"Inosaminoacids": Novel inositol-amino acid hybrid structures accessed by microbial arene oxidation

Article abstract of DOI:10.1039/c1cc10643k

Microbial 1,2-dihydroxylation of sodium benzoate permits the rapid construction of novel inositol-amino acid hybrid structures. Both β- and γ-amino acids are accessible by means of an acylnitroso Diels-Alder cycloaddition. The Royal Society of Chemistry 2

Full text of DOI:10.1039/c1cc10643k

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COMMUNICATION
‘‘Inosaminoacids’’: novel inositol–amino acid hybrid structures accessed
by microbial arene oxidationw
a
a
b
a
¨
Sarah Pilgrim, Gabriele Kociok-Kohn, Matthew D. Lloyd and Simon E. Lewis*
Received 1st February 2011, Accepted 1st March 2011
DOI: 10.1039/c1cc10643k
Microbial 1,2-dihydroxylation of sodium benzoate permits
the rapid construction of novel inositol–amino acid hybrid
structures. Both b- and c-amino acids are accessible by means
of an acylnitroso Diels–Alder cycloaddition.
organisms12 are able to metabolise benzoates so that the diol is
introduced ipso,ortho to the carboxy functionality (Scheme 1b).
The chiron 9 derived from the oxidation of benzoate has
found diverse synthetic applications13 and we have recently
demonstrated access to new reaction manifolds by means of
tricarbonyliron complexes of 9.14 Arene diols are ideal starting
materials for azacarbasugar synthesis and ortho,meta diols of
type 7 have been utilised in this context.15 In contrast, ipso,ortho
diols of type 9 have remained unexploited to date. We targeted
efficient access to C-substituted azacarbasugar structures from 9,
made possible by the pre-existing quaternary centre. Specifically,
we sought to access C-carboxy inosamines (‘‘InosAminoAcids’’),
a hitherto unknown class of compound.
Formation of the known13a,g acetonide of 9, followed by
carboxylate benzylation afforded protected diene 10, which was
employed in an acylnitroso cycloaddition. The dienophile was
generated in situ by the action of tetrabutylammonium periodate
on N-(benzyloxycarbonyl)hydroxylamine 11.15h,16 Selectivity in
cycloadditions employing arene diol-derived dienes has been
extensively studied17 and precedent suggested that the approach
of the dienophile to the diene face opposite the acetonide would
be favoured.13a,15h,16b,18c In the event, only two of four possible
regioisomers were isolated (12 and 13, Scheme 2).
Azacarbasugars are a privileged class of structures for drug
development as the amino functionality can modulate
biological activity with respect to the parent carbohydrate
and the replacement of the endocyclic oxygen with carbon
confers hydrolytic stability.1 Azacarbasugar motifs are present
in many compounds of medicinal interest. Acarbose 1 and
voglibose 2 are a-glucosidase inhibitors used clinically to treat
type II diabetes.2,3 Antibiotic4 and antifungal4b,5 properties of
azacarbasugars have been reported. The use of N-octylvalien-
amine 3 and its 4-epimer as therapies for Gaucher disease and
G
M1-gangliosidosis is under investigation.6 In addition, the
anti-influenza drug oseltamivir 4 may also be considered to be
an azacarbasugar (Fig. 1).7
In the field of peptide engineering, the incorporation of
non-natural b- and g-amino acids has been employed to
furnish peptides with designed properties.8 Constrained cyclic
amino acids are effective for imparting secondary structure to
peptides and the cyclohexane g-amino acid 5 has been
employed for the construction of peptide nanotubes with
hydrophobic cavities.9 Polyhydroxylated analogues of 5 would
permit control of the hydrophobicity of such cavities and
allow for modified secondary structures based on additional
hydrogen bonding interactions.
The major product of the cycloaddition (12) was formed
when the Cbz group was introduced distal to the benzyl ester,
Enzymatic dihydroxylation of arenes to produce
enantiopure building blocks for synthesis is a well established
methodology.10 For the dihydroxylation of monosubstituted
arenes, the most common regiochemical outcome is the
installation of the diol ortho,meta to the pre-existing substituent
(7, Scheme 1a). However, R. eutrophus B911z and certain other
Fig. 1 Representative azacarbasugars and cyclic amino acids.
a Department of Chemistry, University of Bath, Bath, BA2 7AY, UK.
E-mail: S.E.Lewis@bath.ac.uk; Fax: +44 (0)1225 386231;
Tel: +44 (0)1225 386568
b Medicinal Chemistry, Department of Pharmacy and Pharmacology,
University of Bath, Bath, BA2 7AY, UK
w Electronic supplementary information (ESI) available: Experimental
procedures, characterisation data and 1H NMR and 13C NMR spectra
for all novel compounds, as well as selected 2D-NMR data. Crystallo-
graphic data for 15 and 24. CCDC 809598 and 809599. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c1cc10643k
Scheme 1 Regio- and stereoselectivity of dioxygenases.
Chem. Commun., 2011, 47, 4799–4801 4799
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Scheme 2 Acylnitroso cycloaddition.
which we attribute to decreased steric hindrance with respect to
the formation of 13. The major adduct 12 was treated with
molybdenum hexacarbonyl to effect selective N–O bond scission,
followed by the formation of the crystalline p-nitrobenzoate
derivative 15. The absolute structure of 15 was confirmed by
X-ray crystallography, from which the structure of 12 was
inferred. The same sequence of transformations did not furnish
a crystalline derivative when applied to the minor adduct 13.
Thus, the structure of 13 was elucidated by means of NOESY
correlations.w Specifically, an interaction between the olefinic
protons and the acetonide endo methyl protons was observed
for both 12 and 13; such an interaction would not be expected for
cycloadducts arising from the dienophile approach to the diene
face bearing the acetonide. (Scheme 3)
Scheme 3 Structural elucidation of 12 and 13. NOESY correlations
are shown with double-headed arrows. The ORTEP diagram of 15
shows ellipsoids at 50% probability. H atoms are shown as spheres of
arbitrary radius.
Cycloadducts 12 and 13 were subjected to Upjohn
dihydroxylation conditions, affording in each instance the diol
corresponding to the approach of the oxidant to the less
hindered face of the olefin. The stereochemistry of addition
was again elucidated by NOESY correlation,w (Scheme 4). For
both diols 16 and 18, interaction of the acetonide endo methyl
protons with the hydroxyl group methines was observed,
indicative of the axial orientation of the methines and, by
inference, the equatorial orientation of the hydroxyl groups. In
the dihydroxylation of 12, unexpected cyclic carbamate 17 was
also formed. Hydrogenolysis of diols 16 and 18 affected
multiple reductive operations cleanly, allowing access to the
target inosaminoacids 20 and 22 (Scheme 5) simply by removing
the acetonide in aqueous hydrochloric acid.19
Scheme 4 (a) NMO, cat. OsO4, acetone/H2O 4 : 1, 24 h, rt. NOESY
correlations are shown with double-headed arrows.
In addition to the inosaminoacids 20 and 22, less highly
oxygenated structures are also accessible via the acylnitroso
cycloaddition reported here. For example, the major cycloadduct
12 could be subjected directly to hydrogenolysis/acetonide
cleavage as above, in this instance giving rise to dihydro-3-C-
carboxy-ent-conduramine A1 (24, Scheme 6).20 Polyhydroxylated
zwitterionic species such as 19–24 are known to be difficult to
purify and repeated chromatography was required in some
instances.19 Conduramine derivative 24 was highly crystalline
and submitted to X-ray crystallography (Fig. 2). It is noteworthy
that in the solid state 24 adopts a near-perfect chair conformation.
Inosaminoacids 20 and 22 and the conduramine derivative
24 were evaluated for the inhibition of glycosidase activity21
against a-glucosidase (type I from Baker’s yeast), b-D-gluco-
sidase (almond), b-galactosidases (from A. oryzae and E. coli)
and b-D-glucuronidases (from bovine liver, E. coli and
P. vulgata); no inhibitory activity was observed.
Scheme 5 (a) H2, Pd/C, MeOH, 24 h, rt. (b) 1 M HCl(aq), 24 h, rt.
(c) C18 reversed-phase chromatography. (d) Trituration with EtOH.
In summary, we have described a very concise synthetic
route to a novel class of azacarbasugar. Inosaminoacids 20
and 22 contain six contiguous stereocentres (including a
quaternary centre), yet are accessed in just seven steps from
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2
The ORTEP diagram of 24 shows ellipsoids at 50%
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We gratefully acknowledge EPSRC (vacation bursary to
S.P.) and the University of Bath for funding. We thank
Prof. Andrew G. Myers (Harvard) for a generous gift of
R. eutrophus B9 cells. We also thank the EPSRC national
mass spectrometry service centre for analyses.
´
´
,
´
´
Notes and references
´
´
z Formerly known as Alcaligenes eutrophus B9
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Chem. Commun., 2011, 47, 4799–4801 4801