Stereoselective Intramolecular [4 + 3] Cycloadditions of Nitrogen-Stabilized Chiral Oxyallyl Cations via Epoxidation of N-Tethered Allenamides

Article abstract of DOI:10.1021/ja030416n

The first intramolecular [4 + 3] cycloaddition reaction using nitrogen-stabilized chiral oxyallyl cations that are tethered to furan or diene through the nitrogen atom is described here. Formation of these nitrogen-stabilized chiral oxyallyl cations is ac

Full text of DOI:10.1021/ja030416n

Published on Web 09/27/2003
Stereoselective Intramolecular [4 + 3] Cycloadditions of Nitrogen-Stabilized
Chiral Oxyallyl Cations via Epoxidation of N-Tethered Allenamides
Hui Xiong, Jian Huang, Sunil K. Ghosh, and Richard P. Hsung*
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
Received July 9, 2003; E-mail: hsung@chem.umn.edu
Scheme 1
Heteroatom-substituted oxyallyl cations have become the focus
in developing highly regio- and stereoselective [4 + 3] cycloaddi-
tions.1,2 While elegant advances have been made using oxygen-,3
sulfur-,4 and halogen-substituted5 oxyallyl cations, nitrogen-
substituted oxyallyl cations have received much less attention.6-8
As part of our ongoing efforts to develop stereoselective methods
using chiral allenamides,9 we recently discovered that epoxidation
of allenamides 1 can provide a facile entry to nitrogen-stabilized
chiral oxyallyl cations 2b that can undergo subsequent [4 + 3]
cycloadditions with dienes in a highly stereoselective manner
(Scheme 1).10 The trivalent nature of the nitrogen atom allows
simultaneous tethering of a chiral auxiliary (R*) and a coordination
Scheme 2
unit (W), thereby providing greater rigidity in the oxyallyl cation
and presenting a unique opportunity to achieve highly stereoselec-
tive [4 + 3] oxyallyl cycloadditions, which remains a challenge in
this field.1-4,8,11 We have been exploring intramolecular variants
of our [4 + 3] cycloaddition12 via two approaches: I, N-tethered
4 f 5, and II, C-tethered 6 f 7 (Scheme 1).10b We elected to
focus on approach I because it accentuates a distinct advantage of
using nitrogen-stabilized oxyallyl cations: the ability to construct
complex nitrogen heterocycles. We report here the first intramo-
lecular [4 + 3] cycloadditions using nitrogen-stabilized chiral
oxyallyl cations via epoxidation of N-tethered allenamides.
To establish the feasibility, we assembled simple acyclic alle-
namides 9a and 9b with furan attached through a three-carbon tether
in three steps from iodide 813 (Scheme 2). It was quickly found
a diene also underwent epoxidation-cycloaddition to afford the
that the epoxidation by simply adding 2-5 equiv of dimethyl
dioxirane (DMDO) at -45 °C employed in earlier intermolecular
reactions10 was not useful and gave 10a/b in very low yields.
Oxidative ring opening of the furan was the major product.
The critical turning point in our efforts was the recognition that
an excess of diene used (∼10 equiv) in intermolecular reactions
might have absorbed any losses from the competing oxidation of
the diene. In the current reactions, it is not possible to increase the
loading of the furan. Thus, to slow this competing process, we
turned to syringe pump addition of DMDO at -45 °C and found
that the epoxidation became very selective for the allenic double
bond in 11 and 12. The ensuing intramolecular [4 + 3] cycload-
dition of the corresponding oxyallyl cations with furan led to desired
cycloadducts 13 and 14 in 80% and 75% yields, respectively, as
single diastereomers. The stereochemistry of 13 was assigned via
X-ray. An epoxidized cycloadduct 15 was isolated in 14% yield
from the reaction of 11.14
Table 1 summarizes the scope and stereoselectivity of this
intramolecular [4 + 3] cycloaddition of nitrogen-stabilized oxyallyl
cations. To improve cycloadditions of 9a or 9b, syringe pump
addition of DMDO (method A) was examined specifically using
9b (entries 1 and 2). As a result, the yield could be improved, but
only to 20% (entry 1), or a modest 47% if ZnCl2 was added (entry
2). However, the stereoselectivity dropped significantly even in the
presence of 1-2 equiv of ZnCl2 in contrast to findings from
intermolecular reactions.10 In addition, allenamide 16 tethered with
desired cycloadduct 17 in 65% yield with loss of selectivity (entry
3).
We then examined cyclic oxazolidinone-substituted allenamides
18 and 19 in detail (entries 5-9). Both methods A and B (normal
cannulation of DMDO) were applicable for cycloadditions of 18,
leading to cycloadduct 20 in high yields and diastereoselectivities
(entries 4-6). The reaction was also effective even at room
temperature (entry 5). Allenamide 19 (entries 7 and 8) led to 21 in
good yield and with a high ratio also using method B. The X-ray
structure of the hydrogenated 21 gives the basis for stereochemical
assignment in entries 4-16. We are currently examining why certain
systems really required the syringe pump addition protocol, while
some do not.
In contrast to acyclic allenamides, cycloadditions were quite
suitable for cyclic allenamides with longer tethers. In addition to
the success of using 19, reactions of allenamides 22 and 23 (entries
9-11) provided the respective cycloadducts 24 and 25 in good
yields and good selectivity for 22 (entry 10). Both reactions were
best carried out at room temperature using method A (entries 10
and 11),15 although the stereoselectivity was lower for the reaction
of 23 (entry 11). These reactions represent the longest tethers used
for an intramolecular [4 + 3] oxyallyl cycloaddition,1,2,12 leading
to cycloadducts containing a seven- or eight-membered ring fused
to the cycloheptane resulting from the cycloaddition.
Lactam-substituted allenamides 26 and 27 were also examined.
In the case of 26, both methods A and B were useful with the latter
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10.1021/ja030416n CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 1
of 20 or 21. It is noteworthy that the observed high diastereose-
lectivity implies that it is selective for one out of eight possible
transition states. Moreover, with a longer carbon tether (see
allenamides 23 and 27), the corresponding oxyallyl cation species
would possess less rigidity, thereby eroding stereoselectivity by
allowing the endo addition pathway.
We have described here novel intramolecular [4 + 3] cycload-
ditions using nitrogen-stabilized chiral oxyallyl cations via epoxi-
dation of N-tethered allenamides. Efforts in the total synthesis of
natural alkaloids via this cycloaddition are currently underway.
Acknowledgment. The authors thank the NSF (CHE-0094005)
for support, and Dr. Victor Young and Bill Brennessel for X-ray
analysis. R.P.H. is a recipient of 2001-2003 Camille Dreyfus
Teacher-Scholar and UMN McKnight Faculty Award.
Supporting Information Available: Experimental procedures as
well as 1H/13C NMR spectra and characterization data for all new
compounds (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
References
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a Preparations of allenamides are in the Supporting Information. All
reactions were carried out in CH2Cl2 [concentration: 0.025 M] at -45 °C.
b Method A: 2-5 equiv of DMDO was added as a solution in acetone/
CH2Cl2 at -78 °C via a syringe pump. Method B: 2-5 equiv of DMDO
was cannulated. c Isolated yields. d Ratios determined by 1H and 13C NMR.
e 1.0 or 2.0 equiv of ZnCl2 was added as a solution in ether. f Allenamides
19, 23, 26-27, and 30 are optically enriched with C5, with all except 30
being R. g X-ray structure of hydrogenated 21 was obtained.
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Figure 1.
method actually providing better selectivity (entries 12 and 13).
The stereoselectivity again dropped with a longer tether (27), and
the reaction also needed a higher temperature (entry 14).
Finally, dienes also worked well as reaction of allenamide 30
provided 31 in good yields, although in lower selectivity (entries
15 and 16). It is also noteworthy that in all cases where the isomeric
ratios are low (17, 25, 29, and 31), major and minor isomers can
be readily separated.
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A working model was proposed on the basis of stereochemical
assignments (Figure 1). Although two possible approaches, 32-endo
and 32-exo, could both afford the same major isomer of 13 or 14,
the oxyallyl cation 32-endo should experience more A1,3 strain,
whereas 32-exo possesses a more preferred W-conformation.1,2
Thus, approach I to intramolecular [4 + 3] cycloaddition of
nitrogen-stabilized oxyallyl cations likely proceeds in an exo
manner. This current model with both oxygen atoms being
unaligned is also based on the observation that the chelating Zn
cation bears no effect on the stereochemical outcome, unlike those
observed in intermolecular reactions.10
(12) For excellent reviews see: (a) Harmata, M. Acc. Chem. Res. 2001, 34,
595. (b) Harmata, M. Tetrahedron 1997, 53, 6235.
(13) All new compounds were identified and characterized by 1H NMR, 13C
NMR, FTIR, [R]20D, and MS.
(14) This is the first time we observed such epoxidation of [4 + 3] cycloadducts
in the presence of DMDO. The major isomer is shown as drawn with its
stereochemistry being assigned via nOe.
(15) Method B was not useful in these cases even with the reaction being run
at a concentration of 0.0023 M and using g10 equiv of DMDO.
For chiral oxyallyl species 33, a W-conformation and a similar
exo approach would also lead to the observed major diastereomer
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