Intramolecular tandem isomerization-mannich reaction as a new route towards aminocyclopentitols

Article abstract of DOI:10.1002/ejoc.201101130

A new efficient synthetic strategy has been developed to prepare aminocyclopentitols. It is based on an iron-catalyzed tandem isomerization-Mannich reaction and uses chiral N-tert-butanesulfinamide as a chiral auxiliary. This methodology has been applied

Full text of DOI:10.1002/ejoc.201101130

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101130
Intramolecular Tandem Isomerization–Mannich Reaction as a New Route
Towards Aminocyclopentitols
Hai Thuong Cao,[a,b] Thierry Roisnel,[a] and René Grée*[a]
Keywords: Aminocyclopentitols / Iron / Mannich reaction / Domino reactions / Alcohols
A new efficient synthetic strategy has been developed to pre-
pare aminocyclopentitols. It is based on an iron-catalyzed
tandem isomerization–Mannich reaction and uses chiral N-
tert-butanesulfinamide as a chiral auxiliary. This methodol-
ogy has been applied to the enantiocontrolled synthesis of a
mannostatin A analogue, as well as isomers of known fucos-
idase and glycosidase inhibitors.
itors. Therefore, new routes are required towards such at-
tractive molecules.
Introduction
Aminocyclitols are important compounds from a bio-
logical point of view, as many of them have demonstrated
potent inhibition properties against various types of glycos-
idases.[1] On the basis of this activity, they are of much
potential interest for the treatment of diabetes, cancer, and
bacterial and viral infections for instance. This aminocy-
clopentitol structure is found in various natural products
such as mannostatins or trehazoline, as well as in synthetic
analogues such as Merrell Dow’s cyclopentylamine and
BCX-1812 (Figure 1). In spite of many elegant studies per-
formed in this area,[2] there is still a need for designed ana-
logues to obtain a better understanding of glycosidase func-
tioning and also to prepare more potent and selective inhib-
Tandem isomerization–aldolization[3,4] and tandem isom-
erization–Mannich reactions[5] have been successfully devel-
oped as new methodologies for C–C bond formation, and
we have demonstrated recently that the latter reaction, com-
bined with the use of chiral N-sulfinimines,[6] was opening
efficient routes to optically pure β-aminoketones and β-
amino alcohols.[7] The goal of this communication is to
demonstrate that a similar process, in the intramolecular
version, is a short and efficient approach to new aminocy-
clopentitols. We have applied this methodology to the en-
antiosynthesis of an analogue of mannostatin A, as well as
isomers of known fucosidase and glycosidase inhibitors.
The general strategy is indicated in Scheme 1. N-Pro-
tected derivatives B could be obtained from vinylic lactols
A, themselves easily prepared from sugars.[8] By analogy
with our previous work with lactols,[4] it was anticipated
that an intramolecular tandem isomerization–Mannich re-
action could occur to afford amino-protected cyclopenta-
none intermediate C. Then, simple reduction and deprotec-
tion steps should give target molecules E. The choice of
the tert-butanesulfinyl protecting group was based upon the
Figure 1. Some representative bioactive aminocyclopentitols.
[a] Université de Rennes 1, Laboratoire Sciences Chimiques de
Rennes CNRS UMR 6226,
Avenue du Général Leclerc, 35042 Rennes Cedex, France
Fax: +33-2-23236978
E-mail: rene.gree@univ-rennes1.fr
[b] Faculty of Physics and Chemical Engineering, Le Quy Don
Technical University,
100 Hoang Quoc Viet Street, Cau Giay district, Hanoi, Vietnam
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101130.
Scheme 1. General strategy towards aminocyclopentitols and the
first target, a mannostatin A analogue.
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H. T. Cao, T. Roisnel, R. Grée
SHORT COMMUNICATION
great advantages observed previously with respect to high
Starting from isomer 3, the reaction gave cyclopentanone
stability under our transition-metal-catalyzed reaction con- 5 in excellent yield, with a small amount (14%) of sulfin-
ditions and complete stereocontrol.[6,7]
ylimine 6. On the other hand, reaction with sulfinamide 4
gave ketone 7, with imine 6Ј (14%).
The stereochemistry of these compounds was established
by NMR spectroscopy and by correlation with X-ray analy-
sis after the next step. Then, the reduction was performed
on each stereoisomer independently: reaction of 5 with
NaBH4 was fully stereocontrolled, affording exclusively 8 in
82% isolated yield (Scheme 4). The stereochemistry of this
alcohol was established by NMR spectroscopy and con-
firmed by X-ray crystallography (Figure 2).[11] As expected,
the reduction occurred only from the face opposite to the
two bulky substituents (acetonide and sulfinamide).
Results and Discussion
Lactol 1 was easily prepared in three steps and 55% over-
all yield from d-ribose by following a literature procedure.[8]
Condensation of 1 with racemic N-tert-butanesulfinamide
(Ϯ)-2 afforded, in quantitative yield, a 1:1 mixture of sulfin-
amides 3/4, which were easily separated by chromatography.
On the other hand, reactions were performed with each en-
antiomer of starting sulfinamide independently: we ob-
served that the (S)-2 enantiomer yielded only 3, whereas
diastereoisomer 4 was obtained quantitatively from the (R)-
2 enantiomer. Therefore, this condensation was stereospec-
ific and was determined by the configuration of the starting
sulfinamide (Scheme 2). The structures of derivatives 3 and
4 were established from the NMR spectroscopic data
3
3
through small trans J1,2 and J3,4 (0.3–3.8 Hz) values ob-
Scheme 4. Reduction of ketone 5.
served for the protons of the tetrahydrofuran rings.
Figure 2. X-ray diffraction analysis of alcohol 8.
On the other hand, reduction of ketone 7 afforded, in
90% overall yield and a 30:70 ratio, a mixture of alcohols
9/10, which could not be separated by silica gel chromatog-
raphy. However, isolation of both compounds in pure form
was possible by a selective protection–deprotection strategy
(Scheme 5). Upon reaction of the crude mixture of 9/10
with TBSCl (tert-butyldimethylsilyl chloride), imidazole,
and 4-dimethylaminopyridine, only isomer 9 was protected
as silyl ether 11 and alcohol 10 was recovered. After separa-
tion of 10 and 11 by chromatography, deprotection of silyl
ether 11 afforded pure alcohol 9 in very good yield.
Scheme 2. Synthesis of sulfinamides 3 and 4.
The tandem isomerization–Mannich reaction was suc-
cessfully performed by using Fe(CO)5 as the catalyst[9,10]
with full stereocontrol (Scheme 3).
The last step in the synthetic scheme was deprotection of
these derivatives. It was performed in a one-pot process by
reaction first with trifluoroacetic acid overnight at room
temperature, followed by reaction with HCl, affording de-
sired target molecules 12–14 in excellent yields (Scheme 6).
These aminocyclopentitols appear to be of interest for
biological studies and especially derivative 12, which is a
new analogue of mannostatin A. In-depth studies by
Booms et al. have shown that the thioether-containing
hydrophobic pocket was, at least in part, responsible for the
better activity of mannostatin A.[12] Therefore, it will be
very interesting to evaluate analogue 12 (with a Me group),
as well as related compounds with various CH2R groups in
Scheme 3. Tandem isomerization–Mannich from 3 and 4.
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Intramolecular Tandem Isomerization–Mannich Reactions
Scheme 5. Reduction of ketone 7 and isolation of alcohols 9 and 10.
group, and aminocyclopentitols obtained by this route will
be of much use for structure–activity relationships in gly-
cosidase inhibition.
Experimental Section
Tandem Isomerization–Mannich Reaction: To a solution of 3 (125
mg, 0.6 mmol) in anhydrous THF (10 mL) was added Fe(CO)5
(16 μL, 0.12 mmol, 10 mol-%). The mixture was irradiated with a
Philip HPK 125 lamp for 1.5 h. The solvent was removed under
reduced pressure, and the residue was filtered on silica gel (Et2O).
After concentration, the residue was purified by chromatography
on silica gel (pentane/EtOAc, 1:1) to afford 5 (176 mg, 85% overall
yield) and isomerized product 6 (29 mg, 14%).
Representative Procedure for the Synthesis of Aminocyclitols: A
solution of 30% trifluoroacetic acid (1 mL) was added to com-
pound 8 (20 mg, 0.106 mmol). The reaction mixture was stirred
under an atmosphere of nitrogen overnight at room temperature
and then extracted with pentane (3ϫ5 mL) to remove the byprod-
ucts. A few drops of 1 n HCl were added, and the aqueous phase
was co-evaporated in vacuo with toluene to afford hydrochloride
12 as a viscous orange oil (19 mg, quantitative).
Scheme 6. Preparation of aminocyclitols 12–14.
this position, derivatives which should be accessible through
this strategy.
On the other hand, compounds 13 and 14 appear to be
of biological interest, as they are isomers of a series of
aminocyclitols prepared by other routes and active as fucos-
idase (i.e., 15, 16) and glycosidase (i.e., 17) inhibitors (Fig-
ure 3).[2k,2l,13]
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental procedures and characterization of com-
pounds.
Acknowledgments
H. T. C. thanks the Vietnamese Government for a PhD Thesis fel-
lowship. This research has been performed as part of the Indo-
French “Joint Laboratory for Sustainable Chemistry at Interfaces”.
We thank Mrs. D. Grée for NMR experiments and CRMPO
(Rennes) for MS analyses. We thank Dr. Raji Reddy and Dr. S.
Chandrasekhar for fruitful discussions.
Figure 3. Representative examples of fucosidase inhibitors (i.e., 15
and 16) and a glucosidase inhibitor (i.e., 17).
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Conclusions
We have developed a new route to aminocyclopentitols.
The tandem isomerization–Mannich reaction works ef-
ficiently under ironcarbonyl catalysis, with full stereocon-
trol by the N-tert-butanesulfinamide component. Develop-
ment of this methodology is under active study in our
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Published Online: October 11, 2011
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