A chemoenzymatic total synthesis of the protoilludane aryl ester (+)-armillarivin

Article abstract of DOI:10.1021/ol400583c

The title natural product, 1, has been synthesized in 20 steps from the enantiomerically pure cis-1,2-dihydrocatechol 2, itself obtained through the whole-cell biotransformation of toluene. The pivotal steps in the reaction sequence involve a Diels-Alder cycloaddition reaction between diene 2 and cyclopentenone (3) and the photochemically promoted 1,3-acyl rearrangement of the bicyclo[2.2.2]oct-4-en-1-one 20 derived from the cycloadduct 4.

Full text of DOI:10.1021/ol400583c

ORGANIC
LETTERS
2013
Vol. 15, No. 8
1934–1937
A Chemoenzymatic Total Synthesis of the
Protoilludane Aryl Ester (þ)-Armillarivin
ꢀ
ꢀ ꢁ
Brett D. Schwartz, Eliska Matousova, Richard White, Martin G. Banwell,* and
Anthony C. Willis
Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra ACT 0200, Australia
mgb@rsc.anu.edu.au
Received March 3, 2013
ABSTRACT
The title natural product, 1, has been synthesized in 20 steps from the enantiomerically pure cis-1,2-dihydrocatechol 2, itself obtained through the
whole-cell biotransformation of toluene. The pivotal steps in the reaction sequence involve a DielsꢀAlder cycloaddition reaction between diene 2 and
cyclopentenone (3) and the photochemically promoted 1,3-acyl rearrangement of the bicyclo[2.2.2]oct-4-en-1-one 20 derived from the cycloadduct 4.
The significant biological properties and distinctive
perhydrocyclobuta[e]indene framework associated with
the protoilludane class of sesquiterpenoid natural products
have attracted considerable attention since the late 1960s
when the first member of the class was isolated and
characterized by McMorris.1 New members continue to
be identified2 and some of these display properties likely
to be of commercial significance, particularly in veter-
inary settings.3,4 There is a rich history of synthetic
approaches to the protoilludanes, perhaps the most pop-
ular and effective involving photochemically promoted
[2þ2] cycloaddition or cobalt-mediated [2þ2þ2] cycliza-
tion processes.2 The majority of such approaches have
provided the racemic forms of the target natural products.
While the photochemically promoted 1,3-acyl rearrange-
ment of cyclopentannulated bicyclo[2.2.2]oct-4-en-1-ones
has been explored as a means of obtaining the carbocyclic
framework of protoilludanes,5,6 to date it has not been
deployed in a total synthesis of any one of these natural
products. Herein, therefore, we now report the success-
ful implementation of such an approach in the enantio-
selective total synthesis of the protoilludane aryl ester
(þ)-armillarivin (1, Figure 1), the first member of this
subclass of sesquiterpenoid natural product to be so
obtained (by any means). Compound 1 was originally
isolated from the acetone extract of artificially cul-
tured mycelium Armillaria mellea (Vahl. Ex Fr) Quel.
(Tricholomataceae) and its structure established using
1H and 13C NMR spectroscopies.7 It has since been
isolated from Armillaria tabescens, a pathogenic basi-
diomycete that causes root disease in a range of com-
mercially significant plants.8
(1) McMorris, T. C.; Nair, M. S. R.; Anchel, M. J. Am. Chem. Soc.
1967, 89, 4562.
(2) For a recent and comprehensive review of the area, see: Siengalewicz,
(5) (a) Singh, V.; Porinchu, M. J. Chem. Soc., Chem. Commun. 1993,
134. (b) Singh, V.; Sharma, U. J. Chem. Soc., Perkin Trans. 1 1998, 305.
(6) Banwell, M. G.; Harfoot, G. J. Aust. J. Chem. 2004, 57, 895.
(7) Yang, J. S.; Su, Y. L.; Wang, Y. L.; Feng, X. Z.; Yu, D. Q.; Liang,
X. T. Yaoxue Xuebao (Acta Phamaceutica Sinica) 1991, 26, 117.
(8) (a) Cremin, P.; Donnelly, D. M. X.; Wolfender, J.-L.; Hostettmann,
K. J. Chromatogr. A 1995, 710, 273. (b) Donnelly, D. M. X.; Konishi, T.;
Dunne, O.; Cremin, P. Phytochemistry 1997, 44, 1473.
P.; Mulzer, J.; Rinner, U. Eur. J. Org. Chem. 2011, 7041.
€
(3) (a) Kogl, M.; Brecker, L.; Warrass, R.; Mulzer, J. Angew. Chem.,
€
Int. Ed. 2007, 46, 9320. (b) Kogl, M.; Brecker, L.; Warrass, R.; Mulzer, J.
Eur. J. Org. Chem. 2008, 2714.
(4) Assante, G.; Dallavalle, S.; Martino, P. A. J. Antibiot. 2013, 66,
43–45.
r
10.1021/ol400583c
Published on Web 04/03/2013
2013 American Chemical Society

CO and methoxy(methyl)amine13 and thereby providing
the Weinreb amide 14 (98%). Treatment of compound 14
with LiAlH4 then afforded the corresponding allylic alco-
hol 15 (89%).14 Hydrolytic cleavage of the acetonide
residue associated with this last compound was achieved
using acidified DOWEX-50resin inaqueousmethanol and
the resulting triol 16 (70%) selectively protected as the
mono-TBS ether 17 (80%) using TBS-Cl in the presence
of imidazole. Selective oxidation of the hydroxyl group
remote from the bridgehead methyl group within com-
pound 17 could be achieved using the sterically demanding
oxammonium salt obtained by the p-TsOH-promoted
disproportionation of 4-acetamido-TEMPO12 and by such
means the acyloin 18 was obtained in 92% yield. The
readily derived benzoate 19 (96%) was then subjected to
reaction with samarium diiodide15 and thus affording,
through a reductive deoxygenation process, the target
bicyclo[2.2.2]oct-4-en-1-one 20. This was obtained in
98% yield.
The alcohol 10 produced through hydroboration/oxida-
tion of alkene 9 as shown in Scheme 1 could also be
converted into the substrate 20 required for the pivotal
photochemical rearrangement reaction. Thus, as shown in
Scheme 2, oxidation of compound 10 to the corresponding
ketone 21 (87%) followed by reaction of the derived
enolate with Mander’s reagent16 afforded the β-hydroxy-
R,β-unsaturated ester 22 (73%) that was readily converted
into the corresponding triflate 23 (72%)17 or diethylphos-
phate 24 (78%) by treatment with triflic anhydride/
Figure 1. Structure of compound 1.
The synthetic sequence leading to the substrate re-
quired for the pivotal 1,3-acyl rearrangement is shown in
Scheme 1 and starts with the high-pressure promoted
DielsꢀAlder reaction between the enzymatically de-
rived and enantiomerically pure cis-1,2-dihydrocatechol
29 and cyclopent-2-en-1-one (3). The adduct 410 (70%)
so-formed was converted into the corresponding acet-
onide 510 (98%) under standard conditions and this was,
in turn, transformed into the corresponding gem-di-
methylated derivative 610 (95%) using established tech-
niques. Deletion of the carbonyl moiety contained
within the last compound involved its initial lithium
aluminum hydride-promoted reduction to the correspond-
ing alcohol 710 (99% of an 11:1 mixture of epimers), the
xanthate ester derivative, 8,10 of which was subjected to a
BartonꢀMcCombie deoxygenation reaction using tri-n-
butyltin hydride and thus providing alkene 910 (50% from
7). Hydroboration/oxidation of the last compound using
the borane-dimethylsulfide complex then alkaline hydro-
gen peroxide afforded a mixture of the regioisomeric and
chromatographically separable alcohols 10 (39%) and 11
(36%). Various attempts to improve the regioselectivity of
this reaction using other hydroborating agents failed.
Compound 11 was oxidized to the corresponding ketone
12 (91%)11 using the oxammonium salt derived from 4-N-
AcetylTEMPO12 and this was, in turn, converted into the
corresponding nonaflate 13 (90%) under standard condi-
tions. Compound 13 was readily engaged in a Pd0-
catalyzed carboxyamination reaction using a combination of
€
Hunig’s base or ClPO(OEt)2/triethylamine, respectively.
Reaction of the former product with formic acid in the
presence of a Pd0 catalyst and tri-n-butylamine17 or of the
latter product with lithium dimethylcuprate18 afforded the
deoxygenatedester25in85%and77%yields, respectively.
Finally, reduction of compound 25 with DIBAL-H af-
forded the allylic alcohol 15 (95%) that could be converted
intocompound 20bythe means definedinthe later partsof
Scheme 1.
The pivotal 1,3-acyl migration reaction was carried out
(Scheme 3) by irradiating a dichloromethane solution of
substrate 20 with a high-pressure mercury lamp for 1.5 h at
0 °C and thereby generating the desired product 26 (23%
or 57% brsm). This was accompanied by small quantities
of cyclopropane 27 (5% or 12% brsm), diene 28 (7% or
17% brsm) and the oxa-di-π-methane rearrangement19
product 29 (3% or 7% brsm). The first two of these
byproducts, viz. compounds 27 and 28, presumably arise
(9) Bon, D. J.-Y. D.; Lee, B.; Banwell, M. G.; Cade, I. A. Chim. Oggi
2012, 30 (No. 5, Chiral Technologies Supplement), 22.
(10) Banwell, M. G.; Edwards, A. J.; Harfoot, G. J.; Jolliffe, K. A.
Tetrahedron 2004, 60, 535.
(11) The structures of compounds 12 and 1 were confirmed by single-
crystal X-ray analysis (CCDC Nos. 919145 and 919146, respectively).
Details are provided in the Supporting Information.
(12) This protocol is based on one first described by Ma and Bobbitt:
Ma, Z.; Bobbitt, J. M. J. Org. Chem. 1991, 56, 6110.
(13) Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem. Soc.
1996, 118, 11054.
(14) In the original synthetic plan this Weinreb amide was to be
subjected to a late-stage (and direct) reduction to the corresponding
aldehyde (and thus installing this moiety as required in target 1).
However, it transpired that this amide residue is converted into the
corresponding demethoxylated amide upon exposure to samarium
diiodide.
(15) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135.
(16) Crabtree, S. R.; Chu, W. L. A.; Mander, L. N. Synlett 1990, 169.
(17) Ramachandran, S. A.; Kharul, R. K.; Marque, S.; Soucy, P.;
^
Jacques, F.; Chenevert, R.; Deslongchamps, P. J. Org. Chem. 2006,
71, 6149.
(18) For examples of the organocuprate-mediated reductions of enol
phosphates, see: (a) Ishihara, T.; Maekawa, T.; Yamasaki, Y.; Ando, T.
J. Org. Chem. 1987, 52, 300. (b) Paquette, L. A.; Dahnke, K.; Doyon, J.;
He, W.; Wyant, K.; Friedrich, D. J. Org. Chem. 1991, 56, 6199.
(19) For a very recent review of the oxa-di-π-methane rearrange-
ment, see:Rao, V. J.; Srinivas, K. In CRC Handbook of Organic
€
Photochemistry and Photobiology, 3rd ed; Griesbeck, A. G., Oelgemoller,
M., Ghetti, F., Eds.; CRC Press: Boca Raton, FL, 2012; Chapter 22,
pp 527ꢀ548.
Org. Lett., Vol. 15, No. 8, 2013
1935

Scheme 1
Scheme 2
Scheme 3
ultimately proved to be a relatively straightforward matter
(Scheme 4). Thus, the former compound was reduced
stereoselectively, and in the desired manner, by treating it
with LiAlH4 and thus affording the endo-alcohol 30 (78%)
through delivery of hydride to the more accessible exo-face
of the precursor ketone. Coupling of compound 30 with
the readily prepared acid 3121 was accomplished using
DCC in combination with DMAP and the ester 32
(60%) so-formed was oxidized directly to (þ)-armillarivin
(1) (70%) upon exposure to the oxammonium salt derived
from p-TsOH-promoted disproportionation of 4-acetami-
do-TEMPO. The spectral data derived from this synthetic-
ally generated sample of compound 1 were in complete
accord with the assigned structure but final confirmation
of this came from a single-crystal X-ray analysis.11 The
through loss of CO and ketene, respectively, from the
primary photoproduct 26. The s-cissoid nature of the diene
substructure associated with compound 28 was confirmed
through its ready engagement in a DielsꢀAlder cycloaddi-
tion reaction with the potent dienophile 1-phenyltriazo-
line-2,5-dione (PTAD).20
With the key perhydrocyclobuta[e]indene 26 to hand,
completion ofthe synthesis ofthe targetnaturalproduct, 1,
(21) Nicolaou, K. C.; Rodrıguez, R. M.; Mitchell, H. J.; Suzuki, H.;
´
Fylaktakidou, K. C.; Baudoin, O.; van Delft, F. L. Chem.;Eur. J. 2000,
6, 3095.
(20) Alajarin, M.; Bonillo, B.; Marin-Luna, M.; Sanchez-Andrada,
P.; Vidal, A. Eur. J. Org. Chem. 2010, 694.
1936
Org. Lett., Vol. 15, No. 8, 2013

Scheme 4
derived ORTEP is shown in Figure 2. A comparison of
1
the H and 13C NMR spectral data recorded on the nat-
ural product7 with those arising from the present study
established that these were in complete accord with
one another (see Table S1, Supporting Information).
Furthermore, the specific rotations derived from the
two samples of compound 1 were in excellent agreement
{[R]D = þ134.0 (c 0.5, CHCl3) vs [R]D = þ136.6 (c 0.465,
CHCl3)7} as were the corresponding melting points
(176ꢀ181 °C vs 169ꢀ172 °C7).
Figure 2. ORTEP derived from the single-crystal X-ray analysis of
compound 1 (CCDC No. 919146) with labeling of selected atoms.
Anisotropic displacement ellipsoids display 30% probability levels.
Hydrogen atoms are drawn as circles with small radii.
Acknowledgment. We thank the Australian Research
Council and the Institute of Advanced Studies for gener-
ous financial support and Dr Mario Knoke (BASF) for
some exploratory studies.
The present study has identified a new means by which
protoilludane natural products can be synthesized and
thereby offering the prospect of being able to access many
more members of this fascinating class of compound. The
use of the enantiomerically pure metabolite 2 as the start-
ing material in the synthesis reported here serves to further
emphasize the utility of this readily available compound
as a chiron for the construction of a range of terpenoid
compounds.9,22
Supporting Information Available. Full experimental
1
procedures; comparison of the 13C and H NMR data
recorded on synthetically derived 1 with those reported
for (þ)-armillarivin; data derived from the single-crystal
X-ray analyses of compounds 1 and 12 and ORTEP of
1
compound 12; and H and 13C NMR spectra of com-
pounds 1, 10ꢀ22, 24ꢀ30 and 32. This material is available
free of charge via the Internet at http://pubs.acs.org.
(22) Bon, D. J.-Y. D.; Banwell, M. G.; Ward, J. S.; Willis, A. C.
Tetrahedron 2013, 69, 1363.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 8, 2013
1937