Total syntheses of the furanosesquiterpenes crassifolone and dihydrocrassifolone via an Au(I)-catalysed intramolecular Michael addition reaction

Article abstract of DOI:10.1039/c0ob00487a

The racemic modifications of title natural products 1 and 2 have been synthesised for the first time. The key step was the Au(i)-catalysed conversion of the furanyl-substituted ynone 13 into the annulated furan 14.

Full text of DOI:10.1039/c0ob00487a

Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Volume 8 | Number 24 | 21 December 2010 | Pages 5461–5702
ISSN 1477-0520
COMMUNICATION
Rajeev S. Menon and Martin G. Banwell
Total syntheses of the furanosesquiterpenes crassifolone and
dihydrocrassifolone via an Au(I)-catalysed intramolecular Michael
addition reaction
1477-0520(2010)8:24;1-X

COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Total syntheses of the furanosesquiterpenes crassifolone and
dihydrocrassifolone via an Au(I)-catalysed intramolecular Michael addition
reaction†
Rajeev S. Menon and Martin G. Banwell*
Received 26th July 2010, Accepted 13th September 2010
DOI: 10.1039/c0ob00487a
The racemic modifications of title natural products 1 and 2
have been synthesised for the first time. The key step was the
Au(I)-catalysed conversion of the furanyl-substituted ynone
13 into the annulated furan 14.
The assembly of the substrate required for the pivotal in-
tramolecular Michael addition reaction involved the preparation
of two key building blocks, a furanyl-substituted 1-iodopropane
and a protected form of an isobutyl-substituted propargyl alcohol.
The synthesis of the first of these is shown in Scheme 1 and
employed the Doebner modification of the Knoevenagel con-
densation in which malonic acid was treated with commercially
available furan-3-carboxaldehyde (3) in the presence of pyridine.
The 3-furanacrylic acid 47 (96%) so formed was reduced to the
corresponding allylic alcohol 58 (76%) with LiAlH4 and the latter
compound then subjected to hydrogenation using Pd on C as
catalyst and methanol as solvent. The resulting saturated alcohol
69 (82%) was treated with molecular iodine in the presence of
triethylamine and imidazole and thereby affording the required
and previously reported primary iodide 710 (75%).
A recent examination of the essential oils derived from the wood
of the tree Myoporum crassifolium found growing in Noumea,
New Caledonia has resulted in the identification of the fura-
nosesquiterpenes crassifolone (1) and dihydrocrassifolone (2).1
The basic structures of these optically active natural products
were established through detailed 1H and 13C NMR studies
but their absolute configurations remain undefined. They bear
a strong resemblance to a key part of cyclofurospongin-2, a
C21-furanoterpenoid isolated from the sponge Spongia officinalis
(Spongiidae) collected in the infralitoral zone of La Caleta, Ca´diz,
Spain.2 Furthermore, three structurally related C15-hydrocarbons
have been found in the leaf and twig extracts of the flowering
plant Eremophila rotundifolia collected in Kingoonya, South
Australia.3 No significant biological properties have been ascribed
to compounds 1 and 2 although they may have some utility as
fragrances.1
Scheme 1 Reagents and conditions: (i) malonic acid, pyridine, 90 ◦C, 2 h;
(ii) LiAlH4, THF, 18 ◦C, 1 h; (iii) H2, Pd on C, MeOH, 18 ◦C, 3 h; (iv) I2,
Ph3P, imidazole, DCM, 0 → 18 ◦C, 2 h.
Our interest in the synthesis of annulated furan-containing
natural products4 and the possibility of establishing the 4,5,6,7-
tetrahydrobenzofuran core of compounds 1 and 2 via addition of
the nucleophilic furan moiety to a tethered Michael acceptor5
prompted the studies reported herein. A key feature of these
studies, which have resulted in the first total syntheses of the
title natural products, is the identification of a novel and highly
efficient Au(I)-catalysed intramolecular Michael addition reaction
that proceeds rapidly under exceptionally mild conditions. As
such, this unprecedented reaction may represent a useful new
protocol for the construction of other terpenoids incorporating
an annulated furan core.6
The simple, two-step sequence used to obtain the second
building block is shown in Scheme 2 and starts with the addition of
ethynyl magnesium bromide to 3-methylbutanal (8). The resulting
propargyl alcohol 911 (63%) was treated with t-butyldimethylsilyl
chloride (TBS-Cl) in the presence of imidazole and thus producing
the required silyl ether 10 in 67% yield.
Research School of Chemistry, Institute of Advanced Studies, The
Australian National University, Canberra, ACT 0200, Australia. E-mail:
mgb@rsc.anu.edu.au
† Electronic supplementary information (ESI) available: Experimental
procedures, product characterisation, and 1H or 13C NMR spectra for
compounds 4–7, 9, 10, 11–14, ( )-2 and ( )-1 are provided. See DOI:
10.1039/c0ob00487a
Scheme 2 Reagents and conditions: (i) Et2O, 0 → 18 ◦C, 1 h; (ii) TBS-Cl,
imidazole, THF, 0 → 18 ◦C, 6 h.
The coupling of building blocks 7 and 10 in the appropriate
fashion was readily achieved (Scheme 3) by deprotonating the
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 5483–5485 | 5483
©

13 → 14. In the event, treatment of compound 13 with 1 mole % of
the Echavarren’s catalyst in DCM at 18 ◦C for 5 min resulted in the
formation of isomer 14 in quantitative yield. We speculate that this
remarkable transformation involves initial auration at C2 of the
substrate.16 This is followed by intramolecular Michael addition
of the now highly nucleophilic C2 to the sterically uncongested
b-terminus of the tethered ynone.17 Protio-deauration would
then give compound 14 that is obtained as a single geometric
isomer (and tentatively assigned as possessing the illustrated E-
configuration).
The completion of the synthesis of the target natural products
1 and 2 required the construction of the associated quaternary
carbon centre and, in the former case, introduction of the ketone-
conjugated carbon–carbon double bond. Various methods were
investigated in an effort to engage compound 14 in a conjugate
addition reaction with a methyl-based nucleophile. Treatment of
this substrate with the Gilman reagent (Me2CuLi)18,19 resulted in a
1 : 3 mixture (80% combined yield) of dihydrocrassifolone (2) and
the corresponding 1,2-addition product. Reaction of compound
14 with trimethylaluminium in the presence of Ni(acac)220 gave, as
the only characterisable component of a complex reaction mixture,
the undesired 1,2-addition product. A much more satisfactory
outcome was observed when enone 14 was treated with excess
methylmagnesium bromide in the presence of catalytic quantities
of copper(I) bromide dimethyl sulfide complex and stoichiometric
quantities of trimethylsilyl chloride (TMS-Cl).21 Under such
conditions the silyl enol ether 15 (61%) was obtained as the
exclusive product of reaction and when this was treated with
TBAF in THF at 18 ◦C then dihydrocrassifolone (2) was obtained
in 66% yield. Effecting the conversion 2 → 1 proved rather
problematic. After considerable experimentation, and following
a protocol defined by Lalic and Corey,22 we found that treatment
of compound 2 with TMSOTf and Et3N then IBX in presence of
4-methoxypyridine N-oxide (MPO)23 afforded a chromatographi-
cally separable mixture of crassifolone (1) (83% at 73% conversion)
and dihydrocrassifolone (2) (27% recovery).
Scheme 3 Reagents and conditions: (i) n-BuLi, THF/DMPU, -78 →
18 ◦C, 3 h; (ii) TBAF, THF, 18 ◦C, 1 h; (iii) PCC, DCM, 18 ◦C, 2.5 h;
(iv) Au(I), DCM, 18 ◦C, 5 min; (v) MeMgBr, cat. CuBr·Me2S, TMS-Cl,
HMPA, THF, -78 → 18 ◦C, 3 h; (vi) TBAF, THF, 18 ◦C, 0.5 h; (vii)
TMSOTf, Et3N, DCM, 0 → 18 ◦C, 3 h; (viii) IBX, MPO, DMSO, 18 ◦C,
24 h.
1
The H and 13C NMR spectroscopic as well as the mass spec-
trometric data derived from the synthetic samples of compounds
1 and 2 matched those reported for the corresponding natural
products.1 A detailed comparison of the relevant data sets is
presented in the Electronic Supplementary Information associated
with this paper.
latter with n-BuLi in THF/DMPU then alkylating the resulting
acetylide anion with iodide 7. Product 11 (77%) thus obtained was
treated with tetra-n-butylammonium fluoride (TBAF) in THF at
◦
18 C for 1 h and the resulting alcohol 12 (97%) oxidised to the
corresponding ketone 13 (90%) using pyridinium chlorochromate
Efforts to apply the novel Michael addition process disclosed
above to the synthesis of other natural products will be reported
in due course.
(PCC) in dichloromethane at 18 ◦C.
Compound 13 represents the substrate required for the pivotal
intramolecular Michael addition reaction which it was anticipated
would proceed via attack of C212 of the pendant furan ring to
the proximate sp-hybridised carbon of the ynone and thereby
resulting in the formation of the isomeric tetrahydrobenzofuran
14. Various Au(III) and Au(I) species have been used to effect the
intermolecular Michael addition of furan (via C2) to electron-
deficient alkenes, most notably, methyl vinyl ketone.13 However,
the reactions normally require high temperatures and/or co-
catalysts. Furthermore, no examples of intramolecular variants
of such processes appear to have been reported. Our recent
observations14 that Echavarren’s Au(I) catalyst15 (see Scheme 3)
can effect the intramolecular hydroarylation of terminal alkynes
under exceptionally mild conditions prompted us to examine the
capacity of this species to bring about the desired conversion
Acknowledgements
We thank the Australian Research Council for generous financial
support including the provision of an Australian Post-Doctoral
Fellowship to RSM.
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Org. Biomol. Chem., 2010, 8, 5483–5485 | 5485
©