Synthesis and profiling of a diverse collection of azetidine-based scaffolds for the development of CNS-focused lead-like libraries

Article abstract of DOI:10.1021/jo300974j

The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged, and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of a 1976-membered library of spirocyclic azetidines is also described.

Full text of DOI:10.1021/jo300974j

Featured Article
pubs.acs.org/joc
Synthesis and Profiling of a Diverse Collection of Azetidine-Based
Scaffolds for the Development of CNS-Focused Lead-like Libraries
Jason T. Lowe,†,§ Maurice D. Lee IV,† Lakshmi B. Akella,†,§ Emeline Davoine,‡ Etienne J. Donckele,†
Landon Durak,† Jeremy R. Duvall,† Baudouin Gerard,†,§ Edward B. Holson,‡ Adrien Joliton,†
Sarathy Kesavan,†,§ Berenice C. Lemercier,† Haibo Liu,† Jean-Charles Marie,† Carol A. Mulrooney,†
́
Giovanni Muncipinto,† Morgan Welzel-O’Shea,†,§ Laura M. Panko,†,§ Ann Rowley,† Byung-Chul Suh,†
Meryl Thomas,‡ Florence F. Wagner,‡ Jingqiang Wei,† Michael A. Foley,† and Lisa A. Marcaurelle*,†,§
†Chemical Biology Platform and ‡Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 7 Cambridge Center,
Cambridge, Massachusetts 02142, United States
S
* Supporting Information
ABSTRACT: The synthesis and diversification of a densely
functionalized azetidine ring system to gain access to a wide
variety of fused, bridged, and spirocyclic ring systems is
described. The in vitro physicochemical and pharmacokinetic
properties of representative library members are measured in
order to evaluate the use of these scaffolds for the generation of
lead-like molecules to be used in targeting the central nervous
system. The solid-phase synthesis of a 1976-membered library
of spirocyclic azetidines is also described.
context of drug discovery has been less common, however. This
can be attributed in part to the apparent difficulty in accessing
azetidines in their enantioenriched form.10 Recently, Couty and
co-workers demonstrated the convenient preparation of 2-
cyanoazetidines from β-amino alcohols (Figure 1A).11 We
envisioned that expansion of this methodology would permit
access to a number of highly functionalized azetidine-based
scaffolds through the manipulation of the parent core system.
In addition, having the ability to access all stereochemical
permutations of each scaffold would provide the ability to study
stereo/structure−activity relationships (SSAR)12 in biological
contexts.
In designing a template for library development, we chose to
expand upon the previously described ephedrine-based
scaffold.11 This scaffold was especially compelling based on
the observation that embedded within the backbone resides the
phenethylamine structural motif (Figure 1B). This pharmaco-
phoric element is common to a number of hormones,
neurotransmitters, natural products, and drugs known to affect
the central nervous system (CNS) and provides an excellent
core scaffold which can be further derivatized. The incorpo-
ration of an aryl bromide and a pendant hydroxyl group will
allow for downstream functional group pairing,13 diversifica-
tion, and immobilization onto solid support.14
INTRODUCTION
■
Diversity-oriented synthesis (DOS) has received considerable
attention from both academic and industrial sectors over the
past decade as a means to access new chemical space for probe
and drug discovery.1−3 Numerous DOS pathways have been
reported which gain access to unique molecular frameworks;4
however, a common perception associated with these
compounds has been that they possess poor physicochemical
properties.5 While some DOS pathways have yielded
compounds of high molecular weight and lipophilicity, the
properties of DOS molecules are not inherently unfavorable to
a drug discovery program. Simple descriptors such as MW,
topological polar surface area (TPSA), LogP, LogD, rotatable
bonds, and hydrogen bond donors/acceptors (HBD/HBA) can
be readily calculated at the design stage, and filters may be
applied to tailor the properties of prospective library members.6
These parameters are especially important in the context of
designing DOS libraries for CNS applications where the
properties that facilitate blood-brain barrier (BBB) penetration
are particularly stringent.7 In this case, the collection and
analysis of in vitro data such as solubility, protein binding, and
permeability would be especially valuable in prioritizing
synthetic pathways for full library production. Herein we
describe the synthesis, physicochemical and pharmacokinetic
(ADME) characterization, and profiling of several DOS
scaffolds that have been optimized with these key CNS
“drug-like” parameters in mind.8
Azetidine-based ring systems have had enormous application
in medicinal chemistry in the form of β-lactams.9 The use of the
fully reduced form of this four-membered heterocycle in the
Received: June 20, 2012
Published: August 1, 2012
© 2012 American Chemical Society
7187
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
on the conditions employed. Treatment of 4b with LiHMDS at
−50 °C provided ca. 15:1 (5c/5d) ratio of product as a
separable mixture. Alternatively, exposure of 4b to KHMDS at
−78 °C gave nearly exclusively 5d in ca. 1:20 (5c/5d). This
approach gave rise to multigram quantities of all eight
stereoisomers of 5.
Having developed a robust process for the synthesis of
trisubstituted azetidines 5a−d, we turned our attention to
investigating key functional group pairing reactions for
generating skeletal diversity. The sequence began with
DIBAL reduction of the nitrile to the primary amine, which
was immediately treated with o-nitrobenzenesulfonyl chloride
to obtain 6a−d in 71−91% yield over two steps (Scheme 2).
This material could then be utilized to access three structurally
unique molecular scaffolds. The first of these scaffolds (8a and
8d) was inspired by recent work of Pinna and co-workers
describing the synthesis and biological activity of several
diazabicyclo [3.1.1] heptane ligands.18 TFA-mediated trityl
deprotection and subsequent mesylation of the pendant alcohol
7 gave an intermediate compound, which was heated in the
presence of potassium carbonate to afford the meso-[3.1.1]-
bridged bicyclic system in 91% yield for 8a (from 7a) and 86%
yield for 8d (from 7d) over three steps.19 Monoketopiperazine
10 could be readily accessed by removal of the allyl protecting
group of 6a−d followed by reaction of the resulting secondary
amine functionalities with bromoacetyl chloride to afford 9a−d.
Removal of the trityl group provided 10a−d in excellent yields.
A third scaffold containing an azetidine-fused eight-
membered ring could be readily derived from azetidine 6
through the use of ring-closing metathesis. The requisite
material for this approach was obtained through the N-
alkylation of 6a−d with allyl bromide. This material was then
treated with Grubbs first generation catalyst to effect the
formation of the eight-membered ring system 11a−d in 51−
76% yield. Removal of the trityl protecting group and selective
reduction of the olefin with o-nitrobenzenesulfonylhydrazide
(NBSH)20 yielded the final cores 12a−d in 65−72% over two
steps.21
Figure 1. (A) Synthesis of 2-cyanoazetidines from β-amino alcohols
and (B) representative CNS-active agents containing a phenylethyl-
amine motif.
RESULTS AND DISCUSSION
■
Synthesis of Azetidine-Based Scaffolds. The azetidine
core systems required in the formation of the various library
scaffolds were accessed from N-allyl amino diols 1a15 and 1b16
on multigram scale (20 g of 5a−d) over four steps through
adaptation of previously described conditions (Scheme 1).11
The sequence included N-alkylation of a secondary amine with
bromoacetonitrile (92−95%), protection of the primary alcohol
as its trityl ether (95−99%), and formation of the benzylic
chloride to arrive at compounds 4a and 4b (65−71%).17
Treatment of chloride 4a with lithium hexamethyldisilylazide
(LiHMDS) at −50 °C provided a ca. 1.2:1 epimeric mixture of
2-cyanoazetidines 5a and 5b. The resulting products could be
easily separated via flash chromatography on multigram scale to
give 53% for 5a and 40% for 5b. The anti-configured linear
template 4b could selectively provide either 5c or 5d depending
Several papers highlighting the synthesis and physicochem-
ical property analysis of spirocyclic oxetanes and spirocyclic
azetidines for their potential use in drug discovery have recently
been published by Carreira22 and others.23 In an attempt to
Scheme 1. Synthesis of Azetidine-Based Templates 5a−d
7188
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
Scheme 2. Synthesis of Azetidine Scaffolds 8, 10, and 12
access compounds with similar property profiles, we turned our
attention toward the formation of a novel spirocyclic azetidine
scaffold derived from azetidine 5 (Scheme 3). The synthesis
began with the metalation of aminonitrile 5a (or 5b) with
lithium tetramethylpiperidide (LiTMP) at −78 °C in THF.
The resulting anion could then be trapped with formaldehyde
source benzotriazolylmethanol24 to form a single compound.
Treatment of this intermediate with tosyl chloride provided
13a, which was then was reacted with a solution of DIBAL and
immediately capped with o-nitrobenzenesulfonyl chloride. This
material was treated with potassium carbonate to provide the
spirocyclic intermediate 14 in 67% yield.25 Removal of the trityl
group with trifluoroacetic acid completed the synthesis of
15a.26
Access to the trans-configured spirocyclic system (15c) was
envisioned to be obtained through the same sequence of
reactions that was used in the synthesis of 15a (Scheme 3).
Thus, alkylation of 5c (or 5d) furnished approximately a 1:1
mixture of α- and β-alcohols. Tosylation of the mixture
provided 13c in reasonable isolated yield. Treatment of 13c
with DIBAL appeared to immediately provide a cyclized
product based on the observed loss of the pendant tosylate.
Capping the resulting amine with o-nitrobenzenesulfonyl
chloride and unmasking the primary alcohol with trifluoroacetic
acid afforded a white solid, which upon recrystallization yielded
X-ray quality crystals. Surprisingly, upon examination of the
structural data, a [3.3.0] spirocycle was not observed but rather
a [4.2.0] system (16).25 Ring expansions of azetidine systems
have been previously described to give substituted pyrroles
through an intermediate 1-azoniabicyclo [2.1.0] pentane
system;27 however, to the best of our knowledge, this is the
first example of a ring expansion followed by a spirocyclization
to form a [4.2.0] ring system.
In an attempt to circumvent this rearrangement and provide
the complementary trans-spirocyclic system 15c, the nucleo-
philicity of the azetidine nitrogen was attenuated with a Boc
protecting group. Access to this compound was achieved
through the deprotection of the allyl group followed by
treatment with Boc2O. Further manipulation included
alkylation and tosylation of 17 to provide compound 18,
which then underwent nitrile reduction with DIBAL and
nosylation to form the precyclized product. Treatment of this
substrate with potassium carbonate in acetonitrile afforded the
trans-azetidine ring system 19 in 51% yield over three steps.
Subsequent removal of the Boc and trityl groups followed by
N-alkylation with allyl bromide provided 15c in 45% yield.
Conversion of o-bromo amino diols 20a,b to the
corresponding o-bromonitrile azetidines 21a−d allowed for
facile access to a number of fused ring scaffolds (Scheme 4).
The first compound in this series takes advantage of an
intramolecular Buchwald/Hartwig cross-coupling reaction to
access a tetrahydroquinoline core system.28 DIBAL reduction
of the nitrile group followed by nosylation of the resulting
amine yielded 22a and 22c in 68 and 79% yield over two steps.
7189
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
Scheme 3. Synthesis of Spirocyclic Azetidine Scaffold 15
in compounds 21a,b allows for the pairing of the hydroxyl
functionality through an O-arylation on the opposite side of the
azetidine ring system.29 Treating the resulting deprotected
product with palladium acetate and cesium carbonate in the
presence of a phosphine ligand gave the desired dihydrobenzo-
pyran in 66 and 74% yield. Finally, reduction of the nitrile using
DIBAL and nosyl protection afforded scaffolds 25a and 25b.
In Silico Analysis and In Vitro Compound Profiling. As
our overall goal was to use the azetidine-based scaffolds to
produce a diverse collection of compounds “pre-optimized” for
CNS physicochemical and ADME requirements, we set out to
validate our computational approach by collecting in vitro data
on a representative set of library compounds. Early estimates of
ADME properties can be useful to help guide the decision
making process in how to populate a library collection with
compounds having the highest likelihood of success in drug
development. This property evaluation is critical when targeting
the CNS due to penetration of the BBB (blood-brain barrier)
which has been noted to have a narrow window of
physicochemical boundaries for CNS-accessible chemical
space.30 A set of analogues representing various chemotypes
(e.g., sulfonamide, amide, amine) was prepared to represent
potential library members obtained from a full production
(26−32, Figure 2). Full library production would focus only on
those scaffolds which satisfied our CNS lead-like criteria and
possessed no obvious metabolic or chemical instability.
Scheme 4. Synthesis of Scaffolds 24 and 25
In silico analysis of compounds 26−32 for MW, TPSA,
HBD, cLogP, cLogD, and pKa confirms that most compounds
are well within the range of preferred properties for CNS
compounds (Table 1) and compare well to marketed CNS
drugs.31 In addition, computed models of brain partitioning
Treatment of each of these intermediates with copper(I)
iodide, cesium carbonate, and dimethylethane 1,2-diamine in
toluene gave rise to the tricyclic system 23 in quantitative yield.
Removal of the trityl protecting group provided the desired
scaffolds 24a and 24c. Alternatively, removal of the trityl group
7190
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
Figure 2. Representative library members synthesized for in vitro analysis.
a
Table 1. Calculated Physicochemical Properties
cmpd
MW
TPSA
HBD
cLogP
cLogD
pKa
Log BB
BBB cat
P-gp cat
CNS MPO
26a
26b
27a
27b
27c
27d
28a
28b
28c
29a
29b
29c
30a
30b
30c
31a
31b
31c
32a
32b
230
234
258
258
294
324
246
274
310
325
246
260
246
260
288
232
274
310
336
310
47
50
24
24
41
7
1
2
1
0
0
0
1
1
1
2
2
1
2
1
1
2
1
1
1
1
2.26
1.28
2.33
2.33
2.29
4.05
0.66
0.59
0.98
2.28
1.56
1.87
1.43
1.42
1.44
1.68
1.62
1.76
3.68
2.32
0.93
−0.41
0.91
0.91
0.89
3.90
−0.30
0.59
0.98
0.57
0.03
0.79
0.38
1.06
0.47
0.81
0.26
0.16
2.67
0.85
3.9
9.5
8.7
7.1
6.8
7.9
5.4
−1.7
−2.0
9.8
9.9
9.0
9.9
9.4
7.6
8.8
7.9
7.3
8.3
7.2
0.31
0.09
0.67
0.67
0.25
0.82
−0.16
−0.23
−0.40
0.34
0.19
0.40
0.20
0.37
0.27
0.24
0.31
0.50
0.49
0.03
+
+
+
+
+
+
+
−
−
+
+
+
+
+
−
+
−
+
+
+
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
yes
no
5.83
4.75
4.68
5.20
6.00
3.32
5.83
5.83
5.83
4.40
4.35
4.68
4.35
4.48
5.83
4.90
5.83
5.83
5.55
5.83
44
61
78
36
36
27
36
27
44
36
44
61
42
59
a
Preferred physicochemical property ranges for increasing the potential for BBB penetration: MW <450, TPSA <70 Å, HBD 0−1, cLogP 2−4,
cLogD 2−4.31
(log brain/blood, BBB category) and potential P-glycoprotein
(P-gp) substrate status were utilized to assess the probability of
reasonable brain exposures. The CNS multiparameter
optimization (MPO) algorithm developed by Pfizer was also
applied, and all but one compound (21d) displayed a high
desirability score (≥4, using a scale of 0−6).32 Of note, while
maintaining properties in the desired CNS range and
containing a common core structural motif, the azetidine-
based compounds exhibit a high degree of structural diversity
compared to existing CNS drugs as measured by Tanimoto
coefficient (Tc) with a mean similarity less than 0.15 and a
maximum similarity less than 0.26 (Figure 3).33
were found to be highly soluble (>400 μM) in water and
phosphate buffered saline and displayed low to moderate
protein binding in both mouse and human sera. This high
proportion of free or unbound fraction of compound is an
important attribute when considering diffusion into the CNS
compartment.34 Notably, almost all molecules exhibited
excellent stability toward human and mouse plasma, liver
microsomes, and hepatocytes, indicative of good pharmacoki-
netic properties (e.g., T1/2).
The permeability of compounds 26−32 was evaluated using
two distinct model systems: the BBB parallel artificial
membrane permeability assay (BBB-PAMPA)35 and Caco-2
cell lines. The BBB-PAMPA assay is used as a high-throughput
method to predict passive BBB penetration of potential CNS
drugs. Using this assay, most compounds displayed high
As shown in Table 2, several properties were measured in
vitro for compounds 26−32, including solubility, protein
binding, stability, and permeability. Most compounds tested
7191
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
Caco-2 monolayer and displayed no directional bias indicative
of active efflux.36,37 The data suggest that most of these
compounds should be highly permeable at the endothelial
systems present in the gut (oral absorption) and at the blood-
brain barrier.
Representative Solid-Phase Library Synthesis. The
azetidine-based scaffolds described above have served as
starting points for the production of over 20 000 CNS-focused
compounds to date in our lab. Much like compounds 26−32,
the resulting library members retain the desired physicochem-
ical properties for CNS-focused compounds (vide infra). As an
example, we highlight below the synthesis of a 1976-membered
library of spirocyclic azetidine compounds.
Starting from spirocyclic scaffold des-Br-15 (Scheme 3), a
virtual library was constructed using a master list of reagents,
which included sulfonyl chlorides, isocyanates, acids, and
aldehydes.38 All possible building block combinations at R1
(nosyl amine) and R2 (allyl amine) were employed to yield a
total of 9152 compounds per scaffold. The following CNS-
focused property filters were then applied to yield a total of
3089 compounds: MW ≤450, ALogP −1 to 5, H-bond
acceptors <7, H-bond donors ≤3, rotatable bonds ≤8, and
TPSA ≤90. Using chemical similarity principles, maximizing
diversity but retaining near neighbors for built-in SAR,6 this set
was further narrowed down to 494 compounds per stereo-
isomer (or 1976 compounds total). The same set of reagents
was used for all four stereoisomers, thereby maintaining the
ability to generate SSAR for each building block combination.
As shown in Scheme 5, all four stereoisomers of the
spirocyclic scaffold were loaded onto SynPhase L-series
Lanterns via activation of the silicon-fuctionalized Lanterns14
with TfOH. Lanterns were equipped with radio frequency
transponders to enable tracking and sorting of library members.
Figure 3. Multifusion similarity (MFS) map, ECFP_4 fingerprints
(test set = azetidine scaffolds and derivatives (n = 64), reference set =
CNS drugs (n = 70).
permeability values (Pe ≥ 10.0 × 10−6 cm·s−1) suggestive of
effective diffusion across the endothelial cells in CNS blood
vessels. Next, the permeability of each compound was evaluated
using the cell-based Caco-2 system as a surrogate for
permeability across the gut endothelium. Bidirectional analysis
was conducted to evaluate the propensity of these compounds
to act as substrates for efflux mechanisms expressed in Caco-2
(e.g., P-gp efflux transporter) as well as a measure of passive
diffusion. Consistent with our results in the BBB-PAMPA assay,
all compounds displayed high rates of permeation across the
a
Table 2. In Vitro Compound Profiling Data
protein binding (%
bound)
plasma stability (%
remaining)
microsomal stability
(% remaining)
hepatocytes (%
remaining)
solubility (μM)
Caco-2
cmpd
PBS
H2O
mouse
human
mouse
human
mouse
human
mouse
human
BBB-PAMPA
A-B
B-A
26a
26b
27a
27b
27c
27d
28a
28b
28c
29a
29b
29c
30a
30b
30c
31a
31b
31c
32a
32b
402
>500
>500
476
>500
>500
>500
483
65
19
35
13
39
98
65
7
110
100
103
94
109
92
62
68
79
93
72
42
104
109
100
98
89
97
93
98
89
94
64
34
0
88
73
94
93
86
55
112
96
104
96
86
96
95
99
94
85
88
69
0
59
54
67
16
30
54
66
14
43
12
17
14
2
49
8
103
103
83
4
49
23
31
98
102
83
22
56
54
7
94
67
104
72
15
470
490
102
90
113
71
31
335
346
111
>500
>500
>500
485
116
110
106
94
99
31
17
20
32
8
−9.2
−2.3
46
−1.0
−4.6
24
79
78
388
491
97
99
71
104
14
6
>500
494
9
8
94
99
>500
5
1
78
82
9
14
3
21
12
56
35
29
51
64
52
57
>500
>500
>500
>500
489
108
106
97
106
86
−6.0
32
28
37
10
18
45
95
37
33
29
43
48
56
59
66
93
495
496
22
108
98
97
31
14
35
20
106
101
94
32
478
>500
50
107
102
105
43
91
453
37
97
63
73
a
PBS and H2O solubilities are based on a 24 h time point using dry powder; plasma protein binding is measured by rapid equilibrium dialysis
(incubation at 37 °C for 5 h); plasma stability represents the % parent remaining at 5 h; microsome stability represents the % parent remaining at 1
h; hepatocyte stability represents the % parent remaining at 2 h; permeability is measured bidirectionally in the Caco-2 cell line, unit 10−6 cm·s−1
7192
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
Scheme 5. Solid-Phase Library Synthesis on SynPhase Lanterns
Following removal of the nosyl group, the first diversity site
(R1), an amine, was reacted with a total of 55 building blocks
including isocyanates, sulfonyl chlorides, acids, and aldehydes.39
The second diversity site (R2) was then revealed via removal of
the allyl group upon treatment with Pd(PPh3)4 in the presence
of excess 1,3-dimethyl barbituric acid. The second azetidine
nitrogen was capped with 41 building blocks including
isocyanates, sulfonyl chlorides, acids, and aldehydes. This was
followed by cleavage from the Lantern with HF/pyridine in
THF to afford a total of 1976 products (33) with an average
yield of 16 μmol (∼8 mg).
All library products were analyzed by ultraperformance liquid
chromatography, and compound purity was assessed by UV
detection at 210 nm. The average purity of the library was
70%.40 In general, most of the building block classes performed
well with the exception of aldehydes in the first capping (R1).
Interestingly, the compounds were of high purity after the
initial reductive alkylation; however, after carrying the tertiary
amines through allyl deprotection and subsequent capping, low
purities were observed.
Figure 4. CNS MPO score for the spirocyclic azetidine library
members (n = 1976) plotted from low to high CNS MPO score along
the x-axis.
In silico analysis of the spirocyclic azetidine library confirms
that the physicochemical properties of the library members fall
within the preferred range for CNS compounds (Table 3).31
Table 3. Calculated Physicochemical Properties
property
mean value
range
folds, including a focused set of 20 representative compounds
and a 1976-membered library of spirocyclic azetidines. Analysis
of the library members in silico indicated the compounds
demonstrate ideal physicochemical properties for CNS
application, and further analysis of a subset of compounds in
vitro showed a very good ADME profile.
molecular weight
ALogP
392
314−450
−0.77−4.99
−0.93−4.65
26.7−89.5
1−2
3−6
3−8
0.25−0.72
2.06
1.28
70.0
1.15
3.96
5.37
0.47
LogD
TPSA
H-bond donors
H-bond acceptors
rotatable bonds
Fsp3
The importance of populating chemical libraries with
preoptimized structures cannot be overstated in the successful
and efficient growth of new chemical entities in drug and probe
development.43 By utilizing a data-driven approach for scaffold
selection and focusing library production into this optimized
chemical space, we hope to increase efficiency in downstream
multiparametric optimization activities. These considerations
are particularly acute when targeting the CNS due to the
stringent physicochemical requirements for successful blood-
brain barrier (BBB) penetration of small molecules. These
results highlight the fact that through diligent examination of
the scaffold properties one can apply a DOS approach to create
a collection of structurally diverse compounds with good
physicochemical properties for use in screening and follow up
biological evaluation.
Moreover, application of the CNS MPO algorithm34 showed
that the majority of compounds displayed a desirability score
≥4 (Figure 4). In addition, much like other DOS compounds,41
the structural complexity of the spirocyclic azetidine library is
closer to that of natural products than typical commercial
compounds as measured by the fraction of sp3 centers
(Fsp3).4c,42
CONCLUSIONS
In summary, we have reported the synthesis of a collection of
skeletally and stereochemically diverse azetidine-based scaf-
■
7193
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
2-(Allyl((1R,2R)-1-(4-bromophenyl)-1-chloro-3-(trityloxy)-
propan-2-yl)amino)acetonitrile 4a. To a solution of pyridine (43.2
mL, 536 mmol) in CH2Cl2 (950 mL) was added thionyl chloride
(15.64 mL, 214 mmol) at room temperature. The above solution was
then cooled to 0 °C and a solution of benzyl alcohol 3a (60.8 g, 107
mmol) in CH2Cl2 (100 mL) was added dropwise over 10 min and
stirred for an additional 15 min at 0 °C (Note: If the solution is
warmed or stirred for longer than 15 min, the product decomposes).
The mixture was neutralized by the addition of a saturated aqueous
solution of sodium bicarbonate and the aqueous layer extracted two
additional times with CH2Cl2. The combined organic extracts were
dried over MgSO4, filtered, and concentrated under reduced pressure
to provide the crude product, which was purified by chromatography
over silica gel to provide pure product 4a (44.6 g, 71%) as a white
foam: [α]2D0 −47.9 (c 1.22, CHCl3); IR νmax (film) 3057, 3022, 2933,
2885, 1593, 1489, 1448, 1072; 1H NMR (500 MHz, CDCl3) δ 7.44 (d,
J = 10.2 Hz, 2H), 7.39−7.23 (m, 15H), 7.19 (d, J = 8.4 Hz, 2H), 5.72−
5.56 (m, 1H), 5.26−5.10 (m, 3H), 3.68 (d, J = 17.4 Hz, 1H), 3.59 (d, J
= 17.4 Hz, 1H), 3.50−3.35 (m, 2H), 3.32−3.13 (m, 3H); 13C NMR
(125 MHz, CDCl3) δ 143.2, 138.2, 134.6, 131.6, 129.3, 128.5, 127.9,
127.2, 122.3, 118.9, 117.2, 87.5, 66.6, 62.8, 61.5, 55.1, 40.1; HRMS
(ESI) calcd for C33H31BrClN2O [M + H]+ 585.1308, found 585.1342.
Anal. calcd/found for C33H30BrClN2O: C, 67.64%/67.76%; H, 5.16%/
5.44%; N, 4.78%/4.53%; Cl, 6.05%/6.43%; Br, 13.64%/12.13%.
2-(Allyl((1S,2S)-1-(4-bromophenyl)-1-chloro-3-(trityloxy)-
propan-2-yl)amino)acetonitrile ent-4. Following the protocol
above, 116 g of benzyl alcohol ent-3a afforded 69 g (58%) of chloride
ent-4a: [α]2D0 +54.5 (c 0.96, CHCl3).
EXPERIMENTAL SECTION
■
General Methods. All oxygen and/or moisture-sensitive reactions
were carried out under N2 atmosphere in glassware that had been
flame-dried under vacuum (∼0.5 mmHg) and purged with N2 prior to
use. All reagents and solvents were purchased from commercial
vendors and used as received or synthesized according to the
footnoted references. 1H and 13C NMR spectra were recorded on 300
MHz and/or 500 MHz spectrometers. All chemical shifts are reported
in parts per million (δ) referenced to residual nondeuterated solvent.44
Data are reported as follows: chemical shifts, multiplicity (br = broad, s
= singlet, d = doublet, t = triplet, q = quartet, p = pentet, m =
multiplet; coupling constant(s) in Hz; integration). Unless otherwise
indicated, NMR data were collected at 25 °C. IR spectra were obtained
with an FTIR spectrometer and are reported in cm−1. Melting point
experiments were performed on a Buchi M-560 melting point
apparatus. Flash chromatography was performed using 40−60 μm
silica gel (60 Å mesh) with the indicated solvent.
̈
2-(Allyl((1R,2R)-1-(4-bromophenyl)-1,3-dihydroxypropan-2-
yl)amino)acetonitrile 2a. To a solution of amino diol 1a15 (52.9 g,
185 mmol) in acetonitrile (1849 mL) was added potassium carbonate
(38.3 g, 277 mmol) and 2-bromoacetonitrile (38.7 mL, 555 mmol).
The resulting heterogeneous solution was heated to 85 °C and stirred
for 3 h. Once the reaction was complete, the mixture was concentrated
under reduced pressure and the residue was taken up in water and
diethyl ether. The aqueous layer was extracted two additional times
with diethyl ether. The combined organic extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure to provide
the crude product, which was purified by chromatography over silica
gel to provide pure product 2a (59.5 g, 99%) as an oil: [α]2D0 −43.3 (c
1.45, CHCl3); IR νmax (film) 3419, 3080, 2912, 1642, 1592, 1486,
1419, 1070, 1010; 1H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 8.3 Hz,
2H), 7.26 (d, J = 8.4 Hz, 2H), 5.80 (tt, J = 10.4, 6.7 Hz, 1H), 5.36 (d, J
= 17.1 Hz, 1H), 5.30 (d, J = 10.1 Hz, 1H), 4.66 (d, J = 9.2 Hz, 1H),
3.91 (d, J = 17.3 Hz, 1H), 3.74 (d, J = 17.4 Hz, 1H), 3.72−3.66 (m,
1H), 3.61 (dd, J = 13.7, 5.8 Hz, 1H), 3.52 (dd, J = 11.6, 6.5 Hz, 1H),
3.44 (dd, J = 13.6, 6.9 Hz, 1H), 2.91−2.83 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 139.9, 133.8, 131.6, 128.6, 122.0, 120.1, 116.9, 70.5,
69.0, 58.2, 54.7, 39.1; HRMS (ESI) calcd for C14H18BrN2O2 [M + H]+
325.0552, found 325.0551.
2-(Allyl((1S,2R)-1-(4-bromophenyl)-1,3-dihydroxypropan-2-
yl)amino)acetonitrile 2b. Following the protocol above, 50 g of
amino diol 1b16 afforded 54.7 g (96%) of tertiary amine 2b: [α]2D0 +2.1
(c 1.72, CHCl3); IR νmax (film) 3393, 2889, 1485, 1419, 1068, 1023,
1
1008; H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 8.4 Hz, 2H), 7.19
(d, J = 8.3 Hz, 2H), 5.70 (ddt, J = 16.7, 10.0, 6.5 Hz, 1H), 5.33 (dd, J =
17.1, 1.4 Hz, 1H), 5.24 (d, J = 10.1 Hz, 1H), 5.11 (s, 1H), 3.86−3.72
(m, 3H), 3.68 (d, J = 11.2 Hz, 1H), 3.49 (dd, J = 13.9, 6.4 Hz, 1H),
3.40 (dd, J = 13.9, 6.6 Hz, 1H), 3.01 (br s, 1H), 2.84 (dt, J = 5.8, 3.9
Hz, 1H), 2.38 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 141.1,
133.8, 131.4, 127.3, 121.3, 119.5, 116.8, 71.9, 67.0, 57.9, 54.7, 38.8;
HRMS (ESI) calcd for C14H18BrN2O2 [M + H]+ 325.0552, found
325.0551.
2-(Allyl((1R,2S)-1-(4-bromophenyl)-1,3-dihydroxypropan-2-
yl)amino)acetonitrile ent-2b. Following the protocol above, 50 g of
amino diol ent-1b16 afforded 55.7 g (98%) of tertiary amine ent-2b:
[α]2D0 −2.7 (c 1.81, CHCl3).
2-(Allyl((1S,2R)-1-(4-bromophenyl)-1-hydroxy-3-(trityloxy)-
propan-2-yl)amino)acetonitrile 3b. Following the protocol above,
54 g of diol 2b afforded 91 g (97%) of trityl protected product 3b:
[α]2D0 +7.2 (c 1.9, CHCl3); IR νmax (film) 3471, 3057, 1733, 1487,
1447, 1264; 1H NMR (500 MHz, CDCl3) δ 7.40−7.31 (m, 7H),
7.30−7.23 (m, 11H), 7.07 (d, J = 8.3 Hz, 2H), 5.71−5.54 (m, 1H),
5.23 (d, J = 17.6 Hz, 1H), 5.19 (d, J = 10.2 Hz, 1H), 4.96 (d, J = 4.0
Hz, 1H), 3.49 (q, J = 17.5 Hz, 2H), 3.36 (dd, J = 10.5, 4.8 Hz, 1H),
3.30 (dd, J = 10.5, 5.4 Hz, 1H), 3.25−3.17 (m, 2H), 3.10 (q, J = 4.8
Hz, 1H), 3.03 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 148.4,
143.1, 140.7, 134.2, 131.2, 128.5, 128.1, 127.9, 127.9, 127.6, 127.2,
126.6, 121.2, 119.3, 116.7, 87.6, 72.3, 65.9, 60.2, 54.8, 39.6; HRMS
(ESI) calcd for C33H31BrN2NaO2 [M + Na]+ 589.1467, found
589.1453.
2-(Allyl((1R,2S)-1-(4-bromophenyl)-1-hydroxy-3-(trityloxy)-
propan-2-yl)amino)acetonitrile ent-3b. Following the protocol
above, 55.7 g of diol ent-2b afforded 95 g (98%) of trityl protected
product ent-3b: [α]2D0 −7.8 (c 1.5, CHCl3).
2-(Allyl((1S,2R)-1-(4-bromophenyl)-1-chloro-3-(trityloxy)-
propan-2-yl)amino)acetonitrile 4b. Following the protocol above,
91 g of benzyl alcohol 3b afforded 62 g (66%) of chloride 4b: [α]D20
+27.7 (c 3.06, CHCl3); IR νmax (film) 3057, 2936, 2885, 1592, 1488,
1448, 1447; 1H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 7.3 Hz, 5H),
7.39 (d, J = 8.4 Hz, 2H), 7.31 (t, J = 7.5 Hz, 5H), 7.26 (d, J = 7.2 Hz,
3H), 7.12 (d, J = 8.4 Hz, 2H), 5.52−5.21 (m, 1H), 5.09−4.92 (m,
2-(Allyl((1S,2S)-1-(4-bromophenyl)-1,3-dihydroxypropan-2-
yl)amino)acetonitrile ent-2a. Following the protocol above, 62 g of
amino diol ent-1a16 afforded 67 g (95%) of tertiary amine ent-2a: [α]2D0
+39.3 (c 0.99, CHCl3).
2-(Allyl((1R,2R)-1-(4-bromophenyl)-1-hydroxy-3-(trityloxy)
propan-2-yl)amino)acetonitrile 3a. To a solution of tertiary amine
2a (59.5 g, 183 mmol) in CH2Cl2 (1830 mL) was added triethylamine
(77 mL, 549 mmol), and the entire solution was cooled to 0 °C. Trityl
chloride (77 g, 274 mmol) was then added, and the solution was
allowed to slowly warm to room temperature and stirred overnight.
The reaction mixture was quenched with aqueous saturated NH4Cl
solution, and the aqueous layer was extracted two times with CH2Cl2.
The combined organic extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure to provide the crude product,
which was purified by chromatography over silica gel to provide pure
product 3a (103 g, 99%) as a pale yellow oil: [α]2D0 −10.1 (c 1.94,
CHCl3); IR νmax (film) 3060, 3022, 2878, 1594, 1489, 1448, 1071,
1033; 1H NMR (500 MHz, CDCl3) δ 7.38 (d, J = 8.3 Hz, 2H), 7.22 (s,
15H), 7.08 (d, J = 8.4 Hz, 2H), 5.80−5.61 (m, 1H), 5.22 (d, J = 7.6
Hz, 1H), 5.20 (d, J = 14.2 Hz, 1H), 4.35 (d, J = 9.3 Hz, 1H), 3.85 (s,
1H), 3.65 (q, J = 17.0 Hz, 2H), 3.43 (dd, J = 13.9, 5.4 Hz 1H), 3.24
(dd, J = 10.9, 7.2 Hz, 1H), 3.16 (dd, J = 10.9, 3.5 Hz, 1H), 3.09−2.96
(m, 2H); 13C NMR (125 MHz, CDCl3) δ 143.1, 139.9, 134.0, 131.5,
128.9, 128.4, 127.9, 127.2, 121.9, 119.8, 116.9, 87.8, 70.7, 67.8, 59.6,
54.0, 39.7; HRMS (ESI) calcd for C33H32BrN2O2 [M + H]+ 567.1647,
found 567.1646.
2-(Allyl((1S,2S)-1-(4-bromophenyl)-1-hydroxy-3-(trityloxy)-
propan-2-yl)amino)acetonitrile ent-3a. Following the protocol
above, 67 g of ent-2a afforded 116 g (99%) of trityl protected product
ent-3a: [α]2D0 +4.6 (c 1.62, CHCl3).
7194
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
3H), 3.59−3.49 (m, 2H), 3.49−3.42 (m, 1H), 3.40 (s, 1H), 3.02 (dd, J
= 14.1, 5.2 Hz, 1H), 2.89 (dd, J = 14.1, 7.5 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 143.3, 137.9, 134.2, 131.4, 129.4, 128.6, 127.9, 127.9,
127.3, 122.2, 118.9, 116.9, 87.6, 66.9, 60.9, 60.4, 54.0, 39.9. Anal.
calcd/found for C33H30BrClN2O: C, 67.64%/67.57%; H, 5.16%/
5.30%; N, 4.78%/4.70%; Cl, 6.05%/6.30%; Br, 13.64%/12.63%.
2-(Allyl((1R,2S)-1-(4-bromophenyl)-1-chloro-3-(trityloxy)-
propan-2-yl)amino)acetonitrile ent-3b. Following the protocol
above, 95 g of benzyl alcohol ent-3b afforded 60.5 g (62%) of chloride
ent-4b: [α]2D0 −36.8 (c 2.43, CHCl3).
(2S,3R,4R)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-
((trityloxy)methyl) azetidine 5a and (2S,3R,4S)-1-Allyl-3-(4-
bromophenyl)-4-carbonitrile-2-((trityloxy)methyl) azetidine
5b. A solution of benzyl chloride 4a (44.5 g, 76 mmol) in THF
(1.1 L) was cooled to −50 °C. Lithium bis(trimethylsilyl)amide (1 M
solution in THF, 114 mL, 114 mmol) was added dropwise over 15
min and the mixture was stirred for an additional hour at −50 °C. The
reaction mixture was quenched with aqueous saturated NH4Cl
solution and the aqueous layer was extracted two times with
CH2Cl2. The combined organic extracts were dried over MgSO4,
filtered and concentrated under reduced pressure to provide the crude
product, which was purified by chromatography over silica gel to
provide pure products 5a (16.8 g, 40.3%) and 5b (21.9 g, 53%) as a
white solid and a white foam (93% combined yield).
(2S,3R,4R)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-
((trityloxy)methyl) azetidine 5a. [α]2D0 = +29.6 (c 1.92, CHCl3); IR
νmax (film) 3057, 2866, 1488, 1448, 1264; 1H NMR (500 MHz,
CDCl3) δ 7.36 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.23−7.14
(m, 9H), 7.14−7.11 (m, 6H), 5.74 (ddt, J = 17.0, 10.1, 6.7 Hz, 1H),
5.22 (dd, J = 17.1, 1.3 Hz, 1H), 5.11 (d, J = 10.2 Hz, 1H), 4.08 (d, J =
7.9 Hz, 1H), 3.80 (t, J = 7.8 Hz, 1H), 3.67 (td, J = 7.9, 5.3 Hz, 1H),
3.31 (dd, J = 12.9, 6.2 Hz, 1H), 3.12 (dd, J = 12.9, 7.1 Hz, 1H), 3.04
(dd, J = 9.5, 5.3 Hz, 1H), 2.80 (dd, J = 9.4, 8.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 143.4, 133.3, 132.8, 131.4, 131.3, 128.3, 127.7,
126.9, 121.9, 119.6, 117.3, 86.4, 66.2, 61.2, 60.7, 54.4, 42.4; HRMS
(ESI) calcd for C33H30BrN2O [M + H]+ 549.1542, found 549.1545.
(2R,3S,4S)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-
((trityloxy)methyl) azetidine ent-5a. Following the protocol above,
47 g of chloride ent-4a afforded 17.6 g (40%) of ent-5a: [α]2D0 −50.0 (c
2.02, CHCl3).
3.52 (dd, J = 13.8, 5.0 Hz, 1H), 3.37−3.29 (m, 2H), 3.25 (dd, J = 10.2,
4.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 143.6, 134.5, 133.0,
131.7, 129.7, 128.5, 127.8, 127.1, 121.8, 118.9, 115.6, 86.9, 68.2, 65.7,
57.1, 55.4, 41.9; HRMS (ESI) calcd for C33H30BrN2O [M + H]+
549.1541, found 549.1553.
(2R,3R,4R)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-
((trityloxy)methyl) azetidine ent-5c. Following the protocol above,
108.6 g of chloride ent-4c afforded 87.6 g (81%) of ent-5c: [α]2D0 −12.6
(c 1.42, CHCl3).
(2S,3S,4R)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-
((trityloxy)methyl) azetidine 5d. A solution of benzyl chloride 4b
(45 g, 77 mmol) in THF (770 mL) was cooled to −78 °C. Potassium
bis(trimethylsilyl)amide (1 M solution in THF, 115 mL, 115 mmol)
was added dropwise over 15 min and the mixture was stirred for an
additional hour at −78 °C. The reaction mixture was quenched with
aqueous saturated NH4Cl solution and the aqueous layer was extracted
three times with EtOAc. The combined organic extracts were dried
over MgSO4, filtered and concentrated under reduced pressure to
provide the crude product, which was purified by chromatography
over silica gel to provide 5d (35 g, 83%) as a light orange foam: [α]D20
−20.3 (c 2.21, CHCl3); IR νmax (film) 3057, 3031, 2913, 2864, 2810,
1
1643, 1595, 1489, 1447; H NMR (500 MHz, CDCl3) δ 7.48 (d, J =
8.4, 2H), 7.42 (m, 5H), 7.36−7.25 (m, 11H), 7.10 (d, J = 8.3, 2H),
5.95−5.78 (m, 1H), 5.33 (d, J = 17.0, 1H), 5.24 (d, J = 10.2, 1H), 3.70
(t, J = 7.9, 1H), 3.61 (d, J = 8.2, 1H), 3.51 (dd, J = 5.7, 13.0, 1H),
3.44−3.33 (m, 2H), 3.32−3.22 (m, 1H), 3.16 (dd, J = 7.4, 13.1, 1H);
13C NMR (126 MHz, CDCl3) δ 143.6, 136.5, 132.6, 131.8, 128.7,
128.5, 127.8, 127.1, 121.5, 119.7, 119.1, 86.8, 69.0, 66.2, 60.4, 55.1,
44.4; HRMS (ESI) calcd for C33H30BrN2O [M + H]+ 549.1541, found
549.1544.
(2R,3R,4S)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-
((trityloxy)methyl) azetidine ent-5d. Following the protocol above,
30 g of chloride ent-4d afforded 23.7 g (84%) of ent-5d. [α]2D0 = +19.4
(c 1.78, CHCl3) mp 110.9−111.6 °C.
N-(((2S,3R,4R)-1-Allyl-3-(4-bromophenyl)-4-((trityloxy)-
methyl)azetidin-2-yl)methyl)-2-nitrobenzene sulfonamide 6a.
Nitrile azetidine 5a (12.45 g, 22.66 mmol, 1.0 equiv) was dissolved in
CH2Cl2 (227 mL) and subsequently cooled to 0 °C. DIBAL (24.2 mL,
136 mmol, 6.0 equiv) was added over 15 min and the reaction mixture
was allowed to warm to room temperature and stirred for
approximately 2 h. The mixture was quenched by the slow addition
of MeOH (5.50 mL, 136 mmol, 6.0 equiv) until gas evolution ceased.
Then a saturated solution of sodium potassium tartrate (Rochelle’s
salt) was added and the gel like solution was allowed to stir until two
separate layers could be seen. The aqueous layer was then extracted
two additional times with CH2Cl2. The combined organic extracts
were dried over MgSO4, filtered and concentrated under reduced
pressure to provide the crude product, which was deemed pure
enough for the next reaction.
(2S,3R,4S)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-
((trityloxy)methyl) azetidine 5b. [α]2D0 = +12.7 (c 1.37, CHCl3);
1
mp 129.5−133.5 °C IR νmax (film) 3057, 2862, 1488, 1448, 1264; H
NMR (500 MHz, CDCl3) δ 7.32 (d, J = 8.4 Hz, 2H), 7.22−7.09 (m,
17H), 5.71−5.53 (m, 1H), 5.24 (dd, J = 17.2, 1.3 Hz, 1H), 5.09 (d, J =
10.2 Hz, 1H), 4.18 (d, J = 2.2 Hz, 1H), 4.03 (dd, J = 13.0, 7.9 Hz, 1H),
3.79 (dd, J = 7.8, 2.3 Hz, 1H), 3.31 (qd, J = 13.7, 6.2 Hz, 2H), 2.99
(dd, J = 9.5, 5.1 Hz, 1H), 2.64 (t, J = 9.15 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 143.4, 135.1, 132.9, 131.5, 130.1, 128.3, 127.7, 126.9,
121.6, 118.9, 116.9, 86.5, 66.5, 61.5, 55.8, 55.6, 43.6; HRMS (ESI)
calcd for C33H30BrN2O [M + H]+ 549.1542, found 549.1542.
(2R,3S,4R)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-
((trityloxy)methyl) azetidine ent-5b. Following the protocol
above, 47 g of chloride ent-4b afforded 20.3 g (46%) of ent-5b:
[α]2D0 −11.3 (c 2.48, CHCl3).
A portion of the resulting amine (11.35 g, 20.50 mmol, 1.0 equiv)
was dissolved in CH2Cl2 (205 mL) and cooled to 0 °C. 2,6-Lutidine
(7.14 mL, 61.5 mmol, 3.0 equiv) was introduced followed by 2-
nitrobenzene-1-sulfonyl chloride (5.15 g, 22.56 mmol, 1.1 equiv) in
one portion. The solution was then allowed to warm to room
temperature and stir for an additional 3 h. The reaction mixture was
quenched with water and the aqueous layer was extracted two times
with CH2Cl2. The combined organic extracts were dried over MgSO4,
filtered and concentrated under reduced pressure to provide the crude
product, which was purified by chromatography over silica gel using
hexanes/EtOAc to provide pure product 6a (13.16 g, 87% 2-steps) as
a pale yellow foam: [α]D20 −32.4 (c 0.50, CHCl3); IR νmax (film) 3332,
(2S,3S,4S)-1-Allyl-3-(4-bromophenyl)-4-carbonitrile-2-
((trityloxy)methyl) azetidine 5c. A solution of benzyl chloride 4b
(62 g, 106 mmol) in THF (1058 mL) was cooled to −78 °C. Lithium
bis(trimethylsilyl)amide (1 M solution in THF, 127 mL, 127 mmol)
was added dropwise over 15 min and the mixture was stirred for an
additional hour at −50 °C. The reaction mixture was quenched with
aqueous saturated NH4Cl solution and the aqueous layer was extracted
three times with EtOAc. The combined organic extracts were dried
over MgSO4, filtered and concentrated under reduced pressure to
provide the crude product, which was purified by chromatography
over silica gel to provide 5c (21.9 g, 53%) as a light orange foam: [α]D20
+13.9 (c 1.62, CHCl3); IR νmax (film) 3056, 3031, 2913, 2862, 2819,
1734, 1643, 1595, 1489, 1447; 1H NMR (500 MHz, CDCl3) δ 7.49 (d,
J = 8.4 Hz, 2H), 7.39 (d, J = 7.3 Hz, 6H), 7.33−7.24 (m, 9H), 7.16 (d,
J = 8.4 Hz, 2H), 5.81−5.69 (m, 1H), 5.33 (d, J = 16.4 Hz, 1H), 5.17
(d, J = 10.2 Hz, 1H), 4.62 (d, J = 6.8 Hz, 1H), 3.85−3.75 (m, 2H),
1
3056, 2872, 1537, 1348, 1167, 1070; H NMR (500 MHz, CDCl3) δ
7.88−7.79 (m, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H),
7.22−7.16 (m, 6H), 7.16−7.11 (m, 4H), 7.09 (d, J = 2.0 Hz, 2H), 5.70
(dq, J = 6.6, 10.0 Hz, 1H), 5.20 (d, J = 17.1 Hz, 1H), 5.06 (d, J = 10.1
Hz, 1H), 4.91 (d, J = 4.2 Hz, 1H), 3.70−3.64 (m, 1H), 3.62 (dt, J =
6.4, 12.9 Hz, 1H), 3.57−3.42 (m, 1H), 3.28−3.15 (m, 2H), 3.15−2.98
(m, 2H), 2.88 (ddd, J = 6.4, 13.1 Hz, 20.4, 2H); 13C NMR (75 MHz,
CDCl3) δ 147.5, 143.6, 135.2, 134.3, 133.4, 132.7, 132.6, 132.1, 130.8,
130.8, 128.3, 127.6, 126.8, 125.6, 120.9, 118.2, 86.2, 65.6, 65.4, 61.2,
7195
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
60.9, 42.7, 42.2; HRMS (ESI) calcd for C39H37BrN3O5S [M + H]+
738.1637, found 738.1633.
addition of a saturated aqueous solution of sodium bicarbonate and
the aqueous layer extracted 2 additional times with CH2Cl2. The
combined organic extracts were dried over MgSO4, filtered and
concentrated under reduced pressure to provide the crude product,
which was purified by chromatography over silica gel using hexanes/
EtOAc to provide the primary alcohol 7a (8.74 g, 92%) as a foam:
[α]2D0 −46.2 (c 0.59, CHCl3); IR νmax (film) 3335, 2873, 1538, 1346,
N-(((2R,3S,4S)-1-Allyl-3-(4-bromophenyl)-4-((trityloxy)-
methyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfonamide ent-
6a. Following the protocol above, 19.8 g of nitrile azetidine ent-5a
afforded 23 g (87%) of ent-6a: [α]2D0 +33.1 (c 0.41, CHCl3).
N-(((2S,3R,4S)-1-Allyl-3-(4-bromophenyl)-4-((trityloxy)-
methyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfonamide 6b.
Following the protocol above, 11.4 g of nitrile azetidine 5b afforded
13.2 g (87%) of 6b: [α]D20 +62.4 (c 0.33, CHCl3); IR νmax (film) 3340,
3057, 2873, 1525, 1489, 1390, 1358, 1264; 1H NMR (500 MHz,
CDCl3) δ 8.07 (dd, J = 1.7, 7.5 Hz, 1H), 7.86 (dd, J = 1.5, 7.7 Hz, 1H),
7.75−7.61 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.27−7.17 (m, 8H), 7.17
(s, 5H), 6.89 (d, J = 8.3 Hz, 2H), 5.62−5.45 (m, 1H), 4.91 (d, J = 15.5
Hz, 1H), 4.75 (d, J = 9.0 Hz, 1H), 4.07 (dt, J = 4.6, 11.2 Hz, 1H), 3.89
(d, J = 4.4 Hz, 1H), 3.73 (t, J = 8.1, 1H), 3.29 (d, J = 11.0 Hz, 1H),
3.20 (dtd, J = 5.0, 12.5, 17.3 Hz, 3H), 2.90 (ddd, J = 6.5, 12.4, 21.1 Hz,
2H); 13C NMR (75 MHz, CDCl3) δ 147.9, 143.4, 135.9, 135.5, 133.4,
133.2, 132.5, 131.3, 130.9, 129.7, 128.5, 127.6, 126.9, 125.1, 120.4,
116.7, 87.1, 64.9, 64.1, 60.3, 52.8, 44.4, 40.1; HRMS (ESI) calcd for
C39H37BrN3O5S [M + H]+ 738.1637, found 738.1626.
1
1166, 905; H NMR (500 MHz, CDCl3) δ 7.83 (dd, J = 7.8, 1.4 Hz,
1H), 7.79 (dd, J = 7.9, 1.3 Hz, 1H), 7.72 (td, J = 7.7, 1.5 Hz, 1H), 7.66
(td, J = 7.6, 1.3 Hz, 1H), 7.22 (m, 4H), 5.83 (m, 1H), 5.28 (d, J = 17.1
Hz, 1H), 5.17 (d, J = 10.1 Hz, 1H), 4.92 (s, 1H), 3.64 (s, 1H), 3.54 (s,
2H), 3.49−3.42 (m, 1H), 3.37 (m, 1H), 3.21 (s, 3H), 2.92 (t, J = 10.3
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 147.6, 135.5, 133.8, 133.5,
132.7, 132.6, 132.2, 131.2, 130.9, 125.7, 121.4, 118.6, 67.3, 64.8, 61.4,
61.1, 42.8, 41.8; HRMS (ESI) calcd for C20H23BrN3O5S [M + H]+
496.0542, found 496.0545.
N - ( ( ( 2 R , 3 S , 4 S ) - 1 - A l l y l - 3 - ( 4 - b r o m o p h e n y l ) - 4 -
(hydroxymethyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfona-
mide ent-7a. Following the protocol above, 23 g of ent-6a azetidine
afforded 14.6 g (94%) of azetidine ent-7a: [α]2D0 +42.5 (c 1.44, CHCl3).
N - ( ( ( 2 S , 3 S , 4 R ) - 1 - A l l y l - 3 - ( 4 - b r o m o p h e n y l ) - 4 -
(hydroxymethyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfona-
mide 7d. Following the protocol above, 23.5 g of azetidine 6d
afforded 14.6 g (92%) of azetidine 7d: [α]2D0 −37.9 (c 0.49, CHCl3);
N-(((2R,3S,4R)-1-Allyl-3-(4-bromophenyl)-4-((trityloxy)-
methyl)azetidin-2-yl)methyl)-2-nitrobenzene sulfonamide ent-
6b. Following the protocol above, 20 g of nitrile azetidine ent-5b gave
25 g (93%) of ent-6b: [α]2D0 −52.1 (c 0.73, CHCl3).
1
IR νmax (film) 3320, 2872, 1537, 1342, 1162; H NMR (500 MHz,
CDCl3) δ 8.07 (dd, J = 1.6, 6.8 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H),
7.79−7.62 (m, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.2 Hz, 2H),
5.97 (s, 1H), 5.69 (ddt, J = 6.7, 9.9, 16.8 Hz, 1H), 5.18 (d, J = 17.1 Hz,
1H), 5.02 (d, J = 10.1 Hz, 1H), 3.64 (dd, J = 3.1, 12.0 Hz, 1H), 3.48
(d, J = 10.1 Hz, 1H), 3.34 (t, J = 7.7 Hz, 1H), 3.30−3.18 (m, 4H),
3.18−3.05 (m, 2H), 2.27 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
147.5, 138.5, 134.1, 133.4, 132.9, 132.5, 131.2, 130.5, 129.0, 124.9,
120.2, 118.5, 70.0, 67.4, 62.1, 59.6, 45.5, 38.8; HRMS (ESI) calcd for
C20H22BrN3O5S [M + H]+ 496.0542, found 496.0541.
N - ( ( ( 2 R , 3 R , 4 S ) - 1 - A l l y l - 3 - ( 4 - b r o m o p h e n y l ) - 4 -
(hydroxymethyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfona-
mide ent-7d. Following the protocol above, 24 g of ent-6d azetidine
gave 14 g (88%) of azetidine ent-7d: [α]2D0 +38.9 (c 0.28, CHCl3).
6-Allyl-7-(4-bromophenyl)-3-(2-nitrophenylsulfonyl)-3,6-
diazabicyclo[3.1.1] heptanes 8a. Nosyl amine 7a (8.0 g, 16.1
mmol) was dissolved in CH2Cl2 (170 mL), and the reaction was
subsequently cooled to 0 °C. Triethylamine (6.7 mL, 48.4 mmol) was
added followed by the dropwise addition methanesulfonyl chloride
(1.37 mL, 17.7 mmol). The solution was stirred for 30 min at 0 °C.
The reaction mixture was quenched with water, and the aqueous layer
was extracted three times with CH2Cl2. The combined organic extracts
were dried over MgSO4, filtered, and concentrated under reduced
pressure to provide the crude product, which was deemed pure
enough to continue without further purification.
The resulting sulfonate was dissolved in DMF (161 mL), and
potassium carbonate (4.46 g, 32.2 mmol) was added in one portion.
The reaction was heated to 65 °C for 3 h at which point the solvent
was removed and the resulting residue was purified by chromatog-
raphy over silica gel to provide 8.2 g of pure product 8a (99%): IR νmax
(film) 2934, 1542, 1372, 1169, 578, 535; 1H NMR (500 MHz, CDCl3)
δ 7.66 (t, J = 7.7 Hz, 1H), 7.40 (dt, J = 17.0, 7.9 Hz, 3H), 7.07 (d, J =
8.3 Hz, 2H), 6.74 (d, J = 8.1 Hz, 2H), 5.88−5.73 (m, 1H), 5.26 (dd, J
= 17.2, 1.4 Hz, 1H), 5.16 (d, J = 10.2 Hz, 1H), 4.01 (d, J = 5.7 Hz,
2H), 3.90 (t, J = 5.9 Hz, 1H), 3.84 (d, J = 11.7 Hz, 2H), 3.48 (d, J =
11.7 Hz, 2H), 3.28 (d, J = 5.9 Hz, 2H); 13C NMR (125 MHz, CDCl3)
δ 147.4, 134.5, 133.8, 133.2, 131.1, 131.1, 130.4, 129.5, 127.5, 123.4,
120.0, 117.4, 59.6, 47.5, 40.2, 39.4; HRMS (ESI) calcd for
C20H20BrN3O4S [M + H]+ 478.0436, found 478.0438.
6-Allyl-7-(4-bromophenyl)-3-(2-nitrophenylsulfonyl)-3,6-
diazabicyclo[3.1.1]heptanes 8d. Nosyl amine 7d (1.00 g, 2.02
mmol) was dissolved in CH2Cl2 (20 mL), and the reaction was
subsequently cooled to 0 °C. Triethylamine (0.842 mL, 6.04 mmol)
was added followed by the dropwise addition methanesulfonyl
chloride (0.172 mL, 2.22 mmol). The solution was stirred for 30
min at 0 °C. The reaction mixture was quenched with water, and the
aqueous layer was extracted three times with CH2Cl2. The combined
N-(((2S,3S,4S)-1-Allyl-3-(4-bromophenyl)-4-((trityloxy)-
methyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfonamide 6c.
Following the protocol above, 20 g of nitrile azetidine 5c afforded
18 g (67%) of 6c: [α]D20 +56.2 (c 0.21, CHCl3); IR νmax (film) 3332,
1
3056, 2871, 1539, 1346, 1264, 1168; H NMR (500 MHz, CDCl3) δ
7.89 (dd, J = 1.3, 7.8 Hz, 1H), 7.83 (t, J = 6.1 Hz, 1H), 7.74 (td, J =
1.2, 7.7 Hz, 1H), 7.69−7.60 (m, 1H), 7.44 (t, J = 8.9 Hz, 6H), 7.36−
7.30 (m, 7H), 7.27 (dd, J = 2.9, 5.2 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H),
5.71 (ddd, J = 5.9, 10.9, 16.2 Hz, 1H), 5.10−4.97 (m, 2H), 4.94 (s,
1H), 3.97 (td, J = 4.7, 8.3 Hz, 1H), 3.85−3.73 (m, 1H), 3.52−3.45 (m,
1H), 3.45−3.32 (m, 3H), 3.19−3.02 (m, 2H), 2.75 (dt, J = 21.2, 47.3
Hz, 1H), 0.98 (dd, J = 7.5, 14.2 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 147.6, 143.6, 137.0, 136.0, 133.4, 133.0, 132.6, 131.4, 130.7, 130.4,
128.7, 127.8, 127.1, 125.4, 120.9, 116.6, 87.2, 65.9, 64.2, 62.8, 52.8,
43.3, 41.4; HRMS (ESI) calcd for C39H37BrN3O5S [M + H]+
738.1637, found 738.1642.
N-(((2R,3R,4R)-1-Allyl-3-(4-bromophenyl)-4-((trityloxy)-
methyl)azetidin-2-yl)methyl)-2-nitrobenzene sulfonamide ent-
6c. Following the protocol above, 20 g of nitrile azetidine ent-5c
afforded 24 g (90%) of ent-6c: [α]2D0 −84.6 (c 0.45, CHCl3).
N-(((2S,3S,4R)-1-Allyl-3-(4-bromophenyl)-4-((trityloxy)-
methyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfonamide 6d.
Following the protocol above, 20 g of nitrile azetidine 5d afforded
23.5 g (88%) of 6d: [α]D20 −40.1 (c 0.81, CHCl3); IR νmax (film) 3332,
3056, 2869, 1533, 1489, 1447, 1394, 1357, 1264, 1166; 1H NMR (500
MHz, CDCl3) δ 8.09 (dd, J = 1.9, 7.2 Hz, 1H), 7.85 (dd, J = 1.6, 7.5
Hz, 1H), 7.74 (tt, J = 6.7, 13.1 Hz, 1H), 7.41 (t, J = 6.3 Hz, 5H), 7.31
(t, J = 7.5 Hz, 4H), 7.28−7.22 (m, 2H), 7.01 (d, J = 8.3 Hz, 1H), 6.14
(s, 1H), 5.66 (td, J = 8.9, 17.5 Hz, 1H), 5.11 (d, J = 16.8 Hz, 1H), 4.83
(d, J = 9.6 Hz, 1H), 3.43 (dd, J = 5.5, 13.0 Hz, 1H), 3.34 (dd, J = 4.9,
9.7 Hz, 1H), 3.24 (t, J = 5.8 Hz, 3H), 3.18 (dd, J = 4.0, 9.7 Hz, 1H),
3.11−2.99 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 148.1, 143.9,
138.7, 134.8, 133.4, 133.2, 132.4, 131.5, 131.1, 129.2, 128.6, 127.8,
126.9, 125.1, 120.6, 118.1, 86.8, 68.4, 68.0, 66.4, 60.4, 45.1, 41.2;
HRMS (ESI) calcd for C39H37BrN3O5S [M + H]+ 738.1637, found
738.1635.
N-(((2R,3R,4S)-1-Allyl-3-(4-bromophenyl)-4-((trityloxy)-
methyl)azetidin-2-yl)methyl)-2-nitrobenzene sulfonamide ent-
6d. Following the protocol above, 25 g of nitrile azetidine ent-5d
afforded 31 g (93%) of ent-6d. [α]2D0 = +42.6 (c 0.71, CHCl3).
N - ( ( ( 2 S , 3 R , 4 R ) - 1 - A l l y l - 3 - ( 4 - b r o m o p h e n y l ) - 4 -
(hydroxymethyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfona-
mide 7a. Azetidine 6a (14.1 g, 19.09 mmol, 1.0 equiv) was dissolved
in CH2Cl2 (191 mL) and cooled to 0 °C. Trifluoroacetic acid (14.9
mL, 191 mmol, 10 equiv) was then added over approximately 10 min
until the yellow color persisted. The mixture was neutralized by the
7196
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
organic extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure to provide the crude product, which was
deemed pure enough to continue without further purification.
The resulting sulfonate was dissolved in DMF (20 mL), and
potassium carbonate (0.557 g, 4.03 mmol) was added in one portion.
The reaction was heated to 65 °C for 1 h at which point the solvent
was removed and the resulting residue was purified by chromatog-
raphy over silica gel to provide pure product 8d (0.902 g, 94%): IR
7.36 (m, 8H), 7.36−7.18 (m, 9H), 7.03 (d, J = 8.4 Hz, 2H), 5.09 (ddd,
J = 11.4, 8.2, 4.9 Hz, 1H), 4.75 (dd, J = 7.5, 3.6 Hz, 1H), 4.32 (d, J =
17.1 Hz, 1H), 3.98 (dd, J = 8.0, 4.6 Hz, 1H), 3.80−3.62 (m, 3H), 3.40
(dd, J = 10.6, 3.5 Hz, 1H), 2.61 (dd, J = 13.1, 11.2 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 166.2, 148.0, 143.7, 134.39, 134.36, 132.3, 132.1,
131.7, 131.1, 129.4, 128.8, 128.1, 127.4, 124.7, 121.9, 87.2, 66.9, 64.3,
62.5, 48.7, 44.5, 42.9; HRMS (ESI) calcd for C38H32BrN3NaO6S [M +
Na]+ 760.1093, found 760.1097.
1
νmax (film) 2934, 1542, 1372, 1169, 578, 535; H NMR (500 MHz,
(6R,7S,8S)-7-(4-Bromophenyl)-4-((2-nitrophenyl)sulfonyl)-8-
((trityloxy)methyl)-1,4-diazabicyclo[4.2.0]octan-2-one 9d. Fol-
lowing the protocol above, 10.0 g of 6d afforded 6.07 g of 9d (61%
over 2 steps) as a white, foamy solid: [α]2D0 −90.7 (c 0.38, CHCl3); IR
νmax (film) 3058, 1673, 1544, 1490, 1448, 1419, 1370, 1170; 1H NMR
(300 MHz, CDCl3) δ 8.06 (dd, J = 7.4, 1.6 Hz, 1H), 7.84−7.68 (m,
3H), 7.45 (dd, J = 8.1, 1.8 Hz, 6H), 7.32 (d, J = 8.4 Hz, 2H), 7.30−
7.14 (m, 9H), 6.83 (d, J = 8.4 Hz, 2H), 4.63 (ddd, J = 10.6, 6.6, 4.2 Hz,
1H), 4.49−4.39 (m, 1H), 4.35−4.23 (m, 2H), 4.18 (dd, J = 12.4, 4.1
Hz, 1H), 3.87 (d, J = 16.9 Hz, 1H), 3.52 (t, J = 6.8 Hz, 1H), 3.31 (ddd,
J = 13.0, 11.6, 6.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 163.3,
143.7, 137.3, 134.4, 132.1, 132.1, 131.7, 131.5, 128.8, 128.1, 127.4,
124.7, 121.7, 88.0, 72.2, 64.8, 59.4, 48.1, 47.2, 43.2; HRMS (ESI) calcd
for C38H32BrN3NaO6S [M + Na]+ 760.1093, found 760.1085.
(6R,7R,8S)-7-(4-Bromophenyl)-8-(hydroxymethyl)-4-((2-
nitrophenyl)sulfonyl)-1,4-diazabicyclo[4.2.0]octan-2-one 10a.
To a solution of ketopiperazine 9a in CH2Cl2 (92 mL) at room
temperature was added trifluoroacetic acid (7.23 mL, 94 mmol, 10
equiv), followed by triethylsilane (1.5 mL, 9.4 mmol, 1.0 equiv). The
reaction was stirred for 15 min, after which analysis of the reaction by
LC/MS showed complete conversion of the starting material to the
product. The reaction was quenched with MeOH, and then saturated
aqueous NaHCO3 solution until bubbling completely stopped. The
layers were then separated, and the aqueous layer was extracted with
CH2Cl2 (2×). The combined organic layers were dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude residue
was purified by chromatography on silica gel using CH2Cl2/MeOH as
eluent, which provided the pure product 10a (3.4 g, 73%) as a white,
foamy solid: [α]2D0 −55.6 (c 0.30, CHCl3); IR νmax (film) 3361, 2936,
CDCl3) δ 8.14 (dd, J = 1.6, 7.5 Hz, 1H), 7.82−7.73 (m, 2H), 7.70 (dd,
J = 1.6, 7.5 Hz, 1H), 7.47 (s, 4H), 5.75 (ddd, J = 5.8, 10.9, 16.1 Hz,
1H), 5.14−5.06 (m, 2H), 3.88 (d, J = 11.0 Hz, 2H), 3.71 (s, 2H), 3.57
(d, J = 11.0 Hz, 2H), 3.06 (d, J = 5.8 Hz, 2H), 3.00 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 148.0, 139.3, 133.9, 133.8, 131.5, 131.4, 131.2,
131.1, 129.4, 124.1, 120.5, 117.0, 62.1, 47.5, 45.6, 43.3; HRMS (ESI)
calcd for C20H20BrN3O4S [M + H]+ 478.0436, found 478.0438.
(6R,7R,8S)-7-(4-Bromophenyl)-4-((2-nitrophenyl)sulfonyl)-8-
((trityloxy)methyl)-1,4-diazabicyclo[4.2.0]octan-2-one 9a. To a
solution of the nosylated amine 6a (13.2 g, 17.9 mmol, 1.0 equiv) in
EtOH (179 mL) at room temperature was added 1,3-dimethylbarbi-
turic acid (3.92 g, 25.1 mmol, 1.4 equiv) followed by Pd(PPh3)4 (1.66
g, 1.43 mmol, 0.08 equiv). Upon completion of the reaction, the
mixture was filtered through a silica gel plug, eluting with CH2Cl2/
MeOH, and the filtrate was concentrated to provide the crude amine
as a bright red, foamy solid.
The crude allyl-deprotected product was dissolved in acetonitrile
(153 mL), and Cs2CO3 (74.0 g, 227 mmol, 10.0 equiv) was added and
allowed to stir at room temperature for 30 min. Bromoacetyl chloride
(1.89 mL, 22.7 mmol, 1.0 equiv) was then added and stirred until
deemed complete via LC/MS analysis. The reaction was filtered
through Celite, and the filtrate was concentrated under reduced
pressure. The crude residue was partitioned in CH2Cl2 and water/
brine. The layers were separated, and the aqueous layer was extracted
with CH2Cl2 (2×). The combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure. The crude
material was purified by chromatography on silica gel using hexanes/
EtOAc, and again using CH2Cl2/EtOAc, which provided the pure
product 9a (6.96 g, 59% over two steps) as a white, foamy solid: [α]D20
−73.0 (c 0.29, CHCl3); IR νmax (film) 3057, 1667, 1543, 1489, 1448,
1
1644, 1541, 1358, 1166, 1034; H NMR (300 MHz, CDCl3) δ 7.99
(dd, J = 7.4, 1.7 Hz, 1H), 7.80−7.63 (m, 3H), 7.44 (d, J = 8.4 Hz, 2H),
7.12 (d, J = 8.4 Hz, 2H), 5.13−4.94 (m, 2H), 4.27 (d, J = 17.3 Hz,
1H), 4.07 (dd, J = 12.9, 9.7 Hz, 1H), 4.00 (t, J = 8.2 Hz, 1H), 3.84 (d,
J = 17.3 Hz, 1H), 3.74 (dd, J = 13.1, 4.8 Hz, 1H), 3.42−3.23 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 162.6, 148.0, 134.5, 132.3, 132.0, 131.8,
131.7, 131.4, 131.3, 124.8, 122.5, 70.5, 61.8, 60.7, 47.9, 44.8, 42.9;
HRMS (ESI) calcd for C19H19BrN3O6S [M + H]+ 496.0178, found
496.0179.
1
1423, 1369, 1169; H NMR (300 MHz, CDCl3) δ 7.96 (dd, J = 7.7,
1.5 Hz, 1H), 7.77−7.58 (m, 9H), 7.30 (d, J = 8.4 Hz, 2H), 7.23−7.12
(m, 9H), 7.06 (dd, J = 6.7, 3.0 Hz, 6H), 6.99 (d, J = 8.4 Hz, 2H),
5.13−5.01 (m, 1H), 5.00−4.88 (m, 1H), 4.18−3.98 (m, 3H), 3.73 (dd,
J = 13.1, 4.8 Hz, 1H), 3.64 (d, J = 17.1 Hz, 1H), 3.40 (t, J = 10.0 Hz,
1H), 3.23 (dd, J = 12.9, 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
160.6, 148.1, 143.3, 134.3, 132.9, 132.2, 131.8, 131.4, 131.0, 128.6,
127.9, 127.2, 124.7, 121.9, 86.9, 66.1, 61.4, 57.4, 48.0, 45.4, 42.8;
HRMS (ESI) calcd for C38H32BrN3NaO6S [M + Na]+ 760.1093,
found 760.1097.
(6S,7R,8S)-7-(4-Bromophenyl)-4-((2-nitrophenyl)sulfonyl)-8-
((trityloxy)methyl)-1,4-diazabicyclo[4.2.0]octan-2-one 9b. Fol-
lowing the protocol above, 7.3 g of 6b afforded 5.02 g of 9b (69% over
two steps) as a white, foamy solid: [α]2D0 = +72.0 (c 0.25, CHCl3); IR
νmax (film) 3057, 1668, 1543, 1490, 1448, 1415, 1370, 1170; 1H NMR
(300 MHz, CDCl3) δ 8.04 (dd, J = 7.5, 2.1 Hz, 1H), 7.72−7.54 (m,
3H), 7.31 (d, J = 8.4 Hz, 2H), 7.25−7.16 (m, 9H), 7.16−7.04 (m,
6H), 6.96 (d, J = 8.3 Hz, 2H), 5.33−5.21 (m, 1H), 4.90−4.78 (m,
1H), 4.37 (dd, J = 12.6, 4.8 Hz, 1H), 4.33 (d, J = 17.1 Hz, 1H), 3.98 (t,
J = 8.6 Hz, 1H), 3.76 (d, J = 17.0 Hz, 1H), 3.38 (dd, J = 10.7, 5.1 Hz,
1H), 3.20−3.03 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 165.3, 148.1,
143.4, 134.4, 134.2, 132.1, 131.6, 131.4, 131.3, 129.2, 128.6, 127.8,
127.1, 124.6, 121.2, 87.2, 66.4, 64.1, 61.7, 48.6, 48.4, 44.9; HRMS
(ESI) calcd for C38H32BrN3NaO6S [M + Na]+ 760.1093, found
760.1095.
(6S,7R,8S)-7-(4-Bromophenyl)-8-(hydroxymethyl)-4-((2-
nitrophenyl)sulfonyl)-1,4-diazabicyclo[4.2.0]octan-2-one 10b.
Following the protocol above, product 9b (2.71 g, 81%) was obtained
as a white powder: [α]D20 +139.3 (c 0.26, DMSO); IR νmax (film) 3419,
1667, 1548, 1362, 1171; 1H NMR (300 MHz, DMSO-d6) δ 8.14 (dd, J
= 7.7, 1.4 Hz, 1H), 8.05 (dd, J = 7.8, 1.4 Hz, 1H), 7.95 (dt, J = 7.5, 1.5
Hz, 1H), 7.88 (dt, J = 7.5, 1.5 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.26
(d, J = 8.4 Hz, 2H), 5.04−4.92 (m, 1H), 4.69−4.55 (m, 1H), 4.17−
4.05 (m, 3H), 3.68 (d, J = 16.9 Hz, 1H), 3.43 (d, J = 4.6 Hz, 2H),
3.38−3.25 (obscured, 1H); 13C NMR (75 MHz, DMSO-d6) δ 165.0,
147.6, 135.4, 135.1, 132.6, 130.9, 130.5, 130.1, 129.5, 124.3, 119.8,
67.4, 63.3, 59.5, 48.2, 46.9, 43.6; HRMS (ESI) calcd for
C19H19BrN3O6S [M + H]+ 496.0178, found 496.0170.
(6S,7S,8S)-7-(4-Bromophenyl)-8-(hydroxymethyl)-4-((2-
nitrophenyl)sulfonyl)-1,4-diazabicyclo[4.2.0]octan-2-one 10c.
Following the protocol above, product 10c (4.18 g, 72%) was
obtained as a white, foamy solid: [α]2D0 +132.2 (c 0.92, CHCl3); IR νmax
(film) 3422, 2930, 1658, 1541, 1370, 1166; 1H NMR (300 MHz,
CDCl3) δ 7.95 (dd, J = 6.9, 1.5 Hz, 1H), 7.80−7.59 (m, 3H), 7.48 (d, J
= 8.3 Hz, 2H), 7.06 (d, J = 8.3 Hz, 2H), 4.97 (ddd, J = 11.2, 8.7, 4.7
Hz, 1H), 4.78 (dd, J = 8.2, 4.5 Hz, 1H), 4.27 (d, J = 17.2 Hz, 1H),
4.08−3.92 (m, 2H), 3.85 (dd, J = 11.9, 5.0 Hz, 1H), 3.78−3.60 (m,
2H), 2.79 (br s, 1H), 2.64 (dd, J = 12.9, 11.3 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 167.6, 148.0, 134.4, 134.0, 132.4, 132.3, 131.7, 131.3,
(6S,7S,8S)-7-(4-Bromophenyl)-4-((2-nitrophenyl)sulfonyl)-8-
((trityloxy)methyl)-1,4-diazabicyclo[4.2.0]octan-2-one 9c. Fol-
lowing the protocol above, 7.35 g of 6c afforded 4.51 g of 9c (61%
over 2 steps) as a white, foamy solid: [α]2D0 +68.6 (c 1.29; CHCl3); IR
νmax (film) 3058, 1671, 1543, 1490, 1448, 1415, 1370, 1169; 1H NMR
(300 MHz, CDCl3) δ 8.02−7.91 (m, 1H), 7.70−7.52 (m, 3H), 7.52−
7197
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
129.4, 124.7, 122.0, 69.0, 63.7, 62.6, 48.4, 44.6, 41.8; HRMS (ESI)
calcd for C19H19BrN3O6S [M + H]+ 496.0178, found 496.0182.
(6R,7S,8S)-7-(4-Bromophenyl)-8-(hydroxymethyl)-4-((2-
nitrophenyl)sulfonyl)-1,4-diazabicyclo[4.2.0]octan-2-one 10d.
Following the protocol above, product 10d (4.0 g, 73%) was obtained
as a white, foamy solid: [α]2D0 −104.5 (c 0.35, CHCl3); IR νmax (film)
13C NMR (75 MHz, CDCl3) δ 148.0, 143.7, 137.0, 135.8, 133.6, 132.4,
131.7, 131.4, 131.1, 130.3, 128.7, 127.7, 127.0, 124.3, 120.5, 119.7,
116.5, 87.1, 64.8, 64.4, 60.8, 52.7, 51.1, 48.7, 43.3; HRMS (ESI) calcd
for C42H41BrN3O5S [M + H]+ 778.1950, found 778.1936.
A portion of alllyl intermediate (5.0 g, 6.42 mmol, 1.0 equiv) was
then reacted with Grubbs catalyst I (1.06 g, 1.28 mmol, 0.20 equiv) in
the presence of styrene (2.94 mL, 25.7 mmol, 4.0 equiv) in DCE (321
mL) to provide 11b (2.46 g, 51%) as a light brown foamy solid: [α]D20
+81.1 (c 0.26, CHCl3); IR νmax (film) 3031, 2920, 1541, 1488, 1448,
1345, 1161, 1071; 1H NMR (300 MHz, CDCl3) δ 8.09−7.95 (m, 1H),
7.73−7.53 (m, 3H), 7.32 (d, J = 8.3 Hz, 2H), 7.25 (s, 15H), 7.12 (d, J
= 8.4 Hz, 2H), 6.12−5.84 (m, 2H), 4.11−3.85 (m, 4H), 3.84−3.63 (m,
2H), 3.51 (dd, J = 12.3, 8.5 Hz, 1H), 3.27 (dd, J = 8.1, 3.7 Hz, 1H),
3.14 (dd, J = 12.5, 6.4 Hz, 1H), 3.05 (dd, J = 9.6, 5.6 Hz, 1H), 2.72
(dd, J = 9.4, 7.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 147.9, 143.8,
137.0, 133.7, 133.2, 131.8, 131.6, 131.3, 131.0, 130.5, 129.0, 128.6,
127.8, 127.0, 124.2, 120.7, 86.8, 68.2, 64.2, 62.1, 50.3, 46.1, 44.4, 42.7;
HRMS (ESI) calcd for C40H37BrN3O5S [M + H]+ 750.1637, found
750.1627.
1
3389, 2923, 1645, 1541, 1360, 1169; H NMR (300 MHz, CDCl3) δ
8.01 (dd, J = 6.9, 1.5 Hz, 1H), 7.86−7.62 (m, 3H), 7.49 (d, J = 8.4 Hz,
2H), 7.12 (d, J = 8.4 Hz, 2H), 4.80−4.62 (m, 2H), 4.34−4.17 (m,
2H), 4.07 (dd, J = 12.8, 2.2 Hz, 1H), 3.85−3.67 (m, 2H), 3.56 (t, J =
7.5 Hz, 1H), 3.17 (dd, J = 12.7, 10.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 164.5, 148.1, 136.1, 134.5, 132.4, 132.3, 131.5, 131.5, 128.8,
124.7, 122.1, 74.6, 65.5, 62.8, 48.1, 47.6, 44.1; HRMS (ESI) calcd for
C19H19BrN3O6S [M + H]+ 496.0178, found 496.0183.
(8R,9R,10S,Z)-9-(4-Bromophenyl)-6-((2-nitrophenyl)-
sulfonyl)-10-((trityloxy)methyl)-1,6-diazabicyclo[6.2.0]dec-3-
ene 11a. To a solution of the nosylated amine 6a (16.5 g, 22.34
mmol, 1.0 equiv) in DMF (45 mL) at 0 °C were added potassium
carbonate (4.63 g, 33.50 mmol, 1.5 equiv) and allyl bromide (2.08 mL,
24.57 mmol, 1.1 equiv). The reaction was stirred for 2 h, slowly
warming to room temperature. Analysis of the reaction by LC/MS
indicated complete disappearance of the starting material and the
formation of a new product. The reaction mixture was quenched with
water and extracted three times with EtOAc. The combined organic
extracts were dried over MgSO4, filtered, and concentrated under
reduced pressure to provide the crude product, which was purified by
chromatography on silica gel using hexanes/EtOAc to obtain allylated
compound (14.72 g, 85%): [α]2D0 +24.9 (c 0.66, CHCl3); IR νmax (film)
3057, 2855, 1542, 1486, 1448, 1353, 1160, 1072; 1H NMR (300 MHz,
CDCl3) δ 7.68−7.49 (m, 5H), 7.33 (d, J = 8.3 Hz, 2H), 7.28−7.12 (m,
16H), 5.72−5.59 (m, 1H), 5.52−5.39 (m, 1H), 5.10 (d, J = 17.0 Hz,
1H), 5.02 (d, J = 10.2 Hz, 1H), 4.95 (d, J = 10.2 Hz, 1H), 4.82 (d, J =
17.1 Hz, 1H), 3.84 (dd, J = 16.1, 5.7 Hz, 1H), 3.76 (dd, J = 7.4, 7.4 Hz,
1H), 3.60−3.53 (m, 2H), 3.48 (dd, J = 16.2, 6.6 Hz, 1H), 3.28−3.14
(m, 3H), 3.05 (dd, J = 9.2, 4.7 Hz, 1H), 2.96 (dd, J = 13.3, 7.2 Hz,
1H), 2.86 (dd, J = 9.0, 9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
147.9, 143.8, 135.1, 133.4, 132.7, 132.6, 131.1, 128.4, 127.6, 126.7,
124.1, 120.7, 119.0, 117.8, 86.1, 66.6, 66.2, 60.8, 60.6, 51.6, 45.3, 44.2;
HRMS (ESI) calcd for C42H41BrN3O5S [M + H]+ 778.1950, found
778.1948.
(8S,9S,10S,Z)-9-(4-Bromophenyl)-6-((2-nitrophenyl)-
sulfonyl)-10-((trityloxy)methyl)-1,6-diazabicyclo[6.2.0]dec-3-
ene 11c. Following the protocol above, 22.0 g of nosyl amine 6b
afforded 20.99 g (91%) of the allylated product: [α]2D0 −22.8 (c 0.11,
CHCl3); IR νmax (film) 3060, 2890, 1541, 1488, 1447, 1352, 1160,
1
1070; H NMR (300 MHz, CDCl3) δ 7.61 (td, J = 7.3, 1.4 Hz, 2H),
7.53 (d, J = 7.5 Hz, 2H), 7.46 (d, J = 8.1 Hz, 8H), 7.38−7.18 (m,
11H), 5.72−5.54 (m, 1H), 5.54−5.38 (m, 1H), 5.04 (d, J = 10.2 Hz,
1H), 4.99−4.79 (m, 3H), 4.20 (dd, J = 9.8, 5.1 Hz, 1H), 3.84 (dd, J =
16.1, 5.8 Hz, 1H), 3.63 (d, J = 3.1 Hz, 1H), 3.59−3.47 (m, 2H), 3.47−
3.35 (m, 2H), 3.28 (dd, J = 15.1, 6.0 Hz, 1H), 3.20−3.04 (m, 2H),
2.96 (dd, J = 15.3, 7.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 148.1,
143.9, 139.3, 136.3, 133.4, 133.4, 132.9, 131.7, 131.6, 131.3, 131.1,
129.0, 128.0, 127.3, 124.2, 120.8, 119.1, 115.7, 87.4, 67.0, 65.5, 61.9,
52.1, 51.6, 47.3, 43.0; HRMS (ESI) calcd for C42H41BrN3O5S [M +
H]+ 778.1950, found 778.1962.
This product (22.48 g, 28.90 mmol, 1.0 equiv) was then reacted
with Grubbs catalyst I (5.94 g, 7.22 mmol, 0.25 equiv) in benzene (577
mL) to provide 11c (13.10 g, 60.5%) as a light brown foamy solid:
[α]2D0 −6.54 (c 0.15, CHCl3); IR νmax (film) 3027, 2917, 1542, 1489,
1
1448, 1346, 1161, 1061; H NMR (300 MHz, CDCl3) δ 7.72 (d, J =
This material (16.06 g, 20.62 mmol, 1.0 equiv) was dissolved in
benzene and degassed for 30 min. Grubbs catalyst I (4.24 g, 5.16
mmol, 0.25 equiv) was then added, and the reaction was stirred for 24
h at 50 °C, after which analysis of the reaction by LC/MS indicated
complete disappearance of the starting material. The solvent was
evaporated under reduced pressure and purified by flash chromatog-
raphy on silica gel using hexanes/EtOAc, which provided 11a (11.77 g,
76%) as a light brown foamy solid: [α]2D0 +89.7 (c 1.0, CHCl3); IR νmax
(film) 3057, 3030, 2927, 2865, 1543, 1488, 1448, 1352, 1162, 1073;
1H NMR (300 MHz, CDCl3) δ 7.89 (dd, J = 6.9, 2.1 Hz, 1H), 7.76−
7.7 Hz, 1H), 7.68−7.49 (m, 3H), 7.50−7.35 (m, 8H), 7.35−7.21 (m,
9H), 7.07 (d, J = 8.3 Hz, 2H), 6.07−5.87 (m, 2H), 4.20−3.98 (m,
2H), 3.87 (dd, J = 13.1, 5.5 Hz, 1H), 3.73 (dd, J = 15.3, 6.2 Hz, 1H),
3.61 (t, J = 8.2 Hz, 1H), 3.52−3.38 (m, 2H), 3.38−3.26 (m, 2H), 3.09
(dt, J = 21.4, 11.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 147.9,
144.0, 136.5, 133.5, 133.0, 131.7, 131.6, 131.4, 130.9, 130.0, 129.4,
128.8, 128.0, 127.2, 124.2, 120.7, 87.2, 66.6, 66.0, 65.3, 47.6, 46.3, 44.7,
41.8; HRMS (ESI) calcd for C40H37BrN3O5S [M + H]+ 750.1637,
found 750.1641.
(8R,9S,10S,Z)-9-(4-Bromophenyl)-6-((2-nitrophenyl)-
sulfonyl)-10-((trityloxy)methyl)-1,6-diazabicyclo[6.2.0]dec-3-
ene 11d. Following the protocol above, 23.4 g of nosyl amine 6d
afforded 22.42 g (91%) of the allylated product: [α]2D0 −18.1 (c 1.0,
CHCl3); IR νmax (film) 3058, 2911, 2863, 1542, 1490, 1448, 1353,
1161, 1072; 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 7.5 Hz, 1H),
7.68−7.56 (m, 3H), 7.45−7.40 (m, 8H), 7.32−7.25 (m, 9H), 7.12 (d, J
= 8.3 Hz, 2H), 5.87−5.73 (m, 1H), 5.57−5.44 (m, 1H), 5.20 (d, J =
17.1 Hz, 1H), 5.14−5.05 (m, 3H), 4.12 (dd, J = 16.4, 6.6 Hz, 1H),
3.97 (dd, J = 16.1, 6.0 Hz, 1H), 3.54 (d, J = 4.4, 2H), 3.42−3.08 (m,
7H); 13C NMR (75 MHz, CDCl3) δ 148.3, 144.4, 139.7, 135.3, 134.2,
133.7, 132.6, 131.9, 131.7, 131.4, 129.9, 129.1, 128.1, 127.3, 124.4,
120.7, 119.7, 118.4, 87.0, 69.7, 68.4, 67.0, 61.2, 51.5, 50.7, 44.0; HRMS
(ESI) calcd for C42H41BrN3O5S [M + H]+ 778.1950, found 778.1960.
This product (22.3 g, 28.60 mmol, 1.0 equiv) was then reacted with
Grubbs catalyst I (5.89 g, 7.16 mmol, 0.25 equiv) in benzene (573
mL) to provide product 11d (16.43 g, 76%) as a light brown foamy
solid: [α]2D0 −22.5 (c 1.11, CHCl3); IR νmax (film) 3055, 3030, 2908,
2859, 1543, 1489, 1448, 1348, 1161, 1071; 1H NMR (300 MHz,
CDCl3) δ 8.02 (dd, J = 7.1, 1.8 Hz, 1H), 7.73−7.62 (m, 3H), 7.49−
7.39 (m, 9H), 7.32−7.19 (m, 8H), 7.07 (d, J = 8.3 Hz, 2H), 5.90−5.81
7.50 (m, 3H), 7.39−7.06 (m, 19H), 5.89−5.82 (m, 1H), 5.75−5.66
(m, 1H), 4.10 (dd, J = 15.2, 6.9 Hz, 1H), 3.98 (dd, J = 14.6, 9.2 Hz,
1H), 3.64−3.58 (m, 3H), 3.48 (dd, J = 15.3, 6.3 Hz, 1H), 3.26 (d, J =
13.8 Hz, 1H), 3.21−3.01 (m, 3H), 2.92 (dd, J = 9.2, 5.9 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 148.0, 143.7, 134.8, 133.4, 133.0, 132.9,
132.1, 131.6, 131.1, 130.8, 128.5, 127.7, 126.9, 124.8, 124.1, 120.9,
86.5, 77.5, 77.0, 76.6, 67.0, 66.0, 61.9, 54.9, 49.5, 43.5, 43.2; HRMS
(ESI) calcd for C40H37BrN3O5S [M + H]+ 750.1637, found 750.1639.
(8S,9R,10S,Z)-9-(4-Bromophenyl)-6-((2-nitrophenyl)-
sulfonyl)-10-((trityloxy)methyl)-1,6-diazabicyclo[6.2.0]dec-3-
ene 11b. Following the protocol above, 22.0 g of nosyl amine 6b
afforded 20.99 g (91%) of the allylated product: [α]2D0 +20.1 (c 0.26,
CHCl3); IR νmax (film) 3058, 2916, 1542, 1489, 1448, 1353, 1162,
1
1071; H NMR (300 MHz, CDCl3) δ 7.94 (d, J = 7.8 Hz, 1H), 7.58
(td, J = 7.1, 3.5 Hz, 3H), 7.30 (d, J = 8.3 Hz, 2H), 7.26−7.17 (m, 9H),
7.14 (dd, J = 8.2, 5.4 Hz, 6H), 7.01 (d, J = 8.3 Hz, 2H), 5.72−5.43 (m,
2H), 5.17−5.05 (m, 2H), 4.99 (d, J = 18.1 Hz, 1H), 4.94 (d, J = 11.1
Hz, 1H), 4.05 (dd, J = 13.2, 6.0 Hz, 1H), 3.97−3.84 (m, 3H), 3.69−
3.50 (m, 3H), 3.24 (dd, J = 14.6, 5.6 Hz, 1H), 3.16 (dd, J = 9.9, 5.0 Hz,
1H), 3.06 (dd, J = 14.5, 5.9 Hz, 1H), 2.86 (dd, J = 9.9, 6.6 Hz, 1H);
7198
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
(m, 1H), 5.69−5.54 (m, 1H), 4.44 (dd, J = 14.6, 7.9 Hz, 1H), 3.96
(dd, J = 14.6, 8.0 Hz, 1H), 3.86 (d, J = 13.9 Hz, 2H), 3.49−3.36 (m,
2H), 3.29−3.18 (m, 3H), 3.11 (dd, J = 13.5, 10.3 Hz, 1H), 2.97 (dd, J
= 6.9, 6.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 148.5, 144.3, 139.4,
133.7, 133.6, 132.0, 131.9, 131.2, 129.4, 129.0, 128.1, 127.4, 125.3,
124.5, 121.0, 87.0, 71.5, 70.6, 67.2, 59.4, 54.7, 44.8, 42.5; HRMS (ESI)
calcd for C40H37BrN3O5S [M + H]+ 750.1637, found 750.1635.
((8R,9R,10S)-9-(4-Bromophenyl)-6-((2-nitrophenyl)sulfonyl)-
1,6-diazabicyclo[6.2.0] decan-10-yl) methanol 12a. Compound
11a (10.0 g, 13.3 mmol, 1.0 equiv) was dissolved in CH2Cl2 (133 mL)
and cooled to 0 °C. Trifluoroacetic acid (10.3 mL, 133 mmol, 10.0
equiv) was added dropwise, and the reaction was stirred for 1−2 h.
Analysis of the reaction by LC/MS indicated complete disappearance
of the starting material and the formation of a new product. The
reaction mixture was quenched with a saturated solution of NaHCO3
and extracted three times with EtOAc. The combined organic extracts
were dried over MgSO4, filtered, and concentrated under reduced
pressure. The resulting material was purified by chromatography on
silica gel using hexanes/EtOAc to provide the primary alcohol (5.8 g,
86%).
steps) as a light yellow foamy solid: [α]2D0 −112.9 (c 0.185, CHCl3); IR
1
νmax (film) 3426, 2931, 1542, 1373, 1340, 1160; H NMR (300 MHz,
CDCl3) δ 7.92 (dd, 6.6, J = 2.5 Hz, 1H), 7.76−7.56 (m, 3H), 7.45 (d, J
= 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 3.87−3.76 (m, 2H), 3.67−
3.58 (m, 2H), 3.44 (d, J = 12.0 Hz, 1H), 3.36−3.26 (m, 1H), 3.18−
3.16 (m, 2H), 2.97−2.89 (m, 2H), 2.64−2.60 (m, 2H), 2.05−1.92 (m,
2H), 1.74−1.59 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 148.6, 139.0,
133.8, 133.2, 132.1, 131.9, 131.0, 129.4, 128.7, 124.6, 121.2, 73.3, 67.5,
60.8, 56.3, 55.9, 50.6, 40.2, 28.4, 24.1; HRMS (ESI) calcd for
C21H25BrN3O5S [M + H]+ 510.0698, found 510.0681.
(2S,3S,4R)-1-Allyl-2-(trityloxymethyl)-3-para-bromophenyl-
4-cyano-4-(tosyloxymethyl)azetidine 13a. To a freshly prepared
solution of LiTMP (0.4 M in THF, 270.0 mL, 109.0 mmol, 3.0 equiv)
was added dropwise at −78 °C via addition funnel and over 30 to 40
min a solution of azetidine 5a (20.0 g, 36.4 mmol, 1.0 equiv) in dry
THF (100 mL). The mixture was stirred for 2 h at −78 °C, and then
solid benzotriazomethanol (BTM) (10.9 g, 72.8 mmol, 2.0 equiv) was
added in small portions every 15−20 min, over 1.5 h. The reaction
mixture was allowed to warm to room temperature overnight and was
quenched with a saturated solution of NH4Cl. The aqueous layer was
separated and extracted with EtOAc. The combined organic phases
were washed with brine, dried over MgSO4, filtered, and concentrated
to afford a crude material that was quickly purified on silica gel using
hexanes/EtOAc to afford the desired alcohol (15.7 g, 27.1 mmol, 74%
yield) as a colorless foam. Only a single stereoisomer was obtained:
[α]2D0 +56.9 (c 1.5, CHCl3); mp 74.8−77.56 °C; IR νmax (film) 3483,
To a solution of the alcohol described above (5 g, 9.84 mmol, 1.0
equiv) and triethylamine (5.5 mL, 39.3 mmol, 4.0 equiv) in dry THF
(98 mL) was added 2-nitrobenzenesulfonylhydrazide (NBSH) (6.4 g,
29.5 mmol, 3.0 equiv), and the reaction was heated at 40 °C for 6 h.
The reaction mixture was quenched with a saturated solution of
NaHCO3 and extracted three times with diethyl ether. The combined
organic extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure to provide the crude product, which was
purified by chromatography on silica gel using hexanes/EtOAc to
provide pure 12a (4.0 g, 80%): [α]2D0 +27.4 (c 0.255, CHCl3); IR νmax
(film) 3380, 2937, 1541, 1372, 1340, 1160; 1H NMR (300 MHz,
CDCl3) δ 7.77 (dd, J = 7.0, 2.0 Hz, 1H), 7.68−7.51 (m, 3H), 7.42 (d, J
= 8.3 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 3.83 (ddd, J = 14.5, 10.5, 4.7
Hz, 1H), 3.72−3.64 (m, 2H), 3.58−3.48 (m, 3H), 3.24 (d, J = 13.8
Hz, 1H), 3.12−2.99 (m, 2H), 2.91 (dd, J = 14.5, 9.7 Hz, 1H), 2.60−
2.39 (br m, 1H), 1.97−1.75 (m, 3H), 1.63 (br m, 2H); 13C NMR (75
MHz, CDCl3) δ 148.2, 133.3, 132.3, 131.6, 131.3, 130.2, 128.3, 124.1,
121.1, 68.2, 65.9, 60.9, 58.0, 55.1, 50.7, 42.1, 28.1, 25.4; HRMS (ESI)
calcd for C21H25BrN3O5S [M + H]+ 510.0698, found 510.0705.
((8S,9R,10S)-9-(4-Bromophenyl)-6-((2-nitrophenyl)sulfonyl)-
1,6-diazabicyclo[6.2.0]decan-10-yl)methanol 12b. Following the
protocol above, compound 11b afforded 3.17 g of 7b (73% over 2
steps) as a light yellow foamy solid: [α]2D0 +191.5 (c 0.26, CHCl3); IR
1
2996, 2958, 1412, 1139, 1073, 944; H NMR (300 MHz, CDCl3) δ
7.38 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 7.24−7.18 (m, 9H),
7.18−7.12 (m, 6H), 5.74 (ddt, J = 16.7, 10.1, 6.4 Hz, 1H), 5.20 (dd, J
= 17.2, 1.3 Hz, 1H), 5.05 (d, J = 10.1 Hz, 1H), 4.15−3.93 (m, 3H),
3.83 (d, J = 8.0 Hz, 1H), 3.52 (dd, J = 13.8, 6.0 Hz, 1H), 3.31−3.14
(m, 2H), 2.98 (dd, J = 9.5, 7.7 Hz, 1H), 2.20 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 143.5, 134.3, 133.4, 131.3, 128.4, 127.9, 127.7, 126.9,
121.9, 118.4, 118.2, 86.6, 66.9, 64.6, 62.8, 61.1, 52.5, 45.0; HRMS
(ESI) calcd for C34H32BrN2O2 [M + H]+ 579.1647, found 579.1643.
A portion of the primary alcohol described above (3.5 g, 6.0 mmol,
1.0 equiv) was taken up in dry THF (60 mL) and cooled to −78 °C.
LiHMDS (1.0 M in THF, 6.6 mL, 6.6 mmol, 1.1 equiv) was added
dropwise via an addition funnel. After 40 min, a solution of p-
toluenesulfonyl chloride (1.3 g, 6.6 mmol, 1.1 equiv) in dry THF (10
mL) was quickly syringed into the mixture, and the temperature was
slowly raised to room temperature, allowing for complete conversion
of the starting material. The reaction was quenched with saturated
NH4Cl solution, and the layers were separated. The organic phase was
washed with brine, dried over MgSO4, filtered, and concentrated.
Purification on silica gel using hexanes/EtOAc afforded the sulfonate
ester 13a (3.8 g, 5.2 mmol, 85% yield): [α]2D0 +45.4 (c 1.7, CHCl3); IR
1
νmax (film) 3388, 2927, 1541, 1372, 1340, 1160; H NMR (300 MHz,
CDCl3) δ 7.90 (dd, J = 6.9, 2.4 Hz, 1H), 7.71−7.56 (m, 3H), 7.47 (d, J
= 8.4 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 4.23 (t, J = 8.4 Hz, 1H),
3.98−3.89 (m, 1H), 3.88−3.80 (m, 2H), 3.75 (dd, J = 12.3, 4.4 Hz,
1H), 3.62 (dd, J = 12.3, 4.4 Hz, 1H), 3.51 (t, J = 8.5 Hz, 1H), 3.25−
3.10 (m, 1H), 3.03 (dd, J = 14.3, 9.9 Hz, 1H), 2.96−2.84 (m, 2H),
1.87 (br s, 3H), 1.62 (br s, 2H); 13C NMR (75 MHz, CDCl3) δ 148.3,
135.9, 133.5, 133.2, 132.0, 131.8, 130.7, 129.6, 124.4, 121.0, 67.3, 65.8,
60.4, 55.6, 50.4, 49.4, 41.2, 28.1, 25.6; HRMS (ESI) calcd for
C21H25BrN3O5S [M + H]+ 510.0698, found 510.0691.
((8S,9S,10S)-9-(4-Bromophenyl)-6-((2-nitrophenyl)sulfonyl)-
1,6-diazabicyclo[6.2.0]decan-10-yl)methanol 12c. Following the
protocol above, 11c afforded 7.60 g of 12c (7.60 g, 76% over 2 steps)
as a light yellow foamy solid: [α]2D0 +29.2 (c 0.205, CHCl3); IR νmax
(film) 3387, 2931, 1541, 1371, 1342, 1160; 1H NMR (300 MHz,
CDCl3) δ 7.70 (dd, J = 7.5, 1.5 Hz, 1H), 7.67−7.49 (m, 3H), 7.44 (d, J
= 8.3 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 4.11 (dt, J = 10.5, 1.2 Hz,
1H), 3.93−3.61 (m, 5H), 3.15 (d, J = 14.0 Hz, 1H), 3.04 (ddd, J =
14.8, 7.5, 3.8 Hz, 1H), 2.97−2.80 (m, 2H), 2.74 (dd, J = 14.8, 10.4 Hz,
1H), 2.27 (br s, 1H), 1.95−1.69 (m, 3H), 1.69−1.49 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 148.2, 137.1, 133.4, 133.0, 131.8, 131.6,
130.4, 124.3, 120.8, 67.3, 65.2, 61.5, 50.8, 49.1, 47.8, 40.0, 27.5, 25.6;
HRMS (ESI) calcd for C21H25BrN3O5S [M + H]+ 510.0698, found
510.0694.
1
νmax (film) 3056, 2930, 2870, 1489, 1369, 1177, 1074, 993; H NMR
(300 MHz, CDCl3) δ 7.86 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.1 Hz,
2H), 7.36 (d, J = 8.5 Hz, 2H), 7.24−7.17 (m, 11H), 7.15−7.09 (m,
6H), 5.66 (ddt, J = 16.7, 10.0, 6.4 Hz, 1H), 5.06 (dd, J = 17.2, 1.3 Hz,
1H), 4.99 (d, J = 11.2 Hz, 1H), 4.42 (s, 2H), 4.01 (app td, J = 7.8, 5.5
Hz, 1H), 3.70 (d, J = 8.0 Hz, 1H), 3.39 (dd, J = 13.7, 6.8 Hz, 1H), 3.21
(dd, J = 13.7, 6.1 Hz, 1H), 3.12 (dd, J = 9.6, 5.4 Hz, 1H), 2.87 (dd, J =
9.5, 7.9 Hz, 1H), 2.47 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 145.8,
143.4, 133.7, 132.4, 131.8, 131.4, 131.3, 130.1, 128.3, 128.1, 127.7,
126.9, 122.3, 118.8, 116.5, 86.6, 67.7, 64.4, 63.8, 61.2, 52.8, 46.0, 21.7;
HRMS (ESI) calcd for C41H38BrN2O4S [M + H]+ 733.1736, found
733.1730.
(2R,3R,4S)-1-Allyl-2-(trityloxymethyl)-3-para-bromophenyl-
4-cyano-4-(tosyloxymethyl)azetidine ent-13a. Following the
above protocol, 8.3 g of ent-5a afforded 8.8 g of ent-13a (84%):
[α]2D0 −39.8 (c 1.3, CHCl3).
((2S,3S)-1-Allyl-3-(4-bromophenyl)-6-((2-nitrophenyl)-
sulfonyl)-1,6-diazaspiro[3.3]heptan-2-yl)methanol 14a. A 250
mL round-bottom flask was charged with a solution of nitrile 13a (3.0
g, 4.1 mmol, 1.0 equiv) in dry CH2Cl2 (41 mL). At −78 °C, neat
DIBAL (3.7 mL, 20.5 mmol, 5.0 equiv) was added dropwise to the
mixture via syringe. The reaction was kept at this temperature until
complete conversion of the starting material (30 to 45 min, LC/MS
((8R,9S,10S)-9-(4-Bromophenyl)-6-((2-nitrophenyl)sulfonyl)-
1,6-diazabicyclo[6.2.0] decan-10-yl)methanol 12d. Following
the protocol above, 11d afforded 7.43 g of 12d (7.43 g, 65% over 2
7199
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
analysis). A careful addition of dry MeOH (5 mL) was done in order
to quench the reaction mixture, followed by Rochelle’s salt solution
(50 mL). The mixture was stirred at room temperature overnight. The
layers were separated, and the aqueous phase was extracted with
CH2Cl2. The combined organic layers were washed with brine, dried
over MgSO4, filtered, and concentrated to dryness and taken crude to
the next step.
The primary amine was then dissolved in dry CH2Cl2 (41 mL), and
triethylamine (1.1 mL, 8.2 mmol, 2.0 equiv) was quickly added to the
mixture. At 0 °C, nosyl chloride (1.0 g, 4.5 mmol, 1.1 equiv) was
added in one portion and the reaction was stirred for 3 h at room
temperature, resulting in partial cyclization of the nosylated amine.
The mixture was washed with saturated NaHCO3 solution, and the
phases were separated. After extraction of the aqueous phase with
CH2Cl2, the combined organic layers were dried over MgSO4, filtered,
and concentrated.
The nosylated material dissolved in acetonitrile (36 mL) and
K2CO3 (1.5 g, 10.8 mmol, 3.0 equiv) was added, and the mixture was
stirred at 50 °C until complete cyclization of the intermediate as judge
by LC/MS analysis (8 h). Water was then added, and the mixture was
extracted twice with EtOAc. The combined organic fractions were
washed with brine and dried over MgSO4. After filtration and removal
of the solvents in vacuo, the crude was purified by chromatography on
silica gel using hexanes/EtOAc to afford the spiroazetidine 14a (2.1 g,
2.8 mmol, 68% yield over three steps) as a slightly yellow foam: [α]D20
+58.2 (c 1.0, CHCl3); IR νmax (film) 3026, 2870, 1544, 1488, 1368,
1169, 1073, 748; 1H NMR (300 MHz, CDCl3) δ 7.97−7.88 (m, 1H),
7.69−7.59 (m, 3H), 7.32 (d, J = 8.4 Hz, 2H), 7.20−7.14 (m, 9H),
7.13−7.08 (m, 6H), 7.06 (d, J = 8.4 Hz, 2H), 5.61 (ddt, J = 16.8, 10.2,
6.5 Hz, 1H), 5.01 (d, J = 17.1 Hz, 1H), 4.80 (d, J = 8.6 Hz, 2H), 4.12
(d, J = 8.9 Hz, 1H), 3.92 (d, J = 9.3 Hz, 1H), 3.75 (d, J = 9.3 Hz, 1H),
3.70 (dd, J = 8.1, 4.7 Hz, 1H), 3.61 (d, J = 7.6 Hz, 1H), 3.27 (dd, J =
13.3, 6.7 Hz, 1H), 3.12 (dd, J = 13.3, 6.3 Hz, 1H), 2.99 (dd, J = 9.3, 4.8
Hz, 1H), 2.71 (app t, J = 8.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
148.3, 143.6, 134.9, 133.6, 131.7, 131.3, 131.2, 130.7, 129.6, 128.3,
127.6, 126.8, 124.1, 121.1, 117.9, 86.2, 64.7, 64.3, 61.1, 60.7, 57.8, 54.2,
49.9; HRMS (ESI) calcd for C40H37BrN3O5S [M + H]+ 750.1637,
found 750.1654.
protocol above, 3.3 g of ent-15a was obtained from 6.5 g of ent-14a
(75% over 2 steps): [α]2D0 −65.9 (c 1.1, CHCl3).
((3R,6S,7R)-5-Allyl-7-(4-bromophenyl)-1-((2-nitrophenyl)-
sulfonyl)-1,5-diazaspiro [2.4]heptan-6-yl)methanol 16. Applica-
tion of the cyclization sequence described above to 13c as starting
material (4.7 g, 8.6 mmol) led to the formation of spiropyrrolidino
aziridine 16 (358 mg, 0.7 mmol) with 8.2% yield over five steps: [α]D21
+50.5 (c 1.1, CHCl3); mp 82.1−87.0 °C IR νmax (film) 3343, 2921,
1
2865, 1542, 1367, 1333, 1164; H NMR (300 MHz, CDCl3) δ 7.96−
7.89 (m, 1H), 7.70−7.62 (m, 2H), 7.62−7.56 (m, 1H), 7.42 (d, J = 8.4
Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 5.90 (dddd, J = 15.3, 10.1, 7.7, 5.2
Hz, 1H), 5.29 (d, J = 16.2 Hz, 1H), 5.19 (d, J = 10.2 Hz, 1H), 3.78
(dd, J = 11.8, 2.6 Hz, 1H), 3.66−3.50 (m, 2H), 3.59 (d, J = 7.3 Hz,
1H), 3.36 (m, 2H), 3.10 (s, 1H), 3.03 (dd, J = 13.6, 7.8 Hz, 1H), 2.87
(d, J = 9.0 Hz, 1H), 2.54 (d, J = 9.6 Hz, 1H), 2.43 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 148.2, 136.7, 134.2, 134.1, 132.7, 132.0, 131.5,
131.2, 130.8, 124.0, 121.2, 118.4, 72.5, 57.8, 56.6, 56.0, 55.7, 50.7, 42.6;
HRMS (ESI) calcd for C21H23BrN3O5S [M + H]+ 508.0542, found
508.0551.
(2S,3S,4R)-1-tert-Butyloxycarbonyl-2-(trityloxymethyl)-3-
para-bromo-phenyl-4-cyano azetidine 17. A 250 mL round-
bottom flask was charged with a solution of N-allyl azetidine 5d (4.7 g,
8.9 mmol) in 85 mL of CH2Cl2/EtOH = 1:2. N-Methyl barbituric acid
(2.0 g, 12.8 mmol, 1.5 equiv) was added in one portion at room
temperature, followed by Pd(PPh3)4 (0.5 g, 0.4 mmol, 0.05 equiv).
The mixture was stirred at 40 °C for 72 h. The reaction was monitored
by LC/MS and after completion, the solvents were removed in vacuo,
and the crude residue was taken in CH2Cl2 (100 mL). The
temperature was set to 0 °C, and Boc2O (2.8 g, 12.8 mmol, 1.5
equiv) was added. The reaction was stirred at room temperature
overnight and was monitored by LC/MS. After evaporation of the
solvent, the crude was purified on silica gel (hexanes/EtOAc = 85:15)
to afford N-Boc azetidine 17 (4.7 g, 7.7 mmol, 90% yield over two
steps) as a colorless foam: [α]2D0 −18.7 (c 1.0, CHCl3); IR νmax (film)
3056, 2926, 1710, 1367, 1149, 1074, 1010; 1H NMR (300 MHz,
CDCl3) δ 7.45−7.34 (m, 8H), 7.28−7.12 (m, 9H), 7.00 (d, J = 8.4 Hz,
2H), 4.57 (d, J = 6.6 Hz, 1H), 4.15 (s, 1H), 3.95 (app t, J = 6.5 Hz,
1H), 3.56 (dd, J = 4.9, 10.4 Hz, 1H), 3.21 (dd, J = 2.8, 10.4 Hz, 1H),
1.40 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 155.3, 143.6, 136.3,
132.2, 128.6, 128.5, 127.9, 127.2, 122.1, 117.4, 86.9, 82.0, 67.3, 63.1,
51.8, 42.3, 28.2; HRMS (ESI) calcd for C35H33BrN2NaO3 [M + Na]+
631.1572, found 631.1574.
(2R,3R)-1-Allyl-2-(trityloxymethyl)-3-para-bromophenyl-6-
ortho-nosyl-1,6-diazaspiro[3.3]heptane ent-14a. Following the
above protocol, 8.8 g of ent-13a afforded 6.5 g of ent-14a (72%): [α]D20
−48.0 (c 1.8, CHCl3).
(2R,3R,4S)-1-tert-Butyloxycarbonyl-2-(trityloxymethyl)-3-
para-bromo-phenyl-4-cyano azetidine ent-17. Following the
general protocol described above, 40.0 g of N-allyl azetidine ent-5d
afforded 42.5 g (96%) of azetidine ent-17: [α]2D0 +21.4 (c 1.2, CHCl3).
(2S,3R)-1-tert-Butyloxycarbonyl-2-(trityloxymethyl)-3-para-
bromophenyl)-4-cyano-4-(tosyloxymethyl) azetidine 18. To a
freshly prepared solution of LDA in anhydrous THF (made at 0 °C
using 10.0 mL, 70.2 mmol, 3.0 equiv of DIPA in 50 mL of THF and
43.0 mL, 69.9 mmol, 3.0 equiv of n-BuLi 1.6 M in hexanes) was added
dropwise at −78 °C via addition funnel and over 30 to 40 min a
solution of N-Boc azetidine (14.1 g, 23.1 mmol, 1.0 equiv) in 150 mL
of dry THF. The mixture was stirred for 2 h at −78 °C, and then solid
benzotriazomethanol (BTM) was added in small portions every 15−
20 min, over 1.5 h. The reaction mixture was stirred overnight and
allowed to reach room temperature. The reaction mixture was
quenched with a saturated solution of NH4Cl (100 mL), and the
aqueous layer was separated and extracted with EtOAc. The combined
organic phases were washed with brine, dried over MgSO4, filtered,
and concentrated to afford a crude material that was purified on silica
gel (hexanes/EtOAc = 75:25) to afford alcohol as a mixture of two
inseparable diastereomers (10.5 g, 16.4 mmol, 71% yield, colorless
foam).
(2S,3S)-1-Allyl-2-(hydroxymethyl)-3-para-bromophenyl-6-
ortho-nosyl-1,6-diazaspiro[3.3]heptane 15a. A solution of spiro-
cycle 14a (4.3 g, 5.7 mmol, 1.0 equiv) in CH2Cl2 (55 mL) was added
to a 250 mL round-bottom flask. At 0 °C, neat trifluoroacetic acid (6.3
mL, 86.0 mmol, 15.0 equiv) was slowly added via syringe and the
mixture was stirred at this temperature for 1 h. MeOH (25 mL) was
quickly added followed by a careful addition of K2CO3 (12.0 g, 86.0
mmol, 15.0 equiv). The cold bath was removed, and the reaction was
left at room temperature for 1 h. The mixture was partitioned between
water and CH2Cl2. The organic layer was washed one more time with
water, dried over MgSO4, filtered, concentrated, and purified by
chromatography on silica gel using hexanes/EtOAc to afford 15a (2.0
g, 3.9 mmol) with 69% yield: [α]2D0 +80.8 (c 1.2, CHCl3); IR νmax
(film) 3383, 2948, 2870, 1544, 1488, 1369, 1169, 1128, 1011; 1H
NMR (300 MHz, CDCl3) δ 7.98−7.90 (m, 1H), 7.72−7.60 (m, 3H),
7.46 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 5.83 (ddt, J = 16.5,
10.0, 6.4 Hz, 1H), 5.21 (dd, J = 17.2, 1.5 Hz, 1H), 5.02 (dd, J = 10.1,
1.4 Hz, 1H), 4.79 (d, J = 8.9 Hz, 1H), 4.12 (d, J = 9.0 Hz, 1H), 3.99
(d, J = 9.4 Hz, 1H), 3.84 (d, J = 9.5 Hz, 1H), 3.61−3.51 (m, 2H), 3.45
(dd, J = 11.7, 4.8 Hz, 1H), 3.41 (dd, J = 14.5, 5.5 Hz, 2H), 3.25 (dd, J
= 10.9, 5.1 Hz, 1H), 3.19 (dd, J = 13.7, 6.6 Hz, 1H), 1.16 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 148.3, 135.5, 134.5, 133.7, 131.8, 131.5,
131.4, 131.1, 130.7, 124.1, 121.4, 118.0, 66.4, 64.0, 61.9, 60.5, 57.8,
54.2, 49.5; HRMS (ESI) calcd for C21H23BrN3O5S [M + H]+
508.0542, found 508.0542.
A 500 mL round-bottom flask was charged with a solution of
alcohol intermediate (10.5 g, 16.4 mmol, 1.0 equiv) in 135 mL dry
THF. At −78 °C, LiHMDS (1.0 M in THF, 19.0 mL, 19.0 mmol, 1.2
equiv) was added dropwise via an addition funnel. After 40 min, a
solution of p-toluenesulfonyl chloride (TsCl, 3.9 g, 20.5 mmol, 1.3
equiv) in 15 mL dry THF was quickly syringed into the mixture and
(2R,3R)-1-Allyl-2-(hydroxymethyl)-3-para-bromophenyl-6-
ortho-nosyl-1,6-diazaspiro[3.3]heptane ent-15a. Following the
7200
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
the temperature was slowly raised to room temperature, allowing for
complete conversion of the starting material. The reaction was
quenched with saturated NH4Cl solution, and the layers were
separated. The organic phase was washed with brine, dried over
MgSO4, filtered, and concentrated. Purification on silica gel (hexanes/
EtOAc = 75:25) afforded the sulfonate ester 18 (11.4 g, 14.4 mmol,
88% yield). Due to its complexity, no NMR listing is provided for this
compound. A copy of the 1H NMR spectrum is provided in the
Supporting Information. HRMS (ESI) calcd for C43H41BrN2NaO6S
[M + Na]+ 815.1766, found 815.1767.
mL), and K2CO3 (1.5 g, 10.9 mmol, 1.5 equiv) was added, followed by
allyl bromide (0.8 mL, 8.7 mmol, 1.2 equiv). The mixture was stirred
at 80 °C using sealed tube conditions until complete disappearance of
the starting material (3 h, monitored by LC/MS). The mixture was
partitioned between water and EtOAc, and the organic layer was dried
over MgSO4, filtered, concentrated, and purified on silica gel
(hexanes/EtOAc = 20:80) to afford N-allylated spiroazetidine 15c as
a colorless foam (1.9 g, 3.6 mmol, 50% yield over two steps): [α]D20
+37.7 (c 1.3, CHCl3); IR νmax (film) 3396, 2922, 2848, 1543, 1370,
1171, 1010; 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J = 7.5 Hz, 1H),
7.76−7.58 (m, 3H), 7.40 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H),
5.80 (ddt, J = 16.8, 10.0, 6.6 Hz, 1H), 5.22 (d, J = 17.1 Hz, 1H), 5.06
(d, J = 10.0 Hz, 1H), 4.34 (d, J = 9.3 Hz, 1H), 4.22 (d, J = 9.4 Hz,
1H), 4.12 (d, J = 9.4 Hz, 1H), 3.71−3.59 (m, 2H), 3.54 (d, J = 9.3 Hz,
1H), 3.51−3.42 (m, 2H), 3.39 (dd, J = 13.6, 6.6 Hz, 1H), 3.18 (dd, J =
13.4, 6.8 Hz 1H), 2.39 (br d, J = 7.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 148.4, 134.9, 134.5, 133.8, 132.0, 131.7, 131.0, 130.8, 129.6,
124.2, 121.4, 118.7, 66.1, 64.8, 63.6, 61.2, 53.0, 52.9, 45.1; HRMS
(ESI) calcd for C21H23BrN3O5S [M + H]+ 508.0542, found 508.0542.
(2R,3S)-1-Allyl-2-(hydroxymethyl)-3-para-bromophenyl-6-
ortho-nosyl-1,6-diazaspiro[3.3]heptane ent-15c. Following the
above protocol, 2.4 g of ent-15c was obtained starting from 7.4 g of
ent-19 (52% over 2 steps): [α]2D0 −35.9 (c 1.0, CHCl3).
(2S,3R,4R)-1-Allyl-3-(2-bromophenyl)-4-carbonitrile-2-
((trityloxy)methyl)azetidine 21a and (2S,3R,4S)-1-Allyl-3-(2-
bromophenyl)-4-carbonitrile-2-((trityloxy)methyl)azetidine
21b. Compound 20a (41.6 g, 146 mmol, 1 equiv) was treated with
trityl chloride (60.9 g, 218 mmol, 1.5 equiv) and triethylamine (60.9
mL, 437 mmol, 3.0 equiv) in CH2Cl2 (1450 mL). The reaction
mixture was quenched with water extracts and dried over MgSO4,
filtered, and concentrated under reduced pressure to provide the crude
product. The reaction provided, after purification, gave 70 g (91%) of
trityl-20a: [α]2D0 −21.3 (c 1.9, CHCl3); IR νmax (film) 3060, 3021,
1489, 1460, 1448, 1281, 1071, 1031, 753; 1H NMR (300 MHz,
CDCl3) δ 7.67−7.43 (m, 8H), 7.31 (dq, J = 6.8, 14.0 Hz, 10H), 7.15
(dd, J = 4.5, 10.7 Hz, 1H), 5.82 (ddt, J = 6.0, 10.5, 16.6 Hz, 1H),
5.12−4.98 (m, 2H), 4.89 (d, J = 3.3 Hz, 1H), 3.62−3.44 (m, 1H), 3.24
(m, 2H), 3.11−2.89 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 148.6,
147.1, 143.9, 142.3, 136.6, 132.8, 128.8, 128.8, 128.3, 128.2, 128.0,
127.9, 127.4, 127.2, 126.7, 122.5, 116.2, 87.1, 70.9, 63.6, 61.5, 51.2;
HRMS (ESI) calcd for C31H30BrNO2 [M + H]+ 528.1538, found
528.1543.
(2R,3S)-1-tert-Butyloxycarbonyl-2-(trityloxymethyl)-3-para-
bromophenyl)-4-cyano-4-(tosyloxymethyl)azetidine ent-18.
Following the protocol above, 12.6 g (92% yield) of ent-18 was
obtained from 11.1 g of ent-17.
(2S,3R)-1-tert-Butyloxycarbonyl-2-(trityloxymethyl)-3-para-
bromophenyl-6-ortho-nosyl-1,6-diazaspiro[3.3]heptane 19. A
500 mL round-bottom flask was charged with a solution of nitrile 18
(11.3 g, 14.3 mmol, 1.0 equiv) in 140 mL dry CH2Cl2. At −78 °C, neat
DIBAL (12.7 mL, 71.5 mmol, 5.0 equiv) was added dropwise to the
mixture via syringe. The reaction was kept at this temperature until
complete conversion of the starting material (30 to 45 min, LC/MS
analysis). A careful addition of 100 mL dry MeOH was done in order
to quench the reaction, followed by 100 mL of Rochelle’s salt solution.
The mixture was progressively brought to 50 °C and was stirred at this
temperature overnight. The layers were separated, and the aqueous
phase was extracted with CH2Cl2. The combined organic layers were
washed with brine, dried over MgSO4, filtered, and concentrated to
dryness. The crude material was then dissolved in 140 mL of dry
CH2Cl2, and triethylamine (4.0 mL, 28.5 mmol, 2.0 equiv) was quickly
added to the mixture. At 0 °C, nosyl chloride (3.47 g, 15.7 mmol, 1.1
equiv) was added in one portion, and the reaction was stirred
overnight at room temperature, resulting in partial cyclization of the
nosylated amine. The mixture was washed with saturated NaHCO3
solution, and the phases were separated. After extraction of the
aqueous phase with CH2Cl2, the combined organic layers were dried
over MgSO4, filtered, and concentrated. K2CO3 (4.0 g, 28.6 mmol, 2.0
equiv) was added to the crude material dissolved in acetonitrile (140
mL), and the mixture was stirred at 60 °C until complete cyclization of
the intermediate (LC/MS, 3 h). Water was then added, and the
mixture was extracted twice with EtOAc. The combined organic
fractions were washed with brine and dried over MgSO4. After
filtration and removal of the solvents in vacuo, the crude was purified
on silica gel (hexanes/EtOAc = 70:30) to afford the spiroazetidine 19
(5.9 g, 7.3 mmol, 51% yield over three steps) as a slightly yellow foam:
[α]2D0 −35.9 (c 1.2, CHCl3); IR νmax (film) 3056, 3021, 2974, 2930,
Nitrile-20a. The secondary amine (70 g, 132 mmol, 1 equiv)
obtained above was treated with 2-bromoacetonitrile (27.7 g, 397
mmol, 3 equiv) and potassium carbonate (27.5 g, 199 mmol, 1.5
equiv) in acetonitrile (1325 mL). Solvent was removed in vacuo, and
the resulting material was purified directly over silica gel to afford 67 g
(89%) of pure product: [α]2D0 −39.8 (c 0.9, CHCl3); IR νmax (film)
3472, 3059, 2359, 2342, 1490, 1448, 1219, 1073, 1032, 772; 1H NMR
(300 MHz, CDCl3) δ 7.58 (d, J = 7.8 Hz, 1H), 7.50−7.05 (m, 18H),
5.83−5.55 (m, 1H), 5.32−5.12 (m, 2H), 4.92 (d, J = 7.2 Hz, 1H),
3.86−3.69 (m, 2H), 3.68 (m, 1H), 3.44 (m, 2H), 3.30 (m, 2H), 3.14
(dd, J = 7.6, 13.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 143.6,
140.5, 134.5, 132.6, 129.3, 129.1, 128.6, 128.0, 127.9, 127.3, 123.2,
119.6, 87.9, 70.4, 67.6, 60.6, 54.5, 40.3; HRMS (ESI) calcd for
C33H31BrN2O2 [M + Na]+ 589.1467, found 589.1467
1
2870, 1698, 1544, 1367, 1164, 1074; H NMR (300 MHz, CDCl3) δ
7.95 (br s, 1H), 7.66 (s, 3H), 7.49−7.35 (m, 7H), 7.35−7.19 (m,
10H), 6.97 (d, J = 8.3 Hz, 2H), 4.92 (d, J = 8.8 Hz, 1H), 4.48 (br s,
1H), 4.18 (d, J = 8.9 Hz, 1H), 4.17 (br s, 1H), 3.81 (br s, 1H), 3.57 (br
s, 1H), 3.49 (br d, J = 4.3 Hz, 2H), 3.15 (br d, J = 8.2 Hz, 1H), 1.57−
1.21 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 153.6, 148.2, 143.6,
135.7, 133.5, 132.1, 131.8, 129.7, 128.6, 127.9, 127.2, 124.2, 121.7,
86.9, 81.3, 64.0, 63.1, 61.5, 57.2, 47.1, 28.4; HRMS (ESI) calcd for
C42H40BrN3NaO7S [M + Na]+ 832.1668, found 832.1669.
(2R,3S)-1-tert-Butyloxycarbonyl-2-(trityloxymethyl)-3-para-
bromophenyl-6-ortho-nosyl-1,6-diazaspiro[3.3]heptane ent-
19. Following the above protocol, 2.1 g of ent-19 was obtained from
3.3 g of ent-18 (61% yield): [α]2D0 +39.1 (c 1.2, CHCl3).
(2S,3R)-1-Allyl-2-(hydroxymethyl)-3-para-bromophenyl-6-
ortho-nosyl-1,6-diazaspiro[3.3]heptane 15c. A solution of trityl
ether 19 (5.9 g, 7.3 mmol, 1.0 equiv) in 73 mL of CH2Cl2 was added
to a 250 mL round-bottom flask. At 0 °C, trifluoroacetic acid was
slowly added via syringe and the mixture was stirred at this
temperature for 1 h. The cold bath was then removed, and the
reaction was left overnight at room temperature. Then, 36 mL of
MeOH was quickly added followed by a careful addition of K2CO3
(30.2 g, 219.0 mmol, 30.0 equiv). After 1 h, the mixture was
partitioned between water and CH2Cl2. The organic layer was washed
one more time with water, dried over MgSO4, filtered, and
concentrated. The crude material was dissolved in acetonitrile (60
Chloride-20a. The resulting benzyl alcohol (nitrile-20a) (20 g,
35.2 mmol, 1 equiv) was treated with thionyl chloride (5.13 g, 70
mmol, 2 equiv) and pyridine (14.25 mL, 176 mmol, 5 equiv) in
CH2Cl2 (352 mL). The reaction mixture was carefully quenched with
aqueous sodium bicarbonate solution, and the extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure to provide
the crude product. The reaction provided, after purification, 15 g
(73%) of chloride-20a: [α]2D0 −72.9 (c 1.8, CHCl3); IR νmax (film)
3060, 3022, 2882, 2359, 2342, 1490, 1468, 1448, 1219, 1154, 1072,
1
763, 747; H NMR (300 MHz, CDCl3) δ 7.67 (dd, J = 1.4, 7.9 Hz,
1H), 7.56 (dd, J = 0.9, 8.0 Hz, 1H), 7.51−7.42 (m, 6H), 7.40−7.09
(m, 11H), 5.76 (d, J = 4.9 Hz, 1H), 5.44 (dddd, J = 5.5, 7.5, 9.7, 15.2
Hz, 1H), 5.25−5.02 (m, 2H), 3.80−3.57 (m, 2H), 3.57−3.31 (m, 4H),
3.14 (dd, J = 7.5, 13.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 143.6,
7201
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
138.1, 134.6, 132.7, 131.1, 129.8, 128.8, 128.1, 127.6, 127.3, 122.7,
119.0, 117.4, 87.7, 64.5, 62.6, 61.5, 55.8, 40.4; HRMS (ESI) calcd for
C33H30BrClN2O [M + Na]+ 607.1122, found 607.1122.
A solution of the above chloride-20b (17 g, 29.00 mmol, 1 equiv) in
THF (290 mL) was cooled to −78 °C. To this mixture was added a
cooled solution of LiHMDS (1 M in THF 43.5 mL, 43.5 mmol, 1.5
equiv) via cannula. The reaction mixture was stirred for 1 h and
quenched with aqueous saturated NH4Cl solution, and the aqueous
layer was extracted three times with EtOAc. The combined organic
extracts were dried over MgSO4, filtered, and concentrated under
reduced pressure to provide the crude product. The reaction provided,
after purification, 13 g (82%) of 21c and 0.110 g (∼1%) of 21d.
21c: [α]2D0 −14.0 (c 0.1, CHCl3); IR νmax (film) 3035, 2861, 1487,
1452, 1217; 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J = 7.7 Hz, 1H),
7.39 (d, J = 7.8 Hz, 5H), 7.21 (m, 12H), 5.74 (m, 1H), 5.32 (d, J =
17.1 Hz, 1H), 5.15 (d, J = 10.1 Hz, 1H), 4.84 (d, J = 6.3 Hz, 1H), 3.95
(m, 2H), 3.54 (m, 1H), 3.32 (ddd, J = 6.2, 12.2, 18.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 143.9, 135.7, 133.3, 133.1, 129.6, 129.5,
128.9, 128.2, 128.1, 127.8, 127.4, 119.2, 115.5, 87.3, 66.8, 66.4, 57.2,
56.0, 43.5; HRMS (ESI) calcd for C33H29BrN2NaO [M + Na]+
571.1361, found 571.1369.
Chloride-20a (25 g, 43 mmol, 1 equiv) was treated with LiHMDS
(55.5 mL, 55 mmol, 1.3 equiv) in THF (427 mL). The reaction
mixture was quenched with aqueous saturated NH4Cl solution, and
the aqueous layer was extracted three times with EtOAc. The
combined organic extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure to provide the crude product.
The reaction provided, after purification, 11.5 g (49%) of 21a and 11.5
g (49%) of 21b.
21a: [α]2D0 +47.1 (c 1.5, CHCl3); IR νmax (film) 3057, 3021, 2866,
1
2359, 2342, 1489, 1472, 1448, 1220, 1073, 1024, 772, 749; H NMR
(300 MHz, CDCl3) δ 7.96 (dd, J = 1.3, 7.8 Hz, 1H), 7.61 (d, J = 8.0,
1H), 7.26 (m, 17H), 5.80 (ddt, J = 6.6, 10.0, 16.6 Hz, 1H), 5.28 (d, J =
16.6 Hz, 1H), 5.17 (d, J = 10.4 Hz, 1H), 4.65 (t, J = 8.1 Hz, 1H), 4.22
(d, J = 8.2 Hz, 1H), 3.77 (td, J = 5.5, 7.9 Hz, 1H), 3.36 (dd, J = 6.2,
13.0 Hz, 1H), 3.19 (dd, J = 7.1, 12.9 Hz, 1H), 3.06 (dd, J = 5.4, 9.7 Hz,
1H), 3.01−2.86 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 143.8, 133.8,
133.1, 133.0, 131.0, 129.4, 128.7, 128.7, 127.9, 127.4 127.0, 126.0,
119.9, 117.5, 86.7, 77.6, 77.2, 76.8, 66.3, 61.7, 60.8, 54.5, 41.1; HRMS
(ESI) calcd for C33H30BrN2O [M + H]+ 549.1542, found 549.1548.
21b: [α]2D0 +7.9 (c 0.50, CHCl3); IR νmax (film) 3057, 2864, 1489,
1474, 1448, 1069, 1028; 1H NMR (300 MHz, CDCl3) δ 7.52 (ddd, J =
10.9, 7.9, 1.4 Hz, 2H), 7.25−7.17 (m, 15H), 7.17−7.09 (m, 2H), 5.70
(ddt, J = 10.2, 6.5, 6.1 Hz, 1H), 5.27 (dd, J = 17.2, 1.5 Hz, 1H), 5.13
(dd, J = 10.2, 1.3 Hz, 1H), 4.44 (dd, J = 8.1, 3.5 Hz, 1H), 4.34 (d, J =
3.5 Hz, 1H), 4.13 (dd, J = 13.9, 5.9 Hz, 1H), 3.48−3.27 (m, 2H), 2.97
(dd, J = 10.0, 5.4 Hz, 1H), 2.85 (dd, J = 10.0, 6.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 143.7, 135.7, 133.3, 133.0, 129.2, 128.7, 128.6,
127.8, 127.7, 127.0, 125.4, 118.9, 117.4, 87.0, 66.4, 62.2, 55.6, 55.0,
43.1; HRMS (ESI) calcd for C33H30BrN2O [M + H]+ 549.1542, found
549.1537.
21d: [α]2D0 +1.6 (c 0.63, CHCl3); IR (cm−1) 3057, 2866, 1489, 1473,
1447, 1072, 1025; 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J = 7.8 Hz,
1H), 7.45 (dd, J = 8.2, 1.4 Hz, 6H), 7.38−7.21 (m, 11H), 7.21−7.11
(m, 1H), 5.92 (dddd, J = 15.8, 10.1, 7.4, 5.7 Hz, 1H), 5.35 (dd, J =
17.1, 1.2 Hz, 1H), 5.25 (d, J = 10.1 Hz, 1H), 4.21 (t, J = 8.1 Hz, 1H),
3.66−3.52 (m, 3H), 3.41 (dd, J = 10.0, 5.4 Hz, 1H), 3.33 (dd, J = 10.0,
5.0 Hz, 1H), 3.21 (dd, J = 13.1, 7.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 143.9, 136.9, 133.5, 133.0, 129.3, 128.8, 128.7, 128.0, 127.7,
127.2, 124.8, 119.8, 119.5, 87.0, 68.2, 66.6, 60.6, 55.4, 44.2; HRMS
(ESI) calcd for C33H29BrN2NaO [M + Na]+ 571.1361, found
571.1350.
N-(((2S,3R,4R)-1-Allyl-3-(2-bromophenyl)-4-((trityloxy)-
methyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfonamide 22a.
Nitrile azetidine 21a (13 g, 24 mmol, 1 equiv) was treated with
diisobutylaluminium hydride (25 mL, 142 mmol, 6 equiv) in CH2Cl2
(240 mL). The reaction was quenched with MeOH (5.74 mL, 6
equiv). After aqueous extraction, the crude amine (13 g, 23.5 mmol)
was treated with 2-nitrobenzene-1-sulfonyl chloride (5.4 g, 23.5 mmol,
1 equiv) and triethylamine (3.9 mL, 30.5 mmol, 1.3 equiv). The
reaction mixture was quenched with aqueous saturated NH4Cl
solution, and the aqueous layer was extracted three times with
EtOAc. The combined organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure to provide the crude
product. The reaction, after purification, provided 11.7 g (68%) of
pure product 22a: [α]D20 −27.4 (c 1.0, CHCl3); IR νmax (film) 3058,
3021, 2930, 2860, 1540, 1448, 1348, 1169, 1072, 1023, 759; 1H NMR
(500 MHz, CDCl3) δ 7.90 (dd, J = 1.7, 7.4 Hz, 1H), 7.80 (dd, J = 1.7,
7.4 Hz, 1H), 7.70−7.60 (m, 2H), 7.58 (dd, J = 1.6, 7.6 Hz, 1H), 7.54
(dd, J = 1.3, 7.8 Hz, 1H), 7.21 (m, 15H), 7.00 (tdd, J = 4.5, 10.5, 14.9
Hz, 2H), 5.82−5.64 (m, 1H), 5.22 (d, J = 17.1 Hz, 1H), 5.06 (d, J =
9.5 Hz, 2H), 4.45 (t, J = 7.9 Hz, 1H), 3.70 (td, J = 5.4, 8.0 Hz, 1H),
3.60 (td, J = 5.6, 7.9 Hz, 1H), 3.35−3.19 (m, 2H), 3.18−3.05 (m, 2H),
3.00 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 147.7, 143.9, 135.4,
134.8, 133.6, 133.4, 133.4, 132.9, 131.4, 130.9, 128.6, 128.4, 127.7,
126.9, 126.7, 126.3, 125.6, 118.4, 86.3, 65.8, 65.7, 61.5, 61.2, 43.3, 40.8;
HRMS (ESI) calcd for C39H36BrN3O5S [M + H]+ 738.1637, found
738.1635.
(2S,3R,4R)-1-Allyl-3-(2-bromophenyl)-4-carbonitrile-2-
((trityloxy)methyl)azetidine 21c. Following the protocols de-
scribed above for the formation of 21a and 21b, 25 g of trityl-20b
gave 40.5 g (88%) of trityl protected product: [α]2D0 −23.2 (c 0.1,
1
CHCl3); IR νmax (film) 3465, 3065, 2882, 1496, 1443, 904; H NMR
(300 MHz, CDCl3) δ 7.34 (d, J = 7.8 Hz, 1H), 7.31−7.24 (m, 4H),
7.24−7.09 (m, 12H), 7.04 (t, J = 7.5 Hz, 1H), 6.99−6.89 (m, 1H),
5.91 (ddd, J = 16.1, 10.9, 5.8 Hz, 1H), 5.23 (d, J = 17.2 Hz, 1H), 5.14−
5.02 (m, 2H), 4.13 (br s, 1H), 3.41 (dd, J = 14.4, 5.5 Hz, 1H), 3.30
(dd, J = 14.4, 6.1 Hz, 1H), 3.12 (dt, J = 7.0, 3.6 Hz, 1H), 2.99 (qd, J =
9.9, 5.3 Hz, 2H), 2.06 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ
148.8, 143.8, 139.9, 137.1, 132.6, 128.7, 128.6, 128.3, 128.2, 128.08,
128.00, 127.3, 127.2, 126.7, 121.7, 116.2, 87.4, 71.6, 62.6, 59.0, 49.8;
HRMS (ESI) calcd for C31H30BrNO2 [M + H]+ 528.1558, found
528.1560.
The secondary amine (40 g) described above afforded 37 g (86%)
of nitrile-20b: [α]2D0 −15.9 (c 0.1, CHCl3); IR νmax (film) 3465, 3065,
2883, 1496, 1443, 904; 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J = 7.7
Hz, 1H), 7.36 (d, J = 7.1 Hz, 6H), 7.32−7.20 (m, 9H), 7.21−7.03 (m,
2H), 5.70 (dt, J = 17.0, 8.4 Hz, 1H), 5.30 (d, J = 17.2 Hz, 2H), 5.20 (d,
J = 10.5 Hz, 1H), 3.76 (d, J = 17.2 Hz, 1H), 3.63 (d, J = 17.5 Hz, 1H),
3.54−3.40 (m, 3H), 3.30−3.17 (m, 2H), 2.91 (d, J = 4.3 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 143.6, 140.7, 135.0, 132.9, 129.2, 128.8,
128.5, 128.1, 127.6, 127.3, 122.2, 119.1, 117.4, 87.9, 73.3, 64.5, 60.8,
55.3, 39.6; HRMS (ESI) calcd for C33H31BrN2O2 [M + Na]+
589.1467, found 589.1471.
The tertiary amine (18.5 g) described above afforded 12.5 g (65%)
of chloride-20b: IR νmax (film) 3065, 2913, 1491, 1443, 1065; 1H
NMR (300 MHz, CDCl3) δ 7.42 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.7
Hz, 6H), 7.26−7.10 (m, 9H), 7.04 (t, J = 7.3 Hz, 1H), 5.46 (d, J = 8.8
Hz, 1H), 5.28−5.09 (m, 1H), 4.94−4.77 (m, 2H), 3.69 (dd, J = 10.7,
2.0 Hz, 1H), 3.53 (dd, J = 10.6, 6.8 Hz, 1H), 3.44−3.36 (m, 1H), 3.34
(s, 2H), 3.18 (dd, J = 14.2, 5.0 Hz, 1H), 2.73 (dd, J = 14.2, 7.6 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 143.6, 139.0, 134.7, 132.8, 130.0,
129.8, 128.9, 128.1, 128.0, 127.4, 123.8, 118.7, 117.1, 87.9, 66.3, 60.4,
59.5, 54.1, 40.0; HRMS (ESI) calcd for C33H30BrClN2O [M + Na]+
607.1122, found 607.1108.
N-(((2R,3R,4R)-1-Allyl-3-(2-bromophenyl)-4-((trityloxy)-
methyl)azetidin-2-yl)methyl)-2-nitrobenzenesulfonamide 22c.
Following the above protocol, 5.2 g of nitrile azetidine 21c afforded 5.5
g (79%) of nosyl amine 22c: [α]2D0 −28.4 (c 0.1, CHCl3); IR νmax
(film) 3334, 3038, 2887, 1534, 1336, 1169; 13C NMR (126 MHz,
CDCl3) δ 148.1, 143.9, 137.1, 136.1, 133.8, 133.4, 133.0, 132.7, 131.1,
129.5, 128.9, 128.8, 128.0, 127.8, 127.2, 126.6, 125.4, 116.9, 87.2, 64.7,
64.6, 63.6, 52.9, 42.7, 42.4; HRMS (ESI) calcd for C39H36BrN3O5S [M
+ H]+ 738.1637, found 738.1614.
(1S,2aR,8bR)-2-Allyl-4-((2-nitrophenyl)sulfonyl)-1-
((trityloxy)methyl)-1,2,2a,3,4,8b-hexahydroazeto[2,3-c]-
quinolone 23a. To a solution of nosyl amine 22a (11.7 g, 15.9 mmol,
1 equiv) in degassed toluene (160 mL) was added N,N-dimethyl-
ethane-1,2-diamine (0.34 mL, 3.2 mmol, 0.2 equiv), cesium carbonate
(7.7 g, 23.9 mmol, 1.5 equiv), and copper(I) iodide (0.3 g, 1.6 mmol,
7202
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
0.1 equiv). The reaction was heated at 100 °C for 2 h. The reaction
was then cooled, and the solution was then filtered through a pad of
silica gel. The solvent was removed under vacuum to afford 10.4 g
(99%) of the desired product 23a: [α]2D0 −19.8, (c 1.46, CHCl3); mp
96.1−100.7 °C; IR νmax (film) 3060, 3022, 2871, 1542, 1489, 1448,
material had occurred. The reaction mixture was concentrated under
reduced pressure, and the resulting residue was purified by
chromatography on silica gel using hexanes/EtOAc, which provided
204 mg (73%) of pure product that was used in the next reaction
without further characterization.
1
To a flask containing palladium acetate (4.5 mg, 0.020 mmol, 0.03
equiv), 1,1′-binaphthyl-2-yl-di-tert-butylphosphine (12 mg, 0.030
mmol, 0.045 equiv), and cesium carbonate (325 mg, 0.995 mmol,
1.5 equiv) was added a solution of the pure alcohol from the previous
step (204 mg, 0.684 mmol, 1.0 equiv) in toluene (2.2 mL) at room
temperature. The reaction was heated to 55 °C and stirred for 16 h.
Analysis of the reaction showed complete consumption of starting
material and conversion to the desired product. The reaction was
diluted with CH2Cl2 and filtered through Celite. The filtrate was
concentrated, and the resulting yellow residue was purified by
chromatography on silica gel using hexanes/EtOAc, which provided
the pure aryl ether: [α]D20 +130.0 (c 0.24, CHCl3); IR νmax (film) 2975,
2894, 1491, 1463, 1333, 1259, 1225, 1201, 1093; 1H NMR (300 MHz,
CDCl3) δ 7.29−7.20 (m, 1H), 7.09 (d, J = 8.1, 2.1 Hz, 1H), 7.03 (ddd,
J = 7.4, 5.6, 1.2 Hz, 2H), 5.89 (ddt, J = 16.8, 10.1, 6.6 Hz, 1H), 5.32
(dd, J = 17.1, 1.4 Hz, 1H), 5.24 (d, J = 10.1 Hz, 1H), 4.22−4.10 (m,
2H), 3.83−3.67 (m, 2H), 3.62 (dd, J = 12.6, 1.3 Hz, 1H), 3.43−3.24
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 155.1, 133.0, 130.7, 129.1,
122.2, 120.0, 119.7, 118.3, 117.0, 65.4, 62.2, 59.5, 55.8, 31.8; HRMS
(ESI) calcd for C14H15N2O [M + H]+ 227.1184, found 227.1178.
To a solution of the aryl ether (42 mg, 0.186 mmol, 1.0 equiv) in
CH2Cl2 (1.9 mL) at 0 °C was added diisobutylaluminum hydride
(0.198 mL, 1.11 mmol, 6.0 equiv). The reaction was stirred for 1 h,
after which TLC showed complete consumption of starting material.
The reaction was quenched with MeOH and stirred until bubbling
stopped. Then a saturated solution of Rochelle’s salt was added (25
mL), and the mixture was vigorously stirred for about 90 min until the
aqueous and organic layers had clearly separated. The layers were then
separated, and the aqueous layer was extracted once with CH2Cl2 (15
mL). The combined organic layers were dried, filtered, and
concentrated in vacuo, and the crude material (32 mg, 75%) was
used in the next step without further purification.
The crude residue was then redissolved in CH2Cl2 (1.4 mL) at 0
°C, and then triethylamine (39 mL, 0.28 mmol, 2.0 equiv) and 2-
nitrobenzenesulfonyl chloride (32 mg, 0.15 mmol, 1.05 equiv) were
added. The reaction was stirred until all starting material had been
consumed (∼60 min) as determined by LC/MS. The reaction mixture
was concentrated under reduced pressure, and the crude residue was
purified by chromatography on silica gel using hexanes/EtOAc, which
provided 25a as a clear oil: [α]2D0 +46.5 (c 0.195, CHCl3); IR νmax
(film) 3319, 2869, 1539, 1488, 1348, 1167; 1H NMR (300 MHz,
CDCl3) δ 7.92 (dd, J = 6.9, 1.8 Hz, 1H), 7.81 (dd, J = 7.8, 2.4, 1H),
7.75−7.57 (m, 2H), 7.15−6.94 (m, 2H), 6.94−6.78 (m, 2H), 5.86
(ddt, J = 17.0, 10.9, 6.8 Hz, 1H), 5.36 (br s, 1H), 5.27 (dd, J = 17.1, 1.4
Hz, 1H), 5.16 (d, J = 10.0 Hz, 1H), 4.06 (d, J = 12.2 Hz, 1H), 3.78−
3.59 (m, 3H), 3.53 (dd, J = 12.2, 1.3 Hz, 1H), 3.37 (dd, J = 12.7, 6.3
Hz, 1H), 3.24 (d, J = 12.7, 7.2 Hz, 1H), 2.87−2.70 (m, 1H), 2.70−
2.53 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 155.9, 148.1, 134.7,
133.7, 133.5, 132.8, 130.9, 130.1, 128.2, 125.4, 122.0, 121.2, 119.1,
118.4, 66.7, 65.2, 61.9, 60.3, 44.9, 31.0; HRMS (ESI) calcd for
C20H22N3O5S [M + H]+ 416.1280, found 416.1278.
1369, 1219, 1165, 1068, 761; H NMR (500 MHz, CDCl3, 60 °C) δ
8.02 (d, J = 8.0 Hz, 1H), 7.62−7.51 (m, 2H), 7.39−7.15 (m, 17H),
7.16−7.05 (m, 2H), 6.99 (t, J = 7.4 Hz, 1H), 5.60 (ddt, J = 6.8, 9.8,
16.8 Hz, 1H), 5.13 (d, J = 17.0 Hz, 1H), 4.99 (d, J = 10.1 Hz, 1H),
4.31 (dd, J = 2.1, 14.4 Hz, 1H), 3.77−3.58 (m, 3H), 3.17 (m, 2H),
3.08 (dd, J = 1.2, 14.4 Hz, 1H), 2.83 (dd, J = 4.2, 9.9 Hz, 1H), 2.64 (t,
J = 9.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 144.5, 138.2, 136.0,
135.1, 133.1, 132.2, 131.6, 131.0, 129.3, 128.9, 128.8, 128.5, 127.8,
127.1, 127.0, 125.5, 125.5, 124.1, 123.1, 117.9, 95.2, 87.1, 66.1, 64.1,
61.8, 59.6, 48.6, 34.4; HRMS (ESI) calcd for C39H35N3O5S [M + H]+
658.2376, found 658.2371.
(1R,2aR,8bR)-2-Allyl-4-((2-nitrophenyl)sulfonyl)-1-
((trityloxy)methyl)-1,2,2a,3,4,8b-hexahydroazeto[2,3-c]-
quinolone 23c. Following the above protocol, 7.0 g of nosyl amine
22c afforded 6.2 g (99%) of 23c: [α]2D0 +24.1 (c 1.0, CHCl3); IR νmax
(film) 3010, 2891, 1539, 1365, 1209, 1156, 904; 1H NMR (300 MHz,
CDCl3) δ 7.92 (d, J = 7.4 Hz, 1H), 7.69−7.54 (m, 3H), 7.43 (d, J = 7.4
Hz, 4H), 7.34−7.19 (m, 12H), 7.19−6.97 (m, 3H), 5.67 (dq, J = 11.3,
6.1 Hz, 1H), 5.04 (d, J = 17.2 Hz, 1H), 4.95 (d, J = 9.3 Hz, 1H), 4.13
(dd, J = 13.8, 5.5 Hz, 1H), 4.08−3.97 (m, 1H), 3.57 (ddd, J = 15.0,
11.9, 4.3 Hz, 2H), 3.41−3.12 (m, 5H); 13C NMR (75 MHz, CDCl3) δ
148.0, 144.1, 137.3, 135.7, 135.4, 133.7, 131.9, 130.6, 129.5, 128.9,
128.0, 127.3, 126.4, 124.6, 123.9, 117.0, 87.2, 69.3, 65.1, 60.1, 52.6,
48.3, 35.5; HRMS (ESI) calcd for C39H35N3O5S [M + H]+ 658.2376,
found 658.2368.
((1S,2aR,8bR)-2-Allyl-4-((2-nitrophenyl)sulfonyl)-
1,2,2a,3,4,8b-hexahydroazeto[2,3-c]quinolin-1-yl)methanol
24a. Trityl alcohol 23a (0.120 g, 0.162 mmol, 1 equiv) was treated
with trifluoroacetic acid (0.10 mL, 1.30 mmol, 8 equiv) in CH2Cl2 (2
mL) at 0 °C and allowed to warm to room temperature and stir for 1
h. The reaction mixture was quenched with a saturated sodium
bicarbonate solution, and the aqueous layer was extracted three times
with EtOAc. The combined organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure to provide the crude
product. The reaction provided, after purification, 0.405 g (50%) of
pure product 24a: [α]D20 +35.6 (c 1.7, CHCl3); IR νm1ax (film) 3417,
2922, 2857, 1541, 1498, 1350, 1161, 1130, 1027, 770; H NMR (300
MHz, CDCl3) δ 8.28−8.15 (m, 1H), 7.73 (m, 3H), 7.14−6.96 (m,
3H), 6.79 (d, J = 7.9 Hz, 1H), 5.95 (ddt, J = 6.8, 10.1, 16.8 Hz, 1H),
5.21 (d, J = 17.1 Hz, 1H), 5.09 (d, J = 10.1 Hz, 1H), 4.33 (dd, J = 1.9,
14.5 Hz, 1H), 3.72 (d, J = 7.2 Hz, 1H), 3.66−3.51 (m, 2H), 3.45−3.18
(m, 4H), 3.01 (d, J = 14.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
148.0, 137.9, 137.1, 135.7, 133.8, 132.5, 131.1, 131.0, 130.1, 127.2,
126.2, 124.8, 122.9, 118.0, 67.8, 62.2, 61.3, 59.3, 48.6, 34.2; HRMS
(ESI) calcd C20H21N3O5S [M + H]+ 416.1280, found 416.1281.
((1R,2aR,8bR)-2-Allyl-4-((2-nitrophenyl)sulfonyl)-
1,2,2a,3,4,8b-hexahydroazeto[2,3-c]quinolin-1-yl)methanol
24c. Following the protocol above, 0.500 g of 23c afforded 0.160 g
(50%) of 24c: [α]2D0 −28.0 (c 1.7, CHCl3); IR νmax (film) 3417, 2922,
1
2857, 1541, 1498, 1350, 1161, 1130, 1027, 770; H NMR (300 MHz,
CDCl3) δ 7.89 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 3.9 Hz, 2H), 7.74−7.63
(m, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.35−7.21 (m, 1H), 7.15 (s, 2H),
5.84 (qd, J = 11.6, 6.0 Hz, 1H), 5.31 (d, J = 16.7 Hz, 1H), 5.16 (d, J =
10.2 Hz, 1H), 4.39 (dd, J = 14.4, 5.0 Hz, 1H), 4.14 (s, 1H), 3.82−3.45
(m, 6H), 3.42−3.22 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 148.1,
144.1, 137.6, 135.2, 134.1, 132.4, 130.2, 128.9, 128.0, 127.6, 126.6,
125.0, 123.1, 118.3, 72.5, 61.1, 60.4, 51.5, 47.1, 33.3; HRMS (ESI)
calcd for C20H21N3O5S [M + H]+ 416.1280, found 416.1281.
(1S,2aR,8bR)-2-Allyl-2,2a,3,8b-tetrahydro-1H-chromeno[3,4-
b]azete-1-carbonitrile 25a. To a solution of o-bromonitrile
azetidine 21a (500 mg, 0.91 mmol, 1.0 equiv) in CH2Cl2 (9.1 mL)
at room temperature was added trifluoroacetic acid (0.5 mL, 6.5 mmol,
7.0 equiv) followed by triethylsilane (150 mL, 0.96 mmol, 1.05 equiv).
The reaction was stirred for 15 min, after which analysis of the reaction
by TLC and LC/MS showed that complete consumption of starting
(1S,2aR,8bR)-2-Allyl-2,2a,3,8b-tetrahydro-1H-chromeno[3,4-
b]azete-1-carbonitrile 25b. o-Bromonitrile azetidine 21b (1.89 g,
3.44 mmol, 1.0 equiv) in CH2Cl2 (69 mL) was reacted with
trifluoroacetic acid (2.65 mL, 34.4 mmol, 10 equiv). The reaction was
stirred for 15 min, after which analysis of the reaction by TLC and
LC/MS showed that complete consumption of starting material had
occurred. The reaction mixture was concentrated under reduced
pressure, and the resulting residue was purified by chromatography on
silica gel using hexanes/EtOAc, which provided 646 mg (61% yield) of
pure product, and used in the next step without further character-
ization.
The intermediate alcohol (124 mg, 0.404 mmol, 1.0 equiv) was
reacted with palladium acetate (3.90 mg, 0.017 mmol, 4.5 mol %),
1,1′-binaphthyl-2-yl-di-tert-butylphosphine (10.5 mg, 0.026 mmol, 6.5
7203
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
mol %), and cesium carbonate (197 mg, 0.605 mmol, 1.5 equiv) in
toluene (3.0 mL) at 55 °C for 16 h and then at 70 °C for 3 h. The
filtrate was concentrated, and the resulting yellow residue was purified
by chromatography on silica gel using hexanes/EtOAc, which provided
the pure aryl ether (62 mg, 68% yield): [α]2D0 −125.9 (c 0.28, CHCl3);
(103 mL) at 0 °C and allowed to warm to room temperature and stir
for 1 h. The reaction mixture was quenched with a saturated sodium
bicarbonate solution, and the aqueous layer was extracted three times
with EtOAc. The combined organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure to provide the crude
product. The reaction provided, after purification, 1.90 g (81%) of
pure product: [α]2D0 +187.2 (c 1.21, CHCl3); IR νmax (film) 3419, 2867,
1
IR νmax (film) 2861, 2818, 1582, 1489, 1460, 1258, 1229, 1117; H
NMR (300 MHz, CDCl3) δ 7.30 (dd, J = 14.8, 7.5 Hz, 1H), 7.19 (d, J
= 7.6 Hz, 1H), 7.05 (dd, J = 7.3, 6.0 Hz, 2H), 5.89 (ddt, J = 16.5, 10.3,
6.3 Hz, 1H), 5.42 (d, J = 17.1 Hz, 1H), 5.26 (d, J = 10.1 Hz, 1H), 4.33
(d, J = 12.8 Hz, 1H), 4.10 (d, J = 7.8 Hz, 1H), 3.98 (s,1H), 3.85 (d, J =
7.7 Hz, 1H), 3.70 (d, J = 12.8 Hz, 1H), 3.49 (d, J = 6.2 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 155.0, 133.2, 129.8, 129.0, 122.4, 122.0,
119.4, 118.4, 117.6, 65.6, 63.1, 57.6, 55.4, 34.3; HRMS (ESI) calcd for
C14H15N2O [M + H]+ 227.1184, found 227.1185.
The cyclized product (50 mg, 0.221 mmol, 1.0 equiv) was reacted
with diisobutylaluminum hydride (0.28 mL, 1.571 mmol, 7.0 equiv) in
CH2Cl2 (2.2 mL) at 0 °C. The reaction was stirred for 1 h, after which
TLC showed complete consumption of starting material. The reaction
was quenched with MeOH and stirred until bubbling stopped. Then a
saturated solution of Rochelle’s salt was added (25 mL), and the
mixture was vigorously stirred for about 90 min until the aqueous and
organic layers had clearly separated. The layers were then separated,
and the aqueous layer was extracted once with CH2Cl2 (15 mL). The
combined organic layers were dried, filtered, and concentrated in
vacuo, and the crude material (51 mg, 99% yield) was used in the next
step without further purification.
1
1643, 1490, 1414, 1071, 1009; H NMR (300 MHz, CDCl3) δ 7.55
(dd, J = 6.9, 1.5 Hz, 2H), 7.46−7.28 (m, 3H), 5.91 (dt, J = 17.0, 10.1,
6.6 Hz, 1H), 5.34 (dd, J = 17.1, 1.4 Hz, 1H), 5.25 (d, J = 10.1 Hz, 1H),
4.14 (d, J = 8.1 Hz, 1H), 3.81 (t, J = 7.9 Hz, 1H), 3.62−3.44 (m, 2H),
3.45−3.28 (m, 2H), 3.21 (dd, J = 13.1, 6.9 Hz, 1H), 1.42 (br s, 1H);
13C NMR (75 MHz, CDCl3) δ 134.1, 133.4, 129.8, 128.6, 128.3, 119.7,
117.6, 68.0, 62.0, 60.9, 54.3, 42.6; HRMS (ESI) calcd for C14H17N2O
[M + H]+ 229.1341, found 229.1333.
The primary alcohol described above (0.200 g, 0.876 mmol) was
dissolved in methanol (9 mL). Ten percent palladium on carbon (20
mg) was added, and hydrogen gas was bubbled into the solution for 5
min. The reaction was then allowed to stir under an atmosphere of
hydrogen (via balloon) for approximately 2 h. Once the reaction was
complete, the mixture was filtered through Celite and then a short plug
of silica gel. The solvent was removed under reduced pressure to
provide 190 mg (94%) of 26a: [α]2D0 +120.6 (c 1.07, CHCl3); IR νmax
(film) 3190, 2958, 2918, 2873, 1455, 1249, 1049; 1H NMR (300 MHz,
CDCl3) δ 7.55 (d, J = 7.1 Hz, 2H), 7.45−7.20 (m, 3H), 4.08 (d, J = 8.0
Hz, 1H), 3.82 (t, J = 7.7 Hz, 1H), 3.65−3.28 (m, 3H), 2.80−2.61 (m,
1H), 2.61−2.40 (m, 1H), 1.69−1.49 (m, 2H), 1.42 (br s, 1H), 0.98 (t,
J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 134.3, 129.9, 128.6,
128.3, 117.9, 68.2, 62.0, 60.7, 55.0, 42.4, 21.1, 11.9; HRMS (ESI) calcd
for C14H19N2O [M + H]+ 231.1497, found 231.1487.
The crude residue was reacted with triethylamine (62 mL, 0.443
mmol, 2.0 equiv) and 2-nitrobenzenesulfonyl chloride (52 mg, 0.233
mmol, 1.05 equiv) in CH2Cl2 (4.4 mL) at 0 °C for ∼60 min. The
reaction mixture was concentrated under reduced pressure, and the
crude residue was purified by chromatography on silica gel using
hexanes/EtOAc, which provided, after purification, 23 mg (25% yield)
of pure product 25b: [α]D20 −6.3 (c 0.51, CHCl3); IR νmax (film) 3077,
((2S,3R,4R)-4-(Aminomethyl)-3-phenyl-1-propylazetidin-2-
yl)methanol 26b. Nitrile azetidine 26a (0.200 g, 0.868 mmol) was
dissolved in CH2Cl2 (10 mL) and subsequently cooled to 0 °C.
DIBAL (0.929 mL, 5.21 mmol) was added over 15 min, and the
reaction mixture was allowed to warm to room temperature and stirred
for approximately 2 h. The mixture was quenched by the slow addition
of methanol (0.211 mL, 5.21 mmol) until gas evolution ceased. Then a
saturated solution of sodium potassium tartrate (Rochelle’s salt) was
added, and the gel-like solution was allowed to stir until two separate
layers could be seen. The aqueous layer was then extracted two
additional times with CH2Cl2. The combined organic extracts were
dried over MgSO4, filtered, and concentrated under reduced pressure
to provide the crude product which was purified over silica gel
(CH2Cl2/MeOH) to obtain 58 mg (67%) of 26a: [α]2D0 +13.3 (c 0.63,
CHCl3); IR νmax (film) 3363, 3030, 2958, 2931, 2872, 1541, 1493,
1
2914, 1536, 1487, 1346, 1163, 1114; H NMR (300 MHz, CDCl3) δ
8.12 (dd, J = 5.6, 3.6 Hz, 1H), 7.86 (dd, J = 5.8, 3.4 Hz, 1H), 7.75 (dd,
J = 5.8, 3.5 Hz, 2H), 7.23−7.13 (m, 1H), 6.95 (dd, J = 6.8, 1.7 Hz,
3H), 6.46 (s, 1H), 5.66 (ddd, J = 16.6, 11.1, 6.2 Hz, 1H), 5.17 (d, J =
17.2 Hz, 1H), 4.91 (d, J = 10.2 Hz, 1H), 4.58 (d, J = 13.0 Hz, 1H),
4.18 (d, J = 8.2 Hz, 1H), 3.66−3.53 (m, 2H), 3.53−3.38 (m, 2H),
3.32−3.09 (m, 3H), 3.00 (dd, J = 12.7, 3.9 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 156.4, 148.3, 134.8, 133.7, 133.5, 132.7, 131.3, 128.3,
127.2, 125.4, 122.7, 118.0, 117.8, 70.9, 66.2, 61.7, 52.5, 45.2, 33.2;
HRMS (ESI) calcd for C20H22N3O5S [M + H]+ 416.1280, found
416.1266.
(2R,3R,4S)-4-(Carbonitrile)-3-phenyl-1-propylazetidine-2-hy-
droxymethyl 26a. To the solution of 5a (5.00 g, 9.10 mmol) in
isopropyl alcohol (91 mL) were added AIBN (0.299 g, 1.82 mmol)
and tributylchlorostannane (0.368 mL, 1.37 mmol). The reaction
mixture was heated to reflux (∼100 °C) and was allowed to stir of 5
min. After 5 min at reflux, a solution of sodium cyanotrihydroborate
(0.86 g, 13.7 mmol) in isopropyl alcohol (20 mL) was added
simultaneously with a solution of AIBN (0.600 g, 3.64 mmol) in 20
mL of isopropyl alcohol via two separate syringes over a 10 min
period. The reaction was stirred for approximately 1 h. The reaction
was cooled to room temperature, and the solvent was removed under
reduced pressure. The residue was residue was purified over silica gel
to obtain 3.50 g (82%) of the dehalogenated material: [α]2D0 +42.3 (c
1
1455, 1033; H NMR (300 MHz, CDCl3) δ 7.40 (t, J = 9.7 Hz, 2H),
7.35−7.03 (m, 4H), 3.64 (t, J = 8.0 Hz, 1H), 3.49 (d, J = 6.2, 2H), 3.35
(dd, J = 7.2, 13.3, 1H), 3.31−3.09 (m, 1H), 2.71 (dd, J = 9.3, 12.9 Hz,
1H), 2.65−2.53 (m, 1H), 2.59−2.35 (m, 2H), 1.52 (d, J = 8.4 Hz,
2H), 1.47 (s, 3H), 1.05−0.70 (m, 3H); 13C NMR (75 MHz, CDCl3) δ
136.1, 130.8, 128.4, 127.2, 76.5, 69.4, 67.5, 61.3, 42.1, 41.9, 22.3, 12.1;
HRMS (ESI) calcd for C14H23N2O [M + H]+ 235.1810, found
235.1808.
7-Phenyl-6-propyl-3,6-diazabicyclo[3.1.1]heptane 27a. Com-
pound 8a (0.416 g, 0.870 mmol) was dissolved in DMF (11 mL)
followed by the addition of thiophenol (0.357 mL, 3.38 mmol) and
potassium carbonate (0.721 g, 5.22 mmol) at room temperature and
stirred overnight (Note: in some cases, the solution needed to be
heated to 50 °C to drive the reaction to completion). The solvent was
removed and the resulting residue slurried in EtOAc. The solution was
acidified with 1 M HCl and the aqueous layer extracted with additional
EtOAc. The resulting aqueous layer was basified with a 40% KOH
solution until a pH >10 was achieved. The combined organic extracts
were dried over MgSO4, filtered, and concentrated under reduced
pressure to provide the crude product, which was purified by silica gel
chromatography to provide pure product (0.250 g, 98%) as an oil: mp
162.2−164.7 °C (decomp); IR νmax (film) 2917, 2857, 1487, 1398,
1176, 1008, 916, 810; 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 8.3
Hz, 2H), 7.00 (dd, J = 8.4, 1.1 Hz, 2H), 5.86 (ddd, J = 16.2, 11.1, 6.0
Hz, 1H), 5.27 (dd, J = 17.2, 1.7 Hz, 1H), 5.14 (dd, J = 10.3, 1.6 Hz,
1
0.17, CHCl3); IR νmax (film) 3056, 2866, 1490, 1448, 1264, 1063; H
NMR (500 MHz, CDCl3) δ 7.48−7.41 (m, 2H), 7.31−7.25 (m, J =
6.3, 9.6 Hz, 3H), 7.22−7.06 (m, J = 6.0, 7.9, 14H), 5.76 (ddt, J = 6.7,
10.1, 13.3 Hz, 1H), 5.21 (d, J = 17.1 Hz, 1H), 5.10 (d, J = 10.1 Hz,
1H), 4.11−4.03 (m, 1H), 3.81 (t, J = 7.9 Hz, 1H), 3.63 (dd, J = 7.4,
13.5 Hz, 1H), 3.37 (dd, J = 5.9, 12.9 Hz, 1H), 3.11 (dd, J = 7.2, 12.9
Hz, 1H), 3.03 (dd, J = 5.9, 9.6 Hz, 1H), 2.89 (dd, J = 7.3, 9.6 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 143.7, 134.3, 132.9, 129.8, 128.4, 128.2,
127.8, 127.6, 126.8, 119.4, 117.6, 86.5, 66.5, 62.1, 60.8, 54.7, 42.9;
HRMS (ESI) calcd for C33H30N2O [M + H]+ 471.2436, found
471.2448.
The dehalogenated intermediate (4.85 g, 10.31 mmol) was treated
with trifluoroacetic acid (6.35 mL, 82.0 mmol, 8 equiv) in CH2Cl2
7204
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
1H), 4.01 (t, J = 5.6 Hz, 1H), 3.87 (d, J = 5.6 Hz, 2H), 3.40 (d, J = 6.0
Hz, 2H), 3.35 (d, J = 13.5 Hz, 2H), 2.79 (d, J = 13.6 Hz, 2H), 1.67 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 138.3, 134.4, 131.6, 126.9,
119.9, 116.9, 63.2, 48.3, 41.1, 38.8; HRMS (ESI) calcd for C14H18BrN2
[M + H]+ 293.0653, found 293.0655.
water (5 drops), diluted with CH2Cl2 (25 mL), and filtered. The
filtrate was concentrated in vacuo, and the residue was extracted with
diethyl ether. The combined organics were dried over MgSO4, filtered,
and rotoevaporated to get an oil. The compound was purified over
1
silica gel to afford 0.060 mg (40%) of 27d: H NMR (500 MHz,
A solution of the above amine (0.150 g, 0.512 mmol) was dissolved
in methanol (5 mL) at room temperature. Platinum oxide (12 mg,
0.48 mmol) was added, and hydrogen gas was bubbled into the
solution for 5 min. The reaction was then allowed to stir under an
atmosphere of hydrogen (via balloon) overnight (Note: the starting
material must be free of sulfur impurities for reaction to proceed).
Once the reaction was complete, the mixture was filtered through a
plug of Celite and then silica gel. The solvent was removed under
reduced pressure to provide in sufficient purity for the next step.
To a solution of the above product (0.151 g, 0.511 mmol) in
isopropyl alcohol (5 mL) were added AIBN (0.021 g, 0.128 mmol)
and tributylchlorostannane (0.28 mL, 0.102 mmol). The reaction
mixture was heated to reflux (∼100 °C) and was allowed to stir for 5
min. A solution of sodium cyanotrihydroborate (0.048 g, 0.767 mmol)
in isopropyl alcohol (1 mL) was then added simultaneously with a
solution of AIBN (0.042 g, 0.256 mmol) in isopropyl alcohol (1 mL)
via two separate syringes over a 10 min period. The reaction was
stirred for approximately 1 h. The reaction was cooled to room
temperature, and the solvent was removed under reduced pressure.
The residue was residue was purified over silica gel using CH2Cl2/
CDCl3) δ 7.32 (d, J = 6.9, 1H), 7.26 (d, J = 7.1, 0H), 7.05 (d, J = 7.5,
1H), 6.70 (t, J = 8.7, 1H), 6.36 (dd, J = 5.7, 8.3, 1H), 3.97 (s, 0H),
3.93 (s, 1H), 3.43 (s, 1H), 2.94 (d, J = 11.3, 1H), 2.78 (d, J = 11.2,
1H), 2.47 (s, 1H), 1.58−1.36 (m, 1H), 0.96 (t, J = 7.4, 1H); 13C NMR
(126 MHz, CDCl3) δ 162.4, 160.5, 139.8, 134.7, 129.0, 129.0, 128.0,
125.1, 124.6, 114.5, 114.4, 61.8, 58.2, 46.0, 44.6, 42.3, 20.4, 12.1;
HRMS (ESI) calcd for C21H26FN2 [M + H]+ 325.2080, found
325.2091.
(6R,7R,8S)-8-(Hydroxymethyl)-4-methyl-7-phenyl-1,4-
diazabicyclo[4.2.0]octan-2-one 28a. To the solution of 5a (5.00 g,
9.10 mmol) in isopropyl alcohol (91 mL) were added AIBN (0.299 g,
1.82 mmol) and tributylchlorostannane (0.368 mL, 1.37 mmol). The
reaction mixture was heated to reflux (∼100 °C) and was allowed to
stir for 5 min. After 5 min at reflux, a solution of sodium
cyanotrihydroborate (0.86 g, 13.7 mmol) in isopropyl alcohol (20
mL) was added simultaneously with a solution of AIBN (0.600 g, 3.64
mmol) in 20 mL of isopropyl alcohol via two separate syringes over a
10 min period. The reaction was stirred for approximately 1 h. The
reaction was cooled to room temperature, and the solvent was
removed under reduced pressure. The residue was residue was purified
over silica gel to afford 3.50 g (82%) of product: [α]2D0 +42.3 (c 0.17,
CHCl3); IR νmax (film) 3056, 2866, 1490, 1448, 1264, 1063; 1H NMR
(500 MHz, CDCl3) δ 7.48−7.41 (m, 2H), 7.31−7.25 (m, J = 6.3, 9.6
Hz, 3H), 7.22−7.06 (m, J = 6.0, 7.9, 14H), 5.76 (ddt, J = 6.7, 10.1,
13.3 Hz, 1H), 5.21 (d, J = 17.1 Hz, 1H), 5.10 (d, J = 10.1 Hz, 1H),
4.11−4.03 (m, 1H), 3.81 (t, J = 7.9 Hz, 1H), 3.63 (dd, J = 7.4, 13.5 Hz,
1H), 3.37 (dd, J = 5.9, 12.9 Hz, 1H), 3.11 (dd, J = 7.2, 12.9 Hz, 1H),
3.03 (dd, J = 5.9, 9.6 Hz, 1H), 2.89 (dd, J = 7.3, 9.6 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 143.7, 134.3, 132.9, 129.8, 128.4, 128.2,
127.8, 127.6, 126.8, 119.4, 117.6, 86.5, 66.5, 62.1, 60.8, 54.7, 42.9;
HRMS (ESI) calcd for C33H30N2O [M + H]+ 471.2436, found
471.2448.
The nitrile azetidine described above (3.5 g, 7.44 mmol, 1.0 equiv)
was dissolved in CH2Cl2 (75 mL) and subsequently cooled to 0 °C.
DIBAL (7.95 mL, 44.6 mmol, 6.0 equiv) was added over 15 min, and
the reaction mixture was allowed to warm to room temperature and
stirred for approximately 2 h. The mixture was quenched by the slow
addition of MeOH (5.50 mL, 136 mmol, 6.0 equiv) until gas evolution
ceased. Then a saturated solution of sodium potassium tartrate
(Rochelle’s salt) was added, and the gel-like solution was allowed to
stir until two separate layers could be seen. The aqueous layer was
then extracted two additional times with CH2Cl2. The combined
organic extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure to provide the crude product (∼3.53 g), which
was deemed pure enough for the next reaction.
1
MeOH to obtain 52 mg (47% over 2 steps) of 27a: H NMR (500
MHz, CDCl3) δ 7.36 (t, J = 7.6, 2H), 7.26 (d, J = 7.6 Hz, 1H), 7.16 (d,
J = 7.7 Hz, 2H), 5.93 (ddd, J = 5.9, 11.1, 16.4 Hz, 1H), 5.33 (d, J =
17.2 Hz, 1H), 5.19 (d, J = 10.3 Hz, 1H), 4.16 (t, J = 5.6 Hz, 1H), 3.96
(d, J = 5.7 Hz, 2H), 3.48 (d, J = 5.9 Hz, 2H), 3.40 (d, J = 13.7 Hz,
2H), 2.88 (d, J = 13.7 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 139.0,
128.8, 126.4, 125.4, 64.2, 47.0, 41.6, 38.9, 20.6, 12.1; HRMS (ESI)
calcd for C14H21N2 [M + H]+ 217.1705, found 217.1698.
7-Phenyl-6-propyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-
ethanone 27b. A solution of amine 27a (0.90 mg, 416 mmol),
triethylamine (0.218 mL, 1.25 mmol), and PyBOP (0.238 mg, 0.458
mmol) in CH2Cl2 (3 mL) at 0 °C was added to acetic acid (0.026 mL,
0.458 mmol). The solution was warmed to room temperature and
stirred for 5 h, and the solvent was removed. The residue was purified
by silica gel chromatography to afford 0.025 g (24%) of 27b: 1H NMR
(500 MHz, CDCl3) δ 7.30 (t, J = 7.7 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H),
7.03 (d, J = 7.4 Hz, 1H), 4.05 (d, J = 4.6 Hz, 2H), 4.02 (d, J = 2.1 Hz,
1H), 3.70 (dd, J = 8.1, 18.1 Hz, 2H), 3.58 (d, J = 14.2 Hz, 1H), 3.49
(d, J = 12.1 Hz, 1H), 2.65−2.38 (m, 2H), 1.77 (s, 3H), 1.59−1.40 (m,
2H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.6,
136.4, 128.4, 126.3, 125.8, 60.2, 59.7, 46.5, 41.1, 38.3, 21.2, 20.9, 12.0;
HRMS (ESI) calcd for C16H23N2O [M + H]+ 259.1810, found
259.1812.
3-(Methylsulfonyl)-7-phenyl-6-propyl-3,6-diazabicyclo-
[3.1.1]heptane 27c. To a solution of amine 27a (52 mg, 0.240
mmol) and triethylamine (0.101 mL, 0.720 mmol) in CH2Cl2 (2.5
mL) was added methanesulfonyl chloride (0.028 mL, 0.361 mmol) at
0 °C. The reaction was allowed to stir for 1 h at 0 °C. Water was then
added, and the resulting aqueous solution was extracted (3×) with
CH2Cl2. The combined extracts were dried over MgSO4, filtered, and
rotoevaporated to dryness. The resulting oil was chromatographed
The resulting amine (3.5 g, 7.37 mmol, 1.0 equiv) was dissolved in
CH2Cl2 (74 mL) and cooled to 0 °C. 2,6-Lutidine (2.59 mL, 22.1
mmol, 3.0 equiv) was introduced followed by 2-nitrobenzene-1-
sulfonyl chloride (1.85 g, 8.11 mmol, 1.1 equiv) in one portion. The
solution was then allowed to warm to room temperature and stirred
for an additional 3 h. The reaction mixture was quenched with water,
and the aqueous layer was extracted two times with CH2Cl2. The
combined organic extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure to provide the crude product,
which was purified by chromatography over silica gel using hexanes/
EtOAc to provide the nosylated amine (2.91 g, 60% over 2 steps) as a
pale yellow foam.
1
over silica gel to obtain 50.3 mg (71%) of 27c: H NMR (500 MHz,
CDCl3) δ 7.36 (t, J = 7.6, 2H), 7.25 (dd, J = 5.1, 12.7, 1H), 7.06 (d, J =
7.7, 2H), 4.05 (s, 3H), 3.74 (d, J = 11.7, 2H), 3.26 (d, J = 11.7, 2H),
2.77−2.47 (m, 2H), 1.71 (s, 3H), 1.61−1.40 (m, 2H), 0.98 (t, J = 7.4,
3H); 13C NMR (126 MHz, CDCl3) δ 136.65, 128.84, 126.68, 126.16,
59.89, 46.34, 40.73, 39.16, 34.02, 21.21, 12.02; HRMS (ESI) calcd for
C15H23N2O2S [M + H]+ 295.1480, found 295.1477.
To a solution of the nosylated amine (1.00 g, 1.516 mmol) and 1,3-
dimethyl barbaturic acid (0.355 g, 2.273 mmol) in EtOH (30 mL) was
added palladium tetrakis (0.350 g, 0.303 mmol). The resulting orange
solution was stirred for approximately 1 h at room temperature. The
solution was then evaporated and taken up in acetonitrile. The
resulting solid was filtered through Celite and taken on imediately as a
crude solution.
3-(4-Fluorobenzyl)-7-phenyl-6-propyl-3,6-diazabicyclo-
[3.1.1]heptane 27d. To a solution of amine 27a (0.125 g, 0.462
mmol) in ethanol (2 mL) was added 4-bromobenzaldehyde (0.049
mL, 0.462 mmol), and the reaction mixture was stirred for 1 h. An
additional 1.0 mL of ethanol was added followed by 1.4 mL of THF
and sodium borohydride (0.035 g, 0.925 mmol). The reaction mixture
was stirred at room temperature overnight and then quenched with
7205
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
Potassium carbonate (210 g, 15.2 mmol) was added to the orange
solution obtained above and the mixture cooled to 0 °C. 2-
Bromoacetyl chloride (0.380 mL, 4.55 mmol) was then added
dropwise and the resulting mixture warmed to room temperature, and
the solution was stirred for several hours. After the reaction was
deemed complete (LC/MS analysis), the mixture was concentrated in
vacuo. The residue was dissolved in CH2Cl2 and water after which the
aqueous layer was extracted (3×) with CH2Cl2. The combined organic
layers were dried (MgSO4) and concentrated in vacuo to give an oily
residue. The residue was purified by chromatography to obtain 88% of
the fully protected monoketopiperazine des-Br-9a: [α]2D0 −135.8 (c
0.55, CHCl3); IR νmax (film) 3059, 3031, 2942, 1665, 1543, 1453,
1370; 1H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 7.5, 1H), 7.72−7.66
(m, 1H), 7.63 (t, J = 7.0 Hz, 2H), 7.30−7.20 (m, 9H), 7.18−7.10 (m,
8H), 7.06−6.97 (m, 5H), 5.03−4.87 (m, 2H), 4.13−4.04 (m, 2H),
4.00 (dd, J = 4.7, 10.0 Hz, 1H), 3.72 (dd, J = 4.8, 13.0 Hz, 1H), 3.63
(d, J = 17.1 Hz, 1H), 3.50 (t, J = 9.9 Hz, 1H), 3.36−3.23 (m, 2H); 13C
NMR (126 MHz, CDCl3) δ 160.4, 147.8, 143.2, 134.0, 133.8, 131.9,
131.7, 131.1, 129.3, 128.5, 128.4, 127.6, 127.6, 126.8, 124.4, 86.6, 77.2,
77.0, 76.7, 66.2, 61.4, 57.5, 47.7, 45.5, 42.8; HRMS (ESI) calcd
C38H33N3O6S [M + Na]+ 682.1988, found 682.1982.
To a solution of the fully protected monoketopiperazine described
above des-Br-9a (0.615 g, 0.932 mmol) in CH2Cl2 (5 mL) at 0 °C was
added trifluoroacetic acid (0.718 mL, 9.32 mmol). The resulting
solution was then warmed to room temperature and stirred for
approximately 1 h. A saturated sodium bicarbonate solution was added
and stirred until bubbling ceased. The aqueous layer was extracted
with CH2Cl2, and the combined organics were dried over MgSO4,
filtered, and concentrated under reduced pressure to obtain an oil.
After filtering over a plug of silica gel, the detritylated product was
taken forward to the next step.
The above product was dissolved in DMF (9 mL), and potassium
carbonate (0.510 g, 3.69 mmol) was added and the mixture cooled to
0 °C. Thiophenol (0.303 mL, 2.95 mmol) was then added, and the
reaction was heated to 50 °C and stirred for 2 h. After starting material
was consumed, the DMF was rotoevaporated down and taken up in
EtOAc. HCl (2 M) was then added until pH was approximately 1. The
aqueous was washed with EtOAc, and the organics were discarded.
The aqueous solution was basified with 40% KOH solution until pH
>10. The solution was then extracted with CH2Cl2 (3×), and the
combined extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure to obtain a yellowish oil which, was imediately
taken crude to the next step.
To a solution of the free amino alcohol (35 mg, 0.151 mmol), acetic
acid (0.086 mL, 1.507 mmol), and formaldehyde (0.021 mL, 0.753
mmol) in MeOH (5 mL) was added sodium cyanoborohydride (0.047
g, 0.753 mmol) in portions at room temperature. The mixture was
then heated to 60 °C and stirred for approximately 30 min. The
solvent was evaporated, and to the resulting white solid was added
saturated NaHCO3 that was introduced until gas evolution ceased. At
this point, a 1 M NaOH solution was added until pH >11, then the
solution was extracted with EtOAc (3×). The combined organic layers
were dried (MgSO4) and evaporated to dryness to give a cloudy oil.
Purification over silica gel afforded 15 mg (42%) of 28a: [α]2D0 −13.5
(c 1.71, CHCl3); IR νmax (film) 3057, 2944, 1641, 1489, 1447, 1409,
1216, 1071; 1H NMR (500 MHz, CDCl3) δ 7.43−7.33 (m, 3H), 7.23
(d, J = 6.1 Hz, 2H), 5.40−5.29 (m, 1H), 5.20 (t, J = 7.4 Hz, 1H), 4.23
(dd, J = 9.9, 13.0 Hz, 1H), 4.11 (t, J = 7.9 Hz, 1H), 3.75 (d, J = 16.4
Hz, 1H), 3.44 (dd, J = 2.6, 13.0 Hz, 1H), 3.35 (d, J = 16.5 Hz, 1H),
3.16 (dd, J = 4.8, 12.0 Hz, 1H), 2.93 (t, J = 11.8 Hz, 1H), 2.86 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 160.5, 132.0, 129.4, 128.9, 128.6, 71.0,
The organics were combined and dried over MgSO4, filtered, and
concentrated under reduced pressure to obtain an oil. This material
was then purified over silica gel to yield 75% of trityl-protected free
amine of des-Br 9a scaffold: [α]2D0 −182.8 (c 0.42, CHCl3); IR νmax
1
(film) 3306, 3057, 2944, 1641, 1489, 1447, 1409, 1216, 1071; H
NMR (500 MHz, CDCl3) δ 7.33−7.22 (m, 7H), 7.23−7.14 (m, 8H),
7.09 (dd, J = 2.9, 6.6 Hz, 6H), 5.11−4.97 (m, 1H), 4.94−4.84 (m,
1H), 4.08 (dd, J = 4.7, 9.9 Hz, 1H), 4.02 (t, J = 7.4 Hz, 1H), 3.53 (t, J
= 10.1 Hz, 1H), 3.43 (d, J = 9.3 Hz, 1H), 2.97 (dd, J = 10.7, 13.0 Hz,
1H), 2.74 (dd, J = 5.2, 13.1 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ
164.2, 143.5, 134.6, 129.6, 128.4, 128.2, 127.5, 127.3, 126.7, 86.3, 77.2,
77.0, 76.7, 66.2, 63.6, 57.5, 49.2, 47.2, 41.4; HRMS (ESI) calcd
C32H30N2O2 [M + Na]+ 497.2205, found 497.2201.
To a solution of the trityl-protected free amine scaffold obtained
above (0.22 g, 0.46 mmol) in CH2Cl2 (9 mL) at 0 °C was added
triethylamine (0.19 mL, 1.37 mmol) followed by acetyl chloride (0.051
mL, 0.683 mmol). The reaction was stirred for 30 min at which time
water was added. The aqueous layer was and extracted with CH2Cl2
and dried over MgSO4, filtered, and evaporated to obtain an oil. This
material was used directly in the next step without purification.
The resulting oil was dissolved in CH2Cl2 (3 mL) and cooled to 0
°C. Trifluoroacetic acid (0.139 mL, 1.802 mmol) was then added, and
the reaction was warmed to room temperature and stirred for 1 h. A
saturated sodium bicarbonate solution was added and stirred until gas
evolution ceased. The aqueous layer was then extracted with CH2Cl2
(3×), and the combined organics were dried over MgSO4, filtered, and
evaporated to obtain an oil. Purification by silica gel chromatography
afforded 0.069 g (74%) of 28b: [α]2D0 −67.1 (c 0.31, CHCl3); IR νmax
(film) 3401, 2930, 1636, 1417; 1H NMR (500 MHz, CDCl3) δ 7.49−
7.31 (m, 3H), 7.31−7.21 (m, 2H), 5.18−5.04 (m, 1H), 4.94−4.77 (m,
1H), 4.46 (dd, J = 4.8, 13.1 Hz, 1H), 4.30−4.20 (m, J = 8.0, 20.3 Hz,
2H), 4.14−4.00 (m, 2H), 3.78 (d, J = 18.7 Hz, 1H), 3.64−3.50 (m,
1H), 3.41 (td, J = 2.7, 12.7 Hz, 1H), 3.08−2.96 (t, J = 12.7 Hz, 1H),
2.12 (s, 2H), 2.06 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 169.3,
169.0, 164.7, 163.3, 132.7, 132.6, 129.5, 129.4, 128.6, 128.5, 128.2,
128.0, 70.6, 70.3, 61.3, 61.0, 60.8, 49.4, 45.9, 44.9, 43.3, 38.6, 21.5,
21.5; HRMS (ESI) calcd C15H18N2O3 [M + Na]+ 297.1215, found
297.1217.
(6R,7R,8S)-8-(Hydroxymethyl)-4-(methylsulfonyl)-7-phenyl-
1,4-diazabicyclo[4.2.0]octan-2-one 28c. To a solution of the
trityl-protected free amine scaffold described above (0.170 g, 0.358
mmol) and triethylamine (0.150 mL, 1.075 mmol) in CH2Cl2 (3 mL)
was added methanesulfonyl chloride (0.042 mL, 0.537 mmol) at 0 °C.
The solution was allowed to warm to room temperature and stir for
approximately 1 h. Water was then added, and the resulting aqueous
layer was extracted with CH2Cl2 (3×). The combined organics were
dried over MgSO4, filtered, and evaporated. This material was run
through a short plug of silica gel, concentrated, and taken directly to
the next step in the sequence.
The resulting oil was then dissolved in CH2Cl2 (3 mL) and cooled
to 0 °C. Trifluoroacetic acid (0.139 mL, 1.80 mmol) was added, and
the reaction was warmed to room temperature and stirred for 1 h. A
saturated sodium bicarbonate solution was added and stirred until
bubbles ceased. The aqueous layer was then extract with CH2Cl2 (3×),
and the combined organics were dried over MgSO4, filtered, and
evaporated to obtain and oil. Purification by silica gel chromatography
afforded 0.069 g (74%) of 28c: [α]2D0 −34.5 (c 0.40, CHCl3); IR νmax
(film) 3365, 3011, 2928, 1638, 1456, 1426, 1336, 1150; 1H NMR (500
MHz, CDCl3) δ 7.36 (q, J = 6.5, 3H), 7.24 (m, 2H), 5.14 (t, J = 7.8
Hz, 1H), 5.12−4.98 (m, 1H), 4.54 (s, 1H), 4.30 (d, J = 14.6 Hz, 1H),
4.24 (dd, J = 12.6, 25.1 Hz, 2H), 4.04 (t, J = 8.1 Hz, 1H), 3.79 (d, J =
17.2 Hz, 1H), 3.64 (dd, J = 4.9, 12.5 Hz, 1H), 3.40 (t, J = 12.2 Hz,
1H), 3.27−3.13 (m, 1H), 2.87 (s, 3H); 13C NMR (126 MHz, CDCl3)
δ 162.7, 132.6, 129.5, 128.7, 128.3, 70.7, 61.8, 60.75, 47.9, 45.3, 42.2,
37.2; HRMS (ESI) calcd C14H18N2O4S [M + H]+ 311.1066, found
311.1057.
61.1, 60.0, 57.2, 54.6, 54.4, 45.4; HRMS (ESI) calcd C14H19N2O2 [M
+ H]+ 247.1440, found 247.1443.
(6R,7R,8S)-7-Phenyl-8-((trityloxy)methyl)-1,4-diazabicyclo-
[4.2.0]octan-2-one 28b. To a solution of the fully protected
monoketopiperazine des-Br-9a described in the synthesis of 28a (0.580
g, 0.879 mmol) and potassium carbonate (0.607 g, 4.40 mmol) in
DMF (10 mL) was added thiophenol (0.361 mL, 3.52 mmol) at 0 °C.
The reaction was allowed to come to room temperature and stir for 2
h. Water was added and the solution extracted with diethyl ether (3×).
((8R,9R,10S)-9-(4-Bromophenyl)-1,6-diazabicyclo[6.2.0]-
decan-10-yl)methanol 29a. Nosyl amine 12a (0.700 g, 1.37 mmol)
was dissolved in DMF (20 mL), and potassium carbonate (0.948 g,
6.86 mmol) was added followed by thiophenol (0.563 mL, 5.49
7206
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
mmol). The reaction mixture was heated to 50 °C and stirred for 2 h.
Once the reaction was complete, the solvent was removed in vacuo, at
which time water and EtOAc were added to the remaining residue.
HCl (2 M) was added to the biphasic mixture until the water layer
maintained a pH of approximately 1. The organics were removed, and
the remaining aqueous layer was extracted with EtOAc. The aqueous
layer was then basified to pH >10 using a 40% KOH solution. The
water was then extracted with EtOAc three times, and the combined
organics were dried over MgSO4, filtered, and rotoevaporated to
dryness to afford 29a (0.395 g, 89%): [α]2D0 −24.7 (c 0.59, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 7.43 (d, J = 7.6 Hz, 2H), 7.31−7.19 (m,
2H), 3.61 (t, J = 7.9 Hz, 1H), 3.58−3.48 (m, 2H), 3.47−3.38 (m, 2H),
3.07 (dd, J = 5.0, 12.1 Hz, 1H), 2.89 (d, J = 9.1 Hz, 1H), 2.75−2.57
(m, 2H), 2.30 (d, J = 14.3 Hz, 1H), 2.23 (t, J = 11.4 Hz, 1H), 1.82 (s,
4H), 1.56−1.43 (m, 1H), 1.41−1.30 (m, 1H); 13C NMR (126 MHz,
CDCl3) δ 135.5, 132.3, 131.0, 120.7, 68.0, 67.1, 60.7, 60.0, 50.4, 48.6,
43.7, 29.2, 27.1; HRMS (ESI) calcd for C15H22BrN2O [M + H]+
325.0916, found 325.0902.
°C, K2CO3 (0.84 g, 6.07 mmol, 4 equiv) was added, followed by
thiophenol (0.31 mL, 3.04 mmol, 2 equiv). After 1 h at 0 °C, water (15
mL) was added to the mixture and the crude was extracted with Et2O.
The organic phase was dried over MgSO4, filtered, and concentrated.
The material was then dissolved in MeOH (9 mL) and purged with
argon for 10 min. Pd (10% on carbon, 32 mg, 0.20 equiv) was quickly
added, and hydrogen gas was sparged for 1 h. The mixture was stirred
overnight at room temperature under an atmosphere of hydrogen,
carefully filtered through a pad of Celite, and concentrated.
Purification over silica-supported p-TsOH using ammonia (2.0 M in
MeOH) as the mobile phase afforded the desired secondary amine
(439 mg, 0.90 mmol, 59.1% yield over two steps).
(2S,3S)-1-Propyl-2-hydroxymethyl-3-phenyl-1,6-diazaspiro-
[3.3]heptane 30a. To a solution of the amine described above (138
mg, 0.28 mmol) in CH2Cl2 (5.5 mL) was added trifluoroacetic acid
(0.32 mL, 4.24 mmol, 15 equiv) dropwise at 0 °C. Upon completion
of the reaction, MeOH (3 mL) was added via syringe followed by
addition of K2CO3 (0.59 g, 4.24 mmol, 15 equiv) and the mixture was
stirred 30 min at room temperature. The crude reaction mixture was
filtered through a pad of Celite and evaporated. Purification on silica
gel (CH2Cl2/MeOH/2.0 M NH3 in MeOH = 95:4.95:0.05) afforded
amino alcohol 30a (69 mg, 0.28 mmol, 99% yield) as a pale yellow
foam: [α]2D0 +46.2 (c 0.9, MeOH); IR νmax (film) 3382, 3204, 2965,
((8R,9R,10S)-9-Phenyl-1,6-diazabicyclo[6.2.0]decan-10-yl)-
methanol 29b. To the solution of aryl bromide 29a (0.395 g, 1.21
mmol) in isopropyl alcohol (12.1 mL) were added AIBN (0.050 g,
0.304 mmol) and tributylchlorostannane (0.066 mL, 0.243 mmol).
The reaction mixture was then heated to reflux (∼110 °C) and was
allowed to stir for 10 min. A solution of sodium cyanotrihydroborate
(0.114 g, 1.822 mmol) in isopropyl alcohol (5 mL) was added
contemporaneously with a solution of AIBN (0.100 mg) in isopropyl
alcohol (5 mL) over a 15 min period. Upon completion of the
reaction, the solvent was removed in vacuo and the remaining sludge
taken up in EtOAc and water. HCl (2 M) was added to the biphasic
mixture until the water layer maintained a pH of approximately 1. The
organic layer was removed and the remaining aqueous layer extracted
with EtOAc. The aqueous layer was then basified to pH >10 using a
40% KOH solution. The water layer was extracted with CH2Cl2 (3×),
and the combined organics were dried over MgSO4, filtered, and
concentrated to dryness to afford 29b: [α]2D0 −28.5 (c 0.34, CHCl3);
mp 100.9−105.2 °C; IR νmax (film) 3306, 2921, 2845, 1454, 1034; 1H
NMR (500 MHz, CDCl3) δ 7.34 (d, J = 6.1 Hz, 2H), 7.28 (t, J = 7.0
Hz, 2H), 7.24−7.18 (m, 1H), 3.62 (t, J = 7.9 Hz, 1H), 3.60−3.55 (m,
1H), 3.55−3.48 (m, 1H), 3.49−3.34 (m, 4H), 3.11−3.00 (m, 1H),
2.85 (d, J = 9.8 Hz, 1H), 2.74 (dd, J = 8.1, 14.1 Hz, 1H), 2.64 (t, J =
11.7 Hz, 1H), 2.40−2.14 (m, 2H), 1.93−1.55 (m, 6H), 1.55−1.40 (m,
2H), 1.40−1.23 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 136.7, 130.8,
128.0, 126.7, 77.4, 68.1, 67.8, 60.9, 60.3, 50.4, 44.4, 29.1, 27.3; HRMS
(ESI) calcd for C15H23N2O [M + H]+ 247.1810, found 247.1814.
((8R,9R,10S)-6-Methyl-9-phenyl-1,6-diazabicyclo[6.2.0]-
decan-10-yl)methanol 29c. To a solution of 29b (0.070 g, 0.284
mmol), acetic acid (0.163 mL, 2.84 mmol), and formaldehyde (0.039
mL, 1.421 mmol) in MeOH (5 mL) was added NaCNBH3 (0.089 g,
1.421 mmol) portion-wise at room temperature. The mixture was then
heated to 60 °C and stirred for 30 min. The solvent was then
evaporated, and to the resulting white solid was added a saturated
solution of NaHCO3 until gas evolution ceased. At this point, a 1 M
NaOH solution was added until pH >11, then the solution was
extracted with EtOAc (3×). The combined organic layers were dried
over MgSO4 and evaporated to dryness to give a cloudy oil. The oil
was taken up in chloroform and filtered though Celite and dried to
obtain 29c as a clear oil: [α]2D0 −0.73 (c 0.93, CHCl3); IR νmax (film)
1
2874, 1668, 1182, 1132; H NMR (300 MHz, CD3OD) δ 7.33−7.24
(m, 6H), 4.74 (d, J = 11.8 Hz, 1H), 4.16 (d, J = 11.7 Hz, 1H), 3.98 (d,
J = 12.1 Hz, 1H), 3.73 (d, J = 7.9 Hz, 2H), 3.56 (dd, J = 13.5, 6.0 Hz,
1H), 3.37 (dd, J = 11.3, 5.7 Hz, 1H), 3.25 (s, 1H), 3.20 (dd, J = 11.3,
6.2 Hz, 1H), 2.83 (app dt, J = 12.3, 7.7 Hz, 1H), 2.62 (app dt, J = 12.3,
7.0 Hz, 1H), 1.64−1.49 (m, 2H), 0.97 (app t, J = 7.3 Hz, 3H); 13C
NMR (75 MHz, MeOD) δ 136.8, 131.1, 129.7, 128.7, 68.4, 68.2, 63.0,
56.7, 54.3, 54.2, 51.2, 23.3, 12.3; HRMS (ESI) calcd for C15H23N2O
[M + H]+ 247.1810, found 247.1813.
(2S,3S)-1-Propyl-2-hydroxymethyl-3-phenyl-6-methyl-1,6-
diazaspiro[3.3]heptane 30b. To a solution of amine described
above (145 mg, 0.30 mmol) in CH2Cl2 (5.5 mL) was added at rt
MgSO4 (357 mg, 2.97 mmol, 10 equiv) followed by formaldehyde
(37% in H2O, 0.13 mL, 1.78 mmol, 6 equiv). After 15 min at room
temperature, NaBH(OAc)3 (755 mg, 3.56 mmol, 12 equiv) was added
as a solid in one portion, and the mixture was stirred overnight at rt.
Water (10 mL) was then added and the layers separated. The organic
phase was dried over MgSO4, filtered, concentrated, and the crude was
submitted to TFA-mediated trityl removal as described for the
preparation of 30a. Compound 24b was isolated after purification on
silica gel (CH2Cl2/MeOH/2.0 M NH3 in MeOH = 95:4.95:0.05) as a
thick colorless oil (65 mg, 0.25 mmol, 84% yield over two steps): [α]D20
+109.1 (c 0.8, CHCl3); IR νmax (film) 3367, 2960, 2873, 1673, 1199,
1132; 1H NMR (300 MHz, CDCl3) δ 7.39−7.27 (m, 5H), 4.35 (br d, J
= 10.0 Hz, 1H), 3.81 (d, J = 9.6 Hz, 1H), 3.65 (d, J = 7.8 Hz, 2H),
3.60−3.54 (m, 1H), 3.51 (dd, J = 11.5, 4.3 Hz, 1H), 3.45 (d, J = 4.8
Hz, 1H), 3.38 (dd, J = 11.2, 7.2 Hz, 1H), 2.79 (app dt, J = 12.0, 7.8 Hz,
1H), 2.60−2.52 (m, 1H), 2.51 (s, 3H), 1.63−1.41 (m, 2H), 0.97 (app
t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 135.3, 129.6, 128.6,
127.5, 66.6, 64.5, 64.4, 62.3, 61.9, 53.3, 49.8, 43.6, 22.3, 11.8; HRMS
(ESI) calcd for C16H25N2O [M + H]+ 261.1967, found 261.1964.
(2S,3S)-1-Propyl-2-hydroxymethyl-3-phenyl-6-acetyl-1,6-
diazaspiro[3.3]heptane 30c. To a solution of amine described
above (155 mg, 0.32 mmol) in CH2Cl2 (4 mL) at 0 °C was added
NEt3 (88 μL, 0.63 mmol, 2 equiv) followed by Ac2O (36 μL, 0.38
mmol, 1.2 equiv). The mixture was stirred for 1 h at 0 °C and was then
quenched with a saturated solution of aqueous NH4Cl (5 mL). The
organic layer was separated, dried over MgSO4, filtered, and
concentrated to afford a crude product that was submitted to the
TFA-mediated trityl removal step without any further purification (see
preparation of 30a). Purification by silica gel chromatography
(CH2Cl2/MeOH/2.0 M NH3 in MeOH = 95:4.95:0.05) afforded
compound 30c as a colorless foam (73 mg, 0.25 mmol, 78% yield over
two steps): [α]2D0 +126.2 (c 1.1, CHCl3); IR νmax (film) 3376, 2959,
2873, 1622, 1455, 1033, 906; 1H NMR (300 MHz, CDCl3, two
rotamers) δ 7.33−7.16 (m, 5H), 4.75 (A)/4.68 (B) (d, J = 9.4 (A)/
11.1 (B) Hz, 1H), 4.05 (A)/3.92 (B) (d, J = 9.4 (A)/10.3 (B) Hz,
1
3250, 2928, 2851, 1455, 1214, 750; H NMR (500 MHz, CDCl3) δ
7.43 (d, J = 7.2 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.26−7.16 (m, 1H),
3.64 (t, J = 8.2 Hz, 1H), 3.60−3.48 (m, 3H), 3.39 (dd, J = 7.2, 13.4 Hz,
1H), 3.04 (ddd, J = 2.9, 5.7, 12.0 Hz, 1H), 2.73−2.63 (m, 1H), 2.55
(dd, J = 8.7, 13.8 Hz, 1H), 2.43−2.35 (m, 1H), 2.33−2.26 (m, 1H),
2.21 (s, 3H), 2.10 (dd, J = 2.1, 13.8 Hz, 1H), 1.94−1.84 (m, 1H),
1.84−1.74 (m, 1H), 1.68 (s, 1H), 1.62−1.43 (m, 2H).; 13C NMR (75
MHz, CDCl3) δ 135.4, 130.8, 128.7, 127.6, 67.8, 64.9, 61.3, 59.9, 59.1,
57.1, 47.1, 44.4, 26.6, 25.0; HRMS (ESI) calcd for C16H25N2O [M +
H]+ 261.1967, found 261.1969.
Procedure for the Synthesis of Spiroazetidine Derivatives
30a−c. To a 50 mL round-bottom flask was added a solution of des-Br
14a (b or c) (1.02 g, 1.52 mmol, 1 equiv) in dry DMF (15 mL). At 0
7207
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
1H), 3.90 (s, 1H), 3.82 (app q, J = 11.9 Hz, 1H), 3.52 (br s, 2H), 3.43
(br d, J = 9.5 Hz, 1H), 3.37−3.24 (m, 1H), 2.76−2.45 (m, 2H), 2.21
(A)/1.99 (B) (br s, 1H), 1.84 (A)/1.71 (B) (s, 3H), 1.59−1.37 (m,
2H), 0.95 (app t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3, two
rotamers) δ 170.5/170.2, 136.1/135.7, 129.4, 128.2, 127.2, 66.3/66.2,
64.3/64.1, 61.9, 60.5, 57.9/55.9, 53.6/53.3, 49.7, 21.9, 18.9/18.8, 11.9;
HRMS (ESI) calcd for C17H25N2O2 [M + H]+ 289.1916, found
289.1917.
through Celite. The filtrate was concentrated under reduced pressure,
and the crude product (197 mg, 69% yield) was used in the next step
without further purification: [α]2D0 −161.0 (c 0.10, CHCl3); IR νmax
(film) 2971, 2953, 2930, 2900, 1582, 1489, 1460, 1259, 1225, 1202,
1116, 1004; 1H NMR (500 MHz, CDCl3) δ 7.28−7.22 (m, 1H), 7.09
(d, J = 6.8 Hz, 1H), 7.03 (t, J = 7.4 Hz, 2H), 4.15 (dd, J = 12.7, 1.5 Hz,
1H), 4.11 (d, J = 7.8 Hz, 1H), 3.77 (t, J = 7.8 Hz, 1H), 3.70−3.59 (m,
2H), 2.70 dt, J = 11.3, 7.7 Hz, 1H), 2.62 dt, J = 11.4, 7.6 Hz, 1H), 1.54
(q, J = 7.5 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 155.1, 130.7, 129.1, 122.2, 119.8, 118.4, 117.3, 65.6, 62.8,
59.3, 56.6, 31.7, 20.9, 11.8; HRMS (ESI) calcd for C14H17N2O [M +
H]+ 229.1341, found 229.1344.
The resulting N-propyl nitrile azetidine (197 mg, 0.863 mmol, 1.0
equiv) was dissolved in CH2Cl2 (8.6 mL) at 0 °C, and then
diisobutylaluminum hydride (0.923 mL, 5.18 mmol, 6.0 equiv) was
added, and the reaction was stirred for 2 h, after which analysis of the
reaction by TLC showed that all starting material had been consumed.
The reaction was quenched with MeOH (10 mL) until bubbling
stopped, diluted with CH2Cl2, and then quenched further with a
saturated solution of potassium sodium tartrate (∼100 mL). The
mixture was stirred vigorously for about 1.5 h until bubbling stopped
and the two layers had clearly formed. The layers were separated, and
the aqueous layer was extracted further with CH2Cl2 (2 × 15 mL).
The combined organic layers were dried, filtered, and concentrated
under reduced pressure to provide the crude primary amine as a clear
oil, which was used without further purification.
(( )-2-Propyl-1,2,2a,3,4,8b-hexahydroazeto[2,3-c]quinolin-
1-yl)methanol 31a. A solution of des-Ns ( )-24c (0.110 g, 0.478
mmol) was dissolved in methanol (5 mL) at room temperature.
Platinum oxide (11 mg, 0.48 mmol) was added, and hydrogen gas was
bubbled into the solution for 5 min. The reaction was then allowed to
stir under an atmosphere of hydrogen (via balloon) overnight. Once
the reaction was complete, the mixture was filtered through Celite and
then a plug of silica gel. The solvent was removed under reduced
1
pressure to provide 24 mg (22%) of ( )-31a: H NMR (500 MHz,
CDCl3) δ 7.16 (td, J = 1.5, 7.7 Hz, 1H), 7.04 (dd, J = 1.3, 7.5 Hz, 1H),
6.85 (td, J = 1.0, 7.5 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H), 4.87 (d, J = 6.9
Hz, 1H), 4.18−4.11 (m, 1H), 4.09 (s, 1H), 3.97 (dd, J = 2.0, 14.0 Hz,
1H), 3.82 (dd, J = 4.4, 14.0 Hz, 1H), 3.75 (s, 1H), 3.66 (d, J = 14.2 Hz,
1H), 3.39 (td, J = 5.4, 11.7 Hz, 1H), 3.20 (td, J = 5.2, 11.7 Hz, 1H),
3.07 (dd, J = 3.5, 14.3 Hz, 1H), 1.83−1.59 (m, 3H), 0.96 (t, J = 7.4 Hz,
4H); 13C NMR (126 MHz, CDCl3) δ 145.1, 128.6, 128.6, 122.4,
121.0, 116.2, 75.3, 63.5, 59.7, 50.3, 40.5, 31.2, 18.3, 11.2; HRMS (ESI)
calcd for C14H20N2O [M+]+ 232.1654, found 232.1656.
1-(( )-1-(Hydroxymethyl)-2-propyl-1, 2a, 3, 8b-
tetrahydroazeto[2,3-c]quinolin-4(2H)-yl)ethanone 31b. A sol-
ution of acyl ( )-24c (0.094 g, 0.345 mmol) was dissolved in
methanol (4 mL) at room temperature. Ten percent palladium on
carbon (37 mg) was added, and hydrogen gas was bubbled into the
solution for 5 min. The reaction was then allowed to stir under an
atmosphere of hydrogen (via balloon) overnight. Once the reaction
was complete, the mixture was filtered through a pad of Celite and
then silica gel. The solvent was removed under reduced pressure to
N-(((1R,2aS,8bR)-2-Propyl-2,2a,3,8b-tetrahydro-1H-
chromeno[3,4-b]azet-1-yl) methyl)benzamide 32a. To solution
of the crude amine described above (50 mg, 0.215 mmol, 1.0 equiv) in
CH2Cl2 (2.2 mL) at 0 °C were added diisopropylethylamine (111 mL,
0.646 mmol, 3.0 equiv), benzoic acid (39 mg, 0.323 mmol, 1.5 equiv),
and PyBOP (146 mg, 0.280 mmol, 1.3 equiv). The solution was stirred
for 15 h, after which LC/MS of the reaction showed that all starting
material had been consumed. The reaction mixture was concentrated
under reduced pressure, and the crude residue was purified by
chromatography on silica gel using hexanes/EtOAc to provide 42 mg
of 32a (58% yield) as a clear oil: [α]2D0 −121.0 (c 0.14, CHCl3); IR νmax
(film) 3307, 2957, 2924, 2873, 1629, 1578, 1533, 1489, 1459, 1229;
1H NMR (300 MHz, CDCl3) δ 7.61 (d, J = 6.9 Hz, 2H), 7.50−7.31
(m, 3H), 7.05−6.94 (m, 2H), 6.94−6.85 (m, 1H), 6.79 (br s, 1H),
6.75 (d, J = 8.1 Hz, 1H), 4.18 (d, J = 12.0 Hz, 1H), 3.77 (br s, 1H),
3.63 (t, J = 5.4 Hz, 3H), 3.32−3.10 (m, 2H), 2.64 (t, J = 7.6 Hz, 2H),
1.61−1.32 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 166.4, 155.3, 134.3, 131.2, 130.2, 128.3, 128.0, 127.0, 122.3,
122.2, 118.0, 67.4, 64.2, 62.5, 59.5, 40.5, 31.1, 21.8, 12.0; HRMS (ESI)
calcd for C21H25N2O2 [M + H]+ 337.1916, found 337.1917.
N-(((1R,2aS,8bR)-2-Propyl-2,2a,3,8b-tetrahydro-1H-
chromeno[3,4-b]azet-1-yl) methyl)methanesulfonamide 26b.
To solution of the crude amine described above (57 mg, 0.245 mmol,
1.0 equiv) in CH2Cl2 (2.5 mL) at 0 °C were added 2,6-lutidine (85
mL, 0.936 mmol, 3.0 equiv) and methanesulfonyl chloride (29 mL,
0.368 mmol, 1.5 equiv). The solution was stirred for 3 h, after which
TLC of the reaction showed that all starting material had been
consumed. The reaction mixture was concentrated under reduced
pressure, and the crude residue was purified by chromatography on
silica gel using hexanes/EtOAc to provide 27 mg of 26b (36% yield) as
a colorless oil: [α]2D0 −96.4 (c 0.29, CHCl3); IR νmax (film) 3283, 2959,
2930, 2872, 1581, 1489, 1459, 1317, 1228, 1147; 1H NMR (500 MHz,
CDCl3) δ 7.17 (t, J = 8.0 Hz, 1H), 7.08−6.90 (m, 3H), 4.51 (br s,
1H), 4.10 (d, J = 11.3 Hz, 1H), 3.77−3.54 (m, 4H), 2.98−2.85 (m,
1H), 2.74 (ddd, J = 12.9, 6.1, 3.9 Hz, 1H), 2.71−2.59 (m, 2H), 2.55 (s,
3H), 1.55−1.41 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 156.1, 130.1, 128.3, 122.1, 122.0, 118.4, 67.5, 64.6,
62.4, 59.9, 43.8, 39.7, 30.7, 21.7, 12.0; HRMS (ESI) calcd for
C15H23N2O3S [M + H]+ 311.1429, found 311.1434.
1
provide 91 mg (96%) of ( )-31b: H NMR (500 MHz, CDCl3) δ
7.35−7.26 (m, 1H), 7.23−7.12 (m, 3H), 5.19 (s, 1H), 4.38 (s, 1H),
3.96 (s, 1H), 3.66 (d, J = 12.0 Hz, 1H), 3.55 (d, J = 11.7 Hz, 1H), 3.35
(s, 1H), 2.78 (s, 2H), 2.51 (s, 1H), 2.27 (s, 3H), 1.63−1.41 (m, 2H),
0.94 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 168.8, 139.9,
131.5, 128.9, 127.6, 126.2, 124.4, 72.9, 63.3, 60.5, 50.8, 40.3, 34.3, 23.2,
21.2, 11.6; HRMS (ESI) calcd for C16H23N2O2 [M+]+ 275.1760,
found 275.1749.
(( )-4-(Methylsulfonyl)-2-propyl-1,2,2a,3,4,8b-
hexahydroazeto[2,3-c]quinolin-1-yl)methanol 31c. A solution of
mesyl ( )-24c (0.115 g, 0.373 mmol) was dissolved in methanol (4
mL) at room temperature. Ten percent palladium on carbon (40 mg)
was added, and hydrogen gas was bubbled into the solution for 5 min.
The reaction was then allowed to stir under an atmosphere of
hydrogen (via balloon) overnight. Once the reaction was complete, the
mixture was filtered through Celite and then a plug of silica gel. The
solvent was removed under reduced pressure to provide 44 mg (38%)
1
of ( )-31c: H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 8.2, 1H),
7.32−7.24 (m, 1H), 7.18−7.12 (m, 2H), 4.41 (dd, J = 3.7, 13.8 Hz,
1H), 4.15 (dt, J = 3.6, 7.6 Hz, 1H), 3.79−3.73 (t, 1H), 3.71 (dd, J =
3.3, 11.7, 1H), 3.61 (dd, J = 1.6, 11.7, 1H), 3.54−3.48 (m, 1H), 3.30
(dd, J = 3.7, 13.8 Hz, 1H), 3.12 (s, 3H), 2.94−2.82 (m, 2H), 2.68−
2.56 (m, 1H), 1.55−1.38 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR
(126 MHz, CDCl3) δ 137.9, 131.1, 128.9, 127.4, 125.2, 121.6, 71.2,
61.2, 60.9, 50.3, 46.2, 38.9, 33.6, 22.0, 11.9; HRMS (ESI) calcd for
C15H22N2O3S [M+]+ 310.1429, found 310.1433.
Procedure for the Synthesis of Benzopyran Derivatives 32a
and 32b. To a degassed solution of tetrahydrochrome derivative (see
synthesis of 25a) (285 mg, 1.26 mmol, 1.0 equiv) dissolved in MeOH
(12.6 mL) was added palladium hydroxide (20 wt % on activated
carbon, 18 mg, 0.126 mmol, 0.1 equiv). Hydrogen gas was bubbled
through the reaction mixture for 5 min and then placed under a static
H2 atmosphere (balloon pressure) and stirred for 15 h, after which
analysis of the reaction mixture by LC/MS showed that the reaction
was complete. The mixture was diluted with CH2Cl2 and filtered
(2S,3S)-1-Allyl-2-(hydroxymethyl)-3-phenyl-6-ortho-nosyl-
1,6-diazaspiro[3.3]heptane des-Br-15a. Scaffold des-Br-15a was
prepared identical to 15a: [α]2D1 +61.1 (c 0.96, CHCl3); IR νmax (film)
3387, 2952, 2874, 1544, 1370, 1356, 1169, 1031; 1H NMR (300 MHz,
CDCl3) δ 7.95 (m, 1H), 7.66 (m, 3H), 7.31 (m, 5H), 5.84 (ddt, J =
7208
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
6.3, 10.0, 16.4, 1H), 5.22 (d, J = 17.2, 1H), 5.02 (d, J = 10.1, 1H), 4.80
(d, J = 9.0, 1H), 4.14 (d, J = 8.9, 1H), 4.01 (d, J = 9.5, 1H), 3.92 (d, J =
9.4, 1H), 3.43 (m, 2H), 3.23 (m, 2H), 1.12 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 148.67, 136.11, 135.68, 134.01, 132.11, 131.94,
131.04, 129.73, 128.85, 127.80, 124.50, 118.24, 66.98, 64.40, 62.61,
61.21, 58.35, 54.67, 50.30; HRMS (ESI) calcd for C21H24N3O5S [M +
H]+ 430.1437, found 430.1425.
(2R,3R)-1-Allyl-2-(hydroxymethyl)-3-phenyl-6-ortho-nosyl-
1,6-diazaspiro[3.3]heptane ent-des-Br-15a: [α]2D1 −69.3 (c 0.3,
CHCl3); HRMS (ESI) calcd for C21H24N3O5S [M + H]+ 430.1437,
found 430.1428. Spectral data were identical to those provided for
enantiomer des-Br-15a.
(2S,3R)-1-Allyl-2-(hydroxymethyl)-3-phenyl-6-ortho-nosyl-
1,6-diazaspiro[3.3]heptane des-Br-15c. Scaffold des-Br-15c was
prepared identical to 15c: [α]2D1 +75.1 (c 1.0, CHCl3); IR νmax (film)
3399, 2922, 2873, 1542, 1354, 1169, 1126, 1030; 1H NMR (300 MHz,
CDCl3) δ 7.83 (d, J = 7.8, 1H), 7.73−7.59 (m, 3H), 7.31−7.21 (m,
3H), 7.11 (d, J = 7.7, 2H), 5.79 (ddt, J = 6.5, 10.1, 16.6, 1H), 5.18 (d, J
= 17.1, 1H), 4.98 (d, J = 10.1, 1H), 4.33 (d, J = 9.3, 1H), 4.18 (dd, J =
9.4, 20.5, 2H), 3.70−3.63 (m, 2H), 3.60−3.52 (m, 2H), 3.45 (br d, J =
11.4, 1H), 3.34 (dd, J = 6.4, 13.5, 1H), 3.21 (dd, J = 6.6, 13.5, 1H),
2.83 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 148.60, 136.10, 134.83,
134.09, 131.91, 130.87, 130.24, 128.95, 128.01, 127.44, 124.29, 118.44,
66.15, 65.14, 63.86, 61.53, 53.38, 53.01, 45.79; HRMS (ESI) calcd for
C21H24N3O5S [M + H]+ 430.1437, found 430.1428.
(2R,3S)-1-Allyl-2-(hydroxymethyl)-3-phenyl-6-ortho-nosyl-
1,6-diazaspiro[3.3]heptane ent-des-Br-15c: [α]2D1 −79.0 (c 0.38,
CHCl3); HRMS (ESI) calcd for C21H24N3O5S [M + H]+ 430.1437,
found 430.1431. Spectral data were identical to those provided for
enantiomer des-Br-15c.
Solid-Phase Library Synthesis. Solid-phase library synthesis was
conducted on silicon-functionalized polystyrene Lanterns (L-series)14
equipped with radio frequency transponders for directed sorting and
compound tracking. All reactions were conducted in heavy wall
pressure vessels with agitation in an incubator shaker.
Scaffold Loading. To a flame-dried flask containing silicon-
functionalized Lanterns14 was added a freshly prepared solution of
TfOH in anhydrous CH2Cl2 (9.0 equiv, 5 g of TfOH/100 mL of
CH2Cl2). Each flask was shaken at rt for 10 min at which time the
Lanterns had turned bright orange. The deep red TfOH solution was
removed via cannula, and anhydrous 2,6-lutidine (12.0 equiv relative
to Si) was added. Once the Lantern color had changed from orange to
white, the appropriate stereoisomer of des-Br-15 (1.2 equiv relative to
Si) was added as a solution in anhydrous CH2Cl2 (0.4 mL/Lantern)
and the reaction mixture was shaken at rt overnight. The loading
mixture was removed and set aside (to recover any unreacted alcohol),
and the Lanterns were washed with the following solvents for 30 min
intervals: CH2Cl2, THF, 3:1 THF/IPA, 3:1 THF/H2O, DMF, 3:1
THF/H2O, 3:1 THF/IPA, THF, CH2Cl2. The Lanterns were then
dried on a lyophilizer overnight prior to sorting. All four stereoisomers
of des-Br-15 were loaded via the same protocol.
Nosyl Removal. To a flask containing Lanterns was added THF
(0.8 mL/Lantern) followed by thiophenol (20 equiv) and potassium
carbonate (30 equiv). The Lanterns were shaken at rt overnight and
then washed with the following solvents for 30 min intervals: DMF
(two washes), THF/H2O (3:1), THF/isopropyl alcohol (3:1), THF,
and CH2Cl2. The Lanterns were then dried on a lyophilizer overnight
prior to sorting.
THF/H2O, 3:1 THF/IPA, THF, CH2Cl2. The Lanterns were then
dried on a lyophilizer overnight prior to sorting.
N-Capping/Acids. To each flask containing lanterns was added
CH2Cl2 (0.8 mL/Lantern) followed by triethylamine (30 equiv) and
the desired acid (20 equiv). PyBOP (20 equiv) was added, and the
Lanterns were shaken at rt overnight and then washed with the
following solvents for 30 min intervals: CH2Cl2, DMF, 3:1 THF/H2O,
3:1 THF/IPA, THF, CH2Cl2. The Lanterns were then dried on a
lyophilizer overnight prior to sorting
N-Capping/Aromatic Aldehydes. To each flask containing
Lanterns was added DMF with 2% AcOH (0.800 mL/Lantern)
followed by the desired aldehyde (20 equiv). The reaction mixture was
shaken at rt for 1 h, and then sodium triacetoxyborohydride (25 equiv)
was added and shaking was continued. After 3 days, the reaction
mixture was removed and the Lanterns were washed with the
following solvents for 30 min intervals: DMF, 3:1 THF/H2O, 3:1
THF/IPA, THF, CH2Cl2. The Lanterns were then dried on a
lyophilizer overnight prior to sorting.
N-Capping/Aliphatic Aldehydes. To each flask containing
lanterns was added THF/MeOH 4:1 with 2% AcOH (0.800 mL/
Lantern) followed by the desired aldehyde (20 equiv). The reaction
mixture was shaken at rt for 1 h then sodium cyanoborohydride (25
equiv) was added and shaking was continued. After 3 days, the
reaction mixture was removed and the Lanterns were washed with the
following solvents for 30 min intervals: DMF, 3:1 THF/H2O, 3:1
THF/IPA, THF, CH2Cl2. The Lanterns were then dried on a
lyophilizer overnight prior to sorting.
Allyl Removal. To a flask containing Lanterns was added EtOH
(0.8 mL/Lantern) followed by Pd(PPh3)4 (2 equiv) and 1,3-
dimethylbarbituric acid (15 equiv). The Lanterns were shaken at 40
°C for 4 days and then washed with the following solvents for 30 min
intervals: DMF (two washes), THF/H2O (3:1), THF/IPA (3:1),
THF, and CH2Cl2. The Lanterns were then dried on a lyophilizer
overnight prior to sorting.
Cleavage Protocol. To a 96-well plate containing Lanterns was
added a 15% solution of HF/pyridine in stabilized THF (350 μL/
Lantern). After 2 h, the cleavage solution was quenched with
TMSOMe (700 μL/Lantern) and the contents of each well were
transferred to a preweighed 1.4 mL tube. The Lanterns were washed
with an additional 200 μL of stabilized THF (or THF/MeOH), and
the solution was transferred to the same 1.4 mL tube. The samples
were concentrated on a multisample solvent evaporation system
overnight without heating. The recovered mass for each library
member was determined on an automated weighing system.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra for all new compounds, LC/MS data
for representative library members, Charts SI-1 and SI-2 which
were cited in ref 41, Figure SI-1 which was cited in ref 41, and
X-ray crystallographic information for select compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: lisa_marcaurelle@h3biomedicine.com.
■
N-Capping/Sulfonyl Chlorides. To each flask containing
Lanterns was added CH2Cl2 (0.8 mL/Lantern) followed by 2,6-
lutidine (30 equiv) and the desired sulfonyl chloride (15 equiv). The
Lanterns were shaken at rt overnight and then washed with the
following solvents for 30 min intervals: CH2Cl2, DMF, 3:1 THF/H2O,
3:1 THF/IPA, THF, CH2Cl2. The Lanterns were then dried on a
lyophilizer overnight prior to sorting.
N-Capping/Isocyanates. To each flask containing Lanterns was
added CH2Cl2 (0.8 mL/Lantern) followed the desired isocyanate (15
equiv). The Lanterns were shaken at rt overnight and then washed
with the following solvents for 30 min intervals: CH2Cl2, DMF, 3:1
Present Address
§H3 Biomedicine, 300 Technology Square, Cambridge, MA
02139.
ACKNOWLEDGMENTS
■
This work was funded in part by the NIGMS-sponsored Center
of Excellence in Chemical Methodology and Library Develop-
ment (Broad Institute CMLD; P50 GM069721), as well as the
NIH Genomics Based Drug Discovery U54 grants Discovery
Pipeline RL1CA133834 (administratively linked to NIH Grants
7209
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
6751−6756. (b) Wrona, I. E.; Lowe, J. T.; Turbyville, T. J.; Johnson,
T. R.; Beignet, J.; Beutler, J. A.; Panek, J. S. J. Org. Chem. 2008, 74,
1897−1916. (c) Curran, D. P.; Zhang, Q.; Richard, C.; Lu, H.;
Gudipathi, V.; Wilcox, C. S. J. Am. Chem. Soc. 2006, 128, 9561−9573.
(d) Dandapani, S.; Jeske, M.; Curran, D. P. J. Org. Chem. 2005, 70,
9447−9462. (e) Zhang, Q. S.; Lu, H. J.; Curran, D. P. J. Am. Chem.
Soc. 2004, 126, 36−37. (f) Nishii, Y.; Maruyama, N.; Wakasugi, K.;
Tanabe, Y. Bioorg. Med. Chem. 2001, 9, 33−39.
RL1HG004671, RL1GM084437, and UL1DE019585), and the
Stanley Medical Research Institute.
REFERENCES
■
(1) (a) Morton, D.; Leach, S.; Cordier, C.; Warriner, S.; Nelson, A.
Angew. Chem., Int. Ed. 2009, 48, 104−109. (b) Arya, P.; Joseph, R.;
Gan, Z.; Rakic, B. Chem. Biol. 2005, 12, 163−180. (c) Tan, D. S. Nat.
Chem. Biol. 2005, 1, 74−84. (d) Burke, M. D.; Schreiber, S. L. Angew.
Chem., Int. Ed. 2004, 43, 46−58. (e) Schreiber, S. L. Science 2000, 287,
1964−1969.
(2) Tepper, R. I.; Roubenoff, R. In Genomics and Personalized
Medicine; Willard, H. F., Ginsburg, G. S., Eds; Elsevier Inc.:
Amsterdam, 2009; pp 335−342.
(13) Comer, E.; Rohan, E.; Deng, L.; Porco, J. A., Jr. Org. Lett. 2007,
9, 2123−2126.
(14) Ryba, T. D.; Depew, K. M.; Marcaurelle, L. A. J. Comb. Chem.
2009, 11, 110−116.
(15) (1R,2R)-2-Amino-1-(4-bromophenyl)propane-1,3-diol was pur-
chased from Acme Bioscience (http://www.acmeca.com/) and
selectively allylated to provide 1a using a procedure adapted from
ref 11a.
(3) Payne, R. H.; Gwynn, M. N.; Holmes, D. J.; Pompliano, D. L.
Nat. Rev. Drug Discovery 2007, 6, 29−40.
(4) (a) Huryn, D. M.; Jeffrey L. Brodsky, J. L.; Brummond, K. M.;
Chambers, P. G.; Eyer, B.; Ireland, A. W.; Kawasumi, M.; LaPorte, M.
G.; Lloyd, K.; Manteau, B.; Nghiem, P.; Quade, B.; Seguin, S. P.; Wipf,
P. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6757−6762. (b) Cui, J.; Hao,
J.; Ulanovskaya, O. A.; Dundas, J.; Liang, J.; Kozmin, S. A. Proc. Natl.
Acad. Sci. U.S.A. 2011, 108, 6763−6768. (c) Marcaurelle, L. A.; Comer,
E.; Dandapani, S.; Duvall, J. R.; Gerard, B.; Kesavan, S.; Lee, M. D., IV;
Liu, H.; Lowe, J. T.; Marie, J.-C.; Mulrooney, C. A.; Pandya, B. A.;
Rowley, A.; Ryba, T. D.; Suh, B.-C.; Wei, J.; Young, D. W.; Akella, L.
B.; Ross, N. T.; Zhang, Y.-L.; Fass, D. M.; Reis, S. A.; Zhao, W.-Z.;
Haggarty, S. J.; Palmer, M.; Foley, M. A. J. Am. Chem. Soc. 2010, 132,
16962−16976. (d) Bauer, R. A.; DiBlasi, C. M.; Tan, D. S. Org. Lett.
2010, 12, 2084−2087. (e) Diaz-Gavilan, M.; Galloway, W. R. J. D.;
O’Connell, K. M. G.; Hogkingson, J. T.; Spring, D. R. Chem. Commun.
2010, 46, 776−778. (f) Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7,
47−50. (g) Boldi, A. M. Curr. Opin. Chem. Biol. 2004, 8, 281−286.
(h) Taylor, S. J.; Taylor, A. M.; Schreiber, S. L. Angew. Chem., Int. Ed.
2004, 43, 1681−1685. (i) Lo, M. M. C.; Neumann, C. S.; Nagayama,
S.; Perlstein, E. O.; Schreiber, S. L. J. Am. Chem. Soc. 2004, 126,
16077−16086.
(5) (a) Hajduk, P. J. Nature 2011, 470, 42−43. (b) Cooper, T. W. J.;
Campbell, I. B.; Macdonald, S. J. F. Angew. Chem., Int. Ed. 2010, 49,
8082−8091. (c) Shelat, A. A.; Guy, K. Curr. Opin. Chem. Biol. 2007,
11, 244−251.
(6) Akella, L. B.; Marcaurelle, L. A. ACS Comb. Sci. 2011, 13, 357−
364.
(7) (a) Pajouhesh, H.; Lenz, G. R. NeuroRx 2005, 2, 541−553.
(b) Alavijeh, M. S.; Chishty, M.; Qaiser, M. Z.; Palmer, A. M. NeuroRx
2005, 2, 554−571.
(8) Teague, S. J.; Davis, A. M.; Leeson, P. D.; Oprea, T. Angew.
Chem., Int. Ed. 1999, 38, 3745−3747.
(9) For a selection of recent reviews on the biological activity of β-
lactams, see: (a) von Nussbaum, F.; Brands, M.; Hinzen, B.; Weigand,
S.; Habich, D. Angew. Chem., Int. Ed. 2006, 45, 5072−5129. (b) Singh,
G. S. Mini-Rev. Med. Chem. 2004, 4, 69−92. (c) Singh, G. S. Mini-Rev.
Med. Chem. 2004, 4, 93−109. (d) Buynak, J. D. Curr. Med. Chem.
2004, 11, 1951−1964. (e) Veinberg, G.; Vorona, M.; Shestakova, I.;
Kanepe, I.; Lukevics, E. Curr. Med. Chem. 2003, 10, 1741−1757.
(f) Kidwai, M.; Sapra, P.; Bhushan, K. R. Curr. Med. Chem. 1999, 6,
195−215.
(10) For reviews of the synthesis and utility of azetidine compounds,
see: (a) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108,
3988−4035. (b) Couty, F.; Evano, G.; Prim, D. Mini-Rev. Org. Chem.
2004, 1, 133−148.
(16) (1R,2S)-Allyl amino diol 1b was accessed through a modified
literature procedure. See: Martín, R.; Moyano, A.; Pericas
̀
, M. A.;
Riera, A. Org. Lett. 2000, 2, 93−95.
(17) The retention of configuration observed in 2a and 2b is
postulated to arise from a double SN2 reaction pathway involving an
intermediate azeridinium ion. See ref 11e.
(18) (a) Murineddu, G.; Murruzzu, C.; Curzu, M. M.; Chelucci, G.;
Gotti, C.; Gaimarri, A.; Legnani, L.; Toma, L.; Pinna, G. A. Bioorg.
Med. Chem. Lett. 2008, 18, 6147−6150. (b) Loriga, G.; Manca, I.;
Murineddu, G.; Chelucci, G.; Villa, S.; Gessi, S.; Toma, L.; Cignarella,
G.; Pinna, G. A. Bioorg. Med. Chem. 2006, 14, 676−691.
(19) Upon removal of the nosyl group of 5a (not shown), single
crystals suitable for X-ray analysis were obtained as the hydrochloride
salt (see Supporting Information), establishing the formation of the
[1.1.3]-bridged system.
(20) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62,
7507.
(21) The removal of the nosyl protecting group followed by radical
dehalogenation (not shown) of 12a provided X-ray quality crystals,
showing the presence of desired eight-membered ring system (see
Supporting Information).
(22) (a) Wuitschik, G.; Rogers-Evans, M.; Buckl, A.; Bernasconi, M.;
Marki, M.; Godel, T.; Fischer, H.; Wagner, B.; Parrilla, I.; Schuler, F.;
̈
Schneider, J.; Alker, A.; Schweizer, W. B.; Muller, K.; Carreira, E. M.
̈
Angew. Chem., Int. Ed. 2008, 47, 4512−4515. (b) Burkhard, J. A.;
Wuitschik, G.; Rogers-Evans, M.; Muller, K.; Carreira, E. M. Angew.
Chem., Int. Ed. 2010, 49, 9052−9067. (c) Wuitschik, G.; Carreira, E.
M.; Wagner, B.; Fischer, H.; Parrilla, I.; Schuler, F.; Rogers-Evans, M.;
̈
Muller, K. J. Med. Chem. 2010, 53, 3227−3246. (d) Guer
́
ot, C.;
Tchitchanov, B. H.; Knust, H.; Carreira, E. M. Org. Lett. 2011, 13,
ot, C.; Knust, H.; Evans, M. R.;
̈
780−783. (e) Burkhard, J. A.; Guer
́
Carreira, E. M. Org. Lett. 2010, 12, 1944−1947. (f) Burkhard, J. A.;
Wagner, B.; Fischer, H.; Schuler, F.; Muller, K.; Carreira, E. M. Angew.
Chem., Int. Ed. 2010, 49, 3524−3527. (g) Burkhard, J. A.; Guer
́
ot, C.;
Knust, H.; Carreira, E. M. Org. Lett. 2012, 14, 66−69.
(23) (a) Xu, R.; Czarniecki, M.; de Man, J.; Pan, J.; Qiang, L.; Root,
Y.; Ying, S.; Su, J.; Sun, X.; Zhang, Y.; Yu, T.; Zhang, Y.; Hu, T.; Chen,
S.-H. Tetrahedron Lett. 2011, 52, 3266−3270. (b) Meyers, M. J.;
Muizebelt, I.; van Wiltenburg, J.; Brown, D. L.; Thorarensen, A. Org.
Lett. 2009, 11, 3523−3525.
(24) Deguest, G.; Bischoff, L.; Fruit, C.; Marsais, F. Org. Lett. 2007, 9,
1165−1167.
(25) Repeating this sequence to access the p-nosylated spirocycle was
also achieved. This provided material that could be recrystallized to
obtain an X-ray crystal structure showing the desired [3.3]-spirocycle
(see Supporting Information).
(26) See Supporting Information for X-ray structure of 15a.
(27) Drouillat, B.; Couty, F.; David, O.; Evano, G.; Marrot, J. Synlett
2008, 9, 1345−1348.
(28) (a) Kubo, T.; Katoh, C.; Yamada, K.; Okano, K.; Tokuyama, H.;
Fukuyama, T. Tetrahedron 2008, 64, 11230−11236. (b) Omar-Amrani,
R.; Thomas, A.; Brenner, E.; Schneider, R.; Fort, Y. Org. Lett. 2003, 5,
2311−2314. (c) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793−
(11) (a) Drouillat, B.; Couty, F.; Marrot, J. Synlett 2009, 5, 767−770.
(b) Sivaprakasham, M; Couty, F.; Evano, G.; Srinivas, B.; Sridhar, R.;
Rao, K. R. ARKIVOC 2007, 71−93. (c) Couty, F.; Evano, G.; Vargas-
Sanchez, M.; Bouzas, G. J. Org. Chem. 2005, 70, 9028−9031.
(d) Couty, F.; Evano, G.; Rabasso, N. Tetrahedron: Asymmetry 2003,
14, 2407−2412. (e) Couty, F.; Prim, D. Tetrahedron: Asymmetry 2002,
13, 2619−2624. (f) Agami, C.; Couty, F.; Evano, G. Tetrahedron:
Asymmetry 2002, 13, 297−302.
(12) (a) Comer, E.; Liu, H.; Joliton, A.; Clabaut, A.; Johnson, C.;
Akella, L. B.; Marcaurelle, L. A. Proc. Natl. Acad. Sci. U.S.A. 2011, 108,
7210
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211

The Journal of Organic Chemistry
Featured Article
796. (d) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4,
581−584.
(29) (a) Niu, J.; Guo, P.; Kang, J.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem.
2009, 74, 5075−5078. (b) Kuwabe, S. I.; Torraca, K. E.; Buchwald, S.
L. J. Am. Chem. Soc. 2001, 123, 12202−12206.
(30) Hitchcock, S. A.; Pennington, L. D. J. Med. Chem. 2006, 49,
7559−7583.
(31) In silico analysis was performed using Stardrop interactive
software platform: http://www.optibrium.com/stardrop.php.
(32) The CNS MPO score was recently developed by Pfizer to
provide a means to predict the potential success of CNS candidates in
a clinical setting. The algorithm aims to enable greater flexibility in the
design stage by eliminating hard cutoffs with respect to properties
which may be interpreted as a potential hazard in regards to the
behavior of a compound in vivo for details. See: Wager, T. T.; Hou, X.;
Verhoest, P. R.; Villalobos, A. ACS Chem. Neurosci. 2010, 1, 435−449.
(33) Medina-Franco, J. L.; Maggiora, G. M.; Giulianotti, M. A.;
Pinilla, C.; Houghten, R. A. Chem. Biol. Drug Des. 2007, 70, 393−412.
The MFS map was generated using Pipeline Pilot: Pipeline Pilot,
SciTegic, Inc.: 10188 Telesis Court, Suite 100, San Diego, CA 92121,
USA; http://www.scitegic.com/products_services/pipeline_pilot.htm.
(34) (a) Sugano, K.; Kansy, M.; Artursson, P.; Avdeef, A.; Bendels,
S.; Di, L.; Ecker, G. F.; Faller, B.; Fischer, H.; Gerebtzoff, G.;
Lennernaes, H.; Senner, F. Nat. Rev. Drug Discovery 2010, 9, 597−614.
(b) Smith, D. A.; Di, L.; Kerns, E. H. Nat. Rev. Drug Discovery 2010, 9,
929−939.
(35) Dagenais, C.; Avdeef, A.; Tsinman, O.; Dudley, A.; Beliveau, R.
Eur. J. Pharm. Sci. 2009, 38, 121−137.
(36) (a) Irvine, J. D.; Takahashi, L.; Lockhart, K.; Cheong, J.; Tolan,
J. W.; Selick, H. E.; Grove., J. R. J. Pharm. Sci. 1999, 88, 28−33.
(b) Artursson, P. J. Pharm. Sci. 1990, 79, 476−482.
(37) Anderle, P.; Niederer, E.; Rubas, W.; Hilgendorf, C.; Spahn-
Langguth, H.; Wunderli-Allenspach, H.; Merkle, H. P.; Langguth, P. J.
Pharm. Sci. 1998, 87, 757−762.
(38) The master list of reagents used for library enumeration is
provided in ref 6.
(39) See Supporting Information for full list of reagents used for the
library production (Charts SI-1 and SI-2).
(40) See Supporting Information for purity analysis (Figure SI-1).
(41) Dandapani, S.; Marcaurelle, L. A. Nat. Chem. Biol. 2010, 6, 861−
863.
(42) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52,
6752−6756.
(43) Nadin, A.; Hattotuwagama, C.; Churcher, I. Angew. Chem., Int.
Ed. 2012, 51, 1114−1122.
(44) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997,
62, 7512−7515.
7211
dx.doi.org/10.1021/jo300974j | J. Org. Chem. 2012, 77, 7187−7211