Second-generation synthesis of (-)-viriditoxin

Article abstract of DOI:10.1055/s-0031-1289651

Viriditoxin is a secondary metabolite isolated from Aspergillus viridinutans that has been shown to inhibit FtsZ, the bacterial homologue of eukaryotic tubulin. A streamlined, scalable, and highly diastereoselective synthesis of this complex natural product is described. Key advances include a more efficient synthesis of the requisite unsaturated pyranone, scalable assembly of the naphthopyranone monomer, and improved diastereoselectivity in the biaryl-coupling reaction. In addition, we disclose a serendipitous ruthenium-catalyzed anion dimerization resulting from trace metal left by an RCM reaction. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1289651

362
FEATURE ARTICLE
Second-Generation Synthesis of (–)-Viriditoxin
S
econd-Generatio
h
n Synthesis
aof (–)-Viri
r
Department of Chemistry, University of California, One Shields Ave, Davis, CA 95616, USA
E-mail: jtshaw@ucdavis.edu
Received 8 November 2011
bacteria. Importantly, it is not cytotoxic to either yeast or
human cells, suggesting that it has some level of target
specificity. We initiated a project to synthesize viriditoxin
so that we could study its interactions with FtsZ in detail
Abstract: Viriditoxin is a secondary metabolite isolated from
Aspergillus viridinutans that has been shown to inhibit FtsZ, the
bacterial homologue of eukaryotic tubulin. A streamlined, scalable,
and highly diastereoselective synthesis of this complex natural
product is described. Key advances include a more efficient synthe- and eventually identify the molecular interactions be-
sis of the requisite unsaturated pyranone, scalable assembly of the
tween this compound and FtsZ. Although the mammalian
naphthopyranone monomer, and improved diastereoselectivity in
toxicity of this compound limits the extent to which it
the biaryl-coupling reaction. In addition, we disclose a serendipi-
might be a starting point for drug discovery,7 detailed
tous ruthenium-catalyzed anion dimerization resulting from trace
structural knowledge of how viriditoxin interacts with
metal left by an RCM reaction.
FtsZ would serve as a starting point for exploiting this
Key words: natural products, asymmetric synthesis, antibiotics,
protein as a target for new antibiotics.
atropisomerism, biaryls
OH OR2
O
6,6'-binaphtho-
pyran-2-ones:
O
O
Introduction
OR1
OR1
MeO
MeO
The synthesis of natural products as a starting point for
achieving a better understanding of their ability to modu-
late biological processes is an important goal for the dis-
covery of new medicines. Among current health
challenges, the ability of pathogenic bacteria to evade the
activity of current antibiotics has prompted a need for new
chemotypes and new protein targets in prokaryotes. Al-
though there has been some progress in finding new drugs
to inactivate established targets, there is a parallel effort to
find new targets that are susceptible to modulation by
small molecules. Bacterial cell division is modulated by a
group of proteins for which inhibitors could represent
starting points for drug discovery.1 The central cell divi-
sion protein, FtsZ, is a homologue of eukaryotic tubulin
that plays a similarly critical role in the cytokinesis of bac-
terial cells.2 This protein was first characterized in 1992 as
a tubulin-like GTPase3 and in the ensuing decades, several
inhibitors have been discovered from natural and synthet-
ic sources.3d Our group has developed a research program
around the synthesis and study of natural products that in-
hibit bacterial cell division by targeting FtsZ with the long
term goal of elucidating the molecular basis of inhibition.
O
O
OH OR2
1, viriditoxin, (R1 = Me, R2 = H)
2, asteromine, (R1 = H, R2 = Me)
O
OH OH
O OH OH
O
O
O
O
MeO
MeO
HO
HO
n-Pr
n-Pr
(Sa)
(Ra)
O
OH OH
3, pigmentosin A
O
OH OH
4, talaroderxine A
O
OH OH
O
HO
HO
O
O
(Sa)
OH OH
O
Viriditoxin is a polyketide natural product first isolated at
the Northern Regional Research Laboratory (NRRL,
Peoria, IL, USA)4,5 and subsequently discovered to inhibit
the function of FtsZ by researchers at Merck conducting a
high-throughput screen of natural product extracts.6 This
compound inhibited the GTPase activity of FtsZ in vitro
and also exhibited broad activity against Gram-positive
5, cephalochromin (6,6'-binaphthopyran-4-one)
6'
OMe
OH OH
O
O
8
8'
O
O
OH OH
MeO
6
6, vioxanthin (8,8'-binaphthopyran-2-one)
SYNTHESIS 2012, 44, 362–371
Advanced online publication: 16.01.2012
DOI: 10.1055/s-0031-1289651; Art ID: Z105311SS
x
x
.x
x
.2
0
1
1
Figure 1 Structures of dimeric condensed polyketide natural pro-
ducts
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Second-Generation Synthesis of (–)-Viriditoxin
363
Viriditoxin (1) is a 6,6¢-binaphthopyran-2-one that probably stereoselective construction of biaryl linkage, the efficient
arises from a biogenic oxidative dimerization (Figure 1). preparation of the dimerization precursors is of equal im-
The few known related 6,6¢-binaphthopyran-2-ones in- portance to the overall synthetic efficiency. We recently
clude the isomeric diacid asteromine (2)8 as well as the completed a stereoselective synthesis of (–)-viriditoxin
methyl and propyl analogues pigmentosin A (3)9 and that confirmed its configuration and demonstrated the ef-
talaroderxine A (4).10 All have the same relative stereo- ficacy of vanadium-catalyzed phenolic coupling for en-
chemical relationship between the axial chirality of the hancing or reversing remote diastereoselection in this
biaryl linkage and the substituent of the pyranone ring. reaction.15 Although this synthesis answered many impor-
The lone exception to this trend is talaroderxine B (not tant questions and has enabled subsequent biological in-
shown), which is the axial isomer of talaroderxine A and vestigations, we have explored several strategies for
is isolated from the same organism. In addition to the improving efficiency and scalability. Herein we describe
6,6¢-binaphthopyran-2-ones, related natural products aris- studies that culminated in a ‘second-generation’ synthesis
ing from the dimerization of condensed polyketides in- of (–)-viriditoxin with significant improvements to the
clude 8,8¢-binaphthopyran-2-ones (e.g. 6, vioxanthin11) substrate preparation, manipulation of protecting groups,
and 6,6¢-binaphthopyran-4-ones such as cephalochromin and selectivity in the biaryl-coupling reaction.
(5).12 Given the ease with which polyhydroxylated aro-
matic rings can undergo oxidative dimerization, many re-
lated dimeric and oligomeric natural products have been
Retrosynthetic Analysis of Viriditoxin
isolated, usually from fungi.13
Two basic strategies were considered for constructing the
biaryl core of viriditoxin. One approach is to use simpli-
fied phenyl precursors in an early state biaryl coupling
and then construct the polycyclic systems in a bi-direc-
tional synthesis. This pathway was used to prepare
vioxanthin16 and, more recently, to assemble a simplified
model system representing the core of hibarimicin.17 In
At the outset of our studies, there had been no previous
syntheses of 6,6¢-binaphthopyranones. The assembly of
axially chiral natural products has been a long-standing
challenge in organic synthesis for which many elegant ap-
proaches have been developed.14 Although the focus of
many synthetic efforts centers on the construction of the
Biographical Sketches
Charles I. Grove Charles ate research at UC Davis is methods. Charles has re-
received his Bachelor of focused on the synthesis of ceived fellowship support
Science in chemistry from 6,6¢-binapthapyranone natu- from the NSF (AGEP sum-
California State University, ral products and the devel- mer fellowship) and the
Fresno in 2008. His gradu- opment of new synthetic Alfred P. Sloan Foundation.
James C. Fettinger Dr. Fet- with James A. Ibers, Dr. try department at the Uni-
tinger obtained his Ph.D. Fettinger held positions at versity
of
Maryland
with Melvyn Rowen CIBA-Geigy (Basel, Swit- (College Park, MD, 1993–
Churchill from the State zerland, 1988–1992), the 2004) before joining the de-
University of New York at University of Massachusetts partment of Chemistry at
Buffalo, 1987. After a post- Medical Center (Worcester, UC Davis as departmental
doctoral
fellowship
at MA, 1992–1993), and the crystallographer in 2004.
Northwestern
University Chemistry and Biochemis-
Jared T. Shaw Prof. Jared independent career in 2002 Harvard and MIT in 2005.
T. Shaw earned his Ph.D. as an institute fellow at the In July of 2007, Jared joined
under the training of Keith Institute for Chemistry and the faculty of UC Davis
Woerpel at UC Irvine in Cell Biology (ICCB) at Har- where his research interests
1999. He then moved to vard Medical School, which focus on the development of
Harvard as an NIH postdoc- merged with several other new synthetic methods, the
toral fellow with David research organizations to synthesis of natural prod-
Evans. Prof. Shaw began his form the Broad Institute of ucts, and chemical biology.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 362–371

364
C. I. Grove et al.
FEATURE ARTICLE
both cases, key steps involving condensation reactions to sequence [Scheme 1 (B)]. The requisite aldehyde was pre-
build polycyclic ring systems were modest-yielding. A pared with high enantioselectivity using an asymmetric
second approach would involve construction of the con- allylation reaction employing allyltributyltin. Although
densed polycyclic monomers followed by late-stage biar- this was adequate for our first-generation synthesis, we
yl coupling. This strategy has been successful in the sought a route that would be more easily scaled and re-
syntheses of perylenequinone natural products18 and ni- quire fewer air-sensitive steps. As a result, we turned to
gerone,19 which employ oxidative coupling of organome- ring-closing metathesis (RCM) for pyranone formation
tallic intermediates and phenols, respectively. We favored and replaced the allylation reaction with the opening of an
the latter strategy from the outset with the hope that instal- epoxide derived from L-aspartic acid. This feature article
lation of the axial chirality could be executed efficiently details our development of a second-generation synthesis
and with high diastereoselectivity. We first investigated of (–)-viriditoxin in which nearly every step has been re-
dimerization of organometallic intermediates using both placed and improved with respect to scalability and yield.
catalytic cross-coupling or oxidative homocoupling reac-
tions with limited success. The advantage for this ap-
proach stems from installing a methyl group for P2 which Synthesis of the Pyranone Substrate for the Michael–
is part of the final target structure. In the end, a phenolic Dieckmann Reaction
coupling was successful, necessitating a protecting group
(P2) that was orthogonal to two additional phenolic pro- One major goal for the second-generation synthesis of
tecting groups (P3 and P4) as well as the protecting group viriditoxin was to replace the use of allyltributyltin at the
on the primary alcohol (P1).
beginning of the synthesis [Scheme 2 (A)]. Although the
allylation of aldehyde 14 proceeded with excellent enan-
tioselectivity and acceptable yield, the toxicity of the al-
lyltin reagent made scaleup of this reaction undesirable.
An attractive alternative involved the opening of epoxide
15 in which the primary alcohol is protected with either a
triisopropylsilyl (TIPS) or tert-butyldiphenylsilyl
(TBDPS) group [Scheme 2 (B)]. The reason for the change
from TIPS, which was adequate for the first-generation
synthesis, to TBDPS is described later (vide infra). Based
on the work of Volkmann,20 aspartic acid was converted
into the diazonium salt and displaced with bromide in a
Assembly of the tricyclic precursor 7 is achieved through
a condensation reaction between a protected orsellinate
ester 8 and a suitable unsaturated carbonyl compound 9
[Scheme 1 (A)]. The condensation reaction itself can be
executed in either a one-step (Staunton–Weinreb) trans-
formation or Michael–Dieckmann reaction followed by
oxidation to the corresponding naphthol. Both manifolds
were investigated and ultimately the latter proved to be
more efficient. The Michael–Dieckmann pathway neces-
sitated an efficient synthesis of pyranone 9, which was ini-
tially realized by an aldol addition and cyclization
A
OH OH
O
P3O P4O
O
O
O
O
P3O
O
O
OMe
OMe
MeO
MeO
O
OMe
O
OP1
P2O
OP1
P2O
Y
7
8
9
O
X
P2 = OMe, X = halogen: dimerization of organo-
Y = OMe: Staunton–Weinreb
condensation
OH OH
O
metallic intermediate
P2 = X = H: phenolic coupling,
Y = H: Michael–Dieckmann reaction;
oxidation
1, (–)-viriditoxin
P
1 & P2 orthogonal
B
first generation
• problematic deprotection of TIPS (P1)
• large-scale tin-based allylation
OLi
O
OAc
+
O
OP1
O
Bu3Sn
MeO
H
OP1
H
OH
10
11
14
O
OP1
O
OP1
13
9
O
MgBr
OP1
NH2
second generation
O
CO2H
OP1
• acid-stableTBDPS (P1)
• chiral pool starting material
HO2C
12
L-Asp
15
• all reactions easily scaled up
Scheme 1 Retrosynthetic analysis of viriditoxin: (A) oxidative dimerization and assembly of naphthopyranone 7; (B) first- and second-
generation assembly of pyranone 9
Synthesis 2012, 44, 362–371
© Thieme Stuttgart · New York

FEATURE ARTICLE
Second-Generation Synthesis of (–)-Viriditoxin
365
stereospecific process with double inversion. This reac- (Scheme 3C). Although the analogous reaction to produce
tion was easily conducted on large (79 g) scale. The re- 20b from 9b eventually worked in acceptable yield on
sultant diacid was then reduced to diol 16 and large scale (53%), the success of this step was dependent
subsequently, in one pot, treated with base to form the ep- on the source of the pyranone starting material.
oxide and alkoxide anion that was trapped with a silyl
chloride. Epoxides 15a21 and 15b22 were treated with vi-
nylmagnesium chloride to form the homoallylic alcohols
13a and 13b that were then acylated with acryloyl chlo-
ride to 12a23 and 12b,24 respectively. Ring closing meta-
thesis of dienes 12a and 12b with second-generation
Grubbs catalyst proceeded smoothly to give pyranones 9a
and 9b in high yields. In early studies, using progenitors
to the G2 catalyst, we had attempted a similar ring closure
and observed little or no conversion, which led us to ini-
tially avoid this route. In summary, pyranones 9a and 9b
were made in a comparable number of transformations
with improved overall yield of 26% and 49%, respective-
ly. Importantly, this route can be safely and easily execut-
ed on multigram scale.
Bu3Sn
O
A
B
O
3 steps
(reference 14)
O
OTIPS
H
OTIPS
14 (two steps from
propylene glycol)
9a, 38% overall yield
(5 steps)
1) NaNO2, KBr
H2SO4; 82%
79 gram scale
NH2
Br
CO2H
HO
OH
16
2) BH3•DMS, THF
0 °C; 100%
HO2C
L-Asp
OH
NaH;
R3SiCl
MgBr
O
OP1
OP1
15a, P1 = TIPS; 87%
15b, P1 = TBDPS; 80%
CuI (17 mol%)
13a, P1 = TIPS; 57%
13b, P1 = TBDPS; 85%
O
Et3N,
THF
Scheme 3 (A) Optimization of Michael–Dieckmann reaction by re-
moval of trace ruthenium; (B) oxidative dimerization pathway for 19;
(C) optimized Michael–Dieckmann reaction in the preparation of
20a,b
Cl
O
O
Grubbs II
(2 mol%)
O
O
CH2Cl2
reflux
OP1
OP1
We encountered an unforeseen difficulty in the Michael–
Dieckmann reaction of pyranones produced using the
RCM route [Scheme 3 (B)]. While using this method to
prepare substrates for a study of catalyst scope, we exam-
ined the condensation reaction of pyranone 17, which is
derived from (R)-glycidol. Treatment of 17 with the anion
derived from orsellinate 8 resulted in little or no product
formation [Scheme 3 (A)]. It was noticed that, after col-
umn chromatography, batches of 17 had a slightly brown
tinge to them, suggestive of trace ruthenium byproducts
carried over from the RCM step. Although it seemed im-
plausible that trace quantities of any impurity would inter-
fere significantly with the reaction of stoichiometric
quantities of an anion, methods for removing trace metals
were investigated. Thorough pre-treatment with activated
charcoal resulted in 44% yield in the annulation reaction
and washing with a methanolic solution of tris(hydroxy-
methyl)phosphine27 completely restored the yield we had
12a, P1 = TIPS; 66%
9a, P1 = TIPS; 97%
12b, P1 = TBDPS; 89%
9b, P1 = TBDPS; 89%
26% (9a) + 49% (9b)
overall yields (6 steps)
Scheme 2 (A) Summary of first-generation synthesis of pyranone
9a; (B) second-generation synthesis applied to TIPS derivative 9a and
TBDPS derivative 9b
Naphthopyranone Assembly
We initially explored the one-step Staunton–Weinreb
condensation25 and observed unacceptably low yields.
Concurrent with our studies, a synthesis of semi-viriditox-
in was published using this approach with an optimized
yield of 36%,26 consistent with our findings. The two-step
Michael–Dieckmann/oxidation approach to prepare the
same intermediate (20a15) proceeds in 82% yield from 9a
© Thieme Stuttgart · New York
Synthesis 2012, 44, 362–371

366
C. I. Grove et al.
FEATURE ARTICLE
MeO MeO
O
seen previously. In the failed reaction mixtures, complete
consumption of the starting materials was observed and,
after careful chromatography, orsellinate dimer 19 was
isolated [Scheme 3 (B)]. The structure of 19 was deduced
based on 1H and 13C NMR spectroscopy and confirmed by
X-ray crystallography.28 Control experiments revealed
that pure pyranone 17 could be spiked with Grubbs cata-
lyst to divert the reaction toward production of 19. Fur-
thermore, 19 is not formed when pyranone 17 is excluded,
even in the presence of ambient oxygen. We are not in-
clined to speculate on the exact catalytic mechanism of
this reaction, but all available data suggest that this ho-
modimerization is catalyzed by ruthenium and that pyra-
none 17 is the terminal oxidant that enables catalyst
turnover. Although similar reactivity has been observed in
related anion dimerizations, this is one of the few exam-
ples involving metal catalysis and a mild oxidant.
O
MeO
21, X = H
22, X = I
X
NIS, MeCN
MeO MeO
i-PrMgCl
R3SnX or
B(OR)3
MeO
i-Pr
O
O
O
O
MeO
MeO
23
X
24, X = H + 25, X = I (50:50)
MgX
not observed
MeO TsO
O
MeO TsO
O
n-BuLi,
t-BuLi or
i-PrMgBr
O
O
O
then [O]
MeO
MeO
MeO
26, X = I
X
Biaryl Bond Construction and Completion of Viridi-
toxin
n-BuLi, t-BuLi or
i-PrMgBr
then R3SnX or
B(OR)3
28, X = SnR3, B(OR)2
MeO TsO
O
Early studies in our laboratory focused on possible cross-
or homo-coupling reactions. To this end, we employed
model system 21, which is derived from commercially
available 2H-pyran-2-one. This naphthopyranone under-
went regioselective iodination when treated with N-iodo-
succinimide in acetonitrile (Scheme 4). Attempts to use
this substrate for magnesium–halogen exchange were
thwarted by the unexpected displacement of the methoxy
group next to the carbonyl of the pyranone ring. In fact,
only the product of displacement 24 and displacement and
exchange 25 were observed, i.e. no products derived from
the quenching of the expected organomagnesium halide
intermediate 23 were isolated. This result demonstrates
that the displacement occurs at a rate similar to that of ex-
change. We recently published an account of our observa-
tions on the scope of this reaction.29 Use of a 4-toluene-
sulfonyl protecting group in place of the methyl allowed
us to more fully explore exchange reactions.
27
Scheme 4 Attempted metal–halogen exchange and coupling reac-
tions of model naphthopyranone 26
cleaving the EOM group under neutral conditions.30 On
some runs, yields of 29a as high as 70% were observed
(Scheme 5). Unfortunately, slight variations in the tem-
perature or the reaction time were deleterious to this reac-
tion and resulted in either recovery or complete
decomposition of the starting material. Although we used
this method successfully for the first-generation synthesis,
we sought an alternative that would be more reliable.
TBDPS ethers of primary alcohols have similar steric de-
i-PrO MeO
O
O
first generation:
variable yields,
difficult to scale up
HO
OTIPS
OH
29a, up to 70%
Unfortunately, little or no product was observed when we
attempted to prepare aryltin or arylboronates to be em-
ployed in Stille or Suzuki reactions, respectively. More-
over, attempts to prepare arylithium or arylmagnesium
halide intermediates to be used in oxidative homocou-
pling reactions proceeded in low yields.
HO
P1 = TIPS
160 °C, 10 min
O
i-PrO MeO
K2CO3
Me2SO4
20a
or
20b
O
EtO
O
OP1
We next turned our attention to the use of phenolic cou-
pling reactions. This route would necessitate a protecting
group on the orsellinate fragment (P2) that was orthogonal
to the other three hydroxy protecting groups. We initially
explored the use of benzyl or 4-methoxybenzyl, but found
that the Michael–Dieckmann process was low-yielding
(not shown). Ultimately use of the ethoxymethyl (EOM)
group proved suitable for the Michael–Dieckmann reac-
tion and this group could, in theory, be cleaved in the pres-
ence of the TIPS group (P1). Use of various acidic
7a, P1 = TIPS, 72%
7b, P1 = TBDPS, 75%
ZnBr2, n-PrSH
P1 = TBDPS
i-PrO MeO
CH2Cl2, r.t.
O
O
second generation:
consistent yields,
easily scaled up
HO
OTBDPS
29b, 95%
conditions were always accompanied by TIPS cleavage. Scheme 5 EOM group removal under thermal (TIPS) or acidic
(TBDPS) conditions
Thermal conditions reported by Miyake proved useful for
Synthesis 2012, 44, 362–371
© Thieme Stuttgart · New York

FEATURE ARTICLE
Second-Generation Synthesis of (–)-Viriditoxin
367
i-PrO MeO
O
mand when compared to TIPS and significantly higher
acid stability. Given the ease with which phenolic MOM
or EOM ethers can be cleaved, we felt that the TBDPS
might be sufficiently more stable so as to permit acid
hydrolysis. Exposure of 7b to zinc bromide and propane-
thiol31 resulted in rapid EOM removal to produce 29b
with no appreciable silyl group cleavage. This reaction
could be scaled up easily and showed little run-to-run
variation in efficiency.
A
O
O
V cat.
(20 mol%)
OTBDPS
OTBDPS
HO
HO
29b
(Ra)
i-PrO MeO
O
30 65–85%, >95:5 dr
R
N
The vanadium-catalyzed coupling of 29b exhibited sig-
nificant differences when compared to the TIPS analogue.
In our initial exploration of this reaction using Gong-
type32 catalysts derived from (S)-BINOL and L-valine
31a, TIPS-protected 29a underwent phenolic coupling
with 89:11 dr. This same catalyst converted 29b into biar-
yl intermediate 30 in 65% yield and >95:5 diastereoselec-
tivity [Scheme 6 (A)]. Examination of two new catalyst
structures 31b,c derived from tert-leucine and isoleucine,
respectively, proceeded in 85% and 80% yields with sim-
ilarly high diastereoselectivity. Finally, Treatment of 30
with potassium carbonate and dimethyl sulfate followed
by tetrabutylammonium fluoride furnished 33, which in-
tercepted the first-generation synthetic route [Scheme 6
(B)]. This intermediate was carried on to (–)-viriditoxin in
four steps in an optimized overall yield of 42%, which
was a noticeable improvement from our original report.
O
catalyst
R
yield of 30
O
O
V
O
O
31a
31b
31c
i-Pr
t-Bu
s-Bu
65%
85%
80%
O
(Sa)
O
V
O
N
O
31a–c
R
P2O P3O
O
B
O
R
R
P1O
P1O
(Ra)
O
P2O P3O
O
compound
P1
H
P2
P3
R
Synthetic (–)-viriditoxin is identical to naturally derived
material in all respects. At the time of our first synthesis,
30
i-Pr
Me
Me
Me
H
CH2OTBDPS
CH2OTBDPS
OH
Me2SO4,
13
we observed 1H and C NMR spectra that compared fa-
K2CO3; 65%
32
33
Me
Me
i-Pr
i-Pr
H
vorably with reported values. In addition, Dr. Sheo Singh,
who conducted the isolation at Merck, provided us with a
copy of the original 1H NMR spectrum that he recorded.
The only discrepancy was in our observed optical rotation
of –118, which was significantly lower in magnitude than
that reported (–202).4 We observed the same value in both
our initial synthesis and the route disclosed here. Further-
more, we confirmed high isomeric purity, as judged by
HPLC at several stages of the synthesis (compounds 30,
32, and 33). In order to confirm our results, we requested
a sample of Aspergillus viridinutans from NRRL that was
cultured and extracted as described by Lillehoj. Natural
viriditoxin was purified by preparative HPLC and the op-
tical rotation was measured as [a]D22 –125, comparable to
the value we obtained for the synthetic sample. Both nat-
ural and synthetic (–)-viriditoxin yielded identical NMR
TBAF; 83%
4 steps,
42%
(ref. 15)
1, viriditoxin Me
CO2Me
Scheme 6 (A) Vanadium-catalyzed oxidative dimerization of 29b;
(B) conversion of 30 into (–)-viriditoxin
a lithium enolate intermediate. Use of a TBDPS protect-
ing group as a replacement for TIPS protection of the pri-
mary alcohol resulted in two important improvements: (1)
greater stability toward phenolic EOM group removal
during naphthopyranone assembly and (2) enhanced the
diastereoselection of the biaryl bond forming step. Final-
ly, we have addressed the discrepancy between the optical
rotation values of synthetic and natural samples of viridi-
toxin. The results published here show significant im-
provements to our previous synthesis and will allow
access to similar biaryl natural products and in-depth stud-
ies of their biological activity.
13
spectra (1H and C) when analyzed separately. We con-
clude that experimental differences between the original
measurement of the optical rotation and our measure-
ments account for the observed difference.
All reactions were carried out under a argon atmosphere in flame-
dried glassware with magnetic stirring. THF, Et2O, CH2Cl2 were
run through a pad of basic alumina prior to use. Reagents were pu-
rified immediately before use and following the guidelines of Perrin
and Armarego.33 Purification of products were carried out by flash
chromatography unless otherwise stated using Silica gel 400 mesh
obtained from EM science. Analytical TLC was performed on sili-
ca-gel UV254 precoated glass backbone. Visualization was accom-
plished with UV light and KMnO4. 1H NMR spectra were recorded
Conclusion
Our second-generation synthesis of (–)-viriditoxin has al-
lowed us to access larger quantities with greater efficien-
cy. Synthesis of the key unsaturated lactone was achieved
without the use of toxic alkyltin reagents. In addition, the
use of RCM avoided the large-scale use of ozonolysis and
© Thieme Stuttgart · New York
Synthesis 2012, 44, 362–371

368
C. I. Grove et al.
FEATURE ARTICLE
on a Varian Unity Inova NMR spectrometers (300 MHz, 400 MHz
or 600 MHz) using solvent as internal standard (CDCl3 d = 7.26
ppm). Proton-decoupled 13C NMR spectra were recorded on a
Varian Unity Inova NMR spectrometers (75 MHz, 100 MHz or 150
MHz) using solvent as internal standard (CDCl3 d = 77.0 ppm). In-
frared spectra were recorded on a Bruker Tensor 27 FT-IR spectro-
photometer equipped with a DTGS detector and Smart Orbit bounce
diamond ATR accessory. Mass spectra were obtained on a Thermo
Fischer LTQ-Orbitrap mass spectrometer.
11.7 mmol, 97%) as a colorless oil. Spectroscopic data were identi-
cal to those reported in the literature.15
(6S)-6-[2-(tert-Butyldiphenylsiloxy)ethyl]-5,6-dihydro-2H-pyr-
an-2-one (9b)
To a soln of 12b (1.2 g, 2.94 mmol) in CH2Cl2 (200 mL) under ar-
gon was added dropwise a soln of Grubbs II catalyst (0.05 g, 0.058
mmol) in CH2Cl2 (2 mL), and the mixture was refluxed for 15 h. The
mixture was cooled to r.t. and tris(hydroxymethyl)phosphine (0.01
g, 0.09 mmol) was added followed by Et3N (0.016 mL, 0.12 mmol)
and the mixture was stirred vigorously for 15 h. Deionized H2O
(200 mL) was added and the mixture was stirred vigorously for 30
min. The layers were separated and the organic layer was washed
with deionized H2O (150 mL) followed by H2O–brine (1:1, 100
mL), dried (Na2SO4), filtered, and concentrated in vacuo. The resi-
due was purified by flash column chromatography to give 9b (1.0 g,
(S)-1-(Triisopropylsiloxy)hex-5-en-3-yl Acrylate (12a)
To a soln of 13a (5.0 g, 18.3 mmol) in CH2Cl2 (120 mL) and acry-
loyl chloride (2.9 mL, 36.7 mmol) at 0 °C was added Et3N (5.6 mL,
40.3 mmol) dropwise. The mixture was allowed to warm to r.t. over
2 h (TLC monitoring) and quenched with sat. NaHCO3 (100 mL).
The layers were separated and the aqueous layer was extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
flash column chromatography to give 12a (4.0 g, 12.25 mmol, 66%)
as a colorless oil; [a]D22 +30.8 (c 0.57, CHCl3); Rf = 0.65 (hexane–
EtOAc, 9:1).
22
2.62 mmol, 89%) as a light-yellow oil; [a]D –32.59 (c 0.316,
CHCl3); Rf = 0.33 (hexanes–EtOAc, 8:2).
IR (film): 2932, 2851, 1718, 1425, 1378, 1240 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.06 (s, 9 H), 1.90 (m, 1 H), 2.03
(s, 1 H), 2.29–2.39 (m, 2 H), 3.81 (m, 1 H), 3.91 (m, 1 H), 4.63–4.75
(m, 1 H), 6.02 (d, J = 9.8 Hz, 1 H), 6.81–6.93 (m, 1 H), 7.41 (m, 6
H), 7.66 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 19.4, 27.1, 29.7, 37.8, 59.6, 75.3,
121.6, 128.0, 130.0, 133.7, 135.7, 145.4, 164.6.
IR (film): 2944, 2867, 1724, 1406, 1190 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.06 (s, 20 H), 1.84 (q, J = 6.5 Hz,
2 H), 2.40 (m, 2 H), 3.73 (t, J = 6.5 Hz, 2 H), 5.10 (m, 4 H), 5.77 (m,
2 H), 6.09 (m, 1 H), 6.37 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 12.1, 18.2, 36.8, 38.9, 59.9, 71.2,
118.0, 129.0, 130.5, 133.7, 165.9.
HRMS (ESI): m/z [M + H]+ calcd for C23H29O3Si: 381.1881; found:
381.1878.
HRMS (ESI): m/z [M + H]+ calcd for C18H35O3Si: 327.2277; found:
327.2354.
Dimethyl 2,2¢-Ethylenebis[4-(ethoxymethoxy)-6-isopropoxy-
benzoate] (19)
(S)-1-(tert-Butyldiphenylsiloxy)hex-5-en-3-yl Acrylate (12b)
To a soln of 13b (6.35 g, 17.9 mmol) and acryloyl chloride (1.6 mL,
19.7 mmol) in THF (33 mL) at 0 °C was added Et3N (5.0 mL, 35.8
mmol) dropwise with vigorous stirring. The mixture was stirred for
1 h at 0 °C then warmed to r.t. and stirred for an additional 1.5 h.
The Et3N·HCl was filtered off and washed with THF (3 × 20 mL).
The filtrate was dried (Na2SO4) and concentrated in vacuo, and the
residue was purified by flash column chromatography to give the
corresponding olefin (6.5 g, 15.9 mmol, 89%) as a pale-yellow oil;
[a]D22 +17.09 (c 0.772, CHCl3); Rf = 0.83 (hexane–EtOAc, 8:2).
To a soln of i-Pr2NH (0.21 mL, 1.52 mmol) in THF (3.6 mL) at 0
°C was added 2.5 M BuLi in hexane (0.58 mL, 1.46 mmol). The
mixture was allowed to warm to r.t. and stirred for 30 min. After
cooling to –78 °C, a soln of 8 (0.17 g, 0.61 mmol) in THF (1.0 mL)
was added dropwise and stirring was continued for 30 min at –78
°C. DMPU (0.14 mL, 1.22 mmol) was added dropwise and the soln
was stirred for 20 min. A soln of 17 (0.20 g, 1.05 mmol) in THF (1.0
mL) was added dropwise into the soln and the mixture was stirred
for 1 h at –78 °C. Then, the resultant soln was allowed to warm
slowly to r.t. and stirred overnight. The reaction was quenched with
sat. NH4Cl and extracted with EtOAc (3 × 5 mL). The combine or-
ganic extracts were washed with brine, dried (Na2SO4), filtered, and
concentrated in vacuo. The coupled dimer was purified (silica gel)
and isolated (0.056 g, 0.10 mmol, 33% yield) as an orange solid.
IR (film): 3070, 2935, 2855, 1721, 1404 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.07 (s, 9 H), 1.82–1.95 (m, 2 H),
2.40 (s, 2 H), 3.72 (t, J = 6.3 Hz, 2 H), 5.07 (d, J = 12.2 Hz, 2 H),
5.19–5.32 (m, 1 H), 5.68–5.88 (m, 2 H), 6.08 (m, 1 H), 6.31–6.44
(m, 1 H), 7.41 (m, 6 H), 7.67 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 19.3, 27.0, 36.4, 38.8, 60.3, 71.0,
118.0, 127.8, 129.0, 129.8, 130.5, 133.7, 135.8, 165.8.
IR (film): 2866, 1714, 1600, 1277 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.21 (t, J = 7.1 Hz, 3 H), 1.30 (d,
J = 6.1 Hz, 6 H), 2.76 (s, 2 H), 3.70 (q, J = 7.1 Hz, 2 H), 3.89 (s, 3
H), 4.40–4.55 (m, 1 H), 5.18 (s, 2 H), 6.47 (dd, J = 2.1, 10.4 Hz, 2
H).
13C NMR (100 MHz, CDCl3): d = 12.1, 15.3, 18.2, 22.2, 35.9, 52.2,
64.4, 71.6, 93.2, 100.8, 118.9, 141.5, 156.5, 159.2, 168.9.
HRMS (ESI): m/z [M + H]+ calcd for C25H33O3Si: 409.2121; found:
409.2194.
(6S)-6-[2-(Triisopropylsiloxy)ethyl]-5,6-dihydro-2H-pyran-2-
one (9a)
HRMS (ESI): m/z [M + Na]+ calcd for C30H42NaO10: 585.2670;
To a soln of 12a (4.0 g, 12.25 mmol) in CH2Cl2 (700 mL) under ar-
gon was added dropwise a soln of Grubbs II catalyst (0.21 g, 0.24
mmol) in CH2Cl2 (8 mL), and the mixture was refluxed for 15 h. The
mixture was cooled to r.t. and tris(hydroxymethyl)phosphine (0.04
g, 0.37 mmol) was added followed by Et3N (0.30 mL, 2.9 mmol)
and the mixture was stirred vigorously for 15 h. Deionized H2O
(500 mL) was added and the mixture was stirred vigorously for 30
min. The layers were separated and the organic layer was washed
with deionized H2O (300 mL) followed by H2O–brine (1:1, 250
mL), dried (Na2SO4), filtered, and concentrated in vacuo. The resi-
due was purified by flash column chromatography to give 9a (3.5 g,
found: 585.2663.
(3S)-3-[2-(tert-Butyldiphenylsiloxy)ethyl]-7-(ethoxymethoxy)-
10-hydroxy-9-isopropoxy-3,4-dihydro-1H-naphtho[2,3-c]pyr-
an-1-one (20b)
To a soln of i-Pr2NH (0.32 mL, 2.28 mmol) in THF (5 mL) at 0 °C
was added 2.5 M BuLi in hexane (0.87 mL, 2.19 mmol). The mix-
ture was allowed to warm to r.t. and stirred for 30 min. After cooling
to –78 °C, a soln of ester 8 (0.26 g, 0.91 mmol) in THF (1 mL) was
added dropwise and stirring was continued for 30 min at –78 °C.
DMPU (0.22 mL, 1.82 mmol) was added dropwise and the mixture
was stirred for 20 min. A soln of lactone 9b (0.38 g, 1.00 mmol) in
Synthesis 2012, 44, 362–371
© Thieme Stuttgart · New York

FEATURE ARTICLE
Second-Generation Synthesis of (–)-Viriditoxin
369
THF (1 mL) was added dropwise and the mixture was stirred for 1
h at –78 °C. Then, the resultant soln was allowed to warm slowly to
r.t. and stirred for 15 h. The reaction was quenched with sat. NH4Cl
(10 mL) and extracted with EtOAc (3 × 5 mL). The combined or-
ganic extracts were washed with brine, dried (Na2SO4), filtered, and
concentrated in vacuo. The residue was filtered through a silica gel
plug (hexane–EtOAc, 8:2) and used immediately in the next step.
quenched with sat. NaHCO3 (15 mL), and filtered through Celite.
The layers were separated and the aqueous layer was extracted with
CH2Cl2 (3 × 5 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
flash column chromatography to give 29b (0.086 g, 0.147 mmol,
95%) as a colorless oil; [a]D22 –57.0 (c 0.71, CHCl3); Rf = 0.5 (hex-
ane–EtOAc, 6:4).
To a soln of the tricycle (0.3 g, 0.47 mmol) in benzene (8 mL) was
added a soln of DDQ (0.17 g, 0.76 mmol) in benzene (4 mL) drop-
wise at r.t. After stirring for 4 h, the reaction was quenched with sat.
NaHCO3 (30 mL) and then it was stirred vigorously for 1 h. The
mixture was extracted with Et2O (3 × 15 mL). The combined organ-
ic layers were washed with brine (30 mL), dried (Na2SO4), filtered,
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography to give 20b (0.3 g, 0.47 mmol, 53%, two
steps) as a clear oil; [a]D +31.3 (c 0.16, CHCl3); Rf = 0.46 (hex-
ane–EtOAc, 8:2).
IR (film): 3062, 2954, 1738, 1600, 1370 cm–1.
IR (film): 2935, 2857, 1688, 1610, 1562 cm–1.
1H NMR (600 MHz, CDCl3): d = 1.02 (s, 9 H), 1.44 (d, J = 5.9 Hz,
6 H), 1.83–1.98 (m, 1 H), 2.05 (m, 1 H), 2.96 (m, 2 H), 3.75–3.88
(m, 1 H), 3.97 (s, 4 H), 4.68 (m, 2 H), 6.51 (s, 1 H), 6.65 (s, 1 H),
7.06 (s, 1 H), 7.38 (m, 6 H), 7.65 (m, 4 H).
13C NMR (125 MHz, CDCl3): d = 19.4, 21.9, 27.0, 34.8, 37.7, 59.8,
63.5, 71.0, 75.4, 101.3, 102.3, 112.4, 116.1, 120.3, 127.9, 129.9,
133.8, 135.7, 141.3, 156.4, 157.8, 158.3, 162.8, 164.2.
25
HRMS (ESI): m/z [M + H]+ calcd for C35H41O6Si: 585.2594; found:
585.2667.
1H NMR (600 MHz, CDCl3): d = 1.07 (s, 9 H), 1.26 (t, J = 7.1 Hz,
3 H), 1.49 (d, J = 6.0 Hz, 6 H), 2.05 (s, 2 H), 2.99 (s, 2 H), 3.78 (q,
J = 7.1 Hz, 2 H), 3.87 (m, 1 H), 3.96 (m, 1 H), 4.62–4.75 (m, 1 H),
4.80 (m, 1 H), 5.33 (s, 2 H), 6.60 (d, J = 2.1 Hz, 1 H), 6.79–6.90 (m,
2 H), 7.42 (m, 6 H), 7.68 (m, 4 H), 12.85 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 15.4, 19.4, 22.1, 27.1, 33.9, 37.8,
59.7, 64.8, 72.5, 76.5, 93.2, 101.4, 102.1, 102.7, 112.3, 115.6,
128.0, 130.0, 133.5, 133.7, 135.7, 141.4, 159.1, 159.4, 164.3, 170.5.
(Ra,3S,3¢S)-3,3¢-Bis[2-(tert-butyldiphenylsiloxy)ethyl]-7,7¢-dihy-
droxy-9,9¢-diisopropoxy-10,10¢-dimethoxy-3,3¢,4,4¢-tetrahydro-
6,6¢-bi[1H-naphtho[2,3-c]pyran]-1,1¢-dione (30)
To a soln of 29b (0.086 g, 0.147 mmol) in CH2Cl2 (4 mL) was added
(Sa,R)-31a (0.02 g, 0.029 mmol, 20 mol%); the flask was kept under
an O2 atmosphere and stirred at r.t. for 15 h. The crude mixture was
flushed through a silica gel plug before purification by flash column
chromatography to give 30 (0.05 g, 0.043 mmol, 65%) as a colorless
oil; [a]D22 –33.0 (c 0.024, CHCl3); Rf = 0.56 (benzene–acetone 8:2).
HRMS (ESI): m/z [M + H]+ calcd for C37H45O7Si: 629.2856; found:
629.2934.
IR (film): 3370, 2930, 2856, 2371, 1716, 1613 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.98 (s, 9 H), 1.56 (dd, J = 6.0, 9.7
Hz, 6 H), 1.83 (m, 1 H), 2.00 (m, 1 H), 2.74 (m, 2 H), 3.69–3.77 (m,
1 H), 3.92 (m, 1 H), 4.06 (s, 3 H), 4.60 (m, 1 H), 4.78–4.88 (m, 1 H),
5.40 (s, 1 H), 6.60 (s, 1 H), 6.77 (s, 1 H), 7.28–7.45 (m, 6 H), 7.60
(m, 4 H).
13C NMR (125 MHz, CDCl3): d = 19.3, 22.0, 27.1, 35.2, 37.8, 59.6,
63.7, 71.2, 75.0, 99.3, 102.3, 114.0, 117.5, 127.9, 128.0, 128.5,
133.5, 138.3, 140.0, 156.8, 159.3, 162.9, 163.2.
(3S)-3-[2-(tert-Butyldiphenylsiloxy)ethyl]-7-(ethoxymethoxy)-
9-isopropoxy-10-methoxy-3,4-dihydro-1H-naphtho[2,3-c]pyr-
an-1-one (7b)
To a soln of 20b (0.43 g, 0.68 mmol) and K2CO3 (0.26 g, 2.05
mmol) in acetone (10 mL) was added dimethyl sulfate (0.19 mL,
2.05 mmol) and the resulting mixture was heated at 60 °C for 15 h.
After the soln was cooled to r.t., the soln was filtered and the filter
cake was washed with EtOAc (30 mL). Solvent was removed under
reduced pressure, and the residue was purified by flash column
chromatography to give 7b (0.33 g, 0.51 mmol, 75%) as a pale-yel-
HRMS (ESI): m/z [M + H]+ calcd for C70H79O12Si2: 1167.5032;
found: 1167.5124.
22
low oil; [a]D –31.4 (c 0.70, CHCl3); Rf = 0.30 (hexane–EtOAc,
8:2).
(Sa,3S,3¢S)-3,3¢-Bis[2-(tert-butyldiphenylsiloxy)ethyl]-7,7¢-dihy-
droxy-9,9¢-diisopropoxy-10,10¢-dimethoxy-3,3¢,4,4¢-tetrahydro-
6,6¢-bi[1H-naphtho[2,3-c]pyran]-1,1¢-dione (30¢)
IR (film): 2935, 2851, 1714, 1613, 1563 cm–1.
1H NMR (600 MHz, CDCl3): d = 1.03 (s, 9 H), 1.24 (t, J = 7.1 Hz,
3 H), 1.46 (d, J = 6.0 Hz, 6 H), 1.93 (m, 1 H), 2.07 (m, 1 H), 2.93–
3.03 (m, 2 H), 3.76 (q, J = 7.1 Hz, 2 H), 3.82–3.87 (m, 1 H), 3.93 (s,
3 H), 3.95 (m, 1 H), 4.70 (m, 2 H), 5.32 (s, 2 H), 6.59 (d, J = 2.1 Hz,
1 H), 6.88 (d, J = 2.2 Hz, 1 H), 7.18 (s, 1 H), 7.33–7.46 (m, 6 H),
7.65 (m, 4 H).
13C NMR (125 MHz, CDCl3): d = 15.3, 19.4, 21.8, 27.1, 35.0, 37.8,
58.8, 59.9, 63.6, 64.8, 71.0, 75.1, 93.2, 101.8, 113.7, 117.1, 120.9,
127.9, 129.9, 133.6, 133.7, 140.7, 157.4, 158.4, 162.5, 163.0.
To a soln of 29b (0.05 g, 0.085 mmol) in CH2Cl2 (2 mL) was added
(Sa,S)-31a (0.01 g, 0.017 mmol, 20 mol%); the flask was kept under
an O2 atmosphere and stirred at r.t. for 15 h. The crude mixture was
flushed through a silica gel plug before purification by flash column
chromatography to give 30¢ (0.045 g, 0.038 mmol, 90%) as a color-
24
less oil; [a]D –41.0 (c 0.16, CHCl3); Rf = 0.2 (benzene–acetone
8:2).
IR (film): 3345, 2933, 2859, 2361, 1716, 1614 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.92, (s, 18 H), 1.56 (dd, J = 6.0
Hz, 7.6, 12 H), 1.82 (m, 2 H), 2.00 (m, 2 H), 2.79 (m, 4 H), 3.69–
3.75 (m, 2 H), 3.84 (m, 2 H), 4.05 (s, 6 H), 4.52 (m, 2 H), 4.84 (m,
2 H), 5.21 (s, 2 H), 6.67 (s, 2 H), 6.74 (s, 2 H), 7.22–7.39 (m, 16 H),
7.56 (m, 4 H).
13C NMR (125 MHz, CDCl3): d = 19.0, 21.6, 21.9, 26.7, 34.8, 37.5,
59.5, 63.5, 71.0, 74.6, 99.2, 101.7, 113.7, 116.9, 117.2, 127.6,
129.6, 133.2, 138.1, 139.5, 156.9, 159.1, 162.5, 163.1.
HRMS (ESI): m/z [M + H]+ calcd for C38H47O7Si: 643.3013; found:
643.3087.
(3S)-3-[2-(tert-Butyldiphenylsiloxy)ethyl]-7-hydroxy-9-isopro-
poxy-10-methoxy-3,4-dihydro-1H-naphtho[2,3-c]pyran-1-one
(29b)
To a soln of 7b (0.1 g, 0.15 mmol) in CH2Cl2 (1 mL) was added
ZnBr (0.03 g, 0.15 mmol) (Note: ZnBr2 must be dry) followed by n-
PrSH (0.03 mL, 0.31 mmol) at r.t. under argon. The mixture was
stirred (TLC monitoring), after the starting material was consumed,
the mixture was diluted with CH2Cl2 (4 mL) brought down to 0 °C,
HRMS (ESI): m/z [M + H]+ calcd for C70H79O12Si2: 1167.5105;
found: 1167.5125.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 362–371

370
C. I. Grove et al.
FEATURE ARTICLE
(Ra,3S,3¢S)-3,3¢-Bis[2-(tert-butyldiphenylsiloxy)ethyl]-9,9¢-di-
isopropoxy-7,7¢,10,10¢-tetramethoxy-3,3¢,4,4¢-tetrahydro-6,6¢-
bi[1H-naphtho[2,3-c]pyran]-1,1¢-dione (32)
To a soln of 30 (0.06 g, 0.05 mmol) in acetone (2 mL) was added
K2CO3 (0.05 g, 0.40 mmol) followed by dimethyl sulfate (0.04 mL,
0.40 mmol); the reaction was stirred at r.t. for 15 h. The mixture was
filtered and the filter cake was washed with acetone (3 × 5 mL). The
residue was purified by flash column chromatography to give 32
(0.04 g, 0.033 mmol, 65%) as a colorless oil; [a]D25 –36.4 (c 0.022,
CHCl3); Rf = 0.37 (hexane–EtOAc, 6:4).
NH4Cl soln (1 mL) and diluted with EtOAc (5 mL). The layers were
separated and the aqueous phase was washed with EtOAc (3 × 2
mL). The combined organic layers were washed with H2O (5 mL)
and brine, and dried (Na2SO4). The solvent removed in vacuo, and
the residue was purified by flash column chromatography to give
33¢ (0.02 g, 0.027 mmol, 83%) as a white solid; [a]D25 –22 (c 0.05,
CHCl3); Rf = 0.2 (EtOAc 100%).
IR (film): 3403, 2927, 2852, 2361, 2346, 1720 cm–1.
1H NMR (600 MHz, CDCl3): d = 1.56 (dd, J = 2.5, 6.0 Hz, 12 H),
1.84 (m, 2 H), 2.00 (m, 2 H), 2.76 (m, 4 H), 3.76 (s, 6 H), 3.80 (m,
2 H), 3.89 (m, 2 H), 4.06 (s, 6 H), 4.52 (m, 2 H), 4.85 (m, 2 H), 6.57
(s, 2 H), 6.79 (s, 2 H).
13C NMR (125 MHz, CDCl3): d = 21.8, 22.1, 35.0, 37.2, 56.3, 58.7,
63.4, 71.2, 75.2, 97.5, 110.6, 112.8, 116.6, 118.1, 136.0, 139.6,
157.63, 158.2, 162.7, 162.8.
IR (film): 2928, 2855, 1720, 1613 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.97 (s, 18 H), 1.58 (dd, J = 3.8,
5.9 Hz, 12 H), 1.74–1.91 (m, 2 H), 2.05 (m, 2 H), 2.69 (m, 4 H), 3.73
(m, 2 H), 3.81 (s, 6 H), 3.85–3.96 (m, 2 H), 4.06 (s, 6 H), 4.51–4.63
(m, 2 H), 4.87 (m, 2 H), 6.57 (s, 2 H), 6.83 (s, 2 H), 7.33 (m, 12 H),
7.59 (m, 8 H).
13C NMR (125 MHz, CDCl3): d = 19.3, 22.3, 27.0, 35.3, 37.8, 56.7,
59.7, 63.6, 71.5, 75.0, 97.7, 110.9, 113.2, 116.9, 118.4, 127.8,
127.9, 129.9, 133.5, 135.6, 139.8, 157.9, 158.5, 162.9, 163.3.
HRMS (ESI): m/z [M + H]+ calcd for C40H47O12: 719.3062; found:
719.3072.
HRMS (ESI): m/z [M + H]+ calcd for C72H83O12Si2: 1195.5345;
found: 1195.5435.
Primary Data for this article are available online at
http://www.thieme-connect.com/ejournals/toc/synthesis and can be
cited using the following DOI: 10.4125/pd0024th.
(Sa,3S,3¢S)-3,3¢-Bis[2-(tert-butyldiphenylsiloxy)ethyl]-9,9¢-diiso-
propoxy-7,7¢,10,10¢-tetramethoxy-3,3¢,4,4¢-tetrahydro-6,6¢-
bi[1H-naphtho[2,3-c]pyran]-1,1¢-dione (32¢)
Acknowledgment
To a soln of 30¢ (0.045 g, 0.038 mmol) in acetone (2 mL) was added
K2CO3 (0.04 g, 0.30 mmol) followed by dimethyl sulfate (0.03 mL,
0.30 mmol), the reaction was stirred at r.t. for 15 h. The mixture was
filtered and the filter cake was washed with acetone (3 × 5 mL). The
residue was purified by flash column chromatography to give 32¢
The authors acknowledge research support from the NIH/NIAID
(R01AI080931) and support from the NSF (CHE-0840444) for the
purchase of the Bruker SMART DUO diffractometer used for X-ray
crystallography. Dr. Kyria Boundy-Mills (UC Davis, Dept. of Food
Science and Technology) is acknowledged for acquisition and
culturing of the Aspergillus strain used for the isolation of natural
(–)-viriditoxin. Dr. Sheo Singh (Merck Research Laboratories) is
acknowledged for helpful discussions and providing data relating to
the isolation of (–)-viriditoxin.
25
(0.04 g, 0.033 mmol, 87%) as a pale-yellow oil; [a]D –27.8 (c
0.334, CHCl3); Rf = 0.23 (hexane–EtOAc, 6:4).
IR (film): 2927, 2854, 1731, 1617, 1568, 1331 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.92 (s, 18 H), 1.56 (m, 12 H),
1.82 (m, 2 H), 1.99 (m, 2 H), 2.76 (m, 4 H), 3.73 (s, 8 H), 3.85 (m,
2 H), 4.06 (s, 6 H), 4.50 (m, 2 H), 4.85 (m, 2 H), 6.65 (s, 2 H), 6.79
(s, 2 H), 7.28 (m, 12 H), 7.56 (m, 8 H).
13C NMR (125 MHz, CDCl3): d = 19.0, 21.8, 21.8, 22.1, 26.7, 29.6,
34.9, 37.5, 56.3, 59.5, 63.4, 71.2, 74.7, 97.5, 110.7, 112.9, 116.7,
118.1, 127.6, 129.6, 133.2, 135.3, 139.7, 157.6, 158.1, 162.7.
References
(1) Lock, R. L.; Harry, E. J. Nat. Rev. Drug Discovery 2008, 7,
324.
(2) Erickson, H. P.; Anderson, D. E.; Osawa, M. Microbiol.
Mol. Biol. Rev. 2010, 74, 504.
(3) (a) RayChaudhuri, D.; Park, J. T. Nature (London) 1992,
359, 251. (b) De Boer, P.; Crossley, R.; Rothfield, L. Nature
(London) 1992, 359, 254. (c) Mukherjee, A.; Dai, K.;
Lutkenhaus, J. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 1053.
(d) Foss, M.; Eun, Y.-J.; Weibel, D. B. Biochemistry 2011,
50, 7719.
HRMS (ESI): m/z [M + H]+ calcd for C72H82O12Si2: 1195.5418;
found: 1195.5443.
(Ra,3S,3¢S)-3,3¢-Bis(2-hydroxyethyl)-9,9¢-diisopropoxy-
7,7¢,10,10¢-tetramethoxy-3,3¢,4,4¢-tetrahydro-6,6¢-bi[1H-naph-
tho[2,3-c]pyran]-1,1¢-dione (33)
To a soln of 32 (0.04 g, 0.033 mmol) in THF (1 mL) was added
TBAF (1.67 mL, 1.67 mmol) at 0 °C. The mixture was allowed to
warm to r.t. and stirred for 2 h. The mixture was quenched with sat.
NH4Cl soln (1 mL) and diluted with EtOAc (5 mL). The layers were
separated and the aqueous phase was washed with EtOAc (3 × 2
mL). The combined organic layers were washed with H2O (5 mL)
and brine, and dried (Na2SO4). The solvent removed in vacuo, and
the residue was purified by flash column chromatography to give 33
(0.02 g, 0.027 mmol, 83%) as a white solid; Rf = 0.2 (EtOAc 100%).
Spectroscopic data were identical to those reported in the litera-
ture.15
(4) Weisleder, D.; Lillehoj, E. B. Tetrahedron Lett. 1971, 12,
4705.
(5) Suzuki, K.; Nozawa, K.; Nakajima, S.; Kawai, K. Chem.
Pharm. Bull. 1990, 38, 3180.
(6) Wang, J.; Galgoci, A.; Kodali, S.; Herath, K. B.; Jayasuriya,
H.; Dorso, K.; Vicente, F.; Gonzalez, A.; Cully, D.;
Bramhill, D.; Singh, S. J. Biol. Chem. 2003, 278, 44424.
(7) Hood, R. D.; Hayes, A. W.; Scammell, J. G. Food Cosmet.
Toxicol. 1976, 14, 175.
(8) Arone, A.; Assante, G.; Montorsi, M.; Nasini, G.
Phytochemistry 1995, 38, 595.
(9) Elix, J. A.; Wardlaw, J. H. Aust. J. Chem. 2004, 57, 681.
(10) Suzuki, K.; Nozawa, K.; Nakajima, S.; Udagawa, S.; Kawai,
K. Chem. Pharm. Bull. 1992, 40, 1116.
(11) (a) Ng, A. S.; Just, G.; Blank, F. Can. J. Chem. 1969, 47,
1223. (b) Blank, F.; Ng, A. S.; Just, G. Can. J. Chem. 1966,
44, 2873.
(Sa,3S,3¢S)-3,3¢-Bis(2-hydroxyethyl)-9,9¢-diisopropoxy-
7,7¢,10,10¢-tetramethoxy-3,3¢,4,4¢-tetrahydro-6,6¢-bi[1H-naph-
tho[2,3-c]pyran]-1,1¢-dione (33¢)
To a soln of 32¢ (0.04 g, 0.033 mmol) in THF (1 mL) was added
TBAF (1.67 mL, 1.67 mmol) at 0 °C; the mixture was allowed to
warm to r.t. and stirred for 2 h. The mixture was quenched with sat.
Synthesis 2012, 44, 362–371
© Thieme Stuttgart · New York

FEATURE ARTICLE
Second-Generation Synthesis of (–)-Viriditoxin
371
(12) (a) Matsumoto, M.; Minato, H.; Kondo, E.; Mitsugi, T.;
Katagiri, K. J. Antibiot. 1975, 28, 602. (b) Koyama, K.;
Natori, S.; Iitaka, Y. Chem. Pharm. Bull. 1987, 35, 4049.
(13) (a) Gill, M. Nat. Prod. Rep. 2003, 20, 615. (b) Isaka, M.;
Kittakoop, P.; Kirtikara, K.; Hywel-Jones, N. L.;
Thebtaranonth, Y. Acc. Chem. Res. 2005, 38, 813.
(c) Sperry, J.; Bachu, P.; Brimble, M. A. Nat. Prod. Rep.
2008, 25, 376.
(14) (a) Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning,
M. Chem. Rev. 2011, 111, 563. (b) Kozlowski, M. C.;
Morgan, B. J.; Linton, E. C. Chem. Soc. Rev. 2009, 38, 3193.
(15) Park, Y. S.; Grove, C. I.; González-López, M.; Urgaonkar,
S.; Fettinger, J. C.; Shaw, J. T. Angew. Chem. Int. Ed. 2011,
50, 3730.
(22) Murata, T.; Sano, M.; Takamura, H.; Kadota, I.; Uemura, D.
J. Org. Chem. 2009, 74, 4797.
(23) Bolla, M. L.; Patterson, B.; Rychnovsky, S. D. J. Am. Chem.
Soc. 2005, 127, 16044.
(24) Dalgard, J. E.; Rychnovsky, S. D. Org. Lett. 2005, 7, 1589.
(25) (a) Evans, G. E.; Leeper, F. J.; Murphy, J. A.; Staunton, J.
J. Chem. Soc., Chem. Commun. 1979, 205. (b) Dodd, J. H.;
Weinreb, S. M. Tetrahedron Lett. 1979, 20, 3593.
(26) Tan, N. P. H.; Donner, C. D. Tetrahedron 2009, 65, 4007.
(27) Ferguson, M. L.; O’Leary, D. J.; Grubbs, R. H. Org. Synth.
2003, 80, 85.
(28) Crystallographic data for compound 9 have been submitted
to Cambridge Crystallographic Database and assigned
deposition number CCDC 858638.
(16) Bode, S. E.; Drochner, D.; Mueller, M. Angew. Chem. Int.
Ed. 2007, 46, 5916.
(17) Romaine, I. M.; Hempel, J. E.; Shanmugam, G.; Hori, H.;
Igarashi, Y.; Polavarapu, P. L.; Sulikowski, G. A. Org. Lett.
2011, 13, 4538.
(18) Coleman, R. S.; Grant, E. B. J. Am. Chem. Soc. 1995, 117,
10889.
(19) Kozlowski, M. C.; Dugan, E. C.; DiVirgilio, E. S.;
Maksimenka, K.; Bringmann, G. Adv. Synth. Catal. 2007,
349, 583.
(29) Brockway, A. J.; Gonzalez-Lopez, M.; Fettinger, J. C.;
Shaw, J. T. J. Org. Chem. 2011, 76, 3515.
(30) Miyake, H.; Tsumura, T.; Sasaki, M. Tetrahedron Lett.
2004, 45, 7213.
(31) Han, J. H.; Kwon, Y. E.; Sohn, J.-H.; Ryu, D. H.
Tetrahedron 2010, 66, 1673.
(32) Guo, Q.-X.; Wu, Z.-J.; Luo, Z.-B.; Liu, Q.-Z.; Ye, J.-L.; Luo,
S.-W.; Cun, L.-F.; Gong, L.-Z. J. Am. Chem. Soc. 2007, 129,
13927.
(33) Armarego, W. L. F.; Chai, C. Purification of Laboratory
Chemicals, 5th ed.; Butterworth Heinemann: Oxford, 2003,
608.
(20) Volkmann, R. A.; Kelbaugh, P. R.; Nason, D. M.; Jasys, V.
J. J. Org. Chem. 1992, 57, 4352.
(21) Shen, R.; Inoue, T.; Forgac, M.; Porco, J. A. Jr. J. Org.
Chem. 2005, 70, 3686.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 362–371