Formal total synthesis of (±)-dimethyl secologanoside

Article abstract of DOI:10.1002/jccs.200300069

A formal total synthesis of the iridoid monoterpene (±)-dimethyl secologanoside (6) is described. The Norrish I type fragmentation of bicyclo[2.2.1]heptannone 9 is the key step.

Full text of DOI:10.1002/jccs.200300069

Journal of the Chinese Chemical Society, 2003, 50, 441-444
441
Formal Total Synthesis of (±)-Dimethyl Secologanoside
Huo-Mu Tai* (
), Ming-Hsing Huang (
Department of Applied Chemistry, Chia Nan University of Pharmacy and Science,
) and Chau-Chen Yang (
)
Tainan 717, Taiwan, R.O.C.
A formal total synthesis of the iridoid monoterpene (±)-dimethyl secologanoside (6) is described. The
Norrish I type fragmentation of bicyclo[2.2.1]heptannone 9 is the key step.
Keywords: Iridoid monoterpene; Secologanoside; Norrish I type fragmentation; Cyclopentanopyran.
INTRODUCTION
RESULTS AND DISCUSSION
The iridoid monoterpenes represent a large family of
cyclopentanopyran natural products.1 Among the various
iridoids, the cyclopenta[c]pyran bearing the 2-oxa-cis-bi-
cyclo[4.3.0]nonane 1 moiety (Scheme I) as a fundamental
ring system is the most widely distributed. Loganin (2),2 one
of the most important iridoids, is the biosynthetic precursor
to secologanin (3),3 C7-C8 seco ring. The monoterpene gly-
coside secologanin plays a central role in the biosynthesis of
indole alkaloids.4 Secologanin is also the biogenetic key in-
termediate for the biosynthesis of secoiridoids, such as
sweroside (4)5 and gentiopicroside (5).6 The synthesis of this
physiologically active and structurally appealing class of
iridoid monoterpenes continues to be an active area of re-
search even today.7 Here, we wish to describe an efficient for-
mal total synthesis of (±)-dimethyl secologanoside (6),8 an
analogue of secologanin.
Cyclopentene 12 has been reported as a precursor of
secologanside (6).8 Our approach to secologanoside (6) is
based on the Norrish type I cleavage of bicyclo[2.2.1]hep-
tanone derivative 9 for the construction of the all cis-tri-
substituted cyclopentene ring system in compound 10.9 The
logical precursor for compound 10 may be the bicyclo-
[2.2.1]heptanone derivative 8.10 Our synthesis began with the
commercially available 7, a substance which “holds” the de-
sired stereochemistry and the same carbon number in the fi-
nal product.
The key intermediate 8 was easily prepared from di-
cyclopentadiene 7 on a half molar scale in a one-pot reac-
tion.10 Oxidative cleavage of the double bond in 8 was carried
out using an excess of ozone and an oxidative workup with
hydrogen peroxide. Without purification, the resulting diacid
was directly treated with excess diazomethane to afford
dimethyl ester 9 in 78% yield. Photolysis of 9 produced the
Norrish type I cleavage product 10 in 83% yield.11 With com-
pound 10 in hand, its conversion to 12 is quite straightfor-
ward. Reduction of the aldehyde group in 10 with sodium
borohydride in methanol at -23 °C gave the corresponding
hydroxy ester 11 (94%), which was subsequently tosylate
with para-toluenesulfonyl chloride to yield tosylate 12 in
89%. The structure of 12 was confirmed by comparison of the
1H and 13C NMR spectra with those of an authentic sample
provided by Professor Chang.8
Scheme I
MeO2C
CHO
CO2Me
4
1
6
5
9
3
OH
7
O
O
8
2 O
10
GluO
OGlu
1
2
3
O
O
O
O
MeO2C
CO2Me
In conclusion, we have developed a facile route to the
key intermediate 12 for the synthesis of secologanoside (6).
Efforts directed toward the synthesis of other naturally occur-
ring iridoids are currently under way in our laboratory.
O
O
O
GluO
GluO
GluO
4
6
5
* Corresponding author. E-mail: jtaihm@mail.chna.edu.tw

442 J. Chin. Chem. Soc., Vol. 50, No. 3A, 2003
Tai et al.
cooled to room temperature, the mixture was concentrated in
vacuo. Water (20 mL) was added to the residue and the result-
ing solution was extracted with ethyl acetate (4 × 25 mL). The
combined organic extracts were dried, filtered, and concen-
trated. After ethyl acetate (20 mL) was added to that residue,
the resulting solution was treated with diazomethane at 0 °C
for 30 min, after which nitrogen was bubbled into the solution
to remove any excess diazomethane. Removal of the solvent
by evaporation followed by flash column chromatography on
silica gel (elution with 15-30% ethyl acetate in hexane) af-
Scheme II
1) O3 / CH2Cl2
2) H2O2 / HCO2H
rf: 10
O
3) CH2N2
78%
7
8
CO2Me
NaBH4
MeO2C
hv / acetone
83%
O
94%
CO2Me
1
forded compound 9 (1.26 g, 78%) as a light yellow oil: H
CO2Me
9
CHO
10
NMR (CDCl3) d 3.66 (s, 3H), 3.36 (s, 3H), 3.24 (dd, J = 11.2,
4.5 Hz, 1H), 2.75-2.60 (m, 3H), 2.44 (dd, J = 16.4, 7.1 Hz,
1H), 2.27 (dd, J = 18.3, 3.0 Hz, 1H), 2.03 (dd, J = 18.3, 4.2
Hz, 1H), 1.85-1.78 (m, 2H): 13C NMR (CDCl3) d 213.2 (s),
172.6 (s), 172,4 (s), 54.1 (d), 51.5 (q), 51.4 (q), 45.1 (d), 38.7
(d), 37.9 (t), 37.8 (t), 36.9 (d), 32.3 (t); IR (neat) 1725 cm-1;
MS (EI, 70 eV) m/z 240 (11, M+), 209 (49), 79 (100); HRMS
(EI) m/z calcd. for C12H16O5 240.0998, found 240.1000;
Anal. calcd. for C12H16O5: C, 60.03; H, 6.72. Found: C,
60.22; H, 6.90.
MeO2C
CO2Me
CO2Me
OTs
CO2Me
MeO2C
MeO2C
TsCl / py
89%
O
GluO
11
12
6
OH
EXPERIMENTAL SECTION
All reagents and solvents were obtained from commer-
cial sources and used without further purification. A column
chromatograph contained silica gel (70~230 mesh); pre-
coated TLC sheets of silica gel (60 f254 plates) were used for
thin-layer chromatography. All reactions were performed un-
der an atmosphere of nitrogen in dried (except those con-
cerned with aqueous solutions) spherical flasks and stirred
with magnetic bars. Infrared (IR) spectra were recorded on a
(1R*,4S*,5S*)-5-Methoxycarbonylmethyl-4-(2-oxo-ethyl)-
cyclopent-2-enecarboxylic acid methyl ester (10)
A solution of compound 9 (200 mg, 0.83 mmol) in oxy-
gen-free acetone (100 mL) was irradiated under a nitrogen at-
mosphere with a 450-W medium pressure mercury lamp us-
ing a Pyrex glass filter for 3 h while the progress of the reac-
tion was monitored by GC. The solution was concentrated,
and then the residue was purified by flash column chromatog-
raphy on silica gel (elution with 15-25% ethyl acetate in hex-
ane) to yield compound 10 (166 mg, 83%) as a colorless oil:
1H NMR (CDCl3) d 9.63 (br. s, 1H), 5.91 (ddd, J = 5.8, 1.9,
1.8 Hz, 1H), 5.60 (ddd, J = 5.8, 2.7, 1.4 Hz, 1H), 3.53 (s, 3H),
3.51 (s, 3H), 3.46 (ddd, J = 8.2, 2.7, 1.8 Hz, 1H), 3.20-3.05
(m, 1H), 2.89 (p, J = 8.2 Hz, 1H), 2.55-2.45 (m, 2H), 2.36 (dd,
J = 8.2, 4.4 Hz, 2H); 13C NMR (CDCl3) d 201.2 (s), 173.50
(s), 172.5 (s), 137.8 (d), 128.6 (d), 52.1 (d), 51.5 (2c, q), 45.7
(t), 40.5 (d), 38.9 (d), 31.7 (t); IR (neat) 2729, 1732, 1716
cm-1; Ms (EI, 70 eV) m/z 241 [4, (m+1)+], 208 (24), 180 (76),
77 (100); HRMS (EI) m/z C12H16O5 calcd.for 240.0998,
found 240.1002.
1
Perkin-Elmer FTIR-2000 spectrometer. H and 13C NMR
spectra were recorded on a Bruker DPX 200 spectrometer,
with TMS as the internal standard. Mass spectra (MS) were
measured on a VGQUATTRO 5022 mass spectrometer. High
resolution mass (HRMS) values were determined on a JEOL
JMSHY 110 mass spectrometer. Elemental analyses (EA)
were performed on a Heraeus CHN-O analyzer.
(1R*,2S*,3S*,4R*)-3-Methoxycarbonylmethyl-6-oxo-
bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester (9)
A solution of 8 (1.0 g, 6.8 mmol) in dichloromethane
(30 mL) at -60 °C was treated with ozone until the solution
turned blue. After it was stirred at -60 °C for an additional 5
min, the mixture was allowed to warm to room temperature
and then stripped of solvent in vacuo. The residue was
redissolved in formic acid (20 mL) with magnetic stirring,
and then 5 mL of hydrogen peroxide (33%) was added. The
resulting mixture was heated at reflux for 24 h. After it was
(1R*,4S*,5S*)-4-(2-Hydroxyethyl)-5-methoxycarbonyl-
methyl-cyclopent-2-enecarboxylic acid methyl ester (11)
Sodium borohydride (78 mg, 2.0 mmol) was added
gradually to a stirred solution of compound 10 (500 mg, 2.1
mmol) in methanol (15 mL) at -23 °C. After 30 min, the reac-

Formal Total Synthesis of (±)-Dimethyl Secologanoside
J. Chin. Chem. Soc., Vol. 50, No. 3A, 2003 443
tion was quenched with saturated ammonium chloride (30
mL) and the aqueous layer was extracted with ethyl acetate (4
´ 25 mL). The combined organic layers were washed with
brine, and then dried, filtered and stripped of solvent. Purifi-
cation of the residue by flash column chromatography on sil-
ica gel (elution with 20-35% ethyl acetate in hexane) gave
pound 12 to us for comparison.
Received August 16, 2002.
1
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ACKNOWLEDGMENTS
We thank the National Science Council of the Republic
of China for financial support and Professor Nein-Chen
Chang (Department of Chemistry, National Sun Yat-Sen Uni-
versity, Kaohsiung, Taiwan) for sending spectral data of com-

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