A chiral hypervalent iodine(III) reagent for enantioselective dearomatization of phenols

Article abstract of DOI:10.1002/anie.200800464

(Chemical Equation Presented) The hype about iodine(III): A chiral hypervalent iodine(III) reagent (1) is reported to enantioselectively dearomatize phenols in a highly selective manner (see scheme). This result clearly supports existence of the associative pathway in hypervalent iodine(III)-induced phenolic oxidations.

Full text of DOI:10.1002/anie.200800464

Angewandte
Chemie
DOI: 10.1002/anie.200800464
Oxidation
A Chiral Hypervalent Iodine(III) Reagent for Enantioselective
Dearomatization of Phenols**
Toshifumi Dohi, Akinobu Maruyama, Naoko Takenaga, Kento Senami, Yutaka Minamitsuji,
Hiromichi Fujioka, Simon B. Caemmerer, and Yasuyuki Kita*
Asymmetric induction by hypervalent iodine reagent control
is challenging work. Many efforts have been devoted to the
design of new chiral reagents with the aim of achieving
asymmetric oxidations with high stereoselectivities.[1] How-
ever,no effective chiral hypervalent iodine compounds have
been reported thus far. We report herein a promising new
chiral hypervalent iodine(III) reagent ((R)-9),having a rigid
spirobiindane backbone,for the first enantioselective dear-
omatization of phenols [Eq. (1)]. The use of this chiral
activities.[3] Therefore,there exists a continuing interest in
such transformations and hypervalent iodine(III) reagents
can be particularly attractive organo-oxidants because of low-
toxicity and because it is ecologically benign for applications
in natural product syntheses.[4] The key intermediate in the
reaction,phenoxy- l3-iodane species A,would be formed first
by ligand transfer[5] of the phenolic oxygen atom to the
iodine(III) center (Scheme 1). The oxidation to quinone or
Scheme 1. The two postulated types of intermediates: A and B.
R,R ’=alkyl or alkoxy.
reagent also provides important mechanistic insights into the
dearomatization processes of phenols induced by hypervalent
iodine(III) reagents.
For the past two decades we have been engaged in
hypervalent iodine(III)-induced oxidative dearomatizations
of phenols,and applied the transformations to natural
product syntheses.[2] Phenolic oxidations are pivotal steps
frequently involved in the biosynthesis of naturally occurring
products,which possess a variety of important biological
quinol variants (i.e. cyclohexadienones) is typically rational-
ized as proceeding by the attack of a nucleophile on
intermediate A in an associative manner.[6] Alternatively,
the oxidation could include discrete phenoxenium ions of
type B,which are formed after dissociation of iodobenzene
from intermediate A,and subsequent attack by the nucleo-
phile to deliver the product; the mechanism was supported by
both theoretical and experimental evidences. [7]
Elucidation and control of the two distinct mechanisms
would help in the construction of advanced oxidative trans-
formations of phenols by hypervalent iodine reagents,which
are attractive because of recent interest in clean,safe,and
practical methods that avoid the use of toxic metal oxidants.[8]
The possibility for asymmetric induction when using optically
active iodine(III) compounds with suitable chiral environ-
ments is anticipated,especially from intermediates A. How-
ever,preliminary studies on the intermolecular reactions of
phenols with nucleophiles led to the conclusion that there was
no opportunity for such asymmetric induction by chiral
reagent control because of the exclusive formation of
phenoxenium ion B during the reaction.[7b,c] The intramolec-
ular reactions have not yet been examined thus far.
[*] Dr. T. Dohi,A. Maruyama,N. Takenaga,K. Senami,Y. Minamitsuji,
H. Fujioka,S. B. Caemmerer,Prof. Dr. Y. Kita
Graduate School of Pharmaceutical Sciences
Osaka University
1-6 Yamada-oka,Suita,Osaka 565-0871 (Japan)
Fax: (+81)6-6879-8229
E-mail: kita@phs.osaka-u.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research (A) and for Encouragement of Young Scientists,and by
Scientific Research on Priority Areas “Advanced Molecular Trans-
formations of Carbon Resources” from the Ministry of Education
Culture,Sports,Science,and Technology (Japan). T.D. and A.M.
acknowledge support from the Industrial Technology Research
Grant Program from the New Energy and Industrial Technology
Development Organization (NEDO) of Japan and a research
fellowship from J.S.P.S. for Young Scientists.
In this study,we used intramolecular oxidative substitu-
tion of naphthol 1a ([Eq. (1)] where R’’ = H) as a model case
since the resulting five-membered chiral spirolactone naph-
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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thoquinol 2a[9] ([Eq. (1)] where R’’ = H) is amenable to
The synthesis of newly developed iodine(III) compound
isolation.[10] Under the assumption that fast attack of the
internal carboxylic acid at the prochiral carbon center of an
intermediate of type A would alter the course of the reaction
mechanism to one that is concerted and more favorable,we
examined the asymmetric reaction of 1a by using a variety of
reported optically active iodine(III) carboxylates,such as 3–5
(> 98% ee),[1b–d] in dichloromethane,which gave disappoint-
ing ee values (Figure 1).
(R)-9 was accomplished from known triflate precursor
(R)-6[11c] by using
a
four-step conversion sequence
(Scheme 2). Thus,after introduction of the iodine atom by
Scheme 2. Preparation of new chiral iodine(III) compound (R)-9.
Reagents and conditions: a) Pd(OAc)2,BINAP,BnNH 2,Cs 2CO3,tolu-
ene,100 8C,2 h; b) Pd(OH) 2/C,H 2 (1 atm),AcOEt/MeOH,40 8C,16 h
(80% from (R)-6); c) NaNO2,TFA,0 8C,30 min.,then KI,RT !408C,
5 h,52%; d) Selectfluor,AcOH/CH 3CN,RT,12 h,90%. BINAP =2,2’-
bis(diphenylphosphanyl)-1,1’-binaphthyl; TFA=trifluoroacetic acid;
Selectfluor=1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
ditetrafluoroborate.
Figure 1. The enantioselectivities of 2a obtained by the spirocyclization
of 1a with 3–5. Bz=benzoyl. The ee values in the figure are those for
the resulting oxidation product 2a.
The above results imply the involvement of transition
states that have certain chiral environments under the stated
conditions despite their low enantiocontrol. Inspired by this
evidence,intensive studies on the design of new chiral
iodine(III) compounds were pursued in our laboratory. We
hypothesized that one of the major reasons for the low
enantioselectivities observed when using compounds 3–5 was
the liberation of the chiral ligand (for 3),or the formation of
conformationally flexible iodoarenes (for 4 and 5) during the
last step of the reaction. On the basis of this hypothesis we
introduced a rigid 1,1’-spirobiindane backbone;[11] the rigid
structure was selected to maintain the chiral environment
around the iodine(III) center throughout the reaction
(Figure 2).
using conventional protocols to transform diamine 7,treat-
ment of corresponding (R)-8 ([a]2D5 = + 6.38 (c = 0.93,CHCl 3))
with Selectfluor in dilute AcOH/CH3CN[12] afforded optically
pure m-oxo-bridged iodine(III) carboxylate (R)-9 ([a]2D5 = +
21.08 (c = 1.09,CHCl )); (R)-9 is a white powder[13] that is
3
stable in the refrigerator for several months if protected from
light. The formation of 9 was confirmed by high resolution
fast-atom bombardment mass spectroscopy measurements
1
and NMR and IR spectroscopies. The H NMR observation
of (R)-9 at 258C showed a single peak of for the two acetoxy
groups and three different types of aromatic protons,all in
accord with the fine symmetric structure of 9.
One important mechanistic insight into the reaction has
been identified by screening different solvents for the
oxidation of 1a with optically active (R)-9 (Table 1). The
ee values of 2a obtained from the reactions were highly
dependent on the solvent polarities. The results from using a
series of noncoordinative solvent systems showed good
correlation between the ee values and the ET values[14] of the
solvents (Table 1,entries 1–4). One possible explanation for
the phenomenon is that there is participation of discrete
cationic intermediates (B in Scheme 1) in the more polar
Figure 2. New chiral hypervalent iodine(III) reagent (R)-9.
Table 1: Correlation of the solvent polarity and ee values for the reaction
in [Eq. (2)].[a]
Surprisingly,reaction of optically active ( R)-9 with
naphthol 1a under the same conditions significantly enhanced
the selectivity to provide enantioenriched 2a in a good yield
[Eq. (2)].
Entry Solvent
ET(30)[b] [kcalmolꢀ1
]
ee [%] t [h] Yield [%]
1
2
3
4
5
6
CCl4
CHCl3
32.5
39.1
41.1
41.9
46.0
70
72
59
60
20
16
2
2
2
2
2
2
47
64
65
69
50
77
CH2Cl2
ClCH2CH2Cl
CH3CN
CH3CN/AcOH 46.5
(10:1)
7
(CF3)2CHOH
69.3
0
0.5
87
[a] The reactions were performed with 0.55 equiv (110 mol% iodine) of
(R)-9. [b] Reported values from reference [14].
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Angewandte
Chemie
solvents. In fact,the use of more polarizable solvents,such as
CH3CN,AcOH,and ultimately (CF 3)2CHOH,produced
increasingly inferior ee values as the ET values increased
(Table 1,entries 5–7).
Finally,the selected examples of the reactions with the 4-
alkoxy- and 4-alkylnaphthol derivatives 1 are listed in Table 2.
A slightly better ee value was obtained at lower temperature
(ꢀ508C; Table 2,entry 1). As expected from the ambident
oxidations makes the new chiral reagent (9) practical and
versatile.
In summary,we have succeeded in the first enantioselec-
tive oxidative dearomatization of phenols to construct a chiral
ortho-spirolactone structure under reagent control by the use
of new chiral organoiodine(III) compound 9. The reactions
demonstrate the highest level of the asymmetric induction
(c.a. 86% ee) in the field of iodine(III)-mediated trans-
formations,and detailed investigations into the transition-
state model of the present reaction will contribute to the
theoretical design of more effective chiral reagents; under-
standing the reaction mechanism will enable the advance of
phenolic oxidations in accord with the natural product
syntheses.
Table 2: Effect of the 4-substituents (R’’) of 1 on the ee values for the
reaction in [Eq. (1)].[a]
Entry
R’’
Product
ee [%]
Yield [%]
1
2
3
4
5
H (1a)
OMe (1b)
Et (1c)
Cy (1d)
Bn (1e)
(+)-2a
(ꢁ)-2b
(+)-2c
(+)-2d
(+)-2e
78
0
81
81
86
66
30
83
80
86
Received: January 29,2008
Published online: April 4,2008
[a] Performed with 0.55 equiv of (R)-9 in chloroform at ꢀ508C for 2 h.
Cy =cyclohexyl.
Keywords: asymmetric synthesis · hypervalent compounds ·
iodine · oxidation · quinones
.
nature of reaction intermediates A and B,the presence of the
electron-donating group in 1 reduced the ee value of product
2 even though it is located in a remote position (Table 2,
entry 2). In contrast,alkylnaphthols 1c–e were generally
suitable for fully exerting the stereoselective ability of reagent
(R)-9 in the oxidations (Table 2,entries 3–5). The new reagent
((R)-9) showed high reactivity suitable for providing oxida-
tion products 2 in good yields. The ability of reagent (R)-9 to
exert stereocontrol at the quaternary chiral carbon center in
products 2 indicates that the present method is a powerful
alternative to the previously reported oxidation methods of
enol ethers for obtaining chiral a-hydroxy ketones.[15]
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Although further explorations are required,catalytic use
of chiral reagent (R)-9 is possible by using the corresponding
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(mCPBA) as
a catalyst and co-oxidant,respectively
(Scheme 3).[16,17] Thus,both phenol 1a and functionalized 1 f
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and AcOH (1 equiv) in dichloromethane at 08C. After the
completion of the reaction catalyst iodoarene (R)-8 was easily
recovered by using silica gel column chromatography. In this
way,the use of our catalytic strategy for the phenolic
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Scheme 3. Catalytic utilization of the new chiral reagent.
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Communications
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