'Aromatic ring umpolung', a rapid access to the main core of several natural products

Article abstract of DOI:10.1016/j.tet.2010.03.096

Treatment of various substituted phenols in the presence of (diacetoxyiodo)benzene promotes the formation of a phenoxenium ion, a very electrophilic species able to react with various nucleophiles leading rapidly to a plethora of different cores present i

Full text of DOI:10.1016/j.tet.2010.03.096

Tetrahedron 66 (2010) 5893e5901
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‘Aromatic ring umpolung’, a rapid access to the main core of several natural
products
*
Kimiaka C. Guérard, Cyrille Sabot, Marc-André Beaulieu, Marc-André Giroux, Sylvain Canesi
Laboratoire de Méthodologie et Synthèse de Produits Naturels, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, H3C 3P8 Québec, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of various substituted phenols in the presence of (diacetoxyiodo)benzene promotes the for-
mation of a phenoxenium ion, a very electrophilic species able to react with various nucleophiles leading
rapidly to a plethora of different cores present in natural products via several novel oxidative processes.
This strategy fits within the concept of ‘aromatic ring umpolung’; in this paper a personal account by our
laboratory on this thematic is described.
Received 13 February 2010
Accepted 25 March 2010
Available online 8 April 2010
This paper is dedicated to Pr. Marco Ciufolini
on the occasion of his birthday and for all
his noteworthy contributions in the area of
total synthesis
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
If one considers the behavior of the species 3, this reversal of
reactivity may thus be thought of as involving ‘aromatic ring
The umpolung concept or polarity inversion of functional
groups is a well known concept, very used in organic trans-
formation that allows extending chemical possibilities to produce
important structures rapidly. This concept has been first introduced
by Corey and Seebach.1 An extension of this concept to the aromatic
chemistry would provide new strategic opportunities in synthetic
chemistry, by extension of several well known reactions in aliphatic
chemistry to the aromatic chemistry. To accomplish such trans-
positions, the well known electrophilic substitution of aromatic
compounds has to be considered. Indeed, during this important
transformation, electron rich nucleus, such as phenol or aniline
derivatives normally react as a nucleophile; suitable oxidative
activation can convert it into a reactive electrophilic intermediate 3,
which may be intercepted with appropriate nucleophiles (Fig. 1).
umpolung’. If several oxidising agent may be used as demonstrated
first by Kita,2 a hypervalent iodine reagent,3 such as (diacetoxyiodo)
benzene (DIB), was found to be the reagent of choice to promote
rapidly the formation of the phenoxenium ion 3. Such hypervalent
iodine complexes are very used in synthesis4,5 due to their versa-
tility. Indeed, they are considered as environmentally benign and
inexpensive reagents able to substitute heavy metal agents. This
process is best performed in perfluorinated alcohols, such as tri-
fluoroethanol (TFE) or hexafluoroisopropanol (HFIP). On the basis
of this concept, two reactions may be in competition: aromatic
substitution (pathway a) versus oxidative addition (pathway b),
Figure 2.
O
OH
O
OH
Nu
Nu
a
[ O ]
+
b
4
5
OH
1
R
Nu
OH
3
R
R
R
E
2
1
R
Figure 2.
R
E
In bimolecular processes, it has been demonstrated that the
regioselectivity depends on the nucleophiles involved. Indeed, with
heteronucleophiles the pathway b, leading to a dienone core, is
observed, resulting from the attack of the unhindered heteroatom
on the stronger contributor mesomer form to the overall
delocalized system, the tertiary carbocation. However, with more
hindered carbon-based nucleophiles, the pathway a is preferred,
leading to a more substituted aromatic compound 4. Following the
behavior of the nucleophile used, radically different cores are
OH
Nu
oxidative
activation
O
Nu
4
("umpoled
reactivity")
("umpolung")
R
3
R
Figure 1.
* Corresponding author. Tel.: þ1 514 987 3000x5013; fax: þ1 514 987 4054;
e-mail address: canesi.sylvain@uqam.ca (S. Canesi).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.096

5894
K.C. Guérard et al. / Tetrahedron 66 (2010) 5893e5901
obtained. This observation demonstrates the importance of the
species 3 in chemical synthesis. It should be noted that such
intermediate is usually involved in the biosynthesis of several
natural products,6 demonstrating that the aromatic ring umpolung
chemistry is an important concept. This paper is described as
a personal account of our laboratory focusing on the capture of such
intermediates with carbon-based nucleophiles, leading to the
formation of new CeC bonds and the direct application of these
methodologies as key steps in the total synthesis of several natural
products.
As a first application of this methodology, a total synthesis of
panacene has been rapidly accomplished.11 This compound was
isolated in 1977 by Meinwald and co-workers from Aplysia brasi-
liana,9a a sea hare indigenous to the gulf coast of Florida. Panacene
has shark antifeedant properties, and it is thus believed to protect
the sea hare from predatory fish. The unusual architecture of 8 has
elicited substantial interest in the synthetic arena. This has led to
total syntheses of the racemate, and of the natural (ꢀ)-form. Our
approach starts with inexpensive 3-ethyl phenol 10. This material
may be directly converted into a mixture (1:1.3) of 11 and 12 in 46%
yield using the oxidative cycloaddition process in presence of furan.
Despite the fact that these compounds are separable at the next
step, a more selective route evolves from derivative 15, which is
readily accessed from 10 in three steps. The TMS group blocks
position 6 of the phenol and forces the subsequent oxidative
annulation sequence to occur exclusively at position 2. Thus, the
core of panacene is assembled in a single step. It is worthy of note
that the silyl substituent survives the DIB oxidation step largely
unscathed. Indeed, the desired cycloadduct 16 was accompanied by
only a small amount (w5%) of 11 and 12, which clearly arise
through partial loss of the TMS group during the reaction. Without
separation, this crude mixture was treated with TBAF and CsF in
DMF to induce desilylation, Scheme 2.
2. Formal cycloaddition with furan
Interestingly, the use of furan, a weak aromatic system, in
presence of the species 3, leads to tricyclic compounds 7 resulting
from a formal oxidative [2þ3] cycloaddition process7 (Scheme 1).
The reaction, in this case, is best carried out in TFE as solvent
instead of HFIP, which has been observed to be too acidic for the
very unusual dihydrofurobenzofuran core 7 produced.8 The selec-
tivity observed results from the attack of the nucleophilic position 2
of the furan moiety in ortho position of the electrophilic species.
The Wheland like intermediate 6 generated is subsequently trap-
ped by the oxygen atom to afford compound 7, Scheme 1.
OH
O
Et
Et
O
O
H
O
PhI(OAc)2
PhI(OAc)2
O
H
1 : 1.3
+
- H
O
TFE, Furan
10
H
R
O
O
46%
H
Et
O
OH
H
(+/-)
6
7
1
R
R
12
11
PPTS, DHP,
99%
Scheme 1.
Et
Et
CAN, 0°C
In this process, one aromatic system reacts as a nucleophile and
the other one as an electrophile. Only unactivated sp2 carbon
interactions occur between the ortho position of compound 1 and
n-BuLi, THF
14
13
-78 °C, 40 min
CH3CN / H2O
then TMSCl
94%
OTHP
SiMe3
76%
OTHP
position 2 of furan. Most probably secondary
p staking interactions
Et
are present during the transition state. To verify the scope of this
novel reaction, various substituted phenols were converted to 7 in
38e61% yield. A summary of representative experiments with
para-substituted phenols appears in Table 1.
Et
R
O
H
PhI(OAc)2
TFE, Furan
15
TBAF / CsF
16 : R = TMS
11: R = H
DMF, 100 °C
44% over 2 steps
H
OH
O
SiMe3
Table 1
Scheme 2.
[2þ3] cycloaddition process with furan
O
To complete the synthesis of panacene, an oxymercuration
reaction carried out on key compound 11, followed by treatment
with sodium borohydride, affords 17. To illustrate the synthetic
potential of the oxidative annulation process, it should be noted
that compound 17, easily obtained directly in two steps from
3-ethyl phenol 10, is an advanced intermediate previously syn-
thesized in nine steps during the unique asymmetric total synthesis
of (ꢀ)-panacene.9e To achieve the diastereoselective total synthesis,
a ring opening/ring closing strategy has been used. Indeed,
compound 17 is treated with the corresponding Wittig reagent 18
to yield 19 with a great selectivity (9:1) in favor of the trans isomer,
easily separable by flash chromatography. Deprotection of the TMS
group with TBAF affords 20 and a treatment of this latter in pres-
ence of TBCD (tetrabromo-cyclohexadienone)12 in apolar solvents,
such as benzene or cyclohexane leads to a high diastereoselective
synthesis of the unnatural epipanacene 21 Scheme 3.
(+/-)
O
PhI(OAc)2
TFE
R
OH
+
R
1
O
7
Entry
R
Yield (%)
a
b
c
d
e
f
t-Bu
Me
OMe
61
38
41
52
47
59
CH2COOMe
CH2CH2NHTs
SiMe3
The ring system 7 produced by this oxidative cycloaddition
process leads to a main tricyclic core present in some natural
products, such as panacene9 8 and psorofebrin 9, an antileukemic
xanthone,10 Figure 3.
The diastereoselectivity observed has been obtained by a treat-
ment of the free enyne 20 with a brominating agent in an apolar
solvent. To invert the selectivity observed, we have envisaged to
introduce first the bromine on the enyne segment and to treat it
with a protonating agent. The selectivity observed in such solvent
could be explained by an intramolecular hydrogen bond between
the hydroxyl group and the cyclo-ether favoring one conformer
during the transition state. The TMS group on compound 19 was
O
OH
H
H
OH
H
O
O
H
O
R
O
O
O
O
H
H
H
Br
9
7
8
OMe
Figure 3.

K.C. Guérard et al. / Tetrahedron 66 (2010) 5893e5901
5895
Et
18
In order to add different carbon-based nucleophiles on the de-
sired para position, the ortho positions have been blocked with
a bulky tert-butyl group. In addition, a unique example of such an
outstanding transformation has been demonstrated by the trans-
formation of 4-methyl-2,6-di-tert-butylphenol into 4-methyl-4-
phenylcyclohexa-2,5-dienone upon treatment with chlorodi-
Ph3P
OH
O
H
Hg(OAc)2, H2O
SiMe3
11
NaBH4, NaOH
78%
17
O
75%
H
R
H
H
Et
O
Et
H
TBCD, 81%
OH
H
21
phenyl-
l
3-iodane (Ph2ICl) by Quideau and Ozanne-Beaudenon.4c
Benzene or
cyclohexane
19 : R = TMS
20: R = H
TBAF
97%
Br
O
H
With polysubstituted phenols 24a, the oxidation process in pres-
ence of furan leads in high yield to the desired dienones 27, via an
oxidative FriedeleCrafts process,13 Scheme 5.
H
O
H
Scheme 3.
t-Bu
HO
t-Bu
t-Bu
substituted by treatment with silver nitrate and NBS to yield 22.
The latter, treated by mercury acetate in benzene, leads to the
corresponding mercuric compound 23, which was demercurated in
situ, with retention of allene configuration, upon contact with
O
PhI(OAc)2
furan, 87%
O
Me
Me
27
24a
t-Bu
ethanedithiol leading to
a
fully stereoselective synthesis of
Scheme 5.
(ꢁ)-panacene 8, Scheme 4.
Moreover, this reaction may be extended to anisole derivatives,
a quite electron rich system sufficiently nucleophilic to react with
species 25 in good yield. To avoid a potential addition of acetic acid
released during the process, DIB has been substituted by phenyl-
iodine bis-trifluoracetate (PIFA). Indeed, the trifluoroacetic acid
generated during this process is a stronger acid but a weaker
nucleophile than acetic acid. A summary of representative experi-
ments with para-substituted phenols appears in Table 2.
R
H
H
Et
O
H
Hg(OAc)2
benzene
HS
75%
SH
Et
OH
H
8
O
H
19 R = SiMe3
22 R = Br
HgOAc
Br
O
AgNO3,
NBS, 96%
H
23
Scheme 4.
Using this novel oxidative [2þ3] cycloaddition process, a concise
and fully diastereoselective synthesis of panacene was accom-
plished. One may thus reach panacene in an unprecedented five
steps from inexpensive 3-ethyl phenol. Finally, a novel highly
stereoselective oxymercuration-demercuration process has been
devised for the construction of the bromoallene segment of
panacene. This concise synthesis demonstrates the potential of
‘aromatic ring umpolung’ as a powerful tool for the development
of novel methodologies and its application to the rapid synthesis of
natural product.
Table 2
Oxidative addition with di-tert-butylphenols
t-Bu
HO
t-Bu
OMe
X
PIFA, HFIP
MeO
t-Bu
R
O
R
24
29
28
t-Bu
X
Entry
R
X
Yield (%)
a
b
c
d
e
Me
Me
Et
Bu
Me
H
Br
H
H
OMe
80
82
70
73
64
3. Oxidative addition of carbon-based nucleophiles
Normally, carbon-based nucleophiles react at the ortho position
on the electrophile species 3 (pathway a). However, it has been
demonstrated, during the total synthesis of panacene, that some
protecting groups could block these positions and force the
nucleophile to interact at the desired position in a bimolecular
mode. This process would allow controlling the oxidative addition
versus the aromatic substitution that would open up novel
opportunities in the field of chemical synthesis. Indeed, aromatic
compounds have several insaturations, but due to their stability,
few transformations are allowed. However, a mild desaromatising
process, including a CeC bond formation, would produce rapidly
a highly functionalized core containing a quaternary carbon center
and a prochiral dienone system. The use of the remaining insatu-
rations generated could lead to the concise syntheses of several
natural products, Figure 4.
If polysubstituted phenols such as alkyl-di-tert-butyl-phenols
are useful for exploring the scope of such reaction, they are
actually of low potential as starting materials for the total syn-
thesis of natural products. Consequently, in order to move away
from tert-butyl groups, we have investigated easily removable
protecting groups capable of blocking selected positions on the
aromatic ring. The choice of directing groups has to achieve two
possible results: a steric effect similar to that of a tert-butyl, e.g.,
trimethysilyl; or an inductive effect such as that induced by an
electronegative halide. An interesting choice would be the ha-
lides, which can be efficiently introduced onto an aromatic ring
and are convenient handles to generate CeC bonds by means of
palladium chemistry. This synthetic strategy could be useful for
the total synthesis of
a number of natural products. Un-
Pg
Pg
Pg
fortunately, oxidation of 2-6-di-bromo cresol led to inextricable
by-products. A plausible explanation is that the two electron-
withdrawing atoms provide excessive destabilisation of the
generated electrophilic species 25, which rapidly decomposes. In
order to avoid this pitfall, we studied the combination of a halide
and a TMS group as substituents. In this case, the umpoled
intermediate is sufficiently stable to afford the desired
compounds. These compounds are easily obtained from the
corresponding di-bromophenols by a retro-brook reaction on the
corresponding O-TMS-dibromo-phenol,14 as demonstrated with
compound 30, Scheme 6.
R
PhI(OAc)2
Nu
O
R
O
R
OH
Nu
Pg
Pg
24
Pg
25
26
O-Alkylation
O
Addition
OH
R
[Ox]
Nu
Alkylation
Addition
Quaternary
center
C-Alkylation
5
Nu
R
1
prochiral compound
Figure 4.

5896
Br
K.C. Guérard et al. / Tetrahedron 66 (2010) 5893e5901
Br
O2S
MeN
NO2
TMS
TMSO
MsO
1. HMDS, THF
TMS
HO
(p-Ns)NHMe, NaH
DMF, 88%
HO
Et
30
Et
31
HO
2. BuLi, -78°C
86% overall
Me3Si
Br
38
31g
Br
Br
Scheme 6.
X
OMe
PhI(OAc)2, veratrole
HFIP, 18%
Br
O
However, such protected phenols are not compatible with an
oxidant like PIFA, probably due to the high acidity generated in the
medium, and in such cases, DIB has to be used despite the presence
of a small amount of a by-product resulting from the addition of
acetic acid on the electrophilic species (w15%). In order to evaluate
the scope of this reaction, different moderately nucleophilic func-
tionalities were introduced on the side chain and different
substituted anisoles were used. Numerous spectator functionali-
ties, such as alcohols, sulfonamides, and alkenes are compatible
40, X = H
41, X = OMe
or
PhI(OAc)2, anisole
HFIP, 42%
p-Ns
Me3Si
N
Me
Scheme 7.
From these key compounds the main bicyclic core of these
natural products were efficiently accomplished via a treatment of
compounds 40 or 41 with K2CO3 and thiophenol (Fukuyama’s
conditions). This novel transformation, occurring in good yield (71%
yield), takes place via six successive distinct steps: (1) a nucleo-
philic aromatic substitution (SNAr) deprotection leads to the
corresponding free amine; (2) the free amine reacts via a Michael
process to afford the bicyclic compound 42; (3) desylilation
followed by (4) addition of thiophenol leads to compound 43; (5)
substitution of the bromide by an SN2 process occurs to generate
44; (6) a final retro-Michael reaction produces 45 (X¼H) or 46
(X¼OMe). This method may be assimilated to a Fukuyama and
Michael-retro-Michael tandem process, Scheme 8.
with the reaction conditions.
experiments appears in Table 3.
A
summary of representative
Table 3
Oxidative addition with anisole derivatives
R1
OMe
R1
DIB, HFIP
R
HO
X
MeO
32
O
R
Y
Me3Si
31
33
Me3Si
X
Y
Entry
R
R1
X
Y
Yield (%)
X
X
OMe
a
b
c
d
e
f
CH2CH2OTBDPS
CH2CH2OTBDPS
CH2CH2OTBDPS
CH2CH3
CH2CH]CH2
CH2CH2OMs
CH2CH2NMeNs
CH2CH3
Br
Ci
Ci
Br
Br
Br
Br
Br
H
H
H
H
H
H
I
H
H
Br
H
H
Br
H
H
37
38
52
43
42
41
44
37
OMe
Br
PhS
O
K2CO3, PhSH
CH3CN, 71%
O
N
p-Ns
45, X = H
Me3Si
40, X = H
Me
N
46, X = OMe
41, X = OMe
Me
g
h
OMe
X
OMe
X
X
OMe
OMe
SPh
Br
O
SPh
Br
PhS
O
Despite the modest yields observed with such protecting
groups, it should be noted that the starting material used is easily
obtained and leads, in only one step, to a highly functionalised core
containing a quaternary carbon center connected to three sp2
carbons; the formation of such a structure using usual chemistry
could be more problematic. In addition, the skeletons afforded are
present in numerous natural products, such as the family of
Amaryllidaceae alkaloids,15 Figure 5.
O
44
N
43
Me3Si
N
N
42
Me
Me
Me
Scheme 8.
Total syntheses of mesembrine and 4,5-dihydro-40-O-methyl-
sceletenone were completed by treatment of compounds 45 and 46
with Raney Nickel in ethanol to reduce the alkene and remove the
thio-ether, forming the desired natural product in 86% yield,
Scheme 9.
OMe
OMe
OH
34
35
X
X
X
O
O
O
OMe
OMe
O
H
36: X = OMe
37: X = H
N
PhS
O
Ni (Ra)
N
Me2N
Me
O
EtOH, 86%
47: X = H
48: X = OMe
45, X = H
Figure 5.
46, X = OMe
N
N
Me
Me
As a first illustration of the potential of this method, total syn-
Scheme 9.
theses of molecules belonging to this family has been accom-
plished, such as mesembrine 36,16 isolated from Sceletium
tortuosum and the 4,5-dihydro-40-O-methylsceletenone 37,17
a simpler natural derivative isolated from a. cordifolia. These alka-
loids have been shown to be very potent serotonin reuptake
inhibitors. Compound 38 was easily obtained from the available
2-(4-hydroxyphenyl)ethanol using conventional chemistry.13 In
order to introduce the necessary nitrogen moiety, an SN2 reaction
was performed between 38 and the corresponding anion of
N-methyl-para-nosylamide in 88% yield; Compound 31g, when
treated with anisole or veratrole in oxidative conditions, led to the
corresponding dienone 40 and 41 in modest to low yield, Scheme 7.
This bimolecular oxidative process occurring to the CeC bond
formation has been extended to allylsilanes. In this purpose,
different 4-alkyl-2-6-di-tert-butyl phenols 24 were successfully
oxidised leading to an oxidative variant of the famous Hosomi/
Sakurai allylation.18 This approach has already been efficiently used
in an intramolecular process as a key step in the synthesis of
platensimycin by Nicolaou19 and co-workers. Moreover, a first
approach to this reaction was developed by Quideau and co-
workers in aprotic solvents with PIFA, which has provided some
noteworthy examples of oxidative allylation on substituted
1-naphthol.5c By generalizing this reaction to different aromatic

K.C. Guérard et al. / Tetrahedron 66 (2010) 5893e5901
5897
compounds in a bimolecular process, we would introduce novel
opportunities in the field of chemical synthesis. A summary of
representative experiments appears in Table 4.
a key intermediate 56, first described by Stork and Dolfini.22
Since then, many other syntheses or formal syntheses have been
reported, Figure 6.
Table 4
N
H
54 R1 = R2 = H
Oxidative addition with allylsilane
N
aspidospemidine
H
OH
R
O
O
PhI(OAc)2
TFE
55 R1 = OMe and R2
Ac aspidospermine
=
N
R1
56
t-Bu
t-Bu
t-Bu
t-Bu
H
R2
SiMe3
Figure 6.
24
49
R
This synthesis is based on the synthesis of compound 53f,
obtained via the oxidative Hosomi-Sakurai process in 56% yield,
then a hydroboration reaction, producing alcohol 57 in 72% yield.
The latter is activated with mesyl chloride to generate compound
58 in 97% yield. At this point the nitrogen moiety is efficiently
introduced by a SN2 reaction between 58 and the corresponding
anion of 59 to afford the sulfonamide 60 in 89% yield, Scheme 10.
Entry
R
Yield (%)
a
b
c
d
e
f
Me
n-Pen
i-Pr
CH2CH2OH
CH2OTBDMS
CH2CH2NHTs
CH2CO2Me
84
79
74
71
81
61
70
g
OR
SiMe3
9-BBN, THF
57 R = H
58: R = Ms
MsCl, Lutidine
CH2Cl2, 97%
53f
Different removable protecting groups have been tried, such as
a trimethylsilyl group, a motif quite similar to tert-butyl with the
advantage of being easily removed. Consequently, different di-TMS-
phenols 50 have been treated under the oxidative conditions.
A summary of representative experiments appears in Table 5.
O
then H2O2,
K2CO3, 72%
Br
TBDMSO
N
TBDMSO
Ns
NaH, DMF,
30 min, rt
Me3Si
NH
S
O
O
O2N
then 58, 12 h,
O
Table 5
65°C, 89%
60
59
Br
Oxidative addition with di-TMS-phenols
Scheme 10.
OH
R
O
PhI(OAc)2
TFE
SiMe3
Me3Si
SiMe3
Me3Si
This product contains protected secondary amine and alcohol
that represent a good precursor of the main tricyclic core of
aspidospermidine. Indeed, the elaboration of the main tricyclic core
has been produced using the Fukuyama and Michael tandem
process, developed previously for the synthesis of mesembrine.
This transformation, occurring in 85% yield, takes place via four
successive distinct steps: (1) nucleophilic aromatic substitution
(SNAr) deprotection leads to the corresponding free amine 61; (2)
addition of thiophenol leads to compound 62; (3) substitution of
the bromide by an SN2 process generates 63; and (4) a final retro-
Michael reaction produces 64, Scheme 11.
SiMe3
50
51
R
Entry
R
Yield (%)
a
b
c
d
e
Me
Et
i-Pr
Ph
52
46
34
37
41
CH2CH2OH
Unfortunately, yields observed with TMS groups are lower than
yields observed with tert-butyl groups. While the oxidation of
di-bromo-phenols is not efficient, a combination of halogen and
tert-butyl or trimethylsilyl groups affords the desired core 53 in
useful yields, Table 6.
TBDMSO
Me3Si
TBDMSO
Me3Si
N
N
H
Ns
K2CO3, PhSH
CH3CN, 12 h
rt, 85%
O
O
64
60
Br
SPh
Table 6
Oxidative addition with mixed protecting groups
O
OH
R
TBDMSO
TBDMSO
Me3Si
PhI(OAc)2
HFIP
TBDMSO
R1
R2
R2
N
H
R1
N
H
N
H
Me3Si
Me3Si
SiMe3
52
53
R
O
O
62
SPh
SPh
O
61
63
SPh
Br
Br
Entry
R
R1
R2
Yield (%)
Scheme 11.
a
b
c
d
e
f
Me
Cl
Br
I
Br
Br
Br
Br
t-Bu
t-Bu
t-Bu
t-Bu
TMS
TMS
TMS
65
51
45
42
53
56
52
Me
Me
i-Pr
Me
Et
At this point, we were surprised not to observe the addition of
the free amine on the dienone, but a treatment of compound 64
with TBAF produces the free alcohol and bicyclic ring 67 in 87%
yield. Once again, different transformations occurred in the same
pot: (1) desilylation of the TBDMS moiety produces 65; (2) the free
amine reacts via a Michael process to afford the bicyclic compound
66; (3) desilylation of the TMS group occurs to produce 67. The
cyclisation occurring at this point could be explained if we consider
that the free alcohol generated first is able to protonate the enolate
resulting from the 1e4 addition and could move the reaction
equilibrium in favor of the bicyclic core, Scheme 12.
g
n-Bu
As a first application of this oxidative allylation, a total synthesis
of aspidospermidine has been accomplished.20 The complex
architecture and biological activities of this product21 have elicited
substantial interest in the synthetic arena. The usual strategy used
to produce this compound is generally based on the formation of

5898
K.C. Guérard et al. / Tetrahedron 66 (2010) 5893e5901
TBDMSO
reasonable to extend such transpositions known in aliphatic chemi-
stry to the aromatic chemistry via an oxidative process,24 Figure 7.
HO
N
H
N
TBAF, THF
rt, 5 h, 87%
Me3Si
R1
R3
R1
R3
R1
R3
O
O
[ O ]
O
R2
OH
R2
O
3
64
67
SPh
SPh
N
R2
1
73
Figure 7.
HO
HO
Me3Si
N
H
Me3Si
In this purpose, corresponding phenol 74 has been synthesised
to produce, via a kind of oxidative pinacolic transposition, skele-
tons, such as 75. This novel process occurs in an intramolecular way
that does not require the blocking of ortho positions with appro-
priated protecting groups. Compound 74 is easily obtained in high
yield by addition of an excess of allyl Grignard on the corresponding
4-hydroxyphenones. To exemplify this transformation, phenols
containing different alkyl and aryl groups have been oxidised.
A summary of representative experiments appears in Table 7.
O
O
65
66
SPh
SPh
Scheme 12.
The action of mesyl chloride on compound 67 results in the
formation of the corresponding chloride 69 in 79% yield, probably
via the formation of the intermediate aziridinium 68. Treatment of
69 with a base, such as potassium tert-butoxide leads to the desired
tricyclic compound 70 in 84% yield. At this point, treatment of 70
with Raney Nickel in ethanol produces 56 in 85% yield. This
sequence of reactions, including a Fukuyama and Michael tandem
process, offers an efficient access to key intermediate 56, known as
formal synthesis of aspidospermine, aspidospermidine and
quebrachamine,21m Scheme 13.
Table 7
Oxidative transposition process
R2
R2
PhI(OAc)2
R1
OH
O
R1
HO
HFIP, 0°C
2 min
75
O
74
R
R
Cl
Entry
R
R1
R2
Yield (%)
HO
Cl
N
N
N
a
b
c
d
e
f
H
H
Me
H
Me
H
Me
CH2CH]CH2
CH2CH]CH2
CH2CH]CH2
Ph
62
67
63
51
34
34
41
35
MsCl, NEt3
CH2Cl2, 2 h
rt, 79%
CH2CH]CH2
O
O
O
Me
Me
Me
Me
n-Bu
Me
68
PhS
PhS
PhS
67
69
Ph
CH¼CH2
N
g
h
H
H
n-Bu
70
N
t-BuOK,
56
Ni(ra), EtOH
1 h, rt, 85%
n-Bu
THF, 12 h
rt, 84%
O
O
PhS
As expected, during the oxidation of compound 74h the migra-
tion of the n-butyl group is very predominant; only a small amount
of methyl migration is observed (w5%). This oxidative process seems
to occur as a regular rearrangement applicable to a large scope of
aryl, allyl, and alkyl groups. Indeed, the same rules as the ones
applying to a conventional Wagner/Meerwein transposition are
observed. This process seems lesseffectivewith alkyl groups (entries
74g and 74h) probably due to the migration of a sigma bond by
Scheme 13.
To complete the total synthesis, the known tricycle 56,22 is
converted to aspidospermidine via a Fischer indole synthesis.
Indeed, treatment of compound 56 with phenyl hydrazine at reflux
leads to the hydrazone 71, which is converted to imine 72 in acetic
acid. The latter is reduced in the same pot by LiAlH4 to produce the
aspidospermidine, 54, in 43% yield overall, Scheme 14.
comparison with substituents having a
P-bond, such as allyl or aryl
groups (entries 74a, 74b, and 74c). In this case, the migration could
be envisaged via a concerted mechanism or via an areniun ion (en-
tries 74d and 74e). It should be stressed that this process produces, in
one step, highly functionalised cores. Indeed, compounds, such as
75d, 75e, and 75f have a quaternary carbon center connected to four
sp2 carbons, the formation of such architecture using conventional
chemistry could be problematic. The skeleton generated should
have different applications in total synthesis, due to the numerous
natural products containing such core, such as the Amaryllidaceae
alkaloids family.25 In addition, this transposition has been extended
to bicyclic phenols such as tetralone 76, Table 8.
N
N
PhNHNH2, 2 h
Benzene, 80°C
AcOH, 4 h
118°C
O
N
PhHN
56
71
N
H
N
H
LiAlH4, THF
rt, 30 min
43%, overall
N
H
N
( )-54
72
Scheme 14.
Table 8
Contraction versus migration
4. Oxidative transposition, a rapid access to highly
functionalized cores
HO
O
PhI(OAc)2
HFIP
+
O
R
Transpositions are very important processes in chemical trans-
formations; indeed such rearrangements allow modifying, by
a spectacular avenue, simple structures into a variety of more com-
plex motifs. The most known transpositions are the Wagner/Meer-
wein reaction, the pinacolic transformation and the Namyotkin
rearrangement.23 If one considers the behavior of the electrophilic
species 3 generated during the umpolung activation, it seems
R
R
76
HO
77
78
O
O
Entry
R
Yield (%) 77
Yield (%) 78
a
b
c
CH2eCH]CH2
Ph
Me
43
54
d
d
d
53

K.C. Guérard et al. / Tetrahedron 66 (2010) 5893e5901
5899
As envisaged, with good migrating groups such allyl and aryl,
the formation of dienone 77 is observed in reasonable yield. In the
case 76c (R¼Me), a ring contraction26 occurs in 53% yield. These
results, leading rapidly to an interesting bicyclic system, demon-
strate the large potential of this novel transformation and its
potential application in synthesis. In addition, a noteworthy
transformation is observed by oxidation of the protected alcohol 79
leading to the acetal 82 in 58% yield. Indeed, the allyl CeC bond
fragmentation would lead to the intermediate 81 that would be
trapped by the acetic acid released during the reaction to afford 82.
This transformation is similar to an oxidative pinacol/acetalisation
tandem process. Compound 82 is a dienone system having a qua-
ternary carbon center connected to two different carbonyl
precursors, Scheme 15.
compound 90 leads to the acetal 91, in 50% yield. An interesting
aspect of this reaction is the spectacular rearrangement observed
during the umpolung activation. Indeed, a simple phenol containing
an ether functionality is redesigned in only one step into a highly
elaborated core containing several functionalities present on almost
each carbon. Moreover, this transposition can be accomplished on
a bicyclic phenol 92 to yield the dienone 93, Scheme 17.
O
Br
HO
Br
PhI(OAc)2
HO
Br
O
HFIP/DCM
-17°C, 52%
92
93
Br
Scheme 17.
OH
O
The introduction of bromines in ortho position is necessary to
t-Bu
t-Bu
t-Bu
t-Bu
force the allylic group during the oxidative process to react only in
para position. Moreover, we suppose that the migration of the
allylic group should occur stereospecifically with a retention of
configuration, due to the concertness of the mechanism involved.
In addition, the bicyclic compound 93, represents a bicyclic
intermediate of the main core 94 of platensimycin 95, a selective
FabF inhibitor,27 Figure 8.
PhI(OAc)2
HFIP
-AcOH
t-Bu
Si
Si
t-Bu
79
O
O
80
O
O
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
58%
AcOH
O
O
OH
O
O
O
O
O
Si
Si
82
81
t-Bu
N
H
HOOC
95
OH
O
Scheme 15.
94
O
In presence of a substituent such as allyl or propargyl groups,
due to a potential concerted mechanism involving a species, such
as 84, this oxidative rearrangement process can be extended to
an unprecedented 1,3-allyl shift. This transformation could be
assimilated to an unreported homo-Wagner/Merweein process.
The transposition/acetalisation process described previously has
been extended to produce an acetal functionality. Scheme 16.
Figure 8.
Furthermore, compound 87 can lead to the spiro-bicyclic system
of platensimycin 95. Indeed, an ozonolysis on 87 followed by
a Wittig reaction lead to compound 96 in 71% yield and a treatment
of this latter with TFA and in Stetter’s conditions28 produce the
desired bicyclic core 97 in 64% yield, Scheme 18.
OTBS
OAc
OTBS
OAc
1) O3/PPh3,
MeOH, 78°C
O
O
O
PhI(OAc)2
Ot-Bu
HO
83
H
O
Ph3P
2)
Ot-Bu
87
96
42%
O
71%
O
O
HO
O
overall
84
85
O
OTBS
OAc
1) TFA/DCM, 2h.
2) Thiazonium salt
NEt3, i-PrOH, 60°C
PhI(OAc)2
Ot-Bu
O
HO
64%
O
97
overall
HFIP/DCM
-17°C, 42%
O
87
TBSO
86
Scheme 18.
OTBS
OAc
HO
88
PhI(OAc)2
O
5. Conclusion
HFIP/DCM
-17°C, 72%
TBSO
O
89
In conclusion, several novel methodologies have been
developed on the basis of a common phenoxenium ion mediated by
noteworthy and environmentally benign hypervalent iodine
reagents. Indeed, following the substituents present on the phenol
and the nucleophiles introduced in the medium, intriguing oxida-
tive reactions have been performed such as a [2þ3] cycloaddition
process, an aromatic electrophilic substitution extension, an effi-
cient allylation transformation and unprecedented skeleton trans-
positions. All these transformations expand novel strategic
opportunities in the chemical synthesis that has already allowed
rapid accesses to several total syntheses of natural products such as
panacene, mesembrine and its natural analogous, aspidospermine
and two advanced intermediates of the main core of platensimycin.
An important aspect of this umpolung strategy is the ability to
transform quickly an inexpensive and simple phenol into a highly
PhI(OAc)2
HO
O
O
O
HFIP/DCM
-17°C, 50%
OH
90
91
Scheme 16.
Oxidation of compound 88 produces the desired allenic moiety
with a noteworthy global yield of 72%. This process seems to occur
more efficiently with a propargylic group than an allylic group. This
aspect could be rationalized by the linear geometry of the sp.
carbon center that would be more oriented to interact with the
phenoxenium ion generated. In addition, we have also been
interested in trapping the corresponding oxonium generated on the
side chain with an intramolecular nucleophile that does not need
the presence of acetic acid in the medium. The oxidation of

5900
K.C. Guérard et al. / Tetrahedron 66 (2010) 5893e5901
functionalized core containing a prochiral dienone, and a quater-
nary carbon center connected to several sp2 carbons. All these
methodologies using an electron rich aromatic reversal of reactivity
may thus be thought of as involving ‘aromatic ring umpolung’; this
intriguing concept opens up novel chemical strategies. New results
in ongoing investigations and development for asymmetric syn-
theses in this field will be disclosed in due course.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.03.096. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
References and notes
6. Experimental protocols
1. (a) Seebach, D.; Corey, E. J. J. Org Chem. 1975, 40, 231; (b) Seebach, D. Angew.
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ganic Synthesis. Top. Curr. Chem. 2003, 224; (b) Zhdankin, V. V.; Stang, P. J.
Chem. Rev. 2008, 108, 5299; (c) Zhdankin, V. V. ARKIVOC 2009, i, 1.
6.1. General
Unless otherwise noted, NMR spectra were recorded in CDCl3 at
300 MHz for 1H and 75 MHz or 150 MHz for 13C. Chemical shift (
d)
3. (a) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org. Chem. 1987, 52, 3927; (b) Kita,
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rahedron 2009, 65, 10797.
4. (a) Pelter, A.; Drake, R. A. Tetrahedron Lett. 1988, 29, 4181; (b) Quideau, S.;
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Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.; Chai, D. Synthesis 2007, 24, 3759;
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are in parts per million, and coupling constants (J) are in hertz.
Multiplicities are reported as: ‘s’ (singlet), ‘d’ (doublet), ‘dd’ (dou-
blet of doublets), ‘t’ (triplet), ‘q’ (quartet), ‘m’ (multiplet), ‘c’ (com-
plex), ‘br’ broad. All reactions were monitored by TLC. Reagents and
solvents were commercial products and were used as received,
including trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP).
6.1.1. Compound (96). To
a stirred solution of 87 (20 mg,
0.057 mmol) in MeOH (10 mL) at ꢀ78 ꢂC, ozone was passed
through for 15 s. (lightly blue). The solution was then purged with
argon for 10 min and warmed to room temperature. PPh3 (0.19 mg,
0.06 mmol) was added and the reaction mixture was stirred for
10 min. The solution was concentrated under vacuum and the
residue was dissolved in dry THF (1 mL), the corresponding Wittig
reagent was introduced (32 mg, 0.085 mmol, 1.5 equiv) and the
reaction was stirred for 3 h. and concentrated under reduced
pressure. The crude product was purified by chromatography
(n-hexane/ethyl acetate, 3/1) to give 96 (18 mg, 0.04 mmol, 71%) as
a pale yellow oil: 1H NMR (600 MHz, CDCl3)
d¼6.83 (dd, 1H, J¼10.4,
3.3), 6.78 (dd, 1H, J¼10.4, 3.3), 6.55 (dt, 1H, J¼15.4, 7.7), 6.32 (dd, 1H,
J¼10.4, 2.2), 5.80 (t, 1H, J¼5), 5.73 (t, 1H, J¼15.4), 2.41 (d, 2H, J¼7.7),
2.14 (dd, 1H, J¼13.7, 4.4), 2.04 (dd, 1H, J¼13.7, 4.4), 1.96 (s, 3H), 1.44
(s, 9H), 0.85 (s, 9H), 0.00 (s, 3H), ꢀ0.01 (s, 3H); HRMS: calcd for
C24H38O6SiNa (MNa)þ: 473.2330; found: 473.2333.
6.1.2. Compound (97). To
a
stirred solution of 96 (6 mg,
0.0133 mmol) in CH2Cl2 (0.6 mL) was added TFA (0.029 mmol,
2.2 equiv) dissolved in CH2Cl2 (0.1 mL). The solution was stirred for
2 h, then dropwise added on a warm (60 ꢂC) mixture of isopropanol
(0.6 mL), NEt3 (0.1 mL, 0.067 mmol, 2.2 equiv), and 3-benzyl-5-(2-
hydroxyethyl)-4-methylthiazolium chloride (7 mg, 0.0266 mmol).
The solution was stirred for further 2 h and directly filtrated on
a small pad of silica gel (washed with ethyl acetate/hexane,1/1) and
the solution was concentrated under reduced pressure. The crude
product was purified by chromatography (n-hexane/ethyl acetate,
1/1) to give 98 (2.5 mg, 0.009 mmol, 64%) as a pale yellow oil: 1H
6. Baldwin, J. E.; Adlington, R. M.; Sham, V. W. W.; Marquez, R.; Bulger, P. G.
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NMR (600 MHz, CDCl3)
d
¼6.97 (d, 1H, J¼9.4), 6.86 (d, 1H, J¼9.4),
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Acknowledgements
Acknowledgment is made to the Donors of the American
Chemical Society Petroleum Research Fund (ACS PRF) for support of
this research. We are also very grateful to the Natural Sciences and
Engineering Research Council of Canada (NSERC), the Canada
Foundation for Innovation (CFI), the provincial government of
Quebec (FQRNT), and to Boehringer Ingelheim (Canada) Ltd. for
their appreciated financial support.
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