An efficient and robust synthesis of amorfrutin A

Article abstract of DOI:10.1016/j.tetlet.2019.04.028

Amorfrutin A was synthesized via a short sequence in an overall yield of 41% using a green, aerobic oxidation/re-arrangement process as the key-step.

Full text of DOI:10.1016/j.tetlet.2019.04.028

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
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An efficient and robust synthesis of amorfrutin A
⇑
Björn Weber, Benjamin Brandes, Danny Powroznik, Ralph Kluge, René Csuk
Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Amorfrutin A was synthesized via a short sequence in an overall yield of 41% using a green, aerobic oxi-
dation/re-arrangement process as the key-step.
Received 11 March 2019
Revised 14 April 2019
Accepted 16 April 2019
Available online xxxx
Ó 2019 Published by Elsevier Ltd.
Keywords:
Amorfrutin A
Hydroperoxide
Aerobic oxidation
Natural products possess a high chemical diversity, and their
structural diversity continuously inspires the search for new drugs
[1,2]. Thus, they remain one of the best sources of drugs. Recent
statistical data have shown that the number of type 2 diabetes
mellitus patients has increased worldwide during the last decade.
Thus, this metabolic disease has evolved into a global epidemic. It
is assumed that this metabolic syndrome already affects more than
a quarter of the world’s population [3,4].
interested in an efficient synthesis from readily accessible and inex-
pensive starting materials with as few chromatography-based
purification steps as possible. Furthermore, in order to take account
of economic considerations, we attempted to avoid the use sensi-
tive and/or expensive organometallic catalysts and reagents. Sev-
eral years ago, a synthesis was proposed taking account of these
requirements [20] but this approach was unsuccessful in our hands.
Knoevenagel condensation of 3,5-dimethoxy-benzaldehyde (1)
with benzyl cyanide (2) [21] in the presence of sodium hydroxide
gave stilbene derivative 3 in 92% isolated yield. The ratio of starting
materials 1 and 2 as well as their concentration and the reaction
temperature is essential to avoid the formation of bis-adduct 4
[20].
Reduction of 3 with sodium borohydride at room temperature
for 1 day furnished 5 [21] in quantitative yield. Treatment of 5 with
sodium hydroxide in propane-1,2-diol (microwave irradiation) for
4 min gave 6 (85%) [22] together with de-methylated 7 (10%)
[23–25]. This de-methylation was somewhat unexpected since
aromatic methyl ethers are usually cleaved under acid conditions
(Scheme 1).
Reaction of 6 with boron trichloride in CH2Cl2 resulted in an
intramolecular Friedel-Crafts acylation with concomitant selective
mono-de-methylation, and 8 [26,27] was obtained in almost quan-
titative yield. This compound is characterized in its 13C NMR spec-
trum by a signal at d = 207.7 ppm that was assigned to the carbonyl
group. When 8 was treated with sodium methoxide at 40 °C with
continuous bubbling of dry air through the reaction mixture, the
cyclic ketone was transformed into lactone 9. This compound is
characterized in its 1H NMR spectrum by the presence of an olefinic
proton at d = 6.87 ppm, and in the 13C NMR spectrum by two
olefinic carbons at d = 153.3 and 102.8 ppm, respectively.
One of the hallmarks of diabetes mellitus is characterized by
insulin resistance. The nuclear peroxisome proliferator-activated
receptor gamma, PPAR
for example, unsaturated fatty acids and several anti-diabetic
drugs (such as rosiglitazone) are strong activators of PPAR . How-
ever, these activators show some undesired side effects, and the
c, is activated after food intake by binding:
c
search for more selective PPARc activators is still of high scientific
and economic interest [3,5].
Recently, the amorfrutins were identified as selective PPAR
c
modulators, which selectively modulate PPAR gene expression
c
networks in adipocytes. They have successfully been evaluated as
anti-diabetics in mouse models for type 2 diabetes [6–10].
The access to amorfrutin A from natural sources is limited,
although it has been isolated from the fruits of Amorpha fruticose
[11] and from Glycyrrhiza foetida [4,12–14]. The content of amor-
frutin A is low in these plants, and – as a consequence – several
syntheses have been developed to overcome this shortage of mate-
rial [15–19].
All of these syntheses allow the preparation of amorfrutin A,
albeit their scaling up remains difficult. Hence, we became
⇑
Corresponding author.
E-mail address: rene.csuk@chemie.uni-halle.de (R. Csuk).
https://doi.org/10.1016/j.tetlet.2019.04.028
0040-4039/Ó 2019 Published by Elsevier Ltd.
Please cite this article as: B. Weber, B. Brandes, D. Powroznik et al., An efficient and robust synthesis of amorfrutin A, Tetrahedron Letters, https://doi.org/
10.1016/j.tetlet.2019.04.028

2
B. Weber et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. Synthesis of amorfrutin A (14): Reagents and conditions: a) NaOH, EtOH, 12 h, 25 °C, 92%; b) NaBH4, EtOH, 1 d, 50 °C, quant.; c) 1,2-propane-diol, NaOH,
microwave irradiation (180 °C, 4 min, 160 W), 85% (6) + 10% (7); d) BCl3, CH2Cl2, 0 °C ? 25 °C, 98% (from 6); e) NaOMe, MeOH, air, 2 d, 40 °C, 89%; f) H2 (75 psi), Pd/C (10%),
EtOAc/MeOH, 6 h, 25 °C, 93%; g) Cs2CO3, MeI, DMF, 12 h, 25 °C, 98%; h) KH, toluene, prenyl chloride, 20 min, 25 °C ? 70 °C, 12 (72%) + 13 (25%); i) CeCl3, ACN, NaI, 3 h, 25 °C,
95%; j) KOH, MeOH, 7 h, 25 °C, 92%.
Because the reaction of ketone 8 to the lactone 9 is the key step
in our synthesis, it should be discussed in more detail (see
Scheme 2). Ketones possessing a-hydrogens are easily autoxidized
under alkaline conditions to carboxylic or dicarboxylic acids and
other oxidation products [28–30]. Thus, ketone 8 reacts initially
with oxygen in the presence of methanolate to the unstable perox-
ide intermediate A which presumably cyclizes to 1,2-dioxetane
derivative B. Decomposition of B under CACAbond cleavage leads
to the formation of ketocarboxylate C. The cyclization of C in a
(corresponding anion). This reaction appears to be relatively fast
because no significant amounts of products from the competitive
further oxidation of C were obtained. Finally, lactone 9 is formed
after protonation and the elimination of water.
Hydrogenation of 9 with Pd/C (10%) in methanol/ethyl acetate
led to the formation of 10 [22] in 93% yield; this compound was
easily transformed into its methyl ester 11 [6,16,24]. Prenylation
of 11 with prenyl chloride/potassium hydride in dry toluene gave
the methyl ester of amorfrutin A (12, 72%) [16,24,27] together
with prenyl ether 13 (25%). The latter compound could be used
favored 6-exo-trig process yields the hydroxylactone
D
Please cite this article as: B. Weber, B. Brandes, D. Powroznik et al., An efficient and robust synthesis of amorfrutin A, Tetrahedron Letters, https://doi.org/
10.1016/j.tetlet.2019.04.028

B. Weber et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Scheme 2. Proposed reaction sequence for the conversion of ketone 8 to lactone 9: Reagents and conditions: a) O2, NaOMe, MeOH b) H+, –H2O.
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to ‘‘recycle” valuable 11. Thus, its reaction with CeCl3 heptahy-
drate/sodium iodide in acetonitrile furnished 95% of parent 11.
Finally, when methyl ester 12 was treated with KOH in MeOH/
H2O amorfrutin A (14) [15,16,19,26] was obtained in 92% yield
being identical in every respect to an authentic commercially avail-
able reference sample.
In summary, amorfrutin A was obtained from inexpensive, com-
mercially available starting materials using
a short reaction
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sequence. This sequence can easily be scaled up and provides
amorfrutin A in an overall yield of 41%.
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Siems, G. Hetterling, M. Kliem, F.C. Schroeder, S. Sauer, J. Nat. Prod. 79 (2016)
2–12.
Acknowledgments
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2621–2629.
We would like to thank Dr. D. Ströhl and his team for NMR spec-
troscopy; IR- and UV-vis spectra were recorded by B.Sc. V. Simon.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.04.028.
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Please cite this article as: B. Weber, B. Brandes, D. Powroznik et al., An efficient and robust synthesis of amorfrutin A, Tetrahedron Letters, https://doi.org/
10.1016/j.tetlet.2019.04.028