Semisynthesis of fuscoside B analogues and eunicosides, and analysis of anti-inflammatory activity

Article abstract of DOI:10.1016/j.tet.2011.03.006

A small library of semisynthetic analogues of fuscol and eunicol have been prepared and evaluated for in vivo topical anti-inflammatory activity using the mouse-ear edema assay. The first glycosylation of fuscol and eunicol has been achieved using a modif

Full text of DOI:10.1016/j.tet.2011.03.006

Tetrahedron 67 (2011) 3053e3061
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Semisynthesis of fuscoside B analogues and eunicosides, and analysis of
anti-inflammatory activity
*
Douglas H. Marchbank, Russell G. Kerr
Departments of Chemistry and Biomedical Science, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
A small library of semisynthetic analogues of fuscol and eunicol have been prepared and evaluated for in
vivo topical anti-inflammatory activity using the mouse-ear edema assay. The first glycosylation of fuscol
and eunicol has been achieved using a modified KoenigseKnorr glycosylation to synthesize new fus-
cosides and eunicosides, a novel structural class of diterpene glycosides. The availability of adequate
glycosylation methods for this synthesis was limited owing to the instability of the glycosyl acceptors.
Glycosyl donor protecting group type had a pronounced effect on overall glycosylation yields of a model
Received 12 January 2011
Received in revised form 2 March 2011
Accepted 2 March 2011
Keywords:
Fuscoside
Fuscol
Eunicol
Glycosylation
Anti-inflammatory
Mouse-ear assay
glycosyl acceptor. This synthesis provided access to the unnatural b-glycosides allowing for an evaluation
of the effect of differing anomeric stereochemistry on anti-inflammatory activity. The PEGylated
derivatives of fuscol and eunicol were also synthesized by a convenient acid-promoted solvolysis of the
natural product aglycones. This work highlights the importance of the glycan portion of fuscoside B,
notably the stereochemical configuration of the glycosidic linkage, in the observed anti-inflammatory
activity.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
explored; therefore the importance of the carbohydrate moiety for
the anti-inflammatory activity of 2 is not well understood. As
The fuscosides are a family of diterpene arabinose glycosides
first isolated from the Caribbean gorgonian Eunicea fusca by Shin
and Fenical.1 Fuscosides A (1) and B (2) are topical anti-in-
flammatory agents reducing phorbol myristate acetate (PMA)-in-
duced edema in a mouse-ear model with potencies comparable to
the industry standard indomethacin.2,3 Fuscoside B (2) is noted for
being a selective inhibitor of 5-lipoxygenase having no effect on
cyclooxygenases and prostaglandin biosynthesis.4 This family of
glycosides has drawn interest from the synthetic community as the
enantioselective synthesis of fuscol was accomplished by Yamada
et al. establishing its absolute stereochemistry.5 Although an
alternative and more efficient synthesis was later reported by
Kosugi et al.,6 neither group had accomplished the glycosylation to
synthesize 2.
a preliminary effort to assess structureeactivity relationships, this
study focused on the synthesis of the unnatural -glycosides to
b
investigate the importance of anomeric stereochemistry of 2.
PEGylated derivatives of 3 and 4 were also prepared and all com-
pounds were assessed in a murine model of inflammation.
The synthesis of the glycosides was restricted by the poor
availability of compatible glycosylation methods as the glycosyl
acceptors were unstable across a range of glycosylation conditions.
Furthermore, introducing carbohydrate functionalities to hindered
glycosyl acceptors remains a challenging task even with current
glycosylation methodology.9,10 Glycosylations of more sterically
hindered tertiary alcohols often occur with lower yields when
compared to their corresponding primary and secondary glycosyl
accepting alcohols.11 We describe herein the first glycosylation of 3
to generate fuscosides, and of 4 to afford the new class, eunicosides,
using a modified KoenigseKnorr method (Fig. 1).
E. fusca is also a source of fuscol (3),7 the aglycone precursor of 2,
and the biosynthetically related dilophol diterpene eunicol (4).8
While 2 is a trace metabolite, 3 and 4 are major constituents of
the gorgonian and readily available in hundreds of milligrams.
Access to 3 and 4 represents an opportunity to synthesize a library
of fuscosides as well as a new class of glycosides of eunicol.
Although fuscol also inhibits arachidonic acid metabolism in leu-
kocytes,4 its anti-inflammatory potential has not yet been fully
2. Results and discussion
A review of the glycosylation literature indicates the scope and
versatility of the method reported by Schmidt,12e14 which involves
mild activation of glycosyl trichloroacetimidate donors by catalytic
amounts of BF3$Et2O. 2-Methyl-3-buten-2-ol (5) was used as
a model glycosyl acceptor in preliminary studies due to its
* Corresponding author. E-mail address: rkerr@upei.ca (R.G. Kerr).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.006

3054
D.H. Marchbank, R.G. Kerr / Tetrahedron 67 (2011) 3053e3061
Fig. 1. Diterpenes from the Caribbean gorgonian E. fusca.
commercial availability. Attempts to glycosylate 5 with freshly
Table 1
synthesized 2,3,4,6-tetra-O-acetyl-a-D-galactopyranosyl trichloro-
Effect of protecting group manipulations on the glycosylation of 5
acetimidate15 led to the unexpected degradation of 5. As suspected,
3 and 4 also readily decomposed under these conditions to a mix-
ture of nonpolar hydrocarbons, as indicated by TLC analysis. Oxo-
philic BF3$Et2O presumably facilitates the departure of the tertiary
Entry
5 (equiv)
Glycosyl
bromide
(equiv)
Reaction time
(Days)
Product
yield (%)
1
2
3
4
5
6
7
1.0
1.0
1.0
1.0
1.0
1.0
1.0
(6) 4.0
(6) 4.1
(8) 4.0
(8) 4.0
(9) 2.8
(9) 4.2
(9) 3.9
0.6
3.5
0.6
3.5
1.6
3.1
3.5
(7) 15
(7) 26
hydroxyl group to form the tertiary
p-allylic carbocation in-
termediate, which may undergo rearrangement and elimination.
Unfortunately, further attempts to glycosylate 5 using Nicoloau’s16
and Kahne’s17 methodologies were also unsuccessful.
(10) 36
(10) 46
(11) 57
(11) 63
(11) 67
Introducing carbohydrate functionalities to hindered substrates
still remains a formidable challenge despite recent progress being
made in this area.18 However, the successful glycosylation of a -
variety of tertiary alcohols using glycosyl bromides drew our at-
tention to the KoenigseKnorr method.11,19e21 This glycosylation
may take place under neutral or basic reaction conditions22 cir-
cumventing the need for acidic activating reagents. Traditionally,
activation of glycosyl bromides is achieved by Ag2CO3,23,24 although
more efficient methodologies have been developed that combine
Ag2CO3 with AgOTf or AgClO4.25,26 The glycosyl bromides were
was far superior providing glycosylation yields that are comparable
to the literature for tertiary alcohols.11,19 Deprotection of 11 was
achieved by treatment with K2CO3/CH3OH and afforded glycoside
12 in good yields.
Varying the glycosyl donor protecting groups is well known to
influence donor reactivity29,30 and glycosylation yields.31 With
regards to the glycosylation of tertiary alcohol 5, the steric bulki-
ness of the protecting groups was initially expected to be the most
significant factor as glycosyl donors bearing pivaloate esters typi-
cally reduce overall glycosylation yields relative to that of ace-
fashioned with ester protecting groups, which provided
b-glyco-
sides by means of neighbouring group participation.27
2,3,4,6-Tetra-O-acetyl-a-D-galactopyranosyl bromide (6) was
freshly prepared according to known methods.28 The glycosylation
of 5 with AgOTf, Ag2CO3 and donor 6 proceeded to afford glycoside
7, which was isolated by normal phase flash chromatography
(Scheme 1). Increasing the reaction time led to an increase in gly-
cosylation yield (Table 1). To further improve glycosylation yields,
the glycosyl donor was modified to one with pivaloate (8) and
benzoate esters (9). A slight improvement in yields was observed
with the pivaloylated donor 8, however, the benzoylated donor 9
tates.32 Contrary to our expectations,
8
provided higher
glycosylation yields than 6. Self-stabilization of the glycosyl cation
by neighbouring group participation33 may instead be the domi-
nant factor in controlling yields (Scheme 2). Therefore, 8 could have
resulted in higher yields due to greater stabilization of the acy-
loxonium intermediate via induction. Consistent with this expla-
nation, the highest glycosylation yields were achieved with the
ꢀ
Scheme 1. Glycosylation of tertiary alcohol 5 with different glycosyl donors. Reagents and conditions: (a) 5 (1.0 equiv), AgOTf (0.4 equiv), Ag2CO3 (4.0 equiv), 3 A MS, CH2Cl2; (b)
K2CO3, CH3OH.

D.H. Marchbank, R.G. Kerr / Tetrahedron 67 (2011) 3053e3061
3055
benzoylated donor, presumably due to carbocation delocalization
across the phenyl group (13). Although further study is required to
confirm the correlation with higher glycosylation yields, Garegg
et al. have also observed the same trend with these protecting
groups using thioglycosides.34
purification by HPLC less attractive. Instead, a more rational ap-
proach was to utilize the mixture of 3 and 4 as they are virtually
identical with regards to the environment of the tertiary alcohol.
The products of glycosylation could be separated after successful
transformations, thereby providing two new glycosides for each
Scheme 2. Acyloxonium formation and proposed stabilization for benzoylated glycosyl donor 9.
Glycosylation yields were adversely affected by rearrangement
of glycosyl acceptor 5. Isolation of prenyl 2,3,4,6-tetra-O-benzoyl-
-galactopyranoside 14 and prenyl- -galactopyranoside 15 from
reaction and minimizing the overall HPLC work load. The products
would also be acquired with sufficient purity for anti-inflammatory
evaluation.
b
-
D
b-D
the glycosylation and deprotection crudes, respectively, was
indicative of acceptor 5 rearrangement to prenyl alcohol, which
underwent subsequent glycosylation (Fig. 2). This finding was
consistent with our earlier explanations regarding the tertiary hy-
droxyl group’s instability under acidic conditions.
Initial attempts to glycosylate 3 and 4 with the KoenigseKnorr
method established for model 5 resulted in complete and rapid
degradation of the glycosyl acceptors. This was not entirely un-
expected as the presence of 14 and 15 in earlier glycosylation and
deprotection crudes suggested that heterogeneous Ag2CO3 did not
Fig. 2. Glycosylation products of rearranged glycosyl acceptor 5.
From the E. fusca crude extract, 3 was isolated as a mixture with
biosynthetically related dilophol 4. Although the two diterpenes
are separable by RP-HPLC over a semi-preparative phenyl-hexyl
column, it was impractical to purify each metabolite in sufficient
quantities for glycosylation chemistry. The reaction was found to be
inconsistent at times with model acceptor 5, and would therefore
quickly consume any pure samples. Also from our experience, the
ratio of 3 and 4 changes throughout the duration of the glycosyl-
ation indicating possible degradation, thus rendering an upfront
adequately quench HOTf formation. Surprisingly, 3 and 4 continued
to degrade even in the presence of excess TMU. Use of the stronger
base DIEA proved successful as glycosylation was observed. The
glycosylation product mixture containing 16 and 17 was immedi-
ately treated with K2CO3/CH3OH providing access to glycosides 18
and 19. Similarly, the fuscoside B anomer (20) and eunico-b-D-ara-
binopyranoside (21) were synthesized via glycosylation with the
appropriate arabinopyranosyl donor followed immediately by
deprotection of the glycosylationreaction mixture(Scheme 3, Fig. 3).
Scheme 3. Glycosylation of fuscol followed by removal of benzoate esters. Reagents and conditions: (a) 3 (1.0 equiv), AgOTf (0.4 equiv), Ag2CO3 (4.0 equiv), 9 (4.0 equiv), DIEA
ꢀ
(4.0 equiv), 3 A MS, CH2Cl2 (15%); (b) K2CO3, CH3OH (9%, two steps).

3056
D.H. Marchbank, R.G. Kerr / Tetrahedron 67 (2011) 3053e3061
Fig. 3. Novel fuscosides and eunicosides.
All glycosides (16e21) were purified by RP-HPLC. NMR spec-
The new fuscosides (18 and 20), PEGylated derivatives (22e25)
and methyl ethers (26 and 27) of 3 and 4 were assayed for in vivo
topical anti-inflammatory activity in the mouse-ear edema assay.35
The known topical anti-inflammatory agent indomethacin was
administered as a positive control. We did not have access to fus-
coside B (2) for comparison in our bioassays, however, fuscol (3) is
known to exhibit similar anti-inflammatory activity in this assay.
Our data indicate that all unnatural glycosides and PEGylated
derivatives are either inactive or pro-inflammatory. The unnatural
anomer of 2 (20) had no effect while the galactoside (18) was pro-
inflammatory. All PEGylated derivatives of 3 (22 and 24) and of 4
(23 and 25) were either inactive or pro-inflammatory. The tertiary
hydroxyl group of 3 may be required for anti-inflammatory activity
as its methyl ether 26 was pro-inflammatory. We recognize that
this library of fuscosides and related compounds is limited in size,
however this preliminary study suggests that the stereochemistry
of the glycosidic linkage and the identity of the carbohydrate
moiety are important for topical anti-inflammatory activity (Fig. 5).
troscopic analysis of all glycosides demonstrated the presence of
3
the glycosidic linkage via JCH correlation between H-10 and C-15.
The expected 10,20-trans configurations were verified by coupling
constant measurements and NOESY spectra, which exhibited
strong correlations between the anomeric H-10 and axially oriented
H-30/50 of all glycosides.
Since 3 is roughly comparable to 2 with respect to inhibition of
arachidonic acid metabolism,4 we also synthesized PEGylated
derivatives of 3 and 4 rationalizing that such derivatives should
be straightforward to be prepared and may offer similar anti-in-
flammatory activity to the glycoside 2. Considering the ease of
tertiary carbocation formation under acidic conditions, we
developed fuscoside and eunicoside mimics (PEGylated de-
rivatives) via displacement of the tertiary alcohol by solvolysis.
Treatment of 3 and 4 with tri- and tetra-ethylene glycol under
acidic conditions allowed the smooth transformation to their
derivatives 22e25, respectively. It was postulated that the glycol
functionalities may behave like carbohydrate mimics in the sense
that they would increase the polarity of the compound. This
convenient reaction was readily accomplished by either BF3$Et2O
or AcOH with the former providing higher yields. Methyl ethers
26 and 27 were similarly prepared using CH3OH (Scheme 4,
Fig. 4).
3. Conclusion
A modification of the KoenigseKnorr glycosylation method has
been used to synthesize novel fuscoside B analogues and two gly-
cosides of eunicol, the eunicosides, with
b-glycosidic linkages.
Scheme 4. Synthesis of PEGylated and methyl ether derivatives of fuscol. Reagents and conditions: 22: (a) BF3$Et2O, THF/HO(C2H4O)3H (1:1) (60%); 24: (b) BF3$Et2O, THF/HO
(C2H4O)4H (1:1) (36%); 26: (c) BF3$Et2O, CH3OH (54%).

D.H. Marchbank, R.G. Kerr / Tetrahedron 67 (2011) 3053e3061
3057
6'
8'
O
O
O
5'
HO
O
4'
3'
OH
7'
O
O
O
2'
1'
23 (36%)
25 (15%)
O
27 (12%)
Fig. 4. PEGylated and methyl ether derivatives of eunicol.
performed at room temperature unless otherwise specified. Evap-
oration of all solutions was performed in vacuo at 30 ꢀC. All freshly
prepared glycosyl donors were utilized within one week and stored
under high vacuum over anhydrous CaSO4. Molecular sieves (MS)
ꢀ
(3 A) were activated by microwave heating, and all anhydrous
reactions were performed with oven-dried glassware. Glycosyl
ꢀ
acceptor 5 was dried in the presence of anhydrous 3 A MS prior to
utilization. All flash chromatography was performed over RediSep
Columns using a Teledyne Combiflash Rf unless otherwise specified.
Separation of products was carried out using Phenomenex ‘Luna 5
m) or Phenomenex ‘Gemini 5 C18
m) reversed-phase semi-preparative
m
phenyl-hexyl’ (250ꢁ10 mm, 5
m
m
110A’ (250ꢁ10.00 mm, 5
m
columns.
All 1H and 13C NMR spectra were acquired on a Bruker 600 MHz
NMR spectrometer operating at 600 and 150 MHz, respectively. All
chemical shifts are reported in parts per million and were relative
to residual solvent signals: CD3OD (1H: 3.31 ppm, 13C: 49.05 ppm),
C6D6 (1H: 7.15 ppm, 13C: 128.02 ppm). Assignments were made on
the basis of the COSY and HSQC spectra, and ascertained by HMBC
experiments, while NOESY spectra confirmed stereochemistry.
High resolution mass spectra were measured by Xiao Feng at Dal-
housie University on a Bruker microTOF Focus orthogonal ESI-TOF
mass spectrometer. Analysis of samples by LC with hyphenated MS-
ELSD-UV was performed using a Finnigan LXQ ion trap mass
spectrometer and an analytical C18 RP-HPLC column. Optical rota-
tions were measured on a Rudolph Autopol III Polarimeter. Infrared
spectra were acquired using attenuated total reflectance on
a Thermo Nicolet 6700 FT-IR spectrometer.
Fig. 5. PMA-induced mouse-ear edema assay results (INDO¼Indomethacin,
*
Indicates
statistically significant difference (p<0.05) between PMA-control and test groups at
24 h post-PMA treatment).
The latter group represents a new structural class of diterpene
glycosides that may exist as trace metabolites in E. fusca. For the
glycosylation of model glycosyl acceptor 2-methyl-3-buten-2-ol,
the benzoylated glycosyl donor provided the highest yields. A trend
was observed in which the predicted acyloxonium stability corre-
lated with overall glycosylation yields. This may be of future in-
terest when dealing with unreactive nucleophiles. Since the activity
of fuscoside B, the
focused on exploring
portance of anomeric stereochemistry. The bioassay data illustrates
the importance of the natural -anomeric stereochemistry of the
a
-arabinoside, is known, this preliminary study
b
-glycoside analogues to determine the im-
4.2. Collection and isolation of 3 and 4
a
glycosidic linkage of fuscoside B and suggests that the identity of
the carbohydrate moiety may be important for in vivo anti-in-
flammatory activity in the mouse-ear edema assay. Although both
the natural glycoside and aglycone are active in this assay, ‘un-
natural’ substitution at the glycan position had a marked impact on
activity as the methyl ether and PEGylated derivatives were pro-
inflammatory.
E. fusca was collected from Hillsboro Ledge, Florida by SCUBA, air
dried at the surface, and kept frozen during transportation. The
taxonomy was ascertained by TLC analysis comparison with a pure
sample of fuscol. After lyophilization, the gorgonians (124.6 g) were
exhaustively extracted with CH2Cl2. The crude extracts were com-
bined and concentrated to provide a viscous oil (11.47 g), which was
partitioned between hexane and CH3OH/H2O (9:1). The hexane
layer was evaporated (6.319 g) and separated by silica gel vacuum
flash chromatography by a stepwise gradient elution by hexane/
EtOAc mixtures. The hexane/EtOAc 4:1 fraction (592.0 mg) con-
tained 3/4 according to LCeMS analysis. Reversed phase flash
chromatography (CH3OH/H2O gradient) of this fraction provided 3/
4 (289.9 mg, 2.3% of dry coral wt.) as an approximate 1:2.3
(3:4) mixture whose 1H NMR spectrum was in accord with the
literature.7,8
4. Experimental section
4.1. General
All commercially available anhydrous solvents and reagents
were generally obtained from VWR, SigmaeAldrich, or Fisher Sci-
entific and utilized without further purification. All reactions were

3058
D.H. Marchbank, R.G. Kerr / Tetrahedron 67 (2011) 3053e3061
4.3. In vivo mouse-ear edema assay
CH2Cl2: 5 mL) in which DIEA (75
3 and 4.
mL, 0.42 mmol) was added prior to
The assay was completed by Amplia PharmaTek Inc. as pre-
viously described by Martinez et al.36,37 The 7e8 week-old female
CD-1 mice (Charles River Canada Inc.) were provided with food and
4.8. General procedure D: deprotection of benzoylated
fuscosides/eunicosides (18/19)
water ad libitum. PMA (100
mg
mLꢂ1
,
n¼6), indomethacin
(150 mg mLꢂ1, n¼6), and the test compounds (5 mg mLꢂ1, n¼3)
were formulated in acetone, DMSO, and ethanol, respectively. At
time 0, the right ears of each mouse were treated with vehicle
Deprotection was carried out according to general procedure B.
Upon completion, the mixture was diluted with EtOAc and washed
successively with 0.1 M NH4OAc(aq) and satd NaCl(aq). The organic
extract was dried (MgSO4), filtered, and evaporated yielding a crude
oil that was separated by RP-HPLC (CH3OH/H2O).
(ethanol, 20
(3 mg, 20 L). All of the left ears were treated with ethanol (20
One hour later, PMA (2 g, 20 L) was applied to the right ears of all
mL), test compounds (100
mg, 20
mL), or indomethacin
m
mL).
m
m
animals. Edema was measured at 3, 6, and 24 h post-PMA treat-
ment using a digital calliper and calculated by subtracting the
thickness of the left ear from the right. To determine statistical
significance, the student’s t-test was used to compare between test
articles and vehicle controls. The data is shown with standard error
of mean (SEM) to represent the variation.
4.9. General procedure E: solvolysis of fuscol/eunicol (3/4)
To a stirred solution of 3 and 4 (10 mg, 35 mmol) in THF (2 mL)
was added an excess of primary alcohol (HO(C2H4O)3H, HO
(C2H4O)4H, CH3OH) (2 mL). After cooling in an ice bath, BF3$Et2O
(5
mL) was added. After approximately 30 min, TLC analysis in-
dicated the disappearance of 3/4, and the reaction was diluted with
EtOAc. Once this mixture was washed with satd NaHCO3(aq) and
satd NaCl(aq), the organic extract was dried (MgSO4), filtered, and
concentrated to provide a crude oil that was separated by RP-HPLC
(CH3OH/H2O).
4.4. Preparation of galactosyl (6,8,9) and arabinopyranosyl
bromides
The glycosyl bromides were synthesized by known methods,38
using CH3OH/AcBr to generate HBr in situ,31 and purified accord-
ing to the following procedure. The brominated reaction mixture
was diluted with cold EtOAc and washed successively with cold
satd NaHCO3(aq), until gas evolution ceased, followed by cold satd
NaCl(aq). The organic extract was dried (MgSO4), filtered, and
evaporated to provide a crude oil. Silica gel flash chromatography
(TBME/hexane gradient) yielded the galactosyl bromide as a white
powder (6: 38%, 8: 26%, 9: 36%, arabinopyranosyl bromide: 50%). All
spectroscopic data for 6, 8, and 9 was in accord with the
literature.38e41
4.9.1. 2-Methyl-3-buten-2-yl 2,3,4,6-tetra-O-acetyl-
b
-D
-galactopyr-
anoside (7). Aglycone was glycosylated using
5
6 (790 mg,
1.92 mmol) according to general procedure A. The glycosylation
crude was separated by silica gel flash chromatography (hexane/
TBME gradient) to yield the desired glycoside 7 (26%): [
a
]
2D7þ8.98 (c
3.67ꢁ10ꢂ3 in CH2Cl2); IR: 3088, 2982, 1744, 1216, 1643, 1072, 1040.
1H NMR (600 MHz, C6D6):
d
H-3: 5.86 (dd, J¼17.7, 10.5, 1H), H-20:
5.57 (dd, J¼10.5, 8.3, 1H), H-40: 5.41 (dd, J¼3.4, 0.8, 1H), H-30: 5.12
(dd, J¼10.5, 3.4, 1H), H-4: 5.07 (dd, J¼17.7, 1.1, 1H), H-4: 4.99 (dd,
J¼10.5, 1.1, 1H), H-10: 4.39 (d, J¼8.3, 1H), H-60: 4.11 (dd, J¼10.9, 6.8,
1H), H-60: 4.05 (dd, J¼10.9, 6.4, 1H), H-50: 3.24 (ddd, J¼6.4, 1.1, 1H),
1.75 (s, 3H), 1.73 (s, 3H), 1.65 (s, 3H), 1.53 (s, 3H), H-1: 1.24 (s, 3H),
H-5: 1.18 (s, 3H). 13C NMR (150 MHz, C6D6): 170.2 (C), 169.8 (C),
169.5 (C), 168.6 (C), C-3: 143.7 (CH), C-4: 113.9 (CH2), C-10: 96.9
(CH), C-2: 78.0 (C), C-30: 71.6 (CH), C-50: 70.6 (CH), C-20: 69.6 (CH),
C-40: 67.5 (CH), C-60: 61.6 (CH2), C-5: 27.4 (CH3), C-1: 26.2 (CH3),
20.5 (CH3), 20.3 (CH3), 20.2 (CH3), 19.9 (CH3). HRMS (ESI-TOF):
(C19H28O10Na) calcd 439.1575, found 439.1564.
4.5. General procedure A: modified KoenigseKnorr
glycosylation of 2-methyl-3-buten-2-ol (5)
To a stirred mixture of AgOTf (49 mg, 0.19 mmol), Ag2CO3
ꢀ
(530 mg, 1.92 mmol), and 3 A MS (0.5 g) in anhydrous CH2Cl2 (5 mL)
under N2 atmosphere was added glycosyl acceptor 5 (50
mL,
0.48 mmol). After stirring for 15 min, the mixture was cooled to
ꢂ78 ꢀC followed by the dropwise addition of glycosyl bromide
(1.922 mmol) in CH2Cl2 (5 mL). The mixture was stirred for 3.5 days
and afterward diluted with EtOAc and filtered through CeliteÒ.
Washing with satd Na2S2O3(aq) and satd NaCl(aq) and evaporation of
the organic extract yielded the glycosylation crude as an oil.
4.9.2. 2-Methyl-3-buten-2-yl 2,3,4,6-tetra-O-pivaloyl-b-D-galacto-
pyranoside (10). Aglycone 5 was glycosylated using 8 (1.11 g,
1.92 mmol) according to general procedure A. The glycosylation
crude was separated by silica gel flash chromatography (hexane/
TBME gradient) to yield the desired glycoside 10 (46%): [
a
]
2D7þ8.56
(c 1.37ꢁ10ꢂ3 in CH2Cl2); IR: 2975, 2936, 2909, 2874, 1737, 1139,
4.6. General procedure B: deprotection of benzoylated
glycosides
1073, 1037. 1H NMR (600 MHz, C6D6):
d
H-3: 5.93 (dd, J¼17.7, 10.9,
1H), H-20: 5.56 (dd, J¼10.2, 7.9, 1H), H-40: 5.41 (dd, J¼3.0, 1.1, 1H),
H-30: 5.12 (dd, J¼10.5, 3.4, 1H), H-4: 5.06 (dd, J¼17.7, 1.1, 1H), H-4:
5.00 (dd, J¼10.9, 1.1, 1H), H-10: 4.42 (d, J¼8.0, 1H), H-60: 4.12 (dd,
J¼10.9, 7.2, 1H), H-60: 4.06 (dd, J¼10.9, 6.0, 1H), H-50: 3.25 (ddd,
J¼7.2, 6.4, 1.1, 1H), H-1: 1.28 (s, 3H), H-5: 1.22 (s, 3H), 1.21 (s, 9H),
1.17 (s, 9H), 1.17 (s, 9H), 1.10 (s, 9H). 13C NMR (150 MHz, C6D6): 177.1
(C), 177.1 (C), 177.0 (C), 176.0 (C), C-3: 143.9 (CH), C-4: 114.1 (CH2), C-
10: 96.9 (CH), C-2: 78.0 (C), C-30: 71.8 (CH), C-50: 70.8 (CH), C-20: 69.5
(CH), C-40: 67.4 (CH), C-60: 62.0 (CH2), 39.0 (C), 38.9 (C), 38.8 (C),
38.7 (C), C-5: 28.0 (CH3), 27.5 (CH3), 27.3 (CH3), 27.3 (CH3), 27.1
(CH3), C-1: 26.2 (CH3). HRMS (ESI-TOF): (C31H52O10Na) calcd
607.3453, found 607.3426.
To a stirred solution of the glycosylation crude in CH3OH was
added K2CO3 (53 mg, 0.38 mmol). The reaction was stirred until TLC
analysis indicated the disappearance of benzoylated starting
materials. The reaction was neutralized by addition of NH4OAc and
concentrated to 0.5 mL. This mixture was chromatographed over
a C18 plug eluting with H2O/CH3OH 19:1 into fractions. Fractions
containing the deprotected glycosides were evaporated and
lyophilized to provide a white amorphous solid that was separated
by RP-HPLC (CH3OH/H2O).
4.7. General procedure C: modified KoenigseKnorr
glycosylation of fuscol/eunicol (3/4)
4.9.3. 2-Methyl-3-buten-2-yl 2,3,4,6-tetra-O-benzoyl-b-D-galactopyr-
A mixture of aglycones 3 and 4 (30 mg, 0.10 mmol) were gly-
cosylated using a variation of general procedure A (3 A MS: 0.1 g;
anoside (11). Aglycone 5 was glycosylated using 9 (1.27 g,1.92 mmol)
according to general procedure A. The glycosylation crude was
ꢀ

D.H. Marchbank, R.G. Kerr / Tetrahedron 67 (2011) 3053e3061
3059
separated by silica gel flash chromatography (hexane/TBME gradient)
20: 72.6 (CH), C-40: 70.4 (CH), C-1: 66.3 (CH2), C-60: 62.5 (CH2), C-5:
25.9 (CH3), C-4: 18.1 (CH3). HRMS (ESI-TOF): (C11H20O6Na) calcd
271.1152, found 271.1157.
to yield the desired glycoside 11 (67%): [
a]
D27þ162.4 (c 2.833ꢁ10ꢂ3 in
CH2Cl2); IR: 3065, 2980, 1728, 1265, 1108, 710. 1H NMR (600 MHz,
C6D6):d8.21(dd,2H),8.12(dd, 2H),8.08(dd,2H), 7.98(dd,2H), 7.11(tt,
1H), 7.06 (tt, 2H), 7.03 (tt, 1H), 7.00 (tt, 1H), 6.95 (tt, 2H), 6.87 (tt, 2H),
6.83 (tt, 1H), 6.71 (tt, 2H), H-20: 6.29 (dd, J¼10.5, 8.3, 1H), H-40: 6.09
(dd, J¼3.8, 1.1, 1H), H-3: 5.90 (dd, J¼17.6, 10.8, 1H), H-30: 5.70 (dd,
J¼10.2, 3.4, 1H), H-4: 5.01 (dd, J¼17.6, 1.1, 1H), H-4:
4.89 (dd, J¼10.8, 1.1, 1H), H-10: 4.70 (d, J¼8.0, 1H), H-60: 4.65 (dd,
J¼11.3, 7.5, 1H), H-60: 4.29 (dd, J¼11.3, 5.6, 1H), H-50: 3.58 (ddd, J¼5.6,
1.1, 1H), H-1: 1.26 (s, 3H), H-5: 1.14 (s, 3H). 13C NMR (150 MHz, C6D6):
165.8 (C), 165.8 (C), 165.7 (C), 165.2 (C), C-3: 143.7 (CH), 133.2 (CH),
133.1 (CH),133.1 (CH),133.0 (CH),130.5(C),130.4 (C),130.3(CH),130.0
(CH),130.0(CH),129.9 (CH),129.6(C),129.6(C),128.8(CH),128.6 (CH),
128.6 (CH), 128.4 (CH), C-4: 114.1 (CH2), C-10: 97.1 (CH), C-2: 78.4 (C),
C-30: 72.5 (CH), C-50: 71.3 (CH), C-20: 70.7 (CH), C-40: 68.8 (CH), C-60:
62.6 (CH2), C-5: 27.2 (CH3), C-1: 26.4 (CH3). HRMS (ESI-TOF):
(C39H36O10Na) calcd 687.2201, found 687.2186.
4.9.7. Fusco-2,3,4,6-tetra-O-benzoyl-
nico-2,3,4,6-tetra-O-benzoyl- -galactopyranoside (16/17). Aglycones
3 and 4 (34.5 mg, 200 mol) were glycosylated using 9 according to
b-D-galactopyranoside and eu-
b-D
m
general procedure C. The glycosylation crude was chromatographed
over silica gel (MTBE/hexane gradient) and the desired glycosides
were separated by C18 RP-HPLC (94% CH3OH/H2O). 16 (8.6 mg, 15%):
[
a D
]
27 þ135.1 (c 1.192ꢁ10ꢂ3 in CH2Cl2); IR: 3070, 2975, 2929, 2859,
1729, 1265, 1107, 1069, 709. 1H NMR (600 MHz, CD3OD):
d 8.11 (dd
2H), 8.02 (dd, 2H), 7.98 (dd, 2H), 7.72 (dd, 2H), 7.67 (t, 1H), 7.60 (t, 1H),
7.57 (t, 1H), 7.54 (t, 2H), 7.46 (t, 2H), 7.45 (t, 1H), 7.43 (t, 2H), 7.25 (t,
2H), H-13: 6.46 (dd, J¼15.5, 10.7, 1H), H-40: 5.95 (dd, J¼3.0, 1H), H-6:
5.84 (dd, J¼17.5, 10.8, 1H), H-30: 5.74 (dd, J¼10.2, 3.4, 1H), H-12: 5.71
(br d, J¼10.2, 1H), H-20: 5.69 (dd, J¼9.8, 7.5, 1H), H-14: 5.50 (d, J¼15.5,
1H), H-10: 5.09 (d, J¼7.2, 1H), H-5: 4.91 (dd, J¼17.3, 1.4, 1H), H-5: 4.88
(dd, J¼10.5,1.5,1H), H-4: 4.83 (br s,1H), H-4: 4.61 (br s,1H), H-60: 4.54
(dd, J¼10.5, 7.2, 1H), H-50: 4.49 (ddd, J¼7.2, 5.0, 1H), H-60: 4.44 (dd,
J¼10.5, 4.9, 1H), H-2: 2.03 (ddd, J¼12.7, 3.0, 1H), H-10: 1.95e1.89
(m, 1H), H-18: 1.74 (s, 3H), H-16: 1.72 (s, 3H), H-1: 1.63 (ddd, J¼12.8,
12.4, 1H), H-8: 1.56e1.48 (m, J¼11.3, 3.8, 1H), H-9: 1.52e1.47 (m, 2H),
H-1: 1.46e1.40 (m, J¼12.8, 1H), H-8: 1.46e1.41 (m, 1H), H-19: 1.40 (s,
3H), H-20: 1.26 (s, 3H), H-17: 1.02 (s, 3H). 13C NMR (150 MHz, CD3OD):
166.8 (C), 166.7 (C), 167.4 (C), 167.3 (C), C-6: 151.5 (CH), C-3: 149.0 (C),
C-11: 145.3 (C), C-14: 136.8 (CH), 134.9 (CH), 134.7 (CH), 134.6 (CH),
134.5 (CH), 131.0 (CH), 131.0 (C), 130.8 (C), 130.8 (CH), 130.8 (CH), 130.6
(CH),130.6 (C),130.3 (C),129.9 (CH),129.7 (CH),129.7 (CH),129.5 (CH),
127.9 (CH), C-12: 123.8 (CH), C-4: 112.8 (CH2), C-5: 110.5 (CH2), C-10:
97.6 (CH), C-15: 79.9 (C), C-30: 73.4 (CH), C-50: 72.2 (CH), C-20: 71.8
(CH), C-40: 70.3 (CH), C-60: 63.8 (CH2), C-2: 54.0 (CH), C-10: 49.3 (CH),
C-8: 41.1 (CH2), C-7: 40.8 (C), C-1: 33.9 (CH2), C-20: 28.8 (CH3), C-9:
27.8 (CH2), C-19: 26.7 (CH3), C-16: 25.4 (CH3), C-17: 17.2 (CH3), C-18:
15.3 (CH3). HRMS (ESI-TOF): (C54H58O10Na) calcd 889.3922, found
4.9.4. 2-Methyl-3-buten-2-yl-b-D-galactopyranoside (12). The gly-
cosylation crude from general procedure A using 9 was deprotected
according to general procedure B. The desired glycoside was iso-
lated by C18 RP-HPLC (30% CH3OH/H2O). 12: [
a]
2D7ꢂ9.29 (c 1.17ꢁ10ꢂ3
in CH3OH); IR: 3379, 3090, 2980, 2933, 2881, 1642, 1579, 1059. 1H
NMR (600 MHz, CD3OD):
d
H-3: 6.03 (dd, J¼17.7, 10.9, 1H), H-4: 5.20
(dd, J¼17.7, 1.1, 1H), H-4: 5.10 (dd, J¼10.9, 1.1, 1H), H-10: 4.28 (d,
J¼7.2, 1H), H-40: 3.83 (dd, J¼3.0, 0.8, 1H), H-60: 3.71 (dd, J¼10.9, 5.7,
1H), H-60: 3.67 (dd, J¼10.9, 6.4, 1H), H-20: 3.47 (dd, J¼9.8, 7.2, 1H),
H-30: 3.44 (dd, J¼9.8, 3.4, 1H), H-50: 3.41 (ddd, J¼6.4, 0.8, 1H), H-1:
1.37 (s, 3H), H-5: 1.33 (s, 3H). 13C NMR (150 MHz, CD3OD): C-3:
145.6 (CH), C-4: 114.2 (CH2), C-10: 100.2 (CH), C-2: 79.0 (C), C-50:
76.3 (CH), C-30: 75.1 (CH), C-20: 72.6 (CH), C-40: 70.2 (CH), C-60: 62.3
(CH2), C-5: 27.9 (CH3), C-1: 26.7 (CH3). HRMS (ESI-TOF):
(C11H20O6Na) calcd 271.1152, found 271.1159.
4.9.5. Prenyl 2,3,4,6-tetra-O-benzoyl-
b
-D
-galactopyranoside (14).
889.3950. 17 (6.9 mg, 5%): [a D
3068, 3034, 2975, 2929, 2860, 1729, 1265, 1107, 1069, 710. H NMR
]
27þ56.3 (c 1.67ꢁ10ꢂ4 in CH2Cl2); IR:
1
Glycoside 14 was isolated as a side product from the glycosylation
crude reaction mixture of 11 by phenyl-hexyl RP-HPLC (86%
CH3OH/H2O). Compound 14: IR: 3063, 2970, 2931, 1726, 1266, 1108,
(600 MHz, C6D6): d 8.23 (dd 2H), 8.19 (dd, 2H), 8.08 (dd, 2H), 7.97 (dd,
2H), 7.12 (br tt, 1H), 7.08 (br tt, 1H), 7.05 (m, 2H), 7.05 (m, 2H), 7.02 (m,
1H), 6.87 (t, 2H), 6.83 (br tt, 1H), 6.71 (t, 2H), H-13: 6.53 (dd, J¼15.8,
10.9, 1H), H-20: 6.33e6.28 (m, 1H), H-40: 6.07 (dd, J¼3.0, 1H), H-12:
6.09e5.99 (br m, 0.5H), H-12: 5.94 (br d, J¼10.5, 0.5H), H-30:
5.66e5.59 (m,1H), H-14: 5.76 (d, J¼15.8, 1H), H-2/6: 5.20e5.03 (br m,
1H), H-10: 4.82 (d, J¼7.5, 1H), H-6: 4.83e4.80 (br m, 0.5H), H-60:
4.72e4.67 (m, 1H), H-20: 4.55 (br d, 10.2, 0.5H), H-60: 4.32e4.26
(m, 1H), H-8: 2.39e2.33 (m, J¼12.8, 7.5, 1H), H-1: 2.28e2.23 (m, 1H),
H-5: 2.23e2.17 (m, J¼12.8, 4.5, 1H), H-1: 2.18e2.13 (m, 1H), H-4:
2.14e2.09 (m,1H), H-8: 2.10e2.04 (m,1H), H-5: 2.07e2.02 (m,1H), H-
10: 1.96 (ddd, 9.8, 1H), H-4: 1.92e1.87 (m,1H), H-18: 1.69 (s, 3H), H-9:
1.71e1.64 (m, 1H), H-9: 1.55e1.49 (m, 1H), H-16: 1.47 (s, 1.5H), H-17:
1.44 (s, 3H), H-19: 1.44 (s, 3H), H-16: 1.36e1.32 (br s, 1.5H), H-20: 1.28
(br s, 3H). 13C NMR (150 MHz, C6D6): 165.3 (C), 165.3 (C), 165.2 (C),
165.1 (C), C-11: 146.9 (C), C-7: 137.8 (C), C-14: 137.0 (CH), 133.3 (CH),
133.2 (CH), 133.1 (CH), 133.1 (CH), 132.9 (C), 132.8 (C), 132.7 (C), 132.7
(C), C-2: 131.7 (CH), 130.4 (CH), 130.1 (CH), 130.1 (CH), 130.0 (CH), C-3:
129.6 (C), 128.7 (CH), 128.6 (CH), 128.6 (CH), 128.4 (CH), C-6: 127.0
(CH), C-13: 126.6 (CH), C-12: 122.4 (CH), C-10: 97.3 (CH), C-15: 78.8 (C)
C-30: 72.6 (CH), C-20: 71.0 (CH), C-50: 71.0 (CH), C-40: 68.7 (CH), C-60:
62.3 (CH2) C-10: 53.7 (CH), C-8: 42.0 (CH2), C-4: 39.5 (CH2), C-1: 35.2
(CH2), C-9: 33.9 (CH2), C-20: 28.9 (CH3), C-5: 27.1 (CH2), C-19: 26.3
(CH3), C-16: 16.8 (CH3), C-17: 16.5 (CH3), C-18: 14.4 (CH3). HRMS (ESI-
TOF): (C54H58O10Na) calcd 889.3922, found 889.3974.
1070, 709. 1H NMR (600 MHz, C6D6):
d 8.19 (dd, 2H), 8.11 (dd, 2H),
8.09 (dd, 2H), 7.98 (dd, 2H), 7.09 (tt, 2H), 7.03 (m, 2H), 7.03 (m, 1H),
6.97 (tt, 2H), 6.91 (tt, 1H), 6.89 (tt, 1H), 6.83 (tt, 2H), 6.71 (tt, 1H), H-
20: 6.35 (dd, J¼10.5, 7.9, 1H), H-40: 6.19 (dd, J¼3.8, 1.1, 1H), H-30: 5.76
(dd, J¼10.5, 3.8, 1H), H-2: 5.29 (m, J¼7.9, 6.4, 1.5, 1H), H-60: 4.74 (dd,
J¼11.3, 7.2, 1H), H-10: 4.70 (d, J¼8.0, 1H), H-60: 4.33 (dd, J¼11.3, 6.4,
1H), H-1: 4.29 (dd, 12.0, 6.4 1H), H-1: 4.22 (dd, J¼11.8, 7.7, 1H), H-50:
3.75 (ddd, J¼6.4,1.1,1H), H-5: 1.45 (s, 3H), H-4: 1.39 (s, 3H). 13C NMR
(150 MHz, C6D6): 165.3 (C), 165.2 (C), 165.2 (C), 165.1 (C), C-3: 137.8
(C), 132.7 (CH), 132.5 (CH), 132.5 (CH), 132.4 (CH), 130.4 (C), 130.2
(C), 129.8 (C), 129.8 (C), 129.6 (CH), 129.6 (CH), 129.5 (CH), 129.4
(CH), 128.3 (CH), 128.2 (CH), 128.2 (CH), 128.0 (CH) C-2: 120.4 (CH),
C-10: 99.7 (CH), C-30: 72.2 (CH), C-50: 71.0 (CH), C-20: 70.2 (CH), C-40:
68.4 (CH), C-1: 64.9 (CH2), C-60: 62.0 (CH2), C-5: 25.1 (CH3), C-4: 17.3
(CH3).
4.9.6. Prenyl-b-D-galactopyranoside (15). Glycoside 15 was isolated
as a side product from the glycosylation reaction mixture crude of
12 by C18 RP-HPLC (30% CH3OH/H2O). 15: [
a
]
2D7ꢂ21.4 (c 1.33ꢁ10ꢂ3 in
CH3OH); IR: 3384, 3027, 2970, 2915, 2881, 1671, 1646, 1063. 1H NMR
(600 MHz, CD3OD):
d
H-2: 5.38 (m, J¼7.9, 6.4,1.5, 1H), H-1: 4.32 (dd,
J¼12.0, 6.4, 1H), H-10: 4.24 (d, J¼7.9, 1H), H-1: 4.22 (dd, J¼12.0, 7.9,
1H), H-40: 3.83 (dd, J¼3.2, 1.0, 1H), H-60: 3.76 (dd, J¼11.3, 6.8, 1H),
H-60: 3.73 (dd, J¼11.3, 5.6, 1H), H-20: 3.51 (dd, J¼9.8, 7.5, 1H), H-50:
3.48 (ddd, J¼6.8, 1.1, 1H), H-30: 3.45 (dd, J¼9.8, 3.4, 1H), H-4: 1.69 (s,
CH3), H-5: 1.75 (s, CH3). 13C NMR (150 MHz, CD3OD): C-3: 138.4 (C),
C-2: 121.9 (CH2), C-10: 103.5 (CH), C-50: 76.7 (CH), C-30: 75.1 (CH), C-
4.9.8. Fusco-
(18/19). Aglycones 3 and 4 (31.0 mg, 108
using 9 according to general procedure C and the glycosylation
b
-
D
-galactopyranoside/eunico-
b-D-galactopyranoside
mmol) were glycosylated

3060
D.H. Marchbank, R.G. Kerr / Tetrahedron 67 (2011) 3053e3061
crude was deprotected according to general procedure D. The de-
sired glycosides were separated by phenyl-hexyl RP-HPLC (81%
C-30: 74.4 (CH), C-20: 72.7 (CH), C-40: 69.8 (CH), C-50: 66.8 (CH), C-2:
54.0 (CH), C-10: 49.2 (CH), C-8: 41.1 (CH2), C-7: 40.8 (C), C-1: 34.0
(CH2), C-20: 28.7 (CH3), C-9: 27.9 (CH2), C-19: 27.3 (CH3), C-16: 25.3
(CH3), C-17: 17.2 (CH3), C-18: 15.3 (CH3). HRMS (ESI-TOF):
(C25H40O5Na) calcd 443.2768, found 443.2768. 21 (1.0 mg, 3%):
CH3OH/H2O). 18 (1.4 mg, 9%): [
a
]
27ꢂ8.06 (c 5.00ꢁ10ꢂ4 in CH3OH);
D
IR: 3381, 3081, 3046, 2973, 2928, 2860, 1635, 1056. 1H NMR
(600 MHz, CD3OD):
d
H-13: 6.48 (dd, J¼15.4,10.5,1H), H-12: 5.90 (d,
J¼10.5, 1H), H-6: 5.84 (dd, J¼17.3, 10.8, 1H), H-14: 5.76 (d, J¼15.4,
1H), H-5: 4.90 (dd, J¼17.3, 1.1, 1H), H-5: 4.87 (dd, J¼10.9, 1.1, 1H),
H-4: 4.81 (br s, 1H), H-4: 4.60 (br s, 1H), H-10: 4.29 (d, J¼7.5, 1H), H-
40: 3.81 (dd, J¼3.4, 1.1, 1H), H-60: 3.70 (dd, 11.3, J¼6.0, 1H), H-60: 3.68
(dd, J¼11.3, 6.0, 1H), H-20: 3.48 (dd, J¼9.8, 7.5, 1H), H-30: 3.44 (dd,
J¼9.8, 3.4, 1H), H-50: 3.40 (ddd, J¼6.0, 1.1, 1H), H-2: 2.04 (ddd,
J¼12.8, 3.0, 1H), H-10: 2.03e1.97 (m, 1H), H-18: 1.78 (s, 3H), H-16:
1.71 (s, 3H), H-1: 1.66 (ddd, J¼12.8, 12.4, 1H), H-9: 1.57e1.52
(m, 2H), H-8: 1.55e1.51 (m, 1H), H-1: 1.49e1.45 (m, J¼12.8, 1H),
H-8: 1.46e1.42 (m, 1H), H-19: 1.41 (s, 3H), H-20: 1.36 (s, 3H), H-17:
1.03 (s, 3H). 13C NMR (150 MHz, CD3OD): C-6: 151.6 (CH), C-3: 149.0
(C), C-11: 144.3 (C), C-14: 138.4 (CH), C-13: 127.1 (CH), C-12: 124.2
(CH), C-4: 112.7 (CH2), C-5: 110.4 (CH2), C-10: 100.3 (CH), C-15: 79.1
(C), C-50: 76.3 (CH), C-30: 75.1 (CH), C-20: 72.7 (CH), C-40: 70.2 (CH),
C-60: 62.4 (CH2), C-2: 54.1 (CH), C-10: 49.2 (CH), C-8: 41.1 (CH2), C-7:
40.8 (C), C-1: 34.1 (CH2), C-20: 28.7 (CH3), C-9: 27.8 (CH2), C-19: 27.4
(CH3), C-16: 25.3 (CH3), C-17: 17.2 (CH3), C-18: 15.4 (CH3). HRMS
(ESI-TOF): (C26H42O6Na) calcd 473.2874, found 473.2861. Com-
pound 19 (1.6 mg, 4%): IR: 3373, 3047, 2971, 2923, 2856, 1648, 1591,
[a
]
27 ꢂ34.4 (c 5.00ꢁ10ꢂ5 in CH3OH); IR: 3379, 3081, 3041, 2970,
D
2924, 2854, 1634, 1083, 1002. 1H NMR (600 MHz, CD3OD):
d H-13:
6.47e6.40 (m, 1H), H-12: 5.85 (d, J¼10.5, 1H), H-14: 5.71 (d, J¼15.8,
1H), H-2/6: 4.95e5.25 (br m, 1.2H), H-6: 4.80 (br d, J¼13.2, 0.4H),
H-2: 4.55 (br d, J¼9.8, 0.4H), H-10: 4.30e4.24 (m,1H), H-50: 3.80 (dd,
J¼12.4, 2.6, 1H), H-40: 3.78e3.76 (m, 1H), H-20: 3.52e3.49 (m, 1H),
H-30: 3.51e3.49 (m, 1H), H-50: 3.47 (dd, J¼11.7, 3.8, 1H), H-8:
2.40e2.34 (m, 1H), H-5: 2.33e2.25 (m, J¼12.8, 4.9, 1H), H-1:
2.22e2.17 (m, 1H), H-4: 2.19e2.15 (m, 1H), H-1: 2.10e2.04 (m, 1H),
H-8: 2.10e2.04 (m, 1H), H-5: 2.07e2.03 (m, 1H), H-10: 2.01e1.96
(m, 1H), H-4: 1.94e1.87 (m, J¼12.0, 4.9, 1H), H-18: 1.77 (s, 1.2H),
H-18: 1.75 (s, 1.8H), H-9: 1.71e1.63 (m, 2H), H-16: 1.60e1.52 (br s,
1.2H), H-16: 1.54 (s, 1.8H), H-17: 1.53e1.47 (br s, 1.8H), H-17: 1.41
(s, 1.2H), H-19: 1.40 (s, 3H), H-20: 1.35 (s, 3H). 13C NMR (150 MHz,
CD3OD): C-11: 147.9 (C), C-7: 138.9 (C), C-14: 138.0 (CH), C-2: 132.6
(CH), C-3: 130.2 (C), C-6: 127.7 (CH), C-13: 127.1 (CH), C-12: 123.1
(CH), C-10: 100.2 (CH), C-15: 79.1 (C), C-30: 74.4 (CH), C-20: 72.7 (CH),
C-40: 69.8 (CH), C-50: 66.7 (CH2), C-10: 54.8 (CH), C-8: 42.8 (CH2),
C-4: 40.6 (CH2), C-1: 35.8 (CH2), C-9: 34.8 (CH2), C-20: 28.9 (CH3),
C-5: 27.6 (CH2), C-19: 27.3 (CH3), C-16: 17.0 (CH3), C-17: 16.6 (CH3),
C-18: 14.7 (CH3). HRMS (ESI-TOF): (C25H40O5Na) calcd 443.2768,
found 443.2747.
1054. 1H NMR (600 MHz, CD3OD):
d
H-13: 6.43 (dd, J¼15.1,10.5,1H),
H-12: 5.85 (d, J¼10.2, 1H), H-14: 5.74 (d, J¼15.4, 1H), H-2/6:
5.25e4.95 (br m, 1.2H), H-6: 4.79 (br d, J¼11.3, 0.4H), H-2: 4.55 (br
d, J¼10.2, 0.4H), H-10: 4.32e4.28 (m, 1H), H-40: 3.82 (br dd, J¼3.0,
1H), H-60: 3.71 (dd, J¼11.3, 6.0, 1H), H-60: 3.68 (dd, J¼11.3, 6.4, 1H),
H-20: 3.50e3.45 (m, 1H), H-30: 3.47e3.43 (m, 1H), H-50: 3.43e3.39
(m, 1H), H-8: 2.40e2.33 (m, 1H), H-5: 2.33e2.25 (m, J¼12.4, 4.5,
1H), H-1: 2.22e2.17 (m,1H), H-4: 2.20e2.15 (m,1H), H-1: 2.10e2.05
(m, 1H), H-5: 2.08e2.04 (m, 1H), H-8: 2.07e2.05 (m, 1H), H-10:
2.01e1.95 (m, 1H), H-4: 1.94e1.88 (m, 1H), H-18: 1.77 (s, 1.2H),
H-18: 1.75 (s, 1.8H), H-9: 1.72e1.63 (m, 2H), H-16: 1.59e1.53 (br s,
1.2H), H-16: 1.54 (s, 1.8H), H-17: 1.53e1.47 (br s, 1.8H), H-17: 1.41 (s,
1.2H), H-19: 1.41 (s, 3H), H-20: 1.36 (s, 3H). 13C NMR (150 MHz,
CD3OD): C-11: 147.8 (C), C-7: 138.9 (C), C-14: 138.3 (CH), C-2: 132.6
(CH), C-3: 130.2 (C), C-6: 127.6 (CH), C-13: 127.0 (CH), C-12: 123.2
(CH), C-10: 100.2 (CH), C-15: 79.1 (C), C-50: 76.3 (CH), C-30: 75.1 (CH),
C-20: 72.7 (CH), C-40: 70.2 (CH), C-60: 62.4 (CH2) C-10: 54.8 (CH),
C-8: 42.8 (CH2), C-4: 40.6 (CH2), C-1: 35.8 (CH2), C-9: 34.8 (CH2),
C-20: 28.8 (CH3), C-5: 27.6 (CH2), C-19: 27.4 (CH3), C-16: 17.0 (CH3),
C-17: 16.6 (CH3), C-18: 14.8 (CH3). HRMS (ESI-TOF): (C26H42O6Na)
calcd 473.2874, found 473.2868.
4.9.10. Fuscol-PEG-3/eunicol-PEG-3 (22/23). Solvolysis of 3 and 4
(3.8 mg, 13 mmol) was performed according to general procedure E
using triethylene glycol and the desired products were separated by
phenyl-hexyl RP-HPLC (87% CH3OH/H2O). Compound 22 (1.1 mg,
60%): [
a
]
27þ5.31 (c 5.83ꢁ10ꢂ4 in CH3OH); IR: 3435, 3080, 2972,
D
2927, 2864, 1637, 1122, 1082. 1H NMR (600 MHz, CD3OD):
d H-13:
6.45 (dd, J¼15.4, 10.5, 1H), H-12: 5.90 (d, J¼10.5, 1H), H-6: 5.84 (dd,
J¼17.7, 10.9, 1H), H-14: 5.58 (d, J¼15.4, 1H), H-5: 4.90 (dd, J¼17.7, 1.1,
1H), H-5: 4.88 (dd, J¼10.9, 1.1, 1H), H-4: 4.81 (br s, 1H), H-4: 4.61 (br
s, 1H), H-60: 3.66 (dd, J¼5.3, 4.2, 2H), H-30: 3.67e3.63 (m, 2H), H-40:
3.67e3.63 (m, 2H), H-20: 3.59 (dd, J¼5.8, 4.4, 2H), H-50: 3.56 (dd,
J¼5.5, 4.5, 2H), C-10: 3.47 (dd, J¼5.8, 4.4, 2H), H-2: 2.05 (ddd, J¼12.8,
3.0, 1H), H-10: 2.03e1.98 (m, 1H), H-18: 1.79 (s, 3H), H-16: 1.71 (s,
3H), H-1: 1.67 (ddd, J¼12.8, 12.4, 1H), H-9: 1.57e1.53 (m, 2H), H-8:
1.56e1.53 (m, 1H), H-1: 1.49e1.45 (m, 1H), H-8: 1.46e1.43 (m, 1H),
H-19/20: 1.30 (s, 6H), H-17: 1.03 (s, 3H). 13C NMR (150 MHz,
CD3OD): C-6: 151.6 (CH), C-3: 149.0 (C), C-11: 144.3 (C), C-14: 137.8
(CH), C-13: 127.4 (CH), C-12: 124.0 (CH), C-4: 112.7 (CH2), C-5: 110.4
(CH2), C-15: 76.7 (C), C-50: 73.7 (CH2), C-20: 72.2 (CH2), C-30: 71.7
(CH2), C-40: 71.5 (CH2), C-10: 63.2 (CH2), C-60: 62.3 (CH2), C-2: 54.0
(CH), C-10: 49.2 (CH), C-8: 41.1 (CH2), C-7: 40.8 (C), C-1: 34.1 (CH2),
C-9: 27.9 (CH2), C-19: 26.9 (CH3), C-20: 26.9 (CH3), C-16: 25.3 (CH3),
C-17: 17.2 (CH3), C-18: 15.3 (CH3). HRMS (ESI-TOF): (C26H44O4Na)
4.9.9. Fusco-
b
-
D
-arabinopyranoside/eunico-
b-D-arabinopyranoside
(20/21). Aglycones 3 and 4 (33.8 mg, 117
mmol) were glycosylated
using 9 according to general procedure C and the glycosylation
crude was deprotected according to general procedure D. The de-
sired glycosides were separated by phenyl-hexyl RP-HPLC (81%
CH3OH/H2O). 20 (1.3 mg, 9%): [
a
]
27ꢂ6.13 (c 6.67ꢁ10ꢂ4 in CH3OH);
calcd 443.3132, found 443.3124. 23 (1.5 mg, 36%): [
a
]
27 ꢂ14.3
D
D
IR: 3382, 3081, 2972, 2926, 2856, 1636, 1085. 1H NMR (600 MHz,
(c 5.83ꢁ10ꢂ4 in CH3OH); IR: 3449, 3040, 2971, 2923, 2860, 1650,
CD3OD):
d
H-13: 6.48 (dd, J¼15.8, 10.9, 1H), H-12: 5.89 (d, J¼10.5,
1122, 1081. 1H NMR (600 MHz, CD3OD):
d
H-13: 6.40 (dd, J¼15.4,
1H), H-6: 5.84 (dd, J¼17.3, 10.9, 1H), H-14: 5.72 (d, J¼15.4, 1H), H-5:
4.90 (dd, J¼17.3,1.5,1H), H-5: 4.88 (dd, J¼10.9,1.5,1H), H-4: 4.81 (br
s, 1H), H-4: 4.61 (br s, 1H), H-10: 4.27 (d, J¼6.8, 1H), H-50: 3.79 (dd,
J¼12.4, 2.6, 1H), H-40: 3.78e3.76 (m, 1H), H-20: 3.51e3.49 (m, 1H),
H-30: 3.51e3.49 (m, 1H), H-50: 3.47 (dd, J¼12.4, 1.1, 1H), H-2: 2.05
(ddd, J¼12.8, 3.4, 1H), H-10: 2.04e1.98 (m, 1H), H-18: 1.79 (s, 3H),
H-16: 1.71 (s, 3H), H-1: 1.67 (ddd, J¼12.8, 1H), H-9: 1.57e1.53
(m, 2H), H-8: 1.56e1.52 (m, 1H), H-1: 1.49e1.45 (m, 1H), H-8: 1.44
(dd, J¼9.0, 2.6, 1H), H-19: 1.39 (s, 3H), H-20: 1.35 (s, 3H), H-17: 1.03
(s, 3H). 13C NMR (150 MHz, CD3OD): C-6: 151.6 (CH), C-3: 149.0 (C),
C-11: 144.4 (C), C-14: 138.1 (CH), C-13: 127.1 (CH), C-12: 124.1 (CH),
C-4: 112.7 (CH2), C-5: 110.4 (CH2), C-10: 100.2 (CH), C-15: 79.1 (C),
10.9, 1H), H-12: 5.85 (d, J¼10.5, 1H), H-14: 5.57 (d, J¼15.4, 1H), H-2/
6: 5.25e4.94 (br m, 1.2H), H-6: 4.80 (br d, J¼13.2, 0.4H), H-2: 4.56
(br d, J¼10.2, 0.4H), H-60: 3.66 (dd, J¼5.3, 4.5, 2H), H-30: 3.66e3.62
(m, 2H), H-40: 3.66e3.62 (m, 2H), H-20: 3.61e3.58 (m, 2H), H-50:
3.57 (dd, J¼5.3, 4.5, 2H), H-10: 3.49e3.46 (m, 2H), H-8: 2.40e2.34
(m,1H), H-5: 2.33e2.25 (m, J¼12.0, 4.5,1H), H-1: 2.21e2.16 (m, 1H),
H-4: 2.19e2.15 (m, 1H), H-1: 2.10e2.04 (m, 1H), H-8: 2.08e2.03
(m, 1H), H-5: 2.07e2.02 (m, 1H), H-10: 2.02e1.96 (m, 1H), H-4:
1.93e1.87 (m, J¼11.7, 4.9, 1H), H-18: 1.78 (s, 1.2H), H-18: 1.75
(s, 1.8H), H-9: 1.69e1.64 (m, 2H), H-16: 1.60e1.54 (br s, 1.2H), H-16:
1.54 (s, 1.8H), H-17: 1.54e1.46 (br s, 1.8H), H-17: 1.41 (s, 1.2H), H-19/
20: 1.31 (s, 6H). 13C NMR (150 MHz, CD3OD): C-11: 147.8 (C), C-7:

D.H. Marchbank, R.G. Kerr / Tetrahedron 67 (2011) 3053e3061
3061
138.9 (C), C-14: 137.6 (CH), C-2: 132.6 (CH), C-3: 130.2 (C), C-6:
127.6 (CH), C-13: 127.3 (CH), C-12: 123.0 (CH), C-15: 76.8 (C), C-50:
73.7 (CH2), C-20: 72.1 (CH2), C-30: 71.6 (CH2), C-40: 71.4 (CH2), C-10:
63.1 (CH2), C-60: 62.2 (CH2), C-10: 54.8 (CH), C-8: 42.8 (CH2), C-4:
40.6 (CH2), C-1: 35.8 (CH2), C-9: 34.7 (CH2), C-5: 27.6 (CH2), C-19:
26.9 (CH3), C-20: 26.9 (CH3), C-16: 17.0 (CH3), C-17: 16.6 (CH3), C-18:
14.8 (CH3). HRMS (ESI-TOF): (C26H44O4Na) calcd 443.3132, found
443.3111.
(0.9 mg, 12%). All spectroscopic data were in accord with the
literature.8
Acknowledgements
The authors gratefully acknowledge financial support from
Natural Sciences and Engineering Council of Canada (NSERC), the
Canada Research Chair Program, the University of Prince Edward
Island, the Atlantic Innovation Fund, and the Jeanne and Jean-Louis
4.9.11. Fuscol-PEG-4/eunicol-PEG-4 (24/25). Solvolysis of 3 and 4
(11.4 mg, 39.5 mmol) was performed according to general pro-
cedure E using tetraethyleneglycol and the desired products were
separated by phenyl-hexyl RP-HPLC (86% CH3OH/H2O). Compound
ꢁ
Levesque Foundation. The authors would also like to acknowledge
services provided by Amplia PharmaTek Inc. and the mass spec-
trometry laboratory at Dalhousie University.
24 (2.2 mg, 36%): [
a
]
27 þ2.38 (c 1.75ꢁ10ꢂ3 in CH3OH); IR: 3419,
D
Supplementary data
3080, 2971, 2925, 2864, 1638, 1124, 1081. 1H NMR (600 MHz,
CD3OD):
d
H-13: 6.44 (dd, J¼15.4, 10.5, 1H), H-12: 5.89 (d, J¼10.2,
Copies of 1H and 13C NMR spectra of novel fuscol and eunicol
derivatives are available. Supplementary data associated with
this article can be found in online version at doi:10.1016/
j.tet.2011.03.006.
1H), H-6: 5.84 (dd, J¼17.7, 11.3, 1H), H-14: 5.58 (d, J¼15.4, 1H), H-5:
4.90 (dd, J¼17.3, 1.1, 1H), H-5: 4.88 (dd, J¼10.5, 1.5, 1H), H-4: 4.81 (br
s, 1H), H-4: 4.61 (br s, 1H), H-80: 3.66 (dd, J¼5.5, 4.3, 2H), H-30:
3.67e3.62 (m, 2H), H-30: 3.67e3.62 (m, 2H), H-30: 3.67e3.62
(m, 2H), H-30: 3.67e3.62 (m, 2H), H-20: 3.58 (dd, J¼5.8, 4.2, 2H), H-
70: 3.56 (dd, J¼5.6, 4.2, 2H), H-10: 3.47 (dd, J¼5.7, 4.1, 2H), H-2: 2.05
(ddd, J¼12.8, 3.4, 1H), H-10: 2.04e1.98 (m, 1H), H-18: 1.79 (s, 3H),
H-16: 1.71 (s, 3H), H-1: 1.67 (ddd, J¼12.8, 12.4, 1H), H-9: 1.58e1.54
(m, 2H), H-8: 1.56e1.52 (m, 1H), H-1: 1.49e1.45 (m, 1H), H-8:
1.46e1.41 (m, 1H), H-19/20: 1.31 (s, 6H), H-17: 1.03 (s, 3H). 13C NMR
(150 MHz, CD3OD): C-6: 151.6 (CH), C-3: 148.9 (C), C-11: 144.3 (C),
C-14: 137.8 (CH), C-13: 127.3 (CH), C-12: 124.0 (CH), C-4: 112.8
(CH2), C-5: 110.5 (CH2), C-15: 76.8 (C), C-70: 73.7 (CH2), C-20: 72.1
(CH2), C-30: 71.6 (CH2), C-40: 71.5 (CH2), C-50: 71.5 (CH2), C-60: 71.3
(CH2), C-10: 63.2 (CH2), C-80: 62.3 (CH2), C-2: 54.0 (CH), C-10: 49.2
(CH), C-8: 41.1 (CH2), C-7: 40.8 (C), C-1: 34.1 (CH2), C-9: 27.9 (CH2),
C-19: 26.9 (CH3), C-20: 26.9 (CH3), C-16: 25.4 (CH3), C-17: 17.2
References and notes
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14. Reicheneder, S.; Unverzagt, C. Angew. Chem., Int. Ed. 2004, 43, 4353.
15. Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1980, 19, 731.
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27
487.3394, found 448.3394. 25 (2.0 mg, 15%):
[
a]
ꢂ12.0
D
(c 1.58ꢁ10ꢂ3 in CH3OH); IR: 3436, 3040, 2970, 2922, 2860, 1650,
1121, 1079. 1H NMR (600 MHz, CD3OD):
d
H-13: 6.40 (dd, J¼15.5,
ꢂ
ꢂꢂ ꢁ
19. Pís, J.; Hykl, J.;
ˇ Budesínˇ sky, M.; Harmatha, J. Tetrahedron 1994, 32, 9679.
10.9,1H), H-12: 5.85 (d, J¼9.5,1H), H-14: 5.57 (d, J¼15.6,1H), H-2/6:
5.26e4.94 (br m, 1.2H), H-6: 4.80 (br d, J¼12.1, 0.4H), H-2: 4.55 (br
d, J¼10.4, 0.4H), H-80: 3.67 (dd, J¼5.3, 4.5, 2H), H-30: 3.67e3.63
(m, 2H), H-40: 3.67e3.63 (m, 2H), H-50: 3.67e3.63 (m, 2H), H-60:
3.67e3.63 (m, 2H), H-20: 3.60e3.56 (m, 2H), H-70: 3.56 (dd, J¼5.3,
4.1, 2H), H-10: 3.49e3.46 (m, 2H), H-8: 2.40e2.34 (m, 1H), H-5:
2.33e2.25 (m, 1H), H-1: 2.22e2.18 (m, 1H), H-4: 2.20e2.15 (m, 1H),
H-1: 2.10e2.07 (m, 1H), H-8: 2.09e2.04 (m, 1H), H-5: 2.08e2.03
(m, 1H), H-10: 2.02e1.96 (m, 1H), H-4: 1.94e1.87 (m, J¼12.4, 5.3,
1H), H-18: 1.78 (s,1.2H), H-18: 1.75 (s,1.8H), H-9: 1.70e1.64 (m, 2H),
H-16: 1.60e1.54 (br s, 1.2H), H-16: 1.54 (s, 1.8H), H-17: 1.54e1.46 (br
s, 1.8H), H-17: 1.41 (s, 1.2H), H-19/20: 1.31 (s, 6H). 13C NMR
(150 MHz, CD3OD): C-11: 147.8 (C), C-7: 138.9 (C), C-14: 137.7 (CH),
C-2: 132.6 (CH), C-3: 130.2 (C), C-6: 127.7 (CH), C-13: 127.3 (CH),
C-12: 123.0 (CH), C-15: 76.8 (C), C-70: 73.7 (CH2), C-20: 72.2 (CH2), C-
30: 71.6 (CH2), C-40: 71.5 (CH2), C-50: 71.5 (CH2), C-60: 71.4 (CH2), C-
10: 63.2 (CH2), C-80: 62.2 (CH2), C-10: 54.8 (CH), C-8: 42.8 (CH2), C-4:
40.6 (CH2), C-1: 35.8 (CH2), C-9: 34.8 (CH2), C-5: 27.6 (CH2), C-19:
26.9 (CH3), C-20: 26.9 (CH3), C-16: 17.0 (CH3), C-17: 16.6 (CH3), C-18:
14.8 (CH3). HRMS (ESI-TOF): (C28H48O5Na) calcd 487.3394, found
487.3389.
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4.9.12. Fuscol and eunicol methyl ethers (26/27). Solvolysis of 3 and
4 (9.4 mg, 33 mmol) was performed according to general procedure
E (THF not required) using methanol and separation by phenyl-
hexyl RP-HPLC (94% CH3OH/H2O) yielded 26 (1.8 mg, 54%) and 27
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