Cayzer et al.
trans-fused cycloadducts are formed predominantly, ir-
respective of the dienophile geometry. The maleate
Z-dienophiles furnish more trans-selective IMDAs be-
cause of destabilizing overlap repulsion in the TSs
leading to the E-dienophile series trans-adducts.8
Herein, ester-tethered 1,3,8-nonatrienes19-21 are ex-
amined to further explore the influence of diene and
dienophile substitution upon pentadienyl acrylate IMDA
TS overlap repulsion and stereoselectivity (vide supra).
We report the reactivities and trans/cis-stereoselec-
tivities7 of IMDAs of terminally substituted pentadienyl
acrylates (2-5), maleates (6-10), fumarates (11-15),
crotonates (16-17), and chloroacrylates (18-19). To our
knowledge, IMDA reactions of pentadienyl crotonates and
chloroacrylates have not previously been reported in the
literature.
FIGURE 1. 1,3,8-Nonatriene (A) and ester-tethered C3 and
C5-substituted cognates (B-D).
SCHEME 1. Intramolecular Diels-Alder Reaction
trans- and cis-Bicyclic Products
Results and Discussion
IMDA Reactions. The IMDA precursors 1-19 were
prepared by high-yielding esterification reactions be-
tween dienols and dienophile carboxylic acids and deriva-
tives. Trienes 1-19 undergo IMDAs in 25-97% isolated
yields in common aromatic solvents (Table 1). The
cycloadducts are configurationally stable under the reac-
tion conditions.
Cycloadduct stereochemistries were assigned on the
basis of 2D NMR experiments. The stereochemistry of
trans-fused, exo-IMDA adducts trans-2P, trans-fused
C1-(i-Pr) adduct trans-13P, Z- and E-crotonate exo-
cycloadducts trans-16P and trans-17P, and cis-fused,
endo-IMDA adducts pentadienyl maleate cis-6P and
Z-chloroacrylate cis-18P were confirmed by single-crystal
X-ray analysis (Figure 2 and Supporting Information).
Relative Reactivities. Triene reactivity varies con-
siderably with substitution, but the nature and orienta-
tion of the terminal dienophile (C9) substituent has a
much greater influence upon the reaction rate than does
the terminal diene (C1) substituent (see Table 1). For
example, 9-Z-CO2Me-substituted precursors 6-10 un-
dergo complete conversion at 110 °C within 2-7 h,
whereas 9-E-Me precursor 17 requires several weeks at
trans-selective IMDAs.16 Pentadienyl maleates (6, 7) and
fumarates (11, 12) (Scheme 1) also undergo IMDAs at
80-110 °C.8,17,18 The thermodynamically less stable
(13) (a) Paddon-Row, M. N.; Rondan, N. G.; Houk, K. N. J. Am.
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Wu, Y. D.; Metz, J. T.; Paddon-Row, M. N. Tetrahedron 1984, 40, 2257-
2274. (c) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu, Y. D.;
Brown, F. K.; Spellmeyer, D. C.; Metz, J. T.; Li, Y.; Loncharich, R. J.
Science 1986, 231, 1108-1117. (d) Li, Y.; Paddon-Row, M. N.; Houk,
K. N. J. Am. Chem. Soc. 1988, 110, 3684-3686. (e) Paddon-Row, M.
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(14) Calculated Boltzmann product distributions (based upon the
relative energies of respective TSs) and experimental product ratios
(from kinetically controlled reactions) are generally in excellent
agreement, and the computed TSs are used to rationalize the steric
and electronic features that determine the experimental stereochemical
IMDA outcomes.13 Finally, approaches are then devised to optimize
the population of a targeted stereoisomeric product.
(15) For related investigations with pentadienyl acrylates, see:
(a) White, J. D.; Nolen, E. G., Jr.; Miller, C. H. J. Org. Chem. 1986,
51, 1150-1152. (b) White, J. D.; Demnitz, F. W. J.; Oda, H.; Hassler,
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(16) These studies supported the total synthesis of the selective
muscarinic receptor antagonist himbacine. See: (a) Wong, L. S.-M.;
Sharp, L. A.; Xavier, N. M. C.; Turner, P.; Sherburn, M. S. Org. Lett.
2002, 4, 1955-1957. (b) Wong, L. S.-M.; Sherburn, M. S. Org. Lett.
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4, 1579-1582. (d) Gao, L.-J.; Van Cauwenberge, G.; Hosten, N.; Van
Haver, D.; Waelbroeck, M.; De Clercq, P. J. ARKIVOC 2003, iv, 22-
45.
(18) For synthetic studies on IMDA reactions of pentadienyl male-
ates and fumarates, see: (a) Burke, S. D.; Smith Strickland, S. M.;
Powner, T. H. J. Org. Chem. 1983, 48, 454-459. (b) Jenkins, P. R.;
Menear, K. A.; Barraclough, P.; Nobbs, M. S. J. Chem. Soc., Chem.
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(19) 1,3,8-Nonatriene numbering is retained for the esters described
in this paper to facilitate comparisons with other IMDA precursors of
the same general class.
(20) The bicyclic lactone cycloadducts derived from these triene
precursors are common in nature and useful synthetic intermediates.
For example, see: ref 18 and (a) Borzilleri, R. M.; Weinreb, S. M.;
Parvez, M. J. Am. Chem. Soc. 1995, 117, 10905-10913. (b) Carter, R.;
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(17) For seminal synthetic investigations with pentadienyl citra-
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(21) Cayzer, T. N.; Paddon-Row, M. N.; Sherburn, M. S. Eur. J. Org.
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5562 J. Org. Chem., Vol. 70, No. 14, 2005