Synthesis of (-)-berkelic acid

Article abstract of DOI:10.1002/anie.200805488

An extremophilic challenge: Stereospecific condensation of a fully functionalized ketal aldehyde and a 2,6-dihydroxybenzoic acid is the key step in the synthesis of (-)-berkelic acid confirming Fuerstner's reassignment of the stereochemistry at C18 and C1

Full text of DOI:10.1002/anie.200805488

Angewandte
Chemie
DOI: 10.1002/anie.200805488
Natural Products
Synthesis of (À)-Berkelic Acid**
Xiaoxing Wu, Jingye Zhou, and Barry B. Snider*
Stierle and co-workers recently isolated berkelic acid (1) from
an acid mine waste fungal extremophile (Scheme 1).[1] The
structure was determined to be a novel spiroketal from the
analysis of the NMR and mass spectral data. The relative
Scheme 1. Retrosynthesis of berkelic acid (1).
stereochemistry of the side-chain stereocenter (C22) and the
absolute stereochemistry 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. This
potent and selective activity and its limited accessibility from
natural sources make it a significant synthetic target. We
thought that 1 should be accessible by a highly convergent
route starting from ketal aldehyde 2 and 2,6-dihydroxyben-
zoic acid 3. Acid 3, a synthetic, and possibly biosynthetic,
precursor of pulvilloric acid (4), has been prepared in both
racemic[2] and optically pure form.[3]
Scheme 2. Reagents and conditions: a) LDA, tBuOAc, THF, À78 to
À308C, 2 h; b) Dowex 50WX8-400-H+, MeOH, 258C, 12 h (56% from
5); c) DIBAL-H, ether, À788C, 1.5 h; d) (Æ)-3, Dowex 50WX8-400-H+,
MeOH, 258C, 12 h; e) CH2N2, diethyl ether; f) 0.2% TFA in CDCl3,
258C, 12 h (50% of 9 from 3). LDA=lithium diisopropylamide,
DIBAL-H=diisobutylaluminum hydride.
at 258C to provide a mixture of the tetracyclic acids that was
then treated with diazomethane to give a 4:1:4:1 mixture of
tetracycles 9–12, respectively. MMX calculations using con-
formational searching provided the relative strain energies for
9–12 of 28.1, 28.6, 30.5, and 30.8 kcalmolÀ1, respectively,[7]
indicating that the desired product 9 is more stable than the
other major product 11 by 2.4 kcalmolÀ1. Therefore, we
explored the equilibration of this mixture by treatment with
0.2% TFA in CDCl3 for 12 hours at 258C, which provided a
20:2:1:0 mixture of 9–12, respectively, from which 9 could be
isolated in 50% overall yield from (Æ )-3.[8]
In 2007,[4] we reported an efficient route to the tetracyclic
core of berkelic acid by condensing racemic 3[2] with model
ketal aldehyde
8
in an oxa-Pictet–Spengler reaction[5]
(Scheme 2). Addition of the enolate of tert-butyl acetate to
butyrolactone (5) afforded hemiketal ester 6[6] which was
converted into ketal ester 7 in 56% overall yield by treatment
with Dowex 50WX8-400-H+ in MeOH for 12 hours at 258C.
Reduction using DIBAL-H in diethyl ether at À788C
afforded the unstable ketal aldehyde 8, which was treated
with (Æ )-3 and Dowex 50WX8-400-H+ in MeOH for 12 hours
We report herein the preparation of fully functionalized
ketal aldehydes 21 and ent-21 and their condensation with
(R)-(À)-3 leading to the first synthesis of (À)-berkelic acid,
the reassignment of the stereochemistry at C18 and C19, the
assignment of the relative stereochemistry at C22, and the
assignment of the absolute stereochemistry. As this work was
being completed, Fꢀrstner and co-workers reported a syn-
thesis of the enantiomer of the methyl ester of berkelic acid
and reassigned the stereochemistry at C18 and C19.[9] We had
difficulty in scaling up the synthesis[3] of (R)-(À)-3 reported by
[*] X. Wu, Dr. J. Zhou, Prof. B. B. Snider
Department of Chemistry, MS 015, Brandeis University
Waltham, MA 02454-9110 (USA)
Fax: (+1)781-736-2516
E-mail: snider@brandeis.edu
[**] We are grateful to the National Institutes of Health (GM-50151) for
generous financial support. We thank Prof. D. Stierle for copies of
spectral data of berkelic acid and berkelic acid methyl ester and
Artem Shvartsbart for experimental assistance.
Rꢁdel and Gerlach, and therefore modified it as shown in
[10]
Scheme 3. Deprotection of 13 using BBr3
afforded the
resorcinol in 97% yield, which was then protected to give
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805488.
compound 14[11] in 94% yield. Halogen–metal exchange of 14
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ketal aldehyde 21 using the procedure developed for the
conversion of 5 into 8. Addition of the lithium enolate of tert-
butyl acetate and ketal formation afforded 19 in 78% yield.
DIBAL-H reduction then gave aldehyde 21 (43% yield) and
alcohol 20 (39% yield), which was then subjected to Swern
oxidation to give additional aldehyde 21 (52% yield).
Condensation of 21 with (R)-(À)-3 using Dowex 50WX8-
400-H+ in MeOH for 12 hours and subsequent diazomethane
esterification gave a 57% yield of an approximately 4:1:3:0
mixture of 22–25, respectively, for which the stereochemistry
was assigned by analogy to 9–12 (Scheme 5).[4] Surprisingly,
attempted equilibration using 0.2% TFA in CDCl3 had little
Scheme 3. Reagents and conditions: a) BBr3, CH2Cl2, À78 to 258C,
12 h (97%); b) TBSCl, imidazole, DMF, 258C, 12 h (94%); c) tBuLi
(2.2 equiv), THF, À788C, 30 min, then (R)-(+)-1,2-epoxyheptane
(1.2 equiv), À258C, 16 h (74%); d) KOH, EtOH, 558C, 8 h (80%);
e) CO2, KHCO3, glycerol, 1508C, 5 h (59%). TBSCl=tert-butyldimethyl-
chlorosilane, DMF=N,N-dimethylformamide.
with tBuLi at À788C and addition of (R)-(+)-2-pentyloxir-
ane,[12] followed by removal[13] of the TBS groups with KOH in
EtOH at 558C for eight hours provided 15. Carboxylation as
previously described[2,3] gave (R)-(À)-3.
Ketal aldehyde 21 was prepared efficiently using the
procedure reported by Hanessian et al., as shown in
Scheme 4.[14] Metalation of 16 with nBuLi at À1008C,
addition of 2-butenolide at À1008C, and trapping with
excess MeI at À788C afforded 17 in 73% yield with greater
than 95% selectivity. Ozonolysis and subsequent reduction
with NaBH4, and then protection with a TBDPS group
provided 18 in 52% yield. Lactone 18 was converted into
Scheme 5. Reactions and conditions: a) Dowex 50WX8-400-H+,
MeOH, 258C, 12 h; b) CH2N2, ether; c) 0.2% TFA in CDCl3, 258C,
12 h. TFA=trifluoroacetic acid.
effect, giving an approximately 2:trace:1:0 mixture of 22–25,
respectively. The presence of this mixture after equilibration
was of considerable concern, because we had hypothesized
that the stereochemistry at both C15 and C17 in the natural
product was thermodynamically controlled. However, the
MMX calculated relative strain energies for 22–25 of 30.5,
31.0, 31.3, and 33.6 kcalmolÀ1, respectively,[7,15] indicated that
22 was only 0.8 kcalmolÀ1 more stable than 24, whereas model
tetracycle 9 was more stable than 11 by 2.4 kcalmolÀ1.
Therefore the presence of considerable quantities of both 22
and 24 at equilibrium was not surprising.
Of greater concern, the 1H NMR spectrum of the desired
product 22, which could be isolated in low yield from the
mixture, did not fit well with the data for the berkelic acid
methyl ester (see the Supporting Information), even taking
into account the differences in the side chains. This data
suggested that the stereochemistry of the natural product is
not the same as that of 22, which has since been established by
the synthesis of berkelic acid methyl ester by Fꢀrstner and co-
workers.[9] The stereochemistry of berkelic acid was assigned
on the basis of an NOE between the methyl group (C25) and
the b-hydrogen atom on C16 as well as an H atom on C20.
However, MMX calculations indicated that the shortest
Scheme 4. Reagents and conditions: a) nBuLi (1.2 equiv), À1008C,
15 min, À788C, 10 min, recool to À1008C, then 2-butenolide
(1.2 equiv), À1008C, 10 min, À788C, 30 min, then MeI (5 equiv), À78
to 258C, 4 h (73%); b) O3, MeOH/CH2Cl2 (1:1), À788C, 20 min, then
NaBH4, À78 to 258C, 3 h; c) TBDPSCl, imidazole, DMF, 258C, 12 h
(52% from 17); d) tBuOAc (6 equiv), LHMDS (6 equiv), À788C, 1 h,
À78 to 258C, 3 h; e) Dowex 50WX8-400-H+, MeOH, 258C, 12 h (78%
from 18); f) DIBAL-H (4.1 equiv), diethyl ether, À788C, 1.5 h (39% of
20 and 43% of 21); g) oxalyl chloride (3 equiv), DMSO (5 equiv), Et3N
(1 equiv), CH2Cl2, À788C, 2 h, À78 to À308C, 1 h (52%).
TBDPS=tert-butyldiphenylchlorosilane, LHMDS=lithiumhexamethyldi-
silazide, DMSO=dimethylsulfoxide.
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distances from a methyl hydrogen atom in 1 to the C16 Hb
atom is 2.61 ꢂ, and to the C16 Ha atom is 2.46 ꢂ. Therefore,
if 1 were the structure of berkelic acid, there should be an
NOE from the methyl group to both the C16 Hb atom and
C16 Ha atom. MMX calculations indicated that the observed
NOE in berkelic acid to only the C16 Hb atom fits compound
26, which has the opposite stereochemistry at both C18 and
C19. In this isomer, the shortest distance from a methyl
hydrogen atom to the C16 Hb atom is 2.49 ꢂ and to the C16
Ha atom is 3.51 ꢂ (Figure 1). Furthermore, the relative strain
The methyl ester is not a suitable protecting group for the
benzoic acid because it cannot be cleaved in the presence of
the side chain methyl ester.[9] Therefore we condensed ent-21
and (R)-(À)-3 with Dowex 50WX8-400-H+ in MeOH for
60 hours and then treated the crude tetracyclic salicylic acid,
having the partially deprotected side chain, with allyl bromide
and K2CO3 in DMF to give 28 (32% yield) and 29 (20% yield)
without allylation of the primary alcohol of 29 (Scheme 7).[16]
Desilylation of 28 with TBAF/AcOH (1:1) afforded alcohol
29 in 86% yield so that the overall yield of 29 from ent-21 is
48%. Dess–Martin oxidation of 29 afforded aldehyde 30 in
88% yield. Aldol reactions under strongly basic conditions
did not work well. Reaction of 30 with trimethylsilyl ketene
acetal 31,[17] LiCl, and N-methylimidazole[18] afforded an
inseparable mixture of all four possible isomers. Fortunately,
reaction of 30 and 31 as described by Kiyooka et al.[19] using
(S)-32, which is prepared in situ from N-Ts-(S)-valine and
BH3·THF, was selective for the Si face affording only two of
the four aldol adducts from which pure 33 and 34 were each
Figure 1. Proposed and revised structures of berkelic acid showing
NOE correlations to the methyl group.
energy of the four diastereomers of 22–25 having the
stereochemistry inverted at both C18 and C19 are 28.9, 31.3,
32.8, and 33.3 kcalmolÀ1, respectively.[7,15] The desired isomer
27a is calculated to be 3.9 kcalmolÀ1 more stable than the
diastereomer of 24 having stereochemistry inverted at both
C18 and C19. This analysis suggested that the structure of
berkelic acid is 26 rather than 1.
Fortunately this was easy to establish. Compound ent-16
was converted into ent-21 and condensed with (R)-(À)-3 using
Dowex 50WX8-400-H+ in MeOH (Scheme 6). This reaction
Scheme 6. Reagents and conditions: a) (R)-(À)-3, Dowex 50WX8-400-
H+, MeOH, 258C, 60 h; b) CH2N2, diethyl ether (30% of 27a, 22% of
27b).
appears to be slower than that with 21, requiring 60 hours for
complete reaction, which led to partial cleavage of the
TBDPS group. Esterification with diazomethane afforded
30% of 27a and 22% of 27b as the only products. No change
occurred upon TFA equilibration, confirming that 27a is
much more stable than the other three diastereomers as
calculated. As we had hoped the spectral data of 27a fit well
with those of the berkelic acid methyl ester (see the
Supporting Information) suggesting that 26 is the structure
of berkelic acid and that the stereochemistry at both C15 and
C17 in the natural product is thermodynamically controlled.
Scheme 7. Reagents and conditions: a) Dowex 50WX8-400-H+, MeOH,
258C, 60 h; b) allyl bromide, K2CO3, DMF (32% of 28 and 20% of 29
from ent-21); c) TBAF/AcOH (1:1) in THF, 12 h (86%); d) Dess–
Martin (88%); e) N-Ts-(S)-valine, BH3·THF, CH2Cl2, 08C, 30 min,
258C, 30 min, cool to À788C, add 30, add 31, À788C, 4 h (40% of 33
and 40% of 34); f) Dess–Martin (85% from 33, 77% from 34);
g) [Pd(Ph3P)4] (0.2 equiv), HCO2H (40 equiv), Et3N (40 equiv), THF,
258C, 15 h (78% of 35, 72% of 36). TBAF=n-tetrabutylammonium
fluoride.
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reaction, see: E. L. Larghi, T. S. Kaufman, Synthesis 2006, 187 –
220.
[6] P. Kim, M. M. Olmstead, M. H. Nantz, M. J. Kurth, Tetrahedron
Lett. 2000, 41, 4029 – 4032.
isolated in 40% yield. A similar reaction using N-Ts-(R)-
valine resulted in a reduction to give primary alcohol 29.
Apparently, the stereochemical preferences of 30 and (S)-32
are matched, while those of 30 and (R)-32 are mismatched
resulting in a reduction instead of an aldol reaction.[20]
Dess–Martin oxidation (85% yield) of the less polar
isomer 33 and subsequent removal (78% yield) of both allyl
groups with [Pd(Ph3P)4], Et3N, and HCO2H afforded berkelic
[7] 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 complexity. We suspect that the
relative energies of 10 and 12 are too low because the
calculations do not fully reflect the additional stability of 9 and
11 because of the anomeric effect.
[8] For another model study, see: a) M. A. Marsini, Y. Huang, C. C.
Lindsey, K.-L. Wu, T. R. R. Pettus, Org. Lett. 2008, 10, 1477 –
1480; b) Y. Huang, T. R. R. Pettus, Synlett 2008, 1353 – 1356.
[9] P. Buchgraber, T. N. Snaddon, C. Wirtz, R. Mynott, R. Goddard,
A. Fꢀrstner, Angew. Chem. 2008, 120, 8578 – 8582; Angew.
Chem. Int. Ed. 2008, 47, 8450 – 8454.
[10] a) G. C. Dol, P. C. J. Kamer, P. W. N. M. van Leeuwen, Eur. J.
Org. Chem. 1998, 359 – 364; b) M. J. Sienkowska, J. M. Farrar, F.
Zhang, S. Kusuma, P. A. Heiney, P. Kaszynski, J. Mater. Chem.
2007, 17, 1399 – 1411.
[11] P. Bharathi, H. Zhao, S. Thayumanavan, Org. Lett. 2001, 3,
1961 – 1964.
[12] Prepared by hydrolytic kinetic resolution: S. E. Schaus, B. D.
Brandes, J. F. Larrow, M. Tokunaga, K. B. Hansen, A. E. Gould,
M. E. Furrow, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124,
1307 – 1315.
[13] Z.-Y. Jiang, Y.-G. Wang, Chem. Lett. 2003, 32, 568 – 569.
[14] S. Hanessian, A. Gomtsyan, N. Malek, J. Org. Chem. 2000, 65,
5623 – 5631.
[15] Calculations were carried out on analogues in which both the
pentyl and TBDPSOCH2CH2 side chains were replaced by
methyl groups to minimize irrelevant conformational complex-
ity.
[16] For the protection of a salicylic acid with two allyl groups, see: A.
Migita, Y. Shichijo, H. Oguri, M. Watanabe, T. Tokiwano, H.
Oikawa, Tetrahedron Lett. 2008, 49, 1021 – 1025.
1
acid (35). The H and 13C NMR spectral data of 35 in both
CDCl3 and CD3OD are identical to those of the natural
berkelic acid. A similar sequence from the more polar isomer
34 afforded 36. The spectral data of 36 are similar to those of
berkelic acid, but there are significant differences, most
notably in the 1H NMR spectra for the hydrogen atom on C20
and the methyl and ethyl groups on C22.
The Kiyooka aldol reaction leads to two, rather than four,
aldol products making it possible to isolate pure 33 and 34.
Unfortunately, this reaction controls the stereochemistry at
the C21, which is lost in the Dess–Martin oxidation, rather
than at C22. We prepared a series of analogous compounds
from a model aldehyde and established their stereochemistry
unambiguously. Comparison of the differences between the
spectra of 33 and 34 to those between the model compounds,
as is fully described in the Supporting Information, leads to
the tentative C22 stereochemistry assignment shown.[21]
The optical rotation of synthetic berkelic acid (35), [a]2D2 =
À115.58 (c = 0.55, MeOH), has the same sign as that of the
natural product, [a]2D2 = À83.58 (c = 0.0113, MeOH), indicat-
ing that the absolute stereochemistry is as shown. The
differing numerical values may result from the low sample
concentration used for the natural product.
In conclusion, we have completed the first synthesis of
(À)-berkelic acid (35), confirming the reassignment of the
stereochemistry at both C18 and C19 by Fꢀrstner and co-
workers, establishing the absolute stereochemistry, and ten-
tatively assigning the stereochemistry at C22. The synthesis
proceeds with a longest linear sequence of only 13 steps in
2% overall yield by using the novel condensation of (R)-(À)-3
and ent-21 to efficiently and stereospecifically construct the
tetracyclic core.
[17] A. Iida, S. Nakazawa, T. Okabayashi, A. Horii, T. Misaki, Y.
Tanabe, Org. Lett. 2006, 8, 5215 – 5218.
[18] H. Hagiwara, H. Inoguchi, M. Fukushima, T. Hoshi, T. Suzuki,
Tetrahedron Lett. 2006, 47, 5371 – 5373.
[19] a) S.-i. Kiyooka, Y. Kaneko, M. Komura, H. Matsuo, M. Nakano,
J. Org. Chem. 1991, 56, 2276 – 2278; b) S.-i. Kiyooka, K. A.
Shahid, Tetrahedron: Asymmetry 2000, 11, 1537 – 1542; c) S.-i.
Kiyooka, K. A. Shahid, F. Goto, M. Okazaki, Y. Shuto, J. Org.
Chem. 2003, 68, 7967 – 7978; d) S.-i. Kiyooka, M. A. Hena, J.
Org. Chem. 1999, 64, 5511 – 5523; e) R. Fujiyama, K. Goh, S.-i.
Kiyooka, Tetrahedron Lett. 2005, 46, 1211 – 1215.
Received: November 11, 2008
[20] For another example of very different yields when using
matched and mismatched aldehydes, see: S.-i. Kiyooka, H.
Maeda, M. A. Hena, M. Uchida, C.-S. Kim, M. Horiike,
Tetrahedron Lett. 1998, 39, 8287 – 8290.
Published online: January 12, 2009
Keywords: antitumor agents · heterocycles · spiroketals ·
.
structure elucidation
[21] In the synthesis of berkelic acid methyl ester, Fꢀrstner and co-
workers state that the spectral data of the stereoisomer
corresponding to 36, not 35, match well with those of the natural
berkelic acid methyl ester. However, the report later states that
confident assignment of the configuration of the stereochemistry
at C22 mandates direct comparison with an authentic sample.
The spectral data for our sample of 35 corresponds well to those
of natural berkelic acid, while those of 36 do not, but the
stereochemical assignment of 35 is based on comparison to
analogues as described in the Supporting Information and thus is
not fully secure.
[1] A. A. Stierle, D. B. Stierle, K. Kelly, J. Org. Chem. 2006, 71,
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[2] B. K. Bullimore, J. F. W. McOmie, A. B. Turner, M. N. Galbraith,
W. B. Whalley, J. Chem. Soc. C 1967, 1289 – 1293.
[3] T. Rꢁdel, H. Gerlach, Liebigs Ann. Chem. 1997, 213 – 216.
[4] J. Zhou, B. B. Snider, Org. Lett. 2007, 9, 2071 – 2074.
[5] The mechanism of the reaction of 3 with 8 is fully discussed in
our model study.[4] For a review of the oxa-Pictet–Spengler
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