The hetero-Diels-Alder addition of ethyl 2-nitrosoacrylate to electron-rich alkenes as a route to unnatural α-amino acids

Article abstract of DOI:10.1016/S0040-4039(03)00836-0

A new method for the stereoselective synthesis of nonproteinogenic α-amino acids has been developed, which involves hetero-Diels-Alder addition of ethyl 2-nitrosoacrylate to electron-rich alkenes, such as enol ethers, enamines and allylsilanes, and a furt

Full text of DOI:10.1016/S0040-4039(03)00836-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3905–3909
The hetero-Diels–Alder addition of ethyl 2-nitrosoacrylate to
electron-rich alkenes as a route to unnatural a-amino acids
John K. Gallos,* Vassiliki C. Sarli, Anastassia C. Varvogli, Constantina Z. Papadoyanni,
Sofia D. Papaspyrou and Nicolaos G. Argyropoulos
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece
Received 25 February 2003; revised 18 March 2003; accepted 28 March 2003
Abstract—A new method for the stereoselective synthesis of nonproteinogenic a-amino acids has been developed, which involves
hetero-Diels–Alder addition of ethyl 2-nitrosoacrylate to electron-rich alkenes, such as enol ethers, enamines and allylsilanes, and
a further two or three step manipulation of the resulting oxazines. © 2003 Elsevier Science Ltd. All rights reserved.
Initially, we started with the known cycloadduct 9,6a
The increasing interest of modified peptides in the
chemical engineering of proteins and also as therapeutic
agents has refreshed research towards the development
of new methodologies for the stereoselective construc-
tion of natural and unnatural a-amino acids.1,2 The
rational design of nonproteinogenic a-amino acids, in
particular, is of exceptional importance, due to their
implementation into nonscissile peptide mimics and
peptide isosteres.3 Herein, we report a new approach to
d-hydroxy-a-amino acids, based on the addition of
ethyl 2-nitrosoacrylate 2 (R=CO2Et) to alkenes 1
(Scheme 1) as the key reaction.4
prepared in quantitative yield from reaction of the
oxime of ethyl bromopyruvate with ethyl vinyl ether in
the presence of Na2CO3, at room temperature (Scheme
2).
Reissig et al.8 reported that the NaCNBH3 reduction of
compound 9 proceeds with high diastereoselectivity to
give 10 in a 93:7 cis:trans diastereoisomeric ratio and
87% total yield. In our hands, however, and in repeated
The hetero-Diels–Alder additions of nitrosoalkenes are
reverse electron demand reactions5 and proceed
smoothly when electron-rich alkenes, such as enol
ethers and enamines, are used as dienophiles. A useful
synthetic application of the resulting oxazines 3 is their
reductive ring contraction to pyrrolidines 5,6 either
directly or via 4.7 It was expected that a stepwise
reduction of adducts 3 to 4, protection of the NꢀH
group in 4 as N-Boc to give 6 and further NꢀO bond
cleavage, could lead to the formation of amino acids 7
(in the case of R=CO2Et), because the reduced nucle-
ophilicity of nitrogen would not permit a further con-
densation reaction, when X=OR% or NR%. Compound
2
7, depending on the nature of X and the reaction
conditions would be stable or could be subsequently
transformed to a stable product.
Keywords: a-amino acids; hetero-Diels–Alder addition; ethyl 2-nitro-
soacrylate; enol ethers; enamines; allylsilanes.
* Corresponding author. Tel.: +23-10-997-714; fax: +23-10-997-679;
e-mail: igallos@chem.auth.gr
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00836-0

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J. K. Gallos et al. / Tetrahedron Letters 44 (2003) 3905–3909
Scheme 2. Reagents and conditions: (i) BrCH2C(NOH)CO2Et, Na2CO3, 20°C, overnight; (ii) NaCNBH3, AcOH, 0“20°C, 6–12 h;
(iii) Et3N, CHCl3, reflux, 2–12 h; (iv) (Boc)2O, Et3N (or DMAP for 31), CH2Cl2, 20°C, 12–24 h; (v) Raney Ni, H2, H3BO3 (20
equiv.), MgSO4, MeOH, 2–96 h; (vi) NaBH4, EtOH, 20°C, 30 min, then Ac2O, pyridine, overnight; (vii) CH(OMe)3, TsOH, THF,
20°C, overnight.
experiments, this reaction was much less selective,
yielding a varying mixture of cis/trans-10 with an
average ratio of ꢀ65:35. These two isomers were eas-
ily separated chromatographically, the fast-moving
product (cis-10) being a colourless oil and the slow-
moving one (trans-10) a white solid (mp 103–105°C),
both with 1H NMR spectra identical to those
reported by Reissig et al.8 It is most likely that the
reported diastereoisomeric ratio does not reflect the
exact stereochemical outcome of the reduction, but it
is a result of the partial isomerisation of trans- to
cis-10. Indeed, refluxing a solution of trans-10 or the
mixture of cis/trans-10 obtained in CHCl3 for 3 h in
the presence of a catalytic amount of Et3N caused the
complete conversion of trans- to cis-10. Apparently,
the cis-isomer 10 is the thermodynamically more sta-
ble product, since the oxazine ring adopting a chair-
like conformation has the CO2Et group equatorial
and the EtO group axial, the latter being favoured by
the anomeric effect.
according to standard procedures, led to 11 in good
yield. In the last crucial step, NꢀO bond cleavage was
achieved in high yield by Raney Ni catalytic hydro-
genation of 11 in MeOH at room temperature in the
presence of boric acid, a method repeatedly used by
us for such purposes.7,9 It is noteworthy that the
NꢀO bond cleavage was followed by reduction of the
aldehyde group so formed, the final product being the
protected bis-homoserine 12.
Being able to control the stereochemistry of oxazines
10, by favouring the thermodynamically more stable
stereoisomer, it is apparent that branched bis-homo-
serines could be stereoselectively prepared when sub-
stituted enol ethers 8 are used as dienophiles. Thus,
preparation of the known dihydropyran adduct 14
and applying the above procedure, yielded stereoselec-
tively the a-amino acid 17.10 The hemiacetal produced
by the NꢀO bond cleavage was found to be reduced
very slowly under the applied hydrogenation condi-
tions and required the addition of NaBH4 for com-
plete and fast conversion to 17.
Further protection of the NꢀH group of cis-10

J. K. Gallos et al. / Tetrahedron Letters 44 (2003) 3905–3909
3907
It is known that allylsilanes11 react smothly with nitro-
soalkenes to give hetero-Diels–Alder adducts in high
yields. Thus, we prepared the oxazine 19 by adding the
ethyl 2-nitrosoacrylate to the parent allyltrimethylsi-
lane, according to the literature.11 Then, the reaction
sequence already discussed was applied to this adduct.
First, the NaCNBH3 reduction of 19 led to a mixture of
20 and its cis-stereoisomer, which upon treatment with
a catalytic amount of Et3N in refluxing CHCl3 was
completely converted to 20 in 84% overall yield. The
trans-stereochemistry of this product was deduced from
its 1H NMR spectrum and the coupling constants
measured, which indicated that both 3-H (l 3.75, dd,
J=11.2, 3.1 Hz) and 6-H (l 3.68, dddd as ddt, J=11.9,
7.2, 7.1, 2.2 Hz) are in axial positions, the oxazine ring
adopting a chair-like conformation.
but also in the amino acid stereocentre. In both
diastereoisomers of 26 and 27, which are thermody-
namically more stable, the CO2Et and MeO groups
have a cis-disposition, the first one being equatorial and
the anomeric MeO group axial. The catalytic hydro-
genation of 27 caused not only the NꢀO bond scission
but also reduction of the carbonyl group thus generat-
ing a ca. 3:1 diastereoisomeric ratio.
Since asymmetric hetero-Diels–Alder additions to chiral
enol ethers have been reported in the literature,5,14 it
was most likely that the addition of ethyl 2-nitrosoacryl-
ate to chiral enol ethers could be extended to the
asymmetric synthesis of a-amino acids. By addition of
ethyl 2-nitrosoacrylate to a chiral enol ether the chiral-
ity is transferred to the C-6 stereocentre of the oxazine
ring and then to the C-3 carbon (which is the a-carbon
of the final amino acid) by the NaCNBH3 reduction
and subsequent isomerisation. Thus, a homochiral alco-
hol could serve as a chiral auxiliary for the synthesis of
the chiral enol ether, the asymmetric hetero-Diels–
Alder addition of the heterodiene and the chirality
transfer to the a-carbon of the amino acid precursor,
being regenerated in the final step at NꢀO bond
cleavage.
In the next steps, the NH protection of 20 led to 21 in
high yield and this compound upon Raney Ni catalytic
hydrogenation in MeOH at room temperature in the
presence of boric acid afforded the d,o-bisfunctionalised
protected amino acid 22 as a single diastereoisomer.10
It is worth mentioning the presence of the trimethylsilyl
group in 22, not only for its high versatility and utility
in further synthetic transformations, but also because
of the current interest12 in a-amino acids with trialkylsil-
yl side chains, which have increased hydrophobic prop-
erties. For this reason such a-amino acids can be used
as substitutes of natural lipophilic amino acids or as
their replacements in naturally occuring peptides.
To this end, we selected the homochiral enol ether 29
which is known14 to give adduct 30 with ethyl 2-nitro-
soacrylate in acceptable yield (56%) and satisfactory
diastereoselectivity (6:1). In addition, both enantiomers
of the parent alcohol are commercially available, from
which both enantiomers of the final amino acid could
be prepared. Applying the established procedure, 30
was converted to the cis-oxazine 31,15 by complete
isomerisation of the cis/trans mixture intermediately
formed. In contrast to the previous examples, the intro-
duction of the Boc group required the presence of a
more powerful base (DMAP), by which 31 was quanti-
tatively converted to 32. However, any attempt (Raney
Ni/H2, Pd–C/H2, Pd(OH)2/H2, Zn/AcOH, etc) of NꢀO
bond scission and formation of the chiral amino acid 33
failed. It is possible that the overcrowded environment
of the NꢀO bond in 32 does not allow the approach of
the catalyst and is responsible for the failure of this
reaction.
Because of the high electronic density of their double
bonds, enamines are excellent dienophiles in reverse
electron demand Diels–Alder reactions. Such reactions
of enamines with ethyl 2-nitrosoacrylate have been
reported in the literature and the adducts have been
used inter alia as precursors for the synthesis of substi-
tuted prolines and tryptophans.5,6,13 Thus, we added
ethyl 2-nitrosoacrylate to 4-(cyclohexen-1-yl)mor-
pholine 23. The adduct, however, was found to be
susceptible to hydrolysis and during the work-up it was
converted to 24 which was isolated in high yield as a
mixture of two epimeric hemiacetals in equilibrium via
the respective keto form.
Treatment of 24 with trimethyl orthoformate in the
presence of catalytic TsOH yielded the respective acetal
25, as an inseparable mixture of two stereoisomers in
ꢀ1:1 ratio. As expected, the NaCNBH3 reduction of
this mixture led to the formation of four diastereoiso-
mers, separated chromatographically as two fractions,
each one consisting of a mixture of two isomers.
Refluxing of the parent mixture with a catalytic amount
of Et3N in CHCl3 solution caused the complete conver-
sion of the slow moving products to the fast moving
ones, their structures assigned as depicted in 26.
It is known5,6 that reduction of adducts 3 (Scheme 1)
leads directly to proline derivatives 5 (in the case of
R=CO2Et), a method which suffers from lack of
stereoselectivity. However, indirect reduction to 4 (R=
CO2Et), followed by isomerisation to the thermody-
namically more stable isomer of 5 and NꢀO bond
cleavage by catalytic hydrogenation could result in
substituted prolines, stereoselectively. This possibility
initially was checked by Raney Ni catalytic hydrogena-
tion of 10, which gave the parent racemic proline,
isolated as the Boc-protected proline ester 34, in good
overall yield (Scheme 3).
The NꢀH group of 26 was then protected as N-Boc to
give 27, which upon Raney Ni catalytic hydrogenation
led to 28, isolated as a mixture of four diastereoisomers
in the ratio ꢀ3:3:1:1. This revealed that the two iso-
mers of 26 and 27 differed not only in the ring junction
Applying the same procedures, namely Raney Ni cata-
lytic hydrogenation followed by N-Boc protection, the
enantiomerically enriched oxazine 31 was converted to
(R)-34 in enantiomerically pure form {[h]D=+42.3 (c

3908
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Scheme 3. Reagents and conditions: (i) Raney Ni, H2, H3BO3
(20 equiv.), MgSO4, MeOH, 2 h, 20°C; (ii) (Boc)2O, Et3N,
CH2Cl2, 20°C, overnight.
0.5, CHCl3); for (S)-34, lit.16 [h]D=−38.7 (c 2.3, EtOH)
and −47.7 (c 1.1, CHCl3)}, whereas bicyclic oxazine 15
gave stereoselectively the racemic branched proline
ester 35.
In conclusion, the preliminary results reported here
demonstrate that protected nonproteinogenic a-amino
acids, having the structure of a branched bis-homoser-
ine or proline can be prepared stereoselectively by
hetero-Diels–Alder addition of ethyl 2-nitrosoacrylate
to electron-rich alkenes, such as enol ethers and allylsi-
lanes, and a further two or three step manipulation of
the resulting oxazine. The use of enamines as
dienophiles was found to be problematic, regarding the
stereoselectivity of the overall sequence, the unsatisfac-
tory stereoselection being due to hydrolysis of the initial
adduct during the work-up. Attempted asymmetric syn-
thesis, using a chiral enol ether failed in the preparation
of a bis-homoserine, but was successful for the synthe-
sis of (R)-proline. Our efforts are now focused on
exploring the scope and limitations of this method as
well as to overcome the problems raised in the
attempted asymmetric synthesis.
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