Hydrotalcite catalysis for the synthesis of new chiral building blocks

Article abstract of DOI:10.1080/14786419.2015.1075525

The use of hydrotalcites for the synthesis of two chiral building blocks in a simple way is described as a new and green methodology. The synthesis of these compounds implies a regioselective Baeyer-Villiger reaction in a very selective way with ulterior

Full text of DOI:10.1080/14786419.2015.1075525

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
Hydrotalcite catalysis for the synthesis of new
chiral building blocks
Jesus M. Rodilla, Patricia P. Neves, Sofia Pombal, Vicente Rives, Raquel
Trujillano & David Díez
To cite this article: Jesus M. Rodilla, Patricia P. Neves, Sofia Pombal, Vicente Rives, Raquel
Trujillano & David Díez (2015): Hydrotalcite catalysis for the synthesis of new chiral building
blocks, Natural Product Research, DOI: 10.1080/14786419.2015.1075525
To link to this article: http://dx.doi.org/10.1080/14786419.2015.1075525
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Date: 12 October 2015, At: 00:10

Natural Product research, 2015
http://dx.doi.org/10.1080/14786419.2015.1075525
Hydrotalcite catalysis for the synthesis of new chiral building
blocks
Jesus M. Rodillaa, Patricia P. Nevesa, Sofia Pombala, Vicente Rivesb, Raquel Trujillanob
and David Díezc
aFaculdade de ciências, departamento de Química and uMtP-Fibentech, universidade da Beira Interior,
covilhã, Portugal; bGIr-Quescat-departamento de Química Inorgánica, universidad de salamanca,
salamanca, spain; cFacultad de ciencias Químicas, departamento de Química orgánica, universidad de
salamanca, salamanca, spain
ARTICLE HISTORY
received 13 May 2015
accepted 14 July 2015
ABSTRACT
The use of hydrotalcites for the synthesis of two chiral building blocks
in a simple way is described as a new and green methodology. The
synthesis of these compounds implies a regioselective Baeyer–
Villiger reaction in a very selective way with ulterior opening and
lactonisation. This methodology should be considered green for the
use of hydrogen peroxide as the only oxidant and hydrotalcites as
the catalyst, and because no residues are produced apart from water.
The procedure is very adequate for using in gram scale, in order to
increase the value of the obtained compounds. The conditions are
excellent and can be applied for nonstable compounds, as they are
very mild. The synthesised compounds are magnific starting materials
for the synthesis of biologically active or natural compounds. The use
of a cheap, commercial and chiral compound as carvone disposable
in both enantiomeric forms adds an extra value to this methodology.
KEYWORDS
hydrotalcites; natural
products; terpenes; hydrogen
peroxide; carvone
1. Introduction
Carvone 1 is a versatile starting material for the syntheses of biological active natural prod-
ucts and disposable in both enantiomeric forms, terpenes being the main objective from
this natural product (Macaev 2013). One of the more important derivatisations of carvone
structure is the epoxidation. This reaction can be done in a regioselective way with epoxida-
tion of the exocyclic to give 2 or endocyclic double bond to give 3, based on electron-rich
CONTACT Jesus M. rodilla
rodilla@ubi.pt
the supplementary material for this paper is available online at http://dx.doi.org/10.1080/14786419.2015.1075525.
© 2015 taylor & Francis

2
J. M. RODilla eT al.
Figure 1. epoxidation and Baeyer–Villiger products obtained from (R)-carvone.
or electron-deficient epoxidation (Murphy et al. 2003; Mak et al. 2006; Uguina, Delgado,
Carretero 2009; Uguina, Delgado, Carretero, Gomez-Diaz 2009). By contrary, diastereose-
lectivity in this class of epoxidations is not good (Figure 1).
Due to the importance of carvone as starting material, there has been much interest too
in the synthesis of compound 5 by a Baeyer–Villiger type reaction (Frisone et al. 1993; lei
et al. 2007). This compound has been obtained from carvone by heterogeneous Baeyer–
Villiger oxidation with H2O2/acetonitrile using Mg/al hydrotalcite (llamas et al. 2007) or by
transition metals complexes as catalysts (Brunetta & Strukul 2004). These reactions were
followed by GlC or by GC–MS analysis, so in order to obtain compounds as building blocks, it
is necessary to isolate and determine them properly. The interest was to obtain a compound
as 6, using friendly reagents as oxygen peroxide and hydrotalcite as catalyst (Figure 1).
layered double hydroxides, also known as hydrotalcite-like compounds, are layered com-
pounds characterised by their interlayer space, chemical composition and sequence of layer
3+
stacking (Bookin & Drits 2001). Their general formula is [M2+
M
x(OH)2]x+[an−]x/n·mH2O, where
1−x
M2+ and M3+ are the di- and trivalent metal cations, respectively, and an− is the interlayer
anion (Rives 2001). its structure is similar to that of brucite, Mg(OH)2, where each Mg2+ ion
is octahedrally coordinated by six hydroxyl groups and the octahedra share edges forming
infinite layers. These layers are stacked and bonded through hydrogen bond and contain
water molecules between the layers. if some Mg2+ ions are isomorphically replaced by cati-
ons with a higher oxidation state, but similar radii, the brucite layers will become positively
charged; the electrical balance is achieved by means of anions located in the interlayer space,
together with water molecules. The easiness of their synthesis and the possibility of changing
their chemical composition in a wide range make this layered solids and their derivatives
very interesting as catalysts in different reactions. Their performance as catalysts in different
catalytic reactions has been studied by changing their composition, molar ratio, synthesis
method, etc. (Cavani et al. 1991; Rives et al. 1998; Monzón et al. 1999; Jiménez-Sanchidrián
& Ruiz 2008; Rives et al. 2010).
2. Results and discussion
in order to have the required compounds, we start the study with a lewis acid as alCl3 using
as oxidant hydrogen peroxide. in these conditions, entries 1 and 2 were observed that the

NaTURal PRODUCT ReSeaRCH
3
epoxidation only took place in the terminal double bond to give epoxide 2 and moderate
yield of the desired compounds 7 and 8. The absolute stereochemistry was determined by
NOeSY as one of the chiral centres is known in the starting material. as can be understood,
these compounds are the result of terminal double bond epoxidation of carvone, Baeyer–
Villiger oxidation of the ketone and opening of the epoxide by the acid group resulting of
the lactone in compound 6. With these compounds in hand, it was decided to proceed to
obtain them not only in better yield but in more green procedure. For this reason, we decide
to use hydrotalcite in order to obtain these useful compounds. When the reaction was done
with hydrotalcite obtained as described before, using SDS and hydrogen peroxide as oxidant,
the synthesis of compounds 7 and 8 was achieved in good yield entry 7 (Table 1), as it recov-
ered an important quantity of the starting material, and complete recovering of the catalyst
was achieved. it should be underlined that when using Mg4/al-CO3 hydrotalcite as catalyst
instead of alCl3, there is an important change in the nature of the catalyst as hydrotalcite
has a strongly basic character. The catalyst was prepared by simple coprecipitation from
Mg and al nitrates at constant pH. SDS does not enter in the interlayer space, as there is a
strong affinity of hydrotalcite for carbonate; moreover, such an affinity is larger for divalent
(carbonate) than for monovalent (SDS) anions, so the catalyst active form is Mg4/al-CO3. it
has to be signalled that compound 2 is an intermediate to the final compounds 7 and 8. it
was tried to the use of m-CPBa as oxidant and hydrotalcite as catalyst. in this case, we were
able to obtain compound 6 although in low yield.
as we have said before, compound 2 is the intermediate for the target molecules 7 and
8. So as it is a compound already known and easy to obtain, it was decided to use it as start-
ing material and to test our conditions with this compound, using the same methodology,
table 2. When used in conditions with alCl3 and hydrogen peroxide as oxidant, entries 1 and 2,
it was achieved only the desired compounds 7 and 8 in low yield and other compounds as the
diol 9 and epoxide 10 resulting of the opening of the epoxide of 2 and epoxidation of the enol
intermediate, respectively. again the use of hydrotalcite increases considerably the yield of
Table 1. screening of catalysts and conditions for the Baeyer–Villiger reaction of (r)-carvone.
Yielda(%)
entry
1
Conditions
Temperature
Time
2
4
6
7
8
1
2
3
4
5
6
7
8
a
a
B
B
B
B
B
c
75
75
50
40
40
40
60
40
48 h
160 h
96 h
200 h
300 h
400 h
100 h
5 h
40.0
39.0
50.0
10.0
8.0
5.0
14.0
–
28.0
25.0
18.0
31.0
45.0
60.0
25.0
70.0
–
–
2.0
10.0
20.0
30.0
12.0
4.0
–
–
–
–
–
–
–
12.0
10.0
15.0
6.0
25.0
9.2
6.0
27.0
–
6.0
12.0
5.0
19.5
8.4
5.3
26.0
–
conditions: a. etoh (25 ml), alcl (65 mg), h2o2 30% (0.80 ml); B. Benzonitrile (1.50 ml), h2o2 30% (1.30 ml), hydrotalcite
(29 mg), sds (sodium dodecyl s3ulphate) (73 mg), etoh (1.50 ml); c. hydrotalcite (39 mg), m-cPBa (metachloroperbenzoic
acid) (782 mg), ch2cl2 (15 ml).
athe yield until 100% are decomposition or undetermined products.

4
J. M. RODilla eT al.
Table 2. screening of Baeyer–Villiger reaction of the epoxy-carvone.
Yielda(%)
entry
2
Conditions
Temperature
Time
4
7
8
9
10
1
2
3
4
5
6
7
a
a
a
B
B
B
c
40
40
70
65
75
60
40
24 h
30 h
72 h
30.0
33.0
34.1
34.1
33.0
26.0
–
–
–
–
17.2
10.0
9.0
11.0
14.0
18.0
19.0
12.0
27.0
21.0
10.0
12.0
15.0
18.1
11.0
25.0
19.0
8.2
10.5
17.2
–
–
–
–
–
–
–
–
–
15.2
24 h
384 h
168 h
28 h
20.0
–
conditions: a. etoh (25 ml), alcl (65 mg), h2o 30% (0.80 ml); B. Benzonitrile (1.50 ml), h2o2 30% (1.30 ml), hydrotalcite
(29 mg), sds (73 mg), etoh (13.50 ml); c. hy2drotalcite (39 mg), m-cPBa (metachloroperbenzoic acid) (782 mg), ch2cl2
(15 ml).
athe yield until 100% are decomposition or undetermined products.
the desired compounds 7 and 8, taking in account the amount of recovered starting material
(Table 2). The use of m-CPBa as oxidant not increases the yield in the required compounds.
3. Experimental
3.1. General procedure for the reaction with AlCl3
in a round-bottom flask equipped with a reflux condenser, carvone 1 (300 mg, 2 mmol),
alCl3 (60 mg, 0.45 mmol), H2O2 30% (0.12 ml, ~2 eq) and 50 ml of etOH were heated at 75 ºC
while stirring. The progress of the reaction was monitored TlC. after 48 h, the reaction was
extracted with DCM, washed with water, dried and the solvent evaporated. Finally, the pure
compound was obtained by flash chromatography on silica gel (hexane/etOac 8:2) to obtain
1 (39.0%), 2 (25.0%), 7 (15.0%) and 8 (12.0%).
(4R,5S)-5-(hydroxymethyl)-5-methyl-4-(3-oxobutyl)dihydrofuran-2(3H)-one 7
Compound 7 was purified by flash chromatography (silica gel, hexane/etOac 6:4). iR
1
(film): 3419, 2976, 2937, 1746, 1709, 1663, 1382, 1220, 1058, 950 cm−1; H NMR (400 MHz,
CDCl3) δ 3.68 (1H, d, J 12.4 Hz, H-1″a), 3.64 (1H, d, J 12.4, H-1″b), 2.50 (2H, m, H-3), 2.40 (2H,
m, H-2′), 2.21 (1H, m, H-4), 2.14 (3H, s, Me-4′), 1.83 (2H, m, H-1′), 1.29 (3H, s, Me-1ꢀꢀꢀ); 13C NMR
(100 MHz, CDCl3) δ 208.1 C-3′; 177.2 C-2; 36.0 C-3, 44.6 C-4; 22.7 C-1′; 42.1 C-2′; 30.0 C-4′,
88.4 C-5; 66.0 C-1″; 22.4 C-1ꢀꢀꢀ; HRMS (ei) calcd for C10H16O4Na requires (M + Na) 223.0940;
found 223.0934.
(4R,5S)-5-(hydroxymethyl)-5-methyl-4-(3-oxobutyl)dihydrofuran-2(3H)-one 8
Compound 8 was purified by flash chromatography (silica gel, hexane/etOac 6:4).
[α]D20 = −14.7 (c = 0.4, CHCl3); iR (film): 3420, 2977, 2931, 1744, 1708, 1662, 1418, 1367, 1219,
1059, 950 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.74 (1H, d, J 12.4 Hz, H-1″a), 3.54 (1H, d, J 12.4 Hz,
H-1″b), 2.58 (1H, m, H-4), 2.49 (2H, m, H-3′), 2.33 (1H, d, J 10.5 Hz, H-3a), 2.29 (1H, d, J 10.5 Hz,

NaTURal PRODUCT ReSeaRCH
5
H-3b), 2.17 (3H, s, Me-4′), 1.78 (1H, m, H-1′a), 1.57 (1H, m, H-1′b), 1.26 (3H, s,Me-1ꢀꢀꢀ); 13C NMR
(100 MHz, CDCl3) δ 207.5 C-3′; 175.2 C-2; 34.8 C-3; 38.2 C-4; 23.4 C-1′; 41.9 C-2′; 30.3 C-4′,
88.6 C-5; 66.8 C-1″; 17.6 C-1ꢀꢀꢀ; HRMS (ei) calcd for C10H16O4Na requires (M + Na)+ 223.0940;
found 223.0934.
The reaction was also performed from compound 2, under the same conditions. By the
flash CC in the same conditions, we have obtained the following compounds: 2 (34.1%), 7
(18.0%), 8 (15.0%) and 9 (17.2%).
8,9-dihydroxycarvone, 9
Compound 9 was purified by flash chromatography (silica gel, hexane/etOac 7:3) as a mix-
ture of isomers. iR (film): 3436, 2975, 2924, 1655, 1432, 1370, 1104, 1056, 745 cm−1;1H NMR
(400 MHz, CDCl3) δ 6.79 (1H, m, H-6), 3.56 (2H, m, H-9), 2.80–2.20 (5H, m, H-3, 4 and 5), 1.78
(3H, s, Me-7) and 1.26 (3H, s, Me-10); 13C NMR (100 MHz, CDCl3) δ 135.5 C-1; 199.2 C-2; 38.6
C-3; 41.8 C-4; 26.4 C-5; 144.1 C-6; 15.8 C-7; 72.8 C-8; 57.8 C-9; 21.9 C-10; HRMS (ei) calcd for
C22H25O5Na requires (M + Na) 438.1345; found 438.1349.
3.2. General procedure for the reaction with hydrotalcite and H2O2
in a round-bottom flask equipped with a reflux condenser, Carvone 1 (300 mg, 2 mmol), ben-
zonitrile (0.82 ml, 8 mmol), H2O2 30% (0.12 ml, 4 mmol), hydrotalcite Mg4/al–CO3 (17.0 mg),
SDS (35 mg, 0.10 mmol) and etOH (0.87 ml) were heated at 40–60 °C while stirring. The
progress of the reaction was monitored by TlC. after 50–250 h, the reaction was extracted
with DCM, washed with water, dried and the solvent evaporated. Finally, the pure compound
was obtained by flash column chromatography on silica gel, 1 (15.0%), 2 (25.0%), 4 (12.0%)
7 (27.0%) and 8 (26.0%).
The reaction was also performed with compound 2, as starting material under the same
conditions. By flash CC (in the same conditions), the following compounds were obtained:
2 (26.0%), 4 (9.0%), 7 (27.0%) and 8 (25.0%).
3.3. General procedure for the reaction with hydrotalcite and m-CPBA
in a round-bottom flask equipped with a reflux condenser, carvone 1 (505 mg, 3.4 mmol),
hydrotalcite (39.0 mg), MCPBa (782 mg, 4.5 mmol) and DCM (15.0 ml) were heated at 40 ºC
while stirring. The progress of the reaction was monitored by TlC. after 5 h, the reaction
was extracted with DCM, washed with water, dried and the solvent evaporated. Finally, the
pure compound was obtained by flash column chromatography on silica gel, 2 (70.0%), 4
(4.0%) and 6 (12.0%).
8,9-epoxicarvone-1,2-olide 6
Compound 6 was purified by flash chromatography (silica gel, hexane/etOac 8:2) as a
1
mixture of isomers. iR (film): 2973, 2930, 1715, 1660, 1381, 1223, 1058, 950 cm−1; H NMR
(400 MHz, CDCl3) δ 5.23 (1H, td, J1 7.3 Hz and J2 1.2 Hz, H-6), 2.68 (2H, dd, J1 7.0 Hz and J2
1.4 Hz, H-3), 2.64 (1H, dd, J1 4.0 Hz and J2 0.9 Hz, H-9a), 2.57 (1H, d, J 4.5 Hz, H-9b), 2.31 (1H, t, J
7.1 Hz, H-4), 2.20–2.10 (2H, m, H-5), 1.89 (3H, s, Me-7), 1.34 (3H, s, Me-10); 13C NMR (100 MHz,
CDCl3) δ 150.2 C-1; 171.0 C-2; 34.7 C-3; 46.1 C-4; 23.8 C-5; 107.8 C-6; 19.3 C-7; 58.2 C-8, 52.9
C-9, 18.5 C-10; HRMS (ei) calcd for C10H14O3Na requires (M + Na)+ 205.0835; found 205.0832.

6
J. M. RODilla eT al.
The reaction was also performed with compound 2, as starting material under the same
conditions. By flash CC (in the same conditions), we have obtained the following compounds:
4 (20.0%), 7 (21.0%), 8 (19.0%) and 10 (15.2%).
1,6;8,9-Diepoxycarvone-1,2-olide 10
Compound 10 was purified by flash chromatography (silica gel, hexane/etOac 8:2) as a
mixture of isomers. iR (film): 2974, 2927, 1720, 1418, 1380, 1229, 1100, 1069, 958, 750 cm−1;
1H NMR (400 MHz, CDCl3) δ 3.15 (1H, dd, J1 8.6 Hz and J2 5.3 Hz, H-6), 2.83 (2H, dd, J1 8.4 Hz
and J2 2.1 Hz, H-3), 2.66 (1H, dd, J1 4.5 Hz and J2 0.9 Hz, H-9a), 2.62 (1H, d, J 4.5 Hz, H-9b),
2.45 (1H, dt, J1 13.9 Hz and J2 5.3 Hz, H-5a), 2.03 (1H, dddd, J1 13.9 Hz, J2 8.4 Hz, J3 5.3 Hz
and J4 2.1 Hz, H-4), 1.71 (3H, s, Me-7), 1.38 (1H, dt, J1 13.9 Hz and J2 8.6 Hz, H-5b), 1.33 (3H, s,
Me-10);13C NMR (100 MHz, CDCl3) δ 168.5 (C-2); 83.2 (C-1); 58.9 (C-6); 58.6 (C-8); 53.5 (C-9);
37.6 (C-4); 34.8 (C-3); 29.1 (C-5); 20.4 (C-7); 18.0 (C-10); HRMS (ei) calcd for C25H32O5 (M + H)+,
458.1995; found 458.1978.
4. Conclusions
it has been demonstrated that the use of hydrotalcites made possible to obtain in good yield
from a commercially available material in both enantiomeric pure forms chiral compounds
such as lactones 7 and 8 that can be used in organic synthesis as valuable synthons (Valeev
et al. 2010).
Acknowledgements
C. Raposo is acknowledged for the Mass Spectra and Chemical analyses.
Funding
JMR, PPN, SF and DD thank the F.S.e. and Junta de Castilla y león [GR178], and VR and RT thank
Ministerio de Ciencia e innovación [grant number MaT2009-08526] for the financial support.
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