Probing the Lewis Acid-Catalyzed Intramolecular Diels-Alder Cyclizations of Allylic Alkoxy-Substituted (Z)-1,3-Dienes

Article abstract of DOI:10.1021/ol035900+

(Matrix presented) The Lewis acid-promoted Diels-Alder reaction of (E,Z,E)-trienal 1 provides not only the expected cis-fused cycloadduct 16 but also the transfused products 17 and 18. Trans-fused cycloadducts 17 and 18 are also products of the Lewis acid

Full text of DOI:10.1021/ol035900+

ORGANIC
LETTERS
2003
Vol. 5, No. 24
4725-4728
Probing the Lewis Acid-Catalyzed
Intramolecular Diels−Alder Cyclizations
of Allylic Alkoxy-Substituted
(Z)-1,3-Dienes
Thomas A. Dineen and William R. Roush*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
roush@umich.edu
Received September 29, 2003
ABSTRACT
The Lewis acid-promoted Diels−Alder reaction of (E,Z,E)-trienal 1 provides not only the expected cis-fused cycloadduct 16 but also the trans-
fused products 17 and 18. Trans-fused cycloadducts 17 and 18 are also products of the Lewis acid-promoted cyclization of (E,Z,E)-trienyl
acetal 2. These products presumably derive from a stepwise cyclization pathway.
Previous work in this laboratory has explored the application
of Lewis acid catalysis to the Diels-Alder reaction of (Z)-
substituted 1,3-dienes.1,2 Acyclic (Z)-1,3-dienes are substan-
tially less reactive than (E)-dienes in the thermal Diels-
Alder reaction3,4 and are subject to thermal olefin isomeri-
zation.5-9 As a result, their use in Diels-Alder reactions has
been limited.10 We have demonstrated that the synthetic
utility of (Z)-1,3-dienes (and dienes with (Z)-substituents)
is substantially enhanced by using Lewis acid catalysts, in
both inter- and intramolecular Diels-Alder (IMDA) reaction
manifolds. These Lewis acid-promoted reactions proceed
under mild conditions to give cycloadducts in good yield,
generally with excellent stereoselectivity.1,2
In connection with ongoing studies on the synthesis of
macquarimicin A and cochleamycin A,11-13 we became inter-
ested in exploring the IMDA reactions of trienes that possess
an alkoxy function allylic to the diene, as in 3 (Figure 1).
Because of geometric constraints, substrates such as 3 react
thermally only via endo transition states to give cis-fused
products.5,14 Minimization of allylic strain interactions in-
volving the OTBS group should highly bias the IMDA
reaction of 3 to proceed with high selectivity via the endo
transition state A (see Figure 1).15,16 In fact, thermal intra-
molecular Diels-Alder reactions of trienes similar to 3 have
(1) Roush, W. R.; Barda, D. A. J. Am. Chem. Soc. 1997, 119, 7402.
(2) Yakelis, N. A.; Roush, W. R. Org. Lett. 2001, 3, 957 and references
therein.
(3) Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction;
Wiley: New York, 1990.
(4) Oppolzer, W. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, UK, 1991; Vol. 5, pp 315-398.
(5) House, H. O.; Cronin, T. H. J. Org. Chem. 1965, 30, 1061.
(6) Borch, R. F.; Evans, A. J.; Wade, J. J. J. Am. Chem. Soc. 1975, 97,
6282.
(7) Oppolzer, W.; Fehr, C.; Warneke, J. HelV. Chim. Acta 1977, 60, 48.
(8) Martin, S. F.; Williamson, S. A.; Gist, R. P.; Smith, K. M. J. Org.
Chem. 1983, 48, 5170.
(9) Matikainen, J.; Kaltia, S.; Ha¨ma¨la¨inen, M.; Hase, T. Tetrahedron
1997, 53, 4531.
(10) A list of references to previous applications of IMDA reactions of
(Z)-substituted dienes is provided in ref 2.
(11) Shindo, K.; Iijima, H.; Kawai, H. J. Antibiot. 1996, 49, 244.
(12) Hochlowski, J. E.; Mullally, M. M.; Henry, R.; Whittern, D. M.;
McAlpine, J. B. J. Antibiot. 1995, 48, 467.
(13) Tanaka, M.; Nara, F.; Yamasao, Y.; Masuda-Inoue, S.; Soi-
Yoshioka, H.; Kumakura, S.; Enokiat, R.; Ogita, T. J. Antibiot. 1999, 52,
670.
(14) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, UK, 1992; Vol. 5, pp 513-550.
(15) Pyne, S. G.; Hensel, M. J.; Fuchs, P. L. J. Am. Chem. Soc. 1982,
104, 5179.
(16) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
10.1021/ol035900+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/30/2003

Scheme 1a
Figure 1. Diastereoselectivity in the IMDA of alkoxy-substituted
(Z)-1,3-dienes.
recently been accomplished with excellent success by the
Tadano17 and Paquette18 groups in their studies toward the
synthesis of macquarimicin A and cochleamycin A. Never-
theless, we were interested in determining if the IMDA
reactions of substrates such as 3 could be successfully
achieved with Lewis acid catalysis. Marshall has shown that
the best results in Lewis acid-promoted IMDA reactions of
trienes with dienylic ether substituents are obtained with
substrates containing carboxyaldehyde dienophile activating
groups.19 In contrast, dienylic alkoxy-substituted trienes with
carboalkoxy dienophile activation tend to give only decom-
position products under Lewis acid-promoted cycloaddition
conditions.20 Thus, the question we wished to address was
if carboxaldehyde-activated, alkoxy-substituted (Z)-1,3-dienes
such as 3 would be sufficiently reactive to undergo efficient
Lewis acid-promoted IMDA reactions without competitive
decomposition of the sensitive dienylic ether unit. Triene 1
(Scheme 1) served as the initial substrate for these investiga-
tions.
a Reagents and conditions: (a) TBDPS-Cl, imidazole, DMAP,
CH2Cl2:DMF (2:1); (b) Cp2Zr(H)Cl, CH2Cl2, then I2; (c) propargyl
alcohol, Pd(PPh3) Cl2, CuI, Et2N; (d) MnO2, CH2Cl2; (e) diiso-
2
propyl (S,S)-tartrate (E)-crotylboronate, PhCH3, -78 °C; (f) TBS-
Cl, imidazole, CH2Cl2-DMF (2:1); (g) 9-BBN, THF, 0 °C, then
H2O2, aqueous NaOH, 0 °C; (h) Zn, Cu(OAc)2‚H2O, AgNO3,
MeOH:H2O (1:1); (i) Dess-Martin periodinane, pyridine, wet
CH2Cl2; (j) diethyl (N-methoxy-N-methylcarbamoylmethyl)phos-
phonate, NaH, THF; (k) DIBAL-H, THF, -78 °C.
The synthesis of 1 (Scheme 1) began with protection of
3-butyn-1-ol to give the TBDPS ether 7 in 99% yield.
Treatment of 7 with Schwartz’s reagent followed by addition
of I2 gave vinyl iodide 8 in 86% yield.21 Sonogashira
coupling22 of 8 with propargyl alcohol gave alcohol 9 in 83%
yield, which was oxidized with MnO2 to give aldehyde 10
in 80% yield. Treatment of the aldehyde with diisopropyl
(S,S)-tartrate (E)-crotylboronate,23 followed by protection of
the resulting homoallylic alcohol as a TBS ether gave 11 in
70% yield over two steps. Subjection of 11 to a hydrobo-
ration/oxidation sequence then gave primary alcohol 12 in
90% yield. Cis-reduction of the alkyne was best accomp-
lished by using a Zn/Ag couple.24,25 This reaction provided
diene 13 in 79% yield, with excellent (Z) selectivity. The
primary alcohol unit of 13 was then oxidized to aldehyde
14 in 99% yield with use of the Dess-Martin periodinane
reagent.26,27 Horner-Wadsworth-Emmons olefination of 14
yielded the R,â-unsaturated Weinreb amide 15 in 87% yield.
Finally, DIBAL-H reduction of 15 at -78 °C furnished the
targeted triene aldehyde 1 in 74% yield.
Treatment of 1 with 0.6 equiv of MeAlCl2 in CH2Cl2
initially at -78 °C and then for 2 h at -23 °C provided an
ca. 3.7:1:1 mixture of diastereomeric cycloadducts 16, 17,
1
and 18 in 66% combined yield, as determined by H NMR
analysis (Scheme 2). Cycloadduct 16 could be readily
separated from the mixture by HPLC and characterized, but
17 and 18 were inseparable by HPLC. The structure of 16
was assigned as the expected cis-fused cycloadduct by using
NOESY experiments (Figure 2). The structures of trans-fused
cycloadducts 17 and 18 were determined subsequently by
(17) Munaketa, R.; Ueki, T.; Katakai, H.; Takao, K.; Tadano, K. Org.
Lett. 2001, 3, 3029.
(18) Chang, J.; Paquette, L. A. Org. Lett. 2002, 4, 253.
(19) Marshall, J. A.; Audia, J. E.; Grote, J. J. Org. Chem. 1984, 49,
5277.
(20) Roush, W. R.; Hall, S. E. J. Am. Chem. Soc. 1981, 103, 5200.
(21) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1975,
97, 679.
(22) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 2647.
(24) Boland, W.; Schroer, N.; Sieler, C.; Feigel, M. HelV. Chim. Acta
1987, 70, 1025.
(25) Avignon-Tropis, M.; Pougny, J. R. Tetrahedron Lett. 1989, 30, 4951.
(26) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(27) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(23) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.;
Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339.
4726
Org. Lett., Vol. 5, No. 24, 2003

Scheme 2. Lewis Acid-Catalyzed and Thermal IMDA
Cyclizations of (E,Z,E)-Triene 1
Scheme 3. Lewis Acid-Promoted Cyclization of
(E,Z,E)-Triene Acetal 2
spectroscopic correlation with the products of cyclization of
acetal 2 (vide infra). Use of alternative Lewis acids (BF3‚
OEt, SnCl4, TiCl4, and (menthyloxy)AlCl2) for the IMDA
cyclization of 1 gave very low yields of products, while
attempted use of Me2AlCl and 4 M LiClO4 in CH3NO2 failed
to promote any cycloaddition, and only returned unchanged
starting triene. In contrast, heating a solution of 1 at 160 °C
in toluene in a sealed tube in the presence of a small amount
of BHT for 16 h gave 16 in 83% yield along with 3% of a
mixture of 17 and 18. It is assumed that the trans-fused
products 17 and 18 arise from a stepwise cyclization path-
way, because geometric constraints posed by the three-carbon
tether should preclude access to the exo cyclization transition
state necessary for concerted formation of these products
from a (Z)-1,3-diene.5,14 We consider it unlikely that 17 and
18 arise from IMDA cyclization of the (E,E,E)-isomer of 1,
since this species is not present in 1 recovered from
experiments in which the Lewis acid-promoted cycloaddition
does not go to completion.
While it was encouraging that the MeAlCl2-promoted
cyclization of 1 was faster than decomposition pathways
involving ionization of the pentadienyl ether,19,20 we were
very surprised that substantial amounts of trans-fused 17 and
18 were also produced, suggesting a lack of concertedness
under the IMDA reaction conditions. Accordingly we became
interested in exploring alternative strategies for promoting
the IMDA cyclizations of 1 and its derivatives. The Lewis
acid-catalyzed cyclization of acetal 2 was of interest in this
regard, because Lewis acid treatment of the R,â-unsaturated
acetal provides a vinyl dioxolenium ion, a very potent
dienophile.28,29 We hoped that implementation of this strategy
would permit use of a less reactive Lewis acid (compared
to the Lewis acids employed in the IMDA reaction of 1),
thereby enabling the cyclization of 2 to occur under milder
conditions.
catalytic amount of TsOH in THF.30 Treatment of 2 with
0.6 equiv of Me2AlCl in CH2Cl2 at -78 °C and immediately
warming the mixture to -20 °C for 45 min provided a
mixture of products 19 in 57% yield. The same product
mixture was obtained in 65% yield by treatment of the triene
acetal 2 with 4 M LiClO4 in CH3NO2 at room temperature
overnight.31,32 This mixture could not be separated by HPLC,
so product separation was postponed following subsequent
chemical manipulations. Treatment of the cycloadduct mix-
ture with Me2BBr (6 equiv) at -78 to 0 °C gave a mixture
of four aldehydes (1H NMR analysis) in 92% yield.33 This
mixture also could not be separated, so the aldehydes were
reduced by treatment with NaBH4 in MeOH at 0 °C.
(29) (a) Gassman, P. G.; Singleton, D. A.; Wilwerding, J. J.; Chavan, S.
P. J. Am. Chem. Soc. 1987, 109, 2182. (b) Gassman, P. G.; Chavan, S. P.
J. Org. Chem. 1988, 53, 2392. (c) Gassman, P. G.; Chavan, S. P.
Tetrahedron Lett. 1988, 29, 3407. (d) Gassman, P. G.; Chavan, S. P. J.
Chem. Soc., Chem. Commun. 1989, 837. (e) Hashimoto, Y.; Saigo, K.;
Machida, S.; Nagashima, T.; Hasegawa, M.; Saigo, K. Chem. Lett. 1992,
1353. (f) Wipf, P.; Xu, W. Tetrahedron 1995, 51, 4551. (g) Sammakia, T.;
Berliner, M. A. J. Org. Chem. 1995, 60, 6652. (h) Grieco, P. A.; Kaufman,
M. D.; Daeuble, J. F.; Saito, N. J. Am. Chem. Soc. 1996, 118, 2095. (i)
Magnuson, S. R.; Sepp-Lorenzino, L.; Rosen, N.; Danishefsky, S. J. J. Am.
Chem. Soc. 1998, 120, 1615.
Cyclic acetal 2 was prepared in 83% yield by treatment
of 1 with 2-methoxy-1,3-dioxane and 1,3-propanediol and a
(30) Roush, W. R.; Gillis, H. R. J. Org. Chem. 1980, 45, 4283.
(31) Ayerbe, M.; Cossio, F. P. Tetrahedron Lett. 1995, 36, 4447.
(32) Grieco, P. A.; Nunes, J. J.; Gaul, M. D. J. Am. Chem. Soc. 1990,
112, 4595.
(28) Roush, W. R.; Gillis, H. R.; Essenfeld, A. P. J. Org. Chem. 1984,
49, 4674.
Org. Lett., Vol. 5, No. 24, 2003
4727

Fortunately, the mixture of alcohols 20 could be fractionated
at this stage by using HPLC. Pure samples of the two major
stereoisomers were obtained, along with a mixture of two
minor products. Oxidation of the two major alcohols with
Dess-Martin periodinane gave trans-fused perhydroindenes
21 and 22, the stereostructures of which were unambiguously
assigned by using 1D and 2D NMR experiments (Figure 2).
Scheme 4. Proposed Stepwise Pathway for Formation of
Trans-Fused Cycloadducts
hyde < Lewis acid-complexed aldehyde < dioxolenium ion)
appears to increase the asynchronicity of the transition state
to the point where a stepwise mechanism is by far the major
pathway. Interestingly, the allylic strain arguments that have
been advanced to rationalize the high asymmetric induction
in the competing IMDA transition states A vs B do not apply
to the nonconcerted cyclization leading to 17, 18, 21, and
22. Thus, for substrates such as 1, a thermal IMDA cycli-
zation protocol appears to be superior to the Lewis acid
promoted alternative.
Figure 2. 1H NOESY data for cycloadducts 16, 21, and 22.
Further studies of the (Z)-diene Diels-Alder reaction in
natural products synthesis will be reported in due course.
Base-promoted epimerization of 21 and 22 provided authentic
samples of 17 and 18, which were identified as the minor
products of the IMDA cyclization of 1 (vide supra). A
mixture of 17 and 18 was similarly prepared by oxidation
of the mixture of minor alcohols 20 (deriving from 19).
The appearance of trans-fused products in the cyclizations
of 1 and 2 implicates a stepwise cyclization mechanism,
rather than a traditional concerted [4+2] transition state (see
Scheme 4). Increasing the activation of the dienophile (alde-
Acknowledgment. Financial support by the National
Institutes of Health (GM26782) is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization (1H and 13C NMR,
IR, and HRMS) of compounds 1, 2, 8-16, 21, and 22. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(33) Guindon, Y.; Yoakim, C.; Morton, H. E. J. Org. Chem. 1984, 49,
3912.
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