Synthesis of epoxyquinol A and related molecules: Probing chemical reactivity of epoxyquinol dimers and 2H-pyran precursors

Article abstract of DOI:10.1021/jo050897o

Total syntheses of the epoxyquinoid dimers, epoxyquinols A, B, and epoxytwinol A (RKB-3564 D), have been accomplished employing [4 + 2] and [4 + 4] dimerization of 2H-pyran epoxyquinol monomers. Modifications of 2H-pyran precursors have been explored, inc

Full text of DOI:10.1021/jo050897o

Synthesis of Epoxyquinol A and Related Molecules: Probing
Chemical Reactivity of Epoxyquinol Dimers and 2H-Pyran
Precursors
Chaomin Li and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library Development,
Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215
porco@chem.bu.edu
Received May 4, 2005
Total syntheses of the epoxyquinoid dimers, epoxyquinols A, B, and epoxytwinol A (RKB-3564 D),
have been accomplished employing [4 + 2] and [4 + 4] dimerization of 2H-pyran epoxyquinol
monomers. Modifications of 2H-pyran precursors have been explored, including alteration of epoxy
alcohol and diene stereochemistry. A stable 2H-pyran prepared by alteration of the epoxyquinol
2H-pyran nucleus was evaluated as a diene in Diels-Alder cycloaddition with reactive dienophiles.
Extensive studies for improving the [4 + 4] dimerization of selectively protected 2H-pyran monomers
to afford the novel epoxyquinoid dimer epoxytwinol A were carried out, and valuable insight
regarding competitive [4 + 2] and [4 + 4] dimerization processes has been obtained. In addition,
chemical reactivities and structural modifications of epoxyquinol dimers have been evaluated,
including [2 + 2] photocycloaddition and [3,3] sigmatropic rearrangement, indicating the possibility
for production of novel structural diversity from dimeric epoxyquinoid natural product frameworks.
Introduction
Epoxyquinoids represent a large family of natural
products with a wide range of biological activities.1 The
epoxyquinoid family may be divided into two major
classes (Figure 1): (1) epoxyquinones,2 which bear 1,4-
diketone functionality on a cyclohexane epoxide ring, and
(2) epoxyquinols,3 compounds wherein at least one of the
epoxyketone carbonyl groups is transformed to a second-
ary or tertiary alcohol. Notably, epoxyquinoid natural
products exist in both monomeric (2-4, Figure 2) and
dimeric (1, 5-8) forms. The chemical syntheses of
FIGURE 1. General classes of epoxyquinoid natural products.
complex epoxyquinoid natural products (1-8) and de-
rivatives,4 as well as evaluation of their biological proper-
ties,5 have been the subject of considerable investigation
in our laboratory.
(1) For a recent review on biological activities and syntheses of
cyclohexane epoxides, including epoxyquinoids, see: Marco-Contelles,
J.; Molina, M. T.; Anjum, S. Chem. Rev. 2004, 104, 2857.
(2) Torreyanic acid: (a) Lee, J. C.; Strobel, G. A.; Lobkovsky, E.;
Clardy, J. J. Org. Chem. 1996, 61, 3232. Epoxyquinomicins: (b)
Matsumoto, N.; Tsuchida, T.; Umekita, M.; Kinoshita, N.; Iinuma, H.;
Sawa, T.; Hamada, M.; Takeuchi, T. J. Antibiot. 1997, 50, 900.
(3) Manumycin A: (a) Hara, M.; Han, M. Proc. Natl. Acad. Sci.
U.S.A. 1995, 92, 3333. Panepoxydon: (b) Erkel, G.; Anke, T.; Sterner,
O. Biochem. Biophys. Res. Commun. 1996, 226, 214. Cycloepoxydon:
(c) Gehrt, A.; Erkel, G.; Anke, T.; Sterner, O. J. Antibiot. 1998, 51,
455. Panepophenanthrin: (d) Sekizawa, R.; Ikeno, S.; Nakamura, H.;
Naganawa, H.; Matsui, S.; Iinuma, H.; Takeuchi, T. J. Nat. Prod. 2002,
65, 1491.
(4) (a) Li, C.; Lobkovsky, E.; Porco, J. A., Jr. J. Am. Chem. Soc. 2000,
122, 10484. (b) Li, C.; Johnson, R. P.; Porco, J. A., Jr. J. Am. Chem.
Soc. 2003, 125, 5095. (c) Hu, Y.; Li, C.; Kulkarni, B. A.; Strobel, G.;
Lobkovsky, E.; Torczynski, R. M.; Porco, J. A., Jr. Org. Lett. 2001, 3,
1649. (d) Li, C.; Pace, E. A.; Liang, M. C.; Lobkovsky, E.; Gilmore, T.
D.; Porco, J. A., Jr. J. Am. Chem. Soc. 2001, 123, 11308. (e) Lei, X.;
Johnson, R. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2003, 42, 3913.
(f) Li, C.; Bardhan, S.; Pace, E. A.; Liang, M.-C.; Gilmore, T. D.; Porco,
J. A., Jr. Org. Lett. 2002, 4, 3267. (g) Li, C.; Porco, J. A., Jr. J. Am.
Chem. Soc. 2004, 126, 1310.
(5) Liang, M.-C.; Bardhan, S.; Li, C.; Pace, E. A.; Porco, J. A., Jr.;
Gilmore, T. D. Mol. Pharmacol. 2003, 64, 123.
10.1021/jo050897o CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/24/2005
J. Org. Chem. 2005, 70, 6053-6065
6053

Li and Porco, Jr.
FIGURE 2. Representative epoxyquinoid natural products synthesized in our laboratory.
Recently, the polyketides epoxyquinols A (6, Figure 2),
B (7),6 and epoxytwinol A (RKB-3564 D, 8)7 were isolated
by Osada and co-workers and shown to be potent anti-
angiogenesis agents.8 Angiogenesis, the formation of
capillary blood vessels from existing blood vessels,9 occurs
in cancer, chronic inflammation, and atherosclerosis.10
Combined with their novel highly oxygenated, heptacyclic
structures and their potential as probes to elucidate the
basic biological mechanisms of angiogenesis, the ep-
oxyquinols (6 and 7) have attracted immediate attention
in the synthetic community,11 including work in our
laboratory directed toward the syntheses of 6, 7,4f and
the related dimer epoxytwinol A (8).4g In continuation of
our studies toward the synthesis of epoxyquinoid natural
products4 and bioactive analogues,4c,5 herein we present
a full account of our syntheses of epoxyquinol dimers
6-8, including efforts to probe the chemical reactivities
of both epoxyquinol dimers and 2H-pyran precursors.
Synthetic Plan. We recently reported the biomimetic
synthesis12 of torreyanic acid (1), which was highlighted
by oxidation/oxaelectrocyclization13/endo Diels-Alder
dimerization of an epoxyquinone precursor (Figure 3).4a,b
Structural inspection indicates significant similarity
between the frameworks of the dimeric epoxyquinoid
natural products torreyanic acid (1) and epoxyquinol A
(6) (Figure 2).
In contrast to dimer 6, derived from endo [4 + 2]
dimerization of diastereomeric 2H-pyran monomers, ep-
oxyquinol dimer 7 arises from exo Diels-Alder dimer-
ization of two identical epoxyquinol 2H-pyran monomers
(Figure 4). At the outset of our studies, it was unclear
whether monomer 9 would undergo a comparable oxida-
tion/oxaelectrocyclization/Diels-Alder dimerization se-
quence. Epoxytwinol A (8) features a unique 3,8-
dioxatricyclo[4,2,2,22,5]dodeca-9,11-diene ring system,
which presumably arises via [4 + 4] cycloaddition of two
2H-pyran monomers, 10 or 10′. NMR analyses of 8 by
(6) 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.
(7) (a) Osada, H.; Kakeya, H.; Konno, H.; Kanazawa, S. PCT Int.
Appl. 2002, WO 0288137. RKB-3564 D was recently named epoxy-
twinol A: (b) Kakeya, H.; Onose, Rie.; Koshino, H.; Osada, H. Chem.
Commun. 2005, 2575.
(8) Natural products with anti-angiogenesis activity: Fumagillin (a)
Ingber, D.; Fujita, T.; Kishmoto, S.; Sudo, K.; Kanamaru, T.; Brem,
H.; Folkman, J. Nature (London) 1990, 348, 555. Ovalicin (b) Corey,
E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc. 1994, 116,
12109. Borrelidin (c) Wakabayashi, T.; Kageyama, R.; Naruse, N.;
Tsukahara, N.; Funahashi, Y.; Kitoh, K.; Watanabe, Y. J. Antibiot.
1997, 50, 671. Azaspirene (d) Asami, Y.; Kakeya, H.; Onose, R.;
Yoshida, A.; Matsuzaki, H.; Osada, H. Org. Lett. 2002, 4, 2845.
Ageladine A (e) Fujita, M.; Nakao, Y.; Matsunaga, S.; Seiki, M.; Itoh,
Y.; Yamashita, J.; Soest, R. W. M.; Fusetani, N. J. Am. Chem. Soc.
2003, 125, 15700. For a review, see: (f) Paper, D. H. Planta Medica
1998, 64, 686.
(11) (a) Shoji, M.; Yamaguchi, J.; Kakeya, H.; Osada, H.; Hayashi,
Y. Angew. Chem., Int. Ed. 2002, 41, 3192. (b) Shoji, M.; Kishida, S.;
Takeda, M.; Kakeya, H.; Osada, H.; Hayashi, Y. Tetrahedron Lett.
2002, 43, 9155. (c) Mehta, G.; Islam, K. Tetrahedron Lett. 2003, 44,
3569. (d) Shoji, M.; Kishida, S.; Kodera, Y.; Shiina, I.; Kakeya, H.;
Osada, H.; Hayashi, Y. Tetrahedron Lett. 2003, 44, 7205. (e) Shoji, M.;
Imai, H.; Shima, I.; Kakeya, H.; Osada, H.; Hayashi, Y. J. Org. Chem.
2004, 69, 1548. (f) Mehta, G.; Islam, K. Tetrahedron Lett. 2004, 45,
3611. (g) Shoji, M.; Imai, H.; Mukaida, M.; Sakai, K.; Kakeya, H.;
Osada, H.; Hayashi, Y. J. Org. Chem. 2005, 70, 79. (h) Kuwahara, S.;
Imada, S. Tetrahedron Lett. 2005, 46, 547.
(9) Hertig, A. T. Contrib. Embryol. 1935, 25, 37.
(12) Recent review: de la Torre, M. C.; Sierra, M. A. Angew. Chem.,
Int. Ed. 2004, 43, 160.
(10) (a) Kim, K. J.; Li, B.; Winer, J.; Armanini, M.; Gillett, N.;
Phillips, H. S.; Ferrara, N. Nature 1993, 362, 841. (b) Folkman, J. Nat.
Med. 1995, 1, 27. (c) Deplanque, G.; Harris, A. L. Eur. J. Cancer 2000,
36, 1713. (d) Kerbel, R. S. Carcinogenesis 2000, 21, 505.
(13) For a review on valence isomerization of dienones and 2H-
pyrans, see: Krasnaya, Zh. A. Chem. Heterocycl. Compd. 1999, 35,
1255.
6054 J. Org. Chem., Vol. 70, No. 15, 2005

Synthesis of Epoxyquinol A and Related Molecules
FIGURE 3. Biomimetic synthesis of torreyanic acid.
FIGURE 4. Retrosynthetic analysis for epoxyquinols 6-8.
Osada and co-workers7a,b showed seven proton and 10
carbon signals, thus indicating a symmetrical structure.
However, in the preliminary isolation and characteriza-
tion efforts,7a the relative and absolute stereochemistries
of 8 were not assigned. The requisite 2H-pyran monomers
10/10′ for the synthesis of dimers 6-8 may be derived
from selective primary oxidation of 9 followed by 6π-
oxaelectrocyclization of the resulting dienal 11. Ep-
oxyquinol precursor 9 may be prepared from known
chiral, nonracemic intermediate 12 prepared during the
course of our asymmetric synthesis of (-)-cycloepoxydon
(4, Figure 2).4d
(Scheme 1), we planned to install the propenyl side chain
using Stille cross-coupling.14 In our synthesis of torrey-
anic acid (1),4a,b we were able to achieve efficient cross-
coupling of R-substituted epoxyketone 13 and (E)-tribu-
tyl-1-heptenylstannane using Pd(PPh3)4 as catalyst (cf.,
13 f 14, Scheme 1). However, â-diketone 15 was
obtained as the major product (65%) when Pd(PPh3)4 was
employed as catalyst for cross-coupling of 12,15 indicating
that isomerization of the R,â-epoxy ketone to a â-di-
ketone16 is more facile on epoxy ketone substrates lacking
R-substitution. Considering the Lewis basic nature of the
PPh3 ligand, we next employed “ligandless” Stille cou-
pling conditions17 using Pd2dba3 as catalyst, which af-
forded 70-80% of 16 (48 h, 25 mol % of catalyst). Further
improvement using the “accelerating” ligand AsPh318 led
to efficient production of 16 (5% Pd2dba3, 2 h, 98% yield).
Results and Discussion
Preparation of Epoxyquinol Monomer 9. Begin-
ning with the advanced epoxy ketone intermediate 124d
J. Org. Chem, Vol. 70, No. 15, 2005 6055

Li and Porco, Jr.
SCHEME 1. Preparation of Epoxyquinol Monomer Precursorsa
a Reagents and conditions: (a) (E)-tributyl-1-propenylstannane, Pd2dba3, AsPh3, PhCH3, 110 °C, 2 h, 98%; (b) 48% HF, CH3CN, rt, 1
h, 84%; (c) DIBAL-H, THF, -78 °C, 10 min, 9 (72%), 18 (4%).
SCHEME 2. Synthesis of Epoxyquinol Natural Products
Simultaneous deprotection of the cyclic ketal and silyl
ether protecting groups of 16 was accomplished using
aqueous HF/CH3CN to afford chiral, nonracemic quinone
epoxide 17. Epoxyquinol monomer 9 and its diastereomer
18 were obtained in an 18:1 ratio from 17 using a regio-
and diastereoselective reduction with DIBAL-H.4f,19
Synthesis of Epoxyquinols A, B, and RKB-3564 D.
With compound 9 in hand, we next examined a number
of oxidation conditions. Dess-Martin periodinane and
MnO2 were found to oxidize the secondary alcohol of 9.
Notably, MnO2 was used to selectively oxidize the pri-
mary alcohol in the Hayashi synthesis of epoxyquinols
A and B.11a,b,d,e In our hands, use of MnO2 for related
oxidations typically resulted in oxidation of the secondary
alcohol. We thus turned our attention to tetramethylpi-
peridine-based nitroxyl radicals,20 including 2,2,6,6-tet-
ramethyl-1-piperidinyloxy (TEMPO), which have been
employed in chemoselective oxidation of alcohols.21 After
examining a number of TEMPO-based oxidant systems,
we found that the mild condition developed by Semmel-
hack and co-workers (TEMPO, O2, CuCl)22 selectively
oxidized primary alcohol 9 without overoxidation to the
corresponding carboxylic acid and without detectable
oxidation of the secondary alcohol. To our delight, the
crude oxidation product (an equilibrium mixture of 90%
of 10/10′ and 10% of 11 as determined by 1H NMR)
efficiently dimerized in CDCl3 (rt, 30 h) to afford dimers
6 (36%) and 7 (30%) after silica gel chromatography
(Scheme 2). Interestingly, we obtained a higher yield of
endo dimer 6 (55%) and a lesser amount of exo dimer 7
(14%) when the crude oxidation products were dimerized
in 40% aqueous MeOH. This result is consistent with
literature reports on enhancement of endo selectivity in
(14) For a review of the Stille reaction, see: Farina, V.; Krishna-
murthy, V.; Scott, W. J. Org. React. 1997, 50, 1.
(15) See Supporting Information for further details.
(16) Suzuki, M.; Watanabe, A.; Noyori, R. J. Am. Chem. Soc. 1980,
102, 2095.
(17) Williams, D. R.; Myers, B. J.; Mi, L. Org. Lett. 2000, 2, 945.
(18) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585-
9595.
(19) (a) Kiyooka, S.; Kuroda, H.; Shimasaki, Y. Tetrahedron Lett.
1986, 27, 3009. (b) Gautier, E. C. L.; Lewis, N. J.; McKillop, A.; Taylor,
R. J. K. Tetrahedron Lett. 1994, 35, 8759.
(20) For a review, see: de Nooy, A. E. J.; Besemer, A. C.; Bekkum,
H. V. Synthesis 1996, 1153.
6056 J. Org. Chem., Vol. 70, No. 15, 2005

Synthesis of Epoxyquinol A and Related Molecules
TABLE 1. Relative Product Ratios for Dimerization of 10/10′ in Different Solventsa
Relative Product Ratio
epoxyquinol A (6) epoxyquinol B (7)
entry
solvent
10/10′
RKB-3564 D (8)
1
2
3
4
5
6
7
hexane
ND
ND
ND
16
>10
5.2
2.2
10.3
4
3.2
12
6
4.6
1.6
2
1
1
1
1
1
1
1
benzene
4
CH2Cl2
3.5
5
5
2.8
2.1
THF
DMF
MeOH
MeOH/CH2Cl2 (7:100)
a Relative product ratios determined by 1H NMR analysis (reaction time ) 20 h).
SCHEME 3. Dimerization of syn Epoxy Alcohol 2H-Pyransa
a Reagents and conditions: (a) O2 (1 atm), TEMPO, CuCl, DMF, 1 h; (b) CDCl3, 30 min, 19 (26%), 20 (19%).
Diels-Alder reactions using water.23 Using the afore-
mentioned dimerization conditions (40% aqueous MeOH),
we observed the production of <3% of 8. In an effort to
obtain higher overall yields of 8, we examined formation
of dimers 6-8 by systematic evaluation of solvents, as
shown in Table 1. These studies indicated that dimer-
ization of 10/10′ in 14:1 of CH2Cl2:MeOH provided the
highest ratio of [4 + 4] dimer 8 relative to [4 + 2] dimers
6 and 7. Employing this solvent system, we were able to
obtain dimer 8 in an improved overall yield (6-10%).
With the synthetic material obtained from these dimer-
ization experiments, we obtained crystals of both 7 and
8 and established their stereochemistries by X-ray crystal
structure analysis.4f,g,15,24 It is noteworthy that both
natural products 7 (epoxyquinol B) and 8 (RKB-3564 D)
are derived from dimerization of two identical 2H-pyrans.
In the case of 8, a C2-symmetric framework is further
epoxyquinol 9. Fortunately, when a stoichiometric amount
of CuCl and TEMPO was employed, compound 18 was
oxidized smoothly and the resulting intermediate 2H-
pyran dimerized to afford 19 and 20 (Scheme 3). This
result further supports our previously proposed rules for
steric demanding effects in the Diels-Alder dimerization
of 2H-pyran monomers, namely: (i) the methyl groups
of the diene and dienophile tend to orient themselves
away from one another to avoid steric interactions; and
(ii) the dienophile generally approaches the diene anti
to the epoxide moiety.4f
Preparation of a cis-cis Diene Monomer and its
Feasibility as a Precursor to Epoxyquinols A and
B. In our synthetic approach to epoxyquinols A and B,
oxidation precursor 9 (Scheme 2) possesses a trans-cis
diene moiety. Our earlier computational results on a
related epoxyquinone system indicated that a cis-cis
diene may also undergo cyclization to afford a 2H-pyran.4b
We therefore targeted preparation of cis-cis diene mono-
mer 21 and examined its suitability as a substrate for
the oxidation/oxaelectrocyclization/Diels-Alder cascade
process (Scheme 4). The preparation of 21 was initiated
from epoxy ketone 12. Stille cross-coupling of 12 with
tributyl-1-propynylstannane25 afforded alkyne 22, which
was converted to cis-cis diene 23 by Lindlar reduction.
After deprotection of the ketal and silyl ether protecting
groups of 23, diastereoselective reduction of the quinone
epoxide intermediate using DIBAL-H in THF19 generated
anti epoxyquinol 21 (87%). To our delight, 2H-pyrans 10/
10′ were readily obtained by selective oxidation of 21.
Mehta and co-workers have also reported the tandem
oxidation/oxaelectrocyclization/Diels-Alder dimerization
of substrate 21 in their synthesis of epoxyquinols A and
B.11f Interestingly, we observed that the crude reaction
mixture contained 10/10′, trans-cis dienal 11, and cis-
cis dienal 24 in an 8:1:1 ratio (1H NMR, CDCl3). For the
related oxidation of 9 (Scheme 2), we observed ap-
proximately a 9:1 ratio of 10/10′:11, with no detectable
1
supported by H NMR analysis.7 Our structure assign-
ment for dimer 84g was later corroborated by NMR
studies reported by Osada and co-workers.7b
Dimerization of a 2H-Pyran syn Epoxy Alcohol
Monomer. During the reduction of quinone epoxide 17
to epoxyquinol 9 (Scheme 1), the diastereomer of 9, syn
epoxy alcohol 18, was also obtained (4%). To further
understand the structural requirements for 2H-pyran
formation and subsequent Diels-Alder dimerization, we
next studied the selective oxidation of syn epoxyquinol
18. In the event, using catalytic amounts of CuCl and
TEMPO, Semmelhack oxidation22 of 18 was found to
proceed significantly more slowly in comparison to anti
(21) (a) Siedlecka, R.; Skarzewski, J.; Mlochowski, J. Tetrahedron
Lett. 1990, 31, 2177. (b) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre,
J. L. J. Org. Chem. 1996, 61, 7452. (c) De Mico, A.; Margarita, R.;
Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62, 6974.
(d) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3, 3041.
(22) (a) Semmelhack, M. F.; Schmid, C. R.; Cortes, D. A.; Chou, C.
S. J. Am. Chem. Soc. 1984, 106, 3374. For a discussion of the reaction
mechanism, see: (b) Dijksman, A.; Arends, I. W. C. E.; Sheldon, R. A.
Org. Biomol. Chem. 2003, 1, 3232.
(23) Otto, S.; Engberts, J. B. F. N. Pure Appl. Chem. 2000, 72, 1365.
(24) The X-ray crystal structure coordinates for 6 were obtained from
the Cambridge Structural Database (CSD Refcode: MOXHOW).
(25) Warner, B. P.; Buchwald, S. L. J. Org. Chem. 1994, 59, 5822.
J. Org. Chem, Vol. 70, No. 15, 2005 6057

Li and Porco, Jr.
SCHEME 4. Preparation and Oxidation/Oxaelectrocyclization of a cis-cis Diene Precursora
a Reagents and conditions: (a) tributyl-1-propynylstannane, Pd2dba3‚CHCl3, AsPh3, PhCH3, 90 °C, 2 h, 92%; (b) H2, 5% w/w Pd poisoned
with Pb on K2CO3, THF, 93%; (c) 48% HF, CH3CN, rt, 1.5 h, 90%; (d) DIBAL-H, THF, -78 °C, 15 min, 87%; (e) O2 (1 atm), TEMPO, CuCl,
DMF, 1 h.
SCHEME 5. Unexpected Formation of a
Pseudo-Dimera
a Reagents and conditions: (a) DIBAL-H, THF, -78 °C, 15 min;
(b) K-10, CH2Cl2, 5 min, 90% for two steps; (c) 48% HF, CH3CN,
rt, 1 h, 77%; (d) O2 (1 atm), TEMPO, CuCl, DMF, 10 h, 50%; (e)
4-bromobenzoyl chloride, DMAP, Et3N, CH2Cl2, 0 °C, 35 min, 54%.
FIGURE 5. Formation and dimerization properties of related
2H-pyrans.
amount of 24 in the crude reaction mixture, which
indicates a higher activation barrier for retro-6π-electro-
cyclization of 2H-pyrans (10/10′) to cis-cis dienal 24
(Scheme 4). For the related case of epoxyquinone 2H-
pyrans,4b we have calculated the activation barriers from
2H-pyrans to dienals and found that there are signifi-
cantly higher barriers from the 2H-pyrans to a cis-cis
dienal (>20 kcal/mol) relative to a trans-cis dienal (16
kcal/mol).
Preparation and Reactivity of a Stable Isomeric
2H-Pyran. During the course of our studies, we discov-
ered the favored valence isomerization13 of dienals 11 and
24 to 2H-pyrans 10/10′. In our studies directed toward
the synthesis of torreyanic acid (1, Figure 2),4a,b 2H-
pyran-4,5 diones 25/25′ were also found to be favored
relative to the aldehyde valence isomers 26 (Figure 5).
Accordingly, we wished to further investigate the equi-
librium between isomeric dienal 27 and 2H-pyrans 28/
28′, the latter bearing an electron-withdrawing moiety
at the 5-position of the 2H-pyran.26 Since both 2H-pyrans
10/10′ and 25/25′ bear a reactive dienophile, which is
absent in 28/28′, we reasoned that such 2H-pyrans might
be unreactive to Diels-Alder dimerization and, therefore,
stable for isolation and further transformations. Recently,
Hayashi and co-workers reported elegant related studies
in which 2H-pyrans 10/10′ were used as diene compo-
nents in [4 + 2] cycloaddition with a number of
dienophiles.11g
To test this hypothesis, we targeted epoxyquinol 29
(Scheme 5) as a synthetic precursor to regioisomeric 2H-
pyrans of the general structure 28/28′. The synthesis
began with diastereoselective reduction of epoxy ketone
(26) (a) Gosink, T. A. J. Org. Chem. 1974, 39, 1942. (b) Ahluwalia,
V. K.; Rao, J. S. Indian J. Chem., Sect. B. 1989, 28B, 81. (c) Moorhoff,
C. M. Synthesis 1987, 685.
6058 J. Org. Chem., Vol. 70, No. 15, 2005

Synthesis of Epoxyquinol A and Related Molecules
SCHEME 6. Proposed Mechanism for the Formation of Pseudo-Dimer 31
SCHEME 7. Stable Isomeric 2H-Pyran and its Diels-Alder Reactiona
a Reagents and conditions: (a) Dess-Martin periodinane, CH2Cl2, 90%; (b) TCNE (3 equiv), 65 °C, PhCH3/THF (1:1), 2 h, 72%.
16 (Scheme 1), followed by hydrolysis of the cyclic ketal
using montmorillonite K-10 clay,27 to afford epoxyquinol
30, which was converted to 29 by desilylation with
aqueous HF. Simultaneous deprotection of the cyclic
ketal and silyl ether protecting groups using HF was not
applied in this instance due to difficulty in separation of
29 from the hydrolysis product 2,2-diethyl-1,3-pro-
panediol. With alcohol 29 in hand, selective oxidation
using Semmelhack’s conditions (TEMPO, CuCl, O2) was
first evaluated. Surprisingly, the unusual dimeric product
(31) was obtained from this reaction. Unambiguous
structural assignment was achieved by conversion of 31
into p-bromobenzoate 32 followed by single X-ray crystal
analysis.15
Formation of pseudo-dimer 31 may be rationalized by
the general mechanism shown in Scheme 6. Oxonium ion
intermediate 33 may be formed by electrophilic attack28
of the oxoammonium ion (generated by TEMPO/Cu(I))20
to 2H-pyran 34 or 34′, derived from 29 by oxidation/
oxaelectrocyclization. Subsequently, another molecule of
29 may attack 33 to afford acetal intermediate 35, which
may undergo further decomposition29 to afford pseudo-
dimer 31.
4:1 mixture (1:1 after storage, neat) of diastereomers
(Scheme 7). In addition, 2H-pyrans 34/34′ were found to
be stable compounds, and Diels-Alder dimerization was
not observed between these monomers. We next evalu-
ated [4 + 2] reactions between 34/34′ and standard
dienophiles, such as 1,4-benzoquinone and N-benzyl-
maleimide, and found that no [4 + 2] cycloaddition
occurred up to 80 °C in PhCH3 as solvent. Higher reaction
temperatures led to slow decomposition of the 2H-pyran.
However, 34/34′ did undergo Diels-Alder reaction with
the highly reactive dienophile tetracyanoethalene (TCNE,
65 °C)30 to afford cycloadduct 36 (Scheme 7). In this case,
a single diastereomer 36 was isolated in 72% yield, which
suggests facile interconversion of the two diastereomeric
2H-pyrans 34 and 34′ through a dienal intermediate. The
stereochemistry of 36 was confirmed by NOE analysis.15
It is interesting to note that the secondary alcohol of 34/
34′ apparently controls facial selectivity of the Diels-
Alder cycloaddition leading to the formation of 36 as a
single diastereomer.
Improved Synthesis of Epoxytwinol A (RKB-3564
D) and Dimerization of 2H-Pyran Precursors. Even
though solvent optimization afforded up to 6-10% yield
of 8 from dimerization of 10/10′ in CH2Cl2/MeOH (cf.,
Table 1), we also evaluated other conditions reported in
the literature31 for [4 + 4] cycloaddition of dienes,
including photoirradiation and transition metal cataly-
sis,32 in an attempt to afford a higher yield of 8. However,
in all cases tested, no further improvement was observed.
In most reactions, we obtained <10% of 8 from dimer-
According to the general mechanism proposed in
Scheme 6, 2H-pyran intermediates 34/34′ are likely a
synthetic intermediate. Interestingly, oxidation of 29
using Dess-Martin periodinane (1.1 equiv) afforded
epoxyquinoid-fused 2H-pyrans 34/34′ in good yield as a
(27) Gautier, E. C. L.; Graham, A. E.; McKillop, A.; Standen, S. P.;
Taylor, R. J. K. Tetrahedron Lett. 1997, 1881.
(28) For 1,2-addition of oxoammonium salts to electron-rich olefins,
see: Takata, T.; Tsujino, Y.; Nakanishi, S.; Nakamura, K.; Yoshida,
E.; Endo, T. Chem. Lett. 1999, 937.
(30) For Diels-Alder cycloaddition of a 2H-pyran and TCNE, see:
Fischer, G. W.; Zimmermann, T.; Weissenfels, M. Z. Chem. 1981, 21,
260.
(31) For a review on [4 + 4] cycloaddition, see: Sieburth, S. McN.;
Cunard, N. Tetrahedron 1996, 52, 6251.
(29) For decomposition of R-(2,2,6,6-tetramethylpiperidinyloxy)-
ketone to a vic-diketone, see: Liu, Y. C.; Ren, T.; Guo. Q. X. Chin. J.
Chem. 1996, 14, 252.
J. Org. Chem, Vol. 70, No. 15, 2005 6059

Li and Porco, Jr.
SCHEME 8. Synthesis of Stable 2H-Pyrans 39/39′a
a Reagents and conditions: (a) TBDMSCl, imidazole, DMF, 1 h, 97%; (b) TBDPSCl, imidazole, DMF, 4 h, 81%; (c) 48% aq HF, CH3CN,
20 min, 78%; (d) Dess-Martin periodinane, CH2Cl2, 30 min, 100%.
SCHEME 9. Synthesis of Dimethyl Epoxyquinols A and Ba
a Reagents and conditions: (a) Me3O‚BF4, 2,6-di-tert-butyl-4-methylpyridine, CH2Cl2, 3.5 h, 98%; (b) 48% aq HF, CH3CN, 15 min, 98%;
(c) Dess-Martin periodinane, CH2Cl2, 30 min; (d) >4 M in EtOAc, 40 h, 43 (36%), 44 (27%).
ization of 10/10′ along with significant amounts of 6 and
7 (>60% combined yield) due to the facile [4 + 2]
dimerization process. In addition, we found that dimer
8 was not a stable compound and was slowly converted
to 7 at room temperature (<5% conversion in PhCH3, 14
h), which suggested that mild conditions are required for
effective production of dimer 8. Considering the predomi-
nant generation of 6 and 7 from dimerization of 10/10′,
we reasoned that it may be necessary to block the highly
favored [4 + 2] dimerization process. Comparison of the
X-ray crystal structures of natural products 6-815,24
indicates that the secondary alcohol(s) of 6 and 7 are
generally located in more sterically encumbered positions
relative to the corresponding alcohols in dimer 8, which
suggested that installation of a bulky protecting group
on the secondary alcohol of 10/10′ may block formation
of [4 + 2] dimers 6 and 7 and thus favor formation of [4
+ 4] dimer 8. In this regard, tert-butyldimethylsilyl ether
protection of primary alcohol 9 provided 37, which was
further converted to a bissilyl ether with TBDPSCl/
imidazole (Scheme 8). Selective deprotection of the
primary tert-butyldimethylsilyl ether provided oxidation
precursor 38 (62% yield, three steps). In this case,
because there is no possibility for oxidation of the
secondary alcohol, we employed Dess-Martin periodi-
nane to oxidize 38 to the corresponding 2H-pyrans 39/
39′ in nearly quantitative yield. As anticipated, Diels-
Alder dimerization of 39/39′ did not proceed after several
days at room temperature (neat). In addition, the desired
[4 + 4] dimerization of 39/39′ did not occur under various
conditions as described for 10/10′, including thermal,
transition metal catalysis (Ni(0)), and photoirradiation.31
A less sterically encumbered 2H-pyran monomer bear-
ing a secondary methyl ether was next prepared, as
shown in Scheme 9. Methylation of 37 (Me3O‚BF4) cleanly
afforded methyl ether 40, which was desilylated to allylic
alcohol 41 using aqueous HF/CH3CN. Dess-Martin pe-
riodinane oxidation of 41 afforded the corresponding 2H-
pyrans 42/42′, which were found to be stable when stored
at 0 °C for several days. However, in contrast to the
report of Hayashi and co-workers,11e 42/42′ underwent
Diels-Alder dimerization at room temperature slowly (40
h) at high concentration (>4 M in EtOAc) to afford
dimethyl epoxyquinol A (43) and dimethyl epoxyquinol
B (44). Combined with our earlier finding of intramo-
lecular hydrogen bonding in the epoxyquinol B X-ray
structure,4f it is reasonable to suggest that intermolecular
hydrogen bonding may promote the Diels-Alder reaction
to afford dimers of 6 and 7 as also proposed by Hayashi
and co-workers.11e However, the ability of 2H-pyrans,
such as 42/42′, to dimerize to the epoxyquinol framework
indicates that hydrogen bonding is not a strict require-
ment for Diels-Alder dimerization.
On the basis of the observation that no [4 + 4]
dimerization was observed for both secondary alcohol
protected monomers (39/39′ and 42/42′), we reasoned that
the pendant hydroxyl group may somehow facilitate [4
+ 4] dimerization. Further experiments indicated that
dimerization of 10/10′ occurred during silica gel chroma-
tography with slow elution using 2:1 hexane/EtOAc,
leading to improved production of dimer 8 (15%) and
suggesting that [4 + 4] dimerization may be promoted
(32) Ni(0): (a) Wender, P. A.; Tebbe, M. J. Synthesis 1991, 1089.
Pd(0): (b) Murakami, M.; Itami, K.; Ito, Y. Synlett 1999, 951. For a
review of transition metal assisted cycloaddition reactions, see: (c)
Fruharf, H.-W. Chem. Rev. 1997, 97, 523.
6060 J. Org. Chem., Vol. 70, No. 15, 2005

Synthesis of Epoxyquinol A and Related Molecules
SCHEME 10. Alkoxysilanol-Facilitated Synthesis of Dimer 8a
a Reagents and conditions: (a) O2 (1 atm), TEMPO, CuCl, DMF, 1 h; (b) iPr2SiCl2, imidazole, DMF, 15 min, 76% for two steps; (c) neat,
30 h; (d) Et3N‚3HF, THF, 25 min, 40% for two steps.
SCHEME 11. Mechanistic Proposal
by surface silanols33 on silica.34 Combining these consid-
erations, we prepared the novel silanol-protected 2H-
pyrans 45/45′. Due to their facile dimerization, 2H-pyrans
10/10′ were freshly prepared from 9 and immediately
transformed into 45/45′ via a two-step sequence (76%)
(Scheme 10). In contrast to TBDPS-protected 2H-pyrans
39/39′, compounds 45/45′ dimerized smoothly (neat, rt,
30 h) to afford [4 + 4] dimer 46 which after silyl
deprotection afforded RKB-3564 D in an improved overall
yield (40% from 2H-pyrans 45/45′). In this sequence of
transformations, no significant amounts of the [4 + 2]
dimers epoxyquinols A and B (6 and 7) were produced.
[4 + 4] Cycloadditions are electronically forbidden
processes35 and generally require photoirradiation. How-
ever, in our studies, ambient light was excluded during
the dimerization of 10/10′ or 45/45′. In addition, we were
unable to trap any radical intermediates in the [4 + 4]
dimerization of 10/10′ using trapping agents, including
TEMPO and Bu3SnH,36 thus disfavoring a radical mech-
anism. Our initial proposal was that the [4 + 4] process
of 10/10′ and 45/45′ may proceed through a stepwise
mechanism.4g A possible silanol-promoted [4 + 4] process
for 45/45′ is shown in Scheme 11. Two molecules of 45
or 45′ first approach each other by organization facili-
tated by two intermolecular hydrogen bonds. Due to the
electron-rich nature of the oxygen in the 2H-pyran
monomer, zwitterionic intermediate 47 may then be
generated concurrent with C-C bond formation. By
rotation of the newly formed C-C bond, two possible
products may be produced. The less sterically demanding
conformer 47a should afford [4 + 4] dimer 46 through
attack of a dienolate on the oxonium ion. For R ) -Si-
(iPr)2OH, formation of a [4 + 2] dimer precursor to
epoxyquinol B (7) through arrangement 47b should be
disfavored by steric interactions. However, dimerization
of unprotected monomer 10 or 10′ to afford 7 may proceed
through transition state as 47b, which also suggests the
(33) For an excellent review on organosilanols, including hydrogen
bonding, see: (a) Lickiss, P. D. Adv. Inorg. Chem. 1995, 42, 147. (b)
Chandrasekhar, V.; Boomishankar, R.; Nagendran, S. Chem. Rev.
2004, 104, 5847. For an aryldialkylsilanol-directed metalation, see: (c)
Sieburth, S. M.; Fensterbank, L. J. Org. Chem. 1993, 58, 6314.
(34) For examples of silica gel-promoted cycloaddition, see: (a) Leon,
F. M.; Carretero, J. C. Tetrahedron Lett. 1991, 32, 5405. (b) Wang, W.
B.; Roskamp, E. 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. C. Tetrahedron
Lett. 1996, 37, 6955.
(35) (a) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital
Symmetry; Academic Press: New York, 1969. For related [4 + 4]
cyclodimerization of 2,3-dihydroisoquinolines, see: (b) Simig, G.;
Schlosser, M. Tetrahedron Lett. 1994, 35, 3081. (c) Sugiura, M.; Asai,
K.; Hamada, Y.; Hatano, K.; Kurono, Y.; Suezawa, H.; Hirota, M. Chem.
Pharm. Bull. 1998, 46, 1862.
(36) (a) Ding, B.; Bentrude, W. G. J. Am. Chem. Soc. 2003, 125, 3248.
(b) Lin, X.; Stien, D.; Weinreb, S. M. Tetrahedron Lett. 2000, 41, 2333.
J. Org. Chem, Vol. 70, No. 15, 2005 6061

Li and Porco, Jr.
SCHEME 12. Control Experiment Involving Methoxysilane Synthesisa
a Reagents and conditions: (a) O2 (1 atm), TEMPO, CuCl, DMF, 1 h; (b) iPr2SiCl2, imidazole, DMF, 15 min, then quench with methanol,
49/49′ (32.2%), 50 (22%), 45/45′ (20%); (c) neat, 42 h; (d) Et3N‚3HF, THF, 25 min, 33% for two steps.
FIGURE 6. Cope-symmetrical framework of epoxyquinol B; [3,3] sigmatropic framework indicated by blue carbon atoms.
possibility of a stepwise mechanism for exo [4 + 2] dimer
instead of water afforded methoxysilanes 49/49′ in 32%
isolated yield along with 45/45′ (20%) and 50 (22%). The
production of 50 can be explained by intermolecular
formation.37
In the case of 10/10′, a related stepwise mechanism in
the formation of 8 may be imagined involving intermedi-
ate 48 (inset, Scheme 11). For the 2H-pyran silanol
monomers, additional interaction between the Si atoms
and the oxygen anion and carbonyl oxygen may exist in
intermediate 4738 due to the electropositive nature of the
Si atoms facilitated by two Si-O bonds. Further experi-
ments were conducted to test these assumptions and
determine if the silanol moiety was required for hydrogen
bonding.4g As shown in Scheme 12, replacement of the
hydroxyl group of 45/45′ with a methoxy group by
quenching the chlorosilane intermediate with methanol
i
reaction between one molecule of Pr2SiCl2 with two
molecules of 10 followed by exo [4 + 2] cycloaddition. A
small amount of this side product was also found in the
synthesis of 45/45′.39 Interestingly, 2H-pyrans 49/49′ also
dimerized in a similar [4 + 4] fashion to afford 51, which
was further converted to 8 after deprotection. This result
suggests the potential relevancy of transition state 52
(inset, Scheme 12) in which hydrogen bond organization
is not possible.
Thus, a number of secondary alcohol derivatives (39/
39′, 42/42′, 45/45′, and 49/49′) of 2H-pyrans 10/10′ have
been prepared, and different tendencies for dimerization
have been observed. Steric effects seem to play a major
role for [4 + 2] dimerization, as indicated by comparison
(37) (a) Yamashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S. J. Am.
Chem. Soc. 2003, 125, 3793. (b) Danishefsky, S. J.; Larson, E.; Askin,
D.; Kato, N. J. Am. Chem. Soc. 1985, 107, 1246.
(38) For a review on silicon Lewis acid mediated C-C bond forma-
tion, see: Dilman, A. D.; Loffe, S. L. Chem. Rev. 2003, 103, 733.
(39) For an efficient synthesis of 50 and related chemistry, see
Scheme 14.
6062 J. Org. Chem., Vol. 70, No. 15, 2005

Synthesis of Epoxyquinol A and Related Molecules
SCHEME 13. Experimental Support for the Cope-Symmetrical Framework of Epoxyquinol Ba
a Reagents and conditions: (a) Me3O‚BF4, 2,6-di-tert-butyl-4-methylpyridine, CH2Cl2, 4 h, 53 (33%), 54 (62%).
SCHEME 14. Unexpected [2 + 2] Photocycloadditiona
i
a Reagents and conditions: (a) Pr2SiCl2, imidazole, DMF, 3 h, 100%; (b) hν, Pyrex, THF, 40 min, 50%.
of the dimerization of 10/10′, 42/42′, and 39/39′. In
addition, hydrogen bond organization is not required but
may be beneficial for such Diels-Alder dimerization
processes. However, for the [4 + 4] dimerization process,
hydrogen bond organization as indicated by the dimer-
ization of 10/10′ and 45/45′ or related coordinative
interactions40 as indicated by the dimerization of 49/49′
FIGURE 7. Structural relationship between epoxyquinol B
and 45/45′ may play an important role in addition to
steric interactions.
(7) and epoxytwinol A (8).
SCHEME 15
Chemical Reactivity and Structural Modifica-
tions of the Epoxyquinols A and B and Epoxytwinol
A. In our earlier efforts to explore the chemical diversity
of the epoxyquinols,4f two unnatural syn epoxyquinol
dimers were produced by microwave irradiation41 of
epoxyquinol A, while epoxyquinol B was found to be
highly stable, presumably due to intramolecular hydro-
gen bonding. Further examination of the epoxyquinol B
structure revealed that this exo dimeric product pos-
sessed a [3,3] sigmatropic framework and a Cope-sym-
metrical structure; that is, Cope rearrangement of ep-
oxyquinol B is favored by a carbon 3-3′ distance of 3.5
Å and generates itself (Figure 6).
delight, microwave irradiation of either 53 or 54 in THF
(140 °C, 300 W, 20 min) afforded a 3:1 mixture of 53/54,
which thus demonstrated the interconversion between
the two isomers via [3,3] Cope rearrangement.42 A retro
Diels-Alder mechanism is unlikely since we did not
observe other products including epoxyquinol A (6),
epoxyquinol B (7), dimethyl epoxyquinol A (43), and
dimethyl epoxyquinol B (44). However, an alternative
stepwise ionic mechanism proposed by Hayashi and co-
workers cannot be ruled out.11g
To further explore the chemical reactivity of the
epoxyquinols and evaluate [3,3] Cope rearrangement of
the epoxyquinol B core structure, we prepared mono-
methylated epoxyquinols 53 and 54 (Scheme 13) in order
to desymmetrize the sigmatropic framework. To our
(40) For examples of Si-O coordinative interactions, see: (a)
Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432. (b)
Zacuto, M. J.; O’Malley, S. J.; Leighton, J. L. Tetrahedron 2003, 59,
8889.
(41) For select examples of microwave irradiation of natural prod-
ucts, see: (a) Salmoria, G. V.; Dall’Oglio, E. L.; Zucco, C. Synth.
Commun. 1997, 29, 4335. (b) Das, B.; Venkataiah, B. Synth. Commun.
1999, 29, 863. (c) Das, B.; Madhusudhan, P.; Venkataiah, B. Synth.
Commun. 2000, 30, 4001. (d) Das, B.; Venkataiah, B.; Kashinatham,
A. Tetrahedron 1999, 55, 6585. For a recent review of the use of
microwave reactions in modern organic synthesis, see: (e) Kappe, C.
O. Angew. Chem., Int. Ed. 2004, 43, 6250.
Since both dimers of 7 and 8 were obtained from two
identical 2H-pyrans 10 and a 1,3 carbon shift (retention
of stereochemistry)43 may be used to transform 7 into 8
(Figure 7), we next evaluated photoirradiation of 7.
(42) For an example of a microwave-assisted [3,3] sigmatropic
rearrangement (Claisen rearrangement), see: Baxendale, I. R.; Lee,
A.-I.; Ley, S. V. J. Chem. Soc., Perkin Trans. 2002, 1850.
(43) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital
Symmetry; Verlag Chemie: Weinheim, Germany, 1970; p 119.
J. Org. Chem, Vol. 70, No. 15, 2005 6063

Li and Porco, Jr.
SCHEME 16. Two Derivatives of Epoxytwinol Aa
a
Reagents and conditions: (a) 4-BrC6H4COCl, Et3N, DMAP, CH2Cl2, 60 min, 93%; (b) LiEt3BH, THF, -50 to -30 °C, 30 min, 100%.
However, a 1,3 shift failed to occur by UV irradiation of
7 using a 450 W Hanovia lamp (Pyrex filter). During the
course of our preparation of 2H-pyran alkoxysilanols, we
also produced variable amounts of dialkoxysilane 50.
SCHEME 17. Acylation Studies of Epoxyquinols A
and Ba
i
Treatment of epoxyquinol B with Pr2SiCl2 (imidazole,
DMF) provided efficient access to 50 (Scheme 14). Inter-
estingly, photolysis of 50 afforded the C2-symmetric
photocycloaddition product 55,44 which was confirmed by
X-ray crystal structural analysis.15 The propensity of 50
to undergo intramolecular photocycloaddition is consis-
tent with the close proximity between the two olefins in
the scaffold of epoxyquinol B as also evident in the
previously described [3,3] Cope rearrangement studies
(Figure 6 and Scheme 13). Attempted desilylation of 55
(Et3N‚3HF, TBAF/AcOH) provided 7, which indicates
significant ring strain of the bicyclo[2.2.0]hexane ring
system.
In contrast to dimers 6 and 7, as noted previously,
dimer 8 is not a stable compound and is converted slowly
to 7 at room temperature in the dark. This rearrange-
ment was found to be faster in polar solvents. For
example, at a concentration of 8.6 mM, the conversion of
8 to 7 is 5% in PhCH3, 21% in EtOAc, and 59% in MeOH,
respectively, at room temperature (14 h). This solvent
effect supports a possible ionic mechanism for the re-
arrangement, as shown in Scheme 15. Zwitterionic
intermediate 56 may be generated by cleavage of the C1-
C1′ bond facilitated by the electron-rich pyran oxygen.
Additional evidence for the fragility of the C1-C1′ bond
was provided by X-ray structure of 8,15 which shows a
C1-C1′ distance of 1.567 Å, while a typical Csp3 -Csp3
distance is 1.49-1.54 Å. On the other hand, dimer 8 may
be stabilized by two secondary alcohols through delocal-
ization of the electron density of the pyran oxygens by
hydrogen bonding. In the X-ray structure of 8, the
distance between the secondary alcohol and pyran oxygen
is 3.1-3.3 Å, which may be suitable for weak to moderate
intramolecular H-bonding.45 This hydrogen bond stabi-
lization may also explain the relative instability of 8 in
polar solvents. To further support these assumptions and
explore the reactivity of 8, we prepared two derivatives
(Scheme 16). It was found that the bisbromobenzoate
derivative 57 rearranged to the corresponding ep-
oxyquinol B structure 58 significantly faster than 8 to 7.
For example, at 8.6 mM concentration (rt for 14 h), the
conversion of 57 to 58 was 53% in EtOAc compared to
a Reagents and conditions: (a) Ac2O (3 equiv), Et3N, DMAP,
CH2Cl2, 20 min, 95%; (b) Ac2O (3 equiv), Et3N, DMAP, CH2Cl2, 0
°C, 15 min, 61 (78%), 62 (21%); (c) microwave, 300 W, THF, 150
°C, 15 min, 58%.
21% for 8 to 7. The fast transformation of 57 to 58 may
due to the lack of a secondary alcohol to reduce the
electron density of the pyran oxygens. In contrast, tetraol
59, prepared by diastereoselective reduction of 8, was a
stable compound likely due to the absence of the carbonyl
as an electron acceptor, thus eliminating the possibility
for fragmentation of 8 to epoxyquinol B 7 (cf., Scheme
15).
In future work, reporter-tagged versions of the ep-
oxyquinols may be required for molecular target identi-
fication.46 Due to the relative instability of 8, we choose
6 and 7 for evaluation of derivatization reactions. In
principle, there are two functional groups in 6 and 7 that
may be modified. The first involves acylation of the
(44) For [2 + 2] cycloaddition of an enone and vinyl ether, see:
Corey, E. J.; Bass, J. D.; LeMahieu, R.; Mitra, R. B. J. Am. Chem.
Soc. 1964, 86, 5570.
(45) Jeffrey, G. A. An Introduction to Hydrogen Bonding; Oxford
University Press: New York, 1997.
(46) For use of reporter group-tagged versions of a natural product
for identification of molecular targets, see: Adam, G. C.; Vanderwal,
C. D.; Sorensen, E. J.; Cravatt, B. F. Angew. Chem., Int. Ed. 2003, 42,
5480.
6064 J. Org. Chem., Vol. 70, No. 15, 2005

Synthesis of Epoxyquinol A and Related Molecules
SCHEME 18. Alkoxyamine Formationa
alkoxyamine formation should be both regio- and stereo-
selective. In the event, we choose O-benzylhydroxyamine
as a model for oxime formation. To our delight, efficient
condensation was observed between 6 and O-benzylhy-
droxyamine to afford a single oxime diastereomer 64 in
quantitative yield (Scheme 18). However, condensation
between 7 and O-benzylhydroxyamine was found to be
sluggish under the same reaction conditions (25% con-
version after 20 h), presumably due to the lack of
intramolecular H-bonding activation of the carbonyl, as
is the case for 6. However, forcing conditions (microwave,
110 °C, 50 min) afforded a single diastereomeric oxime
product 65 in 68% yield (93% based on recovered starting
material). The successful synthesis of derivatives 64 and
65 thus sets the stage for the preparation of reporter tag-
modified45 derivatives of epoxyquinols A and B for future
molecular target identification studies.
Conclusion
In summary, total syntheses of the angiogenesis in-
hibitors epoxyquinols A (6), B (7), and epoxytwinol A (8)
have been achieved. The relative and absolute stere-
ochemistries of 7 and 8 were confirmed by single-crystal
X-ray structure analysis of synthetic materials. Dimer-
ization of a syn epoxy alcohol 2H-pyran precursor (18)
further reinforced the rules for the Diels-Alder dimer-
ization of 2H-pyrans. A cis-cis diene-bearing 2H-pyran
monomer (21) was found to be a suitable precursor to
epoxyquinols A and B. By alteration of the epoxyquinol
2H-pyran nucleus, the stable isomeric 2H-pyrans 34/34′
were prepared, and their Diels-Alder reactivity toward
reactive dienophiles was evaluated. Extensive studies for
improving the [4 + 4] dimerization of selectively protected
2H-pyran monomers to afford the novel epoxyquinoid
dimer epoxytwinol A were also carried out, which have
provided valuable insight regarding competitive [4 + 2]
and [4 + 4] dimerization processes. In addition, chemical
reactivities and structural modifications of epoxyquinol
dimers have been conducted, including [2 + 2] photocy-
cloaddition and [3,3] sigmatropic rearrangement, indicat-
ing the possibility for production of novel structural
diversity from the natural product frameworks. Contin-
ued studies concerning the chemical synthesis of ep-
oxyquinoid natural products and related molecules are
currently in progress and will be reported in due course.
a Reagents and conditions: (a) BnONH2, EtOAc, AcOH, 1 h,
100%; (b) BnONH2, EtOAc, AcOH, microwave, 110 °C, 50 min,
68% (93% brsm).
secondary alcohols of 6 and 7 with a functionalized
acylating reagent. Alternatively, derivatization of the
carbonyl group may be considered. Acylation of ep-
oxyquinol A (6) was first conducted, as shown in Scheme
17. Monoacylation of the two secondary alcohols in
epoxyquinol A was found to be troublesome. Small
amounts of monoacetylated products along with bisacety-
lated epoxyquinol and recovered starting material were
isolated when 6 was treated with 1.2 equiv of Ac2O.
However, diacylation could be conducted smoothly using
3 equiv of Ac2O to afford bisacetate 60 (95%).
In contrast to epoxyquinol A, monoacylation of ep-
oxyquinol B was found to be facile. Two monoacetates of
epoxyquinol B, 61 and 62, were prepared as shown in
Scheme 17. It is interesting to note that when 3 equiv of
Ac2O was employed, only the monoacetates 61 and 62
were isolated without detection of diacetate products. Not
surprisingly, 61 and 62 are interconvertable under
microwave irradiation (130 °C in THF) due to the facility
of [3,3] sigmatropic rearrangement of the epoxyquinol B
framework (cf., Scheme 13). To our surprise, the novel
caged compound 63 was generated by extended micro-
wave irradiation of either 61 or 62 (150 °C, THF, 300
W). The structure of 63 was determined by X-ray crystal
structure analysis.15 The mechanism for formation of 63
may proceed either through direct intramolecular allylic
displacement of 61 (pathway i, Scheme 17) or via forma-
tion of an oxonium ion intermediate A followed by
electrophilic attack (pathway ii, Scheme 17).
Acknowledgment. Financial support from the
American Cancer Society (RSG-01-135-01, J.A.P, Jr.)
and Bristol Myers-Squibb (Unrestricted Grant in Syn-
thetic Organic Chemistry, J.A.P, Jr.) is gratefully
acknowledged. We thank Prof. James Bobbitt (Univer-
sity of Connecticut) for helpful discussions, Ms. Sujata
Bardhan (Boston University) for experimental assis-
tance, and Dr. Emil Lobkovsky (Cornell University) for
X-ray crystal structure analyses.
Condensation of alkoxyamines with carbonyls is gener-
ally an efficient transformation.47 Considering the dif-
ferent electronic features (one of them is an enone) and
stereochemical environments of the two carbonyl groups
in epoxyquinols A (6) and B (7), we anticipated that
Supporting Information Available: Complete experi-
mental procedures and spectral data for all previously unre-
ported compounds described herein, including X-ray crystal
structure coordinates for 7, 8, 32, 55, and 63. This material is
available free of charge via the Internet at http://pubs.acs.org.
(47) For a review of oxime formation, see: Abele, E.; Lukevics, E.
Org. Prep. Proc. Int. 2000, 32, 235.
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