Nitrogen inversion as a diastereomeric relay in azasugar synthesis: The first synthesis of adenophorine

Article abstract of DOI:10.1002/anie.200351002

A temperature-dependent relay of chirality is based on the inversion of the nitrogen lone pair in cyclic azasugars. Elimination from the conformation preferred at a given temperature leads to a cyclic imine, and in a subsequent nucleophilic attack the ste

Full text of DOI:10.1002/anie.200351002

Communications
Azasugar Synthesis
Nitrogen Inversion as a Diastereomeric Relay in
Azasugar Synthesis: The First Synthesis of
Adenophorine**
Michael A. T. Maughan, Ieuan G. Davies,
Timothy D. W. Claridge, Steve Courtney, Phil Hay, and
Benjamin G. Davis*
Although amine nitrogen atoms are potential stereogenic
centers, their configurational lability arising from lone-pair
inversion[1] has typically prevented their utility in synthesis. N-
Halogenation can dramatically slow lone-pair inversion[2] and
therefore raise the temperature at which the configurational
lability ceases. We therefore considered that if a suitable
system could be found, N-chloramines might provide a new
source of flexible, temperature-dependent stereogenesis. In
turn, existing chiral information may then be relayed and
exploited such that subsequent reactions are regio- or
diastereoselective. Due to the often higher conformational
lability of the acyclic N lone-pair isomers of N-haloamines, we
selected cyclic amines for our study, which are typically, but
not always, less labile due to angular constraint.[1] Cyclic
systems have often been exploited for intramolecular relay of
chirality.[3]
As our model chiral cyclic N-chloramine system we
selected N-chloropiperidine azasugars. Polyhydroxylated
nitrogen heterocycles such as deoxynojirimycin (DNJ, 1 in
Scheme 1) may be considered to be mimics of sugars, for
example, d-glucose, in which the ring oxygen has been
replaced by a nitrogen atom.[4] The often potent inhibitory
activity of many of these compounds towards carbohydrate-
processing enzymes has suggested their use in a wide range of
potential therapeutic strategies,[5–8] including the treatment of
viral infections[9,10] and lysosomal storage diseases,[11,12] and as
invaluable tools in the study of enzyme mechanism.[13]
[*] Dr. B. G. Davis, I. G. Davies, Dr. T. D. W. Claridge
Dyson Perrins Laboratory
Department of Chemistry
University of Oxford
SouthParks Road, Oxford, OX1 3QY (UK)
Fax: (+44)1865-275-674
E-mail: ben.davis@chem.ox.ac.uk
M. A. T. Maughan
Department of Chemistry
University of Durham
SouthRoad, Durham, DH1 3LE (UK)
Dr. S. Courtney, Dr. P. Hay
Oxford Glycosciences Ltd.
The Forum
86 Milton Park, Abingdon, Oxfordshire, OX14 4RY (UK)
[**] This work was supported by the UK Engineering and Physical
Sciences ResearchCouncil (EPSRC) and by Oxford Glycosciences
Ltd. We would like to thank Dr. A. M. Kenwright for technical advice
and Prof. N. Asano for spectroscopic data and the generous gift of
an authentic sample of (+)-adenophorine.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200351002
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recently shown that this is a general reaction that may be
applied with high diastereoselectivity to several pyrrolidine
aldimines.[17,20] We considered that addition of an ethyl
nucleophile to idonojirimycin (INJ) aldimine 12 might
provide convergent access to adenophorine (3) as well as
ready access to analogues.[21]
In this communication, we have applied this stereo-
dynamic strategy to the first synthesis of adenophorine (3)
and 1-epi-adenophorine (4) as well as hydrophobically
modified DNJ variants 5 and 6. To our knowledge this is the
first example of a N-halogen stereogenic center in such a
switchable, stereochemical relay.
Scheme 1.
Azasugars carrying hydrophobic substituents, such as the
butylated azasugar N-butyldeoxynojirimycin (2, NB-DNJ or
Zavesca),[11] may show increased enzyme inhibition and
enhanced bioavailability.[14] Therefore routes amenable to
the ready installation of hydrophobic moieties are of high
value.
Adenophorine, a rare example of a naturally occurring
azasugar with hydrophobic substituents, was isolated from the
roots of Adenophora spp. in 2000 by Asano and co-workers
and was assigned the ethyl-substituted polyhydroxylated
piperidine structure with the relative configuration shown in
3 (Scheme 1) on the basis of NMR investigations; its absolute
configuration was not determined.[15] By virtue of its pseu-
doanomeric substituent,[16] adenophorine is a highly a-glyco-
sidase-specific inhibitor (IC50 values for a-glucosidase: 32 mm,
intestinal sucrase: 20 mm, a-galactosidase: 11 mm) that dis-
plays no detectable inhibition of b-glycosidases.[15]
Central to our approach (vide supra) we established the
ꢀ
stereodynamics of the N Cl bond in two piperidine systems.
Tetrabenzyl DNJ 7[22] and tetrabenzylidonojirimycin (tetra-
benzyl INJ, 8)[23] were prepared from d-glucose and smoothly
N-chlorinated using N-chlorosuccinimide (NCS) to give DNJ-
Cl 9 and INJ-Cl 10, respectively, in excellent yields (Scheme 2
and Scheme 3). N-configurational exchange was evident by
We reasoned that for the synthesis of adenophorine (3) a
two-step process, consisting of regioselective elimination
controlled by the switchable configuration at the chloramine
nitrogen atom followed by addition of suitable nucleophiles
to the resulting imine, might be used as a diastereomeric relay
for the ready addition of hydrophobic functionality to a
starting azasugar with regio- and stereocontrol (Scheme 2).
We have shown previously that the highly functionalized
piperidine azasugar 9 can undergo regioselective elimina-
tion.[17] In addition, building on the pioneering work of
Horenstein and co-workers[18] and Furneauxand co-work-
ers,[19] who demonstrated the addition of organometallic
nucleophiles to a single pyrrolidine aldimine, we have
Scheme 3. a) NCS, CH2Cl2, 93% for 10; b) DBU, Et2O, reflux; c) 12!
16: EtMgBr, Et2O/dioxane, 47% over two steps from 10; d) NaBH4,
THF/H2O, 100%; e) TBDPSCl, imidazole, DMF, 99%; f) Method 1:
MsCl, py, 97% then Bu4N3, toluene, reflux, 23% or Method 2: HN3,
DIAD, PPh3, toluene, 87%; g) TBAF, THF, 100%; h) PCC, CH2Cl2, mol.
sieves, 87% for 19, 72% for 20; i) PPh3, Et2O; j) EtMgBr, Et2O, 70%;
k) 14!15/16: NaBH4, MeOH, 17%:32% of 15/16 or LiAlH4, THF,
69% of 15 only; l) H2, PdCl2, EtOH, 100% for 3, 86% for 4; m) LiTMP,
ꢀ788C, Et2O. DIAD=diisopropyl azodicarboxylate, PCC=pyridinium
chlorochromate, py=pyridine, TBAF=tetrabutylammonium fluoride,
TBDPSCl=tert-butyldiphenylsilyl chloride.
NMR in both 9 and 10 in the marked broadening of the
resonances for C1 and C5 (Figure 1). Encouragingly, variable-
temperature NMR experiments (VT-NMR) confirmed the
existence at ꢀ558C of two species consistent with N-epimers
of 9, one of which was strongly dominant. When the sample
was warmed from ꢀ558C to approximately ꢀ458C, a temper-
ature that is accessible in standard synthesis, the signals of 9
started to broaden. Interestingly, signal broadening due to
exchange was evident in 10 at much lower temperatures
(< ꢀ808C);[24] only the control of the configurational
exchange of 9 was required by our strategy (vide infra).
Gratifyingly and consistent with these observations, treat-
ment of DNJ-Cl 9 with the base DBU at room temperature,
Scheme 2. a) NCS, CH2Cl2, 97% for 9, 93% for 10; b) Base conditions
for 9!11 <ꢀ458C: LiTMP, ꢀ788C, Et2O; Base conditions for 9!13
>ꢀ458C: DBU, RT, Et2O; Base conditions for 10!12: DBU, reflux,
Et2O. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, NCS=N-chlorosuccin-
imide, RT=room temperature, TMP=tetramethylpiperidine.
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Communications
effects cannot be excluded.[29] Thus, addition of the bulky
nucleophile BnMgCl yielded, exclusively by means of mode a,
the highly substituted piperidine 21 as the only addition
product albeit in low yield (19%). The reaction with the
smaller nucleophile MeMgBr yielded a mixture of products
from mode a and mode b (d.r. 1:8, 17%) 22 and 23. Finally,
reaction of 13 with yet smaller nucleophiles hydride and
deuteride from LiAlH4 and LiAlD4 yielded, exclusively by
means of mode b, 7 and [5-D]-7 in 87% and 93% yield,
respectively. We speculate that the two opposing modes may
be influenced by two opposing factors: steric approach
control[30] (mode a, H!S thereby developing strain,
Scheme 4) and stereoelectronic control coupled with strain
relief[31,32] (mode b, H!C, Scheme 4).[29]
Figure 1. 13C NMR spectra (CDCl3, 125 MHz, 294 K) illustrating the
dramatic broadening of the signals of the carbon atoms flanking the
configurationally labile nitrogen atom in chloramines 9 and 10.
The formation of protected epi-adenophorine 16 had
indicated that Et2Mg added to 12 exclusively by mode b.
above the point of N-configurational lability,
yielded ketimine 13 (Scheme 2) (IR: n˜ =
1667 cmꢀ1 (C N), 13C NMR: d = 168.5 ppm (s,
¼
C5)), whereas treatment with LiTMP at ꢀ788C
yielded DNJ-aldimine 11 (IR: n˜ = 1654 cmꢀ1 (C
¼
N), 13C NMR: d = 162.3 ppm (d, C1), 1H NMR: d =
7.60 ppm (brs, 1H, H1)). We interpret these results
as being due to the relative accessibility of the
conformational and configurational manifolds
shown in Scheme 2. Above ꢀ458C elimination
proceeds according to Curtin–Hammett principles
4
via the C1,Clax conformation that allows antiperi-
planar elimination of H5ax and Clax.[25] However,
below ꢀ458C the 4C1,CleqQ4C1,Clax configurational
Scheme 4. Competing modes a and b for the attack on polyhydroxylated imines
are modulated by the size of the nucleophile (see Supporting Information for
discussion).
manifold is inaccessible, and elimination proceeds
via a conformation such as 1C4,Clax,[26,27] which
allows elimination of H1ax and Clax. To test these
interpretations we studied the elimination of INJ-
Cl 10, for which the antiperiplanar elimination of H5 and Cl is
not possible from its preferred 4C1 conformation by virtue of
the opposite configuration of 10 at C5. In accord with this
model, elimination with DBU at refluxgave INJ-aldimine 12
as the exclusive product. To further confirm their identities
imines 12 and 13 were also independently synthesized by
novel routes employing Staudinger aza-Wittig reactions
(Scheme 3).
Addition of EtMgBr to imine 12, with the aim of
synthesizing adenophorine, initially provided disappointing
results, yielding only products consistent with intermediate
tautomerization and/or elimination. To reduce the likelihood
of these base-catalyzed processes, we added imine 12 to a
solution of EtMgBr that had been pretreated with dioxane,[28]
and gratifyingly obtained 16. Subsequent deprotection gave
protected 1-epi-adenophorine 4 as a single diastereomer (de >
98%). Although we were pleased by the level of diastereo-
selectivity, our goal, the synthesis of adenophorine, required
the opposite sense of selectivity, and this stimulated an
investigation of the determining factors. An investigation of
different nucleophile additions to ketimine 13, as a near-
enantiomeric substrate to INJ-aldimine 12, revealed a grad-
uation in the sense of selectivity (from mode a to b, Scheme 4)
as the size of the nucleophile decreased, although electronic
Armed with the above information, we considered that only
nucleophiles larger than Etꢀ would favor the desired addition
mode a, and this appeared to block our convergent approach
to the synthesis of adenophorine through addition of Etꢀ to
12. However, according to this size-dependent model, addi-
tion of the small nucleophile hydride, again by means of
mode b, to ethyl ketimine 14 as an alternative substrate would
yield adenophorine. Ethyl ketimine 14 was synthesized in two
ways: from 16 by our two-step chlorination–elimination
approach and independently by means of a Staudinger aza-
Wittig cyclization from ethylazidoketone 20, which was in
turn synthesized efficiently in 38% yield from 17 in eight
steps. Although the former provided a convenient way of
converting 16 to 14, the regioselectivity of the elimination step
was poor and the latter route 17!14 was more efficient
(overall yields: 16!15 24% over three steps, 17!15 26%
over ten steps, vide infra). Reduction of 14 under various
standard conditions (NaBH3CN/AcOH, H2/Pd, K-selectride)
failed due to degradation or protecting-group incompatibil-
ities. However, reduction with NaBH4/MeOH yielded a
mixture of mode-a and mode-b products (d.r. 1:2) 15 and
16. The formation of 16 as a major mode b product high-
lighted the need for a yet smaller source of hydride. Gratify-
ingly, the use of LiAlH4 yielded tetrabenzyladenophorine 15
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was identical in all respects to a sample of the natural product
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ine to the enantiomer of 3.
In summary, we have exploited configurational dynamics
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controlling stereoselectivity were determined, subsequent
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completed the first synthesis of (ꢀ)-adenophorine, thereby
allowing assignment of the configuration of the natural (+)
isomer.
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[16] Depending on the absolute configuration of adenophorine,
either C1 or C5 of structure
pseudoanomeric center.
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[21] Additions of carbon nucleophiles to polyhydroxylated imines
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3 may be viewed as the
Keywords: asymmetric synthesis · azasugars · carbohydrates ·
glycosidase inhibitors · imines · stereodynamics
.
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[24] The signals of 10 may broaden more readily because of smaller
differences, relative to those of 9, in the chemical shifts of the
two N-epimers in the slow-exchange limit, in addition to, or
possibly instead of, differences in inversion exchange rates.
Unfortunately, it was not possible to decoalesce the resonances
of 10 and thus establish these shift differences.
[25] This Saytzev-sense elimination to form a more substituted imine
is presumably favored by a high degree of double-bond character
in the typically late transition states in imine-forming elimina-
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Am. Chem. Soc. 1964, 86, 2428 and M. Bartok, K. Felfoldi, G.
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Angew. Chem. Int. Ed. 2003, 42, 3788 –3792
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elimination products see H. Oediger, F. Möller, Angew. Chem.
1967, 79, 53; Angew. Chem. Int. Ed. Engl. 1967, 6, 76.
[26] While conformers consistent with 4C1,Cleq and 4C1,Clax were
1
observed in NMR experiments, the C4,Clax conformer was not
directly observed. Assuming the 1C4 conformer is disfavored
over the 4C1 by ~ 25 kJmolꢀ1 (based on the difference in ground-
state energy for b-glucopyranose see P. L. Durette, D. Horton,
Adv. Carbohydr. Chem. Biochem. 1971, 26, 49), this conformer
would be present at < 0.001%.
[27] Other conformations (e.g., 1,4B, BN,3) that would also allow
antiperiplanar alignment of NCl and only H1 or syn elimination
(see N. O. Bruce, J. Am. Chem. Soc. 1964, 86, 2428) cannot be
excluded. Estimates of the relative energy barriers of “ring-flip”
conformational equilibria in cyclohexane of (~ 43.5 kJmolꢀ1 see
M. Squillacote, R. S. Sheridan, O. L. Chapman, F. A. L. Anet, J.
Am. Chem. Soc. 1975, 97, 3244), ring-substituted piperidines
(~ 36 – 41 kJmolꢀ1 see V. M. Gittins, P. J. Heywood, E. Wyn-
Jones, J. Chem. Soc. Perkin Trans. 2 1975, 1642), and glucopyr-
anose (~ 46 kJmolꢀ1, see N. V. Joshi, V. S. R. Rao, Biopolymers
1979, 18, 2993) and the N-configurational equilibrium of N-
chloropiperidine (~ 49–60 kJmol see refs. [2a,b] and references
therein) and ring-substituted N-chloropiperidines (~ 56–
62 kJmolꢀ1 see J. V. Correia, M. N. Simꢀes, A. C. Ferreira,
L. R. Galveia, F. M. S. Brito Palma, Heterocycl. Commun. 2002,
8, 391) support the possibility of a situation in which a suitable
ring-conformation manifold is energetically accessible while the
N-inversion manifold is not. Initial estimates from line-shape
analysis suggest that in 9 a barrier of ~ 48 kJmolꢀ1 to N-
inversion exists at 248 K. Further investigations will be published
in due course.
[28] We considered that displacement of the Schlenk equilibrium (W.
Schlenk, W. Schlenk, Jr., Ber. Dtsch. Chem. Ges. B 1929, 62, 920)
would provide Et2Mg as a more suitable source of Etꢀ with
reduced basicity.
[29] See Supporting Information for a more detailed discussion.
Details of further investigations will be published in due course.
[30] W. G. Dauben, R. E. Bozak, J. Org. Chem. 1959, 24, 1596.
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[32] P. Deslongchamps, Stereoelectronic Effects in Organic Chemistry,
Pergamon, Oxford, 1983, pp. 211 – 221.
[33] The deprotected piperidine adducts produced here as hydro-
phobically modified azasugars were evaluated for their inhib-
itory activity towards panels of human glycoprocessing enzymes.
These revealed that 5 is a good and highly selective inhibitor of
human a-glucosidase (IC50: 1 mm but no inhibition of GCS at
0.1 mm) that is more potent than the archetypal azasugar DNJ 1
(IC50: 1.4 mm towards human a-glucosidase[14d]). This high a-
glucosidase inhibitory power of 5 suggests it as a potential broad-
spectrum antiviral agent.[9c] Further details will be published in
due course.
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ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 3788 –3792