A new, chiral aminoanthracene for the Diels-Alder/retro-Diels-Alder sequence in lactam and butenolide synthesis

Article abstract of DOI:10.1016/j.tetlet.2005.02.046

9-(2-Phenylethyl)aminoanthracene has been prepared and used as a template in the Diels-Alder/retro-Diels-Alder sequence to produce α,β- butenolides and α,β-unsaturated lactams. In this sequence the aminoanthracene serves as a stereo- and regiocontrolling

Full text of DOI:10.1016/j.tetlet.2005.02.046

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2475–2478
A new, chiral aminoanthracene for the Diels–Alder/retro-
Diels–Alder sequence in lactam and butenolide synthesis
Amitav Sanyal, Qian Yuan and John K. Snyder*
Department of Chemistry, and the Center for Methodology and Library Development, Boston University,
590 Commonwealth Ave., Boston, MA 02215, USA
Received 23 December 2004;accepted 8 February 2005
Abstract—9-(2-Phenylethyl)aminoanthracene has been prepared and used as a template in the Diels–Alder/retro-Diels–Alder
sequence to produce a,b-butenolides and a,b-unsaturated lactams. In this sequence the aminoanthracene serves as a stereo- and regio-
controlling chaperone in guiding maleic anhydride or N-alkylmaleimides through transformations to the butenolide or lactam
targets.
ꢀ 2005 Elsevier Ltd. All rights reserved.
O
For the past several years we have been exploring
anthracenes substituted at C9 with a stereogenic center
as chiral templates for use in Diels–Alder/retro-Diels–
Alder sequences1,2 for the purpose of transforming
maleic anhydride and N-alkylmaleimide cycloadducts
into a,b-butenolides and a,b-unsaturated lactams
(Scheme 1). Such a sequence requires a highly diastereo-
selective initial cycloaddition, followed by regio- and
stereoselective transformation of one of the carbonyl
groups of the mounted dienophile. In this approach,
the chiral anthracene template serves as the stereocon-
trolling element in both the cycloaddition and subse-
quent carbonyl chemistry, and must also control the
regiochemistry in the latter reactions.
O
X
O
X
R’
O
X = O, NR2
Xc
Carbonyl
Transformation
Cycloaddition
R4
R3
X
R1
R’
O
Cycloreversion
Xc
Xc
OCH3
R4
1: R1 = H, Xc =
2: R1 = H, Xc =
3: R1 = CH3, Xc =
R3
CH3
X
OCH3
O
Initially we examined the diastereoselectivity of (S)-9-(1-
methoxyethyl)anthracene (1) and (R)-9-(1-methoxy-
2,2,2-trifluoromethyl)anthracene (2, PirkleÕs alcohol) in
cycloadditions with maleic anhydride and N-methylma-
leimide.3 While both of these anthracene templates
worked well in cycloadditions, 1 was unstable to pro-
longed storage, producing detectable amounts of
anthraquinone via oxidation under ambient conditions,
and 2 was less reactive in the cycloadditions toward
other dienophiles.
CF3
OCH3
CF3
OCH3
CH2OCH3
4: R1 = H, Xc =
Scheme 1.
With these results in hand, we then prepared a second
generation of chiral anthracene templates:4 (R)-10-
methyl-9-(1-methoxy-2,2,2-trifluoroethyl)anthracene (3),5
(R)-9-(1,2-dimethoxyethyl)anthracene (4),6 (R)-9-(1-phenyl-
ethyl)aminoanthracene (5),4 and the homochiral 9-acyl-
oxyanthracenes 6a and 6b for use in the Diels–Alder/
retro-Diels–Alder sequence. Placement of the methyl
group at C10 in 3 (Scheme 1 above) improved the react-
ivity in cycloadditions relative to 2 by a factor of 10, and
Keywords: Anthracene;Retro-Diels–Alder;Butenolide;Lactam;Asy-
mmetric cycloaddition.
*
Corresponding author. Tel.: +1 617/353 2621;fax: +1 617/353
6466;e-mail: jsnyder@chem.bu.edu
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.046

2476
A. Sanyal et al. / Tetrahedron Letters 46 (2005) 2475–2478
this anthracene was used as a template in a Diels–Alder/
retro-Diels–Alder sequence to prepare the butenolide
precursor to a rove beetle pheromone.5 The cyclorever-
sion was accomplished by heating to 200 ꢁC under vac-
uum. However, this enhanced reactivity came at the
expense of regioselectivity in the carbonyl reduction as
well as in the cycloaddition with nonsymmetric dieno-
philes such as 5-acetoxyfuranone.4,5
failed to improve the ratios, so these anthracenes were
no longer pursued.
Our attention then turned to homochiral aminoanthra-
cene 5. Rawal has demonstrated the effectiveness of
homochiral 1-aminobutadienes in controlling the stereo-
chemistry in cycloadditions,14 so it was anticipated that
cycloadditions of 5 would also proceed with high diaste-
reoselectivity. Aminoanthracene 5 was readily obtained
by Pd-catalyzed aryl amination of 9-bromoanthracene
with (R)-1-phenylethylamine (Scheme 3).4,15 As antici-
pated, this aminoanthracene oxidized under ambient
conditions,16 but could be stored under nitrogen at
0 ꢁC. Alternatively, 5 could be easily trapped by acetyla-
tion to give the corresponding N-acetate (53%, two
steps), but this N-acetylaminoanthracene proved to be
unreactive in cycloadditions with maleic anhydride and
N-methylmaleimide (NMM). More importantly, 5 could
also be trapped as the cycloadduct immediately after
preparation by the addition of maleic anhydride or N-
alkylmaleimide under nitrogen at room temperature.
Though slow (48 h), cycloadducts 8–10 were isolated
in good to excellent yields and with high diastereoselec-
tivities (P10:1), though in contrast to anthracenes 1–4,
which underwent cycloadditions with maleic anhydride
and N-alkylmaleimides with exclusive diastereoselecti-
vity, the minor diastereomers were detected in each
case.17 The cycloadditions occurred much more rapidly
at higher temperatures, but led to an increased amount
of minor diastereomer. The assignment of the stereo-
chemistry of the cycloadducts is described below.
H3C
NH
O
O
O
O
5
6a
6b
Ph
H3CO
Ph
H3CO
Ph
CF3
Homochiral dimethoxyethylanthracene 4 (Scheme 1
above) also underwent cycloadditions with a variety of
maleic anhydrides and N-alkylmaleimides with exclusive
diastereoselectivity, shown to be under kinetic control.
Regioselectivity in the carbonyl transformations was
also exclusive, with flash vacuum pyrolysis (FVP)
at 400 ꢁC furnishing a,b-unsaturated lactams in
good yields, including indolizidone bicyclic systems.6
Jones has also probed the cycloadditions of chiral
anthracenes.7
In an effort to reduce the temperature required for the
cycloreversion, we also prepared homochiral anthrac-
enes 5, 6a, and 6b. Czarnik has shown that electron
donating substituents at C9 (and C10) of anthracene
cycloadducts accelerate the cycloreversion,8 thus we
anticipated that cycloadducts of 5 should undergo cyclo-
reversion at lower temperatures in comparison to 4.
Esters 6a and 6b were also examined since Trost,9
Thornton10 and others11 had shown that mandelate-type
acyloxy substitution at C1 of butadienes can indeed lead
to excellent diastereoselectivity in cycloadditions. Basic
cleavage of the ester group should then lead to a rapid
oxyanion promoted cycloreversion, as demonstrated
by both Knapp12 and Nicolaou.13
With the cycloadducts in hand, the regioselectivity of
carbonyl transformations was then probed beginning
with adduct 9 (Scheme 4). Reduction with Super-Hy-
dride occurred only at the carbonyl remote to the amino
group, leading to acyl aminal 11, which was allylated
without further purification to lactam 12 (68%, two
steps). Ozonolysis with NaBH4 workup (91%), with sub-
sequent TBDPS protection yielded 13 (77%). This four-
step sequence could also be performed without purifica-
tion of the intermediates, giving 13 in 80% overall yield
from 9.
Trapping the oxyanion produced by treating anthrone
with NaH with the appropriate acid chloride produced
6a and 6b in excellent yields (>90%, Scheme 2). Both
anthracenes were stable to storage. Unfortunately, cyclo-
additions with maleic anhydride and N-methylmale-
imide with 6a, and the latter dienophile with 6b
produced mixtures of diastereomers of 7 in 3:2 ratios
from 6a, and a 1.2:1 ratio from 6b. Lewis acid catalysis
Conditions to accomplish the cycloreversion with 13
were then examined, using both microwave irradiation18
and the more classic flash vacuum pyrolysis.19 After
considerable experimentation it was discovered that
microwave irradiation of a solid mixture of 13 and
Pd2(dba)3, rac-BINAP,
Ph
O
NH2
+
NaOBut, tol, 70 oC
5
O
X
Br
O
X
O
8 X = O (75%, 10:1)
9: X = NCH3 (81%, 10:1)
10: X = NCH2CH=CH2 (94%, 15:1)
X
X
O
O
i) NaH, THF
O
O
6
ii)
O
Ph
R
COCl
OCH3
X = O, NR2
(>90%)
O
(48 h)
O
R
HN
Ph
H3CO
7
Ph
(>90%)
Scheme 2.
Scheme 3.

A. Sanyal et al. / Tetrahedron Letters 46 (2005) 2475–2478
2477
OH
HO
O
TMSCH2CH=CH2,
H3CN
O
MeO2C
.
LiBEt3H,
BF3 OEt2, CH2Cl2
1) O3; Me2S
2) NaClO2,
NaH2PO4
3) CH2N2
H3CN
O
THF, -78 oC
-78 oC to rt
.
i) BH3 SMe3
H3CN
O
H3CN
O
ii) NaOH, H2O2
HN
12
HN
Ph
11
9
Ph
HN
Ph
HN
16
OTBDPS
15
FVP
Ph
1) i) O3, -78 oC
ii) NaBH4, rt
H3CN
O
H3CN
O
FVP
FVP
OH
CO2Me
NCH3
2) TBDPSCl, Im
(80%, 4 steps)
NCH3
HN
HN
NCH3
12
13
O
O
Ph
Ph
O
17 (83%)
19 (65%)
18 (82%)
Scheme 4.
Scheme 6.
NMM20 at 160 ꢁC (3 min) gave a 57% yield of lactam
14 along with 67% yield of adduct 9, though the latter
only with a diastereoselectivity of 2:1 (Scheme 5).
Presumably the higher temperature required for the
cycloreversion results in a hemorrhaging of the diastereo-
selectivity of the cycloaddition when trapping amino-
anthracene 5 in situ, as previously noted with the
thermally promoted cycloadditions. Microwave irradia-
tion at 140 ꢁC led to only 10% cycloreversion, while
longer irradiation at 160 ꢁC reduced the yield of 14.
Microwave irradiation on various solid supports was
also unsuccessful.
the chiral amino substituent to give 20, a regioselectivity
analogous to that observed in Grignard additions to
other chiral anthracenes.4,6 Some retro-Diels–Alder
products were also observed in this reaction, accounting
for the relatively modest yield of 56%. Allylation and
silane reduction to 21 and 22, respectively, then FVP
gave lactams 23 and 24 (Scheme 7).
H
CH3
N
.
i) BF3 OEt2
O
CH3
OH
ii) Et3SiH
Given the somewhat disappointing results of the micro-
wave-promoted cycloreversion (modest yield and poor
diastereoselectivity in trapping 5), flash vacuum pyroly-
sis was also examined. Heating 13 at 190 ꢁC at 2 mmHg
(10 min) gave a 74% yield of 14, recovered in a trap
cooled to À78 ꢁC. Aminoanthracene 5 condensed on
the sides of the exit tube after emerging from the tube
furnace, and could be recovered by washing with tolu-
ene, then adding NNM to give 9 (70%).
N
HN
Ph
MeMgBr
(56%)
(72%) 21
O
10
HN
Ph
20
(52%)
CH3
N
.
O
i) BF3 OEt2
ii) TMSCH2CH=CH2
HN
Ph
Cycloreversion via FVP under the same conditions on
lactam 12, or following routine transformations of 12
to related derivatives, also proceeded comparably to
produce 17–19 (Scheme 6, FVP 190 ꢁC, 10 min). In each
case, aminoanthracene 5 could be trapped as NMR
adduct 9 as described above in a minimum of 70% yield.
Of note in these examples is the successful cyclorever-
sion of 16 without alcohol protection.
22
H3C
R
FVP
(210 oC, 10 min)
23: R = H (44%)
24: R = CH2CH=CH2 (69%)
N
O
Scheme 7.
The known allylated butenolide 27 was also prepared in
analogous fashion beginning with the maleic anhydride
cycloadduct 8 (Scheme 8). Stereoselective reduction of
8 (83%), followed by TiCl4 catalyzed allylation (40%,
14:1) gave lactone 26. Flash vacuum pyrolysis under
the standard conditions gave butenolide 27 in 90% yield,
and 97.4% ee as established by chiral GC.21 Comparison
of the [a]D +94 (c 3.0, CH2Cl2) with that reported in the
literature (+105 c 4.1, CH2Cl2)22 allowed for the assign-
ment of the absolute stereochemistry of 27, and in turn,
the precursors 25 and 26. Furthermore, since it is pre-
sumed that the stereocontrol for the cycloadditions of
maleic anhydride and the N-alkylmaleimides is the
Methyl Grignard addition to N-allylmaleimide cycload-
duct 10 also occurred solely at the carbonyl remote to
OTBDPS
NMM
cycloreversion
13
+
5
9
NCH3
O
14
microwave (160 oC, 3 min): 14 (57%), 9 (67%, 2:1 dr)
FVP (190 oC, 10 min): 14 (74%), 9 (70%, 15:1 dr)
Scheme 5.

2478
A. Sanyal et al. / Tetrahedron Letters 46 (2005) 2475–2478
For some examples since these reviews: (d) Knappwost-
OH
Gieseke, C.;Nerenz, F.;Wartchow, R.;Winterfeldt, E.
Chem. Eur. J. 2003, 9, 3849–3858;(e) Wolter, M.;Borm,
C.;Merten, E.;Wartchow, R.;Winterfeldt, E. Eur. J. Org.
Chem. 2001, 4051–4060;(f) Tran-Huu-Dau, M.-E.;Wart-
O
LiAl(OtBu)3H
TMSCH2CH=CH2
TiCl4, -78 oC to rt
THF, -78 oC to rt
O
8
(40%,14:1)
(83%. 30:1)
HN
Ph
chow, R.;Winterfeldt, E.;Wong, Y.-S.
Chem. Eur. J.
25
2001, 7, 2349–2369;(g) Goldenstein, K.;Fendert, T.;
Proksch, P.;Winterfeldt, E. Tetrahedron 2000, 56, 4173–
4185.
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3. Sanyal, A.;Snyder, J. K. Org. Lett. 2000, 2, 2527–2530.
4. Sanyal, A. PhD Dissertation, Boston University, 2002.
5. Corbett, M. S.;Liu, X.;Sanyal, A.;Snyder, J. K.
Tetrahedron Lett. 2003, 44, 931–935.
6. Burgess, K. L.;Lajkiewicz, N. J.;Sanyal, A.;Yan, W.;
Snyder, J. K. Org. Lett. 2004, ASAP.
FVP
O
190 oC, 10 min
O
27
HN
Ph
(90%)
26
O
7. (a) Jones, S.;Atherton, J. C. C. Tetrahedron: Asymmetry
2001, 12, 1117–1119;(b) Atherton, J. C. C.;Jones, S.
Tetrahedron Lett. 2001, 42, 8239–8241;(c) Atherton, J. C.
C.;Jones, S. Tetrahedron Lett. 2002, 43, 9097–9100;(d)
Atherton, J. C. C.;Jones, S. J. Chem. Soc., Perkin Trans. 1
2002, 2166–2173;(e) Bawa, R. A.;Jones, S. Tetrahedron
2004, 60, 2765–2770.
Scheme 8.
same, the stereochemistry of the maleimide cycloadducts
9 and 10, as well as the a,b-unsaturated lactams 14, 17–
19, 23, and 24 were assigned as shown earlier. The high
ee value for 27 confirms that racemization did not occur
during the pyrolysis. The trace amount of the enantio-
mer results from the less than absolute diastereoselecti-
vity in the original cycloaddition.
8. Chung, Y. S.;Duerr, B. F.;Nanjappan, P.;Czarnik, A. W.
J. Org. Chem. 1988, 53, 1334–1336.
9. (a) Trost, B. M.;Godleski, S. A.;Genet, J. P. J. Am.
Chem. Soc. 1978, 100, 3930–3931;(b) Trost, B. M.;
OÕKrongly, D.;Belletire, J. L. J. Am. Chem. Soc. 1980,
102, 7595–7596;(c) Tucker, J. A.;Houk, K. N.;Trost, B.
M. J. Am. Chem. Soc. 1990, 112, 5465–5471.
10. (a) Siegel, C.;Thornton, E. R. Tetrahedron Lett. 1988, 29,
5225–5228;(b) Tripathy, R.;Carroll, P. J.;Thornton, E.
R. J. Am. Chem. Soc. 1991, 113, 7630–7640.
In competition cycloadditions with unsubstituted
anthracene and NMM, 5 proved to be six times as reac-
tive. Thus, the reactivity of 5 is comparable to that of 1
and 3,3 and about twice as reactive as 4.6
In conclusion, a new, homochiral anthracene (5) has
been prepared and examined in the Diels–Alder/
retro-Diels–Alder sequence for the preparation of a,b-
unsaturated lactams and a,b-butenolides. While 5 was
successful in this sequence, three main areas for
improvement were defined. First, a faster, highly diaste-
reoselective Diels–Alder reaction needs to be achieved.
This objective may be attained if an aminoanthracene
is available that undergoes the cycloadditions at higher
temperatures yet still maintains high diastereoselectivity.
Indeed, 5 proved to be less stereoselective in its cyclo-
additions than chiral anthracenes 1–4. Second, an
aminoanthracene, which yields cycloadducts that are
stable to Grignard additions (avoids cycloreversion)
needs to be discovered. Finally, while the retro-Diels–
Alder reactions were successful at 190 ꢁC, a considerable
improvement over earlier attempts, achieving the cyclo-
reversion at lower temperatures remains a target. We are
currently examining other aminoanthracenes that may
accomplished these goals.
11. Masamune, S.;Choy, W.;Petersen, J. S.;Sita, L. R.
Angew. Chem., Int. Ed. Engl. 1985, 24, 1–30.
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13. Bunnage, M. E.;Nicolaou, K. C. Angew. Chem., Int. Ed.
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15. For the procedure followed: Wagaw, S.;Rennels, R. A.;
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17. Operationally, the coupling mixture containing crude 5
was filtered through Celite, washing with anhydrous ether.
After evaporation of the solvent in vacuo, the residue was
dissolved in anhydrous toluene and the solution was
added dropwise to the solid dienophile (NMM or maleic
anhydride, 1.2 equiv). The final concentration of 5 was
0.3 M. The solution was maintained under nitrogen at rt.
18. Garrigues, P.;Garrigues, B. C.R. Acad. Sci. Paris, IIC
1998, 545–550.
References and notes
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Synth. 1995, 72, 116–124.
20. This solid mixture was prepared by dissolving 13 with
NMM (5 equiv) in CH2Cl2, then removing the solvent
in vacuo.
21. Chromatography was performed on a Shimadzu GC-17A
chromatograph equipped with an autosampler, GANNA
DEX-225 capillary column (Supelco, 30 m · 0.25 mm ·
0.25 lm);flow rate 1 mL/min with He carrier gas;
separation factor (a) = 25.
Org.
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