Asymmetric synthesis of α,α-disubstituted amino acids by cycloaddition of (E)-ketonitrones with vinyl ethers

Article abstract of DOI:10.1021/ol500483t

Original acyclic (E)-α,α-dialkylketonitrones bearing a chiral auxiliary on their nitrogen atom were synthesized and successfully employed for the asymmetric synthesis of α,α-disubstituted amino acids using regio- and stereocontrolled 1,3-dipolar cycloaddition reactions with vinyl ethers. N-Glycosyl chiral auxiliaries were found to provide excellent exo- and π-facial stereocontrol. The obtained enantiopure cycloadducts were selectively transformed into functional α,α-disubstituted amino acids and related β-peptides through the highly regioselective opening of an intermediate quaternary anhydride.

Full text of DOI:10.1021/ol500483t

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of α,α-Disubstituted Amino Acids by
Cycloaddition of (E)‑Ketonitrones with Vinyl Ethers
Xiaofei Zhang,†,‡ Pascale Cividino,† Jean-Franco
̧
is Poisson,† Pavlo Shpak-Kraievskyi,‡ Mathieu Y. Laurent,‡
Arnaud Martel,‡ Gilles Dujardin,*,‡ and Sandrine Py*,†
†Dep
́
artement de Chimie Molec
́
ulaire (SERCO) UMR 5250, ICMG FR-2607, CNRS-Universite
́
Joseph Fourier, BP 53, 38041
Grenoble Cedex 09, France
‡LUNAM Universite
France
́
du Maine, IMMM UMR 6283 CNRS, Equipe Methodologie et Synthese Organique, 72085 Le Mans Cedex 09,
́
̀
S
* Supporting Information
ABSTRACT: Original acyclic (E)-α,α-dialkylketonitrones
bearing a chiral auxiliary on their nitrogen atom were
synthesized and successfully employed for the asymmetric
synthesis of α,α-disubstituted amino acids using regio- and
stereocontrolled 1,3-dipolar cycloaddition reactions with vinyl
ethers. N-Glycosyl chiral auxiliaries were found to provide
excellent exo- and π-facial stereocontrol. The obtained
enantiopure cycloadducts were selectively transformed into
functional α,α-disubstituted amino acids and related β-
peptides through the highly regioselective opening of an intermediate quaternary anhydride.
α,α-Disubstituted amino acids (DAA, quaternary amino acids)
are highly valuable building blocks for the synthesis of
peptidomimetics. Their limited conformational freedom induces
specific restrictions in the secondary structure of oligomers in
which they have been introduced.1 However, the practical
methods for their asymmetric synthesis remain limited.2
Recently, original ketonitrones bearing an ester function α to
Figure 1. Hydroxylamines used as chiral auxiliaries for 1,3-DC involving
ketonitrones.
the CN bond were prepared and found to exhibit an exclusive
(E)-configuration in solution.3,4 Interestingly, these stereo-
chemically defined ketonitrones undergo 1,3-dipolar cyclo-
additions (1,3-DC)5 with various dipolarophiles under thermal
conditions, yielding trans-isoxazolidines in high yields when
opposed to vinyl ethers. The resulting isoxazolidines bearing a
quaternary stereogenic center α to a nitrogen atom could be
successfully transformed into α,α-disubstituted amino acid
derivatives (Scheme 1).6
As enantioselective methods for cycloadditions involving α-
carboxy nitrones and vinyl ethers are still unavailable5b,7 or
poorly efficient,8 we postulated that the diastereoselective 1,3-
DC reaction involving “aspartic” ketonitrones equipped with a
chiral auxiliary at the nitrogen atom would be a robust method to
access enantiopure 5-alkoxyisoxazolidines. In a previous
communication, we have reported the preparation of ketoni-
trones from the α-methylbenzylamine-derived auxiliary ent-1a
(Figure 1) and their thermal 1,3-DC reactions with vinyl ethers.
The latter proved highly exo-selective, but the facial selectivity
was very modest (dr ≈ 70:30).3 In the present work, other N-
hydroxylamines9 have been screened as auxiliaries to evaluate
their steering power in 1,3-DC reactions.
Hydroxylamines 1a,b and 2a,b were easily prepared from the
corresponding primary amines.10 (R)-N-Hydroxy-1-(2,4,6-
triisopropylphenyl)ethylamine (1b) was first considered, as
this auxiliary had already proved superior to its α-methylbenzyl-
amine analogue in our hands.11 We also considered chiral
auxiliaries from the chiral pool, such as amino acid derivatives
2a12 and 2b,13 and the mannose-derived chiral auxiliary 3 (Figure
1). The latter, introduced by Vasella in the 1970s,14 has recently
gained new interest, particularly with the contributions from the
groups of Carreira,15 Skrydstrup,16 and Bode.17
Scheme 1. 1,3-Dipolar Cycloaddition Approach to α,α-
Disubstituted Amino Acid Derivatives
Received: February 14, 2014
Published: March 21, 2014
© 2014 American Chemical Society
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Letter
Ketonitrones 5a−g were synthesized in high yields by
condensation of dialkyl acetylene dicarboxylates 4a (DMAD)
or 4b (DTAD) with chiral N-hydroxylamines 1−3 (Table 1).3,18
nitrones 5a−g and vinyl ethers 6a,b in a sealed tube, the expected
cycloadducts were obtained with complete regiocontrol and
excellent exo stereoselectivities. As a consequence, the major
trans cycloadducts were produced in high yields, with various
degrees of facial selectivities (Table 2).21 As nitrone 5a was found
to be thermally unstable, the reaction of 5a with 6b was
performed at 50 °C (Table 2, entry 1). Under these conditions,
isoxazolidines 7 were isolated in 78% yield, as a mixture of
diastereomers (trans/cis = 88:12, facial selectivity: 84:16).
Nitrones 5b and 5c, bearing a phenylglycinol-derived chiral
auxiliary, were next used in cycloaddition reaction with ethyl
vinyl ether and tert-butyl vinyl ether (Table 2, entries 2−5).
Again, the reactions occurred with complete regiocontrol and
excellent to complete (in case of nitrone 5c) exo-selectivity
(Table 2, entries 4−5). The facial selectivity (dr ≈ 65:35) was
found to be similar but no better than that observed with the 1-
phenylethanamine-derived auxiliary 1a.3 Nitrones 5d and 5e,
exhibiting a valinol-derived chiral auxiliary at the nitrogen atom,
were found to be less reactive toward dipolarophiles 6a and 6b.
Heating at 80 °C for more than one week was required for
complete conversion of the starting materials to isoxazolidines
12−15 (Table 2, entries 6−9). With this bulky substituent on the
nitrogen atom of nitrones, the facial selectivity was significantly
improved (90:10 < dr < 94:6) when compared to the benzylic
chiral auxiliaries. Finally, the most satisfying results were
obtained with nitrones 5f and 5g, equipped with Vasella’s chiral
auxiliary (Table 2, entries 11−16). In these cases, cycloaddition
was complete in 3 days at 80 °C. Cycloadducts 16−19 were
formed quantitatively, again with good exo-selectivities (89:11 <
trans/cis < 94:6) and this time with excellent facial selectivities (≥
98:2 for nitrone 5g). Interestingly, the cycloaddition of nitrone
Table 1. Synthesis of Chiral Nitrones 5a−g
a
entry
R*NHOH
R1
time at rt
nitrone
yield (%)
1
2
3
4
5
6
7
1b
2a
2a
2b
2b
3
Me
2 h
5a
5b
5c
5d
5e
5f
89
92
93
61
92
Me
−
t-Bu
Me
4 days
26 h
5 days
4 days
t-Bu
Me
b
qt
3
t-Bu
7 days
5g
81
a
b
Isolated yield after chromatography. Crude nitrone was obtained
quantitatively but was unstable upon chromatography on silica gel.
Slow addition of acetylene dicarboxylates at 0 °C was essential to
obtain nitrones in good yields.19 The use of dichloromethane as
solvent instead of methanol allowed direct isolation of clean
products that could be used without purification by chromatog-
raphy. Interestingly, nitrones 5a and 5d are crystalline solids, and
their (E)-configuration was confirmed by X-ray analysis.20
With chiral ketonitrones 5a−g in hand, we investigated their
cycloaddition reactions with two representative vinyl ethers, 6a
(R2 = Et) and 6b (R2 = t-Bu). By heating solvent-free mixtures of
Table 2. Diastereoselective Cycloaddition of Nitrones 5 with Vinyl Ethers 6
a
b
c
c
entry
1
nitrone
R2
temp (°C), time
cycloadducts
yield (%)
trans/cis
dr (trans)
5a
5b
5b
5c
5c
5d
5d
5e
5e
5e
5f
t-Bu
Et
50, 3 d
80, 3 d
80, 3 d
80, 3 d
80, 3 d
80, 21 d
80, 13 d
80, 12 d
80, 14 d
140, 4 h
80, 3 d
80, 3 d
80, 3 d
100, 1 h
80, 3 d
100, 1 h
7
78
76
72
80
72
93
83
77
70
88:12
93:7
84:16
68:32
70:30
65:35
65:35
94:6
d
2
8
d
3
t-Bu
Et
9
95:5
4
5
6
7
8
9
10
11
12
13
14
15
15
16
17
18
18
19
19
>98:2
>98:2
98:2
t-Bu
Et
t-Bu
Et
91:9
90:10
93:7
89:11
95:5
t-Bu
t-Bu
Et
92:8
e,
f
g
10
11
12
13
14
15
16
qt
86:14
91:9
83:17
87:13
91:9
h
qt
h
5f
t-Bu
Et
qt
94:6
h
h
h
h
,
i
i
5g
5g
5g
5g
qt
qt
qt
qt
89:11
89:11
94:6
>98:2
>98:2
98:2
e
e
,
Et
t-Bu
t-Bu
93:7
98:2
a
b
c
Temperature (°C), reaction time in days (d) or hours (h). Isolated yield after chromatography. Determined by integration of typical signals on
d
the NMR spectrum of the crude reaction products; see the Supporting Information. Under microwave irradiation (200 W, 100 °C, 2 h) the starting
materials were recovered. Microwave irradiation, 200 W. Under microwave irradiation (200 W, 100 °C, 1 h) only 10% nitrone 5e was converted
into the corresponding cycloadducts. Quantitative conversion; the cycloadducts were not purified by chromatography on silica gel. Quantitative
e
f
g
h
i
conversion; the cycloadducts partially decomposed upon chromatography on silica gel. The major diastereomer 18a could be isolated by
crystallization in EtOH in 51−58% yield.
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Organic Letters
Letter
5g with vinyl ethers 6a,b could be strongly accelerated by
microwave irradiation without alteration of regio- and diaster-
eocontrol (Table 2, entries 14 and 16). However, such
acceleration of the cycloaddition reaction by microwave
irradiation could not be extended favorably to the reaction of
nitrones 5b and 5e with vinyl ethers (Table 2, entries 2−3, note
d; entry 10, note f), and increasing the temperature of reaction to
140 °C (MW irradiation) resulted in lower diastereoselectivities
(entries 9 and 10).
Scheme 3. Conversion of Enantiopure Cycloadduct 18a into
α,α-Disubstituted β-Dipeptides
The high levels of exo and facial selectivities observed in the
cycloaddition of ketonitrones 5f,g with vinyl ethers are
outstanding compared to those reported for 1,3-DC reactions
involving other acyclic nitrones.7 Only a few examples of such
high levels of stereoinduction in 1,3-DC by N-glycosyl chiral
auxiliaries have been reported in the aldonitrone series.14a,22f
Satisfyingly, the major cycloadduct 18a could be isolated as a
pure single isomer by simple crystallization from ethanol. X-ray
diffraction analysis proved its 3R,5S configuration and confirmed
an exo approach of the dipolarophile by the Si face of the O-endo-
arranged (E)-ketonitrone 5g (Scheme 2).14d
Scheme 2. Diastereofacial Approach of the Dipolarophiles
toward the Chiral (E)-Ketonitrone 5f
anhydride 25 could be regioselectively converted into β-
dipeptides 27 and 28, by simple treatment with alanine methyl
ester or phenylalanine methyl ester, in DMF at room
temperature.27 Compound 27 could alternatively be synthesized
in three steps from isoxazolidine 22: regioselective cleavage of
the most accessible tert-butyl ester (10% TFA in DCM, at 0 °C)
yielded the crystalline mono acid 29 whose structure was
confirmed by X-ray analysis.20 Peptidic coupling of 29 with
alanine methyl ester afforded 30, and SmI2 reduction followed by
acidic cleavage of the tert-butyl ester yielded the dipeptide 27,
which was identical to that obtained from opening of the cyclic
anhydride 25 with alanine methyl ester. The quaternary amino
acids 27 and 28 are already dipeptide equivalents and are
adequately equipped for further C- or N-elongation.
Based on NMR analysis,21 we assume that the other
cycloadditions described herein follow the same stereochemical
course (exo approach, trans-cycloadducts formed preferentially).
As the facial selectivity induced by chiral auxiliaries 1a,b and 2a,b
relies on 1,3 allylic strain-induced privileged conformation of the
corresponding nitrones,7 it can be proposed that the major
diastereoisomer obtained from those exhibits a 3S,5R config-
uration in adducts 7−15 (approach of the dipolarophile from the
Re face of the nitrone).
In conclusion, an efficient route to enantiopure functionalized
quaternary amino acids (DAA) is described, based on the
diastereoselective cycloaddition of N-mannosyl-substituted (E)-
ketonitrones. The chiral aspartic-based ketonitrones were readily
prepared from inexpensive and recoverable sugar-derived
auxiliaries. It is worthy to mention that enantiomeric amino
acid precursors are expected to be accessible by using N-D-
erythrosyl,22f N-D-ribosyl,14a,22b or N-D-gulosyl17c−e,22a nitrones,
which have shown complementary facial selectivities in other 1,3-
dipolar cycloadditions. The obtained α,α-disubstituted isoxazo-
lidines provide access to enantiopure tetrafunctional DAA
derivatives and were used for the synthesis of β-dipeptides
containing “superaspartic” units. Further work for their
incorporation in complex peptides is underway.
The mannosyl chiral auxiliary was smoothly removed from
cycloadduct 18a by treatment with hydroxylamine,15,23 provid-
ing the enantiopure isoxazolidine 20 in quantitative yield, with
recovery of the auxiliary 3 (73%) that could be recycled (Scheme
3). After N-acetylation or N-trifluoroacetylation, the isoxazoli-
dines 21 and 22 were, respectively, converted to the β-amino
aldehyde 23 and β-amino ethyl ester 24 by SmI2-mediated
reductive cleavage of the N−O bond.24 The enantiopurity of
aldehyde 23 (and, by consequence of all compounds in Scheme
3) was ascertained by formation of diastereomeric imines (ee >
98%, see the Supporting Information).
At this stage, to demonstrate the utility of the α,α-disubstituted
amino ester 24 for peptide synthesis, differentiation of the two
tert-butyl esters was an essential requirement. This challenge was
overcome by a highly efficient conversion of 24 to the
unsymmetrical cyclic anhydride 25, followed by regioselective
transformations. For instance, treatment of 25 with NaBH4 in
THF at low temperature25 yielded exclusively the lactone 26,
with no trace of regioisomeric reduction.26 In complement,
ASSOCIATED CONTENT
■
S
* Supporting Information
Characterization data, full experimental procedures, copies of 1H
and 13C NMR spectra of all new compounds, and crystallo-
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Organic Letters
Letter
Chem. 2008, 6, 2574. (d) Diez-Martinez, A.; Gultekin, Z.; Delso, I.;
Tejero, T.; Merino, P. Synthesis 2010, 678.
graphic data for compounds 5a, 5d, 18a, and 29 (CIF). This
material is available free of charge via the Internet at http://pubs.
acs.org.
́
(13) Patel, S. K.; Murat, K.; Py, S.; Vallee, Y. Org. Lett. 2003, 5, 4081.
See also ref 12b,d.
(14) (a) Vasella, A. Helv. Chim. Acta 1977, 60, 1273. (b) Vasella, A.;
Voeffray, R.; Pless, J.; Huguenin, R. Helv. Chim. Acta 1983, 66, 1241.
(c) Bernet, B.; Krawczyk, E.; Vasella, A. Helv. Chim. Acta 1985, 68, 2299.
(d) Huber, R.; Vasella, A. Tetrahedron 1990, 46, 33. For an application
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1994, 59, 6103.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gilles.dujardin@univ-lemans.fr.
*E-mail: sandrine.py@ujf-grenoble.fr.
Notes
(15) (a) Fassler, R.; Frantz, D. E.; Oetiker, J.; Carreira, E. M. Angew.
̈
The authors declare no competing financial interest.
Chem., Int. Ed. 2002, 41, 3054. (b) Topic, D.; Aschwanden, P.; Fassler,
̈
R.; Carreira, E. M. Org. Lett. 2005, 7, 5329. (c) Ritter, T.; Carreira, E. M.
ACKNOWLEDGMENTS
■
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Financial support of this study by ANR (BS-07-00501) is
gratefully acknowledged. We thank Drs. C. Philouze and B.
Baptiste (DCM) and J. Lhoste (IMMM) for resolving crystallo-
graphic structures, P. Gangnery (IMMM) for HRMS measure-
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