Enamines of 3-acyltetramic acids from β-enamino amides and amino acids

Article abstract of DOI:10.1016/j.tetlet.2017.11.023

A novel approach for the synthesis of enamine derivatives of N-protected 3-acyltetramic acids is described. The synthetic procedure relies on α-C-acylation of β-enamino amides with N-protected α-amino acids and subsequent cyclisation of the obtained inter

Full text of DOI:10.1016/j.tetlet.2017.11.023

Accepted Manuscript
Enamines of 3-acyltetramic acids from β-enamino amides and amino acids
Plamen Angelov, Silvia Ivanova, Pavel Yanev
PII:
S0040-4039(17)31426-0
https://doi.org/10.1016/j.tetlet.2017.11.023
TETL 49466
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
12 September 2017
8 November 2017
10 November 2017
Please cite this article as: Angelov, P., Ivanova, S., Yanev, P., Enamines of 3-acyltetramic acids from β-enamino
amides and amino acids, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.11.023
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Enamines of 3-acyltetramic acids from β-enamino amides and amino
acids
*
Plamen Angelov , Silvia Ivanova and Pavel Yanev
University of Plovdiv Paisii Hilendarski, Department of Organic Chemistry
24 Tsar Asen Str., 4000 Plovdiv, Bulgaria
e-mail: angelov@uni-plovdiv.bg, Tel. +359 32 261349
Abstract
A novel approach for the synthesis of enamine derivatives of N-protected 3-acyltetramic acids is
described. The synthetic procedure relies on α-C-acylation of β-enamino amides with N-protected α-
amino acids and subsequent cyclisation of the obtained intermediates in refluxing TFA. The tetramic
derivatives are obtained with very good enantiopurity (e.r. ≥ 95:5). Ring-enlarged analogues (piperidine-
2,4-diones) can also be obtained from β-amino acids.
Keywords: tetramic acids, amino acids, enamines, enaminones, C-acylation
Introduction
The pyrrolidine-2,4-dione ring system, commonly referred to as “tetramic acid”, is a key structural motif
1
in many natural products possessing antimicrobial, antifungal and antiviral properties. The chemistry of
tetramic acids has been extensively studied and several excellent reviews have been published in recent
2
years. The substitution pattern of the pyrrolidine-2,4-dione motif in natural products varies greatly, but
most often these compounds bear an acyl substituent at position 3 of the ring system. Enamine
derivatives of 3-acyltetramic acids are rarely found in nature and, with the notable exception of the
3
synthetic inhibitor of microtubule assembly TN16, have received little attention. There are scarce
4
, 3a
reports dealing with their synthesis, as well as antibacterial and herbicidal activity,
in all of which
condensation between a preformed 3-acyltetramic acid and an amine is the synthetic method of choice.
O
O
O
O
R1
R1
HN
3
NHR3
OH R NH2
HN
R2
R2
- H O
2
Scheme 1. Traditional approach towards enamine derivatives of 3-acyltetramic acids.

5
6
In the course of our studies regarding the chemistry of β-enamino amides, a subclass of enaminones,
we have developed a novel approach towards enamine derivatives of N-protected 3-acyltetramic acids.
In contrast to traditional methods, here the enamine moiety is introduced at the very beginning of the
synthesis and the tetramic ring is constructed later by two consecutive reactions involving an amino
acid.
Results and Discussion
5
b
β-enamino amides 2 are easily prepared by the condensation of β-ketoamides and amines. These
compounds are nucleophilic at the α−position and we have previously made use of their reaction with
acid chlorides to obtain α-C-acylated derivatives and subsequently turn them into unsymmetrical
5
a
5b
enaminoketones or β-ketoamides. Searching for an extension of this methodology, an attempt was
made to acylate the β-enamino amides 2 with suitably activated amino acids instead of simple acid
chlorides. The initial experiments with N-ethoxycarbonyl glycine and a range of activating reagents (DCC,
DIC, T3P, alkyl chloroformates) gave promising results; regardless of the activation method, the reaction
with enamino amide 2 gave the expected α-C-acylated product 3a in good yield. For further experiments
we chose the mixed carbonic anhydride method, using ethyl chloroformate as the activating reagent
and a series of eight N-protected amino acids. The mixed carbonic anhydrides were prepared from N-
o
methylmorpholine (NMM) salts of the corresponding N-protected amino acid in CH
2
Cl
2
at 0 C, and after
addition of the β-enamino amide 2 and DMAP (0.2 equiv.) the reaction mixtures were stirred for 1 h at
r.t. In all cases the α-C-acylated products 3 were obtained in high yields and, more importantly, with
excellent retention of configuration when the reaction was carried out with chiral amino acids (Scheme
2, Table 1). To assess the stereochemical outcome of the acylation reaction, the experiments with
alanine and phenylalanine were carried out using both racemic and enantiopure L-amino acids. The
enantiomeric ratios were determined by chiral phase HPLC and were ≥99:1 for all chiral products 3d-j.
R2
R2
O
O
NH O
NH
O
O
i
ii
NHR1
NHR1
NHR1
( )n
NHPG
1
2
3
R3
2
Scheme 2. Preparation of α-C-acylated β-enaminoamides 3. Reagents and conditions: (i) R NH
equiv.), Na SO (10 equiv.), CH Cl , 12 h, r.t.; (ii) Amino acid (1 equiv.), NMM (1 equiv.), EtOCOCl (1
equiv.), DMAP (0.2 equiv.), CH Cl , 1 h, 0 C to r.t. See ESI for full experimental procedures.
2
(1
2
4
2
2
o
2
2

Table 1. Yields of α-C-acylated compounds 3, obtained according to Scheme 2.
1
2
3
3
a
b
c
R
R
R
PG
n
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
Yield 3 (%)
91
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
Et
H
H
COOEt
Troc
Et
73
CH
2
CH
2
Ph
H
COOEt
COOEt
Troc
92
d
e
f
Et
CH
CH
CH
CH
3
3
3
3
73
Et
83
CH
CH
2
CH
CH
Et
2
Ph
Ph
COOEt
Troc
86
g
h
i
2
2
68
CH
CH
CH
2
Ph
2
Ph
2
Ph
COOEt
Troc
69
Et
77
j
CH
CH
CH
2
2
2
CH
CH
CH
Et
2
Ph
2
Ph
2
Ph
COOEt
COOEt
Troc
70
k
l
H
H
H
H
H
H
H
82
H
50
m
n
o
p
q
Ph
Ph
Ph
H
Troc
79
Et
COOEt
COOEt
COOEt
Troc
85
CH
CH
CH
2
2
2
CH
CH
CH
2
Ph
2
Ph
2
Ph
86
55
Ph
83
Next, compounds 3 were heated in TFA at reflux– conditions known to cause C-C bond scission in
5
a
1
simpler analogues. Here, however, no such reaction was observed. When R in 3 was a phenyl group,
heating at reflux in TFA for one hour led to clean formation of enaminotetramic derivatives 4 in nearly
quantitative yield, accompanied by aniline as a co-product (Scheme 3). We were pleased to find that the
enaminotetramic derivatives were obtained with very good enantiopurity, despite the harsh cyclisation
conditions. Enantiomeric ratios of ≥ 95:5 were measured by chiral phase HPLC for all chiral products 4d-
j.
R2
R2
NH
O
NH
O
NHPh TFA, reflux
NHPG
NPG + PhNH
R3
2
O
O
R3
3a-j
4a-j

Scheme 3. Cyclisation of 3a-j to enamine derivatives of 3-acyltetramic acids 4. Reagents and conditions:
in TFA (100mg/mL), reflux, 1 h.
3
Table 2. Yields and enantiomeric ratios of the enaminotetramic derivatives 4, obtained according to
Scheme 3.
2
3
a
4
a
b
c
d
e
f
R
R
PG
Yield 4 (%)
e.r.
Et
Et
H
H
COOEt
Troc
93
90
78
82
88
87
89
95
95
90
-
-
-
CH
2
CH
Et
2
Ph
H
COOEt
COOEt
Troc
CH
CH
CH
CH
3
3
3
3
95 : 5
98 : 2
97 : 3
97 : 3
96 : 4
97 : 3
96 : 4
Et
CH
CH
2
CH
CH
Et
2
Ph
Ph
COOEt
Troc
g
h
i
2
2
CH
CH
CH
2
Ph
2
Ph
2
Ph
COOEt
Troc
Et
j
CH
2
CH
2
Ph
COOEt
a
Enantiomeric ratios are rounded to the nearest percent and were measured by HPLC, using Phenomenex Lux
Amylose-1 or Lux Amylose-2 columns. See ESI for details.
1
Attempts to achieve better atom economy by using the simpler starting material 3k (R =H) were not
successful. Two products, resulting from competing modes of cyclisation, were obtained – the expected
tetramic derivative 4c (17%) and pyrrolin-3-one 5 (42%) (Scheme 3).
O
NH2
O + PhCH CH NH
2 2 2
Ph
NH
O
O
N
EtOOC
Ph
5
(42%)
TFA, reflux
NH2
NHCOOEt
NH
O
3
k
+
NH3
NCOOEt
c (17%)
O
4
Scheme 4. Competing modes of cyclisation in compound 3k.
Similar cyclisation took place with chain-extended analogues 3l-q, leading to piperidine-2,4-diones 6
Scheme 5). Unlike the formation of 5-membered rings, the cyclisation mode here was not affected by
(

1
1
1
the R substituent – the same product 6a was obtained from both 3l (R =H) and 3q (R =Ph) in
1
1
comparable yields. Likewise, 3o (R =Ph) and 3p (R =H) both gave product 6d. Despite the better atom
1
1
economy achieved with analogues in which R =H, the enamino anilides (2, R =Ph) are still preferable
starting compounds with regard to the overall yield, because of their better performance in the
acylation stage.
R2
R2
NH O
NH
O
O
NHR1 TFA, reflux
NPG
1
+
R NH
2
O
l-q
NHPG
3
6
Scheme 5. Cyclisation of chain-extended analogues 3l-o to piperidine-2,4-diones 6. Reagents and
conditions: 3 in TFA (100mg/mL), reflux, 1 h.
Table 3. Yields of piperidine-2,4-diones 6, obtained according to Scheme 5.
1
2
3
l
6
a
b
c
R
R
PG
Yield 6 (%)
H
CH
2
CH
2
Ph
Troc
89
70
92
96
80
92
m
n
o
p
q
Ph
Ph
Ph
H
Et
Troc
Et
COOEt
COOEt
COOEt
Troc
d
d
a
CH
CH
CH
2
2
2
CH
CH
CH
2
Ph
2
Ph
2
Ph
Ph
As reported in earlier publications, the enamines of 3-acyltetramic acids equilibrate between the Z- and
E-isomers in solution. The exchange is slow on the NMR time scale and in CDCl at r.t. they are
registered as a 1:1 mixture. Indeed, all compounds of type 4 showed two broad NH signals in the 10.5
11.3 ppm region, integrating for 0.5H each. The rest of the signals were also affected in a similar way,
3
4
,7
–
but usually to a lesser extent and without clear separation. Compounds 6, on the other hand, showed
only one broad NH signal at about 13 ppm, with the rest of the signals being well resolved. This is likely
an indication of faster Z/E exchange in the ring-enlarged analogues, rather than preference for any of
the isomers, although VT NMR experiments would be necessary to clarify this.
Conclusion

In conclusion, we have successfully acylated β-enamino amides with N-protected amino acids and
discovered a concise and operationally simple approach towards enamine derivatives of 3-acyltetramic
acids and 3-acylpiperidine-2,4-diones. The method appears to be of broad scope and features very low
racemisation.
Acknowledgements
We gratefully acknowledge funding from the Royal Society of Chemistry (Grant RF17-6592) and the
scientific research fund of the Bulgarian Ministry of Education and Science (Grant DN09/15). We thank
Dr Mladen Naydenov for carrying out high resolution mass spectral measurements on equipment
provided under the FP7/REGPOT-2009-1/BioSupport project.
References
1. (a) Royles, B. J. L. Chem. Rev. 1995, 95, 1981-2001; (b) Schobert, R.; Schlenk, A. Bioorg. Med. Chem.
2008, 16, 4203–4221. (c) Jeong, Y.-C.; Moloney, M. G. Synlett 2009, 2487-2491. (d) Wu, G.; Sun, X.; Yu,
G.; Wang, W.; Zhu, T.; Gu Q.; Li, D. J. Nat. Prod. 2014, 77, 270–275.
2. (a) Petermichl, M.; Schobert, R. Synlett 2017, 654-663. (b) Bai, W.-J.; Lu, C.; Wang, X. Journal of
Chemistry 2016, Article ID 8510278, doi:10.1155/2016/8510278. (c) Yoda, H.; Takahashi, M.; Sengoku, T.
Studies in Natural Products Chemistry 2015, 46, 99-131. (d) Mo, X.; Li, Q.; Ju, J. RSC Adv. 2014, 4, 50566-
50593.
3
. (a) Yuki, H.; Kaizu, Y.; Yoshida, S.; Higuchi, S.; Honda, S.; Takiura, K. Chem. Pharm. Bull. 1971, 19, 1664-
668. (b) Arai, T. FEBS Letters 1983, 155, 273-276. (c) Dorléans, A.; Gigant, B.; Ravelli, R. B. G.; Mailliet,
1
P.; Mikol, V.; Knossow, M. Proc. Nat. Acad. Sci. U.S.A. 2009, 106, 13775-13779.
4. (a) Jeong, Y.-C.; Anwar, M.; Moloney, M. G. Bioorg. Med. Chem. Lett. 2014, 24, 1901-1906. (b) Wang,
X.-F.; Si, T.-F.; Li, Q.-B.; Zhu, Z.-Y.; Zhu, X.-J.; Qiang, S.; Yang, C.-L. ARKIVOC 2010, (ii), 31-48. (c) Linder, D.;
Schobert, R. Org. Biomol. Chem. 2017, 15, 7672-7677.
5
6
7
. (a) Venkov, A. P.; Angelov, P. A. Synthesis 2003, 2221-2225. (b) Angelov, P. Synlett, 2010, 1273-1275.
. Greenhill, J.V. Chem. Soc. Rev. 1977, 6, 277–294.
. Tietze, O.; Schiefner, B.; Ziemer, B.; Zschunke, A. Fresenius. J. Anal. Chem. 1997, 357, 477-481.

Highlights
-
-
-
-
β-enamino amides are C-acylated with practically no racemisation.
The C-acylated intermediates cyclise to enamines 3-acyltetramic acids.
Ring-enlarged analogues are accessible.
The enaminotetramic derivatives are obtained with e.r. ≥ 95:5.

Graphical Abstract
Enamines of 3-acyltetramic acids from β-
enamino amides and amino acids
Plamen Angelov, Silvia Ivanova and Pavel Yanev
R2
NH
R2
NH
O
O
OH
+
R3
R3
O
O
NH
PG
PhHN
N
PG
2
3
PG = Troc, COOEt; R = Et, CH CH Ph; R = H, CH , CH Ph
2
2
3
2
6
0 - 85% yield over two steps