Diastereoselective IBX oxidative dearomatization of phenols by remote induction: Towards the epicocconone core framework

Article abstract of DOI:10.1002/chem.201101681

The IBX twist does it: Towards the synthesis of a recently isolated dihydropyranic azaphilone core framework, a 2-iodoxybenzoic acid (IBX)-mediated oxidative dearomatization was performed on a bicyclic substrate with excellent diastereoselectivity. Triflu

Full text of DOI:10.1002/chem.201101681

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DOI: 10.1002/chem.201101681
Diastereoselective IBX Oxidative Dearomatization of Phenols by Remote
Induction: Towards the Epicocconone Core Framework**
Agathe Boulangꢀ, Philippe A. Peixoto, and Xavier Franck*[a]
Pyranic azaphilones are cytotoxic natural products that
have been extensively studied recently.[1] However, no syn-
thesis of dihydro-product, such as epicocconone,[2] has been
reported so far. In this line, a convergent synthesis of epi-
cocconone from synthon A was engaged (Scheme 1). During
these studies, we came across a highly diastereoselective
IBX-mediated double deprotection–dehydration–oxidative
dearomative one-pot process.
reoselective.[5] We wish now to report on the first diastereo-
selective IBX-mediated oxidative ortho-dearomatization of
phenols with a remote stereogenic center, in which the nu-
cleophile is not part of the starting phenol.
The synthesis of protected phenols 8 (Scheme 2) began
with 1,3-dimethoxytoluene 1, which reacts with iPrNCO in
the presence of AlCl3 to give the amide 2 required for or-
Scheme 1. Retrosynthetic pathways: dihydropyranic azaphilones.
Organohypervalent iodine reagents have attracted grow-
ing interest for decades as versatile and environmentally
benign oxidants. Among them, IBX (2-iodoxybenzoic acid,
l5-iodane) is used in numerous classical oxidation reactions,
but a particular case is the oxidative dearomatization, which
almost only hypervalent iodine reagents can perform (less
Scheme 2. Synthesis of lactols 8, 14, and 16. Reaction conditions:
a) iPrNCO, AlCl3, 95%; b) tBuLi/TMEDA then 3a or 3b (4a, 82%; 4b,
52%); c) CSA/toluene reflux; d) AlCl3 (6a, 95%, 2 steps); e) BBr3 (6b,
68%, 2 steps); f) NaH/MOMCl (2 equiv), (7a, 98; 7b, 91%); g) TBSCl/
Et3N then NaH/MOMCl (13a, 89%); h) BnBr/K2CO3 then NaH/MOMCl
(15a, 83%); i) DIBAL-H, toluene, À788C.
used reagents are: PbACTHNUTRGNEUNG
(OAc)4, Ph2Se2O3, NaIO4 and CuI/O2).
Although the mechanism of oxidative dearomatization is
still unclear and depends on the oxidant, hypervalent iodine
reagents are nowadays commonly used.[1,2]
l3-iodane-mediated diastereoselective oxidative dearoma-
tizations of phenols have been reported in the case in which
the nucleophile is present on a substituent of the aromatic
ring and intramolecularly attacks at either the ortho- or para
positions of the phenol.[3c] Quideau reported the S-IBX (l5-
iodane)-mediated oxidative dearomatization of a para-sub-
stituted phenol with a stereogenic center on the a-position
of the substituent, but the dearomatization was not diaste-
thometallation and the subsequent trapping of the organo-
metallic species with either epoxide 3a or 3b. The resulting
alcohols (4a and 4b) were subjected to lactonisation by
simply heating to reflux in toluene in the presence of cam-
phorsulfonic acid (CSA, 1.1 equiv), leading to 5a and 5b.
Diphenol 6a was obtained quantitatively after treatment
with AlCl3 and heating to reflux in dichloromethane, howev-
er, 6b required BBr3 to be prepared cleanly. Compounds 6a
and 6b were subsequently re-protected as MOM ethers 7 by
treatment with methyl chloromethyl ether (MOMCl) and
NaH. Lactones 7 were then cleanly reduced to lactols 8 by
diisobutylaluminum hydride (DIBAL-H) in toluene. Lactol
14a and 16a were also prepared with different protecting
groups from 6a, by using TBS (Et3N/TBSCl) or Bn (BnBr/
K2CO3) regioselective monoprotections at position 6, then
MOM protection (NaH/MOMCl) of the phenol at position
[a] A. Boulangꢀ, Dr. P. A. Peixoto, Dr. X. Franck
Universitꢀ de Rouen, INSA de Rouen
CNRS UMR 6014, C.O.B.R.A.–I.R.C.O.F.
1 Rue Tesniere; 76131 Mont-Saint-Aignan cedex (France)
Fax : (+33)235522959
E-mail: xavier.franck@insa-rouen.fr
[**] IBX=2-iodoxybenzoic acid.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101681.
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8, followed by a DIBAL reduction. Lactols 8, 14, and 16
were obtained as single diastereomers.
Oxidative dearomatization on 8a and 8b was then per-
formed with IBX 11 in the presence of different amounts of
trifluoroacetic acid (TFA, Scheme 3 and Table 1). TFA was
used (IBX was added at the same time, Table 1, entry 1).
Surprisingly, 10a-TFA ester was isolated with 12% yield as
a
single anti diastereomer (Figure 1).[7a] Lowering the
Figure 1. X-ray of 10a-TFA ester.
amount of TFA to 7 equiv resulted in a moderate diastereo-
selective formation of 10a (60/40) along with 10% of 10a-
TFA ester, as a single diastereomer (Table 1, entry 2).
Adding a catalytic amount of tetrabutylammonium iodide
(TBAI)[8] resulted in a lower yield, without affecting the dia-
stereoselectivity significantly (Table 1, entry 4). However,
adding water (2 or 20 equiv) resulted in an increase of both
yield and diastereoselectivity (up to 90/10), compared with
the same anhydrous conditions (also lowers the amount of
TFA ester, compare Table 1, entries 2, 5, and 6). Further-
more, adding 20 equiv of water also afforded a cleaner and
faster reaction. If only 2 equiv of TFA are added, without
water, the diastereoselectivity is maintained but the yield is
less than with water (Table 1, entry 7).[9]
Scheme 3. Diastereoselective oxidative dearomatization.
selected because it rapidly generates oxonium ions from lac-
tols and should deprotect MOM ethers. Furthermore, it has
been reported that TFA accelerates IBX oxidations.[6] The
oxidation of hemiketal 8a afforded alcohol 10a in 32%
yield with no diastereoselectivity when 20 equiv of TFA was
The influence of the protecting group at position 6 was
then studied. Dearomatization of 14a, bearing an acid-labile
TBS group at position 6, yielded 10a with either no or low
diastereoselectivity in either anhydrous or aqueous condi-
tions, respectively (Table 1, en-
Table 1. Diastereoselective oxidative dearomatization.[a]
tries 8 and 9). Treatment of
Entry
Phenol
TFA
[equiv]
Additive
[equiv]
10
Yield
[%]
d.r.
Yield [%]
TFA ester
d.r. TFA
ester
16a, bearing a benzyl protect-
ing group, with TFA and IBX,
resulted also in low diastereo-
selective oxidative dearomati-
zation (Table 1, entry 10).
In the case of the oxidation
of hemiketal 8b bearing the
isopropyl side chain (Table 1,
entries 11–15), 10b was ob-
tained in a similar diastereo-
meric ratio (d.r.) than with 8a
(up to 89/11). Only when the
reaction was performed with
20 equiv of TFA, a moderate
increase to 60:40 d.r. was ob-
served (compared with 50/50
with 8a; compare Table 1, en-
[b]
U
10[b]
1
2
8a
8a
8a
8a
20
7
7
7
7
–
–
–
–
–
–
0.1
2
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10b
10b
10b
10b
10b
32
32
30
22
42
48
34
43
47
32
35
37
41
42
41
50/50
60/40
50/50
62/38
85/15
90/10
83/17
50/50
60/40
65/35
60/40
60/40
61/39
89/11
82/18
12
10
–
10
2
100/0
100/0
–
100/0
100/0
–
100/0
–
–
–
100/0
100/0
–
–
–
3[c]
4
TBAI
H2O
5
8a
6
7
8a
8a
7
2
H2O
–
20
–
–
4
8
9
14a
14a
16a
8b
8b
8b
8b
8b
2
7
7
20
7
7
7
2
–
H2O
–
–
–
–
H2O
–
–
20
–
–
–
–
20
–
–
–
6
2
–
–
–
10
11
12
13[c]
14
15
[a] Typical procedure: 8a was dissolved in CH2Cl2 before adding TFA, additive (when noted) and IBX
(2 equiv). The solution was stirred until complete conversion. [b] Measured by 1H NMR spectroscopy. [c] 8a
(entry 3) or 8b (entry 13) in CH2Cl2 +7 equiv of TFA, stirred overnight before adding IBX.
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Diastereoselective IBX Oxidative Dearomatization of Phenols
COMMUNICATION
tries 1 and 11); 10b-TFA ester was also isolated as a single
diastereomer.
cause the greater the number of equivalents of TFA, the
faster the deprotection occurs (Figure 2). These kinetics are
correlated with the observed diastereoselectivity of 10a
(Table 1, compare entries 1, 2, and 7) and we propose that
the oxidative dearomatization of either monophenol 12a or
17a is diastereoselective, whereas the oxidation of 9a is not.
Furthermore, we have shown that adding water dramatically
accelerated the reaction. In this case, the kinetics of oxida-
tion (kox) increase but do not affect the kinetics of deprotec-
tion significantly (kdep2 and k’dep2). Therefore, in the pres-
ence of water, the oxidation of 12a and 17a takes place
before the second deprotection and results in high diastereo-
selectivity. The water–TFA combination presumably depoly-
merizes IBX and allows for a more favorable liquid–liquid
interaction instead of a solid–liquid interaction, with IBX
being poorly soluble in dichloromethane. In the case of 14a,
the observed diastereoselectivity was lower than with 8a
(Table 1, compare entries 6 and 9). This is due to the faster
deprotection of 17a, compared with 12a (k’dep2>kdep2),
which increases the amount of 9a, for which the oxidation is
not diastereoselective.
The oxidative dearomatization of in situ generated 9a or
9b was performed after TFA treatment of 8a or 8b and
overnight stirring (for complete deprotection of both MOM
groups), before addition of IBX. In these cases, 10a was ob-
tained with no diastereoselectivity (Table 1, entry 3) whereas
10b was obtained with a moderate 61/39 d.r. (Table 1,
entry 13). These two results show the lack of or low diaste-
reoselectivity of the oxidation of free diphenols 9a or 9b;
they also show that iPr substitution induces a better, al-
though to a moderate extent, diastereoselectivity. These re-
sults are also consistent with the d.r. observed in the pres-
ence of 20 equiv of TFA (Table 1, entries 1 and 11), in which
free diphenols are formed very quickly (vide infra,
Figure 2).
In the case of 16a, NMR studies in the presence of TFA
only showed that the benzyl protecting group tolerated
acidic conditions (since only the MOM at position 8 was
cleaved). Accordingly, a high diastereoselectivity was ex-
pected but, to our surprise, low diastereoselectivity was ob-
served. This can be explained by the IBX-mediated depro-
tection and oxidation of the benzyl group,[12] generating di-
phenol 9a, in which oxidative dearomatization is not diaste-
reoselective.
To summarize, the obtained diastereoselectivity of 10 is a
combination of the highly diastereoselective oxidation of
12a, 12b, or 17a, counterbalanced by the non- or low-diaste-
reoselective oxidation of 9a or 9b.
^
Figure 2. Kinetics of formation of 9a from 8a in various conditions.
=
~
&
TFA (7 equiv); =TFA (7 equiv)+H2O (2 equiv); =TFA (20 equiv).
Importantly, the formation of TFA esters do not arise
from esterification of the corresponding alcohols in the reac-
tion medium but certainly during dearomatization by TFA
transfer from TFA–IBX esters.[10] Moderate yields may be
explained by the high sensitivity of 10 on silica and aqueous
conditions, due to Michael addition of water on the enone
moiety. The use of SIBX instead of IBX did not allow us to
increase the yield.[11]
We can then postulate that diastereoselective oxidation
takes place when IBX coordinates to the phenol in position
8 or 6 (the other phenol still being protected) and delivers
oxygen on one side preferentially, anti to the methyl of the
dihydropyran ring (Scheme 4). Indeed, ligand exchange be-
The sequential, but different,
deprotection of protecting
groups on lactols 8a and 14a
has been observed (Scheme 3).
Treatment of either 8a or 14a
with TFA very quickly (mi-
nutes) yielded the oxonium ion
12a (MOM cleavage at posi-
tion 8), or 17a (TBS cleavage
at position 6), respectively.
Then, 12a slowly evolved to di-
phenol 9a (kdep2), whereas 17a
more rapidly evolved to diphe-
nol 9a (k’dep2). The kinetics of
these second deprotections
(kdep2 and k’dep2) were shown
to be [TFA] dependent be-
Scheme 4. Proposed mechanism for diastereoselectivity.
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X. Franck et al.
tween IBX and monophenol 12 leads to conformer I, which
can evolve through a hypervalent twist[4f,13] to I’ in which the
aryl moiety of IBX is on the same face as the methyl of the
oxonium ion. On the other hand, I can also rotate around
À
the aryl O bond to give rise to conformer II, which can
evolve through a sterically more favorable hypervalent twist
to II’ in which the aryl moiety of IBX is opposite to the
anomeric methyl. This leads preferentially to anti-oxidation
and explains the observed diasteroselectivity. In the case of
10-TFA ester, we propose that in situ formation of the TFA
ester of IBX is responsible for the oxidation and that the
corresponding O-TFA-substituted conformers I, I’, II and II’
are more sensitive to steric hindrance, giving rise to com-
plete anti diastereoselectivity
The next challenge towards the epicocconone core was
bypassed using dioxin-4-ones for the one-pot access to acyl-
furanone derivatives.
Lactol 8a, as a mixture of diastereomers, was then heated
with dioxin-4-one 18 (in the presence of Et3N), leading to
acylfuranone 20a, after conversion to b-keto-ester 19a and
completely regioselective cyclization with 6-carbonyl in
86% yield (Scheme 5). Diastereomers of acylfuranone 20a
Figure 3. X-ray of major diastereomer 20a.
this methodology to the yet never synthesized natural prod-
uct and analogues is under investigation and results will be
reported in due course.
Acknowledgements
We gratefully acknowledge the Rꢀgion Haute Normandie for financial
support to A.B. and P.A.P. We also thank Dr. Morgane Sanselme for X-
ray analysis. We gratefully acknowledge Prof. Stꢀphane Quideau (Univer-
sity of Bordeaux, France) for fruitful discussions.
Keywords: diastereoselectivity · iodine · lactones · natural
products · oxidative dearomatization
Scheme 5. Derivatization of 10a and introduction of the furanone ring.
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To conclude, we report the first IBX-mediated diastereo-
selective oxidative dearomatization with remote induction
(over 5 bonds) and show the dramatic effect of water on
this reaction. We also shed light on the mechanism of the
IBX oxidative dearomatization, by validating the hyperva-
lent twist with an internal delivery of the oxygen atom. Al-
though remote stereocontrol has been known for decades,
induction based on hypervalent twisting is a new concept
that could be applied for diastereoselective oxidations. The-
oretical studies on the origin of the diastereoselectivity are
in progress. Dearomatized alcohols were then regioselective-
ly transformed into acylfuranones leading to the core struc-
ture of epicocconone in a one pot sequence. Application of
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Diastereoselective IBX Oxidative Dearomatization of Phenols
COMMUNICATION
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Received: June 1, 2011
Published online: August 2, 2011
Chem. Eur. J. 2011, 17, 10241 – 10245
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