Catalyst-controlled diastereoselective hetero-Diels-Alder reactions

Article abstract of DOI:10.1021/ol0258785

The diastereoselective hetero-Diels-Alder reaction between Danishefsky's diene and chiral aldehydes is catalyzed by chiral chromium-Schiff base complexes. High levels of catalyst control are obtained in several cases, allowing access to all four stereoisomeric products through appropriate choice of aldehyde and catalyst enantiomers.

Full text of DOI:10.1021/ol0258785

ORGANIC
LETTERS
2002
Vol. 4, No. 10
1795-1798
Catalyst-Controlled Diastereoselective
Hetero-Diels−Alder Reactions
Guy D. Joly and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
jacobsen@chemistry.harVard.edu
Received March 14, 2002
ABSTRACT
The diastereoselective hetero-Diels−Alder reaction between Danishefsky’s diene and chiral aldehydes is catalyzed by chiral chromium−Schiff
base complexes. High levels of catalyst control are obtained in several cases, allowing access to all four stereoisomeric products through
appropriate choice of aldehyde and catalyst enantiomers.
The hetero-Diels-Alder (HDA) reaction between 1-meth-
oxy-3-[(trimethylsilyl)oxy]-1,3-butadiene (1, Danishefsky’s
diene) and aldehydes has been the focus of extensive study
and application (Scheme 1).1 Early efforts to control stereo-
reactions of 1 and related electron-rich dienes.3 In the latter
context, our research group has developed two related
catalyst systems for effecting enantioselective hetero-Diels-
Alder reactions.4 The (salen)Cr(III)-BF4 complex 2 was
found to be a reactive and effective catalyst for asymmetric
106, 2455. (e) Danishefsky, S. J.; Larson, E.; Askin, D.; Kato, N. J. Am.
Chem. Soc. 1985, 107, 1246. (f) Danishefsky, S. J.; Myles, D. C.; Harvey,
D. F. J. Am. Chem. Soc. 1987, 109, 862. (g) Danishefsky, S. J.; Kato, N.;
Askin, D.; Kerwin, J. F., Jr. J. Am. Chem. Soc. 1982, 104, 360.
Scheme 1
(3) (a) Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding, K. J. Am. Chem. Soc.
2002, 124, 10. (b) Doyle, M. P.; Phillips, I. M.; Hu, W. J. Am. Chem. Soc.
2001, 123, 5366. (c) Motoyama, Y.; Koga, Y.; Nishiyama, H. Tetrahedron
2001, 57, 853. (d) Aikawa, K.; Irie, R.; Katsuki, T. Tetrahedron 2001, 57,
845. (e) Qian, C.; Wang, L. Tetrahedron Lett. 2000, 41, 2203. (f) Yamada,
T.; Kezuka, S.; Mita, T.; Ikeno, T. Heterocycles 2000, 52, 1041. (g) Furuno,
H.; Hanamoto, T.; Sugimoto, Y.; Inanaga, J. Org. Lett. 2000, 2, 49. (h)
Mihara, J.; Hamada, T.; Takeda, T.; Irie, R.; Katsuki, T. Synlett 1999, 1160.
(i) Li, L.-S.; Wu, Y.; Hu, Y.-J.; Xia, L.-J.; Wu, Y.-L. Tetrahedron:
Asymmetry 1998, 9, 2271. (j) Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J.
Org. Chem. 1995, 60, 5998. (k) Corey, E. J.; Cywin, C. L.; Roper, T. D.
Tetrahedron Lett. 1992, 33, 6907. (l) Ghosh, A. K.; Mathivanan, P.;
Cappiello, J. Tetrahedron Lett. 1997, 38, 2427. (m) Matsukawa, S.; Mikami,
K. Tetrahedron: Asymmetry 1997, 8, 815. (n) Hanamoto, T.; Furuno, H.;
Sugimoto, Y.; Inanaga, J. Synlett 1997, 79. (o) Mikami, K.; Kotera, O.;
Motoyama, Y.; Sakaguchi, H. Synlett 1995, 975. (p) Motoyama, Y.; Mikami,
K. J. Chem. Soc., Chem. Commun. 1994, 1563. (q) Gao, Q.; Maruyama,
T.; Mouri, M.; Yamamoto, H. J. Org. Chem. 1992, 57, 1951. (r) Togni, A.
Organometallics 1990, 9, 3106. (s) Maruoka, K.; Itoh, T.; Shirasaka, T.;
Yamamoto, H. J. Am. Chem. Soc. 1988, 110, 310. (t) Bednarski, M.; Maring,
C.; Danishefsky, S. J. Tetrahedron Lett. 1983, 24, 3451.
selectivity in these reactions focused on the use of chiral
aldehydes in substrate-controlled diastereoselective reac-
tions.2 More recently, attention has been given to the
discovery of chiral catalysts to effect enantioselective HDA
(1) For reviews, see: (a) Jørgensen, K. A. Angew. Chem., Int. Ed. 2000,
39, 3558. (b) Danishefsky, S. J. Chemtracts 1989, 273. (c) Danishefsky, S.
J.; De Ninno, M. P. Angew. Chem., Int. Ed. Engl. 1987, 26, 15. (d)
Danishefsky, S. J. Aldrichimica Acta 1986, 19, 59.
(2) (a) Midland, M. M.; Koops, R. W. J. Org. Chem. 1990, 55, 5058.
(b) Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F.; Maring, C. J.;
Springer, J. P. J. Am. Chem. Soc. 1985, 107, 1256. (c) Danishefsky, S. J.;
Kobayashi, S.; Kerwin, J. F., Jr. J. Org. Chem. 1982, 47, 1981. (d)
Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F. J. Am. Chem. Soc. 1984,
(4) (a) Schaus, S. E.; Brånalt, J.; Jacobsen, E. N. J. Org. Chem. 1998,
63, 403. (b) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 1999, 38, 2398.
10.1021/ol0258785 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/18/2002

Table 1. Diastereoselective Hetero-Diels-Alder Reaction Catalyzed by Tridentate Cr(III) Catalystsa
a All reactions were run on a 1 mmol scale, with 1.2 equiv of aldehyde and 200 mg of BaO, with a 1 h prestir of catalyst and EtOAc prior to addition
of aldehyde and diene. b Isolated yield based on diene. c Determined by 1H NMR. d Relative configuration determined after PMB deprotection and cyclization
to the known bicyclic acetal (ref 2b). e Assigned by analogy to (2R,1′S)-10 and (2R,4′R)- and (2S,4′R)-16. f Relative configuration determined by comparison
to a known compound (ref 2c). g Determined by chiral HPLC analysis of the TBS deprotected derivative. h Determined by chiral HPLC analysis.
HDA reaction between 1 and achiral aldehydes.4a Subse-
quently, the tridentate Schiff base-Cr(III) complexes 3 and
Scheme 2. HDA Catalysts
4 were identified as highly selective catalysts for enantiose-
lective HDA reactions employing mono-oxygenated dienes
(Scheme 2).4b
The goal of the present study was to establish the viability
of chiral catalyst-controlled doubly diastereoselective HDA
reactions between 1 and optically active chiral aldehydes. If
successful, such a strategy would provide selective access
to stereochemically elaborate dihydropyranone derivatives
that are not readily accessible using substrate-controlled
diastereoselective reactions or through simple enantioselec-
tive reactions of achiral substrates.5 The first successful
examples of the application of this approach are described
herein.
The cycloaddition between diene 1 and lactaldehyde
derivative (S)-7 was investigated as a model reaction (Table
1796
Org. Lett., Vol. 4, No. 10, 2002

Table 2. Diastereoselective Hetero-Diels-Alder Reaction Catalyzed by (salen)Cr(III) Catalystsa
a All reactions were run on a 1 mmol scale, with 1.2 equiv of aldehyde and 300 mg of desiccant (no prestir). b Isolated yield based on diene. c Determined
1
by H NMR. d Relative configuration determined by comparison to a known compound (ref 2b). e Relative configuration determined by comparison to a
known compound (ref 2c). f Assigned by analogy to (2R,4′R)- and (2S,4′R)-16. g Determined by chiral HPLC analysis of the TBS deprotected derivative.
h Determined by chiral HPLC analysis.
1, entries 1-3). The best results were obtained by aging ethyl
acetate solutions of catalyst 3 for 1 h in the presence of a
desiccant (4 Å molecular sieves or BaO6) prior to addition
of the aldehyde and diene. Application of these optimized
reaction conditions in the cycloaddition between 1 and 7
using catalysts (1R,2S)-3 and (1S,2R)-3 (5 mol %) provided
the dihydropyranone products (2R,1′S)-8 and (2S,1′S)-8 in
a 1:12 diastereomeric ratio (dr) (96% yield) and a 15:1 dr
(97% yield), respectively (Table 1, entries 2 and 3).7 The
analogous achiral catalyst 5 provided 8 in a diastereomeric
ratio of 1:2.0 (entry 1).
corresponding diastereomerically and enantiomerically en-
riched dihydropyranones in good selectivity (Table 1, entries
4-6). The same conditions were also applied to the HDA
reaction of (S)-citronellal 11 with 1, with good levels of
catalyst control (Table 1, entries 7-9).
While the tridentate Schiff base catalyst 3 provided
satisfactory results with aldehydes 7, 9, and 11, it was far
less effective with the more sterically congested aldehydes
13 and 15 (Table 1, entries 10-15). Thus, aldehyde (S)-13
underwent HDA reaction with diene 1 under the standard
conditions to provide dihydropyranone products 14 in
moderate yields and diastereoselectivities (Table 1, entries
10-12). The HDA reaction of 1 with 15 catalyzed by the
achiral complex 5 displayed a relatively high degree of
substrate control, providing 16 with a dr of 1:4.5 (Table 1,
entry 13), with the major diastereomer derived from cy-
cloaddition on the Felkin face of 15. The matched catalyst/
substrate system in this case provided the highest level of
diastereoselectivity in our study (1:33, entry 15). However,
the mismatched combination failed to overcome the inherent
substrate bias (Table 1, entry 14). These results are consistent
with Danishefsky’s previous studies, revealing that aldehyde
15 is extremely resistant to reaction at its anti-Felkin face.8
Fortunately, improved selectivities in cycloadditions be-
tween 1 and aldehydes 13 and 15 were achievable through
use of the (salen)Cr(III)-BF4 catalyst 2.4a Reaction of
Other chiral aldehydes proved to be suitable as substrates
for the HDA reaction. Thus, subjection of aldehyde (S)-9 to
reaction with 1 in the presence of 3 led to formation of the
(5) To our knowledge, there has been only one report of chiral catalyst-
controlled HDA reactions of chiral aldehydes (ref 3r). In this instance, only
moderate diastereoselectivities were obtained (up to 1.04:1) in the substrate-
catalyst mismatched case.
(6) Because BaO is much more dense than 4 Å molecular sieves, its use
proved to be preferable from a practical perspective. However, in isolated
cases, superior results were obtained employing 4 Å molecular sieves (e.g.,
with aldehyde 13, Table 2).
(7) Representative general procedure (for complete experimental details,
see Supporting Information): A solution of (1R,2S)-3 (0.024 g, 0.05 mmol
in EtOAc (200 µL)) was stirred under N2 for 1 h in the presence of BaO
(200 mg). Aldehyde 7 (0.238 g, 1.26 mmol) was added, and the mixture
was cooled to 0 °C; 1-methoxy-3-[(trimethylsilyl)oxy]butadiene 1 (205 µL,
1.06 mmol) was added, and the mixture was allowed to stir at 4 °C for
22.5 h. CH2Cl2 (2 mL) was added, followed by a drop of TFA. The reaction
mixture was allowed to warm to room temperature and stirred for 10 min.
The mixture was then filtered through a plug of silica gel on Celite. The
filtrate was concentrated in vacuo, and the crude residue was purified by
flash chromatography (85:15 hexanes/EtOAc) to afford (2R,1′S)-8 (0.263
g, 1.02 mmol, 96%) as a pale yellow oil.
(8) Reaction of 15 with 1 under Lewis acid catalysis by MgBr2 in THF
afforded the Felkin cycloadduct with only ca. 10% of the epimeric anti-
Felkin product observed. See refs 2b and 2c.
Org. Lett., Vol. 4, No. 10, 2002
1797

aldehyde (S)-13 with diene 1 catalyzed by (R,R)-2 and (S,S)-2
(2 mol %) in the presence of BaO afforded mixtures of
dihydropyranone products (2R,1′S)-14 and (2S,1′S)-14 in
4.5:1 and 1:5.9 dr, respectively (Table 2, entries 2 and 3). A
prestir with desiccant was not found to be beneficial with
the salen catalysts. Use of 4 Å molecular sieves instead of
BaO provided modest improvements in the diastereoselec-
tivities (Table 2, entries 5 and 6) with this substrate.
Aldehyde (R)-15 underwent cycloaddition with 1 in the
presence of the achiral (salen)Cr(III)-BF4 complex 6 to
provide 16 with a relatively high level of substrate-induced
diastereoselectivity (1:5.6), the major product being that
derived from cyclocondensation on the Felkin face of 15.
The matched catalyst (S,S)-2 reinforced the substrate bias,
with (2S,4′R)-16 obtained in high selectivity (1:32). More
significant, the mismatched catalyst (R,R)-2 provided 16 with
a modest preference for reaction at the anti-Felkin face (1.4:
1). Thus, it was possible to override even strong degrees of
substrate bias with the chiral Diels-Alder catalysts.
In summary, catalyst-controlled doubly diastereoselective
hetero-Diels-Alder reactions between diene 1 and chiral
aldehydes are achievable with chromium-Schiff base cata-
lysts 2 and 3. This methodology provides selective access
to any of the four possible stereoisomers of the dihydro-
pyranone products by judicious use of aldehyde and catalyst
enantiomers.
Acknowledgment. This work was supported by the NIH
(GM-59316) and a predoctoral fellowship to G.D.J. from the
National Science Foundation.
Supporting Information Available: Complete experi-
1
mental procedures, analytical data, H NMR spectra for dr
determination, and chiral chromatographic analyses for ee
determination. This material is available free of charge via
the Internet at http://pubs.acs.org.
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