Total Synthesis of (+/-)-Torreyanic Acid

Full text of DOI:10.1021/ja005552w

10484
J. Am. Chem. Soc. 2000, 122, 10484-10485
Total Synthesis of (()-Torreyanic Acid
Chaomin Li,† Emil Lobkovsky,‡ and John A. Porco, Jr.*,†
Department of Chemistry and Center for Streamlined
Synthesis, Boston UniVersity, 590 Commonwealth AVenue
Boston Massachusetts 02215
Department of Chemistry, Baker Laboratory
Cornell UniVersity, Ithaca, New York 14853-1301
ReceiVed August 25, 2000
In 1996, Lee and co-workers reported the isolation and
structural characterization of the quinone epoxide dimer torreyanic
acid (1), a natural product produced by the fungus Pestalotiopsis
microspora.1 Torreyanic acid was found to be cytotoxic to tumor
cells and 5-10 times more potent in cell lines that are sensitive
to protein kinase C agonists. In their report, a biosynthetic scheme
for the synthesis of the natural product was proposed involving
Diels-Alder dimerization of 2H-pyran monomers epimeric at C9
(C9′) (Figure 1). Recently, a related monomeric epoxyquinol,
ambuic acid (2), was isolated from P. microspora, which supports
the proposed biosynthesis of torreyanic acid via oxidative
dimerization of a monomeric intermediate.2 Although 2H-pyrans
have been employed in intermolecular Diels-Alder reactions with
reactive dienophiles,3 their Diels-Alder dimerization has not been
previously reported, which prompted our interest in torreyanic
acid as a synthetic target. In this Communication, we report the
first total synthesis of (()-torreyanic acid, which confirms its
postulated Diels-Alder biogenesis.
Figure 1.
A retrosynthetic analysis for the synthesis of torreyanic acid
is shown in Figure 2. Bis-tert-butyl ester 3 was chosen as the
immediate precursor to 1 due to the reported stability of quinone
epoxides to acidic conditions4 and the general instability to basic
conditions and nucleophiles.5 Compound 3 may be derived
from Diels-Alder heterodimerization of diastereomeric 2H-pyran
monomers 4/4′. Although dimerization of 2H-pyran-4,5 diones
has not been previously described, room-temperature dimeriza-
tions of 6-spiroepoxycyclohexadienones6 and cyclohexa-2,4-
dienones7 have been reported. It was envisioned that the dia-
stereomers 4/4′ could be derived from epoxy vinyl quinone 5 by
oxidation, and 2H-pyran formation via 6π-electrocyclic ring-
closure of the corresponding dienal (inset).8 Quinone epoxide 5
may be derived from R-bromoenone 6 by consecutive transition
metal coupling of an E-vinyl stannane followed by removal of
protecting groups. In principle, 6 could be obtained by regio- and
stereoselective epoxidation of quinone monoketal 7, followed by
elaboration of the allyl group to a protected tiglic acid side chain.
Figure 2.
Compound 7 could likewise be accessed by allylation and
oxidation of monoprotected hydroquinone 8.
Synthesis of monomeric derivatives required for Diels-Alder
dimerization was initiated by lithiation9 of 1,3-dioxane derivative
9 (hexanes-PhH, -25 °C) followed by bromination and acidic
hydrolysis to afford benzaldehyde 10 (Scheme 1). Regioselective
demethylation of methyl ether 10 to phenol 11 was accomplished
in 52% yield using a modification of the literature procedure for
selective demethylation of 2,5-dimethoxybenzaldehyde.10 11 was
converted by sequential allylation, borohydride reduction, and silyl
protection to 12. The requisite allyl side chain was installed by
thermal Claisen rearrangement of 12 (neat, 180 °C, 2 h) to afford
an unstable allyl phenol which was directly subjected to hyper-
valent iodine oxidation11 to afford quinone monoketal 13.
Dimethoxyacetal 13 was found to be essentially unreactive to
nucleophilic epoxidation conditions known to effect monoepoxi-
dation of quinone monoketals or quinones (e.g., tBuOOH/DBU,12
TBD,5b or BuLi,13 H2O2/K2CO3, and cumene hydroperoxide/
NaH14). After considerable experimentation, it was found that
epoxidation of 13 with Ph3COOH15 (KHMDS, -78 to -35 °C,
72 h) led to approximately 20% conversion to a monoepoxide
product. However, acetal exchange of 13 with 1,3-propanediol
† Boston University.
‡ Cornell University.
(1) (a) Lee, J. C.; Strobel, G. A.; Lobkovsky, E.; Clardy, J. J. Org. Chem.
1996, 61, 3232. (b) Jarvis, B. B. Chemtracts 1997, 10, 10.
(2) Li, J. Y.; Harper, J. K.; Grant, D. M.; Tombe, B. O.; Bashyal, B.; Hess,
W. M.; Strobel, G. A. Phytochemistry 2000, in press.
(3) (a) Schiess, P.; Chia, H. L.; Suter, C. HelV. Chim. Acta 1970, 53, 1713.
(b) Royer, J.; Dreux, J. Bull. Chim. Soc. Fr. 1972, 707. (c) Salomon, R. G.;
Burns, J. R.; Dominic, W. J. Org. Chem. 1976, 41, 2918.
(4) (a) Ulrich, H.; Rao, D. V.; Tucker, B.; Sayigh, A. A. R. J. Org. Chem.
1974, 39, 2437. (b) Enhsen, A.; Karabelas, K.; Heerding, J. M.; Moore, H.
W. J. Org. Chem. 1990, 55, 1177.
(5) (a) Wipf, P.; Jeger, P.; Kim, Y. Bioorg. Med. Chem. Lett. 1998, 8,
351-356. (b) Genski, T.; Macdonald, G.; Wei, X.; Lewis, N.; Taylor, R. J.
K. Synlett 1999, 795.
(6) (a) Bonnarme, V.; Mondon, M.; Cousson, A.; Gesson, J.-P. Chem.
Commun. 1999, 1143. (b) Bonnarme, V.; Bachmann, C.; Cousson, A.; Mondon,
M.; Gesson, J.-P. Tetrahedron 1999, 55, 433.
(7) cf.: Kurti, L.; Szilagyi, L.; Antus, S.; Nogradi, M. Eur. J. Org. Chem.
1999, 2579.
(8) (a) Gosink, T. A. J. Org. Chem. 1974, 39, 1942. (b) Moorhoff, C. M.
Synthesis 1987, 685. (c) Blakemore, P. R.; Kocienski, P. J.; Marzcak, S.;
Wicha, J. Synthesis 1999, 1209. (d) Krasnaya, Z. A. Chem. Heterocycl. Compd.
2000, 35, 1255.
(9) cf.: Winkle, M. A.; Ronald, R. C. J. Org. Chem. 1982, 47, 2101-
2108.
(10) Ulrich, H.; Rao, D. V.; Tucker, B.; Sayigh, A. A. R. J. Org. Chem.
1974, 39, 2437.
(11) (a) Pelter, A.; Elgendy, S. Tetrahedron Lett. 1988, 29, 677. (b) Fleck,
A. E.; Hobart, J. A.; Morrow, G. W. Synth. Commun. 1992, 22, 179.
(12) Schlessinger, R. H.; Bebernitz, G. R.; Lin, P. J. Am. Chem. Soc. 1985,
107, 1777.
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Trans. 1988, 2663.
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(15) cf.: Corey, E. J.; Wu, L. I. J. Am. Chem. Soc. 1993, 115, 9327.
10.1021/ja005552w CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/07/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 42, 2000 10485
Scheme 1a
Scheme 3a
a Reagents: (a) (i) BuLi, 3:1 hexane/benzene, -25 °C, 10 h, (ii)
BrCF2CF2Br, THF, 0.5 h, 70%; (b) 13 M HCl, THF, 10 min, 100%; (c)
H2SO4, 70 °C, 14 h, 52%; (d) allyl bromide, K2CO3, DMF, 3 h; (e)
NaBH4, EtOH, 0.5 h; (f) TBDPSCl, imidazole, DMF, 2.5 h (90% for
three steps); (g) (i) neat, 180 °C, 2 h, (ii) PhI(OAc)2, MeOH, 20 min;
70%; (h) HO(CH2)3OH, PPTS, C6H6, 80 °C, 20 min, 90%; (i) Ph3COOH,
KHMDS, THF, -78 f -20 °C, 6 h, 81%; (j) (E)-tributyl-1-heptenyl
stannane, Pd(PPh3)4, PhCH3, 110 °C, 4 h, 98%; (k) 48% HF, CH3CN, 7
h, 76%.
a Reagents: (a) catalytic OsO4, NMO, acetone/H2O, 25 °C, 15 h; (b)
Pb(OAc)4, THF, 15 min, 96%; (c) PPh3dC(CH3)COOtBu, CH2Cl2, -35
f -10 °C, 4 h, 64%; (d) (E)-tributyl-1-heptenyl stannane, Pd(PPh3)4,
PhCH3, 110 °C, 1.5 h, 97%; (e) TBAF/AcOH (1:1), THF, 18 h, 72%; (f)
48% HF, CH3CN, 15 min, 93%; (g) Dess-Martin periodinane, CH2Cl2,
1 h, SiO2, 80%; (h) TFA/CH2Cl2 (25:75), 2 h, 100%.
and 19 (46%) were isolated, indicating acid catalysis of the
dimerization. The major dimeric product 19 was produced by exo-
Diels-Alder dimerization of 2H-pyran epoxide enantiomers, as
determined by single X-ray crystal structure analysis. The structure
of the minor dimer 18 was assigned as the torreyanic core structure
by comparison to the 1H NMR of the natural product and
subsequent preparation of (()-1. It should be noted that both 18
and 19 are produced from Diels-Alder dimerization reactions in
which the pentyl side chains are anti to one another1a and the
dienophile approaches the diene anti to the epoxide moiety.
Completion of the synthesis of (()-1 required installation of
the 2-methyl-2-butenoic acid side chain, which we elected to
perform at the monomer stage (Scheme 3). This was accomplished
by terminal olefin oxidation to an intermediate aldehyde, which
was converted by two-carbon homologation20 to enoate 20. Stille
vinylation of 20, silyl deprotection (TBAF/AcOH), and acetal
hydrolysis proceeded smoothly to afford quinone epoxide 5.
Treatment of 5 with Dess-Martin periodinane afforded a crude
product mixture, which was purified19 to afford dimeric products
3 and 21 in 39 and 41% yields, respectively. Treatment of 3 and
21 with TFA/CH2Cl2 effected tert-butyl ester removal to afford
torreyanic acid 1 and stereoisomer 22 (iso-torreyanic acid). The
structure of 1 was confirmed to be identical to natural torreyanic
acid by 1H and 13C NMR, IR, and TLC Rf values in three solvent
systems.
Scheme 2
afforded 1,3-dioxane 14, which was smoothly epoxidized to afford
monoepoxide 15 (81%).16 Attachment of the alkenyl side chain
was accomplished by a Stille coupling reaction17 with (E)-tributyl-
1-heptenyl stannane. Exposure of the diene intermediate to HF/
CH3CN effected sequential hydrolysis of cyclic acetal and silyl
ether protecting groups to afford the target quinone epoxide 16.
Gratifyingly, Dess-Martin oxidation of 16 (CH2Cl2, 1 h)
initiated the tandem oxidation-6π-electrocyclization-dimeriza-
tion process to afford a crude mixture of 2H-pyran 17 (ap-
proximately 1:1 mixture of diastereomers) and two dimeric
products (monomer:dimers approximately 2.6:1) (Scheme 2).18
After silica gel chromatography,19 only dimeric products 18 (26%)
In summary, the first total synthesis of racemic torreyanic acid
has been achieved by the proposed biomimetic route employing
a [4 + 2] dimerization of diastereomeric 2H-pyran monomers.
An additional stereoisomer has been identified in these tandem
reactions resulting from dimerization of 2H-pyran enantiomers
to produce a compound which may not be available from Nature.
Continued studies on torreyanic acid and related epoxyquinoids
and further chemistry of 2H-pyrans are in progress and will be
reported in due course.
Acknowledgment. We thank Professor Gary Strobel (Montana State
University) for supplying a sample of natural torreyanic acid and Professor
Jon Clardy (Cornell University) for helpful discussions.
(16) Structural analyses designed to further understand this change in
reactivity are in progress and will be reported separately.
(17) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50,
1-652.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds, including X-ray structural
analyses of compound 19 (PDF). X-ray crystallographic data (CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
1
(18) Partial H NMR for 2H-pyran 17 (CDCl3): δ 7.52 (s, 1H, H6), 6.19
(m, 1H, H2), 6.25 (overlapping d, 1H, J ) 4 Hz, H3) ppm.
(19) The reaction mixture was allowed to stand on a silica gel column for
1 h to effect complete Diels-Alder dimerization prior to elution of products.
See the Supporting Information for further details.
JA005552W
(20) Shing, T. K. M.; Yang, J. J. Org. Chem. 1995, 60, 5785-5789.