Rh(II)-catalyzed enantioselective synthesis of acuminatin through a C-H insertion reaction of a non-stabilized carbenoid

Article abstract of DOI:10.1016/j.tet.2013.04.086

An efficient and practical asymmetric synthesis of the 2,3-dihydrobenzo[b] furan neolignan acuminatin was achieved by using trans-isoeugenol as the starting material. The key step is an intramolecular C-H insertion through a non-stabilized carbenoid, prep

Full text of DOI:10.1016/j.tet.2013.04.086

Tetrahedron 69 (2013) 5511e5516
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Rh(II)-catalyzed enantioselective synthesis of acuminatin through
a CeH insertion reaction of a non-stabilized carbenoid
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~
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Cristobal Lopez-Sanchez, Míriam Alvarez-Corral, Leticia Jimenez-Gonzalez,
*
Manuel Munoz-Dorado, Ignacio Rodríguez-García
ꢀ
Química Organica, Universidad de Almería, Campus de Excelencia Internacional Agroalimentario ceiA3, Almería E-04120, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 March 2013
Received in revised form 16 April 2013
Accepted 18 April 2013
Available online 28 April 2013
An efficient and practical asymmetric synthesis of the 2,3-dihydrobenzo[b]furan neolignan acuminatin
was achieved by using trans-isoeugenol as the starting material. The key step is an intramolecular CeH
insertion through a non-stabilized carbenoid, prepared by decomposition of a tosylhydrazone in the
presence of an anthracenyl-derived cinchonidine quaternary ammonium salt as a chiral phase-transfer
catalyst.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Rh(II) catalyst
1,5 CeH insertion
Chiral phase-transfer catalyst
Cinchonidine quaternary ammonium salt
1. Introduction
quinones.21 However, both are multistep, low yielding and non
stereoselective.
(þ)-Acuminatin (1) is a dihydrobenzofuran neolignan, a sub-
class of natural products with a molecular backbone formed by two
phenylpropane (C6C3) units, whose biological properties have
prompted their use as lead compounds for the development of new
drugs.1 It was first isolated in 1972 from Magnolia acuminata2 and
later from other plants used in traditional medicine, like Myristica
fragans,3,4 Virola pavonis,5 Machilus obovatifolia,6 Machilus thun-
bergii,7 Magnolia denudata,8 Piper futokadsura9 and more recently
Magnolia ovata10 and Nectandra amazonum.11 The lignan structure
initially proposed by Doskotch et al.2 was later revised as a neo-
lignan with a 2,3-dihydrobenzo[b]furan core.12 The absolute con-
figuration for the natural (þ)-enantiomer has been proposed as
(2R,3R)9,10,12e14 on the basis of the chiroptical properties of the
heterocycle.15
One of the most elegant methods for the preparation of dihy-
drobenzofuran neolignans is based on the asymmetric Rh-catalyzed
CeH insertion reaction developed by Davies et al.,22e24 which has
also been described by Hashimoto25 and Fukuyama.26,27 The
method has been extended by the use of other metal complexes.28
In this approach, a diazo compound is treated with a metal salt to
give a metal carbene intermediate, which is able to promote intra-
molecular CeH functionalization to afford new CeC bonds. The
reactivity of the metal carbenes is highly conditioned by the nature
of the substituents (Fig. 1).
R1
R1
MLn
R2
N2
R2 MLn
Among the main biological activities of (þ)-acuminatin are the
H
EWG
MLn
EWG
EDG
MLn
inhibition of DNA-topoisomerases I, II16 and phospholipase C 1,7
g
the inhibition of nitric oxide9 and the inhibition in the production
of transaminases,17 implying, in the last case, potential hep-
atoprotective properties.
EWG
MLn
EWG
EDG
MLn
EDG
Fig. 1. Classes of metal carbenes prepared from diazo compounds.
There are two main strategies for the synthesis of acuminatin:
the use of the Erdtman methodology18,19 through phenol oxidative
coupling,12,20 and the cycloaddition of styrene derivatives to
The acceptor/acceptor carbenes are very reactive species be-
cause the acceptor groups do not stabilize the highly electrophilic
carbene centre, whereas the donor/acceptor metal carbenes are
capable of highly selective CeH functionalization. On the other
hand, donor/donor metal carbenes have been less studied due to
the instability of the required diazo compounds. These can be
* Corresponding author. Tel.: þ34 950015610; fax: þ34 950015008; e-mail address:
irodrigu@ual.es (I. Rodríguez-García).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.086

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C. Lopez-Sanchez et al. / Tetrahedron 69 (2013) 5511e5516
5512
prepared using the BamfordeStevens reaction,29 which utilizes
tosylhydrazones as safe diazo precursors. In the presence of phase-
transfer catalysts (PTC) they can be cleanly converted to diazo
compounds under mild reaction conditions.30
We report here a new method of synthesis of acuminatin based
on an intramolecular CeH insertion reaction through rhodium
carbenoids intermediates prepared in situ by decomposition of
tosylhydrazones with base in the presence of a phase-transfer
catalyst (Scheme 1). The CeH insertion reaction can be performed
in a diastereoselective and enantioselective manner using chiral
rhodium complexes and chiral phase-transfer catalysts.
was transformed into ketone 4 by a three step process involving
Grignard addition, DesseMartin oxidation and hydrolysis of the
carbamate group in alkaline media. Williamson etherification with
4-(iodomethyl)-1,2-dimethoxybenzene (7) and treatment of 3 with
tosylhydrazine yielded the desired tosylhydrazone 2.
When the tosylhydrazone 2 is treated with KHMDS in THF at
ꢀ80 ꢁC, cloudiness appears due to the formation of the potassium
salt, which on heating, is unstable and decomposes in situ to form
the diazo compound derivative (Scheme 3).30 This diazo compound
can be detected by NMR, but our attempts to isolate it failed, pos-
sibly because is not stable enough for the standard purification
methods used with other diazo compounds bearing electron-
withdrawing substituents (like esters or ketones).34,35
OMe
OMe
OMe
OMe
OMe
OMe
O
O
(R)
(R)
OMe
OMe
(E)
OMe
OMe
OMe
OMe
(+)-1
2
NNHTs
O
O
KHMDS
OMe
K
OMe
OMe
OMe
NNTs
NNHTs
2
OH
O
O
Δ
OMe
OMe
N2
OMe
O
OMe
OMe
4
3
OMe
O
O
trans-isoeugenol
Scheme 1. Retrosynthetic analysis of (þ)-acuminatin (1).
Rh(II)
N2
RhII
2. Results and discussion
OMe
OMe
OMe
The synthesis of the required tosylhydrazone 2 from trans-iso-
eugenol was achieved in seven high-yielding conventional steps
(Scheme 2). Initial attempts to introduce an acyl group in ortho
position of the phenolic OH through FriedeleCrafts acylation or
Fries rearrangement of the acetyl derivative31e33 in the presence of
either TiCl4, Ti(i-PrO)4 or Sc(OTf)4 did not gave satisfactory results.
However, the multi-step process depicted in Scheme 2, proved to
be useful. First, the phenolic OH was protected with the ortho-
directing group N,N0-diethylcarbamate to form compound 5. For-
milation in ortho position to give 6 was optimal when s-BuLi as
metallating agent and DMF as electrophile were used. Aldehyde 6
O
1
Scheme 3. Pathway for the CeH insertion reaction through rhodium carbenoids by
decomposition of tosylhydrazone 2.
In the presence of a metal catalyst, the diazo compound reacts
with an activated CeH bond through
mediate.35e40 The process is
1,5-intramolecular carbon-
ehydrogen bond insertion22,24,35,41 to form
five-member
a carbenoid inter-
a
a
heterocycle through a well-established mechanism42e46 (Scheme
3). The reaction can be highly improved by the presence of
phase-transfer catalysts (PTC), like quaternary ammonium salts,
because they favour the transformation of the tosylhydrazone salt
into the diazo compound and promote the solubility of rhodium
catalysts.30
Table 1 shows yields, conditions and diastereoselectivity of the
reaction of tosylhydrazone 2 with a series of rhodium salts. Mix-
tures of cis/trans diastereoisomers are always formed except for
Rh2(OCOCF3)4, which shows complete cis diastereoselectivity. As
a general trend, the more electron-donating the rhodium ligands,
trans-isoeugenol
a
OMe
OMe
OMe
OCON(Et)2
b
OCON(Et)2
c,d,e
OH
Me
H
5
6
4
O
O
f
OMe
OMe
3´´
Table 1
OMe
OMe
CeH insertion reaction with several Rh(II) catalystsa
OMe
OMe
4´´
6
1
O
O
O
Entry
Catalystb
Yield of 1 (%)
dr (cis/trans)
1´´
g
2
Me
NNHTs
Me
1
2
3
4
5
Rh2(OCOCF3)4
Rh2(OAc)4
Rh2(Oct)4
Rh2(5S-MEPY)4
Rh2(S-DOSP)4
90
87
35
70
40
100:0
87:13
80:20
62:38
50:50
4
3´
1´
2
3
a) Et2NCOCl, py, 100 ºC, 90%; b) s-BuLi, DMF, TMEDA,THF, - 90 ºC,
85%; c) Mg, CH3I, Et2O, 0 ºC, 93%; d) Dess-Martin oxidation, 95%; e)
a
KHMDS was added at ꢀ80 ꢁC to a THF solution of 2; then stirred for 30 min at
NaOH, EtOH, , 85%; f) K CO 7, Me CO, , 85%; g) TsNHNH2, MeOH,
Δ
Δ
2
3,
2
25 ꢁC; next, 1% mol Rh(II) catalyst and n-Bu4NBr were added and refluxed for 12 h.
, 92%.
Δ
b
Diastereomeric ratios deduced from the integrals of signals in 1H NMR of the
Scheme 2. Preparation of tosylhydrazone 2 from trans-isoeugenol.
crude mixtures and confirmed after CC isolation of products.

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C. Lopez-Sanchez et al. / Tetrahedron 69 (2013) 5511e5516
5513
the less electrophilic the carbenoid carbon atom, with an associated
OMe
OMe
OMe
decrease in reaction yield and selectivity. Bulkiness of the ligands
has the same effect.
OMe
OMe
OMe
1) KHMDS
O
O
∗
2) PTC, Rh(II)
The reaction is chemoselective, as no side products were
detected, like those due to sigmatropic rearrangement47e50 or
b
-
∗
hydride shift.51,52
NNHTs
2
1
Natural trans-acuminatin can be prepared by acidic treatment of
either the cis/trans mixtures of 1 or the diastereomerically pure cis-
1 formed when Rh2(OCOCF3)4 is used (Scheme 4).
N
N
H
OMe
OMe
7a
OMe
OMe
3´´ OMe
4´´OMe
N
HO
2·Cl
(cinchonidine-derived amonium salt)
Scheme 5. Asymmetric intramolecular CeH insertion reaction.
OH
7
O
O
2
6
a
N
2´
1´´
8
3
3a
5
4
3´
1´
cis-1
trans-1
a) Camphorsulphonic acid (cat.), tol, , 95%.
Δ
Scheme 4. Isomerization of (ꢃ)-cis-acuminatin to natural (ꢃ)-trans-acuminatin in acid
media.
reaction under the influence of a chiral phase-transfer catalyst,
with good yields and moderate enantiomeric excesses.
3. Asymmetric synthesis of acuminatin
5. Experimental
5.1. General
In order to achieve enantioselectivity in the insertion process,
several chiral rhodium complexes were tested, although under the
standard reaction conditions no enantioselectivity was observed
(Table 1, entries 4 and 5). However, when the cyclization step was
performed at a lower temperature, excellent diastereoselectivity
and moderate enantioselectivity levels were observed (Table 2,
entries 1 and 2). The temperature of reaction proved to be critical:
a threshold in the range 30e40 ꢁC was required to complete the
transformation of the tosylhydrazone salt into the diazo com-
pound. The results were also improved by the use of the
anthracenyl-derived cinchonidine quaternary ammonium salt 853
as phase-transfer catalyst (Scheme 5, Table 2, entries 3 and 4).
Surprisingly, when 8 was used in combination with a non-chiral
rhodium salt, a significant enantiomeric excess was found (Table 2,
entry 5), thus indicating that this chiral PTC is involved in the
cyclization step.
1H and 13C NMR spectra were recorded on a Bruker Avance DPX
300 spectrometer. Chemical shifts are given in parts per million
relative to TMS. Carbon substitution degrees were established by
DEPT multipulse sequence, and 13C NMR peak assignments were
made with the aid of 2D NMR (HMBC, HMQC, COSY and NOESY).
Infrared spectra were recorded in liquid film between NaCl plates
on a FT-IR Mattson Genesis II spectrometer, and mass spectra were
performed on a AutoSpec-Q VG-Analitical (Fisons) (HRMS) in-
strument, using the Fast Atom Bomb technique (FAB) with a 1% NaI
doped matrix of thioglycerol or glycerol.
The reactions were monitored by TLC (unless other technique is
specified), using Macherey Nagel Alugram Sil G/UV254 plates. UV
light and 5% phosphomolybdic or sulfuric acid solutions in meth-
anol were employed for revealing. SDS 60 A CC 35e70 mm silica was
Table 2
used for column chromatography. All solvents were purified and
dried following standard procedures. Enantiomeric excesses were
calculated from chiral HPLC performed in a Hewlett Packard Series
1100 chromatograph equipped with a circular dichroism detector
and a Daicel Chiracel OD-H 150ꢂ4.6 mm column and eluting with
mixtures of hexane and isopropanol.
Reaction of 2 with chiral rhodium catalysts and PTC
Entry T (ꢁC) Rhodium catalyst PTC
Yield (%) dr (cis/trans)a ee (%)b
1
2
3
4
5
40
30
40
40
40
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(R-DOSP)4
Rh2(OCOCF3)4
n-Bu4NBr 32
n-Bu4NBr 29
92:8
100:0
100:0
100:0
100:0
24
30
14
20
32
8
8
8
83
80
80
5.1.1. (E)-2-Methoxy-4-(prop-1-enyl)phenyl N,N0-diethylcarbamate
(5). To a solution of trans-isoeugenol (2 g, 11.9 mmol) in dry pyri-
dine (25 mL), diethyl carbamoyl chloride (2.4 g, 17.8 mmol) was
added. The mixture was stirred at 100 ꢁC for 12 h. Then, 20 mL of
HCl (5%) were added, and the whole was extracted with 20 mL of
CH2Cl2. The organic layer was dried with MgSO4, filtered and con-
centrated under reduced pressure. The product was purified by
column chromatography on silica gel (hexane/Et2O, 7:3) to afford 5
(2.8 g, 10.7 mmol, 90%) as a yellow oil. IR (film) nmax 1721 (C]O),
a
Diastereomeric ratios deduced from the integrals of signals in 1H NMR of the
crude mixtures.
b
ee values deduced from chiral HPLC integration.
Although the asymmetric induction by chiral PTCs is well doc-
umented,54e56 to the best of our knowledge, this is the first time
when a chiral phase-transfer catalyst affords asymmetric induction
in an intramolecular CeH bond insertion.
1591 (C]C) cmꢀ1 1H NMR (300 MHz, CDCl3),
; d: 1.23 [3H, t,
4. Conclusions
3J¼7.1 Hz, OCON(CH2CH3)2], 1.27 [3H, t, 3J¼7.1 Hz, OCON(CH2CH3)2],
4
1.94 (3H, dd, 3J¼6.6 Hz, J¼1.5 Hz, H30), 3.38 [2H, c, 3J¼7.1 Hz,
We have described a new method for the synthesis of the
neolignan acuminatin, in good global yield (40%), through the de-
composition of a tosylhydrazone as precursor of the required
arylemethyl diazo compound for a Rh(II) catalyzed CeH insertion.
The reaction affords diastereoselectively the cis isomer, which can
be easily isomerized into the natural trans-acuminatin. We have
also described the asymmetric intramolecular CeH insertion
OCON(CH2CH3)2], 3.42 [2H, c, 3J¼7.1 Hz, OCON(CH2CH3)2], 3.85 (3H,
3
s, OCH3), 6.20 (1H, dc, 3J¼15.7 Hz, J¼6.55 Hz, H20), 6.37 (1H, dd,
4
3J¼15.7 Hz, J¼1.5 Hz, H10), 6.90 (1H, dd, 3J¼8.2 Hz, 4J¼1.7 Hz,
H5), 6.92 (1H, d, 4J¼1.6 Hz, H3), 7.2 (1H, d, 3J¼8.2 Hz, H6). 13C
NMR (75 MHz, CDCl3)
d
:
13.36 [OCON(CH2CH3)2], 13.97
[OCON(CH2CH3)2], 18.37 (CH3, C30), 41.94 [OCON(CH2CH3)2], 42.20
[OCON(CH2CH3)2], 55.80 (OCH3), 109.58 (CH, C3), 118.26 (CH, C5),

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C. Lopez-Sanchez et al. / Tetrahedron 69 (2013) 5511e5516
5514
123.11 (CH, C6), 125.46 (CH, C20), 130.60 (CH, C10), 136.21 (C, C4),
139.49 (C, C1), 151.55 (C, C2), 154.15 (C]O). HRFABMS (m/z)
calcd for C15H21NO3Na 286.1414 [MþNa]þ, found 286.1418.
7.9 mmol, 95%) as a brown-red oil, IR (film) nmax 1588 (C]C), 1714
(C]O) cmꢀ1
;
1H NMR (300 MHz, CDCl3),
d
: 1.15 [3H, t, 3J¼7.0 Hz,
OCON(CH2CH3)2], 1.23 [3H, t, 3J¼7.0 Hz, OCON(CH2CH3)2], 1.81
(3H, dd, 3J¼6.4 Hz; J¼1.3 Hz, H30), 2.50 (3H, s, COCH3), 3.33 [2H,
4
5.1.2. (E)-2-Formyl-6-methoxy-4-(prop-1-enyl)phenyl
N,N0-dieth-
c, 3J¼7.0 Hz, OCON(CH2CH3)2], 3.43 [2H, c, 3J¼7.0 Hz,
OCON(CH2CH3)2], 3.77 (3H, s, OCH3), 6.10 (1H, dc, 3J¼6.3 Hz;
ylcarbamate (6). TMEDA (4.8 mL, 32.1 mmol) was added to a solu-
tion of compound 5 (2.8 g, 10.7 mmol) in dry THF (30 mL) at ꢀ90 ꢁC
under nitrogen atmosphere. The mixture was stirred for 5 min, and
11.7 mL (16 mmol) of s-BuLi (1.4 M) were added dropwise. After 6 h
at ꢀ90 ꢁC, DMF (5 mL, 64.3 mmol) was added. The reaction was
stirred for 12 h and then, 5 mL of a solution of TsOH/MeOH (50% w/
v) was added and the mixture was allowed to reach room tem-
perature. The solvent was removed and the crude dissolved in
CH2Cl2 (50 mL) was washed with HCl (5%) (3ꢂ20 mL) and brine
(20 mL). The organic layer was dried with MgSO4, filtered and
concentrated under reduce pressure. The product was purified by
column chromatography on silica gel (hexane/Et2O, 9:1) to afford
6 (2.6 g, 9.1 mmol, 85%) as a white solid, mp: 81.4 ꢁC; IR (KBr)
3J¼15.7 Hz, H20), 6.20 (1H, d, J¼15.8 Hz, H10), 7.00 (1H, d,
3
4J¼2.0 Hz, H5), 7.20 (1H, d, 4J¼2.0 Hz, H3). 13C NMR (75 MHz,
CDCl3), d: 13.23 [OCON(CH2CH3)2], 13.94 [OCON(CH2CH3)2], 18.26
(CH3, C30), 30.13 (COCH3), 42.03 [OCON(CH2CH3)2], 42.26
[OCON(CH2CH3)2], 56.08 (OCH3), 112.54 (CH, C5), 118.26 (CH, C3),
126.60 (CH, C20), 129.88 (CH, C10), 132.78 (C, C2), 135.64 (C, C4),
138.00 (C, C1), 152.18 (C, C6), 153.31 (OCO), 198.03 (CO).
5.1.5. (E)-2-Acetyl-6-methoxy-4-(prop-1-enyl)phenol (4). Compound
10 (2.4 g, 7.9 mmol) was added to a solution of NaOH (1.27 g,
31.7 mmol) in EtOH (16 mL). The mixture was refluxed during 12 h.
The reaction mixture was cooled to room temperature and a solu-
tion of HCl (5%) was added until an acid pH was reached. The so-
lution was extracted with CH2Cl2 (3ꢂ25 mL), and the organic layers
were washed with water, dried with MgSO4, filtered and concen-
trated under reduce pressure. The residue was purified by column
chromatography on silica gel (hexane/Et2O, 6:4) yielding 4 (1.4 g,
6.8 mmol, 85%) as a green oil. IR (film) nmax 1595 (C]C),1677 (C]O),
nmax 1715 (C]O), 1592 (C]C) cmꢀ1; 1H NMR (300 MHz, CDCl3),
d:
1.23 [3H, t, 3J¼7.1 Hz, OCON(CH2CH3)2], 1.27 [3H, t, 3J¼7.1 Hz,
OCON(CH2CH3)2], 1.80 (3H, d, 3J¼6.6 Hz, H30), 3.38 [2H, c, 3J¼7.1 Hz,
OCON(CH2CH3)2], 3.42 [2H, c, 3J¼7.1 Hz, OCON(CH2CH3)2], 3.76 (3H,
3
s, OCH3), 6.15 (1H, dc, 3J¼6.6 Hz, J¼15.7 Hz, H20), 6.25 (1H, d,
3J¼15.7 Hz, H10), 7.00 (1H, s, H5), 7.3 (1H, s, H3), 10.1 (1H, s, CHO).
13C NMR (75 MHz, CDCl3),
d: 13.20 [OCON(CH2CH3)2], 14.00
3558 (OeH) cmꢀ1
;
1H NMR (300 MHz, CDCl3),
d: 1.84 (3H, dd,
4
[OCON(CH2CH3)2], 18.30 (CH3, C30), 42.10 [OCON(CH2CH3)2], 42.40
[OCON(CH2CH3)2], 56.00 (OCH3), 114.60 (CH, C5), 116.80 (CH, C3),
127.10 (CH, C20), 129.50 (CH, C10), 129.60 (C, C2), 136.10 (C, C4),
141.90 (C, C1), 152.20 (C, C6), 153.30 (OCO), 188.80 (CHO). HRFABMS
(m/z) calcd for C16H21NO4Na 314.1368 [MþNa]þ, found 314.1371.
3J¼6.5 Hz, J¼1.2 Hz, H30), 2.58 (3H, s, COCH3), 3.86 (3H, s, OCH3),
6.10 (1H, dc, 3J¼6.5 Hz; J¼15.7 Hz, H20), 6.27 (1H, d, 3J¼15.7 Hz,
3
H10), 7.02 (1H, d, 4J¼1.6 Hz, H5), 7.14 (1H, d, 4J¼1.6 Hz, H3),12.49 (1H,
sa, OH). 13C NMR (75 MHz, CDCl3), : 18.24 (CH3, C30), 26.91 (COCH3),
d
55.98 (OCH3), 113.60 (CH, C5), 119.20 (CH, C3), 119.39 (CH, C20),
124.51 (CH, C10),128.52 (C, C2)*,129.83 (C, C4)*,148.75 (C, C1),151.83
(C, C6), 204.88 (CO) *may be interchanged. HRFABMS (m/z) calcd for
C12H14O3Na 229.0841 [MþNa]þ, found 229.0835.
5.1.3. (E)-2-(1-Hydroxyethyl)-6-methoxy-4-(prop-1-enyl)phenyl
N,N0-diethylcarbamate (9). To a suspension of Mg (600 mg, 25
mmol) in dry Et2O (25 mL), MeI (2.5 mL, 27 mmol) was added under
nitrogen atmosphere, and the mixture was refluxed until the
magnesium turnings disappeared. Then, the reaction was cooled at
0 ꢁC and a solution of 7 (2.6 mg, 8.9 mmol) in dry Et2O (25 mL) was
added slowly. The mixture was refluxed for 3 h and was quenched
by the addition of a solution of NH4Cl (30%) (100 mL). The organic
layer was washed with HCl (5%) (150 mL) and brine (100 mL), dried
with MgSO4 and concentrated in vacuo. The crude residue was
purified by column chromatography on silica gel (hexane/Et2O, 7:3)
yielding 9 (2.6 g, 8.3 mmol, 93%) as a white solid, mp: 66.5 ꢁC; IR
5.1.6. 4-(Iodomethyl)-1,2-dimethoxybenzene (7). Imidazole (0.82 g,
12 mmol) and PPh3 (3.1 g, 12 mmol) were added to a solution of
(3,4-dimethoxyphenyl)methanol (1.7 g, 10 mmol) in 25 mL of THF.
After stirring for 10 min, iodine (3 g, 12 mmol) was added in
darkness and the mixture was stirred at room temperature for
30 min. Solvent was removed in vacuo, and the residue was dis-
solved in CH2Cl2. The solution was washed with 20 mL NaHSO3 (5%)
and brine (2ꢂ15 mL), then dried over MgSO4 and concentrated in
vacuo. The residue was purified by flash chromatography 1:1
(hexane/Et2O) yielding 757 (2.5 g, 9 mmol, 90% of yield).
(KBr) nmax 3470 (OeH), 1702 (C]O), 1595 (C]C) cmꢀ1 1H NMR
;
(300 MHz, CDCl3),
d
: 1.23 [3H, t, 3J¼7.1 Hz, OCON(CH2CH3)2], 1.27
[3H, t, 3J¼7.06 Hz, OCON(CH2CH3)2], 1,48 [3H, d, 3J¼6.5 Hz,
5.1.7. (E)-2-Acetyl-6-methoxy-4-(prop-1-enyl)phenyl 3,4-dimethoxy
bencyl ether (3). Compound 4 (1.4 g, 6.8 mmol) and K2CO3 (1.4 g,
10.1 mmol) were dissolved in acetone (10 mL). After stirring for
10 min, a solution of 7 (2.3 g, 8.1 mmol) in acetone (10 mL) was
added. The mixture was refluxed for 12 h. Solvent was removed in
vacuo, and the residue was dissolved in CH2Cl2 (20 mL). The solu-
tion was washed with HCl (5%) (3ꢂ15 mL), then dried over MgSO4
and concentrated in vacuo. The residue was purified by column
chromatography 8:2 (hexane/Et2O) yielding 3 (2.2 g, 6 mmol, 85%).
CH3CHOH-], 1.80 (3H, dd, 3J¼6.6 Hz; J¼1.5 Hz, H30), 3.38 [2H, c,
4
3J¼7.0 Hz, OCON(CH2CH3)2], 3.42 [2H, c, 3J¼7.0 Hz,
OCON(CH2CH3)2], 3.83 (3H, s, OCH3), 5.00 (1H, c, 3J¼6.5 Hz, CHOH),
6.15 (1H, dc, 3J¼6.6 Hz; J¼15.6 Hz, H20), 6.25 (1H, dd, 3J¼15.7 Hz;
3
4J¼1.5 Hz, H10), 6.85 (1H, s, H5), 7.00 (1H, s, H3). 13C NMR (75 MHz,
CDCl3), d: 13.29 [OCON(CH2CH3)2], 13.99 [OCON(CH2CH3)2], 18.31
(CH3CHOH-), 22.39 (CH3, C30), 42.10 [OCON(CH2CH3)2], 42.37
[OCON(CH2CH3)2], 55.86 (OCH3), 63.98 (CHOH), 108.33 (CH, C5),
115.41 (CH, C3), 125.71 (CH, C20), 130.73 (CH, C10), 136.23 (C, C2)*,
136.57 (C, C4)*, 139.01 (C, C1), 151.56 (C, C6), 154.50 (OCO) *may be
interchanged.
IR (KBr) nmax 1593 (C]C), 1670 (C]O) cmꢀ1 1H NMR (300 MHz,
;
CDCl3),
d
: 1.88 (3H, d, 3J¼6.4 Hz, H30), 2.55 (3H, s, COCH3), 3.89 (6H,
s, 2ꢂ OCH3), 3.93 (3H, s, OCH3), 4.99 (2H, s, OCH2Ar), 6.21 (1H, dc,
3J¼6.4 Hz; 3J¼16.0 Hz, H20), 6.35 (1H, d, 3J¼16.0 Hz, H10), 6.84 (1H,
d, 3J¼8.2 Hz, H500), 6.93 (1H, dd, 3J¼8.2 Hz; 4J¼1.9 Hz, H600), 6.98 (1H,
d, 4J¼1.9 Hz, H200), 7.05 (1H, d, 4J¼1.9 Hz, H5), 7.13 (1H, d, 4J¼1.9 Hz,
5.1.4. (E)-2-Acetyl-6-methoxy-4-(prop-1-enyl)phenyl N,N0-dieth-
ylcarbamate (10). DesseMartin periodinane (3 g, 12.5 mmol) was
added to a solution of compound 9 (2.6 g, 8.3 mmol) in CH2Cl2
(35 mL) at room temperature. The mixture was stirred for 1 h, and
H3). 13C NMR (75 MHz, CDCl3), : 18.35 (CH3, C30), 31.31(COCH3),
d
55.78 (OCH3), 55.83 (OCH3), 56.00 (OCH3), 75.97 (OCH2Ar), 110.81
(CH, C500), 111.81(CH, C200), 112.52 (CH, C5), 118.21 (CH, C3), 121.14
(CH, C600), 126.20 (CH, C20), 129.49 (C, C100), 129.88 (CH, C10), 134.15
(C, C4)*, 134.46 (C, C2)*, 145.83 (C, C1), 148.88 (C, C400)#, 149.02 (C,
then it was washed with
a saturated solution of NaHCO3
(3ꢂ20 mL). The organic layer was dried with MgSO4, filtered and
concentrated in vacuo. The crude residue was purified by column
chromatography on silica gel (hexane/Et2O, 1:1) yielding 10 (2.4 g,
#
C300)#, 152.96 (C, C6), 200.74 (CO). * and may be interchanged.

ꢀ
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C. Lopez-Sanchez et al. / Tetrahedron 69 (2013) 5511e5516
5515
HRFABMS (m/z) calcd for C21H24O5Na 379.1521 [MþNa]þ, found
(OCH3), 55.77 (OCH3), 93.51 (CH, C2),110.11 (CH, C6),109.90 (CH, C200)
*,113.59 (CH, C4)*,113.17 (CH, C500),119.03 (CH, C600), 123.29 (CH, C20),
134.28 (C, C5),130.89 (CH, C10),132.06 (C, C100),133.20 (C, C3a),146.12
(C, C7a), 146.46 (C, C400), 149.10 (C, C300), 147.60 (C, C7) *may be
interchanged.
379.1550.
5.1.8. Tosylhydrazone of 3 (2). To a solution of 3 (2.2 g, 6 mmol) in
18 mL of MeOH, p-toluenesulfonyl hydrazide (1.1 g, 9 mmol) was
added. The mixture was heated under reflux for 15 min and then, it
was stirred at room temperature for 15 h. Solvent was removed in
vacuo, and the residue was purified by column chromatography on
silica gel (hexane/Et2O, 1:1) yielding 2 (2.5 g, 5.5 mmol, 92%) as
5.1.11. General procedure for the asymmetric synthesis of
acuminatin. A solution of 2 in dry THF (5 mL/mmol) was cooled at
ꢀ80 ꢁC and 1.5 equiv of anhydrous KHMDS were added under ni-
trogen. The reaction was stirred at this temperature for 15 min and
then another 30 min at room temperature. After that, the solution
initially colourless, changed to yellow. Catalytic amount of PTC
(10%) (n-Bu4NBr or 8) and rhodium catalyst (1e2%) were added and
the mixture was heated (see Table 2) during 5e7 days. Then, it was
cooled to room temperature, eluted with diethyl ether and washed
with brine. The organic layer was dried over MgSO4, filtered and
concentrated under reduce pressure. The residue was purified by
column chromatography on silica gel (hexane/Et2O, 98:2) yielding
1 as a yellow oil (see Table 2). The enantiomeric excesses were
determined by chiral HPLCeUV.
a green-yellow foam. IR (KBr) nmax 3270 (NeH), 1596 (eC]N)
3
cmꢀ1
;
1H NMR (300 MHz, CDCl3),
d
: 1.90 (3H, d, J¼6.4 Hz, H30),
2.05 (3H, s, CH3C]Ne), 2.39 (3H, s, SO2PhCH3), 3.86 (3H, s, OCH3),
3.87 (3H, s, OCH3), 3.88 (3H, s, OCH3), 4.74 (2H, s, OCH2Ar), 6.14 (1H,
dc, 3J¼6.9 Hz; J¼15.7 Hz, H20), 6.31 (1H, d, J¼15.7 Hz, H10), 6.72
3
3
(1H, d, 4J¼1.6 Hz, H3), 6.79 (2H, m, H600, H500), 6.90 (2H, m, H5, H200),
3
3
7.29 (2H, d, J¼10.1 Hz, H5000, H3000), 7.36 (2H, d, J¼10.1 Hz, H6000
,
H2000). 13C NMR (75 MHz, CDCl3),
d: 17.07 (CH3C]Ne), 18.33 (CH3,
C30), 21.49 (SO2PhCH3), 55.87 (3ꢂ OCH3), 75.92 (OCH2Ar), 110.41
(CH, C5), 111.86 (CH, C200), 118.82 (CH, C3), 121.05 (CH, C600), 125.61
(CH, C20), 127.98 (C), 128.08 (CH, C500), 128.22 (CH, C6000and C2000),
129.46 (C, C100), 129.88 (CH, C5000 and C3000), 130.21 (CH, C10), 133.20
(C), 134.04 (C), 143.99 (C), 144.52 (C), 145.02 (C), 148.81 (C), 148.90
Acknowledgements
(ArCH3C]NNH), 152.73 (C). HRFABMS (m/z) calcd for C28H32O5N2
-
SNa 531.1930 [MþNa]þ, found 531.1975.
We wish to acknowledge the Spanish Ministerio de Ciencia e
ꢀ
Innovacion for financial support (Projects CTQ2010-17115 and
5.1.9. General procedure to obtain 2-(3,4-dimethoxyphenyl)-7-
methoxy-3-methyl-5-[(E)-prop-1-enyl]-2,3-dihydrobenzo[b]furan
(acuminatin) (1). A solution of 2 in dry THF (5 mL/mmol) was
cooled at ꢀ80 ꢁC and 1.5 equiv of anhydrous KHMDS were added
under nitrogen atmosphere. The reaction was stirred at this tem-
perature for 15 min, then 30 min at room temperature. After that,
the solution initially colourless, changed to yellow. Catalytic
amount of n-Bu4NBr (10% mol) and rhodium catalyst (1% mol) were
added and the mixture was refluxed for 12 h, cooled to room
temperature, eluted with diethyl ether and washed with brine. The
organic layer was dried over MgSO4, filtered and concentrated
under reduce pressure. The residue was purified by column chro-
matography on silica gel (hexane/Et2O, 98:2) yielding 1 as a yellow
oil (see Table 1 for diastereomeric ratio). 1H NMR (300 MHz, CDCl3),
CTQ2011-24443) and to Universidad de Almería for a scholarship to
C.L.-S.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.04.086.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
References and notes
1. Apers, S.; Vlietinck, A.; Pieters, L. Phytochem. Rev. 2004, 2, 201e207.
2. Doskotch, R. W.; Flom, M. S. Tetrahedron 1972, 28, 4711e4717.
3. Davis, D. V.; Cooks, R. G. J. Agric. Food Chem. 1982, 30, 495e504.
d
: 0.86 (3H, d, 3J¼7.3 Hz, CH3eC3),1.89 (3H, dd, 3J¼6.5 Hz; 4J¼1.6 Hz,
ꢀ
€
4. Juhasz, L.; Kurti, L.; Antus, S. J. Nat. Prod. 2000, 63, 866e870.
5. Marques, M. O. M.; Yoshida, M.; Gottlieb, O. R. Phytochemistry 1992, 31,
4380e4381.
H30), 3.62 (1H, q, 3J¼7.3 Hz, H3), 3.88 (3H, s, OCH3), 3.90 (3H, s,
OCH3), 3.94 (3H, s, OCH3), 5.81 (1H, d, 3J¼8.9 Hz, H2), 6.10 (1H, dc,
3J¼6.5 Hz; 3J¼15.3 Hz, H20), 6.38 (1H, d, 3J¼15.4 Hz, H10), 6.85 (5H,
6. Tsai, I. L.; Chen, J. H.; Duh, C. Y.; Chen, I. S. Planta Med. 2001, 67, 559e561.
7. Lee, J. S.; Kim, J.; Yu, Y. U.; Kim, Y. C. Arch. Pharmacal Res. 2004, 27, 1043e1047.
8. Li, J.; Tanaka, M.; Kurasawa, K.; Ikeda, T.; Nohara, T. Chem. Pharm. Bull. 2005, 53,
235e237.
9. Konishi, T.; Konoshima, T.; Daikonya, A.; Kitanaka, S. Chem. Pharm. Bull. 2005,
53, 121e124.
10. Barros, L. F.; Barison, A.; Salvador, M. J.; de Mello-Silva, R.; Cabral, E. C.; Eberlin,
M. N.; Stefanello, M. E. J. Nat. Prod. 2009, 72, 1529e1532.
11. Coy Barrera, E. D.; Cuca Suarez, L. E. Chem. Pharm. Bull. 2009, 57, 639e642.
12. Elferaly, F. S.; Cheatham, S. F.; Hufford, C. D.; Li, W. S. Phytochemistry 1982, 21,
1133e1135.
m, AreH). 13C NMR (75 MHz, CDCl3),
d: 16.90 (CH3eC3), 18.29 (CH3,
C30), 41.47 (CH, C3), 55.81 (OCH3), 55.88 (OCH3), 56.02 (OCH3),
88.60 (CH, C2), 109.37 (CH, C6), 109.78 (CH, C200)*, 110.75 (CH, C4)*,
114.17 (CH, C500), 118.83 (CH, C600), 123.35 (CH, C20), 130.26 (C, C5),
130.89 (CH, C10), 132.19 (C, C100), 134.23 (C, C3a), 144.12 (C, C7a),
146.46 (C, C400), 148.50 (C, C300), 148.68 (C, C7) *may be inter-
changed. HRFABMS (m/z) calcd for C21H24O4Na 363.1572 [MþNa]þ,
found 363.1586.
13. Fernandes, J. B.; Gottlieb, O. R.; Maia, J. G. S. Phytochemistry 1976, 15,
1033e1036.
14. Coy, E. D.; Cuca, L. E.; Sefkow, M. Bioorg. Med. Chem. Lett. 2009, 19, 6922e6925.
15. Antus, S.; Kurtan, T.; Juhasz, L.; Kiss, L.; Hollosi, M.; Majer, Z. Chirality 2001, 13,
493e506.
16. Li, G.; Lee, C. S.; Woo, M. H.; Lee, S. H.; Chang, H. W.; Son, J. K. Biol. Pharm. Bull.
2004, 27, 1147e1150.
17. Yu, Y. U.; Kang, S. Y.; Park, H. Y.; Sung, S. H.; Lee, E. J.; Kim, S. Y.; Kim, Y. C. J.
Pharm. Pharmacol. 2000, 52, 1163e1169.
18. Erdtman, H. Justus Liebigs Ann. Chem. 1933, 503, 283e294.
19. Erdtman, H. Biochem. Z. 1933, 258, 172e180.
20. Ichihara, A.; Nio, N.; Terayama, Y.; Kimura, R.; Sakamura, S. Tetrahedron Lett.
1979, 3731e3734.
21. Engler, T. A.; Chai, W. Y. Tetrahedron Lett. 1996, 37, 6969e6970.
22. Davies, H. M. L.; Denton, J. R. Chem. Soc. Rev. 2009, 38, 3061e3071.
23. Sefkow, M. Synthesis 2003, 2595e2625.
24. Garcia-Munoz, S.; Alvarez-Corral, M.; Jimenez-Gonzalez, L.; Lopez-Sanchez, C.;
Rosales, A.; Munoz-Dorado, M.; Rodriguez-Garcia, I. Tetrahedron 2006, 62,
12182e12190.
25. Natori, Y.; Tsutsui, H.; Sato, N.; Nakamura, S.; Nambu, H.; Shiro, M.; Hashimoto,
S. J. Org. Chem. 2009, 74, 4418e4421.
5.1.10. trans-2-(3,4-Dimethoxyphenyl)-7-methoxy-3-methyl-5-[(E)-
prop-1-enyl]-2,3-dihydrobenzo[b]furan (trans-acuminatin) (1-trans).-
To a solution of 1-cis (50 mg, 0.15 mmol) in toluene (10 mL) cam-
phorsulfonic acid (35 mg, 0.15 mmol) was added. The reaction was
refluxed for 12 h. Then, the solvent was removed under reduce
pressure, the crude was dissolved in CH2Cl2 (10 mL) and washed
with a solution of NaOH (2 M, 10 mL). The organic layer was dried
over MgSO4, filtered and concentrated to afford 1-trans (47 mg, 95%).
1H NMR (300 MHz, CDCl3),
d
: 1.36 (3H, d, 3J¼7.0 Hz, CH3), 1.85 (3H,
dd, 3J¼6.5 Hz; 4J¼1.6 Hz, H30), 3.43 (1H, q, 3J¼7.0 Hz, H3), 3.86 (3H, s,
OCH3), 3.90 (3H, s, OCH3), 3.92 (3H, s, OCH3), 5.10 (1H, d, 3J¼9.2 Hz,
H2), 6.08 (1H, dc, 3J¼6.6 Hz; 3J¼15.5 Hz, H20), 6.35 (1H, d, 3J¼15.5 Hz,
H10), 6.80 (5H, m, AreH). 13C NMR (75 MHz, CDCl3),
d: 17.25
(CH3eC3), 18.40 (CH3, C30), 45.68 (CH, C3), 54.83 (OCH3), 55.40

ꢀ
ꢀ
C. Lopez-Sanchez et al. / Tetrahedron 69 (2013) 5511e5516
5516
26. Kurosawa, W.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 8112e8113.
27. Koizumi, Y.; Kobayashi, H.; Wakimoto, T.; Furuta, T.; Fukuyama, T.; Kan, T. J. Am.
Chem. Soc. 2008, 130, 16854e16855.
44. Taber, D. F.; You, K. K.; Rheingold, A. L. J. Am. Chem. Soc. 1996, 118, 547e556.
45. Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See, M. M.; Boone, W. P.;
Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc. 1993, 115, 958e964.
46. Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124,
7181e7192.
~
28. Lopez-Sanchez, C.; Alvarez-Corral, M.; Munoz-Dorado, M.; Rodriguez-Garcia, I.
Synlett 2012, 2469e2472.
29. Bamford, W. R.; Stevens, T. S. J. Chem. Soc. 1952, 4735e4740.
30. Fulton, J. R.; Aggarwal, V. K.; de Vicente, J. Eur. J. Org. Chem. 2005, 1479e1492.
31. Cullinane, N. M.; Edwards, B. F. R. J. Chem. Soc. 1958, 434e438.
32. Cullinane, N. M.; Edwards, B. F. R. J. Chem. Soc. 1958, 2926e2929.
33. Baltzly, R.; Phillips, A. P. J. Am. Chem. Soc. 1948, 70, 4191e4193.
34. Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704e724.
35. Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861e2903.
36. Davies, H. M. L. J. Mol. Catal. A: Chem. 2002, 189, 125e135.
37. Herrmann, P.; Bach, T. Chem. Soc. Rev. 2011, 40, 2022e2038.
38. Zhang, S. Y.; Zhang, F. M.; Tu, Y. Q. Chem. Soc. Rev. 2011, 40, 1937e1949.
39. Davies, H. M. L.; Loe, O. Synthesis 2004, 2595e2608.
40. Davies, H. M. L.; Antoulinakis, E. G. J. Organomet. Chem. 2001, 617, 47e55.
41. Slattery, C. N.; Ford, A.; Maguire, A. R. Tetrahedron 2010, 66, 6681e6705.
42. Yoshikai, N.; Nakamura, E. Adv. Synth. Catal. 2003, 345, 1159e1171.
43. Hansen, J.; Autschbach, J.; Davies, H. M. L. J. Org. Chem. 2009, 74, 6555e6563.
47. Clark, J. S.; Krowiak, S. A.; Street, L. J. Tetrahedron Lett. 1993, 34, 4385e4388.
48. Muller, P.; Tohill, S. Tetrahedron 2000, 56, 1725e1731.
49. Pierson, N.; Fernandez-Garcia, C.; McKervey, M. A. Tetrahedron Lett. 1997, 38,
4705e4708.
50. Ye, T.; Fernandez Garcia, C.; McKervey, M. A. J. Chem. Soc., Perkin Trans. 1 1995,
1373e1379.
51. Clark, J. S.; Wong, Y. S.; Townsend, R. J. Tetrahedron Lett. 2001, 42, 6187e6190.
52. Zhang, Z.; Shi, W.; Zhang, J.; Zhang, B.; Liu, B.; Liu, Y.; Fan, B.; Xiao, F.; Xu, F.;
Wang, J. Chem.dAsian J. 2010, 5, 1112e1119.
53. Chinchilla, R.; Mazon, P.; Najera, C. Tetrahedron: Asymmetry 2002, 13, 927e931.
54. Hasegawa, K.; Arai, S.; Nishida, A. Tetrahedron 2006, 62, 1390e1401.
55. Lou, S.; Dai, P.; Schaus, S. E. J. Org. Chem. 2007, 72, 9998e10008.
56. Saito, H.; Iwai, R.; Uchiyama, T.; Miyake, M.; Miyairi, S. Chem. Pharm. Bull. 2010,
58, 872e874.
57. Krohn, K.; Steingrover, K.; Rao, M. S. Phytochemistry 2002, 61, 931e936.