ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Total Synthesis of Chaetoquadrins AꢀC
U Bin Kim, Daniel P. Furkert, and Margaret A. Brimble*
School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland,
New Zealand
Received December 19, 2012
ABSTRACT
The first total synthesis of the monoamine oxidase inhibitors chaetoquadrins AꢀC has been accomplished. Key steps in the synthesis include
an aromatic Claisen rearrangement, asymmetric boron aldol reaction and acid-mediated spiroketalization. Comparison of spectral data for the
synthetic spiroketals confirmed the proposed structure for these natural products.
In 2002 Fujimoto and co-workers reported the isolation
of chaetoquadrins AꢀC (1ꢀ3; Figure 1) from an ethyl
acetate extract of the ascomycete, Chaetomium quadrangu-
latum (strain 71-NG-22). They were found to inhibit
mouse liver monoamine oxidase (MAO) using the mod-
ified Kraml assay.1 Recently, chaetoquadrins A (1) and B
(2) were also isolated from Chaetomium aureus by Li
and co-workers.2 These novel spiroketals feature a chromone
(1,4-benzopyran-4-one) fused to a substituted [6,6]-spiroketal
framework, differing from each other by the stereogenic
Figure 1. Structure of chaetoquadrins AꢀC.
pattern around the spiroketal ring. To the best of our knowl-
edge, syntheses of these natural products have not yet been
reported. Owing to our ongoing interest in the synthesis of
bioactive spiroketal-containing natural products and espe-
which was to be accessed via alkylation of the known
chromone, noreugenin (9).
We began our synthesis from noreugenin (9) which itself
cially that of benzannulated spiroketals,3 we were prompted
is readily accessible from 2,4,6-trihydroxyacetophenone.4
to embark on a synthesis of the chaetoquadrins. Chaetoqua-
drin C (3), with the highest inhibitory activity against mouse
liver MAO, was chosen as the initial synthetic target.
(10)5 (Scheme 2). The subsequent alkylation of the hydro-
Our retrosynthetic analysis of chaetoquadrin C (3) is
outlined in Scheme 1. Spiroketal 3 was envisioned to be
constructed via an acid-mediated spiroketalization of
Selective alkylation of the non-hydrogen bonded phenol
with dimethyl sulfate proceeded smoothly to give eugenin
gen-bonded phenol required elevated temperature, which
delivered allyl phenyl ether 8 in good yield. Heating allyl
β-hydroxy ketone 4, which in turn would be prepared from
ether 8 at 200 °C for 2 h effected the aromatic Claisen
rearrangement,6 and the resulting phenol was treated with
benzyl bromide togive benzyl protected allyl chromone 11.
Preliminary investigations had established that this choice
an aldol reaction of aldehyde 5 and its aldol partner
derived from the union of bromide 6 and chiral propionate
fragment 7. We thought to access bromide 6 via means of
an aromatic Claisen rearrangement of allyl phenyl ether 8,
(1) Fujimoto, H.; Nozawa, M.; Okuyama, E.; Ishibashi, M. Chem.
Pharm. Bull. 2002, 50, 330–336.
(4) Bruder, M.; Haseler, P. L.; Muscarella, M.; Lewis, W.; Moody,
C. J. J. Org. Chem. 2009, 75, 353–358.
(2) Li, M. L.; Zou, Q.; Li, G. Y. Chin. Chem. Lett. 2010, 21, 1203–1205.
(3) For selected examples, see: Yuen, T.-Y.; Brimble, M. A. Org. Lett.
2012, 14, 5154–5157 and references within.
(5) Czepa, A.; Hofmann, T. J. Agric. Food Chem. 2003, 51, 3865–3873.
(6) Chromenes, chromanones, and chromones; Ellis, G. P., Ed.; Wiley:
New York, 1977; Chapter 8, pp 698ꢀ699.
r
10.1021/ol303482k
XXXX American Chemical Society