Total syntheses of natural furan derivatives rehmanones A, B, and C

Article abstract of DOI:10.1055/s-2008-1066987

The synthesis of naturally occurring furan derivatives rehmanones A, B, and C is described. Diverse alternative synthetic strategies were developed for the preparation of these natural products. Conjugate addition of a furan to captodative alkene 1-acetylvinyl 4-nitrobenzoate was carried out under Lewis acid catalysis to give the corresponding adduct, which was transformed into rehmanones B and C in three and two steps, respectively. They were also prepared by condensation of acetone with the key furan-2-carbaldehyde intermediates, which could be readily obtained from D-fructose. The bis-furan rehmanone A was not only obtained in a one-step procedure by a double condensation of acetone with 5-(methoxymethyl)furan-2-carbaldehyde, but by condensing the latter with rehmanone B in high overall yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1066987

PAPER
1023
Total Syntheses of Natural Furan Derivatives Rehmanones A, B, and C
Total
S
ynthesesof
é
R
ehmanon
c
es
A
,
B, an
t
d
C
or Quiroz-Florentino, Raúl Aguilar, Blanca M. Santoyo, Francisco Díaz, Joaquín Tamariz*
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala,
11340 México, D.F., Mexico
Fax +52(55)57296300/46211; E-mail: jtamariz@woodward.encb.ipn.mx
Received 16 June 2007; revised 11 October 2007
A first synthetic approach to rehmanones B (2) and C (3)
Abstract: The synthesis of naturally occurring furan derivatives
is depicted in Scheme 1. It starts from a conjugate addi-
rehmanones A, B, and C is described. Diverse alternative synthetic
tion of the correctly protected furfuryl alcohol 5 to the eas-
ily available captodative alkene 4a, to yield adduct 6,
strategies were developed for the preparation of these natural prod-
ucts. Conjugate addition of a furan to captodative alkene 1-acetylvi-
nyl 4-nitrobenzoate was carried out under Lewis acid catalysis to which could be transformed into the desired natural prod-
give the corresponding adduct, which was transformed into reh-
manones B and C in three and two steps, respectively. They were
ucts. Additionally, compound 2 could react with a suitable
substrate to give the bis-furan derivative rehmanone A
also prepared by condensation of acetone with the key furan-2-carb-
(1).
aldehyde intermediates, which could be readily obtained from D-
Conjugate addition of nucleophiles to Michael acceptors
constitutes a milestone reaction in organic synthesis for
the b-functionalization of carbonyl compounds.3 Conju-
gate addition of heterocycles to electron-deficient alkenes
has captured special attention due to the fact that this pro-
cedure can be an easy strategy for the functionalization of
seminal heterocycles such as indoles, pyrroles, and imida-
zoles, among others.4 Although conjugate addition of an
aryl ring5 or even some other heterocycles6 into a Michael
acceptor promoted by Lewis acids has been somehow lim-
ited because of the difficulty in correctly activating the
starting substrates, non-optimum reaction conditions, or
the presence of undesired side products or mixtures of iso-
mers, some successful examples have been reported.7 Pre-
viously, we reported the highly efficient Lewis acid
promoted conjugate addition of substituted aryl com-
pounds to captodative alkene 4a, which proved to be more
reactive than other electron-deficient alkenes.8
fructose. The bis-furan rehmanone A was not only obtained in a
one-step procedure by a double condensation of acetone with 5-
(methoxymethyl)furan-2-carbaldehyde, but by condensing the lat-
ter with rehmanone B in high overall yields.
Key words: rehmanones A, B, and C, conjugate addition, captoda-
tive alkenes, Lewis acids, condensation
The naturally occurring furan derivatives rehmanone A
(1), rehmanone B (2), and rehmanone C (3) have been re-
cently isolated from the dried roots of Rehmannia gluti-
nosa,1 and 3 from Salvia miltiorrhiza Bunge (Labiatae).2
These plants have been widely used in Chinese folk med-
icine for the treatment of menstrual disorders, insomnia,
arthritis, and coronary heart affections, and also as a ton-
ic.1,2 Compounds 1–3 have displayed significant biologi-
cal activity, since 1 inhibited blood platelet aggregation
and, also shown by 3, promoted immune activity. More-
over, the latter activity is inhibited when 2 and 3 are tested
at higher concentrations.1 Therefore, an effective and ver-
satile synthetic procedure for the synthesis of 1–3 is desir-
able. Herein we describe details of diverse synthetic
strategies for the preparation of these attractive natural
products.
Consequently, furfuryl alcohol (5a) was protected with a
methyl group to obtain 5b, which could lead to natural
product 2, and with a benzyl or a trimethylsilyl group to
yield derivatives 5c and 5d, respectively (Scheme 2). The
latter may be deprotected as precursors of natural product
3. When these furfuryl derivatives, 5b–d, were treated in
OMe
MeO
RO
O
O
O
O
O
2, R = Me
3, R = H
1
O
O
O
O
+
RO
RO
O
Ar
O
O
O
Ar
6
5
4a, Ar = 4-O2NC6H4
Scheme 1
SYNTHESIS 2008, No. 7, pp 1023–1028
x
x
.
x
x
.2
0
0
8
Advanced online publication: 06.03.2008
DOI: 10.1055/s-2008-1066987; Art ID: M04407SS
© Georg Thieme Verlag Stuttgart · New York

1024
H. Quiroz-Florentino et al.
PAPER
the presence of 4a with different Lewis acids (ZnCl2, in 90% yield by methylation with methyl iodide of com-
BF3·OEt2, AlCl3) and solvents (CH2Cl2, MeCN), and at pound 3, in the presence of sodium hydride as the base. In
various temperatures (–70 °C, 20 °C), the starting materi- summary, the efficacy of this synthetic pathway led to the
als were recovered. Compounds 5 tend to decompose preparation of compounds 2 and 3 in 54% and 60% over-
when the temperature is increased, without any significant all yields, respectively.14
transformation into the desired products.
O
O
4
4'
3'
It is likely that the low reactivity of these substrates in the
presence of Lewis acids was due to the deactivation of the
furan ring by coordination of the catalyst with the OR sub-
stituent of compounds 5,9 counterbalancing the activation
by coordination with the Michael acceptor 4a. This hy-
pothesis seems to be supported by the fact that captodative
alkene 4a reacted with furan (7) in the presence of catalyt-
ic amounts of boron trifluoride–diethyl ether complex un-
der mild conditions (0 °C, 1 h) to give the corresponding
adduct 8a in moderate yield (60%) (Scheme 2). More-
over, captodative alkene 4b, which is expected to be less
reactive than 4a,10 also undergoes the conjugate addition
satisfactorily to furnish adduct 8b. The yield of 8a could
be improved up to 85% by increasing the reaction temper-
ature to 20 °C and the reaction time to three hours.
O
O
3
i
5'
6'
2'
2
O
7'
O
Ar
O
Ar
97%
O
O
1'
1
H
9, Ar = 4-O2NC6H4
8a, Ar = 4-O2NC6H4
ii
86%
4'
3'
2'
iii
5'
3
2
O
O
RO
iv
O
O
O
1'
84%
6'
4
1
H
10
3, R = H
2, R = Me (90%)
Scheme 3 Reagents and conditions: (i) DMF, POCl3, CH2Cl2, 40
°C, 30 min; (ii) DBN, THF, r.t., 2 h; (iii) NaBH4, wet silica gel,
CH2Cl2, r.t., 20 min; (iv) MeI, NaH, THF, r.t., 2 h.
Once the furan ring was found to be functionalized with
the butanone moiety, we decided to introduce the meth-
oxy- or hydroxymethyl group to the heterocycle by
formylation.11 Thus, compound 8a was treated with N,N-
dimethylformamide/phosphoryl chloride for thirty min-
utes to give an excellent yield of the carbaldehyde deriva-
tive 9 (Scheme 3). Elimination of the 4-nitrobenzoyloxy
group was carried out by reaction of the latter with 1,5-di-
azabicyclo[4.3.0]non-5-ene at room temperature for two
hours, to provide the a,b-unsaturated ketone 10 in good
An alternative strategy was also pursued for the synthesis
of rehmanone B (2), which involved an aldol condensa-
tion between the preformed furanyl scaffold and the car-
bonylic synthon in order to introduce the (E)-butenone
side chain. Thus, the direct condensation between the 5-
substituted furaldehyde 13 and acetone in the presence of
sodium hydroxide led to the desired product 2 in high
yield (Scheme 4). Substituted furan compound 13 was
prepared in two steps, through an acid-catalyzed transfor-
mation of D-fructose (11) into furaldehyde 12,15 which
was methylated with methyl iodide, and sodium hydride
as the base, to give 13 in 64% overall yield (Scheme 4).
The shortness and effectiveness of this strategy prompted
us to use it also for the synthesis of rehmanone C (3).
Thus, condensation of 12 with acetone under the same re-
action conditions led to 3 in comparable overall yield
(62%) to that obtained for 2 (60%), and in only two steps
starting from 11 (Scheme 4).
1
yield as a single E-stereoisomer.12 The H NMR of the
crude mixture did not show any signal attributed to the Z-
isomer. Reduction of the formyl group with sodium boro-
hydride under standard conditions (MeOH, H2O, r.t.)
yielded a mixture of the desired product 3 and the product
of reduction of both carbonyl groups. A more selective
method resulted when using sodium borohydride and wet
silica gel was used with dichloromethane as the solvent,13
since rehmanone C (3) was obtained as the main product
in 84% yield (Scheme 3). Rehmanone B (2) was prepared
O
O
Lewis acid
O
O
+
R1O
R1O
R2
O
R2
O
O
O
5a, R1 = H
4a, R2 = 4-O2NC6H4
4b, R2 = 2-furoyl
6
5b, R1 = Me
5c, R1 = Bn
5d, R1 = TMS
BF3·OEt2
CH2Cl2
O
0–20 °C, 1–3 h
7
O
O
O
R2
O
8a, R2 = 4-O2NC6H4 (60–85%)
8b, R2 = 2-furoyl (65%)
Scheme 2
Synthesis 2008, No. 7, 1023–1028 © Thieme Stuttgart · New York

PAPER
Total Syntheses of Rehmanones A, B, and C
1025
OH
addition, a convergent and highly efficient synthesis of 1
was also reported by reacting rehmanone B (2) with fur-
fural derivative 13. Although the overall efficiency in the
synthesis of 2 and 3 was more practical starting from D-
fructose, the development of diverse synthetic methodol-
ogies for the preparation of natural products 1–3, includ-
ing the isolation of a series of intermediates and
precursors, will allow us to synthesize a large variety of
derivatives with the aim of searching for higher bioactiv-
ity than that shown by the natural furan compounds. This
is currently in process and the results will be reported in
due course.
O
i
RO
O
HO
HO
O
OH
H
OH
12, R = H
13, R = Me
11
ii
iii
RO
O
O
2, R = Me (94%)
3, R = H (91%)
Scheme 4 Reagents and conditions: (i) H2SO4, DMSO, 110 °C, 48
h, 68%; (ii) MeI, NaH, THF, r.t., 16 h, 94%; (iii) acetone (2 equiv),
NaOH, r.t., 24 h.
Melting points (uncorrected) were determined with an Electrother-
mal capillary melting point apparatus. IR spectra were recorded on
a Perkin-Elmer 1600 spectrophotometer. 1H and 13C NMR spectra
were recorded on a Varian Mercury (300 MHz) instrument, with
CDCl3 as the solvent and TMS as internal standard. MS and HRMS
spectra were obtained in EI (70 eV) or FAB+ modes on Thermo-
Finnigan Polaris Q and on Jeol JMS-AX 505 HA spectrometers, re-
spectively. Microanalyses were performed by M-H-W Laboratories
The total synthesis of rehmanone A (1) was carried out
through three related approaches. The first one started
from rehmanone B (2) via a condensation reaction with
furfuryl compound 13 under mild basic conditions to fur-
nish 1 in quantitative yield (Scheme 5). The second ap-
proach was inspired by the fact that 1 has a symmetrical (Phoenix, AZ). Analytical TLC was carried out using E. Merck sil-
ica gel 60 F254 coated 0.25 plates, visualized by a long- and short-
wavelength UV lamps. Flash column chromatography was per-
structure. Therefore, by condensing 2.0 equivalents of 13
with 1.0 equivalent of acetone in the presence of sodium
formed over Natland International Co. silica gel (230–400 mesh).
hydroxide, natural rehmanone A (1) was obtained in 67%
All air moisture sensitive reactions were carried out under N2 using
yield (Scheme 5). Finally, the third pathway consisted of
oven-dried glassware. THF was freshly distilled over Na. DMF,
a condensation of 12 with acetone to give the bis-condens-
ing product 14, which was methylated with methyl iodide
to give 1 in 18% overall yield (Scheme 5). NMR spectral
data assignment of rehmanones A–C, 1–3, was supported
by HMQC and HMBC experiments, and is in agreement
with those reported.1,2
CH2Cl2, and EtOAc were distilled over CaH2 prior to use. DMSO
and acetone were dried by distillation after treatment with 4 Å mo-
lecular sieves. Et3N was freshly distilled from NaOH. All other re-
agents were used without further purification. Alkenes 4a and 4b,16
and furfuryl protected alcohols 5b–d,17 were prepared as reported.
1-(Furan-2-ylmethyl)-2-oxopropyl 4-Nitrobenzoate (8a); Typi-
In conclusion, we have described an efficient total synthe- cal Procedure
To a stirred soln of 4a (1.0 g, 4.26 mmol) in anhyd CH2Cl2 (2 mL),
sis of rehmanones B (2) and C (3) via the key steps of 2,5-
bis-functionalization of furan (7) by Lewis acid catalyzed
conjugate addition to captodative alkene 4a, followed by
formylation. An alternative and shorter strategy was also
developed by condensing acetone with the 2,5-disubstitut-
ed furanic compounds 12 and 13 to give 3 and 2, respec-
tively, in high overall yields. By using the concept of
molecular symmetry, the first total synthesis of reh-
manone A (1) was carried out in one step by bis-aldol con-
densation of acetone with two molecules of 13. In
at 0 °C under N2, was added dropwise 7 (0.35 g, 5.1 mmol). The
mixture was cooled to –78 °C and BF3·OEt2 (0.028 g, 0.2 mmol)
was added dropwise and it was stirred at r.t. for 3 h. H2O (2 mL) was
added and the mixture was extracted with CH2Cl2 (2 × 15 mL) and
washed with aq sat. NaHCO3 until neutral. The organic layer was
dried (Na2SO4) and the solvent was removed under vacuum. The
residue was purified by column chromatography (silica gel, 30 g,
hexane–EtOAc–CH2Cl2, 9:0.5:0.5) to give 8a (1.1 g, 85%) as a pale
yellow solid; mp 75–77 °C (hexane–EtOAc, 1:1); Rf = 0.47 (hex-
ane–EtOAc, 1:1).
3'
4'
5'
3'
4'
5'
4
2
i
2'
2'
MeO
O
OR
RO
3
O
O
1'
O
1'
1
6'
5
O
2
1, R = Me
14, R = H
iv
ii or iii
RO
O
O
H
12, R = H
13, R = Me
Scheme 5 Reagents and conditions: (i) 13, NaOH, EtOH, r.t., 48 h, 99%; (ii) 13 (2.0 equiv), acetone (1.0 equiv), NaOH, r.t., 24 h, 67% of 1;
(iii) 12 (2.0 equiv), acetone (1.0 equiv), NaOH, r.t., 2 h, 60% of 14; (iv) MeI, NaH, THF, r.t., 24 h, 30%.
Synthesis 2008, No. 7, 1023–1028 © Thieme Stuttgart · New York

1026
H. Quiroz-Florentino et al.
PAPER
IR (CH2Cl2): 1726, 1530, 1349, 1104 cm–1.
(E)-5-(3-Oxobut-1-enyl)furan-2-carbaldehyde (10)
To a stirred soln of 9 (0.24 g, 0.73 mmol) in anhyd THF (10 mL), at
20 °C under N2, was added dropwise DBN (0.179 g, 1.46 mmol).
The mixture was stirred at r.t. for 2 h, filtered through Celite, and
washed with THF (10 mL). The solvent was removed under vacuum
and the residue was extracted with CH2Cl2 (2 × 15 mL) and washed
with aq 1 M HCl (2 × 20 mL) and H2O until neutral. The organic
layer was dried (Na2SO4) and the solvent was removed under vacu-
um. The residue was purified by column chromatography (silica
gel, 10 g, hexane–EtOAc, 8:2) to give 10 (0.103 g, 86%) as a pale
yellow solid; mp 110–111 °C (hexane–EtOAc, 8:2) [Lit.12 110–111
°C]; Rf = 0.49 (hexane–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 2.21 (s, 3 H, CH3CO), 3.34 (d,
J = 9.0 Hz, 2 H, H1), 5.56 (t, J = 9.0 Hz, 1 H, H2), 6.18 (br d, J = 3.0
Hz, 1 H, H3¢), 6.32 (dd, J = 3.0, 1.5 Hz, 1 H, H4¢), 7.35 (d, J = 1.5
Hz, 1 H, H5¢), 8.17–8.34 (m, 4 H, ArH).
13C NMR (75 MHz, CDCl3): d = 26.6 (CH3CO), 29.4 (C1), 77.8
(C2), 108.1 (C3¢), 110.6 (C4¢), 123.6 (ArH), 130.9 (ArH), 134.6
(Ar), 142.2 (C5¢), 149.2 (C2¢), 150.8 (Ar), 163.9 (ArCO2), 203.6
(CH3CO).
MS: m/z (%) = 303 ([M]+, 1), 150 (90), 136 (100), 121 (66), 104
(49), 94 (53), 81 (43), 76 (28).
IR (CH2Cl2): 1671, 1618, 1498, 1400, 1361, 1260, 1217, 1174,
1041, 970, 813, 774 cm–1.
Anal. Calcd for C15H13NO6: C, 59.41; H, 4.32; N, 4.62. Found: C,
59.66; H, 4.41; N, 4.81.
1H NMR (300 MHz, CDCl3): d = 2.37 (s, 3 H, CH3CO), 6.80 (d,
J = 3.6 Hz, 1 H, H4), 6.91 (d, J = 16.2 Hz, 1 H, H8), 7.27 (d, J = 3.6
Hz, 1 H, H3), 7.31 (d, J = 16.2 Hz, 1 H, H7), 9.68 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 28.4 (CH3CO), 116.2 (C4), 122.3
(C3), 127.7 (C7), 128.4 (C8), 152.9 (C2), 155.1 (C5), 177.7 (CHO),
197.2 (CH3CO).
1-(Furan-2-ylmethyl)-2-oxopropyl Furan-2-carboxylate (8b)
Following the typical procedure for 8a using a mixture of 4b (0.3 g,
1.67 mmol), 7 (0.566 g, 8.33 mmol), and BF3·OEt2 (0.024 g, 0.17
mmol) in anhyd CH2Cl2 (5 mL) with stirring at r.t. for 1 h, to give
8b (0.27 g, 65%) as a pale yellow oil; Rf = 0.32 (hexane–EtOAc,
8:2).
HRMS (EI): m/z [M]+ calcd for C9H8O3: 164.0473; found:
164.0474.
IR (CH2Cl2): 1721, 1577, 1472, 1394, 1361, 1297, 1175, 1115,
1015, 765 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.17 (s, 3 H, CH3CO), 3.18–3.32
(m, 2 H, H1), 5.47 (dd, J = 6.8, 5.6 Hz, 1 H, H2), 6.13–6.17 (m, 1
H, H3¢), 6.28 (dd, J = 3.2, 1.7 Hz, 1 H, H4¢), 6.53 (dd, J = 3.4, 1.7
Hz, 1 H, H4¢¢), 7.23 (dd, J = 3.4, 0.9 Hz, 1 H, H3¢¢), 7.32 (dd,
J = 1.7, 0.9 Hz, 1 H, H5¢), 7.61 (dd, J = 1.7, 0.9 Hz, 1 H, H5¢¢).
13C NMR (75 MHz, CDCl3): d = 26.6 (C4), 29.4 (C1), 76.8 (C2),
107.9 (C3¢), 110.4 (C4¢), 112.0 (C4¢¢), 119.0 (C3¢¢), 141.9 (C5¢),
143.6 (C2¢¢), 147.0 (C5¢¢), 149.4 (C2¢), 157.6 (CO2), 204.5 (CO).
MS: m/z (%) = 249 ([M + H]+, 1), 231 (1), 136 (17), 95 (83), 94
(70), 81 (27), 53 (34), 43 (100).
HRMS (FAB): m/z [M + H]+ calcd for C13H12O5: 249.0763; found:
249.0762.
Rehmanone C (3)1,2,14
Method A: To a stirred mixture of 10 (0.119 g, 0.73 mmol) in
CH2Cl2 (2 mL) and silica gel (230–400 mesh) (0.146 g, 2.43 mmol)
impregnated with H2O (0.044 g, 30% in weight), at r.t. under N2,
was added dropwise NaBH4 (0.014 g, 0.37 mmol). The mixture was
stirred at 20 °C for 20 min, filtered through Celite, and washed with
CH2Cl2 (10 mL). The solvent was removed under vacuum and the
residue was extracted with CH2Cl2 (2 × 20 mL) and washed with aq
sat. NaHCO3 (2 × 20 mL) and then with H2O until neutral. The or-
ganic layer was dried (Na2SO4) and the solvent was removed under
vacuum. The residue was purified by column chromatography (sil-
ica gel, 10 g, hexane–EtOAc, 8:2) to give 3 (0.1 g, 84%) as a pale
yellow oil.
Method B: To a stirred soln of 12 (0.5 g, 4.0 mmol) in EtOH (20 mL)
and acetone (0.5 g, 8.6 mmol), at r.t. under N2, was added dropwise
10% aq NaOH (3.2 mL). The mixture was stirred at r.t. for 24 h and
the solvent was removed under vacuum. The residue was dissolved
in CH2Cl2 (50 mL) and washed with 5% aq HCl (2 × 25 mL) and
then with H2O until neutral. The aqueous layer was washed with
CH2Cl2 (2 × 25 mL), the combined organic extracts were dried
(Na2SO4) and the solvent was removed under vacuum. The residue
was purified by column chromatography (silica gel, 20 g, hexane–
EtOAc, 8:2) to give 3 (0.6 g, 91%) as a pale yellow oil; Rf = 0.31
(hexane–EtOAc, 1:1).
1-(5-Formylfuran-2-ylmethyl)-2-oxopropyl 4-Nitrobenzoate (9)
A soln of anhyd DMF (0.2 g, 2.7 mmol) and POCl3 (0.403 g, 2.63
mmol) was stirred at 0 °C for 10 min and at r.t. for 20 min under N2.
To this was added dropwise 8a (0.81 g, 2.67 mmol) in anhyd
CH2Cl2 (2 mL) at 0 °C. The mixture was stirred at r.t. for 10 min,
then at 40 °C for 30 min. H2O (2 mL) was added and aq 2 M NaOH
was added dropwise until neutral. The mixture was diluted with
CH2Cl2 (20 mL), the organic layer was washed with H2O (2 × 20
mL) and dried (Na2SO4), and the solvent was removed under vacu-
um. The residue was purified by column chromatography (silica
gel, 30 g, hexane–EtOAc, 8:2) to give 9 (0.86 g, 97%) as a pale yel-
low solid; mp 94–95 °C (hexane–EtOAc, 9:1); Rf = 0.49 (hexane–
EtOAc, 1:1).
IR (film): 3393, 1662, 1623, 1574, 1362, 1266, 1181, 1091, 967,
798 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.31 (s, 3 H, CH3CO), 4.64 (s, 2
H, H6¢), 6.39 (d, J = 3.3 Hz, 1 H, H4¢), 6.59 (d, J = 15.9 Hz, 1 H,
H3), 6.62 (d, J = 3.3 Hz, 1 H, H3¢), 7.22 (d, J = 15.9 Hz, 1 H, H4).
13C NMR (75 MHz, CDCl3): d = 28.0 (CH3CO), 57.6 (C6¢), 110.5
(C4¢), 116.6 (C3¢), 124.1 (C3), 129.3 (C4), 150.8 (C2¢), 157.3 (C5¢),
198.3 (CH3CO).
IR (CH2Cl2): 1724, 1674, 1522, 1399, 1341, 1271, 1103, 1025, 719
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.27 (s, 3 H, CH3CO), 3.31–3.49
(m, 2 H, H1), 5.62 (dd, J = 7.4, 5.3 Hz, 1 H, H2), 6.40 (d, J = 3.5
Hz, 1 H, H3¢), 6.31 (d, J = 3.5 Hz, 1 H, H4¢), 8.34–8.18 (m, 4 H,
ArH), 9.56 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 26.5 (C4), 29.4 (C1), 77.1 (C2),
111.2 (C3¢), 122.8 (C4¢), 123.7 (C10¢), 131.0 (C9¢), 134.1 (C8¢),
150.8 (C11¢), 152.5 (C5¢), 156.4 (C2¢), 163.8 (C7¢), 177.0 (C6¢),
202.9 (C3).
HRMS (EI): m/z [M]+ calcd for C9H10O3: 166.0630; found:
166.0630.
Rehmanone B (2)1,14
Method A: To a stirred soln of NaH (60% in mineral oil, 0.028 g,
0.84 mmol) in anhyd THF (10 mL), at r.t. under N2, was added drop-
wise 3 (0.14 g, 0.84 mmol) in anhyd THF (5 mL). The mixture was
stirred at r.t. for 2 min, MeI (0.12 g, 0.84 mmol) was added, and the
mixture was stirred at r.t. for 2 h. The mixture was filtered through
Anal. Calcd for C16H13NO7: C, 58.01; H, 3.96; N, 4.23. Found: C,
58.07; H, 4.00; N, 4.18.
Synthesis 2008, No. 7, 1023–1028 © Thieme Stuttgart · New York

PAPER
Total Syntheses of Rehmanones A, B, and C
1027
Celite and washed with CH2Cl2 (10 mL). The solvent was removed
under vacuum, the residue was dissolved in CH2Cl2 (10 mL),
washed with aq sat. NaHCO3 (2 × 10 mL) and then with brine until
neutral. The organic layer was dried (Na2SO4) and the solvent was
removed under vacuum. The residue was purified by column chro-
matography (silica gel, 30 g, hexane–EtOAc, 9:1) to give 2 (0.137
g, 90%) as a pale yellow oil.
added dropwise 10% aq NaOH (1 mL). The mixture was stirred at
r.t. for 48 h, the solvent removed under vacuum. The residue was
dissolved in CH2Cl2 (50 mL) and washed with 5% aq HCl (2 × 25
mL) and then H2O until neutral. The aqueous layer was washed with
CH2Cl2 (2 × 25 mL). The combined organic extracts were dried
(Na2SO4) and the solvent was removed under vacuum. The residue
was purified by column chromatography (silica gel, 20 g, hexane–
EtOAc, 95:5) to give 1 (0.33 g, 99%) as a pale yellow gum.
Method B: Following method B for the preparation of 3, a mixture
of 13 (0.5 g, 3.57 mmol), acetone (0.5 g, 8.6 mmol) in EtOH (20
mL), and 10% aq NaOH (3 mL) was stirred at r.t. for 24 h to give 2
(0.61 g, 94%) as a pale yellow oil; Rf = 0.25 (hexane–EtOAc, 8:2).
Method B: To a stirred soln of 13 (0.5 g, 3.57 mmol) in EtOH (20
mL) and acetone (0.10 g, 1.72 mmol), at r.t. under N2, was added
dropwise 10% aq NaOH (3 mL). The mixture was stirred at r.t. for
24 h and then the solvent was removed under vacuum. The residue
was dissolved with CH2Cl2 (50 mL) and washed with 5% aq HCl
(2 × 25 mL) and then H2O until neutral. The aqueous layer was
washed with CH2Cl2 (2 × 25 mL), the combined organic extracts
were dried (Na2SO4), and the solvent was removed under vacuum.
The residue was purified by column chromatography (silica gel, 20
g, hexane–EtOAc, 95:5) to give 1 (0.72 g, 67%) as a pale yellow
gum.
IR (CH2Cl2): 1687, 1665, 1616, 1576, 1360, 1257, 1183, 1091,
1021, 968, 798 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.32 (s, 3 H, CH3CO), 3.40 (s, 3
H, MeO), 4.42 (s, 2 H, H6¢), 6.42 (d, J = 3.3 Hz, 1 H, H4¢), 6.63 (d,
J = 3.3 Hz, 1 H, H3¢), 6.64 (d, J = 16.0 Hz, 1 H, H3), 7.25 (d,
J = 16.0 Hz, 1 H, H4).
13C NMR (75 MHz, CDCl3): d = 27.9 (CH3CO), 58.1 (MeO), 66.3
(C6¢), 111.8 (C4¢), 116.3 (C3¢), 124.1 (C3), 129.1 (C4), 150.9 (C2¢),
154.4 (C5¢), 197.7 (CH3CO).
Method C: Following the method of preparation of 13, a mixture of
NaH (0.03 g, 1.25 mmol) in anhyd THF (1 mL), MeI (1.112 g, 0.79
mmol), and 14 (0.1 g, 0.36 mmol), at r.t. under N2, was stirred for
24 h, to give 1 (0.033 g, 30%) as a pale yellow gum; Rf = 0.53 (hex-
ane–EtOAc, 1:1).
HRMS (FAB): m/z [M + H]+ calcd for C10H13O3: 181.0865; found:
181.0858.
5-(Hydroxymethyl)furan-2-carbaldehyde (12)15
IR (film): 1648, 1620, 1575, 1384, 1258, 1179, 1089, 1022, 973,
801 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.42 (s, 6 H, 2 MeO), 4.45 (s, 4 H,
2 CH2O), 6.43 (d, J = 3.3 Hz, 2 H, H4¢), 6.65 (d, J = 3.3 Hz, 2 H,
H3¢), 6.92 (d, J = 15.6 Hz, 2 H, H2, H4), 7.44 (d, J = 15.6 Hz, 2 H,
H1, H5).
13C NMR (75 MHz, CDCl3): d = 58.2 (MeO), 66.5 (CH2O), 112.0
(C4¢), 116.7 (C3¢), 123.3 (C2, C4), 129.1 (C1, C5), 151.6 (C2¢),
154.5 (C5¢), 188.1 (CO).
A stirred soln of 11 (2.0 g, 0.011 mol) in anhyd DMSO (9 mL) and
concd (98%) H2SO4 (0.108 g, 1.1 mmol) was heated to 110 °C for
48 h. The mixture was diluted with CH2Cl2 (50 mL) and washed
with H2O until neutral. The organic layer was dried (Na2SO4) and
the solvent was removed under vacuum. The residue was purified
by column chromatography (silica gel, 60 g, hexane–EtOAc, 7:3) to
give 12 (0.95 g, 68%) as a pale yellow oil; Rf = 0.31 (hexane–
EtOAc, 1:1).
IR (CH2Cl2): 3346, 1674, 1522, 1436, 1401, 1280, 1191, 1023, 966,
953, 812, 780, 770 cm–1.
HRMS (FAB): m/z [M + H]+ calcd for C17H18O5: 303.1232; found:
303.1241.
1H NMR (300 MHz, CDCl3): d = 4.65 (d, J = 0.6 Hz, 2 H, CH2OH),
6.53 (d, J = 3.6 Hz, 1 H, H4), 7.27 (d, J = 3.6 Hz, 1 H, H3), 9.55 (s,
1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 56.4 (CH2OH), 109.2 (C4), 123.1
(C3), 151.4 (C2), 161.3 (C5), 177.1 (CHO).
(1E,4E)-1,5-Bis[5-(hydroxymethyl)furan-2-yl]penta-1,4-dien-3-
one (14)
Following method B for the preparation of 1, a mixture of 12 (0.208
g, 1.65 mmol) in EtOH (20 mL) and acetone (0.05 g, 0.86 mmol)
and 10% aq NaOH (1 mL) was stirred at r.t. under N2 for 2 h to give
14 (0.27 g, 60%) as a pale yellow oily solid; Rf = 0.10 (hexane–
EtOAc, 1:1).
5-(Methoxymethyl)furan-2-carbaldehyde (13)
To a stirred suspension of NaH (60% in mineral oil, 0.16 g, 6.7
mmol) in anhyd THF (2 mL), at r.t. under N2, was added dropwise
12 (0.5 g, 4.0 mmol) in anhyd THF (5 mL). The mixture was stirred
at r.t. for 2 min, MeI (1.12 g, 7.9 mmol) was added, and the mixture
was stirred at r.t. for 16 h. The mixture was filtered thorough Celite
and washed with THF (10 mL). The solvent was removed under
vacuum and the residue was dissolved in CH2Cl2 (40 mL), washed
with aq sat. NaHCO3 (2 × 30 mL), and then brine until neutral. The
organic layer was dried (Na2SO4) and the solvent was removed un-
der vacuum. The residue was purified by column chromatography
(silica gel, 30 g, hexane–EtOAc, 8:2) to give 13 (0.52 g, 94%) as a
pale yellow oil; Rf = 0.27 (hexane–EtOAc, 8:2).
IR (KBr): 3375, 1616, 1554, 1524, 1383, 1346, 1182, 1117, 1073,
1015, 975, 798 cm–1.
1 H NMR (300 MHz, CDCl3): d = 2.87 (br s, 2 H, OH), 4.61 (s, 4 H,
CH2OH), 6.40 (d, J = 3.3 Hz, 2 H, H4¢), 6.60 (d, J = 3.3 Hz, 2 H,
H3¢), 6.89 (d, J = 15.6 Hz, 2 H, H2, H4), 7.43 (d, J = 15.6 Hz, 2 H,
H1, H5).
13C NMR (75 MHz, CDCl3): d = 56.7 (CH2OH), 109.8 (C4¢), 116.8
(C3¢), 122.3 (C2, C4), 128.9 (C1, C5), 150.5 (C2¢), 157.9 (C5¢),
187.8 (CO).
HRMS (FAB): m/z [M + H]+ calcd for C15H15O5: 275.0919; found:
275.0929.
IR (CH2Cl2): 2924, 2854, 1670, 1520, 1457, 1384, 1084, 753 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.43 (s, 3 H, MeO), 4.50 (s, 2 H,
CH2O), 6.53 (d, J = 3.6 Hz, 1 H, H4), 7.22 (d, J = 3.6 Hz, 1 H, H3),
9.63 (s, 1 H, CHO).
Acknowledgment
13C NMR (75 MHz, CDCl3): d = 58.7 (MeO), 66.5 (CH2O), 111.1
(C4), 121.8 (C3), 152.6 (C2), 158.2 (C5), 177.7 (CHO).
We thank Fernando Labarrios and Fabiola Jiménez for their help in
spectrometric measurements. J.T. acknowledges DEPI/IPN (Grants
20060583 and 20070339) and CONACYT (Grants 43508Q) for fi-
nancial support. H.Q. and B.M.S. thank CONACYT for awarding a
graduate scholarship, and also thank CGPI/IPN (PIFI) for scholar-
Rehmanone A (1)1
Method A: To a stirred soln of 2 (0.2 g, 1.1 mmol) in EtOH (10 mL)
and 13 (0.16 g, 1.14 mmol) in EtOH (10 mL), at r.t. under N2, was
Synthesis 2008, No. 7, 1023–1028 © Thieme Stuttgart · New York

1028
H. Quiroz-Florentino et al.
PAPER
ship complements. F.D. and J.T. are fellows of the EDI-IPN and
COFAA-IPN programs.
Marinelli, F. Synlett 2004, 944. (e) Zhan, Z.-P.;Yang, R.-F.;
Lang, K. Tetrahedron Lett. 2005, 46, 3859. (f) Yadav, J. S.;
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(12) The preparation of compound 10 has been previously
reported by a quite different synthetic route: Domínguez, C.;
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where 2 was the major component, through a cation-
mediated hydroxymethylation reaction with 4-(furan-2-
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