A new chiral anthracene for the asymmetric Diels-Alder/retro-Diels-Alder sequence

Article abstract of DOI:10.1021/ol047968a

(Chemical Equation Presented) (-)-(R)-9-(1,2-Dimethoxyethyl)anthracene (8) is successfully employed as a chiral template in the Diels-Alder/retro-Diels- Alder sequence for the preparation of α,β-unsaturated lactams. The cycloadditions proceed with complet

Full text of DOI:10.1021/ol047968a

ORGANIC
LETTERS
2
005
Vol. 7, No. 1
1-34
A New Chiral Anthracene for the
Asymmetric Diels Alder/
Retro-Diels Alder Sequence
3
−
−
Kerrie L. Burgess, Neil J. Lajkiewicz, Amitav Sanyal, Wanlin Yan, and
John K. Snyder*
Boston UniVersity, Department of Chemistry, Boston, Massachusetts 02215
jsnyder@chem.bu.edu
Received October 4, 2004
ABSTRACT
(
−
)-(R)-9-(1,2-Dimethoxyethyl)anthracene (8) is successfully employed as a chiral template in the Diels
the preparation of -unsaturated lactams. The cycloadditions proceed with complete diastereoselectivity, and regioselectivity in subsequent
transformations of the carbonyl groups is also excellent. Flash vacuum pyrolysis accomplishes the cycloreversion.
−Alder/retro-Diels−Alder sequence for
r,â
Butenolides and R,â-unsaturated γ-lactams are well-known
pharmacophores that have evoked considerable effort in the
development of new synthetic methodologies. We have been
interested in developing a general synthetic route that could
be easily amenable to these compound classes in enantiopure
form and also be readily adaptable to library synthesis. To
this end, a Diels-Alder/retro-Diels-Alder sequence employ-
ing a homochiral anthracene template, which would be
recovered after the cycloreversion, as the stereocontrolling
element seemed attractive (Scheme 1).
additions were very successful, 1 was prone to oxidation
upon prolonged benchtop storage, while the reduced reactiv-
ity of 2 in cycloadditions with less reactive dienophiles was
somewhat disappointing.
In an effort to improve the reactivity of the chiral
anthracene template without compromising its stability, (R)-
9-(1-methoxy-2,2,2-trifluoroethyl)-10-methylanthracene (4)
Scheme 1
In an earlier report, 9-(1-methoxyethyl)anthracene (1) and
9-(1-methoxy-2,2,2-trifluoroethyl)anthracene (2) were used
as chiral, nonracemic anthracenes in highly diastereoselective
cycloadditions with maleic anhydride and N-methylmale-
1
imide. Jones subsequently demonstrated excellent stereo-
selectivity in the photochemically induced cycloadditions of
2
1
and has also shown that the stereoselectivity can also
operate under chelation control using the corresponding
3
alcohol under appropriate conditions. While these cyclo-
(
1) Sanyal, A.; Snyder, J. K. Org. Lett. 2000, 2, 2527.
(2) (a) Jones, S.; Atherton, J. C. C. Tetrahedron: Asymmetry 2001, 12,
1
2
117. (b) Atherton, J. C. C.; Jones, S. J. Chem. Soc., Perkins Trans. 1
002, 2166.
1
0.1021/ol047968a CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/15/2004

Table 1. Cycloadditions of 8 with Maleic Anhydrides and Maleimides (Scheme 3)
a
Isolated yields. b Reactions were run in a sealed tube.
was prepared and examined in cycloadditions with maleate-
derived dienophiles. While 4 proved to be more reactive
than 2, yet retained the good benchtop stability exhibited by
exclusive diastereoselectivity in the cycloadditions with
4
dienophiles such as maleic anhydrides and maleimides, and
(4) show excellent regioselectivity in carbonyl transforma-
tions of its cycloadducts. We now report that 9-(1,2-
dimethoxyethyl)anthracene (8) meets these requirements and
can be applied to a Diels-Alder/retro-Diels-Alder asym-
metric synthetic sequence.
2, the regioselectivity in cycloadditions with nonsymmetric
dienophiles such as 3a was unfortunately compromised,
giving only a 6:1 mixture of cycloadducts 5a and 5b (Scheme
2, eq 1). Furthermore, the regioselectivity in carbonyl
6
Adapting Corey’s procedure, 9-vinylanthracene was di-
hydroxylated with AD-mix-â to give the (R)-diol (93% on
3
a 4 g scale), which was dimethylated (CH I/NaH, 97%) to
produce 8 (Scheme 3). Chiral HPLC established the ee of 8
Scheme 2
Scheme 3
as 99+%. Anthracene 8 underwent cycloadditions with
maleic anhydrides and maleimides to produce single dia-
stereomers 9 in excellent yields (Table 1). Unsymmetric
dienophiles such as bromomaleic anhydride, citraconic
anhydride, and N-methyl-2-bromomaleimide produced solely
the regioisomer with the original dienophile C2 substituent
(Br or Me) remote to the original anthracene C9 stereogenic
substituent (entries 2, 3, and 5).
reductions of the maleic anhydride cycloadduct 6 could only
be optimized to 3:1 (Scheme 2, eq 2).5
We have continued the search for better chiral anthracene
templates that (1) retain good benchtop stability, (2) are at
least as reactive as anthracene in cycloadditions, (3) show
With the cycloadducts in hand, work then focused on
transformations of the succinimide subunits mounted on the
(
(
3) Atherton, J. C. C.; Jones, S. Tetrahedron Lett. 2001, 42, 8239.
4) Corbett, M. S.; Liu, X.; Sanyal, A.; Snyder, J. K. Tetrahedron Lett.
2
003, 44, 931.
5) Sanyal, A. Ph.D. Dissertation, Boston University, 2002.
(
(6) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 11038.
Org. Lett., Vol. 7, No. 1, 2005
32

Table 2. Carbonyl Transforms of Mounted Maleimides 9 through FVP (Schemes 4 and 5)a
b
c
f
g
item/9
R
R′
yield/10 (%)
yield/11 (%)
yield/12 (%)
yield/13 (%)
d
h
NAh
NA
1
2
3
4
5
6
7
8
/9d
/9d
/9f
/9g
/9g
/9g
/9h
/9h
CH3
CH3
-CHdCH2
-CH2CHdCH2
-CH2CHdCH2
-CH2CHdCH2
-CH2CH2CHdCH2
-CH2CH2CHdCH2
Ph
CH3
H
96/10a
83/10b
80/10c
99+/10d
99+/10e
98/10f
99+/10g
99+/10h
91 /11a
NA
NA
d
h
h
73 /11b
0
d
H
94 /11d
87/12d
99/12e
72/12f
84/12g
99/12h
60/13d
75/13e
60/13f
50/13g
77/13h
d
CH3
Ph
H
77 /11e
d
89 /11f
e
77 /11g
e
CH3
72 /11h
a
Isolated yields. Grignard addition or Superhydride reduction. c Allylation with trimethylallysilane. d TiCl4, -78 °C to rt in CH2Cl2. e BF3OEt2, -78
b
f
°
C to rt in CH2Cl2. Ring-closing metathesis and hydrogenation, two steps. g FVP. h NA ) not applicable/attempted.
chiral anthracene template. Regioselective reactivity of the
carbonyl groups in the cycloadducts 9 is critical to the use
of the Diels-Alder/retro-Diels-Alder sequence in enantio-
selective synthesis since the lack of regioselectivity results
in the production of enantiomers following cycloreversion.
Selectivity in reductions and reactions with Grignard reagents
was probed.
diene subunits suitably poised for ring-closing metathesis
(RCM) in the cases of the N-allylmaleimide and N-butenyl-
maleimide adducts derived from 9g and 9h; allylation failed
for 10c. The RCM was routinely accomplished in excellent
yields followed by hydrogenation to produce the desired
indolizidine and the corresponding seven-membered ring
homologue mounted on the anthracene template 12 (n ) 1,
2, Scheme 5). Flash vacuum pyrolysis (400 °C, 4 min) then
3
Superhydride (LiEt BH) reductions resulted in the regio-
chemically clean production of lactams 10c, 10d, and 10g
from 9f, 9g, and 9h, respectively, with hydride addition
occurring solely at the carbonyl remote to the original
anthracene C9 stereocontrolling substituent (Scheme 4, Table
Scheme 5
Scheme 4
yielded the targeted bicycles 13 along with complete recovery
of 8 (Table 2, last column). The bicyclic systems 13 with
methine carbons at the ring fusion center (13, R′ ) H) were
8
not stable to prolonged storage. This strategy to prepare the
indolizidine bicyclic alkaloidal ring system as well as higher
homologues by ring-closing metathesis of the larger ring
parallels earlier approaches by Martin as well as Hanessian.
Resubjecting cycloadduct 9a to the original cycloaddition
conditions in both methanol and toluene in the presence of
N-methylmaleimide led only to fully recovered 9a; no
crossover product was detected. A competition experiment
between maleic anhydride and N-methylmaleimide in the
cycloaddition with 8 revealed both cycloadducts were formed
2
, entries 3, 4, and 7). Grignard additions to the cycloadducts
9d, 9g, and 9h (entries 1, 2, 5, 6, and 8) also occurred solely
9
10
at this remote carbonyl. Presumably, evolving steric interac-
tions between the anthracenyl stereogenic center and the
developing sp hybridization of the near carbonyl during
nucleophilic addition increases the transition-state energy
sufficiently to deny the alternative regiochemical outcome.
Addition occurred solely from the top side of the imide, the
anthracene template blocking approach from the bottom face.
The regio- and stereochemistry of these additions was
3
(
8) Watson, R T.; Gore, V. K.; Chandupatla, K. R.; Dieter, R. K.; Snyder,
J. P. J. Org. Chem. 2004, 69, 6105.
9) Martin, S. F.; Chen, H.-J.; Courtney, A. K.; Liao, Y.; Paetzel, M.;
Ramser, M. N. Wagman, A. S. Tetrahedron 1996, 52, 7251.
10) Hanessian, S.; Sailes, H.; Munro, A.; Therrien, E. J. Org. Chem.
2003, 68, 7219.
7
established by the observed coupling patterns and NOEs.
Subsequent allylation then produced the lactams 11 with the
(
(
(7) See the Supporting Information, 11a, for details.
Org. Lett., Vol. 7, No. 1, 2005
33

(1:3.3, 9a/9d). Thus, if the formation of 9a was reversible
under these conditions, crossover product would certainly
have been detected, and the stereoselectivity was thus
established to be under kinetic control.
Scheme 6
The absolute stereochemistry of 13d was established by
comparison of its optical rotation with that reported in the
1
1
literature, which also allowed for the assignment of the
absolute stereochemistry of 9g and the remaining cyclo-
adducts by analogy. This stereochemistry suggests a transi-
tion state for the cycloaddition wherein the methoxymethyl
group is oriented antiperiplanar to the approaching dienophile
with facial selectivity established through minimization of
electrostatic repulsions between the auxiliary C9 methoxyl
group and the dienophile carbonyl oxygens (Figure 1). Such
an approach also minimizes steric interactions.
In conclusion, a new chiral anthracene template 8, with
excellent benchtop stability, has been prepared for use as
the stereocontrolling element in a cycloaddition/cyclo-
reversion sequence for the asymmetric synthesis of R,â-
unsaturated γ-lactams. Only single stereoisomers were
produced in the cycloadditions with maleimides and maleic
anhydrides, and only single regioisomers were formed in the
carbonyl transformations of the mounted dienophiles. Com-
petition experiments using maleic anhydride as the dienophile
revealed that 8 is 2.8 times more reactive than anthracene.
Flash vacuum pyrolysis releases the transformed dienophile.
Work continues to probe the scope of the cycloadditions of
Figure 1. Proposed transition state to account for observed
stereoselectivity in cycloadditions of 8.
Cycloadduct 14 from the reaction of anthracene 8 with
N-methyl-2-bromoaleimide, followed by near-quantitative
radical allylation, was also subjected to Grignard addition
8
with other dienophiles, as well as to investigate further
(Scheme 6). In this case, phenyl Grignard addition occurred
transformations of the cycloadducts.
at the carbonyl remote to the allyl group and above the
former anthracene C9 stereogenic center, presumably for
steric reasons. A second Grignard addition to the in situ
generated acyl iminium ion produced the γ,γ-disubstituted
lactam 16, which also underwent cycloreversion via flash
vacuum pyrolysis to produce R,â-unsaturated lactam 17.
Thus, excellent regioselectivity was still observed with the
C2-disubstituted succinimide 14, though in this case at the
other carbonyl group in comparison to the maleimide
cycloadducts illustrated in Scheme 4 and Table 2.
Acknowledgment. We thank the donors of the Petroleum
Research Fund (ACS-PRF 35222-AC) for financial support
and the Boston University Undergraduate Research Op-
portunity Program (UROP) for support of K.L.B. and N.J.L.
Supporting Information Available: Experimental pro-
cedures and characterization data including spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(11) Rasmussen, M. O.; Delair, P.; Greene, A. E. J. Org. Chem. 2001
6
6, 5438.
OL047968A
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Org. Lett., Vol. 7, No. 1, 2005