Hypervalent iodine-mediated oxygenative phenol dearomatization reactions

Article abstract of DOI:10.1016/j.tet.2010.05.078

Both λ³- and λ⁵-iodanes have proven to be useful reagents in the oxygenative dearomatization of phenols, and exploitations of their chemistry in the conception of both substrate- and reagent-controlled asymmetric variants of such a transformation of great value for natural product synthesis have shown evident signs of success. Moreover, the use of stabilized IBX (i.e., SIBX) in our methodology for O-demethylation of 2-methoxyphenols, which relies on the same key oxygenating dearomatization event, is reported here to be much more efficacious than that of IBX itself in the chemoselective one-step conversion of homovanillyl alcohol into hydroxytyrosol, and bergenin into norbergenin.

Full text of DOI:10.1016/j.tet.2010.05.078

Tetrahedron 66 (2010) 5908e5917
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Hypervalent iodine-mediated oxygenative phenol dearomatization reactions
Laurent Pouységu a, Tahiri Sylla a, Tony Garnier a, Luis B. Rojas b, Jaime Charris c,
,
Denis Deffieux a, Stéphane Quideau a
*
a Université de Bordeaux, Institut des Sciences Moléculaires (CNRS-UMR 5255) and Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, 33607 Pessac Cedex, France
b Universidad de Los Andes, Laboratorio de Productos Naturales, Facultad de Farmacia y Bioanálisis, 5101 Mérida, Venezuela
c Universidad Central de Venezuela, Laboratorio de Síntesis Orgánica, 1041-A Caracas, Venezuela
a r t i c l e i n f o
a b s t r a c t
Both l l
3- and 5-iodanes have proven to be useful reagents in the oxygenative dearomatization of phenols,
Article history:
Received 4 May 2010
Received in revised form 19 May 2010
Accepted 19 May 2010
Available online 25 May 2010
and exploitations of their chemistry in the conception of both substrate- and reagent-controlled
asymmetric variants of such a transformation of great value for natural product synthesis have shown
evident signs of success. Moreover, the use of stabilized IBX (i.e., SIBX) in our methodology for O-de-
methylation of 2-methoxyphenols, which relies on the same key oxygenating dearomatization event, is
reported here to be much more efficacious than that of IBX itself in the chemoselective one-step con-
version of homovanillyl alcohol into hydroxytyrosol, and bergenin into norbergenin.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Hypervalent iodine
SIBX
Phenol dearomatization
Demethylation
Cyclohexadienones
Quinone monoketal
Quinol
Asymmetric synthesis
1. Introduction
development of catalytic applications of iodanes, together with the
design of chiral iodane-based systems for asymmetric induction
The chemistry of hypervalent (or polyvalent) iodine organic
compounds, also referred to as iodanes, has experienced an im-
pressive development starting from the early 1990s. Since 1992,
four books1 and numerous review articles2 have been dedicated to
the chemistry of hypervalent iodine-containing organic reagents
and their applications in organic synthesis. This increasing interest
essentially stemmed from the very useful oxidizing properties
expressed by these iodanes, both as dehydrogenating and oxy-
genating reagents, combined with the fact that their utilization
constitutes an environmentally benign alternative to that of heavy
metal-based oxidizing reagents. Iodine(III) and iodine(V) de-
purposes,5 and the emergence of iodane-mediated oxidative phe-
nol dearomatization as a tactic of choice in the total synthesis of
many natural products of different metabolic origins.
In this latter context, our own interest in the chemistry of
cyclohexadienones as polyfunctionalized intermediates for the
construction of complex natural products led us to contemplate early
on the use of iodanes as mild and efficient tools to convert phenolic
precursors into cyclohexa-2,4- or -2,5-dienones (Scheme 1).6
O
R'
2
l l
3-iodanes and 5-iodanes, respectively, are now
*
Nu
cyclohexa-
rivatives, i.e.,
Nu
routinely used in organic synthesis for various selective oxidative
transformations of complex organic molecules. Among the several
areas of hypervalent iodine chemistry that have recently been the
topic of intensive investigations, one can cite efforts aimed at
expanding the scope of reactions mediated by 2-iodoxybenzoic
4
OH
R
O
2,4-dienone
R
and/or
O
R'
R'
iodane
ortho
– H+, – 2e–
para
R'
R
2
acid (IBX) and related
l
5-iodane reagents,3 the development of
and
5-iodanes,4 the
Nu
"phenolic
umpolung"
polymer-supported and recyclable l3
-
l
5
Nu
E
*
cyclohexa-
2,5-dienone
R
Nu
Scheme 1. Iodane-mediated (oxygenative) dearomatization of phenols into
cyclohexadienones.
* Corresponding author. Tel.: þ33 5 4000 3010; fax: þ33 5 4000 2215; e-mail
address: s.quideau@iecb.u-bordeaux.fr (S. Quideau).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.078

L. Pouységu et al. / Tetrahedron 66 (2010) 5908e5917
5909
Such transformations rely on the electrophilic character of the
hypervalent iodine center and conceptually impose a reactivity
switch to phenols from being nucleophiles to becoming electro-
philes. This ‘phenolic umpolung’, also more generally first referred
to as ‘aromatic ring umpolung’ by Canesi and co-workers,7 then
enables attack of nucleophiles at the ortho- or para-carbon centers
of the starting phenol thus oxidatively activated (Scheme 1).6
Dearomatization ensues when the reacting phenolic carbon cen-
ter already bears a substituent, hence generating a possibly chiral
sp3-hybridized carbon center. Controlling the configuration of such
a carbon center by iodane-based asymmetric induction means
currently remains the focus of sustained efforts in several research
groups worldwide, as it constitutes the last important challenge of
the development of iodane-mediated phenol dearomatization re-
actions for organic synthesis. Besides this door open to stereo-
selective reactions, the duality of the reactivity expressed by
phenolic species upon treatment with iodane reagents can also be
exploited to transform them in remarkably useful chemo- and
regioselective manners.
designed to permit their dearomatization into spiro-ketals of type
A (see Fig. 1). A substituent was placed at the phenolic para-posi-
tion to prevent or at least retard the self-dimerization of the
dearomatized species through [4þ2] cycloaddition events.11 The
substrates were prepared by a Williamson reaction between 5-
substituted 2-benzyloxyphenols (for 1aed and 1fei) or, alterna-
tively, 2-methoxymethylphenol (for 1e) and enantiomerically
enriched terminal epoxides generated by using the Jacobsen
method.8a In the case of the phenolic alcohol 1j, which was pre-
pared in the aim of evaluating the influence of a larger halogen
atom at the para-position on the extent of the undesired self-di-
merization, a three-step sequence including a bromine exchange
by iodine was implemented to transform efficiently 1i into 1j
(Scheme 2). After silylation of (R)-1i with triethylsilyl triflate
(TESOTf) in the presence of triethylamine to afford (R)-2 (96%
yield), a bromine/lithium exchange was performed upon treatment
with tert-butyllithium at low temperature, and subsequent trap-
ping with iodine furnished the iodobenzene intermediate (R)-3
(80% yield), which was finally submitted to a tetrabutylammonium
fluoride (TBAF)-mediated desilylation (99% yield) to afford pure
(R)-1j in an overall yield of 76% (Scheme 2).
We wish to highlight herein some of our previous results and
report previously unpublished and new observations from our in-
vestigations on iodane-mediated stereoselective oxygenative
dearomatization of ortho-substituted phenols (see Scheme 1,
Nu¼‘oxygen’) and on chemo/regioselective oxygenative O-deme-
thylation of 2-methoxyphenols into catechols.8
Table 1
DIB-mediated spiro-ketalization of phenolic alcohols 1 into ortho-quinone mono-
ketals 4 and 5
2. Results and discussion
2.1. Substrate-controlled asymmetric phenol
dearomatization
ortho-Quinone monoketals (A) and their ortho-quinol variants
(B) are cyclohexa-2,4-dienone derivatives (Fig. 1) that have
proven to be extremely useful in the construction of various
complex natural product architectures.6,9 Oxidative phenol
dearomatization methods, and in particular those mediated by
an iodane reagent, stand out among the most straightforward
tactics to access these synthetically useful derivatives.6,9 How-
ever, an ideal utilization of these cyclohexa-2,4-dienone de-
rivatives in organic synthesis requires the stereocontrol of the
sp3-hybridized C-6 center newly created in the course of the
dearomatization event.
A first and obvious solution to this
challenging task encompasses substrate-controlled preparations
of chiral ortho-quinone monoketals and/or ortho-quinols in non-
racemic form, but surprisingly, only a few examples have been
reported so far.10
a
The products were isolated in quantitative combined yields.
b
The diastereomeric ratios were determined by 1H NMR spectroscopic analysis.
c
Gradual [4þ2] cyclodimerization was observed.
OH
Br
OH
OH
OH
O
O
3 steps
R
R
t-Bu
t-Bu
O
O
OR
R'
O
O
OH
R
76% overall yield
2
2
or
R
6
6
(R)-1i
(R)-1j (99%)
I
4
4
TESOTf, Et3N
CH2Cl2, 0 °C
TBAF, THF
A: ortho-quinone monoketal,
R = alkyl, acyl or aryl
R' = alkoxy, acyloxy or aryloxy
B: ortho-quinol,
R = alkyl or aryl
rt
0 °C
rt
OTES
R
OTES
OTES
OTES
O
O
1) t-BuLi, THF, –78 °C
R
t-Bu
t-Bu
Figure 1. ortho-Quinone monoketal (A) and ortho-quinol (B) types of cyclohexa-2,4-
dienone derivatives.
2) I2, THF, –78 °C
rt
(R)-2 (96%)
(R)-3 (80%)
Br
I
Our last contribution to the development of such substrate-
Scheme 2. Preparation of chiral phenolic alcohol 1j from its brominated analogue 1i.
controlled asymmetric preparations of ortho-quinone monoketals
relied on the use of the l
3-iodane (diacetoxyiodo)benzene (DIB),
also referred to as phenyliodine(III) diacetate (PIDA).8a The starting
phenols 1 bore a chiral ethanol unit O-tethered to the ortho-posi-
tion of the phenolic ring (Table 1). These constructs were thus
The desired oxidative dearomatization of phenols 1 into ortho-

5910
L. Pouységu et al. / Tetrahedron 66 (2010) 5908e5917
quinone monoketals 4 and 5 was then performed using the DIB
reagent (Table 1). Our initial studies were carried out in CH2Cl2, at
either room temperature or ꢀ78 ꢁC, and furnished complex mix-
tures in which only undesired ortho-quinol acetate derivatives,
resulting from the competitive attack of the acetoxy DIB ligands,12
could be identified by 1H NMR analysis. When pure dichloro-
methane was changed to solvent mixtures, such as CH2Cl2/CH3CN
(4:1) at ꢀ78 ꢁC or CH2Cl2/CF3CH2OH (8:1) at ꢀ60 ꢁC, the expected
spiro-ketals were formed as evidenced by 1H NMR detection of
their diagnostic ethylenic signals, but with substantial amounts of
impurities that could not be separated. These preliminary obser-
vations prompted us to further investigate the use of 2,2,2-tri-
fluoroethanol (CF3CH2OH, TFE) as a polar and poorly nucleophilic
solvent.13 Reactions were thus performed in TFE at ꢀ35 ꢁC, and
worked up using saturated aqueous NaHCO3, to give the expected
spiro-ketals that could this time be further purified by column
chromatography and isolated, albeit in moderate yields ranging
from 20 to 50%. After extensive experimentations on both reaction
and workup conditions, it was found that yields drastically im-
proved when the use of DIB (1.0 equiv) in TFE (ca. 0.04 M) at
ꢀ35 ꢁC was followed by quenching of the released acetic acid with
powdered NaHCO3 at the same low temperature without addition
of any water.8a All ten phenolic alcohols 1aej were thus suc-
cessfully converted into the desired spiro-ketals 4 and 5, which
were isolated in a quantitative combined yield with an excellent
level of purity through a simple filtration/evaporation procedure
(Table 1). Although further purification of these products was not
necessary before their use in subsequent reactions, they were
separated by column chromatography for the characterization of
each diastereomer, and their stereochemistry was unambiguously
established by NOESY experiments.8a
Phenolic alcohols 1 with a tert-butyl group on the chiral side-
chain (Table 1, entries 1, 2, 5e7, and 9) underwent a highly dia-
stereoselective transformation, in contrast to those with an ethyl
or n-decanyl group at the same position (Table 1, entries 3, 4, and
8). One can note that the iodide substrate 1j bearing a tert-butyl
substituent gave the expected ortho-quinone monoketals 4j/5j,
but with a surprising (slightly) lower diastereocontrol, especially
when compared to the result obtained with its bromide coun-
terpart 1i (Table 1, entries 10 and 9). In all cases, the configuration
of the starting alcohol dictated which isomer formed as the major
diastereomer: reactions with enantiomers (R)-1 and (S)-1 fur-
nished (R,R)-4 and (S,S)-5 as the major product, respectively.
These ortho-quinone monoketals were isolated as monomers,
despite the tendency of such systems to participate in [4þ2]
cyclodimerization.11 The only exceptions were the unexpected
gradual dimerizations of the halogenated (R,R)-4i and (R,R)-4j that
were clearly observed even during the duration of NMR analyses.
Typically, cyclohexa-2,4-dienone 4i started to transform into its
cyclodimer during 13C NMR data acquisition, and proton NMR
monitoring of the resulting orange oily mixture in a CDCl3 solu-
tion (ca. 0.3 M) indicated that the quasi complete [4þ2] cyclo-
dimerization of 4i was achieved after 15 days at room
temperature, which allowed isolation of the pure dimer in 54%
yield.8a In the case of cyclohexa-2,4-dienone 4j, the cyclo-
dimerization event was even faster, since the 1H NMR spectrum of
the 90:10 diastereomeric mixture of 4j also revealed traces of its
dimer (see the Supplementary data). However, instead of evolving
to a complete conversion of 4j into its cyclodimer, degradation of
cycloaddition behavior of these two halogen-substituted spiro-
ketals vis-à-vis our recently proposed single all-embracing ratio-
nale of the regio-, site-, endo-, and
p-facial selectivities of this
[4þ2] dimerization process involved in the biosynthetic elabora-
tion of many natural products.11d,14
The process leading to the non-dimerizing alkyl-substituted
spiro-ketals was further studied to better understand the mecha-
nism underlying such a highly diastereoselective l
3-iodane-medi-
ated transformation in view of applying it to the synthesis of
natural products. DFT calculations were thus performed on the
reaction leading to ortho-quinone spiro-ketals (R,R)-4a and (R,S)-
5a, and led to the identification of conceivable six-membered cyclic
iodine(III)-containing intermediates, from which we could propose
a stereocontrol rationale on the basis of the stereodifferentiating
ability of these intermediates in ligand coupling reactions.8a Next,
this methodology was successfully applied to the enantioselective
synthesis of the bis(monoterpene) (þ)-biscarvacrol (9) from 4-iso-
propylphenol (6) (Scheme 3). After a four-step conversion of 6 into
the phenolic alcohol (S)-1e,8a our DIB-mediated oxygenative
dearomatization allowed the generation of the requisite spiro-ketal
(S,S)-5e (see Table 1), which was treated immediately with meth-
ylmagnesium bromide (MeMgBr) to furnish the tertiary alcohol (S,
S,R)-7 with a high level of diastereoselectivity (Scheme 3). Other
substrates and organometallic reagents are currently under in-
vestigation to examine the scope of this asymmetric two-step se-
quence. The synthesis of (þ)-9 was then simply completed by an
acidic cleavage of the ketal moiety to furnish the ortho-quinol (R)-8,
OH
OH
OH
O
O
S
O
4 steps
50%
t-Bu
S
t-Bu
DIB
S
O
CF3CH2OH
–35 °C
6
(S)-1e
(S,S)-5e
i-Pr
i-Pr
i-Pr
HO
HO
O
S
O
t-Bu
MeMgBr
p-TsOH•H2O
R
R
S
O
THF
acetone
–78 °C
(S,S,R)-7
(R)-8
i-Pr
i-Pr
dr ≥ 95:5 (NMR)
(isolated in 54% yield after two steps)
[4+2]
HO
O
i-Pr
(+)-9
OH
er 93:7 (HPLC)
O
i-Pr
(isolated in 56% yield after two steps)
Scheme 3. Enantioselective synthesis of (þ)-biscarvacrol (9).8a
which spontaneously underwent the expected cyclodimerization
into (þ)-9 as the major stereoisomer (Scheme 3).8a
2.2. SIBX-mediated oxidative O-demethylation and
hydroxylative phenol dearomatization (HPD)
the mixture was observed after
a
few days (see the
Our interest in hypervalent iodine-based reagents as efficient
Supplementary data). In any event, our initial expectation of
better blocking the self-dimerization process observed with 4i by
having a bulkier halogen atom at the para-position of the starting
phenol was obviously not met. These unexpected DielseAlder
cyclodimerizing events of both 4i and 4j are still under in-
vestigation in the aim of gaining further insight into the
tools to promote oxygenative transformations of phenols also led
us to consider the use of the l
5-iodanes 2-iodoxybenzoic acid (IBX)
and its non-explosive formulation (SIBX, for Stabilized IBX).8c,14,15
Indeed, both of these iodine(V) reagents have proven their capa-
bility to deliver ortho-selectively an oxygen atom during phenol
dearomatization processes,8c,14,15 as first described by Pettus’ and

L. Pouységu et al. / Tetrahedron 66 (2010) 5908e5917
5911
Nicolaou’s groups (Scheme 4).3a,16 An arenol of type 10 can react
4), in which case hydrolysis of the
l
3-iodanyl moiety of D3 fur-
with IBX, presumably through an initial ligand-exchange step with
nishes IBA and an ortho-quinol product 13. We refer to this
transformation as the Hydroxylative Phenol Dearomatization
(HPD) reaction.6c,14b
elimination of water, to give rise to an aryloxy-l
5-iodane of type C.
This species can then rearrange in a sigmatropic-like fashion by
forming regioselectively a single oxygenecarbon bond at one of
the ortho-carbon centers of the aryloxy unit, with concomitant
2.2.1. SIBX-mediated oxidative O-demethylation. Our development,
in partnership with the company Simafex, of stabilized IBX (i.e.,
SIBX) for safe dehydrogenative oxidation of alcohols included the
aforementioned oxygenative O-demethylation of phenolic methyl
aryl ethers.8c Thus, 2-methoxyphenols were conveniently con-
verted into their corresponding catechols using SIBX, which is to-
day commercially available. The ortho-selectivity of the
oxygenating process is a remarkable asset of this reaction, but we
were also curious to examine its chemoselectivity when using 2-
methoxyphenols bearing alcoholic functions, and to compare the
performances of both SIBX and IBX reagents in such scenarios.
Commercially available eugenol (10a), vanillyl alcohol (10b), iso-
vanillyl alcohol (10c), homovanillyl alcohol (10d), the C-galloyl-
glucoside (ꢀ)-bergenin (10e), and its synthetic monobenzylated
derivatives 10f/g (vide infra) were thus selected for this study in the
aim of preparing in one single step their corresponding catechols.
The selection of (ꢀ)-bergenin (10e) and its benzylated de-
rivatives 10f/g was driven by our current interest in delineating the
mechanism of action of 10e as a selective inhibitor of human DNA
topoisomerase II.18a Monobenzylation of the phenolic functions18b
of 10e was achieved upon treatment with benzyl chloride in the
presence of sodium bicarbonate (NaHCO3) and sodium iodide (NaI)
in freshly distilled dimethylformamide (DMF) at room temperature
(Scheme 5). After 2 days, the reaction was worked up and afforded
a small amount of 8,10-di-O-benzylbergenine (14, 19%), decent
amounts of the expected 10-O-benzylbergenine (10f, 30%) and 8-O-
benzylbergenine (10g, 33%), as well as some recovered starting
material (10e, 17%). The regiochemistry of the two monobenzylated
two-electron reduction of the iodine(V) atom leading to a l3
-
iodanyl species of type D. This species can then evolve differently
depending on the substitution pattern of the starting arenol 10. For
example, if the ortho-position does not bear any substituent (i.e.,
R¼H, Scheme 4), it can be argued that D1 will first rearomatize by
prototropy before reductive elimination of the l
3-iodanyl moiety
drives the reaction toward the generation of an ortho-quinonoid
product of type 11, valuable either as such or as its catecholic an-
alogue 12 easily obtained after a reductive workup.8c,16,17 Both 11
and 12 are also accessible if an alkoxy substituent occupies the
ortho-position that has been oxygenated (e.g., R¼OMe, Scheme 4),
for the l
3-iodanyl moiety of D2 can be released by hydrolysis to
give 2-iodosobenzoic acid (IBA) and an hemiketal product E, which
then eliminates methanol to furnish 11, and possibly 12. This
transformation constitutes a valuable means to cleave ortho-phe-
nolic methyl aryl ether bonds8c and has found pertinent applica-
tions in natural products synthesis (vide infra).6d The outcome of
this IBX-mediated ortho-oxygenative reaction is even different
when the ortho-position bears an alkyl group (e.g., R¼Me, Scheme
ortho-selective oxygenation
via sigmatropic-like
ligand
[2,3] rearrangement
exchange
O
O
O
O
O
O
I
O
I
O
I
HO
OH
O
O
O
R
R
IBX
– H2O
R
OMe
OH
OMe
HO
R1O 10
O
NaHCO3,
BnCl, NaI HO
10
C
D
HO
HO
HO
HO
8
O
O
OR2
O
O
HO
R = H
O
I
DMF, rt
O
O
I
O
O
OH
O
O
O
O
H
14: R1 = R2 = Bn (19%)
O
~ H+
10e, bergenin
10f: R1 = Bn, R2 = H (30%)
10g: R1 = H, R2 = Bn (33%)
D1
11
2-iodobenzoic acid
if reductive
Scheme 5. Monobenzylation of (ꢀ)-bergenin (10e).
workup
OH
O
R = alkoxy
e.g., R = OMe
OH
12
bergenins 10f and 10g was unambiguously determined by
a delayed 1He1H COSYanalysis using a fixed delay of 300 ms, which
permitted the observation of a 5-bond correlation between the
benzyloxy protons resonating at 5.15 ppm and the aromatic singlet
H-7 at 7.21 ppm in the case of 10g (see the Supplementary data).
All seven 2-methoxyphenols 10aeg were then subjected to our
oxidative O-demethylation reaction conditions using either IBX or
H2O
oxidative
O-demethylation
O
hydrolysis
O
I
O
if reductive
workup
O
O
OH
OMe
O
OMe
SIBX (Table 2). Treatment of eugenol (10a) with 1.1 equiv of the l5
-
D2
E
11
IBA
H2O
MeOH
iodane reagent in THF at room temperature, followed by reductive
workup of the presumed ortho-quinonoid intermediate product of
type 11 with a freshly prepared aqueous solution of sodium dithionite
(Na2S2O4), furnished the expected catechol 12a. Both IBX and SIBX led
to very good yields of 67 and 77%,8c respectively, with very similar
times of reaction (12 and 16 h, respectively). When vanillyl alcohol
(10b) was submitted to these same experimental conditions, vanillin
(12b) was isolated in good yields of 60 and 51%,19 respectively (Table
2). The absence of catechol products results from the deactivation of
the phenol function by the para-positioned electron-withdrawing
aldehyde group,8c,d,16 which is competitively generated by the facile
R = alkyl
O
e.g., R = Me
O
HPD reaction
I
O
O
O
OH
Me
hydrolysis
Me
D3
13
2-iodosobenzoic acid (IBA)
Scheme 4. Plausible mechanisms of the IBX-mediated ortho-selective oxygenative
dearomatization of arenols.
l
5-iodane-mediated dehydrogenative oxidation of the benzylic

5912
L. Pouységu et al. / Tetrahedron 66 (2010) 5908e5917
Table 2
primary alcoholic oxygen atom during the initial ligand-exchange
step of our proposed mechanistic description (see Scheme 4). How-
ever, thereason(s)of thebetterperformanceofSIBXoverthatofIBXin
this reaction remains obscure. In anyevent, it is worth noting that this
one-step SIBX-mediated access to hydroxytyrosol (12d) from homo-
vanillyl alcohol (10d) constitutes a valuable alternative to recently
reported methods relying on IBX-mediated hydroxylation or deme-
thylation of carboxymethylated derivatives of tyrosol and 10d.21
In the same vein of our investigations, the C-galloylglucoside
(ꢀ)-bergenin (10e) and its monobenzylated derivatives 10f/g were
also chemoselectively O-demethylated upon treatment with SIBX
in acetone/water (9:1) at room temperature. The aqueous Na2S2O4-
based reductive workup was followed by either SephadexÒ LH-20
or semi-preparative reverse phase HPLC purification (see
Experimental section) to furnish (ꢀ)-norbergenin (12e) and its
monobenzylated catecholic derivatives 12f/g in respective yields of
69, 20, and 21% (Table 2). This fairly efficient one-step preparation
of norbergenin (12e), a plant metabolite that has shown an in vitro
anti-HIV activity by inhibiting the gp120/CD4 interaction,22a com-
pares favorably with the previously reported three-step sequence
(71% overall yield) relying on classical protection/deprotection and
Lewis acid (BCl3)-mediated demethylation.22b Surprisingly, the
starting bergenins 10eeg fully degraded upon exposure to IBX. The
resulting intractable mixtures thus obtained led us to think that
the glucose core of these compounds did not resist IBX oxidation,
and furthermore that the benzoic and isophthalic acids present in
the SIBX formulation must play a determining role in modulating
the reactivity of IBX, hence making it a milder reagent with an
enhanced chemoselectivity potential.
SIBX versus IBX-mediated oxidative O-demethylation of 2-methoxyphenols 10 into
catechols 12a
OMe
O
OH
OH
O
OH
12
yield (IBX; SIBX)
a
(S)IBX
aq. Na2S2O4
(workup)
THF, rt
10
11
Z
Z
Z
entry
12
10
OMe
OH
1
OH
OMe
OH
10a
12a (67%; 77%)
OMe
2
3
OH
OMe
OH
OMe
OH
OH
HO
O
10b
10c
12b (60%; 51%)
12c (56%; 52%)b
OH
OH
OH
OH
O
HO
4
12d (16%; 42%)c
HO
HO
OMe
OR2
10d
OH
9
R1O
R1O
O
HO
HO
HO
HO
HO
HO
O
OR2
O
O
O
O
5
6
7
10e: R1 = R2 = H
12e (0%; 69%)c
12f (0%; 20%)c
12g (0%; 21%)c
2.2.2. SIBX-mediated hydroxylative phenol dearomatization (HPD).
We also exploited the capacity of SIBX to oxygenate phenols in an
ortho-selective manner in the synthesis of cyclohexa-2,4-dienones
of the ortho-quinol type (see B in Fig. 1, and Scheme 4, R¼alkyl).
This led us to develop what we referred to as the HPD reaction for
hydroxylative phenol dearomatization,14b which we then applied to
10f: R1 = Bn, R2 = H
10g: R1 = H, R2 = Bn
a
Reactions were carried out with 1.1 equiv of (S)IBX8c
2.2 equiv of (S)IBX were necessary to achieve complete conversion of 10c.
The reaction was conducted in acetone/water (9:1, v/v).
.
b
c
primary alcohol function of 10b. In support of this explanation is the
fact that addition of another equivalent of IBX or SIBX did not allow
any O-demethylation of vanillin (12b). Moreover, iso-vanillyl alcohol
(10c) also showed oxidation of its benzylic alcohol group, but the O-
demethylation was concomitantly operational. A single equivalent of
OH
O
O
6 OH
R
OH
OMe
1
2
2
R
SIBX
*
THF, rt
MeO
4
Z
Z
10
13
O
l
5-iodane clearly afforded a mixture of iso-vanillin and its demethy-
R = alkyl
Z = various substituents
lated analogue, i.e., protocatechualdehyde (12c). The aldehyde func-
tion meta-positioned in iso-vanillin does not affect the capability of
(+)-wasabidienone B1 (15)
purified by HPLC
thenucleophilicphenolfunctiontoengagethel
5-iodanereagent, and
OH
OBz
a second equivalent of IBX or SIBX then allowed complete conversion
of 10c into 12c, which was isolated in moderate yields of 56 or 52%,
respectively (Table 2). We next turned our attention to 2-methoxy-
phenolic alcohols exempt from any benzylic alcohol function in the
aim of further evaluating the chemoselective potential of IBX versus
SIBX in oxidative O-demethylation reactions. Homovanillyl alcohol
(10d) was thus selected as a precursor of hydroxytyrosol (12d),
a naturally occurring catecholic compound exhibiting outstanding
antioxidantproperties.20 Afteracoupleofunsatisfactoryattemptsrun
in THF, the solvent system was changed to acetone/water (9:1), in
which the solubility of the starting material 10d was much better.
Treatment of 10d with 1.1 equiv of IBX over 12 h led to the successful
isolation of 12d, but in a low yield of 16%. Under the same experi-
mental conditions, the use of SIBX proved to be much more promis-
ing, since 12d was in this case isolated in a decent, not optimized but
reproducible, yield of 42% (Table 2). The chemoselectivity thus ob-
served in favor of the ortho-oxygenation of the phenol function over
the dehydrogenation of the primary alcohol function of 10d might be
attributed to a preference of the iodine(V) center of IBX for reacting
with the softer phenolic oxygen atom rather than with the harder
O
HO
HO
OBz
O
i-Pr
O
HO
O
OH
( )-grandifloracin (16b)
OH
( )-biscarvacrol (9)
O
O
i-Pr
(+)-aquaticol (16a)
purified by HPLC
Scheme 6. Examples of natural non-dimerizing ortho-quinol and ortho-quinol-derived
[4þ2] cyclodimers synthesized via our SIBX-mediated HPD reaction.
the (biomimetic) synthesis of several natural products either fea-
turing an ortho-quinol motif, such as (þ)-wasabidienone B1 (15)15b
or derived from the dimerization of such motifs, such as
(þ)-aquaticol (16a), rac-grandifloracin (16b), and rac-biscarvacrol
(9) (Scheme 6).14
Access to the above natural products in enantiomerically
enriched forms, using SIBX in the key step of their construction,
relied on separation of racemic intermediates or diastereomeric
products by (chiral) liquid chromatography techniques. Although

L. Pouységu et al. / Tetrahedron 66 (2010) 5908e5917
5913
we developed an efficient substrate-controlled methodology for
the asymmetric synthesis of such natural products, as exemplified
by the synthesis (þ)-9 (see Section 2.1 and Scheme 3), we were also
particularly interested in developing a reagent-controlled approach
using a chiral analogue of IBX in order to limit both the number of
chemical and separation steps in such synthesis endeavors.
reactions using an external oxygenating species derived from
a chiral iodoarene.
3. Conclusion
There are unarguably more improvements to come in the still
developing field of hypervalent iodine chemistry in general, and in
particular, in its utilization in phenol dearomatization processes.
These highlights of our own contributions and those of others to
the development of substrate-controlled and, most notably, re-
agent-controlled iodane-mediated stereoselective oxygenative
dearomatization of phenols attest to the interest that such a trans-
formation has recently raised in the field and underline its tre-
mendous potential for natural product synthesis. Iodanes, and
2.3. Reagent-controlled asymmetric phenol dearomatization
This aim of developing an asymmetric route to ortho-quinol
systems relying on the use of a chiral oxygenating IBX-like reagent
turned out to be much more difficult than we initially anticipated.
We soon realized that the development of chiral iodanes capable of
efficacious inductions of asymmetry was like the search for the
Holy Grail of hypervalent iodine chemistry. Indeed, despite un-
remitting efforts on the part of several research groups over the last
thirty years or so, no fully satisfactory solution had been found, and
like the others, we stumbled upon many difficulties in trying to
especially IBX and IBX-like
l
5-iodanes, have clearly emerged as
useful external sources of oxygen in oxygenative phenol dear-
omatization reactions. In this context and on the basis of the new
results reported herein, we would like to emphasize the benefits of
using SIBX in place of IBX in the exploitation of this transformation
of phenols in the chemo- and regioselective oxygenating O-
demethylation of 2-methoxyphenols into catechols. For example,
the milder SIBX reagent thus enabled O-demethylation of sub-
strates, such as homovanillyl alcohol (10d) or (ꢀ)-bergenin (10e) in
decent to good yields without prior protection of their alcoholic
functions, whereas IBX failed to exert the same level of
chemoselectivity.
design and prepare chiral l
5-iodane reagents for asymmetric oxy-
genative phenol dearomatization reactions. However, significant
and highly promising progresses have been made over the last two
years.23 In 2008, Kita’s group reported on a chiral bis- 3-iodane
l
spirobiindane-based reagent for intramolecular dearomatizing
spirolactonization of a series of naphthol derivatives in enantio-
meric excesses (ee’s) up to 86%.23a A catalytic version of this re-
action using 0.15 equiv of their bisiodoarene precursor and m-CPBA
as a co-oxidant enabled spirolactonization in up to 69% ee.23a In-
spired by this work, Ishihara’s group reported this year on the same
reaction using 15 mol % of a C2-symmetric bis(N-mesityl amide)-
based iodoarene derived from 2-iodoresorcinol and chiral lactate
4. Experimental section
4.1. General
units, and oxidized in situ into the corresponding l
3-iodane using
All moisture and oxygen sensitive reactions were carried out in
flame-dried glassware under N2. Tetrahydrofuran (THF) was puri-
fied immediately before use by distillation from sodium/benzo-
phenone under N2, or by filtration through alumina under N2.
Methanol (MeOH) and dimethylformamide (DMF) were distilled
under N2 prior to use from Mg/I2 and P2O5, respectively. Acetone,
dichloromethane (CH2Cl2), ethyl acetate (EtOAc), absolute ethanol
(EtOH), and n-butanol (n-BuOH), were used as received. The
iodanes, i.e., (diacetoxyiodo)benzene (DIB; Simafex), 2-iodox-
ybenzoic acid (IBX),24 and stabilized 2-iodoxybenzoic acid (SIBX;
Simafex),8c were used as received. The 2-methoxyphenols 10aed
were all purchased from Aldrich and used as received. (ꢀ)-Bergenin
(10e) was isolated from the methanol extract of either the roots (ca.
9% and 2% yields from the dry methanolic extract and the dry
weight material, respectively) or the stem-bark (ca. 10% and 1.2%
yields from the dry methanolic extract and the dry weight material,
respectively) of Peltophorum africanum Sond. (Fabaceae),25a or
purchased from either Amfinecom Inc. (mp 236e238 ꢁC) or Sig-
maeAldrich as its monohydrate [mp 139e141 ꢁC (lit.25b 140 ꢁC)],
which was further oven-dried at 60 ꢁC overnight to ensure the use
of the anhydrous compound [mp 239e240 ꢁC (lit.25c 238 ꢁC; lit.25d
237 ꢁC)]. Evaporations were conducted under reduced pressure at
temperatures less than 30 ꢁC unless otherwise noted. Column
chromatography was carried out under positive pressure using
m-CPBA, to reach enantioselectivities up to 92% ee.23c In February
2009, Birman’s group described the stoichiometric use of chiral
oxazoline-containing l
5-iodanes in HPD reactions with enantiose-
lectivities up to 77% ee, albeit in only moderate to good yields
(29e65%).23b In May 2009 was published our own contribution,
which involved the use of a presumed l
5-iodane generated in situ
from the chiral iodobinaphthyle derivative 18 and m-CPBA (Scheme
7).8b A twofold excess of 18 led to a HPD of naphthol 17 into the
ortho-quinol 19 in 83% yield and 50% ee. The organocatalytic ver-
sion of this reaction using 0.1 equiv of 18 and 2.5 equiv of m-CPBA
40e63 mm silica gel (Merck) and the indicated solvents. Melting
points were measured in open capillary tubes and are uncorrected.
Optical rotations were determined on a Krüss P3001 digital polar-
imeter at 589 nm, and are given as [a]
20 (concentration in g/100 mL
Scheme 7. Asymmetric HPD reactions through in situ generation of an iodane from
D
a chiral iodoarene (Ar
I) and m-CPBA.8b
*
solvent). IR spectra were recorded with a Bruker IFS55 FT-IR
spectrometer. NMR spectra of samples in the indicated solvent
were run at 300 MHz, and calibrated using residual solvent as an
internal standard. Carbon multiplicities were determined by
DEPT135 experiments. Stereochemical assignments were achieved
by NOESY experiments. Diagnostic correlation information was
obtained with a delayed 1He1H correlative experiment using
enables subsequent epoxidation of 19 in a diastereoselective fash-
ion to furnish the ortho-quinol epoxide 20 in an excellent yield, but
in only 29% ee (Scheme 7).8b Even though the resulting enantio-
selectivities are still moderate, these last examples constitute the
first cases of reagent-controlled asymmetric iodane-mediated HPD

5914
L. Pouységu et al. / Tetrahedron 66 (2010) 5908e5917
a fixed delay of 300 ms. Electron impact (EIMS, 50e70 eV) and
electrospray (ESIMS) low and/or high resolution (HRMS) mass
spectrometric analyses were obtained from the mass spectrometry
laboratory at either the Institut Européen de Chimie et Biologie
(IECB), the Centre d’Etude Structurale et d’Analyse des Molécules
Organiques (CESAMO, Université Bordeaux 1), or the Centre Ré-
gional de Mesures Physiques de l’Ouest (CRMPO, Université Rennes
1), France. Elemental analyses were carried out at the Service
Central d’Analyses du CNRS, Vernaison, France.
(9:1/4:1), to give pure phenolic alcohol (R)-1j as a yellow powder
20
(221 mg, 99%): mp 80e81 ꢁC; [
3396, 2958, 2872, 1499, 1458, 1122, 460 cmꢀ1
300 MHz)
a
]
D
ꢀ11.4 (c 1.14, CHCl3); IR (neat)
;
1H NMR (CDCl3,
d
1.00 (s, 9H), 3.71, (dd, J¼2.2, 9.2 Hz, 1H), 3.84 (br t,
J¼9.5 Hz,1H), 4.18 (dd, J¼2.3, 9.8 Hz, 1H), 6.69 (d, J¼8.5 Hz, 1H), 7.15
(d, J¼1.9 Hz, 1H), 7.21 (dd, J¼1.9, 8.5 Hz, 1H); 13C NMR (CDCl3,
75.5 MHz)
d 147.3, 146.5, 131.1, 122.0, 117.7, 80.6, 77.8, 70.7, 33.7,
25.9; ESIMS m/z (rel intensity) 359 (MNaþ, 100); HRMS (ESI) calcd
for C12H17INaO3 359.0120, found 359.0110.
4.1.1. (R)-(þ)-1-Triethylsilyloxy-2-(2-triethylsilyloxy-3,3-dime-
thylbutoxy)-4-bromobenzene [(R)-2]. To a stirred ice-cold solution
of bromophenol (R)-1i (289 mg, 1.0 mmol) in dry CH2Cl2 (10 mL,
ca. 0.1 M) were successively added Et3N (0.84 mL, 6 mmol) and
TESOTf (0.68 mL, 3 mmol). The mixture was then allowed to
warm to room temperature, and was stirred for 45 min, after
which time saturated aqueous NH4Cl (10 mL) was added, and the
mixture was extracted with CH2Cl2 (3ꢂ15 mL). The combined
organic layers were washed with water (15 mL), dried over
MgSO4, filtered, and evaporated. The resulting oily residue
(658 mg) was purified by column chromatography, eluting with
pure cyclohexane, to give (R)-2 as a colorless oil (497 mg, 96%):
4.2. General procedure for DIB-mediated chiral ortho-
quinone monoketals preparation8a
A stirred solution of phenol 1aej (ca. 110 mg, 1.00 equiv) in
CF3CH2OH (10 mL, ca. 0.04 M) was cooled at ꢀ35 ꢁC, and was
treated dropwise, over 5 min, with a solution of DIB (1.02 equiv)
in CF3CH2OH (1 mL). The reaction mixture immediately became
pale yellow, and then slowly changed to yellow-pink. After
20 min, TLC monitoring [hexanes/Et2O (7:3)] indicated complete
consumption of the starting material. Powdered NaHCO3 was
added in one portion to the reaction mixture, which was kept
under stirring at ꢀ35 ꢁC for 15 min. After CF3CH2OH removal in
vacuo, the residue was taken up with CCl4 (3ꢂ5 mL), filtered, and
evaporated. Further drying under high vacuum allowed complete
removal of the iodobenzene by-product, and afforded a di-
astereomeric mixture of the corresponding chiral ortho-quinone
monoketals 4aej/5aej (dr, i.e., diastereomeric ratios, were de-
termined by 1H NMR analysis; see Table 1) as yellow oils. Al-
though further purification revealed not necessary before
engaging these products in subsequent reactions, they could be
separated by silica gel column chromatography for identification
and characterization purposes.
[
a
]
20 þ10.7 (c 0.94, CHCl3); IR (neat) 2956, 2912, 2877, 1497, 1457,
D
1121, 739, 462 cmꢀ1
; d 0.63 (q,
1H NMR (CDCl3, 300 MHz)
J¼7.7 Hz, 6H), 0.74 (q, J¼7.4 Hz, 6H), 0.91e1.00 (m, 27H), 3.70 (dd,
J¼2.9, 5.9 Hz, 1H), 3.81 (dd, J¼6.1, 9.5 Hz, 1H), 3.97 (dd, J¼2.8,
9.6 Hz, 1H), 6.69 (d, J¼8.3 Hz, 1H), 6.90e6.93 (m, 2H); 13C NMR
(CDCl3, 75.5 MHz)
d 151.3, 144.7, 123.6, 121.3, 117.1, 113.2, 78.8,
72.3, 34.9, 26.2, 7.0, 6.6, 5.1, 5.0; ESIMS m/z (rel intensity) 541
(MNaþ, 100), 539 (MNaþ, 90), 526 (3), 524 (1); HRMS (ESI) calcd
for C24H4579BrNaO3Si2 539.1988, found 539.1981.
4.1.2. (R)-(ꢀ)-1-Triethylsilyloxy-2-(2-triethylsilyloxy-3,3-dime-
thylbutoxy)-4-iodobenzene [(R)-3]. A stirred solution of bromo-
benzene (R)-2 (444 mg, 0.86 mmol) in dry THF (10 mL, ca. 0.1 M)
was cooled at ꢀ78 ꢁC, and treated dropwise with t-BuLi (1.7 M in
pentane, 1.06 mL, 1.8 mmol). The reaction mixture was stirred at
ꢀ78 ꢁC for 50 min, after which time a solution of I2 (436 mg,
1.72 mmol) in dry THF (3 mL) was added dropwise. The reaction
mixture was then allowed to warm to room temperature over 1 h,
and further stirred for 13 h before hydrolysis with saturated
aqueous NH4Cl (10 mL), followed by extraction with EtOAc
(3ꢂ20 mL). The combined organic layers were washed with brine
(20 mL), dried over MgSO4, filtered, and evaporated. The resulting
oily residue (456 mg) was purified by column chromatography,
4.2.1. 2R-tert-Butyl-9-iodo-1,4-dioxaspiro[4.(5R)]deca-7,9-dien-6-
one [(R,R)-4j]. Yellow oil (dr 90:10, quantitative crude yield),
which was identified as a 9:1 mixture of (R,R)-4j and (R,S)-5j: IR
(neat) 1686, 1093, 1002 cmꢀ1 1H NMR (CDCl3, 300 MHz)
; d 0.92
(s, 9H), 3.85 (dd, J¼6.4, 7.4 Hz, 1H), 4.25 (br t, J¼7.4 Hz, 1H), 4.34
(br t, J¼6.8 Hz, 1H), 5.75 (d, J¼10.0 Hz, 1H), 6.70 (d, J¼1.9 Hz,
1H), 6.96 (dd, J¼2.2, 10.1 Hz, 1H); 13C NMR (CDCl3, 75.5 MHz)
d
196.5, 147.3, 147.2, 145.0, 125.5, 98.9, 92.4, 85.3, 85.2, 66.5,
66.1, 33.0, 30.0, 25.9, 25.3; ESIMS m/z (rel intensity) 357 (MNaþ,
100), 230 (6); HRMS (ESI) calcd for C12H15INaO3 356.9958,
found 356.9971.
eluting with pure cyclohexane, to give the iodobenzene (R)-3 as
4.3. Monobenzylation of bergenin
20
a colorless oil (386 mg, 80%): [
a
]
ꢀ21.5 (c 1.07, CHCl3); IR (neat)
D
2956, 2912, 2876, 1496, 1457, 1124, 732, 463 cmꢀ1; 1H NMR (CDCl3,
300 MHz)
To a stirred solution of bergenin (10e, 300 mg, 0.915 mmol) in
dry DMF (12 mL) were added powdered NaHCO3 (154 mg,
1.83 mmol), benzyl chloride (116 mL, 0.915 mmol), and NaI as
d
0.63 (q, J¼7.7 Hz, 6H), 0.74 (q, J¼7.4 Hz, 6H), 0.91e1.00
(m, 27H), 3.69 (dd, J¼2.8, 5.9 Hz, 1H), 3.79 (dd, J¼5.9, 9.5 Hz, 1H),
3.96 (dd, J¼2.9, 9.5 Hz, 1H), 6.57 (d, J¼8.1 Hz, 1H), 7.08e7.12 (m,
a catalyst (30 mg). The resulting mixture was stirred at room
temperature for 48 h, after which time DMF was removed under
high vacuum. The oily residue was dissolved with EtOAc (50 mL)
and washed with brine (2ꢂ15 mL). The organic phase was dried
over Na2SO4, filtered, and evaporated. The resulting brown oil was
then submitted to column chromatography, eluting with CH2Cl2/
MeOH (40:1), to furnish a small amount of dibenzylated bergenin
14 (87 mg, 19%), a ca. 1:1 mixture of the two monobenzylated
compounds 10f and 10g (245 mg, 64%), and some recovered
starting material 10e (52 mg, 17%), which could be recycled. The
10f/10g mixture was separated by semi-preparative reverse phase
HPLC, which was performed on a Varian ProStar system equipped
2H); 13C NMR (CDCl3, 75.5 MHz)
d 151.5, 145.6, 129.9, 122.8, 122.0,
83.1, 78.8, 72.2, 34.9, 26.2, 7.0, 6.6, 5.1, 5.0; ESIMS m/z (rel intensity)
587 (MNaþ, 100); HRMS (ESI) calcd for C24H45INaO3Si2 587.1850,
found 587.1863.
4.1.3. (R)-(ꢀ)-2-(2-Hydroxy-3,3-dimethylbutoxy)-4-iodophenol [(R)-
1j]. To a stirred ice-cold solution of (R)-3 (375 g, 0.66 mmol) in THF
(20 mL, ca. 0.03 M) was added TBAF (1.0 M in THF, 1.46 mL,
1.46 mmol). The mixture was then allowed to warm to room tem-
perature, and was stirred for 30 min, after which time saturated
aqueous NaHCO3 (20 mL) was added, and the mixture was extrac-
ted with EtOAc (3ꢂ20 mL). The combined organic layers were then
washed with brine (20 mL), dried over MgSO4, filtered, and evap-
orated. The resulting oily residue (333 mg) was submitted to col-
umn chromatography, eluting with cyclohexane/acetone
with a Merck LichrospherÒ RP-18 column (250ꢂ25 mm I.D., 5
mm),
eluting with A/B (75:25) [solvent A¼H2O/HCO2H (99:1); solvent
B¼CH3CN/HCO2H (99:1)] at a flow rate of 16 mL/min. Column ef-
fluent was monitored by UV detection at 280 nm using a ProStar

L. Pouységu et al. / Tetrahedron 66 (2010) 5908e5917
5915
320 UV-visible detector [retention time¼16.5 min for 10f, and
19.5 min for 10g] (see the Supplementary data). Both pure 10f
(115 mg, 30%) and 10g (126 mg, 33%) were obtained as white
amorphous solids.
30 min. After discarding the solid IBA by-product by filtration, the
filtrate was evaporated. The resulting crude product was then ei-
ther directly submitted to column chromatography (when using
IBX), or, prior to purification, dissolved in EtOAc (50 mL), washed
with saturated aqueous NaHCO3 (15 mL) and brine (15 mL), dried
over MgSO4, filtered, and evaporated in order to remove the sta-
bilizing agents (when using SIBX).
4.3.1. (ꢀ)-2-
lic acid -lactone (14; 8,10-di-O-benzylbergenin). White amorphous
solid (19% yield after SiO2 column chromatography): mp
b-D-Glucopyranosyl-(8,10-di-O-benzyl-4-O-methyl)gal-
d
20
182e183 ꢁC; [
268 (2.42), 312 (2.35) nm; IR (neat) 3327, 2929, 1739, 1334, 1133,
1038 cmꢀ1 1H NMR [acetone-d6/D2O (9:1), 300 MHz]
3.45e3.49
a]
ꢀ68.7 (c 0.50, MeOH); UV (MeOH) lmax (log
e)
4.4.1. 4-Allylcatechol (12a). SiO2 column chromatography, eluting
with hexane/Et2O (1:2), furnished pure 12a as an orange syrup (67
or 77% yield using IBX or SIBX, respectively): IR (neat) 3369,
D
;
d
(m, 1H), 3.60 (br t, J¼9.2 Hz, 1H), 3.74e3.84 (m, 3H), 3.86 (s, 3H),
4.02 (br t, J¼9.8 Hz, 1H), 4.62 (d, J¼10.2 Hz, 1H), 5.02 (d, J¼11.5 Hz,
1H), 5.07 (d, J¼11.3 Hz, 1H), 5.20 (s, 2H), 7.30e7.49 (m, 11H); 13C
1618 cmꢀ1; 1H NMR (acetone-d6, 300 MHz)
d
3.22 (d, J¼6.8 Hz, 2H),
3.77e3.84 (m, 1H), 4.94e5.06 (m, 2H), 5.84e5.98 (m, 1H), 6.51 (dd,
J¼2.1, 8.1 Hz, 1H), 6.66e6.74 (m, 2H), 7.67 (br s, 1H); 13C NMR (ac-
NMR [acetone-d6/D2O (9:1), 75.5 MHz]
d
165.9, 153.7, 151.0, 150.3,
etone-d6, 75.5 MHz) d 145.8, 144.1, 139.2, 132.5, 120.6, 116.4, 116.0,
138.5, 137.7, 129.9, 129.7, 129.5, 129.4, 128.9, 128.4, 120.2, 112.8,
82.1, 81.5, 76.9, 75.4, 72.9, 72.0, 70.9, 62.1, 61.8; EIMS m/z (rel
intensity) 508 (Mþ, 1.8), 417 (1), 209 (1.6), 208 (1.3), 91 (100);
ESIMS m/z (rel intensity) 531 (MNaþ, 15), 509 (MHþ, 100), 508
(Mþ, 1.5); HRMS (ESI) calcd for C28H28NaO9 531.1631, found
531.1627.
115.2, 40.2; EIMS m/z (rel intensity) 150 (Mþ, 100), 149 (15),
123 (40).
4.4.2. 4-Hydroxy-3-methoxybenzaldehyde (12b; vanillin). SiO2 col-
umn chromatography, eluting with hexane/Et2O (1:2), afforded
pure vanillin 12b as a white solid (60 or 51% yield using IBX or SIBX,
respectively): mp 80e81 ꢁC (lit.8c 79e80 ꢁC); IR (neat) 3192,
4.3.2. (ꢀ)-2-
acid -lactone (10f; 10-O-benzylbergenin). White amorphous solid
(30% yield after SiO2 column chromatography, followed by semi-
b
-
D
-Glucopyranosyl-(10-O-benzyl-4-O-methyl)gallic
1669 cmꢀ1; 1H NMR (CDCl3, 300 MHz)
d 3.90 (s, 3H), 6.70 (br s, 1H),
d
7.00 (d, J¼8.5 Hz, 1H), 7.37e7.40 (m, 2H), 9.78 (s, 1H); 13C NMR
(CDCl3, 75.5 MHz)
d 191.0, 151.8, 147.2, 129.6, 127.4, 114.4, 108.8,
20
preparative HPLC): mp 203e204 ꢁC; [
UV (MeOH) lmax (log ) 267 (2.75), 309 (2.33) nm; IR (neat)
3381, 2942, 1713, 1341, 1097, 1024 cmꢀ1 1H NMR [acetone-d6/
D2O (9:1), 300 MHz]
a
]
ꢀ41.7 (c 0.50, MeOH);
55.9; EIMS m/z (rel intensity) 152 (Mþ, 64), 151 (76), 137 (5), 123
D
e
(12), 81 (100).
;
d
3.43e3.49 (m, 1H), 3.60 (br t, J¼9.2 Hz,
4.4.3. 3,4-Dihydroxybenzaldehyde (12c; protocatechualdehyde).
SiO2 column chromatography, eluting with cyclohexane/EtOAc
(5:1), gave pure protocatechualdehyde 12c as a pale yellow solid
(56 or 52% yield using IBX or SIBX, respectively): mp 153 ꢁC (lit.26
1H), 3.73e3.85 (m, 3H), 3.87 (s, 3H), 4.00 (br t, J¼9.9 Hz, 1H),
4.57 (d, J¼10.4 Hz, 1H), 5.04 (s, 2H), 7.30e7.46 (m, 6H); 13C NMR
[acetone-d6/D2O (9:1), 75.5 MHz]
d 166.0, 152.4, 150.9, 148.7,
138.6, 129.7, 129.6, 129.5, 126.4, 120.3, 115.3, 82.1, 81.6, 76.7, 75.4,
73.0, 70.9, 61.9, 61.8; EIMS m/z (rel intensity) 418 (Mþ, 4), 209
(3), 208 (7), 91 (100); ESIMS m/z (rel intensity) 419 (MHþ, 100);
HRMS (ESI) calcd for C21H22NaO9 441.1162, found 441.1147. Anal.
Calcd for C21H22O9: C, 60.28; H, 5.30; O, 34.42. Found: C, 60.41;
H, 5.41.
154 ꢁC); IR (neat) 3198, 1686 cmꢀ1
300 MHz)
8.69 (br s, 1H), 9.78 (s, 1H); 13C NMR (acetone-d6, 75.5 MHz)
;
1H NMR (acetone-d6,
d
3.01 (br s, 1H), 7.00 (d, J¼8.1 Hz, 1H), 7.33e7.36 (m, 2H),
d
191.1,
152.3, 146.5, 131.0, 125.4, 116.2, 115.2; EIMS m/z (rel intensity) 138
(Mþ, 84), 137 (100), 109 (40).
4.4.4. 3,4-Dihydroxyphenylethanol (12d; hydroxytyrosol). SiO2 col-
umn chromatography, eluting with cyclohexane/EtOAc (5:1), gave
pure hydroxytyrosol 12d as a colorless oil (16 or 42% yield using IBX
or SIBX, respectively): IR (neat) 3185, 2952 cmꢀ1; 1H NMR (acetone-
4.3.3. (ꢀ)-2-
-lactone (10g; 8-O-benzylbergenin). White amorphous solid (33%
yield after SiO2 column chromatography, followed by semi-pre-
b-D-Glucopyranosyl-(8-O-benzyl-4-O-methyl)gallic acid
d
20
parative HPLC): mp 193e194 ꢁC; [
(MeOH) lmax (log ) 275 (2.84), 312 (2.48) nm; IR (neat) 3371, 2930,
1681, 1209, 1144, 1031 cmꢀ1 1H NMR [acetone-d6/D2O (9:1),
300 MHz]
a
]
ꢀ36.3 (c 0.50, MeOH); UV
d6, 300 MHz)
d
2.65 (t, J¼7.1 Hz, 2H), 3.13 (br s, 1H), 3.67 (t, J¼7.1 Hz,
D
e
2H), 6.54 (dd, J¼1.9, 7.9 Hz, 1H), 6.69e6.72 (m, 2H), 7.67 (br s, 1H);
;
13C NMR (acetone-d6, 75.5 MHz)
d 145.6, 144.0, 131.9, 121.0, 116.8,
d
3.48 (br t, J¼9.1 Hz, 1H), 3.64e3.76 (m, 2H), 3.84 (s, 3H),
115.9, 64.2, 39.7; EIMS m/z (rel intensity) 154 (Mþ, 24), 123 (100),
3.89 (br t, J¼9.1 Hz, 1H), 4.06 (br t, J¼10.4 Hz, 1H), 4.09 (br t,
J¼10.0 Hz, 1H), 4.99 (d, J¼10.4 Hz, 1H), 5.15 (s, 2H), 7.21 (s, 1H),
7.26e7.57 (m, 5H); 13C NMR [acetone-d6/D2O (9:1), 75.5 MHz]
31 (80).
4.5. General procedure for the (S)IBX-mediated oxidative
O-demethylation8c of the bergenin derivatives 10eeg
d
165.4, 153.9, 149.8, 143.9, 138.1, 129.9, 129.5, 128.9, 119.5, 108.8,
83.1, 81.3, 75.4, 73.9, 72.0, 71.9, 62.7, 61.5; EIMS m/z (rel intensity)
418 (Mþ, 43), 208 (16), 91 (100); ESIMS m/z (rel intensity) 441
(MNaþ, 10), 419 (MHþ, 100), 408 (Mþ, 1); HRMS (ESI) calcd for
C21H22NaO9 441.1162, found 441.1144. Anal. Calcd for C21H22O9: C,
60.28; H, 5.30; O, 34.42. Found: C, 60.13; H, 5.41.
The reaction was conducted as described in the Section 4.4, but
in acetone/H2O (9:1) instead of THF. When IBX was used, degra-
dation of the starting material 10eeg was observed. When SIBX
was used, after stirring the solution in the dark at room temper-
ature for 24 h, a second portion of SIBX (1.02 equiv, ca. 0.50 equiv
of IBX) was added in order to complete the consumption of 10e, or
to optimize the conversion of 10f/g (see the Supplementary data).
After an additional period of time (24 h for 10e, and 4 h for 10f/g),
the resulting white suspension was treated according to the
general procedure (see the Section 4.4). In the case of bergenin
(10e), after evaporation of the filtrate, the resulting pale yellow
solid was successively washed with n-BuOH (10 mL) and acetone
(15 mL) to discard the stabilizing agents (i.e., isophthalic acid and
benzoic acid, respectively). The resulting crude norbergenin (12e)
was then purified by preparative gel chromatography on
4.4. General procedure for the (S)IBX-mediated oxidative
O-demethylation8c of the 2-methoxyphenols 10aed
To a stirred solution of 2-methoxyphenol 10aed (ca. 150 mg,
1.00 equiv) in dry THF (20 mL, ca. 0.05 M) was added IBX (1.1 equiv)
or SIBX (2.2 equiv) in one portion. The reaction mixture became
immediately bright yellow, and the resulting suspension was stir-
red vigorously at room temperature in the dark for ca. 16e24 h,
after which time it was treated with an aqueous solution (2 mL) of
Na2S2O4 (3.0 equiv) and further vigorously stirred in the dark for

5916
L. Pouységu et al. / Tetrahedron 66 (2010) 5908e5917
SephadexÒ LH-20 (ca. 15 g), packing with pure MeOH and eluting
with pure H2O (ca. 100 mL) followed by H2O/MeOH (1:1, ca.
50 mL) and pure MeOH (ca. 150 mL), to afford pure norbergenin
(12e). In the case of the monobenzylated bergenins 10f/g, after
evaporation of the filtrate, the resulting solid mixture was sepa-
rated by semi-preparative reverse phase HPLC, which was per-
formed on a Varian ProStar system equipped with a Merck
well as the CDCH-Universidad Central de Venezuela for permitting
our colleague Prof. J.C. to join our group in 2006-2007.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.05.078.
LichrospherÒ RP-18 column (250ꢂ25 mm I.D., 5
mm), eluting with
A/B (75:25) [solvent A¼H2O/HCO2H (99:1); solvent B¼CH3CN/
HCO2H (99:1)] at a flow rate of 16 mL/min. Column effluent was
monitored by UV detection at 280 nm using a ProStar 320 UV-
visible detector, and pure catechols 12f and 12g were isolated,
respectively [retention time¼14.2 min for 12f, and 16.9 min for
12g] (see the Supplementary data).
References and notes
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Hypervalent Iodine in Organic Chemistry: Chemical Transformations; Wiley-In-
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4.5.1. (ꢀ)-2-
b
-
D
-Glucopyranosyl-gallic
acid
d
-lactone
(12e;
norbergenin). Beige amorphous solid (69% yield afterpurification on
20
SephadexÒ LH-20): mp 248e249 ꢁC (lit.22b 250 ꢁC); [
a]
ꢀ23.3 (c
D
0.30, MeOH) [lit.22a
[
a]
ꢀ22.0 (c 1.00, EtOH)]; UV (MeOH) lmax
18
D
(log
e
) 288 (2.08) nm; IR (neat) 3383, 2924, 1700, 1319, 1238,
1087 cmꢀ1
;
1H NMR [acetone-d6/D2O (9:1), 300 MHz]
d
3.48 (br t,
J¼9.2 Hz,1H), 3.65e3.79 (m, 2H), 3.89 (br t, J¼9.1 Hz,1H), 4.02e4.09
(m, 2H), 4.98 (d, J¼10.6 Hz, 1H), 7.09 (s, 1H); 13C NMR [acetone-d6/
D2O (9:1), 75.5 MHz]
d 166.2, 147.1, 143.6, 141.1, 117.5, 114.5, 111.1,
82.8, 81.3, 75.3, 74.1, 71.8, 62.6; EIMS m/z (rel intensity) 314 (Mþ, 32),
195 (35),194 (100); ESIMS m/z (rel intensity) 315 (MHþ,100); HRMS
(ESI) calcd for C13H14NaO9 337.0536, found 337.0540.
4.5.2. (ꢀ)-2-
b-D-Glucopyranosyl-10-O-benzyl-gallic acid d-lactone
(12f; 10-O-benzylnorbergenin). White amorphous solid (20% yield
20
after HPLC purification): mp 208e209 ꢁC; [
MeOH); UV (MeOH) lmax (log ) 247 (2.47), 270 (2.27) nm; IR
(neat) 3366, 2926, 1710, 1335, 1223, 1091 cmꢀ1; 1H NMR [acetone-
d6/D2O (9:1), 300 MHz]
1H), 3.68e3.83 (m, 3H), 3.96 (br t, J¼9.8 Hz, 1H), 4.50 (d,
J¼10.2 Hz, 1H), 5.03 (d, J¼11.3 Hz, 1H), 5.09 (d, J¼11.3 Hz, 1H),
7.29e7.46 (m, 6H); 13C NMR [acetone-d6/D2O (9:1), 75.5 MHz]
a
]
ꢀ32.4 (c 0.50,
D
e
d
3.43e3.46 (m, 1H), 3.58 (br t, J¼9.1 Hz,
5. (a) Richardson, R. D.; Wirth, T. Angew. Chem., Int. Ed. 2006, 45, 4402e4404; (b)
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d
166.6, 147.4, 146.9, 144.6, 138.6, 130.0, 129.6, 129.5, 126.7, 115.3,
114.3, 82.2, 81.5, 75.9, 75.5, 73.2, 71.1, 62.0; ESIMS m/z (rel in-
tensity) 405 (MHþ, 100); HRMS (ESI) calcd for C20H20NaO9
427.1005, found 427.0989.
4.5.3. (ꢀ)-2-
b
-D-Glucopyranosyl-8-O-benzyl-gallic acid
d-lactone
(12g; 8-O-benzylnorbergenin). White amorphous solid (21% yield
20
after HPLC purification): mp 197e198 ꢁC; [
MeOH); UV (MeOH) lmax (log ) 248 (2.42), 276 (2.27) nm; IR (neat)
3382, 2926, 1699, 1327, 1092 cmꢀ1; 1H NMR [acetone-d6/D2O (9:1),
300 MHz]
a
]
ꢀ27.9 (c 0.50,
D
e
d
3.48 (br t, J¼9.1 Hz, 1H), 3.65e3.78 (m, 2H), 3.89 (br t,
J¼8.9 Hz, 1H), 4.01e4.09 (m, 2H), 4.99 (d, J¼10.4 Hz, 1H), 5.19 (s,
2H), 7.20 (s,1H), 7.29e7.48 (m, 5H); 13C NMR [acetone-d6/D2O (9:1),
75.5 MHz]
d 166.0, 148.3, 143.6, 142.6, 138.1, 129.8, 129.4, 128.9,
119.4, 114.2, 109.3, 82.8, 81.1, 75.2, 73.9, 71.9, 71.7, 62.5; ESIMS m/z
(rel intensity) 427 (MNaþ, 9), 405 (MHþ, 100); HRMS (ESI) calcd for
C20H20NaO9 427.1005, found 427.0992.
Acknowledgements
We thank the Institut Universitaire de France (IUF), the Minis-
tère de la Recherche, and the CNRS (ATIP ‘Jeunes Chercheurs’
2005e2007) for financial support. We gratefully acknowledge
Simafex for providing us with DIB and SIBX reagents. We also thank
the Ministère de l’Enseignement Supérieur et de la Recherche Sci-
entifique (MESRS) de Côte d’Ivoire, the Ministère de la Recherche
and the Venezuelian FONACIT foundation for Tahiri Sylla’s (Grant
No. 836/MESRS/DB/SD-BHCI), Tony Garnier’s and Luis B. Rojas’
(Grant No. 1220/OC-VE) research assistantships, respectively, as
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L. Pouységu et al. / Tetrahedron 66 (2010) 5908e5917
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€
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