A three-step synthesis of the guaianolide ring system

Article abstract of DOI:10.1002/ejoc.201402170

By using a gallium(III) triflate catalyzed intramolecular (4+3) cycloaddition, a few functionalized furan-derived tricycles that share the common guaianolide sesquiterpene ring system were prepared in a stereoselective manner in only three steps from commercially available starting materials. A discussion of the formation of alternative products is included, with possible substrate requirements to achieve the key cycloaddition step in an efficient way. Copyright

Full text of DOI:10.1002/ejoc.201402170

Job/Unit: O42170
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Date: 10-04-14 18:50:31
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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402170
A Three-Step Synthesis of the Guaianolide Ring System
Jan Hullaert,[a] Duchan R. Laplace,[a] and Johan M. Winne*[a]
Keywords: Total synthesis / Natural products / Terpenoids / Cycloaddition / Oxygen heterocycles
By using a gallium(III) triflate catalyzed intramolecular (4+3)
cycloaddition, a few functionalized furan-derived tricycles
that share the common guaianolide sesquiterpene ring sys-
tem were prepared in a stereoselective manner in only three
steps from commercially available starting materials. A dis-
cussion of the formation of alternative products is included,
with possible substrate requirements to achieve the key cy-
cloaddition step in an efficient way.
Introduction
Guaianolides are a large group of evolutionary-related
secondary metabolites that originated from the common bi-
cyclic guaiane sesquiterpene skeleton.[1] Well over a thou-
sand distinct guaianolides have been isolated from natural
sources (Scheme 1, a),[2] most of which show biological
functions that are associated with chemical-defense strate-
gies for the producing organisms (mainly plants or corals).
As such, these natural products provide a rich source of
biologically validated small-molecule scaffolds that fit the
philosophy of biology-oriented synthesis.[3] In fact, these
natural products have been popular targets for total synthe-
sis for more than three decades,[4] and interest in these tar-
gets has been renewed by recent insight into their biological
and possible pharmacological relevance.[2,5]
Established synthetic strategies for the guaiane and guai-
anolide cores address the challenging hydroazulene frame-
work by using ring-expansion strategies or skeletal re-
arrangements starting from more readily accessible ring sys-
tems (Scheme 1, b).[4a–4d,4i,4j] Alternatively, guaianolides
have been achieved through annulation of suitable 1,2-di-
substituted cyclopentanoid intermediates by using an intra-
molecular carbon–carbon bond-forming reaction such as
ring-closing metathesis (RCM).[4g,4h] A more concise ap-
proach proceeds through a ring-closing metathesis cascade
of a branched ene–yne–ene precursor.[4m,6] An intramolecu-
lar (4+3) cycloaddition strategy[7] would offer a very power-
Scheme 1. (a) Guaianolide sesquiterpenoids, (b) established syn-
thetic strategies for the guaianolide sesquiterpene ring system,
ful entry to the 5-7-5 system, but although hydroazulenes (c) synthesis plan for this work, and (d) mechanism for the furfuryl
cation (4+3) cycloaddition.
have been prepared through intramolecular (4+3) cycload-
ditions in simplified model systems[8] and in natural product
synthesis,[9] guaiane and guaianolide skeletons have not
studied extensively,[10] their use in total synthesis has indeed
been prepared by using this attractive strategy. Although
been somewhat limited owing to narrow substrate scopes,
(oxy)allyl-type cations in (4+3) cycloadditions have been
poor selectivities, and their reliance on synthetically chal-
lenging cation precursors.[11] However, Pattenden and
[a] Department of Organic Chemistry, Ghent University,
Winne reported a (4+3) cycloaddition for the efficient and
stereoselective synthesis of functionalised cycloheptenes
with a procedure that used plain furfuryl alcohols as pre-
cursors for versatile and reliable furanoxonium-type three-
Krijgslaan 281 S4, 9000 Gent, Belgium
E-mail: johan.winne@ugent.be
http://www.orgchem.ugent.be
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402170.
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J. Hullaert, D. R. Laplace, J. M. Winne
SHORT COMMUNICATION
carbon-dienophiles (Scheme 1, d).[12] This reaction was product was shown to be monocyclized product 6. In our
shown to have a wide substrate scope with regard to the previous studies of furfuryl alcohols in cycloadditions,[13]
diene,[13] and it has already been used a few times in total we found that most Lewis acids [such as iron(III) chloride
synthesis of natural products.[14] In this communication, we and zinc(II) chloride] could promote this reaction, although
report the promising preliminary results of our investi- mild and/or catalytic conditions usually resulted in low con-
gations into the application of this furfuryl cation mediated versions and side reactions. Initial screening of various
cycloaddition in the synthesis of the guaianolide ring sys- Lewis acids with precursors 4 also gave low conversions
tem (Scheme 1, c).
and/or complex reaction mixtures. However, we were in-
trigued by a recent report by Wu and co-workers on a de-
hydrative three-component (4+3) cycloaddition,[15] in which
similar cationic dienophiles were generated by catalytic
amounts of gallium(III) triflate [Ga(OTf)3], a highly reac-
tive Lewis acid known to tolerate water. Much to our de-
light, treatment of a simple dichloromethane or chloroform
solution of either diastereomer of β-hydroxy ester 4 gave
rather clean conversion to 6,12-furanoguaiane cycloadduct
7 in just two diastereomeric forms, with a remarkably good
diastereomeric ratio (dr) of 8:1. The crude reaction product
was further contaminated with monocyclized diene prod-
ucts 8, but the major diastereomer of furanoguaiane 7 was
readily separated from the other reaction products by care-
ful chromatography (47–56% yield). A preliminary scan of
the reaction conditions revealed little remarkable effects.
Changing the catalyst loading (10–50 mol-%) or concentra-
tion did not affect the reaction outcome beyond the ex-
pected faster conversion times. Chloroform seemed to give
the best ratio of 7/8, but very similar ratios were observed
in other apolar solvents. Conversely, more polar solvents
such as nitromethane resulted in more complex reaction
mixtures. Furthermore, the use of similar Lewis acid cata-
lysts such as gallium(III) bromide and scandium(III) triflate
proved much less useful, as these also gave more complex
reaction mixtures.
Results and Discussion
Our first cycloaddition precursor was prepared in just
two steps by treating the anion derived from furan β-keto
ester 1 with bromodiene 2 (Scheme 2). Both starting materi-
als 1 and 2 are commercially available, or they can be pre-
pared in 1–2 steps by using only inexpensive chemicals (see
the Supporting Information). A sodium borohydride re-
duction of the resulting alkylated product (3) then gave the
corresponding diastereomeric β-hydroxy esters (4) as sepa-
rable syn and anti diastereomers. The methyl substituent at
the furan 5-position, absent in the target guaiane
(Scheme 1, c, C12), was deliberately installed in initial sub-
strates 4 to avoid possible electrophilic aromatic substitu-
tion at this highly reactive position, a side reaction which
we have often observed with furfuryl cations.[13,14a] Cyclo-
addition precursor 5 without this methyl group was ob-
tained from simple 3-(furan-2-yl)-3-oxopropanoate.
Upon treating 1,3-diol 9 (obtained from β-keto ester 3)
with gallium(III) triflate, a more complex reaction mixture
was obtained. By simple chromatography, an apolar frac-
tion (containing cyclic ether 12) and a very polar fraction
(containing polymeric material) were removed. The remain-
ing fraction (54% of the mass balance) showed a very sim-
ilar composition to that of the previous reaction mixture:
6,12-furanoguaiane 10 was observed as the main product,
again with 8:1dr, and it was contaminated with similar
levels of monocyclized diene products 11. Further purifica-
tion gave cycloadduct 10 as a single diastereomer. These
results implicate the primary hydroxy function as a pro-
moter of side reactions that suppress the yield in the case
of precursor 9. Similar observations were recently made by
Pattenden and Palframan in intermolecular reactions of
hydroxy-substituted furfuryl cations.[16] The stereochemical
Scheme 2. Assembly of the cycloaddition precursors.
Our investigation of the envisaged intramolecular (4+3) identity of the two major cycloadducts obtained from 4 and
cycloaddition reaction (Scheme 1, c) began by exploring the 9 was readily established by converting 7 into 10 by reaction
usual reaction conditions for this transformation: stoichio- with lithium aluminum hydride. Detailed analysis of the
metric amounts of either titanium(IV) chloride or trifluoro- well-resolved 1H NMR resonances at C1, C4, and C5 in 10
acetic acid (TFA).[13,14a] Unfortunately, titanium(IV) chlor- further unambiguously established the formation of the
ide gave a terribly complex reaction mixture, but minor trans-ring fusion in the hydroazulene cores, in accordance
amounts of a furanoguaiane-type cycloadduct were isolated to earlier observations in related systems by Harmata.[17]
from the reaction mixture obtained with trifluoroacetic acid This stereoselectivity is strongly indicative of a stepwise re-
(Scheme 3) in dichloromethane. However, the main reaction action mechanism,[13,16] in which the stereochemistry of the
2
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A Three-Step Synthesis of the Guaianolide Ring System
Scheme 4. Cycloaddition with a monosubstituted furan.
The influence of a relatively remote methyl group in our
cycloaddition precursors is remarkable. The lower reaction
rate can be rationalized by the expected slower formation
of the less-substituted furanoxonium cation. The lower effi-
ciency and selectivity in the ring-closing reaction of the all-
ylic cation intermediate (giving more of dienes 14) can be
related to the reduced nucleophilicity of the 3-position of
the furan (pro-C7). Further experiments are clearly re-
quired to elucidate this matter and will be reported in due
course. In the reactions of 5, we found no evidence of the
alkylation of the reactive 5-position of the furan, as ob-
served in similar intermolecular reactions.[13,14a] Although
the yield of the isolated product is clearly disappointing in
this case, this is the first example in which a monosubsti-
tuted furan is used in a (4+3) cycloaddition reaction of this
type. Furthermore, owing to its very concise nature, our
route to 13 is not beyond practicality even at this stage.
Scheme 3. Intramolecular cycloaddition reactions with precursors
4 and 9.
Conclusions
The dehydrative (4+3) cycloaddition of furfuryl alcohols
and dienes is emerging as a highly enabling synthetic
method for the rapid elaboration of complex functionalized
cycloheptanoid ring systems. Our convergent approach to
the common guaianolide sesquiterpene structure, compris-
ing only a few synthetic steps, opens up possibilities for the
modular generation of natural product inspired collections
of small molecules.[18] The identification of mild catalytic
conditions was crucial for the success of the key intramolec-
ular cycloaddition. Our results also indicate that the reac-
tion can be sensitive to rather subtle substitution patterns,
and some degree of substrate tuning may be required to
achieve efficient cycloaddition. Future work will focus on
the enantiocontrolled synthesis of cycloaddition precursors
and guaianolide (analogues). We hope this work will shed
further light on mechanistic aspects of the reaction and on
the preferred substrate requirements.
initially formed cyclopentanoid allylic cation intermediate
is governed by minimizing steric interactions between the
vicinal cyclopentane substituents. It is thus likely that minor
reaction products 8 and 11 arise from premature proton
elimination from such intermediates.
Given the apparent efficiency and mildness of the galli-
um(III)-catalyzed (4+3) cycloaddition, we next investigated
cycloaddition precursor 5 with a more challenging mono-
substituted furan (Scheme 4). This would afford a more
“natural” guaianolide ring system and also provide a more
versatile synthetic intermediate towards various natural
product target structures. However, our preliminary studies
of these substrates revealed markedly different behavior in
the cycloaddition reaction. The reaction of precursor 5 was
exceedingly slow, requiring 24 h with a catalyst loading of
10 mol-% to reach 75% conversion, and the selectivity of
the reaction also took a turn for the worse. Comparable
amounts of cycloadducts 13 and monocyclized dienes 14
were formed, next to unidentified side products. Moreover,
four distinct diastereomers of cycloadduct 13 were observed
in a 10:3:1:0.6 ratio (NMR integration). By increasing the
catalyst loading to 20 mol-% and adding anhydrous sodium
sulfate as an in situ drying agent, the reaction was com-
pleted in 16 h, but essentially the same mixture of main re-
action products was obtained. Careful chromatography
gave the major diastereomer of cycloadduct 13 in very mod-
est yield (30%) but good dr.
Experimental Section
Methyl 2,6-Dimethyl-4,6a,7,8,9,9a-hexahydroazuleno[4,5-b]furan-9-
carboxylate (7): Solid gallium(III) triflate (23.5 mg, 0.045 mmol)
was added in one portion to a solution of β-hydroxy ester 4
(126 mg, 0. 45 mmol) in chloroform (12.6 mL) with stirring at room
temperature. The resulting mixture was stirred at room temperature
until all of the starting material was consumed, as judged by TLC
(≈30 min). Then, a saturated aqueous solution of sodium hydrogen
carbonate (3 mL) was added, and the organic layer was separated.
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J. Hullaert, D. R. Laplace, J. M. Winne
SHORT COMMUNICATION
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acetate in hexane) = 0.22. IR ν = 2949, 1733 (vs), 1578 (w) cm–1.
˜
1H NMR (500 MHz, CDCl3, 21 °C): δ = 5.73 (ddq, J = 8.2, 3.5,
1.7 Hz, 1 H, C9-H), 5.67 (br. s, 1 H, C11-H), 3.76 (s, 3 H,
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Supporting Information (see footnote on the first page of this arti-
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1
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Acknowledgments
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Received: February 28, 2014
Published Online: ᭿
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A Three-Step Synthesis of the Guaianolide Ring System
Natural Products
J. Hullaert, D. R. Laplace,
J. M. Winne* .................................... 1–5
A Three-Step Synthesis of the Guaianolide
Ring System
The guaianolide ring system, a naturally
abundant tricyclic sesquiterpenoid scaffold,
is assembled in just three straightforward
synthetic operations by using a highly dia-
stereoselective intramolecular (4+3) cyclo-
addition reaction of a catalytically gener-
ated furfuryl cation intermediate.
Keywords: Total synthesis / Natural prod-
ucts / Terpenoids / Cycloaddition / Oxygen
heterocycles
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