Synthesis of the Bicyclic Lactone Core of Leonuketal, Enabled by a Telescoped Diels–Alder Reaction Sequence

Article abstract of DOI:10.1002/asia.201800903

The Diels–Alder cycloaddition reaction has become established as a fundamental approach for the preparation of complex natural products; however, successful application of the intermolecular Diels–Alder cycloaddition reaction to the synthesis of particularly congested scaffolds remains surprisingly problematic. Inspired by the terpenoid spiroketal natural product leonuketal, a challenging telescoped reaction sequence has been realized to access the core [2.2.2]-bicyclic lactone ring system and its [3.2.1] isomer. Our four-step, protecting-group-free process required detailed investigation to circumvent the problems of adduct fragmentation and intermediate instability. Successful solution of these practical issues, along with unambiguous structural determination of the target structures, provide useful insights that will facilitate future applications of the Diels–Alder cycloaddition reaction to challenging, highly congested molecular scaffolds and ongoing synthetic efforts towards this natural product.

Full text of DOI:10.1002/asia.201800903

CHEMISTRY
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Accepted Article
Title: Synthesis of the Bicyclic Lactone Core of Leonuketal Enabled by
a Telescoped Diels-Alder Reaction Sequence
Authors: Phillip Grant, Margaret Brimble, and Daniel Plimmer Furkert
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Synthesis of the Bicyclic Lactone Core of Leonuketal Enabled by
a Telescoped Diels-Alder Reaction Sequence
Phillip S. Grant,[a] Margaret A. Brimble*[a,b] and Daniel P. Furkert*[a,b]
Abstract: The Diels-Alder cycloaddition is established as
a
labdane-type precursor containing a double bond, to give 2,
followed by spirocyclization. To date, no studies towards the
preparation of leonuketal have been reported. The synthetic
challenge posed by the unique and complex architecture of 1
attracted our interest, along with the potential for synthetic and
pharmacological discovery. Our initial attention focused on
identifying a viable route to access the key densely functionalized
[2.2.2]-oxabicyclic core ring system. Larsen and co-workers had
earlier reported the synthesis of bicyclic carbohydrate-derived
[2.2.2] lactone 4 (Scheme 1A) from keto anhydride 3.2–5 These
studies revealed that reduction of the C5 ketone (red) proceeded
with complete diastereoselectivity to afford a single alcohol
epimer, that underwent spontaneous 6-exo-trig cyclization at the
distal carbonyl of the anhydride (blue, Scheme 1, A). This
approach appeared to offer a plausible synthetic route for
application to bicyclic lactone 5 that forms the core of leonuketal
(Scheme 1, B) via analogous cyclization of alcohol 6, if access to
the requisite precursor ketone 7 could be secured.
fundamental approach for preparation of complex natural products,
however application of the intermolecular reaction to the synthesis of
particularly congested scaffolds remains surprisingly problematic.
Inspired by the terpenoid spiroketal natural product, leonuketal, a
challenging telescoped reaction sequence has been realized to
successfully deliver access to the core [2.2.2]-bicyclic lactone ring
system and its [3.2.1] isomer. The four-step, protecting group free
process required detailed investigation to circumvent problems of
adduct fragmentation and intermediate instability encountered en
route. Successful solution of these practical issues along with
unambiguous structural determination of the target structures
provides useful insights that will facilitate further challenging
application of the Diels-Alder cycloaddition to highly congested
molecular scaffolds and ongoing synthetic efforts towards the natural
product.
Introduction
In 2015, Peng and co-workers reported the isolation of the unique
diterpenoid natural product leonuketal (1, Figure 1) from the herb
Leonurus japonicus.1 Leonuketal (1) displayed significant
vasorelaxant activity against KCl-induced contraction of rat aorta
(EC50 2.32 μM), and was assigned an unprecedented tetracyclic
structure.
Scheme 1. Proposed approach to the [2.2.2] bicyclic lactone core of 1
(leonuketal numbering).
Figure 1. Biosynthesis of leonuketal (1) proposed by Peng.
Bicyclic anhydride 7, or a suitable synthon, was anticipated to be
accessible by Diels-Alder cycloaddition (Scheme 2).
Cycloaddition of 1,1-dimethyl Danishefsky-type diene 8 with
methyl-substituted fumarate 9 should lead to 3,4-trans-10, a
synthetic equivalent of 7, possessing the correct relative
stereochemistry for leonuketal (1). The literature contains very
few reports of successful cycloadditions involving such highly-
substituted diene/trans-dienophile combinations. As a synthetic
alternative, we also envisaged that cycloaddition of 8 with the
more reactive commercially available cyclic cis-dienophile,
citraconic anhydride (11) (ca. US$0.70/g), should give access to
the fused cyclic anhydride, 3,4-cis-7, with the additional benefit of
reducing the step count of the synthesis. The stereochemistry of
The bridged spiroketal core of 1 was proposed by Peng and co-
workers to arise from the oxidative cleavage of the B-ring of a
P.S. Grant, M.A. Brimble, D.P. Furkert
[a]
[b]
School of Chemical Sciences
Maurice Wilkins Centre for Molecular Biodiscovery
University of Auckland, Symonds St, Auckland 1010 (NZ)
E-mail: m.brimble@auckland.ac.nz, d.furkert@auckland.ac.nz
Supporting information for this article is given via a link at the end of
the document.
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3,4-cis-7 resulting from this latter sequence would be C3 epimeric
with respect to 1, therefore an epimerization step would be
required later in the synthesis.
efficient total synthesis of three complex natural products; (-)-
enmein, (-)-isodocarpin and (-)-sculponin.11 Interestingly, no
problems of product fragmentation or instability were reported in
the development of this reaction, which was successfully carried
out on multigram scale. In general, [4+2] cycloadditions involving
citraconic anhydride (11) are significantly rarer that those of the
simpler symmetrical congener, maleic anhydride (14).12–14
Trans dienophiles
Our initial investigations towards the cycloaddition of dienes 8a
and 8b proved disappointing (Table 1). Although cycloaddition of
8a and the simple dienophile, methyl methacrolein (15),
proceeded readily to directly afford the cyclic enone 16 in
excellent yield (Table 1, Entry 1), reaction with the corresponding
acrylate ester, methyl methacrolate (17) was unsuccessful,
instead leading only to the diene dimerization product 18 (Table
1, Entry 2). Variation of the Lewis acid catalyst did not alter the
course of this reaction. Thermal cycloaddition of 8a with either of
the trans dienophiles diethyl fumarate (19) (Table 1, Entry 3) or 3-
methyl-4-oxocrotonate (20) (Table 1, Entry 4) failed to give any of
the desired products. In the presence of the Lewis acid catalyst
scandium triflate however, 8a underwent undesired hetero-Diels-
Alder addition to give 21 in moderate yield (Table 1, Entry 5).
Given this lack of success with the trans dienophile series, our
attention turned to the use of the cis alternatives; maleic
anhydride (14) and citraconic anhydride (11).
Scheme 2. Retrosynthetic analysis.
Results and Discussion
The requisite 2-silyloxy butadienes 8a and 8b were readily
prepared by adaptation of a literature approach (Scheme 3).6
Deprotonation of 12 with sodium hydride followed by treatment
with ethyl formate and subsequent methylation afforded ketone
13 in high yield (E/Z, 4:1). Subsequent treatment of the E/Z
mixture with the appropriate silyl triflate afforded the 2-silyloxy
butadienes 8a,8b as single stereoisomers. These modified
conditions proved more successful and reliable in our hands than
those previously reported.
Cis dienophiles
In contrast to the trans dienophiles, thermal reaction of 8a with the
model cis dienophile maleic anhydride (14) pleasingly proceeded
cleanly to afford the corresponding cycloadduct 22 in 36%
isolated yield (Table 1, Entry 6). More pleasingly, on heating with
diene 8a at 150 °C in toluene, citraconic anhydride (11) also
underwent full conversion to the desired cycloaddition product 23,
1
Scheme 3. Preparation of dienes 8a and 8b.
as established by H NMR (Table 1, Entry 7). Importantly, this
result also revealed complete regioselectivity for the desired
cycloadduct regioisomer, likely driven by unfavorable steric
interactions between the 1,1-dimethyl groups of the diene and the
methyl group of dienophile 11 in the transition state required for
the undesired regioisomer. Notwithstanding this encouraging
success, optimization of the reaction was hampered by
concomitant desilylation of diene 8a to give 13 during the reaction,
and the instability of 23 to isolation and purification on silica,
resulting in very low isolated yields (<5%). It was observed that
desilylation of diene 8a to give ketone 13 was less prevalent when
using an equimolar amount of dienophile 11, as opposed to a 2-
or 4-fold excess (Table 1, Entry 7 vs 8 & 9). This suggested that
an acidic impurity in the commercially-sourced dienophile 11,
possibly citraconic acid, was promoting the undesired side
reaction. Accordingly, citraconic anhydride (11) was distilled prior
to use, which was found to reduce diene desilylation in
subsequent runs (Table 1, Entry 10 & 11). A subtle reduction in
the reaction temperature proved to be beneficial (Table 1, Entry
10). These optimized conditions were also found to be compatible
with TMS diene 8b (Table 1, entry 11).
At the outset of the Diels-Alder cycloaddition study, we anticipated
two principal challenges; (a) high steric demand in forming two
tertiary-quaternary C-C bonds and (b) possible regioisomeric
mixtures due to the use of unsymmetrical 1,2-doubly activated
dienophiles e.g. 11. Literature precedent for [4+2] cycloadditions
forming such densely substituted cyclohexenes is scarce, despite
their abundance in terpenoid scaffolds.7 Reports of related
cycloadditions involving either a 1,1-dimethylated 2-silyloxy
butadiene or a fumarate or citraconic anhydride (11) dienophile,
suggest that all of these components are problematic reaction
partners.8 Indeed, at the outset of our studies Sarpong’s work
toward prenylated indole alkaloids had represented to our
knowledge the only related example in which a 1,1-dimethylated
2-silyloxy butadiene system undergoes productive intermolecular
cycloaddition with
a
trisubstituted dienophile.9,10 During
preparation of this manuscript a very closely related example
involving an aryl-substituted maleic anhydride dienophile was
described by the Dong group, forming the foundation of a highly
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Table 1. Diels-Alder cycloadditions of 1,1-dimethyl butadienes 8a,8b with a range of dienophiles.
Result
[reaction type]
Entry[a]
Dienophile
Conditions
Product
ZnCl2, CH2Cl2
0 °C, 3 h
84%
[Diels-Alder]
1
SnCl4, CH2Cl2
-78 °C for 3 h, then
0 °C for 1 h;
Et3N
51%
[diene dimerization]
2
3
40 h, 150 °C
40 h, 150 °C
-
-
-
-
4
5
6
Sc(OTf)3, CH2Cl2, -78 °C for 3 h;
NEt3, rt.
43%
[hetero Diels-Alder]
36%
[Diels-Alder]
PhMe, 100 °C, 2 h
Ratio of Diels-Alder product to desilylation byproduct
(23:13)
7
8
neat, 40 h, 150 °C
80:20[a]
30:70[a,c]
10:90[a,c]
92:8[a,d]
neat, 16 h, 150 °C
11 (2 equiv.)
neat, 16 h, 150 °C
11 (4 equiv.)
9
10
11
neat, 16 h, 140 °C
neat, 16 h, 140 °C
90:10[a,d,e]
[a] Product distribution by 1H NMR at full conversion. [b] Dimerization product of diene 8a. [c] BHT used instead of hydroquinone. [d] Distilled citraconic
anhydride (11) used. [e] Diene 8b used.
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Scheme 4. Optimized telescoped four-step Diels-Alder sequence to afford the bicyclic lactone core of leonuketal (1).
With conditions for formation of the target Diels-Alder cycloadduct
23 identified, the problem of product isolation remained to be
resolved, for productive routine synthesis. Difficulties were
immediately encountered in the desilylation/elimination of
cycloadduct 23 to ketone 7. Following close investigation of the
reaction process, it was determined that 23 underwent retro-
Diels-Alder/diene desilylation to give citraconic anhydride (11)
and ketone 13 upon cooling in the reaction solvent, toluene. This
effect was not observed when the crude adduct was quickly
redissolved in d-chloroform for NMR, implicating a solvent effect
in the fragmentation process. Interestingly, maleic anhydride
cycloadduct 22 (see Table 1, Entry 6) did not undergo retro-Diels-
Alder/desilylation and was stable to purification on silica. This
suggested that the angular methyl group at the ring fusion also
contributed to fragmentation, and further demonstrated the
increase in reaction difficulty moving from maleic to citraconic
anhydride. After detailed dissection of the Diels-Alder procedure,
it was eventually possible to circumvent these issues by
conducting the cycloaddition step neat, to avoid the toluene-
induced fragmentation. Subsequent direct treatment of the crude
reaction mixture with TFA in chloroform successfully afforded
ketone 7 (Scheme 4). This compound also proved unstable to
purification on silica or alumina, and was accordingly used directly
in the next step.
Table 2. Optimization of the reduction step (7 to 6) in the presence
of ZnCl2 for the telescoped sequence (Scheme 4).
Entry
1
Reductant
NaBH4
Solvent
CHCl3
Yield (5+24 from 11)
-
CHCl3:THF
(1:1)[a]
2
3
4
NaCNBH3
NaCNBH3
NaCNBH3
-
CHCl3:THF:AcOH
(1:1:0.1)
33[b]
100[b]
CHCl3:AcOH
(1:1)
[a] AcOH (1 drop) added. [b] Determined by NMR using an internal
standard.
With access to crude ketone 7 established, formation of the [2.2.2]
oxabicyclic core of leonuketal (1) was next undertaken. Reduction
of the -unsaturated ketone by treatment with sodium
cyanoborohydride in acetic acid afforded an inseparable mixture
of the desired product [2.2.2]-5 and [3.2.1]-24. The reaction was
observed to favor the formation of 5 in approximately a 2:1 ratio
for most repetitions, however this selectivity proved somewhat
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variable and was occasionally reversed, for reasons that remain
to be identified.15 The reduction step was found to proceed with
complete exo selectivity to give a single C5 alcohol epimer 6, but
competing cyclisation at either carbonyl of the cyclic anhydride led
to concomitant formation of either a 6-membered lactone (solid
arrow) to give the favoured desired product [2.2.2]-5, or a 5-
membered lactone (dashed arrow) to afford [3.2.1]-24. Similar
competitive cyclization had been previously observed by Larsen
on a substitution dependent basis.[5] It was recognized that [3.2.1]-
24 could still potentially prove a useful intermediate in later studies
if necessary, via a trans-esterification step later in the synthesis.
Carboxylic acids [2.2.2]-5 and [3.2.1]-24 were ultimately
separable by derivatization to their respective esters 25 and 26,
that were obtained in 17% and 7% overall yield respectively, from
citraconic anhydride. The corresponding Weinreb amides 27 and
28 were also prepared, by conversion of the crude mixture of
acids 5 and 24 to the acid chlorides, followed by amide formation
with dimethylhydroxlamine, in 24% combined yield from citraconic
anhydride (Scheme 4). Single crystal X-ray structures of [2.2.2]-
25 and [3.2.1]-28 were able to be obtained, representing both
isomeric manifolds, that allowed unambiguous confirmation of the
structural assignment and relative stereochemistry.
stereochemistry for the bicyclic core of leonuketal (1).
Unfortunately, despite an extensive screen of basic and other
conditions to promote epimerization, it did not prove possible to
access the target C3 epimer 29 (Scheme 5 and Table S1). Further,
no deuterium inclusion was observed upon deuterium oxide
quench of a mixture of 25 and sodium hydride that had been
heated at reflux in 1,4-dioxane. In order to rule out the possibility
of unfavorable interactions of the endocyclic alkene, 25 was
hydrogenated to the saturated analogue 30. Unfortunately, 30
proved likewise recalcitrant to deprotonation. These data suggest
that formation of the enolate is not possible due to either the high
steric demand of deprotonation, or a prohibitively strained
geometry requirement for the enolate. Inversion of the C3
stereochemistry via decarboxylative formation of an alkyl radical
from activated esters of 5 was also briefly pursued, but ultimately
also proved unfruitful.16–21
Conclusions
In summary, an efficient telescoped four-step protocol for
synthetic access to highly congested bicyclic lactone ring systems
similar to that possessed by leonuketal (1) has been developed,
without reliance on protecting groups. The sequence proceeded
through unstable intermediates highly prone to fragmentation and
decomposition, and was only achieved after close dissection of
each individual transformation. The structure and relative
stereochemistry of the highly congested [2.2.2]- and [3.2.1]-
bicyclic lactone products were unambiguously determined by X-
ray crystallography. Surprisingly, it was not possible to effect the
planned C3 epimerization to access the relative stereochemistry
required for leonuketal. The insights gained in successfully
realising this challenging approach should enable wider
application of the Diels-Alder cycloaddition to highly congested
molecular scaffolds and ongoing synthetic efforts towards the
natural product.
With synthetic methods to access bicyclic lactones 25-28
identified and their structures confirmed, from a process point of
view it appeared that a telescoped reaction sequence for
preparation of 25 and 26 directly from 11 and 8a without isolation
would avoid the purification issues encountered for cycloadduct
23 and ketone 7. The key to achieving this involved identification
of suitable conditions for formation of ketone 7 from the crude
Diels-Alder reaction mixture that would be compatible with the
subsequent reductive lactonization. After exploration of a number
of alternative conditions for reduction of the C5 ketone (Table 2)
it was found that desilylation of 23 could be effected with zinc
chloride,
that
did
not
disrupt
the
subsequent
reduction/lactonization step, if the latter was performed using
sodium cyanoborohydride in acetic acid (Table 2, Entry 4,). Using
this telescoped sequence, it proved possible to obtain 25 and 26
in a pleasing combined yield of 33% over 4 steps from diene 8a
with variable selectivity between [2.2.2]-25 and [3.2.1]-26 bicyclic
products as previously observed for the multistep sequence.
Experimental Section
General
Unless otherwise noted, all reactions were performed under an oxygen-
free atmosphere of nitrogen using standard techniques. Tetrahydrofuran
(THF) and dichloromethane (CH2Cl2) were dried by passage through a
column of activated alumina under N2 using an LC Technology solvent
purification system. All other reagents were used as received unless
otherwise noted. Yields refer to chromatographically and spectroscopically
(1H NMR) homogeneous materials, unless otherwise stated. Reactions
were monitored by thin-layer chromatography (TLC) carried out on silica
gel plates using UV light as the visualizing agent and potassium
permanganate as a developing agent. Silica gel (60, 230−400 mesh) was
used for flash column chromatography unless otherwise stated. NMR
spectra were recorded at room temperature in CDCl3 solution on either a
spectrometer operating on a Bruker 400 MHz instrument. Chemical shifts
are reported in parts per million on the  scale, and coupling constants, J,
are in Hertz. Multiplicities are reported as “s” (singlet), “br s” (broad singlet),
Scheme 5. Attempted C3 epimerization of 25 and 30.
Finally, focus was directed towards inversion of the C3
stereochemistry, required to access the correct relative
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“d” (doublet), “dd” (doublet of doublets), “ddd” (doublet of doublets of
doublets), “t” (triplet), and “m” (multiplet). Where distinct from those due to
the major diastereomer, resonances due to minor diastereomers are
denoted by an asterisk. 1H and 13C NMR resonances were assigned using
a combination of DEPT 135, COSY, HSQC, HMBC, and NOESY spectra.
Infrared (IR) spectra were recorded using a thin film on a composite of zinc
selenide and diamond crystal on an FT-IR system transform spectrometer.
Melting points are uncorrected. High-resolution mass spectrometry
(HRMS) was performed using a spectrometer operating at a nominal
accelerating voltage of 70 eV or a TOF-Q mass spectrometer.
Na2CO3 (5 mL) was added and the aqueous phase was extracted with
CH2Cl2 (3 × 5 mL). The combined organic phases were concentrated in
vacuo and the crude oil was purified by flash chromatography (20% EtOAc
in pet. ether) to give adduct 16 as a clear oil (23 mg, 84%). IR (film) νmax
2971, 2931, 1711, 1457, 1386, 1369, 1240, 1166 cm-1; 1H NMR (400 MHz,
CDCl3) δ 9.61 (s, 1H), 6.72 (dd, J = 10.2, 1.8 Hz, 1H), 6.04 (d, J = 10.2 Hz,
1H), 2.34 (dd, J = 14.5, 1.8 Hz, 2H), 1.82 (d, J = 14.5 Hz, 1H), 1.27 (s, 3H)
1.16 (s, 3H), 1.02 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 203.4, 201.5,
148.0, 128.8, 48.6, 43.9, 41.4, 26.7, 25.7, 24.0; HRMS (ESI+) [M + H]+
167.0714 calcd for C10H15O2 167.1067.
Ketone 13. A suspension of 3-methyl-2-butanone (6.21 mL, 58.1 mmol),
ethyl formate (8.58 mL, 116 mmol) and NaH (1.53 g, 63.9 mmol, 60%
dispersion in mineral oil) in THF (120 mL) was heated to reflux and allowed
to stir for 30 min. The solution turned cloudy grey to yellow, then was
allowed to cool to rt before concentration in vacuo. The resultant yellow
gum was dissolved in DMSO (120 mL) under an inert atmosphere, then
dimethyl sulfate (5.51 mL, 58.1 mmol) was added and the reaction was left
to stir for 4 h at rt. The reaction was quenched with H2O (150 mL) then
extracted with CH2Cl2 (3 × 150 mL); the collected organic fractions were
then dried over MgSO4 and concentrated in vacuo. The resultant oil was
purified by vacuum distillation (80 °C, 1.5 mbar) to give ketone 13 (5.92 g,
80%, E/Z 4:1) as a clear oil. 1H NMR (400 MHz, CDCl3) 7.60 (d, J = 12.6
Hz, 1H), 6.40* (d, J = 7.2 Hz, 0.24H), 5.62 (d, J = 12.5 Hz, 1H), 5.08* (d, J
= 7.2 Hz, 0.23H), 3.85* (s, 0.83H), 3.70 (s, 3H), 2.87* (dq, J = 13.9, 6.9 Hz,
0.23H), 2.65 (dq, J = 7.0 Hz, 1H), 1.10 (s, 3H), 1.09 (s, 3H), 1.07* (s, 0.74H),
1.05* (s, 0.68H); 13C NMR (101 MHz, CDCl3)  203.6, 162.7, 158.2*,
105.3*, 103.5, 57.7, 41.2, 39.7*, 18.8, 18.6 *minor isomer. Spectroscopic
data were in good agreement with those previously reported.6
Ketone 18. To a solution of diene 8a (40 mg, 0.16 mmol) and methyl
methacrylate (35 L, 0.32 mmol) in CH2Cl2 (0.5 mL) at -78 ºC was added
SnCl4 (0.1 M in CH2Cl2, 30 L. 0.06 mmol). The resulting solution was
stirred for 3 h at -78 °C, then warmed to 0 ºC and stirred for a further 1 h
before addition of NEt3 (69 L, 0.49 mmol). The reaction mixture was then
concentrated in vacuo and purified by flash chromatography (20% EtOAc
in pet. ether) to afford dimer 18 as a clear oil (yield). IR (film) νmax 2973,
2936, 1672, 1270, 1032, 816; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J =
12.1 Hz, 1H), 6.95 (d, J = 16.1 Hz, 1H), 6.21 (d, J = 16.0 Hz, 1H), 5.73 (d,
J = 12.1 Hz, 1H), 3.71 (s, 3H), 2.85 (sept, J = 6.9 Hz, 1H), 1.30 (s, 6H),
1.12 (d, J = 7.0 Hz, 6 H); 13C NMR (101 MHz, CDCl3) δ 203.9, 199.8,
164.2, 150.2, 126.9, 100.7, 58.3, 49.6, 39.0, 23.9, 18.5.
Adduct 21. To a solution of ethyl 3-methyl-4-oxocrotonate (44 µL, 0.33
mmol) and Sc(OTf)3 (16 mg, 20 mol %) in CH2Cl2 at -78 °C was added
diene 8a (40 mg, 0.16 mmol). The resultant mixture was stirred for 3 h,
then allowed to warm to rt and quenched with NEt3 (69 L, 0.49 mmol).
The reaction mixture was extracted with sat. aq. NH4Cl, washed with brine,
and dried over Mg4SO4. The organic phase was then concentrated in
vacuo and purified by flash chromatography (30% EtOAc in pet. ether) to
give adduct 21 as a clear oil (23 mg, 43%). IR (film) νmax 2978, 2937, 1716,
1466, 1385, 1369, 1269, 1162 cm-1 ;1H NMR (400 MHz, CDCl3)  7.35 (dd,
J = 6.6 Hz, 1H), 5.94 (q, J = 1.1 Hz, 1H), 5.39 (d, J = 5.9 Hz, 1H), 4.54 (s,
1H), 4.19 (q, J = 7.1 Hz, 2H), 2.25 (d, J = 1.5, 3H), 1.30 (t, J = 7.1 Hz, 3H),
1.11 (s, 3H) 1.06 (s, 3H); 13C NMR (101 MHz, CDCl3)  197.6, 166.0, 161.5,
151.1, 120.7, 105.5, 90.4, 60.3, 44.8, 20.0, 19.0, 18.0, 14.4; HRMS (ESI+)
[M + Na] 261.1091 calcd for C13H18NaO4 261.1097.
Diene 8a. To a stirred solution of ketone 13 (2.50 g, 15.6 mmol) and NEt3
(6.52 mL, 46.8 mmol) in Et2O (50 mL) at 0 °C under nitrogen was added
TBSOTf (5.38 mL, 23.4 mmol) dropwise. After 10 min, the solution was
allowed to warm to rt and stir for 3 h by which point two clear layers had
formed. The bottom layer was removed by pipette and the top layer was
concentrated in vacuo. The resultant crude oil was then purified by flash
chromatography on neutral alumina (6% EtOAc in pet. ether) to give diene
1
8a (3.75 g, 99%) as a clear oil. H NMR (400 MHz, CDCl3)  6.63 (d, J =
12.3 Hz, 1H), 5.63 (d, J = 12.4 Hz, 1H), 3.58 (s, 3H), 1.67 (s, 6H), 0.99 (s,
9H), 0.10 (s, 6H); 13C NMR (101 MHz, CDCl3)  149.4, 140.2, 111.2, 101.0,
56.7, 26.2, 19.1, 19.0, 18.5, -3.3. A small impurity corresponding to TBS-
X persists after purification as per report by Rawal et al. Spectroscopic
data were in good agreement with those previously reported by Rawal et
al. 6
Adduct 22. A solution of diene 8a (61 mg, 0.25 mmol) and freshly sublimed
maleic anhydride (49 mg, 0.50 mmol) in toluene (1 mL) was stirred at
100 °C in a round-bottom flask for 2 hours. After cooling to rt, the solution
was concentrated in vacuo and purified by flash chromatography (15%
EtOAc in pet. ether) to afford adduct 14 (31 mg, 36%) as a colorless oil. IR
(film) νmax 2933, 1715, 1637, 1255, 1089 cm-1; 1H NMR (400 MHz, CDCl3)
 4.97 (d, J = 6.4 Hz, 1H), 4.25 (dd, J = 6.4, 5.0 Hz, 1H), 3.36 (dd, J = 10.8,
4.9 Hz, 1H), 3.21 (s, 3H), 3.18 (d, J = 10.9 Hz, 1H), 1.39 (s, 3H), 1.32 (s,
3H), 0.95 (s, 9H), 0.22 (d, J = 1.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) 
171.1, 170.3, 163.1, 97.3, 71.5, 55.5, 49.4, 46.7, 36.8, 28.8, 25.7, 25.2,
18.3, -4.3, -5.1; HRMS (ESI+) [M + Na]+ 363.1598; calc. for C17H28NaO5Si
363.1598.
Diene 8b. To a stirred solution of ketone 13 (1.00 g, 7.80 mmol) and NEt3
(3.26 mL, 23.4 mmol) in Et2O (90 mL) at 0 °C under nitrogen was added
TMSOTf (1.55 mL, 8.58 mmol) dropwise. After 10 min, the solution was
allowed to warm to rt and stir for a further 3 h. The reaction mixture was
quenched by addition of sat. aq. NaHCO3 (30 mL) followed by pentane
(30 mL). The organic layer was then separated and the aqueous phase
was extracted with pentane (30 mL). The combined organic extracts were
then washed with sat. aq. NaHCO3 (2 × 30 mL), H2O (2 × 30 mL), and
brine (2 × 30 mL) and dried over MgSO4. The solvent was removed in
vacuo, and the resultant brown oil was purified by vacuum distillation
(110 °C, 50 mbar) to afford diene 8b (1.20 g, 77%) as a clear oil. IR (film)
νmax 2981, 2936, 1627, 1380, 1045 cm-1; 1H NMR (400 MHz, CDCl3)  6.62
(d, J = 12.6 Hz, 1H), 5.68 (d, J = 12.2 Hz, 1H), 3.58 (s, 3H), 1.66 (s, 3H),
1.66 (s, 3H), 0.18 (s, 9H); 13C NMR (101 MHz, CDCl3) 148.9, 140.6,
111.0, 101.2, 56.8, 18.9, 18.7, 0.82.
Lactone 25 & 26.
Method A. A mixture of diene 8a (1.17 g, 4.82 mmol), distilled citraconic
anhydride (400 mg, 3.57 mmol), and hydroquinone (9.8 mg, 0.09 mmol)
was degassed in a Schlenk tube by prolonged evacuation followed by
back-filling with nitrogen three times. The reaction mixture was then stirred
at 140 °C overnight. After cooling to rt, chloroform (35 mL) and TFA
(1.05 mL) were added and the resulting mixture was stirred for 5 min at rt,
then concentrated in vacuo. The crude mixture was dissolved in AcOH
(40 mL) and NaCNBH3 (1.24 g, 17.9 mmol) was added. The reaction
mixture was stirred at rt for 2 h before concentration in vacuo. The crude
mixture was then dissolved in CH2Cl2 (150 mL) and washed with
Adduct 16. To a solution of methacrolein (30 L, 0.33 mmol) and ZnCl2
(4.5 mg, 0.033 mmol) at 0 ºC in CH2Cl2 (0.5 mL) was added diene 8a
(40 mg, 0.16 mmol). The resultant solution was stirred for 3 h then sat. aq.
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1 M aq. HCl (100 mL). The aqueous phase was then extracted with
CH2Cl2 (3 × 100 mL). The collected organic phases were then washed with
brine (1 × 150 mL), dried over MgSO4 and concentrated in vacuo to afford
a crude mixture of acids 5 and 24. The crude mixture was suspended in
MeOH/benzene (2:1, 30 mL) and TMS diazomethane (2.15 mL, 2 M in
Et2O) added. The resultant mixture was stirred for 15 min then quenched
with AcOH. The reaction mixture was concentrated in vacuo and purified
by flash chromatography (35% EtOAc in pet. ether) to afford a mixture of
lactones 25 (136 mg, 17%) and 26 (60 mg, 7%) as yellow oils.
60.7, 54.4, 48.3, 43.7, 34.2, 27.2, 22.1, 22.0; HRMS (ESI+) [M + H]+
254.1390 calcd for C13H20NO4 254.1387; crystals were obtained for XRD
analysis by evaporation from Et2O; mp. 135-137 °C.
Lactone 30. A mixture of lactone 25 (9.4 mg, 0.042 mmol) and a catalytic
amount of PtO2·H2O in MeOH (1 mL) was stirred at rt under an atmosphere
of H2 (balloon pressure) for 16 h. The mixture was then filtered through
Celite® and the filtrate was concentrated in vacuo to give ester 30 (10 mg,
quant.) as an amorphous white solid. IR (film) νmax 2953, 1755, 1367, 1098,
1040 cm-1;1H NMR (400 MHz, CDCl3)  4.13 (dd, J = 3.8, 1.7 Hz, 1H), 3.68
(s, 3H), 2.51 (s, 1H), 2.12–2.02 (m, 1H), 1.94 (dddd, J = 14.5, 11.7, 6.6,
Method B (One pot optimized): A mixture of diene 8a (141 mg, 0.58 mmol),
distilled citraconic anhydride 11 (45 mg, 0.40 mmol), and hydroquinone (1
mg, 0.01 mmol) was degassed in a Schlenk tube by prolonged evacuation
followed by back-filling with nitrogen three times. The reaction mixture was
then stirred at 140 °C overnight. After cooling to rt, chloroform (5 mL) and
ZnCl2 (1.0 M in Et2O, 150 L) were added and the resulting mixture was
stirred for 20 min before the addition of AcOH (2 mL) and NaCNBH3 (182
mg, 2.9 mmol). The mixture was stirred at rt for a further 30 min before it
was quenched with 1 M aq. HCl (10 mL). The resulting mixture was then
extracted with CH2Cl2 (3 × 15 mL). The collected organic phases were then
washed with brine (1 × 30 mL), dried over MgSO4, and concentrated in
vacuo. Esterification with TMS diazomethane and purification as per
method A afforded a mixture of lactones 25 (8.0 mg, 9%) and 26 (22 mg,
24%) as yellow oils.
3.7 Hz, 1H), 1.81–1.60 (m, 2H), 1.22 (s, 3H), 1.16 (s, 3H), 1.06 (s, 3H); 13
C
NMR (101 MHz, CDCl3)  175.5, 171.3, 83.3, 60.5, 51.6, 40.2, 37.0, 30.6,
28.9, 24.0, 22.5, 19.6; HRMS (ESI+) [M + H]+ 227.1271 calcd for C12H19O4
227.1278.
Associated Content
1
Experimental procedures, analytical data and copies of H and 13C NMR
spectra for novel compounds and ORTEP structures of 25 and 28.
Acknowledgements
[2.2.2]-25: IR (film) νmax 2957, 1436, 1353, 1211, 1100, 1021 cm-1; 1H NMR
(400 MHz, CDCl3)  6.54 (dd, J = 7.6, 5.0 Hz, 1H), 6.14 (dd, J = 7.6, 1.9
Hz, 1H), 4.58 (dd, J = 5.0, 2.0 Hz, 1H), 3.70 (s, 3H), 2.28 (s, 1H), 1.41 (s,
3H), 1.16 (s, 3H), 1.11 (s, 3H); 13C NMR (101 MHz, CDCl3)  173.2, 171.7,
136.8, 133.1, 82.0, 56.6, 51.9, 46.2, 41.4, 29.5, 23.4, 17.2. HRMS (ESI+)
[M + Na]+ 247.0944 calcd for C12H16NaO4 247.0941; Crystals were
obtained for XRD analysis by evaporation from chloroform-hexane, mp
104-107 °C.
The authors thank the University of Auckland for financial support
through a UoA Doctoral Scholarship to PSG.
Keywords: leonuketal • natural products • cycloaddition •
synthetic methods • multistep reaction
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Entry for the Table of Contents (Please choose one layout)
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Phillip S. Grant, Margaret A. Brimble*
and Daniel P. Furkert*
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Synthesis of the Bicyclic Lactone
Core of Leonuketal Enabled by a
Telescoped Diels-Alder Reaction
Sequence
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