Synthesis of 4a-carba-α-D-lyxofuranose from 2,3-O-isopropylidene-L- erythruronolactone via Tebbe-mediated cascade reaction

Article abstract of DOI:10.1039/b802418a

A new, efficient and highly diastereoselective approach for the synthesis of 1,2,3,5-tetraacetylcarba-α-d-lyxofuranose 14 from d-ribose is reported via one-pot conversion of 5 to 1 using Tebbe reagent which involves a cascade reaction sequence of methylenation, cleavage of isopropyl group, carbocyclization and again methylenation. The Royal Society of Chemistry.

Full text of DOI:10.1039/b802418a

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Synthesis of 4a-carba-a-D-lyxofuranose from 2,3-O-isopropylidene-L-
erythruronolactone via Tebbe-mediated cascade reactionw
Girija Prasad Mishra, G. Venkata Ramana and B. Venkateswara Rao*
Received (in Cambridge, UK) 12th February 2008, Accepted 21st April 2008
First published as an Advance Article on the web 21st May 2008
DOI: 10.1039/b802418a
A new, efficient and highly diastereoselective approach for the
synthesis of 1,2,3,5-tetraacetylcarba-a-D-lyxofuranose 14 from
D-ribose is reported via one-pot conversion of 5 to 1 using Tebbe
reagent which involves a cascade reaction sequence of methyle-
nation, cleavage of isopropyl group, carbocyclization and again
methylenation.
In continuation of our work in conversion of carbohydrates
to carbocycles10 herein we report an attractive alternative
route to cyclopentitols from 5-enofuranoside.
Cyclopentitols of varying nature and complexities form an
integral part of a broad class of natural products. Some
examples are the glycoside inhibitors such as mannostatin A,
allosamizoline, trehalostatin, carbafuranoses and carbo-
nucleosides such as neplanomycin, aristeromycin etc.11
After analyzing the retrosynthesis of some of the cyclopen-
titols it was realized that the olefinic cyclopentane derivative 1
can be a suitable intermediate for their synthesis. Since
compound 1, to the best of our knowledge, is not reported
in the literature, therefore we envisaged a novel approach for
its synthesis.
Polyoxygenated carbasugars are a common feature of many
interesting biologically active compounds such as carbocyclic
nucleoside analogues1 and a number of enzyme inhibitors.
Conversion of readily available carbohydrates to these poly-
functionalized carbocyclic derivatives is an attractive route
adopted by many synthetic chemists.2,3 Among these, intra-
molecular ring-closure of carbohydrates to give carbocycles is
a highly useful transformation which gives direct access to the
densely substituted cyclitols. Grosheintz and Fisher first re-
ported the conversion of carbohydrates to carbocycles utiliz-
ing intramolecular aldol reaction.4 Ferrier and co-workers
developed an efficient approach for the synthesis of polyhy-
droxy cyclohexanone derivatives starting from hex-5-eno-
pyranoside via regiospecific hydroxymercuration and aldol-
like intramolecular cyclization.5,6 This approach provided a
practical route to many cyclohexitols. Dalco and Sinay devel-
oped an interesting approach where a 5-enohexopyranose was
converted to cyclohexitols using TIBAL.7 In this process the
transposition of oxygen atom takes place with the exocyclic
carbon without cleaving the anomeric C–O bond and also
TIBAL reduces the carbonyl group generated during the
intramolecular cyclization to give cyclohexitols.. Later on this
transformation was carried out with [TiCl3(OiPr)] under mild
conditions.
Based on retrosynthesis (Scheme 1), it was felt that com-
pound 2 is a logical precursor for 1, which in turn can be
prepared from the enofuranoside 4 via ring-opening followed
by intramolecular aldol reaction. The enofuranoside 4 can be
synthesized from lactone 5 through a one-carbon extension.
In principle, we require a methylenation reagent for two
one-carbon extension steps and a Lewis acid for cleavage of
isopropyl group for carbocyclization to complete all the
transformations of lactone 5 to olefin alcohol 1. It was felt
that Tebbe reagent is a suitable one for the conversion of 5 to
1, and is very well known for one-carbon extension of carbo-
nyl compounds, esters, lactones etc.12 The bimetallic Tebbe
reagent and its dissociated byproducts are known to have
acidic properties. Generally this Lewis acidity is a drawback in
conventional functional group transformations whereas here,
we took the advantage of this property.13
In order to implement the above assumption, we undertook
the synthesis of 4a-carba-a-D-lyxofuranose 13 which is a very
important precursor for accessing carbonucleosides1 whose
synthesis is not as simple as one might presume. For this,
the required lactone 9 was prepared from the 2,3-O-isopropy-
lidene-D-ribose 7 based on the reported protocol14–17 with
good overall yield. Compound 9 was converted to its isopropyl
The above methods are generally useful for making six-
membered carbapyranoses, but to the best of our knowledge
none of these approaches are used for the transformation of
furanosides to cyclopentitols since the molecule has to under-
go an unfavourable 5-(enolendo)-exo-trig cyclization.7 The
solution for this challenging problem was given by Belanger
and Prasit, where the five-membered enolactone was converted
to a cyclopentanone derivative using LiAlH(OtBu)3.8 Recently
Gree et al. developed an another interesting approach which
involves tandem isomerisation–aldolactonisation of vinyl
sugars to cyclopentenone using 5% Fe(CO)5 and photo-
irradiation.9
Organic Division III, Indian Institute of Chemical Technology,
Hyderabad, India 500007. E-mail: drb.venky@gmail.com,
venky@iict.res.in; Tel: 91-40-27193003
w Electronic supplementary information (ESI) available: Experimental
1
section; H and 13C NMR spectra. See DOI: 10.1039/b802418a
Scheme 1 The retrosynthesis of compound 1.
Chem. Commun., 2008, 3423–3425 | 3423
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Scheme 3 The proposed mechanism for the synthesis of the key
intermediate 1.
Scheme 2 Synthesis of key intermediate 1 from D-ribose.
After achieving the five-membered carbocycle product 1
successfully, we turned our efforts for the transformation of
1 to carbafuranose 11 by functionalizing the exocyclic
double bond.
glycoside (5) using isopropanol and catalytic PPTS
(Scheme 2).
When compound 5 was treated with Tebbe reagent (2.2 eq.)
in THF solution at 0 1C for 1 h, it smoothly yielded the
The olefinic compound 1 on stereoselective reduction20 with
BH3ÁDMS and followed by oxidative hydrolysis with
H2O2–NaOH yielded the 2,3-O-isopropylidene 4a-carba-a-D-
lyxofuranose 11 and 2,3-O-isopropylidene 4a-carba-a-L-ribo-
furanose 12 in 3.5 : 1 ratio (Scheme 4). The 1H, 13C NMR and
specific rotation [a]20 +38 (lit [a]20 = +40) values of the
expected compound 1 in 40% yield, [a]20 À125.24 (c 2.67,
D
CHCl3).18 The newly created hydroxyl center is confirmed as
anti to the existing alkoxy groups, through extensive NMR
studies (Fig. 1). The stereoselectivity of the reaction could be
rationalized through a seven-membered transition state (Y) or
through the transition state (Z) where the carbonyl group is
located away from the isopropylidene, thus generating the
trans hydroxy functionality in the cyclized product.
D
D
major compound 11 matched with the reported values.21 The
stereochemistry was further confirmed by NOE studies
(Fig. 2).
In the conversion of 5 to required compound 1, four
transformations are taking place sequentially in one-pot.
These are methylenation of lactone 5 to give 4, cleavage of
the isopropyl group in isopropyl enofuranoside 4 to give 3,
intramolecular aldol reaction of 3 to give 10 and again
methylenation of 10 to give 1. First activation of the enol
oxygen in 4 by Lewis acid helped the cleavage of the ring C–O
bond instead of the anomeric C–O bond and the strategic
presence of the isopropyl unit on the anomeric oxygen led to
its facile cleavage, later thus facilitating the ring-opening
reaction to afford intermediate 3. The intramolecular cycliza-
tion occurred via a disfavoured 5-(enolendo)-exo-trig path-
way19 under Lewis acid catalysed condition (Scheme 3).
Scheme 4 Stereoselective reduction of key intermediate 1.
Diol 11 on acidic hydrolysis with MeOH–HCl afforded
4a-carba-a-D-lyxofuranose 13. For the convenience of purifi-
cation the crude product (tetraol) was converted to its acety-
lated derivative 14 using Ac2O–Et3N (Scheme 5). The spectral
and physical data of 14 were in good agreement with the
reported values.19
In conclusion we have developed a novel strategy for the
transformation of a five-membered carbohydrate lactone to
cyclopentitol using Tebbe reagent and synthesized 4a-carba-
Fig. 1 X NOEs showing the relative stereochemistry of compound 1;
Y and Z are the possible seven-membered transition states.
Fig. 2 The NOEs showing the relative stereochemistry of compound 11.
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Scheme 5 Deprotection and acetylation of major compound 11.
a-DÀlyxofuranose 13 an important carbasugar. Further stu-
dies on application of this strategy for the synthesis of different
five- and six-membered carbasugars are underway.
G. P. M. and G. V. R. thank CSIR (New Delhi) for
fellowship. We would like to thank Dr J. S. Yadav, Dr
A. C. Kunwar, Dr T. K. Chakraborty and Dr N. W. Fadnavis
for their constant support and encouragement, we also thank
DST (SR/S1/OC-14/2007), New Delhi for financial support.
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