Studies on the sequential multi-component coupling/Diels-Alder cycloaddition reaction

Article abstract of DOI:10.1016/S0040-4039(01)02299-7

The synthesis of highly functionalized oxabicyclo[2.2.1]heptadiene derivatives through the sequential use of an Ugi or Passerini multi-component coupling reaction followed by an intramolecular acetylene/furan Diels-Alder reaction was investigated. The nature of the heteroatom in the tether was determined to play a critical role.

Full text of DOI:10.1016/S0040-4039(01)02299-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 943–946
Studies on the sequential multi-component coupling/Diels–Alder
cycloaddition reaction
Dennis L. Wright,* Claude V. Robotham and Khalil Aboud†
Department of Chemistry, University of Florida, Gainesville, FL 32611, USA
Received 17 September 2001; revised 28 September 2001; accepted 30 November 2001
Abstract—The synthesis of highly functionalized oxabicyclo[2.2.1]heptadiene derivatives through the sequential use of an Ugi or
Passerini multi-component coupling reaction followed by an intramolecular acetylene/furan Diels–Alder reaction was investigated.
The nature of the heteroatom in the tether was determined to play a critical role. © 2002 Elsevier Science Ltd. All rights reserved.
Wortmannin (1) and viridin (2) are highly oxygenated
furanosteroids isolated from fungal sources.1 These
compounds have received considerable attention
because they function as potent inhibitors of the signal-
ing enzyme phosphatidylinositol-3-kinase (PI-3K).2
Excessive activity of PI-3K has been associated with
certain types of cancer, prompting the development of
potent and specific inhibitors.3 It is proposed4 that 1
and 2 inhibit PI-3K by covalent modification of the
active site. This occurs through addition of the o-amino
group of lysine 802 to the C21 position followed by
elimination of the furan oxygen. Although typically a
nucleophile, the furan is rendered electrophilic at C21
by virtue of the carbonyl groups at C3 and C7, while
furan opening is promoted by relief of ring strain.
Although these compounds are potent inhibitors of
PI-3K, they are not completely selective, inhibiting
other kinases such as mTOR5 and DNA-dependent
kinase.6
function. The design of these simplified analogs (gener-
alized in structure 3) (Scheme 1) is based on the
hypothesis that the annulated furan in this structure
contains the required features to covalently modify the
enzyme. These simplified analogs retain the furan moi-
ety, deactivated at C21 by two carbonyl groups. The
E-ring is also retained to incorporate strain in the furan
and provide additional sites for modification. A strat-
egy for the synthesis of these analogs was devised that
would maintain a high degree of synthetic flexibility. It
was envisioned that derivatives of 3 could arise from an
oxabicyclo derivative
4 prepared from 5 by an
intramolecular Diels–Alder reaction of furan
(IMDAF)7 with a pendant alkyne. Placement of an
amide function as the C7 carbonyl unit permits the
direct and flexible preparation of 5 through a Passerini
multi-component coupling reaction (MCR).8
Paulvannan9 has described an Ugi MCR reaction fol-
lowed by an IMDAF with an olefinic dienophile to
construct combinatorial scaffolds. This was recently
used by Schreiber10 in an approach to natural product-
We have an ongoing interest in synthesizing simplified
analogs of these compounds to study their biological
Scheme 1. Design of simplified viridin analogs.
* Corresponding author. Tel.: 352-392-6787; fax: 352-846-0296; e-mail: dwright@chem.ufl.edu
† Author to whom questions regarding X-ray structure should be addressed.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02299-7

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D. L. Wright et al. / Tetrahedron Letters 43 (2002) 943–946
like libraries. However, there was no information avail-
able on the use of acetylenic dienophiles or the assembly
of the cycloaddition precursors through a Passerini MCR.
While exploring the use of Lewis acids to catalyze the
Diels–Alder reaction, an unusual cascade process was
observed. Upon exposure to catalytic Yb(OTf)3 in 1,4-
dioxane at high temperatures, the Ugi products 10a–e
were cleanly converted to the isoindolinones 13a–e
(Scheme 3) in high yield.
We initially chose to study the sequential Ugi/IMDAF
sequence using acetylenic dienophiles. Ugi condensation
of 2-furaldehyde 6, acetylenic acids 7, isonitriles 8 and
amines 9 proved very efficient for the generation of
acetylenic amides 10a–f in high yield (Scheme 2).
One possibility for the formation of these novel phenolic
derivatives involves initial conversion to the Diels–Alder
adducts 11a–e. Lewis acid promoted opening of the
oxo-bridge and elimination would give the unsaturated
amides 12a–e, which would be expected to tautomerize
to the phenols 13a–e. This process represents a direct
synthesis of highly substituted isoindolinones in two
operations from simple starting materials (Table 2).
Conversion to the oxabicyclo[2.2.1]heptadiene deriva-
tives was initially studied under Lewis acid catalysis.
Surprisingly, treatment with Me2AlCl, reported11 to be
effective for IMDAF reactions, failed to deliver any of
the cycloadducts, returning either starting material or
extensive decomposition of the Ugi product. However,
it was observed that when the Ugi products were allowed
to stand at room temperature, they would partially
convert to the corresponding cycloadduct. A complete
conversion to the adducts 11a–e12 could be effected
smoothly under thermal conditions in less than 24 h. The
terminal acetylene 10f decomposed under the reaction
conditions (Table 1).
With the successful demonstration that acetylenic
dienophiles were effective with Ugi based substrates, a
series of IMDAF precursors were assembled through a
Passerini MCR process. Addition of the three reagents
to a solution of dichloromethane gave high yields of the
Passerini products 14a–e (Scheme 4).
However, attempts to convert the Passerini products to
the oxabicyclo derivatives failed under thermal condi-
tions. The starting materials were recovered un-
changed after heating to 250°C, except with 14e that
underwent extensive decomposition. Surprisingly, the
Lewis acid-catalyzed reaction that had failed with the
acetylenic amide series proved highly effective with the
acetylenic esters. Treatment of the furans with Me2AlCl11
delivered the Diels–Alder adducts 15a–d in good yields,
except with the terminal acetylene 14e. As before, the
The reactions were highly diastereoselective with less than
10% of any other isomers detected in the crude product.
The minor isomers were easily removed upon purification
of the cycloadduct. The relative orientation of the
carboxamide sidechain could not be assigned by NMR
methods. Fortunately, an X-ray crystal structure of
adduct 11c (Fig. 1) revealed that the major diastereomer
possessed the exo-oriented sidechain. The stereochem-
istry of the other adducts was assigned by analogy.
Scheme 2. Synthesis of bicyclic lactams.
Table 1. Sequential Ugi/IMDAF studies
Entry (MCR)a
R1
R2
R3
MCR yield (%)
Entry (IMDAF)b
IMDAF yieldc (%)
10a
10b
10c
10d
10e
10f
Me
Phd
Me
Me
Ph
Bn
Bn
tBu
Bn
Bn
Bn
Bn
88
74
11a
11b
11c
11d
11e
11f
74
81
81
78
80
Dec.
tBu
tBu
tBu
Bn
N/Ae
92
89
84
H
tBu
a Reactions were run at a concentration of 0.6 M in MeOH at rt.
b A 0.02 M solution of the furan in toluene was heat at 200°C in a sealed tube.
c Yields reported are for a pure diastereomer.
d MCRs with phenyl propiolic acid were run in the dark to limit alkyne dimerization.
e Cyclized spontaneously upon standing at rt.

D. L. Wright et al. / Tetrahedron Letters 43 (2002) 943–946
945
Fig. 1. X-Ray structure of cycloadduct 11c.
Scheme 3. Two-step synthesis of isoindolinones.
Table 2. Synthesis of isoindolinones
Entry (MCR)
R1
R2
R3
Entry (phenol)a
Yield (%)
10a
10b
10d
10e
10f
Me
Ph
Me
Ph
H
Bn
Bn
Bn
Bn
Bn
Bn
13a
13b
13d
13e
13f
80
77
81
91
tBu
tBu
Bn
tBu
Dec.
a Reactions conditions: 0.02 M substrate in 1,4-dioxane, 20 mol% Yb(OTf)3, heated at 100°C in a sealed tube.
Scheme 4. Synthesis of bicyclic lactones.
attempts to directly convert the Passerini products to
isobenzofuranones under ytterbium catalysis have not
been successful (Table 3).
reactions were highly selective, the stereochemistry of
the cycloadducts provisionally assigned based on the
X-ray structure of bridged bicycle 11c. Unfortunately,

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D. L. Wright et al. / Tetrahedron Letters 43 (2002) 943–946
Table 3. Sequential Passerini/IMDAF studies
Entry (MCR)a
R1
R2
MCR yield (%)
Entry (IMDAF)b
IMDAF yieldc (%)
14a
14b
14c
14d
14e
Me
Phd
Phd
Me
H
Bn
86
79
69
82
79
15a
15b
15c
15d
15e
77
72
68
72
tBu
tBu
tBu
Bn
Dec.
a Reactions were run at a concentration of 0.2 M in CH2Cl2 at rt.
b A 0.2 M solution of the furan in CH2Cl2 was treated with Me2AlCl at −78°C to rt.
c Yields reported are for a pure diastereomer.
d All MCRs with phenyl propiolic acid were run in the dark to limit alkyne dimerization.
This striking difference in reactivity is quite interesting
considering the small change from nitrogen to oxygen
in the tether. This difference in reactivity may reflect
the difference in conformation between an ester and
amide sidechain or in the stability of the cycloadducts.
Moreover, it was observed that the IMDAF derivatives
from the Passerini reaction were much less stable than
those derived from the Ugi products. The lactones
quickly undergo retro Diels–Alder reaction at elevated
temperatures while the lactams are completely stable.
This may explain the failure to effect IMDAF reaction
under thermal conditions with the acetylenic esters. An
even greater instability of the lactones was observed in
the presence of acid. For example, a solution of the
cycloadduct 15a prepared in commercial CDCl3 showed
reversion to the starting furan within hours at rt while
solutions in C6D6 are stable for at least one week.
Protic acids have been reported to promote retro-
IMDAF reactions of oxabicyclo[2.2.1]heptadiene
derivatives13 to regenerate furan starting materials. In
sharp contrast, the lactam derivatives do not show any
propensity to undergo cycloreversion upon exposure to
acidic conditions. Despite the structural similarities
present in these two families of oxabicyclo[2.2.1]-
heptadiene derivatives, their reactivities and stabilities
are quite different.
Battiste and Dr. Ion Ghiriviga are thanked for helpful
discussions.
References
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The sequential use of MCRs and cycloadditions can
lead to structurally complex materials in short
sequences. Utilizing Passerini and Ugi reactions in
tandem with an IMDAF led to annulated oxabicy-
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further elaboration. Studies on the conversion of the
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Acknowledgements
The authors would like to thank the American Cancer
Society (Florida Division) and the University of Flor-
ida for generous support of this work. Professor Merle
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