Chiral tertiary 2-furyl alcohols: Diversified key intermediates to bioactive compounds. Their enantioselective synthesis via (2-furyl)aluminium addition to ketones catalyzed by a titanium catalyst of (S)-BINOL

Article abstract of DOI:10.1039/b802441c

Novel asymmetric 2-furyl additions of (2-furyl)AlEt₂(THF) to aromatic ketones and one α,β-unsaturated ketone catalyzed by a titanium catalyst of 10-20 mol% (S)-BINOL are reported to furnish tertiary furyl alcohols in good to excellent enantioselectivities of 87-93% ee. The Royal Society of Chemistry.

Full text of DOI:10.1039/b802441c

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Chiral tertiary 2-furyl alcohols: diversified key intermediates to bioactive
compounds. Their enantioselective synthesis via (2-furyl)aluminium
addition to ketones catalyzed by a titanium catalyst of (S)-BINOLw
Kuo-Hui Wu, Da-Wei Chuang, Chien-An Chen and Han-Mou Gau*
Received (in College Park, MD, USA) 12th February 2008, Accepted 10th March 2008
First published as an Advance Article on the web 17th April 2008
DOI: 10.1039/b802441c
Novel asymmetric 2-furyl additions of (2-furyl)AlEt2(THF) to
aromatic ketones and one a,b-unsaturated ketone catalyzed by a
titanium catalyst of 10–20 mol% (S)-BINOL are reported to
furnish tertiary furyl alcohols in good to excellent enantioselec-
tivities of 87–93% ee.
carbonyls or via additions of organometallic reagents to
furylaldehydes.2a,9 In asymmetric catalysis, studies reported
to date have demonstrated, in general, one example each of an
addition of the organometallic nucleophile to a furyl aldehyde
or a furyl ketone.10 Since organic carbonyls are one of the
most important functionalities in modern synthetic chemistry,
asymmetric catalytic additions of furyl groups to organic
carbonyls are a more appealing synthetic approach. In the
past few years, extensive efforts have been devoted to studies
of addition reactions to carbonyls,10,11 especially works of
nucleophilic additions to ketones.11c,12 Recently, we discov-
ered that triarylaluminium compounds are excellent aryl
sources in asymmetric additions to aldehydes or ketones
catalyzed by titanium complexes of H8-BINOL or BINOL13
and in coupling reactions with aryl bromides or chlorides
catalyzed by the economic Pd(OAc)2/PCy3 system,14 and it is
expected that the furylaluminium addition to organic carbo-
nyls will prove to be a highly potential route for the synthesis
of chiral furyl alcohols 1.
Substituted furans are key sub-structures in many natural
products and medicines,1 and synthetically they are important
intermediates leading to a wide variety of bioactive com-
pounds.2 Due to the diversified flexibilities of the furan
skeleton, furyl alcohols 1 can be converted into many useful
synthetic intermediates or chiral auxiliaries (Scheme 1) such as
a-hydroxy acids 2,3 6-hydroxy-6H-pyran-3-ones (3),4 5-hydro-
xymethyl-5H-furan-2-ones (4),5 (7-oxa-bicyclo[2,2,1]hept-1-
yl)-alcohols (5),6 masked o-benzoquinones (6),7 and others.8
Compounds 2 are unnatural lactic acids which are important
subunits in many peptide drugs and natural products, and 3
and 4 are skeletons of carbohydrates and others. Both chiral
compounds 5 and 6 are precursors of highly substituted ring
systems, and 5 can also be used for the synthesis of chiral
polycyclic systems. Despite the importance of chiral furyl
alcohols, asymmetric syntheses of 1 remains a challenge to
chemists and their syntheses are scattered across some papers
via chiral auxiliary induced metallic furyl additions to organic
To continue our efforts in developing organoaluminium
reagents for asymmetric catalysis, we report herein the first
catalytic asymmetric furylaluminium additions to ketones
employing a titanium catalyst of (S)-BINOL ligand (eqn
(1)). This is a practical catalytic system since the BINOL
ligands, which are commercially available, have been estab-
lished so as to be applicable to the most diversified asymmetric
catalytic reactions.15 The furylaluminium reagent designated
as (2-furyl)AlEt2(THF) (7) can be prepared easily from a
reaction of AlEt2X (X = Cl or Br) and furyllithium, which
is obtained in turn from a reaction of furan and n-butyl-
1
lithium. The H NMR spectrum of 7 reveals only one set of
signals belonging to the coordinated THF. However, three sets
of ethyl resonances and two sets of furyl signals were observed,
indicating that 7 in CDCl3 solution contained a mixture of
three major species. By comparing the spectrum of
AlEt3(THF) with that of 7 and examining integrals of ethyl
and furyl 1H resonances, the three species were assigned as
(2-furyl)xAlEt3ꢀx(THF) (x = 0, 1, or 2) with relative percen-
tages of 25 : 60 : 15% (see the electronic supplementary
information for the spectrum and 1H NMR assignmentsw).
Although the reagent 7 also contained trace amounts of
unidentified impurities, it was used directly in catalytic reac-
tions without a need of further treatment. In this study,
catalytic reaction conditions were optimized on an acetophe-
none (eqn (1)) and results are summarized in Table 1. The
Scheme 1
Department of Chemistry, National Chung Hsing University,
Taichung 402 Taiwan, Republic of China. E-mail:
hmgau@dragon.nchu.edu.tw; Fax: (+)886-4-22862547;
Tel: (+)886-4-22878615
w Electronic supplementary information (ESI) available: The synthesis
and 1H NMR data of (2-furyl)AlEt2(THF) and HPLC analytic
conditions and spectroscopic data of tertiary furyl alcohols. See
DOI: 10.1039/b802441c
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Table 1 Optimizations of (2-furyl)AlEt2(THF) (7) additions to
acetophenone catalyzed by the in situ-formed titanium catalysts of
(S)-BINOLa
Table 2 AlEt2(2-furyl)(THF) additions to ketones catalyzed by the in
situ-formed titanium complex of (S)-BINOLa
(S)-BINOL
(mol%)
Time/ Yieldd
ee
(%)
2-(Furyl)AlEt2(THF)
(equiv.)
Ti(O-i-Pr)4
(equiv.)
Yieldb
(%)
eec
(%)
Entry
1c
Ketone
h
(%)
Entry
10
20
20
12
90
93
90
93
1
2
3
4
5
6
7d
a
2.0
2.0
2.2
2.3
2.2
2.3
2.2
2.1
2.3
2.3
2.3
2.5
2.5
2.3
59
61
75
90
94
94
96
92
92
92
88
89
89
93
2b
12
12
74
78
BINOL: 0.050 mmol, PhCOCH3: 0.50 mmol, temp: 0 1C, time: 12 h,
THF, 6.0 mL. Yields were based 1H NMR. ee values were deter-
d
mined by HPLC using Chiralcel OD column. PhCOCH3 was added
b
c
3b
to the catalytic solution of (S)-BINOL/Ti(O-i-Pr)4 followed by the
addition of 7.
4c
10
12
74
92
reactions were first examined using 10 mol% (S)-BINOL and
Ti(O-i-Pr)4 as catalytic systems followed by an addition of 7
and then the acetophenone [Procedure A].z Under a reaction
condition of 2.1 equiv. Ti(O-i-Pr)4 and 2.0 equiv. furyl reagent
7, the reaction afforded the furyl alcohol in an excellent 92%
ee but the yield was only a moderate 59% (entry 1). In order to
improve product yields, quantities of both furylaluminium and
Ti(O-i-Pr)4 were tuned (entries 2–6). It was found that yields of
the product increased by increasing the quantity of Ti(O-i-
Pr)4. Though the product in excellent 94% yields was obtained
in catalytic systems of 2.5 equiv. Ti(O-i-Pr)4 (entries 5 and 6),
enantioselectivities dropped slightly to 89% ee. We later
discovered that the product in the highest 96% yield and the
best 93% ee (entry 7) was achieved when the substrate was
added prior to the furylaluminium 7 [Procedure B]z in a
reaction condition of 2.2 equiv. 7 and 2.3 equiv. Ti(O-i-Pr)4.
5c
10
10
24
12
70
86
92
91
6c
7b
20
10
24
12
40
92
93
90
8c
ð1Þ
9c
10
20
20
12
12
24
90
88
28
91
92
87
To demonstrate general applications of the furylaluminium
reagent, asymmetric additions of 7 to a variety of ketones (eqn
(2)) were examined by employing titanium catalysts of 10 or 20
mol% (S)-BINOL. Quantities of Ti(O-i-Pr)4 and (2-furyl)Al-
Et2(THF) used in asymmetric reactions varied slightly for
different substrates (see the electronic supplementary informa-
tion for details).w The ketones studied include aromatic ke-
tones with an electron-withdrawing or an electron-donating
substituent at the 20-, 30-, or 40-position on the aromatic ring
and an a,b-unsaturated ketone. Results are listed in Table 2.
For acetophenone, the furyl addition gave the chiral tertiary
furyl alcohol an isolated 90% yield and 93% ee (entry 1), and
the product had a reversed absolute configuration relative to
the furyl alcohol obtained from the phenyl addition to the
furyl methyl ketone.13b For aromatic ketones with an electron-
donating substituent, such as a methyl or a methoxy group at
30- or 40-position, the furyl addition reactions in 12 h afforded
desired furyl alcohols in good yields with excellent enantios-
electivities of 90–93% ee (entries 2–4). In cases of the methyl
substituent on the aromatic ring (entries 2 and 3), a higher
ligand loading of 20 mol% (S)-BINOL was used. The furyl
additions to aromatic ketones with an electron-withdrawing
10b
11b
12c
10
20
12
12
94
88
90
88
13b
a
Ketone/Ti(O-i-Pr)4/AlEt2(2-furyl)(THF) = 0.500/1.00–1.20/1.00–1.15
c
mmol; THF, 6 mL. b Procedure A. Procedure B. Isolated yield.
d
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substituent such as a chloro, a bromo, a CF3, or a NO2 at the
20- or 40-position gave corresponding furyl alcohols also with
excellent enantioselectivities of 90–93% ee (entries 5–10). It is
worth noting that the furyl addition to 20-chloroacetophenone
with a substituent at the ortho-position on the aromatic ring
required a longer reaction time of 24 h to afford the product in
70% yield (entry 5). The furyl addition to 20-bromoacetophe-
none required a higher ligand loading of 20 mol% and a
reaction time of 24 h to give the product in only 40% yield
(entry 7). A similar phenomenon was also observed for the
addition to 10-acetonaphthone employing 20 mol% (S)-BI-
NOL in 24 h, furnishing the product at a mere 28% yield but
with a good enantioselectivity of 87% ee (entry 11). In
contrast, the furyl addition to 20-acetonaphthone afforded
the product an excellent 94% yield and 90% ee (entry 12).
With the use of 20 mol% (S)-BINOL, the furyl addition to the
a,b-unsaturated ketone (entry 13) gave the furyl alcohol an
88% yield and a good 88% ee.
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In summary, the first extensive study of asymmetric catalytic
furylaluminium additions to aromatic ketones and one
a,b-unsaturated ketone are as follows. Though the furylalu-
minium reagent 7 was prepared as a mixture of three species
of formulas (2-furyl)xAlEt3ꢀx(THF) (x = 0, 1, or 2), the
addition reactions gave only chiral furyl alcohol with no
observations of ethylation products. The catalytic system
works excellently for aromatic ketones, having either an
electron-donating or an electron-withdrawing substituent on
the aromatic group, and furyl alcohols in enantioselectivities
from 87 to 93% ee were achieved. This study opens up a new
and easy route for the synthesis of highly reactive and
extremely flexible furyl alcohols 1 in high enantioselectivities.
Further studies of organoaluminium reagents in catalysis are
currently underway.
We would like to thank the National Science Council of
Taiwan, Republic of China for financial support under the
grant number of NSC-96-2113-M-005-007-MY3.
Notes and references
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a, L. K. LaRochelle and P. J. Walsh, J. Am. Chem. Soc.,
z Procedure A: (S)-BINOL (10 or 20 mol%) and Ti(O-i-Pr)4
(1.00–1.20 mmol) were mixed in 3 mL dry THF at room temperature.
The mixture was stirred for 1 h and the solution was cooled to 0 1C. A
solution of (2-furyl)AlEt2(THF) (7) (1.00–1.15 mmol) in 3 mL THF
was added to the above solution followed by a ketone (0.500 mmol).
The mixture was stirred at 0 1C for 12 h and quenched with 4 M
aqueous NaOH. The aqueous phase was extracted with CH2Cl2
(3 ꢂ 10 mL). The combined organic phase was dried over MgSO4,
filtered, and concentrated. The residue was purified by column chro-
matography to give the tertiary alcohol. The enantiomeric purity of
the product was determined by HPLC. The quantities of Ti(O-i-Pr)4
and (2-furyl)AlEt2(THF) used for asymmetric reactions depend on the
substrate and are given in the supporting information.
´
´
´
´
´
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w Procedure B: the procedure is similar to Procedure A except that the
ketone was added prior to (2-furyl)AlEt2(THF).
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Chem. Commun., 2008, 2343–2345 | 2345