Biomimetic synthesis of the tetracyclic core of berkelic acid

Article abstract of DOI:10.1021/ol0704338

Acid-catalyzed condensation of 2,6-dihydroxybenzoic acid 3 with ketal aldehyde 14 in methanol at 25 °C, followed by CH₂N₂ esterification, gave a 4:1:4:1 mixture of diastereomers 15b-18b in 60% yield. Equilibration of this mixture wit

Full text of DOI:10.1021/ol0704338

ORGANIC
LETTERS
2007
Vol. 9, No. 11
2071-2074
Biomimetic Synthesis of the Tetracyclic
Core of Berkelic Acid
Jingye Zhou and Barry B. Snider*
Department of Chemistry, MS 015, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
snider@brandeis.edu
Received February 20, 2007
ABSTRACT
Acid-catalyzed condensation of 2,6-dihydroxybenzoic acid 3 with ketal aldehyde 14 in methanol at 25
°
C, followed by CH2N2 esterification,
gave a 4:1:4:1 mixture of diastereomers 15b−18b in 60% yield. Equilibration of this mixture with TFA in CDCl3 provided tetracycle 15b (83%
yield) with the complete skeleton of berkelic acid. A similar condensation at 0
probably formed by a 1,5-hydride shift.
°C afforded 15b−18b and a reduction product 19b, which was
Stierle and co-workers recently isolated berkelic acid (1), a
novel spiroketal with selective anticancer activity, from an
acid mine waste fungal extremophile (see Scheme 1).1 The
structure was assigned on the basis of analysis of the NMR
and mass spectral data. The absolute stereochemistry and
the relative stereochemistry of the side chain stereocenter
were not assigned. Berkelic acid inhibits MMP-3 and
caspase-1 and shows selective activity toward ovarian cancer
OVCAR-3 with a GI50 of 91 nM. We thought that 1 should
be accessible by a highly convergent route starting from ketal
aldehyde 2 and 2,6-dihydroxybenzoic acid 3. Acid 3, a
synthetic, and presumably biosynthetic, precursor to pul-
villoric acid (4), has been prepared in both racemic2 and
optically pure forms.3
Scheme 1. Retro- and Biosynthesis of Berkelic Acid (1)
An oxa-Pictet-Spengler cyclization4 of 2 and 3 should
give isochroman 8 (see Scheme 2). These cyclizations are
usually suggested to proceed by formation of oxocarbenium
ion 6, followed by a Friedel-Crafts cyclization to give 8. It
is also possible that the first step is an intermolecular
(1) Stierle, A. A.; Stierle, D. B.; Kelly, K. J. Org. Chem. 2006, 71, 5357-
5360.
(2) Bullimore, B. K.; McOmie, J. F. W.; Turner, A. B.; Galbraith, M.
N.; Whalley, W. B. J. Chem. Soc. C 1967, 1289-1293.
(3) Ro¨del, T.; Gerlach, H. Liebigs Ann. Chem. 1997, 213-216.
10.1021/ol0704338 CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/28/2007

cations analogous to 7 and 10 afforded mainly the more
stable trans product.7 Therefore it might be possible to use
either kinetically or thermodynamically controlled conditions
to obtain the desired diastereomer.
Scheme 2. Proposed Oxa-Pictet-Spengler Cyclization to Give
9
Model ketal aldehyde 14 was prepared to investigate this
sequence (see Scheme 3). Addition of the lithium enolate of
Scheme 3. Preparation of Model 15b
Friedel-Crafts reaction to give benzylic alcohol 5. Pro-
tonation of the alcohol and loss of water will give the
stabilized benzylic cation 75 that will cyclize to give 8. Ketal
exchange with loss of methanol will give 9 with the complete
tetracyclic core of berkelic acid.
This sequence generates two new stereocenters so that four
isomers can be produced. The anomeric center of berkelic
acid (1), with the oxygen of the tetrahydrofuran ring axial
on the pyran ring, is probably in the more stable configu-
ration. Therefore this center should be readily set by
equilibration. Oxa-Pictet-Spengler cyclizations that give 1,3-
disubstituted isochromans often give mainly the cis disub-
stituted products such as 8 under kinetically controlled
conditions.6 In some cases, equilibration via the benzylic
tert-butyl acetate to γ-butyrolactone (11) afforded ester 12
as a mixture of hydroxy ketone and hemiketal tautomers.8
Reaction in acidic methanol converted this mixture to ketal
ester 13 in 56% overall yield. Reduction of 13 with
DIBAL-H at -78 °C provided crude ketal aldehyde 14,
which decomposed on chromatography and was used without
purification.
Reaction of acid 39 with 2-3 equiv of crude ketal aldehyde
14 in MeOH containing Dowex 50WX8-400-H+ for 12 h at
25 °C afforded a mixture of the desired tetracyclic acids
15a-18a that was treated with diazomethane in ether to give
a 4:1:4:1 mixture of methyl esters 15b-18b, respectively,
in 60% yield. The four isomers were separated and charac-
terized spectroscopically. Molecular mechanics with con-
formational searching calculated relative strain energies for
(4) For a review see: Larghi, E. L.; Kaufman, T. S. Synthesis 2006,
187-220.
(5) Protonated o- and p-quinone methides are important resonance
contributors stabilizing cation 7.
(6) (a) DeNinno, M. P.; Schoenleber, R.; Perner, R. J.; Lijewski, L.; Asin,
K. E.; Britton, D. R.; MacKenzie, R.; Kebabian, J. W. J. Med. Chem. 1991,
34, 2561-2569. (b) Wu¨nsch, B.; Zott, M. Liebigs Ann. Chem. 1992, 39-
45. (c) Anderson, B. A.; Hansen, M. M.; Harkness, A. R.; Henry, C. L.;
Vincenzi, J. T.; Zmijewski, M. J. J. Am. Chem. Soc. 1995, 117, 12358-
12359. (d) Giles, R. G. F.; Rickards, R. W.; Senanayake, B. S. J. Chem.
Soc., Perkin Trans. 1 1998, 3949-3956. (e) Bianchi, D. A.; Ru´a, F.;
Kaufman, T. S. Tetrahedron Lett. 2004, 45, 411-415.
(7) See ref 6d and footnote 15 in ref 6a.
(8) Kim, P.; Olmstead, M. M.; Nantz, M. H.; Kurth, M. J. Tetrahedron
Lett. 2000, 41, 4029-4032.
(9) Prepared as described by Whalley in ref 2, except that 3,5-
dimethoxyphenylacetyl chloride was treated with n-C5H11MgCl and CuI
rather than an organocadmium reagent.
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Org. Lett., Vol. 9, No. 11, 2007

15b-18b of 28.14, 28.56, 30.51, and 30.84 kcal/mol,
respectively.10 This suggests that isomers 15b and 16b with
H3′a and H5′ cis are significantly more stable than isomers
17b and 18b with these hydrogens trans. Isomers 15b and
17b with the tetrahydrofuran oxygen axial on the pyran ring
are slightly more stable than 16b and 18b, respectively, as
expected from the anomeric effect. The formation of 17b as
one of the two major products indicates that incomplete
equilibration occurs under these reaction conditions.
The coupling constants to H3′a are 10-12 and 5-6 Hz,
indicating that this hydrogen is axial in all four conformers.
The coupling constants between the benzylic methylene
group and the axial hydrogen H5′ in 15b (J ) 10.7, 4.2 Hz)
and 16b (11.7 and 3.9 Hz) are close to the values calculated
for both 15b and 16b of 11.2 and 4.6 Hz. The coupling
constants between the benzylic methylene group and H5′ in
17b (8.8 and 4.9 Hz) and 18b (8.8 and 3.9 Hz) are close to
the calculated values of 7.0 and 4.7 Hz for 17b and 7.2 and
4.5 Hz for 18b, suggesting that these molecules are mixtures
of the conformer drawn with a boat ring and the pentyl
substituent in a pseudoequatorial conformation and the chair
conformer with an axial pentyl substituent.
Scheme 4. Synthesis of Tetracyclic Model 15a
18b, respectively, in only 41% yield. Additionally, we
isolated 30% of 80% pure reduced product 19b as a mixture
of diastereomers. Acetylation of impure 19b afforded 20b,
which could be isolated in pure form in 72% yield (see
Scheme 5).
Scheme 5
The spiroketal stereochemistry can be assigned from the
chemical shift of the axial proton H3′a, which is in a 1,3-
relationship to the anomeric center. The difference between
the two diastereomers is especially pronounced in C6D6.11
In this solvent, H3′a of 15b and 17b with an axial oxygen
absorbs at δ 5.00 and 5.12, respectively, whereas H3′a of 16b
and 18b with an equatorial oxygen absorbs at δ 4.41 and
4.63, respectively. Finally, NOEs between H3′a and H5′ in
15b, between H3′a and both H3 and H5′ in 16b, between H3′a
and both H6′ and the side chain CH2 group in 17b, and
between H3′a and H3, H6′, and the side chain CH2 group in
18b confirmed the stereochemical assignments.
The formation of 19b was unexpected and the presence
of the two diastereomers complicated the structure proof.
We therefore prepared acid 2112 by carboxylation of olivetol
and treated it with 14 to generate the reduced product 22 in
27% yield (see Scheme 6).13
The molecular mechanics calculations suggest that the
desired isomer 15b is most stable. Our structures 15b-18b
differ from simple isochromans in which the trans isomer
may be more stable7 because of the additional fused ring in
15b-18b. Therefore equilibration of the mixture of four
isomers should significantly increase the percentage of 15b
in the mixture. We were delighted to find that equilibration
of the above 4:1:4:1 mixture of 15b-18b with 0.2% TFA
in CDCl3 for 12 h provided a 20:2:1:0 mixture of 15b-
18b, respectively, from which 15b could be isolated in 50%
overall yield from acid 3. The stereochemistry of 15b was
confirmed by X-ray crystal structure determination. Basic
hydrolysis of pure 15b completed the synthesis of berkelic
acid model 15a, which was contaminated with 5% of 16a
resulting from spiroketal equilibration during hydrolysis, in
83% yield (see Scheme 4).
Scheme 6
Reduced products 19b and 22 are probably formed by a
second equivalent of aldehyde acting as a hydride donor.
1,3-Dioxane 23 could be formed from a benzylic alcohol
analogous to 5 and a second equivalent of aldehyde (see
Scheme 7). Protonation of 23 would give benzylic cation
24, which could undergo a 1,5-hydride shift to give 25.
Hydrolysis of the aryl ester of 25 and spiroketalization would
form 19a. Alternatively, a benzylic alcohol analogous to 5
Our initial reactions of 3 and 14, which were carried out
at 0 °C rather than 25 °C, afforded a 4:1:7:1 mixture of 15b-
(10) PCMODEL version 8.0 from Serena Software was used with MMX.
Calculations were carried out on analogues with the pentyl side chain
replaced by a methyl group to minimize irrelevant conformational complex-
ity.
(11) (a) Pothier, N.; Goldstein, S.; Deslongchamps, P. HelV. Chim. Acta
1992, 75, 604-620. (b) Doubsky´, J.; Sˇaman, D.; Zedn´ık, J.; Vasˇ´ıcˇkova´, S.;
Koutek, B. Tetrahedron Lett. 2005, 46, 7923-7926.
(12) (a) Asahina, Y.; Asano, J. Ber. Dtsch. Chem. Ges. 1932, 65B, 475-
482. (b) Liu, G.; Szczepankiewicz, B. G.; Pei, Z.; Xin, Z.; Janowick, D. A.
U. S. Patent Appl. 2002-072,516, 2002; Chem. Abstr. 2002, 137, 33535.
(13) The free phenol 22 could not be fully purified by chromatography.
Pure 22 was obtained by conversion to the acetate ester, careful chroma-
tography, and hydrolysis of the acetate with K2CO3 in MeOH.
Org. Lett., Vol. 9, No. 11, 2007
2073

The formation of reduced product 19a is inconsistent with
the usually proposed mechanism for the oxa-Pictet-Spengler
cyclization. If the isochroman ring is formed by an intra-
molecular Friedel-Crafts reaction of an oxocarbenium ion
analogous to 6, reduction by a 1,5-hydride shift is unlikely.
Such a pathway is impossible for the conversion of 21 to 22
since there is no alcohol in the side chain. This suggests
that the oxa-Pictet-Spengler cyclization of 3 to give 15-18
proceeds at least partially by a Friedel-Crafts reaction to
give a benzylic alcohol analogous to 5 followed by cycliza-
tion to form the isochroman ring.15
Scheme 7
In conclusion, acid-catalyzed condensation of acid 3 with
ketal aldehyde 14 in methanol at 25 °C, followed by CH2N2
esterification, and equilibration with TFA in CDCl3 affords
tetracycle 15b (50% overall yield) with the complete skeleton
of berkelic acid. Application of this route to the total
synthesis of berkelic acid (1) using a more highly function-
alized ketal aldehyde 2, in which R is a precursor to the
side chain, is currently in progress.
Acknowledgment. We are grateful to the National
Institutes of Health (GM-50151) for support of this work.
We thank the National Science Foundation for the partial
support of this work through grant CHE-0521047 for the
purchase of an X-ray diffractometer. We thank Chun-Hsing
Chen, Brandeis University, for determining the crystal
structure of 15b.
Supporting Information Available: Complete experi-
mental procedures, copies of 1H and 13C NMR spectral data,
and X-ray crystallographic data in CIF format for 15b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
could react with a second equivalent of aldehyde to give
1,3-dioxane 26. Protonation of 26 would give benzylic cation
27 that could undergo a 1,5-hydride shift to give ester 28.
Hydrolysis of the ester of 28 and spiroketalization would
form 19a. Only traces of these reduced products are formed
when the reaction is carried out at 25 °C. This is consistent
with the proposed mechanism because the highly ordered
transition state for a 1,5-hydride shift should have a large
negative entropy of activation and therefore be relatively
favored at lower temperatures. 1,5-Hydride shifts of this type
are uncommon, but some related examples have recently
been reported.14
OL0704338
(14) (a) Yoshimatsu, M.; Hatae, N.; Shimizu, H.; Kataoka, T. Chem.
Lett. 1993, 1491-1494. (b) Krohn, K.; Flo¨rke, U.; Ho¨fker, U.; Tra¨ubel, M.
Eur. J. Org. Chem. 1999, 3495-3499. (c) Pastine, S. J.; Sames, D. Org.
Lett. 2005, 7, 5429-5431. (d) Tobisu, M.; Chatani, N. Angew. Chem., Int.
Ed. 2006, 45, 1683-1684.
(15) For another oxa-Pictet-Spengler cyclization that may proceed by
both mechanisms, see: Zhang, X.; Li, X.; Lanter, J. C.; Sui, Z. Org. Lett.
2005, 7, 2043-2046.
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