Illustrating the power of singlet oxygen chemistry in a synthetic context: Biomimetic syntheses of litseaverticillols A-G, I and J and the structural reassignment of litseaverticillol E

Article abstract of DOI:10.1002/chem.200401311

Biomimetic syntheses of the litseaverticillols A-G, I and J are reported herein. The syntheses rely heavily on the application of two different modes of reaction for photochemically generated singlet oxygen, namely, the [4+2] cycloaddition of singlet oxygen (¹O₂) with furans and the ene reaction of ¹O₂ with double bonds. The highlight of these syntheses is a one-pot cascade sequence, involving five synthetic operations initiated by a [4+2] reaction, to form the fully functionalised litseaverticillol core. A series of regioselective ene reactions are then used to appositely functionalise the side chains. The synthesis of litseaverticillol E (both its originally proposed and its actual structures) allows a structural reassignment of this natural product.

Full text of DOI:10.1002/chem.200401311

FULL PAPER
DOI: 10.1002/chem.200401311
Illustrating the Power of Singlet Oxygen Chemistry in a Synthetic Context:
Biomimetic Syntheses of Litseaverticillols A–G, I and J and the Structural
Reassignment of Litseaverticillol E
Georgios Vassilikogiannakis,* Ioannis Margaros, Tamsyn Montagnon, and
[
a]
Manolis Stratakis*
Abstract: Biomimetic syntheses of the
litseaverticillols A–G, I and J are re-
ported herein. The syntheses rely heav-
ily on the application of two different
modes of reaction for photochemically
generated singlet oxygen, namely, the
of these syntheses is a one-pot cascade
sequence, involving five synthetic oper-
ations initiated by a [4+2] reaction, to
form the fully functionalised litseaverti-
cillol core. A series of regioselective
ene reactions are then used to appo-
sitely functionalise the side chains. The
synthesis of litseaverticillol E (both its
originally proposed and its actual struc-
tures) allows a structural reassignment
of this natural product.
Keywords: biomimetic synthesis ·
cascade reactions · litseaverticillol ·
natural products · singlet oxygen
[
(
4+2] cycloaddition of singlet oxygen
1
O ) with furans and the ene reaction
2
1
of O with double bonds. The highlight
2
Introduction
ble, but always unsaturated, side chain (Scheme 1). The iso-
lation and structure elucidation of this novel class of natu-
rally occurring sesquiterpenes, alongside initial biological ac-
A recently isolated family of potent anti-HIV natural prod-
ucts, the litseaverticillols, presented us with a unique oppor-
tunity to blend the aims of developing both environmentally
friendly chemistry and atom-efficient synthetic methods, by
allowing us to devise and realise a highly efficient biomimet-
ic strategy for their synthesis. The plan, which made use of a
[4]
tivity data, were reported in a series of papers, with the
full details for all family members appearing in print in
[4c]
2003.
The litseaverticillols originated in the leaves and
twigs of a perennial shrub or arbor, named Litsea verticillata
Hance, which was found growing in the Cuc Phuong Nation-
al Park, Vietnam. Following bioassay-guided fractionation
of the chloroform extract taken from the biomass, eight
members of this new litseane skeletal class were identified,
litseaverticillols A–H (1–8, Scheme 1), all of which exhibited
inhibitory activity against HIV-1replication in HOG.R5
[1]
sophisticated cascade sequence and the immense versatili-
1
ty of singlet oxygen ( O ) chemistry, was completely devoid
2
of wasteful hindrances, such as protecting groups. The full
evolution of this design from inception to execution is de-
[
2,3]
scribed herein.
ꢀ
1 [4c]
The litseaverticillols as a family all possess a 4-hydroxycy-
clopentenone core substituted at the 5-position with a varia-
cells with IC50 values ranging from 2–15 mgmL . Crucial-
ly, their potent antiviral activity did not affect the growth of
the host cell, so the compounds were considered to have
low in vitro toxicity and were deemed to be important tar-
gets for further biological investigation. Due to the short
supply of several members of this class and the desire for
access to selected analogues, synthetic studies were seen as
imperative.
[
a] Prof. G. Vassilikogiannakis, I. Margaros, Dr. T. Montagnon,
Prof. M. Stratakis
Department of Chemistry
University of Crete
7
1409 Iraklion, Crete (Greece)
Fax : (+30)2810-393-601
E-mail: vasil@chemistry.uoc.gr
stratakis@chemistry.uoc.gr
Development of a proposal for the biogenesis of the litsea-
verticillols: Close inspection of the litseaverticillolsꢀ struc-
tures revealed to us several important features which were
to inform our subsequent hypothesis relating to their bioge-
netic origins (Scheme 2). Firstly, the group could be de-
1
Supporting Information for this article (comprising copies of H and
1
3
C NMR spectra for compounds 1, 2, 4–7, 9, 10, 11a, 11b, 13a, 13b,
8a, 18b, and 25 and HRMS data for 25) is available on the WWW
1
under http://www.chemeurj.org/ or from the authors.
Chem. Eur. J. 2005, 11, 5899 – 5907
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5899

Scheme 1. Structures of litseaverticillols A–J.
lineated into first (litseaverticillols A–C (1–3)) and second
20% in atmospheric air), b) photosensitisers, such as, tan-
nins, chlorophylls and porphyrins, and c) visible light.
(
litseaverticillols D–H (4–8)) generations, with the latter
arising directly from oxidation of the unsaturated side chain
Finally, our newly developed hypothesis that the achiral
1,4-enedicarbonyls 12a and 12b might be key intermediates
in the biogenesis of all the litseaverticillols could be further
justified by the observation that all the litseaverticillols exist
as racemic mixtures. Racemates are found relatively rarely
in nature because of the heavy reliance on homochiral
enzyme-templated reactions. However, the concept of non-
present in the former. The classical modes by which singlet
1
oxygen ( O ) is known to react with trisubstituted double
2
[5]
1
bonds support the idea that O could be responsible for
2
this conversion of the first-generation compounds into the
second. For example, litseaverticillols D (4), F (6) and G (7)
together represent the three possible products that could be
1
[1]
derived from a chemoselective ene reaction between O2
enzymatic biological assembly of whole classes of natural
10,11
and the D
double bond of the side chain of litseaverticil-
products is not without precedent. Most notably, Black and
co-workers proposed such a biosynthesis for the endiandric
lol A (1), that is, the double bond most distal from the 4-hy-
droxycyclopentenone core. Litseaverticillol A (1) could also
be responsible for fathering litseaverticillol H (8) through
two consecutive oxidations. Likewise, litseaverticillol B (2)
could furnish the compound with the proposed structure for
litseaverticillol E (5). Furthermore, the litseaverticillol core
[8]
acids, a hypothesis later supported by a total synthesis of
these racemates accomplished by Nicolaou and co-work-
[9]
ers.
Retrosynthetic analysis and strategy: With our proposed
biogenetic blueprint in hand, we now turned our attention
to how its directives might be implemented in a laboratory
setting and to how our hypothesis might be supported by
empirical results. It was envisioned that the furans 11a and
could conceivably arise from a cascade initiated by another
1
common reaction of O , a [4+2] cycloaddition occurring
2
with the electron-rich diene moiety of a naturally occurring
[6]
[7]
furan, such as sesquirosefuran (11a). The endoperoxide
Ia resulting from this transformation might reasonably be
expected to be susceptible to nucleophilic opening; this fol-
lowed by base-mediated collapse of the lactol intermediate
IIa would give the acyclic (Z)-1,4-enedicarbonyl 12a. A
nonenzymatic intramolecular aldol reaction of this achiral
precursor 12a would then complete the assembly of the lit-
seaverticillol core. At this stage we also entertained the pos-
11b, required as substrates for our investigation into the piv-
1
otal O -initiated cascade sequence, could be accessed by al-
2
kylation of the known furan 14 with either neryl or geranyl
bromide (15 and 16, respectively), as detailed in the retro-
synthetic scheme (Scheme 3).
6
,7
sibility that the deviation in geometry at the D double
bond exhibited amongst the various litseaverticillols could
arise by isomerisation of 12a, under mildly basic conditions,
to afford a mixture of 12a and 12b; thus, just one naturally
occurring furan might be the biogenetic precursor to the
entire litseaverticillol family. This proposed derivation of the
litseverticillols A–H (1–8) is in full accord with the high nat-
ural abundance in plants of the three components necessary
Results and Discussion
Synthesis of the first-generation litseaverticillols A–C: Now
that our full strategy for accomplishing a biomimetic synthe-
sis of the litseverticillol family (A–J, 1–10) had been clearly
delineated, we were ready to embark on the synthetic phase
of the project. Thus, 2-triisopropylsilyloxyfuran 14 was pre-
[10,11]
pared according to a two-step literature precedent
from
1
for photochemically generating the reactive O2 species;
the cheap and readily available citraconic anhydride (17,
Scheme 4). Ortho-metallation at the 5-position of 14 by
these components are a) molecular dioxygen (approximately
5900
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Chem. Eur. J. 2005, 11, 5899 – 5907

Litseaverticillol Syntheses
FULL PAPER
A significant hurdle that execu-
tion of this ambitious one-pot,
five-synthetic-operations
cas-
cade faced was the problem of
chemoselectivity. The sequence
was required to initiate at the
site of the furan core without
concomitant reaction at either
of the two susceptible double
bonds present in the appended
side chain. Indeed, applications
of several literature protocols
known as methods for the
direct oxidation of furans to the
corresponding
(Z)-1,4-ene-
diones, including treatment
with either Br /MeOH/dilute
2
[
13]
H SO
or magnesium monop-
2
4
[
14]
eroxyphthalate,
were unsuc-
cessful as they led primarily to
extensive unwanted bromina-
tion or epoxidation of the side-
chain double bonds. This appar-
ent lack of chemoselectivity
prompted us to examine more
closely the pioneering work of
Foote, Schenck and co-work-
[15]
ers relating to the photosensi-
tised oxidation of alkyl-substi-
tuted furans. In this case, the
conditions used would closely
mimic our biogenetic scenario
for the oxidation of naturally
occurring furans into the litsea-
verticillols. Gratifyingly, it was
found that upon subjecting ses-
quirosefuran (11a), in a metha-
ꢀ
4
nolic solution containing 10
m
methylene blue (as a photosen-
sitiser) and having O2 gently
bubbled through it, to irradia-
Scheme 2. Our proposal for the biogenesis of the litseaverticillol family.
using sec-butyllithium, followed by a quench of the resultant
anion with either neryl or geranyl bromide (15 and 16, re-
spectively) and subsequent in situ acidic hydrolysis of the
triisopropylsilyloxy moiety, furnished the lactones 13a and
1
3b in moderate yields. DIBAL-H was eventually found to
[12]
be the reducing agent of choice for effecting the transfor-
mation of the lactones 13a and 13b into sesquirosefuran
(
11a) and furan 11b, respectively, under carefully controlled
reaction conditions.
With the synthesis of the sesquirosefuran (11a) and furan
1
1b substrates efficiently concluded, the time had come to
1
test the key singlet oxygen ( O ) cascade sequence from
2
Scheme 3. Retrosynthetic analysis of furans 11a and 11b, precursors for
the proposed biomimetic cascade sequence. TIPS=triisopropylsilyl.
which we hoped to derive the complete litseaverticillol core.
Chem. Eur. J. 2005, 11, 5899 – 5907
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5901

G. Vassilikogiannakis, M. Stratakis et al.
studies, as indicated in Scheme 5, which confirmed that it
was the opposite regioisomer to that previously proposed
for the analogous photooxidation of 2-methylfuran and
[15]
menthofuran. These studies of the structure of hydroper-
oxide 18a also proved that the nucleophilic addition of
MeOH to the endoperoxide (Ia, Scheme 5) was not only re-
gioselective but also diastereoselective. The hydroperoxide
moiety of 18a was reduced by treatment with 5.0 equiva-
lents of (CH ) S in CH Cl with progress monitored by use
3
2
2
2
1
of H NMR spectroscopy. After 2 h, the intermediate
anomeric hemiketals (19a, Scheme 5) could be observed in
1
the H NMR spectra along with small amounts of keto alde-
hyde 12a, however, the reaction was left for a further 6 h
until complete conversion into the keto aldehyde 12a had
occurred. The labile keto aldehyde 12a could be isolated in
high yield (90%); alternatively, once it was formed, in situ
treatment with 1equivalent of Hünigꢀs base furnished, after
Scheme 4. Preparation of sesquirosefuran 11a and its Z analogue 11b.
Reagents and conditions: a) see ref. [10,11]; b) Et N (1.4 equiv), TIP-
SOTf (1.2 equiv), CH Cl
, 0!258C, 6 h, 81%; c) TMEDA (1.8 equiv),
sec-BuLi (1.8 equiv), THF, 08C, 2 h, geranyl-Br (15) or neryl-Br (16,
.0 equiv), 08C, 3 h; then TFA (3.0 equiv), 258C, 1h, 63–65%;
d) DIBAL-H (1.7 equiv), THF, ꢀ78!ꢀ58C, 3 h, 80–85%. TIPSOTf=
triisopropylsilyltrifluoromethanesulfonate, TMEDA=N,N,N’,N’-tetrame-
thylethylenediamine, TFA=trifluoroacetic acid, DIBAL-H=diisobutyla-
luminium hydride.
3
2
2
2
6
h stirring, a 19:1 mixture of litseaverticillols A (1) and C
(3). Triethylamine was initially employed as the base in an
attempt to promote this reaction, which mimics the nonen-
zymatic intramolecular aldol reaction proposed in our bioge-
netic hypothesis; however, this choice of base led to a major
degradation of the fragile substrate.
tion with visible light for 1min, hydroperoxide 18a was ex-
clusively formed as the adduct in a quantitative yield
Optimisation of this reaction sequence enabled us to ach-
ieve the desired goal of undertaking the whole series of
transformations (11a!1, 3) in a single pot, with just one ex-
change of solvent from methanol to CH Cl (or CHCl ) at
(
Scheme 5). It was possible to isolate and fully characterise
hydroperoxide 18a; in addition, it was the subject of NOE
2
2
3
the appropriate stage (prior to the addition of (CH ) S), in
3
2
5
5% overall yield. It was also found that premature addition
of the Hünigꢀs base halted the cascade; apparently, anome-
ric hemiketals 19a are stable under basic conditions. If
Hünigꢀs base was added to a solution containing the mixture
of hemiketals and keto aldehyde (19a:12a, 7:3), the elimina-
tion of MeOH was suppressed, thereby leading to a 7:3 mix-
ture of hemiketals and litseaverticillol A (19a:1), even after
three days of stirring at room temperature. This observation
had to be balanced, when seeking optimal timings with the
observed lability of keto aldehyde 12a, which was shown to
decompose completely on standing in solution for two days.
Exactly the same protocol as had been developed for the
one-pot cascade to furnish litseaverticillol A (1) from ses-
quirosefuran (11a) was repeated with furan 11b to access
litseaverticillol B (2) in 51% overall yield. The formation of
litseaverticillol B (2) was accompanied, in accordance with
our previous experience regarding the formation of both lit-
seaverticillols A (1) and C (3) from the same achiral precur-
sor (12a), by production of trace amounts of its C-1diaster-
eoisomer (20:1). It should be noted at this stage that the
1
13
spectra ( H NMR, C NMR, HRMS, see the Supporting In-
formation) of the synthetic litseaverticillols A–C (1–3) were
identical in every way to those of the naturally derived com-
pounds. Perhaps the most intriguing and exciting observa-
tion of this phase of our investigations was that, if the reac-
tion of 11b was left for prolonged periods (12 h) subse-
quently to the addition of Hünigꢀs base, then substantial
amounts of litseaverticillol A (1, 15%) were isolated in ad-
dition to the expected products, litseaverticillol B (2) and its
Scheme 5. Biomimetic total synthesis of the first-generation litseaverticil-
lols A–C from furans 11a and 11b, including the mechanistic rationale.
ꢀ
4
Reagents and conditions: a) 10 m MB, O
min, 97%; b) (CH (5.0 equiv), CH
1.0 equiv), 258C, 6 h, 51–55% over two steps. MB=methylene blue.
2
(bubbling), MeOH, hn, 08C,
1
(
3
)
2
S
2
Cl 258C, 8 h; c) iPr NEt
2
,
2
5902
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Chem. Eur. J. 2005, 11, 5899 – 5907

Litseaverticillol Syntheses
FULL PAPER
1
6,7
C-1diastereoisomer. The furan 11b employed in the reac-
tion cascade is geometrically pure; therefore, this geometri-
cal deviation must be a feature of the cascade itself. Since
no formation of litseaverticillol A (1) was observed with
shorter reaction times, we rationalised that litseaverticillol B
participate in an ene reaction with O and the D double
2
10,11
bond suffers from greater steric encumberance than its D
neighbour; therefore, reaction at the latter should be fastest.
The first-generation parent litseaverticillol A (1), dissolved
in CDCl together with 10 m methylene blue as a photosen-
ꢀ
4
3
(
2) must be undergoing a retroaldol reaction to regenerate
zitiser, was subjected to visible light irradiation for 3 min at
the stabilised anion III (Scheme 2 and Scheme 5). This
08C whilst O was gently bubbled through the solution
(Scheme 6). H NMR analysis of the mixture that was pro-
duced identified the presence of tertiary hydroperoxide 20
and diastereomeric secondary hydroperoxides 21a and 21b
2
1
anion, exhibiting extended conjugation, may allow stereo-
6
,7
chemical scrambling of the D double bond by permitting
rotation around the C-6/C-7 bond. Thus, under these equili-
bration conditions, anion III can suffer one of two fates,
either reformation of litseaverticillol B (2) or rotation
around the C-6/C-7 bond followed by an intramolecular
aldol reaction to afford the thermodynamically more stable
litseaverticillol A (1). These results provide a stark indica-
tion that our biogenetic proposal, including the proposal
that the whole litseaverticillol family might arise from a
single naturally occurring furan, is a valid and substantiated
hypothesis. Further to our proposals presented thus far, we
now suggest that the distribution of isolated natural prod-
ucts may be correlated to their thermodynamic stability, as
it represents an equilibrium mixture.
(20:21, 1:1). In situ reduction of this mixture with PPh in-
3
stantaneously afforded the corresponding naturally occur-
ring diols, litseaverticillols D (4), F (6) and G (7) in good
overall yield (70%). Litseaverticillol D (4, 35%) could be
separated by careful column chromatography from an insep-
arable equimolar mixture (35%) of litseaverticillols F (6)
and G (7). Only trace amounts of the more polar triols aris-
ing from the indiscriminate oxidation of both side chain
double bonds were observed. The favoured published mech-
[
16,17]
anism
for describing the ene reaction of a trisubstituted
1
double bond with O accounts for the product distribution
2
seen upon oxidation of litseaverticillol A (1, Scheme 6).
Thus, the result is consistent with the formation of an inter-
[16]
Synthesis of the second-generation litseaverticillols D–G, I
mediate perepoxide,
in which the negatively charged
and J: Not content to rest upon our laurels with the synthe-
oxygen atom is orientated towards the more substituted side
of the preceding double bond, in accordance with the so-
called cis effect. The subsequent abstraction of the allylic
sis of the first-generation litseaverticillols A–C (1–3) se-
1
[16]
cured, we continued to probe the scope of the O paradigm
2
by attempting to synthesise the second-generation litseaver-
hydrogen atom, possible from either C-9 or C-15, furnishes
a balanced 1:1 mixture of C-11 (tertiary) and C-10 (secon-
dary) hydroperoxides (20 and 21a,b, respectively).
Gratified by the success of this oxidative strategy for the
derivation of the second-generation litseaverticillols, we
were anxious to proceed with the synthesis of the remaining
congeners from the litseaverticillol family, a task which in-
cluded the synthesis of litseaverticillols I and J (9 and 10),
1
ticillols by using O -mediated oxidation of the distal double
2
10,11
bond (D ) in the side chains appended to the litseaverticil-
lol core. We rationalised that this regioselective reaction,
targeting just one out of the three double bonds present in
the first-generation litseaverticillols, was possible for both
2
,3
steric and electronic reasons. The D double bond present
within the moleculeꢀs core is too electron deficient to readily
Scheme 6. Transformation of litseaverticillols A and B (1 and 2) into the second-generation litseaverticillols D (4), F (6), G (7), E (5), I (9) and J (10)
ꢀ
4
through a regioselelective singlet-oxygen ene reaction and the structural reassignment of litseaverticillol E. Reagents and conditions: a) 10 m MB, O
2
ꢀ4
(
bubbling), CHCl
3
, hn, 08C, 3 min; b) PPh
3
(2.0 equiv), CHCl
3
, 258C, 5 min, 35% of 4 plus 35% of 6 and 7 over two steps; c) 10 m MB, O
2
(bubbling),
CH Cl , hn, 08C, 4 min, 90%; d) PPh
2
2
3
(2.0 equiv), CH
2
2
Cl , 258C, 10 min, 35% of 5 plus 22% of 9 and 18% of 10.
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5903

G. Vassilikogiannakis, M. Stratakis et al.
the, as yet, not isolated offspring of litseaverticillol B (2),
and the natural isolate litseaverticillol E (5). We believed
that litseaverticillols I (9) and J (10) had not yet been isolat-
ed precisely because they were the offspring of the minor
tained upon oxidation of litseaverticillol B (2, Scheme 6).
This prompted us to scrutinise the hydroperoxide intermedi-
ates obtained from the analogous oxidation of litseaverticil-
1
lol A (1). Careful inspection of the H NMR spectrum of
6,7
D -isomer first-generation compound litseaverticillol B (2)
the initially inseparable hydroperoxide intermediate mixture
(20, 21a, and 21b, Scheme 6) convinced us that the true
structure for litseaverticillol E was that of tertiary hydroper-
oxide 20. In order to obtain full characterisation of hydro-
and these compounds, as previously discussed, possessed the
6
,7
less thermodynamically stable Z arrangement at the D
double bond. Our interest in litseaverticillols I and J (9 and
6
,7
1
0), which crucially bear both the D Z arrangement and
peroxide 20 to support this assertion, we needed to decon-
1
side-chain oxidation, had been piqued by the initial struc-
ture–activity relationship data, which suggested that each of
these two structural attributes was responsible for rises in
the anti-HIV activity when like-with-like comparisons were
made of the biological data for the known naturally occur-
volute the inseparable mixture obtained from the O -medi-
2
ated oxidation of litseaverticillol A (1). We accomplished
this task by selectively reducing the secondary hydroperox-
ides (21a and 21b) with (CH ) S (5.0 equivalents, 258C,
3
2
12 h) to afford the more polar litseaverticillols F and G (6
and 7) accompanied by unreacted tertiary hydroperoxide 20.
The tertiary hydroperoxide 20, which could now be isolated
and purified with ease, had spectral data that matched those
of naturally occurring litseaverticillol E in every respect (in-
[4c]
ring litseaverticillols A–H (1–8). To enable us to examine
further the biological activity of litseaverticillols I and J (9
and 10) it was necessary to synthesise them; to this end, lit-
seaverticillol B (2) was subjected to the optimal oxidation
conditions as described above. After 4 min irradiation and
1
cluding a signal at 7.51ppm in the H NMR spectrum that
subsequent PPh -mediated reduction, litseaverticillols I and
was assignable to the hydroperoxide proton and HRMS
data confirming that an error in the molecular formula was
made upon isolation by the omission of one oxygen atom).
The structure of naturally occurring litseaverticillol E was
therefore reassigned as hydroperoxide 20.
3
J (9 and 10, 40%, 1.2:1) and compound 5 (35%) were iso-
lated in 75% combined yield (Scheme 6). In contrast to lit-
seaverticillols F (6) and G (7), litseaverticillols I (9) and J
(
10) were separable by column chromatography with pure
samples of each being attained and subsequently submitted
for biological investigations, the results of which will be re-
ported at a later date.
In conclusion, we have achieved the first syntheses of lit-
seaverticillols A–G, I and J by using the biomimetic strategy
which we had developed earlier. The syntheses include an
elegant and highly efficient one-pot cascade, involving five
Structural reassignment of litseaverticillol E: The comple-
tion of one synthesis of the so-called second-generation lit-
seaverticillols did not provide the expected end to the tale.
Whilst the spectra of synthetic litseaverticillols D, F and G
synthetic operations and initiated by the [4+2] cycloaddition
1
of a furan to O , to assemble the fully functionalised litsea-
2
1
verticillol core. The powerful chemistry of O was then fur-
2
ther commandeered to serve our purposes when the requi-
(
4, 6, and 7) matched exactly with those of the naturally oc-
site regioselective side-chain oxidation was also accomplish-
1
curring samples, the spectral data taken for the synthetically
obtained compound 5 showed significant discrepancies with
those of the natural sample of litseaverticillol E. Since, there
could be no doubt that we had synthesised the compound
with the proposed structure for litseaverticillol E (that is,
compound 5), we began to search for an alternative explana-
tion for this apparent mismatch. Close inspection of the
papers reporting the isolation of the litseaverticillols re-
vealed that the structure of litseaverticillol E (proposed
structure 5) had caused some concern to the group responsi-
ed by using ene reactions of O . The syntheses of com-
2
pounds 20 and 5 allowed us to reassign the structure of natu-
rally occurring litseaverticillol E as being the former rather
than the latter, as was originally reported. Furthermore, the
reassignment of litseaverticillol E to hydroperoxide structure
1
20 lent considerable credence to our proposal that O -medi-
2
ated oxidation of the first-generation litseaverticillols is how
nature constructs the second-generation litseaverticillols.
[4]
Overall, these syntheses provide ample evidence that nature
1
uses many of the modes of reaction known for O and that
2
[
4c]
1
ble. Fong and co-workers discuss the incongruous nature
this O chemistry is easily adapted to the laboratory envi-
2
13
of some of the C NMR peaks of the compound they sup-
posed had the structure 5 in comparison to its closest litsea-
verticillol relatives. Specifically, they noted that the C-8 and
ronment where it can provide a set of very valuable tools to
the synthetic chemist.
13
C-14 signals in C NMR spectrum were closer to those in
6,7
6,7
the D E isomers than the D Z isomers; furthermore, the
C-11 peak was shifted downfield from the comparable peak
in litseaverticillol D (4). Our biogenetic proposal for the lit-
seaverticillol family led us to consider that the spectral and
physical properties of litseaverticillol E might be more in ac-
cordance with one of the hydroperoxide intermediates.
However, the H NMR spectrum of natural litseaverticil-
lol E was distinctly different from each of the components
of the mixture of hydroperoxides (22a, 22b, and 23) ob-
Experimental Section
General techniques: Diethyl ether and THF were distilled from Na/ben-
zophenone. TMEDA was refluxed for 24 h with LiAlH4 and kept over
3 Š molecular sieves. Reagents were purchased at the highest available
commercial quality and used without further purification. Irradiation ex-
periments (photooxygenations) were performed with a xenon Variac
Eimac Cermax 300 W lamp. Reactions were monitored by thin-layer
chromatography (TLC) carried out on silica gel plates (60F-254) with
UV light as the visualising method and an acidic mixture of phosphomo-
1
5904
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 5899 – 5907

Litseaverticillol Syntheses
FULL PAPER
lybdic acid/cerium(iv) sulfate accompanied by heating of the plate as a
139.8 (C-1), 136.5 (C-7), 131.5 (C-11), 124.2 (C-10), 119.9 (C-6), 113.4 (C-
developing system. The development agent contains H
centrated H SO (6 mL), Ce(SO ·(H O) (1.0 g) and phosphomolybdic
acid (1.5 g). Column chromatography refers to flash column chromatog-
2
O (94 mL), con-
3), 112.8 (C-2), 39.6 (C-8), 26.6 (C-9), 25.7 (C-5 or CH ), 25.2 (C-5 or
3
2
4
4
)
2
2
n
CH ), 17.6 (CH ), 16.1 (CH ), 9.8 ppm (CH ); HRMS (MALDI): calcd
3
3
3
3
+
for C H O: 219.1743 [M+H] ; found: 219.1752.
1
5
23
raphy carried out on SiO
with the specified eluent.
2
(silica gel 60, particle size 0.040–0.063 mm)
1
1
1b: R
CDCl ): d=7.21(d, J=1.4 Hz, 1H; H-1), 6.16 (d, J=1.4 Hz, 1H; H-2),
.28 (brt, J=7.0 Hz, H-6), 5.16 (brt, J=6.3 Hz, 1H; H-10), 3.29 (d, J=
f
=0.75 (silica gel, EtOAc/hexane (1:2)); H NMR (500 MHz,
3
NMR spectra were recorded on a Bruker AMX-500 instrument and cali-
brated by using residual undeuterated solvent as an internal reference.
The following abbreviations are used to explain the multiplicities: s=sin-
glet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad. Elec-
trospray ionisation mass spectrometry (ESIMS) experiments were per-
formed on an API 100 Perkin–Elmer SCIEX single-quadrupole mass
spectrometer at 4000 V emitter voltage. High-resolution mass spectra
5
7
.1 Hz, 2H; H-5), 2.14 (m, 4H; H-8 and H-9), 1.97 (s, 3H; H-13), 1.73
13
(
brs, 3H; CH
3
), 1.70 (brs, 3H; CH
3
), 1.63 ppm (brs, 3H; CH
3
); C NMR
(
125 MHz, CDCl
3
): d=150.0 (C-4), 139.8 (C-1), 136.7 (C-7), 131.7 (C-11),
24.2 (C-10), 120.7 (C-6), 113.4 (C-3), 112.8 (C-2), 32.0 (C-8), 26.5 (C-9),
5.7 (C-5 or CH ), 24.9 (C-5 or CH ), 23.3 (CH ), 17.6 (CH ), 9.8 ppm
); HRMS (MALDI): calcd for C15 23O: 219.1743 [M+H] ; found:
19.1752.
1
2
3
3
3
3
+
(
CH
3
H
(
HRMS) were recorded on a VG ZAB-ZSE mass spectrometer under
2
matrix-assisted laser desorption/ionisation (MALDI) conditions with 2,5-
dihydroxybenzoic acid (DHB) as the matrix.
Tandem transformation of furans 11a,b into first-generation litseaverticil-
lols A–C(1–3) : A solution of 11a or 11b (150 mg, 0.69 mmol) in MeOH
20 mL) and containing 10 m methylene blue was placed in a test tube
2
with O gently bubbling through it. Irradiation with a xenon Variac
Eimac Cermax 300 W lamp for 1min at 0 8C led to complete tranforma-
tion of the starting material (based on TLC). The solvent was thoroughly
removed in vacuo to yield the hydroperoxide 18a or 18b (188 mg, 97%
Lactones 13a,b: sec-BuLi (2.0 mL of a 1.4m solution in cyclohexane,
ꢀ4
(
2
1
.8 mmol) was added dropwise to a solution of furan 14 (400 mg,
.56 mmol) and TMEDA (417 mL, 2.8 mmol) in anhydrous THF (8 mL)
at 08C. After 2 h, geranyl bromide (15) or neryl bromide (16; 677 mg,
.12 mmol) was added and the reaction was stirred for a further 3 h at
the same temperature. solution of and saturated aqueous
NaHCO (1:1, 10 mL) was added and the resulting mixture was extracted
with Et O (15 mL). The organic phase was treated for 1 h with excess
TFA (358 mL, 4.68 mmol) at ambient temperature. Saturated aqueous
NaHCO (10 mL) was added and the resulting mixture was extracted
with Et O (2ꢂ10 mL). The organic phase was dried over Na SO and
3
A
2
H O
crude) as a gum.
3
1
1
8a: R
CDCl
6.4 Hz, 1H; H-10), 4.91 (brt, J=6.7 Hz, 1H; H-6), 3.19 (s, 3H; H-16),
2.59 (dd, J =14.9, J =6.6 Hz, 1H; H-5a), 2.44 (dd, J =14.9, J =7.5 Hz,
1H; H-5b), 2.01 (m, 4H; H-8 and H-9), 1.70 (brs, 3H; CH ), 1.67 (brs,
3H; CH ), 1.62 (brs, 3H; CH ) 1.59 ppm (brs, 3H; CH
(125 MHz, CDCl ): d=144.7 (C-3), 138.4 (C-7), 131.4 (C-11), 124.1 (C-
10), 121.5 (C-4), 117.0 (C-6), 115.2 (C-1), 108.4 (C-2), 50.1 (C-16), 39.7
f
=0.40 (silica gel, EtOAc/hexane (1:2)); H NMR (500 MHz,
2
3
): d=5.87 (brs, 1H; H-1), 5.59 (brs, 1H; H-2), 5.03 (brt, J=
3
2
2
4
1
2
1
2
concentrated in vacuo. The residue was purified by flash column chroma-
tography (silica gel, EtOAc/hexane (1:4)) to afford 13a or 13b (230–
3
1
3
3
3
3
); C NMR
2
37 mg, 63–65% over two steps) as colourless oils.
3a: R =0.30 (silica gel, EtOAc/hexane (1:2)); H NMR (500 MHz,
): d=5.79 (brs, 1H; H-2), 5.03 (brt, J=6.7 Hz, 2H; H-4 and H-
0), 4.87 (brt, J=5.2 Hz, 1H; H-6), 2.64 (ddd, J =15.3, J =6.3, J
.6 Hz, 1H; H-5a), 2.35 (ddd, J =15.3, J =7.3, J =6.4 Hz, 1H; H-5b),
.03 (brs, 3H; H-13), 2.01 (m, 4H; H-8 and H-9), 1.67 (brs, 3H; CH ),
); C NMR (125 MHz,
): d=173.1 (C-1), 168.2 (C-3), 139.8 (C-7), 131.6 (C-11), 123.9 (C-
0), 117.3 (C-6 or C-2), 116.0 (C-2 or C-6), 84.3 (C-4), 39.7 (C-8), 30.2
C-5), 26.4 (C-9), 25.7 (CH ), 17.7 (CH ), 16.3 (CH ), 13.9 ppm (CH );
HRMS (MALDI): calcd for C15
3
1
1
f
(
C-8), 35.5 (C-5), 26.4 (C-9), 25.7 (CH
11.7 ppm (CH ).
18b: R =0.41(silica gel, EtOAc/hexane (: 12 ));
3
3 3
), 17.6 (CH ), 16.3 (CH ),
CDCl
3
1
5
2
1
1
2
3
=
3
1
1
2
3
f
H NMR (500 MHz,
3
CDCl ): d=5.90 (brs, 1H; H-1), 5.60 (brs, 1H; H-2), 5.09 (brs, 1H; H-
10), 4.93 (brt, J=6.7 Hz, 1H; H-6), 3.17 (s, 3H; H-16), 2.58 (dd, J =15.1,
3
1
3
.63 (brs, 3H; CH
3
), 1.58 ppm (brs, 3H; CH
3
1
CDCl
3
J
2
=6.5 Hz, 1H; H-5a), 2.42 (dd, J
1
=15.1, J
2
=7.3 Hz, 1H; H-5b), 2.04
), 1.68 (brs, 3H; CH ), 1.67
); C NMR (125 MHz, CDCl ):
1
(
(
(
brm, 4H; H-8 and H-9), 1.70 (brs, 3H; CH
brs, 3H; CH
3
3
13
3
3
3
3
), 1.59 ppm (brs, 3H; CH
3
3
3
+
H
22
O
2
Na: 257.1512 [M+Na] ; found:
d=144.7 (C-3), 138.6 (C-7), 131.7 (C-11), 124.1 (C-10), 121.6 (C-4), 117.5
C-6), 114.9 (C-1), 108.4 (C-2), 50.1 (C-16), 35.4 (C-5), 32.2 (C-8), 26.4
(C-9), 25.7 (CH ), 23.6 (CH ), 17.6 (CH ), 11.7 ppm (CH ).
2
57.1514.
(
1
1
3b: R =0.31(silica gel, EtOAc/hexane (: 12 ));
f
H NMR (500 MHz,
3
3
3
3
CDCl
brt, J=6.9 Hz, 1H; H-4), 4.78 (brt, J=5.2 Hz, 1H; H-6), 2.58 (m, 1H;
H-5a), 2.25 (ddd, J =15.3, J =7.4, J =6.5 Hz, 1H; H-5b), 1.98 (brs, 3H;
H-13), 1.98 (brm, 4H; H-8 and H-9), 1.63 (brs, 3H; CH ), 1.61 (brs, 3H;
); C NMR (125 MHz, CDCl ): d=173.0
C-1), 168.3 (C-3), 139.6 (C-7), 131.8 (C-11), 123.8 (C-10), 117.2 (C-2 or
C-6), 116.8 (C-6 or C-2), 84.3 (C-4), 32.0 (C-8), 30.1 (C-5), 26.2 (C-9),
5.6 (CH ), 23.3 (CH ), 17.6 (CH ), 13.9 ppm (CH ); HRMS (MALDI):
calcd for C15 Na: 257.1512 [M+Na] ; found: 257.1514.
3
): d=5.73 (brs, 1H; H-2), 5.03 (brt, J=5.6 Hz, 1H; H-10), 4.99
The hydroperoxide 18a or 18b (188 mg, 0.67) was dissolved in CH
15 mL) at ambient temperature and (CH S (244 mL, 3.35 mmol) was
added. After the mixture had been stirred for 8 h, iPr NEt (114 mL,
.67 mmol) was added and the resultant solution was stirred for a further
h at the same temperature. Removal of the solvent in vacuo and purifi-
cation of the residue by flash column chromatography (silica gel, EtOAc/
hexane (1:5!1:4)) afforded an inseparable mixture of 1 and 3 (19:1,
86 mg, 55%) or an inseparable mixture of 2 and its C-1diastereoisomer
2 2
Cl
(
(
3 2
)
1
2
3
2
3
0
6
1
3
CH
(
3
), 1.54 ppm (brs, 3H; CH
3
3
2
3
3
3
3
+
22 2
H O
(
19:1, 80 mg, 51%) as colourless gums.
6
,7
Sesquirosefuran 11a and its D -cis analogue 11b: DIBAL-H (1.6 mL of
a 1 . 0m solution in THF, 1.6 mmol) was added dropwise to a solution of
lactone 13a or 13b (220 mg, 0.94 mmol) in dry THF (9 mL) at ꢀ788C.
The reaction solution was warmed slowly (3 h) to ꢀ58C and subsequently
Litseaverticillol A (1):
H NMR (500 MHz, CDCl
R
f
=0.24 (silica gel, EtOAc/hexane (1:2));
): d=7.11 (d, J=1.7 Hz, 1H), 5.07 (brt, J=
1
3
6
.1Hz, 1H), 4.99 (brd, J=9.0 Hz, 1H), 4.55 (brs, 1H), 3.13 (dd,
1
J =9.0,
J
1
2
=2.3 Hz, 1H), 2.67 (brs, OH), 2.05 (m, 4H), 1.77 (t, J=1.5 Hz, 3H),
2
treated with 10% HCl (2 mL). The mixture was extracted with Et O
1
3
.72 (brs, 3H), 1.65 (brs, 3H) 1.57 ppm (brs, 3H); C NMR (125 MHz,
): d=206.5, 155.0, 142.7, 141.8, 131.6, 123.9, 118.8, 76.4, 56.2, 39.6,
6.5, 25.6, 17.7, 17.1, 10.2 ppm; HRMS (MALDI): calcd for C15 Na:
(
10 mL), then the organic phase was dried with Na
in vacuo. The residue was purified by flash column chromatography
silica gel, EtOAc/hexane (1:20!1:1)) to afford the unpolar sesquirose-
furan 11a or its D -cis analogue 11b (163–174 mg, 80–85%) as colour-
2 4
SO and concentrated
CDCl
2
3
22 2
H O
(
+
6
,7
257.1512 [M+Na] ; found: 257.1523.
6
,7
less liquids, accompanied by the polar diol or its D -cis analogue (18 mg,
Litseaverticillol B (2): R =0.29 (silica gel, EtOAc/hexane (1:2));
f
1
8
%) as colourless syrups.
1a: R =0.74 (silica gel, EtOAc/hexane (1:2)); H NMR (500 MHz,
): d=7.21(d, J=1.4 Hz, 1H; H-1), 6.15 (d, J=1.4 Hz, 1H; H-2),
.26 (td, J =6.9, J =0.8 Hz, 1H; H-6), 5.08 (brt, J=6.9 Hz, 1H; H-10),
.29 (d, J=7.0 Hz, 2H; H-5), 2.08 (m, 2H; H-9), 2.01(t, J=7.5 Hz, 2H;
), 1.67 (brs, 3H; CH ),
); C NMR (125 MHz, CDCl ): d=150.1 (C-4),
H NMR (500 MHz, CDCl ): d=7.12 (brs, 1H), 5.16 (brs, 1H), 5.02
3
1
1
f
(brd, J=9.5 Hz, 1H), 4.54 (brs, 1H), 3.15 (dd,
1 2
J =9.5, J =2.4 Hz, 1H),
CDCl
5
3
3
2.22 (brd, J=4.9 Hz, OH), 2.15 (m, 4H), 1.80 (brs, 3H), 1.79 (brs, 3H),
1
3
1.69 (brs, 3H) 1.62 ppm (brs, 3H); C NMR (125 MHz, CDCl
3
): d=
1
2
206.2, 154.7, 142.8, 141.8, 132.4, 123.9, 119.7, 76.1, 56.3, 32.5, 26.6, 25.7,
H-8), 1.97 (s, 3H; H-13), 1.71 (brs, 3H; CH
1
3
3
23.3, 17.7, 10.2 ppm; HRMS (MALDI): calcd for C15
[M+Na] ; found: 257.1523.
H
22
O
2
Na: 257.1512
1
3
+
.59 ppm (brs, 3H; CH
3
3
Chem. Eur. J. 2005, 11, 5899 – 5907
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5905

G. Vassilikogiannakis, M. Stratakis et al.
Photooxygenation of litseaverticillols A (1) and B (2) to furnish the
second-generation litseaverticillols D (4), E (5), F (6), G (7), I (9) and J
Full characterisation of 5 unambiguously confirmed our suspicions that
the initially proposed structure for litseaverticillol E is incorrect.
(
10): A solution of litseaverticillols A (1) or B (2) (80 mg, 0.34 mmol) in
Proposed structure of litseaverticillol E (5): Colourless gum; R
f
=0.09
): d=7.13
brs, 1H; H-2), 5.69 (m, 2H; H-9 and H-10), 5.10 (brd, J=9.6 Hz, 1H;
=9.6, J =2.3 Hz, 1H; H-5), 2.94
=3.6 Hz, 1H; H-8a), 2.77 (dd, J =15.0, J =2.7 Hz, 1H;
H-8b), 2.52 (brd, J=4.3 Hz, OH), 1.80 (t, J=1.3 Hz, 3H; CH ), 1.79
brs, 3H; CH ), 1.67 (brs, OH), 1.33 (s, 3H; CH ), 1.32 ppm (s, 3H;
); C NMR (125 MHz, CDCl ): d=206.3 (C-4), 155.2 (C-2), 142.7
(C-3), 139.7 (C-7), 138.6 (C-10), 124.9 (C-9), 121.0 (C-6), 75.8 (C-1), 70.7
(C-11), 56.3 (C-5), 35.2 (C-8), 29.7 (CH ), 29.5 (CH ), 14.0 (CH ),
10.2 ppm (CH ); HRMS (MALDI): calcd for C15
Na] ; found: 273.1464.
ꢀ4
CH
tube with O
2
Cl
2
(15 mL) containing 10 m methylene blue was placed in a test
gently bubbling through it. The solutions were irradiated
1
(
(
silica gel, EtOAc/hexane (1:1)); H NMR (500 MHz, CDCl
3
2
with a xenon Variac Eimac Cermax 300 W lamp for 3 and 4 min, respec-
tively, at 08C to afford a mixture of tertiary and diastereomeric secon-
dary hydroperoxides (83 mg, 91% from 1; 82 mg, 90% from 2) after
evaporation of the solvent.
H-6), 4.57 (brs, 1H; H-1), 3.14 (dd, J
dd, J =15.0, J
1
2
(
1
2
1
2
3
(
3
3
1
13
H NMR absorptions of the tertiary hydroperoxide 20 in the crude mix-
CH
3
3
ture arising from photooxygenation of litseaverticcillol A (1) are identical
to those reported for litseaverticillol E. Treatment of this chromato-
graphically inseparable mixture of hydroperoxides (83 mg, 0.31mmol)
[
4c]
3
3
3
3
H
22
O
3
Na: 273.1461 [M+
+
3 2
with (CH ) S (114 mL, 1.55 mmol) for 12 h at 258C leads to the selective
reduction of the diastereomeric secondary hydroperoxides 21a,b into the
more polar (relative to the hydroperoxides), naturally occurring secon-
dary alcohols litseaverticillols F (6) and G (7). The resulting mixture was
separated by flash column chromatography (silica gel, EtOAc/hexane
9
(less polar diastereoisomer): Colourless gum; R =0.24 (silica gel,
f
1
3
EtOAc/hexane (1:1)); H NMR (500 MHz, CDCl ): d=7.14 (brs, 1H; H-
2
), 5.15 (brd, J=9.3 Hz, 1H; H-6), 4.96 (brs, 1H; H-12a), 4.85 (brs, 1H;
H-12b), 4.53 (q, J=1.7 Hz, 1H; H-1), 4.30 (brs, OH), 3.99 (brd, J=
.2 Hz, 1H; H-10), 3.26 (dd, =9.3, J =1.9 Hz, 1H; H-5), 2.58 (ddd,
=14.0, J =10.3, J =6.4 Hz, 1H; H-8a), 2.36 (brs, OH), 2.06 (dt, J
14.0, J =5.4 Hz, 1H; H-8b), 1.81 (m, 1H; H-9a), 1.81 (brs, 3H; CH
1.77 (brs, 3H; CH
(
1:2!2:1)) to allow purification and full characterisation of 20.
8
J
1
2
Revised structure of litseaverticillol E (20): Colourless gum; R
f
=0.22
): d=7.51
=15.8, J =6.6 Hz,
H; H-9), 5.61 (brd, J=15.8 Hz, 1H; H-10), 5.05 (brd, J=9.1Hz, 1H;
H-6), 4.61 (brs, 1H; H-1), 3.17 (dd, J =9.1, J =2.3 Hz, 1H; H-5), 2.81
brd, J=6.6 Hz, 2H; H-8), 2.12 (brs, OH), 1.81 (brs, 3H; CH ), 1.74
); C NMR (125 MHz, CDCl ):
J
1
2
3
1
=
1
(
(
1
silica gel, EtOAc/hexane (1:1)); H NMR (500 MHz, CDCl
brs, OOH), 7.14 (d, J=1.1 Hz, 1H; H-2), 5.70 (dt, J
3
2
3
),
), 1.67 ppm (m, 1H; H-9b);
): d=207.4 (C-4), 155.7 (C-2), 147.6 (C-11),
3
), 1.75 (brs, 3H; CH
3
1
2
1
3
C NMR (125 MHz, CDCl
3
142.8 (C-3), 140.0 (C-7), 121.9 (C-6), 110.5 (C-12), 76.1 (C-1), 73.7 (C-
10), 56.2 (C-5), 32.4 (C-8), 27.8 (C-9), 22.8 (CH ), 18.8 (CH ), 10.4 ppm
(CH ); HRMS (MALDI): calcd for C15 Na: 273.1461 [M+Na] ;
found: 273.1462.
1
2
(
(
3
3
3
1
3
+
brs, 3H; CH
3
) 1.34 ppm (s, 6H; 2ꢂCH
3
3
3
22 3
H O
d=206.1 (C-4), 155.0 (C-2), 142.8 (C-3), 140.4 (C-7), 135.4 (C-10), 129.1
(
(
C-9), 120.0 (C-6), 82.2 (C-11), 76.3 (C-1), 56.3 (C-5), 42.4 (C-8), 24.3
CH ), 24.2 (CH ), 17.2 (CH ), 10.2 ppm (CH ); HRMS (MALDI): calcd
Na: 289.1410 [M+Na] ; found: 289.1416.
Prolonged treatment (72 h) of the crude mixture of the hydroperoxides
0 and 21a,b (83 mg, 0.31mmol) with (CH S under the previously de-
10 (more polar diastereoisomer): Colourless gum; R =0.20 (silica gel,
f
1
3
3
3
3
EtOAc/hexane (1:1)); H NMR (500 MHz, CDCl ): d=7.16 (brs, 1H; H-
3
+
for C15
H
22
O
4
2), 5.06 (brd, J=8.8 Hz, 1H; H-6), 4.97 (brs, 1H; H-12a), 4.82 (brs, 1H;
H-12b), 4.56 (brs, 1H; H-1), 4.07 (brd, J=8.7 Hz, 1H; H-10), 3.50 (brs,
OH), 3.24 (brd, J=8.7 Hz, 1H; H-5), 2.89 (brs, OH), 2.29 (m, 2H; H-8),
2
3 2
)
scribed conditions resulted in complete reduction to the corresponding
naturally occurring alcohols, litseaverticillols D (4), F (6) and G (7). Re-
moval of the solvent in vacuo and purification by flash column chroma-
tography (silica gel, EtOAc/hexane (1:1!2:1)) afforded 4 (26 mg, 35%)
and an inseparable mixture of 6 and 7 (25 mg, 35%). Similar yields could
be obtained when the mixture of hydroperoxides (20, 21a, and 21b) was
1.86 (m, 1H; H-9a), 1.80 (d, J=1.1 Hz, 3H; CH
1.74 (brs, 3H; CH ), 1.51 ppm (m, 1H; H-9b); C NMR (125 MHz,
CDCl ): d=208.0 (C-4), 156.2 (C-2), 148.0 (C-11), 142.7 (C-3), 141.3 (C-
7), 120.9 (C-6), 110.5 (C-12), 76.4 (C-1), 74.8 (C-10), 56.1 (C-5), 33.7 (C-
8), 29.0 (C-9), 23.2 (CH ), 18.2 (CH ), 10.3 ppm (CH ); HRMS
(MALDI): calcd for C15 Na: 273.1461 [M+Na] ; found: 273.1462.
3 3
), 1.77 (brs, 3H; CH ),
1
3
3
3
3
3
3
+
22 3
H O
treated for 5 min with PPh
advantage of this second protocol is the almost identical R
and the byproduct of the reduction (O=PPh ), which makes separation
difficult.
Litseaverticillols F and G (6 and 7): Colourless gum; R
3
(163 mg, 0.62 mmol) in CH
2
Cl
2
. The only dis-
f
value of diol
4
3
f
=0.14 (silica gel,
): d=7.11 (brs, 2H),
.04 (brd, J=9.0 Hz, 2H), 4.91(s, 2H), 4.81(t, J=1.3 Hz, 2H), 4.57 (brs,
H), 4.04 (m, 2H), 3.14 (dd, J =9.0, J =2.1Hz, 2H), 2.34 (brd, J=
1
EtOAc/hexane (1:1)); H NMR (500 MHz, CDCl
3
Acknowledgements
5
2
5
1
1
2
We thank Professor H. H. S. Fong for generously sharing relevant spectra
with us. This project was cofunded by the European Social Fund and Na-
tional Resources (B’EPEAEK). The research was also supported by a
Marie Curie Intra-European Fellowship (T.M.) within the 6th European
Community Framework Programme and the European Science Founda-
tion (ESF) Cost Action (Program D-28).
.6 Hz, OH), 2.32 (brd, J=5.6 Hz, OH), 2.11 (m, 4H), 1.83 (brs, OH),
.78 (t, J=1.5 Hz, 6H), 1.75 (brd, J=0.7 Hz, 3H), 1.74 (brs, 3H), 1.70
1
3
(
brs, 6H), 1.65 ppm (m, 4H); C NMR (125 MHz, CDCl
3
): d=206.2 (2ꢂ
C), 155.1, 155.0, 147.4, 147.3, 142.7 (2ꢂC), 141.7, 141.5, 119.4, 119.2,
1
1
C
11.0, 110.9, 76.3 (2ꢂC), 75.6, 75.4, 56.3 (2ꢂC), 35.9, 35.7, 33.0, 32.8,
7.7, 17.6, 17.0, 16.9, 10.2 ppm (2ꢂC); HRMS (MALDI): calcd for
+
15
H
22
O
3
Na: 273.1461 [M+Na] ; found: 273.1460.
Litseaverticillol D (4): Colourless gum; R
f
=0.11 (silica gel, EtOAc/
): d=7.12 (brs, 1H), 5.64 (d,
=6.3 Hz, 1H), 5.02 (brd, J=
=9.0, J =2.3 Hz, 1H), 2.75 (brd,
J=5.8 Hz, 2H), 2.26 (brd, J=6.2 Hz, OH), 1.79 (t, J=1.3 Hz, 3H), 1.71
[
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1
hexane (1:1)); H NMR (500 MHz, CDCl
J=15.6 Hz, 1H), 5.58 (dt, J =15.6, J
.0 Hz, 1H), 4.58 (brs, 1H), 3.14 (dd,
3
1
2
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9
J
1
2
[
[
[
5
1
3
(
(
7
C
d, J=0.8 Hz, 3H), 1.51 (brs, OH), 1.29 ppm (s, 6H); C NMR
125 MHz, CDCl ): d=206.2, 155.0, 142.7, 140.6, 139.9, 124.4, 119.8, 76.3,
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3
2
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+
15 22 3
H O Na: 273.1461 [M+Na] ; found: 273.1464.
Complete reduction of the crude mixture of hydroperoxides 22a,b and
3 to the corresponding secondary (9, 10) and tertiary alcohols (5,
2
Scheme 6) was achieved under the previously described conditions. In
this particular case, not only could the separation of the tertiary alcohol 5
from the mixture of the secondary alcohols 9 and 10 be readily achieved
but the separation of 9 from its diastereomer 10 was also accomplished.
5906
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 5899 – 5907

Litseaverticillol Syntheses
FULL PAPER
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Received: December 20, 2004
Published online: June 22, 2005
Chem. Eur. J. 2005, 11, 5899 – 5907
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5907