Stereo- and regioselective synthesis of polysubstituted chiral 1,4-oxazepanes

Article abstract of DOI:10.1021/jo3021715

The number of cyclic molecular scaffolds available to medicinal chemists remains limited, and simple structures such as oxazepanes are still made using multistep procedures, including a number of protection/deprotection steps and purifications. We report

Full text of DOI:10.1021/jo3021715

Article
pubs.acs.org/joc
Stereo- and Regioselective Synthesis of Polysubstituted Chiral 1,4-
Oxazepanes
Michelle Bezanson, Joshua Pottel, Rana Bilbeisi, Sylvestre Toumieux, Mickael Cueto,
̈
and Nicolas Moitessier*
́
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec, Canada H3A 2K6
S
* Supporting Information
ABSTRACT: The number of cyclic molecular scaffolds available
to medicinal chemists remains limited, and simple structures such
as oxazepanes are still made using multistep procedures, including a
number of protection/deprotection steps and purifications. We
report herein an expedient and efficient synthesis of chiral
polysubstituted oxazepanes. The developed method relies on a
regio- and stereoselective 7-endo cyclization through haloether-
ification. Mechanistic studies using a combination of computations and experiments confirmed the expected role of the
asymmetry of the chiral bromonium intermediate on the haloetherification regioselectivity. Computations also suggested that the
bromonium intermediate is formed with no transition state; hence, the stereoselectivity is controlled primarily by the
conformation of the substrate. Applied to a set of 16 substrates, tetra- and pentasubstituted oxazepanes were prepared with good
yields and moderate to excellent regio- and stereoselectivities.
INTRODUCTION
■
Molecular scaffolds such as mono- and bicyclic structures are of
utmost interest in medicinal chemistry and more specifically in
the preparation of geometrically constrained peptidomimetics
or in the preparation of a focused library.1 Thus, a number of
potent enzyme inhibitors2−4 and receptor antagonists5,6 built
around (bi)cyclic scaffolds have been reported. In parallel, a
number of scaffolds inducing turns observed in proteins or
peptides have been developed.7,8 However, the number of
readily available scaffolds remains limited or their lengthy
synthesis remains to be improved. As a result, developing
synthetic strategies to prepare molecular scaffolds is an active
field.9−12
Despite the discovery of bioactive oxazepane derivatives such
as 113 and many reports on synthesis of oxazepinones (e.g.,
214),15 very little attention has been devoted to the synthesis of
polysubtituted chiral oxazepane derivatives. In addition, most of
these reports focus on benzoxazepines.16 In fact, an exhaustive
search of the literature revealed that very few syntheses of chiral
polysubstituted oxazepanes have been reported. For example,
Machetti and co-workers17 and then Ley et al.18 have reported
efficient methods to prepare bridged oxazepanes around acetal
functional groups (3; Figure 1).
In fact, most of the reported syntheses of oxazepanes rely on
acetalization of ketones, intramolecular opening of epoxides, or
ring expansion13 (e.g., from carbohydrates19). A few other
methods have been reported, such as the palladium-catalyzed
cyclization of allenols.20 Hsung and co-workers recently
reported the application of halo-etherification of enamimes to
the preparation of various cyclic structures, including one
oxazepane.21 As part of a medicinal chemistry program aiming
to develop constrained enzyme inhibitors in a green fashion,22
Figure 1. Reported synthetic oxazepanes.
we developed a method to efficiently prepare polysubstituted
oxazepanes, improving upon the aforementioned existing
methods.
We report herein our efforts to develop an efficient and
expedient synthetic route to chiral oxazepanes, which are
underinvestigated heterocycles. Additional computations and
experiments were carried out to investigate the factors
controlling the stereo- and regioselectivity of the key
cyclization.
RESULTS AND DISCUSSION
■
Design of the Synthetic Strategy. Prior to the develop-
ment of this synthetic methodology, we set the stringent criteria
we wished to fulfill, considering that these molecular scaffolds
should be easy to access and use by medical chemists and/or
applicable to large-scale drug synthesis.23 First, the synthesis
should not exceed three to four steps and should be scalable.
Received: October 3, 2012
Published: January 10, 2013
© 2013 American Chemical Society
872
dx.doi.org/10.1021/jo3021715 | J. Org. Chem. 2013, 78, 872−885

The Journal of Organic Chemistry
Article
Second, the obtained cyclic scaffold should bear functionaliz-
able groups. These first two criteria are essential for
applicability to medicinal chemistry programs where diversifi-
cation will follow. Third, it should not use toxic reagents (e.g.,
metal catalysts). Fourth, it should start from inexpensive,
commercially available materials. Fifth, stereogenic centers
should be formed in a controlled manner or taken from the
chiral pool. This is a critical issue, as poor stereoselectivity
renders the synthesis and isolation difficult. Sixth, atom
economy should be considered (i.e., neither chiral auxiliaries
nor excessive protection/deprotection steps). Finally, the
number of tedious and non-green purifications should be
limited. More specifically, simple workups requiring quantita-
tive conversion or crystallization would be preferred over
chromatography of complex mixtures. After extensive inves-
tigations, we developed the strategy outlined in Figure 2.
Preparation of the Unsaturated Alcohols. With this
approach, the first or first two stereocenters bearing R4 and R5
are borrowed from the chiral pool, ensuring that the final
molecule will be enantiopure. The other stereocenters will be
introduced through substrate induction. Throughout the
process, the alcohol will not be protected, thus reducing the
number of steps and chemicals to be used (hence the waste) in
comparison to existing methods.21 Although this strategy may
look straightforward, many issues had to be addressed. The first
hurdle we met was the formation of the intermediate
unsaturated amino alcohol that will be the substrate for the
halo-etherification cyclization. After extensive optimization, the
acyclic compounds were made following the strategy outlined
in Table 1. Other approaches, such as reductive amination
followed by further amine functionalization, proved less
successful.
Thus, threonine methyl ester (5a), serine methyl ester (5b),
and another six highly diverse amino alcohols (5c−h) were
reacted sequentially with tosyl chloride and then cinnamyl
bromide (4a) or other allyl bromides (4b,c), affording the
corresponding secondary amines 6a−j in reasonable to
excellent yields. This approach does not require any protection
of the primary alcohol.
Key Cyclization. With this set of subsrates in hand, the key
cyclization was carried out (Table 2). Throughout the course of
the cyclization reaction, one can expect the formation of
Figure 2. General synthetic strategy.
Table 1. Step 1: Amine Functionalization
a
b
c
d
Amino alcohol. Over two steps. allo-Threonine methyl ester. cis-Indanolamine.
873
dx.doi.org/10.1021/jo3021715 | J. Org. Chem. 2013, 78, 872−885

The Journal of Organic Chemistry
Article
potential regio- and stereoisomers. In order to develop an
efficient method, one has to significantly reduce this number of
possible isomers. Halo-etherification is a stereospecific anti
addition which reduces the number of potential isomers to four.
Although the cyclization was successful, the observed
stereoselectivities were moderate (up to 2.0:1) and called for
further optimization. The solvent, temperature, and additives
were subsequently optimized (Table 3). For instance, the use of
Table 2. Oxazepanes by Halo-Etherification
Table 3. Condition Optimization
temp
(°C)
conversion
a
a
entry
solvent
Brønsted acid
(%)
dr
1
CH3CN
CH3CN
CH3CN
DMF
0
−20
−78
0
( )-CSA
( )-CSA
( )-CSA
( )-CSA
( )-CSA
( )-CSA
( )-CSA
( )-CSA
( )-CSA
( )-CSA
( )-CSA
( )-CSA
( )-CSA
( )-CSA
( )-CSA
(+)-CSA
(-)-CSA
100
97
2.1:1
3.4:1
4.0:1
>20:1
1.9:1
8.6:1
3.1:1
7.7:1
14.3:1
4.4:1
2.9:1
1.2:1
2
3
97
4
100
100
100
74
5
DCM
0
6
THF
0
7
MeOH
0
8
EtOH
0
100
47
9
iPrOH
EtOAc
CHCl3
acetone
1,4-dioxane
benzene
toluene
THF
0
10
11
12
13
14
15
16
17
18
0
61
0
95
0
96
0
0
0
95
7.1:1
0
96
7.3:1
0
66
11.5:1
10.0:1
10.0:1
THF
0
63
THF
0
( )-CSA
(10 mol %)
51
a
As determined by NMR of the crude mixtures.
several different solvents showed excellent conversions
although a wide variety of diastereoselectivities, with DMF
and THF exhibiting the best results for both conversion and
selectivity. For ease of utility, we opted to use THF for further
experiments. We were pleased to see that, rather than a
stoichiometric amount, the use of a catalytic amount of a
Brønsted acid, such as CSA, activating the brominating reagent
retained the significantly improved diastereomeric ratio (dr).
This observation requires more investigations to be truly
understood. Computational studies have been undertaken to
investigate the complete mechanism and the role played by
each partner and will be reported in due course. Lowering the
reaction temperature showed increased diastereoselectivity
below 0 °C. However, running the reaction at lower
temperature reduces the applicability of this methodology to
larger scales or large libraries. With these optimized conditions
(NBS, THF, catalytic ( )-CSA, 0 °C), a variety of oxazepanes
were obtainable.
We next optimized the cyclization conditions and the
selection of the group attached to the ring nitrogen (R6 in
Figure 2), which turned out to be critical. Preliminary
investigations with nonfunctionalized secondary amines (R6 =
H) led to poor-yielding cyclization and bromination of the
nitrogen, while the use of carbamates (R6 = Boc, Cbz) led to
a
b
1
Major diastereomer shown. As determined by H NMR.
oxazepanes through a Markovnikov 7-endo cyclization or
morpholines through an anti-Markovnikov 6-exo cyclization.
In addition, two stereogenic centers are formed, leading to eight
874
dx.doi.org/10.1021/jo3021715 | J. Org. Chem. 2013, 78, 872−885

The Journal of Organic Chemistry
Article
Table 4. Step 1: Amine Functionalization
a
b
c
d
Amino alcohol. Over two steps. allo-Threonine methyl ester. cis-Indanolamine.
the formation of oxazolidinones, as reported by Guindon and
co-workers.24 The use of other protecting groups (R6 = Bn, Ac,
Bzl) also led to poor yields. Fortunately, nosyl derivatives (R6 =
Ns) led to higher yields during the alkylation step to afford 9
(Table 4) and also gave the desired cyclized products 10 with
unexpectedly improved stereoselectivities (Table 5). While this
paper was near completion, nosyl amide was used in the
presence of NBS to open epoxides regioselectively, although no
function was attributed to nosyl.25
At this stage the optimal conditions and nitrogen protecting
group were applied to the combination of a variety of amino
alcohols and alkene bromides. The set of nosylated derivatives
was selected not only to probe the scope of this methodology
but also to investigate the key elements for the observed high
stereo- and regioselectivity (Table 5).
Mechanism. Throughout the cyclization process, the
substrates induce the formation of given stereo- and
regioisomers preferentially. By means of other substrates, we
probed the scope of the reaction and further investigated the
mechanism. As mentioned above, this reaction can potentially
lead to a morpholine derivative through a 6-exo cyclization or to
an oxazepane through a 7-endo cyclization. Haloetherification is
believed to proceed through a bromonium ion (Figure 3a). The
stereochemistry is set at this stage. However, it is well
established that scrambling of the stereochemistry may occur
by halogen transfer to another substrate molecule. Denmark
has shown that this was a slow process that competed with
intermolecular addition of alcohols26 and that presence of a
Lewis base shut down this undesired reaction and enabled
asymmetric cyclization (Figure 3b).27,28 Both the intra-
875
dx.doi.org/10.1021/jo3021715 | J. Org. Chem. 2013, 78, 872−885

The Journal of Organic Chemistry
Article
Table 5. Oxazepanes by Haloetherification
a
b
As determined by NMR for the major isomer. Product is a mixture of enantiomers.
876
dx.doi.org/10.1021/jo3021715 | J. Org. Chem. 2013, 78, 872−885

The Journal of Organic Chemistry
Article
While this work was in progress, haloetherification has been
found to favor the 6-endo over the 5-exo cyclization and the 7-
endo over the 6-exo cyclization when an aromatic or an enamine
group can stabilize the developing positive charge of the
adjacent carbon through conjugation.28 The presence of such
groups controls the regioselectivity by desymmetrizing the
bromonium intermediate. If no such group is found, then the
exo cyclization was competitive. To further investigate this
hypothesis, the reaction was carried out with 9a,f and 9b,g. In
the case of 9a,f, the most distant alkene carbon is adjacent to a
phenyl ring favoring the 7-endo cyclization, while no stabilizing
group are found at the same location in 9b,g. Rather, a methyl
group is branched on the internal alkene carbon, hence favoring
the more entropically favored 6-exo cyclization. With 9e,j, the
regioselectivity is driven not just by the competition of stability
between the tertiary carbocation and the benzylic-stabilized
carbocation. If this were the case, we would expect to see
predominantly the oxazepane product, but the observation of
an approximately 2:1 ratio of oxazepane to morpholine implies
that there is some entropic factor at play that is making the
formation of the morpholine competitive.
Figure 3. Mechanism and outcome (LB = Lewis base).
Stereochemistry. The stereochemistry of the observed
isomers was determined by NOESY experiments (Figure 4b)
and when not possible (i.e., 10h), by analogy with a similar
substrate. First, we were pleased to see that the stereochemistry
of the double bond is transferred to the product in all cases.
This observation demonstrated that alkene to alkene transfer of
the bromonium and scrambling of its stereochemistry does not
occur. Although the rationalization of the regiochemical
outcome and of the relative stereochemistry of the two
stereocenters formed was somewhat straightforward, the
preference for a given diastereoisomer induced by the amino
alcohol stereocenters was more difficult. More specifically,
investigating the mechanistic details of the stereochemistry of
the reaction between NBS and 9 to form the observed
oxazepanes was more challenging, as no obvious preference for
one stereoisomer over the other can be predicted using simple
models. For example, the role of each of the two stereogenic
centers (i.e., methyl and methyl ester) of the threonine
derivative 9a in the observed stereoselectivity (>20:1, Table 5,
entry 1) was evaluated. First, the methyl ester of 9a was found
to be critical, as removal of the methyl group (9f) retained the
high level of selectivity (>20:1, entry 6). However, the methyl
group is also important, as its inversion (9n) led to loss of
stereoselectivity (2:1, entry 14) and poor yield (42%). To
further investigate this observation, the derivative 9m, in which
only the methyl is kept, was prepared and cyclized. With this
derivative (9m), poor selectivity was observed. Thus, we believe
that the major factor impacting the stereoselectivity of 9a is the
methyl ester while the methyl group, if in the right
configuration (matched case), is not essential. We initially
postulated that the cis configuration of 9n might cause
distortion and disruption of the transition states (TS)
conformation adopted by 9a,f. However, the derivatives 9p,
although also in the cis configuration, led to high yield and
stereoselectivity (98%, >20:1, entry 16). In addition, derivative
9k in the trans configuration did not proceed with high
selectivity (2.0:1, entry 11). The rigid nature of 9p,k may
explain their behavior in our cyclization reactions. It rapidly
appeared that the flexible nature of seven-membered rings
made the rationalization difficult.
molecular nature of our process and the presence of the Lewis
basic succinate originating from NBS and acting as Lewis base
should preclude the undesired isomerization.
Regioselectivity. The regioselectivity (Figure 3c) was
attributed on the basis of simple 13C NMR shifts and confirmed
by extensive heteronuclear multiple bond correlation (HMBC)
experiments (Figure 4a) and a crystal structure (Figure 4c).
Figure 4. (a) HMBC signals confirming the regioselectivity. (b)
NOESY signals used to ascertain the stereochemistry. (c) Crystal
structure confirming the regio- and stereochemistry of the major
product.
In light of this, we turned to computational chemistry to
guide the investigation into the mechanistic details of this
877
dx.doi.org/10.1021/jo3021715 | J. Org. Chem. 2013, 78, 872−885

The Journal of Organic Chemistry
Article
reaction. We first investigated the addition of bromine to a
model system. It was our initial hypothesis that the reaction
involved two different TS’s, one upon addition of bromine to
the double bond and one upon formation of the ring by
nucleophilic attack of the alcohol onto the bromonium. With
this in mind, considering the first step, we modeled the reaction
of NBS (protonated by ( )-CSA) and trans-butene. To our
surprise, no TS was observed and the resulting structure was a
cagelike system around the bromine and not a conventional
bromonium ion (Figure 5). A lack of transition state has already
Figure 6. Stereochemical outcome from simple conformational
analysis (9c).
10c features as many as five groups, while 10a has four
stereogenic centers. The strategy relies on the use of the chiral
pool to introduce up to two stereogenic centers and a key
stereo- and regioselective haloetherification to introduce up to
two other stereogenic centers. This is a significant improvement
over the rare existing (lengthy) approaches. The high
regioselectivity observed was rationalized by the desymmetriza-
tion of the bromonium intermediate, while computational
studies revealed that the stereochemistry is primarily controlled
by conformational preferences of the substrates. Further
computational investigations are in progress to explain the
effects of CSA and the unexpected increase in selectivity offered
by the nosyl protecting group. These results will be reported in
due course.
Figure 5. Potential energy surface of the reaction between NBS-H+
and trans-butene.
been observed for the hydroboration of alkenes.29 We further
confirmed this observation replacing butene with 9p, indicating
that this was not an artifact of the model.
EXPERIMENTAL SECTION
■
Since the addition of bromine at this early stage determines
the stereochemistry and no isomerization through intermo-
lecular alkene-to-alkene transfer is expected, we concluded that
the predominance of one stereoisomer should be determined
by a conformational bias opening preferentially one face of the
alkene to NBS. Thus, in practice this reduced our study to a
simple conformational search rather than a TS analysis. Indeed,
the computational prediction agreed, within error, with the
experimentally observed products, predicting a 4:1 ratio of the
R isomer of 10c over the S isomer (Figure 6). Thus, the
stereoselectivity can indeed be rationalized by simple conforma-
tional analysis of ground state reactants.
General Considerations. All commercially available reagents were
used without further purification, unless otherwise stated. Chemical
shifts (δ) are reported in parts per million (ppm) relative to CDCl3
(7.26 ppm for 1H and 77.160 ppm for 13C). 1H and 13C NMR
assignments were confirmed by 2D COSY, HSQC, HMQC, and
NOESY experiments. Chromatography was performed on silica gel 60
(230−40 mesh). Visualization was performed by UV or by
development using ceric ammonim molybdate.
General Procedure for N-alkylation of N-protected Amino
Alcohols. To a suspension of 200 mg (1.18 mmol) of threonine
methyl ester hydrochloride salt in 40 mL of CH2Cl2 was added 330 μL
(2.36 mmol) of NEt3 via syringe, and the mixture was stirred for 0.5 h.
The flask was then chilled to 0 °C, 288 mg (1.30 mmol) of solid nosyl
chloride was added, and the resulting solution was warmed slowly to
room temperature and stirred for 16 h. The product was washed with
water (3 × 100 mL); the organic extract was then dried over Na2SO4,
filtered, and concentrated in vacuo to give (2S,3R)-methyl 3-hydroxy-
2-(4-nitrophenylsulfonamido)butanoate. The product was isolated and
used in subsequent reactions without further purification. Then 260
CONCLUSION
■
We have developed a strategy enabling the synthesis of chiral
polysubstituted oxazepanes such as 10a,f,l,p with excellent
yields and regio- and diastereoselectivity in only three steps.
878
dx.doi.org/10.1021/jo3021715 | J. Org. Chem. 2013, 78, 872−885

The Journal of Organic Chemistry
Article
mg (0.82 mmol) of (2S,3R)-methyl 3-hydroxy-2-(4-nitrophenyl-
sulfonamido)butanoate was dissolved in 40 mL of acetone and a
large excess (>10 equiv) of solid K2CO3 was added to the flask. A 177
mg portion (1.01 mmol) of cinnamyl bromide was then added via
syringe, and the resulting solution was stirred at room temperature for
16 h. The solvent was then removed in vacuo, and the remaining
residue was partitioned between CH2Cl2 and water; the organic layer
was dried over Na2SO4, filtered, and concentrated in vacuo to give 9a.
Products were purified by column chromatography (7/3 Hex/EtOAc
eluent system).
J = 16.0 Hz, 1H), 7.27 (m, 7H), 7.75 (d, J = 8.4 Hz, 2H). 13C NMR
(75 MHz, CDCl3): δ 143.3, 138.0, 136.2, 132.7, 1296, 128.6, 127.9,
127.3, 126.6, 126.5, 63.5, 61.9, 46.0, 22.3, 21.5, 11.1. HRMS: (M + H)
for C20H25NO3SH calcd 360.16334, found 360.16239.
(R)-N-Cinnamyl-N-(2-hydroxypropyl)-4-methylbenzenesulfona-
mide (6g). Colorless oil, isolated yield 292 mg (46%). [α]22D = +11.9°
(c 1.15, CHCl3). Rf = 0.31 (7/3 Hex/EtOAc). 3529.8, 1334.9, 1089.5,
736.4; 1H NMR (400 MHz, CDCl3): δ 1.15 (d, J = 6.0 Hz, 3H), 2.41
(s, 3H), 2.66 (br s, 1H), 3.10 (m, 2H), 4.02 (m, 3H), 5.94 (dt, J = 6.8,
15.6 Hz, 1H), 6.43 (d, J = 15.6 Hz, 1H), 7.25 (m, 7H), 7.74 (d, J = 8.4
Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 143.7, 136.3, 135.9, 134.3,
129.8, 127.4, 126.4, 123.7, 66.2, 55.1, 52.1, 21.5, 20.5. HRMS: (M +
H) for C19H23NO3SH calcd 346.14769, found 346.14652.
(2S,3R)-Methyl 2-(N-Cinnamyl-4-methylphenylsulfonamido)-3-
hydroxybutanoate (6a). White solid, mp 88−90 °C, isolated yield
8.68 g (90%). [α]22 = −57.3° (c 1.00, CHCl3); Rf = 0.19 (1/99
D
MeOH/DCM). IR (film, cm−1) 3531.3, 1737.7, 1335.3, 1153.2, 731.0.
(2S,3S)-Methyl 2-(N-Cinnamyl-4-methylphenylsulfonamido)-3-
1H NMR (400 MHz, CDCl3): δ 1.28 (d, J = 6.4 Hz, 3H), 2.39 (s, 3H),
hydroxybutanoate (6h). Colorless oil, isolated yield 138 mg (67%).
[α]22 = −31.3° (c 1.05, CHCl3). Rf = 0.25 (7/3 Hex/EtOAc). IR
2.56 (br s, 1H), 3.49 (s, 3H), 4.19 (ddd, J = 7.2, 16.0, 23.6 Hz, 2H),
4.36 (br s, 1H), 4.49 (d, J = 5.6 Hz, 1H), 6.20 (m, 1H), 6.48 (d, J =
16.0 Hz, 1H), 7.26 (m, 7H), 7.73 (d, J = 8.4 Hz, 2H). 13C NMR (75
MHz, CDCl3): δ 170.2, 143.6, 136.8, 136.2, 133.4, 129.4, 128.5, 127.9,
127.7, 126.5, 125.9, 66.9, 64.6, 52.1, 49.0, 21.5, 19.9. HRMS: (M + H)
for C21H25NO5SH calcd 404.15317, found 404.15253.
D
1
(film, cm−1): 3518.6, 1739.2, 1340.2, 1090.3, 743.7. H NMR (400
MHz, CDCl3): δ 1.30 (d, J = 6.0 Hz, 3H), 2.42 (s, 3H), 3.49 (s, 3H),
4.00 (ddd, J = 1.2, 6.3, 9.3 Hz, 2H), 4.31 (m, 2H), 6.07 (dt, J = 6.6,
15.9 Hz, 1H), 6.44 (d, J = 15.9 Hz, 1H), 7.27 (m, 7H), 7.74 (d, J = 8.4
Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 171.5, 143.6, 137.1, 136.0,
134.0, 129.4, 128.6, 128.1, 127.7, 126.5, 124.8, 66.9, 64.3, 52.2, 49.3,
21.5, 19.9. HRMS: (M + H) for C21H25NO5SH calcd 404.15317,
found 404.15233.
N-Cinnamyl-N-(2-hydroxyethyl)-4-methylbenzenesulfonamide
(6i). White solid, mp 54−58 °C, isolated yield 224 mg (62%). Rf =
0.15 (7/3 Hex/EtOAc). IR (film, cm−1): 3518.4, 1332.0, 1153.3,
814.5, 719.5 ν. 1H NMR (400 MHz, CDCl3): δ 2.43 (s, 3H), 3.29 (t, J
= 5.6 Hz, 2H), 3.75 (t, J = 5.2 Hz, 2H), 4.02 (dd, J = 0.8, 6.8 Hz, 2H),
5.98 (dt, J = 6.4, 16.0 Hz, 1H), 6.45 (d, J = 16.0 Hz, 1H), 7.28 (m,
7H), 7.74 (d, J = 8.4 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 143.7,
136.3, 136.0, 134.2, 128.6, 127.3, 126.5, 123.8, 61.2, 51.7, 49.7, 21.5.
HRMS: (M + H) for C18H21NO3SH calcd 332.13204, found
332.13094.
(2S,3R)-Methyl 3-Hydroxy-2-(4-methyl-N-(2-methylallyl)-
phenylsulfonamido)butanoate (6b). Colorless oil, isolated yield
142 mg (30%). [α]22 = −44.5° (c 1.30, CHCl3). Rf = 0.23 (1/99
D
MeOH/DCM). IR (film, cm−1): 3526.6, 1738.7, 1338.2, 1156.1,
1
1091.3, 814.8, 661.3. H NMR (400 MHz, CDCl3): δ 1.24 (d, J = 5.8
Hz, 3H), 1.73 (s, 3H), 2.42 (s, 3H), 3.44 (s, 3H), 3.98 (s, 2H), 4.22 (s,
2H), 4.97 (s, 1H), 5.06 (s, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.71 (d, J =
8.1 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 223.0, 169.7, 143.7,
142.2, 136.2, 129.3, 127.8, 114.5, 66.3, 65.4, 52.7, 51.8, 21.5, 20.3, 20.0
19.9. HRMS: (M + H) for C16H23NO5SH calcd 342.13752 found
342.13643.
(2S,3R)-Methyl 3-Hydroxy-2-(4-methyl-N-(3-methylbut-2-en-1-
yl)phenylsulfonamido)butanoate (6c). Colorless oil, isolated yield
279 mg (98%). [α]22D = −91.8° (c 0.55, CHCl3). Rf = 0.42 (7/3 Hex/
EtOAc). IR (film, cm−1): 3529.9, 2978.8, 1738.1, 1335.9, 1090.4,
667.9. 1H NMR (400 MHz, CDCl3): δ 1.27 (d, J = 6.3 Hz, 3H), 1.62
(s, 3H), 1.68 (s, 3H), 2.42 (s, 3H), 3.52 (s, 3H), 4.01 (d, J = 7.5 Hz,
2H), 4.20 (m, 1H), 4.40 (d, J = 6.6 Hz, 1H), 5.23 (m, 1H), 7.28 (d, J =
8.1 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ
170.2, 143.4, 136.5, 129.3, 127.6, 121.0, 66.4, 64.7, 51.9, 44.3, 25.8,
21.5, 19.7, 17.8. HRMS: (M + H) for C17H25NO5SH calcd 356.15317,
found 356.15214.
N-Cinnamyl-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-4-
methylbenzenesulfonamide (6j). Colorless oil, isolated yield 578 mg
(84%). [α]22D = −74.9° (c 1.05, CHCl3); Rf = 0.58 (7/3 Hex/EtOAc);
1
IR (film, cm−1): 3518.0, 1333.8, 1094.1, 815.3, 740.0. H NMR (400
MHz, CDCl3): δ 2.45 (s, 3H), 2.93 (dd, J = 6.0, 16.8 Hz, 1H), 3.21
(dd, J = 7.2, 16.4 Hz, 1H), 3.85 (m, 2H), 4.68 (dq, J = 3.6, 7.6 Hz,
1H), 5.20 (d, J = 6.8 Hz, 1H), 6.03 (m, 1H), 6.58 (d, J = 7.6 Hz, 1H),
7.06 (t, J = 6.8 Hz, 1H), 7.22 (m, 8H), 7.32 (d, J = 8.0 Hz, 2H), 7.82
(d, J = 8.0 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 143.7, 141.4,
137.5, 137.0, 136.4, 132.8, 129.8, 129.2, 128.5, 127.7, 127.4, 126.9,
126.5, 126.3, 125.8, 125.5, 72.3, 64.8, 48.5, 39.5, 21.6. HRMS: (M +
H) for C25H25NO3SH calcd 420.16334, found 420.16206.
(S)-Methyl 2-(N-Cinnamyl-4-methylphenylsulfonamido)-3-hy-
droxypropanoate (6d). Colorless oil, isolated yield 300 mg (39%).
[α]22 = −28.9° (c 1.00, CHCl3). Rf = 0.14 (7/3 Hex/EtOAc). IR
D
1
(film, cm−1): 3524.9, 1737.9, 1334.0, 1153.7, 908.9, 727.0. H NMR
(2S,3R)-Methyl 2-(N-Cinnamyl-4-nitrophenylsulfonamido)-3-hy-
(400 MHz, CDCl3): δ 2.41 (s, 3H), 3.57 (s, 3H), 4.02 (m, 4H), 4.66
(t, J = 4.0 Hz, 1H), 6.12 (dt, J = 8.1, 16.2 Hz, 1H), 6.48 (d, J = 16.2
Hz, 1H), 7.26 (m, 7H), 7.76 (d, J = 8.4 Hz, 2H). 13C NMR (75 MHz,
CDCl3): δ 170.3, 143.7, 137.0, 136.1, 133.6, 129.6, 128.6, 128.0, 127.6,
126.5, 125.1 61.3, 60.9, 52.4, 48.9, 21.5. HRMS: (M + H) for
C20H23NO5SH calcd 390.13752, found 390.13645.
droxybutanoate (9a). Colorless oil, isolated yield 356 mg (>99%).
[α]22 = −57.9° (c 0.50, CHCl3). Rf = 0.48 (6/4 Hex/EtOAc). IR
D
1
(film, cm−1): 3540.7, 1741.3, 1530.0, 1311.1, 1162.3, 742.7. H NMR
(300 MHz, CDCl3): δ 1.35 (d, J = 6.3 Hz, 3H), 3.59 (s, 3H), 4.16 (dd,
J = 0.9, 7.8 Hz, 1H), 4.23 (ddq, J = 1.5, 6.3, 15.9 Hz, 2H), 4.47 (sextet,
J = 6 Hz, 1H), 4.59 (d, J = 5.7 Hz, 1H), 6.11 (ddd, J = 6.3, 7.8, 15.9
Hz, 1H), 6.51 (d, J = 15.9 Hz, 1H), 7.30 (m, 5H), 8.02 (d, J = 9 Hz,
2H), 8.27 (d, J = 9 Hz, 2H). 13C NMR (75 MHz): δ 169.9, 146.0,
135.8, 134.4, 129.0, 128.7, 128.3, 126.7, 126.4, 124.7, 123.9, 67.2, 65.0,
52.5, 49.7, 20.1. HRMS: (M + Na) for C20H22N2O7SNa calcd
457.10454, found 457.10383.
N-Cinnamyl-N-((1R,2R)-2-hydroxycyclohexyl)-4-methylbenzene-
sulfonamide (6e). White solid, mp 121−123 °C, isolated yield 521 mg
(84%). [α]22D = +10.4° (c 1.10, CHCl3). Rf = 0.52 (7/3 Hex/EtOAc).
1
IR (film, cm−1): 3529.6, 1330.7, 1092.6, 735.1, 661.3. H NMR (300
MHz, CDCl3): δ 1.22 (m, 3H), 1.48 (m, 2H), 1.66 (m, 2H), 2.10 (m,
1H), 2.31 (s, 1H), 2.41 (s, 3H), 3.53 (m, 2H), 4.06 (m, 2H), 6.15 (m,
1H), 6.53 (d, J = 16.0 Hz, 1H), 7.29 (m, 7H), 7.74 (d, J = 8.0 Hz, 2H).
13C NMR (75 MHz, CDCl3): δ 143.4, 138.0, 136.2, 132.9, 129.7,
128.6, 127.9, 127.2, 126.5, 70.1, 64.1, 46.2, 34.4, 29.3, 25.4, 24.0, 21.6.
HRMS: (M + H) for C22H27NO3SH calcd 386.17899, found
386.17774.
(2S,3R)-Methyl 3-Hydroxy-2-(N-(2-methylallyl)-4-
nitrophenylsulfonamido)butanoate (9b). Colorless oil, isolated
yield 226 mg (74%). [α]22 = −45.2° (c 1.55, CHCl3). Rf = 0.26
D
(7/3 Hex/EtOAc). IR (film, cm−1): 3545.8, 1739.3, 1529.5, 1309.5,
1161.4, 1090.3, 855.9, 734.7. 1H NMR (300 MHz, CDCl3): δ 1.29 (d,
J = 6.0 Hz, 3H), 1.70 (s, 3H), 3.53 (s, 3H), 3.99 (br s, 2H), 4.32 (m,
2H), 4.99 (s, 1H), 5.03 (s, 1H), 8.04 (d, J = 8.7 Hz, 2H), 8.34 (d, J =
8.7 Hz, 2H). 13C NMR (75 MHz): δ 169.4, 150.0, 145.2, 141.2, 129.1,
123.9, 115.5, 66.4, 65.5, 53.3, 52.2, 20.3. HRMS: (M + Na) for
C15H20N2O7SNa calcd 395.08889, found 395.08907.
(R)-N-Cinnamyl-N-(1-hydroxybutan-2-yl)-4-methylbenzenesulfo-
namide (6f). White solid, mp 70−72 °C, isolated yield 334 mg (51%).
[α]22 = +30.4° (c 1.20, CHCl3). Rf = 0.31 (7/3 Hex/EtOAc). IR
D
(film, cm−1): 3519.0, 1330.7, 1092.6, 657.9. 1H NMR (400 MHz,
CDCl3): δ 0.73 (t, J = 7.6 Hz, 3H), 1.46 (m, 2H), 2.28 (br s, 1H), 2.41
(s, 3H), 3.62 (t, J = 6.4 Hz, 2H), 3.85 (m, 2H), 6.17 (m, 1H), 6.51 (d,
(2S,3R)-Methyl 3-Hydroxy-2-(N-(3-methylbut-2-en-1-yl)-4-
nitrophenylsulfonamido)butanoate (9c). Colorless oil, isolated
879
dx.doi.org/10.1021/jo3021715 | J. Org. Chem. 2013, 78, 872−885

The Journal of Organic Chemistry
Article
yield 317 mg (>99%). [α]22D = −58.8° (c 1.35, CHCl3). Rf = 0.53 (6/4
8.05 (d, J = 9.0 Hz, 2H), 8.35 (d, J = 9.0 Hz, 2H). 13C NMR (75
MHz): δ 169.7, 145.9, 131.5, 128.8, 126.0, 124.1, 124.0, 61.2, 61.1,
52.5, 49.0, 17.7. HRMS: (M + Na) for C14H18N2O7SNa calcd
381.07324, found 381.07244.
Hex/EtOAc). IR (film, cm−1): 3538.0, 1740.3, 1530.1, 1310.8, 1162.7,
1
1090.2, 855.3, 759.6. H NMR (300 MHz, CDCl3): δ 1.32 (d, J = 6.3
Hz, 3H), 1.64 (s, 3H), 1.67 (s, 3H), 2.31 (d, J = 4.8 Hz, 1H), 3.59 (s,
3H), 4.06 (d, J = 6.9 Hz, 2H), 4.32 (q, J = 6.3 Hz, 1H), 4.49 (d, J = 6.0
Hz, 1H), 5.14 (m, 1H), 8.02 (d, J = 9.3 Hz, 2H), 8.33 (d, J = 9.0 Hz,
2H). 13C NMR (75 MHz): δ 169.9, 149.9, 146.1, 137.3, 128.9, 123.8,
120.1, 66.7, 64.9, 52.3, 45.1, 25.8, 20.0, 17.8. HRMS: (M + Na) for
C16H22N2O7SNa calcd 409.10454, found 409.10374.
(S,Z)-Methyl 3-Hydroxy-2-(N-(2-methyl-3-phenylallyl)-4-
nitrophenylsulfonamido)propanoate (9j). White solid, mp 113−
116 °C, isolated yield 152 mg (38%). [α]22 = −10.2° (c 0.50,
D
CHCl3). Rf = 0.52 (6/4 Hex/EtOAc). IR (film, cm−1): 3548.9, 1736.2,
1
1530.3, 1311.3, 1162.3, 743.0. H NMR (300 MHz, CDCl3): δ 1.81
(d, J = 1.2 Hz, 3H), 3.64 (s, 3H), 3.93 (m, 2H), 4.15 (m, 2H), 4.59 (t,
J = 6.6 Hz, 1H), 6.45 (s, 1H), 7.19 (m, 2H), 7.34 (m, 3H), 8.08 (d, J =
9.0 Hz, 2H), 8.35 (d, J = 9.0 Hz, 2H). 13C NMR (75 MHz): δ 169.6,
150.0, 145.6, 136.4, 132.6, 130.3, 129.0, 128.8, 128.3, 127.2, 124.0,
61.4, 61.2, 56.0, 52.6, 15.8. HRMS: (M + Na) for C20H22N2O7SNa
calcd 457.10454, found 457.10355.
N-Cinnamyl-N-((1R,2R)-2-hydroxycyclohexyl)-4-nitrobenzenesul-
fonamide (9k). White solid, mp 147−149 °C, isolated yield 500 mg
(>99%). [α]22D = +8.8° (c 0.50, CHCl3). Rf = 0.61 (6/4 Hex/EtOAc).
IR (film, cm−1): 3548.6, 1528.0, 1347.8, 1162.5, 685.3. 1H NMR (300
MHz, CDCl3): δ 1.19 (m, 4H), 1.61 (m, 3H), 1.80 (d, J = 2.7 Hz, 1H),
2.05 (br s, 1H), 3.54 (m, 2H), 4.04 (m, 2H), 6.01 (dt, J = 6.9, 15.9 Hz,
1H), 6.50 (d, J = 15.9 Hz, 1H), 7.25 (m, 5H), 7.97 (d, J = 8.7 Hz, 2H),
8.19 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz): δ 147.1, 135.8, 133.7,
128.7, 128.6, 128.2, 126.7, 126.4, 125.5, 124.0, 70.1, 64.5, 46.4, 35.0
30.4, 25.3, 24.0. HRMS: (M + Na) for C21H24N2O5SNa calcd
439.13036, found 439.13042.
(2S,3R)-Methyl 2-(N-((E)-But-2-en-1-yl)-4-nitrophenylsulfonami-
do)-3-hydroxybutanoate (9d). Colorless oil, isolated yield 305 mg
(>99%). [α]22 = −40.7° (c 0.85, CHCl3). Rf = 0.54 (6/4 Hex/
D
EtOAc). IR (film, cm−1): 3538.1, 1740.7, 1530.4, 1311.4, 1163.5,
734.6. 1H NMR (300 MHz, CDCl3): δ 1.30 (d, J = 6.0 Hz, 3H), 1.63
(dd, J = 1.2, 6.4 Hz, 3H), 3.56 (s, 3H), 3.97 (dq, J = 6.3, 17.4 Hz, 2H),
4.36 (q, J = 6.0 Hz, 1H), 4.47 (d, J = 5.6 Hz, 1H), 5.44 (qt, J = 1.6, 7.6
Hz, 1H), 5.66 (m, 1H), 8.01 (d, J = 9.2 Hz, 2H), 8.33 (d, J = 8.8 Hz,
2H). 13C NMR (75 MHz): δ 169.8, 145.9, 131.2, 129.0, 128.9, 126.6,
123.8, 66.7, 64.8, 52.2, 49.2, 19.9, 17.6. HRMS: (M + Na) for
C15H20N2O7SNa calcd 395.08889, found 395.08819.
(2S,3R)-Methyl 3-Hydroxy-2-(N-((Z)-2-methyl-3-phenylallyl)-4-
nitrophenylsulfonamido)butanoate (9e). Colorless oil, isolated
yield 368 mg (>99%). [α]22 = −63.4° (c 1.10, CHCl3). Rf = 0.62
D
(6/4 Hex/EtOAc). IR (film, cm−1): 3544.1, 1740.5, 1530.5, 1310.7,
1
1162.9, 733.0. H NMR (300 MHz, CDCl3): δ 1.32 (d, J = 69.0 Hz,
3H), 1.75 (s, 3H), 2.41 (d, J = 4.5 Hz, 1H), 3.58 (s, 3H), 4.14 (s, 2H),
4.42 (t, J = 7.2 Hz, 2H), 6.49 (s, 1H), 7.18 (m, 2H), 7.34 (m, 3H),
8.03 (d, J = 9.0 Hz, 2H), 8.31 (d, J = 9.0 Hz, 2H). 13C NMR (75
MHz): δ 169.5, 149.9, 145.7, 136.5, 132.8, 130.7, 129.2, 128.8, 128.3,
127.1, 123.8, 66.3, 65.4, 56.0, 52.3, 20.6, 16.0. HRMS: (M + Na) for
C21H24N2O7SNa calcd 471.12019, found 471.11926.
(R)-N-Cinnamyl-N-(1-hydroxybutan-2-yl)-4-nitrobenzenesulfona-
mide (9l). Colorless oil, isolated yield 172 mg (53%). [α]22D = 234.8°
(c 0.45, CHCl3). Rf = 0.56 (6/4 Hex/EtOAc). IR (film, cm−1): 3537.4,
1
1527.2, 1346.9, 1157.8, 854.3, 691.7. H NMR (300 MHz, CDCl3): δ
0.82 (t, J = 7.5 Hz, 3H), 1.52 (m, 2H), 3.65 (d, 6.3 Hz, 2H), 3.96 (m,
2H), 4.11 (dd, J = 6.9, 15.9 Hz, 1H), 6.07 (dt, J = 6.6, 15.9 Hz, 1H),
6.54 (d, J = 15.9 Hz, 1H), 7.27 (m, 5H), 8.04 (d, J = 8.7 Hz, 2H), 8.24
(d, J = 8.7 Hz, 2H). 13C NMR (75 MHz): δ 149.7, 147.1, 135.8, 133.7,
128.7, 128.6, 128.2, 126.4, 125.4, 124.0, 63.3, 62.4, 46.1, 22.6, 11.1.
HRMS: (M + Na) for C19H22N2O5SNa calcd 413.11471, found
413.11482.
(S)-Methyl 2-(N-Cinnamyl-4-nitrophenylsulfonamido)-3-hydrox-
ypropanoate (9f). White solid, mp 116−118 °C, isolated yield 306
mg (79%). [α]22 = +6.7° (c 0.55, CHCl3). Rf = 0.39 (6/4 Hex/
D
EtOAc). IR (film, cm−1): 3543.1, 1740.2, 1530.1, 1311.7, 1162.4,
741.4. 1H NMR (300 MHz, CDCl3): δ 3.64 (s, 3H), 4.02 (ddd, J = 1.2,
7.2, 15.9 Hz, 2H), 4.17 (m, 2H), 4.76 (dd, J = 5.7, 7.2 Hz, 1H), 6.09
(ddd, J = 6.6, 7.2, 22.5 Hz, 1H), 6.53 (d, J = 15.9 Hz, 1H), 7.31 (m,
5H), 8.07 (d, J = 9 Hz, 2H), 8.31 (d, J = 9 Hz, 2H). 13C NMR (75
MHz): δ 169.6, 146.0, 145.9, 135.6, 134.5, 128.9, 128.7, 128.4, 126.5,
124.1, 124.0, 61.4, 61.3, 52.7, 49.2. HRMS: (M + Na) for
C19H20N2O7SNa calcd 443.08889, found 443.08873.
(R)-N-Cinnamyl-N-(2-hydroxypropyl)-4-nitrobenzenesulfona-
mide (9m). White solid, mp 87−90 °C, isolated yield 723 mg (91%).
[α]22 = +32.3° (c 0.60, CHCl3). Rf = 0.53 (6/4 Hex/EtOAc). IR
D
1
(film, cm−1): 3541.7, 1529.3, 1310.9, 1161.0 ,740.9. H NMR (300
MHz, CDCl3): δ 1.19 (d, J = 6.3 Hz, 3H), 2.24 (br s, 1H), 3.329 (m,
2H), 4.14 (dd, J = 7.5, 14.1 Hz, 3H), 5.95 (dt, J = 6.9, 15.9 Hz, 1H),
6.49 (d, J = 15.9 Hz, 1H), 7.30 (m, 5H), 8.05 (d, J = 9 Hz, 2H), 8.33
(d, J = 9 Hz, 2H). 13C NMR (75 MHz): δ 145.7, 135.9, 135.6, 135.0,
128.7, 128.6, 128.4, 126.4, 124.3, 122.7, 66.4, 54.8, 51.8, 20.8. HRMS:
(M + Na) for C18H20N2O5SNa calcd 399.09906, found 399.09867.
(2S,3S)-Methyl 2-(N-Cinnamyl-4-nitrophenylsulfonamido)-3-hy-
droxybutanoate (9n). Colorless oil, isolated yield 348 mg (>99%).
( S ) - M e t h y l 3 - H y d r o x y - 2 - ( N - ( 2 - m e t h y l a l l y l ) - 4 -
nitrophenylsulfonamido)propanoate (9g). Colorless oil, isolated
yield 139 mg (42%). [α]22 = +2.4° (c 0.55, CHCl3). Rf = 0.59 (6/
D
4 Hex/EtOAc). IR (film, cm−1): 3545.6, 1736.5, 1530.9, 1311.4,
1
1163.5, 736.9. H NMR (300 MHz, CDCl3): δ 1.70 (s, 3H), 3.63 (s,
3H), 3.74 (d, J = 16.2 Hz, 1H), 3.95 (m, 2H), 4.14 (dd, J = 5.7, 11.7
Hz, 1H), 4.52 (t, J = 6.0 Hz, 1H), 4.98 (s, 1H), 5.02 (s, 1H), 8.05 (d, J
= 9.0 Hz, 2H), 8.36 (d, J = 9.0 Hz, 2H). 13C NMR (75 MHz): δ 169.5,
145.4, 140.9, 129.0, 124.4, 124.0, 115.2, 61.6, 61.5, 53.6, 52.5, 20.0.
HRMS: (M + Na) for C14H18N2O7SNa calcd 381.07324, found
381.07260.
[α]22 = −30.8° (c 0.90, CHCl3). Rf = 0.47 (6/4 Hex/EtOAc). IR
D
1
(film, cm−1): 3537.4, 1740.0, 1530.6, 1311.5, 1164.7, 743.4. H NMR
(300 MHz, CDCl3): δ 1.21 (d, J = 6 Hz, 3H), 3.39 (s, 3H), 3.90 (ddq,
J = 1.2, 7.5, 18.3 Hz, 2H), 4.02 (dd, J = 0.9, 7.5 Hz, 1H), 4.22 (m, 2H),
5.84 (ddd, J = 6.6, 7.8, 15.9 Hz, 1H), 6.35 (d, J = 15.9 Hz, 1H), 7.33
(m, 5H), 8.04 (d, J = 9 Hz, 2H), 8.31 (d, J = 9 Hz, 2H). 13C NMR (75
MHz): δ 170.6, 150.0, 145.9, 135.5, 134.9, 128.9, 128.7, 128.4, 126.4,
123.9, 123.5, 67.0, 64.7, 52.4, 49.5, 20.0. HRMS: (M + Na) for
C20H22N2O7SNa calcd 457.10454, found 457.10427.
(S)-Methyl 3-Hydroxy-2-(N-(3-methylbut-2-en-1-yl)-4-
nitrophenylsulfonamido)propanoate (9h). Colorless oil, isolated
yield 332 mg (97%). [α]22 = 3.2° (c 1.05, CHCl3). Rf = 0.41 (6/4
D
Hex/EtOAc). IR (film, cm−1): 3548.7, 1736.2, 1530.1, 1311.0, 1162.1,
1
855.1, 743.7. H NMR (300 MHz, CDCl3): δ 1.62 (s, 3H), 1.67 (s,
3H), 3.65 (s, 3H), 3.86 (m, 2H), 3.97 (m, 1H), 4.08 (m, 1H), 4.66 (t,
J = 7.2 Hz, 1H), 5.10 (dt, J = 1.5, 7.8 Hz, 1H), 8.05 (d, J = 9.0 Hz,
2H), 8.4 (d, J = 9.0 Hz, 2H). 13C NMR (75 MHz): δ 169.8, 146.1,
138.0, 128.8, 124.0, 119.4, 61.3, 61.2, 52.5, 44.8, 25.7, 17.8. HRMS: (M
+ Na) for C15H20N2O7SNa calcd 395.08889, found 395.08796.
(S,E)-Methyl 2-(N-(But-2-en-1-yl)-4-nitrophenylsulfonamido)-3-
hydroxypropanoate (9i). Colorless oil, isolated yield 119 mg
N-Cinnamyl-N-(2-hydroxyethyl)-4-nitrobenzenesulfonamide
(9o). White solid, mp 85−87 °C, isolated yield 245 mg (93%). Rf =
0.35 (6/4 Hex/EtOAc). IR (film, cm−1): 3536.9, 1528.5, 1348.0,
1
1159.9, 965.2, 692.0. H NMR (300 MHz, CDCl3): δ 3.41 (t, J = 5.4
Hz, 2H), 3.81 (q, J = 5.4 Hz, 2H), 4.11 (d, J = 6.6 Hz, 2H), 6.00 (ddt,
J = 0.9, 6.9, 15.9 Hz, 1H), 6.51 (dd, J = 0.9, 15.9 Hz, 1H), 7.28 (m,
5H), 8.06 (d, J = 9 Hz, 2H), 8.35 (d, J = 9 Hz, 2H). 13C NMR (75
MHz): δ 145.6, 135.5, 135.0, 128.7, 128.5, 128.4, 126.4, 124.4, 122.8,
61.0, 51.5, 49.6. HRMS: (M + Na) for C17H18N2O5SNa calcd
385.08341, found 385.08321.
(36%). [α]22 = −4.9° (c 0.90, CHCl3). Rf = 0.42 (6/4 Hex/
D
EtOAc). IR (film, cm−1): 3547.0, 1736.5, 1530.4, 1311.5, 1163.1,
741.5. 1H NMR (300 MHz, CDCl3): δ 1.66 (d, J = 6.6 Hz, 3H), 2.23
(br s, 1H), 3.64 (s, 3H), 3.78 (m, 1H), 3.92 (m, 2H), 4.10 (dd, J = 5.7,
11.7 Hz, 1H), 4.66 (t, J = 6.9 Hz, 1H), 5.41 (m, 1H), 5.67 (m, 1H),
N-Cinnamyl-N-(2-hydroxy-2,3-dihydro-1H-inden-1-yl)-4-nitro-
benzenesulfonamide (9p). Colorless oil, isolated yield 326 mg (94%).
880
dx.doi.org/10.1021/jo3021715 | J. Org. Chem. 2013, 78, 872−885

The Journal of Organic Chemistry
Article
[α]22D = 75.5° (c 1.40, CHCl3). Rf = 0.66 (6/4 Hex/EtOAc). IR (film,
51.7, 48.5, 48.1, 29.8, 24.9, 23.4, 23.2, 21.6, 21.5, 20.7, 19.8. HRMS: (2
M + K) for 2[C17H24BrNO5S]K calcd 905.0749, found 905.0760.
(3S)-Methyl 6-Bromo-7-phenyl-4-tosyl-1,4-oxazepane-3-carbox-
ylate (7d). Characterized from a 2.0:1 mixture of diastereomers.
Colorless oil, isolated yield 74 mg (69%). Rf = 0.29 (7/3 Hex/EtOAc).
IR (film, cm−1): 3033.1, 2954.0, 1747.3, 1338.4, 1195.3, 1099.8,
1
cm−1): 3538.1, 1529.3, 1344.4, 1162.4, 1094.8, 692.5. H NMR (300
MHz, CDCl3): δ 2.49 (d, J = 2.4 Hz, 1H), 2.97 (dd, J = 4.0, 16.8 Hz,
1H), 3.27 (dd, J = 7.5, 16.8 Hz, 1H), 3.93 (dq, J = 8.1, 15.9 Hz, 2H),
4.16 (d, J = 7.5 Hz, 1H), 4.73 (dq, J = 4.2, 7.2 Hz, 1H), 5.89 (ddd, J =
6.0, 7.8, 15.9 Hz, 1H), 6.19 (d, J = 15.9 Hz, 1H), 7.25 (m, 9H), 8.06
(d, J = 9 Hz, 2H), 8.33 (d, J = 9 Hz, 2H). 13C NMR (75 MHz): δ
146.9, 141.2, 136.6, 136.0, 133.9, 129.6, 128.6, 128.5, 128.1, 127.3,
126.7, 126.4, 125.7, 125.5, 125.1, 124.3, 72.3, 65.3, 49.1, 39.7. HRMS:
(M + Na) for C24H22N2O5SNa calcd 473.11471, found 473.11453.
General Procedure for Cyclization of N-alkylated Amino
Alcohols. A 284 mg portion (0.65 mmol) of 9a was dissolved in 10
mL of THF in a vial. A 15 mg portion of solid ( )-CSA (10 mol %,
0.06 mmol) was added, followed by 128 mg (0.72 mmol) of solid
NBS. The mixture was then cooled to 0 °C and stirred for 12 h. The
flask was warmed slowly to room temperature and was stirred for an
additional 5 h. The reaction was quenched by adding 5 mL of
saturated NaHCO3 solution to the reaction mixture. The product was
then extracted with EtOAc (2 × 40 mL), and the extract was dried
over Na2SO4, filtered, and concentrated in vacuo to give 10a. The
crude product was purified by column chromatography (8/2 Hex/
EtOAc eluent system).
1
1090.6, 1023.7, 757.5, 700.1, 662.2. H NMR (300 MHz, CDCl3): δ
2.44 (s, 1H), 2.47 (s, 2H), 3.63 (s, 2H), 3.69 (dd, J = 8.1, 9.9 Hz,
0.5H), 3.71 (s, 1H), 3.75 (dd, J = 8.7, 12.0 Hz, 1H), 3.96 (dd, J = 4.8,
11.7 Hz, 0.5H), 4.02−4.09 (m, 1H), 4.30−4.37 (m, 1.5H), 4.50 (dd, J
= 5.1, 9.9 Hz, 1H), 4.54 (dd, J = 1.8, 10.2 Hz, 0.5H), 4.62 (d, J = 6.0
Hz, 0.5H), 4.69 (t, J = 1.8 Hz, 0.5H), 4.99 (dd, J = 5.1, 7.8 Hz, 1H),
7.17−7.19 (m, 1H), 7.30−7.37 (m, 5H), 7.77−7.80 (m, 2H). 13C
NMR (75 MHz): δ 169.8, 169.8, 144.0, 139.8, 138.8, 137.2, 136.1,
129.8, 129.7, 128.8, 128.6, 128.5, 128.4, 127.6, 127.3, 127.3, 126.7,
90.6, 88.9, 70.8, 69.8, 61.0, 59.2, 53.7, 52.7, 52.6, 52.5, 52.5, 50.8, 50.2,
49.7, 21.6. HRMS: (M + K) for C20H22BrNO5SK calcd 506.0034,
found 506.0008.
(5aR,9aR)-3-Bromo-2-phenyl-5-tosyldecahydrobenzo[b][1,4]-
oxazepine (7e). Major diastereomer: colorless oil, isolated yield 54 mg
(24%). Rf = 0.16 (1/1 DCM/toluene). IR (film, cm−1): 2927.1,
1
2856.8, 1454.8, 1328.3, 1130.0, 1101.4, 761.8, 728.6. H NMR (300
MHz, CDCl3): δ 1.20 (tt, J = 2.7, 9.6 Hz, 2H), 1.32 (tq, J = 2.7, 9.9 Hz,
1H), 1.45 (dq, J = 2.7, 9.3 Hz, 1H) 1.75 (t, J = 9.6 Hz, 2H), 1.91 (t, J =
11.4 Hz, 2H), 2.14 (dq, J = 2.7, 9.3 Hz, 1H), 2.44 (s, 3H), 3.19 (dt, J =
2.4, 8.7 Hz, 1H), 3.31 (dd, J = 7.8, 10.8 Hz, 1H), 4.07 (dt, J = 3.0, 8.7
Hz, 1H), 4.33 (m, 2H), 4.63 (d, J = 7.2 Hz, 1H), 7.26−7.35 (m, 7H),
7.76 (d, J = 6.3 Hz, 2H). 13C NMR (75 MHz): δ 143.2, 141.0, 139.7,
129.7, 128.3, 128.2, 127.2, 126.7, 78.9, 77.7, 67.6, 58.2, 51.6, 31.4, 30.3,
26.2, 24.5, 21.5. HRMS: (M + Na) for C22H26BrNO3SNa calcd
486.07145, found 486.07080. Minor diastereomer: colorless oil, isolated
yield 31 mg (14%). Rf = 0.24 (1/1 DCM/toluene). IR (film, cm−1):
2937.8, 2860.5, 1335.9, 1180.0, 1087.2, 1000.0, 872.6, 776.6, 659.0. 1H
NMR (300 MHz, CDCl3): δ 1.25−1.49 (m, 4H), 1.71−1.79 (m, 2H),
2.01 (d, J = 9.3 Hz, 1H), 2.14 (d, J = 5.4 Hz, 1H), 2.49 (s, 3H),
3.39(dt, J = 3.0, 7.8 Hz, 1H), 3.63 (dd, J = 9.0, 12.0 Hz, 1H), 3.78 (m,
2H), 4.31 (m, 2H), 6.90 (dd, J = 1.2, 6.0 Hz, 2H), 7.24 (m, 3H), 7.38
(d, J = 6.0 Hz, 2H), 7.84 (d, J = 6.3 Hz, 2H). 13C NMR (75 MHz): δ
143.5, 139.7, 139.0, 130.0, 128.4, 128.1, 127.3, 127.2, 88.4, 82.4, 63.3,
51.4, 48.6, 33.9, 32.4, 24.8, 24.7, 21.6. HRMS: (M + Na) for
C22H26BrNO3SNa calcd 486.07145, found 486.07201.
(3R)-6-Bromo-3-ethyl-7-phenyl-4-tosyl-1,4-oxazepane (7f). Char-
acterized from a 2.0/1 mixture of diastereomers, Colorless oil, isolated
yield 57 mg (>99%). Rf = 0.61 (7/3 Hex/EtOAc). IR (film, cm−1):
3033.3, 2968.4, 2877.5, 1455.0, 1337.4, 1095.9, 1040.0, 760.87, 699.5.
1H NMR (300 MHz, CDCl3): δ 0.79 (t, J = 5.7 Hz, 1H), 0.94 (t, J =
5.7 Hz, 2H), 2.45 (s, 1H), 2.5 (s, 2H), 3.36 (dd, J = 9.9, 11.7 Hz, 1H),
3.51 (dd, J = 9.0, 12.0 Hz, 1H), 3.70 (dd, J = 2.4, 9.3 Hz, 0.5H), 3.77−
3.84 (m, 1H), 3.93−4.00 (m, 1H), 4.18 (d, J = 7.5 Hz, 1H), 4.22−4.30
(m, 2H), 4.38 (dd, J = 2.4, 11.7 Hz, 1H), 5.54 (d, J = 6.9 Hz, 0.5H),
6.85 (dd, J = 1.2, 6.0 Hz, 2H), 7.22−7.26 (m, 1.5H), 7.33−7.35 (m,
2H), 7.38 (d, J = 6.0 Hz, 1.5H), 7.81 (d, J = 6.3 Hz, 0.5H), 7.84 (d, J =
6.3 Hz, 1.5H). 13C NMR (75 MHz): δ 143.5, 140.0, 139.3, 139.2,
137.5, 130.0, 129.7, 128.5, 128.4, 128.1, 127.5, 127.3, 127.1, 126.9,
90.5, 88.6, 73.9, 73.0, 60.2, 58.7, 54.2, 50.2, 49.0, 58.4, 31.6, 24.7, 22.7,
22.3, 21.6, 14.1, 10.9, 10.1. HRMS: (M + Na) for C20H24BrNO3SNa
calcd 460.05525, found 460.05520.
(2R,3S)-Methyl 6-Bromo-2-methyl-7-phenyl-4-tosyl-1,4-oxaze-
pane-3-carboxylate (7a). Major diastereomer: colorless oil, isolated
yield 41 mg (11%). Rf = 0.40 (7/3 Hex/EtOAc). IR (film, cm−1):
2923.6, 1740.3, 1454.5, 1355.6, 1157.1, 1090.9, 1009.3, 699.4. 1H
NMR (300 MHz, CDCl3): δ 1.32 (d, J = 4.5 Hz, 3H), 2.46 (s, 3H),
3.55 (s, 3H), 3.89 (dd, J = 8.7, 11.7 Hz, 1H), 3.94 (dd, J = 4.5, 7.2 Hz,
1H), 4.06−4.13 (m, 1H), 4.32 (dd, J = 2.7, 11.7 Hz, 1H), 4.37 (d, J =
7.8 Hz, 1H), 4.49 (d, J = 7.2 Hz, 1H), 7.20−7.22 (m, 2H), 7.31−7.35
(m, 5H), 7.73 (d, J = 6.3 Hz, 2H). 13C NMR (75 MHz): δ 170.9,
143.8, 139.4, 137.3, 129.8, 128.6, 128.2, 127.4, 127.1, 90.0, 64.6, 52.3,
51.8, 50.1, 21.6, 20.3. HRMS: (M + Na) for C21H24BrNO5SNa calcd
504.04563, found 504.04422. Minor diastereomer: colorless oil, isolated
yield 234 mg (63%). Rf = 0.34 (7/3 Hex/EtOAc). IR (film, cm−1):
2923.6, 2853.0, 1745.4, 1455.8, 1340.9, 1219.8, 1159.0, 1091.7, 699.8.
1H NMR (300 MHz, CDCl3): δ 1.46 (d, J = 5.1 Hz, 3H), 2.45 (s, 3H),
3.62 (s, 3H), 4.05 (dd, J = 3.9, 11.7 Hz, 1H), 4.24 (dd, J = 3.3, 11.7
Hz, 1H), 4.30−4.35 (m, 1H), 4.42 (d, J = 2.7 Hz, 1H), 4.72 (dq, J =
2.4, 5.1 Hz, 1H), 4.89 (d, J = 6.9 Hz, 1H), 7.30−7.34 (m, 7H), 7.77 (d,
J = 6.3 Hz, 2H). 13C NMR (75 MHz): δ 166.9, 141.4, 167.6, 133.5,
127.1, 127.0, 126.0, 125.2, 124.3, 75.7, 70.5, 63.0, 50.5, 50.0, 49.7, 19.0.
HRMS: (M + Na) for C21H24BrNO5SNa calcd 504.04563, found
504.04463.
(2R,3S)-Methyl 6-(Bromomethyl)-2,6-dimethyl-4-tosylmorpho-
line-3-carboxylate (8b). Characterized from a 2.0/1 mixture of
diastereomers. Colorless oil, isolated yield 68 mg (77%). Rf = 0.43 (7/
3 Hex/EtOAc). IR (film, cm−1): 2983.0, 1743.3, 1348.0, 1126.5,
1091.2, 1039.7, 816.2, 663.5. 1H NMR (300 MHz, CDCl3): δ 1.14 (d,
J = 4.5 Hz, 1H), 1.18 (d, J = 4.5 Hz, 2H), 1.24 (s, 1H), 1.39 (s, 2H),
2.43 (s, 2H), 2.44 (s, 1H), 2.60 (d, J = 9.3 Hz, 0.5H), 2.99 (d, J = 9.9
Hz, 0.5H), 3.17 (d, J = 6.9 Hz, 0.5H), 3.21 (s, 1H), 3.37 (d, J = 9.6 Hz,
0.5H), 3.44 (dd, J = 4.8, 8.4 Hz, 1H), 3.55 (d, J = 9.3 Hz, 0.5H), 3.71
(s, 2H), 3.76 (s, 1H), 3.79 (d, J = 8.1 Hz, 0.5H), 3.93−3.99 (m, 1H),
7.33−7.37 (m, 2H), 7.69 (d, J = 6.3 Hz, 2H). 13C NMR (75 MHz): δ
170.0, 169.7, 144.4, 144.2, 133.7, 132.3, 129.8, 129.7, 128.2, 127.9,
74.1, 72.6, 67.7, 67.6, 63.7, 63.6, 52.7, 52.6, 52.5, 49.8, 48.4, 38.5, 35.6,
24.4, 21.6, 20.2, 18.6, 18.3. HRMS: (M + K) for C16H22BrNO5SK
calcd 458.0034, found 458.0008.
(2R)-6-Bromo-2-methyl-7-phenyl-4-tosyl-1,4-oxazepane (7g).
Major diastereomer: colorless oil, isolated yield 22 mg (43%). Rf =
0.63 (7/3 Hex/EtOAc). IR (film, cm−1): 2925.9, 1450.7, 1340.6,
1159.4, 1087.8, 699.4. 1H NMR (400 MHz, CDCl3): δ 1.06 (d, J = 6.4
Hz, 3H), 2.46 (s, 3H), 2.69 (dd, J = 10.0, 14.0 Hz, 1H), 3.29 (dd, J =
10.0, 14.0 Hz, 1H), 3.82 (ddd, J = 1.2, 3.2, 14.0 Hz, 1H), 3.93−3.98
(m, 1H), 4.31 (ddd, J = 1.2, 3.2, 14.0 Hz, 1H), 4.37 (dt, J = 3.6, 10.0
Hz, 1H), 4.81 (d, J = 9.2 Hz, 1H), 7.36 (m, 7H), 7.71 (d, J = 8.4 Hz,
2H). 13C NMR (75 MHz, CDCl3),: δ 143.8, 138.9, 136.2, 129.9, 128.5,
128.4, 127.4, 127.0, 80.3, 71.0, 54.9, 54.7, 49.7, 21.5, 18.4. HRMS: (M
+ H) for C19H22BrNO3SH calcd 424.0567, found 424.0558; Minor
diastereomer: colorless oil, isolated yield 19 mg (37%). Rf = 0.56 (7/3
Hex/EtOAc). IR (film, cm−1): 2925.8, 1450.4, 1342.2, 1161.5, 1088.8,
(2R,3S)-Methyl 6-Bromo-2,7,7-trimethyl-4-tosyl-1,4-oxazepane-
3-carboxylate (7c). Characterized from a 1.5/1 mixture of
diastereomers. Colorless oil, isolated yield 110 mg (47%). Rf = 0.36
(7/3 Hex/EtOAc). IR (film, cm−1): 2981.7, 1739.8, 1351.8, 1334.0,
1
1195.9, 1089.8, 957.1, 771.2, 662.8. H NMR (300 MHz, CDCl3): δ
1.20−1.25 (m, 3H), 1.30−1.34 (m, 6H), 2.40 (s, 3H), 3.47 (s, 2H),
3.63 (s, 1H), 3.73 (dd, J = 8.7, 12.0 Hz, 1H), 3.85−3.93 (m, 2H), 4.03
(m, 0.5H), 4.26 (d, J = 7.2 Hz, 1H), 4.41 (d, J = 5.1 Hz, 0.5H), 7.27−
7.29 (m, 2H), 7.64 (d, J = 6.3 Hz, 1.5H), 7.68 (d, J = 6.0 Hz, 0.5H).
13C NMR (75 MHz): δ 171.4, 171.1, 143.7, 143.6, 137.1, 135.9, 129.6,
129.5, 127.6, 127.0, 78.3, 78.0, 67.6, 66.8, 64.4, 63.9, 56.0, 52.5, 52.1,
881
dx.doi.org/10.1021/jo3021715 | J. Org. Chem. 2013, 78, 872−885

The Journal of Organic Chemistry
Article
1
771.6, 699.6. 1H NMR (400 MHz, CDCl3): δ 1.17 (d, J = 6.0 Hz, 3H),
2.46 (s, 3H), 2.96 (dd, J = 10.4, 12.8 Hz, 1H), 3.57 (ddd, J = 0.8, 3.2,
12.8 Hz, 1H), 3.85 (dd, J = 4.4, 15.2 Hz, 1H), 3.91 (dd, J = 0.8, 5.2 Hz,
1H), 3.93−3.97 (m, 1H), 4.14 (ddd, J = 4.0, 5.2, 9.6 Hz, 1H), 4.60 (d,
J = 9.6 Hz, 1H), 7.32−7.37 (m, 7H), 7.74 (d, J = 8.4 Hz, 2H). 13C
NMR (75 MHz, CDCl3): δ 143.7, 140.0, 135.8, 129.9, 128.3, 128.2,
127.3, 127.1, 87.6, 77,.2, 56.7, 54.0, 53.9, 21.5, 19.5. HRMS: (M + H)
for C19H22BrNO3SH calcd 424.0567, found 424.0555.
1739.2, 1530.3, 1348.4, 1159.0, 1088.5, 1008.3, 699.0. H NMR (300
MHz, CDCl3): δ 1.37 (d, J = 6.0 Hz, 3H), 3.57 (s, 3H), 3.92 (m, 2H),
4.15 (dt, J = 3.9, 11.4 Hz, 1H), 4.27 (dd, J = 3.6, 15.3 Hz, 1H), 4.40 (d,
J = 10.2 Hz, 1H), 4.53 (d, J = 9.6 Hz, 1H), 7.31 (m, 5H), 8.04 (d, J =
8.7 Hz, 2H), 8.40 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz): δ 170.3,
150.1, 145.5, 139.0, 128.8, 128.4, 128.3, 127.3, 124.4, 90.1, 77.5, 64.7,
52.5, 51.5, 50.5, 20.5. HRMS: (M + Na) for C20H21BrN2O7SNa calcd
535.01505, found 535.01620.
(2S,3S)-Methyl 6-Bromo-2-methyl-7-phenyl-4-tosyl-1,4-oxaze-
pane-3-carboxylate (7h). Major diastereomer: colorless oil, isolated
yield 136 mg (31%). Rf = 0.29 (8/2 Hex/EtOAc). IR (film, cm−1):
(2R,3S,6S)-Methyl 6-(Bromomethyl)-2,6-dimethyl-4-((4-
nitrophenyl)sulfonyl)morpholine-3-carboxylate (11b). Colorless oil,
isolated yield 69 mg (49%). [α]22 = −74.7° (c 0.15, CHCl3). Rf =
D
0.55 (7/3 Hex/EtOAc). IR (film, cm−1): 2926.4, 1743.6, 1532.1,
1
2925.0, 1745.9, 1340.7, 1091.2, 1050.5, 902.2, 736.0. H NMR (400
1
1350.8, 1165.3, 1089.8, 855.9, 737.9. H NMR (300 MHz, CDCl3): δ
MHz, CDCl3): δ 1.09 (d, J = 6.8 Hz, 3H), 2.44 (s, 3H), 3.54 (s, 3H),
3.91 (dq, J = 2.4, 5.2 Hz, 1H), 4.32 (m, 2H), 4.54 (dt, J = 2.4, 9.6 Hz,
1H), 4.62 (d, J = 1.6 Hz, 1H), 4.97 (d, J = 9.2 Hz, 1H), 7.31−7.45 (m,
7H), 7.67 (d, J = 8.0 Hz, 2H). 13C NMR (75 MHz): δ 168.6, 143.9,
136.6, 136.5, 129.8, 128.7, 128.6, 127.8, 127.0, 83.0, 73.2, 61.6, 51.9,
50.1, 47.8, 21.6, 19.7. HRMS: (M + Na) for C21H24BrNO5SNa calcd
504.04563, found 504.04558. Minor diastereomer: colorless oil, isolated
yield 70 mg (16%). Rf = 0.21 (8/2 Hex/EtOAc). IR (film, cm−1):
1.22 (d, J = 6.3 Hz, 3H), 1.32 (s, 3H), 3.00 (d, J = 12.9 Hz, 1H), 3.46
(d, J = 10.2 Hz, 1H), 3.53−3.60 (m, 2H), 3.72 (s, 3H), 3.98 (dd, J =
6.0, 9.0 Hz, 1H), 8.02 (d, J = 8.7 Hz, 2H), 8.41 (d, J = 9.0 Hz, 2H).
13C NMR (75 MHz): δ 164.0, 142.8, 142.0, 129.2, 124.3, 73.3, 67.6,
63.2, 52.8, 49.0, 35.6, 24.3, 18.6. HRMS: (M + H) for
C15H19BrN2O7SH calcd 451.0169, found 451.0170.
(2R,3S,6R)-Methyl 6-(Bromomethyl)-2,6-dimethyl-4-((4-
nitrophenyl)sulfonyl)morpholine-3-carboxylate (11b′). Character-
ized from a 1.7/1 mixture of diastereomers. Yellow oil. Rf = 0.48
(7/3 Hex/EtOAc). IR (film, cm−1): 3106.3, 1984.4, 2954.3, 1741.7,
1530.5, 1345.0, 1163.3, 911.6, 855.7, 819.3, 736.3. 1H NMR (300
MHz, CDCl3): δ 1.22 (d, J = 6.0 Hz, 1.5H), 1.26 (d, J = 6.0 Hz, 1.5H),
1.31 (s, 1.5H), 1.36 (s, 1.5H), 2.99 (d, J = 12.9 Hz, 0.5H), 3.25 (s,
1H), 3.37 (d, J = 8.1 Hz, 0.5H), 3.46 (d, J = 10.8 Hz, 0.5H), 3.52−3.58
(m, 1.5H), 3.69 (s, 1.5H), 3.71 (s, 1.5H), 3.75 (d, J = 9.0 Hz, 0.5H),
3.93−4.00 (m, 1H), 8.02 (d, J = 8.7 Hz, 2H), 8.39 (m, 2H). 13C NMR
(75 MHz): δ 169.6, 169.4, 150.4, 150.3, 143.6, 142.8, 129.1, 128.9,
124.3, 74.7, 73.3, 67.6, 67.5, 63.3, 63.2, 52.8, 52.7, 49.0, 47.5, 37.9,
35.6, 24.3, 20.7, 19.0, 18.6. HRMS: (M + H) for C15H19BrN2O7SH
calcd 451.0169, found 451.0173.
1
2950.8, 1744.1, 1343.6, 1219.4, 1160.3, 731.1; H NMR (400 MHz,
CDCl3): δ 1.30 (d, J = 6.8 Hz, 3H), 2.44 (s, 3H). 3.64 (s, 3H), 3.91
(dd, J = 7.2, 15.2 Hz, 1H), 4.33 (dq, J = 2.4, 6.4 Hz, 1H), 4.39 (dt, J =
2.4, 7.2 Hz, 1H), 4.52 (d, J = 2.0 Hz, 1H), 4.60 (dd, J = 2.4, 15.2 Hz,
1H), 4.70 (d, J = 7.2 Hz, 1H), 7.32 (m, 7H), 7.72 (d, J = 8.0 Hz, 2H).
13C NMR (75 MHz): δ 169.3, 144.0, 140.4, 135.9, 129.7, 128.4, 127.5,
126.7, 87.9, 75.6, 69.6, 63.8, 54.7, 52.0, 49.3, 21.6, 19.6. HRMS: (M +
Na) for C21H24BrNO5SNa calcd 504.04563, found 504.04408
6-Bromo-7-phenyl-4-tosyl-1,4-oxazepane (7i). White solid, mp
93−94 °C, isolated yield 1.65 g (>99%). Rf = 0.47 (7/3 Hex/EtOAc).
IR (film, cm−1): 2923.3, 1713.8, 1337.7, 1158.0, 1088.3, 906.1, 771.9,
1
698.2; H NMR (300 MHz, CDCl3): δ 2.46 (s, 3H), 3.40−5.56 (m,
2H), 3.71−3.81 (m, 2H), 4.01 (dd, J = 3.9, 15.3 Hz, 1H), 4.10−4.20
(m, 2H), 4.50 (d, J = 9.3 Hz, 1H), 7.27−7.37 (m, 7H), 7.74 (d, J = 8.4
Hz, 2H). 13C NMR (75 MHz): δ 143.9, 139.5, 135.9, 130.0, 128.5,
128.4, 127.2, 127.1, 88.7, 53.1, 21.6. HRMS: (M + Na) for
C18H20BrNO3SNa calcd 432.02450, found 432.02502
(2R,3S,6R)-Methyl 6-Bromo-2,7,7-trimethyl-4-((4-nitrophenyl)-
sulfonyl)-1,4-oxazepane-3-carboxylate (10c). White solid, mp
119−122 °C, isolated yield 148 mg (61%). [α]22 = −35.0° (c 0.60,
D
CHCl3). Rf = 0.56 (7/3 Hex/EtOAc). IR (film, cm−1): 2982.7, 1739.6,
1531.3, 1349.6, 1157.7, 1088.4, 684.9. 1H NMR (300 MHz, CDCl3): δ
1.26 (d, J = 6.3 Hz, 3H), 1.36 (s, 3H), 1.39 (s, 3H), 3.52 (s, 3H), 3.73
(dd, J = 4.3, 15.6 Hz, 1H), 3.94 (m, 2H), 4.05 (dd, J = 1.8, 15.6 Hz,
1H), 4.33 (d, J = 9.9 Hz, 1H), 7.98 (d, J = 9.0 Hz, 2H), 8.36 (d, J = 9.0
Hz, 2H). 13C NMR (75 MHz): δ 170.8, 150.1, 145.5, 128.3, 124.3,
78.2, 67.6, 64.6, 55.6, 52.4, 48.5, 29.8, 20.9, 19.7. HRMS: (M + Na) for
C16H21BrN2O7SNa calcd 487.01505, found 487.01370.
(5aS,10aR)-3-Bromo-2-phenyl-5-tosyl-3,4,5,5a,10,10a-hexahy-
dro-2H-indeno[2,1-b][1,4]oxazepine (7j). Major diastereomer: color-
less oil, isolated yield 28 mg (18%). Rf = 0.24 (1/1 DMC/toluene). IR
(film, cm−1): 2923.4, 1339.7, 1219.7, 1162.0, 1092.1, 1062.6, 911.0
699.3, 673.0;. 1H NMR (300 MHz, CDCl3): δ 2.50 (s, 3H), 2.89−3.06
(m, 2H), 3.89 (dd, J = 5.1, 16.5 Hz, 1H), 4.01 (dd, J = 4.8, 10.2 Hz,
1H), 4.44−4.51 (m, 2H), 4.63 (d, J = 9.9 Hz, 1H), 5.47 (d, J = 3.9 Hz,
1H), 6.76 (d, J = 7.5 Hz, 1H), 7.15−7.20 (m, 3H), 7.25−7.30 (m,
5H), 7.40 (d, J = 7.8 Hz, 2H), 8.02 (d, J = 8.1 Hz, 2H). 13C NMR (75
MHz): δ 141.3, 138.1, 136.6, 135.2, 134.3, 127.3, 125.8, 125.7, 125.6,
125.3, 124.8, 124.4, 122.9, 121.5, 81.9, 81.8, 64.2, 51.7, 45.9, 35.4, 19.0.
HRMS: (M + Na) for C25H24BrNO3SNa calcd 520.05580, found
520.05545. Minor diastereomer: colorless oil, isolated yield 70 mg
(45%), Rf = 0.14 (1:1 DMC/toluene). IR (film, cm−1): 2924.5, 1598.0,
(2R,3S,6R,7S)-Methyl 6-Bromo-2,7-dimethyl-4-((4-nitrophenyl)-
sulfonyl)-1,4-oxazepane-3-carboxylate (10d). Colorless oil, isolated
yield 128 mg (66%). [α]22D = −29.3° (c 0.90, CHCl3). Rf = 0.55 (7/3
Hex/EtOAc). IR (film, cm−1): 2926.6, 1739.4, 1530.8, 1348.2, 1160.9,
1089.9, 1024.5, 684.9. 1H NMR (300 MHz, CDCl3): δ 1.33 (d, J = 6.3
Hz, 3H), 1.74 (s, 3H), 3.29 (s, 3H), 3.88 (dt, J = 6.0, 15.3 Hz, 1H),
4.24 (d, J = 15.6 Hz, 1H), 4.42 (d, J = 9.6 Hz, 1H), 4.49 (d, J = 15.3
Hz, 1H), 4.69 (s, 1H), 7.34 (m, 3H), 7.45 (m, 2H), 7.98 (d, J = 9.0
Hz, 2H), 8.36 (d, J = 9.0 Hz, 2H). 13C NMR (75 MHz): δ 170.2,
150.1, 145.1, 137.2, 128.8, 128.7, 128.1, 127.3, 124.1, 92.7, 79.2, 66.9,
65.2, 56.9, 52.1, 22.8, 20.7. HRMS: (M + Na) for C15H19BrN2O7SNa
calcd 472.99940, found 472.99854.
1
1456.9, 1337.0, 1157.5, 1093.0, 998.9, 809.3, 698.9, 660.9. H NMR
(300 MHz, CDCl3): δ 2.52 (s, 3H), 3.07−3.35 (m, 3H), 4.04−4.19
(m, 2H), 4.31 (dd, J = 4.2, 15.0 Hz, 1H), 4.94 (dt, J = 1.5, 7.8 Hz, 1H),
5.75 (d, J = 7.5 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 7.13−1.35 (m, 8H),
7.42 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H). 13C NMR (75
MHz): δ 141.3, 138.2, 138.1, 135.5, 134.8, 127.4, 126.6, 125.9, 125.8,
125.1, 124.6, 124.3, 122.5, 122.4, 77.3, 74.8, 62.0, 47.9, 46.5, 34.2, 19.1.
HRMS: (M + Na) for C25H24BrNO3SNa calcd 520.05580, found
520.05555.
(2R,3S,6S)-Methyl 6-((R)-1-Bromoethyl)-2-methyl-4-((4-
nitrophenyl)sulfonyl)morpholine-3-carboxylate (11d). Colorless oil,
isolated yield 62 mg (32%). [α]22 = −48.9° (c 0.70, CHCl3). Rf =
D
0.47 (7/3 Hex/EtOAc). IR (film, cm−1): 3106.1, 2955.4, 1745.2,
1530.7, 1312.8, 1168.8, 995.4, 855.6, 762.8, 736.5. 1H NMR (300
MHz, CDCl3): δ 1.51 (d, J = 6.6 Hz, 3H), 1.65 (d, J = 6.9 Hz, 3H),
3.27 (t, J = 13.2 Hz, 1H), 3.59 (s, 3H), 3.75 (dd, J = 3.0, 12.3 Hz, 1H),
3.93 (m, 2H), 4.35 (s, 1H), 4.69 (q, J = 6.9 Hz, 1H), 7.96 (d, J = 8.7
Hz, 2H), 8.37 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz): δ 168.8,
150.1, 144.7, 128.5, 124.2, 70.5, 69.7, 58.4, 52.6, 47.7, 43.9, 21.2, 16.5.
HRMS: (M + Na) for C15H19BrN2O7SNa calcd 472.99940, found
472.99850.
(3S)-Methyl 6-Bromo-7-phenyl-4-tosyl-1,4-oxazepane-3-carbox-
ylate (7k). Isolated yield 56%, complex mixture of isomers.
(2R,3S)-Methyl 6-Bromo-2,7-dimethyl-4-((4-nitrophenyl)-
sulfonyl)-1,4-oxazepane-3-carboxylate and (2R,3S)-Methyl 6-(1-
Bromoethyl)-2-methyl-4-((4-nitrophenyl)sulfonyl)morpholine-3-car-
boxylate (7l). Isolated yield 81%, complex mixture of isomers.
(2R,3S,6R,7S)-Methyl 6-Bromo-2-methyl-4-((4-nitrophenyl)-
sulfonyl)-7-phenyl-1,4-oxazepane-3-carboxylate (10a). White solid,
mp 138−141 °C, isolated yield 240 mg (72%). [α]22 = −22.1° (c
(2R,3S,6R,7S)-Methyl 6-Bromo-2,6-dimethyl-4-((4-nitrophenyl)-
sulfonyl)-7-phenyl-1,4-oxazepane-3-carboxylate (10e). White solid,
D
1.00, CHCl3). Rf = 0.55 (7/3 Hex/EtOAc). IR (film, cm−1): 2957.6,
882
dx.doi.org/10.1021/jo3021715 | J. Org. Chem. 2013, 78, 872−885

The Journal of Organic Chemistry
Article
mp 213-217 °C, isolated yield 49 mg (39%). [α]22 = +17.1° (c 0.50,
cm−1): 3106.5, 2956.1, 1745.2, 1530.4, 1349.2, 1104.0, 1090.0, 855.4,
773.4, 738.1. 1H NMR (300 MHz, CDCl3): δ 1.42 (d, J = 6.0 Hz, 2H),
1.67−1.74 (m, 1H), 3.52−3.57 (m, 1.5H), 3.61 (s, 3H), 3.68 (s, 1H),
3.7−3.89 (m, 2H), 4.10 (dd, J = 2.7, 15.9 Hz, 1H), 4.44 (dd, J = 6.9,
13.2 Hz, 1H), 4.93 (dd, J = 6.9, 939 Hz, 0.5H), 7.94−8.04 (m, 2H),
8.36 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz): δ 169.3, 168.6, 150.7,
150.2, 145.3, 144.8, 128.9, 128.6, 124.3, 124.2, 84.6, 79.2, 78.5, 77.2,
68.9, 59.2, 54.8, 54.7, 52.8, 52.6, 51.7, 49.9, 46.8, 46.8, 21.9, 20.2.
HRMS: (M + H) for C14H17BrN2O7SH calcd 437.0013, found
436.9992.
D
CHCl3). Rf = 0.58 (7/3 Hex/EtOAc). IR (film, cm−1): 2926.4, 1740.5,
1
1531.3, 1344.5, 1161.1, 1023.5, 910.1, 701.8. H NMR (300 MHz,
CDCl3): δ 1.33 (d, J = 6.3 Hz, 3H), 1.74 (s, 3H), 3.29 (s, 3H), 3.88
(dt, J = 6.0, 15.3 Hz, 1H), 4.24 (d, J = 15.6 Hz, 1H), 4.42 (d, J = 9.6
Hz, 1H), 4.49 (d, J = 15.3 Hz, 1H), 4.69 (s, 1H), 7.34 (m, 3H), 7.45
(m, 2H), 7.98 (d, J = 9.0 Hz, 2H), 8.36 (d, J = 9.0 Hz, 2H). 13C NMR
(75 MHz): δ 170.2, 150.1, 145.1, 137.2, 128.8, 128.7, 128.1, 127.3,
124.1, 92.7, 79.2, 66.9, 65.2, 56.9, 52.1, 22.8, 20.7. HRMS: (M + Na)
for C21H23BrN2O7SNa calcd 549.03070, found 549.03051.
(2R,3S,6S)-Methyl 6-((S)-Bromo(phenyl)methyl)-2,6-dimethyl-4-
((4-nitrophenyl)sulfonyl)morpholine-3-carboxylate (11e). Colorless
oil, isolated yield 25 mg (20%). [α]22D = −78.6° (c 1.55, CHCl3). Rf =
0.48 (7/3 Hex/EtOAc). IR (film, cm−1): 3105.6, 2937.3, 1741.8,
(3S,6R,7R)-Methyl 6-Bromo-6-methyl-4-((4-nitrophenyl)sulfonyl)-
7-phenyl-1,4-oxazepane-3-carboxylate (10j). Colorless oil, isolated
yield 30 mg (25%). [α]22 = +7.9° (c 3.15, CHCl3). Rf = 0.66 (7/3
D
Hex/EtOAc). IR (film, cm−1): 3106.0, 2953.9, 1743.5, 1530.3, 1348.5,
1
1
1530.5, 1311.8, 1161.5, 1090.3, 1039.3, 852.7, 746.2, 736.6. H NMR
1160.1, 1112.1 1021.6, 1011.5, 895.3, 855.1, 701.9. H NMR (300
(300 MHz, CDCl3): δ 1.25 (s, 3H), 1.27 (s, 3H), 3.59 (s, 3H), 3.75 (s,
2H), 4.12 (m, 2H), 5.04 (s, 1H), 7.33 (m, 5H), 7.99 (d, J = 8.7 Hz,
2H), 8.37 (d, J = 9.0 Hz, 2H). 13C NMR (75 MHz): δ 169.6, 150.1,
145.0, 136.6, 129.5, 128.6, 128.5, 128.0, 124.2, 77.9, 67.3, 62.3, 57.4,
52.5, 48.7, 21.3, 18.9. HRMS: (M + H) for C21H23BrN2O7SH calcd
527.0482, found 527.0458.
MHz, CDCl3): δ 1.75 (s, 3H), 3.38 (s, 3H), 3.64 (d, J = 10.8 Hz, 1H),
4.13 (d, J = 15.6 Hz, 1H), 4.53 (dd, J = 0.9, 15.6 Hz, 1H), 4.55 (d, J =
7.5 Hz, 1H), 4.59 (t, J = 7.5 Hz, 1H), 4.91 (dd, J = 7.5, 10.8 Hz, 1H),
7.35 (m, 3H), 7.43 (m, 2H), 7.99 (d, J = 9.0 Hz, 2H), 8.36 (d, J = 9.0
Hz, 2H). 13C NMR (75 MHz): δ 169.2, 150.1, 145.3, 136.7, 128.8,
128.7, 128.3, 127.5, 124.1, 94.1, 71.8, 66.5, 59.6, 56.5, 52.4, 22.8.
HRMS: (M + NH4) for C20H21BrN2O7SNH4 calcd 530.0591, found
530.0567.
(3S)-Methyl 6-(Bromo(phenyl)methyl)-6-methyl-4-((4-
nitrophenyl)sulfonyl)morpholine-3-carboxylate(11j). Colorless oil,
isolated yield 20 mg (17%). [α]22D = −9.8° (c 1.50, CHCl3). Rf = 0.53
(7/3 Hex/EtOAc). IR (film, cm−1): 3106.0, 2953.7, 1746.9, 1530.5,
1311.9, 1164.3, 1089.3, 855.6, 759.4, 734.4. 1H NMR (300 MHz,
CDCl3): δ 1.46 (s, 3H), 3.24 (d, J = 13.2 Hz, 1H), 3.62 (s, 3H), 4.01
(dd, J = 1.5, 12.3 Hz, 1H), 4.16 (dt, J = 4.2, 12.3 Hz, 1H), 4.31 (d, J =
13.5 Hz, 1H), 4.58 (d, J = 3.9 Hz, 1H), 5.53 (s, 1H), 7.32−7.49 (m,
5H), 7.057 (d, J = 8.7 Hz, 2H), 8.39 (d, J = 8.7 Hz, 2H). 13C NMR (75
MHz): δ 168.6, 150.2, 144.5, 136.9, 129.2, 128.9, 128.7, 128.3, 124.2,
75.9, 62.4, 54.6, 52.7, 52.5, 48.7, 21.8. HRMS: (M + H) for
C20H21BrN2O7SH calcd 513.0323, found 513.0294.
(3S,6R,7S)-Methyl 6-Bromo-4-((4-nitrophenyl)sulfonyl)-7-phenyl-
1,4-oxazepane-3-carboxylate (10f). White solid, mp 148−150 °C,
isolated yield 235 mg (94%). [α]22 = −21.1° (c 0.75, CHCl3). Rf =
D
0.45 (7/3 Hex/EtOAc). IR (film, cm−1): 2955.5, 1745.6, 1530.5,
1
1349.3, 1100.9, 739.0. H NMR (300 MHz, CDCl3): δ 3.65 (s, 3H),
3.72 (m, 2H), 4.21 (m, 2H), 4.37 (d, J = 10.2 Hz, 1H), 4.55 (dd, J =
7.2, 13.2 Hz, 1H), 5.06 (dd, J = 7.2, 10.5 Hz, 1H), 7.28 (m, 2H), 7.36
(m, 3H), 8.09 (d, J = 9.0 Hz, 2H), 8.40 (d, J = 9.0 Hz, 2H). 13C NMR
(75 MHz): δ 169.3, 150.2, 145.3, 138.4, 129.0, 128.7, 128.5, 127.3,
124.4, 90.7, 69.6, 59.2, 52.7, 50.7, 50.1. HRMS: (M + Na) for
C19H19BrN2O7SNa calcd 520.99940, found 521.00099.
(3S)-Methyl 6-Bromo-6-methyl-4-((4-nitrophenyl)sulfonyl)-1,4-
oxazepane-3-carboxylate (11g). Characterized from a 1.7:1 mixture
of diastereomers. Yellow oil, isolated yield 77%. Rf = 0.40 (7/3 Hex/
EtOAc). IR (film, cm−1): 2956.0, 1745.4, 1529.9, 1348.9, 1162.6,
(5aR,9aR)-3-Bromo-5-((4-nitrophenyl)sulfonyl)-2-
phenyldecahydrobenzo[b][1,4]oxazepine (10k). Characterized from
a 2.0/1 mixture of diastereomers. Major diastereomer: colorless oil,
isolated yield 267 mg (49%). Rf = 0.78 (7/3 Hex/EtOAc). IR (film,
1
1090.9, 855.4, 768.8, 731.2. H NMR (300 MHz, CDCl3): δ 1.26 (s,
3H), 3.28 (m, 1.5H), 3.46 (d, J = 11.4 Hz, 1H), 3.59 (s, 1H), 3.62 (s,
2H), 3.72 (d, J = 13.2 Hz, 1H), 3.85 (d, J = 11.1 Hz, 1H), 3.99 (dd, J =
4.2, 12.6 Hz, 1H), 4.08−4.14 (m, 0.5H), 4.54−5.57 (m, 1H), 7.7.95
(d, J = 8.7 Hz, 2H), 8.36 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz): δ
168.7, 168.6, 150.2, 150.1, 144.7, 144.5, 128.6, 128.5, 124.2, 124.1,
72.1, 71.4, 62.8, 62.3, 54.6, 54.2, 52.8, 52.7, 48.5, 47.4, 38.7, 33.8, 24.2,
17.9. HRMS: (M + H) for C14H17BrN2O7SH calcd 437.0013, found
436.9996.
(3S)-Methyl 6-Bromo-7,7-dimethyl-4-((4-nitrophenyl)sulfonyl)-
1,4-oxazepane-3-carboxylate (10h). White solid, mp 113−115 °C,
isolated yield 158 mg (>99%). [α]22D = −22.1° (c 0.95, CHCl3). Rf =
0.44 (7/3 Hex/EtOAc). IR (film, cm−1): 2957.2, 1747.0, 1530.3,
1349.0, 1158.2, 1088.0, 706.8. 1H NMR (300 MHz, CDCl3): δ 1.30 (s,
3H), 1.37 (s, 3H), 3.66 (s, 3H), 3.74 (dd, J = 10.2, 15.6 Hz, 1H), 3.97
(m, 3H), 4.11 (dd, J = 3.9, 13.2 Hz, 1H), 4.84 (t, J = 3.6 Hz, 1H), 8.03
(d, J = 8.1 Hz, 2H), 8.37 (d, J = 8.1 Hz, 2H). 13C NMR (75 MHz): δ
169.1, 145.2, 128.7, 128.6, 124.3, 78.7, 63.9, 59.4, 54.9, 52.7, 48.9, 25.4,
24.0. HRMS: (M + Na) for C15H19BrN2O7SNa calcd 472.99940,
found 472.99955.
1
cm−1): 2940, 1529.2, 1311.1, 1157.2, 1086.8, 1000.0, 728.2. H NMR
(300 MHz, CDCl3): δ 1.36 (m, 4H), 1.79 (m, 2H), 2.05 (m, 2H), 3.43
(dt, J = 3.9, 10.8 Hz, 1H), 3.66 (m, 3H), 4.26 (m, 2H), 6.95 (dd, J =
1.8, 7.8 Hz, 2H), 7.26 (m, 3H), 8.14 (d, J = 9.0 Hz, 2H), 8.42 (d, J =
9.0 Hz, 2H). 13C NMR (75 MHz): δ 150.0, 147.4, 139.3, 128.7, 128.4,
128.2, 127.1, 124.7, 88.4, 82.3, 77.4, 77.0, 76.6, 63.7, 51.4, 48.8, 33.8,
32.0, 24.7, 24.6. HRMS: (M + Na) for C21H23BrN2O5SNa calcd
517.04087, found 517.04134. Minor diastereomer: characterized as a
2.0/1 mixture of diastereomers; yellow oil. Rf = 0.67 (7/3 Hex/
EtOAc). IR (film, cm−1): 2940.2, 1530.0, 1348.7, 1219.7, 1158.7,
1
1088.4, 855.3, 772.4. H NMR (300 MHz, CDCl3): δ 1.16−1.37 (br
m, 4H), 1.74−1.82 (br m, 3H), 2.05 (m, 1.5H), 3.21−3.45 (br m, 2H),
3.67 (m, 0.5H), 3.74−3.82 (m, 1H), 4.03−4.11 (M, 0.5H), 4.28−4.39
(M, 2H), 4.66 (d, J = 9.6 Hz, 0.5H, 6.95 (m, 1H), 7.30−7.35 (m, 3H),
8.05 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 9.0 Hz, 1H), 8.37 (d, J = 8.7 Hz,
1H), 8.43 (d, J = 9.0 Hz, 1H). 13C NMR (125 MHz): δ 150.0, 149.8,
148.2, 147.4, 140.6, 139.3, 129.3, 128.7, 128.4, 128.3, 128.2, 128.2,
127.1, 127.1, 124.7, 124.5, 88.3, 82.3, 79.1, 77.7, 63.7, 58.5, 51.4, 51.3,
48.8, 42.2, 33.7, 32.0, 31.3, 30.0, 26.1, 24.7, 24.6, 24.4. HRMS: (M +
K) for C21H23BrN2O5SK calcd 533.0143, found 533.0118.
(3S,6S,7R)-Methyl 6-Bromo-7-methyl-4-((4-nitrophenyl)sulfonyl)-
1,4-oxazepane-3-carboxylate (10i). Colorless oil, isolated yield 48
mg (46%). [α]22 = −35.2° (c 1.65, CHCl3). Rf = 0.42 (7/3 Hex/
D
EtOAc). IR (film, cm−1): 3106.8, 2925.4, 1745.2, 1530.3, 1313.8,
1
(3R,6R,7S)-6-Bromo-3-ethyl-4-((4-nitrophenyl)sulfonyl)-7-phenyl-
1160.9, 1103.9, 1089.8, 1008.2, 855.5, 738.7. H NMR (300 MHz,
1,4-oxazepane (10l). Colorless oil, isolated yield 160 mg (>99%).
CDCl3): δ 1.42 (d, J = 6.0 Hz, 3H), 3.55 (m, 3H), 3.60 (s, 3H), 3.80
(m, 1H), 4.10 (dd, J = 3.0, 15.6 Hz, 1H), 4.44 (dd, J = 6.6, 13.2 Hz,
1H), 4.93 (dd, J = 7.2, 10.2 Hz, 1H), 8.03 (d, J = 8.7 Hz, 2H), 8.37 (d,
J = 8.7 Hz, 2H). 13C NMR (75 MHz): δ 169.3, 150.1, 145.3, 128.6,
124.2, 84.6, 68.9, 59.2, 52.6, 51.7, 59.9, 20.2. HRMS: (M + H) for
C14H17BrN2O7SH calcd 437.0013, found 437.0002.
(3S)-Methyl 6-(1-Bromoethyl)-4-((4-nitrophenyl)sulfonyl)-
morpholine-3-carboxylate (11i). Characterized from a 1.2/1 mixture
of diastereomers. Yellow oil. Rf = 0.35 (7/3 Hex/EtOAc). IR (film,
[α]22 = +54.0° (c 0.80, CHCl3). Rf = 0.60 (7/3 Hex/EtOAc). IR
D
1
(film, cm−1): 2968.0, 1529.2, 1347.7, 1155.6, 1087.8, 907.8, 678.9. H
NMR (300 MHz, CDCl3): δ 0.93 (t, J = 9.0 Hz, 3H), 1.57 (br m, 2H),
3.39 (dd, J = 9.3, 12.0 Hz, 1 H), 3.55 (dd, J = 12.0, 15.6 Hz, 1H), 3.81
(dt, J = 3.6, 10.2 Hz, 1H), 4.23 (d, J = 9.9 Hz, 1H), 4.29 (m, 2H), 4.38
(dd, J = 3.3, 13.2 Hz, 1H), 6.88 (d, J = 7.5 Hz, 2H), 7.25 (m, 3H), 8.14
(d, J = 8.7 Hz, 2H), 8.42 (d, J = 8.7 Hz, 2H). 13C NMR (75 MHz): δ
150.0, 147.5, 138.8, 128.8, 128.6, 128.3, 126.8, 124.6, 90.5, 72.9, 59.1,
883
dx.doi.org/10.1021/jo3021715 | J. Org. Chem. 2013, 78, 872−885

The Journal of Organic Chemistry
Article
50.0, 48.5, 24.5, 10.1. HRMS: (M + Na) for C19H21BrN2O5SNa calcd
491.02522, found 491.02551.
Hz, 1H), 7.10 (dd, J = 1.5, 6.6 Hz, 2H), 7.30 (m, 6H), 8.22 (d, J = 9.0
Hz, 2H), 8.47 (d, J = 9.0 Hz, 2H). 13C NMR (75 MHz): δ 146.7,
140.8, 140.3, 136.5, 129.6, 128.6, 128.5, 128.3, 128.0, 126.7, 125.2,
124.7, 124.6, 79.8, 77.3, 65.0, 49.9, 49.3, 36.7. HRMS: (M + Na) for
C24H21BrN2O5SNa calcd 551.02522, found 551.02607.
Computational Methods. General Considerations. The quan-
tum mechanical calculations were performed using density functional
theory (DFT), more specifically the M06 functional (restricted
Hartree−Fock) and the diffuse 6-31G(d,p) basis set. Certain
convergence parameters were loosened slightly, due to the degrees
of freedom in the molecules and difficulties acquiring a minimum state.
No frequency analysis was required for this work. All calculations were
carried out in a PCM (polarizable continuum model) solvent model of
tetrahydrofuran. The M06 calculations were performed using
GAMESS-US v.Aug2011-64bit.
(2R,6S,7R)-6-Bromo-2-methyl-4-((4-nitrophenyl)sulfonyl)-7-phe-
nyl-1,4-oxazepane (10m). White solid, mp 167−171 °C, isolated
yield 400 mg (47%). [α]22D = −29.4° (c 0.85, CHCl3). Rf = 0.62 (7/3
Hex/EtOAc). IR (film, cm−1): 2926.7, 1530.0, 1311.3, 1163.6, 1087.0,
736.6. 1H NMR (300 MHz, CDCl3): δ 1.09 (d, J = 6.3 Hz, 3H), 2.78
(dd, J = 9.9, 13.8 Hz, 1H), 3.36 (dd, J = 9.6, 13.8 Hz, 1H), 3.85 (dd, J
= 3.6, 14.1 Hz, 1H), 3.99 (m, 1H), 4.35 (m, 2H), 4.81 (d, J = 9.3 Hz,
1H), 7.37 (m, 5H), 8.03 (d, J = 9.0 Hz, 2H), 8.41 (d, J = 9.0 Hz, 2H).
13C NMR (75 MHz): δ 150.2, 145.1, 138.6, 138.5, 128.6, 128.2, 127.3,
124.6, 80.0, 71.1, 54.9, 54.8, 49.4, 18.2. HRMS: (M + H) for
C18H19BrN2O5SH calcd 454.0198, found 454.0174.
(2R,6R,7S)-6-Bromo-2-methyl-4-((4-nitrophenyl)sulfonyl)-7-phe-
nyl-1,4-oxazepane (10m′). Characterized as a 1.2/1 mixture of
diastereomers. Yellow oil. Rf = 0.56 (7/3 Hex/EtOAc). IR (film,
cm−1): 3105.5, 2927.4, 1541.1, 1347.7, 1160.9, 1084.7, 907.1, 775.0,
731.3, 696.0. 1H NMR (300 MHz, CDCl3): δ 1.09 (d, J = 6.3 Hz, 2H),
1.20 (d, J = 6.3 Hz, 1H), 2.78 (dd, J = 10.2, 14.1 Hz, 0.7H), 3.08 (dd, J
= 10.5, 12.6 Hz, 0.3H), 3.37 (dd, J = 9.9, 13.8 Hz, 1H), 3.59 (dd, J =
3.6, 12.6 Hz, 0.3H). 3.85 (dd, J = 3.6, 14.7 Hz, 0.7H), 3.94 (d, J = 5.1
Hz, 0.7H), 3.97−4.04 (M, 0.6H), 4.16 (m, 0.3H), 4.29−4.42 (m,
1.4H), 4.59 (d, J = 9.6 Hz, 0.3H), 4.81 (d, J = 9.3 Hz, 0.7H), 1.33−
7.37 (m, 5H), 8.02−8.08 (m, 2H), 8.39−8.43 (m, 2H). 13C NMR (75
MHz): δ 150.2, 150.2, 145.1, 144.7, 139.6, 138.6, 128.6, 128.5, 128.4,
128.3, 128.2, 127.3, 127.0, 124.6, 87.8, 79.9, 71.1, 56.5, 54.9, 54.8, 53.8,
53.5, 49.5, 19.5, 18.2. HRMS: (M + H) for C18H19BrN2O5SH calcd
454.0198, found 454.0181.
Butene NBS Study. The modeling of the reaction of NBS with
trans-butene involved the exploration of two reaction coordinates. We
systematically varied the length of the C−Br forming bonds along with
the length of the N−Br breaking bonds. The energies of these systems
were compared to the sum of the reactants and plotted in 3D.
Conformational Analysis of 9c. The conformational search was
done in a stepwise fashion. First, molecular mechanics (MM3* as a
forcefield, MacroModel, Schrodinger) was used to generate a set of
̈
over 50 stable conformations. Then, the semiempirical function PM3
(MOPAC) was used to minimize the energy of all generated
conformations. Upon sorting these more accurate energies, we
selected the top 5 structures for the formation of each of the R and
the S conformers and finally optimized their structure by DFT (basis
set/functional mentioned above).
(2S,3S,6R,7S)-Methyl 6-Bromo-2-methyl-4-((4-nitrophenyl)-
sulfonyl)-7-phenyl-1,4-oxazepane-3-carboxylate (10n). White
solid, mp 156−159 °C, isolated yield 71 mg (25%). [α]22
=
ASSOCIATED CONTENT
D
■
−48.2° (c 0.75, CHCl3). Rf = 0.66 (7/3 Hex/EtOAc). IR (film, cm−1):
2954.3, 1742.5, 1530.4, 1347.7, 1154.6, 1050.0, 901.8, 698.6. 1H NMR
(300 MHz, CDCl3): δ 1.13 (d, J = 6.6 Hz, 3H), 3.59 (s, 3H), 3.97 (dq,
J = 2.1, 6.6 Hz, 1H), 4.30 (m, 2H), 4.60 (dt, J = 2.4, 9.6 Hz, 1H), 4.64
(d, J = 2.1 Hz, 1H), 4.98 (d, J = 9.6 Hz, 1H), 7.45 (m, 5H), 7.98 (d, J
= 8.7 Hz, 2H), 8.38 (d, J = 9.0 Hz, 2H). 13C NMR (75 MHz): δ 161.3,
145.0, 136.2, 128.9, 128.7, 128.6, 128.3, 127.8, 124.4, 83.0, 73.4, 62.0,
52.2, 50.5, 47.5, 19.8. HRMS: (M + Na) for C20H21BrN2O7SNa calcd
535.01505, found 535.01630.
S
* Supporting Information
Figures, tables, and a CIF file giving H and 13C NMR spectra
1
for all compounds, COSY, NOESY, HMBC, HSQC 2D spectra
for compound 10a, crystallographic data for compound 10e,
and Cartesian coordinates of the strucures in Figures 5 and 6
(butene/NBS and compounds 9c). This material is available
free of charge via the Internet at http://pubs.acs.org.
(2S,3S,6S,7R)-Methyl 6-Bromo-2-methyl-4-((4-nitrophenyl)-
AUTHOR INFORMATION
Corresponding Author
*E-mail: nicolas.moitessier@mcgill.ca.
Notes
■
sulfonyl)-7-phenyl-1,4-oxazepane-3-carboxylate (10n′). White
solid, mp 174−177 °C, isolated yield 48 mg (17%). [α]22
=
D
−29.2° (c 0.65, CHCl3). Rf = 0.57 (7/3 Hex/EtOAc). IR (film, cm−1):
1
2953.6, 1743.2, 1531.3, 1311.0, 1166.0, 737.7. H NMR (300 MHz,
CDCl3): δ 1.35 (d, J = 6.9 Hz, 3H), 3.66 (s, 3H), 4.01 (dd, J = 6.9,
15.3 Hz, 1H), 4.38 (dt, J = 2.1, 6.6 Hz, 1H), 4.44 (dq, J = 2.4, 6.6 Hz,
1H), 4.60 (m, 2H), 4.79 (d, J = 6.6 Hz, 1H), 7.31 (m, 5H), 8.03 (d, J =
9.0 Hz, 2H), 8.38 (d, J = 9.0 Hz, 2H). 13C NMR (75 MHz): δ 168.9,
144.8, 140.1, 128.7, 128.6, 128.5, 126.4, 124.4, 124.3, 87.8, 75.6, 64.1,
54.4, 52.2, 49.2, 19.6. HRMS: (M + Na) for C20H21BrN2O7SNa calcd
535.01505, found 535.01629
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the CFI (New Opportunities Fund program),
AstraZeneca, NSERC (discovery grant and CRD grant) for
financial support.
6-Bromo-4-((4-nitrophenyl)sulfonyl)-7-phenyl-1,4-oxazepane
(10o). White solid, mp 157−159 °C, isolated yield 119 mg (>99%). Rf
= 0.42 (7/3 Hex/EtOAc). IR (film, cm−1): 2926.6, 1529.0, 1309.5,
REFERENCES
■
1
(1) Smith, A. B.; Charnley, A. K.; Hirschmann, R. Acc. Chem. Res.
2010, 44, 180.
(2) Hanessian, S.; Auzzas, L. Acc. Chem. Res. 2008, 41, 1241.
(3) Hanessian, S.; Moitessier, N. Curr. Top. Med. Chem. 2004, 4,
1269.
(4) Sun, H.; Nikolovska-Coleska, Z.; Yang, C.-Y.; Qian, D.; Lu, J.;
Qiu, S.; Bai, L.; Peng, Y.; Cai, Q.; Wang, S. Acc. Chem. Res. 2008, 41,
1264.
(5) Moitessier, N.; Henry, C.; Aubert, N.; Chapleur, Y. Tetrahedron
Lett. 2005, 46, 6191.
(6) Moitessier, N.; Dufour, S.; Chretien, F.; Thiery, J. P.; Maigret, B.;
Chapleur, Y. Bioorg. Med. Chem. 2001, 9, 511.
(7) Sacchetti, A.; Silvani, A.; Lesma, G.; Pilati, T. J. Org. Chem. 2011,
76, 833.
1163.4, 1087.2, 1025.7, 855.0, 737.1. H NMR (300 MHz, CDCl3): δ
3.46 (dt, J = 2.7, 12.6 Hz, 1H), 3.63 (dt, J = 5.1, 10.8 Hz, 1H), 3.79
(m, 2H), 4.09 (dd, J = 3.9, 15.0 Hz, 1H), 4.19 (m, 2H), 4.50 (d, J = 9.3
Hz, 1H), 7.33 (m, 5H), 8.07 (d, J = 9.0 Hz, 2H), 8.42 (d, J = 9.0 Hz,
2H). 13C NMR (75 MHz): δ 150.2, 144.8, 139.1, 128.7, 128.5, 128.4,
127.0, 124.6, 88.8, 69.6, 53.3, 52.5, 50.1. HRMS: (M + Na) for
C17H17BrN2O5SNa calcd 462.99392, found 462.99495.
(2R,3S,5aS,10aR)-3-Bromo-5-((4-nitrophenyl)sulfonyl)-2-phenyl-
3,4,5,5a,10,10a-hexahydro-2H-indeno[2,1-b][1,4]oxazepine (10p).
White solid, mp 158−161 °C, isolated yield 244 mg (98%). [α]22
D
= −45.2° (c 0.55, CHCl3). Rf = 0.68 (7/3 Hex/EtOAc). IR (neat,
cm−1): 2935.5, 1529.9, 1349.0, 1164.1, 1090.9, 999.0, 906.9, 808.9,
678.9. 1H NMR (300 MHz, CDCl3): δ 3.21 (m, 3H), 4.03 (d, J = 9.9
Hz, 1H), 4.10 (dq, J = 4.2, 10.8 Hz, 1H), 4.26 (dd, J = 4.2, 15.0 Hz,
1H), 4.93 (t, J = 7.5 Hz, 1H), 5.73 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 7.5
́
(8) Proulx, C.; Lubell, W. D. Org. Lett. 2012, 14, 4552.
884
dx.doi.org/10.1021/jo3021715 | J. Org. Chem. 2013, 78, 872−885

The Journal of Organic Chemistry
Article
(9) Liskamp, R. M. J.; Rijkers, D. T. S.; Kruijtzer, J. A. W.; Kemmink,
J. ChemBioChem 2011, 12, 1626.
(10) Ko, E.; Liu, J.; Perez, L. M.; Lu, G.; Schaefer, A.; Burgess, K. J.
Am. Chem. Soc. 2010, 133, 462.
(11) Ko, E.; Burgess, K. Org. Lett. 2011, 13, 980.
(12) Ressurreica̧ o, A. S. M.; Delatouche, R.; Gennari, C.; Piarulli, U.
̃
Eur. J. Org. Chem. 2011, 217.
(13) Kaneko, S.; Arai, M.; Uchida, T.; Harasaki, T.; Fukuoka, T.;
Konosu, T. Bioorg. Med. Chem. Lett. 2002, 12, 1705.
(14) Abrous, L.; Hynes, J.; Friedrich, S. R.; Smith, A. B.; Hirschmann,
R. Org. Lett. 2001, 3, 1089.
(15) Nakano, A.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Org. Lett.
2006, 8, 5357.
(16) Mishra, J. K.; Panda, G. J. Comb. Chem. 2007, 9, 321.
(17) Machetti, F.; Bucelli, I.; Indiani, G.; Kappe, C. O.; Guarna, A. J.
Comb. Chem. 2007, 9, 454.
(18) Dieguez-Vazquez, A.; Tzschucke, C. C.; Lam, W. Y.; Ley, S. V.
́ ́
Angew. Chem., Int. Ed. 2008, 47, 209.
(19) Clark, S. M.; Osborn, H. M. I. Tetrahedron: Asymmetry 2004, 15,
3643.
(20) Ohno, H.; Hamaguchi, H.; Ohata, M.; Kosaka, S.; Tanaka, T. J.
Am. Chem. Soc. 2004, 126, 8744.
(21) Ko, C.; Hsung, R. P.; Al-Rashid, Z. F.; Feltenberger, J. B.; Lu, T.;
Yang, J.-H.; Wei, Y.; Zificsak, C. A. Org. Lett. 2007, 9, 4459.
(22) Huot, M.; Moitessier, N. Tetrahedron Lett. 2010, 51, 2820.
(23) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc.
Chem. Res. 2008, 41, 40.
(24) Guindon, Y.; Slassi, A.; Rancourt, J.; Bantle, G.; Bencheqroun,
́
M.; Murtagh, L.; Ghiro, E.; Jung, G. J. Org. Chem. 1995, 60, 288.
(25) Zhou, J.; Zhou, L.; Yeung, Y.-Y. Org. Lett. 2012, 14, 5250.
(26) Denmark, S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc.
2010, 132, 1232.
(27) Denmark, S. E.; Burk, M. T. Proc. Natl. Acad. Sci. U.S.A. 2010,
107, 20655.
(28) Denmark, S. E.; Burk, M. T. Org. Lett. 2012, 14, 256.
(29) Oyola, Y.; Singleton, D. A. J. Am. Chem. Soc. 2009, 131, 3130.
885
dx.doi.org/10.1021/jo3021715 | J. Org. Chem. 2013, 78, 872−885