Total synthesis of amorfrutin A via a palladium-catalyzed migratory prenylation-aromatization sequence

Article abstract of DOI:10.1016/j.tetlet.2011.11.019

The total synthesis of amorfrutin A, a prenyl bibenzyl natural product has been achieved in five steps from 2,2,6-trimethyl-4H-1,3-dioxin-4-one. The key step of the synthesis is an efficient palladium(0)-catalyzed decarboxylative prenylation migration and

Full text of DOI:10.1016/j.tetlet.2011.11.019

Tetrahedron Letters 53 (2012) 225–227
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of amorfrutin A via a palladium-catalyzed migratory
prenylation–aromatization sequence
⇑
Sylvain Laclef, Katie Anderson, Andrew J. P. White, Anthony G. M. Barrett
Department of Chemistry, Imperial College, London SW7 2AZ, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of amorfrutin A, a prenyl bibenzyl natural product has been achieved in five steps
from 2,2,6-trimethyl-4H-1,3-dioxin-4-one. The key step of the synthesis is an efficient palladium(0)-cat-
alyzed decarboxylative prenylation migration and aromatization sequence.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 29 September 2011
Revised 26 October 2011
Accepted 4 November 2011
Available online 13 November 2011
Keywords:
Amorfrutin A
Natural products
Polyketides
Resorcylates
Bibenzyl
Molecules containing a bibenzyl moiety occur widely in natural
products1 and display interesting biological activities including
antioxidant,2 antimicrobial,3 antifungal,4 antitumor,5 and cyto-
toxic.6 Among this class, amorfrutin A (1)7 (Fig. 1) is a secondary
metabolite isolated in 1981 by Mitscher et al., from the ethanolic
extracts of the powdered fruits, stems, and leaves of Amorpha fruti-
cosa, a shrub originating in North America, China and Korea.
Amorfrutin A (1) exhibits narrow spectrum antimicrobial activ-
ity against Gram-positive and acid-fast microorganisms. Further-
(resorcylic acid) unit, which occurs widely in numerous natural
products.12
The biosynthesis of amorfrutin A (1) and its derivatives involves
plant polyketide synthases of type III, which produce secondary
metabolites of considerable structural diversity.13 They are classi-
fied regarding the late cyclization mode which is, in this case, the
group of STCS (stilbene carboxylate synthase) which produces
the resorcylic acid moiety from the corresponding tetraketide free
acid (Fig. 2).14 Aromatization and reduction are additional steps of
STCS15 with amorfrutin A.
We considered that amorfrutin A (1) should be easily available
using an adaption of our biomimetic synthesis of resorcylates using
dioxinone chemistry,16 which was inspired by the earlier work of
Harris,17 Hyatt,18 and Boeckmann.19,17b–d Recently, we published
the total synthesis of angelicoin A (6) (Fig. 3) using a novel one-pot
palladium(0)-catalyzed migratory decarboxylative prenylation–
aromatization sequence.20
more this natural product inhibits nuclear transcription factor-
(NF- B) activation and related gene expression. The activation of
NF-
jB
j
j
B is known to be related to several inflammatory diseases
such as arthritis, asthma, bowel inflammation, as well as cancer.8
More specifically, amorfrutin A was found to strongly inhibit
NF-
jB activation in a human cervical cancer (HeLa) cells with an
IC50 value of 0.84
l
M.
Several syntheses of prenyl bibenzyl derivatives are reported in
the literature, with the majority of strategies utilizing two-step
sequences, Wittig reaction followed by alkene hydrogenation9 or
benzylic metalation and subsequent alkylation10 from protected
phenolic precursors. The prenyl moiety has been introduced by elec-
Herein, we report a related strategy for introducing the C3-prenyl
moiety in a total synthesis of amorfrutin A (1) (Scheme 1). Regiose-
lective acylation of ketoester 8 by Claisen condensation reaction
trophilic aromatic alkylation with a,a-dimethylallyl alcohol in the
presence of ZnCl2 or BF3ÁOEt2 as catalyst or by using regioselective
metalation of the 2-position with n-butyllithium and subsequent
alkylation with prenyl bromide.11 Apart from its prenyl bibenzyl
scaffold, the molecule contains a 6-alkyl-2,4-dihydroxybenzoic acid
OH
O
OH
MeO
⇑
Corresponding author.
E-mail address: agm.barrett@imperial.ac.uk (A. G. M. Barrett).
Figure 1. Structure of amorfrutin A (1).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.019

226
S. Laclef et al. / Tetrahedron Letters 53 (2012) 225–227
R
R
R
O
OH
S-CoA
HO
Type III PKS
S-CoA
STCS
O
2
5
+
O
O
O
OH
OH
S-CoA
4
O
3
O
O
Figure 2. Cyclization mode of plant stilbene carboxylate synthase.
OH
O
HO
Figure 3. Structure of angelicoin A (6).
with dihydrocinnamoyl chloride 9 in the presence of magnesium
chloride and pyridine gave the corresponding diketoester–dioxi-
none 10 in a 75% yield. Subsequent reaction of diketoester–dioxi-
none 10 with Pd(PPh3)4 and cesium carbonate resulted in
decarboxylative prenyl migration and formation of the resorcylate
13. Under these reaction conditions, the minor branched chain
isomer 12 did not aromatize but could be converted into the corre-
sponding resorcylate 13 under more forcing reaction conditions.
The regioselectivity of the prenyl migration and the structures
of both resorcylates 13 and 14 were confirmed unambiguously
Figure 4. ORTEP structures of resorcylates 13 and 14.
by single crystal X-ray crystal structure determinations (Fig. 4).
Finally, phenol methylation of 13 and saponification of resulting
15 gave amorfrutin A (1).
The biomimetic total synthesis of amorfrutin A (1) was com-
pleted in five steps from dioxinone 7 with an overall yield of
O
O
O
7
Ref21
O
O
O
O
O
O
O
O
O
O
ii
i
+
O
Cl
O
O
O
O
10
8
9
O
O
O
O
O
O
O
O
O
iii
O
O
+
O
HO
11
12
14
O
O
O
O
OH
O
iv
v
O
O
OH
HO
MeO
MeO
amorfrutin A (1)
13
15
Scheme 1. Synthesis of resorcylates 13 and 14 (i) MgCl2, pyridine, CH2Cl2, 0 °C; 9, 0 °C, 1 h, 75%; (ii) Pd(PPh3)4 (2.5 mol %), Cs2CO3, 0–25 °C, 82% (12:13 = 1:3); (iii) Cs2CO3,
THF, reflux, 68%; (iv) MeI, Cs2CO3, 25 °C, THF, 98%; (v) KOH 48%, DMSO, 80 °C, 83%.

S. Laclef et al. / Tetrahedron Letters 53 (2012) 225–227
3. Beck, S.-H.; Phipps, R. K.; Perry, N. J. Nat. Prod. 2004, 67, 718.
227
16%. We have shown the efficiency of a biomimetic approach and
palladium(0)-catalyzed decarboxylative prenyl migration to the
total synthesis of prenyl bibenzyl natural products. Further total
syntheses of resorcylate natural products, application of the meth-
odology to medicinal chemistry and mechanistic studies on the
regioselectivity of allylation and prenylation will be reported in
due course.
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