Chiral aryl iodide catalysts for the enantioselective synthesis of para-quinols

Article abstract of DOI:10.1039/c3cc00013c

Molecular modelling of an iodine(iii) phenoxide was used as a starting point in the design of chiral aryl iodide catalysts for stereoselective oxidative dearomatization reactions. Using this approach, catalysts derived from 8-iodotetralone and tartaric ac

Full text of DOI:10.1039/c3cc00013c

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Chiral aryl iodide catalysts for the enantioselective
synthesis of para-quinols†
Cite this: Chem. Commun., 2013,
49, 3001
Kelly A. Volp and Andrew M. Harned*
Received 1st January 2013,
Accepted 25th February 2013
DOI: 10.1039/c3cc00013c
www.rsc.org/chemcomm
Molecular modelling of an iodine(III) phenoxide was used as a starting report our initial efforts aimed at designing a chiral aryl iodide
point in the design of chiral aryl iodide catalysts for stereoselective catalyst capable of generating enantioenriched para-quinols.
oxidative dearomatization reactions. Using this approach, catalysts
Our group’s interest in using para-quinols as building blocks in
derived from 8-iodotetralone and tartaric acid were constructed and organic synthesis11 led us to consider the use of a chiral aryl iodide
used to synthesize enantioenriched para-quinols from phenols.
catalyst for their preparation. We began by investigating the use of
the easily prepared and modifiable aryl iodide 6,10 developed by
Recent years have seen great progress in the development of Ishihara, as a catalyst for the conversion of phenol 4a into quinol 5a
asymmetric hypervalent iodine reagents and catalysts for use (Scheme 2).12 For simplicity, these reactions were only performed at
in enantioselective oxidation reactions.1 Although high levels of ambient temperatures and were not optimized for yield. Promising
enantiocontrol (>90 : 10 er) can be achieved in oxidative lactoniza- levels of enantiocontrol were realized using catalytic amounts of
tion reactions2 and for dioxygenation3 and amination4 of olefins, 6a–d, however, all of the catalysts resulted in approximately the
analogous results in oxidative dearomatization reactions have been same level of stereocontrol. Although these results were quite
slow to develop.5 Quideau6 and Birman7 have shown that chiral encouraging, further modifications to the catalyst structure did
iodine catalysts can be used for the asymmetric ortho-hydroxylation not improve the stereoselectivity. At this point we began to
of phenols.8 A chiral iodine(V) intermediate is postulated to be the search for alternative catalyst architectures that might lead to
active oxidant in these reactions. Meanwhile, Kita9 and Ishihara10 improved selectivity.
have used chiral iodine(III) catalysts/reagents to perform asym-
The overall behavior of the reaction outlined in Scheme 1 is
metric spirocyclizations of ortho-substituted naphthol derivatives. generally well understood.12,13 However, the mechanism of the
To the best of our knowledge, there have been no reports of using conversion of 1 into 3 is still unclear. This is due to the highly
asymmetric hypervalent iodine reagents for the enantioselective reactive nature of the intermediates in question. The first step is
construction of 2,5-cyclohexadienones (e.g., 1 - 3, Scheme 1), and almost certainly a ligand exchange between phenol 1 and the
a general solution to this problem remains elusive. Herein, we iodine(III) carboxylate to form intermediate 2. Much like the
familiar SN1/SN20 continuum, the reductive decomposition of 2
likely involves a spectrum of reactivity.9,10 On one end would be
direct nucleophilic attack on the aromatic ring of the phenoxide
Scheme 1 Iodine(III)-mediated oxidative dearomatization of phenols to access
2,5-cylohexadienones.
Department of Chemistry, University of Minnesota, 207 Pleasant St SE,
Minneapolis, MN 55455, USA. E-mail: harned@umn.edu; Fax: +1 612-626-7541;
Tel: +1 612-625-1036
† Electronic supplementary information (ESI) available: Synthesis and character-
ization data for all compounds, copies of 1H and 13C NMR spectra. See DOI:
Scheme 2 Initial attempts at asymmetric oxidative dearomatization.
Chem. Commun., 2013, 49, 3001--3003 3001
10.1039/c3cc00013c
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Table 1 Influence of catalyst structurea
(SN20-like). On the other end would be ionization to a highly
reactive and short-lived14 phenoxenium ion (SN1-like).15 Our initial
results (Scheme 2), and those of Kita and Ishihara,9,10 indicate that
the approach of the nucleophile is being controlled no matter
where on the SN1/SN20 continuum the dearomatization reaction of
interest lies. In other words, these systems produce an iodine(III)
phenolate that is capable of shielding one face of the substrate
during direct nucleophilic attack and are able to shield one face of
a rapidly trapped phenoxenium ion. We hypothesized that
the three-dimensional structure of intermediate 2 could be used
as a starting point for designing new aryl iodide catalysts with
improved enantioselectivity.
R1 (4 or 5)
X (8)
Time (h) Yieldc (%)
erd
Entry
1b
2b
3
Me (a)
Me (a)
Br (b)
Br (b)
Br (b)
OH (a)
Morpholine (b)
NHPh (c)
NHCH2Ph (d)
NHMes (e)
1.5
1.5
16
1.5
0.3
36
33
48
20
45
60 : 40
59 : 41
60 : 40
60 : 40
65 : 35
4b
5b
In order to gather additional information about the structure of
iodine(III) phenolates, DFT calculations were performed on structure
7 (Fig. 1). The calculations were carried out using Truhlar’s M06-2X
functionals16 and a mixed basis set (6-31G** for C, H, O and SDD17
for iodine.† The minimized structure (7a) was quite intriguing in
that the phenolate ring had partially slipped beneath the phenyl
ring of the iodane. We saw this as an opportunity to use this
structural feature as a basis for the rational design of new chiral
aryl iodides for use in enantioselective oxidative dearomatization
reactions. Specifically, it was envisioned that asymmetry could be
introduced using a tether bearing stereogenic centers to link one
ortho position of the aryl iodide to the a-carbon of an iodine-bound
carboxylate.
After investigating several alternative catalysts,† we identified
tricyclic aryl iodide 8a as a new lead structure. This structure was
attractive for several reasons. The tetrahydronaphthalene moiety
present in 8a would limit the conformational freedom of the
chiral information, while the two carboxylic acid groups could be
used to introduce various H-bond donors (e.g., amides) that
might interact with the bound phenolate oxygen. Ishihara and
63 : 37
75 : 28
6
7
Br (b)
TMS (c)
16
16
80
94
8
9
Br (b)
94
75
43 : 57
Br (b)
Br (b)
16
16
70
52
63 : 37
60 : 40
10
All reactions were performed on a 0.17 mmol scale. b 2:1 MeCN–H2O was
used. c All yields are following purification using silica gel chromatography.
d Determined by chiral HPLC (see ESI).
a
co-workers have previously found H-bond donors to be beneficial was with catalyst 8g (entry 8), where a reversal of selectivity was
when incorporated into chiral aryl iodide catalysts.10 In the observed in comparison to the other catalysts. Taken as a whole,
end, we found aryl iodide 8a could be prepared easily† from these results show that the identity of the amide has some
L-(+)-dimethyl tartrate and 8-iodotetralone.18
influence on the enantioselectivity, but this is a rather minor
Gratifyingly, the newly designed chiral aryl iodides were ‘‘fine tuning’’ of the selectivity inherent to the structure of
successful in providing enantioenriched para-quinols catalyst 8. In the end, we felt that the mesityl amide 8e (entry 5)
5
(Table 1). Among the various amides that were tested, catalysts offered the most favourable combination of yield and selectivity;
8a–d gave approximately the same level of selectivity. We were therefore, this catalyst was chosen for further studies.19 It should
surprised to find that comparable selectivity was observed when a be noted that a solvent screen revealed that 9 : 1 MeCN–H2O was
tertiary amide was incorporated into the catalyst (entry 2). This the best solvent mixture.†
indicates that factors beyond simple hydrogen bonding are
Having identified a viable catalyst, the substrate scope was
important when biasing the conformation of the presumed investigated using catalyst 8e and various substituted phenols
iodine(III) phenoxide. Catalysts 8f, 8g, and 8h resulted in a higher (Table 2). Overall, the enantioselectivity was moderate and
yield of the quinol product (entries 6–9), but the enantioselectivity ranged from 63 : 37 to 80 : 20 er. In general, an approximately
was not appreciably improved. One of the more intriguing results 10% (relative) increase in selectivity was observed when the
temperature was lowered to 0 1C, however, this often came at
the expense of yield. Increasing the size of the ortho substituent
had a generally positive effect on selectivity (4a–4c, 4g), but
negative effects were seen when larger para substituents were
present (4i and 4j). Substrate 4e shows that an ortho substituent
is required to achieve effective enantiofacial discrimination.
However, substrate 4f demonstrates that a meta substituent is
tolerated as long as an ortho substituent is also present. Our
recent synthesis of sorbicillatone A11b demonstrates the utility of
Fig. 1 Rational design of aryl iodide catalysts.
quinol 5f along with the synthetic potential of an asymmetric
c
3002 Chem. Commun., 2013, 49, 3001--3003
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Table 2 Influence of substrate structurea
We thank the University of Minnesota for financial support
and the NSF for a Graduate Fellowship (K.A.V.). Computational
resources were provided by the Minnesota Supercomputing
Institute. We thank Prof. Christopher Cramer (U. Minn.) for
helpful discussions regarding the modelling experiments.
We would also like to thank Mr. Erik Goebel for helpful
suggestions, and Mr. Patrick Lang and Ms. Alison Thorsness
for early contributions to this project.
R1
R2
R3 Temp (1C)
Yieldb (%)
erc
Cmpd
Time (h)
a
b
b
c
c
d
e
e
f
g
g
h
i
Me
Br
Br
TMS
TMS
Cl
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
25
0
25
0
25
25
0
25
0
0
25
0
25
25
16
3
16
7
16
16
0.5
16
1
16
16
16
16
16
52
21d
52
64 : 36
69 : 31
65 : 35
80 : 20
75 : 25
65 : 35
53 : 47
50 : 50
69 : 31
77 : 23
71 : 29
64 : 36
67 : 33
63 : 37
Notes and references
1 Reviews: (a) M. Ngatimin and D. W. Lupton, Aust. J. Chem., 2010,
63, 653; (b) H. Liang and M. A. Ciufolini, Angew. Chem., Int. Ed.,
2011, 50, 11849.
2 (a) M. Fujita, Y. Yoshida, K. Miyata, A. Wakisaka and T. Sugimura,
Angew. Chem., Int. Ed., 2010, 49, 7068; (b) M. Fujita, K. Mori,
M. Shimogaki and T. Sugimura, Org. Lett., 2012, 14, 1294.
3 M. Fujita, M. Wakita and T. Sugimura, Chem. Commun., 2011,
47, 3983.
58e
79
65
H
H
Me
Me
OMe Me
H
H
H
H
H
23d
43
Me
TBS
TBS
TIPS
TMS
TBS
20d
64
Me
Me
Me
i-Pr
i-Pr
48
56
53
41
¨
´
˜
4 (a) C. Roben, J. A. Souto, Y. Gonzalez, A. Lishchynskyi and K. Muniz,
Angew. Chem., Int. Ed., 2011, 50, 9478; (b) U. Farid and T. Wirth,
Angew. Chem., Int. Ed., 2012, 51, 3462.
j
5 L. Ku¨rti, P. Herczegh, J. Visy, M. Simonyi, S. Antus and A. Pelter,
J. Chem. Soc., Perkin Trans. 1, 1999, 379.
6 S. Quideau, G. Lyvinec, M. Marguerit, K. Bathany, A. Ozanne-
Beaudenon, T. Buffeteau, D. Cavagnat and A. Chenede, Angew.
Chem., Int. Ed., 2009, 48, 4605.
7 J. K. Boppisetti and V. B. Birman, Org. Lett., 2009, 11, 1221.
8 For an asymmetric, copper-mediated oxidation, see: A. R. Germain,
D. M. Bruggemeyer, J. Zhu, C. Genet, P. O’Brien and J. A. Porco, Jr.,
J. Org. Chem., 2011, 76, 2577, and references therein.
9 T. Dohi, A. Maruyama, N. Takenaga, K. Senami, Y. Minamitsuji,
H. Fujioka, S. B. Caemmerer and Y. Kita, Angew. Chem., Int. Ed.,
2008, 47, 3787.
a
b
All reactions were performed on a 0.17 mmol scale. All yields are
c
following purification using silica gel chromatography. Determined
´
´
d
e
by chiral HPLC (see ESI). 2 : 1 MeCN–H2O was used. Repeating this
experiment using catalyst 6a instead of 8e gave the para-quinol in 57%
yield and 63 : 37 er.
10 (a) M. Uyanik, T. Yasui and K. Ishihara, Angew. Chem., Int. Ed., 2010,
49, 2175; (b) M. Uyanik, T. Yasui and K. Ishihara, Tetrahedron, 2010,
66, 5841.
11 (a) R. Tello-Aburto, K. A. Kalstabakken, K. A. Volp and A. M. Harned,
Org. Biomol. Chem., 2011, 9, 7849; (b) K. A. Volp, D. M. Johnson and
A. M. Harned, Org. Lett., 2011, 13, 4486.
Scheme 3 Asymmetric spirocyclization with catalyst 8e.
12 We have not been able to identify products arising from hydroxyla-
tion at other positions. This is in line with our work using achiral
iodine(III) reagents (i.e. PhI(OAc)2) to prepare racemic p-quinols
(see, ref. 11a). Others have made similar observations, for example:
T. Yakura, M. Omoto, Y. Yamauchi, Y. Tian and A. Ozono, Tetra-
hedron, 2010, 66, 5833; F.-X. Felpin, Tetrahedron Lett., 2007, 48, 409;
A. McKillop, L. McLaren and R. J. K. Taylor, J. Chem. Soc., Perkin
Trans. 1, 1994, 2047. The observed regioselectivity is also in accord
with the frontier orbital analysis reported by Pelter and co-workers
(see, ref. 5).
synthesis of para-quinols. The highest enantioselectivity (80 : 20 er)
was observed with substrate 4c.
In order to form the enantioenriched para-quinols, the
chiral catalyst must control the approach of a relatively small,
external nucleophile (i.e., H2O).20 The stereoselective delivery of
such a nucleophile is further complicated by the aforemen-
tioned mechanistic uncertainties associated with this reaction.
With this in mind, we wanted to evaluate the ability of catalyst
13 A. Pelter and R. S. Ward, Tetrahedron, 2001, 57, 273.
8e to control the approach of other nucleophiles. To this end, 14 Lifetimes of phenoxenium ions generated via laser-flash photolysis
have been measured and do not exceed B170 ns. See:
the spirocyclization of phenol 9 was attempted (Scheme 3).
(a) Y.-T. Wang, J. Wang, M. S. Platz and M. Novak, J. Am. Chem.
Gratifyingly, spirocycle 10 was produced with a level of stereo-
Soc., 2007, 129, 14566; (b) Y.-T. Wang, K. J. Jin, S. H. Leopold,
selectivity (70 : 30 er) that was consistent with those reported in
J. Wang, H.-L. Peng, M. S. Platz, J. Xue, D. L. Phillips, S. A. Glover
and M. Novak, J. Am. Chem. Soc., 2008, 130, 16021, and references
therein.
Table 2.21
In summary, we have shown that computational methods
can be used to gain insight into the structure of short-lived
hypervalent iodine intermediates and that the results of this
modelling can serve as a basis for the design of chiral aryl
15 L. Ku¨rti, P. Herczegh, J. Visy, M. Simonyi, S. Antus and A. Pelter,
J. Chem. Soc., Perkin Trans. 1, 1999, 379–380.
16 Y. Zhao and D. G. Truhlar, Theor. Chem. Acc., 2008, 120, 215.
17 A. Bergner, M. Dolg, W. Ku¨chle, H. Stoll and H. Preuß, Mol. Phys.,
1993, 80, 1431.
iodine catalysts. More importantly, we have shown, for the 18 P. Nguyen, E. Corpuz, T. M. Heidelbaugh, K. Chow and M. E. Garst,
J. Org. Chem., 2003, 68, 10195.
19 The oxidation of 4b was attempted using a stoichiometric amount of
first time, that chiral aryl iodide catalysts can be used for
the enantioselective synthesis of 2,5-cyclohexadienones. Our
an iodine(III) reagent derived from aryl iodide 8a. This produced
results indicate that this is a tractable problem, but new catalyst
architectures are needed in order to achieve high selectivity. We
are continuing our efforts in this area and will report our
results in due course.
quinol 5b with 62 : 38 er. See ESI for details.
20 The use of H218O results in labelled product. See ESI for details.
21 We also attempted the dearomatization of 4c and 4g using methanol
as the solvent. Unfortunately, we were unable to separate the
enantiomers using chiral HPLC.
c
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Chem. Commun., 2013, 49, 3001--3003 3003