J. Am. Chem. Soc. 2001, 123, 4607-4608
4607
Scheme 1
Intramolecular Diels-Alder Reactions Employing
Hydroxamate Tethers: The First Examples and
Promising Prospects
Teruhiko Ishikawa,* Mami Senzaki, Ryuuichirou Kadoya,
Takashi Morimoto, Naoki Miyake, Miyoko Izawa, and
Seiki Saito*
Department of Bioscience and Biotechnology
Faculty of Engineering, Okayama UniVersity
Tsushima, Okayama, Japan 700-8530
Scheme 2
Hisayoshi Kobayashi
College of Science and Industrial Technology
Kurashiki UniVersity of Science and the Arts
Nishinoura, Tsurajima-cho, Kurashiki, Japan 712-8505
ReceiVed January 9, 2001
The intramolecular Diels-Alder reaction (IMDA)1 is a power-
ful and important tool for the regio- and stereoselective construc-
tion of functionalized cyclohexene frameworks. In our efforts to
explore promising IMDA systems which fulfill the four criteria,
(1) easy connection between diene and dienophile parts by using
a tethering group,2 (2) high reactivity, (3) homogeneous stereo-
chemical consequences, and (4) highly versatile latent functional-
ity of the tethering group itself, we found that hydroxamate-
tethered triene 1a deserved serious consideration in this context:
when a solution of 1a in toluene was heated at 80 °C for 2 h,
cycloadduct 2a was obtained as a single diastereomer (80%)
(Scheme 1). The potential of 1a became quickly apparent when
the IMDA of trienic amide 3 was examined, which was not
completed even after 48 h at 80 °C and led to 4 as a mixture of
two diastereomers (1:1) in 50% yield (Scheme 1).
One of the factors responsible for these contrasting results can
be the most stable conformation of N-benzylhydroxamates il-
lustrated as C in which the diene and dienophile parts (X and Y)
are in close proximity (Scheme 2): Hartree Fock 6-31G* level
calculation indicated that the conformer C is more stable than an
A-type one by 4.4 kcal/mol in the case of 1a.3 Thus, the IMDA
of 1a must be entropically highly favored.
In Scheme 3 is outlined the typical synthesis of two hydrox-
amate-tethered triene systems (1 and 9). Acylation of N-
benzylhydroxylamine (BHA)4 with alkenoic or alkadienoic acid
chlorides exclusively took place not at the oxygen atom but at
the nitrogen atom to furnish 5 or 7, respectively. Because of
enhanced nucleophilicity of the hydroxy group in these hydrox-
amic acids,5 Mitsunobu reaction6 of 2,4-hexadiene-1-ol (6) or
allylic alcohol (8) with 5 or 7 nicely proceeded to afford trienes
1 or 9, respectively, in high yield [DEAD-Ph3P or 1,1-(azodi-
carbonyl)dipiperidine (ADDP)-Bu3P,7 room temperature/2 h].
Scheme 3
One of the significant and amazing consequences of the IMDA
of 1 and 9 was exclusive stereochemical results, a cis-fused ring
system from 1 or 11 and trans-fused one from 9. As illustrated
in Table 1 and Scheme 4, cis-fused cycloadducts 2 and 13 (or
12) were obtained as a single isomer with an absolute (2f) or
illustrated relative configuration8 in high yield. The reaction of
1c proceeded so rapidly that it was completed when the introduc-
tion of the diene part had finished (THF, rt, 1 h). Although the
reaction became more sluggish when both ends of the triene chain
bore one substituent (1e) or the diene end was geminally
substituted (1g), the stereochemical homogeneity remained intact.
Treating the enone 10, itself obtained similarly as shown in
Scheme 3, with TBSOTf in THF at 0 °C in the presence of Et3N
gave the enol silyl ether 11, which was smoothly converted in
situ into the cis-fused cycloadduct 12, which, on acidic hydrolysis9
led to 13 in high yield. The enol silyl ethers 11b-d were
sufficiently stable to be isolated in quantitative yield; heating to
90-100 °C in toluene led to cycloadducts 12 or 13, depending
on the stability of intermediates 12 to silica gel chromatography.
The observed stereochemical consequences strongly suggest
the existence of an endo-transition state as shown below (TS1:
endo-boat) in which two oxygen atoms in the O-N-CdO unit
can avoid electrostatic repulsion as mentioned above for the
(1) For reviews of IMDA, see: (a) Ciganek, E. Org. React. 1984, 32, 1.
(b) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds; Pergamon: Oxford, 1991; Vol. 5, Chapter 4.4, pp 513-550. (c)
Carruthers, W. Cycloaddition Reactions in Organic Synthesis; Pergamon
Press: Oxford, 1990; pp 269-331. (d) Padwa, A.; Schoffstall, A. M. In
AdVances in Cycloaddition; Curran, D. P., Ed.; JAI Press: Greenwich, 1990;
Vol. 2, pp 1-89.
(2) References to other temporary heteroatom tether strategies for intra-
molecular Diels-Alder reactions are provided in Supporting Information.
(3) Ab initio molecular orbital calculations were performed with the
GAUSSIAN 94/98 program package at the HF 6-31G* level: for details, see
Supporting Information.
(4) A substituent on the nitrogen atom turned out to be crucial: for instance
N-CH3, no substituent, or N-benzoyl resulted in low yield and poor selectivity,
decomposition, or deacylation and decomposition, respectively.
(5) Jencks, W. P.; Carriuolo, J. J. Am. Chem. Soc. 1960, 82, 1778-1785.
(6) (a) Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc. 1972, 94,
679-680. (b) Grochowski, E.; Jurczak, J. Synthesis 1976, 682-684.
(7) Only in the case of sterically nondemanding secondary allylic alcohols,
an SN2′-type pathway competitively took place: it turned out that the super
Mitsunobu conditions [Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron Lett.
1993, 34, 1639-1642] worked much better in such cases in which, fortunately,
the SN2 and SN2′ products could be separated by SiO2 column chromatography.
(8) All products gave satisfactory spectroscopic data (NMR, IR, and MS).
The stereochemistry of all the cycloadducts was determined by NOESY
measurement and the evaluation of JH-H values: see Supporting Information.
(9) The stereochemistry of cycloadducts 12 was determined on the basis
of spectroscopic data at the stage of 13 because the enol silyl ether group of
12 is somewhat unstable and a mixture of 12 and 13 was usually obtained.
10.1021/ja010083z CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/18/2001
Ishikawa
