Expedient stereoselective synthesis of coronafacic acid through intramolecular Diels-Alder cyclization

Article abstract of DOI:10.1021/jo062099j

(Chemical Equation Presented) A stereoselective synthesis of coronafacic acid, a natural component of the phytotoxin coronatin, was achieved using an intramolecular Diels-Alder reaction as the key step. The triene precursor bearing a substituted diene and a vinylketone as dienophile was synthesized and then tested in the thermal intramolecular cyclization. We have devised a new strategy to assemble the E,Z-diene through the stereoselective aldol reaction of an ester enolate followed by a stereoselective dehydration. Following the thermal cyclization, the corresponding hydrindanone thereby obtained with the desired relative stereochemistry could easily be converted into the natural product. The synthesis of the coronafacic acid was accomplished in six steps in 29% overall yield.

Full text of DOI:10.1021/jo062099j

Expedient Stereoselective Synthesis of Coronafacic Acid Through
Intramolecular Diels-Alder Cyclization
Beno ˆı t Moreau, Maryon Ginisty, Dino Alberico, and Andr e´ B. Charette*
D e´ partement de Chimie, UniVersit e´ de Montr e´ al, P.O. Box 6128, Station Downtown, Montr e´ al,
Qu e´ bec, Canada H3C 3J7
andre.charette@umontreal.ca
ReceiVed October 10, 2006
A stereoselective synthesis of coronafacic acid, a natural component of the phytotoxin coronatin, was
achieved using an intramolecular Diels-Alder reaction as the key step. The triene precursor bearing a
substituted diene and a vinylketone as dienophile was synthesized and then tested in the thermal
intramolecular cyclization. We have devised a new strategy to assemble the E,Z-diene through the
stereoselective aldol reaction of an ester enolate followed by a stereoselective dehydration. Following
the thermal cyclization, the corresponding hydrindanone thereby obtained with the desired relative
stereochemistry could easily be converted into the natural product. The synthesis of the coronafacic acid
was accomplished in six steps in 29% overall yield.
Introduction
Isolated back in 1977, coronatin has since attracted the
attention of several synthetic organic chemistry groups. It exists
as two isomers depending upon the recrystallization conditions
that are used. The trans isomer can easily be converted into its
cis isomer through equilibration upon silica treatment. Coro-
natin’s unique structure is composed of two distinct fragments:
coronafacic acid (2), a bicyclic core with three stereogenic
1
Considerable interest has been drawn to coronatin (1), a
natural phytotoxin, due to its unique structure and biological
activities. Coronatin is the most potent phytotoxin of a wide
range of phytotoxic compounds produced by Pseudomonas
syringae, a bacteria that has been abundantly studied and is well
characterized. Pseudomonas syringae is known to induce a
variety of diseases on a number of plants, including leaf spots,
blights and galls. Plant infection by P. syringae induces chlorosis
on Italian rye grass, hypertrophy, root tuberization and cell
expansion on potato (at a concentration of 10 mol/L),
2
7
8
centers, and coronamic acid (3), a cyclopropane amino acid
9
derived from isoleucine (Figure 1). Many research groups have
3
-
7
4
(6) (a) Ferguson, I. B.; Mitchell, R. E. Plant Physiol. 1985, 77, 969-
973. (b) Sakai, R.; Nishiyama, K.; Ichihara, A.; Shiraishi, K.; Sakamura,
S. In Recognition and Specificity in Plant Host-Parasite Interactions; Daly,
J. M., Uritani, I., Eds.; University Park Press: Baltimore, MD, 1979; pp
165-179. (c) V o¨ lksch, B.; Bublitz, F.; Fritsche, W. J. Basic Microbiol.
1989, 29, 463-468.
5
biosynthesis of plant hormone ethylene in tobacco leaves, and
inhibition of cell growth in soy seeds. Moreover, it induces the
biosynthesis of volatile compounds such as ethylene in many
6
plants. Many derivatives possessing different amino acids (Leu,
(7) Coronamic acid synthesis: (a) Adams, L. A.; Aggarwal, V. K.;
Ile, Val) have also been found but are much less active.
Bonnert, R. V.; Bressel, B.; Cox, R. J.; Shepherd, J.; de Vicente, J.; Walter,
M.; Whittingham, W. G.; Winn, C. L. J. Org. Chem. 2003, 68, 9433-
9440. (b) Bertus, P.; Szymoniak, J. J. Org. Chem. 2002, 67, 3965-3968.
(c) Charette, A. B.; C oˆ t e´ , B. J. Am. Chem. Soc. 1995, 117, 12721-12732.
(d) Groth, U.; Halfbrodt, W.; Sch o¨ llkopf, U. Liebigs Ann. Chem. 1992,
351-355.
(8) Asymmetric cyclopropane amino acid synthesis: (a) Davies,
H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M. J. Am. Chem.
Soc. 1996, 118, 6897-6907. (b) Aggarwal, V. K.; de Vincente, J.; Bonnert,
R. V. Org. Lett. 2001, 3, 2785-2788. (c) Moreau, B.; Charette, A. B.
J. Am. Chem. Soc. 2005, 127, 18014-18015.
(9) (a) Parry, R. J.; Mafoti, R. J. Am. Chem. Soc. 1986, 108, 4681-
4682. (b) Parry, R. J.; Lin, M.-H.; Walker, A. E.; Mhaskar, S. J. Am. Chem.
Soc. 1991, 123, 1849-1850.
*
Corresponding author.
(1) Isolation and characterization: Ichihara, A.; Shiraishi, K.; Sato, H.;
Sakamura, S.; Nishiyama, K.; Sakai, R.; Furusaki, A.; Matsumoto, T.
J. Am. Chem. Soc. 1977, 99, 636-637.
(2) Review on Pseudomonas Syringae: Bender, C. L.; Alarc o` n-Chaidez,
F.; Gross, D. C. Microbiol. Mol. Biol. ReV. 1999, 63, 266-292.
3) Gnanamaickam, S. S.; Starratt, A. N.; Ward, E. W. B. Can. J. Bot.
982, 60, 645-650.
4) (a) Koda, Y.; Kikuta, Y.; Tazaki, H.; Sakamura, S.; Yoshihara, T.
(
1
(
Phytochemistry 1991, 30, 1435-1438. (b) Takahashi, K.; Fujino, K.; Kikuta,
Y.; Koda, Y. Plant Sci. 1994, 100, 3-8.
(5) Kenyon, J. S.; Turner, J. G. Plant Physiol. 1992, 100, 219-224.
1
0.1021/jo062099j CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/26/2007
J. Org. Chem. 2007, 72, 1235-1240
1235

Moreau et al.
SCHEME 1
FIGURE 1. Coronatin and its components.
noticed the remarkable structural and functional homology of
coronatin with methyl jasmonate, a growth factor produced by
plants subjected to biological stress.10 Both natural products
induce analogous biological responses in several plants, which
suggests a similar action mode. However, because coronatin
also possesses biological activities different from those of methyl
jasmonate, it does not serve only as a mimic of methyl
SCHEME 2
1
1
jasmonate. It was also found that the coronamic acid is
essential for retaining the biological activity of coronatin.
The synthesis of the bicyclic core of coronatin, the coronafacic
acid, represents a great challenge due to the necessity to control
both the relative and absolute stereochemistry of the three
stereogenic centers. To this day, 14 total syntheses of the
1
2
coronafacic acid have been reported in the literature, as well
13
as a formal synthesis. There are 12 syntheses leading to the
racemic product, one enantioselective synthesis,1
2m
and a
synthesis in which the racemic mixture of an advanced
intermediate was resolved to obtain the two enantiomers
separately.1 In addition to inter- and intramolecular Diels-
Alder cyclization, other methods such as an oxy-Cope rear-
rangement, a cyclopropane ring opening, a Dieckman conden-
sation, a Haller-Bauer-type cleavage, a metathesis, a radical
cyclization, and a conjugated addition have been used as key
steps for the synthesis of the coronafacic acid. In this paper,
we report a total synthesis of (()-coronafacic acid that features
an intramolecular Diels-Alder reaction.
2h
Results and Discussion
The diversity of the approaches that have been used illustrates
the high level of interest generated for the synthesis of this
unique hydrindane skeleton. One of the key elements to consider
is that the synthetic strategy must include a control over the
relative stereochemistry at C3a and C6 centers. This was
accomplished with high selectivity by using an intramolecular
12d,e
Diels-Alder approach (Scheme 1).
In both cases, the triene
precursor was generated at elevated temperatures as part of a
tandem sequence involving a ring opening of an appropriately
substituted cyclobutene. The triene was never isolated, and it
underwent a [4 + 2] cycloaddition to generate the corresponding
hydrindane ring system.
(
10) (a) Sembdner, G.; Parthier, B. Annu. ReV. Plant Physiol. Plant Mol.
Biol. 1993, 44, 569-580. (b) Wasternack, C.; Parthier, B. Trends Plant
Sci. 1997, 2, 302-307. (c) Palmer, D. A.; Bender, C. L. Mol. Plant-
Microbe Interact. 1995, 8, 683-692. (d) Feys, B. J. F.; Benedetti, C. E.;
Penfold, C. N.; Turner, J. G. Plant Cell 1994, 6, 751-759. (e) Greulich,
F.; Yoshihara, T.; Ichihara, A. J. Plant Physiol. 1995, 147, 359-366. (f)
Koda, Y.; Takahashi, K.; Kikuta, Y.; Greulich, F.; Toshima, H.; Ichihara,
A. Phytochemistry 1996, 41, 93-96. (g) Vignutelli, A.; Wasternack, C.;
Apel, K.; Bohlmann, H. Plant J. 1998, 14, 285-295. (h) Weiler, E. W.;
Kutchan, T. M.; Gorba, T.; Brodschelm, W.; Neisel, U.; Bublitz, F. FEBS
Lett. 1994, 345, 9-13.
Our strategy to achieve the synthesis of the coronafacic acid,
with control over the relative stereochemistry, is based on a
similar intramolecular Diels-Alder (IMDA) reaction for the
simultaneous construction of the three stereogenic centers. For
a rapid access to the natural product, the design of an achiral
triene precursor should ideally include a vinyl ketone as
dienophile and a diene bearing an acid under masked form at
the 2-position (Scheme 2). We speculated that access to the
triene would allow us to test the chiral Lewis acid catalyzed
cycloaddition reactions that would lead to the enantioenriched
(
11) Krumm, T.; Bandemer, K.; Boland, W. FEBS Lett. 1995, 377, 523-
29.
12) (a) Ichihara, A.; Kimura, R.; Moryasu, K.; Sakamura, S. Tetrahedron
5
(
Lett. 1977, 18, 4331-4334. (b) Liu, H. J.; Brunet, M. L. Can J. Chem.
1
1
984, 62, 1747. (c) Jung, M. E.; Hudspeth, J. P. J. Am. Chem. Soc. 1980,
02, 2463-2464. (d) Ichihara, A.; Kimura, R.; Moryasu, K.; Sakamura, S.
J. Am. Chem. Soc. 1980, 102, 6353-6355. (e) Jung, M. E.; Halweg, K. M.
Tetrahedron Lett. 1981, 22, 2735-2738. (f) Bhamare, N. K.; Granger, T.;
Macas, T. S.; Yates, P. J. Chem. Soc., Chem. Commun. 1990, 739-740.
14
product. We planned to introduce the vinyl ketone dienophile
moiety at a late stage of the synthesis by oxidation of allylic
(
g) Nakayama, M.; Ohira, S.; Okamura, Y.; Soga, S. Chem. Lett. 1981,
7
31-732. (h) Nakayama, M.; Ohira, S. Agric. Biol. Chem. 1983, 47, 1689-
alcohol 5 (PG ) H). The triene could then come from a
1
690. (i) Tsuji, J. Pure Appl. Chem. 1981, 53, 2371-2378. (j) Mehta, G.;
Praveen, M. J. Chem. Soc., Chem. Commun. 1993, 1573-1575. (k) Hoelder,
S.; Blechert, S. Synlett 1996, 505-506. (l) Nara, S.; Toshima, H.; Ichihara,
A. Tetrahedron Lett. 1996, 37, 6745-6748. (m) Nara, S.; Toshima, H.;
Ichihara, A. Tetrahedron 1997, 53, 9509-9524. (n) Sono, M.; Hashimoto,
A.; Nakashima, K.; Tori, M. Tetrahedron Lett. 2000, 41, 5115-5118.
(14) Catalytic asymmetric Diels-Alder reactions of vinylketones: (a)
Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458-
2460. (b) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002,
124, 9992-9993. (c) Ryu, D. H.; Hawkins, J. M.; Nambu, M.; Loren, S.
Org. Lett. 2003, 5, 4293-4295. (d) Corey, E. J. J. Am. Chem. Soc. 2003,
125, 6388-6390.
(
13) Arai, T.; Sasai, H.; Yamaguchi, K.; Shibazaki, M. J. Am. Chem.
Soc. 1998, 120, 441-442.
1236 J. Org. Chem., Vol. 72, No. 4, 2007

StereoselectiVe Synthesis of Coronafacic Acid
stereoselective dehydration of aldol product 6 obtained from
aldehyde 8 and ester 7.
TABLE 1. Aldol Reaction of Ethyl (3E)-Hex-3-enoate with
Various Aldehydes
Diene Synthesis. We envisioned the synthesis of the Z alkene
by the selective dehydration of a diastereomerically pure aldol
adduct arising from the condensation of â,γ-unsaturated ester
7
with aldehyde 8. As opposed to ketones, the aldol reaction of
15
ester enolates is far less developed. For many years, it has
been assumed that simple esters could not be enolized using a
boron triflate and an amine.1 Lately, the enolization of esters
has been achieved by Abiko17 after careful choice of a boron
triflate coupled with an amine, which allowed for the selective
synthesis of either the syn or anti diastereomer depending upon
conditions. The enolization of a propionate ester with dibutyl-
boron triflate and diisopropylamine at low temperature generated
the Z enolate selectively, which afforded the syn diastereomer
in 95:5 ratio after a reaction with isobutyraldehyde following a
Zimmermann-Traxler transition structure (eq 1).
6
a
Combined yield of both diastereomers. b Ratio determined by H NMR
1
of the crude reaction mixture.
Lewis acid catalyzed reaction proceeds through an open
transition structure.
We wished to use this methodology for the selective synthesis
of an aldol product, which could later be eliminated to form
the unsaturated ester. Unfortunately, the developed conditions
were only reported for the reaction of propionates with isobu-
tyraldehyde. Moreover, since the aldehyde had previously been
used in excess for the study, we had to revisit the reaction
conditions. We began our investigation by the enolization of
ethyl (3E)-hex-3-enoate (11), a â,γ-unsaturated ester, in the
presence of dibutylboron triflate and Hunig’s base to generate
the Z enolate. The stoichiometry of the reagents was adjusted
to allow for the aldehyde to serve as a limiting reagent. When
reacted with isobutyraldehyde, the expected syn diastereomer
aldol product 15a was obtained in good yield (87%) and with
excellent stereocontrol (98:2) (Table 1). Moreover, the integrity
of the E alkene was preserved during the reaction. We then
studied the effect of various aldehydes on the diastereoselectivity
of the aldol reaction. When functionalized aldehyde 12 was used
instead of isobutyraldehyde, a surprising reversal in selectivity
was observed, as the anti adduct was obtained as a major
diastereomer (22:78 syn:anti) in 82% yield (entry 2). This trend
was also observed in the case of an aldehyde 13 that led to a
1
8
For the purpose of the synthesis, we introduced the vinyl
ketone functionality under the masked form of a protected allylic
alcohol. In the case of aldehyde 14, which conveniently allowed
for the deprotection of the acetate under a wide range of
conditions, the aldol product was obtained in 85% yield with
1
3:87 syn:anti selectivity (entry 4). Diastereomers 18a and 18b
were easily separated by flash chromatography.
The selective dehydration of an aldol product in a stereose-
lective fashion would provide the desired Z alkene. Although
typical dehydration procedures often lead to the formation of
the thermodynamic product, the selective dehydration of a
diastereomerically pure aldol product allows for the stereose-
lective synthesis of unsaturated carbonyls. Upon treatment of
an aldol adduct with diethyl azodicarboxylate and triph-
enylphosphine, the anti elimination product was observed.19
A
phosphonium intermediate was first obtained, followed by an
abstraction of the acidic hydrogen accompanied by the elimina-
tion of the triphenylphosphine oxide. Complementarily, the use
of dicyclohexylcarbodiimide with a catalytic copper halide
20
source provided the syn elimination product. In this case, a
18:82 syn:anti ratio (entry 3). The use of butyraldehyde provided
carbamimidate intermediate was formed, which underwent an
intramolecular abstraction of the acidic hydrogen, and the
formation of a urea. These methods proved extremely useful
for the stereoselective synthesis of trisubstituted alkenes.
The selective dehydration of diastereomers 18a and 18b by
different elimination methods would result in a stereoconver-
poorer selectivity (32:68 syn:anti) in favor of the anti diaste-
reomer (entry 5). These results showed that the nature of the
aldehyde has a considerable effect on diastereoselectivity, and
an R-branched aldehyde appeared to be required for high syn
selectivity. Using linear aldehydes, it could be possible that the
(
15) (a) Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am.
(18) An open transition state has been postulated when an excess of boron
triflate is present in the aldol reaction of the boron enolate of an
oxazolidinone: Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org. Chem.
1990, 55, 173-181.
(19) (a) von der Ohe, F.; Br u¨ ckner, R. Tetrahedron Lett. 1998, 39, 1909-
1910. (b) Bradbury, R. H.; Walker, K. A. M. J. Org. Chem. 1983, 48, 1741-
1750.
Chem. Soc. 1989, 111, 5493-5495. (b) Corey, E. J.; Kim, S. S. J. Am.
Chem. Soc. 1990, 112, 4976-4977. (c) Corey, E. J.; Lee, D.-H. Tetrahedron
Lett. 1993, 34, 1737-1740. (d) Ganesan, K.; Brown, H. C. J. Org. Chem.
1
1
994, 59, 2336-2340. (e) Brown, H. C.; Ganesan, K. Tetrahedron Lett.
992, 33, 3421-3424.
(16) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem.
Soc. 1981, 103, 3099-3111.
(20) (a) Corey, E. J.; Andersen, N. H.; Carlson, R. M.; Paust, J.; Vedejs,
E.; Vlatas, I.; Winter, R. E. K. J. Am. Chem. Soc. 1968, 90, 3245-3247.
(b) Alexandre, C.; Rouessac, F. Tetrahedron Lett. 1970, 13, 1011-1012.
(c) Alexandre, C.; Rouessac, F. Bull. Soc. Chim. Fr. 1971, 5, 1837-1842.
(
17) (a) Abiko, A.; Liu, J.-F.; Masamune, S. J. Org. Chem. 1996, 61,
2
590-2591. (b) Inoue, T.; Liu, J.-F.; Buske, D. C.; Abiko, A. J. Org. Chem.
2
002, 67, 5250-5256.
J. Org. Chem, Vol. 72, No. 4, 2007 1237

Moreau et al.
TABLE 2. Diastereoselective Dehydration Reaction
TABLE 3. Thermal Cycloaddition of Triene 24
entry
temp (°C)
solvent
conversion (%)a
1
2
3
4
5
100
120
CD3SOCD3
CD3SOCD3
C6D6
C6D6
C6D6
0
decomp
0
25
>95
135 (sealed tube)
145 (sealed tube)
155 (sealed tube)
a
1
Determined by H NMR using an internal standard.
SCHEME 4
SCHEME 3
gent synthesis of diene E,Z-20. Treatment of anti diastereomer
of the carboxylic acid at C-4. The reduction of both esters with
DIBAL-H afforded corresponding diol 22 in 79% yield (Scheme
3). The protection of the primary alcohol as a TBS ether was
achieved in 88% yield. Finally, the oxidation of alcohol 23 using
PDC provided the desired triene 24 in 42% yield. Although the
triene decomposed slowly over time, it did not undergo
spontaneous cycloaddition reaction.
1
8b with DEAD and PPh3 at -40 °C, afforded the Z isomer in
high yield (88%) and selectivity (97:3), following an anti
elimination pathway (Table 2, entry 1). The dehydration could
also be accomplished at 0 °C; however, a small erosion in the
diastereoselectivity was observed (entry 2). The elimination was
also performed using a phosphonium supported triphenylphos-
2
1
phine reagent 21, which provided the desired product in 71%
yield and a 95:5 Z/E ratio (entry 3). The use of this reagent
was advantageous, since the phosphine oxide side product was
easily precipitated upon ether addition and was removed by
simple filtration.
With triene 24 in hand, we tested the thermal cycloaddition
(
Table 3). The Diels-Alder reaction was first conducted in
1
deuterinated solvent and monitored by H NMR. When the
reaction was performed in DMSO-d6, we observed the degrada-
tion of triene 24 beginning at ca. 120 °C. Under these conditions
only small amounts of cycloadduct 25 could be detected by
NMR. When the reaction was run in benzene-d6 at 145 °C, triene
24 was slowly converted into 25 (25% conversion after 1 h).
Heating the mixture at 155 °C for 1 h led to full consumption
of the starting material, and a significant amount of the desired
product was formed. The relative stereochemistry at C6 and C3a
was trans, resulting from the favored exo cycloaddition.
However, the product epimerized to the desired cis hydrindane
Conversely, syn diastereomer 18a was treated with DCC in
the presence of a catalytic amount of copper chloride, to afford
the desired isomer E,Z-20 exclusively in 86% yield (eq 2).
Products from both diastereoselective dehydrations could then
be combined for the continuation of the synthesis.
2
6 upon purification on silica gel, albeit in low yield (24%).
This epimerization to the more thermodynamically stable cis
isomer has been observed in previous total syntheses.12 The low
isolated yield is due to the thermal unstability of triene 24 that
starts to decompose at temperature lower than the cycloaddition.
Significant improvement in the yield was observed if the
oxidation of the allylic alcohol and the cycloaddition were
We elected to initially examine the synthesis of a Diels-
Alder precursor bearing a protected alcohol as the masked form
(21) Poupon, J.-C.; Boezio, A. A.; Charette, A. B. Angew. Chem., Int.
Ed. 2006, 45, 1415-1420.
1238 J. Org. Chem., Vol. 72, No. 4, 2007

StereoselectiVe Synthesis of Coronafacic Acid
TABLE 4. Intramolecular Diels-Alder Reaction of Triene 29
route, an improved overall yield of 29% in only six steps was
necessary for the synthesis of (()-coronafacic acid (2).
entry
temp (°C)
time
solvent
conversion (%)a
1
2
3
4
5
6
135
145
100
120
140
180
1 h
1 h
1 h
1 h
12 h
5 min
C6D6
C6D6
CD3SOCD3
CD3SOCD3
CD3SOCD3
40
80
30
93
Conclusion
In summary, the stereoselective synthesis of coronafacic acid,
a component of coronatin, was achieved using an intramolecular
Diels-Alder reaction as the key step. We have devised a new
strategy for the construction of trisubstituted alkenes by a two-
step sequence involving a diastereoselective aldol reaction and
a subsequent dehydration. Using this methodology, we devised
a concise synthesis of a triene, which was then cyclized under
thermal conditions to afford the hydrindanone core. Control over
the relative stereochemistry at centers C3a and C6 was success-
fully achieved during the cyclization step. The coronafacic acid
was isolated in 29% overall yield for the six-step sequence. The
development of an asymmetric synthesis of the coronafacic acid
through a chiral Lewis acid catalyzed Diels-Alder reaction
using these trienes is under way and will be reported in due
course.
b
98 (78)
CD3SOCD3/C6D6
96 (78)c
a
1
b
Determined by H NMR. Isolated yield of the cis ring junction product
c
3
1 in parentheses. Microwave irradiation.
SCHEME 5
performed in a one-pot procedure. Under these conditions,
hydrindanone 26 was obtained in an improved yield of 61%
(
Scheme 4).
Experimental Section
Following its thermal cycloaddition, adduct 26 could be
converted into coronafacic acid in a straightforward process
Scheme 4). Deprotection of hydrindanone 26 upon treatment
with TBAF followed by an oxidation led to coronafacic acid
General Procedure for Aldol Reactions of Ethyl (3E)-Hex-
3-enoate with Aldehydes. Ethyl (3E)-hex-3-enoate (5.2 mmol, 1.3
equiv) was dissolved in CH Cl (16 mL), then freshly distilled
2 2
diisopropylethylamine (6 mmol, 1.5 equiv) was added, and the
solution was cooled to -78 °C. Freshly prepared dibutylboron
triflate (5.2 mmol, 1.3 equiv) was slowly added to the solution,
which was then stirred for 2 h at -78 °C. The aldehyde (4 mmol,
(
(2) in 19% overall yield over a seven-step synthesis.
Alternatively, the intramolecular Diels-Alder of triene 29
would lead directly to an ester at C-6 instead of a protected
alcohol. The synthesis of triene 29 simply involved the acetate
deprotection of 20 under mild acidic conditions followed by a
PDC oxidation (Scheme 5).
1
equiv) was dissolved in CH
which was stirred at -78 °C for 1 h, then at 0 °C for an additional
h. Work up: a phosphate buffer solution at pH ) 7 (8 mL) was
2 2
Cl (8 mL) and added to the solution,
1
For the sake of comparison with the reaction involving 24,
the Diels-Alder reaction of triene 29 was initially tested in
benzene-d6. NMR monitoring of the reaction indicated that triene
added along with methanol (12 mL) and hydrogen peroxide (30%
aqueous, 4 mL), and the solution was stirred at room temperature
for 12 h. After this period of time, water was added, and the organic
2
9 was slowly converted into 30 when heated at 135 °C (40%
conversion after 1 h) (Table 4). The conversion increased to
0% when the temperature was raised to 145 °C (entry 2). The
layer was extracted with CH
with brine, dried on Na SO , filtered, and evaporated under reduced
2 2
Cl . The organic layer was washed
2
4
pressure. The residue was purified by flash chromatography on silica
gel to afford separately the diastereomers of the aldol product.
Ethyl (2,3-syn)-6-(Acetyloxy)-2-[(1E)-but-1-enyl]-3-hydroxy-
oct-7-enoate (18a) and Ethyl (2,3-anti)-6-(Acetyloxy)-2-[(1E)-
but-1-enyl]-3-hydroxyoct-7-enoate (18b). Following the general
procedure for aldol reactions using aldehyde 14 (4 mmol) and
purification by flash chromatography on silica gel (20% EtOAc/
hexanes) afforded separately the diastereomers of product 18 as
8
reaction also proceeded well in DMSO-d6, as 30% conversion
was observed within 1 h at 100 °C and 93% conversion at 120
°C after an additional 1 h (entries 3 and 4). The optimal reaction
time and temperature for the cycloaddition were 140 °C for 12
h (entry 5). Under these conditions, the cycloaddition adduct
3
1 was isolated in 78% yield. Alternatively, the reaction could
be carried in a microwave apparatus at 180 °C in a mixture of
DMSO/benzene and was complete after only 5 min (entry 6).
In contrast to triene 24, which underwent cycloaddition at
colorless oils (1.01 g, 85%, 13:87 syn:anti); HRMS (ESI, Pos):
+
calcd for C16
H
26
O
5
Na (M + Na) 321.1673, found 321.1660. 18a:
1
R
f
) 0.23 (20% EtOAc/hexanes); H NMR (400 MHz, CDCl
.81-5.67 (m, 2H, CH dCHCHOAc, CH CHdCHCH), 5.54-5.47
ddd, J ) 15.4, 9.4, 1.4 Hz, 1H, CH CHdCHCH), 5.30-5.15 (m,
H, CH dCHCHOAc), 4.19-4.13 (dq, J ) 7.1, 1.9 Hz, 2H,
CO CH CH ), 3.88-3.82 (m, 1H, CHOH), 2.98-2.95 (dd, J )
.1, 4.7 Hz, 1H, CHCO Et), 2.78-2.67 (b, 1H, OH), 2.11-2.01
m,5H,CHdCHCH CH ,O CCH ),1.89-1.79(m,1H,AcOCHCH
CHOH), 1.71-1.61 (m, 1H, AcOCHCH CH CHOH), 1.55-
3
) δ
5
(
2
2
1
55 °C (>95% conversion), triene 29 reacted at 130 °C (80%
2
conversion). The lower activation energy required for the Diels-
Alder reaction of triene 29 could be explained by the additional
stabilization brought by the ester to the new forming double
bond in the transition state.22 As before, hydrindane 30
epimerized to the cis ring junction product 31 upon purification.
Hydrindanone 31 was hydrolyzed under acidic conditions to
afford coronafacic acid (2) in 92% yield (eq 3). Following this
3
2
2
2
3
9
(
2
2
3
2
3
2
-
CH
2
2
2
1.35 (m, 2H. AcOCHCH CH CHOH), 1.29-1.24 (t, J ) 7.1 Hz,
2
2
3H, CO
2
CH
C NMR (100 MHz, CDCl
21.9, 116.9, 116.8, 74.7, 74.3, 71.1, 70.9, 60.9, 54.8, 54.7, 30.3,
2
CH
3
), 1.02-0.98 (t, J ) 7.4 Hz, 3H, CHdCHCH
2 3
CH );
1
3
3
) δ 173.8, 170.3, 138.9, 136.3, 136.2,
1
(22) Spino, C.; Pesant, M.; Dory, Y. Angew. Chem., Int. Ed. 1998, 37,
3
262-3266.
30.1, 29.5, 29.3, 25.7, 21.2, 14.1, 13.5; IR (neat) 3456, 2961, 2934,
J. Org. Chem, Vol. 72, No. 4, 2007 1239

Moreau et al.
-
1
1
731 (CdO), 1371, 1236, 1021 cm . 18b: R
f
) 0.18 (20% EtOAc/
) δ 5.78-5.65 (m, 2H, CH
CHdCHCH), 5.42-5.33 (ddd, J ) 15.3, 9.1, 1.6
CHdCHCH), 5.25-5.15 (m, 3H, CH dCHCHOAc),
.21-4.13 (dq, J ) 7.1, 1.9 Hz, 2H, CO CH CH ), 3.80-3.77 (m,
H, CHOH), 3.03-2.98 (t, J ) 7.7 Hz, 1H, CHCO Et), 2.7-2.5
CH CHdCH, O CCH ),
CHOH), 1.72-1.53 (m, 2H,
CH-OH, AcO-CHCH CH CH-OH), 1.39-
.34 (m, 1H, AcO-CHCH CH CH-OH), 1.29-1.24 (t, J ) 7.1
Hz, 3H, CO CH CH ), 1.00-0.95 (t, J ) 7.4 Hz, 3H, CHd
); 1 C NMR (75 MHz, CDCl
) δ 138.0, 136.7, 136.6,
23.5, 117.4, 117.2, 75.2, 74.7, 72.7, 72.5, 61.3, 56.3, 56.1, 30.6,
0.4, 30.3, 26.0, 21.6, 14.6, 13.8; IR (neat) 3487 (O-H), 2963,
(5 mg, 0.016 mmol) was dissolved in C
6
D
6
(1 mL) in a sealed
1
hexanes); H NMR (300 MHz, CDCl
CHCHOAc, CH
Hz, 1H, CH
3
2
d
tube, and then the solution was warmed to 155 °C for 3 h. Work
up: the solvent was evaporated under reduced pressure, and then
the residue was purified by flash chromatography on silica gel (5%
EtOAc/hexanes) to afford product 26 as a colorless oil (1.2 mg,
2
2
2
4
1
(
2
2
3
1
2
24%). R ) 0.35 (5% EtOAc/hexanes); H NMR (400 MHz, CDCl )
f
3
b, 1H, OH), 2.07-2.00 (m, 5H, CH
3
2
2
3
δ 5.63-5.59 (b, 1H), 4.24-4.09 (m, 2H), 2.8-2.71 (m, 1H), 2.49-
1
.86-1.82 (m, 1H, AcOCHCH
2 2
CH
2
1
0
1
.17 (m, 3H), 2.09-1.88 (m, 2H) 1.86-1.80 (dt, J ) 12.4, 4.1 Hz,
AcO-CHCH
1
2
CH
2
2
2
H), 1.66-1.49 (m, 1H), 1.44-1.23 (m, 2H), 1.10-0.99 (m, 1H),
13
2
2
.92 (s, 9H), 0.08 (s, 6H); C NMR (100 MHz, CDCl
3
) δ 221.5,
2
2
3
38.0, 127.1, 65.7, 47.0, 38.2, 37.1, 36.7, 28.7, 27.5, 27.2, 25.9
3
CHCH
2
CH
3
3
(
3C), 18.4, 11.1, -5.3, -5.4; IR (neat) 2956, 2927, 2855 1743 (Cd
1
3
1
-1
O), 1462, 1253, 1137, 1069, 836, 775 cm ; HRMS (ESI, Pos):
+
calcd for C18
also C18
3a,6-trans;3a,7a-cis)-4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-
-ethyl-2,3,3a,6,7,7a-hexahydro-1H-inden-1-one (26). Optimized
H
33
O
Si
2 1
(M + H) 309.2244, found 309.2255 (100%);
-
1
738 (CdO), 1241 cm
.
+
H O Si Na (M + Na) 331.2064, found 331.2075 (60%).
32 2 1
Ethyl (2Z)-6-(Acetyloxy)-2-[(1E)-but-1-enyl]octa-2,7-dienoate
20). Alcohol 18a (385 mg, 1.29 mmol) was dissolved in toluene
10 mL), DCC (400 mg, 1.94 mmol), CuBr (19 mg, 0.13 mmol),
and molecular sieves (about 200 mg) were added at once, and the
(
(
(
6
Procedure: Tandem Oxidation and Cyclization. Triene 23 (97
mg, 0.313 mmol) was dissolved in toluene (10 mL) in a Schlenk
flask, PDC (176 mg, 0.469 mmol) was added, and the solution was
heated to 155 °C for 4 h. Work up: the solvent was evaporated
under reduced pressure, and then the residue was purified by flash
chromatography on silica gel (5% EtOAc/hexanes) to afford product
solution was warmed to 80 °C and stirred at this temperature for
1
5 h. Work up: the solution was filtered on Celite then washed
with brine. The organic layer was extracted with EtOAc, dried on
MgSO , filtered, and evaporated under reduced pressure. The
residue was purified by flash chromatography on silica gel (10%
EtOAc/hexanes) to afford product 20 as a colorless oil (311 mg,
4
2
6 as a colorless oil (59 mg, 61%). R
f
) 0.35 (5% EtOAc/hexanes);
) δ 5.63-5.59 (bs, 1H), 4.24-4.09 (m,
H), 2.80-2.71 (m, 1H), 2.49-2.17 (m, 3H), 2.09-1.88 (m, 2H)
.86-1.80 (dt, J ) 12.4, 4.1 Hz, 1H), 1.66-1.49 (m, 1H), 1.44-
1
1
H NMR (400 MHz, CDCl
3
8
6%, Z isomer exclusively). R
f
) 0.30 (10% EtOAc/hexanes); H
) δ 6.03-5.97 (d, J ) 16 Hz, 1H,
dCHCHOAc, CH CHd
dCHCHOAc), 4.31-4.24 (q, J
), 2.31-2.23 (m, 2H, CH CHdCCO
CH CHdCH), 2.06 (s, 3H, O CCH
.81-1.69 (m, 2H, AcO-CHCH ), 1.36-1.31 (t, J ) 7.4 Hz, 3H,
CH CH ), 1.03-0.98 (t, J ) 7.3 Hz, 3H, CHdCHCH CH );
C NMR (100 MHz, CDCl ) δ 170.7, 168.4, 136.4, 134.8, 134.6,
34.2, 127.0, 117.4, 74.6, 61.0, 34.0, 26.3, 25.8, 21.6, 14.7, 13.7;
2
1
1
NMR (400 MHz, CDCl
3
CHCCO
CHCH), 5.28-5.15 (m, 3H, CH
7.4 Hz, 2H, CO CH CH
Et), 2.16-2.06 (m, 2H, CH
2
Et), 5.82-5.69 (m, 3H, CH
2
2
1
3
.23 (m, 2H), 1.10-0.99 (m, 1H), 0.92 (s, 9H), 0.08 (s, 6H);
) δ 221.5, 138.0, 127.1, 65.7, 47.0, 38.2,
7.1, 36.7, 28.7, 27.5, 27.2, 25.9 (3C), 18.4, 11.1, -5.3, -5.4; IR
(neat) 2956, 2927, 2855, 1743 (CdO), 1462, 1253, 1137, 1069,
C
2
NMR (100 MHz, CDCl
3
3
)
2
2
3
2
2
-
3
),
3
2
2
1
2
-
1
CO
2
2
3
2
3
836, 775 cm ; HRMS (ESI, Pos): calcd for C18
H) 309.2244, found 309.2255 (100%); also C18
Na) 331.2064, found 331.2075 (60%).
H
33
O
2
Si
1
(M +
13
+
H
32
O
2
Si
1
Na (M +
3
+
1
IR (neat) 2964, 2934, 1735 (CdO), 1731 (CdO), 1372, 1233 (Cd
Ethyl (3a,6-trans;3a,7a-cis)-6-Ethyl-1-oxo-2,3,3a,6,7,7a-hexahy-
dro-1H-indene-4-carboxylate (31). Triene 29 (30 mg, 0.127 mmol)
was dissolved in benzene (1 mL) and DMSO (1 mL) in a sealed
tube, and then the solution was heated to 180 °C for 5 min in a
microwave apparatus. NMR monitoring of the reaction indicated
that 30 was initially formed by complete epimerization to 31 upon
purification. Work up: the solvent was evaporated under reduced
pressure, and then the residue was purified by flash chromatography
-1
C), 1154, 1021, 963 cm ; HRMS (ESI, Pos): calcd for C16
H
H
24
O
4
-
4
+
Na (M + Na) 303.1567, found 303.1558 (100%); also C16
25
O
+
(
M + H) 281.1747, found 281.1734 (5%).
Ethyl (2Z)-6-(Acetyloxy)-2-[(1E)-but-1-enyl]octa-2,7-dienoate
20). Alcohol 18b (193 mg, 0.65 mmol) was dissolved in THF (3.2
(
mL), PPh
cooled to -40 °C. DEAD (225 mg, 1.29 mmol) was added dropwise
to the solution, which was stirred for 3 h. Work up: NaHCO
saturated aqueous solution) was added, and the organic layer was
extracted with CH Cl and then washed with brine. The organic
layer was dried on Na SO , filtered, and evaporated under reduced
3
(338 mg, 1.29 mmol) was added, and the solution was
3
on silica gel (10% EtOAc/hexanes) to afford product 31 as a
(
1
colorless oil (23.4 mg, 78%). R
NMR (400 MHz, CDCl ) δ 6.93-6.91 (bs, 1H, H
m, 2H, CO CH CH ), 3.13-3.05 (m, 1H, H3a), 2.61-2.53 (m, 1H,
), 2.44-2.25 (m, 3H, H (2H), H7a), 2.23-2.14 (m, 1H, H ),
.89-1.84 (dt, J ) 12.7, 5 Hz, 1H, H ), 1.64-1.47 (m, 2H, CHCH
CH , H ), 1.45-1.37 (m, 1H, CHCH CH ), 1.34-1.30 (t, J ) 7
Hz, 3H, CO CH CH ), 1.12-1.02 (m, 1H, H ), 1.00-0.96 (t, J )
.5 Hz, 3H, CHCH CH ). Product was identical in all respects to
f
) 0.25 (10% EtOAc/hexanes); H
2
2
3
5
), 4.30-4.16
2
4
(
2
2
3
pressure. The residue was purified by flash chromatography on silica
gel (10% EtOAc/hexanes) to afford product 20 as a colorless oil
H
3
2
6
1
7
2
-
1
(
160 mg, 88%, 97:3 Z/E). R
NMR (400 MHz, CDCl
CHCCO Et), 5.82-5.69 (m, 3H, CH
CHCH), 5.28-5.15 (m, 3H, CH dCHCHOAc), 4.31-4.24 (q,
J ) 7.4 Hz, 2H, CO CH CH ), 2.31-2.23 (m, 2H, CH CHdCCO
Et), 2.16-2.06 (m, 2H, CH CH CHdCH), 2.06 (s, 3H, O CCH
.81-1.69 (m, 2H, AcO-CHCH ), 1.36-1.31 (t, J ) 7.4 Hz, 3H,
CH CH ), 1.03-0.98 (t, J ) 7.3 Hz, 3H, CHdCHCH CH );
C NMR (100 MHz, CDCl ) δ 170.7, 168.4, 136.4, 134.8, 134.6,
34.2, 127.0, 117.4, 74.6, 61.0, 34.0, 26.3, 25.8, 21.6, 14.7, 13.7;
f
) 0.30 (10% EtOAc/hexanes); H
3
3
2
3
3
) δ 6.03-5.97 (d, J ) 16 Hz, 1H,
dCHCHOAc, CH CHd
2
2
3
7
2
2
2
7
2
2m
3
2
1
authentic material.
2
2
3
2
2
-
3
2
2
3
),
1
2
Acknowledgment. This work was supported by NSERC
(Canada) and the Universit e´ de Montr e´ al. B.M. is grateful to
Boehringer Ingelheim for postgraduate fellowship.
CO
2
2
3
2
3
1
3
3
1
IR (neat) 2964, 2934, 1735 (CdO), 1731 (CdO), 1372, 1233 (Cd
Supporting Information Available: Experimental procedures
for the preparation of all the compounds and characterization data
for each reaction and detailed structural assignment. This material
is available free of charge via the Internet at http://pubs.acs.org.
-1
C), 1154, 1021, 963 cm ; HRMS (ESI, Pos): calcd for C16
H
H
24
O
4
-
4
+
Na (M + Na) 303.1567, found 303.1558 (100%); also C16
25
O
+
(
M + H) 281.1747, found 281.1734 (5%).
(3a,6-trans;3a,7a-cis)-4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-
6-ethyl-2,3,3a,6,7,7a-hexahydro-1H-inden-1-one (26). Triene 24
JO062099J
1240 J. Org. Chem., Vol. 72, No. 4, 2007