First stereoselective inverse demand [4 + 2] cycloaddition reactions of novel chiral allenamides with heterodienes. Preparation of highly functionalized 2-arylpyranyl heterocycles

Article abstract of DOI:10.1021/ol990345q

matrix presented The first stereoselective inverse demand [4 + 2] cycloaddition reactions of chiral allenamides with heterodienes are described here. These reactions lead to stereoselective synthesis of highly functionalized pyranyl heterocycles. A mechan

Full text of DOI:10.1021/ol990345q

ORGANIC
LETTERS
1999
Vol. 1, No. 13
2145-2148
First Stereoselective Inverse Demand [4
+ 2] Cycloaddition Reactions of Novel
Chiral Allenamides with Heterodienes.
Preparation of Highly Functionalized
2-Arylpyranyl Heterocycles
Lin-Li Wei, Richard P. Hsung,* Hui Xiong, Jason A. Mulder, and
Nancy T. Nkansah†
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received November 1, 1999
ABSTRACT
The first stereoselective inverse demand [4 + 2] cycloaddition reactions of chiral allenamides with heterodienes are described here. These
reactions lead to stereoselective synthesis of highly functionalized pyranyl heterocycles. A mechanistic model is also proposed here based
on the stereochemical assignment and comparisons of stereoselectivities obtained from various chiral allenamides.
Allenes are among the most important building blocks in
organic synthesis, serving critical roles in a diverse array of
modern synthetic methods.1 However, an important subgroup
of allenes, allenamines, has received limited attention in
synthetic applications [Figure 1].1 This lack of attention could
hydrolysis. Because of our interest in developing methodolo-
gies for constructing heterocycles,2,3 we have been exploring
syntheses and reactivities of a new class of allenamines that
can present superior stability to the traditional allenamines
without compromising any reactivity.3a Specifically, they are
(1) For reviews, see: (a) Saalfrank, R. W.; Lurz, C. J. In Methoden Der
Organischen Chemie (Houben-Weyl); Kropf, H., Schaumann, E., Eds.;
Georg Thieme Verlag: Stuttgart, 1993; p 3093. (b) Schuster, H. E.; Coppola,
G. M. Allenes in Organic Synthesis; John Wiley and Sons: New York,
1984.
(2) (a) Hsung, R. P. J. Org. Chem. 1997, 62, 7904. (b) Hsung, R. P.
Heterocycles 1998, 48, 421. (c) Granum, K. G.; Merkel, G.; Mulder, J. A.;
Debbins, S. A.; Hsung, R. P. Tetrahedron Lett. 1998, 9597. (d) Hsung, R.
P.; Shen, H. C.; Douglas, C. J.; Morgan, C. D.; Degen, S. J.; Yao, L. J. J.
Org. Chem. 1999, 64, 690. (e) Degen, S. J.; Mueller, K. L.; Shen, H. C.;
Mulder, J. A.; Golding, G. M.; Wei, L.-L.; Zificsak, C. A.; Hsung, R. P.
Bioorg. Med. Chem. Lett. 1999, 973. (f) Hsung, R. P.; Wei, L.-L.; Sklenicka,
H. M.; Douglas, C. J.; McLaughlin, M. J.; Mulder, J. A.; Yao, L. J. Org.
Lett. 1999, 1, 509. (g) Douglas C. J.; Sklenicka, H.; Shen, H. C.; Golding,
G. M.; Mathias, D. S.; Degen, S. J.; Morgan, C. D.; Shih, R. A.; Mueller,
K. L.; Seurer, L. M.; Johnson, E. W.; Hsung, R. P. Tetrahedron 1999, 55,
13683. (h) Hsung, R. P.; Zificsak, C.; Wei, L.-L.; Zehnder, L.; Park, F.;
Kim, M.; Tran, M. J. Org. Chem. 1999, 64, 8736.
Figure 1.
be attributed to the difficulty in preparation and handling of
allenamines due to their high reactivity and sensitivity toward
(3) (a) Wei, L.-L.; Xiong, H.; Douglas, C. J.; Hsung, R. P. Tetrahedron
Lett. 1999, 6903. (b) Hsung, R. P.; Zificsak, C. A.; Wei, L.-L.; Douglas,
C. J.; Xiong, H.; Mulder, J. A. Org. Lett. 1999, 1, 1237.
† 1999 NSF-REU Summer Undergraduate Research Participant from
Florida A & M University.
10.1021/ol990345q CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/04/1999

allenamides in which the nitrogen atom contains electron-
withdrawing groups. Our design of allenamides would feature
either an imidazolidinone or oxazolidinone moiety, thereby
providing a practical entry that could lead to chiral allena-
mides [Figure 1]. While allenamines are the least studied
among heteroatom-substituted allenes, studies of allenamides
are even more rare.1 Since their first preparations4,5 20-30
years ago, the most common electron deficient allenamines
are those in which the nitrogen atom is part of a heteroaro-
matic system prepared for medicinal purposes.6,7 Some
examples of palladium-catalyzed cross-couplings,8 cycliza-
tions,9 and [2 + 2] cycloaddition reactions10 using electron
deficient allenamines have been reported. We recently
reported synthesis of various new allenamides and explored
their synthetic potential.3a We report here the first examples
of stereoselective inverse demand [4 + 2] cycloaddition
reactions of chiral allenamides with heterodienes.
using NaH and propargyl bromide. Freshly prepared t-BuOK
was used to induce the isomerization in anhydrous THF at
room temperature, leading to the desired chiral allenamides
1-5 in greater than 90% yields.14 Chiral allenamides 1-515
may be obtained in gram quantities as crystalline solids that
can be handled with ease. Purification of these chiral
allenamides simply involved filtration through Celite or
alumina.
Having prepared these chiral allenamides, we proceeded
to examine their reactivity as well as level of stereoinduction
in inverse demand [4 + 2] cycloaddition reactions with
heterodienes. Chiral allenamide 1 containing the imidazoli-
dinone group was found to be reactive toward a diverse array
of heterodienes. The results are summarized in Table 1. Most
of these reactions were carried out at 80 °C leading to pyranyl
heterocycles 6, 7, and 17-2515 in good yields as well as
high enantioselectivities. The more polar CH3CN appears
to be a better solvent than 1,2-dicholorethane given the
reaction time [entries 1-4]. This suggests a stepwise
sequence involving ionic intermediates for the cyclo-
addition.3a,16 The aryl vinyl ketones 9-14 were more reactive
[entries 5-11] than acrolein [entries 1 and 2], methyl vinyl
ketone [entries 3 and 4], and other alkyl vinyl ketones [entries
12 and 13] as indicated by the overall shorter reaction
durations and superior yields. These aryl ketones led to
preparations of an array of highly functionalized 2-aryl-
pyranyl heterocycles 18-23. Heterodienes 8 and 12 appeared
to be the most reactive toward 1 [entries 5 and 9], while the
heterodiene 15 appears to be the least reactive.
The chiral allenamides could be readily prepared using a
base-induced isomerization. As shown in Scheme 1, a variety
Scheme 1
Reactions of chiral allenamide 1 with alkyl and aryl vinyl
ketones also appear to provide the best stereoselectivity, and
for heterodienes 12 and 13, only one isomer was observed
[Table 1, entries 9 and 10]. The stereochemistry was assigned
by X-ray diffraction of a single crystal of pyran 24, and a
consistent 1H NMR correlation allowed stereochemical
assignment of all other cycloadducts.17 The X-ray crystal
structure also indicates that the chiral imidazolidinoe group
is in the pseudoaxial position.
Control experiments showed that these stereochemical
ratios are not affected by the reaction conditions. When pyran
23 containing the enriched minor isomer [an 18:82 ratio of
major:minor] was heated at 80 °C in CD3CN and monitored
of chiral allenamides were obtained in high yields over two
steps starting from Close’s chiral imidazolidinone [leading
to 1],11 Evans’ oxazolidinone auxiliaries [leading to 2-4],12
or Sibi’s dibenzylidene-substituted oxazolidinone [leading
to 5].13 Propargylations were carried out in quantitative yields
1
by H NMR for 12 h, the integrity of the initial diastereo-
meric ratio was not eroded and the final ratio was 13:87
[major:minor] without apparent loss of material. It is
noteworthy that allenamide 1 is more stable than any existing
allenamine because allenamines tend to polymerize at the
temperature at which these reactions were carried out.1a
(4) Dickinson, W. B.; Lang, P. C. Tetrahedron Lett. 1967, 3035.
(5) Overman, L. E.; Marlowe, C. K.; Clizbe, L. A. Tetrahedron Lett.
1979, 599.
(6) (a) Ra´dl, S.; Kova´rova´, L. Collect. Czech. Chem. Commun. 1991,
56, 2413. (b) Reisch, J.; Salehi- Artimani, R. A. J. Heterocycl. Chem. 1989,
26, 1803.
(7) Jones, B. C. N. M.; Silverton, J. V.; Simons, C.; Megati, S.;
Nishimura, H.; Maeda, Y.; Mitsuya, H.; Zemlicka, J. J. Med. Chem. 1995,
38, 1397.
(13) Sibi’s dibenzylidene-substituted oxazolidinone can be purchased
from Aldrich. For synthesis, see: (a) Sibi, M. P.; Deshpande, P. K.; Ji, J.
G. Tetrahedron Lett. 1995, 8965. (b) Sibi, M. P.; Ji, J. G. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 190. (c) Sibi, M. P.; Porter, N. A. Acc. Chem. Res.
1999, 32, 163.
(8) Gardiner, M.; Grigg, R.; Sridharan, V.; Vicker, N. Tetrahedron Lett.
1998, 435, and references cited therein.
(9) (a) Noguchi, M.; Okada, H.; Wantanabe, M.; Okuda, K.; Nakamura,
O. Tetrahedron 1996, 52, 6851. (b) Farina, V.; Kant, J. Tetrahedron Lett.
1992, 3559 and 3563.
(10) Kimura, M.; Horino, Y.; Wakamiya, Y.; Okajima, T.; Tamaru, Y.
J. Am. Chem. Soc. 1997, 119, 9, 10869 and references therein.
(11) Close, W. J. J. Org. Chem. 1950, 15, 1131.
(14) For another example of this isomerization method, see: Pourcelot,
G.; Cadiot, P.; Georgoulis, C. Tetrahedron 1982, 38, 2123.
(15) All new compounds were identified and characterized by 1H NMR,
13C NMR, FTIR, [R]20D, and MS.
(16) Klop, W.; Klusener, P. A. A.; Brandsma, L. Recl. J. R. Neth. Chem.
Soc. 1984, 103, 85.
(17) For all cycloadducts, chemical shifts of the anomeric proton for
major isomers are consistently 0.18-0.40 ppm higher than those from minor
isomers.
(12) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77.
2146
Org. Lett., Vol. 1, No. 13, 1999

Table 1. Reactions of the Chiral Allenamide 1 with
Table 2. Reactions of Chiral Allenamides 2-5 with Acrolein
Heterodienes
and MVK
auxiliary with acrolein [entry 6]. Although these cyclo-
addition reactions of chiral allenamides 2-5 provided lower
stereoselectivity as well as yields than those of 1, and
although we are currently improving these reactions using
other conditions, it is more important to note that these chiral
allenamdies should be useful for other organic transforma-
tions given their ability to withstand higher temperature and
Lewis acidic conditions.
Given the stereochemical assignment and contrast in the
stereochemical outcome between reactions of 1 and those
of 2-5, we obtained minimized structures of chiral allena-
mides 1 and 2 using the Spartan Program [AM1 Calculation].
As shown in Figure 2, the allene fragment is essentially
coplanar with the imidazolidinone or oxazolidinone ring as
indicated by dihedral angles for OdCNCdC. In addition,
our calculations showed no significant difference in the
rotational barriers of 1-5.
These models suggest that the observed diastereoselectivity
is likely due to a preferred addition of heterodienes from
the bottom (less crowded) face of all allenamides leading to
the major isomer with correct stereochemistry. The phenyl
group in allenamide 1, which contains an imidazolidinone
moiety, appears to be the closest to the allene fragment,
thereby providing the best steric presence and leading to the
highest diastereoselectivity. The phenyl group in 2, which
contains an oxazolidinone moiety, actually tilts away from
the allene moiety, thereby diminishing a significant amount
However, at the same time 1 remains reactive in these
cycloaddition reactions.
We then examined reactions using chiral allenamides 2-5
which contain oxazolidinone groups. Reactions of these
allenamides with acrolein and/or MVK are summarized in
Table 2. There are two significant features that are note-
worthy from this study. First, chiral allenamides 2-5 are
more thermally stable than 1 since the allenamide 1 did not
survive temperatures above 100 °C. Thus, they are easier to
handle experimentally than 1. Allenamide 5 containing Sibi’s
auxiliary appears to be the most robust chiral allenamide,
providing cycloadduct 32 in 53% yield after heating at 120
°C for 48 h [entry 7]. Second, these oxazolidinone-substituted
chiral allenamides can tolerate Lewis acidic conditions as
indicated by ZnCl2-catalyzed reaction of 4 containing Evans’
Org. Lett., Vol. 1, No. 13, 1999
2147

Figure 3.
We have described here the synthesis of a novel class of
chiral allenamides and their stability as well as uncompro-
mising reactivity as electron rich dienophiles in stereoselec-
tive inverse demand [4 + 2] cycloaddition reactions with
heterodienes. We are currently exploring transformations
involving these cycloadducts for preparations of unique
C-aryl glycosides and natural products containing these
pyranyl structural features. We are also investigating other
synthetic methods using these chiral allenamides.
Figure 2. Minimized structures of chiral allenamides 1 and 2.
of facial steric bias. The difference in stereoselectivity
between chiral allenamides of 1 and 2-5 may also be
attributed to the electronic difference between imidazolidi-
none and oxazolidinone. However, that is not as clear at this
point and further mechanistic studies are being carried out.
Finally, we have attempted to demonstrate that these
2-arylpyranyl heterocycles 18-23 can be useful templates
for further synthetic elaborations. Toward this purpose, we
hydrogenated compound 23 and were able to obtain mono-
hydrogenated and dihydrogenated products 33 and 34 in 50-
80% yields [Figure 3]. The extent of hydrogenations may
be controlled by using either Lindlar’s catalyst or appropriate
amounts of 5% Pd-C or Pt-C. More significantly, dihy-
dropyran 33 was essentially obtained as a single isomer,
while a diastereomeric ratio ranging from 87:13 to g96:4
was observed at the anomeric carbon of 34 [stereochemistry
in 33 and 34 was assigned by NOE].
Acknowledgment. The authors thank University of
Minnesota for financial support in the form of Start-up Funds
and Grant-in-Aid of Research, Artistry and Scholarship
(CUFS#: 1003-519-5984). R.P.H. thanks the American
Cancer Society for an institutional grant (IRG-58-001-40-
IRG-26). R.P.H. also thanks R. W. Johnson Pharmaceutical
Institutes for a generous grant from the Focused Giving
Program. N.T.N. thanks UMN Chemistry Department and
NSF for an NSF-Lando Summer Undergraduate Research
Fellowship. The authors also thank Drs. Victor Young and
Maren Pink for solving the X-ray structure.
Supporting Information Available: Experimental pro-
1
cedures and H NMR spectral and characterization data for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL990345Q
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