Photooxygenation of a microbial arene oxidation product and regioselective Kornblum-DeLamare rearrangement: Total synthesis of zeylenols and zeylenones

Article abstract of DOI:10.1002/chem.201104035

We report the enantioselective total syntheses of zeylenol (+)-1, as well as its congeners (-)-7 and 16, and of 3-O-debenzoylzeylenone 28. To this end, a new variant of the Kornblum-DeLaMare rearrangement, which utilises neighbouring-group participation to impart regioselectivity, has been developed. The approach employs photooxygenation of building blocks derived from a microbial arene oxidation product. New light on a Korny rearrangement: Biooxidation of benzoic acid with R. eutrophus B9 gives a dearomatised diene diol acid that allows concise access to the zeylenol and zeylenone family of polyoxygenated cyclohexene natural products. The synthesis employs diene photooxygenation and a new regioselective variant of the Kornblum-DeLaMare endoperoxide fragmentation has been developed (see scheme).

Full text of DOI:10.1002/chem.201104035

DOI: 10.1002/chem.201104035
Photooxygenation of a Microbial Arene Oxidation Product and
Regioselective Kornblum–DeLaMare Rearrangement: Total Synthesis of
Zeylenols and Zeylenones
Matthew J. Palframan,[a] Gabriele Kociok-Kçhn,[b] and Simon E. Lewis*[a]
Abstract: We report the enantioselective total syntheses of zeylenol (+)-1, as well
as its congeners (À)-7 and 16, and of 3-O-debenzoylzeylenone 28. To this end,
a new variant of the Kornblum–DeLaMare rearrangement, which utilises neigh-
bouring-group participation to impart regioselectivity, has been developed. The ap-
proach employs photooxygenation of building blocks derived from a microbial
arene oxidation product.
Keywords: biooxidation
products peroxides
genated cyclohexenes · total synthe-
sis · regioselectivity
·
natural
polyoxy-
·
·
Introduction
zeylenol congeners varying in the extent of benzoylation
and/or with additional O-substituents are known (Figure 1,
Tables 1–3).[3–15] Absolute configurations have been deter-
mined for the majority of these and a study has been pub-
lished relating chiroptical properties to the absolute configu-
ration for this class of compounds.[16] In several cases, both
antipodes of a zeylenol congener have been isolated from
different species. Thus, uvarigranol C (À)-4 is enantiomeric
with uvaribonol C (+)-4 and uvarigranol F (+)-7 is enantio-
meric with uvaribonol A (À)-7; the reported optical rota-
tions are in good agreement and of opposite sign. For com-
pounds where the absolute configuration has not yet been
established, caution must be exercised in inferring configu-
ration from the structures of known co-isolates, since poly-
oxygenated cyclohexenes in both enantiomeric series have
been isolated from the same organism.[3f,g,7b,9b,10]
Zeylenol (À)-1 is a polyoxygenated cyclohexene natural
product first isolated from Uvaria zeylanica (Annonaceae)
in 1981 by Cole and Bates.[1] A year later, Ganem was able
to confirm the absolute configuration of (À)-1 (as shown in
Figure 1), by using chemical correlation and circular dichro-
Figure 1. Antipodal zeylenols and related natural products.
In terms of biological activity, (À)-1 has been studied
most extensively, and shows antitumour[9a,17] and antifeedant
activity.[13] Furthermore, (À)-1 affects root and shoot growth
of Lactuca sativa (as do compounds 11, 17 and 18).[3f,g] In
contrast, the antipodal (+)-1 shows selective cytotoxicity to-
wards HL-60 leukaemia cells.[6c] As regards synthetic ap-
proaches, Ogawa has reported both a formal[18a] and a to-
tal[18b,c] synthesis of (À)-1. To our knowledge, no synthetic
endeavours towards (+)-1 or congeners of this absolute con-
figuration have been reported.
The more highly oxidised natural product zeylenone (À)-
22 has thus far only been isolated from Nature[3f,g,9b,12,19] as
one enantiomer,[20] but congeners have once again been re-
ported in both enantiomeric series (Figure 2, Table 4 and Ta-
ble 5).[3f,g,9b,12,19] The literature is contradictory concerning
the configuration of uvarigranone A (24) and 2-O-benzoyl-
3-O-debenzoylzeylenone (29). Whereas opposite absolute
configurations for these two species are claimed, the report-
ed optical rotations of [a]D = +70.4 (c=0.47 in CHCl3)[12]
for 24 and [a]D = +67.1 (c=0.63 in CHCl3)[3g] for 29 suggest
these two natural products are identical; it is unclear which
absolute configuration is correct.
ism spectroscopy.[2] (À)-1 has subsequently been isolated
from other species of the genus Uvaria,[3] as well as from the
genera Kaempferia[4] and Ellipeiopsis.[5] Six years after the
first isolation of (À)-1, the antipodal zeylenol (+)-1 was also
isolated from a natural source, a species initially described
as a member of the Bosenbergia genus,[6a] but subsequently
identified as a Kaempferia species;[6b,c] isolation of (+)-1 has
also been reported from the genera Uvaria[7] and Piper.[8]
Other reports describe the isolation of zeylenol without de-
termination of the absolute configuration.[9,10] Numerous
[a] Dr. M. J. Palframan, Dr. S. E. Lewis
Department of Chemistry, University of Bath
Claverton Down, Bath, BA2 7AY (United Kingdom)
Fax : (+44)1225386231
E-mail: S.E.Lewis@bath.ac.uk
[b] Dr. G. Kociok-Kçhn
Department of Chemical Crystallography, University of Bath
Claverton Down, Bath, BA2 7AY (United Kingdom)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201104035.
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FULL PAPER
Table 1. Natural products possessing the (À)-zeylenol skeleton.
cancer cell lines and displayed potent inhibition of
nucleoside transport in Ehrlich carcinoma cells.[19b]
The biological activity of (À)-22 has spurred the
R1
R2
R3
R4
Name
Species
(À)-1 OBz OH
OBz OH
(À)-zeylenol
Uvaria zeylanica;[1]
Uvaria grandiflora;[3a–c,e] synthesis of analogues for evaluation as antitumour
Uvaria purpurea;[3f–g]
agents.[21]
Kaempferia rotunda[4]
Two contrasting synthetic routes to zeylenone
Uvaria grandiflora[3a,d]
2
3
OBz OH
OBz OAc OBz OH
OH
OBz
uvarigranol A
uvarigranol B
have been described. Ogawaꢁs total synthesis[18b,c] of
Uvaria grandiflora;[3a,d]
Uvaria rufa[9b]
(À)-1 and (À)-22, employed an enzymatic desym-
Uvaria grandiflora[3b]
Uvaria grandiflora[3b]
Uvaria grandiflora[3d,11]
Uvaria grandiflora[3d,11]
Uvaria grandiflora[3e]
Uvaria grandiflora;[12]
metrisation of a meso diol.[22] The approach of Liu,
Xu and co-workers employed a chiral pool starting
material, namely shikimic acid. Their first report-
s[23a–c] were on the synthesis of the non-natural
(+)-22, but they subsequently developed an enan-
tiodivergent synthesis from the same starting mate-
rial to natural (À)-22.[23d]
(À)-4 OBz OH
OBz OEt
OBz OAc OBz OEt
uvarigranol C
uvarigranol D
uvarigranol E
uvarigranol F
uvarigranol H
uvarigranol J;
5
6
OAc OH
OH
OBz OBz
OBz OBz
(+)-7 OH
8
OAc OBz OBz OAc
OBz OH OBz OAc
9[a]
6-O-acetylzeylenol Kaempferia rotunda[13]
10
11
OBz OAc OBz OAc
OBz OAc OBz OMe 2-O-acetyl-6-O-
zeylenyl diacetate
Uvaria grandiflora[3e]
Uvaria purpurea[3 g]
In view of the isolation of polyoxygenated cyclo-
hexenes in both enantiomeric series (as well as nu-
merous epimeric natural products), the biosynthesis
of this class of compounds has been the subject of
much speculation. Ganem was the first to propose
a biosynthetic pathway,[24a] involving an arene oxide
intermediate 30, possibly derived from isochorismic
acid[24b] or from benzyl benzoate.[1] Ring-opening of
this epoxide would give rise to cyclohexadiene
trans-diol 31. Natural products possessing this
motif, the so-called “missing link” diene, have
indeed been isolated from Uvaria species.[25] Epoxi-
dation of the more substituted alkene in 31 and
subsequent SN2 opening at the allylic position
would then afford the zeylenol skeleton
(Scheme 1a). Two explanations for the occurrence
of both enantiomeric series have been put forward.
Arene oxide 30 could spontaneously racemise via
the oxepin tautomer 33[26] (Scheme 1b). Alterna-
tively, a single arene oxide enantiomer could give
rise to both enantiomeric cyclohexadiene trans-
diols, depending on whether the arene oxide is
opened at C3 or C2; this latter process could plausi-
bly involve neighbouring-group participation of the
benzoate ester (Scheme 1c). The relative merits of
these proposals have been re-evaluated over the
years, in light of the natural products known at the
time.[27] Current opinion appears to favour the C2/
C3 epoxide opening argument. However, to our
knowledge, thus far no feeding experiments have
been performed to aid elucidation of the true bio-
synthetic pathway.
methylzeylenol
pipoxide
chlorohydrin
12
OBz OH
OBz Cl
Uvaria grandiflora;[3c]
Piper hookeri;[14a–c]
Piper nigrum;[14c]
Piper attenuatum[14d]
[a] A literature ambiguity has been noted for this compound. The initial report[12]
names 9 as uvarigranol J and gives a positive [a]D value. A subsequent report[13] claims
the same absolute structure as a new compound, named as 6-O-acetylzeylenol and
gives a negative [a]D value. Optical rotations are not directly comparable, however,
since different solvents were used.
Table 2. Natural products possessing the (+)-zeylenol skeleton.
R1
R2
R3
R4
Name
Species
(+)-1 OBz OH OBz OH (+)-zeylenol;
Kaempferia angustifola;[6a–c]
Uvaria boniana;[7a]
Uvaria rufa;[7b]
uvaribonol B
Piper cubeb[8]
(À)-7 OH OH OBz OBz uvaribonol A
(+)-4 OBz OH OBz OEt uvaribonol C
Kaempferia angustifola;[6b]
Uvaria boniana[7a]
Uvaria boniana[7a]
Uvaria boniana[7a]
Uvaria boniana[7a]
Uvaria boniana[7a]
13
14
15
16
OBz OAc OAc OEt uvaribonol E
OBz OAc OAc OH uvaribonol F
OAc OH OAc OBz uvaribonol G
OBz OH OBz OBz 6-O-benzoylzeylenol Kaempferia angustifola[6b]
Table 3. Natural products possessing the zeylenol skeleton of undetermined absolute
configuration
R1
R2
R3
R4
Name
Species
1
OBz OH
OBz OH
zeylenol
Uvaria kweichowensis;[9a–c]
Uvaria tonkinensis var.
subglabra[9d]
17 OBz OH
18 OBz OAc OBz OBz
OBz OMe 6-O-methylzeylenol Uvaria purpurea[3f]
2-O-acetyl-6-O-
benzoylzeylenol
ellipeopsol A
ellipeopsol D
curcuminol F
Uvaria purpurea[3 g]
Arene oxides such as 30 may be formed through
the metabolism of arenes by organisms expressing
arene monooxygenase enzymes. In contrast, certain
microorganisms express arene dioxygenases, which
effect the transformation of arenes to cyclohexa-
19 OBz OH
20 OBz OH
21 OBz OAc OAc OAc
OAc OH
OAc OAc
Ellipeiopsis cherrevensis[5a]
Ellipeiopsis cherrevensis[5a]
Curcuma wenyujin[15]
The biological activity of the zeylenones has been studied
in multiple contexts. The ability of (À)-22, 23, 28 and 29 to
affect root and shoot growth has been contrasted with that
of selected zeylenols (see above).[3f,g] Additionally, (À)-22
has been evaluated for cytotoxicity against a variety of
diene cis-diols. The use of these cis diols in synthesis is an
established field.[28] The dioxygenases that have been most
extensively exploited so far are toluene dioxygenase (TDO),
naphthalene dioxygenase (NDO) and biphenyl dioxygenase
(BPDO). These oxidise substituted arenes in a regio- and
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S. E. Lewis et al.
Table 4. Natural products possessing the (À)-zeylenone skeleton.
The first reported use of 38 is also the most rele-
vant to this current work: Widdowson synthesised
derivatives of 38 which were used in cycloadditions
R1
R2
R3
R4
H
Name
Species
(À)-22 OBz OH
OBz
(À)-zeylenone
Uvaria tonkinesis;[19a]
Uvaria grandiflora;[12,19b] with singlet oxygen and other dienophiles; the ab-
Uvaria purpurea;[3f,g]
solute configuration of 38 was also established by
correlation with an X-ray structure of one of these
Uvaria rufa[9b]
23
24
25
26
27
OBz OAc OBz
OBz OBz
OH OBz
OBz OH
OBz OH
H
H
H
2-acetylzeylenone Uvaria purpurea[3f]
Uvarigranone A
Uvarigranone B
derivatives.[32] Other reports on 38 concern the syn-
thesis of intramolecular Diels–Alder adducts,[33] of
new chirons,[34] of novel carbasugars[35] and of natu-
ral products (tetracyclines[36] and idesolide[37]). In
addition we have reported on the organometallic
chemistry of 38.[38]
OH
OBz
Uvaria grandiflora[12]
Uvaria grandiflora[12]
Uvaria grandiflora[12]
Uvaria grandiflora[12]
OBz OEt Uvarigranone C
OBz OH Uvarigranone D
Table 5. Natural products possessing the (+)-zeylenone skeleton.
Arene cis-dihydrodiols such as 36 and 38 are
ideal chiral-pool starting materials for the synthesis
of cyclitols such as inositols and conduritols.[39] Re-
garding natural products from the Uvaria genus,
two reports have appeared employing arene cis-di-
R1
R2
R3
R4
Name
Species
28
29
OBz
OBz
OH
OBz
OH
OH
H
H
3-O-debenzoylzeylenone
2-O-benzoyl-3-O-
debenzoylzeylenone
Uvaria purpurea[3 g]
Uvaria purpurea;[3 g]
Uvaria rufa[9b]
´
hydrodiols as starting materials. Hudlickyꢁs synthe-
sis[40] of zeylena 40 (isolated from Uvaria zeylanica[1]) em-
ployed the ortho,meta diol 39, derived from styrene
(Scheme 3a), whereas our synthesis[41] of ent-grandifloracin
41 employed the ipso,ortho diol 38, derived from benzoic
acid (Scheme 3b).
Figure 2. Antipodal zeylenones and related natural products.
Scheme 2. Regio- and stereoselectivity of dioxygenases.
Scheme 3. Chemoenzymatic syntheses of zeylena and ent-grandifloracin.
The ipso,ortho diol 38 is particularly appealing as a starting
material to access the (+)-zeylenol architecture due to the
installation of the tertiary alcohol motif in the biocatalytic
step. Here we present concise syntheses of representative
examples of the (+)-zeylenol and (+)-zeylenone families of
natural products.
Scheme 1. Proposed biosynthesis of zeylenols.
stereoselective fashion, with the sense of enantioinduction
being conserved across organisms and substrates[29]
(Scheme 2a, ortho, meta oxygenation). In contrast, organ-
isms that express benzoate dioxygenase[30] (BZDO) oxidise
benzoic acids[31] in a process that exhibits not only different
regioselectivity, but also the opposite absolute sense of
enantioinduction (Scheme 2b, ipso, ortho oxygenation). cis
Diol 38 and its substituted analogues have been compara-
tively underexploited in synthesis so far.
Results and Discussion
Arene cis-dihydrodiol 38 was elaborated to known protected
triol 43 (Scheme 4). We have found that a one-pot proce-
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Total Synthesis of Zeylenols and Zeylenones
FULL PAPER
Scheme 4. a) acetone, 2,2-dimethoxypropane, RT, 6 h, then CH2Cl2,
MeOH, DCC, DMAP, RT, 12 h, 93%. b) LiBH4, THF, 08C, 5 h. c) BzCl,
NEt3, CH2Cl2, RT, 24 h, 68% (2 steps). d) O2, TPP, CCl4, 12 h, 108C,
81%.
Scheme 6. a) TBDMSOTf, NEt3, CH2Cl2, RT, 24 h, 76%. b) O2, TPP,
CCl4, 12 h, 108C, 90%. c) thiourea, CH2Cl2/MeOH, RT, 90 min, 99%.
d) TBAF, THF, À788C to RT, 12 h, 64%. e) BzCl, py, RT, 65% for 47,
63% for 52. f) I2, MeOH, RT, 12 h, 20% of (À)-7; 45% of (+)-1.
dure for formation of 42, coupled with use of lithium boro-
hydride as reductant, gives rise to 43 in an enhanced yield in
comparison with previous reports.[32] For the introduction of
the additional oxygenation required for zeylenols/zeyle-
nones, singlet oxygen photocycloaddition is a well prece-
dented approach[32,42] and we were able to install all necessa-
ry oxygenation by this means. Thus, benzoylation of 43 was
followed by reaction with 1O2 to afford endoperoxide 45
(Scheme 4). The required zeylenol stereochemistry arises
due to the selective approach of the dienophile to the face
opposite to that bearing the acetonide.[31a,32,43]
The reductive cleavage of the endoperoxide and a perben-
zoylation to access 47 were straightforward. Removal of the
acetonide without benzoyl migration or transesterification
required extensive screening of reaction conditions; in the
event, exposure of 47 to iodine in methanol[44] afforded 6-O-
benzoylzeylenol 16 in 7 steps from ipso,ortho diol 38 and in
22% overall yield (Scheme 5). The spectroscopic data for
51, which underwent exhaustive benzoylation to give 47, so
establishing another route to 6-O-debenzoylzeylenone 16.
Alternatively, dibenzoylation of 50 gave 52, a protected
form of uvaribonol A (À)-7. Deprotection of 52 could be
achieved with trifluoroacetic acid/water, or iodine/methanol
as employed previously (the latter being preferable due to
a shorter reaction time). In situ NMR monitoring estab-
lished that for both approaches, cleavage of the silyl ether
occurs more rapidly than acetonide removal. This observa-
tion is significant since (À)-7 was in fact the minor product
of the reaction. Under all reaction conditions employed, the
major product of deprotection was zeylenol (+)-1. This pre-
sumably arises simply by migration of a benzoyl group from
a secondary to the primary hydroxyl group; indeed this
spontaneous isomerisation has been noted previously.[6b]
Thus, for K. angustifola[6] and U. boniana[7a] the possibility
must be entertained that the isolation of zeylenol (+)-1 may
be an artefact, although this seems less likely considering
that (+)-1 has also been isolated from U. rufa[7b] and P.
cubeb.[8] By the route depicted in Scheme 6, uvaribonol A
(À)-7 and zeylenol (+)-1 were accessed in 7 steps and over-
all yields of 8 and 18%, respectively, from ipso,ortho diol 38
(Scheme 6). Spectroscopic data for synthetic (À)-7 and
(+)-1 were again in agreement for those reported for the
natural products.[6b] For zeylenol (+)-1, the recorded optical
rotation of [a]D = +110.9 (c=0.55 in CHCl3) is in good
agreement with the literature values of [a]D = +113.5 (c=
0.6 in CHCl3[6a]; c=0.24 in CHCl3[6b]) and [a]D = +107.0 (c=
0.6 in CHCl3).[7b,45] However, for uvaribonol A (À)-7, the re-
corded optical rotation of [a]D =À32.0 (c=0.25 in CHCl3) is
of the same sign but different in magnitude to the literature
value of [a]D =À55.2 (c=0.05 in CHCl3).[7a] We ascribe this
discrepancy to the seemingly unavoidable isomerisation of
(À)-7 in solution and the lower concentration (and corre-
sponding higher margin of error) at which the literature
value was recorded.
Scheme 5. a) thiourea, CH2Cl2/MeOH, RT, 90 min, 99%. b) BzCl, py, RT,
68%. c) I2, MeOH, RT, 12 h, 63%.
synthetic 16 were in agreement for those reported for the
natural product.[6b] In particular, the recorded optical rota-
tion of [a]D =À56.0 (c=0.50 in CHCl3) is in good agreement
with the literature value of [a]D =À59.7 (c=0.39 in CHCl3),
confirming the absolute stereochemistry of 16.
To access less extensively benzoylated zeylenol congeners,
orthogonal protecting groups were required. Protected triol
1
43 was silylated, then subjected to O2 photocycloaddition
and endoperoxide reduction as previously (Scheme 6). Dif-
ferentially protected diol 50 allowed access to multiple zey-
lenols. Most simply, fluoride-mediated desilylation gave triol
Having synthesised representative zeylenols (+)-1, (À)-7
and 16, we next sought to access the (+)-zeylenone series.
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S. E. Lewis et al.
In the first instance, rather than employ a reductive opening
of bicyclic endoperoxides such as 45 or 49, we instead ex-
plored the redox-neutral Kornblum–DeLaMare fragmenta-
tion[46] to access directly the desired g-hydroxy-a,b-unsatu-
rated ketone motif. The applicability of this methodology to
arene diol-derived endoperoxides has been established by
Carless.[42d,e] Thus, endoperoxides 45 and 49, as well as the
previously reported[32] 53 (prepared from 42) were treated
with Hꢂnigꢁs base[47] in dichloromethane, giving enones 54–
56 (Scheme 7).
protonation at the desired bridgehead position, so affording
the protected skeleton of zeylenone, 61 (Scheme 8c).
In the event, after optimisation, it was determined that
treatment of 49 with TBAF in THF at À228C did indeed
afford 61 in 53% yield; the undesired isomer was not ob-
served. To date, regioselective Kornblum-DeLaMare rear-
rangements have relied on substrate bias[50] (for example as
in the formation of 54–56), or on desymmetrisation of meso-
endoperoxides with homochiral amine bases to impart regio-
selectivity in the deprotonation step.[51] To our knowledge,
formation of 61 is the first example of neighbouring-group
participation overriding inherent substrate bias in a regiose-
lective Kornblum–DeLaMare rearrangement.[52,53] Other re-
ported examples[54] of fluoride-mediated silyl ether cleavage
in the presence of an endoperoxide proceed without Korn-
blum–DeLaMare fragmentation. To explain this, we suggest
that the proposed intramolecular deprotonation in the for-
mation of 61 specifically depends on intermediate 60 adopt-
ing a conformation that places the alkoxide in close proximi-
ty to the appropriate endoperoxide a-proton. Such a confor-
mation is presumably not readily accessible for other report-
ed substrates.
Unfortunately, the yield of 61 could not be improved due
to its instability, which precluded its elaboration to any de-
protected zeylenone. The spontaneous decomposition of 61
afforded material whose identity could not be established
conclusively. However, Spivey has reported[55] that a closely
related 4-hydroxycyclohexenone (Æ)-63 undergoes dimerisa-
tion through oxy-Michael addition affording a diastereomeric
mixture of products (Æ)-64 (Scheme 9); analogous processes
Scheme 7. a) iPr2NEt, CH2Cl2, 94% for 54, 97% for 55, 100% for 56.
In each instance the endoperoxide was smoothly trans-
formed into a single product regioisomer; other bases such
as DBU and DBN did not furnish any product. Unfortu-
nately, the regioisomer obtained was the one in which the
ketone was positioned distal to the quaternary centre, which
is not the regioisomer required for accessing the zeylenone
series. The mechanism of the Kornblum–DeLaMare frag-
mentation has been studied[48,49] and one proposal is that the
reaction proceeds by deprotonation a to the endoperoxide.
Thus, we ascribe this undesired selectivity in the formation
of 54–56 to the approach of the base to the less hindered of
the two endoperoxide a-protons (Scheme 8a). We sought to
override the inherent regioselectivity of this transformation
and instead access the desired isomer 59 (Scheme 8b). To
do so, we envisaged a directed variant of the Kornblum–De-
LaMare fragmentation proceeding by means of an intramo-
lecular deprotonation. Specifically, fluoride-mediated desily-
lation of 49 was expected to furnish alkoxide 61 in situ,
which would be ideally aligned to effect intramolecular de-
Scheme 9. Reported dimerisation of
a
4-hydroxycyclohexenone.
a) iPr2NEt, DMF. b) spontaneous. c) iPr2NEt, TBDMSCl.
have also been reported.[56] In the example at hand, 61 pos-
sesses two oxygen nucleophiles, so scope exists for forma-
tion of numerous isomeric dimers, acetonide migration and/
or polymerisation. Spivey has further reported that (Æ)-63
may be trapped by in situ silylation to afford the stable silyl
ether (Æ)-65. Attempts at trapping 61 with TBDMSOTf or
with BzCl gave intractable mixtures.
Our inability to elaborate 61 to zeylenone natural prod-
ucts necessitated the adoption of a longer route. Diol 46
Scheme 8. Regioselectivity in the Kornblum–DeLaMare fragmentation.
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Total Synthesis of Zeylenols and Zeylenones
FULL PAPER
(derived from endoperoxide reduction as previously) was si-
lylated to give 66; concomitant formation of 67 could not be
suppressed. Swern oxidation of 66 gave protected 4-hydrox-
ycyclohexenone 68; analogously with 65, 68 proved to be
stable. In the case of 52 we had observed cleavage of the
silyl ether prior to the acetonide under all the conditions
tried. However, with 68 we hoped that the TBDPS group
would prove less labile and allow for selective acetonide re-
moval. Treatment of 68 with iodine in methanol did indeed
allow access to the selectively deprotected 69 as the major
product. However, a degree of desilylation was unavoidable
and the global deprotection product was also isolated; the
triol 3-O-debenzoylzeylenone 28 (Scheme 10). This natural
Figure 3. Solid state structure of 28. Ellipsoids are represented at 50%
probability. Hydrogen atoms are shown as spheres of arbitrary radius. A
disordered molecule of water is omitted for clarity.
possible by this approach, the use of a TBDMS group did in
fact allow access to 3-O-debenzoylzeylenone 28 in a higher
yield (Scheme 11). Thus, 3-O-debenzoylzeylenone 28 was
synthesised in eight steps from ipso,ortho diol 38 and in
15% overall yield.
Scheme 10. a) TBDPSCl, Imidazole, DMAP, DMF, RT, 22% of 66; 55%
of 67. b) (COCl)2, DMSO, NEt3, CH2Cl2, À788C to RT, 6 h, 78%. c) I2,
MeOH, RT, 4 h, 21% of 28; 44% of 69.
product once again proved to be unstable upon prolonged
standing in solution, in all likelihood dimerising as for 61
and (Æ)-63. Fortuitously, however, compound 28 is only
sparingly soluble in chloroform and precipitation from this
solvent provided 28 in a pure form.
Scheme 11. a) TBDMSOTf, NEt3, CH2Cl2, RT, 6 h, 85%; b) (COCl)2,
DMSO, NEt3, CH2Cl2, À788C to RT, 12 h, 81%; c) I2, MeOH, 4 h, RT,
43%.
Spectroscopic data for synthetic 28 were in agreement for
those reported for natural 28.[3 g] In particular, the recorded
optical rotation of [a]D = +12.5 (c=0.4 in CHCl3) is in good
agreement with the literature value of [a]D = ++11.7 (c=0.36
in CHCl3), confirming the absolute stereochemistry of 28.
Crystals suitable for X-ray structure determination were ob-
tained from diffusion of hexane into a solution of 28 in ethyl
acetate (Figure 3).
To access 2-O-benzoyl-3-O-debenzoylzeylenone 29 (the
other natural product in the (+)-zeylenone series), benzoy-
lation of the secondary hydroxyl in 69 to give 70 would be
required. However, 69 proved to be inert to benzoylation,
plausibly due to the steric bulk of the TBDPS group. We re-
verted to use of a TBDMS group, effecting monosilylation
of 46 and Swern oxidation to 72. Unfortunately, treatment
of 72 with iodine in methanol afforded only global deprotec-
tion product 28 (as was the case for 52). Whereas access to
2-O-benzoyl-3-O-debenzoylzeylenone 29 was ultimately not
Conclusion
We have demonstrated the synthetic versatility of ipso,ortho
diol 38 by accessing representative examples of the (+)-zey-
lenol and (+)-zeylenone families of natural products in
a concise fashion. The absolute configurations of these natu-
ral products have been confirmed, which is of importance in
the context of the existence of both enantiomeric series in
Nature. We expect that the regioselective desilylative Korn-
blum–DeLaMare endoperoxide fragmentation developed
here will be of use in diverse synthetic applications; further
work in this area will be reported in due course.
Chem. Eur. J. 2012, 18, 4766 – 4774
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4771

S. E. Lewis et al.
(2H, m, OBzCH), 7.40 (2H, app dd, J=7.5, 2.0 Hz, OBzCH), 7.37 (2H, app
dd, J=7.5, 2.0, Hz OBzCH), 6.00 (1H, ddd, J=10.0, 4.0, 1.7 Hz, alkeneCH),
5.86 (1H, ddd, J=10.0, 2.6, 0.5 Hz, alkeneCH), 5.72–5.69 (1H, m, CHOBz),
4.88 (1H, d, J=12.3 Hz, CH2OBz), 4.74 (1H, d, J=12.3 Hz, CH2OBz),
4.34 (1H, d, J=4.0 Hz, CHOH), 4.23 (1H, d, J=6.1 Hz, CHOH), 3.28
(2H, bs, OH), 3.00 ppm (1H, bs, OH); 13C NMR (125 MHz, CDCl3,
238C) d=167.8 (CH2OC(O)Ph), 167.1 (CH2OC(O)Ph), 133.5 (OBzCH),
133.4 (OBzCH), 129.8 (2 ꢃ OBzCH), 129.8 (2 ꢃ OBzCH), 129.6 (alkeneCH),
129.4 (OBzC), 129.2 (OBzC), 128.4 (2 ꢃ OBzCH), 128.4 (2 ꢃ OBzCH), 126.8
Experimental Section
General: Selected experimental procedures are given below; general ex-
perimental details, complete experimental procedures and NMR spectra
are detailed in the electronic Supporting Information.
Synthesis of 16: To
a stirred solution of tribenzoate 47 (26 mg,
0.05 mmol, 1.0 equiv) in MeOH (0.5 mL) at room temperature was
added iodine (13 mg, 0.05 mmol, 1.0 equiv). The progress of the reaction
was followed by TLC; after 12 h the reaction mixture was poured into
Na2S2O3 (aq) (1.0m, 5 mL), and the iodine colour disappeared. The aque-
ous layer was extracted with EtOAc (3ꢃ5 mL), and the combined organ-
ic layers were dried over Na2SO4, and filtered. The filtrate was concen-
trated under reduced pressure and the residue was purified by chroma-
tography (petroleum ether/EtOAc 5:1 to 1:1) to afford 6-O-benzoylzeyle-
nol 16 as a white solid (15 mg, 63%); [a]D =À56.0 (c=0.50 in CHCl3);
Rf =0.33 (petroleum ether/EtOAc 1:1); 1H NMR (500 MHz, CDCl3,
238C): d=8.03 (2H, dd, J=8.4, 1.2 Hz, OBzCH), 8.03 (2H, dd, J=8.4,
1.2 Hz, OBzCH), 7.85 (2H, dd, J=8.4, 1.2 Hz, OBzCH), 7.60–7.42 (3H, m,
OBzCH), 7.43 (2H, app t, J=7.7 Hz, OBzCH), 7.40 (2H, app t, J=7.7 Hz,
OBzCH), 7.32 (2H, app t, J=7.7 Hz, OBzCH), 6.08 (1H, ddd, J=10.0, 3.8,
1.6 Hz, alkeneCH), 6.01 (1H, dd, J=10.1, 2.6 Hz, alkeneCH), 5.83–5.81 (1H,
m, CHOBz), 5.80 (1H, d, J=2.6 Hz, CHOBz), 4.93 (1H, d, J=12.2 Hz,
CH2OBz), 4.63 (1H, d, J=12.2 Hz, CH2OBz), 4.36 (1H, d, J=6.0 Hz,
CHOH), 3.71 (1H, bs, OH), 3.45 ppm (1H, bs, OH); 13C NMR
(100 MHz, CDCl3, 238C) d=167.2 (OC(O)Ph), 167.0 (OC(O)Ph), 165.8
(OC(O)Ph), 133.5 (OBzCH), 133.5 (OBzCH), 133.2 (OBzCH), 129.8 (2 ꢃ
OBzCH), 129.7 (2 ꢃ OBzCH), 129.6 (2 ꢃ OBzCH), 129.3 (OBzC), 129.3 (OBzC),
129.1 (OBzC), 128.6 (alkeneCH), 128.5 (2 ꢃ OBzCH), 128.4 (2 ꢃ OBzCH), 128.3
(2 ꢃ OBzCH), 126.6 (alkeneCH), 75.0 (C), 73.4 (CHOBz), 71.7 (CHOH),
71.3 (CHOBz), 66.8 ppm (CH2OBz); n˜ (thin film) 3451 (wb), 2981 (s),
(
alkeneCH), 76.0 (C), 74.3 (CHOBz), 70.9 (CHOH), 68.6 (CHOH),
66.8 ppm (CH2OBz); HRMS m/z calcd for C42H40NaO14+: 791.2346 [M2 +
+
Na]+; found: 791.2375 (35%); m/z calcd for C21H20NaO7 407.1107 [M+
Na]+; found: 407.1192 (100%); data are in agreement with reported
values.[6–8]
Synthesis of 61: To a stirred solution of silylendoperoxide 49 (66 mg,
0.20 mmol, 1.0 equiv) in THF (6 mL) at À228C was slowly added TBAF
(0.4 mL, 0.4 mmol, 1.0m solution, 2.0 equiv). The resulting solution was
stirred at À228C for 6 h, then quenched by the addition of NH4Cl(aq)
(saturated, 10 mL). The solution was then warmed to room temperature,
and the organic solvent was removed under reduced pressure (water bath
temperature set at 108C). The resulting aqueous solution was extracted
with EtOAc (3ꢃ10 mL) and the combined organic layers were dried over
MgSO4, and then filtered. The filtrate was concentrated under reduced
pressure (water bath temperature set at 108C) and purified by chroma-
tography (petroleum ether/EtOAc 4:1 to 1:1). Pure fractions were con-
centrated in vacuo (water bath temperature set at 108C) to afford the de-
sired hydroxyenone 61 as an oil (23 mg, 53%). It was found that the
compound was unstable and decomposition occurs rapidly; Rf =0.35 (pe-
troleum ether/EtOAc 2:1); 1H NMR (500 MHz, CDCl3, 238C): d=6.99
(1H, ddd, J=10.1, 5.2, 1.9 Hz, CH=CHC=O), 6.17 (1H, d, J=10.1 Hz,
CH=CHC=O), 4.58–4.53 (1H, m, CHOH), 4.45 (1H, app t, J=1.9 Hz,
CHO), 4.15 (1H, d, J=10.0 Hz, CH2OH), 4.10 (1H, bs, OH), 3.68 (1H,
d, J=10.0 Hz, CH2OH), 3.41 (1H, bs, OH), 1.41 (3H, s, CH3), 1.31 ppm
(3H, s, CH3); 13C NMR (125 MHz, CDCl3, 238C) d=199.4 (C=O), 146.6
2972 (s), 2889 (m), 1715 (m), 1601 (w), 1585 (w), 1451 (m), 1382 (s) cmÀ1
;
+
HRMS m/z calcd for C56H48NaO16
999.2903 (45%); C28H24NaO8
:
999.2840 [M2 +Na]+; found:
:
511.1369 [M+Na]+; found: 511.1483
+
(100%); data are in agreement with reported values.[6b]
(CH=CHC=O), 129.3 (CH=CHC=O), 109.7 (O2CACHTNUGTRNEUNG(CH3)2), 82.1 (CHO),
Synthesis of (À)-7 and (+)-1: To a stirred solution of silylacetonide 52
(43 mg, 0.08 mmol, 1.0 equiv) in MeOH (0.5 mL) at room temperature
was added iodine (20 mg, 0.08 mmol, 1.0 equiv). The progress of the reac-
tion was followed by TLC; after 12 h the reaction mixture was poured
into Na2S2O3 (1.0m, 5 mL) and the iodine colour disappeared. The reac-
tion mixture was extracted with EtOAc (3ꢃ5 mL) and the combined or-
ganic layers were dried over Na2SO4 and filtered. The filtrate was con-
centrated under reduced pressure and the crude residue was purified by
chromatography (petroleum ether/EtOAc 2:1) to afford a mixture of
products, which were further purified by chromatography (PhMe/MeCN
3:1). Pure fractions were concentrated in vacuo to afford the two title
compounds. Uvaribonol A (À)-7, the non-migration product, was the
minor compound (6 mg, 20%), an off white solid; [a]D =À32.0 (c=0.25
in CHCl3); Rf =0.33 (PhMe/MeCN 2:1); 1H NMR (500 MHz, CDCl3,
238C): d=8.12 (2H, dd, J=8.2, 1.2 Hz, OBzCH), 8.05 (2H, dd, J=8.2,
1.2 Hz, OBzCH), 7.62 (1H, app tt, J=7.4, 1.2 Hz, OBzCH), 7.62 (1H, app tt,
J=7.4, 1.2 Hz, OBzCH), 7.48 (4H, app t, J=7.8 Hz, OBzCH), 6.06 (1H,
ddd, J=10.0, 4.2, 1.6 Hz, alkeneCH), 6.03 (1H, dd, J=10.0, 1.8 Hz,
alkeneCH), 5.84 (1H, dd, J=7.4, 1.8 Hz, CHOBz), 5.52 (1H, dd, J=4.2,
0.9 Hz, CHOBz), 4.23 (1H, d, J=7.4 Hz, CHOH), 4.10 (1H, d, J=
12.0 Hz, CH2OH), 3.67 (1H, d, J=12.0 Hz, CH2OH), 3.55 (1H, bs, OH),
3.45 (1H, bs, OH), 2.90 ppm (1H, bs, OH); 13C NMR (125 MHz, CDCl3,
238C) d=167.7 (CH2OC(O)Ph), 166.2 (CH2OC(O)Ph), 133.6 (OBzCH),
133.6 (OBzCH), 130.2 (alkeneCH), 129.9 (2 ꢃ OBzCH), 129.8 (2 ꢃ OBzCH),
129.4 (OBzC), 129.2 (OBzC), 128.6 (2 ꢃ OBzCH), 128.5 (2 ꢃ OBzCH), 125.6
80.7 (C), 64.8 (CH2OH), 63.3 (CHOH), 27.3 ppm (2 ꢃ CH3); HRMS m/z
calcd for C20H28NaO10+: 451.1575 [M2 +Na]+; found: 451.1608 (48%); m/
z calcd for C10H14NaO5+: 237.0733 [M+Na]+; found: 237.0729 (100%).
Synthesis of 28 and 69 from TBDPS ether 68: To a stirred solution of
TBDPS-acetonide 68 (84 mg, 0.15 mmol, 1.0 equiv) in MeOH (1.5 mL) at
room temperature was added iodine (38 mg, 0.15 mmol, 1.0 equiv). The
progress of the reaction was followed by TLC of the resulting solution;
after 4 h the reaction mixture was poured into Na2S2O3 (1.0m, 10 mL),
and the iodine colour disappeared. The aqueous layer was extracted with
EtOAc (3ꢃ5 mL), and the combined organic layers were dried over
Na2SO4, and then filtered. The filtrate was concentrated under reduced
pressure. The crude residue was purified by chromatography (petroleum
ether/EtOAc 5:1 to 2:1) to afford silyl diol 69 (34 mg, 44%) as a pale
yellow oil. The fractions containing 3-O-debenzoylzeylenone were con-
centrated in vacuo; the resulting gum was dissolved in CHCl3 and al-
lowed to stand overnight, during which time pure 3-O-debenzoylzeyle-
none precipitated as a white solid (8.9 mg, 21%).
69: Rf =0.78 (petroleum ether/EtOAc 1:1); 1H NMR (500 MHz, CDCl3,
238C): d=8.02 (2H, dd, J=8.4, 1.3 Hz, ArCH), 7.73–7.69 (4H, m, ArCH),
7.58 (1H, app tt, J=7.4, 1.3 Hz, ArCH), 7.51–7.43 (8H, m, ArCH), 6.46
(1H, ddd, J=10.1, 4.5, 2.0 Hz, CH=CHC=O), 6.09 (1H, d, J=10.1 Hz,
CH=CHC=O), 5.10 (1H, d, J=11.7 Hz, CH2OBz), 4.58 (1H, d, J=
11.7 Hz, CH2OBz), 4.56 (1H, dd, J=4.5, 2.0 Hz, CHOSi), 4.20 (1H, app
t, J=2.0 Hz, CHOH), 4.19 (1H, bs, OH), 2.74 (1H, bs, OH), 1.13 ppm
(9H, s, SiCACTHNUTRGNEUNG
(CH3)3); 13C NMR (125 MHz, CDCl3, 238C) d=197.5 (C=O),
(
alkeneCH), 74.7 (C), 73.9 (CHOBz), 73.2 (CHOH), 71.6 (CHOBz),
166.0 (CH2OC(O)Ph), 145.7 (CH=CHC=O), 135.8 (ArCH), 135.7 (ArCH),
133.3 (ArCH), 132.7 (ArC), 132.2 (ArC), 130.4 (ArCH), 130.3 (ArCH), 129.8
64.7 ppm (CH2OH); n˜ (thin film) 3465 (mb), 3021 (s) 2989 (m), 1692 (s),
1372 (s) cmÀ1; HRMS m/z calcd for C42H40NaO14+: 791.2346 [M2 +Na]+;
(
ArCH), 129.5 (ArC), 128.4 (ArCH), 128.1 (ArCH), 128.0 (ArCH), 125.7
+
found: 791.2321 (20%); m/z calcd for C21H20NaO7 407.1107 [M+Na]+;
found: 407.1183 (100%); data are in agreement with reported values.[6b,7a]
Zeylenol (+)-1, the migration product, was the major compound (14 mg,
45%), an off white solid, [a]D = ++110.9 (c=0.55 in CHCl3); Rf =0.42
(CH=CHC=O), 77.7 (C), 73.8 (CHO), 68.6 (CHOSi), 66.6 (CH2OBz),
26.8 (3 ꢃ SiCACHTUNTRGENNUG(CH3)3), 19.1 ppm (SiCCAHTUNGTREN(NUGN CH3)3); n˜ (thin film) 3448 (wb), 3020
(m), 2915 (m), 1720 (s), 1695 (s), 1278 (m) cmÀ1; HRMS m/z calcd for
C60H64NaO12Si2+: 1055.3834 [M2 +Na]+; found: 1055.3873; m/z calcd for
C30H32NaO6Si+: 539.1966 [M+Na]+; found: 539.1986.
1
(PhMe/MeCN 2:1); H NMR (500 MHz, CDCl3, 238C): d=8.01 (2H, dd,
J=8.2, 1.1 Hz, OBzCH), 7.96 (2H, dd, J=8.2, 1.1 Hz, OBzCH), 7.57–7.52
4772
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 4766 – 4774

Total Synthesis of Zeylenols and Zeylenones
FULL PAPER
28: Rf =0.23 (petroleum ether/EtOAc 1:1); [a]D = +12.5 (c=0.4 in
CHCl3); 1H NMR (500 MHz, CDCl3, 238C): d=7.97 (2H, d, J=7.5 Hz,
OBzCH), 7.57 (1H, t, J=7.5 Hz, OBzCH), 7.43 (2H, t, J=7.5 Hz, OBzCH),
6.91 (1H, dd, J=10.3, 3.0 Hz, CH=CHC=O), 6.17 (1H, dd, J=10.3,
1.4 Hz, CH=CHC=O), 4.79 (1H, d, J=11.4 Hz, CH2OBz), 4.71–4.69 (1H,
m, CHOH), 4.59 (1H, d, J=11.4 Hz, CH2OBz), 3.97 (1H, d, J=5.0 Hz,
CHOH), 3.59 (1H, bs, OH), 3.42 (1H, bs, OH), 2.69 ppm (1H, bs, OH);
1H NMR (500 MHz, [D6]Acetone, 238C): d=7.93 (2H, d, J=7.5 Hz,
OBzCH), 7.61 (1H, t, J=7.5 Hz, OBzCH), 7.48 (2H, t, J=7.5 Hz, OBzCH),
6.98 (1H, dd, J=10.3, 2.5 Hz, CH=CHC=O), 6.01 (1H, dd, J=10.3,
1.8 Hz, CH=CHC=O), 4.84 (1H, s, OH), 4.75 (1H, app d, J=5.5 Hz,
OH), 4.70–4.62 (2H, m, CHOH and OH), 4.62 (1H, d, J=10.4 Hz,
CH2OBz), 4.56 (1H, d, J=10.4 Hz, CH2OBz), 4.05 ppm (1H, app t, J=
6.0 Hz, CH); 13C NMR (125 MHz, CDCl3, 238C) d=195.3 (C=O), 166.8
(CH2OC(O)Ph), 147.8 (CH=CHC=O), 133.6 (OBzC), 129.8 (2 ꢃ OBzCH),
129.0 (CH=CHC=O), 128.5 (2 ꢃ OBzCH), 126.9 (OBzCH), 76.2 (C), 74.0
(CHOH), 68.0 (CHOH), 64.1 ppm (CH2OBz); 13C NMR (75 MHz,
[D6]Acetone, 238C) d=197.2 (C=O), 167.0 (CH2OC(O)Ph), 152.7 (CH=
CHC=O), 134.9 (OBzC), 131.9 (OBzCH), 131.7 (2 ꢃ OBzCH), 130.3 (2 ꢃ
OBzCH), 128.1 (CH=CHC=O), 78.1 (C), 76.5 (CHOH), 70.6 (CHOH),
64.8 ppm (CH2OBz); n˜ (thin film) 3452 (wb), 2921 (m), 1719 (s), 1698 (s),
1272 (m) cmÀ1; HRMS: m/z calc for C28H28NaO12+: 579.1473 [M2 +Na]+;
[6] a) P. Tuntiwachwuttikul, O. Pancharoen, W. A. Bubb, T. W. Hambly,
W. C. Taylor, V. Reutrakul, Aust. J. Chem. 1987, 40, 2049–2061;
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[10] Note that in ref. [9b], zeylenol isolated from Uvaria rufa is depicted
as the (À)-1 enantiomer, although no chiroptical data are presented.
A subsequent report on this same species assigned the isolate as
(+)-1 on the basis of its positive [a]D value; see ref. [7b].
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+
found: 579.1504 (29%); C14H14NaO6 [M+Na]+ requires 301.0688,
found 301.0140 (100%); m/z calc for C14H15O6+: 279.0863 [M+H]+;
[13] P. C. Stevenson, N. C. Veitch, M. S. J. Simmonds, Phytochemistry
2007, 68, 1579–1586.
found: 279.0836 (8%); data are in agreement with reported values.[3g]
[14] a) J. Singh, K. L. Dhar, C. K. Atal, Tetrahedron 1970, 26, 4403–
4406; b) J. Singh, K. L. Dhar, C. K. Atal, Indian J. Pharm. 1971, 31,
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Synthesis of 28 from TBDMS ether 72: To a stirred solution of TBDMS-
acetonide 72 (65 mg, 0.15 mmol, 1.0 equiv) in MeOH (1.5 mL) at room
temperature was added iodine (38 mg, 0.15 mmol, 1.0 equiv). The prog-
ress of the reaction was followed by TLC of the resulting solution; after
4 h the reaction mixture was poured into Na2S2O3 (1.0m, 10 mL), and the
iodine colour disappeared. The aqueous layer was extracted with EtOAc
(3ꢃ5 mL), and the combined organic layers were dried over Na2SO4, and
then filtered. The filtrate was concentrated under reduced pressure. The
crude residue was purified by chromatography (petroleum ether/EtOAc
2:1) to afford a mixture of products, which were further purified by chro-
matography (petroleum ether/EtOAc 4:1 to 1:1). Fractions containing
the desired product were concentrated in vacuo, the resulting gum was
taken up into CHCl3 and allowed to stand overnight, during which time
the desired compound 28 precipitated as a white solid (18 mg, 43%);
data as described above.
[20] Note that the substance was initially named as tonkinenin A and in-
correctly assigned (see ref. [9b] and ref. [19a]), but the structure de-
picted here for (À)-22 has been verified by total synthesis; see
ref. [18b].
[21] Z.-Q. Li, Mastersꢀ Thesis, 2009, Suzhou Medical University.
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Acknowledgements
We gratefully acknowledge EPSRC (Grant EP/H049355/1) and the Uni-
versity of Bath for funding. We thank Prof. A. G. Myers (Harvard) for
a gift of R. eutrophus B9 cells.
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Received: December 23, 2011
Published online: February 29, 2012
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