Tandem hetero Diels-Alder reaction: Synthesis of oxygenated macrocycles

Article abstract of DOI:10.1021/ol007040s

Equation presented C2-symmetric oxygenated macrocycles have been synthesized from simple acyclic precursors in a single step by a tandem hetero Diels-Alder reaction. Thermolysis and Lewis acid catalysis can effect this novel transformation. The tandem rea

Full text of DOI:10.1021/ol007040s

ORGANIC
LETTERS
2001
Vol. 3, No. 5
723-726
Tandem Hetero Diels−Alder Reaction:
Synthesis of Oxygenated Macrocycles
Brian R. Bear and Kenneth J. Shea*
Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine,
IrVine, California 92697-2025
kjshea@uci.edu
Received December 21, 2000
ABSTRACT
C2-symmetric, oxygenated macrocycles have been synthesized from simple acyclic precursors in a single step by a tandem hetero Diels−
Alder reaction. Thermolysis and Lewis acid catalysis can effect this novel transformation. The tandem reaction product is formed in preference
to the intramolecular cycloaddition product, and an explanation for this result is proposed.
We have been exploring heteroatom variants of the type 2
intramolecular Diels-Alder (IMDA) reaction.1 If an R,â-
unsaturated ketone is used as the 4π component in the
cycloaddition reaction, the product formed is a bridgehead
pyran (Scheme 1). The bicyclic pyran can be functionalized
olefin2 could provide an entry into R,R′-cis-disubstituted
medium ring ethers (path b).
The intermolecular hetero Diels-Alder reactions of 2-sub-
stituted-1-oxo-butadienes are facilitated by electron-with-
drawing groups.3 Electron-withdrawing groups have been
used at the 2, 3, and 4 positions of the heterodiene, with the
most success realized with activation at positions 2 and 3.
Relevant examples include the work of Sera,4 Evans,5 and
Jorgensen.6
Scheme 1
Our studies of the type 2 intramolecular hetero Diels-
Alder (IMHDA) reaction have led to the discovery of a novel
reaction pathway, the tandem hetero Diels-Alder reaction.
(2) (a) Shea, K. J. Tetrahedron 1980, 36, 1683. (b) Warner, P. M. Chem.
ReV. 1989, 89, 1067.
(3) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in
Organic Synthesis; Pergamon: Oxford, 1987; Chapter 7.
(4) Sera, A.; Ohara, M.; Yamada, H.; Egashira, E.; Ueda, N.; Setsune,
J. Chem. Lett. 1990, 2043.
(5) Evans, D. A.; Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000,
122, 1635.
(6) Thorhauge, J.; Johannsen, M.; Jorgensen, K. A. Angew. Chem., Int.
Ed., Engl. 1998, 37, 2404.
(7) Stetcher, E. D.; Ryder, H. F. J. Am. Chem. Soc. 1952, 74, 4392.
(8) (a) Schmidt, R. R.; Maier, M. Tetrahedron Lett. 1985, 26, 2065. (b)
Tietze, L. F.; Hubsch, T.; Voss, E.; Buback, M.; Trost, W. J. Am. Chem.
Soc. 1988, 110, 4065. (c) Boger, D. L.; Robarge, K. D. J. Org. Chem. 1988,
53, 3373.
by cleaving the tether that spans the dihydropyran, which
would lead to the synthesis of a substituted dihydropyran
(path a). Alternatively, functionalization of the bridgehead
(1) For examples of type 2 intramolecular nitroso Diels-Alder reactions,
see: Sparks, S. M.; Vargas, J. D.; Shea, K. J. Org. Lett. 2000, 2, 1473.
10.1021/ol007040s CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/03/2001

Examination of the type 2 IMHDA reaction commenced
with the synthesis of ester activated heterodiene 2 (Scheme
2). R-Keto acid 17 was converted to ester 2 using standard
ship between the two cis-dihydropyran rings of this product
(Figure 2). Both cycloadditions are stereoselective. In ad-
Scheme 2
Figure 2. Molecular structure of minor product anti-3 from the
thermolysis of R-keto ester 2.
dition, the second cycloaddition exhibits a 12:1 selectivity
for the syn macrocycle. We do not at present have a
compelling explanation for this observation.
Intrigued by these findings, we decided to investigate the
synthesis of other crown-ether-like compounds using the
tandem hetero Diels-Alder reaction. Lewis acid catalysis
and alkyl dienophiles were employed to examine the scope
of the reaction. R-Keto acid 1 was coupled with primary
alcohols 5-79 to provide R-keto esters 8-10 (Scheme 3).
conditions. Thermolysis of R-keto ester 2 did not lead to
the expected type 2 IMHDA product, but instead the major
product had a mass exactly double the expected product.
We tentatively assigned the structure of the major product
as macrocycle 3 and proposed a sequential reaction pathway
to account for its formation: the tandem hetero Diels-Alder
reaction. We believed both cycloadditions would occur
through the endo transition state to produce the cis stereo-
chemistry at both dihydropyrans.8 It was unclear if the
relative stereochemistry of the two bridged ring systems
could be controlled in the macrocyclization. An X-ray crystal
structure confirmed the connectivity and the all-cis relative
stereochemistry of the major product, compound syn-3
(Figure 1).
Scheme 3
A variety of Lewis acids were screened. SnCl4 was found
to be superior for the tandem hetero Diels-Alder cyclization
of R-keto esters 8-10 to produce macrocycles 11-13. The
1
connectivity of compounds 11-13 was determined by H
and 13C correlation to tricycle syn-3 and mass spectral
analysis. In each case, the dimer was the only product
produced. Efforts are underway to grow crystals suitable for
X-ray analysis to permit assignment of the overall relative
stereochemistry of the cycloadducts. Examination of the
crude reaction mixtures indicates two stereomeric products
were formed, similar to that found in the thermolysis of 2.
Figure 1. Molecular structure of macrocycle syn-3. The oxygens
of the 20-membered macrocycle are darkened for clarity.
A minor product anti-3 (<5%) was also isolated from the
reaction. X-ray crystallography established the anti relation-
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Org. Lett., Vol. 3, No. 5, 2001

The mild reaction conditions allow increased functionaliza-
tion of the cycloaddition precursors, making analogue
synthesis a reality.
The preceding results can be understood in terms of the
reactivity of the corresponding bimolecular reactions. In the
intermolecular hetero Diels-Alder reaction of 2-activated
enone dienes with both activated and unactivated dienophiles,
excellent regioselectivity is observed (Figure 3). FMO
mational preferences in place, the tether is effectively
shortened and the dienophile is unable to approach the hetero
diene without the introduction of considerable steric energy;
therefore the type 2 IMHDA reaction is not favorable.
Product 3 therefore is formed in a stepwise process: the
tandem hetero Diels-Alder reaction (Scheme 4). Initially,
Scheme 4
Figure 3. Regioselectivity of the intermolecular hetero Diels-
Alder reaction of 2-activated enone dienes with activated and
unactivated dienophiles.
analysis has been used to explain the regiochemical outcome
of the cycloaddition.10
an endo intermolecular hetero Diels-Alder reaction takes
place to produce cis-substituted dihydropyran intermediate
4. After the first cycloaddition, conformational restrictions
no longer prohibit the intramolecular cyclization. The dilute
reaction conditions (0.01 M) favor intramolecular cyclization;
therefore, dihydropyran 4 can undergo a hetero Diels-Alder
reaction to form macrocycle syn-3.12
In reactions catalyzed by SnCl4, it is believed the Lewis
acid coordinates the R-dicarbonyls, forming an octahedral
complex, which makes the endo cycloaddition mode unfa-
vorable (Figure 5). In addition, the tether is too short to allow
Hetero Diels-Alder reactions of 1-oxobutadienes are often
stereoselective. Under thermal conditions, the endo mode of
cycloaddition typically dominates, producing the 4,6-cis
dihydropyran product.8 Conversely, Lewis acid catalysis
(SnCl4) of similar reactions leads to the 4,6-trans product,
which arises from the exo mode of cycloaddition.4 The tin
complex is believed to be octahedral, and this complex blocks
the dienophile from approaching the heterodiene through the
traditional endo mode; therefore, the exo cycloadduct is
formed.
We can draw upon the preceding to explain the observed
regiochemical and stereochemical outcome of the thermolysis
of R-keto ester 2, while conformational considerations can
be used to account for the absence of the type 2 IMHDA
product. It is known that the R,â-unsaturated R-keto esters
prefer to have the π-system coplanar (Figure 4).11 Also, it
Figure 5. Proposed octahedral complex of the Lewis acid (SnCl4)
and R-keto ester 8 disfavoring the type 2 IMHDA reaction.
the dienophile to interact with the heterodiene through the
exo transition state; therefore, both modes of intramolecular
cycloaddition are shut down. Again, the dienophile reacts
initially intermolecularly, and the macrocycle is formed by
a subsequent intramolecular cycloaddition.
Figure 4. Conformational restrictions of R-keto ester 2 disfavoring
the type 2 IMHDA reaction.
Examination of the type 2 intramolecular hetero Diels-
Alder reaction utilizing 2-alkenyl ester-1-oxa-butadienes as
the 4π components has led to the discovery of a tandem
hetero Diels-Alder reaction. In this reaction sequence, highly
oxygenated macrocycles can be formed from simple acyclic
precursors in a single step under thermal or Lewis acid
has been documented that esters prefer to reside in an s-cis
conformation to the s-trans orientation. With these confor-
(9) Alcohols 6 and 7 were synthesized using the procedure described in
Brunel, Y.; Rousseau, G. Tetrahedron Lett. 1996, 37, 3853.
(10) Fleming, I. Frontier Orbitals and Organic Chemical Reactions; John
Wiley and Sons: New York, 1998; pp 141-142.
(11) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley-Interscience: New York, 1994; p 619.
(12) In addition, very dilute conditions (<1 × 10-6 M) have been
employed attempting to effect the type 2 intramolecular cycloaddition. Even
under these conditions, the only product observed was dimer 3.
Org. Lett., Vol. 3, No. 5, 2001
725

catalyzed conditions. We believe this is the first example of
a transformation of this type. With the ease of synthesis of
the cycloaddition precursors, this chemistry is amenable to
analogue synthesis. Studies to determine the cation affinity
and specific utility of the macrocycles are currently being
conducted.
(X-ray analysis) and Dr. John Greaves and Dr. John Mudd
(mass spectral analysis).
Supporting Information Available: X-ray crystallo-
graphic data for compounds syn-3 and anti-3. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. The authors gratefully acknowledge
OL007040S
the support of the NIH and the assistance of Dr. Joe Ziller
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Org. Lett., Vol. 3, No. 5, 2001