Intramolecular diels-alder/1,3-dipolar cycloaddition cascade of 1,3,4-oxadiazoles

Article abstract of DOI:10.1021/ja0612549

Full details of a systematic exploration of the intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles are disclosed in which the scope and utility of the reaction are defined.

Full text of DOI:10.1021/ja0612549

Published on Web 07/22/2006
Intramolecular Diels-Alder/1,3-Dipolar Cycloaddition Cascade
of 1,3,4-Oxadiazoles
Gregory I. Elliott, James R. Fuchs, Brian S. J. Blagg, Hayato Ishikawa,
Houchao Tao, Z.-Q. Yuan, and Dale L. Boger*
Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Received February 21, 2006; E-mail: boger@scripps.edu
Abstract: Full details of a systematic exploration of the intramolecular [4 + 2]/[3 + 2] cycloaddition cascade
of 1,3,4-oxadiazoles are disclosed in which the scope and utility of the reaction are defined.
Introduction
In the development of a synthetic approach to the vinca
alkaloids based on the cycloaddition reactions of electron-
deficient heterocyclic azadienes,1-3 we reported the first in-
tramolecular examples of a tandem Diels-Alder/1,3-dipolar
cycloaddition reaction of 1,3,4-oxadiazoles.4-6 Prior to these
studies, Vasilev,7 Sauer,8 Seitz,9 and Warrener10 each disclosed
examples of the participation of electron-deficient and typically
symmetrical 1,3,4-oxadiazoles in an intermolecular reaction
cascade with electron-rich or strained olefins providing 2:1
cycloadducts (Figure 1). The reactions with such alkenes proceed
by an initial inverse electron demand Diels-Alder reaction to
provide a cycloadduct that loses N2 to generate a carbonyl ylide
Figure 1. 1,3,4-Oxadiazole cycloaddition cascade.
that in turn further reacts with the alkene in a 1,3-dipolar
cycloaddition (Figure 1). The initial 1:1 adducts were not
observed, and the second 1,3-dipolar cycloaddition proved faster
than the initiating Diels-Alder reaction limiting the synthetic
potential of the process to the generation of symmetrical 2:1
cycloadducts. Herein we provide full details of the examination
of the intramolecular cycloaddition cascade of 1,3,4-oxadiazoles
highlighting the advances made since our initial disclosure4 that
extend the range of alkenes and oxadiazoles that participate in
the reaction, permit the use of unsymmetrical dienophiles and
oxadiazoles, control the cycloaddition regioselectivity and
diastereoselectivity, and define the scope and utility of the
tandem [4 + 2]/[3 + 2] cycloaddition reactions of such hetero-
cyclic azadienes.
(1) The Alkaloids; Brossi, A., Suffness, M., Eds.; Academic: San Diego, 1990.
(2) (a) Boger, D. L. Tetrahedron 1983, 34, 2869. Boger, D. L. Chem. ReV.
1986, 86, 781. (b) Boger, D. L. Chemtracts: Org. Chem. 1996, 9, 149. (c)
Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic
Synthesis; Academic: San Diego, 1987.
(3) Benson, S. C.; Lee, L.; Yang, L.; Snyder, J. K. Tetrahedron 2000, 56,
1165.
(4) Wilkie, G. D.; Elliott, G. I.; Blagg, B. S. J.; Wolkenberg, S. E.; Soenen,
D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J. Am. Chem. Soc. 2002,
124, 11292.
(5) (a) Anhydrolycorinone: Wolkenberg, S. E.; Boger, D. L. J. Org. Chem.
2002, 67, 7361. (b) Minovine: Yuan, Z.-Q.; Ishikawa, H.; Boger, D. L.
Org. Lett. 2005, 7, 741. (c) Vindoline: Choi, Y.; Ishikawa, H.; Velcicky,
J.; Elliott, G. I.; Miller, M. M.; Boger, D. L. Org. Lett. 2005, 7, 4539. (d)
Vindorosine: Elliott, G. I.; Velcicky, J.; Ishikawa, H.; Li, Y.; Boger, D.
L. Angew. Chem., Int. Ed. 2006, 45, 620.
(6) Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J. Am.
Chem. Soc. 2006, 128, 10596.
(7) (a) Vasil´ıev, N. V.; Lyashenko, Y. E.; Kolomiets, A. F.; Sokolskii, G. A.
Khim. Geterostsikl. Soedin. 1987, 562. (b) Vasil´ıev, N. V.; Lyashenko, Y.
E.; Galakhov, M. V.; Kolomiets, A. F.; Contar, A. F.; Sokolskii, G. A.
Khim. Geterotsikl. Soedin. 1990, 95. (c) Vasil´ıev, N. V.; Lyashenko, Y.
E.; Patalakha, A. E.; Sokolskii, G. A. J. Fluorine Chem. 1993, 65, 227.
(8) Thalhammer, F.; Wallfahrer, U.; Sauer, J. Tetrahedron Lett. 1988, 29, 3231.
(9) (a) Seitz, G.; Gerninghaus, C. H. Pharmazie 1994, 49, 102. (b) Seitz, G.;
Wassmuth, H. Chem.-Ztg. 1988, 112, 80.
(10) (a) Warrener, R. N.; Margetic, D.; Foley, P. J.; Butler, D. N.; Winling, A.;
Beales, K. A.; Russell, R. A. Tetrahedron 2001, 57, 571. (b) Warrener, R.
N.; Margetic, D.; Tiekink, E. R. T.; Russell, R. A. Synlett 1997, 196. (c)
Warrener, R. N.; Wang, S.; Maksimovic, L.; Tepperman, P. M.; Butler, D.
N. Tetrahedron Lett. 1995, 36, 6141. (d) Warrener, R. N.; Elsey, G. M.;
Russell, R. A.; Tiekink, E. R. T. Tetrahedron Lett. 1995, 36, 5275. (e)
Warrener, R. N.; Maksimovic, L.; Butler, D. N. J. Chem. Soc., Chem.
Commun. 1994, 1831. (f) Warrener, R. N.; Butler, D. N.; Liao, W. Y.;
Pitt, I. G.; Russell, R. A. Tetrahedron Lett. 1991, 32, 1889. (g) Warrener,
R. N.; Groundwater, P.; Pitt, I. G.; Butler, D. N.; Russell, R. A. Tetrahedron
Lett. 1991, 32, 1885. (h) Review: Warrener, R. N. Eur. J. Org. Chem.
2000, 3363.
Results and Discussion
Initiating Dienophile. Given that our studies to date have
been conducted concurrent with the development of a synthetic
approach to vindoline,6 the initial substrates examined bear a
tethered indole to serve as the dipolarophile trap of the in situ
generated carbonyl ylide.11 An unusually wide range of tethered
dienophiles were found to be effective at initiating the reaction
cascade (Scheme 1). In each case, a single diastereomer of the
(11) (a) Padwa, A.; Price, A. T. J. Org. Chem. 1998, 63, 556 and 1995, 60,
6258. (b) Padwa, A.; Lynch, S. M.; Mejia-Oneta, J. M.; Zhang, H. J. Org.
Chem. 2005, 70, 2206. (c) Mejia-Oneta, J. M.; Padwa, A. Org. Lett. 2004,
6, 3241. (d) Mejia-Oneta, J. M.; Padwa, A. Tetrahedron Lett. 2004, 45,
9115.
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J. AM. CHEM. SOC. 2006, 128, 10589-10595
10589

A R T I C L E S
Scheme 1
Elliott et al.
Scheme 2
is stopped prior to consumption of the starting material.
However, there are notable instances where the initiating
[4 + 2] cycloaddition is faster than the subsequent [3 + 2]
cycloaddition reaction6 and/or that the latter reaction is suf-
ficiently slow that significant amounts of the intermediate
carbonyl ylide or its corresponding cyclobutene epoxide6,10,13
buildup and a premature workup leads to products derived from
their quench. In such instances, extending the reaction time,
increasing the reaction temperature, and enlisting diluted reaction
concentrations (e5 mM, presumably to preclude competitive
intermolecular cycloadditions) were found to enhance the
conversions. Notably, the observation of such products can be
mistakenly interpreted to represent an instability of the inter-
mediate 1,3-dipole under the reaction conditions, and the
behavior of substrates (E)-6a and (Z)-7a are representative of
such cases. Both provide the respective cycloaddition cascade
products 6b and 7b in good conversions when taken to
completion, but both provide the furan 12 if the reactions are
prematurely stopped (Scheme 2). Furan 12, which is derived
from water addition to the 1,3-dipole followed by aromatization
(elimination of water and benzyl alcohol) upon workup, is not
an intermediate enroute to 6b or 7b, nor is it present in the
thermal reaction mixtures (1H NMR). Analogous observations
are described in detail in ref 6 and may arise as a consequence
of dienophile substitutions that accelerate the [4 + 2] cyclo-
addition and that sterically (E-substituent) or electronically (Z-
substituent) slow the typically fast [3 + 2] cycloaddition (Figure
2). Moreover, the subtleties of these effects are beautifully
manifested in the comparisons of (E)-6a and (Z)-7a. The
benzyloxy substituent of (E)-6a accelerates the initiating inverse
electron demand Diels-Alder reaction and may sterically slow
the ensuing [3 + 2] cycloaddition such that the [4 + 2]
cycloaddition reaction is a relatively faster step of the tandem
cascade. If this reaction is not run under relatively dilute reaction
conditions, the yields of 6b are more modest (30-50% at
5 mM, 74% at 1 mM, 82% at 0.5 mM, and 94% at 0.1 mM)
cycloadduct was produced in which the relative stereochemistry
is set by a combination of the dienophile and dipolarophile
geometry (C4/C5 and C2/C12 stereochemistry) and indole endo
[3 + 2] cycloaddition sterically directed to the face opposite
the newly formed lactam11 (C5 vs C2/C12 stereochemistry). This
latter exclusive endo indole diastereoselection is unique to the
intramolecular 1,3-dipolar cycloaddition, and comparable in-
termolecular reactions proceed with indole exo cycloaddition
directed to the analogous sterically less hindered face.12 The
indole endo addition observed with the substrates examined to
date most simply may be attributed to a conformational (strain)
preference for the 1,3-dipolar cycloaddition transition state that
is dictated by the dipolarophile tether since it mirrors the relative
strain energy of the four possible products (For 1a (MM2):
R-face endo < â-face endo (∆E ) 10.4 kcal/mol) < R-face
exo (∆E ) 16.6 kcal/mol) < â-face exo (∆E ) 43.8 kcal/mol))
and is of a magnitude that it is unaffected by the dienophile
substitution.4 The stereochemical assignments for the cyclo-
1
adducts were easily made with observation of diagnostic H
NMR NOEs (N1-R/C4 R-substituent, C4/C5 R-substituents,
C14-H/C5 R-substituent) and, in many instances, confirmed
with X-ray structures. The relative ease of the tandem [4 + 2]/
[3 + 2] cycloaddition reaction with 1-11a is consistent with
the cascade being initiated by an inverse electron demand
Diels-Alder reaction, but even unactivated and electron-
deficient dienophiles participate effectively, and each is followed
by the loss of N2 and a subsequent 1,3-dipolar cycloaddition of
the tethered indole.
In most instances, the [3 + 2] cycloaddition is sufficiently
fast under the reaction conditions that products derived from
the quenched 1,3-dipole are not observed even if the reaction
(12) Muthusamy, S.; Gunanathan, C.; Babu, S. A. Tetrahedron Lett. 2001, 42,
(13) Such cyclobutene epoxides have been utilized as sources of the corre-
sponding carbonyl ylides (1,3-dipoles); see ref 10.
523.
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Intramolecular Cycloaddition Cascade of 1,3,4-Oxadiazoles
A R T I C L E S
Scheme 3
Figure 2. [3+2] Cycloaddition transition state and potential cyclobutene
epoxide intermediates.
suggesting that competitive intermolecular reactions of the
intermediate 1,3-dipole may compete. Similarly, the benzyloxy
substituent of (Z)-7a accelerates the initiating Diels-Alder
reaction and electronically slows the subsequent [3 + 2]
cycloaddition. This latter effect is unique to an electronegative
substituent (e.g., OBn vs Me, compare (Z)-3a vs (Z)-7a), its
magnitude is surprisingly large, and the observations may reflect
the intermediacy of the cyclobutene epoxides. A full discussion
of these effects is provided in ref 6, where their delineation
proved crucial to the total synthesis of vindoline and vindorosine.
However, the important feature of these studies that is intuitively
difficult to appreciate is that the starting material disappearance
need not coincide with cascade product formation and that more
vigorous (not milder) reaction conditions at dilute concentrations
often drive the reactions to successful completion.
dienophile and dipolarophile failed to react even when exposed
to forcing reaction conditions (eq 1). As such, the cascade
The addition of substituents to the tethered dienophile has a
significant impact on the ease of cycloaddition. Even the
addition of activating substituents at the alkene terminus slows
the reaction relative to the unsubstituted terminal alkene (1a,
Scheme 1). As additional unactivating substituents are added
to the dienophile, the reaction slows (1a > (E)-2a or 13a .
14a), and this appears to be relatively independent of the site
of substitution ((E)-2a g 13a, Scheme 3). The exceptions to
these generalizations include the trisubstituted enol ethers
such as 15a, and those disclosed in ref 6, that remain suitably
reactive to initiate the cycloaddition cascade via an inverse
electron demand Diels-Alder reaction. Impressively, the cyclo-
additions remain diastereoselective providing a single detectable
product.
reactions exemplified herein can be confidently described as
being initiated by [4 + 2] cycloaddition of the tethered alkene.
To date, the only exceptions to this generalization represent the
special cases where the N-acyl amide carbonyl is placed in the
dipolarophile tether with a length of two atoms and the substrate
contains a poor initiating alkene dienophile. In these instances
which are detailed in ref 6, products arising only from the initial
indole [4 + 2] cycloaddition are observed but not those arising
from the cycloaddition cascade (no [3 + 2] cycloaddition).
Throughout the course of the studies, the most useful solvents
to emerge from our surveys have been o-dichlorobenzene
(o-Cl2C6H4, 180 °C) and 1,3,5-triisopropylbenzene (TIPB, 230
°C).4-6 Reactions will oftentimes be slightly faster in the former
solvent, but those requiring more extended reaction times are
generally cleaner when conducted in TIPB. Typically, the
reactions are conducted at concentrations of 5 mM although
many may be conducted at higher concentrations without
impacting the conversions. Some, which entail an unusually slow
Although it is possible that an indole [4 + 2] cycloaddition
initiates the reaction cascade especially in the instances where
closure would provide an entropically favored fused five-
membered ring, the substrate 16a containing only an indole
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A R T I C L E S
Elliott et al.
Scheme 4
[3 + 2] cycloaddition, benefit from the use of even lower
reaction concentrations and appear to suffer competitive inter-
molecular reactions.6 Finally, a range of alternative reaction
conditions have been examined for conducting the cycloaddition
cascade including the use of high pressure (13 kbar), Lewis
acid catalyzed reaction conditions, and microwave heating.
Whereas the former two have not yet proven useful, the use of
microwave heating often provides a useful alternative to the
thermal conditions enlisted herein (eq 2). Interestingly, these
generally have not provided improved conversions largely
because the thermal cycloaddition cascades are so clean with
both the starting oxadiazoles and the cycloadducts being
remarkably stable to the thermal conditions.
N-Acylation: Requirement, Substitution, and Location.
The 2-amino-1,3,4-oxadiazoles examined in Schemes 1-3 bear
substituents that enhance a preferred [4 + 2] cycloaddition
regioselectivity that is dictated by the dienophile tether and that
subsequently stabilize the intermediate 1,3-dipole reinforcing a
regioselectivity that is complementary to that of the tethered
indole. However, such oxadiazoles are less electron-deficient
than those previously examined7-10 (Figure 1, R ) CO2Me)
resulting in a diminished reactivity toward the initiating [4 +
2] cycloaddition. Even here, N-acylation of the C2 amino group
is required for observation of the initiating [4 + 2] cycloaddition
(1a or 17a > 18a), and there is typically little distinction whether
it is incorporated into the dienophile or dipolarophile tether for
the tandem cascade reaction (1a vs 17a, Scheme 4).14 Expect-
edly, the reaction rate increases as the electron-withdrawing
properties of the activating amide increases (22a > 21a > 20a).
Similarly, studies to date suggest that the conformational
properties of a tertiary amide (vs secondary amide) facilitate
the initiating Diels-Alder reaction by favoring the adoption of
the compact cis amide conformation required for [4 + 2]
cycloaddition (30a vs 29a and 27a vs 28a and 26a). Although
the presence of such a tertiary amide is inherent in the approach
utilized to access vindoline and related alkaloids, its use is more
central to the success of the cycloaddition cascade than might
be initially envisioned. These latter studies were best exemplified
utilizing tethered alkyne dienophiles limiting the comparisons
to the initiating [4 + 2] cycloadditions and result in the direct
formation of furans derived from the loss of N2 from the initial
oxadiazole cycloadduct (e.g., 19b). Utilizing such reactions, a
series of substrates was additionally examined to define the
importance of the dienophile linker and functionality connecting
the tether to the oxadiazole. Aside from the secondary amine
(20a, X ) NH) which was unreactive under the conditions
examined and the ether (23a, X ) O) and sulfone (23a, X )
SO2) connections which suffered an elimination cleavage of the
dienophile side chain, the remainder (20-28a) participated in
the oxadiazole [4 + 2] cycloaddition reaction effectively.15
Within this series, the thio connection (24a, X ) S) was of
intermediate reactivity relative to the two N-acylamines 21a and
22a; the methylene attachment (25a, X ) CH2) was just as
(15) At 180 °C in o-Cl2C6H4, the reactions of 21a (20% 21b at 24 h), 25a (10%
25b at 60 h), 26a (no reaction), and 28a (32% 28b at 70 h) failed to react
to completion.
(14) An exception to this generalization is discussed in ref 6.
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Intramolecular Cycloaddition Cascade of 1,3,4-Oxadiazoles
A R T I C L E S
Scheme 5
Scheme 6
effective, but noticeably less reactive;15 and the ester (28a, X
) CO2) versus N-methylamide (27a, X ) CONMe) exhibited
a reactivity suggesting its preference for an extended conforma-
tion offsets its enhanced electronic activation.15 However, even
the ketone 26a (X ) CO)15 was less reactive than 21a, 22a, or
24a despite its enhanced electron-deficient character suggesting
either that additional geometrical constraints facilitate their
intramolecular reactions or that a complementary and weakly
electron-donating oxadiazole substituent (X ) N-acyl or S)
enhances the oxadiazole Diels-Alder reaction with an unacti-
vated dienophile.
1,3,4-Oxadiazole C5 Substituent. Beautifully, as detailed
in ref 6, a C5 methyl ester on the 1,3,4-oxadiazole introduces
the vindoline C3 methyl ester while reductive cleavage of the
cycloadduct oxido bridge provides the C3 tertiary alcohol
complete with control of the appropriate C3 stereochemistry.
Consequently, the initial studies on the scope of the oxadiazole
cycloaddition cascade were conducted with this C5 substituent.
However, a study of its impact was conducted with a full range
of C5 substituents. Electron-withdrawing substituents would be
expected to enhance the electron-deficient character of the
oxadiazole promoting the initiating inverse electron demand [4
+ 2] cycloaddition reaction and subsequently stabilize the
intermediate 1,3-dipole. Consistent with these expectations,
electron-withdrawing (CO2Me, CONH2, CN) or conjugating
(Ph) substituents provided oxadiazoles that participated ef-
fectively in the reaction cascade with the reactions of 31a and
32a being comparable with that of 1a, whereas that of 33a
required more vigorous reaction conditions (Scheme 5). Un-
activating (Me, H) or electron-donating substituents (OMe, STol)
failed to support the tandem cycloaddition cascade even though
the initiating [4 + 2] cycloaddition reaction was often observed
providing a range of products derived from a carbene that arises
from cleavage (O-C5 bond) of the unstabilized carbonyl ylide.
Most surprising was the inability of a C5 sulfoxide or sulfone
to support the tandem cycloaddition cascade. The latter oxa-
diazole simply proved unstable to the thermal conditions of the
reaction undergoing a facile C-SO2R homolytic cleavage,
whereas the former intermediate 1,3-dipole preferentially re-
arranges (cleavage of O-C5 bond) to a carbene. Nonetheless,
the clear definition of the oxadiazole C5 substituents that support
the tandem cycloaddition cascade permit its implementation in
studies beyond our own immediate interests.
Tether Lengths. A survey of the impact of the dienophile
and dipolarophile tether lengths was also conducted (Scheme
6). The implementation of the cycloaddition cascade for the
preparation for the vinca alkaloids enlists a dienophile tether
that permits the preparation of the fused six-membered lactam
and occurs with a facility that exceeds that typical of an
unactivated alkene intramolecular Diels-Alder reaction. Further
lengthening of this tether slows, but does not preclude, the
cycloaddition cascade as illustrated with 40a which provided
the fused seven-membered lactam 40b (43%) albeit requiring
more vigorous reaction conditions (TIPB, 230 °C, 24 h). By
contrast, shortening this dienophile tether length such that the
Diels-Alder closure provides a five- versus six-membered ring
leads to even more facile initiation of the cycloaddition cascade
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A R T I C L E S
Scheme 7
Elliott et al.
and 50a) or the less nucleophilic N-carbomethoxyindole (47a
and 51a) participated in the reaction cascade in a manner and
rate indistinguishable from those of 1a or 13a. In fact, reaction
of an equimolar mixture of 1a and 47a provided 1:1 mixtures
of their respective products 1b and 47b at all monitored stages
of the reaction illustrating that the rate-limiting step of these
reactions is the initiating [4 + 2] cycloaddition and that the
modest differences in the dipolarophile reactivity have no
apparent impact. Pertinent to our interests in accessing vindoline
analogues in which the N1 tertiary amine is replaced with
nonbasic heteroatoms, both the tethered benzofurans 48a and
52a and the benzothiophenes 49a and 53a, but not the
corresponding furan or thiophene (58, X ) O or S), participated
effectively in the cycloaddition cascade.11
1,3,4-Oxadiazole versus 1,3,4-Thiadiazole and Oxazole.
Analogous to the results of prior studies indicating that 1,3,4-
thiadiazoles and N1-methyl-1,3,4-triazoles are progressively less
reactive than 1,3,4-oxadiazoles,8-10 the thiadiazoles 59a and 60a
did not undergo the cycloaddition cascade and failed to
participate in the initiating Diels-Alder reaction (Scheme 8).
Similarly, the potential that an oxazole may support an
analogous tandem cycloaddition cascade, requiring the loss of
a nitrile (vs N2) from the initial [4 + 2] cycloadduct with
cleavage of a C-C bond to generate the intermediate 1,3-dipole,
was examined. Even with the addition of substituents that may
facilitate this nitrile loss, the reaction was not found to be viable
although a range of products were observed that were derived
from the initial [4 + 2] cycloaddition reaction.
Alternative Tethering and Transannular Cycloadditions.
Two final features of the cycloaddition cascade were briefly
investigated that highlight several ways in which its scope may
be extended. The first entails tethering the initiating dienophile
through the oxadiazole C5 substituent rather than the C2 amino
substituent. Thus, substrate 73a was prepared and found to
participate in an analogous tandem [4 + 2]/[3 + 2] cycloaddition
cascade to provide 73b (Scheme 9). Consistent with expectations
based on ground-state modeling of the potential products (MM2
∆E ) 7.0 kcal/mol for observed R- vs â-face endo and ∆E >
11.0 kcal for R-endo vs R-face or â-face exo) and intuitive
assessments of a stereochemical outcome (cis vs trans 5,5- and
5,6-fusions with the oxido bridged furans), a single diastereomer
of 73b is produced resulting from a defining and exclusive endo
[3 + 2] cycloaddition of the tethered indole on the 1,3-dipole
face opposite the newly formed lactam. Most significantly, this
illustrates a second of many alternative ways in which the
dienophile and dipolarophile may be tethered to the oxadiazole
to produce alternative pentacyclic ring systems arising from a
predictably diastereoselective cycloaddition cascade.
(41a and 42a). Similarly, extending the dipolarophile tether
length with 43a to access the fused six- vs five-membered ring
cycloadduct provided 43b in superb conversions (89%) and with
an unaltered diastereoselectivity affording a single product (X-
ray)16 derived from endo indole [3 + 2] cycloaddition directed
to the face of the 1,3-dipole opposite the fused lactam. In this
latter instance and unlike 1a versus 13a, substitution of the
dienophile (44a) resulted in a less effective tandem cycloaddition
as did further extensions of the dipolarophile tether length (45a).
Nonetheless, the scope of the cycloaddition cascade is such that
deep-seated modifications in the core structure can be accom-
modated providing access to a remarkable range of ring systems.
The second example illustrated in Scheme 9 constitutes a case
in which the cycloaddition cascade is initiated by a trannsannular
[4 + 2] cycloaddition reaction. Consistent with expectations,
converting the initating intramolecular [4 + 2] cycloaddition
into a transannular Diels-Alder reaction substantially reduced
the reaction temperature needed to initiate the reaction cascade
where reaction was observed at temperatures as low as 80 °C
(refluxing benzene). For the substrate 74a bearing an unactivated
cis olefin as the initiating dienophile, a single diastereomer of
the cascade cycloaddition product was observed in which the
cis C4/C5 stereochemistry is imbedded in the dienophile
geometry and the remainder of the relative stereochemistry is
Tethered Dipolarophile. The examination of variations in
the tethered dipolarophile to date has been conducted largely
to explore the requisite reactivity of the tethered indole or to
probe deep-seated modifications that may be incorporated into
the vindoline structure for accessing the corresponding vinblas-
tine analogues (Scheme 7). Thus, a tethered N-benzylindole (46a
(16) The coordinates for the X-ray structure of 43b (CCDC 297502) have been
deposited with the Cambridge Crystallographic Data Centre.
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Intramolecular Cycloaddition Cascade of 1,3,4-Oxadiazoles
A R T I C L E S
Scheme 8
Scheme 9
a potentially powerful manner in which some of the more
problematic cycloaddition cascades can be adapted to occur
under mild conditions. These and related studies are the subject
of our continuing investigations.
Conclusion
A systematic exploration of a tandem intramolecular [4 +
2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles including
a transannular variant was conducted in which the tethered
initiating dienophile, the tethered dipolarophile, the 1,3,4-
oxadiazole C2 and C5 substituents, the tether lengths and sites,
and the central heterocycle were examined. Conducted largely
with the concurrent development of a synthetic approach to
vindoline6 and relative to the intermolecular reaction cascade,7-10
the studies extend the alkenes and oxadiazoles that participate
in the reaction; permit the use of unsymmetrical dienophiles,
dipolarophiles, and oxadiazoles; control the cycloaddition regio-
selectivity and diastereoselectivity; and define the scope and
utility of the tandem Diels-Alder/1,3-dipolar cycloaddition
reactions of such heterocyclic azadienes.
Acknowledgment. We gratefully acknowledge the National
Institutes of Health (CA42056 and CA115526) and the Skaggs
Institute for Chemical Biology for their financial support and
NIH for postdoctoral fellowships (B.S.J.B., CA86475; J.R.F.,
AI65062). We especially wish to thank Dr. R. P. Schaum for
preliminary studies and Gordon Wilkie (eq 1, substrates 17a,
18a, and 42a), D. Soenen (substrate 19a and the 1,3,4-
thiadiazoles 59a and 60a), S. Wolkenberg (substrates 20-22a),
and S. Pollack (substrates 1a, 3a, 14a, and 15a) for their early
contributions to the work included herein (see also ref 4).
Supporting Information Available: Full experimental details
are provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
set in an endo indole [3 + 2] cycloaddition directed to the 1,3-
dipole face opposite the newly formed fused lactams analogous
to the reactions initiated by the intramolecular Diels-Alder
reaction. Importantly, the ease of cycloaddition of 74a illustrates
JA0612549
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J. AM. CHEM. SOC. VOL. 128, NO. 32, 2006 10595