A short synthesis of 3-enoyltetramic acids employing a new acyl ylide conjugate of Meldrum's acid

Article abstract of DOI:10.1016/j.tetlet.2017.11.025

2,2-Dimethyl-5-(triphenylphosphoranylidene)acetyl-1,3-dioxan-4,6-dione (3) is a new activated β-ketoacyl equivalent, readily prepared in quantitative yield by reaction of Meldrum's acid with the stable ylide Ph₃PCCO. Its reaction with α-amino esters affords the corresponding N-(β-ketoacyl)amino ester ylides which, when treated with aldehydes and KOtBu, undergo a simultaneous Wittig olefination cum Dieckmann cyclisation to yield the respective 3-enoyltetramic acids.

Full text of DOI:10.1016/j.tetlet.2017.11.025

Accepted Manuscript
A short synthesis of 3-enoyltetramic acids employing a new acyl ylide conjugate
of Meldrum’s acid
Kevin Lovmo, Steffen Dütz, Marina Harras, Robert G. Haase, Wolfgang Milius,
Rainer Schobert
PII:
S0040-4039(17)31428-4
https://doi.org/10.1016/j.tetlet.2017.11.025
TETL 49468
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 October 2017
10 November 2017
11 November 2017
Please cite this article as: Lovmo, K., Dütz, S., Harras, M., Haase, R.G., Milius, W., Schobert, R., A short synthesis
of 3-enoyltetramic acids employing a new acyl ylide conjugate of Meldrum’s acid, Tetrahedron Letters (2017), doi:
https://doi.org/10.1016/j.tetlet.2017.11.025
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Graphical Abstract
A short synthesis of 3-enoyltetramic acids employing a Leave this area blank for abstract info.
new acyl ylide conjugate of Meldrum’s acid
Kevin Lovmo, Steffen Dütz, Marina Harras, Robert G. Haase, Wolfgang Milius, Rainer Schobert*

1
Tetrahedron Letters
journal homepage: www.els evier.com
A short synthesis of 3-enoyltetramic acids employing a new acyl ylide conjugate of
Meldrum’s acid
Kevin Lovmo, Steffen Dütz, Marina Harras, Robert G. Haase, Wolfgang Milius, and Rainer Schobert*
Department of Chemistry, University Bayreuth, Universitaetsstraße 30, D-95440 Bayreuth, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2,2-Dimethyl-5-(triphenylphosphoranylidene)acetyl-1,3-dioxan-4,6-dione (3) is a new activated
β-ketoacyl equivalent, readily prepared in quantitative yield by reaction of Meldrum’s acid with
the stable ylide Ph3PCCO. Its reaction with α-amino esters affords the corresponding N-(β-
ketoacyl)amino ester ylides which, when treated with aldehydes and KOtBu, undergo a
simultaneous Wittig olefination cum Dieckmann cyclisation to yield the respective 3-
enoyltetramic acids.
Available online
Keywords:
2017 Elsevier Ltd. All rights reserved.
Meldrum’s acid
Tetramic acids
Phosphorus ylide
Wittig olefination
Introduction
3-Acyltetramic acids occur as metabolites of bacteria, molds,
fungi, and sponges.1–4 Biosynthetically, they are comprised of
polyketides and α-amino acids. 3-Enoyltetramic acids
1
constitute an interesting subclass, frequently associated with
biological activity, and synthetically accessible on various
routes.5-9 In 1988 Boeckman reported the synthesis of 6-
diethylphosphonomethyl-2,2-dimethyl-1,3-dioxen-4-one (2) and
its use as an activated β-ketoester equivalent in the synthesis of
3-enoyltetramic acids.10 As an alternative, we developed a related
acyl ylide 3 derived from Meldrum’s acid which offers access to
compounds 1 in only three steps (Fig. 1).
Results and discussion
2,2-Dimethyl-5-(triphenylphosphoranylidene)acetyl-1,3-diox-
an-4,6-dione (3) was readily obtained as an airstable solid in
virtually quantitative yield from heating THF solutions of
Meldrum’s acid (4) and ketenylidenetriphenylphosphorane,
Ph3PCCO (5). The latter is a stable ylide, not entering into
olefinations with carbonyl compounds, but reacting instead with
OH-, NH-, SH-, and CH-acidic compounds to give acyl ylides.11
It was prepared in three steps from ethyl bromoacetate and
Ph3P.12 The molecular structure of ylide 3, as obtained from a
single crystal X-ray diffraction analysis, revealed bond lengths
and dihedral angles in line with its anticipated enol character
Figure 1. Synthesis of 3-enoyltetramic acids 1 with activated
β-ketoacyl equivalents 2 and 3.
Ylide 3 can be applied to the synthesis of 3-enoyltetramic
acids in two ways differing in the number of steps and the order
of olefination (a/e), amidation (b/d), and Dieckmann cyclisation
(c/e) reactions. The olefination step attaches the 3-acyl side
chain, the amidation step generates the N-(β-ketoacyl)amino
ester, and the Dieckmann cyclisation closes the pyrrolidine ring
(Scheme 1). Three 3-enoyltetramic acids 10a-c derived from L-
alanine and three different aldehydes, p-methoxybenzaldehyde,
p-nitrobenzaldehyde and isobutyraldehyde were prepared on both
routes. Route A begins by converting these aldehydes via
olefination (a) with ylide 3 to the corresponding Wittig products
6a-c in yields above 80%.
1
(Fig. 2). H, 13C, and 31P NMR spectra show the presence of a
mixture of two tautomers, the ylide form depicted in Figure 1 and
the corresponding phosphonium betaine form.
–––––––––––––
∗ Corresponding author. Tel.: +49-921-55-2679; fax: +49-921-
55-2671; e-mail: Rainer.Schobert(at)uni-bayreuth.de

2
Tetrahedron
Meldrum’s acid derivative
3
with methyl L-N-(2,4-
dimethoxybenzyl)alaninate to give ylide 8 in almost 70% yield.
This aminolysis reaction took distinctly longer than the
aminolysis of Meldrum’s acid derivatives 6 with the same amino
ester. Ylide 8 was then treated with KOtBu and the respective
aldehyde to initiate both the olefination and Dieckmann
cyclisation reactions in one step (e) to give the DMB-protected 3-
enoyltetramic acids 9. The overall yields of the shorter route B
were on average slightly higher than those of A (40% vs. 35%).
Deprotection of compounds 9 with TFA in CH2Cl2 (f) afforded
the tetramic acids 10a-c. Table 1 summarises the individual
compounds and yields.
Table 1. Isolated compounds and yields.
Compound
R1
R3
Yield A/B [%]
Figure 2. Synthesis and molecular structure of 3, as thermal
ellipsoid representation at 50% probability level showing the
atomic numbering scheme (H-atoms omitted). CCDC 1564727.
Selected bond lengths [Å] and angles [°]: P–C19 1.723(2), C19–
C20 1.376(3), C20–O1 1.342(3), C20–C21 1.443(3), C21–C26
1.430(3), C21–C22 1.418(3), C22–O2 1.238(3), C26–O5
1.221(3), P–C19–C20–O1 1.7(3), O1–C20–C21–C22 –0.2(3),
O1–C20–C21–C26 177.0(2), C20–C21–C22–O2 6.8(4), C20–
C21–C22–O3 –176.0(2).
3
6a
6b
6c
–
–
98
98
–
p-NO2-Ph
p-OMe-Ph
Isobutyl
p-NO2-Ph
p-OMe-Ph
Isobutyl
–
–
88
–
83
7a
7b
7c
DMB
DMB
DMB
DMB
DMB
DMB
DMB
H
55
40
34
8
68
9a
9b
9c
p-NO2-Ph
p-OMe-Ph
Isobutyl
p-NO2-Ph
p-OMe-Ph
Isobutyl
93/80
93/40
84/55
88
10a
10b
10c
H
90
H
80
The applicability of this approach to natural products was
demonstrated by the synthesis of the tyrosine-derived 3-
acyltetramic acid 13, a bright yellow pigment responsible for the
colour of the slime mould Leocarpus fragilis.14,15 Ylide 3 was
reacted with N-DMB-protected methyl tyrosinate to afford amino
ester ylide 11 in 67% yield. Protection of the phenolic OH-group
was not necessary. Reaction of ylide 11 with a mixture of KOtBu
and (E,E)-2,4-hexadienal gave tetramic acid 12 in 80% yield by a
simultaneous Wittig olefination cum Dieckmann cyclisation.
Deprotection with TFA afforded the natural product 13 in 48%
overall yield (Scheme 2).
Scheme 1. Reagents and conditions: (a) KOtBu, R3CHO, THF,
r.t., 18 h; (b) (DMB)NHCHR5CO2Me, DMAP, dioxane, reflux,
30 min; (c) NaOMe, MeOH, r.t., 20 min; (d)
(DMB)NHCHR5CO2Me, DMAP, dioxane, reflux, 24 h; (e)
KOtBu, R3CHO, THF, r.t., 24 h; (f) TFA, CH2Cl2, r.t., 1h.
The important point is that ylide 3 does not enter into Wittig
olefinations with aldehydes and ketones but needs to get
deprotonated by KOtBu to an anionic Wittig-active species first.
The following amidation (b) with methyl L-N-(2,4-
dimethoxybenzyl)alaninate afforded three β-ketoamides 7a-c in
moderate yields. The 2,4-dimethoxybenzyl (DMB) group is
necessary to orient the ester group of compounds 7 in a way
favourable for the ensuing Dieckmann cyclisation step (c) under
basic conditions, as indicated in scheme 1.13 The product 3-
enoyltetramic acids 9a-c were obtained in good to excellent
yields. The shorter route B starts with an aminolysis (d) of
Scheme 2. Reagents and conditions: (a) N-DMB-Tyr-OMe,
toluene, reflux, 16 h; (b) (2E,4E)-hexadien-1-al, KOtBu, MeOH,
r.t., 24 h; (c) TFA, CH2Cl2, r.t., 1 h.

3
2. Gossauer, A. Monopyrrolic natural compounds including tetramic acid
Conclusion
A new, easy to prepare, Meldrum’s acid ylide conjugate was
developed that acts as an activated β-ketoester equivalent
allowing the synthesis of 3-enoyltetramic acids from α-amino
esters in three steps and up to 50% yield. It is applicable to
tetramic acids derived from amino acids with polar residues, and
with alkyl, alkenyl, or aryl side chains at C-3.
derivatives. In Progress in the Chemistry of Organic Natural Products;
Herz, W.; Falk, H.; Kirby, G. W., Eds.; Springer: Wien, New York,
2003; Vol. 86, pp 1–188.
3. Schobert, R.; Schlenk, A. Bioorg. Med. Chem. 2008, 16, 4203–4221.
4. Zaghouani, M.; Nay, B. Nat. Prod. Rep. 2016, 33, 540–548.
5. Schlessinger, R. H.; Bebernitz, G. R. J. Org. Chem. 1985, 50, 1344–
1346.
6. Royles, B. J. L. Chem. Rev. 1995, 95, 1981–2001.
7. Henning, H.-G.; Gelbin, A. Adv. Heterocycl. Chem. 1993, 57, 139–185.
8. Mo, X.; Li, Q.; Ju, J. RSC Adv. 2014, 4, 50566–50593.
9. Petermichl, M.; Schobert, R. Synlett 2017, 28, 654–663.
10. (a) Boeckman, Jr., R. K.; Perni, R.; Macdonald, J.; Thomas, A. Organic
Syntheses, Coll. Vol. 8, p.192 (1993); Vol. 66, p.194 (1988); (b)
Boeckman, Jr., R. K.; Thomas, A. J. Org. Chem. 1982, 47, 2823.
11. (a) Löffler, J.; Schobert, R. J. Chem. Soc. Perkin Trans. 1, 1996, 2799–
2802; (b) Schobert, R.; Siegfried, S.; Nieuwenhuyzen, M.; Milius, W.;
Hampel, F. J. Chem. Soc. Perkin Trans. 1, 2000, 1723–1730.
12. (a) Bestmann, H. J.; Sandmeier, D. Angew. Chem. Int. Ed. Engl. 1975,
14, 634; (b) Schobert, R.; Boeckman, Jr., R. K.; Pero, J. E. Organic
Syntheses, 2005, 82, 140−143.
Acknowledgements
We thank Dr. Ulrike Lacher (University Bayreuth) for in-
depth MS analyses.
Supplementary data
13. Bruckner, S.; Haase, R. G.; Schobert, R. Chem. Eur. J. 2017, 23, 5692–
Supplementary data associated with this article (experimental
protocols, physical data, and NMR spectra of compounds 3 and
6-13) can be found in the online version, at
doi:xx.xxxx/j.tet.2017.xx.xxx
5695.
14. Riache, N.; Bailly, C.; Deville, A.; Dubost, L.; Nay, B. Eur. J. Org.
Chem. 2010, 5402–5408.
15. Steglich, W. Pure Appl. Chem. 1989, 61, 281–288.
References and notes
1. Ghisalberti, E. L. In Studies in Natural Products Chemistry; Atta-ur-
Rahman, Ed.; Elsevier, 2003; Vol. 28/1, pp 109–163.

4
Tetrahedron
Highlights:
•
•
•
•
A new Meldrum’s acid ylide conjugate acts
as an activated β-ketoester equivalent
It allows the synthesis of 3-enoyltetramic
acids from α-amino esters in three steps
It is compatible with unprotected polar
residues
A yellow pigment from the slime mould
Leocarpus fragilis was prepared in 3 steps