Total synthesis of the antiviral glycolipid cycloviracin B1

Article abstract of DOI:10.1021/ja027346p

The first total synthesis of the antiviral agent cycloviracin B1 (1) is described which provisionally establishes the hitherto unknown configuration of the chiral centers on the lateral fatty acid chains as (3R,19S,25R,3′R,17′S,23′R). Key steps en route t

Full text of DOI:10.1021/ja027346p

Published on Web 08/10/2002
Total Synthesis of the Antiviral Glycolipid Cycloviracin B1
Alois Fu¨rstner,* Jacek Mlynarski, and Martin Albert
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/Ruhr, Germany
Received June 18, 2002
Scheme 1
The actinomycete strain Kibdelosporangium albatum so. nov.
(R761-7) isolated from a soil sample collected on Mindanao Island,
the Philippines, was found to produce the complex glycolipid
cycloviracin B1 (1) which exhibits pronounced antiviral activity.1
Extensive spectroscopic investigations established the constitution
of this metabolite, while the absolute stereochemistry of the six
chiral centers along its alkyl chains remained elusive.
As part of a long-term project on bioactive glycolipids,2 we
embarked upon the structure determination and total synthesis of
this remarkable target. Its complexity together with the stereo-
chemical ambiguities mentioned above calls for a highly convergent
and flexible synthesis route. Assuming that the lactide core of 1 is
C2-symmetrical, a two-directional synthesis strategy3 seemed to be
most promising. Given the different length of the lateral chains,
however, this plan bears a considerable risk for the final assembly
stages (Scheme 1). While established methodology should allow
control of the configuration of the -OH group at C-17′ generated
by coupling of fragments A and B, the formation of the C-C-
bond at the symmetry-related C-17/C-18 position joining segments
A and D is highly problematic. Any attempt to convert fragment
D into a carbon nucleophile (Y ) metal) must result in reductive
elimination with loss of the adjacent glycoside; the inverse
manoeuvre implying the conversion of the entire lactide A into a
suitable nucleophile (X ) metal) is similarly endangered by the
presence of electrophilic and C-H acidic sites in this molecule.
More specifically, deprotonation R to the lactones will necessarily
entail the opening of the macrocycle by expulsion of the adjacent
sugar and formation of an R,â-unsaturated ester. Only a highly
stabilized nucleophile X, if any, might kinetically resist these self-
destructive pathways.
Scheme 2 a
Contemplating that the specific array of O-atoms in the core
region of 1 might endow the molecule with some degree of
ionophoric character, a template directed cyclodimerization of the
hydroxyacid 2 was envisaged for the rapid assembly of the
macrodiolide motif. In fact, this key step turned out to be highly
productive if carried out in the presence of admixed potassium
cations.4 Under optimized conditions, the desired lactide 3 is
obtained in 71% isolated yield (Scheme 2). As an additional bonus,
the inherent flexibility of this approach made it possible to prepare
all conceivable stereoisomers without undue preparative efforts.
Comparison of their quite characteristic NMR data with those of 1
allowed us to deduce the absolute stereochemistry at the branching
points as 3R,3′R.4 Routine protecting-group manipulations then led
to the required desymmetrization of the termini (3 f 4 f 5).
Model studies had provided strong evidence that the distal
stereocenters in 1 at C-23′ and C-25 are also likely R-configured.5
Although no stringent conclusions concerning C-19 and C-17′ could
a Conditions: [a] 71%, see ref 4; [b] TBAF, THF, 92%; [c] tBuPh2SiCl,
Et3N, CH2Cl2, 85%.
be gleaned, it seemed reasonable to assume the symmetry-related
S-configuration6 at these sites for biosynthetic reasons. Therefore,
* To whom correspondence should be addressed. E-mail: fuerstner@mpi-
muelheim.mpg.de.
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J. AM. CHEM. SOC. 2002, 124, 10274-10275
10.1021/ja027346p CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3 a
Scheme 4 a
a Conditions: [a] (i) 1-phenyl-5-mercapto-tetrazole, DIAD, PPh3, THF,
91%; (ii) (NH4)6Mo7O24(H2O)7, EtOH/CH2Cl2, 67%; [b] (i) LiHMDS, DME,
-78 °C, then 6, 61%; (ii) H2 (1 atm), Pd/C, EtOAc, 72%; [c] TBAF, THF,
95%; [d] PCC, CH2Cl2, 83%.
a Conditions: [a] Ti(OiPr)4, ligand 12 (cat.), reagent 11 (5 equiv), 81%;
[b] 3,4,6-tri-O-benzyl-2-O-methyl-R-D-glucopyranosyl trichloroacetimidate,8
TMSOTf cat., CH2Cl2/MeCN, 87%; [c] H2 (1 atm), Pd/C, EtOH/EtOAc
(2:1), 88%.
aldehyde 6 was prepared in high overall yield as surrogate of first
choice for the lateral fragment D.8
With this building block in hand, the delicate fragment coupling
A + D was investigated by taking recourse to a Julia-Kocienski
olefination strategy.7 The somewhat higher kinetic acidity together
with the better accessibility of the terminal sulfone in 7 might allow
for selective deprotonation at that site without damaging the more
encumbered lactone moieties; the resulting anion should be suf-
ficiently stabilized to withstand attack on the ester groups. After
some experimentation it was found that the use of LiHMDS in DME
at -78 °C in fact meets these stringent criteria. Specifically, reaction
of the lithio sulfone derived from 7 with aldehyde 6 delivers the
corresponding alkene in 61% yield (E:Z ≈ 1:1) (Scheme 3) which
was hydrogenated over Pd/C in EtOAc to facilitate the analysis of
the NMR spectra. We are unaware of any precedence for Julia-
type olefination reactions involving sulfones bearing such a base-
labile â-hydroxy ester motif.
Standard deprotection of the residual silyl ether in 8 followed
by oxidation of the resulting alcohol 9 with PCC affords the
rather labile aldehyde 10 which readily reacts with the diorgano-
zinc reagent 118 in the presence of a catalyst formed in situ from
Ti(OiPr)4 and the (S,S)-configured bistriflate 12 as the controller
ligand to give alcohol 13 in 81% yield.9 Subsequent â-selective
glucosidation via the trichloroacetimidate method was ensured by
using TMSOTf in CH2Cl2/MeCN as the promotor system.10
Exhaustive debenzylation of product 14 thus formed by hydro-
genolysis over Pd/C cleanly provided cycloviracin B1 (1) (Scheme
4). Not only are all analytical and spectroscopic data in excellent
agreement with those reported in the literature, but the pattern
signature in the 1H NMR spectrum is superimposable to that
depicted in ref 1. This completes the first total synthesis of this
antiviral agent and provisionally establishes the absolute stereo-
chemistry of the chiral centers residing on the fatty acid residues
as (3R,19S,25R,3′R,17′S,23′R).6 Studies aiming at the elucidation
of the pharmacophore of this compound as well as at the synthesis
of related glycolipids will be reported soon.
Acknowledgment. Generous financial support by the DFG
(Leibniz Award to A.F.), the Alexander von Humboldt Foundation
(fellowship for J.M.), and the Fonds der Chemischen Industrie is
gratefully acknowledged.
Supporting Information Available: Full experimental details,
spectroscopic data, and copies of pertinent NMR spectra of compounds
1 and 14 (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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(5) Details will be reported in a forthcoming full paper.
(6) If the fatty acids are drawn in a zigzag conformation, all hydroxyl groups
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are S-configured while the other ones are R-configured simply reflects
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(7) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998,
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(8) For details see the Supporting Information.
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