Gd(OTf)3-catalyzed synthesis of geranyl esters for the intramolecular radical cyclization of their epoxides mediated by titanocene(III)

Article abstract of DOI:10.1039/c4ob02312a

A selective and mild method for the esterification of a variety of carboxylic acids with geraniol is developed. We demonstrated that the use of triphenylphosphine, I₂, 2-methylimidazole or imidazole and a catalytic amount of Gd(OTf)₃ resulted to be more active than the previous protocols, providing a 16-membered library of geranyl esters in higher yields and in shorter reaction times. The use of essential oil of palmarosa (Cymbopogon martinii), enriched with geraniol, as a raw material for the synthesis of the target compounds complemented and proved how sustainable and eco-friendly this protocol is. Finally, the selective 6,7-epoxidation of the obtained geranyl esters led us to study their regio-controlled radical cyclization mediated by titanocene(iii) for the synthesis of novel (8-hydroxy-9,9-dimethyl-5-methylene cyclohexyl)methyl esters in moderate yields and with excellent stereoselectivities.

Full text of DOI:10.1039/c4ob02312a

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Gd(OTf) -Catalyzed the Synthesis of Geranyl Esters
3
for the Intramolecular Radical Cyclization of their
Cite this: DOI: 10.1039/x0xx00000x
Epoxides Mediated by Titanocene(III)†
William H. García Santos, Carlos E. Puerto Galvis and Vladimir V. Kouznetsov*
Received 00th October 2014,
Accepted 00th xxxx 2014
A selective and mild method for the esterification of a variety of carboxylic acids with geraniol
DOI: 10.1039/x0xx00000x
was developed. We demonstrated that the use of triphenylphosphine, I , 2-methyl imidazole or
2
imidazole and a catalytic amount of Gd(OTf)3 resulted to be more active than the previous
protocols, providing a 16-membered library of geranyl esters in higher yields and in shorter
reaction times. The use of essential oil of palmarosa (Cymbopogon martinii), enriched with
geraniol, as a raw material for the synthesis of the target compounds, complemented and
proved how sustainable and eco-friendly this protocol is. Finally, the selective 6,7-epoxidation
of the obtained geranyl esters, lead us to study their regio-controlled radical cyclization
mediated by Titanocene(III) for the synthesis of novel (8-hydroxy-9,9-dimethyl-5-methylene
cyclohexyl)methyl esters in moderate yields and with excellent stereoselectivities.
www.rsc.org/obc
5
citronellol 3 and nerol 4, are the most important. Traditionally,
Introduction
these esters are obtained by chemical synthesis or extraction from
natural sources, where they are generated as a result of the alcohol
6
The two mainly acyclic monoterpenoids present in the essential oil
7
acetyltransferase (AAT) enzymes.
(EO) of palmarosa (Cymbopogon martinii) are geraniol 1 (85 %) and
1
The esterification reaction has been already accomplished by
several chemical methods, generating many drugs, pharmaceuticals,
synthetic and natural products with the ester linkage, giving the
incorrect impression that there are no remaining synthetic challenges
in this field. When actually, there are a few methods that offer the
direct esterification, especially of terpene alcohols, with functional
group tolerance under mild reaction conditions.
geranyl acetate 2 (12 %). Both terpenoids are of biological and
2
commercial importance due to the antioxidant, antifungal and
3
antimicrobial action of 1 and the presence of 2 in many natural
4
fragrances (Figure 1).
Lipases and esterases have often been used as catalysts to
synthesize flavour esters by esterification of geraniol, citronellol and
8
-10
nerol,
but this approach has some drawbacks: the poor structural
diversity of the obtained terpene ester due to the negative effect of
different carboxylic acids on the enzyme catalytic behavior, and the
low yield in which the desired compound is obtained when the role
of various physicochemical parameters, such as the water activity,
the nature of acetyl donor, the polarity of organic solvent and the
1
1,12
concentration of reactants, is not well controlled.
Fig. 1 Naturally occurring monoterpenoids found in the essential oils of
palmarosa (
1
,
2
), citronella (
3
), and neroli (
4
).
Despite the recent efforts aimed to develop a mild reaction
protocols for the chemoselective esterification of various alcohols,
the substrate scope with terpene alcohols still remains as a challenge:
Among the fragrance compounds used in the food, cosmetic and
pharmaceutical industries. The terpene esters of short-chain
carboxylic acids like 2, and the acetates of terpene alcohols like
(1) imidazole has promoted the exchange of the hydroxyl group
present in the carboxylic acid by the bulky phosphonium ion, leading
the phosphonium-carboxylate salt, which suffers the nucleophilic
*
Laboratorio de Química Orgánica y Biomolecular, Universidad Industrial
13
attack by the alcohol (Method 1, Scheme 1). (2) the phosphonium-
de Santander, Parque Tecnologico Guatiguara, Km via refugio,
Piedecuesta, A.A. 681011, Colombia. Tel: +57 76 344000-Ext. 3593; E-mail:
vkuznechnik@gmail.com; kouznet@uis.edu.co.
2
carboxylate salt generated, is activated by a Lewis acid in order to
facilitate the intermolecular attack of the alcohol at a faster rate to
1
4
†
Electronic
Supplementary
Information
(ESI)
available: produce the corresponding ester (Method 2, Scheme 1).
1
13
Characterization data, including copies of H NMR, C NMR, DEPT- Furthermore, simple primary and secondary commercial alcohols
35, COSY, C HMBC, HSQC and HSQC charts of all synthesized were esterified in these two methods for high efficiency, avoiding
1
3
1
compounds. See DOI: 10.1039/b000000x/
the use of terpene alcohols (e.g. geraniol) from natural sources.
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Therefore, development of a more practical approach, with broad Results and discussion
substrate scope and compatible with terpene alcohols like geraniol 1
1
3
In 2011, Robles et. al. described the utilization of phosphine, I
2
is still attractive. Herein, we report an efficient Gd-catalyzed
esterification of geraniol 1, using the commercial reagent and the EO
of palmarosa, with a variety of carboxylic acids in Ph P/I /imidazole
1
7
and imidazole (conditions for the Garegg-Samuelsson reaction) for
the esterification of various carboxylic acids with mainly methanol
via formation of a phosphonium-carboxylate salt intermediate 10.
The important role of the imidazole could be explained when this
3
2
(IM) or 2-methylimidazole (2-MIM) (Scheme 1).
base shift the equilibrium to the Ph P-imidazole species 9, from the
3
iodotriphenylphosphonium cation 8, and transfer the phosphonium
group to the carboxylic acid, activating the carbonyl function of 10
and promoting the attack of the alcohol (Scheme 2).
Scheme 2 Formation of a phosphonium-carboxylate salt species 10
In accordance with this hypothesis, we initially performed the
reaction between the cinnamic acid 11m and geraniol 1 under these
conditions. However, after 24 hours the reaction did not result in any
detectable amount of the desired ester 12m, not even at room
temperature or 50 °C. (Table 1, entries 1 and 2).
Table 1 Esterification of cinnamic acid 11m with geraniol 1. Screening of
a
Scheme 1 Methods of esterification of different alcohols
bases, Lewis acids and solvent systems.
Developing a novel protocol for the synthesis of geranil esters
from 1, with a low catalyst loading and in good to excellent yields,
was not the only challenge during our research. We notice that the
inclusion of the alkyl fragment of 1 in the structure of the obtained
esters could be the target and the starting point of subsequent
chemical transformations of these compounds in order to prepare
more structurally complex esters with functionalized cyclohexane
skeletons, like the present in the key precursor of Taxol 5,
Lewis
acid (mol %)
b
Entry
Base
Solvent
Yield (%)
c
1
2
3
4
5
6
7
8
9
IM
IM
-
-
-
2
3
3
3
3
3
3
2
3
CH Cl
N.R.
2
2
2
1
5
synthesized from 1 by Takahashi et. al., and the naturally occurring
elegansidiol 6 and farnesiferol B 7, both sesquiterpenoids with
CH Cl
N.R.
N.R.
38
2
Cu(OTf) (10)
CH CN
3
1
6
potent anticancer activities (Figure 2).
IM
IM
IM
IM
IM
IM
IM
IM
-
Sc(OTf) (10)
CH Cl
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Yb(OTf) (10)
CH Cl
45
Dy(OTf) (10)
CH Cl
47
In(OTf) (10)
CH Cl
28
Eu(OTf) (10)
CH Cl
30
La(OTf) (10)
CH Cl
30
1
1
1
0
1
2
Cu(OTf) (10)
CH Cl
82
Gd(OTf) (10)
CH Cl
90
Gd(OTf) (10)
3
CH Cl
2
N.R.
Fig. 2 Potent naturally occurring anticancer compounds with the
cyclohexanol unit derived from geraniol
c
1.
13
22
IM
IM
IM
2-MIM
Py
Gd(OTf)
3
(10)
CH
2
Cl
1
4
Gd(OTf) (5)
CH Cl
90
90
According to the statements described above and with the
knowledge that there are no reports of an efficient method for the
direct esterification of carboxylic acids with geraniol 1, obtained
from commercial and natural sources, our research was focused on:
3
2
1
5
Gd(OTf) (1)
CH Cl
3
2
2
16
17
Gd(OTf) (1)
CH Cl
87
3
2
2
2
2
2
Gd(OTf)
3
(1)
CH
2
Cl
74
(
i) establishing the optimal conditions for the reaction of 1 with
1
1
2
2
8
9
0
1
Pyr
Pyrr
IM
IM
IM
Gd(OTf) (1)
CH Cl
N.R.
< 5
3
3
3
2
several carboxylic acids according to the variables: solvent, reaction
times, temperature, base, catalyst and loading catalyst and the yield
in which the desired product is obtained. (ii) with the established
conditions in hand, preparing a 16-membered library of new geranyl
esters through the direct esterification of carboxylic acids with
geraniol 1, by the activation in situ of the phosphonium-carboxylate
Gd(OTf) (1)
CH Cl
2
Gd(OTf) (1)
PEG-400
DMSO
3
N.R.
N.R.
N.R.
Gd(OTf) (1)
3
22
Gd(OTf) (1)
CH CN
3
a
2 3
Reaction performed on a 1 mmol scale using I (1.5 equiv), PPh (1.5
salt generated. (iii) obtain the EO of palmarosa and use it as a raw equiv), base (3.3 equiv), 11m (1.1 equiv), Lewis acid (1-10 mol%) and
b
material for the direct esterification of some carboxylic acids under
the established conditions. (iv) prepare a few 6,7-epoxygeranyl esters
1 (1 equiv) in the respective solvent (35 mL) for 12-24 h at 50 °C.
Isolated yield.
c
Reaction performed at room temperature. IM:
imidazole, 2-MIM: 2-methylimidazole, Py: pyridine, Pyr: pyrimidine,
Pyrr: pyrrolidine.
and make them react with Cp TiCl, a radical cyclization for the
2
synthesis
of
novel
(8-hydroxy-9,9-dimethyl-5-methylene
cyclohexyl)methyl esters.
2
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1
4
In 2013, Manna et. al. reported the in situ activation of the act as an efficient barrier to protect the intermediates 8-10 from
phosphonium-carboxylate salt intermediate 10 by only Zn-based oxygen and moisture than other hydrophilic solvents.
catalysts, without the use of imidazole as a base, for the
Having the optimized reaction conditions in hand, the versatility,
esterification of carboxylic acids with simple alcohols. The Lewis scope and limitations of our protocol was broadened to other acids
acid (LA) activation, through the coordination with the species 10, with different functional groups (Table 2).
appears to be necessary to enhance the electrophilicity of carbonyl
function and facilitate the attack of the alcohol (Scheme 3).
a
Table 2 Synthesis of geranil esters under the optimized reaction conditions
Nevertheless, this activation was not enough to promote the
condensation of cinnamic acid 11m and geraniol 1, when Cu(OTf)2
was used, in acetonitrile at 60 °C (Table 1, entry 3).
b
Entry Carboxylic acid Time (h)
Product
1
2
3
2
2.5
4
Scheme 3 Activation of the phosphonium-carboxylate salt species 10
by a Lewis acid (LA)
With the same model reaction, we hypothesized that a complete
and efficient protocol for the esterification of less reactive alcohols
like geraniol 1 should include: i) a base, to favor the formation of the
phosphonium-carboxylate salt intermediate 10, according to the
described in Scheme 2, and to regulate the pH of the reaction system
due to the liberation of hydrogen iodide (HI) because it is well
4
5
6
7
3
3
6
6
3
1
8
documented the degradation of 1 under acidic conditions; and ii) a
Lewis acid, to activate the phosphonium-carboxylate salt
intermediate 10, according to the described in Scheme 3, enhancing
the reactivity of this species. Therefore, to investigate the feasibility
of the two statements depicted above, we encouraged our efforts to
accomplish the esterification of cinnamic acid 11m with 1 under
PPh /I system, in CH Cl as a solvent at 50 °C, and using imidazole
3
2
2
2
(IM) as a base, with a catalytic amount (10 mol %) of a series of
triflates as Lewis acid (Table 1, entries 4-9). In this way, we
obtained the desired ester in low to moderate yields (28-45 %) with
most of the triflates tested, being In(OTf) the lowest with 28 %
8
9
3
(
Table 1, entry 7) and Yb(OTf) the higher with 45 %.
3
Having checked the viability of this process under the proposed
conditions, we found that contrary to the Manne's report, Cu(OTf)2
resulted to be an excellent catalyst for this reaction with geraniol 1
and the ester 12m was obtained in 82 % yield in CH Cl at 50 °C
3
3
3
3
2
2
1
0
1
2
(Table 1, entry 10). The best results were obtained with Gd(OTf)3,
affording the title compound in 90 % yield (Table 1, entry 11).
However, even with the better activating agent, this reaction did not
work in the absence of IM as a base (Table 1, entry 12), suggesting
that under this reaction conditions the presence of 1 could affect the
1
1
integrity of
10
or shift the equilibrium to the
iodotriphenylphosphonium cation 8 (Scheme 3). The temperature
plays an important role also, although the activation of the species 10
by the Gd(OTf)3 is enough to carry out the reaction at room
temperature, the yield in which the ester was obtained (22 %) was
lower than the experiments carried at 50 °C (Table 1, entry 13).
Encouraged by these promising results, we decided to optimize the
reaction conditions studying the effect of reducing the catalyst
loading to 5 and 1 mol % (Table 1, entries 14 and 15, respectively).
13
3
6
1
1
4
5
The best result was obtained with 1 mol % of Gd(OTf) catalyst with
3
CH Cl as solvent and IM as a base at 50 °C. Interestingly, when 2-
24
3
2
2
methylimidazole (2-MIM) was tested as a base, the yield in which
the ester was afforded was 87 % (Table 1, entry 16), indicating that
the reaction was not affected for the steric hindrance of the base.
Unfortunately, when other heterocyclic bases such as pyridine (py),
pyrimidine (pyr) and pyrrolidine (pyrr) (Table 1, entries 17-19) were
also tested, only pyridine gave the ester in good yield. Finally, a set
of solvents were studied but the desired product was not obtained
1
6
a
Reaction performed on a 1 mmol scale using I
equiv), IM or 2-MIM (3.3 equiv), 11a-p (1.1 equiv), Gd(OTf)
2
(1.5 equiv), PPh
(1 mol%) and
(35 mL) at 50 °C. Isolated yield after SiO column
3
(1.5
3
b
either (Table 1, entries 20-22). This fact suggests that CH Cl could 1 (1 equiv) in CH
2 2
Cl
2
2
2
chromatography.
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In general, the esterification reaction of geraniol 1 proceeded
Table 3 Synthesis of geranil esters using the EO of palmarosa enriched with
a
smoothly with different carboxylic acids 11a-p (aliphatic, aromatic, 1 as raw material
heterocyclic and α,β-unsaturated carboxylic acids) and afforded the
corresponding esters 12a-p with great efficiency.
The simplest acid, acetic acid 11a, gave the higher yield for the
respective geranyl acetate 12a, result comparable with the previous
8
-10
reports that use enzymes (Table 2, entry 1).
While other aliphatic
carboxylic acids with internal and external double bonds, the geranic
acid 12b itself, and with labile and sensitive groups like the disulfide
bond of (±)-α-lipoic acid 12c, gave moderate to good yields without
the observation of any by products (Table 2, entries 2 and 3).
Aromatic rings bearing different electron withdrawing and electron
donating groups all furnished the target ester 12d-h as well (40-88%
yield). The steric hindrance of the substituent groups at the ortho
position did not affect the reaction and afforded the esters 12e and
1
2f with a higher yield (Table 2, entries 4−8). It is noteworthy that
nicotinic acid (Vitamin B ) 11h also gave the corresponding ester
3
1
2h in 88% yield (Table 2, entry 8), proving the utility of our
protocol for the preparation of heterocyclic esters derived from
niacin, which are uncommon and less studied. Benzyl and
a
Reaction performed on a 1 mmol scale using I
2
(1.5 equiv), PPh
3
(1.5
equiv), IM or 2-MIM (3.3 equiv), 11 (1.1 equiv), Gd(OTf)
3
(1 mol%) and
b
dihydrocinnamic acids could also be transformed into the ester 183.8 mg of the EO of palmarosa in CH Cl (35 mL) at 50 °C. Yields
2
2
scaffold in quite moderate yields, 50-71 % (Table 2, entries 9-12).
Finally, other cinnamic acids also underwent the esterification
reaction to afford the respective cinnamyl esters 12m-p, and except
for 12m, the yields were somewhat very low, 10-47 % (Table 2,
entries 14-16). Nevertheless, even if this esterification method for
the synthesis of geranyl esters seemed original and encouraging, it
had a drawback. When the solubility of the carboxylic acids in
dichloromethane is partial or minimum, the respective esters were
obtained in low yields, as shown in Table 2 (entries 7, 9, 10, 14 and
calculated based on the 83.9 % of 1 present in the EO and after the
purification by SiO column chromatography.
2
Encourage for the efficient protocol developed for the synthesis of
novel geranyl esters and to demonstrate the scope and importance of
including the alkyl fragment of geraniol 1 into the structure of the
esters 12a-m, we focus our attention in explore the reactivity of this
fragment toward the synthesis of the 8-hydroxy-9,9-dimethyl-5-
methylenecyclohexyl
core
through
the
Ti(III)-mediated
1
5). Also, other structurally diverse carboxylic acids were tested but
regiocontrolled radical cyclization of the respective 6,7-monoepoxy
derivatives.
their insolubility in dichloromethane did not yield the desired
compound, even in other solvents different from those described in
Table 1 (results are not shown).
Prioritizing on the use of raw materials as precursors in organic
synthesis and green methodologies, we have already published novel
results on this topic in which the essential oil of anise and bud clove
2
1
The next step of this approach involved the Prilezhaev reaction of
some selected esters 12. Treatment the esters with m-
chloroperbenzoic acid (m-CPBA) afforded, chemoselectively, the
6
,7-epoxy geranyl esters 13a-k in moderate yields (Table 4).
were used as starting materials for the synthesis of N-heterocyclic Table 4 Synthesis of 6,7-epoxy geranyl esters 13a-k under Prilezhaev
1
9
a
compounds.
reaction conditions
For this study, we had the opportunity to work with the EO of
palmarosa acquire by hydrodistillation from the dried leaves and
stems of Cymbopogon martinii. With this conventional warming
procedure the EO of palmarosa was obtained in 0.4 ± 0.2% yield.
The gas chromatography with a selective mass detector of this EO
indicated the presence of two principal components: geraniol 1 (83.9
2
0
%
) and geranyl acetate 12a (9.2 %). This EO of palmarosa,
enriched with geraniol 1, was used to perform the esterification
reaction, under the established conditions in Table 1, with some
selected carboxylic acids in order to examine the scope of our
protocol when this raw material is employed (Table 3).
To our delight, these reactions proceeded smoothly and gave in
moderate yields and with excellent selectivity the desired esters
under the adopted reaction conditions, without detecting any by
product. Although the yields of the esterification reaction, using the
EO of palmarosa, did not lead to comparable results when 1
(commercial reagent) was employed, perhaps due to the fact that the
EO of palmarosa is a complex mixture of compounds where other
reactive terpenes are present (e.g. cinalool, cis- and trans-β-ocimene,
trans-β-caryophyllene). It is still attractive the use of substrates
obtained from natural sources, combined with a good synthetic
protocol, to contribute to the developing of a modern and sustainable
organic chemistry that focus on the synthesis of novel compounds
with a complex molecular architecture.
a
Reaction performed on a 0.8 mmol scale using 12 (0.8 mmol), NaHCO
3
b
(
0.88 mmol) and m-CPBA (0.88 mmol) in CH
2 2
Cl (15 mL) at 0 °C. Isolated
yield after SiO column chromatography.
2
4
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The relative configuration of 13a-k was assigned by analogy with cyclohexanols 14 and 15 as an inseparable mixture in moderate
2
2
siꢀilar epoꢁyesters, reported by Fernꢂndeꢃ-Mateos et. al.
elsewhere, and from the configuration of the products 14a-h, to be always obtained as the major products derived from the 6-endo-trig
explored further below. cyclization pathway, which also generated the compounds with the
yields. The alcohols exo-14a-f, with exocycle double bonds, were
Finally, the last objective of our study was to address the synthesis endocycle double bonds endo-15a-f but in relative minor percentage.
of the (8-hydroxy-9,9-dimethyl-5-methylene cyclohexyl)methyl The preference for the formation of the exo double bond over the
2
5
esters and the Ti(III)-promoted radical cyclization of the epoxy endo double bond was described by Cuerva et al. in 2001, when
derivatives 13 seemed to be an appropriate method to access to the Cp TiCl was used for the first time to promote the cyclization of
2
seven-membered ring present in some natural and bioactive products epoxides derived from commercially available geranyl acetate.
2
3
(
5-7). Our approach was based on the Cp TiCl-catalyzed reductive However, it is worth noting that in the case of the 6,7-epoxy geranyl
2
C-C bond formation, leading to a secondary cyclohexyl alcohol after ester 13d, derived from nicotic acid 11h, the (8-hydroxy-9,9-
the regioselective homolytic opening of the 6,7-epoxy function in dimethyl-5-methylene cyclohexyl)methyl ester 14d was obtained
1
3. To date, a few computational methods have suggested the exclusively without any trace of the endo-15d isomer, as determined
1
determining role played by Cp TiCl in driving the stereochemical by H NMR. Some studies have shown that the double bond
outcome of the reaction. In this way, and under these reaction formation arises from a mixed disproportionation reaction between
2
2
4
conditions, a selected series of epoxides 13 were allowed to react the organic radicals and Cp TiCl, promoted by the presence of an
2
2
6
with Cp TiCl (2.1 equiv), Mn dust (8 equiv) and Et N (1.7 equiv) in oxidant agent in the reaction media. We suggest that the pyridine
2
2
3
degassed THF (0.1 M) at room temperature for 24 hours (Table 5).
ring itself could act as an oxidant group in this case, under the
employed reaction conditions, controlling the final oxidative process
that allows the exclusive formation of the cyclohexanol core with the
exo double bond.
Table 5 Ti(III)-promoted the radical cyclization of the 6,7-epoxy geranyl
a
esters 13
The structure of the (8-hydroxy-9,9-dimethyl-5-methylene
1
13
cyclohexyl)methyl esters 14a-f was elucidated through H, C and
1
2
D NMR spectroscopic data as illustrated for 14d. The H-NMR
spectrum of 14d showed a general group of characteristic signals for
the aromatic protons present in the pyridine ring and the protons of
the cyclohexanol moiety. This six-member ring assumes
a
Yield
14+15)
2
Entry
1
b
exo-14
endo-15
chair conformation due to the present of one carbon atom with sp
hybridization in which both exo double bond and the hydroxyl group
are in equatorial positions. The reaction mechanism could involve
two possible pathways: one in which during the transition state, the
β-titanoxy radical 16 formed when one electron is transferred from
the titanocene(III) complex to the epoxide function, is able to
approach to the 2,3-double bond by a chairlike conformation,
establishing the R configuration of the tetrahedral stereocenter at C-
4. In the second, the β-titanoxy radical 16 approach to the 2,3-double
bond by a botelike conformation will establish the S configuration of
the tetrahedral stereocenter at C-4 (Scheme 4).
(
61
57
59
62
55
54
c
Ratio : 84:16
2
3
4
5
6
c
Ratio : 86:14
c
Ratio : 76:24
c
Ratio 100:0
Scheme 4 Possible chairlike and botelike conformation during the
cyclization of the β-titanoxy radical
c
Ratio : 80:20
The chair conformation has been reported as the most stable form
of alkylidenecyclohexanes when alkyl substituents are present at
position 2, where they adopt an axial conformation due to the strong
2
8
repulsive interaction between alkyl groups in equatorial form. In
this way, this group, the ester function in 16, must be force to adopt
an axial orientation, during the chairlike-transition state (Scheme 4),
to allow and reach the proposed geometry, explaining satisfactorily
the complete R configuration of the stereocenter at C-4.
c
Ratio : 77:23
a
Reaction performed on a 1 mmol scale using Cp
3
8 equiv), the ester 13 (1 mmol) and Et N (1.7 equiv) in strictly deoxygenated
b
2
TiCl
2
(2.1 equiv), Mn dust
(
THF (0.1 M, 9.44 mL) at room temperature for 24 hours. Isolated yield after
c
The HMBC and NOESY experiments were relevant to prove the
relative stereochemistry of C-4 and C-8 (Figure 3).
SiO column chromatography. Ratio of 14 and 15 in the obtained product
mixture determined by H-NMR spectroscopy (H-8/H-8’).
2
1
Having defined the stereochemistry of C-4, the HMBC correlation
of the two methyl groups (axial and equatorial) of C-9 will prove the
orientation of protons H-4 and H-8. Thus, proton H-4 is correlated
During this assays made in our laboratory, the titanocene(III)-
catalyzed cyclization of the 6,7-epoxy esters 13 gave the
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Bearing in mind that the formation of the β-titanoxy radical 16
releases equal amounts of HCl, the cyclization reaction needs to
carried out in the presence of
neutralization of the acid will produce triethylamine hydrochloride
Et N∙HCl), species that proved to be a good hydrogen donor for
a triethylamine. Thus, the
(
3
reducing conjugate systems where the Cp TiCl could easily interact
2
3
0
with, like the α,β-unsaturated carbonyl derivatives (13, 14 and 15).
Fig. 3 Selected HMBC (----) and NOESY ( ) correlations.
Conclusions
just with Me-equatorial, while H-8 is correlated just with Me-axial.
On the other hand, the NOESY correlations of H-4 equatorial with
one of the protons of the exo double bond, with the proton H-6
equatorial and with the protons of the Me-equatorial, confirm the
previous assignation of the stereochemistry of C-4. Moreover, the
NOESY correlations for H-8 axial with the axial groups H-7 and the
protons of the Me, suggest the stereochemistry of C-8. This last
statement was confirmed by the key NOESY correlation of the
methylene protons H-3 with only the protons of the Me-axial.
Finally, because no NOESY correlation between H-4 and H-8 was
found, indicating that they are not in the same plane, the final
relative configuration of the six-membered ring of 14d was
confirmed and also, by the position of the hydroxyl group in the C-8,
the configuration of the respective 6,7-epoxy geranyl esters 13a-k
could be well defined too.
Last, when a couple of 6,7-epoxy geranyl esters derived from
cinnamic acids 13i and 13k were subjected to the reaction conditions
employed for the radical cyclization promoted by Ti(III). We found
that in addition to the respective exo-14g-h and endo-15g-h
products, a third compound was detected in which the sensitive α,β-
unsaturated bond of the cinnamic acid was reduced by the action of
the Ti(III) (Table 6).
We have achieved a new strategy for the straightforward
esterification of geraniol with different carboxylic acids, with
the added value of having used the essential oil of palmarosa
(
Cymbopogon martinii) as a readily available raw material,
complementing the alternative previously reported
esterification methods of simple alcohols. Based on the Garegg-
Samuelsson reaction conditions (triphenylphosphine and I ), we
2
have found the efficiency of gadolinium ion to assist the
activation of the phosphonium-carboxylate salt intermediate 10
and promote the selective esterification of less reactive geraniol
1
under mild reaction conditions without affecting his integrity.
In addition, an expedient two-step procedure for the
stereoselective synthesis of (8-hydroxy-9,9-dimethyl-5-
methylene cyclohexyl)methyl esters 14a-h, based on the
titanocene(III) 6-endo-trig radical cyclization, is reported. We
found that this reaction elapses via a chairlike-transition state
pattern, which allows the relative configuration of the C-4 and
C-8 stereocenters of the six-membered ring of 14. Although the
yields and the selectivity (endo/exo double bond) in some cases
are low, an improvement in reaction conditions might be seen
as desirable for general organic chemistry, taking as a start
point the results shown in this research.
This protocol represents one of the few examples in which
novel esters have been prepared, from a renewed method, to
study their final functionalization for the preparation of several
natural products with the ester linkage and sesquiterpenoids
with different skeletons containing cyclohexane rings like
Table 6 Ti(III)-promoted the radical cyclization and “one-pot” reduction of
a
6
,7-epoxy geranyl esters derived from cinnamic acids 13i and 13k
elegansidiol
6. Our current interest is focused to gain a
comprehensive understanding of the overall reactions and to
widen the scope of these innovative processes for testing them
in the synthesis of bioactive natural products.
Entry
1
exo-14
endo-15
17
Experimental Section
b
c
Yield: 51 %; Ratio (56:5:39)
Infrared (FT-IR) spectra were recorded on a Lumex Infralum
-
1
FT-02 spectroꢀeter, νmax in cm . Bands are characterized
1
according to the functional group. H NMR spectra were
2
recorded on a Bruker Avance-400 (400 MHz) spectrometer.
Chemical shifts are reported in ppm with the solvent resonance
b
c
Yield: 45 %; Ratio (47:15:38)
a
as the internal standard (CDCl : δ 7.26 ppꢀ). Data were
3
Reaction performed on a 1 mmol scale using Cp TiCl (2.1 equiv), Mn dust
2
2
reported as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, dd = doublet of doublets, br = broad, m =
(
8 equiv), the ester 13 (1 mmol) and Et N (1.7 equiv) in strictly deoxygenated
3
b
THF (0.1 M, 9.44 mL) at room temperature for 24 hours. Isolated yield after
1
3
c
SiO
2
column chromatography. Ratio of 14, 15 and 17 in the obtained multiplet), coupling constants (Hz) and integration. C NMR
1
product mixture determined by H-NMR spectroscopy (H-8/H-8’/H-1’).
spectra were recorded on a Bruker Avance-400 (400 MHz)
spectrometer with complete proton decoupling. Chemical shifts
are reported in ppm from solvent resonance as the internal
Although, Cp TiCl has been used widely in different type of
2
2
3
standard (CDCl : δ 77.00 ppꢀ). On DEPT-135 spectra, the
3
reductions, some authors have suggested that the formation of
products 17a-b could be the result of an efficient hydrogen atom
transfer (HAT) process from a titanocene(III) aquocomplex, formed
by the presence of adventitious water, to the α,β-unsaturated bond of
the cinnamic acid. However, due that the reaction is performed
under strictly anhydrous reaction conditions, other should be the
hydrogen donor.
signals of CH and CH carbons are shown as positive (+) and
3
CH carbons are shown negative (-). Quaternary carbons are not
2
shown. A Hewlett Packard 5890a Series II Gas Chromatograph
interfaced to an HP 5972 Mass Selective Detector (MSD) with
an HP MS ChemStation Data system was used for MS
identification at 70 eV using a 60 m capillary column coated
with HP-5 [5%-phenylpoly (dimethylsiloxane)]. Accurate mass
2
9
6
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data were obtained on Micromass Q-TOF by electrospray Research Director CROM-MASS–CENIVAM, Industrial University
ionisation (ESI). of Santander, Colombia, for their generous donation and
Unless otherwise noted, all reactions have been carried out characterization of the EO of palmarosa, to Prof. Jesus Olivero
with distilled and dried solvents and under atmosphere Verbel, from Environmental and Computational Chemistry Group,
pressure. All work-up and purification procedures were carried University of Cartagena, Colombia, for their generous donation of
out with reagent grade solvents (purchased from Aldrich and (±)-α-Lipoic acid 11c, and also to the Mass Spectrometry Laboratory
Merck) in air. Thin-layer chromatography (TLC) was (PTG-EDI) for the HRMS analysis. CEPG thanks the scholarship
performed using E. Merck silica gel 60 F254 precoated plates given by the doctoral program Colciencias-Conv. 617. VVK thanks
(
0.25 mm). Column chromatography was performed using the support given during the sabbatical year by UIS.
silicagel 60 (0.063 - 0.200 mm) 70-230 mesh.
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Acknowledgements
This work was financially supported by and Bio-Red-Co-
CENIVAM-COLCIENCIAS under the project No. RC-0572-2012.
We
wish
to
thank
to
Prof.
Elena
Stashenko,
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