An Enantioselective formal synthesis of berkelic acid

Article abstract of DOI:10.1021/ol202265g

An enantioselective formal synthesis of berkelic acid is described. The key step involves a late-stage silyl enol ether addition to a benzannulated oxonium ion with subsequent spiroketalization leading to construction ofthe tetracyclic core. Thermodynamic

Full text of DOI:10.1021/ol202265g

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5382–5385
An Enantioselective Formal Synthesis of
Berkelic Acid
Michael C. McLeod, Zoe E. Wilson, and Margaret A. Brimble*
School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland,
New Zealand
m.brimble@auckland.ac.nz
Received August 22, 2011
ABSTRACT
An enantioselective formal synthesis of berkelic acid is described. The key step involves a late-stage silyl enol ether addition to a benzannulated
oxonium ion with subsequent spiroketalization leading to construction of the tetracyclic core. Thermodynamically controlled equilibration under
acidic conditions affords the desired spiroketal configuration as a single diastereoisomer.
Berkelic acid (1) belongs to an increasing number of
natural products isolated from organisms that inhabit
extreme environments.1 These so-called extremophiles live
in habitats of high and low temperature, high pressure,
high salt, and high and low pH. Berkelic acid was isolated
as a secondary metabolite from a Penicillium species
belonging to the latter category that survives in a flooded
former copper mine with a pH of ∼2.5.2 The lake waters
were also found to contain a number of heavy metals in
high concentrations. Berkelic acid was found to inhibit
caspase-1 (GI50 98 μM) and matrix metalloprotease-3
(GI50 1.87 μM) as well as exhibiting selective activity
against the ovarian cancer cell line OVCAR-3 (GI50 91 nM).
The potent biological activity and remarkable structural
architecture of this molecule have led to a number of efforts
Snider.4 Further total and formal syntheses have since been
reported by the groups of De Brabander5 and Pettus.6
We wished to develop a synthesis of berkelic acid using a
flexible and convergent approach that would allow future
manipulation of its biological acitivity through analogue
synthesis. Our retrosynthetic strategy of Snider’s berkelic
acid advanced intermediate 2 is outlined in Scheme 1. We
envisaged that deprotection of the benzyl and TBS ethers
of isochroman 3 under acidic conditions would result in
spiroketalization to form 2. In turn, 3 could be accessed by
a HornerÀWadsworthÀEmmons/oxa-Michael (HWE/
oxa-M) cascade reaction of phosphonate 4 and lactol 5.
This route enables the late-stage formation of the spiroke-
tal and C-15 stereocenters and could be readily adapted to
the synthesis of analogues by coupling any 2-benzyloxy
benzannulated lactol with a range of β-ketophosphonates.
Ourretrosynthesis issupported by theprevious synthesis
of a berkelic acid model spiroketal reported by our group
using an HWE/oxa-M strategy.7 Deprotonation of phos-
phonate 6 with sodium hydride, followed by addition of
toward its total synthesis. After reassignment of the relative
3
€
stereochemistry by synthesis of the methyl ester by Furstner,
the first total synthesis of berkelic acid was reported by
(1) Wilson, Z. E.; Brimble, M. A. Nat. Prod. Rep. 2009, 26, 44.
(2) Stierle, A. S.; Stierle, D. B.; Kelly, K. J. Org. Chem. 2006, 71, 5357.
(3) (a) Buchgraber, P.; Snaddon, T. N.; Wirtz, C.; Mynott, R.;
Goddard, R.; Furstner, A. Angew. Chem., Int. Ed. 2008, 47, 8450.
(b) Snaddon, T. N.; Buchgraber, P.; Schulthoff, S.; Wirtz, C.; Mynott,
R.; Furstner, A. Chem.;Eur. J. 2010, 16, 12133.
(5) Bender, C. F.; Yoshimoto, F. K.; Paradise, C. L.; De Brabander,
J. K. J. Am. Chem. Soc. 2009, 131, 11350.
(6) Wenderski, T. A.; Marsini, M. A.; Pettus, T. R. R. Org. Lett.
2011, 13, 118.
(4) (a) Wu, X.; Zhou, J.; Snider, B. B. Angew. Chem., Int. Ed. 2009,
48, 1283. (b) Wu, X.; Zhou, J.; Snider, B. B. J. Org. Chem. 2009, 74, 6245.
(7) Wilson, Z. E.; Brimble, M. A. Org. Biomol. Chem. 2010, 8, 1284.
r
10.1021/ol202265g
Published on Web 09/14/2011
2011 American Chemical Society

afforded Weinreb amide 12. Addition of 1-pentenylmagne-
sium bromide then afforded propargyl ketone 13.
Scheme 1. Retrosynthetic Plan
Scheme 3. Synthesis of Lactol 5
lactol 7, provided isochroman 8 as a 1:1 mixture of diaste-
reoisomers (Scheme 2). Hydrogenolysis of the benzyl ethers
over Pd(OH)2 resulted in formation of spiroketal 9. As
noted in a similar model system,8 the acidic conditions used
in the debenzylation step resulted in equilibration to form
the desired thermodynamically favored cis isomer 9 exclu-
sively, as a 14:1 mixture of anomers at the spirocenter.
Attention next turned to the key chiral reduction step.
After extensive screening of chiral reduction conditions, it
was found that the use of an Me-CBS catalyst10 with
catecholborane imparted the highest levels of enantiocon-
trol for the reduction of 13. Using THF as solvent resulted
in moderate enantioselectivity (72% ee, HPLC). It has
been recently reported that the enantioselectivity of CBS
reductions of allenyl and propargyl ketones can be greatly
enhanced by the use of nitroethane as the solvent.11 Pleas-
ingly, performing the reaction in nitroethane resulted in an
increase in enantioselectivity to 99% ee. The selectivity
displayed by the Me-CBS catalyst is the opposite to that
predicted by the bulk of the chemical literature. This same
observation has been reported for the CBS reduction of a
similar ketone bearing a ÀCH2Ar group.12 Selective re-
duction of the triple bond by hydrogenation over Adam’s
catalyst and cyclization with PTSA afforded lactone 14.
Finally, lactol 5 was prepared by DIBAL reduction of
lactone 14 in CH2Cl2 at À78 °C with careful monitoring of
the reaction by TLC to avoid over-reduction.
Scheme 2. Model Studies
The preparation of phosphonate 4 required initial synth-
esis of lactone 19 (Scheme 4). A route to this lactone has
recently been described by Snider et al. by conjugate addi-
tion of a chiral phosphonamide anion to 2-butenolide.4 Our
route commenced with TiCl4-mediated conjugate addition
of allyltributylstannane to R,β-unsaturated N-acyloxazoli-
dinone 1513 affording allyl oxazolidinone 16 with excellent
diastereoselectivity. The facial selectivity was determined by
Synthesis of lactol 5 commenced from benzoic acid 109 by
benzyl protection of the carboxylic acid and two phenolic
groups (Scheme 3). Selective hydrolysis of the aliphatic
methyl ester 11 with LiOH followed by EDC coupling of
the resultant acid with dimethylhydroxylamine hydrochloride
(10) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551.
(11) Yu, C.-M.; Kim, C.; Kweon, J.-H. Chem. Commun. 2004, 2494.
(12) Gooding, O. W.; Bansal, R. P. Synth. Commun. 1995, 25, 1155.
(13) See Supporting Information.
(8) Zhou, J. Y.; Snider, B. B. Org. Lett. 2007, 9, 2071.
(9) Buechi, G.; Leung, J. C. J. Org. Chem. 1986, 51, 4813.
Org. Lett., Vol. 13, No. 19, 2011
5383

and trapping as the TBS protected alcohol 4 using excess
base and TBSCl.15
Scheme 4. Synthesis of Phosphonate 4
With phosphonate 4 and lactol 5 in hand, we next
attempted the key HWE/oxa-M coupling. Phosphonate 4
was pretreated with base before addition of lactol 5
(Scheme 5). Disappointingly, none of the conditions
screened (NaH, THF; K2CO3, Et2O/H2O; DBU, LiCl,
MeCN or THF; KOtBu, THF) resulted in any of the
Scheme 6. De Brabander’s Cycloaddition Approach to Berkelic
Acid5
Scheme 7. Formal Synthesis of (À)-Berkelic Acid (1)
Scheme 5. Attempted HWE/oxa-M Cascade
conversion to known lactone 19 (vide infra) and is in
agreement with the reported Lewis acid promoted allyla-
tions of similar systems.14 Oxidative cleavage of the olefin
with OsO4/NaIO4 to the corresponding aldehyde followed
by borane reduction and TBDPS protection provided 17. It
was necessary to perform the TBDPS protection step at
relatively high concentrations (>0.4 M) to avoid lactoniza-
tion via displacement of the oxazolidinone by the free
alcohol. The acetate and oxazolidinone were both cleaved
by treatment with LiOH and H2O2 to afford a hydroxy acid
that readily cyclized to lactone 18. Methylation of lactone 18
proceeded in a 7:1 dr to afford 19. The absolute stereo-
chemistry of 19 was confirmed by comparison of the optical
rotation to that reported by Snider.4 Addition of lithiated
dimethyl methylphosphonate to lactone 19 afforded phos-
phonyl substituted lactol 20 that underwent ring-opening
(14) (a) Williams, D. R.; Mullins, R. J.; Miller, N. A. Chem. Commun.
2003, 2220. (b) Wilding, E. E.; Gregg, J. J.; Mullins, R. J. Synlett 2010,
793.
(15) Ditrich, K.; Hoffmann, R. W. Tetrahedron Lett. 1985, 26, 6325.
5384
Org. Lett., Vol. 13, No. 19, 2011

desired product being isolated. This lack of reactivity is
postulated to be due to the lactol-hydroxy aldehyde equili-
brium favoring the unreactive ring-closed form in this case.
Faced with this reality, we proposed that the two frag-
mentscould be unified by addition ofa silyl enol ether toan
oxonium ion derived from lactol 5. A similar approach was
employed by De Brabander et al. in their synthesis of
berkelic acid (1), using a silver-catalyzed dearomatiza-
tionÀcycloisomerizationÀcycloaddition cascade to couple
fragments 22 and 23 and obtain advanced spiroketal
intermediate 24 (Scheme 6).5
To this end, addition of methyllithium to lactone 19 and
treatment of the resulting adduct 25 with KOtBu and
TBSCl afforded methyl ketone 26 (Scheme 7). Silyl enol
€
ether formation with TMSOTf and Hunig’s base pro-
ceeded smoothly to afford 27. Lactol 5 was treated with
Under these conditions, debenzylation, spiroketalization,
and thermodynamic equilibration occurred in one pot to
afford spiroketal 30 as a single diastereoisomer in 58% yield
from methyl ketone 26 after purification by chromatogra-
phy. Finally, the formal synthesis of berkelic acid was
completed by reaction of 30 with allyl bromide and
K2CO3 to provide 2, whose spectroscopic data and optical
rotation agreed with the data reported.4
In conclusion, an enantioselective formal synthesis of
the antitumor agent berkelic acid (1) has been completed
by successful preparation of Snider’s advanced intermedi-
ate 2. The key steps in our synthesis include a silyl enol
etherÀoxonium coupling followed by debenzylation under
acidic conditions to obtain the desired thermodynamically
favored tetracyclic spiroketal. This synthetic approach can
be readily employed for the synthesis of analogues of the
natural product by simple reaction of any 2-benzyloxy
benzannulated lactols with a range of silyl enol ethers.
BF3 OEt2, and the resulting oxonium ion was quenched
3
by addition of silyl enol ether 27 at À78 °C. Pleasingly,
after 30 min at À78 °C complete consumption of starting
material was observed. Under these conditions the TBS
ether was also cleaved, affording lactol 29 as a mixture of
diastereoisomers. Previous synthetic studies directed to-
ward berkelic acid have demonstrated that the two stereo-
centers at C-15 and C-17 can be equilibrated to the desired
spiroketal configuration under acidic conditions.3,4 The
diastereomeric mixture of lactols 29 was therefore subjected
to hydrogenation over 10% Pd/C in the presence of HCl.
Acknowledgment. This work was supported by the Royal
Society of New Zealand Marsden Fund.
Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of 1H and 13
C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
Org. Lett., Vol. 13, No. 19, 2011
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