Synthesis of Enantioenriched γ-Amino-α,β-unsaturated Esters Utilizing Palladium-Catalyzed Rearrangement of Allylic Carbamates for Direct Application to Formal [3 + 2] Cycloaddition

Article abstract of DOI:10.1021/acs.orglett.7b00471

An efficient synthesis of enantioenriched γ-amino-α,β-unsaturated esters was developed by utilizing the palladium-catalyzed decarboxylative rearrangement of enantioenriched allylic carbamates possessing an ester moiety at the allylic position. The reaction proceeded in good yield with a high degree of chirality transfer by making use of Xantphos as a superior ligand for the catalyst. The products directly participated in the formal [3 + 2] cycloaddition reaction with tosyl isocyanate under Br?nsted base catalysis to afford enantioenriched β,γ-diamino acid derived imidazolidin-2-ones as versatile chiral building blocks.

Full text of DOI:10.1021/acs.orglett.7b00471

Letter
pubs.acs.org/OrgLett
Synthesis of Enantioenriched γ‑Amino-α,β-unsaturated Esters
Utilizing Palladium-Catalyzed Rearrangement of Allylic Carbamates
for Direct Application to Formal [3 + 2] Cycloaddition
Azusa Kondoh,† Yuji Kamata,‡ and Masahiro Terada*,†,‡
†Research and Analytical Center for Giant Molecules, Graduate School of Science and ‡Department of Chemistry, Graduate School of
Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
S
* Supporting Information
ABSTRACT: An efficient synthesis of enantioenriched γ-
amino-α,β-unsaturated esters was developed by utilizing the
palladium-catalyzed decarboxylative rearrangement of enan-
tioenriched allylic carbamates possessing an ester moiety at the
allylic position. The reaction proceeded in good yield with a
high degree of chirality transfer by making use of Xantphos as
a superior ligand for the catalyst. The products directly participated in the formal [3 + 2] cycloaddition reaction with tosyl
isocyanate under Brønsted base catalysis to afford enantioenriched β,γ-diamino acid derived imidazolidin-2-ones as versatile chiral
building blocks.
group and an electrophilic alkene moiety, would directly
participate in the formal [3 + 2] cycloaddition reaction with
unsaturated compounds (X = Y) to afford nitrogen-containing
heterocyclic compounds. In particular, we intended to develop
a chirality transfer reaction of readily available enantioenriched
allylic carbamate 1, which has an ethoxycarbonyl group as an
electron-withdrawing group, to provide enantioenriched γ-
amino-α,β-unsaturated esters 2 for application to the synthesis
of enantioenriched nitrogen-containing heterocyclic com-
pounds by the formal [3 + 2] cycloaddition reaction (Scheme
1b). Conventionally, enantioenriched γ-amino-α,β-unsaturated
esters 2 are prepared through the Wittig-type reaction of N-
protected α-amino aldehydes, which are highly sensitive to the
base-induced epimerization and require a tedious multistep
synthesis.6 Direct catalytic methods for the synthesis of those
compounds with a broad scope are still limited.7 Herein, we
report that the decarboxylative rearrangement of enantioen-
riched allylic carbamates 1 proceeds under Pd(0) catalysis with
good chirality transfer to afford enantioenriched γ-amino-α,β-
unsaturated esters 2. The formal [3 + 2] cycloaddition reaction
of 2 with isocyanates under Brønsted base catalysis providing
enantioenriched β,γ-diamino acid derived imidazolidin-2-ones 3
was also investigated.
he decarboxylative [3,3]-rearrangement of allylic carba-
Tmate is one of the most useful methods for the synthesis
of allylic secondary amines, which are important building blocks
in organic synthesis.1 The starting allylic carbamates can be
easily prepared by treating the corresponding allylic alcohols
with isocyanates, and the reaction generally proceeds under
mild conditions by using transition-metal catalysts such as
Pd(II),2 Pd(0),3 Ir(I),4 and Au(I) complexes.5 Recently, as an
application of this method to asymmetric synthesis, catalytic
enantioselective reactions were developed in which achiral
linear allylic carbamates were employed as substrates to provide
chiral branched allylic amines having a monosubstituted alkene
moiety.2c,d,4 We envisioned that allylic carbamates possessing
an electron-withdrawing group at the allylic position would be
applicable to this transformation3a to provide allylic amines
having an electron-deficient alkene moiety that can function as
a Michael acceptor (Scheme 1a). We also expected that the
products, which possess both a nucleophilic secondary amino
Scheme 1. Reaction Design
The initial study was conducted with enantioenriched allylic
carbamate (R)-1a (96% ee) having phenyl groups on both the
nitrogen and the alkene terminus. The enantioenriched
substrates 1 were synthesized from the enantioenriched α-
hydroxy esters, which were easily prepared by palladium-
catalyzed alkenylation of ethyl glyoxylate with vinylsilanes8 or
diastereoselective reduction of chiral β,γ-unsaturated α-oxo
esters,9 with isocyanate.10 Compound 1a was treated with a
Received: February 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00471
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Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Table 2. Substrate Scope
b
c
ee of 1
(%)
yield
es
b
c
entry ligand (mol %)
solvent
toluene
time (h) yield (%) es (%)
entry
R1
R2
2
(%)
(%)
1
PPh3 (20)
20
8
66
<1
63
71
1
2
3-MeOC6H4 Ph
98
98
99
95
90
95
95
96
96
96
2b
2c
2d
2e
2f
75
60
94
96
82
94
43
98
93
97
96
95
2
none
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
4-ClC6H4
1-naphthyl
2-MeC6H4
Ph
Ph
Ph
d
3
DPPE (10)
12
5
39
84
94
94
95
59
83
95
93
3
78
4
DPPB (10)
91
4
65
e
5
DPPF (10)
25
9
11
5
2-MeOC6H4 Ph
35
6
DPEPhos (10)
Xantphos (10)
P(OEt)3 (20)
P(OiPr)3 (20)
Xantphos (10)
Xantphos (10)
Xantphos (10)
Xantphos (10)
55
6
nBu
Me
Ph
Ph
Ph
2g
2h
2i
44
7
8
86
7
52
8
4
95
8
4-MeOC6H4
4-ClC6H4
80
9
11
8
86
9
Ph
2j
(48)
82
10
11
12
13
(49)
(46)
<1
82
10
Ph
2-naphthyl
2k
a
1,4-dioxane
CH3CN
toluene
8
Conditions: (R)-1 (0.20 mmol), Pd(OAc)2 (0.010 mmol), Xantphos
b
8
(0.020 mmol), toluene (3.0 mL). Yields of isolated products. NMR
yield is shown in parentheses. Enantiomeric excess was determined by
chiral stationary-phase HPLC analysis. es (enantiospecificity) = (ee %
d
c
8
97
a
Conditions: (R)-1a (0.20 mmol), Pd(OAc)2 (0.010 mmol), ligand
(0.020−0.040 mmol), solvent (2.0 mL). Yields of isolated products.
NMR yields are shown in parentheses. Enantiomeric excess was
d
b
of product)/(ee % of substrate). The reaction was conducted for 12
e
c
h. The reaction was conducted for 24 h.
determined by chiral stationary-phase HPLC analysis. es (enantiospe-
d
cificity) = (ee % of product)/(ee % of substrate). Toluene (3.0 mL)
was used.
result, 4-methoxyphenyl- and 2-naphthyl-substituted 1i and 1k
underwent the reaction without any problem to afford the
corresponding products 2i and 2k in good yields, respectively.
The reaction of 4-chlorophenyl-substituted 1j proceeded with a
high degree of chirality transfer, but the yield was moderate
because of the instability of product 2j. Substrates having an
alkyl group on the nitrogen instead of an aryl group did not
undergo the reaction. In addition, the reactions of tosyl- and
benzoyl-substituted substrates resulted in complex mixtures of
products. It is worth noting that the reaction could take place
between allylic alcohol 4a and phenyl isocyanate in a one-pot
fashion without isolation of allylic carbamate 1a (Scheme 2).
catalytic amount of Pd(OAc)2 in the presence or absence of
PPh3 in toluene at room temperature for 20 h (Table 1, entries
1 and 2). Whereas no reaction occurred in the absence of PPh3,
the decarboxylative rearrangement proceeded in the presence
of PPh3 to provide γ-amino-α,β-unsaturated ester 2a in 66%
yield with 71% es (68% ee, es (enantiospecificity) = (ee % of
product)/(ee % of substrate)). Ligand screening was carried
out to increase both the chemical yield and the degree of
chirality transfer (entries 3−9). A variety of bidentate
phosphines as well as phosphites were examined, and Xantphos
provided the best result; 2a was obtained in 86% yield with
95% es (entry 7). The screening for the solvent revealed that
toluene was the solvent of choice (entries 7 and 10−12).
Decreasing the concentration of the reaction mixture improved
the enantiospecificity (entry 13).11 The absolute configuration
of product 2a was unambiguously determined to be S by single-
crystal X-ray diffraction analysis after transformation through
the formal [3 + 2] cycloaddition reaction (vide infra).12
Scheme 2. One-pot Synthesis from (R)-4a
With the optimum reaction conditions in hand, the scope of
substrate 1 was investigated (Table 2). At first, the substituent
at the alkene terminus was examined (entries 1−5). The
reaction of 3-methoxyphenyl- and 4-chlorophenyl-substituted
1b and 1c proceeded with high degrees of chirality transfer
(entries 1 and 2). 1-Naphthyl-substituted 1d provided the
desired product with a moderate degree of chirality transfer
(entry 3). Whereas the reaction of 2-methyl-substituted 1e
proceeded smoothly to provide 2e in good yield with a high
degree of chirality transfer (entry 4), the reaction of 2-methoxy-
substituted 1f was sluggish and the ee value of 2f was
significantly decreased (39% ee) compared with that of starting
1f (90% ee) (entry 5). Alkyl groups, such as the n-butyl group
and methyl group, were applicable to this reaction. Compounds
1g and 1h underwent the reaction with high degrees of chirality
transfer albeit in moderate yields (entries 6 and 7). Next, the
substituent on the nitrogen was examined (entries 8−10). As a
At this point, in order to acquire information on the reaction
mechanism, a crossover experiment was carried out (Scheme
3). Equimolar amounts of enantioenriched (R)-1i (96% ee) and
Scheme 3. Crossover Experiment
B
DOI: 10.1021/acs.orglett.7b00471
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Organic Letters
Letter
racemic 1b were treated with catalytic amounts of Pd(OAc)2
and Xantphos. As a result, four products, including normal
products 2i and 2b and crossover products 2a and 2l, were
obtained in almost equal amounts. In addition, 2i and 2a, which
have an allyl moiety derived from enantioenriched 1i, were
obtained with high ee values, whereas 2b and 2l were obtained
in an almost racemic fashion. This result clearly indicates that
the reaction involves the intermolecular addition to a π-allyl
palladium intermediate.
problem to afford the corresponding enantioenriched imidazo-
lidin-2-ones.
Both decarboxylative rearrangement and the formal [3 + 2]
cycloaddition were sufficiently reliable to perform in gram scale
(Scheme 6).
Scheme 6. Gram-Scale Synthesis of 2a and 3a
Scheme 4. Plausible Catalytic Cycle
Finally, the transformation of the products of the formal [3 +
2] cycloaddition reaction was conducted (Scheme 7). Treat-
ment of 3a with an excess amount of LiAlH4 resulted in the
reduction of both the urea moiety and the ester moiety to
provide diamino alcohol 5 in good yield (Scheme 7a).
Hydrolysis under basic conditions provided lactam 6 (Scheme
7b). Both substituents on the nitrogens of 3i were removable.
The 4-methoxyphenyl group could be removed by treatment
with ceric ammonium nitrite in acetonitrile/H2O. The tosyl
group of 7 could be cleaved by treatment with magnesium in
methanol to afford 8. In all cases, erosion of enantiomeric
purity did not occur.
On the basis of this result, a plausible catalytic cycle for the
rearrangement is depicted in Scheme 4. The catalytic cycle is
initiated by the oxidative addition of an allylic carbamate to
Pd(0) generated in situ via the reduction of Pd(OAc)2,
providing cationic π-allyl palladium intermediate A and anionic
species B. Then, the external nucleophilic attack of B on A at
the γ-position of the ester moiety occurs with concomitant
decarboxylation to afford the product and regenerated Pd(0).13
The regiospecificity of this reaction is consistent with the
common feature of the nucleophilic attack on π-allyl palladium
intermediate having an electron-withdrawing group.14 In this
chirality transfer reaction, (R)-1a is transformed into (S)-2a.
This stereochemical outcome is rationalized as follows. The
oxidative addition occurs with the inversion of configuration at
the α-position of the ester moiety. The following nucleophilic
addition to cationic π-allyl palladium intermediate A proceeds
with the inversion of configuration at the γ-position of the ester
moiety prior to the competing racemization of A.
Scheme 7. Transformation of Products
Next, the formal [3 + 2] cycloaddition reaction of γ-amino-
α,β-unsaturated esters with isocyanates, which directly provides
enantioenriched β,γ-diamino acid derived imidazolidin-2-ones,
was investigated (Scheme 5).15,16 As a result, tosyl isocyanate
was a suitable partner, and the reaction proceeded smoothly
under Brønsted base catalysis.17 Treatment of 2a with 1.5 equiv
of tosyl isocyanate in 1,4-dioxane at room temperature followed
by addition of a catalytic amount of N,N-diisopropylethylamine
provided 3a in good yield with perfect diastereoselectivity.12
During the reaction, erosion of enantiomeric purity did not
occur. The reactions of 2g and 2i also proceeded without any
Scheme 5. Formal [3 + 2] Cycloaddition
In conclusion, we have newly developed an efficient synthesis
of enantioenriched γ-amino-α,β-unsaturated esters by utilizing
the palladium-catalyzed decarboxylative rearrangement of
enantioenriched allylic carbamates possessing an ester moiety
at the allylic position. The reaction proceeded in good yield
with a high degree of chirality transfer by making use of
Xantphos as a superior ligand for the catalyst. The products,
C
DOI: 10.1021/acs.orglett.7b00471
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Organic Letters
Letter
(8) Aikawa, K.; Hioki, Y.; Mikami, K. J. Am. Chem. Soc. 2009, 131,
13922.
(9) Sugimura, H.; Yoshida, K. J. Org. Chem. 1993, 58, 4484.
which possess both a nucleophilic secondary amino group and
an electrophilic alkene moiety, directly participated in the
formal [3 + 2] cycloaddition reaction with tosyl isocyanate
under Brønsted base catalysis to afford enantioenriched β,γ-
diamino acid derived imidazolidin-2-ones. The newly devel-
oped sequential methodology offers facile access to versatile
chiral building blocks. Research on further applications of this
methodology is in progress.
(10) See the Supporting Information for details.
(11) Screening of other conditions, such as palladium precatalysts
and the amount of Xantphos, was also conducted. See the Supporting
Information for details.
(12) CCDC no. 1526561 for 3a. See the Supporting Information for
details.
(13) At this stage, the timing of decarboxylation is not clear.
According to the literature (ref 3b), generation of anilide through
decarboxylation prior to nucleophilic attack seems to be feasible.
However, an alternative mechanism, in which the nucleophilic attack
occurs prior to decarboxylation, cannot be ruled out. See ref 4.
(14) Garrido, J. L.; Alonso, I.; Carretero, J. C. J. Org. Chem. 1998, 63,
9406 and references cited therein.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00471.
■
S
(15) (a) Cardillo, G.; Orena, M.; Penna, M.; Sandri, S.; Tomasini, S.
Synlett 1990, 1990, 543. (b) Ciclosi, M.; Fava, C.; Galeazzi, R.; Orena,
M.; Gonzalez-Rosende, M. E.; Sepulveda-Arques, J. Tetrahedron:
́
́
Asymmetry 2004, 15, 1937.
Experimental procedures, screening of reaction con-
ditions, and characterization data (PDF)
Crystallographic data for 3a (CIF)
(16) For selected examples on synthetic studies of enantioenriched
β,γ-diamino acid-derived imidazolidin-2-ones and their applications,
AUTHOR INFORMATION
■
see: (a) Bouiller
Biomol. Chem. 2011, 9, 394. (b) Hoang, C. T.; Bouiller
Johannesen, S.; Zulauf, A.; Panel, C.; Pouilhes, A.; Gori, D.; Alezra, V.;
̀
e, F.; Guillot, R.; Kouklovsky, C.; Alezra, V. Org.
Corresponding Author
*E-mail: mterada@m.tohoku.ac.jp.
ORCID
̀
e, F.;
̀
Kouklovsky, C. J. Org. Chem. 2009, 74, 4177. (c) Hoang, C. T.; Alezra,
V.; Guillot, R.; Kouklovsky, C. Org. Lett. 2007, 9, 2521.
(17) A preliminary study was conducted with racemic 2a. See the
Supporting Information for details.
Azusa Kondoh: 0000-0001-7227-8579
Masahiro Terada: 0000-0002-0554-8652
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from MEXT (Japan) and
a Grant-in-Aid for Scientific Research from the JSPS.
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DOI: 10.1021/acs.orglett.7b00471
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