Inverse electron-demand aza-[4+2] cycloaddition reactions of allenamides

Article abstract of DOI:10.1016/j.tet.2004.05.117

An inverse electron-demand aza-[4+2] cycloaddition reaction of allenamides with 1-azadiene is described here. Effects of solvents on diastereoselectivity along with synthetic scopes and mechanistic insights are illustrated. Despite some synthetic limitations, this aza-[4+2] cycloaddition does provide a useful template for the synthesis of aza-glycoside related heterocycles.

Full text of DOI:10.1016/j.tet.2004.05.117

Tetrahedron 60 (2004) 7629–7636
Inverse electron-demand aza-[412] cycloaddition reactions
of allenamides
†
,
*
Craig R. Berry and Richard P. Hsung
Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
Received 1 April 2004; revised 21 May 2004; accepted 24 May 2004
Available online 25 June 2004
With the deepest gratitude and appreciation, this paper is dedicated to Professor Dieter Seebach on the special occasion of his receiving a Tetrahedron Prize for
Creativity in Organic Chemistry
Abstract—An inverse electron-demand aza-[4þ2] cycloaddition reaction of allenamides with 1-azadiene is described here. Effects of
solvents on diastereoselectivity along with synthetic scopes and mechanistic insights are illustrated. Despite some synthetic limitations, this
aza-[4þ2] cycloaddition does provide a useful template for the synthesis of aza-glycoside related heterocycles.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
constructions of C-glycoside derivatives 4 [W¼O].4,10
Given such synthetic potential, we examined [4þ2]
cycloadditions of 1-azadienes 5 with allenamides 6 to
access nitrogen heterocycles 7.
Allenamides have emerged as attractive building blocks in
organic synthesis.1–6 With vastly improved stability and
comparable reactivity relative to traditional allenamines,
allenamides can be utilized in a diverse array of stereo-
selective methodologies.3–6 We reported [4þ2] cyclo-
additions of chiral allenamide 1 with vinyl ketones 2 that
led to pyrans 3 in a highly stereoselective manner,3a
representing a rare account of an inverse demand hetero
[4þ2] cycloaddition involving a chiral enamide [Fig. 1].7–9
We have also been focusing on applications of this
cycloaddition method as a new approach for stereoselective
1-Azadienes are known to be poor dienes in Diels–Alder
cycloadditions in general because of competing 1,2-
additions to imines along with problems related to
tautomerization to energetically favored enamines prior
to cycloadditions.7 However, elegant efforts from
Boger11–13 and Fowler,14–15 by placing electron-with-
drawing substituents on the nitrogen atom, have rendered
1-azadienes highly useful for inverse demand hetero [4þ2]
Figure 1.
Keywords: Allenamides; Diels–Alder; Cycloaddition; Inverse Demand; 1-Azadiene; Aza-glycoside.
*
Corresponding author. Tel.: þ1-612-625-3045; fax: þ1-612-626-7541; e-mail address: hsung@chem.umn.edu
†
A recipient of 2001–2003 Camille Dreyfus Teacher-Scholar Award.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.117

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C. R. Berry, R. P. Hsung / Tetrahedron 60 (2004) 7629–7636
Scheme 1.
cycloadditions with electron rich dienophiles. While
Boger12 has demonstrated that allenol ethers can be used
in such cycloadditions, nitrogen-substituted allenes have not
been examined.1,16 Success in this endeavor could provide
an opportunity for constructing highly functionalized aza-
sugars and related heterocycles [see also 4: W¼NR], a
concept that we have already demonstrated using pyrans 3.4
We report here our findings in the feasibility and limitation
of inverse electron-demand aza-[4þ2] cycloadditions of
allenamides with 1-azadienes.
unfortunately also did not lead to any improvement in the
diastereoselectivity, as evident with cycloadduct 16.
2.2. Stereochemical and mechanistic issues
2.2.1. Solvent effect. We did observe some interesting
solvent effect on the stereochemical outcome of the
cycloaddition. As shown in Table 1, a very diverse range
of different solvents could be used for the aza-[4þ2]
cycloaddition of allenamide 1 [entries 1–9]. The tempera-
ture could be lowered to 35 8C in some solvents [entries, 4,
and 6–8]. More importantly, there is a small but noticeable
increase in the diastereoselectivity with increasing in the
2. Results and discussion
Table 1.
2.1. Feasibility of the aza-[412] cycloaddition
Entry Allenamidea Solvent Temp Time Cycloadd Yield Ratioc
We quickly demonstrated that more electron-rich 1-aza-
deines,17,18 such as 8 and 9a/b [Scheme 1], did not match
well electronically with an allenamide, leading to no
observable hetero cycloadducts. On the other hand, 1-N-
sulfonyl vinyl aldimine 1011 was a feasible 1-azadiene to
give the desired hetero cycloadducts 11 and 1319 in good
yields, respectively, from chiral allenamides 1 and 12.
However, the diastereoselectivity was not encouraging with
chiral allenamides 1 and 12 substituted with the Close’s
auxiliary20 and Evans’ auxiliary,21 respectively, providing
virtually no stereoselectivity, although 1 appeared to be
more reactive for the reaction could be carried out at a lower
temperature.
(8C)
(h)
(%)b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
Hexane
PhH
EtOAc
Et2O
THF
CH2Cl2
CHCl3
Acetone
MeOH
50
50
50
35
50
35
35
35
50
15 11
15 11
15 11
12 11
15 11
12 11
12 11
12 11
15 11
67
75
75
71
75
70
71
67
59
2.3:1
2.3:1
1.7:1
1.7:1
2.4:1
3.5:1
4.4:1
1.4:1
3.6:1
10
11
12
13
14
15
16
17
18
12
12
12
12
12
12
12
12
12
CHCl3
CHCl3
CHCl3
CH2Cl2
CH2Cl2
MeOH
THF
35
55
65
35
55
65
65
65
65
50 13
24 13
24 13
50 13
24 13
72 13
72 13
72 13
72 13
53
50
52
52
60
62
25
34
52
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1.5:1
1.5:1
We then examined chiral allenamides substituted with other
well known chiral auxiliaries such as Sibi’s22 and
Boeckman’s auxiliaries,23 but neither gave better selectivity
as evident in their respective cycloadducts 14 and 15. The
allenamide substituted with the Boeckman’s auxiliary was
much less stable, and thus, under the same thermal
conditions, much decomposition occurred to give 15 in a
lower yield. Finally, the use of Seebach’s chiral auxiliary24
EtOAc
PhH
a
Reactions were carried out using anhydrous solvent in a sealed tube and
1.0 equiv. of 1-azadiene 10 were used.
Isolated yields.
b
c
Diastereomeric ratios [dr] were assigned by using 1H NMR and represent
ratios of 11/13a : 11/13b with a being the major isomer.

C. R. Berry, R. P. Hsung / Tetrahedron 60 (2004) 7629–7636
7631
solvent polarity, with the best ratio being 4.4:1 when the
reaction was run in CHCl3 at 35 8C [entry 7]. This modest
solvent effect suggests that the cycloaddition could proceed
through a stepwise process that involves perhaps ionic
intermediates. However, we are not clear how exactly the
polarity of the solvent impacts the stereoselectivity of this
cycloaddition, especially when the reaction in CH3CN [see
Scheme 1] did not give a good ratio. Stereochemistry of the
major isomer 11a was assigned using an X-ray structure
[Fig. 2].
ketones,3 the overall stereochemical outcome observed here
in these aza-[4þ2] cycloadditions illustrate a similar trend.
That is, chiral allenamide 1 containing an imidazolidinone
auxiliary provides better stereoselectivity than any of the
oxazolidinone-based allenamides. This trend could be
rationalized using the following proposed mechanistic
model.
ChemDraw reproductions of the minimized structures of
chiral allenamides 1, 12, and ent-17 [containing the
enantiomer of Seebach’s auxiliary24 for ease of comparison]
using SpartanTM AM1-calculations are shown in Figure 3.
The allene fragment is essentially co-planar with the
imidazolidinone or oxazolidinone ring, thereby suggesting
that the observed diastereoselectivity is likely due to a
preferred addition of 1-azadienes from the less crowded
bottom face of all allenamides.
The phenyl group of the imidazolidinone ring in allenamide
1 appears to be much closer to the allene fragment in the
minimized model, thereby providing the best steric presence
or facial differentiation and leading to the highest
diastereoselectivity. The phenyl group in 12 actually tilts
away from the allene moiety, thereby diminishing a
significant amount of facial steric bias. This difference
between 1 and 12, however, is likely not a result of the
methyl group present in the imidazolidinone ring of 1,
which could contribute toward pushing the phenyl ring
closer to the allene fragment. However, if true, ent-
allenamide 17 with Seebach’s auxiliary would have
provided an improved stereoselectivity relative to 12.
Figure 2. X-ray structures of 11a [left] and 13a.
For allenamide 12, while a range of solvents could also be
used [entries 10–18], in most cases, there was no observable
increase in stereoselectivity [entries 10–16], even in CHCl3
at various different temperatures [entries 10–13]. An
exception would be that we did observe a very small but
noticeable selectivity when the reaction was carried out in
EtOAc and PhH. The major isomer 13a was isolated with its
stereochemistry being resolved using X-ray analysis [Fig. 2].
Finally, although this mechanistic model accounts for the
overall stereochemical outcome, it does not account at this
time for the solvent effect that we have observed.
2.3. Synthetic limitations
An apparent limitation of this aza-[4þ2] cycloaddition in
this study is the accessibility of 1-N-sulfonyl vinyl imines.
Although there are several accounts in describing their
preparations,11 we were only able to prepare a few,
2.2.2. A mechanistic model. Although we did not observe
any solvent effect on the stereoselectivity of oxa-[4þ2]
cycloadditions of allenamides with acrolein or various vinyl
Figure 3.

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C. R. Berry, R. P. Hsung / Tetrahedron 60 (2004) 7629–7636
including 1-azadiene 10, consistently. The other two
successful preparations afforded 1-N-sulfonyl vinyl aldi-
mine 18 and ketimine 19 [Scheme 2]. However, cycloaddi-
tion of 18 with allenamide 1 did not produce the desired
cycloadduct 20 in a synthetically useful manner, although
we were able to isolate 21 in 25% yield from the reaction of
19 with 1. In addition, 21 was isolated as a mixture of only
two diastereomers [out of a possible four] with a moderate
ratio of 1.5:1. Their relative stereochemistry was not
assigned vigorously.
Scheme 3.
A more solid support of the template concept was obtained
when azacycle 11a was dihydroxylated in a highly regio-
and stereoselective manner using cat OsO4 to give diol 25 as
a single isomer in 60% yield [Scheme 4]. NOE assignment
of relative stereochemistry confirmed that the dihdyroxyl-
ation occurred exclusively at the top less congested face of
the more accessible C5 exo-cyclic olefin [lower left box].
An ensuing epoxidation of the C2-3 endo-cyclic olefin was
also stereoselective, leading to a surprisingly stable epoxide
25 in 50% yield with an isomeric ratio of 5:1.
Scheme 2.
We are currently exploring improved preparations of 1-N-
sulfonyl vinyl imines to access a broader range of aza-cycles
through this aza-[4þ2] cycloaddition.
2.4. Functionalizations of the aza-[412] cycloadduct and
removal of the auxiliary
These studies suggest that the aza-[4þ2] cycloadduct 22 can
be employed as a template with the imidazolidinone group
at C6 serving as a chiral auxiliary [or blocking one face] for
constructing aza-glycoside related heterocycles.
With the aza-cycles 11, 13, and 14–16 in hand, we
examined the concept of employing them as a template
for constructing aza-glycoside related heterocycles. X-ray
analysis of the major isomer of 11 [Fig. 2] reveals that the
chiral imidazolidinone group at C6 is oriented pseudo-
axially and situated beneath the two olefins: The electron-
rich endo-cyclic at C2/C3, and the accessible exo-cyclic at
C5. Based on this analysis, we envisioned that in a manner
analogous to our work using pyran 3,4 azacycle 22 can also
be utilized as a chiral template with the C6 imidazolidinone
of 22 being the chiral auxiliary, and that transformations
of the two well-differentiated olefins can proceed
selectively from the sterically less congested top face
[Scheme 3].
2.4.1. Removal of the chiral auxiliary. To complete the
concept of the C6 imidazolidinone of 22 serving as a chiral
auxiliary, we carried out its removal and recovery using
related conditions reported for oxa-[4þ2] cycloadducts,4a
To support this concept, the C5 exo-cyclic olefin in 11a was
hydrogenated under standard conditions at rt to give 23a as
the major isomer with a modest ratio of 2:1 [entry 1]. The
assignment of relative stereochemistry in 23a using NOE
confirmed that the addition of hydrogen occurred at the less
congested top face. While the overall selectivity was not as
high as we had expected, we did see a much better
selectivity [entry 3] at lower temperature. In addition, we
consistently isolated 10–15% of dihydropyridine 24,
resulting from isomerization of the exo-cyclic olefin. The
formation of 24 could be related to the erosion of
diastereoselectivity during the hydrogenation.
Scheme 4.

C. R. Berry, R. P. Hsung / Tetrahedron 60 (2004) 7629–7636
7633
but it proved to be quite difficult. As shown in Scheme 5,
after screening through a variety of Lewis acids, only SnBr4
and ZnCl2 appeared to be suitable Lewis acids that would
facilitate a proper departure of the C6 imidazolidinone
group in 23a. An ensuing addition of allyltrimethylsilane to
the presumed aza-carbenium intermediate 27 did give
azacycle 28a/b as an isomeric mixture in only 33% yield
with a ratio of 3:1. The major isomer was again assigned
using NOE experiments.
4.1. General procedure for the aza-[412] cycloadditions
To a solution of 0.83 g of allenamide 1 (3.6 mmol,
1.0 equiv.) in freshly distilled CH3CN (36 mL, 0.10 M)
was added 0.76 g of sulfonyl imine 10 (3.6 mmol,
1.0 equiv.). The reaction mixture was sealed under a blanket
of nitrogen, and the mixture was stirred for 3 h at 50 8C.
After which, the solution was allowed to cool to room
temperature, and solvent was removed under reduced
pressure. Silica gel flash column chromatography (gradient
eluent: 0–25% EtOAc in hexanes) afforded both the major
and minor cycloadduct 11a and 11b in 63% yield (1.00 g) of
as a foamy solid. The two isomers could be separated via
subsequent column chromatography.
4.1.1. Major isomer 11a. Rf¼0.35 [50% EtOAc/hexane];
mp 148–150 8C; [a]D20 266.38 [c 4.1, CH2Cl2]; H NMR
1
(CDCl3) d 0.65 (d, 3H, J¼6 Hz), 1.22 (d, 1H, J¼20.5 Hz),
1.31 (s, 3H), 1.94 (d, 1H, 20.5 Hz), 2.69 (s, 3H), 3.52 (dq,
1H, J¼6, 9 Hz), 4.59 (s, 1H), 4.60 (d, 1H, J¼9 Hz), 5.04 (s,
1H), 6.24 (s, 1H), 6.44 (s, 1H), 7.20–7.24 (m, 4H), 7.47–
7.56 (m, 4H), 7.82 (d, 2H, J¼9 Hz); 13C NMR (CDCl3) d
15.0, 19.8, 28.7, 32.0, 56.8, 59.1, 65.4, 114.9, 116.5, 117.9,
126.4, 127.0, 127.9, 128.6, 129.1, 132.9, 138.1, 138.3,
138.9, 161.1; IR (film) cm21 3212m, 3063s, 2933s, 2882s,
1712s, 1168s; mass spectrum (LRMS): m/e (% relative
intensity) 438 (100) MþþH, 296 (50), 248 (100), 203 (80),
191 (45); m/e calcd for C24H27N3O3SNa 460.1671, found
460.1664.
Scheme 5.
3. Conclusions
We have described here an inverse electron-demand aza-
[4þ2] cycloaddition reaction of allenamides with 1-aza-
dienes. Effect of solvents on diastereoselectivity, along with
synthetic scopes and mechanistic insights are reported.
Despite some of the current synthetic limitations, this aza-
[4þ2] cycloaddition does provide cycloadducts that can be
employed as a template for the synthesis of aza-glycoside
related hetereocycles.
4.1.2. Minor isomer 11b. Rf¼0.30 [50% EtOAc/hexane];
mp 84–87 8C; [a]D20 þ29.88 [c 1.7, CH2Cl2]; 1H NMR
(CDCl3) d 0.74 (d, 3H, J¼6 Hz), 1.60 (s, 3H), 2.35 (d, 1H,
J¼20 Hz), 2.71 (s, 3H), 3.01 (d, 1H, J¼20 Hz), 3.69 (dq,
1H, J¼6, 9 Hz), 4.67–4.70 (m, 3H), 5.80 (s, 1H), 5.93 (s,
1H), 7.31–7.42 (m, 4H), 7.46–7.51 (m, 4H), 7.63 (d, 2H,
J¼9 Hz); 13C NMR (CDCl3) d 14.9, 20.0, 28.7, 33.8, 56.1,
61.7, 66.2, 114.0, 118.5, 120.2, 126.9, 127.0, 127.9, 128.0,
128.7, 132.5, 136.5, 138.0, 138.7, 159.7; IR (film) cm21
3190m, 3090s, 2915s, 2930m, 1722s, 1209m; mass
spectrum (LRMS): m/e (% relative intensity) 438 (100)
MþþH, 296 (50), 248 (100), 203 (80), 191 (45); m/e calcd
for C24H27N3O3SNa 460.1671, found 460.1678.
4. Experimental
All reactions performed in flame-dried glassware under
nitrogen atmosphere. Solvents were distilled prior to use.
Reagents were used as purchased (Aldrich, Acros), except
where noted. Chromatographic separation were performed
4.1.3. Cycloadduct 13a. Rf¼0.30 [50% EtOAc/hexane]; mp
105–108 8C; [a]D20 288.18 [c 5.1, CH2Cl2]; 1H NMR
(CDCl3) d 1.28 (s, 3H), 1.40 (d, 1H, J¼20 Hz), 1.99 (d,
1H, J¼20 Hz), 4.07 (dd, 1H, J¼6, 9 Hz), 4.51 (t, 1H,
J¼9 Hz), 4.08 (d, 1H, J¼2.5 Hz), 4.88 (dd, 1H, J¼6, 9 Hz),
5.07 (d, 1H, J¼2.5 Hz), 5.98 (s, 1H), 6.28 (s, 1H), 7.24–
7.36 (m, 4H), 7.48–7.54 (m, 4H), 7.81 (d, 2H, J¼9 Hz); 13C
NMR (CDCl3) d 19.8, 31.6, 57.6, 67.0, 71.2, 116.1, 116.7,
117.6, 127.0, 127.3, 128.6, 128.7, 129.2, 133.2, 136.8,
138.2, 140.0, 158.5; IR (film) cm21 3010s, 2905s, 2877m,
1709s, 1552m; mass spectrum (LRMS): m/e (% relative
intensity) 411 (100) MþþH, 270 (50), 248 (100), 163 (45);
m/e calcd for C22H22N2O4SNa 433.1198, found 433.1193.
using Bodman 60 A SiO2. 1H and 13C NMR spectra were
˚
obtained on Varian VI-300, VX-300, and VI-500
spectrometers using CDCl3 (except where noted) with
TMS or residual solvent as standard. Melting points were
determined using a Laboratory Devices MEL-TEMP and
are uncorrected/calibrated. Infrared spectra were obtained
using NaCl plates on a Midac M2000 FTIR. TLC analysis
was performed using Aldrich 254 nm polyester-backed
˚
plates (60 A, 250 mm) and visualized using UV and vanillin
or KMnO4 stains. Low-resolution mass spectra were
obtained using an Agilent 1100 series LS/MSD and are
APCI. High-resolution mass spectral analyses performed at
Department of Chemistry Mass Spectrometry Laboratory,
University of Minnesota. X-ray analyses performed at
University of Minnesota Department of Chemistry X-ray
facility. All spectral data obtained for new compounds are
reported here.
4.1.4. Cycloadduct 13b. Rf¼0.22 [50% EtOAc/hexane];
1
mp 121–123 8C; [a]D20 þ59.08 [c 2.7, CH2Cl2]; H NMR
(CDCl3) d 1.59 (s, 3H), 2.36 (d, 1H, J¼20 Hz), 2.96 (d, 1H,
J¼20 Hz), 4.10 (dd, 1H, J¼6, 8.5 Hz), 4.56 (t, 1H, J¼9 Hz),
4.71 (d, 1H, J¼2.5 Hz), 4.77 (d, 1H, J¼2.5 Hz), 4.93 (dd,

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C. R. Berry, R. P. Hsung / Tetrahedron 60 (2004) 7629–7636
1H, J¼6.5, 9 Hz), 5.67 (s, 1H), 5.95 (s, 1H), 7.36–7.44 (m,
6H), 7.50–7.54 (m, 2H), 7.48 (d, 2H, J¼9 Hz); 13C NMR
(CDCl3) d 20.0, 59.6, 66.4, 67.1, 70.3, 112.4, 115.4, 118.0,
127.0, 127.2, 128.8, 128.9, 129.0, 132.9, 136.7, 138.6,
148.0, 156.6; IR (film) cm21 2997m, 2912m, 2815m, 1689s,
1541m; mass spectrum (LRMS): m/e (% relative intensity)
411 (100) MþþH, 270 (50), 248 (100), 163 (45); m/e calcd
for C22H22N2O4SNa 433.1198, found 433.1190.
3H), 2.32 (m, 1H), 2.78 (s, 3H), 3.76 (dq, 1H, J¼7, 9 Hz),
4.64 (s, 1H), 4.75 (d, 1H, J¼9 Hz), 5.01 (s, 1H), 6.56 (s,
1H), 7.02–7.26 (m, 3H), 7.38–7.58 (m, 3H), 7.61 (d, 2H,
J¼8 Hz), 7.67 (d, 2H, J¼8 Hz); 21b: d 0.64 (d, 3H,
J¼7 Hz), 0.80–1.08 (m, 4H), 1.31–1.54 (m, 4H), 1.81 (s,
3H), 2.28 (m, 1H), 2.73 (s, 3H), 3.76 (dq, 1H, J¼7, 9 Hz),
4.54 (s, 1H), 4.64 (s, 1H), 4.75 (d, 1H, J¼9 Hz), 6.43 (s,
1H), 7.02–7.26 (m, 3H), 7.38–7.58 (m, 3H), 7.61 (d, 2H,
J¼8 Hz), 7.67 (d, 2H, J¼8 Hz); IR (film) cm21 3354m,
3024m, 2912m, 1715s, 1498m; mass spectrum (LRMS): m/e
(% relative intensity) 492 (100) MþþH, 351 (20), 302 (15);
m/e calcd for C28H33N3O3SNa 514.2140, found 514.2124.
4.1.5. Cycloadducts 14a/b as a mixture. Rf¼0.22 [50%
EtOAc/hexane]; 1H NMR (CDCl3) 14a d 1.23 (s, 3H), 2.35
(d, 1H, J¼20 Hz), 2.55 (d, 1H, J¼20 Hz), 4.05 (s, 1H),
4.26–4.31 (m, 2H), 4.45 (d, 1H, J¼5 Hz), 4.52 (s, 1H), 4.79
(m, 1H), 5.86 (s, 1H), 6.38 (s, 1H), 7.22–7.38 (m, 8H),
7.49–7.62 (m, 4H), 7.86 (d, 2H, J¼8 Hz), 7.94 (d, 1H,
J¼8 Hz); 14b: d 1.63 (s, 3H), 2.14 (d, 1H, J¼21 Hz), 3.04
(d, 1H, J¼21 Hz), 4.15 (dd, 1H, J¼2, 8 Hz), 4.24 (dd, 1H,
J¼2, 8 Hz), 4.57 (d, 1H, J¼8 Hz), 4.86 (s, 1H), 4.90 (dt, 1H,
J¼2, 8 Hz), 5.03 (s, 1H), 6.27 (s, 1H), 6.42 (s, 1H), 7.22–
7.38 (m, 8H), 7.49–7.62 (m, 4H), 7.86 (d, 2H, J¼8 Hz),
7.94 (d, 1H, J¼8 Hz); IR (film) cm21 3060m, 2914m,
1755s, 1347s, 1166s; mass spectrum (LRMS): m/e (%
relative intensity) 501 (20) MþþH, 359 (50), 266 (100), 193
(10); m/e calcd for C29H28N2O4SNa 523.1668, found
523.1640.
4.2. Synthesis of mono-hydrogenated product 23a
To a solution of 130.0 mg of cycloadduct 11a (0.29 mmol)
in EtOH (3.0 mL, 0.01 M) was added 10% Pt–C (25 mg).
After purging the system with H2 gas, the mixture was
allowed to stir at rt for 2 h. Filtration through celite and
removal of the solvent under reduced pressure provided the
crude mono-hydrogenated product. Silica gel flash column
chromatography (gradient eluent: 0–25% EtOAc in
hexanes) provided the pure mono-hydrogenated 23a [ratio
of a/b: 2:1 at rt] in 65% yield (82.0 mg) along with 10–15%
of the byproduct 24.
4.1.6. Cycloadducts 15a/b as a mixture. Rf¼0.25 [50%
EtOAc/hexane]; 1H NMR (CDCl3) 15a: d 0.83 (s, 3H), 0.86
(s, 3H), 1.00 (s, 3H), 1.48–1.60 (m, 2H), 1.72 (s, 3H), 1.86–
1.96 (m, 2H), 2.43 (d, 1H, J¼20 Hz), 2.77 (d, 1H,
J¼20 Hz), 3.40 (d, 1H, J¼2 Hz), 4.68 (d, 1H, J¼2 Hz),
4.80 (d, 1H, J¼2 Hz), 5.89 (s, 1H), 6.49 (s, 1H), 7.47–7.60
(m, 3H), 7.77 (d, 2H, J¼7 Hz); 15b: d 0.97 (s, 3H), 0.99 (s,
3H), 1.04 (s, 3H), 1.21–1.29 (m, 2H), 1.58–1.62 (m, 2H),
1.65 (s, 3H), 3.45 (d, 1H, J¼2 Hz), 3.76 (d, 1H, J¼13 Hz),
4.01 (d, 1H, J¼13 Hz), 4.68 (d, 1H, J¼2 Hz), 4.80 (d, 1H,
J¼2 Hz), 6.08 (s, 1H), 6.40 (s, 1H), 7.47–7.60 (m, 3H), 7.77
(d, 2H, J¼7 Hz); IR (film) cm21 3045m, 2905m, 2900m,
1710s, 1600m; mass spectrum (LRMS): m/e (% relative
intensity) 400 (100) Mþ, 273 (20), 154 (15); m/e calcd for
C22H28N2O3SNa 423.1718, found 423.1725.
4.2.1. Compound 23a. Rf¼0.41 [50% EtOAc/hexane];
[a]2D0 2116.28 [c 2.6, CH2Cl2]; H NMR (CDCl3) d 0.19–
1
0.25 (m, 1H), 0.71 (d, 3H, J¼7 Hz), 0.84 (d, 3H, J¼7 Hz),
1.22–1.31 (m, 1H), 1.38–1.45 (m, 1H), 1.40 (s, 3H), 2.74
(s, 3H), 3.73 (dq, 1H, J¼7, 10 Hz), 4.50 (d, 1H, J¼10 Hz),
5.70 (d, 1H, J¼4 Hz), 6.62 (s, 1H), 6.95 (d, 1H, J¼9 Hz),
7.21–7.31 (m, 4H), 7.53–7.62 (m, 3H), 7.87 (d, 2H,
J¼9 Hz); 13C NMR (CDCl3) d 15.2, 16.6, 20.4, 29.0, 30.9,
32.1, 57.6, 59.1, 65.8, 116.2, 117.6, 127.1, 127.9, 128.3,
128.6, 129.1, 129.3, 132.9, 138.8, 163.5; IR (film) cm21
3478w, 3061m, 2931s, 2877s, 1715s, 1288s; mass spectrum
(LRMS): m/e (% relative intensity) 440 (100) MþþH, 310
(10), 250 (10), 191 (15); m/e calcd for C24H29N3O3SNa
462.1827, found 462.1835.
4.2.2. Byproduct dihydropyridine 24. Rf¼0.37 [50%
1
4.1.7. Cycloadducts 16a/b as a mixture. Rf¼0.30 [50%
EtOAc/hexane]; 1H NMR (CDCl3) 16a: d 0.73 (d, 6H,
J¼6.5 Hz), 1.32 (d, 1H, J¼11.5 Hz), 1.62 (s, 3H), 1.81–
1.95 (m, 1H), 2.32 (d, 1H, J¼15 Hz), 2.43 (d, 1H,
J¼15 Hz), 4.57 (d, 1H, J¼2.5 Hz), 4.60 (d, 1H,
J¼2.5 Hz), 6.15 (t, 1H, J¼2 Hz), 6.41 (s, 1H), 7.22–7.38
(m, 5H), 7.41–7.59 (m, 6H), 7.82 (d, 2H, J¼8 Hz), 9.62 (d,
2H, J¼9 Hz); 16b: d 0.69 (d, 6H, J¼6 Hz), 1.32 (d, 1H,
J¼11.5 Hz), 1.66 (s, 3H), 1.81–1.95 (m, 1H), 3.72 (d, 1H,
J¼15 Hz), 3.86 (d, 1H, J¼15 Hz), 4.60 (d, 1H, J¼1 Hz),
4.89 (d, 1H, J¼1 Hz), 6.07 (t, 1H, J¼2 Hz), 6.12 (s, 1H),
7.22–7.38 (m, 5H), 7.41–7.59 (m, 6H), 7.82 (d, 2H,
J¼8 Hz), 9.62 (d, 2H, J¼9 Hz); IR (film) cm21 3034m,
2945m, 2815m, 1708s, 1514m; mass spectrum (LRMS): m/e
(% relative intensity) 529 (100) MþþH, 485 (22), 387 (60),
248 (32); m/e calcd for C31H32N2O4SNa 551.1980, found
551.1988.
EtOAc/hexane]; [a]D20 2420.78 [c 2.1, CH2Cl2]; H NMR
(CDCl3) d 0.60 (d, 3H, J¼6.5 Hz), 1.50 (m, 3H), 1.60 (s,
3H), 2.69 (s, 3H), 3.09 (dq, 1H, J¼6.5, 9 Hz), 4.20 (d, 1H,
J¼9 Hz), 4.94 (s, 1H), 6.44 (s, 1H), 6.58 (s, 1H), 7.17–7.23
(m, 4H), 7.51–7.65 (m, 4H), 7.94 (d, 2H, J¼9 Hz); 13C
NMR (CDCl3) d 14.8, 17.6, 19.8, 28.6, 55.9, 59.5, 63.1,
66.9, 115.1, 116.9, 123.3, 126.0, 127.1, 127.8, 129.1, 132.9,
137.3, 139.8, 146.3, 160.0; IR (film) cm21 3063w, 2969m,
2872w, 1699s, 1353m, 1165s; mass spectrum (LRMS): m/e
(% relative intensity) 437 (100) Mþ, 270 (50), 248 (100),
163 (45); m/e calcd for C24H27N3O3SNa 460.1671, found
460.1701.
4.3. Synthesis of diol 25
To a solution of 0.47 g of cycloadduct 11a (1.1 mmol,
1 equiv.) in 10:1 acetone/water mixture (22 mL, 0.05 M)
was added NMO (0.19 g, 1.6 mmol, 1.5 equiv.) followed by
addition of a solution of OsO4 (5.0–13 mg, 0.02–
0.05 mmol, 0.02–0.05 equiv.) in t-BuOH (1.5 mL). The
mixture was allowed to stir for 3 h at rt after which sodium
4.1.8. Cycloadducts 21a/b as a mixture. Rf¼0.28 [50%
EtOAc/hexane]; 1H NMR (CDCl3) 21a: d 0.67 (d, 3H,
J¼7 Hz), 0.80–1.08 (m, 4H), 1.31–1.54 (m, 4H), 2.04 (s,

C. R. Berry, R. P. Hsung / Tetrahedron 60 (2004) 7629–7636
7635
bisulfite (1.0 g) and sodium meta-bisulfite (1.0 g) were
added in large excess. The mixture was allowed to stir for an
additional 5 h, after which gravity filtration followed by
removal of solvent under reduced pressure provided crude
diol 25. Silica gel flash column chromatography (gradient
eluent: 0–40% EtOAc in hexanes) provided the pure diol 25
in 60% yield (303.0 mg).
4.5.1. Compound 28a. Rf¼0.45 [15% ethyl acetate/
1
hexane]; H NMR (CDCl3) d 0.85–0.91 (m, 1H), 1.01 (d,
3H, J¼6.5 Hz), 1.24–1.36 (m, 1H), 1.72–1.79 (m, 1H),
2.05 (s, 3H), 2.61–2.79 (m, 2H), 3.70–3.82 (m, 1H), 4.99–
5.18 (m, 2H), 5.91–6.11 (m, 1H), 6.42 (s, 1H), 7.40–7.61
(m, 3H), 7.87 (d, 2H, J¼9 Hz); 13C NMR (CDCl3) d 20.1,
31.8, 36.9, 37.5, 53.8, 57.3, 112.2, 115.7, 126.9, 127.8,
129.0, 132.4, 134.3, 138.1; IR (film) cm21 3190m, 3022m,
2952m, 1274m; mass spectrum (LRMS): m/e (% relative
intensity) 292 (100) MþþH, 250 (20), 151 (30), 110 (10);
m/e calcd for C16H21NO2SNa 314.1191, found 314.1218.
4.3.1. Compound 25. Rf¼0.20 [50% EtOAc/hexane]; [a]D20
1
2149.28 [c 0.7, CH2Cl2]; H NMR (CDCl3) d 0.32 (d, 1H,
J¼18 Hz), 0.78 (d, 3H, J¼7 Hz), 1.13 (d, 1H, J¼18 Hz),
1.31 (s, 3H), 2.40 (brs, 1H, –OH), 2.80 (s, 3H), 3.67 (dd,
1H, J¼5, 12 Hz), 4.02 (dq, 1H, J¼7, 9 Hz), 4.64 (d, 1H,
J¼9 Hz), 4.86 (brs, 1H, –OH), 5.13 (dd, 1H, J¼5, 12 Hz),
5.32 (s, 1H), 6.93 (s, 1H), 7.01 (d, 1H, J¼7 Hz), 7.24–7.38
(m, 4H), 7.48–7.61 (m, 3H), 7.89 (d, 1H, J¼8 Hz), 7.94 (d,
1H, J¼8 Hz); 13C NMR (CDCl3) d 14.8, 20.1, 28.6, 31.3,
57.9, 59.2, 65.5, 67.4, 71.4, 112.7, 117.0, 127.1, 127.4,
128.1, 129.0, 129.2, 133.2, 138.1, 138.5, 164.1; IR (film)
cm21 3507m, 3354m, 3062m, 2932m, 1679s, 1433s; mass
spectrum (LRMS): m/e (% relative intensity) 472 (100)
MþþH, 331 (58), 282 (50), 191 (20); m/e calcd for
C24H29N3O5SNa 494.1726, found 494.1724.
Acknowledgements
Funding from NSF [CHE-0094005], JnJ-PRI, and the
McKnight Foundation are greatly appreciated. We thank
Mr. William W. Brennessel for solving the X-ray structure.
References and notes
4.4. Preparation of epoxide 26
1. For a review on allenamides, see: (a) Hsung, R. P.; Wei, L.-L.;
Xiong, H. Acc. Chem. Res. 2003, 36, 773. For reviews on
allenes see: (b) Saalfrank, R. W.; Lurz, C. J. In Methoden Der
Organischen Chemie (Houben-Weyl); Kropf, H., Schaumann,
E., Eds.; Georg Thieme Verlag: Stuttgart, 1993. (c) Schuster,
H. E.; Coppola, G. M. Allenes in Organic Synthesis; Wiley:
New York, 1984. For earlier documentations of allenamides,
see: (d) Dickinson, W. B.; Lang, P. C. Tetrahedron Lett. 1967,
To solution of diol 25 (95.0 mg, 0.20 mmol, 1.0 equiv.) in
freshly distilled CH2Cl2 (20 mL, 0.01 M) was added
51.0 mg NaHCO3 (0.60 mmol, 3.0 equiv.). The mixture
was cooled to 210 8C after which 1.5 equiv. of m-CPBA
(52.0 mg, 0.30 mmol) was added. The mixture was allowed
to stir under N2 for 8 h. Gravity filtration followed by
removal of solvent under reduced pressure and silica gel
flash column flash chromatography (gradient eluent: 0–10%
EtOAc in hexanes) afforded epoxide 26 in a 50% yield
(49.0 mg).
¨
8, 3035. (e) Bogentoft, C.; Ericsson, O.; Stenberg, P.;
Danielsson, B. Tetrahedron Lett. 1969, 10, 4745.
(f) Balasubramanian, K. K.; Venugopalan, B. Tetrahedron
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(h) Overman, L. E.; Marlowe, C. K.; Clizbe, L. A. Tetrahedron
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1
4.4.1. Compound 26. Rf¼0.62 [50% EtOAc/hexane]; H
NMR (CDCl3) d 0.80 (d, 1H, J¼15 Hz), 0.91 (d, 3H,
J¼8 Hz), 1.10 (s, 3H), 1.14 (d, 1H, J¼15 Hz), 2.86 (s, 3H),
2.90 (d, 1H, J¼8.5 Hz), 3.65 (d, 1H, J¼12 Hz), 4.26 (dq,
1H, J¼8, 12 Hz), 5.18 (brm, 1H, –OH), 5.31 (t, 1H,
J¼5 Hz), 5.65 (d, 1H, J¼1 Hz), 5.70 (d, 1H, J¼8.5 Hz),
6.91 (s, 1H), 7.39–7.64 (m, 6H), 7.97–8.11 (m, 4H); 13C
NMR (CDCl3) d 14.2, 25.1, 28.3, 33.9, 58.0, 66.7, 69.9,
70.6, 73.9, 84.7, 105.3, 127.8, 128.0, 128.1, 128.6, 129.0,
129.7, 133.6, 133.7, 169.6; IR (film) cm21 3522m, 3317m,
3117m, 2958m, 1684s, 1421s; mass spectrum (LRMS): m/e
(% relative intensity) 488 (100) MþþH, 191 (10); m/e calcd
for C24H29N3O6SNa 510.1675, found 510.1661.
2. For recent chemistry using allenamides, see: (a) Achmatowicz,
M.; Hegedus, L. S. J. Org. Chem. 2004, 69, 2229. (b) Ranslow,
P. D. B.; Hegedus, L. S.; de los Rios, C. J. Org. Chem. 2004,
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4869. (f) Kinderman, S. S.; van Maarseveen, J. H.;
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R.; Koppen, I.; Rasparini, M.; Sridharan, V. Chem. Commun.
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Tetrahedron Lett. 1998, 39, 435. (k) Grigg, R.; Sansano, J. M.;
Santhakumar, V.; Sridharan, V.; Thangavelanthum, R.;
Thornton-Pett, M.; Wilson, D. Tetrahedron 1997, 53, 11803.
(l) Kimura, M.; Horino, Y.; Wakamiya, Y.; Okajima, T.;
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3. For stereoselective oxa-[4þ2] cycloaddition reactions of
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4.5. Removal of the chiral auxiliary
To a solution of 35.0 mg of 23a (0.08 mmol, 1.0 equiv.) in
freshly distilled CH2Cl2 (8.4 mL, 0.01 M) was added at
278 8C 52.0 mg of SnBr4 (0.12 mmol, 1.5 equiv.) followed
by allyltrimethylsilane (0.05 mL, 4.0 equiv.) in dropwise
manner via a syringe. The reaction mixture was allowed to
gradually warm up to rt over 12 h under N2 to give the crude
mixture 28a/b after removal of solvent under reduced
pressure. Silica gel flash column chromatography (gradient
eluent: 0–10% EtOAc in hexanes) provided the isomeric
mixture 28a/b in 33% yield (8.0 mg) as clear oil.

7636
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(b) Wei, L.-L.; Xiong, H.; Douglas, C. J.; Hsung, R. P.
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1
19. All new compounds were identified and characterized by H
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