Thermodynamically driven,: Syn -selective vinylogous aldol reaction of tetronamides

Article abstract of DOI:10.1039/c6ob00895j

A stereoselective vinylogous aldol reaction of N-monosubstituted tetronamides with aldehydes is described. The procedure is simple and scalable, works well with both aromatic and aliphatic aldehydes, and affords mainly the corresponding syn-aldol adducts. In many cases, the latter are obtained essentially free of their anti-isomers (dr > 99:1) in high yields (70-90%). Experimental and computational studies suggest that the observed diastereoselectivity arises through anti-syn isomer interconversion, enabled by an iterative retro-aldol/aldol reaction.

Full text of DOI:10.1039/c6ob00895j

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Thermodynamically Driven, syn-Selective Vinylogous
Aldol Reaction of Tetronamides
Milandip Karaka, b, Luiz C. A. Barbosaa, b *, Jaime A. M. Acostaa, Ariel M. Sarottic,
and John Boukouvalasd
aDepartament of Chemistry, Instituto de Ciências Exatas, Universidade Federal de Minas
Gerais, Av. Pres. Antônio Carlos, 6627, Campus Pampulha, Belo Horizonte, 31270ꢀ901, MG,
Brazil. Eꢀmail: lcab@ufmg.br
b Departament of Chemistry, Universidade Federal de Viçosa, Viçosa, 36570ꢀ900, MG, Brazil.
cInstituto de Química Rosario (IQUIR), Universidad Nacional de Rosario–CONICET, Suipacha
531, S2002LRK Rosario, Argentina.
dDépartement de Chimie, Pavillon AlexandreꢀVachon, Universitè Laval, 1045 Avenue de la
Médecine, Quebec City, Quebec G1V 0A6, Canada.
Abstract: A stereoselective vinylogous aldol reaction of Nꢀmonosubstituted tetronamides
with aldehydes is described. The procedure is simple and scalable, works well with both
aromatic and aliphatic aldehydes, and affords mainly the corresponding synꢀaldol
adducts. In many cases, the latter are obtained essentially free of their antiꢀisomers (dr
>99:1) in high yields (70ꢀ90%). Experimental and computational studies suggest that the
observed diastereoselectivity arises through antiꢀsyn isomer interconversion, enabled by
an iterative retroꢀaldol/aldol reaction.
Keywords: βꢀaminobutenolides, vinylogous aldol reaction, synꢀselectivity, retroꢀaldol
reaction, GIAO NMR calculations.
1

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Introduction
Tetronamides are an important class of β−heterosubstituted butenolides that have
attracted growing attention from synthetic and medicinal chemists alike.1, 2 Although not
nearly as common as their tetronate counterparts,3 several tetronamides have been shown
to display significant biological activities, as represented by the fungal antitumor
antibiotic basidalin 1,4 the newly marketed systemic insecticide flupyradifurone
(Sivanto®, 2),5 some potent antimitotic azaꢀlignans, e.g. 3,6 and broadꢀacting
antibacterials7 (4ꢀ5, Figure 1). Inspired by the structure of the tetronate synꢀaldol adduct
losigamone 6, an experimental drug advanced to phase III clinical trials for the treatment
of epilepsy,3b, 8 we sought to prepare a library of new analogues in which the alkoxy
group is replaced by an aromatic amine (cf. tetronamides A).9
Figure 1 Bioactive tetronamides 1ꢀ5, tetronate 6 and analogues A.
The vinylogous aldol reaction (VAR), carried our either directly from butenolides
or, via conversion to the corresponding 2ꢀsilyloxyfurans (Mukaiyama variant; VMAR),
represents one of the most widely explored avenues for installing a γ−carbon substituent
(Scheme 1).10 Much effort has been devoted in recent years in controlling the relative
12
and absolute configuration of the newly formed stereogenic centers.11,
Although
2

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several heterosubstituted butenolides,11eꢀh, 12c, d including tetronates, have been utilized as
substrates in VA reactions, surprisingly little is known concerning the serviceability of
13
tetronamides.8b,
The few pertinent examples invariably employ N,Nꢀdisubstituted
tetronamides in conjuction with a strong base (tꢀBuLi, –78 °C), leading mainly to antiꢀ
aldolate adducts.14 To date, only two Nꢀsubstituted tetronamideꢀderived aldolates have
been described in the literature; both were obtained as mixtures of diastereoisomers (dr ≈
1:1 to 2:1) using a decarboxylative Knoevenagelꢀtype reaction of γ−carboxymethyl
tetronamides with aldehydes.15 Reported herein is the hitherto unexplored VAR of
unactivated Nꢀsubstituted tetronamides along with the development of a simple, mild and
scalable method enabling stereoselective access to synꢀaldolate adducts.
Scheme 1 VA pathways to substituted butenolides.
Results and discussion
The starting tetronamides of the present work were prepared by utilizing a
procedure reported by Cunha et al.16 Thus, treatment of commercially available
α,β−dihalobutenolides 7aꢀb with aromatic amines in the presence of NaHCO3 at room
temperature readily accomplished an azaꢀMichael addition/elimination17 to deliver the
desired α−halotetronamides 8aꢀc in high yields (Scheme 2).
Scheme 2 Preparation of α−halotetronamides from α,βꢀdihalofuranꢀ2(5H)ꢀones 7aꢀb.
3

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To assess the feasibility of the VAR, unprotected tetronamide 8a and
benzaldehyde were subjected to a range of base/solvent combinations, as outlined in
Table 1. The assignment of syn/anti configuration to the tetronamide aldol adducts
described herein (9-26) is discussed in a separate section (vide infra).
Table 1 Optimization of the VA reaction of tetronamide 8a with benzaldehyde
Base
Solvent
Timea Yieldb
drc
(syn:anti)
Entry
(h)
(%)
Et3N
MeOH
4
14
11
trace
23
21
83
36
48
23
65
78
91
90
NDd
1
DBU
MeOH
MeOH
12
24
24
24
3
NDd
2
3
DIPEA
NaHCO3
Na2CO3
NaOH
NaOH
NaOH
NaOH
KOH
NDd
NDd
MeOH
4
MeOH
50:50
68:32
60:40
44:56
NDd
5
MeOH
6
CH2Cl2
toluene
THF
12
16
8
7
8
9
MeOH
3
63:37
50:50
>99:1
>99:1
10
11
12
13
tꢀBuOK
NaOH
LiOH
MeOH
4
MeOH/H2Oe
3
2
MeOH/H2Oe
a All reactions were run at room temperature and were quenched when 8a was
completely consumed according to TLC. b Yield of isolated product by column
c
1
chromatography. Determined by H NMR analysis; all products are racemic.
d ND = not determined. e Using a 2:1 MeOH/H2O ratio (v/v).
Adaptation of the conditions of Zhang 11g (cf. Et3N/MeOH, rt), which had worked
well for the VAR of α,βꢀdichlorobutenolide with benzaldehydes, were only modestly
effective in providing the desired adducts 9 (14% yield, entry 1, Table 1). Replacing
triethylamine with DBU or DIPEA did not improve matters either (entries 2ꢀ3). A slight
improvement in the yield of 9 was observed when switching to mineral bases such as
NaHCO3 and Na2CO3 (entries 4ꢀ5). Pleasingly, the use of the stronger base NaOH led to
a substantial increase in yield (83%) along with low selectivity in favour of the synꢀ
adduct (68:32, entry 6). Next, the diastereoselectivity issue was addressed by assessing
the effect of different solvents and mineral bases (entries 7ꢀ11). It is immediately seen
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from the results, that replacing MeOH by a less polar solvent, such as dichloromethane,
toluene or THF, has a detrimental effect to product yield and/or diastereoselectivity
(entry 6 vs entries 7ꢀ9). Accordingly, we decided to explore the effect of more polar
solvents, such as the binary system methanol:water (2:1 v/v). Much to our delight, the use
of NaOH or LiOH in this solvent delivered synꢀ9 as the sole detectable isomer in
excellent yield (entries 12ꢀ13).
Whilst water has been successfully employed as solvent/additive in aldol
reactions,18 most of the reported cases involve either pyrroleꢀmediated19 or Mukaiyama
variants.20 A notable example pertains to the use of brine/MeOH in uncatalyzed VMA
reactions of 2ꢀsilyoxyfurans and pyrroles with benzaldehydes, leading mainly to the
corresponding syn and anti aldolꢀadducts, respectively.21 It was suggested that water may
serve as an Hꢀbond donor to activate the aldehyde acceptor and control the arrangement
of the reactants in the transition state.21 Conceivably, the present VAR may also be
speeded by intermolecular Hꢀbonding, although, as will be discussed later, the observed
diasteroselectivity is likely to arise by a thermodynamic process involving syn/antiꢀ
isomer equilibration.
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Table 2 Substrate scope in the VAR of tetronamides with aldehydesa,b
Me
Me
Me
Me
Me
Cl
NH
O
Cl
NH
Cl
NH
Cl
NH
Cl
NH
OH
OH
OH
OH
OH
O
O
O
O
O
O
O
O
O
O
OMe
12 (78:22)
13 (83:17)
10 (>99:1)
9 (>99:1)
S
11 (>99:1)
4 h, 68%
[X-ray]
6 h, 72%
Me
4 h, 74%
[1.9 g, 6 h, 70%]
3 h, 91%
[1 g, 5 h, 81%]
5 h, 64%
Cl
Me
Br
Me
Me
Me
Me
NH
Br
O
NH
Br
NH
Br
NH
Cl
NH
OH
OH
OH
OH
OH
F
O
O
O
O
O
O
O
O
O
Me
Cl
Br
16 (80:20)
17 (>99:1)
18 (64:36)
14 (91:9)
15 (56:44)
N
4 h, 62%
NO2
4 h, 77%
[2.3 g, 6 h, 71%]
7 h, 67%
3 h, 78%
8 h, 54%
Br
Br
Br
Me
Br
Cl
O
NH
Cl
NH
Cl
NH
Cl
NH
Cl
NH
OH
OH
OH
O
OH
O
OH
O
O
O
O
O
O
O
20 (>99:1)
19 (>99:1)
21 (93:7)
23 (53:47)
22 (>99:1)
OMe
6 h, 75%
6 h, 68%
3 h, 81%
NO2
8 h, 51%
3 h, 86%
OMe
NO2
Br
Me
Me
Cl
NH
Cl
O
NH
Cl
NH
OH
OH
Me
OH
O
O
O
O
O
Me
Me
Me
24 (>99:1)
26 (>99:1)
25 (>99:1)
Me
4 h, 71%
8 h, 76%
6 h, 79%
aFor the sake of clarity only the syn (major) isomer is shown along with the syn:anti ratio
b
(in brackets). Similar yields and syn:anti ratios were obtained (cf. 9, 12, 15, 17, and 26)
by replacing NaOH by LiOH.
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Having established a simple and efficient method enabling stereoselective access
to synꢀ9, the next task was to investigate the substrate scope. Thus, tetronamides 8a-c
were screened with several aldehydes using NaOH in methanol:water (2:1 v/v) at room
temperature (Table 2). The results show that product yields are generally good to
excellent (51ꢀ91%), and in most cases, the syn:anti ratio is at least 90:10. The three
tetronamides tried behaved similarly in terms of yield and diastereoselectivity. However,
the nature of the aldehyde did impact selectivity in some cases. Benzaldehydes bearing
electronꢀdonating substituents performed remarkably well, leading uniquely to synꢀ
adducts (10, 11, 17, 19, 20 and 24), as did benzaldehyde itself (9 and 22). High synꢀ
selectivities (>90:10) were also observed with pꢀnitrobenzaldahyde and 2ꢀchloroꢀ4ꢀ
fluorobenzaldahyde (cf. 14 and 21). The lowest selectivities, but still in favour of the synꢀ
isomer, were observed with metaꢀnitrobenzaldehyde (cf. 15 and 2322), 2ꢀ
naphtalenecarbaldehyde (18), and some heteroaromatic aldehydes (12, 13 and 16).
Importantly, excellent results were obtained with the two aliphatic aldehydes tried,
providing solely the synꢀadducts in high yield (25 and 26). As indicated in Table 2, we
have also demonstrated the preparative value of this method by the gramꢀscale synthesis
of synꢀadducts 9, 10 and 17. Indeed, the scaleꢀup did not affect diastereoselectivity, and
yields were fairly close to those obtained from the 1 mmol scale experiments (e.g. 71 vs
77% for 17).
In general, these reactions were fairly clean. Also, no byꢀproducts arising from
dehydration of the aldol adducts could be observed within 3ꢀ12 h. However, we found
that the yield of the desired adducts was time dependent. Careful monitoring of the
progress of these reactions by TLC, further revealed that the syn/anti ratios improved in
favour of the syn isomer. At this point, a more detailed study of the VAR reaction of 8a
with benzaldahyde was performed using our optimized conditions, where the aldol
adducts synꢀ9/antiꢀ9 were isolated at different time intervals (Figure 2). Thus, compound
9 was obtained in 54% yield after 0.5 h with a syn:anti ratio of 45:55. When the reaction
time increased to 2 hours, the yield reached a maximum (94%) while the syn:anti ratio
had improved to 90:10. Further increase in the reaction time to 3 hours led to virtually
complete control of diastereoselectivity (syn:anti >99:1) but a slightly lower yield (91%).
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After 6 hours the product yield decreased to 82% although the selectivity was still
excellent. From the preparative standpoint, these findings show that quenching the VAR
at the right time, in this case 3 hours, is critical to ensure an optimal balance between
diastereoselectivity and yield.
Figure 2 Yield and syn/anti composition (%) of aldol 9 versus time for the VAR of 8a
with benzaldehyde using the procedure outlined in Table 2.
The variation of diastereoselectivity over time can best be explained by a dynamic
resolution process, whereby diastereomeric equilibration ultimately affords the most
stable isomer. We considered two pathways by which antiꢀsyn interconversion may
occur. The first involves an iterative retroꢀaldol/aldol reaction (path A, Scheme 3).
Alternatively, the butenolide stereogenic center may epimerize via intervention of
furanolate F2 (path B). Given the high thermodynamic acidity of butenolides (pKa ca. 12ꢀ
15),23 direct abstraction of the C5ꢀH is possible, especially under basic conditions.
Indeed, furanolate formation has been invoked to explain the racemization of a formal
VARꢀadduct, namely, γ−hydroxymethylbutenolide.24 Moreover, a γ−benzyltetronate was
shown to epimerize in the presence of Hünig’s base, but not pyridine.25
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Scheme 3 Plausible pathways for isomer interconversion.
Whilst some classical retroꢀaldol/aldol reactions have been previously
investigated, notably in the context of catalytic kinetic resolution26 and total synthesis,27
to the best of our knowledge, there have been no such studies on vinylogous variants
involving butenolides. With this in mind, we sought to test the feasibility of path A by
conducting “transferꢀaldol” experiments, such as that shown in Scheme 4.
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Scheme 4 Baseꢀcatalysed transferꢀaldol reaction.
Thus, a 1:1 mixture of antiꢀ10 and antiꢀ22 were subjected to our optimized procedure and
the reaction was quenched after 3 hours. Flash column chromatography afforded three
mixtures, each consisting of only two compounds: (i) tetronamides 8a and 8b (1:1), (ii)
1
synꢀ9 and synꢀ22 (1:2), and (iii) a 3:1 ratio of synꢀ10 and synꢀ24 (Figures S71ꢀ73). H
NMR analysis of these mixtures, and comparison with those of authentic compound
samples, permitted both the identity and yield of each product to be determined. The
crude reaction mixture also revealed signals for the expected aldehydes, but no signals
corresponding to the starting anti compounds (Figure S70). These findings demonstrate
that the retoꢀaldol/aldol sequence (path A) is indeed involved and capable of
accomplishing complete antiꢀtoꢀsyn conversion. However, paths A and B are not
mutually exclusive.
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To explore the possibility of direct C5ꢀH (path B), the following experiment was
performed. Pure antiꢀ9 was dissolved in CD3OD/D2O and a 1H NMR spectrum was taken
immediately and after one hour. Both spectra showed that only the NH and OH protons
underwent deuterium exchange (Figure S74). The doublets at 4.85 ppm (Hꢀ6, J = 5.5 Hz)
and 5.60 ppm (Hꢀ5, J = 5.5 Hz) were used as diagnostic signals to monitor the
isomerization process. To this solution, NaOH was added and the 1H NMR spectrum was
taken after 10 minutes. In this spectrum (Figure S75) the signals corresponding to Hꢀ5
and Hꢀ6 for the antiꢀ9 isomer had disappeared and new signals at 4.88 ppm (Hꢀ6, broad
singlet for synꢀ9) and 5.40 ppm (Hꢀ5, broad singlet for synꢀ9) were observed. The 1:1
integral ratio of the new signals clearly indicates that no deuterium exchange took place
at C5. In addition, new signals corresponding to tetronamide 8a and benzaldehyde could
be seen. Therefore, antiꢀ9 is converted into the synꢀ9 isomer via a retroꢀaldol process and
not via C5ꢀH abstraction. Only after 30 minutes the C5ꢀH signal of synꢀ9 disappeared,
revealing that complete deuterium exchange had taken place (Figure S76). Whether this
occurs by direct abstraction of the C5ꢀH in synꢀ9 (cf. Path B, Scheme 3) or indirectly via
deuteration of furanolate F2 (Path A) is an open question. It is fairly clear though, that
C5ꢀdeuteration is substantially slower than the iterative retroꢀaldol/aldol reaction.
Taken together, the experiments just described leave little doubt that (i) a retroꢀ
aldol/aldol sequence is involved, and (ii) that the latter readily accomplishes conversion
of the anti to the presumably more stable synꢀisomer.
To verify that this is indeed the case, we computed the stability of the syn and anti
isomers for the simplified model compound 27 using the increasingly popular meta
hybrid exchangeꢀcorrelation functional M06ꢀ2X developed by Truhlar and coꢀworkers,
coupled with the high 6ꢀ311+G** basis set. This functional has been shown to perform
well in mainꢀgroup thermochemistry, and to describe nonꢀcovalent interactions.28 The
enthalpies and Gibbs free energies differences (ꢁH and ꢁG, respectively) between
syn/anti aldol adducts were computed to provide computational support to the proposed
thermadynamic equilibration. As shown in Figure 3, the synꢀ27 aldol was found to be
more stable than its antiꢀ27 isomer (ꢁH = 0.5 kcal/mol; ꢁG = 0.7 kcal/mol), in line with
our expectation. Interestingly, when similar calculations were carried out for compound
9, the preference towards the syn aldol was increased (ꢁH = 1.5 kcal/mol; ꢁG = 1.9
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kcal/mol). Under equilibration conditions at room temperature, such energy differences
predict a syn/anti ratio of 93/7 and 96/4 (based on formation enthalpies and Gibbs free
energies, respectively), which are in good agreement with the experimental findings.
Similar calculations were carried out for compounds 13 and 18 (their syn and anti
isomers). The ratios computed from the ꢁG values (90:10 and 70:30 respectively) are
close to those found experimentally (83:17 and 64:36).
Figure 3 M06ꢀ2X/6ꢀ311+G** optimized geometries (global minima) found for syn and
anti aldol adducts 27 (model compounds) 9, 13 and 18, with selected distances in Å.
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Computational and NMR studies on the relative configuration of aldol adducts
All the discussion up to this point was made considering that the relative
1
configuration of the major and minor isomers were assigned based on the HꢀNMR data.
1
Here, we take a representative example of the HꢀNMR of both isomers of compound 9
(Figure 4) for the detailed discussion on this assignment.
Figure 4 Expansion (4.8ꢀ5.6 ppm) of the 1HꢀNMR (300 MHz, acetoneꢀd6) spectra of synꢀ
9 (4A) and antiꢀ9 (4C) isomers. The corresponding D2O exchange spectra are shown in
4B (synꢀ9) and 4D (antiꢀ9)
The major difference in the spectra of both isomers is the value of 3J between Hꢀ5
and Hꢀ6. In the spectra rum in acetoneꢀd6 the signal for Hꢀ5 is a doublet with J5ꢀ6 = 2.0
Hz for the major isomer (Figure 4A) and a doublet with J5ꢀ6 = 3.9 Hz for the minor
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isomer (Figure 4C). The signals for Hꢀ6 around
δ = 4.9ꢀ5.1 is a multiplet due to a further
coupling between Hꢀ6 and OH (Figure 4A, 4C). So, doing a D2O exchange a clear
doublet is observed in both cases (Figure 4B and 4D), confirming the coupling reported
for Hꢀ5. Since no one has prepared these types of aldolꢀtetronamides before, we need a
reliable way to secure a correct assignment of the stereochemistry of the synthesized
compounds. To accomplish this, we undertook a DFT study using Gaussian 09.29
Since the coupling constant J5ꢀ6 strongly depends on the conformational
preference of the aldols, we first performed an extensive conformational search of a
simplified system (compounds synꢀ27 and antiꢀ27, Figure 5) at the B3LYP/6ꢀ31G* level
of theory.30
Figure 5 B3LYP/6ꢀ31G* optimized geometries (global minima) found for compounds
27, with selected distances in Å.
In both cases, we found a clear preference towards the conformer characterized by
an intramolecular NꢀHꢀꢀꢀOH hydrogen bond. In such conformation, a gauche relationship
between Hꢀ5 and Hꢀ6 was found for the syn isomer (φ 62.4°), and an anti relationship
between both hydrogen atoms in the case of the anti isomer (φ 173.7°), indicating that the
lower J5ꢀ6 value should be expected for the former. This was further confirmed after
Boltzmannꢀaveraged Jꢀcoupling calculations of all significantly populated conformers at
the B3LYP/6ꢀ31G**//B3LYP/6ꢀ31G* level: the computed J5ꢀ6 was 4.1 Hz (syn-27) and
7.4 Hz (anti-27).30 To validate our assignment, we next performed a full conformational
search over three selected aldol pairs synthesized in this work: compounds 9, 12 and 13
(Figure 6).
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2.01
2.08
9-syn_c1
5-6 = 60.7º
9-anti_c1
φ5-6 = 177.8º
φ
2.02
2.10
12-syn_c1
5-6 = 64.6º
12-anti_c1
φ5-6 = 179.1º
φ
2.11
2.02
13-syn_c1
5-6 = 61.4º
13-anti_c1
φ5-6 = 179.4º
φ
Figure 6 B3LYP/6ꢀ31G* optimized geometries (global minima) found for compounds 9,
12 and 13, with selected distances in Å.
Interestingly, despite the degree of conformational freedom was higher than that
of the simplified model, in all cases the rotational preference towards the conformers
showing intramolecular NꢀHꢀꢀꢀOH hydrogen bond was found.30 This result suggested that
the major isolated adducts, showing smaller J5ꢀ6 coupling values, should display a syn
stereochemistry. In an additional supporting of our findings, we next performed GIAO
13CꢀNMR calculations, which represent a valuable and indisputable tool in modern
structural elucidation.31 The magnetic shielding tensors of all significantly populated
conformers were computed at the mPW1PW91/6ꢀ31+G**//B3LYP/6ꢀ31G* level of
theory in solution (PCM, CHCl3), using the multiꢀstandard approach to extract the
chemical shifts.30, 32 Next, we computed the Goodman’s CP3 parameter to address the
question of assigning two sets of experimental data to two plausible candidates.33 In all
cases, positive CP3 values were computed for the “matched” cases (major-syn/minor-
anti), while negative CP3 values were found for the "mismatched" cases (major-
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anti/minor-syn).30 It is important to recall that positive values indicate good agreement
(assignment likely to be correct), whereas negative values indicate poor agreement
(assignment likely to be incorrect).33
Finally, the in silico stereochemical assignments were validated by Xꢀray
diffraction analysis on single crystals of both diastereoisomers of compound 12 (Figure
7).
Figure 7 Xꢀray structures for both diastereomers of compound 12.
As seen from Figure 7, the major aldol adduct of compound 12 is the syn isomer,
while the minor is the anti, as predicted by the computational studies. In the particular
case of compound 12, it is also clear that in the solid crystalline form no intramolecular
NꢀHꢀꢀꢀOH hydrogen bond is observed, as predicted by calculations in the gas phase and
in solution.
Conclusions
The foregoing inaugural study of the vinylogous aldol reaction (VAR) of Nꢀ
monosubstituted tetronamides has enabled the development of a viable new method for
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constructing medicinally relevant aldols. Of great practicality, the method employs
NaOH in aq. MeOH at ambient temperature and works well with both aromatic and
aliphatic aldehydes. Importantly, most of the VA reactions tried afforded single
diastereoisomers (syn/anti > 99:1) in good to excellent yields. Several lines of evidence
suggest that the observed selectivity arises from antiꢀtoꢀsyn isomer interconversion via an
iterative retroꢀaldol/aldol reaction sequence. Studies on the wider scope of this chemistry
are in progress, and the results will be reported in due course.
Experimental section
General experimental
All reactions were performed using analytical grade solvents without further
1
13
purifications, unless otherwise stated. The H and C NMR spectra were recorded on a
Varian Mercury 300 instrument (300 MHz and 75 MHz, respectively), using deuterated
chloroform, acetone or DMSO as a solvent and tetramethylsilane (TMS) as internal
standard (δ = 0). The experiments were performed at controlled probe temperature of 25
°C, using a number of scans (nt) of 16, a number of points in the FID of 43686 (np); 90°
pulse width; spectral width of 4800.8 Hz; acquisition time (at) of 4.550 s; delay time (D1)
1
13
of 1.00 s. Chemical shifts of H and C NMR spectra are reported in ppm. All coupling
constants (J values) were expressed in Hertz (Hz). Multiplicities are reported as follows:
singlet (s), doublet (d), doublet of doublets (dd), triplet (t), multiplet (m) and broad (br).
Infrared spectra were recorded on a Varian 660ꢀIR, equipped with GladiATR scanning
from 4000 to 500 cmꢀ1. Melting points are uncorrected and were obtained from MQAPFꢀ
301 melting point apparatus (Microquimica, Brazil). High resolution mass spectra were
recorded on a Bruker MicroTof (resolution = 10,000 FWHM) under electrospray
ionization (ESI) and are given to four decimal places. XRD was recorded on Bruker D8
focus Xꢀray Diffraction spectrometer. Analytical thin layer chromatography analysis was
conducted on aluminum packed precoated silica gel plates. Column chromatography was
performed over silica gel (230ꢀ400 mesh).
General procedure for the preparation of compound 8a-c
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3ꢀchloroꢀ4ꢀ(pꢀtolylamino)furanꢀ2(5H)ꢀone (8a). To a 100 mL round bottomed flask, were
added 7a (2 g, 13.08 mmol), MeOH (20 mL for a 13.08 mmol scale reaction), NaHCO3
(550 mg, 6.54 mmol) and pꢀtoluidine (1.4 g, 13.08 mmol). The reaction mixture was
stirred at room temperature for 12 h. After the consumption of the starting butenolide 7a,
the reaction mixture was quenched by addition of aqueous HCl solution (1M, 10 mL).
The methanol was then removed under reduced pressure and the aqueous mixture was
extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtrated and the solvent evaporated. The crude residue was purified
by silica gel column chromatography, eluted with hexane/ethyl acetate (70:30 v/v) to
afford compound 8a as white solid in 93% yield (2.7 g, 12.16 mmol). Mp: 213.8ꢀ215.1
ºC. Rf = 0.4 (hexane: ethyl acetate, 1:1, v/v). FTIR (KBr) νmax 3234, 3068, 1741, 1629,
1052, 982, 899, 741, 531 cmꢀ1. 1H NMR (300 MHz, Acetoneꢀd6:DMSOꢀd6; 9:1) δ 9.06 (s,
1H, ꢀNH), 7.19 (apparent singlet, 4H, Hꢀ3′, Hꢀ4′, Hꢀ6′ and Hꢀ7′), 4.99 (s, 2H, Hꢀ5), 2.31
(s, 3H, Hꢀ8′). 13C NMR (75 MHz, Acetoneꢀd6:DMSOꢀd6; 9:1) δ: 168.76 (Cꢀ2), 158.51
(Cꢀ4), 135.95 (Cꢀ2′), 134.85 (Cꢀ5′), 129.78 (2C, Cꢀ4′ and Cꢀ6′), 122.48(2C, Cꢀ3′ and Cꢀ
7′), 87.21 (Cꢀ3), 66.07 (Cꢀ5), 20.01 (Cꢀ8′). HRMS (ESI) [MꢀH]ꢀ calculated for
C11H9ClNO2, 222.0322; found, 222.0326
4ꢀ[(4ꢀbromophenyl)amino]ꢀ3ꢀchlorofuranꢀ2(5H)ꢀone (8b). Compound 8b was
synthesized using a method similar to that of 8a and was isolated as white solid in 87%
yield (3.3 g, 11.38 mmol); purified by column chromatography, eluent hexane/ethyl
acetate (68:32 v/v). Mp: 221.3ꢀ222.6 ºC. Rf = 0.4 (hexane: ethyl acetate, 1:1, v/v). FTIR
1
(KBr) νmax 3235, 3061, 1749, 1632, 1054, 977, 891, 739, 515 cmꢀ1. H NMR (300 MHz,
Acetoneꢀd6) δ: 8.80 (s, 1H, ꢀNH), 7.56 (d, J= 8.9 Hz, 2H, Hꢀ4′ and Hꢀ6′), 7.27 (d, J= 8.9
13
Hz, 2H, Hꢀ3′ and Hꢀ7′), 5.12 (s, 2H, Hꢀ5) . C NMR (75 MHz, Acetoneꢀd6) δ: 168.38
(Cꢀ2), 157.65 (Cꢀ4), 137.90 (Cꢀ2′), 132.31 (2C, Cꢀ4′ and Cꢀ6′), 123.69 (Cꢀ3′), 123.58 (Cꢀ
7′), 117.36 (Cꢀ5′), 89.13 (Cꢀ3), 66.15 (Cꢀ5). HRMS (ESI) [MꢀH]ꢀ calculated for
C10H6BrClNO2, 285.9270; found, 285.9273
3ꢀbromoꢀ4ꢀ(pꢀtolylamino)furanꢀ2(5H)ꢀone (8c). Compound 8c was synthesized using a
method similar to that of 8a and was isolated as orange solid in 82% yield (1.8 g, 6.78
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mmol); purified by column chromatography, eluent hexane/ethyl acetate (70:30 v/v). Mp:
225.2ꢀ226.8 ºC. Rf = 0.4 (hexane: ethyl acetate, 1:1, v/v). FTIR (KBr) νmax 3230, 3074,
1
1729, 1628, 1050, 985, 896, 740, 520 cmꢀ1. H NMR (300 MHz, DMSOꢀd6) δ: 9.45 (s,
1H, ꢀNH), 7.15 (apparent singlet, 4H, Hꢀ3′, Hꢀ4′, Hꢀ6′ and Hꢀ7′), 4.99 (s, 2H, Hꢀ5), 2.27
13
(s, 3H, Hꢀ8′). C NMR (75 MHz, DMSOꢀd6) δ: 170.09 (Cꢀ2), 162.19 (Cꢀ4), 135.91 (Cꢀ
2′), 135.05 (Cꢀ5′), 130.09 (2C, Cꢀ4′ and Cꢀ6′), 123.21 (2C, Cꢀ3′ and Cꢀ7′), 73.82 (Cꢀ3),
67.66 (Cꢀ5), 20.87 (Cꢀ8′). HRMS (ESI) [MꢀH]ꢀ calculated for C11H9BrNO2, 265.9817;
found, 265.9832
Typical procedure for the VAR of tetronamides (9–26)
3ꢀChloroꢀ5ꢀ[hydroxy(phenyl)methyl]ꢀ4ꢀ(pꢀtolylamino)furanꢀ2(5H)ꢀone (synꢀ9). To a 25
mL one neck round bottomed flask were added tetronamide 8a (200 mg, 0.89 mmol), a
mixture of MeOH and H2O (4 and 2 mL, v/v), followed by NaOH (36 mg, 0.89 mmol).
After stirring the reaction mixture for 5 min at room temperature, benzaldehyde (114 mg,
1.07 mmol) was added slowly. The reaction mixture was stirred at room temperature until
TLC analysis revealed total consumption of 8a. The reaction was then quenched by
addition of an aqueous solution of HCl (1M, 10 mL). The methanol was removed under
reduced pressure and the aqueous mixture was extracted with ethyl acetate (3×15 mL).
The combined organic layers were dried over anhydrous Na2SO4, filtrated and the solvent
evaporated. The crude residue was purified by silica gel column chromatography eluting
with hexane/ethyl acetate (80:20 v/v) to afford pure synꢀ9 as white solid in 91% yield
(267 mg, 0.81 mmol). Mp: 192.3ꢀ194.6 °C. Rf = 0.35 (hexane: ethyl acetate, 80:20, v/v).
FTIR (KBr) νmax 3386, 3282, 3228, 3070, 3037, 3002, 2971, 1754, 1635, 1197, 1029, 647
1
cm−1. H NMR (300 MHz, Acetoneꢀd6) δ: 8.54 (s, 1H, ꢀNH), 7.40ꢀ7.25 (m, 5H, Hꢀ8 to
Hꢀ12), 7.25 (d, J = 8.7 Hz, 2H, Hꢀ4′ and Hꢀ6′), 7.21 (d, J = 8.7 Hz, 2H, Hꢀ3′ and Hꢀ7′),
5.45 (d, J = 2.0 Hz, 1H, Hꢀ5), 5.09 (d, J = 6.0 Hz, 1H, ꢀOH), 5.00 (m, 1H, Hꢀ6), 2.35 (s,
1
3H, Hꢀ8′). H NMR (300 MHz, D2O Exchange) δ: 7.23ꢀ7.39 (m, 5H, Hꢀ8 to Hꢀ12), 7.21
(d, J = 8.6 Hz, 2H, Hꢀ4′ and Hꢀ6′), 7.16 (d, J = 8.6 Hz, 2H, Hꢀ3′ and Hꢀ7′), 5.40 (d, J =
1
2.0 Hz, 1H, Hꢀ5), 5.00 (d, J = 2.0 Hz, 1H, Hꢀ6), 2.32 (s, 1H, Hꢀ8′). H NMR (300 MHz,
CDCl3: DMSOꢀd6; 9:1) δ: 7.83(s, 1H, ꢀNH), 7.32ꢀ7.18 (m, 5H, Hꢀ8 to Hꢀ12), 7.07 (d, J =
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8.3 Hz, 2H, Hꢀ4′ and Hꢀ6′), 6.89 (d, J= 8.3 Hz, 2H, Hꢀ3′ and Hꢀ7′), 5.15 (d, J = 3.6 Hz,
13
1H, Hꢀ5), 5.03 (d, J = 3.6 Hz, 1H, Hꢀ6), 2.27 (s, 3H, Hꢀ8′). C NMR (75 MHz, CDCl3:
DMSOꢀd6; 9:1) δ: 169.74 (Cꢀ2), 156.24 (Cꢀ4), 138.85 (Cꢀ7), 135.28 (Cꢀ2′), 134.24 (Cꢀ5′),
129.10 (2C, Cꢀ4′ and Cꢀ6′), 127.89 (2C, Cꢀ8 and Cꢀ12), 127.78 (Cꢀ10), 126.40 (2C, Cꢀ8
and Cꢀ12), 123.96 (2C, Cꢀ3′ and Cꢀ7′), 88.62 (Cꢀ3), 79.40 (Cꢀ5), 71.26 (Cꢀ6), 20.80 (Cꢀ
8′). HRMS (ESI) [MꢀH]ꢀ calculated for C18H15ClNO3, 328.0740; found, 328.0732
Compounds 10-26 were synthesized using a method similar to that described for
1
compound synꢀ9. Characterization data of all synthesized products and copies of H and
13C NMR spectra are available on supporting information.
3ꢀchloroꢀ5ꢀ[hydroxy(phenyl)methyl]ꢀ4ꢀ(pꢀtolylamino)furanꢀ2(5H)ꢀone (anti-9). To a dry
25 mL one neck round bottomed flask were added tetronamide 8a (200 mg, 0.89 mmol),
anhydrous MeOH (5 mL), followed by tꢀBuOK (99 mg, 0.89 mmol). After stirring the
reaction mixture for 5 min at room temperature, benzaldehyde (114 mg, 1.07 mmol) was
added slowly. The reaction mixture was stirred at room temperature under nitrogen
atmosphere until TLC analysis revealed total consumption of 8a. The reaction was then
quenched by addition of an aqueous solution of HCl (1M, 10 mL). The methanol was
removed under reduced pressure and the aqueous mixture was extracted with ethyl
acetate (3×15 mL). The combined organic layers were dried over anhydrous Na2SO4,
filtrated and the solvent evaporated. The crude residue was purified by silica gel column
chromatography eluting with hexane/ethyl acetate (80:20 v/v) to afford the synꢀ9 (117
mg, 0.36 mmol ) as white solid in 40% yield and eluting with hexane/ethyl acetate
(79.5:20.5 v/v) to afford antiꢀ9 as light yellow solid in 39% yield (114 mg, 0.35 mmol).
Data for antiꢀ9: Mp: 190.1ꢀ191.2 °C. Rf = 0.33 (hexane: ethyl acetate, 3:2, v/v). FTIR
(KBr) νmax 3309, 3278, 3191, 3081, 3068, 3029, 1743, 1631, 1583, 1195, 1008, 734 cm−1.
1H NMR (300 MHz, Acetoneꢀd6) δ: 8.44 (s, 1H, ꢀNH), 7.43ꢀ7.26 (m, 5H, Hꢀ8 to Hꢀ12),
7.24 (d, J = 8.5 Hz, 2H, Hꢀ4′ and Hꢀ6′), 7.18 (d, J = 8.5 Hz, 2H, Hꢀ3′ and Hꢀ7′), 5.51 (d, J
= 4.3 Hz, 1H, Hꢀ5), 5.20 (d, J = 4.8 Hz, 1H, ꢀOH), 4.91 (m, 1H, Hꢀ6), 2.34 (s, 3H, Hꢀ8′).
1H NMR (300 MHz, D2O Exchange) δ: 7.24ꢀ7.40 (m, 5H, Hꢀ8 to Hꢀ12), 7.20 (d, J = 8.4
Hz, 2H, Hꢀ4′ and Hꢀ6′), 7.12 (d, J = 8.4 Hz, 2H, Hꢀ3′ and Hꢀ7′), 5.50 (d, J = 3.9 Hz, 1H,
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1
Hꢀ5), 4.92 (d, J = 3.9, 1H, Hꢀ6), 2.31 (s, 3H, Hꢀ8′). H NMR (300 MHz; CDCl3:DMSOꢀ
d6; 9:1) δ: 8.04 (s, 1H, ꢀNH), 7.31ꢀ7.10 (m, 5H, Hꢀ8 to Hꢀ12), 7.05ꢀ6.94 (m, 2H, Hꢀ4′ and
Hꢀ6′), 6.91ꢀ6.81 (m, 2H, Hꢀ3′ and Hꢀ7′), 4.97 (dd, J = 6.0, 4.3 Hz, 1H, Hꢀ5), 4.70 (dd, J =
13
6.0, 4.3 Hz, 1H, Hꢀ6), 2.22 (s, 3H, Hꢀ8′). C NMR (75 MHz, CDCl3: DMSOꢀd6 9:1) δ:
169.62 (Cꢀ2), 156.80 (Cꢀ4), 139.21 (Cꢀ7), 135.34 (Cꢀ2′), 134.11 (Cꢀ5′), 129.18 (2C, Cꢀ4′
and Cꢀ6′), 128.48 (Cꢀ10), 128.26 (2C, Cꢀ8 and Cꢀ12), 127.16 (2C, Cꢀ8 and Cꢀ12), 123.76
(2C, Cꢀ3′ and Cꢀ7′), 88.86 (Cꢀ3), 79.36 (Cꢀ5), 74.49 (Cꢀ6), 20.89 (Cꢀ8′). HRMS (ESI)
[MꢀH]ꢀ calculated for C18H15ClNO3, 328.0740; found, 328.0678
Compound antiꢀ10 and antiꢀ22 were synthesized using a method similar to that described
for compound antiꢀ9. Characterization data of synthesized products and copies of 1H and
13C NMR spectra are available on supporting information.
Procedure for the retro-aldol reaction
To a solution of aldol compound antiꢀ10 (87 mg, 0.25 mmol) and antiꢀ22 (100 mg, 0.25
mmol) in MeOH/H2O (2:1 mL, v/v), NaOH (10 mg, 0.25 mmol) was added with
continuous stirring at room temperature. The reaction mixture was then stirred at room
temperature for 3 h and quenched by addition of aqueous HCl solution (1M, 5 mL). The
methanol was then removed under reduced pressure and the aqueous mixture was
extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtrated and the solvent evaporated. The crude residue was subjected
to silica gel column chromatography, eluting with hexane/ethyl acetate (82:18 v/v) and
isolated three different fractions as a mixture of tetronamides 8a/8b (21 mg) synꢀ9/22(52
mg and synꢀ10/24 (28 mg) respectively. Characterization data of retroꢀaldol products and
copies of 1H NMR spectra are available on supporting information.
Experimental procedure for the ‘D’ incorporation vs. isomerization
A solution of antiꢀ9 (25 mg, 0.08 mmol) in CD3OD:D2O (0.7 mL, 4:1 v/v) was
1
transferred to a NMR tube and the H NMR spectrum was obtained. Then anhydrous
NaOH (3 mg, 0.08 mmol) was added to the solution and the NMR was obtained after 10,
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20, 40 and 180 minutes. The spectra obtained are presented in the supporting
information.
Acknowledgements
We thank the Brazilian agencies CNPq for a research fellowship (LCAB), a Special
Visiting Researcher Fellowship (JB) and a PhD fellowship (JAMA); CAPES for a PhD
fellowship (MK) and FAPEMIG for financial support. We also thank NSERC (Canada)
for a Discovery grant to JB.
Notes and references
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