The dimethoxyphenylbenzyl protecting group: An alternative to the p-methoxybenzyl group for protection of carbohydrates

Article abstract of DOI:10.1021/jo4004184

A reliable reagent system for the cleavage of 4-(3,4-dimethoxyphenyl)benzyl (DMPBn) ethers under acidic conditions has been established. Treatment of DMPBn-protected mono- and pseudodisaccharides with TFA in anhydrous CH ₂Cl₂ and 3,4-(methylenedioxy)toluene as a cation scavenger resulted in the selective cleavage of the DMPBn ether giving the corresponding deprotected products in moderate to high yields. Examples are reported which show that allyl, benzyl, and p-bromobenzyl ethers, esters, and glycosidic linkages are stable to these reaction conditions. The selective cleavage of allyl, p-bromobenzyl, and PMB ethers in protected carbohydrates containing DMPBn ethers are also demonstrated. This work establishes the 4-(3,4-dimethoxyphenyl) benzyl ether as an effective and robust alternative to p-methoxybenzyl as a protecting group for alcohols.

Full text of DOI:10.1021/jo4004184

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Article
The Dimethoxyphenylbenzyl Protecting Group: An
Alternative to the PMB Group for Protection of Carbohydrates
Gregory Murray Rankin, Isobel Maxwell-Cameron, Gavin F. Painter, and David S Larsen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4004184 • Publication Date (Web): 07 May 2013
Downloaded from http://pubs.acs.org on May 13, 2013
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The Dimethoxyphenylbenzyl Protecting Group: An Alternative to the PMB
Group for Protection of Carbohydrates
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Gregory M. Rankin,a Isobel MaxwellꢀCameron,a Gavin F. Painter,b and David S. Larsen*, a
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aUniversity of Otago, PO Box 56, Dunedin, New Zealand
bCarbohydrate Chemistry Team, Industrial Research Limited, PO Box 31310, Lower Hutt, New Zealand
dlarsen@chemistry.otago.ac.nz
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OMe
OMe
OBn
OH
OBn
BnO
O
O
BnO
OBn
30% TFA/CH2Cl2
OBn
OBn
O
O
BnO
OBn
OBn
OBn
O
O
OBn
OBn
OBn
O
OBn
79%
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OBn
Four further examples are reported with yields ranging from 75 to 87%
Graphical Abstract
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ABSTRACT
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A reliable reagent system for the cleavage of 4ꢀ(3,4ꢀdimethoxyphenyl)benzyl (DMPBn)
ethers under acidic conditions has been established. Treatment of DMPBnꢀprotected monoꢀ
and pseudoꢀdiꢀsaccharides with TFA in anhydrous CH2Cl2 and 3,4ꢀmethylenedioxytoluene as
a cation scavenger resulted in the selective cleavage of the DMPBn ether giving the
corresponding deprotected products in moderate to high yields. Examples are reported which
show that allyl, benzyl and pꢀbromobenzyl ethers, esters, and glycosidic linkages are stable to
these reaction conditions. The selective cleavage of allyl, pꢀbromobenzyl, and PMB ethers in
protected carbohydrates containing DMPBn ethers are also demonstrated. This work
establishes the 4ꢀ(3,4ꢀdimethoxyphenyl)benzyl ether as an effective and robust alternative to
pꢀmethoxybenzyl as a protecting group for alcohols.
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INTRODUCTION
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Phosphatidylinositol mannosides (PIMs), compounds that are found in the cell wall of
mycobacteria, have received much attention due to their immune regulatory properties. In a
programme of research aimed at utilising synthetic PIMs for the treatment of diseases such as
asthma and also for natural product structural elucidation we have developed syntheses of the
major PIM species found in the cell wall as well as simplified analogues that retain some
aspects of their biological activities.1ꢀ8 More recently, we have reported the first total
synthesis of a fully lipidated PIM, Ac2PIM2 19 that contains four fatty acid residues (Figure
1).
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6''
RO
OH
O
HO
HO
O
O
2
R'O
O
3
OH
HO
HO
sn-2
O
O
O
P
6
1
sn-1
O
O
O
OH
OH
O
OH
OH
1
(16:0,18:0)(19:0/16:0)-PIM2
R = C15H31CO, R' = C17H35CO
Figure 1. Ac2PIM2 1.
The synthesis of 1 required orthogonal protection of a myoꢀinositol intermediate that allowed
sequential introduction of each of the mannose residues, the Oꢀ6” fatty ester, the Oꢀ3 fatty
ester and finally the Oꢀ1 phosphatidyl group. The choice of protecting groups proved crucial.
In the course of our work we found that the lability of pꢀmethoxybenzyl (PMB) ethers was
problematic; conditions required for glycosylation reactions resulted in the undesired removal
of the PMB group. A similar hydrolysis has been observed by Seeberger et al., who used it to
their advantage, in the synthesis of a fully lipidated GPI anchor of T. gondii.10 Our results
prompted us to explore the use of the 4ꢀ(3,4ꢀdimethoxyphenyl)benzyl (DMPBn) group,
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developed by the Seeberger group,11 as a robust alternative to the PMB group for the
protection of alcohols. They found that DMPBn ethers were as labile as PMB ethers when
treated with DDQ but were more resistant to acid hydrolysis. Furthermore, oxidative removal
of this group could be carried out selectively in the presence of ester, TBS, benzyl and allyl
protecting groups as exemplified using protected monoꢀ and diꢀsaccharides.
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Our strategy for the synthesis of Ac2PIM2 relied on the intermediacy of protected pseudoꢀ
trisaccharide 2.9 Unfortunately, removal of the DMPBn protecting group proved problematic.
Using the reported reaction conditions of three equivalents of DDQ in a 10 to 1 mixture of
CH2Cl2 and water for three hours, a complex mixture of products was formed (Scheme 1,
TLC provided in supporting information). Mass spectral analyses of column fractions
revealed that they contained 3 and compounds where the DMPBn group had been removed
along with loss of some of the benzyl protecting groups. Seeberger et al. had noted that the
DDQꢀlabile DMPBn group could not be removed selectively when operating on a
hexasaccharide intermediate for the synthesis of a fully lipidated GPI anchor of P.
falciparum.12 Given our investment in preparing late stage intermediate 2 we investigated
developing reaction conditions for the selective deprotection of DMPBn ethers, thereby
increasing the scope and utility of this protecting group.
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O
O
C15H31
O
OBn
O
C15H31
O
OBn
O
BnO
BnO
BnO
BnO
O
O
HO
O
O
DMPBnO
BnO
a, b or c
OAll
BnO
BnO
OAll
BnO
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OBn
OBn
OBn
O
OBn
OBn
OBn
O
OBn
OBn
2
3
Reagents and conditions: (a) DDQ (3 eq.), CH2Cl2/H2O, 3 h; (b) DDQ (1.2 eq.) CH2Cl2/H2O, 1 h; (c) DDQ (3 eq.),
Mn(OAc)3.H2O (3 eq.), CH2Cl2/H2O, 12 h.
Scheme 1. Deprotection of pseudoꢀtrisaccharide 2 using DDQ.
RESULTS AND DISCUSSION
We proposed to optimise the conditions required for the selective removal of the DMPBn
protecting group using inositols 4aꢀc, prepared from bisꢀisopropylideneꢀmyoꢀinositol 513ꢀ15
(Scheme 2). DMPBn protected inositol 6 was prepared by the selective alkylation of 5 with 4ꢀ
(3,4ꢀdimethoxyphenyl)benzyl bromide in 85% yield. Allylation of DMPBn alcohol 6
furnished allyl ether 7a in 91% yield. Acidic cleavage of the isopropylidene groups and
subsequent benzylation afforded model inositol 4a. PMB and PBB inositol ethers 4b and 4c
were prepared using the same approach. Given literature precedence for the successful
hydrolysis of DMPBn protected monosaccharides,11 4a should undergo oxidative
deprotection with minimal side reactions occurring.
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O
O
OBn
OR
RO
DMPBnO
DMPBnO
BnO
BnO
O
O
b
c, d
O
O
O
OBn
O
OH
OR
7a
4a R = All
5 R = H
R = All
a
4b
4c
7b R = PMB
7c R = PBB
R = PMB
R = PBB
6
R = DMPBn
9
OCH3
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DMPBn =
OCH3
Reagents and conditions: (a) DMPBnBr, NaH, THF, 85%; (b) for 7a AllBr, NaH, DMF, 91%; for 7b, PMBCl, NaH,
THF, 86%; for 7c, PBBBr, NaH, THF, 89%; (c) TFA, MeOH, CH2Cl2; (d) BnBr, NaH, DMF, for 7a, 45%; for 7b,
24%, for 7c, 74% (2 steps) .
Scheme 2. Synthesis of model protected inositols 4aꢀc.
Unexpectedly, reaction of 4a with 3 equivalents of DDQ in a 10 to 1 mixture of CH2Cl2 and
water for 3 hours gave a complex mixture of products as determined by TLC and NMR
analysis (Scheme 3a). Loss of benzyl groups was evident from the mass spectrum of the
crude product. None of the starting material 4a remained and the desired product 8a was
isolated in 11% yield. Reducing the reaction time to 1 hour showed an improvement giving a
2.5:1 inseparable mixture of product to starting material along with decomposition products.
Reducing the amount of DDQ to 1.2 equivalents gave the best result with a 50% conversion
of 4a into 8a with no evidence of decomposition products. Column chromatography of this
reaction gave an 80% recovery of material containing a 1:1 inseparable mixture of 4a and 8a
along with 4ꢀ(3,4ꢀdimethoxyphenyl)benzaldehyde. Given the latter result these reaction
conditions were trialled with pseudoꢀtrisaccharide 2, but unexpectedly no reaction occurred.
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OBn
OBn
OAll
DMPBnO
HO
a or b
BnO
BnO
OBn
OBn
BnO
BnO
OAll
4a
8a
6
7
8
Reagents and conditions: (a) DDQ, CH2Cl2/H2O, 11%; (b) DDQ, Mn(OAc)3.H2O, CH2Cl2/H2O.
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Scheme 3. Deprotection of model DMPBn protected inositol 4a.
Sharma et al.16 have reported that Mn(OAc)3 is a mild and efficient reagent for regenerating
DDQ for the deprotection of PMB ethers. The use of this as a coꢀoxidant would minimise the
amount of DDQH2 present. Treatment of 4a with 0.1 equivalents of DDQ and 3 equivalents
of Mn(OAc)3 for 12 hours resulted in a 30% conversion into 8a with no sign of byproduct
formation (Scheme 3 reagents b). Increasing the amount of DDQ to 1 equivalent cleanly gave
an 80% conversion into 8a. Unfortunately, reaction of pseudoꢀtrisaccharide 2 under these
conditions gave a complex mixture of products along with starting material.
Given the disappointing results using DDQ to deprotect DMPBn ethers our attention turned
to exploiting its acid lability. Treatment of 2 with 20% TFA in CH2Cl2 at room temperature
for 1 h gave a mixture of products as shown by TLC (Scheme 4, TLC provided in supporting
information) and after column chromatography gave returned starting material 2 (18%), the
target pseudoꢀtrisaccharide 3 (58%), along with 10% of a higher molecular weight product 9
that resulted from the electrophilic addition of the released benzylic cation to the substituted
dimethoxyphenyl moiety of 2 (Scheme 4). Mass spectra of the trace amounts of lower Rf
products indicated that further substitution of the dimethoxyphenyl moiety had also occurred.
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A
O
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C15H31
O
OBn
O
BnO
BnO
H3CO
OBn
OCH3
9
O
O
OCH3
OCH3
2
RO
20%
TFA/CH2Cl2
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BnO
OAll
BnO
O
OBn
3
R = H
9 R = A
OBn
OBn
Scheme 4. Deprotection of 2 using 20% TFA for 1 h.
The use of a cation scavenger such as anisole might circumvent this problem. However, we
believed that the electron rich benzyl substituted dimethoxyphenyl moiety of the protecting
group might still be a more effective cation trap. To test this, anisole was treated with five
equivalents of 4ꢀ(3,4ꢀdimethoxyphenyl)benzyl alcohol (10)11 in 30% TFA in CH2Cl2. A
complex mixture of products was produced where further substitution of the activated rings
had occurred. Using the more electron rich scavenger 1,4ꢀdimethoxybenzene (11a) also gave
a mixture of products from which 12a (21%), 13a (13%) and 14a (3%) were isolated
(Scheme 5). Given these results scavengers with similar structural features to the activated
ring of the DMPBn group were investigated. Under the same reaction conditions 3,4ꢀ
dimethoxytoluene (11b)17 gave mainly the monoꢀsubstituted adduct 12b (85%) along with a
small amount of the further substituted species 13b. 3,4ꢀMethylenedioxytoluene (11c)17 gave
a single scavenged product 12c in 93% yield.
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OMe
4
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R4
OMe
OMe
R1
R1
R2
R2
10
+
30% TFA/CH2Cl2
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OMe
OMe
R1
R3
R3
R3
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R2
11a-c
12 a-c
a R1 = R3 = OMe, R2 = H
b
R1 = R2 = OMe, R3 = Me
c R1, R2 = OCH2O, R3 = Me
13a b
,
R4 = H
14a R4 = 4-(3,4 dimethoxyphenyl)benzyl
HO
OMe
10
OMe
Scheme 5. Reactions of 10 with cation scavengers 11aꢀc in 30% TFA in CH2Cl2.
The latter two results were pleasing and the fact that only one product was formed when 11c
was used as the cation trap would facilitate isolation of deprotected DMPBn ethers. Reaction
of 4a with 30% TFA in CH2Cl2 and 5 equivalents of 11c cleanly afforded the deprotected
material 8a in 87% yield (Scheme 6). The scavenged product 12c was isolated in near
quantitative yield. In a similar fashion, PBB ether 4c gave 8c in 75% yield. Further examples
were investigated and subjected to these reaction conditions. DMPBn glucoside 1511 gave the
desired deprotected derivative 16 (86%) and the scavenged product 12c in quantitative yield.
OBn
OR
OBn
OR
DMPBnO
BnO
BnO
HO
a
BnO
BnO
OBn
OBn
12c
+
8a
8c
4a
R = All (87%)
R = PBB (75%)
R = All
4c R = PBB
OH
ODMPBn
O
a
O
BnO
BnO
BnO
BnO
12c
+
BnO
BnO
OCH3
OCH3
15
16
(86%)
Reagents and conditions: (a) 11c (5 eq.), 30% TFA/CH2Cl2.
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Scheme 6. Deprotection of DMPBn inositols 4a and 4c, and glucoside 15 using 30% TFA for 1 h.
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DMPBn protected pseudoꢀdisaccharide 17 was prepared in five steps using standard chemical
transformations from 189 (Scheme 7). Selective hydrolysis of the transꢀfused isopropylidene
group and benzylation afforded 19. Hydrolysis of the cisꢀfused isopropylidene group giving
20, a SuzukiꢀMiyaura coupling of the PBB group with 3,4ꢀdimethoxyphenylboronic acid to
21 and benzylation of the remaining hydroxyl group gave the target compound 17.
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O
O
OH
O
O
O
OPBB
OBn
OBn
OR
OPBB
OBn
O
O
O
HO
O
OBn
a, b
c
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
O
O
O
OBn
19
OBn
OH
18
20
21
R = PBB
R = DMPBn
d
e
OBn
ODMPBn
OBn
OBn
BnO
O
OBn
OBn
OBn
O
OBn
17
Reagents and conditions: (a) TFA, H2O, CH2Cl2, 0 °C, 2.5 h; (b) BnBr, NaH, DMF, 74% 2 steps; (c) TFA, MeOH,
CH2Cl2, 12 h, 85%; (d) K3PO4, Bu4NBr, Pd(OAc)2, 3,4-dimethoxyphenyl boronic acid, EtOH, 69%; (e) BnBr, NaH,
DMF, 80%.
Scheme 7. Synthesis of DMPBn pseudoꢀdisaccharide 17.
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The reaction of pseudoꢀdisaccharide 17 with 30% TFA and scavenger 11c in CH2Cl2 cleanly
gave the selectively deprotected product 22 in 79% yield (Scheme 8).
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OBn
OBn
ODMPBn
OH
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OBn
OBn
a
BnO
BnO
OBn
OBn
12c
+
O
O
O
O
OBn
OBn
OBn
OBn
OBn
OBn
OBn
17
OBn
22
Reagents and conditions: (a) 11c (5 eq.), 30% TFA/CH2Cl2, 22 79%, 12c quant.
Scheme 8. Deprotection of DMPBn pseudoꢀdisaccharide 17 using 30% TFA for 1 h.
The compatibility of the DMPBn protecting group with allyl, PMB and PBB ethers was
examined (Scheme 9). The allyl protecting group of 4a was selectively removed by treatment
with hydrogen activated iridium(I) catalyst 23 and subsequent treatment with methanolic HCl
to give 24 in 63% yield. The PMB ether of 4b was selectively hydrolysed upon treatment
with 1% TFA in CH2Cl2 and scavenger 11c providing inositol 24 in 77% yield and scavenged
product 25 in quantitative yield. Deprotection of the PBB ether of 4c was achieved using a
palladium(0) catalysed amination with Nꢀmethylaniline followed by treatment with
methanolic HCl which provided 24 in an unoptimized yield of 52%.
OBn
OR
OBn
OH
DMPBnO
DMPBnO
a, b or c
BnO
BnO
OBn
BnO
OBn
BnO
O
O
24
4a
MeO
R = All
4b R = PMB
4c
R = PBB
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Reagents and conditions: (a) for 4a, (COD)(MePh2P)2Ir+PF6- (23), H2, THF then AcCl, MeOH/CH2Cl2 (63%); (b)
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for 4b, 1% TFA in CH2Cl2, 11c, 1 h (77%); (c) for 4c, MeNHC5H4N, (o-biphenyl)P(t-Bu)2, Pd2dba3, NaOt-Bu, tol
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(52%)
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Scheme 9. Selective deprotections of 4aꢀc in the presence of a DMPBn ether.
The ultimate test of this reagent system was for the removal of the DMPBn group on 2. As
reported in our earlier paper9 this reaction cleanly afforded the pseudoꢀtrisaccharide 3 in 74%
yield.
CONCLUSION
In conclusion, we have developed an alternative method for the deprotection of DMPBn
ethers, using anhydrous TFA in CH2Cl2, in the presence of either 3,4ꢀdimethoxyꢀ or 3,4
methylenedioxyꢀtoluene as a cation scavenger. Allyl and benzyl ethers, esters, and glycosidic
bonds were unaffected by this reagent system. Furthermore, we have demonstrated that allyl,
PMB and PBB ethers can be selectively removed in the presence of the DMPBn group. This
method, along with the use of either DDQ or a combination of DDQ and Mn(OAc)3,
increases the scope of the DMPBn protecting group in organic synthesis by providing an
alternative to the acidꢀlabile PMB protecting group.
EXPERIMENTAL SECTION
1H NMR spectra were obtained at 400 or 500 MHz and referenced to the residual solvent
peak (1H CHCl3 δ 7.26 ppm). 13C NMR spectra were recorded at 125 MHz and referenced to
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the internal solvent (CDCl3, δ 77.0 ppm). Electroꢀspray ionization (ESI) mass spectra were
recorded on a microTOFQ mass spectrometer. Anhydrous solvents were sourced either
commercially or from a solvent purification system and used without further treatment unless
stated. Powdered molecular sieves were flame dried under vacuum immediately prior to use.
Flash column chromatography was carried out using 40–63 ꢁm silica gel unless otherwise
stated. All flash chromatography solvents were LRꢀgrade. Petroleum ether with a bp range
60–80°C was used. All compounds were isolated after silicaꢀgel column chromatography and
fractions collected were one spot by TLC. Thin layer chromatography (TLC) plates were
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visualised under an UV lamp and/or with
a
spray consisting of 5% w/v
dodecamolybdophosphoric acid in ethanol with subsequent heating.
(±)ꢀ3ꢀOꢀ(4ꢀ(3,4ꢀDimethoxyphenyl)benzyl)ꢀ1,2:4,5ꢀdiꢀOꢀisopropylideneꢀmyoꢀinositol (6)
To a solution of diol 513ꢀ15 (3.05 g, 11.7 mmol) in dry THF (150 mL) was added NaH (60%
dispersion in oil, 0.558 g, 23.26 mmol) and 4ꢀ(3,4ꢀdimethoxyphenyl)benzyl bromide11 (1.79
g, 5.81 mmol) and refluxed overnight under an atmosphere of nitrogen. The reaction mixture
was quenched with H2O (5 mL) and extracted into EtOAc (3 × 100 mL), washed with H2O
(100 mL) and brine (100 mL). The organic extract was dried (MgSO4), filtered and the
solvent removed in vacuo. The residue was purified by column chromatography on silica gel
(EtOAc/petroleum ether = 2:3 to 1:1) to give the title compound 6 as a white solid (2.41 g,
85%). m.p. 143ꢀ146 °C (EtOAc/PE); νmax (ATRꢀIR) 3519, 2985, 2934, 2888, 2832, 1603,
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1590, 1525, 1464, 1465, 1399, 1371, 1242, 1215, 1168, 1140, 1120, 1073, 1046 cmꢀ1; H
NMR (500 MHz, CDCl3) δ 1.36 (s, 3H), 1.47 (s, 3H), 1.50 (s, 3H), 1.55 (s, 3H), 2.55 (d, J =
2.6 Hz, 1H), 3.28 (dd, J = 9.4, 10.5 Hz, 1H), 3.83 (dd, J = 4.2, 10.1 Hz, 1H), 3.88ꢀ3.96 (m,
2H), 3.92 (s, 3H), 3.95 (s, 3H), 4.06 (t, J = 9.7 Hz, 1H), 4.35 (t, J = 4.5 Hz, 1H), 4.83 (d, J =
12.6 Hz, 1H), 4.93 (d, J = 12.5 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 2.1 Hz, 1H),
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7.15 (dd, J = 2.1, 8.3 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H); C NMR
(125 MHz, CDCl3) δ 26.0, 27.02, 27.06, 28.3, 56.02, 56.06, 71.6, 74.4, 74.6, 76.7, 77.4, 78.4,
81.7, 110.3, 110.5, 111.6, 112.6, 119.4, 126.9, 128.9, 133.9, 136.4, 140.8, 148.8, 149.3;
HRMSꢀESI [M+Na]+ Calcd for C27H34NaO8: 509.2146. Found: 509.2163; Anal. Calcd for
C27H34O8: C, 66.65; H, 7.04. Found: C, 66.41; H, 7.22.
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(±)ꢀ6ꢀOꢀAllylꢀ3ꢀOꢀ(4ꢀ(3,4ꢀdimethoxyphenyl)benzyl)ꢀ1,2:4,5ꢀdiꢀOꢀisopropylideneꢀmyoꢀ
inositol (7a)
To a solution of alcohol 6 (1.400 g, 2.87 mmol) in anhydrous DMF (20 mL) was added NaH
(60% dispersion in oil, 0.138 g, 5.75 mmol) and allyl bromide (0.50 mL, 5.75 mmol) at 0 °C
and the reaction mixture was left to stir overnight. The reaction was quenched with H2O and
extracted into CH2Cl2 (3 × 50 mL). The combined organic layers were washed with H2O (50
mL) and brine (50 mL), then dried (MgSO4), filtered and the solvent removed in vacuo. The
residue was purified by column chromatography on silica gel (EtOAc/petroleum ether = 1:2)
to give the title compound 7a (1.38 g, 91%) as a white solid. m.p. 123ꢀ126 °C (EtOAc/PE);
vmax (ATRꢀIR) 2991, 2932, 2882, 2837, 1603, 1590, 1525, 1504, 1455, 1417, 1397, 1374,
1329, 1279, 1239, 1214, 1168, 1157, 1138, 1122, 1085, 1070, 1055 cmꢀ1; H NMR (500
1
MHz, CDCl3) δ 1.35 (s, 3H), 1.46 (s, 3H), 1.49 (s, 3H), 1.55 (s, 3H), 3.30 (dd, J = 9.4, 10.6
Hz, 1H), 3.66 (dd, J = 6.5, 10.7 Hz, 1H), 3.78 (dd, J = 4.2, 10.1 Hz, 1H), 3.93 (s, 3H), 3.95 (s,
3H), 4.01ꢀ4.08 (m, 2H), 4.27 (dt, J = 1.4, 5.7 Hz, 2H), 4.34 (t, J = 4.6 Hz, 1H), 4.83 (d, J =
12.6 Hz, 1H), 4.93 (d, J = 12.7 Hz, 1H), 5.18 (dq, J = 10.4, 1.4 Hz, 1H), 5.31 (dq, J = 17.1,
1.6 Hz, 1H), 5.94 (dddd, J = 5.7, 5.7, 10.4, 17.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 7.10 (d, J
= 2.1 Hz, 1H), 7.15 (dd, J = 2.2, 8.2 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz,
2H); 13C NMR (125 MHz, CDCl3) δ 26.0, 27.09, 27.13, 28.1, 56.02, 56.06, 71.3, 71.6, 74.4,
76.9, 77.2, 78.7, 80.1, 81.4, 110.0, 110.5, 111.6, 112.2, 117.4, 119.4, 126.9, 128.9, 133.9,
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134.8, 136.5, 140.7, 148.8, 149.2; HRMSꢀESI [M+Na]+ Calcd for C30H38NaO8: 549.2459.
Found: 549.2491.
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(±)ꢀ6ꢀOꢀAllylꢀ3ꢀOꢀ(4ꢀ(3,4ꢀdimethoxyphenyl)benzyl)ꢀ1,2,4,5ꢀtetraꢀOꢀbenzylꢀmyoꢀinositol
(4a)
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To a solution of allyl ether 7a (0.708 g, 1.34 mmol) in CH2Cl2 (10 mL) was added MeOH
(0.136 mL, 3.36 mmol) and TFA (0.518 mL, 6.72 mmol) and the reaction mixture was stirred
at rt overnight. The solvent was evaporated under reduced pressure to afford (±)ꢀ6ꢀOꢀallylꢀ3ꢀ
Oꢀ(4ꢀ(3,4ꢀdimethoxyphenyl)benzyl)ꢀmyoꢀinositol (0.60 g) as a white foam which was used
without further purification. HRMSꢀESI [M+Na]+ Calcd for C24H30O8Na: 469.1833. Found:
469.1826. NaH (0.322 g, 60% dispersion in oil, 13.4 mmol) was added to a stirred solution of
crude tetraol (0.60 g, 1.34 mmol) and BnBr (1.28 mL, 10.8 mmol) in dry DMF (10 mL) at 0
°C. The reaction was left to warm to rt and stirred overnight. Excess NaH was quenched with
MeOH (2 mL) and the solvent was removed in vacuo. The residue was extracted into CH2Cl2
(3 × 50 mL) and the combined organic layers were washed with H2O (3 × 25 mL), brine (25
mL) and dried (MgSO4). The solution was filtered and the solvent removed in vacuo. The
residue was purified by column chromatography on silica gel (EtOAc/petroleum ether = 1:9
to 1:2) to give the title compound 4a (0.492 g, 45%) as a white solid. m.p. 132ꢀ136 °C
(EtOAc/PE); vmax (ATRꢀIR) 3087, 3062, 3028, 2923, 2882, 1603, 1589, 1566, 1504, 1453,
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1396, 1359, 1326, 1275, 1256, 1217, 1172, 1134, 1086, 1066, 1024 cmꢀ1; H NMR (500
MHz, CDCl3) δ 3.31 (dd, J = 2.2, 9.9 Hz, 1H), 3.37 (dd, J = 2.3, 9.8 Hz, 1H), 3.44 (t, J = 9.3
Hz, 1H), 3.93ꢀ3.98 (m, 1H), 3.94 (s, 3H), 3.96 (s, 3H), 4.04ꢀ4.08 (m, 2H), 4.33 (ddt, J = 1.1,
5.7, 12.3 Hz, 1H), 4.41 (ddt, J = 1.3, 5.9, 12.2 Hz, 1H), 4.60 (d, J = 11.8 Hz, 1H), 4.62ꢀ4.71
(m, 3H), 4.81ꢀ4.90 (m, 5H), 4.93 (d, J = 10.8 Hz, 1H), 5.15 (dq, J = 10.3, 1.4 Hz, 1H), 5.27
(dq, J = 17.2, 1.6 Hz, 1H), 5.98 (dddd, J = 5.8, 5.8, 10.4, 17.1 Hz, 1H), 6.95 (d, J = 8.3 Hz,
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1H), 7.11 (d, J = 2.1 Hz, 1H), 7.16 (dd, J = 2.1, 8.3 Hz, 1H), 7.26ꢀ7.38 (m, 20H), 7.40ꢀ7.42
(m, 2H), 7.49ꢀ7.52 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 56.04, 56.08, 72.5, 72.9, 74.2,
74.6, 74.7, 75.9, 76.0, 80.90, 80.94, 81.5, 81.7, 83.8, 110.5, 111.6, 116.7, 119.4, 126.9, 127.0,
127.4, 127.54, 127.55, 127.58, 127.62, 127.8, 128.0, 128.10, 128.12, 128.2, 128.37, 128.39,
128.4, 128.6, 134.0, 135.5, 137.1, 138.6, 138.9, 139.0, 139.1, 140.42, 148.7, 149.3; HRMSꢀ
ESI [M+Na]+ Calcd for C52H54NaO8: 829.3711. Found: 829.3680.
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(±)ꢀ6ꢀOꢀparaꢀMethoxybenzylꢀ3ꢀOꢀ(4ꢀ(3,4ꢀdimethoxyphenyl)benzyl)ꢀ1,2:4,5ꢀdiꢀOꢀ
isopropylideneꢀmyoꢀinositol (7b)
To a solution of alcohol 6 (134 mg, 0.275 mmol) and 4ꢀmethoxybenzyl chloride (110 ꢂL,
0.811 mmol) in anhydrous THF (5 mL) was added NaH (60% dispersion in oil, 33 mg, 0.826
mmol) and the mixture refluxed for 1 h, then stirred at rt overnight. The reaction was
quenched with water (30 mL), and the product extracted into CH2Cl2 (3 × 30 mL). The
combined organic layers were washed with brine (30 mL), dried (MgSO4), and the solvent
removed in vacuo. The residue was purified by column chromatography on silica gel
(EtOAc/petroleum ether = 1:9 to 3:7) to give the title compound 7b (144 mg, 86%) as a white
solid. m.p. 122ꢀ124 (EtOAc/PE); νmax (ATRꢀIR) 2982, 2931, 2904, 2836, 1611, 1588, 1566,
1
1504, 1455, 1399, 1372, 1327, 1302, 1242, 1216, 1170, 1142, 1082, 1055, 1023; H NMR
(500 MHz, CDCl3) δ 1.34 (s, 3H), 1.41 (s, 3H), 1.47 (s, 3H), 1.51 (s, 3H), 3.34 (dd, J = 9.5,
10.4 Hz, 1H), 3.67 (dd, J = 6.5, 10.6 Hz, 1H), 3.79 (s, 3H), 3.77ꢀ3.81 (m, 1H), 3.92 (s, 3H),
3.95 (s, 3H), 4.03 (t, J = 9.8 Hz, 1H), 4.05 (dd, J = 5.1, 6.4 Hz, 1H), 4.33 (t, J = 4.6 H, 1H),
4.74 (app. s, 2H), 4.85 (d, J = 12.6 Hz, 1H), 4.92 (d, J = 12.6 Hz, 1H), 6.86 (d, J = 8.7 Hz,
2H), 6.95 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 8.3, 2.1 Hz, 1H), 7.32 (d,
J = 8.6 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H); 13C NMR (125 MHz,
CDCl3) δ 25.9, 27.0, 27.1, 27.9, 55.2, 55.92, 55.96, 71.5, 71.6, 74.3, 76.7, 77.2, 78.8, 79.5,
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81.12, 109.9, 110.4, 111.5, 112.1, 113.6, 119.3, 126.8, 128.8, 129.6, 130.3, 133.8, 138.5,
140.6, 148.7, 149.2, 159.1; HRMSꢀESI [M+Na]+ Calcd for C35H42O9Na: 629.2721. Found:
629.2730.
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(±)ꢀ6ꢀOꢀparaꢀMethoxybenzylꢀ3ꢀOꢀ(4ꢀ(3,4ꢀdimethoxyphenyl)benzyl)ꢀ1,2,4,5ꢀtetraꢀOꢀ
benzylꢀmyoꢀinositol (4b)
Methanol (40 ꢂL, 0.988 mmol) and TFA (26 ꢂL, 0.337 mmol) were added to a solution of
the paraꢀmethoxybenzyl ether 7b (148 mg, 0.244 mmol) in CH2Cl2 (8 mL) and the mixture
was stirred at rt for 7 days. The solvent was removed in vacuo, and the residue dissolved in
CH2Cl2 (30 mL), and washed with water (30 mL), NaHCO3 (30 mL), brine (30 mL), dried
(MgSO4), filtered, and the solvent removed in vacuo. The residue was purified by column
chromatography on silica gel (MeOH/CHCl3 = 1:9) to give (±)ꢀ6ꢀOꢀparaꢀmethoxybenzylꢀ3ꢀ
Oꢀ(4ꢀ(3,4ꢀdimethoxyphenyl)benzyl)ꢀmyoꢀinositol (53 mg) as a slightly impure white solid.
HRMSꢀESI [M+Na]+ Calcd for C29H34O8Na: 549.2095. Found: 549.2114. Anhydrous DMF
(5 mL) and BnBr (230 ꢂL, 1.95 mmol) were added and the mixture cooled to 0 °C under
argon. NaH (98 mg, 2.44 mmol, 60% dispersion in oil) was added with stirring and the
reaction was warmed to rt overnight. Excess NaH was quenched by the addition of H2O (30
mL) and the mixture extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were
washed with NaHCO3 (30 mL), brine (30 mL), dried (MgSO4), filtered, and the solvent
removed in vacuo. The residue was purified by column chromatography on silica gel
(EtOAc/petroleum ether = 1:9 to 3:7) to give the title compound 4b (51 mg, 24%) as a white
solid. m.p. 129ꢀ133 °C (EtOAc/PE); νmax (ATRꢀIR) 3025, 2932, 1730, 1611, 1588, 1503,
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1454, 1400, 1360, 1327, 1302, 1247, 1217, 1171, 1141, 1071, 1027; H NMR (500 MHz,
CDCl3) δ 3.28ꢀ3.33 (m, 2H), 3.41 (t, J = 9.3 Hz, 1H), 3.71 (s, 3H), 3.87 (s, 3H), 3.89 (s, 3H),
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= 8.4 Hz, 2H), 6.89 (d, J = 8.3 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 7.08 (d, J = 2.1 Hz, 1H),
7.10 (d, J = 1.7 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 7.19ꢀ7.38 (m, 21H), 7.44 (d, J = 8.0 Hz,
2H); 13C NMR (125 MHz, CDCl3) δ 55.2, 55.95, 55.99, 72.4, 72.8, 74.1, 74.4, 75.5, 75.9,
80.9, 81.0, 81.7, 83.7, 110.4, 110.5, 113.7, 119.3, 126.8, 127.4, 127.5, 127.7, 127.8, 128.01,
128.07, 128.14, 128.29, 128.31, 128.35, 129.7, 131.0, 133.9, 137.0, 138.4, 138.85, 138.9,
140.0, 140.4, 148.7, 149.2, 150.1; HRMSꢀESI [M+Na]+ Calcd for C57H58O9Na: 909.3973.
Found: 909.3943.
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(±)ꢀ6ꢀOꢀparaꢀBromobenzylꢀ3ꢀOꢀ(4ꢀ(3,4ꢀdimethoxyphenyl)benzyl)ꢀ1,2:4,5ꢀdiꢀOꢀ
isopropylideneꢀmyoꢀinositol (7c)
NaH (60% dispersion in oil, 49 mg, 1.23 mmol) was added to a stirred solution of inositol 6
(155 mg, 0.319 mmol) and 4ꢀbromobenzyl bromide (159 mg, 0.637 mmol) in anhydrous THF
(5 mL) under argon. The reaction mixture was allowed to warm to rt, then heated at reflux
for 30 min. The reaction was quenched with water (30 mL), and the product extracted into
CH2Cl2 (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried
(MgSO4), and the solvent removed in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc/petroleum ether = 1:9 to 3:7) to give the title compound
7c (186 mg, 89%) as a white solid. m.p. 140ꢀ143 °C (EtOAc/PE); νmax (ATRꢀIR) 2987, 2933,
1590, 1566, 1527, 1503, 1488, 1454, 1399, 1372, 1327, 1302, 1421, 1216, 1169, 1141, 1083,
1056, 1025, 1011; 1H NMR (500 MHz, CDCl3) δ 1.34 (s, 3H), 1.42 (s, 3H), 1.47 (s, 3H), 1.49
(s, 3H), 3.34 (dd, J = 10.5, 9.5 Hz, 1H), 3.64 (dd, J = 10.6, 6.5 Hz, 1H), 3.79 (dd, J = 10.2,
4.2 Hz, 1H), 3.93 (s, 3H), 3.95 (s, 3H), 4.01ꢀ4.07 (m, 2H), 4.34 (dd, J = 4.8, 4.3 Hz, 1H), 4.76
(app. s, 2H), 4.83 (d, J = 12.6 Hz, 1H), 4.92 (d, J = 12.6 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H),
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8.4 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H); 13C NMR (125 MHz, CDCl3)
δ 25.9, 27.0, 27.1, 28.0, 55.95, 55.99, 71.2, 71.5, 74.2, 76.8, 77.2, 78.7, 80.2, 81.1, 110.0,
110.4, 111.5, 112.2, 119.4, 121.3, 126.8, 128.8, 129.5, 131.3, 133.8, 136.4, 137.3, 140.7,
148.7, 149.2; HRMSꢀESI [M+Na]+ Calcd for C34H3981BrO8Na: 679.1670. Found: 679.1702.
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(±)ꢀ6ꢀOꢀparaꢀBromobenzylꢀ3ꢀOꢀ(4ꢀ(3,4ꢀdimethoxyphenyl)benzyl)ꢀ1,2,4,5ꢀtetraꢀOꢀbenzylꢀ
myoꢀinositol (4c)
MeOH (24 ꢂL, 0.60 mmol) and TFA (56 ꢂL, 0.73 mmol) were added to a solution of inositol
7c (157 mg, 0.239 mmol) in CH2Cl2 (4 mL) and the reaction mixture was stirred at rt
overnight. The solvent was removed in vacuo to give (±)ꢀ6ꢀOꢀparaꢀbromobenzylꢀ3ꢀOꢀ(4ꢀ(3,4ꢀ
dimethoxyphenyl)benzyl)ꢀmyoꢀinositol as a white solid which was used without further
purification. HRMSꢀESI [M+Na]+ Calcd for C28H3179BrO8Na: 597.1095. Found: 597.1093.
Anhydrous DMF (5 mL) and BnBr (230 ꢂL, 1.93 mmol) were added and the solution cooled
to 0 °C under argon. NaH (60% dispersion in oil, 96 mg, 2.40 mmol) was added and the
reaction was left to warm to rt overnight with stirring. Excess NaH was quenched by the
addition of water (50 mL). The reaction mixture was extracted into CH2Cl2 (3 × 30 mL) and
the combined organic layers were washed with brine (50 mL), dried (MgSO4), and the
solvent removed in vacuo. The residue was purified by column chromatography on silica gel
(EtOAc/petroleum ether = 1:9 to 3:7) to give the title compound 4c (166 mg, 74%) as a white
solid. m.p. 154ꢀ157 °C (EtOAc/PE); νmax (ATRꢀIR) 3029, 2918, 1590, 1529, 1505, 1453,
1
1395, 1359, 1328, 1275, 1256, 1217, 1172, 1134, 1088, 1067, 1036, 1024; H NMR (500
MHz, CDCl3) δ 3.38 (dd, J = 9.9, 2.2 Hz, 1H), 3.41 (dd, J = 9.8, 2.2 Hz, 1H), 3.49 (t, J = 9.3
Hz, 1H), 3.95 (s, 3H), 3.97 (s, 3H), 4.06ꢀ4.14 (m, 3H), 4.62 (app. s, 2H), 4.67 (d, J = 11.8 Hz,
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1H), 4.71 (d, J = 11.8 Hz, 1H), 4.77 (d, J = 11.2 Hz, 1H), 4.83ꢀ4.94 (m, 6H), 4.97 (d, J = 10.7
Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 7.13ꢀ7.15 (m, 3H), 7.18 (dd, J = 8.3, 2.1 Hz, 1H), 7.27ꢀ
7.45 (m, 24H), 7.53 (d, J = 8.2 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 55.9, 56.0, 72.5,
72.7, 74.16, 74.22, 74.8, 75.83, 75.84, 80.85, 80.88, 81.5, 81.7, 83.6, 110.4, 111.5, 119.3,
121.3, 126.8, 127.4, 127.5, 127.6, 127.7, 128.0, 128.2, 128.29, 128.32, 128.36, 129.6, 131.3,
133.8, 136.9, 137.9, 138.2, 138.7, 138.78, 138.89, , 140.9, 148.7, 149.2; HRMSꢀESI [M+Na]+
Calcd for C56H5581BrO8Na: 959.2924. Found: 959.2957.
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(±)ꢀ6ꢀOꢀAllylꢀ1,2,4,5ꢀtetraꢀOꢀbenzylꢀmyoꢀinositol (8a)
Method 1: DDQ (0.042 g, 0.186 mmol) was added to a solution of 4a (0.05 g, 0.062 mmol)
in CH2Cl2/H2O (10:1, 1.1 mL) at rt. After 3 h the reaction mixture was diluted with CH2Cl2
(40 mL) and washed with a freshly prepared aqueous solution of sodium ascorbate (1 mol Lꢀ1,
20 mL) to remove excess DDQ. The aqueous solution was reꢀextracted with CH2Cl2 (3 × 10
mL) and the combined organic fractions were washed with NaHCO3 (30 mL), brine (30 mL)
and dried (MgSO4). The solution was filtered and the solvent removed in vacuo. The residue
was purified by column chromatography on silica gel (EtOAc/petroleum ether = 1:2 to 1:1) to
give the title compound 8a (4 mg, 11%) as a colourless oil.
Method 2: To a solution of 4a (0.030 g, 0.037 mmol) and scavenger 11c (0.025 g, 0.186
mmol) in CH2Cl2 (3.5 mL) was added TFA (1.5 mL) and the reaction was stirred at rt for 1 h.
The reaction was diluted with H2O (40 mL) and extracted into CH2Cl2 (3 × 20 mL). The
combined organic layers were washed with NaHCO3 (20 mL), H2O (20 mL), brine (20 mL),
dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by
column chromatography on silica gel (EtOAc/petroleum ether = 1:4) to give 6ꢀ(4ꢀ(3,4ꢀ
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dimethoxyphenyl)benzyl)ꢀ3,4ꢀ(methylenedioxy)toluene (12c) (0.016 g, quant, Rf = 0.60,
EtOAc/petroleum ether 1:2) and the title compound 8a (0.019 g, 87%, Rf = 0.55,
EtOAc/petroleum ether 1:2) both as colourless oils. Data for 8a: 1H NMR (500 MHz, CDCl3)
δ 2.19 (brs, 1H), 3.38ꢀ3.46 (m, 2H), 3.48 (dd, J = 2.1, 9.7 Hz, 1H), 3.77 (t, J = 9.4 Hz, 1H),
3.92 (t, J = 9.5 Hz, 1H), 4.01 (t, J = 2.4 Hz, 1H), 4.34 (ddt, J = 1.3, 5.7, 12.1 Hz, 1H), 4.43
(ddt, J = 1.3, 5.8, 12.2 Hz, 1H), 4.66ꢀ4.78 (m, 4H), 4.82 (d, J = 10.6 Hz, 1H), 4.89 (d, J =
11.2 Hz, 1H), 4.92 (d, J = 10.7 Hz, 1H), 4.97 (d, J = 11.5 Hz, 1H), 5.16 (dq, J = 10.5, 1.2 Hz,
1H), 5.29 (dq, J = 17.2, 1.6 Hz, 1H), 5.99 (dddd, J = 5.7, 5.7, 10.5, 16.2 Hz, 1H), 7.28ꢀ7.38
(m, 20H); 13C NMR (125 MHz, CDCl3) δ 72.4, 73.1, 74.7, 74.8, 75.6, 75.9, 77.3, 81.0, 81.7,
82.2, 83.6, 116.7, 127.61, 127.63, 127.69, 127.7, 127.8, 128.07, 128.1, 128.4, 128.45, 128.47,
128.5, 135.4, 138.4, 138.68, 138.69, 138.8; HRMSꢀESI [M+Na]+ Calcd for C37H40NaO6:
603.2723. Found: 603.2724.
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Data for 12c: vmax (ATRꢀIR) 2997, 2920, 2850, 1601, 1588, 1530, 1500, 1485, 1467, 1399,
1353, 1312, 1274, 1252, 1217, 1195, 1170, 1148, 1122 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ
2.21 (s, 3H), 3.92 (s, 5H), 3.94 (s, 3H), 5.90 (s, 2H), 6.64 (s, 1H), 6.68 (s, 1H), 6.94 (d, J =
8.3 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 7.12 (dd, J = 2.1, 8.3 Hz, 1H), 7.17 (d, J = 8.2 Hz, 2H),
7.47 (d, J = 8.2 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 19.7, 38.8, 55.98, 56.03, 100.7,
110.3, 110.4, 110.5, 111.5, 119.3, 126.9, 129.0, 129.5, 131.8, 134.1, 138.8, 139.3, 145.7,
145.9, 148.5, 149.2; HRMSꢀESI [M+Na]+ Calcd for C23H22NaO4: 385.1416. Found:
385.1414.
(±)ꢀ6ꢀOꢀparaꢀBromobenzylꢀ1,2,4,5ꢀtetraꢀOꢀbenzylꢀmyoꢀinositol (8c)
TFA (1.5 mL) was added to a solution of 4c (30 mg, 0.032 mmol) and 11c (43 mg, 0.316
mmol) in CH2Cl2 (3.5 mL) and the mixture was stirred at rt for 1 hour. The solvent was
removed in vacuo and the residue was redissolved in CH2Cl2 (30 mL), washed with water (30
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mL), NaHCO3 (30 mL), and brine (30 mL), dried (MgSO4), and the solvent removed in
vacuo. The residue was purified by column chromatography on silica gel (EtOAc/petroleum
ether = 1:9 to 1:3) to give 12c (10 mg, 86%, Rf = 0.60, EtOAc/petroleum ether 1:2) and the
title compound 8c (17 mg, 75%, Rf = 0.55 EtOAc/petroleum ether 1:2) both as colourless
oils. Data for 8c: νmax (ATRꢀIR) 3553, 2918, 2868, 1496, 1488, 1454, 1392, 1360, 1307,
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1208, 1129, 1069, 1027, 1012; H NMR (500 MHz, CDCl3) δ 2.20 (d, J = 6.3 Hz, 1H), 3.43ꢀ
3.51 (m, 3H), 3.80 (t, J = 9.5 Hz, 1H), 4.02 (t, J = 9.6 Hz, 1H), 4.04 (t, J = 2.6 Hz, 1H), 4.64
(d, J = 11.7 Hz, 1H), 4.68 (d, J = 11.7 Hz, 1H), 4.72 (d, J = 11.5 Hz, 1H), 4.76 (d, J = 11.1
Hz, 1H), 4.76 (d, J = 11.1 Hz, 1H), 4.85 (app. s, 2H), 4.86 (d, J = 11.4 Hz, 1H), 4.88 (d, J =
11.1 Hz, 1H), 4.97 (d, J = 11.5 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.26ꢀ7.36 (m, 23H), 7.38
(d, J = 8.4 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 72.4, 72.9, 74.8, 74.9, 75.5, 75.7, 81.0,
81.7, 82.1, 83.5, 121.4, 121.57, 127.61, 127.64, 127.68, 127.76, 127.77, 127.81, 128.1,
128.35, 128.4, 128.45, 128.5, 129.6, 131.4, 137.7, 138.1, 138.51, 138.53, 138.6; HRMSꢀESI
[M+Na]+ Calcd for C41H4179BrO6Na: 731.1979. Found: 731.1928.
1ꢀOꢀAllylꢀ4,5ꢀdiꢀOꢀbenzylꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀαꢀDꢀmannopyranosyl)ꢀ2ꢀOꢀ(2,3,4ꢀ
triꢀOꢀbenzylꢀ6ꢀOꢀpalmitoylꢀαꢀDꢀmannopyranosyl)ꢀD
ꢀmyoꢀinositol (3)9 and 1ꢀOꢀAllylꢀ4,5ꢀ
diꢀOꢀbenzylꢀ3ꢀOꢀ(4ꢀ(3,4ꢀdimethoxyꢀ(6ꢀ(4ꢀ(3,4ꢀdimethoxyphenyl)benzyl))ꢀphenyl)benzyl)ꢀ
6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀαꢀ ꢀmannopyranosyl)ꢀ2ꢀOꢀ(2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀOꢀ
palmitoylꢀαꢀ ꢀmannopyranosyl)ꢀ ꢀmyoꢀinositol (9)
D
D
D
To a solution of 29 (0.085 g, 0.047 mmol) in CH2Cl2 (2.4 mL) was added TFA (0.6 mL) and
the reaction was stirred at rt for 1 h. The reaction was diluted with H2O (50 mL) and
extracted into CH2Cl2 (3 × 30 mL). The combined organic layers were washed with NaHCO3
(20 mL), H2O (20 mL), brine (20 mL), dried (MgSO4), filtered and the solvent removed in
vacuo. The residue was purified by column chromatography on silica gel (EtOAc/petroleum
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ether = 1:9 to 1:2) to give the title compound 39 (0.043 g, 58%, Rf = 0.52, EtOAc/petroleum
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ether 1:2) and the title compound 9 (0.009 g, 10%, Rf = 0.37, EtOAc/petroleum ether 1:2)
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8
ͧͤ
both as colourless oils. Data for 9: ʞ ʟ +25.4 (c = 0.95, CHCl3); νmax (ATRꢀIR) 3063, 3029,
͸
9
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2922, 2852, 1732, 1604, 1587, 1524, 1453, 1358, 1248, 1210, 1071, 1090, 1026 cmꢀ1; H
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NMR (500 MHz, CDCl3) δ 0.88 (t, J = 6.9 Hz, 3H), 1.17ꢀ1.27 (m, 24H), 1.51ꢀ1.59 (m, 2H),
2.22 (t, J = 7.6 Hz, 2H), 3.19 (dd, J = 1.5, 9.7 Hz, 1H), 3.24ꢀ3.29 (m, 2H), 3.33 (dd, J = 2.3,
10.0 Hz, 1H), 3.38 (dd, J = 2.7, 11.1 Hz, 1H), 3.78ꢀ4.05 (m, 13H), 3.84 (s, 3H), 3.88 (s, 3H),
3.898 (s, 3H), 3.905 (s, 3H), 4.15ꢀ4.23 (m, 3H), 4.33ꢀ4.34 (m, 1H), 4.45ꢀ4.93 (m, 20H), 5.09
(dd, J = 10.4, 1.1 Hz, 1H), 5.21 (dd, J = 17.2, 1.4 Hz, 1H), 5.21 (d, J = 0.9 Hz, 1H), 5.53 (d, J
= 1.3 Hz, 1H), 5.72 (dddd, J = 5.5, 5.5, 10.7, 17.1 Hz, 1H), 6.73 (s, 1H), 6.84 (s, 1H), 6.90 (d,
J = 8.3 Hz, 1H), 7.04ꢀ7.42 (m, 55H); 13C NMR (125 MHz, CDCl3) δ 14.2, 22.8, 24.9, 29.3,
29.35, 29.43, 29.6, 29.7, 29.73, 29.74, 29.8, 32.0, 34.2, 38.2, 55.98, 56.04, 56.07, 56.09, 62.9,
68.6, 70.2, 71.2, 71.3, 71.5, 71.97, 72.01, 72.3, 72.5, 73.3, 74.0, 74.5, 74.8, 75.0, 75.3, 75.7,
75.8, 75.9, 76.1, 78.76, 78.84, 80.3, 81.4, 81.5, 81.8, 98.75, 98.83, 110.4, 111.5, 113.3, 113.4,
117.9, 119.2, 126.8, 127.0, 127.30, 127.32, 127.4, 127.48, 127.5, 127.51, 127.56, 127.6,
127.63, 127.72, 127.76, 127.77, 127.9, 128.0, 128.09, 128.14, 128.17, 128.22, 128.25,
128.26, 128.31, 128.34, 128.37, 128.41, 128.6, 129.1, 129.6, 130.1, 133.9, 134.1, 134.4,
136.3, 138.0, 138.2, 138.3, 138.4, 138.5, 138.6, 138.76, 138.82, 139.1, 140.6, 141.0, 147.3,
148.4, 148.5, 149.2, 173.6; HRMSꢀESI [M+Na]+ Calcd for C130H148NaO21: 2068.0405.
Found: 2068.0367.
Reaction of 4ꢀ(3,4ꢀdimethoxyphenyl)benzyl alcohol (10) with 1,4ꢀdimethoxybenzene
(11a)
To a solution of alcohol 1011 (0.050 g, 0.205 mmol) and 1,4ꢀdimethoxybenzene (11a) (0.141
g, 1.023 mmol) in CH2Cl2 (3.5 mL) was added TFA (1.5 mL) and the reaction was stirred at
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rt for 1 h. The reaction was diluted with H2O (40 mL) and extracted into CH2Cl2 (3 × 20 mL).
The combined organic layers were washed with NaHCO3 (20 mL), H2O (20 mL), brine (20
mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by
column chromatography on silica gel (EtOAc/petroleum ether = 1:4 to 1:2) to give 3ꢀ(4ꢀ(3,4ꢀ
dimethoxyphenyl)benzyl)ꢀ1,4ꢀdimethoxybenzene (12a) (0.015 g, 21%, Rf = 0.76,
EtOAc/petroleum ether 1:1), 3ꢀ(4ꢀ(3,4ꢀdimethoxyꢀ(6ꢀ(4ꢀ(3,4ꢀdimethoxyphenyl)benzyl))ꢀ
phenyl)benzyl)ꢀ1,4ꢀdimethoxybenzene (13a) (0.016 g, 13%, Rf = 0.63, EtOAc/petroleum
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ether
1:1)
and
3ꢀ(4ꢀ(3,4ꢀdimethoxyꢀ(6ꢀ(4ꢀ(3,4ꢀdimethoxyꢀ(6ꢀ(4ꢀ(3,4ꢀ
dimethoxyphenyl)benzyl))ꢀphenyl)benzyl))ꢀphenyl)benzyl)ꢀ1,4ꢀdimethoxybenzene
(14a)
1
(0.005 g, 3%, Rf = 0.34, EtOAc/petroleum ether 1:1) all as colourless oils. Data for 12a: H
NMR (500 MHz, CDCl3) δ 3.74 (s, 3H), 3.80 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 3.98 (s, 2H),
6.70 (d, J = 3.0 Hz, 1H), 6.73 (dd, J = 3.1, 8.7 Hz, 1H), 6.81 (d, J = 8.7 Hz, 1H), 6.93 (d, J =
8.3 Hz, 1H), 7.09 (d, J = 2.1 Hz, 1H), 7.12 (dd, J = 2.1, 8.3 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H),
7.46 (d, J = 8.2 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 35.7, 55.7, 55.97, 56.0, 56.1, 110.5,
111.3, 111.48, 111.52, 117.0, 119.3, 126.8, 129.4, 130.9, 134.3, 138.7, 139.5, 148.5, 149.1,
151.7, 153.6; HRMSꢀESI [M+H]+ Calcd for C23H25O4: 365.1753. Found: 365.1756.
Data for 13a: 1H NMR (500 MHz, CDCl3) δ 3.73 (s, 3H), 3.79 (s, 3H), 3.84 (s, 3H), 3.87 (s,
3H), 3.92 (s, 3H), 3.94 (s, 3H), 3.95 (s, 2H), 3.98 (s, 2H), 6.70ꢀ6.74 (m, 3H), 6.79ꢀ6.83 (m,
2H), 6.93 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 1.8 Hz, 1H), 7.11 (dd, J =
1.8, 8.2 Hz, 1H), 7.18ꢀ7.23 (m, 4H), 7.41 (d, J = 8.1 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ
35.7, 38.2, 55.7, 55.99, 56.0, 56.05, 56.07, 56.13, 110.4, 111.2, 111.49, 111.54, 113.3, 113.4,
117.1, 119.2, 126.7, 128.7, 129.1, 129.4, 130.2, 131.0, 134.1, 134.7, 138.5, 139.1, 139.4,
140.7, 147.2, 148.2, 148.5, 149.2, 151.8, 153.6; HRMSꢀESI [M+Na]+ Calcd for C38H38NaO6:
613.2566. Found: 613.2565.
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Data for 14a: 1H NMR (500 MHz, CDCl3) δ 3.70 (s, 3H), 3.77 (s, 3H), 3.82 (s, 3H), 3.83 (s,
3H), 3.86 (s, 3H), 3.87 (s, 3H), 3.91ꢀ3.98 (m, 12H), 6.68ꢀ7.47 (m, 22H); 13C NMR (125
MHz, CDCl3) δ 35.7, 38.2, 38.4, 55.7, 55.99, 56.01, 56.02, 56.06, 56.07, 56.1, 56.11, 110.36,
110.4, 111.1, 111.5, 111.6, 113.3, 113.33, 113.38, 113.4, 117.1, 119.2, 126.7, 126.8, 128.5,
128.6, 128.7, 129.0, 129.1, 129.2, 129.38, 129.43, 129.45, 130.1, 130.2, 131.0, 134.1, 134.6,
134.8, 138.5, 139.0, 139.1, 139.4, 140.6, 140.7, 147.2, 148.17, 148.24, 148.25, 148.5, 149.2,
151.7, 153.6; HRMSꢀESI [M+Na]+ Calcd for C53H52NaO8: 839.3560. Found: 839.3563.
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Reaction of 4ꢀ(3,4ꢀdimethoxyphenyl)benzyl alcohol (10) with 3,4ꢀdimethoxytoluene
(11b)
To a solution of alcohol 1011 (0.020 g, 0.082 mmol) and 3,4ꢀdimethoxytoluene (11b)17 (0.062
g, 0.409 mmol) in CH2Cl2 (3.5 mL) was added TFA (1.5 mL) and the reaction was stirred at
rt for 1 h. The reaction was diluted with H2O (40 mL) and extracted into CH2Cl2 (3 × 20 mL).
The combined organic layers were washed with saturated NaHCO3 (20 mL), H2O (20 mL),
brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc/petroleum ether = 1:4 to 1:2) to
give 6ꢀ(4ꢀ(3,4ꢀdimethoxyphenyl)benzyl)ꢀ3,4ꢀdimethoxytoluene (12b) (0.026 g, 85%, Rf =
0.59,
EtOAc/petroleum
ether
1:1)
and
6ꢀ(4ꢀ(3,4ꢀdimethoxyꢀ(6ꢀ(4ꢀ(3,4ꢀ
dimethoxyphenyl)benzyl))ꢀphenyl)benzyl)ꢀ3,4ꢀdimethoxytoluene (13b) (0.004 g, 8%, Rf =
0.43, EtOAc/petroleum ether 1:1) both as colourless oils. Data for 12b: vmax (ATRꢀIR) 3017,
3000, 2920, 2851, 1605, 1588, 1562, 1517, 1503, 1451, 1397, 1332, 1319, 1301, 1270, 1250,
1219, 1198, 1170, 1144, 1095, 1070, 1050 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 2.22 (s, 3H),
3.83 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 3.96 (s, 2H), 6.70 (s, 1H), 6.72 (s, 1H),
6.93 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 2.1, 8.2 Hz, 1H), 7.17 (d, J =
8.1 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 19.3, 38.7, 55.97,
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55.99, 56.03, 56.1, 110.4, 111.5, 113.8, 119.2, 126.9, 128.6, 128.9, 130.6, 134.1, 138.7,
139.5, 147.0, 147.4, 148.5, 149.2; HRMSꢀESI [M+Na]+ Calcd for C24H26NaO4: 401.1729.
Found: 401.1738.
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Data for 13b: 1H NMR (500 MHz, CDCl3) δ 2.22 (s, 3H), 3.81 (s, 3H), 3.83 (s, 3H), 3.86 (s,
3H), 3.87 (s, 3H), 3.91 (s, 3H), 3.93 (s, 5H), 3.96 (s, 2H), 6.69 (s, 1H), 6.71 (s, 1H), 6.73 (s,
1H), 6.79 (s, 1H), 6.93 (d, J = 8.3 Hz, 1H), 7.04 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 2.0 Hz, 1H),
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7.09ꢀ7.12 (m, 3H), 7.20 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H); C NMR (125 MHz,
CDCl3) δ 19.3, 38.2, 38.8, 56.0, 56.01, 56.02, 56.06, 56.08, 56.14, 110.4, 111.6, 113.3,
113.34, 113.8, 113.9, 119.2, 126.7, 128.3, 128.7, 129.0, 129.5, 130.1, 130.7, 134.1, 134.6,
138.6, 139.2, 139.4, 140.7, 147.0, 147.2, 147.4, 148.3, 148.5, 149.2; HRMSꢀESI [M+Na]+
Calcd for C39H40NaO6: 627.2723. Found: 627.2726.
6ꢀ(4ꢀ(3,4ꢀDimethoxyphenyl)benzyl)ꢀ3,4ꢀ(methylenedioxy)toluene (12c)
To a solution of alcohol 1011 (0.020 g, 0.082 mmol) and 3,4ꢀ(methylenedioxy)toluene (11c)17
(0.056 g, 0.409 mmol) in CH2Cl2 (3.5 mL) was added TFA (1.5 mL) and the reaction was
stirred at rt for 1 h. The reaction was diluted with H2O (40 mL) and extracted into CH2Cl2 (3
× 20 mL). The combined organic layers were washed with NaHCO3 (20 mL), H2O (20 mL),
brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc/petroleum ether = 1:4 to 1:2) to
give the title compound 12c (0.028 g, 93%) as a colourless oil.
2,3,4ꢀTriꢀOꢀbenzylꢀ6ꢀαꢀ
D
ꢀglucopyranoside (16)18
To a solution of methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀOꢀ(4ꢀ(3,4ꢀdimethoxyphenyl)benzyl)ꢀαꢀ
Dꢀ
glucopyranoside (15)11 (0.040 g, 0.058 mmol) and 3,4ꢀ(methylenedioxy)toluene (11c)17
(0.039 g, 0.290 mmol) in CH2Cl2 (3.5 mL) was added TFA (1.5 mL) and the reaction was
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stirred at rt for 1 h. The reaction was diluted with H2O (50 mL) and extracted into CH2Cl2 (3
× 25 mL). The combined organic layers were washed with NaHCO3 (20 mL), brine (20 mL),
dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by
column chromatography on silica gel (EtOAc/petroleum ether = 1:4 to 1:2) to give 6ꢀ(4ꢀ(3,4ꢀ
dimethoxyphenyl)benzyl)ꢀ3,4ꢀ(methylenedioxy)toluene (12c) (0.021 g, quant, Rf = 0.60,
EtOAc/petroleum ether 1:2) and the title compound 16 (0.023 g, 86%, Rf = 0.32,
EtOAc/petroleum ether 1:2) both as colourless oils. Data for 16: 1H NMR (500 MHz, CDCl3)
δ 1.57ꢀ1.63 (m, 1H), 3.37 (s, 3H), 3.48ꢀ3.45 (m, 2H), 3.63ꢀ3.72 (m, 2H), 3.74ꢀ3.79 (m, 1H),
4.01 (t, J = 8.9 Hz, 1H), 4.57 (d, J = 3.5 Hz, 1H), 4.62ꢀ4.68 (m, 2H), 4.80 (d, J = 12.0 Hz,
1H), 4.84 (d, J = 10.9 Hz, 1H), 4.88 (d, J = 11.1 Hz, 1H), 4.99 (d, J = 10.9 Hz, 1H), 7.27ꢀ7.38
(m, 15H); 13C NMR (125 MHz, CDCl3) δ 55.3, 62.0, 70.7, 73.5, 75.1, 75.8, 77.5, 80.0, 82.0,
98.3, 127.7, 127.9, 128.00, 128.02, 128.1, 128.2, 128.46, 128.53, 128.54, 138.17, 138.19,
138.8; HRMSꢀESI [M+Na]+ Calcd for C28H32NaO6: 487.2091. Found: 487.2117.
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3ꢀOꢀ(4ꢀBromobenzyl)ꢀ4,5ꢀdiꢀOꢀbenzylꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀαꢀ
Dꢀ
mannopyranosyl)ꢀ1,2ꢀdiꢀOꢀisopropylideneꢀLꢀmyoꢀinositol (19)
To a solution of 189 (2.06 g, 2.44 mmol) in CH2Cl2 (25 mL) was added H2O (44 ꢂL, 2.44
mmol) and TFA (0.376 mL, 4.88 mmol) at 0 °C. The solution was stirred for 2.5 h, then
diluted with CH2Cl2 (100 mL) and washed with saturated NaHCO3 (50 mL) and saturated
NaCl (50 mL). The organic phase was dried (MgSO4), filtered and the solvent was
evaporated under reduced pressure to give 3ꢀOꢀ(4ꢀbromobenzyl)ꢀ6ꢀOꢀ(3,4,6ꢀtriꢀOꢀbenzylꢀαꢀ
Dꢀmannopyranosyl)ꢀ1,2ꢀdiꢀOꢀisopropylideneꢀLꢀmyoꢀinositol (1.97 g) as a white foam. To a
solution of crude triol (1.97 g, 2.40 mmol) in dry DMF (20 mL) was added NaH (60%
dispersion in oil, (0.517 g, 21.6 mmol) and benzyl bromide (1.71 mL, 14.4 mmol) at 0 °C and
the reaction mixture was stirred overnight. The reaction was quenched by careful addition of
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H2O (5 mL) and then extracted into EtOAc (3 × 100 mL). The combined organic layers were
washed with H2O (100 mL) and saturated NaCl (100 mL), then dried (MgSO4), filtered and
the solvent removed in vacuo. The residue was purified by column chromatography on silica
gel (EtOAc/petroleum ether = 1:9 to 1:2) to give the title compound 19 (1.88 g, 72%) as a
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ͦͪ
colourless oil. ʞ ʟ +24.2 (c = 1.20, CHCl3); H NMR (500 MHz, CDCl3) δ 1.29 (s, 3H),
͸
1.52 (s, 3H), 3.31 (t, J = 8.6 Hz, 1H), 3.61ꢀ3.64 (m, 2H), 3.67 (dd, J = 1.9, 10.8 Hz, 1H),
3.85ꢀ3.98 (m, 5H), 4.03 (dt, J = 2.5, 10.0 Hz, 1H), 4.17 (t, J = 9.8 Hz, 1H), 4.26 (t, J = 4.5
Hz, 1H), 4.29 (d, J = 12.4 Hz, 1H), 4.32 (d, J = 12.4 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.54
(d, J = 10.8 Hz, 1H), 4.57 (d, J = 11.8 Hz, 1H), 4.58 (d, J = 11.8 Hz, 1H), 4.64 (d, J = 11.8
Hz, 1H), 4.69ꢀ4.75 (m, 4H), 4.78 (d, J = 10.8 Hz, 1H), 4.85 (d, J = 11.7 Hz, 1H), 4.86 (d, J =
10.7 Hz, 1H), 5.31 (d, J = 1.8 Hz, 1H), 7.14ꢀ7.36 (m, 32H), 7.41ꢀ7.45 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 25.8, 27.9, 68.9, 72.0, 72.1, 72.2, 72.4, 73.5, 74.1, 74.6, 74.9, 75.2,
75.3, 75.7, 77.2, 77.5, 78.9, 80.2, 81.0, 82.6, 98.7, 109.8, 121.8, 127.0, 127.1, 127.3, 127.4,
127.5, 127.57, 127.61, 127.82, 127.83, 128.07, 128.19, 128.26, 128.32, 128.44, 128.45,
129.6, 131.6, 137.2, 138.2, 138.4, 138.66, 138.68, 138.8, 138.9; HRMSꢀESI [M+Na]+ Calcd
for C64H6779BrNaO11: 1113.3759. Found: 1113.3718.
3ꢀOꢀ(4ꢀBromobenzyl)ꢀ4,5ꢀdiꢀOꢀbenzylꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀαꢀ
Dꢀ
mannopyranosyl)ꢀLꢀmyoꢀinositol (20)
To a solution of 19 (1.48 g, 1.36 mmol) in CH2Cl2 (50 mL) was added MeOH (0.084 mL,
2.03 mmol) and TFA (0.522 mL, 6.78 mmol) and the reaction mixture was stirred at rt
overnight. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with saturated
NaHCO3 (50 mL) and saturated NaCl (50 mL). The organic phase was dried (MgSO4),
filtered and the solvent was evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel (EtOAc/petroleum ether = 1:2 to 1:1) to give the title
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