Synthesis of dihydrodehydrodiconiferyl alcohol and derivatives through intramolecular C-H insertion

Article abstract of DOI:10.1016/j.tet.2006.10.018

The natural dihydrobenzofuran neolignan 1 and its derivative 3 have been prepared through intramolecular C-H insertion catalyzed by a Rh(II) chiral complex. Moderate diastereo and enantioselectivities were observed. The cis and trans diastereomers were se

Full text of DOI:10.1016/j.tet.2006.10.018

Tetrahedron 62 (2006) 12182–12190
Synthesis of dihydrodehydrodiconiferyl alcohol and derivatives
through intramolecular C–H insertion
ꢀ
Sergio Garcıa-Munoz, Mıriam Alvarez-Corral, Leticia Jimenez-Gonzalez, Cristobal Lopez-
´
Sanchez, Antonio Rosales, Manuel Munoz-Dorado and Ignacio Rodrıguez-Garcıa
´
~
ꢀ
ꢀ
ꢀ
ꢀ
*
´
´
ꢀ
~
´
Dpto. de Quımica Organica, Universidad de Almerıa, 04120 Almerıa, Spain
ꢀ
´
´
Received 25 September 2006; revised 9 October 2006; accepted 10 October 2006
Available online 27 October 2006
Abstract—The natural dihydrobenzofuran neolignan 1 and its derivative 3 have been prepared through intramolecular C–H insertion cata-
lyzed by a Rh(II) chiral complex. Moderate diastereo and enantioselectivities were observed. The cis and trans diastereomers were separated
and unambiguously identified. The absolute configurations of the major isomers were established through chiral HPLC analysis and study of
the Cotton effects in their circular dichroism curves.
Ó 2006 Elsevier Ltd. All rights reserved.
OH
3
1. Introduction
R1
R3
OH
R2
Dihydrobenzofuran neolignans are a subtype of natural
products of great interest regarding to their biological activ-
ities. Thus, they have been proved to have antioxidant,1 an-
titumoral,2 neuritogenic3 and antimicrobial4 activities, to be
useful in the treatment of liver fibrosis,5 and to be able to act
as adenosine antagonist agents.6 They possess a core skele-
ton of 2,3-dihydrobenzofuran with an aryl substituent on C-2
and a methyl, hydroxymethyl or methoxycarbonyl group on
C-3. Most of them have been assigned a trans 2,3 relative
stereochemistry, and some of which have been described
as cis had to be reassigned.7 The main synthetic approaches
to these neolignans are biomimetic oxidative coupling of
phenylpropenes,8 pericyclic reactions8 or intramolecular
C–H coupling of aryl tosylhydrazones with Ru(II) salts.9
We have reported the preparation of this kind of compounds
through the reaction of benzoxasilepins with benzaldehydes
in the presence of Lewis acids,10 a modification of the
Sakurai–Hosomi reaction.11 Now we present a different
way of synthesis based on the intramolecular C–H insertion
of the products resulting from treatment of diazo compounds
with Rh(II) salts.12 Here we advance the synthesis of the nat-
ural bioactive neolignans dihydrodehydrodiconiferyl alco-
hol (1)13, 3-O-demethyldihydrodehydrodiconiferyl alcohol
(2)14 and the synthetic derivative 3, which incorporates
a phenyl ring with three methoxy groups, a common pattern
in this class of compounds.
2
O
OCH3
1: R1=H, R2=OH, R3=OMe
2: R1=H, R2=R3=OH
3: R1=R2=R3=OMe
2. Results and discussion
2.1. Strategy
Scheme 1 shows the retrosynthetic analysis for these com-
pounds. After decomposition of the diazo compounds and
C–H insertion, the dihydrobenzofurans would be formed.
Simple transformations would lead to the desired products.
Diazoesters can be prepared from the condensation products
of appropriate aromatic precursors. This strategy allows the
presence of different substitution patterns on the rings,
which could afford, not only the desired structures, but other
neolignans with this skeleton.
2.2. Synthetic approach
Eugenol was transformed into alcohol 4,10 and then the hy-
droxy group protected as pivaloate to give 5 (see Scheme 2).
Claisen rearrangement by heating in N,N0-dimethylaniline
yielded 6. Its coupling with several benzyl iodides15 in the
presence of potassium carbonate in acetone allowed the iso-
lation of the esters 7, 8 and 9. Ozonization of these com-
pounds in DCM in the presence of NaOH, MeOH16 and
* Corresponding author. Tel.: +34 950 015610; fax: +34 950 015481;
e-mail: irodrigu@ual.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.018

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S. Garcıa-Munoz et al. / Tetrahedron 62 (2006) 12182–12190
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12183
OH
2.3. Stereoselectivity in the C–H insertion
R1
R3
OH
OP
The insertion step was performed using the rhodium chiral
complex Rh2[(S)-DOSP]4 (tetrakis[(S)-(ꢀ)-N-(p-dodecyl-
phenylsulfonyl)prolinato]dirhodium (II)) as catalyst,18
which had previously been reported to give the best results
on similar substrates.12d,19 In order to get the reaction to pro-
ceed, strict anhydrous conditions were needed, as very small
traces of water react with the intermediate carbenoids to
yield a-hydroxy esters. In all three cases the insertion pro-
ceeds instantly with quantitative yields (Scheme 3).
R2
O
R1
OMe
X
R2
R3
+
CO2Me
R1
R3
N2
R2
CO2Me
O
OMe
OP
HO
10, 11, 12
OMe
a
N2
O
Scheme 1. Retrosynthetic analysis for preparation of compounds 1–3.
MeO
OPiv
R1
O
CO2Me
b
1'
3'
5''
3''
4
3a
OMe
3
5
R1
R2
pyridine resulted in the double bond degradation into the
corresponding methyl esters,17 thus allowing good isolated
yields of 10, 11 and 12.
1''
OPiv
2'
R2
2
6
O
7
R3
OMe
R3
R
OPiv
13 R1= H, R2= OPiv, R3= OMe
14 R1= H, R2= OPiv, R3= OPiv
16
17
b
15 R1= OMe, R2= OMe, R3= OMe 18
O
HO
Scheme 3. Reagents and conditions: (a) p-ABSA, DBU, CH3CN, from 0 ꢁC
to rt 27, 30 and 29% (13, 14 and 15, respectively) and (b) Rh2[(S)-DOSP]4,
toluene, 0 ꢁC, quantitative.
OMe
OMe
4 R = OH
6
a
I
5 R = OPiv
However, the reaction always afforded cis/trans mixtures
(Table 1); a 3:1 diastereoselectivity in favour of the cis iso-
mer was observed with 16 and 17, while 18 gave no dia-
stereoselectivity. The observed enantioselectivities were
also low (Table 1), and all the efforts to improve them were
unsuccessful as the reaction did not proceed below 0 ꢁC. It
was highly surprising to see these poor stereoselectivities
on the basis of the published results for the simple 2-phenyl-
2,3-dihydrobenzofuran core skeleton.12d Fortunately, the
diastereomers could be separated by column chromato-
graphy, and the mixture of enantiomers analyzed by HPLC
(providedwithachiralcolumnandacirculardichroismdetec-
tor), which allowed us to assign their absolute configuration.
c
R1
R3
1''
R2
OPiv
3'
OPiv
6
1
4
1'
MeO
3
O
O
O
R1
R2
OMe
R1
R2
OMe
d
1'''
R3
R3
10 R1= H, R2= OPiv, R3= OMe
11 R1= H, R2= OPiv, R3= OPiv
7
8
12 R1= OMe, R2= OMe, R3= OMe 9
2D-NOESY spectra allowed us to differentiate between cis
and trans isomers, although not in a definitive manner. H-2
Scheme 2. Reagents and conditions: (a) pivaloyl chloride, DMAP, Py, D,
79%; (b) DMA, D, 91%; (c) K2CO3, acetone, D, 74, 61 and 82% to yield
7, 8 and 9, respectively and (d) O3, NaOH, CH2Cl2, MeOH, Py, ꢀ78 ꢁC;
90, 61 and 74% (10, 11 and 12, respectively).
Table 1. Stereoselectivity in the intramolecular C–H insertionsa
16 (R1¼OMe,
17 (R1¼R2¼
OPiv, R3¼H)
77:23
18 (R1¼R2¼
R3¼OMe)
50:50
R2¼OPiv, R3¼H)
75:25
cis:trans
trans
The presence of a benzylic methylene a to ester position in
10, 11 and 12, allowed the introduction of a diazo group by
reaction of these compounds with azides in basic media.
Several organic azides, different bases and reaction condi-
tions were tested, and in all cases low yields were obtained.
Alternative activation procedures also failed. The best
results were obtained by direct treatment with p-ABSA
(p-acetamidobenzenesulfonylazide) and DBU in CH3CN
(around 30% yield). In this way, diazo derivatives 13, 14
and 15 were obtained. The low yields in our substrates
when compared with those reported for model systems12d
could be attributed to undesired reactions due to the presence
of the oxygenated aliphatic side chains.
b
ee¼34%,
tR1¼12.8
(ꢀ) major,
tR2¼14.8
(+) minor
ee¼29%,
tR1¼15.5
(ꢀ) minor,
tR2¼26.5
(+) major
ee¼6%,
tR1¼14.3
(+) minor,
tR2¼17.8
(ꢀ) major
ee¼20%,
tR1¼24.3
(+) major,
tR2¼27.5
(ꢀ) minor
cis
ee¼28%,
tR1¼19.7
(ꢀ) minor,
tR2¼22.5
(+) major
a
Retention times (tR) in minutes. Signs in parenthesis are due to the Cotton
effect observed for the circular dichroism spectrum.
Reliable HPLC analysis could not be performed with the available sample
of the minor trans isomer.
b

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S. Garcıa-Munoz et al. / Tetrahedron 62 (2006) 12182–12190
12184
Figure 2. 2D-NOESY spectrum of 16-cis.
Figure 1. 2D-NOESY spectrum of 16-trans.
and H-3 show cross peaks in both compounds, but much
stronger in the cis compounds, as it can be observed for 16-
cis and 16-trans (Figs. 1 and 2). It can also be observed that
the coupling constants between H-2 and H-3 are very similar:
8.4 Hz for 16-cis and 9.5 Hz for 16-trans. Therefore, J values
are not useful to distinguish cis/trans diastereomers. How-
ever, as we had previously observedfor similar compounds,10
there is a significant difference in chemical shifts between the
methoxycarbonyl groups, appearing at 3.81 ppm in the trans
isomer and at 3.27 ppm in the cis one; this effect is due to the
fact that in the cis isomer this methyl is located in the shield-
ing zone of the phenyl group on C-2. Similar results were
obtained for 1720 and 18 (Table 1).
conformation, with a characteristic torsion angle (C7a–O–
C2–C3), in which the phenyl ring on C-2 is in an equatorial
disposition. Therefore, it can establish a correlation between
the sign of the band 1Lb (a) in the dichroism spectrum, which
appears around 280 nm, and the helicity (P or M) of the five-
membered ring in the dihydrobenzofuran. The sign of the
Cotton effect is highly influenced by the nature of the sub-
stituents on the aromatic rings, especially if there is a
methoxy group on the position 7. As the products we pre-
pared, 16 and 18, have that methoxy group, the P helicity
is connected with a positive Cotton effect, and M with a neg-
ative. Following these criteria, the absolute configurations of
16 and 18-trans have been assigned (Table 2).
The analysis of the circular dichroism spectra allowed to
establish the absolute configurations of the prepared trans-
2-phenyl-2,3-dihydrobenzofurans, as their observed Cotton
effect can be connected with the configuration through the
well established rules given by Antus.21 The five-membered
ring in the dihydrobenzofuran should adopt an envelope
However, the application of the same rules to the cis diaste-
reomers was somewhat obscured because the Lb band is
hardly perceptible. This phenomenon could be due to the
fact that, in these compounds, the five-membered ring is al-
most in a planar conformation, and therefore there is no hel-
icity. X-ray structures previously described by us22 confirm
1
Table 2. Absolute configuration of the major enantiomer from the insertion reaction
trans isomers
cis isomers
O
O
OH
MeO
OH
MeO
R1
R1
R3
3
3
(R)
(R)
(S)
R2
(R)
R2
2
2
O
7a
O
7a
R3
OMe
OMe
16-cis: R1= H, R2= OPiv, R3= OMe
17-cis: R1= H, R2= OPiv, R3= OPiv
18-cis: R1= OMe, R2= OMe, R3= OMe
16-trans: R1= H, R2= OPiv, R3= OMe
18-trans: R1= OMe, R2= OMe, R3= OMe
H
R
H
H
3a
3
3
3a
7a
2
R
OMe
Ar
OMe
Projection of the dihydrobenzofuran ring
7a
2
O
O
CO2Me
CO2Me
Ar
H
C3
Newman projection
through O–C2 bonda
C7a
C3
θ = + 7°
O
O
θ = -23°
C7a
Helicity
Cotton effect
M
P
Negative (1Lb band)
Positive (1La band)
a
Calculated dihedral q values (MOPAC, AM1).

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S. Garcıa-Munoz et al. / Tetrahedron 62 (2006) 12182–12190
~
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1
this point. However, as the strong La band (which appears
G/UV254 plates. UV light and 5% phosphomolibdic or sulfu-
ric acid solutions in methanol were employed for revealing.
SDS 60 A CC 35–70 mm silica was used for column chroma-
tography. All solvents were purified and dried following
standard procedures.24 Enantiomeric excesses were calcu-
lated from chiral HPLC performed in a Jasco HPLC chro-
matograph equipped with a circular dichroism detector and
a Daicel Chiracel OD-H 150ꢂ4.6 mm column and eluting
with mixtures of hexane and isopropanol.
around 250 nm) has the same sign as the 1Lb band, it could
be used to establish the absolute configuration23 for the cis
isomers (Table 2). As a result, we can propose that the abso-
lute configuration for the major enantiomer of the trans com-
pounds is (2R,3R), while for the cis is (2S,3R), in all the
studied cases.
2.4. Preparation of the target molecules
To conclude the synthesis, 16 and 18 (cis and trans) were
treated with LiAlH4, with excellent results, in order to reduce
the methyl ester and to remove the pivaloyl protecting group
in a single step. Strict anhydrous conditions had to be used to
avoid epimerization of the cis isomers into the trans, and for
the same reason, the cis isomers had to be reduced at low
temperature. In this way we obtained 1-trans and 1-cis (81,
100% yield). Their spectroscopic data are in agreement with
those described for the natural products (trans)13 and its
isomer.10 The same conditions were used to prepare 3-trans
and 3-cis (81, 80% yield, respectively). No loss of stereo-
chemical integrity was observed under those conditions.
Again NOE effects between H-2 and H-3 were observed in
both diastereomers of 3, although the comparison of chemi-
cal shifts of the signals in 1H NMR due to H-2 proved to be
a better tool to distinguish both diastereomers, 5.84 ppm
(8.4 Hz) for trans and 5.57 ppm (7.4 Hz) for the cis.
4.2. Synthesis of dihydrobenzofuran neolignans 1 and 3
4.2.1. Allyl 2-methoxy-4-(3-pivaloyloxypropyl)phenyl
ether (5). A solution of 4 (0.535 g, 2.4 mmol) in anhyd
CH2Cl2 (2.4 mL) was added to a mixture of dimethylamino-
pyridine (30 mg, 0.24 mmol) and pyridine (0.6 mL,
7.2 mmol) under an argon atmosphere. Pivaloyl chloride
(0.3 mL, 2.4 mmol) was added and the solution was refluxed
for 14 h. The reaction crude mixture was washed with 5%
HCl (3ꢂ40 mL) and brine (40 mL), dried over anhyd
MgSO4 and concentrated in vacuo. The residue was purified
by flash chromatography yielding 5 (0.594 g, 1.9 mmol,
79%). Colourless oil. 1H NMR (300 MHz, CDCl3):
d (ppm) 6.82 (1H, d, J¼7.9 Hz, H6); 6.72 (1H, d,
J¼2.1 Hz, H3); 6.70 (1H, dd, J¼7.9 Hz, J¼2.1 Hz, H5);
6.09 (1H, ddt, J¼17.3 Hz, J¼10.8 Hz, J¼5.4 Hz, H200);
5.40 (1H, ddd, J¼17.3 Hz, J¼3.0 Hz, J¼1.5 Hz, H300);
5.28 (1H, ddd, J¼10.4 Hz, J¼3.0 Hz, J¼1.5 Hz, H300);
4.60 (2H, dt, J¼5.4 Hz, J¼1.5 Hz, H100); 4.09 (2H, t,
J¼6.5 Hz, H30); 3.88 (3H, s, OMe); 2.65 (2H, t, J¼7.6 Hz,
H10); 1.95 (2H, m, H20); 1.23 (9H, s, OCOC(CH3)3). 13C
NMR (75 MHz, CDCl3): d (ppm) 178.50 (C, CO); 149.34
(C, C2); 146.23 (C, C1); 134.25 (C, C4); 133.514 (CH,
C200); 120.13 (CH, C5); 117.75 (CH2, C300); 113.62 (CH,
C6); 112.10 (CH, C3); 69.98 (CH2, C100); 63.48 (CH2,
C30); 55.84 (CH3, OMe); 38.72 (C, OCOC(CH3)3); 31.67
(CH2, C10); 30.35 (CH2, C20); 27.18 (CH3, OCOC(CH3)3).
IR (film) nmax: 2959, 2936, 2871, 1726, 1514, 1463, 1283,
1263, 1230, 1159, 1034, 997, 926, 804 cmꢀ1. HRFABMS
(m/z): calcd (C18H26O4Na): 329.1723, found: 329.1725
[M+Na]+.
3. Conclusion
Two dihydrobenzofuran neolignans have been prepared
through a convergent strategy in which the key step is an
intramolecular C–H insertion in the presence of a chiral rho-
dium catalyst. The process can be extended to the prepara-
tion of other natural products with different substitution
patterns on the aromatic rings. Although the stereoselectiv-
ity of the reaction was moderate to low, both cis and trans
isomers could be isolated and identified thoroughly using
several NMR techniques. Additionally, the circular dichro-
ism data allowed to establish the absolute configuration of
all the chiral compounds.
4.2.2. 2-Methoxy-4-(3-pivaloyloxypropyl)-6-(2-prope-
nyl)phenol (6). A solution of 5 (9.792 g, 32 mmol) in
N,N0-dimethylaniline (82 mL, 640 mmol) was refluxed un-
der an inert atmosphere for 24 h. The reaction crude mixture
was diluted with CH2Cl2 (80 mL), washed with 5% HCl
(9ꢂ50 mL) and brine (100 mL), dried over anhyd MgSO4
and concentrated in vacuo. The residue was purified by flash
chromatography yielding 6 (8.743 g, 29 mmol, 91%). Yel-
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on a Bruker Avance
DPX 300 or Avance DRX 500 spectrometer. Chemical shifts
are given in parts per million relative to TMS. Carbon sub-
stitution degrees were established by DEPT multipulse se-
quence, 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-Analytical
(Fisons) (HRMS) instrument, using the Fast Atom Bomb
technique (FAB) with a 1% NaI doped matrix of thioglycerol
or glycerol.
1
low oil. H NMR (300 MHz, CDCl3): d (ppm) 6.58 (2H, s,
H3, H5); 6.02 (ddt, 1H, J¼16.6 Hz, J¼10.0 Hz, J¼6.6 Hz,
H200); 5.58 (1H, s, OH); 5.10 (1H, ddd, J¼17.1 Hz, J¼
3.4 Hz, J¼1.4 Hz, H300); 5.06 (1H, ddd, J¼10.4 Hz, J¼
3.4 Hz, J¼1.4 Hz, H300); 4.09 (2H, t, J¼6.5 Hz, H30); 3.89
(3H, s, OMe); 3.40 (2H, dt, J¼6.5 Hz, J¼1.4 Hz, H100);
2.62 (2H, t, J¼7.7 Hz, H10); 1.94 (2H, m, H20); 1.24 (9H,
s, OCOC(CH3)3). 13C NMR (75 MHz, CDCl3): d (ppm)
178.51 (C, CO); 146.20 (C, C2); 141.48 (C, C1); 136.64
(CH, C200); 132.29 (C, C4); 125.52 (C, C6); 121.83 (CH,
C5); 115.35 (CH2, C300); 108.82 (CH, C3); 63.53 (CH2,
C30); 55.95 (CH3, OMe); 38.73 (C, OCOC(CH3)3); 33.82
(CH2, C100); 31.81 (CH2, C10); 30.52 (CH2, C20); 27.18
The reactions were monitored by TLC (unless other tech-
nique is specified), using Macherey Nagel Alugram Sil

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S. Garcıa-Munoz et al. / Tetrahedron 62 (2006) 12182–12190
12186
(CH3, OCOC(CH3)3). IR (film) nmax: 3453, 2971, 2936,
2871, 1724, 1604, 1499, 1462, 1435, 1286, 1156, 1075,
125.36 (CH, C6000); 123.07 (CH, C5000); 122.58 (CH, C2000);
121.74 (CH, C5); 115.58 (CH2, C300); 110.63 (CH,
C3); 73.46 (CH2, ArCH2O); 63.53 (CH2, C30); 55.68
(CH3, OCH3); 39.09 (C, ArOCOC(CH3)3); 38.73 (C,
ROCOC(CH3)3); 34.18 (CH2, C100); 31.99 (CH2, C10);
909 cmꢀ1
.
HRFABMS (m/z): calcd (C18H26O4Na):
323.1723, found: 329.1728 [M+Na]+.
´
4.3. General procedure for the reaction between 6 and
several benzyl iodides
30.26 (CH2, C2); 27.20 (CH3, OCOC(CH3)3). * Assign-
ments may be interchanged. IR (film) nmax: 2964, 2926,
2900, 2862, 1750, 1716, 1578, 1472, 1272, 1248, 1144,
1107 cmꢀ1
K2CO3 (1.5 equiv) was added to a solution of 6 (1.0 equiv)
and benzyl iodide (1.0–1.5 equiv) in acetone (7 mL) under
an inert atmosphere. The mixture was refluxed until the re-
action was completed (TLC monitoring). The reaction crude
mixture was diluted with water (30 mL) and extracted with
CH2Cl2 (3ꢂ30 mL). The organic extracts dried over anhyd
MgSO4 and concentrated in vacuo. The residue was purified
by flash chromatography.
.
HRFABMS (m/z): calcd (C35H48O8Na):
619.3241, found: 619.3239 [M+Na]+.
4.3.3. [2-Methoxy-4-(3-pivaloyloxypropyl)-6-(2-prope-
nyl)phenyl] (3,4,5-trimethoxybenzyl) ether (9). Starting
from 3,4,5-trimethoxybenzyl iodide (1.04 g, 3.3 mmol)
and 1.0 g (3.3 mmol) of 6, and following the general proce-
dure for 15 h, 9 was obtained as a colourless oil (82%). 1H
NMR (300 MHz, CDCl3): d (ppm) 6.72 (2H, s, H2000,
H6000); 6.65 (1H, d, J¼1.9 Hz, H3); 6.61 (1H, d, J¼1.9 Hz,
H5); 5.94 (1H, ddt, J¼17.5 Hz, J¼9.5 Hz, J¼6.5 Hz,
H200); 5.04 (2H, m, H300); 4.91 (2H, s, ArCH2O); 4.10 (2H,
4.3.1. (3-Methoxy-4-pivaloyloxybenzyl) [2-methoxy-4-(3-
pivaloyloxypropyl)-6-(2-propenyl)phenyl] ether (7).
Starting from 4-methoxy-3-pivaloyloxybenzyl iodide
(1.5 g, 4.3 mmol) and 0.88 g (2.9 mmol) of 6, and following
the general procedure during 6 h, 7 was obtained as a colour-
t, J¼6.5 Hz, H30); 3.89 (9H, s, CH3O); 3.87 (3H, s,
00
000
CH3O–C4 ); 3.38 (2H, dt, J¼6.5 Hz, J¼1.5 Hz, H1 ); 2.66
1
less oil (74%). H NMR (300 MHz, CDCl3): d (ppm) 7.14
(2H, t, J¼7.7 Hz, H10); 1.96 (2H, m, H20); 1.24 (9H, s,
OCOC(CH3)3). 13C NMR (75 MHz, CDCl3): d (ppm)
178.48 (C, ROCO); 153.13 (C, C3000, C5000)*; 152.6 (C,
C2)*; 143.93 (C, C1); 137.52 (C, C4000); 137.24 (CH, C200);
137.12 (C, C4); 133.81 (C, C1000); 133.72 (C, C6); 121.73
(CH, C5); 115.56 (CH2, C300); 110.66 (CH, C3); 104.93
(1H, br s, H2000); 7.00 (2H, br s, H5000, H6000); 6.65 (1H, d,
J¼1.9 Hz, H3); 6.61 (1H, d, J¼1.9 Hz, H5); 5.94 (1H, ddt,
J¼17.5 Hz, J¼9.7 Hz, J¼6.4 Hz, H200); 5.04 (2H, m,
H300); 4.97 (2H, s, ArCH2O); 4.10 (2H, t, J¼6.5 Hz, H30);
3.88 (3H, s, CH3O–C2); 3.84 (3H, s, CH3O–C3000); 3.37
(2H, dt, J¼6.5 Hz, J¼1.5 Hz, H100); 2.66 (2H, t, J¼7.7 Hz,
H10); 1.97 (2H, m, H20); 1.40 (9H, s, ArOCOC(CH3)3);
1.25 (9H, s, ROCOC(CH3)3). 13C NMR (75 MHz, CDCl3):
d (ppm) 178.49 (C, ROCO); 176.64 (C, ArOCO); 152.56
(C, C2); 151.08 (C, C3000); 143.89 (C, C1); 139.70 (C,
C4000); 137.20 (CH, C200); 137.10 (C, C4); 136.74 (C,
C1000); 133.84 (C, C6); 122.34 (CH, C5000); 121.74 (CH,
C5); 119.97 (CH, C6000); 115.58 (CH2, C300); 112.08 (CH,
C2000); 110.65 (CH, C3); 74.27 (CH2, ArCH2O); 63.53
(CH2, C30); 55.88 (CH3, OCH3); 55.75 (CH3, OCH3);
39.03 (C, ArOCOC(CH3)3); 38.75 (C, ROCOC(CH3)3);
34.24 (CH2, C100); 32.01 (CH2, C10); 30.28 (CH2, C20);
27.22 (CH3, OCOC(CH3)3). IR (film) nmax: 2970, 2934,
2870, 1753, 1725, 1588, 1509, 1480, 1462, 1282, 1154,
1117, 1034 cmꢀ1. HRFABMS (m/z): calcd (C31H42O7Na):
549.2823, found: 549.2818 [M+Na]+.
(CH, C2000, C6000); 74.77 (CH2, ArCH2O); 63.50 (CH2,
000
C3 ); 60.81 (CH3, C4 –OCH3); 56.04 (CH3, C3 –OCH3 y
0
000
#
#
000
C5 –OCH3) ; 55.75 (CH3, C2–OCH3) ; 38.74 (C, RO-
COC(CH3)3); 34.21 (CH2, C100); 31.99 (CH2, C10); 30.28
#
(CH2, C20); 27.21 (CH3, ROCOC(CH3)3). * and Assign-
ments may be interchanged. IR (film) nmax: 2957, 2936,
2835, 1721, 1587, 1457, 1420, 1282, 1234, 1152, 1125,
1004 cmꢀ1
.
HRFABMS (m/z): calcd (C28H38O7Na):
509.2510, found: 509.2509 [M+Na]+.
4.4. General procedure for ozonolysis of 7, 8 and 9
A solution of NaOH (5 equiv) in MeOH (5 mL) was added to
a solution of allyl derivatives in CH2Cl2 (25 mL) and the
mixture cooled to ꢀ80 ꢁC. A stream of O3 was bubbled
through the stirred solution (20 min, TLC monitoring).
The reaction crude mixture was diluted with water
(30 mL) and 5% HCl (10 mL), and then extracted with
CH2Cl2 (3ꢂ30 mL). The combined organic extracts were
washed with 5% HCl (2ꢂ10 mL) and brine (2ꢂ10 mL),
dried over anhyd MgSO4 and concentrated in vacuo. The
residue was purified by flash chromatography.
4.3.2. [2-Methoxy-4-(3-pivaloyloxypropyl)-6-(2-prope-
nyl)phenyl] (3,4-dipivaloyloxybenzyl) ether (8). Starting
from 3,4-dipivaloyloxybenzyl iodide (1.43 g, 3.4 mmol)
and 1.04 g (3.4 mmol) of 6, and following the general proce-
1
dure for 15 h, 8 was obtained as a colourless oil (65%). H
NMR (300 MHz, CDCl3):
d (ppm) 7.32 (1H, dd,
J¼8.3 Hz, J¼2.0 Hz, H6000); 7.27 (1H, d, J¼2.0 Hz, H2000);
7.13 (1H, d, J¼8.3 Hz, H5000); 6.64 (1H, d, J¼2.0 Hz, H3);
6.61 (1H, d, J¼2.0 Hz, H5); 5.94 (1H, ddt, J¼17.7 Hz,
J¼9.4 Hz, J¼6.5 Hz, H200); 5.03 (2H, m, H300); 4.96 (2H,
s, ArCH2O); 4.10 (2H, t, J¼6.5 Hz, H30); 3.86 (3H, s,
OCH3); 3.37 (2H, dt, J¼6.5 Hz, J¼1.4 Hz, H100); 2.65
(2H, t, J¼7.7 Hz, H10); 1.97 (2H, m, H20); 1.37 (18H, s, Ar-
OCOC(CH3)3); 1.24 (9H, s, ROCOC(CH3)3). 13C NMR
(75 MHz, CDCl3): d (ppm) 178.50 (C, ROCO); 175.85 (C,
ArOCO); 175.76 (C, ArOCO); 152.51 (C, C2); 143.83 (C,
C1); 142.38 (C, C3000)*; 141.96 (C, C4000)*; 137.19 (CH,
C200); 137.16 (C, C4); 136.73 (C, C1000); 133.77 (C, C6);
When required, the isolated aldehydes were oxidized as fol-
lows. A solution of NaClO2 (6 mmol) and Na2HPO4$H2O
(6 mmol) in water (7 mL) was added dropwise to a solution
of the aldehyde (2 mmol) and 2-methyl-2-butene (4 mL) in
tBuOH (20 mL). After 18 h the mixture was diluted with
H2O (60 mL) and extracted with Et2O (3ꢂ60 mL). The com-
bined organic extracts were washed with 1 M aq NaOH
(2ꢂ10 mL), brine (2ꢂ10 mL) and dried over anhyd
MgSO4. The filtratewas cooled to 0 ꢁC and treated with a sat-
urated solution of CH2N2 in Et2O (4 mL). The solution was
concentrated in vacuo and the residue was purified by flash
chromatography.

´
S. Garcıa-Munoz et al. / Tetrahedron 62 (2006) 12182–12190
~
12187
4.4.1. [2-Methoxy-6-(methoxycarbonylmethyl)-4-(3-
pivaloyloxypropyl)phenyl] (3-methoxy-4-pivaloyloxy-
benzyl) ether (10). Starting from 0.52 g (2 mmol) of 7 and
following the general procedure, 10 was obtained as a colour-
(2H, t, J¼7.6 Hz, H10); 1.97 (2H, m, H20); 1.23 (9H, s,
OCOC(CH3)3). 13C NMR (75 MHz, CDCl3): d (ppm)
178.54 (C, ROCO); 172.12 (C, COOCH3); 153.10 (C, C3000,
C5000); 152.46 (C, C2); 144.25 (C, C1); 137.45 (C, C4000);
137.19 (C, C4); 133.52 (C, C1000); 128.22 (C, C6); 122.36
(CH, C5); 111.82 (CH, C3); 104.93 (CH, C2000, C6000); 74.64
(CH2, ArCH2O); 63.51 (CH2, C30); 60.81 (CH3, C2–
OCH3); 56.03 (CH3, OCH3); 55.75 (CH3, OCH3); 51.89
(CH3, COOCH3); 38.74 (C, OCOC(CH3)3); 35.72 (CH2,
C100); 31.92 (CH2, C10); 30.18 (CH2, C20); 27.19 (CH3,
OCOC(CH3)3). IR (film) nmax: 2957, 2839, 1723, 1589,
1460, 1154, 1125, 1006 cmꢀ1. HRFABMS (m/z): calcd
(C28H38O9Na): 541.2408, found: 541.2408 [M+Na]+.
1
less oil (90%). H NMR (300 MHz, CDCl3): d (ppm) 7.12
(1H, br s, H2000); 6.98 (2H, br s, H5000, H6000); 6.71 (1H, d,
J¼1.8 Hz, H3); 6.65 (1H, d, J¼1.8 Hz, H5); 4.99 (2H, s,
ArCH2O); 4.10 (2H, t, J¼6.4 Hz, H30); 3.88 (3H, s, C2–
000
OCH3); 3.84 (3H, s, C3 –OCH3); 3.62 (3H, s, COOCH3);
3.59 (2H, s, H100); 2.66 (2H, t, J¼7.7 Hz, H10); 1.97 (2H,
m, H20); 1.39 (9H, s, ArOCOC(CH3)3); 1.24 (9H, s,
ROCOC(CH3)3). 13C NMR (75 MHz, CDCl3): d (ppm)
178.51 (C, ROCOC(CH3)3); 176.64 (C, ArOCOC(CH3)3);
172.12 (C, COOMe); 152.45 (C, C2); 151.07 (C, C3000);
144.23 (C, C1); 139.72 (C, C4000); 137.14 (C, C4); 136.54
(C, C1000); 128.25 (C, C6); 122.37 (CH, C5); 122.31 (CH,
C5000); 119.10 (CH, C6000); 112.12 (CH, C3); 111.86 (CH,
C2000); 74.10 (CH2, ArCH2O); 63.52 (CH2, C30); 55.87
(CH3, OCH3); 55.74 (CH3, OCH3); 51.86 (CH3, COOCH3);
39.01 (C, ArOCOC(CH3)3); 38.74 (C, ROCOC(CH3)3);
35.74 (CH2, C100); 31.93 (CH2, C10); 30.19 (CH2, C20);
27.18 (CH3, ArOCOC(CH3)3, ROCOC(CH3)3). IR (film)
nmax: 2968, 2935, 2870, 1752, 1725, 1509, 1478, 1462,
1282, 1154, 1118, 1033, 888 cmꢀ1. HRFABMS (m/z): calcd
(C31H42O9Na): 581.2721, found: 581.2724 [M+Na]+.
4.5. General procedure for the diazo transfer to 10, 11
and 12
DBU was added to a solution of the diazo derivatives and p-
ABSA in CH3CN (5 mL, freshly distilled) at 0 ꢁC under an
argon atmosphere. The mixture was allowed to reach room
temperature and stirred for 18–24 h (TLC monitoring). The
reaction crude mixture was diluted with CH2Cl2 (30 mL),
washed with NH4Cl aq saturated solution (3ꢂ10 mL) and
brine (10 mL), dried over anhyd MgSO4, concentrated in
vacuo, and the residue was purified by flash chromatography.
4.4.2. [2-Methoxy-6-(methoxycarbonylmethyl)-4-(3-piv-
aloyloxypropyl)phenyl] (3,4-dipivaloyloxybenzyl) ether
(11). Starting from 1.83 g (3.1 mmol) of 8 and following
the general procedure, 11 was obtained as a colourless oil
4.5.1. [6-(Diazo(methoxycarbonyl)methyl)-2-methoxy-4-
(3-pivaloyloxypropyl)phenyl] (3-methoxy-4-pivaloyloxy-
benzyl) ether (13). Compound 10 (0.555 g, 1 mmol),
p-ABSA (1.486 g, 6 mmol) and DBU (1.2 mL) were reacted
as described previously to yield 13 (0.159 g, 0.27 mmol,
1
(61%). H NMR (300 MHz, CDCl3): d (ppm) 7.30 (1H,
1
dd, J¼8.3 Hz, J¼2.0 Hz, H6000); 7.25 (1H, d, J¼1.9 Hz,
H2000); 7.12 (1H, d, J¼8.3 Hz, H5000); 6.69 (1H, d,
J¼1.9 Hz, H3); 6.65 (1H, d, J¼1.9 Hz, H5); 4.99 (2H, s,
ArCH2O); 4.10 (2H, t, J¼6.4 Hz, H30); 3.85 (3H, s,
OCH3); 3.62 (3H, s, COOCH3); 3.60 (2H, s, H100); 2.65
(2H, t, J¼7.7 Hz, H10); 1.96 (2H, m, H20); 1.36 (9H, s,
ArOCOC(CH3)3); 1.36 (9H, s, ArOCOC(CH3)3); 1.23 (9H,
s, ROCOC(CH3)3). 13C NMR (75 MHz, CDCl3): d (ppm)
178.46 (C, ROCO); 175.82 (C, ArOCO); 175.73 (C,
ArOCO); 172.14 (C, COOMe); 152.41 (C, C2); 144.15 (C,
C1); 142.37 (C, C4000); 141.98 (C, C3000); 137.21 (C, C4);
136.59 (C, C1000); 128.20 (C, C6); 125.42 (CH, C6000);
123.07 (CH, C5000); 122.62 (CH, C2000); 122.34 (CH, C5);
111.84 (CH, C3); 73.27 (CH2, ArCH2O); 63.52 (CH2,
C30); 55.68 (CH3, OCH3); 51.88 (CH3, COOCH3); 39.09
(C, ArOCOC(CH3)3); 39.07 (C, ArOCOC(CH3)3); 38.74
(C, ROCOC(CH3)3); 35.73 (CH2, C100); 31.93 (CH2,
C10); 30.20 (CH2, C20); 27.21 (CH3, ArOCOC(CH3)3,
ROCOC(CH3)3). IR (film) nmax: 2971, 2873, 1758, 1726,
27%). Yellow oil. H NMR (300 MHz, CDCl3): d (ppm)
7.04 (1H, d, J¼1.7 Hz, H200); 7.01 (1H, d, J¼1.9 Hz, H5);
6.96 (1H, d, J¼8.0 Hz, H500); 6.89 (1H, dd, J¼8.0 Hz,
J¼1.8 Hz, H600); 6.69 (1H, d, J¼1.9 Hz, H3); 4.95 (2H, s,
ArCH2O); 4.10 (2H, t, J¼6.5 Hz, H30); 3.89 (3H, s, C2–
00
OCH3); 3.81 (3H, s, C3 –OCH3); 3.79 (3H, s, COOCH3);
2.68 (2H, t, J¼7.7 Hz, H10); 1.98 (2H, m, H20); 1.38 (9H, s,
ArOCOC(CH3)3); 1.23 (9H, s, ROCOC(CH3)3). 13C NMR
(75 MHz, CDCl3): d (ppm) 178.46 (C, ROCO); 176.49 (C,
ArOCO); 166.10 (C, COOCH3); 152.42 (C, C2); 151.06
(C, C300); 142.08 (C, C1); 140.04 (C, C100); 137.71 (C, C4);
135.41 (C, C400); 122.34 (CH, C500); 121.12 (CH, C5);
120.52 (CH, C600); 120.06 (C, C6); 112.38 (CH, C200);
111.71 (CH, C3); 74.92 (CH2, ArCH2O); 74.71 (C, CN2);
63.45 (CH2, C30); 55.86 (CH3, C2–OCH3); 55.76 (CH3,
00
C3 –OCH3); 51.81 (CH3, COOCH3); 38.99 (C, C(CH3)3);
38.72 (C, C(CH3)3); 32.12 (CH2, C10); 30.18 (CH2, C20);
27.17 (CH3, C(CH3)3). IR (film) nmax: 2967, 2934,
2870, 2102, 1751, 1725, 1605, 1499, 1479, 1461,
1282, 1154, 1113, 1034 cmꢀ1. HRFABMS (m/z): calcd
(C31H40N2O9Na): 607.2626, found: 607.2631 [M+Na]+.
1590, 1480, 1278, 1258, 1156, 1026, 1116 cmꢀ1
.
HRFABMS (m/z): calcd (C35H48O10Na): 651.3140, found:
651.3139 [M+Na]+.
4.5.2. [6-(Diazo(methoxycarbonyl)methyl)-2-methoxy-4-
(3-pivaloyloxypropyl)phenyl] (3,4-dipivaloyloxybenzyl)
ether (14). Compound 11 (0.497 g, 0.79 mmol), p-ABSA
(1.1646 g, 4.7 mmol) and DBU (2.4 mL) were reacted as de-
scribed previously to yield 14 (0.162 g, 0.25 mmol, 30%).
Yellow oil. 1H NMR (300 MHz, CDCl3): d (ppm) 7.25
(1H, dd, J¼7.8 Hz, J¼2.1 Hz, H600); 7.23 (1H, br s, H200);
7.12 (1H, d, J¼7.8 Hz, H500); 7.04 (1H, d, J¼1.6 Hz, H5);
6.68 (1H, d, J¼1.7 Hz, H3); 4.96 (2H, s, ArCH2O); 4.10
(2H, t, J¼6.1 Hz, H30); 3.85 (3H, s, OCH3); 3.82 (3H, s,
4.4.3. [2-Methoxy-6-(methoxycarbonylmethyl)-4-(3-piv-
aloyloxypropyl)phenyl] (3,4,5-trimethoxybenzyl) ether
(12). Starting from 0.89 g (1.8 mmol) of 9 and following
the general procedure, 12 was obtained as a colourless oil
1
(74%). H NMR (300 MHz, CDCl3): d (ppm) 6.71 (2H, s,
H2000, H6000); 6.70 (1H, d, J¼2.4 Hz, H3); 6.66 (1H, d,
J¼2.4 Hz, H5); 4.94 (2H, s, ArCH2O); 4.10 (2H, t,
J¼6.4 Hz, H30); 3.89 (9H, s, OCH3); 3.86 (3H, s, C2–
OCH3); 3.64 (3H, s, COOCH3); 3.62 (2H, s, H100); 2.66

´
~
S. Garcıa-Munoz et al. / Tetrahedron 62 (2006) 12182–12190
12188
COOCH3); 2.68 (2H, t, J¼7.7 Hz, H10); 1.98 (2H, m,
H20); 1.36 (18H, s, ArOCOC(CH3)3); 1.23 (9H, s,
ROCOC(CH3)3). 13C NMR (75 MHz, CDCl3): d (ppm)
178.51 (C, ROCO); 175.75 (C, ArOCO); 175.70 (C,
ArOCO); 166.20 (C, COOCH3); 152.39 (C, C2); 142.38
(C, C300)*; 142.21 (C, C400)*; 142.08 (C, C1); 137.80 (C,
C4); 135.57 (C, C100); 125.74 (CH, C600); 123.12 (CH,
C200); 122.93 (CH, C500); 121.01 (CH, C5); 119.83 (C, C6);
111.68 (CH, C3); 73.90 (CH2, ArCH2O); 71.09 (C, CN2);
63.50 (CH2, C30); 55.81 (CH3, OCH3); 51.92 (CH3,
COOCH3); 39.10 (C, ArOCOC(CH3)3); 38.75 (C,
ROCOC(CH3)3); 32.16 (CH2, C10); 30.20 (CH2, C20); 27.20
(CH3, OCOC(CH3)3). * Assignments may be interchanged.
IR (film) nmax: 2971, 2872, 2105, 1758, 1725, 1590,
1480, 1279, 1154, 1116 cmꢀ1. HRFABMS (m/z): calcd
(C35H46N2O10Na): 677.3045, found: 677.3041 [M+Na]+.
16-trans. Colourless oil. 1H NMR (300 MHz, CDCl3):
d (ppm) 7.04 (1H, br s, H500); 7.00 (2H, br s, H200, H600);
6.79 (1H, d, J¼1.0 Hz, H4); 6.69 (1H, d, J¼1.0 Hz, H6);
6.12 (1H, d, J¼8.4 Hz, H2); 4.31 (1H, d, J¼8.3 Hz, H3);
4.10 (2H, t, J¼6.4 Hz, H30); 3.91 (3H, s, C7–OCH3); 3.85
00
(3H, s, COOCH3); 3.81 (3H, s, C3 –OCH3); 2.67 (2H, t,
J¼6.9 Hz, H10); 1.96 (2H, m, H20); 1.37 (9H, s,
OCOC(CH3)3); 1.24 (9H, s, OCOC(CH3)3). 13C NMR
(75 MHz, CDCl3): d (ppm) 178.51 (C, ROCO); 176.61 (C,
ArOCO); 171.09 (C, COOCH3); 151.32 (C, C300); 146.02
(C, C7a); 144.22 (C, C7); 140.15 (C, C400); 138.68 (C,
C100); 135.08 (C, C5); 124.86 (C, C3a); 122.80 (CH,
C200)*; 118.25 (CH, C600)*; 116.54 (CH, C4); 112.96 (CH,
C6); 110.14 (CH, C500); 86.21 (CH, C2); 63.44 (CH2, C30);
56.16 (CH, C3); 56.12 (CH3, C7–OCH3)#; 55.98 (CH3,
#
00
C3 –OCH3) ; 52.69 (CH3, COOCH3); 39.04 (C,
OCOC(CH3)3); 38.76 (C, OCOC(CH3)3); 31.97 (CH2,
4.5.3. 2-[Diazo(methoxycarbonyl)methyl)-6-methoxy-4-
(3-pivaloyloxypropyl)phenyl] (3,4,5-trimethoxybenzyl)
ether (15). Compound 13 (0.443 g, 1 mmol), p-ABSA
(1.337 g, 5.4 mmol) and DBU (1.1 mL) were reacted as de-
scribed previously to yield 15 (0.144 g, 0.26 mmol, 29%).
Yellow oil. 1H NMR (300 MHz, CDCl3): d (ppm) 6.99
(1H, d, J¼1.8 Hz, H5); 6.69 (1H, d, J¼1.9 Hz, H3); 6.60
(2H, s, H200, H600); 4.90 (2H, s, ArCH2O); 4.09 (2H, t,
J¼6.5 Hz, H30); 3.90 (3H, s, C2–OCH3); 3.84 (9H, s,
OCH3); 3.78 (3H, s, COOCH3); 2.67 (2H, t, J¼7.7 Hz,
H10); 1.96 (2H, m, H20); 1.22 (9H, s, ROCOC(CH3)3). 13C
NMR (75 MHz, CDCl3): d (ppm) 178.47 (C, ROCO);
166.08 (C, COOCH3); 153.02 (C, C300, C400); 152.39 (C,
C2); 142.08 (C, C1); 137.70 (C, C4); 132.32 (C, C100);
121.12 (CH, C5); 120.10 (C, C6); 111.65 (CH, C3);
C10); 30.59 (CH2, C20); 27.21 (CH3, OCOC(CH3)3); 27.17
(CH3, OCOC(CH3)3). * and Assignments may be inter-
#
changed. IR (film) nmax: 2966, 2935, 2870, 1750,
1725, 1606, 1499, 1460, 1281, 1201, 1154, 1112, 1032,
731 cmꢀ1
.
HRFABMS (m/z): calcd (C31H40O9Na):
579.2565, found: 579.2560 [M+Na]+.
16-cis. Colourless oil. 1H NMR (300 MHz, CDCl3): d (ppm)
7.03 (1H, br s, H500)*; 6.96 (2H, br s, H200, H600)*; 6.70 (1H,
d, J¼1.6 Hz, H4); 6.68 (1H, d, J¼1.6 Hz, H6); 6.00 (1H, d,
J¼9.7 Hz, H2); 4.52 (1H, d, J¼9.7 Hz, H3); 4.09 (2H, t,
0
00
J¼6.4 Hz, H3 ); 3.93 (3H, s, C7–OCH3); 3.80 (6H, s, C3 –
OCH3); 3.27 (3H, s, COOCH3); 2.67 (2H, t, J¼7.7 Hz,
H10); 1.96 (2H, m, H20); 1.37 (9H, s, OCOC(CH3)3); 1.24
(9H, s, OCOC(CH3)3). * Assignments may be interchanged.
13C NMR (75 MHz, CDCl3): d (ppm) 178.51 (C, ROCO);
176.59 (C, ArOCO); 170.43 (C, COOCH3); 151.00 (C,
C300); 147.10 (C, C7a); 144.31 (C, C7); 140.11 (C, C400);
135.32 (C, C5); 125.80 (C, C3a); 122.23 (CH, C200)*;
118.68 (CH, C600)*; 117.19 (CH, C6); 112.96 (CH, C4);
110.53 (CH, C500); 86.20 (CH, C2); 63.49 (CH2, C30);
105.37 (CH, C200, C600); 75.48 (CH2, ArCH2O); 60.15 (C,
0
00
CN2); 63.41 (CH2, C3 ); 60.77 (CH3, C4 –OCH3); 55.95
00
(CH3, C2–OCH3)*; 55.86 (CH3, C3 –OCH3)*; 51.85 (CH3,
COOCH3); 38.71 (C, OCOC(CH3)3); 32.10 (CH2, C10);
30.19 (CH2, C2’); 27.16 (CH3, OCOC(CH3)3). * Assign-
ments may be interchanged. IR (film) nmax: 2955,
2840, 2099, 1723, 1590, 1492, 1459, 1426, 1279, 1234,
1154, 1126, 1006, 735 cmꢀ1. HRFABMS (m/z): calcd
(C28H36N2O9Na): 567.2313, found: 567.2316 [M+Na]+.
00
56.03 (CH3, C7–OCH3, C3 –OCH3); 54.55 (CH, C3);
51.93 (CH3, COOCH3); 39.02 (C, OCOC(CH3)3); 38.75
(C, OCOC(CH3)3); 31.97 (CH2, C10); 30.54 (CH2, C20);
27.21 (CH3, OCOC(CH3)3); 27.17 (CH3, OCOC(CH3)3).
* Assignments may be interchanged. IR (film) nmax: 2966,
2935, 2870, 1750, 1725, 1605, 1500, 1478, 1461, 1281,
1153, 1111, 1032, 731 cmꢀ1. HRFABMS (m/z): calcd
(C31H40O9Na): 579.2565, found: 579.2561 [M+Na]+.
4.6. General procedure for the C–H insertion
of 13, 14 and 15
˚
A Schlenk flask with 4 A molecular sieves was purged with
argon. A solution of the diazocompound in freshly distilled
(sodium) toluene (2 mL) was introduced and the mixture
cooled to 0 ꢁC. A solution of tetrakis[(S)-(ꢀ)-N-(p-do-
decylphenylsulfonyl)prolinato]dirhodium (0.01 equiv) in
anhydrous toluene (1 mL) was cannulated into the flask.
Nitrogen bubbled immediately and the yellow colour dis-
appeared instantly. The mixture was concentrated in vacuo
and the residue purified by flash chromatography.
4.6.2. 7-Methoxy-3-(methoxycarbonyl)-2-(3,4-dipivaloyl-
oxy)phenyl-5-(3-pivaloyloxypropyl)-2,3-dihydrobenzo-
[b]furan (17). Starting from 14 (0.042 g, 0.06 mmol) and
following the general procedure, 17 was obtained (17 mg,
0.03 mmol, 50%) as a cis:trans mixture (77:23). The enan-
tiomeric excess of 17-cis was determined by chiral HPLC
as 28%.
4.6.1. 7-Methoxy-3-(methoxycarbonyl)-2-(3-methoxy-4-
pivaloyloxy)phenyl-5-(3-pivaloyloxy-propyl)-2,3-di-
hydrobenzo[b]furan (16). Starting from 13 (0.12 g,
0.21 mmol) and following the general procedure, 16 was ob-
tained (0.10 g, 0.19 mmol, 90%) as a cis:trans mixture (3:1),
which could be separated by flash chromatography. Enantio-
meric excesses were determined by chiral HPLC, being 34%
for 16-trans and 29% for 16-cis.
4.6.3. 7-Methoxy-3-(methoxycarbonyl)-5-(3-pivaloyloxy-
propyl)-2-(3,4,5-trimethoxy)phenyl-2,3-dihydrobenzo-
[b]furan (18). Starting from 15 (0.17 g, 0.31 mmol) and
following the general procedure, 18 was obtained (0.16 g,
0.31 mmol, 99.8%) as a cis:trans mixture (1:1), which could
be separated by flash chromatography. Enantiomeric ex-
cesses were determined by chiral HPLC, being 6.0% for
18-trans and 20% for 18-cis.

´
S. Garcıa-Munoz et al. / Tetrahedron 62 (2006) 12182–12190
~
12189
18-trans. Colourless oil. 1H NMR (300 MHz, CDCl3):
d (ppm) 6.79 (1H, d, J¼1.0 Hz, H4); 6.69 (1H, d, J¼
1.0 Hz, H6); 6.66 (2H, s, H200, H600); 6.05 (1H, d,
the general procedure, 1-cis10 was obtained as a colourless
oil (21 g, 0.06 mmol, 100%).
J¼8.6 Hz, H2); 4.33 (1H, d, J¼8.6 Hz, H3); 4.10 (2H, t,
4.7.3. trans-3-(Hydroxymethyl)-5-(3-hydroxypropyl)-7-
methoxy-2-(3,4,5-trimethoxyphenyl)-2,3-dihydrobenzo-
[b]furan (3-trans). Starting from 72 mg (0.14 mmol) of 18-
trans, and following the general procedure, 3-trans was ob-
0
00
J¼6.5 Hz, H3 ); 3.91 (3H, s, C7–OCH3); 3.86 (6H, s, C3 –
00
00
OCH3, C5 –OCH3); 3.85 (3H, s, C4 –OCH3); 3.84 (3H, s,
COOCH3); 2.67 (2H, t, J¼6.8 Hz, H10); 1.96 (2H, m, H20);
1.24 (9H, s, OCOC(CH3)3). 13C NMR (75 MHz, CDCl3):
d (ppm) 178.51 (C, ROCO); 171.14 (C, COOCH3); 153.38
(C, C300, C500); 146.02 (C, C7a); 144.25 (C, C7); 137.94
(C, C400); 135.60 (C, C100); 135.02 (C, C5); 124.89 (C,
C3a); 116.48 (CH, C4); 112.94 (CH, C6); 103.11 (CH,
1
tained as a colourless oil (46 mg, 0.11 mmol, 81%). H
NMR (500 MHz, CDCl3): d (ppm) 6.69 (2H, br s, H4,
H6); 6.66 (2H, s, H200); 5.57 (1H, d, J¼7.4 Hz, H2); 4.00
(1H, dd, J¼10.9 Hz, J¼6.0 Hz, CH2OH); 3.93 (1H, dd,
J¼11.0 Hz, J¼4.7 Hz, CH2OH); 3.90 (3H, s, C7–OCH3);
00
0
00
C2 ); 86.69 (CH, C2); 63.39 (CH2, C3 ); 60.78 (CH3, C4 –
00
00
00
3.85 (6H, s, C3 –OCH3, C5 –OCH3); 3.84 (3H, s, C4 –
OCH3); 3.70 (2H, t, J¼6.3 Hz, H30); 3.63 (1H, m, H3);
2.68 (2H, t, J¼7.7 Hz, H10); 1.90 (2H, m, H20). 13C NMR
(75 MHz, CDCl3): d (ppm) 153.31 (C, C300, C500); 146.46
(C, C7a); 144.18 (C, C7); 137.67 (C, C400); 136.85 (C,
C100); 135.53 (C, C5); 127.50 (C, C3a); 115.90 (CH, C4)*;
112.45 (CH, C6)*; 103.10 (CH, C200, C600); 87.80 (CH,
C2); 63.84 (CH2, CH2OH); 62.24 (CH2, C30); 60.81 (CH3,
00
OCH3); 56.14 (CH3, C3 –OCH3); 56.09 (CH3, C7–
OCH3)*; 56.08 (CH, C3)*; 52.68 (CH3, COOCH3); 38.73
(C, OCOC(CH3)3); 31.93 (CH2, C10); 30.54 (CH2, C20);
27.18 (CH3, OCOC(CH3)3). * Assignments may be inter-
changed. IR (film) nmax: 2955, 2837, 1722, 1587, 1458,
1282, 1153, 1123, 1005 cmꢀ1. HRFABMS (m/z): calcd
(C28H36O9Na): 539.2252, found: 539.2248 [M+Na]+.
00
00
00
C4 –OCH3); 56.13 (CH3, C3 –OCH3, C5 –OCH3); 55.99
(CH3, C7–OCH3); 53.84 (CH, C3); 34.58 (CH2, C20);
31.98 (CH2, C10). * Assignments may be interchanged. IR
(film) nmax: 3379, 2934, 2876, 2837, 1592, 1494, 1458,
1420, 1324, 1123, 909, 729 cmꢀ1. HRFABMS (m/z): calcd
(C22H30O8Na): 445.1833, found: 445.1830 [M+Na]+.
18-cis. Colourless oil. 1H NMR (300 MHz, CDCl3): d (ppm)
6.70 (1H, d, J¼1.3 Hz, H6); 6.68 (1H, d, J¼1.3 Hz, H4);
6.64 (2H, s, H200, H600); 5.94 (1H, d, J¼9.6 Hz, H2); 4.51
(1H, d, J¼9.6 Hz, H3); 4.10 (2H, t, J¼6.5 Hz, H30); 3.93
00
00
(3H, s, C7–OCH3); 3.86 (6H, s, C3 –OCH3, C5 –OCH3);
00
3.84 (3H, s, C4 –OCH3); 3.31 (3H, s, COOCH3); 2.67 (2H,
t, J¼7.7 Hz, H10); 1.96 (2H, m, H20); 1.24 (9H, s,
OCOC(CH3)3). 13C NMR (75 MHz, CDCl3): d (ppm)
178.51 (C, ROCO); 170.48 (C, COOCH3); 152.93 (C, C300,
C500); 147.06 (C, C7a); 144.34 (C, C7); 137.74 (C, C400);
135.30 (C, C5); 132.26 (C, C100); 125.91 (C, C3a); 117.12
4.7.4. cis-3-(Hydroxymethyl)-5-(3-hydroxypropyl)-7-meth-
oxy-2-(3,4,5-trimethoxyphenyl)-2,3-dihydrobenzo[b]-
furan (3-cis). Starting from 24 mg (0.05 mmol) of 18-cis,
and following the general procedure, 3-cis was obtained
as a colourless oil (15 mg, 0.04 mmol, 80%). 1H NMR
(500 MHz, CDCl3): d (ppm) 6.77 (1H, d, J¼1.3 Hz, H4);
6.72 (1H, d, J¼1.3 Hz, H6); 6.71 (2H, s, H200); 5.85 (1H,
d, J¼8.4 Hz, H2); 3.94 (3H, s, C7–OCH3); 3.91 (1H, dd,
J¼8.7 Hz, J¼5.0 Hz, CH2OH); 3.87 (1H, dd, J¼8.7 Hz,
(CH, C4); 112.94 (CH, C6); 103.54 (CH, C200, C600); 86.63
0
00
(CH, C2); 63.46 (CH2, C3 ); 60.82 (CH3, C4 –OCH3);
00
00
56.13 (CH3, C3 –OCH3, C5 –OCH3); 55.98 (CH3, C7–
OCH3); 54.43 (CH, C3); 51.85 (CH3, COOCH3); 38.74 (C,
OCOC(CH3)3); 31.95 (CH2, C10); 30.52 (CH2, C20); 27.19
(CH3, OCOC(CH3)3). IR (film) nmax: 2955, 2837, 1722,
1588, 1459, 1233, 1153, 1124, 1005 cmꢀ1. HRFABMS
(m/z): calcd (C28H36O9Na): 539.2252, found: 539.2250
[M+Na]+.
00
00
J¼6.7 Hz, CH2OH); 3.89 (6H, s, C3 –OCH3, C5 –OCH3);
0
00
3.88 (3H, s, C4 –OCH3); 3.73 (2H, t, J¼6.3 Hz, H3 ); 3.69
(1H, m, H3); 2.71 (2H, t, J¼7.7 Hz, H10); 1.92 (2H, m,
H20). 13C NMR (75 MHz, CDCl3): d (ppm) 153.40 (C, C300,
C500); 145.95 (C, C7a); 144.21 (C, C7); 135.73 (C, C5, C400);
132.23 (C, C100); 129.20 (C, C3a); 116.88 (CH, C4); 112.45
4.7. General procedure for the reduction and deprotec-
tion of 16 and 18 (cis and trans)
(CH, C6); 103.14 (CH, C200, C600); 87.07 (CH, C2); 63.00
0
00
(CH2, CH2OH); 62.27 (CH2, C3 ); 60.90 (CH3, C4 –
00
00
OCH3); 56.16 (CH3, C3 –OCH3, C5 –OCH3); 55.99 (CH3,
C7–OCH3); 49.50 (CH, C3); 34.60 (CH2, C20); 31.99 (CH2,
C10). IR (film) nmax: 3379, 2936, 2835, 2998, 1591, 1494,
1459, 1421, 1123, 1324, 1233, 1208 cmꢀ1. HRFABMS
(m/z): calcd (C22H30O8Na): 445.1833, found: 445.1834
[M+Na]+.
A solution of esters in THF (1.5 mL) was added dropwise to
a cooled suspension (ꢀ20 ꢁC for cis isomers and 0 ꢁC for
trans) of LiAlH4 (20 equiv) in THF (1.5 mL). The mixture
was stirred for 1 h and quenched by dropwise addition of wa-
ter at the same temperature until the bubbling stopped. Then
5% aq HCl (20 mL) was added and the mixture was allowed
to reach room temperature and extracted with CH2Cl2
(3ꢂ20 mL). The combined organic extracts were washed
with brine (40 mL), dried over anhyd MgSO4, concentrated
in vacuo, and the residue purified by flash chromatography.
Acknowledgements
We wish to acknowledge the Spanish Ministerio de Educa-
ꢀ
cion y Ciencia for financial support (Project BQU2002-
03254) and for scholarships to L.J.-G. and S.G.-M.
4.7.1. trans-Dihydrodehydrodiconiferyl alcohol (1-trans).
Starting from 23 mg (0.04 mmol) of 16-trans, and following
the general procedure, 1-trans13 was obtained as a colourless
oil (12 mg, 0.033 mmol, 81%).
References and notes
4.7.2. cis-Dihydrodehydrodiconiferyl alcohol (1-cis).
Starting from 35 mg (0.06 mmol) of 16-cis, and following
1. (a) 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, 1163–

´
~
S. Garcıa-Munoz et al. / Tetrahedron 62 (2006) 12182–12190
12190
1169; (b) Kikuzaki, H.; Kayano, S.; Fukutsuka, N.; Aoki, A.;
15. Benzyl iodide derivatives were prepared from the correspond-
ing aldehydes by reduction with NaBH4/MeOH to obtain the
alcohols, which were treated with iodine, PPh3 and imidazol
in THF.
16. Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58, 3675–
3680.
Kasamatsu, K.; Yamasaki, Y.; Mitani, T.; Nakatani, N. J.
Agric. Food Chem. 2004, 52, 344–349; (c) Carini, M.; Aldini,
G.; Orioli, M.; Facino, R. M. Planta Med. 2002, 68, 193–197.
2. Apers, S.; Vlietinck, A.; Pieters, L. Phytochem. Rev. 2003, 2,
201–217.
3. Shin, J. S.; Kim, Y. M.; Hong, S. S.; Kang, H. S.; Yang, Y. J.;
Lee, D. K.; Hwang, B. Y.; Ro, J. S.; Lee, M. K. Arch. Pharm.
Res. 2005, 28, 1337–1340.
17. Small amounts of by-products were formed in all the cases,
mainly aldehydes. These aldehydes were treated with
NaClO2, Na2HPO4 and 2-methyl-2-butene as chlorine trap, fol-
lowed by methylation with diazomethane to afford the corre-
ꢀ
4. Pauletti, P. M.; Araujo, A. R.; Young, M. C. M.; Giesbrecht,
€
A. M.; Bolzani, V. S. Phytochemistry 2000, 55, 597–601.
5. Liu, P.; Hu, Y.-Y.; Liu, C.; Zhu, D.-Y.; Xue, H.-M.; Xu, Z.-Q.;
Xu, L.-M.; Liu, C.-H.; Gu, H.-T.; Zhang, Z.-Q. World J.
Gastroenterol. 2002, 8, 679–685.
sponding esters. Gorgen, G.; Boland, W.; Preiss, U.; Simon,
H. Helv. Chim. Acta 1989, 72, 917–928.
18. (a) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459–2469; (b)
Ye, T.; Garcia, F. C.; McKervey, M. A. J. Chem. Soc., Perkin
Trans. 1 1995, 1373–1379.
19. Davies, H. M. L.; Grazini, M. V. A.; Aouad, E. Org. Lett. 2001,
3, 1475–1477.
20. The small available amount of 17 did not allow to separate both
diastereomers by flash chromatography. However, the ee of the
major diastereomer, 17-cis, could be measured by chiral
HPLC.
6. (a) Scammells, P. J.; Baker, S. P.; Beauglehole, A. R. Bioorg.
€
Med. Chem. 1998, 6, 1517–1524; (b) Lutjens, H.; Scammells,
P. J. Tetrahedron Lett. 1998, 39, 6581–6584.
7. Li, S.; Iliefski, T.; Lundquist, K.; Wallis, A. F. A.
Phytochemistry 1997, 46, 929–934.
8. Sefkow, M. Synthesis 2003, 2595–2625.
9. Zheng, S. L.; Yu, W. Y.; Xu, W. X.; Che, C. M. Tetrahedron
Lett. 2003, 44, 1445–1447.
ꢀ
´
ꢀ
ꢀ
21. (a) Kurtan, T.; Batıs-Gacs, E.; Majer, Z.; Antus, S. J. Chem.
ꢀ
´
10. Garcıa-Munoz, S.; Jimenez-Gonzalez, L.; Alvarez-Corral, M.;
Munoz-Dorado, M.; Rodrıguez-Garcıa. Synlett 2005, 3011–
~
ꢀ
ꢀ
ꢀ
Soc., Perkin Trans. 1 2000, 453–461; (b) Antus, S.; Kurtan,
~
´
´
ꢀ
ꢀ
T.; Juhasz, L.; Kiss, L.; Hollosi, M.; Majer, Z. S. Chirality
ꢀ
3013.
2001, 13, 493–506.
ꢀ
´
ꢀ ꢀ ~
22. Jimenez-Gonzalez, L.; Garcıa-Munoz, S.; Alvarez-Corral, M.;
11. Sakurai, A.;Hosomi, H. TetrahedronLett. 1976, 16, 1295–1298.
12. (a) Doyle, M. P. Acc. Chem. Res. 1986, 19, 348–356; (b) Ye, T.;
McKervey, M. A. Chem. Rev. 1994, 94, 1091–1160; (c) Davies,
H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861–2903;
(d) Saito, H.; Oishi, H.; Kitagaki, S.; Nakamura, S.; Anada, M.;
Hashimoto, S. Org. Lett. 2002, 4, 3887–3890.
13. Lo, W.-L.; Wu, Y.-C.; Hsieh, T.-J.; Kuo, S.-H.; Lin, H.-C. Chin.
Pharm. J. 2004, 56, 69–75.
~
´
Munoz-Dorado, M.; Rodrıguez-Garcıa, I. Chem.—Eur. J.
2006, doi:10.1002/chem200601017.
´
23. Smith, H. E. Circular Dichroism of the Benzene Chromophore.
In Circular Dichroism. Principles and Applications;
Nakanishi, K., Berova, N., Woody, R. W., Eds.; VCH: New
York, NY, 1994; p 413.
24. Casey, M.; Leonard, J.; Lygo, B.; Procter, G. Advanced
Practical Organic Chemistry; Chapman and Hall: New York,
NY, 1990.
14. Yang, S.; Fang, J.; Cheng, Y. J. Chin. Chem. Soc. 1999, 46,
811–818.