Stereoselective synthesis of highly O-functionalized enantiopure 2,3,4-trisubstituted tetrahydrofurans by tandem debenzylative cyclization of glycal derived 2,3-epoxy alcohols

Article abstract of DOI:10.1039/b606519h

A new and highly efficient methodology for the construction of synthetically important highly O-functionalized enantiopure 2,3,4-trisubstituted tetrahydrofurans with three contiguous stereocenters is reported. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b606519h

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Stereoselective synthesis of highly O-functionalized enantiopure 2,3,4-
trisubstituted tetrahydrofurans by tandem debenzylative cyclization of
glycal derived 2,3-epoxy alcohols{{
L. Vijaya Raghava Reddy,a Abhijeet Deb Roy,b Raja Royb and Arun K. Shaw*a
Received (in Cambridge, UK) 9th May 2006, Accepted 13th June 2006
First published as an Advance Article on the web 10th July 2006
DOI: 10.1039/b606519h
regioselective cyclization has been paid considerable attention
during the past decades.15
A new and highly efficient methodology for the construction of
synthetically important highly O-functionalized enantiopure
2,3,4-trisubstituted tetrahydrofurans with three contiguous
stereocenters is reported.
As a part of our ongoing effort to explore the utility of glycal
derived 2,3-epoxy alcohols of general structure A,16 we describe
herein an efficient strategy for the synthesis of highly substituted
enantiopure tetrahydrofurans starting from the glycal derived 2,3-
epoxy alcohols.
Functionalized tetrahydrofurans (oxolanes) are found in many
naturally occurring compounds.1–3 The dihydroxylated tetrahy-
drofuran unit is a common heterocyclic fragment present in
natural products of great biological importance. Such units have
constituted important synthons for the synthesis of pharmacolo-
gically important furanoid groups, such as cytotoxic anhydrophy-
tosphingosine,4 goniothalesdiol,5 and the inhibitor of endogenous
DNA polymerase of hepatitis B virus (HBV), virgutasin.6
Polysubstituted tetrahydrofurans play an important role in organic
chemistry due to the fact that they are important intermediates in
the synthesis of novel nucleosides with potent chemotherapeutic
activity such as tiazofurin and selenazofurin.7 In addition, many
anhydro-alditols (sugar derived tetrahydrofurans) are of great
interest due to their industrial applications and biological proper-
ties, an example of which is SPAN-40,8 a sorbitan fatty acid ester
employed to use microbubbles for use in diagnostic ultrasound.
Moreover, oxolane units that occur widely in nature as
constituents of marine and terrestrial organisms9,10 exhibit
remarkable antibiotic or cytotoxic effects, which have opened
perspectives for selected clinical applications.9 This circumstance
has bought about a growing demand for cyclic ethers in general
and tetrahydrofuran derived natural products in particular.10,11
Since their supply cannot be met from natural sources alone, the
invention of methods for stereoselective construction of tetrahy-
drofuran has received considerable attention.
Our idea for the synthesis of the tetrahydrofuran has emanated
from the recent report by White et al. on the preparation of
tetrahydrofuran by an intramolecular iodoetherification reaction
involving the participation of secondary benzyl protected oxygen
in cyclization followed by debenzylation.17
As it is well known that C-2 selective substitution reaction of
2,3-epoxy alcohol is extremely difficult.18 Therefore, our retro-
synthetic strategy (Fig. 1) involves the regioselective opening of the
2,3-epoxy ring at C-3 by intramolecular nucleophilic attack of the
oxygen atom of the C-6 benzyloxy group to furnish the required
THF derivative.
Scheme 1 unfolds the details of the route followed for the
stereoselective synthesis of the highly functionalized tetrahydro-
furan. The allylic alcohol 3 was prepared from glycal 1 in two steps
by its Perlin hydrolysis19 followed by Luche reduction20 of
aldehyde 2. Catalytic Sharpless asymmetric epoxidation21 of 3
afforded the enantiomerically pure epoxide 4 (>99% diastereo-
selectivity) in good yield.
Among the number of known methods available in the
literature12,13 intramolecular cyclization of epoxy alcohols is one
of the useful strategies for the construction of the oxygen
heterocycles. In fact, many biologically active compounds have
been synthesized according to this strategy.12,14 An epoxide may
result in five or six membered oxygen heterocycles depending upon
its mode of opening in a regioselective manner. Therefore
Being aware of the report that heating D-glucitol with
anhydrous pyridinium chloride at 120–160 uC over several hours
affords the 1,4-anhydro-D-glucitol in fairly good yield,8,22 our
journey towards the goal started with the use of hydrazine salts.
Initial attempt to achieve the goal proceeded by stirring of the
epoxide 4 in refluxing ethanol in the presence of a catalytic amount
of t-butyl hydrazine hydrochloride. After 6 h of continuous stirring
we noticed 100% conversion of reactant 4 to furnish the product, 5,
whose structure was elucidated by preparing its acetyl derivative
aDivision of Medicinal and Process Chemistry, Central Drug Research
Institute (CDRI), Lucknow 226001, India.
E-mail: akshaw55@yahoo.com
bDivision of Sophisticated Analytical Instrumentation Facility, Central
Drug Research Institute(CDRI), Lucknow 226001, India.
E-mail: rajaroy_cdri@yahoo.com
{ CDRI Communication No. 6946.
{ Electronic supplementary information (ESI) available: Experimental
procedure, 1H and 13C NMR spectra of all the THFs along with 2D
NMR spectra of 5, 5a, 9, 9a. See DOI: 10.1039/b606519h
Fig. 1 Retro synthetic pathway.
3444 | Chem. Commun., 2006, 3444–3446
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Scheme 1 Synthetic route starting from tribenzylated galactal.
(5a). The structure of the chromatographically pure compound 5a
was established by the combined use of one and two dimensional
NMR experiments (ESI{).
In the 1H NMR spectrum the presence of five aromatic protons
along with two benzylic methylene proton (AB spin system) signals
clearly suggested the presence of one benzyl group in the system.
The three methyl signals of the acetate at 1.86, 2.06 and 2.10 ppm,
corresponded to the number of hydroxyl groups in 5, indicated the
opening of the epoxide ring during the course of the reaction. The
differentiation of the two methylene carbon signals (C-1 and C-6)
were carried out based on the corresponding downfield 13C
chemical shifts for the C-6 carbon (71.5 ppm) with respect to C-1
(63.1 ppm). Further, the long range heteronuclear correlations of
the H-6 methylene protons with C-5, C-4 as well as with C-3
carbon atoms unequivocally supported the formation of the
tetrahydrofuran like structure. Moreover, the HMBC correlations
observed for the H-2, H-3 methine protons and H-1 methylene
protons were found in accordance with the expected structure and
explicitly confirmed the formation of the tetrahydrofuran
derivative (5a). Further, the relative stereochemistry of the acetate
product 5a was deduced from the 2D NOESY spectrum, where
the correlations indicated the H-3 and H-4 protons to be cis in
nature.
Scheme 2 Debenzylative cyclizations of 2,3-epoxy alcohols.
spectrum of 9a indicated that the H-3 and H-4 protons are trans
in nature as expected.
Further, we were interested to notice whether there would be
any change in the course of the reaction if the 5-OH group was
protected. So, a 5-OH acyl protected diastereomeric mixture of
epoxide 12 (dr 32 : 68) prepared by m-CPBA epoxidation of its
corresponding allylic alcohol, was subjected to the above
transformation, and was found to be intolerant of the reaction
conditions resulting in the deacetylated diastereomeric mixture of
tetrahydrofuran 13. Then this transformation was performed with
the 5-OH benzyl protected epoxide 14 (dr 28 : 72). To our delight
expected tetrahydrofuran 15 was obtained in 77% yield. Later the
same procedure was extended for the preparation of the dibenzyl
protected tetrahydrofurans 17 and 19 from their respective
enantiomerically pure epoxides 16 and 18. In total the results
obtained (Scheme 2) were general and satisfactory.
After confirming the structure of 523 the same transformation
was carried out using piperazine salts24 and hydrazine salts.
Among them hydrazine salts (Table 1), especially phenyl hydrazine
hydrochloride, were found to be the most effective in terms of the
yield of the THF.
After optimizing the reaction a series of enantiomerically pure
epoxides21b 6, 8 and 10 were subjected to debenzylative stereo-
selective cyclization (Scheme 2) to afford their respective THFs 7, 9
and 11. The tetrahydrofuran 9 was acetylated and the structure of
the acetate derivative 9a was checked by the combined use of one
and two dimensional NMR experiments. The 2D NOESY
This transformation thus led to confirmation that irrespective of
the nature of 5-OH, whether it is protected or unprotected, the ring
opening of the 2,3-epoxy alcohols is highly regio- and stereo-
selective leading to highly functionalized tetrahydrofurans via
intramolecular cyclization by nucleophilic attack of oxygen atom
of the C-6 benzyloxy group followed by debenzylation.
Based on the above results it seems that the facile cleavage
(Fig. 2) of the oxonium ion intermediate (c) resulted in the
expected trisubstituted tetrahydrofuran. All the spectroscopic data
are in accord with their structures.
Table 1 Results with different hydrazine salts
Salt No.
Amine salt
Time/h
Yield (%)
1
2
3
4
Hydrazine hydrochloride
t-Butyl hydrazine hydrochloride
Phenyl hydrazine hydrochloride
2,4-Difluoro phenyl hydrazine
hydrochloride
6.0
4.0
2.0
1.5
55
60
82
62
In summary, a general method for the synthesis of 2,3,4-
trisubstituted tetrahydrofurans (having 5-OH protected/unpro-
tected) with high enantiomeric purity in good yield has been
disclosed. To the best of our knowledge this is the first report on
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 3444–3446 | 3445

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Fig. 2 Proposed mechanism.
Fig. 3 Sites of diversification.
the illustrated chemistry described herein to obtain densely
functionalized enantiomerically pure tetrahydrofurans. Moreover,
the tetrahydrofurans synthesised above are unique due to the four
point diversity (Fig. 3) and multiple stereocenters present in them.
The utility of these templates (THFs) in the synthesis of
biologically important natural products, including oligosacchar-
ides, along with their analogues will be presented in due course.
We are thankful to Mr A. K. Pandey for technical assistance.
LVRR and ADR to CSIR New Delhi for financial assistance.
Notes and references
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3446 | Chem. Commun., 2006, 3444–3446
This journal is ß The Royal Society of Chemistry 2006