A diastereoselective formal synthesis of berkelic acid

Article abstract of DOI:10.1021/ol102652t

A formal synthesis of berkelic acid is reported. The strategy employs the combination of a chiral exocyclic enol ether and an achiral isochromanone to afford the chroman spiroketal core via a base-triggered generation and cycloaddition of an o-quinone met

Full text of DOI:10.1021/ol102652t

ORGANIC
LETTERS
2011
Vol. 13, No. 1
118-121
A Diastereoselective Formal Synthesis
of Berkelic Acid
Todd A. Wenderski, Maurice A. Marsini, and Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, UniVersity of California at Santa Barbara,
Santa Barbara, California 93106-9510, United States
pettus@chem.ucsb.edu
Received November 1, 2010
ABSTRACT
A formal synthesis of berkelic acid is reported. The strategy employs the combination of a chiral exocyclic enol ether and an achiral
isochromanone to afford the chroman spiroketal core via a base-triggered generation and cycloaddition of an o-quinone methide intermediate.
Other key steps include equilibration of the spiroketal, intramolecular benzylic oxidation, and lactone addition/hemiketal reduction; all occur
with good diastereoselectivity.
The natural product berkelic acid, isolated by Stierle et al.
in 2006, is a secondary metabolite produced by a species of
Penicillium that thrives in Berkely Pit Lake outside of Butte,
Montana.1 The toxic lake, which is an abandoned copper
mine that has since filled with over 40 billion gallons of
contaminated groundwater, was designated in 1994 as an
EPA superfund site.2 Given the proximity of other extreme
environments, such as hotsprings of Yellowstone National
Park some hundred miles to the south, it is doubtful that the
extremophile evolved in the waste pit. However, researchers
have speculated that some natural products produced in
extreme environments serve to protect their progenitor.
Berkelic acid, in particular, emerged from an assay-driven
study aimed at identifying metal dependent enzyme inhibi-
tors. The compound was reported to inhibit the cysteine
protease caspase-1 (98 µM) and matrix metalloproteinase-3
(MMP-3, 1.87 µM). In further studies with the NCI-60 cancer
cell panel, potent and selective cytotoxicity was observed
toward a particularly aggressive ovarian cancer cell line
(OVCAR-3, 91 nM).
Originally assigned as compound 1, berkelic acid belongs
to a very select group of chroman spiroketal natural products
of considerable synthetic interest and biological importance
(Scheme 1).3 The unknown relative stereochemistry at the
quaternary carbon, however, gave us pause. We first envi-
sioned a diastereoselective plan that might address this
question toward the end of the synthesis. Late stage introduc-
tion of the aryl acid utilizing an aryl-X substituent of
compound 2, in principle, made this functionality more
distinguishable from the methyl ester. Furthermore, research-
ers had theorized that MMP inhibitors less dependent upon
metal chelation might prove more selective toward validated
isoforms of the enzyme; this would allow for analog
development along the synthetic pathway.4 We further
imagined construction of the isobenzopyran ring by utiliza-
tion of a stereocontrolled benzylic oxidation of the benzopy-
ran with concomitant reduction of the ketone functionality
within the R′′ residue of compound 3. To construct the
chroman spiroketal motif, we sought to employ chiral
exocyclic enol ethers, such as 5, in a diastereoselective
(3) Sperry, J.; Wilson, Z. E.; Rathwell, D. C. K.; Brimble, M. A. Nat.
Prod. Rep. 2010, 27, 1117.
(1) Stierle, A. A.; Stierle, D. B.; Kelly, K. J. Org. Chem. 2006, 71,
5357.
(4) (a) Itoh, Y.; Nagase, H. Essays Biochem. 2002, 38, 21. (b) Zucker,
S.; Cao, J.; Chen, W. T. Oncogene 2000, 19, 6642.
(2) EPA ID: MTD980502777.
10.1021/ol102652t  2011 American Chemical Society
Published on Web 12/07/2010

kinetic spiroketal epimer could be equilibrated to the
corresponding thermodynamic epimer spiroketal 8 (>1:2)
with a protic acid.8 A short time thereafter, Fu¨rstner reported
the synthesis of berkelic acid methyl ester 12 by coupling
three separate chiral components together. Their observations
led to the revision of three stereocenters and an assignment
of the relative stereochemistry including the quaternary
stereocenter (Figure 1).9 This landmark effort paved the way
Scheme 1. An Early Retrosynthetic Plan
Figure 1. Subsequent revisions by Fu¨rstner and Snider.
for future synthetic successes, and soon afterward, Snider
reported the first total synthesis establishing the absolute
structure of berkelic acid as its enantiomer (-)-1'.10 The
Snider synthesis, which involved an acid-catalyzed coupling
of two chiral components followed by late-stage chromato-
graphic resolution of the quaternary center, is masterful in
its overall efficiency. Sometime later, De Brabander reported
a biomimetic total synthesis combining spicifernin and
pulvilloric acid surrogates.11
inverse demand Diels-Alder reaction with an o-quinone
methide (o-QM) 4 generated at low temperature using our
magnesium base-triggering methods in conjunction with
various o-OBoc compounds 7.5
Hence, we began by devising a short synthesis of exocyclic
enol ethers (5a-c) derived from γ-lactone 9, which could
be produced later in the desired enantiomeric form (Scheme
2).6 These enol ethers were then evaluated in conjunction
These successes and structural revisions forced us to
reevaluate our strategy with the prime intention of preserving
our initial diastereoselective approach. While we remained
confident that enol ethers 5a-c would react to form chroman
spiroketals,12 we needed to redesign our o-QM precursor so
that a new substituent could be elaborated into the desired
tetracycle. We postulated that compound 17 might prove to
be a novel o-QM precursor participating in our base-
triggering procedure and thereby lead to the o-QM carboxy-
late 16 and the spiroketal 15 (Scheme 3). Unfortunately, the
cycloaddition was expected to afford the kinetic diastereomer.
Although our prior equilibration studies were encouraging,
the final (2:1) ratio would be a challenge to improve.
However, we hoped that the added carboxylic acid residue
and aryl iodide might bolster the ratio afforded by a
thermodynamic equilibration. While the specifics of the
sequence needed for isobenzopyran formation remained
Scheme 2. Construction of Enol Ether Coupling Partners
with assorted o-QM precursors 7 (R′′ ) -H; X ) -H, -Br;
R′ ) -Me, -Bn) using our standard magnesium base-
triggering methodology.
Our early experiments showed that the low temperature
cycloaddition afforded what we believed to be the desired
relative stereochemistry, whereby the methyl residue in the
enol ether had controlled the spiroketal stereocenter (>4:1)
in compound 3.7 We further observed and reported that this
(7) Marsini, M. A.; Huang, Y.; Lindsey, C. C.; Wu, K.-L.; Pettus,
T. R. R. Org. Lett. 2008, 10, 1477.
(8) Huang, Y.; Pettus, T. R. R. Synlett 2008, 1353.
(9) (a) Buchgraber, P.; Snaddon, T. N.; Wirtz, C.; Mynott, R.; Goddard,
R.; Fu¨rstner, A. Angew. Chem., Int. Ed. 2008, 47, 8450. (b) Snaddon, T. N.;
Buchgraber, P.; Schulthoff, S.; Wirtz, C.; Mynott, R.; Fu¨rstner, A.
Chem.sEur. J. 2010, 16, 12133.
(10) (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.
(5) (a) Selenski, C.; Pettus, T. R. R. J. Org. Chem. 2004, 69, 9196. (b)
Jones, R. M.; Van de Water, R. W.; Lindsey, C. C.; Pettus, T. R. R. J.
Org. Chem. 2001, 66, 3435.
(11) Bender, C. F.; Yoshimoto, F. K.; Paradise, C. L.; De Brabander,
J. K. J. Am. Chem. Soc. 2009, 131, 11350.
(12) Compound 5b was made by Snider and coworkers in enantiopure
form by 1,4-addition of metallated chiral phosphoramides: see ref 10a and
Hanessian, S.; Gomtsyan, A.; Malek, N. J. Org. Chem. 2000, 65, 5623.
(6) See Supporting Information and Pirrung, M. C.; Dunlap, S. E.;
Trinks, U. P. HelV. Chim. Acta 1989, 72, 1301.
Org. Lett., Vol. 13, No. 1, 2011
119

Scheme 3
.
Revised Diastereoselective Strategy
Scheme 4. Diastereoselective Construction of Enol Ether 23
undetermined, it mandated stereoselective benzylic oxidation,
etherification, and stereoselective incorporation of the pentyl
residue to produce the fully elaborated tetracycle 13. Acy-
lation could then be used to introduce the quaternary center
and methyl ester. The exact timing for carboxylation,
however, depended on the concluding events and surrounding
functionality.
Our next hurdle involved selective mono addition of the
desired pentyl alkyl chain to the lactone scaffold 21. The
methylene adjoining the lactone carbonyl in compound 21
was problematicsaddition of most organometallic species
resulted in deprotonation and returned starting material upon
workup. Weinreb amides derived from 21 were also inves-
tigated in the hope that an acyclic system would prove less
acidic and undergo mono addition to afford the corresponding
ketone. However, we eventually uncovered observations by
Cohen et al.15 that describe the selective mono addition of
organocerium species, prepared by the normal Imamato
process, to lactones.16 After confirming the integrity of the
desired pentylcerium reagent (generated by the method of
Knochel)17 by testing its reaction with 1,3-diphenylacetone,
we were pleased to observe its selective mono addition to
lactone 21 produces the corresponding hemiketal 22 in
greater than 80% yield. The hemiketal 22, however, exists
in equilibrium with its ketone counterpart, which thwarted
its complete spectroscopic identification. We therefore sought
to reduce it in situ. Conventional reduction tactics, such as
the combined action of triethylsilane and protic or Lewis
acids, afforded a mixture of isobenzopyran diastereomers
favoring the undesired stereochemistry. In the absence of a
reductant, however, treatment of the cerium alkoxy hemiketal
22 (0.02 M in CH2Cl2, -78 °C) in situ with TFA resulted in
smooth formation of the corresponding enol ether 23 in 75%
yield over the one-pot operation from lactone 21.
Proceeding in the forward direction, tert-butyl magnesium
chloride (1.05 equiv) is added to the lactone 18 (0.1 M in
THF, -78 °C), which we had previously prepared in seven
steps from commercial materials,13 followed by the addition
of the enol ether 5a or 5b (neat, 2.1 equiv). Subsequent
warming of the mixture to room temperature affords the
respective spiroketals 19a-b in 60-65% yield with a 3:1
ratio of spiroketal epimers favoring the endo isomer (Scheme
4). Treatment of the mixture 19a (0.01 M in CHCl3, 65 °C)
with DDQ afforded the spiroketal 20a of opposite config-
uration with a 1:1 ratio at the oxidized benzylic carbon atom.
This result indicated to us that, under the reaction conditions,
equilibration of the spiroketal was occurring more slowly
than benzylic oxidation. To circumvent this issue, equilibra-
tion was carried out before exposure to the oxidant. Relative
energy calculations for all of the possible diastereomers of
spiroketal 19a indicated that the desired spiroketal epimer
19b is more stable by greater than 4.5 kcal/mol.14 Gratify-
ingly, treatment of the 3:1 mixture of 19a or 19b (0.06 M in
CHCl3, rt) with TFA (0.3% in CHCl3) confirms these
calculations and results in a nearly quantitative yield of the
corresponding thermodynamic spiroketals in a 10:1 diaster-
eomeric ratio. Separation and intramolecular benzylic oxida-
tion using the prior conditions produced the respective
lactones 21a-b as single diastereomers.
We had planned to conclude our synthesis with carbony-
lation, and compound 23 enabled us to investigate a variety
(15) (a) Ahn, Y.; Cohen, T. J. Org. Chem. 1994, 59, 3142. (b) Mudryk,
B.; Shook, C. A.; Cohen, T. J. Am. Chem. Soc. 1990, 112, 6389.
(16) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y; Mita,
T. J. Org. Chem. 1984, 49, 3904.
(13) See the Supporting Information for experimental details.
(14) Calculations were performed using Macromodel MM3 Monte Carlo
conformational analysis.
(17) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem., Int. Ed. 2006,
45, 497.
120
Org. Lett., Vol. 13, No. 1, 2011

of plausible, mild conditions that might prove compatible
with the ꢀ-keto ester functionality. Unfortunately, all pal-
ladium- and zinc-mediated coupling processes failed in our
hands. In addition, we found that all homogeneous and
heterogeneous hydrogenations of the enol ether in 23 caused
hydrogenolysis of the aryl iodo functionality. These problems
forced us to proceed with carbonylation before reduction of
the enol ether, much earlier than originally planned. Lithium-
halogen exchange proceeds with iodide 23 (0.01 M in THF,
-110 °C) upon addition of t-BuLi (2 equiv), whereupon
cannulation onto carbon dioxide affords the desired acid upon
acidic workup (Scheme 5). Subsequent hydrogenation of the
Snider’s, thereby confirming all of the stereochemical
assignments and resulting in a formal synthesis of berkelic
acid with the synthesis of the acid 24.
Nevertheless, we sought to shorten the potential endgame
for our route by one additional step. Thus, the iodo compound
23 was subjected to lithium-halogen exchange and addition
of carbon dioxide as before. In this instance, however, the
carboxylate anion was intercepted with benzyl bromide to
produce the corresponding benzyl ester in 84% yield. We
further discovered that this material (0.025 M in toluene)
could be selectively reduced with rhodium on carbon at 65
psi of hydrogen pressure with the benzyl ether and ester
remaining intact, thereby yielding compound 26 in 87%
yield. In view of the newly reported synthesis of (-)-1' by
Fu¨rstner in which a benzyl ester is used for orthogonal
deprotection in the presence of a methyl ester, the benzylated
material 26 should prove as viable in the Snider endgame
as ester 25.
Scheme 5. Formal Syntheis of (()-Berkelic Acid (1′)
In conclusion, we have successfully accomplished a
diastereoselective formal synthesis of berkelic acid by
interception of Snider’s previously uncharacterized salicylic
acid 24. We believe that our strategy has merit since our
tactical construction of the isobenzopyran ring is orthogonal
to previous syntheses; all the prior strategies utilize the
combination of various chiral components together with
various chiral isobenzopyran derivatives to arrive at the
tetracycle. In our case, the relative stereochemistry of the
tetracyclic core is efficiently relayed from the stereocenters
derived from the original enol ether o-QM coupling partner.
Furthermore, the flexibility of this route allows for the
introduction of various scaffold modifications of the tetracylic
core (acid removal, spiroketal epimierization, alkyl deriva-
tization) that may shed light on the mechanism of action of
this interesting natural product.19
crude acid (0.01 M in EtOAc) over palladium on carbon
(10%, 1 atm H2) occurs from the less hindered face to afford
salicylic acid 24 in a 64% yield over two steps with >10:1
dr.18
The salicylic acid 24 had been a key intermediate in the
Snider synthesis, and it is positioned six steps from the
natural product. However, this acid had not been fully
characterized. We therefore constructed the published allyl
derivative 25 from acid 24. Spectroscopic comparison of the
1H NMR showed our synthetic material to be the same as
Acknowledgment. This work was funded with support
from the National Institute of General Medical Sciences
(GM064831).
Supporting Information Available: Experimental details
for the preparation of new compounds and complete spectral
data for new compounds accessible and stable as single
entities (5a-c, 18, 19a-b, 21a-b, 22-26). This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) Reduction of hemiacetal analogs is reported to stereoselectively
provide the corresponding 2,6-cis-tetrahydropyran. See: Nicolaou, K. C.;
Cole, K. P.; Frederick, M. O.; Aversa, R. J.; Denton, R. M. Angew. Chem.,
Int. Ed. 2007, 119, 9031.
OL102652T
(19) Fischbach, M. A.; Walsh, C. T. Science 2009, 325, 1089.
Org. Lett., Vol. 13, No. 1, 2011
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