Reagent controlled stereoselective synthesis of teichoic acid α-(1,2)-glucans

Article abstract of DOI:10.1039/d0ob00240b

The stereoselective construction of 1,2-cis-glycosidic linkages is key in the assembly of biologically relevant glycans, but remains a synthetic challenge. Reagent-controlled glycosylation methodologies, in which external nucleophiles are employed to modu

Full text of DOI:10.1039/d0ob00240b

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DOI: 10.1039/D0OB00240B
ARTICLE
Reagent Controlled Stereoselective Synthesis of Teichoic Acid α-
(1,2)-Glucans
Liming Wanga, Francesca Bernia, Jacopo Enotarpia, Hermen S. Overkleefta, Gijs van der Marela,
Received 00th January 20xx,
Accepted 00th January 20xx
Jeroen D. C. Codée*a
DOI: 10.1039/x0xx00000x
The stereoselective construction of 1,2-cis-glycosidic linkages is key in the assembly of biologically relevant glycans, but
remains a synthetic challenge. Reagent-controlled glycosylation methodologies, in which external nucleophiles are
employed to modulate the reactivity of the glycosylation system, have become powerful means for the construction of 1,2-
cis-glycosidic linkages. Here we establish that nucleophilic additives can support the construction of α-1,2-glucans, and apply
our findings in the construction of a D-alanine kojibiose functionalized glycerol phosphate teichoic acid fragment. This latter
molecule can be found in the cell wall of the opportunistic Gram-positive bacterium, Enterococcus faecalis and represents a
structural element that can possibly be used in the development of therapeutic vaccines and diagnostic tools.
faecalis LTA fragments, containing
a single α-glucosyl
Introduction
substituent have previously been explored as components in
synthetic vaccine conjugates,[8] and antibodies raised by these
conjugates have been shown to be opsonophagocytic and
capable of inducing killing of the bacteria in both active and
passive immunization strategies.[9]
α-Glucans,
polysaccharides
composed
of
glucose
monosaccharides connected through α-glycosidic linkages, are
widely found in nature.[1] The most abundant α-glucans are the
α-1,4-glucans, that occur as starch and glycogen, and can be
found as extracellular polysaccharides surrounding bacteria,
such as Mycobacterium tuberculosis.[2] α-1,3-Glucans are
prominent components of fungal cell walls and play a role in the
interaction between the pathogenic fungus Aspergillus
fumigatus and the host immune system.[3] α-1,2-Glucans, also
referred to as kojioligosaccharides, have been found in koji
extract, sake, beer and honey and they have also been
encountered in bacterial cell walls.[4] Kojibiose, kojitriose and
kojitetraose have been found as part of the lipoteichoic acid
(LTA) of Enterococcus faecalis, which is a commensal Gram-
positive bacterium.[5] Although this bacterium is generally of
low virulence, it is the causative agent of life-threatening
infections in immunocompromised patients and one of the
most prominent hospital bacteria.[6] LTA is an anionic polymer
featuring a glycolipid tail, through which it is anchored in the
cell wall of the bacteria. The polyanionic part is composed of
glycerol phosphate repeating units, which can be functionalised
Figure 1. The structure of E. faecalis
D-alanine kojibiose
functionalized LTA.
The microheterogeneity of naturally occurring LTA makes it
challenging -if not impossible- to establish clear structure-
activity relationships for these molecules, and therefore organic
synthesis is the method of choice to generate well-defined
single LTA molecules.[9-10] Only a few chemical syntheses of α-
(1,2)-glucans have been reported. Takeo and Suzuki reported a
procedure to assemble kojitriose, kojitetraose and kojipentaose
based on Koenings-Knorr-type glycosylations, using anomeric
chlorides under the activation of silver perchlorate.[11]
Hogendorf et al. relied on Crich’s α-glucosylation protocol,
which involves the use of benzylidene glucose donors for the
synthesis of a kojibiose glycerol building block.[9] We have
previously shown that additive-controlled glycosylations[12] of
per-benzylated glucosyl imidate donors can be used effectively
for the introduction of α-(1,4)- and α-(1,3)-glucosyl linkages,
which we used to assemble a set of M. tuberculosis α-(1,4)-
glucans and A. fumigatus α-(1,3)-glucans.[13] In this strategy we
with glycans and
moieties.[7] Kojibiose is a prominent appendage of E. faecalis
LTA, and it can be decorated with -alanyl esters at both C6-
hydroxyl groups of the disaccharide.[7]
-Alanylation plays a
critical role in the virulence of the bacteria and it renders the
bacteria less susceptible to (cationic) antimicrobial peptides. E.
D-alanine esters at C2 of the glycerol
D
D
a. Leiden Institute of Chemistry, Leiden University
Einsteinweg 55, 2333 CC Leiden, The Netherlands
E-mail: jcodee@chem.leidenuniv.nl
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Journal Name
exploited a suite of orthogonal benzyl ethers to discriminate which under the agency of Ph3P=O is isomerized into its less
View Article Online
DOI: 10.1039/D0OB00240B
between different hydroxyl functionalities that had to be stable but more reactive β-counterpart. These conditions
protected permanently (using a benzyl (Bn) group), and formed azidopropyl glucoside
7
in good yield and
hydroxyl groups that were used for chain elongation (protected stereoselectivity (α:β = 10:1), in line with results previously
with 2-methylnaphthyl (Nap) ethers) and hydroxyl groups from described.[13a,14] Deprotection of the C2-O-Nap ether under
which branching occurred (using para-methoxybenzyl (PMB) oxidative conditions (dichlorodicyanobenzoquinone (DDQ) in
ethers). The use of solely benzylic ethers to protect the DCM/H2O, 10:1 v/v) provided alcohol
hydroxyls ensured that the nature of the protecting groups does silica gel column chromatography to deliver the pure α-anomer.
not induce variation in the reactivity of the building blocks and Next the secondary and less reactive alcohol acceptor was
that we could rely on reactivity tuning by the used external glycosylated with donor under the agency of TfOH and DMF.
8 which was purified by
8
6
nucleophile to control the stereoselective construction of the α- This latter additive generates a mixture α/β-glucosyl imidinium
glucan linkages. This strategy could provide an effective entry ions, which are in rapid equilibrium. Substitution of the more
to construct α-(1,2)-linkages and generate (substituted) reactive β-ion then leads to the stereoselective formation of α-
kojioligosaccharides such as encountered in E. faecalis LTA. We glucosyl linkages. This additive has found wide application in the
here describe the use of additive-controlled glycosylation construction of various 1,2-cis-linked oligosaccharides.[15] The
methodology for the construction of α-(1,2)-glucans and we condensation of
8 and 6 provided disaccharide 9 in 95% yield
show the application of the methodology in the preparation of and a 15:1 α:β-ratio. Deprotection of the C2-O-Nap ether by
a
D
-alanine-kojibiose functionalized LTA fragment.
DDQ provided disaccharide acceptor 10 and the third
glycosylation, again performed under DMF mediated
glycosylation conditions, then provided trisaccharide 11. The
stereoselectivity of this glycosylation diminished slightly and 11
Results and discussion
was formed as
a 10:1 α:β-mixture. The erosion of
We first explored the assembly of spacer-functionalized
stereoselectivity developed further upon elongation of the
trisaccharide, as the DMF-mediated glycosylation of acceptor
12, obtained after DDQ treatment of 11, with per-benzyl donor
13 delivered tetrasaccharide 14 as a 2:1 α:β-mixture. Possibly
the overall structure of the twisted α-(1,2)-oligosaccharide is at
the root of the erosion of stereoselectivity, with increasing
steric demands leading to lower yields and poorer selectivity.
kojioligosaccharides. To achieve this aim, donor
6 (Scheme 1)
was designed and assembled. The building block bears three
permanent Bn-ethers to mask the C3, C4 and C6 hydroxyls and
a Nap-ether as a temporary protecting group at the C2-OH. The
synthesis of this building block used benzylidene protected
glucose building block
1 as starting compound. Selective
protection of the C3-OH as the benzyl ether was achieved
through the formation of an intermediate tin ketal which was
treated with benzyl bromide and cesium fluoride to give
compound
ether then provided compound
benzylidene and protection of the liberated primary alcohol
provided the fully benzylated thiodonor . The anomeric
2
. Protection of the remaining C2-OH with a Nap
3
. Selective opening of the
5
thioacetal in this building block was hydrolyzed using N-
iodosuccinimide (NIS) in acetone/water to liberate the
anomeric hydroxyl group, which could then be turned into the
required N-phenyltrifluoroacetimidate 6.
o
Scheme 1. Synthesis of donor 6. a) i) Bu2SnO, Toluene, 120 C;
ii) CsF, BnBr, 76%. b) NapBr, NaH, DMF, 91%. c) BF3.Et2O, TES,
DCM. d) BnBr, NaH, DMF, 88%. e) i) NIS, Acetone/H2O (10:1, v:v);
ii) 2,2,2-trifluoro-N-phenylacetimidoyl chloride, Cs2CO3,
acetone, 81% (over two steps).
Scheme 2. The assembly of kojioligosaccharides. a) TMSI,
Ph3P=O, DCM, 36 h, 75%, α:β = 10:1. b) DDQ, DCM:H2O = 10:1
(v:v),
8: 75%; 10: 49%; 12: 47%. c) DMF, TfOH, DCM, 9: 95%, α:β
= 15:1; 11: 67%, α:β = 10:1; 14: 67%, α:β = 2:1.
With donor
6
in hand, the assembly of kojioligosaccharides was
was
Although a limitation of the DMF-mediated glycosylation
protocol come forward in the above described kojitetraose
assembly, the synthesis also showed that the additive
controlled glycosylation approach can provide a rapid entry into
the assembly of smaller kojibiose derivatives. Therefore, the
explored as depicted in Scheme 2. Firstly, donor
6
glycosylated with azidopropanol, a primary and relatively
reactive alcohol, using the TMSI-Ph3P=O activation couple. TMSI
transforms the anomeric imidate into the α-glucosyl iodide,
2 | J. Name., 2012, 00, 1-3
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ARTICLE
assembly of an E. faecalis
explored. The synthesis of
availability of compound 19 featuring the kojibiose, decorated DMF-mediated glycosylation conditions to form the
with two -alanine esters at both primary alcohols, attached to disaccharide 28 with good selectivity and excellent yield. To set
the glycerol through an α-bond (Scheme 3). Compound 19 can the stage for the introduction of the -alanyl esters, first the
D-Ala-kojibiose LTA fragment was next benzyl ethers remained unaffected under these conditions.
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D
-Ala-kojibiose LTA requires the Acceptor 27 was then glycosylated witDhOdI:o10n.o10r391/5D0uOsBin0g024th0Be
D
D
be assembled from four building blocks: two benzyl type glycerol benzoate was replaced by a TBDPS ether, after which
protected glucosyl donors, 15 and 16, glycerol 17 protected the two C-6-O-Nap ethers were removed to give diol 31. The
with
a
benzoyl ester (Bz) and allyl ether and N- introduction of the two
D-alanine esters was accomplished
benzyloxycarbonyl protected
D-alanine 18 (Scheme 3). The using PyBOP as a condensing agent to form 6,6-di-alanyl-α-
glucosyl donors are protected with the triad of Bn, PMB and kojibiose 32 in 90% yield. To transform this building block into a
Nap-ethers to discriminate the alcohol groups that required synthon suitable for the assembly of TA-fragments, the allyl
permanent protection or needed to be removed to introduce ether was replaced by a 4,4′-dimethoxytrityl (DMTr) group.
the next glucose residue or introduce the
D-alanine esters.
Therefore, the allyl group was isomerized to the corresponding
enol ether using an iridium catalyst, which was subsequently
hydrolyzed using I2 in combination with sodium bicarbonate.
The liberated primary alcohol was treated with DMTrCl in DCM
to give compound 34, which was treated with HF-pyridine to
give the 6,6-di-alanyl-α-kojibiose 19 in 86% yield. For the
construction of the kojibiobiosyl glycerol trimer 40, we chose to
use benzyl phosphoramidites, as opposed to the more
commonly employed cyanoethyl reagents.[10] The latter group
however requires basic conditions for its removal, that may
jeopardize the labile D
-alanine esters in the target compound.[17]
Thus, compound 19 and phosporamidite 35 were coupled
under the agency of dicyanoimidazole (DCI), to provide the
intermediate phosphite triester, which was immediately
oxidized to the phosphate using (1S)-(+)-(10-camphorsulfonyl)-
oxaziridine (CSO), and the resulting dimer 36 was treated with
a
catalytic amount of p-toluenesulfonic acid (TsOH) in
DCM/MeOH to provide compound 37 in 93% over three steps.
A similar coupling of phophoramidite 38 and alcohol 37 then
provided trimer 39 in 88% yield. Removal of all benzyl ethers,
benzyl carbamates and benzyl phosphotriesters in 39 in a single
Scheme 3. Building blocks applied in the here-presented studies
in the synthesis of -alanine kojibiose functionalized LTA-
fragments of Enterococcus faecalis.
D
hydrogenolysis event delivered 40
.
The synthesis of the used building blocks is depicted in Scheme
4. Firstly, donor 15 was synthesized from compound
1 by
benzylation of the C2 and C3-hydroxyls, regioselective opening
of the benzylidene acetal and protection of the liberated
primary alcohol with a Nap-ether, to give thio donor 22
.
Hydrolysis of the thioacetal and introduction of the 2,2,2-
trifluoro-N-phenylacetimidate formed donor 15. Donor 16 was
obtained from compound
reactions: protection of the C2-OH with
regioselective opening of the benzylidene acetal and
2
following a similar sequence of
a
PMB-ether,
installation of the C6-O-Nap ether provided thioacetal 25, which Scheme 4. Synthesis of donor 15 and 16. a) BnBr, NaH, DMF, 20
:
.
was transformed into the corresponding imidate donor 16
.
96%. b) BH3 THF, Cu(OTf)2, 21: 80%; 24: 76%. c) NapBr, NaH,
With all the required building blocks available, we explored the DMF, 22: 91%; 25: 93%. d) 1) NIS, acetone:H2O = 10:1 (v:v); 2)
assembly of a kojibiose LTA fragment as depicted in Scheme 5. 2,2,2-trifluoro-N-phenylacetimidoyl chloride, Cs2CO3, acetone,
First, glycerol building block 19 was assembled. To this end yield 15: 86%; 16: 84%. e) PMBCl, NaH, DMF, 94%.
glycerol 17 was glycosylated with donor 16, of which the
primary alcohol groups were protected by a benzoate ester and
an allyl ether, using the TMSI-Ph3P=O activation conditions to
give the compound 26 in good yield and excellent selectivity.
Next, the C2-O-PMB was selectively removed using a catalytic
amount of HCl in a mixture of hexafluoro-iso-propanol (HFIP)
and DCM to give C2-OH acceptor 27 in 95% yield.[16] All other
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DOI: 10.1039/D0OB00240B
Scheme 5. Synthesis of a di-alanyl-α-kojibiose containing LTA fragment. a) TMSI, Ph3P=O, DCM, 36 h, 76%, α:β > 20:1. b) TES, HCl/HFIP,
DCM:HFIP = 1:1 (v:v), 93%. c) DMF, TfOH, 24 h, 95%, α:β > 10:1. d) CH3ONa, DCM:CH3OH = 1:1 (v:v), 92%. e) TBDPSCl, imidozole, DMF, 99%.
f) DDQ, DCM:H2O = 10:1 (v:v), 77%. g) PyBOP, NMI, DCM, 90%. h) 1) Ir(COD)(Ph2MeP)2PF6; 2) I2, NaHCO3, H2, THF, 85%. i) DMTrCl, DIPEA,
DCM, 95%. j) HF-pyridine, THF/pyridine, 86%. k) 1) DCI, CH3CN; 2) CSO. l) TsOH, DCM/CH3OH = 1:1 (v:v), 93%. m) DCI, CH3CN; 2) CSO, 88%. n)
H2, Pd/C, dioxane/H2O = 2:1 (v:v), 3 day, 95%.
All reagents were of commercial grade and used as received. All
moisture sensitive reactions were performed under an argon
atmosphere. DCM used in the glycosylation reactions was dried with
Conclusion
flamed 4Å molecular sieves before being used. Reactions were
monitored by TLC analysis with detection by UV (254 nm) and where
applicable by spraying with 20% sulfuric acid in EtOH or with a
In conclusion, we have here explored additive controlled
glycosylations for the construction of α-1,2-glucosyl linkages.
After the successful construction of α-1,3-glucosyl and α-1,4-
glucosyl linkages, described previously, we have shown that solution of (NH4)6Mo7O24∙4H2O (25 g/L) and (NH4)4Ce(SO4)4∙2H2O (10
conditions, involving the activation of per-benzylated glucosyl
imidate donors with stoichiometric TfOH in the presence of an
excess DMF, can be profitably used for the construction of α-
1,2-glucosyl linkages. The assembly of a linear kojitetraose
however has brought to light that the stereoselectivity of the
glycosylation reactions decrease with growing chain length. A
kojibiose was assembled with excellent stereoselectivity (α:β =
15:1) and elongation of this disaccharide proceeded with good
selectivity (α:β = 10:1), but extension of the trisaccharide with a
fourth residue led to an anomeric mixture (α:β = 2:1). Using the
methodology and building on a triad of benzyl-type protecting
g/L) in 10% sulfuric acid (aq.) followed by charring at ~150 °C. Column
chromatography was carried out using silica gel (0.040-0.063 mm).
Size-exclusion chromatography was carried out using Sephadex LH-
20. 1H and 13C spectra were recorded on a Bruker AV 400 and Bruker
AV 500 in CDCl3 or D2O. Chemical shifts (δ) are given in ppm relative
to tetramethylsilane as internal standard (1H NMR in CDCl3) or the
residual signal of the deuterated solvent. Coupling constants (J) are
given in Hz. All 13C spectra are proton decoupled. NMR peak
assignments were made using COSY and HSQC experiments, where
applicable Clean TOCSY, HMBC and GATED experiments were used
to further elucidate the structure. The anomeric product ratios were
analysed through integration of proton NMR signals.
groups, a
faecalis cell wall was synthesized. Through the use of mild global
deprotection conditions the labile -alanine esters were
D-alanine-kojibiose functionalized LTA from the E.
D
Experimental Procedures and Characterization Data of Products
maintained in the final product. The generation of this structure
will enable binding studies with antibodies, which may pave the
way to the generation of a synthetic vaccine, based on this
structure, directed at this important nosocomial pathogen.
For the synthesis procedure and data of known compounds 13[13]
,
17[18], 22[19], 23[20] see references. We used "a", "b", "c" and "d" to
specify the H-1 and C-13 NMR signals of sugar rings from the
“reducing” to the “non-reducing” end and “°” to specify the H-1 and
C-13 NMR signals of the spacer.
Experimental
General experimental procedures
Standard procedures
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Procedure A for the glycosylation of secondary alcohols:
A mixture of donor (1.0 eq), acceptor (0.7 eq) (donors and acceptors stirring at 0 C untill the reaction was completed by TLC monitoring.
co-evaporated with toluene three times), DMF (16 eq) in dry DCM Then the mixture was dilutted with EtOAc and washed with H2O and
were stirred over fresh flame-dried molecular sieves 3A under brine. The organic phase was dried with anhydrous MgSO4, filtered
ARTICLE
g, 20.6 mmol) were added the mixture under N2. The reaction was
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o
DOI: 10.1039/D0OB00240B
and concentrated in vacuo, and the product purified by column
chromatography. Compound 3 was obtained with 91% yield. 1H-NMR
(CDCl3, 400 MHz) δ 7.80-7.77 (m, 4 H, aromatic H), 7.55-7.22 (m, 18
H, aromatic H), 5.54 (s, 1 H), 5.02-4.94 (m, 3 H, 3 CHH), 4.79-4.76 (m,
2 H, H-1, 1 CHH), 4.35 (dd, J1 = 4.8 Hz, J2 = 10.4 Hz, 1 H, H-6a), 3.86-
3.66 (m, 3 H, H-6, H-4, H-3), 3.56 (t, J = 8.4 Hz, 1 H, H-2), 3.47-3.41 (m,
1 H, H-5). 13C-APT (CDCl3, 100 MHz) δ 138.34, 137.29, 135.56, 133.29,
133.18, 133.08 (aromatic C), 132.31, 129.05, 128.99, 128.41, 128.28,
128.12, 128.99, 128.87, 127.78, 127.73, 126.90, 126.26, 126.07,
126.03, 125.94 (aromatic CH), 101.08 (PhCH), 88.27 (C-1), 82.99 (C-
3), 81.45 (C-4), 80.48 (C-2), 75.92, 75.28 (CH2), 70.22 (C-5), 68.67 (C-
6).
nitrogen. The solution was cooled to -78 ℃, after which TfOH (1.0 eq)
was added. After 30 min, the reaction was stirred at 0 or -10 ℃ until
TLC-analysis showed complete conversion of the acceptor. The
reaction was quenched with Et3N, filtered and concentrated in vacuo.
The products were purified by size exclusion and silica gel column
chromatography.
Procedure B for the glycosylation of primary alcohols:
A mixture of donor (1.0 eq), acceptor (0.7 eq) (donor and acceptor
co-evaporated with toluene three times), Ph3P=O (6 eq) in dry DCM
were stirred over fresh flame-dried molecular sieves 3A under
nitrogen. Then TMSI (1.0 eq) was added slowly in the mixture. The
reaction was stirred at room temperature until TLC-analysis
indicated the reaction to be complete. The solution was diluted and
the reaction quenched with saturated Na2S2O3. The organic phase
was washed with water and brine, dried with anhydrous MgSO4,
filtered and concentrated in vacuo. The products were purified by
size exclusion and silica gel column chromatography.
Phenyl 3,4,6-tri-O-benzyl-2-O-(naphthalen-2-ylmethyl)-1-thio-β-D-
glucopyranoside 5: Compound 3 (8.7 g, 14.7 mmol) was dissolved in
.
dry DCM under N2 at 0 oC. Then TES (23 mL, 144 mmol) and BF3 Et2O
(3.7 mL, 29 mmol) were added in the solution. The reaction was
strring at t 0 oC untill the reaction was completed by TLC monitoring.
Then the mixture was dilutted with EtOAc and washed with H2O and
brine. The organic phase was dried with anhydrous MgSO4, filtered
and concentrated in vacuo. Crude compound 4 was dissolved in DMF
Procedure C for deprotection of the PMB protecting group:
The starting material (1 eq) was dissolved in DCM:HFIP (1:1, 0.1 M).
TES (1.0 eq) and 0.1M HCl/HFIP (0.1eq) were added to the mixture.
The reaction stirred until TLC-analysis indicated full consumption of
the starting material (15min-2h). Then the mixture was diluted with
DCM and the reaction quenched with saturated NaHCO3. The organic
phase was washed with water and brine, dried with anhydrous
MgSO4, filtered and concentrated in vacuo. The product was purified
by silica gel column chromatography.
o
at 0 C. Then NaH (1.8 g, 45 mmol) and BnBr (2.6 mL, 21.9 mmol)
o
were added the mixture under N2. The reaction was stirring at 0 C
untill the reaction was completed by TLC monitoring. Then the
mixture was dilutted with EtOAc and washed with H2O and brine. The
organic phase was dried with anhydrous MgSO4, filtered and
concentrated in vacuo, and the product purified by column
chromatography. Compound 5 was obtained with 88% yield. 1H-NMR
(CDCl3, 400 MHz) δ 7.81-7.75 (m, 4 H, aromatic H), 7.62-7.18 (m, 23
H, aromatic H), 5.04 (d, J = 10.4 Hz, 1 H, 1 CHH), 4.93-4.82 (m, 4 H, 4
CHH), 4.71 (d, J = 9.6 Hz, 1 H, H-1), 4.62-4.52 (m, 3 H, 3 CHH), 3.81-
3.65 (m, 4 H, H-6, H-4, H-3), 3.60-3.50 (m, 2 H, H-2, H-5). 13C-APT
(CDCl3, 100 MHz) δ 138.49, 138.37, 138.11, 135.62, 133.94, 133.37,
133.16 (aromatic C), 132.01, 129.02, 128.55, 128.45, 128.25, 128.07,
128.04, 127.92, 127.85, 127.79, 127.76, 127.67, 127.54, 127.00,
126.34, 126.12, 126.00 (aromatic CH), 87.57 (C-1), 86.86 (C-3), 80.92
(C-2), 79.18 (C-4), 77.89 (C-5), 75.93, 75.59, 75.16, 73.50 (CH2), 69.08
(C-6).
Procedure D for deprotection of the Nap protecting group:
The starting material (1 eq) was dissolved in DCM:H2O (10:1, 0.1 M).
DDQ (1.1 eq) was added to the mixture. The reaction stirred until
TLC-analysis indicated full consumption of the starting material (± 2h).
Then the mixture was diluted with DCM and the reaction quenched
with saturated Na2S2O3. The organic phase was washed with water
and brine, dried with anhydrous MgSO4, filtered and concentrated in
vacuo. The product was purified by silica gel column chromatography.
Phenyl 4,6-O-benzelidine-2-O-(naphthalen-2-ylmethyl)-3-O-benzyl-
1-thio-β-D- glucopyranoside 3: Compound 1 (7.7 g, 21.4 mmol) and
Bu2SnO (5.9 g, 23.7 mmol) was dissolved in dry toluene. The mixture
was refluxed at 120 oC for 3 h. Then CsF (3.6 g, 23.7 mmol) and BnBr
(2.8 mL, 23.7 mmol) were added in the mixture. The mixture was
refluxed at 120 oC until the reaction was completed by TLC
monitoring. Then the mixture was dilutted with EtOAc and washed
with 1 mol/L KF and brine. The organic phase was dried with
anhydrous MgSO4, filtered and concentrated in vacuo, and the
product purified by column chromatography. Compound 2 was
obtained with 76% yield. Then compound 2 (7.3 g, 16.2 mmol) was
dissolved in DMF at 0 oC. Then NaH (1.95 g, 48.6 mmol) and NapBr (5
3,4,6-Tri-O-benzyl-2-O-(naphthalen-2-ylmethyl)-α/β-D-
glucopyranosyl N-phenyltrifluoroacetimidate 6: Compound 5 (11.5
g, 16.8 mmol) was dissolved in acetone (200 mL). N-Iodosuccinimide
(NIS, 7.5 g, 33.6 mmol) was added in one portion and the reaction
was stirred at room temperature for 2 hours. The solution was
diluted with DCM and the reaction was quenched with saturated
aqueous Na2S2O3. Then the organic layer was washed with water and
brine. The organic layer was dried with anhydrous MgSO4, filtered
and concentrated in vacuo, and the product purified by column
chromatography. The lactol (8.7 g, 90% yield) was obtained as a
white solid. Next, the lactol (8.7 g, 15.1 mmol) was dissolved in
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acetone (150 mL). Cs2CO3 (7.4 g, 22.6 mmol) and 2,2,2-trifluoro-N- 127.80, 127.77 (aromatic CH), 98.66 (C-1), 83.31 (C-3), 77.46 (C-4),
View Article Online
DOI: 10.1039/D0OB00240B
phenylacetimidoyl chloride (3.5 mL, 25.1 mmol) were added to the 75.43, 75.11, 73.59 (CH2), 72.94 (C-2), 70.82 (C-5), 68.47 (C-6), 65.15
solution respectively. The reaction was stirred overnight, then (C-1º), 48.53 (C-3º), 28.86 (C-2º). HR-MS: Calculated for C30H35N3O6
quenched with Et3N, filtered and concentrated in vacuo. The product [M+NH4]+: 551.28641, found: 551.28604.
was purified by column chromatography (pentane:EA = 40:1-20:1).
Compound 6 (9.6 g, 92% yield, α:β = 1:1) was obtained as yellow Synthesis of 9: The reaction was carried out according to the
syrup. 1H-NMR (CDCl3, 500 MHz, 60℃) δ 7.79-7.74 (m, aromatic H),
7.49- 7.01 (m, aromatic H), 6.83-6.73 (m, aromatic H), 6.40 (bs, 1 H,
H-1α), 5.58 (bs, 1 H, H-1β), 4.96-4.53 (m), 4.02-3.95 (m), 3.79-3.59
(m), 3.40 (bs, 1 H). 13 C-APT (CDCl3, 125 MHz, 60℃) δ 159.77, 159.73,
143.96, 143.73, 143.42, 138.99, 138.77, 138.38, 138.31, 135.81,
135.70, 133.57, 133.32, 130.33, 130.26 (aromatic C), 129.86, 129.43,
128.80, 128.46, 128.43, 128.33, 128.28, 128.06, 127.98, 127.94,
127.91, 127.84, 127.78, 127.69, 127.65, 127.60, 126.78, 126.72,
126.22, 126.20, 126.01, 125.97, 124.41, 124.28, 119.69, 119.58,
114.20, 114.17 (aromatic CH), 117.62 (q, CF3), 97.71, 94.00, 84.78,
81.75, 80.86, 79.41, 77.61, 77.36, 76.06, 75.31, 75.63, 75.55, 75.27,
75.02, 74.72, 73.82, 73.73, 73.48, 73.24, 68.73, 68.66, 55.83, 55.36.
HR-MS: Calculated for C46H42F3NO6 [M-[O(C=NPh)CF3]+OH+NH4]+:
608.30066, found: 608.29853.
standard procedure B, using 6 (845 mg, 1.11 mmol), 8 (455 mg, 0.85
mmol, 0.05 M in DCM), DMF (1.4 mL, 17.7 mmol) and TfOH (98 μL,
1.11 mmol). The reaction was stirred at -78-0 C until TLC-analysis
o
showed complete conversion of the acceptor. The reaction was
quenched with Et3N, filtered and concentrated in vacuo. The product
was purified by size exclusion chromatography (DCM:MeOH = 1:1).
Compound 9 (1160 mg, 95% yield, α:β = 15:1) was obtained as a
colourless syrup. [α]D20 +75.4 (c=1, CHCl3). IR (neat, cm-1) ν 697, 736,
1029, 1069, 1359, 1454, 1497, 2098, 2866, 2922. 1H-NMR (CDCl3, 400
MHz) δ 7.83-7.71 (m, 4 H, aromatic H), 7.49-7.45 (m, 3 H, aromatic
H), 7.34-7.21 (m, 23 H, aromatic H), 7.16-7.03 (m, 7 H, aromatic H),
5.07 (d, J = 3.2 Hz, 1 H, H-1b), 5.05 (d, J = 3.2 Hz, 1 H, H-1a), 5.01-4.79
(m, 8 H, 8 CHH), 4.63-4.39 (m, 5 H, 5 CHH), 4.31 (d, J = 12.4 Hz, 1 H, 1
CHH), 4.11 (t, J = 91.6 Hz, 1 H, H-3b), 4.06-3.99 (m, 2 H, H-3a, H-5a),
3.83 (dd, J1 = 3.2 Hz, J2 = 9.6 Hz, 1 H, H-2a), 3.78-3.61 (m, 7 H, H-6, H-
5b, H-4b, H-4a, H-2b, H-3ºa), 3.55-3.39 (m, 3 H, H-6, H-3ºb), 3.29-3.19
(m, 2 H, H-1º), 1.84-1.70 (m, 2 H, H-2º). 13C-APT (CDCl3, 100 MHz) δ
138.81, 138.72, 138.32, 138.25, 138.00, 137.98, 135.69, 133.29,
133.11 (aromatic C), 128.49, 128.43, 128.42, 128.39, 128.29, 128.09,
128.03, 128.01, 127.97, 127.90, 127.81, 127.80, 127.71, 127.66,
127.62, 127.52, 126.87, 126.33, 126.12, 125.89 (aromatic CH), 96.06
(C-1a), 94.72 (C-1b), 82.17 (C-3b), 80.79 (C-3a), 79.14 (C-2b), 78.07
(C-4), 77.68 (C-4), 76.18, 75.71 (CH2), 75.45 (C-2a), 75.20, 74.95,
73.60, 73.45, 72.99 (CH2), 70.61 (C-5b), 70.44 (C-5a), 68.52 (C-6),
68.04 (C-6), 65.15 (C-1º), 48.36 (C-3º), 28.02 (C-2º). HR-MS:
Calculated for C68H71N3O6 [M+NH4]+: 1123.54269, found: 1123.54104.
Synthesis of 7: The reaction was carried out according to the
standard procedure B, using 6 (2000 mg, 2.6 mmol, 0.1 M in DCM),
3-aminopropanol (370 μL, 3.9 mmol), Ph3P=O (4.4 g, 15.8 mmol) and
TMSI (371 μL, 2.6 mmol). The product was purified by silica gel
column chromatography (pentane:EA = 10:1). Compound 7 (1300 mg,
75 % yield, α:β = 10:1) was obtained as a colourless syrup. IR (neat,
cm-1) ν 697, 735, 818, 1027, 1155, 1358, 1454, 2095, 2866, 2922. 1H-
NMR (CDCl3, 400 MHz) δ 7.83-7.74 (m, 4 H, aromatic H), 7.49-7.12 (m,
18 H, aromatic H), 5.02 (d, J = 11.2 Hz, 1 H, 1 CHH), 4.92 (d, J = 12.4
Hz, 1 H, 1 CHH), 4.86-4.77 (m, 3 H, 3 CHH), 4.74 (d, J = 3.6 Hz, 1 H, H-
1), 4.59 (d, J = 11.6 Hz, 1 H, 1 CHH), 4.48-4.41 (m, 2 H, 2 CHH), 3.99 (t,
J = 9.2 Hz, 1 H, H-2), 3.75-3.59 (m, 6 H, H-6, H-5, H-4, H-2, H-1ºa), 3.48-
3.35 (m, 3 H, H-3º, H-1ºb), 1.97-1.81 (m, 2 H, H-2º). 13C-APT (CDCl3,
100 MHz) δ 138.93, 138.25, 138.14, 127.98, 135.72, 133.29, 133.17
(aromatic C), 128.52, 128.49, 128.46, 128.40, 128.06, 128.00, 127.84,
127.79, 127.70, 127.03, 126.29, 126.13, 126.06 (aromatic CH), 97.31
(C-1), 82.10 (C-3), 80.10 (C-2), 77.75 (C-4), 75.81, 75.24, 73.57, 73.53
(CH2), 70.43 (C-5), 68.50 (C-6), 64.83 (C-1º), 48.41 (C-3º), 28.96 (C-2º).
HR-MS: Calculated for C41H43N3O6 [M+NH4]+: 691.34901, found:
691.34807.
Synthesis of 10: The reaction was carried out according to the
general procedure D, using 9 (970 mg, 0.88 mmol, 0.1 M in DCM:H2O)
and DDQ (217 mg, 0.96 mmol). The product was purified by silica gel
column chromatography. Compound 10 (416 mg, 49% yield) was
obtained as a colourless syrup. [α]D20 +90.8 (c=1, CHCl3). IR (neat, cm-
1
1) ν 697, 735, 1027, 1050, 1132, 1361, 1454, 2098, 2866, 2929. H-
NMR (CDCl3, 400 MHz) δ 7.38-7.06 (m, 30 H, aromatic H), 5.02-4.97
(m, 3 H, H-1a, H-1b, 1 CHH), 4.87-4.75 (m, 5 H, 5 CHH), 4.63-4.44 (m,
5 H, 5 CHH), 4.32 (d, J = 12.0 Hz, 1 H, 1 CHH), 3.94-3.65 (m, 11 H),
3.53-3.33 (m, 5 H, H-6), 1.91-1.84 (m, 2 H, H-2º). 13C-APT (CDCl3, 100
MHz) δ 138.69, 138.61, 137.97, 137.86, 737.83 (aromatic C), 128.41,
128.39, 128.34, 128.30, 128.28, 128.16, 128.08, 127.97, 127.95,
127.87, 127.82, 127.78, 127.72, 127.65, 127.60, 127.55, 127.41
(aromatic CH), 96.21 (C-1b), 85.58 (C-1a), 83.28 (C-3b), 80.50 (C-3a),
77.79 (C-4), 76.94 (C-4), 76.00 (CH2), 75.37 (C-2a), 75.12, 74.75, 73.48,
73.29 (CH2), 72.79 (C-2b), 70.62 (C-5), 70.58 (C-5), 68.28 (C-6), 67.86
(C-6), 64.83 (C-1º), 48.33 (C-3º), 28.62 (C-2º). HR-MS: Calculated for
C68H71N3O11 [M+NH4]+: 983.48003, found: 983.47815.
Synthesis of 8: The reaction was carried out according to the general
procedure D, using 7 (1.3 g, 1.93 mmol, 0.1 M in DCM:H2O) and DDQ
(482 mg, 2.1 mmol). The product was purified by silica gel column
chromatography. Compound 8 (770 mg, 75% yield) was obtained as
a colourless syrup. [α]D20 +90.5 (c=1, CHCl3). IR (neat, cm-1) ν 697, 735,
1027, 1066, 1038, 1359, 1454, 1497, 2095, 2870, 2923. 1H-NMR
(CDCl3, 400 MHz) δ 7.39-7.13 (m, 15 H, aromatic H), 4.94-4.80 (m, 4
H, H-1, 3 CHH), 4.63 (d, J = 12.4 Hz, 1 H, 1 CHH), 4.52-4.48 (m, 2 H, 2
CHH), 3.85-3.61 (m, 7 H, H-6, H-5, H-4, H-3, H-2, H-3ºa), 3.56-3.51 (m,
1 H, H-3ºb), 3.43-3.32 (m, 2 H, H-1º), 2.18 (d, J = 7.6 Hz, 1 H, OH), 1.94-
1.82 (m, 2 H, H-2º). 13C-APT (CDCl3, 100 MHz) δ 138.69, 138.11,
137.93 (aromatic C), 128.50, 128.47, 128.02, 127.97, 127.96, 127.84,
Synthesis of 11: The reaction was carried out according to the
standard procedure B, using 6 (547 mg, 0.72 mmol), 10 (347 mg, 0.36
6 | J. Name., 2012, 00, 1-3
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mmol, 0.05 M in DCM), DMF (900 μL, 11.4 mmol) and TfOH (64 μL, was purified by size exclusion chromatography (DCMV:MieweOArtHicle=O1n:l1in)e.
o
DOI: 10.1039/D0OB00240B
0.72 mmol). The reaction was stirred at -78-0 C until TLC-analysis Compound 14 (64 mg, 67% yield, α:β = 2:1) was obtained as a
showed complete conversion of the acceptor. The reaction was colourless syrup. IR (neat, cm-1) ν 695, 734, 1027, 1069, 1209, 1359,
quenched with Et3N, filtered and concentrated in vacuo. The product 1454, 1497, 1729, 2096, 2859, 2923. HR-MS: Calculated for
was purified by size exclusion chromatography (DCM:MeOH = 1:1). C118H125N3O21 [M+NH4]+: 1937.91438, found: 1937.91440.
Compound 11 (372 mg, 67% yield, α:β = 10:1) was obtained as a
colourless syrup. [α]D20 +96.5 (c=1, CHCl3). IR (neat, cm-1) ν 697, 735, Synthesis of 15: Compound 22 (1.0 g, 1.46 mmol) was dissolved in
1029, 1069, 1359, 1454, 1497, 2098, 2845, 2921. 1H-NMR (CDCl3, 400 acetone:H2O (10:1, 15 mL). N-Iodosuccinimide (NIS) (660 mg, 2.93
MHz) δ 7.82 (s, 1 H, aromatic H), 7.71-7.62 (m, 3 H, aromatic H), 7.52- mmol) was added in one portion and the reaction was stirred at room
7.50 (m, 1 H, aromatic H), 7.41-7.37 (m, 1H, aromatic H), 7.32-6.96 temperature for 2 hours. The solution was diluted with DCM and the
(m, 46 H, aromatic H), 5.49 (d, J = 3.6 Hz, 1 H, H-1c), 5.41 (d, J = 3.6 reaction was quenched with saturated aqueous Na2S2O3. Then the
Hz, 1 H, H-1b), 5.23 (d, J = 2.0 Hz, 1 H, H-1a), 5.16 (d, J = 12.0 Hz, 1 H, organic layer was washed with water and brine. The organic layer
1 CHH), 4.99-4.34 (m, 18 H, 18 CHH), 44.18-3.52 (m, 21 H), 3.31-3.22 was dried with anhydrous MgSO4, filtered and concentrated in vacuo,
(m, 2 H, H-3º), 1.93-1.82 (m, 2 H, H-2º). 13C-APT (CDCl3, 100 MHz) δ and the product purified by column chromatography. The lactol was
138.78, 138.76, 138.74, 138.45, 138.26, 138.16, 138.09, 137.98, obtained as a white solid. Next, the lactol was dissolved in acetone
137.90, 136.09, 133.35, 132.94 (aromatic C), 128.72, 128.45, 128.44, (15 mL). Cs2CO3 (713 mg, 2.19 mmol) and 2,2,2-trifluoro-N-
128.40, 128.38, 128.29, 128.26, 128.13, 128.06, 128.04, 127.93, phenylacetimidoyl chloride (355 μL, 2.19 mmol) were added to the
127.79, 127.72, 127.65, 127.60, 127.56, 127.51, 127.46, 126.11, solution respectively. The reaction was stirred overnight, then
125.84, 125.77, 125.55 (aromatic CH), 95.84 (C-1c), 92.77 (C-1b), quenched with Et3N, filtered and concentrated in vacuo. The product
92.09 (C-1a), 81.96 (C-3c), 81.45 (C-3a), 80.99 (C-3b), 79.97 (C-2c), was purified by column chromatography. Compound 15 (959 mg, 86%
77.37 (2 C-4), 77.05 (C-4), 76.08, 75.99, 75.65, 74.94, 74.84 (CH2), yield over two steps, α:β = 1:1) was obtained as yellow syrup. IR (neat,
74.71 (C-2), 74.60 (C-2), 73.58, 73.50, 71.60 (CH2), 70.94 (C-5), 70.80 cm-1) ν 695, 734, 1027, 1073, 1153, 1208, 1314, 1454, 1597, 1716,
1
(C-5), 70.61 (C-5), 68.61 (C-6), 68.34 (C-6), 68.07 (C-6), 65.16 (C-1º), 2869, 2915. H-NMR (CDCl3, 400 MHz) δ 7.82-6.50 (m, aromatic H),
48.31 (C-3º), 29.20 (C-2º). HR-MS: Calculated for C95H99N3O16 6.53 (bs, 1 H, H-1), 5.67 (bs, 1 H, H-1), 5.00-4.61 (m), 4.52-4.46 (m),
[M+NH4]+: 1555.73636, found: 1555.73599.
4.06-3.97 (m), 3.81-3.66 (m). 13 C-APT (CDCl3, 125 MHz) δ 143.78,
143.55, 138.67, 138.64, 137.92, 137.83, 135.45, 135.28, 133.35,
Synthesis of 12: The reaction was carried out according to the 133.19, 133.16 (aromatic C), 129.51, 128.82, 128.64, 128.61, 128.57,
general procedure D, using 11 (700 mg, 0.45 mmol, 0.1 M in 128.55, 128.49, 128.43, 128.36, 128.33, 128.13, 128.05, 127.99,
DCM:H2O) and DDQ (140 mg, 0.6 mmol). The product was purified by 127.92, 127.88, 127.84, 127.81, 127.78, 127.00, 126.88, 126.49,
silica gel column chromatography. Compound 12 (300 mg, 47% yield) 126.30, 126.26, 126.10, 126.08, 126.05, 124.39, 120.57, 119.44
20
was obtained as a colourless syrup. [α]D +122.1 (c=1, CHCl3). IR (aromatic CH), 84.64, 81.62, 81.04, 79.37, 77.27, 76.94, 75.91, 75.82,
(neat, cm-1) ν 697, 735, 1027, 1050, 1132, 1361, 1454, 2098, 2866, 75.74, 75.44, 75.31, 75.17, 73.76, 73.65, 73.44, 73.19, 68.12.
1
2929. H-NMR (CDCl3, 400 MHz) δ 7.37-6.98 (m, 45 H, aromatic H),
5.18 (d, J = 3.2 Hz, 1 H, H-1b), 5.06 (d, J = 3.2 Hz, 1 H, H-1a), 5.00-4.90 Synthesis of 16: Compound 23 (2.57 g, 4.5 mmol) was dissolved in
.
(m, 3 H, H-1a, 2 CHH), 4.84-4.30 (m, 16 H, 16 CHH), 4.01-3.34 (m, 22 dry DCM under N2 at 0 oC. Then TES (7.2 mL, 45 mmol) and BF3 Et2O
H), 2.41 (s, 1 H, OH), 2.06-1.85 (m, 2 H, H-2º). 13C-APT (CDCl3, 100 (1.2 mL, 9 mmol) were added in the solution. The reaction was strring
MHz) δ 138.89, 138.85, 138.56, 138.24, 138.22, 138.02, 137.96, at t 0 oC untill the reaction was completed by TLC monitoring. Then
137.95, 137.89 (aromatic C), 128.56, 128.53, 128.51, 128.50, 128.42, the mixture was dilutted with EtOAc and washed with H2O and brine.
128.38, 128.36, 128.28, 128.08, 128.07, 127.86, 127.82, 127.79, The organic phase was dried with anhydrous MgSO4, filtered and
127.74, 127.67, 127.63, 127.60, 127.50 (aromatic CH), 96.03 (C-1c), concentrated in vacuo. the product purified by column
o
95.04 (C-1a), 91.66 (C-1b), 83.42 (C-3c), 80.90 (C-3a), 80.62 (C-3b), chromatography. Compound 24 was dissolved in DMF at 0 C. Then
77.89 (C-4), 77.73 (C-4), 76.84 (C-4), 76.30, 76.25, 75.20, 75.15, 74.94, NaH (540 g, 13.05 mmol) and NapBr (1.4 g, 6.7 mmol) were added
74.92 (CH2), 74.67 (C-2b), 74.00 (C-2a), 73.65, 73.59, 73.45 (CH2), the mixture under N2. The reaction was stirring at 0 oC untill the
72.67 (C-2c), 70.69 (C-5), 70.64 (C-5), 70.57 (C-5), 68.38 (C-6), 68.00 reaction was completed by TLC monitoring. Then the mixture was
(C-6), 67.97 (C-6), 64.50 (C-1º), 48.51 (C-3º), 28.77 (C-2º). HR-MS: dilutted with EtOAc and washed with H2O and brine. The organic
Calculated for C84H91N3O16 [M+NH4]+: 1415.67376, found: phase was dried with anhydrous MgSO4, filtered and concentrated in
1415.67378.
vacuo, and the product purified by column chromatography.
Compound 25 was obtained with 83% yield over two steps.
Synthesis of 14: The reaction was carried out according to the Compound 25 (4.8 g, 6.73 mmol) was dissolved in acetone:H2O (10:1,
standard procedure B, using 13 (190 mg, 0.27 mmol), 12 (70 mg, 0.05 77 mL). N-Iodosuccinimide (NIS) (3.0 g, 13.3 mmol) was added in one
mmol, 0.05 M in DCM), DMF (78 μL, 0.99 mmol) and TfOH (23 μL, portion and the reaction was stirred at room temperature for 2 hours.
o
0.27 mmol). The reaction was stirred at -78-0 C until TLC-analysis The solution was diluted with DCM and the reaction was quenched
showed complete conversion of the acceptor. The reaction was with saturated aqueous Na2S2O3. Then the organic layer was washed
quenched with Et3N, filtered and concentrated in vacuo. The product with water and brine. The organic layer was dried with anhydrous
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MgSO4, filtered and concentrated in vacuo, and the product purified (aromatic CH), 117.19 (C-6º), 113.78 (aromatic CH),Vi9ew6.A1r3ticl(eCO-n1lain)e,
DOI: 10.1039/D0OB00240B
by column chromatography. The lactol was obtained as a white solid. 81.83 (C-5a), 79.26 (C-2a), 77.47 (C-4a), 75.59, 74.83 (CH2), 73.59 (C-
Next, the lactol was dissolved in acetone (70 mL). Cs2CO3 (6.3 g, 19.5 2º), 73.52, 72.43 (CH2), 72.35 (C-4º), 70.23 (C-3a), 69.59 (C-3º), 67.97
mmol) and 2,2,2-trifluoro-N-phenylacetimidoyl chloride (3.2 mL, (C-6a), 65.01 (C-1º), 55.16 (OCH3). HR-MS: Calculated for C52H54O10
19.5 mmol) were added to the solution respectively. The reaction [M+Na]+: 861.3609, found: 861.3647.
was stirred overnight, then quenched with Et3N, filtered and
concentrated in vacuo. The product was purified by column Synthesis of 27: The reaction was carried out according to the
chromatography. Compound 16 (4.48 g, 84% yield over two steps, general procedure C, using 26 (1000 mg, 1.19 mmol, 0.1 M in
1
α:β = 1:1) was obtained as yellow syrup. H-NMR (CDCl3, 500 MHz, DCM:HFIP), triethylsilane (190 μL, 1.19 mmol) and 0.1M HCl/HFIP
(1.2 ml, 0.12 mmol). The product was purified by silica gel column
chromatography (PE:EA = 6:1). Compound 27 (800 mg, 93% yield)
was obtained as a colourless syrup. [α]D20 +73.0 (c=1, CHCl3). IR (neat,
cm-1) ν 710, 713, 738, 1027, 1070, 1095, 1272, 1452, 1721, 2866,
60℃) δ 7.79-7.74 (m, aromatic H), 7.49- 7.01 (m, aromatic H), 6.83-
6.73 (m, aromatic H), 6.40 (bs, 1 H, H-1α), 5.58 (bs, 1 H, H-1β), 4.96-
4.53 (m), 4.02-3.95 (m), 3.79-3.59 (m), 3.40 (bs, 1 H). 13 C-APT (CDCl3,
125 MHz, 60℃) δ 159.77, 159.73, 143.96, 143.73, 143.42, 138.99,
138.77, 138.38, 138.31, 135.81, 135.70, 133.57, 133.32, 130.33,
130.26 (aromatic C), 129.86, 129.43, 128.80, 128.46, 128.43, 128.33,
128.28, 128.06, 127.98, 127.94, 127.91, 127.84, 127.78, 127.69,
127.65, 127.60, 126.78, 126.72, 126.22, 126.20, 126.01, 125.97,
124.41, 124.28, 119.69, 119.58, 114.20, 114.17 (aromatic CH),
117.62 (q, CF3), 97.71, 94.00, 84.78, 81.75, 80.86, 79.41, 77.61, 77.36,
76.06, 75.31, 75.63, 75.55, 75.27, 75.02, 74.72, 73.82, 73.73, 73.48,
73.24, 68.73, 68.66, 55.83, 55.36. HR-MS: Calculated for C47H44F3NO7
[M-[O(C=NPh)CF3]+OH+Na]+: 643.26662, found: 643.26659.
1
2915. H-NMR (CDCl3, 400 MHz) δ 8.02-8.00 (m, 2 H, aromatic H),
7.78-7.66 (m, 4 H, aromatic H), 7.49-7.09 (m, 14 H, aromatic H), 6.96-
6.94 (m, 4 H, aromatic H), 5.93-5.84 (m, 1 H, H-5º), 5.32-5.26 (m, 1 H,
H-6ºa), 5.23-5.19 (m, 1 H, H-6ºb), 5.12 (d, J = 3.2 Hz, 1 H, H-1a), 4.99
(d, J = 11.2 Hz, 1 H, 1 CHH), 4.81 (d, J = 11.2 Hz, 1 H, 1 CHH), 4.78 (d,
J = 11.2 Hz, 1 H, 1 CHH), 4.69 (d, J = 12.4 Hz, 1 H, 1 CHH), 4.49-4.38
(m, 4 H, 3 CHH, H-1º),4.24-4.18 (m, 1 H, H-2º), 4.07-3.98 (m, 2 H, H-
4º), 3.97-3.93 (m, 1 H, H-3a), 3.80-3.73 (m, 2 H, H-2a, H-5a), 3.68-
3.57 (m, 4 H, H-3º, H-4a, H-6aa), 3.42 (dd, 1 H, J1 = 2.0 Hz, J2 = 10.4 Hz,
H-6ab), 2.77 (d, 1 H, J = 8.0 Hz, OH). 13C-APT (CDCl3, 100 MHz) δ 166.29
(C=O), 138.93, 138.25, 135.30 (aromatic C), 134.03 (C-5º), 133.24
(aromatic C), 133.18 (aromatic CH), 133.07, 129.83 (aromatic C),
129.75, 128.47, 128.41, 128.26, 127.99, 127.94, 127.80, 127.77,
127.61, 127.59, 126.86, 126.16, 126.05, 125.95 (aromatic CH),
117.92 (C-6º), 99.40 (C-1a), 83.53 (C-5a), 77.02 (C-4a), 76.14 (C-2º),
75.33, 74.95, 73.65 (CH2), 73.44 (C-2a), 72.46 (C-4º), 71.08 (C-3a),
69.23 (C-3º), 68.11 (C-6a), 64.80 (C-1º). HR-MS: Calculated for
C44H46O9 [M+Na]+: 741.3034, found: 741.3062.
1
(S)-3-(allyloxy)-2-hydroxypropyl benzoate 17: H-NMR (CDCl3, 400
MHz) δ 8.07-8.04 (m, 2 H, aromatic H), 7.58-7.53 (m, 1 H, aromatic
H), 7.45-7.41 (m, 2 H, aromatic H), 5.95-5.85 (m, 1 H, H-5), 5.31-5.17
(m, 2 H, H-6), 4.45-4.36 (m, 2 H, H-1), 4.19-4.14 (m, 1 H, H-2), 4.05-
4.03 (m, 2 H, H-4), 3.63-3.53 (m, 2 H, H-3), 3.01 (bs, 1 H, OH). 13C-APT
(CDCl3, 100 MHz) δ 166.69 (C=O), 134.30, 133.18 (aromatic CH),
129.87 (aromatic C), 129.80 (aromatic CH), 128.43 (C-5), 117.54 (C-
6), 772.43, 71.02, 68.93 (C-2), 66.07. HR-MS: Calculated for C13H16O4
[M+Na]+: 259.0941, found: 259.0948.
Synthesis of 28: The reaction was carried out according to the
standard procedure B, using 15 (1210 mg, 1.59 mmol), 27 (760 mg,
1.05 mmol, 0.1 M in DCM), DMF (1.3 mL, 16.8 mmol) and TfOH (140
μL, 1.59 mmol). The reaction was stirred at -78-0 oC until TLC-analysis
showed complete conversion of the acceptor. The reaction was
quenched with Et3N, filtered and concentrated in vacuo. The product
was purified by size exclusion chromatography (DCM:MeOH = 1:1).
Compound 28 (2.06 g, 95% yield, α:β > 10:1) was obtained as a
colourless syrup. Then the compound was purified by silica gel
Synthesis of 26: The reaction was carried out according to the
standard procedure B, using 15 (1.5 g, 1.9 mmol), 17 (410 mg, 1.74
mmol, 0.1 M in DCM), Ph3P=O (3.16 g, 11.4 mmol) and TMSI (270 μL,
1.9 mmol). The product was purified by silica gel column
chromatography. Compound 26 (1100 mg, 76 % yield, α:β > 20:1) was
obtained as a colourless syrup. [α]D20 +38.9 (c=1, CHCl3). IR (neat, cm-
1) ν 698, 713, 820, 1037, 1072, 1095, 1249, 1272, 1452, 1513, 1720,
2865, 2912. 1H-NMR (CDCl3, 400 MHz) δ 7.99-7.97 (m, 2 H, aromatic
H), 7.76-7.63 (m, 4 H, aromatic H), 7.46-7.08 (m, 16 H, aromatic H),
6.92 (bd, 2 H, aromatic H), 6.85-6.82 (m, 2 H, aromatic H), 5.93-5.84
(m, 1 H, H-5º), 5.31-5.25 (m, 1 H, H-6ºa), 5.19-5.16 (m, 2 H, H-1a, H-
6ºb), 4.99 (d, J = 10.8 Hz, 1 H, CHH), 4.81-4.77 (m, 2 H, 2 CHH), 4.70-
4.63 (m, 3 H, 3 CHH), 4.57 (dd, J1 = 3.6 Hz, J2 = 11.6 Hz, 1 H, H-1ºa),
4.45-4.35 (m, 3 H, 2 CHH, H-1ºb), 4.28-4.24 (m, 1 H, H-2º), 4.04-3.99
(m, 4 H, H-3a, H-5a, H-4º), 3.74 (s, 3 H, OCH3), 3.73-3.58 (m, 4 H, H-
2a, H-4a, H-3º), 3.50 (dd, 1 H, J1 = 2.8 Hz, J2 = 11.8 Hz, H-6aa), 3.37
(dd, 1 H, J1 = 2.0 Hz, J2 = 10.4 Hz, H-6ab). 13C-APT (CDCl3, 100 MHz) δ
166.19 (C=O), 159.30, 138.91, 138.22, 135.16 (aromatic C), 134.38 (C-
5º), 133.11, 132.96 (aromatic C), 132.88 (aromatic CH), 130.27,
129.84 (aromatic C), 129.62, 129.60, 128.31, 128.28, 128.11, 127.85,
127.82, 127.67, 127.48, 127.44, 126.80, 126.03, 125.97, 125.83
20
column chromatography to get pure α product. [α]D +75.1 (c=1,
CHCl3). IR (neat, cm-1) ν 698, 713, 820, 1046, 1070, 1095, 1272, 1359,
1454, 1721, 2863, 2919. 1H-NMR (CDCl3, 400 MHz) δ 8.00-7.81 (m, 2
H, aromatic H), 7.78-7.63 (m, 8 H, aromatic H), 7.44-6.91 (m, 34 H,
aromatic H), 5.81-5.76 (m, 1 H, H-5º), 5.46 (d, J = 3.6 Hz, 1 H, H-1a),
5.29 (d, J = 3.6 Hz, 1 H, H-1b), 5.22-5.10 (m, 2 H, H-6º), 4.98-4.67 (m,
10 H, 10 CHH), 4.56-4.33 (m, 6 H, 4 CHH, H-1º), 4.29-4.23 (m, 1 H, H-
2º), 4.14-4.04 (m, 4 H, H-5a, H-5b, H-3a, H-3b), 3.91-3.88 (m, 3 H, H-
3a, H-4º), 3.80-3.43 (m, 9 H, H-3º, H-2b, H-4a, H-4b, H-6a, H-6b). 13C-
APT (CDCl3, 100 MHz) δ 166.23 (C=O), 138.69, 138.46, 138.34, 138.31,
138.27, 135.33, 135.22 (aromatic C), 134.27 (C-5º), 133.18, 133.15,
133.01, 132.99 (aromatic C), 132.91 (aromatic CH), 129.92 (aromatic
C), 129.62, 128.41, 128.38, 128.35, 128.31, 128.19, 128.17, 128.15,
8 | J. Name., 2012, 00, 1-3
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128.09, 127.92, 127.87, 127.74, 127.69, 127.63, 127.54, 127.51, 5º), 133.44, 133.43, 133.32, 133.13 (aromatic C), 129.77, 129.76,
View Article Online
DOI: 10.1039/D0OB00240B
127.46, 127.43, 127.34, 126.88, 126.80, 126.09, 126.06, 125.98, 128.68, 128.43, 128.40, 128.38, 128.31, 128.23, 128.19, 128.13,
125.85, 125.84 (aromatic CH), 117.41 (C-6º), 99.70 (C-1b), 94.53 (C- 128.05, 128.01, 127.98, 127.86, 127.84, 127.73, 127.60, 127.58,
1a), 82.10 (C-5b), 80.73 (C-5a), 79.35 (C-2b), 77.80 (C-4), 77.56 (C-4), 127.45, 127.41, 126.98, 126.89, 126.23, 126.21, 126.15, 125.98,
76.03, 75.54 (CH2), 75.39 (C-2a), 74.85, 74.82, 73.54, 73.53 (CH2), 125.93 (aromatic CH), 117.33 (C-6º), 94.22 (C-1a), 93.60 (C-1b), 82.16
73.14 (C-2º), 72.36, 72.22 (CH2), 70.46 (C-3a and 3b), 69.23 (C-3º), (C-5b), 81.01 (C-5a), 79.44 (C-2b), 77.76 (C-4), 77.57 (C-4), 76.29,
68.98 (C-6a and 6b), 64.96 (C-1º). HR-MS: Calculated for C82H82O14 75.67 (CH2), 75.12 (C-2º), 74.94, 74.85 (CH2), 74.79 (C-2a), 73.70,
[M+Na]+: 1313.5597, found: 1313.5624.
72.28, 71.91 (CH2), 70.43 (C-3b), 70.34 (C-3a), 69.29, 68.22, 63.77
(CH2), 27.00 (3 CH3), 19.30. HR-MS: Calculated for C91H96O13Si
Synthesis of 29: Compound 28 (1100 mg, 0.85 mmol) was dissolved [M+Na]+: 1447.6512, found: 1447.6539.
in DCM:CH3OH (1:1/v:v, 8.5 mL) stirring at room temperatura. Then
5 drops of solution of CH3ONa in CH3OH (5.4 M) was added in the Synthesis of 31: The reaction was carried out according to the
mixture. The reaction was stirred at rt until TLC-analysis showed general procedure D, using 30 (460 mg, 0.32 mmol, 0.1 M in
complete conversion of the starting martial (3 h). Then the mixture DCM:H2O) and DDQ (170 mg, 0.75 mmol). The product was purified
was diluted with DCM. The organic phase was washed with water by silica gel column chromatography. Compound 31 (280 mg, 77%
and brine, dried with anhydrous MgSO4, filtered and concentrated in yield, pentane:EA = 4:1, Rf = 0.33) was obtained as a colourless syrup.
vacuo. The product was purified by silica gel column chromatography. [α]D20 +72.3 (c=1, CHCl3). IR (neat, cm-1) ν 698, 737, 1027, 1072, 1209,
Compound 29 (930 mg, 92% yield) was obtained as a colourless syrup. 1361, 1454, 2858, 2929. 1H-NMR (CDCl3, 400 MHz) δ 7.66-7.63 (m, 4
[α]D20 +69.4 (c=1, CHCl3). IR (neat, cm-1) ν 698, 737, 818, 1069, 1209, H, aromatic H), 7.41-7.07 (m, 31 H, aromatic H), 5.88-5.78 (m, 1 H, H-
1359, 1454, 2865, 2921. 1H-NMR (CDCl3, 400 MHz) δ 7.83-7.69 (m, 8 5º), 5.44 (d, J = 3.2 Hz, 1 H, H-1a), 5.34 (d, J = 3.6 Hz, 1 H, H-1b), 5.23-
H, aromatic H), 7.49-7.09 (m, 25 H, aromatic H), 7.03-6.92 (m, 6 H, 5.13 (m, 2 H, H-6º), 4.99-4.58 (m, 10 H, 10 CHH), 4.11-4.00 (m, 3 H,
aromatic H), 5.86-5.76 (m, 1 H, H-5º), 5.31 (d, J = 3.6 Hz, 1 H, H-1b), H-5a, H-5b, H-2º), 3.92-3.88 (m, 3 H, H-3b, H-4º), 3.76-3.51 (m, 14 H),
5.22-5.10 (m, 3 H, H-6º, H-1a), 4.94-4.35 (m, 14 H, 14 CHH), 4.09-3.98 1.76 (s, 1 H, OH), 1.64 (s, 1 H, OH), 1.04 (s, 9 H, 3 CH3). 13C-APT (CDCl3,
(m, 4 H, H-5a, H-5b, H-3a, H-3b), 3.89-3.45 (m, 14 H). 13C-APT (CDCl3, 100 MHz) δ 138.69, 138.58, 138.44, 138.38, 138.35 (aromatic C),
100 MHz) δ 138.73, 138.52, 138.31, 138.21, 137.98135.41, 135.20 135.62, 135.61 (aromatic CH), 134.52 (C-5º), 133.27, 133.24
(aromatic C), 134.56 (C-5º), 133.33, 133.29, 133.18, 133.12 (aromatic (aromatic C), 129.81, 128.46, 128.44, 128.41, 128.38, 128.36, 128.05,
C), 128.60, 128.45, 128.42, 128.31, 128.22, 128.07, 128.04, 128.01, 127.87, 127.84, 127.77, 127.70, 127.67, 127.62, 127.58 (aromatic
127.95, 127.84, 127.81, 127.78, 127.74, 127.67, 127.64, 127.49, CH), 117.28 (C-6º), 94.19 (C-1a), 93.40 (C-1b), 81.80 (C-5b), 80.69 (C-
126.98, 126.26, 126.19, 126.06, 126.04, 125.97 (aromatic CH), 5a), 79.65 (C-2b), 77.31 (C-4), 77.25 (C-4), 76.09, 75.57 (CH2), 75.04
117.25 (C-6º), 95.62 (C-1b), 95.08 (C-1a), 82.22 (C-5a), 80.73 (C-5b), (C-2º), 74.93 (CH2), 74.90 (C-2a), 72.24, 71.93 (CH2), 71.25 (C-3b),
79.24 (C-2b), 78.89 (C-2b), 78.28 (C-4), 77.71 (C-4), 76.15 (CH2), 75.73 70.94 (C-3a), 69.84, 63.67, 61.68, 61.50 (CH2), 26.93 (3 CH3), 19.22.
(C-2º), 75.69, 75.16, 74.99, 73.70, 73.61, 72.86 (CH2), 72.34 (C-4º), HR-MS: Calculated for C69H80O13Si [M+Na]+: 1167.5260, found:
70.86 (C-3b), 70.59 C-3a), 69.67 (C-3º), 68.64, 68.08 (C-6a and 6b), 1167.5280.
63.61 (C-1º). HR-MS: Calculated for C75H78O13 [M+Na]+: 1209.5335,
found: 1209.5356.
Synthesis of 32: Compound 31 (650 mg, 0.57 mmol) and 18 (633mg,
2.83 mmol) were dissolved in DCM (6 mL) stirring at room
Synthesis of 30: Compound 29 (350 mg, 0.3 mmol) was dissolved in temperature. Then TPyBOP (1.48 g, 2.85 mmol) and NMI (454 μL, 5.7
DMF (6 mL) stirring at room temperature. Then TBDPSCl (153 μL, 0.6 mmol) were added in the mixture. The reaction was stirred at rt until
mmol) and imidazole (120 mg, 1.8 mmol) were added in the mixture. TLC-analysis showed complete conversion of the starting martial.
The reaction was stirred at rt until TLC-analysis showed complete Then the mixture was diluted with DCM. The organic phase was
conversion of the starting martial. Then the mixture was diluted with washed with water and brine, dried with anhydrous MgSO4, filtered
DCM. The organic phase was washed with water and brine, dried and concentrated in vacuo. The product was purified by silica gel
with anhydrous MgSO4, filtered and concentrated in vacuo. The column chromatography. Compound 29 (800 mg, 90% yield) was
product was purified by silica gel column chromatography. obtained as a colourless syrup. [α]D20 +66.3 (c=1, CHCl3). IR (neat, cm-
Compound 29 (423 mg, 99% yield) was obtained as a colourless syrup. 1) ν 698, 738, 1029, 1070, 1171, 1208, 1251, 1454, 1498, 1725, 2858,
1
[α]D20 +62.1 (c=1, CHCl3). IR (neat, cm-1) ν 698, 738, 818, 1047, 1070, 2931. H-NMR (CDCl3, 400 MHz) δ 7.67-7.63 (m, 4 H, aromatic H),
1361, 1454, 2858, 2928. 1H-NMR (CDCl3, 400 MHz) δ 7.80-7.62 (m, 12 7.41-7.06 (m, 41 H, aromatic H), 5.85-5.75 (m, 1 H, H-5º), 5.42-5.34
H, aromatic H), 7.48-7.06 (m, 31 H, aromatic H), 6.97-6.94 (m, 6 H, (m, 3 H, H-1a, H-1b, H-6º), 5.21-4.73 (m, 13 H), 4.59-4.50 (m, 3 H),
aromatic H), 5.87-5.77 (m, 1 H, H-5º), 5.48 (d, J = 3.2 Hz, 1 H, H-1a), 4.35-3.45 (m, 22 H), 1.36 (d, J = 6.8 Hz, 1 H, CH3), 1.25 (d, J = 7.2 Hz,
5.34 (d, J = 3.2 Hz, 1 H, H-1b), 5.22-5.10 (m, 2 H, H-6º), 4.95-4.35 (m, 1 H, CH3), 1.04 (s, 9 H, 3 CH3). 13C-APT (CDCl3, 100 MHz) δ 172.78,
14 H, 14 CHH), 4.11-4.00 (m, 4 H, H-5a, H-5b, H-3a, H-2º), 3.89-3.84 172.69, 155.62 (4 C=O), 138.54, 138.32, 138.26, 138.19, 136.33
(m, 4 H, H-3b, H-2a, H-4º), 3.78-3.40 (m, 11 H), 1.01 (s, 9 H, 3 CH3). (aromatic C), 135.62, 135.60 (aromatic CH), 134.46 (C-5º), 133.20
13C-APT (CDCl3, 100 MHz) δ 138.86, 138.70, 138.58, 138.54, 138.44 (aromatic C), 129.86, 128.57, 128.46, 128.40, 128.35, 128.19, 128.10,
(aromatic C), 135.68 (aromatic CH), 135.52 (aromatic C), 134.70 (C- 128.03, 127.88, 127.76, 127.70, 127.66, 127.60 (aromatic CH),
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117.39 (C-6º), 96.64 (C-1a), 93.00 (C-1b), 81.86 (C-5b), 80.79 (C-5a), 3.82-3.66 (m, 10 H), 3.59-3.52 (m, 2 H, H-2b, H-6a), 3.34-3.31 (m, 1 H,
View Article Online
13
DOI: 10.1039/D0OB00240B
79.60, 77.36, 76.12, 75.63, 74.96, 74.68, 72.22, 71.84, 69.30, 69.12, H-6b), 1.49-1.45 (m, 6 H, 2 CH3), 1.04 (s, 9 H, 3 CH3). C-APT (d-
68.71, 66.95, 63.73, 63.66, 63.50, 49.69 (2 CHNH), 29.34 (CH3), 26.95 acetone, 100 MHz) δ 173.52, 173.41 (2 C=O), 159.55 (aromatic C),
(3 CH3), 19.23, 18.73 (CH3). HR-MS: Calculated for C91H102N2O19Si 156.90, 156.87 (2 C=O), 146.16, 139.99, 139.74, 139.68, 138.48,
[M+Na]+: 1577.67383, found: 1577.67285.
139.32, 138.03, 137.98, 136.85, 136.69 (aromatic C), 136.40, 136.38
(aromatic CH), 134.06, 134.03 (aromatic C), 131.04, 131.00, 130.67,
Synthesis of 33: A solution of 32 (600 mg, 0.38 mmol) and freshly 130.65, 129.10, 129.07, 129.01, 128.95, 128.83, 128.67, 128.55,
activated molecular sieves 3A in freshly distilled THF (4 ml) was 128.40, 128.33, 128.26, 128.24, 128.17, 127.58, 114.08, 114.06
stirred under argon for 30 min. After the addition of (aromatic CH), 94.97 (C-1a), 93.94 (C-1b), 87.37 (quaternary C), 82.55
Ir(COD)(Ph2MeP)2PF6 (33 mg, 10 mol %) the solution turned red and (C-5a), 81.79 (C-5b), 80.87 (C-2b), 78.59 (C-4), 78.26 (C-4), 76.90 (C-
the mixture was purged with H2 until the solution turned colourless 2º), 76.58 (CH2), 76.03 (C-2a), 75.86, 75.64, 75.53, 72.41 (CH2), 70.29
again (5-15 seconds). After stirring under argon for 4 h, the solution (C-3b), 70.11 (C-3a), 66.93, 66.90, 64.59, 64.54, 63.86 (CH2), 55.53 (2
was diluted with THF and satd aq NaHCO3. After the addition of I2 (73 OCH3), 50.72 (2 CHNH), 27.39 (3 CH3), 19.73 (quaternary C), 17.97
mg, 0.57 mmol), the mixture was allowed to stir overnight at room (CH3), 17.93 (CH3). HR-MS: Calculated for C109H116N2O21Si [M+Na]+:
temperature. The mixture was diluted with EtOAc and washed with 1839.77321, found: 1839.77281.
satd aq NaS2O3 and brine, respectively. The organic layer was dried
over MgSO4 and concentrated in vacuo. Column chromatography Synthesis of 19: Compound 33 (730 mg, 0.4 mmol) was dissolved in
20
afforded 33 (734 mg, 85%) as colourless syrup. [α]D +55.9 (c=1, THF/pyridine (1:1/v:v, 6 mL) stirring at room temperature. Then HF-
CHCl3). IR (neat, cm-1) ν 697, 737, 1027, 1069, 1168, 1208, 1258, 1454, pyridine (0.4 mL) was added in the mixture. The reaction was stirred
1498, 1720, 2858, 2929. 1H-NMR (CDCl3, 400 MHz) δ 7.66-7.64 (m, 4 at rt until TLC-analysis showed complete conversion of the starting
H, aromatic H), 7.43-7.07 (m, 41 H, aromatic H), 5.33 (d, J = 7.2 Hz, 1 martial (10 h). Then the mixture was diluted with EtOAc. The organic
H, NH), 5.26 (d, J = 7.6 Hz, 1 H, NH), 5.11-4.73 (m, 14 H, 12 CHH, H- phase was washed with water and brine, dried with anhydrous
1a, H-1b), 4.52 (bt, 2 H, 2 CHH), 4.32-4.25 (m, 2 H, 2 CHNH), 4.17-3.99 MgSO4, filtered and concentrated in vacuo. The product was purified
(m, 6 H, H-5a, H-5b, H-3, 3 CHH), 3.91-3.74 (m, 5 H, H-3, H-2º, 3 CHH), by silica gel column chromatography. Compound 19 (548 mg, 86%
3.67-3.61 (m, 3 H, H-2a, 2 CHH), 3.50-3.42 (m, 3 H, H-2b, H-4a, H-4b), yield) was obtained as a colourless syrup. [α]D20 +64.0 (c=1, CHCl3). IR
1.35 (d, J = 6.8 Hz, 1 H, CH3), 1.28 (d, J = 7.2 Hz, 1 H, CH3), 1.06 (s, 9 H, (neat, cm-1) ν 698, 751, 830, 1029, 1070, 1176, 1213, 1251, 1302,
3 CH3). 13C-APT (CDCl3, 100 MHz) δ 172.82, 172.65, 155.65, 155.57 (4 1454, 1508, 1608, 1724, 2928. 1H-NMR (d-acetone, 400 MHz) δ 7.49-
C=O), 138.38, 138.15, 137.92, 137.83, 137.55, 136.29 (aromatic C), 7.10 (m, 44 H, aromatic H), 6.87-6.73 (m, 5 H, 4 aromatic H, 1 NH),
135.65, 135.62 (aromatic CH), 133.17, 133.09 (aromatic C), 128.71, 6.74 (d, J = 7.6 Hz, 1 H, NH), 5.52 (d, J = 2.8 Hz, 1 H, H-1a), 5.26 (d, J =
128.58, 128.52, 128.48, 128.43, 128.39, 128.22, 128.20, 128.18, 2.8 Hz, 1 H, H-1b), 5.10-5.02 (m, 5 H, 5 CHH), 4.93-4.80 (m, 4 H, 2
128.16, 127.98, 127.95, 127.93, 127.90, 127.77, 127.73 (aromatic CHH), 4.70-4.62 (m, 3 H), 4.56-4.48 (m, 2 H), 4.42-4.21 (m, 7 H), 4.17-
CH), 96.63 (C-1a), 95.90 (C-1b), 82.27 (C-5b), 80.14 (C-5a), 79.57 (C- 4.01 (m, 4 H), 3.88-3.86 (m, 2 H), 3.75-3.47 (m, 12 H), 3.19 (dd, J1 =
2º), 77.97 (C-2b), 77.67 (C-4), 77.59 (C-4), 76.41 (C-2a), 75.95, 75.61, 5.6 Hz, J2 = 10.0 Hz, 1 H), 1.47-1.38 (m, 6 H, 2 CH3). 13C-APT (d-acetone,
75.08, 75.03, 73.81 (CH2), 69.21 (C-3b), 69.06 (C-3a), 69.97, 63.84, 100 MHz) δ 173.50, 173.43 (2 C=O), 159.60, 159.58 (aromatic C),
63.09, 63.03, 62.12 (CH2), 49.68 (CHNH), 49.60 (CHNH), 26.94 (3 CH3), 156.99, 156.89 (2 C=O), 146.16, 140.03, 139.77, 139.58, 139.50,
19.26, 18.70 (CH3), 18.57 (CH3). HR-MS: Calculated for C88H98N2O19Si 138.07, 138.04, 136.93, 136.71 (aromatic C), 131.07, 130.99, 129.25,
[M+Na]+: 1537.64253, found: 1537.64262.
129.14, 129.13, 129.09, 129.07, 129.05, 129.04, 128.99, 128.83,
128.76, 128.67, 128.64, 128.43, 128.34, 128.25, 128.19, 128.62,
Synthesis of 34: Compound 32 (610 mg, 0.4 mmol) and DMTrCl (273 114.06, 114.04 (aromatic CH), 95.52 (C-1a), 93.96 (C-1b), 87.35
mg, 0.8 mmol) were dissolved in DCM (4 mL) stirring at room (quaternary C), 82.63, 81.72, 80.85, 78.83, 78.59, 78.29, 76.48, 76.06,
temperature. Then DIPEA (283 μL, 1.6 mmol) was added in the 75.86, 75.63, 72.42, 70.34, 70.20, 66.92, 65.28, 64.32, 63.92, 63.43,
mixture. The reaction was stirred at rt until TLC-analysis showed 55.54 (2 OCH3), 50.78 (CHNH), 50.74 (CHNH), 17.98 (2 CH3). HR-MS:
complete conversion of the starting martial. Then the mixture was Calculated for C93H98N2O21 [M+NH4]+: 1596.70003, found:
diluted with DCM. The organic phase was washed with water and 1596.69828.
brine, dried with anhydrous MgSO4, filtered and concentrated in
vacuo. The product was purified by silica gel column chromatography. Synthesis of 36: Compound 19 (40 mg, 0.025 mmol) and DCI (1.5 eq,
Compound 34 (691 mg, 95% yield) was obtained as a colourless syrup. 0.25 M in CH3CN) was dissolved in dry CH3CN (1 mL) stirring at room
[α]D20 +118.8 (c=1, CHCl3). IR (neat, cm-1) ν698, 738, 827, 1029, 1070, temperature. Then compound 35 (1.1 eq) was added in the solution.
1175, 1209, 1249, 1454, 1508, 1607, 1724, 2931. 1H-NMR (d-acetone, The reaction was stirred at rt until TLC-analysis showed complete
400 MHz) δ 7.74-7.68 (m, 4 H, aromatic H), 7.55-7.12 (m, 50 H, conversion of the starting martial (2-3 h). Then CSO (0.5 M in CH3CN)
aromatic H), 6.89 (bd, 4 H, aromatic H), 6.82 (d, J = 7.6 Hz, 1 H, NH), was added in the mixture. The reaction was stirred at rt until TLC-
6.79 (d, J = 8.0 Hz, 1 H, NH), 5.58 (d, J = 2.8 Hz, 1 H, H-1a), 5.25 (d, J = analysis showed complete conversion of the starting martial (10-30
2.8 Hz, 1 H, H-1b), 5.15-5.05 (m, 5 H, 5 CHH), 4.97-4.71 (m, 6 H, 2 min). Then the mixture was diluted with DCM. The organic phase was
CHH), 4.56-4.11 (m, 13 H), 3.91 (dd, J1 = 2.8 Hz, J2 = 9.6 Hz, 1 H, H-2a), washed with water and brine, dried with anhydrous MgSO4, filtered
10 | J. Name., 2012, 00, 1-3
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and concentrated in vacuo. Crude compound 36 (50 mg) was 0.68, 0.78, 0.82. HR-MS: Calculated for C120H130N2O29P2 [M+Na]+:
View Article Online
DOI: 10.1039/D0OB00240B
obtained as a colourless syrup.
2147.81267, found: 2147.81610.
Synthesis of 37: Crude compound 36 (50 mg, 0.025 mmol) was Synthesis of 40: Crude compound 39 (11 mg, 0.005 mmol) was
dissolved in CH3OH/DCM = 1:1 (v:v, 1 mL) stirring at room dissolved in dioxane/H2O = 2:1 (v:v, 1 mL) stirring at room
temperature. Then TsOH (0.1 eq) was added in the solution. The temperature. Then Pd/C was added in the solution. The reaction was
reaction was stirred at rt until TLC-analysis showed complete stirred at rt for 3 days under a H2 atmosphere, filtered and
conversion of the starting martial (2-3 h). Then the reaction was concentrated in vacuo. Compound 40 (~5 mg, 93%) was obtained as
quenched with Et3N, diluted with DCM. The organic phase was a white solid. 1H-NMR (d-acetone, 400 MHz) δ 5.42 (d, 1 H, H-1), 5.11
washed with water and brine, dried with anhydrous MgSO4, filtered (d, 1 H, H-1), 4.63-4.57 (m, 2 H), 4.42-4.38 (m, 2 H), 4.21-4.15 (m, 5
and concentrated in vacuo. The product was purified by size H), 3.98-3.56 (m, 20 H), 3.50-3.38 (m, 2 H), 1.87 (s, 1 H), 1.57-1.53 (m,
exclusion chromatography (DCM:MeOH = 1:1). Compound 37 (40 mg, 6 H, 2 CH3). 13C-APT (d-acetone, 100 MHz) δ 170.46, 170.38 (2 C=O),
93%) was obtained as a colourless syrup. 1H-NMR (d-acetone, 400 96.00, 94.42, 75.04, 74.70, 72.37, 72.17, 71.71, 71.54, 71.04, 70.85,
MHz) δ 7.47-7.05 (m, 50 H, aromatic H), 6.95 (d, J = 7.6 Hz, 1 H, 1 NH), 70.72, 70.68, 70.64, 70.61, 69.82, 69.43, 69.20, 66.42, 66.37, 66.32,
6.74 (d, J = 7.6 Hz, 1 H, NH), 5.42-5.35 (m, 2 H, 2 H-1), 5.12-3.58 (m, 65.22, 64.90, 64.50, 62.47, 62.04, 62.01, 60.38, 50.45, 48.72, 16.06,
44 H), 2.89 (s, 1 H), 1.42-1.37 (m, 6 H, 2 CH3). 13C-APT (d-acetone, 100 15.20. 31P (d-acetone, 400 MHz) δ 1.22, 1.13. HR-MS: Calculated for
MHz) δ 173.52, 173.33, 156.93, 156.82 (4 C=O), 138.91, 139.64, C27H52N2O25P2 [M+H]+: 867.24071, found: 867.24106.
139.49, 139.39, 139.33, 138.03 (aromatic C), 129.36, 129.17, 129.09,
129.04, 129.02, 128.87, 128.85, 128.77, 128.71, 128.68, 128.60,
128.53, 128.52, 128.46, 128.35, 128.24, 128.22, 128.17, 128.14
Conflicts of interest
(aromatic CH), 96.03 (C-1), 85.08 (C-1), 82.74, 81.47, 79.96, 78.89,
78.53, 77.80, 77.71, 77.67, 77.60, 76.43, 76.09, 75.93, 75.56, 73.72,
73.07, 72.50, 70.22, 70.15, 69.87, 69.84, 67.89, 67.73, 66.81, 64.14,
63.64, 61.32, 61.25, 63.43, 55.54, 50.76, 50.65 (CHNH), 50.74 (CHNH),
17.85, 17.79 (2 CH3). 31P (d-acetone, 400 MHz) δ 0.77, 0.66.
There are no conflicts to declare.
Acknowledgements
This work was supported by the Chinese Scholarship Council (CSC
grant to L.W.), the European Research Council (ERC-CoG-726072-
‘GLYCONTROL’, to J.D.C.C.) and the European Union’s Horizon 2020
research and innovation program under the Marie Skłodowska-Curie
grant agreement Glycovax No. 675671.
Synthesis of 39: Compound 37 (40 mg, 0.023 mmol) and DCI (1.5 eq,
0.25 M in CH3CN) was dissolved in dry CH3CN (1 mL) stirring at room
temperature. Then compound 38 (1.1 eq) was added in the solution.
The reaction was stirred at rt until TLC-analysis showed complete
conversion of the starting martial (2-3 h). Then CSO (0.5 M in CH3CN)
was added in the mixture. The reaction was stirred at rt until TLC-
analysis showed complete conversion of the starting martial (10-30
min). Then the mixture was diluted with DCM. The organic phase was
washed with water and brine, dried with anhydrous MgSO4, filtered
and concentrated in vacuo. The product was purified by size
exclusion chromatography (DCM:MeOH = 1:1). Compound 39 (44 mg,
Notes and references
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DOI: 10.1039/D0OB00240B
H3N
H3N
Additive
controlled
glycosylations
O
O
O
O
HO
HO
NapO
O
P
O
BnO
BnO
O
NPh
OH
O
PMBO
O
HO
OH
CF3
O
OH
OH
HO
O
O
O
O
OH
P
O
O
O
O
E. faecalis LTA
Additive controlled glycosylation reactions are used for the construction of a-(1,2)-
glucosidic linkages, such as those featuring in E. faecalis lipoteichoic acid.