Stereoselective diels-alder reactions of chiral anthracenes

Article abstract of DOI:10.1021/ol006206m

(equation presentd) Various chiral (9-anthryl)carbinol templates undergo Diels-Alder cycloadditions with a variety of symmetric and nonsymmetric dienophiles with excellent π-facial selectivity and regioselectivity, under both thermal and Lewis acid cataly

Full text of DOI:10.1021/ol006206m

ORGANIC
LETTERS
2000
Vol. 2, No. 16
2527-2530
Stereoselective Diels−Alder Reactions of
Chiral Anthracenes
Amitav Sanyal and John K. Snyder*
Department of Chemistry, Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
jsnyder@chem.bu.edu
Received June 15, 2000
ABSTRACT
Various chiral (9-anthryl)carbinol templates undergo Diels−Alder cycloadditions with a variety of symmetric and nonsymmetric dienophiles
with excellent π-facial selectivity and regioselectivity, under both thermal and Lewis acid catalyzed conditions.
Chiral anthracene derivatives and chiral anthracene cycload-
ducts have found numerous applications in organic chemstry.
For example, 2,2,2-trifluoro-1-(9-anthryl)ethan-ol (Pirkle’s
alcohol) has been widely used as a chiral solvating agent1
and more recently as a chiral auxiliary,2 while chiral
cycloadducts of anthracene have been employed as ligands
in enantioselective transition metal catalyzed reactions.3 The
well-known biological activities of the butenolide pharma-
cophore stimulated our research into the enantioselective
synthesis of γ-substituted butenolides through a Diels-Alder/
retro Diels-Alder route4 (Scheme 1) using a chiral, recy-
clable anthracene template. Other diene systems suitable for
a Diels-Alder/retro Diels-Alder sequence are those based
on furan and cyclopentadiene. While chiral analogues of
these basic diene systems are known to participate in
diastereoselective cycloadditions,5 to the best of our knowl-
edge, there is only a single series of reports of a chiral diene
system employed as a stereocontrolling element in a Diels-
Alder/retro Diels-Alder scheme.6 In this work Winterfeldt
prepared several chiral hydrindane cyclopentadiene-based
templates which undergo diastereoselective cycloadditions
with maleic anhydride and maleimides under high pressure.
The use of a chiral anthracene template has advantages,
however. These include elimination of the endo/exo issue
in the cycloaddition, as well as the large, rigid anthracene
skeleton that can be exploited for stereocontrol in further
transformations of the adduct. The rich topology of the
anthracene nucleus may also enable incorporation of func-
tional groups to assist such transformations.
(1) (a) Pirkle, W. H.; Hoover, D. J. Top. Stereochem. 1982, 13, 263-
331. (b) Rinaldi, P. Prog. NMR Spec. 1982, 15, 291-352.
(2) (a) Carriere, A.; Virgili, A. Tetrahedron: Asymmetry 1996, 7, 227-
230. (b) Carriere, A.; Virgili, A.; Figueredo, M. Tetrahedron: Asymmetry
1996, 7, 2793-2796.
(3) Trost, B. M.; Vidal, B.; Thommen, M. Chem. Eur. J. 1999, 5, 1055-
1069.
In the past, enantioenriched or enantiopure cycloadducts
of anthracene have been derived by diastereoselective Diels-
Alder reactions of achiral anthracenes with chiral dienophiles7
(4) For seminal studies in Diels-Alder/retro Diels-Alder sequences
involving anthracene: (a) Chung, Y.-S.; Duerr, B. F.; McKelvey, T. A.;
Nanjappan, P.; Czarnik, A. W. J. Org. Chem. 1989, 54, 1018-1032 and
references therein. Also see: (b) Keck, G. E.; Webb, R. R., II J. Am. Chem.
Soc. 1981, 103, 3173-3177. (c) Siwapinyoyos, T.; Thebtaranonth, Y. J.
Org. Chem. 1982, 47, 598-599. (d) Knapp, S.; Ornaf, R. M.; Rodriques,
K. E. J. Am. Chem. Soc. 1983, 105, 5494-5495. (e) Kodpinid, M.;
Siwapinyoyos, T.; Thebtaranonth, Y. J. Am. Chem. Soc. 1984, 106, 4862-
4865. (f) Bloch, R.; Guibe-Jampel, E.; Girard, C. Tetrahedron Lett. 1985,
26, 4087-4090. (g) Bloch, R.; Gilbert, L. J. Org. Chem. 1987, 52, 4603-
4605. Reviews: (h) Rickborn, B. Org. React. 1988, 52, 1-393. (i) Klunder,
A. J. H.; Zhu, J.; Zwanenburg, B. Chem. ReV. 1999, 99, 1163-1190.
(5) (a) Schlessinger, R. H.; Bergstrom, C. P. Tetrahedron Lett. 1996,
37, 2133-2136 and references therein. (b) Matcheva, K.; Beckmann, M.;
Schomberg, D.; Winterfeldt, E. Synthesis 1989, 814-817.
(6) (a) Riviere, P.; Mauvais, A.; Winterfeldt, E. Tetrahedron: Asymmetry
1994, 5, 1831-1846. (b) Beil, W.; Jones, P. G.; Nerenz, F.; Winterfeldt,
E. Tetrahedron 1998, 54, 7273-7292. (c) Gerstenberger, I.; Hansen, M.;
Mauvais, A.; Wartchow, R.; Winterfeldt, E. Eur. J. Org. Chem. 1939, 4,
643-650.
10.1021/ol006206m CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/13/2000

Scheme 1. General Strategy for Using Anthracene as a Diels-Alder/Retro Diels-Alder Template for the Asymmetric Synthesis of
Butenolides and Related Derivatives
and enantioselective desymmetrization of meso adducts.8
However, there are no prior studies of the use of chiral
anthracenes in Diels-Alder reactions. This necessitated the
development of chiral anthracenes as templates for cycload-
ditions with maleate derivatives.
Several reports of diastereoselective intermolecular Diels-
Alder reactions of allylically chiral butadienes9 prompted us
to investigate the behavior of analogous anthracene carbinols
and their derivatives as diene systems in Diels-Alder
reactions. To this end, racemic 9-(1-hydroxyethyl)anthracene
(1a) and enantiopure Pirkle’s alcohol 2a were chosen as
candidates since both parent alcohols are readily available
in enantiopure forms.10
(Table 1). All reactions required thermal promotion, with a
competition experiment establishing that methyl ether 1b was
four times more reactive than anthracene toward maleic
anhydride.11 It was gratifying to find that all ether derivatives
1b-d and 2b reacted with maleic anhydride and the
maleimides with complete diastereoselectivity and in good
yields. In contrast, acetate 1e produced an 83:17 mixture of
diastereomers in refluxing benzene (Table 1, entry 8), while
1a showed poor diastereoselection (Table 1, entry 1). Hence,
to further the scope of the reaction, Lewis acid catalysis was
also examined (Table 2).
The mild catalyst system generated by complexing Cu-
(OTf)2 and the bisbenzyliminoethane (L*)12 enabled the
cycloaddition of 1e with maleic anhydride to proceed at a
lower temperature, thereby enhancing the diastereoselectivity
Initially, the behavior of 1a-e and 2b in thermal cycload-
ditions with maleic anhydride and maleimides was surveyed
Table 1. Thermal Diels-Alder Cycloadditions with C2V-Symmetrical Dienophiles
entry
1/2
R
R1
X
conditions
adduct
% yielda
drb
1
2
3
4
5
6
7
8
1a
1b
1b
1b
1c
1d
1d
1e
2b
2b
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CF3
CF3
H
NMe
O
NH
NMe
O
O
NMe
O
benzene, 80 °C, 9 h
benzene, 80 °C, 9 h
benzene, 80 °C, 9 h
benzene, 80 °C, 9 h
benzene, 80 °C, 9 h
benzene, 80 °C, 9 h
benzene, 80 °C, 9 h
benzene, 80 °C, 9 h
toluene, 110 °C, 18 h
toluene, 110 °C, 18 h
3a
3b
3c
3d
3e
3f
3g
3h
3i
66
89
88
92
69
70
78
74
75
76
1:1.7
>99:1
CH3
CH3
CH3
n-Butyl
Bn
Bn
Ac
CH3
CH3
>99:1
>99:1
>99:1
>99:1
>99:1
83:17
>99:1
>99:1
9
10
O
NMe
3j
a Isolated yields; b Determined by 400 MHz NMR.
2528
Org. Lett., Vol. 2, No. 16, 2000

the major product (>15:1). Similar reactions with 2b gave
only trace amounts of products. As expected the sense of
diastereoselection remains the same for both symmetric and
nonsymmetric dienophiles, which was confirmed upon
subjecting the cycloadduct 4c to debromination using Pd/C,
Et3N, and H2 to obtain the diastereomer 3f.
To probe the origin of the diastereoselection, 5 and 7 were
subjected to cycloadditions with NMM under the same
conditions that furnished a single diastereomer in the reaction
of 1b with NMM (Table 1, entry 4). The observed diastereo-
selectivity with both 5 and 7 was ca. 3:2 (Scheme 2). From
Table 2. Lewis Acid Catalyzed Diels-Alder Cycloadditionsa
item
sub
X
Lewis acidb
3
% yield
dr
1
2
3
4
1b
1e
2b
2b
O
O
NMe
NMe
L*Cu(OTf)2
L*Cu(OTf)2
MeAlCl2
AlCl3
3b
3h
3j
83
52
50c
72
>99:1
>97:3
>99:1
>99:1
3j
a 1.1 equiv of Lewis acid. b L*: N,N′-dibenzylideneethylenediamine.
c NMR conversion. d All reactions were carried out in CH2Cl2 at room
temperature, using 1 equiv of catalyst and 1 0.2 equiv of dienophile.
to ca. 97:3 (Table 2, entry 2). The less reactive anthracene
2b also underwent cycloadditions in good yield and complete
diastereoselectivity at rt upon using AlCl3, though no reaction
resulted in the presence of the Cu(II) catalyst, while a milder
aluminum catalyst such as MeAlCl2 led to a much lower
extent of reaction.
Scheme 2. Model Anthracenes To Ascertain Minimal
Requirements for Diastereoselection in Diels-Alder Reaction
Reactions of 1b and 1d with the unsymmetrical dieno-
philes bromomaleic anhydride and citraconic anhydride were
both highly diastereoselective and regioselective (Table 3).
Table 3. Diels-Alder Reaction with Unsymmetrical
Maleate-Type Dienophiles
1
a dr determined by H NMR (400 MHz).
these studies it was evident that an oxygen functionality on
a chiral center adjacent to the anthracene greatly enhanced
the diastereoselectivity.
entry
sub
Y
adduct
drc
% yield
The facial selectivity in the reactions of 1b-e may be
controlled by electrostatic repulsion between the maleic
anhydride carbonyl oxygens and the alkoxy oxygen on the
C9 substituent, with the methyl group oriented away from
the approaching dienophile to minimize steric interactions
and maximize σ-donation (Scheme 3). This model, which is
1
2
3
4
1b
1b
1d
1d
Bra
CH3
Bra
4a
4b
4c
4d
>99:1
>99:1
>99:1
>99:1
82
84
80
86
b
b
CH3
a Reactions were performed with 1.1 equiv of dienophile. b Reactions
were performed with 4 equiv of dienophile. c dr reported based on 1H NMR
(400 MHz). Regioselectivity by H NMR (>15:1).
1
Scheme 3. Proposed Model for Observed Facial Selectivity
In all cases, the regioisomer with the dienophile substituent
located away from the C9 substituent of anthracene, which
minimizes crowding in the transition state, was formed as
(7) Helmchen, G.; Ihrig, K.; Schindler, H. Tetrahedron Lett. 1987, 28,
183-186. (b) Chau, T.-Y.; Lin, H.-C.; Hu, W. Synth. Commun. 1996, 26,
1867-1874.
(8) Trost, B. M.; Patterson, D. E. Chem. Eur. J. 1999, 5, 3279-3284.
(9) (a) Franck, R. W.; Argade, S.; Subramaniam, C. S.; Frechet, D. M.
Tetrahedron Lett. 1985, 26, 3187-3190. (b) Tripathy, R.; Franck, R. W.;
Onan, K. D. J. Am. Chem. Soc. 1988, 110, 3257-3262.
(10) (a) Martens, J.; Reiner, I. Tetrahedron: Asymmetry 1997, 8, 27-
28. (b) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611-614.
Enantiopure Pirkle’s alcohol 2 is commercially available.
(11) Equimolar amounts of anthracene and 1b were reacted with 1 equiv
of maleic anydride in C6H6 at 80 °C under Ar for 6 h. Product distribution
was analyzed by integration of 400 MHz 1H NMR. Refluxing the individual
cycloadducts in the presence of the other anthracene in C6H6 did not show
any scrambling.
analogous to the “inside alkoxide model”,13 predicts the
observed diastereoselectivity.
(13) (a) Houk, K. N.; Moses, S. R.; Wu, Y.-D.; Rondan, N. G.; Jaeger,
V.; Schohe, R.; Fronczek, F. R. J. Am. Chem. Soc. 1984, 106, 3880-3882.
(b) Haller, J.; Niwayama, S.; Duh, H.-Y.; Houk, K. N. J. Org. Chem. 1997,
62, 5728-5731.
(12) Toth, A.; Floriani, C.; Pasquali, M.; Chiesi-Villa, A.; Gaetani-
Manfredotti, A.; Guastini, C. Inorg. Chem. 1985, 24, 648-653.
Org. Lett., Vol. 2, No. 16, 2000
2529

Scheme 4. Assignment of the Stereochemistry of 4da
Scheme 5. Diels-Alder Reaction of PEG-Supported Chiral
Anthracene
a Reaction conditions: (a) DDQ, CH2Cl2, 70%; (b) NaOMe,
CH3OH, 65%; (c) CH2N2, Et2O, 99%.
reaction of 2c gave with NMM a single diastereomer as
shown by NMR (yield 68%).
In conclusion, chiral C9-substituted anthracenes undergo
highly selective cycloadditions with various symmetric and
nonsymmetric dienophiles under both thermal and Lewis acid
catalyzed conditions, which makes them potential candidates
as chiral templates for a Diels-Alder/retro Diels-Alder
sequence. Adaptation to the polymer support without dete-
rioration of the diastereoselectivity provides a handle for the
application in parallel synthesis.
To confirm that this was the case, cycloadduct 4d was
transformed into lactone 10, where the syn relation of Ha to
Hb was established by NOE’s (Scheme 4). Subsequent NOE
studies on the methyl ester 11 revealed that epimerization
had occurred during lactonization to produce 10. Reversal
in diastereoselection was found for the alcohol 1a,14 which
may be due to “hydrogen bonding” between the hydroxy
group on the anthracene and the carbonyl of the approaching
dienophile.9b
Current interest in parallel solid and solution phase
chemistry prompted a preliminary effort to attach these chiral
anthracenes to a polymer support. Incorporation onto a
polyethylene glycol polymer support (PEG5000), which
allows liquid phase homogeneity under reaction conditions
with subsequent solid phase purification, was undertaken.
Anthracene 2a was bonded to PEG5000 by a mesylate
displacement to give 2c (Scheme 5).15 The Diels-Alder
Acknowledgment. We thank the donors of the Petroleum
Research Fund, administered by the American Chemical
Society, for financial support (ACS-PRF 35222-ACI).
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 1a-e, 2a-
c, 3a-k, 4a-d, and 6-11. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL006206M
(14) Debenzylation of 3g with DDQ gave the diastereomer corresponding
to the minor one obtained in reaction of 1a with NMM.
(15) Zhao, X.; Janda, K. D. Tetrahedron Lett. 1997, 38, 5437-5440.
2530
Org. Lett., Vol. 2, No. 16, 2000