Unnatural α-amino ethyl esters from diethyl malonate or ethyl β-bromo-α-hydroxyiminocarboxylate

Article abstract of DOI:10.3762/bjoc.14.264

We have explored here the scope of the age-old diethyl malonate-based accesses to α-amino esters involving Knoevenagel condensations of diethyl malonate on aldehydes, reductions of the resulting alkylidenemalonates, the preparation of the corresponding α-hydroxyimino esters and their final reduction. This synthetic pathway turned out to be general although some unexpected limitations were encountered. The synthetic modifications of some of the intermediates - using Suzuki-Miyaura coupling or cycloadditions - before undertaking the oximation step - provided accesses to further α-amino esters. Moreover, other pathways to α-hydroxyimino esters were explored including an attempt to improve the cycloadditions between ethyl β-bromo-α-hydroxyiminocarboxylate and various alkylfuranes.

Full text of DOI:10.3762/bjoc.14.264

Unnatural α-amino ethyl esters from diethyl malonate
or ethyl β-bromo-α-hydroxyiminocarboxylate
Eloi P. Coutant1,2, Vincent Hervin1,2, Glwadys Gagnot1,2,3, Candice Ford1,2,
Racha Baatallah1,2 and Yves L. Janin*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2853–2860.
1Unité de Chimie et Biocatalyse, Département de Biologie Structurale
et Chimie, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex
15, France, 2Unité Mixte de Recherche 3523, Centre National de la
Recherche Scientifique, 28 rue du Dr. Roux, 75724 Paris Cedex 15,
France and 3Université Paris Descartes, Sorbonne Paris Cité, 12 rue
de l'École de Médecine, 75006 Paris, France
doi:10.3762/bjoc.14.264
Received: 09 August 2018
Accepted: 08 November 2018
Published: 16 November 2018
Associate Editor: B. Stoltz
Email:
Yves L. Janin* - yves.janin@pasteur.fr
© 2018 Coutant et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
α-amino ester; α-hydroxyimino ester; [2 + 4] cycloadditions;
[2 + 3] cycloadditions; Knoevenagel; nitrosoacrylate; Suzuki–Miyaura
Abstract
We have explored here the scope of the age-old diethyl malonate-based accesses to α-amino esters involving Knoevenagel conden-
sations of diethyl malonate on aldehydes, reductions of the resulting alkylidenemalonates, the preparation of the corresponding
α-hydroxyimino esters and their final reduction. This synthetic pathway turned out to be general although some unexpected limita-
tions were encountered. The synthetic modifications of some of the intermediates – using Suzuki–Miyaura coupling or cycloaddi-
tions – before undertaking the oximation step – provided accesses to further α-amino esters. Moreover, other pathways to
α-hydroxyimino esters were explored including an attempt to improve the cycloadditions between ethyl β-bromo-α-hydroxy-
iminocarboxylate and various alkylfuranes.
Introduction
Our current work on the chemistry of imidazo[1,2-a]pyrazin- lysine from diethyl malonate and γ-chlorobutyronitrile [4]
3(7H)-one luciferins [1] has led us to require a large variety of and appears to be of a very large scope. The key α-hydroxy-
α-amino esters as starting material. In view of the limitations we imino esters 2 precursors to the α-amino esters 1 are usually
encountered in the use of ethyl nitroacetate to reach such variety prepared by oximation of substituted malonates 3, themselves
[2], we have focused here on diethyl malonate-based methods made, for instance, from diethyl malonate (4) and an alkylation
as an alternative. Indeed, as we reviewed recently [3], this reaction or a Knoevenagel condensation–reduction sequence
approach was used for the historic preparation of racemic (Scheme 1).
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Beilstein J. Org. Chem. 2018, 14, 2853–2860.
Table 1: Synthesis of α-amino esters 1b–al via α-hydroxyimino esters
2a–al.
Scheme 1: Malonate-based retrosynthesis of α-amino esters.
Results and Discussion
As depicted in Table 1, Knoevenagel condensations of diethyl
malonate (4) and aldehydes 5a–al followed by reduction of the
intermediate alkylidenemalonates 6a–al led to the substituted
malonates 3a–al. A simple and general procedure was adopted
for the condensation using fairly concentrated ethanolic solu-
tions of diethyl malonate (4) and aldehydes 5a–al along with
catalytic amounts of piperidine and acetic acid as well as some
4 Å molecular sieves to trap the water formed in situ. The
1H NMR monitoring of crude samples pointed out a complete
conversion, most often overnight at 60 °C, and the resulting
solutions of alkylidenemalonates 6a–al were then directly
reduced to give the malonates 3a–al. For this reduction step,
palladium-based catalytic hydrogenation was preferably used
although, when incompatible with the substrates, sodium boro-
hydride was employed. In most cases, large proportion of the
expected substituted malonates 3a–al were observed by
1H NMR. Thus, in order to simplify even further this procedure,
these crude malonates were subjected to the next step after a
minimal work-up. Accordingly, they were dissolved in ethanol
and treated first with sodium ethoxide followed by isoamyl
nitrite (iAmONO) to give the corresponding α-hydroxyimino
esters 2a–al. These resulting compounds were then purified and
isolated in yields reported in Table 1. These values usually re-
flected the eventual problems encountered in the course of the
reduction or the oximation steps since the condensation was
very often more than 98% complete. As further commented on
and depicted in Scheme 2, in few instances (preparations of
2t–v and 2ae), explanations were found for the low yield ob-
served and could be sometimes acted upon. In any case, the
final reduction of the α-hydroxyimino esters 2b–al using zinc
and hydrochloric acid in ethanol gave the α-amino esters 1b–al,
which were usually of a high purity grade without recourse to a
chromatography. In few cases, only a sample of the intermedi-
ate α-hydroxyimino esters was purified for analytical purposes.
For instance, pure α-amino esters 1m and 1y were obtained in
four steps from the corresponding aldehydes 5m and 5y with-
out the recourse to any chromatography in quite acceptable
overall yields.
Ar
R
% 2a
% 1
a
b
Ph
2-MeC6H4
60
61
nd
85
85
87
91
85
92
86
78
91
88
89
81b
85
94
92
95
84
94
94
92
85
86
83
75b
91
92
94
56
63
89
88
90
94
95
92
89
87
c
3-MeC6H4
63
d
4-MeC6H4
60
e
4-iPrC6H4
48
f
cyclopentyl
35
g
cyclohexyl
50
h
2-CF3C6H4
39
i
3-CF3C6H4
41
j
4-CF3C6H4
62
k
2-FC6H4
57
l
3-FC6H4
65
m
n
4-FC6H4
–
2,4-F2C6H3
2,6-F2C6H3
2,3-F2C6H3
2,5-F2C6H3
3,5-F2C6H3
2,3,5-F3C6H2
2-ClC6H4
50
o
54
p
51
q
50
r
46
s
35
t
23/49c
26/59c
37/62c
42
u
3-ClC6H4
v
4-ClC6H4
w
x
4-BrC6H4
2-MeOC6H4
3-MeOC6H4
2-BnOC6H4
3-BnOC6H4
4-BnOC6H4
2-pyridyl
60
y
–
z
48
aa
ab
ac
ad
ae
af
ag
ah
ai
aj
ak
al
37
40
49
3-pyridyl
43
furan-2-yl
33/47d
33
5-methylfuran-2-yl
4,5-dimethylfuran-2-yl
5-ethylfuran-2-yl
5-trifluoromethylfuran-2-yl
5-ethylthiophen-2-yl
3-methylthiophen-2-yl
4,5-dimethylthiophen-2-yl
10/23e
34
36
29
32
31
aIsolated yield from aldehydes 5. bOverall isolated yield from alde-
hydes 5m or 5y. cReactions run in isopropanol and NMe4BH4 used as
a reductant. dReduction run at –10 °C for 90 minutes. eSame as note d
but using a THF/ethanol mixture.
Out of these results, we first sought an explanation for the
modest yields observed for the preparation of the 2, 3 or
4-chlorophenyl-α-hydroxyimino esters 2t–v. As depicted in
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Beilstein J. Org. Chem. 2018, 14, 2853–2860.
malonate 6ae using a palladium-based catalytic hydrogenation
also led to the concomitant hydrogenation of the furan ring to
give compound 8. As depicted, this actually allowed us to
prepare to the 2-tetrahydrofuranyl-bearing α-aminoester 10 in a
35% overall yield via α-hydroxyimino ester 9, but it also forced
us to use borohydrides to avoid the furan ring hydrogenation.
Accordingly, an extensive study of the reduction of compound
6ae with borohydrides was made. Trials included reactions run
at 0 °C overnight, the use of wet ethanol or dry THF, the addi-
tion of less than one equivalent of the sodium borohydride as
well as the use of tetramethylammonium borohydride or sodi-
um cyanoborohydride, but none were overly successful. Indeed,
a representative assay (dry THF, 24 hours at 0 °C, 0.7 equiva-
lents of NaBH4) led to the isolation of 49% of compound 3ae.
Moreover, extensive purification procedures of the complex
reaction mixtures led to the full characterization of compound
11 and 12 stemming from over-reduction. Interestingly, the
latter one has actually been reported to occur upon a 48 hour
long sodium borohydride reduction of S,S-diethyl 2-(furan-2-
ylmethylene)propanebis(thioate), the bisthioester homolog of
compound 6ae [5]. Finally, the oximation of the pure malonate
3ae only led to a 64% yield of the corresponding α-hydroxy-
imino ester 2ae, thus accounting for the 33% overall yield re-
ported in Table 1 when we proceeded without purification. It is
only later that we found that shortening the reaction of the sodi-
um borohydride reduction of 6ae down to 1.5 hours and
lowering the temperature to –10 °C led to a sizable improve-
ment in the overall yield (47% instead of 33%). However, these
Scheme 2: Some side products and synthesis of α-amino ester 10.
Scheme 2, the 1H NMR monitoring of the ethanolic solution of conditions were a trade-off between reduction of 6ae into 3ae
the alkylidenemalonate 6u pointed out a slow but steady 1,4-ad- and over-reduction since 1H NMR analysis of this trial pointed
dition of ethanol to give compound 7 (a 30% conversion was out the coexistence of unreacted material 6ae along with
observed over 3 weeks). Moreover, even if a fresh solution of (traces) of the over-reduced compounds 11 and 12. We applied
compound 6u was immediately treated with sodium borohy- this finding to the reduction of 6ag and had to allow for the low
dride, a proportion of this 1,4-adduct was seen in the reaction solubility of this compound in ethanol and thus run the reaction
mixture amongst other side products. We also tried to allow for in a mixture of ethanol and THF. In any case, we could obtain
an eventual reversal of the ethanol addition and thus increased more of the corresponding α-hydroxyimino ester 2ag but in a
the reaction time of the reduction step, but compound 7 still very modest 23% overall yield. This last result, likely due
remained unaffected and even more side products arose. To to additional problems at the oximation stage, is thus only em-
avoid this 1,4-addition, we then resorted to use a less nucleo- phasizing the vagaries of this synthetic access that will some-
philic solvent, and tried isopropanol instead of ethanol. Howev- time require a specific study.
er, even if the ensuing reduction of 6u using sodium borohy-
dride led to a somewhat better yield of compound 3u (as esti- As shown in Scheme 3, the lack or the cost of some more exotic
mated by 1H NMR), side products resulting from over-reduc- aldehydes 5 were circumvented as we found out that
tions of the ester moieties were still observed. It is only when Suzuki–Miyaura carbon–carbon coupling reactions could be
switching to tetramethylammonium borohydride that this was achieved with the brominated alkylidenemalonates 13 or 17 as
alleviated and the yields of α-hydroxyimino esters 2t–v reached well as the 5-bromofuran derivative 29. Indeed, coupling these
49, 59 and 62% from aldehydes 5t–v, respectively. Of note is compounds with cyclopropylboronic acid gave the correspond-
that we also tried this reducing agent to improve the overall ing cyclopropyl derivatives 14, 18 or 30 in 60, 47 and
yield of the benzyloxy-bearing oxime 2ab, but to no avail. We 75% yield, respectively. The palladium-based reduction of com-
next focused on the furan-bearing α-hydroxyimino esters such pound 14 and 18 also led to the hydrogenation of their cyclo-
as compound 2ae. First of all, reduction of the alkylidene- propyl ring into a propyl side chain to give compounds 15 and
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Beilstein J. Org. Chem. 2018, 14, 2853–2860.
scribed below. We suggest a somehow forbidding cation chela-
tion by the oxygen of the furan ring which would prevent its
reaction with isoamyl nitrite. Interestingly, a literature search
for similar reactions starting from β,β-disubstituted malonates,
led to two reports [7,8], whereas from β,β-substituted aceto-
acetates three examples were reported [9-11], but only one sub-
strate [7] out of these features an aromatic substituent.
As depicted in Scheme 4 and contrary to our attempt to prepare
the furan-bearing β-methyl oxime 35, the phenyl-bearing
β-methyl aminoester 38 was obtained via the substituted
malonate 36 to give upon oximation the α-hydroxyimino ester
37 (although in only a 14% yield). A slightly different ap-
proach was used for the preparation of the even more hindered
β,β-dimethyl aminoester 41. Treatment of the monoester 39
[12,13] with lithium diisopropylamide and isoamyl nitrite
overnight was once again not really successful as a rather poor
15% yield of the corresponding α-hydroxyimino ester 40 was
isolated. Nevertheless, the ensuing reduction gave the desired
α-amino esters 38 and 41. The model reduction of the
α-hydroxyimino ester 2a into the corresponding N-hydroxyl-
amino ester 42 was also studied. Initial trials using reported pro-
cedures [14-16] pointed out an exceedingly slow reaction
requiring repeated additions of trimethylamine–borane com-
plex on a solution of compound 2a in diethyl ether saturated
with hydrogen chloride (ether containing trifluoromethane-
sulfonic acid was also tried). This led only to a 40% yield prob-
ably because of the occurrence of stable boron-based com-
plexes. In an attempt to improve this, we applied the reported
use of triethylsilane for reducing oximes into N-hydroxyl-
amines [17] to the case of the α-hydroxyimino ester 2a. Howev-
er, bringing the reduction of 2a into the N-hydroxylamino deriv-
ative 42 to completion with this reagent still required a repeated
Scheme 3: Syntheses of α-amino esters 22, 24, 26, 28 and 33.
19. Alternatively, the recourse to sodium borohydride reduced addition of triethylsilane over a week and led to a 69% isolated
these compounds as well as the furan-bearing derivative 30 into yield. Interestingly, further literature search pointed out a very
the target cyclopropyl-bearing derivatives 16, 20 and 31. The different synthetic access to such N-hydroxylamine derivative
ensuing oximation of all these compounds provided the (via nitrones) which appears to be far more efficient [18-22].
α-hydroxyimino esters 21, 23, 25, 27 and 32 in 31–88% overall The isoxazole-bearing α-amino esters 46a,b were also prepared
yield. These were then reduced into the corresponding α-amino via α-hydroxyimino esters. Their preparation started with the
esters 22, 24, 26, 28 and 33 using zinc and hydrochloric acid. alkylation of diethyl malonate (4) with propargyl bromide to
We also focused on the preparation of the β-methylated furan- give compound 43 (which could not be separated from unre-
bearing α-hydroxyimino ester 35. The introduction of the acted malonate and the bis-alkylated derivative). In the next
methyl group was achieved using the previously reported step, [2 + 3] cycloaddition reactions with nitroethane or 1-nitro-
methylmagnesium chloride 1,4-addition on diethyl furfuryli- propane gave the isoxazole-bearing compounds 44a,b in 23 and
denemalonate (6ae) [6]. Quite unexpectedly, repeated attempts 33% yield, respectively. Then, oximation of these compounds
to obtain the α-hydroxyimino ester 35 from the resulting gave the α-hydroxyimino esters 45a,b in 50 and 58% and upon
β-methylated derivative 34 failed. Trials were made not only their reduction, the expected α-amino esters 46a,b.
with sodium ethoxide but also with the stronger lithium diiso-
propylamide. We do not have an explanation for this observa- As depicted in Table 2, in order to avoid the recourse to the
tion, although such oximation was achieved (in a low yield) sometime expensive furan-bearing aldehydes 5 and reach an
when starting from the phenyl-bearing analogue 36 as de- even more diverse set of α-amino esters, we investigated the use
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Beilstein J. Org. Chem. 2018, 14, 2853–2860.
Scheme 4: Syntheses of α-amino esters 38, 41 and 46a,b.
of ethyl β-bromo-α-hydroxyiminocarboxylate 47 which has
been developed by Gilchrist for the synthesis of many types of
α-hydroxyimino esters [23-26] and then extensively used to
prepare a wide range of amino acids [3,27]. This proceeds via a
[2 + 4] cycloaddition between ethyl nitrosoacrylate, generated
in situ from the reaction of sodium carbonate and furan 48, to
give the cycloadduct 49. Then, upon heating, a rearrangement
leads to the furan-bearing α-hydroxyimino esters 2. Reports
have thus described the preparation of 2ae in a 46% yield from
furan (48ae) [24] and compound 2af in a 50% yield from
2-methylfuran (48af) [25]. For our part, we first made exten-
sive trials to improve such yields using 2-methylfuran (48af) as
a model substrate. It turned out that this [2 + 4] cycloaddition
can proceed under a wide range of conditions. The original
conditions stirring compound 47, an excess of 2-methylfuran
(48af) and solid sodium carbonate in dichloromethane for
24 hours gave the expected cycloadduct 49af but we found out
that a chromatography was enough to achieve its isomerisation
into 2af. Interestingly, we also found out that the excess
2-methylfuran (48af) was not required and that the reaction
proceeded much faster and led directly to the α-hydroxyimino
ester 2af if tetrabutylammonium bromide was added as a phase
transfer catalyst. For instance, (note b in Table 2), stirring a
1:1.1 proportion of compounds 47 and 48af, sodium carbonate,
and 0.01 equiv tetrabutylammonium bromide in toluene for
1.5 hours led to a 42% yield of the α-hydroxyimino ester 2af.
Table 2: Synthesis of furan-bearing α-amino esters by a [2 + 4] cyclo-
addition.
Ar
R1
R2
% 2a
% 1a
ae
af
H
Me
H
H
–
42b/41c/50d
38b/48c/50e
43b
–
–
ag
ah
am
an
ao
ap
aq
ar
Me
Me
H
–
Et
–
n-Pr
n-pentyl
Me
H
40b
79
90
82
82
90
86
H
32c
Et
21c,f
(CH2)4
40b,g
Et
Me
Me
25c, h
30c,i
iPr
aIsolated yield. bToluene, NBu4Br (cat.), Na2CO3. cH2O/AcOEt, NH3/
HCO3H. dH2O/AcOEt, Li2CO3. eH2O/AcOEt, Na2CO3. fOverall yield
from 1-(2-methylfuran-3-yl)ethan-1-one. gOverall yield from 6,7-dihy-
drobenzofuran-4(5H)-one. hOverall yield from ethyl 2-ethylfuran-3-
carboxylate. iOverall yield from ethyl 2-isopropylfuran-3-carboxylate.
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Beilstein J. Org. Chem. 2018, 14, 2853–2860.
On the other hand, such catalysis was not required when stir- homolog 58 from the readily available dioxane derivative 56
ring a 1:1.1 proportion of compounds 47 and 48af in a mixture [35] in a 46% overall yield. However, the final oxime reduction
of ethyl acetate and water and an array of bases such as ammo- turned out to be much improved when using hydrogen and
nium bicarbonate (41% yield, note c in Table 2). We tried under palladium over charcoal in acetic acid.
these conditions 1:2 or 2:1 proportions of compounds 47 and
48af but the isolated yields of α-hydroxyimino ester 2af were of
(only) 56% and 54%, respectively. Later on, when using a
1:1 proportion of compounds 47 and 48af, a slightly improved
yield of 50% was achieved when switching from ammonium
bicarbonate to lithium carbonate (note d in Table 2) or in the
case of the preparation of compound 2ag switching to sodium
carbonate (note e in Table 2). Unfortunately, if the 1H NMR
analysis of another chromatographic fraction obtained when
purifying these trials pointed out the occurrence of inseparable
mixture of aliphatic compounds, these could never be properly
purified and identified. A mechanistic explanation for these av-
erage yields could be the occurrence upon the base reaction
with compound 47 of cis and trans conformations of the
nitrosoacrylate. The cis one would be susceptible to undergo an
immediate [2 + 4] cycloaddition with the furan whereas the
trans form would not, and since the equilibration between the
two forms was reported [28] to be a slow process, it would
potentially lead to decomposition materials. In any case, as
depicted in Table 2, from the commercially available furans
48af–an or from crude solutions of the less accessible (and vol-
atile) compounds 48ao–ar (their preparation greatly benefitted
from the reported [29] synthesis of compound 48ap and is fully
described in the experimental section), we could isolate the cor-
responding α-hydroxyimino esters using a variety of conditions
which were then reduced into the α-amino esters. Of note is that
Scheme 5: Syntheses of α-amino esters 53 and 58.
extensive decomposition was observed when starting from
2-methoxyfuran and as seen by 1H NMR, no oxime occurrence
was observed from 2,3,4-trimethylfuran.
Conclusion
As in our previous report [2], the goal of this investigation was
Finally, as described in Scheme 5, we also prepared the dioxo- to reach a very large variety of racemic α-amino esters. In the
lane-bearing α-amino esters 53 and 58. An approach involving a course of this study, we could point out that, in comparison with
key Curtius reaction was first tried for the preparation of 53. ethyl nitroacetate [2], the use of diethyl malonate (4) is at least
As reported [30], alkylation of diethyl malonate (4) with as efficient and far more general, especially for the initial con-
2-(bromomethyl)-1,3-dioxolane (50) gave the diester 51. A con- densation step. However, as for the reduction of nitroacrylates
trolled saponification led to the mono acid 52 and its reaction [2], the use of borohydrides to reduce some of the resulting
with diphenylphosphoryl azide [31-33] gave 16% of the target alkylidenemalonates 6 turned out to be limiting, even in some
aminoester 53 upon treatment with hydrochloric acid. Alterna- cases, tetramethylammonium borohydride instead of sodium
tively, oximation of the diester 51 gave 28% (from diethyl borohydride could alleviate this limitation. Besides, out of the
malonate) of the α-hydroxyimino ester 54, which turned out to many preparations of α-hydroxyimino esters described above,
be not stable in CDCl3 because of hydrogen chloride traces. For another limitation was encountered when steric hindrance be-
this reason, no attempt was made to reduce its oxime function came a previously unreported limiting factor for the oximation
under the acidic conditions used above (hydrochloric and of compound 34, and to a lesser degree compounds 36 or 39.
powdered zinc) and we successfully used instead the much Finally, the use of the ethyl β-bromo-α-hydroxyimino carboxyl-
milder [34] mixture of ammonium formate and zinc in ethanol ate 47 in a [2 + 4] cycloaddition reaction led us to suggest a
at room temperature to give 43% of the target α-amino ester 53. simple, reliable and robust alternative for the preparation of
The same strategy gave the corresponding α-amino ester many furan-bearing α-amino esters.
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Beilstein J. Org. Chem. 2018, 14, 2853–2860.
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This work was supported by the Agence Nationale de la
Recherche (ANR), grant ANR-11-CRNT-0004, in the context
of the investment program ‘GLOBAL CARE’, an association of
the Instituts Carnot ‘Pasteur-Maladies Infectieuses’, ‘Curie-
Cancer’, ‘Voir et Entendre’, ‘Institut du Cerveau et de la moelle
Épinière’ and the ‘Consortium pour l’Accélération de l’Innova-
tion et de son Transfert dans le domaine du Lymphome’
(CALYM). This project also benefited from the Valoexpress
funding call of the Institut Pasteur. Prof. Christian Bréchot, Dr.
Muriel Delepierre and Dr. Daniel Larzul, from the Institut
Pasteur are acknowledged for their interest and support. The
Amgen foundation is acknowledged for the benefit of an
Amgen Scholars Program fellowship for CF.
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ORCID® iDs
Eloi P. Coutant - https://orcid.org/0000-0002-5571-7442
Glwadys Gagnot - https://orcid.org/0000-0002-5778-995X
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