General entries to C-aryl glycosides. Formal synthesis of galtamycinone

Article abstract of DOI:10.1016/S0040-4039(02)02666-7

Utilizing a general entry we had developed for the synthesis of C-aryl glycosides, we have prepared the juglone derivatives 18-20 as well as the juglone precursor 13. Because 19 had been previously converted in two steps by Suzuki into galtamycinone (1), its preparation constitutes a total synthesis of 1.

Full text of DOI:10.1016/S0040-4039(02)02666-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1075–1077
General entries to C-aryl glycosides. Formal synthesis of
galtamycinone
Beth Apsel, John A. Bender, Maya Escobar, David E. Kaelin, Jr., Omar D. Lopez and
Stephen F. Martin*
Department of Chemistry and Biochemistry, The University of Texas, Austin, TX 78712, USA
Received 10 August 2002; revised 23 November 2002; accepted 25 November 2002
Abstract—Utilizing a general entry we had developed for the synthesis of C-aryl glycosides, we have prepared the juglone
derivatives 18–20 as well as the juglone precursor 13. Because 19 had been previously converted in two steps by Suzuki into
galtamycinone (1), its preparation constitutes a total synthesis of 1. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
verted a juglone related to 4 into 1 using the Tamura
protocol to annelate the requisite naphthalene sub-
unit.4,5a While our primary focus was upon applying
our methodology to the syntheses of C-glycosylated
juglones 4 via combinations of 5 and 6 or 7 and 8, we
were also intrigued by the possibility of developing a
different annelation strategy for the end-game of the
synthesis. In particular, we wondered whether juglones
such as 4 might undergo regioselective Diels–Alder
The C-aryl glycoside antibiotics comprise a subclass of
the family of naturally occurring C-glycosides that have
gained considerable attention because of their range of
biological activities and their resistance to enzymatic
hydrolysis.1 Consequent to this interest, a number of
methods have been developed for their synthesis,2 and
we recently unveiled a unified approach that may be
applied to the preparation of each of the four common
structural types of C-aryl glycosides.3 Toward estab-
lishing these methods in the context of total synthesis,
we became interested in galtamycinone (1),4 a member
of the angucycline family of C-aryl glycosides. Gal-
tamycinone posed a challenge not only with respect to
C-aryl glycoside synthesis but also for the efficient
assembly of the linear tetracyclic framework repre-
sented by its aglycone SS-228R (2),5 which is also a
natural product.
In developing our approach to 1 (Scheme 1), we were
influenced by the prior art. Namely, Suzuki had con-
Keywords: C-aryl glycosides; Diels–Alder reaction; palladium-cata-
lyzed ring openings.
* Corresponding author. Tel.: +1-512-471-3915; fax: +1-512-471-4180;
e-mail: sfmartin@mail.utexas.edu
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02666-7

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B. Apsel et al. / Tetrahedron Letters 44 (2003) 1075–1077
cycloadditions with isobenzofurans like 3 to form the
requisite tetracyclic framework of 1. We now report
some of the results of these investigations.
2. Results and discussion
In our first entry to a potential precursor of a juglone
of general type 4,
D
-olivose glycal (9)6 was converted
into the protected iodo glycal 10 according to the
protocol of Friesen (Scheme 2).7 The Pd-catalyzed
opening of 11 with 10 then furnished 12,8 which was
transformed into the desired C-aryl glycoside 13 in 50%
overall yield from 10 by sequential oxidation of the
dihydronaphthol moiety and stereoselective reduction
of the glycal.3,9
Scheme 3.
into galtamycinone by Suzuki,4 its preparation consti-
tutes a formal synthesis of 1.
Scheme 2.
With the successful application of our methodology for
preparing C-aryl glycosides to the formal synthesis of 1,
a major goal had been achieved. However, we wanted
to explore the annelation strategy depicted in Scheme 1
to see if a more concise route to the tetracyclic aromatic
core of 1 might be developed. The central question was
whether glycosylated juglones as 18–20 would undergo
a regioselective Diels–Alder reaction with an isobenzo-
furan related to 3.
One may easily envision ways of transforming 13 into a
juglone derivative related to 4 that could be elaborated
into galtamycinone by straightforward modifications of
the prior art of Suzuki.4 However, we opted instead to
prepare the corresponding dibenzyl ether as this inter-
mediate would bear protecting groups identical to those
previously reported. In this way, we would also be able
to highlight the effectiveness of an alternative entry to
juglones like 4 that features our benzyne–glycosyl furan
Diels–Alder approach to C-aryl glycosides.3
In order to address this question, we conducted an
exploratory study in which 18 was allowed to react with
the isobenzofuran 23, which was generated in situ by
dehydration of 22. Unfortunately this reaction gave an
uncharacterized mixture of regio- and stereoisomeric
products of general structures 24a,b (Scheme 4). The
composition of this mixture was simplified by treating
24a,b with N-chlorosuccinimide (NCS) in the presence
of NaH to introduce a double bond and form the
central quinone ring in 25a,b. Reaction of 23 with the
bromojuglone derivative 20 also gave a mixture of
25a,b, albeit in lower overall yield. The TMS–OTf
induced opening of the oxabicyclic rings in 25a,b was
directed by the proximal benzyloxy group to give a
separable mixture (ca 1.1:1) of the regioisomers 26 and
27. The C-aryl glycoside 26 thus obtained exhibited
spectral properties consistent with those reported by
Suzuki for the penultimate intermediate in his synthesis
of galtamycinone (1).4
In the event, the lactone 14, which was prepared by the
same procedure reported for its enantiomer,10 was first
converted into the furyl glycoside 15 (Scheme 3). The
subsequent reaction of 15 with the benzyne generated in
situ from 2-chloro-1,4-dimethoxybenzene furnished a
mixture of the diastereomeric Diels–Alder adducts 16.
These compounds were not separated because they
converged to the desired C-aryl glycoside 17 (74%
overall yield from 15) upon acid-catalyzed rearrange-
ment. O-Methylation of 17 followed by selective oxida-
tion of the dimethyl hydroquinone ring gave the
juglone 18. Sequential chlorination–dehydrochlorina-
tion of 18 proceeded with essentially complete regiose-
lectivity to give chlorojuglone 19 in 93% yield.11
Bromination–dehydrobromination (Br2, CHCl3, 0°C;
EtOH, AcOH, reflux; 61%) of 18 similarly gave 20.
Because 19 had been efficiently converted in two steps

B. Apsel et al. / Tetrahedron Letters 44 (2003) 1075–1077
1077
and Merck Research Laboratories for their generous
support of this research.
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Acknowledgements
We thank the National Institutes of Health (GM
31077), the Robert A. Welch Foundation, Pfizer, Inc.,