Silver-catalyzed asymmetric synthesis of 2,3-dihydrobenzofurans: A new chiral synthesis of pterocarpans

Article abstract of DOI:10.1002/chem.200600332

2,3-Dihydrobenzofurans can be diastereoselectively prepared by condensation of aromatic aldehydes with 2,3-dihydrobenzoxasilepines under the catalysis of Ag¹ complexes, and in the presence of a source of fluoride ion. The application of this st

Full text of DOI:10.1002/chem.200600332

DOI: 10.1002/chem.200600332
Silver-Catalyzed Asymmetric Synthesis of2,3-Dihydrobenzofurans: A New
Chiral Synthesis ofPterocarpans
Leticia JimØnez-Gonzµlez, Sergio García-MuÇoz, Miriam lvarez-Corral,
Manuel MuÇoz-Dorado, and Ignacio Rodríguez-García*[a]
Abstract: 2,3-Dihydrobenzofurans can be diastereoselectively prepared by conden-
sation of aromatic aldehydes with 2,3-dihydrobenzoxasilepines under the catalysis
of AgI complexes, and in the presence of a source of fluoride ion. The application
Keywords: allylation · enantioselec-
of this strategy by using chiral catalysts leads to a new enantioselective total syn-
tivity · natural products · oxygen
thesis of natural cis-pterocarpans and their trans isomers. Through this method,
heterocycles · silanes
the first enantioselective total synthesis of the antifungal agent (À)-pterocarpin
was achieved. In addition, a new entry into the heteroaromatic system of 2,5-dihy-
drobenzoxepine is also presented.
Introduction
acid (Sakura—Hosomi modified reaction). In this paper, we
investigated the possibility of using a chiral Lewis acid to
perform an asymmetric condensation. In this way, 2,3-disub-
stituted-2,3-dihydrobenzofurans can be enantioselectively
prepared, which is the crucial step in the asymmetric synthe-
sis of pterocarpans by our methodology.
2,3-Dihydrobenzofuran (coumaran) is a basic skeleton often
found in natural products (pterocarpans, lignans) and other
biologically active molecules. Therefore, efficient and enan-
tioselective methods to construct such a moiety are strongly
desirable. Many of the procedures used in the construction
of this structure involve radical cyclizations that show low
diastereoselectivity and no enantioselectivity.[1–5]
Results and Discussion
On the other hand, pterocarpans constitute numerous nat-
ural isoflavonoids[6] that have a benzofuranyl–benzopyran
skeleton. These are produced by plants in response to phy-
topathogenic fungi infections[7] and are interesting due to
their wide range of biological activities against, for example,
tumors,[8] HIV,[9,10] malaria,[11] and snake venom.[12] Not
many syntheses of enantiomerically pure pterocarpans have
been reported so far, and most of these are based on race-
mic resolutions.[13–16]
Recently, we described a new strategy for a total synthesis
of pterocarpans[17] in which one of the key reactions is the
diastereoselective condensation of a 2,3-dihydrobenzoxasile-
pine with an aromatic aldehyde in the presence of a Lewis
Synthesis of2-aryl-3-vinyl-2,3-dihydrobenzoufrans by using
AgI complexes as Lewis acids: In a previous work we report-
ed that the condensation between compounds 1 and 2
(Scheme 1) in the presence of BF3·Et2O yields the corre-
sponding 2,3-dihydrobenzofuran with cis geometry.[17] The
desirable enantioselection for this process could be derived
from the use of Lewis acids that integrate chiral ligands into
their structure. Firstly, we examined the TiF4/BINOL system
that had proved to be useful for the catalytic allylsilylation
of aldehydes by using allyltrimethylsilane,[18] but in our case,
we just recovered the starting materials. The same result
was obtained with Ti
workers reported that the BINAP·AgF (BINAP=2,2’-bis-
(diphenylphosphino)-1,1’-binaphthyl) complex in metha-
A
[a] Dr. L. JimØnez-Gonzµlez, Dr. S. García-MuÇoz,
Dr. M. lvarez-Corral, Dr. M. MuÇoz-Dorado,
Dr. I. Rodríguez-García
AHCTREUNG
nol[20] and the system KF/[18]crown-6 ether with the BINAP·
AgOTf complex (TfO=trifluoro methanesulfonate) in polar
aprotic solvents[21] are reactive chiral catalysts for asymmet-
ric allylation with trimethoxysilanes. When we applied these
methodologies to our substrates, the reaction was complete-
ly diastereoselective, but only the trans diastereoisomer
Departamento de Química Orgµnica
Universidad de Almería, 04120 Almería (Spain)
Fax : (+34)950-015-481
E-mail: irodrigu@ual.es
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
8762
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Chem. Eur. J. 2006, 12, 8762 – 8769

FULL PAPER
(Æ)-3 was obtained (Scheme 1). The results are summarized
in Table 1. The relative stereochemistry of (Æ)-3 was as-
signed from NMR properties, the NOE effect observed be-
tween H-2 and H-1’’ atoms being especially significant. The
the reaction was needed. By using the optimized conditions
(entry VII) several benzo[f][1,2]oxasilepines were con-
G
densed with a range of aromatic aldehydes. Only the trans
diastereoisomers were obtained, with moderate to good
yields (Scheme 2 and Table 2). The stereochemistry of 6a–g
was established in the same way as for compound 3.
Scheme 1. Formation of dihydrobenzofuran (Æ)-3.
Table 1. Reaction conditions for the synthesis of 3.
Scheme 2. Formation of 2,3-dihydrobenzofuran derivatives (Æ)-6a–g.
Entry
I
2[a]
1[a]
System[a,b]
Solvent
MeOH
T
t[h]
Yield
s.m[e]
1.5
1
0.1 (A)
RT
22
The 2,3-dihydrobenzofuran derivatives reported in en-
tries 5–8 of the table can be transformed by following a pre-
viously reported methodology[17] into the natural pterocar-
pans pterocarpin, homopterocarpin, medicarpin, and maack-
reflux
reflux
RT
2.5
1.5
1.5
4
II
III
IV
1
1
1
2
2
2
1 (A)
1 (A)
0.2 (A)
MeOH
s.m[d]
s.m
40 %
[c]
CH2Cl2
THF[c]
RT
reflux
reflux
RT
24
ianin, respectively. The behavior of benzo[f][1,2]oxasilepines
A
V
VI
VII
1
1
1
2
1.5
1.5
1 (A)
0.2 (B)
0.2 (C)
THF[c]
THF
THF
1.5
0.5
0.5
55%
15%
70%
5b and 5c is remarkable and is in contrast with their low re-
activity upon using BF3·Et2O as Lewis acid.[25]
RT
We initially chose all the aldehydes that have an esterified
hydroxy group in the 2-position to allow a later cyclization
of the B ring of the pterocarpan skeleton. As deprotection
of the OH is observed in all the reactions, we can conceive
that the protective group plays a role in the reaction mecha-
nism (Scheme 3). The silver complex can coordinate both
oxygen atoms of the aldehyde and the ester to form an
eight-membered ring. The addition of the allylsiloxane to
[a] Amounts of compounds refer to equivalents. [b] System A: AgF/(Æ)-
BINAP (1:1); system B: AgOTf/(Æ)-BINAP/KF/[18]crown-6 (1:1:1:1);
system C: AgOTf/(Æ)-BINAP/KF/[18]crown-6 (1:1:5:5). [c] System
A
was prepared in MeOH (5 min), then the MeOH was removed and the
indicated solvent was added. [d] Compound 2 was recovered unaltered
and compound 1 was recovered as its dimethylacetal derivative. [e] s.m.=
starting material.
shielding of the signal of H-2
in the trans isomer compared
Table 2. 2,3-Dihydrobenzofuran synthesis.
to the cis isomer (formed in
the BF3·Et2O-promoted reac-
tion[17]) is also significant. This
behavior was reported previ-
Entry
Substrates[a]
4a R1 =Piv, R2 =H; 5a R3 =R4 =H
Product
6a R2 =R3 =R4 =H
Yield
1
2
3
4
5
6
7
8
65
70
60
75
70
65
60
70
4b R1 =Ac, R2 =H; 2 R3 =OCH3, R4 =H
4c R1 =Piv, R2 =OPiv; 2 R3 =OCH3, R4 =H
4a R1 =Piv, R2 =H; 2 R3 =OCH3, R4 =H
4d R1 =Piv, R2 =OCH3; 5b R3 =R4 =OCH2O
4d R1 =Piv, R2 =OCH3; 5c R3 =R2 =H, R4 =OCH3
4c R1 =Piv, R2 =OPiv; 5c R3 =H, R4 =OCH3
4c R1 =Piv, R2 =OPiv; 5b R3 =R4 =OCH2O
6b R2 =R4 =H, R3 =OCH3
6c R2 =OPiv, R3 =OCH3, R4 =H
6b R2 =R4 =H, R3 =OCH3
6d R2 =OCH3, R3 =R4 =OCH2O
6e R2 =R4 =OCH3, R3 =H
6 f R2 =OPiv, R3 =H, R4 =OCH3
6g R2 =OPiv, R3 =R4 =OCH2O
ously
for
similar
com-
pounds.[22,23]
From analysis of Table 1 it
can be concluded that the
choice of solvent is critical.
Thus, the previously successful
[a] For the synthesis of the starting materials, see Supporting Information.
system A (AgF/(Æ)-BINAP in
MeOH)[20] gave only the dimethylacetal derivative of the al-
dehyde (entry II). In CH2Cl2 and by using a separately pre-
pared complex, no progress was observed (entry III). Mod-
erate yields were obtained in THF (entries IV and V). To
avoid this two-step procedure the source of fluoride was
this complex gives the intermediate I that, after silver-cata-
lyzed transesterification, leads to the intermediate II. Even-
tually cyclization takes place to form the 2,3-dihydrobenzo-
furan system.
The most stable diastereoisomer (trans) is formed, and
this can be easily understood by considering that the first
step (Scheme 4) is under steric-approach control, path A
being more feasible than path B. A Lewis acid-promoted
isomerization could also take place through reversible ring-
opening of the final benzofuran, as reported previously by
Marsden and co-workers.[23] However, as there are no
changes in diastereoselectivity in response to reaction tem-
perature, we consider this last option less feasible.
changed to KF, by using [18]crown-6 ether to solubilize it
(system B). Although the conditions described
[21,24]
gave us
a low yield, we could improve it by using a stoichiometric
amount of KF/[18]crown-6 (system C), with the extra ad-
vantage of shorter reaction times and lower working temper-
atures.
As the diastereoselectivity of the reaction was the oppo-
site to that observed upon using BF3·Et2O, a closer study of
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8763

I. Rodríguez-García et al.
a leaving group would preclude
the intramolecular cyclization
that gives rise to the benzofur-
an ring closure.
Careful column chromatog-
raphy allowed the separation
of both diastereoisomers in
each of the reactions depicted
in Scheme 5. Although their
structures were confirmed by
their NMR properties, the rela-
tive stereochemistry of the
vinyl and hydroxy group could
be only proposed, and was
Scheme 3. Proposed mechanism for the formation of dihydrobenzofurans (Æ)-6a–g.
confirmed after the subsequent transformation. It was our
intention to prepare the corresponding 2,3-dihydrobenzofur-
an systems from the isolated diastereoisomers of the homo-
allylic alcohols. Therefore, compounds 8 and 9 were subject-
ed to Mitsunobu reaction conditions (diisopropyl diazodicar-
boxylate (DIAD)/PPh3/THF, Scheme 6). In each case, one
Scheme 4. Steric-approach control in the diastereospecific formation of
dihydrobenzofurans (Æ)-6a–g. Path A depicts the most favored approach
of one side of the allylsiloxane, path B shows how the attack from the
other side is always disfavored.
Scheme 6. Differences in behavior towards Mitsunobu cyclization of the
syn and anti diastereoisomers of 8 and 9.
To confirm this hypothesis we next tried the reaction with
a series of aldehydes lacking ortho substituents, so we could
check whether the ester was really involved in the process.
Condensation of the same benzoxasilepines with several
para-substituted benzaldehydes under the same reaction
conditions gave a different result. The reaction was com-
plete within a shorter time, but no cyclic products were ob-
tained (Scheme 5). Furthermore, no diastereoselectivity was
observed this time as 1:1 mixtures of both possible diaster-
eoisomers were formed in all cases. In the reactions depicted
in Scheme 5, silver would coordinate only the oxygen of the
aldehyde, which would lead to the formation of both diaster-
eoisomers through an open-chain intermediate. The lack of
of the diastereoisomers led to the desired product (10 or 11)
that has a trans relative disposition of the substituents in the
oxygenated ring, indicating a syn relative configuration of
the initial homoallylic alcohol (8 or 9). To our surprise, each
one of the anti diastereoisomers leads, under the same reac-
tion conditions, to the 5-phenyl-2,5-dihydrobenzo[b]oxepines
12 and 13, respectively. Possibly, the stereoelectronic re-
quirements for the intramolecular SN2 cyclization in the Mit-
sunobu reaction are not easily reached.
The transition state in a benzylic substitution is stabilized
by the p-bond overlap that may arise if the nuclei and p or-
bitals are arranged in such a
way that the (ideally straight)
line joining the attacking atom
of the nucleophile (Nu), the
carbon atom being substituted
(C), and the departing atom of
the leaving group (LG) is or-
thogonal to the plane defined
by the nuclei of the aromatic
Scheme 5. Synthesis of compounds (Æ)-7–9.
ring (Scheme 7).[26]
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Chem. Eur. J. 2006, 12, 8762 – 8769

Asymmetric Synthesis of 2,3-Dihydrobenzofurans
FULL PAPER
H bond of an olefin in arene–chromium tricarbonyl com-
plexes,[34] and Pd-catalyzed annulation of O-substituted 1,3-
dienes.[35]
Asymmetric synthesis of trans-pterocarpin: The last stage
was to check the applicability of the method to the asym-
metric total synthesis of natural pterocarpans. Here, we de-
scribe the enantioselective total synthesis of (À)-trans-ptero-
carpin and its isomerization into the natural (À)-cis-ptero-
carpin. Compound (+)-6d was prepared by using the previ-
ously optimized reaction conditions and silver complexes
with enantiomerically pure ligands. With (+)-(R)-BINAP at
room temperature, the ee is low, however, it can be in-
creased by decreasing the reaction temperature and by
using (+)-TolBINAP (84% ee at À808C). The results are
summarized in Table 3. The optical purity was assessed by
1H NMR spectroscopy by employing europium tris[3-(hepta-
fluoropropylhydroxymethylene)-(+)-camphorate] (Eu(hfc)3)
A
as a chiral-shift reagent, followed by confirmation by con-
ducting chiral HPLC.
Scheme 7. Benzylic substitution leading to 10 and 11, and proposed rear-
rangement for the formation of 12 and 13.
Table 3. Effects of ligand and temperature on enantioselectivity in the
preparation of (+)-6d.[a]
Entry
Ligand
T[8C]
t[h]
Yield[%]
ee[%]
Although for the syn diastereoisomers this requirement is
easily achieved (III), a similar arrangement in the anti dia-
stereoisomers would suffer from steric destabilization (IV),
because one of the hydrogen atoms on the aromatic ring
and one of the carbon atoms in the vinyl group would be
too close. In the alternative arrangement shown in V, the
Nu-C-LG line is coplanar with the aromatic carbons and,
hence, any benzylic substitution would proceed much more
slowly than in the unconstrained analogue. In this situation,
a phenyl group migration would take place more readily,
generating an allylic cation (VI) that will collapse into the
2,5-dihydrobenzo[b]oxepines 12 and 13.
An alternative path leading to the formation of structures
like 12 and 13 was described previously for similar com-
pounds.[27] Departure of the leaving group (Ph3P=O) would
lead to formation of a cyclopropane intermediate that
would form the seven-membered ring through a [3s,3s] peri-
cyclic reaction. However, the reported temperature is so
high that this would be very unlikely in our particular case.
2,5-Dihydrobenzo[b]oxepines are of pharmacological rele-
vance and occur in a number
1
2
3
4
5
6
7
8
(+)-(R)-BINAP
(+)-(R)-BINAP
(+)-(R)-BINAP
RT
0.5
0.5
1
70
74
69
70
71
72
70
75
29
39
54
69
39
57
63
84
À20
À45
À80
RT
À20
À45
À80
(+)-(R)-BINAP
3
(+)-(R)-TolBINAP
(+)-(R)-TolBINAP
(+)-(R)-TolBINAP
(+)-(R)-TolBINAP
0.5
0.5
1
3
[a] See entry VII in Table 1 for relative quantities.
The total synthesis of natural (À)-pterocarpin was com-
pleted as shown in Scheme 8 by the ring closure of the dihy-
drobenzopyran unit through the double-bond degradation
(catalytic osmium tetroxide in excess of NaIO4), aldehyde
reduction (LiAlH4), and Mitsunobu cyclization (DIAD/
PPh3) of the dihydroxy derivative. The trans pterocarpan
was isomerized into the more stable natural cis structure
through a high-yielding (97%) treatment with camphorsul-
fonic acid (CSA) in toluene at 1108C.[36]
of natural products, such as
heliannuol B[28] and in the ra-
dulanins A, H, and L.[29,30] Nev-
ertheless, there are very few
methods of synthesis of this
heterocyclic system, mainly
ring-closing metathesis[31] and
the Mitsunobu cyclization.[32]
This system has also been
formed as minor byproducts of
radical homoallylation,[33] inser-
À
tion of a triple bond into a C
Scheme 8. Synthesis of (À)-cis-pterocarpin.
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I. Rodríguez-García et al.
(CH, C-6), 110.3## (CH, C-6’), 89.7 (CH, C-2), 55.9 (CH3, OCH3), 55.7
Conclusion
#
##
(CH3, OCH3), 54.7 ppm (CH, C-3) (*, and may be interchanged); IR
(film): n˜max =3396, 2999, 2932, 2833, 1486, 1432, 1270, 1202, 1034,
750 cmÀ1; HRMS (EI): m/z: calcd for C18H18O4: 298.1205 [M]+; found:
298.1203.
We have described a convergent strategy for the silver-cata-
lyzed diastereoselective synthesis of trans-2-aryl-3-vinyl-2,3-
dihydrobenzofurans. This methodology can be applied to
the asymmetric synthesis of natural and unnatural pterocar-
pans, such as pterocarpin. The presence of an ester group in
the C-2 position of the benzaldehyde is required for the het-
erocyclization. The lack of this ester leads, under the same
reaction conditions, to open-chain alcohols. Attempts to
transform these alcohols into 2,3-dihydrobenzofurans under
Mitsunobu cyclization conditions gives the desired product
only if the syn diastereoisomers are used. A high-yielding
rearrangement leading to 2,5-dihydrobenzoxepines is ob-
served with the anti diastereoisomers.
(2R*,3R*)-2-(2-Hydroxyphenyl)-5-methoxy-3-vinyl-2,3-dihydrobenzofur-
an (6b): Reaction of 2 (50 mg, 0.23 mmol) and the aldehyde 4a (51 mg,
0.25 mmol) with the mixture of (Æ-BINAP (28 mg, 0.046 mmol),
[18]crown-6 ether (61 mg, 0.23 mmol), KF (13 mg, 0.23 mmol), and
TfOAg (12 mg, 0.046 mmol) in dry THF (1.5 mL) yielded 6b (45 mg,
0.17 mmol, 75%) as
a colorless oil; Rf =0.29 (hexane/Et2O 85:15);
1H NMR (300 MHz, CDCl3): d=7.25 (dt, J=8.0, 1.6 Hz, 1H; H-4’), 7.14
(dd, J=7.6, 1.6 Hz, 1H; H-6’), 6.93 (m, 2H; H-3’, 5’), 6.87 (brd, J=
8.6 Hz, 1H; H-7), 6.77 (dd, J=8.6, 2.6 Hz, 1H; H-6), 6.71 (dd, J=2.5,
1.0 Hz, 1H; H-4), 5.96 (ddd, J=17.0, 10.0, 8.5 Hz, 1H; H-1’’), 5.50 (d, J=
10.3 Hz, 1H; H-2), 5.32 (dd, J=10.0, 1.4 Hz, 1H; H-2’’a), 5.24 (brd, J=
17.2 Hz, 1H; H-2’’b), 4.18 (dd, J=9.5, 9.2 Hz, 1H; H-3), 3.80 ppm (s, 3H;
OCH3); 13C NMR (75 MHz, CDCl3): d=155.1 (C, C-5), 154.8 (C, C-2’),
151.7 (C, C-7a), 135.8 (CH, C-1’’), 130.8 (C, C-3a), 129.5 (CH, C-4’),
127.5 (CH, C-6’), 123.4 (C, C-1’), 120.0* (CH, C-3’), 119.2 (CH2, C-2’’),
117.2* (CH, C-5’), 113.8 (CH, C-6), 110.7 (CH, C-4), 110.4 (CH, C-7),
90.2 (CH, C-2), 55.9 (CH3, OCH3), 54.6 ppm (CH, C-3) (* may be inter-
changed); IR (film): n˜max =3393, 2958, 2921, 1660, 1638, 1596, 1483, 1454,
1429, 1255, 1199, 1027, 873, 800, 756 cmÀ1; HRMS (EI): m/z: calcd for
C17H16O3: 268.1099 [M]+; found: 268.1097.
Experimental Section
Infrared spectra were recorded in liquid film between NaCl plates by
using an FTIR Mattson Genesis II spectrometer. NMR spectra were de-
termined by using Bruker Avance DPX 300 and Bruker Avance-500 spec-
trometers. 1H NMR and 13C NMR spectra were recorded in deuterated
solvents and are reported relative to tetramethylsilane. Degrees of
carbon substitution were established by DEPT multipulse sequence, and
13C NMR peak assignments were made with the aid of two-dimensional
NMR (HMBC, HMQC, COSY, and NOESY). HRMS data was recorded
by using an Autospec-Q VG Analytical (FISONS) mass spectrometer.
Enantiomer ratios were determined by integration of significant signals
observed in the 1H NMR spectra after addition of an adequate quantity
of a solution of europium tris[3-(heptafluoropropylhydroxymethylene)-
(+)-camphorate] in CDCl3 (7 mgmLÀ1). Calculated eeꢁs were in agree-
ment with the values obtained by chiral HPLC analysis relative to the au-
thentic racemic products. A JASCO HPLC system with a Chiral Detector
CD-2095 and a Chiracel OD-H column (25”0.46 cm, Daicel Chem.) was
used. Gradients of hexane/iPrOH, from 100:0 to 70:30 in 20 min, flow
rate 0.5 mLminÀ1, were used. Optical rotations were measured by using a
JASCO P-1030 polarimeter. All solvents were purified and dried by fol-
lowing standard procedures.
(2R*,3R*)-2-(2-Hydroxy-4-pivaloyloxyphenyl)-5-methoxy-3-vinyl-2,3-di-
hydrobenzofuran (6c): Reaction of 2 (50 mg, 0.23 mmol) and the alde-
hyde 4c (69 mg, 0.23 mmol) with the mixture of (Æ-BINAP (28 mg,
0.05 mmol), [18]crown-6 ether (61 mg, 0.23 mmol), KF (13 mg,
0.23 mmol), and TfOAg (12 mg, 0.05 mmol) in dry THF (1.5 mL) yielded
6c (50 mg, 0.14 mmol, 60%) as a colorless oil; Rf =0.29 (hexane/Et2O
85:15); 1H NMR (300 MHz, CDCl3): d=7.20 (s, 1H; OH), 7.11 (d, J=
8.4 Hz, 1H; H-6’), 6.86 (d, J=8.6 Hz, 1H; H-7), 6.75 (dd, J=8.6, 2.8 Hz,
1H; H-6), 6.71 (d, J=2.1 Hz, 1H; H-4), 6.67 (d, J=2.1 Hz, 1H; H-3’),
6.62 (dd, J=8.2, 2.1 Hz, 1H; H-5’), 5.93 (ddd, J=17.0, 10.0, 8.8 Hz, 1H;
H-1’’), 5.48 (d, J=10.0 Hz, 1H; H-2), 5.30 (d, J=9.8 Hz, 1H; H-2’’a),
5.24 (d, J=17.0 Hz, 1H; H-2’’b), 4.14 (dd, J=10.0, 8.8 Hz, 1H; H-3), 3.79
(s, 3H; OCH3), 2.18 ppm (s, 9H; OCOC
A
CDCl3): d=176.7 (C, OCOC(CH3)3), 155.6 (C, C-5), 155.2 (C, C-2’),
AHCTREUNG
151.9 (C, C-4’), 151.7 (C, C-7a), 135.7 (CH, C-1’’), 130.6 (C, C-3a), 127.9
(CH, C-6’), 121.0 (C, C-1’), 119.2 (CH2, C-2’’), 113.8 (CH, C-6), 113.0
(CH, C-5’), 110.7 (CH, C-4), 110.5 (CH, C-3’), 110.3 (CH, C-7), 89.7
(CH, C-2), 55.9 (CH3, OCH3), 54.7 (CH, C-3), 39.0 (C, OCOC
30.8 ppm (CH3, OCOC(CH3)3); HRMS (EI): m/z: calcd for C22H24O5:
368.1624 [M]+; found: 368.1626.
A
AHCTREUNG
Condensation between benzoxasilepines and aldehydes by using AgI
complexes as Lewis acid:
A mixture of AgOTf, BINAP, KF, and
(2R*,3R*)-2-(2-Hydroxy-4-methoxyphenyl)-5,6-methylenedioxy-3-vinyl-
2,3-dihydrobenzofuran (6d): Reaction of 5b (200 mg, 0.85 mmol) and the
aldehyde 4d (222 mg, 0.236 mmol) with the mixture of (Æ-BINAP
(105 mg, 0.17 mmol), [18]crown-6 (224 mg, 0.85 mmol), KF (49 mg,
0.85 mmol), and TfOAg (44 mg, 0.17 mmol) in dry THF (3 mL) yielded
6d (188 mg, 0.60 mmol, 70%) as a colorless oil; Rf =0.30 (hexane/Et2O
85:15); 1H NMR (300 MHz, CDCl3): d=7.02 (d, J=8.5 Hz, 1H; H-6’),
6.80 (brs, 1H; OH), 6.60 (brs, 1H; H-4), 6.51* (s, 1H; H-7), 6.50* (s,
1H; H-3’), 6.47 (dd, J=8.5, 2.5 Hz, 1H; H-5’), 5.95 (d, J=1.4 Hz, 1H;
OCH2O), 5.94 (d, J=1.4 Hz, 1H; OCH2O), 5.87 (ddd, J=16.9, 10.0,
8.6 Hz, 1H; H-1’’), 5.43 (d, J=10.3 Hz, 1H; H-2), 5.27 (dd, J=10.0,
1.5 Hz, 1H; H-2’’a), 5.21 (dd, J=16.9, 1.5 Hz, 1H; H-2’’b), 4.09 (dd, J=
10.3, 8.6 Hz, 1H; H-3), 3.80 ppm (s, 3H; OCH3); 13C NMR (75 MHz,
CDCl3): d=160.9 (C, C-4’), 155.9 (C, C-2’), 152.2 (C, C-7a), 147.7 (C, C-
6), 142.5 (C, C-5), 136.3 (CH, C-1’’), 128.3 (CH, C-6’), 121.0 (C, C-3a),
118.8 (CH2, C-2’’), 115.9 (C, C-1’), 106.1 (CH, C-5’), 104.8 (CH, C-4),
102.7 (CH, C-3’), 101.3 (CH2, OCH2O), 93.7 (CH, C-7), 91.5 (CH, C-2),
55.2 (CH3, OCH3), 54.2 ppm (CH, C-3) (* may be interchanged); IR
(film): n˜max =3408, 3079, 2957, 2917, 2849, 1619, 1500, 1471, 1289, 1157,
112, 1036, 964, 936, 835 cmÀ1; HRMS (EI): m/z: calcd for C18H16O5:
312.0998 [M]+; found: 312.0996.
[18]crown-6 ether was dissolved in dry THF under an argon atmosphere
from which direct light was excluded. This solution was stirred at RT for
10–15 min. Next, the corresponding aldehyde and benzoxasilepine deriva-
tives in THF were added dropwise. The mixture was stirred for 30 min at
RT. Brine was added and the resulting suspension was extracted with
CH2Cl2. The organic layer was dried over anhydrous Na2SO4 and concen-
trated in vacuo. The residual crude product was purified by flash chroma-
tography.
(2R*,3R*)-2-(2-Hydroxy-5-methoxyphenyl)-5-methoxy-3-vinyl-2,3-dihy-
drobenzofuran (3): Reaction of 2 (67 mg, 0.30 mmol) and the aldehyde 1
(79 mg, 0.33 mmol) with the mixture of (Æ)-BINAP (37 mg, 0.06 mmol),
[18]crown-6 (79 mg, 0.3 mmol), KF (17 mg, 0.3 mmol), and TfOAg
(15 mg, 0.06 mmol) in dry THF (1.5 mL) yielded 3 (63 mg, 0.21 mmol,
70%) as
a
colorless oil; Rf =0.28 (hexane/Et2O 85:15); 1H NM R
(300 MHz, CDCl3): d=6.87 (d, J=8.8 Hz, 2H; H-7, H-3’), 6.84 (d, J=
2.9 Hz, 1H; H-6’), 6.76 (dd, J=8.6, 3.0 Hz, 2H; H-6, H-4’), 6.72 (m, 1H;
H-4), 6.46 (brs, 1H; OH), 5.96 (ddd, J=16.8, 10.0, 8.4 Hz, 1H; H-1’’),
5.47 (d, J=10.0 Hz, 1H; H-2), 5.31 (dd, J=10.0, 1.4 Hz, 1H; H-2’’a), 5.26
(dd, J=16.8, 0.9 Hz, 1H; H-2’’b), 4.17 (t, J=9.2 Hz, 1H; H-3), 3.79 (s,
3H; OCH3), 3.77 ppm (s, 3H; OCH3); 13C NMR (75 MHz, CDCl3): d=
155.1* (C, C-5’), 153.1* (C, C-5), 151.8 (C, C-7a), 148.4 (C, C-2’), 136.0
(CH, C-1’’), 130.6 (C, C-1’), 124.5 (C, C-3a), 119.1 (CH2, C-2’’), 117.8
(CH, C-3’), 114.5 (CH, C-7), 113.8# (CH, C-4), 112.9# (CH, C-4’), 110.7##
(2R*,3R*)-2-(2-Hydroxy-4-methoxyphenyl)-6-methoxy-3-vinyl-2,3-dihy-
drobenzofuran (6e): Reaction of 5c (65 mg, 0.29 mmol) and the aldehyde
8766
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8762 – 8769

Asymmetric Synthesis of 2,3-Dihydrobenzofurans
FULL PAPER
4d (70 mg, 0.29 mmol) with the mixture of (Æ-BINAP (36 mg,
0.06 mmol), [18]crown-6 (76 mg, 0.29 mmol), KF (17 mg, 0.29 mmol), and
TfOAg (15 mg, 0.06 mmol) in dry THF (1.5 mL) yielded 6e (56 mg,
3.0 Hz, 1H; H-4’’), 6.47 (d, J=3.0 Hz, 1H; H-6’’), 6.17 (ddd, J=16.9,
10.4, 8.5 Hz, 1H; H-3), 5.20 (dt, J=10.4, 1.7 Hz, 1H; H-4a), 5.11 (d, J=
3.2 Hz, 1H; H-1), 5.09 (dt, J=16.9, 1.7 Hz, 1H; H-4b), 3.81 (brdd, J=
8.5, 3.2 Hz, 1H; H-2), 3.70 (s, 3H; OCH3), 1.36 ppm (s, 9H; OCOC-
0.19 mmol, 65%) as
a colorless oil; Rf =0.27 (hexane/Et2O 85:15);
1H NMR (300 MHz, CDCl3): d=7.06 (d, J=8.4 Hz, 1H; H-6’), 7.03 (brd,
J=9.0 Hz, 1H; H-4), 6.80 (brs, 1H; OH), 6.54 (dd, J=9.0, 2.3 Hz, 1H;
H-5), 6.53 (d, J=2.1 Hz, 1H; H-7), 6.50 (d, J=2.4 Hz, 1H; H-3’), 6.47
(dd, J=8.3, 2.4 Hz, 1H; H-5’), 5.92 (ddd, J=16.9, 10.2, 8.4 Hz, 1H; H-
1’’), 5.48 (d, J=9.9 Hz, 1H; H-2), 5.26 (d, J=10.2 Hz, 1H; H-2’’a), 5.22
(d, J=16.9 Hz, 1H; H-2’’b), 4.12 (t, J=9.2 Hz, 1H; H-3), 3.82 (s, 3H;
OCH3), 3.79 ppm (s, 3H; OCH3); 13C NMR (75 MHz, CDCl3): d=160.8*
(C, C-6), 160.8* (C, C-4’), 159.0 (C, C-7a), 155.9 (C, C-2’), 136.4 (CH, C-
1’’), 128.3 (CH, C-6’), 124.9 (CH, C-4), 121.7 (C, C-3a), 118.5 (CH2, C-
2’’), 116.0 (C, C-1’), 107.3 (CH, C-5), 106.1 (CH, C-5’), 102.7 (CH, C-3’),
96.8 (CH, C-7), 90.4 (CH, C-2), 55.5 (CH3, OCH3), 55.2 (CH3, OCH3),
53.5 ppm (CH, C-3) (* may be interchanged); HRMS (EI): m/z: calcd for
C18H18O4: 298.1205 [M]+; found: 298.1204.
N
A
(C, C-5’’), 150.4 (C, C-4’), 148.3 (C, C-2’’), 138.8 (C, C-1’), 134.2 (CH, C-
3), 128.2 (C, C-1’’), 127.5 (CH, C-2’, C-6’), 120.9 (CH, C-3’, C-5’), 118.6
(CH2, C-4), 117.8 (CH, C-3’’), 115.8 (CH, C-6’’), 113.1 (CH, C-4’’), 77.4
(CH, C-1), 55.6 (CH3, OCH3), 54.1 (CH, C-2), 39.0 (C, OCOC
27.0 ppm (CH3, OCOC(CH3)3); HRMS (EI): m/z: calcd for C22H26O5:
370.1780 [M]+; found: 370.1776.
Compound anti-7: Rf =0.28 (hexane/Et2O 8:2); colorless oil; 1H NM R
(CDCl3, 300 MHz): d=7.22 (d, J=8.6 Hz, 2H; H-2’, 6’), 6.96 (d, J=
8.6 Hz, 2H; H-3’, 5’), 6.84 (d, J=8.7 Hz, 1H; H-3’’), 6.68 (dd, J=8.7,
3.0 Hz, 1H; H-4’’), 6.37 (d, J=3.0 Hz, 1H; H-6’’), 6.17 (ddd, J=17.5,
10.5, 7.3 Hz, 1H; H-3), 5.14 (dt, J=10.5, 1.4 Hz, 1H; H-4a), 5.10 (d, J=
5.6 Hz, 1H; H-1), 5.06 (dt, J=17.5, 1.4 Hz, 1H; H-4b), 3.70 (m, 1H; H-
2), 3.67 (s, 3H; OCH3), 1.35 ppm (s, 9H; OCOC
(CDCl3, 75 MHz): d=177.1 (C, OCOC(CH3)3), 153.3 (C, C-5’’), 150.4 (C,
C-4’), 148.7 (C, C-2’’), 139.2 (C, C-1’), 136.3 (CH, C-3), 127.3 (CH, C-2’,
C-6’), 126.9 (C, C-1’’), 121.2 (CH, C-3’, C-5’), 118.0 (CH, C-3’’), 117.3
(CH2, C-4), 116.5 (CH, C-6’’), 113.2 (CH, C-4’’), 78.1 (CH, C-1), 55.6
(CH3)3),
AHCTREUNG
(2R*,3R*)-2-(2-Hydroxy-4-pivaloyloxyphenyl)-6-methoxy-3-vinyl-2,3-di-
hydrobenzofuran (6 f): Reaction of 5c (50 mg, 0.23 mmol) and the alde-
hyde 4c (69 mg, 0.23 mmol) with the mixture of (Æ-BINAP (28 mg,
0.05 mmol), [18]crown-6 ether (61 mg, 0.23 mmol), KF (13 mg,
0.23 mmol), and TfOAg (11 mg, 0.05 mmol) in dry THF (1.5 mL) yielded
6 f (50 mg, 0.13 mmol, 60%) as a colorless oil; Rf =0.29 (hexane/Et2O
85:15); 1H NMR (300 MHz, CDCl3): d=7.15 (d, J=8.1 Hz, 1H; H-6’),
7.02 (dd, J=8.9, 1.2 Hz, 1H; H-4), 6.67 (d, J=2.4 Hz, 1H; H-3’), 6.63
(dd, J=8.1, 2.4 Hz, 1H; H-5’), 6.55 (dd, J=8.9, 2.4 Hz, 1H; H-5), 6.54 (d,
J=2.4 Hz, 1H; H-7), 5.94 (ddd, J=16.9, 10.1, 8.5 Hz, 1H; H-1’’), 5.53 (d,
J=9.7 Hz, 1H; H-2), 5.27 (dd, J=10.1, 1.6 Hz, 1H; H-2’’a), 5.22 (dd, J=
16.9, 1.6 Hz, 1H; H-2’’b), 4.10 (dd, J=9.7, 8.5 Hz, 1H; H-3), 3.82 (s, 3H;
U
AHCTREUNG
(CH3, OCH3), 54.8 (CH, C-2), 39.0 (C, OCOC(CH3)3), 27.0 ppm (CH3,
T
OCOC(CH3)3); IR (film): n˜max =3385, 2970, 2934, 2906, 2873, 1747, 1636,
E
1604, 1495, 1395, 1366, 1276, 1200, 1164, 1125, 1039, 811 cmÀ1; HRMS
(EI): m/z: calcd for C22H26O5: 370.1780 [M]+; found: 370.1781.
(1R*,2S*)-2-(2-Hydroxy-5-methoxyphenyl)-1-phenyl-3-buten-1-ol (syn-8)
and
(anti-8): Reaction of 2 (85 mg, 0.38 mmol) and benzaldehyde 4 f (45 mg,
0.42 mmol) with the mixture of (Æ)-BINAP (47 mg, 0.07 mmol),
[18]crown-6 (100 mg, 0.38 mmol), KF (22 mg, 0.38 mmol), and TfOAg
(19 mg, 0.07 mmol) in dry THF (2 mL) yielded 8 (syn/anti 1:1) with an
overall yield of 85%.
OCH3), 1.37 ppm (s, 9H; OCOC
A
d=160.8 (C, C-6, OCOC(CH3)3), 159.0 (C, C-7a), 155.3 (C, C-2’), 151.9
AHCTREUNG
(C, C-4’), 136.4 (CH, C-1’’), 127.8 (CH, C-6’), 125.0 (CH, C-4), 121.5* (C,
C-1’), 121.4* (C, C-3a), 118.5 (CH2, C-2’’), 113.2 (CH, C-5’), 110.5 (CH,
C-3’), 107.4 (CH, C-5), 96.8 (CH, C-7), 89.8 (CH, C-2), 55.5 (CH3,
Compound syn-8: Rf =0.29 (hexane/Et2O 8:2); colorless oil; 1H NM R
(300 MHz, CDCl3): d=7.32 (m, 3H; H-3’, 4’, 5’), 7.25 (m, 2H; H-2’, 6’),
6.83 (d, J=8.6 Hz, 1H; H-3’’), 6.71 (dd, J=8.6, 3.1 Hz, 1H; H-4’’), 6.49
(d, J=3.1 Hz, 1H; H-6’’), 6.20 (ddd, J=17.0, 10.1, 8.0 Hz, 1H; H-3), 5.22
(ddd, J=10.1, 1.6, 1.0 Hz, 1H; H-4a), 5.18 (d, J=4.0 Hz, 1H; H-1), 5.09
(dt, J=17.0, 1.6 Hz, 1H; H-4b), 3.86 (brdd, J=8.0, 4.0 Hz, 1H; H-2),
3.70 ppm (s, 3H; OCH3); 13C NMR (75 MHz, CDCl3): d=153.3 (C, C-
5’’), 148.3 (C, C-2’’), 141.3 (C, C-1’), 134.0 (CH, C-3), 128.3 (C, C-1’’),
128.0 (CH, C-3’, C-5’), 127.8 (CH, C-4’), 126.3 (CH, C-2’, C-6’), 118.6
(CH2, C-4), 118.0 (CH, C-3’’), 116.0 (CH, C-6’’), 113.1 (CH, C-4’’), 78.0
(CH, C-1), 55.6 (CH3, OCH3), 54.2 ppm (CH, C-2); IR (film): n˜max =3371,
3077, 3030, 2956, 2906, 1715, 1699, 1635, 1603, 1496, 1258, 1205, 1038,
920, 749, 700 cmÀ1; HRMS (EI): m/z: calcd for C17H18O3: 270.1255
[M+H]+; found: 271.1256.
Compound anti-8: Rf =0.30 (hexane/Et2O 8:2); colorless oil; 1H NM R
(300 MHz, CDCl3): d=7.39 (brs, 1H; OH), 7.27 (m, 5H; H-2’, 3’, 4’, 5’,
6’), 6.85 (d, J=8.9 Hz, 1H; H-3’’), 6.69 (dd, J=8.9, 3.2 Hz, 1H; H-4’’),
6.39 (d, J=3.2 Hz, 1H; H-6’’), 6.18 (ddd, J=17.4, 10.5, 7.3 Hz, 1H; H-3),
5.14 (dt, J=10.5, 1.2 Hz, 1H; H-4a), 5.11 (d, J=5.6 Hz, 1H; H-1), 5.07
(dt, J=17.4, 1.2 Hz, 1H; H-4b), 3.78 (brdd, J=7.3, 5.6 Hz, 1H; H-2),
3.66 (s, 3H; OCH3), 2.91 ppm (brs, 1H; OH); 13C NMR (75 MHz,
CDCl3): d=153.2 (C, C-5’’), 148.7 (C, C-2’’), 141.6 (C, C-1’), 136.3 (CH,
C-3), 128.2 (CH, C-3’, C-5’), 127.9 (CH, C-4’), 127.2 (C, C-1’’), 126.2 (CH,
C-2’, C-6’), 118.1 (CH, C-3’’), 117.3 (CH2, C-4), 116.4 (CH, C-6’’), 113.1
(CH, C-4’’), 78.8 (CH, C-1), 55.6 (CH3, OCH3), 54.6 ppm (CH, C-2): IR
(film): n˜max =3354, 2955, 2924, 2853, 1717, 1634, 1600, 1496, 1452, 1432,
1244, 1205, 1153, 1040, 918, 810, 699 cmÀ1; HRMS (EI): m/z: calcd for
C17H18O3: 270.1255 [M+H]+: found; 271.1248.
OCH3), 53.7 (CH, C-3), 39.0 (C, OCOC
(CH3)3) (* may be interchanged): HRMS (EI): m/z: calcd for C22H24O5:
368.1624 [M]+; found: 368.1622.
(CH3)3), 27.0 ppm (CH3, OCOC-
ACHTREUNG
(2R*,3R*)-2-(2-Hydroxy-4-pivaloyloxyphenyl)-5,6-methylenedioxy-3-
vinyl-2,3-dihydrobenzofuran (6g): Reaction of 5b (50 mg, 0.23 mmol)
and the aldehyde 4c (73 mg, 0.23 mmol) with the mixture of (Æ)-BINAP
(30 mg, 0.05 mmol), [18]crown-6 (63 mg, 0.23 mmol), KF (14 mg,
0.23 mmol), and TfOAg (11 mg, 0.05 mmol) in dry THF (1.5 mL) yielded
6g (57 mg, 0.15 mmol, 70%) as a colorless oil; Rf =0.30 (hexane/Et2O
85:15); 1H NMR (300 MHz, CDCl3): d=7.12 (d, J=8.2 Hz, 1H; H-6’),
6.64 (d, J=2.2 Hz, 1H; H-3’), 6.62 (dd, J=8.2, 2.3 Hz, 1H; H-5’), 6.59 (d,
J=0.9 Hz, 1H; H-4), 6.52 (brs, 1H; H-7), 5.95 (d, J=1.4 Hz, 1H;
OCH2O), 5.94 (d, J=1.4 Hz, 1H; OCH2O), 5.91 (ddd, J=16.9, 10.2,
8.5 Hz, 1H; H-1’’), 5.50 (d, J=9.7 Hz, 1H; H-2), 5.26 (dd, J=10.2,
1.1 Hz, 1H; H-2’’a), 5.20 (dd, J=16.9, 1.1 Hz, 1H; H-2’’b), 4.06 (dd, J=
9.7, 8.5 Hz, 1H; H-3), 1.36 ppm (s, 9H; OCOC
A
(75 MHz, CDCl3): d=155.4 (C, C-2’, OCOC(CH3)3), 152.3 (C, C-7a),
AHCTREUNG
151.9 (C, C-4’), 147.8 (C, C-6), 142.5 (C, C-5), 136.3 (CH, C-1’’), 127.8
(CH, C-6’), 121.4 (C, C-1’), 120.7 (C, C-3a), 118.7 (CH2, C-2’’), 113.0
(CH, C-5’), 110.4 (CH, C-3’), 104.8 (CH, C-4), 101.3 (CH2, OCH2O), 93.6
(CH, C-7), 89.9 (CH, C-2), 54.3 (CH, C-3), 39.0 (C, OCOC(CH3)3),
U
27.0 ppm (CH3, OCOC(CH3)3; IR (film): n˜max =3415, 2972, 2934, 2904,
R
2875, 1751, 1726, 1608, 1501, 1474, 1285, 1271, 1155, 1119, 1036, 975 cmÀ1
;
HRMS (EI): m/z: calcd for C22H22O6: 382.1416 [M]+; found: 382.1418.
(1R*,2S*)-2-(2-Hydroxy-5-methoxyphenyl)-1-(4-pivaloyloxyphenyl)-3-
buten-1-ol (syn-7) and (1R*,2R*)-2-(2-Hydroxy-5-methoxyphenyl)-1-(4-
pivaloyloxyphenyl)-3-buten-1-ol (anti-7): Reaction of (50 mg,
2
0.23 mmol) and 4e (51 mg, 0.25 mmol) with the mixture of (Æ)-BINAP
(28 mg, 0.04 mmol), [18]crown-6 (60 mg, 0.23 mmol), KF (13 mg,
0.23 mmol), and TfOAg (11 mg, 0.04 mmol) in dry THF (2 mL) yielded 7
(syn/anti 1:1) with an overall yield of 83%.
Compound syn-7: Rf =0.29 (hexane/Et2O 8:2); colorless oil; 1H NM R
(300 MHz, CDCl3): d=7.22 (d, J=8.5 Hz, 2H; H-2’, 6’), 6.97 (d, J=
8.5 Hz, 2H; H-3’, 5’), 6.80 (d, J=8.7 Hz, 1H; H-3’’), 6.68 (dd, J=8.7,
(1R*,2S*)-2-(2-Hydroxyphenyl)-1-phenyl-3-buten-1-ol
(syn-9)
and
(1R*,2R*)-2-(2-hydroxyphenyl)-1-phenyl-3-buten-1-ol (anti-9): Reaction
of 5a (54 mg, 0.28 mmol) and benzaldehyde 4 f (33 mg, 0.31 mmol) with
the mixture of (Æ)-BINAP (38 mg, 0.06 mmol), [18]crown-6 (74 mg,
0.28 mmol), KF (16 mg, 0.28 mmol), and TfOAg (16 mg, 0.06 mmol) in
dry THF (1.5 mL) yielded 9 (syn/anti 1:1) with an overall yield of 82%.
Chem. Eur. J. 2006, 12, 8762 – 8769
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8767

I. Rodríguez-García et al.
Compound syn-9: Rf =0.27 (hexane/Et2O 8:2); white solid; m.p. 90–
928C; 1H NMR (300 MHz, CDCl3): d=7.30 (m, 5H; H-2’, 3’, 4’, 5’,6’),
7.16 (ddd, J=8.1, 7.4, 1.8 Hz, 1H; H-4’’), 6.94 (dd, J=7.6, 1.8 Hz, 1H; H-
6’’), 6.90 (brd, J=8.1 Hz, 1H; H-3’’), 6.83 (dt, J=7.4, 1.2 Hz, 1H; H-5’’),
6.23 (ddd, J=17.3, 10.5, 8.1 Hz, 1H; H-3), 5.22 (d, J=4.0 Hz, 1H; H-1),
5.20 (dt, J=10.5, 1.6 Hz, 1H; H-4a), 5.05 (dt, J=17.3, 1.6 Hz, 1H; H-4b),
3.87 (brdd, J=8.1, 4.0 Hz, 1H; H-2), 2.85 ppm (brs, 1H; OH); 13C NM R
(75 MHz, CDCl3): d=154.4 (C, C-2’’), 141.5 (C, C-1’), 134.0 (CH, C-3),
130.5 (CH, C-6’’), 128.2 (CH, C-4’’), 128.0 (CH, C-3’, C-5’), 127.7 (CH, C-
4’), 127.3 (C, C-1’’), 126.3 (CH, C-2’, C-6’), 120.4 (CH, C-5’’), 118.4 (CH2,
oil; 1H NMR (300 MHz, CDCl3): d=7.41 (d, J=7.4 Hz, 2H; H-2’, 6’),
7.33 (dd, J=7.4, 7.1 Hz, 2H; H-3’, 5’), 7.23 (t, J=7.1 Hz, 1H; H-4’), 7.01
(d, J=8.5 Hz, 1H; H-9), 6.71 (dd, J=8.1, 3.1 Hz, 1H; H-8), 6.54 (d, J=
3.1 Hz, 1H; H-6), 6.06 (dddd, J=6.0, 4.6, 3.3, 2.2 Hz, 1H; H-3), 5.68 (m,
1H; H-4), 4.82 (m, 1H; H-5), 4.69 (dddd, J=17.0, 3.3, 1.8, 1.8 Hz, 1H;
H-2b), 4.56 (ddd, J=17.0, 4.6, 2.4 Hz, 1H; H-2a), 3.73 ppm (s, 3H;
OCH3); 13C NMR (75 MHz, CDCl3): d=155.8 (C, C-7), 151.6 (C, C-9a),
142.6 (C, C-1’), 140.6 (C, C-5a), 129.4 (CH, C-3), 128.4* (CH, C-3’, C-5’),
128.2* (CH, C-2’, C-6’), 127.9 (CH, C-4), 126.4 (CH, C-4’), 122.5 (CH, C-
9), 114.8 (CH, C-6), 112.1 (CH, C-8), 71.0 (CH2, C-2), 55.4 (CH3, OCH3),
49.0 ppm (CH, C-5) (* may be interchanged); IR (film): n˜max =3023,
2941, 2882, 2834, 1726, 1659, 1600, 1487, 1265, 1202, 1066, 1037, 827, 749,
700 cmÀ1; HRMS (EI): m/z: calcd for C17H16O2: 252.1150 [M]+; found:
252.1149.
C-4), 117.4 (CH, C-3’’), 77.9 (CH, C-1), 54.5 ppm (CH, C-2); IR(film):
A
n˜max =3366, 2920, 2852, 1647, 1633, 1581, 1486, 1453, 1416, 1246, 1024,
875, 752, 698, 667 cmÀ1; HRMS (EI): m/z: calcd for C16H16O2: 222.1044
[MÀH2O]+; found: 222.1048.
Compound anti-9: Rf =0.26 (hexane/Et2O 8:2); colorless oil; 1H NM R
(300 MHz, CDCl3): d=7.83 (brs, 1H; OH), 7.27 (m, 5H; H-2’, 3’, 4’, 5’,
6’), 7.14 (ddd, J=8.1, 6.5, 2.4 Hz, 1H; H-4’’), 6.93 (brd, J=7.7 Hz, 1H;
H-6’’), 6.76 (m, 2H; H-3’’, 5’’), 6.24 (ddd, J=17.4, 10.5, 6.9 Hz, 1H; H-3),
5.20 (d, J=6.5 Hz, 1H; H-1), 5.16 (dt, J=10.5, 1.6 Hz, 1H; H-4a), 5.09
(dt, J=17.4, 1.6 Hz, 1H; H-4b), 3.79 (brdd, J=6.9, 6.5 Hz, 1H; H-2),
2.83 ppm (brs, 1H; OH); 13C NMR (75 MHz, CDCl3): d=154.9 (C, C-
2’’), 141.5 (C, C-1’), 136.4 (CH, C-3), 131.2 (CH, C-6’’), 128.4 (CH, C-4’’),
128.2 (CH, C-3’, C-5’), 127.9 (CH, C-4’), 126.1 (CH, C-2’, 6’), 125.7 (C, C-
1’’), 120.3 (CH, C-5’’), 117.5 (CH2, C-4), 117.2 (CH, C-3’’), 78.7 (CH, C-
1), 55.1 ppm (CH, C-2): HRMS (EI): m/z: calcd for C16H16O2: 222.1044
[MÀH2O]+; found: 222.1041.
5-Phenyl-2,5-dihydrobenzo[b]oxepine (13): PPh3 (17 mg, 0.06 mmol) and
DIAD (0.013 mL, 0.06 mmol) were added to a solution of anti-9 (13 mg,
0.05 mmol) in anhyd THF (1 mL). After 30 min the solvent was removed
in vacuo. Flash chromatography of the residue afforded 13 (10 mg,
0.045 mmol, 88%); Rf =0.29 (hexane/Et2O 9:1); colorless oil; 1H NM R
(300 MHz, CDCl3): d=7.47–7.33 (m, 5H; H-2’–6’), 6.92–6.70 (m, 4H; H-
6–9), 6.15 (dddd, J=6.1, 4.3, 3.3, 2.2 Hz, 1H; H-3), 5.60 (m, 1H; H-4),
4.76 (m, 1H; H-5), 4.62 (dddd, J=16.8, 3.3, 1.7, 1.7 Hz, 1H; H-2a),
4.59 ppm (ddd, J=16.8, 4.3, 2.2 Hz, 1H; H-2b); 13C NMR (75 MHz,
CDCl3): d=153.4 (C, C-9a), 143.0 (C, C-1’), 140.2 (C, C-5a), 133.1 (CH),
129.2 (CH), 128.9* (CH, C-3’, C-5’), 128.2* (CH, C-2’, C-6’), 127.2 (CH),
126.2 (CH), 124.3 (CH), 123.6 (CH), 114.7 (CH), 69.8 (CH2, C-2),
47.1 ppm (CH, C-5) (* may be interchanged); HRMS (EI): m/z: calcd for
C16H14O: 222.1045 [M]+; found: 222.1049.
Mitsunobu cyclization ofthe syn and anti diastereoisomers of8 and 9:
Synthesis of10–13
Asymmetric synthesis of trans-pterocarpin: (+)-(2S,3S)-2-(2-hydroxy-4-
methoxyphenyl)-3,4-methylenedioxy-3-vinyl-2,3-dihydrobenzofuran (6d):
Reaction of 5b (50 mg, 0.21 mmol) and the aldehyde 4d (50 mg,
0.21 mmol) with (+)-(R)-TolBINAP (27 mg, 0.042 mmol) at À808C, by
using the procedure described for the racemic version, yielded (+)-6d
(46 mg, 0.16 mmol, 75%) with an ee of 84%; [a]2D0 =+3.48 (c=0.1,
CH2Cl2).
(2R*,3R*)-5-Methoxy-2-phenyl-3-vinyl-2,3-dihydrobenzofuran (10): PPh3
(12 mg, 0.045 mmol) and DIAD (0.008 mL, 0.04 mmol) were added to a
solution of syn-8 (10 mg, 0.037 mmol) in anhyd THF (1 mL). After
30 min the solvent was removed in vacuo. Flash chromatography of the
residue afforded 10 (7 mg, 0.03 mmol, 72%); Rf =0.29 (hexane/Et2O
1
9:1); colorless oil; H NMR (CDCl3, 300 MHz): d=7.40 (m, 5H; H-2’, 3’,
4’, 5’,6’), 6.83 (d, J=8.6 Hz, 1H; H-7), 6.77 (dd, J=8.6, 0.8 Hz, 1H; H-6),
6.70 (d, J=0.8 Hz, 1H; H-4), 5.99 (ddd, J=16.9, 10.0, 8.5 Hz, 1H; H-1’’),
5.39 (d, J=9.0 Hz, 1H; H-2), 5.26 (dd, J=10.0, 1.5 Hz, 1H; H-2a), 5.23
(dd, J=16.9, 1.5 Hz, 1H; H-2b), 4.01 (t, J=8.5 Hz, 1H; H-3), 3.79 ppm
(s, 3H; OCH3); 13C NMR (CDCl3, 75 MHz): d=153.3 (C, C-5, C-7a),
140.4 (C, C-1’), 136.8 (CH, C-1’’), 130.1 (C, C-3a), 128.4 (3CH), 128.0
(CH), 125.8 (CH), 117.9 (CH2, C-2’’), 113.8 (CH, C-6), 110.7 (CH, C-4),
109.5 (CH, C-7), 90.0 (CH, C-2), 56.5 (CH3, OCH3), 56.0 ppm (CH, C-3);
IR (film): n˜max =2937, 2830, 1603, 1490, 1452, 1263, 1200, 1030, 985, 920,
750 cmÀ1: HRMS (EI): m/z: calcd for C17H16O2: 252.1150 [M]+; found:
252.1154.
(À)-(2S,3R)-3-Hydroxymethyl-5,6-methylenedioxy-2-(4-methoxy-2-hy-
droxyphenyl)-2,3-dihydrobenzofuran (14): Compound 6d (84% ee)
(16 mg, 0.051 mmol) was dissolved in THF/H2O (1 mL, 1:1 v/v) and
cooled at 08C. The flask was protected from the light. OsO4 (44 mL,
0.01 mmol, 2.5% in isopropanol) and NaIO4 (43 mg, 0.2 mmol) were
added. The mixture was stirred at 08C for 5 h, then water was added and
the mixture was extracted with CH2Cl2. The dried (Na2SO4) extract was
concentrated in vacuo. The residue was dissolved in THF (2 mL) and was
cooled at À408C. Then, LiAlH4 (5 mg, 0.13 mmol) was added and the
suspension was stirred for 1 h. Next, a saturated solution of NH4Cl/H2O
was added and the mixture was extracted with CH2Cl2. The organic layer
was dried over anhyd Na2SO4 and the solvent was removed in vacuo.
Flash chromatography of the residue (hexane/Et2O 6:4) gave 14 (14 mg,
(2R*,3R*)-2-Phenyl-3-vinyl-2,3-dihydrobenzofuran (11): PPh3 (25 mg,
0.096 mmol) and DIAD (0.018 mL, 0.096 mmol) were added to a solution
of syn-9 (20 mg, 0.08 mmol) in anhyd THF (2 mL). After 30 min the sol-
vent was removed in vacuo. Flash chromatography of the residue afford-
ed 11 (14 mg, 0.063 mmol, 75%); Rf =0.29 (hexane/Et2O 95:5); colorless
oil; 1H NMR (300 MHz, CDCl3): d=7.47–7.33 (m, 5H; H-2’, H-3’, H-4’,
H-5’, H-6’), 7.23 (dd, J=7.9, 7.3 Hz, 1H; H-6), 7.12 (d, J=7.3 Hz, 1H;
H-4), 6.94 (t, J=7.3 Hz, 1H; H-5), 6.92 (d, J=7.9 Hz, 1H; H-7), 6.00
(ddd, J=18.5, 10.2, 8.8 Hz, 1H; H-1’’), 5.42 (d, J=8.8 Hz, 1H; H-2), 5.25
(brd, J=10.2 Hz, 1H; H-2’’a), 5.20 (brd, J=18.5 Hz, 1H; H-2’’b),
4.04 ppm (t, J=8.8 Hz, 1H; H-3); 13C NMR (75 MHz, CDCl3): d=159.2
(C, C-7a), 140.4 (C, C-1’), 137.0 (CH, C-1’’), 129.1 (C, C-3a), 128.7 (CH,
C-6), 128.5 (CH, C-3’, C-5’), 128.0 (CH, C-4’), 125.8 (CH, C-2’, C-6’),
124.7 (CH, C-4), 120.8 (CH, C-5), 117.8 (CH2, C-2’’), 109.5 (CH, C-7),
89.7 (CH, C-2), 56.2 ppm (CH, C-3); IR (film): n˜max =3064, 3031, 2959,
2922, 2885, 1638, 1596, 1476, 1262, 1228, 1099, 1014, 982, 922, 865, 750,
697 cmÀ1; HRMS (EI): m/z: calcd for C16H15O: 223.1123 [M+H]+; found:
223.1128.
0.044 mmol, 86%) as
a
solid foam; [a]2D0 =À44.08 (c=0.3, CH2Cl2);
1H NMR (300 MHz, CDCl3): d=7.18 (d, J=9.0 Hz, 1H; H-6’), 6.60 (s,
1H; H-4), 6.55 (s, 1H; H-7), 6.49 (d, J=2.5 Hz, 1H; H-3’), 6.48 (dd, J=
6.2, 2.5 Hz, 1H; H-5’), 5.93 (s, 2H; OCH2O), 5.81 (d, J=11.6 Hz, 1H; H-
2), 4.01 (dd, J=10.1, 4.6 Hz, 1H; H-1’’a), 3.89 (t, J=10.1 Hz, 1H; H-
1’’b), 3.78 (s, 3H; OCH3), 3.51 ppm (m, 1H; H-3); 13C NMR (75 MHz,
CDCl3): d=160.4 (C, C-4’), 154.0 (C, C-7a), 153.7 (C, C-2’), 148.2 (C, C-
6), 141.9 (C, C-5), 126.2 (CH, C-6’), 119.7 (C, C-1’), 116.2 (C, C-3a), 106.2
(CH, C-5’), 104.4 (CH, C-4), 102.8 (CH, C-3’), 101.3 (CH2, OCH2O), 93.3
(CH, C-7), 84.4 (CH, C-2), 65.3 (CH2, C-1’’), 55.2 (CH3, OCH3), 52.8 ppm
(CH, C-3); IR (film): n˜max =3397, 2932, 2895, 1709, 1618, 1500, 1474,
1458, 1294, 1200, 1150, 1036, 936, 828, 736 cmÀ1; HRMS (EI): m/z: calcd
for C17H16O6: 316.0947 [M]+; found; 316.0949.
(À)-trans-Pterocarpin: PPh3 (16 mg, 0.04 mmol) and DIAD (0.012 mL,
0.06 mmol) were added to a solution of 14 (12 mg, 0.038 mmol) in anhyd
THF (1 mL). After 30 min the solvent was removed in vacuo. Flash chro-
matography of the residue afforded trans-pterocarpin (11 mg,
0.037 mmol, 97%); Rf =0.289 (hexane/Et2O 9:1); white solid; m.p. 160–
1628C; [a]2D0 =À35.08 (c=0.1, CH2Cl2); 1H NMR (300 MHz, CDCl3): d=
7.30 (m, 1H; H-1), 6.67 (d, J=1.2 Hz, 1H; H-7), 6.64 (s, 1H; H-10), 6.54
7-Methoxy-5-phenyl-2,5-dihydrobenzo[b]oxepine (12): PPh3 (14 mg,
0.05 mmol) and DIAD (0.010 mL, 0.05 mmol) were added to a solution
of anti-8 (12 mg, 0.04 mmol) in anhyd THF (1 mL). After 30 min the sol-
vent was removed in vacuo. Flash chromatography of the residue afford-
ed 12 (10 mg, 0.04 mmol, 90%); Rf =0.29 (hexane/Et2O 9:1); colorless
8768
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8762 – 8769

Asymmetric Synthesis of 2,3-Dihydrobenzofurans
FULL PAPER
(dd, J=8.1, 2.4 Hz, 1H; H-2), 6.47 (d, J=2.4 Hz, 1H; H-4), 5.96 (d, J=
1.2 Hz, 1H; OCH2O), 5.95 (d, J=1.2 Hz, 1H; OCH2O), 5.13 (dd, J=
13.3, 0.8 Hz, 1H; H-11a), 4.85 (dd, J=9.7, 4.4 Hz, 1H; H-6’), 4.44 (dd,
J=11.9, 9.7 Hz, 1H; H-6), 3.80 (s, 3H; OCH3), 3.53 ppm (ddd, J=13.3,
11.9, 4.4 Hz, 1H; H-6a); 13C NMR (75 MHz, CDCl3): d=160.4 (C, C-3),
156.3 (C, C-10a), 153.8 (C, C-4a), 147.5 (C, C-9), 142.0 (C, C-8), 123.6
(CH, C-1), 118.7 (C, C-6b), 116.8 (C, C-11b), 106.2 (CH, C-2), 103.7 (CH,
C-7), 102.0 (CH, C-4), 101.2 (CH2, OCH2O), 94.9 (CH, C-10), 84.5 (CH,
C-11a), 69.0 (CH2, C-6), 55.3 (CH3, OCH3), 45.4 ppm (CH, C-6a); IR
(film): n˜max =2959, 2923, 2852, 1740, 1619, 1585, 1505, 1460, 1441, 1384,
1260, 1159, 1112, 1094, 1034, 800 cmÀ1; HRMS (EI): m/z: calcd for
C17H14O5: 298.0841 [M]+; found: 298.0838.
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(À)-cis-Pterocarpin:
A
solution of (À)-trans-pterocarpin (11 mg,
0.037 mmol) in toluene (1.5 mL) was stirred in the presence of (Æ)-10-
camphorsulfonic acid (4 mg, 0.017 mmol) for 6 h. The cooled mixture was
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concentrated, and then purified over silica gel (hexane/Et2O 9:1) yielding
cis-pterocarpin (10 mg, 0.034 mmol, 92%). Spectral data were in agree-
[15]
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Received: March 9, 2006
Published online: September 5, 2006
Chem. Eur. J. 2006, 12, 8762 – 8769
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8769