A new class of chiral lewis acid catalysts for highly enantioselective hetero-diels-alder reactions: Exceptionally high turnover numbers from dirhodium(II) carboxamidates [10]

Full text of DOI:10.1021/ja015692l

5366
J. Am. Chem. Soc. 2001, 123, 5366-5367
formation of dihydropyran 1, whereas treatment with 5% Et3N/
MeOH gave acetal 2 that we used to monitor the syn/anti
diasteromer ratio which, by reason of oxonium ion formation, is
an indicator of the Lewis acidity of the catalyst (high activity f
isomerization).
A comparison of results from the use of a broad selection of
chiral dirhodium(II) catalysts is presented in Table 1. Both chiral
carboxamidate-ligated (3-6) and carboxylate-ligated (7) dirhod-
ium complexes were employed. Dirhodium(II) complexes with
A New Class of Chiral Lewis Acid Catalysts for
Highly Enantioselective Hetero-Diels-Alder
Reactions: Exceptionally High Turnover Numbers
from Dirhodium(II) Carboxamidates
Michael P. Doyle,* Iain M. Phillips, and Wenhao Hu
Department of Chemistry, The UniVersity of Arizona
Tucson, Arizona 85721
ReceiVed February 19, 2001
ReVised Manuscript ReceiVed April 11, 2001
The hetero-Diels-Alder reactions of carbonyl compounds with
conjugated dienes is an important methodology for the synthesis
of dihydropyrans.1 Accelerated by Lewis acids, these reactions
have been a veritable training ground for evaluation of the
effectiveness of chiral catalysts as Lewis acids for enantioselective
transformations.2-8 Although selectivities of 99% ee have been
achieved in select cases, a major drawback of this methodology
has been its high catalyst loading [substrate/catalyst (S/C) usually
e50]. We have previously developed chiral dirhodium(II) car-
boxamidate catalysts for effective and efficient metal carbene
transformations,3-11 and we now report a major extension of their
applications to hetero-Diels-Alder reactions where their opera-
tions allow substrate-to-catalyst loadings of up to 10,000.
To ascertain the viability of the approach with dirhodium(II)
catalysts, we first employed rhodium acetate at 1.0 mol % for
the cycloaddition of Danishefsky’s diene with an equivalent
amount of p-nitrobenzaldehyde (eq 1), and this reaction was
complete within 6 h at room temperature in CH2Cl2. Treatment
of the reaction solution with trifluoroacetic acid resulted in the
(1) Boger, D. L.; Weinreb, S. H. Hetero-Diels-Alder Methodology in
Organic Synthesis; Academic Press: New York, 1987. Nicolaou, K. C.;
Sorensen, E. J. Classics in Total Synthesis: Targets, Strategies, Methods;
VCH: New York, 1996. Waldmann, H. Synthesis 1994, 535. Tietze, L. F.;
Kettschau, G. Top. Curr. Chem. 1997, 190, 1. Tietze, L. F. Curr. Org. Chem.
1998, 2, 19.
(2) Jorgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558.
(3) Maruoka, K. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
Wiley-VCH: New York, 2000; Chapter 8A.
(4) Chiral aluminum and boron complexes: (a) Maruoka, K.; Itoh, T.;
Shirasaka, T.; Yamamoto, H. J. Am. Chem. Soc. 1988, 110, 310. (b) Maruoka,
K.; Yamamoto, H. J. Am. Chem. Soc. 1989, 111, 789. (c) Corey, E. J.;
Guzman-Perez, A.; Loh, T.-P. J. Am. Chem. Soc. 1994, 116, 3611. (e)
Simonsen, K. B.; Svenstrup, N.; Robertson, M.; Jorgensen, K. A. Chem. Eur.
J. 2000, 6, 123.
(5) Chiral lanthanide complexes: (a) Bednarski, M.; Danishefsky, S. J.
Am. Chem. Soc. 1983, 105, 6968 and 1986, 108, 7060. (b) Hanamoto, T.;
Furuno, H.; Sugimoto, Y.; Inanaga, J. Synlett 1997, 79. (c) Furuno, H.;
Hanamoto, T.; Sugimoto, Y.; Inanaga, J. Org. Lett. 2000, 2, 49.
(6) Chiral titanium complexes: (a) Mikami, K.; Matsukawa, S. J. Am.
Chem. Soc. 1993, 115, 7039. (b) Keck, G. E.; Krishnamurthy, D. J. Am. Chem.
Soc. 1995, 117, 2363. (c) Duthaler, R. O. Angew. Chem., Int. Ed. Engl. 1997,
36, 43. (d) Wang, B.; Feng, X.; Cui, X.; Liu, H.; Jiang, Y. J. Chem. Soc.,
Chem. Commun. 2000, 1605.
the new fluorinated MEPY (3b) and IBAZ (5a) or CHAZ (5b)
ligands12 were expected to provide enhanced Lewis acid activity
to dirhodium(II) even beyond that from representative azetidinone
ligands13 or from chiral carboxylates.14 However, the highest level
of enantiocontrol was achieved with the less Lewis acidic Rh2-
(4S-MPPIM)4, which in metal carbene reactions was considered
(9) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds; John Wiley & Sons: New York,
1998.
(7) Chiral chromium complexes: (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.
(8) Chiral copper complexes: (a) Johnson, J. S.; Evans, D. A. Acc. Chem.
Res. 2000, 33, 325. (b) Jorgensen, K. A.; Johannsen, M.; Yao, S.; Audrain,
H.; Thorhauge, J. Acc. Chem. Res. 1999, 32, 605. (c) Pfaltz, A. Acc. Chem.
Res. 1993, 26, 339. (d) Evans, D. A.; Johnson, J. S.; Olhava, E. J. J. Am.
Chem. Soc. 2000, 122, 1635.
(10) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911.
(11) Doyle, M. P. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I.,
Ed.; Wiley-VCH: New York, 2000; Chapter 5.
(12) Doyle M. P.; Hu, W.; Phillips, I. M.; Moody, C. J.; Pepper, A. G.
AdV. Synth. Catal. 2001, 343, 112.
(13) Doyle, M. P.; Davies, S. B.; Hu, W. Org. Lett. 2000, 2, 1145.
(14) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459. Davies, H. M. L.
Curr. Org. Chem. 1998, 2, 463.
10.1021/ja015692l CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/10/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 22, 2001 5367
Table 1. Enantioselectivity in Catalytic Cycloaddition of
p-Nitrobenzaldehyde to Danishefsky’s Dienea
Table 2. Hetero-Diels-Alder Reactions of Representative
Aldehydes with the Danishefsky Dienea
catalyst
Rh2(OAc)4
Rh2(5R-MEPY)4
Rh2(5S-dFMEPY)4
Rh2(4S-MEAZ)4
Rh2(4S-IBAZ)4
Rh2(4R-dFIBAZ)4
Rh2(4R-dFIBAZ)4
Rh2(4S-CHAZ)4
Rh2(4R-dFCHAZ)4
Rh2(4S-MACIM)4
Rh2(4S-MPPIM)4
Rh2(S-DOSP)4
yield, %b 1 (syn:anti 2)
ee, %c 1 (config.)
67 (100:0)
53 (100:0)
53 (50:50)
63 (95:5)
62 (100:0)
68 (60:40)
93d
-
73 (R)
78 (S)
56 (S)
66 (S)
70 (R)
72 (R)
61 (S)
76 (R)
74 (S)
95 (S)
20 (S)
16 (S)
54 (100:0)
98d
76d
82d
68
61
Rh2(S-TBSP)4
a Unless indicated otherwise, reactions were performed at room
temperature in anhydrous CH2Cl2 using equivalent amounts of reactants
and 1.0 mol % of catalyst with a reaction time of 24 h. b Isolated yield
after column chromatography. The syn:anti ratio was determined by
1H NMR after quenching with 5% Et3N in MeOH: syn at δ 4.82, anti
at δ 5.32 and 5.18; syn f anti. c Determined by HPLC using a Chiralpak
OD column (hexane:iPrOH ) 85:15). d Reactions were performed with
a 5-fold molar excess of aldehyde.
a Reactions were performed as described in Table 1. b Isolated yield
after chromatography. c Determined by HPLC using a Chiralpak OD
column. d A 5-fold molar excess of aldehyde was used. e Reaction in
refluxing CH2Cl2.
Table 3. Substrate-to-Catalyst Ratios in Hetero-Diels-Alder
Reactions of Aldehydes with the Danishefsky Dienea
to be the least reactive of dirhodium(II) carboxamidate catalysts
for diazo decomposition.15 By comparison, the normally more
reactive chiral dirhodium(II) carboxylates (7) provided low
enantiocontrol for this reaction.
A survey of aldehyde substrates considered to be representative
was undertaken, and the results obtained with two catalysts (5b
and 6b) are reported in Table 2. As can be seen from data for
reactions of substituted benzaldehydes, there is a significant
electronic influence on enantiocontrol so that % ee values increase
with increasing electron withdrawal from a para-substituent. Also,
the effect of catalyst ligands on enantioselectivity (compare 3-6
for selectivity) is substantial but not apparently uniform (steric
or electronic effects).10-12 Still, enantiomeric excess beyond 90%
can be achieved with several substrates (Tables 1 and 2), but
additional efforts will be required for full optimization.
We are aware of only one example of a hetero-Diels-Alder
reaction in which less than 1.0 mol % of catalyst was effectively
employed, and that one used 0.5 mol % of a copper(II)-bis-
oxazoline complex in nitromethane.16,17 Consequently, we were
surprised to find that the substrate-to-catalyst ratio could be
reduced by more than 2 orders of magnitude below commonly
used S/C ratios of 10-50. Representative data are given in Table
3 with two catalysts.
a Reactions were performed as described in Table 1 using a five-
fold molar excess of aldehyde.
The slight decrease in % ee values as the S/C ratio is increased
may be due to a background reaction, but this is unclear at this
time. What is evident is that dirhodium(II) catalysts do not have
the same restrictions for catalyst turnover that are common with
previously reported Lewis acid catalysts. The implications of this
for other Lewis acid catalyzed reactions are currently under
investigation.
(15) Doyle, M. P. In Catalysis by Di- and Polynuclear Metal Cluster
Complexes; Adams, R. D.; Cotton, F. A., Eds.; Wiley-VCH: New York, 1998.
(16) Johannsen, M.; Jorgensen, K. A. Tetrahedron 1996, 52, 7321.
(17) In this case aldehyde was the limiting reagent. With dirhodium(II)
catalyst the hetero-Diels-Alder reaction occurs with the same % ee value
whether aldehyde or Danishevsky’s diene is in excess, but the rate of reaction
increases with increasing concentration of aldehyde.
Acknowledgment. We are grateful to the National Science Foundation
and the National Institutes of Health (GM-46503) for their support of
this research.
JA015692L