A Glucose-Derived α-Hydroxy Aldehyde for the Petasis Reaction: Facile Access to Polyfunctional δ-Amino Acids

Article abstract of DOI:10.1002/ejoc.202000600

The multicomponent Petasis borono-Mannich reaction proceeds via an imine with the boronic acid acting as the nucleophile for the preparation of amines and their derivatives, including amino acids. In view of the expansion of the poorly-exploited carbohydr

Full text of DOI:10.1002/ejoc.202000600

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: A glucose-derived α-hydroxy aldehyde for the Petasis reaction:
facile access to polyfunctional δ-amino acids
Authors: Elena Lenci, Raffaele Bellini Puglielli, Elisabetta Bucaletti,
Riccardo Innocenti, and Andrea Trabocchi
This manuscript has been accepted after peer review and appears as an
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000600
Link to VoR: https://doi.org/10.1002/ejoc.202000600
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1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202000600
FULL PAPER
A glucose-derived α-hydroxy aldehyde for the Petasis reaction:
facile access to polyfunctional δ-amino acids
Elena Lenci,*[a] Raffaele Bellini Puglielli,[a] Elisabetta Bucaletti,[a] Riccardo Innocenti,[a] and Andrea
Trabocchi*[a],[b]
[
a]
Department of Chemistry “Ugo Schiff”,
University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy.
E-mail: andrea.trabocchi@unifi.it; elena.lenci@unifi.it:
[
b]
Interdepartmental Center for Preclinical Development of Molecular Imaging (CISPIM),
University of Florence, Viale Morgagni 85, 50134 Florence, Italy.
Supporting information for this article is given via a link at the end of the document.
Abstract: The multicomponent Petasis borono-Mannich reaction
proceeds via an imine with the boronic acid acting as the nucleophile
for the preparation of amines and their derivatives, including amino
acids. In view of expanding the poorly-exploited carbohydrate
chemistry using this reaction, a new α-hydroxy aldehyde moiety from
the terminal diol of D-glucose diacetonide was synthesized and
applied to this multicomponent reaction, demonstrating the scope of
this method and the applicability to the convenient preparation of a
protected polyfunctional δ-amino acid in only three synthetic steps
from the Petasis reaction intermediate.
To develop a short and versatile synthetic strategy, a key
intermediate, the α-D-glucodialdofuranose, was studied as a new
interesting substrate for the Petasis reaction (Scheme 1). Such
building block allows for the stereoselective functionalization of
the C-6 carbon atom with two novel substituents. Hexose
monosaccarides16 have proven to be useful intermediates for
accessing complex biologically active molecules, and their
construction still represent a challenge in modern organic
chemistry, especially for installing a stereogenic carbon atom in a
stereocontrolled manner.17
Introduction
The Petasis borono–Mannich reaction, or Petasis reaction, is a
powerful approach for the synthesis of highly functionalized
amines, by combination of aldehydes, amines and boronic acids.1
This multicomponent reaction has proven to be very useful as a
2
starting point in Diversity-Oriented Synthesis, and its exploitation
3
in Build/Couple/Pair strategies has shown interesting properties
for the generation of both stereochemical and skeletal diversity.4
Despite some contributions on the application of carbohydrates or
their derivatives in DOS have appeared in the literature recently,5
there are no examples of DOS strategies that combine the Petasis
reaction with hexoses as building blocks. In fact, the Petasis
reaction starting from carbohydrates has been used mainly in the
total synthesis of natural products, including conduramine,6
Scheme 1. Synthetic approach involving the D-glucodialdofuranose for the
Petasis reaction.
pyrrolidine alkaloids,7 calystegine B4,8 and hyacinthacine C
.9
5
However, there is still room left for the exploitation of this
multicomponent reaction with carbohydrates, especially for the
construction of high quality chemical libraries following DOS
principles. Carbohydrates are interesting building blocks for this
purpose, for their intrinsic stereochemical diversity, structural bias,
and polyfunctional opportunities, as well as for their capability to
cross biological membranes and selectivity for a wide number of
targets.10
As our previous contribution to DOS consisted of the generation
of amino acid derivatives,11 we reasoned to exploit the
Herein, we disclose
a novel methodology for the C-6
functionalization of glucose, by the application of the Petasis
reaction to protected α-D-glucodialdofuranose. Thus, a new
protocol for accessing chemoselectively the α-hydroxy aldehyde
moiety from the terminal diol of the glucose diacetonide was
investigated, considering that the only procedure reported in the
literature requires inconvenient reagents, such as MeI, NaBH
4
1
8
2 2
and HgCl -H 0. The α-hydroxy aldehyde was then applied to the
Petasis reaction, confirming the versatility and the scope of this
method by using different amines and boronic acids, and finally
demonstrating the achievement of a polyfunctional protected δ-
amino acid starting from one coupling intermediate in only three
combination of the Petasis reaction with sugar derivatives to
expand the panorama of polyhydroxylated nitrogen-containing
peptidomimetics.12 In particular, we focused the attention to δ-
amino acids, as they represent powerful dipeptide isosteres used
for the synthesis of several protease inhibitors,13 including
neurotoxin B metalloprotease,14 and HIV-protease.15
synthetic steps (Scheme 1)
.
1
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European Journal of Organic Chemistry
10.1002/ejoc.202000600
FULL PAPER
Results and Discussion
With the D-glucodialdofuranose 3 in hands, we moved our study
to the optimization of the Petasis reaction conditions, using this
aldehyde in combination with dibenzylamine and styrylboronic
acid, as reference reactants (Table 2).
The synthesis of the benzylated 1,2-O-isopropylidene-D-
glucodialdofuranose 3 was studied as a model system starting
from the corresponding diol 2, obtained from glucose diacetonide
(
1) following a reported procedure (Table 1).19 For the oxidation
Table 2. Optimization of the Petasis reaction conditions using α-hydroxy
aldehyde 3, dibenzylamine and trans-styrylboronic acid.
of the vicinal diol to the α-hydroxy aldehyde moiety a protocol
developed by Porcheddu and coworkers was initially applied,20
involving trichloroisocyanuric acid (TCICA) as the oxidant and
2
,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) as a catalyst,
which allowed for the chemoselective oxidation of the primary
alcohol in the presence of a secondary one, when the mixture was
kept reacting at 0 °C for 15 minutes. However, with these reaction
conditions (Table 1, entry 1), a low conversion was observed, as
calculated by the ratio of the integrals of the 1H NMR peaks
corresponding to the anomeric proton of compound 2 (that
appears as a doublet at 5.94 ppm) and 3 (that appears as a
doublet at 6.00 ppm) (see Figure S1 in Supporting Information).
Upon increasing the reaction time and the temperature (entries 2
and 3, respectively) such conditions proved to be even
detrimental, as no aldehyde 3 was observed. As a major issue
was attributed to the low solubility of the starting material 2 in
dichloromethane (DCM), more polar solvents were screened in
this reaction, without obtaining successful results neither with
Entry[a]
Solvent
Time
16 h
16 h
16 h
16 h
16 h
16 h
16 h
2 h
Temperature (°C)
25 °C
Yield
39%
36%
42%
27%
48%
60%
72%
22%
1
2
3
4
5
6
7
8
EtOH
EtOH/HFIP 4:1
DCM/HFIP 4:1
THF/MeOH 4:1
EtOH
25 °C
25 °C
70 °C
40 °C
EtOH
80 °C
3
THF, nor with CH CN (entries 4 and 5, respectively). On the other
EtOH/H
EtOH/H
2
O 4:1
80 °C
hand, an increase in the reaction conversion was observed when
using dry DCM and an inert atmosphere (43%, entry 6), as these
features promoted higher chemoselectivity of the TCICA reagent,
which is known to give a hypochlorite ion in the presence of water,
thus oxidizing the aldehyde species to the corresponding
2
O 4:1
80 °C
[a] All the reactions were performed using 3, obtained by the in situ oxidation of
2 (1 eq.), dibenzylamine (1 eq.), styrylboronic acid (1 eq.), solvent (1 mL/mmol),
at the indicated temperature and time. In all cases the Petasis reaction
proceeded forming exclusively the anti products in greater than 99% de.
2
1
carboxylic acid. By increasing the dilution of the starting material
tenfold (i.e. from 2.5 mL/mmol to 25 mL/mmol) a significant
increase in the conversion was obtained (77%, entry 7). Finally,
complete disappearance of the starting material was obtained by
increasing slightly the reaction time (30 minutes) and lowering the
amount of catalytic TCICA from 0.1 to 0.05 equivalents (100%
conversion, entry 8). After acid-base work-up, compound 3 was
isolated in 93% yield, and sufficiently pure to be used directly in
the following step.
As compound 3 proved to be rather unstable, even for a short
period of time after being isolated, we decided to perform the
oxidation and the subsequent Petasis reaction in a two-step one-
pot procedure. When using EtOH, as a widely reported solvent for
the Petasis reaction, compound 4 was obtained only in 39% yield
(Table 2, entry 1).
Table 1. Synthesis of diol 2 and optimization of the reaction conditions for its oxidation to the corresponding α-hydroxy aldehyde 3
Conversion[a]
isolated yield)
Concentration
Time
(min)
15
Temperature
(°C)
TCICA
(eq)
TEMPO
(eq)
0.1
Entry
Solvent
(
(mL/mmol)
1
2
3
4
5
6
7
DCM
DCM
DCM
THF
2.5
0 °C
1.05
1.05
1.05
1.05
1.05
1.05
1.05
20%
0%
2.5
150
15
0 °C
0.1
2.5
25 °C
0 °C
0.1
0%
2.5
30
0.1
0%
CH
3
CN
2.5
120
15
0 °C
0.1
22%
43%
77%
DCM dry
DCM dry
2.5
0 °C
0.1
25
15
0 °C
0.1
1
00%
8
DCM dry
25
30
0 °C
1.05
0.05
(93%)
1
[
a] Calculated by the ratio of the integrals of the H NMR peaks corresponding to the C-H anomeric proton of compounds 2 and 3 (Figure S1, Supporting Information)
2
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European Journal of Organic Chemistry
10.1002/ejoc.202000600
FULL PAPER
The addition of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), as a
more interactive solvent for stabilizing the polar intermediate,22
did not show a significant improvement of the overall yield (entry
most reactive, as compound 14 was obtained in 55% yield.
Similarly, boronic acid containing electron-rich aromatic rings
gave good results (see compound 17, 52%), whereas lower
conversions were observed with 2-naphthylboronic acid and 1-
pentynylboronic acid pinacol ester (37% and 29%, respectively).
On the other hand, the reaction seemed not tolerating the
presence of heteroaromatic rings, as the reaction with thienyl
boronic acid gave no results. Finally, the versatility of the Petasis
reaction was studied also referring to different functional groups
on the sugar scaffold. Thus, the oxidation protocol was applied to
2
). A comparable result was obtained replacing EtOH with a polar
aprotic solvent, such as DCM (entry 3). The use of THF-MeOH as
a different solvent mixture showed low conversion despite the
temperature at 70 °C (entry 4). The use of EtOH proved beneficial,
and the temperature affected significantly the conversion,
resulting in 48% yield at 40 °C (entry 5) and 60% yield at 80 °C
(
entry 6). The application of 4:1 EtOH-water solvent mixture23
2
5
additionally increased the yield, thus providing the best reaction
conditions for this protocol (72%, entry 7). However, this addition
did not allow us to decrease the reaction time, as the same
reaction performed in 2 h instead of 16 h gave compound 4 in only
3-(O-tosyl)-1,2-O-isopropylidine-D-glucofuranose
azido-1,2-O-isopropylidine-D-glucofuranose
6,26
5
and 3-
and the
corresponding α-hydroxy aldehydes were left reacting with styryl
boronic acid and dibenzylamine. Compounds 19-21 were
obtained with similar yields (57%, 42%, 45%, respectively) as
those observed for compounds 4 and 7, thus confirming the
general versatility of this protocol for different functional groups
on the sugar ring. The slightly lower yields can be attributed to the
lower conversion in the oxidation step, especially in the case of
the azido derivative (91% conversion for 5 and 70% conversion
for 6). In all cases the Petasis reaction proceeded with a very high
degree of diastereocontrol, forming exclusively the anti products
in greater than 99% de. This is in agreement with what reported
in the literature,27 as the Petasis reaction performed on chiral α-
hydroxy aldehydes gives preferentially the anti diastereomer, in
order to minimize the steric strain in the zwitterionic ate complex
intermediate.
2
2% yield (entry 8). Then, to study the scope of the Petasis
reaction, the amine component was initially varied (Table 3). This
screening showed that secondary amines gave higher yield, as
compared to the corresponding primary amines (51% yield of
compound 7, as compared to 72% of 4), in agreement to what
reported in the literature.24 The steric hindrance played a
contributing factor to the success of the reaction, as the use of
diethylamine and pyrrolidine allowed to obtain the corresponding
products 8 and 9 (in 35% and 47% yield, respectively), whereas
no reaction was observed with more hindered analogues, such as
diisopropylamine and piperidine. Nucleophilic aromatic amines
were found to be unreactive, although N-methyl p-anisidine gave
compound 11 in 39% yield. Then, we tested the tolerance of
different boronic acids, confirming that vinyl boronic acids are the
Table 3. Scope of the oxidation-Petasis protocol.[a]
[
a] Reagents and conditions: (1) sugar (1 eq.), TCICA (1.05 eq.), TEMPO (0.05 eq.), DCM (25 mL/mmol), 0 °C, 30 min; (2) aldehyde (1 eq.), amine (1 eq.), boronic
acid (1 eq.), EtOH/H O 4:1 (1 mL/mmol), 80 °C, 16 h. In all cases the Petasis reaction proceeded forming exclusively the anti products in greater than 99% de. [b]
2
In this case, commercially available 1-pentynylboronic acid pinacol ester was used in place of the boronic acid.
3
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European Journal of Organic Chemistry
10.1002/ejoc.202000600
FULL PAPER
The putative mechanism involves the formation of a zwitterionic
iminium boronate, followed by the intramolecular transfer of the
nucleophilic organic group to the iminium carbon atom. When
using chiral α-hydroxy aldehydes, the anti diastereoselectivity has
been rationalized by considering a reactive conformation that
minimizes the allylic strain in the iminium boronate intermediate
Then, after quantitative deprotection of the isopropylidene moiety
using a mixture of TFA-water (3:2), the oxidative cleavage with
sodium metaperiodate in acetone–water allowed to obtain the
aldehyde 23.29 This unstable intermediate was immediately
treated with sodium chlorite and 30%
corresponding carboxylic acid, that was in situ protected at the
developing carboxylic acid group by reaction with SOCl in MeOH
2 2
H O to form the
(
Figure 1). The stereochemistry of the newly formed stereocenter
2
was established by analyzing the values of the 3J coupling
constants between the protons H-5 and H-6 of compound 21, and
comparing them with those of a similar compound reported in the
to provide the corresponding methyl ester 24. The fully protected
polyfunctional δ-amino acid 24 was thus obtained in 48% from the
intermediate 22 over two synthetic steps.
2
8
literature (see Figures S2 e S3, Supporting Information).
Conclusion
Herein we reported the introduction of a novel α-hydroxy aldehyde
deriving from 1,2-O-isopropylidene D-glucoaldofuranose as a
convenient and useful building block for the stereoselective
synthesis of glucose-derived amines using the multicomponent
Petasis reaction.
The α-hydroxy aldehyde D-glucodialdofuranose was conveniently
achieved by chemoselective oxidation of the terminal deprotected
diol of 1,2-O-isopropylidene D-glucoaldofuranose using TCICA /
TEMPO oxidation system. The optimization of the oxidation
reaction conditions allowed for the application of this carbonyl
species to the Petasis reaction with a range of amines and boronic
acids, and showing the stereoselective outcome of the reaction
taking advantage of the sugar chiral environment. The synthetic
utility of the Petasis products was exemplified in the synthesis of
a protected polyfunctional δ-amino acid from the coupling adduct
resulting from the Petasis reaction in only three synthetic steps.
Figure 1. The anti diastereoselectivity of the Petasis reaction using chiral α-
hydroxy aldehydes can be explained by considering the existence of
a
conformation that minimizes the allylic strain in the iminium boronate
intermediate.
Finally, to prove the synthetic utility of the coupling product for the Experimental Section
synthesis of polyfunctional δ-amino acids, compound 7 was
subjected to follow-up chemistry (Scheme 2). In particular, the
hydroxyl and amine group were simultaneously protected by
forming the corresponding cis-oxazolidinone 22 using Boc O and
2
triethylamine (62% yield),6 further confirming the anti
General. 1H NMR and C NMR spectra were recorded on a Varian
13
1
13
1
Mercury 400 ( H: 400 MHz, C: 100 MHz), or a Varian Gemini 200 ( H:
00 MHz, 13C: 50 MHz). The chemical shifts (δ) and coupling constants (J)
2
are expressed in parts per million (ppm) and hertz (Hz), respectively. Flash
column chromatography (FCC) purifications were performed manually
using glass columns with Merck silica gel (0.040–0.063 mm), or using the
Biotage Isolera system and SNAP silica cartridges. TLC analyses were
performed on Merck silica gel 60 F254 plates. Elemental analyses were
performed on a Perkin Elmer 240 C, H, N analyzer. ESI mass spectra were
recorded on a Thermo LCQ-Fleet ion-trap double quadrupole mass
stereoselectivity of the Petasis reaction.
+
spectrometer using electrospray (ES ) ionization techniques. Microwave
reactions were carried out on an automated single-mode microwave
synthesizer (InitiatorTM Sixty, Biotage AB) using sealed reaction vessels
and built-in internal pressure and temperature sensors. Optical rotations
were measured with JASCO DIP-360 digital polarimeter. All commercially
available reagents and solvents were used as received, unless otherwise
specified.
(
[
R)-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro-
2,3-d][1,3]dioxol-5-yl)ethane-1,2-diol (2). Compound 2 was prepared
19
following a procedure reported in the literature. D- glucose diacetonide 1
8.30 g, 26.90 mmol) was dissolved in dry THF (80 mL) under a nitrogen
(
atmosphere, the temperature was kept to 0 °C with an ice bath, NaH (60%
in mineral oil) (1.55 g, 38.53 mmol) was added portionwise and the
reaction mixture was left stirring for 30 minutes. Benzyl bromide (4.00 mL,
33.64 mmol) was added dropwise over 15 minutes, the temperature was
left reaching 25 °C and the reaction mixture was left reacting overnight.
Then, water was added (200 mL), the aqueous phase was extracted with
ethyl acetate (3 x 100mL), and the combined organic phases were washed
Scheme 2. Synthesis of protected δ-amino acid 24 from compound 7. Reagents
and conditions: i) DMAP (1 eq.), Boc
r. t., 16 h; ii) TFA/H O 3:2 (10 mL/mmol), r. t., 16 h, then NaIO
20 mL/mmol), r. t., 25 min; iii) NaClO (1.6 eq.), NaH PO (0.3 eq.), H
1 eq.), CH CN (20 mL/mmol), r. t., 10 h, then SOCl (3 eq.), MeOH (20
2
O (1.5 eq.), Et
3
N (3 eq.), THF (5 mL/mmol),
(1.5 eq.), CH CN
(30 %)
2
4
3
(
(
2
2
4
2 2
O
3
2
mL/mmol), reflux, 2 h.
2 4
with brine (1 x 100 mL), dried over Na SO , filtered and concentrated under
4
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European Journal of Organic Chemistry
10.1002/ejoc.202000600
FULL PAPER
reduced pressure. The crude obtained was dissolved in MeOH (26.90 mL),
aqueous acetic acid (66%, 50 mL) was added and the reaction mixture
was left refluxing at 60 °C for 1 h. Then, the mixture was allowed to reach
General procedure for synthesis of compounds 4, 7-21. In a dry round
bottom flask compound 2, 5 or 6 (1 eq) was dissolved in freshly distilled
dry DCM (25 mL/mmol), then TEMPO (0.05 eq.) and TCICA (1.05 eq.)
were added successively at 0 °C in a ice bath. The reaction mixture was
left stirring at 0 °C for 30 minutes, then it was filtered over Celite, washed
room temperature, a saturated solution of NaHCO
resulting mixture was extracted with ethyl ether (3 x 60 mL). The combined
organic phases were washed with brine (1 x 50 mL), dried over Na SO
3
was added and the
2
4
,
with a saturated solution of NaHCO
and concentrated under reduced pressure. The crude α-hydroxy aldehyde
was then dissolved in EtOH/H O 4:1 (1M), and the amine component (1
3 2 4
and brine, dried over Na SO , filtered
filtered and concentrated under reduced pressure to give the title
compound 2 in 75% yield (6.25 g). Spectroscopic data were in agreement
with literature values.
2
eq.) was added. The resulting mixture was left stirring at room temperature
for 10 minutes, then the boronic acid (1 eq.) was added, the temperature
was raised to 80 °C and left refluxing overnight. After cooling to room
temperature, the solvent was evaporated, and the residue was purified by
flash column chromatography to give the title product.
(
[
S)-2-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro-
2,3-d][1,3]dioxol-5-yl)-2-hydroxyacetaldehyde (3). In dry round
a
bottom flask, compound 2 (300 mg, 0.97 mmol) was dissolved in freshly
distilled dry DCM (24.50 mL) at 0 °C in a ice bath, successively TEMPO (8
mg, 0.05 mmol) and TCICA (236 mg, 1.02 mmol) were added and the
resulting mixture was left stirring at 0 °C for 30 minutes. Successively, the
mixture was filtered over Celite, washed with a saturated solution of
(1R,2R,E)-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-2-(dibenzylamino)-4-phenylbut-
3-en-1-ol (4). According to the general procedure, compound 4 was
obtained as a brown oil in 72% yield (414 mg) using compound 2 (300 mg,
0.97 mmol), TEMPO (8 mg, 0.05 mmol), TCICA (236 mg, 1.02 mmol),
dibenzylamine (103 µL, 0.97 mmol) and trans-2-phenylvinylboronic acid
(144 mg, 0.97 mmol), after flash chromatography on silica gel (Petr
3 2 4
NaHCO and brine, dried over Na SO , filtered and concentrated under
reduced pressure to obtain the aldehyde 3 in 93% yield (277 mg), that was
not purified due to instability, but enough pure to be used in the next step
1
as obtained. H NMR (200 MHz, CDCl
3
) δ ppm = 9.92 (s, 1H), 7.39-7.32
22
3 3
Et/EtOAc 3:2). [α]퐷 = -37.5 (c 1.0, CHCl ) δ
). 1H NMR (400 MHz, CDCl
(
4
m, 5H), 6.00 (d, J = 3.7 Hz, 1H), 4.71 - 4.61 (m, 3H), 4.67 - 4.52 (m, 2H),
.25 - 4.16 (m, 2H), 1.47 (s, 3H), 1.33 (s, 3H). 13C NMR (100 MHz, CDCl
ppm = 7.47 – 7.45 (m, 2H), 7.38 – 7.27 (m, 16H), 7.15 – 7.13 (m, 2H), 6.53
(d, J = 15.6 Hz, 1H), 6.43 – 6.37 (dd, J = 16.0, 9.6 Hz, 1H), 5.99 (d, J = 4.0
Hz, 1H), 4.54 – 4.51 (m, 1H), 4.49 (d, J = 4.0 Hz, 1H), 4.38 – 4.32 (m, 2H),
3
)
δ ppm = 202.9, 137.0, 128.6 (2C), 128.2, 127.9 (2C), 112.2, 105.6, 82.3,
1.8, 81.0, 74.5, 72.7, 26.8, 26.3.
8
3
2
.93 (d, J = 12.4 Hz, 3H), 3.73 (d, J = 3.2 Hz, 1H), 3.48 (d, J = 13.6 Hz,
H), 3.35 (t, J = 8.0 Hz, 1H), 1.46 (s, 3H), 1.32 (s, 3H). 13C NMR (100 MHz,
(
3aR,5R,6S,6aR)-5-((R)-1,2-dihydroxyethyl)-2,2-dimethyltetra-
CDCl
3
) δ ppm = 139.7, 136.9, 136.8, 135.6, 129.2 (4C), 128.5 (4C), 128.5
hydrofuro[2,3-d][1,3]dioxol-6-yl 4-methylbenzenesulfonate
(5).
(
2C), 128.5 (3C), 128.1, 127.7 (2C), 127.6, 127.1 (2C), 126.6 (2C), 125.1,
Compound 5 was prepared following a procedure reported in the
literature.25 D-glucose diacetonide 1 (1.30 g, 5.00 mmol) was dissolved in
dry pyridine (5 mL) at 0 °C, in a ice bath, and p-toluenesulfonyl chloride
111.5, 104.7, 83.6, 82.0, 79.1, 72.0, 70.5, 65.1, 54.9 (2C), 26.7, 26.4. MS
+
(ESI) m/z (%): 591.95 (100, [M+H] ). Anal. Calcd. for C38
H
5
41NO : C, 77.13;
H, 6.98; N, 2.37. Found: C, 77.32; H, 7.01; N, 2.29.
(1.63 g, 9.99 mmol) was added dropwise. The resulting suspension was
left stirring for 20 h at room temperature. The reaction mixture was then
poured into ice-water, the precipitate was filtered, washed with cold water
and concentrated under reduced pressure. The obtained crude was
dissolved in MeOH (5 mL), aqueous acetic acid (66%, 10 mL) was added
and the reaction mixture was left reacting at 60 °C for 1 h. Then, the
mixture was allowed to reach room temperature, a saturated solution of
(1R,2R,E)-2-(benzylamino)-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-4-phenyl-but-3-en-1-ol
(7). According to the general procedure, compound 7 was obtained as a
brown oil in 51% yield (250 mg) from compound 2 (300 mg, 0.97 mmol),
TEMPO (8 mg, 0.05 mmol), TCICA (236 mg, 1.02 mmol), benzylamine
(187 µL, 0.97 mmol) and trans-2-phenylvinylboronic acid (144 mg, 0.97
NaHCO
ether (3 x 60 mL). The combined organic phases were washed with brine
1 x 50 mL), dried over Na SO , filtered and concentrated under reduced
pressure. The crude compound was purified by flash chromatography
Et.Pet/Et O 3:1) to give the title compound 5 in 78% yield (1.4 g).
Spectroscopic data were in agreement with literature values.
3
was added and the resulting mixture was extracted with ethyl
22
mmol), after flash chromatography on silica gel (Petr Et/EtOAc 2:1). [α]
=
퐷
1
(
2
4
-24.3 (c 1.0, CHCl
3
). H NMR (400 MHz, CDCl
3
) δ ppm = 7.39 – 7.36 (m,
2H), 7.32 – 7.27 (m, 11H), 7.24 – 7.21 (m, 2H), 6.63 (d, J = 16.0 Hz, 1H),
6.20 (dd, J = 16.4, 9.2 Hz, 1H), 5.91 (d, J = 4.0 Hz, 1H), 4.71 – 4.64 (m,
1H), 4.56 – 4.52 (m, 2H), 4.14 (dd, J = 8.4, 2.8 Hz, 1H), 4.10 (d, J = 2.8
Hz, 1H), 4.08 – 4.05(m, 1H), 3.89 (d, J = 13.2 Hz, 1H), 3.75 (d, J = 13.2
Hz, 1H), 3.56 (dd, J = 9.2, 2.8 Hz, 1H), 1.85 (br s, 1H), 1.27 (s, 6H). 13C
(
2
(
R)-1-((3aR,5S,6S,6aR)-6-azido-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxol-5-yl)ethane-1,2-diol (6). Compound was prepared
following a procedure reported in the literature. D-glucose diacetonide 1
1.60 g, 6.14 mmol) was dissolved in dry DCM (18.2 mL) at -30 °C, and
pyridine (0.98 mL, 12.9 mmol) and Tf O were subsequently added
NMR (50 MHz, CDCl
3
) δ ppm = 137.5, 136.7, 134.3, 128.6 (2C), 128.5
6
26
(2C), 128.4 (2C), 128.3 (2C), 128.0, 127.8 (2C), 127.6, 127.2, 126.5 (2C),
1
11.9, 105.1, 82.2, 81.9, 80.0, 72.3, 69.8, 62.5, 51.0, 26.8, 26.5. MS (ESI)
(
+
m/z (%): 501.95 (100, [M+H] ). Anal. Calcd. for C31
H
5
35NO : C, 74.23; H,
2
7.03; N, 2.79. Found: C, 74.39; H, 7.08; N, 2.70.
dropwise. The resulting mixture was left reacting at -30 °C for 20 minutes,
then it was quenched with MeOH, diluted in DCM and washed with water.
The organic phase was dried over Na
under reduced pressure. The obtained crude was dissolved in DMF (13
mL), NaN (1.6 g, 24.58 mmol) was added, and the mixture was left stirring
at 50 °C overnight. The mixture was then diluted with Et O, washed three
times with water, dried over Na SO , filtered and concentrated under
reduced pressure. Finally, the crude was dissolved in MeOH (5 mL),
aqueous acetic acid (66%, 10 mL) was added and the reaction mixture
was left reacting at 60 °C for 1 h. Then, the mixture was allowed to reach
2
SO
4
, filtered and concentrated
(1R,2R,E)-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetra-
hydrofuro[2,3-d][1,3]dioxol-5-yl)-2-(diethylamino)-4-phenyl-but-3-en-
1-ol (8). According to the general procedure, compound 8 was obtained
as a brown oil in 35% yield (116 mg) from compound 2 (220 mg, 0.71
mmol), TEMPO (5 mg, 0.03 mmol), TCICA (172 mg, 0.75 mmol),
diethylamine (75 μL, 0.71 mmol) and trans-2-phenylvinylboronic acid (106
mg, 0.71 mmol), after flash chromatography on silica gel (DCM/MeOH
3
2
2
4
22
1
3 3
20:1). [α]퐷 = -16.4 (c 1.0, CHCl ). H NMR (400 MHz, CDCl ) δ ppm = 7.41
room temperature, a saturated solution of NaHCO
resulting mixture was extracted with ethyl ether (3 x 60 mL). The combined
4
organic phases were washed with brine (1 x 50 mL), dried over Na SO ,
filtered and concentrated under reduced pressure. The crude compound
was purified by flash chromatography (DCM/MeOH 30:1) to give the title
compound 6 in 85% yield (1.28 g). Spectroscopic data were in agreement
with literature values.
3
was added and the
– 7.23 (m, 10H), 6.68 (d, J = 16.4 Hz, 1H), 6.42 (dd, J = 16.0, 9.6 Hz, 1H),
5.87 (d, J = 3.6 Hz, 1H), 4.68 (s, 2H), 4.52 (d, J = 3.6 Hz, 1H), 4.47 (dd, J
= 9.2, 1.6 Hz, 1H), 4.09 (d, J = 2.8 Hz, 1H), 4.02 (dd, J = 9.2, 2.8 Hz, 1H),
3.70 (dd, J = 10.0, 1.2 Hz, 1H), 3.18 – 3.04 (m, 2H), 3.01 – 2.93 (m, 2H),
1.24 (s, 3H), 1.21 (t, J = 7.2 Hz, 6H), 1.17(s, 3H). 13C NMR (50 MHz,
2
CDCl
(2C), 127.9, 126.7 (2C), 121.2, 112.1, 105.0, 82.5, 81.2, 79.7, 72.9, 68.3,
6.3, 44.1 (2C), 26.7, 26.6, 9.8 (2C). MS (ESI) m/z (%): 468.01 (100,
3
) δ ppm = 137.5, 137.0, 135.6, 128.6 (2C), 128.5 (2C), 128.3, 128.1
6
5
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000600
FULL PAPER
+
[
7
M+H] ). Anal. Calcd. for C28
H
5
37NO : C, 71.92; H, 7.98; N, 3.00. Found: C,
– 7.27 (m, 10H), 7.24 – 7.20 (m, 3H), 7.11 – 7.08 (m, 2H), 5.95 (d, J = 4.0
Hz, 1H), 5.64 – 5.53 (m, 2H), 4.54 – 4.51 (m, 1H), 4.44 (d, J = 4.0 Hz, 1H),
2.10; H, 7.99; N, 2.95.
4
.24 (d, J = 11.2 Hz, 2H), 3.83 – 3.78 (m, 3H), 3.63 (d, J = 3.2 Hz, 1H),
.35 (d, J = 13.6 Hz, 2H), 3.13 (t, J = 8.4 Hz, 1H), 2.17 – 2.12 (m, 2H), 1.51
3
(
1S,2R,E)-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetra-
(
s, 6H), 1.31 (s, 3H), 0.98 (t, J = 7.6 Hz, 3H).13C NMR (100 MHz, CDCl
)
3
hydrofuro[2,3-d][1,3]dioxol-5-yl)-4-phenyl-2-(pyrrolidin-1-yl)-but-3-
en-1-ol (9). According to the general procedure, compound 9 was obtained
as a brown oil in 47% yield (200 mg) from compound 2 (280 mg, 0.91
mmol), TEMPO (7 mg, 0.05 mmol), TCICA (221 mg, 0.95 mmol),
pyrrolidine (75 μL, 0.91 mmol) and trans-2-phenylvinylboronic acid (135
mg, 0.91 mmol), after flash chromatography on silica gel (DCM/MeOH
δ ppm = 139.9 (2C), 137.4, 136.9, 129.2 (4C), 128.5 (4C), 128.4 (2C),
1
7
5
2
28.0, 127.7 (2C), 127.0 (2C), 124.5, 111.3, 104.7, 83.7, 82.0, 79.0, 72.0,
0.4, 64.6, 54.6 (2C), 34.8, 26.7, 26.3, 22.7, 13.8. MS (ESI) m/z (%):
+
80.17 (100, [M+Na] ). Anal. Calcd. for C35
5
H43NO : C, 75.37; H, 7.77; N,
.51. Found: C, 75.49; H, 7.70; N, 2.46.
22
). 1H NMR (400 MHz, CDCl
2
0:1). [α] = -21.5 (c 1.0, CHCl
3
3
) δ ppm =
퐷
7.39–7.30 (m, 5H), 7.29–7.22 (m, 5H), 6.71 (d, J = 16.0 Hz, 1H), 6.44 (dd,
(1R,2R)-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetra-
J = 16.0, 9.6 Hz, 1H), 5.84 (d, J = 3.6 Hz, 1H), 4.66 (q, J = 11.6 Hz, 2H),
hydrofuro[2,3-d][1,3]dioxol-5-yl)-2-(dibenzylamino)-2-(naphthalen-2-
yl)ethanol (15). According to the general procedure, compound 15 was
obtained as a brown oil in 37% yield (201 mg) from compound 2 (271 mg,
0.88 mmol), TEMPO (7 mg, 0.04 mmol), TCICA (214 mg, 0.92 mmol),
dibenzylamine (170 μL, 0.88 mmol) and naphthalen-2-ylboronic acid (151
mg, 0.88 mmol), after flash chromatography on silica gel (Petr Et/EtOAc
4
3
.49 (d, J = 3.6 Hz, 1H), 4.45 (d, J = 9.2 Hz, 1H), 4.06 (d, J = 2.8 Hz, 1H),
.98 (dd, J = 9.6, 2.8 Hz, 1H), 3.56 (d, J = 9.6 Hz, 1H), 3.21 (br s, 2H), 3.03
(
br s, 2H), 1.96 (br s, 4H), 1.21 (s, 3H), 1.15 (s, 3H). 13C NMR (100 MHz,
CDCl ) δ ppm = 137.5, 137.1, 135.6, 128.6 (4C), 128.1 (4C), 126.8 (2C),
21.2, 112.1, 105.0, 82.6, 81.1, 79.7, 73.0, 72.2, 67.1, 52.9 (2C), 26.9,
6.5, 23.0 (2C). MS (ESI) m/z (%): 466.01 (100, [M+H] ). Anal. Calcd. for
: C, 72.23; H, 7.58; N, 3.01. Found: C, 72.43; H, 7.60; N, 2.96.
3
1
2
+
21
1
3:1). [α]퐷 = -68.6 (c 1.0, CHCl
– 7.89 (m, 2H), 7.84 – 7.75 (m, 2H), 7.67 (t, J = 8.4 Hz, 1H), 7.61 – 7.54
m, 3H), 7.46 – 7.29 (m, 11H), 7.13 – 7.04 (m, 3H), 6.10 (d, J = 3.6 Hz,
3 3
). H NMR (400 MHz, CDCl ) δ ppm = 7.95
28 5
C H35NO
(
1
1
3
H), 4.89 (br s, 1H), 4.71 (s, 1H), 4.58 – 4.55 (m, 2H), 4.36 (d, J = 11.2 Hz,
H), 4.04 (d, J = 8.0 Hz, 1H), 4.00 – 3.97 (m, 2H), 3.86 (d, J = 3.2 Hz, 1H),
.26 (d, J = 13.6 Hz, 2H), 3.11 (br s, 1H), 1.53 (s, 3H), 1.39 (s, 3H). 13C
(
1S,2R,E)-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetra-
hydrofuro[2,3-d][1,3]dioxol-5-yl)-2-(isobutylamino)-4-phenyl-but-3-
en-1-ol (10). According to the general procedure, compound 10 was
obtained as a brown oil in 49% yield (117 mg) from compound 2 (156 mg,
NMR (100 MHz, CDCl
3
) δ ppm = 139.8 (2C), 136.8, 133.4, 133.1, 133.0,
1
1
1
29.6, 129.5, 129.2 (2C), 128.5 (4C), 128.1, 128.0, 127.7, 127.7, 127.6,
27.6, 127.5, 127.2, 127.0, 126.3, 126.2, 126.0, 125.8, 123.2, 111.7, 109.4,
0
.51 mmol), TEMPO (5 mg, 0.03 mmol), TCICA (124 mg, 0.53 mmol), 2-
methylpropan-1-amine (51 μL, 0.51 mmol) and trans-2-phenylvinylboronic
acid (75 mg, 0.51 mmol), after flash chromatography on silica gel
04.7, 83.2, 82.2, 79.2, 72.1, 69.1, 67.4, 55.1, 26.7, 26.4. MS (ESI) m/z
+
22
). 1H NMR (400 MHz,
(%): 638.10 (100, [M+Na] ). Anal. Calcd. for C40
N, 2.27. Found: C, 78.18; H, 6.78; N, 2.19.
5
H41NO : C, 78.02; H, 6.71;
(Hexane/EtOAc 2:1). [α]퐷 = -25.5 (c 1.0, CHCl
3
3
CDCl ) δ ppm = 7.41 – 7.28 (m, 8H), 7.24 – 7.20 (m, 2H), 6.71 (d, J = 16.0
Hz, 1H), 6.31 (dd, J = 16.0, 9.2 Hz, 1H), 5.89 (d, J = 3.6 Hz, 1H), 4.67 (s,
2
H), 4.54 (d, J = 3.6 Hz, 1H), 4.38 – 4.35 (m, 1H), 4.08 – 4.04 (m, 2H),
.68 – 3.65 (m, 1H), 2.66 (dd, J = 12.0, 7.2 Hz, 1H), 2.54 (dd, J = 12.0, 6.4
(1R,2R)-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetra-
3
hydrofuro[2,3-d][1,3]dioxol-5-yl)-2-(dibenzylamino)hept-3-yn-1-ol
(16). According to the general procedure, compound 16 was obtained as
a brown oil in 29% yield (128 mg) from compound 2 (243 mg, 0.78 mmol),
TEMPO (6 mg, 0.04 mmol), TCICA (190 mg, 0.81 mmol), dibenzylamine
(151 μL, 0.78 mmol) and 4,4,5,5-tetramethyl-2-(pent-1-yn-1-yl)-1,3,2-
dioxaborolane (170 μL, 0.78 mmol), after flash chromatography on silica
Hz, 1H), 1.92 (m, 1H), 1.26 (s, 3H), 1.23 (s, 3H), 0.96 (m, 6H). 13C NMR
(50 MHz, CDCl
3
) δ ppm = 137.6, 136.2, 135.4, 128.6 (4C), 127.9 (4C),
1
2
26.6 (2C), 124.1, 111.9, 105.1, 82.3, 81.4, 80.0, 72.5, 68.3, 63.7, 54.6,
7.2, 26.7, 26.5, 20.6, 20.5. MS (ESI) m/z (%): 467.98 (100, [M+H] ). Anal.
+
Calcd. for C28
N, 2.96.
5
H37NO : C, 71.92; H, 7.98; N, 3.00. Found: C, 72.08; H, 8.01;
21
). 1H NMR (400 MHz,
gel (Petr Et/EtOAc 3:1). [α]퐷 = -53.1 (c 1.0, CHCl
CDCl ) δ ppm = 7.42 – 7.39 (m, 3H), 7.37 – 7.25 (m, 10H), 7.14 – 7.12 (m,
H), 6.95 (d, J = 4.0 Hz, 1H), 4.47 – 4.45 (m, 2H), 4.29 (br s, 1H), 4.17 (d,
J = 11.2 Hz, 1H), 3.85 (d, J = 13.6 Hz, 2H), 3.80 (d, J = 3.2 Hz, 1H), 3.71
3
3
2
(
1S,2R,E)-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetra-
hydrofuro[2,3-d][1,3]dioxol-5-yl)-2-((4-methoxyphenyl)-
methyl)amino)-4-phenylbut-3-en-1-ol (11). According to the general
(
(
(
(
(
d, J = 11.2 Hz, 1H), 3.65 – 3.63 (m, 1H), 3.49 (d, J = 13.2 Hz, 2H), 2.37
td, J = 7.2, 1.6 Hz, 2H), 1.71 – 1.66 (m, J = 7.2 Hz, 2H), 1.55 (s, 3H), 1.33
s, 3H), 1.13 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl
) δ ppm = 139.1
3
2C), 136.8, 129.3 (4C), 128.5 (4C), 128.1, 127.6 (2C), 128.5 (2C), 127.2
2C), 111.4, 104.6, 87.0, 83.6, 81.9, 78.6, 74.8, 71.7, 71.4, 56.3 (2C), 55.5,
(
procedure, compound 11 was obtained as a brown oil in 39% yield (155
mg) from compound 2 (231 mg, 0.75 mmol), TEMPO (6 mg, 0.04 mmol),
TCICA (182 mg, 0.79 mmol), 4-methoxy-N-methylaniline (103 mg, 0.75
mmol) and trans-2-phenylvinylboronic acid (111 mg, 0.75 mmol), after
flash chromatography on silica gel (Petr Et/EtOAc 2:3). [α] = -25.1 (c 1.0,
CHCl
+
2
2
26.7, 26.2, 22.6, 20.9, 13.7. MS (ESI) m/z (%): 578.17 (100, [M+Na] ). Anal.
퐷
1
5
Calcd. for C35H41NO : C, 75.65; H, 7.44; N, 2.52. Found: C, 75.71; H, 7.50;
3
). H NMR (400 MHz, CDCl
3
) δ ppm = 7.32 – 7.27 (m, 5H), 7.23 –
N, 2.47.
7
3
1
=
3
.18 (m, 5H), 6.79 – 6.76 (m, 1H), 6.69 (d, J = 2.8 Hz, 1H), 6.62 – 6.58 (m,
H), 6.23 (dd, J = 16.4, 8.0 Hz, 1H), 5.98 (d, J = 4.0 Hz, 1H), 5.51 (dd, J =
6.0, 6.8 Hz, 1H), 4.71 (d, J = 7.2 Hz, 1H), 4.60 - 4.56 (m, 3H), 4.34 (d, J
11.2 Hz, 1H), 4.07 (t, J = 2.4 Hz, 1H), 4.05 (t, J = 3.6 Hz, 1H), 3.71 (s,
(1R,2R)-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetra-
hydrofuro[2,3-d][1,3]dioxol-5-yl)-2-(dibenzylamino)-2-(4-
H), 2.70 (s, 3H), 1.48 (s, 3H), 1.32 (s, 3H). 13C NMR (100 MHz, CDCl
methoxyphenyl)ethanol (17). According to the general procedure,
compound 17 was obtained as a brown oil in 52% yield (200 mg) from
compound 2 (200 mg, 0.65 mmol), TEMPO (5 mg, 0.03 mmol), TCICA
(158 mg, 0.68 mmol), dibenzylamine (125 μL, 0.65 mmol) and (4-
methoxyphenyl)boronic acid (145 mg, 0.65 mmol), after flash
3
) δ
ppm = 151.9, 141.8, 141.1, 136.7, 133.7, 131.6, 129.5, 128.7 (3C), 128.6,
128.2 (3C), 127.9, 126.8, 113.7, 111.7 (2C), 111.6 (2C), 105.1, 83.0, 81.8,
81.6, 72.1, 70.3, 55.7, 48.8, 31.4, 26.8, 26.3. MS (ESI) m/z (%): 532.06
+
(100, [M+H] ). Anal. Calcd. for C32
H
6
37NO : C, 72.29; H, 7.01; N, 2.63.
2
1
Found: C, 72.40; H, 7.07; N, 2.57.
chromatography on silica gel (Petr Et/EtOAc 2:1). [α] = -49.1 (c 1.0,
퐷
1
CHCl
3
). H NMR (400 MHz, CDCl
3
) δ ppm = 7.43 – 7.28 (m, 15H), 7.10 –
7
1
3
1
1
.08 (m, 2H), 7.01 – 6.99 (m, 2H), 6.04 (d, J = 4.0 Hz, 1H), 4.70 – 4.68 (m,
(
1R,2R,E)-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyl-
H), 4.52 – 4.49 (m, 2H), 4.30 (d, J = 11.2 Hz, 1H), 3.92 – 3.88 (m, 3H),
.86 (s, 3H), 3.81 – 3.78 (m, 2H), 3.19 (d, J = 14.0 Hz, 2H), 1.57 (s, 3H),
tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-2-(dibenzylamino)-hept-3-en-1-
ol (14). According to the general procedure, compound 14 was obtained
as a brown oil in 55% yield (205 mg) from compound 2 (207 mg, 0.67
mmol), TEMPO (5 mg, 0.03 mmol), TCICA (163 mg, 0.70 mmol),
dibenzylamine (129 μL, 0.67 mmol) and (E)-pent-1-en-1-ylboronic acid (76
mg, 0.67 mmol), after flash chromatography on silica gel (Petr Et/EtOAc
.37 (s, 3H). 13C NMR (100 MHz, CDCl
3
) δ ppm = 158.9, 139.8 (2C), 136.9,
31.1, 129.2 (4C), 128.6 (2C), 128.5 (4C), 128.0, 127.8, 127.7 (2C), 127.1
(2C), 126.9, 116.0, 114.7, 113.4, 111.5, 104.7, 83.2, 82.1, 79.2, 72.0, 69.2,
+
66.5, 55.2, 54.9, 26.7, 26.4. MS (ESI) m/z (%): 595.84 (100, [M+H] ). Anal.
21
1
3
퐷
3 3
:1). [α] = -9.45 (c 1.0, CHCl ). H NMR (400 MHz, CDCl ) δ ppm = 7.34
6
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000600
FULL PAPER
Calcd. for C37
N, 2.28.
H
41NO
6
: C, 74.60; H, 6.94; N, 2.35. Found: C, 74.71; H, 7.02;
M (3 x 40 mL), a saturated solution of Na
mL), dried over Na SO , filtered and concentrated under reduced pressure.
The crude compound was purified by chromatography on silica gel
2 3
CO (3 x 40 mL), brine (1 x 40
2
4
20
(
3
Hexane/EtOAc 2:1) to give compound 22 (328 mg) in 62% yield. [α] = -
(
1R,2R,E)-1-((3aR,5S,6S,6aR)-6-azido-2,2-dimethyltetrahydro-
furo[2,3-d][1,3]dioxol-5-yl)-2-(dibenzylamino)-4-phenylbut-3-en-1-ol
19). According to the general procedure, compound 19 was obtained as
퐷
1
2.4 (c 1.0, CHCl
3
). H NMR (400 MHz, CDCl
3
) δ ppm = 7.43 – 7.24 (m,
15H), 6.50 (dd, J = 15.9, 8.7 Hz, 1H), 6.16 – 6.05 (m, 1H), 5.83 (d, J = 3.4
(
Hz, 1H), 4.91 (d, J = 14.9 Hz, 1H), 4.76 (dd, J = 9.5, 8.1 Hz, 1H), 4.69 (d,
J = 11.5 Hz, 1H), 4.64 (d, J = 11.5 Hz, 1H), 4.56 – 4.50 (m, 1H), 4.30 (m,
a brown oil in 57% yield (257 mg) from compound 6 (210 mg, 0.86 mmol),
TEMPO (7 mg, 0.04 mmol), TCICA (210 mg, 0.93 mmol), dibenzylamine
2
H), 4.16 – 4.10 (m, 1H), 4.03 (d, J = 14.9 Hz, 1H), 1.26 (s, 3H), 1.20 (s,
3H). 13C NMR (50 MHz, CDCl
) δ ppm = 157.4, 137.4, 135.8, 135.7, 135.3
(2C), 128.8 (2C), 128.6 (2C), 128.5 (2C), 128.3 (2C), 128.1 (2C), 127.8,
(
165 μL, 0.86 mmol) and trans-2-phenylvinylboronic acid (127 mg, 0.86
22
3
mmol), after flash chromatography on silica gel (Petr Et/EtOAc2:1). [α]
-
=
퐷
1
137.2 (c 1.0, CHCl
3
). H NMR (400 MHz, CDCl
3
) δ ppm = 7.41 – 7.39 (m,
1
27.7 (2C), 126.7 (2C), 121.9, 112.3, 105.3, 82.2, 81.7, 73.4, 72.9, 58.7,
2
6
H), 7.35 – 7.31 (m, 10H), 7.29 – 7.25 (m, 3H), 6.65 (d, J = 16.0 Hz, 1H),
.31 (dd, J = 16.0, 9.6 Hz, 1H), 5.88 (d, J = 3.6 Hz, 1H), 4.51 (d, J = 3.6
+
46.2, 26.7, 26.5. MS (ESI) m/z (%): 550.13 (100, [M+Na] ). Anal. Calcd.
for C32
6
H33NO : C, 72.85; H, 6.30; N, 2.65. Found: C, 72.99; H, 6.38; N,
Hz, 1H), 4.28 (dd, J = 7.6, 2.8 Hz, 1H), 4.20 (t, J = 5.6 Hz, 1H), 3.90 (d, J
14.0 Hz, 2H), 3.82 (d, J = 3.2 Hz, 2H), 3.59 (d, J = 14.0 Hz, 2H), 3.50
dd, J = 10.0, 5.2 Hz, 1H), 1.28 (s, 3H), 1.25 (s, 3H). 13C NMR (100 MHz,
CDCl ) δ ppm = 139.4 (2C), 136.5, 135.6, 129.1 (4C), 128.5 (4C), 127.8
2C), 127.2 (2C), 126.6 (2C), 124.9 (2C), 112.2, 104.6, 83.1, 78.8, 69.5,
2.58.
=
(
3
(2S,3R)-methyl 3-((4R,5R)-3-benzyl-2-oxo-4-((E)-styryl)oxa-zolidin-5-
yl)-2-(benzyloxy)-3-hydroxypropanoate (24). An ice-cold solution of 22
(170 mg, 0.32 mmol) in TFA-H O (3:2, 3 mL) was stirred at 0 °C for 15
2
(
6
6.4, 55.7 (2C), 26.4, 26.3, 25.7. MS (ESI) m/z (%): 526.95 (100, [M+H]+).
Anal. Calcd. for C31
H, 6.57; N, 10.58.
H
34
N
4
O
4
: C, 70.70; H, 6.51; N, 10.64. Found: C, 70.98;
minutes and at 25 °C for other additional 16 hours. Then, trifluoroacetic
acid was co-evaporated with toluene under reduced pressure to furnish
the corresponding hemiacetal as a thick liquid. This intermediate was
dissolved in a mixture of acetone-water (9:1, 6.50 mL) and sodium
metaperiodate (103 mg, 0.49 mmol) was successively added. The
resulting solution was stirred for 30 minutes at room temperature, then the
reaction was quenched with ethylene glycol (0.10 mL). The organic solvent
was evaporated under reduced pressure, water (40 mL) was added and
the aldehyde 23 was extracted with chloroform (3 × 15 mL). Aldehyde 23
was then re-dissolved in acetonitrile (6.5 mL) and a solution of sodium
dihydrogen phosphate (10 mg, 0.065 mmol) in water (500 μL) was added.
(
1R,2R,E)-1-((3aR,5S,6S,6aR)-6-azido-2,2-dimethyl-tetra-
hydrofuro[2,3-d][1,3]dioxol-5-yl)-2-(benzylamino)-4-phenyl-but-3-en-
-ol (20). According to the general procedure, compound 20 was obtained
1
as a brown oil in 42% yield (157 mg) from compound 6 (210 mg, 0.86
mmol), TEMPO (7 mg, 0.04 mmol), TCICA (210 mg, 0.93 mmol),
benzylamine (173 μL, 0.86 mmol) and trans-2-phenylvinylboronic acid
(
127 mg, 0.86 mmol), after flash chromatography on silica gel (Petr
22
1
Et/EtOAc 2:1). [α] = -107.7 (c 1.0, CHCl
3
). H NMR (400 MHz, CDCl
ppm = 7.34 – 7.27 (m, 4H), 7.24 – 7.15 (m, 6H), 6.59 (d, J = 16.0 Hz, 1H),
.13 (dd, J = 16.0, 9.2 Hz, 1H), 5.79 (d, J = 3.6 Hz, 1H), 4.51 (d, J = 3.6
Hz, 1H), 4.08 – 4.04 (m, 2H), 3.89 (dd, J = 9.2, 2.4 Hz, 1H), 3.77 (dd, J =
3
) δ
퐷
The corresponding mixture was cooled to 0 °C, H
μL, 0.36 mmol) and a 0.5 M solution of NaClO (1.10 mL, 0.52 mmol) were
sequentially added, the reaction mixture was allowed to reach room
temperature and left reacting at this temperature for 10 h. Then, Na SO
3
2 2
O (30% in water) (43
2
6
3
3
1
7
3.2, 13.2 Hz, 2H), 3.52 (dd, J = 9.2, 3.2 Hz, 1H), 1.21 (s, 3H), 1.18 (s,
H).13C NMR (100 MHz, CDCl
): δ ppm = 139.8, 136.5, 134.5, 128.6 (2C),
28.5 (2C), 128.2 (2C), 127.7, 127.2, 126.5 (2C), 126.4, 112.4, 104.8, 83.0,
2
(100 mg) was added to quench the reaction, the solution was acidified with
a 1M solution of HCl (15 mL) until pH < 1 was reached, and the resulting
mixture was extracted with DCM (3 x 20 mL). The combined organic
3
9.2, 69.8, 66.6, 62.6, 51.2, 26.5 (2C). MS (ESI) m/z (%): 436.94 (100,
+
phases were dried over Na
pressure to give the free acid. This crude compound was re-dissolved in
MeOH (6.5 mL), cooled to 0 °C, then SOCl (70 μL, 0.97 mmol) was added
2 4
SO , filtered and concentrated under reduced
[M+H] ). Anal. Calcd. for C24
H
28
N
4 4
O : C, 66.04; H, 6.47; N, 12.84. Found:
C, 66.19; H, 6.53; N, 12.75.
2
dropwise, and the resulting mixture was heated to reflux and left reacting
at this temperature for 2 h. Finally, the solvent was evaporated under
reduced pressure and the crude was purified by flash chromatography on
silica gel (Hexane/EtOAc 3:2) to give compound 24 (75 mg) in 48% yield
(
3aR,5R,6S,6aR)-5-((1R,2R,E)-2-(benzylamino)-1-hydroxy-4-
phenylbut-3-en-1-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]-dioxol-6-
yl 4-methylbenzenesulfonate (21). According to the general procedure,
compound 21 was obtained as a brown oil in 45% yield (51 mg) from
compound 5 (75 mg, 0.20 mmol), TEMPO (2 mg, 0.01 mmol), TCICA (49
mg, 0.21 mmol), benzylamine (220 μL, 0.20 mmol) and trans-2-
phenylvinylboronic acid (30 mg, 0.20 mmol), after flash chromatography
22
1
3 3
over 4 steps. [α]퐷 = -19.4 (c 1.0, CHCl ). H NMR (400 MHz, CDCl ) δ 7.43
–
7.27 (m, 15H), 6.52 (d, J = 15.8 Hz, 1H), 6.15 (dd, J = 15.9, 8.1 Hz, 1H),
4.88 (d, J = 15.0 Hz, 1H), 4.68 (d, J = 11.0 Hz, 1H), 4.57 (d, J = 11.2 Hz,
22
1
1H), 4.47 – 4.36 (m, 2H), 4.30 (t, J = 7.7 Hz, 1H), 4.08 (d, J = 9.7 Hz, 1H),
.01 (d, J = 15.0 Hz, 1H), 3.69 (s, 3H), 3.36 (br s, 1H). 13C NMR (100 MHz,
CDCl ) δ 172.6, 153.9, 137.3, 136.7, 135.9, 135.9 (2C), 128.8 (3C), 128.7
3C), 128.5, 128.3 (2C), 128.1 (2C), 128.0, 127.9 (2C), 126.8, 121.4, 74.9,
on silica gel (Petr Et/EtOAc 3:2). [α]퐷 = -39.1 (c 1.0, CHCl
MHz, CDCl ) δ ppm = 7.82 (d, J = 8.2 Hz, 2H), 7.38 – 7.27 (m, 12H), 6.60
d, J = 16.0 Hz, 1H), 6.14 (dd, J = 16.0, 9.1 Hz, 1H), 5.88 (d, J = 3.6 Hz,
3
). H NMR (400
4
3
3
(
(
7
1
1
3
2
=
1
8
H), 4.91 (d, J = 2.5 Hz, 1H), 4.61 (d, J = 3.6 Hz, 1H), 4.12 – 4.05 (m, J =
1.0, 5.5 Hz, 1H), 3.93 (dd, J = 9.5, 2.8 Hz, 1H), 3.86 (d, J = 13.2 Hz, 1H),
.72 (d, J = 13.2 Hz, 1H), 3.52 (dd, J = 9.1, 2.8 Hz, 1H), 2.52 (br s, 2H),
.44 (s, 3H), 1.22 (s, 3H), 1.19 (s, 3H).13C NMR (100 MHz, CDCl
145.4, 139.9, 136.6, 134.4, 132.5, 129.9 (2C), 128.5 (2C), 128.4 (2C),
28.2 (2C), 128.1 (2C), 127.6 (2C), 127.1, 126.4 (2C), 112.8, 104.8, 82.7,
+
3.1, 71.3, 59.2, 52.8, 46.1. MS (ESI) m/z (%): 488.20 (100, [M+H] ). Anal.
6
Calcd. for C29H29NO : C, 71.44; H, 6.00; N, 2.87. Found: C, 71.58; H, 6.07;
N, 2.80.
3
) δ ppm
2.1, 79.1, 68.9, 61.9, 51.0, 26.6, 26.5, 21.7. MS (ESI) m/z (%): 565.86
Acknowledgements
+
(100, [M+H] ). Anal. Calcd. for C31
H
7
35NO S: C, 65.82; H, 6.24; N, 2.48.
Found: C, 65.99; H, 6.30; N, 2.40.
The authors acknowledge MIUR (“Progetto Dipartimenti di
Eccellenza 2018-2022” allocated to the Department of Chemistry
(
4R,5R)-3-benzyl-5-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-
“
Ugo Schiff”), Fondazione Cassa di Risparmio di Pistoia e Pescia
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-4-((E)-styryl)-
(
Bando Giovani@Ricerca scientifica 2018), Fondazione CR
oxazolidin-2-one (22). To a stirred solution of compound 7 (500 mg, 1
mmol) in dry THF (5 mL), Et
mmol) were added, the temperature was decreased to 0 °C and Boc
326 mg, 1.5 mmol) was added in small portions. The mixture was allowed
3
N (417 µL, 3 mmol) and DMAP (122 mg, 1
Firenze (cod. 2017.0721) and CNR roadmap europea
ESFRI:CISPIM for financial support.
2
O
(
to reach room temperature and left reacting overnight. EtOAc (60 mL) was
successively added, the resulting organic phase was washed with HCl 1
7
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European Journal of Organic Chemistry
10.1002/ejoc.202000600
FULL PAPER
[
26] a) A. Wang, C. Liu, S. Yang, Z. Zhao, P. Lei, Tetrahedron 2016, 72, 285-
Keywords: multicomponent reaction • peptidomimetics •
carbohydrates • diversity-oriented synthesis • aminosugars
297; b) D. C. Kapeller, F. Hammerschmidt, Tetrahedron 2010, 66, 591-
598.
[
[
[
27] a) N. A. Petasis, I. A. Zavialov, J. Am. Chem. Soc. 1998, 120, 11798-
1799; b) C. W. G. Au, S. G. Pyne, J. Org. Chem. 2006, 71, 7097-7099.
[
[
1]
2]
P. Wu, M. Givskov, T. E. Nielsen, Chem. Rev. 2019, 119, 11245-11290.
a) J. E. Biggs-Houck, A. Younai, J. T. Shaw, Curr. Opin. Chem. Biol.
1
28] N. Oña, A. Romero-Carrasco, M. S. Pino-González, Tetrahedron:
Asymmetry 2013, 24, 156-163.
2010, 14, 371-382; b) J. M. Knapp, M. J. Kurth, J. T. Shaw, A. Younai, in
Diversity-Oriented Synthesis: Basics and Applications in Organic
Synthesis, Drug Discovery, and Chemical Biology (Ed.: A. Trabocchi),
John Wiley & Sons: Hoboken, NJ, 2013, pp. 29-57; c) H. Eckert,
Molecules 2012, 17, 1074-1102.
29] N. B. Kalamkar, V. M. Kasture, D. D. Dhavale, J. Org. Chem. 2008, 73,
3619-3622.
[
[
3]
4]
a) T. E. Nielsen, S. L. Schreiber, Angew. Chem. Int. Ed. 2008, 47, 48-56;
b) S. L. Schreiber, Nature 2009, 457, 153-154.
a) N. Kumagai, G. Muncipinto, S. L. Schreiber, Angew. Chem. Int. Ed.
2006, 45, 3635-3638; b) G. Muncipinto, T. Kaya, J. A. Wilson, N.
Kumagai, P. A. Clemons, S. L. Schreiber, Org. Lett. 2010, 12, 5230-
5233; c) J. D. Sunderhaus, S. E. Martin, Chem. Eur. J. 2009, 15, 1300-
1308.
[
5]
E. Lenci, G. Menchi, A. Trabocchi, Org. Biomol. Chem. 2016, 14, 808-
25.
8
[
[
[
6]
7]
8]
P. Ghosal, A. K. Shaw, J. Org. Chem. 2012, 77, 7627-7632.
M. E. Bouillon, S. G. Pyne, Tetrahedron Lett. 2014, 55, 475-478.
a) S. G. Pyne, A. S. Davis, T. Ritthiwigrom, C. W. G. Au, K. Savaspun,
M. Wotherspoon, Pure Appl. Chem. 2012, 85, 1215-1225; b) P.
Moosophon, M. C. Baird, S. Kanokmedhakul, S. G. Pyne, Eur. J. Org.
Chem. 2010, 3337-3344.
[
[
9]
A. W. Carroll, K. Savaspun, A. C. Willis, M. Hoshino, A. Kato, S. G. Pyne,
J. Org. Chem. 2018, 83, 5558-5576.
10] a) U. Hünger, J. Ohnsmann, H. Kunz, Angew. Chem. Int. Ed. 2004,
3, 1104-1107; b) G. T. Le, G. Abbenante, B. Becker, M. Grathwohl, J.
Halliday, G. Tometzki, J. Zuegg, W. Meutermans, Drug Discov. Today
003, 8, 701-709; c) T. K. Chakraborty, S. Jayaprakash, S. Ghosh, Comb.
4
2
Chem. High Throughput Screen. 2002, 5, 373-387.
[
11] a) R. Innocenti, E. Lenci, L. Baldini, C. Faggi, G. Menchi, A. Trabocchi,
Eur. J. Org. Chem. 2019, 6203-6210; b) R. Innocenti, E. Lenci, G. Menchi,
A. Trabocchi, Beilstein J. Org. Chem. 2020, 16, 200-211; c) E. Lenci, R.
Innocenti, G. Menchi, A. Trabocchi, Front. Chem. 2018, 6: 522; d) E.
Lenci, A. Rossi, G. Menchi, A. Trabocchi, Org. Biomol. Chem. 2017, 15,
9710-9717; e) E. Lenci, R. Innocenti, G. Menchi, C. Faggi, A. Trabocchi,
Org. Biomol. Chem. 2015, 13, 7013-7019.
[
[
12]
a) E. Lenci and A. Trabocchi, Chem. Soc. Rev. 2020, ASAP,
https://doi.org/10.1039/D0CS00102C; b) E. Lenci, G. Menchi, A. Guarna, A.
Trabocchi, J. Org. Chem. 2015, 80, 2182-2191.
13] C. Baldauf, R. Günther, H. J. Hofmann, J. Org. Chem. 2004, 69, 6214-
220.
6
[
[
[
14] B. E. Haug, D. H. Rich, Org. Lett. 2004, 6, 4783-4786.
15] M. Brewer, C. A. James, D. H. Rich, Org Lett. 2004, 6, 4779-4882.
16] a) A. Osuch-Kwiatkowska, M. Cieplak, S. Jarosz, Curr. Org. Chem. 2014,
18, 327-340; b) Ł. Szyszka, A. Osuch-Kwiatkowska, M. A. Potopnyk, S.
Jarosz, Beilstein J. Org. Chem. 2017, 13, 2146-2152.
[
17] a) J. S. Brimacombe, A. K. M. S. Kabir, Carbohydr. Res. 1986, 150, 35-
51; b) D. Craig, M. W. Pennington, P. Warner, Tetrahedron, 1999, 55,
13495-12512; c) M. A. Potopnyk, P. Cmoch, M. Cieplak, A. Gajewska, S.
Jarosz, Tetrahedron: Asymmetry 2011, 22, 780-786.
18] a) A. Dondoni, G. Fantin, M. Fogagnolo, A. Medici, Angew. Chem. lnt.
Ed. Engl. 1986, 2, 835-837; b) A. Dondoni, G. Fantin, M. Fogagnolo, A.
Medici, Tetrahedron 1987, 43, 3533.
[
[
19] G. J. S. Lohman, D. K. Hunt, J. A. Högermeier, P. H. Seeberger, J. Org.
Chem. 2003, 68, 7559-7561.
[
[
[
20] L. De Luca, G. Giacomelli, A. Porcheddu, Org. Lett. 2001, 3, 3041-3043.
21] Y. Jing, C. G. Daniliuc, A. Studer, Org. Lett. 2014, 16, 4932-4935.
22] a) B. Jiang, M. Xu, Org. Lett. 2002, 4, 4077-4080; b) Q. I. Churches, J.
K. Johnson, N. L. Fifer, C. A. Hutton, Aust. J. Chem. 2011, 64, 62-67.
23] H. Jourdan, G. Gouhier, L. Van Hijfte, P. Angibaud, S. R. Piettre,
Tetrahedron Lett. 2005, 46, 8027.
[
[
[
24] N. R. Candeias, F. Montalbano, P. M. S. D. Cal, P. M. P. Gois, Chem.
Rev. 2010, 110, 6169-6193.
25] A. Nagy, B. Csordás, V. Zsoldos‑Mády, I. Pintér, V. Farkas, A. Perczel,
Amino Acids 2017, 49, 223-240.
8
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European Journal of Organic Chemistry
10.1002/ejoc.202000600
FULL PAPER
Multicomponent reactions
Entry for the Table of Contents
The facile synthesis of protected D-glucodialdofuranoses from D-glucose diacetonide enabled the multicomponent Petasis borono-
Mannich reaction at C-6 carbon atom to give corresponding aminosugars, useful intermediates for the convenient preparation of
polyfunctional δ-amino acids.
9
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