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 °C afforded 15b-18b and a reduction product 19b, which was probably formed by a 1,5-hydride shift.
Stierle and coworkers 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 based on the 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 pulvilloric 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 Friedel-Crafts reaction to give benzylic alcohol 5. Protonation 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.
Scheme 2.
Proposed Oxa-Pictet-Spengler Cyclization to Give 9
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 configuration. Therefore this center should be readily set by equilibration. Oxa-Pictet-Spengler cyclizations that give 1,3-disubstituted isochromans often give mainly the cis disubstituted products such as 8 under kinetically controlled conditions.6 In some cases, equilibration via the benzylic 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.
Model ketal aldehyde 14 was prepared to investigate this sequence (see Scheme 3). Addition of the lithium enolate of 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.
Scheme 3.
Preparation of Model 15b
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 characterized spectroscopically. Molecular mechanics with conformational searching calculated relative strain energies for 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.
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 δ 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 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 4.
Synthesis of Tetracyclic Model 15a
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-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 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
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 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
Scheme 7.
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 intramolecular 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 cyclization to form the isochroman ring.15
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 functionalized ketal aldehyde 2, in which R is a precursor to the side chain, is currently in progress.
Supplementary Material
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.
Footnotes
Supporting Information Available: Complete experimental procedures, copies of 1H and 13C NMR spectral data, and X-ray crystallographic data (CIF file) for 15b. This material is available free of charge via the Internet at http://pubs.acs.org.
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