Theoretical and experimental determination of the effects governing the transannular Diels-Alder reaction of trans-trans-cis systems with or without activation of the dienophile

Article abstract of DOI:10.1021/ja0109491

A thorough study of the transannular Diels-Alder (TADA) reaction of trans-trans-cis macrocyclic trienes was carried out. It led to a better understanding of various parameters that govern the TADA reaction in particular and the Diels-Alder reaction in general. Thus, carbonyl activation of the dienophile and substitution of the diene are discussed, as well as the presence of substituents on the macrocycle and their respective effects at the transition-state level.

Full text of DOI:10.1021/ja0109491

8210
J. Am. Chem. Soc. 2001, 123, 8210-8216
Theoretical and Experimental Determination of the Effects Governing
the Transannular Diels-Alder Reaction of Trans-Trans-Cis Systems
with or without Activation of the Dienophile
Samuel Fortin,† Louis Barriault,‡ Yves L. Dory,§ and Pierre Deslongchamps*,†
Contribution from the De´partement de chimie, Institut de Pharmacologie, UniVersite´ de Sherbrooke,
3001 13e aVenue nord, Sherbrooke, Que´bec, Canada, J1H-5N4
ReceiVed April 12, 2001
Abstract: A thorough study of the transannular Diels-Alder (TADA) reaction of trans-trans-cis macrocyclic
trienes was carried out. It led to a better understanding of various parameters that govern the TADA reaction
in particular and the Diels-Alder reaction in general. Thus, carbonyl activation of the dienophile and substitution
of the diene are discussed, as well as the presence of substituents on the macrocycle and their respective
effects at the transition-state level.
Table 1. Macrocyclic Trienes and Their Corresponding Tricyclic
TADA Adducts. Nomenclature Used To Describe the Double Bond
Stereochemistry of the Reactant: Diene Geometry (Cis C or Trans
T) Followed by Dienophile Geometry
Introduction
Transannular reactions are very impressive methods for the
synthetic organic chemists. This general approach coupled with
the use of the Diels-Alder reaction leads to a very powerful
strategy known as the transannular Diels-Alder (TADA)
strategy.1 It is therefore not surprising that several research
groups have already used this impressive tool in their synthetic
efforts.2 During our own systematic and general studies of the
TADA reaction,3 we considered the eight possible combinations
as regards the geometry of the diene and dienophile, each
insaturation being either cis or trans. On a few occasions,
competing 1,5-hydrogen shifts4 and ene reactions5 led to side
products, but on the whole, the outcome of the reaction is highly
predictable, as indicated in Table 1. This predictability can be
used to design and carry out syntheses of natural products6 or
their analogues.7 Thus, cis-cis dienes are of no use (cis-cis-
cis, cis-cis-trans) because they always lead to rearranged
products. This comes from the fact that the cisoid conformation
of the diene is energetically very high. On the contrary, the
cisoid conformation requires less energy in the cis-trans and
trans-cis diene systems; only small amounts of rearranged side
products are sometimes observed beside the expected adduct.
It is worth noting that in all those cases (cis-trans-cis, cis-
trans-trans, trans-cis-cis, trans-cis-cis) predictions are
straightforward because there is always only one possible TADA
adduct. Such is not the case for the trans-trans dienes (trans-
trans-cis, trans-trans-trans), which can theoretically lead to
the formation of two adducts each due to easy flipping of the
plane constituted by the diene in its flat cisoid conformation
(Scheme 1). In those cases, the ratio of TADA adducts is rather
difficult to forecast because it is influenced by so many factors
such as steric effects from various groups on the macrocyclic
rings;8 the problem can become even more complicated
when the dienophile is activated since the so-called endo
effect9 can either antagonize all other effects or act in a synergic
way.10 The purpose of this work is precisely to untangle these
* Corresponding author: (fax) (819) 820-6823; (e-mail) pierre.
deslongchamps@courrier.usherb.ca.
† Laboratoire de synthe`se organique.
‡ Current address: Department of Chemistry, University of Ottawa,
Ottawa, ON, K1N 6N5 Canada.
§ Laboratoire de mode´lisation mole´culaire.
(1) Marsault, E.; Toro´, A.; Nowak, P.; Deslongchamps, P. Tetrahedron
2001, 57, 4243.
(2) (a) Takahashi, T.; Katsuya, S.; Doi, T.; Tsuji, J. J. Am. Chem. Soc.
1988, 110, 2674. (b) Takahashi, T.; Sakamoto, Y.; Doi, T. Tetrahedron
Lett. 1992, 33, 3519. (c) Wood, J. L.; Porco, J. A.; Taunton, J.; Lee, A. Y.;
Vlardy, J.; Schreiber, S. L. J. Am. Chem. Soc. 1992, 114, 5898. (d) Marshall,
J. A.; Wang, X.-j. J. Org. Chem. 1992, 57, 3387. (e) Jung, S. H.; Lee, Y.
S.; Park, H.; Kwon, D.-S. Tetrahedron Lett. 1995, 36, 1051. (f) Roush, W.
R.; Works, A. B. Tetrahedron Lett. 1996, 37, 8065. (g) Jones, P.; Li, W.-
S.; Pattenden, G.; Thomson, N. M. Tetrahedron Lett. 1997, 38, 9069.
(3) (a) Lamothe, S.; Ndibwami, A.; Deslongchamps, P. Tetrahedron Lett.
1988, 29, 1639. (b) Deslongchamps, P. Pure Appl. Chem. 1992, 64, 1831.
(4) Ndibwami, A. Lamothe, S.; Soucy, P.; Goldstein, S.; Deslongchamps,
P. Can. J. Chem. 1993, 71, 714.
(5) Xu, Y. C.; Roughton, A. L.; Plante, R.; Goldstein, S.; Deslongchamps,
P. Can. J. Chem. 1993, 71, 1152.
(6) Toro, A.; Nowak, P.; Deslongchamps, P. J. Am. Chem. Soc. 2000,
122, 4526.
(8) Dory, Y. L.; Soucy, P.; Drouin, M.; Deslongchamps, P. J. Am. Chem.
Soc. 1995, 117, 518.
(9) (a) Kobuke, Y.; Sugimoto, T.; Furukawa, J.; Funco, T. J. Am. Chem.
Soc. 1972, 94, 3633. (b) Williamson, K. L.; Hsu, Y.-F. L. J. Am. Chem.
1970, 92, 7385.
(7) Be´langer, G.; Deslongchamps, P. Org. Lett. 2000, 2, 285.
10.1021/ja0109491 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/02/2001

Diels-Alder Reaction of Trans-Trans-Cis Systems
J. Am. Chem. Soc., Vol. 123, No. 34, 2001 8211
Scheme 1
Chart 1. Two Natural Products Suitable for the TADA
Strategy
Scheme 2
Scheme 3a
various factors in the case of trans-trans-cis macrocyclic
trienes.
a Conditions: (a) m-CPBA, CH2Cl2, 0 °C; (b) NaIO4, HCl, THF/
H2O, room temperature. (c) HCl, MeOH, room temperature. (d) K2CO3,
MeOH, room temperature. (e) (COCl)2, DMSO, CH2Cl2; then Et3N,
-78 °C. (f) BrCH2Cl, Li, THF, - 78 °C. (g) TIPSOTf, 2,6-lutidine,
CH2Cl2, 0 °C. (h) TFA, CH2Cl2/H2O, room temperature. (i) (R)-3-(1-
Oxopropyl)-4-benzyl-2-oxazolidinone, Bu2BOTf, CH2Cl2, 0 to -78
°C. (j) AlMe3, NH(OMe)Me‚HCl, CH2Cl2, 0 °C. (k) MeI, NaH, THF/
DMF, °C. (l) DIBAL-H, THF, - 78 °C.
Choice of Models
To understand the activation of the dienophile by a carbonyl,
one must first understand the behavior of the trans-trans-cis
system without that activating carbonyl. In fact, compounds 1
and 2 (Scheme 2), which could allow such study, have already
been prepared by us.4,11 These two compounds differ only from
each other by a methyl group at position 8 (numbering
corresponding to the steroid-like adducts). The reason those two
models had been made comes from the fact that many potential
polycyclic natural product targets exist with or without a methyl
substituent at that position.12 It is also worth noting that many
natural products have either an alcohol or a carbonyl group at
position 11, hence the reason for studying the effect of a
carbonyl at that position in 3 and 4. The use of a carbonyl at
position 11 is also meant to fix a particular problem: trans-
trans-cis macrocyclic compounds such as 2 that have a methyl
group at position 8 necessitate high temperatures to yield the
corresponding tricyclic adducts. In the process, side reactions
have been observed but carbonyl activation of the dienophile
should sufficiently reduce the temperature of reaction so that
all unwanted side reactions could be eradicated. Beside the
addition of a carbonyl at position 11 in 3 and 4, a methoxy
group at position 3 and a methyl group at position 4 (instead of
the malonate group at position 3 in 1 and 2) have also been
added in order to induce chirality in the TADA adducts and
also because these two substituents are found in many natural
products. Compounds such as fusidic acid13 (Chart 1) and other
fusidanes such as cephalosporin P114 and helvolic acid could
result from the TADA reaction of 4 (or related macrocycles)
provided that the trans-syn-trans tricyclic adduct could be
obtained selectively.
n
Synthesis
The synthesis of the macrocycles 3 and 4 was started with
the selective epoxidation of neryl acetate 5 followed by opening
of the epoxide and cleavage of the resulting diol leading to the
corresponding aldehyde (Scheme 3).15 The aldehyde was
protected as a dimethoxy acetal and the acetate was hydrolyzed;
the resulting allylic alcohol was oxidized16 to furnish the
aldehyde 6. A 1,2 addition on the aldehyde 6 with chlorobro-
momethane and lithium gave the chlorohydrin 7.17 Protection
of the alcohol18 and hydrolysis of the acetal led to the aldehyde
8. Evans asymmetric aldolization19 was performed on that
aldehyde to give the adduct 9. The chiral auxiliary was removed
via transamidation, according to Weinreb’s technique,20 yielding
the amide 10. The alcohol was protected as a methyl ether 11,21
and the amide was then quantitatively reduced to give the
aldehyde 12. Horner-Emmons reactions22 with the phospho-
nates (E)(MeO)2POCH2CHdCHCO2Me and (E)(MeO)2POCH2-
CHdC(Me)CO2Me led respectively to the trans-trans diene
13 and to the substituted trans-trans diene 14 (Scheme 4). An
identical six-step sequence was then applied to 13 and 14 to
obtain the two precursors of cyclization 25 and 26, respectively.
Thus, reduction of the methyl ester 13 gave the alcohol 15 that
(15) Prestwich, G. D.; Boehm, M. F. J. Org. Chem. 1986, 51, 5447.
(16) Swern, D.; Huang, S. L.; Mancuso, A. J. J. Org. Chem. 1979, 43,
2480.
(10) Dory, Y. L.; Hall, D. G.; Deslongchamps, P. Tetrahedron 1998,
54, 12279.
(11) Xu, Y. C.; Roughton, A. L.; Soucy, P.; Goldstein, S.; Deslong-
champs, P. Can. J. Chem. 1993, 71, 1169.
(12) Devon, T. K.; Scott, A. I. Handbook of Naturally Occurring
Compounds, Terpenes; Academic Press: New York, 1972.
(13) (a) Godtfredsen, W. O.; Vangedal, S. Tetrahedron 1962, 18, 1029.
(b) Godtfredsen, W. O.; Von Daehne, W.; Vangedal, S.; Marquet, A.;
Arigoni, D.; Melera, A. Tetrahedron 1965, 21, 3505. (c) Godtfredsen, W.
O.; Von Daehne, W.; Rasmussen, P. R. AdV. Appl. Microbiol. 1979, 25,
95.
(17) (a) Tarhouni, R.; Kirshleger, B.; Rambaud, M.; Villieras, J.
Tetrahedron Lett. 1984, 25, 835. (b) Sadhu, K. M.; Matteson, D. S.
Tetrahedron Lett. 1986, 27, 795.
(18) Corey, E. J.; Cho, H.; Ru¨cker, C.; Hua, D. H. Tetrahedron Lett.
1981, 22, 3455.
(19) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127.
(20) (a) Weinreb, S. M.; Lipton, M.; Basha, A. Tetrahedron Lett. 1977,
18, 4171. (b) Weinreb, S. M.; Turos, E.; Levin, J. I. Synth. Commun. 1982,
12, 989.
(21) Evans, D. A.; Miller, S. J.; Ennis, M. D. J. Org. Chem. 1993, 58,
471.
(22) Pattenden, G.; Weedon, B. C. L. J. Chem. Soc. C 1968, 1984.
(14) Burton, H. S.; Abraham, E. P.; Cardwell, H. M. E. Biochem. J.
1956, 62, 171.

8212 J. Am. Chem. Soc., Vol. 123, No. 34, 2001
Fortin et al.
Scheme 4a
Scheme 5a
a Conditions: (a) (E)(MeO)2P(O)CH2CHdCHCO2Me (to 13) or
(E)(MeO)2P(O)CH2CHdC(Me)CO2Me (to 14), BuLi, Et2O, -20 °C.
(b) DIBAH, THF, - 78 °C. (c) 2-Methoxypropene, PPTS, CH2Cl2.
(d) TBAF, THF. (e) TPAP, NMO, CH3CN, room temperature. (f)
Dimethyl malonate, NaH, NaI, DMF, room temperature. (g) AcOH,
THF/H2O, room temperature. (h) Hexachloroacetone, PPh3, 2,6-lutidine,
THF, - 40 °C. (i) Cs2CO3, NaI, CH3CN, 85 °C.
a Conditions: (a) see Scheme 4. (b) TFA, CHCl3, room temperature.
In the case of the substituted trans-trans diene series, it was
possible to isolate the macrocycle 4 from 26 with the rather
poor yield of 33%. The TADA reaction with 4 was then carried
out under two types of conditions: thermal and catalyzed. When
heated at 125 °C in toluene (sealed tube) for 24 h, the two
possible cis-syn-cis and trans-syn-trans TADA adducts 29
and 30 were obtained as a 1:1 mixture and with a yield of 80%
(the two compounds were separated by chromatography). The
identity of 29 was established by X-ray diffraction analysis. As
for 30, the compound was treated with TFA to provoke
epimerization at position 9. The resulting more stable trans-
anti-cis tricycle 31 was obtained quantitatively, and its identity
was also established by X-ray diffraction analysis. On the other
hand, under catalytic (SnCl4) conditions, only the trans-syn-
trans exo adduct 30 was obtained in 100% yield. This latter
result is extremely interesting since it opens a route to fusidic
acid for which the ABC ring system is in a trans-syn-trans
arrangement (Chart 1).
was transformed into the acetal 17. Deprotection of the silyl
ether with tetrabutylammonium fluoride yielded the alcohol 19.
The chloroketone 21 was obtained by oxidation of the resulting
secondary alcohol.23 The dimethylmalonate connector was
introduced by SN2 alkylation of the chloroketone 21. Subsequent
hydrolysis of the acetal group with aqueous acetic acid yielded
the allylic alcohol 23. The alcohol was transformed into the
allylic chloride 25 according to Schreiber’s chlorination method.24
25 was obtained from 13 with an overall yield of 23%; similarly,
the other allylic chloride 26 was obtained from 14 with the
overall yield of 25% for the six consecutive reactions.
The macrocyclization of 25 to obtain the macrocycle 3 was
carried out under the usual conditions by means of cesium
carbonate at 85 °C in acetonitrile.25 As previously observed with
trans-trans dienes having no additional substituents, the
expected macrocycle was not isolated; rather, the TADA
reaction took place during the macrocyclization reaction.26 Thus,
the trans-anti-cis tricycle 28 (structure established by X-ray
diffraction analysis) was obtained in 34% yield from the allylic
chloride 25 (Scheme 5). However, a trans-anti-cis tricycle
cannot issue directly from the TADA reaction of a trans-trans-
cis macrocycle (Table 1), instead a trans-syn-trans or a cis-
syn-cis tricyclic adduct (or both) should have been obtained.3a
Therefore, this result shows that only the trans-syn-trans
tricycle 27 must have been produced and directly isomerized
with cesium carbonate present in the reaction medium to the
more stable trans-anti-cis tricycle 28 as shown in Scheme 5.
Alternatively, the same adduct 28 could have arisen from IMDA
(intramolecular Diels-Alder)27 reaction of the trienone 25
immediately followed by malonate cyclization of the resulting
bicyclic adduct to produce 27 then 28. However, this route can
be ruled out since there exist many IMDA precedents that
demonstrate clearly that 25 cannot be expected to react below
150 °C.2e,28
Theoretical Rationalization
Beside the obvious interest in total synthesis of suitable targets
by means of the TADA reaction, we are also very much
interested in shedding new light on the famous, but also not
yet fully understood, Diels-Alder reaction. Clearly the tran-
sannular environment can provide an excellent tool to study
reactions in general, Diels-Alder in particular, since mobility
of the reactants is greatly reduced. Under such conditions,
entropy (a factor not easily monitored) should be minimized.
Therefore, the results should be mostly influenced by enthalpy,
which can be discussed in terms of disfavored steric interactions
and disfavored or favored electrostatic or stereoelectronic
interactions. The five correlated experimental data are shown
in Table 2. They cannot be easily rationalized because there
are at least three questions that are difficult to address in a simple
and satisfactory manner: (i) Why is the trans-syn-trans tricycle
the only product in the unsubstituted cases (entries 1 and 3) ?
(ii) Why does the cis-syn-cis adduct appear in the presence
of a methyl on the diene at position 8 (entries 2 and 4)? (iii)
Why is Lewis acid catalysis favoring the trans-syn-trans exo
product (entries 4 and 5)?
(23) Griffith, W. P.; Ley, S. V. J. Chem. Soc., Chem. Commun. 1987,
1625.
(24) Schreiber, S. L.; Meyer, S. D.; Miwa, T.; Nakatsuka, M. J. Org.
Chem. 1992, 57, 5058.
(25) Couturier, M.; Dory, Y. L.; Rouillard, F.; Deslongchamps, P.
Tetrahedron 1998, 54, 1529.
(26) Lamothe, S.; Ndibwami, A.; Deslongchamps, P. Tetrahedron Lett.
1988, 29, 1641.
To put sufficiently accurate figures on all those interactions,
we calculated the different transition states (TSs) corresponding
to these reactions at the RHF/3-21G theory level29 by means of
(27) Roush, W. R.; Hall, S. E. J. Am. Chem. Soc. 1981, 103, 5200.
(28) Craig, D. Chem. Soc. ReV. 1987, 16, 187.
(29) Binkley, J. S.; Pople, J. A.; Hehre, W. J. J. Am. Chem. Soc. 1980,
102, 939.

Diels-Alder Reaction of Trans-Trans-Cis Systems
Table 2. Experimental Results
J. Am. Chem. Soc., Vol. 123, No. 34, 2001 8213
position
products
3
4
8
11
H2
H2
11CdO
11CdO
11CdO
13
macrocyle
conditions
80 °C
310 °C
85 °C
125 °C
TST
CSC
entry
E2
E2
E2
E2
R-Me
R-Me
R-Me
H
Me
H
Me
Me
E2
E2
E2
E2
E2
1
2
3
4
4
100
85
100
50
0
15
0
50
0
1
2
3
4
5
â-MeO
â-MeO
â-MeO
SnCl4, -25 °C
100
GAMESS.30 The zero point energy corrections were not applied
due to the large size of the systems, which always prevented
us from calculating them. However, these corrections are known
not to affect the relative energies between TSs in a significant
way.31
We also reasoned that it should be possible to deconvolute
the effect of each substituent found at positions 3, 4, 8, 11, and
13. We can safely assume that the substituents in ring A and
the ones in ring C that act in an antagonistic or synergistic way
can be studied separately. Thus, the calculations to be carried
out were selected according to this purpose. The most influential
factors with a direct impact on the TADA reaction mechanism
itself should be the presence or the absence of a carbonyl at
position 11 (with the possibility of Lewis acid catalysis with
the carbonyl) and then the substitution of the diene at position
8. All the other substituents, which are away from the reaction
site, should be less influential but can still modulate the effect
of the substituents at positions 11 and 8.
The best way of analyzing the problem would be to isolate
each factor that influences the TADA reaction. Thus, the factors
that we must account for are the following: (a) the geometry
of the macrocycle at the TS which can be cbc (chair-boat-
chair), bbc, cbb, or even bbb; (b) the effect of the most
influential substituents at positions 11 and 8; and (c) the effect
of the substituents far away from the reaction site at positions
3, 4, and 13.
The theoretical study that follows is precisely intended to
isolate all these various factors; the results of the calculations
are shown in the Tables 3 and 4. Table 3 relates to not-activated
TADA reactions (CH2 at position 11) and corresponds to the
experimental results of the macrocycles 1 and 2. Table 4 relates
to reactions with a dienophile activated by a carbonyl at position
11; it corresponds to the experimental results of the macrocycles
3 and 4 under purely thermal conditions and to the macrocycle
4 catalyzed by a Lewis acid.
boat from calculations) must be taken into account (11% for a
cbb cis-syn-cis TS in Table 3) or is even preferred to the cbc
geometry (see Table 4: cbc cis-syn-cis TS, 3.83 kcal/mol vs
cbb cis-syn-cis TS, 3.36 kcal/mol) because there are no major
detrimental 1,4 interactions in those cases. Such is not the case
for the geometry bbc (twist boat-boat-chair) in which the
methyl of the dienophile (position 10) always leads to a severe
steric 1,4 interaction with the substituents in position 3 even if
those are hydrogens. The bbc geometry is on average destabi-
lized by 6.28 kcal/mol and is therefore omitted in the tables.
The bbb (twist boat-boat-twist boat) geometry was not
considered for the same reasons. The theoretical results also
show that the cbb trans-syn-trans TSs cannot really compete
with the cbc trans-syn-trans TSs; indeed, the differences in
energies (Ecbb - Ecbc) calculated in these cases are 5.11, 5.22
(6.55-1.33), 2.41, 3.91, and 6.11 kcal/mol. For the cis-syn-
cis TSs, the situation is quite different because the differences
in energy (Ecbb - Ecbc) are now much smaller with values of
3.95 (4.86-0.91), 2.13, 0.17 (2.32-2.15), -0.47 (3.36-3.83;
cbb more stable), and 1.10 kcal/mol (4.99-3.89). These figures
confirm that a boat conformation for the tether ring is only
possible close to a cis junction but not trans. According to this
principle, only the transition states trans-syn-trans cbc, cis-
syn-cis cbc, and cis-syn-cis cbb can lead to adducts.
(b) Influence of the Substitution on the Diene at Position
8. When there are no substituents at position 8, the cbc trans-
syn-trans geometry is favored by 0.91 kcal/mol compared to
the cbc cis-syn-cis geometry (Table 3, top, Ra ) H and Rc
) H) because the latter has two diene-H interactions that are
not found in the trans-syn-trans geometry. For this reason,
trans-syn-trans adducts are naturally favored when the diene
is not substituted. That is also confirmed in the case of an
activated dienophile (Table 4, top, R ) H and Rc ) H) since
the trans-syn-trans adduct is now more stable than the cis-
syn-cis adduct by as much as 2.15 kcal/mol. The addition of
a methyl in position 8 introduced a methyl-H interaction into
the cbc trans-syn-trans geometry (Table 3, bottom, Ra ) H
and Rc ) H), but it is also necessary to mention the appearance
of an interaction undoubtedly much more severe between the
methyl of the diene and the pseudoaxial hydrogen in position
11. Calculations reveal indeed that one of the hydrogens of this
methyl group and the axial hydrogen in position 11 are very
close in space with a separation of only 1.98 Å (two van der
Waals radii of H, 2.2 Å). There is also evidence of such an
unfavorable steric interaction in the distances b (distance
between C8 and C9) in the transition state. Thus, it should be
noted that this distance b is 0.04 Å (2.28 - 2.24 Å) shorter in
the cbc cis-syn-cis TS (Table 3, bottom) compared to the cbc
(a) Influence of the Geometry of the Macrocycle at the
Transition State. For the five studied cases, it was initially
necessary to determine by calculation which TS would have
been the probable pathway without the presence of the various
substituents at positions 3, 4, and 13. These results indicated in
the left-hand column of Tables 3 and 4 show that the cbc
geometry is generally favored. However, it is sometimes possible
that the cbb geometry (better described as chair-boat-twist
(30) Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.;
Gordon, M. S.; Jensen, J. H.; Koseki, S.; Matsuraga, N.; Nguyen, K. A.;
Su, S. J.; Windus, T. L.; Dupuis, M.; Montgomery, J. A. J. Comput. Chem.
1993, 14, 1347.
(31) Garc´ıa, J. I.; Mart´ınez-Merino, V.; Mayoral, J. A.; Salvatella, L. J.
Am. Chem. Soc. 1998, 120, 2415.

8214 J. Am. Chem. Soc., Vol. 123, No. 34, 2001
Fortin et al.
Table 3. Theoretical and Experimental Results: TADA of 1 (H at position 8) (80 °C) (top) and TADA of 2 (Me at position 8)(310 °C)
(bottom)
trans-syn-trans TS whereas there is no difference (0.01 Å )
2.20 - 2.19 Å) when the diene is not substituted (Table 3, top).
As a result from this methyl(8)-H(11) interaction the cbc cis-
syn-cis TS is now favored by 1.33 kcal/mol.
between the carbonyl and the axial hydrogen at position 1 of
pro-ring A. This interaction, which seems equivalent for both
the trans-syn-trans and the cis-syn-cis cases, is more
unfavorable in the cbc cis-syn-cis TS geometry. Thus; the
CdO‚‚‚ HaxsC1 distance for the cbc trans-syn-trans TSs is
2.18 (top), 2.24 (middle), and 2.18 Å (bottom); whereas for the
competing cbc cis-syn-cis TSs this distance takes the follow-
ing values: 2.15, 2.10, and 2.09 Å. The fact that the distance
differences and the energy differences between the correspond-
ing TSs vary in a similar way (0.03 Å/2.15 kcal/mol; 0.14 Å/3.83
kcal/mol; 0.10 Å/3.89 kcal/mol) indicates that this factor is
particularly significant to explain the trans-syn-trans selectivity
when there is a carbonyl at position 11. No improvements are
observed for the trans-syn-trans cbb structures (2.18, 2.23,
and 2.15 Å), and their energies are always definitely higher than
the trans-syn-trans cbc structures. On the contrary, cbb cis-
syn-cis structures really make it possible to slacken the tension
of this steric interaction with respective distances of 2.21, 2.22,
and 2.16 Å; that explains why the cbb cis-syn-cis TSs become
significant and can even be more stable than the cbc cis-syn-
cis TSs. However, in all cases, the cbc trans-syn-trans TSs
are energetically favored.
(c) Influence of a Carbonyl in Position 11. (Table 4,
Column R ) H and Rc ) H). Thus, trans-syn-trans adducts
are intrinsically preferred during the TADA reaction of a trans-
trans-cis macrocycle. This tendency can be reversed by adding
a methyl on the diene in position 8 because a significant
transannular interaction appears between the methyl of the diene
and the axial hydrogen at C11. By introducing a carbonyl at
C11, the length of bond b in formation increases in the TS
(toward 2.3-2.5 Å without catalysis and 2.8-3.2 Å with
catalysis). Consequently, any transannular interaction on both
sides of bond b should be reduced particularly in the case of
the catalyzed reaction; in this case, the only observed adduct
has the trans-syn-trans geometry (bottom). Obviously, when
there are no substituents on the diene, the trans-syn-trans
adduct is also favored (top). On the other hand, this effect is
not so clear in the intermediate case, i.e., when the methyl in
position 8 of the diene is found adjacent to the carbonyl at C11
in the geometry of the cbc trans-syn-trans TS and under
thermal conditions (middle). In this case, indeed, calculations
show that the unfavorable transannular interaction has not really
disappeared because the CdO‚‚‚ HsCH2C8 distance, 2.20 Å,
is still definitely smaller than the sum of the van der Waals
radii of O and H (2.45 Å). In fact, in this case, this factor should
support adduct cis-syn-cis; but a more complete examination
of the transition states calculated show than the addition of a
carbonyl at C11 introduced a new and more severe interaction
(d) Influence of Substituents on Rings A and C at Positions
3, 4, and 13. To this point, calculations without the substituents
on pro-rings A and C do not give an exact representation of
the experimental results, which suggests that these substituents
must bring a considerable influence on the selectivity. Thus,
although the tendencies are in general well predicted (Tables 3
and 4, left column), the case of the thermal TADA reaction of
the macrocycle 4 is particularly far away from reality (Table 4,

Diels-Alder Reaction of Trans-Trans-Cis Systems
J. Am. Chem. Soc., Vol. 123, No. 34, 2001 8215
Table 4. Theoretical and Experimental Results: TADA of 3 (H at Position 8) (85 °C) (Top) and TADA of 4 (Me at Position 8) (125 °C)
(Middle) and TADA of 4 (-25 °C, LA ) BF3 in Calculations and SnCl4 in Experiments) (Bottom)
middle). The subsequent theoretical study consists of the
progressive introduction of these substituents to check their
individual impact.
because the relative energies of these transition states remained
similar whether they are substituted at position 13 (Table 3,
bottom, column Ra ) H and Rc ) E, 1.46 kcal/mol) or not
(column Ra ) H and Rc ) H, 1.33 kcal/mol). It is particularly
interesting to note that the cbb cis-syn-cis TS can easily
accommodate a gem diester in 13 since that enables the
avoidance of the unfavorable diene-ester interaction. When two
gem diesters are present at positions 3 and 13 (Table 3, column
Ra ) E and Rc ) E), the calculations correspond to the real
cases and the theoretical results reproduce the experimental
results well. When the two diene-ester interactions energies
(0.7 kcal/mol each) are added to the basic cbc cis-syn-cis TS
energy (0.91 kcal/mol, Table 3), the resulting value (2.31 kcal/
mol) is very close to the computed value for the cbc cis-syn-
cis TS with four methyl esters (2.12 kcal/mol). In this case, the
According to the study carried out on macrocycles 1 and 2,
one first notes that the effect of a gem diester in position 3
(Table 3, column Ra ) E and Rc ) H) is always to disadvantage
the cbc cis-syn-cis TSs compared to the cbc trans-syn-trans
TSs by a value close to 0.7 kcal/mol (1.65 - 0.91 and 1.33 -
0.65 kcal/mol) because of a diene-ester interaction in the cbc
cis-syn-cis structures. As expected, the effect is the same for
a gem diester in position 13 (Table 3, top, column Ra ) H and
Rc ) E, 1.55 - 0.91 kcal/mol) because a diene-ester interaction
is also present. These calculations also indicate that a Me(8)-
ester interaction in a cbc trans-syn-trans TS is equivalent to
a diene-ester interaction found in a cbc cis-syn-cis TS

8216 J. Am. Chem. Soc., Vol. 123, No. 34, 2001
Fortin et al.
calculated trans-syn-trans/cis-syn-cis ratio is 95:5 whereas
it is 100:0 experimentally. For the macrocycle 2, this experi-
mental ratio is 15:85 (trans-syn-trans/cis-syn-cis); calcula-
tions give a ratio of 37:73 once again in excellent agreement
with reality.
(c) A carbonyl at position 11 activates the dienophile; its most
important effect is to relieve transannular interactions across
the BC ring junction at the transition state. This effect is very
strong with Lewis acids, and a methyl at position 8 which
usually favors the cis-syn-cis adduct because of those tran-
sannular interactions has no effect any more. On the whole,
the trans-syn-trans adduct is favored, despite the fact that it
corresponds to an exo approach at the transition state. This result
confirms once more that the Diels-Alder endo rule may be
exaggerated.32
(d) Axial substituents at positions 3 and 13 enhance the
natural tendency to lead to the trans-syn-trans adducts because
cis-syn-cis transition states suffer diaxial interaction with the
diene.
(e) An equatorial methyl group next to the diene at position
4 also enhances the trans-syn-trans preference by ∼0.5 kcal/
mol for no obvious reasons.
For the macrocycles 3 and 4, there is no gem diester at
position 3 but a methyl ether at this position and a methyl group
in position 4. Since these two groups can be placed easily in an
equatorial position on the tether in a chair conformation, we
considered it useless to study the effect of the methoxy group
in 3. On the other hand, the methyl in position 4 is directly
adjacent with the diene and should thus exert a certain influence
to be defined. Indeed, calculations (Table 4, rows cbc, column
R ) H and Rc ) H and column R ) Me and Rc ) H) show
that in all cases the trans-syn-trans TSs are favored by ∼0.5
kcal/mol (2.62 - 2.15, 4.41 - 3.83, 4.40 - 3.89 kcal/mol) when
one adds an equatorial methyl in 4. The effect of a gem diester
in position 13 was already described, and it is accentuated even
more here since the cbc cis-syn-cis TSs (column R ) H and
Rc ) E) are now impossible. Thus, the series of macrocycle 3
(top) is very well represented since the theory (column R )
Me and Rc ) E) predicts a trans-syn-trans/cis-syn-cis ratio
of 99:1 for an experimental ratio of 100:0. For the macrocycle
4 (without its methyl group at position 4) under thermal
conditions (middle) or under Lewis acid catalysis (bottom), the
cbb trans-syn-trans TS geometry allows to avoid a doubly
unfavorable methyl-ester and carbonyl-ester interaction; the
approximate relative energy gain of 2.2 kcal/mol (middle, 3.91
- 1.61 kcal/mol; bottom, 6.11 - 3.99 kcal/mol) is sufficient
for the cbb trans-syn-trans TS to become more favored than
the cbc trans-syn-trans TS under thermal conditions (middle).
However, this substantial profit of energy does not make it
possible for the cbb trans-syn-trans TS to become the major
under catalysis (bottom) because the basic cbb trans-syn-trans
TS (without substituents) is much too penalized (6.11 kcal/mol).
By finally adding the methyl at position 4 (which favors trans-
syn-trans TSs by ∼0.5 kcal/mol), one obtains the final
theoretical trans-syn-trans/cis-syn-cis ratios of 24:76 (ther-
mal) and 88:12 (catalysis) which represent well the experimental
ratios of 50:50 and 100:0.
(f) The cbc macrocycle geometry is usually favored at the
transition state, but the cbb geometry can also be found mostly
in the transition states leading to cis-syn-cis adducts. The cbb
geometry is normally disfavored in the trans-syn-trans transi-
tion states.
All these elements will now allow us to pursue our synthesis
of fusidic acid and related compounds. The trans-syn-trans
tricycle is required for that purpose, and our experimental data
(Table 2) have already shown that this tricycle can be obtained
as the sole TADA adduct from 4. Nevertheless, the calculations
also suggest that the cis-syn-cis adduct is not very much
disfavored because the gem diester at position 13 destabilizes
the trans-syn-trans transition state. The presence of a gem
diester can in fact become a burden for the rest of the synthesis,
and we can see that removing it before the TADA reaction
would be very advantageous because the trans-syn-trans
adduct would become so much favored (4.40 kcal/mol instead
of 1.01 kcal/mol by calculations, Lewis acid catalysis) so that
we could introduce other necessary substituents (e.g., at position
14) without losing the trans-syn-trans selectivity.
Acknowledgment. This research was financially supported
by the Natural Sciences and Engineering Research Concil of
Canada (NSERCC, Ottawa) and by the “Ministe`re de l’Enseigne-
ment Supe´rieur et de la Science” (Fonds FCAR, Que´bec). L.B.
thanks FCAR and Biomega/Boehringer Ingelheim Research Inc.
for a Postgraduate Award Fellowship. S.F. thanks NSERCC and
Biomega/Boehringer Ingelheim Research Inc. for a Postgraduate
Award Fellowship.
Conclusion
The TADA reaction of trans-trans-cis 14-membered ring
trienes having a methyl on the dienophile can lead to two
adducts: a trans-syn-trans tricycle and a cis-syn-cis tricycle.
Rules concerning the outcome of this particular reaction were
drawn out from experimental and theoretical data. These rules
can be summarized as follows:
(a) The trans-syn-trans tricycle is inherently favored over
the cis-syn-cis tricycle by less than 1 kcal/mol. This slight
difference can therefore be supported or fought by other factors.
The most influential factors are the substituents that are directly
situated on the site of the reaction at positions 8 and 11.
(b) A methyl on the diene at position 8 favors the cis-syn-
cis tricycle adduct. No cis-syn-cis adducts were ever observed
in series not having a methyl at that position. This factor is
considered to be the only one that can force the trans-syn-
trans tricycle to become disfavored.
Supporting Information Available: Experimental proce-
dures and data, X-ray structures of tricycles 28, 29, and 31,
and Cartesian coordinates (supplied as a ZIP file) of the TSs
calculated at the 3.21G level of ab initio theory (left and right
columns of Tables 3 and 4). See any current masthead page for
ordering information and Web access instructions. This material
is available free of charge via the Internet at http://pubs.acs.org.
JA0109491
(32) Garc´ıa, J. I.; Mayoral, J. A.; Salvatella, L. Acc. Chem. Res. 2000,
33, 658.