Lewis acid catalyzed intramolecular Diels-Alder reactions of acyclic (Z)-substituted 1,3-dienes

Article abstract of DOI:10.1021/ol015667k

matrix presented Lewis acid catalyzed intramolecular Diels-Alder reactions of trienes (E,E,Z)-1a-d, (E,E,Z)-4a-d, and (E,Z,Z)-7a,b are described. Trienes containing enal or enone dienophiles cyclize in excellent yield under mild conditions using substoich

Full text of DOI:10.1021/ol015667k

ORGANIC
LETTERS
2001
Vol. 3, No. 6
957-960
Lewis Acid Catalyzed Intramolecular
Diels−Alder Reactions of Acyclic
(Z)-Substituted 1,3-Dienes
Neal A. Yakelis and William R. Roush*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
roush@umich.edu
Received February 6, 2001
ABSTRACT
Lewis acid catalyzed intramolecular Diels−Alder reactions of trienes (E,E,Z)-1a−d, (E,E,Z)-4a−d, and (E,Z,Z)-7a,b are described. Trienes containing
enal or enone dienophiles cyclize in excellent yield under mild conditions using substoichiometric amounts of MeAlCl2, in most cases with
high levels of diastereoselectivity. The thermal IMDA reactions of 1a, 4a, and 7a require forcing conditions and proceed in low yield with
reversed stereoselectivity in the cases of 1a and 4a.
The intramolecular Diels-Alder (IMDA) reactions of (E,E,E)-
and (Z,E,E)-1,6,8-nonatrienes and -1,7,9-decatrienes are now
regarded as classic methods for the synthesis of the hexahy-
dro-1H-indene and octahydronaphthalene substructures that
occur in a wide range of natural products.1-3 However, use
of acyclic (Z)-1,3-dienes or dienes with (Z)-substituents as
substrates for intramolecular Diels-Alder has been limited
owing to their substantially diminished reactivity4,5 and
propensity for olefin isomerization under thermal reaction
conditions.6-10 Apart from (Z)-1,3-dienes (or dienes with (Z)-
substituents) constrained in macrocyclic ring systems,11 the
available accounts of IMDA reactions of acyclic alkyl-
substituted (Z)-dienes have not adequately addressed the
scope or utility of such systems.12-28 In particular, use of
Lewis acid catalysts to circumvent the harsh conditions
(11) Deslongchamps, P. Tetrahedron 2001, in press.
(12) Pyne, S. G.; Hensel, M. J.; Byrn, S. R.; McKenzie, A. T.; Fuchs, P.
L. J. Am. Chem. Soc. 1980, 102, 5960.
(13) Pyne, S. G.; Hensel, M. J.; Fuchs, P. L. J. Am. Chem. Soc. 1982,
104, 5719.
(14) Boeckman, R. K., Jr.; Alessi, T. R. J. Am. Chem. Soc. 1982, 104,
3216.
(15) Koreeda, M.; Luengo, J. I. J. Org. Chem. 1984, 49, 2079.
(16) Yoshioka, M.; Nakai, H.; Ohno, M. J. Am. Chem. Soc. 1984, 106,
1133.
(1) Ciganek, B. Org. React. 1984, 32, 1.
(2) Craig, D. Chem. Soc. ReV. 1987, 16, 187.
(3) Roush, W. R. In ComprehensiVe Organic Synthesis; B. M. Trost,
Ed.; Pergamon Press: Oxford, 1991; Vol. 5, pp 513-550.
(4) Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction;
Wiley: New York, 1990.
(17) Wattanasin, S.; Kathawala, F. G.; Boeckman, R. K., Jr. J. Org.
Chem. 1985, 50, 3810.
(18) Ziegler, F. E.; Jaynes, B. H.; Saindane, M. T. Tetrahedron Lett.
1985, 36, 3307.
(19) Burke, S. D.; Armistead, D. M.; Shankaran, K. Tetrahedron Lett.
1986, 27, 6295.
(5) Oppolzer, W. In ComprehensiVe Organic Synthesis; B. M. Trost, Ed.;
Pergamon Press: Oxford, 1991; Vol. 5, pp 315-398.
(6) House, H. O.; Cronin, T. H. J. Org. Chem. 1965, 30, 1061.
(7) Borch, R. F.; Evans, A. J.; Wade, J. J. J. Am. Chem. Soc. 1975, 97,
6282.
(8) Oppolzer, W.; Fehr, C.; Warneke, J. HelV. Chim. Acta 1977, 60, 48.
(9) Martin, S. F.; Williamson, S. A.; Gist, R. P.; Smith, K. M. J. Org.
Chem. 1983, 48, 5170.
(20) Magnus, P.; Walker, C.; Jenkins, P. R.; Menear, K. Tetrahedron
Lett. 1986, 27, 651.
(21) Koreeda, M.; Ricca, D. J.; Luengo, J. I. J. Org. Chem. 1988, 53,
5586.
(22) Corey, E. J.; Jardine, P. S.; Rohloff, J. C. J. Am. Chem. Soc. 1988,
110, 3672.
(23) Kozikowski, A. P.; Tu¨ckmantel, W. J. Org. Chem. 1991, 56, 2826.
(24) Jackson, R. W.; Shea, K. J. Tetrahedron Lett. 1994, 35, 1317.
(25) Tatsuta, K.; Itoh, M.; Hirama, R.; Araki, N.; Kitagawa, M.
Tetrahedron Lett. 1997, 38, 583.
(10) Matikainen, J.; Kaltia, S.; Ha¨ma¨la¨inen, M.; Hase, T. Tetrahedron
1997, 53, 4531.
10.1021/ol015667k CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/22/2001

required for thermal IMDA reactions of acyclic dienes with
(Z)-substituents has largely been restricted21 to Type II IMDA
cyclizations in the taxanoid series.29-34 Recent work in our
laboratory has established that intermolecular Diels-Alder
reactions of (Z)-substituted dienes can proceed in high yields
with excellent regio- and endo-selectivity at low temperatures
in the presence of Lewis acid catalysts.35 This prompted us
to explore the Lewis acid catalyzed Type I IMDA reactions
of trienes containing acyclic (Z)-substituted diene units, with
hope that this tactic would lead to efficient cycloaddition in
these cases.
We targeted trienes (E,E,Z)-1, (E,E,Z)-4, and (E,Z,Z)-7 to
assess the applicability of Lewis acid catalyzed IMDA
reactions of (Z)-substituted 1,3-dienes leading to angularly
methylated hexahydroindene and octahydronaphthalene ring
systems (Figure 1). Substrates 1 and 4, with terminally
activated (E)-dienophiles, potentially can give rise to two
products: the trans-fused cycloadducts 2 and 5 via endo
transition states, and the cis-fused products 3 and 6 via exo
transition states. Substrates with (6Z)-diene geometry as in
7 are known to react thermally via cis-fused transition states,
which are the only transition structures that are geometrically
feasible in such cases.3 The effect of Lewis acid catalysis
on trienes such as 1, 4, and 7 has not been documented
previously.
several-hour period to the final temperatures indicated in the
table led to smooth Diels-Alder reaction in the cases of
aldehyde (a, c) and methyl ketone (b) activated substrates.
However, the less reactive methoxycarbonyl (d) activated
substrates did not cyclize under a variety of conditions
(entries 5 and 10).37 Monitoring of the reaction progress by
TLC indicated that product formation began to occur in the
MeAlCl2-promoted cyclizations of 1a, 1b, 4a, and 4b at
approximately -40 °C, while products began to appear in
the cyclizations of 1c, 4c, 7a, and 7b at -25 to -15 °C.
Competing acid-promoted pathways were observed in several
instances, in particular cleavage of TBDPS ethers (for
reactions above 0 °C) and acid-catalyzed diene isomerization/
oligomerization depending upon reactions conditions. Use
of strong Lewis acids (AlCl3, TiCl4, SnCl4) and longer
reaction times (especially with sluggish substrates) promoted
substrate decomposition. While results obtained using Me2-
AlCl as the Lewis acid catalyst were similar to those obtained
with MeAlCl2, Me3Al (the weakest Lewis acid in the series)
failed to promote IMDA reactions of the most reactive
substrate, aldehyde 1a. Comparative thermal IMDA reactions
of 1a (entry 2) and 7a (entry 12) proceeded slowly at 180
°C. The homolog 4a (entry 8) did not react at 180 or 250
°C, even after 96 h. Heating 4a in a sand bath at 355 °C for
24 h finally gave a low yield of the IMDA products 5a and
6a, plus a complex mixture of isomerized diene.
The Lewis acid catalyzed IMDA reactions of trienes 1, 4,
and 7 were initiated by addition of the Lewis acid to a 0.08
M solution of the substrate at -78 °C, typically in CH2Cl2
(see Table 1).36 Warming the reaction mixtures over a
The MeAlCl2-catalyzed cyclizations of aldehydes 1a (entry
1) and 4a (entry 6) and methyl ketones 1b (entry 2) and 4b
(entry 8) were highly selective for the trans-fused products
2a, 2b, 5a, and 5b, paralleling the behavior of corresponding
(E,E)-diene substrates.3,38 The selectivity in these cases can
be explained by invoking transition states A and E, respec-
tively. Since 1 and 4 have externally activated dienophiles,
these reactions are thought to proceed via concerted but
asynchronous pathways with advanced bonding between the
internal carbons due to the high LUMO coefficient on the
dienophile â-carbon.3 Endo orientation of the s-trans, Lewis
acid complexed dienophile is believed to be favored as a
(26) Grimaud, L.; Fe´re´zou, J.-P.; Prunet, J.; Lallemand, J.-Y. Tetrahedron
1997, 27, 9253.
(27) Back, T. G.; Payne, J. E. Org. Lett. 1999, 1, 663.
(28) Martin, S. F.; Humphrey, J. M.; Ali, A.; Hillier, M. C. J. Am. Chem.
Soc. 1999, 121, 866.
(29) Brown, P. A.; Jenkins., P. R. J. Chem. Soc., Perkin Trans. 1 1986,
1303.
(30) Bonnert, R. V.; Jenkins, P. R. Tetrahedron Lett. 1987, 28, 697.
(31) Rubenstein, S. M.; Williams, R. M. J. Org. Chem. 1995, 60, 7215.
(32) Winkler, J. D.; Kim, H. S.; Kim, S. Tetrahedron Lett. 1995, 36,
687.
(33) Jenkins, P. R. Pure Appl. Chem. 1996, 68, 771.
(34) Forgione, P.; Wilson, P. D.; Yap, G. P. A.; Fallis, A. G. Synthesis
2000, 921.
(35) Roush, W. R.; Barda, D. A. J. Am. Chem. Soc. 1997, 119, 7402.
(36) Syntheses of trienes 1, 4, and 7 are described in the Supporting
Information.
(37) We also synthesized an acyl oxazolidine activated triene in series
1. Attempts to promote the Lewis acid catalyzed cyclization of this substrate
were also unsuccessful under a variety of conditions.
(38) Roush, W. R.; Essenfeld, A. P.; Warmus, J. S.; Brown, B. B.
Tetrahedron Lett. 1989, 30, 7305.
(39) Brown, F. K.; Houk, K. N. Tetrahedron Lett. 1985, 26, 2297.
(40) Raimondi, L.; Brown, F. K.; Gonzalez, J.; Houk, K. N. J. Am. Chem.
Soc. 1992, 114, 4796.
(41) Roush, W. R.; Essenfeld, A. P.; Warmus, J. S. Tetrahedron Lett.
1987, 28, 2447.
Figure 1.
958
Org. Lett., Vol. 3, No. 6, 2001

Table 1. Thermal and Lewis Acid Catalyzed Intramolecular Diels-Alder Reactions of Trienes 1, 4, and 7
entry
substrate
conditionsa
product yield (%)b
products
ratioc
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1a
1b
1c
1d
4a
4a
4b
4c
4d
7a
7a
7b
0.4 equiv MeAlCl2, -78 f 23 °C, 2 h
184 °C, toluene, sealed tube, 45 h
62
23
86
77
0
66
39
78
87
0
2a :3a
2a :3a
2b:3b
2c:3c
>99:1
37:63
>99:1
37:63
0.8 equiv MeAlCl2, -78 f 23 °C, 45 min
0.8 equiv MeAlCl2, -78 f 0 °C, 1.5 h
1.3 equiv MeAlCl2, toluene, -78 f 110 °C, 7 h
0.9 equiv MeAlCl2, -78 f -30 °C, 4 h
355 °C, toluene, sealed tube, 22 h
0.4 equiv MeAlCl2, -78 f -10 °C, 2 h
0.7 equiv MeAlCl2, -78 f -10 °C, 4.5 h
1.0 equiv SnCl4, -78 f -10 °C, 3 h
0.6 equiv MeAlCl2, -78 f -15 °C, 2 h
180 °C, toluene, sealed tube, 23 h
5a :6a
5a :6a
5b:6b
5c:6c
89:11
20:80
>99:1
94:6
83
50
94
8a
8a
8b
1:>99
1:>99
1:>99
0.4 equiv MeAlCl2, -78 f -20 °C, 2 h
a Reactions performed in CH2Cl2 unless otherwise noted. MeAlCl2 was added as a 1.0 M solution in hexane. b Combined yield of products after purification
by silica gel chromatography. c Product ratios determined by 1H NMR analysis of crude reaction mixtures. Stereostructures were assigned by using 1H NOE
and J data.
result of the steric constraints of the methylene tether and
enhanced diene HOMO/dienophile LUMO orbital interac-
tions.39,40
the four-carbon tether of 4a adopts a chairlike conformation,
1,3-diaxial interactions involving the dienyl (Z)-methyl group
destabilize the trans transition state E compared to the cis-
fused t.s. F by up to 1.8 kcal/mol in the thermal reaction
(Figure 2). The less pronounced selectivity for the cis-fused
product 3a in the thermal reaction of 1a possibly can be
attributed to the easing of these steric interactions, since the
shorter three-carbon tether adopts an envelope conformation
in which the pseudoaxial vinyl methyl group experiences
less severe 1,3-interactions in transition state C. Evidently,
Lewis acid activation of 1a and 4a must decrease the HOMO/
LUMO gap by such a degree so as to overcome the steric
demands of the trans transition states, such that transition
states A and E are favored in the Lewis acid promoted
reactions.
The switch in selectivity for the thermal IMDA reactions
of trienes 1a (entry 2) and 4a (entry 7) compared to the Lewis
acid catalyzed reactions (entries 1 and 6, respectively) is
especially noteworthy. The thermal reactions of these trienes
led to a predominance of the cis-fused cycloadducts in both
cases. Trienes containing disubstituted (E,E)-dienes generally
display good to excellent trans ring fusion selectivity in
thermal IMDA reactions, and the preference for the trans-
fused product is always enhanced in the presence of Lewis
acids.3,41 To reconcile this striking difference in selectivity
in the thermal vs Lewis acid promoted cyclizations of 1a
and 4a, we suggest that the thermal reaction is dominated
by an overriding steric effect induced by the diene (Z)-methyl
group (see interactions highlighted in t.s. E). Assuming that
The results for the Lewis acid promoted cyclizations of
the R-methyl enal substrates 1c (entry 4) and 4c (entry 9)
Figure 2. Transition States for the IMDA Reactions.
Org. Lett., Vol. 3, No. 6, 2001
959

also warrant brief comment. The cyclization of 4c gave high
trans selectivity via t.s. G, similar to the selectivity pattern
observed with the aldehyde (4a) and methyl ketone (4b)
activated substrates. Surprisingly, however, the Lewis acid
promoted cyclization of 1c preferentially led to the cis-fused
product 3c, a result that deviates from the highly trans
selectivity realized with 1a and 1b. Analysis of the possible
transition states for 1c reveals that the trans transition state
C is destabilized by an interaction between the dienophile
R-methyl group and the (Z)-methyl group of the diene.
Application of the precepts of twist asynchronicity39,40 in t.s.
C for the Lewis acid promoted reaction of 1c suggests that
these methyl groups will be pushed toward one another,
thereby magnifying this destabilizing interaction. Accord-
ingly, the sterically less demanding exo transition state D is
favored in this case. However, the steric requirements must
be relaxed in the analogous trans transition state G for 4c
(as compared to t.s. C for 1c) as a result of the extra
methylene of the tether and the corresponding decreased
contribution of twist asynchronicity in the IMDA reactions
of 1,8,10-undecatrienes.39 Thus, frontier orbital interactions
predominate to impart the observed high trans-fused, endo
selectivity in the IMDA reaction of 4c.
with 1,1,4-trisubstitution patterns in the diene units, undergo
efficient and usually highly stereoselective Lewis acid
catalyzed intramolecular Diels-Alder reactions in the pres-
ence of substoichiometric amounts of MeAlCl2 or Me2AlCl
at subambient temperatures. Accordingly, (Z)-alkyl-substi-
tuted 1,3-dienes may now be considered to be synthetically
viable IMDA substrates. Applications of this technology in
natural products synthesis will be reported in due course.
Acknowledgment. Financial support provided by the
National Institutes of Health to W.R.R. (GM 26782) is
gratefully acknowledged.
Note Added after ASAP: The substituent key for R groups
in Figure 1 was omitted in the version posted ASAP on
2/22/01. This error was corrected in the version posted
2/27/01.
Supporting Information Available: Summaries of the
syntheses of trienes 1a-c, 4a-c, and 7a,b; representative
procedure for the Lewis acid catalyzed intramolecular Diels-
Alder reactions of 1a-c, 4a-c, and 7a,b; tabulated spec-
troscopic data for cycloadducts 2a-c, 3a, 3c, 5a-c, 6a, 6c,
and 8a,b; and summaries of cycloadduct stereochemical
assignments. This material is available free of charge via
the Internet at http://pubs.acs.org.
The thermal and Lewis acid catalyzed cyclizations of
trienes 7a,b proceed with excellent selectivity via t.s. B. The
corresponding exo- (or trans-fused) transition state is geo-
metrically inaccessible with (E,Z,Z)-trienes of this type.3
In summary, we have demonstrated that carboxaldehyde
or methyl ketone activated trienes 1a-c, 4a-c, and 7a,b,
OL015667K
960
Org. Lett., Vol. 3, No. 6, 2001