Cu-Catalyzed [3 + 3] Cycloaddition of Isocyanoacetates with Aziridines and Stereoselective Access to α,γ-Diamino Acids

Article abstract of DOI:10.1021/acs.orglett.8b01948

We report herein an efficient Cu-catalyzed formal [3 + 3] cycloaddition of isocyanoacetates with readily available aziridines of different substitution patterns, which provides a practical access to valuable 1,4,5,6-tetrahydropyrimidine derivatives. In pa

Full text of DOI:10.1021/acs.orglett.8b01948

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cu-Catalyzed [3 + 3] Cycloaddition of Isocyanoacetates with
Aziridines and Stereoselective Access to α,γ-Diamino Acids
Germaine Pui Yann Kok, Hui Yang, Ming Wah Wong,* and Yu Zhao*
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Republic of Singapore 117543
S
* Supporting Information
ABSTRACT: We report herein an efficient Cu-catalyzed
formal [3 + 3] cycloaddition of isocyanoacetates with readily
available aziridines of different substitution patterns, which
provides a practical access to valuable 1,4,5,6-tetrahydropyr-
imidine derivatives. In particular, the use of enantiopure
aziridines delivers disubstituted tetrahydropyrimidines bearing
a 1,3-diamino unit in good yields as a single stereoisomer
(>20:1 dr, > 99% ee). The heterocyclic products can also be
easily converted to synthetically useful amino alcohol
derivatives or α,γ-diamino acids.
N-Heterocycles such as 1,4,5,6-tetrahydropyrimidines represent
key structural motifs found in natural and synthetic molecules
displaying a wide array of biological activities. Ectoine and
hydroxyectoine (Scheme 1a), for example, are osmoprotectants
Since the introduction of isocyanoacetates by Ugi in 1961,6
they have served as efficient building blocks for the synthesis of
N-heterocycles due to the immense potential of their versatile
functionality.7 A plethora of examples have been reported on the
stereoselective cycloaddition reactions of isocyanoacetates with
various π-systems including carbonyls,8 imines,9 α,β-unsatu-
rated carbonyls,10 and activated alkenes or alkynes11 to furnish a
wide range of five-membered heterocycles. In contrast, cyclo-
additions of isocyanoacetates with other synthons bearing three
or more atoms to form six-membered or larger heterocycles
remains largely unexplored. In 2014, Liu and co-workers
reported the first formal [3 + 3] cycloaddition of azomethine
ylides or N-iminoisoquinolinium ylides with isocyanoacetate
using Cu or Ag catalysis to yield di- and tricyclic 1,2,4-triazines in
moderate to good yields as a racemate.12 During the preparation
of this manuscript, Ghorai and co-workers also published an
elegant domino ring-opening cyclization of aziridines with p-
toluenesulfonylmethyl isocyanide (TosMIC) to furnish tetrahy-
dropyrimidine derivatives with good yields and excellent
diastereoselectivity.3c
Scheme 1. [3 + 3] Cycloaddition of Isocyanoacetates
Our group has been interested in the application of
isocyanoacetates to new modes of heterocyclic synthe-
sis.8f,9e,10c,11e,f,13 In particular, we were attracted to the discovery
of suitable partners for the synthesis of heterocycles other than
five-membered ones. We hypothesized that the use of epoxides
or aziridines would prove fruitful due to the favorable opening of
the strained rings. Herein, we report our efforts on the [3 + 3]
cycloaddition of simple and substituted N-Ts aziridines with
isocyanoacetates to deliver tetrahydropyrimidines in excellent
stereopurity (Scheme 1b). These products can also be readily
produced by bacteria that protects biopolymers from extreme
conditions.1 Despite the great utility of these compounds, their
preparation in a diastereo- and enantioselective manner remains
a challenging objective in synthetic organic chemistry.2,3
In addition to tetrahydropyrimidines, the related 1,3-diamino-
containing acyclic compounds have also shown great potential in
medicinal chemistry. α,γ-Diaminobutyric acid, for instance, is
shown to cause inhibition of M1 aminopeptidases that is
associated with a wide range of cellular functions.4 To the best of
our knowledge, access to such diamino acid derivatives in a
highly diastereo- and enantioselective fashion remains elusive in
the literature.5
Received: June 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01948
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
converted to synthetically valuable amino alcohols as well as α,γ-
diamino acids in nearly quantitative yield and enantiopurity.
We initiated our investigation using simple aziridine 1a and α-
benzyl-substituted isocyanoacetate 2a as the model substrate
(Table 1). No reaction between 1a and 2a was observed simply
Scheme 2. Scope for [3 + 3] Cycloaddition of 1a with
Substituted Isocyanoacetates
a
a
Table 1. Optimization of [3 + 3] Cycloaddition
b
entry
LA
ligand
base
solvent
yield (%)
1
2
3
4
5
6
7
8
9
−
−
−
−
PPh3
PPh3
DBU
DBU
DBU
DBU
−
DBU
DBU
DBU
DBU
DBU
DBU
KOtBu
THF
THF
THF
THF
THF
THF
THF
THF
<2
<2
<2
65
13
42
70
72
76
Sc(OTf)3
BF3·OEt2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
a
b
See the SI for the detailed procedure. Reaction carried out at 60 °C.
stereoselectivity was obtained at all. To achieve highly
stereoselective access to valuable tetrahydropyrimidines, we
then turned our attention to an alternative approach focusing on
the cycloaddition of enantiopure monosubstituted aziridines.
These compounds are easily accessed from commercially
available enantiopure amino alcohols or through catalytic
enantioselective aziridination of alkenes.14 If high diastereose-
lectivity can be achieved for the formal [3 + 3] cycloaddition,
disubstituted tetrahydropyrimidines could be accessed in high
stereopurity.
c
PPh3
Bipyridine
XantPhos
DPPF
DPPF
DPPF
DPPF
THF
d
10
11
12
toluene
MeCN
toluene
83
29
<2
CuI
CuI
a
The reaction was conducted using 1a (1.0 equiv), 2a (1.5 equiv), LA
(10 mol %), ligand (20 mol %), and base (20 mol %) in solvent (0.1
b
M) at 40 °C, unless stated otherwise. 1H NMR yield using 1,3,5-
c
To test our hypothesis, aziridine 1b was reacted with methyl
isocyanoacetate 2f using CuI and DPPF (Scheme 3). To our
trimethoxybenzene as internal standard. 1.0 equiv of 2a was used.
Isolated yield.
d
Scheme 3. Diastereoselective [3 + 3] Cycloaddition
in the presence of bases such as DBU (entry 1). The use of Lewis
acids such as Sc(OTf)3 and BF3·OEt2 (entries 2 and 3) did not
furnish the desired product. However, to our delight, with the
use of CuI and PPh3, we were able to obtain the desired product
3a in moderate yields (entry 4). The reaction proceeded poorly
without the use of base (entry 5). When 1.0 equiv of
isocyanoacetate 2a was used, a drop in the yield was observed
(entry 6). This was postulated to be due to the self-dimerization
of 2a, thus reducing the amount of reactant. Next, the screening
of ligands (entries 7−9) showed DPPF to be the optimal choice,
producing 3a in 76% yield. Screening of various solvents showed
that nonpolar solvents such as toluene proved superior, giving
83% isolated yield (entry 10) as compared to polar solvents such
as MeCN, which only gave 29% yield (entry 11). The choice of
bases was critical to the reaction as other strong bases such as
KOtBu did not produce 3a (entry 12).
With the optimal conditions in hand, the scope of substituted
isocyanoacetates for the reaction with 1a was examined (Scheme
2). Alkyl substituents such as benzyl, methyl, and allyl (3a−c)
were well tolerated, giving good yields of 83%, 79%, and 84%,
respectively. Bulky groups such as isopropyl (3d) achieved only
49% yield. Aryl substituents such as phenyl (3e) were also well
tolerated, giving a good yield of 77%. Next, the variation of the
ester groups on unsubstituted isocyanoacetates was also
examined. Increasing the bulk of the ester groups from methyl
to tert-butyl (3f−i) was well tolerated, with the yields becoming
slightly lower as the steric bulk of the ester groups increased.
In attempts to realize an enantioselective variant of this
transformation, we screened a large number of chiral ligands
including bisphosphine, monophosphine, P,N-, as well as
diamine-based ones (see the SI for details). However, good
enantioselectivity was not achieved. In many other cases, no
delight, the reaction proceeded with excellent regioselectivity
and diastereoselectivity (>20:1), albeit with a moderate yield.
Further optimization of the reaction conditions (see the SI for
details) gave an improved yield of 86% for this process by using
(PPh3)3CuCl as the catalyst and Cs2CO3 as the base (Scheme
4). When enantiopure 1b (>99% ee) was used, 5a was obtained
as a single stereoisomer with a complete transfer of
enantioselectivity.
We then turned our attention to explore the scope of the
reaction. Increasing the steric bulk of the ester group on the
unsubstituted isocyanoacetate was well tolerated to yield 5a−d
in good yields. The reactions with aziridines bearing alkyl groups
such as methyl, isopropyl, 2-isobutyl, and tert-butyl afforded
desired products 5e−h with good yields. The relative and
absolute configuration of 5f was unambiguously assigned by
single-crystal X-ray analysis, and other compounds were
assigned by analogy. Aziridine 1g bearing a tertiary TMS ether
moiety reacted with methyl isocyanoacetate 2f to afford 5i in a
moderate yield of 57%. The reaction also tolerated a chiral
aziridine bearing an indole moiety, and 5j was obtained with a
good yield of 78%. It is noteworthy that we did not observe any
corrosion of diastereoselectivity across all examples of
compound 5. Aryl-substituted aziridines were also examined,
the use of which unfortunately led to the formation of a mixture
(by nonregioselective addition to aziridines) in low efficiency.
B
DOI: 10.1021/acs.orglett.8b01948
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. [3 + 3] Cycloaddition with Enantiopure
Aziridines
Scheme 6. Calculated Conformations of 5e and 5e′
a
To showcase the utility of our methodology, we began by
conducting a gram-scale reaction of enantiopure aziridine 1b
and methyl isocyanoacetate 2f. Under the standard conditions,
the reaction proceeded smoothly to produce 5a with good yield
of 89% and excellent diastereoselectivity (>20:1) (Scheme 7a).
Scheme 7. Gram-Scale Synthesis and Derivatization of
Tetrahydropyrimidines
a
b
See the SI for the detailed procedure. The reaction was carried out
for 48 h. TMS = trimethylsilyl.
We were pleasantly surprised that aziridine 1i containing a
hydroxy group did not furnish 5 but instead underwent a double
cyclization to give bicyclic 6 in 53% yield as a single diastereomer
(Scheme 5a). It is interesting to note that the diastereoselectivity
Reduction of 5a with lithium aluminum hydride in anhydrous
THF afforded cyclic amino alcohol 8 with high yields (93%) and
complete retention of enantioselectivity (Scheme 7b). Amino
alcohols and their derivatives are oftentimes used as ligands,
chiral auxiliaries, and chiral organocatalysts.15 Therefore,
compound 8 bearing a six-membered ring structure and multiple
stereocenters may find application as a valuable amino alcohol
ligand.
Scheme 5. Reactions of Aziridines 1i and 1j
Incorporation of nonstandard amino acids is reported to be
able to engineer protein−drug conjugates and even to extend the
function and properties of biomaterials.16 We proposed that the
hydrolysis of 5 would yield an α,γ-diamino acid. When 5a was
subjected to 2 M aqueous HCl at reflux temperature, the
reaction proceeded smoothly to produce α,γ-diamino acid 9a in
nearly quantitative yields in an enantiopure form (Scheme 8).
Scheme 8. Synthesis of α,γ-Diamino Acids 9
of 6 is different from that of 5. To further expand the scope of
this methodology, we subjected meso-aziridine 1j to react with
isocyanoacetate 2f (Scheme 5b). From this, we obtained
compounds 7a and 7b in 32% yield and 34% yield, respectively.
The relative configuration of 7a was assigned by single-crystal X-
ray analysis. The relative configuration of 7b was assigned by 2D
COSY and selective 1D NOESY (see the SI for more details).
To gain more insight on the various diastereoselectivity of
these reactions, DFT calculations at M06-2X/6-311+G(2d,
p)//M06-2X/6-31G* level with G16 software suits were carried
out. SMD was used as the solvation model with THF as the
solvent. The energy difference between 7a and 7b was found to
be very small (0.14 kcal/mol). In contrast, 5e was found to be
2.91 kcal/mol lower in free energy than its corresponding
diastereomer 5e′. Conformational studies suggest that the steric
hindrance from the neighboring Ts group has a more significant
effect than 1,3-axial interaction of two substituents (Scheme 6).
These data strongly suggests that the cycloaddition products can
epimerize under the basic conditions. While 5e was formed as a
single trans-isomer, the intramolecular lactonization in 6 served
as a driving force for the formation of the cis-isomer.
Compounds 5b and 5c also underwent smooth transition to the
desired diamino acids 9b and 9c, respectively. This represents a
valuable addition to the library of unnatural amino acids that
serve as building blocks and molecular scaffolds in combinatorial
libraries.
In conclusion, we have developed an efficient and stereo-
selective [3 + 3] cycloaddition of isocyanoacetates with
aziridines to furnish substituted tetrahydropyrimidines. These
heterocycles can be readily reduced to form cyclic amino
alcohols. Simple hydrolysis of them gave α,γ-diamino acids. The
unique structure of the products reported herein, bearing
C
DOI: 10.1021/acs.orglett.8b01948
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
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S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01948.
Experimental details and characterization data (PDF)
Accession Codes
CCDC 1850997−1850998 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chmwmw@nus.edu.sg.
*E-mail: zhaoyu@nus.edu.sg.
ORCID
Hui Yang: 0000-0002-0435-6763
Ming Wah Wong: 0000-0003-2162-1220
Yu Zhao: 0000-0002-2944-1315
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(13) Zhao, Y.; Kok, G. P. Y.; Shao, P.-L.; Liao, J.-Y.; Ismail, S. N. F. S.;
Yao, W.; Lu, Y. Chem. - Eur. J. 2018, 24, 10513.
̈
(14) (a) Muller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905. (b) Sweeney,
J. B. Chem. Soc. Rev. 2002, 31, 247.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(15) (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,
We are grateful for the financial support from A*STAR SERC
(R-143-000-648-305), the Singapore EDB, and GlaxoSmithK-
line (R-143-000-564-592). We thank Dr. Ji’en Wu for helpful
discussions.
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Kjærsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296.
(c) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, Ł.; Jørgensen, K. A.
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