Enantio- and diastereoselective synthesis of highly substituted benzazepines by a multicomponent strategy coupled with organocatalytic and enzymatic procedures

Article abstract of DOI:10.1021/jo402527w

Enantiomerically pure 4,5-dihydro-1H-benzo[c]azepines with three contiguous stereogenic centers have been assembled by convergent strategy with a good control of diastereoselectivity. The two steps are as follows: an asymmetric organocatalytic Mannich reaction performed on Boc-imines of o-(azidomethyl) benzaldehydes, followed by a one-pot Staudinger/aza-Wittig/Ugi-Joullie sequence. The latter reaction represents one of the first examples of diastereoselective Ugi three-component reaction on a seven-membered cyclic imine. The o-azidomethylbenzaldehydes have been synthesized employing a simple and efficient chemoenzymatic strategy from commercially available building blocks.

Full text of DOI:10.1021/jo402527w

Article
pubs.acs.org/joc
Enantio- and Diastereoselective Synthesis of Highly Substituted
Benzazepines by a Multicomponent Strategy Coupled with
Organocatalytic and Enzymatic Procedures
Lisa Moni, Luca Banfi, Andrea Basso, Andrea Galatini, Martina Spallarossa, and Renata Riva*
Department of Chemistry and Industrial Chemistry, University of Genova, Via Dodecaneso, 31, 16146 Genova, Italy
S
* Supporting Information
ABSTRACT: Enantiomerically pure 4,5-dihydro-1H-benzo[c]azepines with three contiguous stereogenic centers have been
assembled by convergent strategy with a good control of diastereoselectivity. The two steps are as follows: an asymmetric
organocatalytic Mannich reaction performed on Boc-imines of o-(azidomethyl)benzaldehydes, followed by a one-pot Staudinger/
aza-Wittig/Ugi−Joullie sequence. The latter reaction represents one of the first examples of diastereoselective Ugi three-
́
component reaction on a seven-membered cyclic imine. The o-azidomethylbenzaldehydes have been synthesized employing a
simple and efficient chemoenzymatic strategy from commercially available building blocks.
at C5 and a carboxy moiety at C3 are unknown. Many different
approaches for assembling this heterocycle are known. Within
the most recent papers, two different ring closures to give the 2-
benzazepine skeleton, based on a Friedel−Crafts reaction, have
been described: the first one couples 3-arylpropionamides and
formaldehyde,6 and the second one involves a 7-endo selective
cyclization of vinyloxirane.7 In addition, other approaches have
been reported in recent years, including, for example, ring-
closing metathesis8 and lactamization.9,10
In this paper, we present a new stereoselective approach to
an unprecedented class of chiral seven-membered 2-benzaze-
pines, namely 4,5-dihydro-1H-benzo[c]azepine of general
structure 1, characterized by three adjacent stereogenic centers.
The synthetic strategy, depicted in Scheme 2, allows the
introduction of at least four diversity points.
INTRODUCTION
■
The benzazepine scaffold is a privileged structure in medicinal
chemistry and can be found in many biologically active
compounds. Some of them are the active pharmaceutical
ingredient (API) of marketed drugs, such as galanthamine, used
to treat mild to moderate Alzheimer’s disease and lorcaserin, a
weight-loss drug (Scheme 1). Within this heterocyclic group, 2-
Scheme 1. Examples of APIs Containing a Benzazepine
Scaffold
The key step in our synthetic plan is the three-component
Ugi−Joullie
́
reaction11,12 using chiral, enantiomerically pure,
cyclic imines 2. This Ugi three-component reaction has recently
emerged as a powerful method for synthesizing in a
stereocontrolled way and, in just one step, various druglike
nitrogen heterocycles. Two diversity points are embodied by
the appendages derived from the isocyanide and carboxylic acid
components. The third diversity point is the heterocyclic
scaffold itself resulting from the cyclic imine. In order to fully
explore the scaffold diversity, efficient and short synthetic
pathways to access a variety of chiral cyclic imines with different
ring size in enantiomerically pure form are needed. For this
purpose, the ideal methodology would be diversity-oriented as
benzazepines have been deeply investigated in the last decades,
and recently several interesting biological properties have been
reported. For example, they can act as kinase inhibitors,1
histone deacetylase inhibitors,2 glycine transporter 1 inhibitors
(antipsychotic drugs),3 selective PPARδ agonists,4 and
inhibitors of factor Xa (anticoagulants),5 and they may also
be involved in new drug therapies to treat skin wounds.6
While a huge variety of substituents has been introduced on
the benzene ring and on the heterocyclic nitrogen, the diversity
of the appendages on the seven-membered heterocyclic ring
has been little explored to date and very few enantio- and/or
diastereoselective approaches to these scaffolds have been
reported. In particular, compounds with a nitrogen substituent
Received: November 14, 2013
Published: December 11, 2013
© 2013 American Chemical Society
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Article
privileged scaffold in medicinal chemistry. In this context, we
are developing diversity-oriented and enantioselective ap-
proaches to dihydrobenz(oxa)azepines to be used as input in
Scheme 2. Retrosynthetic Analysis
́
the Ugi−Joullie reaction. We have recently reported a first
successful achievement of this strategy, where the imine was
constructed by joining a salicylaldehyde derivative with a chiral
alcohol using a Mitsunobu reaction.28,29 This has represented
́
the first example of a diastereoselective Ugi−Joullie reaction on
a seven-membered cyclic imine. While in that work the
stereochemistry of the dihydrobenzoxazepine was controlled by
the starting chiral alcohol, in this report we decided to follow a
truly enantioselective approach.
To accomplish the enantioselective synthesis of imine 2 we
planned to apply an organocatalytic methodology, involving an
asymmetric Mannich reaction on Boc-protected imines 4, to
give β-amino aldehydes 3. This methodology allows to
introduce two diversity points and requires just two synthetic
steps from readily available ureido sulfones 5. The latter
intermediates can be prepared through an efficient sequence
where the two alcoholic moieties of 6 are differentiated by a
chemoenzymatic approach.
well, allowing the introduction of additional diversity points
during the construction of the cyclic imines.
Most examples of the Ugi−Joullie reaction on enantiomeri-
́
RESULTS AND DISCUSSION
■
In an exploratory study we chose to synthesize first aldehyde 13
(Scheme 3). For our purposes we needed to differentiate the
two equivalent hydroxy groups of 1,2-phenylenedimethanol 8,
obtained in nearly quantitative yield from commercially
available phthalide 7. Every attempt to selectively manipulate
just one of the hydroxy groups under classical chemical
conditions gave poor results30 until we discovered that an
enzymatic acylation mediated by supported porcine pancreatic
lipase31 is able to afford monoacetate 9 in excellent yield.
Starting from this monoacetate, azido alcohol 1030 was
obtained in excellent overall yield and without the need of any
purification. The following oxidation to give 11 was successfully
performed using catalytic tetraproylammonium perruthenate
(TPAP) even with only 2% of the catalyst but with a 2 days
reaction time.32 However, a shorter reaction time (2 h) and
comparable yields were obtained using a more practical (no dry
solvents nor inert atmosphere needed) and less expensive
cally pure substrates reported to date involve chiral pyrrolines,
which have been obtained either by a Staudinger/aza-Wittig
reaction on acyclic precursors, derived from the chiral pool12−17
or through enzymatic desymmetrizations18,19 or by biocatalytic
oxidation of meso-pyrrolidines.20,21 On the other hand, chiral
six-membered cyclic imines have been mostly used as
racemates22,23 and only in few cases in enantiomerically pure
form.24−27 In most cases, although not always, a good control
of the diastereoselectivity has been observed. All the chiral five-
membered or six-membered cyclic imines employed to date in
́
Ugi−Joullie reactions have been prepared in a target-oriented
way, without the possibility of introducing diversity prior to the
multicomponent reaction.
In the last years, we have been particularly interested in the
use of isocyanide multicomponent reactions for the synthesis of
seven-membered heterocycles, which represent a typical
Scheme 3. Organocatalytic Synthesis of Mannich Product 13
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Scheme 4. Stereoselective Ugi−Joullie Reaction from Chiral Aldehyde 13
Article
́
oxidant, which is catalytic TEMPO (2,2,6,6-tetramethyl-1-
piperidinyl oxide, free radical) in the presence of
(diacetoxyiodo)benzene as stoichiometric oxidant.33
have no explanation for the formation of several byproducts
and for the low ee observed.
In order to gain access to the anti stereoisomer of 13, we
tried the “complementary” Jørgensen−Hayashi catalyst 15,
known to induce the opposite relative stereochemistry with
respect to proline in both aldol and Mannich reactions.38 This
catalyst showed poor activity: after 10 days only 20% of 13 was
isolated with a 1:0.8 anti:syn ratio, while the prevailing product
was aldehyde 11, arising from the decomposition of the Boc-
imine. For reasons that will become clear below, we decided
not to pursue further the synthesis of anti isomers.
Also thanks to the high yield (>90%) and to the purity of
aldehyde 11, we decided not to isolate it because of its
volatility, and after a rapid filtration over silica gel, the
concentrated solution was directly used for the synthesis of
ureidosulfone 12. The standard method to prepare these ureido
sulfones,34,35 using a large excess of aldehyde, was not practical
in this case. After several attempts, we finally obtained good
results using an excess of sodium p-toluenesulfinate and
isolating 12 in pure form by precipitation after sonication of
the crude reaction mixture. It is worth noting that pure 12 was
obtained in 44% overall yield from monoacetate 9 (five steps)
using a single final purification operation (precipitation). The
base-mediated elimination step to give the key Boc-protected
imine 4 (R1 = H) was not trivial as well, and only cesium
carbonate at 40 °C19 was successful.36 The following Mannich
reaction was directly performed using either L- or D-proline as
the catalyst, according to List’s protocol,34,35 and the respective
aldehydes 13 or ent-13 were isolated in 77% overall yield from
12. The ee, determined by HPLC on chiral stationary phase on
the corresponding alcohol 14,37 was >99% for both
enantiomers. The absolute and relative stereochemistry of 13
and its enantiomer were established according to literature
precedent.38
To avoid the epimerization of 13, we decided to investigate
the following transformations on the crude aldehyde (Scheme
4). The Staudinger/aza-Wittig reaction is an efficient method
for the construction of carbon−nitrogen double bonds.40 The
possibility of coupling the Staudinger reduction of azides with
the aza-Wittig reaction in a one-pot sequence has been applied
to the synthesis of five- and six-membered cyclic
imines14−16,18,24 but never to build a seven-membered ring.
The conditions previously developed in our group for the
sequential Staudinger/aza-Wittig/Ugi−Joullie
́
reaction18 did
not afford any trace of the expected products. An extensive
investigation of the reaction outcome, by repeatedly recording
proton spectra of the reaction mixture in the appropriate
deuterated solvent (THF or toluene), unequivocally demon-
strated the instability of imine 16. After careful optimization
(see Table 1), we found that the most important factor was a
very short reaction time (30 min) for the Staudinger/aza-Wittig
reaction. For this step we found that PPh3 at 0 °C in THF
represents the best conditions. However, the following MCR
could not be performed in THF because the reaction was too
slow in this solvent.15,29 On the other hand, the use of
methanol, one of the solvents of choice for the Ugi reaction, for
both steps, afforded 19 only in traces. Eventually, the best
results were obtained by a quick evaporation of THF, followed
by addition of methylene chloride, a solvent often used in
MCRs on other cyclic imines.15,20,41 The possible competition
with the Passerini reaction, favored by less polar solvents,42 was
not a problem, since we were working on a preformed imine. In
Also the diastereoselectivity, if determined by NMR on the
crude aldehyde, was excellent, but after chromatography, a
significant degree of epimerization occurred. In our experience,
13 has a stronger tendency to epimerize than other similar
products devoid of the azido group. We also tried the one-pot
elimination−Mannich reaction, starting from 12, following the
procedure reported by Cor
́
dova (KF as base).39 In our hands,
the reaction was sluggish, and starting 12 was completely
consumed only after 63 h. In addition, crude 13 was an
equimolar mixture of syn (ee 80%) and anti stereoisomers, and
the isolated yield was only around 30%. The extended reaction
time and the coexistence of an easily epimerizable aldehyde
with a base may explain the lack of diastereoselectivity, while we
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Table 1. Optimization of the Staudinger/Aza-Wittig/Ugi−
Joullie Protocol on 13
́
temp (°C)
yield
c
(Staudinger/
solvent
a
dr
of 19
b
entry phosphine aza-Wittig)
(Ugi)
(19a:19b:19c)
(%)
1
2
3
4
5
6
7
8
PPh3
PPh3
PPh3
PPh3
PPh3
PMe3
PBu3
PPh3
rt
rt
rt
rt
0
MeOH
52:28:20
59:27:14
48:27:25
54:30:16
64:22:14
37:42:21
43:37:20
69:20:11
19
18
13
14
58
26
8
CH2Cl2
CF3CH2OH
toluene
CH2Cl2
CH2Cl2
CH2Cl2
0
0
d
0
CH2Cl2
54
a
b
c
All reactions performed at rt. By HPLC. Isolated yields from 12 of
d
the whole stereoisomeric mixture of 19. Results of the one-pot
procedure from 12 to 13 using KF as base.
the end, we were able to obtain a good overall yield of
benzazepines 19 (58% from 12 for four steps).
As far as stereoselectivity was concerned, we expected the
formation of two diastereomers, hopefully in a good ratio,
thanks to the close position of the preexisting stereogenic
centers.
We were therefore quite surprised when the crude reaction
mixture displayed the presence of three isobaric (HPLC−MS)
compounds, with one of them highly prevailing. The major
stereoisomer was very easily separated from the other two by
chromatography, whereas the obtainment in pure form of the
other two was rather difficult, but eventually feasible. Analysis
1
of H and 13C NMR spectra, also supported by computational
methods, allowed us to assign structures 19a to the major
product and 19b and 19c to the minor ones (a detailed
discussion is reported in the Supporting Information). Starting
from 13, we expected to obtain 19b and 19c, but the prevailing
product was 19a instead, with the opposite configuration at C4
(with respect to 16). The most likely explanation of our
experimental results is an equilibration between the two
epimeric imines 16 and 18, through the enamine 17.
This hypothesis is corroborated by semiempirical calculations
carried out on 16, 17, and 18 (see the Supporting Information),
which indicated the following order of stability: 17 > 18 ≈ 16.
Moreover, when we started from a nearly 1:1 syn/anti mixture
of aldehydes (derived from the poorly stereoselective one-pot
Mannich reaction accomplished in the presence of potassium
fluoride), the diastereomeric ratio between 19a, 19b, and 19c
was nearly the same (Table 1, entry 8).
This result suggests a fast pre-equilibrium between the three
species. Due to this equilibration, the search for an appropriate
organocatalyst able to afford the anti stereoisomer of 13 was
useless. From our evidence we cannot decide whether the
preference for diastereomer 19a relative to 19b,c derives from
the fact that pre-equilibrium favors 18 (thermodynamic
control) or from a faster reaction of 18 compared to 16
(kinetic control). However, we guess that the second
hypothesis is more likely, in view of the similar energy of 16
and 18 as deduced from our calculations. From the stereo-
chemical results it is clear that cis imine 18 undergoes a highly
Figure 1. Preferred conformation of cyclic imines 16 (top) and 18
(bottom).
expected to be highly favored. On the other hand, for trans
imine 16, a clear preference for one of the two diastereotopic
faces can not be envisaged because the upper face is
encumbered by the axial NH(Boc) group, whereas the lower
face is encumbered by the axial methyl group. This fact
probably makes reaction of 16 slower compared to 18.
Eventually, under the best conditions, the major stereoisomer
19a was obtained in 64% ratio with respect to the other two
1
(entry 5). We also demonstrated, by H NMR of Mosher
amides derived from 19a, that its ee corresponds with that
determined on the Mannich aldehyde 13 (through the
corresponding alcohol 14).
In order to study the scope of our procedure, apart from
using diverse aldehydes, isocyanides, and carboxylic acids, we
also planned to synthesize different ureido sulfones, charac-
terized by the presence of a derivatizable group on the aromatic
ring. We therefore targeted regioisomers 26 and 27 (Scheme 5)
through a regiodivergent approach starting from 5-bromoph-
thalide 20 that was reduced with LiBH4 to avoid the loss of
bromine from the aromatic ring, which occurred in part using
LiAlH4 instead. This time, the two hydroxy groups are no
longer equivalent, and therefore, a problem of regioselectivity
arose. We again found valuable help in the enzymatic catalysis,
and some representative results are reported in Table 2 (more
information is available in the Supporting Information). Several
parameters have been varied: the reaction (acylation or
hydrolysis), the lipase, and its amount with respect to substrate,
temperature, and reaction time.
́
diastereoselective Ugi−Joullie reaction (19d was not detected
at all), whereas the reaction of the corresponding epimeric trans
imine 16 is less diastereoselective. The calculations reported in
the Supporting Information indicate that both imines 16 and
18 should exist essentially in a single conformation, depicted in
Figure 1. In 18 attack from the bottom, leading to 19a, is
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Article
this strategy is less convenient from the point of view of step
and atom economy. Therefore, for preparative reactions, we
preferred to perform acetylations.
Scheme 5. Synthesis of Ureido Sulfones 26 and 27
The transformation of 22 and 23 into 26 and 27 followed
exactly the same strategy reported in Scheme 3 on compound
9. The yields of ureido sulfones 26 and 27 were in this case
lower, most likely for the difficulty to precipitate them from the
reaction mixture.
Another point of diversity that was considered is the
aldehyde to be used as donor in the organocatalytic Mannich
reaction. Using hydrocinnamaldehyde we obtained comparable
results with only a small decrease of diastereoselectivity starting
from the bromine-bearing ureido sulfones 26 and 27 (Scheme
6).44 On the contrary, when we switched to the branched
Scheme 6. Scope of the Organocatalytic Mannich Reaction
isovaleraldeyde, no reaction occurred at all with ureidosulfone
12. This aldehyde was chosen hoping to obtain a cyclic imine
less prone to be converted into the enamine. However, the
observed result is really unexpected as isovaleraldehyde behaves
as a good donor with several Boc-imines with different
substituents on the aromatic ring (also in ortho position) but
lacking the azidomethyl group.19
We were not able to obtain a single regioisomer unless at a
very high degree of conversion, but this was at the expense of
the yield. Eventually, the best compromise was a conversion
around 50%, which implies an acceptable ratio between the two
regioisomers in such a way that the chromatographic separation
becomes straightforward enough. Depending on the lipase, the
acylation afforded preferentially 22 (vinyl acetate as acyl donor)
and 28 (vinyl butyrate as acyl donor) or 23 (vinyl acetate) and
29 (vinyl butyrate): with supported PPL and CAL 22 and 28
prevailed (entries 2, 4, and 5). On the contrary, supported
lipase Amano PS43 and lipase Amano AK gave larger amounts
of 23 and 29 (entries 1 and 3).
The possibility of increasing the diversity is ensured by the
Ugi−Joullie reaction: actually, we synthesized a small library of
́
4,5-dihydro-1H-benzo[c]azepines by changing, in addition to
the cyclic imine, the isocyanide and the carboxylic acid.
Contrary to what we have done in the optimization step, we
preferred to isolate and purify the Mannich aldehyde. Even if a
bit longer, this procedure allowed to obtain the final products
with a higher overall yield and a higher degree of purity. Thanks
to the fact that the diastereomeric ratio of the final products is
independent from the syn/anti ratio of the Mannich product,
We also studied the monohydrolysis of either diacetate 30 or
dibutyrate 31, prepared by standard acylation of 21 in 93% and
89% yield. The results were less encouraging, and most of all,
Table 2. Regioselective Enzymatic Monoacyclation of Diol 21 or Monohydrolysis of Diesters 30 and 31
a
b
b
b,c
entry subs products
lipase
solvent
lipase/substrate (mg/mmol) temp (°C) time (h)
a:b
yield (a + b) (%) conv (%)
1
2
3
4
5
6
7
21
21
21
21
21
30
31
22, 23
22, 23
28, 29
28, 29
28, 29
22, 23
28, 29
S-Amano PS
S-PPL
vinyl acetate
vinyl acetate
vinyl butyrate
vinyl butyrate
vinyl butyrate
22
65
22
44
22
29
29
10
20
0
2
2
37:63
75:25
0:100
100:0
68:32
21:79
12:88
77
76
40
66
76
20
25
60
50
80
67
62
85
33
Amano AK
S-PPL
6
10
10
20
10
24
6
CAL
d
CAL
buffer/iPr2O
15
19
d
CAL
buffer/iPr2O
a
Key: lipase Amano PS, from Burkholderia cepacia; lipase Amano AK, from Pseudomonas fluorescens; PPL, lipase from porcine pancreas; CAL, lipase
b
c
from Candida anctartica; S-PPL or S-Amano PS, lipase supported on Celite. Determined by 1H NMR. Conversion is the ratio of acylated hydroxy
groups vs initially present hydroxy groups (acylation) or the ratio of hydrolyzed acyl groups vs initially present acyl groups (hydrolysis). pH
d
(buffer): 7.0; ratio (buffer/cosolvent): 9:1.
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Table 3. Scope of the Staudinger/Aza-Wittig reaction Followed by Ugi−Joullie Reaction
́
a
a,
b
c
entry aldehyde product
R1
R2
R3
R4
R5
yield (a) (%) yield (a + b + c) (%) ratio (a:b:c)
1
13
13
13
13
13
13
13
13
32
32
33
33
34
19
36
37
38
39
40
41
42
43
44
45
46
47
H
H
H
H
H
H
H
H
H
H
Br
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Me
Me
Me
Me
Me
Me
Me
Me
Bn
t-Bu
n-Bu
n-Bu
5-chloro-2-thienyl
3-Br-C6H4
Ph
53
48
60
55
53
48
55
55
42
47
33
47
30
83
76
86
84
83
68
78
73
69
70
46
57
41
64:22:14
63:28:9
70:23:7
65:31:4
2
3
4
2,6-(Me2)-C6H3
CH2CO2Et
cyclohexyl
nC5H11
Bn
Et
d
5
Et
64:36
6
S-BnCHNHFmoc
S-iPrCHNHCbz
MeOCH2
5-chloro-2-thienyl
3-OMe-C6H4
Ph
70:17:13
70:21:9
75:19:6
61:30:9
67:30:3
72:24:4
7
8
9
t-Bu
10
11
12
13
Bn
Me
Bn
CH2CO2Et
Bn
d
Bn
CH2NHFmoc
Et
82:18
Bn
t-Bu
73:19:8
a
b
Isolated yield after chromatography. With the exception of 19b and 19c, isolated only as analytical samples, in all other cases b and c have been
c
obtained as a mixture, because of impossible chromatographic separation. For 19 determined by HPLC on the crude mixture. In the other cases, the
ratio a:(b + c) was determined by weight after chromatography (b + c coeluted), whereas the ratio b:c was determined by HPLC (the two isomers
have been recognized through MS detection for their m/z ratio). Since they have not been isolated and characterized, the fact that b is the prevailing
d
one is only guessed. The b:c ratio has not been determined because the diastereomers are not separated in HPLC.
the partial epimerization during the first chromatography does
not influence the stereochemical outcome of the reaction.
The results of the library synthesis are summarized in Table
3. Different isocyanides (including aliphatic, aromatic, branched
aliphatic, and functionalized ones) and carboxylic acids
(including aliphatic, aromatic and heteroaromatic ones, and
also N-protected amino acids) have been combined with
different aldehydes. The overall yields of the Staudinger/aza-
Wittig-MCR protocol are good and, in most cases, excellent.
In all cases, we obtained a mixture of the previously described
diastereomers, with stereoisomer a, which was very easily
obtained in pure form by chromatography, always prevailing.
The average ratio a:(b + c) ranges from a minimum of 2:1 up
to around 5:1 (entry 12). Within the minor stereoisomers, one
of them, presumably b, is sometimes highly prevailing.45 The
noticeable variety of the decorations introduced in these
scaffolds demonstrates the robustness of this highly convergent
methodology.
Scheme 7. Suzuki Reaction on Compound 47a
coupling. This enables, after easy chromatography, the isolation
in good overall yield of a single stereoisomer (out of eight) of a
new heterocyclic structure endowed with three contiguous
stereogenic centers. It is also worth noting that the sequence
from the o-azido benzyl alcohols 10, 24, and 25 to the final
products requires just two separation steps and that the final
products can be further derivatized using the NHBoc group or
the bromine present on derivatives 45, 46, or 47.
We also wanted to demonstrate that the presence of a
bromine atom on the aromatic ring (47a) may be exploited for
further derivatization. As shown in Scheme 7, the possibility of
forming a new C(sp2)−C(sp2) bond by means of a Suzuki
coupling (48) has been fully proved.
CONCLUSION
■
In conclusion, we developed a new method for fast assembly of
a new family of seven-membered heterocycles. Our strategy
relies on the possibility of synthesizing, in high enantiomeric
excess, unknown custom-made azido aldehydes by an organo-
catalytic procedure. These aldehydes then undergo a chemically
efficient and operationally simple one-pot sequence involving a
Staudinger/aza-Wittig reaction followed by an Ugi−Joullie
EXPERIMENTAL SECTION
■
General Experimental Methods. NMR spectra were taken in
CDCl3 or in DMSO-d6 at 300 MHz (1H) and 75 MHz (13C) using, as
internal standard, TMS (1H NMR in CDCl3; 0.000 ppm), the central
peak of DMSO (1H NMR in DMSO-d6; 2.506 ppm), the central peak
of CDCl3 (13C in CDCl3; 77.02 ppm), or the central peak of DMSO
́
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(13C in DMSO-d6; 39.43 ppm). Chemical shifts are reported in ppm
(δ scale); coupling constants are reported in hertz. Peak assignments
were also made with the aid of gCOSY and gHSQC experiments. In an
ABX system, the proton A is considered upfield and the B proton is
considered downfield. IR spectra were recorded as CHCl3 solutions or
directly on solid, oil, or foamy samples, with the ATR (attenuated total
reflectance) technique. TLC analyses were carried out on silica gel
plates, viewed at UV (λ = 254 nm) and developed with Hanessian
stain (dipping into a solution of (NH4)4MoO4·4H2O (21 g) and
Ce(SO4)2·4H2O (1 g) in H2SO4 (31 mL) and H2O (469 mL) and
warming), or (only for compounds 13, 32−34) with ninhydrin
(ninhydrin (900 mg) in n-BuOH (300 mL) and AcOH (9 mL),
followed by warming. Rf values were measured after an elution of 7−9
cm. GC−MS were carried out using an HP-1 column (12 m long, 0.2
mm wide), electron impact at 70 eV, and a mass temperature of about
170 °C. Only m/z > 33 were detected. All analyses were performed
(unless otherwise stated) with a constant He flow of 1.0 mL/min with
initial temperature 50 °C, initial time 2 min, rate 20 °C/min, final
temperature 260 °C, inj temperature 250 °C, det temperature 280 °C.
HPLC analyses for the determination of enantiomeric ratios were
performed on a DAICEL Chiral Pak AD 250 × 4.6 mm column, at
25−28 °C with a flow of 1 mL/min (UV detection at λ = 220 nm).
HPLC−MS analyses were performed on Synergi Hydro RP 150 × 3
mm column, at 30 °C with a flow of 0.5 mL/min (where not otherwise
stated). For MS the ESI+ ionization method was used. HRMS were
performed employing an ESI+ ionization method and TOF as
analyzer. Column chromatography was performed with the “flash”
methodology using 220−400 mesh silica. Petroleum ether (40−60 °C)
is abbreviated as PE. All reactions employing dry solvents were carried
out under a nitrogen atmosphere. Amano PS and AK enzymes were a
kind gift of Amano-Mitsubishi Italia. Lipase from Candida antarctica
(Novozym 435) was a kind gift of Novo Nordisk.
1,5-Benzenedimethanol (8). To a suspension of LiAlH4 (3.33 g,
87.69 mmol) in Et2O (130 mL) at 0 °C under nitrogen atmosphere
was added dropwise (30 min) a solution of phthalide (6.43 g, 48.71
mmol) in dry THF (30 mL). The mixture was allowed to reach room
temperature over a period of 3 h, and then it was cooled to 0 °C and
carefully quenched with a solution of NaOH (3.99 g, 13.4 mL of H2O;
added dropwise in 45 min). The mixture was diluted with THF (40
mL), stirred for 3 h, filtered on a sintered funnel, and washed with
THF. In order to fully recover the product, which in part remains
adsorbed on the aluminates, they were dissolved in 1 M HCl (20 mL)
and extracted with EtOAc (3 × 40 mL). The organic phase was dried
over Na2SO4 and united with the THF filtrate above. Evaporation to
dryness gave 8 (6.58 g, 98%) as a white solid: mp 68.1−69.4 °C. The
analytical data conform to those reported in literature.46
then it was treated with saturated aqueous NH4Cl (100 mL) and
extracted with CH2Cl2 (2 × 100 mL). The combined organic phases
were washed with brine (100 mL), dried (Na2SO4), and concentrated.
The crude was taken up in dry DMF (34 mL), treated with NaN3
(4.37 g, 67.26 mmol), stirred for 18 h at room temperature, diluted
with H2O (100 mL), and extracted with Et2O (2 × 100 mL). The
combined organic phases were dried (Na2SO4) and concentrated. To a
solution of this crude in MeOH (200 mL) at 0 °C was added a 1 M
solution of KOH in MeOH (50.5 mL, 50.5 mmol). The reaction
mixture was stirred for 1 h at 0 °C and then treated with saturated
aqueous NH4Cl (100 mL), and most of the MeOH was evaporated
under reduced pressure. The aqueous phase was extracted with Et2O
(3 × 80 mL), washed with H2O (80 mL), dried (Na2SO4), and
concentrated to give azido alcohol 10 as a colorless oil (4.83 g, 88%).
The analytical data conform to those reported in literature.48
tert-Butyl ((4-Methylsulfonyl)(2-azidomethyl)phenyl)-
carbamate (12). To a solution of (2-azidomethyl)benzyl alcohol
(10) (4.04 g, 24.8 mmol) and TEMPO (2,2,6,6-tetramethyl-1-
piperidinyl oxide, free radical, 387 mg, 2.48 mmol) in dry CH2Cl2
(25 mL) at 0 °C was added (diacetoxyiodo)benzene (8.79 g, 27.3
mmol). The solution was stirred for ca. 10 min and then for 1 h at
room temperature. The reaction mixture was diluted with Na2S2O3 0.4
M solution (50 mL) and extracted with CH2Cl2 (2 × 100 mL). The
organic phase was washed with saturated aq NaHCO3 (80 mL), dried
(Na2SO4), and concentrated. The residue was filtered through a
column of silica gel (60 g) and eluted with 4:1 PE−Et2O to give a
solution of 2-(azidomethyl)benzaldehyde (11) that was concentrated
to about 5−6 mL at about 100 mbar (it was not completely evaporated
at higher vacuum because of its relative volatility). After dilution with
methanol (10 mL), H2O (20 mL), sodium p-toluenesulfinate (5.30 g,
29.7 mmol), tert-butyl carbamate (2.90 g, 24.8 mmol), and finally,
formic acid (1.12 mL, 29.7 mmol) were added. The reaction mixture
was vigorously stirred at room temperature for 48 h, diluted with H2O
(30 mL), and sonicated for 30 min. The resulting fine crystalline solid
was filtered through a sintered funnel and washed first with H2O and
then with Et2O/pentane to give ureidosulfone 12a as a white powder
(5.16 g, 12.4 mmol, 50%). This compound was relatively stable as a
solid at low temperature but tended to rapidly decompose in solution
1
in the presence of traces of water. Therefore, only fast H NMR were
recorded. For the same reason, HRMS (ESI+) and elemental analysis
were not feasible. Only p-toluenesulfinic acid was detected at HRMS.
Mp: 124.1−124.7. IR (ATR): ν = 3372, 2987, 2953, 2227, 2100, 1701,
1508, 1491, 1463, 1455, 1433, 1363, 1338, 1315, 1307, 1290, 1278,
1244, 1159, 1140, 1083, 1047, 1019 cm−1. 1H NMR (CDCl3, 25 °C):
δ = 8.32 (d, J = 8.2 Hz, 2H, H ortho to SO2), 7.62−7.55 (m, 1H,
aromatic H), 7.49−7.36 (m, 3H, aromatic H), 7.35 (d, J = 8.2 Hz, 2H,
H meta to SO2), 6.29 and 5.85 (AB syst, J = 10.7 Hz, 2H, ArCH and
NH), 4.66 and 4.48 (AB syst, J = 14.1 Hz, 2H, CH2N3), 2.43 (s, 3H,
CH3), 1.25 (s, 9H, C(CH3)3).
tert-Butyl ((3R,4R,5S)-3-(tert-Butylcarbamoyl)-2-(5-chloro-
thiophene-2-carbonyl)-4-methyl-2,3,4,5-tetrahydro-1H-benzo-
[c]azepin-5-yl)carbamate (19a) and Its Diastereoisomers 19b
and 19c. Ureidosulfone 12 (388 mg, 0.93 mmol) in dry THF (9 mL)
was treated, under a nitrogen atmosphere, with Cs2CO3 (763 mg, 2.34
mmol). The mixture was warmed at 40 °C and stirred for 2 h, then
filtered on a sintered funnel, washed with CH2Cl2, and concentrated.
The residue was dissolved in dry CH3CN (9 mL), cooled to 0 °C, and
treated with propanal (142 μL, 1.98 mmol) and L-proline (23 mg,
0.198 mmol) for 44 h at 0 °C. The crude was then diluted with H2O,
extracted with CH2Cl2, dried (Na2SO4), and concentrated. The dr was
determined as 97:3 on the crude by 1H NMR. The residue was eluted
from a column of silica gel with 6:1 PE/EtOAc to give 13 (229 mg,
77%), which was directly submitted to the next Staudinger/aza-Wittig/
2-(Hydroxymethyl)benzyl Acetate (9). Diol 8 (5.54 g, 40.1
mmol) was dissolved in vinyl acetate (60 mL) and diisopropyl ether
(120 mL) and treated with 2.00 g of pig pancreatic lipase (PPL,
Sigma) supported on Celite as previously described.31 [(SPPL-4): 1 g
of this supported enzyme corresponds to 0.23 g of crude PPL]. After
being stirred for 40 h at rt (when the amounts of starting 8 and of its
diacetate seem equal at TLC), the suspension was filtered through a
sintered funnel. The filtrate was evaporated and chromatographed
(PE/Et2O 75:25) to give pure 9 as an oil (6.60 g, 91%). A partial
characterization of 9 has already been reported.47 Rf = 0.40 (PE/Et2O
1
25:75). IR: see literature. H NMR (CDCl3, 25 °C): δ = 7.50−7.30
(m, 4 H); 5.24 (s, 2 H, CH2OAc); 4.76 (d, J = 6.0 Hz, 2 H, CH2OH);
2.10 (s, 3 H, CH3CO); 2.07 (t, J = 6.0 Hz, 1 H, OH). 13C NMR
(CDCl3, 25 °C): δ = 170.8 (CO), 139.3, 133.8 (quat), 129.8, 128.9,
128.8, 128.2 (aromatic CH), 63.9 (CH2OAc), 62.9 (CH2OH), 21.0
(CH3). GC−MS (initial temp 80 °C, initial time 2 min, rate 20 °C/
min, final temp 260 °C): tR 6.36 min. m/z: 162 (M+−18, 1.1); 120
(100); 119 (58); 92 (5.4); 91 (33); 77 (13); 65 (6.8); 51 (4.4); 43
(31). Anal. Calcd for C10H12O3: C, 66.65; H, 6.71. Found: C, 66.7; H,
6.8.
́
Ugi−Joullie sequence (due to the partial epimerization during the
purification step it was not possible to characterize 13). This crude
aldehyde (229 mg, 0.72 mmol) was dissolved in dry THF (18 mL).
Triphenylphosphine (227 mg, 0.86 mmol) was added at room
temperature. The reaction mixture was stirred for 30 min and then
rapidly concentrated under reduced pressure. The residue was
immediately dissolved in CH2Cl2 (1.8 mL) and treated with 5-
2-(Azidomethyl)benzyl Alcohol (10). A solution of monoacetate
9 (6.06 g, 33.6 mmol) in dry CH2Cl2 (100 mL) was cooled to −30 °C
and treated with Et3N (6.10 mL, 43.72 mmol) and methanesulfonyl
chloride (3.12 mL, 40.36 mmol). The mixture was stirred for 2 h, and
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chloro-2-thienoic acid (129 mg, 0.79 mmol) and tert-butyl isocyanide
(90 μL, 0.79 mmol). Then it was stirred at room temperature for 18 h,
diluted with saturated aq NaHCO3, extracted with CH2Cl2, dried
(Na2SO4), and concentrated. The diastereomeric ratio was determined
as 64:22:14 (19a:19b:19c) by reversed-phase HPLC on this crude
mixture: tR (19a) = 8.44 min, tR (19b) = 6.80 min, tR (19c) = 5.85
min. The crude product was purified by chromatography using 6:1
PE−Et2O to give first 19a (198 mg, 53% from 13, 41% from 12) as a
white foam and then the mixture of 19b and 19c (112 mg, 30% from
13, 23% from 12). Analytically pure samples of 19b and 19c were
obtained by repeated chromatographies on silica gel using 4:1 PE/
EtOAc. (3R,4R,5S) Diastereomer 19a. Rf = 0.57 (PE/Et2O 1:1).
3.50−3.33 (m, 2H, CH2OH), 3.17−3.05 (broad s, 1H, OH), 2.08−
1.93 (m, 1H, H-2), 1.42 (s, 9H, C(CH3)3), 0.90 (d, J = 6.8 Hz, 3H,
CH3). 13C NMR (CDCl3, 25 °C): δ = 156.1 (CO), 139.9, 132.9 (2
quat), 130.1, 128.6, 127.4, 126.4 (4 aromatic CH), 80.1 (C(CH3)3),
64.7 (C-1), 52.3 (CH2N3), 50.1 (C-3), 41.0 (C-2), 28.3 (C(CH3)3),
11.3 (CH3). HRMS (ESI+) m/z: [M + Na]+ calcd for C16H24N4O3Na
343.1746, found 343.1743.
Determination of Enantiomeric Excess of Diastereomer 19a.
Product 19a (10 mg, 24 μmol), obtained using L-proline as the catalyst
for the Mannich step, was treated with 1:2 TFA/CH2Cl2 (1.5 mL).
The mixture was stirred at room temperature for 30 min and then
coevaporated with n-heptane. The crude was solubilized in dry CH2Cl2
(1 mL) and treated with 4-(dimethylamino)pyridine (DMAP) (12 mg,
96 μmol) and (R)- or (S)-α-methoxy-α-trifluoromethylphenylacetyl
chloride (7 μL, 36 μmol). The mixture was stirred at room
temperature for 1 h and then it was concentrated. The crude was
purified by preparative TLC (PE−Et2O 2:3) to give the corresponding
Mosher amides. The ee (97.3%) was determined by reversed-phase
HPLC on the (S) Mosher amide, obtained starting from the (R)
Mosher chloride. Conditions: column phenyl C6 150 × 3 mm, 3 μm.
Flow: 0.34 mL/min. Temperature: 25 °C, isocratic elution with
MeOH/H2O 70:30, Detection: UV (280 nm). tR 36.59 min. tR of (R)
amide: 34.47 min (see the Supporting Information for the HPLC
chromatograms).
4-Bromo-1,2-benzenedimethanol (21). To a suspension of
LiBH4 (0.45 g, 20.65 mmol) in Et2O (30 mL) at 0 °C under a nitrogen
atmosphere was added dropwise (30 min) a solution of 5-
bromophthalide (2.00 g, 9.39 mmol) in dry THF (35 mL). The
mixture was allowed to reach room temperature and was stirred for 44
h. Then the mixture was cooled to 0 °C, carefully quenched with a
saturated solution of NH4Cl (50 mL; added dropwise in 20 min), and
extracted with Et2O (60 mL) and EtOAc (60 mL). The organic phase
was dried over Na2SO4 and concentrated. The residue was eluted from
a column of silica gel with 2:1 EtOAc−Et2O to give 21 (1.89 g, 93%)
as a white solid. Mp: 73.1−74.0 °C. The analytical data conform to
those reported in the literature.49
[α]20 +81.5 (c 1.1, CHCl3). IR (ATR): ν = 3343, 2969, 2932, 1703,
D
1673, 1610, 1588, 1543, 1481, 1431, 1389, 1364, 1315, 1222, 1153,
1
1101, 1065, 1009 cm−1. H NMR (d6-DMSO-d6, 70 °C): δ = 7.56
(broad s, 1H, NHtBu), 7.28−7.15 (m, 4H, aromatic H), 7.11 (d, J =
4.0 Hz, 1H, H thienyl), 7.05 (d, J = 4.0 Hz, 1H, H thienyl), 6.69
(broad s, 1H, NHBoc), 5.17 (d, J = 9.3 Hz, 1H, H-5), 5.08, 4.84 (AB
syst, J = 16.1 Hz, 2H, H-1), 4.61 (d, J = 6.5 Hz, 1H, H-3), 2.64 (dq, Jd
= 6.5, Jq = 6.3 Hz, 1H, H-4), 1.42 (s, 9H, Boc), 1.34 (s, 9H, C(CH3)3),
0.74 (broad s, 3H, CH3). 13C NMR (DMSO-d6, 70 °C): δ = 168.9,
163.0, 154.8 (3 CO), 139.9, 136.0, 134.7, 131.5 (quat), 128.3, 126.9,
126.5, 126.2 (aromatic CH), 77.8 (C(CH3)3), 61.9 (C-3), 54.2 (C-5),
50.2 (quat), 48.3 (C-1), 37.9 (C-4), 28.1 (CH3 of tBu), 27.8 (CH3 of
Boc), 14.4 (CH3). HPLC−MS: see the Supporting Information.
HRMS (ESI+) m/z: [M + H]+ calcd for C26H35ClN3O4S 520.2037,
found 520.2043. (3R,4R,5S) Diastereomer 19b. Rf = 0.40 (PE/Et2O
1:1). [α]20 −74.1 (c 1.6, CHCl3). IR (ATR): ν = 3340, 2972, 1707,
D
1671, 1600, 1518, 1455, 1431, 1390, 1364, 1244, 1163, 1046, 1010
1
cm−1. H NMR (DMSO-d6, 70 °C): δ = 7.33−7.18 (m, 5H, NHtBu
and aromatic H), 7.14 (d, J = 9.6 Hz, 1H, NHBoc), 7.10 (d, J = 4.0 Hz,
1H, H thienyl), 7.08 (d, J = 4.0 Hz, 1H, H thienyl), 5.21, 4.82 (AB
syst, J = 16.3 Hz, 2H, H-1), 4.59 (d, J = 6.9 Hz, 1H, H-3), 4.55 (dd, J =
9.6, 8.7 Hz, 1H, H-5), 2.73 (ddq, J = 8.7, 6.9, 6.6 Hz, 1H, H-4), 1.41
(s, 9H, Boc), 1.22 (s, 9H, C(CH3)3), 0.95 (d, J = 6.6 Hz, 3H, CH3).
13C NMR (DMSO-d6, 70 °C): δ = 168.8, 162.8, 155.7 (3 CO),
140.0, 136.3, 134.3, 132.1 (quat), 128.5, 126.8, 126.7, 126.4 (aromatic
CH), 77.6 (C(CH3)3), 62.9 (C-3), 54.8 (C-5), 50.1 (quat), 49.2 (C-1),
37.8 (C-4), 27.9 (CH3 of tBu), 27.8 (CH3 of Boc), 15.7 (CH3).
HPLC−MS: see the Supporting Information. HRMS (ESI+) m/z: [M
+ H]+ calcd for C26H35ClN3O4S 520.2037, found 520.2048.
4-Bromo-2-(hydroxymethyl)benzyl Acetate (22). To a sol-
ution of diol 21 (1.85 g, 8.55 mmol) in vinyl acetate (104 mL) at 20
°C, porcine pancreatic lipase supported on Celite as described in
literature (SPPL-4)31 (2.44 g; 1 g of this supported enzyme
corresponds to 0.23 g of crude Lipase) was added. The reaction
mixture was stirred at 20 °C for 2 h, filtered through a sintered funnel,
and washed with CH2Cl2 (100 mL). The filtrate was concentrated
(3R,4S,5S) Diastereomer 19c. Rf = 0.38 (PE/Et2O 1:1). [α]20
D
−16.8 (c 1.2, CHCl3). IR (ATR): ν = 2968, 1667, 1615, 1531,
1
1
1429, 1366, 1260, 1200, 1131, 1009 cm−1. H NMR (DMSO-d6, 70
(regioisomers ratio 75:25 by H NMR analysis of the crude), and the
residue was eluted from a column of silica gel with PE/Et2O (2:3) to
give first 22 (1.16 g, 52%) as a white solid and then a mixture of 22
and 23 (0.53 g, 24%) as a white solid. Further chromatography of
these mixed fractions afforded other 110 mg of 22. The overall yield
was 1.27 g, 57%. Rf = 0.43 (PE/Et2O 3:7). Mp: 40.3−41.0 °C. IR
(ATR): ν = 3230, 2866, 1728, 1689, 1482, 1455, 1404, 1385, 1360,
1254, 1207, 1176, 1104, 1086, 1051, 1025, 802 cm−1. 1H NMR
(CDCl3, 25 °C): δ = 7.61 (d, J = 2.1 Hz, 1H, H-2), 7.44 (dd, J = 8.1,
2.1 Hz, 1H, H-6), 7.25 (d, J = 8.1 Hz, 1H, H-5), 5.14 (s, 2H,
CH2OAc), 4.72 (d, J = 5.4 Hz, 2H, CH2OH), 2.20 (t, J = 5.4 Hz, 1 H,
OH), 2.09 (s, 3H, CH3). 13C NMR (CDCl3, 25 °C): δ = 170.8 (C
O), 141.3, 132.5 (quat), 131.4, 131.3, 130.9 (aromatic CH), 122.8
(quat), 63.2 (CH2OAc), 62.2 (CH2OH), 20.9 (CH3). GC−MS: tR 9.19
min. m/z: 200 (M+ −60, 62, (81Br)), 199 (29), 198 (M+ −60, 62,
(79Br)), 197 (24), 171 (8.3), 169 (8.8), 92 (18), 91 (33), 90 (14), 89
(16), 78 (8.0), 77 (13), 65 (9.1), 63 (9.9), 51 (9.5), 43 (100), 39
(7.0). HRMS (ESI+) m/z: [M + H]+ calcd for C10H12BrO3 258.9970,
found 258.9975.
5-Bromo-2-(hydroxymethyl)benzyl Acetate (23). Preparation
of the Catalyst. Amano PS lipase (from Burkholderia cepacia) (3.00 g)
was suspended in 0.067 M pH 7 buffer (phosphate) (50 mL) and
immediately treated with Hyflo Supercel (10 g). The suspension was
magnetically stirred for 15 min at rt and then allowed to stand still for
9 h. The resulting suspension was frozen at −25 °C while gently
manually stirring. The frozen mixture was then lyophilized at 10−2
mbar. The resulting solid was removed from the flask, gently ground,
°C): δ = 7.33−7.13 (m, 5H, NHtBu and aromatic H), 7.12 (d, J = 4.0
Hz, 1H, H thienyl), 7.09 (d, J = 4.0 Hz, 1H, H thienyl), 6.24 (broad d,
J = 7.7 Hz, 1H, NHBoc), 4.99 (dd, J = 8.7, 7.2 Hz, 1H, H-5), 4.98, 4.87
(AB syst, J = 16.7 Hz, 2H, H-1), 4.80 (d, J = 6.0 Hz, 1H, H-3), 2.83 (d
of quint, Jq = 7.2, Jd = 6.0 Hz, 1H, H-4), 1.39 (s, 9H, Boc), 1.23 (s, 9H,
C(CH3)3), 1.06 (d, J = 7.2 Hz, 3H, CH3). 13C NMR (DMSO-d6, 70
°C): δ = 168.6, 162.7, 155.9 (CO), 138.5, 136.6, 136.0, 131.9
(quat), 131.2, 128.7, 128.0, 127.5, 127.1, 126.7 (aromatic CH), 77.9
(C(CH3)3), 59.8 (C-3), 57.1 (C-5), 50.1 (quat), 49.6 (C-1), 36.5 (C-
4), 28.2 (CH3 of tertBut), 27.9 (CH3 of Boc), 14.9 (CH3). HPLC−
MS: see the Supporting Information. HRMS (ESI+) m/z: [M + H]+
calcd for C26H35ClN3O4S 520.2037, found 520.2041.
(2S,3S) 3-(2-(Azidomethyl)phenyl)-3-tert-butoxycarbonyla-
mino-2-methylpropanol (14). Crude aldehyde 13 (0.24 mmol),
obtained as described above, was diluted with MeOH (1 mL) and
treated with NaBH4 (13.6 mg, 0.36 mmol) at 0 °C. After being stirred
for 30 min, the reaction mixture was diluted with H2O, extracted with
EtOAc, dried (Na2SO4), and concentrated. The crude residue was
purified by silica gel column chromatography with PE/EtOAc 5:2 to
give 14 (41 mg, 54% from 12) as a colorless oil. HPLC on chiral
stationary phase: hexane/iPrOH 95:5. tR = 28.80 min (tR of ent-14
prepared using D-proline: 25.10 min); ee > 98%. [α]20 +15.2 (c 1.5,
D
CHCl3). IR (ATR): ν = 3353, 2974, 2932, 2097, 1687, 1646, 1525,
1365, 1289, 1247, 1160, 1075, 1031 cm−1. 1H NMR (CDCl3, 25 °C):
δ = 7.39−7.22 (m, 4H, aromatic H), 5.21−5.09 (m, 1H, H-3), 5.11 (d,
J = 9 Hz, 1H, NH), 4.63, 4.52 (AB syst, J = 13.8 Hz, 2H, CH2N3),
346
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Article
and further stripped at 10−2 mbar in a desiccator over P2O5. Yield =
13.452 g. Thus, 1 g of this supported catalyst corresponds to 0.223 g of
native Amano PS.
tert-Butyl ((4-Methylsulfonyl)(2-azidomethyl-5-bromo)-
phenyl)carbamate (27) (R = 4-Br). Compound 27 was obtained
as a white powder in 35% yield starting from 400 mg of 25, using the
same procedure above-described for 12. This compound was relatively
stable as a solid at low temperature but tended to rapidly decompose
To a solution of diol 21 (1.10 g, 5.07 mmol) in vinyl acetate (60
mL) at 10 °C was added lipase Amano PS supported on Celite as
described above (0.47 g). The reaction mixture was stirred at 10 °C for
2 h, filtered through a sintered funnel, and washed with CH2Cl2 (80
1
in solution in the presence of traces of water. Therefore, only fast H
NMR were recorded. For the same reason HRMS (ESI+) and
elemental analysis were not feasible. Mp: 134.3−136.0 °C. IR (ATR):
ν = 3353, 2956, 2098, 1698, 1595, 1516, 1483, 1365, 1361, 1271, 1249,
1162, 1144, 1083 cm−1. 1H NMR (CDCl3, 25 °C): δ = 7.83 (d, J = 8.1
Hz, 2H, H ortho to SO2), 7.67 (broad s, 1H, aromatic H), 7.57 (dd, J
= 8.1 (ortho), 1.8 (meta) Hz, 1H, aromatic H), 7.37 (d, J = 8.1 Hz,
2H, H meta to SO2), 7.28 (d, J = 8.1 Hz, 1H, aromatic H), 6.22 and
5.70 (AB syst, J = 10.5 Hz, 2H, ArCH and NH), 4.63 and 4.47 (AB
syst, J = 14.1 Hz, 2H, CH2N3), 2.45 (s, 3H, CH3), 1.25 (s, 9H,
C(CH3)3).
1
mL). The filtrate was concentrated (regioisomers ratio 37:63 by H
NMR analysis of the crude), and the residue was eluted from a column
of silica gel with PE/Et2O (2:3) to give first a mixture of 22 and 23
(0.64 g, 49%) as a white solid and then 23 (0.37 g, 28%) as a white
solid. A second chromatography of the mixed fractions afforded other
0.22 g of 23. Overall yield: 0.59 g (45%). Rf = 0.35 (PE/Et2O 3:7).
Mp: 70.2−71.1 °C; IR (ATR): ν = 3507, 3071, 2930, 2872, 2808,
1726, 1595, 1567, 1482, 1454, 1428, 1406, 1378, 1360, 1313, 1245,
1210, 1179, 1114, 1086, 1042, 989 cm−1. 1H NMR (CDCl3, 25 °C): δ
= 7.53 (d, J = 2.1 (meta) Hz, 1H, H-2), 7.46 (dd, J = 8.1 (ortho), 2.1
(meta) Hz, 1H, H-6), 7.29 (d, J = 8.1 Hz, 1H, H-5), 5.17 (s, 2H,
CH2OAc), 4.69 (d, J = 5.7 Hz, 2H, CH2OH), 2.20 (t, J = 5.4 Hz, 1H,
OH), 2.11 (s, 3H, CH3). 13C NMR (CDCl3, 25 °C): δ = 170.7 (C
O), 137.8, 135.9 (quat), 132.1, 131.6, 130.3 (aromatic CH), 121.8
(quat), 62.9 (CH2OAc), 62.2 (CH2OH), 20.9 (CH3). GC−MS: tR 9.12
min. m/z: 200 (M+ − 60, 36, (81Br)), 199 (25), 198 (M+ −60, 38,
(79Br)), 197 (23), 171 (6.7), 169 (6.8), 92 (14), 91 (30), 90 (14), 89
(16), 78 (8.3), 77 (14), 65 (14), 64 (10), 63 (11), 51 (10), 50 (4.9),
44 (4.6), 43 (100), 39 (7.3). HRMS (ESI+) m/z: [M + H]+ calcd for
C10H12BrO3 258.9970, found 258.9973.
1,2-Bis(acetoxymethyl)-4-bromobenzene (30). A solution of
diol 21 (1.89 g, 8.70 mmol) in dry CH2Cl2 (17 mL) was cooled to 0
°C and treated with pyridine (3.5 mL, 43.50 mmol) and acetic
anhydride (2.5 mL, 26.10 mmol). The mixture was allowed to reach
room temperature in 1 h and stirred at this temperature for 11 h, and
then it was was treated with 1 M HCl (40 mL) and extracted with
CH2Cl2 (2 × 80 mL). The combined organic phases were washed with
brine (20 mL), dried (Na2SO4), and concentrated to give 30 (2.43 g,
93%) as a white solid, pure enough for characterization. Rf = 0.71 (PE/
EtOAc 6:4). Mp: 38.5−39.7 °C (CH2Cl2). IR (ATR): ν = 2937, 2166,
1735, 1597, 1573, 1485, 1460, 1378, 1362, 1260, 1230, 1179, 1110,
1
1091, 1044 cm−1. H NMR (CDCl3, 25 °C): δ = 7.56 (d, J = 1.8
(2-(Azidomethyl)-4-bromophenyl)methanol (24). Compound
24 was prepared using the same procedure described for 10, starting
from 0.97 g of 22. Oil. Yield from 22: 77%. Rf = 0.42 (PE/EtOAc 3:2);
IR (ATR): ν = 3331, 2885, 2093, 1594, 1568, 1482, 1450, 1400, 1339,
(meta) Hz, 1H, H-2), 7.47 (dd, J = 8.4 (ortho), 1.8 (meta) Hz, 1H, H-
6), 7.28 (d, J = 8.4 Hz, 1H, H-5), 5.15 (s, 2H, CH2OAc), 5.13 (s, 2H,
CH2OAc), 2.12 (s, 3H, CH3), 2.09 (s, 3H, CH3). 13C NMR (CDCl3,
25 °C): δ = 170.5 (CO), 136.7, 133.2 (quat), 132.3, 131.6, 131.4
(aromatic CH), 122.6 (quat), 63.1 (CH2OAc), 62.8 (CH2OAc), 20.9
(CH3). GC−MS: tR 9.54 min. m/z: 242 (M+ −60, 6.1, (81Br)), 240
(M+ − 60, 6.1, (79Br)), 200 (23), 198 (25), 89 (5.2), 43 (100). HRMS
(ESI+) m/z: [M + H]+ calcd for C12H14BrO4 301.0075, found
301.0084.
1
1285, 1244, 1216, 1174, 1116, 1084, 1042, 1005, 821 cm−1; H NMR
(CDCl3, 25 °C): δ = 7.50 (s, 1H, H-3), 7.48 (dd, J = 7.8 (ortho), 2.1
(meta) Hz, 1H, H-5), 7.30 (d, J = 7.8 Hz, 1H, H-6), 4.69 (broad d, J =
3.6 Hz, 2H, CH2OH). 13C NMR (CDCl3, 25 °C): δ = 137.8, 135.8
(quat), 132.3, 131.7, 130.6 (aromatic CH), 122.0 (quat), 62.5
(CH2OH), 51.8 (CH2N3). GC−MS: tR 8.94 min. m/z: 214 (M+
−29, 6.3, (81Br)), 212 (M+ −29, 6.2, (79Br)), 198 (21), 169 (6.4), 157
(5.9), 133 (10), 116 (69), 104 (18), 89 (100), 77 (81), 63 (54), 51
(68), 39 (49). HRMS (ESI+) m/z: [M + Na]+ calcd for
C8H8BrN3NaO 263.9748, found 263.9755.
1,2-Bis(butyryloxymethyl)-4-bromobenzene (31). A solution
of diol 21 (0.50 g, 2.30 mmol) in dry CH2Cl2 (25 mL) was cooled to 0
°C and treated with Et3N (1.7 mL, 12.19 mmol) and butyryl chloride
(0.5 mL, 4.83 mmol). The mixture was allowed to reach room
temperature for 2 h, and then it was was treated with saturated
aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (2 × 50 mL).
The combined organic phases were dried (Na2SO4) and concentrated.
The residue was eluted from a column of silica gel with 9:1 PE/EtOAc
to give 31 (0.73 g, 89%) as colorless oil. Rf = 0.70 (PE/EtOAc 8:2). IR
(ATR): ν = 2965, 2876, 1736, 1597, 1571, 1487, 1458, 1417, 1382,
(2-(Azidomethyl)-5-bromophenyl)methanol (25). Compound
25 was prepared using the same procedure described for 10, starting
from 740 mg of 23. Oil. Yield from 23: 78%. Rf = 0.41 (PE/EtOAc
3:2). IR (ATR): ν = 3359, 2927, 2099, 1594, 1481, 1403, 1246, 1014
1
cm−1. H NMR (CDCl3, 25 °C): δ = 7.61 (d, J = 2.1 Hz, 1H, H-6),
7.46 (dd, J = 8.1 (ortho), 2.1(meta) Hz, 1H, H-4), 7.21 (d, J = 8.1 Hz,
1H, H-3), 4.72 (d, J = 4.2 Hz, 2H, CH2OH), 4.41 (d, 2H, CH2N3),
1.95 (t, J = 4.2 Hz, 1H, OH). 13C NMR (DCl3, 25 °C): δ = 141.1,
132.3 (quat), 131.8, 131.3, 131.2 (aromatic CH), 122.8 (quat), 62.4
(CH2OH), 51.9 (CH2N3); GC−MS: tR 9.10 min; m/z: 214 (M+ − 29,
7.6, (81Br)), 212 (M+ − 29, 7.3, (79Br)), 198 (30), 169 (6.6), 157
(6.5), 133 (9.3), 116 (71), 104 (19), 92 (60), 89 (100), 77 (99), 63
(58), 51 (71), 39 (41). HRMS (ESI+) m/z: [M + Na]+ calcd for
C8H8BrN3NaO 263.9748, found 263.9764.
1
1303, 1252, 1165, 1087, 1042 cm−1. H NMR (CDCl3, 25 °C): δ =
7.55 (d, J = 2.1 (meta) Hz, 1H, H-2), 7.46 (dd, J = 8.1 (ortho), 2.1
(meta) Hz, 1H, H-6), 7.26 (d, J = 8.1 Hz, 1H, H-5), 5.15 (s, 2H,
ArCH2O), 5.13 (s, 2H, ArCH2O), 2.35 (t, J = 7.2 Hz, 2H, OCH2),
2.32 (t, J = 7.5 Hz, 2H, OCH2), 1.74−1.57 (m, 4H, 2 OCH2CH2),
0.95 (t, J = 7.5 Hz, 3H, CH3), 0.94 (t, J = 7.5 Hz, 3H, CH3). 13C NMR
(CDCl3, 25 °C): δ = 173.1, 173.0 (CO), 136.8, 133.4 (quat), 132.1,
131.4, 131.2 (aromatic CH), 122.5 (quat), 62.9, 62.6 (CH2O), 36.0
(OCH2CH2), 18.3 (CH2CH3), 13.6 (CH3). GC−MS: tR 11.17 min. m/
z: 270 (M+ − 86; 0.86 (81Br)), 268 (M+ − 86; 0.86 (79Br)), 71 (100),
44 (8.4), 43 (33), 40 (5.7). HRMS (ESI+) m/z: [M + H]+ calcd for
C16H22BrO4 357.0701, found 357.0695
tert-Butyl ((3R,4R,5S)-2-(3-Bromobenzoyl)-3-(butylcarbamo-
yl)-4-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-
carbamate (36a). Compound 36a was prepared from 300 mg of
ureidosulfone 12 (0.72 mmol) through aldehyde 13, following the
typical procedure described above for 19a. n-Butyl isocyanide and 3-
tert-Butyl ((4-Methylsulfonyl)(2-azidomethyl-4-bromo)-
phenyl)carbamate (26). Compound 26 was obtained as a white
powder in 26% yield starting from 550 mg of 24, using the same
procedure above-described for 12. This compound was relatively
stable as a solid at low temperature, but tended to rapidly decompose
1
in solution in the presence of traces of water. Therefore only fast H
NMR were recorded. For the same reason HRMS (ESI+) and
elemental analysis were not feasible. Mp: 173.4−174.5 °C. IR (ATR):
ν = 3353, 2956, 2098, 1698, 1595, 1516, 1483, 1365, 1335, 1316, 1307,
́
bromobenzoic acid have been use in the Ugi−Joullie reaction. The
1
1249, 1181, 1162, 1143, 1082 cm−1. H NMR (CDCl3, 25 °C): δ =
residue was eluted from a column of silica gel with 1:1 PE/Et2O to
give first 36a (149 mg, 48% from 13, 37% from 12) as a white foam
and a mixture of 36b and 36c (87 mg, 22% from 13) (foam). 36a. Rf =
7.83 (d, J = 8.2 Hz, 2H, H ortho to SO2), 7.63−7.56 (m, 2H, aromatic
H), 7.46−7.34 (m, 3H, aromatic H), 6.20 and 5.70 (AB syst, J = 10.4
Hz, 2H, ArCH and NH), 4.65 and 4.49 (AB syst, J = 14.4 Hz, 2H,
CH2N3), 2.44 (s, 3H, CH3), 1.25 (s, 9H, C(CH3)3).
0.50 (PE/Et2O 1:1). [α]20 −16.3 (c 1.0, CHCl3). IR (ATR): ν =
D
3317, 2967, 2931, 1655, 1621, 1560, 1516, 1454, 1422, 1364, 1291,
347
dx.doi.org/10.1021/jo402527w | J. Org. Chem. 2014, 79, 339−351

The Journal of Organic Chemistry
Article
1246, 1160, 1069 cm−1. 1H NMR (CDCl3, 40 °C): δ = 7.57 (ddd, J =
8.0 (ortho), 1.7, 1.1 (meta) Hz, 1H, H ortho to CO), 7.48 (broad d,
J = 7.5 Hz, 1H, H ortho to CHNHBoc), 7.30 (t, J = 7.5 Hz, 1H, H
meta to CHNHBoc), 7.27−7.19 (m, 2H, aromatic H), 7.18 (t, J = 8.0
Hz, 1H, H meta to Br), 7.03 (broad d, J = 8.0 Hz, 1H, H ortho to Br),
6.68 (broad d, J = 7.5 Hz, 1H, H ortho to CH2), 6.60 (broad t, J = 4.9
Hz, 1H, NHnBu), 5.19 (d, J = 10.1 Hz, 1H, H-5), 4.99, 4.16 (AB syst, J
= 17.2 Hz, 2H, H-1), 4.69 (d, J = 10.8 Hz, 1H, H-3), 4.47 (broad d, J =
10.1 Hz, 1H, NHBoc), 3.33 (dt, J = 6.6, 4.9 Hz, 2H, CH2NH), 3.04
(dq, J = 10.8, 6.5 Hz, 1H, H-4), 1.61−1.33 (m, 4H, 2 CH2 nBu), 1.46
(s, 9H, Boc), 1.17 (broad d, J = 6.6 Hz, 3H, CH3), 0.97 (t, J = 7.3 Hz,
3H, CH3). 13C NMR (CDCl3, 40 °C): δ = 171.1, 169.2, 155.9 (C
O), 140.2, 136.6, 136.4 (quat), 133.7, 131.9, 130.3, 129.9, 128.2, 127.7,
125.4 (aromatic CH), 122.4, 80.1 (quat), 59.4 (C-3), 57.7 (C-5), 50.6
(C-1), 39.2 (CH2), 35.5 (C-4), 31.6 (CH2), 28.4 (CH3 of Boc), 20.0
(CH2), 16.8 (CH3), 13.7 (CH3). HPLC−MS: see the Supporting
Information. HRMS (ESI+) m/z: [M + H]+ calcd for C28H37BrN3O4
558.1967, found 558.1972.
128.2, 127.6, 127.5, 127.3 (aromatic CH), 79.9 (quat), 58.3 (C-3),
57.8 (C-5), 48.2 (C-1), 35.0 (C-4), 28.4 (CH3 of Boc), 26.9 (CH2),
18.3 (2 CH3), 16.7 (CH3), 9.3 (CH3). HPLC−MS: see the Supporting
Information. HRMS (ESI+) m/z: [M + H]+ calcd for C28H38N3O4
480.2862, found 480.2862.
Ethyl 2-((3R,4R,5S)-5-((tert-Butoxycarbonyl)amino)-4-meth-
yl-2-propionyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine-3-
carboxamido)acetate (39a). Compound 39a was prepared from
300 mg of ureidosulfone 12 (0.72 mmol) through aldehyde 13,
following the typical procedure described above for 19a. Ethyl
isocyanoacetate and propanoic acid have been use in the Ugi−Joullie
reaction. The residue was eluted from a column of silica gel with 1:1
PE/EtOAc to give first 39a (136 mg, 53% from 13, 41% from 12) as
an pale yellow foam and a mixture of 39b and 39c (77 mg, 30% from
́
13, 23% from 12) (foam). 39a. Rf = 0.55 (PE/EtOAc 1:1). [α]20
D
−26.9 (c 2.2, CHCl3). IR (ATR): ν = 3318, 2978, 2938, 1742, 1683,
1631, 1495, 1425, 1366, 1231, 1198, 1160, 1067, 1025 cm−1. 1H NMR
(CDCl3, 25 °C): δ = 7.45 (broad d, J = 7.2 Hz, 1H, H ortho to
CHNHBoc), 7.27 (dt, J = 7.2 (ortho), 1.4 (meta) Hz, 1H, H meta to
CHNHBoc), 7.22 (dt, J = 7.2 (ortho), 1.5 (meta) Hz, 1H, H meta to
CH2), 7.10 (broad d, J = 7.2 Hz, 1H, H ortho to CH2), 6.88 (broad t, J
= 5.4 Hz, 1H, NHCH2CO2Et), 5.14 (broad d, J = 10.3 Hz, 1H, H-5),
4.87 (broad s, 1H, H-3), 4.86, 4.39 (AB syst, J = 17.4 Hz, 2H, H-1),
4.43 (broad s, 1H, NHBoc), 4.20 (q, J = 7.1 Hz, 2H, COOCH2CH3),
4.06 (dd, J = 18.0, 6.2 Hz, 1H, CH2COOEt), 3.96 (dd, J = 18.0, 5.6
Hz, 1H, CH2CO2Et), 2.97 (dq, J = 12.8, 6.5 Hz, 1H, H-4), 2.48, 2.17
(AB part of ABX3 syst, J = 14.9, 7.3 Hz, 2H, CH2CH3), 1.44 (s, 9H,
Boc), 1.28 (t, J = 7.1 Hz, 3H, CO2CH2CH3), 1.15 (broad s, 3H, CH3),
1.07 (q, J = 7.3 Hz, 3H, CH3). 13C NMR (CDCl3, 25 °C): δ = 174.5,
170.3, 169.3, 155.9 (CO), 140.2, 135.6 (quat), 132.0, 128.1, 127.6,
127.4 (aromatic CH), 79.7 (quat), 61.3 (CH2CH3), 57.7 (C-3), 57.5
(C-5), 48.1 (C-1), 41.2 (CH2NH), 35.2 (C-4), 28.3 (CH3 of Boc),
26.8 (CH2), 16.4 (CH3), 14.1 (CH3), 9.1 (CH3). HPLC−MS: see the
Supporting Information. HRMS (ESI+) m/z: [M + H]+ calcd for
C24H36N3O6 462.2609, found 462.2604.
tert-Butyl ((3R,4R,5S)-2-Benzoyl-3-(butylcarbamoyl)-4-meth-
yl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)carbamate (37a).
Compound 37a was prepared from 300 mg of ureidosulfone 12 (0.72
mmol) through aldehyde 13, following the typical procedure described
above for 19a. n-Butyl isocyanide and benzoic acid have been use in
́
the Ugi−Joullie reaction. The residue was eluted from a column of
silica gel with 1:1 PE/Et2O to give first 37a (160 mg, 60% from 13,
46% from 12) as a pale yellow foam and a mixture of 37b and 37c (69
mg, 26% from 13, 20% from 12) as a yellow foam. 37a: Rf = 0.50 (PE/
Et2O 1:1). [α]20 +0.4 (c 0.5, CHCl3). IR (ATR): ν = 3316, 2969,
D
2932, 1711, 1665, 1619, 1577, 1517, 1494, 1447, 1418, 1365, 1232,
1
1160 cm−1. H NMR (CDCl3, 25 °C): δ = 7.49 (broad d, J = 7.5 Hz,
1H, H ortho to CHNHBoc), 7.43 (dt, J = 7.5 (ortho), 1.0 (meta) Hz,
1H, aromatic H), 7.37−7.24 (m, 3H, aromatic H), 7.16 (dt, J = 7.5
(ortho), 1.1 (meta) Hz, 1H, aromatic H), 7.11 (broad d, J = 7.3 Hz,
2H, aromatic H), 6.81 (broad t, J = 5.5 Hz, 1H, NHnBu), 6.66 (broad
d, J = 7.5 Hz, 1H, H ortho to CH2), 5.19 (broad d, J = 10.0 Hz, 1H, H-
5), 4.96, 4.23 (AB syst, J = 17.1 Hz, 2H, H-1), 4.73 (broad d, J = 10.8
Hz, 1H, H-3), 4.60 (broad d, J = 10.0 Hz, 1H, NH-Boc), 3.41−3.24
(m, 2H, CH2 nBu), 3.03 (dq, J = 10.8, 6.4 Hz, 1H, H-4), 1.61−1.33
(m, 4H, 2 CH2 nBu), 1.44 (s, 9H, Boc), 1.12 (broad d, J = 6.4 Hz, 3H,
CH3), 0.96 (t, J = 7.3 Hz, 3H, CH3 nBu). 13C NMR (CDCl3, 25 °C): δ
= 172.8, 169.3, 155.9 (CO), 140.2, 136.7, 134.5 (quat), 131.9,
130.6, 128.1, 127.9, 127.6, 127.4, 127.1 (aromatic CH), 79.8 (quat),
59.2 (C-3), 57.6 (C-5), 50.5 (C-1), 39.0 (CH2 nBu), 35.3 (C-4), 31.5
(CH2 nBu), 28.3 (CH3 Boc), 19.9 (CH2 nBu), 16.8 (CH3), 13.6 (CH3
nBu). HPLC−MS: see the Supporting Information. HRMS (ESI+) m/
z: [M + H]+ calcd for C28H38N3O4 480.2862, found 480.2868.
tert-Butyl ((3R,4R,5S)-3-((2,6-Dimethylphenyl)carbamoyl)-4-
methyl-2-propionyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-
yl)carbamate (38a). Compound 38a was prepared from 300 mg of
ureidosulfone 12 (0.72 mmol) through aldehyde 13, following the
typical procedure described above for 19a. 2,6-Dimethylphenylisocya-
tert-Butyl ((3R,4R,5S)-3-(Cyclohexylcarbamoyl)-4-methyl-2-
((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-phenyl-
propanoyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-
carbamate (40a). Compound 40a was prepared from 200 mg of
ureidosulfone 12 (0.48 mmol) through aldehyde 13, following the
typical procedure described above for 19a. Cyclohexyl isocyanide and
́
Fmoc-L-phenylalanine have been use in the Ugi−Joullie reaction. The
residue was eluted from a column of silica gel with 1:1 PE/Et2O to
give first 40a (137 mg, 48% from 13, 37% from 12) as a pale yellow
foam and a mixture of 40b and 40c (57 mg, 20% from 13, 15% from
12) (foam). 40a. Rf = 0.57 (PE/Et2O 1:1). [α]20 +32.1 (c 1.0,
D
CHCl3). IR (ATR): ν = 3303, 2931, 2854, 1709, 1631, 1492, 1449,
1391, 1365, 1332, 1247, 1228, 1158, 1066, 1031 cm−1. 1H NMR
(CDCl3, 40 °C): δ = 7.77 (broad d, J = 7.5 Hz, 2H, aromatic H),
7.59−7.52 (m, 2H, aromatic H), 7.41 (t, J = 7.5 Hz, 2H, aromatic H),
7.35−7.23 (m, 9H, aromatic H), 7.05−6.94 (m, 3H, aromatic H), 6.74
(broad s, 1H, aromatic H), 6.29 (broad d, J = 7.9 Hz, 1H,
NHcyclohexyl), 5.22 (broad d, J = 8.5 Hz, 1H, NHFmoc), 5.02 (broad
d, J = 9.8 Hz, 1H, H-5), 4.96−4.77 (m, 3H, Hα and 2 H-1), 4.49−4.29
(m, 3H, H-3 and CH2 Fmoc), 4.19 (t, J = 6.7 Hz, 1H, CH Fmoc),
3.80−3.60 (m, 2H, CH cyclohexyl and NHBoc), 2.94 (dq, J = 10.8, 6.3
Hz, 1H, H-4), 2.83−2.66 (m, 2H, CH2Ph), 1.90−1.03 (m, 10H,
cyclohexyl), 1.46 (s, 9H, Boc), 1.02 (broad s, 3H, CH3). 13C NMR
(CDCl3, 40 °C): δ = 171.9, 168.0, 155.7 (CO), 143.6, 143.5, 141.2,
139.6, 135.8, 135.3 (quat), 132.1, 128.5, 128.1, 127.7, 127.4, 127.0,
126.6, 124.9, 119.9 (aromatic CH), 79.5 (quat), 67.3 (CH2 Fmoc),
58.8 (C-3), 57.1 (C-5), 52.0 (CH Fmoc), 48.0 (CHα), 47.7 (C-1),
47.1 (CH2 Fmoc), 38.4 (CH2 Ph), 35.2 (C-4), 32.8, 32.6, 25.4, 24.5
(CH2 cyclohexyl), 28.3 (CH3 Boc), 16.3 (CH3). HPLC−MS: see
Supporting Information. HRMS (ESI+) m/z: [M + H]+ calcd for
C47H55N4O6 771.4129, found 771.4122.
́
nide and propanoic acid have been use in the Ugi−Joullie reaction.
The residue was eluted from a column of silica gel with 1:1 PE/Et2O
to give first 38a (146 mg, 55% from 13, 42% from 12) as an pale
yellow foam and a mixture of 38b and 38c (77 mg, 29% from 13, 22%
from 12) (foam) (this mixture was found by HPLC to contain indeed
10% of 38a). 38a. Rf = 0.52 (PE/Et2O 1:1). [α]20 +8.6 (c 1.0,
D
CHCl3). IR (ATR): ν = 3303, 2972, 1686, 1628, 1426, 1365, 1231,
1206, 1158, 1066 cm−1. 1H NMR (CDCl3, 40 °C): δ = 7.72 (broad s,
1H, NH(CH3)2Ph), 7.47 (broad d, J = 7.1 Hz, 1H, H ortho to
CHNHBoc), 7.29 (dt, J = 7.1 (ortho), 1.5 (meta) Hz, 1H, H meta to
CHNHBoc), 7.22 (dt, J = 7.1 (ortho), 1.5 (meta) Hz, 1H, H meta to
CH2), 7.10 (broad d, J = 7.1 Hz, 1H, H ortho to CH2), 7.10−7.03 (m,
3H, aromatic H), 5.17 (broad d, J = 10.4 Hz, 1H, H-5), 4.99 (d, J =
10.9 Hz, 1H, H-3), 4.96, 4.39 (AB syst, J = 17.4 Hz, 2H, H-1), 4.38
(broad d, J = 10.4 Hz, 1H, NHBoc), 3.07 (dq, J = 10.9, 6.6 Hz, 1H, H-
4), 2.48, 2.23 (AB part of ABX3 syst, J = 15.0, 7.5 Hz, 2H, CH2), 2.19
(s, 6H, 2 CH3), 1.46 (s, 9H, Boc), 1.24 (broad d, J = 6.6 Hz, 3H,
CH3), 1.12 (t, J = 7.5 Hz, 3H, CH3). 13C NMR (CDCl3, 40 °C: δ =
174.5, 168.0, (CO), 140.5, 135.6, 135.1, 133.6 (quat), 132.3, 128.3,
tert-Butyl ((3R,4R,5S)-2-((S)-2-(((Benzyloxy)carbonyl)amino)-
3-methylbutanoyl)-4-methyl-3-(pentylcarbamoyl)-2,3,4,5-tet-
rahydro-1H-benzo[c]azepin-5-yl)carbamate (41a). Compound
41a was prepared from 200 mg of ureidosulfone 12 (0.48 mmol)
348
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The Journal of Organic Chemistry
Article
through aldehyde 13, following the typical procedure described above
for 19a. Pentyl isocyanide and Cbz-L-valine have been used in the
(broad d, J = 4.1 Hz, 1H, H thienyl), 6.81 (broad s, 1H, NHtBu), 6.79
(d, J = 4.1 Hz, 1H, H thienyl), 5.23 (d, J = 9.9 Hz, 1H, H-5), 5.09, 4.69
(AB syst, J = 17.4 Hz, 2H, H-1), 4.67 (d, J = 11.1 Hz, 1H, H-3), 4.37
(broad d, J = 9.9 Hz, 1H, NHBoc), 3.07 (dd, J = 11.1, 10.2 Hz, 1H, H-
4), 2.67 (broad d, J = 12.9 Hz, 1H, CH2Ph), 2.54 (broad dd, J = 12.9,
10.2 Hz, 1H, CH2Ph), 1.46 (s, 9H, Boc), 1.40 (s, 9H, C(CH3)3). 13C
NMR (CDCl3, 25 °C): δ = 168.0, 164.3, 155.8 (CO), 140.6, 139.5,
136.4, 136.2, 135.4 (quat), 132.5, 129.7, 129.1, 128.4, 128.1, 127.8,
127.3, 126.4, 126.3 (aromatic CH), 79.9 (quat), 59.7 (C-3), 52.9 (C-
5), 51.5 (quat), 50.5 (C-1), 43.6 (C-4), 35.5 (CH2Ph), 28.7 (CH3 of
Boc), 28.3 (CH3 of tBu). HPLC−MS: see the Supporting Information.
HRMS (ESI+) m/z: [M + H]+ calcd for C32H39ClN3O4S 596.2346,
found 596.2350.
tert-Butyl ((3R,4R,5S)-4-Benzyl-2-(3-methoxybenzoyl)-3-
(methylcarbamoyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-
yl)carbamate (44a). Compound 44a was prepared from 255 mg of
ureidosulfone 12 (0.61 mmol) through aldehyde 32, following the
typical procedure described above for 19a. Hydrocinnamaldehyde was
used for the Mannich reaction. The dr of this reaction was determined
as 96:4 by 1H NMR of the crude. The crude was purified by
chromatography with 6:1 PE/EtOAc to give 32 (71%) as a pale yellow
oil. Methyl isocyanide and 3-methoxybenzoic acid were then used in
́
Ugi−Joullie reaction. The residue was eluted from a column of silica
gel with 1:1 PE/Et2O to give first 41a (127 mg, 55% from 13, 42%
from 12) as an pale yellow foam and a mixture of 41b and 41c (53 mg,
23%, 18% from 12) (foam). 41a. Rf = 0.46 (PE/Et2O 1:1). [α]20
D
+10.3 (c 1.0, CHCl3). IR (ATR): ν = 3319, 2964, 2931, 2873, 1713,
1634, 1497, 1454, 1433, 1366, 1233, 1160, 1068, 1044, 1026 cm−1. 1H
NMR (CDCl3, 25 °C): δ = 7.48−7.21 (m, 9H, aromatic H), 6.40
(broad s, 1H, NHpentyl), 5.25 (broad d, J = 9.2 Hz, 1H, NHVal), 5.17,
5.07 (AB syst, J = 12.2 Hz, 2H, CH2 Cbz), 5.07−4.69 (m, 3H, H-5 and
2 H-1), 4.55 (broad s, 1H, H-3), 4.43 (dd, J = 8.8, 6.5 Hz, 1H, Hα
Val), 4.26 (broad s, 1H, NH-Boc), 3.33−3.14 (m, 2H, CH2 pentyl),
3.02 (dq, J = 12.9, 6.6 Hz, 1H, H-4), 1.57−1.21 (m, 5H, CH Val and 2
CH2pentyl), 1.40 (s, 9H, Boc), 1.12 (broad s, 3H, CH3), 0.88 (t, J =
6.6 Hz, 3H, CH3pentyl), 0.75 (d, J = 6.5 Hz, 3H, CH3Val), 0.54 (d, J =
6.5 Hz, 3H, CH3Val). 13C NMR (CDCl3, 25 °C): δ = 173.0, 168.8,
156.3, 155.7 (CO), 140.0, 135.9, 135.6 (quat), 131.7, 128.5, 128.3,
128.2, 127.9, 127.6, 127.5 (aromatic CH), 79.5 (quat), 67.1 (CH2
Cbz), 58.9 (C-3), 57.6 (C-5), 56.4 (CHα), 48.1 (C-1), 39.3 (CH2
pentyl), 35.1 (C-4), 30.7 (CH Val), 28.9, 28.8 (2 CH2 pentyl), 28.2
(CH3 Boc), 22.1 (CH2 pentyl), 19.4 (CH3Val), 16.8 (CH3), 13.9 (CH3
pentyl). HPLC−MS: see the Supporting Information. HRMS (ESI+)
m/z: [M + H]+ calcd for C35H51N4O6 623.3813, found 623.3809.
tert-Butyl ((3R,4R,5S)-3-(Benzylcarbamoyl)-2-(2-methoxya-
cetyl)-4-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-
carbamate (42a). Compound 42a was prepared from 200 mg of
ureidosulfone 12 (0.48 mmol) through aldehyde 13, following the
typical procedure described above for 19a. Benzyl isocyanide and
́
the Ugi-Joullie reaction. The residue was eluted from a column of silica
gel with 1:1 PE/EtOAc to give first 44a (111 mg, 47% from 32, 33%
from 12) as a white foam and a mixture of 44b and 44c (54 mg, 23%
from 32, 16% from 12) (foam). 44a. Rf = 0.36 (PE/EtOAc 1:1).
[α]20 +2.4 (c 0.7, CHCl3). IR (ATR): ν = 2964, 1671, 1619, 1455,
D
1
1411, 1365, 1260, 1160, 1019 cm−1. H NMR (CDCl3, 25 °C): δ =
7.54−7.43 (m, 1H, aromatic H), 7.40−7.07 (m, 8H, aromatic H),
7.07−6.87 (m, 2H, NHMe and aromatic H), 6.74−6.59 (m, 3H,
aromatic H), 5.26 (broad d, J = 9.9 Hz, 1H, H-5), 4.90, 4.24 (AB syst, J
= 17.2 Hz, 2H, H-1), 4.90 (d, J = 12.1 Hz, 1H, H-3), 4.57 (broad d, J =
9.9 Hz, 1H, NHBoc), 3.59 (s, 3H, OCH3), 3.13 (dd, J = 12.1, 10.4 Hz,
1H, H-4), 2.91 (d, J = 9.8 Hz, 3H, NHCH3), 2.69 (broad d, J = 12.2
Hz, 1H, CH2Ph), 2.54 (broad t, J = 12.2 Hz, 1H, CH2Ph), 1.47 (s, 9H,
Boc). 13C NMR (CDCl3, 25 °C): δ = 172.9, 169.7 (CO), 159.2
(quat), 155.9 (CO), 140.3, 139.4, 136.7, 135.5 (quat), 132.1, 129.7,
129.4, 128.4, 127.9, 127.5, 126.3, 119.5, 117.4, 111.9 (aromatic CH),
79.9 (quat), 58.3 (C-3), 55.1 (OCH3), 52.9 (C-5), 50.7 (C-1), 43.5
(C-4), 35.7 (CH2Ph), 28.4 (CH3 of Boc), 26.4 (NHCH3). HPLC−
MS: see Supporting Information. HRMS (ESI+) m/z: [M + H]+ calcd
for C32H38N3O5 544.2816, found 544.2811.
́
methoxyacetic acid have been used in the Ugi−Joullie reaction. The
residue was eluted from a column of silica gel with 1:1 PE/EtOAC to
give first pure 42a (90 mg) as a pale yellow foam and then a mixture of
42a, 42b, and 42c (40 mg) (foam). HPLC (see the Supporting
Information) showed that the percent of 42a in this mixture was 24%.
Thus, the yield of 42a was calculated to be 98 mg, 55% from 13, or
42% from 12, whereas the yield of 4ab + 42c was 32 mg, 18% from 13,
14% from 12. 42a. Rf = 0.33 (PE/EtOAc 1:1). [α]20 −26.6 (c 1.0,
D
CHCl3). IR (ATR): ν = 3307, 2971, 2931, 1709, 1645, 1495, 1454,
1432, 1365, 1336, 1239, 1159, 1126 cm−1. 1H NMR (CDCl3, 25 °C):
δ = 7.44 (broad d, J = 7.2 Hz, 1H, H ortho to CHNHBoc), 7.36−7.17
(m, 7H, aromatic H), 7.07 (broad d, J = 7.2 Hz, 1H, H ortho to CH2),
6.73 (t, J = 6.0 Hz, 1H, NHCH2Ph), 5.14 (broad d, J = 10.1 Hz, 1H,
H-5), 4.99, 4.34 (AB syst, J = 17.7 Hz, 2H, H-1), 4.74 (d, J = 10.6 Hz,
1H, H-3), 4.52, 4.36 (AB part of ABX syst, J = 14.8, 6.0, 6.0 Hz, 2H,
NHCH2Ph), 4.47 (broad s, 1H, NHBoc), 4.14, 3.86 (AB syst, J = 14.2
Hz, 2H, CH2OMe), 3.26 (s, 3H, OCH3), 3.02 (dq, J = 10.6, 6.3 Hz,
Ethyl 2-((3R,4R,5S)-2-Benzoyl-4-benzyl-8-bromo-5-((tert-
butoxycarbonyl)amino)-2,3,4,5-tetrahydro-1H-benzo[c]-
azepine-3-carboxamido)acetate (45a). Compound 45a was
prepared from 310 mg of ureidosulfone 26 (0.63 mmol) through
aldehyde 33, following the typical procedure described above for 19a.
Hydrocinnamaldehyde was used for the Mannich reaction. The dr of
1H, H-4), 1.43 (s, 9H, Boc), 1.14 (broad d, J = 6.3 Hz, 3H, CH3). 13
C
NMR (CDCl3, 25 °C): δ = 169.6, 169.2, 155.9 (CO), 139.9, 137.8,
135.2 (quat), 131.9, 128.6, 128.2, 127.7, 127.5, 127.4 (aromatic CH),
79.7 (quat), 71.1 (CH2OMe), 59.0 (OCH3), 58.1 (C-3), 57.4 (C-5),
47.3 (C-1), 43.36 (CH2Ph), 35.1 (C-4), 28.3 (CH3 of Boc), 16.4
(CH3). HPLC−MS: see the Supporting Information. HRMS (ESI+)
m/z: [M + H]+ calcd for C27H36N3O5 482.2662, found 482.2655.
tert-Butyl ((3R,4R,5S)-4-Benzyl-3-(tert-butylcarbamoyl)-2-(5-
chlorothiophene-2-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[c]-
azepin-5-yl)carbamate (43a). Compound 43a was prepared from
230 mg of ureidosulfone 12 (0.55 mmol) through aldehyde 32,
following the typical procedure described above for 19a. Hydro-
cinnamaldehyde was used for the Mannich reaction. The dr of this
reaction was determined as 96:4 by 1H NMR of the crude. The crude
was purified by chromatography with 6:1 PE/EtOAc to give 32 (71%)
as a pale yellow oil. tert-Butyl isocyanide and 5-chloro-2-thienoic acid
1
this reaction was determined as 88:12 by H NMR of the crude. The
crude was purified by chromatography with 6:1 PE/EtOAc to give 33
(68%) as a pale yellow oil. Ethyl isocyanoacetate and benzoic acid
were then used in the Ugi−Joullie reaction. The residue was eluted
́
from a column of silica gel with 1:2 PE/Et2O to give first pure 45a (93
mg, 33% from 33, 22% from 26) as a pale yellow foam and then a
mixture of 45b and 45c (37 mg, 13% from 33, 9% from 26) (foam).
45a. Rf = 0.41 (PE/Et2O 1:2). [α]20D −21.1 (c 1, CHCl3). IR (ATR):
1
ν = 2671, 1682, 1622, 1494, 1455, 1365, 1198, 1161, 1020 cm−1. H
NMR (CDCl3, 25 °C): δ = 7.53−7.11 (m, 14H, NHCH2 and aromatic
H), 6.77 (s, 1H, aromatic H), 5.22 (broad d, J = 10.1 Hz, 1H, H-5),
5.04 (broad d, J = 11.4 Hz, 1H, H-3), 4.75, 4.20 (AB syst, J = 17.4 Hz,
2H, H-1), 4.58 (broad d, J = 10.1 Hz, 1H, NH-Boc), 4.27 and 3.95
(AB part of a ABX syst, J = 17.9, 7.0, 4.9 Hz, 2H, NHCH2), 4.23 (q, J
= 7.1 Hz, 2H, CH2CH3), 3.07 (dd, J = 11.4, 10.7 Hz, 1H, H-4), 2.74
(broad d, J = 12.9 Hz, 1H, CH2Ph), 2.58 (broad dd, J = 12.9, 10.7 Hz,
́
were then used in the Ugi−Joullie reaction. The residue was eluted
from a column of silica gel with 4:1 PE/Et2O to give first 43a (98 mg,
42% from 32, 30% from 12) as a white foam and then with EtOAc to
give a mixture of 43b and 43c (63 mg, 27% from 32, 19% from 12).
43a. Rf = 0.45 (PE/Et2O 2:1). [α]20D +62.4 (c 1.1, CHCl3). IR (ATR):
1H, CH2Ph), 1.48 (s, 9H, Boc), 1.29 (t, J = 7.1 Hz, 3H, CH2CH3). 13
C
NMR (CDCl3, 25 °C): δ = 173.6, 169.7, 169.3, 155.8 (CO), 139.4,
139.2, 138.6, 134.1 (quat), 133.8, 131.1, 131.0, 130.1, 129.7, 128.6,
128.4, 127.3, 126.4 (aromatic CH), 80.2 (quat), 61.5 (CH2CH3), 57.8
(C-3), 52.3 (C-5), 50.0 (C-1), 43.2 (C-4), 41.4 (NHCH2), 35.6
(CH2Ph), 28.4 (CH3 Boc), 14.2 (CH3). HPLC−MS: see the
1
ν = 2963, 1681, 1600, 1531, 1429, 1365, 1259, 1161, 1017 cm−1. H
NMR (CDCl3, 25 °C): δ = 7.52−7.43 (m, 2H, aromatic H), 7.39−
7.15 (m, 6H, aromatic H), 7.03−6.97 (m, 1H, aromatic H), 6.88
349
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Article
Supporting Information. HRMS (ESI+) m/z: [M + H]+ calcd for
C34H39BrN3O6 664.2029, found 664.2022.
99.5:0.5. Crude alcohols derived from 33 or ent-33: Conditions: hexane/
iPrOH 90:10. tR = 22.61 min. (tR of ent-33: 11.62 min); er > 99.5:0.5.
Crude alcohols derived from 34 or ent-34: in this case HPLC analysis
was not feasible. Therefore the ee of 34 has been determined as 99%
tert-Butyl ((3R,4R,5S)-4-Benzyl-3-(benzylcarbamoyl)-8-
bromo-2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-
acetyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)carbamate
(46a). Compound 46a was prepared from 310 mg of ureidosulfone 26
(0.63 mmol) through aldehyde 33, following the typical procedure
described above for 19a. Hydrocinnamaldehyde was used for the
Mannich reaction. The dr of this reaction was determined as 88:12 by
1H NMR of the crude. The crude was purified by chromatography
1
by comparison of the H NMR spectra of the S-Mosher esters of the
crude alcohols. For this purpose, a solution of the alcohols derived
from 34 or ent-34 (10 mg, 21 μmol) in dry CH2Cl2 (1 mL) was cooled
to 0 °C and treated with 4,4-dimethylaminopyridine (10 mg, 84 μmol)
and R-α-methoxy-α-trifluoromethylphenylacetyl chloride (6 μL, 31
μmol). The mixture was allowed to reach room temperature for 1 h,
and then it was concentrated and directly purified by preparative TLC
(PE/EtOAc 8:1) to give the Mosher esters which were examined at 1H
NMR (see the Supporting Information).
with 6:1 PE/EtOAc to give 33 (68%) as a pale yellow oil. Benzyl
isocyanide and Fmoc-glycine were then used in the Ugi−Joullie
reaction. The residue was eluted from a column of silica gel with 1:2
PE/Et2O to give first 46a (169 mg, 47% from 33, 32% from 26) as a
pale yellow foam and a mixture of 46b and 46c (36 mg, 10% from 33,
7% from 26) (foam). 46a. Rf = 0.36 (PE/Et2O 1:2). [α]20D −41.8 (c 2,
CHCl3). IR (ATR): ν = 3323, 2931, 1704, 1651, 1496, 1450, 1391,
́
tert-Butyl ((3R,4R,5S)-4-Benzyl-3-(tert-butylcarbamoyl)-7-
phenyl-2-propionyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-
yl)carbamate (48). To a solution of 47a (50 mg, 85 μmol),
phenylboronic acid (22 mg, 180 μmol), and triphenylphosphine (3.5
mg, 14 μmol) in dry THF (0.6 mL) under an argon atmosphere,
Na2CO3 (29 mg solubilized in 60 μL of H2O) and Pd(OAc)2 (1 mg,
4.5 μmol) were added. The mixture was heated in the presence of
microwaves for 2 h at 100 °C with magnetic stirring, treated with H2O
(10 mL), and extracted with CH2Cl2 (2 × 30 mL). The combined
organic phases were dried (Na2SO4) and concentrated. The residue
was eluted from a column of silica gel with PE/CH2Cl2/Et2O (3:2:1)
to give 48 (40 mg, 76%) as a pale yellow foam. Rf = 0.55 (PE/CH2Cl2/
Et2O 2:2:1). [α]20D −61.1 (c 1.3, CHCl3). IR (ATR): ν = 3323, 2972,
2930, 1710, 1681, 1630, 1486, 1455, 1426, 1391, 1365, 1325, 1225,
1
1365, 1231, 1159, 1104, 1050 cm−1. H NMR (CDCl3, 25 °C): δ =
7.76 (d, J = 7.5 Hz, 2H, aromatic H), 7.57 (d, J = 7.4 Hz, 2H, aromatic
H), 7.47−7.16 (m, 17H, aromatic H), 6.65 (broad s, 1H, NHFmoc),
5.55 (broad s, 1H, NHBn), 5.17 (broad d, J = 10.0 Hz, 1H, H-5), 4.99,
4.21 (AB syst, J = 17.7 Hz, 2H, H-1), 4.88 (broad d, J = 10.4 Hz, 1H,
H-3), 4.67−4.54 (m, 2H, NH-Boc and Hα), 4.41−4.15 (m, 5H, Hα, 1
H of CH2Bn, CH and CH2 of Fmoc), 3.69 (broad d, J = 14.1 Hz, 1H,
1 H of CH2Bn), 3.05 (t, J = 10.4 Hz, 1H, H-4), 2.73−2.45 (m, 2H,
CH2Ph), 1.45 (s, 9H, Boc). 13C NMR (CDCl3, 25 °C): δ = 169.2,
168.7, 156.2, 155.9 (CO), 143.7, 143.6, 141.2, 139.0, 137.6, 136.4,
131.6 (quat), 133.9, 130.2, 129.7, 128.8, 128.5, 127.7, 127.6, 127.0,
126.5, 125.0, 121.4, 120.0 (aromatic CH), 80.1 (quat), 67.2 (CH2
Fmoc), 57.7 (C-3), 52.3 (C-5), 46.9 (CH Fmoc), 46.8 (C-1), 43.7
(CH2NHFmoc), 43.5 (C-4), 43.1 (NHCH2Ph), 35.1 (CH2Ph), 28.3
(CH3 Boc). HPLC−MS: see the Supporting Information. HRMS (ESI
+) m/z: [M + H]+ calcd for C47H48BrN4O6 843.2775, found 843.2757.
tert-Butyl ((3R,4R,5S)-4-Benzyl-7-bromo-3-(tert-butylcarba-
moyl)-2-propionyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-
carbamate (47a). Compound 47a was prepared from 400 mg of
ureidosulfone 27 (0.81 mmol) through aldehyde 34, following the
typical procedure described above for 19a. Hydrocinnamaldehyde was
used for the Mannich reaction. The dr of this reaction was determined
as 87:13 by 1H NMR of the crude. The crude was purified by
chromatography with 6:1 PE/EtOAc to give 34 (76%) as a pale yellow
oil. tert-Butyl isocyanide and propanoic acid were then used in the
1
1165, 1059, 1019 cm−1. H NMR (CDCl3, 25 °C): δ = 7.58 (s, 1H,
aromatic H), 7.51−7.10 (m, 12H, aromatic H), 6.28 (broad s, 1H,
NHtBu), 5.25 (d, J = 10.8 Hz, 1H, H-5), 4.99, 4.35 (AB syst, J = 17.4
Hz, 2H, H-1), 4.81 (d, J = 10.8 Hz, 1H, H-3), 4.45 (broad d, J = 10.8
Hz, 1H, NH-Boc), 3.05 (t, J = 10.8 Hz, 1H, H-4), 2.68, 2.52 (AB syst, J
= 13.2 Hz, 2H, CH2Ph), 2.57−2.42 (m, 1H, CH2CH3), 2.27−2.15 (m,
1H, CH2CH3), 1.38 (s, 9H, Boc), 1.38 (s, 9H, C(CH3)3), 1.11 (t, J =
7.5 Hz, 3H, CH3). 13C NMR (CDCl3, 25 °C): δ = 174.4, 168.8, 155.9
(CO), 141.1, 140.9, 139.9, 139.6, 134.5 (quat), 130.7, 129.7, 128.7,
128.4, 128.0, 127.5, 127.0, 126.3, 125.9 (aromatic CH), 79.7 (quat),
57.7 (C-3), 53.0 (C-5), 51.5 (quat), 47.7 (C-1), 43.7 (C-4), 35.3
(CH2Ph), 28.7 (CH3 tBu), 28.4 (CH3 Boc), 27.0 (CH2CH3), 9.4
(CH2CH3). HRMS (ESI+) m/z: [M + H]+ calcd for C36H46N3O4
584.3494, found 584.3488.
ASSOCIATED CONTENT
* Supporting Information
́
Ugi−Joullie reaction. The residue was eluted from a column of silica
■
gel with 3:2:1 PE/CH2Cl2/Et2O to give first 47a (108 mg, 30% from
34, 23% from 27) as a pale yellow foam and a mixture of 47b and 47c
(39 mg, 11% from 34, 8% from 27). 47a. Rf = 0.48 (PE/CH2Cl2/Et2O
S
Details of the optimization of regioselective synthesis of 22 and
23; discussion on the assignment of relative configuration to
19a−c; rationalization of observed stereochemical course;
HPLC−MS/UV data and chromatograms of 36−47; copies
of HPLC chromatograms (reversed-phase and on chiral
2:2:1). [α]20 −52.7 (c 1, CHCl3). IR (ATR): ν = 3317, 2971, 1709,
D
1676, 1632, 1489, 1455, 1391, 1365, 1224, 1162, 1050, 1019 cm−1. 1H
NMR (CDCl3, 25 °C): δ = 7.92 (d, J = 8.1 Hz, 1H, aromatic H),
7.51−7.18 (m, 7H, aromatic H), 6.22 (broad s, 1H, NHtBu), 5.11
(broad d, J = 10.3 Hz, 1H, H-5), 4.90, 4.21 (AB syst, J = 17.4 Hz, 2H,
H-1), 4.78 (broad d, J = 11.4 Hz, 1H, H-3), 4.41 (broad d, J = 10.3 Hz,
1H, NH-Boc), 2.96 (t, J = 10.5 Hz, 1H, H-4), 2.65, 2.50 (AB syst, J =
12.3 Hz, 2H, CH2Ph), 2.51−2.37 (m, 1H, CH2CH3), 2.20−2.04 (m,
1H, CH2CH3), 1.49 (s, 9H, Boc), 1.37 (s, 9H, C(CH3)3), 1.09 (t, J =
7.5 Hz, 3H, CH3). 13C NMR (CDCl3, 25 °C): δ = 174.3, 168.6, 155.7
(CO), 142.5, 139.4, 134.6 (quat), 134.9, 130.4, 129.7, 128.9, 128.5,
126.4 (aromatic CH), 80.0 (quat), 57.5 (C-3), 52.3 (C-5), 51.5 (quat),
47.4 (C-1), 43.7 (C-4), 35.2 (CH2Ph), 28.6 (CH3 tBu), 28.3 (CH3
Boc), 26.9 (CH2CH3), 9.3 (CH2CH3). HPLC−MS: see the
Supporting Information. HRMS (ESI+) m/z: [M + H]+ calcd for
C30H41BrN3O4 586.2289, found 586.2280.
1
stationary phases); H NMR of Mosher esters and amides;
1
copies of H and NMR spectra of all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Fax: (+) 390103536118. E-mail: riva@chimica.unige.it.
■
Notes
The authors declare no competing financial interest.
Determination of ee of Intermediate Aldehydes 32−34 and
of Their Enantiomers. The crude aldehydes were prepared as
described for the synthesis of 19a either using L-proline or D-proline as
catalyst. Then they were reduced to the corresponding alcohols with
NaBH4 (following the same procedure employed for the synthesis of
14) and the crude alcohols were examined at HPLC using a chiral
stationary phase. Crude alcohols derived from 32 or ent-32: Conditions:
hexane/iPrOH 90:10. tR = 15.45 min. (tR of ent-32: 11.66 min); er >
ACKNOWLEDGMENTS
■
We thank Dr. Valeria Rocca, Dr. Carlo Scapolla, and Dr.
Andrea Armirotti for performing HPLC, HPLC−MS, and
HRMS, Romina Vitale for preliminary experiments on
enzymatic acylation of 21. We acknowledge MIUR (PRIN
2009 project “Synthetic Methodologies for Generation of
Biologically Relevant Molecular Diversity”) and the University
350
dx.doi.org/10.1021/jo402527w | J. Org. Chem. 2014, 79, 339−351

The Journal of Organic Chemistry
Article
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of Genova (PRA2011) for financial assistance and thank
Amano-Mitsubishi and Novo Nordisk for a kind gift of
enzymes.
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