Conversion of 5-Deoxypulchelloside I to Caudatoside A

Article abstract of DOI:10.1021/np0303613

The iridoid caudatoside A (2) was synthesized in seven steps from the naturally occurring iridoid 5-deoxypulchelloside I (1) using a straightforward series of protection and deprotection procedures to introduce the requisite C-6 cinnamoyl ester.

Full text of DOI:10.1021/np0303613

J . Nat. Prod. 2004, 67, 221-224
221
Notes
Con ver sion of 5-Deoxyp u lch ellosid e I to Ca u d a tosid e A†
Sloan Ayers and Albert T. Sneden*
Department of Chemistry, Virginia Commonwealth University, P.O. Box 842006, Richmond, Virginia 23284-2006
Received August 5, 2003
The iridoid caudatoside A (2) was synthesized in seven steps from the naturally occurring iridoid
5-deoxypulchelloside I (1) using a straightforward series of protection and deprotection procedures to
introduce the requisite C-6 cinnamoyl ester.
Recently, we reported the isolation and structure eluci-
dation of caudatosides A-F, six new iridoids from Cithar-
exylum caudatum L., which are C-6 and C-7 phenylpro-
panoid esters of 5-deoxypulchelloside I (1).1 Many phenyl-
propanoid esters of iridoids have shown biological activity.
For example, the three arbortristosides, phenylpropanoid
esters of 6â-hydroxyloganin, from Nyctanthes arbortristis
have shown leishmanicidal activity,2 and picroliv, a stan-
dardized extract of Picrorhiza kurroa containing kutkoside
(the 10-cinnamoyl ester of catalpol) and picroside I, has
exhibited hepatoprotective activity.3 The three arbortris-
tosides are nearly identical to caudatosides A-C, differing
only in stereochemistry at C-8. Although the leishmanicidal
activity of the caudatosides has not yet been determined,
the possibility of preparing a series of natural and un-
natural derivatives for future work prompted us to develop
numerous protecting groups exist for protecting cis-diols,
acetonides are probably the most common. Use of an
acetonide in this case was initially of some concern since
acidic conditions are used for their removal, and the glucose
moieties of iridoids are somewhat susceptible to acid
hydrolysis. However, an acetonide has been removed from
an iridoid in a previous literature example without remov-
ing the glucose,9 so the acetonide moiety was chosen as the
cis-diol protecting group because of its ease of formation.
When 1 was reacted with 2,2-dimethoxypropane (2,2-DMP)
in the presence of acid catalyst, however, a diacetonide (4)
was formed in 72% yield, as clearly indicated by NMR data
(four methyl singlets between δ 1.23 and 1.47). This was
not unexpected, since the 4′,6′-diol of the glucose is also
known to readily form six-membered acetonides. Since,
under the proper conditions, dioxane acetonides can be
removed in the presence of dioxolane acetonides,10 this
formation of a diacetonide was not viewed as a problem.
Using dilute aqueous acidic (1% HOAc) conditions9 the
glucose acetonide was easily removed to give monoac-
etonide 5 in 55% yield. The only byproduct formed in this
reaction was 1, and this was by choice. The reaction could
be stopped prior to the point where 1 began to form, but
this would have required separation by chromatography
of three compounds, 1, 4, and 5. By allowing the reaction
to proceed until all of 4 had been consumed, the only
byproduct was 1, from which 5 could be removed by
extraction with EtOAc.
the methodology necessary to synthesize these esters, as
well as other analogues, from 1.
Synthetic work involving iridoids was recently reviewed.4
In addition to the syntheses of iridoids themselves, iridoids
have been used as chiral starting materials in the synthe-
ses of cyclopentanoid marine diterpenoids,5 nucleoside
analogues,6 and prostaglandin analogues.7 Directly related
to the current work, Bhaduri et al. reported the semisyn-
thesis of esters of loganin, as well as analogues of loganin
and arbortristoside A with a modified glucose moiety in
the hope of finding derivatives with antihepatotoxic activ-
ity.8 Unfortunately, the final deprotection step of the
synthesized compounds was not accomplished, so the
products retained the acetate moieties used as protecting
groups.
To develop the methodology for the synthesis of C-6 and
C-7 ester derivatives of 1 (Figure 1), we chose to focus on
the conversion of 1 into caudatoside A (7-cinnamoyl-5-
deoxypulchelloside I, 2) and caudatoside B (3), since this
would obviate the need to protect phenolic moieties present
in the phenylpropanoid esters of caudatosides C-F. Selec-
tive addition of the cinnamoyl ester at C-6 or C-7 of 1
required differential protection of the hydroxyl groups in
the glucose and aglucon halves of 1. To accomplish this
differential protection, we took advantage of the fact that
the OH-6 and -7 groups in 1 have a cis-relationship. While
† Dedicated to the late Dr. Monroe E. Wall and to Dr. Mansukh C. Wani
of Research Triangle Institute for their pioneering work on bioactive natural
products.
* Corresponding author. Tel: (804)827-0857. Fax: (804)828-2171.
E-mail: atsneden@vcu.edu.
Protection of the free glucose hydroxyl groups in 5 now
required a protecting group that would not be susceptible
to the acidic conditions required to remove the remaining
10.1021/np0303613 CCC: $27.50
© 2004 American Chemical Society and American Society of Pharmacognosy
Published on Web 10/17/2003

222 J ournal of Natural Products, 2004, Vol. 67, No. 2
Notes
F igu r e 1. Conversion of 5-deoxypulchelloside I (1) to caudatoside A (2): (i) 2,2-dimethoxypropane, dry acetone, PPTS, rt, 1 h, 40 °C, 0.5 h; (ii) 1%
HOAc, rt, 18 h; (iii) Ac2O, rt, 24 h; (iv) 80% HOAc, rt, 38 h; (v) cinnamoyl chloride, DMAP, 80 °C, 16 h; (vi) 6% NH3-MeOH, rt, 24 h.
acetonide. After consideration of a number of different
protecting groups, acetate was chosen as the protecting
group because of its acid stability (needed for removal of
the remaining acetonide), the mild conditions required for
reaction, and the generally high yield of the reactions.
Accordingly, 5 was smoothly converted under standard
conditions in 92% yield to monoacetonide tetraacetate 6.
The next step was to remove the remaining acetonide of
6 to release the C-6 and C-7 hydroxyl moieties. In searching
for a method that would not result in hydrolysis of the
protected glucose group, the use of acidic ion-exchange
resin was attempted. While the product was formed, the
reaction was very slow and numerous side products were
also formed. Consequently, standard acetonide removal
conditions were used, treating 6 with 80% HOAc to remove
the acetonide and produce 7 in 72% yield.
Tetraacetate 7 was acylated with cinnamoyl chloride in
pyridine with DMAP as an additional catalyst to give a
mixture of the 6-cinnamoyl tetraacetate (8) and the 7-cin-
namoyl tetraacetate (9), in an approximate ratio of 1:2. This
mixture was separated by preparative TLC to give a 26%
yield of 8 and a 44% yield of 9. On a larger scale, the
mixture would be carried on through the next steps and
the isomers separated in the final step, which would likely
increase the overall yield of this method.
Before attempting the final deprotection of the acetates
of 8, the deprotection reaction was attempted on a model
compound. Caudatoside A pentaacetate (10), prepared from
caudatoside A during the isolation and structure elucida-
tion work,1 was used as the model for the removal of the
acetates in the presence of the cinnamoyl group. Several
methods have been successfully used for the removal of
acetate in the presence of benzoate,11 but no general
method for acetate removal in the presence of a cinnamoyl
moiety was found. Since relatively mild conditions would
be required, two separate methods, the use of dilute NH3
in MeOH12 and guanidine in MeOH,11f were investigated
for the deprotection of 10. In both cases, the two major
products were the desired caudatoside A (2) and caudato-
side A 7-acetate (11), as well as a small amount of 1.
Since tetraacetate 8 did not contain an acetate at the
7-position, it was thought that this method would be
applicable to 8, giving only the desired 2. However, when
the reaction was carried out on 8 with dilute NH3-MeOH
or with guanidine, only starting material 8 and 1 were
present in the reaction mixture. Presumably, the presence
of the free hydroxyl group at C-7 promotes hydrolysis of
the 6-cinnamoyl ester. Consequently, tetraacetate 8 was
converted to pentaacetate 10 in 94% yield, and the acetate
groups were removed with dilute NH3-MeOH to give the
mixture of 2 and 11. Preparative TLC of this mixture gave
caudatoside A (2) in 51% yield, 3.3% overall from 1.
This work demonstrated that the synthesis of caudato-
side A (2) and other C-6 or C-7 ester derivatives from
5-deoxypulchelloside I (1) was relatively straightforward.
The only major complication with this method was that
the acetate at O-7 in 10 was not as labile as the glucose
acetates, likely due to steric factors. This scheme produced
caudatoside A from 5-deoxypulchelloside I in seven steps,
with an overall yield of 3.3%. While this yield is low, this
method creates both caudatoside A and caudatoside B from
the same intermediates. If the caudatoside B tetraacetate
(8) had been carried through the last two steps, assuming
similar yields for the last two steps as for caudatoside A,
then caudatoside B (3) would have been produced in
approximately 5.5% yield. The overall yield, therefore, for
caudatosides A and B would be approximately 8.8%. In
addition, in the removal of the glucose acetonide from 6,
the major byproduct is 5-deoxypulchelloside I, which can
be recycled. This method should be directly applicable to
the synthesis of the other caudatosides, as well as ana-
logues, from 1.

Notes
J ournal of Natural Products, 2004, Vol. 67, No. 2 223
Exp er im en ta l Section
5-Deoxyp u lch ellosid e I Tetr a a ceta te (7). Compound 6
(2.98 g, 4.85 mmol) was treated with 70 mL of 80% AcOH in
water for 38 h, at which time no more starting material could
be detected by TLC. The reaction mixture was neutralized by
addition of concentrated NH4OH. The aqueous mixture was
extracted three times with EtOAc (40 mL each). The combined
EtOAc layers were washed with 1 N HCl (three times, 30 mL
each), 5% NaHCO3 (once, 30 mL), and saturated NaCl (once,
30 mL). The EtOAc layer was dried over Na2SO4, filtered, and
evaporated to yield 7 as a tan solid (2.01 g, 72%): 1H NMR
(CDCl3, 400 MHz) δ 7.34 (1H, d, J ) <0.6 Hz, H-3), 5.28 (1H,
d, J ) 2.4 Hz, H-1), 5.21 (1H, dd, J ) 9.6, 9.6 Hz, H-3′), 5.10
(1H, dd, J ) 9.6, 9.6 Hz, H-4′), 4.96 (1H, dd, J ) 9.6, 8.0 Hz,
H-2′), 4.84 (1H, d, J ) 8.0 Hz, H-1′), 4.26 (1H, dd, J ) 12.4,
4.0 Hz, H-6′b), 4.15 (1H, dd, J ) 12.4, 2.0 Hz, H-6′a), 3.93 (1H,
dd, J ) 4.0, 4.0 Hz, H-6), 3.83 (1H, dd, J ) 4.0, 2.8 Hz, H-7),
3.75 (3H, s, -CO2CH3), 3.71 (1H, ddd, J ) 9.6, 4.0, 3.2 Hz,
H-5′), 3.00 (1H, ddd, J ) 10.8, 7.6, 2.4 Hz, H-9), 2.72 (1H, ddd,
J ) 10.8, 4.8, <0.6 Hz, H-5), 2.36 (1H, qdd, J ) 7.6, 7.6, 2.8
Hz, H-8), 2.09, 2.02, 2.00, 1.92 (12H, s, acetate -CH3’s), 0.93
(3H, d, J ) 7.6 Hz, H-10); ESMS m/z 597 [M + Na+].
Ca u d a tosid e A Tetr a a ceta te (8) a n d Ca u d a tosid e B
Tetr a a ceta te (9). To 7 (22 mg, 38 µmol) in 250 µL of pyridine
and 175 µL of CH2Cl2 were added cinnamoyl chloride (41 mg,
0.25 mmol) and a catalytic amount of DMAP. The reaction was
heated in a tightly capped reaction vial to 80 °C for 16 h with
stirring. After cooling to room temperature, the reaction
mixture was suspended in 5 mL of water and extracted three
times with CHCl3 (5 mL each). The combined CHCl3 layers
were washed twice with 1 N HCl (5 mL each), once with 5%
NaHCO3 (5 mL), and once with saturated NaCl (5 mL). The
CHCl3 layer was dried over Na2SO4 and the solvent concen-
trated to ∼100 µL. The product mixture was then applied to a
silica gel preparative TLC plate and developed with 97:3 CH2-
Cl2-MeOH. The bands were scraped from the plate and
desorbed twice with 4:1 CH2Cl2-MeOH to yield 8 (low Rf band,
7 mg, 26%) and 9 (high Rf band, 12 mg, 44%): 1H NMR (CDCl3,
400 MHz): 8: δ 7.73 (1H, d, J ) 16.0 Hz, H-â), 7.54-7.56 (2H,
m, H-2′′, H-6′′), 7.40-7.41 (3H, m, H-3′′, H-4′′, H-5′′), 6.48 (1H,
d, J ) 16.0 Hz, H-R), 5.41 (1H, m, H-6), 5.40 (1H, d, J ) 1.6
Hz, H-1), 5.21 (1H, dd, J ) 9.6, 9.6 Hz, H-3′), 5.10 (1H, dd, J
) 9.6, 9.6 Hz, H-4′), 4.97 (1H, dd, J ) 9.6, 8.0 Hz, H-2′), 4.83
(1H, d, J ) 8.0 Hz, H-1′), 4.29 (1H, dd, J ) 12.4, 4.4 Hz, H-6′b),
4.17 (1H, dd, J ) 12.4, 2.0 Hz, H-6′a), 3.84 (1H, dd, J ) 8.0,
4.4 Hz, H-7), 3.71-3.75 (4H, m, H-5′, -CO2CH3), 3.06 (1H,
dd, J ) 9.6, <0.4 Hz, H-5), 2.98 (1H, ddd, J ) 9.6, 9.6, 1.6 Hz,
H-9), 2.35 (1H, ddd, J ) 9.6, 8.0, 7.2 Hz, H-8), 2.11, 2.03, 2.00,
1.90 (12H, s, acetate -CH3’s), 1.12 (3H, d, J ) 7.2 Hz, H-10);
ESMS m/z 727 [M + Na+], 705 [M + H+]; 9: δ 7.72 (1H, d, J
) 16.0 Hz, H-â), 7.53-7.55 (2H, m, H-2′′, H-6′′), 7.38-7.40 (3H,
m, H-3′′, H-4′′, H-5′′), 6.50 (1H, d, J ) 16.0 Hz, H-R), 5.32 (1H,
d, J ) 2.4 Hz, H-1), 5.22 (1H, dd, J ) 9.6, 9.6 Hz, H-3′), 5.11
(1H, dd, J ) 9.6, 9.6 Hz, H-4′), 5.02-4.97 (2H, m, H-7, H-2′),
4.86 (1H, d, J ) 8.0 Hz, H-1′), 4.24-4.31 (2H, m, H-6, H-6′b),
4.15 (1H, dd, J ) 12.4, 2.0 Hz, H-6′a), 3.68-3.75 (4H, m, H-5′,
-CO2CH3), 2.88-2.99 (2H, m, H-5, H-9), 2.59 (1H, m, H-8),
2.09, 2.03, 2.01, 1.94 (12H, s, acetate -CH3’s), 1.07 (3H, d, J
) 7.2 Hz, H-10).
Gen er a l Exp er im en ta l P r oced u r es. 1H NMR spectra
were obtained on either a Varian Mercury 300 MHz spectrom-
eter equipped with a Sun Microsystems Ultra 5 processor and
VNMR version 5.1b software or a Varian Inova 400 MHz
spectrometer with a Sun Microsystems Ultra 1 processor and
VNMR version 5.1c software. Mass spectra were obtained in
the positive-ion mode on a Micromass (Beverly, MA) quadru-
pole time-of-flight (Q-ToF2) mass spectrometer with a modified
dual micro-electrospray source for internal calibration. Sol-
vents were reagent grade and used as purchased. 5-Deoxyp-
ulchelloside I (1) was isolated from C. caudatum as previously
described.1
6,7:4′,6′-Di-O-isop r op ylid en e 5-Deoxyp u lch ellosid e I
(4). To 1 (8.13 g, 20 mmol) in dry acetone (170 mL) were added
2,2-dimethoxypropane (50 mL, 0.4 mol) and PPTS (10.18 g,
40 mmol). Sonication at room temperature for 1 h was followed
by stirring for 30 min at 40 °C, then triethylamine (9 mL, 65
mmol) was added and the reaction mixture concentrated. The
oily, pale yellow residue was suspended in water (50 mL) and
extracted three times with CHCl3 (16 mL each). The combined
CHCl3 layers were extracted twice with 1 N HCl, once with
5% aqueous NaHCO3, and finally once with saturated NaCl.
The CHCl3 layer was dried over Na2SO4, filtered, and evapo-
rated to yield 2 (7.05 g, 72%) as a hygroscopic foam: 1H NMR
(acetone-d6, 300 MHz) δ 7.31 (1H, d, J ) 1.8 Hz, H-3), 5.51
(1H, d, J ) 1.2 Hz, H-1), 4.71 (1H, d, J ) 7.8 Hz, H-1′), 4.66
(1H, d, J ) 5.4 Hz, H-6), 4.25 (1H, d, J ) 5.4 Hz, H-7), 3.84
(1H, dd, J ) 5.7, 10.8 Hz, H-6′a), 3.68 (3H, s, -CO2CH3), 3.24-
3.77 (5H, glucose protons), 2.83 (1H, m, H-5), 2.80 (1H, m, H-9),
2.39 (1H, m, H-8), 1.47, 1.39, 1.32, 1.23 (12H, s, isopropylidene
-CH3’s), 0.96 (3H, d, J ) 7.5 Hz, H-10); ESMS m/z 509 [M +
Na+].
6,7-O-Isop r op ylid en e 5-Deoxyp u lch ellosid e I (5). To 4
(6.60 g, 13.6 mmol) was added 1% aqueous acetic acid (200
mL). The reaction mixture was stirred at room temperature
for 18 h, at which time no more starting material could be
detected by TLC (CH2Cl2-MeOH, 13:2, Rf 0.51 and 0.28 for
diacetonide and monoacetonide, respectively). The reaction was
halted by addition of triethylamine (5 mL). Solid NaCl was
added to the mixture while stirring until the solution was
saturated. The reaction mixture was then extracted four times
with ethyl acetate, and the combined ethyl acetate layers were
dried over Na2SO4, filtered, and evaporated to yield 5 as a
white solid (3.32 g, 55%): 1H NMR (acetone-d6, 300 MHz) δ
7.33 (1H, d, J ) 1.8 Hz, H-3), 5.64 (1H, d, J ) 1.5 Hz, H-1),
4.66 (2H, m, H-6, H-1′), 4.26 (1H, d, J ) 5.4 Hz, H-7), 3.86
(1H, dd, J ) 11.7, 2.1 Hz, H-6′a), 3.68 (3H, s, -CO2CH3), 3.63
(1H, dd, J ) 11.7, 5.7, H-6′b), 3.30-3.45 (3H, m, H-3′, H-4′,
H-5′), 3.21 (1H, dd, J ) 8.1, 8.1 Hz, H-2′), 2.84 (1H, m, H-5),
2.80 (1H, m, H-9), 2.38 (1H, m, H-8), 1.40, 1.24 (6H, s,
isopropylidene -CH3’s), 0.96 (3H, d, J ) 7.8 Hz, H-10); ESMS
m/z 469 [M + Na+], 447 [M + H+].
6,7-O-Isop r op ylid en e 5-Deoxyp u lch ellosid e I Tetr a a c-
eta te (6). Compound 5 (2.44 g, 5.5 mmol) was treated with
Ac2O (10 mL) and pyridine (10 mL) at room temperature for
24 h. The reaction mixture was suspended in 10 mL of H2O
and then subsequently extracted three times with CHCl3 (10
mL each). The combined CHCl3 layers were extracted twice
with 1 N HCl (50 mL each), once with 5% NaHCO3 (50 mL),
and once with saturated NaCl (50 mL). The CHCl3 layer was
dried over Na2SO4, filtered, and evaporated to yield 6 as a tan
solid (3.09 g, 92%): 1H NMR (CDCl3, 300 MHz) δ 7.23 (1H, d,
J ) 1.2 Hz, H-3), 5.34 (1H, d, J ) <0.6 Hz, H-1), 5.13 (1H, dd,
J ) 9.6, 9.6 Hz, H-3′), 5.02 (1H, dd, J ) 9.6, 9.6 Hz, H-4′),
4.89 (1H, dd, J ) 9.6, 7.8 Hz, H-2′), 4.81 (1H, d, J ) 7.8 Hz,
H-1′), 4.54 (1H, dd, J ) 5.4, <0.6 Hz, H-6), 4.16-4.24 (2H, m,
H-7, H-6′b), 4.07 (1H, dd, J ) 12.3, 2.1 Hz, H-6′a), 3.66-3.70
(4H, m, H-5′, -CO2CH3), 2.88 (1H, ddd, J ) 9.0, 8.7, <0.6 Hz,
H-9), 2.76 (1H, ddd, J ) 9.0, 1.2, <0.6 Hz, H-5), 2.37 (1H, ddd,
J ) 9.3, 8.7, 7.8, H-8), 2.02, 1.95, 1.92, 1.80 (12H, s, acetate
-CH3’s), 1.38, 1.20 (6H, s, isopropylidene -CH3’s), 0.87 (3H,
d, J ) 7.8 Hz, H-10); ESMS m/z 637 [M + Na+].
Ca u d a tosid e A P en ta a ceta te (10). To 8 (4 mg, 5.6 µmol)
were added 0.5 mL of pyridine and 0.5 mL of acetic anhydride.
The reaction mixture was stirred at room temperature for 24
h. The reaction mixture was then suspended in 10 mL of H2O
and subsequently extracted three times with CHCl3 (10 mL
each). The combined CHCl3 layers were extracted twice with
1 N HCl (10 mL each), once with 5% NaHCO3 (10 mL), and
finally once with saturated NaCl (10 mL). Each CHCl3 layer
was dried over Na2SO4, filtered, and evaporated to yield 10 (4
mg, 94%). 1H NMR data for 10 were identical to data
previously reported.1
Ca u d a tosid e A (2). To 10 (11 mg, 0.015 mmol) was added
0.5 mL of dry methanol with stirring at room temperature.
Then, 30 µL of concentrated NH4OH was added to the mixture
and was allowed to stir for 24 h. The reaction mixture was
neutralized with acetic acid and separated by silica gel
preparative TLC (9:1 CH2Cl2-MeOH). The band corresponding

224 J ournal of Natural Products, 2004, Vol. 67, No. 2
Notes
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M.; Rodewald, H. Liebigs Ann. Chem. 1984, 761-772.
(8) Raj, K.; Mathad, V. T.; Bhaduri, A. P. Indian J . Chem. 1996, 35B,
1056-1061.
to Rf 0.14 was scraped and desorbed with 4:1 CH2Cl2-MeOH
to yield 2 (4 mg, 51%). 1H NMR data were identical to data
previously obtained for 2.1
Ack n ow led gm en t. This work was supported by a grant
from the Thomas F. J effress and Kate Miller J effress Memorial
Trust, and the Department of Chemistry at VCU.
(9) Franzyk, H.; Frederiksen, S. M.; J ensen, S. R. J . Nat. Prod. 1997,
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(10) Chung, S.-K.; Moon, S.-H. J . Chem. Soc., Chem. Commun. 1992, 77-
79.
(11) (a) Neilson, T.; Werstiuk, E. S. Can. J . Chem. 1971, 49, 493-499. (b)
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NP0303613