Highly enantioselective inverse-electron-demand hetero-Diels-Alder reactions of α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/1521-3773(20020816)41:16<3059::AID-ANIE3059>3.0.CO;2-I

Straightforward access to useful synthetic intermediates is provided by this new method. Simple, α,β-unsaturated aldehydes are excellent substrates in the hetero-Diels-Alder reaction with inverse electron demand, catalyzed by Cr^III-Schiff base complexes (see scheme; R¹, R² = alkyl or aryl) in the presence of 4-A molecular sieves and no solvent. The resulting dihydropyrans are obtained in high enantio- (89-98 % ee) and diastereoselectivity (> 95 % de) and yield (40-95 %).

Full text of DOI:10.1002/1521-3773(20020816)41:16<3059::AID-ANIE3059>3.0.CO;2-I

COMMUNICATIONS
Me
Highly Enantioselective Inverse-Electron-
Demand Hetero-Diels Alder Reactions
of a,b-Unsaturated Aldehydes**
N
O
O
Karl Gademann, David E. Chavez, and
Eric N. Jacobsen*
Cr
Cl
R2
R2
R1
R1
(1S, 2R)-1
Dihydro- and tetrahydropyran derivatives are prevalent
structural subunits in a variety of biologically important
compounds, includingcarbohydrates, pheromones, iridoids,
and polyether antibiotics. The inverse-electron-demand het-
ero-Diels Alder (HDA) reaction of oxabutadienes with
electron-rich olefins is a synthetically attractive route to such
heterocycles, allowingthe direct formation of dihydropyran
derivatives with up to three stereogenic centers in one
convergent step from simple achiral precursors.[1] Although
there are numerous diastereoselective variants of the inverse-
electron-demand HDA reaction known,[2] very few examples
of catalytic, enantioselective versions have been identified to
date.[3] The scope of reported methods is limited to oxabuta-
diene derivatives bearingelectron-withdrawinggroups such
as sulfone groups,[3a] phosphonate groups,[3b] or ester groups.[3c]
These ancillary groups serve both to activate the oxadiene
electronically and to anchor the substrate to the catalyst by
two-point binding(Scheme 1a). Chelation in this manner
appears to be essential for attainingogod reactivity and
stereoselectivity.
+
4
MS, neat
O
OEt
O
OEt
2a-o
(10 equiv)
3a-o
>95% de
89-98% ee
70-95% yield
Scheme 2. Hetero-Diels Alder reactions catalyzed by 1; MS ¼ molecular
sieves, de ¼ diastereomeric excess.
rich dienophile partners. Herein we describe the first example
of a successful solution to this problem, in the highly
enantioselective (Schiff base)CrIII-catalyzed HDA reactions
of alkyl vinyl ethers with a,b-unsaturated aldehydes.
The tridentate (Schiff base)chromium complex (1, see
Scheme 2) has been identified as a highly diastereoselective
and enantioselective catalyst in hetero-Diels Alder (HDA)
reactions between aldehydes and mono-oxygenated 1,3-diene
derivatives.[5] The crucial feature of this catalyst system lies in
its ability to effect activation of simple aldehydes toward
pericyclic reactions with only mildly nucleophilic partners,
with concomitant high enantioselectivity.[6] With an eye
toward determiningwhether such properties might be ex-
tended to reactions of conjugated aldehydes, we evaluated the
reaction of crotonaldehyde and ethyl vinyl ether as a model
system for the inverse-demand HDA. The uncatalyzed HDA
reaction takes place only at elevated temperatures and
M
M
H
b)
a)
O
O
X
O
( )n
R
R
X = COR, P(OR)2 (n = 0)
SOR (n = 1)
Scheme 1. a) Two-point bindingof oxabutadiene derivatives to a Lewis
acid (M ¼ Lewis acid); b) one-point bindingof an a,b-unsaturated alde-
hyde to a Lewis acid.
pressures, yieldingthe correspondingdihydropyran
3a in
good yields but poor endo/exo selectivity.[7] We were encour-
aged to find that the same reaction proceeded in the presence
of 4 ä molecular sieves with 5 mol% 1[8] in tert-butyl methyl
ether (TBME) or CH2Cl2 solution at RT to provide 3a with
excellent diastereoselectivity (endo/exo > 96:4),[9] and prom-
isingenantioselectivity (72 78% ee; ee ¼ enantiomeric ex-
cess). Unfortunately, aldehyde conversions of only approx-
imately 20% were achieved using1:1 molar ratios of the
reactants at 1m concentration. A dramatic improvement was
observed in reactions carried out under solvent-free condi-
tions and excess ethyl vinyl ether[10] (94% ee and 75%
isolated yield, Table 1, 2a). Indeed, introduction of solvents
(CH2Cl2, toluene, acetone, and tert-butyl methyl ether)
generally resulted in significantly lower enantioselectivity in
the cycloaddition (40 80% ee). Ethyl vinyl ether was shown
to be the optimal dienophile partner. The selectivity and
reactivity decreased as the steric bulk of the alkyl group was
increased (Et > nPr> nBu ꢀ iBu), to the point that tert-butyl
vinyl ether was found to be unreactive.
Development of asymmetric inverse-demand HDA reac-
tions involvingsimple a,b-unsaturated aldehyde substrates
would expand the utility of this methodology significantly
(Scheme 2).[4] This task presents a clear challenge, however,
which requires effective activation and enantiofacial discrim-
ination of the carbonyl solely through one-point binding to
catalyst (Scheme 1b), while simultaneously avoidingunpro-
ductive decomposition of the sensitive oxadiene and electron-
[*] Prof. Dr. E. N. Jacobsen, Dr. K. Gademann, D. E. Chavez
Department of Chemistry and Chemical Biology
Harvard University
Cambridge, MA 02138 (USA)
Fax : (þ 1)617-496-1880
E-mail: jacobsen@chemistry.harvard.edu
[**] This work was supported by the NIH (GM-59316), with additional
support from the Schweizerischer Nationalfonds zur Fˆrderungder
wissenschaftlichen Forschung(postdoctoral fellowship to K.G.), and
the National Science Foundation (predoctoral fellowship to D.E.C.).
We are grateful to Dr. R. Staples for carrying out the X-ray crystal
structure analysis of 1.
With these reaction parameters defined, a variety of
aldehydes were examined in the inverse-electron-demand
HDA reaction with ethyl vinyl ether (Table 1). A wide range
of a,b-unsaturated aldehydes bearingaliphatic b substituents
(2a e) underwent cycloaddition with high enantioselectivity
Supportinginformation for this article is available on the WWW under
http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2002, 41, No. 16
¹ 2002 WILEY-VCH VerlagGmbH & Co. KGaA, Weinheim
0044-8249/02/4116-3059 $ 20.00+.50/0
3059

COMMUNICATIONS
Table 1. Asymmetric inverse-electron-demand hetero-Diels Alder reactions of
The absolute configuration of the products was established
by conversion into the known 4-subtituted pyranones
(Scheme 4).[12] Thus, reduction of the dihydropyrans 3a, 3c,
and 3 f with H2 in the presence of Pd on charcoal, followed by
hydrolysis (TsOH, H2O, acetone; Ts ¼ tosyl) and pyridinium
chlorochromate (PCC) oxidation of the resultinglactol
afforded the correspondinglactones ( 4). This straightforward
procedure provides a relatively concise and high-yielding (60
80% overall) route to synthetically useful 4-substituted
pyranone derivatives in an enantioenriched form.[13]
a,b-unsaturated aldehydes with ethyl vinyl ether, catalyzed by 1.[a]
Aldehyde R1
R2
Catalyst loadingReaction Yield
ee
[mol%][b]
time [h]
[%][c] [%][d]
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
2o
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Me
Et
iPr
nPr
nBu
Ph
5
5
10
5
5
24
48
48
48
48
48
96
72
120
24
24
24
48
48
96
75
75
72
73
70
75
40
90
80
90
95
90
80
75
75
94
94
94
94
95
98
98
98
98
95
92
95
89
98
92
10
4-MeO-C6H4 10
4-NO2-C6H4
2-NO2-C6H4
CH2OBn
CH2OTBS
CO2Et
10
10
5
5
5
5
5
7
R
R
1. H2, Pd/C
OBz
Ph
2. TsOH, H2O, acetone
3. PCC, CH2Cl2
O
OEt
O
O
Me Me
3a, R = Me
3c, R = iPr
3f, R = Ph
4a (60% yield)
4c (73% yield)
4f (80% yield)
[a] Reactions were performed with aldehyde (1 mmol) and ethyl vinyl ether
(10 equiv), in the presence of finely powdered 4 ä molecular sieves (150 mg).
[b] Catalyst loadings refer to the amount of chromium employed, assuming the
molecular structure depicted in Scheme 2. [c] Product isolation was accomplished by
dilution of the reaction mixture with pentane, filtration, and distillation or column
chromatography. Yields given are after isolation. [d] Enantioselectivities were
determined either by HPLC or GC analysis, usingcommercially available chiral
stationary phases. For details see the SupportingInformation.
Scheme 4. Preparation of b-substituted pyranones from dihydropyrans 3a,
3c, and 3 f.
In an effort to render the HDA methodology as useful and
accessible as possible, we have devised a new and significantly
improved synthesis of catalyst 1 (Scheme 5).[14] As compared
(94 95% ee, 70 75% yield). Whereas use of 5 mol% catalyst
was adequate in most cases, the sterically more demanding4-
methyl-2-pentenal (2c) required 10 mol% of 1 to attain
complete conversion within 48 h. Cinnamaldehyde deriva-
tives (2 f i) underwent reactions with ethyl vinyl ether with
very high enantioselectivity, and excellent diastereoselectivity.
Me
Me
OH
CH2Cl2, H2SO4
1-adamantanol
OH
2
Substrates bearingfunctionality within R (e.g. 2j l) were
78%
amongthe very best in all respects, displayinggood reactivity
and consistently high enantioselectivity and yields (92
95% ee, 90 95% yield). The successful application of 3-
benzoylacrolein (2m) in the HDA reaction provides ready
access to the 4-benzoyl-substituted dihydropyran derivative, a
versatile intermediate poised for an assortment of useful
substitution reactions (Scheme 3).[11] Finally, the promising
scope of this method is illustrated further by the demonstrated
tolerance for substituents at the 2-position of the aldehyde.
Both 2-bromocinnamaldehyde (2n) and 2-methyl-2-butenal
(2o) provided cycloadducts with high enantioselectivity.
1.SnCl4, 2,6-lutidine
(CHO)n
2. aminoindanol
Me
CrCl3(thf)3, 2,6 lutidine
CH2Cl2
1
N
OH
75%, 2 steps
OH
Scheme 5. Practical synthesis of catalyst (1R,1S)-1.
to the procedure disclosed previously,[5] the new route avoids
the use of sensitive and expensive CrII salts and can be carried
out conveniently on the bench. More significant, it provides
material of higher quality with respect to its chemical
properties. In particular, compound 1 obtained from the new
procedure requires no aging with molecular sieves to attain
optimal performance, and confers 5 10% higher enantiose-
lectivity than does catalyst prepared by the original proce-
dure.[15]
OBz
O
I
EtO
PhZnCl
OEt
O
OEt
Zn/Cu
EtO2C
Ph
O
O
OEt
ClZn
SiiPr3
85%
60%
Insight into the basis for stereoinduction in these cyclo-
addition reactions will rely on a detailed understandingof the
mechanism of catalysis. In this context, inspection of the
crystal structure of 1 may provide a valuable startingpoint
(Figure 1).[16] In the solid state, catalyst 1 exists as a dimeric
O
OEt
iPr3Si
65%
Scheme 3. Substitution reactions of the dihydropyran derivative 3m, Bz ¼
benzyl.
3060
¹ 2002 WILEY-VCH VerlagGmbH & Co. KGaA, Weinheim
0044-8249/02/4116-3060 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 16

COMMUNICATIONS
U. Chin, S. Kanemasa, Tetrahedron 1996, 52, 1205 1220; b) phos-
phonate-activated oxabutadienes: D. A. Evans, J. S. Johnson, J. Am.
Chem. Soc. 1998, 120, 4895 4896; c) carboxylic ester-activated
oxabutadienes: J. Thorhauge, M. Johannsen, K. A. J˘rgensen, Angew.
Chem. 1998, 110, 2543 2546; Angew. Chem. Int. Ed. 1998, 37, 2404
2406; D. A. Evans, E. J. Olhava, J. S. Johnson, J. M. Janey, Angew.
Chem. 1998, 110, 3554 3557; Angew. Chem. Int. Ed. 1998, 37, 3372
3375; D. A. Evans, J. S. Johnson, E. J. Olhava, J. Am. Chem. Soc. 2000,
122, 1635 1649; H. Audrain, J. Thorhauge, R. G. Hazell, K. A.
J˘rgensen, J. Org. Chem. 2000, 65, 4487 4497.
[4] In particular, this pattern of substitution is found in iridoid and
pheromone natural products. For examples, see: Comprehensive
Natural Products Chemistry, Vol. 8 (Eds.: D. H. R. Barton, K.
Nakanishi, O. Meth-Cohn, K. Mori), Pergamon-Elsevier, Oxford,
1999, pp. 197 373.
[5] A. G. Dossetter, T. F. Jamison, E. N. Jacobsen, Angew. Chem. 1999,
111, 2549 2552; Angew. Chem. Int. Ed. 1999, 38, 2398 2400.
[6] For applications of closely related catalysts to asymmetric hetero-ene
reactions, see: R. T. Ruck, E. N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 2882 2883.
[7] R. I. Longley, W. S. Emerson, J. Am. Chem. Soc. 1950, 72, 3079 3081;
C. W. Smith, D. G. Norton, S. A. Ballard, J. Am. Chem. Soc. 1951, 73,
5267 5270; B. B. Snider, G. B. Phillips, J. Org. Chem. 1983, 48, 2789
2792. Danishefsky et al. and Spino et al. have noted the acceleration of
this reaction by achiral Lewis acids: S. J. Danishefsky, M. Bednarski,
Tetrahedron Lett. 1984, 25, 721 724; C. Spino, L. Clouston, D. J. Berg,
Can. J. Chem. 1996, 74, 1762 1764; C. Spino, L. L. Clouston, D. J.
Berg, Can. J. Chem. 1997, 75, 1047 1054.
Figure 1. X-ray crystal structure of catalyst 1; ellipsoids drawn at the 50%
probability level.
structure, bridged through a single water molecule and
bearingone terminal water ligand on each chromium center.
On the basis of preliminary solution molecular-weight and
kinetic studies,[17] it appears that this dimeric structure is
maintained in the catalytic cycle. Dissociation of a terminal
water molecule to open a coordination site for complexation
of the aldehyde substrate is expected to be energetically
difficult, and may serve to explain the crucial role of
molecular sieves in these reactions.[18]
[8] A variety of chiral tridentate (Schiff base)chromium complexes were
evaluated, and complex 1 afforded the best results with regard both to
enantioselectivity and reactivity.
[9] No exo diastereoisomer could be detected by analysis of the crude
1
reaction mixture by H NMR spectroscopy.
[10] The use of excess ethyl vinyl ether had a beneficial effect on
conversion and prevented aldehyde self-condensation in the case of
substrates with aliphatic b substituents.
In summary, the scope of (Schiff base)CrIII-catalyzed cyclo-
addition reactions has been expanded to inverse-demand
HDA reactions of simple a,b-unsaturated aldehydes. The
broad range of aldehydes utilized effectively by catalyst 1
allows access to a series of synthetically useful dihydropyran
derivatives in a highly enantioenriched form. Future studies
will be directed toward further extendingthe scope of this
promisingmethodoloyg in the context of more elaborate
intermediates and natural product targets.
[11] D. P. Steinhuebel, J. J. Fleming, J. Du Bois, Org. Lett. 2002, 4, 293
295.
[12] J. B. Jones, A. J. Irwin, J. Am. Chem. Soc. 1977, 99, 556; D. A. Evans,
J. S. Johnson, E. J. Olhava, J. Am. Chem. Soc. 2000, 122, 1635 1649.
[13] This class of compounds can be prepared by desymmetrization of the
cyclic anhydrides, for examples see: Y. Cheng, L. Deng, J. Am. Chem.
Soc. 2000, 122, 9542 9543; R. Verma, S. Mithram, S. K. Ghosh, J.
Chem. Soc. Perkin Trans. 1 1999, 257 264; G. Jaeschke, D. Seebach, J.
Org. Chem. 1998, 63, 1190 1193; P. D. Theisen, C. H. Heathcock, J.
Org. Chem. 1993, 58, 142 156; K. Yamamoto, T. Nishioka, J. Oda, Y.
Yamamoto, Tetrahedron Lett. 1988, 29, 1717 1720.
[14] Full experimental details are provided as SupportingInformation.
[15] Improvement in catalyst performance extends to normal-demand
HDA reactions as well. For example, the reaction of 1-benzyloxybu-
tadiene with 3-(triisopropylsilyl)propynal produced cycloadduct in
89% ee usingcatalyst prepared by the original procedure, and 94% ee
usingthe new catalyst. This reaction served as the startingpoint for
the synthesis of fostriecin: D. E. Chavez, E. N. Jacobsen, Angew.
Chem. 2001, 113, 3779 3782; Angew. Chem. Int. Ed. 2001, 40, 3667
3670.
[16] Details of the crystal structure analysis are provided as Supporting
Information. CCDC-189470 (1) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB21EZ,
UK; fax: (þ 44)1223-336-033; or deposit@ccdc.cam.ac.uk).
[17] R. T. Ruck, E. N. Jacobsen, unpublished results.
Received: June 11, 2002 [Z19516]
[1] a) L. F. Tietze, G. Kettschau, J. A. Gewart, A. Schuffenhauer, Curr.
Org. Chem. 1998, 2, 19 62; b) L. Tietze, G. Kettschau, Top. Curr.
Chem. 1997, 189, 1 120; c) D. L. Boger in Comprehensive Organic
Synthesis, Vol. 5 (Eds.: B. M. Trost, I. Fleming, L. A. Paquette);
Pergamon, Oxford, 1991, pp. 451 512; d) D. L. Boger, S. M. Weinreb,
Hetero Diels Alder Methodology in OrganicSynthesis , Academic
Press, San Diego, 1987.
[2] See, for example a) R. R. Schmidt, M. Maier, Tetrahedron Lett. 1985,
26, 2065 2068; b) R. R. Schmidt, B. Haag-Zeino, M. Hoch, Liebigs
Ann. Chem. 1988, 885 889; c) G. Dujardin, S. Molato, E. Brown,
Tetrahedron: Asymmetry 1993, 4, 193 196; d) L. F. Tietze, A.
Montenbruck, C. Schneider, Synlett 1994, 509 510; e) L. F. Tietze,
C. Schneider, C. A. Grote, Chem. Eur. J. 1996, 2, 139 148; f) G.
Dujardin, S. Rossignol, E. Brown, Tetrahedron 1996, 52, 4007 4010.
[3] a) Sulfone-activated oxabutadienes: E. Wada, H. Yasuoka, S. Kane-
masa, Chem. Lett. 1994, 9, 1637 1640; E. Wada, W. Pei, H. Yasuoka,
[18] No cycloaddition is observed in the absence of dessicant. For a
discussion on a related system, see ref [6].
Angew. Chem. Int. Ed. 2002, 41, No. 16
¹ 2002 WILEY-VCH VerlagGmbH & Co. KGaA, Weinheim
0044-8249/02/4116-3061 $ 20.00+.50/0
3061