Total synthesis of the natural succinate derivative of 5-(hydroxymethyl) furfural isolated from the Noni fruit (Morinda citrifolia)

Article abstract of DOI:10.1080/14786410903040477

Three alternative synthetic routes for the synthesis of naturally occurring n-butyl (5-formylfuran-2-yl)methyl succinate (1) are described. One of them started from furfuryl alcohol (4), and the other two synthetic strategies started from 5-(hydroxymethyl)furfural (6), which could be readily obtained from D-fructose. One of the latter involved a two-step reaction sequence: esterification of 6 with succinic anhydride (5) and esterification of the resultant mono-succinate 2 with n-butyl bromide, to give 1 in 85% overall yield. The second, a one-pot two-step synthesis, consisted of treating 6 with 5 followed by the addition of n-butyl bromide to afford the desired natural product 1 in 85% yield.

Full text of DOI:10.1080/14786410903040477

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Total synthesis of the natural succinate
derivative of 5-(hydroxymethyl)furfural
isolated from the Noni fruit (Morinda
citrifolia)
a
a
Héctor Quiroz-Florentino , Abraham García , Eleuterio
a
a
Burgueño-Tapia & Joaquín Tamariz
a
Departamento de Química Orgánica, Escuela Nacional de
Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y
Plan de Ayala s/n, 11340 México, D.F., Mexico
Version of record first published: 30 Jul 2010.
To cite this article: Héctor Quiroz-Florentino , Abraham García , Eleuterio Burgueño-
Tapia & Joaquín Tamariz (2009): Total synthesis of the natural succinate derivative of 5-
(hydroxymethyl)furfural isolated from the Noni fruit (Morinda citrifolia), Natural Product Research:
Formerly Natural Product Letters, 23:14, 1355-1362
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Natural Product Research
Vol. 23, No. 14, 20 September 2009, 1355–1362
Total synthesis of the natural succinate derivative of
5-(hydroxymethyl)furfural isolated from the
Noni fruit (Morinda citrifolia)
He
´
Joaquı
ctor Quiroz-Florentino, Abraham Garcı
n Tamariz*
´
˜
a, Eleuterio Burgueno-Tapia and
´
Departamento de Quı ´m ica Orga´nica, Escuela Nacional de Ciencias Biolo´gicas, Instituto Polite´cnico
Nacional, Prol. Carpio y Plan de Ayala s/n, 11340 Me´xico, D.F., Mexico
(
Received 21 March 2009; final version received 14 May 2009)
Three alternative synthetic routes for the synthesis of naturally occurring n-butyl
(
5-formylfuran-2-yl)methyl succinate (1) are described. One of them started from
furfuryl alcohol (4), and the other two synthetic strategies started from
-(hydroxymethyl)furfural (6), which could be readily obtained from D-fructose.
5
One of the latter involved a two-step reaction sequence: esterification of 6 with
succinic anhydride (5) and esterification of the resultant mono-succinate 2 with
n-butyl bromide, to give 1 in 85% overall yield. The second, a one-pot two-step
synthesis, consisted of treating 6 with 5 followed by the addition of n-butyl
bromide to afford the desired natural product 1 in 85% yield.
Keywords: n-butyl (5-formylfuran-2-yl)methyl succinate; 5-(hydroxymethyl)fur-
fural; D-fructose; succinic anhydride; Morinda citrifolia L.
1
. Introduction
A broad range curative potential has been attributed to Morinda citrifolia L. (Wang et al.,
002), commonly known as Noni fruit, in oriental traditional and folk medicine, including
2
therapeutic effects such as analgaesic, antimicrobial, antifungal, anti-inflammatory,
antioxidant, antitumour, antiviral, anthelmintic, hypotensive, and immunomodulator
effects, among others (Pak-Dek, Abdul-Hamid, Osman, & Soh, 2008; Wang, Anderson,
Nowicki, & Jensen, 2008; Wang et al., 2002; Zhang, Wei, Shi, & Liu, 2007). It has been
reported that Noni fruit juice inhibits tumour growth by immune system stimulation
(
Hirazumi & Furusawa, 1999), and extends the life of mice into which a Lewis pulmonary
carcinoma has been implanted (Hirazumi, Furusawa, Chou, & Hokama, 1994). The
nutritional value of Noni fruit juice has also been well documented (Bui, Bacic, &
Pettolino, 2006; West, Tolson, Vest, Jensen, & Lundell, 2006). Phytochemical studies of
this fruit have revealed the presence of many metabolites, including coumarins, flavones,
iridoids, polysaccharides, anthraquinones and phenolic compounds, exhibiting potent
pharmacological effects (Deng et al., 2007; Kamiya et al., 2008; Pawlus & Kinghorn, 2008;
Potterat & Hamburger, 2007). Recently, new compounds have been isolated and
structurally characterised (Lin, Ni, Huang, Sheu, & Chen, 2007; Siddiqui, Sattar,
*
Corresponding author. Email: jtamariz@woodward.encb.ipn.mx
ISSN 1478–6419 print/ISSN 1029–2349 online
ß 2009 Taylor & Francis
DOI: 10.1080/14786410903040477
http://www.informaworld.com

1
356
H. Quiroz-Florentino et al.
Begum, Gulzar, & Ahmad, 2007; Takashima et al., 2007; West & Zhou, 2008), among
them the furan derivative n-butyl (5-formylfuran-2-yl)methyl succinate (1) (Samoylenko
et al., 2006). Owing to its potential biological activity and its use as a chemical marker
to control the quality of the commercial juice of the Noni fruit (Samoylenko et al., 2006),
an effective and short synthesis of 1 is highly desirable. Therefore, a synthetic study of 1 is
described herein, in which three approaches have been developed.
2
. Results and discussion
A retrosynthetic analysis of the preparation of 1 is depicted in Scheme 1. The last step of
any of the possible routes involved the esterification of the key precursor 2 with the proper
alcohol or alkyl halide. The first approach was considered to reach compound 2 by a
formylation of the furan derivative 3, which in turn may be obtained by an esterification
reaction between furfuryl alcohol (4) and succinic anhydride (5). For the second approach,
the key starting material might be 5-(hydroxymethyl)furfural (6), which by treatment with
5 may furnish mono-succinate 2. A third and shorter pathway may be carried out: the
transformation of 6 into 1 in a single reaction, without isolation of 2.
The first synthesis was started by the esterification of furfuryl alcohol (4) with succinic
ꢀ
anhydride (5) under mild basic conditions (NaH, 20 C, 24 h) to give ester 3 in good yield
(
90%) (Scheme 2). Upon formylation of the latter under Vilsmeier–Haack reaction
conditions, furancarboxylic acid 2 was obtained in 84% (Garber, Jones, & Robinson,
961; Ono, Tadata, Harumi, & Isshiki, 1999). Although the preparation of 1 was carried
out by acid-catalysed esterification in the presence of n-butyl alcohol, the yield was low
52%). A better procedure consisted of the treatment of 2 with 1-bromobutane, promoted
1
(
by triethylamine at room temperature, to afford the desired natural product in 90% yield.
Recently, we have described the synthesis of furan natural compounds rehmanones
A–C through several routes, including that which starts from 6 (Quiroz-Florentino,
Aguilar, Santoyo, Dıaz, & Tamariz, 2008). The latter is a natural metabolite isolated
´
from Gastrodia elata, which shows significant anti-platelet activity (Pyo, Jin, Koo,
Scheme 1. Retrosynthetic analysis of n-butyl (5-formylfuran-2-yl)methyl succinate (1).

Natural Product Research
1357
Scheme 2. Synthetic approach to 1 starting from furfuryl alcohol (4).
Yun-Choi, 2004). It has also recently attracted strong and deep interest for its value as a
&
natural versatile and key synthon in fine-chemical industry (Taarning, Nielsen, Egeblad,
Madsen, & Christensen, 2007), and mainly as a promising precursor to produce biomass-
derived automotive fuels, as a renewable energy source, and an industrial chemical
feedstock (Kamm, 2007; Mascal & Nikitin, 2008; Roman-Leshkov, Barrett, Liu, &
´
Dumesic, 2007; Yong, Zhang, & Ying, 2008). It has been efficiently prepared in a single
step by acidic treatment of D-fructose (Halliday, Young, & Grushin, 2003). We have found
ꢀ
that in the reaction of the latter with sulphuric acid in DMSO at 110 C for 48 h, the
furfural compound 6 is obtained in 68% yield (Quiroz-Florentino et al., 2008). However,
ꢀ
we herein optimised this method by slightly increasing the temperature (115 C) and
keeping the same reaction conditions to afford 6 in 80% yield (Scheme 3). Moreover, 6
rose in 70% yield by treating D-glucose, as the starting carbohydrate (Goswami, Dey, &
ꢀ
Jana, 2008), with a solution of 10 mol% of sulphuric acid in DMSO (115 C, 48 h).
Once having the furfural moiety of the target molecule in our hands, its conversion into
the natural product took place through a sequence of two steps, under similar conditions
to the previous approach. Thus, the reaction of 6 with succinic anhydride (5) in the
presence of sodium hydride provided the mono-ester acid derivative (2) in excellent yield
(95%) (Scheme 3), which by treatment with 1-bromobutane and triethylamine furnished
the desired product (1) in 90% yield.
In spite of the fact that compound 1 was prepared in fairly good overall yield (68%)
starting from D-fructose, we decided to improve the strategy by shortening the conversion
of 6 into 1 in a one-pot two-step procedure. Thus, after performing the reaction between 5
and 6 under identical conditions as shown in Scheme 3, a solution of 1-bromobutane was
added to the reaction mixture, which was maintained under stirring at room temperature
for 24 h to give 1 in 85% yield (Scheme 3). Although this second synthetic pathway
provided an identical overall yield (starting from D-fructose) of 1 (68%) to that of the
previous route, the methodology was shortened and the workup was simplified.
Structures of the intermediates 2 and 3 and final product 1 were characterised by NMR
spectroscopy, high-resolution mass spectrometry or elemental analysis. The recorded
spectral data for 1 are in agreement with those reported for the natural product
(
Samoylenko et al., 2006).

1
358
H. Quiroz-Florentino et al.
Scheme 3. Synthetic approaches to 1 starting from D-fructose or D-glucose.
In summary, we have described an efficient total synthesis of n-butyl (5-formylfuran-2-yl)
methyl succinate (1) through a mono-esterification of furan derivative 6 with succinic
anhydride (5), followed by a second esterification with 1-bromobutane. A shorter strategy
was developed by doing both esterifications in a single step in a high overall yield. In
addition, a longer but also efficient alternative synthetic pathway of 1 was also described,
via the preparation of furan carboxylic acid 3, starting from furfuryl alcohol (4), followed
by formylation and final esterification, to afford compound 1 in three steps and a 68%
overall yield.
3
. Experimental section
Melting points (uncorrected) were determined with an Electrothermal capillary melting
1
point apparatus. IR spectra were recorded on a Perkin–Elmer 2000 spectrophotometer. H
1
and C NMR spectra were recorded on Varian Mercury (300 MHz) and Varian VNMR
3
System (500 MHz) NMR instruments, with CDCl as the solvent and TMS as internal
3
standard. High-resolution mass spectra (HRMS) were obtained in electron impact (EI)
(
70 eV) mode on a Jeol JSM-GCMate II spectrometer. Microanalyses were performed by
M-H-W Laboratories (Phoenix, AZ). Analytical TLC was carried out using E. Merck
silica gel 60 F254 coated 0.25 plates, visualised by a long- and short-wavelength UV lamp.
Flash column chromatography was performed over Natland International Co. silica gel
(
dried glassware. THF was freshly distilled over sodium, and CH Cl over CaH , prior to
230–400 mesh). All air moisture sensitive reactions were carried out under N using oven-
2
2
2
2
use. DMSO was not dried. Et N was freshly distilled from NaOH. All other reagents were
3
used without further purification.
3
.1. Procedures
.1.1. 4-[(Furan-2 -yl)methoxy]-4-oxobutanoic acid (3)
0
3
ꢀ
To a stirred solution of 4 (0.51 g, 5.2 mmol) in anhydrous THF (6 mL) at 0 C under N ,
2
ꢀ
NaH (0.15 g, 6.25 mmol) was added. The reaction mixture was stirred for 20 min at 4 C,
then succinic anhydride (5) (1.04 g, 10.4 mmol) was added in one portion and the stirring
was continued at room temperature for 24 h. The solvent was removed under vacuum and

Natural Product Research
1359
the residue was dissolved with CH Cl (40 mL) and washed with water (2 ꢁ 40 mL). The
2
2
organic layer was dried (Na SO ) and the solvent was removed under vacuum. The residue
2
4
was purified by column chromatography over silica gel (32 g, hexane/EtOAc, 7 : 3) to give
0
.93 g (90%) of 3 as a colourless oil. R 0.29 (hexane : EtOAc, 6 : 4); IR (film): ꢀmax 3800–
f
ꢂ1
1
290, 1738, 1714, 1503, 1410, 1380, 1349, 1229, 1164, 1016, 998, 919, 823, 750 cm ; H
2
NMR (500 MHz, CDCl ): ꢁ 2.62–2.71 (m, 4H, CH CH CO H), 5.02 (s, 2H, CH O), 6.36
3
2
2
2
2
0
0
(
1
(
1
1
dd, J ¼ 3.5, 2.0 Hz, 1H, H-3 ), 6.41 (dd, J ¼ 3.5, 1.0 Hz, 1H, H-4 ), 7.42 (dd, J ¼ 2.0,
0
13
.0 Hz, 1H, H-5 ); C NMR (125 MHz, CDCl ): ꢁ 28.7 (CH CO ), 28.8 (CH CO ), 58.4
3
2
2
2
2
0
0
0
0
0
0
CH O), 110.5 (C-3 or C-4 ), 110.7 (C-4 or C-3 ), 143.3 (C-5 ), 149.2 (C-2 ), 171.8 (O C-1),
2
2
þ
78.1 (O C-4); HRMS (EI, [M] ) m/z Anal. Calcd for C H O : 198.0528; found:
2
9
10
5
98.0528.
3
3
.1.2. 5-(Hydroxymethyl)furan-2-carbaldehyde (6)
.1.2.1. Method A. A solution of D-fructose (1.0 g, 5.6 mmol) in DMSO (5 mL)
ꢀ
and concentrated (98%) H SO (0.055 g, 0.56 mmol) was stirred at 20 C for 30 min. The
4
2
flask was provided with a Dean–Stark trap and a condenser, the mixture was heated at
ꢀ ꢀ
1
15 C for 48 h, diluted with EtOAc (20 mL) and stirred at 20 C for 20 min. The mixture
was filtered over Celite, and the solvent was removed under high vacuum. The residue was
purified by column chromatography over silica gel (30 g, hexane : EtOAc, 7 : 3), to give
0
.56 g (80%) of 6 as a pale yellow oil (Quiroz-Florentino et al., 2008).
3
and concentrated (98%) H SO (0.055 g, 0.56 mmol) was stirred at 20 C for 30 min. The
.1.2.2. Method B. A solution of D-glucose (1.0 g, 5.6 mmol) in DMSO (5 mL)
ꢀ
2
4
flask was provided with a Dean–Stark trap and a condenser, the mixture was heated at
ꢀ ꢀ
1
15 C for 48 h, diluted with EtOAc (20 mL) and stirred at 20 C for 20 min. The mixture
was filtered over Celite, and the solvent was removed under high vacuum. The residue was
purified by column chromatography over silica gel (30 g, hexane : EtOAc, 7 : 3), to give
0
.49 g (70%) of 6 as a pale yellow oil. R 0.31 (hexane : EtOAc, 1 : 1).
f
0
0
3
.1.3. 4-[(5 -Formylfuran-2 -yl)methoxy]-4-oxobutanoic acid (2)
3
.1.3.1. Method A. A solution of dry DMF (0.22 g, 3.01 mmol) and POCl (0.461 g,
3
ꢀ
3
for 20 min under N . To this mixture, 3 (0.50 g, 2.53 mmol) in dry CH Cl (4 mL) was
added dropwise. The mixture was stirred at 40 C for 2 h, diluted with CH Cl (40 mL) and
2
.03 mmol) in dry CH Cl (1 mL) was stirred at 0 C for 30 min, then at room temperature
2
2
2
2
2
ꢀ
2
H O (20 mL) was added, then a 2.0 M aqueous solution of NaOH was added dropwise till
2
it becomes neutral. The organic layer was washed with H O (2 ꢁ 20 mL), dried (Na SO ),
2
2
4
and the solvent was removed under vacuum. The residue was purified by column
chromatography over silica gel (30 g, hexane : EtOAc, 8 : 2), to give 0.48 g (84%) of 2 as
colourless amorphous crystals.
ꢀ
3
under N , NaH (0.15 g, 6.25 mmol) was added. The reaction mixture was stirred at 4 C for
.1.3.2. Method B. To a stirred solution of 6 (0.66 g, 5.24 mmol) in dry THF (6 mL) at 0 C
ꢀ
2
2
0 min, then succinic anhydride (1.04 g, 10.4 mmol) was added in one portion and the
stirring was continued at room temperature for 24 h. The solvent was removed under
vacuum, and the residue was dissolved with CH Cl (40 mL) and washed with water
2
2

1
360
H. Quiroz-Florentino et al.
(
vacuum. The residue was purified by column chromatography over silica gel (32 g,
2 ꢁ 40 mL). The organic layer was dried (Na SO ) and the solvent was removed under
2
4
hexane : EtOAc, 7 : 3), to give 1.13 g (95%) of 2 as colourless amorphous crystals. M.p. 84–
ꢀ
8
1
(
5 C; R 0.25 (hexane : EtOAc, 6 : 4); IR (film): ꢀ
1
3330–2550, 1731, 1699, 1674, 1533,
407, 1344, 1258, 1233, 1208, 1169, 940 cm ; H NMR (500 MHz, CDCl ): ꢁ 2.66–2.73
f
max
ꢂ1
3
0
m, 4H, CH CH CO H), 5.17 (s, 2H, CH O), 6.59 (d, J ¼ 3.8 Hz, 1H, H-3 ), 7.21 (d,
2
2
2
2
0
13
J ¼ 3.8 Hz, 1H, H-4 ), 9.64 (s, 1H, CHO); C NMR (125 MHz, CDCl ): ꢁ 28.6 (CH CO ),
3
2
2
0 0 0 0
8.7 (CH CO ), 58.1 (CH O), 112.6 (C-3 ), 121.7 (C-4 ), 152.8 (C-5 ), 155.2 (C-2 ), 171.5
2 2 2
2
(O C-1), 177.2 (O C-4), 177.9 (CHO). Anal. Calcd for C H O : C, 53.10; H, 4.46.
2 2 10 10 6
Found: C, 53.03; H, 4.73.
0
0
3
3
.1.4. n-Butyl (5 -formylfuran-2 -yl)methyl succinate (1)
.1.4.1. Method A. To a solution of 2 (0.105 g, 0.465 mmol) in dry CH Cl (1.5 mL) at
2
2
room temperature under N , Et N (0.06 g, 0.59 mmol) was added, followed by addition of
2
3
1
-bromobutane (0.075 g, 0.55 mmol). The mixture was stirred at room temperature for 24 h
and extracted with water (2 ꢁ 20 mL). The aqueous layer was extracted with CH Cl
2
2
(2 ꢁ 20 mL). The combined organic layers were dried over Na SO , and the solvent was
removed under vacuum. The residue was purified by column chromatography over silica
2
4
gel (12 g, hexane : EtOAc, 9 : 1), to give 0.118 g (90%) of 1 as a colourless oil.
3
0
4
.1.4.2. Method B. To a stirred solution of 6 (0.66 g, 5.24 mmol) in dry THF (6 mL), at
ꢀ
C under N , NaH (0.15 g, 6.25 mmol) was added. The reaction mixture was stirred at
2
ꢀ
C for 20 min, then 5 (1.04 g, 10.4 mmol) was added in one portion, and the stirring
was continued at room temperature for 24 h. Then, 1-bromobutane (0.86 g, 6.29 mmol)
was added and the mixture was stirred at room temperature for 16 h. The mixture was
extracted with water (2 ꢁ 20 mL) and CH Cl (2 ꢁ 20 mL), the organic layers were
2
2
combined, dried over Na SO and the solvent was removed under vacuum. The residue
2
4
was purified by column chromatography over silica gel (32 g, hexane : EtOAc, 7 : 3), to give
1
.26 g (85%) of 1 as a colourless oil. R 0.27 (hexane/EtOAc, 8 : 2); IR (film): ꢀ
f
2964,
max
ꢂ1
1
738, 1683, 1526, 1407, 1350, 1270, 1203, 1156, 1021, 950, 813 cm ; H NMR (300 MHz,
1
CDCl ): ꢁ 0.93 (t, J ¼ 7.2 Hz, 3H, O(CH ) CH ), 1.30–1.43 (m, 2H, O(CH ) CH CH ),
3
2 3
3
2 2
2
3
1
.55–1.65 (m, 2H, OCH CH Et), 2.58–2.75 (m, 4H, CH CH CO nBu), 4.09 (t, 2H,
2 2 2 2 2
0
J ¼ 6.6 Hz, OCH (CH ) CH ), 5.16 (s, 2H, CH O), 6.59 (d, J ¼ 3.3 Hz, 1H, H-3 ), 7.21
2
2 2
0
3
2
13
(
(
(
(
d, J ¼ 3.3 Hz, 1H, H-4 ), 9.64 (s, 1H, CHO); C NMR (75.4 MHz, CDCl ): ꢁ 13.6
3
O(CH ) CH ), 19.0 (O(CH ) CH CH ), 28.8 (CH CO ), 28.9 (CH CO ), 30.5
2
3
3
2 2
2
3
2
2
2
2
0
0
OCH CH Et), 58.0 (CH O), 64.7 (OCH (CH ) CH ), 112.5 (C-3 ), 121.6 (C-4 ), 152.8
3
2
2
2
2
2 2
0
0
+
C-5 ), 155.3 (C-2 ), 171.7 (C-1), 172.1 (C-4), 177.8 (CHO); HRMS (EI, [M] ) m/z Anal.
Calcd for C H O : 282.1103; found: 282.1111.
1
4
18
6
Acknowledgements
J. Tamariz acknowledges SIP/IPN (Grants 20060583, 20070339, 20080527 and 20090519) and
CONACYT (Grants 43508Q and 83446) for financial support. H. Quiroz-Florentino thanks
CONACYT for awarding a graduate scholarship, and also SIP/IPN (PIFI) for a scholarship
complement. A. Garcıa thanks CONACYT for a postdoctoral fellowship awarded. E. Burgueno-
´
˜
Tapia and J. Tamariz are fellows of the EDI-IPN and COFAA-IPN programs.

Natural Product Research
1361
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