Isoxazole-assisted direct substitution of the hydroxy group in α-ketols: Introduction of angular substituents in a polycyclic system

Article abstract of DOI:10.1002/anie.200801577

(Chemical Equation Presented) The facile introduction of an angular substituent has become viable for the synthesis of natural products such as 2. Ketol 1 serves to achieve this through the direct substitution of its hydroxy group by a Lewis acid (see sch

Full text of DOI:10.1002/anie.200801577

Angewandte
Chemie
DOI: 10.1002/anie.200801577
Substitution Reactions
Isoxazole-Assisted Direct Substitution of the Hydroxy Group in
a-Ketols: Introduction of Angular Substituents in a Polycyclic System**
Hiroshi Takikawa, Katsuyoshi Hikita, and Keisuke Suzuki*
The type-II polyketide biosynthetic pathway produces a vast
array of polycyclic natural products such as 1[1] and 2,[2]
attracting the attention of the biochemical and synthetic
communities.[3] In our continued synthetic endeavors towards
these compounds, we searched for viable methods for
introducing the characteristic angular substituents
(Scheme 1).[4] We envisaged a-ketol A[5] as a key platform
to achieve this goal, hoping that the isoxazole moiety would
serve not only as a 1,3-dicarbonyl equivalent,[6] but also as a
hydroxy group (Scheme 2).[8] Although formation of a cation
next to a carbonyl group is disfavored,[9] we hoped that the
isoxazole unit would override the deficit. If viable, the process
would become a straightforward approach to angularly
substituted polycyclic natural products, such as 1 and 2.
Scheme 2. Direct installation of an angular substituent. Bn=benzyl.
Herein, we report the affirmative answer to this challenge,
that is, the isoxazole-assisted, direct substitution of a-ketol 3
with various nucleophiles to therefore allow the installation of
angular substituents in polycyclic systems.
The initial feasibility study is illustrative [Eq. (1)]: Upon
treatment of enantiomerically enriched a-ketol (R)-3
(98% ee)[5] with allyltrimethylsilane (3.0 equiv) in the pres-
ence of BF3·OEt2 (1.0 equiv, CH2Cl2, RT, 0.5 h), the desired
reaction proceeded smoothly to give the a-allyl ketone 4a in
94% yield. Notably, 4a was completely racemic, thus
suggesting the intermediacy of a well-developed cationic
species next to the isoxazole.
Scheme 1. Approach to polyketide-derived polycyclic natural products
with angular substituents.
“guiding functionality” to install an angular substituent (A!
B). This installation can hopefully be facilitated by the
recently discovered ability of isoxazoles to stabilize the a-
cationic species C.[7]
By recognizing these aspects, we reasoned that ketol 3
would be amenable to the direct SN1-type substitution of the
Encouraged by the promising opportunities for installing
various angular substituents by the SN1 pathway, we examined
the scope of this reaction, which led us to confirm its broad
applicability (Table 1). Heteronucleophiles, such as alcohol 5
and thiol 6, smoothly reacted at 08C to give ether 4b and
sulfide 4c in excellent yields (Table 1, entries 1 and 2).
Furthermore, installation of angular aryl or (hetero)aryl
groups by the Friedel–Crafts pathway proved to be achievable
(Table 1, entries 3–9). Phloroglucinol derivative 7 cleanly
gave ketone 4d in 92% yield (Table 1, entry 3), and N-
methylindole (8) reacted at ambient temperature, to give
exclusively the 3-substituted product 4e in 95% yield
(Table 1, entry 4). While phenol (9) gave a regioisomeric
[*] Dr. H. Takikawa, K. Hikita, Prof. Dr. K. Suzuki
Department of Chemistry
Tokyo Institute of Technology, SORST-JST Agency
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551 (Japan)
Fax: (+81)3-5734-2788
E-mail: ksuzuki@chem.titech.ac.jp
Homepage: http://www.chemistry.titech.ac.jp/~org_synth/
[**] We are grateful to Dr. Hidehiro Uekusa and Sachiyo Kubo for
X-ray analyses. This work was partially supported by the Global COE
program (Tokyo Institute of Technology) and a Grant-in-Aid for
Scientific Research (JSPS). A JSPS Research Fellowship for Young
Scientists to H.T. is also gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801577.
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Table 1: Reaction of a-ketol 3 with various nucleophiles.[a]
Entry
1[c]
Nucleophile
R[b]
T [8C]
t [h]
Yield [%]
0
10
87 (4b)
2
3
0
0
6
9
93 (4c)
92 (4d)
95 (4e)
4
5
RT
8.5
1
0!RT
36[d] (4 f)
48[d] (4g)
6[e]
7[e]
8[e]
9[e]
0
4
93 (4h)
90 (4i)
90 (4j)
94 (4k)
0
8
Scheme 3. Model studies toward 1 and 2.
15.[13] Gratifyingly, both substitution reactions smoothly
proceeded in an ortho-selective manner to afford the
corresponding products 4m and 4n in high yields.
RT
RT
1.5
16.5
Scheme 4 is an example for the diastereoselective version
of the process, in which a-ketol 16, having a methyl group at
the b position to the reacting center, was used as the model
substrate.[14] Notably, the stereochemical complementarity to
the pinacol-based approach was observed in the case of the
allylation to ketol 16. Upon treatment with allylsilane and
BF3·OEt2, ketol 16 underwent a retentive allylation from the
opposite side to the methyl group, to afford ketone 17a in
high yield. By contrast, the inverted installation of an angular
allyl group to a-ketol 16 by the pinacol-based approach gave
access to the isomeric ketone 19 as the sole product through
the nucleophilic addition and the 1,2-shift.
[a] Unless otherwise indicated, BF3·OEt2 (1.0 equiv) and nucleophile
(3.0 equiv) in CH2Cl2 (0.1m) at the temperature indicated. [b] Dots
represent the position of the connectivity. [c] BF3·OEt2 (1.5 equiv).
[d] Crude products were acetylated prior to the analysis. [e] Nucleophile
(2.0 equiv).
mixture of ortho- and para-products, 4 f and 4g (Table 1,
entry 5), substituted phenols 10–13 selectively reacted at the
ortho position to give 4h–4k (Table 1, entries 6–9). Electron-
rich phenols, 10 and 11, reacted smoothly at 08C (Table 1,
entries 6 and 7). Although the phenols 12 and 13 with
electron-withdrawing groups were less reactive, the reactions
smoothly proceeded at room temperature to afford the
corresponding products 4j and 4k in excellent yields.
At this stage, we embarked on the advanced model
studies, en route to isoprenoid hybrid 1 and bis(anthraqui-
none) 2 (Scheme 3). Associated with the regioselective
installation of an angular prenyl group, we examined an
indirect approach through cross metathesis:[10] The angular
allyl group in 4a was converted into a prenyl group to give 4l
in 78% yield by treatment with an excess amount of 2-methyl-
2-butene in the presence of the second-generation Grubbs
catalyst.
As a model for the stereoselective installation of an
angular anthraquinone unit, which is characteristic to 2,[11] we
examined the reactions of iodophenol 14[12] and naphthol
Scheme 4. Complementary approaches for an angular allylation.
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The diastereoselectivity was also observed with other
nucleophiles (Table 2). Heteronucleophiles exclusively gave
the corresponding trans products 17b and 17c in high yields
(Table 2, entries 1 and 2). The reactions of phenol 13 and
naphthol 15 occurred regio- and stereoselectively to afford
17d and 17e in excellent yields (Table 2, entries 3 and 4).
Experimental Section
Typical procedure for the SN1 substitution of a-ketol 3 with allyl-
trimethylsilane: BF3·OEt2 (20 mL, 0.16 mmol) was added to a solution
of a-ketol 3 (53 mg, 0.15 mmol) and allyltrimethylsilane (52 mg,
0.46 mmol) in CH2Cl2 (1.5 mL) at 08C. The reaction mixture was
allowed to warm to room temperature. After stirring for 0.5 h, it was
cooled to 08C and saturated NaHCO3 was added. The products were
extracted with EtOAc (ꢀ 3) and the combined organic extracts were
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by PTLC with n-hexane/
EtOAc (2:1) to give ketone 4a (53 mg, 94%) as a white solid.
Table 2: Reaction of a-ketol 16.[a]
Received: April 4, 2008
Published online: November 14, 2008
Keywords: Friedel–Crafts reactions · isoxazoles · polyketides ·
.
Entry
R
T [8C]
t [h]
Yield [%]
SN1 reaction
(trans/cis)[b]
80 (17b)
(>99:<1)
1[c]
2
0!RT
0!RT
3
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[a] Unless otherwise indicated, BF3·OEt2 (1.0 equiv) and nucleophile
(1.1 equiv) in CH2Cl2 (0.1m) at the temperature indicated. [b] The
stereochemical outcomes were determined by X-ray analysis (see the
Supporting Information). [c] BF3·OEt2 (3.0 equiv).
Scheme 5 illustrates the unmasking of b-diketone 21
through the reductive conversion of ketone 4a.[15] The
reductive opening of the isoxazole ring in 4a with molybde-
num hexacarbonyl[16] gave vinylogous amide 20, which turned
out to be unexpectedly resistant at undergoing hydrolysis by
usual acid hydrolysis.[17] However, we were pleased to find
that the desired hydrolysis could be executed with nitro-
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Scheme 5. Conversion of isoxazole 4a into 1,3-diketone 21.
[7] This ability is exploited in our previously reported method for
the stereocontrolled introduction of angular substituents: chiral,
non-racemic a-ketol 3 undergoes stereoselective addition of a
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In conclusion, the isoxazole-assisted SN1 substitution of a-
ketol allows facile introduction of angular substituents to
polycyclic structures. The efficient ability of the isoxazole unit
to stabilize the a-cation has promising potential in organic
synthesis, and further studies are underway in our laborato-
ries.
[8] For recent studies on SN1-type displacements of an hydroxy
group, see; a) A. Baba, M. Yasuda, Y. Nishimoto, T. Saito, Y.
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