Developing a diastereoselective intramolecular [4 + 3] cycloaddition of nitrogen-stabilized oxyallyl cations derived from N-sulfonyl-substituted allenamides

Article abstract of DOI:10.1021/jo200147h

Efforts toward achieving a practical and diastereoselective intramolecular [4 + 3] cycloaddition of nitrogen-stabilized oxyallyl cations with tethered dienes are described. Epoxidation of N-sulfonyl substituted allenamides with dimethyldioxirane (DMDO) generates nitrogen-stabilized oxyallyl cations that readily undergo stereoselective [4 + 3] cycloaddition with dienes. Selectivity is found to depend on the tethering length as well as the stability of the oxyallyl cation intermediate, whether generated from N-carbamoyl- or N-sulfonyl-substituted allenamides. The use of chiral N-sulfonyl-substituted allenamides provided minimal diastereoselectivity in the cycloaddition, while high diastereoselectivity can be achieved with a stereocenter present on the tether. These studies provide further support for the synthetic utility of allenamides.

Full text of DOI:10.1021/jo200147h

ARTICLE
pubs.acs.org/joc
Developing a Diastereoselective Intramolecular [4 þ 3] Cycloaddition
of Nitrogen-Stabilized Oxyallyl Cations Derived from
N-Sulfonyl-Substituted Allenamides
Andrew G. Lohse, Richard P. Hsung,* Mitchell D. Leider, and Sunil K. Ghosh
Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53705, United States
S Supporting Information
b
ABSTRACT: Efforts toward achieving a practical and diaster-
eoselective intramolecular [4 þ 3] cycloaddition of nitrogen-
stabilized oxyallyl cations with tethered dienes are described.
Epoxidation of N-sulfonyl substituted allenamides with di-
methyldioxirane (DMDO) generates nitrogen-stabilized oxyal-
lyl cations that readily undergo stereoselective [4 þ 3]
cycloaddition with dienes. Selectivity is found to depend on
the tethering length as well as the stability of the oxyallyl cation
intermediate, whether generated from N-carbamoyl- or N-sulfonyl-
substituted allenamides. The use of chiral N-sulfonyl-substi-
tuted allenamides provided minimal diastereoselectivity in the
cycloaddition, while high diastereoselectivity can be achieved
with a stereocenter present on the tether. These studies provide
further support for the synthetic utility of allenamides.
’ INTRODUCTION
two approaches: I, N-tethered 4 f 6; and II, C-tethered
through either the R-position 7 f 8 or γ-position 9 f 10
[Scheme 2]. We elected to focus on approach I because it
underscores a distinct advantage as well as significance of using
nitrogen-stabilized oxyallyl cations in constructing complex
nitrogen heterocycles for natural or non-natural product
synthesis,15 thereby also further accentuating the synthetic
utility of allenamides.
Our first report on the intramolecular [4 þ 3] cycloaddition
utilized N-carbamoyl-substituted N-tethered allenamides that
could be prepared in three steps from furanyl iodide 11
[Scheme 3].11e Initial attempts using a direct addition of
2ꢀ5 equiv of DMDO led to low yields of the desired
cycloadducts 13a and 13b with mostly oxidative ring opening
of the furan. However, it was quickly found that slow addition
of DMDO via a syringe pump allowed for selective epoxidation
of the allenic double bond in 14 or 15 and slowed the
competing oxidation of furan. The ensuing intramolecular
[4 þ 3] cycloaddition of the corresponding oxyallyl cations with
furan led to the desired cycloadducts 16 and 17 in 80% and
75% yields, respectively, as single diastereomers. In addition,
a small amount of the epoxidized cycloadduct 18 as also
isolated from the reaction of 14. Although using the improved
syringe pump addition protocol we were able to show that a
few other N-carbamoyl-substituted allenamides could also
Over the past 30 years, the utility of heteroatom-stabilized
oxyallyl cations has risen to the forefront of [4 þ 3] cyclo-
additions.1,2 Heteroatom substituents such as oxygen3 and
sulfur,4 as well as halogens,5 provide electronically biased oxyallyl
cations that have become attractive intermediates for developing
not only highly regioselective but also stereoselective [4 þ 3]
cycloadditions.1,2 However, only recently has the utility of nitro-
gen-substituted oxyallyl cations in these cycloadditions received
significant attention.6 Almost 10 years ago, we first developed
stereoselective [4 þ 3] cycloadditions of chiral nitrogen-
stabilized7 oxyallyl cations 2b derived from allenamides 1 via
epoxidation [Scheme 1].8 These efforts rendered allenamides
highly visible as a new organicfunctional group,9 while allowing us
to contribute to the area of [4 þ 3] cycloadditions through
advancing its regio-10 and stereoselective manifolds,11,12 as well as
establishing the first asymmetric [4 þ 3] cycloaddition using
Cu(II)-bisoxazoline catalysts.13,14
The trivalency of the nitrogen atom offers the flexibility to
simultaneously tune its electron-donating ability toward the
oxyallyl cation through various substitutions while tethering a
chiral auxiliary [R*] and a coordinating unit [W] to achieve
both highly regio- and stereoselective [4 þ 3] oxyallyl cycload-
ditions, which remain a challenge in this field.1,11,12 While we
recently reported the first systematic study on the regioselec-
tivity of intermolecular [4 þ 3] cycloadditions with unsymmet-
rical furans,10a we have also been engaging in developing
intramolecular variants11d,e of our [4 þ 3] cycloaddition via
Received: January 20, 2011
Published: March 30, 2011
r
2011 American Chemical Society
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Scheme 1. Intermolecular [4 þ 3] Cycloaddition
Scheme 4. [4 þ 3] Cycloaddition of Chiral Allenamides
Scheme 2. Approaches to Intramolecular [4 þ 3]
Figure 1. One-to-one mixture of diastereomeric 20.
of N-carbamoyl-substituted allenamides but chose to use those
containing a chiral carbamoyl group, which could serve as an
auxiliary to provide asymmetric induction in the intramolecular
cycloaddition and gain access to optically enriched cycloadducts.
Consequently, our first attempt using chiral allenamide 19 with
the menthyl auxiliary gave cycloadduct 20 in 78% yield and what
appeared to be a single diastereomer based on NMR [Scheme 4].
Using a 3-carbon tether, the yield dropped dramatically in giving
cycloadduct 22. The stereoselectivity also dropped significantly
with respect to the ring fusion with only a 60:40 diastereomeric
ratio, which was also observed with achiral allenamides in our
previous work.11e Furthermore, an increase to the 4-carbon
tether failed to give the desired cycloadduct 24 regardless of
reaction temperature, most likely due to the increase in con-
formational entropy associated with the longer carbon tether.
While we were quite pleased with the apparent asymmetric
induction achieved in cycloadduct 20 when using the chiral
menthyl auxiliary for the 2-carbon tether, the excitement did not
last long. Upon examination of the X-ray crystal structure
obtained for cycloadduct 20, we were very surprised to find that
the X-ray structure contains a 1:1 mixture of diastereomers with
respect to the chiral auxiliary [Figure 1]. While it is quite unusual
to co-crystallize two diastereomers, this data suggests that the
chiral influence of the carbamate auxiliary is too far removed from
the rest of the molecule to provide any facial bias during the
cycloaddition and that it exerted very little influence in differ-
entiating the two diastereomers spectroscopically based on
proton NMR [Figure 2].16
Scheme 3. Previous Work on [4 þ 3] Cycloadditions
undergo successful intramolecular [4 þ 3] cycloaddition,11e
most of these examples in our communication were overengi-
neered, and the generality as well as practicality remained elusive.
We report here details of our efforts in evolving this intramole-
cular reaction into a useful and stereoselective cycloaddition
manifold for constructing nitrogen heterocycles.
’ RESULTS AND DISCUSSION
N-Carbamoyl-Substituted Allenamides. To commence our
studies, we reinvestigated intramolecular [4 þ 3] cycloadditions
N-Sulfonyl-Substituted Allenamides. We then decided to shift
our efforts from N-carbamoyl-substituted to N-sulfonyl-substituted
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Figure 2. 1H NMR of the [4 þ 3] cycloadduct 20.
Scheme 5. Synthesis of N-Sulfonyl Allenamides
Scheme 6. Intramolecular [4 þ 3] Cycloaddition
reaction time after addition of DMDO. This is in great contrast
with the reactivity of N-carbamoyl-substituted allenamides in
which DMDO epoxidation is much slower at temperatures
below ꢀ45 °C and often results in competing oxidative ring
opening of the furan.
We proceeded to examine the scope of the intramolecular
[4 þ 3] cycloaddition of N-sulfonyl-substituted allenamides
[Table 1]. First, methyl substitution at the R- or γ-allenic
position (entries 1 and 2, respectively) gave cycloadducts 36
and 37a with the major isomer of 37a shown as assigned via NOE
experiments. Attempts with γ-phenyl-substituted allenamide
(()-29b (entries 3 and 4) gave mostly hydrolysis of the
allenamide and oxidation of furan, perhaps resulting from a more
stabilized and less reactive oxyallyl cation. However, a cyclohexyl
substitution was well-tolerated (entry 6) giving cycloadduct 39
containing a spirocenter in 90% yield.
Various furan substitutions were also investigated (entries
7ꢀ10). Disubstituted furans with either benzyl- or silyl-ethers
afforded highly functionalized cycloadducts 41a and 41b, respec-
tively, in excellent yields. This suggests that even at low tem-
peratures, epoxidation of the allenic double bond is still favored
over oxidation of furan, which again contrasts with the reactivity
of N-carbamoyl allenamides. However, when using a trisubsti-
tuted furan (see 42) under the reaction conditions, epoxidation
of furan and oxidative ring opening occurred exclusively regard-
less of the reaction temperature. These results provide an
interesting comparison between the electron-donating ability
of the N-sulfonyl into the allenic double bond with that of the
electron-rich furan.
allenamides to investigate the difference in reactivity of N-sulfonyl
oxyallyl cations and perhaps improve overall selectivity in the
[4 þ 3] cycloaddition. Having recently published a facile route to
N-sulfonyl-substituted allenamides17 featuring a Mitsunobu reac-
tion, allenamide 27 could be prepared in two steps from alcohol 25
in excellent yield. [Scheme 5]. Alternatively, γ-substituted allena-
mide (()-29a and R-substituted allenamide 32 could be obtained
from alcohols 25 and 30, respectively, utilizing a four-step sequence
featuring two Mitsunobu reactions.18 It is worth noting that all of the
alcohols are commercially available, making it possible to quickly
access a variety of substituted allenamides depending on the
substituted alcohol.
Our initial examination of N-Ts-substituted allenamide 27 in
the [4 þ 3] cycloaddition revealed N-sulfonyl allenamides to be
much more reactive toward epoxidation as the reaction took
place readily at ꢀ78 °C giving cycloadduct 34 in almost
quantitative yield [Scheme 6]. The more electron-deficient
N-p-nitrobenzenesulfonyl-substituted allenamide 33 also af-
forded cycloadduct 35 in 93% yield requiring only slightly longer
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Table 1. Scope of [4 þ 3] Cycloadditions
Figure 3. Proposed model for [4 þ 3] cycloaddition.
Scheme 7. Previous Work on [4 þ 3] Cycloaddition
Scheme 8. Cycloadditions of Camphor-Derived Allenamides
a All reactions were carried out in CH2Cl2 at 0.05 M with MS 4 Å.
b Single diastereomers unless otherwise noted. c Isolated yields. d Major
isomer shown. e Mostly decomposition by hydrolysis or oxidation
of furan. f dr = 75:25. g dr = 90:10.
The three-carbon tethered allenamides 44 and 46 showed
significantly better results compared with the N-carbamoyl
allenamides (vide supra). Not only were yields much higher with
or without a gem-dimethyl group, but the overall diastereoselec-
tivity also increased (entries 12 and 14). Furthermore, despite a
large entropic barrier, the four-carbon tethered allenamide 48 did
afford the desired cycloadduct 49, albeit in a modest 17% yield.
It is worth noting that higher temperatures were required for the
longer tethers to overcome the entropic barrier needed for furan
to orient itself with the oxyallyl cation before competing oxida-
tion or hydrolysis took place. Finally, the cycloaddition pro-
ceeded with a simple butadiene giving cycloadduct 51 in 73%
yield (entry 17). Higher temperature was also required in this
case as the unreactive S-trans conformation likely dominates
at ꢀ78 °C.
cycloadduct, the oxyallyl cation 52-endo should experience more
A
1,3 strain with the planar nitrogen substituents whereas 52-exo
possesses a more preferred W-conformation.1,2 DFT calculations
of the two possible transition state conformations also shows a
tremendous preference for 52-exo.20 Thus, approach I in the
intramolecular [4 þ 3] cycloaddition of nitrogen-stabilized
oxyallyl cations likely proceeds in an exo manner.
X-ray analysis of cycloadduct 35 unambiguously confirmed the
[4 þ 3] cycloaddition pathway with N-sulfonyl allenamides and
provides a general mechanistic model of the cycloaddition as
shown in Figure 3. Although two possible transition structures
are at play, 52-endo [or compact]19 and 52-exo [or extended],19
which could both provide the observed stereochemistry in the
Achieving Diastereoselectivity in the [4 þ 3] Cycloaddi-
tion. With the improved reactivity of N-sulfonyl-substituted
allenamides in the intramolecular [4 þ 3] cycloaddition, we
decided to once again investigate the effect of a chiral auxiliary in
the reaction. From our previous work, we were able to achieve
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Scheme 9. Initial Route to Chiral Allenamide 63
Scheme 10. Revised Route to (()-63: Showing One
Enantiomer
high diastereoselectivities and gain access to optically active
cycloadducts containing seven- or eight-membered rings fused
to the cycloheptane when using chiral oxazolidinone-substituted
allenamides 53 [Scheme 7]11e In the ensuing cycloaddition, the
preferred W-conformation and a similar exo approach with chiral
oxyallyl 54 would lead to the observed major diastereomer of 55.
However, the multistep synthesis required to make the cyclic
allenamides as well as the potential difficulty in cleaving the
auxiliary somewhat limited the utility of this approach.
Table 2. Diastereoselective [4 þ 3] Cycloadditions
We chose to investigate the chiral camphor-derived auxiliary
for our N-sulfonyl-substituted allenamides for two reasons: 1)
the possible coordinating effect of the ketone with a Lewis acid
during the cycloaddition; 2) previously reported success in other
cycloadditions using camphor auxiliaries.21 As shown in
Scheme 8, reaction of camphor-derived allenamide 56 in the
presence of ZnCl2 gave cycloadduct 57 in excellent yield but with
only modest diastereoselectivity. Similar results were obtained
upon conversion of the ketone to a silyl-ether on the auxiliary
(58 f59). Despite the improved reactivity of N-sulfonyl-substituted
allenamides in the [4 þ 3] cycloaddition, these results further
support our previous conclusion that N-substituted auxiliaries are
too far removed to provide asymmetric induction during the
cycloaddition.
temp
yield
major:
minor
entry allenamidea
X
[°C] cycloadduct [%]b
1
2
3
4
5
6
(()-63
(()-63
(()-68
(()-70
(()-72
(()-72
-OTIPS
-OTIPS
-OTES
-OPiv
ꢀ78
0
67
67
69
71
73
73
85
86
97
94
<5
49
80:20
75:25
83:17
>95:5
ꢀ78
ꢀ78
-NBocp-Ns ꢀ78
-NBocp-Ns
0
>95:5
a All reactions were carried out at 0.05 M with 50 mg MS 4 Å. b Isolated
yields.
of the nitrile to a primary amine followed by tosylation then
provided sulfonamide (()-66 in good overall yield. Finally,
propargylation and subsequent isomerization using our protocol
afforded the desired allenamide (()-63. It is worth noting that
Hashmi’s synthesis was also done asymmetrically using enzyme
catalysis for the cyanohydrin formation.25,26 We are also aware of
the fact that O’Doherty has documented an array of beautiful and
practical asymmetric protocols for accessing diols and amino
alcohols related to 60 and 66 that we could adopt in future
applications.27
Other derivatives were also prepared in order to investigate
their effect on the diastereoselectivity in the [4 þ 3] cycloaddi-
tion. As shown in Table 2, our first attempt using TIPS-protected
allenamide (()-63 under our standard conditions gave the
desired cycloadduct in 85% yield with an 80:20 diastereomeric
ratio, similar to that of the [4 þ 2] product. The yield remained
the same at a higher reaction temperature, although a slight
decrease in selectivity was observed (entry 2). Interestingly, the
smaller TES group gave a slight increase in selectivity and yield
(entry 3).
Knowing that the chiral auxiliary had little effect on the overall
conformation during the cycloaddition, we chose to prepare
allenamides containing a stereocenter on the tether in order to
provide more of a conformational bias and perhaps lead to better
selectivity [Scheme 9]. We chose to prepare diol 60 from the
commercially available tri-O-acetyl-D-glucal using a previously
reported protocol.22 However, using either FeCl3 6H2O or
3
InCl3 3H2O, we found poor overall conversion under the
3
reaction conditions. Selective protection of the primary alcohol
with tosyl chloride in the presence of dibutyltin oxide23 followed
by protection of the secondary hydroxyl group provided tosylate
61 in good yield.24 Interestingly, in an attempt to displace the
tosylate with N-tosyl propargyl amine to obtain propargyl amide
62, we instead obtained the [4 þ 2] cycloadduct 64 in 65% yield,
presumably through our previously reported tandem isomeriza-
tionꢀcycloaddition sequence.17 Although the [4 þ 2] product
was not desired, we were impressed by the overall yield for the
three-step tandem sequence. Furthermore, we were encouraged
by the diastereoselectivity observed, hoping for similar or better
results in the [4 þ 3] cycloaddition.
While we were pleased with the reasonable selectivity ob-
served using silyl-protecting groups, we reasoned that we might
be able to achieve even better diastereoselectivity using a pivalate
protecting group because the shorter oxygenꢀcarbon bond
could provide a stronger conformational bias during the ensuing
Using a revised route reported by Hashmi,25 we were able to
obtain the racemic propargyl amide (()-62 starting from furfural
[Scheme 10]. Cyanohydrin formation followed by silyl protec-
tion of the resultant alcohol gave (()-65 in 72% yield. Reduction
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Table 3. Comparison of [4 þ 2] and [4 þ 3] Cycloadducts
δ ppm (500 MHz)
6.58 (s, Ha)
1.91 (dd, Hb, J = 1.5,14.0 Hz)
2.52 (ddd, Hc, J = 1.0, 4.5,14.0 Hz) 0.66 3.18 (dd, Hc, J = 5.0, 15.0 Hz)
Δδ ppm
3.16 3.42 (s, Ha)
0.48 2.39 (d, Hb, J = 15.0 Hz)
δ ppm (500 MHz)
5.05 (d, Hd, J = 1.5, 4.5 Hz)
6.27 (dd, He, J = 1.5, 5.5 Hz)
6.22 (d, Hf, J = 6.0 Hz)
0.03 5.08 (d, Hd, J = 5.0 Hz)
0.07 6.34 (d, He, J = 6.0 Hz)
0.05 6.17 (d, Hf, J = 6.0 Hz)
Figure 4. NOE experiments and proposed model.
Scheme 11. Divergent Reactivity of N-Sulfonyl Allenamides
cycloaddition. To our delight, the pivalate-protected allenamide
(()-70 afforded the desired cycloadduct not only in excellent yield
but also with excellent diastereoselectivity (entry 4). Furthermore,
while reaction of nitrogen-substituted allenamide (()-72 failed
at ꢀ78 °C, giving only oxidative ring-opening and hydrolysis
products, the desired cycloadduct 73 could also be obtained with
excellent selectivity and reasonable yield at higher temperature
(entry 6). We reasoned that the steric bulk of the substituents on
the nitrogen atom may actually hinder the ensuing cycloaddition,
thus allowing the competing oxidative ring-opening pathway to
dominate, especially at low temperatures.
facile preparation from a variety of commercially available
starting materials also provides a practical approach to accessing
a diverse array of complex heterocyclic scaffolds via thermal or
electrophilic activation conditions.
’ CONCLUSION
Spectroscopic Comparisons of [4 þ 2] and [4 þ 3] Cyclo-
adducts and Mechanistic Pathways. An interesting comparison
can be made between [4 þ 2] and [4 þ 3] cycloadducts derived
from TIPS-protected allenamide (()-63. As shown in Table 3, the
We have described here our efforts toward achieving a
practical and diastereoselective intramolecular [4 þ 3] cycload-
dition of nitrogen-stabilized oxyallyl cations with tethered dienes.
Selectivity is found to depend greatly on the tethering length as
well as the stability of the oxyallyl cation intermediate, whether
generated from N-carbamoyl- or N-sulfonyl-substituted allena-
mides. Oxyallyl cations derived from the N-sulfonyl-substituted
allenamides show overall improved reactivity in the cycloaddi-
tion, allowing for greater diversity in substrate scope. While the
use of chiral auxiliaries provided minimal diastereoselectivity in
the cycloaddition, high diastereoselectivity can be achieved with a
stereocenter present on the tether. These studies provide further
support for the synthetic utility of allenamides and promising
potential for future development in intramolecular [4 þ 3]
cycloadditions of nitrogen-stabilized oxyallyl cations.
1
two cycloadducts have similar key H NMR resonances with
the largest difference obviously being the Ha proton on an sp2
versus sp3 carbon. However, an interesting dichotomy arises when
comparing the major isomers of [4 þ 2] and [4 þ 3] cycloadducts
(64-major and 67-major, respectively). The major isomer from the
[4 þ 2] cycloaddition possesses an anti relationship between the
silyl-ether and the oxa-bicyclic bridge, whereas that of the [4 þ 3]
cycloadduct possesses a syn relationship as assigned via NOE
experiments.
A working model was proposed based on the stereochemical
assignments and our previous mechanistic understanding of the
[4 þ 2] and [4 þ 3] pathways [Figure 4]. In the [4 þ 2]
pathway, the most stable conformation would place the large
silyl-ether substituent in a pseudoequatorial position away from
the ensuing cycloaddition thus leading to the observed isomer.
For the [4 þ 3] pathway, if we maintain the preferred W-con-
formation of the oxyallyl-cation, we can envision two possible
exo-approaches. While exo-I would suffer from steric interaction
of the large silyl-ether pointing into the ensuing cycloaddition
thereby leading to the minor isomer, exo-II places the silyl-ether
away from the cycloaddition and would lead to the observed
major isomer.
’ EXPERIMENTAL SECTION
General Experimental Methods. All reactions were performed
in flame-dried glassware under nitrogen atmosphere. Solvents were
distilled prior to use. 1H and 13C NMR spectra were obtained on 400 or
500 MHz spectrometers using CDCl3 with TMS or residual solvent as
standard unless otherwise noted. Infrared spectra were obtained in
CHCl3 or neat. Optical rotations were measured on a digital polarimeter,
using a 1 mL cell with a 1 dm path length. For low (MS) and high
(HRMS) resolution, m/z ratios are reported as values in atomic mass
units. Mass analysis was done in either APCI mode or EI mode. All
spectral data obtained for new compounds are reported here.
The ability to access both [4 þ 2] and [4 þ 3] cycloadducts
through divergent pathways highlights yet another synthetic
utility of N-sulfonyl allenamides [Scheme 11]. Not only do
N-sulfonyl-substituted allenamides show improved reactivity
compared to N-carbamoyl-substituted allenamides, but their
General Procedure for Isomerizaton of Propargyl Amides
to Allenamides. To a flame-dried 25 mL RB flask filled were added
propargyl amide 26 (245 mg, 0.8 mmol) and anhydrous THF (0.3 M)
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under N2. The solution was cooled to 0 °C, and t-BuOK (20 mol % from
1 M solution in THF) was added. The resulting mixture was warmed to
room temperature or the reported reaction temperature and stirred for
2ꢀ6 h. The reaction was monitored by TLC and after completion was
filtered through Celite or a small bed of silica gel with ethyl acetate and
concentrated under reduced pressure. The crude residue was purified via
silica gel flash column chromatography (isocratic eluent: EtOAc in
hexanes) to provide the desired allenamide 27 (235 mg, 96%) as a
colorless oil.
(% relative intensity) 461.2 (10) (M þ Na þ H)þ, 460.2 (100) (M þ
Na)þ, 438.2 (10) (M þ H)þ; HRMS (ESI) m/e calcd for C25H27NO4Sþ
(M þ Na)þ 460.1553, found 460.1551.
Allenamide 44 (170 mg, 0.49 mmol) was prepared in 68% yield from
the corresponding propargyl amide according to the general procedure.
Rf = 0.45 [1:5 EtOAc/hexanes]; white solid; mp = 64ꢀ65 °C; 1H NMR
(500 MHz, CDCl3) δ 0.96 (s, 6H), 2.42 (s, 3H), 2.61 (s, 2H), 2.98
(s, 2H), 5.17 (d, 2H, J = 6.5 Hz), 6.03 (d, 1H, J = 3.0 Hz), 6.28 (dd, 1H,
J = 1.5, 2.5 Hz), 6.74 (t, 1H, J = 6.5 Hz), 7.29 (d, 1H, J = 1.5 Hz), 7.31 (d,
2H, J = 8.0 Hz), 7.66 (d, 2H, J = 8.0 Hz); 13C NMR (125 MHz, CDCl3) δ
21.7, 25.6, 36.3, 39.1, 56.0, 88.0, 102.5, 107.8, 110.3, 127.7, 129.7, 134.8,
141.2, 143.8, 153.6, 203.1; IR (neat) cmꢀ1 2925 m, 2189w, 1659w, 1459 m,
1166s; MS (ESI) m/e (% relative intensity) 341.3 (15) (M þ Na þ H)þ,
340.2 (100) (M þ Na)þ, 318.3 (5) (M þ H)þ; HRMS (ESI) m/e calcd
for C17H19NO3Sþ (M þ Na)þ 340.0978, found 340.0980.
Allenamide 21 (178 mg, 0.51 mmol) was prepared in 85% yield
according to the general procedure. Rf = 0.65 [1:9 EtOAc/hexanes];
1
[R]23 ꢀ45.4° [c 1.0, CH2Cl2]; pale yellow oil; H NMR (500 MHz,
D
CDCl3) (dueto rotamers, many ofthesignals were notwell-resolvedand/
or line-broadened) δ 0.79 (d, 3H, J = 7.0 Hz), 0.87ꢀ0.91 (m, 6H),
0.92ꢀ0.98 (m, 1H), 1.00ꢀ1.08 (m, 1H), 1.10 (t, 1H, J = 7.0 Hz),
1.33ꢀ1.40 (m, 1H), 1.44ꢀ1.53 (m, 1H), 1.64ꢀ1.71 (m, 2H), 1.85ꢀ1.96
(m, 2H), 2.24ꢀ2.29 (m, 1H), 2.62 (t, 1H, J = 7.5 Hz), 3.26 (brs, 1H),
3.35ꢀ3.49 (m, 2H), 4.63 (td, 1H, J = 4.0, 10.5 Hz), [extra resonance due
to rotamer, 4.56 (td, J = 4.0, 10.5 Hz)] 5.31 (brs, 2H), 5.99 (brs, 1H), 6.27
(brs, 1H), due to rotamers, R-H on allenamide split into two signals: 7.01
Allenamide 48 (296 mg, 0.89 mmol) was prepared in 99% yield from
the corresponding propargyl amide according to the general procedure.
Rf = 0.47 [1:3 EtOAc/hexanes]; pale yellow oil; 1H NMR (500 MHz,
CDCl3) δ 1.57 (sept, 2H, J = 7.0 Hz), 1.65 (sept, 2H, J = 7.5 Hz), 2.42
(s, 3H), 2.61 (t, 2H, J = 7.0 Hz), 3.10 (t, 2H, J = 7.0 Hz), 5.25 (d, 2H,
J = 6.5 Hz), 5.96 (dd, 1H, J = 0.5, 8.0 Hz), 6.26 (dd, 1H, J = 2.0, 8.0 Hz),
6.81 (t, 1H, J = 6.0 Hz), 7.28 (d, 1H, J = 1.5 Hz), 7.30 (d, 2H, J = 8.0
Hz), 7.67 (d, 2H, J = 8.0 Hz); 13C NMR (125 MHz, CDCl3) δ 21.7,
25.1, 27.4, 27.6, 46.4, 87.6, 100.3, 105.1, 110.2, 127.3, 129.9, 135.6,
140.9, 143.8, 155.9, 201.6; IR (thin film) cmꢀ1 3260w, 2926 m, 1597w,
1347s, 1160s; MS (ESI) m/e (% relative intensity) 355.3 (10) (M þ
Na þ H)þ, 354.3 (100) (M þ Na)þ, 332.3 (10) (M þ H)þ;HRMS(ESI)
m/e calcd for C18H21NO3Sþ (M þ Na)þ 354.1135, found 354.1142.
Allenamide 56 (70 mg, 0.19 mmol) was prepared in 70% yield from
the corresponding propargyl amide according to the general procedure.
(t, 0.5H, J = 6.0 Hz) and 7.17 (t, 0.5H, J = 6.0 Hz), 7.29 (br s, 1H); 13
C
NMR (125 MHz, CDCl3) not recorded to due to rotamers; IR
(neat) cmꢀ1 2952s, 2930 m, 1703s, 1457 m, 1236 m; MS (ESI) m/e
(% relative intensity) 369.4(5) (M þ Na þ H)þ, 369.4 (80) (M þ Na)þ,
346.4 (5) (M þ H)þ, 310.4 (100); HRMS (ESI) m/e calcd for
C21H31NO 3þ (M þ Na)þ 368.2197, found 368.2203.
Allenamide 23 (1.01 g, 2.8 mmol) was prepared in 89% yield
according to the general procedure. Rf = 0.80 [1:4 EtOAc/hexanes];
[R]23D ꢀ44.4° [ c 1.0, CH2Cl2]; pale yellow oil; 1H NMR (400 MHz,
CDCl3) (due to rotamers, many of the signals were not well-resolved
and/or line-broadened) δ 0.78 (d, 3H, J = 7.2 Hz), 0.90 (dd, 6H, J = 2.4,
7.2 Hz), 1.05 (qd, 2H, J = 3.2, 12.8 Hz), 1.26ꢀ1.29 (m, 1H), 1.35ꢀ1.40
(m, 1H), 1.44ꢀ1.49 (m, 1H), 1.55ꢀ1.64 (m, 4H), 1.65ꢀ1.72 (m, 2H),
1.88ꢀ1.94 (m, 1H), 2.05 (d, 1H, J = 12.8 Hz), 2.63 (t, 2H, J = 7.6 Hz),
3.32ꢀ3.46 (m, 2H), 4.63 (td, 1H, J = 4.4, 10.4 Hz), 5.30ꢀ5.34 (m, 2H),
5.96 (d, 1H, J = 2.4 Hz), 6.26 (brs, 1H), due to rotamers, R-H on
allenamide split into two signals: 7.01 (t, 0.5H, J = 6.2 Hz) and 7.17
(t, 0.5H, J = 6.2 Hz), 7.28 (brs, 1H); 13C NMR (125 MHz, CDCl3) not
recorded to due to rotamers; IR (neat) cmꢀ1 2953 m, 1698s, 1457 m,
1401s, 1302 m; MS (ESI) m/e (% relative intensity) 383.4 (10) (M þ
Na þ H)þ, 382.4 (100) (M þ Na)þþ, 360.4 (20) (M þ H)þ; HRMS
Rf = 0.51 [1:2 EtOAc/hexanes]; [R]23 þ14.2° [ c 0.55, CH2Cl2];
D
yellow oil; 1H NMR (400 MHz, CDCl3) δ 0.87, (s, 3H), 1.13 (s, 3H),
1.42 (ddd, 1H, J = 4.0, 5.6, 13.2 Hz), 1.65 (ddd, 1H, J = 4.4, 5.2, 14.0 Hz),
1.93 (d, 1H, J = 18.4 Hz), 2.01ꢀ2.07 (m, 1H), 2.10 (t, 1H, J = 4.4 Hz),
2.38 (dt, 1H, J = 4.0, 18.4 Hz), 2.45ꢀ2.52 (m, 1H), 2.81 (d, 1H, J = 14.8
Hz), 2.95 (t, 2H, J = 7.6 Hz), 3.38 (d, 1H, J = 14.4 Hz), 3.62 (sept, 1H,
J = 7.6 Hz), 3.67 (sept, 1H, J = 7.6 Hz), 5.45 (d, 2H, J = 6.0 Hz), 6.10 (d,
1H, J = 3.6 Hz), 6.28 (t, 1H, J = 2.4 Hz), 6.74 (t, 1H, J = 6.4 Hz), 7.31 (dd,
1H, J = 1.2, 2.0 Hz); 13C NMR (100 MHz, CDCl 3) δ 19.9, 20.1, 25.4,
27.0, 27.6, 42.7, 43.0, 45.6, 47.9, 48.0, 58.5, 88.2, 99.8, 106.7, 110.4,
141.6, 152.3, 200.8, 214.9; IR (thin film) cmꢀ1 2921 m, 1742s, 1350s,
1235 m, 1089s; MS (ESI) m/e (% relative intensity) 386.8 (10) (M þ
Na)þ, 385.9 (100), 363.9 (20) (M)þ; HRMS (ESI) m/e calcd for
C19H25NO 4Sþ (M þ Na)þ 386.1397, found 386.1394.
(ESI) m/e calcd for C22H33NO
382.2364.
(M þ Na)þ 382.2353, found
3
Allenamide 32 (40 mg, 0.13 mmol) was prepared in 40% yield
according to the general procedure at 40 °C. Rf = 0.42 [1:5 EtOAc/
hexanes]; colorless oil; 1H NMR (400 MHz, CDCl3) δ 1.99 (t, 3H, J =
3.2 Hz), 2.41 (s, 3H), 2.87 (t, 2H, J = 7.2 Hz), 3.39 (t, 2H, J = 7.2 Hz),
4.66 (qt, 2H, J = 3.2 Hz), 6.09 (dd, 1H, J = 0.4, 3.2 Hz), 6.27 (dd, 1H, J =
2.0, 3.2 Hz), 7.26 (brs, 1H), 7.27 (d, 2H, J = 8.4 Hz), 7.64 (d, 2H, J = 8.4
Hz);13C NMR (100 MHz, CDCl3) δ 21.3, 21.7, 48.9, 81.6, 106.6, 107.3,
110.4, 128.0, 129.4, 134.2, 141.5, 143.6, 152.5, 207.1; IR (neat) cmꢀ1
2925 m, 1597 m, 1348s, 1159s, 1092 m; MS (ESI) m/e (% relative
intensity) 340.9 (10) (M þ Na)þ, 339.8 (100), 318.9 (10) (M þ H)þ,
317.9 (60) (M)þ ; HRMS (ESI) m/e calcd for C17H19NO3Sþ (M þ
Na)þ 340.1159, found 340.1163.
Allenamide 40a (90 mg, 0.205 mmol) was prepared in 75% yield
according to the general procedure. Rf = 0.30 [1:5 EtOAc/hexanes];
colorless oil; 1H NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 2.83 (t, 2H,
J = 7.6 Hz), 2.88 (t, 2H, J = 7.2 Hz), 3.36 (t, 2H, J = 7.6 Hz), 3.69 (t, 2H,
J = 7.2 Hz), 4.52 (s, 2H), 5.30(d, 2H, J = 6.0Hz), 5.93 (s, 2H), 6.83 (t, 1H,
J = 6.0 Hz), 7.24ꢀ7.32 (m, 7H), 7.68 (d, 2H, J = 8.4 Hz); 13C NMR (100
MHz, CDCl3) δ 21.7, 27.3, 29.0, 45.4, 68.5, 73.1, 88.0, 100.2, 106.7, 107.1,
127.3, 127.7, 127.8, 128.5, 129.9, 135.6, 138.4, 143.9, 150.8, 152.0, 201.3;
IR (neat) cmꢀ1 2861w, 1597w, 1453 m, 1353s, 1161s; MS (ESI) m/e
Allenamide 58 (107 mg, 0.22 mmol) was prepared in 97% yield from
the corresponding propargyl amide according to the general procedure.
Rf = 0.43 [1:10 EtOAc/hexanes]; [R]23D ꢀ22.8° [ c 0.54, CH2Cl2]; pale
yellow oil; 1H NMR (400 MHz, CDCl3) δ 0.06 (s, 3H), 0.11 (s, 3H),
0.84 (s, 3H), 0.87 (s, 9H), 0.99 (s, 3H), 1.06ꢀ1.12 (m, 1H), 1.39 (ddd,
1H, J = 3.6, 9.6, 11.2 Hz), 1.68ꢀ1.75 (m, 4H), 1.98 (td, 1H, J = 3.2, 11.6
Hz), 2.63 (d, 1H, J = 13.6 Hz), 2.90 (t, 2H, J = 7.6 Hz), 3.48 (d, 1H, J =
13.2 Hz), 3.56 (sept, 1H, J = 6.4 Hz), 3.60 (sept, 1H, J = 6.8 Hz), 4.01
(dd, 1H, J = 3.6, 6.8 Hz), 5.42 (d, 2H, J = 6.0 Hz), 6.08 (d, 1H, J = 0.8, 3.2
Hz), 6.28 (dd, 1H, J = 2.0, 3.2 Hz), 6.74 (t, 1H, J = 6.0 Hz), 7.31 (dd, 1H,
J = 0.8, 1.6 Hz); 13C NMR (100 MHz, CDCl3) δ ꢀ4.8, ꢀ3.7, 17.9, 20.3,
20.9, 26.1, 27.4, 27.7, 29.3, 42.5, 44.7, 45.3, 48.7, 49.1, 50.2, 76.3, 88.0,
100.1, 106.6, 110.5, 141.6, 152.5, 200.7; IR (thin film) cmꢀ1 2928 m,
1595w, 1358s, 1151s, 1083s; MS (ESI) m/e (% relative intensity) 503.5
(15) (M þ Na þ H) þ, 502.5 (100) (M þ Na)þ; HRMS (ESI) m/e
calcd for C25H41NO 4SSiþ (M þ Na)þ 502.2418, found 502.2401.
Allenamide (()-63 (153 mg, 0.32 mmol) was prepared in 61% yield
according to the general procedure. Rf = 0.36 [1:8 EtOAc/hexanes];
colorless oil; 1H NMR (400 MHz, CDCl3) δ 0.98 (d, 9H, J = 5.6 Hz),
1.01ꢀ1.07 (m, 12H), 2.41 (s, 3H), 3.30 (dd, 1H, J = 7.2, 13.6 Hz), 3.45
3252
dx.doi.org/10.1021/jo200147h |J. Org. Chem. 2011, 76, 3246–3257

The Journal of Organic Chemistry
ARTICLE
(dd, 1H, J = 6.8, 13.6 Hz), 5.08 (t, 2H, J = 7.2 Hz), 5.24 (d, 2H, J = 6.0
Hz), 6.26 (dd, 1H, J = 3.2 Hz), 6.29ꢀ6.31 (m, 1H), 6.68 (t, 1H, J = 6.4
Hz), 7.29 (d, 2H, J = 8.0 Hz), 7.34 (dd, 1H, J = 0.8, 1.2 Hz), 7.66 (d, 2H,
J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 12.4, 17.9, 18.0, 21.7, 51.7,
67.1, 88.2, 101.0, 107.8, 110.2, 127.4, 129.8, 135.2, 141.9, 143.8, 154.5,
201.4; IR (neat) cmꢀ1 2943 m, 2866w, 1462w, 1359s, 1164s; MS (ESI)
m/e (% relative intensity) 499.2 (5) (M þ Na þ H)þ, 498.2 (25) (M þ
Na)þ, 476.2 (100) (M þ H)þ; HRMS (ESI) m/e calcd for
C25H37NO4SSiþ (M þ H)þ 476.2286, found 476.2269.
General Procedure for the Intramolecular [4 þ 3] Cycload-
dition of Allenamides. To a solution of allenamide (()-70 (40 mg,
0.10 mmol) and 50 mg of 4 Å molecular sieves in CH2Cl2 (2 mL) was
added DMDO (2.8 mL, 0.07 M in acetone, 2 equiv) as a chilled
solution (at ꢀ78 °C) via syringe pump over ∼1ꢀ2 h. The syringe
pump was cooled by dry ice at all times during the addition. After the
addition, the solution was filtered through Celite with ethyl acetate and
concentrated under reduced pressure. The resulting crude residue
was purified via silica gel flash column chromatography (isocratic
eluent: EtOAc in hexanes) to provide the desired cycloadduct 71 (39
mg, 0.093 mmol, 94% yield, >95:5 dr). Rf = 0.11 [1:3 EtOAc/hexanes];
colorless oil; 1H NMR (400 MHz, CDCl3) δ 0.98 (s, 9H), 2.41 (s, 3H),
2.42 (d, 1H, J = 16.0 Hz), 3.13 (dd, 1H, J = 5.6, 16.0 Hz), 3.52 (d, 1H,
J = 12.8 Hz), 3.56 (s, 1H), 4.02 (dd, 1H, J = 4.0, 12.8 Hz), 5.07 (d, 1H, J =
4.0 Hz), 5.11 (d, 1H, J = 6.4 Hz), 6.05 (dd, 1H, J = 0.4, 6.0 Hz), 6.42 (dd,
1H, J = 1.6, 6.0 Hz), 7.33 (d, 2H, J = 8.0 Hz), 7.81 (d, 2H, J = 8.0 Hz); 13C
NMR (100 MHz, CDCl3) δ 21.6, 26.8, 27.1, 38.6, 44.2, 55.6, 69.1, 78.5,
93.6, 128.1, 128.2, 129.8, 134.1, 137.3, 144.0, 176.8, 200.4; IR (thin
film) cmꢀ1 2976 m, 1733s, 1597 m, 1240s, 1140s; MS (ESI) m/e
(% relative intensity) 443.2 (10) (M þ Na þ H)þ, 442.1 (100) (M þ
Na)þ, 420.1 (40) (M þ H)þ; HRMS(ESI) m/e calcd forC21H25NO6Sþ
(M þ H)þ 420.1476, found 420.1490.
Allenamide (()-68 (115 mg, 0.26 mmol) was prepared in 82% yield
according to the general procedure. Rf = 0.35 [1:8 EtOAc/hexanes];
colorless oil; 1H NMR (400 MHz, CDCl3) δ 0.57 (qt, 6H, J = 7.6 Hz),
0.90 (t, 9H, J = 8.0 Hz), 2.41 (s, 3H), 3.37 (AB of ABX, 2H, JAX = JBX
=
6.8, JAB = 13.6 Hz), 4.96 (t, 1H, J = 6.8 Hz), 5.27 (d, 2H, J = 6.4 Hz), 6.26
(d, 1H, J = 3.2 Hz), 6.30 (dd, 1H, J = 1.6, 3.2 Hz), 6.73 (t, 1H, J = 6.4 Hz),
7.29 (d, 2H, J = 8.0 Hz), 7.37 (d, 1H, J = 1.6 Hz), 7.67 (d, 2H, J = 8.0 Hz);
13C NMR (100 MHz, CDCl3) δ 4.7, 6.8, 21.7, 51.5, 66.7, 88.1, 100.9,
107.5, 110.3, 127.4, 129.8, 135.2, 142.0, 143.8, 154.4, 201.5; IR
(neat) cmꢀ1 2940 m, 1460w, 1355s, 1159s, 1090s; MS (ESI) m/e (%
relative intensity) 457.2 (15) (M þ Na þ H)þ, 456.1 (50) (M þ Na)þ,
434.2 (100) (M þ H)þ; HRMS (ESI) m/e calcd for C22H31NO4SSiþ
(M þ Na)þ 456.1636, found 456.1634.
Allenamide (()-70 (90 mg, 0.22 mmol) was prepared in 52% yield
according to the general procedure. Rf = 0.31 [1:8 EtOAc/hexanes];
Cycloadduct 20 (40 mg, 0.115 mmol) was isolated in 78% yield from
allenamide 19 as a 1:1 mixture of diastereomers according to the general
1
procedure. Rf = 0.15 [1:2 EtOAc/hexanes]; [R]23 ꢀ469.1° [c 0.13,
white solid; mp = 47ꢀ49 °C; H NMR (400 MHz, CDCl3) δ 1.22
D
CH2Cl2]; white solid; 1H NMR (500 MHz, CDCl3) (due to rotamers,
many of thesignals were not well-resolvedand/or line-broadened) δ 0.79
(d, 3H, J = 7.0 Hz), 0.89 (d, 6H, J = 6.5 Hz); 0.80ꢀ1.08 (m, 3H),
1.26ꢀ1.34 (m, 1H), 1.45ꢀ1.50 (m, 1H), 1.65 (d, 2H, J = 10.0 Hz),
1.92ꢀ1.96 (m, 1H), 2.10 (dd, 1H, J = 6.0, 13.0 Hz), 2.14ꢀ2.20 (m, 1H),
2.41 (ddd, 1H, J = 1.0, 4.0, 16.0 Hz), 2.93 (ddd, 1H, J = 2.5, 9.5, 16.0 Hz),
3.52 (td, 1H, J = 6.0, 11.5 Hz), 3.90 (brs, 1H), 4.05 (brs, 1H), 4.58
(td, 1H, J = 4.0, 11.0 Hz), 5.03 (d, 1H, J = 6.5 Hz), 6.27 (d, 1H, J = 6.0
Hz), 6.45 (dt, 1H, J = 1.5, 6.0 Hz); 13C NMR (125 MHz, CDCl3) not
recorded to due to rotamers; IR (thin film) cmꢀ1 2954s, 2870s, 1731s,
1694s, 1416 m; MS (ESI) m/e (% relative intensity) 371.3 (15) (M þ Na
(s, 9H), 2.42 (s, 3H), 3.31(dd, 1H, J = 4.0, 14.0 Hz), 3.84 (dd, 1H, J =
9.2, 14.0 Hz), 5.29 (dd, 1H, J = 6.4, 10.0 Hz), 5.41 (dd, 1H, J = 6.4, 10.4
Hz), 6.05 (dd, 1H, J = 4.4, 9.2 Hz), 6.32 (dd, 1H, J = 2.0, 3.2 Hz), 6.34
(d, 1H, J = 3.6 Hz), 6.76 (t, 1H, J = 6.4 Hz), 7.31 (d, 2H, J = 8.4 Hz),
7.36 (dd, 1H, J = 0.8, 1.6 Hz), 7.68 (d, 2H, J = 8.4 Hz); 13C NMR (100
MHz, CDCl3) δ 21.7, 27.2, 39.0, 48.2, 65.2, 88.5, 100.4, 109.1, 110.5,
127.4, 129.9, 135.0, 142.8, 144.0, 150.3, 177.6, 201.6; IR (neat) cmꢀ1
2972w, 1728s, 1357s, 1166s, 1146s; MS (ESI) m/e (% relative
intensity) 426.1 (20) (M þ Na)þ, 421.2 (100), 404.2 (5) (M þ
H)þ; HRMS (ESI) m/e calcd for C21H25NO5Sþ (M þ Na)þ
426.1346, found 426.1337.
þ
þ H)þ, 370.3 (100) (M þ Na)þ;HRMS(ESI) m/ecalcd for C20H29NO 4
Allenamide (()-72 (65 mg, 0.107 mmol) was prepared in 59% yield
according to the general procedure. Rf1= 0.32 [1:8 EtOAc/hexanes];
orange foam solid; mp = 73ꢀ75 °C; H NMR (400 MHz, CDCl3)
δ 1.33 (s, 9H), 2.44 (s, 3H), 3.53 (dd, 1H, J = 4.0, 14.0 Hz), 4.24 (dd, 1H,
J = 9.6, 14.0 Hz), 5.35 (dd, 1H, J = 6.0, 10.4 Hz), 5.47 (dd, 1H, J = 6.0,
10.4 Hz), 5.92 (dd, 1H, J = 4.4, 9.2 Hz), 6.36 (s, 2H), 6.90 (t, 1H, J = 6.0
Hz), 7.34 (d, 2H, J = 8.4 Hz), 7.36 (brs, 1H), 7.67 (d, 2H, J = 8.4 Hz),
8.25 (d, 2H, J = 8.8 Hz), 8.37 (d, 2H, J = 8.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 21.7, 27.9, 46.6, 52.8, 85.8, 89.1, 100.1, 108.1, 110.8, 123.9,
127.4, 130.1, 130.3, 134.5, 142.0, 144.4, 145.6, 149.6, 150.1, 150.5, 201.3;
IR (neat) cmꢀ1 3154w, 1730s, 1597 m, 1531s, 1148s; MS (ESI) m/e (%
relative intensity) 627.1 (25) (M þ Na þ H)þ, 626.1 (80) (M þ Na)þ,
621.2 (100), 604.2 (5) (M þ H)þ; HRMS (ESI) m/e calcd for
C27H29N3O9S2þ (M þ Na)þ 626.1238, found 626.1208.
(M þ Na)þ 370.1989, found 370.1999.
Cycloadduct 22 (14 mg, 0.038 mmol) was isolated in 26% yield
(60:40 mixture of diastereomers with respect to the ring fusion) from
allenamide 21 according to the general procedure. Major: Rf = 0.18 [1:2
EtOAc/hexanes]; colorless oil; 1:1 mixture with respect to the auxiliary
(due to rotamers, many of the signals were not well-resolved and/or line-
broadened). 1H NMR (500 MHz, CDCl3) [extra resonances from
rotamers reported in brackets] δ 0.77 (d, 1.5H, J = 7.0 Hz), [0.81,
(d, 1.5H, J = 7.0 Hz)], 0.82ꢀ0.92 (m, 6H); 0.95ꢀ1.08 (m, 2H),
1.24ꢀ1.32 (m, 2H), 1.41ꢀ1.46 (m, 1H), 1.58ꢀ1.68 (m, 3H),
1.76ꢀ1.82 (m, 1H), 1.86ꢀ1.98 (m, 2H), 2.02ꢀ2.18 (m, 2H), 2.45
(dd, 1H, J = 7.5, 16.0 Hz), 2.85 (dd, 1H, J = 5.0, 16.0 Hz), 3.24 (brs, 1H),
3.70ꢀ3.86 (m, 2H), 4.52 (m, 1H), 5.01 (d, 1H, J = 5.0 Hz), 6.17 (dd, 1H,
J = 6.0, 15.0 Hz), 6.34 (td, 1H, J = 1.5, 6.0 Hz); 13C NMR (125 MHz,
CDCl3) not recorded to due to rotamers. IR (thin film) cmꢀ1 2949s,
1725s, 1705s, 1425 m, 1355 m; MS (ESI) m/e (% relative intensity)
385.4 (15) (M þ Na þ H)þ, 384.4 (100) (M þ Na)þ; HRMS (ESI)
Allenamide 38 (110 mg, 0.296 mmol) was prepared in 44% yield
(77% brsm) from amide 28 and (2-iodovinylidene)cyclohexane accord-
ing to our previously reported Cu(I) cross-coupling procedure.28 Rf =
0.56 [1:2 EtOAc/hexanes]; pale yellow oil; 1H NMR (400 MHz,
CDCl3) δ 1.47ꢀ1.52 (m, 3H), 1.54 (s, 2H), 1.58ꢀ1.65 (m, 2H),
2.09 (t, 3H, J = 5.0 Hz), 2.41 (s, 3H), 2.86 (t, 2H, J = 8.0 Hz), 3.33
(t, 2H, J = 8.0 Hz), 6.03 (d, 1H, J = 3.0 Hz), 6.26 (t, 1H, J = 2.5 Hz), 6.58
(brs, 1H), 7.28 (brs, 1H), 7.29 (d, 2H, J = 8.5 Hz), 7.69 (d, 2H, J = 8.5
Hz); 13C NMR (100 MHz, CDCl3) δ 21.6, 25.9, 26.8, 27.3, 32.8, 45.3,
96.8, 106.3, 110.3, 116.1, 127.3, 129.7, 135.6, 141.4, 143.6, 152.6, 189.0;
IR (neat) cmꢀ1 2929 m, 1447w, 1348 m, 1163s; MS (ESI) m/e
(% relative intensity) 394.9 (10) (M þ Na)þ, 393.9 (100), 372.9 (10)
(M þ H)þ, 371.9 (60) (M)þ; HRMS (ESI) m/e calcd for
C21H25NO3Sþ (M þ H)þ 372.1628, found 372.1625.
þ
m/e calcd for C21H31NO4 (M þ Na)þ 384.2146, found 384.2146.
Minor: Rf = 0.24 [1:2 EtOAc/hexanes]; colorless oil; 1:1 mixture
1
with respect to the auxiliary. H NMR (400 MHz, CDCl3) (due to
rotamers, many of the signals were not well-resolved and/or line-broad-
ened) [extra resonances from rotamers reported in brackets] δ 0.75
(d, 1.5H, J = 6.8 Hz), [0.80 (d, 1.5H, J = 6.8 Hz)], 0.86ꢀ0.93 (m, 6H);
0.95ꢀ1.08 (m, 2H), 1.31ꢀ1.48 (m, 2H), 1.62ꢀ1.29 (m, 3H), 1.78
(dd, 1H, J = 4.6, 13.2 Hz), 1.84ꢀ1.94 (m, 2H), 2.02ꢀ2.10 (m, 2H), 2.38
(dd, 1H, J = 4.6, 14.4 Hz), 2.80 (dq, 1H, J = 3.2, 11.6 Hz), 3.27 (dt, 1H, J =
4.6, 14.4 Hz) 3.46 (d, 1H, J = 5.6 Hz), 4.05ꢀ4.18 (m, 1H), 4.55 (td, 0.5H,
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J = 4.5, 11.2 Hz), [4.48 (td, 0.5H, J = 4.5, 11.2 Hz)], 5.01ꢀ5.04 (m, 1H),
5.91 (t, 1H, J = 6.0 Hz), 6.33 (dt, 1H, J = 2.0, 6.0 Hz); 13C NMR (100
MHz, CDCl3) not recorded to due to rotamers; IR (thin film) cmꢀ1
2946s, 1727s, 1703s, 1424 m, 1356 m; MS (ESI) m/e (% relative
intensity) 385.4 (15) (M þ Na þ H)þ, 384.4 (100) (M þ Na)þ,
360.5 (15) (M þ H)þ, 360.5 (20) (M-H)þ; HRMS (ESI) m/e calcd for
C21H31NO4þ (M þ Na)þ 384.2146, found 384.2140.
Cycloadduct 39 (28 mg, 0.072 mmol) was obtained in 90% yield from
allenamide 38 according to the general procedure. Rf = 0.25 [1:2 EtOAc/
hexanes]; light brown solid; mp = 134ꢀ135 °C; 1H NMR (400 MHz,
CDCl3) δ 1.16ꢀ1.20 (m, 1H), 1.36ꢀ1.48 (m, 3H), 1.56ꢀ1.66 (m, 2H),
1.69ꢀ1.86 (m, 3H), 1.89ꢀ2.10 (m, 2H), 2.15 (ddd, 1H, J = 4.4, 8.4,
13.2 Hz), 2.43 (s, 3H), 3.19 (s, 1H), 3.50 (td, 1H, J = 1.2, 10.4 Hz), 3.80
(td, 1H, J = 7.2, 10.4 Hz), 4.82 (s, 1H), 6.03 (d, 1H, J = 6.0 Hz), 6.40
(dd, 1H, J = 0.8, 6.0 Hz), 7.34 (d, 2H, J = 8.0 Hz), 7.84 (d, 2H,
J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 21.7, 21.8, 22.1, 25.6, 29.8,
31.1, 33.0, 49.2, 56.2, 69.6, 84.3, 93.1, 128.3, 129.8, 131.9, 133.3, 136.2,
143.9, 206.3; IR (neat) cmꢀ1 2921 m, 1721s, 1464 m, 1333 m, 1165 m;
MS (ESI) m/e (% relative intensity) 410.9 (10) (M þ Na)þ, 409.8
(100), 387.9 (20) (M)þ; HRMS (ESI) m/e calcd for C21H25NO4Sþ
(M þ Na)þ 410.1397, found 410.1403.
Cycloadduct 34 (41 mg, 0.128 mmol) was obtained in 98% yield from
allenamide 27 according to the general procedure. Rf = 0.17 [1:2 EtOAc/
hexanes]; white solid; mp = 157ꢀ158 °C; 1H NMR (500 MHz, CDCl3)
δ 1.89ꢀ1.96 (m, 1H), 2.08 (ddd, 1H, J = 2.0, 5.5, 13.5 Hz), 2.40 (d, 1H,
J = 16.0 Hz), 2.43 (s, 3H), 3.03 (dd, 1H, J = 6.5, 16.0), 3.61 (s, 1H),
3.62ꢀ3.67 (m, 2H), 5.04 (d, 1H, J = 6.5 Hz), 6.09 (d, 1H, J = 6.0 Hz),
6.40 (dd, 1H, J = 1.5, 6.0 Hz), 7.34 (d, 2H, J = 8.0 Hz), 7.83 (d, 2H,
J = 8.0 Hz); 13C NMR (125 MHz, CDCl3) δ 21.7, 31.9, 44.2, 48.9, 71.4,
77.6, 92.8, 128.0, 129.8, 131.7, 134.9, 137.0, 143.8, 201.4; IR (neat) cmꢀ1
2950 m, 1705s, 1465w, 1325 m, 1155s; MS (ESI) m/e (% relative
intensity) 342.8 (10) (M þ Na)þ, 341.9 (100), 319.9 (20) (M)þ;
HRMS (ESI) m/e calcd for C16H17NO4Sþ (M þ Na)þ 342.0771, found
342.0764.
Cycloadduct 41a (25 mg, 0.055 mmol) was obtained in 81% yield
from allenamide 40a according to the general procedure. Rf = 0.22 [1:2
1
EtOAc/hexanes]; colorless oil; H NMR (400 MHz, CDCl3) δ 1.91
(q, 1H, J = 9.6 Hz), 2.04ꢀ2.08 (m, 1H), 2.09 (q, 2H, J = 5.6 Hz), 2.43
(s, 3H), 2.52 (d, 1H, J = 16.0 Hz), 2.82 (d, 1H, J = 16.0 Hz), 3.55ꢀ3.64
(m, 5H), 4.48 (s, 2H), 5.97 (d, 1H, J = 6.0 Hz), 6.31 (d, 1H, J = 6.0 Hz),
7.28ꢀ7.36 (m, 7H), 7.84 (d, 2H, J = 8.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 21.7, 32.2, 37.1, 48.9, 49.3, 65.6, 70.1, 73.3, 85.9, 92.7, 127.8,
127.9, 128.1, 128.6, 129.8, 130.9, 135.0, 138.3, 139.7, 143.8, 202.0; IR
(thin film) cmꢀ1 2925 m, 1719s, 1352 m, 1267 m, 1165s; MS (ESI) m/e
(% relative intensity) 477.2 (10) (M þ Na)þ, 476.2 (100), 454.2 (10)
(M)þ; HRMS (ESI) m/e calcd for C25H27NO5Sþ (M þ H)þ 454.1683,
found 454.1684.
Cycloadduct 41b (33 mg, 0.068 mmol) was obtained in 97% yield
from allenamide 40b according to the general procedure. Rf = 0.10 [1:6
EtOAc/hexanes]; white solid; mp = 106ꢀ107 °C; 1H NMR (400 MHz,
CDCl3) δ 0.03 (s, 3H), 0.04 (s, 3H), 0.87 (s, 9H), 1.87ꢀ1.95 (m, 1H),
2.00 (td, 2H, J = 3.6, 6.4 Hz), 2.08 (ddd, 1H, J = 2.4, 5.2, 13.2 Hz), 2.44
(s, 3H), 2.54 (d, 1H, J = 16.0 Hz), 2.82 (dd, 1H, J = 0.4, 16.0 Hz),
3.61ꢀ3.65 (m, 2H), 3.74 (t, 2H, J = 6.4 Hz), 5.96 (d, 1H, J = 5.6 Hz),
6.33 (d, 1H, J = 6.0 Hz), 7.33 (dd, 2H, J = 0.8, 8.8 Hz), 7.84 (d, 2H,
J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ ꢀ5.2, ꢀ5.1, 18.4, 21.8,
26.1, 32.3, 40.0, 48.9, 49.4, 58.6, 70.2, 86.0, 92.6, 128.1, 129.8, 130.7,
135.2, 140.0, 143.8, 202.1; IR (neat) cmꢀ1 2883 m, 1735s, 1507w, 1365
m, 1216 m; MS (ESI) m/e (% relative intensity) 500.8 (20) (M þ Na)þ,
499.8 (100), 477.9 (5) (M)þ; HRMS (ESI) m/e calcd for
C24H35NO5SSiþ (M þ Na)þ 500.1898, found 500.1906.
Cycloadduct 35 (33 mg, 0.084 mmol) was obtained in 93% yield
from allenamide 33 according to the general procedure. Rf = 0.14 [1:2
EtOAc/hexanes]; white solid; mp = 194ꢀ195 °C; 1H NMR (400
MHz, CDCl3) δ 2.17ꢀ2.21 (m, 2H), 2.41 (dd, 1H, J = 0.8, 16.4 Hz),
2.96 (ddd, 1H, J = 0.8, 6.8, 16.8 Hz), 3.61 (td, 1H, J = 7.2, 10.0 Hz),
3.85ꢀ3.90 (m, 1H), 3.94 (s, 1H), 5.06 (dd, 1H, J = 0.8, 6.8 Hz), 6.21 (d,
1H, J = 6.0 Hz), 6.47 (dd, 1H, J = 2.4, 6.0 Hz), 8.16 (d, 2H, J = 8.8 Hz),
8.37 (d, 2H, J = 8.8 Hz); 13C NMR (100 MHz, CDCl3) δ 32.9, 44.0,
49.1, 71.6, 77.3, 92.8, 124.3, 129.0, 131.9, 137.4, 145.2, 150.2, 201.7; IR
(neat) cmꢀ1 2961 m, 2923w, 1599 m, 1258 m, 1013s; MS (ESI) m/e
(% relative intensity) 373.8 (10) (M þ Na)þ, 372.8 (100), 350.8 (5)
(M)þ; HRMS (ESI) m/e calcd for C15H14N2O6Sþ (M þ Na)þ
373.0465, found 373.0451.
Cycloadduct 36 (23 mg, 0.069 mmol) was obtained in 69% yield from
allenamide 32 according to the general procedure. Rf = 0.15 [1:2 EtOAc/
1
hexanes]; colorless oil; H NMR (500 MHz, CDCl3) δ 0.97 (s, 3H),
2.17 (ddd, 1H, J = 2.0, 8.0, 13.5 Hz), 2.31 (d, 1H, J = 16.0 Hz),
2.30ꢀ2.35 (m, 1H), 2.41 (s, 3H), 2.83 (dd, 1H, J = 5.5, 15.5 Hz), 3.68
(td, 1H, J = 2.0, 9.5 Hz), 3.99 (qt, 1H, J = 9.0 Hz), 4.94 (d, 1H, J = 5.5
Hz), 6.04 (d, 1H, J = 6.0 Hz), 6.33 (dd, 1H, J = 1.5, 6.0 Hz), 7.28 (d, 2H,
J = 8.0 Hz), 7.70 (d, 2H, J = 8.0 Hz); 13C NMR (125 MHz, CDCl3)
δ 18.0, 21.7, 29.3, 43.6, 47.6, 74.4, 77.5, 95.2, 127.5, 129.7, 130.5, 137.1,
138.2, 143.4, 201.8; IR (thin film) cmꢀ1 2925 m, 1718s, 1460w, 1334 m,
1158s; MS (ESI) m/e (% relative intensity) 356.8 (15) (M þ Na)þ,
355.8 (100), 333.9 (10) (M)þ; HRMS (ESI) m/e calcd for
C17H19NO4Sþ (M þ Na)þ 356.0927, found 356.0934.
Cycloadduct 45 (14 mg, 0.042 mmol) was obtained in 45% yield as a
3:1 mixture of diastereomers from allenamide 44 according to the
general procedure. Minor isomer was found to epimerize upon column
chromatography. Rf = 0.15 [1:2 EtOAc/hexanes]; white solid; mp =
184ꢀ185 °C; 1H NMR (500 MHz, CDCl3) δ 1.51 (td, 1H, J = 5.0, 14.0
Hz), 1.68 (dquint, 1H, J = 2.5, 13.0 Hz), 1.99 (d, 1H, J = 14.0 Hz), 2.09
(qd, 1H, J = 2.5, 13.0 Hz), 2.17 (quartet of triplets, 1H, J = 3.5, 13.5 Hz),
2.42 (d, 1H, J = 16.0 Hz), 2.43 (s, 3H), 2.72 (s, 1H), 3.54 (dd, 1H, J = 5.0,
15.5 Hz), 3.93 (dd, 1H, J = 3.0, 11.5 Hz), 5.11 (d, 1H, J = 4.5 Hz), 5.80
(d, 1H, J = 6.0 Hz), 6.34 (dd, 1H, J = 2.0, 6.0 Hz), 7.35 (d, 2H, J = 8.0
Hz), 7.70 (d, 2H, J = 8.5 Hz); 13C NMR (125 MHz, CDCl3) δ 20.2, 21.7,
30.6, 46.3, 47.4, 71.4, 79.9, 85.1, 128.6, 129.8, 131.9, 132.9, 137.2, 144.1,
202.1; IR (neat) cmꢀ1 2971 m, 1738s, 1337 m, 1158s, 1098 m; MS (ESI)
m/e (% relative intensity) 356.1 (100) (M þ Na þ H)þ, 334.1 (95)
(M þ H)þ; HRMS (ESI) m/e calcd for C17H19NO4Sþ (M þ H)þ
334.1108, found 334.1115.
Cycloadduct 47 (28 mg, 0.072 mmol) was obtained in 90% yield from
allenamide 46 according to the general procedure. Rf = 0.25 [1:2 EtOAc/
hexanes]; white solid; mp = 155ꢀ156 °C; 1H NMR (500 MHz, CDCl3)
δ 0.91 (s, 3H), 1.36 (s, 3H), 1.42 (d, 1H, J = 14.5 Hz), 1.82
(dd, 1H, J = 2.0, 14.5 Hz), 1.89 (d, 1H, J = 11.5 Hz), 2.43 (s, 3H), 2.44
(d, 1H, J = 13.5 Hz), 2.71 (s, 1H), 3.52 (dd, 1H, J = 2.0, 12.0 Hz), 3.55 (dd,
1H, J = 4.5, 14.0 Hz), 5.11 (d, 1H, J = 4.5 Hz), 5.72 (d, 1H, J = 6.0 Hz),
Cycloadduct 37a (15 mg, 0.045 mmol) was obtained in 95% yield as
∼80:20 inseparable mixture from allenamide (()-29a according to the
1
general procedure. Rf = 0.10 [1:2 EtOAc/hexanes]; colorless oil; H
NMR (500 MHz, CDCl3) Major δ 1.0 (d, 3H, J = 7.0 Hz), 1.91 (q, 1H,
J = 10.0 Hz), 2.13 (ddd, 1H, J = 2.0, 7.0, 13.5 Hz), 2.43 (s, 3H), 3.10 (s,
1H), 3.23 (quint, 1H, J = 7.0 Hz), 3.44 (td, 1H, J = 2.0, 10.0 Hz), 3.86
(qd, 1H, J = 1.5, 10.0 Hz), 4.88 (d, 1H, J = 5.0 Hz), 6.05 (d, 1H, J = 6.0
Hz), 6.36 (dd, 1H, J = 1.5, 6.0 Hz), 7.35 (d, 2H, J = 8.5 Hz), 7.81 (d, 2H,
J = 8.5 Hz); Select resonances for minor δ 1.37 (d, 3H, J = 7.0 Hz), 2.13
(dd, 1H, J = 6.0, 13.5 Hz), 2.45 (s, 3H), 3.14 (s, 1H), 3.55 (td, 1H, J =
6.0, 11.0 Hz), 3.68 (t, 1H, J = 10.0 Hz), 4.22 (ddd, 1H, J = 5.5, 8.0, 13.5
Hz), 4.65 (brs, 1H), 6.11 (d, 1H, J = 6.0 Hz), 6.46 (dd, 1H, J = 1.5, 6.0
Hz), 7.87 (d, 2H, J = 8.5 Hz); 13C NMR (125 MHz, CDCl3) δ 10.3,
21.7, 27.8, 30.7, 48.7, 70.1, 82.7, 93.3, 128.2, 129.9, 132.1, 133.3, 135.8,
144.0, 203.7; IR (thin film) cmꢀ1 2916s, 2848s, 1717s, 1349 m, 1163s;
MS (ESI) m/e (% relative intensity) 356.8 (10) (M þ Na)þ, 355.8
(100), 333.9 (20) (M)þ; HRMS (ESI) m/e calcd for C17H19NO4Sþ
(M þ Na)þ 356.0927, found 356.0937.
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6.30 (dd, 1H, J = 1.5, 6.0 Hz), 7.34 (d, 2H, J = 8.0 Hz), 7.70 (d, 2H, J =
8.0 Hz); 13C NMR (125 MHz, CDCl3) δ 21.7, 25.8, 29.8, 30.8, 43.2, 46.7,
59.1, 71.5, 80.1, 86.1, 128.4, 129.8, 133.0, 133.8, 136.7, 143.9, 202.2;
IR (neat) cmꢀ1 2923 m, 1709s, 1327 m, 1162s, 1095s; MS (ESI) m/e
(% relative intensity) 385.2 (10) (M þ Na þ H)þ, 384.1 (100) (M þ
Na)þ ; HRMS (ESI) m/e calcd for C19H23NO4Sþ (M þ H)þ 362.1421,
found 362.1408.
Cycloadduct 59 (25 mg, 0.065 mmol) was obtained in 97% yield as a
60:40 inseparable mixture of diastereomers from allenamide 58 accord-
ing to the general procedure. Rf = 0.50 [1:5 EtOAc/hexanes]; pale
1
yellow oil; H NMR (500 MHz, CDCl3) Major δ 0.07 (s, 3H), 0.19
(s, 3H), 0.89 (s, 9H), 0.90 (s, 3H), 1.03 (s, 3H), 1.05ꢀ1.10 (m, 1H),
1.35ꢀ1.41 (m, 1H), 1.67ꢀ1.78 (m, 4H), 1.92ꢀ1.94 (m, 1H),
2.00ꢀ2.10 (m, 2H), 2.24 (td, 1H, J = 8.0, 12.8 Hz), 2.40 (d, 1H, J =
17.2 Hz), 2.95 (dd, 1H, J = 7.6, 17.2 Hz), 3.35ꢀ3.42 (m, 1H), 3.48
(d, 1H, J = 13.6 Hz), 3.59 (d, 1H, J = 13.6 Hz), 4.00ꢀ4.07 (m, 2H), 4.32
(s, 1H), 5.04 (d, 1H, J = 7.2 Hz),6.29 (d, 1H, J = 5.6 Hz), 6.46ꢀ6.48
(m, 1H); Select resonances for minor δ 0.05 (s, 3H), 0.90 (s, 3H), 0.87
(s, 9H), 0.91 (s, 3H), 1.25 (s, 3H), 2.39 (d, 1H, J = 17.6 Hz), 2.94 (dd,
1H, J = 7.6, 17.6 Hz), 3.45 (d, 1H, J = 14.0 Hz), 3.73 (d, 1H, J = 14.4
Hz), 4.17 (dd, 1H, J = 8.0, 11.6 Hz), 4.27 (s, 1H), 6.27 (d, 1H, J = 5.6
Hz); 13C NMR (125 MHz, CDCl3) not obtained for inseparable
mixture; IR (thin film) cmꢀ1 2955 m, 1737s, 1329s, 1248 m, 1099 m;
MS (ESI) m/e (% relative intensity) 519.5 (20) (M þ Na þ H)þ, 518.5
(100) (M þ Na)þ; HRMS (ESI) m/e calcd for C25H41NO5SSiþ (M þ
Na)þ 518.2367, found 518.2383.
Cycloadduct 49 (7 mg, 0.020 mmol) was obtained in 17% yield from
allenamide 48 according to the general procedure. Rf = 0.17 [1:3
EtOAc/hexanes]; colorless oil; 1H NMR (500 MHz, CDCl3) δ 1.71 (br
d, 2H, J = 14.0 Hz), 1.84ꢀ1.95 (m, 2H), 2.02 (dd, 1H, J = 6.0, 14.5 Hz),
2.22 (t, 1H, J = 14.0 Hz), 2.38 (d, 1H, J = 18.0 Hz), 2.41 (s, 3H),
2.75ꢀ2.80 (m, 1H), 3.58 (d, 1H, J = 15.0 Hz), 4.38 (s, 1H), 4.98 (d, 1H,
J = 6.5 Hz), 6.26 (d, 1H, J = 5.5 Hz), 6.33 (d, 1H, J = 6.0 Hz), 7.27 (d,
2H, J = 8.0 Hz), 7.73 (d, 2H, J = 8.0 Hz); 13C NMR (125 MHz, CDCl3)
δ 21.7, 21.8, 30.6, 33.5, 46.5, 47.3, 70.3, 76.7, 89.8, 128.1, 129.3, 133.7,
137.3, 137.5, 143.3, 205.1; IR (thin film) cmꢀ1 2926 m, 1723s, 1330s,
1265 m, 1153s; MS (ESI) m/e (% relative intensity) 371.3 (10) (M þ
Na þ H)þ, 370.3 (100) (M þ Na)þ; HRMS (ESI) m/e calcd for
C18H21NO4Sþ (M þ Na)þ 370.1084, found 370.1101.
Cycloadduct 67 (35 mg, 0.071 mmol) was obtained in 85% yield as a
4:1 mixture of diastereomers from allenamide (()-63 according to the
general procedure. Major: Rf = 0.19 [1:4 EtOAc/hexanes]; white solid;
mp = 97ꢀ98 °C; 1H NMR (500 MHz, CDCl3) δ 0.91ꢀ0.95 (m, 3H),
0.90 (d, 18H, J = 8.0 Hz), 2.39 (d, 1H, J = 15.0 Hz), 2.40 (s, 3H), 3.18
(dd, 1H, J = 5.0, 15.0 Hz), 3.33 (d, 1H, J = 11.0 Hz), 3.42 (s, 1H), 4.04
(dd, 1H, J = 4.0, 11.5 Hz), 4.30 (d, 1H, J = 4.0 Hz), 5.08 (d, 1H, J = 5.0
Hz), 6.17 (d, 1H, J = 6.0 Hz), 6.34 (d, 1H, J = 6.0 Hz), 7.31 (d, 2H, J = 8.0
Hz), 7.80 (d, 2H, J = 8.0 Hz); 13C NMR (125 MHz, CDCl3) δ 21.1, 17.9,
18.0, 21.6, 44.4, 59.3, 68.4, 72.5, 78.8, 95.7, 128.1, 128.9, 129.8, 133.5,
136.5, 143.8, 200.9; IR (neat) cmꢀ1 2944 m, 1721s, 1462 m, 1352s,
1165s; MS (ESI) m/e (% relative intensity) 515.2 (5) (M þ Na þ H)þ,
509.2 (100), 492.2 (75) (M þ H)þ; HRMS (ESI) m/e calcd for
C25H37NO5SSiþ (M þ H)þ 492.2235, found 492.2236. Minor:
Cycloadduct 51 (24 mg, 0.078 mmol) was obtained in 73% yield as a
3:1 mixture of diastereomers from allenamide 50 according to the general
procedure. Major: Rf = 0.20 [1:3 EtOAc/hexanes]; white solid; mp =
1
83ꢀ84 °C; H NMR (500 MHz, CDCl3) δ 1.67ꢀ1.72 (m, 1H), 1.99
(quintet of doublets, 1H, J = 3.0, 7.0 Hz), 2.31ꢀ2.36 (m, 1H), 2.43 (s,
3H), 2.45 (d, 1H, J = 15.0 Hz), 2.54ꢀ2.59 (m, 1H), 2.68 (d, 1H, J = 5.0
Hz) 2.70 (dd, 1H, J = 2.0, 5.0 Hz), 2.97ꢀ3.00 (m, 1H), 3.27 (q, 1H,
J = 9.0 Hz), 3.44 (td, 1H, J = 3.0, 8.0 Hz), 4.91 (d, 1H, J = 9.0 Hz), 5.48
(ddd, 1H, J = 1.0, 4.5, 11.0 Hz), 5.84 (ddd, 1H, J = 1.5, 2.5, 7.5 Hz), 7.31
(d, 2H, J = 8.5 Hz), 7.75 (d, 2H, J = 8.5 Hz); 13C NMR (125 MHz,
CDCl3) δ 21.4, 21.7, 31.6, 42.4, 43.3, 46.3, 67.5, 127.8, 129.6, 129.8, 129.9,
135.5, 143.7, 206.4; IR (neat) cmꢀ1 2917s, 1726s, 1340 m, 1154s, 1105 m;
MS (ESI) m/e (% relative intensity) 329.1 (10) (M þ Na þ H)þ, 328.1
(55) (M þ Na)þ, 306.1 (100) (M þ H)þ; HRMS (ESI) m/e calcd for
C16H19NO3Sþ (M þ H)þ 306.1159, found 306.1147. Minor: Rf = 0.16
1
Rf = 0.09 [1:4 EtOAc/hexanes]; white solid; mp = 126ꢀ128 °C; H
NMR (500 MHz, CDCl3) δ 0.89ꢀ0.97 (m, 3H), 1.00 (s, 18H), 2.40
(d, 1H, J = 17.0 Hz), 2.43 (s, 3H), 3.01 (dd, 1H, J = 6.5, 17.0 Hz), 3.40
(t, 1H, J = 10.5 Hz), 3.81 (dd, 1H, J = 7.5, 10.5 Hz), 3.83 (s, 1H), 4.19
(dd, 1H, J = 7.5, 9.5 Hz), 5.13 (d, 1H, J = 6.5 Hz), 6.10 (d, 1H, J = 6.0
Hz), 6.47 (dd, 1H, J = 1.5, 6.0 Hz), 7.33 (d, 2H, J = 8.0 Hz), 7.83 (d, 2H,
J = 8.5 Hz); 13C NMR (125 MHz, CDCl3) δ 12.3, 18.0, 18.1, 21.7, 44.4,
53.5, 69.2, 70.4, 77.3, 91.8, 127.9, 129.8, 131.0, 135.8, 138.0, 144.0,
201.4; IR (neat) cmꢀ1 2918s, 1724s, 1460 m, 1347s, 1116s; MS (ESI)
m/e (% relative intensity) 514.2 (20) (M þ Na)þ, 509.2 (100), 492.2
(75) (M þ H)þ; HRMS (ESI) m/e calcd for C25H37NO5SSiþ (M þ
H)þ 492.2235, found 492.2231.
1
[1:3 EtOAc/hexanes]; colorless oil; H NMR (500 MHz, CDCl3) δ
1.63ꢀ1.70 (m, 2H), 2.08 (dt, 1H, J = 5.5, 11.5 Hz), 2.13ꢀ2.16 (m, 1H),
2.43 (s, 3H), 2.53ꢀ2.62 (m, 4H), 3.15 (ddd, 1H, J = 5.5, 6.0, 7.0 Hz), 3.73
(dd, 1H, J = 8.0, 10.5 Hz), 4.43 (d, 1H, J = 11.5Hz), 5.84 (ddd, 1H, J = 1.5,
3.0, 11.0 Hz), 6.02 (quintet of doublets, 1H, J = 2.5, 6.0 Hz), 7.31 (d, 2H,
J = 8.0 Hz), 7.88 (d, 2H, J = 8.5 Hz); 13C NMR (125 MHz, CDCl3)
δ 21.7, 23.9, 32.3, 40.7, 43.2, 48.3, 72.0, 127.9, 129.7, 131.0, 132.1, 136.9,
143.6, 205.8; IR (thin film) cmꢀ1 2849 m, 1723s, 1335 m, 1140s, 1098 m;
MS (ESI) m/e (% relative intensity) 328.1 (10) (M þ Na)þ, 306.1 (100)
(M þ H)þ; HRMS (ESI) m/e calcd for C16H19NO3Sþ (M þ H)þ
306.1159, found 306.1151.
Cycloadduct 69 (35 mg, 0.071 mmol) was obtained in 85% yield as a
4:1 mixture of diastereomers from allenamide (()-68 according to
the general procedure. Major: Rf = 0.24 [1:3 EtOAc/hexanes]; white
solid; mp = 73ꢀ74 °C; 1H NMR (500 MHz, CDCl3) δ 0.44 (qd, 6H,
J = 3.5, 7.5 Hz), 0.79 (t, 9H, J = 7.5 Hz), 2.39 (d, 1H, J = 15.5 Hz), 2.41
(s, 3H), 3.14 (dd, 1H, J = 5.0, 15.5 Hz), 3.32 (d, 1H, J = 11.5 Hz), 3.42 (s,
1H), 3.99 (dd, 1H, J = 4.0, 11.5 Hz), 4.12 (d, 1H, J = 3.5 Hz), 5.06 (d, 1H,
J = 5.5 Hz), 6.11 (d, 1H, J = 6.0 Hz), 6.34 (dd, 1H, J = 1.5, 6.0 Hz), 7.32
(d, 2H, J = 8.0 Hz), 7.79 (d, 2H, J = 8.5 Hz); 13C NMR (100 MHz,
CDCl3) δ 4.6, 6.7, 21.6, 44.4, 59.2, 68.3, 71.7, 78.7, 95.5, 128.1, 128.8,
129.6, 133.5, 136.7, 143.7, 200.9; IR (neat) cmꢀ1 2866 m, 1719s, 1415w,
1350s, 1166s; MS (ESI) m/e (% relative intensity) 473.2 (10) (M þ Na þ
H)þ, 467.2 (80), 450.2 (100) (M þ H)þ; HRMS (ESI) m/e calcd
for C22H31NO5SSiþ (M þ H)þ 450.1765, found 450.1750. Minor:
Cycloadduct 57 (25 mg, 0.065 mmol) was obtained in 80% yield as a
65:35 inseparable mixture of diastereomers from allenamide 56 according to
1
the general procedure. Rf = 0.24 [1:1 EtOAc/hexanes]; colorless oil; H
NMR (500 MHz, CDCl3) Major δ 0.91 (s, 3H), 1.13 (s, 3H), 1.42 (td, 1H,
J = 4.0, 9.5 Hz), 1.67ꢀ1.75 (m, 1H), 1.93 (d, 1H, J = 18.0 Hz), 2.01ꢀ2.07
(m, 1H), 2.09 (t, 1H, J = 5.0 Hz), 2.11ꢀ2.15 (m, 1H), 2.28 (td, 1H, J = 8.5,
13.0 Hz), 2.36ꢀ2.42 (m, 1H), 2.41 (dd, 1H, J = 5.0, 17.5 Hz), 2.45ꢀ2.54
(m, 1H), 2.96 (dd, 1H, J = 7.5, 17.5 Hz), 3.17 (d, 1H, J = 15.0 Hz),
3.48ꢀ3.56 (m, 1H), 3.60 (s, 1H), 3.90 (d, 1H, J = 15.0 Hz), 4.10 (dd, 1H,
J = 8.5, 10.5 Hz), 4.26 (s, 1H), 5.05 (d, 1H, J = 7.5 Hz), 6.28 (d, 1H, J = 6.0
Hz), 6.48 (dd, 1H, J = 1.5, 6.0 Hz); Select resonances for minor δ 1.11 (s,
3H), 1.91 (d, 1H, J=18.0Hz), 2.99(dd, 1H, J= 7.0, 17.0 Hz), 4.03 (dd, 1H,
J= 8.5, 10.5 Hz), 4.22 (s, 1H), 6.27 (d, 1H, J= 6.5 Hz), 6.46 (dd, 1H, J=2.0,
6.5 Hz); 13C NMR (125 MHz, CDCl3) not obtained for inseparable
mixture; IR (thin film) cmꢀ1 2959 m, 1739s, 1415w, 1332s, 1144s; MS
(ESI) m/e (% relative intensity) 403.1 (10) (M þ Na þ H)þ, 402.2 (100)
(M þ Na)þ, 380.2 (10) (M þ H)þ; HRMS (ESI) m/e calcd for
C19H25NO5Sþ (M þ Na)þ 402.1346, found 402.1351.
1
Rf = 0.12 [1:3 EtOAc/hexanes]; white solid; mp = 129ꢀ131 °C; H
NMR (500 MHz, CDCl3) δ 0.56 (q, 6H, J = 8.0 Hz), 0.90 (t, 9H,
J = 8.0 Hz), 2.40 (d, 1H, J = 17.0 Hz), 2.44 (s, 3H), 3.00 (dd, 1H, J = 6.5,
17.0 Hz), 3.38 (t, 1H, J = 10.5 Hz), 3.77 (dd, 1H, J = 7.5, 10.5 Hz),
3.85 (s, 1H), 4.07 (dd, 1H, J = 7.5, 9.5 Hz), 5.14 (d, 1H, J = 6.5 Hz), 6.08
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The Journal of Organic Chemistry
ARTICLE
(d, 1H, J = 6.0 Hz), 6.48 (dd, 1H, J = 1.5, 6.0 Hz), 7.34 (d, 2H,
J = 8.0 Hz), 7.83 (d, 2H, J = 8.0 Hz); 13C NMR (125 MHz, CDCl3)
δ 0.2, 4.7, 6.7, 21.8, 44.4, 53.3, 69.1, 70.1, 91.7, 127.9, 129.8, 130.8, 135.9,
138.3, 144.0, 201.3; IR (neat) cmꢀ1 2849 m, 1725s, 1462 m, 1352s,
1163s; MS (ESI) m/e (% relative intensity) 472.2 (30) (M þ Na)þ,
467.2 (80), 451.2 (20) (M þ 2H)þ, 450.2 (100) (M þ H)þ; HRMS
(ESI) m/e calcd for C22H31NO5SSiþ (M þ H)þ 450.1765, found
450.1756.
(dd, 1H, J = 1.2, 2.4 Hz), 7.29 (d, 2H, J = 8.0 Hz), 7.30 (brs, 1H), 7.70 (d,
2H, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 12.3, 17.9, 18.0, 21.7,
48.2, 67.3, 108.0, 110.4, 127.3, 129.9, 137.0, 142.2, 143.6, 153.8; IR
(neat) cmꢀ1 3289 m, 2944 m, 2865 m, 1738w, 1326s, 1160s; MS (ESI)
m/e (% relative intensity) 461.4 (15) (M þ Na þ H)þ, 460.4 (100) (M þ
Na)þ; HRMS (ESI) m/e calcd for C22H35NO4SSiþ (M þ Na)þ
460.1949, found 460.1934.
Amide (()-62 (2.8 g, 5.88 mmol) was prepared in 95% yield
Cycloadduct 73 (15 mg, 0.024 mmol) was obtained in 49% yield with
>95:5 dr from allenamide (()-72 according to the general procedure.
according to the procedure reported by Hashmi.25 Rf = 0.51 [1:4
1
EtOAc/hexanes]; colorless oil; H NMR (400 MHz, CDCl3) δ 0.97
1
Rf = 0.11 [1:3 EtOAc/hexanes]; yellow solid; mp = 104ꢀ106 °C; H
(d, 9H, J = 6.0 Hz), 1.02ꢀ1.05 (m, 3H), 1.03 (d, 9H, J = 6.0 Hz), 1.98 (t,
1H, J = 2.4 Hz), 2.41 (s, 3H), 3.40 (dd, 1H, J = 7.2, 14.4 Hz), 3.52 (ddd,
1H, J = 0.8, 6.4, 14.4 Hz), 3.62 (dd, 1H, J = 2.4, 18.4 Hz), 4.19 (ddd, 1H,
J = 0.8, 2.4, 18.4 Hz), 5.08 (t, 1H, J = 6.8 Hz), 6.30 (dd, 1H, J = 0.8, 3.2
Hz), 6.32 (dd, 1H, J = 2.0, 3.2 Hz), 7.27 (d, 2H, J = 8.0 Hz), 7.37 (dd, 1H,
J = 0.8, 2.0 Hz), 7.71 (d, 2H, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3)
δ 12.4, 17.9, 18.1, 21.7, 38.5, 51.5, 68.4, 73.6, 77.4, 108.3, 110.5, 128.0,
129.6, 136.2, 142.1, 143.6, 154.5; IR (neat) cmꢀ1 3285 m, 2928 m, 2854
m, 1348s, 1159s; MS (ESI) m/e (% relative intensity) 499.2 (5) (M þ
Na þ H)þ, 498.2 (30) (M þ Na)þ, 493.3 (100); HRMS (ESI) m/e
calcd for C25H37NO4SSiþ (M þ Na)þ 498.2105, found 498.2124.
NMR (500 MHz, CDCl3) δ 1.35 (s, 9H), 2.46 (s, 3H), 2.47 (d, 1H, J =
16.5 Hz), 3.07 (dd, 1H, J = 6.5, 16.5 Hz), 3.72 (dd, 1H, J = 9.0, 10.5 Hz),
3.82 (s, 1H), 4.43 (dd, 1H, J = 9.0, 10.5 Hz), 4.93 (t, 1H J = 9.0 Hz), 5.10
(d, 1H, J = 6.5 Hz), 6.20 (d, 1H, J = 6.0 Hz), 6.48 (dd, 1H, J = 2.0, 6.0
Hz), 7.38 (d, 2H, J = 8.0 Hz), 7.89 (d, 2H, J = 8.5 Hz), 8.08 (d, 2H, J = 8.5
Hz), 8.32 (d, 2H, J = 8.5 Hz); 13C NMR (125 MHz, CDCl3) δ 0.2, 21.8,
27.9, 44.4, 49.3, 56.2, 69.5, 77.7, 86.6, 91.7, 124.0, 128.3, 129.5, 130.0,
131.7, 134.5, 137.8, 144.5, 146.0, 150.4, 200.1; IR (neat) cmꢀ1 2928w,
1732s, 1717s, 1350s, 1265 m, 1147s; MS (ESI) m/e (% relative
intensity) 644.4 (5) (M þ Na þ 2H)þ, 643.4 (20) (M þ Na þ H)þþ,
642.4 (100) (M þ Na)þ; HRMS (ESI) m/e calcd for C27H29N3O10S2
(M þ Na)þ 642.1187, found 642.1213.
’ ASSOCIATED CONTENT
A solution of tosylate 61 (50 mg, 0.11 mmol), N-tosyl propargyl
amine (36 mg, 0.17 mmol), and Cs2CO3 (45 mg, 0.13 mmol) in DMF
(0.11 mL) was heated to 80 °C overnight. The solution was then filtered
through Celite with ethyl acetate and concentrated under reduced
pressure. The resulting crude residue was purified via silica gel flash
column chromatography (isocratic eluent: EtOAc in hexanes) to
provide the desired cycloadduct 64 (35 mg, 0.074 mmol) in 65% yield
as ∼80:20 mixture of diastereomers. Rf1= 0.20 [1:10 EtOAc/hexanes];
colorless oil; Major isomer reported. H NMR (500 MHz, CDCl3)
δ 0.91ꢀ0.96 (m, 3H), 0.97 (s, 18H), 1.91 (dd, 1H, J = 1.5, 14.0 Hz), 2.42
(s, 3H), 2.52 (ddd, 1H, J = 1.0, 4.5, 14.0 Hz), 2.85ꢀ2.90 (m, 1H),
3.79ꢀ3.96 (m, 2H), 5.05 (d, 1H, J = 1.5, 4.5 Hz), 6.22 (d, 1H, J = 6.0
Hz), 6.27 (dd, 1H, J = 1.5, 5.5 Hz), 6.58 (s, 1H), 7.30 (d, 2H, J = 8.0 Hz),
7.67 (d, 2H, J = 8.0 Hz); 13C NMR (125 MHz, CDCl3): δ 12.3, 18.0,
18.1, 21.7, 31.0, 48.0, 65.9, 78.3, 89.4, 117.3, 119.2, 127.3, 130.0, 133.0,
134.9, 135.2, 144.0; 1H NMR (500 MHz, C6D6) δ 1.02 (sept, 3H, J = 6.5
Hz), 1.05 (d, 18H, J = 6.5 Hz), 1.40 (dd, 1H, J = 1.0, 14.0 Hz), 1.80 (s,
3H), 2.12 (ddd, 1H, J = 1.0, 4.0, 14.0 Hz), 2.93 (dd, 1H, J = 11.5, 12.0
Hz), 4.17 (dd, 1H, J = 5.0, 11.0 Hz), 4.26 (ddd, 1H, J = 0.5, 5.0, 12.0 Hz),
4.54 (dd, 1H, J = 1.5, 4.5 Hz), 5.72 (d, 1H, J = 6.0 Hz), 6.01 (d, 1H, J =
5.5 Hz), 6.68 (d, 2H, J = 8.0 Hz), 6.74 (s, 1H), 7.69 (d, 2H, J = 8.0 Hz);
IR (thin film) cmꢀ1 2943 m, 2866 m, 1735w, 1357 m, 1165s; MS (ESI)
m/e (% relative intensity) 498.2 (10) (M þ Na)þ, 477.2 (20) (M þ
2H)þ, 476.2 (100) (M þ H)þ; HRMS (ESI) m/e calcd for
C25H37NO4SSiþ (M þ H)þ 476.2286, found 476.2266.
Supporting Information. 1H NMR, 13C NMR spectra,
S
b
and X-ray structural data. This material is available free of charge
via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: rhsung@wisc.edu.
’ ACKNOWLEDGMENT
The authors thank NIH [GM066055] for financial support
and Dr. Victor Young, University of Minnesota for X-ray
structural analysis.
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Compound (()-65 (12 g, 42.94 mmol) was prepared in 72% yield
over two steps according to the procedure reported by Hashmi.25 Rf =
0.63 [1:4 EtOAc/hexanes]; colorless oil; 1H NMR (400 MHz, CDCl3)
δ 1.07 (d, 9H, J = 6.8 Hz), 1.09 (d, 9H, J = 6.8 Hz), 1.13ꢀ1.22 (m, 3H),
5.63 (s, 1H), 6.38 (dd, 1H, J = 2.0, 3.6 Hz), 6.52 (dd, 1H, J = 0.8, 3.6 Hz),
7.42 (dd, 1H, J = 0.8, 2.0 Hz); 13C NMR (100 MHz, CDCl3) δ 12.1,
17.7, 17.8, 58.4, 109.3, 110.8, 117.4, 143.7, 148.0; IR (neat) cmꢀ1 2945s,
2868 m, 1719w, 1463s, 1091s; MS (ESI) m/e (% relative intensity) 302.3
(100) (M þ Na)þ, 253 (20) (M ꢀCN)þ; HRMS (ESI) m/e calcd for
C15H25NO2Siþ (M þ Na)þ 302.1547, found 302.1557.
Compound (()-66 (3.09 g, 7.06 mmol) was prepared in 66% yield
over two steps according to the procedure reported by Hashmi.25 Rf =
0.47 [1:4 EtOAc/hexanes]; white solid; mp = 41ꢀ42 °C; 1H NMR (400
MHz, CDCl3) δ 0.93 (d, 9H, J = 5.6 Hz), 0.95ꢀ1.03 (m, 12H), 2.42 (s,
3H), 3.22 (dt, 1H, J = 6.0, 12.0 Hz), 3.30 (dt, 1H, J = 6.0, 12.0 Hz), 4.63
(t, 1H, J = 6.0 Hz), 4.85 (t, 1H, J = 6.0 Hz), 6.22 (d, 1H, J = 3.2 Hz), 6.29
3256
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ARTICLE
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