Intramolecular Diels-Alder and tandem intramolecular Diels-Alder/1,3-dipolar cycloaddition reactions of 1,3,4-oxadiazoles

Article abstract of DOI:10.1021/ja027533n

The scope of intramolecular Diels-Alder and a novel tandem Diels-Alder/1,3-dipolar cycloaddition cascade of 1,3,4-oxadiazoles is disclosed. In the cases examined, the tandem cycloadditions construct three new rings with formation of four new C-C bonds and

Full text of DOI:10.1021/ja027533n

Published on Web 08/29/2002
Intramolecular Diels-Alder and Tandem Intramolecular Diels-Alder/
1,3-Dipolar Cycloaddition Reactions of 1,3,4-Oxadiazoles
Gordon D. Wilkie, Gregory I. Elliott, Brian S. J. Blagg, Scott E. Wolkenberg, Danielle R. Soenen,
Michael M. Miller, Scott Pollack, and Dale L. Boger*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037
Received July 2, 2002
In exploration of a new synthetic approach to the vinca alkaloids1
based on the cycloaddition reactions of electron-deficient hetero-
cyclic azadienes,2 we report herein the first examples of intramo-
lecular Diels-Alder and tandem intramolecular Diels-Alder/1,3-
dipolar cycloaddition reactions3 of 1,3,4-oxadiazoles. Limited
reports of the cycloaddition reactions of electron-deficient and
typically symmetrical 1,3,4-oxadiazoles (1, R ) CF3, SO2Et,
CO2Me) have been detailed (Figure 1).4-10 In these studies of
Vasil´ıev,4 Sauer,5 Seitz,6 and most recently Warrener,7,8 the 1,3,4-
oxadiazoles were found to behave as electron-deficient azadienes
in inverse electron demand Diels-Alder reactions although most
examples disclosed have employed strained dienophiles. Reactions
of olefinic dienophiles proceed through an initial [4 + 2] cycload-
duct that loses N211 to generate a carbonyl ylid which further reacts
with the olefin in a 1,3-dipolar cycloaddition (Figure 1). The initial
1:1 adducts are not observed, and the second 1,3-dipolar cycload-
dition is more facile than the initial Diels-Alder reaction which
limits the reaction to the generation of symmetrical 2:1 cycload-
ducts. However, its implementation in tandem intramolecular
cycloadditions could expand the range of oxadiazoles that participate
in the reaction cascade, extend their use to unsymmetrical dieno-
philes and oxadiazoles, control the cycloaddition regioselectivity,
and increase the utility of tandem Diels-Alder/1,3-dipolar cycload-
dition reactions of such heterocyclic azadienes.
Figure 1.
Scheme 1
Initial studies were conducted largely with the synthetic target
vindoline in mind. Thus, the substrates bear a tethered indole to
trap the in situ generated carbonyl ylid analogous to that in
the work of Padwa.12 Comparison of the relative ease of tandem
[4 + 2]/[3 + 2] cycloadditions of substrates 1-11a is consistent
with the cascade being initiated by an inverse electron demand
Diels-Alder reaction, and each is followed by loss of N2 and an
effective 1,3-dipolar cycloaddition with the tethered indole provid-
ing the cycloadducts in excellent conversions (Scheme 1). Although
the reaction appears most facile when initiated by an inverse electron
demand Diels-Alder reaction, even unactivated or electron-
deficient tethered dienophiles participate effectively with the (E)-
dienophiles typically being more reactive. In each case, a single
diastereomer is produced in which the relative stereochemistry is
set by a combination of (1) the dienophile geometry and (2)
exclusive indole endo [3 + 2] cycloaddition sterically directed to
the R-face of the 1,3-dipole by the fused lactam as first observed
by Padwa.12 Further alkene substitution does not alter this remark-
able diastereoselectivity, although it does typically slow the
cycloaddition cascade (1 > 2 or 12, 3 . 13), Schemes 1 and 2.
Notably, the trisubstituted enol ethers 14-17 (vs 5 and 6) constitute
exceptions to this generalization. They are more reactive or remain
a TIPB ) triisopropylbenzene.
suitably reactive to participate in the cycloaddition cascade with
the E-isomers exhibiting a more pronounced reactivity (e.g., 16 vs
17), presumably attributable to endo versus a slower exo [4 + 2]
cycloaddition. Impressively, the tandem cycloadditions construct
three new rings with formation of four new C-C bonds and set all
six stereocenters about the central six-membered ring in a single
step without trace of a second diastereomer. Important for our
* To whom correspondence should be addressed. E-mail: boger@scripps.edu.
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10.1021/ja027533n CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
by its use in an intramolecular Diels-Alder reaction. Even here,
N-acylation of the oxadiazole C2 amino group is required for
sufficient [4 + 2] cycloaddition reactivity, and there is little
distinction whether it is incorporated into the dienophile or
dipolarophile tether (eq 1). Analogous to prior observations,4-8 the
corresponding 1,3,4-thiadiazoles 23 and 24 were significantly less
reactive than the oxadiazoles (eq 2).
Although prior studies of Warrener indicate that a cyclobutene
epoxide (e.g., C, eq 3) need not be an intermediate in the reaction
cascade,8 we have made observations that suggest they may be
reversible, transient intermediates in the slower thermal reactions.
Thus, TLC monitoring or premature workup of the slower reactions
in which the initial [4 + 2] cycloaddition appears to be much faster
than the subsequent [3 + 2] cycloaddition (e.g., 17a) allows
detection or isolation of products resulting from only the first [4 +
2] cycloaddition reaction and subsequent loss of N2.15 However,
when these reactions are taken to completion or run under more
vigorous conditions, the yields increase and no intermediate
cycloadduct is isolated, suggesting the generation of an intermediate
(e.g., C) more stable than the 1,3-dipole B and its ultimate
conversion to the final product. Although the potential intermediacy
of C is immaterial to the reaction outcome, the observations that
the disappearance of starting material does not necessarily coincide
with the appearance of final product and that more vigorous, not
less vigorous, reaction conditions typically improve conversions
even with sensitive 1,3-dipoles (e.g., 16/17) can be key to the
successful implementation of the reaction cascade. Finally, although
it is possible that an indole [4 + 2] cycloaddition initiates the
reaction cascade, especially in those examples where closure would
provide an entropically preferred fused five-membered ring, all
attempts to detect such reactivity have not been successful. Thus,
a Relative stereochemistry determined by 1H NMR NOE’s. b Relative
stereochemistry determined by X-ray, ref 14.
projected application, the closure of 17 incorporates and sets all
six stereocenters characteristic of vindoline in a single operation
including three contiguous and four total quaternary centers.13,14
As anticipated, initiation of the cycloaddition cascade occurs
more rapidly with tethered Diels-Alder closure to provide a five-
versus six-membered fused ring (19 and 20 vs 18), although it is
notable that even the latter closures occur with a facility that exceeds
typical unactivated alkene intramolecular Diels-Alder reactions.
The complementary substitution of the oxadiazole reinforces a
preferred [4 + 2] and [3 + 2] cycloaddition regioselectivity that is
consonant with use in a synthesis of vindoline, and it further
stabilizes the intermediate carbonyl ylid 1,3-dipole relative to 1.
However, it does constitute a less electron-deficient oxadiazole than
those previously examined.4-8 This loss of intrinsic reactivity for
the initial [4 + 2] cycloaddition, which is marginal even for the
parent oxadiazole 1 (Figure 1, R ) CO2Me),9 is compensated for
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C O M M U N I C A T I O N S
Scheme 3
tion to provide a pyrrole. Analogous observations have been made
in the cycloaddition reactions of tethered allenyl 1,2-diazines.16
Further exploration of the cascade cycloaddition reactions of
1,3,4-oxadiazoles and their applications are in progress and will
be reported in due course.
Acknowledgment. We acknowledge the National Institutes of
Health (CA42056) and the Skaggs Institute for Chemical Biology
for their financial support, NIH for a postdoctoral fellowship
(B.S.J.B., CA86475), Bauce (G.D.W.), Bristol-Myers Squibb
(D.R.S.), and the ACS Organic Division (S.E.W., Procter and
Gamble) for predoctoral fellowships, and Dr. Robert P. Schaum
for preliminary studies. G.D.W., D.R.S., S.E.W., and M.M.M. are
Skaggs Fellows.
Supporting Information Available: Full experimental details for
the preparation of 1a-33a and 1b-33b (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
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cycloaddition are detected if the reaction is prematurely worked
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dipolarophile failed to undergo reaction (eq 4), and (3) substrate
28 provided the product derived only from alkyne, not indole,
[4 + 2] cycloaddition as detailed above.
(7) Warrener, R. N.; Margetic, D.; Foley, P. J.; Butler, D. N.; Winling, A.;
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has been shown to occur at temperatures as low as -40 °C (t1/2 ) ca. 1
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Interestingly, this endo diastereoselection is unique to the intramolecular
1,3-dipolar cycloaddition and intermolecular reactions proceed with indole
exo cycloaddition directed to an analogous R-face, see: Muthusamy, S.;
Gunanathan, C.; Babu, S. A. Tetrahedron Lett. 2001, 42, 523. The endo
diastereoselection observed herein may be attributed simply to a confor-
mational (strain) preference dictated by the dipolarophile tether since it
mirrors the relative energy of the four possible products (R-face endo <
â-face endo ∆E ) 5.2 kcal/mol < R-face exo ∆E ) 13.1 kcal/mol <
â-face exo ∆E ) 151 kcal/mol for 14a, MM2 force field).
(13) Stereochemical assignments for 16b and 17b have been confirmed by
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(15) The cyclobutene epoxide itself is not detected, and a range of products
can be observed that would be consistent with its instability toward SiO2
detection or isolation.
(16) Boger, D. L.; Sakya, S. M. J. Org. Chem. 1988, 53, 1415. Boger, D. L.;
Zhang, M. J. Am. Chem. Soc. 1991, 113, 4230. For additional examples
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Whereas unactivated alkynes fail to react with oxadiazoles in
intermolecular Diels-Alder reactions,10 tethered alkynes cleanly
provide furan [4 + 2] cycloadducts (Scheme 3). Like observations
made in eq 1, the reactions of 29-31 improve with substitution of
the C2 amine with progressively stronger electron-withdrawing
groups. Similar products can also be obtained using alkyne
equivalents (e.g., 33) in the absence of an effective tethered
[3 + 2] dipolarophile. In the case of 33, the enhanced reactivity of
the enol ether is sufficient to supersede the typical entropic
preference for closure to provide a fused five- versus six-membered
ring. Similarly, the unactivated alkyne [4 + 2] cycloaddition of 28
supersedes a potential indole [4 + 2] cycloaddition to cleanly
provide the furan also overriding the entropic preference for closure
to provide a five- versus six-membered ring. Finally, [4 + 2]
reaction of allene 32 is much faster than that of the corresponding
alkene or alkyne and is followed by an isomerization and elimina-
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