A new reaction manifold for the Barton radical intermediates: Synthesis of N-heterocyclic furanosides and pyranosides via the formation of the C1-C2 bond

Article abstract of DOI:10.1021/ja028617z

The first radical intermediate in the thiourethane-mediated deoxygenation of an alcohol (Barton-McCombie reaction) can participate in an exo-hex-5-enyl- or exo-hept-6-enyl-type radical cyclization when a suitable radical acceptor (e.g., α,β-unsaturated es

Full text of DOI:10.1021/ja028617z

Published on Web 01/18/2003
A New Reaction Manifold for the Barton Radical Intermediates: Synthesis of
N-Heterocyclic Furanosides and Pyranosides via the Formation of the C1-C2
Bond
Jong Uk Rhee, Brian I. Bliss, and T. V. RajanBabu*
Department of Chemistry, 100 West 18th AVenue, The Ohio State UniVersity, Columbus, Ohio 43210
Received September 19, 2002 ; E-mail: rajanbabu.1@osu.edu
Deoxygenation of secondary alcohols through the use of the
corresponding xanthate and thiourethane derivatives (The Barton-
McCombie reaction) is one of the most useful radical reactions
(Scheme 1).1 In the presence of suitable radical acceptors, the
Scheme 1. Intermediates in the Barton Deoxygenation Reaction
ethyl (E)-hex-2-enoate derivative 6 with 2 equiv of Bu3SnH in
refluxing toluene gave the expected thiolactone 7 (cis/trans ) 2.1/
1.0) in 58% yield. After an extensive investigation12 in which we
systematically varied the concentrations of the reactants, rates of
additions, and reaction temperatures, it was found that when a dilute
solution of the substrate in benzene was added to an excess (5 equiv)
of a good hydrogen donor (Ph3SnH) maintained at 80 °C (reVerse
addition), a surprisingly high yield (88%) of an imidazole glycoside
(8) was produced. The product, not unexpectedly, was a mixture
(51:15:29:5) of all possible isomers of the furanosides. Even though
the major isomer could be separated, no attempts were made to
identify the individual isomers. Instead, we decided to explore ways
of improving the stereochemical outcome and expanding the scope
intermediate radical 2 can be used for intra-2 and intermolecular3
carbon-carbon bond-forming reactions.4 The slow step in the
deoxygenation process is the collapse of the intermediate 1. Under
carefully controlled conditions, this intermediate is also able to take
part in various radical reactions including exo-hex-5-enyl type
cyclizations5,6 leading to lactones after hydrolytic workup. Except
for one isolated example,7 in which the expected thiolactone was
formed, the fate of the intermediate radicals generated from the
thiocarbonyl imidazolides (eq 1, 1, X ) 1-imidazolyl f 3) and
related thiourethanes has not been examined. Under the optimum
conditions, a radical such as 3 can be expected to undergo
cyclization leading to a product in which the heterocyclic moiety
is retained in the product 5 (eq 1). With an appropriately substituted
carbohydrate precursor this could lead to N-heterocyclic glycosides8
of 2-amino- or C2-branched sugars.9 Additionally, this would
provide direct support for the involvement of the radical 1 in the
major reaction pathway leading to deoxygenation.10 These expecta-
tions have been borne out, and in this communication we report
our initial results which demonstrate the generality of this concept
in the context of hex-5-enyl and hept-6-enyl radical cyclizations
with a variety of radical acceptors (3) which include R,â-unsaturated
esters, oxime ethers, and hydrazone derivatives.
of the reaction through the use of alternate radical acceptors and
heterocyclic thiocarbonyl derivatives.
Conformational control by a preexisting ring can often be used
to improve the stereoselectivity of radical annulation processes.13
To explore this possibility in the present context, we prepared12
a
series of thiocarbonyl imidazolides (12a-12d) starting from readily
available 4,6-O-phenylmethylglucopyranose (9) and subjected them
to the cyclization conditions (Scheme 2). The substrates with
Scheme 2. Synthesis of Imidazole Furanosides via Radical
Cyclization
Initial feasibility studies were carried out on a simple carbohydrate-
derived imidazole thioate 6 (eq 2). This readily available substrate11
with a tert-butyldimethylsiloxy-methyl substituent at the C3-position
(radical numbering) was chosen not only to optimize the reaction
conditions but also to examine any inherent stereochemical prefer-
ences in the cyclization in an unbiased system. Reaction of the
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10.1021/ja028617z CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
electron-deficient acceptor olefins gave moderate-to-good yields
of the furanoside product (13) as a mixture of the two anomers
(entries 1, 2). Substrates with oxime ether14 and hydrazone15
acceptors, which would serve as 2-amino-2-deoxy-furanoside
precursors, likewise gave good yields of the imidazole glycosides
(entries 3, 4). These glycosides can be separated by column
chromatography. Even though there is little stereochemical control
in the formation of the two anomers, there is exquisite control at
the C2-position. In each case only the â-epimer is formed.
Formation of cyclohexane derivatives via 6-exo-heptenyl radical
cyclization is approximately 20-30 times slower than hex-5-enyl
radical cyclization,16 and synthetic applications involving these
reactions are few compared to those involving the latter. Therefore,
we were surprised to find that the imidazolide 14a prepared from
a ribose-derived precursor gave 71% isolated yield of a C2-branched
glycoside 15a (eq 3) rather than deoxygenation/reduction products.
In general, (Z)-isomers of the acrylate or the acrylonitrile were found
to give exclusively the altro-isomers as a mixture of anomers, the
â-isomer being the major one.17 The corresponding E-olefins (e.g.,
14b) gave, in addition, minor amounts of the allo-isomers of the
products.12 As we had recognized12 in our initial scouting studies,
at higher temperature with lower amounts of the hydride source,
the expected thionolactone (16) was the sole cyclization product.
The oxime ether (17) was also found to undergo the cyclization
giving the 2-deoxy-2-amino-mannopyranoside derivatives 18 in
remarkably high yield.
We are currently investigating new methods for the synthesis of
novel carbohydrate-derived thiourethanes and mixed thiocarbonates
with the hope of expanding the scope of the newly discovered
cyclization reactions for the synthesis of nucleosides, N-glycosyl
amino acids, and unusual O- and C- disaccharides.
Acknowledgment. We acknowledge the financial support by
NSF (CHE 0079948) and an Alumni Association Fellowship from
Myong Ji University (Korea) to J.U.R.
Supporting Information Available: Details of the synthesis and
characterization of radical precursors and products of reactions (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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Experiments with thiocarbonyl triazole derivatives suggest for
the first time that the new glycoside synthesis may not be limited
to imidazolides. Thus, the hept-6-enyl radical precursors 19a and
19b gave the triazole glycosides 20a and 20b in acceptable yields
(eq 4).
(11) Synthesized from (S)-3-hydroxy-γ-butyrolactone in five steps12 (Huang,
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(12) See Supporting Information for details.
(13) (a) RajanBabu, T. V. Acc. Chem. Res. 1991, 24, 139. (b) Several natural
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