Indium-mediated coupling of 3-bromopropenyl acetate with (S)-Garner aldehyde: a route to 1,4-dideoxy-1,4-L-iminoribitol

Article abstract of DOI:10.1016/j.tetlet.2003.10.050

The indium organometallic complex generated by metallic indium and 3-bromopropenyl acetate in THF adds to the Garner aldehyde in excellent yield and with high diastereoselectivity; the usefulness of the corresponding anti-anti adduct was demonstrated by developing a short synthesis of the title compound, an azasugar known as a glycosidase inhibitor.

Full text of DOI:10.1016/j.tetlet.2003.10.050

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9147–9149
Indium-mediated coupling of 3-bromopropenyl acetate with
(S)-Garner aldehyde: a route to 1,4-dideoxy-1,4- -iminoribitol
L
Marco Lombardo,* Sebastiano Licciulli and Claudio Trombini*
Dipartimento di Chimica ‘G. Ciamician’, Universita` di Bologna, via Selmi 2, I-40126 Bologna, Italy
Received 16 September 2003; revised 29 September 2003; accepted 7 October 2003
Abstract—The indium organometallic complex generated by metallic indium and 3-bromopropenyl acetate in THF adds to the
Garner aldehyde in excellent yield and with high diastereoselectivity; the usefulness of the corresponding anti–anti adduct was
demonstrated by developing a short synthesis of the title compound, an azasugar known as a glycosidase inhibitor.
© 2003 Elsevier Ltd. All rights reserved.
A challenge for synthetic chemists is offered by
molecules containing sequences of contiguous hetero-
substituted stereocenters, a structure motif which is
widespread in natural products (monosaccharides, etc.)
as well as in important families of natural and synthetic
drugs. An example of a densely functionalised carbon
chain is represented by structure 1, where substituents
Y1–Y4 are oxygen or nitrogen groups. We focused our
attention on the synthetic strategy depicted in Scheme
1.
toxyallylation of (S)-N-Boc-serinal acetonide 7 (Garner
aldehyde)14 to give the anti–anti adduct 8 (Scheme 3).15
Scheme 1.
An attractive precursor of 1 is provided by alkene 2,
thanks to the number of stereoselective functionalisa-
tion reactions of carbonꢀcarbon double bonds available
in the literature.1–5 In turn, 2 is accessible via stereocon-
trolled addition of a g-heterofunctionalised allylic
organometallic reagent 3 to a carbonyl compound or to
an azomethine derivative.6
The usefulness of 3-halopropenyl esters 4 as precursors
of heterofunctionalised allylic organometallic com-
pounds 5 using zinc,7–9 indium9,10 and chromium,11,12 in
water or aprotic solvents, has been recently disclosed
(Scheme 2).
Scheme 2.
In conjunction with our efforts to develop new stereo-
controlled routes to alk-1-ene-3,4-diols 6 from 4,7–12 we
now report the indium mediated13 asymmetric ace-
Keywords: 3-bromopropenyl acetate; Garner aldehyde; a-hydroxallyl-
ation; 1,4-dideoxy-1,4-L-iminoribitol.
* Corresponding author. Tel.: +39-051-2099513; fax: +39-051-
2099456; e-mail: marlom@ciam.unibo.it; trombini@ciam.unibo.it
Scheme 3.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.050

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M. Lombardo et al. / Tetrahedron Letters 44 (2003) 9147–9149
A typical Grignard protocol was adopted for the for-
mation of 5 (R=Me); 3-bromopropenyl acetate (0.67 g,
3.75 mmol) was added at 0°C to a suspension of indium
(0.67 g, 3.75 mmol) in anhydrous THF (5 mL). The
heterogeneous mixture was stirred for 30 min at 0°C,
then stirring was continued for 3.5 h at rt. Garner
aldehyde 7 (0.57 g, 2.5 mmol) was added at 0°C and the
reaction mixture was stirred for 4 h at rt. After quench-
ing with aq. NaHCO3, an alkaline hydrolysis (K2CO3/
MeOH/H2O) was performed on the crude extract;16
flash-chromatography on silica-gel (cyclohexane/ethyl
acetate/triethylamine 85:14:1) first provided a fraction
containing a mixture of isomers of 8 in 15% overall
yield, then diol 8 was isolated in 80% yield as a pure
isomer.17 The relative anti–anti configuration of the
major isomer 8, established by chemical correlation
with the known title compound, was the consequence
of an excellent control of both diastereo- and diastereo-
facial selectivity. Diastereoselectivity was anti, in
agreement with the general observed trend in previous
studies; indeed, Z-configured indium and zinc com-
plexes derived from oxidative addition of Zn(0) and
In(0) to the carbonꢀbromine bond of 4 displayed an
interesting behaviour in the addition to prochiral alde-
hydes. When aromatic or a,b-unsaturated aldehydes are
used the addition is syn-stereoselective, but in the case
of saturated aldehydes the opposite anti adducts are
preferentially formed. A rationale for the latter stereo-
chemical outcome was proposed,9 assuming bicy-
clo[3.2.2]nonane-type TS structure A is the favoured
one on the basis of steric grounds (Fig. 1).
Scheme 4.
(2,2-dimethoxypropane, Amberlyst® 15H, CH2Cl2, 24
h, 70%);23 the subsequent reaction sequence was carried
out without isolation of intermediates. This involved
ozonisation of 9 (O3, CH2Cl2, −78°C, 30 min then
Me2S, 12 h), exhaustive acidic deprotection of 10 (TFA/
H2O 20:1, 30 min, 0°C, then evaporation of excess TFA
under vacuum), neutralisation to free amino aldehyde
11 (Amberlyst® A26, OH−), and finally, reductive cycli-
sation to the target molecule 12 (H2/Pd, MeOH, 12 h,
45 psi).
The overall sequence starting from 9 took place in 30%
yield. Purification of 1,4-dideoxy-1,4-L-iminoribitol
12 was carried out by elution through a small pad of
silica eluting with CH2Cl2/MeOH/EtOH/NH4OH
50:20:20:10;24,25 optical and NMR data of the derived
hydrochloride (12·HCl)26 corresponded to literature
data.27–29
With regard to p-facial discrimination, the preferential
attack to the re or si face of the (S)-Garner aldehyde
strongly depends on the carbon nucleophile and on the
metal counterion;14,15 furthermore, stereoselectivity is
known to be modified by the addition of chelating
additives or by using different solvents.18
In conclusion, the usefulness of 3-halopropenyl esters as
precursors of the formal 1-hydroxyallyl anion was
confirmed by the asymmetric hydroxyallylation of Gar-
ner aldehyde, which opens a route to 1,4-dideoxy-1,4-L-
iminoribitol 12 and to ent-12, both enantiomers of
Both to confirm stereoassignments and to demonstrate
which are enzymatic inhibitors.18–21
the synthetic utility of adduct 8, we converted it into
1,4-dideoxy-1,4- -iminoribitol 12, as shown in Scheme
L
4. Both 12 and its enantiomer are known to display
remarkable bioactivity as inhibitors of mammalian gly-
cosidases,19,20 of eukaryotic DNA polymerases21 and of
HIV replication.22
Acknowledgements
This work was supported by MIUR-Rome (FIRB
Funds to C.T., 2002).
The reaction sequence required ozonisation of 8 which,
unfortunately, produced the expected aldehyde in
unsatisfactory yield. This drawback was easily over-
come by protecting the diol moiety as acetonide 9
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