Diels - Alder reactions of cyclic isoimidium salts

Article abstract of DOI:10.1021/ol101831b

Diels - Alder reactions of cyclic isoimidium salts are described. The corresponding cycloadducts are obtained with high regio- and stereoselectivity. The use of homochiral cyclic isoimidium salts delivers cycloadducts with excellent diastereoselectivity (

Full text of DOI:10.1021/ol101831b

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4524-4527
Diels-Alder Reactions of Cyclic
Isoimidium Salts
Robert K. Boeckman, Jr.,* Yan Miller, and Todd R. Ryder
Department of Chemistry, UniVersity of Rochester, Rochester,
New York 14627-0216, United States
rkb@rkbmac.chem.rochester.edu
Received August 5, 2010
ABSTRACT
Diels-Alder reactions of cyclic isoimidium salts are described. The corresponding cycloadducts are obtained with high regio- and
stereoselectivity. The use of homochiral cyclic isoimidium salts delivers cycloadducts with excellent diastereoselectivity (>99:1) that can be
efficiently converted to enantiomerically pure lactones.
The treatment of a variety of N-substituted amic acids with
acetic anhydride and aqueous perchloric acid has been shown
by Boyd and co-workers to result in the formation of cyclic
isoimidium salts (eq 1).1 These salts are typically isolable, air-
stable materials that display a distinctive, high-frequency IR
absorption around 1860 cm-1, similar to that of an acid chloride.
Although Diels-Alder reactions of isoimidium salts had not
been described in the literature, we became interested in the
synthetic potential of these salts as dienophiles. We reasoned
that such compounds should behave as highly activated unsym-
metrical dienophiles affording predictably high regioselectivity
in cycloadditions with unsymmetrical dienes owing to our
expectation that polarization of the olefin would be enhanced
by the iminium moiety [the largest LUMO coefficient resides
on the carbon ꢀ to the iminium moiety (ꢀ ) -0.488, R ) 0.363
by ΑΜ1)]. Thus, these species would not require Lewis acid
activation and should be more compatible with Lewis acid and
thermally sensitive dienes.
Simple elaboration of the adducts could potentially regio-,
stereo-, and enantioselectively lead to unsymmetrical γ-buty-
rolactones bearing multiple chiral centers. Although such
enantiomerically pure γ-lactones have been previously prepared
by enantioselective reduction of meso-anhydrides,2a methanoly-
sis of meso-anhydrides followed by reduction,2b or oxidation
of meso-diols,2c those methods require a meso-precursor that
precludessynthesisofunsymmetricalsystems.DirectDiels-Alder
reactions of 2(5H)-furanone with dienes promoted by achiral
Lewis acids have also been reported but afford mixtures of
regioisomers.3
The Boyd group had explored the reactivity of these
compounds. In particular, they found that amine, alcohol,
and azide nucleophiles added to the carbonyl group in a
regiospecific fashion to give the corresponding ring-opened
products in good yields. Friedel-Crafts acylation products
were also obtained in moderate yields when isoimidium salts
were treated with aromatic compounds.1
(1) (a) Boyd, G. V. Chem. Commun. 1969, 1147–1148. (b) Boyd, G. V.;
Monteil, R. L. J. Chem. Soc., Perkin Trans. 1 1978, 1338–1350. (c) Baydar,
A. E.; Boyd, G. V. J. Chem. Soc., Perkin Trans. 1 1978, 1360–1366. (d)
Baydar, A. E.; Boyd, G. V. J. Chem. Soc., Perkin Trans. 1 1981, 2871–
2877. (e) Baydar, A. E.; Boyd, G. V.; Aupers, J.; Lindley, P. F. J. Chem.
Soc., Perkin Trans. 1 1981, 2890–2894. (f) Balaban, A. R.; Balaban, T. S.;
Boyd, G. V. Synthesis 1987, 577–578.
(2) (a) Matsuki, K.; Inoue, H.; Takeda, M. Tetrahedron Lett. 1993, 34,
1167–1170. (b) Okamatsu, T.; Irie, R.; Katsuki, T. Synlett 2007, 10, 1569–
1572. (c) Lok, K. P.; Jakovac, I. J.; Jones, J. B. J. Am. Chem. Soc. 1985,
107, 2521–2526.
10.1021/ol101831b  2010 American Chemical Society
Published on Web 09/15/2010

When we initiated our studies, only one partially characterized
example of an isoimidium tetrafluoroborate salt could be found
in the literature.1b Nevertheless, we felt it was highly desirable
to employ isoimidium tetrafluoroborate salts rather than the
related perchlorate salts1 to avoid the preparation and handling
of potentially explosive intermediates on scale. Thus, amic acid
1 derived from maleic anhyride and diethylamine was treated
with acetic anhydride and tetrafluoroboric acid to afford the
desired isoimidium tetrafluoroborate salt 2 in good yield
(Scheme 1). As an additional benefit, we also found that tetra-
Table 1. Reactions of Cyclic Isoimidium Salt 2
Scheme 1
.
Formation of Cyclic Isoimidium Salt 2 with
Tetrafluoroboric Acid
fluoroborate salts such as 2 exhibited improved solubility in
nonpolar organic solvents relative to the corresponding per-
chlorates. Formation of the isoimidium salt 2 was confirmed
by observation of the diagnostic IR peak at 1828 cm-1 and the
downfield shift of the olefinic signals (1H NMR/CDCl3) from
6.41 and 6.60 to 8.41 and 7.49 ppm, respectively.1 This increase
in the chemical shift (∆δ ) 2 ppm for the proton ꢀ to the amide)
was in accord with our postulate regarding differential polariza-
tion of the olefin in 2. Moreover, treatment of the salt with
methanol gave a quantitative yield of the known methyl ester
3.1 Isoimidium salt 2 could also be generated by treatment of
the potassium salt of 1 with oxalyl chloride followed by exposure
to AgBF4 or in situ by exposure of the acid to TFAA in CH2Cl2,
the latter affording the analogous trifluoroacetate salt.
a All reactions conducted in CH3CN. b Determined by 1H NMR
spectroscopy (>98% dr). c Isolated product after purification.
assigned based upon NOE measurements (entry 2). The degree
of stereoselectivity observed in the formation of 5 was also
significantly improved relative to that reported for related acyclic
dienophiles.4 Sensitive electron-rich oxygenated dienes 6 and
85 worked well (entries 3 and 4), each affording a single enone
diastereoisomer after hydrolysis/elimination. Even ethyl sorbate,
an electron-poor diene, afforded a moderate yield of the
expected cycloadduct 10 as a single regioisomer (entry 5). The
sensitive heterodiene 11 also reacted smoothly with the isoi-
midium salt 2 affording a single regioisomer (entry 6) to yield
enamide 12 in high yield (85%) after elimination of TBSOH.6
Heartened by the high regio- and stereoselectivity of the
cycloadditions of isoimidium salt 2, we then explored use
of a chiral isoimidium salt that could potentially provide
access to enantiomerically enriched products.
We then examined the reactivity of isoimidium salt 2 toward
dienes. Upon treatment with isoprene in CH3CN at 0 °C, we
were pleased to find rapid formation of a single cycloadduct 4
1
(>98% dr by H NMR) in high yield that was isolated after
methanolysis to the ester (eq 2). The structure of 4 confirmed
our expectation that the regioselectivity would be high and
dominated by the iminium moiety in 2. The observed high
selectivity can be contrasted with the related acyclic fumaric
and maleic acid derived amide-ester substrates, which have been
reported to give mixtures of regioisomers when reacted with
isoprene (∼5:1, ∼1:1 endo/exo).4
(3) (a) Saito, A.; Yanai, H.; Taguchi, T. Tetrahedron Lett. 2004, 45,
9439–9442. (b) Seebach, D.; Jaeschke, G.; Gottwald, K.; Matsuda, K.;
Formisano, R.; Chaplin, D. A.; Breuning, M.; Bringmann, G. Tetrahedron
1997, 53, 7539–7556.
(4) (a) Bienayme, H.; Longeau, A. Tetrahedron 1997, 53, 9637–9646.
(b) Beccalli, E. M.; Clerici, F.; Gelmi, M. L. Tetrahedron 1999, 55, 8579–
8586.
(5) (a) Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807–
7808. (b) Danishefsky, S.; Yan, C.-F.; Singh, R. K.; Gammill, R. B.;
McCurry, P. M.; Fritsch, N.; Clardy, J. J. Am. Chem. Soc. 1979, 101, 7001–
7008. (c) Danishefsky, S.; Chao, K. H.; Schulte, G. J. Org. Chem. 1985,
50, 4650–4652.
Initial results in hand, we explored the scope of the reaction
with a panel of dienes chosen to illustrate the pertinent features
of the reaction (Table 1). The endo selectivity was notably high
as demonstrated by reaction with 1,3-cyclohexadiene providing
5 as a single diastereomer whose relative stereochemistry was
(6) Sainte, F.; Serckx-Poncin, B.; Hesbain-Frisque, A.-M.; Ghosez, L.
J. Am. Chem. Soc. 1982, 104, 1428–1430.
Org. Lett., Vol. 12, No. 20, 2010
4525

(+)-Bis[(R)-1-phenylethyl]amine, which is both C2 sym-
metric and sterically demanding, was selected for our initial
studies owing to its commercial availability and relatively
low cost. Ring opening of maleic anhydride with (+)-bis[(R)-
1-phenylethyl]amine afforded chiral acid 13, followed by
treatment with acetic anhydride and tetrafluoroboric acid at
10 °C which provided the somewhat less stable chiral
isoimidium salt 14 (Scheme 2).
Table 3. Reactions of Cyclic Isoimidium Salt 14
Scheme 2. Formation of Chiral Cyclic Isoimidium Salt 14
Cycloaddition of isoimidium salt 14 was initially con-
ducted with isoprene at 0 °C in CH2Cl2 affording 15 (Table
2 entry 1); however, the observed diastereomeric ratio (dr)
a All reactions conducted in CH2Cl2 at -45 °C. b Based on isolated
c
1
yields after chromatography. Determined by H NMR spectroscopy.
(entries 3 and 4). Less stable, highly reactive dienes 6,3 11,
and 177 afforded no cycloadduct at -45 °C supporting this
conclusion.
Table 2. Temperature Effect on Cycloaddition of Cyclic
Isoimidium Salt 14 with Isoprene
X-ray crystallographic analysis of the Diels-Alder adducts
15 and 19 revealed both the relative and absolute stereochem-
istry of these adducts and defined the geometry of the most
favorable cycloaddition transition state (see Supporting Informa-
tion for crystallographic details). A combination of secondary
orbital interactions8 and differential nonbonded interactions
between the phenyl and methyl groups, in the transition state
arising from the conformation minimizing A1,2 strain, account
for the observed relative and absolute stereochemistry of 15
and 19. As depicted (Figure 1), phenyl groups in isoimidium
salt 14 block the bottom face of 14 leading to preferential top
face attack.
These results led us to consider modification of the chiral
auxiliary. We postulated that changing the reactive conformation
of the auxiliary would increase the differential stereofacially
defining steric interactions between the diene and dienophile
(phenyl vs hydrogen). We chose to examine the rigid chiral
isoimidium salt 20 that we expected would render the endo top
face approach even more favorable and provide significantly
improved diastereoselectivity.
entry
t (°C)
time (h)
yield (%)a
drb
1
2
3
4
5
0 °C
-30 °C
-45 °C
-60 °C
-78 °C
3
6
8
18
24
91
89
89
62
0
1:1
4:1
8:1
8:1
-
a Based on isolated yields after chromatography. Determined by H
NMR spectroscopy.
b
1
was minimal (∼1:1). Thus, we examined the effect of
temperature on diastereoselectivity (Table 2). As expected
when the cycloaddition was performed at lower temperatures,
the dr increased with decreasing temperature. The optimal
temperature proved to be ∼-45 °C, affording an 8:1 dr (entry
3). Further decrease in the reaction temperature to -60 °C
or below slowed significantly or stopped the reaction but
provided no further increase in dr (entries 4 and 5).
Isoimidium salt 20 was prepared in analogous fashion to
14 from maleic anhydride and the known chiral auxiliary
(2R,5R)-2,5-diphenylpyrrolidine in 60% overall yield (Scheme
2).9 Gratifyingly, cycloaddition reactions of isoimidium salt
20 at -45 °C afforded both excellent regioselectivity and
diastereoselectivity (Table 4).
Having optimized the temperature (-45 °C), we next ex-
plored the reaction scope of isoimidium salt 14 with a variety
of dienes (Table 3). Cycloadducts of isoprene and cyclohexa-
diene gave high yield and promising diastereoselectivity (entries
1 and 2). Danishefsky dienes 8 and 165 gave lower yields and
diastereoselectivity owing to the higher reactivity of these dienes
(7) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626–
9627.
(8) Arrieta, A.; Cossio, F. P.; Lecea, B. J. Org. Chem. 2001, 66, 6178–
6180.
4526
Org. Lett., Vol. 12, No. 20, 2010

to a variety of mild acidic, basic, and oxidative reaction con-
ditions.10 Cleavage of the amide alcohols derived from reduction
of amide esters 21-23, which was observed to occur under
strongly acidic conditions, must be rapid owing to competing
addition of the hydroxyl group to the proximal olefin affording
bicyclic ethers. Recently, Scheidt and co-workers reported
efficient cleavage of a similar hindered amide chiral auxiliary
without epimerization using HCl under microwave irradiation
at 150 °C.11 Accordingly, L-Selectride reduction of cycloadducts
21-23 to the corresponding alcohol, followed by microwave-
mediated ring closure, afforded the enantiomerically pure
lactones 24-26 in very good to excellent yields. Preparative
scale reactions can be conducted at 150 °C (preheated oil bath)
using a sealed tube (Scheme 3) in similar yields (unoptimized).
Figure 1. Endo top/bottom face approach for cycloaddition of
isoimidium salt 14 with a diene.
Scheme 3. Cleavage of the Chiral Auxiliary
Table 4. Reactions of Cyclic Isoimidium Salt 20
The foregoing studies demonstrate that isoimidium salts serve
as reactive dienophiles toward a variety of dienes. Chiral
analogues afford excellent regio- and diastereoselectivity pro-
viding a useful, reasonably general route to prepare differentially
functionalized, enantiomerically pure bicyclic γ-lactones while
permitting efficient recovery of the chiral amine auxiliary.
a All reactions conducted in CH2Cl2 at -45 °C. b Based on isolated
c
1
yields after chromatography. Determined by H NMR spectroscopy.
Acknowledgment. We are grateful for partial support of
these studies by the National Science Foundation and
Novartis Pharma AG.
Cycloaddition with isoprene and 1,3-cyclohexadiene provided
adducts 21 and 22 in high yield (90%) and excellent dr (>99:
1) (entries 1 and 2). It is especially noteworthy that excellent
endo selectivity is also observed in the formation of adduct 22,
whose stereochemistry was confirmed by X-ray crystallographic
analysis. Cycloaddition with Danishefsky dienes 8 and 163 also
proceeded cleanly to afford Diels-Alder adduct 23 in 56-65%
yields, again with >99:1 dr (entries 3 and 4).
Supporting Information Available: General experimental
procedures and characterization data for compounds 4, 5, 7,
9, 10, 12-15, and 18-26. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL101831B
Limitations in the scope of reactions of 20 with dienes
still exist. Less stable dienes 6 and 17 failed to undergo
Diels-Alder reaction under standard conditions, and less
reactive azadiene 11 required higher temperatures to effect
cycloaddition leading to low observed dr.
Cleavage of the hindered amide chiral auxiliary moiety
proved to be challenging since 21-23 are remarkably robust
(9) (a) Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1997, 119, 7165–
7166. (b) Taber, D F.; Gorski, G. J.; Liable-Sands, L. M.; Rheingold, A. L.
Tetrahedron Lett. 1997, 38, 6317–6318. (c) Chong, J. M.; Clarke, I. S.;
Koch, I.; Olbach, P. C.; Taylor, N. J. Tetrahedron: Asymmetry 1995, 6,
409–418.
(10) Spletstoser, J. T.; White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am.
Chem. Soc. 2007, 129, 3408–3419.
(11) Lettan, R. B., II; Woodward, C. C.; Scheidt, K. A. Angew. Chem.,
Int. Ed. 2008, 47, 2294–2297.
Org. Lett., Vol. 12, No. 20, 2010
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