Diels-alder exo selectivity in terminal-substituted dienes and dienophiles: Experimental discoveries and computational explanations

Article abstract of DOI:10.1021/ja8079548

The Diels-Alder reactions of a series of silyloxydienes and silylated dienes with acyclic α,β-unsaturated ketones and N-acyloxazolidinones have been investigated. The endo/exo stereochemical outcome is strongly influenced by the substitution pattern of th

Full text of DOI:10.1021/ja8079548

Published on Web 01/20/2009
Diels-Alder Exo Selectivity in Terminal-Substituted Dienes
and Dienophiles: Experimental Discoveries and
Computational Explanations
Yu-hong Lam,† Paul Ha-Yeon Cheong,‡ Jose´ M. Blasco Mata,† Steven J. Stanway,§
Ve´ronique Gouverneur,*,† and K. N. Houk*,‡
Chemistry Research Laboratory, UniVersity of Oxford, U.K., Department of Chemistry and
Biochemistry, UniVersity of California, Los Angeles, California 90095, and Neurology and GI
Centre of Excellence for Drug DiscoVery, GlaxoSmithKline, Harlow, Essex, U.K.
Received October 8, 2008; E-mail: veronique.gouverneur@chem.ox.ac.uk; houk@chem.ucla.edu
Abstract: The Diels-Alder reactions of a series of silyloxydienes and silylated dienes with acyclic R,ꢀ-
unsaturated ketones and N-acyloxazolidinones have been investigated. The endo/exo stereochemical
outcome is strongly influenced by the substitution pattern of the reactants. High exo selectivity was observed
when the termini of the diene and the dienophile involved in the shorter of the forming bonds were both
substituted, while the normal endo preference was found otherwise. The exo-selective asymmetric
Diels-Alder reactions using Evans’ oxazolidinone chiral auxiliary furnished a high level of π-facial selectivity
in the same sense as their well-documented endo-selective counterparts. Computational results for these
Diels-Alder reactions were consistent with the experimental endo/exo selectivity in most cases. A twist-
asynchronous model accounts for the geometries and energies of the computed transition structures.
Introduction
materials that incorporate strategic design features. These
features are often anticipated to sterically encumber the endo
Precise control of stereoselectivity in the installation of
asymmetric centers constitutes a prominent goal in organic
synthesis. The Diels-Alder reaction is indispensable for the
stereoselective construction of six-membered rings,1 a structural
motif widely found in natural products. In its intermolecular
variant, a cyclohexene ring with up to four stereocenters can
be formed in a single step from acyclic precursors, often with
high levels of regio- and stereocontrol. A familiar property of
this reaction, whether thermal or catalyzed, is its endo diaste-
reoselectivity.2 As a result, the formation of these stereogenic
centers on the ring is often regarded as “predictable in a relative
sense”.3
In contrast, instances of the Diels-Alder reaction showing
exo selectivity occur less frequently, at least in an intermolecular
context. Apart from some isolated cases,4,5 certain structural
motifs on the dienophile are well-known to lead predominantly
to exo cycloadducts, including conformationally restricted cyclic
s-cis dienophiles6 and R-halo R,ꢀ-unsaturated carbonyl com-
pounds.7
mode of approach of the reactants (Scheme 1). Danishefsky and
co-workers8 utilized a gem-dimethyl group and a bulky aroyl
group on the diene and dienophile, respectively, to divert the
cycloaddition into the desired exo manifold by virtue of their
steric bulk. This was applied in the total synthesis of racemic
mamanuthaquinone (eq 1 in Scheme 1).
(4) (a) Sammis, G. M.; Flamme, E. M.; Xie, H.; Ho, D. M.; Sorensen,
E. J. J. Am. Chem. Soc. 2005, 127, 8612. (b) Pritchard, R. G.; Stoodley,
R. J.; Yuen, W.-H. Org. Biomol. Chem. 2005, 3, 162. (c) Pellegrinet,
S. C.; Spanevello, R. A. Org. Lett. 2000, 2, 1073. (d) Kozmin, S. A.;
Rawal, V. H. J. Org. Chem. 1997, 62, 5252. (e) Fraile, J. M.; Garc´ıa,
J. I.; Gracia, D.; Mayoral, J. A.; Pires, E. J. Org. Chem. 1996, 61,
9479. (f) Node, M.; Nishide, K.; Imazato, H.; Kurosaki, R.; Inoue,
T.; Ikariya, T. Chem. Commun. 1996, 2559. (g) Ward, D. E.; Gai, Y.
Tetrahedron Lett. 1992, 33, 1851. (h) Lamy-Schelkens, H.; Giomi,
D.; Ghosez, L. Tetrahedron Lett. 1989, 30, 5887. Exo-selective
catalytic asymmetric Diels-Alder reactions of Danishefsky-type dienes
and R,ꢀ-unsaturated N-acyloxazolidinones have also been disclosed
very recently. See: (i) Sudo, Y; Shirasaki, D.; Harada, S.; Nishida, A.
J. Am. Chem. Soc. 2008, 130, 12588. For a report on an exo-selective
Diels-Alder reaction that also includes a mechanistic discussion, see:
(j) Ge, M.; Stoltz, B. M.; Corey, E. J. Org. Lett. 2000, 2, 1927.
(5) Boren, B.; Hirschi, J. S.; Reibenspies, J. H.; Tallant, M. D.; Singleton,
D. A.; Sulikowski, G. A. J. Org. Chem. 2003, 68, 8991.
Synthetic protocols geared toward an exo-selective Diels-Alder
reaction usually entail the use of structurally elaborate starting
(6) (a) Cernak, T. A.; Gleason, J. L. J. Org. Chem. 2008, 73, 102. (b) Qi,
J.; Roush, W. R. Org. Lett. 2006, 8, 2795. (c) Roush, W. R.; Barda,
D. A.; Limberakis, C.; Kunz, R. K. Tetrahedron 2002, 58, 6433. (d)
Takeda, K.; Imaoka, I.; Yoshii, E. Tetrahedron 1994, 50, 10839. (e)
Pyne, S. G.; Safaei-G, J.; Hockless, D. C. R.; Skelton, B. W.; Sobolev,
A. N.; White, A. H. Tetrahedron 1994, 50, 941. (f) Roush, W. R.;
Brown, B. B. J. Org. Chem. 1992, 57, 3380. (g) Adam, W.; Albert,
R.; Hasemann, L.; Nava Salgado, V. O.; Nestler, B.; Peters, E.-M.;
Peters, K.; Prechtl, F.; von Schnering, H. G. J. Org. Chem. 1991, 56,
5782.
† University of Oxford.
‡ University of California, Los Angeles.
§ GlaxoSmithKline.
(1) Fringuelli, F.; Taticchi, A. The Diels-Alder Reaction: Selected
Practical Methods; Wiley: Chichester, U.K., 2002.
(2) (a) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry, Part
A: Structure and Mechanisms, 5th ed.; Springer: New York, 2007;
pp 834-873. (b) Ku¨rti, L.; Czako´, B. Strategic Applications of Named
Reactions in Organic Synthesis; Elsevier: Burlington, MA, 2005; pp
140-141.
(7) Corey, E. J.; Loh, T.-P. J. Am. Chem. Soc. 1991, 113, 8966.
(8) Yoon, T.; Danishefsky, S. J.; de Gala, S. Angew. Chem., Int. Ed. Engl.
1994, 33, 853.
(3) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis,
G. Angew. Chem., Int. Ed. 2002, 41, 1668.
9
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2009 American Chemical Society
J. AM. CHEM. SOC. 2009, 131, 1947–1957 1947

A R T I C L E S
Lam et al.
Scheme 1. Selected Examples of Substrate- and Catalyst-Controlled Exo-Selective Intermolecular Diels-Alder Reactions
Homochiral R,ꢀ-unsaturated N-acylamino Fischer carbenes
containing an oxazolidinone or imidazolidinone moiety have
been used as exo-selective dienophiles in cycloadditions of
cyclopentadiene and other acyclic dienes.9 The apically disposed
carbonyl ligands on the octahedrally coordinated metal center
furnished the steric hindrance for impeding the endo trajectory
(eq 2 in Scheme 1). Other stoichiometric organometallic reagents
have also been reported to give a high exo selectivity.10
An early example of catalyst-controlled exo-selective
Diels-Alder reactions was reported by Yamamoto and co-
workers.11 The bulky Lewis acid aluminum tris(2,6-diphe-
nylphenoxide) was shown to facilitate exo cycloaddition of
cyclopentadiene and phenyl vinyl ketone, a pair of reactants
that give predominantly an endo cycloadduct otherwise (eq 3
in Scheme 1). Exo-selective cycloadditions of cyclopentadiene
or diphenylisobenzofuran and R,ꢀ-unsaturated aldehydes were
documented by MacMillan and co-workers12 among the first
highly enantioselective organocatalytic Diels-Alder reactions.
More recently, Ishihara and Nakano13 reported the use of a chiral
binaphthyl-substituted diamine in cycloadditions using R-acy-
loxyacroleins as dienophiles. A structurally related, binaphthyl-
based diamine was found by Maruoka and co-workers14 to be
an effective catalyst in the exo-selective cycloadditions with
trans-cinnamaldehyde and two other R,ꢀ-unsaturated aldehydes.
The high exo selectivity has been attributed to the steric
hindrance of the binaphthyl moiety in the reactive iminium
intermediate formed from the dienophile and the catalyst (eq 4
in Scheme 1).15 Gotoh and Hayashi16 extended the scope of
R,ꢀ-unsaturated aldehydes suitable for exo-selective cycload-
ditions by using a diarylprolinol silyl ether as the organocatalyst.
In all of these reports on organocatalyzed Diels-Alder reactions,
instances where a high exo-selectivity is observed involve the
use of cyclopentadiene as the diene component.
(9) Powers, T. S.; Jiang, W.; Su, J.; Wulff, W. D.; Waltermire, B. E.;
Rheingold, A. L. J. Am. Chem. Soc. 1997, 119, 6438.
(10) (a) Barluenga, J.; Canteli, R.-M.; Flo´rez, J.; Garc´ıa-Granda, S.;
Gutie´rrez-Rodr´ıguez, A.; Mart´ın, E. J. Am. Chem. Soc. 1998, 120,
2514. (b) Richardson, B. M.; Welker, M. E. J. Org. Chem. 1997, 62,
1299. (c) Wright, M. W.; Smalley, T. L.; Welker, M. E.; Rheingold,
A. L. J. Am. Chem. Soc. 1994, 116, 6777. (d) Sabat, M.; Reynolds,
K. A.; Finn, M. G. Organometallics 1994, 13, 2084. (e) Gilbertson,
S. R.; Zhao, X.; Dawson, D. P.; Marshall, K. L. J. Am. Chem. Soc.
1993, 115, 8517.
(12) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243.
(13) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127, 10504.
(14) Kano, T.; Tanaka, Y.; Maruoka, K. Org. Lett. 2006, 8, 2687.
(15) Kano, T.; Tanaka, Y.; Maruoka, K. Chem.sAsian J. 2007, 2, 1161.
(16) Gotoh, H.; Hayashi, Y. Org. Lett. 2007, 9, 2859.
(11) Maruoka, K.; Imoto, H.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116,
12115.
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Exo-Selective Diels-Alder Reactions
A R T I C L E S
Scheme 2. Stereochemical Dependence on the Substitution Pattern of the Starting Materials
Chart 1. Structures of Dienes 1 and 2 and Dienophiles 3-6
Examples of exo-selective Diels-Alder reactions are also
found in host-guest chemistry. Thus, a trimeric porphyrin host
facilitates an exclusively exo cycloaddition of a furan and a
maleimide by orienting them in the required disposition.17 The
exo orientation can also be fulfilled by hydrogen bonding within
the supramolecular complex.18 Monoclonal antibodies that
catalyze enantioselective Diels-Alder reactions of N-acylamino-
1,3-butadienes and N,N-dimethylacrylamide in an either endo-
or exo-specific fashion have also been derived.19
During the study of the preparation of enantioenriched
fluorinated carbocycles,20 we synthesized an array of Diels-Alder
cycloadducts featuring an allylsilane or a silyl enol ether, starting
from all-carbon silylated dienes21 or silyloxy dienes, respectively
(Scheme 2).22,23 We observed a remarkable change in the endo/
exo stereoselectivity of the cycloaddition that depends on the
substitution pattern of the starting material. As depicted in
Scheme 2, when both R1 and R2 are a methyl group (Scheme
2, right), the adducts with four stereocenters are formed with a
consistently high exo selectivity. Use of the desmethyl diene
and/or dienophile leads to the “normal” endo products predomi-
nantly (Scheme 2, left). The observation that such a minor
modification of the substituents on these common substrates
could lead to a dramatic change in endo/exo selectivity is
intriguing, not least because it holds obvious implications for
the stereodefined synthesis of carbocycles in general. We now
detail the synthetic results obtained with this class of substituent-
dependent, exo-selective Diels-Alder reactions as well as the
results of computational studies that reveal the origins of these
selectivities.
Synthetic Results and Discussion
(17) Walter, C. J.; Anderson, H. L.; Sanders, J. K. M. J. Chem. Soc., Chem.
Commun. 1993, 458.
The dienes 1 and 2 and dienophiles 3-6 that form the basis
of this work are shown in Chart 1. The silylated dienes and
silyloxydienes24 and the dienophiles25 were either readily
synthesized by reported methods or were commercially avail-
able. The numbering of the product cycloadducts is shown in
Figure 1.
(18) Pearson, R. J.; Kassianidis, E.; Philp, D. Tetrahedron Lett. 2004, 45,
4777.
(19) (a) Cannizzaro, C. E.; Ashley, J. A.; Janda, K. D.; Houk, K. N. J. Am.
Chem. Soc. 2003, 125, 2489. (b) Heine, A.; Stura, E. A.; Yli-
Kauhaluoma, J. T.; Gao, C.; Deng, Q.; Beno, B. R.; Houk, K. N.;
Janda, K. D.; Wilson, I. A. Science 1998, 279, 1934. (c) Yli-
Kauhaluoma, J. T.; Ashley, J. A.; Lo, C.-H.; Tucker, L.; Wolfe, M. M.;
Janda, K. D. J. Am. Chem. Soc. 1995, 117, 7041. (d) Gouverneur,
V. E.; Houk, K. N.; de Pascual-Teresa, B.; Beno, B.; Janda, K. D.;
Lerner, R. A. Science 1993, 262, 204.
The Diels-Alder reactions involving the R,ꢀ-unsaturated
N-acyloxazolidinone 3 and their asymmetric variants mediated
by Evans’ chiral auxiliary 3* 26 are listed in entries 1-8 of Table
1. These were performed in dichloromethane at -40 °C
promoted by 1.4 equiv of Me2AlCl. As previously reported,20
the asymmetric Diels-Alder reaction of silylated diene 1a with
the homochiral 3* delivered endo-7 as the major product with
complete CR-Re facial selectivity (entry 1).26 Under otherwise
identical conditions, however, diene 1b, which has an extra
methyl group at C1, afforded exo-8 as the sole isolated product
(entry 2). As proved by X-ray crystallography of exo-8, this
cycloaddition also arises from attack on the homochiral dieno-
phile at its CR-Re face exclusively. The sense of asymmetric
induction in this case is thus identical to that observed in their
endo-selective counterparts involving 1a and other reported
dienes.26 Reaction of diene 1c bearing an additional methyl
group at C3 yielded comparable results (entry 3). The sense of
(20) Lam, Y.-h.; Bobbio, C.; Cooper, I. R.; Gouverneur, V. Angew. Chem.,
Int. Ed. 2007, 46, 5106.
(21) For related Diels-Alder reactions of all-carbon silylated dienes, see:
(a) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388. (b)
Vedejs, E.; Duncan, S. M. J. Org. Chem. 2000, 65, 6073. (c) Organ,
M. G.; Winkle, D. D. J. Org. Chem. 1997, 62, 1881. (d) Corey, E. J.;
Letavic, M. A. J. Am. Chem. Soc. 1995, 117, 9616. (e) Krafft, G. A.;
Garcia, E. A.; Guram, A.; O’Shaughnessy, B.; Xu, X. Tetrahedron
Lett. 1986, 27, 2691. (f) Sakurai, H.; Hosomi, A.; Saito, M.; Sasaki,
K.; Iguchi, H.; Sasaki, J.-I.; Araki, Y. Tetrahedron 1983, 39, 883. (g)
Trost, B. M.; Shimizu, M. J. Am. Chem. Soc. 1982, 104, 4299. (h)
Ojima, I.; Yatabe, M.; Fuchikami, T. J. Org. Chem. 1982, 47, 2051.
(22) (a) Frankowski, K. J.; Golden, J. E.; Zeng, Y.; Lei, Y.; Aube´, J. J. Am.
Chem. Soc. 2008, 130, 6018. (b) Alonso, D.; Caballero, E.; Medarde,
M.; Tome´, F. Tetrahedron Lett. 2007, 48, 907. (c) Caballero, E.;
´
Alonso, D.; Pela´ez, R.; Alvarez, C.; Puebla, P.; Sanz, F.; Medarde,
M.; Tome´, F. Tetrahedron 2005, 61, 6871. (d) Caballero, E.; Alonso,
D.; Pela´ez, R.; Alvarez, C.; Puebla, P.; Sanz, F.; Medarde, M.; Tome´,
F. Tetrahedron Lett. 2004, 45, 1631.
(23) (a) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626.
(b) Ruijter, E.; Schu¨ltingkemper, H.; Wessjohann, L. A. J. Org. Chem.
2005, 70, 2820. (c) Boezio, A. A.; Jarvo, E. R.; Lawrence, B. M.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 6046. (d) Chaplin,
J. H.; Edwards, A. J.; Flynn, B. L. Org. Biomol. Chem. 2003, 1, 1842.
(e) Kraus, G. A.; Hon, Y. S.; Sy, J.; Raggon, J. J. Org. Chem. 1988,
53, 1397. (f) Bell, V. L.; Holmes, A. B.; Hsu, S.-Y.; Mock, G. A.;
Raphael, R. A. J. Chem. Soc., Perkin Trans. 1 1986, 1507.
Figure 1. Numbering of cycloadducts.
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A R T I C L E S
Lam et al.
Table 1. Intermolecular Diels-Alder Reactions Involving Oxazolidinone Dienophiles
a
By 400 MHz H NMR of the product mixture after aqueous workup. b Reference 20. c 1b was used as an inseparable isomeric mixture with (Z,E)/
1
(E,E) ) 3:1. Reaction of only the major isomer was observed unless otherwise stated. d 1c was used as a mixture with (Z,E)/(E,E) ) 5:1. Reaction of
only the major isomer was observed. e At -100 °C. f The product of protodesilylation of the primary endo cycloadduct, epimerized at C5, was isolated
after chromatographic purification over silica gel. g Four sets of signals were observed by 1H NMR of the crude mixture. Two of the adducts were
assigned as exo-17 and its C5 epimer. The other two minor adducts were tentatively assigned as the corresponding endo isomers.
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Exo-Selective Diels-Alder Reactions
A R T I C L E S
Figure 3. Key NMR coupling constants for stereochemical assignments,
illustrated for endo- and exo-15.
of diene 1b and dienophile 5, each of which contained a terminal
methyl group on the reacting double bonds, the reaction was
exo-selective (entry 11).
The stereochemistries of all of the cycloadducts were readily
assigned on the basis of proton NMR coupling constants (Figure
3) and confirmed in the case of exo-8 by X-ray crystallography.
In the exo cycloadducts, the signal due to the methine ring
proton H1 (see Figure 1 for numbering) geminal to the carbonyl
group appears as a triplet of ∼10 Hz, consistent with vicinal
coupling of H1 to two trans-diaxial protons (H2 and H6). In
the endo counterparts with a C6 Me group (endo-720 and endo-
15), this signal exists as a doublet of doublets with coupling
constants of ∼10 and 6 Hz, which respectively arise from one
trans-diaxial pair and one axial-equatorial pair of coupled spins.
The couplings of H1 in cycloadducts derived from acryloyl
dienophiles (endo-10 and endo-16) were also consistent with
their stereochemistry.
Figure 2. Rationalization of the sense of asymmetric induction in the 1a-c
+ 3* cycloadditions.
asymmetric induction in both the endo- and exo-selective
cycloadditions could be explained by Evans’ model26 (Figure
2). The oxazolidinone-Lewis acid complex is rigidified by
chelation of both carbonyl groups to the aluminum. The benzyl
group of the chiral auxiliary effectively shields the CR-Si face
of the dienophile, giving rise to the sense of facial selectivity
observed.
The same substituent-dependent variation in endo/exo selec-
tivity was observed in the Diels-Alder reactions of 2-silyloxy-
1,3-butadienes with 3 and 4. Thus, the cycloaddition of diene
2a and the achiral acryloyl oxazolidinone 4 was highly endo-
selective (entry 4), while the same reaction with the crotonyl
oxazolidinone 3 gave the exo cycloadduct 11 as the only product
(entry 5). The stereoselectivity was not affected to any ap-
preciable extent by changing either the silyl protecting group
or the C4 substituent of the diene. The TIPS-protected sily-
loxydiene 2b and the 1,4-dimethylsilyloxydiene 2c respectively
delivered exo-12 (entry 6) and exo-13 (entry 7) with high
selectivity upon cycloaddition with 3. The asymmetric cycload-
dition of the silyloxydiene 2d with 3* also yielded the expected
product exo-14 with high exo/endo and facial selectivities (entry
8). The high exo selectivity of asymmetric carbo Diels-Alder
reactions using the auxiliary of 3* is rare in an intermolecular
context.27
Acyclic 2-silyloxy-1,3-butadienes substituted at one or both
termini are useful dienes in Diels-Alder reactions directed
toward a number of medicinally relevant targets. Despite their
structural simplicity, the stereochemical outcomes observed with
these substrates and cyclic dienophiles prove to be subtly
dependent on the structure of the reactants and the Lewis
acid.22,28 The variation of the observed endo/exo selectivity with
substitution pattern was rationalized in terms of steric clash
between substituents on the approaching diene and dienophile.
On the other hand, the use of oxazolidinone-containing dieno-
philes of the type 3* in R2AlCl-mediated Diels-Alder reactions
is well-precedented for simple dienes, and the use of 2-sily-
loxydienes was documented recently.29 We computationally
investigated the transition states (TSs) of the current series of
cycloadditions, focusing on how the substitution pattern of the
starting material impacts the stereochemical outcome.
R,ꢀ-Unsaturated ketones were also studied with silylated
dienes in the presence of catalytic Me2AlCl (entries 9-11). The
same trend in endo/exo selectivity with substitution pattern was
found. Thus, predominantly endo cycloaddition occurred when
either C1 of the diene (entry 9) or the ꢀ-position of the
dienophile (entry 10) was unsubstituted. For the combination
Computational Methodology
Geometry optimizations and thermodynamic corrections were
performed with hybrid density functional theory (B3LYP)30 using
the 6-31G(d)31 basis set. MP2(default, frozen core)/6-31+G(d)//
B3LYP/6-31G(d) single-point energies of endo and exo TSs were
also computed and compared with the B3LYP-derived values and
experimental data where available. Solvation corrections for the
experimentally used solvent, dichloromethane, were calculated using
(24) (a) Narayanan, B. A.; Bunnelle, W. H. Tetrahedron Lett. 1987, 28,
6261. (b) Hayashi, T.; Katsuro, Y.; Kumada, M. Tetrahedron Lett.
1980, 21, 3915. (c) Yamamoto, Y.; Yamamoto, H. Angew. Chem.,
Int. Ed. 2005, 44, 7082. (d) Kanemasa, S.; Kumegawa, M.; Wada, E.;
Nomura, M. Bull. Chem. Soc. Jpn. 1991, 64, 2990. Also see refs 20
and 23a.
(28) (a) Zeng, Y.; Aube´, J. J. Am. Chem. Soc. 2005, 127, 15712. (b) Zeng,
Y.; Reddy, D. S.; Hirt, E.; Aube´, J. Org. Lett. 2004, 6, 4993.
(29) Armstrong, A.; Davies, N. G. M.; Martin, N. G.; Rutherford, A. P.
Tetrahedron Lett. 2003, 44, 3915.
(25) (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1984,
106, 4261. (b) Thom, C.; Kocienski, P. Synthesis 1992, 582. (c)
Kanemasa, S.; Kanai, T. J. Am. Chem. Soc. 2000, 122, 10710.
(26) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988,
110, 1238.
(30) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 1372. (b) Becke, A. D.
J. Chem. Phys. 1993, 98, 5648. (c) Lee, C.; Yang, W.; Parr, R. G.
Phys. ReV. B 1988, 37, 785.
(27) For a recent example of the use of this chiral auxiliary in an exo-
selective asymmetric hetero-Diels-Alder reaction, see: Evans, D. A.;
Scheidt, K. A.; Downey, C. W. Org. Lett. 2001, 3, 3009.
(31) (a) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56,
2257. (b) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28,
213.
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A R T I C L E S
Lam et al.
Table 2. Activation Barriers and Their Dissection into Distortion
and Interaction Energies (all in kcal/mol) for the Endo and Exo
TSs of 2c + A2
∆Edq
dienophile
complex A2
entry
method
pathway
∆Eq
diene 2c
∆Eiq
1
2
3
4
B3LYP/ 6-31G(d) endo
exo
-0.1
-3.0
9.5
7.9
9.8
8.3
11.9
8.8
12.0
8.8
-21.4
-19.7
-33.1
-30.6
MP2/ 6-31+G(d)
endo -11.4
exo -13.5
consistent with computation. The activation enthalpies (∆Hq)
refer to the difference between the enthalpy of the TS and the
sum of enthalpies of the diene and the dienophile complex at
infinite separation in the gas phase. The small, negative gas-
phase ∆Hq values (and the negative ∆Eq values; see below) are
often observed in modeling gas-phase ion/molecule reactions
in general.37,38 In the present case, they are consistent with the
more favorable electrostatic attractions expected to exist between
the diene’s electrons and the cationic A2 at the TS compared
with the separate, unbound state.
Decomposition of the activation barrier ∆Eq into a distortion
Figure 4. Endo and exo TSs of the 2c + A2 cycloadditions. Gas-phase
enthalpies of activation were computed at the B3LYP/6-31G(d) level, and
free energies of activation were computed by B3LYP/6-31G(d) and corrected
for solvent effects by PCM single-point calculations at the HF/6-31+G(d,p)
level. Interatomic distances (Å) around the forming ring and angles of
pyramidalization at the termini of the partially formed bonds are labeled.
37,39
q
energy (∆Ed ) and an interaction energy (∆Eiq)
yields
valuable insight into the difference between the activation
energies of the endo and exo pathways. This analysis has
previously been applied in understanding 1,3-dipolar and
Diels-Alder cycloadditions.40 The distortion energy is the
energy required to distort the diene and the dienophile complex
into the geometries they have at the TS without allowing
interaction between them. The activation barrier is then the sum
of the distortion and interaction energies: ∆Eq ) ∆Edq + ∆Eiq,
where the interaction energy term encompasses all of the
stabilizing and repulsive interactions between the diene and
dienophile fragments at the TS. Table 2 lists the activation
barriers and distortion and interaction energies for the endo and
exo Diels-Alder TSs of 2c + A2, computed using the B3LYP
and MP2 methods.
the PCM method32 and UAKS radii with single-point calculations
at the HF/6-31+G(d,p) level of theory.33
Optimization of transition-structure geometries was started from
a boatlike input structure expected from the general Diels-Alder
reaction. The distance of the shorter of the forming bonds (C5-C6)
was first held fixed and the remainder of the structure optimized.
This distance constraint was then lifted, and the structure was
reoptimized to the TS.34 All of the energy minima and transition
structures were characterized by frequency analysis.
All of the calculations were performed with Gaussian 03.35
Computational Results and Discussion
The distortion energy values calculated using B3LYP or MP2
are very similar in most cases, but MP2 predicts that the
interactions at the endo TS are more stabilizing than those at
the exo TS by a larger margin than B3LYP does. MP2 favors
the endo pathway to a greater extent than B3LYP for all of the
investigated cycloadditions. The underestimation of endo/exo
selectivity by B3LYP due to problems in describing long-range
dispersion interactions has been noted.41,42
It is noteworthy that the interactions between the diene and
dienophile fragments are more stabilizing at the endo TS than
at the exo TS, regardless of the computational method used.
The net preference for exo selectivity observed in 2c + A2 is
therefore the result of more severe reactant distortions that
overwhelm the more favorable interaction energies in the endo
TS. The geometries of reactants 2c and A2 in their cycloaddition
We first computationally examined a Diels-Alder reaction
involving the oxazolidinone-containing dienophile 3 for which
experimental data were available. Dienophile 3 in the presence
of Me2AlCl was represented by the bidentate complex A2
(Figure 4) in computations. Chiral complexes of the type A2
have been invoked as the reactive species in R2AlCl-mediated
asymmetric Diels-Alder reactions26 and have been character-
ized in solution by NMR.36
The Me2AlCl-mediated cycloaddition of silyloxydiene 2c and
3 was completely exo-selective (Table 1, entry 7). The endo
and exo TSs of the 2c + A2 addition are presented in Figure 4,
which shows their boatlike geometries. B3LYP and second-
order Møller-Plesset perturbation theory (MP2) calculations
predict differences of 2.9 and 2.1 kcal/mol, respectively, in the
electronic activation barriers (∆Eq), both in favor of the exo
pathway (Table 2). The difference in the free energies of
activation (∆Gq) for the endo and exo approaches, after
correcting for solvent effects, is 4.0 kcal/mol (Figure 4). The
experimental level and sense of diastereoselectivity was thus
(37) Bickelhaupt, F. M. J. Comput. Chem. 1999, 20, 114.
(38) DeChancie, J.; Acevedo, O.; Evanseck, J. D. J. Am. Chem. Soc. 2004,
126, 6043.
(39) Nagase, S.; Morokuma, K. J. Am. Chem. Soc. 1978, 100, 1666.
(40) (a) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2008, 130, 10187. (b)
Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2007, 129, 10646. (c) Ess,
D. H.; Jones, G. O.; Houk, K. N. Org. Lett. 2008, 10, 1633. (d) Garc´ıa,
J. I.; Mart´ınez-Merino, V.; Mayoral, J. A.; Salvatella, L. J. Am. Chem.
Soc. 1998, 120, 2415. (e) Sbai, A.; Branchadell, V.; Ortun˜o, R. M.;
Oliva, A. J. Org. Chem. 1997, 62, 3049.
(32) Tomasi, J.; Persico, M. Chem. ReV. 1994, 94, 2027.
(33) Takano, Y.; Houk, K. N. J. Chem. Theory Comput. 2005, 1, 70.
(34) Birney, D. M.; Houk, K. N. J. Am. Chem. Soc. 1990, 112, 4127.
(35) Frisch, M. J.; et al. Gaussian 03, revisions C.02 and D.01; Gaussian,
Inc.: Wallingford, CT, 2004.
(41) Wannere, C. S.; Paul, A.; Herges, R.; Houk, K. N.; Schaefer, H. F.,
III; Schleyer, P. v. R. J. Comput. Chem. 2007, 28, 344.
(42) Tsuzuki, S.; Lu¨thi, H. P. J. Chem. Phys. 2001, 114, 3949.
(36) Castellino, S.; Dwight, W. J. J. Am. Chem. Soc. 1993, 115, 2986.
9
1952 J. AM. CHEM. SOC. VOL. 131, NO. 5, 2009

Exo-Selective Diels-Alder Reactions
A R T I C L E S
twist-asynchronous model was first put forward by Brown and
Houk47 to account for substituent-induced selectivity variation
in the context of intramolecular Diels-Alder (IMDA) reactions.
This has seen extensive application in the rationalization of
stereoselectivity in the IMDA reactions of other substrates.48
Table 3 lists the endo and exo TSs for the Diels-Alder
reactions of a series of silyloxydienes and other model dienes
with the oxazolidinone-bearing dienophile 3, either in the
presence of Me2AlCl (represented by the dienophile complex
A2) or in its absence. These are presented as Newman projec-
tions along the shorter of the forming bonds (C5-C6).
It is clear from Table 3 that the endo series of TSs displays
a wider range of twist-mode asynchronicities than the exo TSs.
Depending on diene substitution, θ varies from +12 to -33°
for the endo TSs and from +10 to +23° for the exo TSs. The
endo TS of the exo-selective 2c + A2 cycloaddition is highly
twisted, with θ ) -33°, and features a very small Me-Me
dihedral angle of 23° (entry 1). The corresponding exo TS is
much less twisted and places the vicinal Me groups at a dihedral
angle of 72°. The large difference in the Me-Me dihedral angles
of the two TSs explains why the dienophile complex experiences
a higher distortion at the endo TS.
Figure 5. Side view of the A2 dienophile fragment in the (a) endo and (b)
exo 2c + A2 TSs. (c) Overlay of the A2 dienophile fragments in the two
TSs of 2c + A2 (green atoms, endo; other-colored atoms, exo).
Replacing the C1 methyl group of 2c with hydrogen, resulting
in the desmethyl diene 2e, reduces the allylic 1,3-strain across
the silyl enol ether and allows TSs containing the s-syn rotamer
of 2e to be located. These TSs, which are displayed in entry 2,
are more stable than the corresponding TSs containing the s-anti
conformer of 2e. The levels of twisting are smaller, leading to
similar H-Me dihedral angles in the two TSs, concomitant with
a much smaller relative stability of the exo TS. MP2 even
predicts that the endo TS is more stable. The TS geometries
and energies are therefore heavily affected by the C1 methyl
substituent in this system.
What causes the drastic asynchronous twist in the endo 2c
+ A2 TS? To assess its origin, we modeled the TSs involving
diene 2f, in which a methoxy group replaces the silyloxy group
in 2c (entry 3). The computed free energies of activation indicate
that as a result of this replacement, the exo/endo difference
decreases from 4.0 kcal/mol (entry 1) to 2.3 kcal/mol (entry 3).
The endo TS is also less twisted, with θ ) -13°, placing the
vicinal Me groups at a dihedral angle of 44°. The twist-
asynchronicity and the resultant Me-Me dihedral angle are
practically the same in the exo TSs involving either the methoxy
or the silyloxy diene. Since the methoxy and trimethylsilyloxy
groups can be expected to possess similar electronic properties
(both dominated by oxygen), steric interactions, plausibly
between the trimethylsilyloxy group and the dimethylaluminum
portion of A2, are one contributor to the high twist-asynchro-
nicity in the endo 2c + A2 TS. Another destabilizing factor is
electrostatic repulsion between the oxygenated group and the
aluminum-bound dienophile. As the TSs of 2c + 3 (entry 4)
show, the asynchronous twist is considerably less severe in the
absence of the Lewis acid, resulting in the more typical Me-Me
Figure 6. Schematic illustration of the two modes of asynchronicity at
the TS of a Diels-Alder reaction.
TS geometries provide an illustrative example of reactant
distortions (Table 2). The diene fragment is more heavily
deformed at the endo TS by ∼1.5 kcal/mol, and the dienophile
is distorted twice as much (3.1 kcal/mol). The origin of the
dramatic difference in distortion energies of A2 in the two TSs
is most easily visualized by a side-on view of the dienophile
complex, as shown in Figure 5. The methyl group of dienophile
A2 is bent out of the olefinic plane more severely in the endo
TS (25°, Figure 5a) than in the exo TS (14°, Figure 5b),
indicating that it suffers greater repulsion from the vicinal diene
methyl group in the endo TS.
A twist-asynchronous model shows how vicinal disubstitution
can lead to a large distortion in the endo TS, which is chiefly
responsible for the exo selectivity found computationally and
experimentally.
In general, Diels-Alder reactions of unsymmetrical dienes
and dienophiles proceed through concerted43 asynchronous44
mechanisms.45 Two modes of asynchronicity in Diels-Alder
reactions can be distinguished (Figure 6). The stretch mode
refers to the differing lengths of the two forming C-C bonds
at the transition state (Figure 6a). The twist mode refers to the
deviation of the diene and the dienophile backbones from being
parallel and can be measured by a twist-asynchronicity param-
eter, θ, given by the C2-C5-C6-C1 dihedral angle, where
C5-C6 is the shorter of the forming C-C bonds (Figure 6b).
The impact of catalyst coordination on stretch-mode asynchro-
nicity of Diels-Alder reactions has been well-discussed.46
A
(43) (a) Goldstein, E.; Beno, B.; Houk, K. N. J. Am. Chem. Soc. 1996,
118, 6036. (b) Storer, J. W.; Raimondi, L.; Houk, K. N. J. Am. Chem.
Soc. 1994, 116, 9675. (c) Houk, K. N.; Lin, Y. T.; Brown, F. K. J. Am.
Chem. Soc. 1986, 108, 554.
(46) Garc´ıa, J. I.; Mayoral, J. A.; Salvatella, L. J. Am. Chem. Soc. 1996,
118, 11680. Also see refs 34 and 40d,e.
(47) (a) Brown, F. K.; Houk, K. N. Tetrahedron Lett. 1985, 26, 2297. (b)
Wu, T.-C.; Houk, K. N. Tetrahedron Lett. 1985, 26, 2293.
(48) (a) Tripoli, R.; Cayzer, T. N.; Willis, A. C.; Sherburn, M. S.; Paddon-
Row, M. N. Org. Biomol. Chem. 2007, 5, 2606. (b) Paddon-Row,
M. N.; Moran, D.; Jones, G. A.; Sherburn, M. S. J. Org. Chem. 2005,
70, 10841. (c) Cayzer, T. N.; Paddon-Row, M. N.; Moran, D.; Payne,
A. D.; Sherburn, M. S.; Turner, P. J. Org. Chem. 2005, 70, 5561. (d)
Lilly, M. J.; Paddon-Row, M. N.; Sherburn, M. S.; Turner, C. I. Chem.
Commun. 2000, 2213.
(44) (a) Singleton, D. A.; Schulmeier, B. E.; Hang, C.; Thomas, A. A.;
Leung, S.-W.; Merrigan, S. R. Tetrahedron 2001, 57, 5149. (b) Beno,
B. R.; Houk, K. N.; Singleton, D. A. J. Am. Chem. Soc. 1996, 118,
9984.
(45) Houk, K. N.; Gonzalez, J.; Li, Y. Acc. Chem. Res. 1995, 28, 81. For
an up-to-date discussion of Diels-Alder mechanisms, also see:
Bachrach, S. M. Computational Organic Chemistry; Wiley: Hoboken,
NJ, 2007; pp 128-133.
9
J. AM. CHEM. SOC. VOL. 131, NO. 5, 2009 1953

A R T I C L E S
Lam et al.
Table 3. Endo (n) and Exo (x) TS Geometries and Energetics (kcal/mol) for a Range of Silyloxydienes and Other Model Dienes with
Dienophile Complex A2 or Dienophile 3, with an Emphasis on Twist-Mode Asynchronicity
a Gas-phase Gibbs free energy of activation at B3LYP/6-31G(d) level, corrected for solvent effects by PCM single-point calculations at the HF/
6-31+G(d,p) level on B3LYP/6-31G(d) vacuum-optimized geometries. b Gas-phase uncorrected electronic energy at the B3LYP/6-31G(d)//B3LYP/
6-31G(d) level. The corresponding energy at the MP2/6-31+G(d)//B3LYP/6-31G(d) level is given in parentheses. c Twist-asynchronicity parameter. See
Figure 6b for definition. d In the absence of Me2AlCl (i.e., with dienophile 3).
dihedral angles of 67° (endo) and 75° (exo). The exo preference
is again diminished, and the MP2 energies even indicate an endo
preference. Electrostatic repulsion between the lone pair on a
heterodienophile and the diene is well-known to influence
9
1954 J. AM. CHEM. SOC. VOL. 131, NO. 5, 2009

Exo-Selective Diels-Alder Reactions
A R T I C L E S
Figure 7. Twist-asynchronicity model delineating the origin of exo
selectivity in Diels-Alder reactions involving oxygenated dienes.
stereochemical preferences49 and dictate reaction trajectories50
of hetero-Diels-Alder reactions. Analogous interactions should
also operate in the endo 2c + A2 system.
Figure 8. B3LYP/6-31G(d) endo TSs for the reaction of isoprene with
acrolein·AlMe2Cl obtained by (a) Singleton/Houk and (b) Evanseck.
On the basis of the above discussion, a twist-asynchronous
model rationalizing the substituent effects on the relative endo
and exo TS energies in the Diels-Alder reactions of silyloxy-
dienes is presented in Figure 7. In the endo series of TSs (Figure
7a), steric and electrostatic interactions between the diene C2
substituent and the aluminum-complexed dienophile drives the
rotation of the latter in the outward direction. This motion is
disfavored when both ends of the shorter of the forming bonds
(C5-C6) are methyl-substituted, since the rotation brings them
close together and aggravates the vicinal repulsion between
them. The twist-asynchronicity of these TSs reflects the tradeoff
between the two types of repulsion arising from their respective
local environments within the TSs. In contrast, the exo TSs are
less prone to these destabilizing interactions. As Figure 7b
shows, the twisting that would alleviate the steric and electro-
static interactions also moves any vicinal methyl substituents
on the forming C5-C6 bond further apart. The exo series of
TSs could therefore relax by asynchronous twisting as appropri-
ate. Indeed, when the 2-silyloxy- or 2-methoxydiene is methyl-
substituted at both termini, the exo TSs consistently displays a
narrow range of Me-Me dihedral angles between 69 and 75°
(Table 3, entries 1, 3, and 4). This model explains why the
relative energies of the endo and the exo TSs for a given
cycloaddition depend heavily on the substitution pattern and
why the exo TS is, in most cases, less destabilized than the
endo TS.
level and sense of the endo/exo selectivity. The twisting of these
TSs is small and comparable to that of the TSs involving the
2-trimethylsilyloxydiene 2e (entry 2). The substituents around
the shorter of the forming C-C bonds are arranged in an
approximately staggered manner. The low level of twisting of
the endo 18 + A2 TS could be favorably compared to that of
the TSs computed in the dialkylaluminum chloride-catalyzed
Diels-Alder reaction of isoprene and acrolein. Singleton, Houk,
and co-workers51 and Acevedo and Evanseck52 have shown that
the TS of this reaction, which was validated by experimental
and calculated kinetic isotope effects, corresponds to the endo
approach of the two reactants. The computed TSs (Figure 8)
display a low level of asynchronous twist and a nearly staggered
arrangement of substituents around the shorter of the forming
C-C bonds, similar to the endo 18 + A2 TS. Consequently,
the greater stabilization of the endo TSs determines the
stereoselectivity.
Adding a terminal methyl substituent to trans-piperylene gives
2,4-hexadiene (19). Exo selectivity is now found (Table 3, entry
6). In the endo TS, the backbones of the diene and the dienophile
are skewed, with θ ) +12°. The Me-Me repulsion forces the
dienophile away from ideal overlap with the remote terminus
of the diene. Although the endo TS is now more destabilized
(according to B3LYP energies), the magnitude of such desta-
bilization is small (a 1.4 kcal/mol free-energy difference)
compared with the cases where the diene is additionally
substituted at the 2-position (2-4 kcal/mol, Table 3, entries 1
and 3). The “back side” of the endo 19 + A2 TS is not hindered
by substituents. This allows the dienophile to rotate inward to
alleviate the vicinal dimethyl repulsion and the accompanying
destabilization.
Computations of Diels-Alder TSs of the dienophile complex
A2 with a series of structurally simpler dienes give further
support to the twist-asynchronicity model. trans-Piperylene (18)
was reported by Evans et al.26 to react with 3* in the presence
of Et2AlCl with an endo/exo selectivity superior to 95:5.
Modeling of the TSs of the 18 + A2 addition (Table 3, entry
5), with MP2 single-point energies, reproduced the experimental
The phenyl-substituted silylated dienes 1b and 1a used in
the experimental studies were modeled by the methyl analogs
(49) Iafe, R. G.; Houk, K. N. J. Org. Chem. 2008, 73, 2679.
(50) (a) Leach, A. G.; Houk, K. N. J. Org. Chem. 2001, 66, 5192. (b)
McCarrick, M. A.; Wu, Y. D.; Houk, K. N. J. Org. Chem. 1993, 58,
3330.
(51) Singleton, D. A.; Merrigan, S. R.; Beno, B. R.; Houk, K. N.
Tetrahedron Lett. 1999, 40, 5817.
(52) Acevedo, O.; Evanseck, J. D. Org. Lett. 2003, 5, 649.
9
J. AM. CHEM. SOC. VOL. 131, NO. 5, 2009 1955

A R T I C L E S
Lam et al.
Figure 9. Endo and exo TSs of the 1d + A2 and 1e + A2 cycloadditions. Gas-phase enthalpies of activation were computed at the B3LYP/6-31G(d) level,
and free energies of activation were computed by B3LYP/6-31G(d) and corrected for solvent effects by PCM single-point calculations at the HF/6-31+G(d,p)
level. Interatomic distances (Å) around the forming ring and angles of pyramidalization at the termini of the partially formed bonds are labeled.
Table 4. Activation Barriers and Their Dissection into Distortion
and Interaction Energies (all in kcal/mol) for the Endo and Exo
endo TS than in the exo TS, while the corresponding difference
TSs of 1d + A2 and 1e + A2
1d and dienophile complex A2 is 3.2 kcal/mol higher in the
involving the desmethyl analog 1e favors the endo pathway by
only ∼0.9 kcal/mol.
∆Edq
dienophile
complex A2
Replacing the oxygen in 2c and 2e with methylene, giving
the all-carbon silylated dienes 1d and 1e, respectively, leads to
considerable alleviation of the twisting in both the endo and
exo TSs with A2 (Table 5, entries 1 and 2). These TSs display
θ values between -6 and -15°. This is consistent with the
reduction of electrostatic repulsion between the diene and
dienophile fragments as a result of this replacement. To
investigate the influence of the silyl functionality, we computed
model TSs for the reaction of A2 with 3-methylhexa-2,4-diene
(20), in which the silyl group is replaced by a hydrogen (Table
5, entry 3). For the 20 + A2 addition, a difference of 1.4 kcal/
mol in the free energies of activation favoring the exo product
was computed; this is the same in magnitude and direction as
that involving the C2-desmethyl diene 19 (Table 3, entry 6)
but only half of that observed for the corresponding silylated
diene 1d (Table 5, entry 1). The C2 methyl substituent on the
diene does perturb the endo TS geometry, as the vicinal methyl
groups are now set at a dihedral angle of 51° compared with
71° in its absence. The change in the exo TS geometry is
negligible. An extra trimethylsilyl group on the diene, however,
causes little perturbation in the geometry of either the endo or
the exo TS in terms of twist-mode asynchronicity and vicinal
Me-Me dihedral angles in 1d + A2. The amplified exo
selectivity caused by the presence of the silyl group is likely to
be electronic rather than steric in origin, although the precise
underpinnings are more subtle in these cases.
entry reactants
method
pathway
∆Eq
diene
∆Eiq
1
1d +
B3LYP/6-31G(d) endo
exo
2.0 10.9
14.2
-23.2
A2
2
3
4
5
-0.1 9.2
12.7
14.3
12.7
7.6
-22.0
-39.1
-35.2
-15.0
MP2/6-31+G(d) endo -14.8 10.0
exo
-14.1 8.4
-1.4 6.0
1e +
A2
B3LYP/6-31G(d) endo
6
7
8
exo
-1.3 6.3
8.2
7.6
8.2
-15.8
-26.3
-25.4
MP2/6-31+G(d) endo -12.9 5.9
exo
-11.2 6.1
1d and 1e, respectively. The free energies of activation of their
cycloadditions with A2 indicate that the exo preference is very
strong in the case of diene 1d and much diminished for diene
1e, where the C1 methyl group on the diene is replaced by
hydrogen (Figure 9). This trend is consistent with the experi-
mental results for the cycloadditions of 3* with 1a and 1b (Table
1, entries 1 and 2). The moderate endo selectivity in the
experimental 1a + 3* reaction could not be reproduced by the
B3LYP energies of the 1e + A2 TSs, although the MP2 single-
point energies predicted a much higher proportion of the endo
product. MP2 methods have been shown in some cases to be
more accurate in reproducing experimental trends, particularly
when weak nonbonding interactions are involved.5,41,53
An analysis of the distortion and interaction energies (Table
4) shows that the distortion energies in the endo TS again
overwhelm the more favorable interaction energies in the
presence of vicinal disubstitution, accounting for the observed
exo preference. The sum of the distortion energies of the diene
Conclusion
Anewseriesofsubstituent-dependentexo-selectiveDiels-Alder
reactions involving silylated dienes or silyloxydienes and R,ꢀ-
unsaturated N-acyloxazolidinone or ketone dienophiles has been
studied experimentally and computationally. These reactions
demonstrate the maximal stereochemical efficiency of the
Diels-Alder reaction by installing four contiguous stereocenters
in the cycloadduct with a very favorable exo selectivity and
(53) (a) Dinadayalane, T. C.; Vijaya, R.; Smitha, A.; Sastry, G. N. J. Phys.
Chem. A 2002, 106, 1627. (b) Baki, S.; Maddaluno, J.; Derdour, A.;
Chaquin, P. Eur. J. Org. Chem. 2008, 3200. (c) Bakalova, S. M.;
Santos, A. G. J. Org. Chem. 2004, 69, 8475. (d) Bakalova, S. M.;
Kaneti, J. J. Phys. Chem. A 2008, 112, 13006.
9
1956 J. AM. CHEM. SOC. VOL. 131, NO. 5, 2009

Exo-Selective Diels-Alder Reactions
A R T I C L E S
Table 5. Endo (n) and Exo (x) TS Geometries and Energetics (kcal/mol) for a Range of Substituted Silylated Dienes and a Model Diene
with Dienophile Complex A2, with an Emphasis on Twist-Mode Asynchronicity
a Gas-phase Gibbs free energy of activation at the B3LYP/6-31G(d) level, corrected for solvent effects by PCM single-point calculations at the HF/
6-31+G(d,p) level on the B3LYP/6-31G(d) vacuum-optimized geometries. b Gas-phase uncorrected electronic energy at the B3LYP/6-31G(d)//B3LYP/
6-31G(d) level. The corresponding energy at the MP2/6-31+G(d)//B3LYP/6-31G(d) level is given in parentheses. c Twist-asynchronicity parameter. See
Figure 6b for definition.
Acknowledgment. We thank Dr. Andrew Cowley for assistance
with X-ray structure determination. This work was funded by the
Croucher Foundation, Hong Kong (Y.-h.L.), the U.K. Overseas
Research Studentship (Y.-h.L.), GlaxoSmithKline (Y.-h.L.), the
U.K. Engineering and Physical Sciences Research Council
(J.M.B.M.), and the National Institute of General Medical Sciences,
National Institutes of Health (P.H.-Y.C., K.N.H.). Computational
resources were provided by Academic Technology Services, UCLA,
and the National Service for Computational Chemistry Software,
EPSRC.
π-facial selectivity. A systematic experimental study identified
the structural prerequisites in the starting materials for such a
high level of exo preference, namely, simultaneous methyl
substitution on the diene and dienophile termini involved in the
shorter of the forming C-C bonds. On the basis of computa-
tional investigations of both experimental and other model
systems, a twist-mode asynchronicity model for understanding
the origin of the endo/exo stereocontrol was put forward.
Specifically, this work showed how the vicinal disubstituent
effect could destabilize the highly asynchronous endo TSs,
requiring rotations that reduce steric and electrostatic repulsion
within the TSs at the expense of reactant distortion. Interaction
energies favor the endo pathway, but this is overwhelmed by
distortion that relieves gauche-type Me-Me repulsions. This
work has moved us closer to a more comprehensive understand-
ing of the factors controlling Diels-Alder endo/exo stereose-
lectivity. It should also contribute to more effective experimental
planning in using this reaction in the stereodefined synthesis of
many molecular targets featuring six-membered rings.
Supporting Information Available: Complete ref 35; crystal-
lographic data for exo-8 in CIF format; full experimental
procedures and characterization data for all new compounds;
and Cartesian coordinates, energies, and thermal corrections for
all of the optimized reactants and transition structures. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA8079548
9
J. AM. CHEM. SOC. VOL. 131, NO. 5, 2009 1957