Total Synthesis of (±)-Englerin A and Its Tuncated Analogues

Article abstract of DOI:10.1002/ejoc.201801544

A convergent approach allowed total synthesis of (±)-Englerin A, and its truncated analogues, employing a thermal 1,3-dipolar cycloaddition of a highly substituted pyrylium ylide with vinyl acetate as the key step. The key intermediate, a 8-oxabicyclo[3,2,1]octane oxygenated at the C6 position, was directly converted into a truncated Englerin A analogue. Cu^I catalyzed conjugate addition of vinyl Grignard to an enone, ozonolysis, and epimerisation of the resulting aldehyde allowed stereoselective introduction of the side-chain leading to a total synthesis of the racemic natural product. The developed chemistry will allow synthesis of more complex analogues of the natural product based on the use of the key bicyclo[3,2,1]octane scaffold.

Full text of DOI:10.1002/ejoc.201801544

DOI: 10.1002/ejoc.201801544
Full Paper
Total Synthesis
Total Synthesis of ( )-Englerin A and Its Tuncated Analogues
Colleen Reagan,[a] Graham Trevitt,[b] and Kirill Tchabanenko*[a]
Abstract: A convergent approach allowed total synthesis of ozonolysis, and epimerisation of the resulting aldehyde allowed
( )-Englerin A, and its truncated analogues, employing a ther-
mal 1,3-dipolar cycloaddition of a highly substituted pyrylium
ylide with vinyl acetate as the key step. The key intermediate,
a 8-oxabicyclo[3,2,1]octane oxygenated at the C6 position, was
directly converted into a truncated Englerin A analogue. CuI
catalyzed conjugate addition of vinyl Grignard to an enone,
stereoselective introduction of the side-chain leading to a total
synthesis of the racemic natural product. The developed chem-
istry will allow synthesis of more complex analogues of the nat-
ural product based on the use of the key bicyclo[3,2,1]octane
scaffold.
Introduction
the supervision of Beutler in 2008.[1,2] It shows high potency
and selectivity against a panel of renal cancers with no toxicity
against normal renal cells. The remarkable properties and chal-
lenging structure have rendered Englerin A as a highly attract-
ive synthetic target resulting in a number of elegant total syn-
theses and synthetic approaches.[3–18] Many of the authors have
identified the oxygen-bridged seven-membered ring of the
natural product as the key component and applied 1,3-dipolar
cycloaddition strategies for its construction. [4+3] Cycloaddi-
tions of furans with oxy-allyl cation equivalents[9,10,12] and [5+2]
cycloadditions of pyrylium ylides[5] and carbonyl ylides[15,16]
have become reactions of choice for rapidly assembling this
skeleton (Figure 1).
Englerin A (1) is a naturally occurring sesquiterpene that was
isolated from bark of Phyllanthus engleri by the NCI group under
Our group has been involved in developing new applications
for the 1,3-dipolar cycloaddition of pyrylium ylides over a num-
ber of years.[19,20] We also became interested in developing a
novel rapid approach to Englerin A and a number of analogues
using this versatile reaction.
Results and Discussion
Synthetic Strategy
Early on we decided to develop a cycloaddition of a substituted
pyrylium species 2 with an oxygen substituted dipolarophile
(Scheme 1) that would enable direct synthesis of the hydroxyl
function at the C-6 position of the seven-membered ring of
the natural product. Next we decided to develop a convergent
approach to a number of Englerin A analogues via a common
cycloadduct. Thus reduction of the enone double bond fol-
lowed by simple functional group conversion will lead to a trun-
cated analogue 3,[21] whilst a conjugate addition to the enone
would require the correction of stereochemistry at C-4, and
eventually lead to the required natural product. In addition, we
envisaged the possibility to perform further cycloaddition reac-
tions, for example the Diels-Alder reaction of the enone, shown
in Scheme 1, thus allowing approach to more complex ana-
logues like 4.
Figure 1. Dipolar cycloaddition strategies to 1.
[a] School of Chemistry and Chemical Engineering, Queen's University Belfast
David Keir Building, Belfast, BT9 5AG, United Kingdom
E-mail: k.tchabanenko@qub.ac
[b] Almac Discovery Ltd.
Almac House, 20 Seagoe Industrial Estate, Craigavon, BT63 5QD United
Kingdom
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201801544.
Eur. J. Org. Chem. 0000, 0–0
1
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 1. Convergent strategy towards 1 and its analogues.
Synthesis of a Simple Analogue 9
Although the earlier SAR studies by Christmann and co-work-
ers[4] showed the importance of the isopropyl group for the
biological activity of Englerin A, we decided to start our investi-
gation with the synthesis of a fully truncated analogue 9
(Scheme 2). We anticipated that the search for a suitable oxy-
genated dipolarophile and the optimization of the functional
group transformations would be easier to carry out starting
with a simple acetoxy pyrone 5, a product of oxidation and
acetylation of furfuryl alcohol.[22,23] With multigram quantities
of the pyrone 5 in hand we quickly discovered that a thermal
cycloaddition was possible with vinyl acetate[24] giving a mix-
ture of diastereo-, and regioisomeric adducts 6, 7 and 8
(Scheme 2). The reaction was best carried out using vinyl acet-
ate as a solvent and the cycloadducts, 6–8, were easily sepa-
rated by column chromatography.
Scheme 2. Synthesis of a simple analogue 9.
complications with chemoselective hydrolysis of an acetate in
the presence of a cinnamate ester later in the synthesis. Sodium
borohydride reduction of the ketone was followed by Yamagu-
chi esterification. Synthesis of 9 was accomplished by reaction
with the cesium salt of glycolic acid introducing the glycolate
ester with inversion of stereochemistry at the C-6.[11] The se-
quence allowed rapid synthesis of the fully truncated analogue
9, which we were now ready to investigate for the adduct bear-
ing the isopropyl and methyl groups.
The reaction required 18 hours to achieve full consumption
of the acetoxy pyrone starting material. The attempt to further
Cycloaddition of a Substituted Pyrylium Ylide
heat the mixture of 6, 7 and 8 expecting isomerization to the The acetoxy pyrone precursor 10 was readily prepared from com-
most stable adduct failed. We could not determine any equili- mercially available 5-methylfurfuryl aldehyde (Scheme 3).[10]
bration of the products in the mixture, instead we only ob- Although we discovered that all our attempts to purify 10 led
served gradual decomposition of the products under the high to hydrolysis of the acetate, it was possible to obtain a very
temperature. The structure and stereochemistry of the regioiso- pure product if the acetylation step was followed by a rapid
meric cycloadduct 8 was confirmed by X-ray crystallography.[25] aqueous workup and removal of the excess acetic anhydride
under reduced pressure. The crude pyrone 10 was heated with
vinyl acetate as previously discussed for the simple pyrone 5.
But this time the reaction noticeably became darker in color
and was stopped after 45 minutes. NMR analysis showed that
no starting pyrone remained, and a complex product mixture
was obtained. Purification by flash chromatgrahy allowed sepa-
ration of five new products 11–15 (Scheme 3 and Table 1).
Analysis of the product structures immediately identified the
Our next aim was to develop a straight-forward conversion
of the major endo adduct 6 into 9 (Scheme 2) including an
inversion of the C-6 hydroxyl stereochemistry. We planned to
accomplish this in analogy to the chemistry described by Chain
and co-workers in their remarkably short total synthesis of
(–)-1.[11] The enone double bond in 6 was reduced over palla-
dium on carbon and the acetate was then substituted for a
sulfonylimidazole group required for the inversion step. We rea-
soned that an early protecting group exchange would avoid problem with the cycloaddition of 10 – formation of the alkene
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
2
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 3. Cycloaddition of substituted pyrone 10.
Table 1. Optimization of conditions.
the initial double bond reduction and exchange of the acetate
for the sulfonyl imidazole group worked well, the sodium boro-
hydride ketone reduction produced a 1:1 mixture of epimeric
alcohols. The attempted Yamaguchi esterification of the mixture
of both epimers resulted in the loss of the sulfonylimidazole
group and formation of multiple products resulting from non-
selective esterification of two diastereoisomeric diols. Thus
showing that a different protecting strategy for the alcohol at
C-6 was required. At this point in the synthesis we had a signifi-
cant amount of alcohol 14 which we submitted to the Luche
reduction conditions. Under these conditions the desired epi-
mer of the diol 15 was obtained as a major product. It was
isolated and its structure was confirmed by X-ray analysis.[28]
Double Yamaguchi esterification was then attempted giving the
bis-cinnamate ester 16, which was subjected to mild ester hy-
drolysis conditions.[5] This resulted in selective hydrolysis of the
ester at the C-6 position of the seven membered ring. The ob-
served change in reactivity and selectivity is mostly due to the
presence of the isopropyl group in the more substituted series.
Whereas in the simple analogue case all reagents approached
the bicyclic system from the face of the oxygen bridge giving
remarkable selectivity, the presence of the isopropyl group in
the latter case makes the face of the oxygen bridge more hin-
dered, what leads to lower facial selectivity of the observed
transformations. The isopropyl group also hinders the ester at
C-2 making it unreactive towards mild nucleophiles.
Additive/Product yield
11[a]
12[b]
13[b]
14[b]
15[b]
No additive
25
16
23
trace
2
trace
10
8
16
28
30
6
4
9
15
16
5
3
7
14
15
10 mol-% AcOH
45
50 mol-% pyridine
1 equiv. 2,6-lutidine
1 equiv. 2,6-ditBu-pyridine
trace
5
trace
[a] Yields from analysis of crude nmrs. [b] Isolated yields.
11 and its subsequent cycloaddition with pyrylium 2 to give
the spirocyclic dimer 12,[26] whose structure was confirmed by
X-ray analysis.[27] The pyrylium species 2 and alkene 11 are iso-
mers, and it was our aim to establish whether equilibration and
overall formation of unwanted by-products could be overcome
by controlling the reaction pH. Thus 10 mol-% of acetic acid
was added to the reaction mixture. This increased the yields of
the unwanted elimination product 11 and the dimer 12,
(Table 1 row 2). On the contrary, addition of pyridine eliminated
the formation of these side products. (Table 1 row 3). Use of
less nucleophilic 2,6-lutidine and 2,6-di-tert-butylpyridine led to
further increase in the yield of the desired cycloadduct 13.
Once again, we were unable to achieve interconversion of the
products 13–15 on attempted heating in toluene, showing that
the cycloaddition with vinyl acetate is irreversible under neutral
conditions. A threefold improvement in the reaction yield from
the initial attempt allowed multigram synthesis of the required
cycloadduct 13 from the readily available acetoxy pyrone 10.
With this in mind we attempted an approach to the trun-
cated Englerin A analogue 3 keeping the acetate protecting
group until the final steps of the synthesis (Scheme 5). Also we
decided to perform the Luche reduction on the enone 13 prior
to the hydrogenation of the enone double bond, similar to the
strategy of Theodorakis and co-workers.[10]
Synthesis of the Truncated Analogue 3
Initially we intended to carry out the same sequence of reac-
tions which were successfully applied in the synthesis of the
simple analogue 5 but this time on the cycloadduct 13 possess-
Reduction of the ketone group in 13 proceeded with even
ing an extra isopropyl and methyl groups (Scheme 4). Whereas higher stereoselectivity, giving only trace amounts of the un-
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
3
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 4. Initial attempts to make 3.
Scheme 5. Completion of the truncated analogue 3.
wanted epimer at the C-2 position. This time we were able to would allow epimerization if needed and further direct build-
use the acetate as protecting group for the C-6 alcohol and over up of the side chain. We were able to incorporate the aldehyde
a short number of steps (Scheme 5) completed the synthesis of via a CuI catalyzed conjugate addition of vinyl Grignard[29] and
truncated analogue 3, which further streamlined our strategy ozonolysis of the double bond (Scheme 6). The conjugate addi-
for the synthesis of ( )-Englerin A (1).
tion was stereoselective giving a single adduct 16 (Scheme 6)
with the opposite stereochemistry of the newly formed C-C
bond to the one required for the total synthesis. Thus the vinyl
group was ozonolyzed to an aldehyde 17. Epimerization of the
Introduction of the Side Chain
From the outset we envisaged installation of an aldehyde moi- aldehyde group in 17 was complicated by the possibility of the
ety at the C4 of the oxygen bridged seven membered ring. This oxygen bridge elimination, and a mild procedure was required.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
4
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 6. Synthesis of the aldol precursor 19.
The best result was obtained when we used pyrrolidine and tions.[30] Standard hydrogenation afforded the intramolecular
acetic acid at low temperature.
aldol precursor 18.
Epimerization took over 2 days resulting in a 3:1 mixture
of epimers favoring the isomer with relative stereochemistry
required for the total synthesis of Englerin A. This fortunate
outcome was probably due to the preference of the aldehyde
Completion of the Synthesis
group to adopt an equatorial position in 17′ as shown in Next we performed the intramolecular aldol cyclisation to form
Scheme 6. No further conversion of 17 into 17′ was possible the five-membered ring of the natural product. Although our
on prolonged treatment under indicated conditions. Careful advanced intermediate 19 was close in structure to the similar
column chromatography allowed isolation of essentially pure aldol precursor in Nicolaou and Chen's route,[5] we discovered
aldehyde 17′. Wittig olefination with 1-(triphenylphosphoranyl- that the acetoxy protecting group was incompatible with the
idene)-2-propanone was carried out under literature condi- highly basic conditions required for a direct conversion of 18
Scheme 7. Completion of the total synthesis.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
5
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
5.0 Hz), 6.02 (1H, d, J 10 Hz), 5.16 (1H, dd, J 7.0, 2.5 Hz), 4.74 (1H, d,
5.0 Hz), 4.69 (1H, d, J 8.0 Hz), 2.35 (1H, ddd, J 14.0, 8.0, 2.5 Hz), 2.26
(1H, dd, J 14.0, 7.0 Hz); 2.10 (3H, s); 13C (100 MHz, CDCl3) 195.6,
170.9, 147.8, 127.4, 81.4, 78.6, 74.8, 32.7, 21.0; m/z (ES+) found
183.0664 (MH+) C9H11O4 requires 183.0657.
into the enone 19. But treatment of the diketone 18 with one
equivalent of base, allowing the aldol to go to completion and
quenching with acid at low temperature allowed separation of
two diastereomeric adducts in nearly 1:1 ratio (Scheme 7). The
syn ring fusion was assigned for both products based on the
same coupling constant between the ring junction hydrogens.
Both adducts were submitted to mild elimination conditions
giving the enone 19. Luche reduction, Crabtree directed hyd-
rogenation and Yamaguchi esterification were performed ac-
cording to literature procedures.[5] As previously in the synthesis
of the truncated analogue 3 we were able to selectively hydro-
lyse the acetate, leaving the cinnamate ester intact, and the
final two steps were carried out according to Chain's meth-
ods[11] resulting in formation of racemic Englerin A (1).
Cycloadduct 8: White crystalline solid (111.0 mg, 10 %) m.p. 148 °C;
νmax(KBr) 1741 (s), 1712 (s), 1040 (m); 1H (400 MHz, CDCl3) 7.37 (1H,
dd, J 10.0, 4.5 Hz), 6.10 (1H, d, J 10.0 Hz), 5.59 (1H, m), 4.77 (2H, m),
2.61 (1H, ddd, J 13.0, 9.0, 2.5 Hz), 1.95 (3H, s), 1.90 (1H, dd, J 13.0,
2.5 Hz); 13C (100 MHz, CDCl3) 193.2, 170.0, 152.6, 127.4, 82.3, 72.8,
71.1, 35.1, 20.6; m/z (ES+) found 183.0644 (MH+) C9H11O4 requires
183.0657.
(rel-1R,5R,6R)-2-Oxo-8-oxabicyclo[3.2.1]octan-6-yl Acetate: To a
solution of cycloadduct 6 (1.1 g, 6.1 mmol) in ethyl acetate (30 mL)
was added palladium on carbon (5 wt.-%, 100 mg) and the resulting
mixture was stirred under an atmosphere of hydrogen (atmospheric
pressure) for 4 h. On completion the reaction was filtered through
a pad of Celite and concentrated to give an essentially pure product
as a colorless oil (1.109 g, quant), which was used further without
extra purification. νmax(thin film) 1731 (s), 1607 (s), 1275 (m), 1254
Conclusions
In conclusion total synthesis of ( )-Englerin A based on a 1,3-
dipolar cycloaddition of a substituted pyrylium ylide with vinyl
acetate was achieved in 17 steps. New strategy allowed the
synthesis of truncated analogues alongside with the natural
product. Interesting stereochemical effects of the bridgehead
substituents on the reactivity of the 8-oxabicyclo[3.2.1]octanes
were uncovered. Synthesis of new analogues of the natural
product, based, on the new methodology, is currently under
way in our research laboratory.
1
(m); H (500 MHz, CDCl3) 5.22 (1H, ddd, J 8.0, 6.0, 4.5 Hz), 4.57 (1H,
app t, J 6.0 Hz), 4.16 (1H, d, J 8.0 Hz), 2.65 (1H, ddd, J 10.0, 9.0,
6.0 Hz), 2.51 (1H, dd, J 17.0, 9.0 Hz), 2.38 (1H, dd, J 17.0, 8.0 Hz),
2.13 (1H, m), 2.03 (3H, s), 1.92 (1H, ddd, J 14.0, 8.0, 6.0 Hz), 1.72 (1H,
dd 14.0, 4.5 Hz); 13C (125 MHz, CDCl3) 207.0, 170.4, 80.8, 74.3, 73.1,
35.2, 32.50, 24.6, 20.8; m/z (EI+) found 184.0705 (M+) C9H12O4 re-
quires 184.0692.
(rel-1R,5R,6R)-6-Hydroxy-8-oxabicyclo[3.2.1]octan-2-one: To
solution of acetate ester starting material (500 mg, 2.75 mmol) in
THF (10 mL) was added aqueous lithium hydroxide (1 , 3 mL)
a
M
dropwise over a period of 2 min and the resulting mixture was
stirred for 2 h. Solvents were removed under reduced pressure and
the residue was purified by filtration through a short pad of silica
using ethyl acetate as eluent to give the product as a colorless oil
(347 mg, 89 %); νmax(thin film) 3661 (br s), 1727 (s), 1273 (s); 1H
(500 MHz, CDCl3) 4.62 (1H, m), 4.36 (1H, app t, J 6.0 Hz), 4.10 (1H,
d, J 8.5 Hz), 2.65 (1H, m), 2.57 (1H, ddd, J 12.5, 8.0, 6.5 Hz), 2.33 (1H,
dd, J 17.0, 7.5 Hz), 2.23 (1H, m) 2.07 (1H, m), 1.61 (1H, dd, J 14.0,
2.0 Hz); 13C (125 MHz, CDCl3) 208.6, 81.2, 76.0, 71.2, 38.2, 32.7, 24.1;
m/z (EI+) found 142.0630 (M+) C7H10O3 requires 142.0631.
Experimental Section
General Experimental: All reactions were carried out under atmos-
phere of argon unless stated otherwise. Reaction solvents (THF, di-
ethyl ether) were freshly distilled from sodium/benzophenone un-
der argon atmosphere prior to use. Dichloromethane and toluene
were freshly distilled from calcium hydride under an argon atmos-
phere. All reagents were purchased from Sigma-Aldrich and were
used as received unless specified. All NMR spectroscopic data was
collected on a Bruker DRX-500, Bruker AV-400 or Bruker Av-300
spectrometers. All NMR experiments were run in CDCl3 apart from
the final sample of ( )-Englerin A, which was run in [D6]DMSO for
comparison with literature data. IR spectra were collected on a Per-
kin-Elmer Spectrum One FT-IR spectrometer and mass-spec data
was collected on a Waters GCT-Premier Spectrometer with nano-
mate attachment.
(rel-1R,5R,6R)-2-Oxo-8-oxabicyclo[3.2.1]octan-6-yl 1H-Imidaz-
ole-1-sulfonate: A stirred solution of free alcohol starting material
(150 mg, 1.05 mmol) in THF (10 mL) was cooled to –40 °C and
sodium hydride (60 % dispersion in mineral oil, 44 mg, 1.1 mmol)
was added in one portion. The resulting mixture was stirred for 1 h
at –40 °C and solid sulfonyldiimidazole (396 mg, 1.5 mmol) was
added. The solution was warmed to room temperature and stirring
was continued for 3 h. The reaction was diluted ethyl acetate (2 ×
20 mL), and washed with brine (2 × 10 mL), dried (MgSO4), and the
solvent was evaporated to give the crude oil, which was purified by
column chromatography (2:1 petroleum ether/ethyl acetate) to give
the product as a pale yellow oil (205 mg, 72 %); νmax(thin film) 1729
(rel-1R,5R,6R)-2-Oxo-8-oxabicyclo[3.2.1]oct-3-en-6-yl
Acetate
(6): A solution of an unsubstituted acetoxy pyrone[22] (2 g,
12.8 mmol) in vinyl acetate (30 mL, excess) was placed in a sealed
tube and heated in an oil bath at 180 °C for 18 h. The solvent was
removed in vacuo and the residual oil was purified by flash column
chromatography (3:1 petroleum ether/ethyl acetate eluent).
1
(s), 1350 (br s), 1273 (m), 1045 (s); H (500 MHz, CDCl3) 8.01 (1H, s),
Cycloadduct 6: A colorless oil (1.11 g, 48 %); νmax(thin film) 1737
(s), 1710 (s), 1693 (m), 1072 (m); H (400 MHz, CDCl3) 7.12 (1H, dd,
1
7.34 (1H, s), 7.22 (1H, s), 5.13 (1H, ddd, J 10.5, 6.0, 3.0 Hz), 4.57 (1H,
app t, J 6.0 Hz), 2.63 (1H, ddd, J 15.0, 10.0, 8.5 Hz), 2.51 (2H, m),
2.25 (1H, m), 2.11 (1H, m), 1.76 (1H, ddd, J 15.0, 3.0, 2.0 Hz); 13C
(125 MHz, CDCl3) 205.0, 136.9, 131.9, 117.7, 82.0, 80.2, 73.9, 34.1,
31.8, 24.0; m/z (EI+) found 272.0492 (M+) C10H12O5N2S requires
272.0467.
J 10.0, 4.5 Hz), 6.20 (1H, d, J 10.0 Hz), 5.29 (1H, ddd, J 9.0, 5.5,
4.0 Hz), 5.02 (1H, dd, J 5.5, 4.5 Hz), 4.48 (1H, d, J 8.5 Hz), 2.85 (1H,
ddd, J 13.5, 9.0, 4.5 Hz), 2.03 (3H, s), 1.70 (1H, dd, J 13.5, 4.0 Hz); 13
C
(100 MHz, CDCl3) 195.9, 170.6, 149.1, 128.4, 80.7, 74.5, 72.9, 31.7,
20.6; m/z (ES+) found 183.0665 (MH+) C9H11O4 requires 183.0657.
Cycloadduct 7: A colorless oil (302 mg, 13 %); νmax(thin film) 1738
(rel-1R,2R,5R,6R)-2-Hydroxy-8-oxabicyclo[3.2.1]octan-6-yl 1H-
(s), 1732 (s), 1072 (m); 1H (400 MHz, CDCl3) 7.22 (1H, dd, J 10.0, Imidazole-1-sulfonate: To a stirred solution of ketone starting ma-
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
terial (150 mg, 0.55 mmol) in methanol (8 mL) at 0 °C was added
sodiumborohydride (21 mg, 0.55 mmol) in one portion. The reac-
tion was stirred for 30 min and was concentrated under reduced
pressure. The residue was purified by column chromatography (1:1
and was diluted with DCM (100 mL). The resulting solution was
successively washed with CuSO4 (10 % aqueous, 3 × 100 mL), deion-
ised water (2 × 30 mL), NaHCO3 (sat. aq. 2 × 50 mL) and brine (2 ×
50 mL), dried (Na2SO4) and all volatiles were removed in vacuo[31]
petroleum ether/ethyl acetate as eluent). The product was isolated giving the crude acetoxy pyrone 10 (2.5 g, quant.). Which was
as a colorless oil (89 mg, 59 %); νmax(thin film) 3501 (br s), 1345 (br mixed with vinyl acetate (30 mL) and 2,6-lutidine (1.36 mL,
1
s), 1262 (m), 1053 (s); H (300 MHz, CDCl3) 8.01 (1H, s), 7.36 (1H, s),
7.20 (1H, s), 5.00 (1H, ddd, J 10.0, 6.0, 4.0 Hz), 4.23 (1H, app t, J
6.0 Hz), 4.12 (1H, dd, J 7.5, 4.0 Hz), 3.94 (1H, ddd, J 10.0, 5.5, 4.0 Hz),
2.27 (1H, ddd, J 14.5, 10.0, 7.5 Hz), 2.01–1.68 (4H, m), 1.53 (1H, ddd,
J 12.0, 10.0, 6.0 Hz); 13C (100 MHz, CDCl3) 137.1, 132.0, 118.0, 83.2,
78.8, 76.1, 67.5, 30.6, 29.7, 25.6; m/z (ES+) found 275.0702 (MH+)
11.76 mmol) and the resulting solution was transferred into a sealed
tube which was immersed into an oil bath pre-heated at 180 °C.
The reaction was continued for 45 min when the sealed tube was
lifted from the oil bath and was cooled down to room temperature
over a period of 1 h. Removal of volatiles was followed by silica gel
column chromatography (5:1 petroleum ether/ethyl acetate) to give
the reaction products.
C
10H15O5N2S requires 275.0712.
Elimination Product 11 was never isolated in pure form due to its
low polarity and volatility. The yield of 11 was assumed based on
the relative integration of characteristic vinylic region peaks to
those of the isolated adduts in the crude 1H nmr. 1H (300 MHz,
CDCl3) 6.99 (1H, d, J 10.0 Hz), 6.04 (1H, d, J 10.0 Hz), 4.93 (1H, s),
4.62 (1H, s), 4.22 (1H, d, J 5.0 Hz), 2.25 (1H, m), 1.02 (3H, d, J 6.5 Hz),
0.96 (3H, d, J 6.5 Hz).
(rel-1R,2R,5R,6R)-6-{[(1H-Imidazol-1-yl)sulfonyl]oxy}-8-oxa-bi-
cyclo[3.2.1]octan-2-yl Cinnamate: To a stirred solution of alcohol
starting material (45 mg, 0.17 mmol) in toluene (7 mL) were added
cinnamic acid (50 mg, 0.34 mmol), triethylamine (50 μL, 0.36 mmol),
2,4,6-trichlorobenzoyl chloride (55 μL, 0.35 mmol) and DMAP (3 mg,
0.024 mmol) in succession and the mixture was stirred at room
temperature for 16 h. The reaction was quenched with NaHCO3 (sat.
aq., 2 mL) and was extracted with ethyl acetate (2 × 10 mL). The
combined organic layers were washed with brine (10 mL), dried
(MgSO4) and concentrated in vacuo. Flash column chromatography
(3:1 petroleum ether ether/ethyl acetate) afforded a colorless oil
(35.7 mg, 52 %); νmax(thin film) 1692 (s), 1420 (m), 1387 (br s), 1372,
(m), 1127 (m); 1H (400 MHz, CDCl3) 8.03 (1H, s), 7.64 (1H, d,
J 16.5 Hz), 7.53 (2H, m), 7.39 (4H, m), 7.23 (1H, s), 6.37 (1H, d, J
16.5 Hz), 5.09 (1H, ddd, J 10.0, 5.5, 4.0 Hz), 4.96 (1H, ddd, J 10.0, 6.0,
4.0 Hz), 4.51 (1H, app t, J 6.0 Hz), 4.40 (1H, dd, J 8.0, 4.0 Hz), 2.21
(1H, ddd, J 15.0, 10.9, 6.5 Hz), 2.03 (1H, dd, J 15.0, 4.5 Hz), 1.89–1.75
(2H, m), 1.66 (2H, m); 13C (100 MHz, CDCl3) 165.8, 145.9, 137.0, 134.1,
131.6, 130.5, 128.9, 128.1, 117.9, 117.4, 82.9, 79.8, 76.2, 70.1, 30.2,
24.8, 22.5; m/z (ES+) found 405.1120 (MH+) C19H21O6N2S requires
405.1120.
Spirocycle 12: A white crystalline solid (35.8 mg, 2 %) m.p. 156 °C;
νmax(KBr) 1739 (s), 1768 (s), 1256 (m), 1140 (m); 1H (400 MHz, CDCl3)
6.99 (1H, d, J 9.0 Hz), 6.95 (1H, d, J 11.0 Hz), 6.11 (1H, d, J 11.0 Hz),
6.10 (1H, 9.0 Hz), 3.85 (1H, d, J 2.5 Hz), 2.41 (1H, m), 2.38 (1H, d, J
13.5 Hz), 2.25 (1H, m), 2.18 (1H, d, J 13.5), 1.41 (3H, s), 1.03 (6H, d, J
7.5 Hz), 0.94 (3H, d, J 7.0 Hz), 0.82 (3H, d, J 7.0 Hz); 13C (100 MHz,
CDCl3) 197.4, 195.5, 154.1, 150.4, 126.6, 125.8, 88.3, 84.9, 81.4, 82.0,
38.7, 30.5, 28.3, 19.1, 18.8, 17.3, 16.3, 15.7; m/z (ES+) found 305.1768
(MH+) C18H25O4 requires 305.1753.
Cycloadduct 13: A colorless oil (783 mg, 28 %); νmax(thin film) 1738
(s), 1732 (s), 1072 (m); 1H (400 MHz, CDCl3) 6.93 (1H, d, 10.0 Hz),
6.10 (1H, d, J 10.0 Hz), 4.93 (1H, dd, J 9.0, 5.0 Hz), 2.75 (1H, dd J
14.0, 9.0 Hz), 2.19 (1H, sept, J 5.0 Hz), 2.03 (3H, s), 1.52 (1H, dd, J
14.0, 5.0 Hz), 1.52 (3H, s), 1.02 (3H, d, J 5.0 Hz), 1.00 (3H, d, J 5.0 Hz);
13C (100 MHz, CDCl3) 198.0, 170.4, 152.2, 128.3, 89.0, 79.7, 78.9, 36.2,
30.5, 21.7, 20.8, 17.3, 16.2; m/z (ES+) found 239.1292 (MH+) C13H19O4
requires 239.1283.
Cesium Glycolate: Glycolic acid (91.6 g, 20.3 mmol) and cesium
carbonate (3 g, 9.23 mmol) were added to a steel reaction vessel
containing a steel ball bearing. The reaction was carried out in a
shaker mill at 25 MHz for 30 minutes. The solid product was dried
in high vacuum of a Schlenk line (0.1 mm Hg) while heated at 40 °C
in an oil bath for 16 h. This gave a white solid material (2.65 g,
63 %) which was used without any further purification.
Cycloadducts 14 & 15: Were isolated as a 1.1:1 mixture, a pale
yellow oil (807.5 mg, 29 % combined yield); 1H (400 MHz, CDCl3)
7.06 (1H, d, J 9.5 Hz), 6.93 (1H, d, J 9.5 Hz), 6.02 (1H, d, J 9.5 Hz),
5.93 (1H, d, J 9.5 Hz), 5.52 (1H, dd, J 8.5, 2.0 Hz), 5.18 (1H, dd, J 7.0,
2.0 Hz), 2.37 (1H, sept,7.5 Hz), 2.24 (m, 3H), 2.12 (3H, s), 2.18–2.01
(2H, m), 1.93 (3H, s), 1.49 (3H,s), 1.42 (3H, s), 1.05 (6H, d, J 7.5 Hz),1.05
(3H, d, J 7.0 Hz), 0.98 (3H, d, J 7.0 Hz); 13C (100 MHz, CDCl3) 197.9,
195.3, 170.5, 170.1, 154.8, 151.8, 128.1, 127.5, 91.9, 89.5, 82.3, 78.7,
75.4, 73.8, 43.9, 37.2, 30.5, 29.4, 33.5, 20.9, 18.3, 17.6, 16.7, 16.1; m/z
(ES+) found 239.1275 (MH+) C13H19O4 requires 239.1283.
(rel-1R,2R,5R,6S)-6-(2-Hydroxyacetoxy)-8-oxabicyclo[3.2.1]-
octan-2-yl Cinnamate (9): Cesium glycolate (55.6 mg, 0.27 mmol)
was added to the solution of monoester starting material (21.7 mg,
0.054 mmol) and 18-crown-6 (71 mg, 0.27 mmol) in toluene (3 mL).
The resultant mixture was heated at reflux for 18 h. The solvent was
removed in vacuo and the crude mixture was purified by silica gel
column chromatography (2:1 petroleum ether ether/ethyl acetate)
to give 9 as a colorless oil (8.6 mg, 48 %); νmax(thin film) 3527 (br
s), 1720 (s), 1638 (s), 1470 (m), 1273 (s); 1H (500 MHz, CDCl3) 7.67
(1H, d, J 16.0 Hz), 7.52 (2H, m), 7.39 (3H, m), 6.39 (1H, d, J 16.0 Hz),
5.24 (1H, dd, J 8.0, 3.0 Hz), 5.00 (1H, ddd, J 10.5, 5.5, 4.0 Hz), 4.26
(1H, m), 4.17 (2H, s), 2.59 (1H, dd, J 14.0, 7.5 Hz), 2.33 (1H, br s OH),
2.10 (1H, m), 1.99 (1H, ddd, J 13.5, 7.0, 2.5 Hz), 1.91–1.71 (2H, m),
1.46 (1H, m); 13C (125 MHz, CDCl3) 177.3, 165.9, 145.3, 134.2, 130.5,
128.9, 128.1, 117.7, 79.8, 78.4, 76.1, 68.8, 60.8, 33.7, 26.3, 22.6; m/z
(ES+) found 355.0696 (MNa+) C18H20O6Na requires 355.0681.
(rel-1S,5R,6R)-1-Isopropyl-5-methyl-2-oxo-8-oxabicyclo[3.2.1]-
octan-6-yl Acetate: To a solution of adduct 13 (250 mg, 1.05 mmol)
in ethyl acetate (8 mL) was added palladium on carbon (5 wt.-%,
15 mg) and the resulting mixture was stirred under an atmosphere
of hydrogen (atmospheric pressure) for 4 h. On completion the re-
action was filtered through a pad of Celite and concentrated to give
an essentially pure reduction product as a colorless oil (250.5 mg,
quant), which was used further without extra purification. νmax(thin
1
film) 1750 (s), 1705 (s), 1020 (m); H (400 MHz, CDCl3) 4.90 (1H, dd,
J 10.0, 3.5 Hz), 2.57 (2H, m), 2.47 (1H, ddd, J 16.5,8.5, 4.5 Hz), 2.20
(1H, ddd, J 13.5, 10.0, 3.5 Hz), 2.12(1H, m), 2.10 (3H, s), 1.96 (1H,
(rel-1S,5R,6R)-1-Isopropyl-5-methyl-2-oxo-8-oxabicyclo[3.2.1]-
oct-3-en-6-yl Acetate (13): To the solution of substituted hydroxyl- ddd, J 13.5, 8.5, 8.5 Hz), 1.65 (1H, dd, J 13.5, 3.5 Hz), 1.39 (3H, s),
pyrone[10] (2.00 g, 11.76 mmol) in DCM (30 mL) at 0 °C were succes-
sively added acetic anhydride (20 mL), pyridine (10 mL) and DMAP
(95 mg, 0.78 mmol). The reaction mixture was stirred for 4 h at 0OC
0.94 (3H, d, J 6.5 Hz), 0.93 (3H, d, J 6.5 Hz); 13C (100 MHz, CDCl3)
209.6, 170.4, 88.8, 80.6, 78.40, 38.0, 34.3, 31.7, 30.4, 24.9, 20.9, 17.1,
16.7; m/z (ES+) found 241.1455 (MH+) C13H21O4 requires 241.1440.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
7
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(rel-1S,2R,5R,6R)-1-Isopropyl-5-methyl-8-oxabicyclo[3.2.1]- (1H, dd, J 9.5, 6.5 Hz), 4.63 (1H, m), 2.29 (1H, dd, J 14.0, 9.5 Hz), 2.04
octane-2,6-diol (15): To a stirred solution of the ketone (200 mg,
1.01 mmol) in methanol (7 mL) were added cerium trichloride hep-
tahydrate (745 mg, 2 mmol) followed by sodiumborohydride
(76 mg, 2 mmol) and the reaction mixture was stirred for 1 h. The
reaction was quenched by addition of NH4Cl (sat. aqueous, 0.5 mL)
and extracted with ethyl acetate (2 × 50 mL). Combined organic
extracts were dried (MgSO4) and concentrated in vacuo. The residue
was purified by flash column chromatography (SiO2, petrol/ethyl
acetate, 1:2) to give the syn-diol 15 as a white crystalline solid
(3H, s), 2.02 (1H, dd, J 14.0, 6.5 Hz), 1.91 (1H, sept, J 6.5 Hz), 1.30
(3H, s), 1.03 (3H, d, J 6.5 Hz), 1.00 (3H, d, J 6.5 Hz); 13C (100 MHz,
CDCl3) 170.8, 133.7, 129.6, 84.8, 80.8, 78.0, 70.4, 34.3, 32.3, 21.3,
21.0, 17.2, 17.1; m/z (EI+) found 240.1351 (MH+) C13H21O4 requires
240.1362.
(rel-1S,2R,5R,6R)-2-Hydroxy-1-isopropyl-5-methyl-8-oxabicy-
clo[3.2.1]octan-6-yl Acetate: To a solution of the allylic alcohol
starting material (350 mg, 1.45 mmol) in ethyl acetate (8 mL) was
added palladium on carbon (5 wt.-%, 15 mg) and the resulting mix-
ture was stirred under an atmosphere of hydrogen (atmospheric
pressure) for 8 h. On completion the reaction was filtered through
a pad of Celite and concentrated. Flash column chromatography
(silica gel, 4:1 petroleum ether ether/ethyl acetate eluent) gave the
reduction product as a pale yellow oil (322 mg, 92 %); νmax(thin
1
(112.5 mg, 56 %); νmax(KBr) 3691 (br, s), 1273 (m), 1019 (m); H
(400 MHz, CDCl3) 3.84 (1H, dd, J 11.0, 5.5 Hz), 3.57 (1H, m), 2.33–
2.04 (3H, m), 2.16 (1H, dd, J 12.5, 9.5 Hz), 1.66 (1H, dd, J 12.5,
6.5 Hz),1.64–1.48 (2H, m), 1.27 (1H, dd, J 13.5, 5.5 Hz), 1.14 (3H, s),
0.89 (3H, d, J 6.0 Hz), 0.76 (3H, d, J 6.0 Hz); 13C (100 MHz, CDCl3)
86.1, 81.4, 77.5, 67.0, 35.9, 28.9, 26.8, 26.3, 24.9, 17.4, 15.4; m/z (ES+)
found 201.1427 (MH+) C13H21O3 requires 201.1447.
1
film) 3645 (br s), 1725 (s), 1422 (m), 1156 (m); H (400 MHz, CDCl3)
4.75 (1H, dd, J 11.0, 5.0 Hz), 3.89 (1H, dd, J 10.5, 6.0 Hz), 2.31 (1H,
dd, J 14.5, 11.0 Hz), 2.08 (3H,s), 1.95–1.50 (6H, m), 1.39 (1H, br s,
OH) 1.21 (3H, s), 1.00 (3H, d, J 6.5 Hz), 0.99 (3H, d, J 6.5 Hz); 13C
(100 MHz, CDCl3) 170.7, 84.9, 79.7, 79.0, 69.2, 34.6, 32.3, 27.9, 24.4,
21.0, 17.4, 16.6; m/z (EI+) found 242.1535 (M+) C13H21O4 requires
242.1518.
anti-Diol as a colorless oil (38.6 mg, 19 %); νmax(thin film) 3685 (br,
1
s), 3697 (br, s), 2983 (s), 1273 (s); H (400 MHz, CDCl3) 3.96 (1H, dd,
J 10.0, 5.0 Hz), 3.88 (1H, dd, J 9.0, 5.0 Hz), 2.16 (1H, dd, J 13.5,
10.5 Hz), 1.95–1.82 (3H, m), 1.77 (1H, dd, J 13.5, 5.0 Hz), 1.74 (1H,
m), 1.52 (1H, ddd, J 13.0, 6.5, 6.5), 1.25 (1H, m), 1.19 (3H, s), 1.00
(3H, d, J 7.0 Hz), 0.96 (3H, d, J 7.0 Hz); 13C (100 MHz, CDCl3) 84.5,
80.5, 78.5, 69.5, 36.7, 32.2, 31.4, 28.2, 24.4, 17.4, 16.6; m/z (ES+) found
201.1429 (MH+) C13H21O3 requires 201.1447.
(rel-1S,2R,5R,6R)-6-Acetoxy-1-isopropyl-5-methyl-8-oxa-bicy-
clo[3.2.1]octan-2-yl Cinnamate: To a stirred solution of cinnamic
acid (296 mg, 2 mmol) and triethyl amine (272 μL, 2 mmol ) in
(rel-1S,2R,5R,6R)-1-Isopropyl-5-methyl-8-oxabicyclo[3.2.1]- toluene (7 mL) was added 2,4,6-trichlorobenzoyl chloride (496 mg,
octane-2,6-diyl Biscinnamate: To a stirred solution of cinnamic
acid (207 mg, 1.4 mmol) and triethyl amine (190 μL, 1.4 mmol ) in
THF (5 mL) was added 2,4,6-trichlorobenzoyl chloride (361.5 mg,
1.5 mmol) and the reaction was stirred at room temperature for
30 min when a solution of diol 15 (112 mg, 0.56 mmol) in THF
(3 mL) was added followed by DMAP (8.5 mg, 0.07 mmol), and the
reaction was stirred for 18 h, was diluted with ethyl acetate (30 mL)
2.05 mmol) and the reaction was stirred at room temperature for
30 min when a solution of the alcohol starting material (250 mg,
1.03 mmol) in toluene (3 mL) was added followed by DMAP (10 mg,
0.08 mmol), and the reaction was stirred for 18 h, was diluted with
ethyl acetate (50 mL) and was washed with NaHCO3 (sat. aq. 2 ×
20 mL). Organic layer was separated, dried (MgSO4) and concen-
trated in vacuo to give a crude oil, which was purified by flash
and was washed with NaHCO3 (sat. aq. 2 × 10 mL). Organic layer column chromatography (silica gel, 3:1 petroleum ether ether/ethyl
was separated, dried (MgSO4) and concentrated in vacuo to give a
crude oil, which was purified by flash column chromatography (sil-
ica gel, 3:1 petroleum ether ether/ethyl acetate as eluent) to give
the diester as a colorless oil (185 mg, 72 %); νmax(thin film) 1695 (s),
acetate as eluent) to give the diester product as a colorless oil
(332 mg, 87 %); νmax(thin film) 1695 (s), 1690 (s), 1425 (m), 1370,
1
(m), 1125 (m); H (400 MHz, CDCl3) 7.64 (1H, d, J 18.0 Hz), 7.52 (2H,
m), 7.38 (3H, m); 6.38 (1H. d. J 18.0 Hz), 5.12 (1H, dd, J 10.0, 6.0 Hz),
1690 (s), 1465 (m), 1442 (m), 1127 (m); 1H (400 MHz, CDCl3) 7.71 4.80 (1H, dd, J 10.5, 5.0 Hz), 2.47 (1H, dd, J 14.0, 10.5 Hz), 2.16 (1H,
(1H, d, J 18.0 Hz), 7.63 (1H, d, 17.0 Hz), 7.52 (4H, m), 7.38 (6H, m),
6.48 (1H, d, J 18.0 Hz), 6.38 (1H, d, J 17.0 Hz), 5.16 (1H, dd, J 10.0,
6.0 Hz), 4.96 (1H, dd, J 11.5, 6.0 Hz), 2.55 (1H, dd, J 14.5, 10.0 Hz),
2.21 (1H, m), 2.07 (1H, dd, J 14.5, 6.0 Hz), 1.97 (1H, dd, J 14.5, 6.0 Hz),
1.92–1.82 (2H, m), 1.71 (1H, m), 1.30 (3H, s), 1.00 (3H, d, J 7.0 Hz),
0.96 (3H, d, J 7.0 Hz); 13C (100 MHz, CDCl3) 166.7, 165.9, 145.3, 145.0,
134.3, 134.2, 130.5, 130.3, 128.9, 128.9, 128.1, 128.1, 118.1, 117.8,
84.0, 80.5, 79.0, 71.3, 36.5, 33.2, 32.1, 24.7, 24.6, 17.5, 16.6; m/z (ES+)
found 461.2345 (MH+) C29H33O5 requires 461.2328.
m), 2.10 (3H, s), 1.96 (1H, dd, J 14.0, 5.0 Hz) 1.91–1.60 (4H, m), 1.25
(3H, s), 0.97 (3H, d, J 7.0 Hz), 0.93 (3H, d, J 7.0 Hz); 13C (100 MHz,
CDCl3) 170.7, 165.9, 144.9, 134.3, 130.3, 128.9, 128.1, 118.1, 83.9,
80.2, 79.0, 71.3, 36.3, 33.1, 31.9, 24.6, 24.5, 21.1, 17.4, 16.6; m/z (ES+)
found 373.2032 (MH+) C22H29O5 requires 373.2015.
(rel-1S,2R,5R,6R)-6-Hydroxy-1-isopropyl-5-methyl-8-oxa-bicy-
clo[3.2.1]octan-2-yl Cinnamate: To a stirred solution of the diester
starting material (250 mg, 0.67 mmol) in methanol (7 mL) was
added potassium carbonate (276 mg, 2 mmol) and the resulting
(rel-1S,2R,5R,6R)-2-Hydroxy-1-isopropyl-5-methyl-8-oxabicyclo- mixture was stirred for 1.5 h. The reaction was diluted with ethyl
[3.2.1]oct-3-en-6-yl Acetate: To a solution of enone 13 (500 mg,
2.1 mmol) in methanol (10 mL) was added cerium trichloride hepta-
hydrate (1.56 g, 4.2 mmol) and the solution was stirred for 30 min
and cooled to 0OC and sodium borohydride (160 mg, 4.2 mmol)
was added in one portion. The reaction was stirred at 0OC for 1 h
and was quenched by addition of ammonium chloride (sat. aq.
acetate (20 mL), washed with brine (2 × 10 mL), dried (MgSO4) and
evaporated to give the crude product, which was purified by flash
column chromatography (silica gel, 2:1 petroleum ether ether/ethyl
acetate eluent) to give the pure monoester as a colorless oil
(190 mg, 86 %); νmax(thin film) 3459 (br s), 1693 (s), 1430 (m), 1370,
1
(m), 1122 (m); H (400 MHz, CDCl3) 7.64 (1H, d, J 16.0 Hz), 7.51 (2H,
5 mL). To the resulting mixture was added ethyl acetate (50 mL), m), 7.37 (3H, m), 6.38 (1H, d, J 16.0 Hz), 5.12 (1H, dd, J 10.0, 6.5 Hz),
layers were separated and the organic layer was washed with brine
(2 × 20 mL) and was concentrated to give the crude product. Flash
4.04 (1H, dd, J 10.5, 5.0 Hz), 2.31 (1H, dd, 13.0, 11.0 Hz), 2.13 (1H,
m), 2.02–1.77 (4H, m), 1.60 (1H, m), 1.23 (3H, s), 0.96 (3H, d, J 7.0 Hz),
column chromatography (silica gel, 3:1 petroleum ether ether/ethyl 0.93 (3H, d, J 7.0 Hz); 13C (100 MHz, CDCl3) 166.0, 144.9, 134.4, 130.3,
acetate eluent) gave the allylic alcohol as a colorless oil (448 mg,
89 %); νmax(thin film) 3650 (br, s), 1739 (s), 1052 (m); H (400 MHz,
CDCl3) 5.80 (1H, dd, J 9.0, 1.0 Hz), 5.62 (1H, dd, J 9.0, 1.5 Hz), 4.68
128.9, 128.0, 118.3, 83.6, 81.1, 78.4, 71.7, 38.3, 33.1, 31.1, 24.8, 24.4,
17.5, 16.6; m/z (ES+) found 331.1892 (MH+) C20H27O4 requires
331.1909.
1
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
8
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(rel-1S,2R,5R,6R)-6-{[(1H-Imidazol-1-yl)sulfonyl]oxy}-1-iso-
propyl-5-methyl-8-oxabicyclo[3.2.1]octan-2-yl Cinnamate: To a
stirred solution of the alcohol starting material (110 mg, 0.33 mmol)
in THF (5 mL) at –78OC was added LiHMDS (1.06 M soln. in THF,
350 μL, 0.371 mmol) and after 30 min a solution of sulfonyldiimidaz-
(rel-1S,4R,5R,6R)-4-Formyl-1-isopropyl-5-methyl-2-oxo-8-oxa-bi-
cyclo[3.2.1]octan-6-yl Acetate (17): Through a pre-cooled color-
less solution of alkene 16 (500 mg, 1.9 mmol) in DCM (20 mL) was
passed a mixture of ozone and oxygen (Fisher ozone generator)
until the solution became pale blue in colour. The ozone generator
ole (99 mg, 0.5 mmol) in THF (2 mL). Stirring was continued over- was turned off and oxygen was passed through the solution until
night allowing the dry ice/acetone bath to slowly warm to room the blue colour dissipated. To the resulting solution was added di-
temperature. The resulting mixture was quenched by addition of
ammonium chloride (sat. aq. 2 mL) and extracted with ethyl acetate
(20 mL). Organic extracts were washed with brine (2 × 10 mL), dried
(MgSO4) and the solvents evaporated in vacuo to give the crude
product. Pure sulfonamide product was obtained after flash column
chromatography (silica gel, 4:1 petroleum ether ether/ethyl acetate
eluent) as a pale yellow oil (113 mg, 75 %); νmax(thin film) 1705 (s),
1430 (m), 1379 (br s), 1350, (m), 1140 (m); 1H (400 MHz, CDCl3) 8.04
methylsulfide (3 mL, excess) and the resulting mixture was warmed
to room temperature and was stirred overnight. The solution was
concentrated and the crude product mixture was purified by col-
umn chromatography (petrol/EtOAc, 10:1) to give 17 as a colorless
oil (408 mg, 81 %); νmax(thin film) 1764 (s), 1749 (s), 1745 (s), 1373
(m), 1273 (m); H (400 MHz, CDCl3) 9.85 (1H, d, J 3.0 Hz), 4.93 (1H,
dd, J 10.0, 4.0 Hz), 3.02 (1H, ddd, J 7.5, 5.0, 3.0 Hz), 2.78 (1H,dd, J
17.5, 5.0Hz), 2.68 (1H, dd, J 17.5, 7.5 Hz), 2.57 (1H, dd. J 14.0,
1
(1H, s), 7.64 (1H, d, J 16.0 Hz), 7.53 (2H, m), 7.39 (4H, m), 7.23 (1H, 10.0 Hz), 2.12 (3H, s), 2.12 (1H, sept., J 7.0 Hz), 1.60 (1H, dd, J 14.0,
s), 6.36 (1H, d, J 16.0 Hz), 5.09 (1H, dd, J 9.5, 6.0 Hz), 4.51 (1H, dd, J
10.5, 5.0 Hz), 2.25 (1H, dd, J 14.5, 10.5 Hz), 2.18 (1H, m), 2.03 (1H,
dd, J 14.5, 5.0 Hz), 1.90–1.57 (4H, m), 1.13 (3H, s), 0.91 (3H, d, J
6.0 Hz), 0.89 (3H, d, J 6.0 Hz); 13C (100 MHz, CDCl3) 165.7, 145.4,
137.1, 134.2, 131.7, 130.5, 128.9, 128.1, 117.8, 117.6, 88.7, 84.3, 80.2,
70.2, 34.6, 32.7, 31.4, 24.4, 23.6, 17.2, 16.4; m/z (ES+) found 461.1752
(MH+) C23H27O6N2S requires 461.1746.
3.0 Hz),1.53 (3H, s), 0.96 (6H, d, J 7.0 Hz); 13C (100 MHz, CDCl3) 208.0,
200.7, 170.0, 90.7, 81.5, 80.0, 38.4, 34.5, 30.7, 22.8, 20.8, 16.0, 16.7;
m/z (ES+) found 269.1360 (MH+) C14H21O5 requires 269.1389.
(rel-1S,4S,5R,6R)-4-Formyl-1-isopropyl-5-methyl-2-oxo-8-oxa-
bicyclo[3.2.1]octan-6-yl Acetate (17′): To a stirred pre-cooled
(–20 °C) solution of aldehyde 17 (360 mg, 1.34 mmol) in DCM
(10 mL) was added acetic acid (24 μL, 0.4 mmol) and pyrrolidine
(22 μL, 0.26 mmol). The resulting mixture was stirred at –20 °C for
2 days and concentrated under reduced pressure. Column chroma-
tography (silica gel, petrol/EtOAc, 20:1) allowed separation of epi-
meric aldehydes 17 (81 mg, 22.5 %) and essentially pure 17′
(243 mg, 67.5 %) as a colorless oil; νmax(thin film) 3980 (m),1764 (s),
1750 (s), 1747 (s), 1380 (m), 1256 (m); 1H (400 MHz, CDCl3)
9.72(1H,s), 5.00 (1H, dd, J 10.5, 4.0 Hz), 3.08–2.98 (2H, m), 2.64–2.55
(2H, m), 2.19–2.12 (1H, m), 1.99 (3H, s), 1.74 (3H, s), 1.65 (1H, dd, J
15.0, 4.0 Hz), 0.96 (6H. d, J 7.0 Hz); 13C (100 MHz, CDCl3) 205.6,
198.2, 169.8, 89.2, 82.5, 78.4, 58.4, 37.8, 34.1, 30.0, 23.9, 20.5, 17.2,
16.5; m/z (ES+) found 269.1360 (MH+) C14H21O5 requires 269.1389.
(rel-1S,2R,5R,6S)-6-(2-Hydroxyacetoxy)-1-isopropyl-5-methyl-8-
oxabicyclo[3.2.1]octan-2-yl Cinnamate (3):[10] Cesium glycolate
(166 mg, 0.8 mmol) was added to solution of the sulfonylimidazole
derivative (76 mg, 0.16 mmol) and 18-crown-6 (211 mg, 0.8 mmol)
in toluene (10 mL). The resultant mixture was heated at reflux for
18 h. The solvent was removed in vacuo and the crude mixture was
purified by silica gel column chromatography (4:1 petroleum ether
ether/ethyl acetate) to give 3 as a colorless oil (62 mg, 58 %);
νmax(thin film) 3540 (br s), 1718 (s), 1650 (s), 1468 (m); 1H (400 MHz,
CDCl3) 7.65 (1H, d, J 16 Hz), 7.53 (2H, m), 7.39 (3H, m), 6.38 (1H, d,
J 16.0 Hz), 5.25 (1H, dd, J 7.5, 2.5 Hz), 5.03 (1H, dd, J 10.0, 5.5 Hz),
4.20 (2H, s), 2.70 (1H, dd, J 14.0, 7.5 Hz), 2.38 (1H, br s, OH), 2.19
(1H, m), 1.90 (1H, m), 1.82 (1H, m), 1.75–1.64 (2H, m), 1.59 (1H, m),
1.47 (1H, m), 1.21 (3H, s), 0.99 (3H, d, J 7.0 Hz), 0.96 (3H, d, J 7.0 Hz);
13C (100 MHz, CDCl3) 172.9, 156.8, 145.2, 134.2, 130.4, 128.8, 128.1,
117.9, 85.2, 82.3, 79.6, 70.4, 60.6, 38.8, 34.2, 33.2, 24.4, 20.3, 17.9,
17.0; m/z (ES+) found 411.1772 (MNa+) C22H28O6Na requires
411.1784.
(rel-1S,4R,5R,6R)-1-Isopropyl-5-methyl-2-oxo-4-[(E)-3-oxobut-1-
en-1-yl]-8-oxabicyclo[3.2.1]octan-6-yl Acetate: To a stirred solu-
tion of aldehyde 17′ (350 mg, 1.3 mmol) was added 1-(triphenyl-
phosphoranylidene) propan-2-one (955 mg, 3.25 mmol) and the re-
sulting solution was stirred at room temperature for 1 hour and
then was heated at reflux for additional 5 hours, allowing complete
consumption of the starting material. The resulting mixture was
concentrated and purified by column chromatography (silica gel,
petrol/EtOAc, 6:1) to give the product as a colorless oil (300.6 mg,
75 %); νmax(thin film) 1730 (s), 1710 (s), 1690 (s), 1031 (m); 1H
(400 MHz, CDCl3) 6.85 (1H,dd, J 16.0, 9.0 Hz), 6.07 (1H, d, J 16 Hz),
5.04 (1H, dd, J 10.0, 6.0 Hz), 3.04–2.97 (2H, m), 2.62 (1H, dd, J 15.0,
10.0 Hz), 2.30–2.23 (1H, m), 2.28 (3H, s), 2.17 (1H, sept., J 7.0 Hz),
2.14 (3H, s), 1.71 (1H, dd, J 15.0, 6.0 Hz), 1.28 (3H, s), 0.96 (6H, app
dd, J 7.0, 2.0 Hz); 13C (100 MHz, CDCl3) 206.8, 198.2, 170.2, 146.1,
132.7, 89.6, 82.1, 79.8, 45.1, 40.2, 37.9, 30.0, 27.1, 23.4, 21.1, 17.3,
16.4; m/z (ES+) found 309.1700 (MH+) C17H25O5 requires 309.1702.
(rel-1S,4S,5R,6R)-1-Isopropyl-5-methyl-2-oxo-4-vinyl-8-oxa-bi-
cyclo[3.2.1]octan-6-yl Acetate (16): To a pre-cooled (–78 °C) sus-
pension of enone 13 (250 mg, 1.05 mmol) and Copper(I) iodide
(19 mg, 0.1 mmol) in THF (10 mL) was added 1
M vinylmagnesium
bromide solution in THF (1.2 mL, 1.2 mmol) dropwise over a period
of 10 minutes. The mixture was stirred at –78 °C for an hour and
was quenched at low temperature by addition of aqueous saturated
ammonium chloride solution (3 mL). The reaction was warmed to
room temperature and the organic compounds were extracted with
ethyl acetate (2 × 10 mL portions). Combined organic extracts were
dried (MgSO4) filtered and evaporated, the residue was purified by
column chromatography (silica gel, 10:1 petroleum ether ether/
EtOAc ) to give the conjugate addition product 16 as pale yellow
oil (201.3 mg, 72 %). νmax(thin film) 2971 (m), 1743 (s), 1680 (s),
1590 (m); 1H (400 MHz, CDCl3) 5.94 (1H, ddd, J 17.0, 10.0, 7.5 Hz),
5.12 (1H, dd J 10/0, 1.5 Hz). 5.05 (1H, dd, J 17.0, 1.5 Hz), 5.02 (1H,
(rel-1S,4S,5R,6R)-1-Isopropyl-5-methyl-2-oxo-4-(3-oxobutyl)-8-
oxabicyclo[3.2.1]octan-6-yl Acetate (18): A mixture of the enone
starting material (300 mg, 0.97 mmol) and palladium on activated
carbon (5wt.-%, 3 mg) in ethyl acetate (8 mL) was placed under
atmosphere of hydrogen and stirred for 8 hours at ambient temper-
dd, J 10.5, 4.0 Hz), 2.93 (1H, dd, J 17.0, 7.0 Hz), 2.85–2/79 (1H, m), ature. The solids were removed via filtration through a short pad of
2.58 (1H, dd, J 19.0, 10.5 Hz), 2.26 (1H, dd, J 15.0, 2.5 Hz), 2.13 (1H,
sep, J 7/0 Hz), 2.12 (3H, s), 1.68 (1H, dd, J 15.0, 4.0 Hz), 1.29 (3H, s),
0.95 (6H, d, J 7.0 Hz); 13C (100 MHz, CDCl3) 208.4, 170.4, 138.0, 116.6,
Celite (approximately 0.5 g of filtration agent) and the volatiles were
removed. The residue was purified by column chromatography (sil-
ica gel, petrol/EtOAc, 10:1) to give the reduction product 18 as a
98.2, 62.2, 79.8, 46.1, 41.2, 38.1, 30.1, 23.2, 21.0, 17.2, 16.5; m/z (ES+) colorless oil (270.6 mg, 90 %); νmax(thin film) 3920 (m), 1725 (multi-
found 267.1605 (MH+) C15H23O4 requires 267.1596.
ple overlapping peaks s), 1051 (m), 1066 (m); H (400 MHz, CDCl3)
1
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
9
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
4.98 (1H, dd, J 10.0, 4.0 Hz), 2.77 (1H, dd, J 16.0, 8.0 Hz), 2.69 (1H,
ddd, J 17.0, 10.0, 5.0 Hz), 2.59 (1H, dd, J 15.0, 10.0 Hz), 2.48 (1H,
ddd, J 17.0, 10.0, 6.0 Hz), 2.32–2.04 (3H, m), 2.15 (3H, s), 2.09 (3H,
0OC was added CeCl37H2O (275 mg, 0.74 mmol) and the mixture
was stirred for 10 min and NaBH4 (28 mg, 0.74 mmol) was added.
The resulting mixture was stirred for 1 h and was quenched with
s), 1.96- 1.88 (1H, m), 1.69–1.60 (2H, m), 1.39 (3H, s), 0.94 (6H, app ammonium chloride (sat. aq., 2 mL). To the resulting mixture was
dd, J 7.0, 0.5 Hz); 13C (100 MHz, CDCl3) 209.6, 208.2, 170.3, 89.3,
83.0, 80.5, 40.8, 40.1, 38.5, 30.3, 30.0, 24.4, 22.4, 21.1, 17.1, 16.6; m/z
(ES+) found 311.1841 (MH+) C17H27O5 requires 311.1858.
added ethyl acetate (30 mL) and the layers were separated. The
aqueous layer was extracted with ethyl acetate (20 mL) and the
combined organic layers were washed with brine (2 × 20 mL). dried
(MgSO4) and concentrated in vacuo. Purification by flash column
chromatography (silica gel, 5:1 petroleum ether ether/ethyl acetate
eluent) gave alcohol product as a colorless oil (78 mg, 72 %);
νmax(thin film) 3520 (br s), 1735 (s), 1380 (m), 1255 (m), 1110 (m);
1H (400 MHz, CDCl3) 4.77 (1H, dd, J 7.5, 3.0 Hz), 4.34 (1H, s), 2.85
(1H, dd, J 15.0, 9.0 Hz), 2.41–2.26 (2H, m), 2.04 (3H, s),1.90–1.80 (1H,
m), 1.76 (3H, s), 1.73–1.60 (2H, m), 1/42–1.37 (1H, m), 1.32 (3H. s),
1.07 (6H. d, J 7.0 Hz); 13C (100 MHz, CDCl3) 169.8, 132.1, 129.2, 88.6,
86.5, 72.4, 61.9, 46.9, 44.7, 36.3, 34.6, 30.1, 24.9, 21.2, 19.0, 18.4, 15.5;
m/z (ES+) found 317.1705 (MNa+) C17H26O4Na requires 317.1729.
(rel-3aS,4R,5R,7S,8aS)-1-Hydroxy-7-isopropyl-1,4-dimethyl-8-
oxodecahydro-4,7-epoxyazulen-5-yl Acetate: To a stirred solution
of diketone 18 (360 mg, 1.16 mmol) in THF (6 mL) at –78 °C was
added lithium hexamethyldisilazide (1.0
M soln. in THF, 1.1 mL) and
the reaction was stirred at –78 °C for 30 minutes and the tempera-
ture in the cooling bath was allowed to increase to –30 °C and
maintained at that temperature for an hour, when the reaction was
quenched by addition of acetic acid (0.3 mL, 5 mmol). The mixture
was warmed to room temperature and the volatiles were evapo-
rated. Column chromatography of the residue (silica gel, petrol/
EtOAc, 10:1) allowed separation of two diastereomeric products, (rel-1S,3aS,4R,5R,7S,8R,8aS)-8-Hydroxy-7-isopropyl-1,4-dimeth-
which were assigned the structure as indicated above due to the
same coupling constant exhibited by the hydrogens at the ring
junction J 9.5 Hz common for syn-fused 5,6 ring systems.
yldecahydro-4,7-epoxyazulen-5-yl Acetate: To a solution of allylic
alcohol (75 mg, 0.25 mmol) in DCM (5 mL) was added (1,5-Cyclooc-
tadiene)(pyridine)(tricyclohexylphosphine)-iridium(I) hexa fluoro-
phosphate (56 mg, 0.07 mmol) and the resulting mixture was stirred
under H2 (1 atm.) for 18 h before it was concentrated in vacuo.
Flash column chromatography (silica gel, 5:1 petroleum ether ether/
ethyl acetate) gave the saturated product 24 (51.5 mg, 68 %) as a
colorless oil; νmax(thin film) 3510 (br s), 1735 (s), 1369 (m), 1190 (m);
1H (400 MHz, CDCl3) 5.02 (1H, dd, J 7.5 Hz, 3.0 Hz), 3.65 (1H, d, J
10.0 Hz), 2.44 (1H, dd, J 14.0, 7.5 Hz), 2.35–2.29 (1H, m), 2.06 (3H, s),
2.03–1.97 (2H, m), 1.70–1.64 (3H, m), 1.35–1.29 (2H, m), 1.22–1.20
(1H, m), 1.17 (3H, s), 1.06 (6H, d J 7.0 Hz), 0.89 (3H, d, J 5.5 Hz); 13C
(100 MHz, CDCl3) 170.7, 85.8, 84.3, 75.1, 70.7, 48.0, 47.9, 38.7, 32.3,
31.2, 30.5, 25.5, 21.1, 18.9, 18.3, 17.4, 16.8; m/z (ES+) found 319.1907
(MNa+) C17H28O4Na requires 319.1885.
Aldol-product I (135.5 mg, 37 %); νmax(thin film) 3190 (br, s), 1751
1
(s), 1722 (s), 1373 (m), 1350 (m); H (400 MHz, CDCl3) 4.95 (1H, dd,
J 9.0, 3.0 Hz), 3.05 (1H, br, s), 2.69 (1H, d, J 9.5 Hz), 2.59–2.45 (2H,
m), 2.16 (1H, sept., J 6.5 Hz), 2.07 (3H. s), 2.06–1.97 (1H, m), 1.86–
1.74 (2H, m), 1/61 (1H, dd, J 14.0, 3.0 Hz), 1.55–1.47 (1H, m), 1.47
(3H, s), 1.36 (3H, s), 0.99 (3H, d, J 6.5 Hz), 0.96 (3H, d, J 6.5 Hz); 13C
(100 MHz, CDCl3) 212.2, 170.2, 89.9, 82.4, 81.9, 79.7, 57.2, 43.4, 40.4,
38.1, 30.4, 38.3, 26.4, 28.6, 21.1, 17.5, 17.3; m/z (ES+) found 311.1869
(MH+) C17H27O5 requires 311.1858.
Aldol product II (111.5 mg, 31 %); νmax(thin film) 3169 (br, s), 1750
1
(s), 1725 (s), 1350 (m), 1290 (m); H (400 MHz, CDCl3) 4.91 (1H, dd,
J 10.0, 4.0 Hz), 2.87 (1H, d, J 10.0 Hz), 2.79–2.71 (1H, m), 2.52 (1H,
dd, J 15.0, 10.0, Hz), 2.12 (1H, sept, J 6.0 Hz), 2.08 (3H, s), 1.86–1.71
(4H, m), 1.55 (1H, dd, J 15.0, 4.0 Hz), 1.34 (3H, s), 1.33 (3H, s), 0.99
(3H, d, J 6.5 Hz), 0.98 (3H, d, J 6.5 Hz); 13C (100 MHz, CDCl3) 211.5,
170.4, 89.6, 82.6, 82.2, 79.5, 58.1, 41.5, 40.0, 38.7, 30.9, 26.4, 26.0,
22.3, 21.1, 17.6, 17.3; m/z (ES+) found 311.1855 (MH+) C17H27O5 re-
quires 311.1858.
(rel-1S,3aS,4R,5R,7S,8R,8aS)-5-Acetoxy-7-isopropyl-1,4-dimeth-
yldecahydro-4,7-epoxyazulen-8-yl Cinnamate: To a stirred solu-
tion of cinnamic acid (50 mg, 0.34 mmol) in toluene (5 mL) was
added triethyl amine (100 μL, 0.7 mmol) and 2,4,6-trichlorobenzoyl
chloride (97 mg, 0.4 mmol) and the resulting mixture was stirred
for 1 h before a solution of alcohol (50 mg, 0.17 mmol) in toluene
(3 mL) followed by DMAP (61 mg, 0.5 mmol). The resulting mixture
was heated at 80OC for 4 h, when it was cooled to room tempera-
ture and quenched by addition of NaHCO3 (sat. aq. 2 mL). Layers
were separated and the aqueous layer was extracted with ethyl
acetate (2 × 10 mL). Combined organic extracts were washed with
brine (2 × 10 mL), dried (MgSO4) and the solvents evaporated in
vacuo. Flash column chromatography (silica gel, 10:1 petroleum
ether ether/ethyl acetate) to give the cinnamic ester (61.5 mg, 85 %)
as a colorless oil;( %); νmax(thin film) 1716 (s), 1714 (s), 1649 (m),
1450 (m), 1245 (m), 1040 (m); 1H (400 MHz, CDCl3) 7.65 (1H, d, J
15.5 Hz), 7.54–7.51 (2H, m), 7.40–7.31 (3H, m), 6.40 (1H, d, J 15.5 Hz);
5.13 (1H, d, J 10.0 Hz), 5.09 (1H, dd, J 7.5, 3.0 Hz), 2.65 (1H, dd, J
14.0, 8.0 Hz), 2.16–2.10 (1H, m), 2.09 (3H, s), 1,97–1.86 (2H, m), 1.73–
1.67 (3H, m), 1.55–1.53 (1H, m), 1.28–1.23 (2H, m), 1.21 (3H,s), 1.02
(3H, d, J 5.5 Hz), 0.93 (3H, d, J 7.0 Hz), 0.34 (3H. d, J 7.0 Hz); 13C
(100 MHz, CDCl3) 170.8, 165.6, 144.9, 134.3, 130.3, 129.0, 128.1,
118.1, 85.5, 84.4, 75.0, 71.4, 47.5, 46.9, 40.2, 33.2, 31.3, 30.9, 24.6,
21.1, 19.0, 18.3, 17.5, 16.9; m/z (ES+) found 427.2509 (MH+) C26H35O5
requires 427.2484.
(rel-3aS,4R,5R,7S)-7-Isopropyl-1,4-dimethyl-8-oxo-
2,3,3a,4,5,6,7,8-octahydro-4,7-epoxyazulen-5-yl Acetate (19):
To a pre-cooled (0 °C) solution of aldol adducts (200 mg, 0.64 mmol)
in DCM (6 mL) was added triethylamine (177 μL, 1.3 mmol) and
methanesulfonyl chloride (51 μL, 0.66 mmol). The resulting mixture
was stirred at 0 °C for an hour and was warmed to room tempera-
ture and stirred for additional 3 hours. To the reaction was added
water (10 mL) and DCM (20 mL), the layers were separated and the
organic layer was dried (Na2SO4) and the solvents evaporated. The
residue was purified by column chromatography (silica gel, petrol/
EtOAc, 6:1) to give the enone 19 as a colorless oil (149.5 mg, 80 %);
1
νmax(thin film) 1726 (s), 1695 (s), 1475 (m), 1376 (m); H (400 MHz,
CDCl3) 4.72 (1H, dd, J 9.5, 7.0 Hz), 3.19–3.12 (1H, m), 2.60 (1H, dd, J
14.5, 9.5 Hz), 2.55–2.42 (1H, m), 2.33–2.16 (2H, m), 2.12 (3H, s), 2.07
(3H. s), 2.00–1.80 (2H, m), 1.58–1.52 (2H, m), 1.32 (3H, s), 1.01 (3H,
d, J 6.5 Hz), 0.94 (3H, d, J 6.5 Hz); 13C (100 MHz, CDCl3) 200.0, 170.4,
156.4, 133.1, 88.7, 80.5, 79.0, 44.8, 36.5, 35.8, 30.7, 30.2, 21.0, 20.5,
17.5, 16.2, 16.1; m/z (ES+) found 293.1775 (MH+) C17H25O4 requires
293.1753.
(rel-1S,3aS,4R,5R,7S,8R,8aS)-5-Hydroxy-7-isopropyl-1,4-dimeth-
yldecahydro-4,7-epoxyazulen-8-yl Cinnamate: To a stirred solu-
tion of diester starting material (60 mg, 0.14 mmol) in methanol
(5 mL) was added potassium carbonate (58 mg, 0.42 mmol) and
(rel-3aS,4R,5R,7S,8R)-8-Hydroxy-7-isopropyl-1,4-dimethyl-
2,3,3a,4,5,6,7,8-octahydro-4,7-epoxyazulen-5-yl Acetate: To a
solution of enone 19 (110 mg, 0.37 mmol) in methanol (10 mL) at
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
10
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
the mixture was stirred for 1 h when it was diluted with ethyl acet-
ate (20 mL) and washed with brine (2 × 10 mL), dried (MgSO4) and
concentrated in vacuo. Flash column chromatography (silica gel, 5:1
petroleum ether ether/ethyl acetate) gave the pure hydroxyl ester
(31.2 mg, 85 %) as a colorless oil; νmax(thin film) 3440 (br s), 1720
Keywords: Total synthesis · Englerin A · Truncated
analogue · 1,3-Dipolar cycloaddition · Synthetic strategy
1
(s), 1640 (m), 1460 (m), 1200 (m); H (400 MHz, CDCl3) 7.67 (1H, d,
[1] R. Ratnayake, D. Covell, T. T. Ransom, K. R. Gustafson, J. A. Beutler, Org.
Lett. 2009, 11, 57.
[2] J. A. Beutler, R. Ratnayake, D. Covell, T. R. Johnson, WO 2009/088854,
2009.
[3] M. Willot, L. Radtke, D. Könning, R. Fröhlich, V. H. Gessner, C. Strohmann,
M. Christmann, Angew. Chem. Int. Ed. 2009, 48, 9105; Angew. Chem. 2009,
121, 9269.
[4] L. Radtke, M. Willot, H. Sun, S. Ziegler, S. Sauerland, C. Strohmann, R.
Fröhlich, P. Habenberger, H. Waldmann, M. Christmann, Angew. Chem.
Int. Ed. 2011, 50, 3998; Angew. Chem. 2011, 123, 4084.
[5] K. C. Nicolaou, Q. Kang, S. Y. Ng, D. Y.-K. Chen, J. Am. Chem. Soc. 2010,
132, 8219.
[6] Q. Zhou, X. Chen, D. Ma, Angew. Chem. Int. Ed. 2010, 49, 3513; Angew.
Chem. 2010, 122, 3591.
[7] E. Jiménez-Núñez, C. K. Claverie, C. Nieto-Oberhuber, A. M. Echavarren,
Angew. Chem. Int. Ed. 2006, 45, 5452; Angew. Chem. 2006, 118, 5578.
[8] K. Molawi, N. Delpont, A. M. Echavarren, Angew. Chem. Int. Ed. 2010, 49,
3517; Angew. Chem. 2010, 122, 3595.
[9] J. Xu, E. J. Caro-Diaz, E. A. Theodorakis, Org. Lett. 2010, 12, 3708.
[10] J. Xu, E. J. Caro-Diaz, S. D. Sullivan, E. A. Theodorakis, Chem. Asian J. 2012,
7, 1052.
[11] Z. Li, M. Nakashige, W. J. Chain, J. Am. Chem. Soc. 2011, 133, 6553.
[12] J. Wang, S.-G. Chen, B.-F. Sun, G.-Q. Lin, Y.-J. Shang, Chem. Eur. J. 2013,
19, 2539.
[13] M. Zahel, A. Keßberg, P. Metz, Angew. Chem. Int. Ed. 2013, 52, 5390;
Angew. Chem. 2013, 125, 5500.
[14] K. Takahashi, K. Kornine, Y. Yokoi, J. Ishihara, S. Hatakayama, J. Org. Chem.
2012, 77, 7364.
[15] T. Hanari, N. Shimada, Y. Kurosaki, N. Thrimurtulu, H. Nambu, M. Anada,
S. Hashimoto, Chem. Eur. J. 2015, 21, 11671.
[16] H. Kusama, A. Tazawa, K. Ishida, N. Iwasawa, Chem. Asian J. 2016, 11, 64.
[17] R. Nelson, M. Gulias, J. L. Mascarenas, F. Lopez, Angew. Chem. Int. Ed.
2016, 55, 14359; Angew. Chem. 2016, 128, 14571.
[18] S. Hagihara, K. Hanaya, T. Sugai, M. Shoji, J. Antibiot. 2018, 71, 257.
[19] K. Tchabanenko, P. McIntyre, J. F. Malone, Tetrahedron Lett. 2010, 51, 86.
[20] K. Tchabanenko, C. Sloan, Y.-M. Bunetel, P. Mullen, Org. Biomol. Chem.
2012, 10, 4215.
[21] Alternative synthesis of truncated Englerin A 3 and its anticancer activity
were previously reported by Theodorakis et al. ref. 10.
[22] O. Achmatowicz Jr., P. Bukowski, B. Szechner, Z. Zwierzchowska, A. Zam-
ojski, Tetrahedron 1971, 27, 1973.
[23] J. B. Hendrickson, J. S. Farina, J. Org. Chem. 1980, 45, 3359.
[24] Examples of other dipolarophiles suitable for such cycloadditions see in:
V. Singh, H. M. Krishna, Vikrant, G. K. Trivedi, Tetrahedron 2008, 64,
3405.
[25] CCDC 1870185. CCDC 1870185 (for 8), 1870184 (for 12), 1870186 (for
15) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre.
J 16.5 Hz), 7.52 (2H, m), 7.38 (3H, m), 6.39 (1H, d, J 16.5 Hz), 5.22
(1H, d, J 10.5 Hz), 4.19 (1H, dd, J 10.5, 5.0 Hz), 2.37 (1H, m), 2.30
(1H, dd, J 14.5, 10.5 Hz), 2.12 (1H, m), 2.04 (1H, dd, J 14.5, 5.0 Hz),
1.98–1.65 (6H, m), 1.32 (3H, s), 1.20 (1H, m), 0.93 (3H, d, J 6.0 Hz),
0.89 (3H, d, J 6.0 Hz), 0.88 (3H, d, J 9.0 Hz); 13C (100 MHz, CDCl3)
166.5, 134.2, 134.7, 130.4, 129.1, 128.3, 118.6, 84.7, 81.5, 81.2, 72.8,
49.4, 46.4, 39.5, 33.1, 31.7, 31.4, 24.6, 23.5, 17.9, 17.3, 17.1; m/z (ES+)
found 407.2173 (MNa+) C24H32O4Na requires 407.2198.
(rel-1S,3aS,4R,5R,7S,8R,8aS)-5-{[(1H-Imidazol-1-yl)sulfonyl]oxy}-
7-isopropyl-1,4-dimethyldecahydro-4,7-epoxyazulen-8-yl
Cinnamate:[11] To a stirred solution of alcohol starting material
(30 mg, 0.078 mmol) in THF (3 mL) at –78OC was added LiHMDS
(1.06
M soln. in THF, 0.36 mL, 0.39 mmol mmol) and after 30 min a
solution of sulfonyldiimidazole (77.2 mg, 0.39 mmol) in THF (2 mL),
and the resulting mixture was warmed to room temperature over
a period of 16 h. To the reaction were added DCM (10 mL) and
NaHCO3 (sat. aq., 3 mL) and layers were separated. Aqueous layer
was extracted with DCM (2 × 10 mL), organic extracts were com-
bined, washed with brine (2 × 10 mL), dried (Na2SO4) and the sol-
vents evaporated in vacuo. Flash column chromatography (silica gel,
6:1 petroleum ether ether/ethyl acetate) of the residue gave the
protected alcohol (40.1 mg, 72 %) as a colorless oil; νmax(thin film)
2960 (m), 1715 (s), 1650 (m), 1380 (br s), 1140 (m); 1H (400 MHz,
CDCl3) 8.03 (1H, s), 7.65 (1H, d, J 16.0 Hz), 7.53 (m, 2H), 7.40 [m, 4H,
7.24 (s, 1H), 6.38 (1H, d, J 16.0 Hz), 5.20 (1H, d, J 10.0 Hz), 4.59 (1H,
dd, J 10.5, 5.0 Hz), 2.23 (1H, dd, J 14.0, 6.5 Hz), 2.19–2.09 (2H, m),
2.08–1.99 (2H, m), 1.90 (1H, m), 1.81–1.62 (3H, m), 1.22–1.18 (1H,
m), 1.19 93H, s], 0.95–0.88 (9H, m); 13C (100 MHz, CDCl3) 165.8,
145.6, 137.4, 134.4, 131.8, 129.2, 128.4, 118.2, 118.9, 90.7, 85.4, 81.3,
71.3, 49.0, 46.4, 35.8, 32.7, 31.4, 31.3, 24.1, 22.6, 17.6, 17.0, 17.0; m/z
(ES+) found 515.2198 (MH+) C27H35N2O6 requires 515.2216.
( )-Englerin A (1):[11] To a stirred solution of the activated alcohol
(15 mg, 0.029 mmol) in toluene (3 mL) was added cesium glycolate
(6 mg, 0.145 mmol) and 18-crown-6 (38.3 mg, 0.145 mmol) and the
resulting mixture was heated at reflux for 18 h, then was cooled
and diluted with DCM (5 mL) and water (5 mL). The layers were
separated and the aqueous layer was extracted with DCM (2 ×
5 mL), combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo. Flash column chromatography (silica gel, 6:1 petro-
leum ether ether/ethyl acetate) gave ( )-1 (7.8 mg, 61 %) as a color-
less oil; νmax(thin film) 3460 (br s), 1715 (s), 1640 (m), 1205; 1165
(m); 1H (400 MHz, [D6]DMSO) 7.73–7.70 (2H, m), 7.68 (1H, d, J
16.0 Hz), 7.45–7.40 (3H, m), 6.59 (1H, d, J 16.0 Hz), 5.15 (1H, dd, J
9.0, 2.0 Hz), 4.96 (1H, d, J 10.0 Hz), 4.04 (2H, s), 2.64 (1H, dd, J 14.5,
8.0 Hz), 2.07–2.00 (1H, m), 1.97–1.89 (1H, m), 1.78 (1H, sept, J 7.0 Hz),
1.73 (1H, dd, J 14.5, 2.0 Hz), 1.69–1.60 (3H, m), 1.27–1.10 (2H, m),
1.10 (3H, s), 0.94 (3H, d, J 7.0 Hz), 0.88 (3H, d, J 7.0 Hz), 0.84 (3H, d,
J 7.0 Hz); 13C (100 MHz, [D6]DMSO) 172.5, 165.2, 145.3, 133.9, 130.6,
129.0, 128.4, 117.8, 84.6, 84.3, 74.5, 70.5, 59.7, 47.1, 46.0, 32.8, 30.7,
30.5, 24.1, 18.7, 18.1, 17.4, 16.7 (one 13C resonance is missing due
to overlap with solvent peaks); m/z (ES+) found 465.2229 (MNa+)
C26H34O6Na requires 465.2253.
[26] Formation of a spirocyclic dimer was previously observed by Heathcock
et al.: K. A. Marshall, A. K. Mapp, C. H. Heathcock, J. Org. Chem. 1996, 61,
9135.
[27] CCDC 1870184.
[28] CCDC 1870186.
[29] A. G. Csaky, G. De la Herran, M. C. Murcia, Chem. Soc. Rev. 2010, 39, 4080.
[30] T. W. Bell, F. Sondheimer, J. Org. Chem. 1981, 46, 217.
[31] It is extremely important to keep the rotary evaporator temperature be-
low 40 °C to avoid thermal decomposition of the pyrone 10. Thus we
usually performed evaporation of DCM using a regular rotary evaporator
(vacuum 5 mm Hg) followed by removal of acetic anhydride and acetic
acid using a Cold finger rotary evaporator attached to an oil pump (vac-
uum 0.1 mm Hg).
Acknowledgments
We would like to acknowledge DEL for PhD funding (C. R.) and
Dr P. Nockemann (QUB) for assistance with the X-ray analysis.
Received: October 12, 2018
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
11
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Total Synthesis
C. Reagan, G. Trevitt,
K. Tchabanenko* ............................. 1–12
Total Synthesis of ( )-Englerin A and
Its Tuncated Analogues
Total synthesis of ( )-Englerin A and a analogue and the natural product. In-
number of truncated analogues was teresting stereochemical effects of the
developed based on a 1,3-dipolar bridgehead substituents on the reac-
cycloaddition of a substituted pyryl- tivity of the 8-oxabicyclo[3.2.1]octanes
ium ylide. The bicyclic enone scaffold were uncovered.
was further converted into a truncated
DOI: 10.1002/ejoc.201801544
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
12
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim