Ring-Opening Reactions of the N-4-Nosyl Hough-Richardson Aziridine with Nitrogen Nucleophiles

Article abstract of DOI:10.1021/acs.joc.6b01942

Dinosylated α-d-glucopyranoside was directly transformed into α-d-altropyranosides via in situ formed N-4-nosyl Hough-Richardson aziridine with nitrogen nucleophiles under mild conditions in fair to excellent yields. The scope of the aziridine ring-opening reaction was substantially broadened contrary to the conventional methods introducing solely the azide anion at high temperatures. If necessary, the N-4-nosyl Hough-Richardson aziridine can be isolated by filtration in a very good yield and high purity.

Full text of DOI:10.1021/acs.joc.6b01942

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Note
Ring-opening Reactions of the N-4-Nosyl Hough-
Richardson Aziridine with Nitrogen Nucleophiles
Tomáš Ru#il, Zdenek Travnicek, and Petr Canka#
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 07 Nov 2016
Downloaded from http://pubs.acs.org on November 7, 2016
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Ring-opening Reactions of the N-4-Nosyl Hough-Richardson Aziridine with
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Nitrogen Nucleophiles
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Tomáš Ručil,a Zdeněk Trávníček,b and Petr Cankař c*
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a
Institute of Molecular and Translation Medicine, Faculty of Medicine, Palacký University, Hněvotínská 5, 77900
Olomouc, Czech Republic
b
Department of Inorganic Chemistry, Faculty of Science, Palacký University, 17. listopadu 1192/12, 77146
Olomouc, Czech Republic
c Department of Organic Chemistry, Faculty of Science, Palacký University, 17. listopadu 1192/12, 77146 Olomouc,
Czech Republic
Abstract
Dinosylated αꢀDꢀglucopyranoside was directly transformed into αꢀDꢀaltropyranosides via in situ
formed Nꢀ4ꢀnosyl HoughꢀRichardson aziridine with nitrogen nucleophiles under mild conditions
in fair to excellent yields. The scope of the aziridine ringꢀopening reaction was substantially
broadened contrary to the conventional methods introducing solely the azide anion at high
temperatures. If necessary, the Nꢀ4ꢀnosyl HoughꢀRichardson aziridine can be isolated by
filtration in a very good yield and high purity.
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Hexopyranosides containing the 2,3ꢀdiamino functionality are useful chiral synthetic
intermediates in the synthesis of highly functionalized compounds with interesting biological or
chemical properties. These intermediates were used directly as chiral ligands in halfꢀsandwich
ruthenium, rhodium and iridium complexes with antitumor activity,1 Palladium and platinum
complexes,2 or molybdenum complexes to catalyze asymmetric allylic alkylations.3 Further, 2,3ꢀ
diaminohexopyranosides also served as a key precursor in the synthesis of the glycophospholipid
ligand of lipopolysaccharide receptor,4 chimeric scaffolds with the benzodiazepine moiety,5 and
Weinreb´s advanced intermediate for (ꢀ)ꢀAgelastatin A formal total synthesis.6
One of the frequently used methods leading to the derivatives of 2,3ꢀdiaminohexapyranosides is
the ringꢀopening reaction of the HoughꢀRichardson aziridine,7 which is commonly synthesized
from Dꢀglucosamine. This valuable chiral intermediate can be transformed by regioselective ringꢀ
opening reaction of the strainꢀloaded threeꢀmembered ring into the corresponding
diastereoisomers with αꢀDꢀaltroꢀ or αꢀDꢀglucoꢀ configurations.
The HoughꢀRichardson aziridine was firstly described by Goodman8 and, later on, the aziridine
ringꢀformation and ring–opening reaction conditions were particularly studied by Guthrie,9ꢀ11
Hough,12 Meyer zu Reckendorf,13ꢀ15 Richardson7,16 and Baker.17ꢀ20
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Formerly, some syntheses were based on precursors with the altroꢀ configuration but these
starting materials were difficult to access.21,22 Concurrently, as expected, the syntheses starting
from more readily available Dꢀglucosamine derivatives prevailed.
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The transformation sequence of aziridine into the corresponding 2,3ꢀdiaminohexapyranosides is
always predominantly complicated at the ringꢀopening step with the azide anion by the formation
of a mixture of αꢀDꢀaltroꢀ and αꢀDꢀglucoꢀ diastereoisomers, where the altroꢀconfiguration is
markedly preferred. A further complication can result from the formation of side oxazoline
products or Nꢀdeacylation of aziridine leading to a relatively stable aziridine sideꢀproduct with
regard to the ringꢀopening reaction.7,16 Then, the aziridine ringꢀopening reactivity must be
recovered by additional Nꢀbenzoylation,4 Nꢀalkoxycarbonylation,6 or methylation resulting in a
reactive quaternary salt.15
The ratio of diastereoisomers strongly depends on the Nꢀsubstitution of the aziridine ring and the
presence of ammonium chloride.16 For example, the methoxycarbonylated aziridine undergoes
the highly regioselective transꢀdiaxial ringꢀopening reaction with the azide anion leading to the
αꢀDꢀaltroꢀconfiguration in a very good yield.6 Contrary, the Nꢀbenzoylated aziridine usually
provided a significant amount of αꢀDꢀgluco- isomer, which was attributed to the possible
formation of an oxazolinium ion intermediate.14
The side reactions associated with deacylation can be eliminated by utilization of mesyl or tosyl
group in the sulfonamidoꢀsulfonate system which undergoes cyclization to aziridine under mild
conditions.16 However, mesyl or tosyl group is difficult to remove from the resulting sulfonamide
functionality after the ringꢀopening reaction.
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Herein we present the first synthesis and the ringꢀopening reactions of Nꢀ4ꢀnosyl Houghꢀ
Richardson aziridine with nitrogen nucleophiles. The electronꢀwithdrawing effect of the nitro
group in this new valuable advanced intermediate brings several significant practical advantages,
especially (i) synthesis of aziridine under mild conditions and, if necessary, this intermediate can
be isolated by a simple filtration in a very good yield and high purity, (ii) to perform the highly
regioselective aziridine ringꢀopening reactions in absence of ammonium chloride resulting in
products preferring the αꢀDꢀaltroꢀ prior to αꢀDꢀglucoꢀ configuration in a ratio no less than 90:10
under mild reaction conditions utilizing more practical solvent and temperature, (iii) the scope of
applicable nitrogen nucleophiles for the ringꢀopening reaction is substantially broadened, (iv)
further modification of nosylamide functionality particularly by Nꢀalkylation under classical or
Fukuyama protocols,23 and (v) potential mild deprotection conditions of nosyl group in
comparison to the mesyl or tosyl group.
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We chose commercially available Nꢀacetyl Dꢀglucosamine 1 as a starting compound, which was
transformed according to known literature24,25 to amino sugar 4 with small modifications in
isolation process and reaction conditions (Scheme 1). Further, amine 4 on treatment with 4ꢀ
nitrobenzenesulfonyl chloride provided dinosylated glucosamine 5 in 77% on a multigram scale.
Scheme 1. Synthesis of N-4-nosyl Hough-Richardson Aziridine 7
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Finally, aziridine 7 was isolated via filtration in good yield and high purity after addition of
DIPEA if 2ꢀmethoxyethanol was used. Poor solubility of 7 in 2ꢀmethoxyethanol obstructed the
subsequent aziridine opening. However, this reaction was possible in DMSO. Glucosamine 5 on
reaction with nitrogen nucleophile 6 in DIPEA/DMSO at 60°C gave 2,3ꢀdiaminoaltropyranoside
8 via in situ formation of aziridine 7 (Table 1).
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The assumed mechanism of the aziridine formation involves a transition state of nosylamide 5 in
the boat conformation directing the nosyl ester and nosyl amide groups in the transꢀdiaxial
relationship. Formation of nosylamide anion and increased departing ability of the adjacent
nosylate group was accelerated by the nitro group which led to the fast aziridine ring closure. The
αꢀDꢀallo configuration of aziridine 7 was confirmed by NMR spectra. Subsequent aziridine ringꢀ
opening reaction with nitrogen nucleophile 6 resulted in the cleavage of C2ꢀN bond by the Fürstꢀ
Plattner rule26 to provide transꢀdiaxial products 8 in the preferred chair conformation with the αꢀ
Dꢀaltro configuration. The high ringꢀopening regioselectivity is enforced by the synergy of the
conformation lock at C4 and C6 through the benzylidene protection and αꢀOꢀmethyl
configuration. Reckendorf observed at the similar HoughꢀRichardson aziridines a dominant
formation of the gluco configuration when the Cꢀ4 and the Cꢀ6 position was acetylated and a
mixture of gluco, allo, and altro diastereoisomers when the βꢀOꢀmethyl configuration was
introduced.10,11 Additionally, the αꢀDꢀaltro configuration of 8a was unequivocally determined by
a single crystal Xꢀray structure analysis (see Supporting Information).
To explore the aziridine ringꢀopening reactivity scope with regard to the structure diversity of a
nitrogen nucleophile we started a set of reactions (Table 1). Since the aziridine ring closure is
much faster than potential nosyl ester substitution/hydrolysis and subsequent ringꢀopening
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reaction, we utilized the direct synthesis of αꢀDꢀaltropyranosides 8 from dinosylated pyranoside 5
via in situ formed aziridine 7.
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Table 1. Reactions of dinosylated glucosamine 5 with nitrogen nucleophiles (6a-6s)
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Entry
10
Nu-H
Product
Time Yielda
O
O
OMe
O
OMe
Nu
O
O
DIPEA
DMSO
60°C, 16-72 h
Ns
N
+
Nu-H
Ph
O
Ph
O
O
OMe
H
O
HN
6a-6s
Ns
Ns
48h
72h
51%
OH
OH
H2N
O
Ph
O
N
5
8a-8s
38-91%
H
HN
Ns
6j
8j
O
OMe
Yielda
72%
OH
OH
O
Entry
1
Nu-H
NaN3
Product
Time
NH2
Ph
O
O
Ph
O
11
47%
Ph
O
N
H
O
O
O
OMe
N3
O
NH
O
O
Ns
16h
16h
24h
24h
24h
16h
16h
16h
24h
6k
8k
O
Ph
HN
O
6a
8a
Ns
O
OMe
O
N2H4.H2O
12
13
14
15
16
17
18
19
24h
24h
24h
24h
16h
16h
24h
72h
68%
47%
73%
69%
68%
56%
56%
38%
NH2
O
Ph
OMe
NH2
N
O
H
HN
2
3
4
5
6
7
8
9
NH3/H2O
91%
59%
55%
79%
68%
87%
59%
80%
Ns
O
Ph
8l
6l
HN
8b
8c
6b
6c
6d
Ns
O
OMe
O
NH2
NH2
H2N
O
OMe
O
O
Ph
N
H
O
HN
Ph
NH2
Ns
O
O
Ph
N
H
Ph
6m
8m
HN
Ns
OMe
H
N
O
OMe
O
Ph
Ph
O
N
NH2
HN
O
Ph
N
Ns
6n
6o
8n
8o
H
HN
O
Ns
8d
8e
O
OMe
N
H
N
O
OMe
N
O
O
NH2
O
HN
O
O
O
Ph
Ns
4
H
HN
Ns
6e
OMe
OH
OH
OH
O
H
N
O
OMe
NH2
O
O
Ph
N
O
Ph
N
H
HN
Ns
6p
6q
8p
8q
HN
O
Ns
6f
8f
O
HN
O
OMe
N
OH
H
N
O
OMe
O
NH2
O
Ph
OH
HO
O
Ph
N
H
Ns
HN
Ns
8g
6g
OMe
O
OMe
NH2
O
O
HO
NH2
O
Ph
N
H
O
Ph
N
OH
COOH
H
HN
COOH
HN
Ns
Ns
8h
8r
6r
6h
O
OMe
H
N
O
OMe
O
O
O
O
NH2
Ph
O
O
HOC2H4
C2H4NH2
Ph
N
O
Ph
O
N
Ph
N
H
C2H4OH
H
H
HN
HN
6s
8s
6i
8i
Ns
Ns
a Isolated yields
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Dinosylated amine 5 on treatment with sodium azide 6a provided altropyranoside 8a in good
yield (Entry 1). In comparison to the related Nꢀsubstituted HoughꢀRichardson aziridines, the ringꢀ
opening reaction was performed at 60 °C, not at conventional temperatures in the range of 120ꢀ
150°C.6,10,11,14 The increased ringꢀopening reactivity induced by the nosyl group directly afforded
amine 8b with aqueous ammonia in the excellent yield (Entry 2). In comparison to the classical
protocols, involving the aziridine ringꢀopening reaction with the azide anion and essential
reduction step,6 this methodology allowed substantial simplification.
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Monofunctional primary amines 6c-f provided 8c-f in fair to good yields (Entry 3ꢀ6). The
prolonged reaction time was utilized in the reactions with 6c-e. Later on, the method was
extended to aminoalcohols 6g-j to yield 8g-j from fair to very good yields as well (Entry 7ꢀ10).
The reaction time was necessary to extend to 48 h with amine 6j. Further increase of steric
hindrance of 6k necessitated an extension of reaction time to 72 h to give 8k (Entry 11). The
yield was predominantly reduced by the isolation process. Preliminary attempts to cyclize
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nosylamides 8g-j under FukuyamaꢀMitsunobu conditions failed. We assumed that prerequisite
change of the altropyranoside ring from the chair to boat conformation did not occur and,
consequently, both diaxially oriented reacting groups were not redirected to the equatorial
conformation.
Other bifunctional nucleophiles, hydrazine 6l and ethylenediamine 6m, provided fair yields
(Entry 12 and 13). Besides primary amines, the reactivity of secondary amines 6n-q was also
tested to give 8n-q from fair to good yields (Entry 14ꢀ17). Preliminary attempts to carry out the
ringꢀopening reactions with anilines afforded unsatisfactory yields particularly due to low
reactivity and difficulties in the isolation process. The exception was anthranilic acid 6r
providing 8r in fair yield (Entry 18). In connection with the good ringꢀopening reactivity with
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hydrazine (Entry 12), we also tried benzohydrazide 6s to obtain 8s in a poor yield which was
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8
predominantly caused by problematic separation and decomposition during the reaction (Entry
19).
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To demonstrate further possible modification of nosylamide group at C3 after the ringꢀopening
reaction, azide 8a was alkylated with propargyl alcohol under FukuyamaꢀMitsunobu conditions
to give 9 (Scheme 2). Subsequent intramolecular copper catalyzed 1,3ꢀdipolar cycloaddition28 led
to novel interesting scaffold 10 containing the 1,2,3ꢀtriazolopiperazine moiety. Similar scaffolds
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have been reported as glycosidase inhibitors. The 1,3ꢀdipolar cycloaddition was completed in
14 days at 60 °C. Higher temperature at 80 °C immensely reduced the reaction time to 3 days.
The rate of the cycloaddition step was very likely associated with the conformation change of the
pyranoside ring from chair to twistꢀboat which redirects both reacting groups into the equatorial
conformation. The evidence of the twistꢀboat conformation was strongly supported by the vicinal
coupling constants of the hydrogen signals at C1, C2, C3, and C4. These peaks were assigned by
the COSY spectrum. The observed coupling of the anomeric hydrogen was 7.3 Hz. This value is
typical for an axialꢀaxial coupling. Furthermore, the signal of the hydrogen at C2 was split into
the double doublet by 7.3 and 12.2 Hz and the hydrogen at C4 showed a triplet with the coupling
constant 8.9 Hz. The triplet of the hydrogen at C3 was overlapped with the hydrogen signal at
C5. If we consider the chair conformation with the altro configuration the vicinal coupling
constants should be lower because all hydrogens at C1, C2, and C3 should be equatorially
oriented.
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Scheme 2. Synthesis of triazolopiperazine 10 and denosylation of 8p resulting in 11
5
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7
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O
OMe
N
O
OMe
N
OH
PhSH, K2CO3
O
OH
O
O
Ph
O
Ph
ACN, 50°C,
2 days
NH
NH2
Nos
11, 75%
8p
The second example illustrates denosylation conditions applied on 8p to provide amine 11 under
mild conditions.
In conclusion, the synthesis of new Nꢀ4ꢀnosyl HoughꢀRichardson aziridine has been described.
We demonstrated that this valuable advanced intermediate can be transformed by highly
regioselective transꢀdiaxial ringꢀopening reactions with nitrogen nucleophiles into the
corresponding αꢀDꢀaltropyranosides. The increased ringꢀopening reactivity induced by the nosyl
group allowed direct synthesis of the aminoaltropyranoside with aqueous ammonia in the
excellent yield in comparison to the conventional methods based on the ringꢀopening reaction
with azide anion and subsequent reduction of the azide functionality. Sodium azide, primary and
secondary amines, hydrazine, and benzohydrazide provided altropyranosides in fair to very good
yield.
Experimental part
General:
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All starting materials are commercially available. Commercial reagents were used without any
purification. Melting points were determined with a Boetius stage apparatus and are uncorrected. Flash
column chromatography was performed on silica gel (pore size 60 Å, 40–63 ꢁm particle size). Purification
of compounds was performed with semiꢀpreparative HPLC, column specifications: particle size 5 µm,
inner diameter 20 mm, packing C18, Length 100 mm. Mobile phase was A=CH3CN, B=water (gradient
elution, A=60ꢀ90ꢀ90%, 0ꢀ5ꢀ10 min). Reactions were monitored by LC/MS analyses with a UHPLCꢀMS
system consisting of a UHPLC chromatography with photodiode array detector and a triple quadrupole
mass spectrometer using a C18 column at 30 °C and flow rate of 800 mL/min. The mobile phase was (A;
0.01 M ammonium acetate in water) and (B; CH3CN), linearly programmed from 10 to 80% B over 2.5
min, kept for 1.5 min. The column was reequilibrated with 10% B for 1 min. The APCI source operated at
a discharge current of 5 mA, a vaporizer temperature of 400 °C, and a capillary temperature of 200 °C.
Highꢀresolution mass spectrometer based on the orbitrap mass analyzer was equipped with Heated
Electrospray Ionization (HESI). The spectrometer was tuned to obtain a maximum response for m/z 70ꢀ
700. The source parameters were set to the following values: HESI temperature 30 °C, spray voltage
+3.5kV, ꢀ3kV; transfer capillary temperature 270 °C, sheath gas/aux gas (nitrogen) flow rates 35/10. The
HRMS spectra of target peaks allowed evaluating their elemental composition with less than 3 ppm
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difference between experimental and theoretically calculated value. The H and 13C NMR spectra were
measured in DMSOꢀd6, CDCl3 or DMFꢀd7 at 25 °C using 400 MHz spectrometer.
N-((2S,3R,4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3-
yl)acetamide 2.24,25 Nꢀacetyl Dꢀglucosamine 1 (15.0 g, 67.8 mmol) was dissolved in dry methanol
(150 mL) and ion exchange resin Amberlite IR 120 hydrogen form (IR 120 H+) (15.0 g, dried in
130 °C for 8 h) was added. The mixture was refluxed for 10 h. Then the mixture was filtrated and
the solvent was removed under reduced pressure. The residue (13.2 g) was directly used for the
preparation of compound 3 without further purification.
N-((4aR,6S,7R,8R,8aS)-8-hydroxy-6-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-
yl)acetamide 3.24,25 Pyranoside 2 (13.2 g) was dissolved in 1,4ꢀdioxane (400 mL), then
benzaldehyde dimethyl acetal (BDA) (16.8 mL, 112.0 mmol) and TsOH.H2O (2.142 g, 11.2
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mmol) was added. The mixture was heated under stirring at 60 °C for 5 h. After the reaction was
finished, the solvent was removed under reduced pressure and the crude product was
recrystallized from ethyl acetate (900 mL) to afford 3 in overall yield 50% (9.0 g) as a white
solid. 1H NMR (400 MHz, DMSOꢀd6) δ 1.85 (s, 3 H), 3.29 (s, 3 H), 3.48 (t, J=8.8 Hz, 1 H), 3.59
(dt, J=9.9, 4.9 Hz, 1 H), 3.65 (t, J=8.8 Hz, 1 H), 3.74 (t, J=9.9 Hz, 1 H), 3.80ꢀ3.87 (m, 1 H), 4.17
(dd, J=10.1, 4.9 Hz, 1 H), 4.61 (d, J=3.6 Hz, 1 H), 5.12 (br. s, 1H), 5.61 (s, 1 H), 7.35ꢀ7.40 (m, 3
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H), 7.43ꢀ7.48 (m, 2 H), 7.90 (d, J=8.3 Hz, 1 H); C NMR (101 MHz, DMSOꢀd6) δ 22.6, 54.1,
54.7, 62.5, 67.4, 68.0, 82.0, 98.7, 100.9, 126.4, 128.0, 128.9, 137.8, 169.5.
(4aR,6S,7R,8R,8aS)-7-amino-6-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ol 4.24,25
Nꢀacetylated sugar 3 (9.0 g, 27.9 mmol) was added to a solution of 4 M KOH (50.4 g, 900.0
mmol) in EtOH (225 mL) in one portion and mixture was refluxed for 4 h. After starting material
was consumed, one third of ethanol was removed under reduced pressure. CH2Cl2 (225 mL) was
added and the mixture was washed with water (2x350 mL) and brine (100 mL). Organic layer
was dried with MgSO4 and concentrated under reduced pressure. The crude product was purified
on silica gel chromatography (CHCl3/MeOH = 10/1) to give 4 in yield 84% (6.6 g) as a white
solid. 1H NMR (400 MHz, DMSOꢀd6) δ 1.41 (br. s, 2 H), 2.52ꢀ2.56 (m, 1 H), 3.32 (s, 3 H), 3.36ꢀ
3.38 (m, 1 H), 3.38ꢀ3.40 (m, 1 H), 3.5ꢀ3.64 (m, 1 H), 3.71 (t, J=10.1 Hz, 1 H), 4.16 (dd, J=9.9,
4.7 Hz, 1 H), 4.62 (d, J=3.4 Hz, 1 H), 5.23 (br. s, 1 H), 5.58 (s, 1 H), 7.35ꢀ7.40 (m, 3 H), 7.42ꢀ
7.48 (m, 2 H); 13C NMR (101 MHz, DMSOꢀd6) δ 54.8, 57.1, 62.8, 68.2, 71.5, 81.6, 100.8, 100.9,
126.4, 128.0, 128.8, 137.9.
(4aR,6S,7R,8R,8aR)-6-methoxy-7-(4-nitrophenylsulfonamido)-2-phenylhexahydropyrano[3,2-
d][1,3]dioxin-8-yl 4-nitrobenzenesulfonate 5. Nꢀdeacylated sugar 4 (6.8 g, 24.2 mmol) was
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dissolved in a mixture of CH2Cl2/pyridine (320/160 mL) and the reaction flask was cooled at 0°C
with an ice bath. Subsequently, 4ꢀnosyl chloride (4ꢀNsCl) (4.2 equiv, 22.5 g, 101.6 mmol) was
added and the mixture was heated at 60 °C. After 3 days, the solvents were removed under
reduced pressure; the residue was dissolved in EtOAc (700 mL) and washed with water (3x700
mL). The organic layer was washed with brine (300 mL) and dried with MgSO4. The crude
product was purified on silica gel chromatography (CHCl3/MeOH = 100/1) to give 5 in yield
77% (12.0 g) as a pale yellow solid, mp. 149ꢀ151 °C. 1H NMR (400 MHz, DMSOꢀd6) δ 3.17 (s, 3
H), 3.56ꢀ3.6 (m, 1 H), 3.62ꢀ3.69 (m, 1 H), 3.82ꢀ3.86 (m, 1 H), 3.87ꢀ3.91 (m, 1 H), 4.15 (dd,
J=4.2, 1.0 Hz, 1 H), 4.37 (d, J=3.6 Hz, 1 H), 4.78 (t, J=9.9 Hz, 1 H), 5.32 (s, 1 H), 7.10ꢀ7,16 (m,
2 H), 7.20ꢀ7.32 (m, 3 H), 7.87ꢀ7.97 (m, 4 H), 8.09 (dt, J=8.8, 2.6 Hz, 2 H), 8.35 (dt, J=8.8, 2.1
Hz, 2 H), 8.94 (d, J=9.9 Hz, 1 H); 13C NMR (101 MHz, DMSOꢀd6) δ 55.2, 55.9, 62.3, 67.5, 77.9,
79.4, 99.1, 100.8, 124.0, 124.5, 126.1, 127.8, 127.9, 128.7, 129.1, 136.6, 142.2, 147.4, 149.5,
149.6; HRMS (Orbitrap) m/z [M ꢀ H]ꢀ calcd for C26H25N3O13S2 did not found; we found m/z [M –
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ꢀSO2ꢀC6H4ꢀNO2 ꢀ H]ꢀ calcd for C20H21N2O9S 465.0962, found 465.0967; [α]D + 18 (c 1.41,
CH2Cl2).
(4aR,6S,6aR,7aS,7bS)-6-methoxy-7-((4-nitrophenyl)sulfonyl)-2-phenylhexahydro-4H-
[1,3]dioxino[4',5':5,6]pyrano[3,4-b]azirine 7. Compound 5 (400.0 mg, 0.62 mmol) was
suspended in 2ꢀmethoxyethanol (12 mL) and DIPEA (0.332 mL, 1.91 mmol) was added. The
mixture was heated to 60 °C and stirred for 24 h. Then the precipitate was filtered off and washed
with a small portion of 2ꢀmethoxy ethanol. Compound 7 was obtained in 83% yield (229.0 mg)
as a yellow solid, mp. 260ꢀ262 °C. 1H NMR (400 MHz, DMFꢀd7) δ 3.37 (s, 3 H), 3.59 (dd, J=7.3,
2.6 Hz, 1 H), 3.75 (dd, J=10.9, 9.3 Hz, 1 H), 3.77ꢀ3.84 (m, 1 H), 3.86 (dd, J=7.3, 4.2 Hz, 1 H),
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4.08 (dd, J=8.8, 2.6 Hz, 1 H), 4.15 (dd, J=9.6, 4.4 Hz, 1 H), 5.15 (d, J=4.2 Hz, 1 H), 5.70 (s, 1
H), 7.24ꢀ7.42 (m, 5 H), 8.33ꢀ8.39 (m, 2 H), 8.50ꢀ8.56 (m, 2 H); 13C NMR (DMFꢀd7) δ 40.1, 42.3,
55.3, 60.9, 68.5, 74.7, 94.2, 101.9, 124.9, 126.5, 128.2, 129.3, 129.9, 138.2, 143.9, 151.1; HRMS
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(Orbitrap) m/z [M + NH4]+ calcd for C20H24N3O8S 466.1279, found 466.1279; [α]D + 108 (c
0.56, CH2Cl2).
General Procedure. Direct synthesis of altropyranosides 8 from 5 via in situ formed aziridine 7
The reaction was carried out at a 0.15 mmol scale unless otherwise noted. Compound 5 (0.15
mmol, 100.0 mg) was dissolved in DMSO (3 mL) and DIPEA (0.083 mL, 0.48 mmol) was
added. The mixture was stirred for 5 minutes, then nucleophile 6 (2.1 equiv) was added and the
mixture was heated to 60 °C. After the reaction was finished, CH2Cl2 (10 mL) and water (10 mL)
was added and the organic layer was washed with water (3x10 mL), brine (10 mL), and dried
with MgSO4. The crude product was purified by silica gel chromatography using
chloroform/methanol as solvents.
N-((4aR,6S,7S,8S,8aS)-7-azido-6-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)-4-
nitrobenzenesulfonamide 8a. Following the general procedure on a 0.6 mmol scale, the reaction
was heated with sodium azide 6a for 16 h to afford 8a in 72% yield (212.0 mg) as a pale yellow
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solid (purification on silica gel chromatography was not necessary), mp. 190ꢀ191 °C. H NMR
(400 MHz, DMSOꢀd6) δ 3.35 (s, 3 H), 3.62 (t, J=10.1 Hz, 1 H), 3.81 (br. s., 1 H), 3.86 (dd, J=9.9,
4.7 Hz, 1 H), 3.99 (dd, J=2.6, 1.0 Hz, 1 H), 4.03 ꢀ 4.13 (m, 1 H), 4.17 (dd, J=9.9, 5.2 Hz, 1 H),
4.74 (s, 1 H), 5.50 (s, 1 H), 7.04 ꢀ 7.13 (m, 2 H), 7.17 ꢀ 7.30 (m, 3 H), 7.89 ꢀ 8.01 (m, 4 H), 8.40
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(br. s., 1 H); C NMR (101 MHz, DMSOꢀd6) δ 51.8, 54.9, 58.2, 62.5, 68.1, 72.5, 97.9, 100.8,
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123.7, 126.1, 127.6, 128.0, 128.7, 137.1, 146.8, 148.8; HRMS (Orbitrap) m/z [M + H]+ calcd for
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C20H22N5O8S 492.1184, found 492.1182; [α]D23 + 96 (c 0.67, CH2Cl2).
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N-((4aR,6S,7S,8S,8aS)-7-amino-6-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)-4-
nitrobenzenesulfonamide 8b. Following the general procedure, the reaction was heated with
concentrated aqueous ammonia 6b (25% in water) for 16 h to afford 8b in 91% yield (65.0 mg)
as a pale yellow solid (after purification on silica gel chromatography, CHCl3/MeOH =30/1), mp.
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132ꢀ134 °C. H NMR (400 MHz, DMSOꢀd6) δ 1.95 (br. s., 2 H), 3.00 (d, J=1.6 Hz, 1 H), 3.29 (s,
3 H), 3.64 (t, J=9.9 Hz, 1 H), 3.67 ꢀ 3.73 (m, 1 H), 3.92 ꢀ 4.09 (m, 2 H), 4.15 (dd, J=10.1, 4.9 Hz,
1 H), 4.45 (s, 1 H), 5.44 (s, 1 H), 7.09 (dd, J=8.3, 1.6 Hz, 2 H), 7.16 ꢀ 7.32 (m, 3 H), 7.95 (s, 4 H);
13C NMR (101 MHz, DMSOꢀd6) δ 54.6, 54.6, 55.6, 58.5, 68.4, 72.8, 100.8, 102.1, 123.6, 126.0,
127.5, 128.0, 128.6, 137.3, 147.4, 148.7; HRMS (Orbitrap) m/z [M + H]+ calcd for C20H24N3O8S
466.1279, found 466.1280; [α]D23 + 56 (c 0.75, CH2Cl2).
N-((4aR,6S,7S,8S,8aS)-7-(benzylamino)-6-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-
8-yl)-4-nitrobenzenesulfonamide 8c. Following the general procedure on a 0.3 mmol scale, the
reaction was heated with benzylamine 6c for 24 h to afford 8c in 59% yield (100.0 mg) as a pale
yellow solid (after purification on silica gel chromatography, CHCl3/MeOH =100/1), mp. 175ꢀ
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177 °C. H NMR (400 MHz, DMSOꢀd6) δ 2.56 (q, J=6.1 Hz, 1 H,), 2.73 (d, J=4.2 Hz, 1 H), 3.26
(s, 3 H), 3.64 (t, J=10.1 Hz, 1 H), 3.76 (qd, J=14.4, 5.7 Hz, 2 H), 3.89 (br. s., 1 H), 3.97 ꢀ 4.05 (m,
1 H), 4.08 (dd, J=9.9, 4.7 Hz, 1 H), 4.16 (dd, J=10.1, 4.9 Hz, 1 H), 4.59 (s, 1 H), 5.47 (s, 1 H),
7.09 ꢀ 7.15 (m, 2 H), 7.19 ꢀ 7.28 (m, 3 H), 7.28 ꢀ 7.36 (m, 5 H), 7.86 (br. s, 1 H), 7.90 ꢀ 7.96 (m, 4
H); 13C NMR (101 MHz, DMSOꢀd6) δ 50.7, 51.6, 54.5, 58.5, 60.5, 68.4, 73.2, 100.1, 100.9,
123.6, 126.1, 126.7, 127.6, 128.0, 128.1, 128.6, 137.4, 140.3, 140.3, 147.4, 148.7; HRMS
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(Orbitrap) m/z [M + H]+ calcd for C27H30N3O8S 556.1748, found 556.1750; [α]D + 47 (c 0.4,
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CH2Cl2).
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d][1,3]dioxin-8-yl)-4-nitrobenzenesulfonamide 8d. Following the general procedure, the reaction
was heated with methylamine 6d for 24 h to afford 8d in 55% yield (41.0 mg) as a pale yellow
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solid (after purification on silica gel chromatography, CHCl3/MeOH =50/1), mp. 187ꢀ189 °C. H
NMR (400 MHz, DMSOꢀd6) δ 1.23 (br. s., 1 H), 2.32 (s, 3 H), 2.65 (d, J=2.1 Hz, 1 H), 3.30 (s, 3
H), 3.60 (t, J=9.6 Hz, 1 H), 3.82 (br. s., 1 H), 3.92 ꢀ 4.06 (m, 2 H), 4.14 (dd, J=10.1, 4.4 Hz, 1 H),
4.57 (s, 1 H), 5.43 (s, 1 H), 7.04 ꢀ 7.14 (m, 2 H), 7.16 ꢀ 7.29 (m, 3 H), 7.89 (br. d, J=7.8 Hz, 1 H),
7.94 ꢀ 7.98 (m, 4 H); 13C NMR (101 MHz, DMSOꢀd6) δ 34.6, 51.1, 54.6, 58.5, 64.1, 68.4, 73.2,
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99.8, 100.9, 123.7, 126.1, 127.6, 128.0, 128.6, 137.3, 147.3, 148.7; H NMR (400 MHz, CDCl3)
δ 2.58 (s, 3 H) 3.06 (d, J=2.1 Hz, 1 H), 3.48 (s, 3 H), 3.73 (t, J=10.4 Hz, 1 H), 3.87 (td, J=9.9, 4.7
Hz, 1 H), 3.94 (dd, J=9.9, 4.2 Hz, 1 H), 4.11 (m, 1 H), 4.26 (dd, J=10.4, 4.7 Hz, 1 H), 4.72 (s, 1
H), 5.43 (s, 1 H), 6.05 (d, J=9.3 Hz, 1 H), 7.12 (m, 2 H), 7.25 (m, 2 H), 7.33 (m, 1 H), 7.79 (m, 2
H), 7.89 (m, 2 H); 13C NMR (101 MHz, CDCl3) δ 34.7, 55.9, 59.6, 63.0, 68.9, 74.1, 77.2, 100.8,
101.8, 123.5, 125.8, 128.0, 128.2, 129.3, 136.6, 146.6, 149.3; HRMS (Orbitrap) m/z [M + H]+
calcd for C21H26N3O8S 480.1435, found 480.1436; [α]D23 + 70 (c 0.69, CH2Cl2).
N-((4aR,6S,7S,8S,8aS)-6-methoxy-7-(pentylamino)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-
8-yl)-4-nitrobenzenesulfonamide 8e. Following the general procedure, the reaction was heated
with pentylamine 6e for 24 h to afford 8e in 79% yield (65.0 mg) as an amorphous yellow solid
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(after purification on silica gel chromatography, CHCl3/MeOH =80/1). H NMR (400 MHz,
DMSOꢀd6) δ 0.87 (t, J=6.7 Hz, 3 H), 1.20 ꢀ 1.33 (m, 5 H), 1.33 ꢀ 1.42 (m, 2 H), 1.88 (br. s., 1 H),
2.53 ꢀ 2.59 (m, 1 H), 2.73 (br. s, 1 H), 3.30 (s, 3 H), 3.62 (t, J=9.6 Hz, 1 H), 3.78 (br. d, J=8.3 Hz,
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1 H), 3.95 ꢀ 4.03 (m, 2 H), 4.14 (dd, J=9.3, 3.6 Hz, 1 H), 4.57 (s, 1 H), 5.45 (s, 1 H), 7.06 ꢀ 7.15
(m, 2 H), 7.18 ꢀ 7.29 (m, 3 H), 7.89 (d, J=9.3 Hz, 1 H), 7.96 (s, 4 H); 13C NMR (101 MHz,
DMSOꢀd6) δ 14.0, 22.1, 28.9, 29.2, 47.7, 51.7, 54.5, 58.4, 62.0, 68.4, 73.1, 100.2, 100.8, 123.6,
126.1, 127.6, 128.0, 128.6, 137.3, 147.3, 148.7; HRMS (Orbitrap) m/z [M + H]+ calcd for
C25H34N3O8S 536.2061, found 536.2064; [α]D23 + 59 (c 0.73, CH2Cl2).
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N-((4aR,6S,7S,8S,8aS)-7-(cyclohexylamino)-6-methoxy-2-phenylhexahydropyrano[3,2-
d][1,3]dioxin-8-yl)-4-nitrobenzenesulfonamide 8f. Following the general procedure, the reaction
was heated with cyclohexylamine 6f for 16 h to afford 8f in 68% yield (57.0 mg) as a pale yellow
solid (after purification on silica gel chromatography, CHCl3/MeOH =80/1), mp. 176ꢀ178 °C. 1H
NMR (400 MHz, DMSOꢀd6) δ 0.87 ꢀ 1.04 (m, 2 H), 1.06 ꢀ 1.24 (m, 3 H), 1.49 ꢀ 1.59 (m, 1 H),
1.60 ꢀ 1.69 (m, 3 H), 1.69 ꢀ 1.82 (m, 2 H), 2.35 ꢀ 2.46 (m, 1 H), 2.84 (d, J=2.6 Hz, 1 H), 3.29 (s, 3
H), 3.64 (t, J=9.6 Hz, 1 H), 3.67 ꢀ 3.72 (m, 1 H), 3.92 ꢀ 4.05 (m, 2 H), 4.14 (dd, J=9.9, 4.2 Hz, 1
H), 4.52 (s, 1 H), 5.47 (s, 1 H), 7.05 ꢀ 7.18 (m, 2 H), 7.18 ꢀ 7.31 (m, 3 H), 7.89 (br. d, J=8.3 Hz, 1
H), 7.93ꢀ8.01 (m, 4 H); 13C NMR (101 MHz, DMSOꢀd6) δ 24.3, 25.7, 29.7, 32.5, 33.2, 52.6,
54.4, 54.5, 58.4, 58.4, 68.3, 73.1, 100.8, 101.0, 123.7, 126.1, 127.6, 128.1, 128.6, 137.4, 147.3,
148.7; HRMS (Orbitrap) m/z [M + H]+ calcd for C26H34N3O8S 548.2061, found 548.2065; [α]D
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+ 57 (c 0.4, CH2Cl2).
N-((4aR,6S,7S,8S,8aS)-7-((2-hydroxyethyl)amino)-6-methoxy-2-phenylhexahydropyrano[3,2-
d][1,3]dioxin-8-yl)-4-nitrobenzenesulfonamide 8g. Following the general procedure on a 0.6
mmol scale, the reaction was heated with 2ꢀaminoethanol 6g for 16 h to afford 8g in 87% yield
(272.0 mg) as a pale yellow solid (after purification on silica gel chromatography, CHCl3/MeOH
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=30/1), mp. 203ꢀ204 °C. H NMR (400 MHz, DMSOꢀd6) δ 1.93 (br. s., 1 H), 2.57 ꢀ 2.72 (m, 2
H), 2.78 (d, J=1.6 Hz, 1 H), 3.30 (s, 3 H), 3.39 ꢀ 3.47 (m, 2 H), 3.62 (t, J=9.9 Hz, 1 H), 3.75 ꢀ
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(s, 1 H), 5.45 (s, 1 H), 7.10 (dd, J=8.0, 1.3 Hz, 2 H), 7.15 ꢀ 7.31 (m, 3 H), 7.92 (s, 1 H), 7.94 ꢀ
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H]+ calcd for C22H28N3O9S 510.1541, found 510.1543; [α]D23 + 56 (c 0.62, CH2Cl2).
N-((4aR,6S,7S,8S,8aS)-7-((3-hydroxypropyl)amino)-6-methoxy-2-phenylhexahydropyrano[3,2-
d][1,3]dioxin-8-yl)-4-nitrobenzenesulfonamide 8h. Following the general procedure on a 0.6
mmol scale, the reaction was heated with 3ꢀaminopropanol 6h for 16 h affording 8h in 59% yield
(188.0 mg) as a pale yellow solid (after purification on silica gel chromatography, CHCl3/MeOH
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=40/1), mp. 171ꢀ173 °C. H NMR (400 MHz, DMSOꢀd6) δ 1.54 (quin, J=6.6 Hz, 2 H), 1.84 ꢀ
1.98 (m, 1 H), 2.53 ꢀ 2.70 (m, 2 H), 2.74 (br. s., 1 H), 3.30 (s, 3 H), 3.45 (dd, J=6.2, 4.7 Hz, 2 H),
3.62 (t, J=9.6 Hz, 1 H), 3.75 ꢀ 3.84 (m, 1 H), 3.93 ꢀ 4.06 (m, 2 H), 4.15 (dd, J=9.6, 4.4 Hz, 1 H),
4.41 (t, J=4.9 Hz, 1 H), 4.57 (s, 1 H), 5.45 (s, 1 H), 7.10 (dd, J=8.0, 1.3 Hz, 2 H), 7.17 ꢀ 7.28 (m,
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3 H), 7.89 (d, J=8.8 Hz, 1 H), 7.96 (s, 4 H); C NMR (101 MHz, DMSOꢀd6) δ 33.3, 45.6, 52.2,
55.1, 58.9, 59.6, 62.7, 68.9, 73.7, 100.8, 101.4, 124.2, 126.6, 128.1, 128.5, 129.1, 137.9, 147.9,
149.3; HRMS (Orbitrap) m/z [M + H]+ calcd for C23H30N3O9S 524.1697, found 524.1699; [α]D
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+ 60 (c 0.59, CH2Cl2).
N-(8-((2-(2-hydroxyethoxy)ethyl)amino)-6-methoxy-2-phenylhexahydropyrano[3,2-
d][1,3]dioxin-7-yl)-4-nitrobenzenesulfonamide 8i. Following the general procedure, the reaction
was heated with aminoalcohol 6i for 24 h to afford 8i in 80% yield (68.0 mg) as a pale yellow
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solid (after purification on silica gel chromatography, CHCl3/MeOH =20/1), mp. 68ꢀ70 °C. H
NMR (400 MHz, DMSOꢀd6) d ppm 1.98 (br. s., 1 H), 2.74 (d, J=4.7 Hz, 2 H), 2.79 (br. s., 1 H),
3.30 (s, 3 H), 3.43 (m, 4 H), 3.50 (q, J=5.2 Hz, 2 H), 3.62 (t, J=9.9 Hz, 1 H), 3.80 (m, 1 H), 4.00
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(m, 2 H), 4.15 (dd, J=10.1, 4.4 Hz, 1 H), 4.57 (t, J=5.2 Hz, 1 H), 4.59 (s, 1 H), 5.46 (s, 1 H), 7.10
(m, 2 H), 7.24 (m, 3 H), 7.90 (d, J=9.3 Hz, 1 H), 7.96 (s, 4 H); 13C NMR (101 MHz, DMSOꢀd6)
d ppm 47.2, 51.8, 54.5, 58.4, 60.2, 62.1, 68.3, 69.8, 72.1, 73.1, 100.2, 100.8, 123.6, 126.1, 127.5,
128.0, 128.5, 137.3, 147.3, 148.7; HRMS (Orbitrap) m/z [M + H]+ calcd for C24H32N3O10S
554.1803, found 554.1806; [α]D23 + 50 (c 0.56, CH2Cl2).
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N-((4aR,6S,7S,8S,8aS)-7-(((S)-1-hydroxypropan-2-yl)amino)-6-methoxy-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)-4-nitrobenzenesulfonamide 8j. Following the
general procedure, the reaction was heated with Sꢀalaninol 6j for 48 h to afford 8j in 51% yield
(41.3 mg) as a pale yellow solid (after purification on silica gel chromatography, CHCl3/MeOH
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=40/1), mp. 195ꢀ197 °C. H NMR (400 MHz, DMSOꢀd6) δ 0.91 (d, J=6.2 Hz, 3 H), 1.73 ꢀ 1.81
(m, 1 H), 2.69 ꢀ 2.78 (m, 1 H), 2.91 (br. d, J=6.2 Hz, 1 H), 3.19 ꢀ 3.27 (m, 2 H), 3.31 (s, 3 H),
3.62 (t, J=10.1 Hz, 1 H), 3.77 (br. s., 1 H), 3.88 ꢀ 3.95 (m, 1 H), 3.99 ꢀ 4.07 (m, 1 H), 4.15 (dd,
J=10.1, 4.9 Hz, 1 H), 4.54 (s, 1 H), 4.60 (t, J=5.7 Hz, 1 H), 5.45 (s, 1 H), 7.09 ꢀ 7.15 (m, 2 H),
7.19 ꢀ 7.30 (m, 3 H), 7.94 ꢀ 7.95 (m, 1 H), 7.96 (s, 4 H); 13C NMR (101 MHz, DMSOꢀd6) δ 16.9,
51.2, 52.3, 54.5, 58.4, 58.6, 65.6, 68.4, 73.1, 100.9, 101.5, 123.6, 126.1, 127.6, 128.0, 128.6,
137.3, 147.3, 148.7; HRMS (Orbitrap) m/z [M + H]+ calcd for C23H30N3O9S 524.1697, found
524.1700; [α]D23 + 79 (c 0.55, CH2Cl2).
N-((4aR,6S,7S,8S,8aS)-7-(((4aS,6R,7S,8S,8aR)-8-hydroxy-6-methoxy-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)amino)-6-methoxy-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)-4-nitrobenzenesulfonamide 8k. Following the
general procedure on a 0.6 mmol scale, the reaction was heated with glucosamine 6k for 72 h to
afford 8k in 47% yield (212.0 mg) as a pale yellow solid (after purification on silica gel
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chromatography, CHCl3/MeOH =80/1), mp. 130ꢀ132 °C. H NMR (400 MHz, DMSOꢀd6) δ 1.77
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(t, J=6.7 Hz, 1 H), 2.56 ꢀ 2.64 (m, 1 H), 2.98 (dd, J=6.0, 2.3 Hz, 1 H), 3.32 (s, 3 H), 3.33 (s, 3 H),
3.44 ꢀ 3.52 (m, 2 H), 3.53 ꢀ 3.68 (m, 2 H), 3.74 (t, J=9.9 Hz, 1 H), 3.95 (br. s., 1 H), 3.97 ꢀ 4.10
(m, 2 H), 4.12 ꢀ 4.22 (m, 2 H), 4.59 (s, 1 H), 4.73 (d, J=3.6 Hz, 1 H), 5.28 (d, J=4.7 Hz, 1 H),
5.44 (s, 1 H), 5.63 (s, 1 H), 7.07 ꢀ 7.13 (m, 2 H), 7.18 ꢀ 7.27 (m, 3 H), 7.35 ꢀ 7.40 (m, 3 H), 7.43 ꢀ
7.48 (m, 2 H), 7.83 (br. s., 1 H), 7.99 (s, 4 H); 13C NMR (101 MHz, DMSOꢀd6) δ 51.6, 54.6,
54.9, 58.5, 59.6, 61.3, 62.4, 68.1, 68.4, 68.6, 73.0, 79.2, 81.7, 98.9, 100.8, 100.9, 101.2, 123.6,
126.1, 126.4, 127.5, 128.0, 128.6, 128.8, 137.4, 137.8, 147.4, 148.7; HRMS (Orbitrap) m/z [M +
H]+ calcd for C34H40N3O13S 730.2276, found 730.2276; [α]D23 + 83 (c 0.79, CH2Cl2).
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N-((4aR,6S,7S,8S,8aS)-7-hydrazinyl-6-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-
yl)-4-nitrobenzenesulfonamide 8l. Following the general procedure, the reaction was heated with
hydrazine hydrate 6l for 24 h to afford 8l in 68% yield (50.0 mg) as a pale yellow solid (after
purification on silica gel chromatography, CHCl3/MeOH =40/1), mp. 168ꢀ170 °C. 1H NMR (400
MHz, DMSOꢀd6) δ 2.81 (d, J=2.1 Hz, 1 H), 3.30 (s, 3 H), 3.59 (t, J=9.9 Hz, 1 H), 3.90 (dd, J=4.7
Hz, 2 H), 3.96 ꢀ 4.04 (m, 1 H), 4.05 ꢀ 4.11 (m, 1 H), 4.14 (dd, J=10.1, 4.9 Hz, 1 H), 4.66 (s, 1 H),
5.43 (s, 1 H), 7.00 ꢀ 7.15 (m, 2 H), 7.16 ꢀ 7.29 (m, 3 H), 7.74 (br. s., 1 H), 7.96 (s, 4 H); 13C NMR
(101 MHz, DMSOꢀd6) δ 50.8, 55.2, 59.0, 67.0, 69.0, 74.0, 99.0, 101.3, 124.1, 126.6, 128.1,
128.5, 129.1, 137.9, 148.0, 149.2; HRMS (Orbitrap) m/z [M + H]+ calcd for C20H25N4O8S
481.1388, found 481.1389; [α]D23 + 65 (c 0.72, CH2Cl2).
N-((4aR,6S,7S,8S,8aS)-7-((2-aminoethyl)amino)-6-methoxy-2-phenylhexahydropyrano[3,2-
d][1,3]dioxin-8-yl)-4-nitrobenzenesulfonamide 8m. Following the general procedure except using
semipreparative HPLC for purification, the reaction was heated with ethylene diamine 6m for 24
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h to afford 8m in 47% yield (37.0 mg) as a pale yellow solid, mp. 152ꢀ154 °C. H NMR (400
MHz, DMSOꢀd6) δ 2.59 ꢀ 2.74 (m, 4 H), 2.75 (d, J=1.6 Hz, 1 H), 3.30 (s, 3 H), 3.62 (t, J=9.9 Hz,
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1 H), 3.80 (br. s., 1 H), 3.96 ꢀ 4.06 (m, 2 H), 4.12 ꢀ 4.19 (m, 1 H), 4.59 (s, 1 H), 5.44 (s, 1 H),
7.02 ꢀ 7.17 (m, 2 H), 7.18 ꢀ 7.31 (m, 3 H), 7.96 (s, 4 H); 13C NMR (101 MHz, DMSOꢀd6) δ 40.6,
48.9, 52.1, 55.1, 58.9, 62.5, 68.9, 73.6, 100.9, 101.4, 124.2, 126.6, 128.1, 128.5, 129.1, 137.9,
147.9, 149.2; HRMS (Orbitrap) m/z [M + H]+ calcd for C22H29N4O8S 509.1701, found 509.1703;
[α]D23 + 59 (c 0.58, CH2Cl2).
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N-((4aR,6S,7S,8S,8aS)-6-methoxy-2-phenyl-7-(piperidin-1-yl)hexahydropyrano[3,2-
d][1,3]dioxin-8-yl)-4-nitrobenzenesulfonamide 8n. Following the general procedure, the reaction
was heated with piperidine 6n for 24 h to afford 8n in 73% yield (60.0 mg) as a pale yellow solid
(purification on silica gel chromatography was not necessary), mp. 188ꢀ190 °C. 1H NMR (400
MHz, DMSOꢀd6) δ 1.34 ꢀ 1.44 (m, 2 H), 1.44 ꢀ 1.54 (m, 4 H), 2.44 ꢀ 2.49 (m, 2 H), 2.62 ꢀ 2.69
(m, 2 H), 2.70 (d, J=1.0 Hz, 1 H), 3.30 (s, 3 H), 3.59 (t, J=10.1 Hz, 1 H), 3.78 ꢀ 3.90 (m, 2 H),
3.95 ꢀ 4.07 (m, 1 H), 4.16 (dd, J=9.9, 5.2 Hz, 1 H), 4.74 (s, 1 H), 5.49 (s, 1 H), 7.12 (dd, J=8.0,
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1.3 Hz, 2 H), 7.17 ꢀ 7.31 (m, 3 H), 7.93 (d, J=2.1 Hz, 4 H), 8.07 (br. s., 1 H); C NMR (101
MHz, DMSOꢀd6) δ 23.9, 26.2, 49.6, 51.2, 54.4, 57.7, 68.5, 69.0, 74.3, 99.7, 100.9, 123.6, 126.2,
127.6, 128.0, 128.6, 137.4, 147.2, 148.7; HRMS (Orbitrap) m/z [M + H]+ calcd for C25H32N3O8S
534.1905, found 534.1906; [α]D23 + 72 (c 0.81, CH2Cl2).
N-((4aR,6S,7S,8S,8aS)-6-methoxy-7-morpholino-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-
yl)-4-nitrobenzenesulfonamide 8o. Following the general procedure, the reaction was heated with
morpholine 6o for 24 h to afford 8o in 69% yield (57.0 mg) as a pale yellow solid (after
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purification on silica gel chromatography, CHCl3/MeOH =60/1), mp. 203ꢀ205 °C. H NMR (400
MHz, DMSOꢀd6) δ 2.49 ꢀ 2.53 (m, 2 H), 2.56 ꢀ 2.66 (m, 3 H), 3.27 (s, 3 H), 3.50 ꢀ 3.60 (m, 5 H),
3.76 ꢀ 3.83 (m, 1 H), 3.83 ꢀ 3.91 (m, 1 H), 3.92 ꢀ 4.03 (m, 1 H), 4.12 (dd, J=9.9, 5.2 Hz, 1 H),
4.77 (s, 1 H), 5.46 (s, 1 H), 7.02 ꢀ 7.11 (m, 2 H), 7.13 ꢀ 7.26 (m, 3 H), 7.84 ꢀ 7.96 (m, 4 H), 8.02
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(d, J=7.8 Hz, 1 H); C NMR (101 MHz, DMSOꢀd6) δ 50.1, 50.7, 54.5, 57.9, 66.6, 68.2, 68.4,
73.9, 98.4, 100.8, 123.6, 126.2, 127.6, 128.0, 128.6, 137.3, 147.2, 148.7; HRMS (Orbitrap) m/z
[M + H]+ calcd for C24H30N3O9S 536.1697, found 536.1699; [α]D23 + 71 (c 0.77, CH2Cl2).
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N-((4aR,6S,7S,8S,8aS)-7-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)-6-methoxy-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)-4-nitrobenzenesulfonamide 8p. Following the
general procedure on a 0.6 mmol scale, the reaction was heated with (R)ꢀpyrrolidinꢀ2ꢀylmethanol
6p for 16 h to afford 8p in 68% yield (230.0 mg) as a pale yellow solid(after purification on silica
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gel chromatography, CHCl3/MeOH =50/1), mp. 106ꢀ108 °C. H NMR (400 MHz, DMSOꢀd6)
δ 1.56 ꢀ 1.81 (m, 4 H), 2.52 ꢀ 2.58 (m, 1 H), 2.83 ꢀ 2.95 (m, 2 H), 2.96 ꢀ 3.11 (m, 2 H), 3.21 ꢀ 3.31
(m, 1 H), 3.33 (s, 3 H), 3.61 (t, J=10.1 Hz, 1 H), 3.86 ꢀ 4.05 (m, 3 H), 4.16 (dd, J=10.1, 4.9 Hz, 1
H), 4.35 (t, J=5.4 Hz, 1 H), 4.76 (s, 1 H), 5.50 (s, 1 H), 7.08 (dd, J=8.0, 1.3 Hz, 2 H), 7.15 ꢀ 7.28
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(m, 3 H), 7.88 (d, J=8.8 Hz, 1 H), 7.95 (s, 4 H); C NMR (101 MHz, DMSOꢀd6) δ 23.8, 28.1,
51.3, 52.4, 55.2, 58.7, 61.9, 64.2, 67.1, 69.0, 74.0, 100.7, 101.4, 124.2, 126.7, 128.1, 128.5,
129.1, 137.9, 147.9, 149.2; HRMS (Orbitrap) m/z [M + H]+ calcd for C25H32N3O9S 550.1854,
found 550.1853; [α]D23 + 43 (c 0.69, CH2Cl2).
N-((4aR,6S,7S,8S,8aS)-7-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-6-methoxy-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)-4-nitrobenzenesulfonamide 8q. Following the
general procedure on a 0.6 mmol scale, the reaction was heated with (S)ꢀpyrrolidinꢀ2ꢀylmethanol
6q for 16 h to afford 8q in 56% yield (186.0 mg) as a pale yellow solid (after purification on
silica gel chromatography, CHCl3/MeOH =50/1), mp. 67ꢀ69 °C. 1H NMR (400 MHz, DMSOꢀd6)
δ 1.58 ꢀ 1.74 (m, 4 H), 2.56 ꢀ 2.65 (m, 1 H), 2.83 ꢀ 2.95 (m, 3 H), 3.07 ꢀ 3.17 (m, 1 H), 3.31 (s, 3
H), 3.32 ꢀ 3.37 (m, 1 H), 3.63 (t, J=9.6 Hz, 1 H), 3.85 (br. d, J=8.8 Hz, 1 H), 3.91 ꢀ 4.06 (m, 2 H),
4.15 (dd, J=10.1, 4.4 Hz, 1 H), 4.57 (t, J=5.2 Hz, 1 H), 4.82 (s, 1 H), 5.49 (s, 1 H), 7.09 (dd,
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J=8.0, 1.8 Hz, 2 H), 7.16 ꢀ 7.30 (m, 3 H), 7.95 (br. s., 1 H), 7.96 (s, 4 H); C NMR (101 MHz,
DMSOꢀd6) δ 23.6, 27.4, 50.9, 53.7, 54.6, 58.0, 64.2, 64.2, 66.2, 68.4, 73.4, 98.4, 100.8, 123.6,
126.1, 127.5, 128.0, 128.6, 137.4, 147.2, 148.7; HRMS (Orbitrap) m/z [M + H]+ calcd for
C25H32N3O9S 550.1854, found 550.1856; [α]D23 + 49 (c 0.61, CH2Cl2).
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2-(((4aR,6S,7S,8S,8aS)-6-methoxy-8-(4-nitrophenylsulfonamido)-2-phenylhexahydropyrano[3,2-
d][1,3]dioxin-7-yl)amino)benzoic acid 8r. Following the general procedure on a 0.6 mmol scale,
the reaction was heated with anthranilic acid 6r for 24 h to afford 8r in 56% yield (200.0 mg) as a
yellow solid (after purification on silica gel chromatography, CHCl3/MeOH =100/1), mp. 119ꢀ
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121 °C. H NMR (400 MHz, DMSOꢀd6) δ 3.37 (s, 3 H), 3.71 (t, J=9.6 Hz, 1 H), 3.93 (m, 1 H),
4.06 (dd, J=9.7, 4.8 Hz, 1 H), 4.20 (m, 2 H), 4.71 (s, 1 H), 5.00 (dd, J=2.6, 1.0 Hz, 1 H), 5.59 (s, 1
H), 6.56 (ddd, J=8.0, 7.0, 1.0 Hz, 1 H), 6.72 (br. s, 2 H), 6.80 (dd, J=8.6, 0.8 Hz, 1 H), 7.13 (m, 2
H), 7.26 (m, 4 H), 7.80 (dd, J=8.0, 1.6 Hz, 1 H), 7.96 (dt, J=9.6, 2.3 Hz, 4 H), 8.42 (d, J=8.8 Hz,
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1 H); C NMR (101 MHz, DMSOꢀd6) δ 51.4, 54.9, 58.2, 68.2, 71.4, 73.1, 97.9, 100.8, 107.5,
114.8, 116.6, 123.6, 126.2, 127.6, 128.2, 128.7, 131.0, 134.7, 137.2, 146.8, 148.8, 151.9, 165.6;
HRMS (Orbitrap) m/z [M + H]+ calcd for C27H28N3O10S 586.1490, found 586.1491; [α]D + 56
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(c 1.08, CH2Cl2).
N-((4aR,6S,7S,8S,8aS)-7-(2-benzoylhydrazinyl)-6-methoxy-2-phenylhexahydropyrano[3,2-
d][1,3]dioxin-8-yl)-4-nitrobenzenesulfonamide 8s. Following the general procedure, the reaction
was heated with benzohydrazide 6s for 72 h to afford 8s in 38% yield (34.0 mg) as an amorphous
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yellow solid (after purification on silica gel chromatography, CHCl3/MeOH =70/1). H NMR
(400 MHz, DMSOꢀd6) δ 3.20 (t, J=2.3 Hz, 1 H), 3.31 ꢀ 3.32 (s, 3 H), 3.67 (t, J=9.9 Hz, 1 H), 4.01
ꢀ 4.16 (m, 3 H), 4.20 (dd, J=10.1, 4.9 Hz, 1 H), 4.74 (s, 1 H), 5.44 (dd, J=5.4, 3.4 Hz, 1 H), 5.52
(s, 1 H), 7.16 (dd, J=7.8, 1.6 Hz, 2 H), 7.21 ꢀ 7.32 (m, 3 H), 7.45 ꢀ 7.61 (m, 3 H), 7.79 ꢀ 7.86 (m,
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2 H), 7.90 ꢀ 7.93 (m, 5 H), 10.12 (d, J=5.7 Hz, 1 H); C NMR (101 MHz, DMSOꢀd6) δ 50.3,
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54.6, 58.5, 63.3, 68.4, 73.2, 98.4, 100.9, 123.6, 126.1, 127.2, 127.6, 127.9, 128.4, 128.6, 131.5,
133.1, 137.4, 147.3, 148.7, 166.3; HRMS (Orbitrap) m/z [M + H]+ calcd for C27H29N4O9S
585.1650, found 585.1651; [α]D23 + 55 (c 0.79, CH2Cl2).
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N-((4aR,6S,7S,8S,8aS)-7-azido-6-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)-4-
nitro-N-(prop-2-yn-1-yl)benzenesulfonamide 9. To a solution of triphenylphosphine (TPP) (0.40
mmol, 104 mg) and DIAD (0.40 mmol, 79 ꢁL) in dry dioxane (4 mL) compound 8a (0.20 mmol,
100 mg) was added. After 5 minutes, propargyl alcohol (0.40 mmol, 24 ꢁL) was added in one
portion. The reaction mixture was stirred at room temperature for 18 h, then the solvent was
removed under reduced pressure and the residue was purified by silica gel chromatography using
CHCl3/MeOH (50/1) as a mobile phase to afford 9 in 74% yield (80 mg) as a yellow solid, mp.
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99ꢀ102 °C. H NMR (400 MHz, DMSOꢀd6) δ 3.36 (t, J=2.3 Hz, 1 H), 3.43 (s, 3 H), 3.49 (m, 1
H), 3.86 (t, J=9.9 Hz, 1 H), 4.16 (m, 3 H), 4.32 (dd, J=19.2, 2.1 Hz, 1 H), 4.42 (dd, J=10.4, 6.7
Hz, 1 H), 4.51 (t, J=9.9 Hz, 1 H), 4.77 (d, J=6.7 Hz, 1 H), 5.15 (s, 1 H), 6.99 (d, J=7.3 Hz, 2 H),
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7.18 (t, J=7.5 Hz, 2 H), 7.26 (m, 1 H), 7.97 (m, 4 H); C NMR (101 MHz, DMSOꢀd6) δ 54.2,
55.3, 60.0, 62.7, 66.3, 68.8, 73.7, 74.8, 80.5, 100.9, 101.2, 123.7, 125.9, 127.7, 128.6, 128.8,
136.6, 144.5, 149.0; HRMS (Orbitrap) m/z [M + H]+ calcd for C23H24N5O8S 530.1340, found
530.1341; [α]D23 + 1 (c 1.85, CH2Cl2).
(4aS,5S,6aR,10aS,10bS)-5-methoxy-11-((4-nitrophenyl)sulfonyl)-9-phenyl-
4a,5,6a,7,10a,10b,11,12-octahydro-[1,3]dioxino[4',5':5,6]pyrano[4,3-e][1,2,3]triazolo[1,5-
a]pyrazine 10. Method A: Azide 9 (0.08 mmol, 40 mg) was dissolved in 1 mL of DMF and 0.3
mL of water. Then a freshly prepared aqueous solution of sodium ascorbate (NaAsc.) (1 M in
water, 16 ꢁL) and CuSO4.5H2O (0.1 M, 16 ꢁL) was added and the reaction mixture was heated
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under stirring at 60 °C for 14 days. Caution: Sodium ascorbate must be properly stored and its
solution freshly prepared. When the reaction was completed, water (5 mL) was added and the
mixture was extracted with chloroform (3x5 mL). Collected organic layers were dried with brine
and MgSO4, evaporated under reduced pressure, and the residue was purified by silica gel
chromatography using chloroform as a mobile phase to afford 10 in 90% yield (36 mg) as a
yellow solid, mp. 89ꢀ91 °C. Method B: The reaction was carried out at 80°C for 3 days in 20 mg
scale. Isolation process followed Method A and afforded 10 in 70% yield (14 mg) as a yellow
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solid. H NMR (400 MHz, DMSOꢀd6) δ 3.51 (s, 3 H, OCH3), 3.95 (t, J=9.6 Hz, 1 H, HC6ax),
4.02ꢀ4.11 (m, 2 H, HC3+HC5), 4.16 (t, J=8.9 Hz, 1 H, HC4), 4.38 (dd, J=9.3, 3.9 Hz, 1 H,
HC6eq), 4.52 (d, J=16.6 Hz, 1 H, CH2ꢀpiperazine), 5.05 (d, J=16.6 Hz, 1 H, CH2ꢀpiperazine), 5.24
(dd, J=12.2, 7.3 Hz, 1 H, HC2), 5.60 (d, J=7.3 Hz, 1 H, HC1), 5.72 (s, 1 H, CHꢀPh), 7.34 (s, 1 H,
CHꢀtriazole), 7.36ꢀ7.41 (m, 3 H, Ph), 7.41ꢀ7.47 (m, 2H, Ph), 8.05 (d, J=9.1 Hz, 2 H, Ns), 8.11 (d,
J=9.1 Hz, 2H, Ns); 13C NMR (101 MHz, DMSOꢀd6) δ 40.3, 54.3, 56.0, 56.0, 65.7, 69.5, 76.8,
99.9, 102.3, 124.7, 126.8, 128.5, 129.4, 129.5, 129.6, 133.0, 137.8, 143.1, 150.3; HRMS
(Orbitrap) m/z [M + H]+ calcd for C23H24N5O8S 530.1340, found 530.1341; [α]D ꢀ60 (c 0.6,
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CH2Cl2).
((2R)-1-((4aR,6S,7S,8S,8aS)-8-amino-6-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-
yl)pyrrolidin-2-yl)methanol 11. Sugar derivate 8p (0.09mmol, 50mg) was dissolved in
acetonitrile (2mL), then K2CO3 (0.36mmol, 50mg) and thiophenol (0.27mmol, 28ꢁL) was added.
The suspension was heated at 50°C for 2 days and the solvent was evaporated. The residue was
dissolved in CHCl3 (15mL). The organic layer was washed with water (3x15mL) and brine
(15mL), dried with MgSO4, and concentrated under reduced pressure. The purification on silica
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gel chromatography afforded 11 in 75% yield (25mg) as a yellow solid, mp. 52ꢀ54 °C. H NMR
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(400 MHz, DMSOꢀd6) δ 7.50 ꢀ 7.43 (m, 2 H), 7.40 ꢀ 7.33 (m, 3 H), 7.29 ꢀ 7.12 (m, 1 H), 5.73 (s,
1 H), 4.73 (s, 1 H), 4.40 (br. s., 1 H), 4.22 (dd, J = 4.7, 9.9 Hz, 1 H), 4.00 ꢀ 3.82 (m, 2 H), 3.74 (t,
J = 9.6 Hz, 1 H), 3.31 (s, 3 H), 3.29 (br. s., 2 H), 3.05 (t, J = 8.3 Hz, 1 H), 2.94 (t, J = 6.7 Hz, 1
H), 2.88 ꢀ 2.79 (m, 2 H), 1.87 (br. s., 2 H), 1.76 ꢀ 1.53 (m, 4 H); 13C NMR (101MHz ,DMSOꢀd6)
δ = 128.8, 128.0, 126.4, 119.5, 101.3, 100.8, 76.7, 68.5, 65.6, 64.0, 61.8, 57.2, 54.7, 51.7, 48.3,
27.6, 23.3; HRMS (Orbitrap) m/z [M + H]+ calcd for C19H28N2O5 365.2071, found 365.2071;
[α]D26 + 40 (c 0.77, CH2Cl2).
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Associated content
1H and 13C NMR spectra for all compounds; crystallographic information file (CIF) for
compound 8a.
Author information
Corresponding Author: Petr Cankař
*Eꢀmail: petr.cankar@upol.cz
Notes: The authors declare no competing financial interest
Acknowledgments
This work was supported by the Czech National Program for Sustainability (project LO1304) and
from internal faculty project IGA (IGA_PrF_2016_020) (T.R., P.C.). The financial support from
institutional sources of Dept. of Inorganic Chemistry (Z.T.) is also acknowledged.
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