Total synthesis of candicanoside A, a rearranged cholestane disaccharide, and its 4″-O-(p-methoxybenzoate) congener

Article abstract of DOI:10.1002/ejoc.200800879

Candicanoside A (1) and its 4″-O-(p-methoxybenzoate) derivative 2 are congeners of the novel 24(23→22)abeo-cholestane glycosides that occur in the genus Ornithogalum indigenous to Southern Africa and have remarkable cytostatic activities. These two saponi

Full text of DOI:10.1002/ejoc.200800879

FULL PAPER
DOI: 10.1002/ejoc.200800879
Total Synthesis of Candicanoside A, a Rearranged Cholestane Disaccharide,
and Its 4ЈЈ-O-(p-Methoxybenzoate) Congener
Pingping Tang[a] and Biao Yu*[a]
Keywords: Glycosylation / Steroids / Synthesis design / Natural products
Candicanoside A (1) and its 4ЈЈ-O-(p-methoxybenzoate) de- ates as the donors. The synthesis of the rearranged steroid
rivative 2 are congeners of the novel 24(23Ǟ22)abeo-choles-
tane glycosides that occur in the genus Ornithogalum indige-
nous to Southern Africa and have remarkable cytostatic ac-
tivities. These two saponins have been synthesized starting
aglycon employs a 20-alkoxy radical-mediated functionaliza-
tion of the angular 18-methyl group, a Johnson–Claisen re-
arrangement for the alkylation at C-20, an aldol condensa-
tion at C-22, and a photodeconjugation of an α,β-unsaturated
lactone as the key steps.
from dehydroisoandrosterone, D-glucose, and L-rhamnose in
37 and 44 steps, respectively. The reaction protocols feature
a stereocontrolled stepwise glycosylation with glycosyl imid-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
During the extensive research into the antitumor compo-
nents of the genus Ornithogalum indigenous to Southern
Africa,[1] Mimaki, Sashida, and co-workers disclosed a
group of minor saponins that contain rearranged steroidal
side-chains.[2,3] These novel 24(23Ǟ22)abeo-cholestane gly-
cosides, such as 3–6 (Figure 1), exhibit considerable inhibi-
tory activity against the growth of tumor cells depending
on their saccharide structures. Thus, the α--rhamnopyr-
anosyl-(1Ǟ2)-β--glucopyranosides (e.g., 3 and 5) are inac-
tive, whereas their 4ЈЈ-O-(p-methoxybenzoate) (MBz) deriv-
atives (4 and 6) are highly cytostatic towards human leuke-
mia HL-60 cells (IC50 = 0.019 and 0.052 µ, respectiv-
ely).[2d,2e] Candicanoside A (1),[3] isolated from the fresh
bulbs of Galtonia candicans, is unique in this family of sapo-
nins with a fused-ring scaffold resulting from acetal forma-
tion between the aldehyde group at C-23 and the hydroxy
groups at C-16 and C-18. In addition, it is the only conge-
ner to show remarkable cytostatic activity (IC50 = 0.032 µ
against the HL-60 cells) without benzoate substitution on
the saccharide moiety.[2,3] Herein we report a full account
of the total synthesis of Candicanoside A (1) and its 4ЈЈ-O-
(p-methoxybenzoate) derivative 2.[4]
Figure 1. Candicanoside A (1) and its congeners 2–6.
Results and Discussion
The assembly of the target disaccharide saponin 1 de-
mands a mild and stereocontrolled approach to the glycosy-
lation of the cholestane aglycon 7, which contains two
double bonds and an acetal function.[5] Thus, stepwise gly-
cosylation with 3,4,6-tri-O-acetyl-2-O-[2-(azidomethyl)-
benzoyl]--glucopyranosyl trichloroacetimidate (8) and
2,3,4-tri-O-benzoyl--rhamnopyranosyl trichloroacetimid-
ate (9), which requires only a catalytic amount of the Lewis
acid to promote the reaction,[6] was planned (Figure 2). The
[a] State Key Laboratory of Bio-organic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
Fax: +86-21-64166128
E-mail: byu@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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acetyl (Ac) and benzoyl (Bz) groups were permanent pro-
Thus, conversion of the steroidal 3-hydroxy-5,6-ene func-
tecting groups; the 2-(azidomethyl)benzoyl (AZMB) tionality in 12 into the 3,5-cyclo-6β-methoxy form (TsCl,
group,[7] selectively removable in the presence of the acetyl pyridine, room temp., overnight; KOAc, HOMe, reflux, 5 h,
groups, was chosen as a temporary protecting group that is 81%) followed by Wittig olefination at the C-17 ketone
able to serve as a neighboring participating group to control (Ph3PEtBr, tBuOK, THF, reflux, 4 h, 84%) provided 13
the construction of the 1,2-trans-glycosidic bond and mean- (20-H: 5.11 ppm, qd, J = 7.2, 2.1 Hz; Scheme 1).[10] The
while minimize the formation of the corresponding orthoes- allylic 16-CH2 in 13 was oxidized with SeO2 and tBuOOH
ter.[8]
(CH2Cl2, 0 °C, 92%).[10] The resulting 16-α-hydroxy group
(16-H: 4.44 ppm, br. d, J = 4.0 Hz) was then reversed by
Swern oxidation (DMSO, ClCOCOCl, CH2Cl2, –50 °C,
98%) and subsequent reduction (NaBH4, CeCl3·7H2O,
THF, 0 °C, 77%) to afford the 16-β-ol 14 (16-H: 4.35 ppm,
t, J = 7.5 Hz) as the major product.[11] Protecting groups,
including acetyl (Ac), triethylsilyl (TES), tert-butyldimethyl-
silyl (TBS), and benzyl (Bn), on the 16-β-OH of 14 were
found susceptible to the hydroboration (BH3 or 9-BBN)/
oxidation (H2O2) process required to introduce a hydroxy
group at C-20. Thus, 16β,20(S)-diol 15 was prepared from
the corresponding 17(20)-ene-16-O-TES ether (BH3·THF,
45 °C; and then H2O2, Na2CO3, room temp.) stereoselec-
tively in 92% yield (20-H: 4.11 ppm, m). Attempts to mono-
protect the diol in 15 with TBS (TBSOTf, 2,6-lutidine,
CH2Cl2, –78 °C)[12] or the Bz group (Bu2SnO, toluene, re-
flux; and then BzCl, THF, CH2Cl2, room temp.)[13] led to
the 16β-O-TBS and -Bz derivative 16 (63%) or 17 (80%;
16-H: 5.64 ppm, m) as the major product, respectively. The
structure of 16 was unambiguously confirmed by an X-ray
diffraction analysis, which showed the β configuration of
the 16-O-TBS ether and the S configuration at C-20 (Fig-
ure 4).[14]
The presence of 20-OH could facilitate the functionaliza-
tion of the proximal 18-methyl group by 1,5-hydrogen
transfer to the corresponding alkoxyl radical.[15] Thus, irra-
diation of 16 or 17 in the presence of iodine (1.0 equiv.) and
(diacetoxyiodo)benzene (DIB) (1.1 equiv.) in cyclohexane
with a 300-W tungsten lamp at room temp. provided the
desired 18-iodide 18 (18-H: 3.91 and 3.46 ppm, 2 d, AB, J
= 10.5 Hz) or 19 (18-H: 3.91 and 3.57 ppm, 2 d, AB, J =
10.5 Hz), respectively, albeit in moderate yields (22 and
44%, respectively).[16] Most of the starting materials were
recovered, however, increasing the amounts of reagents or
Figure 2. Retrosynthesis of the (1Ǟ2)-linked disaccharides 1 and
2.
The assembly of the 4ЈЈ-O-benzoate congener 2, however,
requires a totally different arrangement of protecting
groups. Thus, 3,4,6-tri-O-(p-methoxybenzyl)-2-O-benzoyl-
-glucopyranosyl trichloroacetimidate (10) and 2,3-di-O-(p-
methoxybenzyl)-4-O-(p-methoxybenzoyl)--rhamnopyran-
osyl trifluoroacetimidate (11) were designed as the mono-
saccharide donors. The orthogonal p-methoxybenzyl
(PMB) and Bz groups were chosen as the permanent and
temporary protecting groups, respectively. Because of the
poor stability of the armed rhamnosyl trichloroacetimidate,
the trifluoroacetimidate counterpart 11 was used instead.[9]
Attempts at the Synthesis of the Steroid Aglycone 7
Starting from the cheap industrial material dehydro- the reaction temperature led to more side-reactions. Ad-
isoandrosterone 12, we planned to commence the synthesis dition of K2CO3 to the reaction mixture to neutralize the
of the novel steroid 7 by installation of C-20 and C-21 at resulting acetic acid, which might affect the 3,5-cyclo-6-
C-17 followed by elaboration of the 16,18,20-triol derivative methoxy function in the substrate, raised the yield of 18 to
C (Figure 3). Acetal formation with the 16,18-dihydroxy 37%.[17] The use of other trivalent organoiodine reagents,
groups would provide compound B, which might undergo that is, [bis(trifluoroacetoxy)iodo]benzene (TFIB) and iodo-
an intramolecular SN2 substitution reaction to furnish the sylbenzene (PhIO), led to similar results.[16] The 20-OH
required fused-ring scaffold.
group should be blocked prior to hydrolysis of the 18-iodide
Figure 3. Retrosynthetic consideration of the steroid aglycon 7.
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Total Synthesis of Candicanoside A
Scheme 1. Attempts at the synthesis of the 16,18,20-triol derivative C.
Synthesis of the Steroid Aglycone 7
The previous attempts proved that the presence of the
16β-OR substituent affected the functionalization at the
angular C-18 position. Thus, we planned to introduce 18-
OH before elaboration of 16β-OH (Figure 5). C-22 and C-
23 could then be installed at C-20 in diol F (possibly by
allylic alkylation).[19] Introduction of the 16β-OH into E
might facilitate lactone formation to give D, which could
serve as the precursor to the target scaffold.
Thus, the (Z)-17(20)-olefin 13 was subjected to hydro-
boration (9-BBN, THF, room temp.) and oxidation (H2O2,
NaOH, room temp.) to provide the 20-ol 20 stereoselec-
tively (90%; 20-H: 3.71 ppm, m).[20] Irradiation of 20 in the
presence of DIB and I2 under a 300-W tungsten lamp for
30 min followed by oxidation of the 20-OH immediately
Figure 4. ORTEP drawing of compound 16.
to avoid 18,20-anhydro formation. However, the 20-OH with pyridinium chlorochromate (NaOAc, CH2Cl2, room
group in the 16β-O-TBS ether 18 was found to be inert temp.) provided the desired 18-iodo-20-ketone 21 (18-H:
towards protection with TBS or the methoxymethyl 3.36 and 3.21 ppm, 2 d, AB, J = 10.5 Hz) in a satisfactory
(MOM) group. Even acetylation under forced conditions 50% yield (cf. 16/17Ǟ18/19).[17] Hydrolysis of the 18-iodide
(AcCl, pyridine, 50 °C, overnight) failed to provide the cor- in 21 with AgOAc (dioxane, H2O, 65 °C) proceeded
responding 20-O-acetate. In contrast, 20-OH in the 16β-O- smoothly, furnishing the 18,20-hemiketal 22 (18-H: 3.80
Bz ester 19 was easily protected with a TBS or MOM and 3.40 ppm, 2 d, AB, J = 9.0 Hz) in an excellent 92%
group. Unfortunately, the resulting 16-O-Bz-20-O-TBS(or yield (cf. 18/19ǞC).[17] Reduction of 22 with NaBH4
MOM)-18-iodide derivatives either stayed intact (Ag2CO3 (CH2Cl2, MeOH, room temp.) yielded a mixture of the
or Ag2O, dioxane, H2O, 60 °C) or led to the 18,20-epoxy 18,20(R/S)-diols, which was subjected to selective acety-
derivatives (mCPBA, CH2Cl2, H2O, room temp.)[18] under lation (AcCl, pyridine, –20 °C) to provide the 18-acetoxy-
hydrolytic conditions. These results might be explained by 20(R)-ol 23 (18-H: 4.40 and 3.90 ppm, 2 d, AB, J = 11.4 Hz;
the stereohindrance of the 18-iodide in the presence of the 20-H: 3.67 ppm, m) as an easily isolable major product
proximal 16,17-β-substituents (Scheme 1).
(50% for two steps) (Scheme 2).[21]
Figure 5. Reconsideration of the synthesis of the steroid aglycon 7.
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We then envisioned alkylation at C-20 from the α face
of the steroid. Thus, Johnson–Claisen rearrangement of a
17(20)-en-16α-ol substrate (via the intermediates G and H,
Scheme 4) turned out to be the choice. Treatment of 20-ol
23 with POCl3 in pyridine at 0 °C yielded (Z)-17(20)-olefin
27 (79%; 20-H: 5.29 ppm, q, J = 7.2 Hz),[26] which was sub-
jected to allylic oxidation with SeO2 and tBuOOH (CH2Cl2,
0 °C) to afford the required 16α-ol 28 stereoselectively
(82%; 16-H: 4.51 ppm, br. s).[27] Heating the allylic alcohol
28 at 140 °C with CH3C(OCH3)3 in the presence of a cata-
lytic amount of propionic acid gave the expected ester 29
(16-H: 5.53 ppm, br. s; H-21: 1.03 ppm, d, J = 7.2 Hz) in a
stereoselective manner and in excellent yield (87%) with the
3,5-cyclo-6-methoxy protection intact.[28] The R configura-
tion at C-20 is secured by the transition state H of the John-
son–Claisen rearrangement and confirmed by X-ray diffrac-
tion analysis of a derivative.[4]
Attempts to introduce a hydroxy group at C-16 in 29 by
hydroboration/oxidation were found problematic under a
variety of conditions; both the 18-O-Ac group and the C-
23 ester could be reduced with boron hydrides. Thus, the
18-O-Ac group was removed (NaOMe, MeOH, CH2Cl2,
room temp.) and the resulting hydroxy group was protected
with TBS ether (TBSOTf, 2,6-lutidine, room temp.), leading
to compound 30 (90%). Hydroboration/oxidation of 30 led
to diol 31 (16-H: 4.22 ppm, m; 23-H: 3.86 and 3.73 ppm,
m) as the major product in moderate yields (40–60%). In-
stead, the 23-ester in 30 was first reduced into the corre-
sponding alcohol with LiAlH4 (THF, room temp.) and sub-
sequent treatment of the resulting 16(17)-en-23-ol with BH3
(THF, 0 °C) followed by H2O2 and NaOH afforded the de-
sired 16α,23-diol 31 stereoselectively in good yield (80%).
We did try to protect the 18-OH with TBS ether instead of
the acetate in 22Ǟ23, however, the resulting 18-O-TBS-20-
ol failed to provide the desired 17(20)-ene with POCl3 (cf.,
23Ǟ27).
Scheme 2. Synthesis of the 18,20-diol derivative 23.
The desired allylic 20-acetate 26 was then readily pre-
pared from 20-ol 23 (Scheme 3); oxidation of 23 with PCC
(NaOAc, CH2Cl2, room temp.) provided 20-ketone 24
(92%). Bromination [NBS, (PhCO)2, CCl4, reflux][22] of 24
followed by elimination (Li2CO3, LiBr, DMF, 120 °C)[23]
yielded the enone 25 in 45% yield (16-H: 6.87 ppm, m).
Reduction of the 20-ketone in 25 with BH3·SMe2 in the
presence of an equimolar amount of the chiral oxazaboroli-
dine (R)-CBS {(R)-1-methyl-3,3-diphenyltetrahydro-3H-
pyrrolo[1,2-c][1,3,2]oxazaborole} (purchased from Aldrich)
in THF at –45 °C afforded the 20(S)-alcohol,[24] which was
directly subjected to acetylation to provide the acetate 26
(80% for two steps; 20-H: 5.61 ppm, m). Unfortunately,
treatment of 26 with [Pd(PPh3)4], Ph3P, and NaCH-
(CO2CH3)2 in THF did not lead to the alkylation product
E. It might be that the additional 18-acetoxy group in 26,
Swern oxidation of diol 31 (ClCOCOCl, DMSO, Et3N,
compared with the steroid substrates used by Trost and Ver- CH2Cl2) followed by further oxidation of the resulting 23-
hoeven for a similar alkylation,[25] led to the formation of a aldehyde (NaClO2, Na2HPO4, 2-methyl-2-butene, tBuOH,
π-allylpalladium complex with the palladium at the α face room temp.) into the carboxylic acid[29] and subsequent
and then prevented the approach of the dimethyl malonate methyl ester formation (CH2N2, ether, room temp.) pro-
from the β face.
vided the 16-keto 23-methyl ester 32 in 87% yield (for three
Scheme 3. Preparation of the allylic acetate 26 and attempts at allylic alkylation.
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Total Synthesis of Candicanoside A
Scheme 4. Synthesis of lactone 33.
steps). Selective reduction of the 16-ketone into the 16β-ol temp.) to provide the α,β-unsaturated lactone 34 (24-H:
was achieved with LiAlH(tBuO)3 in THF at room temp.[30] 5.54 ppm, dd, J = 9.9, 2.7 Hz) in 50% yield. For the aldol
and simultaneous intramolecular lactone formation af- reaction we also tried KHMDS as base,[33] the presence of
forded 33 (81%; 16-H: 4.69 ppm, m). Other reducing HMPA in the solvent, and Bu2BOTf/diisopropylethylam-
[31]
agents, such as NaBH4/CeCl3
and -selectride,[32] led to ine,[34] but no improvements in the yields and stereoselecti-
considerable amounts of the over-reduced acetal products.
vities were found. Rearrangement of the conjugated 22,24-
The rest of the side-chain C-24–27 was then introduced double bond (in lactone 34) into the unconjugated 24,25-
onto C-22 (in lactone 33) by aldol condensation double bond was fortunately achieved by ultraviolet light
(Scheme 5). Thus, treatment of 33 with LDA in THF at (λ = 254 nm) irradiation,[35] providing 35 as a single stereo-
–78 °C followed by the addition of isobutyraldehyde pro- isomer (at C-22) in an excellent 90% yield. Other methods
vided a diastereoisomeric mixture of the aldol adduct I, such as the use of DBU or LDA as base did not lead to
which was dehydrated directly (POCl3, pyridine, room the desired product.
Scheme 5. Completion of the synthesis of the aglycon 7.
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NOE correlations between 22-H (δ = 2.89 ppm, dd, J = glucose in five steps (20%) by a literature procedure.[39]
12.3, 9.8 Hz) and 16-H (δ = 4.75 ppm, m), 24-H (δ = Then 3,4,6-tri-O-PMB-1,2-orthoester 39 was converted into
5.06 ppm, d, J = 9.6 Hz) and 20-H (2.35–2.27 ppm, m), but the desired α-trichloroacetimidate 10 (1-H: 6.61 ppm, d, J
not between 22-H and 20-H, were found, which proved the = 3.0 Hz) in five routine steps and in a good 61% overall
desired R configuration at C-22.
yield. These steps include 1) cleavage of the orthoester
The lactone 35 was then reduced with -selectride and (Dowex H+, EtOH, room temp.) to afford the correspond-
the resulting lactol lithium was trapped in situ with acetic ing 2-O-acetyl derivative, 2) removal of the resulting Ac
anhydride to give the acetate 36 in 97% yield (23-H: group (NaOMe, MeOH, THF, room temp.), 3) protection
5.73 ppm, d, J = 7.8 Hz).[36] Finally, HF (40% in water, of the resulting 1,2-diol with Bz groups (BzCl, Et3N,
CH3CN, room temp.) was applied to remove the 18-O-TBS DMAP, CH2Cl2, room temp.), 4) selective removal of the
group in 36. The desired 18,23-acetal was formed simulta- anomeric Bz group (NH3, THF, MeOH, room temp.), and
neously. Meanwhile the 3-hydroxy-5,6-ene was recovered 5) α-trichloroacetimidate formation (CNCCl3, DBU,
from the 3,5-cyclo-6-methoxy protection, which had stayed CH2Cl2, room temp.).
intact since the beginning of the synthesis, furnishing the
1
desired aglycon 7 in 85% yield. The diagnostic H NMR
signals include those of 3-H (δ = 3.52 ppm, m), 6-H (δ =
5.37 ppm, m), 16-H (δ = 4.55 ppm, m), 18-H (3.98 and
3.46 ppm, 2 d, AB, J = 12.6 Hz), 23-H (δ = 4.99 ppm, d, J
= 3.9 Hz), and 24-H (δ = 5.16 ppm, d, J = 9.6 Hz). Thus,
the aglycon 7 was successfully elaborated in 23 steps and in
1.5% overall yield from the industrial material dehydro-
isoandrosterone 12.
Preparation of the Monosaccharide Donors 8–11
Scheme 7. Preparation of the glucopyranosyl trichloroacetimidate
10.
The required perbenzoyl rhamnosyl trichloroacetimidate
9 was easily prepared from -rhamnose in three steps (76%
yield).[37] Three other imidate donors 8, 10, and 11 were
synthesized as shown in Schemes 6, 7, and 8. The 2-OH of
allyl 4,6-O-benzylidene-α--glucopyranoside could be selec-
tively acylated with AZMBCl to give 37 (Scheme 6).[7d] Re-
moval of the anomeric allyl group in the presence of a 4,6-
O-benzylidene group might be problematic.[38] Thus, the
4,6-O-benzylidene group in 37 was removed (70% HOAc,
70 °C) and the resulting 3,4,6-triol was then acetylated
(Ac2O, Et3N, DMAP, CH2Cl2, room temp.) to provide 38
(86%). Cleavage of the α-allyl group in 38 proceeded well
with PdCl2 in a mixture of CH2Cl2 and MeOH at room
temp. The resulting lactol was treated with CNCCl3 in the
presence of a catalytic amount of DBU (CH2Cl2, room
temp.) to afford the desired α-trichloroacetimidate 8 in ex-
cellent yield (90%; 1-H: 6.71 ppm, d, J = 3.0 Hz).
Allyl 2,3-O-isopropylidene-α--rhamnopyranoside (40),
prepared from -rhamnose in two steps,[40] was treated with
MBzCl in the presence of Et3N and DMAP (CH2Cl2, room
temp.) to provide the 4-O-MBz derivative 41 (97%; 4-H:
5.12 ppm, dd, J = 9.6, 8.1 Hz; Scheme 8). The isopropylid-
ene group was then removed cleanly with 70% HOAc at
70 °C (90%) and the resulting 2,3-OH groups were pro-
tected with PMB groups (PMBBr, NaH, THF, room temp.)
to give 42 (70%). Removal of the anomeric allyl group was
achieved with PdCl2 in a mixture of CH2Cl2 and MeOH at
room temp. (89%) and the resulting lactol was converted
readily into the desired trifluoroacetimidate 11 [ClC(NPh)-
CF3, K2CO3, acetone, room temp., 92%], which could be
purified by flash column chromatography on silica gel and
Scheme 6. Preparation of the glucopyranosyl trichloroacetimidate
8.
In the synthesis of the glucopyranosyl trichloroacetimid-
ate 10, the 1,2-OH groups of glucopyranose were distin-
guished from the 3,4,6-OH groups by 1,2-orthoester forma-
Scheme 8. Preparation of the rhamnopyranosyl trifluoroacetimid-
tion (Scheme 7). Thus, compound 39 was prepared from - ate 11.
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Total Synthesis of Candicanoside A
used directly in the subsequent glycosylation reaction.[9] signals include 1Ј-H (δ = 5.05 ppm, d, J = 6.3 Hz), 1ЈЈ-H (δ
The corresponding trichloroacetimidate counterpart de- = 6.40 ppm, br. s), 3-H (δ = 3.96 ppm, m), 6-H (δ =
composed completely upon silica gel chromatography.
5.37 ppm, d, J = 9.0 Hz), 16-H (δ = 4.66 ppm, m), 18-H
(4.04 and 3.55 ppm, 2 d, AB, J = 13.0 Hz), and 24-H (δ =
5.43 ppm, d, J = 9.0 Hz).
Synthesis of Candicanoside A (1)
Glycosylation of steroid 7 with glucosyl trichloroacetim-
idate 8 bearing an AZMB group at 2-OH and promoted by
TMSOTf (0.05 equiv.) in CH2Cl2 at 0 °C provided the de-
sired β-glycoside 43 in only moderate yield (ca. 40%). The
major byproduct was believed to be the corresponding or-
thoester. Therefore, TfOH was used instead as the pro-
moter; the glycosylation reaction was completed in the pres-
ence of 0.2 equiv. of TfOH at room temp. within 1 h, fur-
nishing 43 (1Ј-H: 4.75 ppm, d, J = 7.8 Hz) in an excellent
96% yield (Scheme 9). X-ray diffraction analysis of com-
pound 43 not only proved the nascent β-glycosidic configu-
ration, but also confirmed unambiguously the correctness
of the synthesized aglycon (Figure 6). The 2Ј-O-AZMB
group in 43 was removed cleanly in the presence of the Ac
groups with PBu3 in a wet THF solvent at room temp.[7]
The resulting 2Ј-OH was successfully glycosylated with the
perbenzoyl rhamnopyranosyl trichloroacetimidate 9 under
similar conditions to those used in the previous glycosyla-
tion (0.2 equiv. TfOH, CH2Cl2, room temp.) to provide the
disaccharide 45 in a good 81% yield (two steps; 1ЈЈ-H:
5.02 ppm, d, J = 3.9 Hz). Note that replacement of the per-
benzoyl imidate 9 with its 2,3,4-tri-O-acetyl-rhamnopyr-
anosyl trichloroacetimidate counterpart as the donor did
not lead to the corresponding disaccharide under a variety
of conditions (TfOH or TMSOTf, CH2Cl2, –78 °C to room
temp.).[8] Finally, removal of the three Ac and three Bz
groups on the saccharide residue in 45 was achieved with
NaOMe in a mixed solvent of MeOH and THF at room
temp., furnishing the target Candicanoside A (1) in 90%
yield. The analytical data for 1 are in good agreement with
Figure 6. ORTEP drawing of compound 43.
Synthesis of the 4ЈЈ-O-MBz Derivative 2
As with the previous coupling of steroid 7 with glucosyl
imidate 8, glycosylation of 7 with 3,4,6-tri-O-PMB-2-O-Bz-
-glucopyranosyl trichloroacetimidate (10) proceeded
smoothly under the promotion of TfOH (0.1 equiv.) in
CH2Cl2 at room temp. to provide the corresponding β-gly-
coside in 87% yield (Scheme 10). The 2-O-Bz group in the
resulting glycoside was removed cleanly with NaOMe in a
mixture of MeOH and THF at room temp. to afford 46
1
those reported in the literature.[3] The diagnostic H NMR
Scheme 9. Completion of the synthesis of candicanoside A (1).
Scheme 10. Completion of the synthesis of compound 2.
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265

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ybdic acid (PMA) or acidic methanol. Optical rotations were mea-
sured at the sodium D-line at ambient temperature with a Perkin-
(91%). Glycosylation of the 2Ј-OH in 46 with the newly
prepared 2,3-di-O-PMB-4-O-MBz--rhamnopyranosyl tri-
fluoroacetimidate (11) under slightly modified conditions to
those used for the previous glycosylation (0.2 equiv. TfOH,
toluene, –15 °C to room temp.) led to the desired disaccha-
ride 47 stereoselectively in good yield (81%; 1ЈЈ-H:
5.38 ppm, br. s). Attempts to remove the five PMB groups
in 47 with DDQ led to complex mixtures. Gratifyingly,
1
Elmer 241MC polarimeter. H NMR and 13C NMR spectra were
recorded with a Bruker Avance spectrometer at 300 and 75 MHz,
respectively. Chemical shifts of 1H NMR and 13C NMR spectra are
reported in ppm with a solvent resonance as an internal standard.
For the synthesis of compounds 1, 7, 8, 20–23, 27–38, and 43–45,
see the Supporting Information in ref.[4]
these PMB groups could be cleaved cleanly with 10% TFA 16,20-Diol 15: 2,6-Lutidine (1.20 mL, 10.1 mmol) and TESOTf
(0.92 mL, 4.04 mmol) were added to a solution of 14[11] (666 mg,
2.02 mmol) in dry CH2Cl2 (5 mL). After stirring at room temp. for
1 h, the mixture was diluted with CH2Cl2. The organic layer was
washed with NaHCO3, dried with Na2SO4, and filtered. The fil-
trate was concentrated in vacuo to give a residue, which was puri-
fied by column chromatography on silica gel (petroleum ether/
EtOAc, 20:1) to give the corresponding 16-O-TES ester as a color-
less oil (896 mg, 100%). BH3·THF (1.0  in THF, 10 mL) was
added to a solution of the resulting oil (896 mg, 2.02 mmol) in dry
THF (10 mL). After being stirred at 45 °C overnight, the mixture
was cooled in an ice bath and then saturated aqueous NaHCO3
(30 mL) was added slowly, followed by the addition of 30% aque-
ous H2O2 (20 mL) over a period of 10–15 min. The resulting sus-
pension was stirred at 0 °C for 2 h and then extracted twice with
EtOAc. The combined organic layers were washed with 10%
NaHSO4, water, and brine, respectively, and then dried, and the
solvents evaporated. The residue was purified by silica gel column
chromatography (petroleum ether/EtOAc, 3:1) to afford 15
in CH2Cl2 at room temp.[41] to furnish the target compound
2 in 85% yield. Comparison of the H NMR spectra of 1
and 2 shows the presence of the MBz group at 4ЈЈ-OH in 2
leads to the downfield shift of 4ЈЈ-H from 4.36 ppm (in 1)
to 6.22 ppm (in 2; dd, J = 9.9, 9.2 Hz).[2]
1
Conclusions
Candicanoside A (1) and its 4ЈЈ-O-(p-methoxybenzoate)
derivative 2 are congeners of the novel 24(23Ǟ22)abeo-cho-
lestane glycosides that occur in the genus Ornithogalum in-
digenous to Southern Africa and have remarkable cytostatic
activity. These two (1Ǟ2)-linked disaccharides (1 and 2)
have been synthesized by stepwise glycosylation with mono-
saccharide imidate donors 8–11 to form the glycosidic
bonds in a stereocontrolled manner. The additional MBz
group in 2 demanded a totally different protecting group
arrangement (PMB as permanent and Bz as temporary pro-
tecting groups) compared with that employed in the synthe-
sis of 1 (Ac and Bz as permanent and AZMB as temporary
protecting groups). The rearranged steroid aglycon 7 was
synthesized starting from dehydroisoandrosterone in 23
steps and 1.5% overall yield. Key steps include the 20-alk-
oxy radical-mediated functionalization of the angular 18-
(645 mg, 92%) as a white foam. [α]2D3 = 59.3 (c = 1.1, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 4.50–4.45 (m, 1 H), 4.15–4.08 (m, 1
H), 3.31 (s, 3 H), 2.77 (t, J = 2.8 Hz, 1 H), 2.26–2.19 (m, 1 H), 1.27
(d, J = 6.4 Hz, 3 H), 1.04 (s, 3 H), 0.91 (s, 3 H), 0.65–0.63 (m, 1
H), 0.44–0.41 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
82.2, 73.2, 66.5, 63.0, 56.5, 54.0, 48.0, 43.4, 41.5, 39.7, 35.6, 35.2,
35.0, 33.3, 29.7, 24.9, 23.4, 22.2, 21.5, 19.3, 14.3, 13.1 ppm. HRMS
(ESI): calcd. for C22H36NaO3 [M + Na]+ 371.2562; found 371.2565.
methyl group (20Ǟ21), Johnson–Claisen rearrangement for 16-O-TBS-20-ol 16: A solution of 15 (78 mg, 0.22 mmol) in dry
CH2Cl2 (1 mL) was cooled to –78 °C and then 2,6-lutidine
(0.08 mL, 0.66 mmol) and TBSOTf (0.06 mL, 0.24 mmol) were
added. The mixture was stirred at this temperature for 2 h and then
MeOH was added and diluted with CH2Cl2. The organic layer was
washed with NaHCO3, dried with Na2SO4, and filtered. The fil-
trate was concentrated in vacuo to give a residue, which was puri-
fied by silica gel column chromatography (petroleum ether/EtOAc,
20:1) to give 16 (63 mg, 63%) as a white foam. 1H NMR (300 MHz,
CDC13): δ = 4.56–4.50 (m, 1 H), 4.15–4.09 (m, 1 H), 3.38 (s, 3 H),
3.11 (m, 1 H), 2.82 (m, 1 H), 2.24–2.15 (m, 1 H), 1.26 (d, J =
the alkylation at C-20 (28Ǟ29), aldol condensation at C-22
(33Ǟ34), ultraviolet-light-induced deconjugation of the
α,β-conjugated lactone (34Ǟ35), and simultaneous acetal
formation upon deprotection of the 18-O-TBS ether with
HF (36Ǟ7). The stereochemistry of the transformations
was well controlled by the substrates (except for the CBS
reduction of 25Ǟ26) and was unambiguously confirmed by
X-ray diffraction analysis of the key compounds (16, 18,
and 43). The natural saponin 1 and its congener 2 were
successfully synthesized from dehydroisoandrosterone, - 6.3 Hz, 3 H), 1.08 (s, 3 H), 0.95 (s, 3 H), 0.87 (s, 9 H), 0.66 (d, J =
4.5 Hz, 1 H), 0.45 (dd, J = 7.8, 5.1 Hz, 1 H), 0.10 (s, 6 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 82.2, 74.2, 65.9, 63.4, 56.7, 54.3,
48.2, 43.5, 41.6, 39.6, 37.5, 35.6, 34.9, 33.3, 29.8, 25.8, 24.9, 22.4,
22.2, 21.1, 19.2, 17.7, 14.3, 13.3 ppm.
glucose, and -rhamnose in 37 (1.0% yield) and 44 steps
(0.8% overall yield), respectively.
Experimental Section
16-O-Bz-20-ol 17: Bu2SnO (173 mL, 0.69 mmol) was added to a
solution of 15 (100 mg, 0.29 mmol) in dry toluene (5 mL). The
mixture was stirred at reflux for 3 h and was then cooled to room
temp. and concentrated in vacuo. The residue was dissolved in THF
and CH2Cl2 (v/v 4:1, 5 mL) and cooled to 0 °C. Then BzCl
(0.07 mL, 0.60 mmol) was added. After stirring at room temp. for
12 h, the mixture was diluted with CH2Cl2. The organic layer was
washed with NaHCO3, dried with Na2SO4, and filtered. The fil-
trate was concentrated in vacuo to give a residue, which was puri-
fied by silica gel column chromatography (petroleum ether/EtOAc,
8:1) to give 17 (114 mg, 80%) as a white foam. [α]2D0 = 21.6 (c =
General: All solvents were distilled prior to use except where noted.
Commercially available reagents were used without further purifi-
cation unless otherwise stated. All reactions sensitive to moisture or
oxygen were conducted under an atmosphere of nitrogen or argon.
Crushed 4 Å molecular sieves were activated by thorough flame-
drying immediately prior to use. Flash column chromatography
was performed on silica gel H (10–40 µ). Analytical thin layer
chromatography (TLC) was performed on glass plates pre-coated
with a 0.25 mm thickness of silica gel. The TLC plates were visual-
ized with UV light and/or by staining with ethanolic phosphomol-
266
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Total Synthesis of Candicanoside A
1.1, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 8.03–8.00 (m, 2 H), ture was stirred at 120 °C for 3 h and was then cooled to room
7.58–7.56 (m, 1 H), 7.48–7.43 (m, 2 H), 5.66–5.62 (m, 1 H), 4.10–
temp. and diluted with CH2Cl2. The organic layer was washed with
4.05 (m, 1 H), 3.32 (s, 3 H), 2.78 (br. s, 1 H), 2.56–2.46 (m, 1 H), NaHCO3, dried with Na2SO4, and filtered. The filtrates were con-
1.30 (d, J = 6.5 Hz, 3 H), 1.09 (s, 3 H), 1.05 (s, 3 H), 0.68–0.65 (m, centrated in vacuo to give a residue, which was purified by silica
1 H), 0.47–0.43 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = gel column chromatography (petroleum ether/EtOAc, 10:1) to af-
166.7, 133.0, 130.2, 129.5, 128.4, 82.1, 76.4, 65.1, 63.3, 56.5, 54.4,
47.8, 43.3, 41.9, 39.2, 35.2, 34.8, 34.3, 33.2, 29.8, 24.9, 22.2, 22.1,
ford 25 (90 mg, 45%) as a white foam. [α]2D3 = 94.8 (c = 0.9, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 6.86 (s, 1 H), 4.43 and 4.02 (2
21.5, 19.2, 13.4, 13.0 ppm. HRMS (ESI): calcd. for C29H40NaO4 d, J = 11.2 Hz, 2 H, AB), 3.34 (s, 3 H), 2.79 (br. s, 1 H), 2.62–2.57
[M + Na]+ 475.2816; found 475.2819.
(m, 1 H), 2.31–2.28 (m, 3 H), 2.26 (s, 3 H), 1.96 (s, 3 H), 1.05 (s, 3
H), 0.68 (t, J = 4.3 Hz, 1 H), 0.45 (dd, J = 7.6, 5.6 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 196.3, 171.2, 151.4, 146.1, 81.8,
65.0, 56.7, 56.6, 49.9, 48.4, 43.5, 35.4, 35.1, 33.0, 32.7, 31.8, 29.0,
27.2, 24.8, 22.2, 21.2, 21.0, 19.2, 13.2 ppm. HRMS (ESI): calcd. for
C24H34NaO4 [M + Na]+ 409.2355; found 409.2356.
18-Iodide 18: A degassed mixture of 16 (64 mg, 0.14 mmol), DIB
(89 mg, 0.27 mmol), iodine (35 mg, 0.14 mmol), and K2CO3
(38 mg, 0.27 mmol) in dry cyclohexane (2 mL) was irradiated with
visible light (300-W tungsten filament lamp) for 2 h at reflux. The
solution was washed with saturated aqueous Na2S2O3 and the or-
ganic phase was dried (Na2SO4), filtered, and concentrated in
vacuo. The residue was purified by silica gel column chromatog-
raphy (petroleum ether/EtOAc, 30:1) to afford 18 (30 mg, 37%) as
18,20-Diacetoxy-16(17)-ene 26: (R)-CBS (1.26  in toluene,
0.30 mL, 0.37 mmol) and BH3·SMe2 (5  in THF, 0.15 mL,
0.75 mmol) were added to a stirred solution of 25 (50 mg,
0.13 mmol) in dry THF (2 mL) at –45 °C. After stirring for 1 h at
–45 °C, the reaction was quenched with MeOH and the mixture
was concentrated in vacuo. The residue was dissolved in CH2Cl2
(2 mL) and then Et3N (0.09 mL, 0.65 mmol), DMAP (5 mg,
0.04 mmol), and Ac2O (0.05 mL, 0.53 mmol) were added. The mix-
ture was stirred for 4 h at room temp. The reaction was quenched
with MeOH and the mixture concentrated in vacuo. The residue
was purified by silica gel column chromatography (petroleum ether/
1
a white foam. H NMR (300 MHz, CDC13): δ = 4.56–4.51 (m, 2
H), 3.92 and 3.45 (2 d, J = 10.5 Hz, 2 H, AB), 3.36 (s, 3 H), 2.81
(m, 1 H), 2.36–2.24 (m, 2 H), 1.36 (d, J = 6.0 Hz, 3 H), 1.03 (s, 3
H), 0.95 (s, 3 H), 0.91 (s, 9 H), 0.66 (d, J = 4.5 Hz, 1 H), 0.47 (dd,
J = 7.8, 5.1 Hz, 1 H), 0.10 (s, 6 H) ppm.
18-Iodide 19: A degassed solution of 17 (90 mg, 0.20 mmol), DIB
(78 mg, 0.22 mol), and iodine (56 mg, 0.22 mmol) in dry cyclohex-
ane (7 mL) was irradiated with visible light (300 W) for 2 h. The
solution was washed with saturated aqueous Na2S2O3 and the or-
ganic phase was dried with Na2SO4 and then filtered and concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (petroleum ether/EtOAc, 6:1) to give 19 (51 mg,
44%) as a white foam. [α]2D4 = 72.6 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDC13): δ = 8.06–8.05 (m, 2 H), 7.62–7.59 (m, 1 H),
7.53–7.48 (m, 2 H), 5.72–5.67 (m, 1 H), 4.66–4.61 (m, 1 H), 3.93
and 3.63 (2 d, J = 10.8 Hz, 2 H, AB), 3.32 (s, 3 H), 2.80 (br. s, 1
H), 2.60–2.52 (m, 1 H), 1.47 (d, J = 6.0 Hz, 3 H), 1.07 (s, 3 H),
0.70–0.68 (m, 1 H), 0.50–0.46 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 166.2, 133.2, 130.0, 129.5, 128.6, 81.8, 76.0, 64.6, 64.1,
56.6, 55.4, 47.8, 44.1, 43.4, 38.6, 35.1, 34.7, 34.4, 33.2, 30.5, 24.8,
23.3, 21.5, 21.4, 19.2, 13.0, 9.5 ppm. HRMS (ESI): calcd. for
C29H39INaO4 [M + Na]+ 601.1788; found 601.1785.
EtOAc, 10:1) to afford 26 (45 mg, 80%) as a white foam. [α]2D7
=
1
42.4 (c = 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ = 5.84 (s, 1
H), 5.62–5.61 (m, 1 H), 4.41 and 3.92 (2 d, J = 10.8 Hz, 2 H, AB),
3.34 (s, 3 H), 2.79 (br. s, 1 H), 2.06 (s, 3 H), 2.05 (s, 3 H), 1.32 (d,
J = 6.4 Hz, 3 H), 1.06 (s, 3 H), 0.68 (t, J = 4.4 Hz, 1 H), 0.46 (dd,
J = 8.0, 5.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
171.5, 170.0, 153.0, 126.7, 81.9, 68.7, 66.4, 57.1, 56.6, 49.1, 48.5,
43.5, 35.3, 35.1, 33.1, 31.3, 31.1, 29.6, 29.1, 24.8, 22.0, 21.8, 21.3,
20.9, 19.2, 13.1 ppm. HRMS (ESI): calcd. for C26H38NaO5 [M +
Na]+ 453.2617; found 453.2614.
2-O-Benzoyl-3,4,6-tri-O-(p-methoxybenzyl)-α-D-glucopyranosyl Tri-
chloroacetimidate (10): Dowex H+ resin (260 mg) was added to a
solution of the orthoester 39[39] (2.6 g, 4.4 mmol) in 95% ethanol
(30 mL). The mixture was stirred for 2 h at room temp. and then
concentrated in vacuo. The residue was dissolved in THF and
MeOH (v/v, 1:1, 20 mL) and NaOMe (23 mg, 0.44 mmol) was
added. The mixture was stirred until TLC indicated the reaction
was finished and was then neutralized with Dowex H+ resin. The
resulting mixture was filtered. The filtrates were concentrated to
give a residue, which was purified by column chromatography on
silica gel (petroleum ether/EtOAc, 3:1) to provide 3,4,6-tri-O-(p-
18-Acetoxy-20-one 24: PCC (342 mg, 1.60 mmol), NaOAc (324 mg,
3.90 mmol), and 4-Å MS were added to a solution of the 20-ol 23
(310 mg, 0.79 mmol) in CH2Cl2 (10 mL). After stirring at room
temp. for 2 h, the mixture was filtered. The filtrates were concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (petroleum ether/EtOAc, 6:1) to give 24 (282 mg,
92%) as a white foam. [α]2D4 = 93.8 (c = 1.1, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 4.19 and 3.85 (2 d, J = 11.4 Hz, 2 H, AB),
3.30 (s, 3 H), 2.77 (m, 1 H), 2.58–2.48 (m, 2 H), 2.36 (m, 1 H), 2.21
(s, 3 H), 1.97 (s, 3 H), 1.01 (s, 3 H), 0.66 (t, J = 4.5 Hz, 1 H), 0.44
(dd, J = 7.8, 5.4 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
208.2, 170.6, 81.8, 62.1, 61.5, 56.5, 56.4, 48.1, 47.9, 43.4, 35.2, 35.0,
33.9, 33.3, 31.3, 30.6, 24.9, 24.0, 22.3, 21.5, 20.4, 19.3, 13.0 ppm.
HRMS (ESI): calcd. for C24H36NaO4 [M + Na]+ 411.2510; found
411.2506.
methoxybenzyl)--glucopyranose (1.88 g, 80%) as
a colorless
syrup. Et3N (1.2 mL, 8.4 mmol), DMAP (34 mg, 0.28 mmol), and
BzCl (0.8 mL, 7 mmol) were added to a solution of the above prod-
uct (1.5 g, 2.8 mmol) in dry CH2Cl2 (20 mL). The mixture was
stirred at room temp. overnight and was then diluted with CH2Cl2.
The organic layer was washed with NaHCO3, dried with Na2SO4,
and filtered. The filtrates were concentrated in vacuo to give a resi-
due, which was purified by column chromatography on silica gel
(petroleum ether/EtOAc, 5:1) to give 1,2-di-O-benzoyl-3,4,6-tri-O-
16(17)-En-18-acetoxy-20-one 25: NBS (130 mg, 0.73 mmol) and (p-methoxybenzyl)--glucopyranoside (1.97 g, 95%) as a colorless
(BzO)2 (30 mg, 0.12 mmol) were added to a solution of 24 (200 mg, syrup. This compound (748 mg, 1 mmol) was dissolved in THF and
0.52 mmol) in CCl4 (5 mL). The mixture was stirred at reflux for
4 h and then filtered. The filtrates were concentrated in vacuo. The
residue was purified by silica gel column chromatography (petro-
leum ether/EtOAc, 15:1) to give a colorless oil, which was dissolved
MeOH (v/v, 1:1, 20 mL) and the solution saturated with dry NH3.
The solution was kept at room temp. overnight and then concen-
trated. The residue was dissolved in a solution of CH2Cl2 (20 mL)
and CCl3CN (0.5 mL, 5.0 mmol) containing DBU (cat). The re-
in DMF (2 mL). Li2CO3 (85 mg, 1.15 mmol) and LiBr (60 mg, sulting mixture was stirred for 2 h at room temp. and then concen-
0.69 mmol) were added to the DMF solution. The resulting mix- trated in vacuo. The residue was purified by silica gel column
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267

P. Tang, B. Yu
FULL PAPER
chromatography (petroleum ether/EtOAc, 3:1) to afford 10
(639 mg, 80%) as a colorless syrup. [α]2D5 = 82.9 (c = 0.9, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 8.47 (s, 1 H), 7.93 (d, J = 7.2 Hz,
K2CO3 (73 mg, 0.53 mmol) and ClC(NPh)CF3 (70 mg, 0.34 mmol)
were added to a stirred mixture of the above product (58 mg,
0.11 mmol) in acetone (2 mL). After stirring at room temp. over-
2 H), 7.55–6.67 (m, 15 H), 6.61 (d, J = 3.3 Hz, 1 H), 5.53 (dd, J = night, the mixture was filtered and concentrated. The residue was
9.6, 3.3 Hz, 1 H), 4.78–4.72 (m, 2 H), 4.60 (d, J = 11.7 Hz, 1 H), purified by flash column chromatography on silica gel (petroleum
4.46 (dd, J = 11.4, 9.3 Hz, 2 H), 4.22 (t, J = 9.6 Hz, 1 H), 4.06–
ether/EtOAc, 5:1) to afford 11 (70 mg, 92%) as a colorless syrup.
4.02 (m, 1 H), 3.89 (m, 1 H), 3.79 (s, 3 H), 3.78 (s, 3 H), 3.72 (s, 3
1H NMR (300 MHz, CDCl3): δ = 8.00 (d, J = 9.0 Hz, 2 H), 7.35–
H), 3.81–3.65 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 6.73 (m, 15 H), 6.10 (m, 1 H), 5.49 (dd, J = 9.9, 9.6 Hz, 1 H), 4.73–
165.3, 160.5, 159.3, 159.2, 159.1, 133.1, 130.1, 130.0, 129.8, 129.7,
129.5, 129.5, 129.3, 128.2, 113.7, 113.6, 94.1, 91.0, 78.9, 76.9, 74.9,
73.5, 73.0, 72.5, 67.4, 55.1, 55.1, 55.0 ppm.
4.58 (m, 2 H), 4.43 (m, 2 H), 3.98–3.75 (m, 12 H), 1.28 (d, J =
6.0 Hz, 3 H) ppm.
β-Glucopyranoside 46:
A mixture of the steroid 7 (5 mg,
0.012 mmol), glucopyranosyl imidate 10 (20 mg, 0.024 mmol), and
powered 4-Å molecular sieves in anhydrous CH2Cl2 (1 mL) was
stirred for 1 h at room temp. under Ar and then a solution of TfOH
in CH2Cl2 (0.1 equiv.) was added. After stirring for 1 h, Et3N was
added and then the resulting mixture was filtered. The filtrates were
concentrated to give a residue, which was purified by column
chromatography on silica gel (petroleum ether/EtOAc, 3:1) to pro-
vide the corresponding glycoside (11 mg, 87%) as a colorless syrup.
NaOMe (cat.) was added to a stirred solution of the above glyco-
side (11 mg, 0.011 mmol) in THF and MeOH (v/v, 1:1, 2 mL). Af-
ter stirring at room temp. overnight, the mixture was neutralized
with Dowex 50-X8 (H+) resin. The resin was filtered off and
washed with CH2Cl2. The filtrate and washings were combined and
concentrated. The residue was purified by silica gel column
chromatography (petroleum ether–EtOAc, 5:1) to give 46 (9 mg,
91%) as a colorless syrup. [α]2D2 = –13.6 (c = 0.4, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.33–7.24 (m, 4 H), 7.08 (d, J = 8.4 Hz, 2
H), 6.88–6.81 (m, 6 H), 5.35 (br. s, 1 H), 5.15 (d, J = 9.0 Hz, 1 H),
5.00 (d, J = 3.9 Hz, 1 H), 4.87–4.73 (m, 3 H), 4.57–4.41 (m, 4 H),
4.33 (d, J = 7.2 Hz, 1 H), 3.98 and 3.64 (2 d, J = 12.6 Hz, 2 H,
AB), 3.80–3.79 (m, 9 H), 3.70–3.45 (m, 7 H), 1.74 (s, 3 H), 1.66 (s,
3 H), 1.18 (d, J = 7.1 Hz, 3 H), 1.01 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 159.5, 159.4, 140.7, 134.6, 131.3, 130.7,
129.5, 129.3, 124.9, 121.8, 114.0, 113.9, 101.5, 98.2, 84.6, 79.0, 77.7,
75.5, 74.9, 74.6, 74.5, 73.2, 73.1, 69.2, 66.6, 55.3, 55.3, 53.8, 53.0,
51.1, 47.5, 45.2, 39.1, 38.6, 37.5, 37.0, 35.6, 32.0, 31.8, 30.4, 29.8,
29.7, 26.1, 23.9, 21.1, 19.3, 18.3 ppm. HRMS (ESI): calcd. for
C57H74NaO11 [M + Na]+ 957.5129; found 957.5123.
Allyl 2,3-O-Isopropylidene-4-O-(p-methoxybenzoyl)-α-L-rhamnopyr-
anoside (41): Et3N (0.67 mL, 4.8 mmol), DMAP (24 mg,
0.2 mmol), and MBzCl (408 mg, 2.4 mmol) were added to a solu-
tion of 40[40] (390 mg, 1.6 mmol) in dry CH2Cl2 (5 mL). The mix-
ture was stirred at room temp. overnight and was then diluted with
CH2Cl2. The organic phase was washed with NaHCO3, dried with
Na2SO4, and filtered. The filtrates were concentrated in vacuo to
give a residue, which was purified by silica gel column chromatog-
raphy (petroleum ether/EtOAc, 15:1) to afford 41 (25 mg, 97%) as
a colorless syrup. [α]2D5 = –8.1 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 8.03–7.99 (m, 2 H), 6.93–6.90 (m, 2 H),
6.00–5.91 (m, 1 H), 5.38–5.24 (m, 2 H), 5.14–5.08 (m, 2 H), 4.36
(dd, J = 7.8, 5.4 Hz, 1 H), 4.26–4.20 (m, 2 H), 4.09–4.03 (m, 1 H),
3.95–3.90 (m, 1 H), 3.87 (s, 3 H), 1.63 (s, 3 H), 1.37 (s, 3 H), 1.22
(d, J = 6.3 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.4,
163.5, 133.5, 131.8, 122.1, 117.8, 113.5, 109.7, 96.1, 75.9, 75.8, 74.6,
68.1, 64.2, 55.4, 27.7, 26.3, 17.0 ppm. HRMS (ESI): calcd. for
C20H26NaO7 [M + Na]+ 401.1575; found 401.1571.
Allyl
2,3-Di-O-(p-methoxybenzyl)-4-O-(p-methoxybenzoyl)-α-L-
rhamnopyranoside (42): Compound 41 (600 mg, 1.59 mmol) was
dissolved in 70% HOAc (6 mL). The mixture was stirred for 4 h at
70 °C and was then concentrated in vacuo. The residue was purified
by silica gel column chromatography (petroleum ether/EtOAc, 2:1)
to afford the corresponding 2,3-diol (485 mg, 90%) as a colorless
syrup. NaH (140 mg, 3.5 mmol) was added to a solution of the diol
(300 mg, 0.89 mmol) in dry THF (10 mL) at 0 °C. The mixture was
stirred for 30 min at this temperature and then PMBBr (700 mg,
3.5 mmol) was added. After stirring at room temp. overnight, the
mixture was diluted with EtOAc and then washed with saturated
aq. NH4Cl, dried with Na2SO4, and filtered. The filtrates were con-
centrated in vacuo to give a residue, which was purified by silica
gel column chromatography (petroleum ether/EtOAc, 5:1) to afford
42 (360 mg, 70%) as a colorless syrup. [α]2D4 = 7.5 (c = 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.96 (d, J = 8.7 Hz, 2 H), 7.31–
6.67 (m, 10 H), 5.88 (m, 1 H), 5.42 (t, J = 9.6 Hz, 1 H), 5.45–5.17
(m, 2 H), 4.80–4.61 (m, 3 H), 4.48 and 4.35 (2 d, J = 11.7 Hz, 2
H, AB), 4.18–4.13 (m, 1 H), 3.98–3.74 (m, 13 H), 1.22 (d, J =
6.0 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.3, 163.5,
159.3, 159.2, 134.0, 131.8, 130.6, 130.5, 129.5, 129.1, 122.9, 116.9,
113.8, 113.9, 113.6, 97.9, 76.9, 74.6, 73.6, 72.7, 71.6, 67.9, 67.3,
55.4, 55.2, 55.1, 17.6 ppm. HRMS (ESI): calcd. for C33H38NaO9
[M + Na]+ 601.2414; found 601.2408.
Disaccharide 47: A mixture of the 46 (8 mg, 0.009 mmol), the newly
prepared rhamnosyl trifluoroacetimidate 11 (16 mg, 0.023 mmol),
and powered 4-Å molecular sieves in anhydrous toluene (1 mL) was
stirred for 1 h at room temp. under Ar. A solution of TfOH in
toluene (0.1 equiv.) was added. After stirring for 1 h, Et3N was
added and the mixture was filtered. The filtrates were concentrated
to give a residue, which was purified by silica gel column
chromatography (petroleum ether/EtOAc, 3:1) to provide 47
(10 mg, 81%) as a white foam. [α]2D2 = 23.1 (c = 0.4, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.87 (d, J = 9.0 Hz, 2 H), 7.27–7.23
(m, 4 H), 7.10–6.99 (m, 6 H), 6.85–6.76 (m, 8 H), 6.66–6.62 (m, 4
H), 5.43–5.38 (m, 3 H), 5.16 (d, J = 9.0 Hz, 1 H), 5.00 (d, J =
4.2 Hz, 1 H), 4.82 and 4.32 (2 d, J = 12.0 Hz, 2 H, AB), 4.64–4.38
(m, 11 H), 3.98 (d, J = 12.9 Hz, 1 H), 3.90–3.85 (m, 4 H), 3.82–
3.79 (m, 6 H), 3.75 (s, 3 H), 3.72–3.71 (m, 6 H), 3.71–3.45 (m, 8
H), 1.75 (s, 3 H), 1.67 (s, 3 H), 1.20 (d, J = 6.3 Hz, 3 H), 0.92 (s,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.4, 163.5, 159.5,
159.4, 159.2, 141.0, 134.6, 131.8, 130.9, 130.7, 130.4, 129.6, 129.3,
2,3-Di-O-(p-methoxybenzyl)-4-O-(p-methoxybenzoyl)-α-L-rhamno-
pyranosyl Trifluoroacetimidate (11): A dark suspension of PdCl2
(10 mg, 0.056 mmol) and compound 42 (70 mg, 0.12 mmol) in
MeOH/CH2Cl2 (v/v, 1:1, 4 mL) was stirred at room temp. until 129.2, 129.1, 128.5, 124.8, 123.0, 121.7, 114.1, 113.9, 113.7, 113.6,
TLC indicated that the reaction was complete. The mixture was
filtered through a pad of Celite. The filtrates were concentrated in
vacuo to give a dark syrup, which was purified by column
chromatography on silica gel (petroleum ether/EtOAc/CH2Cl2,
5:1:1) to give a mixture of the α and β anomers (58 mg, 89%).
100.5, 98.6, 98.2, 86.0, 79.0, 78.4, 75.8, 75.3, 74.6, 74.4, 73.9, 73.2,
72.4, 71.6, 69.1, 67.2, 66.6, 55.5, 55.3, 55.3, 55.2, 53.8, 52.9, 51.1,
47.5, 45.2, 39.1, 38.8, 37.5, 37.1, 35.5, 32.1, 32.0, 30.4, 30.0, 29.7,
26.1, 23.9, 21.1, 19.3, 18.3, 17.4 ppm. HRMS (ESI): calcd. for
C87H106NaO19 [M + Na]+ 1477.7225; found 1477.7221.
268
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Eur. J. Org. Chem. 2009, 259–269

Total Synthesis of Candicanoside A
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[D5]pyridine): δ = 8.36–8.33 (m, 2 H), 7.12–7.07 (m, 2 H), 6.54 (s,
1 H), 6.22 (dd, J = 9.9, 9.2 Hz, 1 H), 5.60 (br. s, 1 H), 5.50 (d, J =
8.6 Hz, 1 H), 5.42 (d, J = 3.8 Hz, 1 H), 5.31–5.28 (m, 1 H), 5.15
(d, J = 7.5 Hz, 1 H), 4.92 (s, 1 H), 4.76–4.72 (m, 1 H), 4.61 (d, J
= 11.8 Hz, 1 H), 4.47–4.35 (m, 3 H), 4.26 (dd, J = 9.4, 8.8 Hz, 1
H), 4.09 and 3.61 (2 d, J = 13.1 Hz, 2 H, AB), 4.08–4.00 (m, 2 H),
3.84 (s, 3 H), 3.02–2.96 (m, 1 H), 2.89–2.83 (m, 1 H), 2.65–2.60 (m,
1 H), 2.40–2.32 (m, 1 H), 2.25–2.15 (m, 1 H), 1.85 (s, 3 H), 1.70 (s,
3 H), 1.65 (d, J = 6.2 Hz, 3 H), 1.30 (d, J = 6.9 Hz, 3 H), 1.11 (s,
3 H) ppm. 13C NMR (75 MHz, [D5]pyridine): δ = 166.5, 164.1,
141.1, 134.5, 132.3, 125.8, 122.1, 114.3, 101.6, 101.2, 98.5, 79.7,
78.8, 78.2, 77.6, 76.9, 73.4, 72.7, 72.2, 70.7, 67.0, 66.8, 63.0, 55.7,
52.9, 51.3, 47.7, 45.9, 39.7, 39.2, 37.7, 37.4, 35.6, 32.5, 30.8, 30.6,
30.0, 26.2, 24.1, 21.4, 19.6, 18.3, 18.1 ppm. HRMS (ESI): calcd. for
C47H66NaO14 [M + Na]+ 877.4347; found 877.4345.
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Acknowledgments
Financial support from the Chinese Academy of Sciences
(KGCX2-SW-213 and KJCX2-YW-H08), the National Natural
Science Foundation of China (20621062), and the Committee of
Science and Technology of Shanghai (07DZ22001) are gratefully
acknowledged.
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Received: September 10, 2008
Published Online: November 28, 2008
Eur. J. Org. Chem. 2009, 259–269
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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