). We thank Dr. Milan Gembicky (UC
San Diego) for X-ray crystallographic analysis. We thank
Solvias AG for donating commercial MeO-BIPHEP L6.
Conflict of interest
The authors declare no conflict of interest.
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Keywords: alkynes · amino acids · nitroester · rhodium hydride ·
tandem catalysis
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Manuscript received: October 19, 2020
Revised manuscript received: November 16, 2020
Version of record online: January 7, 2021
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