Asymmetric organocatalytic synthesis of cis-substituted dihydrobenzofuranols via intramolecular aldol reactions

Article abstract of DOI:10.1055/s-2006-956454

The diastereo- and enantioselective synthesis of 3-hydroxy 2,3-dihydrobenzofurans via an intramolecular cis-selective aldol reaction employing proline-type organocatalysts is described enabling a new entry to coumarine natural products. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-956454

LETTER
3399
Asymmetric Organocatalytic Synthesis of cis-Substituted
Dihydrobenzofuranols via Intramolecular Aldol Reactions
Asymmetric
O
rga
n
i
ocataly
e
tic Synthe
t
c
e
r
d
D
ihydroben
E
zofuranols nders,*a Oliver Niemeier,a Leo Straverb
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
b
Bruker AXS B. V., Application SCD, Oostsingel 209, 2600AV Delft, The Netherlands
Received 28 September 2006
bon–carbon bond forming reaction.6 The intermolecular
cross-coupling between ketones and aldehydes7,8 as well
as between different aldehydes9 with mostly high stereo-
selectivities has been reported. In contrast, catalytic asym-
metric intramolecular aldol reactions, both enolendo and
enolexo aldolizations, are less well developed. The
proline-catalyzed Eder–Sauer–Wiechert–Hajos–Parrish
reaction10, a 6-enolendo aldolization, as well as its
application11 have been established. Only recently a 6-
enolexo aldolization of dicarbonyl compounds was de-
scribed by List et al.12a The corresponding 5-enolexo
aldolizations have been reported to be much less
stereoselective. In 2005 Iwabuchi et al. reported an asym-
metric intramolecular enolexo aldolization starting from
s-symmetric keto-aldehydes as an entry to bicyc-
lo[3.n.1]alkanones.12b
During our efforts in carbene organocatalysis13,14 2,3-di-
hydrobenzofuranols were obtained as an undesired side
product in the generation of 4-chromanones via intramo-
lecular benzoin cyclizations which could be suppressed.15
In continuation of our recent investigations in asymmetric
organocatalysis16 directed towards the synthesis of bioac-
tive natural products, we herein wish to report a proline-
catalyzed asymmetric intramolecular cis 5-enolexo al-
dolization affording various 2,3-dihydrobenzofuranols
(Scheme 1).
Abstract: The diastereo- and enantioselective synthesis of 3-hy-
droxy 2,3-dihydrobenzofurans via an intramolecular cis-selective
aldol reaction employing proline-type organocatalysts is described
enabling a new entry to coumarine natural products.
Key words: organocatalysis, aldol reaction, asymmetric synthesis,
proline, dihydrobenzofuran
The natural product class of dihydrobenzofuranols has re-
cently received considerable attention since they have
been shown to possess antimicrobial activity.1 In addition,
the
2,3-dihydro-3-hydroxy-2-[1-hydroxy-1-(meth-
yl)alkyl]benzofuran moiety 1, accessible from the title
compounds by a simple 1,2-addition, is present in numer-
ous natural products2 including the enantiopure cis-con-
figured coumarins smyrindiol (2)3 and vaginidiol (3,
Figure 1).4 While closely related structures of smyrindiol
(2) are found to possess poisonous properties, they are
also used as drugs for the treatment of vitiligo and are
claimed to be potent coronary vasodilatators. Vaginidiol
(3) is a plant growth regulating substance. The preparation
of 2 and 3 starting from enantiopure epoxy aldehydes re-
sulting in cis and trans mixtures has been reported recent-
ly.2 An asymmetric synthesis of this class of natural
products has not been reported so far.
OH
We initially screened several solvents and additives with
(S)-proline as catalyst (30 mol%) at room temperature to
find appropriate reaction conditions for the cyclization of
the aldehyde-ketone 4a17 to favor the desired aldol reac-
tion to the dihydrobenzofuranol 5a over the competing
condensation reaction. DMF (0.1 M) as solvent gave the
best results (91% yield) in combination with an excellent
diastereoselectivity of 94% and an enantiomeric excess of
76%. The diastereo- and enantiopure 5a could be obtained
after simple recrystallization from ethyl acetate–n-hexane
(Table 1).
*
Me
OH
*
O
1
R
.
O
.
OH
O
OH
Me
OH
.
Me
OH
O
Me
O
O
O
Me
2
3
Figure 1 2,3-Dihydrobenzofuran moiety 1 and the natural products
smyrindiol (2) and vaginidiol (3)
Then, we carried out a catalyst screening with the enan-
tiopure pyrrolidine derivatives 6–13 at different tempera-
tures to find the optimal catalyst system (Table 1).
However, (S)-proline turned out to give the best stereose-
lectivities combined with a high yield. To our surprise, the
selectivities could not be improved by performing the re-
action at lower temperatures. Catalysts more soluble in
DMF like (S)-7, (S)-10 or (S)-11 showed shorter reaction
times, but lower yields due to the condensation of the
Asymmetric organocatalysis is a rapidly growing and im-
portant field of organic chemistry.5 Especially the proline-
catalyzed aldol reaction plays an important role as car-
SYNLETT 2006, No. 20, pp 3399–3402
Advanced online publication: 08.12.2006
DOI: 10.1055/s-2006-956454; Art ID: G31106ST
© Georg Thieme Verlag Stuttgart · New York
1
8
.1
2
.2
0
0
6

3400
D. Enders et al.
LETTER
The dihydrobenzofuran 5b (R2 = Et) could be obtained
with a slightly decreased yield of 74% due to the compet-
ing condensation reaction and still high diastereo- and
enantioselectivities. Again a recrystallization from ethyl
acetate–n-hexane yielded the enantiopure product. More
sterically demanding substituents at R2 such as n-propyl
and isobutyl caused much lower yields accompanied by a
significant decrease of the stereoselectivity.
O
OH
*
30 mol%
catalyst 6–13,
solvent, temp.
*
O
.
.
.
.
.
O
O
Me
O
Me
4a
5a
XO
OH
OH
NHTs
N
H
N
H
N
H
O
O
O
O
.
R3
1
(S)-6
(S)-7, X = TBS, TBDPS
(R)-8
catalyst 6/9 (30 mol%),
DMF (0.1 M), r.t.
OH
R3
2
O
.
.
.
O
.
.
.
3
N
38–96%
NHTf
R2
O
O
R2
N
R1
4
R1
N
N
N
4a–f
5a–f
N
N
N
H
H
H
H
de 71–99%, ee 64–87%
(de, ee = 99%)a
(R)-9
(S)-10
(R)-11
O
Me
N
Scheme 2 Scope of 3-hydroxy 2,3-dihydrobenzofurans (Table 2).
Ar
Ar
a After recrystallization.
Me
N
H
Bn
N
OTMS
Me
H2
Cl
However, a broad range of aryl substituents R1 is tolerat-
ed. The 2-methyl-substituted aldehyde-ketone 4c could be
cyclized with an increased enantiomeric excess of 86%
and obtained enantiopure after recrystallization. Activat-
ed substrates required short reaction times. The reaction to
yield the 2,3-methylenedioxo-substituted dihydrobenzo-
furan 5d showed a full conversion after seven hours with
87% ee. In this case the diastereomeric excess of 71%
could be slightly increased by performing the reaction
at 5 °C, but a much longer reaction time of 72 hours,
probably due to the low solubility of the catalyst, was
observed.
(S)-12
(S)-13, Ar = 3,5-difluorophenyl
Scheme 1 Optimization studies of the organocatalytic dihydroben-
zofuranol synthesis (Table 1)
product to the corresponding benzofuran and a significant
decrease of the stereoselectivity.
After the adjustment of the reaction parameters, several
aldehyde-ketones 4a–f could be transformed cis-selec-
tively into the corresponding 3-hydroxy-2,3-dihydroben-
zofurans 5a–f (Scheme 2, Table 2).
Table 1 Optimization of the Intramolecular cis-Selective Aldol Reactiona
Entry
Catalyst
Time
24 h
72 h
75 min
75 min
48 h
3 d
Yield (%)
de/ee (%)b
94/76 (99/99)d
91/69
74/61
91/57
84/68
89/77
96/68
19/–
Config.c
2S,3R
2S,3R
2S,3R
2S,3R
2S,3R
2R,3S
2R,3S
–
1
2
(S)-6
91 (69)d
90
(S)-6e
3
(S)-7 (X = TBS)
(S)-7 (X = TBDPS)
(S)-7 (X = TBDPS)f
(R)-8
89
4
64
5
68
6
66
7
(R)-9
15 h
2 h
86
8
(S)-10
32
9
(R)-11
3 h
82
83/71
–
2R,3S
–
10
11
(S)-12
4 d
–
(S)-13
7 d
–
–
–
a Reagents and conditions: catalyst (30 mol%), DMF (1.0 M), r.t.
b Determined by chiral stationary phase HPLC (Daicel Chiracel OD).
c The absolute configuration was determined by X-ray analysis of 5b.18
d After recrystallization.
e Reaction at 5 °C.
f Reaction at 0 °C.
Synlett 2006, No. 20, 3399–3402 © Thieme Stuttgart · New York

LETTER
Asymmetric Organocatalytic Synthesis of cis-Substituted Dihydrobenzofuranols
3401
Table 2 Scope of the Intramolecular cis-Aldolization of 4 to Yield the Dihydrobenzofurans 5a
Product 5
R1
R2
R3
H
Catalyst
(S)-6
(S)-6
(S)-6
(S)-6
(S)-6
(R)-9
(S)-6
(S)-6
Time
24 h
24 h
20 h
7 h
Yield (%) de/eeb (%)
Config.c
a
H
Me
Et
91 (69)d
74 (52)d
89 (72)d
87
94/76 (99/99)d
2S,3R
2S,3R
2S,3R
2S,3R
2S,3R
2R,3S
2S,3R
2S,3R
b
c
H
H
88/77 (99/99)d
97/86 (99/99)d
71/87
2-Methyl
Me
Me
Me
Et
H
d
de
e
2,3-Methylenedioxo
H
2,3-Methylenedioxo
H
72 h
7 d
85
73/87
2,4-Dibromo
H
38 (21)d
96
73/64 (99/99)d
99/73
f
H
H
Me
Me
Me
Me
20 h
5 d
Fe
96
99/79
a Reagents and conditions: catalyst (30 mol%), DMF (0.1 M), r.t.20
b Determined by chiral stationary phase HPLC (Daicel Chiracel OD/OJ, Daicel Chiralpak IA).
c The absolute configuration was confirmed by X-ray analysis of 5b.18
d After recrystallization.
e Reaction at 5 °C.
The 2,4-dibromo-substituted substrate 4e could only be The relative topicity and thus the relative and absolute
converted into the aldol condensation product with (S)- configuration observed might be explained by an intramo-
proline [(S)-6] at room temperature. Utilizing the tetrazol lecular version of a Houk–List-type transition-state
catalyst (R)-9 the desired cis-aldol product could be model19 shown in Figure 3.
obtained albeit with a moderate yield of 38% and a
O
decreased stereoselectivity of 64% ee. After recrystalliza-
R3
(R)
tion, again a single stereoisomer was isolated.
HO
like-attack
OH
O
Si
O
The acetyl-substituted dicarbonyl substrate 4f (R3 = Me)
was also tested in the organocatalytic dihydrobenzofura-
nol synthesis generating a quaternary stereocenter. We
were delighted to obtain the dihydrobenzofuranol 5f as a
single product and diastereomer. The possible 7-enolendo
aldolization was not observed. The enantiomeric excess of
73% was increased by performing the reaction at 5 °C to
79%.
R2
.
N
R3
.
.
(S)
(E)
R2
O
R1
Si
O
R1
Figure 3 Postulated transition state
In conclusion, we have developed an efficient asymmetric
organocatalytic intramolecular 5-enolexo aldol reaction
affording cis-selectively the title 3-hydroxy 2,3-dihy-
drobenzofurans. The application of our protocol in the or-
ganocatalytic asymmetric synthesis of natural products
bearing this key structural motif, for example the cou-
marins smyrindiol and vaginidiol, are currently in
progress.
The absolute configuration of the dihydrobenzofuranols 5
was assigned by X-ray structure analysis of 5b18 to be
2S,3R utilizing (S)-proline as catalyst (Figure 2). The cis-
selectivity of the reaction was further confirmed by com-
parison of the coupling constants of the methine protons a
1
to oxygen of the cis and trans isomers in the H NMR
spectra. The coupling constant was found to be 6.6 Hz for
the major isomer and 3.3 Hz for the minor isomer, which
indicates the cis configuration of the ring, and in addition
was confirmed by NOESY measurements.
Acknowledgment
This work was supported by the Deutsche Forschungsgemein-
schaft (Priority Programme 1179 Organocatalysis) and the Fonds
der Chemischen Industrie. We thank Degussa AG, BASF AG,
Bayer AG and Wacker Chemie for the donation of chemicals.
References and Notes
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1761.
Figure 2 X-ray structure of 5b
Synlett 2006, No. 20, 3399–3402 © Thieme Stuttgart · New York

3402
D. Enders et al.
LETTER
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(17) Aldehyde ketones of type 4 can be synthesized by reaction
of the corresponding salicyl aldehydes, K2CO3 and a-bromo
ketones in DMF at r.t.
(18) CCDC 617162 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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Asymmetric Organocatalytic Intramolecular cis-Aldol
Reaction to 5b – Typical Procedure.
To a suspension of (S)-proline (17.3 mg, 0.15 mmol, 30
mol%) in DMF (0.5 mL) was added the aldehyde-ketone 4b
(96 mg, 0.5 mmol) and stirred at r.t. for 24 h. The mixture
was quenched with a pH 7 buffer solution, extracted with
Et2O (3 ×) and dried over MgSO4. The solvent was
evaporated and the crude product was purified by flash
chromatography on silica gel (Et2O–n-pentane, 1:2) to yield
5b (71 mg, 74%) as a colorless solid; mp. 106 °C; de 88%
(99% after recrystallization, determined by GC); ee 77%
[99% after recrystallization, determined by chiral stationary
phase HPLC (Daicel Chiralpak IA)]; [a]D23 –149.5 (c 1.7,
CHCl3). IR (KBr): 3363, 2971, 2927, 1720, 1601, 1469,
1394, 1311, 1237, 1166, 1024, 981, 939, 847, 748, 634, 490
cm–1. 1H NMR (400 MHz, CDCl3, TMS): d = 1.09 (t, 3 H,
J = 7.3 Hz, CH3), 2.58 (s, 1 H, OH), 2.63 (dq, 1 H, J = 7.2,
18.7 Hz, CHH), 2.80 (dq, 1 H, J = 7.2, 18.7 Hz, CHH), 4.98
(d, 1 H, J = 6.6 Hz, CH), 5.54 (d, 1 H, J = 6.6 Hz, CH), 6.95–
6.97 (m, 1 H, ArH), 6.98–7.01 (m, 1 H, ArH), 7.29–7.33 (m,
1 H, ArH), 7.40–7.42 (m, 1 H, ArH). 13C NMR (100 MHz,
CDCl3): d = 6.7 (CH3), 34.1 (CH2), 73.0, 89.9, 110.6, 121.6,
125.7 (CH), 126.6 (C), 131.0 (CH), 159.3 (C), 208.7 (CO).
MS (EI): m/z (%) 192 (25) [M+], 121 (7), 119 (9), 118 (100),
107 (7), 79 (10), 77 (11), 57 (13). Anal. Calcd for C11H12O3:
C, 68.74; H, 6.29. Found: C, 68.96; H, 6.65.
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in Asymmetric Synthesis, In Enantioselective
Synlett 2006, No. 20, 3399–3402 © Thieme Stuttgart · New York