Multicomponent Approach to Homo-and Hetero-Multivalent Glycomimetics Bearing Rare Monosaccharides

Article abstract of DOI:10.1021/acs.joc.9b03401

We applied a multicomponent approach to access a library of densely functionalized homo-and hetero-multivalent glycomimetics comprising aldehyde, amine, and isocyanide components related to isopropylidene-protected d-fructose, l-sorbose, d-galactose, and d-Allose. Passerini products were obtained in very good yields (up to 78%) and high diastereoselectivities (up to 98:2). Three types of products were obtained by the Ugi reaction; along with the "classical" four-component product, α-Acylaminoamides, a three-component α-Aminoamides, and a four-component α-Aminoacylamides were isolated. The presence of multiple pathways is rationalized by the structure of the imidate intermediate, mainly influenced by the amine component.

Full text of DOI:10.1021/acs.joc.9b03401

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Article
Multicomponent approach to homo- and hetero-
multivalent glycomimetics bearing rare monosaccharides
Andreja Jakas, Aleksandar Višnjevac, and Ivanka Jeric
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03401 • Publication Date (Web): 31 Jan 2020
Downloaded from pubs.acs.org on February 3, 2020
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Multicomponent approach to homo- and hetero-multivalent glycomimetics bearing rare
monosaccharides
a
b
a
Andreja Jakas, Aleksandar Višnjevac, and Ivanka Jerić *
1
1
1
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a
Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54,
Zagreb, Croatia
b
Division of Physical Chemistry, Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia
Corresponding author: ijeric@irb.hr
O
H
N
O
-CHO -NC -NH2 -CO2H
O
H
O
N
D-fructose
L-sorbose
N
O
H
N
D-galactose
D-allose
O
H
N
N
H
O
N
O
4
8 examples
up to 89 % yield
O
H
N
O
O
N
N
H
O
Abstract
We applied a multicomponent approach to access a library of densely functionalized homo- and
hetero-multivalent glycomimetics comprising aldehyde, amine and isocyanide components
related to isopropylidene-protected D-fructose, L-sorbose, D-galactose and D-allose. Passerini
products were obtained in very good yields (up to 78 %) and high diastereoselectivities (up to
98:2). Three types of products were obtained by the Ugi reaction; along with the “classical” four-
component product - -acylaminoamides, a three-component -aminoamides and a four-
component -aminoacylamides were isolated. Presence of multiple pathways is rationalized by
the structure of imidate intermediate, mainly influenced by the amine component.
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Introduction
Carbohydrates are ubiquitous group of natural compounds, and essential components of life we
1
know. Assembled at the surface of all living cells, carbohydrates mobilize binding and recognition
events and play a key role in organism development, immunological responses and disease
progression. In addition, glycosylation is the most prominent, and the most diverse post-
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translational modification that governs protein’s life and function. The advances in carbohydrate
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synthesis, and analysis have led to the impactful discoveries that widen our understanding of
carbohydrate-participating events at the molecular level and enabled creation of therapeutics that
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control human health and disease. Some of the most successful examples include antiviral
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compounds zanamivir (Relenza) and oseltamivir (Tamiflu), type II diabetes mellitus drugs
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miglitol (Glyset) and acarbose (Precose, Glucobay), STARFISH, a Shiga-like toxin inhibitor, and
recently carbohydrate-based vaccines.4b A basic principle underlying carbohydrate-protein
interactions is their multivalency, which results in stronger and/or more specific binding of
9
carbohydrate ligands to their cognate receptors. Development of multivalent glycomimetics relies
on the utilization of nanoparticles, polymers or dendrimers as scaffolds, providing multiple
anchoring points for carbohydrate molecules.10 While homo-multivalent glycomimetics carry
several copies of identical sugar motifs, hetero-multivalent glycomimetics display structurally
11
different saccharide motifs in a highly controlled manner. Since biological systems are inherently
heterogeneous, it has been presumed that hetero-multivalent glycomimetics are invaluable tools
to determine contribution of not just valences and density, but also synergistic or antagonistic
effects to molecular recognition events.
From a synthetic point of view, access to hetero-multivalent glycomimetics presents a
daunting challenge, and various methods of solution12 and solid-phase synthesis,13 as well as
dynamic combinatorial chemistry (DCC),14 copper(I)-catalysed alkyne-azide cycloaddition
(
CuAAC),15 combinatorial strategies,16 and others were exploited.11 Multicomponent reactions
MCRs) offer an attractive one-pot strategy for generating a library of highly functionalized and
(
complex compounds like glycomimetics.17 A large number of MCRs comprising carbohydrates
were developed, providing access to structurally diverse glycoconjugates. Of particular interest
are isocyanide-based MCRs (e.g., Passerini, Ugi reaction, Scheme 1), widely exploited for the
1
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generation of drug-like molecules. Acetyl- and benzyl-protected galactose- and fucose-derived
aldehydes were used in the synthesis of focused library of monovalent sialyl Lewis x
19
glycomimetics. Lockhoff used per-O-benzylated carbohydrate building blocks for the synthesis
of glycoconjugate library,20 while Westermann and Dőrner utilized the Ugi reaction for the
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synthesis of multivalent aminoglycoside mimics aimed to bind to RNA targets. Main advantages
of MCRs for the synthesis of multivalent glycomimetics are their convergent nature, high atom
economy, and control over structural identity of products, while -elimination of carbohydrate-
derived aldehydes, observed as a side-reaction in MCRs, and partial N-acetylation of the amine
components when O-acetylated components are used,19 present main drawbacks of the
multicomponent methodology.
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Scheme 1. Formation of Passerini and Ugi products.
O
O
Passerini reaction
O
R2
H
R1
OH
N
R2
O
R1
R3
+
R3 N C-
O

-acyloxy carboxamides
O
O
O
R2
H
Ugi reaction
N
R2
N
R1
OH
R1
R3
O
+
R4
R3 N C- R4 NH2

-acylaminoamides
In our previous work, we utilised isopropylidene-protected fructose-derived aldehyde as a
carbonyl component to gain Passerini products in high yields and diastereoselectivities up to 92:8
d.r. without any detected side-reactions.22 Moreover, isopropylidene protecting groups lock
anomeric configuration thus facilitating purification and characterization of products, and can be
smoothly removed under acidic conditions. In an endeavour to provide a multicomponent route to
homo- and hetero-multivalent glycomimetics, herein we expend the pool of isopropylidene-
protected carbohydrate-derived building blocks. A simple one-pot procedure comprising carbonyl
components, amines, isocyanides and a carboxylic acid related to four different carbohydrates
afforded highly functionalized Passerini and Ugi products with up to four carbohydrate units.
Having reliable access to a library of compounds adorned with different, including uncommon
carbohydrates represents an attractive alternative to the traditional approach relying solely on
utilization of saccharides found in protein glycans. It has been shown that “non-self” sugars can
break immune tolerance and might provide a means to create successful non-self antigens.23
Therefore, in this work we selected carbohydrate scaffolds less frequently utilised in glycomimetic
synthesis. Along with D-fructose and D-galactose, we opted for L-sorbose, known as a starting
material in the synthesis of vitamin C, and D-allose, a rare monosaccharide found in nature with
numerous reports claiming its protective effects against various disease states.24 D-allose has
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been found to inhibit the proliferation and metastasis of various cancer cells. Studies revealed
that mechanism of D-allose activity is probably related to up-regulation of thioredoxin-interacting
protein (TXNIP) which, in turn prohibit cancer cells from absorbing glucose, as a major energy
source. Moreover, RbsB ribose binding protein from Escherichia coli and PA1946 protein from
Pseudomonas aeruginosa were shown to bind specifically D-ribose and D-allose, with affinities in
the lower micromolar range.25 L-sorbose participates in carbohydrate-specific regulation of gene
expression in bacteria, particularly lactic acid bacteria.26 Recent study found that L-sorbose and
xylitol promote the growth and metabolic activity of specific butyrate-producing bacteria in human
colon and are therefore likely to have prebiotic benefits.27
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Results and Discussion
Bis-isopropylidene-protected -D-fructopyranose (Fru), -L-sorbofuranose (Sor), -D-
galactopyranose (Gal) and -D-glucofuranose (Glc) were used as starting compounds for the
synthesis of building blocks to be used in MCRs. Details are given in the Experimental section,
but briefly, aldehydes 1-3 and ketone 4 (Table 1) were obtained in excellent yields (70-98 %) by
oxidation with Dess−Martin periodinane. A two-step approach from amine component was used
to obtain sugar isocyanides 5-8 in 30-40 % yield, while amines 9-12 were gained by reduction of
corresponding azides in 37-69 % yield over three steps. Bis-isopropyldine protected L-gulonic
acid 13 was used as carboxylic acid component. Aromatic amino acids are markedly preferred in
carbohydrate-binding sites, and there is a growing body of evidence showing that presence of
hydrophobic amino acids can improve interactions of glycomimetics with carbohydrate-binding
proteins.28 Therefore, we included phenylalanine and tyrosine-related carboxylic and amine
components in MCRs (Table 1).
All Passerini reactions were performed with equimolar amounts of an aldehyde, an
isocyanide and a carboxylic acid (0.1 mmol) in 100 L methanol in closed vials at room
temperature for 24 h. Higher temperature (up to 50 ºC), and longer reaction time (up to 48h) led
to lower reaction yield. First set of reactions were performed with bis-isopropylidene protected
fructose-related aldehyde 1, isocyanide 5 and different carboxylic acids; acetic and benzoic acid
and Boc-protected phenylalanine. The corresponding Passerini products 14-16 were isolated in
74-78 % yield (Figure 1). The formation of new stereocenter is inherent to the Passerini reaction,
therefore access to stereochemically defined compounds is of utmost importance for any strategy
1
aimed to deliver libraries of chiral, structurally diverse compounds. H NMR spectrum of the
compound 14 revealed presence of two diastereoisomers in the ratio 88:12 d.r. (Supporting
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Information). Increasing the complexity of products hampers determination of diastereoselectivity
from 1H NMR spectra, however, two diastereoisomers were separated by column
chromatography in most cases, and d.r. was determined as the ratio of isolated products. As seen
at the Figure 1, presence of benzoic acid in the product 15 instead of acetic acid did not disturb
stereochemical outcome of the reaction. Absolute configuration of the major isomer was
unequivocally determined by the x-ray crystallographic analysis. The configuration of new
stereocentre was confirmed to be S, and by analogy S configuration was assigned to all major
isomers of the Passerini products comprising aldehyde 1. Decreased stereoselectivity of the
Passerini reaction observed with Boc-Phe-OH as carboxylic acid can be attributed to the
purification procedure, where due to the partial overlapping with reactants or degradation
byproducts, major diastereoisomer we isolated in lower yield. Finally, the Passerini reaction
performed with L-gulonic acid 13 furnished trivalent Passerini product 17 in moderate yield (39 %,
Figure 1) as a single diastereoisomer.
1
1
1
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Table 1. Scope of carbonyl, isocyanide, amine and acid components used in the Passerini and Ugi
reactions
Fructose
Sorbose
Galactose
Allose
OHC
O
CHO
O
CHO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
4
O
O
1
2
3
R1 CHO
R2 CHO
R3 CHO
R4
C O
CN
O
O
NC
O
NC
O
O
O
O
O
O
O
O
O
O
O
O
O
O
CN
O
O
O
5
6
7
8
R1 CH2NC
R2 CH2NC
R3 CH2NC
R4 NC
H2N
NH2
O
O
NH2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H2N
12
9
10
11
R1 CH2NH2
R2 CH2NH2
R3 CH2NH2
R4 NH2
COOH
O
O
O
O
O
13
R2 COOH
Other carboxylic acid components: acetil acid, benzoic acid, Boc-
Phe-OH, Boc-Tyr(Boc)-OH
Other amine components: benzyl amine, H-Phe-OMe, H-Tyr-OBn
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1
1
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2
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2
2
2
2
2
2
2
3
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3
3
3
4
4
4
4
4
4
4
4
4
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5
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5
5
5
5
5
5
5
5
6
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
H
H
H
H
N
N
N
O
N
N
O
O
O
O
O
O
O
O
O
O
O
O
Boc-Phe
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
0
1
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3
4
5
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7
8
9
0
1
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3
4
5
6
7
8
9
0
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4 (74 %)
d.r. 88:12
15 (78 %)
d.r. 90:10
16 (78 %)
d.r. 68:32
17 (39 %)
d.r. >99:1
18 (62 %)
d.r. 92:8
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
H
O
H
O
H
O
O
O
N
N
O
N
O
O
O
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Boc-Phe
O
O
O
O
O
O
19 (31 %)
20 (66 %)
d.r. 88:12
21 (70 %)
d.r. 80:20
22 (44 %)
d.r. 82:18
d.r. >99:1
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
N
O
H
O
O
H
N
O
O
O O
O
O
O
O
O
O
N
H
N
H
O
O
O
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Boc-Phe
O
O
O
O
O
O
O
2
3 (61 %)
d.r. 74:26
24 (40 %)
d.r. >99:1
25 (71 %)
d.r. >99:1
26 (53 %)
d.r. 81:19
27 (45 %)
d.r. 72:28
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
O
H
O
O
H
H
O
O
N
N
H
N
O
N
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
2
8 (64 %)
d.r. 85:15
29 (71 %)
d.r. 89:11
30 (41 %)
d.r. 83:17
31 (18 %)
d.r. 87:13
32 (12 %)
d.r. >99:1
Figure 1. Products isolated from the Passerini reactions comprising selected carbohydrate derivatives
from Table 1. d.r. was determined from the ratio of isolated products, while for compounds 14, 15, 27, 28,
1
and 31 it was determined from H NMR spectrum of product isolated as a mixture of diastereoisomers.
Next, we prepared two hetero-multivalent Passerini products utilizing sorbose-related
aldehyde 2 and fructose-related isocyanide 5. Bivalent product 18 was obtained in 62 % yield,
while trivalent product 19 comprising L-gulonic acid was isolated in somewhat lower yield (31 %).
To our delight, both products were isolated as single isomers, as detected by the NMR
spectroscopy, while x-ray analysis of product 18 confirmed S configuration of the newly formed
chiral centre. We further used sorbose-derived aldehyde 2 in reaction with isocyanides 6-8 and
products 20-27 were gained in 40-70 % yield, and with very good diastereoselectivity (Figure 1).
In this series, x-ray analysis of the major isomer of compound 23 and a single isomer of compound
2
5 confirmed S configuration of the chiral center. Galactose-derived aldehyde 3 was reacted with
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the homologous isocyanide 7 and the corresponding products 28-30 were isolated in good yields
(41-71 %) with diastereomeric ratio  85:15. (Figure 1). Finally, we performed two reactions in the
allose series; ketone 4 and isocyanide 8 in the reaction with acetic and benzoic acid afforded
products 31 and 32, respectively, in low yield but high diastereoselectivity (Figure 1).
Stereocontrol of MCRs, despite many efforts, remains an open issue. Stereoselective
outcome of the Passerini reaction is influenced primarily by the aldehyde component,17b however,
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
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2
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
when carbohydrate-derived components are used, the nature of OH protecting groups and other
components in the reaction are not neglected. All Passerini reactions performed in this study with
isopropylidene-protected components proceeded with high diastereoselectivity, and the individual
isomers were successfully isolated in pure forms. Single crystal x-ray analysis of five Passerini
products (15, 18, 20, 23 and 25) revealed S configuration of the newly formed stereocentre in
predominant diastereoisomer. Such stereoselective outcome can be rationalized by the
mechanistic pathway for the Passerini reaction proposed by Ramozzi and Morokumaled29 and
22
also observed in our previous work. The first step, complexation of an aldehyde, an isocyanide
and two acid molecules results in two pre-complexes (a starting points leading to two
diastereisomers) of different stabilities. Moreover, the rearrangement of imidate-acid cluster to
dioxolane-acid cluster is the rate-determining step of the reaction, and the main factor explaining
the diastereoselectivity of the Passerini reaction. We observed that the corresponding transition
state leading to the S diastereoisomer is by ca. 10 kJ mol−1 more stable that the transition state
leading to the R diastereoisomer. Presence of components bearing bulky isopropylidene groups
increases the crowd close to the reaction centre, and could be responsible for the observed
predominance of one diastereoisomer.
In order to increase molecular complexity and diversity of glycomimetics, we applied the four-
component Ugi reaction approach to access homo- and hetero-multivalent -acylaminoamides
(Figure 2). Reactions were performed with equimolar amounts of all components (0.1 mmol) in
100 L methanol in closed vials at room temperature for 24 h. An aldehyde and an amine
component were allowed to react for 60 min, followed by the addition of acid and isocyanide
component. First batch of reactions was performed with D-fructose series of compounds;
aldehyde 1, isocyanide 5 and amine 9. Reactions performed with acetic and benzoic acid gave
homo-trivalent Ugi products 33 and 34 in very good yield (72 and 89 %, respectively) but different
diastereoselectivity. While product 33 was isolated as 63:37 d.r. mixture, a single diastereoisomer
was isolated for product 34. When Boc-Phe-OH was used as acid component, Ugi product 35
was isolated in 67 % yield and the ratio of diastereoisomers, determined from isolated products
was 57:43 d.r. Product comprising D-gulonic acid (36, Figure 2) was isolated in moderate yield
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
32 %) with 53:47 d.r. Comparable result was obtained with benzyl amine, and product 37 was
isolated in 47 % yield. Further reactions were performed with amino acid components to gain
hybrid amino acid-carbohydrate structures. In the reaction with H-Phe-OMe as amine component
and acetic acid, expected Ugi product 38 was identified only in traces (based on mass
spectrometry analysis). Instead, a three-component Ugi product 38a was isolated in 67 % yield
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Figure 2). In the reaction with Boc-Phe-OH as acid component and H-Phe-OMe as amine
component, expected Ugi product 39 was again present in traces, while a three-component Ugi
product 38a was isolated in 48 % yield. Contrary to that, in the reaction with H-Tyr-OBn as amine
component and acetic acid, Ugi product 40 was isolated in 73 % yield. When reaction was
performed with Boc -Tyr-OH and H-Tyr-OBn, a four-component Ugi product 41 was isolated as a
2
main product (49 %) with concomitant isolation of the three-component Ugi product 41a (16 %,
Figure 2). Next set of reaction was performed with sorbose-derived aldehyde 2. Ugi product 42
comprising fructose derived isocyanide 5, benzylamine and L-gulonic acid 13 was isolated in very
good yield (60 %, Figure 2) as racemic mixture of two diastereoisomers. When benzoic acid was
used with three sorbose-derived components, Ugi product 43 was also isolated in good yield
1
(64 %) as inseparable mixture of diastereoisomers with 74:26 d.r. as determined by the H NMR
analysis. Next, we combined aldehyde 2 with sterically hindered allose-related isocyanide 8,
amine 12 (Table 1), and various acid components. While reaction conducted with acetic acid
furnished Ugi product 44 in fair yield (55 %, Figure 2), when benzoic acid was used, reaction
mixture indicated formation of multiple products. In addition to four-component Ugi product 45
isolated in 16 % and a three-component-Ugi product 45a isolated in 15 % yield, Ugi product 45b
was isolated as the main product (36 % yield, Figure 2) and its structure was unambitiously
confirmed by a single crystal x-ray analysis (Figure 3). Similar results were obtained with Boc-
Phe-OH as acid component; four-component Ugi product 46 was isolated in 3 % yield, three-
component-Ugi product 46a was isolated in 24 % yield, and Ugi product 46b was isolated in 29 %
yield. Finally, when gulonic acid was introduced, main product isolated from the reaction mixture
was a three-component Ugi product 45a (43 %), with 17 % of a four-component Ugi product 47.
Replacement of amine 12 with sterically less hindered benzylamine afforded four-component Ugi
product 48 in fair yield (50 %, 60:40 d.r.), without observed formation of other Ugi products.
Finally, a set of reactions was performed with galactose-derived components. Ugi product 49
comprising acetic acid was isolated in good yield (78 %) and diastereoselectivity 77:23 d.r. while
those comprising benzoic acid was isolated in excellent yield (50, 83 %, 63:37 d.r.). Influence of
amino acids as amine components was tested again with phenylalanine and tyrosine-related
derivatives. Reaction performed with H-Phe-OMe and acetic acid furnished three-component Ugi
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product 51a in 50 % yield, while corresponding four-component product 51 was not detected in
the reaction. When acetic acid was replaced with Boc-Phe-OH, four-component Ugi product 52
was isolated in low yield (14 %), while major product, a three-component Ugi product 51a was
isolated in 50 % yield. Contrary to that, the Ugi reaction performed with H-Tyr-OBn and acetic
acid provided expected four-component product 53 as a main product (63 % yiled) a three-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
component Ugi product 53a in 18 % yield. The Ugi reaction performed with Boc -Tyr-OH as acid
2
component afforded single product 54 in 78 % yield.
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
H
H
O
O
H
O
O
H
N
N
N
N
N
N
N
N
N
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
3
3 (72 %)
34 (89 %)
d.r. > 99:1
35 (67 %)
d.r. 57:43
36 (32 %)
d.r. 53:47
37 (47 %)
d.r. 51:49
d.r. 63:37
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
H
H
H
H
N
MeO
N
N
N
N
MeO
N
N
N
N
O
N
O
O
O
O
O
O
O
H
O
O
O
O
H
O
O
O
O
MeO
O
MeO
BnO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OH
38 (traces)
38a (67 %)
d.r. 54:46
39 (traces)
38a (48
%)
40 (73 %)
d.r. 74:26
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
HO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
N
O O
O
H
O
H
H
BnO
N
N
H
N
N
O
O
N
N
N
N
O
O
O
O
N
O
H
O
O
O
O
O
O
O
O
O
O
BnO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OH
4
1 (49 %)
d.r. nd
41a (16 %)
d.r. nd
42 (60 %)
d.r. 1:1
43 (64 %)
d.r.74:26
44 (55 %)
d.r. 56:44
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O O
O
O
O
O
H
N
H
O
H
O
O
O
O
N
O
O
N
O
O
N
N
H
N
O
O
O
N
O
O
O
N
O
N
O
N
O
O
O
O
O
O
O
H
O
H
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
4
5 (14 %)
d.r. nd
45a (15 %)
d.r. 69:31
45b (36 %)
d.r. nd
46 (3 %)
d.r. nd
45a (24 %)
d.r. 58:42
46b (29 %)
d.r. nd
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
H
O
O
H
N
H
O
O
H
N
N
O
N
N
N
N
N
N
H
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
7 (17 %)
d.r. 59:41
45a (43 %)
d.r. 54:46
48 (50 %)
d.r. 60:40
49 (78 %)
d.r. 77:23
50 (83 %)
d.r. 63:37
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
O
O
H
O
H
O
O
N
N
H
O
MeO
N
MeO
N
N
N
N
O
O
N
O
H
O
O
O
O
Boc-Phe
O
O
O
O
O
O
O
H
O
O
MeO
MeO
5
1a (41 %)
d.r. 80:20
52 (14 %)
d.r. nd
51a (25 %)
d.r. nd
5
1 no
O
O
O
O
O
O
O
O
O
O
HO
O
O
O
O
O
O
O
O
O
O
O
O
O
H
N
O
H
N
O
H
O
BnO
N
N
N
N
O
O
O
O
H
O
O
O
O
O
O
O
O
Boc-Tyr(Boc)
BnO
BnO
OH
OH
5
3 (62 %)
d.r. 51:49
53a (18 %)
d.r. nd
54 (78 %)
d.r. 67:33
Figure 2. Products isolated from the Ugi reactions comprising selected carbohydrate derivatives from Table
1
. d.r. was determined from the ratio of isolated products, and for compounds 43, 49 and 51a it was
1
determined from the H NMR spectrum of the product isolated as a mixture of two diastereoisomers.
Products obtained from the same reaction mixture, but through different pathways are placed in rectangles
(
see text).
Figure 3. Molecular structure of 45b with atom numbering and absolute configurations of chiral C atoms.
Thermal ellipsoids are represented at the 30% probability level. Hydrogen atoms and a water molecule
localized within the structure are omitted for clarity.
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Analysis of obtained results in the Ugi product series revealed that multiple reaction paths
must be envisioned. The general mechanism of the reaction, proposed by Ugi30 involves in situ
formation of an imine from the carbonyl compound and the primary amine in the first step,
protonation of an imine followed by α-addition of the isocyanide and subsequent Mumm
rearrangement to furnish substituted α-amino acid derivatives (Scheme 2). Many efforts has been
devoted to elucidate each reaction step, role of the solvent, and possibility to control the
stereochemical outcome of the reaction. A thorough theoretical study of the reaction, performed
by Chéron et al. showed that the imine formed in the first reaction step is not activated by proton
transfer, but through a hydrogen-bonded complex with the acidic substrate (Scheme 2).31 The
isocyanide addition is the rate-determining step and the non-reversibility of the nitrilium formation
indicates that it should be possible to control the stereochemistry of the reaction. It was shown
previously for the Passerini reaction that an extra carboxylic acid molecule is required, as a fourth
partner, to allow the Mumm rearrangement of the imidate intermediate to proceed. Similar
approach was applied in a study of Chéron et al. However, for the Ugi reaction, proton transfer
might be mediated by the solvent or by the acid (Scheme 2). In both cases, the Mumm
rearrangement of the imidate cluster leading to the four-component Ugi product, -
acylaminoamide, was found to proceed through very low barriers.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 2. Mechanism of the Ugi reaction; different paths for the imidate intermediate.
O
O
R3
O
R3
OH
R2
HO
C-
R2
R1
N
N
R1
C-
N+
R1
R2 NH2
N+
R4
R4
H C
3
O
H
H
R3
O
N
H C
3
O
-O
H
O
R3
O
+
N
R4
N
*
H
R2
H O
N
2
R1 R4
R2
R1
imidate
O
R1
*
R1
O
O
H
H
N
H
N
R2
N
R3
N
R4
N
*
R4
*
R3
R2
N
H
R2
O
O
R1 R4
-aminoacylamide

-acylaminoamide
-aminoamide
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Next possible reaction path includes participation of water released during the imine
formation in the first reaction step. Water, but also polar protic solvents, like methanol, can be
responsible for a competitive reaction - addition to the imidate intermediate with concomitant acid
elimination, giving a three-component Ugi product, -aminoamides (Scheme 2). This pathway
32
was exploited in the design of first catalytic three-component Ugi reaction. Insight into our results
of the Ugi reaction revealed a prevalence of the three-component Ugi pathway over a four-
component one in some cases, particularly when phenylalanine was used as amine component
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(products 38/38a, 39/38a, 51/51a and 52/51a, Figure 2). In these examples, fructose or galactose
components were used as an aldehyde and an isocyanide components, while two carboxylic
acids were tested, acetic acid and Boc-Phe-OH with the same reaction outcome. It was therefore
intriguing when we realised that replacement of phenylalanine-related amine component with
tyrosine-related one, led to the opposite result. So, reactions performed with fructose or galactose
aldehyde and isocyanide components along with acetic acid or tyrosine-related acid (Boc -Tyr-
2
OH) furnished “classical” four-component Ugi products as the only or main products (40, 41/41a,
53/53a, 54, Figure 2). Possible explanation can be sought in the structure of imidate-methanol
cluster. Calculations performed by Chéron et al. showed that solvation of imidate by a methanol
dimer is more favourable that with only one, or more than two methanol molecules. However,
presence of protected ester group when an amino acid is used as an amine component might be
responsible for the formation of more flexible, energetically less favourable imidate cluster with
longer methanol bridges. Another possibility is that imidate cluster comprising amino acid-related
amine component undergo conformational changes that induce formation of alternative hydrogen
bonds between imidate and methanol molecule(s). In our previous work on the Passerini reaction
comprising hydrazino acids, we observed the disparity in reaction yields of products obtained by
different hydrazino acid derivatives.33 This disparity was rationalised by the DFT calculations
showing that alternative hydrogen bonds stabilize thermodynamically very stable non-productive
conformations of imidate clusters which hamper the rearrangement into final products. Similar
scenario is also possible here; occurrence of stable non-productive form of imidate cluster opens
possibility for another nucleophile (water or methanol) to take part in the reaction leading to
another type of the Ugi product. Presence of OH group in the tyrosine side-chain, which can
participate in the formation of hydrogen bond networks, and possibly stabilise imidate cluster,
might be responsible for the observed difference between phenylalanine and tyrosine-type of the
Ugi products.
To determine the potential role of the solvent in predominance of one pathway over the other,
we performed the Ugi reaction comprising galactose-related aldehyde 3 and isocyanide 7 with
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phenylalanine-related amine and acid components and results are presented in Table 2. When
reaction was performed with molecular sieves, we noticed change in the ratio of 52:51a from 1:2
in the standard reaction conditions to 2:3. This outcome is consistent with the removal of water
released during an imine formation by molecular sieves, but it also points that as expected,
methanol can attack the imidate intermediate. Reaction performed in the absence of acid
component yielded a three-component product 51a in 58 %. Therefore, presence of acid in not
necessary for the activation of imine and the formation of imidate intermediate (Scheme 2),
instead solvent in acidic enough the imine activation. Reactions performed in more acidic
trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP) did not improve reaction yield, and the
ratio of two products remained 52:51a = 1:2, as with methanol as a solvent (Table 2).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 2. Influence of solvent on the distribution of four-component (52) and three-component (51a) Ugi
products.a
Product (%)b
Solvent
Reactants
RCHO
RNH
2
RNC
RCOOH
52
51a
25
MeOH
3
3
H-Phe-OMe
7
7
Boc-Phe-OH 14
Boc-Phe-OH 23
MeOH/
H-Phe-OMe
30
mol. sieves
MeOH
TFE
3
3
3
H-Phe-OMe
H-Phe-OMe
H-Phe-OMe
7
7
7
-
-
58
29
17
Boc-Phe-OH 15
Boc-Phe-OH
HFIP
9
a
Reaction conditions: 0.1 mmol of all components in 100 L solvent, room temperature, 24h. b Isolated
yields.
Finally, inspection of the Ugi products presented at Figure 2, points toward occurrence of
third pathway, particularly when sorbose-related aldehyde 2 was utilized with allose-related
isocyanide 8 and amine 12. In the reaction performed with benzoic acid, a “classical” four-
component Ugi product 45 was isolated in low yield (14 %), along with a three-component Ugi
product 45a (15 %). Surprisingly, main product isolated from the reaction was product 45b (36 %,
Figure 2). When reaction was performed with Boc-Phe-OH as acid component, only 3 % of the
expected four-component Ugi product 46 was isolated, while three-component Ugi product 45a
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1
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2
2
2
2
2
2
2
2
2
3
3
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was isolated in 24 %, and product 46b was isolated in 29 % yield (Figure 2). Formation of products
45b and 46b, -aminoamides, can be rationalized by 1,3 (O-N) acyl transfer (Scheme 2),
34
otherwise typical for the Ugi reactions comprising secondary amines. When secondary amines
are utilized in the Ugi reaction, imidate intermediate formed in the course of the reaction is tertiary,
and can no longer be acylated. If an imine formation is slow, or the reaction is performed with an
excess of amine component, secondary amine can intercept the imidate intermediate.
Alternatively, polar solvent, like methanol can do the same, leading to a three-component Ugi
product of type 45a.34 However, in the absence of nucleophilic groups (equimolar amounts of
components or reaction performed in nonpolar solvent), the isocyanide nitrogen atom is
responsible for the 1,3(O-N) acyl transfer of the imidate intermediate and the formation of -
aminoamides (Scheme 2). The fact that we isolated -aminoamides from the Ugi reaction
performed with primary amine and in methanol as a solvent, prompted us to take a closer look at
components involved in the reaction. Along with aldehyde 2, allose-related amine and isocyanide
participated, both with their functional groups attached to the secondary carbon atom, and
contrary to all other amines and isocyanides in our selection of building blocks. We can speculate
that the increased steric hindrance around amine nitrogen impeded acyl transfer; instead, acyl
transfer is initiated by an isocyanide nitrogen or methanol. Replacement of amine 12 with simple
benzyl amine thus furnished “classical” Ugi product 48 in 50 % yield (Figure 2).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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9
0
1
2
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4
5
6
7
8
9
0
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2
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4
5
6
7
8
9
0
Mass spectrometry can be used as an elegant method for the fast identification and
discrimination between -acylaminoamides (45, 46) and -aminoacylamides (45b, 46b), since
both structures have identical molecular masses. Inspired by a work of de Angelis et al.35 we
+
undertook a closer insight into the fragmentation pattern of the molecular [M+H] ions of Ugi
products 45 and 45b, looking for the fragment ions characteristic for two compounds. The MS/MS
+
spectrum of the molecular [M+H] ion m/z 891 of compound 45 is shown at Figure 4. A highly
abundant fragment ion m/z 834 corresponds to the loss of one isopropylidene group (58 Da),
while low abundant ion m/z 632 is a b-type fragment ion and corresponds to the formation of
oxazolone structure (Figure 4a). Further elimination of one isopropylidene group from m/z 632
gave rise to high intensity fragment ion m/z 574. Contrary to that, the MS/MS spectrum of the
+
molecular [M+H] ion m/z 891 of the compound 45b is characterized by a rich fragmentation,
resulting mainly from the multiple elimination of isopropylidene protecting groups. However,
fragment ion m/z 500 is a-type fragment ion and corresponds to the iminium ion presented at
Figure 4b. The same fragments were also found in products 46 and 46b (Supporting Information
file). Oxazolone- and iminium-type ions can thus, be used for the fast screening of reaction
mixtures and identification of two reaction pathways. This was confirmed by the MS analysis of a
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number of Ugi reactions; oxazolone fragment ions were found in all Ugi reactions giving “classical”
four-component product, while imonium fragment ions were found only in two examples presented
at Figure 2, where three parallel reaction pathways occurred.
(a)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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6
0
1
2
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6
7
8
9
0
1
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9
0
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9
0
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6
7
8
9
0
632
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
O
N+
O
N
N
O
O
O
O
O
O
O
O
O
O
O
O
m/z 632
45
(b)
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
+
O
N
N
N
H
H
O
O
O
O
O
O
O
O
5
00
45b
m/z 500
+
Figure 4. (a) The MS/MS spectrum of the molecular [M+H] ion m/z 891 of Ugi product 45 and the rationale
+
for the formation of the fragment ion m/z 632. (b) The MS/MS spectrum of the molecular [M+H] ion m/z
891 of Ugi product 45b and the rationale for the formation of the fragment ion m/z 500.
Many efforts have been devoted to the improvement of generally poor diastereoselectivity of
the Ugi reaction. It is nowadays well-documented that utilization of chiral isocyanides, carbonyl
components and carboxylic acids has little effect on diastereoselectivity, while some chiral
induction has been reported only with chiral amines or chiral cyclic imines.36 Contrary to that, in
our work we did not observe any substantial influence of the chiral amine on the diastereoselective
outcome of the Ugi reaction (Figure 2, compounds 36 and 37, 47 and 48). However, structure of
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2
2
2
2
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5
6
an amine component in great deal determined the fate of the imidate intermediate. In addition to
the disparity in the ratio of four- and three-component Ugi products observed with phenylalanine-
and tyrosine-derived amine components, another intriguing finding arose from reactions
performed with allose-related amine 12. When simple, acetic acid was used in the reaction with
sorbose-related aldehyde 2 and allose-related isocyanide 8, the four-component Ugi compound
0
1
2
3
4
5
6
7
8
9
0
1
2
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7
8
9
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5
6
7
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9
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2
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9
0
1
2
3
4
5
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7
8
9
0
44 was isolated as the only product. However, utilization of sterically more demanding carboxylic
acids with amine 12 changed the course of the reaction. In addition to the four-component
products (45, 46 and 47), three-component products (45a, 46a and 47a) appeared along with -
aminoamides 45b, 46b (Figure 2). It should be emphasized that such alternative pathways were
not observed with amines 9, 10 and 11. So, structure of imidate intermediate in terms of its bulky
groups arrangement, can favor internal or external nucleophile attack or discriminate between two
potential nucleophile sites within the molecule.
Final step prior to probing the biological potential of glycomimetics is removal of protecting
isopropylidene groups. Access to deprotected glycomimetics was varified on Ugi product 33.
Treatment of compound 33 with TFA/H O (9/1) at room temeprature resulted in removal of
2
isopropylidene groups after 3 hours, and derivative 55 was obtained in 89 % as a mixute of
multiple anomeric forms (Scheme 3).
Scheme 3. Deprotection of Ugi product 33.
O
O
OH
O
O
O
O
HO
HO
OH
O
O
H
H
TFA/H2O (9/1)
N
N
N
N
O
OH
OH
O
R.T. 3h
HO
O
O
O
O
O
O
O
O
OH
O
HO
O
OH
O
O
HO
OH
33
55 (89 %)
Conclusions
We applied a multicomponent strategy to afford a library of homo- and hetero-multivalent
Passerini and Ugi products utilizing isopropylidene-protected D-fructose-, L-sorbose-, D-
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galactose-, and D-allose-related building blocks. Passerini products were isolated in good yields
and very good to excellent diastereoselectivities, with S diastereoisomer being the predominant
one, as determined by the single crystal x-ray analysis. Three types of products were obtained by
the Ugi reaction; along with the “classical” four-component product, -acylaminoamides, a three-
component -aminoamides and a four-component -aminoacylamides were isolated in some
cases. Presence of multiple pathways is rationalized by the structure of imidate intermediate,
mainly influenced by the amine component. Our library of homo- and hetero-multivalent
glycomimetics thus consists of Passerini and three types of Ugi products bearing isopropylidene-
protected uncommon carbohydrates that can be deprotected in a single step under acidic
conditions. Binding of glycomimetic ligands to carbohydrate-binding proteins is a combination of
different interactions, including hydrogen bonding, metal-chelation, ionic and hydrophobic
interactions, and they are influenced by valency, topology and density of carbohydrates’
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
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0
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2
3
4
5
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0
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4
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8
9
0
9
distribution. Our next step is therefore, to probe the interaction of selected glacomimetics bearing
non-self carbohydrates with lectins and to elucidate the role of different factors on the binding.
Experimental Section
General methods: All experiments were monitored by analytical thin layer chromatography (TLC)
on Silica Gel 60 F254 plates (Merck; Darmstadt, Germany) after spraying with 10 % H SO and
2
4
heating. Flash column chromatography was performed on silica gel (Merck, 40−63 μm particle
size) by standard techniques eluting with solvents as indicated. An oil bath was used for reactions
requiring heating. All NMR experiments were carried out by using Bruker Avance 600
1
13
spectrometer (600.13 MHz, H; 150.91 MHz, C). Samples in CDCl solutions were recorded in
3
5
mm NMR tubes at 298 K. Chemical shifts in parts per million were referenced to TMS as internal
standard. Spectra were assigned based on 2D homonuclear (COSY) and heteronuclear (HMQC,
1
HMBC) experiments. H chemical shifts are assigned to the particular starting component, and
the following abbreviations are used: Fru = fructose; Sor = sorbose; Gal = galactose, All = allose,
ald = aldehyde, isoc = isocyanide. High resolution mass spectrometry (HRMS) was performed on
a MALDI-TOF/TOF spectrometer in positive ionization mode. Calibration type was internal with
calibrants produced by matrix ionization dissolved in α-cyano-4-hydroxycinnamic acid matrix.
Accurately measured spectra were internally calibrated and elemental analysis was performed on
Data Explorer v. 4.9 software with mass accuracy better than 5 ppm. Synthesis of 1 is described
in Ref. 37, while compound 13 is commertially available. When two diastereoisomers were
separated, they were marked as DS1 and DS2.
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4
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5
6
Synthesis
(3aS,3bR,7aS,8aR)-2,2,5,5-tetramethyltetrahydro-8aH-
[1,3]dioxolo[4',5':4,5]furo[3,2-d][1,3]dioxine-8a-carbaldehyde (2)38
2,3,4,6-di-O-isopropylidene-α-L-sorbofuranose (1-OH-isop-Sor, 130 mg, 0.50 mmol) was
dissolved in anhydrous DCM (3 mL) and Dess Martin's (DMP) reagent (254.45 mg, 0.6 mmol)
was added. The reaction mixture was stirred for 1 h at room temperature under nitrogen. The
reaction was terminated by the addition of 720 mg of Na S O /4.2 mL of water and 4.2 mL of a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
3
saturated aq. NaHCO . This mixture was stirred for another 10 min and then extracted with 3x8
3
mL EtOAc and washed with 1x8 mL saturated aq. NaCl. The organic layer was dried over
anhydrous MgSO . The product was purified by flash chromatography on silica gel column in a
4
1
solvent system: PE:EtOAc 1:2. Yield: 70 % (90 mg); R = 0.56 (toluene:EtOAc 1:2, v/v). H NMR
f
(600 MHz, CDCl ) δ = 9.65 CHO (s, 1H), 4.53 H-3 (s, 1H), 4.34 H-4 (dd, J=3.1, 2.5, 1H), 4.21 H-
3
5
3
(dd, J=3.9, 1.9, 1H), 4.10 H-6 (dd, J=4.9, 2.0, 2H), 1.52 CH isop, (s, 3H), 1.42 CH isop, (s,
3 3
13
H), 1.37 CH isop, (s, 3H), 1.32 CH isop, (s, 3H). C NMR{1H} (151 MHz, CDCl ) δ = 194.6
3
3
3
CO, 114.54 Cq isop, C-2, 97.8 Cq isop, 86.73 C-3, 74.1 C-5, 72.7 C-4, 60.2 C-6, 29.1 CH isop,
3
2
7.1 CH isop, 26.1 CH isop, 18.9 CH isop. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C H O
3 3 3 12 19 6
259.1182; Found 259.1180.
Scale-up: for 1 mmol (260 mg) 1-OH-isop-Sor 76 % (196 mg) of 2 was obtained; for 1.5 mmol
390 mg) 1-OH-isop-Sor 69 % (267 mg) of 2 was obtained.
(
Synthesis of (3aR,5S,5aR,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-
b:4',5'-d]pyran-5-carbaldehyde (3)39
1,2:34-di-O-isopropylidene-α-D-galactopyranose (520 mg, 2 mmol) was dissolved in anhydous
DCM (12 mL), and Dess Martin's reagent (DMP, 1040 mg, 2.4 mmol) was added. The reaction
mixture was stirred for 1 h at room temperature under nitrogen. The reaction was terminated by
addition of 2.88 g Na S O / 16.8 mL water and 16.8 mL saturated NaHCO solution. This mixture
2
2
3
3
was stirred for another 10 min and then extracted with 3x32 mL EtOAc and washed with 1x32 mL
saturated aq. NaCl. The organic layer was dried over anhydrous MgSO . The product was purified
4
by flash chromatography on silica gel column in a solvent system: toluene:EtOAc 3:2. Yield: 98 %
1
(505 mg); R = 0.6 (toluene:EtOAc 3:2, v/v). H NMR (600 MHz, CDCl ) δ 9.62 (H-6, s, 1H), 5.67
f
3
(H-1, d, J = 4.9 Hz, 1H), 4.65 (H-3, dd, J = 7.8, 2.5 Hz, 1H), 4.60 (H-4, dd, J = 7.8, 2.2 Hz, 1H),
4.38 (H-2, dd, J = 4.9, 2.5 Hz, 1H), 4.19 (H-5, d, J = 2.2 Hz, 1H), 1.51 (CH , s, 4H), 1.44 (CH s,
3 3,
13
4H), 1.35 (CH s, 4H), 1.32 (CH s, 4H). C NMR{1H} (151 MHz, CDCl ) δ 200.3 C-6, 110.3 Cq-
3
,
3,
3
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isop, 109.3 Cq-isop, 96.5 C-1, 73.4 C-5, 71.9 C-4, 70.7 C-2, 70.6 C-5, 26.2 CH -isop, 26.0 CH -
3
3
isop, 25.0 CH -isop, 24.4 CH -isop.
3
3
Scale up: from 5.76 mmol (1.5 g) of 1,2:34-di-O-isopropylidene-α-D-galactopyranose, 86 % (1.28
g) of 3 was obtained.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis of (3aR,5R,6aS)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-
dimethyldihydrofuro[2,3-d][1,3]dioxol-6(5H)-one (4)40
1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (260 mg, 1 mmol) was dissolved in 6 mL of dry
DCM and DMP reagent (508.9 mg, 1.2 mmol) was added. The reaction was stirred for 1 h at room
temperature under nitrogen. After that Na S O (1.44 g, 5.8 mmol) / 8.4 mL water and 8.4 mL
2
2
3
saturated aq. NaHCO were added. This mixture was stirred for another 10 min, and then
3
extracted with 3x16 mL EtOAc and washed with 1x16 mL saturated aq. NaCl. The organic layer
was dried over anhydrous MgSO . The product was purified by flash chromatography on silica
4
gel column in a solvent system: PE:EtOAc 1:1. Yiel: 89 % (230 mg); R = 0.56 (PE:EtOAc 1:1,
f
1
v/v). H NMR (600 MHz, CDCl ) δ 6.11 H-1 (d, J = 4.5 Hz, 1H), 4.36 H-2 (m, 1H), 4.33 H-5, H-4
3
(
m, 2H), 4.00 H-6 (m, 2H), 1.43 CH isop (s 3H), 1.41 CH isop (s, 3H), 1.31 CH isop (s, 6H).
3 3 3
13
C NMR{1H} (151 MHz, CDCl ) δ = 209.0 C-3, 114.5 Cq isop, 110.6 Cq isop, 103.3 C-1, 79.2
3
C-5, 77.4 C-2, 76.6 C-4, 64.5 C-6, 27.8 CH isop, 27.4 CH isop, 26.2 CH isop, 25.5 CH isop.
3
3
3
3
Synthesis of (3aS,5aR,8aR,8bS)-3a-(isocyanomethyl)-2,2,7,7-tetramethyltetrahydro-5H-
bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran (5)
((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-3a-
yl)methanamine (1-NH -isop-Fru) (45 mg, 0.17 mmol) was dissolved in saturated aq. NaHCO
2
3
(1.36 mL), methyl formate (1.36 mL, 22.1 mmol) was added and the mixture was stirred for 24 h
at room temperature with the addition of methyl formate (2x1 mL). The reaction was monitored
by TLC in a solvent system: EtOAc : HOAc : H O 70:2:2. Purification on silica gel column in this
2
system yielded 64 % (31 mg) of the formamide derivative (N-(((3aS,5aR,8aR,8bS)-2,2,7,7-
tetramethyltetrahydro-3aH-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-3a-yl)methyl)formamide, R = 0.18
f
(ETOAc:HOAc:H O 70:2:2).
2
In the second reaction step, formamide derivative (31 mg, 0.108 mmol) was dissolved in DCM
(
600 μL), and Et N (58.5 μL) and POCl (15.8 μL) were added. The reaction was stirred at room
3
3
temperature for 1h after which Na CO (28.7 mg) dissolved in water (0.114 mL) was added. The
2
3
reaction mixture was stirred for 1 h at room temperature. DCM and water were added, and
extracted. The organic layers were collected and dried over K CO , filtered and evaporated. The
2
3
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1
1
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1
1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
3
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4
4
4
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6
residue was purified on a silica gel column in a solvent system: toluene:EtOAc 1:1. Yield: 63 %
1
(18 mg); yield over two steps 40 %; R = 0.76 (toluene:EtOAc 1:1, v/v). H NMR (600 MHz, CDCl )
f
3
δ = 4.63 H-4 (dd, J=7.9, 2.7, 1H), 4.36 H-3 (d, J=2.7, 1H), 4.22 H-5 (dd, J=7.9, 1.3, 1H), 3.90 H-
6a (dd, J=13.0, 1.9, 1H), 3.78 – 3.71 H-6b, H-1 (m, 2H), 3.63 H-1 (d, J=15.2, 1H), 1.55 CH isop
3
1
3
(
s, 3H), 1.49 CH isop (s, 3H), 1.45 CH isop (s, 3H), 1.33 CH isop (s, 3H). C NMR{1H} (151
3 3 3
0
1
2
3
4
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8
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0
1
2
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6
7
8
9
0
1
2
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8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
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7
8
9
0
MHz, CDCl ) δ = 159.3 NC, 109.7 Cq isop, 109.5 Cq isop, 100.4 C-2, 70.8 C-5, 70.5 C-3, 70.2
3
C-4, 62.2 C-6, 47.4 C-1, 26.9 CH isop, 26.1 CH isop, 25.8 CH isop., 24.2 CH isop. HRMS
3
3
3
3
(
ESI-TOF) m/z: [M + H]+ Calcd for C H NO 270.1341; Found 270.1347.
13 20 5
Scale up: from 1 mmol (259 mg) 1-NH -isop-Fru, 48 % (129 mg) of 5 was obtained over two
2
reaction steps; from 1.8 mmol (466 mg) 1-NH -isop-Fru, 55 % (266 mg) of 5 was obtained over
2
two reaction steps.
Synthesis of (3aS,3bR,7aS,8aS)-8a-(isocyanomethyl)-2,2,5,5-tetramethyltetrahydro-7H-
[1,3]dioxolo[4',5':4,5]furo[3,2-d][1,3]dioxine (6)
I step
DCC (176.8 mg, 0.852 mmol, 1.3 eq) was dissolved in dry DCM (10 mL) at 0 ° C followed by slow
addition of HCOOH (32.3 μL, 0.852 mmol, 1.3 eq). A white suspension was stirred for 10 min. To
this reaction mixture was added ((3aS,3bR,7aS,8aS)-2,2,5,5-tetramethyltetrahydro-8aH-
[
1,3]dioxolo[4',5':4,5]furo[3,2-d][1,3]dioxin-8a-yl)methanamine (172 mg, 0.66 mmol), DMAP (16.2
o
mg, 0.132 mmol, 0.2 eq.) and Et N (146.2 μL, 1.05 mmol, 1.6 eq) and mixed at 0 C another 30
3
min and overnight at room temperature. At the end of the reaction, the precipitate of the urea was
filtered off and the filtrate was evaporated. The residue was purified by flash liquid
chromatography in a solvent system: EtOAc:HOAc:H O 70:2:2 to obtain formamide derivative N-
2
(((3aS,3bR,7aS,8aS)-2,2,5,5-tetramethyltetrahydro-8aH-[1,3]dioxolo[4',5':4,5]furo[3,2-
d][1,3]dioxin-8a-yl)methyl)formamide in 58 % (111 mg) (R = 0.69).
f
In the second reaction step, formamide derivative (111 mg, 0.386 mmol) was dissolved in DCM
(2 mL), Et N (205.2 μL) and POCl (54.6 μL). The reaction was stirred at room temperature for 80
3
3
min after which Na CO (98.4 mg) dissolved in water (394.8 μL) was added. The reaction mixture
2
3
was stirred for 1 h at room temperature. DCM and water were added and extracted. The organic
layers were collected and dried over K CO filtered and evaporated. The residue was purified on
2
3
a silica gel column in a solvent system: PE:EtOAc 2:1. Yield: 69 % (72 mg); yield 40 % over two
1
steps; R = 0.48 (PE:EtOAc 2:1, v/v). H NMR (600 MHz, CDCl ) δ = 4.48 H-3 (s, 1H), 4.35 H-4
f
3
(d, J=2.2, 1H), 4.13 H-5 (dd, J=3.5, 2.1, 1H), 4.03 H-6 (dd, J=13.7, 2.2, 1H), 3.96 H-6 (d, J=13.7,
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H), 3.88 H-1 (s, 1H), 3.78 H-1 (d, J=15.3, 1H), 1.51 CH isop (s, 3H), 1.47 CH isop (s, 3H), 1.41
3
3
13
CH isop (s, 3H), 1.36 CH isop (s, 3H). C NMR{1H} (151 MHz, CDCl ) δ = 157.8 NC, 113.6 Cq
3
3
3
isop, 111.7 C-2, 97.7 Cq isop, 84.3, 73.5 C-4, 72.8 C-5, 60.3 C-6, 45.5 C-1, 29.1 CH isop, 27.8
3
CH isop, 26.6 CH isop, 18.7 CH isop. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C H NO
5
3
3
3
13 20
270.1341; Found 270.1338.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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4
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5
5
5
5
5
5
5
5
5
5
6
0
1
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5
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7
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9
0
1
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9
0
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1
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8
9
0
1
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5
6
7
8
9
0
Synthesis of (3aR,5R,5aS,8aS,8bR)-5-(isocyanomethyl)-2,2,7,7-tetramethyltetrahydro-5H-
bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran (7)
1,2,3,4-di-O-isopropylidene-6-deoxy-6-amino-α-D-galactopyranose (6-NH -isop-Gal) (140 mg,
2
0.54 mmol) was dissolved in saturated in saturated NaHCO solution and methyl formate (4.46
3
mL) was added. The reaction was stirred at room temperature with the addition of 2x 4.46 mL
methylformate overnight. Solvent was evaporated and the residue purified on a silica gel column
in a solvent system: EtOAc:HOAc:H O 70:2:2 to give 32 % of formamide derivative N-
2
(((3aR,5S,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-
5-yl)methyl)formamide (R = 0.62).
f
Alternativelly, formamide derivative can be obtained following tje procedure: DCC (370 mg, 2.989
mmol, 1.3 eq) was dissolved in anhydrous DCM (10 mL) at 0 °C and CHOOH (112.8 μL, 2.989
mmol, 1.3 eq) was slowly added. A white suspension was stirred for 10 min. To this reaction
mixture 6-NH -iprop-Gal (595 mg, 2.32 mmol), DMAP (56.4 mg, 0.46 mmol, 0.2 equiv) and Et N
2
3
(509 μL, 3.67 mmol, 1.6 eq) were added, and stired overnight at room temperature. The
precipitate of the urea was filtered off and the filtrate was evaporated. The residue was purified
by flash liquid chromatography in a solvent system of EtOAc:HOAc:H O 70:2:2. to afford 69 % of
2
formamide product.
In the second reaction step, formamide derivative (436 mg, 1.519 mmol) was dissolved in DCM
(4.15 mL), Et N (820 μL) and POCl (222.6 μL) were added. The reaction was stirred at room
3
3
temperature for 1h after which Na CO (401 mg) dissolved in water (1.6 mL) was added. The
2
3
reaction mixture was stirred for 1 h at room temperature. DCM and water were added and
extracted. The organic layers were collected and dried over K CO filtered and evaporated. The
2
3
residue was purified on a silica gel column in a solvent system: PE:EtOAc 2:1. Yield: 44 % (180
1
mg); yield 30 % over two steps; H NMR (600 MHz, CDCl ) δ 5.49 H-1 (d, J = 5.0 Hz, 1H), 4.64
3
H-3 (dd, J = 7.8, 2.5 Hz, 1H), 4.32 H-2 (dd, J = 5.0, 2.5 Hz, 1H), 4.28 H-4 (dd, J = 7.8, 1.9 Hz,
1H), 3.99 H-5 (td, J = 6.9, 1.7 Hz, 1H), 3.62 H-6 (dd, J = 14.7, 7.0 Hz, 1H), 3.55 H-6 (dd, J = 14.7,
6.8 Hz, 1H), 1.53 CH -isop (d, J = 1.0 Hz, 3H), 1.42 CH -isop (s, 3H), 1.33 CH -isop (s, 3H), 1.32
3
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3
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13
CH -isop (s, 3H). C NMR{1H} (151 MHz, CDCl ) δ 158.3 NC, 110.1 Cq-isop (1,2), 109.3 Cq-
3
3
isop (3,4), 96.5 C-1, 70.8 C-3, 70.6 C-2, 70.4 C-4, 66.4 C-5, 41.8 C-6, 26.3 CH -isop, 26.1 CH -
3
3
isop, 25.1 CH -isop, 24.6 CH -isop. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C H NO
3
3
13 20
5
270.1341; Found 270.1350.
Scale up: from 1 mmol (259 mg) 6-NH -isop-Gal, 68 % (183 mg) of 7 was obtained over two
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reaction steps; from 2.2 mmol (570 mg) 6-NH -isop-Gal, 55 % (326 mg) of 7 was obtained over
2
two reaction steps.
Synthesis of (3aR,5S,6R,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-6-isocyano-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxole (8)
DCC (106 mg, 0.518 mmol) was dissolved in anhydrous DCM (3 mL) at 0 °C followed by a slow
addition of CHOOH (19.6 μL, 0.518 mmol). A white suspension was stirred for 10 min. To this
reaction mixture amine derivative (3aR,5S,6R,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-amine (104 mg, 0.4 mmol), DMAP (9.8 mg, 0.08 mmol)
and Et N (88.58 μL; 0.638 mmol) were added and the reaction was stirred 2.5 h at room
3
temperature. The formed precipitate of the urea was filtered off, and the filtrate was evaporated.
The residue was purified by liquid flash chromatography in EtOAc:HOAc:H O 70:2:2 solvent
2
system to give 91 % of formamide derivative N-((3aR,5S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-
4
-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl)formamide.
In the second reaction step, formamide derivative (105 mg, 0.365 mmol) was dissolved in DCM
1 mL), and Et N (106.8 μL) and POCl (53.2 μL) were added. The reaction was stirred at room
(
3
3
temperature for 1h, and than Na CO (96.2 mg) dissolved in water (0.384 mL) was added. The
2
3
reaction mixture was stirred for 1 h at room temperature. After extraction, the organic layers were
collected, dried over K CO , and evaporated. The residue was purified on silica gel column in a
2
3
solvent system: PE:EtOAc 2:1. Yield: 37 % (36 mg); yield 33 % ovet two steps; R = 0.63
f
1
(
PE:EtOAc 2:1). H NMR (600 MHz, CDCl ) δ 5.80 H-1 (d, J = 3.7 Hz, 1H), 4.70 H-2 (dd, J = 4.6,
3
4
.1 Hz, 1H), 4.25 H-5 (dd, J = 11.7, 5.5 Hz, 1H), 4.11 H-4, H-6 (m, 2H), 4.00 H-6 (dd, J = 8.9,
.7 Hz, 1H), 3.85 H-3 (dd, J = 8.9, 5.1 Hz, 1H), 1.57 CH isop (d, J = 19.8 Hz, 3H), 1.44 CH isop
5
3
3
13
(d, J = 48.5 Hz, 3H), 1.36 CH isop (s, 6H). C NMR{1H} (151 MHz, CDCl ) δ 161.8 NC, 113.8
3
3
Cq isop, 110.6 Cq isop, 104.4 C-1, 79.6 C-4, 78.9 C-2, 75.6 C-5, 66.3 C-6, 55.3 C-3, 2696 CH3
isop, 26.8 CH isop, 26.7 CH isop, 25.3 CH isop. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
3
3
3
C H NO 270.1341; Found 270.1346.
13
20
5
Synthesis of ((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis([1,3]dioxolo)[4,5-
b:4',5'-d]pyran-3a-yl)methanamine (9)
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9
A solution of trifluoromethanesulfonyl anhydride (314 μL, 1.89 mmol) in anhydrous DCM (3.5 mL)
o
was added dropwise at -20 C under argon to a solution of 2,3,4,5-di-O-isopropylidene β-D-
fructopyranose (325.08 mg, 1.26 mmol) in anhydrous DCM (14 mL) and pyridine (273 μL). The
o
reaction mixture was stirred at -20 C. for 1 h. The mixture was then diluted with DCM (10 mL)
and extracted with water (15 mL). The organic layer was washed with saturated KHSO solution
4
1
1
1
1
1
1
1
1
1
1
2
2
2
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5
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5
5
5
5
5
6
0
1
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5
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7
8
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0
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7
8
9
0
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5
6
7
8
9
0
(
15 mL), saturated aq. NaHCO (10 mL) and saturated aq. NaCl, and dried over Na SO , filtered
3
2
4
and evaporated. The triflate derivative was used in synthesis without further purification.
Sodium azide (333 mg, 5.1 mmol) was added to a solution of the triflate derivative (322 mg, 1.25
o
mmol) in anhydrous DMF (18.2 mL). The reaction mixture was stirred at 80 C. for 1 h and
evaporated. The residue was dissolved in EtOAc (50 mL). The organic layer was washed with
water (20 mL) and saturated aq. NaCl (20 mL), dried over Na SO and evaporated. The residue
2
4
was purified on silica gel column in solvent system: toluene:EtOAc 2:1 to give azide derivative
3aS,5aR,8aR,8bS)-3a-(azidomethyl)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-
(
b:4',5'-d]pyran in 87 % yield.
Azide derivative (313 mg, 1.098 mmol) was dissolved in dry DCM (8 mL) and dry EtOH (39 mL)
and NaBH (82.8 mg) and catalytic amount of NiCl · 6H O was added. After 1 hour at room
4
2
2
temperature, the reaction mixture was evaporated and purified on silica gel column in a solvent
system: EtOAc:EtOH:HOAc:H O 70:15:15:15. Yield: 98 % (279 mg); yield 57 % over three steps.
2
1
H NMR (600 MHz, DMSO-d ) δ = 4.55 H-3 (dd, J=8.0, 2.5, 1H), 4.32 H-4 (d, J=2.5, 1H), 4.21 H-5
6
(
dd, J=8.0, 1.1, 1H), 1.44 CH isop (s, 3H), 1.35 CH isop (s, 3H), 1.34 CH isop (s, 3H), 1.28 CH
3
3
3
3
13
isop (s, 3H). C NMR{1H} (151 MHz, DMSO) δ = 107.9 Cq isop, 107.2 Cq- isop, 103.5 C-2, 70.2
C-3, 70.1 C-4, 69.5 C-5, 60.3 C-6, 47.6 C-1 26.3 CH isop, 25.6 CH isop , 25.5 CH isop, 23.9
3
3
3
CH isop. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C H NO 260.1498; Found 260.1502.
3
12 22
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Scale up: from 2 mmol (520 mg) 1-OH-isop-Fru, 42 % (217 mg) of 9 was obtained over three
reaction steps.
Synthesis of ((3aS,3bR,7aS,8aS)-2,2,5,5-tetramethyltetrahydro-
8aH[1,3]dioxolo[4',5':4,5]furo[3,2-d][1,3]dioxin-8a-yl)methanamine (10)41
A solution of trifluoromethanesulfonyl anhydride (497 μL) in anhydrous DCM (5.5 mL) was added
o
dropwise at -20 C.under nitrogen to a solution of 2,3,4,6-di-O-isopropylidene sorbofuranose (520
mg, 2 mmol) in anhydrous DCM (22 mL) and pyridine (432 μL). The reaction mixture was stirred
o
at -20 C. for 2 h. The mixture was then diluted with DCM (20 mL) and extracted with water (24
mL). The organic layer was washed with saturated KHSO solution (24 mL), saturated aq.
4
NaHCO (16 mL) and saturated aq.NaCl (16 mL), dried over Na SO , filtered and evaporated.
3
2
4
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6
The triflate derivative (88 %) was used in synthesis without further purification.
Sodium azide (460 mg, 7.1 mmol) was added to a solution of the triflate derivative (695 mg, 1.77
°
mmol) in anhydrous DMF (24 mL). The reaction mixture was stirred at 80 C for 1 h. After
evaporation the residue was dissolved in EtOAc (80 mL). The organic layer was washed with
water (36 mL) and saturated aq. NaCl (36 mL), dried over Na SO and evaporated. The residue
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
was purified on silica gel column in PE:EtOAc 3:1. to give azide derivative (3aS,3bR,7aS,8aS)-
8a-(azidomethyl)-2,2,5,5-tetramethyltetrahydro-7H-[1,3]dioxolo[4',5':4,5]furo[3,2-d][1,3]dioxine in
8
1 % yield R = 0.41 (PE:EtOAc 3:1, v/v).
f
Azide derivative (407 mg, 1.428 mmol) was dissolved in dry DCM (21 mL) and dry EtOH (102 mL)
and NaBH (107.9 mg, 2.856 mmol) and catalytic amount of NiCl · 6H O was added. After 1 hour
4
2
2
at room temperature, the reaction mixture was evaporated and purified on silica gel column in a
solvent system of EtOAc:EtOH:HOAc:H O 7:1:1:1. Yield: 98 % (358 mg); yield 69 % over 3 steps;
2
1
R = 0.43 (EtOAc:EtOH:HOAc:H O 7:1:1:1, v/v). H NMR (600 MHz, DMSO-d ) δ = 4.41 H-3 (s,
f
2
6
1H), 4.29 H-4 (d, J=2.2, 1H), 4.06 – 3.96 H-6, H-5 (m, 3H), 3.81 H-6 (d, J=13.3, 1H), 2.83 H-1 (q,
J=13.7, 2H), 1.39 CH isop (t, J=4.8, 6H), 1.31 CH isop (s, 3H), 1.23 CH isop. (d, J=4.1, 3H).
3
3
3
13C NMR{1H} (151 MHz, DMSO) δ = 115.2 Cq isop., 110.7 C-2, 96.6 Cq isop, 84.2, 83.8 C-3,
72.7 C-4, 72.7, 71.5 C-5, 71.4, 59.6 C-6, 45.6 C-1, 28.9 CH isop, 27.4 CH isop, 27.3 CH isop,
3 3 3
1
8.7 CH isop. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C H NO 260.1498; Found 260.1505.
3
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Synthesis of ((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-
bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methanamine (11)42
1,2;3,4-di-O-isopropylidene-α-galactopyranose (260 mg, 1.00 mmol) was dissolved in dry DCM
(11 mL) under nitrogen at -20 °C with pyridine (216 μL) and then trifluoromethanesulfonic acid
anhydride (248.8 μL) dissolved in dry DCM (2.7 mL) were added slowly in 20 min time period.
After 1 h of stirring the reaction was washed with 15 mL water, 15 mL KHSO (10 %), 10 mL
4
saturated aq. NaHCO and 10 mL saturated aq. NaCl. Product (83 %) was dried and used in the
3
next step.
The triflate derivative (328 mg, 0.83 mmol) was dissolved in dry DMF (11.6 mL), NaN (216 mg,
3
33.2 mmol) was added and reaction mixture stirred for 1 h at 80 °C. DMF was evaporated, the
residue was dissolved in EtOAc (40 mL) and extracted with 18 mL water, and 18 mL saturated
aq. NaCl. The organic layer was dried over Na SO .Crude product was purified by flash
2
4
chromatography on silica gel column in solvent system: toluene:EtOAc (2:1) to afford 78 % of
azide derivative 1,2:3,4-di-O-isopropylidene-6-deoxy-6-azido-α-D-galactopyranose Rf = 0.7
(toluene:EtOAc 2:1, v/v).
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Azide derivative (185 mg, 0.64 mmol) was dissolved in dry DCM (9.48 mL) and dry EtOH (45.9
mL), NaBH (48.4 mg) and a catalytic amount of NiCl x6H O were added. After 1 hour at room
4
2
2
temperature, the reaction mixture was evaporated and purified on silica gel column in a system:
EtOAcEtOH:HOAc:H O 7:1:1:1. Yield: 89 % (148 mg); yield 57 % over three steps; R = 0.5
2
f
1
(
EtOAc:EtOH:HOAc:H O 7:1:1:1, v/v). H NMR (600 MHz, DMSO-d ) δ 5.47 H-1 (d, J = 5.0 Hz,
2
6
1
1
1
1
1
1
1
1
1
1
2
2
2
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0
1
1
2
H), 4.61H-3 (dd, J = 7.9, 2.3 Hz, 1H), 4.36 H-2 (dd, J = 5.0, 2.4 Hz, 1H), 4.24 H-4 (dd, J = 8.0,
.3 Hz, 1H), 3.81 H-5 (d, J = 4.4 Hz, 1H), 2.81 H-6 (ddd, J = 21.1, 12.8, 6.2 Hz, 1H), 1.89 NH (s,
2
13
H), 1.49 CH -isop (m, 3H), 1.32 CH -isop (m, 9H). C NMR{1H} (151 MHz, DMSO-d ) δ 108.4
3
3
6
Cq-isop, 108.0 Cq-isop, 95.5 C-1, 70.4 C-4, 69.9 C-3, 69.7 C-2, 66.4 C-5, 40.2 C-6, 25.9 CH3-
isop, 25.8 CH -isop, 24.8 CH -isop, 24.2 CH -isop.
3
3
3
Scale up: from 2.5 mmol (650 mg) 6-OH-isop-Gal, 63 % (408 mg) of 11 was obtained over three
steps; from 3.5 mmol (910 mg) 6-OH-isop-Gal, 59 % (535 mg) of 11 was obtained over three
steps; from 6.4 mmol (1664 mg) 6-OH-isop-Gal, 45 % (746 mg) of 11 was obtained over three
steps.
Synthesis
of
(3aR,5S,6R,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-amine (12)43
1,2;5,6-di-O-isopropylidene-α-D-Glucofuranose (520 mg, 2.00 mmol) was dissolved in dry DCM
°
(
22 mL) under nitrogen at -20 C and then pyridine (432 μL) anhydride of trifluoromethanesulfonic
acid (497 μL) dissolved in dry DCM (5.5 mL) were added slowly over 20 min. After 1 h of stirring
the reaction mixture was rinsed with 24 mL water, 24 mL KHSO (10 %), 16 mL sat. solution of
4
NaHCO and 16 mL sat. solution of NaCl. Solvent was evaporated and the residue (94 %) dried
3
and used in the next reaction step. R = 0.74 (toluene:EtOAc 2:1, v/v).
f
The triflate derivative (740 mg, 1.88 mmol) was dissolved in dry DMF (21 mL) and NaN (530 mg,
3
o
6
6 mmol) was added and stirred for 1 h at 80 C. DMF was evaporated, the residue was dissolved
in EtOAc (80 mL) and extracted with 36 mL water, 36 mL sat. solution of NaCl. The organic layer
was dried over Na SO , evaporated and the residue purified by flash chromatography on silica
2
4
gel column in a solvent system: PE:EtOAc 3:1 to give 40 % of azide derivative.
Azide derivative (220 mg, 0.77 mmol) was dissolved in dry DCM (6.8 mL) and dry EtOH (34.5
mL), NaBH (54 mg) and a catalytic amount of NiCl x6H O were added. Reaction was stirred at
4
2
2
room temperature for 2h. Solvent was evaporated and the residue purified on silica gel column in
a system: EtOAc:EtOH:HOAc:H O 7:1:1:1. Yield: 97 % (194 mg); 37 % over 3 steps; R = 0.46
2
f
1
(EtOAc:EtOH:HOAc:H O 7:1:1:1, v/v) . H NMR (600 MHz, CDCl ) δ 5.73 H-1 (d, J = 3.7 Hz, 1H),
2
3
4.53 H-2 (m, 1H), 4.09 H-5; H-6 (ddd, J = 14.8, 10.3, 6.3 Hz, 2H), 3.99 H-6 (dd, J = 8.4, 5.6 Hz,
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H), 3.60 H-4 (dd, J = 9.0, 6.4 Hz, 6H), 3.12 H-3 (dd, J = 9.0, 4.8 Hz, 1H), 1.52 CH isop (s, 3H),
3
1.42 CH isop (s, 3H), 1.34 CH isop (s, 3H), 1.32 CH isop (s, 3H). 13C NMR{1H} (151 MHz,
3
3
3
CDCl ) δ 112.4 Cq isop, 109.9 Cq isop, 10448 C-1, 81.7 C-4, 81.4 C-2, 77.3 C-5, 67.4 C-6, 58.4
3
C-3, 26.9 CH isop, 26.8 CH isop, 26.5 CH isop, 25.4 CH isop.
3
3
3
3
0
1
2
3
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7
8
9
0
1
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5
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General procedure for Passerini reactions: To a glass vial containing an aldehyde (0.1 mmol)
in anhydrous MeOH (100 µL) were added acid component (0.1 mmol, 1 eq.) and an isocyanide
component (0.1 mmol, 1 eq.). With all reactants added, the solution was allowed to stir for 24 h in
closed vial at room temperature. The reactions were concentrated under reduced pressure and
reaction mixtures were purified by flash column chromatography.
2-oxo-1-((3aR,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis([1,3]dioxolo)[4,5-b:4',5'-
d]pyran-3a-yl)-2-((((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-
bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-3a-yl)methyl)amino)ethyl acetate (14): Yield 74 % (43
mg); mp = 94-100 °C; R = 0.26 (PE:EtOAc 1:1, v/v), R = 0.55 (PE:EtOAc 1:2, v/v); d.r. 88:12
f
f
1
22
(determined from the H NMR spectrum); [α]
+ 1 (c 1, CHCl ). Chemical shifts are given for
D
3
1
the major diastereoisomer. H NMR (600 MHz, CDCl ):  6.67 NH isoc (d, J = 8.9, 2.8 Hz, 1H),
3
5
.06 H-1 ald (s, 1H), 4.58 H-4 ald (m, 1H), 4.57 H-4 isoc (m, 1H), 4.40 H-3 isoc (d, J = 2.7 Hz,
H), 4.22 H-5 (dd, J = 7.9, 1.2 Hz, 1H), 4.19 H-5 (dd, J = 7.8, 1.4 Hz, 1H), 4.17 H-3 ald (d, J = 2.8
1
Hz, 1H), 4.12 H-1 isoc (dd, J = 14.2, 9.1 Hz, 1H), 3.90 H-6 isoc (m, 2H), 3.79 H-6 ald (d, J = 13.0
Hz, 1H), 3.71 H-6 ald (d, J = 12.9 Hz, 1H), 3.16 H-1 isoc (dd, J = 14.2, 3.3 Hz, 1H), 2.18 CH -ac.
3
(s, 3H), 1.51 CH -isop. (s, 3H), 1.50 CH -isop (s, 3H) 1.48 CH -isop (s, 3H), 1.44 CH -isop (s,
3
3
3
3
3H), 1.43 CH -isop (s, 3H), 1.39 CH -isop (s, 3H), 1.31 CH -isop (s, 3H), 1.31 CH -isop (s, 3H).
3 3 3 3
13
C NMR{1H} (151 MHz, CDCl ):  169.5 CO-ac, 165.6 CO-amid, 109.9 Cq-isop 109.5 Cq-isop,
3
109.4 Cq-isop, 108.9 Cq-isop, 102.8 C-2 isoc, 102.2 C-2 ald, 74.1 C-1 ald, 71.1, 71.0 C-3 ald,
isoc, 70.8, 70.7 C-4 ald, isoc, 70.5, 70.3 C-5 ald, isoc, 62.0, 61.8 C-6 ald, isoc, 44.5 C-1 isoc,
+
[26.9, 26.7, 26.2, 25.7, 25.5, 24.4, 24.2] CH -isop, 21.05 CH -ac. HRMS (ESI-TOF) m/z: [M+H]
3
3
Calcd for C H NO 588.2656; Found 588.2655.
27
42
13
(S)-2-oxo-1-((3aR,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis([1,3]dioxolo)[4,5-
b:4',5'-d]pyran-3a-yl)-2-((((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-
bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-3a-yl)methyl)amino)ethyl benzoate (15): Yield 78 % (51
22
mg); white solid; mp = 125-132 °C; R = 0.25 (PE:EtOAc 2:1, v/v); [α]
+ 10 (c 1, CHCl ); d.r.
3
f
D
1
90:10 (determined from the H NMR spectrum); Chemical shifts are given for the major
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diastereoisomer. H NMR (600 MHz, CDCl )  = 8.15-8.04 (m, 2H, benzoic acid), 7.55 (t, J = 7.4
3
Hz, 1H, benzoic acid), 7.42 (t, J = 7.8 Hz, 2H, benzoic acid), 6.78 (dd, J = 8.5, 3.1 Hz, 1H, NH),
5
2
4
.84 (s, 1H, H-1, Fru-ald), 5.03 (d, J = 2.8 Hz, 1H, H-3 Fru-ald), 4.56 (ddd, J = 23.8, 7.9, 2.7 Hz,
H, H-4 Fru-ald, isoc), 4.22-4.14 (m, 2H, H-5 Fru-ald, isoc), 4.11 (t, J = 3.8 Hz, 1H, H-3 Fru-isoc),
.03 (dd, J = 14.1, 8.7 Hz, 1H, H-1 Fru-isoc), 3.84 (ddd, J = 22.1, 13.0, 1.9 Hz, 2H, H-6 Fru), 3.69
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
d, J = 13.0 Hz, 2H, H-6 Fru), 3.25 (dd, J = 14.1, 3.5 Hz, 1H, H-1 Fru-isoc), 1.52 (dd, J = 20.4,
10.7 Hz, 9H, Fru-CH ), 1.41 (m, 3H, Fru-CH ), 1.38 (s, 3H, Fru-CH ), 1.33 (s, 3H, Fru-CH ), 1.31
3
3
3
3
13
(
s, 3H, Fru-CH ), 1.28 CH -isop (s, 3H, Fru-CH ). C NMR{1H} (151 MHz, CDCl )  166.9), 165.3,
3
3
3
3
1
33.5, 130.5, 129.9, 128.6, 109.5, 109.5, 109.4, 108.7, 102.3 C-2, 102.0 C-2, 76.5, 71.4, 71.1,
7
1.0, 70.7, 70.4, 70.3, 62.1, 61.8, 45.1, 26.9, 26.6, 26.2, 25.9, 25.5, 24.3, 24.2. HRMS (ESI-TOF)
+
m/z: [M+Na] Calcd for C H NO Na 672.2632; Found 672.2612.
32
43
13
2-oxo-1-((3aR,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis([1,3]dioxolo)[4,5-b:4',5'-
d]pyran-3a-yl)-2-((((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-
bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-3a-yl)methyl)amino)ethyl
2-((tert-
butoxycarbonyl)amino)-3-phenylpropanoate (16): Yield 78 % (62 mg); DS1: Yield 25 % (20
mg); R = 0.43 (PE:EtOAc 1.5:1, v/v). DS2: Yield 53 %; mp = 147-149 °C, R = 0.3 (PE:EtOAc
f
f
1
1
.5:1, v/v); [α]D22 - 2 (c 1, CHCl ).. Chemical shifts are given for DS2. H NMR (600 MHz, CDCl )
3
3

7.26 Phe (m, 2H), 7.21 Phe (m, 2H), 6.72 NH (m, 1H), 5.14 H-1 ald (s, 1H), 4.91 NH Phe (d, J
= 8.5 Hz, 1H), 4.63 Phe-α (m, 1H), 4.58 H-4 ald, isoc (m, 2H), 4.39 H-3 ald (d, J = 2.7 Hz, 1H),
4
1
1
.21 H-5 ald, isoc (dd, J = 7.7, 1.2 Hz, 2H), 4.16 H-3 isoc (d, J = 2.8 Hz, 1H), 4.13 H-1 isoc.(m,
H), 3.91 H-6 (ddd, J = 20.0, 13.0, 1.7 Hz, 2H), 3.79 H-6 (d, J = 13.0 Hz, 1H), 3.72 H-6 (d, J =
2.8 Hz, 1H), 3.37 Phe-β (dd, J = 14.2, 5.2 Hz, 1H), 3.20 H-1 isoc. (dd, J = 14.2, 3.1 Hz, 1H), 3.12
Phe-β (dd, J = 14.1, 7.1 Hz, 1H), [1.56 (s, 3H), 1.51 (s, 3H), 1.50 (s, 3H), 1.49 (s, 3H), 1.45 (s,
2H), 1.43 (s, 3H), 1.38 (s, 3H), 1.36 (s, 6H), 1.34 (s, 3H), 1.31 (s, 3H)] CH -isop. 13C NMR{1H}
3
(
151 MHz, CDCl )  170.7 CO, 165.1 CO, 136.4 Phe-γ, 130.1 Phe-ζ, 128.6 Phe-δ, 127.0 Phe-ε,
3
1
10.0 Cq-isop, 109.5 Cq-isop, 109.4 Cq-isop, 108.9 Cq-isop, 102.67 C-2, 102.06 C-2, 74.2 C-1
ald, [71.2, 70.8, 70.6, 70.5, 70.2] C-3, C-4, C-5, 61.9 C-6 ald, isoc, 54.4 Phe-α, 44.7 C-1 isoc,
3
8.1 Phe β, [28.5, 26.9, 26.7, 26.2, 25.8, 25.6, 24.5, 24.2] CH -isop. HRMS (ESI-TOF) m/z:
3
+
[M+Na] Calcd. for C H N2O Na 815.3578; Found 815.3557.
39
56
15
(
3aS,3bR,7aS,8aR)-2-oxo-1-((3aR,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-
bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-3a-yl)-2-((((3aS,5aR,8aR,8bS)-2,2,7,7-
tetramethyltetrahydro-3aH-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-3a-yl)methyl)amino)ethyl
2
,2,5,5-tetramethyltetrahydro-3aH-[1,3]dioxolo[4',5':4,5]furo[3,2-d][1,3]dioxine-8a-
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5
5
5
5
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6
22
carboxylate (17): Yield = 39 % (31 mg); mp = 141-142 °C, R = 0.64 (PE:EtOAc 1:2, v/v); [α]
f
D
1
- 11.8 (c 0.846, CHCl ).. H NMR (600 MHz, CDCl )  6.79 NH (dd, J = 8.9, 2.8 Hz, 1H), 5.25
3
3
H-1 ald. (s, 1H), 4.93 H-3 GulA (s, 1H), 4.55 H-4 (m, 3H), 4.30 H-3 (d, J = 2.3 Hz, 1H), 4.19 (m,
H), 4.15 (d, J = 1.4 Hz, 1H), 4.05 H-1 isoc (m, 3H), 3.90 (ddd, J = 22.7, 12.9, 1.9 Hz, 2H), 3.74
dd, J = 41.1, 12.9 Hz, 2H), 3.21 H-1 isoc (dd, J = 14.2, 3.1 Hz, 1H), [1.58 (s, J = 12.3 Hz, 3H),
.55 (s, 3H), 1.50 (d, J = 1.7 Hz, 6H), 1.48 (s, 3H), 1.47 (s, 3H), 1.45 (d, J = 4.7 Hz, 6H), 1.40 (s,
3
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
3H), 1.39 (s, 3H), 1.35 (s, 3H), 1.31 (s, 3H), 1.26 (s, 3H)]CH -isop. C NMR{1H} (151 MHz, CDCl )
3
3

165.4 CO, 165.0 CO, 114.5 C-2 GulA, 110.4 Cq-isop, 109.5 Cq-isop, 109.47 Cq-isop, 108.9 Cq-
isop, 102.7 C-2 ald, 102.3 C-2 isoc, 97.7 Cq-isop GulA, 88.0 C-3 GulA, 74.4 C-1 ald, [74.1, 73.0,
7
1.2, 71.17, 71.0, 70.6, 70.5, 70.2] C-3, C-4, C-5, 62.1 C-6 ald, 62.0 C-6 isoc, 60.2 C-6 GulA,
4
4.9 C-1 isoc, [28.7, 27.2, 26.9, 26.8, 26.2, 26.0, 25.9, 25.8, 24.5, 24.3, 19.0] CH -isop. HRMS
3
+
(ESI-TOF) m/z: [M+Na] Calcd for C H NO Na 824.3317; Found 824.3322.
37
55
18
2-oxo-1-((3aS,3bR,7aS,8aR)-2,2,5,5-tetramethyltetrahydro-3aH-
[1,3]dioxolo[4',5':4,5]furo[3,2-d][1,3]dioxin-8a-yl)-2-((((3aS,5aR,8aR,8bS)-2,2,7,7-
tetramethyltetrahydro-3aH-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-3a-yl)methyl)amino)ethyl
benzoate (18): Yield 62 % (40 mg). DS1: Yield 5 % (3 mg); R = 0.6 (toluene:EtOAc 1:2). DS2: S
f
22
configuration, Yield 57 % (37 mg); mp = 191-197 °C; R = 0.57 (toluene:EtOAc 1:2); [α]
+ 28
f
D
1
(
c 1, CHCl ). Chemical shifts are given for DS2. H NMR (600 MHz, CDCl )  8.09 benz-γ (dd, J
3
3
= 8.2, 1.1 Hz, 2H), 7.55 benz-ε (dd, J = 10.6, 4.3 Hz, 1H), 7.42 benz-δ (t, J = 7.8 Hz, 2H), 6.85
NH (dd, J = 9.3, 2.9 Hz, 1H), 5.61 H-1 ald (s, 1H), 4.57 H-5 isoc (dd, J = 7.8, 2.8 Hz, 1H), 4.51
H-3 ald (s, 1H), 4.33 H-5 ald (d, J = 2.0 Hz, 1H), 4.23 H-1 isoc, H-3 isoc, H-4 ald (m, 3H), 4.19
H-4 isoc (dd, J = 7.8, 1.2 Hz, 1H), 4.07 H-6 ald (m, 2H), 3.90 H-6 isoc (dd, J = 12.9, 1.8 Hz, 1H),
3
.71 H-6 isoc (d, J = 12.9 Hz, 1H), 3.19 H-1 isoc (dd, J = 14.3, 3.3 Hz, 1H), [1.53 (s, 3H), 1.51 (d,
1
3
J = 2.9 Hz, 6H), 1.49 (s, 3H), 1.46 (s, 3H), 1.40 (s, 3H), 1.33 (s, 3H), 1.27 (s, 3H)] CH -isop. C
3
NMR{1H} (151 MHz, CDCl )  165.6 CO (amide), 165.4 CO (ester), 133.5 benz-ε, 130.3 benz-γ,
3
1
29.86 benz-β, 128.60 benz-δ, 114.03Cq-isop, 113.47 C-2 ald, 109.44 Cq-isop, 109.1 Cq-isop.,
1
02.8 C-2 isoc, 97.8 Cq-isop, 85.4 C-3 ald, 74.0 C-4 ald, 73.0 C-4 isoc, 72.7 C-1 ald, 71.1 C-4
isoc, 70.9 C-5 ald, 70.45 C-5 isoc, 61.91 C-6 isoc, 60.41 C-6 ald, 44.13 C-1 isoc, 29.1 CH -isop,
3
27.8 CH -isop, 27.0 CH -isop., 26.9 CH -isop, 26.1 CH -isop, 25.9 CH -isop, 24.2 CH -isop, 18.8
3
3
3
3
3
3
+
CH -isop. HRMS (ESI_TOF) m/z: [M+H] Calcd for C H NO 650.2813; Found 650.2789.
3
32 44
13
(3aS,3bR,7aS,8aR)-2-oxo-1-((3aS,3bR,7aS,8aR)-2,2,5,5-tetramethyltetrahydro-3aH-
[1,3]dioxolo[4',5':4,5]furo[3,2-d][1,3]dioxin-8a-yl)-2-((((3aS,5aR,8aR,8bS)-2,2,7,7-
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tetramethyltetrahydro-3aH-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-3a-yl)methyl)amino)ethyl
2,2,5,5-tetramethyltetrahydro-3aH-[1,3]dioxolo[4',5':4,5]furo[3,2-d][1,3]dioxine-8a-
22
carboxylate (19): Yield 31 % (25 mg), mp = 143-145 °C, R = 0.39 (PE:EtOAc 1:1, v/v); [α]
-
f
D
1
2.2 (c 0.9, CHCl ). H NMR (600 MHz, CDCl )  6.75 NH (d, J = 8.0 Hz, 1H), 5.42 H-1 ald (s, 1H),
3
3
4
.94 H-3 ald* (s, 1H), 4.59 H-3 GulA* (s, 1H), 4.56 (d, J = 7.7 Hz, 1H), 4.31 (s, 1H), 4.27 (s, 1H),
.18 (m, 5H), 4.13 H-1 isoc (m, 1H), 4.04 H-6 ald, GulA (s, 2H), 4.01 H-6 ald, GulA (d, J = 13.2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
Hz, 2H), 3.88 H-6 isoc (d, J = 12.9 Hz, 1H), 3.70 H-6 isoc (d, J = 12.9 Hz, 1H), 3.20 H-1 isoc (d,
13
J = 11.9 Hz, 1H), 1.70-1.30 CH -isop. (36H). C NMR{1H} (151 MHz, CDCl ) δ 165.3 CO, 164.7
3
3
CO, 114.5 C-2 GulA, 114.1 Cq-isop., 113.4 C-2 ald, 110.6 Cq-isop., 109.5 Cq-isop, 109.0 Cq-
isop, 102.8 C-2 isop, 97.7 Cq-isop, 97.7 Cq-isop, 88.0 C-3 ald, 85.4 C-3 GulA, 74.2, 74.1, 73.5
C-1 ald, [72.9, 72.6, 71.2, 71.1, 70.6] C-3, C-4, C-5, 62.0 C-6 isoc, 60.4 C-6 ald, 60.2 C-6 GulA,
4
4.5 C-1 isoc, 29.0 CH -isop, 28.7 CH isop, 27.9 CH -isop, 27.3 CH -isop, 26.9 CH -isop, 26.8
3 3- 3 3 3
CH -isop, 26.2 CH -isop, 26.2 CH -isop, 25.9 CH isop, 24.4 CH -isop, 19.0 CH -isop., 18.9 CH -
3
3
3
3-
3
3
3
+
isop. HRMS (ESI-TOF) m/z: [M+Na] Calcd for C H NO Na 824.3317; Found 824.3303.2-oxo-
37
55
18
1
-((3aS,3bR,7aS,8aR)-2,2,5,5-tetramethyltetrahydro-8aH-[1,3]dioxolo[4',5':4,5]furo[3,2-
d][1,3]dioxin-8a-yl)-2-((((3aS,3bR,7aS,8aS)-2,2,5,5-tetramethyltetrahydro-8aH-
1,3]dioxolo[4',5':4,5]furo[3,2-d][1,3]dioxin-8a-yl)methyl)amino)ethyl benzoate (20): Yield 66
[
%
%
(43 mg). DS1: Yield 8 % (5 mg), R = 0.48 (PE:EtOAc 1:1, v/v). DS2: S configuration; Yield 58
f
22
f
(38 mg), mp = 205-206 ºC; R = 0.3 (PE:EtOAc 1:1, v/v); [α]D
+ 25 (c 1 CHCl ). Chemical
3
1
shifts are given for DS2. H NMR (600 MHz, CDCl ) δ 8.10 benz. (d, J = 8.3 Hz, 2H), 7.55 benz.
3
(t, J = 7.5 Hz, 1H), 7.42 benz. (t, J = 7.8 Hz, 2H), 6.79 NH (d, J = 6.2 Hz, 1H), 5.63 H-1 ald. (s,
1
4
1
H), 4.53 H-3 (s, 1H), 4.39 H- 3 (s, 1H), 4.34 – 4.32 H-1 isoc., H-5 (m, 1H), 4.27 H-4 (m, 1H),
.24 H-4 (m, 1H), 4.12 – 3.94 H-6, H-5 (m, 1H), 3.35 H-1 isoc. (dd, J = 14.4, 3.4 Hz, 1H), 1.57-
13
.34 (24H) CH -isop. C NMR{1H} (151 MHz, CDCl ) δ 165.4 CO, 165.3 CO, 133.4 benz., 130.3
3
3
benz., 130.0 benz, 128.6 benz, 114.3 C-2 isoc., 114.0 Cq-isop., 113.6 C-2 ald, 112.6 Cq isop,
97.8 Cq-isop., 97.7 Cq-isop, 85.6 C-3, 84.6 C-3, 74.1 C-4, 73.5 C-4, 73.1 C-1 ald, 72.9 C-5, 72.8
C-5, 60.6 C-6, 60.5 C-6, 42.2 C-1 isoc. (29.1, 29.1, 28.0, 27.9, 27.2, 27.1, 18.9, 18.8) CH -isop.
3
+
HRMS (ESI-TOF) m/z: [M+Na] Calcd for C H NO Na 672.2632; Found 672.2648.
32
43
13
2-oxo-1-((3aS,3bR,7aS,8aR)-2,2,5,5-tetramethyltetrahydro-8aH-
[1,3]dioxolo[4',5':4,5]furo[3,2-d][1,3]dioxin-8a-yl)-2-((((3aS,3bR,7aS,8aS)-2,2,5,5-
tetramethyltetrahydro-8aH-[1,3]dioxolo[4',5':4,5]furo[3,2-d][1,3]dioxin-8a-
yl)methyl)amino)ethyl (tert-butoxycarbonyl)phenylalaninate (21): Yield 70 %. DS1: Yield
29
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