Organocatalytic asymmetric synthesis of α-amino esters from sulfoxonium ylides

Article abstract of DOI:10.1039/d1sc02439f

Described here is the first organocatalytic asymmetric N-H insertion reaction of α-carbonyl sulfoxonium ylides. Without a metal catalyst, this reaction represents an attractive complement to the well-established carbene insertion reactions. As a stable surrogate of diazocarbonyl compounds, sulfoxonium ylides reacted with a range of aryl amines to provide efficient access to α-aryl glycines with excellent enantiocontrol in the presence of a suitable chiral phosphoric acid catalyst. The high stability and weak basicity of sulfoxonium ylides not only enable this protocol to be user-friendly and practically useful, but also preclude catalyst decomposition, which is crucial to the excellent amenability to electron-poor amine nucleophiles. Detailed mechanistic studies indicated that the initial protonation is reversible and the C-N bond formation is rate-determining.

Full text of DOI:10.1039/d1sc02439f

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Organocatalytic asymmetric synthesis of a-amino
esters from sulfoxonium ylides†
Cite this: DOI: 10.1039/d1sc02439f
All publication charges for this article Wengang Guo, Min Wang, Zhengyu Han, Hai Huang* and Jianwei Sun *ab
a
a
a
a
have been paid for by the Royal Society
of Chemistry
Described here is the first organocatalytic asymmetric N–H insertion reaction of a-carbonyl sulfoxonium
ylides. Without a metal catalyst, this reaction represents an attractive complement to the well-
established carbene insertion reactions. As a stable surrogate of diazocarbonyl compounds, sulfoxonium
ylides reacted with a range of aryl amines to provide efficient access to a-aryl glycines with excellent
enantiocontrol in the presence of a suitable chiral phosphoric acid catalyst. The high stability and weak
Received 4th May 2021
Accepted 28th June 2021
basicity of sulfoxonium ylides not only enable this protocol to be user-friendly and practically useful, but
also preclude catalyst decomposition, which is crucial to the excellent amenability to electron-poor
DOI: 10.1039/d1sc02439f
amine nucleophiles. Detailed mechanistic studies indicated that the initial protonation is reversible and
rsc.li/chemical-science
the C–N bond formation is rate-determining.
copper catalyst is essential for the observed reactivity (Scheme
). In contrast, a metal-free asymmetric variant of this trans-
Introduction
1
Enantioenriched a-amino esters, particularly a-aryl glycines, are formation without involving a carbene intermediate remains
7,8
not only useful building blocks in organic synthesis, but also unknown but highly desirable. Herein we report such an
important subunits widely present in biologically active mole- organocatalytic complementary process with excellent enan-
1,2
cules including pharmaceutical agents. Consequently, their tioselectivity and high efficiency (up to 97% ee).
asymmetric synthesis has been a topic of intense investigations
Recently, the laboratories of Burtoloso and us have demon-
2,3
in the past few decades. Among the various strategies, metal- strated that sulfoxonium and sulfonium ylides can be activated
catalyzed asymmetric N–H insertion of a-diazo esters via by chiral Brønsted acids either by weak hydrogen bonding or
a metal–carbene complex intermediate represents an attractive strong protonation to form s bonds, respectively, for asymmetric
6,7b
and straightforward approach, leading to high levels of enan- induction in the following bond-forming events. We wondered
tioselectivity, despite the concerns on the stability and safety whether such interactions could be utilized for the successful
issues associated with diazocarbonyl compounds particularly in amination of sulfoxonium ylides, which are much more stable
4
large scale synthesis. Recently, a-carbonyl sulfoxonium ylides and practically useful than their analogues, sulfonium ylides.
have been demonstrated as safe, stable, and versatile surrogates However, sulfoxonium ylides are less basic due to the polarized
4
for a-diazocarbonyl compounds. However, the exploitation of S]O bond. The decreased basicity may weaken the interaction
these species for catalytic asymmetric X–H bond insertion with the catalyst and thus lead to low reactivity and/or difficulty in
5
reactions remains scarce. During the preparation of this enantiocontrol. Nevertheless, their weaker basicity might also be
manuscript, Burtoloso and coworkers reported the use of advantageous and more compatible with acid catalytic systems,
a copper/squaramide co-catalyzed system to achieve the asym- e.g., obviation of catalyst decomposition (vide infra).
metric N–H insertion of a-carbonyl sulfoxonium ylides, leading
to various a-amino esters with moderate enantioselectivities (up
6
to 84% ee). Mechanistically, this reaction shares the same
copper carbene intermediate as those from diazo esters, i.e., the
a
Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of
Petrochemical Engineering, Changzhou University, Changzhou, China. E-mail:
huanghai@cczu.edu.cn
b
Department of Chemistry, The Hong Kong University of Science and Technology, Clear
Water Bay, Kowloon, Hong Kong SAR, China. E-mail: sunjw@ust.hk
1
13
19
†
Electronic supplementary information (ESI) available: H, C, and F NMR
spectra, HPLC chromatograms, and X-ray crystallographic data for 3f. CCDC
080963. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d1sc02439f
2
Scheme 1 Introduction to asymmetric N–H insertion of a-carbonyl
sulfoxonium ylides.
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anthryl substituent (C4) led to both high reactivity and prom-
ising enantioselectivity (>95% conversion within 15 min, 54%
Results and discussion
Initially we tested the catalytic activity of chiral thiourea A for ee, entry 6). This result prompted us to modify the catalyst
the reaction between a-carbonyl sulfoxonium ylide 1a and p- structure by introducing an additional phenyl group in the 9-
methoxyaniline 2a, since it has been the catalyst of choice for anthryl substituent. To our delight, this catalyst C5 led to
5
S–H insertion (Table 1, entry 1). Unfortunately, it resulted in a dramatic increase in enantioselectivity while maintaining
completely no reactivity. Furthermore, squaramide B alone was high chemical efficiency (79% ee). Notably, SPINOL-derived
also catalytically incompetent although it could serve as a co- CPAs were inferior (see the ESI for details†). Further screening
6
catalyst for the Cu-catalyzed N–H insertion (entry 2), which other solvents indicated that the reaction in polar Lewis basic
corroborated the essential role of a metal catalyst as well as the solvents, such as CH CN and THF, resulted in low reactivity and
3
carbene intermediate. We next resorted to stronger Brønsted no improvement in enantioselectivity, presumably due to
9
acids, chiral phosphoric acids (CPAs), in hope of achieving competing catalyst binding by these solvents. In contrast,
sufficient reactivity. With BINOL-derived bulky chiral phos- halogenated solvents, DCM and DCE, resulted in an obvious
phoric acid C1, which contains two tricyclohexylphenyl improvement in enantioselectivity, with the former being the
0
substituents in the 3,3 -positions, the desired transformation best (90% ee). Finally, decreasing the reaction temperature
proceeded cleanly to 50% conversion within 12 h at room could further boost the enantioselectivity (entries 13 and 14). To
ꢁ
temperature. Unfortunately, the desired product 3a was almost compensate the low reaction rate at ꢀ10 C, a higher concen-
racemic (entry 3). Next, we screened a range of other CPAs tration was employed, which proved to be optimal (95% ee, 93%
(
entries 4–7). Among them, we found that the one bearing the 9- isolated yield, entry 14).
We next investigated the substrate scope of this asymmetric
N–H insertion reaction for the synthesis of a-aryl glycines
(Scheme 2). First, various sulfoxonium ylide esters successfully
participated in this process with high efficiency and enantio-
selectivity. Different ester groups, including methyl, ethyl, allyl,
benzyl and phenyl esters, were all reactive to form the desired
products with good to high ee (3a–f, Scheme 2). The absolute
conguration of 3f was determined unambiguously by X-ray
crystallography. The enantioselectivity slightly decreased if the
size of this unit became larger. Substrates with various
substituents at the a-phenyl group were also examined. Of note,
the presence of a strong electron-withdrawing group, such as
a
Table 1 Evaluation of reaction conditions
3
k–m, resulted in slightly lower reactivity, which required
ꢁ
a relatively higher temperature (25 C) to reach complete
conversion. Furthermore, glycines bearing other a-aryl groups
(3r–s), such as naphthyl and thiophenyl, could also be synthe-
sized by this protocol with excellent enantioselectivity. The mild
reaction conditions were compatible with a diverse array of
functional groups, including alkene, aryl halide, ketone, nitrile,
and nitro groups. Finally, late-stage functionalization of natural
products was also possible with this process. For example,
installation of a glycine unit in estrone and cholesterol could be
achieved with high diastereocontrol.
As shown in Scheme 3, a broad range of aryl amines,
including electron-rich and electron-poor ones, could all serve
as good nucleophiles for this process. The reaction with elec-
tron-rich amines was generally faster than that with electron-
poor ones. It is also worth mentioning that good chemo-
selectivity was observed. For example, for aryl amines with other
nucleophilic positions, such as 8-aminonaphthalen-2-ol and 5-
aminoindole, the reaction occurred only in the amine motif
with excellent enantioselectivity. Aniline bearing a para-boronic
ester group worked equally well with the boronate moiety
untouched, which would allow further coupling or
ꢁ
b
b
Entry
HA*
Solvent
T/ C
t
Conv. (%)
ee (%)
1
2
3
4
5
6
7
8
9
A
B
DCM
DCM
25
25
25
25
25
25
25
25
25
25
25
25
0
24 h
24 h
12 h
6 h
0
0
50
>95
>95
>95
>95
>95
82
—
—
3
(S)-C1
(S)-C2
(S)-C3
(S)-C4
(S)-C5
(S)-C5
(S)-C5
(S)-C5
(S)-C5
(S)-C5
(S)-C5
(S)-C5
CHCl
CHCl
CHCl
CHCl
CHCl
3
3
3
3
3
20
21
54
79
79
80
72
90
88
93
95
6 h
15 min
15 min
14 h
14 h
14 h
15 min
15 min
48 h
EtOAc
THF
10
11
12
13
14
3
CH CN
70
DCM
DCE
DCM
DCM
>95
>95
>95
c
c,d
e
ꢀ10
48 h
>95 (93)
a
Reaction conditions: 1a (0.05 mmol), 2a (1.1 equiv.), 1catalyst
b
(
10 mol%), solvent (0.5 mL). Conversion was determined by H NMR functionalization.
analysis of the crude reaction mixture. The reaction was clean, which
means the yield was essentially the same as conversion. ee was
determined by chiral HPLC. Run with 0.2 mmol of 1a. c ¼ 0.2 M.
To demonstrate the robustness of our reaction, we also
carried out a gram-scale reaction. Without modication, highly
enantioenriched a-phenyl glycine 3a was obtained in 91% yield
c
d
e
Yield in parentheses was the isolated yield.
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a
b
ꢁ
Scheme 2 Scope of sulfoxonium ylides. 1 (0.2 mmol), 2 (0.22 mmol), catalyst (10 mol%) in DCM (1.0 mL). Run with (R)-C5 at 25 C.
and 95% ee (Scheme 4). The catalyst was also recovered in 95%
Some mechanistic studies were conducted to help under-
yield. It has been known that 3a is a useful precursor to free stand the reaction pathway (Fig. 1). First of all, we monitored
10a
amine 4, which is a synthetic precursor to a wide range of the reaction progress of the standard reaction of 1a and 2a, and
useful molecules, including drugs and drug candidates with the product ee remained constant during the reaction progress,
2i,10
various biological activities as well as chiral catalysts.
suggesting that this is not simple kinetic resolution (Fig. 1a).
a
b
Scheme 3 Scope of amines. 1 (0.2 mmol), 2 (0.22 mmol), catalyst (10 mol%) in DCM (1.0 mL). Yield in parentheses was based on the recovered
c
starting material. The corresponding methyl esters were used as the substrates.
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results are consistent with the C–N bond formation as the rate-
determining step.
In addition, non-linear effect (NLE) experiments were per-
formed (Fig. 1d). Under the standard conditions (10 mol% of
C5, ꢀ10 ꢁC), the reaction exhibited a strong positive NLE.
Interestingly, reducing the catalyst loading to 5 mol% while
maintaining other reaction parameters led to less pronounced
deviation of this positive NLE. Furthermore, if the reaction was
run at room temperature with 5 mol% of catalyst, a perfect
linear relationship was observed. These observations prompted
us to test the catalyst solubility under similar conditions.
ꢁ
Indeed, upon cooling to ꢀ10 C, a solution of racemic catalyst
C5 in DCM at a concentration equivalent to that with 5 mol%
and 10 mol% catalyst loadings resulted in immediate precipi-
tation. In contrast, a clear solution (equivalent to 5 mol%)
remains homogeneous at room temperature, even aer
standing for 24 h. Moreover, the solutions of enantiopure C5 of
the same concentration (5 or 10 mol%) did not form any
Scheme 4 Gram-scale synthesis of 3a and its utility.
ꢁ
precipitate even at ꢀ10 C. These observations indicated that
the formation of less soluble heterochiral aggregates might be
responsible for the observed NLE, and the reaction concentra-
Moreover, we employed a F-labeled amine to study the reaction
1
9
kinetics using in situ F NMR analysis (Fig. 1b). The time-
dependence curves of both product formation and amine
consumption were in agreement with rst-order kinetics with
12
tion and temperature may inuence the outcome.
On the basis of the above experiment, we proposed the
following mechanism (with 1e as an example, Scheme 5).
Despite the weak basicity of the sulfoxonium ylide, its interac-
tion with CPA still favors the formation of an adduct (e.g., IM).
The reversible nature of this step also provides a pathway for
epimerization of the a-chiral center. Next, the rate-determining
nucleophilic attack by amine delivers the product 3e. The chiral
phosphate anion controls the stereochemistry in the C–N bond
formation via dynamic kinetic resolution. Although efforts to
obtain the pure intermediate for characterization were fruitless,
11
respect to amine. All these results suggested that the C–N
bond formation is likely the rate-determining step and the
sulfoxonium protonation is reversible. We were also able to
identify a linear correlation between log (e. r.) and the substit-
uent electronic parameter (s ) of the a-phenyl group in the
p
sulfoxonium substrate (Fig. 1c). The negative slope indicated
that the electron-withdrawing substituent does not help in
enantiocontrol. Combined with the lower reaction rates with
the electron-withdrawing substituent at this position, these
Fig. 1 Mechanistic studies. (a) Time-dependence of product ee in the formation of 3a. (b) Reaction progress in the formation of 4e. (c)
31
Correlation of enantioselectivity and the substituent electronic effect. (d) Non-linear effects. (e) Dependence of chemical shift in P NMR on the
31
ratio of 1e and C5 in the NMR titration experiment. (f) Study of the catalyst resting state based on P NMR signals of C5 in different mixtures.
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Conclusions
We have developed the rst organocatalytic asymmetric N–H
insertion reaction of a-carbonyl sulfoxonium ylides, a safe and
stable surrogate of diazocarbonyl compounds. In contrast to the
well-established asymmetric insertion reactions of diazo-
carbonyl compounds, this protocol does not require a metal
catalyst or involve a carbenoid intermediate. With the suitable
chiral phosphoric acid catalyst, a range of sulfoxonium ylides
could be sufficiently activated and achieve excellent enantio-
control in the C–N bond formation. This protocol provided
efficient access to a wide range of a-aryl glycines with high
enantioselectivity. The mild conditions also tolerated various
functional groups. More importantly, the high stability and
weak basicity of sulfoxonium ylides not only enable this
protocol to be more user-friendly and particularly useful, but
also preclude catalyst decomposition, which is crucial to the
excellent amenability to electron-poor amine nucleophiles. A
series of detailed mechanistic studies provided important
insights into understanding the reaction pathway, in which the
initial protonation is reversible and the C–N bond formation is
rate-determining.
Scheme 5 Proposed mechanism.
it is important to note that the solution of this intermediate did
not gradually decompose, for example, to form phosphate ester
5, even aer an extended period of time. It could even be used to
catalyze the reactions of other pairs of reactants with excellent
yield and enantioselectivity. This is in sharp contrast to the
situation using sulfonium ylides, which suffered from
competitive and irreversible catalyst decomposition in this way
and thus required high catalyst loading for electron-poor
amines or no reactivity with many strong electron-poor ami-
7
b
nes. Indeed, absence of catalyst decomposition with sulfoxo-
nium ylides led to a substantial improvement in the amenability
to electron-poor amines of the present protocol.
To further substantiate this mechanism, the interaction
between the catalyst and sulfoxonium ylide was also investi-
3
1
gated by titration experiments using P NMR analysis (Fig. 1e),
which indicated that the protonation step is reversible favoring
Data availability
11b
the intermediate. Furthermore, based on the in situ NMR
Details of experimental procedures, characterizations, and copy
of NMR spectra as well as HPLC traces are provided in the ESI.
experiment, the intermediate is the catalyst resting state
(Fig. 1f). These results are all consistent with the proposed
mechanism.
Author contributions
Finally, we have also assessed the sensitivity of this trans-
formation to various reaction parameters to understand the
robustness of this protocol according to the method developed
W. G., Z. H. and M. W. conceived and performed the experi-
ments and wrote the paper. H. H. performed and directed the
experiments. J. S. conceived and directed this work and wrote
the paper. All the authors discussed the results and commented
on the manuscript.
13
by Glorius and coworkers. In this set of experiments, the
inuence of the reaction temperature, concentration, catalyst
loading, water and oxygen content, as well as reaction scale on
yield and enantioselectivity was systematically examined using
the standard reaction between 1a and 2a as the reference. Only
one parameter was varied in each experiment. The changes in
product yield and enantioselectivity of 3a in comparison to the
standard reaction conditions were illustrated using a radar
chart (Fig. 2, see the ESI for details†). The results indicated that
this organocatalytic asymmetric N–H insertion of sulfoxonium
Conflicts of interest
There are no conicts to declare.
Acknowledgements
ylide is remarkably robust. Variation of the above mentioned Financial support was provided by the National Natural Science
parameters had little inuence on the excellent outcome, indi- Foundation of China (91956114), Hong Kong Research Grants
cating the good reproducibility of this protocol.
Council (16302318, 16303420), Innovation and Technology
Commission (ITC-CNERC14SC01) and Jiangsu specially
appointed professors program. We thank Herman H. Y. Sung
for help in structural elucidation by X-ray crystallography and
Shijia Li and Chang Liu for assistance in experiments.
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k /k ¼ 1.0 (see the ESI for details†), which suggested that
4
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H
D
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might be due to additional CPA interaction with the
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Chem. Sci.
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