Synthesis and glycosidase inhibition of conformationally locked DNJ and DMJ derivatives exploiting a 2-oxo-C -allyl iminosugar

Article abstract of DOI:10.1039/c9ob01402k

A series of analogs of the iminosugars 1-deoxynojirimycin (DNJ) and 1-deoxymannojirimycin (DMJ), in which an extra five or six-membered ring has been fused to the C1-C2 bond have been prepared. The synthetic strategy exploits a key 2-keto-C-allyl iminosugar, easily accessible from gluconolactam, which upon Grignard addition and RCM furnishes a bicyclic scaffold that can be further hydroxylated at the CC bond. This strategy furnished DNJ mimics with the piperidine ring locked in a ¹C₄ conformation with all substituents in axial orientation when fused to a six-membered ring. Addition of an extra ring to DNJ and DMJ motif proved to strongly modify the glycosidase inhibition profile of the parent iminosugars leading to modest inhibitors. The 2-keto-C-allyl iminosugar scaffold was further used to access N-acetylglycosamine analogs via oxime formation.

Full text of DOI:10.1039/c9ob01402k

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Shimadate, J. Marrot, A. Kato, J. Desire and Y. Blériot, Org. Biomol. Chem., 2019, DOI:
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DOI: 10.1039/C9OB01402K
ARTICLE
Synthesis and glycosidase inhibition of conformationally locked
DNJ and DMJ derivatives exploiting a 2-oxo-C-allyl iminosugar
Received 00th January 20xx,
Accepted 00th January 20xx
Quentin Foucart,a Yuna Shimadate,b Jérôme Marrot,c Atsushi Kato,*b Jérôme Désiré*a and Yves
Blériot*a
DOI: 10.1039/x0xx00000x
A series of analogs of the iminosugars deoxynojirimycin (DNJ) and deoxymannojirimycin (DMJ), in which an extra five or
six-membered ring has been fused to the C1-C2 bond have been prepared. The synthetic strategy exploits a key 2-keto-C-
allyl iminosugar, easily accessible from gluconolactam, which upon Grignard addition and RCM furnishes a bicyclic scaffold
that can be further hydroxylated at the C=C bond. This strategy furnished DNJ mimics with the piperidine ring locked in a
1C4 conformation with all substituents in axial orientation when fused to a six-memebered ring. Addition of an extra ring to
DNJ and DMJ motif proved to strongly modify the glycosidase inhibition profile of the parent iminosugars leading to
modest inhibitors. The 2-keto-C-allyl iminosugar scaffold was further used to access N-acetylglycosamine analogs via
oxime formation.
well as conidines,13 has been reported (Figure 1). In
continuation of our efforts dedicated to the design and
biological evaluation of conformationally biased iminosugars
Introduction
The biology and synthesis of the polyhydroxylated indolizidine
alkaloid castanospermine1 has been the subject of intensive
research. This naturally occuring bicyclic iminosugar, in which
the endocyclic oxygen atom of the parent sugar is replaced by
including flexible structures14,15,16 and locked derivatives,17 we
have investigated herein the relevance as glycosidase
inhibitors of bicyclic compounds in which the ring fused to the
iminosugar ring found in castanospermine has been moved
from the C5-N bond to the iminosugar C1-C2 bond as in A
(Figure 1). Actually, such 1,2-annulated carbohydrate motif has
attracted special attention within the structurally rich class of
carbon-branched carbohydrates18,19 but this scaffold is scarce
in the iminosugar field.20,21 We expected that introduction of a
five- or six-membered ring 1,2-annulated to the
polyhydroxylated piperidine ring would lock the iminosugar
ring into a unique conformation22,23 while maintaining the
hydroxyl pattern of the polyhydroxylated piperidine affording
unprecedented bicyclic analogs of the canonical
deoxynojirimycin (Figure 1). We reasoned that structures of
type A could be accessed from gluconolactam 1a via a
regioselective deprotection at C-2 followed by conversion into
a C-allyl iminosugar with subsequent introduction of an alkene
at C-2 to allow final RCM and deprotection.
a
nitrogen atom, has indeed demonstrated significant
therapeutic potential2 for the treatment of a number of
pathologies.3 Therefore, many synthetic analogues have been
designed to improve the pharmacological properties and
selectivity of the parent molecule.3,4 Along with chemical
modifications of the hydroxyl groups of this molecule,5,6
branched derivatives,7 as well as other analogs with a modified
five-membered ring,8 have been explored. As the five-
membered ring present in castanospermine plays a crucial role
to lock the deoxynojirimycin (DNJ) iminosugar moiety in a
precise conformation, orientating the OH group at C-6 in a
pseudoaxial orientation9 that has been shown important for
binding,10 an array of bicyclic derivatives, in which the ring size
a. Université de Poitiers, IC2MP, UMR CNRS 7285
Equipe “Synthèse Organique”, Groupe Glycochimie
4 rue Michel Brunet, 86073 Poitiers cedex 9, France
E-mail: jerome.desire@univ-poitiers.fr; yves.bleriot@univ-poitiers.fr
b. Department of Hospital Pharmacy, University of Toyama,
2630 Sugitani, Toyama 930-0194, Japan
Results and discussion
Synthesis
E-mail: kato@med.u-toyama.ac.jp
c. Institut Lavoisier de Versailles, UMR-CNRS 8180, Université de Versailles, 45
avenue des États-Unis, 78035 Versailles Cedex, France.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: Copies of 1H, 13C NMR
spectra of all new compounds and X-ray crystallography data for compound 10b.
See DOI: 10.1039/x0xx00000x
Furman has reported the synthesis of C-alkyl and C-aryl
iminosugars exploiting sugar lactams24 via formation of the
corresponding imine, using the Schwartz’s reagent,25 followed
by its trapping with nucleophiles. We envisioned that this
sequence could be applied to a 2-hydroxy derivative that could
be further modified at C-2 position en route to A. To this end,
of one of the two rings has been modified, leading respectively
to polyhydroxylated quinolizidines,11 perhydroazaazulenes12 as
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the regioselective debenzylation of 1a was achieved with
BCl326 to yield the 2-hydroxy lactam 2a in 83% yield.
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Scheme 1 : Synthesis of C-allyl iminosugar 6 from D-gluconolactam 1a
DOI: 10.1039/C9OB01402K
Overall, the C-allyl iminosugar 6 was obtained in 27% yield
from D-gluconolactam 1 over five steps. This sequence is
complementary to the one recently reported to access 2-
hydroxy -C-allyl iminosugars.31 Oxidation of 6 with PDCP and
DMSO furnished the ketone 7 in 91% yield. Its allylation with
allyl magnesium bromide at -78°C afforded a 1:1 separable
mixture of the D-manno 8a (39%) and D-gluco 8b (39%)
configured 1,2-di-C-allyl piperidines. Each compound was then
submitted to ring closing metathesis using Hoveyda-Grubbs
catalyst in CH2Cl2 at 40°C and provided the corresponding
bicycles 9a (89%) and 9b (87%), which upon hydrogenolysis,
uneventfully and quantitatively provided the expected
tetrahydroxylated cis- and trans-decahydroquinolines 10a and
10b respectively (Scheme 2). The conformation in solution of
the D- gluco-like isomer 10b was studied by NMR, allowing the
assignment of a 1C4 conformation for the polyhydroxylated
piperidine ring (J3-4 = 2.4 Hz), a conformation also observed in
the solid state by X-ray crystallography (Scheme 2).
Interestingly, compound 10b can be seen as a DNJ analogue
with all hydroxyl groups adopting a pseudo-axial orientation.
Such conformation has been invoked to explain the strong
glucocerebrosidase inhibition developed by imino-D-xylitols
(DIX) derivatives.32 We next examined the dihydroxylation of
alkenes 9a and 9b. Using a standard protocol (OsO4, NMO in
wet acetone), 9a furnished the separable endo diol 11a (22%)
and exo diol 11a’ (39%) in reasonable yield (see SI). The same
reaction applied to alkene 9b furnished the endo diol 11b
(19%) along with the exo diol 11b’ (35%). Separate
hydrogenolysis of these four triols provided the
hexahydroxylated decahydroquinolines 12a, 12a’, 12b and
12b’ respectively (Scheme 2). To investigate the eventual
impact of the size of the additional ring on the glycosidase
inhibition profile of these derivatives, the synthesis of
Figure 1: Structures of known natural and synthetic bicyclic
iminosugars and proposed new synthetic derivatives To
further exemplify the generality of this deprotection that also
works with the D-manno configured lactam,27 it was
succesfully applied to the D-galactonolactam 1b to produce
the corresponding alcohol 2b in good yield (93%). Alcohol 2a
was then treated with the Schwartz’s reagent followed by
AllSnBu3 and Yb(OTf)3. Unfortunately, no C-allyl iminosugar 5
was detected and only the starting lactam was recovered,
demonstrating the detrimental role of the OH at C-2 in this
transformation. The 2-OH was therefore orthogonally
protected as its silyl ether with TBDMSOTf to afford lactam 328
(89%) that, upon Furman’s procedure, provided the -C-allyl
piperidine 4 (68%) as a single diastereomer, resulting from
addition of AllSnBu3 syn to the TBSO group of the imine B
adopting a 4H3 conformation, in agreement with Woerpel’s
model.29 As manipulation of Schwartz’s reagent proved tricky,
we investigated a one-pot procedure,30 in which the reagent
was generated in situ from Cp2ZrCl2, that furnished compound
4 in a similar 66% yield. Removal of the TBDMS group with
TBAF provided the 2-hydroxypiperidine 5 (74%) that was
further N-benzylated to obtain the key intermediate 6 (74%)
(Scheme 1).
polyhydroxylated
octahydro-1H-Cyclopenta[b]
pyridine
analogues bearing a six-five fused rings system was examined
starting from ketone 7 (Scheme 3). Vinylation of 7 with
CH2=CHMgBr produced the separable D-manno (60%) and D-
gluco- configured (15%) dienes 13a and 13b respectively. Their
ring closing metathesis yielded the bicyclic alkene 14a (87%)
and 14b (84%) that, upon hydrogenolysis, furnished the five-
six fused analogs 15a and 15b respectively. Unlike the previous
alkenes 9a and 9b, dihydroxylation of alkenes 14a and 14b
failed in our hands while such reaction has been reported for
related systems (Scheme 3).33
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in order to introduce a pseudoanomeric CH2OH group, yielding
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DOI: 10.1039/C9OB01402K
only 19 in 32% yield with no trace of the target compound 20
(Scheme 4). Nevertheless, compound 19 is a useful synthon to
introduce structural diversity at the C-4 position of the C-allyl
iminosugar scaffold.
Scheme 3 : Synthesis of bicyclic iminosugars 15a and 15b
Scheme 2 : Synthesis of bicyclic iminosugars 10a, 10b, 12a, 12a’, 12b, 12b’ and X-ray
structure of 10b
The 2-oxo-C-allyl iminosugar 7 holds an important synthetic
potential and could be useful to access other types of
iminosugars. Because of our interest for hexosaminidase
inhibitors,15,16 compound 7 was converted to its crude oxime
(NH2OH, pyr.) that was directly reduced with LiAlH4 and further
acetylated with Ac2O to provide the D-gluco 16 (8%) and the D-
manno- 17 (28%) configured 2-acetamido C-allyl iminosugars.
This sequence, that does not involve nucleophilic displacement
of the hydroxyl at C-2 position to introduce an acetamide, is
appealing as it avoids competitive ring contraction,31 providing
only the piperidine derivatives albeit in modest yield. In
parallel, we also examined the introduction of an additional
allyl group at the pseudoanomeric position in order to access a
1,1-diallyl piperidine scaffold12 en route to bisubstrate analogs
and spiro-iminosugars.34 We expected the ketone at C-2 to
guide the allylation at C-1. Unfortunately, when derivative 7
was treated with LiHMDS and allyl bromide at -78°C in THF, no
trace of the diallyl derivative 18 was detected and only an
unsaturated product 19 resulting from the elimination of the
benzyloxy group at C-4 was isolated in 20%. A similar product
has been reported in the C-allyl glucoside series when treated
with 10% Et3N in MeOH.35 Applying these reaction conditions
to 7 raised the yield of this transformation to 91%. A similar
result was observed when aldol conditions36 were applied to 7
Scheme 4 : Chemical exploration of 2-oxo-C-allyl iminosugar 7
Glycosidase inhibition
Finally, all the polyhydroxylated bicyclic piperidines were
assayed on a panel of fifteen targeted glycosidases and proved
to be modest glycosidase inhibitors. As shown in Table 1, the
basic structure, 1-deoxymannojirimycin (DMJ) is a known weak
inhibitor of Jack bean α-mannosidase and bovine kidney α-L-
fucosidase, with IC50 values of 803 and 354 μM, respectively. In
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contrast, the corresponding bicyclic iminosugar 10a was of the additional ring have a significant influence on the
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DOI: 10.1039/C9OB01402K
completely inactive on all glycosidases tested even at glycosidase inhibition spectrum of this family of iminosugars
concentrations as high as 1000 μM demonstrating the leading to molecules with profile distinct from the one found
detrimental role of the additional six-membered ring on for the parent monocyclic compound.
inhibition. Cis-dihydroxylation of this ring as in 12a’ and 12a
led to molecules that weakly inhibited rice α-glucosidase, with
IC50 values of 564 and 967 μM, respectively. These results
clearly suggest that the presence of two hydroxyl groups in the
tetrahydroquinoline ring is one of the essential features for
recognition by the active site of α-glycosidase. It is noteworthy
that 15a, displaying a smaller five-membered fused ring,
showed a broader inhibition spectrum including activity
towards rice α-glycosidase, bovine liver β-glucosidase, coffee
beans α-galactosidase and bovine liver β-galactosidase, with
IC50 values of 654, 298, 560, and 359 μM, respectively.
Experimental
General Methods. All starting materials and reagents were
purchased from commercial sources, and used as received without
further purification. Air and H2O sensitive reactions were performed
in oven dried glassware under Ar atmosphere. Moisture sensitive
reagents were introduced via a dry syringe. Anhydrous solvents
were supplied over molecular sieves, and used as received.
Petroleum ether (PE) refers to the 40-60 °C boiling fraction.
Powdered molecular sieves were activated before use by heating
for ~5 min under high vacuum. Reactions were monitored by thin-
layer chromatography (TLC) with silica gel 60 F254 0.25 mm pre-
coated aluminum foil plates, visualized by using UV254 and/or
1-Deoxynojirimycin (DNJ) is well known as potent inhibitor
phosphomolybdic acid stain [3 g 12MoO3.H3PO4.xH2O in 100 mL
toward rice and intestinal maltases (Table 2). This compound
EtOH] followed by heating with
a heat gun. Flash column
also showed porcine kidney trehalase and A. niger
amyloglucosidase inhibition, with IC50 values of 64 and 781
μM, respectively. As for 10a, introduction of an additional six-
membered ring in 10b almost completely abolished the
inhibition profile of the parent DNJ and led only to a weak
inhibitor of bovine liver β-galactosidase. Dihydroxylation of the
extra ring present in 10b produced 12b’ and 12b that proved
much weaker inhibitors against α-glucosidases compared to
DNJ. However, it should be noted that 12b’ and 12b showed
some inhibition toward coffee beans α-galactosidase and P.
decumbens α-L-rhamnosidase. As in the mannose series with
15a, the gluco-configured bicycle 15b showed a broader
inhibition spectrum compared to its congeners and
competitively inhibited bovine liver β-glucosidase, β-
galactosidase, and E.coli β-glucuronidase. Altogether, these
data clearly suggested that the size and hydroxylation pattern
chromatography was performed using Macherey-Nagel silica gel 60
(15–40 μm). NMR experiments were recorded with a Bruker Avance
1
400 spectrometer at 400 MHz for H nuclei and at 100 MHz for 13C
nuclei. The chemical shifts are expressed in part per million (ppm)
relative to TMS ( = 0 ppm) and the coupling constant J in Hertz
(Hz). NMR multiplicities are reported using the following
abbreviations: br = broad, s = singlet, d = doublet, t = triplet, q =
quadruplet, m = multiplet. HRMS were recorded on a Bruker
micrOTOF spectrometer. The melting points were recorded with a
SMP50 Stuart Scientific melting point apparatus. Optical rotations
were measured using an Anton Paar MCP100 Polarimeter.
General procedure A for RCM. To a solution of 1,2-bis-allyl or 1-
allyl-2-vinyl derivative in dry CH2Cl2 (0.05 M) under Ar atmosphere
was added Hoveyda-Grubbs catalyst 2nd generation (0.1 eq.). The
reaction mixture was stirred at 50 °C for 2 h by which time TLC
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monitoring showed the total consumption of the starting material. 4.09 mmol, 92%) as a colorless oil. Analytical data were in agreement with
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Lead(IV) acetate (1.5 eq. per eq. of catalyst) was added and the literature.28
DOI: 10.1039/C9OB01402K
reaction mixture was stirred at room temperature for 3 h. The α-C-allyl-3,4,6-tri-O-benzyl-2-O-[(tert-butyl)dimethylsilyl]-1-deoxynojirimycin
mixture was concentrated under reduced pressure and purified by (4). Compound 3 (2.30 g, 4.09 mmol) and Cp2ZrCl2 (3.59 g, 12.28 mmol, 3 eq.)
flash chromatography.
were dissolved in freshly distilled THF (82 mL) under Ar atmosphere at room
General procedure B for total debenzylation. The benzylated temperature. A 1 M solution of LiAlH(OBu-t)3 in THF (12.28 mL, 12.28 mmol, 3
substrate was dissolved in a 1:1 mixture of i-PrOH/THF (0.05 M - eq.) was rapidly added and the mixture was stirred at room temperature.
v/v). The mixture was flushed 4 times with Ar then a 1M solution of After 30 min, the solution became clear, indicating the end of the reduction.
HCl (3 eq.), palladium black (0.5 mass eq.) and palladium on carbon The mixture was cooled to -25 °C and Yb(OTf)3 (2.54 g, 4.09 mmol, 1 eq.) and
(0.5 mass eq.) were added. The mixture was flushed 4 times with H2 AllSnBu3 (3.8 mL, 12.28 mmol, 3 eq.) were added. The mixture was stirred for
and stirred at room temperature under H2 atmosphere. After 24 h, 18 h at room temperature then concentrated under reduced pressure. The
the mixture was filtered on a celite pad and the filtrate was crude residue was purified by flash chromatography on a silica gel containing
concentrated under reduced pressure to give the fully deprotected 10% of K2CO3 (petroleum ether/EtOAc 90:10), affording compound 4 (1.59 g,
product as its hydrochloride salt.
[훂]ퟐퟎ
=+22.0 (c
퐃
2.70 mmol, 66%) as a yellow oil. Rf = 0.35 (PE/EtOAc 90:10);
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.37-7.10 (m, 20H, CH-Ar), 5.82-5.72
(m, 1H, H-2’), 5.13-5.09 (m, 2H, H-3’), 4.91 (d, J = 11.4 Hz, 1H, OCHH-Ph), 4.80-
4.77 (m, 2H, OCHH-Ph), 4.51(d, J = 11.9 Hz, 1H, OCHH-Ph), 4.43 (d, J =11.2Hz,
2H, OCHH-Ph), 3.88 (dd, J = 9.2 Hz, J = 5.6 Hz, 1H, H-2), 3.64 (dd, J = 9.2 Hz, J =
2.6Hz, 1H, H-6a), 3.56(t, J=9.1Hz, 1H, H-3), 3.51(dd, J=9.1Hz, J=6.4Hz, 1H,
H-6b),3.36(t,J=9.4Hz,1H,H-4),3.06-3.01(m,2H,H-5,H-1),2.56-2.49(m,1H,
H-1’a),2.34-2.26(m,1H,H-1’b),0.91(s,9H,C(CH3)3),0.08(s,3H,SiCH3),0.06(s,
General procedure C for dihydroxylation. To a solution of olefin
substrate in a 1:1 mixture of acetone/H2O (0.06 M – v/v) were
added citric acid (1.1 eq.), 4-methylmorpholine N-oxide (1.2 eq) and
OsO4 (0.2 eq.). The mixture was stirred at room temperature for 18
h when TLC showed total consumption of the starting material.
Na2S2O5 (1.2 eq.) was added and the mixture was stirred at room
temperature for 1 h. The mixture was extracted 3 times with EtOAc
and the combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The crude residue was
purified by flash chromatography.
IV
3H, SiCH3); 13C NMR (100 MHz, CDCl3): δ 139.2, 138.4, 138.3 (C -Ar), 136.1 (C-
2’), 128.5-127.4 (CH-Ar), 117.6 (C-3’), 84.1 (C-3), 80.6 (C-4), 75.5, 75.3 (OCH2-
Ph), 74.8 (C-2), 73.3 (OCH2-Ph), 70.6 (C-6), 57.0 (C-1), 52.8 (C-5), 29.4 (C-1’),
26.1 (C(CH3)3), 18.1 (C(CH3)3), -4.4 (SiCH3), -4.5 (SiCH3); HRMS (ESI+) calcld for
C36H49NO4Si[M+H]+:588.8733,found:588.8731.
α-C-allyl-3,4,6-tri-O-benzyl-1-deoxynojirimycin(5).Toasolutionofcompound
4 (1.59 g, 2.71 mmol) in dry THF (45 mL) under Ar atmosphere was added a
TBAF solution (1 M/THF, 4.1 mL, 4.06 mmol, 1.5 eq.) at room temperature.
The mixture was stirred overnight at room temperature and quenched with
H2O (90 mL). The mixture was extracted with EtOAc (3x45 mL) and the
combined organic layers were dried over MgSO4 and concentrated under
reduced pressure. Flash chromatography (RediSep® 24 g, petroleum
ether/EtOAc 90:10 to 60:40) afforded compound 5 (948 mg, 2.00 mmol, 74%)
asawhitesolid.Analyticaldatawereinagreementwithliterature.31
α-C-allyl-3,4,6-tri-O-benzyl-N-benzyl-1-deoxynojirimycin (6). To a solution a
compound5(948mg,2.00mmol)ina1:1mixtureofEtOAc/H2O(40mL)were
added benzyl bromide (476 µL, 4.00 mmol, 2 eq.) and KHCO3 (2.00 g, 20.02
mmol, 10 eq.). The mixture was stirred at 80 °C for 24 h and quenched with
H2O (80 mL). The mixture was extracted with Et2O (3x40 mL), the combined
organic layers were dried over MgSO4 and concentrated under reduced
pressure. Flashchromatography(RediSep® 12g, petroleumether/EtOAc95:05
to 90:10) afforded compound 6 as a yellow oil (835 mg, 1.48 mmol, 74%).
Analyticaldatawereinagreementwithliterature.31
3,4,6-tri-O-benzyl-galactono-δ-lactam (2b). To a solution of lactam 1b (119
mg, 0.22 mmol) in dry CH2Cl2 (0.03 M) under Ar atmosphere was added
Bu4NBr (106 mg, 0.33 mmol, 1.5 eq.). The solution was cooled to -78 °C and a
1M solution of BCl3 in CH2Cl2 (420 µL, 0.44 mmol, 2 eq.) was added dropwise
over a 30 min period. The mixture was stirred from -78 °C to 0 °C overnight
when TLC analysis showed no trace of the starting material. The mixture was
quenched with a saturated solution of Na2CO3 and the aqueous layer was
extracted three times with CH2Cl2. The combined organic layers were dried
over MgSO4 and concentrated under reduced pressure. The crude residue
was purified by flash chromatography (RediSep® 4 g, petroleum ether/EtOAc
35:65)togivecompound2b(91mg,0.21mmol,93%)asawhitewaxysolid.Rf
[훂]ퟐퟎ
1
= 0.29 (PE/EtOAc 35:65);
=+25.3 (c 1.5, CHCl3); H NMR (400 MHz,
퐃
CDCl3):δ7.42-7.25(m,15H,CH-Ar),6.18(br.s,1H,NH),4.99(d,J=11.5Hz,1H,
OCHH-Ph), 4.93 (d, J = 12,1 Hz, 1H, OCHH-Ph), 4.76 (d, J = 12.1 Hz, 1H, OCHH-
Ph), 4.61-4.57 (m, 2H, OCHH-Ph, H-2), 4.47 (ABq, J = 11.7 Hz, 2H, OCH2-Ph),
3.99 (br. s, 1H, H-4), 3.75 (dd, J = 9.9 Hz, J = 1.8 Hz, 1H, H-3), 3.59-3.53 (m, 2H,
H-6a, H-5), 3.43-3.40 (m, 1H, H-6b); 13C NMR (100 MHz, CDCl3): δ 172.4 (C-1),
IV
138.3, 138.0, 137.4 (C -Ar), 128.7-127.8 (CH-Ar), 81.0 (C-3), 74.5, 73.7 (OCH2-
Ph), 73.4 (C-4), 73.1 (OCH2-Ph), 70.4 (C-2), 70.4 (C-6), 54.2 (C-5); HRMS (ESI+)
calcldforC27H29NaNO5 [M+Na]+:470.1938,found:470.1947.
α-C-allyl-3,4,6-tri-O-benzyl-N-benzyl-2-keto-1-deoxynojirimycin (7). To
a
3,4,6-tri-O-benzyl-2-O-[(tert-butyl)dimethylsilyl]-D-glucono--lactam (3). To a
solution of compound 2a (1.97 g, 4.44 mmol) in dry CH2Cl2 (44 mL) under Ar
atmosphere was added pyridine (1.6 mL, 19.99 mmol, 4.5 eq.) The mixture
was cooled to 0 °C and TBDMSOTf (1.5 mL, 6.66 mmol, 1.5 eq.) was added.
The mixture was stirred for 1 h at room temperature and quenched with H2O
(80 mL). The mixture was extracted with CH2Cl2 (3x40 mL) and the combined
organic layers were dried over MgSO4 and concentrated under reduced
pressure. The crude residue was purified by flash chromatography (RediSep®
24 g, petroleum ether/EtOAc 100:0 to 70:30), affording compound 3 (2.30 g,
solution of DMSO (1.14 mL, 16.02 mmol, 5 eq), Et3N (2.25 mL, 16.02 mmol, 5
eq.) and phenyl dichlorophosphate (1.44 mL, 9.61 mmol, 3 eq) in dry CH2Cl2
(32 mL) at -10 °C under Ar atmosphere was added a solution of compound 5
(1.80g, 3.20mmol)indryCH2Cl2 (32mL)at-10°C. Themixturewasallowedto
warm up to room temperature and after 2 h stirring, the mixture was
quenched with water (100 mL) and extracted with CH2Cl2 (3x50 mL). The
combined organic layers were dried over MgSO4, filtered and concentrated
under reduced pressure. Flash chromatography (RediSep® 24 g, petroleum
ether/EtOAc 90:10) afforded compound 7 (1.63 g, 91%) as a yellow oil. Rf =
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
[훂]ퟐퟎ
OCHH-Ph), 4.59 (d, J = 11.4 Hz, 1H, OCHH-Ph), 4.50 (d, J = 10.9 Hz, 1H, OCHH-
DOI: 10.1039/C9OB01402K
Ph), 4.36 (m, 2H, OCHH-Ph), 4.16 (d, J = 13.4 Hz, 1H, NCHH-Ph), 3.99 (t, J = 9.5
0.44 (PE/EtOAc 90:10);
=-6.2 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3): δ
퐃
View Article Online
7.44-7.19(m,20H,CH-Ar),5.78-5.68(m,1H,H-2’),5.04-5.00(m,2H,H-3’),4.88
(d, J=11.5Hz, 1H, OCHH-Ph), 4.65(d, J=11.3Hz, 1H, OCHH-Ph), 4.54-5.47(m,
3H, OCHH-Ph, H-3), 4.43 (s, 2H, OCHH-Ph), 3.96 (d, J = 14.3 Hz, 1H, NCHH-Ph),
3.88 (dd, J = 7.3 Hz, J = 5.1 Hz, 1 H, H-4), 3.83 (d, J = 14.3 Hz, NCHH-Ph), 3.68
(dd, J=10.0Hz, J=5.3Hz, 1H, H-6a), 3.57(dd, J=10.0Hz, J=4.7Hz, 1H, H-6b),
3.41-3.37 (m, 2H, H-5, H-1), 2.60-2.44 (m, 2H, H-1’a, H-1’b); 13C NMR (100
Hz, 1H, H-3), 3.76 (m, 2H, CH2-OBn), 3.61 (d, J = 9.3 Hz, 1H, H-4), 3.54 (s, 1H,
OH), 3.42 (d, J = 13.3 Hz, 1H, NCHH-Ph), 2.96-2.80 (m, 2H, H-8a, H-2), 2.59 (dd,
J = 17.7, 5.4 Hz, 1H, H-5), 2.29-2.12 (m, 2H, H-7), 1.87-1.82 (m, 1H, H-5); 13
C
IV
NMR (100 MHz, CDCl3): δ 139.2, 138.5, 138.2 (C -Ar), 128.7-127.3 (CH-Ar),
124.8 (C-6), 124.2(C-7), 80.37(C-4), 78.6 (C-3), 75.6, 75.6, 73.1 (OCH2-Ph), 71.0
(C-4a), 67.3 (CH2-OBn), 60.1 (C-2), 58.9 (C-8a), 52.7 (NCH2-Ph), 33.2 (C-5), 20.1
(C-8);HRMS(ESI+)calcldforC38H42NO4 [M+H]+:576.3130,found:576.3108.
(2R,3R,4S,4aS,8aR)-1-benzyl-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-
1,3,4,5,8,8a-hexahydroquinolin-4a(2H)-ol (9b). Compound 9b was
synthesized according to procedure A from 8b (400 mg, 0.66 mmol). Flash
chromatography (RediSep® 12 g, petroleum ether/EtOAc 90:10) afforded
[훂]ퟐퟎ
IV
MHz, CDCl3): δ 208.1 (C-2), 138.9, 138.3, 137.9, 137.8 (C -Ar), 132.9 (C-2’),
128.5-127.1 (CH-Ar), 118.1 (C-3’), 86.0 (C-3), 81.7 (C-4), 73.4, 73.3, 72.9 (OCH2-
Ph), 67.5 (C-6), 67.0 (C-1), 58.4 (C-5), 52.7 (NCH2-Ph), 34.4 (C-1’); HRMS (ESI+)
calcldforC37H40NaNO4 [M+Na]+:584.2771,found:584.2779.
α-C-allyl-2-C-allyl-3,4,6-tri-O-benzyl-N-benzyl-1-deoxymannojirimycin (8a)
and α-C-allyl-2-C-allyl-3,4,6-tri-O-benzyl-N-benzyl-1-deoxynojirimycin (8b).
Compound 7 (1.00 g, 1.78 mmol) was dissolved in a 2:1 mixture of dry compound 9b (339 mg, 89%) as a brown oil. Rf = 0.40 (PE/EtOAc 90:10);
퐃
toluene/CH2Cl2 (24 mL) under Ar atmosphere. The mixture was cooled to -78 =-75.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.37-7.18 (m, 20H, CH-Ar),
°C and a solution of AllMgBr (1M/THF, 4.6 mL, 4.63 mmol, 2.6 eq.) was added 5.62-5.56(m, 2H, H-6+H-7), 4.52(d, J=11.4Hz, 1H, OCHH-Ph), 4.42(d, J=11.4
dropwise. The mixture was stirred for 2 h at -78 °C and quenched with a Hz, 1H, OCHH-Ph), 4.38-4.28 (m, 4H, OCHH-Ph), 4.20 (d, J = 2.4 Hz, 1H, OH),
saturated aqueous solution of NH4Cl (30 mL). The organic layer was extracted 4.04 (d, J = 14.1 Hz, NCHH-Ph), 3.92 (dd, J = 9.5 Hz, J = 5.5 Hz, 1H, CHH-OBn),
with Et2O (3x15 mL) and the combined organic layers were dried over MgSO4, 3.85 (t, J = 2.3 Hz, 1H, H-3), 3.80 (dd, J = 9.4 Hz, J = 7.5 Hz, 1H, CHH-OBn), 3.69
filtered and concentrated under reduced pressure. Flash chromatography (d, J = 14.1 Hz, NCHH-Ph), 3.46 (broad s, 1H, H-4), 3.37-3.33 (m, 1H, H-2), 3.23
(RediSep®12g, petroleumether/EtOAc95:05)affordedcompound8a(yellow (dd, J = 10.4 Hz, J = 5.9 Hz, 1H, H-8a), 2.73-2.68 (m, 1H, H-5), 2.28-2.11 (m, 2H,
oil, 419 mg, 39%) and 8b (yellow oil, 419 mg, 39%). Analytical data for 8a: Rf = H-8), 1.96-1.92 (m, 1H, H-5); 13C NMR (100 MHz, CDCl3): δ141.0, 138.6, 138.0,
[훂]ퟐퟎ
137.8 (C -Ar), 128.5-126.8 (CH-Ar), 123.9, 123.7 (C-6, C-7), 78.7 (C-4), 73.5 (C-
3), 73.1, 73.0, 70.9 (OCH2-Ph), 70.5 (C-4a), 65.5 (CH2-OBn), 56.7 (C-2), 52.8 (C-
8a), 51.7 (OCH2-Ph), 32.9 (C-5), 27.8 (C-8); HRMS (ESI+) calcld for C38H42NO4
[M+H]+:576.3108,found:576.3131.
IV
0.31(PE/EtOAc95:05);
=-32.0(c0.5,CHCl3);1HNMR(400MHz,CDCl3):δ
퐃
7.37-7.14 (m, 20H, CH-Ar), 5.81-5.64 (m, 2H, H-2’, H-2”), 5.08-4.95 (m, 2H, H-
3’), 4.93-4.88 (m, 3H, OCHH-Ph, H-3”), 4.80 (d, J = 10.9 Hz, 1H, OCHH-Ph), 4.63
(d, J=11.1Hz, 1H, OCHH-Ph), 4.48(d, J=10.9Hz, 1H, OCHH-Ph), 4.22(ABq, J=
16.1 Hz, 2H, OCHH-Ph), 4.08 (d, J = 13.9 Hz, 1H, NCHH-Ph), 3.98 (t, J = 9.1 Hz,
1H, H-4), 3.78-3.64 (m, 3H, NCHH-Ph, H-6a, H-6b), 3.47 (d, J = 8.7 Hz, 1H, H-3),
3.39 (broad s, 1H, OH), 2.96-2.94 (m, 1H, H-5), 2.81 (dd, J = 7.6 Hz, J = 4.6 Hz,
1H, H-1), 2.71-2.66 (m, 1H, H-1”a), 2.52-2.44 (m, 1H, H-1’a), 2.22-2.10 (m, 1H, oil.
(2R,3R,4S,4aR,8aR)-2-(hydroxymethyl)octahydroquinoline-3,4,4a(2H)-triol
hydrochloride(10a). ApplicationofprocedureBtocompound9a(60mg, 0.10
mmol)affordedcompound10a(26mg, 99%, hydrochloridesalt)asacolorless
[훂]ퟐퟎ
=14.0 (c 1.0, MeOH); 1H NMR (400 MHz, methanol-d4): δ 3.93 (dd, J
퐃
H-1’b), 1.89-1.83 (m, 1H, H-1”b); 13C NMR (100 MHz, CDCl3): δ 140.2, 138.6, = 11.7 Hz, 1H, CHH-OH), 3.84-3.76 (m, 3H, CHH-OH, H-4, H-3), 3.28-3.27 (m,
IV
138.4, 138.2 (C -Ar), 137.8 (C-2’), 133.7 (C-2”), 128.8-127.0 (CH-Ar), 117.5 (C- 1H, H-8a), 3.25-3.21 (m, 1H, H-2), 2.31-2.28, 1.92-1.80, 1.64-1.62, 1.44-1.35,
3”), 116.1 (C-3’), 84.0 (C-3), 78.4 (C-4), 75.6 (C-2), 75.5, 75.3, 73.0 (OCH2-Ph), 1.29-1.23(m,8H,H-5,H-6,H-7,H-8);13CNMR(100MHz,methanol-d4):δ72.8
67.0(C-6), 62.4(C-1), 59.5(C-5), 53.6(NCH2-Ph), 38.2(C-1”), 29.3(C-1’);HRMS (C-4a), 70.9 (C-4), 68-7 (C-3), 62.2 (C-8a), 59.5 (CH2-OH), 57.4 (C-2), 34.7, 25.7,
(ESI+) calcld for C40H46NO4 [M+H]+: 604.3421, found: 604.3438. Analytical data 25.4, 23.1 (C-5, C-6, C-7, C-8); HRMS (ESI+) calcld for C10H19NO4: [M+H]+:
[훂]ퟐퟎ
218.1387,found:218.1399.
for 8b: Rf = 0.38 (PE/EtOAc 95:05);
=-26.7 (c 0.6, CHCl3); 1H NMR (400
퐃
(2R,3R,4S,4aS,8aR)-2-(hydroxymethyl)octahydroquinoline-3,4,4a(2H)-triol
hydrochloride(10b).ApplicationofprocedureBtocompound9b(60mg,0.10
mmol) afforded compound 10b (26 mg, 99%, hydrochloride salt) as a white
MHz, acetone-d6): δ 7.42-7.22 (m, 20H, CH-Ar), 6.04-5.93 (m, 1H, H-2’), 5.59-
5.49 (m, 1H, H-2’’), 5.14-4.94 (m, 2H, H-3’), 4.90-4.80 (m, 5H, OCHH-Ph, H-3’’),
4.55 (d, J = 11.1 Hz, 1H, OCHH-Ph), 4.35 (s, 2H, OCHH-Ph), 4.17 (d, J = 13.9 Hz,
1H, NCHH-Ph), 3.84-3.76(m, 3H, H-6a, H-6b, H-4), 3.74-3.69(m, 2H, NCHH-Ph, waxy solid.
[훂]ퟐퟎ
=45.0 (c 1.0, MeOH); 1H NMR (400 MHz, methanol-d4): δ
퐃
H-3), 3.23 (br. s, 1H, OH), 2.99-2.97 (m, 1H, H-5), 2.91-2.89 (m, 1H, H-1), 2.68- 4.17(dd, J=11.9, 10.5Hz, 1H, CHH-OH), 3.88(d, J=1.3Hz, 1H, H-3), 3.78(dd, J
2.61 (m, 3H, H-1’a, H-1’’), 2.53-2.49 (m, 1H, H1’b); 13C NMR (100 MHz, = 12.3, 4.7 Hz, 1H, CHH-OH), 3.55 (dd, J = 10.0, 4.4 Hz, 1H, H-2), 3.50 (d, J = 2.4
acetone-d6): δ 141.6 (C -Ar), 140.8 (C-2’), 140.3, 139.7, 139.5 (CIV-Ar), 135.1 Hz,1H,H-4),3.42-3.38(m,1H,H-8a),1.85-1.35(m,8H,H-7,H-8,H-9,H-10);13C
IV
(C-2’’), 130.0-127.3(CH-Ar), 118.4(C-3’’), 115.1(C-3’), 85.6(C-3), 78.6(C-4), 76- NMR (100 MHz, methanol-d4): δ 72.1 (C-4a), 71.7 (C-4), 70.2 (C-3), 63.1 (C-2),
6 (C-2), 75.4, 75.0, 73.3 (OCH2-Ph), 68.5 (C-6), 62.0 (C-1), 60.4 (C-5), 53.6 58.4 (CH2-OH), 51.9 (C-4a), 34.1, 25.7, 25.3, 20.5 (C-7, C-8, C-9, C-10); HRMS
(NCH2-Ph), 38.3 (C-1’’), 28.8 (C-1’); HRMS (ESI+) calcld for C40H46NaNO4 (ESI+)calcldforC10H19NO4:[M+H]+:218.1387,found:218.1396.
[M+Na]+:626.3241,found:626.3258.
(2R,3R,4S,4aR,6R,7S,8aR)-1-benzyl-3,4-bis(benzyloxy)-2-
(2R,3R,4S,4aR,8aR)-1-benzyl-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-
(benzyloxymethyl)octahydro quinolone-4a,6,7(2H)-triol (11a) and
1,3,4,5,8,8a-hexahydroquinolin-4a(2H)-ol (9a). Compound 9a was (2R,3R,4S,4aR,6S,7R,8aR)-1-benzyl-3,4-bis(benzyloxy)-2-
synthesized according to procedure A from 8a (400 mg, 0.66 mmol). Flash (benzyloxymethyl)octahydroquinoline-4a,6,7(2H)-triol (11a’). Compounds
chromatography (RediSep® 12 g, petroleum ether/EtOAc 85:15) afforded 11a and 11a’ were synthesized according to procedure C from compound 9a
[훂]ퟐퟎ (200 mg, 0.35 mmol). Flash chromatography (RediSep® 4 g, petroleum
compound 9a (339 mg, 89%) as a brown oil. Rf = 0.14 (PE/EtOAc 90:10);
퐃
=-0.95 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.37-7.20 (m, 20H, CH-Ar),
5.54-5.51 (m, 1H, H-7), 5.31-5.27 (m, 1H, H-6), 4.89 (dd, J = 11.1, 8.0 Hz, 2H,
ether/EtOAc 50:50 to 40:60) afforded compound 11a (46 mg, 22%, yellow oil)
and 11a’ (93 mg, 39%, yellow oil). Analytical data for 11a: Rf = 0.36 (PE/EtOAc
6 | J. Name., 2012, 00, 1-3
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Page 7 of 10
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
[훂]ퟐퟎ
oil) and 11b’ (74 mg, 35%, yellow oil). Analytical data forV1ie1wbA:rtRicfle=O0nl.i1n4e
50:50);
=-4.0 (c 1.0, CHCl3); 1H NMR (400 MHz, acetone-d6): δ 7.45-7.21
퐃
[훂]ퟐퟎ
1
(m, 20H, CH-Ar), 5.12 (d, J = 11.4 Hz, 1H, OCHH-Ph), 4.91-4.85 (m, 2H, OCHH- (PE/EtOAc 60:40);
=-46.0 (c 1.0, CHCl3); HDNOMI:R10(.4100039M/CH9zO, BC0D1C4l30):2Kδ
퐃
Ph), 4.60 (d, J = 11.1 Hz, 1H, OCHH-Ph), 4.39 (s, 2H, OCHH-Ph), 4.30-4.24 (m, 7.36-7.17 (m, 20H, CH-Ar), 4.48-4.45 (m, 2H, OH-4a, OCHH-Ph), 4.40 (d, J =
2H, NCHH-Ph, H-4), 3.92 (t, J = 9.7 Hz, 1H, H-3), 3.85-3.81 (m, 3H, CH2-OBn, H- 12.1 Hz, 1H, OCHH-Ph), 4.36-4.30 (m, 3H, OCHH-Ph), 4.24 (d, J = 11.8 Hz,
6), 3.70 (d, J = 13.8 Hz, 1H, NCHH-Ph), 3.49 (dt, J = 11.3 Hz, J = 4.1 Hz, 1H, H-7), OCHH-Ph), 4.16 (d, J = 10.0 Hz, OH-6), 4.09 (d, J = 13.8 Hz, 1H, NCHH-Ph), 3.89-
3.28(br.s,1H,OH),3.00(dt,J=9.9Hz,J=2.3Hz,1H,H-2),2.61(dd,J=12.9Hz, 3.84 (m, 2H, CHH-OBn, H-6), 3.80 (t, J = 2.1 Hz, 1H, H-3), 3.77-3.70 (m, 2H,
J=3.7Hz, 1H,H-8a),2.50(dd, J=14.6Hz, J=3.0Hz, 1H, H-5), 2.03-1.94(m, 1H, NCHH-Ph, CHH-OBn), 3.54-3.52 (m, 1H, H-7), 3.41 (br. s, 1H, H-4), 3.32 (t, J =
H-8), 1.83-1.78 (m, 1H, H-8), 1.18 (dd, J = 14.6 Hz, J = 3.3 Hz, 1H, H5); 13C NMR 6.7 Hz, 1H, H-2), 3.04 (dd, J = 12.2 Hz, J = 4.1 Hz, 1H, H-8a), 2.56 (br. s, 1H, OH-
IV
(100 MHz, acetone-d6): δ 141.6, 140.8, 140.0, 139.4 (C -Ar), 129.3-127.4 (CH- 7), 2.03(dt, J=11.8Hz, J=4.2Hz, 1H, H-8), 1.91-1.90(m, 2H, H-5), 1.64(dd, J=
Ar), 84.3 (C-4), 79.3 (C-3), 75.4, 74.9, 73.4 (OCH2-Ph), 73.0 (C-4a), 71.5 (C-7), 24.0Hz,J=12.0Hz,1H,H-8);13CNMR(100MHz,CDCl3):δ140.4,138.4,137.7,
IV
70.0 (C-6), 68.4 (CH2-OBn), 62.1 (C-8a), 61.0 (C-2), 53.0 (NCH2-Ph), 37.8 (C-5), 137.4 (C -Ar), 128.6-127.0 (CH-Ar), 78.4 (C-4), 73.2 (C-3), 73.1 (C-4a), 73.0,
24.1 (C-8); HRMS (ESI+) calcld for C38H44NO6: [M+H]+: 610.3163, found: 72.8, 71.1 (OCH2-Ph), 70.8 (C-7), 70.2 (C-6), 65.1 (CH2-OBn), 56.8 (C-2), 54.0 (C-
[훂]ퟐퟎ
8a), 52.1 (NCH2-Ph), 34.6 (C-5), 29.9 (C-8); HRMS (ESI+) calcld for C38H44NO6:
[M+H]+: 610.3163, found: 610.3169. Analytical data for 11b’: Rf = 0.08
610.3174. Analytical data for 11a’: Rf = 0.18 (PE/EtOAc 50:50);
=-1.3 (c
퐃
2.0, CHCl3);1HNMR(400MHz, acetone-d6):δ7.45-7.18(m, 20H, CH-Ar), 4.93-
4.79 (m, 2H, OCHH-Ph), 4.74 (d, J = 11.2 Hz, 1H, OCHH-Ph), 4.58-4.55 (m, 1H, (PE/EtOAc 60:40);
[훂]ퟐퟎ
1
=-24.0 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3): δ
퐃
OCHH-Ph), 4.36 (s, 2H, OCHH-Ph), 4.22 (d, J = 14.1 Hz, 1H, NCHH-Ph), 4.02 (br. 7.34-7.18 (m, 20H, CH-Ar), 4.49 (d, J = 11.6 Hz, 1H, OCHH-Ph), 4.41 (d, J = 11.6
s, 1H, H-7), 3.96 (t, J = 8.6 Hz, 1H, H-3), 3.87-3.80 (m, 3H, CH2-OBn, H-6), 3.73- Hz,1H,OCHH-Ph),4.34-4.32(m,3H,OCHH-Ph),4.29(d,J=11.8Hz,1H,OCHH-
3.66(m,2H,NCHH-Ph,H-4),3.13(dd,J=11.7Hz,J=3.9Hz,1H,H-8a),2.99(br. Ph), 4.15 (br. s, 1H, OH), 4.07-3.99 (m, 3H, NCHH-Ph, H-7, H-6), 3.85 (d, J = 6.7
s, 1H, H-2), 2.29 (br. s, 1H, H-5), 2.02-1.97 (m, 1H, H-8), 1.85-1.79 (m, 1H, H-8), Hz, 2H, CH2-OBn), 3.81 (t, J = 2.1 Hz, 1H, H-3), 3.71 (d, J = 14.1 Hz, 1H, NCHH-
1.66-1.60(m, 1H, H-5);13CNMR(100MHz, acetone-d6):δ141.7, 139.8, 139.4, Ph),3.39-3.35(m,2H,H-8a,H-4),3.31(t,J=6.6Hz,1H,H-2),2.18(t,J=12.3Hz,
IV
139.4 (C -Ar), 129.2-127.3 (CH-Ar), 82.3 (C-4), 78.9 (C-3), 75.7, 75.1 (OCH2-Ph), 1H, H-5), 2.06-2.03 (m, 1H, H-8), 1.70-1.64 (m, 1H, H-8), 1.57 (dd, J = 12.8 Hz, J
IV
73.8 (C-4a), 73.3 (OCH2-Ph), 69.8 (C-7), 69.3 (C-6), 68.2 (CH2-OBn), 60.5 (C-2), =4.3Hz, 1H, H-5);13CNMR(100MHz, CDCl3):δ141.1, 138.6, 138.0, 137.8(C -
68.2 (C-8a), 52.9 (NCH2-Ph), 36.7 (C-5), 25.1 (C-8); HRMS (ESI+) calcld for Ar), 128.6-126.8 (CH-Ar), 79.3 (C-4), 73.5 (C-3), 73.1, 72.8 (OCH2-Ph), 72.4 (C-
C38H44NO6:[M+H]+:610.3163,found:610.3180.
(2R,3R,4S,4aR,6R,7S,8aR)-2-(hydroxymethyl)octahydroquinoline-
3,4,4a,6,7(2H)-pentaol hydrochloride (12a). Application of procedure B to [M+H]+:610.3163,found:610.3189.
4a), 71.0 (OCH2-Ph), 69.6 (C-7), 67.7 (C-6), 65.5 (CH2-OBn), 58.1 (C-2), 52.8
(NCH2-Ph), 50.1 (C-8a), 34.5 (C-5), 30.8 (C-8); HRMS (ESI+) calcld for C38H44NO6:
compound 11a (30 mg, 0.05 mmol) afforded compound 12a (13 mg, quant., (2R,3R,4S,4aS,6R,7S,8aR)-2-(hydroxymethyl)octahydroquinoline-
[훂]ퟐퟎ
3,4,4a,6,7(2H)-pentaol hydrochloride (12b). Application of procedure B to
hydrochloride salt) as a colorless oil.
=+7.7 (c 2.2, MeOH); 1H NMR (400
퐃
compound 11b (30 mg, 0.05 mmol) afforded compound 12b (13 mg, quant.,
MHz, methanol-d4): δ 4.19 (br. d, J = 7.9 Hz, 1H, H-4), 4.00-3.97 (m, 2H, CHH-
[훂]ퟐퟎ
OH, H-6), 3.83-3.79(m, 2H, CHH-OH, H-7), 3.74(t, J=9.7Hz, 1H, H-3), 3.42(dd, hydrochloridesalt) as acolorless oil.
=+10.4(c2.3, MeOH);1HNMR(400
퐃
J=13.2Hz,J=3.9Hz,1H,H-8a),3.26-3.23(m,1H,H-2),2.57(dd,J=14.6Hz,J= MHz,methanol-d4):δ4.16-4.11(m,2H,CHH-OH,H-6),3.79-3.73(m,3H,CHH-
3.4Hz, 1H, H-5), 2.20(dd, J=24.2Hz, J=12.0Hz, 1H, H-8), 1.96-1.90(m, 1H, H- OH,H-7,H-3),3.61(m,1H,H-4),3.57-3.52(m,2H,H-8a,H-2),2.16-2.05(m,2H,
5), 1.44(dd, J=14.6Hz, J=2.9Hz, 1H, H-8);13CNMR(100MHz, methanol-d4): H-8), 1.97-1.88 (m, 2H, H-5); 13C NMR (100 MHz, methanol-d4): δ 73.8 (C-4a),
δ74.0(C-4), 72.0(C-4a), 70.8(C-7), 69.6(C-6), 68.5(C-3), 59.7(C-8a), 59.6(CH2- 71.5 (C-6), 70.9 (C-4), 70.5 (C-3), 70.1 (C-7), 63.2 (C-2), 58.4 (CH2-OH), 49.7 (C-
OH), 58.1 (C-2), 37.9 (C-5), 28.2 (C-8); HRMS (ESI+) calcld for C10H20NO6: 8a), 35.9 (C-5), 28.3 (C-8); HRMS (ESI+) calcld for C10H20NO6: [M+H]+: 250.1285,
[M+H]+:250.1285,found:250.1285.
found:250.1284.
(2R,3R,4S,4aR,6S,7R,8aR)-2-(hydroxymethyl)octahydroquinoline-
(2R,3R,4S,4aS,6S,7R,8aR)-2-(hydroxymethyl)octahydroquinoline-
3,4,4a,6,7(2H)-pentaol hydrochloride (12a’). Application of procedure B to 3,4,4a,6,7(2H)-pentaol hydrochloride (12b’). Application of procedure B to
compound 11a’ (30 mg, 0.05 mmol) afforded compound 12a’ (13 mg, quant., compound 11b’ (30 mg, 0.05 mmol) afforded compound 12b’ (13 mg, quant.,
[훂]ퟐퟎ
[훂]ퟐퟎ
=+21.0(c1.0, MeOH);1HNMR(400
퐃
hydrochloride salt) as a colorless oil.
=+3.9 (c 1.0, MeOH); 1H NMR (400 hydrochloridesalt) as acolorless oil.
퐃
MHz, methanol-d4): δ4.06 (br. s, 1H, H-6), 3.96 (dd, J = 11.6 Hz, J = 3.0 Hz, 1H, MHz,methanol-d4):δ4.14-4.07(m,2H,CHH-OH,H-6),3.76-3.67(m,3H,CHH-
CHH-OH), 3.82-3.77 (m, 2H, CHH-OH, H-3), 3.74-3.66 (m, 2H, H-8a, H-7), 3.63 OH,H-7,H-3),3.59(m,1H,H-4),3.55-3.50(m,2H,H-8a,H-2),2.13-2.02(m,2H,
(d, J = 9.1 Hz, 1H, H-4), 3.20-3.16 (m, 1H, H-2), 2.34 (dd, J = 12.5 Hz, J = 4.4 Hz, H-8), 1.91 (qd, J = 15.1 Hz, J = 2.9 Hz, 2H, H-5); 13C NMR (100 MHz, methanol-
1H, H-5), 2.08-2.01 (m, 2H, H-5), 1.76 (t, J = 12.4 Hz, 1H, H-8); 13C NMR (100 d4): δ 73.8 (C-4a), 71.5 (C-6), 71.0 (C-4), 70.5 (C-3), 70.1 (C-7), 63.3 (C-2), 58.4
MHz, methanol-d4): δ 72.7 (C-4a), 71.7 (C-4), 69.3 (C-6), 68.9 (C-7), 68.6 (C-3), (CH2-OH), 49.7 (C-8a), 35.9 (C-5), 28.3 (C-8); HRMS (ESI+) calcld for C10H20NO6:
59.6 (CH2-OH), 57.6 (C-2), 57.1 (C-8a), 36.1 (C-5), 29.9 (C-8); HRMS (ESI+) calcld [M+H]+:250.1285,found:250.1295.
forC10H20NO6:[M+H]+:250.1285,found:250.1285.
(2R,3R,4S,4aS,6R,7S,8aR)-1-benzyl-3,4-bis(benzyloxy)-2-
α-C-allyl-2-C-vinyl-3,4,6-tri-O-benzyl-N-benzyl-1-deoxymannojirimycin (13a)
and α-C-allyl-2-C-vinyl-3,4,6-tri-O-benzyl-N-benzyl-1-deoxynojirimycin (13b).
(benzyloxymethyl)octahydro quinolone-4a,6,7(2H)-triol (11b) and Compound 7 (1.00 g, 1.78 mmol) was dissolved in a 2:1 mixture of dry
(2R,3R,4S,4aS,6S,7R,8aR)-1-benzyl-3,4-bis(benzyloxy)-2- toluene/CH2Cl2 (24 mL) under Ar atmosphere. The mixture was cooled to -78
(benzyloxymethyl)octahydroquinoline-4a,6,7(2H)-triol (11b’). Compounds °C and a solution of vinylMgBr (1M/THF, 4.6 mL, 4.63 mmol, 2.6 eq.) was
11b and 11b’ were synthesized according to procedure C from compound 9b addeddropwise.Themixturewasstirredfor2hat-78°Candquenchedwitha
(200 mg, 0.35 mmol). Flash chromatography (RediSep® 4 g, petroleum saturated aqueous solution of NH4Cl (30 mL). The organic layer was extracted
ether/EtOAc 60:40 to 50:50) afforded compounds 11b (40 mg, 19%, yellow with Et2O (3x15 mL) and the combined organic layers were dried over MgSO4,
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Journal Name
filtered and concentrated under reduced pressure. Flash chromatography =4.6Hz, 1H, H-2), 3.28(dd, J=9.4Hz, 6.5Hz, 1H, H-7a), 2.41-2.35(m, 1H, H-7),
View Article Online
13
DOI: 10.1039/C9OB01402K
(petroleum ether/EtOAc 95:05 to 90:10) afforded compounds 13a (630 mg, 2.22 (ddd, J = 14.3 Hz, J = 6.4 Hz, J = 2.9 Hz, 1H, H-7); C NMR (100 MHz,
IV
60%, yellowoil)and13b(157mg, 15%, yellowoil). Analyticaldatafor13a:Rf= CDCl3): δ 139.9, 138.5, 138.1, 137.9 (C -Ar), 135.2 (C-6), 134.2 (C-5), 128.5-
[훂]ퟐퟎ
127.0 (CH-Ar), 80.2 (C-4a), 76.6 (C-4), 75.0 (C-3), 73.2, 72.1, 71.2 (OCH2-Ph),
64.8(CH2-OBn), 60.2(C-7a), 58.9(C-2), 54.4(NCH2-Ph), 32.4(C-7);HRMS(ESI+)
calcldforC37H40NO4:[M+H]+:562.2952,found:562.2951.
(2R,3R,4S,4aR,7aR)-2-(hydroxymethyl)octahydro-4aH-
0.43(PE/EtOAc90:10);
=-40.0(c1.0,CHCl3);1HNMR(400MHz,CDCl3):δ
퐃
7.39-7.22 (m, 20H, CH-Ar), 5.90 (dd, J = 16.9 Hz, J = 10.7 Hz, 1H, H-1”), 5.80-
5.70(m, 1H, H-2’), 5.56(dd, J=17.0Hz, J=2.1Hz, 1H, H-2”a), 5.19(dd, J=10.7
Hz, J = 2.1 Hz, 1H, H-2”b), 5.09-5.01 (m, 2H, H-3’), 4.86 (d, J = 11.0 Hz, 1H,
OCHH-Ph), 4.80 (d, J = 10.8 Hz, 1H, OCHH-Ph), 4.71 (d, J = 10.8 Hz, 1H, OCHH-
Ph),4.58(d,J=10.9Hz,1H,OCHH-Ph),4.36-4.30(m,2H,OCHH-Ph),4.21(d,J=
cyclopenta[b]pyridine-3,4,4a-triol hydrochloride (15a). Application of
procedure B to compound 14a (60 mg, 0.10 mmol) afforded compound 15a
[훂]ퟐퟎ
13.8Hz,1H,NCHH-Ph),4.06(t,J=8.8Hz,1H,H-4),3.86-3.80(m,2H,NCHH-Ph, (26 mg, quant., hydrochloride salt) as a colorless oil.
=+29.0 (c 1.0,
퐃
H-6a), 3.76-3.73 (m, 2H, H-6b, H-3), 3.43 (br. s, 1H, OH), 3.04 (dt, J = 9.1 Hz, J = MeOH); 1H NMR (400 MHz, methanol-d4): δ 3.95 (dd, J = 11.8, J = 3.4, 1H,
3.3 Hz, 1H, H-5), 2.79 (t, J =6.4Hz, 1H, H-1), 2.55-2.47 (m, 1H, H-1’a), 2.36-2.29 CHH-OH), 3.87(dd, J=11.8, J=6.4Hz, 1H, CHH-OH), 3.78(t, J=16.4Hz, 6.8Hz,
IV
(m, 1H, H-1’b); 13C NMR (100 MHz, CDCl3): δ140.3 (C -Ar), 139.1 (C-1”), 138.6, 1H,H-3),3.67-3.62(m,1H,H-7a), 3.49(d,J=9.3Hz,1H,H-4), 3.29-3.25(m,1H,
IV
138.3, 137.6 (C -Ar), 137.6 (C-2’), 128.8-126.8 (CH-Ar), 115.8 (C-3’), 115.7 (C- H-2), 2.24-1.60 (m, 6H, H-7, H-6, H-5); 13C NMR (100 MHz, methanol-d4): δ
2”), 83.6(C-3), 77.1(C-4), 77.0(C-2), 75.1, 75.0, 72.9(OCH2-Ph), 67.4(C-6), 64.9 79.8 (C-4), 73.1 (C-4), 67.85 (C-3), 62.3 (C-7a), 59.4 (CH2-OH), 57.7 (C-2), 34.2,
(C-1), 58.9 (C-5), 53.2 (NCH2-Ph), 30.2 (C-1’); HRMS (ESI+) calcld for C39H44NO4: 23.7, 19.0 (C-7, C-6, C-5); HRMS (ESI+) calcld for C10H18NO4: [M+H]+: 204.1230,
[M+H]+: 590.6265, found: 590.6264. Analytical data for 13b: Rf = 0.49 found:204.1232.
[훂]ퟐퟎ
(2R,3R,4S,4aS,7aR)-2-(hydroxymethyl)octahydro-4aH-
cyclopenta[b]pyridine-3,4,4a-triol hydrochloride (15b). Application of
procedure B to compound 14b (60 mg, 0.10 mmol) afforded compound 15b
[훂]ퟐퟎ
(PE/EtOAc90:10);
=+4.0(c1.0,CHCl3);1HNMR(400MHz,CDCl3):δ7.32-
퐃
7.14 (m, 20H, CH-Ar), 6.15 (dd, J = 17.1 Hz, J = 11.0 Hz, 1H, H-1”), 5.91-5.81 (m,
1H, H-2’), 5.46 (dd, J = 17.3 Hz, J = 1.6 Hz, 1H, H-2”a), 5.19 (dd, J = 10.9 Hz, J =
2.0 Hz, 1H, H-2”b), 5.01-4.94 (m, 2H, H-3’), 4.55-4.47 (m, 2H, OCHH-Ph), 4.43- (26 mg, quant., hydrochloride salt) as a colorless oil.
=+57.0 (c 1.0,
퐃
4.35 (m, 2H, OCHH-Ph), 4.31-4.25 (m, 2H, OCHH-Ph), 4.15 (d, J = 14.2 Hz, 1H, MeOH); 1H NMR (400 MHz, methanol-d4): δ 4.07 (dd, J = 12.0 Hz, J = 10.6 Hz,
NCHH-Ph), 3.90 (d, J = 14.2 Hz, 1H, NCHH-Ph), 3.83-3.78 (m, 2H, H-6a, H-4), 1H, CHH-OH), 3.85-3.82 (m, 2H, H-4, H-3), 3.74 (dd, J = 12.1 Hz, 4.8 Hz, 1H,
3.69 (dd, J = 9.6 Hz, J = 5.1 Hz, 1H, H-6b), 3.52 (d, J = 4.0 Hz, 1H, H-3), 3.22-3.18 CHH-OH), 3.61 (dd, J= 10.4 Hz, J = 4.5 Hz, 1H, H-2), 3.40 (dd, J = 10.6 Hz, J = 7.7
(m, 2H, H-5, H-1), 2.47-2.32 (m, 2H, H-1’); 13C NMR (100 MHz, CDCl3): δ 141.1 Hz, 1H, H-7a), 2.09-1.58 (m, 6H, H-7, H-6, H-5); 13C NMR (100 MHz, methanol-
IV
IV
IV
(C -Ar), 140.8 (C-1”), 138.6 (C -Ar), 138.4 (C-2’), 138.2, 137.8 (C -Ar), 128.7- d4): δ 80.1 (C-4a), 70.8, 70.5 (C-4, C-3), 63.9 (C-2), 58.3 (CH2-OH), 52.7 (C-7a),
126.8 (CH-Ar), 115.5 (C-3’), 114.5 (C-2”), 82.6 (C-3), 75.9 (C-2), 75.1 (C-4), 73.9, 31.1, 25.4, 19.1 (C-7, C-6, C-5); HRMS (ESI+) calcld for C10H18NO4: [M+H]+:
72.9, 72.2 (OCH2-Ph), 67.8 (C-6), 58.7 (C-1), 57.0 (C-5), 53.1 (NCH2-Ph), 30.9 (C- 204.1230,found:204.1226.
1’);HRMS(ESI+)calcldforC39H44NO4:[M+H]+:590.6265,found:590.6295.
(2R,3R,4S,4aR,7aR)-1-benzyl-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-
α-C-allyl-2-acetamido-3,4,6-tri-O-benzyl-N-benzyl-1,2-dideoxy-D-nojirimycin
(16) and α-C-allyl-2-acetamido-3,4,6-tri-O-benzyl-N-benzyl-1,2-dideoxy-D-
1,2,3,4,7,7a-hexahydro-4aH-cyclopenta[b]pyridin-4a-ol (14a). Compound mannojirimycin (17). To a solution of compound 7 (339 mg, 0.60 mmol) in
14awassynthesizedaccordingtoprocedureAfrom13a(400mg, 0.66mmol). absolute ethanol (2 mL) under Ar atmosphere were added hydroxylamine
Flashchromatography(RediSep® 12g, petroleumether/EtOAc95:05to90:10) hydrochloride (126 mg, 1.81 mmol, 3 eq.) and pyridine (195 µL, 2.41 mmol, 4
afforded compound 14a (331 mg, 87%) as a brown oil. Rf = 0.68 (PE/EtOAc eq.)atroomtemperature. Themixturewasstirredfor30minat60°Candthe
[훂]ퟐퟎ
reaction was quenched with H2O (10 mL). The aqueous layer was extracted
EtOAc(3x10mL)andthecombinedorganiclayersweredriedoverMgSO4 and
concentrated under reduced pressure. The crude residue was directly used in
the next step. The crude residue was dissolved in dry THF (2 mL) under Ar
atmosphere and a 1 M solution of LiAlH4 in THF was added (1.8 mL, 1.81
mmol, 3 eq.). The reaction mixture was stirred at 40 °C for 3 h by which time
TLC monitoring revealed no trace of the starting material. The reaction was
sequentially quenched with EtOAc (20 mL) and a 1 M solution of HCl (2.5 mL).
The aqueous layer was neutralized with a saturated aqueous solution of
NaHCO3 (20 mL) and extracted with EtOAc (3x20 mL). The combined organic
layers were dried over MgSO4 and concentrated under reduced pressure. The
cruderesiduewasdissolvedina2:1mixtureofdrypyridine/Ac2O(2mL)under
Ar atmosphere at room temperature. After 5 h stirring at room temperature,
the mixture was quenched with H2O (15 mL) and extracted with EtOAc (3x10
mL). The combined organic layers were dried over MgSO4 and concentrated
under reduced pressure. Flash chromatography (RediSep® 12 g, petroleum
ether/EtOAc90:10to60:40)affordedcompounds16(29mg,8%,brownsolid)
and 17 (103 mg, 28%, brown oil). Analytical data for compound 16 were in
agreement with literature.31 Analytical data for compound 17: Rf = 0.28
85:10);
=-13.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.41-7.15 (m,
퐃
20H, CH-Ar), 5.81-5.76 (m, 2H, H-6, H-5), 4.88 (d, J = 11.2 Hz, 1H, OCHH-Ph),
4.65 (d, J = 11.2 Hz, 1H, OCHH-Ph), 4.52-4.46 (m, 4H, OCHH-Ph), 3.94-3.90 (m,
2H, CHH-OBn, NCHH-Ph), 3.83-3.80 (m, 3H, CHH-OBn, H-4, H-3), 3.70 (d, J =
14.2 Hz, 1H, NCHH-Ph), 3.42 (t, J = 7.3 Hz, 1H, H-7a), 3.19-3.17 (m, 1H, H-2),
3.05 (broad s, 1H, OH), 2.67 (ddd, J = 16.2 Hz, J = 7.7 Hz, J = 1.9 Hz, 1H, H-7),
2.35 (ddd, J = 16.2 Hz, J = 9.0 Hz, J = 4.4 Hz, 1H, H-7); 13C NMR (100 MHz,
IV
CDCl3): δ 139.6, 138.8, 138.7, 138.4 (C -Ar), 135.7 (C-5), 130.4 (C-6), 128.5-
126.5 (CH-Ar), 85.2 (C-4), 85.0 (C-4a), 80.5 (C-3), 75.1, 73.3, 71.7 (OCH2-Ph),
67.0(C-7a), 66.5(CH2-OBn), 60.2(C-2), 54.6(NCH2-Ph), 38.1(C-7);HRMS(ESI+)
calcldforC37H40NO4:[M+H]+:562.2952,found:562.2960.
(2R,3R,4S,4aS,7aR)-1-benzyl-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-
1,2,3,4,7,7a-hexahydro-4aH-cyclopenta[b]pyridin-4a-ol (14b). Compound
14bwassynthesizedaccordingtoprocedureAfrom13b(150mg,0.25mmol).
Flash chromatography (RediSep® 4 g, petroleum ether/EtOAc 95:05 to 90:10)
afforded compound 14b (120 mg, 84%) as a brown oil. Rf = 0.75 (PE/EtOAc
[훂]ퟐퟎ
85:15);
=-46.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.42-7.19 (m,
퐃
20H, CH-Ar), 6.05-6.03 (m, 1H, H-6), 6.00 (dd, J = 6.0 Hz, J = 1.8 Hz, 1H, H-5),
4.49-4.36 (m, 6H, OCHH-Ph), 4.26 (broad s, 1H, OH), 3.94-3.89 (m, 5H, NCHH-
Ph, CHH-OBn, H-4, H-3), 3.81(t, J=8.8Hz, 1H, CHH-OBn), 3.34(dd, J=8.3Hz, J
[훂]ퟐퟎ
(PE/EtOAc 60:40);
=+55.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ
퐃
8 | J. Name., 2012, 00, 1-3
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7.38-7.23 (m, 20H, CH-Ar), 6.10 (d, J = 9.5 Hz, 1H, NH), 5.67-5.57 (m, 1H, H-2’),
5.06-4.99 (m, 2H, H-3’), 4.92 (d, J = 10.8 Hz, 1H, OCHH-Ph), 4.78 (d, J = 11.1 Hz,
1H, OCHH-Ph), 4.49-4.37 (m, 5H, OCHH-Ph, H-2), 4.14 (d, J = 13.1 Hz, 1H,
NCHH-Ph), 3.81-3.78 (m, 3H, H-6a, H-6b, H-3), 3.71 (t, J = 8.8 Hz, 1H, H-4), 3.46
(d, J = 13.1 Hz, 1H, NCHH-Ph), 2.88-2.85 (m, 1H, H-5), 2.73-2.68 (m, 1H, H-1),
2.45-2.39 (m, 1H, H-1’a), 2.23-2.15 (m, 1H, H-1’b), 1.88 (s, 3H, CH3); 13C NMR
The authors (QF, JD, YB) acknowledge financial support from
the European Union (ERDF) and "Région Nouvelle Aquitaine".
This work was supported in part by a Grant-in-Aid for Scientific
Research (C) from the Japanese Society for the Promotion of
Science (JSPS KAKENHI Grant Number JP17K08362) (AK).
View Article Online
DOI: 10.1039/C9OB01402K
IV
(100MHz, CDCl3):δ169.6(CO), 140.0, 138.7, 138.2, 138.2(C -Ar), 134.9(C-2’),
Notes and references
‡ The registration number for the crystallographic data of
compound 10b is CCDC 1921458.
128.9-127.4 (CH-Ar), 117.7 (C-3’), 78.5 (C-3), 76.4 (C-4), 75.3, 73.3, 71.2 (OCH2-
Ph), 67.2(C-6), 59.2(C-5), 57.8(C-1), 51.6(NCH2-Ph), 45.4(C-2), 27.9(C-7), 23.8
(CH3);HRMS(ESI+)calcldforC39H45N2O4:[M+H]+:605.3374,found:605.3381.
(2R,6S)-2-allyl-1-benzyl-4-(benzyloxy)-6-(benzyloxymethyl)-1,6-
1
Hohenschutz, L. D.; Bell, E. A.; Jewess, P. J.; Leworthy, D. P.; Pryce, R. J.;
Arnold, E.; Clardy, J. Phytochemistry 1981, 20, 811.
R. J. Nash, A. Kato, C.-Y. Yu and G. W. Fleet, Future Medicinal Chemistry, 2011,
3, 1513–1521.
dihydropyridin-3(2H)-one (19). Compound 7 (50 mg, 0.09 mmol) was
dissolved in a 9:1 mixture of MeOH/Et3N (8 mL) at room temperature under
Ar atmosphere. The mixture was stirred 18 h at room temperature and
concentrated under reduced pressure. Flash chromatography (RediSep® 4 g,
petroleum ether/EtOAc 90/10) afforded compound 19 (37 mg, 0.08 mmol,
2
3
P. C. Tyler and B. G. Winchester, in Iminosugars as Glycosidase Inhibitors, ed.
A. E. Stütz, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, FRG, 1998, pp. 125–
156.
4
5
S. G. Pyne, Curr. Org. Synth. 2005, 2, 39-57.
R. H. Furneaux, G. J. Gainsford, J. M. Manson and P. C. Tyler, Tetrahedron,
[훂]ퟐퟎ
91%) as a yellow oil. Rf = 0.39 (PE/EtOAc90:10);
=+16.0 (c 1.0, CHCl3);1H
퐃
1994, 50, 2131–2160.
6
7
P. S. Liu, M. S. Kang, P. S. Sunkara, Tetrahedron Lett. 1991, 32, 719-720.
J. Boisson, A. Thomasset, E. Racine, P. Cividino, T. Banchelin Sainte-Luce, J.-F.
NMR(400MHz, CDCl3):δ7.30-7.14(m, 15H, CH-Ar), 5.77-5.67(m, 2H, H-2’, H-
Poisson, J.-B. Behr and S. Py, Organic Letters, 2015, 17, 3662–3665.
K. Søndergaard, X. Liang and M. Bols, Chemistry, 2001, 7, 2324–2331; M. I.
5), 5.03-4.95 (m, 2H, H-3’), 4.80 (s, 2H, OCHH-Ph), 4.35 (s, 2H, OCHH-Ph), 3.74-
3.67 (m, 2H, NCHH-Ph, H-6),3.63-3.56 (m, 3H, NCHH-Ph, CHH-OBn, H-2), 3.45
(dd, J = 9.4 Hz, J = 7.0 Hz, 1H, CHH-OBn), 2.52-2.40 (m, 2H, H-1’);13C NMR (100
8
García-Moreno, J. M. Benito, C. Ortiz Mellet and J. M. García Fernández, J. Org.
Chem., 2001, 66, 7604; P. Díaz Pérez, M. I. García-Moreno, C. Ortiz Mellet and J. M.
García Fernández, Synlett, 2003, 3, 341; M. I. García-Moreno, D. Rodríguez- Lucena,
C. Ortiz Mellet and J. M. García Fernández, J. Org. Chem., 2004, 69, 3578. S. Jarosz,
K. Tiara and M. A. Potopnyk, Pure App. Chem. 2019, doi.org/10.1515/pac-2019-
0116
IV
MHz,CDCl3):δ193.8(C-3),148.5(C-4),138.8,136.0,136.3(C -Ar),134.8(C-2’),
128.7-127.5 (C-3’), 115.5 (C-5), 73.4 (OCH2-Ph), 71.3 (CH2-OBn), 69.9 (OCH2-
Ph), 64.5 (C-2), 55.5 (C-6), 51.9 (NCH2-Ph), 30.9 (C-1’); HRMS (ESI+) calcld for
C30H32NO3:[M+H]+:454.2387,found:454.2384.
9
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Conflicts of interest
“There are no conflicts to declare”.
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Acknowledgements
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