A pattern recognition approach to 14-epi-hydrophenanthrene core of the morphine alkaloids based on shikimic acid

Article abstract of DOI:10.1016/j.tet.2011.03.063

An expeditious and stereoselective construction of C-14-epimer of the tetracyclic hydrophenanthrene framework of the morphine alkaloids is described. The core structure is obtained in nine steps in 11% overall yield from shikimic acid via three key transf

Full text of DOI:10.1016/j.tet.2011.03.063

Tetrahedron 67 (2011) 3363e3368
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A pattern recognition approach to 14-epi-hydrophenanthrene core of the
morphine alkaloids based on shikimic acid
,
a,b,
Tung N. Dinh a, Anqi Chen a , Christina L.L. Chai
*
*
a Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), n8 Biomedical Grove, Neuros #07-01, Singapore 138665
b Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543
a r t i c l e i n f o
a b s t r a c t
Article history:
An expeditious and stereoselective construction of C-14-epimer of the tetracyclic hydrophenanthrene
framework of the morphine alkaloids is described. The core structure is obtained in nine steps in 11%
overall yield from shikimic acid via three key transformations: (i) coupling of shikimic acid with 2-
iodoisovanillin at C-3 by double SN2 inversion to form the aryl ether 5; (ii) an intramolecular Heck
reaction to construct the dihydrobenzofuran ring and (iii) a McMurry coupling to furnish the hydro-
phenanthrene core.
Received 15 January 2011
Received in revised form 1 March 2011
Accepted 21 March 2011
Available online 26 March 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Pattern recognition
Hydrophenanthrene
Shikimic acid
Intramolecular Heck coupling
Intramolecular McMurry coupling
1. Introduction
Pattern recognition is a concept coined by Danishefsky for
synthesis planning, especially in natural product synthesis.1 This
concept, which complements that of retrosynthetic analysis pio-
neered by Corey,2 emphasizes the importance in the recognition of
the connection between a synthetic target and the substructure(s)
that is/are easily accessible.
Morphine alkaloids, represented by morphine (1a) and codeine
(1b) (Fig. 1), have long been used as potent analgesics. From
a synthetic point of view, these complex natural products, which
contain a heavily functionalized pentacyclic skeleton, have stimu-
lated extensive synthetic efforts with a plethora of synthetic studies
and total syntheses being reported.3 Among them, construction of
the hydrophenanthrene framework followed by mounting the
ethanamine bridge onto this core structure between C-9 and C-13
(morphine numbering) has proven to be a successful strategy.3f,aaeff
(ꢀ)-Shikimic acid (2), a natural product isolated from star anise
fruits, has been used as a versatile chiral building block for the
synthesis of many targets including therapeutic drugs4aed such as
oseltamivir (Tamiflu).4b During our recent work on the synthesis of
Tamiflu,5 we recognized that shikimic acid resembles the lower half
of the morphine alkaloid skeleton and could therefore be used as
Fig. 1. Structures of shikimic acid, morphine and codeine with the portion in red to be
derived from 2.
a building block for the synthesis of these alkaloids. On the one
hand, the stereogenic centre at C-3 (shikimic acid numbering) is not
only to be incorporated into C-5 (morphine numbering) of the
morphine system but could also serve to control the installation of
the rest of the stereogenic centres in the molecule. The hydroxyl
groups at C-4 and C-5 of shikimic acid would provide the latent
allylic alcohol motif of the alkaloids via a three-step sequence, i.e.,
epoxide formation6 followed by phenylselenide opening-selen-
oxide elimination.3jj On the other hand, the
a,b-unsaturated moiety
of 2 should enable the installation of the top half of the alkaloids via
an intramolecular Heck coupling reaction with 2-iodoisovanillin
(3). These insights promoted us to embark on the development of
a synthetic strategy that would allow us to expeditiously build the
hydrophenanthrene framework 7 of the alkaloids as well as gain
* Corresponding authors. E-mail addresses: chen_anqi@ices.a-star.edu.sg
(A. Chen), christina_chai@ices.a-star.edu.sg (C.L.L. Chai).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.063

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T.N. Dinh et al. / Tetrahedron 67 (2011) 3363e3368
access to a series of simplified morphine analogues for biological
evaluation as potential analgesics.
which was reacted with lithium bromide to provide a separable
mixture of bromide 9 and its C-3 epimer in a ratio of 17:1 in 85%
combined yield.
Reaction of 9 with 3 in the presence of potassium carbonate in
DMF at room temperature for 18 h, led to an inseparable mixture of
aryl ether 5 and its C-3 epimer in a ratio of 8.5:1 in 73% yield. The
formation of the epimeric product was rationalized by the epime-
rization of bromide 9 caused by reversible bromide anion dis-
placement. Based on this rationale, we envisaged that an additive
that could capture the bromide anion formed in the reaction would
inhibit the formation of the undesired epimer. Indeed, when the
reaction was carried out at room temperature in the presence of
silver(I) oxide (1 equiv), the formation of the epimer was com-
pletely suppressed and the desired aryl ether 5 was obtained as the
sole product. The reaction time was significantly shortened to 5 h
by heating the reaction at 60 ꢁC, providing 5 in 84% yield.
With the aryl ether (5) in hand, we next examined the intra-
molecular Heck reaction (Table 1).
2. Results and discussion
Our strategy (Fig. 2) was to first couple the protected shikimic
acid (4) at C-3 with 2-iodoisovanillin (3) to form the aryl ether 5 via
a double SN2 inversion sequence. The aryl ether 5 would then be
cyclized by an intramolecular Heck reaction to provide the dihy-
drobenzofuran 6 with desired stereochemistry at C-13 as governed
by the known C-5 (morphine numbering) configuration inherited
from shikimic acid. The fourth ring of the hydrophenanthrene core
would be formed either by a ring closing olefin metathesis (RCM)
reaction or a McMurry coupling whilst the configuration of C-14
would depend on the stereochemical outcome of the saturation of
the double bond in 6, leading to either the morphine core structure
7a (R¼
b
-H) or its C-14-epimer 7b (R¼
a-H).
Table 1
Heck reaction of aryl ether 5
Entry
Catalyst systema,b
Yieldc (%)
5
6
6a
6b
1
2
3
4
5
6
7
Pd2(dba)3, P(o-Tol)3
Pd2(dba)3
0
50
37
27
63
24
3
0
6
<1
0
26
2
5
22
60
56
0
57
67
0
0
0
Pd(OAc)2, Bu4NI
Pd(OAc)2, PPh3
Pd(OAc)2, dppe
Pd(OAc)2, PCy3
Pd(PPh3)4
39
43
0
100 (71d)
0
Fig. 2. Forward synthetic analysis of 7.
a
Reactions were carried out with 0.1 M of 5 in toluene in a sealed tube at 90 ꢁC for
18 h with a catalyst (20 mol %) and a ligand (20 mol %) as indicated.
In order to couple at the C-3 position of shikimic acid with 2-
iodoisovanillin (3),7 it is necessary to protect C-4 and C-5 hydroxyl
groups as well as the carboxylic acid. This was achieved selectively in
an efficient one-pot protocol8 by heating 2 with 2,2,3,3-tetrame-
thoxybutane (TMB) formed in situ from 2,3-butanedione and tri-
methyl orthoformate in methanol in the presenceof CSA (Scheme 1).9
Our initial plan was to couple 3 and 4 using a double Mitsunobu re-
action sequence, i.e., by first inversion of the allylic alcohol of 4 with
benzoic acid follow by a second inversion with 3. Although the first
inversion proceeded well to provide the desired epimeric alcohol 8
after methanolysis (77% yield over two steps), the second inversion
with 3 was unsuccessful under a range of reaction conditions
attempted, returning only the starting materials.
b
Triethylamine (2 equiv) was used as the base except for entry 7 where K2CO3
(2 equiv) was used.
c
Yields were based on 1H NMR spectroscopic analysis of the crude.
Isolated yield.
d
10
Initial reaction using Pd2(dba)3 resulted in the formation of
a mixture of the desired dihydrobenzofuran 6, its isomeric product
6a and diene 6b (entry 1), which apparently resulted from the
elimination of the aryloxy moiety as has been reported pre-
viously.3jj In view of the poor yields of the desired product and
complex product profile, a number of catalyst systems and condi-
tions were screened. While Pd(OAc)2 in combination with different
phosphine ligands (entries 4e6) did not improve the formation of
the elimination product 6b, ‘ligandless’11a (entry 2) and Jeffery-
type11b (entry 3) conditions gave rather poor conversion although
the amount of 6b formed in the reaction was decreased. Gratify-
ingly it was found that reaction carried out using Pd(PPh3)4 as the
catalyst, potassium carbonate as the base in toluene at 80 ꢁC,11c
afforded cleanly the desired product 6 in 71% isolated yield with-
out formation of 6b (entry 7). The stereochemistry of 6 was con-
firmed by single crystal X-ray diffraction analysis,12 revealing a syn
relationship between C-13 and C-5 as anticipated (Fig. 3).
Scheme 1. Synthesis of aryl ether 5. Reagents and conditions: (a) (MeCO)2, HC(OMe)3,
CSA (cat.), MeOH, reflux, 2 days, 70%; (b) (i)-DEAD, Ph3P, benzoic acid, (ii) K2CO3,
MeOH, 77% over two steps; (c) (i) MsCl, Et3N, DCM, 0 ꢁC, 1 h; (ii) LiBr, THF, rt, overnight,
80.5% for 9 over two steps; (d) 3, K2CO3, Ag2O, DMF, 60 ꢁC, 5 h, 84%.
This also confirmed that the two methoxy groups of the ketal
protecting group adopt the anti orientation due to the stabilizing
effects of the anomeric interactions within the ketal motif.13
With the Heck product 6 in hand, we set out to reduce the
Given the difficulties encountered in the second Mitsunobu
reaction, an alternative double SN2 inversion sequence, i.e., for-
mation of the more reactive bromide 9 followed by substitution
with 3 was investigated. Thus, 4 was converted to its mesylate,
double bond of the
a,b-unsaturated ester. When 6 was hydroge-
nated under an atmosphere of hydrogen (1 atm) with 10% Pd/C as

T.N. Dinh et al. / Tetrahedron 67 (2011) 3363e3368
3365
To this end, the McMurry coupling18 approach was explored
taking advantage of the dialdehyde 14 that had been obtained for
the synthesis of the diene 15. Gratifyingly, treatment of 14 with
a low-valent titanium species generated in situ from titanium(IV)
chloride and zinc dust as a reducing agent yielded the hydro-
phenanthrene 7b in 53% yield.
3. Conclusions
In summary, we have successfully developed a nine-step, ster-
eoselective route to the 14-epi-hydrophenanthrene framework 7 of
the morphine alkaloids in 11% overall yield using shikimic acid from
the chiral pool as the key building block. The key features of this
exploratory route include: coupling of shikimic acid (2) with 2-
iodoisovanillin (3) to form the aryl ether 5 via a double SN2 in-
version, an intramolecular Heck reaction to form the dihy-
drobenzofuran ring and a McMurry coupling to build the fourth
ring of the hydrophenanthrene. This development should enable
access to a series of simplified morphine analogues that could have
potential analgesic application.
Fig. 3. CHIMERAÒ representation of the X-ray structure of 6.
the catalyst, the over-reduced product 10 was obtained instead of
the desired aldehyde 12 (Scheme 2). This unexpected product is
likely to have formed by the hydrogenation of the aldehyde group
to the corresponding benzyl alcohol 11, which underwent further
hydrogenolysis.
4. Experimental section
4.1. General methods
Melting points were recorded on a capillary melting point ap-
paratus and were uncorrected. Infrared spectra were recorded as
KBr discs or evaporated films the data are reported as wavenumber
(cmꢀ1). Nuclear magnetic resonance spectra were recorded at
400 MHz for proton and 100 MHz for carbon spectroscopy using
Scheme 2. Completion of the synthesis of 7b. Reagents and conditions: (a) 10% Pd/C,
H2 (1 atm), quant. for (10); (b) 10% Pd/C, NH3 (7 M solution in MeOH, 6 equiv), H2
(1 atm), quant. for (11); (c) DIBAL (4 equiv), THF, 0 ꢁC to rt, quant.; (d) DesseMartin
periodinane, t-BuOH, DCM, rt, 2 h, 63%; (e) Ph3PþCH3,Brꢀ (3 equiv), LiHMDS (3 equiv),
THF, 0 ꢁC to rt, 42%; (f) Zn, TiCl4, Py, THF, ꢀ10 ꢁC then reflux overnight, 53%.
CDCl3 as the solvent unless otherwise stated. The chemical shifts (d)
are reported as the shift in parts per million from tetramethylsilane
(TMS, 0.00 ppm). High-resolution mass spectra (HRMS) were
obtained using electrospray time-of-flight ionization techniques.
Microanalyses were performed on a CHNS analyser. Analytical thin
layer chromatography (TLC) was conducted on aluminium sheets
with silica gel 60 F254. The chromatograms were analyzed under
a 254 nm UV lamp and developed using a potassium permanganate
‘dipping’ solution [KMnO4/potassium carbonate/5% aqueous so-
dium hydroxide/water (3 g:20 g:5 mL:300 mL)] followed by heat-
ing. Flash column chromatography was conducted by using Merck
It is reported that hydrogenolysis of benzylic ethers can be
inhibited by additives such as ammonia, pyridine or ammonium
acetate.14 Screening these additives found that addition of ammo-
nia (6 equiv) gave the best result with the compound 11 being
obtained in quantitative yield as a single stereoisomer. The con-
figuration of the newly formed stereogenic centre in 11 was
assigned by NOE experiments, which revealed that the hydrogen at
C-14 is anti to that at C-13 (Fig. 4), which is epimeric in relation to
that in morphine alkaloids.
silica gel 60 (40e63 mm) and analytical reagent (AR) grade solvents
indicated. All solvents used were of AR grade, purified by literature
procedures and where appropriate, stored over freshly activated
molecular sieves. All reactions were carried out under an atmo-
sphere of dry, oxygen-free argon unless otherwise specified. Re-
actions that involved moisture sensitive compounds were carried
out using oven-dried apparatus and with anhydrous solvents.
4.2. (2S,3S,4aR,8R,8aS)-Methyl 2,3-dimethoxy-2,3-dimethyl-8-
(methylsulfonyloxy)-2,3,4a,5,8,8a-hexahydrobenzo[b][1,4]
dioxine-6-carboxylate (mesylate of 4)
Fig. 4. Energy minimized conformation15 and NOE’s of 11.
Mesyl chloride (7.12 mL, 91.0 mmol) was added dropwise to
a solution of alcohol 48 (21.36 g, 70.6 mmol) and triethylamine
(12.9 mL, 92.5 mmol) in CH2Cl2 (100 mL) at 0 ꢁC. The ice bath was
then removed and the mixture was stirred at room temperature for
2 h. Saturated NH4Cl (100 mL) was added. The organic layer was
separated and washed with brine (100 mL), dried over MgSO4 then
evaporated to dryness under reduced pressure to give the crude
mesylate (26.9 g, 100%) as a brown solid pure enough (as judged by
1H NMR). A sample was purified by column chromatography by
gradient elution with ethyl acetate in hexanes (0e20%) to afford the
pure title compound as a white solid. Rf¼0.34 (30% EtOAc/hexane);
The formation of the fourth ring was explored on 11 with RCM as
the first option. In this regard, it was necessary to convert both the
hydroxyl and the ester groups of 11 into terminal alkenes required
for the RCM reaction. Using an excess of DIBAL,11 was reduced tothe
diol 13, which was further oxidized to the dialdehyde 14 (63% yield)
with DesseMartin reagent in the presence of t-BuOH to accelerate
the reaction.16 The dialdehyde was then treated with an excess of
Wittig reagent generated from methyltriphenylphosphonium
bromide, providing the diene 15 in an unoptimized 42% yield.
Unfortunately, despite screening several commercially available
ruthenium-based RCM catalysts under various conditions,17 15
failed to cyclize and only the starting material was recovered.
mp: 127e128 ꢁC; ½a D21
ꢂ
ꢀ30 (c 1.0, CHCl3); IR (neat) 1707, 1345, 1260,
1173, 1137, 1115, 1043, 918, 890, 872 cmꢀ1
;
1H NMR (400 MHz,

3366
T.N. Dinh et al. / Tetrahedron 67 (2011) 3363e3368
CDCl3)
d
6.82 (dd, J¼5.7, 2.5 Hz, 1H), 5.30e5.24 (m, 1H), 4.09 (td,
(dd, J¼5.4, 2.1 Hz, 1H), 5.36e5.33 (m, 1H), 4.78 (td, J¼10.0, 6.3 Hz,
1H), 3.95 (s, 3H), 3.77e3.74 (m,1H), 3.72 (s, 3H), 3.32 (s, 3H), 3.25 (s,
3H), 3.00 (dd, J¼18.3, 6.3 Hz,1H), 2.36 (ddd, J¼18.3,10.0, 2.1 Hz,1H),
J¼10.5, 6.0 Hz, 1H), 3.78e3.74 (m, 1H), 3.76 (s, 3H), 3.28 (s, 3H), 3.25
(s, 3H), 3.15 (s, 3H), 2.88 (ddd, J¼18.1, 6.0, 0.8 Hz, 1H), 2.29 (dddd,
J¼18.1, 10.5, 2.5, 0.8 Hz, 1H), 1.30 (s, 3H), 1.29 (s, 3H); 13C NMR
1.32 (s, 3H), 1.30 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 196.0, 166.6,
(100 MHz, CDCl3)
d
166.0, 134.8, 130.9, 100.2, 99.3, 75.3, 69.3, 62.6,
156.8, 146.7, 133.4, 133.4, 129.5, 126.4, 112.0, 100.2, 100.2, 99.3, 73.7,
70.6, 63.1, 56.4, 52.4, 48.1, 48.0, 30.8, 18.1, 18.0; HRMS (ESI-TOF):
585.0588 ([MþNa]þ); C22H27INaO9 calcd 585.0597.
52.5, 48.4, 48.3, 39.2, 30.4, 17.9, 17.7; HRMS (ESI-TOF): 403.1033
([MþNa]þ); C15H24NaO9S calcd 403.1038.
4.3. (2S,3S,4aR,8S,8aS)-Methyl 8-bromo-2,3-dimethoxy-2,3-
dimethyl-2,3,4a,5,8,8a-hexahydrobenzo[b][1,4]dioxine-6-
carboxylate (9)
4.6. (2S,3S,4aR,6aR,11aR,11bR)-Methyl 7-formyl-2,3,10-trime-
thoxy-2,3-dimethyl-2,3,4a,6a,11a,11b-hexahydrobenzo[b][1,4]
dioxino[2,3-g]benzofuran-6-carboxylate (6)
LiBr (153 mg, 1.76 mmol) was added portionwise to a solution of
the above mesylate (191 mg, 0.50 mmol) in THF (4 mL) at room
temperature. The mixture was stirred vigorously overnight before
a mixture of dichloromethane (10 mL) and water (10 mL) was
added. The organic phase was extracted with dichloromethane
(3ꢃ10 mL). The combined organic layer was then washed with
brine, dried over MgSO4, concentrated to dryness to give yellow oil.
Purification by column chromatography (gradient elution with
hexane/ethyl acetate (0e10%)) afforded bromide 9 (147 mg, 80.5%),
then its 3-epimer (8.3 mg, 4.5%). Data for 9: Rf¼0.51 (20% EtOAc/
In a sealed tube containing 5 (2.6 g, 4.63 mmol), Pd(PPh3)4
(1.08 g, 0.93 mmol) and K2CO3 (1.29 g, 9.31 mmol) in toluene
(28 mL) was heated at 90 ꢁC for 2 days under argon atmosphere.
The reaction mixture was filtered through a pad of Celite. The fil-
trate was concentrated and the crude product was purified by
column chromatography on silica gel (hexane/ethyl acetate 4:1) to
yield 6 (1.43 g, 71%) as a brown solid. A further recrystallization
(hexane/ethyl acetate) afforded white crystals from which a suit-
able single crystal was selected for X-ray analysis. Rf¼0.57 (50%
a 23
ꢁ
EtOAc/hexane); mp: 222e223 C; ½ ꢂD ꢀ12 (c 0.9, CHCl3); IR (neat)
1714, 1683, 1603, 1284, 1254, 1142, 1103, 1026, 942 cmꢀ1 1H NMR
(400 MHz, CDCl3)
hexane); mp: 91e92 ꢁC; ½a D23
ꢂ
þ214 (c 1.3, CHCl3); IR (neat) 1714,
;
1273, 1185, 1081, 1034 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
6.85 (t,
d
10.15 (s, 1H), 7.45 (d, J¼8.5 Hz, 1H), 6.86 (d,
J¼2.7 Hz,1H), 4.66 (dddd, J¼8.6, 4.1, 2.7,1.5 Hz,1H), 3.93 (dd, J¼10.5,
8.6 Hz, 1H), 3.76 (s, 3H), 3.78e3.72 (m, 1H), 3.34 (s, 3H), 3.26 (s, 3H),
2.78 (ddd, J¼17.5, 5.5,1.5 Hz,1H), 2.38 (dddd, J¼17.5,10.5, 4.1, 2.7 Hz,
J¼8.5 Hz, 1H), 6.79e6.77 (m, 1H), 5.10 (dd, J¼6.6, 2.4 Hz, 1H), 4.95
(ddd, J¼6.6, 2.1, 1.1 Hz, 1H), 4.79 (dt, J¼9.5, 1.8 Hz, 1H), 3.98 (dd,
J¼9.5, 2.4 Hz, 1H), 3.91 (s, 3H), 3.69 (s, 3H), 3.28 (s, 3H), 3.27 (s, 3H),
1H), 1.35 (s, 3H), 1.30 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
166.0,
1.40 (s, 3H), 1.34 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 190.2, 166.5,
137.2, 129.5, 100.0, 99.6, 75.3, 66.6, 52.4, 48.3, 48.3, 47.1, 29.4, 17.8,
17.7; HRMS (ESI-TOF): 387.0414 ([MþNa]þ); C14H2179BrNaO6 calcd
387.0419 and 389.0408 ([MþNa]þ); C14H2181BrNaO6 calcd 389.0399.
Anal. Calcd for C14H21BrO6: C, 46.04%; H, 5.80%. Found C, 46.17%; H,
5.85%.
149.5, 148.6, 139.2, 130.2, 130.0, 126.3, 123.4, 112.0, 100.6, 100.2,
81.9, 69.4, 63.3, 56.0, 52.3, 48.1, 48.2, 42.9, 17.8, 17.7; HRMS (ESI-
TOF): 435.1657 ([MþH]þ); C22H27O9 calcd 435.1655 and 457.1474
([MþNa]þ); C22H26NaO9 calcd 457.1475.
4.7. (2S,3S,4aR,6S,6aS,11aR,11bS)-Methyl 7-(hydroxymethyl)-2,3,
10-trimethoxy-2,3-dimethyl-2,3,4a,5,6,6a,11a,11b-octahydrobe-
nzo[b][1,4]dioxino[2,3-g]benzofuran-6-carboxylate (11)
4.4. (2S,3S,4aR,8R,8aS)-Methyl 8-bromo-2,3-dimethoxy-2,3-
dimethyl-2,3,4a,5,8,8a-hexahydrobenzo[b][1,4]dioxine-6-
carboxylate (3-epi 9)
To a solution of 6 (100.7 mg, 0.23 mmol) in EtOH (5 mL) was
added 5% Pd/C (50 mg, 10 mol %) and NH3 (7 M solution in MeOH)
(200 mL, 1.4 mmol). The reaction mixture was stirred at room
Data for 3-epi 9: Rf¼0.32 (20% EtOAc/hexane); mp: 137e138 ꢁC;
½
a 2D1
ꢂ
ꢀ92 (c 1.6, CHCl3); IR (neat) 1716, 1441, 1251, 1136, 1117,
1039 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
6.96 (dd, J¼5.5, 2.7 Hz, 1H),
temperature under H2 (1 atm) for 1 h then filtered through a pad of
Celite. The filtrate was concentrated to give 11 as a white solid
(101.6 mg, 100%). Rf¼0.37 (60% EtOAc/hexane); mp: 213e214 ꢁC;
4.76e4.74 (m,1H), 4.19 (td, J¼10.5, 6.3 Hz,1H), 3.76 (s, 3H), 3.62 (dd,
J¼10.5, 4.4 Hz, 1H), 3.28 (s, 3H), 3.27 (s, 3H), 2.93 (dd, J¼18.1, 6.3 Hz,
1H), 2.46 (dddd, J¼18.1,10.5, 2.7,1.3 Hz,1H),1.36 (s, 3H),1.31 (s, 3H);
½
a 2D9
ꢂ
þ100.9 (c 1.0, CHCl3); IR (neat) 3000, 1709, 1509, 1274, 1131,
13C NMR (100 MHz, CDCl3)
d
166.3, 135.4, 129.7, 100.2, 99.3, 68.2,
1098, 1034, 940 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 6.86
63.7, 52.4, 48.3, 48.2, 46.6, 30.4, 18.0, 17.8; HRMS (ESI-TOF):
387.0426([MþNa]þ); C14H2179BrNaO6 calcd 387.0419 and 389.0408
([MþNa]þ); C14H2181BrNaO6 calcd 389.0399.
(d, J¼8.4 Hz, 1H), 6.77 (d, J¼8.4 Hz, 1H), 4.68 (dd, J¼5.2, 3.7 Hz, 1H),
4.48 (d, J¼12.5 Hz, 1H), 4.34 (d, J¼12.5 Hz, 1H), 4.10e4.03 (m, 1H),
3.91 (dd, J¼10.3, 3.7 Hz, 1H), 3.84 (s, 3H), 3.70 (s, 3H), 3.68 (dd,
J¼10.3, 5.2 Hz, 1H), 3.27 (s, 3H), 3.25 (s, 3H), 2.53e2.46 (m, 1H), 2.04
(dt, J¼7.9, 4.2 Hz, 1H), 1.96 (br s, 1H), 1.72 (q, J¼12.8 Hz, 1H), 1.37
4.5. (2S,3S,4aR,8R,8aS)-Methyl 8-(3-formyl-2-iodo-6-methoxy-
phenoxy)-2,3-dimethoxy-2,3-dimethyl-2,3,4a,5,8,8a-hexahyd-
robenzo[b][1,4]dioxine-6-carboxylate (5)
(s, 3H), 1.30 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 175.3, 147.3, 145.0,
130.8, 129.2, 122.2, 112.3, 100.6, 99.9, 84.9, 70.7, 64.5, 62.6, 55.8,
52.6, 48.1, 48.0, 46.1, 43.3, 32.3, 18.1, 17.8; HRMS (ESI-TOF): 461.1776
([MþNa]þ); C22H30NaO9 calcd 461.1787.
In a sealed tube, a suspension of 9 (2.01 g, 5.5 mmol), 2-iodoi-
sovanillin (3)7 (1.53 g, 5.5 mmol), silver(I) oxide (1.27 g, 5.5 mmol)
and K2CO3 (1.56 g, 11.3 mmol) in DMF (50 mL) was heated at 60 ꢁC
for 5 h. The crude reaction mixture was then filtered through a pad
of Celite. Water (20 mL) was added to the filtrate, which was
extracted with ethyl acetate (5ꢃ50 mL). The combined organic
phases were washed with brine (200 mL), dried over MgSO4 and
concentrated to give a yellow oil. Purification by column chroma-
tography on silica gel (hexane/ethyl acetate 4:1) afforded 5 (2.6 g,
84%) as a light yellow foam. Rf¼0.66 (50% EtOAc/hexane); mp:
4.8. ((2S,3S,4aR,6S,6aS,11aR,11bS)-2,3,10-Trimethoxy-2,3-dime-
thyl-2,3,4a,5,6,6a,11a,11b-octahydrobenzo[b][1,4]dioxino[2,3-
g]benzofuran-6,7-diyl)dimethanol (13)
To a stirred solution of 11 (350 mg, 0.8 mmol) in THF (20 mL)
was added diisobutylaluminium hydride (5.6 mL of 1.0 M solution
in toluene, 5.6 mmol) dropwise at 0 ꢁC. The reaction mixture was
stirred at room temperature overnight and then cooled down to
0 ꢁC, quenched by saturated NH4Cl (20 mL) and extracted with
ether (3ꢃ10 mL). The combined organic layers was washed with
brine (20 mL) and dried over MgSO4. The solvent was evaporated
77e78 ꢁC; ½a 2D6
ꢂ
ꢀ76 (c 1.0, CHCl3); IR (neat): 1720, 1683, 1575, 1475,
10.04
1274, 1131, 1037, 927, 856 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
(d, J¼0.6 Hz, 1H), 7.65 (d, J¼8.6 Hz, 1H), 6.95 (d, J¼8.6 Hz, 1H), 6.79

T.N. Dinh et al. / Tetrahedron 67 (2011) 3363e3368
3367
under reduced pressure to give 13 (328 mg, 100%) as a white solid.
46.9, 44.4, 34.2, 18.2, 17.9; HRMS (ESI-TOF): 425.1950 ([MþNa]þ);
Rf¼0.11 (70% EtOAc/hexane); mp: 240e241 ꢁC; ½a D21
ꢂ
þ52 (c 1.0,
C23H30NaO6 calcd 425.1940.
CHCl3); IR (neat) 3100, 1508, 1281, 1117, 1081, 1031 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d
6.79 (d, J¼8.4 Hz, 1H), 6.74 (d, J¼8.4 Hz, 1H),
4.11. (5aR,1S,6aR,8S,9S,10aS,10bR)-1,8,9-Trimethoxy-8,9-
dimethyl-5a,5a1,6,6a,8,9,10a,10b-octahydrofuro[20,30,40,50:4,5]
phenanthro[2,3-b][1,4]dioxine (7b)
4.77 (d, J¼12.9 Hz, 1H), 4.64e4.60 (m, 2H), 4.11 (td, J¼10.8, 4.1 Hz,
1H), 3.85e3.82 (m, 1H), 3.82 (s, 3H), 3.64 (dd, J¼11.5, 3.6 Hz), 3.56
(dd, J¼11.5, 1.9 Hz, 1H), 3.38 (dd, J¼10.4, 4.7 Hz, 1H), 3.25 (s, 3H),
3.23 (s, 3H), 1.77 (dt, J¼11.5, 3.3 Hz, 1H), 1.66 (q, J¼12.0 Hz, 1H), 1.58
(t, J¼11.3 Hz, 1H), 1.36 (s, 3H), 1.30 (s, 3H); 13C NMR (100 MHz,
In a sealed tube containing 14 (40.6 mg, 0.10 mmol) and zinc
dust (40 mg, 0.61 mmol) in dry THF (1 mL) was added pyridine
(100
m
L, 1.24 mmol). The stirred mixture was cooled to ꢀ10 ꢁC and
CDCl3) d 147.7, 144.8, 132.0, 129.0, 121.2, 111.7, 100.6, 99.8, 86.0, 71.4,
66.2, 63.9, 63.7, 55.9, 48.1, 48.0, 42.2, 42.0, 32.3, 18.1, 17.8; HRMS
titanium(IV) chloride (33 mL, 0.30 mmol) was added dropwise. The
(ESI-TOF): 409.1870 ([MꢀH]ꢀ); C21H29O8 calcd 409.1862.
mixture was then heated at 80 ꢁC for 20 h before being cooled to
room temperature and filtered through a pad of Celite. The filtrate
was diluted with ether (5 mL) and washed sequentially with sat-
urated aqueous NaHCO3 solution, brine and dried over MgSO4.
Evaporation of the solvent under reduced pressure and purification
of the crude product by column chromatography by gradient elu-
tion with ethyl acetate in hexane (0e30%) afforded 7b as a colour-
4.9. (2S,3S,4aR,6S,6aS,11aR,11bS)-2,3,10-Trimethoxy-2,3-
dimethyl-2,3,4a,5,6,6a,11a,11b-octahydrobenzo[b][1,4]dioxino
[2,3-g]benzofuran-6,7-dicarbaldehyde (14)
To a stirred solution of 13 (678 mg, 1.65 mmol) in dichloro-
methane (5.5 mL) at room temperature was added sequentially
tert-butyl alcohol (1.56 mL, 16.4 mmol) and DesseMartin period-
inane (15 mL of 0.3 M solution in dichloromethane, 4.5 mmol).
After stirring for 3 h, saturated aqueous sodium hydrogen carbon-
ate (20 mL) and saturated aqueous sodium thiosulfate (20 mL)
were added to the mixture, which was extracted with dichloro-
methane (2ꢃ20 mL). The organic layer was washed with water and
dried over MgSO4. The solvent was evaporated under reduced
pressure and the residue was purified by silica gel column by gra-
dient elution with ethyl acetate in hexane (0e30%) to give 14
(420 mg, 63%) as a white solid. Rf¼0.38 (50% EtOAc/hexane); mp:
less film (20 mg, 53%). Rf¼0.45 (30% EtOAc/hexane); ½a D19
ꢂ
ꢀ91 (c 1.0,
CHCl3); IR (neat) 1499, 1436, 1262, 1117, 1045 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d
6.69 (d, J¼8.0 Hz, 1H), 6.62 (d, J¼8.0 Hz, 1H),
6.58 (dd, J¼9.1, 2.9 Hz, 1H), 5.92 (dd, J¼9.1, 2.7 Hz, 1H), 4.89e4.86
(m, 1H), 4.13 (dd, J¼10.3, 6.1 Hz, 1H), 3.86 (s, 3H), 3.83 (dd, J¼10.3,
7.0 Hz, 1H), 3.32 (s, 3H), 3.20 (s, 3H), 2.96 (dd, J¼14.6, 7.6 Hz, 1H),
1.96e1.87 (m, 1H), 1.82 (dt, J¼11.8, 3.3 Hz, 1H), 1.56e1.50 (m, 1H),
1.38 (s, 3H), 1.30 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 145.4, 144.7,
133.1, 132.2, 128.0, 126.8, 118.2, 112.7, 100.9, 100.0, 81.0, 72.4, 69.4,
56.4, 48.3, 47.9, 44.7, 40.5, 30.8, 18.1, 17.8; HRMS (ESI-TOF): 397.1629
([MþNa]þ); C21H26NaO6 calcd 397.1627.
235e236 ꢁC; ½a 2D0
ꢀ18.2 (c 1.06, CHCl3); IR (neat) 1728, 1714, 1683,
ꢂ
Acknowledgements
1612, 1580, 1434, 1294, 1145, 1084 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
9.77 (s, 1H), 9.58 (d, J¼4.2 Hz, 1H), 7.34 (d, J¼8.4 Hz, 1H), 6.92 (d,
We thank Dr. Aitipamula Srinivasulu (ICES) and Ms. Chia Sze
Chen (ICES) for X-ray crystallographic analysis. Financial support
for this work was provided by Agency for Science, Technology and
J¼8.4 Hz, 1H), 4.77 (dd, J¼5.4, 3.7 Hz, 1H), 4.14e4.12 (m, 1H),
4.11e4.09 (m, 1H), 3.96e3.92 (m, 1H), 3.94 (s, 3H), 3.28 (s, 3H), 3.25
(s, 3H), 2.28 (ddt, J¼13.0, 10.3, 4.2 Hz, 1H), 1.85 (dt, J¼13.0, 4.2 Hz,
1H), 1.72 (q, J¼12.1 Hz, 1H), 1.39 (s, 3H), 1.31 (s, 3H); 13C NMR
Research (A STAR), Singapore.
*
(100 MHz, CDCl3)
d 200.5, 191.4, 150.3, 148.2, 131.2, 129.3, 125.0,
Supplementary data
111.3, 100.5, 99.8, 85.3, 70.3, 64.4, 55.9, 53.1, 48.0, 47.9, 41.2, 28.3,
17.7, 17.6; HRMS (ESI-TOF): 407.1701 ([MþH]þ); C21H27O8 calcd
407.1700 and 429.1518 ([MþNa]þ); C21H26NaO8 calcd 429.1525.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.03.063. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
4.10. (2S,3S,4aR,6R,6aS,11aR,11bS)-2,3,10-Trimethoxy-2,3-
dimethyl-6,7-divinyl-2,3,4a,5,6,6a,11a,11b-octahydrobenzo[b]
[1,4]dioxino[2,3-g]benzofuran (15)
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d
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d
147.1, 144.9, 139.9, 135.1, 132.1, 126.6,
117.8, 116.1, 112.3, 112.0, 100.6, 99.8, 85.5, 71.4, 65.7, 55.9, 48.1, 48.0,

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