Building blocks from monosaccharides for synthesis of scaffolds, including macrocycles. Application of allylic azide rearrangement, azide-alkyne cycloaddition and ring closing metathesis

Article abstract of DOI:10.1016/j.tet.2020.131495

Synthesis of compounds with characteristics of natural products are required to increase the diversity and biological relevance of compounds for screening. These include new frameworks/scaffolds, with multiple stereogenic centres and various functional gr

Full text of DOI:10.1016/j.tet.2020.131495

Journal Pre-proof
Building blocks from monosaccharides for synthesis of scaffolds, including
macrocycles. Application of allylic azide rearrangement, azide-alkyne cycloaddition
and ring closing metathesis
Karen Fox, Rekha Chadda, Francisco Cardona, Stephen Barron, Patrick McArdle,
Paul V. Murphy
PII:
S0040-4020(20)30679-7
https://doi.org/10.1016/j.tet.2020.131495
TET 131495
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 June 2020
Revised Date: 31 July 2020
Accepted Date: 10 August 2020
Please cite this article as: Fox K, Chadda R, Cardona F, Barron S, McArdle P, Murphy PV, Building
blocks from monosaccharides for synthesis of scaffolds, including macrocycles. Application of allylic
azide rearrangement, azide-alkyne cycloaddition and ring closing metathesis, Tetrahedron (2020), doi:
https://doi.org/10.1016/j.tet.2020.131495.
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Building blocks from monosaccharides for synthesis of scaffolds,
including macrocycles. Application of allylic azide rearrangement,
azide-alkyne cycloaddition and ring closing metathesis
Karen Fox,a Rekha Chadda,a Francisco Cardona,a Stephen Barron,a Patrick McArdle,
Paul V. Murphy*
School of Chemistry, National University of Ireland Galway, University Road, Galway,
Ireland, H91 TK33
ABSTRACT
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Synthesis of compounds with characteristics of natural products are required to increase
the diversity and biological relevance of compounds for screening. These include new
frameworks/scaffolds, with multiple stereogenic centres and various functional groups.
Carbohydrates are renewable and are readily available with stereochemical diversity and
functionality. Herein, building blocks derived from monosaccharides with alkene,
alkyne and organic azide functional groups are used. The build-couple-pair strategy of
diversity oriented synthesis was employed taking advantage of RuAAC, CuAAC and
thermally promoted azide-alkyne cycloadditions, allylic azide (Winstein) rearrangement
and ring closing metathesis, leading to polyhydroxylated small, medium and
macrocyclic ring containing scaffolds. There is potential to graft appendages (e.g.
pharmacophoric groups) to further increase diversity of compounds available for
screening, or to consider the scaffolds in ligand design.
1

1. INTRODUCTION
Drug discovery and chemical biology rely on the identification of at least one hit
compound for a target at an early stage.1 Strategies for hit identification include
structure based design, ligand design2 or screening of chemical libraries,3 with both
synthetic and natural product research being sources of compounds, including
providing inspiration for scaffold selection. In an analysis of over 24 million known
compounds, Lipkus and co-workers showed that, as of 2008, as few as 143 scaffolds or
frameworks accounted for ~50% of all known compounds, with frameworks tending to
occur more frequently once reliable and relatively inexpensive synthesis had been
established.4
As well, many synthetic compounds reported have different properties to those of drugs
or natural products and may not be as biologically relevant.5 The most recent Newman
and Cragg analysis6 has shown that in the area of anti-cancer drug discovery from
1981-2014 that 49% of the approved drugs are natural products or directly derived from
them. Natural products are believed to be more successful in drug discovery, partly
because they have ‘privileged scaffolds’. 7 Many natural products are structurally
complex (poly)cyclic rigid molecules, including macrocycles,8 containing a variety of
functional groups and multiple stereogenic centres as well as heteroatoms, such as
oxygen or nitrogen that have evolved to have the capability to interact with protein
targets.9 As a consequence of such observations, there have been proposals, including
from industry, for chemists to produce synthetically tractable ‘natural product like
compounds’ as a basis to increase the diversity and biological relevance of chemical
libraries.10 These observations have inspired areas such as ‘diverted total synthesis’,11
‘diversity oriented synthesis’ and ‘biology oriented synthesis’,12,13,14 all with a goal to
improve the quality and quantity of hits for chemical biology and drug discovery.15,16
2

Carbohydrates are chiral, renewable, readily available precursors for synthesis, which
are rich in stereogenic centres, with various functional groups and they are components
of natural products of medicinal relevance.17 They have been used as precursors in both
18 , 19
20
natural product
and scaffold
syntheses as well as in diversity oriented
synthesis. 21 , 22 , 23 In earlier work we have used carbohydrate building blocks for
synthesis of scaffolds that are appended with pharmacophoric groups, giving rise, for
example, to multitargeting ligands for G-protein coupled receptors and the sodium
channel (see chart 1).24,25,26 In this paper, building blocks derived from carbohydrates,
already available from other projects, were instead used to generate new appendable
scaffolds.
The ‘build-couple-pair’ strategy of diversity oriented synthesis was
applied.27 The building blocks had alkenes, alkynes and azides and the synthesis
strategy included various types of azide alkyne cycloaddition, including the
incorporation of allylic azide rearrangement and ring closing metathesis.
Chart 1: A. Previous work: Bioactive compounds with pharmacophoric groups
(grey) appended to macrocyclic scaffold. Disconnections and key reactions used to
generate the frameworks are indicated (DRAM = double reductive amination
macrocyclization; CuAAC = copper catalysed azide-alkyne cycloaddition; RCM = ring
closure metathesis). B. Examples from this work: Scaffolds prepared using RuAAC
(ruthenium catalysed azide-alkene cycloaddition); IAAC (intramolecular azide alkyne
cycloaddition) combined with AAR (allylic azide rearrangement) and RCM.
3

2.
RESULTS AND DISCUSSION
2.1
Synthesis of building blocks (build)
The use of building blocks containing at least two functional groups, drawn from that of
alkene, alkyne and organic azide, was envisaged for the generation of frameworks.
Compound 1, derived from D
-glucuronolactone,28 was converted to 2, containing the
alkene and azide groups in addition to protected hydroxyl groups. Thus, reaction of 1
with p-methoxybenzyl chloride under basic conditions, then regioselective acetonide
hydrolysis followed by oxidative cleavage of the resulting diol to an aldehyde and
subsequent Wittig reaction gave 2 (Scheme 1). Intermediate 3 has been used in the
synthesis of peptidomimetics based on macrocycles with embedded carbohydrates
(MECs).29 Here, propargylation of the free hydroxyl group of 3 gave building block 4
with alkene and alkyne groups. Also 3 was used to give 5 and 6 (Scheme 1), with these
similarly containing alkene and alkyne groups. Aside from the napththylmethyl ether
being a protecting group,30,31 which can be removed in the presence of other benzyl like
protecting groups, it is also pharmacophoric.32
4

Scheme 1: Synthesis of building blocks 2, 4 and 6
Intermediate 7, derived from methyl α- -mannopyranoside was used previously in the
D
synthesis of iminosugars with quaternary centres.33 Here, a propargyl group was
grafted to the 2-oxygen atom of 7 giving 8, a building block with allylic azide, alkene
and alkyne groups. A regioisomer of 8 was also generated from 9, an intermediate used
for the synthesis of 8.33 Thus, the TES and acetonide groups were first removed from 9
using TBAF-THF in aqueous acetic acid to give a triol. Then reaction of this triol with
2,2-dimethoxypropane in the presence of p-toluenesulfonic acid followed by
propargylation, reduction of the ester and finally azidation gave 10 (Scheme 2).
5

Scheme 2: Synthesis of 8 and 10
2.2. Use of the saccharide building blocks in scaffold synthesis (couple and pair)
The joining together of two building blocks (couple) with azide and alkyne groups was
envisaged by using either the ruthenium catalysed azide-alkyne cycloaddition
(RuAAC)34 or copper catalysed azide-alkyne cycloaddition (CuAAC)35 to produce
triazoles, to be followed by RCM36 to effect cyclisation (pair). By having allylic azide
functionality in both 8 and 10, the possibility for incorporating Winstein
rearrangement37 in tandem with Huisgen cycloaddition for the new scaffold synthesis
was included.
Reaction of intermediate 11, (see experimental section for synthesis), with alkyne 12,29
in the presence of copper sulfate and sodium ascorbate gave a 1,5-triazole intermediate
(67%) that after ring closing metathesis gave macrocycle 13 (64%) with trans alkene
(Scheme 3).
6

Scheme 3. Synthesis of 13
Reaction of 4 with 14,29 previously used for the synthesis of macrocyclic
peptidomimetics, either gave 15 or 16, depending on whether RuAAC or CuAAC was
used (Scheme 4). Ring closure metathesis using the Hoyveda-Grubbs II catalyst gave in
the case of 15 a mixture of alkene stereoisomers 17 (17-cis:17-trans = 2:3). In contrast,
the reaction from 16 gave the trans isomer 18 isolated as the major product. The
protecting groups were removed from 17-trans and 18 to give the new
polyhydroxylated macrocycles 19 and 20. The yield for removal of the TBS groups was
low from 17; this reaction has not been optimised. These MECs (macrocycles with
embedded carbohydrates). They are digalactosyl derivatives and both α- and β-D-
galactopyranose derivatives have been of interest, for example, as galectin inhibitors,38
and could be screened against such lectin targets.
Pairing 2 and 5, using either RuAAC or CuAAC (Scheme 5) and subsequent ring
closure metathesis using the Grubbs II catalyst gave 21 and 22. Precursor 23 was
prepared from 11 and diol 6 using CuAAC. Subsequent RCM from 23 proceeded to
give 26, this time with the Hoveyda-Grubbs II catalyst in the presence of benzoquinone,
the latter used to prevent or reduce alkene isomerisation during metathesis.39
7

Scheme 4. Synthesis of MECs with two embedded galactopyranose residues.
8

Scheme 5 Synthesis of MECs with one embedded pyranose residue
Next, allylic azide rearrangement and intramolecular cycloaddition were combined for
the generation of new scaffolds (Scheme 6 & 7). In this regard the thermally promoted
reactions of regioisomers 8 and 10 were investigated. Reaction of 8 gave two isolated
products, 25 and 26. The imine 25 resulted from allylic azide rearrangement of primary
azide 8 to tertiary azide 8a, which then underwent thermally promoted azide-alkene
cycloaddition to give triazoline intermediate 8b and the latter’s subsequent
decomposition to the imine 25. Formation of an imine is known to occur from
triazolines, or alternatively, an aziridine intermediate is formed that can be trapped with
nucleophiles.40 The medium ten membered ring product 26 was formed directly from
primary azide 8 by competitive intramolecular azide-alkyne cycloaddition.
Determination of the crystal structure of 26 confirmed its structure. Removal of the
acetonide under acidic conditions gave the diol 27.
9

Scheme 6 Synthesis of medium ring 26 and 27. Crystal structure of 26
The thermally promoted reaction of 10 gave a mixture of dienes 28 and 29, which have
quaternary centers adjacent to a triazole nitrogen atom. Either intramolecular azide-
alkene or azide-alkyne cycloaddition were possible from reaction of 10a, formed via
allylic azide rearrangement.
However, triazole formation via alkyne-azide
cycloaddition were clearly preferred. Ring closing metathesis from the major product
29 was investigated, and while occurring in low yield (not optimised), it did give rise to
a product with similarity to naturally occurring conduramine-A.41 It is likely that the
10

yield is low due to steric hindrance caused by the quaternary centre adjacent to the
alkene.
Scheme 7 Synthesis of 30 and structure of (-)-conduramine A-1
Other scaffolds generated herein can also be considered ‘natural product like’, if one
considers structures of frameworks found in eunicin42 and ipomoeassin A (Chart 2), for
example. The latter, known as a resin glycoside, is a macrolactone with embedded
discaccharides, where the hydroxyl groups have appendages and it belongs to a family
of compounds with interesting cytotoxic properties.43
Chart 2. Structures of selected natural products
11

3.
SUMMARY
Expanding the number and diversity of scaffolds or frameworks is desired in order to
provide a basis for synthesis of new compounds for chemical biology and drug
discovery.44 We have demonstrated herein, the synthesis of a set of (poly)cyclic
functionalised scaffolds via intermediates derived from carbohydrates.45 The reactions
chosen to generate the scaffolds, such as allylic azide rearrangement used in tandem
with various types of cycloaddition, or CuAAC/RuAAC followed by metathesis, have
led to small to medium to macrocyclic ring containing products. The frameworks
generated incorporate features of natural products (rigidity, complexity, chirality,
scaffold diversity, increased aliphatic content, stereogenic centres, increased oxygen
content). They are appendable, meaning pharmacophoric groups can be attached via
the hydroxyl groups.46 This is facilitated by regioselectively protected carbohydrate
precursors, which will allow further chemical modification of the framework in due
course. Although macrocycles, like many natural products, do not often fit within the
Lipinski ‘rule of 5’ for drug-likeness47 they are still finding application as drugs or as
tools for research. Macrocycles with embedded carbohydrates with pharmacophoric
appendages were reported recently and were used to develop multitargeting ligands for
protein receptors.29 To conclude, carbohydrate derived intermediates can be used to
generate new frameworks, providing a strategy that can be considered in medicinal
chemistry projects and topics such as structure and ligand based design.48
4. EXPERIMENTAL SECTION
General: NMR spectra were recorded with 500 MHz Varian spectrometers. Chemical
shifts are reported relative to internal Me4Si in CDCl3 (δ 0.0) or CHCl3 (δ 7.26) HOD
for D2O (δ 4.84) or CD2HOD (δ 3.31) for 1H and CDCl3 (77.16) or CD3OD (49.05) for
12

1
13C NMR spectra were processed and analysed using MestReNova software. H-NMR
signals were assigned with the aid of gCOSY. 13C-NMR signals were assigned with the
aid of APT, gHSQCAD and/or gHMBCAD. Coupling constants are reported in Hertz,
with all J values reported uncorrected. Low- and high-resolution mass spectra were
measured on a Waters LCT Premier XE Spectrometer, measuring in both positive
and/or negative mode as, using MeCN, H2O and/or MeOH as solvent. Thin layer
chromatography (TLC) was performed on aluminium sheets precoated with silica gel 60
(HF254, E. Merck) and spots visualized by UV and charring with H2SO4-EtOH (1:20),
cerium molybdate or phosphomolybdic acid staining agents. Flash chromatography was
carried out with silica gel 60 (0.040-0.630 mm, E. Merck or Aldrich) and using a
stepwise solvent polarity gradient (starting with the conditions indicated in each case
and increasing the polarity as required), correlated with TLC mobility. Chromatography
solvents, cyclohexane, EtOAc, CH2Cl2 and MeOH were used as obtained from suppliers
(Fisher Scientific and Sigma-Aldrich). Anhydrous pyridine and DMF were purchased
from Sigma Aldrich with other dried solvents (methanol, THF, dicholoromethane,
toluene, diethyl ether) being used as obtained after treating with Pure Solv™ Solvent
Purification System. Purity of compounds synthesised may be qualitatively assessed by
examination of NMR spectra provided in the supporting information. Well known
impurities in NMR spectra were identified on the basis of previously reported NMR
data49 and where possible these are labelled on the spectra in supporting information.
Unidentified components are also indicated. The yields calculated are maximum yields
based on the weight of the final substance reported and may contain impurities as can be
evaluated by examination of the spectra.
13

(4S,5R)-4-((S)-2-Azido-1-(4-methoxybenzyloxy)ethyl)-2,2-dimethyl-5-vinyl-1,3-
dioxolane 2 To a stirred solution of 1 (9.52 g, 33.1 mmol) in anhydrous THF (66 mL,
0.5 M) at 0 ºC was added NaH (60 % in mineral oil, 1.19 g, 49.7 mmol) portion wise,
and the suspension was stirred at this temperature for 30 min. Then PMBCl (46 mmol,
6.3 mL) and TBAI (1.1 g, 3.3 mmol) were added sequentially at 0 ºC, and the resulting
mixture was stirred at 25 ºC for 16 h under argon. Satd aq NH4Cl was added and the
resulting mixture was extracted with EtOAc, and the combined organic layers were
washed with brine, dried over Na2SO4, and the solvent was removed under reduced
pressure. Flash column chromatography (silica gel, petroleum ether-EtOAc) of the
residue gave the PMB derivative, which was used in the next step without further
purification; ESI-HRMS: calcd for C16H23 N3O5Na [M + MeCN + Na]+ 471.2220; found
471.2228. The PMB derviative (5.36 g, 13.2 mmol) was then dissolved in 60% AcOH
(50 mL) and the mixture was stirred at room temp for 15 h. The mixture was neutralized
with satd aq NaHCO3 (20 mL) and 1M NaOH (30 mL), and then extracted with CH2Cl2
(3 x 20 mL). The organic portions were combined and washed with brine (25 mL), dried
over Na2SO4 and the solvent was removed under reduce pressure. Flash column
chromatography (silica gel, petroleum ether-EtOAc, 1:1) gave the desired diol
intermediate (2.44 g, 50 %) as a green pale oil. To this diol (1.9 g, 5.2 mmol) in CH2Cl2
(52 mL) was added PhI(OAc)2 (2.0 g, 6.2 mmol). The mixture was stirred at room
temperature for 3 h and then the solvent was removed at reduced pressure. Flash
column chromatography (silica gel, petroleum ether-EtOAc, 1:1) gave the intermediate
aldehyde (1.6 g, 91 %) as a yellow oil.
To a cooled solution of
methyltriphenylphosphonium iodide (Ph3PCH3I, 2.5 g, 6.2 mmol) in anhydrous THF
(69 mL) at -78 °C was added 1.0 M NaHMDS solution (5.8 mL, 5.8 mmol) dropwise
and stirring was continued at -78 °C for 25 min followed by 15 min at 0 °C and a further
14

30 min at room temperature under argon atmosphere. The mixture was cooled again to -
78 °C and the intermediate aldehyde (1.5 g, 4.4 mmol) in anhydrous THF (40 mL) was
then added dropwise via syringe. The mixture was then stirred at -78 °C for 10 min and
stirring was continued at room temp for a further 2 h under argon atmosphere. The
mixture was quenched by the addition of water (100 mL). The aqueous layer was
extracted with EtOAc (3 x 100 mL) and the combined organic layer dried over Na2SO4,
filtered and the solvent was removed under reduced pressure. Flash column
chromatography (silica gel, petroleum ether-EtOAc, 9:1) gave 2 (810 mg, 55%) as a
1
green pale oil; δ H NMR (500 MHz, chloroform-d) δ 7.49 – 7.06 (overlapped signals,
2H, aromatic H), 6.96 – 6.77 (overlapped signals, 2H, aromatic H), 5.77 (ddd, J = 16.5,
10.8, 7.4 Hz, 1H, alkene H), 5.20-5.23 (2H, overlapped signals, alkene H), 4.69 (d, J =
11.5 Hz, 1H, benzyl CH(H)), 4.59 (d, J = 11.4 Hz, 1H, benzyl CH(H)), 4.29 (t, J = 7.8
Hz, 1H), 3.84 – 3.76 (overlapped signals, 5H), 3.57 (ddd, J = 6.3, 5.3, 4.0 Hz, 1H), 3.42
13
(dd, J = 5.9, 3.5 Hz, 2H), 1.42 (s, 3H, CH3), 1.41 (s, 3H, CH3); C NMR (126 MHz,
chloroform-d) δ 159.5 (C), 135.2 (CH, 2C), 129.8 (CH, 2C), 129.7 (C), 119.2 (alkene
CH2), 113.8 (CH), 109.4 (C), 80.7 (CH), 78.3 (CH), 75.6 (CH), 73.0 (CH2), 55.3
(OCH3), 51.7 (CH2), 29.7 (CH3), 26.9 (CH3); ESI-HRMS: Calcd for C17H24N3O4
[M+H]+ 334.1767; found 334.1780.
1-Allyl-1-deoxy-6-O-dimethyl-tert-butylsilyl-2-O-propargyl-3,4-O-isopropylidene-
α-D-galactopyranose 4. To 3 (0.35 g, 0.96 mmol) in dry DMF (10 mL) was added NaH
(60% dispersion on mineral oil, 153 mg, 3.84 mmol) and the mixture was stirred at
room temp for 0.5 h. To this was added propargyl bromide (0.33 mL, 3.84 mmol) and
the mixture stirred for a further 1 h. Then MeOH (5 mL) was added and stirring was
continued for 5 min and EtOAc was added. The mixture was washed with H2O, brine,
filtered and the solvent was removed under reduced pressure. Flash chromatography
15

(cyclohexane-EtOAc 9:1) gave the title compound 4 (363 mg, 95 %) as a yellow oil; δ
1H NMR (500 MHz, chloroform-d ) δ 5.82 (ddt, J = 17.1, 10.3, 6.9 Hz, 1H), 5.13 (dd, J
= 17.1, 1.9 Hz, 1H), 5.06 (dd, J = 10.3, 1.8 Hz, 1H), 4.37 (dd, J = 7.0, 1.8 Hz, 1H), 4.33
(dd, J = 7.0, 3.7 Hz, 1H), 4.28 (d, J = 2.4 Hz, 2H), 4.05 (ddd, J = 7.8, 6.5, 3.0 Hz, 1H),
3.92 (ddd, J = 7.8, 5.8, 1.8 Hz, 1H), 3.76 (dd, J = 9.7, 7.9 Hz, 1H), 3.71 (dd, J = 9.6, 5.7
Hz, 1H), 3.64 (t, J = 3.4 Hz, 1H). 2.43 (1H, t, J =2.3 Hz, alkyne CH), 2.38 – 2.33 (2H,
overlapped signals, CH2CH=CH2), 1.50 (3H, s, isopropylidene CH3), 1.34 (3H, s,
isopropylidene CH3), 0.06 (6H, d, J = 1.9 Hz, each SiCH3); 13C-NMR (126 MHz,
chloroform-d) δ 134.5 (CH2CH=CH2), 117.1 (CH2CH=CH2), 109.1 (isopropylidene C),
79.7 (alkyne CH), 75.9 (C-2), 74.7 (alkyne C), 72.2 (C-4), 72.1 (C-3), 70.9 (C-1), 69.5
(C-5), 62.4 (C-6), 57.7 (alkyne CH2), 34.0 (CH2CH=CH2), 27.1, 25.9, 24.8 (each CH3),
18.3 (C), -5.4, -5.5 (each SiCH3); ESI-HRMS: calcd. for C21H37O5Si, 397.2369; found
m/z 397.2386 [M+H]+; FT-IR 3307, 2930, 1472, 1257, 1085, 834, 737 cm-1.
3-[2-O-(2-Naphthylmethyl)-3,4-O-isopropylidene-6-O-propargyl-α-
D-
galactopyranosyl]-1-propene 5 The reaction of 3 (5.22 g, 14.6 mmol), NaH (60 %
in mineral oil, 520 mg, 21.8 mmol), 2-(bromomethyl)naphthalene (4.50 g, 20.4 mmol),
TBAI (470 mg, 1.45 mmol) in anhydrous THF (29 mL), as described earlier for the
preparation of 2, gave, after flash column chromatography (silica gel, petroleum ether-
EtOAc, 19:1), the title compound 5 (5.80 g, 80%) as a yellow oil. Flash column
chromatography (silica gel, petroleum ether:EtOAc) gave the corresponding alcohol and
to this intermediate (5.78 g, 11.6 mmol) in anhydrous THF (116 mL) TBAF (1.0 M in
THF, 23.2 mmol, 23.2 mL) was added and the mixture stirred for 16 h under argon.
Water was added and the mixture was extracted with EtOAc. The organic layer was
washed with brine, dried over Na2SO4 and the solvent was removed under reduced
16

pressure. Flash column chromatography (silica gel, petroleum ether-EtOAc, 6:4) gave
the desired alcohol intermediate (4.0 g, ~95 %) as a colorless oil. Reaction of this
intermediate (3.96 g, 11.4 mmol), NaH (60 % in mineral oil, 409 mg, 17.0 mmol),
propargyl bromide (16 mmol, 1.4 mL) and TBAI (37 mg, 0.11 mmol) in anhydrous
THF (22.7 mL) as described in the methoxybenzylation of 1 gave the title compound
(4.1 g, 92 %) as a yellow oil after flash column chromatography (silica gel, petroleum
1
ether-EtOAc, 8.5:1.5); H NMR (500 MHz, chloroform-d): δ 7.86-7.81 (overlapped
signals, 3H, aromatic H), 7.77 (br s, 1H, aromatic H), 7.51-7.43 (overlapped signals,
3H, aromatic H), 5.74 (dddd, J = 16.9, 10.2, 7.5, 6.4 Hz, 1H, CH=CH2), 5.10-4.97
(overlapped signals, 2H, CH=CH2), 4.86 (d, J = 12.2 Hz, 1H, C(H)HPh), 4.70 (d, J =
12.2 Hz, 1H, C(H)HPh), 4.42 (dd, J = 7.3, 3.3 Hz, 1H, H-3), 4.33 (dd, J = 7.3, 1.8 Hz,
1H, H-4), 4.27-4.16 (overlapped signals, 3H), 4.06 (td, J = 7.3, 3.3 Hz, 1H, H-1), 3.73
(dd, J = 9.8, 5.9 Hz, 1H, H-6a), 3.67 (dd, J = 9.8, 6.6 Hz, 1H, H-6b), 3.58 (t, J = 3.3 Hz,
1H, 2-H), 2.48-2.35 (overlapped signals, 3H, CH2-CH=CH2, C≡CH), 1.47 (s, 3H, Me),
13
1.34 (s, 3H, Me); C NMR (126 MHz, chloroform-d) δ 135.3 (C), 134.5 (CH), 133.2
(C), 133.0 (C), 128.2, 127.9 (CH), 127.7 (CH), 126.5 (CH), 126.1 (CH), 125.9 (CH),
125.7 (CH), 117.2 (C), 109.5 (CH), 79.8 (C), 75.6 (CH), 74.4 (C), 72.9 (CH2), 72.6
(CH), 71.8 (CH), 71.1 (CH), 69.9 (CH2), 68.4 (C≡CH), 58.6 (CH2), 34.7 (CH2), 26.9
(CH3), 24.8 (CH3); ESI-HRMS: calcd for C26H34NO5 [M + NH4]+ 440.2437; found
440.2426.
3-[2-O-(2-Naphthylmethyl)-6-O-propargyl-α-D-galactopyranosyl]-1-propene
6
Propene 5 (201 mg, 0.475 mmol) was dissolved in 80% AcOH and the solution was
stirred at 80°C for 2 h. The solvent was removed under reduced pressure and flash
chromatography of the residue (petroleum ether-EtOAc, 1:1) gave the title compound 6
17

as a white solid (145 mg, 0.38 mmol, 80%); 1H NMR (500 MHz, chloroform-d): δ 7.86
– 7.81 (overlapped signals, 3H, aromatic H), 7.77 (s, 1H, aromatic H), 7.51 – 7.44
(overlapped signals, 3H, aromatic H), 5.81 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H, CH=CH2),
5.14 – 5.06 (overlapped signals, 2H, CH=CH2), 4.79 (d, J = 11.7 Hz, 1H, OCHHAr),
4.74 (d, J = 11.8 Hz, 1H, OCHHAr), 4.24 – 4.14 (overlapped signals, 3H, H-1 and
CH2C≡CH), 4.07 – 4.05 (br signal, 1H, H-4), 3.92 (dd, J = 9.3, 5.6 Hz, 1H, H-2), 3.85 –
3.75 (overlapped signals, 3H, H-3, H-5 and H-6a), 3.71 (dd, J = 9.4, 5.2 Hz, 1H, H-6b),
2.73 (d, J = 4.1 Hz, 1H, 4-OH), 2.68 (d, J = 3.0 Hz, 1H, 3-OH), 2.50 – 2.38 (overlapped
signals, 3H, CH2CH=CH2 and CH2C≡CH); 13C NMR (125 MHz, chloroform-d): δ
135.2 (C), 134.6 (CH), 133.2 (C), 133.1 (C), 128.4 (CH), 127.9 (CH), 127.7 (CH),
126.8 (CH), 126.3 (CH), 126.1 (CH), 125.7 (CH), 117.1 (CH2), 79.3 (C), 76.7 (CH),
74.8 (CH), 73.5 (CH), 72.9 (CH), 69.6 (CH), 69.4 (2s, 2x CH and CH2), 58.7 (CH2),
29.6 (CH2); ESI-HRMS: Found 405.1686 required 405.1678 [M+Na]+.
(4S,5S)-4-((E)-4-azidobut-2-en-2-yl)-2,2-dimethyl-5-((R)-1-(prop-2-ynyloxy)allyl)-
1,3-dioxolane 8
Alcohol 7 (1.0 g, 4.0 mmol) in anhydrous DMF was cooled to 0
°C and NaH (0.2 g, 60% in mineral oil, 5.1 mmol) charged portion wise and the mixture
was stirred for 30 min and propargyl bromide (0.8 mL, 80 wt. % in toluene, 7.10 mmol)
then added. The reaction mixture was allowed attain room temp and stirred for 16 h.
Et2O was added and the mixture was then washed with satd aq NH4Cl. The organic
layer was separated, dried over Na2SO4, filtered and the solvent was removed under
reduced pressure. Flash chromatography (hexane-EtOAc, 4:1) afforded alkyne 8 (0.92
g, 80 %) as a clear oil; Rf = 0.51 (hexane-EtOAc, 4:1); 1H NMR (500 MHz, chloroform-
d ) δ 5.77-5.68 (overlapped signals, 2H), 5.40 – 5.34 (overlapped signals, 2H), 4.48 (d, J
= 8.2 Hz, 1H), 4.29 (dd, J = 16.0, 2.5 Hz, 1H), 4.09 (dd, J = 16.2, 2.2 Hz, 1H), 4.05 (dd,
J = 8.4, 4.3 Hz, 1H), 3.89 (dd, J = 14.0, 7.7 Hz, 1H), 3.83 (ddd, J = 8.2, 4.2 Hz, 1H),
18

3.77 (dd, J = 14.0, 6.7 Hz, 1H); 2.42 (t, 2.4 Hz, 1H), 1.74 (s, 3H, CH3), 1.45 (s, 6H,
13
C(CH3)2); C NMR (126 MHz, chloroform-d ) δ 138.4 (alkene C), 133.7 (alkene CH),
122.9 (alkene CH), 120.7 (alkene CH2), 109.6 (C(CH3)2), 81.7 (CH), 80.7 (CH), 79.6
(alkyne C), 78.1 (CH), 74.5 (alkyne CH), 55.2 (CH2), 47.7 (CH2), 27.1 (C(CH3)2), 26.9
(C(CH3)2), 11.8 (CH3); ESI-HRMS: m/z calc for C15H22N3O3: 292.1661 found:
292.1665 [M+H]+.
(4S,5R)-4-((S,E)-4-Azido-2-methyl-1-(prop-2-ynyloxy)but-2-enyl)-2,2-dimethyl-5-
vinyl-1,3-dioxolane 10
To compound 9 (2.12 g, 5.51 mmol) in anhydrous THF
(40 mL), TBAF (11.0 mL, 1 M in THF buffered with 20 % AcOH) was charged slowly
and the mixture was stirred at room temp for 2 h, followed by the addition of pH 7
buffer (30 mL). The aqueous layer was then extracted with EtOAc and the combined
organic layers were then dried over Na2SO4, filtered and solvent removed under reduced
pressure. Flash chromatography (EtOAc-hexane, 3:7) afforded alcohol intermediate (1.3
g, 90 %) as a clear oil (Rf = 0.63, EtOAc-hexane, 3:7). This alcohol (1.25 g, 4.62
mmol) was dissolved in 2M HCl (10 mL) and the mixture stirred at room temp for 1 h.
The solution was extracted with EtOAc, dried over Na2SO4, filtered and solvent
removed under reduced pressure. Flash chromatography (hexanes-EtOAc, 7:3) afforded
the required triol (0.88 g, 82 %) as a clear oil (Rf = 0.53 (hexanes-EtOAc, 7:3)). The
triol (2.67 g, 11.6 mmol) was dissolved in CH2Cl2 (30 mL). The solution was cooled to
0 ˚C and p-TsOH (0.4 g, 2.3 mmol) added. After stirring for 10 mins, 2,2-
dimethoxypropane (2.85 mL, 23.2 mmol) was added. The reaction mixture was
subsequently stirred at room temp for 15 mins and triethylamine (1.60 mL, 11.6 mmol)
charged. The solvent was then removed under reduced pressure. Flash chromatography
(hexanes-EtOAc, 7:3) afforded the needed isopropylidene intermediate (2.85 g, 91 %)
19

as a clear oil. This oil (0.93 g, 3.4 mmol) was dissolved in anhydrous DMF (30 mL).
The solution was cooled to 0 °C and NaH (190 mg, 60% in mineral oil, 4.8 mmol)
charged portionwise. The reaction mixture was stirred for a further 30 min and
propargyl bromide (0.7 mL, 80 wt. % in toluene, 6.2 mmol) added, reaction mixture
warmed to rt and stirred for 4 h. The solution was quenched with satd. NH4Cl (aq),
extracted with EtOAc, dried over Na2SO4, filtered & solvent removed under reduced
pressure. Flash chromatography (hexanes-EtOAc, 4:1) gave the desired alkyne (0.74 g,
70 %) as a clear oil; Rf 0.4 (hexanes-EtOAc, 4:1); ESI-HRMS: m/z calc for C18H29O6:
341.1964, found 341.1971 [M+H+CH3OH]+. This alkyne (0.40 g, 1.3 mmol) was
dissolved in CH2Cl2 (5 mL) and the solution was cooled to -78 ºC and DIBAL-H (3.9
mL, 1M in THF, 3.9 mmol) was charged slowly. The solution was then stirred at -78 ˚C
for 4 h and the mixture was subsequently quenched with the slow addition of MeOH.
The solution was warmed to room temp and stirred with potassium tartrate (aq) until
clear. The organic layer was separated and subsequently washed with H2O, dried over
Na2SO4, filtered and solvent removed under reduced pressure to afford the desired
primary alcohol (0.3 g, 86 %) as a clear oil; ESI-HRMS: m/z calc for C15H21O4:
265.1440, found 265.1436 [M-H]-. Finally, this alcohol (0.3 g, 1.1 mmol) was
dissolved in anhydrous THF (6 mL) and PPh3 (0.53 g, 1.92 mmol) charged. The solution
was cooled to 0 ˚C, followed by the addition of DIAD (0.38 mL, 1.92 mmol) and DPPA
(0.4 mL, 1.9 mmol). The reaction mixture was adjusted to room temp and stirred for a
further 12 h. The solvent was then removed under reduced pressure. Flash
chromatography (hexanes-EtOAc, 10:1) gave the azide 10 (220 mg, 69 %) as a clear oil;
Rf = 0.75 (EtOAc-hexanes, 1:4); FTIR 3414, 2983, 1712, 1654, 1372, 1214, 1151, 1097,
1
1040, 994, 928, 873, 764 cm-1; H NMR (500 MHz, chloroform-d): δ 5.77 (ddd, J =
17.4, 10.3, 7.4 Hz, 1H, alkene H), 5.69 (t, J = 7.1 Hz, 1H, alkene H), 5.34 (d, J = 17.1
20

Hz, 1H, alkene H), 5.25 (d, J = 10.3 Hz, 1H, alkene H), 4.31 – 4.24 (overlapped signals,
2H), 4.07 – 3.98 (overlapped signals, 2H), 3.92 (dd, J = 14.1, 7.2 Hz, 1H), 3.85 (dd, J =
8.1, 6.2 Hz, 1H), 3.79 (dd, J = 14.1, 6.9 Hz, 1H), 2.42 (t, J = 2.4 Hz, 1H), 1.66 (s, 3H,
CH3), 1.46 (s, 3H, C(CH3)2), 1.44 (s, 3H, C(CH3)2); 13C NMR (126 MHz, chloroform-d
) δ 137.5 (alkene C), 135.4 (alkene CH), 124.2 (alkene CH), 119.1 (alkene CH2), 109.6
(C(CH3)2), 83.1 (CH), 81.2 (CH), 79.2 (alkyne C), 79.1 (CH), 74.7 (alkyne CH), 55.4
(CH2), 47.7 (CH2), 27.0 (C(CH3)2), 26.8 (C(CH3)2), 12.8 (CH3); ESI-HRMS: m/z calc
for C15H22O3N3: 292.1661, found 292.1650 [M+H]+.
(3S,4S,5R,E)-3-(Benzyloxy)-4,5-O-isopropylidene-13-oxa-1,16,17-
triazabicyclo[13.2.1]octadeca-6,15(18),16-triene-4,5-diol 13
The benzylation of 1
using benzyl bromide, and subsequent reactions as described for the preparation of 2
gave (4S,5R)-4-((S)-2-azido-1-(benzyloxy)ethyl)-2,2-dimethyl-5-vinyl-1,3-dioxolane as
a clear oil (140 mg, 0.46 mmol, 46%); 13C NMR (125 MHz, chloroform-d): δ 137.6 (C),
135.2 (CH), 128.5 (CH), 128.2 (CH), 128.0 (CH), 119.3 (CH2), 109.4 (C), 80.7 (CH),
78.3 (CH), 76.1 (CH), 73.3 (CH2), 51.7 (CH2), 26.9 (CH3), 26.8 (CH3). To this azide
(54 mg, 0.178 mmol) and 7-O-propargyl-hept-1-ene 1229 (54 mg, 0.36 mmol) in
THF:H2O (1:1, 3mL), in a microwave vial was added copper sulphate pentahydrate (18
µL of a 0.2 M solution, 0.0036 mmol) and sodium ascorbate (4 mg, 0.02 mmol). The
mixture was stirred in a microwave (120 W, 60 °C) for 15 mins and then diluted with
EtOAc. The layers were separated and the organic layer washed with brine, dried
(Na2SO4), filtered and the solvent was removed under reduced pressure. Flash
chromatography (petroleum ether-EtOAc, 3:1 to 1:1) of the residue gave 1,4-triazole as
a clear oil (53 mg, 0.12 mmol, 67%). A solution of this intermediate (10 mg, 0.022
mmol) in dry, degassed toluene (10 mL) in an oven dried, two necked round bottomed
21

flask, equipped with a reflux condenser, was stirred under N2. The solution was heated
to 80 °C and the 2nd generation Hoveyda-Grubbs II catalyst (3 mg, 0.005 mmol) in dry,
degassed toluene (0.3 mL) was added via cannula. The solution was stirred for 6 h after
which the solvent was removed under reduced pressure. Flash chromatography
(cyclohexane-EtOAc, 3:1 to 1:1) gave 13 as a clear oil (6 mg, 64%); 1H NMR (500
MHz, CDCl3): δ 7.45 (s, 1H, triazole H), 7.40-7.33 (overlapped signals, 5H, phenyl H),
5.07-5.04 (overlapped signals, 2H, alkene H), 4.90 (d, J = 12.1 Hz, 1H, OCHHPh), 4.71
(overlapped signals, 2H), 4.67 (d, J = 12.1 Hz, 1H, OCHHPh), 4.62 (d, J = 13.4 Hz, 1H,
OCHH-triazole), 4.56 (d, J = 13.4 Hz, 1H, OCHH-triazole), 4.14-4.10 (m, 1H), 3.47-
3.39 (overlapped signals, 2H), 3.37 (td, J = 6.1, 1.3 Hz, 1H), 3.33 (dd, J = 8.4, 1.3 Hz,
1H), 1.95-1.83 (overlapped signals, 2H), 1.47 (s, 3H, CH3), 1.44 (s, 3H, CH3), 1.41-1.34
(overlapped signals, 2H), 1.28-1.19 (m, 1H), 1.16 – 1.07 (m, 1H), 0.91 – 0.74
13
(overlapped signals, 2H); C NMR (125 MHz, chloroform-d): δ 146.8 (C), 136.6 (C),
134.3 (CH), 129.0 (CH), 128.7 (CH), 128.5 (CH), 127.4 (CH), 122.7 (CH), 109.8 (C),
80.7 (CH), 76.6 (CH), 73.1 (CH), 72.2 (CH2), 69.3 (CH2), 63.4 (CH2), 49.7 (CH2), 31.6
(CH2), 29.3 (CH2), 27.3 (CH2), 27.2 (CH3), 26.6 (CH3), 25.3 (CH2); ESI-HRMS: Found
462.2150 required 462.2160 [M+Cl]−.
(3aS,4R,6R,7S,7aR)-6-Allyl-4-((5-(((3aS,4R,6R,7S,7aR)-6-allyl-4-((tert-
butyldimethylsilyloxy)methyl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-
c]pyran-7-yloxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-2,2-dimethyltetrahydro-
3aH-[1,3]dioxolo[4,5-c]pyran-7-ol 15. To compounds 4 (170 mg, 0.44 mmol) and 14
(130 mg, 0.44 mmol) in DMA (2 mL) was added Cp*RuCl(COD) (33 mg, 0.088 mol).
The mixture was transferred to a microwave via, which was sealed and placed in a
microwave reactor for 30 min at 60 °C and 120 W. The mixture was then diluted with
Et2O, washed with H2O, brine, dried over Na2SO4, filtered and the solvent removed
22

under reduced pressure. Flash chromatography (cyclohexane-EtOAc 2:1) gave 15 (125
mg, 43 %) as a colourless oil; 1H NMR (500 MHz, chloroform-d): δ 7.60 (1H, s, triazole
H), 5.75 – 5.63 (2H, overlapped signals, 2 CH2CH=CH2), 5.08 – 4.98 (4H, overlapped
signals, each CH2CH=CH2), 4.92 (1H, d, J = 12.6), 4.61 (2H, overlapped signals), 4.52-
4.45 (2H, overlapped signals), 4.37 (1H, dd, J = 6.9, 1.8 Hz, galactose H-4), 4.28-4.33
(2H, overlapped signals, galactose H-3 signals), 4.26 (1H, dd, J = 7.4, 1.7, galactose H-
4), 4.04 (1H, td, J = 7.8, 7.4, 2.8 Hz, anomeric H), 4.00 (td, J = 7.5, 7.0, 3.0 Hz,
anomeric H), 3.90 (1H, ddd, J = 7.7, 5.8, 1.8 Hz, galactose H-5), 3.82 (1H, q, J = 3.4
Hz), 3.76 (1H, dd, J = 9.6, 7.9 Hz, galactose H-6), 3.70 (1H, dd, J = 9.6, 5.8 Hz,
galactose H-6), 3.46 (1H, t, J = 3.6 Hz, galactose H-2), 2.33 (1H, ddd, J = 14.4, 8.2, 6.4
Hz, allylic H), 2.28 – 2.16 (3H, overlapped signals), 2.08 (1H, d, J = 4.3 Hz, OH), 1.53
(3H, s, isopropylidene CH3), 1.47 (3H, s, isopropylidene CH3), 1.35 (3H, s,
isopropylidene CH3), 1.33 (3H, s, isopropylidene CH3), 0.89 (9H, s, t-Bu), 0.06 (2 x s,
6H, CH3); 13C NMR (126 MHz, chloroform-d ) δ 134.3 (triazole C=C), 134.1
(CH=CH), 134.0 (CH=CH), 133.6 (triazole CH), 117.6 (alkene CH2), 117.3 (alkene
CH2), 109.9 (isopropylidene C), 109.3 (isopropylidene C), 76.73 (galactose (gal) C-2),
74.35 (gal C-3), 72.54 (gal C-4), 72.27 (gal C-4’), 72.15 (gal C-3), 70.94 (gal C-1),
70.90 (gal C-1), 69.50 (gal C-5), 69.47 (gal C-5), 68.44 (gal C-2), 62.48 (gal C-6),
60.61 (OCH2), 50.01 (gal C-6), 35.15 (CH2CH=CH2), 33.86 (CH2CH=CH2), 27.19
(isopropylidene CH3), 26.73 (isopropylidene CH3), 25.86 (CH3), 24.91 (isopropylidene
CH3), 24.54 (isopropylidene CH3), 18.3 (C), -5.35, -5.47 (each CH3); ESI-HRMS:
calcd. for C33H55N3O9SiNa, 688.3626; found m/z 688.3629 [M+Na]+; FT-IR 3374,
2929, 1724, 1461, 1380, 1210, 1061, 835, 777 cm-1.
23

(3aS,4R,6R,7S,7aR)-6-Allyl-4-((4-(((3aS,4R,6R,7S,7aR)-6-allyl-4-((tert-
butyldimethylsilyloxy)methyl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-
c]pyran-7-yloxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-2,2-dimethyltetrahydro-
3aH-[1,3]dioxolo[4,5-c]pyran-7-ol 16. In a microwave vial in THF-H2O (1:1, 5 mL),
was placed 14 (60 mg, 0.20 mmol), 4 (91 mg, 0.20 mmol), CuSO4.5H2O (50 mg, 0.20
mmol) and sodium-L-ascorbate (20 mg, 0.10 mmol). The vial was sealed, and the
mixture was heated to 60 °C for 10 min at 120 W in a microwave reactor. The mixture
was diluted with Et2O, washed with H2O, brine, dried over Na2SO4 and the solvent was
removed under reduced pressure. Flash chromatography (cyclohexane-EtOAc, 1:1) gave
16 (97 mg, 73 %) as a colourless oil; 1H NMR (500 MHz, chloroform-d): δ 7.70 (1H, s,
triazole H), 5.75 (2H, overlapped signals, alkene H), 5.14 – 4.99 (4H, overlapped
signals, alkene H), 4.83 (1H, d, J = 12.1 Hz), 4.66 (1H, d, J = 12.2 Hz), 4.62 (1H, dd, J
= 13.9, 4.1 Hz, gal H-6), 4.44 (1H, dd, J = 13.9, 8.5 Hz, gal H-6b), 4.38-4.31 (3H,
overlapped signals), 4.23 (1H, dd, J = 7.5, 1.9 Hz, gal H-5), 4.08 (1H, td, J = 7.2, 2.0
Hz, gal H-1), 4.00 (1H, td, J = 7.3, 2.9 Hz, gal H-1), 3.93 (1H, ddd, J = 7.5, 5.5, 1.5 Hz,
gal H-5), 3.85 (1H, q, J = 3.2 Hz, gal H-2), 3.74 (1H, dd, J = 9.6, 8.0 Hz, gal H-6), 3.68
(1H, dd, J = 9.6, 5.7 Hz, gal H-6), 3.54 (1H, t, J = 3.1, gal H-2), 2.37 – 2.24 (4H,
overlapped signals), 1.92 (d, J = 4.1 Hz, 1H, OH), 1.53 (3H, s, isopropylidene CH3),
1.47 (3H, s, isopropylidene CH3), 1.35 (3H, s, isopropylidene CH3), 1.33 (3H, s,
13
isopropylidene CH3), 0.88 (9H, s, 3 x CH3), 0.05 (6H, 2 s, each CH3); C-NMR (126
MHz, chloroform-d): δ 144.9 (triazole C) 134.5 (alkene CH), 134.1 (alkene CH), 124.1
(triazole CH) 117.7 (alkene CH2), 117.1 (alkene CH2), 110.0 (isopropylidene C), 109.1
(isopropylidene C), 76.3 (gal C-2), 74.3 (CH), 72.5 (gal C-5), 72.0 (CH), 70.9 (gal C-1),
70.7 (gal C-1’), 69.5 (gal H-5), 68.9 (CH), 68.4 (gal C-2), 64.1 (OCH2), 62.5 (CH2),
51.9 (CH2N), 35.2 (allylic CH2), 34.5 (allylic CH2), 27.1 (isopropylidene CH3), 26.6
24

(isopropylidene CH3), 25.9 (CH3), 24.7 (isopropylidene CH3), 24.5 (isopropylidene
CH3), 18.3 (C) -5.3, -5.5 (each CH3); ESI-HRMS: calcd. for C33H55N3O9SiNa,
688.3584; found m/z 688.3605 [M+Na]+; FT-IR 3384, 2929, 2100, 1373, 1210, 1058,
910, 835, 777, 732 cm-1.
Macrocycles 17-cis and 17-trans To diene 15 (65 mg, 0.1 mmol) in toluene (150 mL),
was added the first generation Hoveyda-Grubbs II catalyst (12 mg, 0.02 mmol) and the
mixture stirred at 90 °C for 24 h. The solvent was then removed under reduced pressure
and flash chromatography (cyclohexane-EtOAc, 7:3) of the residue gave 17-cis (15 mg)
and 17-trans (23 mg) both as white solids (overall yield, 60 %). Analytical data for 17-
cis: 1H NMR (500 MHz, chloroform-d ) δ 7.62 (1H, s, triazole H), 5.45 (1H, t, J = 11.2
Hz, CH=CH), 5.33 (1H, t, J = 10.3 Hz, CH=CH), 4.96 (1H, d, J = 12.2 Hz), 4.77 (1H,
dd, J = 14.4, 3.2 Hz, gal H-6), 4.71 (1H, d, J = 12.1 Hz), 4.48 (1H, dd, J = 7.3, 1.6 Hz,
H-4), 4.41 (2H, overlapped signals), 4.31 (1H, dd, J = 14.5, 7.0 Hz, gal H-6), 4.26 (1H,
dd, J = 7.1, 4.0 Hz, gal H-3), 4.22 – 4.16 (1H, m, gal H-5), 4.12 (1H, ddd, J = 10.1, 6.0,
2.1 Hz, gal H-1), 4.05 (1H, dt, J = 10.9, 2.1 Hz, gal H-1), 4.00 (1H, ddd, J = 8.0, 5.9,
1.5 Hz, gal H-5), 3.81 (q, J = 3.4 Hz, 1H, gal H-2), 3.78 – 3.70 (2H, overlapped signals,
H-6a & H-6b), 3.52 (1H, t, J = 2.5 Hz, H-2), 2.59 (2H, overlapped signals), 2.22 (2H,
overlapped signals), 1.95 (1H, d, J = 14.9 Hz), 1.52 (6H, overlapped signals, 2 x
isopropylidene CH3), 1.38 (6H, overlapped signals, 2 x isopropylidene CH3), 0.91 (9H,
s, 3 x CH3), 0.08 (6H, s, 2 x CH3); 13C NMR (126 MHz, chloroform-d ) δ 134.4
(triazole C), 133.6 (triazole CH), 128.8 (alkene CH), 126.1 (alkene CH), 109.9
(isopropylidene C), 109.3 (isopropylidene C), 75.6 (gal C-2), 75.0 (gal C-3), 73.2 (CH),
71.8 (CH), 71.4 (CH), 70.6 (gal C-1), 70.3 (gal C-4), 70.2 (gal C-5), 69.9 (gal C-5), 62.4
(gal C-6), 61.9 (CH2), 51.2 (CH2N), 29.4 (CH2), 28.3 (CH2), 27.0 (2s, each
25

isopropylidene CH3), 25.9 (CH3), 24.7, 24.4 (each isopropylidene CH3), 18.4 (C), -5.3, -
5.4 (each CH3); ESI-HRMS: calcd. for C31H51O9N3SiNa, 660.3250; found m/z 660.3249
[M+Na]+; FT-IR 2931, 2298, 1462, 1379, 1248, 1210, 1060, 834, 777, 660 cm-1.
Analytical data for 17-trans: 1H NMR (500 MHz, chloroform-d ) δ 7.65 (1H, s, triazole
H), 5.36-5.19 (2H, overlapped signals, CH=CH), 4.92 (1H, d, J = 12.2 Hz), 4.73 (1H, d,
J = 12.2 Hz), 4.56 (1H, dd, J = 14.4, 2.1 Hz, H-6’a), 4.45 – 4.31 (5H, overlapped
signals), 4.19 – 4.10 (2H, overlapped signals), 3.98 (1H, t, J = 6.8 Hz, gal H-5), 3.92
(1H, dt, J = 11.2, 2.7, gal H-1), 3.83 – 3.70 (3H, overlapped signals), 3.61 – 3.52 (1H,
m, gal H-2), 2.48 (1H, ddd, J = 13.6, 10.4, 7.6, CHHCH=CHCH2), 2.24-2.17 (2H,
overlapped signals), 1.90 (1H, ddd, J = 13.5, 7.0, 2.9, CH2=CHCHH), 1.54 (3H, s,
isopropylidene CH3), 1.49 (3H, s, isopropylidene CH3), 1.38 (3H, s, isopropylidene
CH3), 1.36 (3H, s, isopropylidene CH3), 0.91 (9H, s, CH3 x 3), 0.09 (6H, s, CH3 x 2);
13C NMR (126 MHz, chloroform-d ) δ 136.8 (triazole C=C), 131.9 (triazole CH), 129.7
(alkene CH), 127.4 (alkene CH), 109.9 (isopropylidene C), 109.3 (isopropylidene C),
78.3 (gal C-2), 74.5, 72.6, 72.0, 71.6 (each CH), 71.2 (gal C-1), 71.1 (gal C-1), 70.4 (gal
C-5), 69.8 (CH), 68.7 (gal C-2), 64.1 (CH2), 62.5 (gal C-6), 50.4 (gal C-6), 34.8 (allyl
CH2), 33.4 (allyl CH2), 26.9, 26.7 (each isopropylidene CH3), 25.9 (3 signals, each
CH3), 24.6, 24.4 (each isopropylidene CH3), 18.4 (C), -5.3, -5.4 (each CH3); ESI-
HRMS: calcd. for C31H52O9N3Si, 638.3416; found m/z 638.3405 [M+H]+; FT-IR 3386,
2928, 1462, 1379, 1249, 1209, 1057, 982, 835 cm-1.
Macrocycle 18. The diene 16 (532 mg, 0.835 mmol) in degassed toluene (200 mL) was
preheated and the second generation Grubbs catalyst (75 mg, 0.12 mmol) was then
added. The mixture was stirred at 120 °C for 10 min and the solvent was then removed
under reduced pressure. Flash chromatography (cyclohexane-EtOAc 1:3) of the
26

1
residue gave trans isomer 18 (253 mg, 40 %) as a white solid; H NMR (500 MHz,
chloroform-d): δ 7.68 (1H, s, triazole H), 5.03 (1H, dt, J = 15.9, 6.0, CH=CH), 4.95
(1H, d, J = 13.4 Hz), 4.82 (1H, dt, J = 14.7, 7.0, CH=CH), 4.75 (1H, dd, J = 14.2, 2.0,
gal H-6), 4.50 (1H, dd, J = 7.6, 1.5, gal H-4), 4.47 (1H, d, J = 13.4), 4.45 – 4.42 (1H,
m, gal H-6’), 4.41 – 4.39 (1H, m, H-3), 4.28 (1H, dd, J = 5.9, 2.2, H-3’), 4.16 (1H, t, J
= 6.3, H-2’), 4.04 – 3.99 (2H, overlapped signals, H-5 & H-5’), 3.99 – 3.96 (1H, m, H-
1), 3.96 – 3.92 (2H, overlapped signals, H-1’ & H-4’), 3.75 – 3.68 (2H, overlapped
signals, H-6a & H-6b), 3.33 (1H, t, J = 1.8, H-2), 2.23 (1H, d, J = 3.5,
CHHCH=CHCH2), 2.20 – 2.15 (1H, m, CHHCH=CHCH2), 2.02 – 1.97 (1H, m,
CH2CH=CHCHH), 1.96 – 1.91 (1H, m, CH2=CHCHH), 1.55 (3H, s, isopropylidene
CH3), 1.48 (3H, s, isopropylidene CH3), 1.39 (3H, s, isopropylidene CH3), 1.37 (3H, s,
13
isopropylidene CH3), 0.90 (9H, s, CH3 x 3), 0.07 (3H, s, CH3), 0.06 (3H, s, CH3); C
NMR (126 MHz, chloroform-d) δ 142.7 (triazole C=C), 128.6 (CH=CH), 125.8
(triazole CH), 125.6 (CH=CH), 110.3 (isopropylidene C), 109.0 (isopropylidene C),
76.7 (C-2’), 74.2 (C-1), 73.5 (H-3’), 72.1 (C-2), 71.8 (C-4), 70.7 (C-1’ or C-4’), 70.0
(C-3), 69.7 (C-5 or C-5’), 68.6 (C-1’), 67.9 C-5 or C-5’), 62.4 (C-6), 60.8 (C-7), 51.4
(C-6’), 32.6 (CH2CH=CHCH2), 28.2 (CH2CH=CHCH2), 27.9, 26.9, 26.1 (each
isopropylidene CH3), 25.9 (3 signals, each CH3), 24.2 (isopropylidene CH3), 18.3 (C), -
5.3, -5.5 (each CH3); ESI-HRMS: calcd. for C31H51O9SiNa, 660.3266; found m/z
660.3292 [M+Na]+
Macrocycle 19 Macrocycle 17-trans (23 mg, 0.036 mmol) was first dissolved in THF
(2 mL) and TBAF (1 M in THF, 0.11 mL, 0.36 mmol) was added dropwise. The
resulting solution was stirred at room temperature for 3 h. Then EtOAc was added, and
the mixture was washed with 1 M HCl, water, brine, dried over Na2SO4, filtered and the
solvent was removed under reduced pressure. Flash chromatography (EtOAc) gave
27

desilylated intermediate (4.0 mg, 21 %) as a white solid; ESI-HRMS: calcd. for
C25H37O9N3Na, 546.2402; found m/z 546.2427 [M+Na]+; FT-IR 3383, 2921, 1617,
1458, 1375, 1210, 1057, 790 cm-1. This intermediate (4 mg, 0.008 mmol) was dissolved
in TFA-H2O (4:1, 0.25 mL) and the mixture was stirred at room temperature for 2 h.
Toluene was added and the volatile materials were removed under reduced pressure.
The resulting residue was taken up in MeOH and Dowex M-43 ion exchange resin was
added, adjusting the pH to 8, and the mixture was then filtered and the solvent was
removed under reduced pressure. Flash chromatography (CH2Cl2:MeOH 4:1) gave the
title compound (3 mg, ~75%) as a white solid; 1H NMR (600 MHz, D2O): δ 7.74 (1H, s,
triazole H), 5.41 (1H, dt, J = 15.1, 7.4 Hz, alkene H), 5.19 (1H, dt, J = 15.6, 7.4 Hz,
alkene H), 4.78 (d, J = 12.8 Hz, 1H), 4.73 (d, J = 12.8 Hz, 1H), 4.59 (1H, dd, J = 15.3,
3.3 Hz, gal H-6), 4.33 (1H, dd, J = 15.1, 7.2 Hz, gal H-6), 4.15 – 4.06 (2H, overlapped
signals), 4.00-3.70 (8H, overlapped signals), 3.58 (1H, q, J = 8.5 Hz, gal H-6), 2.41
(1H, m), 2.22 – 2.02 (3H, overlapped signals); 13C NMR (151 MHz, D2O) δ 136.3
(triazole C), 133.2 (triazole CH), 129.2 (alkene CH), 129.0 (alkene CH), 79.3, 74.2
(each CH), 71.6 (CH), 69.7 (CH), 69.1 (gal C-5), 68.3, 68.1, 68.0 (each CH), 68.0 (CH),
62.8 (CH2), 59.7 (gal C-6), 47.8 (gal C-6), 32.2 (CH2), 28.8 (CH2); ESI-HRMS: calcd.
for C19H29O9N3Na, 466.1808; found m/z 466.1801 [M+Na]+; FT-IR 3360, 1636, 1362,
1077, cm-1.
Macrocycle 20 Macrocycle 18 (15 mg, 0.02 mmol) was dissolved in THF (6 mL) and
TBAF (1 M in THF, 0.06 mL, 0.2 mmol) was added dropwise. The resulting solution
was stirred at room temperature for 3 h. Then CaCO3, Dowex-50X8 and MeOH were
added and stirring was continued for a further 1 h. The slurry was filtered through
Celite®, washed thoroughly with MeOH and the solvent was removed under reduced
28

pressure. Flash chromatography (EtOAc only) gave the desilylated intermediate (9 mg,
81 %) as a white solid; ESI-HRMS: calcd. for C25H35O9N3Na, 546.2401; found m/z
546.2403 [M+Na]+. This intermediate (8.0 mg, 0.015 mmol) was dissolved in TFA-
H2O (4:1, 0.25 mL) and the mixture was stirred at room temp for 2 h. Toluene was
added and the volatile materials were removed under reduced pressure. The residue was
taken up in MeOH and Dowex M-43 ion exchange resin was added until the pH reached
8. The mixture was then filtered and the solvent removed under reduced pressure. Flash
chromatography (CH2Cl2-MeOH 4:1) gave the title compound (4 mg, ~60 %) as a white
1
solid; H NMR (600 MHz, D2O) δ 8.02 (1H, s, triazole H), 5.31 (1H, dt, J = 17.0, 5.1
Hz, alkene H), 5.03 (1H, d, J = 14.2 Hz), 4.86 (1H, m, alkene H), 4.66 (1H, dd, J =
14.6, 2.1 Hz, gal H-6), 4.58 (1H, d, J = 14.2 Hz), 4.54 (1H, dd, J = 14.6, 10.5 Hz, gal
H-6), 4.13 (1H, d, J = 3.5 Hz, gal H-4), 4.09 – 3.75 (8H, overlapped signals), 3.69 (1H,
13
dd, J = 11.6, 3.9, gal H-6b), 2.33 – 2.12 (3H, overlapped signals), 1.90 (1H, m); C
NMR (126 MHz, D2O) δ 144.4 (triazole C), 128.8 (alkene CH), 126.3 (triazole CH),
126.2 (alkene CH), 75.6 (gal C-1’), 72.4 (gal C-5), 70.2 (CH), 69.7 (gal C-4), 69.4
(CH), 68.4 (2 signals, each CH), 68.1 (gal C-1), 67.9 (2 signals, each CH), 63.3 (CH2),
60.2 (gal C-6), 51.7 (gal C-6), 26.7 (CH2), 25.3 (CH2); ESI-HRMS: calcd. for
C19H29O9N3Na, 466.1794; found m/z 466.1794 [M+Na]+; FT-IR 3386, 2446, 1717,
1448, 1062, 710 cm-1.
Macrocycle 21
Compounds 5 (50 mg, 0.12 mmol) and 2 (80 mg, 0.24 mmol) and
Cp*RuCl(PPh3)2 (6 mg, 7 µmol) in DMA (1.8 mL) were placed in a microwave vial,
which was flushed with argon for 12 min and sealed. The sealed vial containing the
mixture was then heated to 100 ºC for 30 min in a microwave reactor. To the resulting
mixture was added water (15 mL) and the aqueous phase was extracted with EtOAc (3 x
29