Synthetic studies towards the core tricyclic ring system of pradimicin A

Article abstract of DOI:10.1002/ejoc.201200294

Pradimicins are structurally intriguing natural products that possess potent biological activity as antifungal and antiviral agents through a unique mode of action as carbohydrate binding agents. A preliminary synthetic approach towards pradimicin A has focused on a model study of the core tricyclic ring system. The route features an alkoxyallylboration/cycloisomerization/Diels-Alder cycloaddition sequence as the key steps. The alkoxyallylboration was critical for differentiating the hydroxy groups in the central cyclohexadienediol unit of pradimycins, which will ensure a regiocontrolled glycosylation. For the cycloisomerization reaction, various substrates and conditions were tested for a ring-closing enyne metathesis reaction. With enyne substrate 23, dimerization-prone bicyclic diene 24 was isolated as the major product under the conditions of both ruthenium-catalyzed metathesis and palladium-catalyzed cycloisomerization. In the end, the optimal route found for the synthesis of the model functionalized tricyclic ring system 31 features a one-pot sequential palladium-catalyzed cycloisomerization, Diels-Alder reaction, and oxidative aromatization. A model study towards the synthesis of the C-D-E tricyclic core of the carbohydrate binding agent, pradimicin A, is described. Alkoxyallylboration provided the differentially protected diol unit of the central ring. Optimization of a key enyne cycloisomerization reaction led to the synthesis of the tricycle by a one-pot Pd-catalyzed cycloisomerization/Diels- Alder cycloaddition/aromatization.

Full text of DOI:10.1002/ejoc.201200294

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FULL PAPER
DOI: 10.1002/ejoc.201200294
Synthetic Studies Towards the Core Tricyclic Ring System of Pradimicin A
Laura Zilke[a] and Dennis G. Hall*[a]
Keywords: Allylboration / Aromatization / Cycloaddition / Metathesis / Natural products / Synthesis design
Pradimicins are structurally intriguing natural products that
possess potent biological activity as antifungal and antiviral
agents through a unique mode of action as carbohydrate
binding agents. A preliminary synthetic approach towards
pradimicin A has focused on a model study of the core tricy-
clic ring system. The route features an alkoxyallylboration/
cycloisomerization/Diels–Alder cycloaddition sequence as
the key steps. The alkoxyallylboration was critical for differ-
entiating the hydroxy groups in the central cyclohexadien-
ediol unit of pradimycins, which will ensure a regiocontrolled
glycosylation. For the cycloisomerization reaction, various
substrates and conditions were tested for a ring-closing en-
yne metathesis reaction. With enyne substrate 23, dimeriza-
tion-prone bicyclic diene 24 was isolated as the major prod-
uct under the conditions of both ruthenium-catalyzed me-
tathesis and palladium-catalyzed cycloisomerization. In the
end, the optimal route found for the synthesis of the model
functionalized tricyclic ring system 31 features a one-pot se-
quential palladium-catalyzed cycloisomerization, Diels–
Alder reaction, and oxidative aromatization.
BMY-28864, BMS-181184, and, more recently, PRM-S,
which have different and more water-soluble amino acid
and disaccharide functionalities (Table 1).[7–13]
Introduction
In 1988, efforts to discover novel microbial metabolites
led to the isolation of a new class of natural products, called
pradimicins and benanomicins, by Oki and Takeuchi and
their co-workers.[1–6] Oki and co-workers found that a cul-
tured broth of Actinomadura hibisca bacteria, isolated from
a Fiji Island soil sample, contained red pigments that pre-
cipitated from the broth at pH = 5, and these were purified
by column chromatography.[3] The components were later
identified and characterized to be pradimicins A, B, and C
(Table 1) and were shown to be active against various fungi,
yeasts, and viruses.[5] Takeuchi and co-workers isolated be-
nanomicin A and B from a cultured broth of Actinomadura
species in the same year.[2,4] The unique biological activity
that this class of compounds exhibits and the ongoing need
for antifungal and antiviral treatments makes it a valuable
target in synthetic chemistry. The structures of the pradim-
icins and benanomicins consist of an amino acid, a disac-
charide, and a benzo[a]naphthacenequinone core. There are
approximately 20 congeners in this family to date, and their
specific structures vary according to their amino acid and
disaccharide components (Table 1). Pradimicin A (PRM-
A), one of the first and most abundant congeners isolated,
was initially subjected to biological testing, but was claimed
to have limited solubility in water (Յ50 μm).[7] To overcome
this issue, testing was also performed with the analogues
Pradimicins and benanomicins exhibit their antifungal
and antiviral biological activities by acting as carbohydrate-
binding agents (CBAs). As low-molecular-weight natural
products, the ability of pradimicins to bind to carbo-
hydrates is very rare, proving them to be unique and with
great potential for antifungal and antiviral applications.
Aside from avoiding some of the disadvantages of protein-
based CBAs, such as cost and lower stability, the main ad-
vantage of non-proteinageneous CBAs is their low molecu-
lar weight, which is beneficial in scale-up, purification, and
production.[14]
The pradimicins show specificity towards high-mannose-
type glycans. The molecular architecture of pradimicins is
proposed to be crucial, with the aglycon core, the amino
acid, and the disaccharide all involved in the binding
mechanism.[15–18] According to a study conducted by Oki
and co-workers, a calcium ion coordinates to two molecules
of pradimicin A (PRM-A) through the carboxylic acid
groups, and the other two moieties are involved in binding
to the target oligomannan.[15–18] This model correlates with
the finding that when the carboxylic acid is methylated,
PRM-A loses its biological activity.[15–18] It is unclear
whether the function of calcium is solely to bridge two
PRM-A units or whether it plays a role in coordinating
mannose to the antibiotic.[19]
[a] Department of Chemistry, University of Alberta, 4-010 Centre
for Multidisciplinary Science,
Pradimicins have shown activity against numerous
pathogens, including systemic fungal infections and, poten-
tially more importantly, against the human immunodefici-
ency virus (HIV).[1,7,8,14,20–22] It prevents viral entry into the
host cell by binding to gp120, a glycoprotein present on the
Edmonton, Alberta, T6G 2G2, Canada
Fax: +1-780-492-8231
E-mail: dennis.hall@ualberta.ca
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200294.
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L. Zilke, D. G. Hall
FULL PAPER
Table 1. Pradimicin and benanomicin analogues.
a trans-1,2-diol, and a disaccharide that requires regioselec-
tive introduction. The core C, D, and E rings of pradim-
icin A (see Scheme 1) would therefore require the most con-
sideration. In fact, most of the previous synthetic efforts of
Suzuki,[27–30] Krohn,[31,32] Hauser,[33,34] and other
groups,[35–37] as well as the work reported herein, have been
directed towards this tricyclic system. The key to the syn-
thesis lies in the formation and functionalization of the D
ring. It would be ideal if the diol were introduced in a man-
ner that would afford different protecting groups on each
alcohol. Sequential deprotection of the alcohol would then
allow glycosylation to occur chemoselectively and therefore
increase the efficiency of the overall synthetic plan.
There is only one total synthesis to date of the pradim-
icin and benanomicin family,[30] but there have also been a
few interesting partial syntheses that have targeted varia-
tions of the aglycon core.[31–37] In 1999, Suzuki and co-
workers published the first synthesis of pradimicinone, an
aglycon of the pradimicins and benanomicins that lacks the
disaccharide moiety and contains a free trans-diol.[28,30]
They completed the first total synthesis of benanomicin B
in 2005 by a Bringmann-type asymmetric ring-opening of
a biaryl lactone instead of having to resort to optical resolu-
tion to acquire the required enantioenriched biaryl aldehyde
precursor.[29,30] Suzuki and co-workers successfully synthe-
sized three naturally occurring congeners, benanomicin B,
benanomicin A, and pradimicin A, by the introduction of
the appropriate amino acid and disaccharide functionali-
ties.[30]
We became interested in developing an alternative and
efficient synthetic route to the pradimicin/benanomicin nat-
ural products that would allow access to analogues and the
design of libraries of synthetic CBAs. In particular, we
hoped to achieve a more direct and enantioselective route
towards the differentiated trans-diol compared with the syn-
thesis of Suzuki and co-workers, which requires several ma-
nipulations.[30] Our proposed retrosynthetic analysis is pre-
sented in Scheme 1. The introduction of the amine and di-
saccharide onto pentacycle 2 was envisioned to occur in the
later stages of the synthesis to allow an easily accessible
route to analogues. The projected intramolecular metathesis
of enyne 5 followed by a Diels–Alder reaction via diene 3
or 4 to close rings D and E would be an interesting, new,
and expedient approach towards the synthesis of these nat-
ural products. The enyne 5 was envisioned to be synthesized
by a Brown alkoxyallylboration of aldehyde 6, which would
derive from precursors 7–9.
HIV envelope that mediates entry into the host cell.[7,8] The
glycans that make up gp120 have been found to contain
a large amount of mannose and, as previously mentioned,
pradimicins have a specific binding affinity towards man-
nose.[7] Mammalian cells have a significantly lower amount
of high-mannose-type glycans on the cell surface, which re-
sults in little to no binding with mannose-targeting CBAs.
This implies that pradimicin CBAs could be selective
towards the viral cells with little toxicity towards the host.[8]
Owing to our interest in synthetic CBAs,[23–26] we were
interested in developing a synthetic strategy that would
eventually enable the design of a receptor library approach
Results and Discussion
A model study was proposed to test the key reactions
to target various cell-surface oligosaccharides. A number of involved in the synthesis of the C–D–E tricyclic ring system
factors must be taken into consideration when designing a 10 from precursors 11–14 (Scheme 2). Our efforts in this
synthetic route towards the pradimycin/benanomycin fam- synthesis began by designing a route towards enyne precur-
ily of natural products. The main challenges associated with sor 12 from aldehyde 14. The chosen route involved an alk-
this molecule include a highly substituted pentacyclic core, oxyallylboration to directly introduce both the diol and
2
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Towards the Core Tricyclic Ring System of Pradimicin A
Scheme 1. Proposed retrosynthesis of pradimycin A (PRM-A).
on a large scale. The synthesis of 14 by halogenation of 3-
alkoxybenzaldehydes proved to be more troublesome than
anticipated. We therefore looked towards introducing a
triflate group at the ortho position as a pseudohalide for the
required Sonogashira cross-coupling reaction. Thus, trifla-
tion of commercially available phenol 15 with triflic anhy-
dride afforded product 16 in a 67% yield (Scheme 3). To
avoid the formation of Heck products between the aryl trifl-
ate and a pendent alkene, we opted to introduce the alkyne
prior to the Brown alkoxyallylboration. To this end, a Son-
ogashira reaction was performed on 16 to obtain alkyne 17
in excellent yield (Scheme 3).[38]
Scheme 2. Retrosynthetic rourte to the target C–D–E tricyclic core
of PRM-A.
terminal alkene functionalities in alkyne 13 in one step. To
this end, our initial objective was to prepare trisubstituted
arene 14.
Synthesis of Enyne Substrate 19
Synthesis of Trisubstituted Benzaldehyde 17
An inexpensive and high-yielding synthetic route towards
aldehyde 14 was preferable in order to obtain the product Scheme 3. Preparation of key enyne intermediate 19.
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L. Zilke, D. G. Hall
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Alkoxyallylboration of Aldehyde 17
Enyne Metathesis for the Preparation of the D and E Rings
As seen in the proposed retrosynthesis (Scheme 2), tricy-
cle 10 was to be obtained from an enyne of type 12. It was
envisioned that the E ring would be formed from the Diels–
Alder cycloaddition of diene 11. Diene 11 was designed to
be more activated by introducing a carboxylic acid on to
the terminal alkene by a cross-metathesis reaction that
would lead to a more regioselective inverse-demand Diels–
Alder reaction with the dienophile. It also allowed the de-
sired substitution to occur on ring E. Diene 11 was envi-
sioned to arise from a ruthenium–carbene-catalyzed enyne
metathesis reaction with precursor 12/19. The decision to
introduce a trimethylsilyl group on the alkyne arose from
the idea of first testing the tolerability of a silyl group and
later replacing it with a dimethyl(phenyl)silyl group that
would be capable of undergoing Tamao–Fleming oxidation
to form the requisite E ring phenol in 10 (Scheme 2).
The main advantage associated with the preparation of
precursor 19 by an alkoxyallylboration resides in the intro-
duction of the monoprotected diol and terminal alkene into
the aldehyde in one step. The allylboration reaction is a
widely used reaction for the formation of homoallylic
alcohols by an allyl transfer reaction between an allylic bor-
ane or boronate and carbonyl compounds.[39] It is a useful
process, because a new C–C bond is formed as well as up
to two stereogenic centers with high diastereoselectivity. We
planned to utilize the stoichiometric chiral allylborane 18
(Scheme 3) derived from α-pinene developed by Brown et
al.[40] This alkoxyallylboration can be applied to a wide
range of aldehyde substrates, and the syntheses of several
higher-order alkoxyallylboranes in situ are well known.[39]
The preparation of the allylboration reagent (–)-[(Z)-γ-alk-
oxyallyl](diisopinocampheyl)borane 18 is followed by in
situ addition to the aldehyde.[40] The 1,2-syn-alkoxy homo-
allylic alcohol products are obtained with high ee and dr. In
2002, Ramachandran et al. reported an alkoxyallylboration
between 18 and benzaldehyde, which afforded the α-alkoxy
homoallylic alcohol product in 71% yield and 98% ee.[41]
By using similar conditions with aldehyde 17, homoallylic
alcohol product 19 was obtained in 66% yield and 72% ee
(Scheme 3). Various reaction conditions were altered, in-
cluding increasing the equivalents of borane as well as other
workup conditions, but it did not significantly impact the
outcome of the reaction. The ee was lower than expected,
possibly due to our substrate. 9-Methoxy-9-borabicy-
clo[3.3.1]nonane (9-MeO-9-BBN) was used to form the ra-
cemic homoallylic alcohol product rac-19 for an HPLC
standard to determine the ee when using 18. Because larger
quantities are readily available, this racemic product was
used to test future cyclization reactions.
Enyne Metathesis with Substrate 19
Initial attempts towards the enyne metathesis of 19 began
with the most often used Grubbs I and II catalysts. Al-
though previous evidence suggested that a free alcohol may
hinder the enyne metathesis by coordinating to the catalyst,
Granja and co-workers in 2001 showed metathesis occur-
ring in the presence of a free homoallylic alcohol.[50] Thus,
the cyclization reaction was performed on alcohol 19 in
dichloromethane at reflux as well as in toluene at room tem-
perature and at 80 °C, but no conversion was observed. It
was therefore assumed that the enyne metathesis reaction
was not tolerated by the free alcohol in enyne 19, probably
as a result of intramolecular coordination of the homoall-
ylic alcohol to the catalyst. The next step was to protect
the alcohol in 19 to enable the metathesis reaction. A silyl
protecting group was chosen in order to differentiate the
protecting group from the MEM group and to prevent any
interference in the cyclization reaction. The silylation reac-
tion gave 20 in an excellent 90% yield at 0 °C in 24 h
(Scheme 4). Enyne 20 was then subjected to various metath-
esis conditions with ruthenium–carbene, Grubbs I,
Grubbs II, and Hoveyda–Grubbs II catalysts. Disappoint-
Formation of the D and E Rings
Introduction to Enyne Metathesis
A transition-metal-induced cycloisomerization of a 1,7-
enyne would be both a unique and attractive strategy for
the construction of the D ring of pradimicin A. This pro-
cess gives access to the 1,3-dienes required for the construc-
tion of the E ring by an intermolecular Diels–Alder reac-
tion. Our initial attempts at ring-closing enyne metathesis
(RCEM)[42–45] of precursor 19 utilized the Grubbs ruthe-
nium–carbene system. The mechanism of enyne metathesis
is not as well studied as that of diene metathesis.[42] The
low-valent-transition-metal-catalyzed and metal–carbene-
catalyzed systems operate through different mechanisms.
The ability of the ruthenium atom to complex to either the
alkene or alkyne results in different mechanistic pathways
leading to two different isomeric diene products.[42] The cy-
clization is known to proceed successfully with alkyl groups
on the alkyne and particularly well with esters of boronic
acids, silyl ethers, and silyl groups.[46–49]
Scheme 4. Attempted enyne metathesis with substrate 20.
4
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Towards the Core Tricyclic Ring System of Pradimicin A
ingly, at temperatures ranging from 23 to 80 °C in both tol- is possible with a variety of transition metals and unsatu-
uene and dichloromethane, the enyne metathesis did not oc- rated partners, and it has been generated in the presence of
cur to produce the desired product 21. In all cases, starting an RuII catalyst.[52,53] In 1994, Murai and co-workers ob-
material was recovered at the end of the reaction as well as served the first example of a 1,7-enyne undergoing skeletal
an undesired product later characterized as 22 (Scheme 4). reorganization in the presence of the catalyst [RuCl2-
A number of other catalysts were tested for the cyclization (CO3)]2 to form a vinylcyclohexene product.[54] They did
of substrate 20, including PtCl2 and AuCl3, but complex not, however, postulate a mechanism. Given that the cata-
mixtures were obtained with no indication of the desired lyst system is different, metallacyclopentene 26 was consid-
diene product. It was concluded that the alkyne is not in ered to be a possible intermediate in the formation of diene
close enough proximity to the alkene to react or is sterically 24. In this case, the metal atom would first coordinate to
hindered by either the ortho-methoxy group or the TMS both points of unsaturation and then undergo oxidative
substituent.
coupling to form metallacyclopentene 26. β-Hydride elimi-
nation to form 27 and reductive elimination would lead to
the 1,3-diene 24. The exact cause of the formation of diene
product 24 over 25 is unclear.
Enyne Metathesis with Modified Substrate 23
Owing to the unexpected formation of diene 24 over 25,
we were interested to see which diene would be favored by
the use of low-valent-transition-metal catalysts. We then
looked towards various palladium catalysts as a less expens-
ive and potentially more efficient alternative.
The next step was to test the enyne metathesis in the
absence of the TMS group on the alkyne to see whether
it was this group that hindered the reaction. As shown in
Scheme 5, the silyl-capped alkyne was successfully cleaved
with potassium carbonate to give 23 in 89% yield at room
temperature. Although removal of the TMS group was not
ideal for forming the desired substitution on ring E, we be-
lieved that the ring E phenol (e.g., as in 10, Scheme 2) could
be introduced by catalytic C–H borylation/oxidation[51] or
ortho-lithiation/borylation at a later stage. After obtaining
terminal alkyne 23, the enyne metathesis was conducted
again under the previous conditions in toluene at 80 °C. A
Palladium-Catalyzed Cycloisomerization of Substrate 23
Palladium-catalyzed enyne reorganization has undergone
extensive studies since the first Alder-ene reaction reported
by Trost and co-workers in 1985.[55] It has led to numerous
useful cycloisomerization reactions as well as tandem trans-
formations with cycloaddition reactions.[52,53] In 1994, Trost
and co-workers proposed a mechanism for the Pd-catalyzed
cycloisomerization transformation proceeding through a
palladacyclopentene intermediate. Typical Pd sources in-
clude Pd(OAc)2 and [Pd2(dba)3].[56] Trost and co-workers
had previously shown that the ligand N,N-dibenzylidenee-
thylenediamine (BBEDA) can increase catalytic activity for
sluggish enyne cycloisomerization reactions. Therefore, this
ligand was synthesized and employed here.[56] An alterna-
tive catalytic system was also employed in which acetic acid
was used to oxidatively add to a Pd0 source to form an
H–PdII–OAc species.[57] In this case, the cycloisomerization
occurred by a slightly different mechanism.
1
new alkene product was formed, based on initial H NMR
data, and all the starting material was consumed. However,
further analysis showed that diene 24 was unexpectedly
formed along with the predicted 25 in a ratio of 95:5
(Scheme 5). The low-yielding mixture could not be isolated
due to the instability of the products over time and when
subjected to column chromatography. Mechanistically,
diene 24 was an unexpected product from this catalytic sys-
tem. The formation of a ruthenacyclopentene intermediate
The palladium-catalyzed cycloisomerization was initially
tested on substrate 20 in which the alkyne is substituted
with TMS. However, only the starting material was ob-
tained in the reaction under a variety of conditions (Table 2,
Entries 1–5), including with the use of both sources of Pd,
the BBEDA ligand, and acetic acid as the additive. Sub-
strate 23 was then subjected to the same reaction conditions
and actually provided more promising results. In the pres-
ence of the catalyst Pd(OAc)2 at room temperature, a mini-
mal amount of starting material was converted into the de-
sired diene 24. At this stage, the temperature was raised to
60 °C, and this resulted in a 100% conversion of the start-
1
ing material into the product, based on H NMR analysis
(Entry 7). The reaction was also performed with Pd(OAc)2,
PPh3, and the acetic acid additive at room temperature and
resulted in a cleaner crude product than that obtained at
the higher temperature (Entry 8). Therefore, these reaction
conditions were used in all subsequent cycloisomerization
reactions.
Scheme 5. Enyne metathesis with terminal alkyne 23.
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Table 2. Conditions for the Pd-catalyzed cycloisomerization of en- 24 and a nonsymmetric dienophile proved attractive for the
ynes 20 and 23.
formation of ring E. However, this theory is dependent on
which regioisomer is formed from the Diels–Alder reaction,
as it would be hard to predict molecular orbital coefficients
on the diene carbon atoms of 24. Furthermore, because
diene 24 is unstable and dimerized easily after a short
period of time, we then explored the potential of a one-
pot or tandem Pd-catalyzed cycloisomerization and Diels–
Alder cycloaddition. To further examine this possibility, the
Diels–Alder reaction was first tested by using the fairly
pure, crude diene 24 to determine whether the reaction
would proceed at all, and with which dienophiles. As pre-
viously mentioned, an asymmetric alkynic dienophile such
as methyl 2-butynoate would be ideal for introducing
methyl and ester groups into the E ring. Therefore, during
preliminary testing of the Diels–Alder reaction, various
asymmetric dienophiles were tested.
Entry
Catalyst/ligand[a]
Additive
R
T [°C] Conversion [%][b]
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2/BBEDA
Pd(OAc)2/BBEDA
Pd2(dba)3/PPh3
Pd2(dba)3/PPh3
Pd(OAc)2
–
–
–
TMS
TMS
TMS
TMS
TMS
H
r.t.
60
0
0
110
r.t.
80
0
0
0
AcOH
AcOH
–
r.t.
60
r.t.
Ͻ10 (24)
100 (24)
100 (24)
Pd(OAc)2
Pd(OAc)2/PPh3
–
H
H
AcOH
The conditions that were first examined included ther-
mal, Lewis acid catalyzed, and boronic acid catalyzed
Diels–Alder cycloadditions, as illustrated in Table 3. The
Lewis acid catalyzed Diels–Alder reaction proved to be un-
successful, as shown in Entries 1–3. With scandium triflate
as catalyst (Entry 1) at room temperature, diene 24 dimer-
izes instead of reacting with the dienophile, which indicates
the possible need for higher temperatures. The addition of
catalytic aluminium chloride resulted in immediate decom-
position (Entries 2 and 3). In the boronic acid catalyzed
cycloaddition, a method developed by Zheng and Hall,
with 2-alkynoic acids, a complex mixture was obtained (En-
tries 4 and 5).[59] As seen in Entry 6, the use of a base as
additive was tested in the hope that it would act as a scaven-
ger of possible adventitious acid, but also only led to a com-
plex mixture. After many failed attempts, the use of a co-
balt-catalyzed system developed by Hilt and Danz pro-
duced the desired tricycle 30 in 22% yield at room tempera-
ture (Entry 7).[60] Furthermore, a thermal Diels–Alder reac-
tion at higher temperatures proved promising, giving the
desired product in a yield of 32% (Entry 8). Butylated hy-
droxytoluene (BHT) was added as a potential radical scav-
enger, but it had no effect on the reaction (Entries 8 vs. 9).
Because the crude cycloisomerization product was em-
ployed as a substrate, the yields obtained are for both the
cycloisomerization and Diels–Alder cycloaddition steps.
Unfortunately, a nonsymmetric monoactivated dienophile
failed to give the desired product under similar thermal
conditions, giving the dimer 29 as the only product (En-
try 10).
[a] Entries 3, 6–8: 15 mol-% Pd catalyst. BBEDA: N,N-dibenzylid-
eneethylenediamine. MEM: (2-methoxyethoxy)methyl. TIPS: tri-
isopropylsilyl. [b] Determined by 1H NMR analysis of the crude
reaction product.
Isolation of Diene 24 and Dimer 29
During the preparation of diene 24, it was noted that
when the product was subjected to purification by column
chromatography, a decomposition or alternative product
seemed to be formed. Furthermore, after a period of ap-
proximately 24 h in solvent (CDCl3), new peaks appeared in
the 1H NMR spectra. After the crude diene had completely
converted (at room temperature for several days, based on
1H NMR spectra), the unknown compound was purified
1
by column chromatography and characterized. The H and
13C NMR spectra of the final product were not entirely
clean due to the presence of numerous diastereomers; how-
ever, mass spectrometry revealed the presence of putative
dimer 29 (Scheme 6). The probable formation of this par-
ticular isomer was established based on the findings of Vo-
gel and co-workers in 2002.[58] This group reported the
[4+2] formation of a dimer like 29 as the sole isomer from
the corresponding diene based on a diradical intermedi-
ate.[58]
In the hope of increasing the yield of the Diels–Alder
cycloaddition step, the use of microwave heating was con-
sidered. This would allow higher temperatures to be
reached in a shorter time, potentially resulting in less dimer-
ization of the unstable diene. Some of the microwave condi-
tions that were examined are shown in Table 4. The cyclo-
isomerization reactions were performed in the microwave
tube so that the dienophile could be added directly to the
Scheme 6. Proposed dimer formed from diene 24.
Diels–Alder Cycloaddition with Crude Substrate 24
Having successfully synthesized diene 24, we then investi- crude product to undergo the cycloaddition reaction. The
gated potential routes that would use this intermediate. The use of a higher temperature, 140 °C, for both 5 min and
potential to perform a Diels–Alder cycloaddition with diene 30 s resulted in lower yields (Entries 2 and 3). The ideal
6
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Towards the Core Tricyclic Ring System of Pradimicin A
Table 3. Study of the Diels–Alder cycloaddition reactions of substrate 24.
Entry
Catalyst or additive
R1
R2
Conditions
Result[a]
1
2
3
4
5
6
7
8
9
Sc(OTf)3 (20 mol-%)
AlCl3 (2 equiv.)
AlCl3 (2 equiv.)
o-BrC6H4B(OH)2 (20 mol-%)
CO2Me CO2Me
CO2Me CO2Me
THF, r.t., 48 h
CH2Cl2, RT
CH2Cl2, RT
CH2Cl2, r.t., 26 h
CH2Cl2, r.t., 26 h
toluene, 80 °C, 24 h
toluene, r.t., 24 h
toluene, 80 °C, 24 h
toluene, 80 °C, 24 h
toluene, 50 °C, 24 h
dimer 29
decomp.
H
H
H
CO2Me
CO2H
CO2H
decomposition
complex mixture
complex mixture
complex mixture
30 (22%)
o-NO2C6H4B(OH)2 (20 mol-%)
Et3N
CO2Me CO2Me
CO2Me CO2Me
CO2Me CO2Me
CO2Me CO2Me
[CoCl2dppe] (10 mol-%), ZnI2 (20 mol-%), Zn (10 mol-%)
none
BHT (20 mol-%)
none
30 (32%)
30 (29%)
10
Me
CO2Me
dimer 29
1
[a] Determined by H NMR analysis of the crude reaction product. dppe: 1,2-bis(diphenylphosphanyl)ethane. BHT: 2,6-di-tert-butyl-4-
methylphenol.
microwave conditions were found to be 120 °C for 1 min as newly formed cyclohexadiene ring E in 30 (Scheme 7).
these produced the highest yield over the two steps (En- Treatment of 30 with DDQ at room temperature for 24 h
try 4). Again, the BHT additive was tested, but it had no provided a 70% yield of tricycle 31.
effect under microwave conditions (Entry 5).
One-Pot Cycloisomerization/Diels–Alder Cycloaddition/
Aromatization
Table 4. Diels–Alder cycloaddition reaction of substrate 24b under
microwave reaction conditions.
A tandem reaction strategy to access tricycle 31 in which
the enyne precursor 23, catalyst, and dienophile are all pres-
ent at the beginning of the reaction would be an elegant
route towards the desired tricycle 31. Up to this stage, diene
30 was purified prior to subjecting it to DDQ aromatiza-
tion. Considering that the first two steps, cycloisomeriza-
tion and Diels–Alder cycloaddition, were performed in tol-
uene, the possibility arose of performing the DDQ-pro-
moted oxidation reaction on the same crude mixture di-
rectly after the cycloaddition, because it is proven to work
in toluene as well. A one-pot reaction was tested in which
the DDQ was added at the same time as the reactants for
the Diels–Alder cycloaddition step and subjected to the mi-
crowave conditions. However, this only resulted in a com-
plex mixture. Therefore, an alternative one-pot procedure in
which the DDQ was added directly to the crude mixture
after the Diels–Alder reaction was examined, as illustrated
in Scheme 8. This sequence worked quite well and produced
31 in an overall yield of 45% for the three steps, which
compares with the 44% yield obtained previously for just
the first two steps. This sequence averaged to a yield of
approximately 77% per step, with the stability of diene 24
under the thermal Diels–Alder cycloaddition conditions be-
ing the limiting factor. The benefits of this process include
minimizing solvent waste, eliminating purification steps,
and maximizing the yield through the use of crude prod-
ucts. This one-pot procedure provides an efficient and
unique route to tricycle 31 that may be applied in the syn-
thesis of the core ring system of pradimicin A.
Entry
T [°C]
Time [min]
Yield [%][a]
1
2
3
80
3
5
0.5
1
33
Ͻ10
22
44
42
140
140
120
120
4
5[b]
1
[a] Isolated yield after chromatographic purification. [b] With
20 mol-% BHT.
Oxidative Aromatization of Tricycle 30
The next step in the synthesis of the C–D–E tricycle
needed to be addressed, namely the aromatization of the
Scheme 7. Aromatization of diene 30.
Eur. J. Org. Chem. 0000, 0–0
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L. Zilke, D. G. Hall
FULL PAPER
and CH2Cl2 were distilled from CaH2. THF and Et2O were distilled
from sodium/benzophenone ketyl. THF, toluene, dichloromethane,
and methanol were also used following treatment with the Fisher
Scientific-MBraun MB SPS* solvent system. Molecular sieves were
prepared by heating under vacuum at 130 °C (overnight) and then
stored inside an oven maintained at 125 °C. TLC was performed
on Merck silica gel 60 F254 plates and visualized with UV light
and KMnO4. NMR spectra were recorded with Varian INOVA-
300, INOVA-400, INOVA-500, or Unity 500 instruments. The re-
sidual solvent protons (1H) or the solvent carbon atoms (13C) were
used as internal standards. The 1H NMR spectroscopic data are
presented as follows: chemical shift in ppm relative to tetramethyl-
silane (multiplicity, coupling constant, integration). The following
abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet;
dd, doublet of doublets; ddd, doublet of doublet of doublets; dt,
doublet of triplets; app. dt, apparent doublet of triplets; m, mul-
tiplet. HR mass spectra were recorded by using either EI or ES
ionization techniques at the University of Alberta Mass Spectrome-
try Services Laboratory. IR spectra and optical rotations were re-
corded at the University of Alberta Spectral Services. The optical
purities of α-alkoxy homoallylic alcohol products were measured
by chiral HPLC (Daicel OD Column, 0.46ϫ25 cm) or by forma-
tion of Mosher esters and subsequent H or 19F NMR analysis of
1
Scheme 8. One-pot, three-step reaction for the synthesis of tricycle
31.
the crude product. Specific details are indicated in the Experimen-
tal Section for each individual product. Compound 17[38] was syn-
thesized according to the literature. For microwave-promoted reac-
tions, a Biotage Initiator SW reactor was employed (2.5 mL vials).
Conclusions
Synthesis of Enyne Precursors
A model study towards the synthesis of the carbohydrate
binding agent, pradimicin A, has led to the synthesis of tri-
cycle 31 by a one-pot palladium-catalyzed cycloisomeriza-
tion/Diels–Alder cycloaddition/aromatization. The initial
synthetic route involving a Grubbs II-catalyzed enyne me-
tathesis failed with TMS-alkyne substrate 20, but it pro-
ceeded efficiently once the TMS group had been removed
to yield the unexpected diene 24 as the major product. With
the formation of this new diene came an alternative syn-
thetic route to the tricyclic target in which 24 was applied.
Other catalysts were tested to determine which product was
produced under different catalyst systems. A palladium-cat-
alyzed cycloisomerization was the most efficient and clean
reaction to yield diene 24. Diene 24 proved to be difficult
to work with, because it spontaneously dimerizes to prod-
uct 29. At this point, a one-pot process combining the cy-
cloisomerization and Diels–Alder reaction was developed
to ensure quick reaction of the crude diene. A one-pot tan-
dem process in which each reaction was performed directly
on the crude material in the same reaction flask produced
final tricycle 31 in a 45% yield over three steps. Ideally, if
this route were to be applied to the synthesis of pradici-
min A, an alternative dienophile would be required to ac-
cess the specific substitution pattern of ring E. Another op-
tion would be to enhance the reactivity of the diene by sub-
stituting it with an electron-donating group, allowing re-
gioselective access to the desired trisubstituted ring at the
same time.
(1R,2R)-2-[(2-Methoxyethoxy)methoxy]-1-{3-methoxy-2-[(tri-
methylsilyl)ethynyl]phenyl}but-3-en-1-ol (19): 3-[(2-Methoxy-
ethoxy)methoxy]prop-1-ene (0.79 g, 5.4 mmol, 1.1 equiv.) was
added to a long-necked round-bottomed flask along with THF
(9 mL). The solution was cooled to –78 °C, sBuLi (4.9 mL,
5.4 mmol, 1.1 equiv.) was added dropwise, and the mixture stirred
for 30 min to form a yellow solution. (+)-Ipc2BOMe (3.4 g,
9.8 mmol, 2.0 equiv.) dissolved in THF (5 mL) was added dropwise
to form a colorless solution that was stirred for 1 h. BF3·OEt2
(1.2 mL, 9.8 mmol, 2.0 equiv.) was then added dropwise followed
directly by aldehyde 17 (1.1 g, 4.9 mmol, 1.0 equiv.) dissolved in
THF (2 mL). The reaction mixture was stirred at –78 °C for 24 h
at which point it was quenched by the addition of 30 % H2O2
(5 mL) and 2 m NaOH (5 mL) and warmed to room temperature.
The reaction mixture was stirred at room temperature for 12 h. The
aqueous layer was washed with diethyl ether (2ϫ10 mL), and the
combined organic layers were washed with brine (10 mL) and dried
with MgSO4. The solution was filtered, concentrated in vacuo, and
purified by column chromatography (10 % ethyl acetate/DCM).
The product (1.22 g) was obtained as a yellow oil in 66% yield and
72% ee. [α]2D5 = 139.5 (c = 0.28, DCM). IR (cast film): ν = 3448,
˜
2957, 2893, 2151, 1596, 1574, 1456 cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 7.23 (t, J = 8.1 Hz, 1 H), 7.10 (d, J = 7.8 Hz, 1 H),
6.72 (dd, J = 0.8, 8.3 Hz, 1 H), 5.75–5.82 (m, 1 H), 5.17 (m, 2 H),
5.15 (m, 1 H), 4.66 (d, J = 6.9 Hz, 1 H), 4.54 (d, J = 6.9 Hz, 1 H),
4.26 (m, 1 H), 3.81 (s, 3 H), 3.44 (m, 1 H), 3.31–3.37 (m, 3 H), 3.29
(s, 3 H), 0.22 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
160.3, 145.3, 134.4, 129.2, 118.9, 110.7, 109.3, 104.5, 98.9, 93.1,
81.2, 73.6, 71.6, 67.0, 58.9, 55.9, 0.1 ppm. HRMS (EI): calcd. for
C20H30NaO5Si 401.1755; found 401.1750.
(8R,9R)-11,11-Diisopropyl-9-{3-methoxy-2-[(trimethylsilyl)ethyn-
yl]phenyl}-12-methyl-8-vinyl-2,5,7,10-tetraoxa-11-silatridecane (20):
In a round-bottomed flask, alcohol 19 (1.16 g, 3.06 mmol,
1.00 equiv.) was dissolved in DCM (7 mL). The solution was cooled
Experimental Section
General: Unless otherwise noted, all the reactions were performed
under argon or nitrogen in flame-dried glassware. Toluene, hexanes,
8
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Towards the Core Tricyclic Ring System of Pradimicin A
to 0 °C, and 2,6-lutidine (1.07 mL, 9.18 mmol, 3.00 equiv.) was
slowly added. TIPSOTf (1.00 mL, 3.76 mmol, 1.20 equiv.) was then
added dropwise to the solution, which was stirred at 0 °C for 24 h.
The solution was warmed to room temperature and diluted with
diethyl ether (5 mL). The organic layer was washed with NaHCO3
(2ϫ10 mL) and brine (10 mL) and dried with MgSO4. The solu-
tion was gravity-filtered and concentrated in vacuo to produce the
crude material, which was purified by column chromatography
(20% ethyl acetate/hexane). The product (1.25 g) was obtained as
a yellow oil in 90% yield. [α]2D5 = 32.44 (c = 0.27, DCM). IR (cast
One-Pot Cycloisomerization and Diels–Alder Cycloaddition
Dimethyl (9R,10R)-5-Methoxy-10-[(2-methoxyethoxy)methoxy]-9-
(triisopropylsilyloxy)-1,4,9,10-tetrahydrophenanthrene-2,3-di-
carboxylate (30): The following procedure applies to the synthesis
of diene 24 by using the palladium catalyst followed directly by
subjecting the crude product to the Diels–Alder reaction. Enyne 23
(0.10 g, 0.22 mmol, 1 equiv.) was dissolved in toluene (1.2 mL) in a
2.5 mL microwave tube. Pd(OAc)2 (8.6 mg, 33 μmol, 15 mol-%),
PPh3 (9.9 mg, 44 μmol, 20 mol-%), and AcOH (5.3 μL, 88 μmol,
40 mol-%) were added to the reaction flask. The reaction mixture
was stirred at room temperature for 24 h at which point the dien-
ophile, dimethyl butynedioate (0.27 mL, 2.2 mmol, 10 equiv.), was
added. The reaction vessel was sealed under nitrogen and subjected
to microwave heating at 120 °C at a normal absorbance level for
1 min. The solution was then concentrated in vacuo and purified
by quick column chromatography (30% ethyl acetate/hexane). The
one-pot reaction yielded 58.5 mg (44% yield) of 30 as a yellow oil.
film): ν = 2944, 2891, 2867, 2153, 1575, 1471 cm–1 1H NMR
.
˜
(400 MHz, CDCl3): δ = 7.24 (app. t, J = 7.9 Hz, 1 H), 7.17 (dd, J
= 0.9, 7.7 Hz, 1 H), 6.72 (dd, J = 1.2, 8.0 Hz, 1 H), 5.68–5.80 (m,
1 H), 5.45 (d, J = 6.0 Hz, 1 H), 5.11 (m, 1 H), 5.05–5.08 (m, 1 H),
4.74 (s, 2 H), 4.18 (t, J = 6.5 Hz, 1 H), 3.85 (s, 3 H), 3.39–3.55 (m,
4 H), 3.35 (s, 3 H), 1.02–1.05 (m, 21 H), 0.25 (s, 9 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 159.8, 146.5, 134.9, 128.8, 120.4,
118.3, 110.9, 108.8, 103.7, 99.2, 93.6, 81.7, 74.5, 71.7, 66.5, 58.9,
55.8, 18.1, 18.0, 17.9, 17.7, 12.4, 12.3, 0.0 ppm. HRMS (EI): calcd.
for C20H30NaO5Si 557.3089; found 557.3084.
As a result of its instability and tendency to dimerize, compound
24 was employed immediately after its isolation and only partially
1
characterized. H NMR (500 MHz, CDCl3): δ = 7.20 (t, J = 7 Hz,
(8R,9R)-11,11-Diisopropyl-9-{3-methoxy-2-[(trimethylsilyl)-
ethynyl]phenyl}-12-methyl-8-styryl-2,5,7,10-tetraoxa-11-silatri-
decane (22): Side-product of attempted metathesis of 20. IR (cast
1 H), 6.98 (d, J = 7 Hz, 1 H), 6.91 (d, J = 7.3 Hz, 1 H), 6.29 (s, 1
H), 5.89 (s, 1 H), 5.78 (s, 1 H), 5.20 (s, 1 H), 4.93 (d, 1 H), 4.84 (d,
1 H), 4.64 (d, 1 H), 4.50 (d, 1 H), 3.85 (s, 3 H), 3.55 (m, 4 H), 3.40
(s, 3 H), 1.09 (d, 18 H), 1.01 (m, 3 H) ppm.
film): ν = 2924, 2866, 2153, 1735, 1575, 1470 cm–1 1H NMR
.
˜
(500 MHz, CDCl3): δ = 7.27–7.37 (m, 7 H), 6.78 (d, J = 7.4 Hz, 1
H), 6.52 (d, J = 16.0 Hz, 1 H), 6.25 (dd, J = 7.9, 16.0 Hz, 1 H),
5.63 (d, J = 5.2 Hz, 1 H), 4.84 (d, J = 6.9 Hz, 1 H), 4.78 (d, J =
6.9 Hz, 1 H), 4.45 (t, J = 6.4 Hz, 1 H), 3.90 (s, 3 H), 3.56–3.67 (m,
2 H), 3.42–3.51 (m, 2 H), 3.40 (s, 3 H), 1.02–1.10 (m, 21 H), 0.33
(s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.0, 146.5,
137.0, 133.3, 128.8, 128.5, 127.4, 126.9, 126.6, 120.6, 110.9, 109.2,
103.6, 99.3, 93.4, 80.9, 74.7, 71.7, 66.5, 58.9, 55.9, 29.8, 18.1, 17.9,
12.5, 0.1 ppm. HRMS (EI): calcd. for C35H54NaO5Si2 633.3402;
found 633.3392.
The following procedure applies to the synthesis of diene 24 by
using Grubbs II ruthenium catalyst followed by subjection of the
crude product to the Diels–Alder reaction conditions. Enyne 23
(0.20 g, 0.43 mmol, 1 equiv.) was dissolved in toluene (10 mL) in a
round-bottomed flask equipped with a condenser. Grubbs II cata-
lyst (73 mg, 86 μmol, 20 mol-%) was subsequently added to the re-
action mixture. The solution was stirred at 80 °C for 24 h, then
cooled to room temperature, transferred to a 2.5 mL microwave
tube, and the dienophile, dimethyl butynedioate (0.55 mL,
4.3 mmol, 10 equiv.), was added. The reaction vessel was sealed
under nitrogen and subjected to microwave heating at 120 °C at a
normal absorbance level for 1 min. The solution was then concen-
trated in vacuo and purified by column chromatography (30% ethyl
acetate/hexane). The one-pot reaction yielded 27.5 mg and a 10%
(8R,9R)-9-(2-Ethynyl-3-methoxyphenyl)-11,11-diisopropyl-12-
methyl-8-vinyl-2,5,7,10-tetraoxa-11-silatridecane (23): In a round-
bottomed flask, enyne 20 (7.68 g, 14.4 mmol, 1.00 equiv.) was dis-
solved in THF (50 mL) and MeOH (50 mL). K2CO3 was then
added to the solution, which was stirred at room temperature for
24 h. The solution was then concentrated in vacuo, the residue dis-
solved in diethyl ether (20 mL), and purified through a plug of
silica gel by using diethyl ether as the eluent to obtain the product
(6.19 g) as a yellow oil in 93% yield. [α]2D5 = 25.64 (c = 0.45, DCM).
yield of 30 as a yellow oil. IR (cast film): ν = 2945, 2890, 2866,
˜
1
1725, 1578, 1471 cm–1. H NMR (500 MHz, CDCl3): δ = 7.15 (t,
J = 7.5 Hz, 1 H), 6.91 (dd, J = 0.9, 7.3 Hz, 1 H), 6.84 (dd, J = 0.9,
8.4 Hz, 1 H), 4.77 (d, J = 7.1 Hz, 1 H), 4.75 (d, J = 7.2 Hz, 1 H),
4.72 (d, J = 4.1 Hz, 1 H), 4.01–4.14 (m, 1 H), 3.91–3.94 (m, 1 H),
3.82 (s, 3 H), 3.78 (s, 6 H), 3.48–3.60 (m, 6 H), 3.37 (s, 3 H), 3.05–
3.15 (m, 1 H), 0.93–1.07 (m, 21 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 169.3, 167.5, 156.9, 138.1, 136.1, 128.9, 128.1, 127.1,
125.7, 121.9, 121.7, 112.7, 95.4, 78.5, 71.6, 67.1, 59.0, 55.5, 52.3,
52.1, 32.5, 31.9, 18.1, 18.0, 12.7 ppm. HRMS (EI): calcd. for
C32H48NaO9Si 627.2960; found 627.2941.
IR (cast film): ν = 3295, 2943, 2890, 2867, 2103, 1577, 1471 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 7.28 (t, J = 7.9 Hz, 1 H), 7.17
(dd, J = 0.7, 7.7 Hz, 1 H), 6.76 (dd, J = 1.0, 8.2 Hz, 1 H), 5.70–
5.82 (ddd, J = 7.5, 11.1, 16.7 Hz, 1 H), 5.45 (d, J = 6.0 Hz, 1 H),
5.11 (m, 1 H), 5.07 (ddd, J = 0.9, 1.9, 8.1 Hz, 1 H), 4.73 (s, 2 H),
4.27 (t, J = 6.4 Hz, 1 H), 3.88 (s, 3 H), 3.54–3.58 (m, 2 H), 3.52 (s,
1 H), 3.42–3.45 (m, 2 H), 3.36 (s, 3 H), 0.99–1.05 (m, 21 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 160.2, 146.5, 134.6, 129.0, 120.5,
110.7, 118.5, 109.9, 108.9, 93.4, 86.1, 81.3, 78.3, 71.7, 66.6, 58.9,
55.8, 16.0, 17.7, 12.4 ppm. HRMS (EI): calcd. for C26H42NaO5Si
485.2694; found 485.2689.
Dimethyl (9R,10R)-5-Methoxy-10-[(2-methoxyethoxy)methoxy]-9-
(triisopropylsilyloxy)-9,10-dihydrophenanthrene-2,3-dicarboxylate
(31): Diene 30 (0.10 g, 0.16 mmol, 1.0 equiv.) was dissolved in tolu-
ene (2 mL) in a round-bottomed flask. DDQ (44 mg, 0.19 mmol,
1.2 equiv.) was then added to the solution, and the mixture was
stirred at room temperature for 24 h. The crude material was con-
centrated in vacuo and purified by column chromatography to pro-
duce 67.5 mg of the product as a yellow oil in 70% yield. IR (cast
Dimerization of Diene 24. Formation of Compound 29: Diene 24
spontaneously dimerized at room temperature after a period of ap-
proximately 24 h or when subjected to column chromatography.
1
The H and 13C NMR spectra were not clean enough to fully dis-
film): ν = 2944, 2892, 2866, 1729, 1612, 1598 cm–1 1H NMR
.
˜
tinguish all the necessary peaks due to the presence of numerous
(500 MHz, CDCl3): δ = 8.75 (s, 1 H), 7.82 (s, 1 H), 7.32 (t, J =
7.8 Hz, 1 H), 7.05 (d, J = 7.3 Hz, 1 H), 7.01 (d, J = 8.3 Hz, 1 H),
diastereomers. IR (cast film): ν = 2942, 2889, 2866, 1577,
˜
1467 cm–1. HRMS (EI): calcd. for C52H84NaO10Si2 947.5495; 4.93 (d, J = 4.5 Hz, 1 H), 4.79 (d, J = 7.0 Hz, 1 H), 4.75 (m, 2 H),
found 947.5488.
3.95 (s, 3 H), 3.94 (s, 3 H), 3.93 (s, 3 H), 3.67–3.71 (m, 1 H), 3.52–
Eur. J. Org. Chem. 0000, 0–0
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L. Zilke, D. G. Hall
FULL PAPER
[13]
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3.58 (m, 3 H), 3.40 (s, 3 H), 0.98–1.06 (sept., J = 7.6 Hz, 3 H),
0.88–0.96 (m, 18 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.0,
167.5, 157.3, 135.6, 132.6, 129.7, 129.0, 128.6, 119.9, 112.4, 71.5,
67.1, 59.0, 55.7, 52.6, 52.5, 18.0, 17.9 ppm. HRMS (EI): calcd. for
C32H47O9Si 603.2984; found 603.2984.
[14]
[15]
[16]
[17]
[18]
Synthesis of Product 31 by a One-Pot Cycloisomerization/
Diels–Alder/Aromatization: The following procedure was per-
formed in the same reaction vessel and the same solvent. No con-
centration or purification was performed between the steps. Enyne
23 (0.10 g, 0.22 mmol, 1 equiv.) and toluene (1.2 mL) were added
to a 2.5 mL microwave tube. Next, Pd(OAc)2 (8.6 mg, 33 μmol,
15 mol-%), PPh3 (9.9 mg, 44 μmol, 20 mol-%), and AcOH (5.3 μL,
88 μmol, 40 mol-%) were added to the reaction mixture, which was
then stirred for 24 h. The dienophile, dimethyl butynedioate
(0.27 mL, 2.2 mmol, 10 equiv.), was added to the mixture and sub-
jected to microwave heating at 120 °C at normal absorbance for
1 min (not including preheating time). Once cooled to room tem-
perature, DDQ (59 mg, 0.26 mmol, 1.2 equiv.) was added to the
reaction flask, and the mixture was stirred for 24 h. Upon comple-
tion of the reaction, the solution was concentrated in vacuo and
purified by column chromatography (30% ethyl acetate/hexane) to
give 59.7 mg of the product as a light-yellow oil in 45% yield over
the three steps.
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10
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Job/Unit: O20294
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Date: 19-06-12 15:19:01
Pages: 12
Towards the Core Tricyclic Ring System of Pradimicin A
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Published Online: ᭿
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11

Job/Unit: O20294
/KAP1
Date: 19-06-12 15:19:01
Pages: 12
L. Zilke, D. G. Hall
FULL PAPER
Natural Product Synthesis
A model study towards the synthesis of the
C–D–E tricyclic core of the carbohydrate
binding agent, pradimicin A, is described.
Alkoxyallylboration provided the differen-
tially protected diol unit of the central ring.
Optimization of a key enyne cycloisomeri-
zation reaction led to the synthesis of the
tricycle by a one-pot Pd-catalyzed cycloiso-
merization/Diels–Alder cycloaddition/aro-
matization.
L. Zilke, D. G. Hall* ...................... 1–12
Synthetic Studies Towards the Core Tri-
cyclic Ring System of Pradimicin A
Keywords: Allylboration / Aromatization /
Cycloaddition / Metathesis / Natural prod-
ucts / Synthesis design
12
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