Total synthesis of the quinone epoxide dimer (+)-torreyanic acid: Application of a biomimetic oxidation/electrocyclization/Diels-Alder dimerization cascade

Article abstract of DOI:10.1021/ja021396c

An asymmetric synthesis of the quinone epoxide dimer (+)-torreyanic acid (48) has been accomplished employing [4 + 2] dimerization of diastereomeric 2H-pyran monomers. Synthesis of the related monomeric natural product (+)-ambuic acid (2) has also been achieved which establishes the biosynthetic relationship between these two natural products. A tartrate-mediated nucleophilic epoxidation involving hydroxyl group direction facilitated the asymmetric synthesis of a key chiral quinone monoepoxide intermediate. Thermolysis experiments have also been conducted on a model dimer based on the torreyanic acid core structure and facile retro Diels-Alder reaction processes and equilibration of diastereomeric 2H-pyrans have been observed. Theoretical calculations of Diels-Alder transition states have been performed to evaluate alternative transition states for Diels-Alder dimerization of 2H-pyran quinone epoxide monomers and provide insight into the stereocontrol elements for these reactions.

Full text of DOI:10.1021/ja021396c

Published on Web 04/03/2003
Total Synthesis of the Quinone Epoxide Dimer (+)-Torreyanic
Acid: Application of a Biomimetic Oxidation/
Electrocyclization/Diels-Alder Dimerization Cascade1
Chaomin Li,† Richard P. Johnson,‡ and John A. Porco, Jr.*,†
Contribution from the Department of Chemistry and Center for Methodology and Library
DeVelopment, Boston UniVersity, 590 Commonwealth AVenue, Boston, Massachusetts 02215, and
Department of Chemistry, UniVersity of New Hampshire, Durham, New Hampshire 03824
Received December 2, 2002; E-mail: porco@chem.bu.edu
Abstract: An asymmetric synthesis of the quinone epoxide dimer (+)-torreyanic acid (48) has been
accomplished employing [4 + 2] dimerization of diastereomeric 2H-pyran monomers. Synthesis of the related
monomeric natural product (+)-ambuic acid (2) has also been achieved which establishes the biosynthetic
relationship between these two natural products. A tartrate-mediated nucleophilic epoxidation involving
hydroxyl group direction facilitated the asymmetric synthesis of a key chiral quinone monoepoxide
intermediate. Thermolysis experiments have also been conducted on a model dimer based on the torreyanic
acid core structure and facile retro Diels-Alder reaction processes and equilibration of diastereomeric
2H-pyrans have been observed. Theoretical calculations of Diels-Alder transition states have been
performed to evaluate alternative transition states for Diels-Alder dimerization of 2H-pyran quinone epoxide
monomers and provide insight into the stereocontrol elements for these reactions.
Introduction
related epoxyquinoid dimers (+)-epoxyquinol A (5) and B (6)
were recently isolated by Osada and co-workers from an
uncharacterized fungus and were found to have potent antian-
giogenic activity.8
Recently, a number of novel compounds have been isolated
from Pestalotiopsis spp., a fungal genus that is well-known for
the production of numerous bioactive secondary metabolites,
including Taxol.2 In 1996 Lee and co-workers reported the
impressive dimeric quinone epoxide torreyanic acid (1, Figure
1)3, produced by an endophytic fungus Pestalotiopsis micro-
spora associated with the Florida torreya tree. This natural
product was found to be 5-10 times more potent in cell lines
that are sensitive to the protein kinase C (PKC) agonist, 12-o-
tetradecanoyl phorbol-13-acetate (TPA), and showed G1 arrest
of G0 synchronized cells (1-5 µg/mL). The biochemical target
of the compound has not been fully elucidated, although initial
studies have implicated the eukaryotic translation initiation factor
EIF-4a as a possible molecular target.4 The related monomeric
epoxyquinols, ambuic acid (2)5 and jesterone (3),6 were isolated
from Pestalotiopsis and closely resemble cycloepoxydon (4),
an inhibitor of the phosphorylation of the NF-κB inhibitory
protein IκB, from fermentations of a deuteromycete strain.7 The
In the original report on the isolation and structural charac-
terization of torreyanic acid, a biosynthetic scheme for the
synthesis of the natural product was proposed involving Diels-
Alder dimerization9 of 2H-pyran monomers epimeric at C9 (C9′)
(Figure 2). In this endo-selective [4 + 2] cycloaddition,10,11 the
two pentyl side chains are oriented away from one another in
(7) (a) Gehrt, A.; Erkel, G.; Anke, H.; Anke, T.; Sterner, O. Nat. Prod. Lett.
1997, 9, 259. (b) Gehrt, A. Erkel, G.; Anke, T.; Sterner, O. J. Antibiot.
1998, 51, 455.
(8) For isolation and antiangiogenic activity of epoxyquinol A: (a) Kakeya,
H.; Onose, R.; Koshino, H.; Yoshida, A.; Kobayashi, K.; Kageyama, S.-I.;
Osada, H. J. Am. Chem. Soc. 2002, 124, 3496. Epoxyquinol B: (b) Kakeya,
H.; Onose, R.; Yoshida, A.; Koshino, H.; Osada, H. J. Antibiot. 2002, 55,
829 For synthetic studies, see: (c) Li, C.; Bardhan, S.; Pace, E. A.; Liang,
M.-C.; Gilmore, T. D.; Porco, J. A., Jr. Org. Lett. 2002, 4, 3267. (d) Shoji,
M.; Yamaguchi, J.; Kakeya, H.; Osada, H.; Hayashi, Y. Angew. Chem.,
Int. Ed. 2002, 41, 3192. (e) Shoji, M.; Kishida, S.; Takeda, M.; Kakeya,
H.; Osada, H.; Hayashi, Y. Tetrahedron Lett. 2002, 43, 9155.
(9) For additional, select examples of natural products that are apparently
produced by Diels-Alder dimerization reactions, see the following.
Absinthin: (a) Beauhaire, J.; Fourrey, J. L.; Vuilhorgne, M.; Lallemand,
J. Y. Tetrahedron Lett. 1980, 21, 3191. Bistheonellasterone: (b) Kobayashi,
M.; Kawazoe, K.; Katori, T.; Kitagawa, I. Chem. Pharm. Bull. 1992, 40,
1773. Longithorones: (c) Fu, X.; Hossain, M. B.; Schmitz, F. J.; van der
Helm, D. J. Org. Chem. 1997, 62, 3810. (d) Layton, M. E.; Morales, C.
A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773. Bisgersolanolide: (e)
Rodriguez, A. D.; Shi, J.-G.; Org. Lett. 1999, 1, 337. (f) Nicolaou, K. C.;
Vassilikogiannakis, G.; Simonsen, K. B.; Baran, P. S.; Zhong, Y.-L.; Vidali,
V. P.; Pitsinos, E. N.; Couladouros, E. A. J. Am. Chem. Soc. 2000, 122,
3071 and references therein. (g) For a recent review of Diels-Alder type
natural products, see: Ichihara, A.; Oikawa, H. Curr. Org. Chem. 1998, 2,
365.
† Boston University.
‡ University of New Hampshire.
(1) Presented in part at the 224th National Meeting of the American Chemical
Society, Boston, MA, August 18-22, 2002; ORGN abstract 899.
(2) (a) Strobel, G.; Yang, X.; Sears, J.; Kramer, R.; Sidhu, R. S.; Hess, W. M.
Microbiology 1996, 142, 435. (b) Strobel, G. A. Can. J. Plant Pathol. 2003,
24, 14.
(3) (a) Lee, J. C.; Yang, X.; Schwartz, M.; Strobel, G. A.; Clardy, J. Chem.
Biol. 1995, 2, 721. (b) Lee, J. C.; Strobel, G. A.; Lobkovsky, E.; Clardy,
J. J. Org. Chem. 1996, 61, 3232. (c) Jarvis, B. B. Chemtracts: Org. Chem.
1997, 10, 10.
(4) Justman, C. J. Ph.D. Thesis, Harvard University, 2000. Diss. Abstr. Int., B
2000, 61, 2521.
(10) Li, C.; Lobkovsky, E.; Porco, J. A., Jr. J. Am. Chem. Soc. 2000, 122, 10484.
(11) In refs 8a and 10, epoxyquinol and epoxyquinone dimers were referred to
as “exo”. However, it is more appropriate to refer to the dimers as “endo”
with respect to the carbonyl substituent on the 2H-pyran dienophile.
(5) Li, J. Y.; Harper, J. K.; Grant, D. M.; Tombe, B. O.; Bashyal, B.; Hess,
W. M.; Strobel, G. A. Phytochemistry 2001, 56, 463.
(6) Li, J. Y.; Strobel, G. A. Phytochemistry 2001, 57, 261.
9
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A R T I C L E S
Li et al.
Figure 1. Torreyanic acid and related epoxyquinoid natural products.
of the pyrans are anti to each other presumably to avoid severe
steric interactions. Diastereomers 8/8′ may be derived from
quinone monoepoxide 9 by oxidation, and 2H-pyran formation,
via 6π-electrocyclic ring-closure16 of the corresponding dienal
10. Quinone monoepoxide 9 will be derived from quinone
monoketal 11 by consecutive regio- and stereoselective epoxi-
dation, transition-metal coupling17 of an E-vinyl stannane,
followed by removal of protecting groups. The elaboration of
the allyl group to a protected 2-methyl-2-butenoic acid side chain
may be achieved by alkene oxidation and Wittig olefination.
Compound 11 could likewise be accessed by successive
aromatic Claisen rearrangement and oxidation of aryl allyl ether
12.
Figure 2. Proposed biosynthesis of torreyanic acid.
At the outset of our investigation, the factors involving
formation and Diels-Alder dimerization of 2H-pyrans such as
8/8′ were not entirely clear. Our approach to torreyanic acid
(Figure 3) required valence isomerization of dienal 10 to 2H-
pyrans 8/8′. The parent disrotatory cyclization of (2Z)-2,4-
pentadienal to 2H-pyran has previously been studied at various
levels of theory.18 Depending on the starting conformation, ring-
closure is slightly endothermic, and the barrier is approximately
21-24 kcal/mol. This indicates a process that should easily
proceed at ambient temperature. Figure 4 shows several literature
examples delineating substituent effects on equilibria of dienal/
dienone and 2H-pyran valence isomers formed by 6π-electro-
cyclization.19 On the basis of these and related literature
precedents, two generalizations may be formulated. First,
increase in steric bulk shifts the equilibrium from the cis-dienal
or dienone toward the 2H-pyran (cf. 13 f 1420a vs 15 f 1620b).
Second, the presence of electron-withdrawing groups, in par-
ticular at the 5-position of the 2H-pyran, shifts the equilbrium
toward the 2H-pyran valence isomer (cf. 17f 1820c and 19 f
2020d). These examples also gave us confidence that the
equilibrium 10 / 8 (Figure 3) would lie to the right and favor
the Diels-Alder transition state. The isolation of the monomeric
epoxyquinol, ambuic acid (2, Figure 1), from P. microspora
further supports the proposed biosynthesis of torreyanic acid
via oxidative dimerization of monomeric intermediates.
In a previous report,10 we described a synthesis of racemic
torreyanic acid which demonstrated the feasibility of a biomi-
metic oxaelectrocyclization/Diels-Alder cascade. Herein, we
report full account of the total synthesis and absolute stereo-
chemical assignment of (+)-torreyanic acid. The asymmetric
synthesis was facilitated by an adaptation of our recently
developed method for tartrate-mediated nucleophilic epoxidation
of quinone monoketals involving hydroxyl group direction.12
Synthetic Plan. A retrosynthetic analysis for the synthesis
of torreyanic acid is depicted in Figure 3. Bis-tert-butyl ester 7
was chosen as the immediate precursor to 1 due to the reported
stability of quinone epoxides to acidic conditions13 and general
instability to basic conditions and nucleophiles.14 Compound 7
may be synthesized by oxidation/electrocyclization/Diels-Alder
heterodimerization of diastereomeric 2H-pyran monomers 8/8′.
Although 2H-pyrans have been employed in intermolecular
Diels-Alder reactions with reactive dienophiles,15 at the outset
of our studies Diels-Alder dimerization of 2H-pyran-4,5 diones
had not been previously described. In this biomimetic, endo-
selective Diels-Alder heterodimerization, the pentyl side chains
(15) (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.
(16) Krasnaya, Zh. A. Chem. Heterocycl. Compd. 2000, 35, 1255.
(17) For a review of the Stille reaction, see: Farina, V.; Krishnamurthy, V.;
Scott, W. J. Org. React. 1997, 50, 1.
(12) Li, C.; Pace, E. A.; Liang, M.-C.; Lobkovsky, E.; Gilmore, T. D.; Porco,
J. A., Jr. J. Am. Chem. Soc. 2001, 123, 11308.
(18) Rodriguez-Otero, J. J. Org. Chem. 1999, 64, 6842.
(19) For a discussion of substituent effects on equilibria between 2H-pyrans
and cis-dienones, see: Gosink, T. A. J. Org. Chem. 1974, 39, 1942.
(20) (a) Blakemore, P. R.; Kocienski, P. J.; Marzcak, S.; Wicha, J. Synthesis
1999, 1209. (b) Buchi, G.; Yang, N. C. J. Am. Chem. Soc. 1957, 79, 2318.
(c) Ahluwalia, V. K.; Rao, J. S. Indian J. Chem., Sect. B 1989, 28B, 81.
(d) Moorhoff, C. M. Synthesis 1987, 685.
(13) (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.
(14) Genski, T.; Macdonald, G.; Wei, X.; Lewis, N.; Taylor, R. J. K. Synlett
1999, 795.
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Synthesis of (+)-Torreyanic Acid
A R T I C L E S
Figure 3. Retrosynthetic analysis.
Figure 4. Dienal (dienone)/2H-pyran valence isomerization.
the 2H-pyran valence isomer. Second, successful production of
torreyanic acid required an endo11 Diels-Alder reaction, well-
controlled diene facial selectivity, and an anti arrangement of
the pentyl side chains. An intriguing aspect of the chemical
synthesis of torreyanic acid was to determine whether diaster-
eomeric products would be produced and further define the
stereocontrol elements involved in the dimerization of these
novel 2H-pyran-4,5 dione monomers.
pyran formation. In our first-generation approach (Scheme 1),10
acetal 22 was converted to 23 by a cyclic acetal-directed
lithiation-bromination protocol21 followed by acidic hydrolysis
of the acetal. Regioselective demethylation22 of 23 afforded
phenol 24, which was converted to 12 by a reaction sequence
of steps involving allylation, borohydride reduction, and silyl
protection. Due to the difficulty in performing large-scale
lithiation reactions and moderate yields obtained in the selective
demethylation of 23, we subsequently developed a second-
generation synthesis of aromatic precursor 12.23 The latter
synthesis began with commercially available 2,5-dimethoxy
benzaldehyde, 25. Demethylation of 25 with boron tribromide
(2.5 equiv) followed by regioselective bromination24 and selec-
tive silylation25 (TBSCl, imidazole) provided phenol 26. Me-
thylation of 26, followed by reduction and protection of the
derived alcohol with TBDPSCl, afforded bis-silyl ether 27. After
Results and Discussion
Synthesis of a Racemic, Model Substrate for Dimerization
Studies. Our initial goal was to examine the synthesis and
dimerization chemistry of a model 2H-pyran quinone epoxide
substrate. Accordingly, we first targeted preparation of racemic
quinone epoxide 21. Studies were initiated to prepare aryl allyl
(21) For directed ortho-lithiation of aromatic acetals, see: (a) Plaumann, H. P.;
Keay, B. A.; Rodrigo, R. Tetrahedron Lett. 1979, 20, 4921. (b) Costa, P.
R. R.; Lopes, C. C.; Lopes, R. S. C.; Marinho, M. F. G.; Castro, R. N.
Synth. Commun. 1988, 18, 1723.
(22) Ulrich, H.; Rao, D. V.; Tucher, B.; Sayigh, A. A. R. J. Org. Chem. 1974,
39, 2437.
(23) Hu, Y., Li, C.; Kulkarni, B.; Strobel, G.; Lobkovsky, E.; Torczynski, R.
M.; Porco, J. A., Jr. Org. Lett. 2001, 3, 1649.
ether 12 which contains a protected hydroquinone precursor to
a quinone monoketal, an aryl bromide for coupling to vinylmetal
reagents, and a silyl-protected hydroxymethyl for use in 2H-
(24) Narayanan, V. L.; Sausville, E. A.; Kaur, G.; Varma, R. K. PCT Int. Appl.
WO 9943636, 1999.
(25) For example, see: Liu, A.; Dillon, K.; Campbell, R. M.; Cox, D. C.; Huryn,
D. M. Tetrahedron Lett. 1996, 37, 3785.
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Scheme 1. Syntheses of a Protected Hydroquinone Precursora
a Reagents and conditions: (a) (i) BuLi, 3:1 hexane/benzene, -25 °C, 10 h, (ii) BrCF2CF2Br, THF, 0.5 h, 70%; (b) 11 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, imid., DMF, 2.5 h (90% for three steps); (g) BBr3,
CH2Cl2, -78 f 0 °C, 1 h, 97%; (h) Br2, CHCl3, rt, 2.5 h, 94%; (i) TBDMSCl, imidazole, CH2Cl2, rt, 20 min, 94%; (j) MeI, NaH, THF, 65 °C, 7 h, 72%;
(k) NaBH4, EtOH, 0 °C, 0.5 h, 100%; (l) TBDPSCl, imidazole, DMF, rt, 6 h, 93%; (m) TBAF, THF, 0 °C, 5 min, 100%; (n) allyl bromide, K2CO3, DMF,
3 h, 97%.
Scheme 2. Synthesis of Quinone Epoxide 21a
epoxidation of 28 with Ph3COOH29 (KHMDS, -78 f -35 °C,
72 h) led to approximately 20% conversion to a monoepoxide
product. However, acetal exchange of 28 with 1,3-propanediol
afforded 1,3-dioxane 29 which was smoothly epoxidized to
afford monoepoxide 30 (81%). Attachment of the alkenyl side
chain was accomplished by Stille coupling17 with (E)-tributyl-
1-heptenyl stannane. Exposure of the diene intermediate to
aqueous HF/CH3CN effected sequential hydrolysis of cyclic
acetal and silyl ether protecting groups to afford the target
quinone epoxide 21. It should be noted that the additional
conjugation afforded by the R-heptenyl enone facilitated rapid
(5 min) acetal hydrolysis to the quinone monoepoxide. Hydroly-
sis of bromo-acetal 30 using identical conditions (48% aqueous
HF/CH3CN) provided the corresponding quinone epoxide less
efficiently (acetal hydrolysis incomplete after 2 h).
a Reagents and conditions: (a) (i) neat, 180 °C, 2 h (ii) PhI(OAc)2,
MeOH, 20 min; 70%; (b) HO(CH2)3OH, PPTS, benzene, 80 °C, 20 min,
To understand the difference in epoxidation reactivity of
dimethoxyketal 28 and cyclic ketal 29, we first compared their
1H and 13C NMR spectra. Examination of the 1H NMR
resonance for C5-H in 29 showed a downfield shift of 0.83
90%; (c) Ph3COOH, KHMDS, THF, -78 f -20 °C, 6 h, 81%; (d) (E)-
tributyl-1-heptenyl-stannane, Pd(PPh3)4, PhCH3, 110 °C, 4 h, 98%; (e) 48%
aq HF, CH3CN, 7 h, 76%.
ppm relative to 28 and a 7.0 ppm upfield shift of C5 in the 13
C
selective deprotection of 27 (TBAF), the resulting phenol was
allylated to afford the desired phenyl allyl ether 12 (10-20 g
scale).
NMR spectrum (Figure 5). To further understand the relative
NMR chemical shifts as well as the reactivity differences, single-
crystal X-ray structures of 28 and 29 were obtained (Figure 5).
The X-ray structures show that cyclic ketal 29 adopts chair
conformation A instead of B to avoid severe steric interactions
between the indicated methylene hydrogens and the allylic silyl
ether.23 In this X-ray structure, the two axial hydrogens of the
cyclic ketal show close contact with the C5 vinylic hydrogen
(2.20-2.21 Å). It has been demonstrated that nonbonded
repulsions between proximate hydrogens can cause an increase
in shielding experienced by the associated 13C nuclei30 (γ-gauche
interaction31), as well as lower-field proton chemical shifts due
to sterically induced charge polarization by H-H repulsion.32
The NMR chemical shift differences observed in 28 and 29 may
Thermolysis of 12 (neat) led to facile aromatic Claisen
rearrangement to afford an ortho-allylated phenol, which was
directly oxidized26 to dimethoxyketal 28 (Scheme 2). On the
basis of the well-described use of quinone monoacetals as
substrates for nucleophilic epoxidation,27 we proceeded with
evaluation of substrate 28. However, dimethoxyacetal 28 was
found to be essentially unreactive to nucleophilic epoxidation
conditions known to effect monoepoxidation of quinone monoket-
t
als or quinones (e.g., BuOOH (DBU,28a TBD,14 or BuLi28b),
H2O2/K2CO3, NaBO3/aq EtOH,28c and cumene hydroperoxide/
NaH28d). After considerable experimentation, we found that
(26) (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.
(27) (a) Wipf, P.; Kim, Y. J. Org. Chem. 1994, 59, 3518. (b) Wipf, P.; Kim,
Y.; Jahn, H. Synthesis 1995, 12, 1549. (c) Wipf, P.; Coish, P. D. G. J.
Org. Chem. 1999, 64, 5053. (d) Alcaraz, L.; Macdonald, G.; Ragot, J. P.;
Taylor, R. J. K.; Alcaraz, L.; Kapfer-Eyer, I.; Macdonald, G.; Wei, X.;
Lewis, N. Synthesis 1998, 15, 775. (e) Alcaraz, L.; Macdonald, G.; Ragot,
J. P.; Lewis, N.; Taylor, R. J. K. J. Org. Chem. 1998, 63, 3526. (f) Alcaraz,
L.; Macdonald, G.; Ragot, J.; Lewis, N. J. Tetrahedron 1999, 55, 3707.
(g) Cronje Grove, J. J.; Wei, X.; Taylor, R. J. K. Chem. Commun. 1999, 5,
421.
(28) (a) Schlessinger, R. H.; Bebernitz, G. R.; Lin, P. J. Am. Chem. Soc. 1985,
107, 1777. (b) Meth-Cohn, O.; Moore, C.; Taljaard, H. C. J. Chem. Soc.,
Perkin. Trans. 1988, 2663. (c) Ichihara, A.; Oda, K.; Sakamura, S.
Tetrahedron Lett. 1972, 50, 5105. (d) Wipf, P.; Jung, J.-K. J. Org. Chem.
1998, 63, 3531.
(29) Corey, E. J.; Wu, L. I. J. Am. Chem. Soc. 1993, 115, 9327.
(30) Grant, D. M.; Cheney, B. V. J. Am. Chem. Soc. 1967, 89, 5315.
(31) Also known as the γ effect, see: (a) Dalling, D. K.; Grant, D. M. J. Am.
Chem. Soc. 1972, 94, 5318. (b) Smith, D. H.; Jurs, P. C. J. Am. Chem.
Soc. 1978, 100, 3316.
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A R T I C L E S
Figure 5. X-ray crystal structures of acyclic and cyclic quinone monoketals.
Scheme 3. Model Dimerization Study
thus be explained by the X-ray structure but are not necessarily
correlated with the epoxidation reactivity of these substrates.
However, further comparison of the X-ray structures provides
additional clues about the epoxidation reactivity. As shown in
the X-ray structure of 29, the fixed 1,3-dioxane chair conforma-
tion may minimize electrostatic repulsion between the oxygen
lone pairs and the incoming electron-rich peroxide.33 Moreover,
free rotation of methoxy groups in 28 may disturb 1,4-addition
of the approaching peroxide anion, which is the rate-determining
step for nucleophilic epoxidation.34
racemic quinone epoxide 21 with Dess-Martin periodinane
afforded a crude mixture of 2H-pyran 31 (approximately 1:1
mixture of diastereomers) and two dimeric products (monomers:
dimers approximately 2.6:1) (Scheme 3). After silica gel
chromatography, only dimeric products 32 (26%) and 33 (46%)
were isolated, indicating acid catalysis of the dimerization. In
practice, following oxidation 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.35 Similarly,
incubation of the crude oxidation reaction mixture with the
mildly Lewis acidic clay, Montmorillonite K10 (CH2Cl2), was
found to afford dimeric products.36 The major dimeric product
Feasibility Study for Diels-Alder Dimerization. A model
study for the tandem oxidation/6π-electrocyclization/dimeriza-
tion process was next undertaken. Gratifyingly, treatment of
(35) For recent examples of Diels-Alder reactions catalyzed by silica gel, see:
1. (a) Leon, F. M.; Carretero, J. C. Tetrahedron Lett. 1991, 32, 5405. (b)
Wang, W. B.; Roskamp, Eric J. Tetrahedron Lett. 1992, 33, 763. (c) Posner,
G. H.; Carry, J. C.; Lee, J. K.; Bull, D. S.; Dai, H. Tetrahedron Lett. 1994,
35, 132. (d) Cativiela, C.; Garcia, J. I.; Mayoral, J. A.; Pires, E.; Royo, A.
J.; Figueras, F. Tetrahedron 1995, 51, 1295. (e) Perez, J. M.; Lopez-
Alvarado, P.; Alonso, M. A.; Avendano, C.; Menendez, J. Carlos.
Tetrahedron Lett. 1996, 37, 6955.
(32) Cheney, B. V. J. Am. Chem. Soc. 1968, 90, 5386.
(33) For an example of nucleophilic addition anti to an alkoxy group due to
apparent repulsive interactions, see: Smith, A. B., III; Dunlap, N. K.;
Sulikowski, G. A. Tetrahedron Lett. 1988, 29, 439.
(34) Bunton, C. A.; Minkoff, G. J. J. Chem. Soc. 1949, 665.
9
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Li et al.
Figure 6. Apparent stereocontrol elements in Diels-Alder dimerization of 2H-pyran quinone epoxide monomers.
Figure 7. Chemical Structures used for transition-state energy calculation.
33 was produced by endo-selective Diels-Alder dimerization
of heterochiral 2H-pyran epoxides as determined by single-
crystal X-ray structure analysis. The structure of the minor dimer
32 was assigned as the torreyanic acid core structure by
heterochiral dimer 33. However, 33 can only be prepared as a
racemate since it arises by dimerization of a pair of enantiomers.
Transition-State Analysis of Model Dimerization. To
further understand the Diels-Alder dimerization results ob-
served by experiments, we carried out theoretical calculations38
of Diels-Alder transition states.39 The torreyanic acid structure
was first simplified to an allyl side chain (cf. Scheme 3, 32),
for which we have experimental results. For illustration of the
two stereocontrol elements (pentyl side chain and epoxide of
the diene), we compared transition-state energies of structures
32-35 (Figure 7). In structure 34, the pentyl side chain of the
diene is syn to the approaching dienophile. In structure 35, the
epoxide of the diene is syn to the approaching dienophile.
1
comparison to the H NMR spectrum of the natural product
and subsequent preparation of torreyanic acid. It should be noted
that both 32 and 33 are produced from Diels-Alder dimerization
reactions in which the pentyl side chains are anti to one another
in the [4 + 2] transition state and the dienophile approaches
the diene anti to the epoxide moiety.37
These initial model studies in the racemic series provided
insight into the stereocontrol elements involved in the dimer-
ization of 2H-pyran-4,5 dione monomers produced by tandem
oxidation/electrocyclization. As illustrated in Figure 6, if we
restrict the Diels-Alder dimerization reaction to be endo- and
regioselective, 4 × 4 ) 16 possible diastereomers may be
produced. An additional set of 16 enantiomers of these structures
may be produced by altering the facial selectivity of the diene
and dienophile. Our experimental results thus far may be
explained by restrictions imposed by a series of apparent
stereocontrol elements (Figure 6). First, anti orientation of the
pentyl side chains reduces the total number of diastereomers
from sixteen to four. Second, Diels-Alder cycloaddition in
which the diene face selectivity is anti to the epoxide37 further
reduces the number of possibilities to two diastereomers, which
is observed experimentally (four enantiomers). Utilization of a
nonracemic sample of the epoxide monomer is expected to pro-
duce a single enantiomer of torreyanic acid, which will be dis-
cussed in a later section regarding asymmetric synthesis. From
the aforementioned analysis one important conclusion can be
made: by employing a nonracemic epoxide, it is possible to gen-
erate either enantiomer of compound 32 to the exclusion of the
To rapidly locate the numerous minima and transition
states on this complex potential energy surface, we chose a
hybrid theoretical method. All structures were optimized and
(36) For select examples of Diels-Alder reactions catalyzed by montmorillonite
K10 clay, see: (a) Laszlo, P.; Lucchetti, J. Tetrahedron Lett. 1984, 25,
2147. (b) Cativiela, C.; Figueras, F.; Fraile, J. M.; Garcia, J. I.; Mayoral,
J. A. Tetrahedron: Asymmetry 1993, 4, 223. (c) Chiba, K.; Hirano, T.;
Kitano, Y.; Tada, M. Chem. Commun. 1999, 8, 691. (d) Kamath, C. R.;
Samant, S. D. Indian J. Chem., Sect. B 1999, 38B, 1214. (e) For a review
of recent advances in clay-catalyzed organic transformations, see: Nikalje,
M. D.; Phukan, P.; Sudalai, A. Org. Prep. Proced. Int. 2000, 32, 1.
(37) For an example of Diels-Alder cycloaddition with π-facial selectivity anti
to the diene epoxide moiety, see: J. R. Gillard, M. J. Newlands, J. N.
Bridson, D. J. Burnell, Can. J. Chem. 1991, 69, 1337.
(38) All calculations were performed using Spartan 02 (Version 1.01, Wave-
function, Inc., Irvine, CA.).
(39) For recent theoretical calculations of Diels-Alder transition states, see:
(a) Ujaque, G.; Norton, J. E.; Houk, K. N. J. Org. Chem. 2002, 67, 7179.
(b) Cayzer, T. N.; Wong, L. S.-M.; Turner, P.; Paddon-Row: M. N.;
Sherburn, M. S. Chem. Eur. J. 2002, 8, 739. (c) Singleton, D. A.;
Schulmeier, B. E.; Hang, C.; Thomas, A.; Leung, S.-W.; Merrigan, S. R.
Tetrahedron 2001, 57, 5149. (d) Paddon-Row: M. N.; Sherburn, M. S.
Chem. Commun. 2000, 22, 2215 (e) Bachmann, C.; Boeker, N.; Mondon,
M.; Gesson, J.-P. J. Org. Chem. 2000, 65, 8089. (f) Bradley, A. Z.;
Kociolek, M. G.; Johnson, R. P. J. Org. Chem. 2000, 65, 7134.
9
5100 J. AM. CHEM. SOC. VOL. 125, NO. 17, 2003

Synthesis of (+)-Torreyanic Acid
A R T I C L E S
Figure 8. Model transition states leading to 32 and 33.
Figure 9. Optimized geometries for the pyrans.
subjected to frequency analysis with the semiempirical AM1
method, followed by a single-point B3LYP/6-31G* calculation.
AM1 zero-point corrections were then applied to arrive at a
final relative energy.40 Transition-state models were initially
constructed with the pentyl side chain in the most extended
conformation. Other conformations are possible but should not
significantly change the energetics.
of (+)-torreyanic acid). Lewis acid catalysis is also possible,
but we have not carried out calculations on this process.
Figure 9 shows the B3LYP/6-31G* optimized structures
(hydrogens omitted for clarity) for the diastereomeric pyrans
31 and 31′. In each case, only one ring conformer could be
located. For anti-pyran 31′, the pentyl side chain adopts an
equatorial orentation, while for the syn-pyran 31, the pentyl side
chain adopts an axial orientation, which leaves the other face
(also anti to epoxide) open to the dienophile. These conforma-
tions suggest that only the syn-pyran may serve as a diene
because it has a more sterically accessible face (anti to the
epoxide) for an incoming dienophile, which is consistent with
our experimental results. Thus, the orientation of the pentyl
groups in the lower-energy transition states may largely be
controlled by steric factors. Analysis of the frontier molecular
orbitals revealed no obvious basis for facial selectivity. The
observed regio- and stereochemistry of cycloaddition can be
explained by a conventional frontier MO analysis, which pairs
the diene HOMO with the dienophile LUMO. Symmetry-
favorable secondary interactions further support the endo
orientation. The same is true for the complementary LUMO-
HOMO pair of orbitals.
At the B3LYP//AM1 level of theory, transition states leading
to 32, 33, 34, and 35 were predicted to be 18.5, 20.0, 27.9, and
31.6 kcal/mol above reactants, respectively. Other selected regio-
and stereochemical modes of addition were investigated; all gave
predicted barriers of >25 kcal/mol. We conclude from these
studies that the lowest-energy [4 + 2] transition state leads to
32, which resembles the torreyanic acid core structure. In
contrast, dimerization of a racemic mixture 31 affords a second
energetically competitive transition state, which leads to dimer
33. Transition-state structures leading to diastereomers 32 and
33 are shown in Figure 8. These computational results are
consistent with our experiments on racemic and enantiomerically
pure material (see later section regarding asymmetric synthesis
(40) This method is denoted as B3LYP/6-31G*//AM1(+ZPVE). Selected DFT
optimizations were carried out to validate this method. For example, the
barrier to closure for the trans-dienal to syn-pyran 31 (epoxide and pentyl
chain syn refer to the pyran-fused quinone plane) was calculated to be 10.2
kcal/mol at the DFT//AM1 level and 12.6 kcal/mol with B3LYP/6-31G*
theory. The parent dienal cyclization has a predicted barrier of ca. 22 kcal/
mol, see ref 18.
The Diels-Alder cycloaddition normally is exothermic by
approximately 30-40 kcal/mol.41 In the present case, structural
congestion in the product is expected to diminish this value
significantly. At the B3LYP//AM1 level, the predicted energy
9
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A R T I C L E S
Li et al.
Scheme 4. Novel Reaction of 33 by Thermolysis in Toluene
Scheme 5. Proposed Pericyclic Cascade to Form Monomer 42a
a Barriers (italics) and energetics (boldface in brackets).
change upon formation of 32 and 33 by cycloaddition is -8.0
and -5.3 kcal/mol, respectively. These modest exothermicities
suggest facile reversibility in the cycloaddition reactions (vide
infra).
mol) in each direction. Two low-energy, disrotatory pathways
exist for cyclization to diastereomeric syn or anti 2H-pyrans
31 or 31′. The predicted barriers are consistent with the facile
electrocyclization we observe experimentally. Two additional
disrotatory paths connect the pyrans with cis-dienal 38. The cis-
dienal then presents a favorable geometry for subsequent
antarafacial 1,7-hydrogen migration43 to trienol 39, which then
isomerizes to the lower-energy hydrogen-bonded stereoisomer
40, presumably by trace-acid catalysis. The final step may be
disrotatory cyclization to 36. This final step should not be easily
reversible because 36 lies in the deepest energy well on the
surface. On the basis of this general mechanism, 36 should also
be produced by 32. In the event, thermolysis of 32 at 110 °C
also produces monomeric compound 36 in 38% yield.
Thermolysis Studies of Quinone Epoxide Dimers. Given
the moderate calculated exothermicities of 2H-pyran dimeriza-
tions (vide supra), we reasoned that retro Diels-Alder reaction
of the dimers should occur under thermolytic conditions.
Thermolysis of dimer 33 was first conducted at 105 °C (toluene,
9 h) in which case a novel monomeric compound (36) was
formed in 53% yield (Scheme 4). The relative configuration of
the stereocenters in 36 was determined by single-crystal X-ray
structure analysis.
Scheme 5 presents a proposed mechanism42 for formation of
36, including a summary of proposed intermediates and energet-
ics calculated using the B3LYP//AM1 method. trans-Dienal 37
is the experimental starting point and energetic reference.
Numbers indicated above the arrows represent barriers (kcal/
Since the aforementioned mechanism is initiated by a facile
retro Diels-Alder reaction, we reasoned that thermolysis at
lower temperature may prevent generation of 36 and lead to
equilibration between two dimers 32 and 33. In the event, simple
(43) The geometric requirements for antarafacial [1,7] sigmatropic shifts are
well-known, see: (a) Jiao, H.; Schleyer, P. v. R. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1763. (b) Enas, J. D.; Shen, G. Y.; Okamura, W. H. J. Am.
Chem. Soc. 1991, 113, 3873. (c) Shimizu, M.; Iwasaki, Y.; Ohno, A.;
Yamada, S. Chem. Pharm. Bull. 2000, 48, 1484. (d) Millar, J. G.
Tetrahedron Lett. 1997, 38, 7971. (e) Daniel, D.; Middleton, R.; Henry,
H. L.; Okamura, W. H. J. Org. Chem. 1996, 61, 5617. (f) Pohnert, G.;
Boland, W. Tetrahedron 1994, 50, 10235.
(41) On the basis of heats of formation, the parent [4 + 2] reaction is exothermic
by 40 kcal/mol which is reduced in bicyclic structures, cf.: Wilsey, S.;
Houk, K. N.; Zewail, A. H. J. Am. Chem. Soc. 1999, 121, 5772.
(42) Another possible mechanism for the production of alcohol 36 involves an
ene reaction of 38 leading to a vinyl cyclobutene intermediate that either
opens to 39 or 40, or undergoes a vinyl cyclobutane rearrangement directly
to 36. We thank a reviewer for pointing out this possibility.
9
5102 J. AM. CHEM. SOC. VOL. 125, NO. 17, 2003

Synthesis of (+)-Torreyanic Acid
A R T I C L E S
Scheme 6. Interchange of Two Dimers through Retro Diels-Alder and Electrocyclic Ring-Opening
Scheme 7. Asymmetric Synthesis of Quinone Epoxide 9a
a Reagents and conditions: (a) NaIO4, OsO4, THF/H2O, 1.5 h, 62%; (b) BH3. tBuNH2, MeOH/H2O, THF, 0 °C, 20 min, 76%; (c) Ph3COOH, NaHMDS,
L-DIPT, 4 Å MS, PhCH3, -40 °C, 50 h, 91%, 91% ee; (d) (i) Dess-Martin periodinane, CH2Cl2, 35 min (ii) PPh3dC(CH3)COOtBu, CH2Cl2, -78 f -5
°C, 4 h, 94%; (e) (E)-tributyl-1-heptenylstannane, Pd(PPh3)4, PhCH3, 110 °C, 2 h, 94%; (f) TBAF/AcOH (1:1), THF, 20 h, 76%; (g) 48% aq HF, CH3CN,
15 min, 93%.
heating of dimer 33 (0.004 M, CDCl3, 60 °C) was found to be
effective. After 1 h, NMR analysis showed the appearance of
2H-pyran monomers. Interestingly, after 24 h, dimer 32 was
the major compound by NMR analysis. After 2 days, dimer 32
was isolated as the major product in 38% yield after silica gel
chromatography. A parallel experiment showed that 33 is also
formed by thermolysis of 32. NMR integration showed that the
equilibrium ratio of 31/31′:32:33 (60 °C, 48 h in CDCl3) was
5:4:1. Since the two pyrans of 33 are both syn and 32 is
comprised of one syn- and one anti-pyran, it is apparent that
this equilibration may occur through a process involving retro
Diels-Alder reaction followed by electrocyclic ring-opening
of the 2H-pyran (Scheme 6). No aldehyde proton signals were
observed in the proton NMR spectra, which is related to the
observation that no aldehyde peak was observed in the crude
1H NMR spectrum after Dess-Martin oxidation (cf. Scheme
3). This reinforces the favorable equilibrium of the 2H-pyran
valence isomer relative to the dienal form.
relative to a workable substrate 41, using our recently developed
tartrate-mediated nucleophilic epoxidation method.12 However,
29 gave very low reactivity (rt, 20 h, <40% conversion) and
afforded virtually no enantioselectivity (<10% ee). We decided
to modify 29 to homoallylic alcohol 42 with the hope that the
hydroxyl group could facilitate the epoxidation by directing
group effects (Scheme 7).45 The desired substrate 42 was
prepared by Lemieux-Johnson oxidation of 29 and selective
reduction of the aldehyde in the presence of the dienone
(BH3‚tBuNH2).46 Gratifyingly, by using the tartrate-mediated
Asymmetric Syntheses of (+)-Torreyanic Acid and (+)-
Ambuic Acid. In our racemic synthesis of model compound
21, an nonstereoselective epoxidation was conducted on quinone
monoketal 29. We sought to develop reagent-controlled asym-
metric nucleophilic epoxidation44 of 29 to establish an asym-
metric synthesis of torreyanic acid. We first studied the reactivity
of substrate 29, which bears an additional R-allyl substituent
(44) For a recent review of asymmetric epoxidation of electron-deficient olefins,
see: Porter, M. J.; Skidmore, J. Chem. Commun. 2000, 14, 1215.
(45) For recent example of hydroxyl-directed nucleophilic epoxidation of an
enone, see: Evarts, J. B., Jr.; Fuchs, P. L. Tetrahedron Lett. 1999, 40,
2703.
(46) Andrews, G. C. Tetrahedron Lett. 1980, 21, 697.
9
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A R T I C L E S
Li et al.
Scheme 8. Correlation for Determining the Absolute Stereochemistry of 9a
a Reagents and conditions: (a) (2R, 4R)-pentanediol, PPTS, PhH, 70 °C, 30 min, 82%; (b) Ph3COOH, KHMDS, THF, -35 °C, 25 h, 73%; (c) NMO,
OsO4, Acetone/H2O, 30 h; (d) Pb(OAc)4, THF, 5 min; (e) PPh3dC(CH3)COOtBu, CH2Cl2, -78 °C f -5 °C, 2 h, 60% for three steps; (f) (E)-tributyl-1-
heptenylstannane, Pd(PPh3)4, PhCH3, 110 °C, 3 h, 94%; (g) TBAF/AcOH (1:1), THF, 20 h, 80%; (h) 48% HF, CH3CN, 0 °C, 10 min, 96%.
nucleophilic epoxidation method, substrate 42 was epoxidized
smoothly with high enantioselectivity (91% yield, 91% ee (chiral
HPLC)) to afford epoxide 43. Dess-Martin oxidation of 43
followed by two-carbon homologation provided enoate 44. Stille
reaction of 44, silyl deprotection (TBAF/AcOH), and acetal
hydrolysis proceeded smoothly to afford quinone epoxide 9,
which is ready for the Diels-Alder dimerization protocol. The
absolute configuration of 9 was assigned by correlation with
material produced by diastereoselective epoxidation of a chiral
quinone monoketal (Scheme 8). Dimethoxyketal 28 was con-
verted into epoxide 45 by transketalization with a chiral diol,
followed by diastereoselective epoxidation (dr ) 100:0).23,27b,29
The diastereoselective formation of 45 can be explained by steric
blocking of the R-face of the dienone by the axial methyl group
in the preferred chair conformer A. Installation of the protected
Figure 10. Mechanistic proposal for hydroxyl-directed asymmetric nu-
cleophilic epoxidation.
oxygen,45 which may help anchor the substrate to the putative
2-methyl-2-butenoic acid side chain was accomplished by
terminal olefin oxidation to an intermediate aldehyde followed
by two-carbon homologation to afford enoate 46.10 Stille
vinylation of 46, silyl deprotection (TBAF/AcOH), and acetal
hydrolysis proceeded smoothly to afford nonracemic quinone
epoxide 9 (â-epoxide). Compound 9 produced using both
protocols showed comparable optical rotations (9 (Scheme 8):
[R]23D ) + 59.3° (c ) 1.0, CHCl3), 9 (Scheme 7): [R]23D ) +
59.2° (c ) 0.5, CHCl3)) and thus confirmed the absolute
configuration of 9 produced using the tartrate-mediated nucleo-
philic epoxidation protocol.
In view of this stereochemical correlation, we suggest a
mechanistic proposal for tartrate-mediated nucleophilic epoxi-
dation of homoallylic alcohol substrate 42 as shown in Figure
10. In accord with our proposed model,12 the asymmetric
epoxidation may be facilitated by hydrogen-bond-directing
influence between the homoallylic alcohol and the peroxide
bowl-shaped chelate.
Final steps toward (+)-torreyanic acid are shown in Scheme
9. Dess-Martin oxidation of (+)-9 (CH2Cl2, 1 h) initiated the
tandem oxidation/electrocyclization/dimerization process to af-
ford a single dimeric product 47 (80%), which confirmed the
prediction advanced earlier (cf. Figure 6). Treatment of 47 with
TFA/CH2Cl2 effected tert-butyl ester removal to afford 48. The
structure of 48 was confirmed to be identical to natural
1
torreyanic acid by H and 13C NMR, IR, TLC Rf values (in
three solvent systems) and [R]D (natural: [R]D ) + 92.3°, c )
0.11, MeOH; synthetic: [R]D ) + 88.2°, c ) 0.4, MeOH). The
absolute configuration of natural (+)-torreyanic acid was thus
determined to be 48, the antipode of 1, and therefore in the
same enantiomeric series as the antiangiogenesis agents ep-
oxyquinol A and B (Figure 1).
Finally, we also accomplished the synthesis of the monomeric
epoxyquinoid (+)-ambuic acid5 from intermediate (+)-9 (Scheme
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5104 J. AM. CHEM. SOC. VOL. 125, NO. 17, 2003

Synthesis of (+)-Torreyanic Acid
A R T I C L E S
Scheme 9. Syntheses of (+)-Torreyanic Acid and (+)-Ambuic Acida
a Reagents and conditions: (a) Dess-Martin periodinane, CH2Cl2, 1.5 h, 80%; (b) TFA/CH2Cl2, 0 °C, 2 h, 100%; (c) MeOBEt2, NaBH4, -78°C, 30 min,
49 (48%) and 50 (39%); (d) 48% HF, CH3CN, 1 h, 70%.
Scheme 10. Biosynthetic Relationship of Torreyanic Acid and Ambuic Acid
9). Reduction of (+)-9 using NaBH4/MeOBEt247 afforded syn-
epoxyquinol 49 and epimer 50 in a 1.2:1 ratio. Attempted
reduction using a variety of borohydride reagents (LiEt3BH,
LiEt3BH/MeOBEt2, NaBH4, NaBH(OAc)3/MeOBEt2) did not
lead to observable increases in diastereoselectivity. Final depro-
tection of 49 with HF/CH3CN gave (+)-ambuic acid 2. The
structure of 2 was confirmed to be identical to natural ambuic
ship between these two natural products. A tartrate-mediated
nucleophilic epoxidation involving hydroxyl group direction
facilitated the asymmetric synthesis of the key chiral quinone
monoepoxide intermediate. Thermolysis experiments have also
been conducted on a model dimer based on the torreyanic acid
core structure and facile retro Diels-Alder reaction processes
and equilibration of diastereomeric 2H-pyrans have been
observed. Higher-temperature thermolysis of the model dimer
led to the production of a novel monomeric compound by an
apparent pericyclic cascade involving retro [4 + 2], electrocyclic
ring-opening, 1,7-hydride shift, and final disrotatory 6π-
electrocyclization. In addition, theoretical calculations of Diels-
Alder transition states have been performed to evaluate alter-
native transition states for Diels-Alder dimerization of 2H-
pyran quinone epoxide monomers and provide insight into the
stereocontrol elements for these reactions. Continued studies
concerning torreyanic acid and related dimeric and monomeric
epoxyquinoid compounds and applications of tartrate-mediated
asymmetric nucleophilic epoxidation are in progress and will
be reported in due course.
1
acid by H and 13C NMR, IR, TLC Rf values (in three solvent
systems) and [R]D (natural: [R]D ) + 92.1°, c ) 1.0, MeOH;
synthetic: [R]D ) + 93°, c ) 1.0, MeOH). In addition, recent
stereochemical analysis of ambuic acid by solid-state NMR
confirms the syn epoxy alcohol relative stereochemistry deter-
mined in this study. 48 Since natural torreyanic acid and ambuic
acid possess the same epoxide chirality, it is likely that both
natural products are produced by either oxidation or reduction
of quinone epoxide 51 or a related derivative (Scheme 10).
Conclusions
In summary, the first total synthesis and absolute stereo-
chemical assignment of the quinone epoxide dimer (+)-
torreyanic acid has been accomplished by employing a [4 + 2]
dimerization of diastereomeric 2H-pyran monomers. Synthesis
of the related monomeric natural product (+)-ambuic acid has
also been achieved, which establishes the biosynthetic relation-
Acknowledgment. Financial support from Boston University
and the American Cancer Society (RSG-01-135-01, J.A.P, Jr.)
is gratefully acknowledged. We thank Dr. Emil Lobkovsky
(Cornell University) for X-ray structure analyses, Professor Gary
Strobel (Montana State University) for supplying samples of
(47) Chen, K.-M.; Hardmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J.
Tetrahedron Lett. 1987, 28, 155.
(48) Harper, J. K.; Barich, D. H.; Hu, J. Z.; Strobel, G. A.; Grant, D. M. J.
Org. Chem. 2003, 68, ASAP, Web Release Date: January 24, 2003.
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A R T I C L E S
Li et al.
natural torreyanic and ambuic acids, Dr. James Harper (Uni-
versity of Utah) for providing a preprint of their paper, and
Professor John Snyder (Boston University) for helpful discus-
sions.
coordinates for 28, 29, 33, and 36, Cartesian coordinates for
calculated Diels-Alder transition states, and NMR spectra for
selected compounds (PDF). X-ray crystallographic file in CIF
format. This material is available free of charge via the Internet
at http://pubs.acs.org.
Supporting Information Available: Complete experimental
procedures and spectral data for all previously unreported
compounds described herein, including X-ray crystal structure
JA021396C
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5106 J. AM. CHEM. SOC. VOL. 125, NO. 17, 2003