An efficient and versatile synthesis of GlcNAcstatins - Potent and selective O-GlcNAcase inhibitors built on the tetrahydroimidazo[1,2-a]pyridine scaffold

Article abstract of DOI:10.1016/j.tet.2010.07.037

We report a novel approach to the synthesis of GlcNAcstatins - members of an emerging family of potent and selective inhibitors of peptidyl O-GlcNAc hydrolase build upon tetrahydroimidazo[1,2-a]pyridine scaffold. Making use of a streamlined synthetic sequence featuring de novo synthesis of imidazoles from glyoxal, ammonia and aldehydes, a properly functionalised linear GlcNAcstatin precursor has been efficiently prepared starting from methyl 3,4-O-(2′,3′-dimethoxybutane-2′,3′-diyl) -α-d-mannopyranoside. Subsequent ring closure of the linear precursor in an intramolecular S_N2 process furnished the key fused d-mannose-imidazole GlcNAcstatin precursor in excellent yield. Finally, a sequence of transformations of this key intermediate granted expeditious access to a variety of the target compounds bearing a C(2)-phenethyl group and a range of N(8) acyl substituents. The versatility of the new approach stems from an appropriate choice of a set of acid labile permanent protecting groups on the monosaccharide starting material. Application was demonstrated by the synthesis of GlcNAcstatins containing polyunsaturated and thiol-containing amido substituents.

Full text of DOI:10.1016/j.tet.2010.07.037

Tetrahedron 66 (2010) 7838e7849
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An efficient and versatile synthesis of GlcNAcstatinsdpotent and selective
O-GlcNAcase inhibitors built on the tetrahydroimidazo[1,2-a]pyridine scaffold
*
*
Vladimir S. Borodkin , Daan M.F. van Aalten
Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a novel approach to the synthesis of GlcNAcstatinsdmembers of an emerging family of potent
and selective inhibitors of peptidyl O-GlcNAc hydrolase build upon tetrahydroimidazo[1,2-a]pyridine
scaffold. Making use of a streamlined synthetic sequence featuring de novo synthesis of imidazoles from
glyoxal, ammonia and aldehydes, a properly functionalised linear GlcNAcstatin precursor has been ef-
Received 25 March 2010
Received in revised form 24 June 2010
Accepted 15 July 2010
Available online 22 July 2010
ficiently prepared starting from methyl 3,4-O-(20,30-dimethoxybutane-20,30-diyl)-
Subsequent ring closure of the linear precursor in an intramolecular SN2 process furnished the key fused
-mannose-imidazole GlcNAcstatin precursor in excellent yield. Finally, a sequence of transformations of
a-D-mannopyranoside.
D
this key intermediate granted expeditious access to a variety of the target compounds bearing a C(2)-
phenethyl group and a range of N(8) acyl substituents. The versatility of the new approach stems from an
appropriate choice of a set of acid labile permanent protecting groups on the monosaccharide starting
material. Application was demonstrated by the synthesis of GlcNAcstatins containing polyunsaturated
and thiol-containing amido substituents.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
by a plethora of highly specific kinases and phosphatases, the dy-
namic cycling of O-GlcNAc in eukaryotes is achieved by a single pair
Reversible posttranslational modification of cytoplasmic and
nuclear proteins in eukaryotic cells by glycosylation of (surface
of enzymes: peptidyl O-GlcNAc transferase (OGT, CAZY family
GT417) and peptidyl O-GlcNAc hydrolase (OGA, GH84).
exposed) serines and threonines with 2-acetamido-2-deoxy-
b
-
D
-
It has so far not been possible to study the cell biological effect
of hypo-O-GlcNAcylation due to a lack of OGT inhibitors. However,
OGA, with a number of stable functional substrate analogues
available, provides an excellent opportunity to study the cellular
effects of inhibitor-induced hyper-O-GlcNAcylation.
A number of potent OGA inhibitors have been developed in the
recent decades, including PUGNAc (Ki¼50 nM, hOGA)8e10 and NAG-
thiazoline (Ki¼70 nM, hOGA)11,12 (Fig. 1). Although both com-
pounds are prone to hydrolysis in aqueous solutions and also
glucopyranosyl residues (O-GlcNAc) is believed to play important
roles in diverse cellular processes, such as transcription, trans-
lation, signal transduction and protein trafficking and degrada-
tion.1e3 There is evidence to suggest that the faulty interplay
between O-GlcNAcylation and competitive or synergistic phos-
phorylation of specific proteins is involved in progression and
pathology of several metabolic and neurodegenerative diseases.
Thus an increased level of O-GlcNAcylation on proteins along the
insulin signalling pathway has been proposed to be involved in
insulin sensitivity,4,5 and hyper-phosphorylation of the microtu-
bule-associated protein tau that marks the development of the
Alzheimer disease was shown to be reciprocal with the abnor-
mally low O-GlcNAcylation.6
potently inhibit lysosomal b-hexosaminidases (HexA/HexB), they
became the standard tools for studying protein over O-GlcNAcyla-
tion. Recently, systematic variation of the size and electronic
properties of the thiazoline substituent resulted in the discovery of
the highly potent, selective and hydrolytically stable inhibitor
Thiamet-G (Ki¼21ꢀ3 nM, hOGA).13
The molecular mechanisms and biological implications of
O-GlcNAc attachment/hydrolysis are currently the subject of in-
tense multidisciplinary investigation. In a striking contrast to the
conceptually related reversible protein phosphorylation, regulated
In parallel, a search for novel, potent and selective OGA inhibitors
focussed our attention on the naturally occurring hexosaminidase
inhibitor nagstatin14,15 (Fig. 1). Its unique tetrahydroimidazo[1,2-a]
pyridine (fused sugar-imidazole) bicyclic scaffold and outstanding
potency fuelled the research of Tatsuta et al. on the total synthesis of
the parent compound and analogues.16,17 Ensuing work of Vasella
et al. has established sugar-imidazoles among the most powerful
* Corresponding authors.
E-mail
addresses:
vsborodkin@dundee.ac.uk
(V.S. Borodkin), dmfvanaalten@dundee.ac.uk (D.M.F. van Aalten).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.037

V.S. Borodkin, D.M.F. van Aalten / Tetrahedron 66 (2010) 7838e7849
7839
Figure 1.
b
-glycosidase inhibitors.18 The origin of this potency was attributed
The synthesis of GlcNAcstatin was provisionally designed as
a consolidation of two existing pathways to the fused sugar-imid-
azoles (Fig. 2).25 It exploited the highly efficient SN2 substitution of
the OH(8) group in the manno-configured C(2)-branched derivative
4 (tetrahydroimidazo[1,2-a]pyridine numbering) leading to the
gluco-azide 5 in accordancewith Vasella’s findings.23 In turn, the key
iodo-imidazole 3 was prepared using an extensively modified Tat-
to the half-chair conformation of the bicyclic core mimicking the
flattened geometry of the putative pyranosyl oxocarbenium ion
during the hydrolysis of glycosidic bond. The importance of the [1,2-
a] fused imidazole ring was deduced to stem from in-plane pro-
tonation of the pseudo-anomeric nitrogen atom with a laterally
positioned catalytic acid, that would proceed along the same tra-
jectory as protonation of a glycosidic bond to yield the
b
-anomeric
suta’s approach from the
L
-xylose 1 through the linear poly-
oxygen leaving group.19 Additionally, in contradiction with the
earlier Tatsuta’s data, C(2) substituted fused sugar-imidazoles were
found to show improved inhibition over unsubstituted analogues.
The effect, particularly profound in the phenethyl-substituted fused
hexose-imidazoles,20 has been also replicated for the series of C(2)
phenethyl-substituted fused pentose-imidazoles.21 Surprisingly,
the inhibition of hexosaminidases with nagstatin and analogous
fused 2-acetamido-2-deoxy sugar-imidazoles, was only tested very
recently, when synthesis of gluco-nagstatin was reported by Vasella
et al.22,23
hydroxylated
L
-gulo-imidazole 2.16 The overall competence of the
synthesis, however, was undermined by the poor efficacy of the
opening step, which required separation of mixtures of di-
astereomers and unproductive protective group exchange. Further
progress on the synthesis of GlcNAcstatins aimed at the de-
velopment of more potent/selective inhibitors of hOGA was ham-
pered by routine supply of the required intermediates. Aiming at the
synthesis of derivatives bearing unsaturated or thiol-containing
amide substituents, the abolishment of an array of permanent
benzyl protecting groups on the sugar moiety would result in opti-
mization of the synthetic scheme. To fulfil these objectives we de-
veloped a novel synthetic approach to GlcNAcstatins, making use of
de novo synthesis of linear polyhydroxylated imidazoles21,27 from
glyoxal, ammonia and chiral aldehydes available by reductive
cleavage of sugar primary iodides (BerneteVasella reaction).28
Based on these data and the availability of the crystal structure
of a bacterial OGA (bOGA) homologue from Clostridium perfringens
in complex with PUGNAc24 we designed GlcNAcstatin 6 (Fig. 1)d
the founding member of a novel family of OGA inhibitors built on
the fused
D-glucosamine-imidazole scaffold. In a preliminary
communication we reported synthesis and enzymatic profiling of
this compound to reveal its outstanding potency and selectivity
(Ki¼4 pM, bOGA).25 Recently we reported the evaluation of a small
set of GlcNAcstatins as inhibitors of human OGA to confirm that
both potency and selectivity could also be achieved with the human
enzyme.26
2. Results and discussion
We identified methyl 3,4-O-(20,30-dimethoxybutane-20,30-diyl)-
a-D
-mannopyranoside 12, easily available on a large scale,29 as the
optimal monosaccharide starting material (Scheme 1). Robust 3,4-
Figure 2.

7840
V.S. Borodkin, D.M.F. van Aalten / Tetrahedron 66 (2010) 7838e7849
Scheme 1.
O-bis-acetal protecting group in 12, meeting the criteria for the acid
labile permanent protecting group, would keep corresponding hy-
droxyls intact through the synthesis. The rigid bicyclic framework of
12 would also allow efficient differentiation of the remaining hy-
droxyl groups via selective alkylation of the OH(2) according to the
yield after flash chromatography. This observation was used ad-
vantageously to increase the overall yield of the requisite com-
pound 13 to 60%, starting from the bis-acetal 12. Substitution of the
OH(6) in 13 was then achieved using PPh3/imidazole/I2 in hot tol-
uene31 to furnish the iodo-derivative 15 in 75% yield on 30 mmol
scale. The ensuing reductive splitting of the pyranoside ring of 15
using a variant of the BerneteVasella reaction28 with freshly acti-
vated zinc in aqueous THF at 65 ꢁC gave the intermediate open-
chain aldehyde, which on treatment with 40% glyoxal solution in
7 M methanolic ammonia initially at 0 ꢁC and then at 70 ꢁC for 2 h
consistently produced the key intermediate imidazole 16 in a re-
warding 70% overall yield.
Ley’s protocol30 thus securing
a streamlined subsequent in-
troduction of the 6-iodo substituent (12/11). Reductive cleavage of
11 would then afford the open-chain aldehyde, which is instantly
ready for the three component construction of the imidazole ring
(11/10). Asymmetric dihydroxylation of the double bond in 10
followed by selective protection of OH(6) with suitable silyl ether
(acid labile) and bis-iodination of the imidazole ring would generate
the required
L
-gulo configured cyclisation precursor 9.
Initial catalytic dihydroxylation of the double bond in the open-
chain imidazole 16 with K2(OsO4)/K3[Fe(CN)6] was found to be
highly stereoselective, yet unfortunately providing the unwanted
We anticipated that after this point a synthetic sequence com-
prising of tetrahydroimidazo[1,2-a]pyridine ring closure (9/7)
and selective C(3) deiodination of the imidazole (7/8) would give
D-manno-configured derivative 17 as a sole product isolated in 78%
access to the key fused
D
-mannose-imidazole precursor of
yield after selective silylation of the primary hydroxy group with
triisopropyl chlorosilane (Scheme 3). Strikingly, running the re-
GlcNAcstatins 8, similar to the one successfully transformed into
GlcNAcstatin in the provisional synthesis.25
action in the presence of varying amounts of the
b-selective
In the event selective p-methoxybenzylation of the starting
mannoside 12 with 1.15 equiv of p-methoxybenzyl chloride
(PMBCl) in the presence of n-Bu4NI provided the expected 2-O-PMB
ether 13 in about 50% yield along with 25% of 2,6-di-O-PMB de-
rivative 14 (Scheme 2). Notably, the control experiment with benzyl
bromide afforded the corresponding 2-O-Bn ether in 78% yield, in
agreement with the original data.30 We found that the primary
PMB group in compound 14 could be selectively removed by
hydrogenolysis under controlled conditions to give a 10:1:9 mix-
ture of 2-O- and 6-O-monoalkylated derivatives and the starting
material 14 from which the 2-O-PMB ether 13 was isolated in 50%
(DHQD)2-PHAL ligand (0.1e5%) did not affect the stereochemical
outcome or efficiency of the process, suggesting an overpowering
intrinsic facial stereospecificity of the substrate.32 The absolute
configuration of 17 was established after its transformation into the
fused sugar-imidazole derivative 18 by treatment with Tf2O in pyr-
idine for 1 h at rt. Formation of the bicyclic compound was con-
firmed by HRMS and NMR spectra. In particular, the presence of the
(C8a)e(H5) and (C3)e(H5) (tetrahydroimidazo[1,2-a]pyridine
numbering) cross-peaks in the HMBC spectra proved that imidazole
moiety was covalently bound to C(5). Assuming clean inversion of
the configuration at C(5) occurred during cyclisation, observation of
Scheme 2. Reagents and conditions: (i) PMBCl, NaH, n-Bu4NI, DMF, rt, 16 h, 50%; (ii) I2, ImH, PPh3, toluene, 70 ꢁC, 3 h, 75%; (iii) H2, Pd/C, MeOH/EtOAc, 3 h, 50%; (iv) (a) Zn, THF/H2O
(10:1), 65 ꢁC, 1 h, (b) 40% aqueous glyoxal, 7 M NH3/MeOH, 0e70 ꢁC, 2 h, 70%.

V.S. Borodkin, D.M.F. van Aalten / Tetrahedron 66 (2010) 7838e7849
7841
Scheme 3. Reagents and conditions: (i) (a) K2(OsO4)/K3[Fe(CN)6], K2CO3, CH3SO2NH2, t-BuOH/THF/water, rt, 24 h, (b) TIPSCl, Py, 50 ꢁC, 16 h, 78%; (ii) Tf2O, pyridine, ꢂ15 ꢁC tort, 1 h,
92%; (iii) (a) (COCl)2, DMSO, DCM, ꢂ60 ꢁC then Et3N, (b) NaBH4, EtOH, rt, 16 h, 80%; (iv) Tf2O, Py, C2H4Cl2, ꢂ15 ꢁC then 50 ꢁC, 3 h, 90%.
the nuclear Overhauser effect (NOE) between protons H(7) and H
(5 a, b) in compound 18 was only compatible with its -gulo con-
-manno configuration of the starting
esterification with DIAD/PPh3/p-nitrobenzoic acid. However,
a simple two-step Swern oxidation34dNaBH4 reduction sequence
cleanly provided a 1:10 mixture of the epimeric alcohols 17 and 19.
The ample difference of the retention factors allowed the individual
isomers to be isolated in 9% and 80% yields, respectively, by chro-
matographic separation. Operational simplicity and scalability of
the devised sequence resulted in only a limited exploration of
alternative, more selective, reducing agents. Addition of cerium
chloride (NaBH4, CeCl3$7H2O/MeOH; ꢂ78 ꢁC to rt) did not change
the stereoselectivity, whereas DIBAL failed to reduce the
intermediate ketone even at ambient temperature.
*
L
figuration and, respectively,
compound 17.
D
The origin of the exceptional substrate-controlled selectivity of
the dihydroxylation reaction is not immediately obvious. It is pos-
sible that it could stem from formation of a complex of osmium
tetroxide with the imidazole; in this case, formation of the
D-manno-configured product would result from the intramolecular
delivery of the reagent onto the eclipsed rotamer of the double
bond. On the other hand, the same stereochemical outcome could
result from an effective shielding of one of the diastereotopic faces
of the double bond by the bulky C1 substituent. In this case, how-
ever, the double bond should react in a less favourable bisecting
conformation. Whatever the origin of the unique stereoselectivity
of the process, the reported observations provide a rare glimpse on
the barely explored stereodirecting properties of bis-acetal pro-
tected substrates in dihydroxylation reactions.33
The configuration of OH(4) in compound 19 was formally
established after closure of the bicyclic compound 20, which
required heating of the intermediate bis-triflate at 50 ꢁC for 3 h to
go to completion (Scheme 3). The observation of the NOE between
H(6) and H(5
*
a, b) in compound 20 established its
D-manno abso-
lute configuration and consequently the
compound 19.
L-gulo configuration of
In an attempt to invert the configuration of OH(4) in compound
17 we have found that it remained unchanged in the Mitsunobu
Similar to the stereochemical outcome of the dihydroxylation of
16, the formal FelkineAnh stereochemistry of the reduction of the
Scheme 4. Reagents and conditions: (i) NIS 2.5 equiv, MeCN, 6 h, rt, 95%; (ii) Tf2O, Py, C2H4Cl2, ꢂ15 ꢁC then 50 ꢁC; (iii) NIS 10 equiv, DMF, 85 ꢁC, 36 h, 80% or NIS 3 equiv, MeCN, PPTS,
80 ꢁC, 3 h, 65%; (iv) EtMgBr, THF, 0 ꢁC, 10 min, 88%.

7842
V.S. Borodkin, D.M.F. van Aalten / Tetrahedron 66 (2010) 7838e7849
intermediate ketone leading to the preferential formation of the
alcohol 19 is difficult to rationalise. Due to the presence of the rigid
bis-acetal framework adorned with the imidazole ring and multiple
alkoxy substituents, a choice of opportunities for remote chelate
formation is endless making the analysis in terms of chelate or non-
chelate models not conclusive.
using 3 equiv of NIS in MeCN at 80 ꢁC in the presence of 1 equiv of
PPTS36 giving the requisite compound 22 in 60% yield. The detected
formation of p-methoxybenzyl iodide as a by-product pointed at an
inadequate stability of the PMB protective group towards the NIS/
PPTS combination as a principal reason for the diminished efficacy
of bis-iodination. In the concluding step, the regioselective mono-
deiodination of 22 at C(3) with EtMgBr/THF at 0 ꢁC was executed
without incident to give the key mono-iodoimidazole 23 in 88%
yield.
It is worth noting that explorative one-step iodination/iodo-
cyclisation of the unsaturated open-chain imidazole 16 with
3 equiv of NIS resulted in transient formation of the bis-iodinated
imidazole 24 and, finally, triply iodinated tetrahydro-5H-imidazo
In line with our previous findings25 we initially decided to
convert the open-chain imidazole 19 into the bis-iodo-derivative 21
prior to cyclisation to avoid the drastic iodination conditions used
by Vasella et al. for iodination of preformed fused sugar-imidaz-
oles.35 As expected, iodination of 19 with 2.5 equiv of NIS in MeCN
proceeded smoothly to give the requisite compound 21 (Scheme 4).
However, all attempts to effect its annulation into the targeted
Scheme 5. Reagents and conditions: (i) NIS 3 equiv, MeCN, 6 h, rt, 78%.
tetrahydroimidazo[l,2-a]pyridine derivative 22 failed in marked
contrast with the highly effective cyclisation of the parent non-
iodinated compound 19 and previously observed smooth cyclisa-
tion of the benzylated/benzoylated analogue not possessing bis-
acetal protection.25 The lack of reactivity may be explained by the
spatial congestion developing in a transition state between the
iodine substituent at C(3) position of the imidazole ring and the
bulky primary triisopropylsilyloxy group.
Finally we found that post-cyclisation iodination of the fused
sugar-imidazole 20 using an even more vigorous variant of Vasel-
la’s original conditions (10 equiv NIS, DMF, 85 ꢁC, 36 h) furnished
the key diiodide 22 as slightly yellow oil in 80% yield after chro-
matographic purification of the very dark reaction mixture
(Scheme 4). Alternatively, iodination of 20 could be performed
[1,2-a]azepine derivative 25 in 78% yield as a result of apparent
anti-Baldwin 6-endo-trig cyclisation (Scheme 5). The structure of
the compound 25 was initially deduced from the high field shift of C
(6) (d
26.7) (imidazo-azepine numbering) in the 13C NMR spectrum,
pointing at the iodine substitution site. This was further confirmed
by observation of the (C9a)e(H5a)/(5b) cross-peaks in the HMBC
spectrum, revealing covalent connection of the imidazole and the
methylene group of the azepine ring. The configuration of the C(6)
iodo substituent was established from the presence of the H(6)eH
(8) cross-peak in the NOESY spectrum showing spatial proximity of
the corresponding protons.
Subsequently, a highly efficient Sonogashira coupling37 of the
key iodoimidazole 23 with phenylacetylene provided the fully as-
sembled precursor of GlcNAcstatins 26 with the C(2) phenylethynyl
Scheme 6. Reagents and conditions: (i) PhCCH, CuI, Et3N, Pd(PPh3)4, DMF, 80 ꢁC, 16 h, 93%; (ii) DDQ, DCM/H2O, 4 h, 83%; (iii) DPPA, DBU, toluene, rt then 80 ꢁC, 2 h, 93%; (iv) (a) H2,
Pd/C, MeOH or EtOAc, 1 h (b) (RCO)2O, Et3N, DCM for 29e31 or PyBOP, DIPEA, RCO2H, DCM, rt, 16 h, for 32e34; (v) TFA/H2O (95:5), rt, 36 h, 60e80%; (vi) DMF, MeONa/MeOH, DTT,
2 h, 56%.

V.S. Borodkin, D.M.F. van Aalten / Tetrahedron 66 (2010) 7838e7849
7843
substituent in place in 93% yield (Scheme 6). Critical stereoselective
conversion of the manno-configured 26 into the gluco-azide 28 was
achieved in two steps starting with oxidative removal of the PMB
protective group with DDQ (26/27; 83%) followed by azidation of
the alcohol 27 with DPPA/DBU under optimized conditions (tolu-
ene, 80 ꢁC, 2 h) to produce the requisite azide 28 in 93% yield as the
single product. The gluco-configuration of the compound 28 was
unambiguously deduced from the value of the corresponding
coupling constant (J7,8 9.5 Hz) as well as the presence of H(6)eH(8)
cross-peak in the NOESY spectrum.
permanent triisopropylsilyl and cyclic bis-acetal protections was
found to be rather sluggish, the versatility of the new synthetic
approach was clearly demonstrated by the preparation of
GlcNAcstatin derivatives of 2,4-pentanedioic and 3-mercaptopro-
pionic acids intrinsically incompatible with the hydrogenolytic
deprotection routines. The new approach also gives access to rapid
future exploration of alternative C(2) substituents that may yield
even more potent, selective and cell-permeable GlcNAcstatin
derivatives.
Starting from the azide 28 a panel of fully protected N-acylated
GlcNAcstatins precursors 29e34 encompassed derivatives of acetic,
propionic, iso-butyric, valeric, 2,4-pentanedioic38 and 3-(ace-
tylthio)propionic acids has been prepared using a uniform se-
quence consisted of simultaneous hydrogenation both of the triple
bond and the azido group over Pd catalyst followed by reaction of
the intermediate amine with suitable acylating agents.
4. Experimental
4.1. General
All reactions were performed in oven-dried glassware under an
inert atmosphere (argon) unless noted otherwise. Dichloro-
methane, acetonitrile, triethylamine were anhydrous grade sol-
vents from Fluka kept over molecular sieves. Analytical thin layer
chromatography (TLC) was performed on Merck silica gel 60 F254
aluminium plates (0.25 mm). Compounds were visualized by UV
light, or by dipping the plate into acidic potassium permanganate
aqueous solution followed by washing out the excess of the re-
agent, or by charring the plate at ca. 300 ꢁC after dipping in a 5%
phosphomolybdic acid solution in ethanol. Flash chromatographic
separations were performed on Isco RediSep flash columns using
Buchi gradient pump system. NMR spectra were recorded on
Bruker AVANCE II 500 spectrometer. Splitting patterns of spectral
multiplets are indicated as s, singlet; d, doublet; br s broad singlet;
br d broad doublet; t triplet; quint quintet. Signals were assigned by
means of DEPT, COSY, HSQC, and HMBC spectra. High-resolution
mass spectra (HRMS) were obtained on a microTOF Bruker Dal-
tonics instrument. Optical rotations were measured in chloroform
on a PerkineElmer 343 polarimeter at 20 ꢁC.
As the concluding step of the synthesis, removal of the perma-
nent protecting groups (TIPS and 3,4-O-dimethoxybutanediyl bis-
acetal) was intended to be achieved with acid hydrolysis in one step.
In the event the reaction was found to be prohibitively slow. When
solutions of a substrate in DCM were exposed to the increasing
(10e50%) concentrations of TFA/water (95:5) in DCM, both pro-
tecting groups remained intact for a period of several hours. More-
over, it appeared that the TIPS group could be selectively removed by
treatment with 4 M HCl in THF for 16 h, leaving the butanediyl bis-
acetal protection mostly unchanged. Our findings appear to be in
agreement with a singular report suggesting that removal of 3,4-O-
bis-acetal protection in N-acetyl glucosamine derivatives could be
a slow process.39 It seems that protonation of the imidazole ring of
the fused N-acetylated glucosamine-imidazoles 29e34 contributes
significantly to the acid stability of the butanediyl bis-acetal pro-
tection making it even more resistant towards hydrolysis than in N-
acetyl glucosamine derivatives. Finally, global deprotection of 29e34
was achieved by 36 h treatment with aqueous TFA (95:5) to furnish
the requisite compounds 35e40 in acceptable yields after reversed
phase chromatography purification. To obtain the 3-thiopropionic
acid derivative 41, S-acetyl protection was finally removed from 40
with MeONa/MeOH in the presence of dithioerythrol.
FT-IR spectra were recorded on PerkineElmer Spectrum BX
instrument.
4.1.1. (20S,30S)-Methyl 2-O-(4-methoxybenzyl)-3,4-O-(20,30-dimethoxy-
butane-20,30-diyl)- -mannopyranoside (13) and (20S,30S)-methyl 2,6-
a-D
di-O-(4-methoxybenzyl)-3,4-O-(20,30-dimethoxybutane-20,30-diyl)-
a-D-
mannopyranoside (14). To a cooled (ice-bath) solution of 12 (15.16 g,
49.16 mmol) and p-methoxybenzyl chloride (7.5 mL, 55.31 mmol)
in DMF (250 mL) sodium hydride (60% in oil; 4 g, 100 mmol) was
added in portions. The reaction was stirred for 1 h and then re-
moved from the ice-bath; n-Bu4NI (1.8 g, 4.87 mmol) was added at
this moment. The reaction was further stirred for 16 h at rt. An
excess of sodium hydride was quenched by careful addition of ice
chips with external cooling (ice-bath). After gas evolution ceased
the reaction was partitioned between water and ethyl acetate and
the layers were separated. The organic layer was washed with
water. The aqueous layers were additionally extracted with ethyl
acetate. The combined organic layer was dried and concentrated.
The residue was purified by flash chromatography in Tol/EA
5/50% to give and 11.37 g (26.5 mmol, 54%) of the title compound
13 as foam and 6.58 g (11.99 mmol, 25%) of the title compound 14 as
clear syrup.
3. Conclusions
We reported here a novel approach to the synthesis of a family
of potent and selective inhibitors of peptidyl O-GlcNAcase
(GlcNAcstatins) built on the fused D-glucosamine-imidazole scaf-
fold. At the outset of the synthesis a short practical route to the
densely functionalised open-chain imidazole bearing a terminal
double bond has been developed using a novel combination of
BerneteVasella reaction and de novo imidazole synthesis. Dihy-
droxylation of the double bond in this intermediate was found to
be exclusive substrate controlled process leading to formation of
the unwanted
D-manno-configured product. The inversion of
configuration of the OH(4) group has been achieved by a seren-
dipitously found by-pass method using stereoselective reduction
of the intermediate ketone. The obtained L-gulo substrate resisted
all attempts to be cyclised into bicyclic derivative when iodine
atoms have been preinstalled at the imidazole ring. In contrast,
seamless cyclisation of the non-iodinated precursor into the req-
4.1.2. Compound 13. dH (500 MHz, CDCl3) 7.38e7.32 (2H, m,
CH2PhOMe), 6.88e6.82 (2H, m, CH2PhOMe), 4.87 and 4.58 (AB
spectrum, J 11.4 Hz, CH2PhOMe), 4.63 (1H, d, J1,2 1.3 Hz, H-1), 4.18
(1H, t, J3,4¼J4,5¼10.3 Hz, H-4), 4.05 (1H, dd, J3,4 10.3, J2,3 2.8 Hz, H-3),
3.81 (1H, dd, J6a,6b 11.7, J6a,5 2.6 Hz, H-6a), 3.77 (3H, s, OMe),
3.78e3.75 (1H, m, H-6b), 3.72e3.68 (1H, m, H-5), 3.68 (1H, dd, J2,3
2.8, J1,2 1.3 Hz, H-2), 3.28 (6H, s, 2ꢃOMe), 3.27 (3H, s, OMe), 1.34 (3H,
s, Me), 1.29 (3H, s, Me).
uisite fused D-mannose-imidazole was easily achieved using the
standard protocol. Ultimately, a Sonogashira reaction of C(2) iodo-
derivative of the cyclised compound with phenylacetylene pro-
vided highly efficient access to the advanced intermediate in the
GlcNAcstatin synthesis bearing a phenylethynyl substituent at the
C(2) position. Starting from this compound, a set of GlcNAcstatins
with assorted amido substituents has been prepared. Although the
very last step of the synthesis, i.e., acidolytic removal of the
dC (126 MHz, CDCl3) 159.1, 130.7, 129.7, 129.1, 128.2, 113.62, 113.6,
113.5, 100.6 (C-1), 99.8, 99.5, 75.2 (C-2), 72.9, 71.1 (C-5), 69 (C-3),

7844
V.S. Borodkin, D.M.F. van Aalten / Tetrahedron 66 (2010) 7838e7849
63.6 (C-4), 61.4 (C-6), 55.2, 54.6, 47.9, 47.8,17.8,17.7. nmax (KBr) 3060,
through a pad of Celite. The filter cake was washed with ether. The
combined filtrate was concentrated, diluted with CHCl3 and
washed with brine. The aqueous layer was extracted additionally
with CHCl3 twice. The combined organic layer was dried, concen-
trated and dried briefly in vacuum to give clear oily residue (about
10 g). The residue was dissolved in 7 M methanolic ammonia
(100 mL) at 4 ꢁC (ice-bath) and mixed with 40% aqueous glyoxal
solution (10 mL). The reaction was removed from the cooling bath
and further stirred at rt for 1.5 h while the initially formed thick
white precipitate dissolved and solution progressively turned yel-
low. The reaction was then heated up to 70 ꢁC and kept at this
temperature for 2 h; the solution turned brown with brown sedi-
ment. The reaction was cooled and volatiles were removed in
vacuum. The residue was dissolved in CHCl3/MeOH, absorbed on
silica (50 g) and purified by flash chromatography in Tol/Me2CO
5/30% to give 6.1 g (14.58 mmol, 70%) of the title compound 16 as
clear syrup.
3030, 2981, 2950, 1487, 1382, 1216, 1134, 892 cmꢂ1. [
a
]
þ132.3 (c
D
1.0, CHCl3). Rf¼0.28; Tol/EA 30%. HRMS-(TOF): MHþ, found
429.2128. C21H33O9 requires 429.2125.
4.1.3. Compound 14. dH (500 MHz, CDCl3) 7.41e7.35 (2H, m,
CH2PhOMe), 7.28e7.23 (2H, m, CH2PhOMe), 6.90e6.81 (4H, m,
2ꢃCH2PhOMe), 4.88 and 4.63 (2H, AB spectrum,
J 11.7 Hz,
CH2PhOMe), 4.70 (1H, d, J1,2 1.4 Hz, H-1), 4.59 and 4.53 (2H, AB
spectrum, J 11.6 Hz, CH2PhOMe), 4.17 (1H, t, J3,4¼J4,5¼10.2 Hz, H-4),
4.07 (1H, dd, J3,4 10.2, J3,2 2.9 Hz, H-3), 3.90e3.85 (1H, m, H-5), 3.83
(s, 3H, OMe), 3.82 (s, 3H, OMe), 3.76 (1H, dd, J6a,6b 11.1, J6a,5 2.2 Hz,
H-6a), 3.72 (1H, dd, J6a,6b 11.1, J6b,5 5.5 Hz, H-6b), 3.68 (1H, dd, J3,2
2.9, J1,2 1.6 Hz, H-2), 3.35 (3H, s, OMe), 3.29 (3H, s, OMe), 3.21 (3H, s,
OMe), 1.35 (3H, s, Me), 1.29 (3H, s, Me).
dC (126 MHz, CDCl3) 159.1, 159, 130.9, 130.7, 129.6, 129.1, 113.6,
100.4 (C-1), 99.8, 99.5, 75.4 (C-2), 73.1, 72.7, 71 (C-5), 69.2 (C-3),
68.6 (C-6), 63.8 (C-4), 55.1, 54.5, 47.83, 47.8, 17.85, 17.8. [
a
]
D þ140.6
dH (500 MHz, CDCl3) 7.27e7.21 (2H, m, CH2PhOMe), 7.07 (2H, s,
H-40, H-50), 6.87e6.82 (2H, m, CH2PhOMe), 5.69 (1H, ddd, J4,5 trans
17.3, J4,5 cis 10.3, J3,4 7.7 Hz, H-4), 5.24 (2H, m, H-5a, H-5b), 4.60 (1H,
d, J1,2 2.4, H-1), 4.52e4.45 (2H, m, CH2PhOMe), 4.12 (1H, dd, J2,3 10.4,
J1,2 2.4 Hz, H-2), 3.79 (3H, s, OMe), 3.66 (1H, ddt, J2,3 10.4, J3,4 7.8, J3,5
0.8 Hz, H-3), 3.38 (s, 3H, OMe), 3.12 (3H, s, OMe), 1.41 (3H, s, Me),
1.30 (3H, s, Me).
(c 1.0, CHCl3). Rf¼0.6; Tol/EA 30%. HRMS-(TOF): MHþ, found
549.2691. C29H41O10 requires 549.2700.
4.1.4. Compound 13 from 14. A solution of 13 (6.5 g, 11.84 mmol) in
MeOH/ethyl acetate 1:1 (120 mL) was hydrogenated under slight
positive pressure of H2 (balloon) in the presence of Pd/C 20% cat-
alyst (0.6 g) for 3 h at rt. The reaction mixture was filtered through
a pad of Celite. The filter cake was washed additionally with MeOH;
the combined filtrate was concentrated. The residue was purified
by flash chromatography in Tol/EA 5/50% to give 2.56 g
(5.98 mmol, 50%) of the title compound 13 and 2.72 g (4.95 mmol,
41%) of the starting material 14.
dC (126 MHz, CDCl3) 159.1, 144.7 (C-20), 133.0 (C-4), 130.1, 129.2
(br s, C-40/50),120.9 (C-5),116.4 (br s, C-40/50),113.7, 98.7, 98.5, 73 (C-
2), 72.4 (C-1), 70.7, 70.3 (C-3), 55.2, 48.3, 48, 17.8, 17.5. nmax (KBr)
3067, 3033, 2869, 1877, 1812, 1599, 1535, 1497, 1455, 1364, 1343,
1113, 1028, 963 cmꢂ1. Rf¼0.25; Tol/Me2CO 30%, [
a
]
D
þ41.6 (c 0.62,
CHCl3). HRMS-(TOF): MHþ, found 419.2185. C22H31N2O6 requires
419.2182.
4.1.5. (20S,30S)-Methyl 6-deoxy-2-O-(4-methoxybenzyl)-3,4-O-(20,30-
dimethoxybutane-20,30-diyl)-6-iodo-
a-D
-mannopyranoside (15). To
4.1.7. (1R)-1-[(2R,3R,5R,6R)-3-[(R)-1H-Imidazol-2-yl-[(4-methoxy-
phenyl)methoxy]methyl]-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-
2-yl]-2-triisopropylsilyloxy-ethanol (17)40. Freshly prepared solu-
tion of K3Fe(CN)6 (0.888 g, 2.7 mmol), K2CO3 (0.373 g, 2.7 mmol) and
K2OsO4$2H2O (0.008 g, 0.022 mmol) in t-BuOH/water 1:1 (16 mL)
was added to a solution of 16 (0.375 g, 0.9 mmol) and meth-
anesulfonamide (0.095 g, 1 mmol) in t-BuOH/THF 1:1 (2.7 mL). The
resulting slurry was vigorously stirred for 16 h. The reaction was
quenched by addition of an excess of Na2S2O5 (1 g), stirred for 0.5 h
rt, diluted with water and extracted with ethyl acetate three times.
The combined organic layer was dried and concentrated to give
0.41 g (0.9 mmol) of the crude product; the TLC revealed complete
consumption of the starting material and formation of a more polar
single product (Tol/Me2CO 40%; Rf¼0.15), (DCM/MeOH 5%; Rf¼0.3).
The residue was dissolved in pyridine (5 mL) and treated with
triisopropyl chlorosilane (0.213 mL, 1 mmol). The reaction was kept
at 50 ꢁC for 16 h. The reaction was cooled to rt, quenched by ad-
dition of MeOH (0.5 mL), kept for 20 min at rt and concentrated.
The residue was dissolved in DCM and washed with water. The
layers were separated; the aqueous layer was extracted with DCM
once more. The combined organic layer was dried and concen-
trated. The residue was purified by flash chromatography in PE/EA
5/50% to give 0.422 g (0.693 mmol, 77%) of the title compound 17
as viscous syrup.
a solution of 13 (11.37 g, 26.53 mmol) and PPh3 (10.23 g, 39 mmol)
in toluene (270 mL) imidazole (5.41 g, 79.5 mmol) and iodine
(9.13 g, 36 mmol) were sequentially added to form a biphasic
mixture with brown coloured lower layer. The reaction was placed
into preheated oil bath (70 ꢁC) and stirred for 4 h while the colour
gradually faded. The reaction was cooled and concentrated. The
residue was dissolved in CHCl3, absorbed on silica (80 g) and pu-
rified by flash chromatography in PE/EA 0/20% to give 11.13 g
(20.67 mmol, 78%) of the title compound 15 as white solid.
dH (500 MHz, CDCl3) 7.39e7.35 (2H, m, CH2PhOMe), 6.90e6.86
(2H, m, CH2PhOMe), 4.87 and 4.62 (2H, AB spectrum, J 11.7 Hz,
CH2PhOMe), 4.68 (1H, d, J1,2 1.3 Hz, H-1), 4.04 (1H, dd, J3,4 10.1, J3,2
2.8 Hz, H-3), 3.95 (1H, dd, J3,4 10.1, J4,5 9.1 Hz, H-4), 3.83 (3H, s, OMe),
3.69 (1H, m, H-5), 3.68 (1H, dd, J2,3 2.8, J1,2 1.3 Hz, H-2), 3.59 (1H, dd,
J6a,6b 10.5, J6a,5 2.2 Hz, H-6a), 3.39 (3H, s, OMe), 3.31 (3H, s, OMe),
3.29 (3H, s, OMe), 3.26 (1H, dd, J6a,6b 10.5, J6b,5 8.8 Hz, H-6b), 1.36
(3H, s, Me), 1.32 (3H, s, Me).
dC (126 MHz, CDCl3) 159.1, 130.7, 129.6, 113.6, 100.5 (C-1), 99.9,
99.7, 75.2 (C-2), 72.8, 70.7 (C-5), 68.7 (C-3), 67.7 (C-4), 55.3, 54.9,
48.2, 48.1, 17.8, 5.2 (C-6). nmax (KBr) 3084, 3052, 2968, 2934, 2863,
1591, 1472, 1430, 988, 763 cmꢂ1. Rf¼0.35; PE/EA 10%, [
a] 151.5 (c
D
1.00, CHCl3). Mp 82.5 ꢁC petroleum ether/chloroform. HRMS-(TOF):
MNaþ, found 561.0977. C21H31INaO8 requires 561.0961.
dH (500 MHz, CDCl3) 7.28e7.24 (2H, m, CH2PhOMe), 7.04 (2H, s,
H-40, H-50), 6.88e6.83 (2H, m, CH2PhOMe), 5.35 (1H, d, J1,2 2.9 Hz,
H-1), 4.55 (2H, s, CH2PhOMe), 4.26 (1H, dd, J2,3 10.1, J1,2 2.9 Hz, H-2),
3.89 (1H, dd, J5a,5b 9.9, J5a,4 3.6 Hz, H-5a), 3.80 (3H, s, OMe), 3.77 (1H,
dd, J5a,5b 9.9, J5b,4 3.4 Hz, H-5b), 3.61 (1H, dt, J4,5 8.5, J4,5b¼J4,5b
3.5 Hz, H-4), 3.38 (3H, s, OMe), 3.34 (1H, dd, J2,3 10.1, J3,4 8.6, H-3),
3.11 (3H, s, OMe),1.38 (3H, s, Me),1.26 (3H, s, Me),1.11e0.97 (21H, m,
Si(CH(Me)2)3).
4.1.6. 2-[(R)-[(2S,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-3-vinyl-
1,4-dioxan-2-yl]-[(4-methoxyphenyl)methoxy]methyl]-1H-imidazole
(16)40. Zinc dust (13.7 g, 210 mmol) was activated by swirling with
3 M HCl (50 ml) for 3 min. The acid was decanted and the sediment
was washed (3ꢃ50 ml) with water, then EtOH (50 ml) and finally
with ether (50 ml). The light grey powder was dried in vacuum and
added to a solution of 15 (11.13 g, 20.67 mmol) in THF/water (10:1)
(100 mL). The reaction was brought to reflux (85 ꢁC oil bath) and
stirred for 40 min. The reaction was cooled to rt and filtered
dC (126 MHz, CDCl3) 159, 145.8 (C-20), 130.5, 129.1, 113.7, 98.4,
98.3, 73.3 (C-1), 73.0 (C-2), 71.7 (C-4), 71.1, 67.2 (C-3), 63.1 (C-5),

V.S. Borodkin, D.M.F. van Aalten / Tetrahedron 66 (2010) 7838e7849
7845
55.2, 48.3, 48, 17.9, 17.7, 17.4, 11.9. nmax (KBr) 3028, 3012, 2989, 2899,
1732, 1455, 1383, 1229, 1159, 1072, 857 cmꢂ1. Rf¼0.33; PE/EA 40%,
(1H, dd, J2,3 10.4, J2,1 2.6 Hz, H-2), 3.80 (3H, s, OMe), 3.74e3.64 (3H,
m, H-3, H-5a, H-5b), 3.53 (1H, ddd, J 7.7, 6.3,1.4 Hz, H-4), 3.35 (3H, s,
OMe), 3.16 (3H, s, OMe), 1.38 (3H, s, Me), 1.31 (3H, s, Me), 1.07e0.94
(21H, m, Si(CH(Me)2)3).
[
a]
þ54.2 (c 1.0, CHCl3). HRMS-(TOF): MHþ, found 609.3565.
D
C31H53N2O8Si requires 609.3571.
dC (126 MHz, CDCl3) 159.1, 145.1 (C-20/C30), 130.3, 129.2, 113.7,
98.7, 73.2 (C-1), 71.3, 69.94 (C-4/C-2), 69.9 (C-4/C-2), 66.6 (C-3),
62.7 (C-5), 55.2, 48.2, 47.95, 17.95, 17.8, 17.4, 11.8. nmax (KBr) 3030,
4.1.8. (2S,3S,4aS,5R,10S,10aR)-2,3-Dimethoxy-5-((4-methoxybenzyl)
oxy)-2,3-dimethyl-10-(((triisopropylsilyl)oxy)methyl)-
2,3,4a,5,10,10a-hexahydro-[1,4]dioxino[2,3-d]imidazo[1,2-a]pyridine
(18)41. To a solution of 17 (0.057 g, 0.095 mmol) and Py (0.032 mL,
0.38 mmol) in DCM (1.5 mL) cooled to ꢂ15 ꢁC trifluoromethane-
sulfonic anhydride (0.047 mL, 0.28 mmol) was added dropwise. The
reactionwas allowed towarm-uptothe rt andstirred for1 h at rt. The
reaction was diluted with DCM and washed with a mixture of
NaHCO3 solution and brine. The aqueous layer was extracted with
DCM once more. The combined organic layer was dried and con-
centrated. The residue was purified by flash chromatography Tol/EA
10/40% to give 0.055 g (0.094 mmol,100%) of the title compound 18
as glassy solid.
3015, 2993, 2899, 1735, 1455, 1383, 1230, 1161, 1072, 855 cmꢂ1
.
Rf¼0.35; Tol/EA 40%, [
a
]
þ68.6 (c 1.0, CHCl3). HRMS-(TOF): MHþ,
D
found 609.3562. C31H53N2O8Si requires 609.3571.
4.1.10. (2S,3S,4aS,5R,10R,10aR)-2,3-Dimethoxy-5-((4-methoxy-
benzyl)oxy)-2,3-dimethyl-10-(((triisopropylsilyl)oxy)methyl)-
2,3,4a,5,10,10a-hexahydro-[1,4]dioxino[2,3-d]imidazo[1,2-a]pyridine
(20)41. To a solution of 19 (4.57 g, 7.5 mmol) and pyridine (2.42 mL,
30 mmol) in C2H4Cl2 (75 mL) cooled to ꢂ15 ꢁC trifluoromethane-
sulfonic anhydride (3.8 mL, 22.58 mmol) was added dropwise. The
reaction was warmed to rt. After 10 min the reaction was placed
into preheated oil bath (50 ꢁC) and stirred for 3 h. The reaction was
cooled down, diluted with DCM and washed with a mixture of
NaHCO3 solution and brine. The aqueous layer was extracted with
DCM once more. The combined organic layer was dried and con-
centrated. The residue was purified by flash chromatography Tol/EA
10/40% to give 4.29 g (7.26 mmol, 97%) of the title compound 20
as clear syrup.
dH (500 MHz, CDCl3) 7.47e7.41 (2H, m, CH2PhOMe), 7.07 (1H, d,
J2,3 1.3 Hz, H-2), 7.01 (1H, d, J2,3 1.3 Hz, H-3), 6.90e6.83 (2H, m,
CH2PhOMe), 4.95 and 4.78 (2H, AB spectrum, J 11.1 Hz, CH2PhOMe),
4.83 (1H, dd, J6,7 11.1, J6,5 7.0 Hz, H-6), 4.78 (1H, d, J8,7 3.8 Hz, H-8),
4.39 (1H, dd, J7,6 11.1, J7,8 3.8 Hz, H-7), 4.34e4.29 (1H, m, H-5), 4.12
(1H, dd, J5*a,5*b 10.5, J5*a,5 3.0 Hz, H-5
*
a), 3.98 (1H, dd, J5*a,5*b 10.6,
J5*b,5 5.1 Hz, H-5 b), 3.80 (3H, s, OMe), 3.32 (3H, s, OMe), 3.25 (3H, s,
*
OMe), 1.41 (3H, s, Me), 1.34 (3H, s, Me), 1.10e0.97 (21H, m, Si(CH
(Me)2)3).
dC (126 MHz, CDCl3) 158.9, 143.5 (C-8a), 131, 129.5, 129.2 (C-2),
119.1 (C-3), 113.54, 113.5, 113.4, 99.4, 99.3, 72.0, 70.1 (C-8), 67.2 (C-
dH (500 MHz, CDCl3) 7.31e7.26 (2H, m, CH2PhOMe), 7.24 (1H, d,
J2,3 1.2 Hz, H-2), 6.99 (1H, d, J2,3 1.2 Hz, H-3), 6.79e6.73 (2H, m,
CH2PhOMe), 4.77 and 4.65 (2H, AB spectrum, J 11.4 Hz, CH2PhOMe),
4.69 (1H, d, J8,7 3.2 Hz, H-8), 4.35 (1H, dd, J6,7 10.5, J6,5 9.2 Hz, H-6),
7), 62.8 (C-6), 62.5 (C-5
*
), 58.2 (C-5), 55.2, 48.1, 48.03, 18.01, 17.9,
4.13 (1H, dd, J5*a,5*b 10.7, J5*a,5 1.9 Hz, H-5
J5,5*b 7.2, J5,5*a 1.9 Hz, H-5), 3.92 (1H, dd, J7,6 10.6, J7,8 3.3 Hz, H-7),
3.84 (1H, dd, J5*b,5*a 10.7, J5*b,5 7.2 Hz, H-5 b), 3.71 (3H, s, OMe), 3.21
*
a), 3.96 (1H, ddd, J5,6 9.1,
17.6, 11.8. nmax (KBr) 3090, 3067, 1952, 1879, 1810, 1751, 1603, 1525,
1496, 1310, 1085, 1028, 980 cmꢂ1. Rf¼0.3; Tol/EA 30%, [
a
]
D ꢂ27.6 (c
*
1.0, CHCl3). HRMS-(TOF): MHþ, found 591.3460. C31H51N2O7Si re-
(3H, s, OMe), 3.19 (3H, s, OMe), 1.32 (3H, s, Me), 1.27 (3H, s, Me),
1.07e0.87 (21H, m, Si(CH(Me)2)3).
quires 591.3466.
dC (126 MHz, CDCl3) 158.9, 143.2 (C-8a), 130.8, 129.5 (C-3), 129.2,
4.1.9. (1S)-1-[(2R,3R,5R,6R)-3-[(R)-1H-Imidazol-2-yl-[(4-methoxy-
phenyl)methoxy]methyl]-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-
yl]-2-triisopropylsilyloxy-ethanol (19)40. To a solution of DMSO
(0.97 mL, 13.7 mmol) in DCM (65 mL) trifluoroacetic anhydride
(1.43 mL, 10.25 mmol) was added dropwise at ꢂ60 ꢁC. The reaction
was stirred for 20 min then a solution of 17 (5.2 g, 8.54 mmol) in
DCM (20 mL) was added via capillary. The reaction was further
stirred for 45 min before Et3N (4.76 mL, 34.16 mmol) was added
dropwise. The reaction was stirred for 5 min at ꢂ60 ꢁC and then
was warmed to rt. The reaction was quenched by addition of 10%
citric acid solution and diluted with DCM. The layers were sepa-
rated; the organic layer was successively washed with water and
a mixture of saturated NaHCO3 solution and brine. The aqueous
layers were additionally extracted with DCM; the combined or-
ganic layer was dried and concentrated to yield a semi-solid residue
(5.25 g); TLC PE/EA 50% showed disappearance of the starting
material (Rf¼0.45) and formation of more polar product (Rf¼0.35).
The residue was dissolved in EtOH (60 mL) and treated with
NaBH4 (0.37 g, 10 mmol) at rt for 16 h. The reaction was quenched
by addition of acetic acid and concentrated. The residue was par-
titioned between 1 M HCl and DCM and the layers were separated.
The organic layer was washed successively with water and a mix-
ture of saturated NaHCO3 solution and brine. The aqueous layers
were additionally extracted with DCM. The combined organic layer
was dried and concentrated. The residue was purified by flash
chromatography in Tol/EA 20/50% to give 0.53 g (0.88 mmol, 9%)
of the starting material 17 and 4.8 g (7.9 mmol, 81%) of the title
compound 19 as viscous syrup.
118.8 (C-2), 113.4, 99.5, 99.3, 71.3, 69.7 (C-8), 69.4 (C-7), 64.6 (C-5 ),
*
62.5 (C-6), 60.6 (C-5), 55.2, 48.2, 48.1, 17.9, 17.6, 17.7, 11.8. nmax (KBr)
3088, 3060,1946,1880,1801, 1751,1603,1525,1499,1310,1083,1034,
982 cmꢂ1. Rf¼0.38; Tol/EA 40%, [
a]
D
þ40.4 (c 1.0, CHCl3). HRMS-
(TOF): MHþ, found 591.3465. C31H51N2O7Si requires 591.3466.
4.1.11. (S)-1-((2R,3R,5S,6S)-3-((R)-(4,5-Diiodo-1H-imidazol-2-yl)((4-
methoxybenzyl)oxy)methyl)-5,6-dimethoxy-5,6-dimethyl-1,4-di-
oxan-2-yl)-2-((triisopropylsilyl)oxy)ethanol (21)40. To a solution of
19 (0.121 g, 0.2 mmol) in MeCN (2 mL) NIS (0.099 g, 0.44 mmol)
was added at rt. The reaction was further stirred for 40 min in the
dark. The reaction was diluted with DCM and washed with 0.5 M
aqueous sodium thiosulfate (Na2S2O3) solution. The aqueous layer
was extracted with DCM once more. The combined organic layer
was dried and concentrated. The residue was absorbed on silica
(2 g) and purified by flash column chromatography in Tol/EA gra-
dient 5/20% to give 0.133 g (0.15 mmol, 77%) of the title com-
pound 21 as foam.
dH (500 MHz, CDCl3) 7.28e7.23 (2H, m, CH2PhOMe), 6.88e6.83
(2H, m, CH2PhOMe), 4.64 and 4.6 (2H, AB spectrum, J 11.4 Hz,
CH2PhOMe), 4.62 (1H, d, J1,2 2.6 Hz, H-1), 4.58 (1H, dd, J2,3 10.8,
J2,12.5 Hz, H-2), 3.80 (3H, s, OMe), 3.70 (1H, dd, J5a,5b 9.2, J5a,4 6.2 Hz,
H-5a), 3.65 (1H, t, J5a,5b¼J5b,5¼9.3 Hz, H-5b), 3.60 (1H, dd, J3,2 10.8,
J3,41.2 Hz, H-3), 3.56e3.47 (1H, m, H-4), 3.36 (3H, s, OMe), 3.23 (3H,
s, OMe), 2.46 (1H, br d, OH-4), 1.41 (3H, s, Me), 1.33 (3H, s, Me),
1.09e0.86 (21H, m, Si(CH(Me)2)3).
dC (126 MHz, CDCl3) 159.1, 150.7 (C-20), 129.9, 129.2, 113.7, 98.7,
98.5, 94.6 (br s, C-40/50), 75.9 (br s, C-40/50), 72.2 (C-1), 71.3, 70.1 (C-
4), 69.4 (C-2), 65.7 (C-3), 62.4 (C-5), 55.3, 48.5, 48.3, 18.0, 17.9, 17.8,
dH (500 MHz, CDCl3) 7.29e7.24 (2H, m, CH2PhOMe), 7.03 (2H, s,
H-40, H-50), 6.88e6.81 (2H, m, CH2PhOMe), 4.77 (1H, d, J1,2 2.6 Hz,
H-1), 4.66 and 4.58 (2H, AB spectrum, J 11.5 Hz, CH2PhOMe), 4.66
17.2, 11.8. Rf¼0.18; Tol/EA 10%. [
a
]
D
ꢂ13.3 (c 1.00, CHCl3). HRMS-
(TOF): MHþ, found 861.1510. C31H51I2N2O8Si requires 861.1504.

7846
V.S. Borodkin, D.M.F. van Aalten / Tetrahedron 66 (2010) 7838e7849
4.1.12. (2S,3S,4aS,5R,10R,10aR)-7,8-Diiodo-2,3-dimethoxy-5-((4-me-
thoxybenzyl)oxy)-2,3-dimethyl-10-(((triisopropylsilyl)oxy)methyl)-
2,3,4a,5,10,10a-hexahydro-[1,4]dioxino[2,3-d]imidazo[1,2-a]pyridine
(22)41. A solution of 20 (3.2 g, 5.4 mmol) in DMF (60 mL) was
treated with NIS (12.1 g, 53.78 mmol) at 80 ꢁC for 36 h. The reaction
was cooled, diluted with ethyl acetate and washed with 0.5 M so-
dium thiosulfate solution. The layers were separated. The aqueous
layer was extracted with ethyl acetate once more. The combined
organic layer was dried and concentrated. The residue was absor-
bed on silica (60 g) and purified by flash chromatography PE/EE
5/30% to give 3.3 g (3.9 mmol, 73%) of the title compound 22 as
yellowish foam.
solution of 16 (0.063 g, 0.15 mmol) in MeCN (3 mL) NIS (0.111 g,
0.5 mmol) was added at rt. The reaction was further stirred for 24 h
in the dark. The reaction was diluted with DCM and washed with
0.5 M sodium thiosulfate solution. The aqueous layer was extracted
with DCM once more. The combined organic layer was dried and
concentrated. The residue was purified by flash column chroma-
tography in PE/EA 5/15% to give 0.093 g (0.12 mmol, 78%) of the
title compound 25 as viscous syrup.
dH (500 MHz, CDCl3) 7.15e7.10 (2H, m, CH2PhOMe), 6.83e6.78
(2H, m, CH2PhOMe), 4.80 (1H, d, J9,8 1.4 Hz, H-9), 4.77 and 4.43
(2H, AB spectrum, J 11.9 Hz, CH2PhOMe), 4.50 (1H, dd, J5a,5b 14.6,
J5a,6 2.8 Hz, H-5a), 4.43 (1H, dd, J5a,5b 14.6, J5b,6 11.4 Hz, H-5b),
4.31 (1H, dd, J7,6 10.8, J7,8 9.2 Hz, H-7), 3.86 (1H, br dt, J6,5b 11.4,
J6,5a 2.8 Hz, H-6), 3.81 (3H, s, OMe), 3.66 (1H, dd, J8,7 9.2, J8,9
1.4 Hz, H-8), 3.43 (3H, s, OMe), 3.18 (3H, s, OMe), 1.36 (3H, s, Me),
1.31 (3H, s, Me).
4.1.13. With NIS/PPTS. A solution of 20 (0.296 g, 0.5 mmol), NIS
(0.338 g, 0.35 mmol) and pyridinium p-toluenesulfonate (0.125 g,
0.11 mmol) in MeCN (5 mL) was stirred at 80 ꢁC for 1 h. The reaction
was cooled, diluted with ethyl acetate and washed with 0.5 M sodium
thiosulfate solution. The aqueous layer was extracted with ethyl ac-
etate once more. The combined organic layer was dried and con-
centrated. The residue was purified by flash chromatography PE/EE
5/30% to give 0.259 g (0.31 mmol, 62%) of the title compound 22.
dH (500 MHz, CDCl3) 7.28e7.23 (2H, m, CH2PhOMe), 6.78e6.74
(2H, m, CH2PhOMe), 4.94 (1H, dd, J6,7 10.7, J6,5 6.5 Hz, H-6), 4.69 and
4.59 (2H, AB spectrum, J 11.4 Hz, CH2PhOMe), 4.61 (1H, d, J8,7 2.8 Hz,
dC (126 MHz, CDCl3) 159.2, 149.3 (C-9a), 129.7, 129.2, 113.6, 113.5,
100.29, 100.0, 99.9, 94.3 (C-2), 85.5 (C-3), 76.5 (C-9), 72.6, 72.1 (C-7
and C-8), 72.0, 55.3 (C-5), 54.2, 49.1, 48.3, 26.7 (C-6), 17.4, 17.2.
Rf¼0.32; PE/EA 15%, [
a
]
þ3.4 (c 1.0, CHCl3). HRMS-(TOF): MHþ,
D
found 796.9078. C22H28I3N2O6 requires 796.9082.
4.1.16. (2S,3S,4aS,5R,10R,10aR)-2,3-Dimethoxy-5-((4-methoxy-
benzyl)oxy)-2,3-dimethyl-7-(phenylethynyl)-10-(((triisopropylsilyl)
oxy)methyl)-2,3,4a,5,10,10a-hexahydro-[1,4]dioxino[2,3-d]imidazo
[1,2-a]pyridine (26)41. A solution of 23 (1.43 g, 2.0 mmol), phe-
nylacetylene (1.1 mL, 10 mmol) and Et3N (1.4 mL, 10 mmol) in
DMF (20 mL) was degassed by freezing, evacuating and thawing
three times. Cuprous iodide (0.038 g, 0.2 mmol) and Pd(PPh3)4
(0.23 g, 0.2 mmol) were then added to the reaction flask. The
reaction was placed in the preheated (80 ꢁC) oil bath stirred for
16 h. The reaction was cooled and concentrated. The residue was
dissolved in ethyl acetate and washed with water and brine. The
aqueous layer was extracted with ethyl acetate once more. The
combined organic layer was dried and concentrated. The brown
residue was purified by flash column chromatography in PE/EA
10/20% to give 1.28 g (1.86 mmol, 93%) of the title compound 26
as amber amorphous solid.
H-8), 4.26 (1H, dd, J5*a,5*b 10.7, J5*a,5 4.8 Hz, H-5
6.7, J5,5*a 4.8, J5,5*b 2.5 Hz, H-5), 3.87 (1H, dd, J5*a,5*b 10.7, J5*b,5 2.5 Hz,
H-5 b), 3.80 (1H, dd, J7,6 10.6, J7,8 2.8 Hz, H-7), 3.73 (3H, s, OMe), 3.26
*
a), 4.03 (1H, ddd, J5,6
*
(3H, s, OMe), 3.15 (3H, s, OMe), 1.31 (3H, s, Me), 1.26 (3H, s, Me),
0.88e0.77 (21H, m, Si(CH(Me)2)3).
dC (126 MHz, CDCl3) 158.9, 150 (C-8a), 130.3, 129.6, 113.4, 99.8,
99.6, 97.4 (C-3), 80.1 (C-2), 71.4, 70.1 (C-8), 68.9 (C-7), 63.6 (C-6),
62.9 (C-5 ), 62.1 (C-5), 55.3, 48.2, 48.1, 17.8, 17.7, 17.6, 11.8. nmax (KBr)
*
3063, 2865, 1880, 1812, 1613, 1501, 1454, 1352, 1173, 1100, 1031,
911 cmꢂ1. Rf¼0.3; PE/EE 30%, [
D ꢂ28.5 (c 1.0, CHCl3). HRMS-(TOF):
a]
MHþ, found 843.1421. C31H49I2N2O7Si requires 843.1399.
4.1.14. (2S,3S,4aS,5R,10R,10aR)-7-Iodo-2,3-dimethoxy-5-((4-meth-
oxybenzyl)oxy)-2,3-dimethyl-10-(((triisopropylsilyl)oxy)methyl)-
2,3,4a,5,10,10a-hexahydro-[1,4]dioxino[2,3-d]imidazo[1,2-a]pyridine
(23)41. To a solution of 22 (2.02 g, 2.39 mmol) in THF (25 mL)
a stock 1 M solution of EtMgBr in THF (3 mL, 3 mmol) was added at
4 ꢁC (ice-bath). After 10 min the reaction was quenched with sat-
urated NH4Cl solution. The reaction mixture was diluted with ethyl
acetate and brine and the layers were separated. The aqueous layer
was extracted with ethyl acetate once more. The combined organic
layer was dried and concentrated. The residue was absorbed on
silica (15 g) and purified by flash chromatography PE/EA 5/15% to
give 1.438 g (2.06 mmol, 84%) of the title compound 23 as foam.
dH (500 MHz, CDCl3) 7.39 (1H, s, H-3), 7.37e7.32 (2H, m,
CH2PhOMe), 6.87e6.81 (2H, m, CH2PhOMe), 4.86 and 4.71 (2H, AB
spectrum, J 11.2 Hz, CH2PhOMe), 4.75 (1H, d, J8,7 3.2 Hz, H-8), 4.42
(1H, dd, J6,7 10.6, J6,5 9.2 Hz, H-6), 4.16 (1H, dd, J5*a,5*b 10.8, J5*a,5
dH (500 MHz, CDCl3) 7.56 (1H, s, H-3), 7.55e7.52 (2H, m,
CH2PhOMe), 7.41e7.36 (2H, m, Ph), 7.35e7.30 (3H, m, Ph), 6.88e6.82
(2H, m, CH2PhOMe), 4.90 and 4.80 (2H, AB spectrum, J 11.2 Hz,
CH2PhOMe), 4.87e4.83 (1H, br d, H-8), 4.43 (1H, dd, J6,7 10.5, J6,5 9.2,
Hz, H-6), 4.20 (1H, dd, J5*a,5*b 10.8, J5*a,5 1.9 Hz, H-5
ddd, J5,6 9.3, J5,5*b 7.3, J5,5*a 1.9 Hz, H-5), 4.03 (1H, dd, J7,6 10.6, J7,8
3.2 Hz, H-7), 3.90 (1H, dd, J5*a,5*b 10.8, J5*b,5 7.4 Hz, H-5 b), 3.81 (3H,
*
a), 4.06 (1H,
*
s, OMe), 3.30 (3H, s, OMe), 3.30 (3H, s, OMe), 1.42 (3H, s, Me), 1.36
(3H, s, OMe), 1.17e1.04 (21H, m, Si(CH(Me)2)3).
dC (126 MHz, CDCl3) 158.9, 143.7 (C-8a),131.6, 130.7, 129.6, 128.2,
128.0, 124.4 (C-2), 123.3, 122.8 (C-3), 113.4, 99.6, 99.3, 89.3 (C-200),
82.9 (C-20), 71.8, 69.9 (C-8), 69.2 (C-7), 64.7 (C-5
), 62.2 (C-6), 61.0
*
(C-5), 55.2, 48.2, 48.1, 18.0, 17.9, 17.72, 17.7, 11.8. nmax (KBr) 3089,
2941, 2100, 1599, 1496, 1454, 1364, 1301, 1174, 1112, 1050, 1028,
2.0 Hz, H-5
(1H, dd, J7,6 10.6, J7,8 3.2 Hz, H-7), 3.87 (1H, dd, J5*a,5*b 10.7, J5*b,5
7.1 Hz, H-5 b), 3.79 (3H, s, OMe), 3.29 (3H, s, OMe), 3.27 (3H, s, OMe),
*
a), 4.04 (1H, ddd, J5,6 9.1, J5,5*b 7.2, J5,5*a 2.0 Hz, H-5), 3.98
913 cmꢂ1. Rf¼0.25; PE/EA 15%, [
a
]
D
þ91.4 (c 1.0, CHCl3). HRMS-
(TOF): MHþ, found 691.3774. C39H55N2O7Si requires 691.3779.
*
1.40 (3H, s, Me), 1.34 (3H, s, Me), 1.13e1.01 (21H, m, Si(CH(Me)2)3).
dC (126 MHz, CDCl3) 158.9, 145.4 (C-8a), 130.6, 129.5, 124.6 (C-3),
4.1.17. (2S,3S,4aR,5R,10R,10aR)-2,3-Dimethoxy-2,3-dimethyl-7-(phe-
nylethynyl)-10-(((triisopropylsilyl)oxy)methyl)-2,3,4a,5,10,10a-hexahy-
dro-[1,4]dioxino[2,3-d]imidazo[1,2-a]pyridin-5-ol (27)41. A solution of
26 (0.266 g, 0.38 mmol) in DCM/water (20:1; 5 mL) DDQ (0.15 g,
0.67 mmol) was added in one portion. The reaction was stirred for
4 h at rt. The reaction was quenched by addition of sodium meta-
bisulfite (Na2S2O5) solution, diluted with DCM and washed suc-
cessively with sodium metabisulfite (Na2S2O5) solution and
a mixture of concentrated NaHCO3 solution and brine. The aqueous
layer was extracted with DCM once more. The combined organic
layer was dried and evaporated. The residue was purified by flash
113.4, 99.6, 99.3, 82.2 (C-2), 71.8, 69.6 (C-8), 69.2 (C-7), 64.5 (C-5
*
),
62.2 (C-6), 60.8 (C-5), 55.2, 48.2, 48.1, 17.9, 17.8, 11.8. nmax (KBr)
3063, 2874,1875, 1734, 1495, 1453,1368,1257,1112,1023, 943 cmꢂ1
.
Rf¼0.38; PE/EA 15%, [
a
]
þ53.2 (c 1.0, CHCl3). HRMS-(TOF): MHþ,
D
found 717.2435. C31H50IN2O7Si requires 717.2432.
4.1.15. (2S,3S,4aR,5R,11S,11aS)-7,8,11-Triiodo-2,3-dimethoxy-5-
((4-methoxybenzyl)oxy)-2,3-dimethyl-3,4a,5,10,11,11a-hexahydro-
2H-[1,4]dioxino[2,3-d]imidazo[1,2-a]azepine (25)42. To
a stirred

V.S. Borodkin, D.M.F. van Aalten / Tetrahedron 66 (2010) 7838e7849
7847
column chromatography in Tol/EA 5/50% to give 0.173 g
(0.3 mmol, 80%) of the title compound 27.
dH (500 MHz, CDCl3) 7.55 (1H, s, H-3), 7.54e7.50 (2H, m, Ph),
7.34e7.27 (3H, m, Ph), 5.08 (1H, d, J8,7 3.4 Hz, H-8), 4.46 (1H, br s, OH-
8), 4.38 (1H, dd, J6,7 10.5, J6,5 9.5 Hz, H-6), 4.24 (1H, dd, J5*a,5*b 10.8,
(COCH3), 18.0, 17.9, 17.6, 17.5, 12.0. Rf¼0.22; Tol/Me2CO 30%, [
a]
D
þ105.3 (c 1.0, CHCl3). HRMS-(TOF): MHþ, found 616.3775.
C33H54N3O6Si requires 616.3782.
4.1.20. N-((2S,3S,4aR,5S,10R,10aR)-2,3-Dimethoxy-2,3-dimethyl-7-
phenethyl-10-(((triisopropylsilyl)oxy)methyl)-2,3,4a,5,10,10a-hex-
ahydro-[1,4]dioxino[2,3-d]imidazo[1,2-a]pyridin-5-yl)propionamide
(30)41. Prepared from 28 in 83% yield as described for preparation
of 29 with replacement of acetic anhydride for propionic anhydride.
dH (500 MHz, CDCl3) 7.22e7.15 (2H, m, Ph), 7.14e7.06 (3H, m, Ph),
6.88 (1H, s, H-3), 4.53e4.38 (2H, m, H-7, H-8), 4.21 (1H, d, J5*a,5*b
J5*a,5 1.6 Hz, H-5
*
a), 4.06 (1H, ddd, J5,6 9.2, J5,5*b 7.4, J5,5*a 1.6 Hz, H-5),
b, H-7), 3.30 (3H, s, OMe), 3.27 (3H, s, OMe),
4.01e3.94 (2H, m, H-5
*
1.40 (3H, s, Me), 1.34 (3H, s, Me), 1.16e1.03 (21H, m, Si(CH(Me)2)3).
dC (126 MHz, CDCl3) 144.7 (C-8a), 131.5, 128.2, 128, 124.3, 123.4,
122.4 (C-3), 100.0, 99.9, 99.4, 89.2 (C-200), 83.0 (C-20), 68.5 (C-7),
64.5 (C-5 ), 63.2 (C-8), 61.8 (C-6), 60.8 (C-5), 48.2, 48.1, 17.9, 17.9,
*
17.7, 17.6, 11.8. nmax (KBr) 3089, 2945, 1951, 1731, 1686, 1602, 1534,
10.9 Hz, H-5
J5*a,5*b 11.0, J5*b,5 5.9 Hz, H-5
3.16 (3H, s, OMe), 3.08 (3H, s, OMe), 2.92 (1H, dt, J2 a
*
a), 4.04 (1H, dd, J5,6 9.6, J5*b,5 5.8 Hz, H-5), 3.90 (1H, dd,
1496, 1384, 1263, 1092, 1028, 909 cmꢂ1. Rf¼0.2; Tol/EA 40%, [
a
]
*
b), 3.73 (1H, t, J6,5¼J6,7¼9.9 Hz, H-6),
D
þ80.3 (c 1.0, CHCl3). HRMS-(TOF): MHþ, found 571.3209.
,
0
0
2 b 13.8, J 7.1 Hz,
C31H47N2O6Si requires 571.3203.
H-20a), 2.84e2.70 (3H, m, H-20b, H-200a, H-200b), 2.23 (2H, m,
COCH2CH3), 1.22 (4H, s, Me), 1.15 (3H, s, Me), 1.06 (4H, t, J 7.5 Hz,
COCH2CH3), 1.04e0.93 (21H, m, Si(CH(Me)2)3).
4.1.18. (2S,3S,4aR,5S,10R,10aR)-5-Azido-2,3-dimethoxy-2,3-dimethyl-
7-(phenylethynyl)-10-(((triisopropylsilyl)oxy)methyl)-2,3,4a,5,10,10a-
dC (126 MHz, CDCl3) 174.1 (COCH2CH3), 143.5 (C-8a), 142.1, 141.4,
128.4, 128.3,125.8,113.6 (C-3), 99.3, 99.2, 68.0 (C-7), 65.7 (C-6), 62.7
hexahydro-[1,4]dioxino[2,3-d]imidazo[1,2-a]pyridine (28)41. To
a
stirred solution of 27 (0.648 g, 1.14 mmol) in toluene (20 mL)
diphenylphosphoryl azide (1.23 mL, 5.7 mmol) followed by DBU
(0.852 mL, 5.7 mmol) was added at rt. The reaction was placed in
a preheated oil bath (80 ꢁC) and kept for 2 h. The reaction was cooled
and concentrated. The brown residue was absorbed on silica and
purified by flash chromatography PE/EE 5/30% to give 0.574 g
(0.96 mmol, 85%) of the title compound 28 as foam.
(C-5
), 59.2 (C-5), 49.3 (C-8), 48.1, 47.7, 35.7 (C-20), 30.4 (C-200), 29.6
*
(COCH2CH3), 18.0, 17.95, 17.6, 17.4, 12.0, 9.8 (COCH2CH3). Rf¼0.35;
Tol/Me2CO 30%, [
a
]
D
þ103.5 (c 1.0, CHCl3). HRMS-(TOF): MHþ,
found 630.3931. C34H56N3O6Si requires 630.3938.
4.1.21. N-((2S,3S,4aR,5S,10R,10aR)-2,3-Dimethoxy-2,3-dimethyl-7-
phenethyl-10-(((triisopropylsilyl)oxy)methyl)-2,3,4a,5,10,10a-hex-
ahydro-[1,4]dioxino[2,3-d]imidazo[1,2-a]pyridin-5-yl)isobutyramide
(31)41. Prepared from 28 in 78% yield as described for preparation
of 29 with replacement of acetic anhydride for iso-butyric
anhydride.
dH (500 MHz, CDCl3) 7.19e7.15 (2H, m, Ph), 7.12e7.05 (3H, m, Ph),
6.86 (1H, s, H-3), 4.52 (1H, t, J 9.9 Hz, H-7), 4.44e4.36 (1H, br t, H-8),
4.22 (1H, dd, J5*a,5*b 11.0, J5*a,5 1.7 Hz, H-5
dH (500 MHz, CDCl3) 7.55e7.51 (2H, m, Ph), 7.47 (1H, s, H-3),
7.37e7.30 (3H, m, Ph), 4.73 (1H, d, J8,7 9.5 Hz, H-8), 4.29 (1H, d, J
9.7 Hz, H-5
*
a), 4.09e3.93 (4H, m, H-5, H-5 b, H-6, H-7), 3.38 (3H, s,
*
OMe), 3.30 (3H, s, OMe), 1.42 (3H, s, Me), 1.37 (3H, s, Me), 1.17e1.04
(21H, m, Si(CH(Me)2)3).
dC (126 MHz, CDCl3) 141.7 (C-8a), 131.5, 128.2, 128.1, 125.3 (C-2),
123.2, 121.4 (C-3), 99.65, 99.6, 89.4 (C-200), 82.7 (C-20), 70.6 (C-7),
*
a), 4.05 (1H, ddd, J5,6 9.9,
64.3, 62.4 (C-5 ), 59.7, 57.5 (C-8), 48.4, 48.3, 17.9, 17.8, 17.6, 17.4, 11.9.
*
J5*b,5 6.2, J5*a,5 1.3 Hz, H-5), 3.88 (1H, dd, J5*a,5*b 11.0, J5*b,5 6.1 Hz, H-
nmax (KBr) 3089, 3032, 2950, 2835, 2109, 1454, 1407, 1362, 1332,
5
*
b), 3.71 (1H, t, J6,5¼J6,7 10.1 Hz, H-6), 3.16 (3H, s, OMe), 3.09 (3H, s,
1269, 1145, 1098, 1018, 917 cmꢂ1. Rf¼0.26; PE/EE 20%, [
a
]D þ98.7 (c
OMe), 2.88 (1H, ddd, J 14.0,11.2, 6.3 Hz, H-20a), 2.83e2.67 (3H, m, H-
20b, H-200a, H-200b), 2.45e2.36 (1H, m, COCH(CH3)2), 1.21 (3H, s, Me),
1.15 (3H, s, Me), 1.09 (3H, d, J 6.9 Hz, COCH(CH3)2), 1.02 (3H, d, J
6.8 Hz, COCH(CH3)2), 1.01e0.94 (21H, m, Si(CH(Me)2)3).
0.51, CHCl3). HRMS-(TOF): MHþ, found 596.3275. C31H46N5O5Si
requires 596.3268.
4.1.19. N-((2S,3S,4aR,5S,10R,10aR)-2,3-Dimethoxy-2,3-dimethyl-7-
phenethyl-10-(((triisopropylsilyl)oxy)methyl)-2,3,4a,5,10,10a-hex-
ahydro-[1,4]dioxino[2,3-d]imidazo[1,2-a]pyridin-5-yl)acetamide
(29)41. A solution of 28 (0.045 g, 0.076 mmol) in ethyl acetate
(2 mL) was stirred under slight positive pressure of H2 (balloon) in
the presence of 20% Pd2(OH)2 on carbon (0.025 g) for 40 min. The
reaction was filtered through a pad of Celite and concentrated. The
residue was dissolved in DCM (2 mL) and treated with an excess of
acetic anhydride (0.05 mL), and Et3N (0.2 mL) for 2 h at rt. The re-
action was quenched with MeOH (0.1 mL), stirred for 20 min, di-
luted with DCM and washed successively with 1 M HCl, water and
a mixture of saturated NaHCO3 solution and brine. The aqueous
layers were additionally extracted with DCM. The combined or-
ganic layer was dried and concentrated. The residue was purified by
flash chromatography Tol/Me2CO 5/40% to give 0.047 g
(0.071 mmol, 93%) of the title compound 29 as foam.
dC (126 MHz, CDCl3) 177.3 (COCH(CH3)2), 143.7 (C-8a), 142.1,
141.1, 128.3, 128.2, 125.7, 113.5 (C-3), 99.3, 99.2, 67.9 (C-7), 65.7 (C-
6), 62.6 (C-5
*
), 59.1 (C-5), 49.3 (C-8), 48.1, 47.6, 35.6 (C-20), 35.2
(COCH(CH3)2), 30.2 (C-200), 20.0 (COCH(CH3)2), 19.2 (COCH(CH3)2),
18.0, 17.9, 17.6, 17.4, 11.9. Rf¼0.35; [DCM/PE 1:1]-Me2CO 30%, [
a]
D
þ101.4 (c 1.0, CHCl3). HRMS-(TOF): MHþ, found 644.4105.
C35H58N3O6Si requires 644.4095.
4.1.22. N-((2S,3S,4aR,5S,10R,10aR)-2,3-Dimethoxy-2,3-dimethyl-7-
phenethyl-10-(((triisopropylsilyl)oxy)methyl)-2,3,4a,5,10,10a-hex-
ahydro-[1,4]dioxino[2,3-d]imidazo[1,2-a]pyridin-5-yl)pentanamide
(32)41. A solution of 28 (0.05 g, 0.084 mmol) in MeOH (1.5 mL) was
stirred under slight positive pressure of H2 (balloon) of H2 in the
presence of 20% Pd2(OH)2 on carbon (0.05 g) for 2 h. The reaction
was filtered through a pad of Celite and concentrated in vacuum.
The residue was dissolved in DCM (2 mL) and treated with valeric
acid (0.027 mL, 0.25 mmol), PyBOP (0.13 g, 0.25 mmol) and DIPEA
(0.5 mL) for 2 h at rt. The reaction was diluted with DCM and
washed successively with 1 M HCl, water and a mixture of satu-
rated NaHCO3 solution and brine. The aqueous layers were addi-
tionally extracted with DCM. The combined organic layer was dried
and concentrated. The residue was purified by flash chromatogra-
phy Tol/Me2CO 5/25% to give 0.046 g (0.076 mmol, 90%) of the
title compound 32 as foam.
dH (500 MHz, CDCl3) 7.21e7.16 (2H, m, Ph), 7.14e7.07 (3H, m, Ph),
6.89 (1H, s, H-3), 4.50 (1H, t, J7,6¼J7,8¼10.0 Hz, H-7), 4.43e4.34 (1H,
br t, H-8), 4.21 (1H, dd, J5*a,5*b 11.0, J5*a,5 1.7 Hz, H-5 a), 4.03 (1H,
*
ddd, J5,6 9.8, J5*b,5 5.8, J5*a,5 1.7 Hz, H-5), 3.91 (1H, dd, J5*a,5*b 11.0,
J5*b,5 5.8 Hz, H-5
*
b), 3.72 (1H, t, J6,7¼J6,5¼10 Hz, H-6), 3.16 (3H, s,
OMe), 3.07 (3H, s, OMe), 2.99e2.91 (1H, m, H-20a), 2.83e2.70 (3H,
m, H-20b, H-200a, H-200b), 1.99 (3H, s, COCH3), 1.21 (3H, s, Me), 1.12
(3H, s, Me), 1.08e0.90 (21H, m, Si(CH(Me)2)3).
dC (126 MHz, CDCl3) 170.4 (COCH3), 143.6 (C-8a), 142.2, 141.6,
128.4, 128.3, 125.8, 113.6 (C-3), 99.4, 99.2, 67.9 (C-7), 65.8 (C-6), 62.7
dH (500 MHz, CDCl3) 7.20e7.16 (2H, m, Ph), 7.13e7.07 (3H, m, Ph),
6.88 (1H, s, H-3), 4.50 (1H, t, J7,6¼J7,8¼10.0 Hz, H-7), 4.41e4.32 (1H,
(C-5
*
), 59.14 (C-5), 49.5 (C-8), 48.1, 47.7, 35.8 (C-20), 30.6 (C-200), 23.4
br t, H-8), 4.21 (1H, dd, J5*a,5*b 11.0, J5*a,5 1.8 Hz, H-5 a), 4.04 (1H,
*

7848
V.S. Borodkin, D.M.F. van Aalten / Tetrahedron 66 (2010) 7838e7849
ddd, J5,6 9.7, J5*b,5 5.8, J5*a,5 1.5 Hz, H-5), 3.90 (1H, dd, J5*a,5*b 11.0,
J5*b,5 5.9 Hz, H-5
once more. The residue was purified on Phenomenex Luna 21ꢃ100
5 mm C18(2) column, gradient 5e95% MeCN in water (0.1% NH3) at
flow rate 25 mL/min. Appropriate fractions were pooled, concen-
trated to approximately 1/3 of the initial volume in vacuum and
freeze dried to give 0.02 g (0.058 mmol, 77%) of the title compound
35 as amorphous solid.
*
b), 3.72 (1H, t, J6,7¼J6,5¼10.0 Hz, H-6), 3.16 (3H, s,
OMe), 3.07 (3H, s OMe), 2.98e2.87 (1H, m, H-20a), 2.83e2.68 (3H, m,
H-20b, H-200a, H-200b), 2.26 (1H, dt, J 15.1, 7.7 Hz, COCH2C2H4CH3),
2.21e2.11 (1H, m, COCH2CH2CH2CH3), 1.58e1.48 (2H, m,
COCH2CH2CH2CH3), 1.28 (2H, dq, J 14.7, 7.4 Hz, COCH2CH2CH2CH3),
1.21 (3H, s, Me), 1.13 (3H, s, Me), 1.07e0.93 (21H, m, Si(CH(Me)2)3),
0.79 (3H, t, J 7.4 Hz, COCH2CH2CH2CH3).
dH (500 MHz, CDCl3/CD3OD) 7.07e7.01 (2H, m, Ph), 6.98e6.92
(3H, m, Ph), 6.65 (1H, s, H-3), 4.68 (1H, d, J8,7 8.3 Hz, H-8), 3.86 (1H,
dC (126 MHz, CDCl3) 173.4 (COCH2CH2CH2CH3),143.6 (C-8a),142.1,
141.4, 128.3, 128.2, 125.7, 113.4 (C-3), 99.3, 99.1, 67.9 (C-7), 65.7 (C-6),
dd, J5*a,5*b 12.2, J5*a,5 2.8 Hz, H-5 a), 3.71 (1H, dd, J5*a,5*b 12.2, J5*b,5
*
4 Hz, H-5 b), 3.63 (2H, m, H-5, H-6), 3.53 (1H, dd, J7,8 8.5, J7,6 8.3 Hz,
*
*
62.6 (C-5 ), 59.0 (C-5), 49.4 (C-8), 48.1, 47.6, 36.4 (COCH2CH2CH2CH3),
H-7), 2.66 (2H, m, H-20a, H-20b), 2.57 (2H, m, H-200a, H-200b), 1.86
35.7 (C-20), 30.5 (C-200), 27.8 (COCH2CH2CH2CH3), 22.4
(COCH2CH2CH2CH3), 18.0, 17.9, 17.5, 17.4, 13.8 (COCH2CH2CH2CH3),
(3H, s, COCH3).
dC (126 MHz, CDCl3/CD3OD)
d 177.2 (COCH3), 146.5, 144.4 (C-8a),
11.9. Rf¼0.32; Tol/Me2CO 20%, [
a
]
þ101.3 (c 0.35, CHCl3). HRMS-
130.8, 128.5 (C-2), 117.2 (C-3), 78.0 (C-7), 72.8 (C-6), 64.4 (C-5), 64.2
D
(TOF): MHþ, found 658.4239. C36H60N3O6Si requires 658.4251.
(C-5
), 54.5 (C-8), 37.9 (C-20), 34.1 (C-200), 22.4 (COCH3). HRMS-
*
(TOF): MHþ, found 346.1761. C18H24N3O4 requires 346.1767.
4.1.23. (E)-N-((2S,3S,4aR,5S,10R,10aR)-2,3-Dimethoxy-2,3-dimethyl-
7-phenethyl-10-(((triisopropylsilyl)oxy)methyl)-2,3,4a,5,10,10a-hex-
ahydro-[1,4]dioxino[2,3-d]imidazo[1,2-a]pyridin-5-yl)penta-2,4-di-
enamide (33)41. Prepared from 28 in 93% yield as described for
preparation of 32 with replacement of valeric acid for 2,4-penta-
nedienic acid.
dH (500 MHz, CDCl3) 7.16 (2H, m, Ph), 7.11e7.05 (3H, m, Ph), 7.00
(1H, dd, J 15.1, 11.0 Hz, COCHCHCHCH2), 6.96 (1H, s, H-3), 6.26 (1H,
dt, J 17.0, 10.5, 10.5 Hz, COCHCHCHCH2), 6.00 (1H, d, J 15.2 Hz,
COCHCHCHCH2), 5.34 (1H, d, Jtrans 16.9 Hz, COCHCHCHCH2), 5.23
(1H, d, Jcis 10.1 Hz, COCHCHCHCH2), 4.63e4.43 (2H, m, H-7, H-8),
4.1.26. N-((5R,6R,7R,8S)-6,7-Dihydroxy-5-(hydroxymethyl)-2-phe-
nethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl)propionamide
(36)41. Prepared starting from compound 30 as described for 35 in
73% yield; amorphous solid.
dH (500 MHz, pyridine-d5) 8.97 (1H, d, JNH,8 8.2 Hz, NHCOC2H5),
7.40 (1H, s, H-3), 7.30 (3H, m, Ph), 7.21 (2H, m, Ph), 5.85 (1H, t,
J8,7¼JNH,8¼8.5 Hz, H-8), 4.67 (1H, dd, J5*a,5*b 11.5, J5*a,5 1.8 Hz, H-5
*
a),
4.59 (1H, t, J6,7¼J6,5¼8.6 Hz, H-6), 4.43 (2H, m, H-5
*
b, H-7), 4.32 (1H,
ddd, J5,6 8.6, J5*b,55.4, J5*a,5 2.4 Hz, H-5), 3.07 (4H, m, H-20a, H-20b, H-
200a, H-200b), 2.45(2H, m, COCH2CH3),1.21 (3H, t, J¼7.5 Hz, COCH2CH3).
dC (126 MHz, pyridine-d5) 176.8 (COCH2CH3), 146.5, 144.9, 144.4
(C-8a), 130.8, 130.7, 128.1 (C-2), 116.4 (C-3), 77.5 (C-7), 72.3 (C-6),
4.24 (1H, d, J5*a,5*b 11 Hz, H-5
*
a), 4.09 (1H, dd, J5,6 9.9, J5*b,5 6.5 Hz,
b), 3.71 (1H, t,
H-5), 3.92 (1H, dd, J5*a,5*b 11.1, J5*b,5 6.1 Hz, H-5
*
J6,7¼J6,5¼10.0 Hz, H-6), 3.15 (3H, s, OMe), 2.98 (3H, s, OMe), 2.92 (1H,
m, H-20a), 2.84e2.70 (3H, m, H-20b, H-200a, H-200b), 1.20 (3H, s, Me),
1.06 (3H, s, Me), 1.05e0.91 (21H, m, Si(CH(Me)2)3).
64.7 (C-5), 64.0 (C-5
), 53.7 (C-8), 38.3 (C-20), 33.3 (C-200), 31.7
*
(COCH2CH3), 12 (COCH2CH3). HRMS-(TOF): MHþ, found 360.1922.
C19H26N3O4 requires 360.1923.
dC (126 MHz, CDCl3)
d 164.2 (COCHCHCHCH2), 152.3, 143.2
(C-8a), 142.1 (COCHCHCHCH2), 135.2 (COCHCHCHCH2), 132.9, 128.6,
127.7, 125.9 (COHCHCHCH2), 121.7 (COCHCHCHCH2), 118.5, 116.1
4.1.27. N-((5R,6R,7R,8S)-6,7-Dihydroxy-5-(hydroxymethyl)-2-phe-
nethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl)isobutyramide
(37)41. Prepared starting from compound 31 as described for 35 in
70% yield; amorphous solid.
(C-3), 99.3, 99.1, 68.1 (C-7), 65.3 (C-6), 63.0 (C-5
*
), 58.7 (C-5), 49.7
(C-8), 48.6, 47.9, 35.4 (C-20), 35.0 (C-200), 18.0, 17.7, 17.5, 17.4, 12.0.
Rf¼0.3; Tol/Me2CO 20%. [
a
]
D
þ97.4 (c 0.85, CHCl3). HRMS-(TOF):
dH (500 MHz,pyridine-d5)8.81(1H, brd,JNH,8 NHCO), 7.28(1H, brs,
H-3), 7.17e7.2 (4H, m, Ph), 7.07e7.11 (1H, m, Ph), 5.73 (1H, t,
MHþ, found 654.3943. C36H60N3O6Si requires 654.3938.
J8,7¼JNH,8¼8.4 Hz, H-8), 4.55 (1H, dd, J5*a,5*b 11.7, 2.6 Hz, H-5
*
a), 4.47
4.1.24. S-(3-(((2S,3S,4aR,5S,10R,10aR)-2,3-Dimethoxy-2,3-dimethyl-
7-phenethyl-10-(((triisopropylsilyl)oxy)methyl)-2,3,4a,5,10,10a-hex-
ahydro-[1,4]dioxino[2,3-d]imidazo[1,2-a]pyridin-5-yl)amino)-3-ox-
opropyl) ethanethioate (34)41. Prepared from 28 in 74% yield as
described for preparation of 32 with replacement of valeric acid for
S-acetyl-3-mercaptopropionic acid.
(1H, t, J7,6¼J7,8¼8.6 Hz, H-7), 4.3 (2H, m, H-5
*
b, H-6), 4.2 (1H, m, H-5),
2.95 (4H, m, H-20a, H-20b,H-200a, H-200b), 2.66(1H, quint, COCH(CH3)2),
1.19 (3H, d, J 6.8 Hz, COCH(CH3)2), 1.18 (3H, d, J 6.8 Hz, COCH(CH3)2).
dC (126 MHz, pyridine-d5) 180.1 (COCH(CH3)2), 146.4, 144.9,
144.4 (C-8a),130.8, 130.7, 128.1 (C-2),116.5 (C-3), 77.6 (C-7), 72.3 (C-
6), 64.8 (C-5), 64.1 (C-5
), 53.7 (C-8), 38.3 (C-20), 37.7 (C-200), 33.3
*
dH (500 MHz, CDCl3) 7.21e7.15 (2H, m, Ph), 7.12e7.07 (3H, m, Ph),
6.87 (1H, s, H-3), 4.46 (1H, t, J 9.9 Hz, H-7), 4.4 (1H, br t, H-8), 4.21
(COCH(CH3)2), 22.1 (COCH(CH3)2), 21.9 (COCH(CH3)2). HRMS-(TOF):
MHþ, found 374.2075. C20H28N3O4 requires 374.2080.
(1H, d, J 10.8 Hz, H-5
dd, J 10.9, 5.9 Hz, H-5
*
a), 4.03 (1H, dd, J 9.8, 5.8 Hz, H-5), 3.89 (1H,
*
b), 3.72 (1H, t, J 9.9 Hz, H-6), 3.15 (3H, s, OMe),
4.1.28. N-((5R,6R,7R,8S)-6,7-Dihydroxy-5-(hydroxymethyl)-2-phe-
nethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl)pentanamide
(38)41. Prepared starting from compound 32 as described for 35 in
68% yield; amorphous solid.
3.09 (3H, s, OMe), 3.02 (2H, m, H-20a, H-20b), 2.92 (1H, m, H-200a),
2.75 (3H, m, H-200b, COCH2CH2SAc), 2.51 (2H, m, COCH2CH2SAc),
2.17 (3H, s, SCOCH3), 1.22 (3H, s, Me), 1.15 (3H, s, Me), 1.02e0.95
(21H, m, Si(CH(Me)2)3).
dH (500 MHz, DMSO) 7.98 (1H, d, JNH,8 9.0 Hz, NHCO), 7.32e7.22
(4H, m, Ph), 7.21e7.15 (1H, m, Ph), 7.01 (1H, s, H-3), 5.42 (1H, d, J
dC (126 MHz, CDCl3)195.7(SCOCH3),170.8 (COC2H4SAc),143.2(C-
8a),142.1,141.7,128.4,128.2,125.8,113.6 (C-3), 99.3, 99.2, 68.0 (C-7),
4.8 Hz, OH-6), 5.24 (1H, d, J 4.8 Hz, OH-7), 4.98 (1H, t, J 7.6 Hz, OH-5
4.75 (1H, t, J8,7¼J8,NH¼8.8 Hz, H-8), 4.00 (1H, ddd, J5*a,5*b 11.3, 4.4,
1.4 Hz, H-5 a), 3.75e3.68 (1H, m, H-5 b), 3.69e3.61 (2H, m, H-6, H-
*
),
65.7 (C-6), 62.7 (C-5
*
), 59.1 (C-5), 49.6 (C-8), 48.1, 47.8, 36.1
(COCH2CH2SAc), 35.7 (C-20), 30.4 (C-200), 24.7 (SCOCH3), 18.0, 17.9,
*
*
17.6,17.4,11.9. Rf¼0.35; Tol/EA 20%, [
a
]D þ101.4 (c 1.0, CHCl3). HRMS-
5), 3.62e3.53 (1H, m, H-7), 2.91e2.78 (2H, m, H-20a, H-20b), 2.68 (2H,
t, J 8.3 Hz, H-200a, H-200b), 2.15 (2H, t, J 7.4 Hz, COCH2CH2CH2CH3),
1.59e1.47 (2H, m, COCH2CH2CH2CH3), 1.44e1.30 (2H, m,
COCH2CH2CH2CH3), 0.89 (3H, t, J 7.3 Hz, COC3H6CH3).
(TOF): MHþ, found 704.3763. C36H58N3O7SSi requires 704.3765.
4.1.25. N-((5R,6R,7R,8S)-6,7-Dihydroxy-5-(hydroxymethyl)-2-phe-
nethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl)acetamide
(35)41. A solution of 29 (0.046 g, 0.075 mmol) in 95% trifluoroacetic
acid (2 mL) was kept for 36 h at rt. The reaction was diluted with
toluene, concentrated in vacuum and co-evaporated with toluene
dC (126 MHz, DMSO d6) 173.4 (NHCO), 144.5, 142.1 (C-8a), 141.6,
129.0, 126.7, 113.9 (C-3), 73.3 (C-6), 69.4 (C-5/C-7), 61.9 (C-5/C-7), 61.1
(C-5
*
), 50.2 (C-8), 36.0 (COCH2CH2CH2CH3, C-20), 31.2 (C-200), 28.3
(COCH2CH2CH2CH3), 22.6 (COCH2CH2CH2CH3), 14.3 (COCH2CH2CH2

V.S. Borodkin, D.M.F. van Aalten / Tetrahedron 66 (2010) 7838e7849
7849
CH3). HRMS-(TOF): MHþ, found 388.2232. C21H30N3O4 requires
Supplementary data
388.2236.
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.07.037.
4.1.29. (E)-N-((5R,6R,7R,8S)-6,7-Dihydroxy-5-(hydroxymethyl)-2-
phenethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl)penta-2,4-
dienamide (39)41. Prepared staring from compound 33 as described
for 35 in 48% yield; amorphous solid.
References and notes
dH (500 MHz, DMSO) 8.39 (1H, d, JNH,8 8.7 Hz, NHCO), 7.31e7.23 (4H,
1. Torres, C. R.; Hart, G. W. J. Biol. Chem. 1984, 259, 3308e3317.
2. Zachara, N. E.; Hart, G. W. Biochim. Biophys. Acta 2004, 1673, 13e28.
3. Love, D. C.; Hanover, J. A. Sci. STKE 2005, 312, 1e14.
4. Wells, L.; Gao, Y.; Mahoney, J. A.; Vosseller, K.; Chen, C.; Rosen, A.; Hart, G. W.
J. Biol. Chem. 2002, 277, 1755e1761.
5. Lehman, D. M.; Fu, D. J.; Freeman, A. B.; Hunt, K. J.; Leach, R. J.; Johnson-Pais, T.;
HamLington, J.; Dyer, T. D.; Arya, R.; Abboud, H.; Goring, H. H.; Duggirala, R.;
Blangero, J.; Konrad, R. J.; Stern, M. P. Diabetes 2005, 54, 1214e1221.
6. Dias, W. B.; Hart, G. W. Mol. Biosyst. 2007, 3, 766e772.
7. Cantarel, B. L.; Coutinho, P. M.; Rancurel, C.; Bernard, T.; Lombard, V.; Henrissat,
B. Nucleic Acids Res. 2009, 37, D233eD238.
m, Ph), 7.22e7.14 (1H, m, Ph), 7.09 (1H, dd,
J 15.2, 11.1 Hz,
COCHCHCHCH2), 7.06 (1H, s, H-3), 6.54 (1H, dt, J 16.9, 10.5 Hz,
COCHCHCHCH2), 6.15 (1H, d, J 15.2 Hz, COCHCHCHCH2), 5.63 (1H, d,
Jtrans 16.7 Hz, COCHCHCHCH2), 5.44 (1H, d, Jcis 11.4 Hz, COCHCHCHCH2),
5.5 (1H, br s, OH-6), 5.38 (1H, br s, OH-7), 5.03 (1H, br s, OH-5
(1H, t, J8,7¼J8,NH¼8.9 Hz, H-8), 4.01 (1H, dd, J5*a,5*b 10.9, 2.8 Hz, H-5
3.79e3.64 (3H, m, H-5, H-5 b, H-6), 3.63e3.56 (1H, m, H-7), 2.93e2.73
(2H, m, H-20a, H-20b), 2.68 (2H, t, J 8.1 Hz, H-200a, H-200b).
*
), 4.86
*
a),
*
8. Haltiwanger, R. S.; Grove, K.; Philipsberg, G. A. J. Biol. Chem. 1998, 273,
3611e3617.
9. Horsch, M.; Hoesch, L.; Vasella, A.; Rast, D. M. Eur. J. Biochem. 1991, 197,
815e818.
dC (126 MHz, DMSO d6) 164.7 (COCHCHCHCH2), 158.8, 152.7,
143.1 (C-8a), 141.9 (COCHCHCHCH2), 139.3, 135.2 (COCHCHCHCH2),
128.2, 128.0, 126.6, 125.7 (COCHCHCHCH2), 123.8 (COCHCHCHCH2),
10. Stubbs, K. A.; Zhang, N.; Vocadlo, D. J. Org. Biomol. Chem. 2006, 4, 839e845.
11. Knapp, S.; Vocadlo, D.; Gao, Z. N.; Kirk, B.; Lou, J. P.; Withers, S. G. J. Am. Chem.
Soc. 1996, 118, 6804e6805.
113.6(C-3), 72.8 (C-7), 68.5 (C-6), 61.0 (C-5 ), 60.2 (C-5), 49.5 (C-8),
*
38.8 (C-20), 35.2 (C-200). HRMS-(TOF): MHþ, found 384.1919.
C21H26N3O4 requires 384.1923.
12. Macauley, M. S.; Whitworth, G. E.; Debowski, A. W.; Chin, D.; Vocadlo, D. J.
J. Biol. Chem. 2005, 280, 25313e25322.
13. Yuzwa, S. A.; Macauley, M. S.; Heinonen, J. E.; Shan, X.; Dennis, R. J.; He, Y.;
Whitworth, G. E.; Stubbs, K. A.; McEachern, E. J.; Davies, G. J.; Vocadlo, D. J. Nat.
Chem. Biol. 2008, 4, 483e490.
4.1.30. S-(3-(((5R,6R,7R,8S)-6,7-Dihydroxy-5-(hydroxymethyl)-2-
phenethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl)amino)-3-
oxopropyl) ethanethioate (40)41. Prepared starting from compound
34 as described for 35 in 75% yield; amorphous solid.
dH (500 MHz, pyridine-d5) 9.31 (1H, d, JNH,8 8.4 Hz, NHCO), 7.40
(1H, s, H-3), 7.33e7.27 (2H, m, Ph), 7.24e7.17 (3H, m, Ph), 5.87 (1H, t,
14. Aoyagi, T.; Suda, H.; Uotani, K.; Kojima, F.; Aoyama, T.; Horiguchi, K.; Hamada,
M.; Takeuchi, T. J. Antibiot. (Tokyo) 1992, 45, 1404e1408.
15. Aoyama, T.; Naganawa, H.; Suda, H.; Uotani, K.; Aoyagi, T.; Takeuchi, T. J. Anti-
biot. (Tokyo) 1992, 45, 1557e1558.
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17. Tatsuta, K.; Miura, S.; Ohta, S.; Gunji, H. J. Antibiot. (Tokyo) 1995, 48, 286e288.
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20. Panday, N.; Canac, Y.; Vasella, A. Helv. Chim. Acta 2000, 83, 58e79.
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2006, 610e626.
22. Shanmugasundaram, B.; Debowski, A. W.; Dennis, R. J.; Davies, G. J.; Vocadlo,
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D. M. F. EMBO J. 2006, 25, 1569e1578.
J8,7¼J8,NH¼8.6 Hz, H-8), 4.67 (1H, dd, J5*a,5*b 11.4, J5*a,5 1.6 Hz, H-5
*
a),
4.60 (1H, t, J6,7¼J6,5¼8.6 Hz, H-6), 4.44 (2H, m, H-5
*
b, H-7), 4.32 (1H,
ddd, J5,6 8.6, J5*b,5 4.7, J5*a,5 1.6 Hz, H-5), 3.52e3.36 (2H, m),
3.17e2.97 (4H, m), 2.96e2.82 (2H, m), 2.16 (3H, s, SCOCH3).
dC (126 MHz, pyridine-d5) 197.4 (SCOCH3), 173.8 (CONH), 146.3,
144.9, 144.4 (C-8a), 130.8, 130.7, 128.1, 116.5 (C-3), 77.2 (C-7), 72.3
(C-6), 64.8 (C-5), 64.0 (C-5 ), 53.8 (C-8), 38.4, 38.2, 33.3, 32.3
*
(SCOCH3), 27.3. HRMS-(TOF): MHþ, found 434.1756. C21H28N3O5S
requires 434.1750.
25. Dorfmueller, H. C.; Borodkin, V. S.; Schimpl, M.; Shepherd, S. M.; Shpiro, N. A.;
van Aalten, D. M. J. Am. Chem. Soc. 2006, 128, 16484e16485.
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Perkin Trans. 1 1997, 351e363.
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32. Kolb, H. C.; Vannieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94,
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33. Ley, S. V.; Polara, A. J. Org. Chem. 2007, 72, 5943e5959.
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I.; Qian, K. C.; Sorcek, R. J.; Jeanfavre, D. D.; Kishimoto, K.; Mainolfi, E. A.;
Nabozny, G., Jr.; Peng, C.; Reilly, P.; Rothlein, R.; Sellati, R. H.; Woska, J. R., Jr.;
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2249e2261.
40. Numbering used for the spectra description is based on 1-(1H-imidazol-2-yl)
pent-4-ene-1,2,3-triol backbone as shown for compound 16 (Scheme 2).
41. Numbering used for the spectra description is based on the 5-(hydroxymethyl)-
5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6,7,8-triol backbone as shown for
compound 18 (Scheme 3).
4.1.31. N-((5R,6R,7R,8S)-6,7-Dihydroxy-5-(hydroxymethyl)-2-phe-
nethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl)-3-mercapto-
propanamide (41)41. To a solution of 40 (0.042 g, 0.1 mmol) and
dithiothreitol (0.015 g) in DMF (1.5 mL) stock 25% solution of
MeONa in MeOH (0.03 mL) was added at rt. The reaction was stirred
for 2 h and quenched with AcOH (0.05 mL). The reaction was con-
centrated in vacuum and the residue was purified on the C18(2)
column as described above to give 0.023 g (0.056 mmol, 56%) of the
title compound 41 as amorphous solid.
dH (500 MHz, MeOD) 7.29 (2H, m, Ph), 7.24 (1H, s, H-3), 7.23e7.15
(3H, m, Ph), 4.90 (1H, d, J8,7 7.6 Hz, H-8), 4.15 (1H, dd, J5*a,5*b 12.1,
2.6 Hz, H-5
*
a), 4.10e4.05 (1H, m, H-5), 4.02 (1H, dd, J7,6 8.5, J7,8
b), 3.92 (1H, dd,
7.8 Hz, H-7), 3.99 (1H, dd, J5*a,5*b 12.5, 5.2 Hz, H-5
*
J6,7 8.6, J6,5 7.7 Hz, H-6), 2.98e2.88 (4H, m), 2.84e2.74 (2H, m),
2.70e2.60 (2H, m).
dC (126 MHz, MeOD) 174.5 (NHCO), 145.3, 144.9, 144.4 (C-8a),
130.8, 128.7, 128.5, 126.7, 116.5 (C-3), 71.0 (C-7), 68.1 (C-6), 62.9 (C-
5), 60.1 (C-5
), 49.2 (C-8), 39.8, 34.8, 27.6, 20.0. HRMS-(TOF): MHþ,
*
found 392.1641. C19H26N3O4S requires 392.1644.
Acknowledgements
42. Numbering used for the spectra description is based on 6,7,8,9-tetrahydro-5H-
imidazo[1,2-a]azepine-7,8,9-triol backbone as shown for compound 25
(Scheme 5).
This work was supported by a Wellcome Trust Senior Research
Fellowship to DvA.