A flexible asymmetric synthesis of the tetracyclic core of berkelic acid using a Horner-Wadsworth-Emmons/oxa-Michael cascade

Article abstract of DOI:10.1039/b927219b

The one-pot Horner-Wadsworth-Emmons/oxa-Michael cascade followed by spiroketalisation affords the tetracyclic benzannulated spiroketal core of berkelic acid, an extremophile natural product with selective activity against ovarian cancer.

Full text of DOI:10.1039/b927219b

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
A flexible asymmetric synthesis of the tetracyclic core of berkelic acid using a
Horner–Wadsworth–Emmons/oxa-Michael cascade†
Zoe E. Wilson and Margaret A. Brimble*
Received 23rd December 2009, Accepted 18th January 2010
First published as an Advance Article on the web 26th January 2010
DOI: 10.1039/b927219b
The one-pot Horner–Wadsworth–Emmons/oxa-Michael cas-
cade followed by spiroketalisation affords the tetracyclic ben-
zannulated spiroketal core of berkelic acid, an extremophile
natural product with selective activity against ovarian cancer.
Since its isolation in 2006,1 berkelic acid 1 has attracted significant
interest due to its unusual source, medicinal potential and
unprecedented tetracyclic structure.2 Berkelic acid was isolated
by Stierle et al. from a Penicillium fungus collected from Berkeley
Pit Lake in Butte, Montana.1 Berkeley Pit Lake formed when an
abandoned copper mine filled with infiltrating ground water to
give an extremely acidic (pH 2.5) and metal contaminated lake.1
Berkelic acid is one of an increasing number of novel secondary
metabolites isolated from extreme dwelling microorganisms3 and
inhibits caspase-1 (GI50 0.098 mM) and matrix metalloprotease-3
(GI50 1.87 mM), as well as exhibiting selective activity (GI50 91 nM)
against the OVCAR-3 (ovarian cancer) cell line.1 The stereochem-
istry at C22 was initially not determined, but subsequent total
syntheses established this stereocentre as (S) and reassigned the
Scheme 1 Berkelic acid 1, the target tetracyclic core 2 and the synthetic
absolute stereochemistry at C18 and C19.4–6
strategy employed.
The ambiguity in the chemical structure, together with future
Compared to the previous biomimetic approaches to berkelic
acid4–6 the present strategy provides increased flexibility with the
stereochemistry installed at a late stage and the HWE/oxa-M
cascade allowing access to a range of berkelic acid analogues by
reacting any 2-benzyloxy benzannulated lactol with a library of
phosphonates derived from 5-membered lactones in two simple
operations.
manipulation of biological activity through analogue synthesis
prompts development of a flexible convergent approach to this
important bioactive natural product. Furthermore, the planned
bioremediation of Berkeley Pit Lake may eliminate the natural
source of this compound. To this end, we herein report an enan-
tioselective synthesis of the tetracyclic benzannulated spiroketal
core 2 of berkelic acid 1 (Scheme 1).
The required phosphonate coupling partner 5 was conve-
niently synthesised by ring opening of g-butyrolactone with
benzyl bromide followed by displacement with lithium dimethyl
methylphosphonate (Scheme 2).
Our retrosynthetic approach to the tetracyclic core of berkelic
acid 2 is outlined in Scheme 1. It was envisaged that isochroman 3
would spontaneously undergo acid catalyzed spiroketalisation to
give 2 upon debenzylation. In turn, isochroman 3 is accessed via
union of chiral lactol 4 and phosphonate 5 using a novel Horner–
Wadsworth–Emmons/oxa-Michael (HWE/oxa-M) cascade. The
chiral centre at C3 in lactol 4 thus provides an anchor on which the
absolute stereochemistry of the entire core structure is established.
To our knowledge, the reaction of a chiral benzannulated lactol
in a HWE/oxa-M cascade has not been used in natural product
synthesis. However, achiral HWE/oxa-M cascades have been
reported leading to an undesired by-product7 and for the synthesis
of simple 5-HT1D antagonists and 5-HT reuptake inhibitors.8
Scheme 2 Synthesis of phosphonate 5.
Department of Chemistry, University of Auckland, 23 Symonds St., Auck-
land, 1010, New Zealand. E-mail: m.brimble@auckland.ac.nz; Fax: +649
373 7422; Tel: +649 373 7599 ext. 88259
† Electronic supplementary information (ESI) available: Experimental
procedures, full characterisation for all novel compounds, chiral HPLC
traces for all chiral molecules and structural confirmation. See DOI:
10.1039/b927219b
The synthesis of the precursor for key lactol 4, namely lactone
7, began with dibenzylation of methyl orsellinate 89 followed by
conversion to amide 9. The key steps involved addition of Weinreb
amide 1010 to the toluate anion of 9 followed by enantioselective
reduction of the resultant ketone 11 before cyclisation to lactone 7.
1284 | Org. Biomol. Chem., 2010, 8, 1284–1286
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
The toluate anion addition proceeded in high yield. An extensive
range of chiral reductions were investigated using ketone 11
with the rotameric alcohols subjected to immediate cyclisation
to lactone 7, thus facilitating determination of the enantiomeric
excess by chiral HPLC. Harsh conditions, resulting in partial
deprotection of the phenol, were required to afford lactone 7 from
the hydroxy amide in acceptable yield. Disappointingly, the best
conditions, namely (S)-methyl-CBS11 catalysed reduction, only
resulted in a moderate yield (57%) and enantiomeric excess (e.e.,
51%). In an attempt to improve the e.e. and yield for the chiral
reduction/lactonisation step diethyl amide 11 was converted to a
methyl ester 13, thereby avoiding the formation of rotamers and
facilitating the lactonisation step.
effect complete conversion to lactone 7. Pleasingly, (L)-TarB-
NO2 reduction of 13 gave 7 in much improved yield of 97%
and an e.e. of 73% (Scheme 3). Lactone 7 was easily purified by
12
preparatory scale chiral HPLC affording essentially enantiopure
12
7 (>99% e.e.). Correspondingly, (D)-TarB-NO2 afforded (S)-
lactone (ent-7) with similar levels of enantiocontrol providing an
enantiodivergent synthesis of 7 for future analogue synthesis.
Lactone 7 (>99% e.e.) was reduced with DIBAL-H and the
crude lactol 4 added directly to the anion of 5 triggering a
HWE/oxa-M cascade to afford isochroman 3 as an approximately
1 : 1 mixture of cis : trans isomers 3a and 3b. Using HCl in
THF this ~1 : 1 mixture steadily equilibrated providing trans 3b
predominantly (see Supporting Information). Pleasingly, when
this diastereomeric mixture of 3a : 3b (~1 : 1) was subjected to
the deprotection/cyclization step, the desired cis configured
tetracyclic core 2, was obtained in 72% yield as a 14 : 1 ratio
with its non-anomerically stabilised diastereomer (Scheme 4). This
observation is in agreement with an earlier published synthesis
of this tetracyclic core,13 in which a mixture of the 4 possible
spiroketals underwent equilibration to the desired product upon
Earlier attempts to synthesise 13 by addition of the toluate
anion of benzylated methyl orsellinate to Weinreb amide 10
were unsuccessful. Methyl ketone 13 was eventually formed by
effecting cyclisation of ketone 11 to isocoumarin 12, followed by
ring-opening to the keto-acid and esterification. Methyl ester 13
rapidly reconverted to isocoumarin 12 in the presence of acid or
base but with careful handling it could be subjected to further
manipulation. Partial cyclisation of the alcohol obtained after the
chiral reduction step was observed hence the mixture was routinely
1
treatment with acid. The H NMR of 2 was in agreement with
this previously published model compound, differing only in the
presence of a methyl ester at C9¢.13 A strong nOe was observed
R
treated with Amberlyst 15ꢀ (H+ resin) in dichloromethane to
Scheme 3 Synthesis of lactone 7.
Scheme 4 HWE/oxa-M cascade and cyclisation to give tetracyclic core 2.
The Royal Society of Chemistry 2010 Org. Biomol. Chem., 2010, 8, 1284–1286 | 1285
This journal is
©

View Article Online
between H3a¢ and H5¢, further confirming the cis relationship.
The lack of nOe correlations between H3a¢ and H3 also supported
the fact that the major product was the anomerically stabilised
spiroketal (see Supporting Information).
In summary, an efficient enantioselective synthesis of 2, the
tetracyclic core of berkelic acid has been achieved. Studies towards
the total synthesis of berkelic acid using this methodology are
ongoing and will be reported in due course.
We thank the Royal Society of New Zealand Marsden Fund for
financial support, the University of Auckland for a University of
Auckland Doctoral Scholarship (Z.E.W.) and Dr Jonathan Sperry
(University of Auckland) for helpful discussions.
2 X. X. Wu, J. Y. Zhou and B. B. Snider, J. Org. Chem., 2009, 74, 6245–
6252 and references therein.
3 Z. E. Wilson and M. A. Brimble, Nat. Prod. Rep., 2009, 26, 44–71.
4 P. Buchgraber, T. N. Snaddon, C. Wirtz, R. Mynott, R. Goddard and
A. Furstner, Angew. Chem., Int. Ed., 2008, 47, 8450–8454.
5 X. X. Wu, J. Y. Zhou and B. B. Snider, Angew. Chem., Int. Ed., 2009,
48, 1283–1286.
6 C. F. Bender, F. K. Yoshimoto, C. L. Paradise and J. K. De Brabander,
J. Am. Chem. Soc., 2009, 131, 11350–11352.
7 F. Kienzle and R. E. Minder, Helv. Chim. Acta, 1980, 63, 1425–1433.
8 A. B. Bueno, J. Gilmore, J. Boot, R. Broadmore, J. Cooper, J. Findlay,
L. Hayhurst, A. Marcos, C. Montero, S. Mitchell, G. Timms, R.
Tomlinson, L. Wallace and L. Walton, Bioorg. Med. Chem. Lett., 2007,
17, 3344–3348.
9 J. Chiarello and M. M. Joullie´, Tetrahedron, 1988, 44, 41–48.
10 N. Satyamurthi, J. Singh and I. S. Aidhen, Synthesis, 2000, 375–382.
11 E. J. Corey and C. J. Helal, Angew. Chem., Int. Ed., 1998, 37, 1986–
2012.
Notes and references
12 D. B. Cordes, T. M. Nguyen, T. J. Kwong, J. T. Suri, R. T. Luibrand
and B. Singaram, Eur. J. Org. Chem., 2005, 5289–5295.
13 J. Y. Zhou and B. B. Snider, Org. Lett., 2007, 9, 2071–2074.
1 A. A. Stierle, D. B. Stierle and K. Kelly, J. Org. Chem., 2006, 71, 5357–
5360.
1286 | Org. Biomol. Chem., 2010, 8, 1284–1286
This journal is
The Royal Society of Chemistry 2010
©