Intramolecular Diels-Alder reactions using α-methylene lactones as dienophile

Article abstract of DOI:10.1021/jo016116a

Several dienals were prepared and reacted in the presence of zinc metal with ethyl 2-bromomethylacrylate to provide in a Reformatsky-like reaction α-methylene lactones carrying a dienyl side chain. Thermolysis of these compounds (11, 21, 29, and 37) gave in an intramolecular Diels-Alder reaction the corresponding tricyclic cycloadducts (51, 52, 53, and 54). The cycloadditions took place with good diastereoselectivity and yields. The stereochemistry of the major isomer is in accordance with an endo transition state for cycloadducts 51, 52, and 54. In one instance (compound 58), the structure was supported by X-ray crystallography. In contrast to the other substrates, the nonatriene 29 cyclized to the exo product 53exo. The stereochemical situation could also be proven by NOESY NMR. However, the intramolecular Diels-Alder reaction did not work with furan as dienophile (compound 41) and substrate 50 featuring a densely functionalized tether connecting diene and α-methylene lactone.

Full text of DOI:10.1021/jo016116a

2474
J . Org. Chem. 2002, 67, 2474-2480
In tr a m olecu la r Diels-Ald er Rea ction s Usin g r-Meth ylen e
La cton es a s Dien op h ile
Frank Richter,† Matthias Bauer,† Caroline Perez,† Ca¨cilia Maichle-Mo¨ssmer,‡ and
Martin E. Maier*,†
Institut fu¨r Organische Chemie and Institut fu¨r Anorganische Chemie, Universita¨t Tu¨bingen,
Auf der Morgenstelle 18, D-72076 Tu¨bingen, Germany
martin.e.maier@uni-tuebingen.de
Received September 13, 2001
Several dienals were prepared and reacted in the presence of zinc metal with ethyl 2-bromo-
methylacrylate to provide in a Reformatsky-like reaction R-methylene lactones carrying a dienyl
side chain. Thermolysis of these compounds (11, 21, 29, and 37) gave in an intramolecular Diels-
Alder reaction the corresponding tricyclic cycloadducts (51, 52, 53, and 54). The cycloadditions
took place with good diastereoselectivity and yields. The stereochemistry of the major isomer is in
accordance with an endo transition state for cycloadducts 51, 52, and 54. In one instance (compound
58), the structure was supported by X-ray crystallography. In contrast to the other substrates, the
nonatriene 29 cyclized to the exo product 53exo. The stereochemical situation could also be proven
by NOESY NMR. However, the intramolecular Diels-Alder reaction did not work with furan as
dienophile (compound 41) and substrate 50 featuring a densely functionalized tether connecting
diene and R-methylene lactone.
In tr od u ction
Among the methods for the creation of polycyclic ring
systems, the intramolecular Diels-Alder reaction oc-
cupies a dominant role. This has to do with the fact that
the number of rings increases by two in the cycloaddition
step. In many cases, the reaction is highly stereoselective.
Over the years, a large variety of substrates for the
intramolecular Diels-Alder reaction have been studied.1-5
Thus, there might be one or more stereocenters in the
chain connecting the diene and dienophile. Furthermore,
the diene, part of the diene, or the dienophile might be
part of a ring. Then there can be a ring in the connecting
chain. Other variables include the attachment of the
tether at the diene (type 1 vs type 2) and the inclusion
of heteroatoms in the reacting π-bonds. Owing to its
synthetic power, the intramolecular Diels-Alder reaction
has been a cornerstone in many natural product synthe-
ses.6 However, this powerful strategy can have its
problems. For example, the preparation of the substrate
is often a difficult undertaking. Another point is that the
stereochemical outcome of an intramolecular Diels-Alder
reaction sometimes is difficult to predict without the
assistance of molecular modeling.7-9 For certain sub-
F igu r e 1. Polycyclic natural products with a quaternary
brigdehead center.
strates, however, some general rules could be deduced.3
A particular challenge from a synthetic point of view is
represented by polycyclic compounds with a quaternary
bridgehead center at the fusion point of two rings. If one
of the rings is a cyclohexane, a Diels-Alder approach can
be envisioned. Figure 1 lists some representative natural
products that show this structural feature.
† Institut fu¨r Organische Chemie.
‡ Institut fu¨r Anorganische Chemie.
(1) Ciganek, E. Org. React. 1984, 32, 1-374.
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864-894; Angew. Chem., Int. Ed. 2001, 40, 820-849.
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Angew. Chem. 2000, 112, 46-126; Angew. Chem., Int. Ed. 2000, 39,
44-122.
These include the antitumor compound Taxol10 or the
labdane diterpene forskolin,11-14 an activator of adenylate
(9) Tantillo, D.; Houk, K. N.; J ung, M. E. J . Org. Chem. 2001, 66,
1938-1940.
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1988, 110, 3672-3673.
10.1021/jo016116a CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/26/2002

Intramolecular Diels-Alder Reactions of R-Methylene Lactones
J . Org. Chem., Vol. 67, No. 8, 2002 2475
Sch em e 1. P r eviou sly Rep or ted Exa m p le for a n
In tr a m olecu la r Diels-Ald er Rea ction of a n
r-Meth ylen e La cton e
Sch em e 2. Syn th esis of Su bstr a te 11 Ca r r yin g a
gem -Dim eth yl Su bstitu en t Next to th e Dien e
F igu r e 2. Angular methyl groups by intramolecular Diels-
Alder reactions.
cyclase. Another interesting molecule is akaterpin, which
functions as a selective inhibitor of phosphatidylinositol-
specific phospholipase C.15 As has been demonstrated
with forskolin, the angular methyl group can be built into
the decalin system via an intramolecular Diels-Alder
reaction. The methyl group can be attached to either the
diene or the dienophile. For example, in the Corey
synthesis of forskolin, the methyl group is attached to
the diene, whereas Ikegami chose to put it on the
dienophile (Figure 2). In the case of Taxol, several
intramolecular Diels-Alder have been pursued; however,
none of them has ultimately led to the target molecule.16
If the angular substituent is a carboxylic group, then
the intramolecular Diels-Alder approach is even more
obvious. The drimane-type sequiterpenes mniopetal E
and kuehneromycin A can be mentioned as examples
(Figure 1). The mniopetals were isolated in 1994 by
Steglich et al. and found to be inhibitors of reverse
transcriptase.17 A similar activity was reported for kue-
hneromycin A. Very recently, total syntheses for kueh-
neromycin A,18 mniopetal F,19 and mniopetal E20 based
on intramolecular Diels-Alder strategies were achieved
by J auch and Tadano. In these cases, the dienophile is a
butenolide. Alternatively, the angular carboxylic group
might be connected to a hydroxyl group at the tether
connecting diene and dienophile. In the simplest setting,
this corresponds to an intramolecular Diels-Alder reac-
tion of an R-methylene lactone with an attached dienyl
residue. We recently communicated an example for such
a reaction (Scheme 1).21 Thus, the thermolysis of 1 led
with a selectivity of 6:1 to the cycloadduct 2.
With a view toward delineating the scope of this
reaction and its potential application in natural products
chemistry, we examined more substrates. The results of
this study are presented in this paper.
Resu lts a n d Discu ssion
Syn th esis of th e Tr ien e Su bstr a tes. A certain
advantage is the fact that R-methylene lactones are easily
available from aldehydes by a Reformatsky-type reaction
of ethyl 2-bromomethylacrylate22,23 in the presence of zinc
or some other metal.24,25 It should be noted that this
process also can be done in an asymmetric manner. Thus,
the synthetic challenge is basically reduced to the
synthesis of diene-containing alcohols. Depending on the
distance between the alcohol function, the type of sub-
stituents at the tether, and the terminal position of the
diene, several routes to the advanced substrates were
followed. We first targeted some 4-dien-1-ols. Starting
from crotonal, a Reformatsky reaction with methyl R-bro-
moisobutyrate gave the 3-hydroxy ester 3. Treatment of
3 with phosphorus pentoxide gave the dienoate 4.26
Following reduction with lithium aluminum hydride, the
dienol 5 was produced (Scheme 2). The synthesis con-
tinued with the Swern oxidation27 of alcohol 5 giving the
(13) Hashimoto, S.-i.; Sakata, S.; Sonegawa, M.; Ikegami, S. J . Am.
Chem. Soc. 1988, 110, 3670-3672.
(14) Hanna, I.; Wlodyka, P. J . Org. Chem. 1997, 62, 6985-6990.
(15) Kawai, N.; Fujibayashi, Y.; Kuwabara, S.; Takao, K.-i.; Ijuin,
Y.; Kobayashi, S. Tetrahedron 2000, 56, 6467-6478.
(16) Winkler, J . D.; Kim, H. S.; Kim, S.; Ando, K.; Houk, K. N. J .
Org. Chem. 1997, 62, 2957-2962.
(17) Velten, R.; Klostermeyer, D.; Steffan, B.; Steglich, W.; Kuschel,
A.; Anke, T. J . Antibiot. 1994, 47, 1017-1024.
(21) Maier, M. E.; Perez, C. Synlett 1998, 159-160.
(22) Villieras, J .; Rambaud, M. Synthesis 1982, 924-926.
(23) Villieras, J .; Rambaud, M. Org. Synth. 1987, 66, 220-224.
(24) Fu¨rstner, A. Synthesis 1989, 571-590.
(25) Hanessian, S.; Park, H.; Yang, R.-Y. Synlett 1997, 351-352.
(26) Bigley, D. B.; Weatherhead, R. H. J . Chem. Soc., Perkin Trans.
2 1976, 704-706.
(18) J auch, J . Angew. Chem. 2000, 112, 2874-2875; Angew. Chem.,
Int. Ed. 2000, 39, 2764-2765.
(19) J auch, J . Eur. J . Org. Chem. 2001, 473-476.
(20) Suzuki, Y.; Nishimaki, R.; Ishikawa, M.; Murata, T.; Takao,
K.-i.; Tadano, K.-i. J . Org. Chem. 2000, 65, 8595-8607.

2476 J . Org. Chem., Vol. 67, No. 8, 2002
Richter et al.
Sch em e 4. Syn th esis of Su bstr a te 29
Sch em e 3. Syn th esis of Su bstr a te 21 F ea tu r in g a
Disu bstitu ted Dien e
aldehyde 6. This aldehyde was subjected to a Wittig
reaction with the ylide derived from (methoxymethyl)-
triphenylphosphonium chloride. This step resulted in the
formation of the separable enol ethers 7Z and 7E (ratio
) 4:1). However, it proved to be limiting in that the yields
were moderate. Hydrolysis of the mixture provided the
somewhat labile aldehyde 8. This was used as such in
the subsequent Reformatsky reaction, which delivered
the alcohol 10 in reasonable yield. The lactonization of
10 to the R-methylene lactone 11 was performed with a
suspension of sodium hydride in THF. The acrylate of
type 10 and the R-methylene lactones are prone to
polymerization. This could be suppressed by adding
hydroquinone to solutions of these compounds. The
diastereotopic nature of the methylene and methyl
groups in compound 11 is clearly evident from the NMR
spectra. For example, the methyl groups are separated
by 0.05 ppm and the H-4 protons appear as multiplets
at δ ) 2.51 and 3.00, respectively.
Due to the biosynthetic pathways, decalin-ontaining
terpenes are characterized by the presence of a gem-
dimethyl group next to a bridgehead atom. Another issue
is the substitutent at the terminal position of the diene.
In this regard, a hydroxymethyl group is of interest as a
precursor for an aldehyde group that is found in the
mnipetals and kuehneromycin A. The synthesis of a
corresponding diene began with the reduction of 2,2-
dimethylsuccinic acid to the diol 12. A selective mono-
protection of the less hindered primary hydroxy group
was achieved with triisopropylsilyl chloride in dimeth-
ylformamide (Scheme 3). Oxidation of the alcohol 13
provided the aldehyde 14, which was extended via a
Wittig-Horner reaction with ethyl 4-(diethylphosphono)-
crotonate28 to the dienoate 16. The conditions put forward
by Takacs et al.29 turned out to be advantageous with
regard to yield and isomeric purity of the double bonds.
The ester 16 was reduced to the alcohol with DIBAH.
Protection of the hydroxyl group as a methoxyethoxy-
methyl ether furnished the protected diene-diol 18.
Removal of the silyl protecting group of 18 gave the
alcohol 19. Oxidation of 19 with the Dess-Martin perio-
dinane30,31
provided the aldehyde 20, which was con-
verted to the R-methylenelactone 21 by a Reformatsky
reaction with 9 to give the intermediate hydroxy ester
followed by in situ lactonization with hydrochloric acid.
A similar sequence of reactions was used to prepare
the R-methylenelactone 29. In comparison to 21, the
lactone 29 carries a side chain that is shortened by one
methylene group (Scheme 4). Thus, monosilylation of 2,2-
dimethyl-1,3-propanediol gave the alcohol 22.32 Oxidation
of 22 under Swern conditions27 furnished 23. Chain
extension by Wittig-Horner reaction29 led to the dienoate
24. Reduction of the ester produced the alcohol 25, and
subsequent protection gave the MEM ether 26. Again,
the remainder of the steps proceeded uneventfully.
Removal of the silyl protecting group delivered the
alcohol 27 whose oxidation furnished the aldehyde 28.
The formation of the R-methylene lactone was achieved
as described previously.
To find out how this intramolecular Diels-Alder reac-
tion performs with a longer tether between diene and
dienophile, we targeted the R-methylenelactone 37
(Scheme 5). The synthesis began with a Wittig-Horner
reaction of the commercially available aldehyde 30 with
the phosphonate 15 yielding the trieneoate 31. Next, the
ester was reduced followed by conversion of the resulting
alcohol 32 to the corresponding MEM ether 33 under
standard conditions. Treatment of the triene 33 with a
slight excess of 9-BBN allowed for a selective hydrobo-
(27) Tidwell, T. T. Org. React. 1990, 39, 297-572.
(28) Sato, K.; Mizuno, S.; Hirayama, M. J . Org. Chem. 1967, 32,
177-180.
(29) Takacs, J . M.; J aber, M. R.; Clement, F.; Walters, C. J . Org.
Chem. 1998, 63, 6757-6760.
(30) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277-
7287.
(31) Meyer, S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549-
7552.
(32) Sano, S.; Mori, K. Eur. J . Org. Chem. 1999, 1679, 9-1686.

Intramolecular Diels-Alder Reactions of R-Methylene Lactones
J . Org. Chem., Vol. 67, No. 8, 2002 2477
Sch em e 5. Syn th esis of Su bstr a te 37
Sch em e 7. Retr osyn th etic An a lysis for Ta xol
Ba sed on a n In tr a m olecu la r Diels-Ald er Rea ction
With the presence of a hydroxy function in position 10,
we reasoned that the Taxol skeleton might be accessible
by an intramolecular Diels-Alder strategy using an
R-methylenelactone as dienophile.35-39 The corresponding
retrosynthetic analysis is shown in Scheme 7. The Taxol-
like structure A incorporates the R-butyrolactone.40 Dis-
connection according to a Diels-Alder reaction leads to
the R-methylene lactone B. Removal of both the dieno-
phile and dienyl group provides the cyclohexenal C as a
potential starting material.
This compound itself is easily available by an inter-
molecular Diels-Alder reaction41 (Scheme 8). A certain
problem is clearly the control of the relative stereochem-
istry at positions 2 and 10. This study would serve to
reveal the scope and limitation of this intramolecular
Diels-Alder strategy. The synthesis began with the
construction of the A-ring and attachment of a diene or
suitable precursor thereof, respectively. As described by
Dai et al., the cyclohexenal 43 could be obtained on a
large scale by the borontrifluoride etherate (BF3‚Et2O)-
catalyzed cycloaddition between the diene 4242 and
acrolein. To prevent decomposition, it is best to use the
cycloadduct 43 directly after chromatographic purifica-
tion. With the aldehyde function present, it seemed
appropriate to continue the synthesis with the attach-
ment of the dienyl part. Although a dienyl anion can be
generated by transmetalation of (E)-1,3-(1-tributylstan-
nyl)butadiene, this compound is difficult to obtain.43,44 We
Sch em e 6. Syn th esis of Su bstr a te 41 F ea tu r in g a
F u r a n a s Dien e
ration of the terminal double bond providing the alcohol
34 after oxidative workup. Oxidation of 34 with the
Dess-Martin periodinane led to the aldehyde 35 that was
extended with the allyl bromide 9 under Reformatsky
conditions to yield the hydroxy ester 36. Subsequent
lactonization of 36 under basic conditions furnished the
R-methylenelactone 37. In this case the two-step proce-
(35) Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P.
E.; Glass, T. E.; Houze, J . B.; Krauss, N. E.; Lee, D.; Marquess, D. G.;
McGrane, P. L.; Meng, W.; Natchus, M. G.; Shuker, A. J .; Sutton, J .
C.; Taylor, R. E. J . Am. Chem. Soc. 1997, 119, 2757-2758.
(36) Morihira, K.; Hara, R.; Kawahara, S.; Nishimori, T.; Nakamura,
N.; Kusama, H.; Kuwajima, I. J . Am. Chem. Soc. 1998, 120, 12980-
12981.
dure for the establishment of the lactone moiety gave
better yields than the one-pot variant.
(37) Paquette, L. A.; Wang, H.-L.; Su, Z.; Zhao, M. J . Am. Chem.
Soc. 1998, 120, 5213-5225.
To probe the reactivity of the dienophile, we also
prepared the furan-containing substrate 41 (Scheme
6).33,34 This was accessible by Swern oxidation of 3-(2-
furyl)propanol (38). The aldehyde 39 was converted to
the 2-substituted acrylate 40 by the Reformatsky reaction
with the allylic bromide 9 in aqueous ammonium chlo-
ride. Lactonization to 41 was cleanly achieved by treat-
ment of the 4-hydroxy ester 40 with sodium hydride.
Compound 41 proved to be more stable toward polym-
erization than the other R-methylene lactones. The
diastereotopic protons in the lactone ring of 41 appear
as two ddd (δ ) 2.53, 3.03).
(38) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura,
T.; Ohkawa, N.; Sakoh, H.; Nishimura, K.; Tani, Y.-i.; Hasegawa, M.;
Yamada, K.; Saitoh, K. Chem. Eur. J . 1999, 5, 121-161.
(39) Intramolecular Diels-Alder approaches: (a) Sakan, K.; Craven,
B. M. J . Am. Chem. Soc. 1983, 105, 3732-3734. (b) Shea, K. J .; Gilman,
J . W.; Haffner, C. D.; Dougherty, T. K. J . Am. Chem. Soc. 1986, 108,
4953-4956. (c) Brown, P. A.; J enkins, P. R. J . Chem. Soc., Perkin
Trans. 1 1986, 1303-1309.
(40) Proposal for
a common pharmacophore: Giannakakou, P.;
Gussio, R.; Nogales, E.; Downing, K. H.; Zaharevitz, D.; Bollbuck, B.;
Poy, G.; Sackett, D.; Nicolaou, K. C.; Fojo, T. Proc. Natl. Acad. Sci.
U.S.A. 2000, 97, 2904-2909.
(41) Dai, W. M.; Lau, C. W.; Chung, S. H.; Wu, Y. D. J . Org. Chem.
1995, 60, 8128-8129.
(42) Nicolaou, K. C.; Liu, J .-J .; Yang, Z.; Ueno, H.; Sorensen, E. J .;
Claiborne, C. F.; Guy, R. K.; Hwang, C.-K.; Nakada, M.; Nantermet,
P. G. J . Am. Chem. Soc. 1995, 117, 634-644.
(43) Wender, P. A.; Sieburth, S. M. Tetrahedron Lett. 1981, 22,
2471-2474.
(33) Grootaert, W. M.; De Clercq, P. J . Tetrahedron Lett. 1986, 27,
1731-1734.
(34) J ung, M. E.; Gervay, J . J . Am. Chem. Soc. 1989, 111, 5469-
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1984, 534.
5470.

2478 J . Org. Chem., Vol. 67, No. 8, 2002
Richter et al.
Sch em e 8. Syn th esis of Su bstr a te 50 F ea tu r in g
th e Ta xol A Rin g
F igu r e 3. Structures and characteristic chemical shifts for
the isomers 50.
as well as deacylation at position 10 providing compound
48 in almost quantitative yield (Scheme 8). With the
lower section completed, we could now concentrate on the
introduction of the R-methylene-γ-butyrolactone. This
was initiated by the tetrapropylammonium perruthenate
mediated oxidation51 of the alcohol to the corresponding
aldehyde. The latter compound was not further charac-
terized. Instead it was directly reacted with ethyl R-bro-
momethylacrylate (9) in the presence of zinc. Lactone
formation to the γ-butyrolactone 50 took place smoothly
by adding two equivalents of sodium hydride to the
hydroxy ester 49 (Scheme 8).
If the diastereomeric mixture of 48 is used, four
compounds 50 are produced. There is essentially no
diastereoselection in the formation of the asymmetric
center at C-10. That means that the ratio of 50a /50b/
50c/50d is about 3:3:1:1. By careful and repeated chro-
matography the isomers could be separated. Their struc-
tures are depicted in Figure 3 together with some
characteristic chemical shifts. It is seen that for 50a and
50b H-3 appears at lower field than in 50c and 50d . In
contrast, H-2 has for all isomers about the same chemical
shift. On the basis of the similar chemical shift in 50a ,
50c and 50b, 50d , respectively, the stereochemistry at
C-10 was assumed to be the same in these pairs.
However, the relative assignment also might be ex-
changed.
In tr a m olecu la r Cycloa d d ition . The intramolecular
cycloaddition reactions went smoothly for the substrates
11, 21, and 29 (Table 1). Typically, a solution of the triene
in toluene was refluxed for 2-3 d. To prevent polymer-
ization, hydroquinone was added. Concentration of the
reaction mixture and purification by flash chromatogra-
phy gave the pure products 51, 52, and 53, respectively.
Under the same conditions, the substrate 37 did not give
any product. However, changing the solvent to o-dichlo-
robenzene and keeping the solution at reflux temperature
for 2 d brought about the desired cycloaddition, yielding
a mixture of the endo and exo isomers 54en d o and 54exo
in a ratio of 56:44. The diastereomeric ratios were
determined by 1H NMR (51, 52), by GC-MS (52, 53), and
by weighing of the fractions (54). Unfortunately, ther-
molysis (110 or 180 °C) of the furan derivative 41 did
not give the corresponding cycloadduct. Heating of 41 in
DMSO for 18 h at 190 °C gave a black polymer. Lewis
therefore sought a more practical alternative. This was
found with the protected 3-butyn-1-ol 44.45 Hydrozir-
conation with the Schwartz reagent (Cp2ZrHCl) gave the
intermediate vinylzirconocene.46-48 Addition of the alde-
hyde and a catalytic amount of silver perchlorate
(AgClO4)49 resulted in the formation of the secondary
alcohol 45 in 74% yield. This reaction afforded two
diastereomers in a ratio of 77:23. The stereochemical
assignment was done in analogy to compounds reported
by Fallis.50 Whereas H-2 of the major diastereomer
appears at δ ) 4.42, the corresponding signal of the minor
isomer is shifted to higher field (δ ) 4.20). A similar shift
difference, although in the opposite direction is observed
for H-1. This proton resonates at δ ) 1.30-1.37 in the
major isomer and δ ) 1.52-1.55 of the minor isomer,
respectively. In the next step the secondary alcohol was
protected as methoxyethoxymethyl ether 46 using MEMCl
and diisopropylamine as base. The long reaction time of
2 d indicates some steric hindrance around the secondary
hydroxyl group. The stage was now set for the liberation
of the diene. First, the silyl protecting group was removed
with HF in aqueous acetonitrile. After workup, the free
primary alcohol was directly converted to the correspond-
ing tosylate using pyridine/(dimethylamino)pyridine. Sub-
sequent treatment of the tosylate 47 with three equiva-
lents of potassium tert-butoxide induced E2 elimination
(45) Cliff, M. D.; Pyne, S. G. Tetrahedron 1996, 52, 13703-13712.
(46) Hart, D. W.; Blackburn, T. F.; Schwartz, J . J . Am. Chem. Soc.
1975, 97, 679-680.
(47) Sun, R. C.; Okabe, M.; Coffen, D. L.; Schwartz, J . Org. Synth.
1992, 71, 83-88.
(48) Wipf, P.; J ahn, H. Tetrahedron 1996, 52, 12853-12910.
(49) Maeta, H.; Hashimoto, T.; Hasegawa, T.; Suzuki, K. Tetrahe-
dron Lett. 1992, 33, 5965-5968.
(51) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
(50) Lu, Y.-F.; Fallis, A. G. Can. J . Chem. 1995, 73, 2239-2252.

Intramolecular Diels-Alder Reactions of R-Methylene Lactones
J . Org. Chem., Vol. 67, No. 8, 2002 2479
Ta ble 1. In tr a m olecu la r Diels-Ald er Rea ction s of
Va r iou s r-Meth ylen e La cton es
F igu r e 4. NOESY spectrum of the endo cycloadduct 52.
F igu r e 5. X-ray structure of the cycloadduct 58 (Chem-3D
rendering).
acid catalysis (1 equiv of MeAlCl2, CH2Cl2, -60-23 °C,
18 h) also left 41 unchanged. It is difficult to explain the
failure of the Diels-Alder reaction of 41. One might
speculate that the presence of several rings in the
cycloadduct favors the retro-Diels-Alder reaction due to
ring strain. For the intramolecular Diels-Alder reaction
toward the taxol-like structure 56 each of the four
diastereomers 50a -d was heated as a toluene solution
in a sealed tube at 160 °C. The presence of catalytic
amounts of hydroquinone prevented decomposition. Un-
fortunately, only starting material was observed even
after heating for 48 h. We also attempted the Diels-Alder
reaction in the presence of dimethylaluminum chloride
(1.2 equiv, CH2Cl2, -78 °C). This, however, resulted in
the destruction of the tetraene 50.
Ster eoch em ica l Assign m en t. The structures of the
cycloadducts were assigned mainly by 2D NMR spectros-
copy. Figure 4 depicts the NOESY spectrum of tricycle
52. Most revealing are the cross-peaks of the bridgehead
proton H-6 with the three axial protons H-2, H-8, and
H-12. The relatively strong intensity of the H-6/H-12a
cross-peak points to a short distance between these two
protons.
Sch em e 9. Syn th esis of th e Cycloa d d u ct 58
cyclized to the corresponding lactone using trifluoroacetic
acid. The crude product was then subjected to thermolysis
in toluene giving rise to the cycloadduct 58. Somewhere
en route to 58 the MEM protecting group was replaced
with a trifluoroacetate. Surprisingly, the OH-free com-
pound was not obtained under these conditions (Scheme
9). However, this transformation was of particular value
in that the product formed crystals suitable for X-ray
analysis.
The X-ray structure of 58 reveals the trans-decalin ring
and the pseudoaxial orientation of the hydroxymethyl
groups at position 3. The structure 58 is characterized
by the following distances: H-6/H-2 262.4 pm, H-6/H-8
272.8 pm, H-6-H/12 231.1 pm. This is in agreement with
the trends seen in the NOESY spectrum of 52. The
trifluoromethyl group turned out to be highly disordered.
Further structural proof for the trans-decalin substruc-
ture came from the X-ray analysis of the trifluoroacetate
58 (Figure 5). This compound was obtained when the
hydroxyester 57, which was formed from the reaction of
the bromomethylacrylate 9 with the aldehyde 20, was

2480 J . Org. Chem., Vol. 67, No. 8, 2002
Richter et al.
F igu r e 7. Transition states for 53en d oTS and 53exoTS as
calculated by MacroModel V7.0.
F igu r e 6. Transition states for 52en d oTS and 52exoTS as
calculated by MacroModel V7.0.
That is, the X-ray structure localized nine fluorine atoms.
For clarity, only three are depicted in Figure 5.
By analogy, the cycloadduct 51 was also assigned the
endo structure. It should be noted that the 1H NMR
spectra of 51 and 52 show striking similarities between
1.0 and 2.5 ppm. The high selectivity in favor of the trans-
decalin products (endo cycloadduct) can be understood
by looking at the two diastereomeric transition states
52en d oTS and 52exoTS (to simplify matters, the meth-
oxymethyl was replaced with a methyl group). The endo
transition state 52en d oTS is clearly favored because of
favorable secondary orbital interactions between diene
and the dienophile activating group. On the other hand,
the exo transition state 52exoTS is disfavored by the
axial position of the butadiene moiety and possibly by
steric interactions of H-5 (product numbering) with the
axial H-8 and H-12. Transition-state modeling using
MacroModel indicates an energy difference in favor of the
52en d oTS of 9.14 kJ mol-1 (Figure 6).52 A substantial
asynchronicity in the bond formation is revealed by the
calculations. Thus, the peripheral bond of 52en d oTS was
calculated to be 209.6 pm, whereas the internal bond is
much longer (244.2 pm).
F igu r e 8. Calculated conformations (MacroModel V7.0) of
54en d o and 54exo.
heating to 180 °C in order to realize the cycloaddition.
The thermolysis produced a 53:47 mixture of the endo
and exo isomers 54en d o and 54exo. Again, the structure
of the major isomer was elucidated with the help of a
NOESY spectrum. Thus, the bridgehead proton must be
in proximity to the axial H-8a, H-2a, and H-13a. The
calculated conformations of 54en d o and 54exo are
shown in Figure 8.
Su m m a r y
We demonstrated that the intramolecular Diels-Alder
reaction of R-methylene lactones represents an efficient
approach to tricyclic structures. The cycloadditions are
characterized by high diastereoselectivity and reasonable
yields. The major isomer is in accordance with an endo
transition state. An exception is the cycloaddition of the
nonatriene substrate 29. Another advantage is the fact
that the dienophile, the R-methylene lactone, can be very
easily installed. However, as it turned out, the intramo-
lecular Diels-Alder reaction did not work with a furan
as a dienophile and a densely functionalized tether
connecting the diene and the R-methylene lactone. In the
course of the synthesis of the triene 50, we also developed
a novel dienyl equivalent.
In the case of the nonatriene system 29, thermolysis
led essentially only to the product having cis-annulated
carbocyclic rings. The NOESY spectrum of 53 is charac-
terized by cross-peaks of the bridgehead hydrogen H-6
with H-3. In addition, NOE correlations were observed
between the olefinic proton H-5 and the axial methyl
group at C-7 (C7-CH3). The two possible transition states
are depicted in Figure 7. It is seen that the endo
transition structure 53en d oTS is disfavored because of
eclipsing interactions of the two methyl groups with the
butadiene. This must even override the usual endo
preference. However, the experimental results are not
reflected in the force-field calculations. Surprisingly,
according to the calculations transition state 53en d oTS
is favored by 12.5 kJ mol-1
.
Ack n ow led gm en t. Financial support by the Deut-
sche Forschungsgemeinschaft and the Fonds der Che-
mischen Industrie is gratefully acknowledged.
The fact that the length of the tether connecting diene
and dienophile has a profound influence on the diaste-
reoselectivity of this type of Diels-Alder reaction is
evident from the thermolysis of 37. This triene required
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and copies of NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(52) Raimondi, L.; Brown, F. K.; Gonzalez, J .; Houk, K. N. J . Am.
Chem. Soc. 1992, 114, 4796-4804.
J O016116A