NMR studies on epoxidations of allenamides. Evidence for formation of nitrogen-substituted allene oxide and spiro-epoxide via trapping experiments

Article abstract of DOI:10.1021/jo011048d

Two epoxidations of chiral allenamides are described here. While treatment with m-CPBA led to highly stereoselective formation of an α-keto aminal that can be useful synthetically, DMDO oxidation led to conclusive evidence for both nitrogen-substituted allene oxide (via mono-epoxidation) and spiro-epoxide (via bis-epoxidation) using intramolecular nucleophilic trapping experiments. NMR studies provide reliable evidence for a 3-oxetanone that can be derived from the spiro-epoxide and also suggest the presence of an allene oxide. Despite a facile second epoxidation as evidenced by the predominant formation of the 3-oxetanone, in the presence of furan, [4 + 3] cycloaddition of the nitrogen-substituted allene oxide or oxyallyl cation with furan occurs faster than the second epoxidation efficiently leading to cycloadducts. This rate difference plays an invaluable role for the success of a stereoselective sequential epoxidation-[4 + 3] cycloaddition reaction via DMDO epoxidations of chiral allenamides.

Full text of DOI:10.1021/jo011048d

J . Org. Chem. 2002, 67, 1339-1345
1339
NMR Stu d ies on Ep oxid a tion s of Allen a m id es. Evid en ce for
F or m a tion of Nitr ogen -Su bstitu ted Allen e Oxid e a n d
Sp ir o-Ep oxid e via Tr a p p in g Exp er im en ts†
C. Rameshkumar, Hui Xiong, Michael R. Tracey, Craig R. Berry, Letitia J . Yao,1 and
Richard P. Hsung*,2
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received November 2, 2001
Two epoxidations of chiral allenamides are described here. While treatment with m-CPBA led to
highly stereoselective formation of an R-keto aminal that can be useful synthetically, DMDO
oxidation led to conclusive evidence for both nitrogen-substituted allene oxide (via mono-epoxidation)
and spiro-epoxide (via bis-epoxidation) using intramolecular nucleophilic trapping experiments.
NMR studies provide reliable evidence for a 3-oxetanone that can be derived from the spiro-epoxide
and also suggest the presence of an allene oxide. Despite a facile second epoxidation as evidenced
by the predominant formation of the 3-oxetanone, in the presence of furan, [4 + 3] cycloaddition of
the nitrogen-substituted allene oxide or oxyallyl cation with furan occurs faster than the second
epoxidation efficiently leading to cycloadducts. This rate difference plays an invaluable role for the
success of a stereoselective sequential epoxidation-[4 + 3] cycloaddition reaction via DMDO
epoxidations of chiral allenamides.
In tr od u ction
epoxidize and sequentially utilize the epoxidized inter-
mediates in situ as nitrogen-stabilized oxyallyl cation
equivalents in highly stereoselective [4 + 3] cycloaddi-
tions (Scheme 1).11 The versatility of oxyallyl cations,
especially of those that are heteroatom-substituted, in
1,3-dipolar cycloadditions has attracted much attention
from the synthetic community.12-16 Our study represents
the first attempt at generating heteroatom-substituted
oxyallyl cations by epoxidizing heteroatom-substituted
Epoxidations of allenes provide reactive intermediates
that can be useful in organic synthesis.3,4 Synthetic
applications of heteroatom-substituted allene oxides
derived from epoxidations of allenol ethers have been
revealed recently.5,6 Epoxidation of nitrogen-substituted
allenes such as allenamines, however, remained un-
known.3 Our interest in the synthesis7 and reactivity8 of
chiral allenamides such as 1, a superior equivalent of
traditional allenamines,3,9-10 has led us to successfully
(9) Electron deficient allenamines or allenamides are superior
because of their improved stability without compromising any reactiv-
ity. Although their preparations occurred 20-30 years ago, their
reactivities have been uncovered only recently. For their first prepara-
tions, see: (a) Dickinson, W. B.; Lang, P. C. Tetrahedron Lett. 1967,
3035. (b) Overman, L. E.; Marlowe, C. K.; Clizbe, L. A. Tetrahedron
Lett. 1979, 599. (c) Ra´dl, S.; Kova´rova´, L. Collect. Czech. Chem.
Commun. 1991, 56, 2413. (d) Reisch, J .; Salehi-Artimani, R. A. J .
Heterocycl. Chem. 1989, 26, 1803. (e) J ones, 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.
(10) For examples of palladium catalyzed cross-couplings, see: (a)
Gardiner, M.; Grigg, R.; Sridharan, V.; Vicker, N. Tetrahedron Lett.
1998, 435, and references therein. For cyclizations, see: (b) Noguchi,
M.; Okada, H.; Wantanabe, M.; Okuda, K.; Nakamura, O. Tetrahedron
1996, 52, 6581. (c) Farina, V.; Kant, J . Tetrahedron Lett. 1992, 3559
and 3563. For [2 + 2] cycloaddition reactions, see: (d) Kimura, M.;
Horino, Y.; Wakamiya, Y.; Okajima, T.; Tamaru, Y. J . Am. Chem. Soc.
1997, 119, 10869, and references therein.
† With the deepest appreciation and respect, this paper is dedicated
to Professor Gilbert Stork on the occasion of his 80th birthday.
(1) NMR Research Associate, Department of Chemistry. The author
of correspondence for NMR studies.
(2) A recipient of 2001 Camille Dreyfus Teacher-Scholar Award.
(3) For reviews on allenes see: (a) Saalfrank, R. W.; Lurz, C. J . In
Methoden Der Organischen Chemie (Houben-Weyl); Kropf, H., Schau-
mann, E., Eds.; Georg Thieme Verlag: Stuttgart, 1993; p 3093. (b)
Schuster, H. E.; Coppola, G. M. Allenes in Organic Synthesis; J ohn
Wiley and Sons: New York, 1984. For a review on chemistry of allene
oxide, see: (c) Chan, T. H.; Ong, B. S. Tetrahedron 1980, 36, 2269.
(4) For recent examples of allene oxide chemistry, see: (a) Santelli-
Rouvier, C.; Lefre`re, S.; Santelli, M. Tetrahedron Lett. 1999, 40, 5491.
(b) Crandall, J . K.; Rambo, E. Tetrahedron Lett. 1994, 35, 1489. (c)
Crandall, J . K.; Reix, T. Tetrahedron Lett. 1994, 35, 2513. (d) Erden,
I.; Xu, F.-P.; Drummond, J .; Alstad, R. J . Org. Chem. 1993, 58, 3611.
(e) Crandall, J . K.; Batal, D. J .; Lin, F.; Reix, T.; Nadol, G. S.; Ng, R.
A. Tetrahedron 1992, 48, 1427. (f) Crandall, J . K.; Rambo, E. J . Org.
Chem. 1990, 55, 5929. (g) Kim, S. J .; Cha, J . K. Tetrahedron Lett. 1988,
29, 5613.
(5) For the first epoxidation of allenol ether, see: Reich, H. J .; Kelly,
M. J . J . Am. Chem. Soc. 1982, 104, 1119.
(6) For a recent application using epoxidized allenol ethers, see:
Hayakawa, R.; Shimizu, M. Org. Lett. 2000, 2, 4079.
(7) Wei, L.-L.; Mulder, J . A.; Xiong, H.; Zificsak, C. A.; Douglas, C.
J .; Hsung, R. P. Tetrahedron 2001, 57, 459.
(8) (a) Xiong, H.; Hsung, R. P.; Wei, L.-L.; Berry, C. R.; Mulder, J .
A.; Stockwell, B. Org. Lett. 2000, 2, 2869. (b) Wei, L.-L.; Hsung, R. P.;
Xiong, H.; Mulder, J . A.; Nkansah, N. T. Org. Lett. 1999, 1, 2145. (c)
Hsung, R. P.; Zificsak, C. A.; Wei, L.-L.; Douglas, C. J .; Xiong, H.;
Mulder, J . A. Org. Lett. 1999, 1, 1237. (d) Wei, L.-L.; Xiong, H.; Douglas,
C. J .; Hsung, R. P. Tetrahedron Lett. 1999, 40, 6903.
(11) Xiong, H.; Hsung, R. P.; Berry, C. R.; Rameshkumar, C. J . Am.
Chem. Soc. 2001, 123, 7174.
(12) For reviews on oxyallyl and [4 + 3] cycloaddition reactions,
see: (a) Harmata, M. Acc. Chem. Res. 2001, 34, 595. (b) Harmata, M.
In Advances in Cycloaddition; Lautens, M., Ed.; J AI: Greenwich, CT,
1997; Vol. 4, pp 41-86. (c) West, F. G. In Advances in Cycloaddition;
Lautens, M., Ed.; J AI: Greenwich, CT, 1997; Vol. 4, pp 1-40. (d) Rigby,
J . H.; Pigge, F. C. Org. React. 1997, 51, pp 351-478. (e) Harmata, M.
Tetrahedron 1997, 53, 6235. (f) Hosomi, A.; Tominaga, Y. In Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 5, Chapter 5.1, pp 593-615. (g) Padwa, A.;
Schoffstall, A. In Advances in Cycloaddition; Curran, D. P., Ed.; J AI
Press: Greenwich, CT, 1990; 2, pp 1-89.
(13) For a recent review on heteroatom-stabilized oxyallyl cations
in [4 + 3] cycloaddition reactions, see: Harmata, M. Recent Res. Devel.
Org. Chem. 1997, 1, 523-535.
10.1021/jo011048d CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/31/2002

1340 J . Org. Chem., Vol. 67, No. 4, 2002
Rameshkumar et al.
Sch em e 1
isomer with an isomeric ratio of 90:10 in the presence of
basic alumina at room temperature. However, it is not
clear at this point why 6-R is the thermodynamically
favored isomer.
The same epoxidation reaction of 5 was subsequently
carried out in CD2Cl2 and monitored by 1H NMR. As
shown in Figure 1, the epoxidation of 5 was very slow at
temperatures below -40 °C with no noticeable new
intermediates. However, at -25 °C, the epoxidation
occurred steadily leading to the R-keto aminal 6-S as the
only product, with no other observable intermediates
through the course of the reaction. This study suggests
that at the given NMR time scale, m-CPBA epoxidation
of allenamides does not provide a discrete allene oxide
intermediate such as 2 (see Scheme 1) or other related
intermediates. It also implies that the epoxy intermediate
could ring-open in situ quickly, affording no observable
or appreciable build-up of epoxidized allene intermedi-
ates.
Sch em e 2
To verify that this ring-opening is a fast process, the
allenamide 7 was prepared8a,18 to generate the allenamide
8 (Scheme 3) tethered with the alcohol functionality for
setting up an intramolecular trapping experiment as was
used by Crandall.4 However, it was quickly found that
the allenamide 8 was not very stable, especially under
acidic conditions, and thus, the allenamide 8 is poten-
tially incompatible with the m-CPBA conditions. Removal
of the TBS group in 7 could be carried out carefully at
low temperatures but gave 8 only in a 40-50% modest
yield. However, attempts to purify 8 using silica gel led
us to identify the furan 10 as an inseparable minor
component on numerous occasions.
The furan 10 is likely derived from 5-exo addition of
the hydroxyl group to the R,â-unsaturated N-acyl imin-
ium intermediate 9 via protonation of 8. A relatively
clean sample of 8, upon standing in CH2Cl2 at 0 °C in
the presence of a small amount of silica gel, quickly
decomposed to the furan 10 in 56% yield with an isomeric
ratio of 4:1. Stereochemistry of the major isomer 10a can
be assigned as shown in Scheme 3 based on 1H NMR
correlation with an analogous pyran example that was
assigned by NOE experiments (see 27 in Scheme 7).
Using a catalytic amount of pyridinium p-tolylsulfonic
acid (PPTS) at room-temperature enhanced the reaction
rate but provided the furan 10 in only 25% yield with an
identical isomeric ratio. Initial attempts to epoxidize a
relatively pure sample of allenamide 8 using various
conditions led to the isolation of the furan 10 instead.
In contrast, the allenamide 11, containing one extra
carbon in the tether that was prepared in a similar
manner8a,18 was found to be much more stable than 8
under acidic conditions. Upon subjecting 11 to the same
m-CPBA epoxidation conditions described above for 5, the
R-keto aminal 12 was the only product isolated in 58%
yield as a single diastereomer (stereochemistry assigned
based on analogy with the R-keto aminal 6-S).
As shown in Scheme 4, pyranyl heterocycles 15 and
16 represent potential products from intramolecular
nucleophilic trapping of the mono-epoxidized allene 13
(or allene oxide) and the bis-epoxidized allene 14 (or
spiro-epoxide), respectively. However, neither 15 nor 16
were observed in the m-CPBA epoxidation of the allen-
amide 11, although Crandall has elegantly demonstrated
allenes, thereby providing a general entry to novel
nitrogen-substituted oxyallyl cations. Given its synthetic
significance, we pursued spectroscopic studies of this new
epoxidation reaction in an attempt to identify relevant
intermediates. We report here our NMR investigations
of epoxidations of allenamides and experimental evidence
for formation of nitrogen-substituted mono-epoxidized
and bis-epoxidized allenic intermediates.
Resu lts a n d Discu ssion .
1. m -CP BA Ep oxid a tion . Two major epoxidation
protocols were investigated. As shown in Scheme 2,
epoxidation of the allenamide 5 using 2.0 equiv of
m-CPBA under a buffered environment led to the forma-
tion of the R-keto aminal 617 almost quantitatively. A
diastereoselectivity of 91:9 was observed by 1H NMR, and
stereochemistry of the major isomer was unambiguously
assigned as 6-S by X-ray structural analysis.18 The
selectivity for the 6-S isomer was believed to be kinetic
because the 6-S isomer readily epimerized to the 6-R
(14) (a) Lee, K.; Cha, J . K. Org. Lett. 1999, 1, 523. (b) Lee, J . C.;
J in, S.-J .; Cha, J . K. J . Org. Chem. 1998, 63, 2804. (c) Masuya, K.;
Domon, K.; Tanino, K.; Kuwajima, I. J . Am. Chem. Soc. 1998, 120,
1724. (d) Harmata, M.; J ones, D. E. J . Org. Chem. 1997, 62, 1578. (e)
Harmata, M.; Elomari, S.; Barnes, C. J . J . Am. Chem. Soc. 1996, 118,
2860, and references cited within. (f) Hardinger, S. A.; Bayne, C.;
Kantorowski, E.; McClellan, R.; Larres, L.; Nuesse, M.-A. J . Org. Chem.
1995, 60, 1104. (g) Harmata, M.; Fletcher, V.; Claassen, R. J . J . Am.
Chem. Soc. 1991, 113, 9861. (h) Murray, D. H.; Albizati, K. Tetrahedron
Lett. 1990, 31, 4109. (i) Fo¨hlisch, B.; Krimmer, D.; Gehrlach, E.;
Kashammer, D. Chem. Ber. 1988, 121, 1585.
(15) (a) Katritzky, A. R.; Dennis, N. Chem. Rev. 1989, 89, 827. (b)
Dennis, N.; Ibrahim, B.; Katritzky, A. R. J . Chem. Soc., Perkin Trans.
1 1976, 2307. (c) Sung, M. J .; Lee, H. I.; Chong, Y.; Cha, J . K. Org.
Lett. 1999, 1, 2017. (d) Walters, M. A.; Arcand, H. R. J . Org. Chem.
1996, 61, 1478. (e) Walters, M. A.; Arcand, H. R.; Lawrie, D. J .
Tetrahedron Lett. 1995, 36, 23.
(16) Myers, A. G.; Barbay, J . K. Org. Lett. 2001, 3, 425.
(17) All new compounds were identified and characterized by 1H
NMR, 13C NMR, FTIR, [R]20D, and MS.
(18) See Supporting Information for further details.

NMR Studies on Epoxidations of Allenamides
J . Org. Chem., Vol. 67, No. 4, 2002 1341
F igu r e 1. 1H NMR monitoring of allene epoxidation by mCPBA.
Sch em e 3
Sch em e 4
silylation gave the silylated pyran 17 that could be fully
characterized. The diastereomeric ratio was found to be
9:1 for 17 after silylation in favor of the major isomer
shown in Scheme 5. This trapping experiment supports
the presence of a nitrogen-substituted spiro-epoxide
intermediate such as 14.
In the presence of 0.5 equiv of pyridinium p-tolylsul-
fonic acid (PPTS), DMDO epoxidation of 11 led to the
formation of 15 and 16 in 70% overall yield with a ratio
of 1:3. While the diastereomeric ratio of 16 dropped from
9:1 in the absence of PPTS (as suggested by 17) to 3.5:1;
the diastereomeric ratio of 15 was observed to be 5:1.
Stereochemical assignments for compounds 15-17 are
done based on 1H NMR correlation with an analogous
pyran that was unambiguously assigned using NOE
experiments (see 28 in Scheme 8). The isolation of 15
represents the first evidence for the formation of nitrogen-
that similar trapping experiments can be used to study
intermediates derived from epoxidations of allenes.4
2. DMDO Ep oxid a tion . Distinctly different results
were obtained when we turned to the second epoxidation
protocol: dimethyldioxirane (DMDO) oxidation. As shown
in Scheme 5, epoxidation of the allenamide 11 using 2.0-
5.0 equiv of DMDO in the absence of a protic additive
led to the pyran 16 as the only product in 86% yield.
Because the pyran 16 was not easy to purify, further

1342 J . Org. Chem., Vol. 67, No. 4, 2002
Rameshkumar et al.
Sch em e 5
pounds A and B with a ratio of about ∼ 2.2:1 in addition
to the unreacted 5 (labeled with “s”). The new major
compound A (labeled with “a ”) have the following assign-
able proton resonances: δ 3.91 (d, J ) 20.1 Hz, 1H), 4.25
(d, J ) 20.1 Hz, 1H), and 5.45 (broad-s, 1H). The new
minor compound B (labeled “b”) have the following
assignable proton resonances: δ 4.52 (d, J ) 8.5 Hz, 1H)
and 5.64 (broad-s, 1H). A careful tabulation of integra-
tions of the overlapping regions could unambiguously
account for all other overlapping protons for 5, A, and B
in the region.
When the reaction was allowed to go to completion,
compound A was the major product observed. It was
difficult to completely characterize compound A because
it was not very stable. Given known chemical shifts and
coupling constants of related spiro-epoxides,4e-f this major
product A is not consistent with the spiro-epoxide 22.
However, it is quite consistent with the assignment of
the 3-oxetanone 23 based on information reported by
Crandall.4e-f,19 The H4 of 23 may be assigned to 5.45 ppm,
and diastereotopic protons H5 and H6 of 23 to 3.91 and
4.25 ppm. 3-Oxetanones such as 23 are secondary prod-
ucts derived from corrresponding spiro-epoxides (see
Scheme 9).4e-f The assignment of compound B, on the
other hand, can be intriguing, although it is also not
consistent with the spiro-epoxide 22. While it is not
conclusive to assign B as the allene oxide 21,20 the
following 1H NMR experiment suggests such a possibility.
Sch em e 6
When DMDO epoxidation of 5 was carried out in the
presence of 5-10 equiv of furan where [4 + 3] cycload-
dition would take place,11 1H NMR indicated that the
ratio of A to B had switched from ∼2.2:1 to ∼1:5 in favor
of B but not A (or the assigned 3-oxetanone).18 However,
this is true only initially.18 As the concentration of the
correponding [4 + 3] cycloadduct was accumulating, the
ratio of A and B increased from ∼1:5 but never went
above 1:1.5 (still in favor of B).18
substituted allene oxide 13. Thus, this also suggests that
the second epoxidation proceeded slower leading to 16
under protic DMDO conditions.
On the other hand, when oxone was used as a DMDO
equivalent, the cyclic ether 19 was isolated in 40% yield
(Scheme 6). In addition, the pyran 15 was also isolated
in 10% yield. The formation of 19 can be proposed as
shown where again in a more acidic medium during the
oxidation, rapid ring-opening of the allene oxide 13 could
occur to provide the R,â-unsaturated N-acyl iminium
intermediate 20. An ensuing 1,4-addition would lead to
19. This trapping experiment is an additional evidence
suggesting the formation of nitrogen-substituted allene
oxide 13.
These NMR ratios suggest that compound B is likely
the allene oxide 21. In the presence of furan, [4 + 3]
cycloaddition involving the ring-opened oxyallyl cation
intermediate derived from 21 with furan could occur
faster than its second epoxidation, thereby suppressing
the buildup of the spiro-epoxide intermediate 22 that
ultimately leads to the 3-oxetanone intermediate 23 (or
compound A, and thus, suppression of A). At the same
time, the initial jump in the concentration of compound
B, if it is related to the allene oxide 21, should taper off
as observed due to the subsequent cycloaddition.
It is noteworthy that the same allenamide 11 provided
a very different major product using oxone from that of
using DMDO in the presence of PPTS. While reasons are
not very clear for such a mechanistic difference, it could
be suggested that allene oxide 13 derived from DMDO
oxidation of 11 could undergo rapid ring-opening in the
presence of PPTS to proceed to an intermediate that
would be the keto form of 20. Thus, the trapping of the
N-acyl iminium ion with the hydroxyl group could only
be possible in a 1,2-addition manner to give the pyran
15 as the major product. On the other hand, by using
oxone, the ring-open of the allene oxide 13 could lead to
predominately 20 (the enol form) that could be trapped
in either 1,2 or 1,4-addition manner.
The assertion that [4 + 3] cycloaddition of 21 occurs
faster than its second epoxidation should be valid based
on our cycloaddition study.11 In the presence of furan or
another diene, we did not isolate any products related to
the spiro-epoxide intermediate 22 and/or 3-oxetanone 23.
Instead, the only products were the [4 + 3] cycloadducts
derived from the allene oxide 21 or its ring-opened
oxyallyl cation intermediate.11
3. Ster eoch em ica l Assign m en ts. Because it was
difficult to assign the stereochemistry of the furan 10 (in
Scheme 3) and the pyran 17 (in Scheme 5) using crystal
structures, the allenamide 26 was specifically prepared
from the propargyl silyl ether 24 in five steps as shown
Having obtained these results using DMDO, DMDO
epoxidation of 5 was carried out in acetone-d6 and
1
monitored by H NMR. As shown in Figure 2, DMDO
(19) Pusion, A.; Rosnati, V.; Solinas, C. Tetrahedron 1983, 39, 2259.
(20) For chemical shifts of a related allene oxide, see: Konoike, T.;
Hayashi, T.; Araki, Y. Tetrahedron: Asymm. 1994, 5, 1559.
epoxidation of 5 occurred at a temperature as low as -60
°C. Within the first 30 min, there were two new com-

NMR Studies on Epoxidations of Allenamides
J . Org. Chem., Vol. 67, No. 4, 2002 1343
F igu r e 2. 1H NMR monitoring of DMDO oxidation of allenamide.
Sch em e 7
27b with those of corresponding protons in furans 10a
and 10b, assignments of 27a /b lent strong support to the
stereochemical outcome for the isomers 10a /b.
On the other hand, DMDO oxidation of 26 followed by
silylation with TBDPSCl gave the desired pyran 28 in
47% overall yield, but the diastereomeric ratio dropped
to 1:1. When the DMDO oxidation was carried out at -40
°C, the diastereomeric ratio improved to 2:1 but did not
change when the reaction was carried out at -78 °C.
Although we are uncertain why there is a large difference
between diastereomeric ratios obtained for 17 and 28,
this difference can be interesting mechanistically.
NOE experiments of both the major and minor isomers
of 28 again unambiguously indicate that the major
isomer 28a contains the absolute stereochemistry of
(R,S,S) (see the key NOE enhancements in Scheme 8).
By correlating chemical shifts of the methylene protons
R to the ketone carbonyl and anomeric protons in pyrans
28a /b with those corresponding protons in pyrans 16a /b
or 17a /b, stereochemistry at the anomeric center of the
major isomer 16a or 17a should be the same as in 28a .
Chemical shift correlation of the R-methylene protons in
pyrans 28a /b with R-methyl protons in pyrans 15a /b also
firmly supports that the major isomers 15a possess the
stereochemistry as in 28a . In addition, chemical shifts
of the anomeric methine protons and methyl groups in
28a and 28b also correlate very well with the corre-
sponding ones in 27a and 27b. These correlations suggest
that in all cases, the major isomers favor the same
stereoselectivity at the anomeric center.
in Scheme 7. Treatment of the allenamide 26 using PPTS
in CH2Cl2 led to the pyran 27 in 36% yield with an
isomeric ratio of g9:1. NOE experiments of both the
major and minor isomers unambiguously indicate that
the major isomer 27a contains the absolute stereochem-
istry of (R,S,S) (see the key NOE enhancements in
Scheme 7). By correlating chemical shifts of the three
olefinic protons and anomeric protons in pyrans 27a and
4. Mech a n istic Con sid er a tion s. A proposed mecha-
nistic sequence that can account for these observations
is shown in Scheme 9. Given the stereochemical assign-
ment of 6-S, NMR observations, and the unsuccessful

1344 J . Org. Chem., Vol. 67, No. 4, 2002
Rameshkumar et al.
Sch em e 8
Sch em e 10
cation intermediate) need to take place faster than the
second epoxidation to give predominantly the desired
cycloadducts and a small amount of 3-oxetanone 23 as
Sch em e 9
1
observed by H NMR. This rate difference between the
second epoxidation and cycloaddition likely provides the
valuable window of opportunity for the success of devel-
oping stereoselective [4 + 3] cycloadditions via mono-
epoxidized chiral allenamides.11
Finally, based on the available stereochemical assign-
ments, the observed diastereoselectivity from PPTS reac-
tions and DMDO epoxidations may be explained using
the favored transition states shown in Scheme 10,
respectively, for compounds 10, 16, 27, and 28.
Con clu sion
We have described here the first 1H NMR studies of
two epoxidations of chiral allenamides. While m-CPBA
led to highly stereoselective formation of R-keto aminals
that can be useful as synthetic precursors to nitrogen-
stabilized oxyallyl cations, DMDO oxidation led to con-
clusive evidence for nitrogen-substituted allene oxide and
spiro-epoxide intermediates using various intramolecular
nucleophilic trapping experiments. 1H NMR studies
provide reliable support for a 3-oxetanone that can be
derived from the spiro-epoxide intermediate and suggest
the potential presence of an allene oxide.
Despite a facile second epoxidation as evidenced by the
predominant formation of the 3-oxetanone, in the pres-
ence of furan, [4 + 3] cycloaddition of the allene oxide
intermediate (or the oxyallyl cation intermediate) with
furan has to occur faster than its second epoxidation
leading to predominantly the desired cycloadducts. This
rate differentiation plays a critical role that was mecha-
nistically unknown to us in developing a successful
stereoselective sequential epoxidation-[4 + 3] cycload-
dition via DMDO epoxidations of chiral allenamides.
Synthetic applications of R-keto aminal and various
oxygen heterocycles resulting from this study are being
pursued.
intramolecular trapping experiment, it may be suggested
that not only does the addition of m-CPBA occur from
the less hindered bottom face of 5a which is more stable
than 5b (∆E ) 1.47 kcal mol-1 via PM3 calculations using
Spartan), but more intriguingly, that the ring-opening
of the transient epoxide 29 is facile and may be proposed
as pseudo-intramolecular.
On the other hand, DMDO oxidation of 5a may proceed
through the transition state intermediate 30 leading to
the allene oxide 21. A second expoxidation leading to the
spiro-epoxide 22 is likely quite fast especially in nonacidic
conditions leading predominatly to the 3-oxetanone 23
1
as observed by H NMR.18 Transformation of 22 to 23
may proceed via intermediates 31 and 32 as shown in
Scheme 9.4e-f
Ack n ow led gm en t. The authors thank the National
Science Foundation (CHE-0094005) for support of this
work. R.P.H. also thanks R. W. J ohnson Pharmaceutical
It is again noteworthy that in the presence of furan,
[4 + 3] cycloadditions of 21 (or the ring-opened oxyallyl

NMR Studies on Epoxidations of Allenamides
J . Org. Chem., Vol. 67, No. 4, 2002 1345
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures as well as H NMR spectra, characterization data, and
X-ray data are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
Institute for a generous Focused Giving Award and the
McKnight Foundation for a McKnight Faculty Award.
H.X. thanks the Chemistry Department for a Graduate
Dissertation Fellowship. The authors thank Dr. Neil R.
Brook for solving the X-ray structure.
1
J O011048D