Highly selective synthesis of enantiopure (S,E)-α,β-unsaturated γ-amino esters through a sequential reaction of ethyl dibromoacetate with α-amino aldehydes promoted by chromium dichloride

Article abstract of DOI:10.1002/ejoc.200700515

A sequential reaction of ethyl dibromoacetate with various enantiopure N,N-dibenzyl- or N-Boc-α-amino aldehydes (derived from natural α-amino acids), promoted by chromium dichloride, afforded optically active (S,E)-α,β-unsaturated γ-amino esters. The C=C

Full text of DOI:10.1002/ejoc.200700515

FULL PAPER
DOI: 10.1002/ejoc.200700515
Highly Selective Synthesis of Enantiopure (S,E)-α,β-Unsaturated γ-Amino
Esters Through a Sequential Reaction of Ethyl Dibromoacetate with α-Amino
Aldehydes Promoted by Chromium Dichloride
José M. Concellón*[a] and Carmen Méjica[a]
Keywords: Diastereoselectivity / Chromium / Asymmetric synthesis / Amino esters / Sequential reactions
A sequential reaction of ethyl dibromoacetate with various
enantiopure N,N-dibenzyl- or N-Boc-α-amino aldehydes (de-
rived from natural α-amino acids), promoted by chromium
dichloride, afforded optically active (S,E)-α,β-unsaturated γ-
amino esters. The C=C double bond was generated with total
or very high E-selectivity and the (S,E)-α,β-unsaturated γ-
amino esters were obtained with complete enantiomeric pu-
rity, except from N-Boc-phenylalaninal (as determined by
chiral HPLC). A mechanism is proposed to explain this trans-
formation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
These results prompted us to apply this synthetic method
to the synthesis of α,β-unsaturated γ-amino esters with
complete optical purity and with the C=C double bond
generated with total E selectivity. There were two main ob-
jectives of this proposed study. On the one hand, to test
the use of enantiopure α-amino aldehydes (highly prone to
racemization) as starting materials, conserving their enan-
tiomeric purity during the course of the reaction. On the
other hand, to develop an easy and efficient sequential reac-
tion to prepare α,β-unsaturated γ-amino esters which could
constitute an alternative to the previously reported meth-
ods.
Thus, we describe herein a CrCl2-mediated sequential re-
action of ethyl dibromoacetate with a variety of optically
active N,N-dibenzyl- or N-Boc-α-amino aldehydes derived
from natural amino acids which readily affords the corre-
sponding enantiopure (S,E)-α,β-unsaturated N,N-dibenzyl-
or N-Boc-γ-amino esters, respectively. Unsaturated γ-amino
esters (N,N-dibenzyl- or N-Boc-protected) were obtained
with complete or high enantiomeric purity, except from N-
Boc-phenylalaninal (as determined by chiral HPLC), and
the C=C double bond was generated with total or very high
E selectivity (assessed by NMR and/or GC). A mechanism
is proposed to explain this transformation.
Introduction
The transformation of natural α-amino acids into γ-
amino acids is of interest owing to their potential biological
activity, for example, as GABA analogues.[1] Thus, enantio-
pure vinylogous amino acid derivatives are important build-
ing blocks in organic synthesis and a great deal of effort
has been invested in the conjugate addition reactions of α,β-
unsaturated γ-amino esters.[2]
Most commonly, α,β-unsaturated γ-amino esters with the
amino function dibenzylated or N-Boc-protected can be
prepared from α-amino aldehydes by the Horner–Wittig re-
action[3] or by the Wittig reaction.[4] In some cases, α,β-
unsaturated γ-amino esters have been obtained with partial
racemization.[4a] Hence, an alternative synthesis of enantio-
pure α,β-unsaturated γ-amino esters, without racemization,
starting from amino aldehydes and commercially available
compounds such as ethyl dibromoacetate and chromium di-
chloride, obviating the use of phosphorus compounds,
would be desirable.
Moreover, chromium dichloride has been used to per-
form a variety of organic transformations, including car-
bon–carbon bond formation or β-elimination reactions.[5]
In this context, we recently reported a completely stereose-
lective synthesis of (E)-α,β-unsaturated esters by reaction of
a variety of aldehydes with ethyl dibromoacetate promoted
by CrCl2.[6] This transformation took place as two sequen-
tial reactions: an aldol-type reaction in the first step fol-
lowed by a β-elimination reaction in the second step.[7]
Results and Discussion
Our first approach to enantiopure α,β-unsaturated γ-
amino esters was conceptually very simple and was based
on a previous methodology developed by our group in
which α,β-unsaturated esters were obtained in high yields
with complete E selectivity by treatment of α-chloro-β-hy-
droxy esters with CrCl2.[8] Therefore, we expected that the
reaction of CrCl2 with an appropriate optically active
[a] Department of Organic Chemistry, University of Oviedo, Fa-
culty of Chemistry,
Julián Clavería, 8, 33071, Oviedo, Spain
Fax: +34-985-10-34-46
E-mail: jmcg@uniovi.es
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Synthesis of Enantiopure (S,E)-α,β-Unsaturated γ-Amino Esters
amino-containing compound such as α-chloro-β-hydroxy-γ-
dibenzylamino ester 2, which theoretically could be readily
available, should allow access to the corresponding alkyl γ-
dibenzylaminoalk-2-enoate 3.
Consequently, various attempts were made to prepare the
starting α-chloro-β-hydroxy-γ-dibenzylamino esters 2 by re-
action of lithium or potassium enolates derived from chlo-
roacetate or 2-chloropropanoate esters with a range of α-
dibenzylamino aldehydes 1, such as alaninal, phenylalani-
nal or leucinal, under various reaction conditions. Surpris-
ingly, the reactions led to the requisite compounds 2 in very
low yields. Under the best reaction conditions (lithium ethyl
acetate enolate and leucinal in THF at –90 °C for 7 h), the
corresponding α-chloro-β-hydroxy-γ-dibenzylamino esters
2 were obtained in only 20% yield (based on the starting
amino aldehyde 1). Therefore, owing to the lack of access
to the starting compounds 2, this synthetic route to γ-
amino α,β-unsaturated esters was abandoned (Scheme 1).
Scheme 2. Synthesis of (S,E)-α,β-unsaturated γ-dibenzylamino es-
ters 3.
Table 1. Synthesis of (S,E)-α,β-unsaturated γ-dibenzylamino esters
3.
3
R
% Yield[a]
% de[b]
Enantiomeric purity[c]
[d]
3a
3b
3c
Me
iBu
BnOCH2
60
58
64
Ͼ99
95
Ͼ99
–
99:1
97.5:2.5
[a] Isolated yield after column chromatography (based on the start-
ing α-amino aldehyde 1). [b] Determined by GC–MS and/or
300 MHz 1H NMR analysis of the crude products. [c] Ratio of
enantiomers, as determined by HPLC analysis (see ref.[12]). [d] The
enantiomeric purity of this product was not determined.
The E stereochemistry of compounds 3 was established
on the basis of the value of the 1H NMR coupling constant
between the olefinic protons, ranging between 15.6 and
15.9 Hz, in accordance with literature values.[11] In ad-
dition, the spectroscopic data of compound 3a were in
agreement with those previously reported in the litera-
ture.[3a] The diastereomeric excess (de) of the C=C double
bond was determined by 1H NMR spectroscopy (300 MHz)
and/or GC of the crude reaction mixtures. The determined
de values are compiled in Table 1 and show that the β-elimi-
nation reaction takes place with very high or complete dia-
stereoselectivity.
Scheme 1. Failed initial synthesic proposal for obtaining α,β-unsat-
urated γ-amino esters.
Synthesis of Enantiopure (S,E)-α,β-Unsaturated γ-
Dibenzylamino Esters 3
The enantiomeric purity of 3b and 3c was determined by
Consequently, bearing the above result in mind and tak- chiral HPLC analysis, showing an enantiomeric ratio of
ing into account our previous work on the synthesis of α,β- 99:1 and 97.5:2.5, respectively. A racemic mixture of 3b and
unsaturated esters,[6] we examined an alternative method for 3c was used as a reference to exclude the possibility of the
obtaining α,β-unsaturated γ-amino esters through a CrCl2- coelution of both enantiomers.[12] The enantiomeric purity
mediated sequential process (C–C bond formation followed of 3a was not determined as a result of the very high enan-
by an elimination reaction). Taking into account our pre- tiomeric purity of 3b and 3c and the configurational sta-
vious experience in the development of synthetic applica- bility of the α-dibenzylalaninal 1a. Both values (enantio-
tions of N,N-dibenzylated α-amino aldehydes 1,[9] initially meric purity and de) demonstrate that the sequential pro-
we tested the sequential reaction using N,N-dibenzylated al- cess promoted by CrCl2 is effective in the synthesis of
dehydes 1. Thus, treatment of a suspension of 6 equiv. of enantiopure (S,E)-α,β-unsaturated γ-dibenzylamino esters
CrCl2 in 10 mL of THF with a solution of various α-diben- 3, giving complete E selectivity and very high or complete
zylamino aldehydes 1[10] (1 equiv.) and ethyl dibromoacetate enantiomeric purity (enantiomeric ratio Ͼ97.5:2.5).
(1.2 equiv.) in 8 mL of THF at –15 °C for 30 min followed
This sequential reaction is an attractive synthetic method
by stirring for 15 min at room temperature and heating at due to its simplicity. In general, sequential reactions are the
reflux for 1.5 h afforded the corresponding (S,E)-α,β-unsat- methods of choice due to their experimental advantages in
urated γ-dibenzylamino esters 3 with high or total E selec- comparison with the most conventional multistep method-
tivity and in moderate-to-good yields (Scheme 2 and ologies. Thus, this synthesis takes place in a shorter time,
Table 1).
the starting materials are, in general, commercially avail-
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J. M. Concellón C. Méjica
FULL PAPER
able, higher overall yields are obtained and time and effort Table 2. Synthesis of (S,E)-α,β-unsaturated γ-(tert-butoxycarb-
onyl)amino esters 4 and 6.
are saved. In addition, this method negates the use of phos-
% Yield[a] % de[b]
% Enantiomeric
purity[c]
phorus derivatives which is advantageous (in comparison to
the Wittig or Horner reactions). For these reasons, we
tested the generality of the reaction by using 2-amino alde-
hydes with other nitrogen-protecting groups.
4 or 6
R
4a
Me
iBu
PhCH2
MeSCH2CH2
54
55
57
52
57
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
98
86
Ͼ99
Ͼ99
4b
4c
4d[c]
6S
–
Synthesis of Enantiopure (S,E)-α,β-Unsaturated γ-(tert-
Butoxycarbonyl)amino Esters 4 or 6
CH2OCMe2–
–
CH2OCMe2–
6R
51
94
Ͼ99
We selected tert-butyloxycarbonyl (Boc) as the protecting
group of the amino function as a result of its extensive use
in organic synthesis.[13] Thus, the reaction of freshly pre-
pared N-Boc-α-amino aldehyde 5[14] (1 equiv.) with ethyl di-
bromoacetate (1.2 equiv.) in 8 mL of THF in the presence
of a solution of 6 equiv. of CrCl2 in 10 mL of THF at 0 °C
for 2 h and at reflux for 30 min afforded the corresponding
(S,E)-α,β-unsaturated γ-(tert-butyloxycarbonyl)amino ester
4 with high E selectivity and in good yield (Scheme 3 and
Table 2).
[a] Isolated yield of the pure compounds 4 or 6 after column
chromatography (based on the starting α-amino aldehyde 5 or 7).
1
[b] Determined by GC–MS and/or 300 MHz H NMR analysis of
the crude products. [c] Determined by chiral HPLC analysis (see
ref.[19]).
E configuration of 4 or 6 was established on the basis of
1
the value of the H NMR coupling constant between the
olefinic protons.[11] The spectroscopic data of compounds
4a,[3c,3d,16] 4c,[17] 6R[4g,4k] and 6S[4f] are in agreement with
those previously reported in the literature.
The optical instability of the N-Boc-protected α-amino
aldehydes 5 (especially phenylalaninal) has been carefully
documented[18] and, for this reason, to reproduce the results
shown in Table 2, it was essential to carry out the sequential
reaction with the corresponding N-Boc-amino aldehyde im-
mediately after its preparation. Storage at low temperatures
for 0.5–12 h produced partial racemization of the N-Boc-
amino aldehydes (especially phenylalaninal).
Compounds 4a–d, 6R and 6S were analysed by chiral
HPLC[19] to check their enantiomeric purity. Racemic mix-
tures of each compound were used as a reference to exclude
the possibility of coelution of both enantiomers. These de-
terminations showed the presence of only one enantiomer
in all cases except for compound 4c which suffered partial
racemization (ee = 86%) during its synthesis. This loss of
enantiomeric purity could be explained by the low configu-
rational stability of the N-Boc-phenylalaninal.[18] However,
it is noteworthy that the ee of 4c is higher than the values
obtained by using other previously reported methodolo-
gies.[4a]
Scheme 3. Synthesis of (S,E)-α,β-unsaturated γ-(tert-butyloxycar-
bonyl)amino esters 4 and 6.
Mechanism
In the case of serinal, two enantiomers of the corre-
sponding N-Boc-α,β-unsaturated γ-amino esters 6R and 6S
This reaction may be rationalised by assuming a sequen-
were prepared from the two commercially available enantio- tial process comprising two steps. Thus, in the first step of
mers, Gardner’s aldehydes 7S and 7R.[15]
the reaction 2 equivalents of CrCl2 react with ethyl dibro-
The results obtained are shown in Table 2 and demon- moacetate to generate a chromium enolate 8 which reacts
strate that the method, starting from the N-Boc-amino al- with the starting α-amino aldehyde 1, 5 or 7, affording the
dehydes, is general and works efficiently. Indeed, no impor- corresponding intermediate α-bromo ester 9 as a mixture of
tant differences were observed in the synthesis of (S,E)-α,β- syn and anti diastereoisomers. In the second step, another
unsaturated γ-(tert-butyloxycarbonyl)amino esters 4 or 6 on metallation of 9 with a further 2 equivalents of CrCl2 gives
varying the structure of R in the starting amino aldehyde. the amino enolate intermediate 10 (as a mixture of dia-
In all cases, only the E diastereoisomer of 4 or 6 was de- stereoisomers) which undergoes spontaneous β-elimination
1
tected by H NMR spectroscopy (300 MHz) of the crude to give the α,β-unsaturated γ-amino esters 3, 4 or 6
reaction mixtures. Similarly as indicated above, the relative (Scheme 4).
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Synthesis of Enantiopure (S,E)-α,β-Unsaturated γ-Amino Esters
Scheme 4. Proposed reaction mechanism.
To explain the E selectivity, we tentatively propose a che- place through a sequential process: an aldol-type reaction
lation of the CrIII centre of both diastereoisomeric enolates as the first step followed by a very high or totally E stereo-
10 with the oxygen atom of the alcoholate group which selective β-elimination reaction as the second step. A
could produce a six-membered ring. This coordination of mechanism to explain the high or total E selectivity of the
the CrIII centre with the leaving oxygen could facilitate the elimination reaction has been proposed.
elimination reaction. Thus, the elimination from each dia-
stereoisomer 10 could take place through half-chair transi-
tion-state models I or II with the bulkier RCH(NGp) group
in the equatorial orientation in both diastereoisomeric tran-
sition states. Owing to steric hindrance, both transition
states would be favoured above those in which the
Experimental Section
General: Reactions requiring an inert atmosphere were conducted
under dry nitrogen and the glassware was oven-dried (120 °C).
THF was distilled from sodium/benzophenone ketyl immediately
prior to use. All reagents were purchased in the highest quality
RCH(NGp) group was in an axial position. Elimination
from I and II affords the same (S,E)-α,β-unsaturated γ-
amino esters 3, 4 or 6. Supporting this explanation, the syn-
thesis of α,β-unsaturated esters with total E selectivity by
β-elimination of a diastereoisomeric mixture of α-halo-β-
hydroxy esters has been previously reported.[8] This mecha-
nism has also been previously proposed to explain other β-
elimination reactions promoted by CrCl2.[6,7]
available and were used without further purification. 1H NMR
spectra were recorded at 300 or 400 MHz. 13C NMR spectra and
DEPT experiments were recorded at 75 MHz. GC-MS spectra were
measured at 70 eV with an Agilent 5973 N A.
General Procedure for the Synthesis of Compounds 3: Anhydrous
CrCl2 (6 mmol) was suspended in THF (10 mL) under nitrogen. A
solution of the corresponding aldehyde (1 mmol) and ethyl dibro-
moacetate (1.2 mmol) in THF (8 mL) was added dropwise to this
suspension at –15 °C. After stirring for 30 min, the reaction mixture
was warmed to room temperature and after 15 min was refluxed
for 1.5 h and the reaction mixture was hydrolysed with 0.1  HCl
and extracted with diethyl ether (3ϫ10 mL). The combined ex-
tracts were dried with Na2SO4 and concentrated. Then the organic
layer was filtered through a pad of Celite® and the solvents re-
moved in vacuo. Purification by column chromatography on silica
gel afforded the (S,E)-α,β-unsaturated γ-dibenzylamino esters 3.
Conclusions
We have presented an easy, rapid, straightforward, gene-
ral method for the preparation of enantiopure (S,E)-α,β-
unsaturated γ-amino esters in good yields, with very high
or total E stereoselectivity and with high or complete enan-
tiomeric purity, except from N-Boc-phenylalaninal. This
synthesis takes place by the reaction of dibromoacetate with
N,N-dibenzyl- or N-Boc-α-amino aldehydes promoted by
Ethyl (S,E)-4-(Dibenzylamino)pent-2-enoate[3a] (3a): Yellow oil.
1
[α]2D5 = –66.2 (c = 0.7, CHCl3). Rf = 0.49 (hexane/EtOAc, 3:1). H
NMR (300 MHz, CDCl3): δ = 7.3–57.11 (m, 10 H), 7.10 (dd, J =
chromium dichloride. The described transformation takes 15.9, 6.0 Hz, 1 H), 5.94 (dd, J = 15.9, 1.6 Hz, 1 H), 4.24 (q, J =
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J. M. Concellón C. Méjica
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7.1 Hz, 2 H), 3.67 (d, J = 13.9 Hz, 2 H), 3.60 (d, J = 13.9 Hz, 2
H), 3.58–3.48 (m, 1 H), 1.34 (t, J = 7.1 Hz, 3 H), 1.26 (d, J =
6.8 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.4 (C),
150.2 (CH), 139.8 (2ϫC), 128.4 (4ϫCH), 128.2 (4ϫCH), 128.0
1
EtOAc, 5:1). H NMR (300 MHz, CDCl3): δ = 6.81 (dd, J = 15.6,
5.4 Hz, 1 H), 5.90 (d, J = 15.6 Hz, 1 H), 4.47 (s, 1 H), 4.32 (s, 1
H), 4.17 (q, J = 7.1 Hz, 2 H), 1.83–1.62 (m, 2 H), 1.42 (s, 9 H),
1.36–1.28 (m, 1 H), 1.26 (t, J = 7.1 Hz, 3 H), 0.91 (d, J = 6.4 Hz,
(CH), 126.8 (CH), 121.8 (CH), 60.3 (CH2), 53.6 (CH), 53.6 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.3 (C), 155.0 (C),
(2ϫCH ), 14.2 (CH ), 14.0 (CH ) ppm. IR (neat): ν = 2927, 2360,
148.8 (CH), 120.3 (CH), 79.6 (C), 60.3 (CH2), 49.7 (CH), 43.7
˜
2
3
3
2342, 1717 cm–1. MS (70 eV, EI): m/z (%) = 323 (Ͻ1) [M]+, 308 (CH2), 28.3 (3ϫCH3), 24.6 (CH), 22.6 (CH3), 22.1 (CH3), 14.1
(66), 232 (71), 91(100). C21H25NO2 (323.43): calcd. C 77.98, H 7.79, (CH ) ppm. IR (neat): ν = 3356, 2960, 2930, 1717, 1522 cm–1. MS
N 4.33; found C 78.20, H 7.91, N 4.28.
˜
3
(70 eV, EI): m/z (%) = 285 (Ͻ1) [M]+, 187 (12), 228 (24), 212 (8),
128 (100), 57 (32). HRMS (70 eV): m/z calcd. for C15H27NO4
285.1940; found 285.1705.
Ethyl (S,E)-4-(Dibenzylamino)-6-methylhep-2-enoate[3a] (3b): Yellow
oil. [α]2D5 = –26.9 (c = 0.2, CHCl3). Rf = 0.56 (hexane/EtOAc, 5:1).
1H NMR (300 MHz, CDCl3): δ = 7.31–7.23 (m, 10 H), 7.00 (dd, J
= 15.7, 8.4 Hz, 1 H), 5.86 (d, J = 15.7 Hz, 1 H), 4.25 (q, J = 7.2 Hz,
2 H), 3.92–3.88 (m, 1 H), 3.82 (d, J = 13.7 Hz, 2 H), 3.42 (d, J =
13.7 Hz, 2 H), 1.77–1.63 (m, 2 H), 1.35 (t, J = 7.1 Hz, 3 H), 0.89–
0.86 (m, 1 H), 0.79 (d, J = 6.5 Hz, 3 H), 0.70 (d, J = 6.3 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.3 (C), 147.5 (CH),
139.8 (2ϫC), 128.6 (2ϫCH), 128.2 (2ϫCH), 128.0 (4ϫCH),
126.9 (2ϫCH), 123.2 (CH), 60.4 (CH2), 56.6 (CH), 53.7 (2ϫCH2),
40.5 (CH2), 24.4 (CH), 22.7 (CH3), 22.4 (CH3), 14.2 (CH3) ppm.
Ethyl (S,E)-4-(tert-Butoxycarbonylamino)-5-phenylpent-2-enoate[17]
(4c): Yellow oil. [α]2D5 = +9.52 (c = 0.4, CHCl3). Rf = 0.47 (hexane/
EtOAc, 5:1). 1H NMR (400 MHz, CDCl3): δ = 7.31–7.16 (m, 5 H),
7.20 (dd, J = 16.5, 6.7 Hz, 1 H), 5.87 (d, J = 15.6 Hz, 1 H), 4.59
(s, 2 H), 4.19 (q, J = 7.0 Hz, 2 H), 3.01–2.85 (m, 2 H), 1.40 (s, 9
H), 1.28 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 166.1 (C), 154.9 (C), 147.5 (CH), 136.3 (C), 129.3 (2ϫCH), 128.5
(2ϫCH), 126.8 (CH), 121.0 (CH), 79.8 (C), 60.4 (CH2), 40.8
(CH ), 28.2 (3ϫCH ), 14.1 (CH ) ppm. IR (neat): ν = 3355, 2979,
˜
2
3
3
IR (neat): ν = 3355, 2979, 2932, 1717, 1519 cm–1. MS (70 eV, EI):
˜
2932, 1717, 1519 cm–1. MS (70 eV, EI): m/z (%) = 319 (Ͻ1) [M]+,
228 (52), 128 (100), 57 (62). HRMS (70 eV): m/z calcd. for
C18H25NO4 319.1784; found 319.1880.
m/z (%) = 365 (Ͻ1) [M]+, 320 (10), 308 (100), 274 (32), 181 (17),
91 (99). C24H31NO3 (381.51): calcd. C 75.56, H 8.19, N 3.67; found
C 75.39, H 8.28, N 3.71.
Ethyl (S,E)-4-(tert-Butoxycarbonylamino)-6-methylsulfanylhex-2-
enoate (4d): Yellow oil. [α]2D5 = –4.89 (c = 0.5, CHCl3). Rf = 0.30
(hexane/EtOAc, 3:1). H NMR (300 MHz, CDCl3): δ = 6.86 (dd,
Ethyl (S,E)-5-Benzyloxy-4-(dibenzylamino)pent-2-enoate (3c): Yel-
low oil. [α]2D5 = –18.5 (c = 0.4, CHCl3). Rf = 0.47 (hexane/EtOAc,
5:1). H NMR (300 MHz, CDCl3): δ = 7.35–7.11 (m, 15 H), 6.96
1
1
J = 15.6, 5.1 Hz, 1 H), 5.96 (dd, J = 15.6, 1.6 Hz, 1 H), 4.58 (s, 1
H), 4.33 (s, 1 H), 4.21 (q, J = 7.0 Hz, 2 H), 3.49 (q, J = 7.0 Hz, 2
H), 2.42 (t, J = 6.9 Hz, 2 H), 2.13 (s, 3 H), 1.46 (s, 9 H), 1.27 (t, J
= 9.3, 7.0 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.1
(C), 155.0 (C), 147.4 (CH), 121.2 (CH), 79.9 (C), 60.5 (CH2), 50.8
(CH), 33.9 (CH2), 30.3 (CH2), 28.3 (3ϫCH3), 15.5 (CH3), 14.1
(ddd, J = 15.9, 6.5, 2.8 Hz, 1 H), 5.95 (d, J = 15.9 Hz, 1 H), 4.39
(s, 2 H), 4.15 (q, J = 7.1 Hz, 2 H), 3.91–3.73 (m, 1 H), 3.87 (d, J
= 14.0 Hz, 2 H), 3.72–3.55 (m, 2 H), 3.53 (d, J = 14.0 Hz, 2 H),
1.24 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
166.2 (C), 145.7 (CH), 139.6 (2ϫC), 138.0 (C), 128.4 (4ϫCH),
128.2 (5ϫCH), 127.6 (2ϫCH), 127.5 (2ϫCH), 126.9 (2ϫCH),
123.8 (CH), 73.1 (CH2), 70.1 (CH2), 60.3 (CH2), 58.1 (CH), 54.5
(CH ) ppm. IR (neat): ν = 2963, 2923, 2853, 1717 cm–1. MS (70 eV,
˜
3
EI): m/z (%) = 303 (9) [M]+, 247 (43), 156 (100), 128 (56). HRMS
(2ϫCH ), 14.2 (CH ) ppm. IR (neat): ν = 3345, 2989, 1719 cm–1.
˜
2
3
(70 eV): m/z calcd. for C14H25NO4S 303.1504. found 303.1502.
C28H31NO3 (429.56): calcd. C 78.29, H 7.27, N 3.26; found C
78.17, H 7.32, N 3.31.
Ethyl (R,E)-3-(3-tert-Butoxycarbonyl-2,2-dimethyl-1,3-oxazolidin-4-
yl)propenoate[4g,4k] (6S): Pale yellow oil. [α]2D5 = +56.46 (c = 1.0,
CHCl3). Rf = 0.32 (hexane/EtOAc, 5:1). 1H NMR (300 MHz,
CDCl3): δ = 6.81 (d, J = 15.4 Hz 1 H), 5.91 (t, J = 15.4 Hz, 1 H),
4.56–4.42 (m, 1 H), 4.21–4.19 (m, 2 H), 4.08 (dd, J = 9.0, 6.6 Hz,
1 H), 3.78 (ddd, J = 11.2, 9.0, 2.2 Hz, 1 H), 1.63 (s, 3 H), 1.48 (s,
3 H), 1.42 (s, 9 H), 1.29 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 166.2 (C), 146.0 (CH), 145.7 (C), 122.3
(CH), 94.5 (C), 80.4 (C), 67.3 (CH2), 60.5 (CH2), 58.0 (CH), 28.4
General Procedure for the Synthesis of Compounds 4 or 6: Anhy-
drous CrCl2 (6 mmol) was suspended in THF (10 mL) under nitro-
gen. A solution of the corresponding aldehyde 5 or 7 (1 mmol)
and ethyl dibromoacetate (1.2 mmol) in THF (8 mL) was added
dropwise to this suspension at 0 °C. After stirring for 2 h, the reac-
tion mixture was refluxed for 0.5 h. Then the reaction mixture was
hydrolysed with 0.1  HCl and extracted with diethyl ether
(3ϫ10 mL). The combined extracts were dried with Na2SO4 and
concentrated. The organic layer was filtered through a pad of Ce-
lite® and the solvents were removed in vacuo. Purification by col-
umn chromatography on silica gel afforded the (S,E)-α,β-unsatu-
rated γ-(tert-butoxycarbonylamino) esters 4 or 6.
(3ϫCH ), 26.4 (CH ), 23.6 (CH ), 14.2 (CH ) ppm. IR (neat): ν =
˜
3
3
3
3
2855, 1719, 1520 cm–1. MS (70 eV, EI): m/z (%) = 299 (Ͻ1) [M]+,
284 (9), 184 (100), 96 (27), 57 (98). C15H25NO5 (299.37): calcd. C
60.18, H 8.42, N 4.68; found C 60.27, H 8.36, N 4.60.
Ethyl (S,E)-4-(tert-Butoxycarbonylamino)pent-2-enoate[3c,3d,16] (4a):
Yellow oil. [α]2D5 = –17.2 (c = 0.7, CHCl3). Rf = 0.51 (hexane/
EtOAc, 5:1). H NMR (300 MHz, CDCl3): δ = 6.87 (dd, J = 15.7,
Ethyl (S,E)-3-(3-tert-Butoxycarbonyl-2,2-dimethyl-1,3-oxazolidin-4-
yl)propenoate[4f] (6R): Yellowish oil. [α]2D5 = –55.92 (c = 0.3, CHCl3).
Rf = 0.32 (hexane/EtOAc, 5:1). H NMR (300 MHz, CDCl3): δ =
1
1
4.9 Hz, 1 H), 5.89 (dd, J = 15.7, 1.6 Hz, 1 H), 4.74 (s, 1 H), 4.41
(s,1 H), 4.19 (q, J = 7.0 Hz, 2 H), 1.44 (s, 9 H), 1.28 (t, J = 7.0 Hz,
3 H), 1.26 (d, J = 8.3 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 166.3 (C), 154.8 (C), 149.3 (CH), 120.0 (CH), 79.7 (C), 60.3
(CH2), 46.9 (CH), 28.2 (3ϫCH3), 20.2 (CH3), 14.1 (CH3) ppm. IR
6.82 (d, J = 15.4 Hz, 1 H), 5.91 (t, J = 15.4 Hz, 1 H), 4.55–4.44
(m, 1 H), 4.20–4.19 (m, 2 H), 4.08 (dd, J = 9.0, 6.6 Hz, 1 H), 3.77
(ddd, J = 11.2, 9.0, 2.2 Hz, 1 H), 1.63 (s, 3 H), 1.48 (s, 3 H), 1.42 (s,
9 H), 1.30 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 166.2 (C), 146.0 (CH), 145.6 (C), 122.3 (CH), 94.6 (C), 80.4 (C),
67.3 (CH2), 60.4 (CH2), 58.0 (CH), 28.5 (3ϫCH3), 26.4 (CH3),
(neat): ν = 3437, 3360, 2980, 2931, 1708 cm–1. MS (70 eV, EI): m/z
˜
(%) = 244 (8) [M + 1]+, 188 (100), 144 (48), 57 (94). HRMS (70 eV):
23.6 (CH ), 14.2 (CH ) ppm. IR (neat): ν = 2854, 1720, 1519 cm–1.
˜
3
3
m/z calcd. for C12H21NO4 243.1471; found 243.1236.
MS (70 eV, EI): m/z (%) = 299 (Ͻ1) [M]+, 284 (9), 184 (100), 96
Ethyl
(S,E)-4-(tert-Butoxycarbonylamino)-6-methylhep-2-enoate (27), 57 (98). C15H25NO5 (299.37): calcd. C 60.18, H 8.42, N 4.68;
(4b): Yellow oil. [α]2D5 = +2.63 (c = 0.5, CHCl3). Rf = 0.47 (hexane/
found C 60.39, H 8.32, N 4.61.
5254
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5250–5255

Synthesis of Enantiopure (S,E)-α,β-Unsaturated γ-Amino Esters
Concellón, P. L. Bernad, J. A. Pérez-Andrés, J. Org. Chem.
1997, 62, 8902–8906; c) J. M. Concellón, B. Baragaña, E. Ri-
ego, Tetrahedron Lett. 2000, 41, 4361–4362; d) J. M. Concellón,
E. Riego, H. Rodríguez-Solla, A. M. Plutín, J. Org. Chem.
2001, 66, 8661–8665; e) J. M. Concellón, E. Riego, I. A. Rivero,
A. Ochoa, J. Org. Chem. 2004, 69, 6244–6248.
Acknowledgments
We thank the Ministerio de Educación
y Ciencia (MEC)
(CTQ2004-1191/BQU) for financial support and to Euan C. God-
dard for his revision of the English. C. M. thanks the Ministerio
de Educación y Ciencia, Cultura y Deportes for a predoctoral fel-
lowship. J. M. C. thanks Carmen Fernández-Flórez for her time.
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[12] 3b: Chiracel ODH, UV detector 210 nm, 0.5 mL/min, 95:5 hex-
ane/propan-2-ol, retention time: 11.154 min, enantiomer of 3b:
12.023 min. 3c: Chiracel ODH, UV detector 210 nm, 0.5 mL/
min, 90:10 hexane/propan-2-ol, retention time: 11.028 min, en-
antiomer of 3c: 12.501 min.
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[19] 4a: Chiracel OD-RH, UV detector 210 nm, 0.3 mL/min, 60:40
acetonitrile/water, retention time: 12.917 min, enantiomer of
4a: 13.716 min. 4b: Chiracel OD-RH, UV detector 210 nm,
0.3 mL/min, 60:40 acetonitrile/water, retention time:
13.084 min, enantiomer of 4b: 15.216 min. 4c: Chiracel OD,
UV detector 210 nm, 0.9 mL/min, 55:45 acetonitrile/water, re-
tention time: 15.244 min, enantiomer of 4c: 14.285 min. 4d:
Chiracel OD-H, UV detector 210 nm, 0.5 mL/min, 95:5 hex-
ane/propan-2-ol, retention time: 25.840 min, enantiomer of 4d:
28.819 min. 4e: Chiracel OD-RH, UV detector 210 nm,
0.3 mL/min, 58:42 acetonitrile/water, retention time:
11.002 min, enantiomer of 4e: 12.502 min. 6R: Chiracel OD-
H, UV detector 210 nm, 0.8 mL/min, 98:2 hexane/propan-2-ol,
retention time: 8.060 min, enantiomer of 6R: 8.794 min.
Received: June 4, 2007
[9] For previous papers about the synthetic applications of N,N-
dibenzyl-α-amino aldehydes, see: a) J. Barluenga, B. Baragaña,
J. M. Concellón, J. Org. Chem. 1995, 60, 6696–6699; b) J. M.
Published Online: August 23, 2007
Eur. J. Org. Chem. 2007, 5250–5255
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5255