Synthesis of novel sugar-lactam conjugates using the Aube reaction

Article abstract of DOI:10.1039/c0ob00719f

An efficient and convenient method for the synthesis of sugar-lactam conjugates is reported starting from readily available sugar azides using the Aube reaction. Cyclic azido alcohols are used in the Aube reaction for the first time in a carbohydrate setting. The resulting glycoconjugates could be further used to increase the chemical diversity on the sugar backbone, and may find potential applications as glycomimetics, peptidomimetics, in glycotargeting and in CNS drug delivery.

Full text of DOI:10.1039/c0ob00719f

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´
Synthesis of novel sugar-lactam conjugates using the Aube reaction†
Suresh E. Kurhade, Tanaji Mengawade, Debnath Bhuniya, Venkata P. Palle and D. Srinivasa Reddy*
Received 14th September 2010, Accepted 19th October 2010
DOI: 10.1039/c0ob00719f
An efficient and convenient method for the synthesis of sugar-lactam conjugates is reported starting
from readily available sugar azides using the Aube´ reaction. Cyclic azido alcohols are used in the Aube´
reaction for the first time in a carbohydrate setting. The resulting glycoconjugates could be further used
to increase the chemical diversity on the sugar backbone, and may find potential applications as
glycomimetics, peptidomimetics, in glycotargeting and in CNS drug delivery.
Introduction
Among the several methods available in the literature for the
synthesis of lactams,1 the method introduced by Aube´ et al. has
become more popular in recent times as an efficient and simple to
use methodology.2 This reaction continuously finds wide spread
applications in organic synthesis, in particular for the synthesis of
natural products. The Aube´ reaction,2 an intermolecular reaction
of hydroxyalkyl azides with cyclic ketones to provide lactams,
proceeds through an in situ-generated hemiacetal as a temporary
tether that renders azide addition in an intramolecular fashion,
followed by ring expansion. Interestingly, this reaction results in
Scheme 2 A strategy to access sugar-lactam conjugates.
N-substitution of the pendant group on the azide (Scheme 1).
resulting from the present method are expected to be important
structural scaffolds in drug discovery.4 Apart from their very differ-
ent pharmacodynamic effects, these hybrid molecules often exhibit
unusual pharmacokinetic properties, such as tissue permeability.5
For example, by attaching a polar moiety like a sugar reduces the
passive transport in some classes of hybrid molecule, and in other
cases attachment of a carbohydrate may increase their ability to
cross the Blood Brain Barrier (BBB) through active transport, re-
sulting in a higher drug exposure in the brain. This latter technique
is one of the recent approaches to CNS drug delivery.5b,c,f,i
Results and discussion
To start with, mannose azide 16 was readily prepared from com-
mercially available methyl-a-D-mannopyranoside and the reaction
with cyclohexanone in presence of BF3·Et2O was attempted,
followed by treatment with an aqueous KOH solution, which
resulted in the desired mannose-caprolactam as a mixture of
products 2 and 3. Compound 2 is the result of 2,3-hydroxy
protection as a ketal, and which can be converted into desired
sugar-lactam 3 by treatment with 80% aqueous acetic acid at 80 ◦C
(Scheme 3).7 Interestingly, this transformation does not require
protection of the hydroxyl groups on the sugar moiety. It is note-
worthy to mention that the intermediate-like 2, where the C2- and
C3-hydroxy groups are protected, can be utilized for the selective
manipulation at the anomeric- or C4-position of the mannose
moiety. Alternatively, compound 3 can be synthesized through
N-alkylation of the caprolactam using a protected mannose iodide
derivative in very poor yield.8 This route requires additional steps,
and the lactams are not readily available in many cases (Scheme 4).
Hence, the Aube´ reaction is a superior method for accessing sugar-
lactam conjugates.
Scheme 1 The Aube´ reaction.
The azido alcohol, a key component of the Aube´ reaction, can
be visualized in a readily available sugar-azide derivative and can
be reacted with a variety of cyclic ketones to produce sugar-
lactam conjugates (see the blue-colored portion in Scheme 2).
As such, medium-sized, in particular 5–7-membered ring, lactams
are of considerable interest in pharmaceutical research due to
their appealing biological activities.3 The sugar-lactam conjugates
Discovery Chemistry, Advinus Therapeutics Ltd., Quantum Towers, Plot
No. 9, Rajiv Gandhi Infotech Park, Phase-I, Hinjewadi, Pune, 411057, India.
E-mail: dsrinivas.reddy@advinus.com, dsreddy88@yahoo.com; Fax: +91 20
6653 9620; Tel: +91 20 6653 9600
† Electronic supplementary information (ESI) available: Experimental
procedures and analytical data (1H NMR, 13C NMR and HRMS)
for all new compounds. CCDC reference number 783639. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob00719f
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Scheme 3 The synthetic route for accessing sugar-lactam conjugates.
Chart 1 Products obtained from the reactions of 1 with various ketones
under Aube´ reaction conditions.
Scheme 4 An alternative attempted route to sugar-lactam conjugates.
Having the protocol in hand, we tested the scope of this
methodology with different ketones; the results are outlined in
Chart 1. The reaction of mannose azide 1 with cyclobutanone
and cyclopentanone resulted in products 4 and 5, respectively,
in good yields. Pyranone and its corresponding sulfur analogue
produced sugar-lactam conjugates 6 and 7, respectively. Next, we
looked at the effect of 4-substitution on cyclohexanone and found
that 4-phenyl cyclohexanone and 4-t-butyl cyclohexanone gave
desired lactams 8 and 9, respectively, in a highly diastereoselective
manner.9 The stereochemistry of the newly formed center was
determined to be of R-configuration (as drawn) using X-ray
crystallographic data† from the tetraacetate of sugar-lactam 8 (see
Fig. 1).10 This phenomenon can be utilized for the synthesis of
chiral lactams and their derivatives using readily available sugar-
based hydroxy azides, and this method could be complimentary to
those already existing.2c,e As many drug-like compounds possess
the diazepinone moiety in their core structure,11 gaining access
to related scaffolds with sugar hybrids would be rewarding.
Accordingly, N-protected 4-piperidone was reacted with 1 to yield
10 in moderate yield. Under the same reaction conditions, 2-
indanone produced corresponding bicyclic lactam 11 in poor yield.
To amplify the scope of this method and also to understand the
structural requirements of the sugar moiety, different sugar azides
were reacted using cyclopentanone under the same conditions;
Fig. 1 An ORTEP diagram of the triacetate of 8 (hydrogens are omitted
for clarity).
the results are compiled in Chart 2. The reaction on glucose
derivative 1212 proceeded smoothly and furnished desired sugar-
lactam 20 in 66% isolated yield. In this case, no intermediate
such as 2 was observed as the C2- and C3-hydroxy groups
were trans to each other on the pyranose moiety. Deoxy sugar
azides 13 and 14, prepared from D-glucal,13 resulted in 21 and
22, respectively. The reaction of furanose sugar azide derivative
1514 with cyclopentanone also produced desired lactam 2315 in
good yield. As expected in the Aube´ reaction on 4-deoxy glucose
azide derivative 16 using cyclopentanone, no ring expansion took
place and no trace of compound 24 was observed. In the case of
galactose azide derivative 17,16 forcing conditions were required
to correspondingly yield 25. Compound 18,17 being a secondary
azide, also reacted with cyclopentanone to produce corresponding
sugar-lactam conjugate 2615 in 52% yield. It is interesting to
note that in examples 15 and 18, a 1,2-azido alcohol moiety is
present, unlike the 1,3-azido alcohol moiety found in the rest of the
examples. To understand the role of the free hydroxy group in the
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Fig. 2 A plausible intermediate for the reaction of glucose azide 12 with
cyclopentanone.
substituted cyclohexanones could be explored further to generate
enantiopure lactams and their derivatives. We have also shown in
this paper for the first time that cyclic azido alcohols can be used
in Aube´ reactions, in particular, in a carbohydrate setting.
Conclusions
In summary, we have developed a new method to access sugar-
lactam conjugates using the Aube´ reaction. We have studied this
reaction using various ketones and sugar azides to increase the
scope of the method and also to understand the structural re-
quirements of the sugar moiety. These multifunctional compounds
could be used to increase the diversity of sugar frameworks and
may find applications as potential glycomimetics, peptidomimetics
or as building blocks for the synthesis of novel glycoconjugates and
molecular receptors. Biological screening of these compounds and
further exploration of the chemistry of cyclic azido alcohols will
be the subject of future work.
Experimental
General methods
All reagents, starting materials and solvents (including dry sol-
vents) were obtained from commercial suppliers and used as
such without further purification. Reactions were carried out
in oven-dried glassware under a positive pressure of argon or
nitrogen unless otherwise specified. Column chromatography was
performed on silica gel (Rankem, 100–200 mesh). Deuterated
solvents (Cambridge Isotope Laboratories) for NMR spectro-
scopic analyses were used as received. All NMR spectra were
recorded on a Varian 400 MHz spectrometer. Coupling constants
are measured in Hz. All chemical shifts are quoted in ppm relative
to tetramethylsilane using the residual solvent peak as a reference
standard. Optical rotations were recorded using a Rudolph
Autopol-V polarimeter at 589 nm (sodium D-line). Mass spectra
were measured withESI ionization. Mass spectroscopywas carried
out on an Agilent MSD/VL spectrometer, an API QStar Pulsar
(Hybrid Quadrupole-TOF LC/MS/MS) spectrometer or a JMS-
T100LC, Accu TOF (DARTMS) instrument. Infrared (IR) spectra
were recorded on a Perkin-Elmer 100 FT-IR spectrometer. Melting
points were measured (uncorrected) using BUCHI melting point
B-545.
Chart 2 The products obtained from the reactions of 1 with various
ketones under Aube´ reaction conditions.
sugar azide, we prepared sugar azide 19, where the hydroxy group
is protected as a methyl ether, and reacted it with cyclopentanone
under the same conditions. As anticipated, the reaction did not
take place to produce 27. Based on these observations, we propose
that the presence of a free 4-hydoxy group is necessary on the
pyranonse moiety. The trans stereochemistry of 4-hydroxy group
with respect to the azidomethyl group may facilitate the reaction.
A plausible intermediate for the reaction of glucose azide 12 with
cyclopentanone is shown in Fig. 2. To the best of our knowledge,
no methods for the synthesis of sugar-lactam conjugates exist in
the literature. The present protocol has the potential to expedite, or
at least provide a valuable alternative route, to the others already
known. The observed diastereoselectivity during the reaction with
Methyl 6-deoxy-6-N-azepan-2-one-a-D-mannopyranoside (3).
To a mixture of 6-azido-6-deoxy-methyl-a-D-mannopyranoside
(1)6 (0.25 g, 1.14 mmol) and cyclohexanone (0.18 mL, 3.50 mmol)
in dichloromethane (5 mL) was added BF3·Et2O (0.57 mL,
4.57 mmol) drop-wise under an argon atmosphere at 0 ◦C. The
reaction mixture was allowed to warm up to room temperature,
and stirring was continued for 24 h. The reaction mixture was
diluted with diethyl ether (5 mL) and 50% aqueous KOH (1 mL)
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was added. After stirring for an additional 1 h, the reaction
mixture was evaporated to dryness and purified by column
chromatography using 30% ethyl acetate : hexane to neat ethyl
acetate to obtain 2 and 3 in 230◦and 36 mg quantities, respectively.
Compound 2: mp = 89–91 C; [a]2D5 = -15.6◦ (c 1, CH3OH);
IR (CHCl3): 1071, 1099, 1623 and 3368 cm-1; 1H NMR (CD3OD,
400 MHz) d 1.34–1.79 (series of m, 15H), 2.51–2.61 (m, 2H), 3.33
(d, J = 3.6 Hz, 1H), 3.36 (s, 3H), 3.49 (d, J = 2.4 Hz, 1H), 3.52–
3.55 (m, 1H), 3.58–3.64 (m, 2H), 3.85 (d, J = 4.80 Hz, 1H), 3.88
(d, J = 4.80 Hz, 1H), 4.00 (dd, J = 5.6, 7.6 Hz, 1H), 4.09 (d, J =
5.6 Hz, 1H) and 4.87 (s, 1H); 13C NMR (100.6 MHz, CD3OD) d
179.9, 110.9, 99.6, 78.5, 76.5, 71.5, 70.6, 55.3, 53.1, 50.7, 39.2, 37.5,
36.4, 30.7, 28.7, 26.0, 25.0, 24.7 and 24.5; LCMS = 370.2 (M + 1);
HRMS (ESI) m/z calc. for C19H31NO6Na [M + Na]+: 392.2049,
found: 392.2096.
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(m, 4H), 3.66 (dd, J = 3.6, 9.2 Hz, 1H), 3.76–3.81 (m, 2H) and
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Conversion of compound 2 to compound 3. Compound 2
(230 mg) was dissolved in 80% aqueous acetic acid (5 mL) and
stirred at 80 ◦C. After 24 h, the reaction mixture was evaporated
to dryness to furnish the crude product. The crude compound was
purifiedby column chromatographyusingsilicageland eluted with
50% ethyl acetate : hexane to neat ethyl acetate to obtain 170 mg
of title product 3; overall yield: 205 mg (64%). Experimental
compounds 4–11 were prepared using an analogous procedure to
that described for the synthesis of 3. See the ESI for experimental
details for all the compounds.†
6 X. J. Wu, X. Tang, M. Xian, P. G. Braunschweiger and P. G. Wang,
Bioorg. Med. Chem., 2002, 10, 2303.
7 See the ESI for detailed experimental information†.
8 During the alkylation step, unwanted olefin II was obtained as a major
compound. The spectral data of compound 3 prepared via this route
was compared with that of 3 obtained by the Aube´ reaction and found
to be identical. Experimental details and all other unsuccessful attempts
to prepare sugar-lactam conjugate 3 are available in the ESI†.
9 HPLC analysis of the reaction mixture showed a >95 : 5 diastereose-
lectivity. Only the major isomer was isolated.
Acknowledgements
10 The stereochemistry of the newly formed chiral center in compound 9
is assumed to be as drawn based on the X-ray structure of the triacetate
of 8†.
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We are grateful to Dr Rashmi Barbhaiya and Dr Kasim Mookhtiar
for their support and encouragement. Mr Prasad Punde, summer
project student from Ahmednagar College, Ahmednagar, India,
is thanked for his help with initial experiments. We thank Dr
Binoy K. Saha, Department of Chemistry, Pondicherry University,
India, for determining the X-ray crystal structure. Help from
the analytical department in recording the spectral data is also
acknowledged. SEK acknowledge Andhra University (AU) for
registering in PhD program. In this regard, help from Advinus HR,
Profs. YLN Murthy and V. Siddaiah of AU are acknowledged.
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