Synthesis of (-)-viriditoxin: A 6,6′-binaphthopyran-2-one that targets the bacterial cell division protein FtsZ

Article abstract of DOI:10.1002/anie.201007298

(Chemical Equation Presented) Remote control: Vanadium catalysts provide the key to synthesizing the bacteria-fighting natural product viriditoxin. An achiral catalyst shows modest levels of remote diastereocontrol induced by the lactone stereogenic center and chiral catalysts can be used to enhance or reverse this inherent selectivity.

Full text of DOI:10.1002/anie.201007298

Communications
DOI: 10.1002/anie.201007298
Natural Product Synthesis
Synthesis of (À)-Viriditoxin: A 6,6’-Binaphthopyran-2-one that Targets
the Bacterial Cell Division Protein FtsZ**
Young Sam Park, Charles I. Grove, Marcos Gonzꢀlez-Lꢁpez, Sameer Urgaonkar,
James C. Fettinger, and Jared T. Shaw*
The inhibition of bacterial cell division offers a new approach
to controlling resistant bacterial infections.[1,2] FtsZ is a
protein of central importance to cell division that is often
described as the prokaryotic homolog of tubulin because of
the structural similarity of these two proteins, in spite of low
sequence homology.[3–5] Both proteins undergo GTP-driven
oligomerization and the active sites of both proteins are
similar. Tubulin forms microtubules in the bipolar spindle
assembly, which mediates chromosome separation in eukar-
yotes. FtsZ oligomerizes at midcell during bacterial cell
division to form the Z-ring, which constricts to induce
septation. Inhibition of FtsZ has been validated as a potential
new therapeutic strategy for fighting resistant infections,
including methicillin-resistant Staphylococcus aureus
(MRSA).[6–8] In stark contrast to tubulin, few FtsZ-targeting
natural products are known and no information regarding the
molecular basis of their inhibition of FtsZ has been docu-
mented.[9–12] The development of efficient syntheses for FtsZ-
targeting natural products will enable elucidation of their
mechanisms of inhibition and enable further development of
this target. Here, we describe the synthesis of viriditoxin, one
the most potent FtsZ-targeting natural products and the first
6,6’-binaphthopyranone to be synthesized.[13]
Viriditoxin was discovered as an FtsZ inhibitor by
researchers at Merck in a high-throughput biochemical
screen.[14] The 6,6’-binaphthopyranone structure, previously
Scheme 1. A) Structures of viriditoxin, semiviriditoxin, and semi-vioxan-
thin; retrosynthesis of viriditoxin. B) Structures of vioxanthin (6a), an
isolated from Aspergillus viridinutans (Scheme 1) was origi-
nally misassigned as having 8–8’ linkage like that of vioxan-
example of an 8,8’-binaphthopyran-2-one, and cephalochromin (6b),
thin (6a, Scheme 1).[15–17] 6,6’-Binaphthopyran-2-ones are
an example 6,6’-binaphthopyran-4-one.
uncommon natural products and so far only four others
have been reported.[18–20] A small number of the biosynthet-
ically related binaphthopyran-4-ones, such as cephalochromin
(6b, Scheme 1), have also been reported.[21–25] Although the
[*] Dr. Y. S. Park, C. I. Grove, Dr. M. Gonzꢀlez-Lꢁpez, Dr. S. Urgaonkar,
absolute configuration at C3 of semiviriditoxin was recently
confirmed by synthesis,[26] the axial configuration of viridi-
Dr. J. C. Fettinger, Prof. J. T. Shaw
Department of Chemistry, University of California
toxin was not known unequivocally at the outset of our
One Shields Ave, Davis, CA 95616 (USA)
E-mail: shaw@chem.ucdavis.edu
studies.
The key bond construction in viriditoxin is the stereose-
lective formation of the 6–6’ biaryl linkage. Strategies for
[**] This research was supported by start-up funds from the University
of California, Davis, the Petroleum Research Fund (administered by
achieving atropselectivity in the construction of complex
molecules have been recently reviewed.[27,28] Subsequent
recent examples for asymmetric biaryl construction often
employ auxillary- and catalyst-controlled oxidative homo-
coupling[29–31] and cross-coupling reactions.[32–35] In two com-
plementary approaches, atropselectivity can also be realized
by the asymmetric de novo assembly of aromatic rings in
cycloadditions[36–41] and by dynamic kinetic resolution poly-
cyclic lactones through aminolysis[42] or reduction.[43] Most of
these strategies rely on either the influence of chiral catalysts
the ACS), and the NIH/NIAID (R56AI80931-01 & R01AI080931-01).
This work was initiated at the Broad Institute of Harvard and MIT,
where it was supported by the NIH/NIAID (R03 AI062905-01) and
the Scientific Planning and Allocation of Resources Committee
(SPARC). M.G.L. thanks the Fundaciꢁn Ramon Areces for a
postdoctoral fellowship. The authors thank Prof. Jon Clardy
(Harvard Medical School) for helpful discussions, Prof. Dean
Tantillo for DFT calculations, and Dr. Sheo Singh (Merck Research
Laboratories) for providing copies of NMR spectra for viriditoxin.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007298.
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or proximal stereogenic centers in the substrate or covalently
linked chiral auxiliary. We set out to explore the influence of
remote stereogenic centers, that is, those located more than
three bonds from the reacting aromatic carbon center, in the
catalytic oxidative dimerization of naphthols. Two previous
examples of similarly remote influence in the oxidative
dimerization of arylcuprate intermediates have been reported
in studies leading to the synthesis of phleichrome and related
perylenequnione natural products.[44,45]
Several oxidation catalysts have been employed in the
dimerization of naphthols and the vanadium-catalyzed pro-
cess reported by Uang et al. was best suited to the substitution
pattern of 4.[46] Two diastereomeric transition states (A and B,
Scheme 2) could lead to the two possible isomers of biaryl
Scheme 3. Stereoselective assembly of core of viriditoxin. LDA=
lithium diisopropylamide; DMPU=N,N’-Dimethylpropyleneurea;
DDQ=2,3-dichloro-5,6-dicyanobenzoquinone; DMS=dimethylsulfide;
TIPS=triisopropylsilyl; EOM=ethoxymethyl.
process.[55,56] The ethoxymethyl (EOM) ether was readily
cleaved by propylene glycol providing the dimerization
precursor 14.[57] When 14 was treated with 20 mol% of
[VO(acac)2], a rapid reaction ensued, producing a single
regioisomer of desired product 15 with respectable diaster-
eoselection favoring proposed transition state B (Scheme 2).
This is one of the few cases of biaryl bond formation in which
appreciable levels of stereocontrol are induced by a distal
stereogenic center of the substrate without concomitant ring-
formation.[44,45] The stereochemistry of 15 was established
though X-ray crystallography (Figure 1).
In order to enhance the atropselectivity of the biaryl bond
formation, we explored the possibility of double diastereo-
differentiation[58] induced by a chiral vanadium catalyst. Gong
et al. have previously demonstrated that BINOL-derived
bimetallic vanadium catalysts exhibit appreciable levels of
Scheme 2. Remote asymmetric induction in the dimerization of 4.
intermediate 4. Although the mechanism of this reaction is
unclear, several studies suggest that the active catalyst might
be bimetallic,[47] possibly a m-oxo dimer,[48] albeit of undefined
oxidation state and ligation. Under this assumption, the
naphthopyranone rings could be expected to react in an anti-
parallel fashion in which the stereogenic centers of the
pyranone ring would be forced into proximity. This ring
system favors the equatorial conformation (shown), which
forces an interaction between either the axial hydrogen atoms
(A) or the equatorial alkyl substituents (B). These two
transition structures lead to the (M)/(Ra) or (P)/(Sa) isomers
of binaphthopyranone 7, the latter of which leads to the
proposed configuration of viriditoxin.
A suitable tricyclic precursor for viriditoxin was prepared
from orsellinic acid derivative 9 and pyranone 12, each of
which was available in two steps from known compounds
(Scheme 3).[49–52] A Michael addition–Dieckmann condensa-
tion sequence was employed to yield naphthopyranone 13
after subsequent oxidation and methylation. Although this
route is ostensibly less efficient than the Staunton–Weinreb
condensation of the corresponding b-alkoxy pyranone,[17,53,54]
we observed significantly higher yields in the two-step
Figure 1. X-ray crystal structure of 15. Red O, purple Si, gray C.
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Communications
desired isomer of 15 with selectivity that was enhanced to
89:11 (Table 1, entry 5) whereas the catalyst differing only
in the amino acid configuration reversed the selectivity to
12:88 (Table 1, entry 4). The isomeric catalysts derived
from R-BINOL were mismatched and showed the same
sense of induction controlled by the amino acid with lesser
degrees of induction. A similar trend was observed for the
other substrates for which the selectivity of [VO(acac)2]
was modest and the choice of Gong-type catalysts could
produce either isomer as the major product. In addition,
the bimetallic catalysts generally provided higher yields
than [VO(acac)2].
Scheme 4. Chiral vanadium catalysts and variously substituted naphtho-
pyranones for evaluating substrate scope.
The synthesis of viriditoxin was completed in five steps
[Eq. (2); DMP = Dess–Martin periodinane]. The 7 and 7’
hydroxy groups of 15 were methylated with dimethyl sulfate
enantioselectivity in the oxidative dimerization of naph-
thols.[48] We prepared four catalysts derived from R- and
S-BINOL and d- and l-valine (Scheme 4).
Although substrate 14 is central to the goal of preparing
viriditoxin, we wanted to explore the scope of diastereose-
lectivity enabled by this new remotely induced axial chirality.
Pyranones 17–19, prepared in three steps from the requisite
chiral epoxides, were converted to naphthopyranones 20–22
in analogy to 14 (Scheme 4).
The chiral bimetallic vanadium catalysts exhibited supe-
rior diastereoselectivity and reactivity [Eq. (1), Table 1].
Naphthopyranone 14 was treated with all four isomers of
Gong-type catalyst 16 and showed pairwise matched and
mismatched selectivity. Specifically, (Sa,R)-16 produced the
followed by removal of the TIPS protecting groups. The
resultant diol was oxidized to the corresponding diacid and
converted to the requisite diester in 57% overall yield. The
9,9’-isopropyl and 10,10’-methyl ethers were cleaved readily
with BCl3 to yield (À)-viriditoxin. The synthetic material
exhibited NMR spectra (1H and 13C) that compared favorably
with reported values.[59] Synthetic viriditoxin was thus pro-
duced in a longest linear sequence of 12 steps from the alkene
precursor of 10.[60]
In conclusion, we have described the first synthesis of a
6,6’-binaphthopyranone natural product and, in so doing,
established the relative configuration of viriditoxin. This
synthesis represents a general route to related natural
products[18,20] and it will enable the exploration of the
interactions that result in inhibition of the bacterial cell
division protein FtsZ.
Table 1: Double diastereodifferentiating oxidative couplings with chiral
bimetallic vanadium catalysts.
Entry
Substrate, R
Product
Catalyst
d.r. (yield)
1
2
3
4
5
6
7
8
14, (CH2)2OTIPS
14
14
14
14
20, CH3
20
20
21, CH2OTIPS
21
21
22, c-C6H11
22
22
15
15
15
15
15
23
23
23
24
24
24
25
25
25
[VO(acac)2]
(Ra,S)-16
(Ra,R)-16
(Sa,S)-16
(Sa,R)-16
[VO(acac)2]
(Sa,R)-16
(Sa,S)-16
[VO(acac)2]
(Sa,R)-16
(Sa,S)-16
[VO(acac)2]
(Sa,R)-16
(Sa,S)-16
76:24 (67%)
19:81
82:18
Received: November 19, 2010
Published online: March 16, 2011
12:88
89:11 (87%)
60:40 (90%)
90:10 (85%)
18:82 (57%)
61:39 (68%)
96:4 (84%)
30:70 (76%)
56:44 (78%)
83:17 (67%)
11:89 (74%)
Keywords: biaryls · enantioselective catalysis ·
.
natural product synthesis · vanadium catalysis · viriditoxin
9
10
11
12
13
14
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