Ortho-Carborane-Modified N-Substituted Deoxynojirimycins

Article abstract of DOI:10.1002/ejoc.201500364

N-alkyl-deoxynojirimycins (DNMs) are an important class of glycoprocessing enzyme inhibitors. Our work on DNMs focuses on identifying potent and selective inhibitors of the human enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA)

Full text of DOI:10.1002/ejoc.201500364

FULL PAPER
DOI: 10.1002/ejoc.201500364
ortho-Carborane-Modified N-Substituted Deoxynojirimycins
[
a][‡]
[a][‡]
Anneke Strijland,[b]
Sascha Hoogendoorn,
Elliot D. Mock,
[b]
[a]
[a]
Wilma E. Donker-Koopman, Hans van den Elst, Richard J. B. H. N. van den Berg,
Johannes M. F. G. Aerts, Gijsbert A. van der Marel, and Herman S. Overkleeft*
[a]
[a]
[a]
Keywords: Medicinal chemistry / Enzymes / Inhibitors / Glucosylceramide / Carboranes
N-alkyl-deoxynojirimycins (DNMs) are an important class of
glycoprocessing enzyme inhibitors. Our work on DNMs fo-
cuses on identifying potent and selective inhibitors of the hu-
man enzymes, glucosylceramide synthase (GCS), lysosomal
glucosylceramidase (GBA) and neutral glucosylceramidase
derivatives bearing various hydrophobic head groups (ali-
phatic, aromatic, branched, cyclic). In this study we report
effective procedures for the synthesis of ortho-carborane-
modified DNMs and establish the inhibitory potency of six
new DNM derivatives 3–8 against GCS, GBA and GBA2.
(
GBA2). We have previously reported on N-alkylated DNM
Introduction
2, the C5-epimer of AMP-DNM 1 (glucopyranose number-
ing), inhibits GCS slightly more potently, is somewhat less
active against GBA (though an equally effective GBA2 in-
hibitor) and has little to no intestinal glycosidase inhibitory
Deoxynojirimycin (DNM) derivatives bearing alkyl sub-
stituents at the piperidine nitrogen constitute an important
class of inhibitors of glycoprocessing enzymes.
Hydroxyethyl-DNM (Miglitol), a broad-spectrum intestinal
glycosidase inhibitor, is in clinical use as an antidiabetic
agent for the treatment of type 2 diabetes.[ The glucosyl-
ceramide synthase (GCS) inhibitor, N-butyl-DNM (Za-
vesca), is used to treat the lysosomal storage disorder,
[
1]
N-
[6]
activity relative to 1. At this time, GCS was identified as
[7]
a potential target for the treatment of type 2 diabetes and
we proposed AMP-DNM 1 as a lead for type 2 diabetes
therapy development based on its dual activity as a GCS
inhibitor and inhibitor of intestinal glycosidases (the main
2]
[8]
target of the aforementioned antidiabetic agent, Miglitol).
[
3]
Gaucher disease.
l-ido-AMP-DNM 2, in turn and based on its more selective
inhibition of enzymes involved in glucosylceramide metabo-
lism (GCS, GBA2), was viewed as a promising lead for new
Besides these clinically approved drugs, numerous stud-
ies, conducted by several research groups worldwide de-
scribe the design, synthesis and evaluation of DNM deriva-
tives varying in configuration and bearing a variety of pre-
dominantly hydrophobic and bulky N-substitutions as
glycosidase/glycosyl transferase inhibitors.[ Our early
forays in this area of research involved the evaluation of
adamantane-containing N-alkyl-DNM 1 (AMP-DNM,
[9]
therapies aimed at lysosomal storage disorders.
4]
[
5]
Figure 1) as glucosylceramide synthase inhibitor. We
found that AMP-DNM 1 outperforms the clinical drug, N-
butyl-DNM, in that 1 is the more potent GCS inhibitor.
Compound 1, however, also displays broad-spectrum ac-
tivity against human lysosomal glucosylceramidase (GBA –
the enzyme deficient in Gaucher patients), human neutral
glucosylceramidase (GBA2) as well as intestinal glycosid-
ases. In a subsequent study, we found that ido-AMP-DNM
Figure 1. Lead structures AMP-DNM 1 and ido-AMP-DNM 2
and ortho-carborane-substituted analogues 3–8 subject of the here-
presented studies.
[
a] Leiden Institute of Chemistry, Leiden University,
Einsteinweg 55, 2300 RA Leiden, The Netherlands
E-mail: h.s.overkleeft@chem.leidenunv.nl
http://lic.leidenuniv.nl/
Based on the above considerations we recently carried
out studies in which we varied the hydrophobic moiety, at-
tached to the DNM and l-ido-DNM core through a pent-
yloxy spacer, and assessed inhibitory potency of the re-
sulting focused library against GCS, GBA and GBA2.[
[
[
b] Department of Medical Biochemistry, Academic Medical
Centre, University of Amsterdam,
1
105 AZ Amsterdam, The Netherlands
‡] S. H. and E. D. M. contributed equally to this work.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500364.
10]
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H. S. Overkleeft et al.
FULL PAPER
From these series, in which both aliphatic and aromatic Results and Discussion
functionalities varying in size and structure were included,
we found that compounds bearing (substituted) biphenyls
The synthesis of ortho-carborane-modified N-alkyl-
are considerably more potent inhibitors of both GCS and DNM 3 and N-alkyl-ido-DNM 6 – the structurally closest
GBA2. Selectivity profiles appeared otherwise unchanged, analogues of lead structures 1 and 2, respectively – is de-
with the DNM series being broad-spectrum inhibitors picted in Scheme 1. In a first attempt to generate bromide
against both glucosylceramide metabolism enzymes and in- 11 as the DNM/ido-DNM alkylating agent, ortho-carbor-
testinal enzymes, and the l-ido-congeners selective for the ane 9 was treated with formaldehyde and tetrabutylammo-
[
12]
former. One hydrophobic moiety not included in these stud- nium fluoride.
The resulting hydroxymethylated ortho-
ies is the ortho-carborane, and our attention was drawn to carborane 10 was obtained in good yield, but subsequent
this moiety specifically because of literature precedence in O-alkylation (10 to 11) proved troublesome, possibly due to
which carboranes are used as isosteres both for phenyl and the relative acidity of the remaining carborane-CH in 10;
adamantyl substituents.[11] This invited the question of low yields were obtained when using stoichiometric NaH
whether ortho-carborane – considered a highly stable phar- and double alkylation at the –OH and –CH positions was
macophore less prone to catabolic degradation than phenyl/ observed upon increasing the amount of base. We therefore
adamantyl – appended to DNM or l-ido-DNM, would lead turned our attention to an alternative route.
to effective GCS/GBA/GBA2 inhibitors. And, if so, would
This alternative route is based on literature precedence
the inhibitory profile resemble those of AMP-DNM 1 and demonstrating that modified ortho-carboranes can be ob-
l-ido-AMP-DNM 2 or those of the more potent biphenyl- tained by reacting decaborane with an appropriately modi-
substituted derivatives. With the aim of answering this ques- fied, terminal alkyne, under the agency of the ionic liquid,
tion, and in general, to arrive at synthetic strategies that 1-butyl-3-methylimidazolium chloride (BmimCl) as the ac-
[
13]
enable the introduction of ortho-carborane moieties into tivating agent. Propargyl ether 13 was therefore prepared
glycosidase inhibitors, we set out to synthesize and evaluate by alkylation of TMS-propargyl alcohol 12 with 1,5-di-
ortho-carborane-DNM derivatives 3–5 and the correspond- bromopentane, using sodium hydride as the base, and tetra-
ing l-ido-analogues 6–8, all featuring the pentyloxy moiety butylammonium iodide (TBAI) as a catalyst. Reaction of
as in parent compounds 1 and 2 and varying in the number 13 and decaborane in toluene at elevated temperature and
of carbons (n = 1, 2, 3) separating the linker and the ortho- in the presence of BmimCl afforded target ortho-carborane
carborane. The results of these studies pertaining to both 11 in good yield, but as a mixture of the expected bromide
compound synthesis and inhibition potency of compounds and the corresponding chloride. This mixture – resulting
3–8 against the glucosylceramide processing enzymes, GCS, from nucleophilic substitution of the bromide by chloride
GBA and GBA2, are presented here. anion present in the reaction mixture – was used without
Scheme 1. Reagents and conditions: (a) TBAF, formaldehyde (37% v/v in H
2
O), THF (86%); (b) 1,5-dibromopentane, NaH, TBAI, THF,
°C to reflux (9%); (c) NaH, 1,5-dibromopentane, TBAI, THF, 0 °C to room temp. (58%); (d) decaborane, BmimCl, toluene, 80 °C to
05 °C (62%); (e) 14 or 16, K CO , CH CN, reflux (15: 59%, 17: 78%); (f) H (4 bar), Pd/C, 0.01 m HCl (aq), EtOH (3: 13%, 6: 19%).
0
1
2
3
3
2
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Eur. J. Org. Chem. 2015, 4437–4446

ortho-Carborane-Modified N-Substituted Deoxynojirimycins
further purification in the next step. At this stage we at-
The final set of C5-epimeric compounds 5 and 8 was
tempted to N-alkylate unprotected DNM (DNM, DMF, 11, obtained from mono-(tert-butyldimethylsilyl)-protected or-
[
14]
9
0 °C).
degradation of the ortho-carborane. Reaction of 11 with viously reported procedures. Reaction of 20 with oxetane
,3,4,6-tetra-O-benzyl-DNM 14 in refluxing acetonitrile under basic conditions (deprotonation using a slight excess
However, this approach proved abortive due to tho-carborane 20, prepared from carborane 9 using pre-
[
16]
2
with potassium carbonate as the base proceeded slowly, but of nBuLi in THF, followed by addition of oxetane) gave
over the course of 4 d protected carborane-DNM derivative hydroxypropyl carborane 21 in good yield and without mi-
5 was obtained in 59% yield.[
15]
Palladium-catalyzed gration of the TBDMS group from the carborane carbon
1
hydrogenolysis of the benzyl ethers in 15 followed by re- to the hydroxyl group (a side reaction that occurred when
versed phase HPLC purification afforded target 3 in poor reacting 20 with ethylene oxide, as we found when at-
yield but as a completely homogenous substance. In a sim- tempting to synthesize 18 from 20). Hydroxy group alkyl-
ilar fashion, and with comparable efficiency, but involving ation of 21 with 1,5-dibromopentane followed by N-alkyl-
benzyl-protected ido-DNM derivative 16, the C5 epimer 6 ation of benzylated DNM and ido-DNM derivatives 14 and
(
with respect to 3) was obtained.
Production of compounds 4 and 5 (one and two-carbon target compounds 5 and 8 in relatively good overall yields
homologues respectively of 3) as well as compounds 7 and (relative to 4 and 7).
(homologues of 6) is depicted in Scheme 2. In a two-step The inhibitory potencies of carborane-DNM derivatives
16, TBDMS removal, and final catalytic hydrogenation gave
8
procedure ortho-carborane 9 was deprotonated (nBuLi in 3–8 against GCS, GBA and GBA2 were assessed in com-
THF) and then treated with ethylene oxide to give carbor- parative studies including lead structures AMP-DNM 1
ane derivative 18 as the one-carbon homologue of carbor- and AMP-ido-DNM 2.
ane 10. In contrast to O-alkylation of 10, which proceeded
The overall trends in activity and specificity of the two
with difficulty necessitating an alternative route, O-alkyl- sets of new carborane compounds (DNM compounds 3–5
ation of 18 with 1,5-dibromopentane proceeded without vs. ido-DNM compounds 6–8) parallel, to a large extent,
complications to give bromide 19. With this alkylating those of parent compounds 1 and 2, respectively (Table 1).
agent and following the synthesis used to generate 3 and 6, Compounds 3–5 are less potent GCS inhibitors relative to
DNM derivative 4 and ido-DNM derivative 7 were pre- AMP-DNM 1 whereas the corresponding ido-DNM deriva-
pared with comparable efficiency.
tives 6–8 display GCS inhibitory activities on par with par-
ent compound. Thus, the slightly improved GCS inhibition
displayed by ido-DNM relative to DNM, and taking into
account the otherwise identical structures, appears some-
what more pronounced in the ortho-carborane series than
in the adamantine series. Importantly, substituting ada-
mantane for ortho-carborane did not lead to the marked
improvement in GCS inhibition previously observed for
,4-biphenyl derivatives – especially in the l-ido-series.[
10]
1
With respect to GBA, compounds in both the DNM and
ido-DNM series are somewhat more potent inhibitors than
parent compounds 1 and 2. Conversely, all eight com-
pounds are highly potent GBA2 inhibitors. Within the
series of compounds evaluated here one- or two-carbon ho-
mologation appears to have little influence on the potency
of enzyme inhibitory activity with relation to all three en-
zymes studies.
Table 1. IC50 values (numbers are micromolar) for compounds 1–8
as inhibitors of GCS, GBA and GBA2. The SD values were always
less than 20% in the case of GCS measurements, and always less
than 15% in the case of GBA and GBA2 measurements.
1
2
3
4
5
6
7
8
GCS 0.2
GBA 0.1
0.1
2.0
0.75 0.9
0.02 0.03 0.03 0.8
0.5
0.1
0.1
0.5
0.08
0.5
GBA2 0.002 0.001 0.002 0.001 0.001 0.001 0.002 0.001
Scheme 2. Reagents and conditions: (a) 1) nBuLi, THF; 2) ethylene
oxide (2.5–3.3 m), THF (65%); (b) 1,5-dibromopentane, NaH,
TBAI, THF, 0 °C to reflux (79% 19, 65% 22); (c) 1) 14 or 16,
K
2
CO
EtOH (3% 4, 7% 7); (d) nBuLi, TBDMSCl, toluene/Et
to room temp. (87%); (e) 1) nBuLi, THF; 2) oxetane, THF (76%); Conclusions
f) 1) 14 or 16, K CO , CH CN, reflux; 2) TFA/TBAF, THF,
78 °C to room temp.; 3) H (4 bar), Pd/C, 0.01 m HCl (aq), EtOH
18% 5, 17% 8).
3
, CH
3
CN, reflux; 2) H
2
(4 bar), Pd/C, 0.01 m HCl (aq),
2
O, 0 °C
(
2
3
3
In conclusion, we have reported synthetic procedures en-
abling facile access to deoxynojirimycin derivatives featur-
–
2
(
Eur. J. Org. Chem. 2015, 4437–4446
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4439

H. S. Overkleeft et al.
FULL PAPER
ing an ortho-carborane-modified N-alkyl substituent. To with an Agilent Technologies 1200 series automated HPLC system
with a Quadropole MS 6130, equipped with a C18 semiprep col-
umn (Gemini, 250ϫ10 mm, 5μ particle size, Phenomenex). High
the best of our knowledge, the six new DNM derivatives
described here constitute the first examples in which car-
resolution mass spectra (HRMS) were recorded with a LTQ Or-
borane moieties – attracting increasing attention from the
bitrap (Thermo Finnigan) mass spectrometer equipped with an
medicinal chemistry community in recent years as pharma-
electron spray ion source in positive mode (source voltage 3.5 kV,
cophores – are combined with iminosugars. Thus, even
though the adamantane-for-carborane substitution does
not result in improved inhibitors for the glucosylceramide
sheath gas flow 10 mLmin-1, capillary temperature 250 °C) with
resolution R = 60000 at m/z 400 (mass range m/z = 150–2000) and
dioctylphthalate (m/z = 391.28428) as a lock mass. Optical rotation
processing enzymes (GCS, GBA and GBA2) studied here, measurements were performed with a Propol automatic polarime-
the synthetic routes outlined here enable generation of re- ter at room temperature. IR spectra were recorded using a Shim-
–
1
lated compounds. For instance, other configurational DNM adzu FTIR-8300 and absorptions are given in cm .
analogues or, alternatively, pyrrolidine iminosugars are now
(
1Ј-Hydroxymethyl)-1,2-dicarba-closo-dodecaborane (10): To a solu-
accessible. For instance, other configurational DNM ana- tion of ortho-carborane 9 (288 mg, 2.0 mmol, 1 equiv.) in THF
logues or, alternatively, pyrrolidine immunosugars are now (10 mL) was added formaldehyde (37% w/w in water, 164 μL,
accesible, allowing the preparation of focused libaries aimed 2.2 mmol, 1.1 equiv.) at room temp. under an argon atmosphere.
Next, TBAF (1.0 m in THF, 6.0 mL, 6.0 mmol, 3 equiv.) was added
at different biological targets. From a synthetic point of
dropwise affording a pale yellow solution. The reaction was stirred
view, yields are not impressive, especially for the final de-
for 2 h after which TLC showed complete conversion of starting
benzylation steps and alkylation of unprotected imi-
4
material and the mixture was quenched with a satd. aq. NH Cl
nosugars proved abortive. However, we stress that all com-
pounds were obtained with relative ease, in suitable quanti-
ties for biological evaluation and in good purity. Our results
also highlight effective synthetic strategies for generating or-
solution (15 mL). Water (15 mL) was added and the aqueous layer
was extracted with Et O (3ϫ 30 mL). The combined organic layers
were washed with brine (80 mL), dried with MgSO , filtered and
concentrated under reduced pressure. Silica column chromatog-
2
4
tho-carborane-alkyl halides 11, 19 and 22, which may find raphy (5%Ǟ30% EtOAc in PE) yielded alcohol 10 as a white pow-
use in the synthesis of carborane-containing bioactive mol- der (297 mg, 1.71 mmol, 86%), m.p. 223 °C. R = 0.3 (4:1 PE/
): δ = 4.06 (s, 2 H, CH ), 3.89
s, 1 H, BCH), 3.15–1.36 (m, 10 H, BH), 2.47 (s, 1 H, OH) ppm.
f
1
ecules other than those based on iminosugars and aimed at EtOAc). H NMR (400 MHz, CDCl
3
2
(
targets other than the glycoprocessing enzymes evaluated
here.
1
3
11
C NMR (101 MHz, CDCl
NMR (128 MHz, CDCl ): δ = –2.87, –5.16, –9.22, –11.84,
13.19 ppm. FT-IR (thin film): ν˜ = 3590, 3385, 3079 (BCH), 2578
3
): δ = 74.95, 65.03, 57.89 ppm.
B
3
–
–
1
(
B–H), 1703, 1377, 1262, 1212, 1115, 1044, 1018, 995, 908 cm .
Experimental Section
+
ESI-HRMS (m/z): calculated for [C
16.23861, observed 216.23882.
3 14 3
H B10O + CH CN + H]
2
General: All general chemicals (Sigma–Aldrich, Fluka, Acros,
Merck) were used as received. ortho-Carborane was purchased
from Katchem spol. s. r.o. (Czech Republic). All solvents used for
reactions were of analytical grade. Tetrahydrofuran, diethyl ether,
toluene, DMF and dichloromethane were dried overnight over acti-
vated molecular sieves (4 Å). Methanol, acetonitrile and dimethyl
sulfoxide were stored over molecular sieves (3 Å). Flash chromatog-
raphy was performed on silica gel (Screening Devices BV, 40–
[1Ј-(5ЈЈ-Bromopentyl)methoxy]-1,2-dicarba-closo-dodecaborane (11):
Procedure starting from 10: Alcohol 10 (347 mg, 2.0 mmol,
1 equiv.) was dissolved in dry THF (20 mL) and cooled to 0 °C
under an argon atmosphere. NaH (60% dispersion in mineral oil,
88 mg, 2.0 mmol, 1.1 equiv.) was added, and a white suspension
was formed. Next, 1,5-dibromopentane (1.36 mL, 10 mmol,
5 equiv.) and TBAI (74 mg, 0.20 mmol, 0.1 equiv.) were added. The
mixture was stirred for 5 min at 0 °C and then brought to reflux.
After 4.5 h NaH (40 mg, 1.0 mmol, 0.5 equiv.) was added and the
reaction was refluxed for 72 h. Another portion of NaH (0.5 equiv.)
was added and refluxing was continued overnight. Although the
starting material was not completely converted, the reaction was
63 μm, 60 Å). The eluents ethyl acetate, toluene and petroleum
ether (40–60 °C boiling point range) were of technical grade and
distilled before use. Reactions were monitored by thin layer
chromatography (TLC) analysis using Merck aluminum sheets (Sil-
ica gel 60, F254). Compounds were visualized by UV absorption
(
254 nm) and spraying for general compounds with an aqueous
solution of KMnO (20 g/L) and K CO (10 g/L), for carboranes
.5% PdCl in 10% hydrochloric acid in acetone and for amines tracted with CH
ninhydrin (0.75 g/L) and acetic acid (12.5 mL/L) in ethanol, fol- were washed with brine (240 mL), dried with MgSO
quenched by dropwise addition of a satd. aq. NH
(30 mL). Water (30 mL) was added and the aqueous layer was ex-
Cl (3ϫ 70 mL). The combined organic layers
, filtered and
4
Cl solution
4
2
3
0
2
2
2
4
1
13
11
lowed by charring at ca. 150 °C. H, C, COSY, HSQC and
B
concentrated under reduced pressure. Silica column chromatog-
raphy (0%Ǟ32% EtOAc in PE) afforded primary bromide 11 as a
pale yellow oil (55 mg, 0.17 mmol, 9%) as well as recovered starting
NMR spectra were recorded with a Bruker AV-400 (400/100 MHz)
or Bruker DMX-600 (600/150 MHz). 11B spectra were recorded
with BF
3
etherate as internal standard. Chemical shifts are given in
or CD OD as internal
compound 10 (104 mg, 0.60 mmol, 30%). R
H NMR (400 MHz, CDCl
3
f
= 0.7 (4:1 PE/EtOAc).
): δ = 3.95 (s, 1 H, BCH), 3.84 (s, 2 H,
O), 3.47 (t, J = 6.2 Hz, 2 H, CH ), 3.41 (t, J = 6.7 Hz, 2 H,
), 2.76 (s, 10 H, BH), 1.87 (p, J = 14.1, 6.8 Hz, 2 H, CH ),
) ppm. C NMR
): δ = 71.87, 71.82, 57.69, 33.66, 32.39, 28.51,
24.71 ppm. B NMR (128 MHz, CDCl ): δ = –3.17, –5.00, –9.21,
–11.68, –13.32 ppm. FT-IR (thin film): ν˜ = 3082 (BCH), 2938,
1
ppm (δ) relative to tetramethylsilane, CDCl
3
3
13
standards. Coupling constants (J) are given in Hz. All C-NMR
spectra are proton decoupled APT measurements. LC/MS mea-
surements were conducted using a Thermo Finnigan LCQ Advan-
tage MAX ion-trap mass spectrometer (ESI ) coupled to a Sur-
veyor HPLC system (Thermo Finnigan) equipped with a standard
C18 (Gemini, 4.6 mmD ϫ 50 mmL, 5μ particle size, Phenomenex)
analytical column and buffers A: H
TFA. HPLC-MS purifications of final compounds were performed
CH
CH
2
2
2
2
1
3
1.61–1.54 (m, 2 H, CH
(101 MHz, CDCl
2 2
), 1.53–1.45 (m, 2 H, CH
+
3
1
1
3
–
1
2
O, B: CH
3
CN, C: 0.1% aq. 2868, 2584 (BH), 1455, 1364, 1252, 1123, 1067, 1017 cm . Pro-
cedure starting from 13: To a solution of 13 (0.80 g, 4.0 mmol) in
4440
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ortho-Carborane-Modified N-Substituted Deoxynojirimycins
a
(
1
biphasic mixture of 1-butyl-3-methylimidazolium chloride
0.20 g) and toluene (5 mL) was added decaborane (0.18 g,
.5 mmol) at 80 °C under an argon atmosphere. The reaction was
(2 mL) and cooled to 0 °C under an argon atmosphere. NaH (60%
dispersion in mineral oil, 11 mg, 0.26 mmol, 1.5 equiv.) was added
forming a white suspension. Next, 1,5-dibromopentane (0.12 mL,
0.90 mmol, 5 equiv.) and TBAI (7 mg, 0.02 mmol, 0.1 equiv.) were
added. The mixture was stirred for 5 min at 0 °C and then brought
to reflux. After 6 h the mixture was cooled to 0 °C and quenched
heated to 105 °C for 3 h. The ionic liquid layer was then extracted
with toluene and the combined toluene layers were loaded onto a
silica column (pentane). The product was purified (0%Ǟ7%
EtOAc in pentane) resulting in a mixture of the title compound
4
by dropwise addition of a satd. aq. NH Cl solution (5 mL). Water
2
and its chloro-derivative according to NMR analysis (2:1) in 62% (20 mL) was added and the aqueous layer was extracted with Et O
1
yield (289 mg, 0.93 mmol). H NMR (400 MHz, CDCl
s, 1 H, BCH), 3.84 (s, 2 H, OCH ), 3.54 (t, J = 6.6 Hz, 0.7 H, (75 mL), dried with MgSO
CH Cl), 3.47 (t, J = 6.2 Hz, 2 H, CH ), 3.41 (t, J = 6.7 Hz, 1.5 duced pressure. Primary bromide 19 was obtained by silica column
H, CH Br), 3.07–1.34 (m, 10 H, 10ϫ BH), 1.92–1.83 (m, 1.5 H, chromatography (0%Ǟ8% EtOAc in pentane) as colorless oil
CH Br), 1.81–1.74 (m, 0.7 H, CH CH Cl), 1.62–1.54 (m, 2 H, (48 mg, 0.14 mmol, 79%). R
= 0.7 (4:1 PE/EtOAc). 1H NMR
), 1.54–1.44 (m, 2 H, CH ) ppm. C NMR (101 MHz, (400 MHz, CDCl ): δ = 3.92 (s, 1 H, BCH), 3.49 (t, J = 5.6 Hz, 2
): δ = 72.79, 71.87, 71.82, 57.70, 44.91 (CH Cl), 33.66, 32.39, H, CH ), 3.45–3.33 (m, 4 H, 2ϫ CH ), 2.94–1.10 (m, 10 H, BH),
2.26 (CH -2,Cl), 28.64 (CH -4,Cl), 28.51, 24.70, 23.44 (CH 2.50 (t, J = 5.6 Hz, 2 H, CH ), 1.87 (p, J = 13.8, 6.7 Hz, 2 H, CH
,Cl) ppm. 1.64–1.40 (m, 4 H, 2ϫ CH
3
): δ = 3.94 (3ϫ 25 mL). The combined organic layers were washed with brine
(
2
4
, filtered and concentrated under re-
2
2
2
CH
CH
CDCl
3
3
2
2
2
2
2
1
f
3
2
3
3
2
2
2
2
2
2
-
2
2
),
):
1
3
2
) ppm. C NMR (101 MHz, CDCl
3
δ = 73.47, 70.89, 68.37, 60.24, 37.68, 33.76, 32.49, 28.81,
1
-Bromo-5-(prop-2-yn-1-yloxy)pentane (13): Sodium hydride (60%
11
2
–
2
1
3
4.96 ppm. B NMR (128 MHz, CDCl ): δ = –2.12, –5.51, –9.77,
10.87, –12.10, –12.91 ppm. FT-IR (thin film): ν˜ = 3074 (BCH),
dispersion in mineral oil, 1.4 g, 35 mmol) was added to a cooled
0 °C) solution of TMS-propargyl alcohol (1 mL, 0.90 g, 7.0 mmol)
in dry THF (120 mL) under argon. The reaction was stirred for
(
936, 2866, 2576 (BH), 1483, 1457, 1429, 1364, 1282, 1249, 1115,
–1
9 25
020 cm . ESI-HRMS (m/z): calculated for [C H B10BrO +
5
2
0
min before the addition of dibromopentane (19 mL, 140 mmol,
0 equiv.) and tetrabutyl ammonium iodide (200 mg, 0.7 mmol,
.1 equiv.). The reaction was stirred for 2 h at room temperature
CN + H]+ 380.24098, observed 380.24050.
CH
-(tert-Butyldimethylsilyl)-1,2-dicarba-closo-dodecaborane (20):[16]
To a solution of ortho-carborane 9 (2.88 g, 20.0 mmol, 1 equiv.) in
dry toluene and Et O (18 mL, 2:1, v/v) was added nBuLi (2.5 m in
3
1
and carefully poured onto a cooled mixture of ammonium chloride
sat aq.)/ice. The product was extracted with DCM (3ϫ), the or-
ganic layers dried with MgSO , filtered, and concentrated in vacuo.
(
2
hexane, 8.4 mL, 21.0 mmol, 1.05 equiv.) at 0 °C under an argon
atmosphere. The solution immediately became turbid and was
stirred for 2 h while gradually warming to room temp. The mixture
was cooled again to 0 °C and TBDMSCl (3.32 g, 22.0 mmol,
4
Purification by silica column chromatography (1%Ǟ5% EtOAc in
pentane) gave the product as slightly yellow oil (838 mg, 4.1 mmol,
1
5
=
3
1
8%). R
4.13 (d, J = 2.3 Hz, 2 H, CH
.42 (t, J = 6.8 Hz, 2 H, CH ), 2.45 (d, J = 2.3 Hz, 1 H, CH), 1.94–
.84 (m, 2 H, CH ), 1.67–1.58 (m, 2 H, CH ), 1.56–1.48 (m, 2 H,
) ppm. 1 C NMR (101 MHz, CDCl
): δ = 79.97, 74.32, 69.80,
f
= 0.6 (10:1 PE/EtOAc). H NMR (400 MHz, CDCl
3
): δ
2
1.1 equiv.) in a 3 mL solution of toluene and Et O (2:1, v/v) was
2
), 3.52 (t, J = 6.3 Hz, 2 H, CH
2
),
added with a syringe and stirred overnight at room temp. After
addition of water (50 mL), the aqueous layer was extracted with
Et O (3ϫ 50 mL). The combined organic layers were dried with
2
MgSO , filtered, and concentrated in vacuo. Flash column
4
chromatography (0%Ǟ30% EtOAc in PE) afforded 20 as a color-
2
2
2
3
CH
2
3
5
8.13, 33.79, 32.60, 28.73, 24.91 ppm. ESI-HRMS (m/z): calculated
+
for [C
3
8 23 3
H B10BrO + CH CN + H] 366.22533, observed
less oil, which solidified to a white powder upon standing (4.48 g,
66.22587.
1
17.3 mmol, 87%). R
f
= 0.8 (19:1 pentane/EtOAc). H NMR
(2Ј-Hydroxyethyl)-1,2-dicarba-closo-dodecaborane (18): ortho-Car-
(
1
400 MHz, CDCl
3
): δ = 3.44 (s, 1 H, CHB), 3.24–1.38 (m, 10 H,
borane 9 (72 mg, 0.50 mmol, 1 equiv.) was dissolved in dry THF
13
0ϫ BH), 1.02 (s, 9 H, 3ϫ CH
):
4.42 ppm. 11B NMR (128 MHz, CDCl
10.81, –12.34, –13.32 ppm. FT-IR (thin film): ν˜ = 3080 (BCH),
976, 2961, 2937, 2863, 2611, 2589, 2566 (BH), 1468, 1364, 1265,
3
), 0.23 (s, 6 H, 2ϫ CH
66.16, 60.39, 27.11, 19.45,
): δ = 0.18, –1.88, –7.10,
3
) ppm.
C
(
(
5 mL) and cooled to 0 °C under an argon atmosphere. nBuLi
1.6 m in THF, 0.33 mL, 0.53 mmol, 1.05 equiv.) was added drop-
NMR (101 MHz, CDCl
3
δ =
–
–
2
1
3
wise and the reaction was brought to room temp. after 20 min and
stirred for 2.5 h. The mixture was again cooled to 0 °C and ethylene
oxide (2.5–3.3 m in THF, 0.17 mL, 0.43–0.56 mmol, 0.85–
–1
256, 1072, 1030, 1003, 872 cm . ESI-HRMS (m/z): calculated for
1
0
.1 equiv.) was added, affording a turbid solution. After 10 min at
°C, the mixture was stirred for 3 h at room temp. Water (40 mL)
CN + H]+ 300.31452; observed 300.31492.
[C
8
H
26
B
10Si + CH
3
1
-(tert-Butyldimethylsilyl)-2-(3Ј-hydroxypropyl)-1,2-dicarba-closo-
was added and extracted with Et
organic layers were washed with brine (100 mL), dried with
MgSO filtered, and concentrated in vacuo. Silica column
chromatography (10%Ǟ40% EtOAc in pentane) yielded alcohol
8 as a white powder (61 mg, 0.32 mmol, 65%). R = 0.2 (4:1 PE/
): δ = 3.98 (s, 1 H, CCarbH),
OH), 3.11–1.45 (m, 10 H, BH), 2.50
2
O (3ϫ 40 mL). The combined
dodecaborane (21): Compound 20 (2.59 g, 10.0 mmol) was dis-
solved in dry THF (50 mL) and nBuLi (1.6 m in hexane, 6.88 mL,
4
,
11.0 mmol, 1.1 equiv.) was added slowly, upon which the reaction
mixture changed from colorless to bright orange/red. After stirring
for 1 h, trimethylene oxide (1.30 mL, 20.0 mmol, 2 equiv.) was
added and the mixture was stirred overnight at room temperature
under an argon atmosphere. Subsequently, nBuLi (1.6 m in hexane,
1.56 mL, 2.5 mmol, 0.25 equiv.) and trimethylene oxide (0.33 mL,
1
f
1
EtOAc). H NMR (400 MHz, CDCl
.80 (t, J = 5.8 Hz, 2 H, CH
t, J = 5.9 Hz, 2 H, CH CH
): δ = 73.13, 60.81, 60.52, 39.87 ppm.
): δ = –2.19, –5.48, –9.55, –11.01, –12.13,
3
3
(
2
1
3
2
2
OH), 1.62 (s, 1 H, OH) ppm.
C
B
1
1
NMR (101 MHz, CDCl
NMR (128 MHz, CDCl
3
5
3
.0 mmol, 0.5 equiv.) were added and the mixture was stirred for
h. The mixture was diluted with diethyl ether and washed with
3
–
2
12.90 ppm. FT-IR (thin film): ν˜ = 3601, 3389, 3075 (BCH), 2961,
934, 2893, 2572 (BH), 1426, 1123, 1076, 1046, 1020, 866 cm .
–
1
water (1ϫ 40 mL). After the layers were separated, the aqueous
layer was extracted with diethyl ether (2ϫ 30 mL) and the com-
CN + H]+
4 16 3
H B10O + CH
ESI-HRMS (m/z): calculated for [C
30.25426, observed 230.25446.
4
bined organic layers were dried (MgSO ), filtered and concentrated
2
under reduced pressure. Flash silica column chromatography
[
2Ј-(5ЈЈ-Bromopentyl)ethoxy]-1,2-dicarba-closo-dodecaborane (19): (5%Ǟ25% EtOAc in PE) afforded alcohol 21 as a white powder
Alcohol 18 (33 mg, 0.18 mmol, 1 equiv.) was dissolved in dry THF (3.08 g, 8.6 mmol, 86 %). R
f
= 0.3 (4:1 PE/EtOAc). 1H NMR
Eur. J. Org. Chem. 2015, 4437–4446
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4441

H. S. Overkleeft et al.
FULL PAPER
(400 MHz, CDCl
3
): δ = 3.61 (t, J = 5.9 Hz, 2 H, CH
2
), 3.09–1.58 2,3,4,6-Tetra-O-benzyl-N-{5Ј-[1ЈЈ-(1ЈЈЈ,2ЈЈЈ-dicarba-closo-do-
(
m, 10 H, 10ϫ BH), 2.39–2.30 (m, 2 H, CH
2
), 1.81–1.72 (m, 2 H, decaboranyl)methoxy]pentyl}-
), 1.51 (s, 1 H, OH), 1.06 (s, 9 H, 3ϫ CH ), 0.33 (s, 6 H, 2ϫ Compound 11 (63 mg, 0.20 mmol, 1.2 equiv.) was treated with
) ppm. 13C NMR (101 MHz, CDCl
): δ = 81.40, 76.58, 61.71, 2,3,4,6-tetra-O-benzyl-d-gluco-1-deoxynojirimycin 14 (87 mg,
D-gluco-1-deoxynojirimycin (15):
CH
CH
3
CDCl
3
2
3
3
3
1
1
4.74, 33.08, 27.72, 20.48, –2.35 ppm. B NMR (128 MHz, 0.17 mmol, 1 equiv.) according to general procedure A, providing
1
3
): δ = 0.09, –4.06, –7.43, –10.42 ppm. FT-IR (thin film): ν˜ = 15 (75 mg, 0.10 mmol, 59%). R
f
= 0.6 (2:1 pentane/EtOAc).
): δ = 7.38–7.21 (m, 18 H, CHAr), 7.18–
CN + H] 358.35639; 7.08 (m, 2 H, CHAr), 4.95 (d, J = 11.1 Hz, 1 H, CH -H), 4.88 (d,
J = 10.8 Hz, 1 H, CH -H), 4.81 (d, J = 11.1 Hz, 1 H, CH -H), 4.70
d, J = 11.6 Hz, 1 H, CH -H), 4.65 (d, J = 11.6 Hz, 1 H, CH -H),
.48 (d, J = 12.2 Hz, 1 H, CH -H), 4.45 (d, J = 12.2 Hz, 1 H, CH
-H), 3.90 (s, 1 H, BCH), 3.80
), 3.69–3.61 (m, 2 H, CH, CH -H), 3.61–3.50 (m, 2 H,
-H), 3.50–3.42 (t, J = 9.0 Hz, 1 H, CH), 3.38 (t, J =
), 3.07 (dd, J = 11.1, 4.8 Hz, 1 H, CH -H), 2.97–
.54 (m, 10 H, BH), 2.72–2.62 (m, 1 H, CH -H), 2.60–2.50 (m, 1
-H), 2.30 (d, J = 9.5 Hz, 1 H, CH), 2.21 (t, J = 10.8 Hz, 1
-H), 1.48 (p, J = 7.0 Hz, 2 H, CH ), 1.43–1.30 (m, 2 H,
H
–1
560, 3323, 2936, 2569, 1466, 1258, 1057, 838 cm . ESI-HRMS NMR (400 MHz, CDCl
3
+
(
m/z): calculated for [C11
H
32
B
10OSi + CH
3
2
observed 358.35701.
2
2
(
2
2
1
-(tert-Butyldimethylsilyl)-2-[3Ј-(5ЈЈ-bromopentyl)propoxy]-1,2-di-
carba-closo-dodecaborane (22): Alcohol 21 (317 mg, 1.0 mmol,
equiv.) was dissolved in dry THF (10 mL) and cooled to 0 °C
under an argon atmosphere. NaH (60% dispersion in mineral oil,
00 mg, 5.0 mmol, 5 equiv.) was added forming a white suspension.
4
2
2
-
H), 4.42 (d, J = 11.1 Hz, 1 H, CH
2
1
(
s, 2 H, CH
2
2
CH, CH
2
2
6
1
.4 Hz, 2 H, CH
2
2
Next, 1,5-dibromopentane (2.72 mL, 20 mmol, 20 equiv.) and
TBAI (37 mg, 0.10 mmol, 0.1 equiv.) were added. The mixture was
stirred for 5 min at 0 °C and then heated to reflux. After 1.5 h of
stirring TLC showed complete conversion of starting material and
the mixture was cooled to 0 °C and quenched by dropwise addition
of a satd. aq. NH
and the aqueous layer was extracted with CH
combined organic layers were washed with brine (80 mL), dried
with MgSO , filtered and concentrated under reduced pressure. Pu-
2
H, CH
H, CH
CH ), 1.24–1.08 (m, 2 H, CH
CDCl ): δ = 139.09, 138.63, 137.90, 128.49, 128.48, 128.45, 128.43,
2
2
2
13
2
2
) ppm. C NMR (101 MHz,
3
4
Cl solution (20 mL). Water (20 mL) was added
1
7
2
–
27.97, 127.92, 127.75, 127.67, 127.56, 87.46, 78.69, 78.62, 75.43,
2
2
Cl (2ϫ 40 mL). The
5.31, 73.55, 72.90, 72.10, 71.84, 65.63, 63.93, 57.67, 54.58, 52.25,
11
9.23, 23.97, 23.61 ppm. B NMR (128 MHz, CDCl
3
): δ = –3.10,
4
20
4.96, –9.17, –11.67, –13.23 ppm. [α]
D
= +4.6 (c = 1.3, CH Cl ).
2
2
rification by silica column chromatography (50%Ǟ0% PE in tolu-
ene) yielded primary bromide 22 as a colorless oil (304 mg,
FT-IR (thin film): ν˜ = 3085 (BCH), 3063, 3030, 2934, 2864, 2585
–1
(
BH), 1496, 1454, 1361, 1207, 1172, 1092, 1072, 1028, 910 cm .
1
0
.65 mmol, 65%). R
CDCl ): δ = 3.47–3.27 (m, 6 H, 3ϫ CH
BH), 2.37–2.27 (m, 2 H, CH ), 1.86 (p, J = 14.0, 6.8 Hz, 2 H, CH
.76 (m, 2 H, CH
CH ), 0.33 (s, 6 H, 2ϫ CH
f
= 0.9 (4:1 PE/EtOAc). H NMR (400 MHz,
+
59 5
ESI-HRMS (m/z): calculated for [C42H B10NO + H] 767.54637,
3
2
), 3.06–1.39 (m, 10 H,
observed 767.54556.
2
2
),
2
,3,4,6-Tetra-O-benzyl-N-{5Ј-[1ЈЈ-(1ЈЈЈ,2ЈЈЈ-dicarba-closo-do-
1
2
), 1.61–1.43 (m, 4 H, 2ϫ CH
2
), 1.06 (s, 9 H, 3ϫ
) ppm. 13C NMR (101 MHz, CDCl
decaboranyl)methoxy]pentyl}-L-ido-1-deoxynojirimycin (17): Com-
pound 11 (55 mg, 0.17 mmol, 1.1 equiv.) was treated with 2,3,4,6-
tetra-O-benzyl-1-l-ido-deoxynojirimycin 16 (81 mg, 0.15 mmol,
3
3
3
):
δ = 81.55, 76.53, 70.83, 69.51, 35.20, 33.76, 32.69, 30.56, 29.01,
2
0
2
calculated for [C16
served 508.34328.
7.75, 25.05, 20.46, –2.39 ppm. 1 B NMR (128 MHz, CDCl
1
3
): δ =
1
equiv.) according to general procedure A, affording title com-
.12, –4.04, –7.40, –10.32 ppm. FT-IR (thin film): ν˜ = 2936, 2862,
568 (BH), 1473, 1365, 1256, 1116, 1067 cm . ESI-HRMS (m/z):
–1
pound 17 (86 mg, 0.11 mmol, 75%). R = 0.9 (1:1 pentane/EtOAc).
H NMR (400 MHz, CDCl ): δ = 7.44–7.14 (m, 20 H, CHAr), 4.85
3
f
1
+
H
41
B
10BrOSi + CH
3
CN + H] 508.34310, ob-
(
4
d, J = 10.9 Hz, 1 H, CH
2
-H), 4.79 (d, J = 10.9 Hz, 1 H, CH
.71 (d, J = 11.6 Hz, 1 H, CH -H), 4.68–4.60 (m, 3 H, CH
), 4.52 (d, J = 12.2 Hz, 1 H, CH -H), 4.48 (d, J = 12.2 Hz, 1
-H), 3.91 (s, 1 H, BCH), 3.86–3.75 (m, 3 H, CH -H, CH ),
.75–3.68 (m, 1 H, CH -H), 3.65 (dd, J = 9.0, 5.8 Hz, 1 H, CH),
.60–3.45 (m, 2 H, 2ϫ CH), 3.44–3.30 (m, 3 H, CH , CH), 3.04–
.56 (m, 10 H, BH), 2.85 (dd, J = 11.7, 5.1 Hz, 1 H, CH -H), 2.75–
.65 (m, 1 H, CH -H), 2.57–2.48 (m, 2 H, CH -H, CH -H), 1.50
), 1.46–1.35 (m, 2 H, CH ), 1.31–
) ppm. C NMR (101 MHz, CDCl ): δ = 139.17,
2
-H),
2
2
-H,
General Procedure A – N-Alkylation with 2,3,4,6-Tetra-O-benzyl-1-
-gluco-deoxynojirimycin or 2,3,4,6-Tetra-O-benzyl- -ido-1-deoxy-
nojirimycin: To a solution of the carborane compound (1.1 equiv.)
in dry CH CN (0.1 m) at room temperature under an argon atmo-
sphere was added the corresponding DNM derivative (1 equiv.,
CH
H, CH
3
3
1
2
2
2
D
L
2
2
2
2
3
2
2
[
6]
2 3
syntheses as described previously ) and K CO (4 equiv.). The
2
2
2
mixture was brought to reflux and stirred until TLC showed com-
plete conversion (typically after 3–7 d). Work-up involved the ad-
dition of water (30 mL) and extraction of the aqueous layer with
EtOAc (3 ϫ 30 mL). The combined organic layers were washed
(
p, J = 14.2, 6.7 Hz, 2 H, CH
2
2
13
1
1
1
7
2
–
.19 (m, 2 H, CH
2
3
38.74, 138.67, 138.61, 128.47, 128.42, 128.37, 128.05, 127.86,
27.72, 127.64, 127.59, 127.54, 83.14, 80.34, 78.92, 75.48, 73.37,
with brine (1ϫ 90 mL), dried with MgSO
trated in vacuo. Purification by silica flash column chromatography
5% Ǟ40% EtOAc in pentane) afforded the N-alkylated DNM
4
, filtered, and concen-
3.14, 72.86, 72.81, 72.20, 71.78, 64.50, 59.85, 57.67, 54.63, 49.97,
11
9.20, 27.68, 23.73 ppm. B NMR (128 MHz, CDCl
3
): δ = –3.14,
(
20
4.98, –9.18, –11.67, –13.25 ppm. [α]
D
= –19.3 (c = 1.4, CH Cl ).
2
2
compounds as colorless oils.
FT-IR (thin film): ν˜ = 3085 (BCH), 3062, 3030, 2932, 2862, 2585,
–
1
1
496, 1453, 1363, 1206, 1091, 1071, 1028, 910 cm . ESI-HRMS
General Procedure B – Pd/C Catalyzed Hydrogenolysis: In a Parr
shaker flask the N-alkylated DNM derivative was dissolved in
EtOH (0.01 m) and acidified with 1 m aq. HCl to pH ≈ 2. The flask
was evacuated and back-filled with argon. A catalytic amount of
Pd/C (10 % on activated carbon) was added and the flask was
brought under vacuum and ventilated with hydrogen gas (3ϫ). The
flask was filled with 4 bar of hydrogen gas and mechanically agi-
tated in a Parr apparatus for 24 h. The reaction was filtered over a
Whatman glass microfiber filter, which was washed with EtOH.
The solvents were removed by co-evaporation with toluene (3ϫ)
under reduced pressure. HPLC-MS purification afforded the title
compounds as the corresponding TFA salt.
(
m/z): calculated for [C42
59 5
H B10NO
+ H]+ 767.54562, observed
767.54556.
N-{5Ј-[1Ј-(1ЈЈЈ,2ЈЈЈ-Dicarba-closo-dodecaboranyl)methoxy]pentyl}-
-gluco-1-deoxynojirimycin TFA Salt (3): Compound 15 (75 mg,
0.10 mmol) was treated according to general procedure B. HPLC-
MS purification (A: 0.1 % TFA in H O; B: linear gradient
36%Ǟ42% CH CN in 12 min; flow: 5 mL/min) followed by lyo-
D
2
3
philisation provided the TFA salt of iminosugar 3 as a colorless oil
1
(6.9 mg, 13.3 μmol, 13%). H NMR (600 MHz, MeOD): δ = 4.52
(s, 1 H, BCH), 4.12 (d, J = 12.5 Hz, 1 H, CH
2
-H), 3.92 (s, 2 H,
CH ), 3.90 (d, J = 12.8 Hz, 1 H, CH -H), 3.68 (td, J = 10.8, 4.9 Hz,
2
2
4442
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4437–4446

ortho-Carborane-Modified N-Substituted Deoxynojirimycins
1
H, CH), 3.59 (t, J = 9.8 Hz, 1 H, CH), 3.53 (t, J = 6.2 Hz, 2 H, cording to general procedure B. HPLC-MS purification (A: 0.1%
CH ), 3.44 (dd, J = 12.0, 4.8 Hz, 1 H, CH -H), 3.41–3.33 (m, 2 H, TFA in H O; B: linear gradient 36%Ǟ42% CH CN in 12 min;
CH, CH -H), 3.20 (td, J = 12.5, 4.8 Hz, 1 H, CH -H), 3.03 (d, J flow: 5 mL/min) followed by lyophilization provided the TFA salt
9.9 Hz, 1 H, CH), 2.98 (t, J = 11.7 Hz, 1 H, CH -H), 2.80–1.57 of iminosugar 4 as a colorless oil (2.2 mg, 4.2 μmol, 4%). H NMR
m, 10 H, BH), 1.84–1.78 (m, 1 H, CH -H), 1.77–1.71 (m, 1 H, (600 MHz, MeOD): δ = 4.48 (s, 1 H, BCH), 4.12 (d, J = 12.4 Hz,
), 1.46 (dq, J = 14.3, 7.3 Hz, 1 H, CH -H), 3.90 (d, J = 10.5 Hz, 1 H, CH -H), 3.67 (td, J =
) ppm. 13C NMR (151 MHz, MeOD): δ = 162.42
10.8, 4.8 Hz, 1 H, CH), 3.59 (t, J = 9.7 Hz, 1 H, CH), 3.52 (t, J =
H), 77.80, 74.83, 72.84, 72.11, 68.40, 67.44, 67.01, 60.66, 5.9 Hz, 2 H, CH ), 3.47–3.41 (m, 3 H, CH -H, CH ), 3.39–3.33 (m,
2 H, CH, CH -H), 3.23–3.15 (m, 1 H, CH -H), 3.03 (d, J = 9.2 Hz,
1 H, CH), 3.01–2.94 (m, 1 H, CH -H), 2.78–1.59 (m, 10 H, BH),
2.54 (t, J = 5.9 Hz, 2 H, CH ), 1.86–1.78 (m, 1 H, CH -H), 1.74
322, 1672, 1435, 1362, 1204, 1187, 1132, 1032 cm . ESI-HRMS (d, J = 5.9 Hz, 1 H, CH -H), 1.64 (p, J = 6.9 Hz, 2 H, CH ), 1.47
) ppm. C NMR (151 MHz,
H), 78.18, 75.15, 71.36, 69.46, 68.81,
7.85, 67.39, 63.06, 54.93, 54.27, 38.59, 30.14, 24.49, 23.91 ppm.
2
2
2
3
2
2
1
=
2
(
2
CH
2
-H), 1.66 (p, J = 6.9 Hz, 2 H, CH
2
2
2
2
(
5
H, CH
CF CO
4.52, 54.48, 53.84, 29.53, 23.95, 23.50 ppm. B NMR (128 MHz,
2
3
2
2
2
2
11
2
2
2
0
MeOD): δ = –3.24, –5.21, –9.61, –11.72, –13.26 ppm. [α]
D
= –3.1
2
(
2
c = 0.13, MeOH). FT-IR (thin film): ν˜ = 3333, 2940, 2866, 2587,
2
2
–1
2
2
+
13
(m/z): calculated for [C14
H
35
B
10NO
5
+ H] 406.35986, observed
(dq, J = 14.1, 7.7 Hz, 2 H, CH
MeOD): δ = 162.94 (CF CO
2
4
06.35918.
3
2
6
1
1
N-{5Ј-[1ЈЈ-(1ЈЈЈ,2ЈЈЈ-Dicarba-closo-dodecaboranyl)methoxy]pentyl}-
-ido-1-deoxynojirimycin TFA Salt (6): Compound 17 (86 mg,
.11 mmol) was subjected to general procedure B. HPLC-MS puri-
B NMR (128 MHz, MeOD): δ = –2.69, –5.83, –9.82, –11.20,
2
0
L
–11.88, –13.07 ppm. [α]D = –4.6 (c = 0.04, MeOH). FT-IR (thin
film): ν˜ = 3348, 2938, 2870, 2588 (BH), 1674, 1436, 1204, 1133,
0
–
1
fication (A: 0.1 % TFA in H
CH
vided the TFA salt of iminosugar 6 as a colorless oil (11.0 mg,
2
O; B: linear gradient 36 Ǟ 42 % 1032 cm . ESI-HRMS (m/z): calculated for [C15H37B10NO +
5
+
3
CN in 12 min; flow: 5 mL/min) followed by lyophilization pro- H] 420.37556, observed 420.37515.
1
2
1.2 μmol, 19%). H NMR (600 MHz, MeOD): δ = 4.52 (s, 1 H,
BCH), 4.08–3.94 (m, 4 H, CH , 2ϫ CH), 3.92 (s, 2 H, CH
), 3.90– ido-1-deoxynojirimycin TFA Salt (7): Compound 19 (65 mg,
.84 (m, 1 H, CH), 3.56–3.47 (m, 4 H, CH , CH -H, CH), 3.40–
0.19 mmol, 1.2 equiv.) was treated with 2,3,4,6-tetra-O-benzyl-1-l-
.27 (m, 3 H, CH -H, CH
), 2.72–1.61 (m, 10 H, BH), 1.91–1.83 ido-deoxynojirimycin 16 (86 mg, 0.16 mmol, 1 equiv.) according to
-H), 1.79–1.70 (m, 1 H, CH -H), 1.66 (p, J = 6.3 Hz,
general procedure A affording benzylated 7 as a colorless oil
), 1.45 (p, J = 7.5, 7.0 Hz, 2 H, CH
N-{5Ј-[2ЈЈ-(1ЈЈЈ,2ЈЈЈ-Dicarba-closo-dodecaboranyl)ethoxy]pentyl}-L-
2
2
3
3
2
2
2
2
(
2
m, 1 H, CH
2
2
1
3
1
H, CH
2
2
) ppm. C NMR
(78 mg, 0.10 mmol, 63%). R
(400 MHz, CDCl ): δ = 7.39–7.23 (m, 20 H, CHAr), 4.85 (d, J =
10.9 Hz, 1 H, CH -H), 4.79 (d, J = 10.9 Hz, 1 H, CH -H), 4.71 (d,
J = 11.6 Hz, 1 H, CH -H), 4.68–4.60 (m, 3 H, CH -H, CH ), 4.52
(d, J = 12.2 Hz, 1 H, CH -H), 4.48 (d, J = 12.2 Hz, 1 H, CH -H),
3.89 (s, 1 H, BCH), 3.81 (dd, J = 10.1, 6.6 Hz, 1 H, CH -H), 3.71
(dd, J = 10.1, 2.3 Hz, 1 H, CH -H), 3.66 (dd, J = 9.3, 5.7 Hz, 1 H,
CH), 3.59–3.48 (m, 2 H, 2ϫ CH), 3.45 (t, J = 5.7 Hz, 2 H, CH ),
), 3.10–1.55 (m, 10 H, BH), 2.85 (dd,
f
= 0.9 (1:1 EtOAc/pentane). H NMR
(
151 MHz, MeOD): δ = 162.94, 162.70, 162.47, 162.25 (4 ϫ
CF CO H), 75.21, 73.20, 72.55, 72.40, 68.96, 68.02, 63.83, 61.48,
1.00, 55.04, 54.47, 29.91, 24.37, 23.23 ppm. B NMR (128 MHz,
3
3
2
2
2
11
6
2
2
2
2
0
MeOD): δ = –3.26, –5.24, –9.66, –11.71, –13.29 ppm. [α]
D
= +9.1
2
2
(
2
c = 0.22, MeOH). FT-IR (thin film): ν˜ = 3351, 2950, 2928, 2871,
2
–1
588, 1672, 1433, 1362, 1202, 1132, 1071 cm . ESI-HRMS (m/z):
2
+
calculated for [C14
06.35907.
H
35
B
10NO
5
+ H] 406.35986, observed
2
4
3.39–3.28 (m, 3 H, CH, CH
J = 11.9, 5.3 Hz, 1 H, CH
2.48 (m, 2 H, 2ϫ CH
J = 14.6, 6.6 Hz, 2 H, CH
2
2
-H), 2.74–2.66 (m, 1 H, CH
2
-H), 2.57–
N-{5Ј-[2ЈЈ-(1ЈЈЈ,2ЈЈЈ-Dicarba-closo-dodecaboranyl)ethoxy]pentyl}- ), 1.50 (p,
-gluco-1-deoxynojirimycin TFA Salt (4): Compound 19 (61 mg, ), 1.26 (p, J =
2 3
.18 mmol, 1.1 equiv.) was treated with 2,3,4,6-tetra-O-benzyl-d- 7.3 Hz, 2 H, CH ) ppm. C NMR (101 MHz, CDCl ): δ = 139.19,
2
-H), 2.46 (t, J = 5.7 Hz, 2 H, CH
), 1.46–1.37 (m, 2 H, CH
2
D
2
2
1
3
0
gluco-1-deoxynojirimycin 14 (86 mg, 0.16 mmol, 1 equiv.) accord-
ing to general procedure A yielding benzyl-protected 4 (85 mg,
0
138.75, 138.69, 138.63, 128.48, 128.43, 128.41, 128.38, 128.06,
127.87, 127.85, 127.72, 127.64, 127.56, 127.54, 83.16, 80.37, 78.96,
.11 mmol, 68 %). R
f
= 0.9 (1:1 pentane/EtOAc). 1H NMR 75.49, 73.50, 73.36, 73.14, 72.78, 71.21, 68.28, 64.49, 60.21, 59.85,
1
1
(400 MHz, CDCl
3
): δ = 7.41–7.18 (m, 18 H, CHAr), 7.18–7.02 (m, 54.69, 49.95, 37.61, 29.50, 27.77, 23.95 ppm. B NMR (128 MHz,
2
0
2
1
H, CHAr), 4.96 (d, J = 11.1 Hz, 1 H, CH
2
-H), 4.87 (d, J =
CDCl
3
): δ = –2.07, –5.46, –9.73, –10.82, –12.13, –12.84 ppm. [α]
Cl ). FT-IR (neat): ν˜ = 3086 (BCH), 3063,
-H), 4.47 3030, 2933, 2862, 2582 (BH), 1496, 1453, 1363, 1091, 1028,
D
0.8 Hz, 1 H, CH
2
-H), 4.81 (d, J = 11.1 Hz, 1 H, CH
-H), 4.65 (d, J = 11.6 Hz, 1 H, CH
2
-H), 4.69 (d, = –18.9 (c = 1.0, CH
2
2
J = 11.6 Hz, 1 H, CH
s, 2 H, CH ), 4.40 (d, J = 10.8 Hz, 1 H, CH
BCH), 3.70–3.61 (m, 2 H, CH, CH
2
2
–
1
+
(
2
2
-H), 3.88 (s, 1 H,
909 cm . ESI-HRMS (m/z): calculated for [C43
781.56208, observed 781.56147. Benzylated 7 (78 mg, 0.10 mmol)
), 3.31 (t, J = 6.4 Hz, 2 H, was subjected to general procedure B. HPLC-MS purification (A:
), 3.08 (dd, J = 11.1, 4.8 Hz, 1 H, CH -H), 2.98–1.54 (m, 10 0.1 % TFA in H O; B: linear gradient 36 % Ǟ 42 % CH CN in
-H), 2.62–2.52 (m, 1 H, CH -H), 12 min; flow: 5 mL/min) followed by lyophilisation provided the
), 2.30 (d, J = 9.5 Hz, 1 H, CH), 2.23 TFA salt of iminosugar 7 as a colorless oil (6.0 mg, 11.3 μmol,
61 5
H B10NO + H]
2
-H), 3.61–3.50 (m, 2 H, CH,
-H), 3.50–3.41 (m, 3 H, CH, CH
CH
CH
2
2
2
2
2
3
H, BH), 2.73–2.63 (m, 1 H, CH
.47 (t, J = 5.7 Hz, 2 H, CH
t, J = 10.8 Hz, 1 H, CH -H), 1.48 (p, J = 14.3, 7.1 Hz, 2 H, CH
2
2
2
(
1
2
1
2
2
), 11%). H NMR (600 MHz, MeOD): δ = 4.47 (s, 1 H, BCH), 4.06–
) ppm. 1 C NMR
3.91 (m, 4 H, CH , 2ϫ CH), 3.90–3.83 (m, 1 H, CH), 3.55–3.47
): δ = 139.08, 138.62, 137.90, 128.51, 128.48, (m, 4 H, CH , CH -H, CH), 3.43 (t, J = 6.2 Hz, 2 H, CH ), 3.38–
28.46, 128.43, 128.42, 127.96, 127.91, 127.74, 127.65, 127.55, 3.26 (m, 3 H, CH , CH -H), 2.81–1.55 (m, 10 H, BH), 2.53 (t, J =
), 1.91–1.82 (m, 1 H CH -H), 1.79–1.70 (m, 1 H,
-H), 1.64 (p, J = 6.5 Hz, 2 H, CH ), 1.46 (p, J = 7.3, 6.6 Hz,
2 H, CH
) ppm. 13C NMR (151 MHz, MeOD): δ = 162.77
(CF CO H), 75.16, 72.38, 71.39, 69.44, 68.96, 68.02, 63.83, 63.03,
3
.43–1.31 (m, 2 H, CH
2
), 1.24–1.13 (m, 2 H, CH
2
2
(
101 MHz, CDCl
3
2
2
2
1
8
6
2
2
7.46, 78.67, 78.62, 75.43, 75.29, 73.53, 73.45, 72.88, 71.06, 68.31,
5.54, 63.84, 60.22, 54.57, 52.33, 37.62, 29.52, 24.18, 23.54 ppm.
5.9 Hz, 2 H, CH
CH
2
2
2
2
1
1
B NMR (128 MHz, CDCl
3
): δ = –2.07, –5.47, –9.72, –10.86,
2
0
–
12.13, –12.87 ppm. [α]2
D
= +4.8 (c = 1.2, CH Cl ). FT-IR (thin
2
2
3
2
1
1
film): ν˜ = 3086 (BCH), 3063, 3030, 2933, 2863, 2804, 2581 (BH),
61.44, 55.09, 54.49, 38.59, 30.15, 24.50, 23.24 ppm. B NMR
–
1
1
722, 1496, 1454, 1361, 1315, 1274, 1207, 1091, 1028 cm . ESI-
(128 MHz, MeOD): δ = –2.69, –5.83, –9.85, –11.21, –11.92,
+
20
HRMS (m/z): calculated for [C43
61 5 D
H B10NO + H] 781.56208, ob- –13.10 ppm. [α] = +9.9 (c = 0.12, MeOH). FT-IR (thin film): ν˜
served 781.56143. Benzylated 4 (85 mg, 0.11 mmol) was treated ac-
= 3337, 3078 (BC–H), 2941, 2869, 2586 (B–H), 1674, 1433, 1203,
4443
Eur. J. Org. Chem. 2015, 4437–4446
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

H. S. Overkleeft et al.
FULL PAPER
–1
1
133, 1070 cm . ESI-HRMS (m/z): calculated for [C15
H
37
B
10NO
5
795.57710. The benzylated iminosugar (107 mg, 0.13 mmol) was
treated according to general procedure B. HPLC-MS purification
+
+
H] 420.37556, observed 420.37511.
(
1
A: 0.1% TFA in H
2 min; flow: 5 mL/min) followed by lyophilisation provided the
TFA salt of iminosugar 5 as a white powder (17.8 mg, 32.5 μmol,
2 3
O; B: linear gradient 37%Ǟ43% CH CN in
N-{5Ј-[3ЈЈ-(1ЈЈЈ,2ЈЈЈ-Dicarba-closo-dodecaboranyl)propoxy]pentyl}-
-gluco-1-deoxynojirimycin TFA Salt (5): Compound 22 (143 mg,
.31 mmol, 1.5 equiv.) was treated with 2,3,4,6-tetra-O-benzyl-d-
gluco-1-deoxynojirimycin 14 (107 mg, 0.20 mmol, 1 equiv.) accord-
ing to general procedure A. Flash column chromatography (100%
PEǞ30% EtOAc in PE) afforded protected iminosugar as a color-
D
0
1
2
(
3
3
5%). H NMR (600 MHz, MeOD): δ = 4.53 (s, 1 H, BCH), 4.12
d, J = 12.5 Hz, 1 H, CH -H), 3.90 (d, J = 10.9 Hz, 1 H, CH -H),
.68 (td, J = 10.7, 4.9 Hz, 1 H, CH), 3.60 (t, J = 9.8 Hz, 1 H, CH),
.48–3.41 (m, 3 H, CH -H, CH ), 3.41–3.33 (m, 4 H, CH , CH
-H), 3.04 (d, J =
-H), 2.77–1.55 (m,
), 1.85–1.77 (m, 1 H, CH -H),
), 1.63 (p, J = 6.9 Hz, 2 H, CH ),
) ppm. C NMR (151 MHz,
2
2
2
2
2
2
-
less oil (142 mg, 0.16 mmol, 78%), as well as starting material 22
H, CH), 3.19 (td, J = 12.4, 4.7 Hz, 1 H, CH
2
1
(
(
2
1
34 mg, 0.07 mmol). R
400 MHz, CDCl
f
= 0.5 (4:1 pentane/EtOAc). H NMR
9
1
1
1
.9 Hz, 1 H, CH), 2.98 (t, J = 11.7 Hz, 1 H, CH
0 H, BH), 2.38–2.32 (m, 2 H, CH
.77–1.69 (m, 3 H, CH -H, CH
.45 (dq, J = 14.5, 7.2 Hz, 2 H, CH
2
3
): δ = 7.43–7.19 (m, 18 H, CHAr), 7.18–7.06 (m,
H, CHAr), 4.95 (d, J = 11.1 Hz, 1 H, CH -H), 4.87 (d, J =
0.8 Hz, 1 H, CH -H), 4.81 (d, J = 11.1 Hz, 1 H, CH -H), 4.69 (d,
-H), 4.64 (d, J = 11.6 Hz, 1 H, CH -H), 4.46
), 4.40 (d, J = 10.8 Hz, 1 H, CH -H), 3.69–3.59 (m, 2
-H), 3.60–3.50 (m, 2 H, CH, CH
2
2
2
2
2
2
13
2
2
2
J = 11.6 Hz, 1 H, CH
s, 2 H, CH
H, CH, CH
H, CH), 3.32 (m, 4 H, 2ϫ CH
dd, J = 11.1, 4.8 Hz, 1 H, CH
.62–2.52 (m, 1 H, CH -H), 2.35–2.27 (m, 3 H, CH
J = 10.8 Hz, 1 H, CH -H), 1.82–1.70 (m, 2 H, CH
.1 Hz, 2 H, CH ), 1.43–1.30 (m, 2 H, CH ), 1.27–1.12 (m, 2 H,
CH ), 1.05 (s, 9 H, 3ϫ CH), 0.31 (s, 6 H, 2ϫ CH
) ppm. 13C NMR
101 MHz, CDCl ): δ = 139.08, 138.64, 137.89, 128.47, 128.41,
2
2
MeOD): δ = 162.86, 162.63, 162.40, 162.16, 120.88, 118.94, 117.02,
1
(
2
2
15.07 (8ϫ CF
3 2
CO H), 78.13, 77.01, 71.46, 70.33, 68.77, 67.80,
2
2
-H), 3.50–3.41 (m, 1
6
7.44, 63.76, 54.87, 54.28, 35.86, 30.66, 30.12, 24.44, 23.93 ppm.
2
), 3.17–1.63 (m, 10 H, BH), 3.07
11
B NMR (128 MHz, MeOD): δ = –2.90, –6.14, –9.67, –11.72,
(
2
2
-H), 2.73–2.62 (m, 1 H, CH
, CH), 2.23 (t,
), 1.47 (p, J =
2
-H),
20
–
3
1
13.09 ppm. [α]
D
= –2.8 (c = 0.36, MeOH). FT-IR (thin film): ν˜ =
2
2
333, 3065, 2936, 2865, 2592 (B–H), 1671, 1456, 1375, 1203, 1132,
–1
2
2
032 cm . ESI-HRMS (m/z): calculated for [C16
39 5
H B10NO +
7
2
2
+
H] 434.39125, observed 434.39056.
2
3
(
3
N-{5Ј-[3ЈЈ-(1ЈЈЈ,2ЈЈЈ-Dicarba-closo-dodecaboranyl)propoxy]pentyl}-
L-ido-1-deoxynojirimycin TFA Salt (8): Compound 22 (112 mg,
0.24 mmol, 1.2 equiv.) was treated with 2,3,4,6-tetra-O-benzyl-1-l-
ido-deoxynojirimycin 16 (104 mg, 0.20 mmol, 1 equiv.) according to
general procedure A. Flash column chromatography (100 %
PEǞ30% EtOAc in PE) afforded protected iminosugar as a color-
1
7
5
27.94, 127.88, 127.73, 127.63, 127.54, 87.47, 81.49, 78.69, 78.64,
6.49, 75.41, 75.27, 73.55, 72.87, 71.03, 69.44, 65.53, 63.81, 54.61,
2.41, 35.15, 30.52, 29.73, 27.75, 24.23, 23.59, 20.43, –2.41 ppm.
11
B NMR (128 MHz, CDCl
3
): δ = 0.19, –3.97, –7.35, –10.25 ppm.
20
[α] = +3.5 (c = 1.2, CH Cl ). FT-IR (thin film): ν˜ = 3089, 3063,
D 2 2
3
1
031, 2934, 2862, 2801, 2573 (B–H), 1454, 1362, 1265, 1208, 1173, less oil (108 mg, 0.12 mmol, 59%) as well as the TBDMS depro-
–
1
091, 1071, 1028 cm . ESI-HRMS (m/z): calculated for tected product (27 mg, 0.03 mmol, 17%). R
f
= 0.7 (4:1 pentane/
): δ = 7.60–6.98 (m, 20 H,
-H), 4.79 (d, J = 11.0 Hz, 1
-H), 4.71 (d, J = 11.6 Hz, 1 H, CH -H), 4.68–4.58 (m, 3 H,
, CH -H), 4.52 (d, J = 12.2 Hz, 1 H, CH -H), 4.48 (d, J =
12.2 Hz, 1 H, CH -H), 3.81 (dd, J = 10.1, 6.5 Hz, 1 H, CH -H),
3.71 (dd, J = 10.1, 2.3 Hz, 1 H, CH -H), 3.65 (dd, J = 9.0, 5.8 Hz,
1 H, CH), 3.58–3.45 (m, 2 H, 2ϫ CH), 3.39–3.26 (m, 5 H, CH,
2ϫ CH ), 3.11–1.57 (m, 10 H, BH), 2.85 (dd, J = 11.8, 5.1 Hz, 1
H, CH -H), 2.74–2.65 (m, 1 H, CH -H), 2.57–2.47 (m, 2 H, 2ϫ
CH -H), 2.35–2.27 (m, 2 H, CH ), 1.81–1.71 (m, 2 H, CH ), 1.50
(p, J = 14.5, 6.7 Hz, 2 H, CH ), 1.45–1.36 (m, 2 H, CH ), 1.26 (p,
J = 7.4 Hz, 2 H, CH ), 1.04 (s, 9 H, 3ϫ CH ), 0.31 (s, 6 H, 2ϫ
) ppm. C NMR (101 MHz, CDCl ): δ = 139.22, 138.79,
138.72, 138.66, 128.47, 128.42, 128.41, 128.36, 128.06, 127.85,
-H), 4.81 (d, 127.70, 127.63, 127.56, 127.52, 83.18, 81.56, 80.40, 78.99, 76.54,
-H), 4.69 (d, J = 11.6 Hz, 1 H, CH -H), 4.64 75.46, 73.37, 73.13, 72.81, 71.16, 69.42, 64.56, 59.90, 54.75, 50.01,
d, J = 11.6 Hz, 1 H), 4.46 (s, 2 H, CH ), 4.41 (d, J = 10.9 Hz, 1 35.19, 30.56, 29.70, 27.90, 27.76, 23.93, 20.44, –2.40 ppm.
+
1
[C
50
H
77
B
10NO
5
Si + H] 909.66474, observed 909.66473. Protected
EtOAc). H NMR (400 MHz, CDCl
CHAr), 4.84 (d, J = 11.0 Hz, 1 H, CH
H, CH
3
iminosugar (140 mg, 0.15 mmol, 1 equiv.) was dissolved in dry
THF (1 mL) under an argon atmosphere and cooled to –78 °C.
2
2
2
TFA (11.1 μL, 0.15 mmol, 1 equiv.) and TBAF (1 m in THF, CH
.18 mL, 0.18 mmol, 1.2 equiv.) were added. The mixture was
2
2
2
0
2
2
stirred at –78 °C for 15 min, then for 1.5 h at room temp. until
TLC showed complete conversion of the starting material. Water
2
(
20 mL) was added and extracted with EtOAc (3ϫ 20 mL). The
combined organic layers were washed with brine (1ϫ 60 mL), dried
with MgSO , filtered, and concentrated in vacuo. Flash column
chromatography (10 %Ǟ 40 % EtOAc in PE) yielded benzylated
iminosugar as a pale yellow oil (107 mg, 0.13 mmol, 90%). R
2
2
2
4
2
2
2
2
2
f
=
2
3
1
13
0.4 (4:1 pentane/EtOAc). H NMR (400 MHz, CDCl
7.20 (m, 18 H, CHAr), 7.17–7.09 (m, 2 H, CHAr), 4.95 (d, J =
11.1 Hz, 1 H, CH -H), 4.87 (d, J = 10.9 Hz, 1 H, CH
3
): δ = 7.36– CH
3
3
2
2
J = 11.1 Hz, 1 H, CH
(
2
2
1
1
2
B
H, CH
BCH, CH, CH
2
-H), 3.70–3.61 (m, 2 H, CH, CH
2
-H), 3.61–3.51 (m, 3 H,
NMR (128 MHz, CDCl
3
): δ = 0.18, –4.00, –7.36, –10.27 ppm.
Cl ). ESI-HRMS (m/z): calculated for
2
0
2
-H), 3.50–3.41 (t, J = 9.0 Hz, 1 H, CH), 3.37–3.27 [α]
D
= –17.3 (c = 1.8, CH
2
2
+
(
1
1
m, 4 H, 2ϫ CH
2
), 3.08 (dd, J = 11.1, 4.8 Hz, 1 H, CH
.54 (m, 10 H, 10ϫ BH), 2.73–2.63 (m, 1 H, CH -H), 2.61–2.51 (m,
H, CH -H), 2.33–2.26 (m, 3 H, CH , CH), 2.22 (t, J = 10.8 Hz, 1 tected product (0.03 mmol) was dissolved in dry THF (1 mL) under
-H), 1.76–1.67 (m, 2 H, CH ), 1.49 (p, J = 7.3, 6.9 Hz, 2 an argon atmosphere and cooled to –78 °C. TFA (10.8 μL,
), 1.45–1.31 (m, 2 H, CH ), 1.28–1.14 (m, 2 H, CH ) ppm. 0.15 mmol, 1 equiv.) and TBAF (1 m in THF, 0.17 mL, 0.17 mmol,
C NMR (101 MHz, CDCl ): δ = 139.11, 138.66, 137.95, 128.47,
2
-H), 2.94–
[C50
H
77
B
10NO
5
Si + H] 909.66474, observed 909.66459. Fully pro-
2
tected iminosugar (0.15 mmol) containing some TBDMS-depro-
2
2
H, CH
H, CH
2
2
2
2
2
1
3
3
1.2 equiv.) were added. The mixture was stirred at –78 °C for
15 min, then for 1 h at room temp. until TLC showed complete
conversion of the starting material. Water (30 mL) was added and
extracted with EtOAc (3ϫ 30 mL). The combined organic layers
were washed with brine (1ϫ 90 mL), dried with MgSO
and concentrated under reduced pressure. Flash column
1
7
6
28.43, 128.42, 127.96, 127.91, 127.74, 127.64, 127.54, 87.49, 78.72,
8.66, 75.41, 75.29, 75.22, 73.54, 72.89, 71.10, 69.21, 65.65, 63.92,
1.43, 54.60, 52.38, 35.36, 29.60, 29.58, 24.24, 23.70 ppm.
): δ = –2.30, –5.79, –9.29, –11.47, –12.05,
= +5.1 (c = 1.1, CH Cl ). FT-IR (thin film): ν˜ =
088, 3061, 3030, 2933, 2861, 2801, 2583 (B–H), 1496, 1453, 1360, chromatography (10%Ǟ40% EtOAc in PE) yielded the benzylated
1
1
B
NMR (128 MHz, CDCl
3
4
, filtered
13.03 ppm. [α]2
0
–
3
1
D
2
2
–1
310, 1207, 1172, 1091, 1072, 1027, 909 cm . ESI-HRMS (m/z):
iminosugar as pale yellow oil (103 mg, 0.13 mmol, 89%). R
f
= 0.5
+
1
calculated for [C44
H
63
B
10NO
5
+ H] 795.57779, observed
(4:1 pentane/EtOAc). H NMR (400 MHz, CDCl ): δ = 7.44–7.11
3
4444 www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4437–4446

ortho-Carborane-Modified N-Substituted Deoxynojirimycins
m, 20 H, CHAr), 4.85 (d, J = 11.0 Hz, 1 H, CH
(
2
-H), 4.79 (d, J = the same substrate as earlier described.[19] Briefly, GBA2 rich mem-
-H), 4.71 (d, J = 11.5 Hz, 1 H, CH -H), 4.68– brane suspensions were prepared from Gaucher disease spleen and
-H, CH ), 4.52 (d, J = 12.2 Hz, 1 H, CH -H), incubated with 3.7 mm 4-MU-β-glucoside in McIlvaine buffer
.48 (d, J = 12.2 Hz, 1 H, CH -H), 3.81 (dd, J = 10.1, 6.6 Hz, 1 (0.1 m citrate and 0.2 m phosphate buffer), pH 5.8, with or without
-H), 3.71 (dd, J = 10.1, 2.4 Hz, 1 H, CH -H), 3.65 (dd, J pre-incubation for 30 min at 4 °C with 1 mm CBE (Sigma) to in-
9.2, 5.8 Hz, 1 H, CH), 3.59–3.44 (m, 3 H, BCH, 2ϫ CH), 3.38– hibit the lysosomal glucocerebrosidase, GBA. Assays were incu-
.28 (m, 5 H, CH, 2ϫ CH ), 3.08–1.58 (m, 10 H, BH), 2.86 (dd, J bated at 37 °C and stopped by the addition of glycine/NaOH
-H), 2.76–2.65 (m, 1 H, CH -H), 2.57– (pH 10.6). The amount of liberated 4-MU was determined with a
-H), 2.33–2.24 (m, 2 H, CH ), 1.76–1.66 (m, Perkin–Elmer Life Sciences LS30 fluorometer. Assays were per-
), 1.51 (p, J = 14.5, 6.8 Hz, 2 H, CH ), 1.47–1.38 (m, 2
), 1.26 (p, J = 7.3 Hz, 2 H, CH
) ppm. 13C NMR (101 MHz,
): δ = 139.20, 138.77, 138.71, 138.66, 128.49, 128.44, 128.42,
28.38, 128.08, 127.86, 127.72, 127.65, 127.57, 127.53, 83.18, 80.38,
8.97, 75.50, 73.36, 73.14, 72.80, 71.20, 69.18, 64.54, 61.43, 59.87,
1
4
4
1.0 Hz, 1 H, CH
.58 (m, 3 H, CH
2
2
2
2
2
2
H, CH
=
3
=
2
2
H, CH
CDCl
1
7
5
(
–
=
1
2
2
2
11.8, 5.3 Hz, 1 H, CH
2
2
.48 (m, 2 H, 2ϫ CH
H, CH
2
2
2
2
formed in triplicate.
2
2
3
Acknowledgments
The authors are grateful for financial support from the European
Research Council (ERC AdG) (grant to H. S. O.) and the Nether-
lands Organization of Scientific Research (NWO-CW) (grant to
H. S. O.). The authors thank C. Erkelens, F. Lefeber and K. B. S. S.
Gupta for assistance with NMR measurements.
1
1
4.70, 49.95, 35.36, 29.59, 29.58, 27.83, 23.90 ppm. B NMR
): δ = –2.36, –5.85, –9.33, –11.51, –12.12,
= –19.4 (c = 1.7, CH Cl ). FT-IR (thin film): ν˜
3086, 3060, 3030, 2932, 2860, 2581 (B–H), 1496, 1453, 1362,
128 MHz, CDCl
3
13.09 ppm. [α]2
0
D
2
2
–1
309, 1250, 1207, 1090, 1069, 1026, 910 cm . ESI-HRMS (m/z):
+
calculated for [C44
95.57722. Benzylated iminosugar (107 mg, 0.13 mmol) was treated
according to general procedure B. HPLC-MS purification (A: 0.1%
TFA in H O; B: linear gradient 37%Ǟ44% CH CN in 12 min;
63 5
H B10NO + H] 795.57779, observed
[
1] a) P. Compain, O. R. Martin, Iminosugars: from synthesis to
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2
3
561–574.
flow: 5 mL/min) followed by lyophilisation provided the TFA salt
[
2] a) I. Hildebrand, R. Englert, H. Schulz, Diabetes 1986, 35,
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1
H NMR (600 MHz, MeOD): δ = 4.54 (s, 1 H, BCH), 4.06–3.92
(
m, 4 H, 2ϫ CH, CH
H, CH, CH -H), 3.43 (t, J = 6.3 Hz, 2 H, CH
H, CH ), 3.38–3.31 (m, 3 H, CH -H, CH ), 2.78–1.58 (m, 10 H,
BH), 2.38–2.33 (m, 2 H, CH ), 1.90–1.80 (m, 1 H, CH -H), 1.77–
.69 (m, 3 H, CH -H, CH ), 1.63 (p, J = 6.4 Hz, 2 H, CH ), 1.44
p, J = 7.5 Hz, 2 H, CH
) ppm. 13C NMR (151 MHz, MeOD): δ
162.69 (CF CO H), 77.02, 72.35, 71.48, 70.31, 68.94, 68.02,
2
), 3.91–3.84 (m, 1 H, CH), 3.56–3.46 (m, 2
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2
2
), 3.39 (t, J = 6.0 Hz,
2
2
2
2
2
2
355, 1481–1485.
1
(
=
6
2
–
2
2
2
[
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2
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1
11.75, –13.12 ppm. [α]2
0
= +10.0 (c = 0.36, MeOH). FT-IR (thin
D
film): ν˜ = 3348, 3065, 2934, 2870, 2592 (B–H), 1673, 1435, 1202,
1
+
–1
Asymmetry
2005,
16,
1747–1756;
d)
L. A. G. M.
39 5
133, 1072 cm . ESI-HRMS (m/z): calculated for [C16H B10NO
+
van den Broek, D. J. Vermaas, F. J. van Kemenade, M. C. C. A.
Tan, F. T. M. Rotteveel, P. Zandberg, T. D. Butters, F. Mied-
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Pays-Bas 1994, 113, 507–516.
H] 434.39125, observed 434.39052.
Biology: The inhibitory potencies (IC50 values) of 1–8 for various
enzyme activities were determined by exposing cells or enzyme
preparations to an appropriate range of iminosugar concentrations.
IC50 values for GCS activity were measured using living cells with
NBD-ceramide as substrate. Briefly, cells were incubated in 1 mL
of medium with 50 nmol C6-NBD-ceramide {6-[N-methyl-N-(7-ni-
[
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trobenz-2-oxa-1,3-diazol-4-yl)aminododecanoyl]sphingosine}
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ase was incubated with increasing amounts of compounds 1–8. En-
zyme activity was determined with 3.7 mm 4-methylumbelliferyl β-
glucoside (4-MU-β-glucoside) in McIlvaine buffer (0.1 m citrate
and 0.2 m phosphate buffer), pH 5.2, 0.1% Triton X100 (v/V) and
18]
[
0.2% (W/v) sodium taurocholate. Assays, performed in triplicate,
were incubated at 37 °C and stopped by the addition of glycine/
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the nonlysosomal glucocerebrosidase (GBA2) were measured with
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Published Online: June 9, 2015
4446
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4437–4446