Total synthesis of cristatic acid.

Article abstract of DOI:10.1021/ol0061236

The first total synthesis of cristatic acid 1, an antibiotic endowed with considerable activity against Gram-positive bacteria, hemolytic properties, and significant cytotoxicity, is described. Key to success are the formation of its 2,4-disubstituted fur

Full text of DOI:10.1021/ol0061236

ORGANIC
LETTERS
2000
Vol. 2, No. 16
2467-2470
Total Synthesis of Cristatic Acid
Alois Fu1rstner* and Thomas Gastner
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/Ruhr, Germany
fuerstner@mpi-muelheim.mpg.de
Received May 29, 2000
ABSTRACT
The first total synthesis of cristatic acid 1, an antibiotic endowed with considerable activity against Gram-positive bacteria, hemolytic properties,
and significant cytotoxicity, is described. Key to success are the formation of its 2,4-disubstituted furan moiety via a palladium-catalyzed
alkylation of vinylepoxide 10 derived from sulfonium salt 8 and the use of SEM ethers as the protecting groups for the phenolic OH functions.
Cristatic acid 1, a secondary metabolite isolated by Steglich
et al. from the fruiting bodies of the higher mushroom
Albatrellus cristatus,1 exhibits an interesting range of bio-
logical properties including (i) antibiotic activity against
gram-positive bacteria, (ii) strong hemolytic function, and
(iii) a considerable inhibitory effect against cells of the ascites
form of Ehrlich carcinoma. Notably, permethylation of 1
enhances the latter property to a significant extent but leads
to a total loss of its antibacterial effect.1 This pronounced
yet hardly understood structure/activity profile renders this
particular farneyl phenol derivative an attractive target for
total synthesis and makes further studies of the biological
response to changes in functionality called for.
With these lessons in mind, we redesigned a synthesis
which avoids such complications (Figure 1). Rather than
Figure 1. Retrosynthetic analysis of cristatic acid 1.
The only preparative approach toward cristatic acid
reported in the literature,2 however, reveals some significant
challenges posed by this target. In particular, difficulties arise
from the electron rich and hence rather labile furan moiety,
which severely restricts the choice of reaction conditions once
this ring is formed. Thus, the attempted total synthesis
described by Joullie´ et al. failed because these authors were
unable to find conditions for the final deprotection of the
phenolic OR groups without destroying the furan.2,3 More-
over, the sensitivity of some precursors rendered the attach-
ment of the tether between the phenolic and the heterocyclic
ring quite problematic.2,4
assembling the target from the individual building blocks
by alkylation of the furan, we chose to use allylic and
benzylic C-C bonds within the tether as more promising
sites of
(3) See the following for leading references on studies towards related
farnesyl phenol natural products; some of them further illustrate the
difficulties arising in the final deprotection steps of the aryl ether groups:
(a) Chen, K.-M.; Semple, J. E.; Joullie´, M. M. J. Org. Chem. 1985, 50,
3997. (b) Safaryn, J. E.; Chiarello, J.; Chen, K.-M.; Joullie´, M. M.
Tetrahedron 1986, 42, 2635. (c) Guthrie, A. E.; Semple, J. E.; Joullie´, M.
M. J. Org. Chem. 1982, 47, 2369. (d) Chen, K.-M.; Joullie´, M. M.
Tetrahedron Lett. 1982, 23, 4567. (e) Mori, K.; Takechi, S. Tetrahedron
1985, 41, 3049. (f) Mori, K.; Fujioka, T. Tetrahedron 1984, 40, 2711. (g)
Saimoto, H.; Hiyama, T. Tetrahedron Lett. 1986, 27, 597.
(4) Only a few general methods for the preparation of 2,4-disubstituted
furans are known; for a review see: Hou, X. L.; Cheung, H. Y.; Hon, T.
Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H. N. C. Tetrahedron
1998, 54, 1955.
(1) Zechlin, L.; Wolf, M.; Steglich, W.; Anke, T. Liebigs Ann. Chem.
1981, 2099.
(2) Chiarello, J.; Joullie´, M. M. Tetrahedron 1988, 44, 41.
10.1021/ol0061236 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/13/2000

disconnection. Judicious choice of protecting groups that are
labile under neutral or only slightly basic conditions should
enable us to carry out the final deprotection step and therefore
bring cristatic acid into reach. Summarized below is the
successful reduction of these ideas to practice.
Our approach starts from methyl orsellinate 2 which is
easily accessible on a large scale in one-pot from methyl
acetoacetate (Scheme 1).5 The voluminous precipitate formed
Allylic oxidation of 4 thus formed with SeO2 and tert-
BuOOH delivers the required allylic alcohol 5 in good yield.
An X-ray analysis of its deprotected form 6 was carried out
which confirmed the attachment of the prenyl side chain at
the C-3 position of the orsellinic acid and the (E)-configu-
ration of the trisubstituted double bond (Figure 2).11 Alcohol
Scheme 1a
Figure 2. ORTEP diagram of the molecular structure of compound
6. Anisotropic displacement parameter ellipsoids are drawn at 50%
probability; hydrogen atoms are omitted for clarity. For details, see
the Supporting Information. Selected bond lengths (Å) and angles
(deg): O25-C25 1.4464(6), C25-C23 1.5083(18), C23-C22
1.3332(19), C22-C21 1.5077(18), C21-C2 1.5160(17), C61-O61
1.2188(18), C3-C2-C21 122.77(12), C23-C22-C21 127.30(12),
C22-C23-C25 119.43(12), O61-C61-O62 120.52(12).
5 was finally converted into allyl bromide 7 on treatment
with mesyl chloride and LiBr in a mixed solvent system.
a (a) NaH, prenyl bromide, toluene, 35 °C, 19h, 73%; (b) SEMCl,
KH, 18-crown-6 cat., THF, 5 h, rt, 84%; (c) SeO2, t-BuOOH (70%
in water), CH2Cl2, 5 h, rt, 61%; (d) MeSO2Cl, LiBr, Et3N, CH2Cl2/
THF, 0 °C, 3 h, 76%.
The second fragment required for the assembly of cristatic
acid was prepared from the functionalized sulfonium salt 8
which had previously been used in our laboratory as a
versatile building block for the synthesis of heterocyclic
natural products of different complexity.12,13 Deprotonation
with tert-BuLi at low temperature and reaction of the
resulting sulfur ylide with 2-(4-methoxybenzyl)oxyacetal-
dehyde 914 affords epoxide 10 in 62% yield (Scheme 2).
Treatment of this compound with catalytic amounts of Pd-
(PPh3)4 and dppe selectively activates its vinyloxirane
entity.15 The resulting alkoxide deprotonates admixed bis-
(phenylsulfonyl)methane which then attacks the π-allyl
upon deprotonation of 2 with NaH in toluene reacts with
prenyl bromide at 35 °C to afford compound 3 in 73% yield,
which itself is a natural product isolated from the Japanese
mushroom Polyporus dispansus (“komori-take”).6 The excel-
lent selectivity in favor of alkylation at the C-3 position rather
than the three other possible sites (C-5, O-2, O-4) in substrate
2 is remarkable. In line with the well-understood reactivity
pattern of ambident nucleophiles,7 the formation of the
sodium salt of 2 is essential for this favorable outcome,
whereas the corresponding potassium salt previously used
in a similar context turned out to be much less appropriate.2
Compound 3 was then converted into the bis(2-trimeth-
ylsilylethoxy)methyl (SEM) ether 4.8,9 This particular pro-
tecting group was chosen in light of previous successful
applications to studies on farnesyl phenol derivatives in
which the final deprotections were similarly crucial.3,10
(10) Saimoto, H.; Kusano, Y.; Hiyama, T. Tetrahedron Lett. 1986, 27,
1607.
(11) For details see the Supporting Information.
(12) Furans: (a) Fu¨rstner, A.; Gastner, T.; Rust, J. Synlett 1999, 29. (b)
Fu¨rstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999,
121, 11108. (c) Fu¨rstner, A. Synlett 1999, 1523.
(13) Pyrroles: (a) Fu¨rstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998,
120, 2817. (b) Fu¨rstner, A.; Weintritt, H. J. Am. Chem. Soc. 1997, 119,
2944. (c) Fu¨rstner, A.; Gastner, T.; Weintritt, H. J. Org. Chem. 1999, 64,
2361. (d) Fu¨rstner, A.; Krause, H. J. Org. Chem. 1999, 64, 8281.
(14) Prepared by alkylation of 2-butene-1,4-diol with p-MeOC6H4CH2-
Cl in the presence of NaH (DMF, n-Bu4NI cat., rt, 77%) and cleavage of
the resulting product with OsO4 cat./NaIO4 (pyridine/Et2O/H2O, rt, 77%)
in analogy to a procedure described in: Garner, P.; Park, J. M. Synth.
Commun. 1987, 17, 189.
(15) For leading references on Pd(0)-catalyzed reactions of vinyloxiranes,
see: (a) Tsuji, J.; Kataoka, H.; Kobayashi, Y. Tetrahedron Lett. 1981, 22,
2575. (b) Trost, B. M.; Molander, G. A. J. Am. Chem. Soc. 1981, 103,
5969. (c) Trost, B. M.; Warner, R. W. J. Am. Chem. Soc. 1983, 105, 5940.
(d) Review: Tsuji, J. Palladium Reagents and Catalysts; Wiley: New York,
1995.
(5) Barrett, A. G. M.; Morris, T. M.; Barton, D. H. R. J. Chem. Soc.,
Perkin Trans. 1 1980, 2272. See also the Supporting Information for a
multigram synthesis of this compound.
(6) Ishii, N.; Takahashi, A.; Kusano, G.; Nozoe, S. Chem. Pharm. Bull.
1988, 36, 2918.
(7) (a) Le Noble, W. J. Synthesis 1970, 1. (b) Gompper, R. Angew. Chem.,
Int. Ed. Engl. 1964, 3, 560.
(8) Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343.
(9) Silyl ethers instead of SEM groups were ruled out for the reason
given in ref 19.
2468
Org. Lett., Vol. 2, No. 16, 2000

of the resulting alcohol 14 with MnO2 in CH2Cl2 and
subsequent Wittig reaction of the ensuing unstable aldehyde
with Ph3PdC(CH3)2 under standard conditions. This se-
quence was carried through without rigorous purification of
the intermediates and provides the desired product 15 in 57%
overall yield. Recrystallization from ether gave a sample
suitable for X-ray analysis (Figure 3) which confirms the
structural integrity of this key compound.11
Scheme 2a
Figure 3. ORTEP diagram of the molecular structure of compound
15. Anisotropic displacement parameter ellipsoids are drawn at 50%
probability; hydrogen atoms are omitted for clarity. Selected bond
lengths (Å) and angles (deg): C7-C8 1.3438(18), C7-C5 1.4517-
(18), C5-O1 1.3785(15), O1-C4 1.3679(16), C3-C4 1.3536(18),
C3-C6 1.4385(17), C5-C6 1.3649(17), C2-C3 1.5004(17), C1-
C2 1.5369(17), C1-S1 1.8313(13), C1-S2 1.8161(12), C1-C2-
C3 111.38 (10), C5-C7-C8 126.82(12), O1-C5-C7 114.32(10),
C6-C5-C7 136.29(12), C6-C3-C2 126.46(11). For details, see
the Supporting Information.
Because attempted reductive metalation of 15 with lithium
naphthalenide and in situ alkylation of the resulting species
with bromide 7 turned out to be low yielding,18 we decided
to proceed in a stepwise manner. Thus, one of the sulfone
groups of 15 was first cleaved off by treatment with Al(Hg)
in aqueous THF. The resulting monosulfone 16 was then
deprotonated with n-BuLi, and the alkylation of the resulting
organolithium intermediate with bromide 7 was carried out
at low temperature in the presence of HMPA as cosolvent.19
The remaining PhSO2 group in crude 17 thus obtained was
removed by means of Na(Hg) in buffered MeOH as the
reaction medium,20 providing product 18 in 55% yield over
both steps.
a (a) (i) t-BuLi, THF, 10 min, -78 °C; (ii) aldehyde 9, -78 f
0 °C, 62%; (b) (PhO2S)2CH2, Pd(PPh3)4 cat., dppe cat., THF, 14 h,
rt, 98%; (c) 3,4-dihydro-2H-pyran, pyridinium tosylate cat., CH2Cl2,
0 °C f rt, 4h, 91%; (d) n-Bu4NF‚3H2O, THF, 50 °C, 16h, 95%;
(e) (i) MnO2, CH2Cl2, rt, 3 h; (ii) aqueous HCl, EtOAc, rt, 12 h,
87%; (f) DDQ, CH2Cl2/H2O (20/1), 7 h, 0 °C; (g) MnO2, CH2Cl2,
3 h, rt; (h) Ph3PdC(CH3)2, THF, 0 °C, 14 h, 57% (over steps f-h);
(i) Al(Hg), aqueous THF, 3 h, rt, 96%; (j) (i) n-BuLi, 0 °C, THF,
5 min; (ii) allyl bromide 7, HMPA, -78 f 0 °C, 2 h; (k) Na(Hg),
MeOH, Na2HPO4, 0 °C f rt, 5 h, 55% (over steps j-k); (l)
n-Bu4NF‚3H2O, HMPA, 50 °C, 12 h, 60%.
palladium complex to afford product 11 in almost quantita-
tive yield; this compound encodes the furan ring in its 1,4-
dihydroxy skeleton.16 Temporary protection of the allylic
alcohol group as a THP acetal followed by cleavage of the
primary -OTBDMS ether with n-Bu4NF cleanly affords
compound 12. Subsequent oxidation with MnO2 in CH2Cl2
and treatment of the resulting enal with aqueous HCl delivers
the required 2,4-disubstitued furan 13 in excellent yield.
The missing isobutenyl side chain was installed by
deprotection of the PMB ether of 13 with DDQ,17 oxidation
Although earlier studies on related farnesyl phenols had
suggested that SEM ethers were suitable protecting groups
that can be removed under conditions mild enough to
(17) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885. (b) At this point it is essential to have chosen a PMB group rather
than a simple Bn ether as the protecting group for the benzylic alcohol. All
attempts to cleave the corresponding benzyl ether failed to afford the desired
product 14. For example, attempted hydrogenation over Pd/C reduces the
furan ring without cleaving the benzyl ether.
(18) Yu, J.; Cho, H.-S.; Chandrasekhar, S.; Falck, J. R.; Mioskowski,
C. Tetrahedron Lett. 1994, 35, 5437.
(19) Note that attempted alkylations of the metalated sulfone with an
allyl bromide analogous to 7 carrying -OTBDMS instead of -OSEM groups
gave the desired compound in less than 5% yield.
(20) Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R.
Tetrahedron Lett. 1976, 3477.
(16) Compounds 10-12 are obtained as mixtures of stereoisomers. Since
all of them converge into product 13, the synthesis depicted in Scheme 2
was carried out with these mixtures and no attempts were made to isolate
the individual isomers.
Org. Lett., Vol. 2, No. 16, 2000
2469

preserve labile functionalities,3g,8,10 our initial attempts to
unmask cristatic acid were quite unrewarding.
Acknowledgment. Generous financial support by the
Deutsche Forschungsgemeinschaft (Leibniz program) and the
Fonds der Chemischen Industrie is acknowledged with
gratitude. We thank Dr. C. W. Lehmann for the X-ray
analysis of compounds 6 and 15.
Specifically, the protocol using P2I4 in CH2Cl2 gave none
of the desired product but readily decomposed the starting
material.10 Attempted deprotection with n-Bu4NF in THF led
to the regioselective cleavage of the SEM group at O-4 but
did not touch the second one at all even under forcing
conditions.8 An improved method recommended by Lipshutz
et al.,21 employing n-Bu4NF in DMPU, essentially led to the
same outcome and gave only tiny amounts of the desired
product. Good results, however, were obtained with n-Bu4-
NF in HMPA at 50 °C.22 Under these conditions we were
able to isolate cristatic acid as its methyl ester 19 in a
respectable 60% yield. This completes the first total synthesis
of this interesting bioactive target. The analytical and
spectroscopic data are in full agreement with those reported
in the literature.11
Supporting Information Available: Full experimental
details together with analytical and spectroscopic data of all
new compounds. Details concerning the X-ray structures of
compounds 6 and 15. This material is available free of charge
via the Internet at http://acs.pubs.org.
OL0061236
(23) For previous studies on bioactive heterocycles from our laboratory,
see: (a) Fu¨rstner, A.; Szillat, H.; Gabor, B.; Mynott, R. J. Am. Chem. Soc.
1998, 120, 8305. (b) Fu¨rstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995,
117, 4468. (c) Fu¨rstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J. Org.
Chem. 1994, 59, 5215. (d) Fu¨rstner, A.; Ernst, A.; Krause, H.; Ptock, A.
Tetrahedron 1996, 52, 7329. (e) Fu¨rstner, A.; Weintritt, H.; Hupperts, A.
J. Org. Chem. 1995, 60, 6637. (f) Fu¨rstner, A.; Ernst, A. Tetrahedron 1995,
51, 773. (g) Fu¨rstner, A.; Grabowski, J.; Lehmann, C. W. J. Org. Chem.
1999, 64, 8275. (h) Fu¨rstner, A.; Thiel, O. R. J. Org. Chem. 2000, 65,
1738.
Further studies on the synthesis and biological evaluation
of heterocyclic natural products are in progress and will be
reported in due course.23
(21) Lipshutz, B. H.; Miller, T. A. Tetrahedron Lett. 1989, 30, 7149.
(22) Kan, T.; Hashimoto, M.; Yanagiya, M.; Shirahama, H. Tetrahedron
Lett. 1988, 29, 5417.
2470
Org. Lett., Vol. 2, No. 16, 2000