Regioselective Synthesis of Unsymmetrical C-Aryl Glycosides Using Silicon Tethers as Disposable Linkers

Article abstract of DOI:10.1021/ja0375582

Silicon tethers were employed to control the regiochemistry of Diels-Alder reactions between substituted benzynes and glycosyl furans as a key step in the syntheses of unsymmetrical representatives of three major groups of C-aryl glycosides. The cycloaddi

Full text of DOI:10.1021/ja0375582

Published on Web 10/04/2003
Regioselective Synthesis of Unsymmetrical C-Aryl Glycosides Using Silicon
Tethers as Disposable Linkers
David E. Kaelin, Jr., Steven M. Sparks, Hilary R. Plake, and Stephen F. Martin*
Department of Chemistry and Biochemistry, UniVersity of Texas, Austin, Texas 78712-0615
Received July 26, 2003; E-mail: sfmartin@mail.utexas.edu
C-Aryl glycoside antibiotics comprise an important subclass of
the C-glycoside family of natural products, a group of compounds
that has attracted considerable interest because of their range of
significant biological activities and resistance to enzymatic hy-
drolysis.1,2 We recently disclosed two general approaches to prepare
the four major classes of C-aryl glycosides.3,4 The first of these
involved the acid-catalyzed ring openings of the cycloadducts
obtained from the Diels-Alder reaction of benzynes with glycosyl
furans, and the other featured the palladium-catalyzed SN2′-type
ring opening of benzyne-furan cycloadducts with iodoglycals
followed by appropriate adjustment of oxidation levels.
In these studies, symmetrical benzynes were universally em-
ployed as reaction partners, so the regiochemistry of the cycload-
dition was never an issue. Although unsymmetrical benzynes are
known to undergo regioselective Diels-Alder reactions,5 such
cycloadditions typically proceed with poor regioselectivity.6 This
problem became manifest during recent work that culminated in a
formal synthesis of the C-aryl glycoside galtamycinone.7 Hence,
to apply our methodology to the synthesis of naturally occurring
C-aryl glycosides, it is essential to control the regiochemistry of
the pivotal benzyne-furan cycloadditions. We now report that
disposable silicon tethers may be exploited to control the regio-
chemistry of benzyne-furan cycloadditions that lead to the major
groups of C-aryl glycosides.8
naphthols 6 (R4 ) H or Me), depending on the nature of the tether
and the precise tactics used to effect its removal.
The use of silicon tethers to access C-aryl glycosides belonging
to Group I4 may be exemplified by two related strategies that differ
in the number of carbon atoms that are present in the connecting
chain. In the first of these, the known glycosyl furan 73 was
converted into the furylsilane 8 by sequential metalation (n-BuLi,
THF, -78 °C) and reaction with bromomethylchlorodimethylsilane
(Scheme 2).10 O-Alkylation of 2,6-dichloro-4-methoxyphenol (9)11
with 8 then provided the Diels-Alder precursor 10. When 10 was
treated with s-BuLi in THF at -95 °C, facile deprotonation ortho
to one of the chlorine atoms ensued. The resultant anion underwent
elimination upon warming to generate an intermediate benzyne that
then cyclized via an intramolecular Diels-Alder reaction with the
pendant glycosyl furan to provide cycloadduct 11 as a diastereo-
meric mixture.
Scheme 2a
Two protocols differing only in the number of carbon atoms in
the tether were developed as outlined in Scheme 1. Regioselective
metalation of glycosyl furan derivatives 1 followed by reaction with
an appropriate chlorosilane and refunctionalization as needed leads
to the silanes 2, which are coupled with halophenols to give 3.
Selective deprotonation of 3 generates the benzynes 4, and
subsequent intramolecular Diels-Alder reaction then occurs spon-
taneously to furnish the cycloadducts 5. On the basis of the prior
art of Rickborn and Stork,9 we anticipated that fluoride would
induce the cleavage of the silicon-carbon bonds in the tethers in
5 to give intermediates that could undergo acid-catalyzed opening
of the oxabicycloheptadiene ring to deliver either the glycosyl
a Reaction conditions: (a) LDA, THF, -78 °C; Me2Si(Cl)CH2Br, 73%;
(b) 9, Bu4NI, K2CO3, Me2CO, 83%; (c) s-BuLi, THF -95 °C; warm to -5
°C, 68%; (d) Bu4NF, DMF, 79%; (e) Bu4NF, THF; H2O2, MeOH, 62%; (f)
TFA, CH2Cl2, ca. 100%; (g) NaH, BnBr, 95%; TFA, CH2Cl2, 90%.
Scheme 1a
Two tactics were developed for converting the cycloadduct 11
into substituted naphthols. In the event, reacting 11 with excess
Bu4NF (TBAF) in DMF cleaved both carbon-silicon bonds to
afford dimethyl ether 12, which underwent acid-catalyzed ring
opening to furnish 13, a representative C-aryl glycoside of Group
I. Alternatively, when 11 was treated with TBAF in THF, only the
bridgehead carbon-silicon bond was cleaved; subsequent Tamao
oxidation furnished the phenol 14.12,13 O-Alkylation of 14 followed
by acid-catalyzed ring opening gave 15 in which each of the
phenolic oxygens is differentiated for subsequent transformations.
We found that O-alkylations of other phenols with bromometh-
ylsilanes such as 8 may be problematic because of competing
nucleophilic attack on silicon.14 We developed a solution to this
a n ) 1, 2; R1, R2 ) H, sugar combinations; Ar ) 2,6-Cl2-4-MeO-C6H2;
R4 ) H, Me.
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J. AM. CHEM. SOC. 2003, 125, 12994-12995
10.1021/ja0375582 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 5a
problem that features use of a tether containing an additional carbon
atom. Thus, 7 was converted into the silyl alcohol 17 by metalation
and reaction with chlorodimethyl-vinylsilane followed by regiose-
lective hydroboration and oxidation (9-BBN, THF; NaOOH)15 of
the intermediate vinylsilane 16 (Scheme 3). Mitsunobu16 coupling
of 17 with 9 then afforded 18. Deprotonation of 18 with t-BuLi
led to the formation of an intermediate benzyne that underwent
cycloaddition to deliver 19. When 19 was treated with TBAF in
DMF at 70 °C, the tether, which resembles a SEM protecting
group,17 was cleaved, and 14 was obtained in 80% yield.
a Reaction conditions: (a) LDA, THF, -78 °C; Me2Si(Cl)CH2Br, 82%;
(b) 9, K2CO3, Bu4NI, Me2CO, 88%; (c) t-BuLi, THF, -90 °C to -10 °C,
61%; (d) Bu4NF, DMF, room temperature; TFA, CH2Cl2, 0 °C to room
temperature, 72%.
Scheme 3a
is the subject of several active investigations in our laboratories,
the results of which will be disclosed in due course.
Acknowledgment. We thank the National Institute of General
Medical Sciences (GM 31077), the Robert A. Welch Foundation,
Pfizer, Inc., and Merck Research Laboratories for their generous
support of this research.
a Reaction conditions: (a) n-BuLi, THF, -78 °C; Me2Si(Cl)CHdCH2,
88%; (b) 9-BBN, THF; H2O2, NaOH, 88%; (c) 9, DIAD, PPh3, THF, 75%;
(d) t-BuLi, THF, -95 °C; warm to -10 °C, 81%; (e) Bu4NF, DMF, 70 °C,
80%.
Note Added after ASAP. In the version posted 10/4/03, there
was an error in the reaction conditions given in Scheme 5. The
version posted 10/9/03 and the print version are correct.
1
Supporting Information Available: Copies of H NMR spectra
of all new compounds and representative experimental procedures for
preparing 13 from 7 and 14 from 16 (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
Having developed an effective regioselective strategy for prepar-
ing Group I C-aryl glycosides, it remained to extend this approach
to representative glycosides of Groups II and III.4 Toward this end,
the known glycosyl furan 203 was converted into 21 by directed
metalation (LDA, THF, -78 °C) and reaction with bromomethyl-
chlorodimethylsilane (Scheme 4). O-Alkylation of phenol 9 with
21 afforded 22. Deprotonation of 22 occurred selectively on the
phenyl ring, and the benzyne that formed upon warming cyclized
to provide cycloadduct 23 in 91% yield as a mixture of diastere-
omers. Cleavage of both carbon-silicon bonds using TBAF in DMF
provided an intermediate dimethyl ether that underwent ring opening
upon exposure to TFA to afford naphthol 24 as a single isomer.
References
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Scheme 4a
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a Reaction conditions: (a) LDA, THF, -78 °C; Me2Si(Cl)CH2Br, 88%;
(b) 9, K2CO3, Bu4NI, Me2CO, 78%; (c) s-BuLi, THF, -95 °C; warm to
-30 °C, 91%; (d) Bu4NF, DMF, room temperature, TFA, CH2Cl2, -5 °C
to room temperature, 71%.
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the anomeric proton was a dd or a d with one large (ax-ax, 11.0-12.0
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A regiochemical controlled entry to Group III C-aryl glycosides
commenced with converting the glycosyl furan 25, which was
prepared as a mixture (ca. 6:1) of epimers as reported previously,3
into the furylsilane 26 by metalation and silylation (Scheme 5).
O-Alkylation of the phenol 9 with 26 produced 27, which was
transformed into a mixture of diastereomeric cycloadducts 28 via
benzyne formation-cycloaddition. Exhaustive cleavage of the
carbon-silicon bonds as before followed by acid-catalyzed ring
opening delivered the naphthol 29 as a single diastereomer.
We have thus demonstrated the utility of silicon tethers to control
the regiochemistry of Diels-Alder cycloadditions of substituted
benzynes and glycosyl furans to provide ready access to unsym-
metrical representatives of the three major groups of C-aryl
glycosides. The application of this novel methodology to the
efficient synthesis of naturally occurring C-aryl glycoside antibiotics
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