Total Facial Discrimination of 1,3-Dipolar Cycloadditions in a d -Erythrose 1,3-Dioxane Template: Computational Studies of a Concerted Mechanism

Article abstract of DOI:10.1021/acs.joc.6b02518

A new d-erythrose 1,3-dioxane derivative was synthesized from d-glucose and found to be a highly stereoselective template as a dipolarophile. Different 1,3-dipoles of allenyl-type were employed, giving different regioselectivities, depending on its nature; the regioselectivity is complete with alkyl azides and phenyldiazomethane, but is inexistence with nitrile oxides. Computational studies were performed to understand the mechanisms of cycloadditions. All the studied cycloadditions were found to be concerted involving small free activation energies and are all exoenergonic. The stereoselectivity is due to a combined result of the steric effect H-8a and the hyperconjugative effect of the?C-O to the incoming 1,3-dipole. The regioselectivity observed in alkyl azides and phenyldiazomethane is mostly dependent on the distortion effect during the cycloaddition process. This distortion effect is however higher in the alkyl azide compounds than in phenyldiazomethane.

Full text of DOI:10.1021/acs.joc.6b02518

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Article
Total Facial Discrimination of 1,3-Dipolar Cycloadditions in a D-Erythrose
1,3-Dioxane Template. Computational Studies of a Concerted Mechanism
Cristina E. A. Sousa, António M. P. Ribeiro, António Gil
Fortes, Nuno M. F. Sousa A Cerqueira, and M. Jose Alves
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 29 Dec 2016
Downloaded from http://pubs.acs.org on December 29, 2016
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Total Facial Discrimination of 1,3-Dipolar Cycloadditions in a
D-Erythrose 1,3-Dioxane Template. Computational Studies of a
Concerted Mechanism
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a)
a)
a)
Cristina E. A. Sousa , António M. P. Ribeiro ,António Gil Fortes , Nuno M. F. S. A. Cerqueira
b)*
a)*
,and Maria J. Alves
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a)
Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
b)
REQUIMTE/UCIBIO, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua
do Campo Alegre s/n, 4169-007 Porto, Portugal
*mja@quimica.uminho.pt; nscerque@fc.up.pt
Abstract- A new D-erythrose 1,3-dioxane derivative was synthetized from D-glucose and
found to be a highly stereo-selective template as dipolarophile. Different 1,3-dipoles of allenyl-
type were employed, giving different regio-selectivities, depending on its nature; the regio-
selectivity is complete with alkyl azides and phenyldiazomethane, but is inexistent with nitrile
oxides. Computational studies were performed to understand the mechanisms of cycloadditions.
All the studied cycloadditons were found to be concerted involving small free activation
energies and are all exoenergonic. The stereo-selectivity is due to a combined result of the steric
effect H-8a, and the hyperconjugative effect of the *C-O to the incoming 1,3-dipole. The regio-
selectivity observed in alkyl azides and phenyldiazomethane is mostly dependent on the
distortion effect during the cycloaddition process. This distortion effect is however higher in the
alkyl azide compounds than in phenyldiazomethane.
Introduction
The synthesis of a multiple stereogenic centre molecules, can be efficiently made by adding up
small chiral synthons to build larger structures.1 Tetroses are in this context interesting versatile
fragments, useful in the synthesis of iminosugars of several types.2 2,4-O-
Ethylidene/benzylidene-D-erythroses are tetroses easily accessed in large scale from cheap D-
glucose in two steps. In particular, the synthesis of benzylidene-D-erythrose3,4 is a quite
accessible starting material. Wittig elongation of the aldehyde function would generate α,β-
unsaturated carbonyl compounds to which many applications in syntheses can be ascribed.5 In
fact, the compounds are scarcely known in the literature. This is probably due to a poor facial
selectivity of the olefinic portion in reactions, connected to its high degree of freedom.
Elongation of 2,4-O-ethylidene D-erythrose with simultaneous functionalization of the olefinic
portion was attempted before by reaction with sulfur ylides, but a 3:2 mixture of diastereomeric
epoxides was obtained.6 Reasoning that the lock of the double bond into a six-membered ring
would improve the stereo-selectivity of the reactions, a δ-lactone was obtained from the Z-
stereoisomer. Besides, the α,β-unsaturated lactone bearing a well exposed electronic π cloud
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would enable a better reactivity than the open-chain precursor. This compound can be envisaged
as a good 1,4-Michael acceptor, and as an electron-poor dipolarophile/dienophile.
In the present work the lactone was synthetized and reacted with alkyl azides,
phenyldiazomethane and nitrile oxides by [3π+2π] cycloaddition to afford the respective
adducts. The concept of “cycloaddition” gives a formal description of the overall reaction but
not a mechanistic interpretation. Unlike the Diels−Alder reaction, in the case of [3+2]
cycloadditions the principal question is whether the new σ-bonds that are generated during the
fusion of the 1,3-dipole with the dipolarophile, and from which results a five-membered ring,
occurs in a concerted or stepwise way. In addition, the cycloaddition can follow different routes
depending on the nature of the 1,3-dipole molecule. It can have a polar character, when the
reactant displays electrophile or nucleophile activities,7 a bi-radical character8 or even a non-
polar character.9
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In order to understand the mechanism of the [3+2] cycloadditions, the free energy profile of
these reactions was studied by theoretical and computational means.
Results and Discussion
1. Synthesis of lactone 1
As far as we know lactone 1 is a new compound with non-studied reactivity and selectivity. It
was obtained from D-erythrose derivative
2
by Wittig olefination with methyl
(triphenylphosphoranylidene)acetate. First a 2.3:1 ratio of Z and E isomers 3 was obtained. The
isomeric mixture was heated in dry toluene in the presence of silica in a rotary evaporator for
several hours. After consumption of the Z isomer, the crude was chromatographed to give
lactone 1 in 63 % overall yield, from D-erythrose derivative 2 (Scheme 1).
Ph
Ph
Ph
i)
93 %
ii)
2
O
O
O
O
CO2Et
O
O
8a
D-Glucose
63 %
4a
6
OH O
OH
O
2
3
O
2.3(Z):1(E)
1
Scheme 1 - Synthesis of lactone 1
i) methyl (triphenylphosphoranylidene)acetate, TsOH (cat), dry THF, 23h, rt; ii) silica, dry
toluene, 75 ºC, vacuum.
2. 1,3-Cycloadditions of lactone 1 with 1,3-dipoles
Lactone 1 was reacted with three types of 1,3-dipoles: alkyl azides (4), nitrile oxides (5), and a
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diazo compound (6). According to the nature of the 1,3-dipole, reactions took place within a
large range of temperatures, from rt to 102 ºC. In the cases of alkyl azides and the diazo
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7
1
compound products are isolated as single isomers, within the detection limit of HNMR
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9
spectroscopy. With nitrile oxides the stereo-selectivity of reactions continue to be effective, but
the regio-selectivity is not (Scheme 2).
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Ph
Ph
Ph
O
O
9b
R
R
N O
5
O
O
9a
R N3
4
R
O
O
8
9a
5a
1
O
N
4a
1
9a
6a
+
9b
9b
N
N
i)
N
ii)
O
4
O
O
O
3a
N
3a
R
O
O
O
iii)
9a, R= 2,6-Cl-C6H3, 50%a)
9b, R= Ph, 24 %
9c, R= Mec)
10a, R= 2,6-Cl-C6H3, 19%
10b, R= Ph, 56 %b)
10c, R= Me, 28 %
7a, R= Bn, 81.3 %
7b, R= (CH2)3-OBn, 54.8 %
7c, R= n-Pr, 86.0 %
PhCHN2
6
Ph
a) contaminated with 25% of isomer 10a
b) contaminated with 25% of isomer 9b
c) contaminated with an impurity
O
O
Ph
9b
9a
4a
N
6a
O
N
H
O
8, 76.3 %
Scheme 2 - 1,3-Dipolar cycloaddition of lactone 1 to azides, nitrile oxides and
phenyldiazomethane.
i) a) benzyl azide (2 equiv.), HC(OMe)3, reflux, 65 h; b) (3-azidopropoxy)methyl benzene
(2equiv.), 95 ºC, 44 h; c) n-propyl azide, (1 equiv., every 3 hours for 30h); 95 °C; ii) a) 2,6-
dichloro-N-hydroxybenzimidoyl chloride, dry ether, Et3N, 0º
-
rt, 15 h; b) N-
hydroxybenzimidoyl chloride, dry ether, Et3N, 0º - rt, 12 h; c) NCS, acetaldehyde oxime,
pyridine then Et3N in toluene, 0º - rt, 15h; iii) phenyldiazomethane, toluene, 60-70 ºC, 1h15m.
Intermolecular reactions of alkenes to azides are known but not common, and require harsh
conditions, due to the poor reactivity of the reactants.10 On the other hand, intramolecular 1,3-
cycloadditions are frequent, although triazoline cycloadducts are rarely isolated, and in most
cases the chiral centre(s) formed are destroyed in the following rearrangements. Nevertheless,
reaction of tri-O-acetyl-D-glucal with alkyl azides occurred before at high temperature in
trimethyl- or triethylorthoformate, and the respective triazolines were isolated in good yields
and with complete stereo-selectivity.11 Inspired by these reactions lactone 1 was combined with
three alkyl azides under reflux in trimethylorthoformate. Triazolines were obtained in high
yields in two cases (7a,c), and in moderate yield in one case (7b). Stereo- and regio-selectivities
are complete in every case. An ORTEP X-ray analysis of the adduct 7a is consistent with the
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attack of alkyl azide on the re face of the lactone ring (see Figure 1 in supporting information).
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1
Reaction of lactone 1 with phenyldiazomethane gave a single product in 76 % yield. H NMR
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9
spectrum evidenced that the primary cycloadduct suffered a 1,3-H-shift rearrangement to form
compound 8. The regio-selectivity of the reaction was elucidated by a NOE experiment on
compound 8: irradiation of 9a-H induced an increase of 9b-H and H-aromatic signals (Figure 1).
These observations are consistent with the regio-chemistry of compound 8 in scheme 2. NOE
experiment also showed that phenyldiazomethane approaches lactone by the re face, since 9a-H
and 9b-H protons are located at the same side of the molecule.
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Ph
O
O
9b
Ph
N
N
H
H
H
9a
4a
O
H
O
8
Figure 1: NOE interaction elucidates both the regio-chemistry and stereochemistry of the newly
formed chiral centres.
Reactions of lactone 1 with nitrile oxides gave a pair of regio-isomers 9 and 10, in
1
approximately 1:1 ratio. Identification of isomers was conclusive after H MNR spectra
analysis: the oxygen position in the fused-oxazole 9/10 is likely to affect the proton chemical
shift attached to its neighbour carbon atom. In fact, isomers 9 showed consistently H-6a at a
higher chemical shift (δH 5.33-5.10 ppm) than H-9a (δH 4.86-3.95 ppm); the opposite trend
occurs in isomers 10 where H-9a appears at δH 5.37-5.09, higher than H-6a (δH 4.98-4.34 ppm).
Irradiation of 6a-H’s signal in compound 10b induced a 13.9 % increase of the aromatic peak,
demonstrating its neighbourhood to the aromatic ring. The facial approach of the nitrile oxide to
the lactone 1 was also determined by NOE experiment: irradiation of H-9b’s signals in the pair
9b/10b indicated that H-9a and H-9b are located on the same side in both isomers. As C-9b’s
configuration refers to the starting material, it is clear that the approach of reagents would had
occurred from the re face of the lactone. Additionally, H-2 signals also increase by H-9b’s
irradiation in both isomers.
3. Computational results
A. Stereo-specificity of the cycloadducts
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The high stereo-selectivity of the compounds is one of the key features of the studied reactions.
In all of the studied cases, the cycloaddition of the 1,3-dipoles was found to occur by the re face
of the lactone ring, i.e., in the opposite plane where the hydrogen atom covalently bonded to
carbon C8a is located at. (Figure 2A) The transition state structures of these reactions show that
the main moiety of the lactone, including the keto group, are perpendicular to the new bonds
formed during the 1,3-dipoles approach in the top face of the lactone (Figure 2B). This process
is facilitated by the small size of the 1,3-dipole molecules, allowing them to react in largely
occluded areas where other reagents cannot fit due to steric bulk. Hydrogens 8a in the lactone is
very close to the reactive region and it was found to play an important role in the stereo-
specificity of the cycloaddition process. Hydrogen 8a located at the si face precludes the correct
alignment of the 1,3-dipole to the lactone. This is patent on free energies calculated for the
nitrile oxide, R=Ph, that requires an activation energy of 40 kcal/mol, and the reaction is
endothermic by 15 kcal/mol. On the other hand the hydrogen 4a is located further away from
the region where the reaction takes place, at the re face of the lactone, leading way to a more
suitable approach of the 1,3-dipole at the re face of the lactone. Overmore the attack at the re
face is also favored by an hyperconjugative interaction of the sigma*C-O to the electron
positively charged atom of the 1,3 dipole. So the re face is more favored either by steric and
electronic reasons.12 In fact, the cycloaddition process at the re face requires a free activation
energy of 21.3 kcal/mol and a free reaction energy of -17.8 kcal/mol. The same conclusion are
applied to the azides, diazo and nitrile oxide compounds.
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Ph
R
A
B
O
X
O
N
H
O
Y
H
re face
reaction
H
H
Ph
O
R
X
N
Y
O
H
O
H
O
H
H
H4a
Ph
O
O
O
si face
reaction
H8a
H
H
re face
si face
H
O
R
H
O
X
N
Y
Figure 2: A: Stereo-selectivity of the reactions of the lactone 1 with 1,3-dipole compounds.
The red pathway shows the attack in the re (top) face of the lactone ring. The blue pathway
shows the attack in the si (bottom) face of the lactone ring (do not happen). B: Transition state
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structure obtained from cycloaddition of an azide compound at the re face of the lactone.
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B. Regio-specificity of the compounds
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The cycloaddition involving unsymmetrical 1,3-dipole and the lactone 1, can potentially
generate two regio-isomeric products, depending on the orientation of the 1,3-dipole molecules
in relation to the lactone. When the R group of the 1,3-dipole molecule is pointing to the same
side of the phenyl group of the lactone, the cycloaddition follows pathway A (Figure 3)).
Otherwise, when the R group is pointing towards the opposite direction of the phenyl group of
the lactone, the cycloaddition follows pathway B (Figure 3). In principle a mixture of both
regio-isomers could be obtained in these type of reactions, as it was observed in the reactions
with the nitrile oxides 5. However, alkyl azides 4 and diazo compound 6 gave a single regio-
isomer cycloadduct.
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Figure 3: Possible catalytic mechanisms of lactone 1 with 1,3-dipoles. Y,X=N in the case of alkyl azides;
X=C, Y=O in the case of nitrile oxides; X=C, Y=NH in the case of phenyldiazomethane.
The most generally satisfactory interpretation of the regio-chemistry of dipolar cycloadditions is
based on frontier molecular orbitals (FMO) concepts. As with the Diels-Alder reaction, the most
favourable orientation is the one that involves the complementary interaction between the
frontier orbitals.
Generally, the 1,3-cycloadditions can be classified in three types based on the relative FMO
energies between the dipole and the dipolarophile. In 1,3-cycloadditions type I, the dominant
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FMO interaction is that of the HOMO dipole with the LUMO’s dipolarophile. For 1,3-
cycloadditions type II, the similarity of the dipole and dipolarophile FMO energies implies that
both HOMO-LUMO interactions are important. In 1,3-cycloadditions type III the interaction is
obtained between the LUMO’s dipole and the HOMO’s dipolarophile.
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The evaluation of the energies of the HOMO and LUMO of all the transition state structure
involving the reaction of diazo, azide and nitrile oxides compounds with the lactone reveal that
the diazo compounds follow a mechanism of type I and the azide and nitrile oxides compounds
follow a mechanism of type II. The mechanism of type II is a characteristic of the reactions
involving 1,3-dipole molecules with high nucleophilic nature, as it is the case of the nitrile
oxides and alkyl azides, which turns the energy gap between the HOMO and LUMO of the
dipole and dipolarophile very close to each other. (See supporting SI-1 for detailed description
of the energy involved in this process)
This interpretation of the results is however not sufficient to explain the origin of the regio-
specificity present on the studied reactions. For example, the mechanism of cycloadditions
involving either nitrile oxides and alkyl azides are type II, however the energy gap between the
HOMO and LUMO in the transition state cannot be use to explain why with nitrile oxides gave
two regio-isomers and alkyl azides gave only one isomer.
A better explanation to understand the regio-specificity of the studied reactions was obtained
analyzing the energetic profiles of the cycloaddition process.
B1. Mechanism of the 1,3-cicloadditions
The computational results have shown that the 1,3-cycloadditions are controlled by the
electronic/stereo-electronic and steric factors that require highly ordered transition states and
only moderate free energies requirements.
Independently on the pathway that is followed (pathway A or B), the full process is complete in
a unique step involving the concerted formation of two covalent bonds between the 1,3-dipole
molecules and the lactone. This is confirmed by all the transition state structures, from all the
studied reactions, that present a single imaginary frequency, and in which the 1,3-dipole
molecule adopts a partially folded conformation well-aligned and in close contact to C7 and C8
carbons of the lactone. Examples of the transition state structures involved in the cycloaddition
process of lactone 1 and each of the 1,3-dipole molecules are shown in Figure 4.
Independent on the 1,3-dipole molecule that was studied and on the substitutions, present on
these molecules, all the reactions require relative small free activation energies (below 28
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kcal/mol) and are all exoenergonic (Figure 5). Despite these similarities, the free energetic
profile of the studied reactions, whenever pathway A or B is followed, are distinct and allow to
understand the origin of the regio-specificity of the cycloadditions of the studied 1,3-dipole
molecules.
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Pathway A
Pathway B
-369.24 cm⁻¹
-404.66 cm⁻¹
-394.27 cm⁻¹
-416.57 cm⁻¹
2.131Å
2.128Å
2.080Å
2.202Å
-394.76 cm⁻¹
2.199Å
2.282Å
2.162Å
2.137Å
-412.10 cm⁻¹
2.181Å
2.272Å
2.170Å
2.382Å
Figure 4: Transition state structures of the cycloaddition process of lactone 1 and benzyl azide
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(7a), phenylnitrileoxide (9b/10b) and the diazo compound (8).
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The calculated free energies involving the cycloaddition of the 1,3-dipole azides with lactone 1
reveal that pathway A is always favored either from the kinetic or thermodynamic points of
views in relation to pathway B. This is more clear in the cycloaddition process involving the
1,3-dipole azides that are substituted with propyl and benzyl groups, in which pathway A is
favoured kinetically in more than 3.5 kcal/mol and thermodynamically in more than 2.3
kcal/mol. When the 1,3-dipole azides has a (CH₂)₃-OBn group, pathway A continues to be
kinetically favoured in 2.6 kcal/mol but it is only thermodynamically favoured in 1 kcal/mol.
These results agree to what is observed experimentally, since only one isomer is observed and
isolated (Figure 5).
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37.5
Activation free energy
Reaction free energy
29.3
29.1
28.1
26.7
26.0
23.0
25.4
24.1
24.6
24.3
23.5
25 21.9
22.2
21.3
12.5
0
-12.5
-25
-2.0
-2.9
-3.1
-3.7
-4.1
-4.0
-4.9
-6.3
-12.3
-15.1
-16.4
-17.0
-17.8
-19.6
-37.5
-50
A
B
A
B
A
B
A
B
A
B
A
B
A
B
R=n-Pr
R=Bn
Alkyl Azides
R= (CH₂)₃-OBn
R=Me
R=Ph
Nitrile Oxides
R=2,6-Cl-C₆H₃
phenyldiazomethane
Figure 5: Activation and reaction free energies of the cycloaddition process involving lactone 1
and the alkyl azides, nitrile oxides and phenyldiazomethane.
The cycloaddition process of the 1,3-dipole nitrile oxides with lactone 1 produces two isomers
instead of a single one, contrasting to what is observed with 1,3-dipole azides. The
computational results indicate that the energetic profiles of pathways A and B for these
reactions are very similar either from the kinetic (energy differences below 1.2 kcal/mol) and
thermodynamic (energy differences below 2.8 kcal/mol) points of views, indicating that both
pathways should be competitive. These results go in line with what is observed experimentally
since, a mixture of two isomers are obtained (Figure 5). For example in the case of compounds
9b and 10b, compound 9b is obtained in 24% yield and compound 10b in 56%. However, as
compound 10b is contaminated with 25% of compound 9b, the ratio between the yields is near
1:1, in agreement with the computational results.
The cycloaddition of lactone 1 with the 1,3-dipole phenyldiazomethane was also studied
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through pathways A and B. However, and contrarily to what was found with nitrile oxides and
the alkyl azides, the formation of compound 8 requires two steps instead of one. First occurs the
cycloaddition process. Afterwards takes place the 1,3-H shift.
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The calculated free energy profiles for pathway A (Ea=23.0 kcal/mol and Er=-4.0 kcal/mol) and
pathway B (Ea=26.0 kcal/mol and Er=-3.1 kcal/mol) indicate that pathway A is from the kinetic
and thermodynamic points of views favoured in relation to pathway B (Figure 5). These results
go in line with the experimental observations in which only one isomer is isolated from this
reaction.
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The second step of the reaction involves the 1,3-H shift. Since pathway A was the most
favoured one, this reaction was only studied for the product of this reaction. The 1,3-H shift
requires the participation of two water molecules that form a hydrogen bond network allowing
the proton exchange between the carbon and nitrogen atoms from the cycloaddition product
obtained in pathway A. The transition state of this reaction is characterized by an imaginary
frequency at -944.57cm-1 and the full process requires a free activation energy of 38.14 kcal/mol
and it is exoenergonic in -8.03 kcal/mol.
40
1,3-H shift
1,3-H shift
cycloaddition
30
20
10
0
1.67Å
1.11Å
1.16Å
1.31Å
-10
-20
1.72Å
1.02Å
Step 1
Step 2
Reaction Coordinate
Figure 6: Left: Transition state structure of the 1,3-H shift mechanism. Right: Free energetic
profile for the formation of compound 8.
The full energetic profile obtained for the formation of compound 8 is depicted in figure 6. The
computational results reveal that the 1,3-H shift mechanism is the rate limiting step in the
formation of compound 8.
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B2. Origin of the regio-specificity of the cycloadditions
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In order to evaluate the origin of the regio-specificity of the alkyl azides and
phenyldiazomethane in relation to the nitrile oxide compounds we have decomposed the free
activation energies in different energetic terms: the distortion energy, interaction energy,
entropic contribution and solvent effects.
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The distortion energy was calculated summing up the energy difference between the geometry
of lactone and 1,3-dipole per se and for each reagent in the transition state. The interaction
energy was calculated based on the energy difference between the energies of the 1,3-dipole and
the lactone molecules together and alone in the transition state and reactants of all the studied
reactions. The entropic contributions and the solvent effect on each reaction were obtained
directly from the calculations. The results from these analyses are displayed on figure 9.
35.0
Distortion
Entropic
Interaction
Solvent
30.0
25.0
20.0
15.0
10.0
5.0
0.0
-5.0
-10.0
A
B
A
B
A
B
A
B
A
B
A
B
A
B
R=n-Pr
R=Bn
Alkyl Azides
R= (CH₂)₃-OBn
R=Me
R=Pn
Nitrile Oxides
R=2,6-Cl-C₆H₃
phenyldiazomethane
Decomposition of the activation energies (kcal/mol)
Distortion Entropic Interaction Solvent
26.8 4.4 -8.0 -5.8
1,3-Dipole Molecule
Pathway
R=n-Pr
R= Bn
A
B
A
B
A
30.7
30.1
30.3
28.5
31.7
23.9
23.7
26.8
25.6
26.7
25.2
25.6
27.9
5.3
3.0
4.3
4.2
4.7
3.1
2.9
2.9
3.7
4.3
4.4
5.1
4.6
-5.6
-7.6
-4.9
-5.3
-6.5
-5.4
-3.7
-6.2
-4.4
-5.9
-4.5
-7.1
-5.8
-6.6
-3.9
-5.9
-4.9
-5.2
-3.3
-3.5
-2.8
-4.2
-4.0
-5.4
-5.5
-5.2
Alkyl Azide
R= (CH₂)₃-OBn
B
A
B
A
B
A
B
A
B
R=Me
R=Ph
Nitrile Oxides
R=2,6-Cl-C₆H₃
Phenyldiazomethane
Figure 7: Decomposition of the activation energies of the cycloaddition process involving
lactone 1 and the alkyl azides, nitrile oxides and the diazo compound.
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The results indicate that the main contributor for all the calculated activation energies is the
distortion energy, i.e. the energy that is required to move the 1,3-dipole molecules and the
lactone in a proper way to endorse the concerted cycloaddition process. From these two
molecules, the 1,3-dipoles are the ones that suffer the highest distortion effect. The calculations
also reveal that the distortion of these molecules accounts in average 70% of the total distortion
energy (see supporting information SI-2). The other negative contributor for the activation
energies of all the studied reactions is the entropy. This is expected since the cyclization process
is from the entropic point of view unfavourable. However, its contribution is very small (below
5 kcal/mol) when compared to the distortion energy. The calculated interaction energy and
solvent effects have a positive contribution to the calculated activation energies; in average they
decrease the activation energies in -5.9 kcal/mol and -4.2 kcal/mol respectively. The interaction
energy is the one that makes the cycloaddition process possible. The solvent effect was
introduced in the calculations with the inclusion of a dielectric constant. This was found to be
important for the stabilization of zwiterionic species particularly during the distortion of these
molecules nearby the transition state.
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From all the studied reactions, the cycloaddition of alkyl azides with lactone 1 are the ones that
require higher activation energies. The results shown that this is proportional to the higher
distortion effect that is observed in the 1,3-dipole molecules. These results also shown that the
distortion effect of alkyl azides in pathway B is higher than in pathway A and justify why this
reactions are regio-selectives (pathway A).
In the case of nitrile oxides, a similar contribution of the energetic terms that were calculated is
observed on pathways A and B, justifying why in this case two isomers are obtained.
The energy decomposition of the cycloaddition of phenyldiazomethane with lactone 1 reveal
that the energetic profile is similar to the one observed with nitrile oxides. However in this case
the distortion energy is smaller in pathway A than in pathway B turning this reaction regio-
selective for pathway A, similarly to what happens in the mechanism of alkyl azides.
C. The effect on the substituents of the 1,3-dipoles on the calculated free energies.
The cycloaddition of the lactone with the 1,3-dipoles, nitrile oxides and alkyl azides, having
different substituents, were also carried out in order to understand the effect of such substituents
on the free energies of the reactions and so in the obtained yields (Figure 5). With the alkyl
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azides bearing propyl, and benzyl groups pathway A is favoured either from the kinetic and
thermodynamic points of view relatively to pathway B. The computational results with
(propoxymethyl)benzene showed to be less favourable than in the other two cycloadditions,
which go in line with the experimental results; compound 7b was obtained with a lower yield
(55 %) than the others. The computational results indicate that the energetic profile of pathway
A is less favoured because of the volume of the (propoxymethyl)benzene that creates a steric
hindrance either with the Ph group of the lactone in pathway A and with the carbonyl group in
pathway B
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The cycloaddition of the nitrile oxides was also investigated with the methyl, phenyl and
dichorophenyl groups. The computational results reveal that in all of the three reactions,
pathway A and pathway B present similar energetic profiles. For each compound the activation
free energies for each pathway differ only in 1 kcal/mol, and the reaction free energies are
below 3 kcal/mol. This indicates that the cycloadditions of the nitrile oxides with the two
different orientations are competitive and therefore a mixture of both isomers should be
obtained in the end. This is in accordance with the experimental results where both isomers
were obtained in similar amounts in the three reactions.
5. Conclusion
A new D-erythrose 1,3-dioxane derivative, lactone 1, has been synthetized and found to be a
highly selective template in 1,3-dipolar cycloadditons. Alkyl azides, nitrile oxides and
diazoalkanes were reacted as models. The computational results showed the stereo-selectivity is
due to the steric effect of the hydrogen atom (H8a). The activation and reaction free energies
calculated for the cycloadditions allow to explain the origin of the regio-selectivity observed
with alkyl azides and diazo compounds in relation to the nitrile oxides.
The cycloaddition processes can occur with two different orientations of the 1,3-dipole
molecule in relation to the lactone (pathway A and B). In the nitrile oxides cases, pathways A
and B are competitive and both isomers are obtained. However, in the cases of the alkyl azides
and diazo compounds only one isomer is favoured from kinetic and thermodynamic points of
view. The detailed analysis about energies involved in the cycloaddition process indicate that
pathway A is favoured because it requires a lower distortion of the 1,3-dipole molecules during
the reaction.
6. Experimental
6.1 General
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Solvents were used as purchased except: dichlorometane and methanol, dried under CaH2 and
Mg/I2, respectively; tetrahydrofurane, and ether, dried under Na-benzophenone, and DMF and
toluene distilled with elimination of the head distilation fractions. Petroleum ether 40-60 °C
used in chromatography was submitted to distillation. D-erythrose benzylidene acetal was
obtained according to lit.3,4 Alkylazides were obtained from the respective alkyl bromides, by
reaction with sodium azide under standard conditions.13 Benzyloxypropyl azide was prepared
from 3-bromopropanol by reaction with sodium azide followed by protection of the hydroxyl
group with benzyl bromide.14 Nitrile oxides were obtained in situ from α-chlorobenzaldoximes
in the presence of triethylamine.15 Phenyldiazomethane was obtained from the aldehyde and
tosylhydrazone according to lit.16
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All other reagents were purchased and used without further purification. Glassware was dried
prior to use. Compounds were purified by dry flash chromatography using silica 60, <0.063 mm
and water pump vacuum or by flash-chromatography using silica 60Å 230−400 mesh as
stationary phases. TLC plates (silica gel 60 F254) were visualized either at a UV lamp or in I2
chamber.
6.2. Synthesis of Lactone 1
i) Synthesis of methyl 3-((2’R,4’S,5’R)-5’-hydroxy-2’-phenyl-1’,3’-dioxan-4’-
yl)acrylate
To a solution of aldehyde 2 (1.0 g, 4.8 mmol) in dry THF (20 mL), stirred under nitrogen in the
presence of a catalytic amount of p-toluene sulfonic acid (5 mg) was added a solution of methyl
(triphenylphosphoranylidene)acetate (1.6 g, 4.8 mmol) in dry THF (10 mL). The solvent was
evaporated till dryness after 23 h, and the crude subjected to column chromatography (ethyl
acetate / petroleum ether 1:1). A mixture of Z /E isomers were obtained in a 2.3: 1 ratio (1.18 g,
4.5 mmol, 92.8%). The mixture was submitted to the next step without further purification.
1
Some H NMR peaks of the Z isomer in the spectrum of the crude product are: 1H NMR (300
MHz, CDCl3) δ 3.80 (s, 3H, OMe), 5.21 (td, J = 9.0, 1.2 Hz, 1H, 4’-H), 5.57 (s, 1H, 2’-H), 6.19
(dd, J = 11.8, 1.4 Hz, 1H, 2-H), 6.36 (dd, J = 11.8, 7.7 Hz, 1H, 3-H).
ii) Synthesis of (2R,4aR,8aS)-2-phenyl-4,4a-dihydropyrano[3,2-d][1,3]dioxin-
6(8aH)-one (1)
To a solution of the crude material obtained in i) (0.80 g, 3.03 mmol) in ethyl acetate (70 mL)
was added silica (ca. 40 g). The mixture was heated at 75 ° C for 10 h in a rotary evaporator
under water pump vacuum. Successive portions of dry toluene (5 x 100 mL) were added to the
flask to avoid dryness. The residue was purified by column chromatography (ethyl acetate:
petroleum ether 1: 1), giving a white solid (0.03 g, 1.29 mmol, 63.0 %), identified as lactone 1.
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M.p.: 135.9 – 136.8 ºC; [α]D25= + 17.6 (conc. 0.5%, DCM); IR (nujol mull): νmax/cm-1 3070,
3
4
5
6
1
3054, 1753 (s, C=O); H NMR (400 MHz, CDCl3) δ 4.02 (t, J = 10.0 Hz, 1H, 4-H), 4.40 (dd, J
= 10.4, 4.8 Hz, 1H, 4a-H), 4.69 (dd, J = 10.4, 4.8 Hz, 1H, 4-H), 4.89 (ddd, J = 10.0, 2.4, 1.6 Hz,
1H, 8a-H), 5.65 (s, 1H, 2-H), 6.04 (dd, J = 10.0, 2.8 Hz, 1H, 7-H), 7.03 (dm, J = 10.0 Hz, 1H, 8-
H), 7.42-7.40 (m, 3H, 3’-H + 4’-H), 7.51-7.50 (m, 2H, 2’-H), 13C NMR (100.6 MHz, CDCl3) δ
68.2 (4-C), 72.7 (4a-C), 73.9 (8a-C), 102.4 (2-C), 120.7 (7-C), 126.1 (CH), 128.5 (CH), 129.6
(CH), 136.3 (Cq), 146.9 (8-C), 161.8 (6-C); HRMS (ESI-TOF) found for C13H12O4Na:
255.0621; calcd: 255.0628.
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6.3 Synthesis of 1,3-Dipoles
6.3.1 Nitrile oxides 5
A solution of 2,6-dichlorobenzaldehyde / benzaldehyde oximes (0.104-0.143 g) in dry DMF (10
mL) was pre-heated at 40-43 °C. A solution of N-chlorosuccinimide (NCS) (0.100 g; 0.75
mmol) in dry DMF (5 mL) was added dropwise, under magnetic stirring and N2 atmosphere.
The reaction mixture was kept for 3 h, followed by another 15-19h period at rt. The reaction
was quenched in ice/water (ca. 30 mL) and extracted with ether (4 x 20 mL). The etheral
solution was washed with sat. aq. sol. NaCl (2 x 10 mL) and water (2 x 10 mL). The organic
phases were combined and dried over MgSO4. The solvent was removed in the rotary
evaporator to give the respective chloro oximes (η= 77% - 89%).
6.3.1.1 2,6-Dichloro-N-hydroxybenzimidoyl chloride
2,6-dichlorobenzaldehyde oxime (0.143 g; 0.75 mmol); 43 °C; 15h rt.; beige solid (0.130 g;
1
0.58 mmol; η= 77%); H-NMR: δ (300 MHz, CDCl3) 7.20-7.40 (3H, m, Ar); 10.11 (1H, sl,
OH).
6.3.1.2 N-hydroxybenzimidoyl chloride
benzaldehyde oxime (0.104 g; 0.86 mmol); 40 °C; 19h rt.; brownish oil (0.123 g; 0.790 mmol;
1
η= 89%); H-NMR: δ 300 MHz, CDCl3) 7.32-7.41 (3H, m, Ar), 7.80-7.88 (2H, m, Ar); 10.9
(1H, br s, OH).
6.3.1.3 N-hydroxymethylimidoyl chloride
N-hydroxymethylimidoyl chloride, was generated “in situ” by a similar methodology described
to the synthesis of previous chloro oximes, and used immediately in the 1,3-dipolar
cycloaddition.
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5
6
6.4.1 with alkyl azides 4
To a solution of lactone 1 (0.10-0.360 g; 0.431 mmol - 1.55 mmol) in methyl orthoformate (20-
25 mL) was added the alkyl azide 4 (2 - 20 equiv.). The reaction mixture was heated under
nitrogen atmosphere for 30 to 65 h. The solvent was evaporated and the resulting solid residue
recrystallized from ethanol. The title compound was obtained as white solid (38.3 - 86 %).
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6.4.1.1 Synthesis of (3aS,5aR,9aS,9bR)-1-benzyl-8-phenyl-(5a,6,9a,9b)-tetrahydro-
1H-[1,3]dioxino(4’,5’:5,6)pyrano[3,4-d][1,2,3]triazol-4(3aH)-one (7a)
Lactone 1 (0.36 g, 1.55 mmol); methyl orthoformate (25 mL); benzyl azide (2 equiv., 387 µL,
3.10 mmol); reflux; 65 h; obtained product (0.46 g, 1.26 mmol, 81.3%); m.p. 177.4 – 178.1 ºC;
[〈]D = – 438.0 º (conc. 2.7%, DCM); UV-Vis: 267.1 nm; IR (nujol mull): νmax/cm-1 1753 (s,
25
1
C=O); H NMR (400 MHz, CDCl3) δ 3.85-3.78 (m, 1H, 6-H), 3.83 (dd, J = 13.2, 4.0 Hz, 1H, 9b-
H), 4.10 (dd, J = 9.6, 4.0 Hz, 1H, 9a-H), 4.39 (dd, J = 10.0, 5.6 Hz, 1H, 5a-H), 4.49 (dd, J =
10.8, 5.6 Hz, 1H, 6-H), 4.69 (d, J = 14.8 Hz, 1H, CH2), 5.31 (d, J = 13.2 Hz, 1H, 3a-H), 5.43 (d,
13
J = 14.8 Hz, 1H, CH2), 5.60 (s, 1H, 8-H), 7.18-7.16 (m, 2H, Ar), 7.53-7.32 (m, 8H, Ar); C
NMR (100.6 MHz, CDCl3) δ 52.7 (9b-C), 54.2 (CH2), 65.8 (5a-C), 67.8 (6-C), 76.1 (9a-C), 80.8
(3a-C), 102.3 (8-C), 128.2 (CH, Ph), 128.5 (CH, Ph), 128.8 (CH, Ph), 128.9 (CH, Ph), 134.8
(Cq, Ph), 136.3 (Cq, Ph), 161.6 (4-C); Crystallography: Formula: C20H19N3O4; Molecular weight:
365.38; Temperature: 100(2) K; a (Å) = 5.6268(11); b (Å) = 17.614(3); c (Å) = 9.1708(17); ®
(°) = 105.330(2); GoF: 1.064; R = 0.0390.
6.4.1.2
Synthesis
of
(3aS,5aR,9aS,9bR)-1-(propyl-3’-benzyloxy)-8-phenyl-
(5a,6,9a,9b)-tetrahydro-1H-[1,3]dioxino(4’,5’:5,6)pyrano[3,4-d][1,2,3]triazol-
4(3aH)-one (7b)
Lactone 1 (0.10 g, 0.431 mmol); methyl orthoformate (20 mL); (3-azidopropoxy)methyl)
benzene (2 equiv., 166 mg, 0.862 mmol; 100 ºC; 44 h; obtained product (70 mg, 0.165 mmol,
38.3 %); m.p. 110.3 – 110.5 ºC; [α]D25= - 235.6 (conc. 2.4%, CH2Cl2); IR (nujol mull): νmax/cm-1
2097 m, 1772 i (C=O); 1H NMR (400 MHz, CDCl3) δ 2.05-2.02 (m, 2H, 2’-H), 3.50 (dt, J = 6.4,
3.6 Hz, 2H, 3’-H), 3.78 (t, J = 10.8 Hz, 1H, 6-H), 3.82 (t, J = 6.4 Hz, 1H, 1’-H), 4.07-4.05 (m,
3H, 9b-H+9a-H +1’-H), 4.22 (dt, J = 9.6, 5.6 Hz, 1H, 5a-H), 4.43 (dd, J = 10.8, 5.6 Hz, 1H, 6-
H), 4.43 (s, 2H, 4’-H), 5.25 (d, J = 12.8 Hz, 1H, 3a-H), 5.56 (s, 1H, 8-H), 7.39-7.27 (m, 8H,
Ph), 7.47-7.46 (m, 2H, Ph); 13C NMR (100.6 MHz, CDCl3) δ 28.2 (2’-C), 48.1 (1’-C), 54.7 (9b-
C), 65.6 (5a-C), 67.6 (3’-C), 67.8 (6-C), 73.0 (4’-C), 76.0 (9a-C), 80.2 (3a-C), 102.1 (8-C),
125.9 (CH, Ph), 127.6 (CH, Ph), 127.7 (CH, Ph), 128.3 (CH, Ph), 128.4 (CH, Ph), 129.4 (CH,
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Ph), 136.2 (Cq, Ph), 138.0 (Cq, Ph), 162.0 (4-C); HRMS (ESI-TOF), found for C23H26N3O5:
424.1860, calcd: 424.1867.
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6.4.1.3 Synthesis of (3aS,5aR,9aS,9bR)-1-propyl-8-phenyl-(5a,6,9a,9b)-tetrahydro-
1H-[1,3]dioxino(4’,5’:5,6)pyrano[3,4-d][1,2,3]triazol-4(3aH)-one (7c)
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Lactone 1 (0.20 g, 0.86 mmol); methyl orthoformate (20 mL); propyl azide (2 equiv., every 3
25
h); 95 °C; 30 hours; obtained product (0.25 g, 0.754 mmol, 86%). M.p. 125.4 – 126.3 ºC; [α]D
= – 279.1 (conc. 3.2%, CH2Cl2); IR (nujol mull): νmax/cm-1 1774 s (C=O); 1H NMR (400 MHz,
CDCl3) δ 0.91 (t, J = 7.4 Hz, 3H, 3’-H), 1.78 (m, 1H, 2’-H), 3.65 (ddd, J = 13.6, 8.0, 5.6 Hz,
1H, 1’-H), 3.80 (t, J = 10.4 Hz, 1H, 6-H), 3.87-3.80 (m, 1H,1’-H), 4.13-4.08 (m, 2H, 9b-H+9a-
H), 4.27 (dt, J = 9.4, 5.4 Hz, 1H, 5a-H), 4.47 (dd, J = 11.0, 5.4 Hz, 1H, 6-H), 5.41 (d, J = 13.2
Hz, 1H, 3a-H), 5.57 (s, 1H, 8-H), 7.46-7.27 (m, 5H, H-Ar); 13C NMR (100.6 MHz, CDCl3) δ
11.2 (3’-C), 21.4 (2’-C), 52.1 (1’-C), 54.8 (9b-C), 65.6 (5a-C), 67.9 (6-C), 76.2 (9a-C), 80.1
(3a-C), 102.3 (8-C), 126.0 (CH, Ph), 128.4 (CH, Ph), 129.6 (CH, Ph), 136.3 (Cq, Ph), 162.0 (4-
C); HRMS (ESI-TOF), found for C16H20N3O4: 318.1455; calcd: 318.1448.
6.4.2 with diazomethyl benzene (6)
Diazomethyl benzene (6)12 (3 equiv.; 0.35 g; 2.99 mmol) recently obtained, and contained in a
round bottom flask was added a solution of lactone 1 (0.212 g; 0.999 mmol) in dry toluene (18
mL). The reaction mixture was kept under nitrogen, stirring and submitted to heat in a pre-
heated oil bath 60ºC - 70ºC. After some time a light pink colour develops and fades away after
1h 25 min. The reaction mixture was refrigerated in an ice/water bath. A solid precipitated out,
was removed by filtration, and the mother-liquid evaporated to a residue. A white solid (0.210
g; 0.598 mmol; η = 76.3%) was recrystallized from ethanol giving compound 8.
6.4.2.1 Synthesis of (4aR,6aR,9aR,9bS)-2,9-diphenyl-6a,7,9a,9b-tetrahydro-4H-
[1,3]dioxino[4’,5’:5,6]pyrano[3,4-c]pyrazol-6(4aH)-one (8)
m.p. = 159.5 – 160.7 (dec.); [α]D25 = – 116 (0.7 %, CH2Cl2); IR (nujol mull): νmax/cm-1 3337
1
(s, NH); 1750 (s, C=O); 1586. H-NMR ( 400 MHz, CDCl3): δ 3.79 (1H, dd, J = 9.0, 15.2 Hz,
H-9a); 3.98 (1H, dd, J = 9.6, 10.4 Hz, H-4ax); 4.28-4.37 (2H, m, H-4a + H-9b); 4.59 (1H, dd, J =
4.8, 10.4 Hz, H-4eq); 4.44 (1H, d, J = 15.2 Hz, H-6a); 5.57 (1H, s, H-2); 6.56 (1H, br s, H-7);
7.32-7.35 (3H, m, Ph); 7.40-7.42 (5H, m, Ph); 7.50-7.54 (2H, m, Ph); 13C-NMR δ 100.6 MHz,
CDCl3) 50.1 (C-9a); 68.0 (C-4); 69.5 (C-4a); 73.2 (C-6a); 75.2 (C-9b); 101.1 (C-2); 125.9 (CH,
Ph); 128.0 (CH, Ph); 128.2 (CH, Ph); 128.5 (CH, Ph); 128.6 (CH, Ph);; 129.2 (CH, Ph);; 136.4
(Cq, Ph); 137.8 (Cq, Ph); 140.7 (C-9); 161.0 (C-6). Elem. Anal. Found: C, 68.48 %; H, 5.05 %;
N, 7.72 %; calcd for C20H18N2O4 C, 68.56 %; H, 5.18 %; N, 8.00 %.
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6.4.3 with nitrile oxides
Method A
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9
A solution of 2,6-dichloro-N-hydroxybenzimidoyl chloride / N-hydroxybenzimidoyl chloride
(0.11 - 0.130 g; 0.58 - 0.70 mmol) in dry ether (3-5 mL) was added to lactone 1 (0.084-0.091 g;
0.40 mmol - 0.43 mmol) contained in a round bottom flask kept under nitrogen and in an
ice/water bath. To the previous mixture was added dropwise triethylamine (51-55 mL; 0.037 -
0.040 g; 0.37 - 0.39 mmol) recently distilled, in dry ether (6 mL) during 30 - 40 min. The
reaction mixture was stirred at rt for 12-15 h. The volatiles were removed in the rotary
evaporator, and the residue re-dissolved in dichloromethane (10 mL) and passed through a pad
of celite. The filtrate was evaporated to give solids, as mixtures of isomers 9a,b and 10a,b.
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6.4.3.1 Synthesis of (2R,4aR,6aR,9aR,9bS)-9-(2,6-dichlorophenyl)-2-phenyl-
4,4a,9a,9b-tetrahydro-[1,3]dioxino[4’,5’:5,6]pyrano[4,3-d]isoxazol-6(6aH)-one (9a)
and
(5aR,8R,9aR,9bR)-3-(2,6-dichlorophenyl)-8-phenyl-5a,6,9a,9b-tetrahydro-
[1,3]dioxino[4’,5’:5,6]pyrano[3,4-d]isoxazol-4(3aH)-one (10a)
2,6-dichloro-N-hydroxybenzimidoyl chloride (0.130 g; 0.58 mmol); ether (5 mL); lactone 1
(0.084 g; 0.40 mmol); triethylamine (55 mL; 0.040 g; 0.39 mmol); rt; 15h; white-greenish solid
(0.172 g; 0.409 mmol; η= quant.)a) recrystalized from ethanol, giving two fractions: the first
fraction contained isomer 10a as white solid (0.031 g; 0.074 mmol; 19 %); the second fraction
contained a 3 (9a): 1(10a) mixture of isomers (0.083 g; 0.198 mmol; 50 %).
a) The 1H NMR spectrum showed a 1.25(9a):1 (10a) mixture of isomers.
Isomer 9aa) 1H-NMR (400 MHz, CDCl3) δ 3.79 (1H, dd, J = 10.4, 10.8 Hz, H-4ax); 4.07 (1H,
dd, J =7.2, 9.6 Hz, H-9b); 4.54 (1H, dd, J = 5.6, 10.8 Hz, H-4eq); 4.83 (1H, dt, J = 5.6, 10.0 Hz,
H-4a); 4.86 (1H, dd, J =7.2, 10.8 Hz, H-9a); 5.33 (1H, d, J =10.4 Hz, H-6a); 5.41 (1H, s, H-2);
6.94-6.98 (2H, m, Ar) 7.15-7.46 (6H, m, Ar); 13C-NMR δ (100.6 MHz, CDCl3) 51.5 (C-9a);
66.6 (C-4a); 67.9 (C-4); 74.8 (C-9b); 80.4 (C-6a); 101.5 (C-2); 125.6 (CH, Ar); 127.8 (CH, Ar);
128.9 (CH, Ar); 130.7 (Cq, Ar); 135.7 (Cq, Ar); 153.4 (C-9); 163.1 (C-6).
a) contaminated with 25 % of isomer 10a
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Isomer 10a m.p. = 209.5-211.0 (dec,); [α]D = + 86.7 (0.3 %, CH2Cl2); IR (nujol mull):
1
νmax/cm-1 1749 cm-1; H-NMR (400 MHz, CDCl3) δ 3.87 (1H, t, J =10.4 Hz, H-4ax); 4.17 (1H,
dd, J =3.6, 10.0 Hz, H-9b); 4.58 (1H, dd, J =5.2, 10.8 Hz, H-4eq); 4.90 (1H, m, H-4a); 4.91 (1H,
d, J = 10.8 Hz, H-6a); 5.37 (1H, dd, J = 3.2, 11.2 Hz, H-9a); 5.68 (1H, s, H-2); 7.34-7.45 (6H,
m, H-Ar); 7.55-7.59 (2H, m, H-Ar); 13C-NMR δ (100.6 MHz, CDCl3) 56.6 (C-6a); 65.2 (C-4a);
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68.0 (C-4); 75.1 (C-9b); 77.9 (C-9a); 102.6 (C-2); 125.5 (CH, Ar); 126.4 (CH, Ar); 128.2 (CH,
Ar); 128.4 (CH, Ar); 129.6 (CH, Ar); 132.0 (Cq, Ar); 135.1 (Cq, Ar); 136.1 (Cq, Ar); 149.6 (C-
9); 161.4 (C-6). HRMSa) (ESI-TOF), found for C20H15Cl2NO5: 420.0397; calcd 420.0400.
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6.4.3.2
Synthesis
of
(2R,4aR,6aR,9aR,9bS)-2,9-diphenyl-4,4a,9a,9b-
tetrahydro[1,3]dioxino [4’,5’:5,6]pyrano[4,3-d]isoxazol-6(6aH)-one (9b) and
(3aR,5aR,8R,9aR,9bS)-3,8-diphenyl-5a,6,9a,9b-tetrahydro-
[1,3]dioxino[4’,5’:5,6]pyrano[3,4-d]isoxazol-4(3aH)-one (10b)
N-hydroxybenzimidoyl chloride (0.11 g; 0.70 mmol); dry ether (3 mL); lactone 1 (0.091 g; 0.43
mmol); triethylamine (51 mL; 0.037 g; 0.37 mmol); 12h; white solid (0.132 g; 0.38 mmol; µ=
87.6 %) constituted by a mixture 1 (9b) :1.25 (10b). Isomer 9b was obtained from
dichloromethane (0.036 g; 0.102 mmol; 24 %). Isomer 10b recrystalized from dichloromethane
(0.085 g; 0.24 mmol; 56 %), contaminated with 25 % of isomer 9b.
Isomer 9b m.p. = 296.0 – 298.0 ºC (dec.); [α]D25= – 93.6 (0.25%; CH3CN); IR (nujol mull):
νmax/cm-1 1758; H-NMR (400 MHz, CDCl3) δ 3.80 (1H, dd, J = 10.2, 10.8 Hz, H-4ax); 4.18
1
(1H, dd, J = 7.4, 9.8 Hz, H-9b); 4.46 (1H, dd, J =5.2, 10.2 Hz, H-4eq); 4.58 (1H, dt, J = 5.6, 10
Hz, H-4a), 4.60 (1H, dd, J = 7.2, 9.2 Hz, H-9a); 5.20 (1H, d, J = 9.6 Hz, H-6a); 5.46 (1H, s, H-
2); 6.71-6.76 (2H, m, Ph); 7.07-7.13 (2H, m, Ph); 7.20-7.26 (1H, m, Ph); 7.36-7.49 (3H, m, Ph);
7.75-7.80 (2H, m, Ph); 13C-NMR (100.6 MHz, CDCl3) δ 46.7 (C-9a); 66.6 (C-4a); 67.9 (C-4);
74.9 (C-9b); 80.8 (C-6a); 101.6 (C-2); 125.8 (CH, Ph); 128.0 (CH, Ph); 128.1 (CH, Ph); 128.5
(CH, Ph); 128.9 (CH, Ph); 129.1 (CH, Ph); 130.4 (Cq, Ph); 135.7 (Cq, Ph); 157.3 (C-9); 163.7
(C-6). Elem. Anal. Found: C 67.32; H, 4.79; N 4.09; calcd for C20H17NO5 1/3H2O: C, 67.22; H,
4.98; N, 3.92.
Isomer 10b m.p. = 220.7 – 222.5 ºC (dec.); [α]D25= + 184 (0.3%; CH2Cl2); IR (nujol mull):
νmax/cm-1 1749 cm-1; H-NMR ( 400 MHz, CDCl3) δ 3.83 (1H, t, J = 10.4 Hz, H-4ax); 4.12 (1H,
1
dd, J = 3.2, 9.6 Hz, H-9b); 4.50 (1H, dd, J = 5.4, 11.0 Hz, H-4eq); 4.72 (1H, dt, J = 5.6, 10.0 Hz,
H-4a); 4.98 (1H, d, J = 10.8 Hz, H-6a); 5.32 (1H, dd, J = 3.2, 10.8 Hz, H-9a); 5.65 (1H, s, H-2);
7.38-7.48 (6H, m, Ph); 7.53-7.58 (2H, m, Ph); 7.89-7.93 (2H, m, Ph); 13C-NMR ( 100.6 MHz,
CDCl3) δ 55.0 (C-6a); 65.3 (C-4a); 68.0 (C-4); 75.5 (C-9b); 78.5 (C-9a); 102.5 (C-2); 126.4
(CH, Ph); 126.7 (CH, Ph); 127.7 (CH, Ph); 128.4 (CH, Ph); 128.8 (CH, Ph); 129.6 (CH, Ph);
131.0 (Cq, Ph); 136.2 (Cq, Ph); 152.4 (C-7); 162.5 (C-6). Elem. Anal. found: C, 67.32; H, 4.79;
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N 4.09; calcd for C20H17NO5 1/3H2O: C, 67.22; H, 4.98; N 3.92.
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Method B
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To a suspension of N-chlorosuccinimide (0.227 g; 1.70 mmol) in dichloromethane (3 mL) was
added a solution of acetaldehyde oxime (0.127 g; 2.14 mmol), and pyridine (0.05 mL) in
dichloromethane (2 mL). The mixture was kept under stirring till complete NCS dissolution. To
this mixture was added lactone 1.
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6.4.3.3
Synthesis
of
(2R,4aR,6aR,9aR,9bS)-9-methyl-2-phenyl-4,4a,9a,9b-
tetrahydro[1,3]dioxino[4’,5’:5,6]pyrano[4,3-d]isoxazol-6(6aH)-one
(3aR,5aR,8R,9aR,9bR)-3-methyl-8-phenyl-5a,6,9a,9b-tetrahydro-
[1,3]dioxino[4’,5’:5,6]pyrano[3,4-d]isoxazol-4(3aH)-ona (10c)
(9c)
and
A solution of lactone 1 (0.10 g; 0.431 mmol) in dry toluene (18 mL) was added to the
acetaldehyde oxime generated “in situ” followed by dropwise addition of triethylamine (0.5 mL;
3.16 mmol) in dry toluene (5 mL), during 2h. The reaction mixture was stirred at rt for 15h. The
solvents were removed in rotary evaporator, and the residue re-dissolved in dichloromethane
and passed through a pad of celite. The filtrate was evaporated to give a solid consisting a 1.2
(9c):1 (10c) mixture of adducts. The crude product was recrystallized form ethanol to give two
fractions: the first fraction contained pure isomer (10c) as white solid (0.035 g; 0.12 mmol; 28
%); the second fraction contained the other isomer 9c which was not possible to purify from
impurities (0.075g).
1
Isomer 9c H-NMR (400 MHz, CDCl3)a) δ 2.15 (3H, d, J =0.8 Hz, CH3); 3.85-3.77 (m, 1H);
3,90 (1 H, dd, J =7.6, 9.80 Hz, H-4a); 4.12 (1H, dd, J =7.3, 9.6 Hz, H-9b); 4.46-4.53 (m, 1H);
5.01 (1H, d, J = 10.8 Hz, H-6a); 5.54 (1H, s, H-2); 7.31-7.35 (3H, m, Ph); 7.37-7.42 (2H, m,
Ph).
a) some peaks of isomer 9c, taken from a spectrum containing both isomers (9c and 10c)
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Isomer 10c m.p. = 229.7 – 231.5 (dec.); [α]D = + 33.6 (0.75%; CH2Cl2); IR (nujol mull):
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νmax/cm-1 1744 cm-1 (s, C=O); H-NMR (400 MHz, CDCl3) δ 2.11 (3H, d, J =0.8 Hz, CH3);
3.82 (1H, t, J =10.6 Hz, H-4ax); 4.06 (1H, dd, J =3.4, 10.0 Hz, H-9b); 4.34 (1H, dd, J =0.8, 10.0
Hz, H-3a); 4.51 (1H, dd, J =5.6, 10.8 Hz, H-4eq); 4.62 (1H, dt; J =5.2, 10.0 Hz, H-4a); 5.09 (1H,
dd, J = 3.2, 10.8 Hz, H-9a); 5.62 (1H, s, H-2); 7.37-7.42 (3H, m, Ph); 7.50-7.54 (2H, m, Ph);
13C-NMR ( 100.6 MHz, CDCl3) δ 11.6 (CH3); 58.2 (C-6a); 65.3 (C-4a); 67.9 (C-4); 75.2 (C-9b);
76.7 (C-9a); 102.5 (C-2); 126.3 (CH, Ph); 128.4 (CH, Ph); 129.6 (CH, Ph); 136.1 (Cq, Ph);
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150.8 (C-3); 162.2 (C-4). Elem. Anal., found: C, 61.36; H, 5.54; N 4.89; calcd for C15H15NO5
1/3H2O, C, 61.01; H, 5.35; N, 4.74.
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All geometry optimizations were performed with Gaussian 0917, applying density functional
theory18, with the B3LYP functional19 together with the 6-31G(d) basis set20. The geometry
optimizations were conducted with a conductor-like polarizable continuum model using the
integral equation formalism variant (IEF-PCM)21.
In all geometry optimizations, we first searched for the transition state starting from a
structure similar to the reactant model. This was generally obtained with un-dimensional scans
along the particular reaction coordinate in which we were interested. Once a putative transition
structure was located, it was fully optimized. The reactants and the products associated with it
were determined after intrinsic reaction coordinate (IRC) calculations. In all cases, the geometry
optimizations and the stationary points were obtained with standard Gaussian convergence
criteria. The transition state structures were all verified by vibrational frequency calculations,
having exactly one imaginary frequency with the correct transition vector, even using frozen
atoms, which shows that the frozen atoms were almost free from steric strain. The ZPE and
thermal and entropic energy corrections were calculated using the same method and basis set (T
= 310.15 K, P = 1 bar).
The final electronic energies were calculated using the all-electron 6-311++G(3df,2pd)
basis set and the functional M06-2X22,23. A conductor-like polarizable continuum model using
the integral equation formalism variant (IEF-PCM), as implemented in Gaussian 09, with a
dielectric constant of 2.4, 4.0, 33.0 was used to simulate the toluene, diethyl ether, methanol
solvent, respectively 21.
All the activation and reaction energies provided in the text and figures refer to free energy
differences calculated at theM06-2x/6-311++(3df,2pd) level detailed above, while the atomic
charge distributions were calculated at the B3LYP level by employing a Mulliken population
analysis, using the basis set 6-31G(d).
Acknowledgements
We thank FCT for project funding PTDC/QEQ-MED/1671/2012; the NMR Portuguese network
(PTNMR, Bruker Avance III 400-Univ. Minho), and FCT and FEDER (European Fund for
Regional Development)-COMPETE-QREN-EU for financial support to CQ/UM.
Supplementary data
NMR spectra and X-ray data for 7a.
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All the structures of reactants, transition states and products of the studied reactions are
available in supporting information, in mol2 format.
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References
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Graphical Abstract
Ph
Ph
O
O
O
O
1,3-dipole
X
Y
D-Glucose
N
O
O
R
O
O
X,Y=C,N,O
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