Directed and undirected asymmetric dihydroxylation reactions: Application in the synthesis of a C-linked analogue of allolactose

Article abstract of DOI:10.1039/b107643d

The complex OsO₄·(S,S)-1,2-diphenyl-N,N′-bis(2,4,6- trimethylbenzyl) ethane-1,2-diamine is an effective reagent for the desymmetrisation of meso-1,2-bis(3,6-dihydro-2H-pyran-2-yl)ethanes by asymmetric dihydroxylation; this process, whose sense of diastereoselectivity depends on substitution and stereochemistry, has been exploited in the synthesis of a C-linked analogue of allolactose.

Full text of DOI:10.1039/b107643d

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Directed and undirected asymmetric dihydroxylation reactions:
application in the synthesis of a C-linked analogue of allolactose
Robert Hodgson,a Tajir Mahidb and Adam Nelson*a
a School of Chemistry, University of Leeds, Leeds, UK LS2 9JT. E-mail: adamn@chem.leeds.ac.uk
b Aventis Pharma US, Route 202–206, Bridgewater, New Jersey 08807, USA
Received (in Cambridge, UK) 24th August 2001, Accepted 5th September 2001
First published as an Advance Article on the web 1st October 2001
The complex OsO4·(S,S)-1,2-diphenyl-N,NA-bis(2,4,6-tri-
ee (Scheme 2). Dihydroxylation occurred anti2 to the pseudo-
methylbenzyl)ethane-1,2-diamine is an effective reagent for
equatorial allylic p-methoxybenzoyloxy group. Previously,
prochiral cyclic dienes have been desymmetrised using AD-mix
b, with dihydroxylation occurring on the outside of their
bicyclic structure.6 This natural diastereoselectivity could be
reversed by delivery of OsO4·10 to the double bond: dihydrox-
ylation of 8 was highly syn selective, and gave, after
peracetylation, the tetraacetate 11 with 93% ee (87% yield
based on recovered starting material). We believe that
diastereoselectivity stems from hydrogen bonding of the
reagent to the pseudoaxial hydroxy group,3 and that this
reaction is the first example of a directed asymmetric dihy-
droxylation.
the desymmetrisation of
meso-1,2-bis(3,6-dihydro-2H-
pyran-2-yl)ethanes by asymmetric dihydroxylation; this
process, whose sense of diastereoselectivity depends on
substitution and stereochemistry, has been exploited in the
synthesis of a C-linked analogue of allolactose.
Previously, we have described methods for the synthesis of
some stereoisomeric C-linked disaccharide mimetics.1 A key
feature of our approach was that diastereomeric mimetics could
be prepared by minor variation of a general reaction sequence.
For example, complementary undirected2 and directed3 dihy-
droxylation reactions were exploited in the two-directional
elaboration of diols (such as C2-symmetric 1) to give products
of general stucture 2 with 1,4-syn stereochemistry. In order to
As a prelude to the diastereoselective functionalisation of the
remaining double bond of 9, we studied the functionalisation of
the allylic p-methoxybenzoate 15 using iodine and silver
benzoate in dry carbon tetrachloride (Scheme 3).7 In view of the
synthesise the mimetics with the opposite 1,4-stereochemical
relationship, an efficient method for the desymmetrisation4 of
the meso difuryl diol1 3 or one of its derivatives would be
required.
Oxidative ring expansion of the furan rings of the diol 3 using
VO(acac)2–tBuOOH, and acetalisation, gave the dipyranone 4
as a 75+25 mixture of meso and unsymmetrical anomers, from
which the required meso diastereoisomer was crystallised in
52% yield (Scheme 1). Reduction of 4 under Luche’s conditions
gave the diol 5 in > 98% yield, which was converted into the p-
methoxybenzoyl diester 6. The diastereoisomeric diol 8 was
synthesised by hydrolysis of the diacetate 7 obtained by
inversion of the dimesylate derived from 5.
Treatment of 6 with OsO4·10 at 220 °C lead to complete
consumption of the starting material and gave the desymmetr-
ised diol 9† as a single diastereoisomer in 84% yield with 60%
Scheme 1
Scheme 2
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Chem. Commun., 2001, 2076–2077
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b107643d

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Scheme 3
Our synthesis of the C-linked disaccharide mimetic ent-25 is
unusual in that neither ring derives directly from a sugar, though
Vogel has reported the use of a non-carbohydrate based
template to introduce one of the sugar rings to some C-linked
disaccharides.14 Key steps in our synthesis include the de-
symmetrisation of a highly functionalised meso di-DHP using
an asymmetric dihydroxylation reaction, and the use of a p-
methoxybenzoate ester to control the stereospecificity of a
Prévost reaction.
Scheme 4
rigorously dry reaction conditions of these reactions, the syn
stereospecificity of this process (15 ? 16, 17) and the absence
of benzoate from the products are remarkable. Presumably,
participation8 of the p-methoxybenzoyloxy group gave the
dioxonium ion 22 which was stable to the reaction conditions;
subsequent hydrolysis of this intermediate, presumably on
aqueous work-up, gave the observed syn hydroxy p-methoxy-
benzoates 16 and 17. In general, syn hydroxyesters are only
obtained when Prévost reactions are conducted in the presence
of water because, under these conditions, the intermediate
dioxonium is hydrolysed in situ.9
We thank EPSRC and Aventis for providing funds under the
CASE scheme for new appointees, the Royal Society for a grant
and Pfizer and AstraZeneca for strategic research funding.
Notes and references
† The absolute configuration of 9 was deduced by comparing the 500 MHz
1H NMR spectra of its (R)- and (S)-Mosher diesters with those of the diol 13,
which was derived from the pyranone5 (2R)-12.
‡ For the hydrolysis of similar epoxides, see ref. 10.
Treatment of the iodoesters 16–17 (4+1 mixture of regio-
isomers) with potassium hydoxide in water–THF, followed by
peracetylation, gave a 3+1 diastereomeric mixture of the
triacetates 18 and 19. Presumably, 16 and 17 were converted
into the same epoxide which was opened by hydroxide ion.‡
trans-Diaxial opening11 of the major conformer (20 ? 19,
Scheme 4) requires opening at the site which is b to the two
oxygens of the acetal;12 consequently, reaction via the con-
former 21 (? 18)—that is, away from the two b oxygens12—is
competitive with, and in fact dominates over, this process.
In a similar vein, treatment of the desymmetrised compound
23 with iodine and silver benzoate in dry carbon tetrachloride,
followed by treatment with aqueous potassium hydroxide
solution, gave the C-linked disaccharide mimetic ent-25
(Scheme 5); peracetylation gave the hexaacetate 24 in 64%
yield over 3 steps. The C-linked allolactose mimetic 25, in
which C-6 of the galactose ring has been replaced by a methoxy
group, could clearly have been prepared by the same synthetic
methods using the enantiomeric diamine ligand in the key
desymmetrisation step. It has been suggested that stable
analogues of allolactose, the intracellular inducer of the lactose
(lac) operon, may also exert negative control over gene
expression.13
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14 R. Ferritto and P. Vogel, Tetrahedron: Asymmetry, 1994, 5, 2077; R. M.
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Scheme 5
Chem. Commun., 2001, 2076–2077
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