diene reacted with high selectivity as well, giving the
cycloadducts with de values in the range of 93-94%. Under
optimum conditions, the Diels-Alder cycloadditions pro-
ceeded in >94% yield to give solid products that were
purified by recrystallization or chromatography to 100% de.
The structures of the major cycloadducts 6a, 7a, 8a, and 9a
are shown in Scheme 2 and were determined unequivocally
The acid-stable cycloadduct 10a (93.5% de) was trans-
esterified by n-PrOH at 85 °C in 20 h, in the presence of
excess methanesulfonic acid (MeSO3H). Workup and silica
gel chromatography afforded n-propyl ester (+)-10b in 90%
yield and 93% ee.
Alternatively, 6a and 7a were cleaved reductively with
diisobutylaluminum hydride (DIBAL-H). For example, re-
duction of (-)-6a by 2.0 equiv of DIBAL-H in CH2Cl2 at
-78 °C for 1 h afforded endo alcohol (-)-6d in 88% yield
and controller (+)-2 in 93% yield after silica gel chroma-
tography.
Scheme 2
r-Alkylation of Esters of (+)- and (-)-2. Aryl acetate
esters 11, 12, and 13 derived from controllers (+)- and (-)-2
underwent highly stereoselective enolization-alkylation
reactions with a variety of electrophiles. Ester (-)-11 was
after removal of the controller group. Assignment of the
stereochemistry of major product 10a was done by correla-
tion to the structurally related products 8a and 9a.
BF3 and BF3‚OEt2 were also effective catalysts for the
reaction of (+)-5 and cyclopentadiene. Acrylate esters of the
(+)- and (-)-â-hydroxy sulfides 4 were inferior to the
corresponding sulfones with regard to stereoselectivity in
Lewis acid-catalyzed Diels-Alder reactions. It is possible
that Lewis acid complexation with the basic sulfur of 4 is a
complicating factor.
Removal and recovery of the chiral auxiliary from the
Diels-Alder products was achieved by titanium(IV) isopro-
poxide-catalyzed transesterification to isopropyl esters. For
example, cycloadduct (-)-6a was cleaved by being heated
at 85 °C in 2-propanol containing 3.3 equiv of Ti(i-PrO)4
for 52 h, according to Seebach’s protocol.17 After silica gel
chromatography, isopropyl ester (-)-6b was obtained in 91%
yield and controller (+)-2 was recovered in 88% yield. The
isopropyl ester (-)-6b was hydrolyzed in aqueous LiOH in
CH3OH at 23 °C in 36 h to give the pure endo carboxylic
acid (-)-6c in 90% yield.
prepared in 89% yield from (-)-2 and phenylacetic acid in
CH2Cl2 in the presence of 1,3-dicyclohexylcarbodiimide
(DCC), 4-(dimethylamino)pyridine (DMAP), and activated
4 Å molecular sieves at 23 °C for 4.5 h. Similarly, esters
(+)-12 and (+)-13 were synthesized from (+)-2 and 6-meth-
oxynaphthylacetic acid18 or 4-isobutylphenylacetic acid by
DCC coupling in 85% and 90% yields, respectively.
The best alkylation results were obtained via the potassium
enolate which was formed with triphenylmethylpotassium
as the base. Tritylpotassium was readily prepared in quantity
in dimethoxyethane (DME) solution by the procedure of
House19 or more conveniently by reaction of potassium
hydride, triphenylmethane, and a catalytic amount of di-
methyl sulfoxide (DMSO).20
The results of the alkylation reaction of ester (-)-11 with
five different electrophiles are shown in Table 2. In a typical
experiment, 1.0 equiv of a solution of Ph3CK in DME (ca.
0.6 M) was diluted to ca. 0.1 M with DME and N,N′-
dimethylpropyleneurea (DMPU) to a final solvent ratio of
4:1, cooled to -78 °C, and treated with a solution of (-)-
11 in 4:1 DME-DMPU. The enolate of 11, which was
rapidly formed as evidenced by the change in color from
blood-red to deep orange, was then treated with the alkylating
agent. The alkylation reactions were complete within a few
minutes, as judged by the decolorization of the reaction
mixture. Diastereomerically pure alkylation products were
obtained by recrystallization. The stereochemical assignment
Cycloadducts 8a and 9a were conveniently cleaved by
methanolysis followed by hydrolysis in a one-pot sequence.
Substrate 8a (93.5% de) was treated with an excess of
LiOCH3 in CH3OH-THF at -10 °C for 24 h, followed by
1.0 equiv of 0.5 M aqueous LiOH at 23 °C for 2 h. After
standard workup, carboxylic acid (+)-8b was obtained in
98% yield and 92.5% ee along with auxiliary (-)-2 (92%
yield).
(18) Gonza´lez, A. Synth. Commun. 1991, 21, 1353.
(19) House, H. O.; Kramar, V. J. Org. Chem. 1962, 27, 4146.
(20) (a) Huffman, J. W.; Harris, P. G. Synth. Commun. 1977, 7, 137. (b)
Matthews, F. J. J. Chem. Educ. 1997, 74, 996.
(17) Seebach, D.; Hungerbu¨hler, E.; Naef, R.; Schnurrenberger, P.;
Weidmann, B.; Zu¨ger, M. Synthesis 1982, 138.
Org. Lett., Vol. 1, No. 11, 1999
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