Stereoselective total syntheses of herbicidin C and aureonuclemycin through late-stage glycosylation

Article abstract of DOI:10.1002/anie.201201826

Better late than never! Two herbicidins, members of an important family of nucleoside antibiotics, have been synthesized for the first time. The route integrates a stereoselective C-glycosylation with several reagent-controlled stereoselective transformations and a surprisingly facile and highly diastereoselective late-stage N-glycosylation. Copyright

Full text of DOI:10.1002/anie.201201826

Angewandte
Chemie
DOI: 10.1002/anie.201201826
Natural Product Synthesis
Stereoselective Total Syntheses of Herbicidin C and Aureonuclemycin
through Late-Stage Glycosylation
Dominik Hager, Peter Mayer, Christian Paulitz, Jçrg Tiebes, and Dirk Trauner*
Nucleosides and their phosphates are involved in innumer-
able biochemical pathways, serving, for example, as building
blocks for nucleic acids or as enzymatic cofactors. As such, it
is not surprising that secondary metabolites have evolved that
interfere with their elementary role in life. Many of these are
nucleosides themselves that retain the canonical nucleobases,
but feature more sophisticated carbohydrate residues than
ribose. An important subclass are the so-called undecose
nucleoside antibiotics, which include the herbicidins,[1] repre-
sented by herbicidin A (1), B (2), C (3), and aureonuclemycin
(4),[2] as well as the tunicamycins (5)[3] and hikizimycin (6)[4]
(Figure 1). All of these natural products contain a linear chain
of 11 carbon atoms that can be incorporated in a variety of
heterocyclic ring systems.
The herbicidins were isolated from different strains of
Streptomyces and exhibit several interesting biological activi-
ties.[1a–d,g,2,5] For example, herbicidins A (1) and B (2) are
efficient inhibitors of Xanthomas oryzae, a bacterium that
causes leaf blight infection in rice crops. Furthermore,
reduced seed germination and diminished algal growth, as
well as selective toxicity towards dicotyledonous plants, but
no toxicity against animals, was observed.[1a,b]
Structurally, the herbicidins also show a number of
intriguing characteristics. Their common undecose sugar
Figure 1. Congeners of undecose nucleoside antibiotics.
moiety comprises a linear carbon chain that is folded into
a tricyclic furano-pyrano-pyran skeleton, which includes nine
stereogenic centers. Adenine, as the nucleobase, resides in
a sterically congested concave position. In addition, the
hemiketal at C-7 fuses the pyrano-pyran system in such a way
that all of its substituents adopt axial orientations. Their
individual members differ from each other through various
methylation and esterification patterns.
As a consequence of their structural beauty and potent
biological activities, the undecose nucleoside antibiotics have
attracted much attention from the synthetic community.[6]
However, despite considerable efforts, only one total syn-
thesis of a herbicidin, namely herbicidin B (2) has been
reported to date.[6l] The synthesis started with adenosine, with
the purine base carried through the whole pathway. All other
published approaches to the herbicidins opted for introduc-
tion of the nucleobase at a late stage, but have not yet reached
their intended target.[6a–k,m] We now report a total synthesis of
herbicidin C (3) and its hydrolysis product aureonuclemycin
(4) which is based on a late-stage glycosylation strategy and
marked by a high degree of stereoselectivity.
Our retrosynthetic analysis of herbicidin C (3) is shown in
Scheme 1. We reasoned that the challenging late-stage
glycosylation could be stereochemically controlled by a neigh-
boring benzoate at C-2, thereby yielding hemiacetal 7 as
a logical precursor. This intermediate, in turn, could be traced
back to C-glycoside 8, wherein C-7 and C-11 already possess
the correct oxidation state. Further retrosynthetic simplifica-
tion of the side chain would give ester 9, which could be
ultimately derived from glucose (10).
[*] D. Hager, P. Mayer, Prof. Dr. D. Trauner
Department of Chemistry, Ludwig-Maximilians-Universitꢀt Mꢁnchen
and Center of Integrated Protein Science
81377 Munich (Germany)
E-mail: dirk.trauner@lmu.de
In the forward direction, glucose (10) was converted into
the protected anhydro sugar 11, by combining a practical,
large-scale synthesis for 1,6-anhydrohexopyranoses with
a standard benzylation protocol (Scheme 2).[7] Reaction of
compound 11 with allyltrimethylsilane in the presence of
a Lewis acid gave the known C-glycoside 12.[7b,8] This
compound could be selectively debenzylated through a two-
step protocol involving formation of the iodo ether (!13)
C. Paulitz
Bayer CropScience AG Research
Alfred-Nobel-Strasse 50, 40789 Monheim (Germany)
J. Tiebes
Bayer CropScience AG Research, Industriepark Hçchst
Gebꢀude G836, 65926 Frankfurt am Main (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201826.
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Installation of the next stereocenter (C-2 in herbicidin)
proved to be more challenging than anticipated. Reduction of
the carbonyl group in 18 with stoichiometric amounts of the
R-configured Corey–Bakshi–Shibata (CBS) reagent (R)-19
gave a 4.4:1 mixture of separable diastereomers 20 and 21
(Scheme 3). Unfortunately, we eventually established that the
undesired diastereomer 20 was formed as the major product
Scheme 1. Retrosynthetic analysis for herbicidin C (3). Bz=benzoyl,
Bn=benzyl, TBS=tert-butyldimethylsilyl.
Scheme 3. Synthesis of an undesired diastereomer 20 and establish-
ment of the tricyclic core 26. TBAF=tetrabutylammonium fluoride,
TEMPO=2,2,6,6-tetramethylpiperidine 1-oxyl, DAIB=(diacetoxyiodo)-
benzene, DMP=Dess–Martin periodinane, TFA=trifluoroacetic acid,
DMAP=dimethylaminopyridine; Tf=trifluoromethanesulfonyl.
under these conditions (see below). This result was unex-
pected since the generally accepted transition-state model[11]
with the (R)-CBS-Me reagent predicts the opposite config-
uration of alcohol 20.
Scheme 2. Synthesis of vinyl ketone 18. TMS=trimethylsilyl, im=
imidazole, CSA=camphorsulfonic acid, CDI=N,N’-carbonyldiimide,
Tf =trifluoromethanesulfonyl.
The structure of the major isomer 20 could only be
established after further synthetic transformations, which also
served as a training ground for our eventually successful
synthesis. Benzoylation of alcohol 20 followed by removal of
the silyl groups afforded diol 22. This compound was
subjected to a variety of oxidation conditions, most of which
gave intractable mixtures with little or no desired product.
Only oxidation with TEMPO and diacetoxyiodobenzene in
the presence of water proved efficient. Notably, under these
conditions, only the primary hydroxy group was oxidized to
the corresponding carboxylic acid, whilst the secondary
alcohol remained untouched. Ester formation with (trime-
thylsilyl)diazomethane followed by oxidation of the secon-
dary alcohol with Dess–Martin periodinane (DMP) then
provided ketone 23. Cleavage of the acetonide with trifluoro-
acetic acid provided a mixture of isomeric hemiacetals. The
X-ray structure[12] of the major isomer, compound 24, which
confirmed the undesired configuration at C-2, is shown in
and subsequent reductive elimination to yield diol 14.[9]
Subsequent protection then yielded the twofold silyl ether
15. Notably, this opening sequence not only installs the C-6
stereocenter (herbicidin numbering) with the correct absolute
configuration but also differentiates the two desired positions
toward eventual adjustment of the oxidation states.
Next, the allyl side chain of intermediate 15 was elongated
through a Grubbs cross-metathesis with methyl acrylate,
which gave the unsaturated ester 9 in excellent yield.[10]
A
highly diastereoselective Sharpless dihydroxylation and sub-
sequent acetonide formation installed two additional stereo-
centers to yield methyl ester 16. Saponification and formation
of the corresponding Weinreb amide 17, followed by reaction
with vinylmagnesium bromide then provided vinyl ketone 18,
wherein the double bond is intended to later serve as
a carbonyl equivalent.
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Figure 2. Following ozonolysis and acetylation of 24, we
isolated undecose 25, which features the furano-pyrano-pyran
framework of herbicidin C (3). Selective acetylation of the
more-accessible hemiacetal then yielded undecose 26 as
single diastereomer in 72% yield over three steps.
be reduced to catalytic quantities (10 mol%) whilst keeping
the d.r. value at 14:1.
With our stereochemical problem surmounted, we could
proceed with the total synthesis (Scheme 4). First, a benzoyl
group was installed at C-2 to assist the late-stage glycosyla-
tion. Subsequent deprotection with TBAF yielded diol 27,
which was converted into ketoester 8 by using the previously
established oxidation/esterification sequence. Reiteration of
our cyclization conditions (TFA, O3, Ac2O) provided unde-
cose 28 as a mixture of diastereomers in 72% yield over three
steps. Since debenzylation was found to be impossible at the
end of the synthesis, the two remaining benzyl protecting
groups in 28 had to be swapped for acetyl groups at this stage,
which yielded tricyclic intermediate 29.
With compound 29 in hand, we proceeded to investigate
the crucial late-stage glycosylation. Much to our satisfaction,
this proved to be possible by using a modification of the
Hilbert–Johnson–Vorbrꢀggen protocol.[13] Under these con-
ditions, glycoside 30 was isolated in 55% yield as a single
diastereomer. The correct stereo- and regiochemical outcome
of the glycosylation was confirmed by NMR spectroscopy and
ultimately proven by our successful total synthesis. This was
achieved by global deprotection under Zemplꢁn conditions,
which gave herbicidin C (3) as a colorless solid. The identity
of our synthetic material was confirmed by detailed spectro-
scopic studies, including NMR titration with an authentic
sample of the natural product (see Supporting Information).
Saponification of the base-labile herbicidin C (3) under mild
conditions yielded aureonuclemycin (4), the third member of
the herbicidin class accessible by total synthesis.
Figure 2. X-ray structure of hemiacetal 24.
To correct the stereochemistry at C-2 we revisited the
diastereoselective reduction of ketone 18 (Scheme 4). Simple
reduction with BH3·SMe2 gave a 1.4:1 mixture of diastereo-
mers in favor of the desired diastereomer 21. However, use of
the S-configured CBS-Me enantiomer (S)-19, again in stoi-
chiometric amounts, provided the desired alcohol 21 in d.r=
14:1. These results suggest a matched case of substrate 18 and
the (S)-CBS-Me reagent. Notably, the amount of (S)-19 could
In summary, we have achieved the first total synthesis of
two complex undecose nucleoside antibiotics, namely herbi-
cidin C (3) and aureonuclemycin (4). Our route integrates
a stereoselective C-glycosylation with several reagent-con-
trolled stereoselective transformations and a surprisingly
facile and highly diastereoselective late-stage N-glycosyla-
tion. Our synthetic strategy could give rise to several other
members of the class. Investigations in this regard are well
underway and will be reported in due course.
Received: March 7, 2012
Published online: May 29, 2012
Keywords: antibiotics · glycosylation · nucleosides ·
.
stereoselective synthesis · total synthesis
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[12] 24: C34H36O10, Mr = 604.644 gmolꢀ1, colorless rod, 0.38 ꢂ 0.14 ꢂ
0.12 mm3, tetragonal, P43, a = 13.3203(3), b = 13.3203(3), c =
18.4658(3) ꢃ, a = 90, b = 90, g = 908, V= 3276.39(11) ꢃ3, Z = 4,
1 = 1.22580(4) gcmꢀ3, m(MoKa) = 0.090 mmꢀ1, MoKa radiation
(l = 0.71073 ꢃ), T= 173(2) K, 2qmax 50.648, 20777 reflections,
5911 independent, 4680 with I ꢁ 2s(I), Rint = 0.0395, mean s(I)/
I = 0.0338, 360 parameters, R(Fobs) = 0.0606, Rw(F2) = 0.1727, S =
1.021, min./max. residual electron density: ꢀ0.205/0.309 eꢃꢀ3
;
data collection by means of a Nonius KappaCCD diffractometer
equipped with a rotating anode generator (f and w scans),
structure solution by direct methods with SIR97, structure
refinement with SHELXL-97, disorder of the phenyl rings and
ethyl groups has been handled by split models; crystallographic
data (excluding structure factors) for the structure reported in
this paper have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication no.
CCDC 859056 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
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6528
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