Chemoenzymatic total synthesis of ent-neopinone and formal total synthesis of ent -codeinone from β-bromoethylbenzene

Article abstract of DOI:10.1139/v11-071

Formal total synthesis of ent-codeinone and ent-codeine was accomplished via the total synthesis of ent-neopinone attained in 14 steps from β-bromoethylbenzene. The key steps included (i) enzymatic dihydroxylation of β-bromoethylbenzene with E. coli JM109

Full text of DOI:10.1139/v11-071

709
AWARD LECTURE / CONFÉRENCE D'HONNEUR
Chemoenzymatic total synthesis of ent-neopinone
and formal total synthesis of ent-codeinone from
β-bromoethylbenzene*
Jan Duchek, T. Graeme Piercy, Jacqueline Gilmet, and Tomas Hudlicky
Abstract: Formal total synthesis of ent-codeinone and ent-codeine was accomplished via the total synthesis of ent-neopi-
none attained in 14 steps from b-bromoethylbenzene. The key steps included (i) enzymatic dihydroxylation of b-bromoethyl-
benzene with E. coli JM109 (pDTG601a), an organism that overexpresses toluene dioxygenase, (ii) a Heck reaction to
establish C-13 stereogenic center, (iii) aldol condensation, and (iv) 1,6-conjugate addition of the ethylamino side chain to C-
9. Several other modes of construction of the C-9 and C-14 centers were also investigated: Mannich cyclization, and aza-
Prins reaction. The synthesis of ent-codeinone was formalized by intersecting Fukuyama’s recently published approach. Ex-
perimental and spectral data are provided for all new compounds.
Key words: synthesis of morphine alkaloids, ent-codeinone synthesis, ent-neopinone synthesis, enzymatic dihydroxylation of
aromatics, Heck reaction.
Résumé : On a réalisé une synthèse totale formelle de l’ent-codéinone et de l’ent-codéine par le biais d’une synthèse totale
de l’ent-néopinone qui a été obtenue en quatorze étapes à partir du b-bromoéthylbenzène. Les étapes clés comportent (i)
une dihydroxylation enzymatique du b-bromoéthylbenzène à l’aide d’E. coli JM109 (pDTG601a), un organisme qui imite la
dioxygénase du toluène, (ii) une réaction de Heck pour établir le centre stéréogénique en C-13, (iii) une condensation aldo-
lique et (iv) une addition 1,6-conjuguée de la chaîne latérale éthylamino sur le site C-9. On a aussi examiné plusieurs autres
modes de construction des centres C-9 et C-14, dont une cyclisation de Mannich et une réaction aza-Prins. La synthèse de
l’ent-codéinone a été formalisée en procédant à une intersection avec la méthode de Fukuyama publiée récemment. Les don-
nées expérimentales et spectrales pour tous les nouveaux produits.
Mots‐clés : synthèse d’alcaloïdes de la morphine, synthèse de l’ent-codéinone, synthèse de l’ent-néopinone, dihydroxylation
enzymatique de produits aromatiques, réaction de Heck.
[Traduit par la Rédaction]
in designing a practical synthesis of this unique compound
has not waned. Two hundred years after its isolation by Ser-
turner,12,13 chemists are still designing new and imaginative
routes to this challenging molecule.14–19
In 2009 we published the enantiodivergent synthesis of co-
deine that originated in the enzymatically derived cis-diol 3
produced from b-bromoethylbenzene by the whole-cell fer-
mentation with the recombinant organism E. coli JM109
(pDTG601a), capable of over-expressing toluene dioxyge-
nase.20 In that particular approach, a series of Heck reactions
and a hydroamination were used to complete the synthesis of
codeine (1) and its enantiomer.21,22 One of the advanced in-
termediates used in that synthesis was aldehyde 5.
Introduction
There has not been a shortage of interest in new synthetic
approaches to morphine (1) in the last decade. The most re-
cent review, published in 2011,1 summarized all published
syntheses of morphine and its congeners (there were nine
syntheses in total, including the most recent synthesis of co-
deine (2)2), (Fig. 1), since the last major review on this topic,
which appeared in 2005.3 Altogether, more than 25 total and
formal syntheses of the opiate alkaloids have been reported
since the first milestone total synthesis by Gates in 1952.4,5
Given the rich chemical6–8 as well as societal9–11 history of
morphine and the impact that this molecule has had on the
human condition, it should not be surprising that the interest
This aldehyde was also easily converted to a homologue 6
Received 15 February 2011. Accepted 5 April 2011. Published at www.nrcresearchpress.com/cjc on 23 June 2011.
J. Duchek, T.G. Piercy, J. Gilmet, and T. Hudlicky. Chemistry Department and Centre for Biotechnology, Brock University, 500
Glenridge Avenue, St. Catharines, ON L2S 3A1, Canada.
Corresponding author: Tomas Hudlicky (e-mail: thudlicky@brocku.ca).
*Based on the 2010 Bader Award Lecture.
Can. J. Chem. 89: 709–728 (2011)
doi:10.1139/V11-071
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Can. J. Chem. Vol. 89, 2011
Fig. 1. Chemoenzymatic approach to ent-codeine via toluene dioxygenase-mediated dihydroxylation of b-bromoethylbenzene.
RO
Br
Br
HO
HO
O
NMe
H
3
4
HO
(1)
R = H, morphine
R = Me, codeine (2)
Fig. 2. Three approaches to ent-codeine synthesis from protected aldehyde 6.
MeO
MeO
O
O
NMeBoc
2 steps
CHO
O
O
NMeBoc
TBSO
TBSO
6
5
aza-Prins approach
aldol approach
Mannich aproach
MeO
MeO
MeO
O
13
6
O
O
9
13
6
13
9
NHMe
NMe
X
9
5
14
5
NMe
5
14
14
6
X
HO
O
HO
9
8
7
g-Mannich closure
C-9/C-14
1,6-conjugate addition
at C-9
aza-Prins closure
C-9/C-14
MeO
O
NMe
H
HO
ent-codeine (2)
enone. This type of strategy was used by Fuchs to access the
natural enantiomer of morphine.23–26 In this paper, we report
the outcome of these approaches and the total synthesis of ent-
neopinone, as well as formal total synthesis of ent-codeinone
and ent-codeine via the intermediate dienone 9.27
via a Wittig reaction and transketalization. We envisioned
three different approaches, shown in Fig. 2, emanating from
this compound, which was prepared on intermediate scale in
eight steps from diol 3.
In the first approach we considered a C-9 and C-14 closure
by an aza-Prins reaction of the iminium salt 7 derived from
the condensation of the ethylamino side chain with the
masked aldehyde in 6. Similarly, the oxidized version of this
compound, enone 8 (depicted in its enolized form in Fig. 2),
was expected to undergo a g-Mannich closure to the iminium
species. The third approach assumed the formation of the di-
enone 9 from the aldehyde and the C-ring enone, to be fol-
lowed by a 1,6-conjugate addition of the amine at C-9,
which closure would yield the more energetically favored
Results and discussion
The inspiration for the approach to codeine depicted in
Fig. 2 came from Wiesner’s zizanoic acid synthesis published
in 1972.28 In one of his many ingenious solutions to the syn-
thetic problems of that particular era, he conceived the con-
struction of tricyclic enone 12, the key intermediate in his
synthesis of zizanoic acids, from the b,g-deconjugated enone
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Duchek et al.
711
Scheme 1. Reagents and conditions: (i) NBS, CHCl3, reflux, 68%; (ii) MOM-Cl, iPr2NEt, CH2Cl2, 4 °C; (iii) ClPh3PCH2OCH3, tBuLi,
THF, –78 °C to 4 °C; (iv) (CH2OH)2, pTsOH, THF, reflux, 76% from 14; (v) E. coli JM109 (pDTG601a), 10–15 g L–1 h–1; (vi) potassium
azodicarboxylate, AcOH, MeOH, 0 °C, 83%; (vii) 2,2-dimethoxypropane, acetone, pTsOH, 80%; (viii) NH2Me, K2CO3, THF, sealed tube,
90%; (ix) 3 mol L–1 HCl, EtOH; (x) Boc2O, NaHCO3, EtOH, 72% (2 steps); (xi) TBSCl, imidazole, CH2Cl2, –78 °C to 25 °C, 80%–88%.
Ring A fragment:
MeO
HO
MeO
HO
MeO
O
i
ii
CHO
CHO
MeO
CHO
Br
14
Br
15
13
iii
MeO
HO
iv
MeO
O
O
O
MeO
OMe
Br
17
Br
16
Ring C fragment:
Br
Br
Br
Br
O
OH
OH
vi
v
vii
O
OH
OH
4
3
18
19
viii
NMeBoc
OH
NMeBoc
NHMe
xi
ix, x
OH
OH
O
O
OTBS
21
22
20
10 under both acid- and base-catalyzed conditions, as shown
in Fig. 3 in an abbreviated manner.
Fig. 3. Wiesner’s strategy toward the construction of a tricyclic core
of zizanoic acid.
Whereas the stereochemical outcome of these closures dif-
fered slightly depending on the conditions of the reaction, the
mechanism of the closure could be interpreted in a number of
ways, each of which would lead to the same product.29,30
Thus, whether the closures proceeded via equilibrating aldol
reactions in the enolized version 11, the Prins reaction in 10,
or an ene reaction between the aldehyde and the olefin in 10,
in each case the final outcome would be enone 12.
When we noticed the similarity in connectivity of the two
asterisked carbons in 12 (Fig. 3) with C-9 and C-14 of the
morphine skeleton, we saw the opportunity to explore the re-
active options of intermediates such as 7 and 8, whose func-
tional disposition closely resembles the compounds used by
Wiesner.28
aldol?
Prins?
ene?
O
OH
O
*
*
HO
O
O
10
12
11
proceeded at medium scale as shown in Scheme 1 and was
subjected to a moderate degree of optimization.
The A-ring derives from the isovanillin (13), which was
brominated with N-bromo-succinimide (NBS) to provide bro-
moisovanillin 14. Subsequent protection of the hydroxy
group as its MOM ether furnished 15, which was converted
to the enol ether 16 by a Wittig reaction using the ylide gen-
erated from (methoxymethyl)triphenylphosphonium chloride.
Treatment of the resulting crude mixture of (E)- and (Z)-enol
ethers with ethylene glycol under acidic conditions furnished
phenol 17 in 48% overall yield from 13.
The synthesis of the key protected aldehyde 6 required the
connection of ring A and ring C fragments via Mitsunobu re-
action, followed by Heck cyclization, to establish the C-13
stereogenic center. The synthesis of both fragments, adopted
from our previous synthesis of codeine and its enantiomer,
The synthesis of the intermediate comprising the C-ring
started from (2-bromoethyl)benzene (4), which was converted
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Can. J. Chem. Vol. 89, 2011
Scheme 2. Reagents and conditions: (i) DIAD, Bu3P, THF, 0 °C to 25 °C, 76% (10 g scale); (ii) Pd2(dba)3, (tBu)3P, K2CO3, toluene, 110 °C,
85%–95%; (iii) TBAF, THF, –78 °C to 25 °C, 83%–85%.
O
O
NMeBoc
OH
MeO
HO
Br
MeO
O
i
+
NMeBoc
O
O
OTBS
Br
TBSO
22
17
23
ii
MeO
MeO
O
O
O
O
O
O
+
NMeBoc
NMeBoc
RO
iii
RO
iii
(3:1)
24
26
R = TBS
R = H
25
27
R = TBS
R = H
to diol 3 by microbial dihydroxylation using E. coli JM109
(pDGT601A) in space-time yields of 10–15 g L –1 h–1 on
15 L fermentor scale, as described previously.21 Diimide re-
duction of the sterically less hindered double bond led to
diol 18, whose protection as its isopropylidene ketal gave
19. Substitution of the bromine by MeNH2 provided the
methyl amine 20. This was followed by the removal of the
isopropylidene group and protection of the secondary amine
as its Boc carbamate to afford diol 21, whose regioselective
silylation provided the key ring C fragment 22 in 31% overall
yield from 3. This optimized route to fragment 22 is more
robust than the one we reported in the context of an earlier
total synthesis of codeine.22
Following the preparation of the two fragments 17 and 22,
their union was accomplished by the Mitsunobu reaction, as
shown in Scheme 2, to provide the aryl ether 23 in yields in
the range of 76%–85% and on a maximum scale of 10 g. By-
products from the large-scale Mitsunobu coupling isolated by
chromatography included phenol 17 (8%) and its silylated de-
rivative (4%). The latter compound likely resulted from the
trans-silylation of the free phenol by the TBS ether 22 and
(or) the product 23.
should provide the same dienolate or dienolate anion to be
tested in various cyclization schemes.
Treatment of the crude ketone 28 or enone 29 with tri-
fluoroacetic acid resulted in a clean conversion to the [3.3.1]
bicyclic adduct 30, formed in 45%–55% yield over the two
steps, and without the expected condensation of the secon-
dary amine with the masked aldehyde as shown in Scheme 3.
This was a disappointing turn of events, as it appeared that
the conjugate addition of the free secondary amine occurred
much faster than the formation of the required iminium spe-
cies.
The precursors to the aza-Prins and Mannich cyclizations
were generated from the protected aldehyde derivative 26 or,
in the earlier approach, also from the enol ether equivalent
33,35 synthesized from aldehyde 5 by a Wittig reaction. Thus
the enamine 32 was generated by treatment of 31 with tri-
fluoroacetic acid, as shown in Scheme 4. Treatment of alco-
hol 26 with trifluoroacetic acid in CH2Cl2 resulted in a
mixture of secondary amine 31 (49%–65%) and enamine 32
(10%–21%) in an approximate 3:1 ratio. Secondary amine 31
was smoothly converted to enamine 32 with treatment of ox-
alic acid in water, with a yield of 88%.
To set the C-13 quarternary center, the aryl ether 23 was
subjected to an intramolecular Heck coupling using Pd2(dba)3
with tri-tert-butylphosphine and K2CO3 in toluene31–33 to
provide an inseparable mixture of homoallylic and allylic
TBS ethers 24 and 25 in an approximate 5:1 ratio and in
86% combined yield.34 The minor allylic alcohol 25 is likely
the product of palladium-mediated isomerization of the dou-
ble bond (24 → 25). The mixture of 24 and 25 was treated
with TBAF in THF to furnish alcohols 26 and 27, respec-
tively, which were separated by chromatography.
The cyclic enamine 32 was a minor product in the TFA-
mediated deprotection of 26, but was the exclusive product
in the corresponding deprotection of 33 with TFA. The cyclic
enamine proved reasonably stable to storage and manipula-
tion. Reduction of 32 with cyanoborohydride provided amine
34, and served to confirm the structure of the enamine.
With these results we turned to the investigations of the
cyclizations proposed in Fig. 2. The summary of our at-
tempts, most of which proved unsuccessful, is shown in
Scheme 5.
The two regioisomeric alcohols 26 and 27 obtained on de-
silylation were oxidized with IBX to the key intermediates
ketone 28 and its conjugated isomer 29, respectively
(Scheme 3), which under either acidic or basic conditions
Enamine 32 was subjected to Lewis-acid-catalyzed cycliza-
tions to attempt the C-9/C-14 closure via the aza-Prins reac-
tion of the iminium ion 7 (Scheme 5). All attempts resulted
only in the recovery of the starting material and traces of
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Duchek et al.
713
Scheme 3. Reagents and conditions: (i) IBX, AcOEt, reflux; (ii) TFA, CH2Cl2, 45%–55% (2 steps).
MeO
MeO
O
O
O
O
O
O
+
NMeBoc
NMeBoc
HO
HO
26
27
i
i
MeO
MeO
MeO
O
O
O
O
O
O
ii
ii
O
O
O
NMeBoc
NMe
NMeBoc
O
O
O
28
30
29
Scheme 4. Reagents and conditions: (i) TFA, CH2Cl2, 49%–65% of 31, 10%–21% of 32; (ii) oxalic acid, H2O, 45 °C, 88%; (iii) TFA, CH2Cl2,
0 °C to 25 °C; (iv) NaBH3CN, AcOH, MeOH, 0 °C to 25 °C, 41% (from 33).
MeO
MeO
MeO
O
O
O
O
i
O
O
O
+
NMe
NMeBoc
NHMe
HO
HO
HO
26
(3:1)
ii
31
32
MeO
MeO
MeO
OMe
NMeBoc
iv
O
iii
O
O
NMe
NMe
HO
HO
HO
34
33
32
minor products that were not further identified. The presence
of ent-isocodeine 35 (or its neopine isomer, with the olefin at
C-8/C-14) was not detected by either TLC or HPLC analysis.
As mentioned above, the attempted generation of 8, the
precursor for the Mannich cyclization, failed and only the
[3.3.1]bicyclic adduct 30 was formed, presumably via the
a,b-conjugated isomer generated under the reaction condi-
tions.
We were not able to produce intermediates, such as 36 or
38, required for the enolized enone-iminium species 8
(Scheme 5) essential for the Mannich reaction. In addition,
any attempts to establish an equilibrium between 39 and 38
also failed.
The free aldehyde 39 was obtained by treating 30 with
aqueous oxalic acid at 40 °C (88%–92% yield), Fig. 4. Inter-
estingly, when the hydrolysis was conducted with HCl in
aqueous acetonitrile at pH 1 and 40 °C, a mixture of 39 and
40 was obtained in various ratios depending on the reaction
time. When we subjected aldehyde 39 to HCl in aqueous ace-
tonitrile, it was cleanly converted to 40 over 20 h. Benzalde-
hyde 40 exhibits a typical downfield shift of the CHO and
aromatic CH signals in the 1H-NMR spectrum, found at
9.91 ppm (CHO) and at 7.43 and 6.91 ppm (Ar CH), while
the same signals of 39 resonate upfield, at 9.70 ppm (CHO)
and at 6.79 and 6.66 ppm (Ar CH). We were interested in
whether this “demethylenation” could be applied to other
substrates, and therefore subjected the structurally related
phenol 17 (Fig. 4) to the same conditions. Treatment of phe-
nol 17 with aqueous oxalic acid at 40 °C afforded a mixture
of homobenzaldehyde 41 and benzaldehyde 14 in a 3:1 ratio,
while the reaction in aqueous acetonitrile in the presence of
HCl afforded benzaldehyde 14 as the major product (41/14,
1:3.5). These results suggested that in addition to apparent
solvent effects, there must be another factor affecting the out-
come of this reaction. Indeed, degassing the HCl–H2O–
MeCN mixture, prior to the addition of phenol 17, and stir-
ring at 40 °C led to homobenzaldehyde 41 as the major prod-
uct, accompanied by traces of 14. When these reaction
conditions (degassed HCl–H2O–MeCN) were applied to the
acetal cleavage in 30, we isolated homobenzaldehyde 39 as
the major product, with only traces of 40. The proposed
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714
Can. J. Chem. Vol. 89, 2011
Fig. 4. Generation of byproducts during the hydrolysis of acetals 30 and 17.
MeO
MeO
O
MeO
O
CHO
(CO2H)2, H2O
O
CHO
NMe
O
O
or
HCl, MeCN
+
NMe
NMe
O
O
O
30
39
40
MeO
HO
MeO
HO
MeO
HO
O
+
CHO
O
CHO
Br
17
Br
41
Br
14
41:14:
Conditions:
H2O, (CO2H)2
H2O, MeCN, H+
H2O, MeCN, H+, degassed
75:25
22:78
95:5
mechanism for the formation of benzaldehyde 40 is shown in
Fig. 5. We speculate that in the presence of oxygen (Option
A) the transformation likely involves an oxidation at the ben-
zylic position leading to intermediate 42, which is then con-
verted, via 43, to hydroperoxide 44. Fragmentation of 44
then leads to benzaldehyde 40 and formic acid. The fact that
trace amounts of benzaldehydes 40 and 14 were present even
in the degassed oxygen-free reaction mixtures led us to pro-
pose an alternative mechanism shown in option B. This path-
way would assume the formation of the acetonitrile adduct 47
from the readily enolisable 39 via the enol form 46, followed
by the formation of epoxide 48. Opening of the oxirane ring
with water generates 49 and the retro aldol reaction then
leads to 40. This option is indeed highly speculative as we
did not isolate 51, an expected by-product of this pathway,
during the initial experiments. However, further studies of
this transformation are warranted to assess both the mecha-
nism as well as potential general utility.
Returning to the synthesis of ent-codeinone, we expected
that base-catalyzed treatment of 39 would generate the de-
sired dienone 9, while acid catalysis would ultimately lead to
the dienolate-iminium species 8, as indicated in Scheme 5;
however, neither of these attempts led to appreciable concen-
trations of the enone or dienone species. The presence of ent-
codeinone or ent-neopinone 37 was not detected in the reaction
mixtures. We were unable to solve the functional incompati-
bility issues between the hydrolysis of the acetal and the de-
protection of the Boc group.
diastereoisomer possessed free OH while the OH group of
the other diastereoisomer participated in hydrogen bonding.
This was supported also by the H NMR spectrum in which
only one diastereoisomer displayed two rotameric sets of sig-
nals, typical for amides. We assumed that the a-hydroxy dia-
stereoisomer of 54, the isomer having the OH and NMeAc
groups on the same face, forms an intramolecular hydrogen
bond favoring one of the rotamers. Isolation of 54 validated
the aldol approach as the alcohols 54 would be convertible
to the required dienone of type 9.
1
As our work was nearing completion, Fukuyama36 re-
ported a conceptually identical approach to the natural enan-
tiomer of morphine, using a derivative of type 54 bearing a
DNS protecting group on the nitrogen atom, so we have de-
cided to formalize our synthesis. Thus the problem of aldol
cyclization and the ultimate 1,6-addition of the ethylamino
side chain was solved in a similar way as was done in Fu-
kuyama’s synthesis. ent-Neopinone was prepared as shown
in Scheme 7.
After generating the DNS protected amine 55, we sub-
jected it to the sequence used in the Fukuyama’s synthesis,
namely hydrolysis of the acetal with aqueous trifluoroacetic
acid, intramolecular aldol reaction, and mesylation of the re-
sulting hydroxy group. The repetition of the aforementioned
sequence with the ethylene glycol acetal 55 provided lower
yields than those reported for the route utilizing the dime-
thoxy acetal. The robust nature of the acetal in 56 required
longer reaction times to generate the free aldehyde that
would undergo the aldol reaction whose product was isolated
as the mesylate 57. The use of 1.2 equiv of MsCl and 1.5
equiv of Hünig’s base (Fukuyama’s conditions) in the reac-
tion following the aldol closure led to isolation of 57 in only
6% yield from 55. We speculated that traces of ethylene gly-
col present in the reaction mixture contributed to the low
yield. Performing the mesylation with large excess of both
MsCl (4.5 equiv) and Hünig’s base (5 equiv) led directly to
in situ elimination and a mixture of 58 and 59 was obtained
in 42% and 13% yield, respectively, over the two steps from
To test the feasibility of formation of dienone 9 (Scheme 5)
we exchanged the Boc group in 26 for a more robust acetyl
group in 52 (Scheme 6). Deprotection of 26 with TFA pro-
vided the secondary amine 31 whose acetylation gave 52.
Oxidation of 52 with IBX provided the deconjugated enone
53, whose treatment under acidic conditions led to the forma-
tion of the inseparable mixture of diastereomeric alcohols 54
in 22% in a 1:1 ratio. The IR spectrum exhibited two bands
corresponding to the OH groups. Presence of a sharp band at
3606 cm–1 and a broad band at 3386 cm–1 suggested that one
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Duchek et al.
715
Scheme 5. Reagents and conditions: (i) various Brønsted and Lewis acids; (ii) TFA, CH2Cl2, 56% from 26; (iii) oxalic acid, 45 °C, 68%–75%
(crude).
(A) aza-Prins attempt:
MeO
MeO
MeO
O
O
O
i
X
NMe
X
NMe
NMe
HO
HO
HO
32
35
7
(B)
Mannich attempt:
MeO
MeO
MeO
i
O
O
O
X
NMe
X
NMe
NMe
HO
O
O
36
8
37
i
MeO
O
O
MeO
O
NMeBoc
CHO
NHMe
O
O
29
O
38
ii
ii
C. aldol attempt:
MeO
O
MeO
MeO
O
CHO
O
iii
O
O
X
NHMe
NMe
NMe
O
O
O
30
9
39
neopinone also formalizes the synthesis of ent-codeinone and
ent-codeine.
55. Enantiomers of both 57 and 58 have been converted via
neopinone and codeinone to (–)-codeine by Fukuyama,36 thus
their attainment completed the formal synthesis.
To ensure that the low yields obtained from acetal 55 were
indeed the function of the robust protecting group, we de-
cided to repeat the chemistry with Fukuyama’s acetal, gener-
ated by treatment of 55 with pTsOH in MeOH at reflux
(Scheme 8). Oxidation of 62 with IBX in AcOEt at 80 °C
afforded ketone 63 having optical rotation of +25.5°, oppo-
site to that of ent-63 (–24.2°).36 Treatment of 63 with aque-
ous trifluoroacetic acid, followed by mesylation afforded
mesylate 57 in 28% and dienone 58 in 24% yield from 62.
The cyclization of 63 indeed provided higher yields of 57
and 58 than the corresponding reaction of the acetal 56.
The desired dienone 58 was separated and treated with thi-
oglycolic acid in the presence of triethylamine. NMR and
TLC analysis of the reaction mixture confirmed the formation
of ent-neopinone (61) accompanied by a small amount of
ent-codeinone (60). For the purpose of direct comparison, a
sample of neopinone was prepared from thebaine according
to Rapoport’s procedure,37 and matched with the product of
this reaction. Fukuyama36 reported isomerization of neopi-
none obtained from the cyclization to codeinone followed by
reduction of the latter to codeine. Thus the attainment of ent-
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716
Can. J. Chem. Vol. 89, 2011
Fig. 5. Proposed mechanism for the formation of benzaldehyde 40.
(A) Oxygen-assisted cleavage
MeO
MeO
MeO
O
OH
OH
OH
O
OH
O
H2O, O2
H+
O2
O
O
O
O
+
OOH
NMe
NMe
NMe
O
O
O
30
42
43
MeO
MeO
MeO
OH
OH
OH
OH
O OH
NMe
H2O, H+
CHO
+
O
O
O
HCO2H
O
OH
H
NMe
NMe
O
O
O
40
45
44
(B) Nitrile-assisted cleavage
MeO
MeO
MeO
MeO
O
OH
N
CHO
O
OH
TFA, MeCN
H2O
O
O
O
O
NH
NMe
NMe
NMe
NMe
O
O
O
O
30
39
46
47
MeO
MeO
MeO
H2O, H+
OH
O
H
N
O
CHO
NMe
O
O
O
+
OH
NH
NH
NMe
NMe
N
H
NH2
50
O
O
O
51
40
49
48
Scheme 6. Reagents and conditions: (i) (a) AcCl, Et3N, CH2Cl2, (b) MeONa, MeOH, 87%; (ii) 52, IBX, AcOEt, 80 °C; (iii) 50% aqueous
TFA, toluene, 50 °C, 22% from 52.
MeO
MeO
MeO
O
O
O
O
NMeAc
OH
iii
ii
O
O
O
NMeR
NMeAc
H
HO
i
O
O
31
52
R = H
R = Ac
53
54
Published by NRC Research Press

Duchek et al.
717
Scheme 7. Reagents and conditions: (i) 2,4-dinitrobenzenesulfonyl chloride, iPr2NEt, CH2Cl2 (51%); (ii) IBX, AcOEt, 80 °C; (iii) (a) 50%
aqueous TFA, toluene, 50 °C, (b) MsCl (4.5 equiv), iPr2NEt (5 equiv), CH2Cl2, 0 °C (42% of 58 from 55, 13% of 59 from 55); (iv) thiogly-
colic acid, iPr2NEt, CH2Cl2, 0 °C .
MeO
MeO
MeO
O
O
O
O
O
O
O
O
O
ii
i
NHMe
NMeDNS
NMeDNS
HO
HO
O
31
55
56
iii
MeO
MeO
MeO
NMeDNS
OMs
NMeDNS
NMeDNS
O
O
O
+
H
O
O
O
57
58
59
iv
MeO
MeO
+
O
O
O
(2)
ent-codeine
NMe
NMe
H
O
H+
61
60
Scheme 8. Reagents and conditions: (i) MeOH, pTsOH, reflux (86%); (ii) IBX, AcOEt, 80 °C; (iii) 50% aqueous TFA, toluene, 50 °C; MsCl
iPr2NEt, CH2Cl2, 0 °C (24% of 58 from 62, 28% of 57 from 62); (iv) thioglycolic acid, iPr2NEt, CH2Cl2, 0 °C.
MeO
MeO
MeO
OMe
OMe
O
OMe
OMe
O
i
ii
O
O
O
NMeDNS
NMeDNS
NMeDNS
O
HO
HO
63
62
55
iii
MeO
MeO
MeO
NMeDNS
NMeDNS
OMs
iv
+
O
O
O
NMe
H
O
O
O
61
58
57
Treatment of the mixture of 57 and 58 with thioglycolic acid
and Hünig’s base, as reported by Fukuyama,36 afforded a full
conversion to ent-neopinone (61), matched with authentic
samples.
to establish the C-13 stereogenic center, and 1,6-conjugate
addition of the ethylamono side chain to C-9 of the dienone
9, obtained by aldol cyclization. Attempts at intramolecular
Mannich cyclizations or aza-Prins cyclizations to iminium
species derived from enamines of type 32 or 36 proved un-
successful. The synthesis of ent-neopinone by the route de-
scribed also constitutes a formal synthesis of ent-codeinone
and ent-codeine.
Conclusions
ent-Neopinone was synthesized from b-bromoethyl ben-
zene in 14 steps via enzymatic dihydroxylation, Heck closure
Published by NRC Research Press

718
Can. J. Chem. Vol. 89, 2011
4.34 (d, J = 5.5 Hz, 1H), 4.27 (td, J = 5.8, 3.2 Hz, 1H), 2.78–
2.72 (m, 2H), 2.41 (s, 3H), 2.38–2.31 (m, 1H), 2.25 (q, J =
7.4 Hz, 1H), 2.14 (dddd, J = 9.0, 7.3, 3.9, 1.7 Hz, 1H), 1.91
(t, J = 5.3 Hz, 1H), 1.86–1.79 (m, 1H), 1.75–1.69 (m, 1H),
1.48 (s, 1H), 1.36 (s, 6H); 13C NMR (CDCl3, 150 MHz): d
133.97, 126.58, 108.24, 73.64, 73.47, 49.81, 36.32, 34.28,
27.91, 26.46, 25.56, 20.80; LRMS-EI (m/z): M+ 196 (3), 153
(14), 136 (5), 44 (100); anal. calcd. for C12H21NO2·(COOH)2:
C, 55.80; H, 7.69; found C, 55.75; H, 7.66.
Experimental section
General
Reactions were carried out under inert atmosphere in oven-
dried glassware unless stated otherwise. Solvents were dis-
tilled: CH2Cl2, DMF, iPr2NEt, and pyridine from CaH2;
MeOH from magnesium methoxide; THF from Na/benzophe-
none; toluene from Na. Qualitative TLC was done with pre-
coated silica gel aluminium sheets (EMD silica gel 60 F254);
detection by UV or by spraying with “CAM” solution (5 g of
(NH4)6Mo7O24·4H2O, 1 g of Ce(SO4)2, 100 mL of 10%
H2SO4) or 0.5% aqueous KMnO4 solution followed by heat-
ing. Column chromatography was performed using silica gel
SiliaFlash P60 from Silicycle (40–66 µm). Optical rotation
was measured in a 1 dm cell at 20–25 °C and 589 nm; con-
centration c in g 100 mL–1. IR spectra were recorded as ca. 2%
tert-Butyl 2-((5S,6R)-5,6-dihydroxycyclohex-1-enyl)ethyl
(methyl)carbamate (21)
NMeBoc
OH
solutions in CHCl3 or as a thin film. H NMR and 13C NMR
1
spectra were recorded at 300 or 600 MHz and 75 or 150 MHz,
respectively, and were calibrated to the solvent signal or tet-
ramethylsilane; the chemical shifts are reported in ppm. Mass
spectra were recorded on Kratos/MsI Concept 1S mass spec-
trometer at Brock University. Combustion analyses were per-
formed by Atlantic Microlabs, Norcross, Georgia, USA.
OH
21
A solution of acetonide 20 (7.02 g, 33.2 mmol) in EtOH
(40 mL) and H2O (4 mL) was treated with 3 mol L–1 HCl
(16.6 mL, 49.8 mmol). The reaction mixture was stirred for
4 h, treated with NaHCO3 (42 g, 498 mmol), and stirred vig-
orously for 1 h. Then Boc anhydride (10.9 g, 49.8 mmol) was
added, reaction mixture was stirred for additional 4 h, filtered,
and evaporated. The residue was diluted with H2O (25 mL)
and extracted with CH2Cl2 (3 × 20 mL). The combined or-
ganic layers were washed with saturated aqueous NH4Cl sol-
ution (2 × 10 mL), brine, dried (Na2SO4), filtered, and
evaporated. Flash column chromatography (hexanes/AcOEt,
6:1 → 1:2) afforded 21 (6.48 g, 72%) as a colorless oil. Rf
2-(2,2-Dimethyl-3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxol-4-
yl)-N-methylethanamine (20)
NHMe
O
O
20
23
(hexanes/AcOEt, 1:1) 0.20; ½aꢀ = –95.5° (c 0.75, CHCl3);
IR (film): n 3394 (s), 2975 (s),D2931 (s), 1674 (s), 1483 (s),
1353 (s), 1397 (s), 1366 (s), 1308 (m), 1247 (m), 1220 (m),
1160 (s), 1075 (m), 1053 (m), 989 (m), 945 (w), 919 (w) cm–1;
A solution of diol 1822 (45.2 g, 204.5 mmol) in acetone
(400 mL) was treated with 2,2,-dimethoxypropane (37.6 mL,
306.8 mmol) and pTsOH. The reaction was stirred for 4 h at
room temperature, whereupon the solvent was evaporated. The
residue was diluted with H2O (50 mL) and extracted with
CH2Cl2 (3 × 200 mL). The combined organic layers were
washed with saturated aqueous Na2CO3 solution (2 × 20 mL),
and brine, then dried (Na2SO4), filtered, and evaporated to
yield bromide 19 (46.1 g) as a clear colorless oil, which was
used without further purification. Bromide 19 (10.05 g,
38.3 mmol) was dissolved in THF (35 mL) and transferred to a
200 mL thick-walled reaction vessel containing K2CO3 (2.64 g,
19.1 mmol) and a magnetic stirring bar. The reaction vessel
was cooled to –40 °C, and the solution was saturated with
methylamine by passing gaseous methylamine from a lecture
bottle through the solution for 15 min. The reaction vessel was
sealed, and the mixture was stirred at 25 °C for 18 h. The mix-
ture was cooled to –40 °C before the vessel was opened. Potas-
sium salts were removed by filtration and rinsed with CH2Cl2.
The solvent was evaporated to obtain amine 20 (7.56 g, 94%),
which was used without further purification. Rf (AcOEt/
MeOH/aqueous NH3, 7:3:1) 0.3; Mp 143–147 °C (oxalate
1H NMR (CDCl3, 300 MHz): 5.43 (s, 1H), 4.87 (s, 1H), 3.96
(s, 2H), 3.56 (s, 1H), 2.99 (d, J = 8.8 Hz, 1H), 2.91 (s, 1H),
2.86 (s, 3H), 2.42–2.30 (m, 1H), 2.18 (d, J = 13.4 Hz, 1H),
2.03 (s, 2H), 1.74–1.63 (m, 1H), 1.60–1.45 (m, 1H), 1.43 (s,
9H); 13C NMR (CDCl3, 150 MHz): 157.0, 133.9, 128.8, 79.9,
70.0, 69.8, 48.3, 34.8, 34.0, 28.3, 25.4, 24.8; LRMS-EI (m/z):
M+ 271 (1), 197 (3), 171 (1), 153 (9), 144 (29), 110 (23), 88
(16), 57 (88), 44 (100); HRMS-EI (m/z): M+ calcd. for
C14H25NO4: 271.1784, found 271.1796.
tert-Butyl 2-((5S,6R)-5-(tert-butyldimethylsilyloxy)-6-
hydroxycyclohex-1-enyl)ethyl(methyl)carbamate (22)
NMeBoc
OH
OTBS
24
22
salt); ½aꢀD = 25.8 (c 1, MeOH); IR (film): n 3324 (w), 2983
(s), 2932 (s), 2844 (s), 2790 (m), 1674 (m), 1563 (w), 1443
(m), 1367 (s), 1242 (s), 1221 (s), 1156 (m), 1077 (s), 1030 (s),
A solution of carbamate 21 (7.76 g, 28.6 mmol) and imi-
dazole (3.89 g, 57.2 mmol) in CH2Cl2 (50 mL) was treated
1
869 (m) cm–1; H NMR (CDCl3, 300 MHz): d 5.63 (s, 1H);
Published by NRC Research Press

Duchek et al.
719
with TBSCl (4.75 g, 31.5 mmol) at –78 °C, the reaction mix-
ture was left to warm slowly to 25 °C overnight and treated
with saturated aqueous NH4Cl solution (15 mL). After ex-
traction with CH2Cl2 (3 × 100 mL), the combined organic
layers were washed with saturated aqueous NaHCO3 solution
(20 mL), brine (20 mL), dried (MgSO4), filtered, and evapo-
rated. Flash column chromatography (hexanes/AcOEt, 3:1)
afforded 22 (8.54 g, 77%) as a clear colorless oil. Rf
A solution of crude 16 (32.2 g, 106 mmol) in THF
(300 mL) was treated with pTsOH (10.1 g, 53.0 mmol), eth-
ylene glycol (29.6 mL, 530.3 mmol), and refluxed for 2 h.
Reaction mixture was cooled to 25 °C, concentrated, diluted
with AcOEt (150 mL), and washed with H2O (2 × 20 mL).
Organic layer was washed with brine, dried (MgSO4), fil-
tered, and evaporated. The residue was dissolved in CH2Cl2
(100 mL) and extracted with 0.5 mol L–1 NaOH (3 ×
10 mL). The combined aqueous layers were neutralized with
1 mol L–1 HCl to pH 7 and extracted with AcOEt (3 ×
15 mL). Combined organic layers were washed saturated
aqueous NaHSO3 solution (5 × 15 mL), and brine, then dried
(MgSO4), filtered, and evaporated to yield 17 (16.2 g, 76%
from 14) as a light yellow solid. Sample for analysis was re-
crystallized from AcOEt/hexanes. Rf (hexanes/AcOEt, 1:1)
0.59; Mp 118–120 °C (AcOEt/hexanes); IR (CHCl3): n 3370
(w), 2959 (w), 2892 (w), 1607 (w), 1577 (w), 1490 (s), 1465
(w), 1441 (m), 1404 (w), 1362 (w), 1336 (w), 1283 (s), 1232
(m), 1199 (w), 1169 (w), 1130 (m), 1034 (s), 986 (w), 942
24
(CH2Cl2/AcOEt, 96:4) 0.47; ½aꢀD = –22.6 (c 0.5, CHCl3);
IR (film): n 3556 (w), 3475 (w), 2953 (s), 2857 (s), 1692
1
(s), 1472 (s), 1392 (s), 1253 (s), 1085 (s) cm–1; H NMR
(CDCl3, 600 MHz, mixture of rotamers): d 5.54 (s, 1H),
5.52 (s, 1H), 3.98 (s, 1H), 3.90 (s, 1H), 3.79 (s, 1H), 3.77
(s, 1H), 3.26–3.20 (m, 2H), 2.85 (s, 3H), 2.82 (s, 3H), 2.39–
2.32 (m, 2H), 2.30–2.23 (m, 2H), 2.13 (br s, 2H),1.98 (br s,
2H) 1.80–1.72 (m, 2H),1.54 (s, 2H),1.44 (s,18H), 0.9
(s,18H), 0.11 (s, 6H), 0.10 (s, 6H); 13C NMR (CDCl3,
150 MHz): d 155.7, 134.8, 126.6, 79.0, 71.0, 68.8, 48.4,
47.2, 34.1, 33.3, 32.8, 28.4, 25.8, 25.4, 25.3, 24.3, 24.1,
18.1, –4.4, –4.8; LRMS-EI (m/z): M+ 228 (21), 197 (21),
136 (12), 74 (22), 73 (15), 57 (63), 44 (100); HRMS-EI (m/z):
[M-57]+ calcd. for C12H30NO4Si: 328.1944, found 328.1946;
anal. calcd for C20H39NO4Si: C, 62.10, H,10.22; found C,
62.29, H,10.19.
1
(w), 820 (w), 802 (w) cm–1; H NMR (CDCl3, 300 MHz):
6.88 (d, J = 8.3 Hz, Ar H), 6.79 (d, J = 8.3 Hz, 1H), 5.95
(s, exchange with D2O, 1H), 5.12 (t, J = 4.9 Hz, 1H), 4.03–
3.80 (m, 4H), 3.89 (s, 3H), 3.09 (d, J = 4.9 Hz, 1H); 13C
NMR (CDCl3, 150 MHz): d 145.97, 143.20, 128.86, 111.36,
122.13, 109.66, 103.51, 65.05, 56.41, 40.17; LRMS-EI (m/z):
M+ 289 (1), 73 (100), 45 (14); HRMS-EI (m/z): M+ calcd.
for C11H13BrO4: 287.9997, found 287.9994; anal. calcd. for
C11H13BrO4: C, 45.70, H, 4.53; found: C, 45.99, H, 4.47.
2-Bromo-3-(1,3-dioxolan-2-ylmethyl)-6-methoxyphenol (17)
MeO
O
tert-Butyl 2-((50S,60S)-60-(3@-((1,3-dioxolan-2-yl)methyl)-2@-
bromo-6@-methoxyphenoxy)-50-(tert-butyldimethylsilyloxy)
cyclohex-10-enyl)ethyl(methyl)carbamate (23)
O
HO
Br
17
O
O
A solution of bromoisovanillin 14 (10.0g, 43.4 mmol) in
CH2Cl2 (300 mL) was cooled to 0 °C and treated with iPr2-
NEt (15.1 mL, 86.7 mmol) and MOM-Cl (4.94 mL,
65.1 mmol). Reaction mixture was stirred for 3 h while the
light yellow solution turned clear. The reaction mixture was
diluted with H2O (100 mL), the layers were separated and
the aqueous layer was extracted with AcOEt (3 × 40 mL).
The combined organic layers were washed with brine, dried
(MgSO4), filtered, and evaporated to yield crude 15 as a light
yellow/brown solid (12.2 g) which was used without further
purification. Rf (hexanes/AcOEt, 1:1) 0.69.
Br
MeO
NMeBoc
O
TBSO
23
An orange solution of DIAD (7 mL, 35.6 mmol) in de-
gassed THF (45 mL) was cooled to –10 °C and treated with
PBu3 (9.5 mL, 38.5 mmol) at one portion. The resulting pale
yellow solution was stirred for 25 min at –10 °C and cannu-
lated during 35 min into a chilled (4 °C) solution of alcohol
22 (10.6 g, 27.4 mmol) and phenol 17 (8.7 g, 30.2 mmol) in
degassed THF (90 mL). The mixture was allowed to reach
25 °C, stirred for 12 h, and evaporated. The residue was ad-
sorbed on silica gel and subjected to chromatography (hex-
anes/AcOEt, 8:1) obtaining 23 (13.8 g, 76%) and recovered
phenol 17 (664 mg, 8%). Data for 23: Yellow oil; Rf (hex-
A solution of Ph3P+CH2OCH3Cl– (23.1 g, 67.2 mmol) in
THF (125 mL) was cooled to –78 °C, treated with tBuLi
(35.9 mL, 61.1 mmol) dropwise over 10 min, and stirred for
15 min. The solution was warmed to 0 °C and treated with
crude 15 (16.3 g, 61.1 mmol) in THF (17 mL) dropwise
over 5 min while the deep orange solution turned to a deep
yellow suspension. The suspension was refluxed for 3.5 h,
cooled to 25 °C, diluted with AcOEt (100 mL), and washed
with H2O (100 mL). The aqueous layer was extracted with
AcOEt (3 × 50 mL) and the combined organic layers were
washed with brine, dried (MgSO4), filtered, and evaporated
to yield crude 16 as a yellow solid (30.8 g) which was used
without further purification.
20
anes/AcOEt, 2:1) 0.75; ½aꢀ = + 43.7 (c 0.125, CHCl3); IR
(CHCl3): n 3294 (w), 2930D(s), 2857 (m), 1736 (w), 1697 (s),
1594 (w), 1482 (s), 1441 (m), 1393 (m), 1365 (m), 1293 (m),
1252 (s), 1171 (s), 1137 (s), 1105 (m), 1085 (m), 1035 (s),
Published by NRC Research Press

720
Can. J. Chem. Vol. 89, 2011
1007 (m), 943 (w) cm–1; H NMR (CDCl3, 600 MHz, two
rotamers): 7.04 (d, J = 8.3 Hz, 1H), 6.83 (d, J = 8.3 Hz,
1H), 5.80, 5.77 (2 br. s, 1H), 5.06 (t, J = 4.9 Hz, 1H), 4.48
(br. s, 1H), 4.00–3.92 (m, 3H), 3.87–3.78 (m, 2H), 3.83 (s,
3H), 3.55 (br. s, 0.4H), 3.41 (br. s, 0.6H), 3.22–3.15 (m,
1H), 3.13 (dd, J = 14.0, 4.5 Hz, 1H), 3.07 (dd, J = 14.0,
5.3 Hz, 1H), 2.81 (br. s, 3H), 2.52 (br. s, 0.4 H), 2.46 (br. s,
0.6H), 2.42–2.35 (m, 1H), 2.25–2.13 (m, 2H), 2.02–1.94 (m,
1H), 1.67–1.60 (m, 1H), 1.44 (s, 9H), 0.72 (s, 9H), –0.18,
–0.21 (2 s, 6H); 13C NMR (CDCl3, 150 MHz, 2 rotamers):
155.93, 155.74, 152.00, 144.55, 131.39, 129.17, 121.33,
131.39, 126.16, 111.14, 103.51, 79.84, 79.60, 79.05, 67.50,
65.00, 55.78, 49.08, 48.30, 40.58, 35.25, 35.10, 33.70,
32.85, 28.60, 25.77, 25.29, 20.83, 18.13, –5.09; LRMS-EI
(m/z): M+ 656 (1), 368 (8), 312 (45), 268 (39), 237 (52),
180 (8), 136 (28), 105 (10), 73 (100), 57 (58), 44 (35);
HRMS-EI (m/z): M+ calcd. for C31H51BrNO7Si: 656.2540,
found 656.2595; anal. calcd. for C31H51BrNO7Si: C, 56.70;
H, 7.67; found C, 56.95; H, 7.77.
1
NMR (CDCl3, 150 MHz): d 155.5, 146.1, 143.9, 132.3,
129.4, 124.8, 123.1, 111.7, 104.7, 104.5, 89.8, 79.4, 68.4,
65.0, 64.9, 55.8, 51.4, 45.2, 37.5, 36.3, 35.4, 34.2, 30.8,
29.7, 28.4, 25.8, 25.7, 18.1; LRMS-EI (m/z): 310 (7), 237
(1), 184 (10), 139 (4), 91 (22), 73 (66), 57 (80), 43 (100);
HRMS-EI (m/z): M+ calcd. for C31H49NO7Si: 575.3278,
found 575.3276.
tert-Butyl 2-((5aS,6S,9aR)-1-((1,3-dioxolan-2-yl)methyl)-6-
hydroxy-4-methoxy-5a,6,7,9a tetrahydrodibenzo[b,d]furan-
9a-yl)ethyl(methyl)carbamate (26) and tert-butyl 2-
((5aS,6S,9aR)-1-((1,3-dioxolan-2-yl)methyl)-6-hydroxy-4-
methoxy-5a,6,9,9a-tetrahydrodibenzo[b,d]furan-9a-yl)ethyl
(methyl)carbamate (27)
MeO
MeO
O
O
O
O
O
O
+
tert-Butyl 2-((5aS,6S,9aR)-1-((1,3-dioxolan-2-yl)methyl)-6-
(tert-butyldimethyl-silyloxy)-4-methoxy-5a,6,7,9a-
tetrahydrodibenzo[b,d]furan-9a-yl)ethyl(methyl)-carbamate
(24) and tert-butyl 2-((5aS,6S,9aR)-1-((1,3-dioxolan-2-yl)
methyl)-6-(tert-butyldimethylsilyloxy)-4-methoxy-5a,6,9,9a-
tetrahydrodibenzo[b,d]furan-9a-yl)ethyl(methyl)carbamate
(25)
NMeBoc
NMeBoc
HO
HO
26
27
A solution of 24 and 25 (24/25 ≈ 5:1, 4.818 g,
8.34 mmol) in THF (50 mL) was cooled to 0 °C and treated
with a 1.0 mol L–1 solution of TBAF in THF (12.6 mL,
12.6 mmol). The mixture was stirred for 16 h at 25 °C, di-
luted with AcOEt (40 mL), and washed with H2O (25 mL).
The aqueous layer was extracted with AcOEt (3 × 45 mL)
and the combined organic layers were washed with brine,
dried (Na2SO4), filtered, and evaporated. Flash column chro-
MeO
MeO
O
O
O
O
O
O
+
NMeBoc
NMeBoc
TBSO
matography (hexanes/AcOEt, 4:1
→ 1:1) afforded 27
TBSO
(593 mg, 15%) as a light yellow foam and 26 (3.14 g, 82%)
as a light yellow foam.
24
25
Data for 26
A solution of 23 (6.38 g, 9.7 mmol) in degassed toluene
(60 mL) was treated with K2CO3 (2.01 g, 14.6 mmol), Pd2
(dba)3 (888 mg, 0.97 mmol), and tBu3P (393 mg,
1.94 mmol), immersed in a preheated oil bath (110 °C), and
stirred for 16 h. The reaction mixture was filtered through a
plug of Celite (washing with CH2Cl2) and evaporated. Flash
column chromatography (hexanes/AcOEt, 4:1) afforded an
inseparable mixture of 24 and 25 (24/25 ≈ 5:1, 4.82 g, 86%)
20
Rf (hexanes/AcOEt, 1:2) 0.26; ½aꢀD +9.5 (c 3.2, CHCl3);
IR (film): n 3629 (m), 3018 (s), 1732 (m), 1683 (s), 1625
(w), 1584 (w), 1507 (m), 1400 (m), 1367 (m), 1318 (w)
1280 (m), 1216 (s), 1156 (m), 1097 (m), 1047 (m), 978 (w)
1
cm–1; H NMR (CDCl3, 300 MHz, 2 rotamers): d 6.81 (d, J =
8.3 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.03 (dd, J = 9.8,
1.5 Hz, 1H), 5.78 (ddd, J = 9.8, 5.7, 2.3 Hz, 1H), 5.04 (dd,
J = 6.0, 3.8 Hz, 1H), 4.55–4.37 (br. s, 1H), 4.05–3.95 (m,
2H), 3.90–3.80 (m, 2H); 3.85 (s, 3H), 3.47–3.20 (m, 1H),
3.06 (dd, J = 14.3, 3.4 Hz, 1H), 2.94–2.82 (m, 1H), 2.89
(dd, J = 14.3, 6.0 Hz, 1H), 2.77 (s, 3H), 2.45–2.30 (m, 1H),
2.19–2.03 (m, 1H), 2.03–1.78 (m, 2H), 1.43 (s, 9H); 13C
NMR (CDCl3, 150 MHz): d 155.61, 145.76, 144.18, 129.29,
125.10, 129.49, 124.66, 123.92, 111.80, 104.67, 90.64,
90.12, 79.67, 68.18, 65.10, 65.06, 56.03, 51.84, 36.59,
34.41, 29.41, 28.61; LRMS-EI (m/z): M+ 461 (6), 388 (3),
340 (8), 285 (16), 271 (6), 241 (2), 213 (8), 142 (31), 103
(20), 84 (31), 73 (100), 57 (81); HRMS-EI (m/z): M+ calcd.
for C25H35NO7: 461.2414, found 461.2414; Anal. calcd. for
C25H35NO7: C, 65.06; H, 7.64; found C, 64.94; H, 7.67.
20
as a brown oil. Rf (hexanes/AcOEt, 2:1) 0.59; ½aꢀ = +34.8
(c 1.00, CHCl3); IR (CHCl3): n 3010 (w), 2956D(m), 2931
(m), 2895 (w), 2857 (w), 1730 (w), 1683 (m), 1626 (w),
1584 (w), 1506 (m), 1482 (w), 1472 (w), 1438 (w), 1401
(w), 1394 (w), 1367 (w), 1321 (w), 1282 (w), 1258 (m),
1221 (s), 1216 (s), 1213 (s), 1210 (s), 1155 (m), 1127 (m),
1
1048 (w), 1009 (w) cm–1; H NMR (CDCl3, 300 MHz): d
6.78 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.01–
5.97 (m, 1H), 5.73–5.68 (m, 1H), 5.05 (m, 1H), 4.45 (m,
1H), 4.01 (m, 2H), 3.90–3.86 (m, 3H), 3.82 (s, 3H), 3.07
(m, 1H), 3.00–2.88 (m, 2H), 2.77 (s, 3H), 2.28–2.18 (m,
1H), 2.13–1.95 (m, 1H), 1.92–1.83 (m, 2H), 1.57 (m, 2H),
1.43 (s, 9H), 0.89 (s, 9H), 0.13 (s, 3H), 0.01 (s, 3H); 13C
Published by NRC Research Press

Duchek et al.
721
Data for 27
tert-Butyl 2-((5aS,9aS)-1-((1,3-dioxolan-2-yl)methyl)-4-
20
methoxy-6-oxo-5a,6,9,9a-tetrahydrodibenzo[b,d]furan-9a-yl)
Rf (hexanes/AcOEt, 1:2) 0.58; ½aꢀD = +11.7 (c 1.00,
CHCl3); IR (CHCl3): n 3596 (w), 3024 (w), 3010 (m), 2979
(m), 2935 (m), 2895 (m), 2840 (w), 1729 (w), 1683 (s), 1626
(w), 1585 (w), 1507 (s), 1482 (m), 1463 (m), 1453 (m), 1436
(m), 1401 (m), 1367 (m), 1344 (w), 1320 (w), 1282 (m),
1167 (s), 1154 (s), 1097 (m), 1047 (m), 1020 (m), 987 (m)
ethyl(methyl)carbamate (29)
MeO
O
O
1
cm–1; H NMR (CDCl3, 600 MHz, 2 rotamers): d 6.85 (d,
O
J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.94 (br. s, 1H),
5.89 (br. s, 1H), 5.07 (br. s, 1H), 4.36 (br. d, J = 6.4 Hz,
1H), 4.30–4.25 (m, 1H), 4.02–3.95 (m, 2H), 3.90–3.80 (m,
2H), 3.85 (s, 3H), 3.24 (ddd, J = 13.9, 12.3, 4.0 Hz, 1H),
2.98 (dd, J = 14.4, 4.3 Hz, 1H), 2.96–2.90 (m, 1H), 2.84–
2.60 (m, 3H), 2.46 (d, J = 15.1 Hz, 1H), 2.15–2.00 (m, 1H),
1.92–1.77 (m, 1H), 1.41 (s, 3H); 13C NMR (CDCl3,
150 MHz, 2 rotamers): d 155.56, 146.94, 143.37, 131,75,
124.85, 130.52, 127.49, 123.41, 111.62, 104.76, 92.96,
79.65, 70.39, 65.09, 65.01, 55.93, 48.60, 45.48, 40.08,
35.64, 35.48, 34.43, 28.58; LRMS-FAB (m/z): [M+H]+ 462
(7), 344 (38), 285 (17), 241 (9), 159 (7), 103 (36), 73 (100),
57 (73); HRMS-FAB (m/z): [M+H]+ calcd. for C25H36NO7:
462.2492, found: 462.2428.
NMeBoc
O
29
A solution of alcohol 27 (229 mg, 0.496 mmol) in DMF
(10 mL) was cooled to 0 °C and treated with IBX (139 mg,
0.496 mmol). The reaction mixture was stirred for 16 h at
25 °C, diluted with H2O (4 mL), and the layers were sepa-
rated. The aqueous layer was extracted with CHCl3 (3 ×
8 mL). The combined organic layers were washed with brine,
dried (Na2SO4), filtered, and evaporated. Flash column chro-
matography (hexanes/AcOEt, 3:1 → 1.5:1) afforded 27
(12 mg, 5%) as a light yellow foam and 29 (159 mg, 70%)
as a light yellow oil. Rf (hexanes/AcOEt, 1:2) 0.32;
tert-Butyl 2-((5aS,6S,9aR)-1-((1,3-dioxolan-2-yl)methyl)-6-
hydroxy-4-methoxy-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-
9a-yl)ethyl(methyl)carbamate (28)
20
½aꢀD = +91.3° (c 1.415, CHCl3); IR (film): n 2979 (w),
1685 (s), 1625 (w), 1507 (m), 1393 (w), 1366 (w), 1284
(w), 1148 (m), 1044 (w) cm–1; H NMR (CDCl3, 300 MHz):
1
d 6.92 (m, 1H), 6.82 (d, J = 8.4, 1H), 6.73 (d, J = 8.4, 1H),
6.20 (d, J = 9.6, 1H), 5.05 (t, J = 4.5, 1H), 4.66 (br s, 1H),
3.98–3.88 (m, 2H), 3.87–3.79 (m, 6H), 3.34–3.24 (m, 1H),
3.17–3.03 (m, 1H), 3.03–2.94 (m, 2H), 2.88–2.82 (m, 1H),
2.77 (s, 4H), 2.15–2.09 (m, 2H), 1.42 (s, 9H); 13C NMR
(CDCl3, 150 MHz): d 155.36, 148.63, 147.28, 143.69,
128.96, 124.57, 124.04, 112.52, 104.55, 86.31, 79.80, 65.03,
64.97, 60.39, 56.05, 49.62, 45.23, 38.45, 35.77, 34.27, 28.45,
21.05, 14.20; LRMS-EI (m/z): M+ 386(2), 359(12), 301(21),
257(14), 216(5), 190(4), 149(4), 103(7), 84(20), 73(100), 57
(33), 43(82); HRMS-EI (m/z): M+ calcd. for C25H33NO7:
459.2257, found 459.2260.
MeO
O
O
O
NMeBoc
O
28
A solution of 26 (499 mg, 1.081 mmol) in AcOEt (20 mL)
was treated with IBX (457 mg, 1.632 mmol), the resulting
suspension was stirred for 6 h at 80 °C, and cooled to 0 °C.
Filtration through Celite (washing with cold AcOEt) afforded
crude 28 (601 mg), which was used in the next step without
further purification. Rf (hexanes/AcOEt, 1:1) 0.35; IR
(CHCl3): n 3025 (w), 3010 (m), 2979 (m), 2934 (m), 2894
(w), 2840 (w), 1736 (m), 1683 (s), 1627 (w), 1583 (w),
1508 (m), 1481 (m), 1462 (m), 1454 (m), 1428 (m), 1399
(m), 1367 (m), 1319 (w), 1283 (s), 1168 (s), 1154 (s), 1092
(w), 1078 (w), 1042 (m), 1017 (m), 984 (w), 944 (w), 909
(w) cm–1; 1H NMR (CDCl3, 300 MHz): d 6.84 (d, J =
8.3 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.03 (br. s, 1H), 5.81
(dt, J = 9.8, 3.8 Hz, 1H), 5.03 (br. t, J ≈ 4.5 Hz, 1H), 4.99
(br. s, 0.33H), 4.75 (br. s, 0.66H), 4.03–3.94 (m, 2H), 3.94–
3.80 (m, 2H), 3.87 (s, 3H), 3.30–2.87 (m, 6H), 2.81 (s, 3H),
2.23–2.02 (m, 2H), 1.44 (s, 9H); 13C NMR (CDCl3,
150 MHz, 2 rotamers): d 146.90, 143.96, 129.75, 129.40,
124.56, 124.16, 124.16, 123.64, 112.49, 104.57, 87.81,
87.47, 79.93, 65.08, 56.24, 45.34, 44.83, 37.64, 37.20,
36.43, 34.40, 34.44, 28.58; LRMS-FAB (m/z): M+ 459 (1),
85 (67), 83 (100), 73 (81), 57 (27), 47 (19), 44 (22), 41
(18); HRMS-EI (m/z): M+ calcd. for C25H33NO7: 459.2257,
found 459.2252.
(4S, 6aS, 11bR)-11-(1,3-Dioxolan-2-ylmethyl)-8-methoxy-3-
methyl-2,3,4,5-tetra-hydro-1H-4,11b-methano[1]benzofuro
[3,2-d]azocin-6-one (30)
MeO
O
O
O
NMe
O
30
A solution of crude 28 (theoretical content 1.081 mmol) in
CH2Cl2 (8 mL) was treated with TFA (2 mL), the mixture
was stirred for 1 h, and poured into saturated aqueous
Na2CO3 solution (30 mL) containing solid Na2CO3 (6 g).
The biphasic mixture was stirred for 10 min (effervescence),
diluted with CH2Cl2 (30 mL), and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (3 × 30 mL).
Published by NRC Research Press

722
Can. J. Chem. Vol. 89, 2011
The combined organic layers were washed with brine
(40 mL), dried (Na2SO4), and evaporated. Flash column
chromatography (AcOEt/MeOH, 6:1) afforded 30 (217 mg,
56% from 26) as a brown foam. Rf (CHCl3/MeOH/aqueous
NH3, 92:8:1) 0.52; IR (CHCl3): n 3021 (m), 3011 (m), 2959
(m), 2935 (m), 2893 (m), 2794 (w), 1727 (s), 1628 (w), 1584
(w), 1508 (s), 1475 (w), 1462 (w), 1452 (m), 1452 (m), 1437
(m), 1401 (m), 1377 (w), 1359 (w), 1340 (w), 1283 (s), 1267
(m), 1167 (m), 1142 (s), 1115 (s), 1017 (s), 990 (m), 951
2.12 (m, 2H), 2.02–2.00 (m, 1H); 13C NMR (CDCl3,
150 MHz): d 145.87, 143.71, 133.12, 129.68, 125.15,
124.54, 123.50, 111.33, 104.53, 89.46, 66.77, 64.94, 64.92,
55.82, 47.70, 41.46, 39.19, 36.82, 36.24, 35.87, 28.74;
LRMS-FAB (m/z): [M + H]+ 362 (100), 73 (45), 59 (32), 45
(12), 44 (40); HRMS-EI (m/z): M+ calcd. for C20H27NO5:
361.1889, found 361.1891. Anal. calcd. for C20H27NO5: C,
66.46; H, 7.53; found C, 66.17; H, 7.56.
Data for 32
1
(w), 944 (w), 924 (w) cm–1; H NMR (CDCl3, 300 MHz): d
Ocre solid; Rf (CH2Cl2/MeOH/aqueous NH3, 100:10:1)
0.57; IR (CHCl3): n 3593 (w), 3027 (w), 3008 (m), 2958
(m), 2932 (m), 2854 (w), 2801 (w), 1723 (w), 1690 (w),
1666 (w), 1627 (s), 1572 (w), 1503 (s), 1464 (m), 1438 (m),
1427 (m), 1415 (m), 1380 (m), 1339 (w), 1285 (s), 1263 (s),
1160 (m), 1103 (s), 1087 (s), 1074 (m), 1055 (s), 1020 (m),
1005 (m), 976 (w), 968 (w), 955 (w), 908 (w) cm–1. 1H NMR
(CDCl3, 300 MHz): d 6.66 (d, J = 8.5 Hz, 1H), 6.58 (d, J =
8.5 Hz, 1H), 6.53 (dd, J = 10.2, 3.0 Hz, 1H), 5.75 (d, J =
9.4 Hz, 1H), 5.64 (ddd, J ≈ 10.2, 6.4, 1.9 Hz, 1H), 4.88 (d,
J = 9.4 Hz, 1H), 4.30 (d, J = 9.0 Hz, 1H), 3.85 (s, 3H), 3.82–
3.69 (m, 1H), 3.61 (ddd, J = 15.1, 12.8, 3.4 Hz, 1H), 2.87 (s,
3H), 2.87 (s, 3H), 2.82–2.67 (m, 1H), 2.36 (dt, J = 16.6,
6.0 Hz, 1H), 2.10 (ddd, J ≈ 10.9, 2.3 Hz, 1H), 1.86 (dt, J =
13.0, 4.3 Hz, 1H), 1.51 (dt, J ≈ 13.6, 2.6 Hz, 1H); 13C NMR
(CDCl3, 150 MHz): d 145.30, 142.94, 137.41, 129.80,
129.04, 127.48, 122.83, 121.36, 111.45, 94.96, 93.82, 68.66,
55.97, 52.88, 48.47, 42.19, 30.92, 29.39; LRMS-FAB (m/z):
[M + H]+ 300 (23), M+ 299 (54), [M - OMe]+ 268 (12), 136
(23), 91 (20), 73 (100), 69 (26), 57 (57), 55 (42), 44 (30), 43
(43), 41 (37); HRMS-FAB (m/z): M+ calcd. for C18H21NO3:
299.1521, found 299.1523.
6.82 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 5.02 (t,
J = 4.8 Hz, 1H), 4.72 (s, 1H), 4.00–3.90 (m, 2H), 3.90–3.79
(m, 2H), 3.83 (s, 3H); 3.51 (m, 1H), 3.01 (dd, J = 14.5,
4.7 Hz, 1H), 2.97 (dd, J = 14.5, 5.1 Hz, 1H), 2.96–2.85 (m,
1H), 2.71–2.55 (m, 2H), 2.50–2.30 (m, 2H), 2.34 (s, 3H),
1.85 (br. d, J = 12.9 Hz, 1H), 1.70 (dt, J = 13.2, 2.8 Hz,
1H); 13C NMR (CDCl3, 75 MHz): d 205.76, 147.02, 143.69,
131.30, 124.72, 124.13, 111.98, 104.81, 89.16, 65.09, 55.98,
49.39, 46.92, 42.96, 36.28, 35.67, 34.25; LRMS-EI (m/z):
290 (18), 288 (18), 217 (21), 215 (22), 74 (11), 73 (100), 45
(41); HR MS-EI (m/z): M+ calcd. for C20H25NO5: 359.1733,
found 359.1740. Anal. calcd. for C20H25NO5: C, 66.83; H,
7.01; found C, 66.83; H, 7.02.
(4S,4aS,9bR)-9-((1,3-Dioxolan-2-yl)methyl)-6-methoxy-9b-
(2-(methylamino)ethyl)-3,4,4a,9b-tetrahydrodibenzo[b,d]
furan-4-ol (31) and (4aS,5S,8aR,E)-3-methoxy-11-methyl-
4a,5,6,9,10,11-hexahydrobenzo[2,3]benzo-furo[3,4-de]
azocin-5-ol (32)
MeO
MeO
O
O
(E)- and (Z)-tert-Butyl 2-((5aS,6S,9aR)-6-hydroxy-4-
methoxy-1-(2-methoxyvinyl)-5a,6,7,9a-tetrahydrodibenzo[b,
d]furan-9a-yl)ethyl(methyl)carbamate (33)
O
O
+
NMe
NHMe
HO
HO
MeO
31
32
OMe
A solution of carbamate 26 (514 mg, 1.13 mmol) in CH2Cl2
(1 mL) was cooled to 0 °C and treated with TFA (0.25 mL)
over 10 min. The mixture was stirred for 15 min, concentrated,
diluted with saturated aqueous Na2CO3 solution (3 mL), and
extracted with CH2Cl2 (3 × 5 mL). The combined organic
layers were washed with brine (5 mL), dried (MgSO4), and
evaporated. Flash column chromatography (CH2Cl2/MeOH/
aqueous NH3, 100:10:1) afforded secondary amine 31
(202 mg, 0.559 mmol, 49%) and enamine 32 (34 mg, 10%).
O
NMeBoc
HO
33
TBS-protected derivative of the enol ether 33 was prepared
from aldehyde 5 by a Wittig reaction with (methoxymethyl)
triphenyl-phosphonium chloride as previously described.35
The TBS ether (384 mg, 0.704 mmol) was dissolved in THF
(6 mL) at 0 °C, and then TBAF (1.0 mol L–1 in THF,
775 µL, 0.775 mmol) was added. The reaction mixture was
stirred at 25 °C for 3 h. A second portion of TBAF (352 µL,
0.352 mmol) was added at 25 °C and the reaction was stirred
for 2 h, diluted with H2O (10 mL) and extracted with CH2Cl2
(3 × 15 mL). The combined organic layers were washed with
brine and dried (Na2SO4). Flash column chromatography
(AcOEt/hexanes, 1:9 → 1:4 → 1:1) afforded 33 (mixture of
E and Z isomers, 225 mg, 74%) as an oil. Rf (hexanes/
AcOEt, 1:1) 0.2; IR (film): n 3426 (m), 2933 (s), 1682 (s),
Data for 31
Colorless oil; Rf (CH2Cl2/MeOH/aqueous NH3, 100:10:1)
20
0.33; ½aꢀD = +22.8 (c 0.875, CHCl3); IR (CHCl3): n 3588
(w), 3027 (w), 2936 (m), 1624 (m), 1582 (m), 1506 (s), 1438
(m), 1280 (s), 1131 (s), 1099 (s), 1043 (s), 975 (s) cm–1;
1H NMR (CDCl3, 600 MHz): d 6.80 (d, J = 8.4 Hz, 1H),
6.72 (d, J = 8.4 Hz, 1H), 6.00 (d, J = 9.6 Hz, 1H), 5.04 (dd,
J = 5.4, 4.2 Hz, 1H), 4.65 (d, J = 6.0 Hz, 1H), 4.04–4.00 (m,
3H), 3.88–3.85 (m, 2H), 3.03 (dd, J = 14.4, 5.4 Hz, 1H),
2.92 (dd, J = 14.4, 5.4 Hz, 1H), 2.78–2.71 (m, 1H), 2.60–
2.54 (m, 1H), 2.38 (s, 1H), 2.31 (d, J = 1.8 Hz, 1H), 2.15–
Published by NRC Research Press

Duchek et al.
723
1572 (m), 1504 (s), 1483 (s), 1423 (s), 1399 (s), 1366 (s),
1282 (s), 1215 (s), 1156 (s), 1098 (s), 1046 (s), 1012 (s),
[(4S,6aS,11bR)-8-Methoxy-3-methyl-6-oxo-2,3,4,5,6,6a-
hexahydro-1H-4,11b-methano[1]benzofuro[3,2-d]azocin-11-
1
882 (m) cm–1. H NMR (CDCl3, 300 MHz, mixture of 2
yl]acetaldehyde (39)
diastereoisomers): d 6.79–6.65 (m, 3H), 6.20–6.05 (m, 1H),
5.85–5.70 (m, 1H), 4.70–4.25 (m, 1H), 4.00–3.80 (m, 5H),
3.76 (d, J = 3.6 Hz, 1H), 3.71 (s, 3H), 3.60–3.10 (m, 2H),
3.00–2.50 (m, 7H), 2.50–2.30 (m, 2H), 2.20–1.70 (m, 6H),
1.45 (s, 12H), 1.01–0.80 (m, 2H); 13C NMR (CDCl3,
75 MHz, mixture of 2 diastereoisomers): d 155.51, 149.27,
147.60, 145.70, 145.52, 143.73, 143.43, 143.09, 130.10,
129.18, 127.59, 125.36, 124.69, 124.58, 124.42, 123.05,
119.26, 111.74, 111.68, 111.28, 111.22, 101.53, 101.31,
96.13, 90.30, 89.64, 79.48, 78.07, 77.25, 77.04, 68.21,
67.81, 60.65, 60.61, 57.00, 56.09, 55.96, 55.89, 55.86,
53.45, 51.39, 51.33, 48.42, 45.21, 44.76, 37.14, 36.64,
36.10, 34.30, 31.95, 29.75, 29.38, 28.97, 28.46, 24.70,
22.72, 14.15, 13.74, 1.04. LRMS-EI (m/z): M+ 142 (25), 84
(100), 71 (28), 57 (43), 43 (88); HRMS-EI (m/z): M+ calcd.
for C24H33NO6: 431.2308, found 431.2308.
MeO
CHO
O
NMe
O
39
A mixture of 30 (231 mg, 0.643) and oxalic acid (159 mg,
1.766 mmol) in H2O (6 mL) was stirred at 40 °C for 13 h,
cooled to 25 °C, poured into saturated aqueous NaHCO3 solu-
tion (15 mL), and extracted with CHCl3 (3 × 15 mL). The
combined organic layers were washed with brine (15 mL),
dried (MgSO4), and evaporated to get crude aldehyde 39
(227 mg) that was used without further purification. A sample
was purified by flash column chromatography (CHCl3/MeOH/
aqueous NH3, 92:8:1). Colorless oil; Rf (CHCl3/MeOH/aque-
ous NH3, 92:8:1) 0.52; 1H NMR (CDCl3, 600 MHz, crude): d
9.70 (br t, J = 1.9 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 6.66 (d,
J = 8.3 Hz, 1H), 4.76 (s, 1H), 3.86 (s, 3H), 3.78 (dd, J = 17.0,
1.9 Hz, 1H), 3.72 (dd, J = 17.0, 1.9 Hz, 1H), 3.53–3.48 (m,
1H), 2.96–2.91 (m, 1H); 2.68 (d, J = 17.4 Hz, 1H), 2.50–2.30
(m, 3H), 2.35 (s, 3H), 2.19 (br d, J = 12.8 Hz, 1H), 1.89–1.84
(m, 1H), 1.71 (dt, J ≈ 12.8, 2.3 Hz, 1H); LRMS-EI (m/z): M+
315 (3), [M-OH]+ 298 (21), [M-H2O]+ 297 (100), 282 (11),
229 (18), 214 (20), 188 (10), 43 (11), 42 (14); HRMS-EI (m/z):
M+ calcd. for C18H21NO4: 315.1471, found 315.1469.
(4aS,5S,8aR)-3-Methoxy-11-methyl-4a,5,6,9,10,11,12,13-
octahydrobenzo[2,3]benzofuro[3,4-de]azocin-5-ol (34)
MeO
O
NMe
HO
34
(4S,6aS,11bR)-8-Methoxy-3-methyl-6-oxo-2,3,4,5,6,6a-
hexahydro-1H-4,11b-methano[1]benzofuro[3,2-d]azocine-
11-carbaldehyde (40)
Enol ether 33 (146 mg, 0.34 mmol) was dissolved in a 4/1
mixture of CH2Cl2 and TFA (0.5 mL) at 0 °C. The reaction
mixture was warmed to 25 °C and stirred overnight before
being treated with cold saturated aqueous NaHCO3 solution
(2 mL) and extracted with CHCl3 (3 × 4 mL). The combined
organic layers were dried (Na2SO4) and evaporated. The re-
sulting enamine 32 was dissolved in dry MeOH (0.3 mL)
and treated with NaBH3CN (7 mg, 0.11 mmol) and AcOH
(19 µL, 0.34 mmol) at 0 °C. The reaction mixture was
warmed to 25 °C, stirred overnight and treated with cold sa-
turated aqueous NaHCO3 solution (2 mL). Methanol was
evaporated and the aqueous residue was extracted with
CHCl3 (3 × 3 mL) and dried (NaSO4). Flash column chroma-
tography (CH2Cl2/AcOEt, 4:1) afforded amine 34 (42 mg,
MeO
CHO
O
NMe
O
40
A solution of crude aldehyde 39 (4 mg) in MeCN
(0.2 mL) and H2O (0.2 mL) was treated with concentrated
HCl until the pH reached 1, the mixture was stirred at 40 °C
for 22 h, cooled to 25 °C, poured into saturated aqueous
NaHCO3 solution (5 mL), and extracted with CHCl3 (4 ×
5 mL). The combined organic layers were washed with brine
(5 mL), dried (MgSO4), and evaporated to furnish crude 40
(4 mg). A pure sample was obtained by flash column chro-
matography (AcOEt/MeOH, 7:1 → 5:1). Rf (AcOEt/MeOH,
5:1) 0.33; IR (CHCl3): n 3027 (w), 3012 (w), 2963 (m),
2964 (m), 2845 (w), 2789 (w), 2745 (w), 1726 (s), 1691 (s),
1615 (s), 1574 (m), 1507 (m), 1447 (m), 1438 (m), 1410 (w),
1377 (w), 1340 (w), 1293 (s), 1270 (m), 1260 (m), 1169 (m),
1144 (m), 1117 (m), 1102 (m), 1066 (w), 1054 (w), 1017
(m), 981 (w), 953 (w), 927 (w) cm–1; 1H NMR (CDCl3,
1
41%) as a colorless oil. Rf (CH2Cl2/AcOEt, 96:4) 0.49; H
NMR (CDCl3, 600 MHz): d 6.71 (d, J = 8.1 Hz, 1H), 6.59
(d, J = 8.1 Hz, 1H), 5.74–5.68 (m, 1H), 4.32 (m, 1H), 4.00–
4.93 (m, 1H), 3.87 (s, 3H), 3.13–3.05 (m, 1H), 2.85–2.76 (m,
1H), 2.74–2.65 (m, 1H), 2.59–2.52 (m, 2H), 2.46–2.38 (m,
2H), 2.31 (s, 3H), 2.17–2.11 (m, 1H), 2.01–1.96 (m, 1H),
1.83–1.75 (m, 1H), 1.32–1.25 (m, 2H); 13C NMR (CDCl3,
150 MHz): d 145.54, 143.79, 132.20, 129.65, 122.74,
122.09, 111.18, 96.13, 67.48, 60.51, 55.79, 52.60, 47.51,
42.29, 33.06, 29.22; LRMS-EI (m/z): M+ 42 (27), 43 (50),
44 (27), 57 (38), 58 (56), 70 (100), 71 (27), 83 (22), 149
(49), 179 (62), 301 (41); HRMS-EI (m/z): M+ calcd. for
C18H23NO3: 301.1678, found 301.1678.
Published by NRC Research Press

724
Can. J. Chem. Vol. 89, 2011
300 MHz): d 9.91 (s, 1H), 7.43 (d, J = 8.3 Hz, 1H), 6.91 (d,
J = 8.3 Hz, 1H), 4.93 (s, 1H), 3.95 (s, 3H), 3.51–3.46 (m,
1H), 3.05 (td, J = 12.5, 5.3 Hz, 1H), 2.95 (br dd, J ≈ 12.8,
4.2 Hz 1H), 2.85 (br d, J ≈12.1 Hz, 1H), 2.67 (br d, J ≈
17.4 Hz, 1H); 2.53 (br t, J ≈ 11.3 Hz, 1H); 2.42 (dd, J =
17.0, 8.7 Hz, 1H), 2.37 (s, 3H), 1.70 (br d, J ≈ 12.8 Hz,
1H), 1.54 (br dt, J ≈ 12.8, 2.6 Hz, 1H); 13C NMR (CDCl3,
150 MHz): d 206.07, 190.54, 150.03, 148.00, 132.57,
126.45, 131.08, 110.88, 90.22, 56.17, 55.76, 50.45, 46.38,
43.10, 34.34, 34.18; LRMS-EI (m/z): M+ 301 (23), 273 (23),
272 (20), 258 (34), 231 (29), 230 (72), 215 (40), 167 (30),
150 (26), 149 (100), 112 (21), 83 (28), 71 (36), 70 (84), 69
(20), 57 (52), 55 (26), 44 (41), 43 (49), 41 (31); HRMS-EI
(m/z): M+ calcd. for C17H19NO4: 301.1314, found 301.1310.
101 (27), 100 (16), 86 (11), 85 (16), 83 (23), 80 (100), 73
(35), 44 (14), 43 (50); HRMS-EI (m/z): M+ calcd. for
C22H29NO6: 403.1995, found 403.2000.
N-(2-((5aS,9aR)-1-((1,3-Dioxolan-2-yl)methyl)-4-methoxy-6-
oxo-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-9a-yl)ethyl)-N-
methylacetamide (53)
MeO
O
O
O
NMeAc
O
N-(2-((5aS,6S,9aR)-1-((1,3-Dioxolan-2-yl)methyl)-6-
hydroxy-4-methoxy-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-
9a-yl)ethyl)-N-methylacetamide (52)
53
A suspension of 52 (30 mg, 0.074 mmol) and IBX
(31 mg, 0.11 mmol) in AcOEt (2 mL) was stirred at 80 °C
for 4 h, cooled to 25 °C, filtered through Celite (washing
with AcOEt), and evaporated to get crude ketone 53 (15 mg)
which was used in the next step without further purification.
Rf (AcOEt/MeOH, 10:1) 0.30.
MeO
O
O
O
N-(2-((2S,2a1R,5aS)-2-Hydroxy-7-methoxy-5-oxo-
1,2,2a,2a1,5,5a-hexahydrophenanthro[4,5-bcd]furan-2a1-
yl)ethyl)-N-methylacetamide (54)
NMeAc
HO
52
MeO
A solution of 31 (21 mg, 0.058 mmol) in CH2Cl2 (1.5 mL)
and pyridine (0.1 mL, 1.239 mmol) was treated with AcCl
(25 µL, 0.352 mmol) at 4 °C. The suspension was stirred
2.5 h at 4 °C and 1 h at 25 °C, diluted with CH2Cl2
(10 mL) and washed with 1 mol L–1 HCl (6 mL), saturated
aqueous NaHCO3 solution (6 mL), and brine (6 mL), dried
(MgSO4), and evaporated. The crude diacetate was pure,
NMeAc
O
OH
H
O
1
54
based on H NMR spectrum, and was used directly in the
next step. A solution of crude diacetate in 0.12 mol L–1 solu-
tion of MeONa in MeOH was stirred for 4 h and treated with
DOWEX 50WX8–100(H+ form). Filtration, evaporation, and
liquid chromatography (AcOEt/MeOH, 5:1) afforded 52
(20 mg, 87%) as a colorless oil. Rf (CH2Cl2/MeOH/aqueous,
A solution of crude ketone 53 (15 mg, 0.037 mmol) in tol-
uene (1 mL) was treated with 50% aqueous TFA (0.3 mL), the
mixture was stirred at 50 °C for 4 h, concentrated, and the res-
idue extracted with CH2Cl2 (3 × 15 mL). The combined or-
ganic layers were washed with saturated aqueous NaHCO3
solution (1 × 2 mL), brine (1 × 2 mL), dried (MgSO4), fil-
tered, and evaporated. Flash column chromatography
(CH2Cl2/MeOH/aqueous NH3, 92:8:1) afforded a mixture of
alcohols 54 (3 mg, 22% from 52). Rf (AcOEt/MeOH, 5:1)
0.33; IR (CHCl3): n 3606 (w), 3386 (w), 3021 (w), 3006 (w),
2934 (w), 1799 (w), 1730 (w), 1686 (m), 1631 (s), 1508 (m),
1453 (m), 1439 (m), 1413 (m), 1363 (w), 1283 (m), 1265 (m),
1159 (w), 1092 (w), 1035 (m), 908 (m) cm–1; 1H NMR
(CDCl3, 600 MHz, 1/1 mixture of 2 diastereoisomers): d 7.13
(dd, J = 10.8, 3.0 Hz, 0.5H), 7.07 (dd, J = 10.2, 4.2 Hz,
0.5H), 7.01 (dd, J = 10.4, 4.0 Hz, 1H), 6.75–6.60 (m, 1H),
6.19 (dd, J = 10.8, 3.0 Hz, 0.5H), 6.14 (dd, J = 10.2, 1.9 Hz,
0.5H), 6.10 (dd, J = 10.4, 2.1 Hz, 1H), 4.82 (s, 1H), 4.78,
4.76 (2s, 1H), 3.88, 3.85 (2s, 3H), 3.87 (s, 3H), 3.83–3.72
(m, 2H), 3.20–2.75 (m, 12H), 2.10–2.00 (10H); LRMS-EI
(m/z): M+ 357 (3), 304 (13), 303 (17), 257 (22), 251 (10),
240 (14), 239 (23), 227 (19), 211 (10), 115 (10), 101 (67),
100 (61), 87 (10), 86 (81), 84 (61), 75 (25), 73 (68), 58 (30),
57 (19), 56 (13), 55 (13), 51 (11), 49 (26), 47 (31), 45 (18),
20
NH3 100:10:1) 0.51; ½aꢀD +17.5 (c 1.00, CHCl3); IR
(CHCl3): n 3593 (w), 3024 (w), 3010 (m), 2937 (m), 2896
(w), 2841 (w), 1732 (w), 1633 (s), 1584 (w), 1507 (m),
1463 (w), 1439 (m), 1428 (m), 1402 (m), 1379 (w), 1362
(w), 1315 (w), 1280 (m), 1262 (m), 1255 (m), 1167 (w),
1130 (m), 1091 (m), 1049 (m), 1017 (m), 980 (w), 944 (w),
1
909 (w) cm–1; H NMR (CDCl3, 300 MHz, 2 rotamers): d
6.85–6.69 (m, 2H), 6.04 (br s, 0.6H), 6.01 (br s, 0.4H),
5.85–5.72 (m, 1H), 5.08–4.99 (m, 1H), 4.56–4.49 (m, 0.6H),
4.35 (d, J = 8.5 Hz, 0.4H), 4.03–3.79 (m, 1H), 7H), 3.65–
3.59 (m, 0.6H), 3.40–3.26 (m, 1.4H), 3.10–2.78 (m, 6H),
2.47–2.29 (m, 1H), 2.21–1.78 (m, 3H), 2.00 (s, 1.7H), 1.95
(1.3H). 13C NMR (CDCl3, 150 MHz, 2 rotamers): d 170.49,
170.39, 145.76, 145.59, 144.14, 144.06, 132.52, 131.73,
129.19, 128.91, 125.58, 125.18, 124.74, 124.53, 124.17,
123.77, 111.90, 111.72, 104.62, 104.60, 90.75, 90.05, 67.90,
67.86, 65.11, 65.05, 56.02, 55.97, 55.95, 51.74, 51.65, 46.84,
44.10, 38.39, 36.51, 36.48, 36.46, 36.37, 33.41, 21.94,
21.06; LRMS-EI (m/z): M+ 403 (1.1), 122 (18), 102 (18),
Published by NRC Research Press

Duchek et al.
725
44 (100), 43 (68), 42 (24), 41 (13); HRMS-EI (m/z): M+
calcd. for C20H23NO5: 357.1576, found 357.1571.
A suspension of alcohol 55 (64 mg, 0.11 mmol) and IBX
(45 mg, 0.16 mmol) in AcOEt (3 mL) was stirred at 80 °C
for 4 h, cooled to 25 °C, and filtered through Celite (washing
with AcOEt) affording crude 56 (60 mg), which was used
without further purification. Rf (hexanes/AcOEt, 1:1) 0.23;
IR (CHCl3): n 3101 (w), 3032 (w), 2981 (w), 2893 (w),
1738 (m), 1556 (s), 1541 (s), 1508 (m), 1366 (s), 1351 (s),
N-(2-((5aS,6S,9aR)-1-((1,3-Dioxolan-2-yl)methyl)-6-
hydroxy-4-methoxy-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-
9a-yl)ethyl)-N-methyl-2,4-dinitrobenzenesulfonamide (55)
1
1283 (m), 1164 (s), 1131 (m), 1044 (m), 908 (s) cm–1; H
MeO
O
NMR (CDCl3, 600 MHz): d 8.49 (dd, J = 8.6, 1.9 Hz, 1H);
8.44 (d, J = 1.9 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 6.85 (d,
J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.03 (d, J =
9.9 Hz, 1H), 5.87 (ddd, J = 10.0, 3.9, 3.9 Hz, 1H), 5.02
(dd, J = 5.6, 4.1, 1H), 4.81 (s, 1H); 4.00–3.96 (m, 2H),
3.92–3.84 (m, 2H), 3.87 (s, 3H), 3.40–3.35 (m, 1H), 3.09
(ddd, J = 19.31, 3.86, 1.99, 1H), 3.07–3.02 (m, 2H), 2.96–
2.93 (m, 1H), 2.94 (s, 3H), 2.30–2.22 (m, 2H); 13C NMR
(CDCl3, 150 MHz): d 203.68, 149.70, 148.09, 146.74,
143.84, 137.65, 132.65, 129.82, 128.73, 126.17, 124.71,
124.53, 124.12, 119.77, 112.67, 104.37, 87.68, 64.99, 64.97,
57.38, 56.17, 46.37, 37.30, 36.86, 36.14, 35.05; LRMS-EI
(m/z): M+ 591 (12), 147 (16), 136 (24), 91 (14), 89 (14), 77
(13), 73 (100); HRMS-EI (m/z): M+ calcd. for
C26H29N3O11S: 591.1507, found 591.1522.
O
O
NMeDNS
HO
55
A solution of secondary amine 31 (61 mg, 0.169 mmol) in
CH2Cl2 (1.5 mL) was treated with iPr2NEt (35 µL,
0.203 mmol) and dinitrobezenesulfonyl chloride (49.6 mg,
0.186 mmol) and stirred for 20 min. The reaction mixture
treated with water (1 mL) and extracted with CH2Cl2 (3 ×
10 mL). The combined organic layers were washed with sa-
turated aqueous Na2CO3 solution and brine, dried (MgSO4),
filtered, and evaporated. Flash column chromatography (hex-
anes/AcOEt, 1:1) afforded sulfonamide 55 (51 mg, 51%) as a
(2a2R,6aS,9aS)-5-Methoxy-2a2-(2-(N-methyl-2,4-
dinitrophenylsulfonamido)ethyl)-7-oxo-1,2,2a2,6a,7,9a-
hexahydrophenanthro[4,5-bcd]furan-1-yl methanesulfonate
(57)
20
yellow oil. Rf (hexanes/AcOEt, 1:1) 0.35; ½aꢀ = +8.34° (c
1.0, CHCl3); IR (CHCl3): n 3592 (w), 3029 D(w), 2983 (w),
2893 (w), 1731 (w), 1556 (s), 1541 (s), 1366 (s), 1351 (s),
1279 (m), 1165 (s), 1131 (m), 1049 (s), 946 (m) cm–1; H
1
NMR (CDCl3, 600 MHz): d 8.47 (dd, J = 6.6., 2.2 Hz, 1H),
8.45 (d, J = 2.4 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 6.86 (d,
J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.04 (dd, J =
10.1, 1.7 Hz, 1H), 5.86–5.83 (m, 1H), 5.05 (dd, J = 6.3,
3.5, 1H), 4.39 (d, J = 8.4, 1H), 4.03 (ddd, J = 15.5, 10.1,
7.4, 2H), 3.92–3.85 (m, 3H), 3.87 (s, 3H), 3.41–3.35 (m,
1H), 3.01 (dd, J = 14.5, 3.5, 1H), 2.96–2.91 (m, 1H), 2.93
(s, 3H), 2.89 (dd, J = 14.5, 6.4, 1H), 2.40 (dt, J = 17.4, 5.4,
1H), 2.16–2.11 (m, 2H), 1.99 (td, J = 12.1, 4.7, 1H); 13C
NMR (CDCl3, 75 MHz): d 149.60, 148.05, 145.46, 144.07,
137.93, 132.58, 131.61, 128.47, 126.03, 125.72, 124.60,
124.03, 119.72, 111.80, 104.39, 90.24, 67.77, 64.99, 64.94,
55.87, 51.50, 46.38, 37.64, 36.33, 29.31; LRMS-EI (m/z): M+
591 (12), 147 (16), 136 (24), 91 (14), 89 (14), 77 (13), 73
(100); HRMS-EI (m/z): M+ cald. for C26H29N3O11S:
591.1507, found 591.1522.
MeO
NMeDNS
O
OMs
H
O
57
A solution of crude 56 (15 mg, 0.025 mmol) in toluene
(1 mL) was treated with 50% aqueous TFA (0.14 mL) and
the biphasic mixture was stirred at 50 °C for 2 h. The vola-
tiles were removed in vacuo, the residue was dissolved in
CH2Cl2 (1 mL) and treated with iPr2NEt (5 µL, 0.038 mmol)
and MsCl (2.4 µL, 0.031 mmol) at 0 °C. The mixture was
stirred for 30 min at 0 °C, treated with saturated aqueous
NH4Cl solution (1 mL) and extracted with CH2Cl (3 ×
5 mL). The combined organic layers were washed with brine,
dried (Na2SO4), filtered, and evaporated. Flash column chro-
matography (CHCl3/EtOAc, 3:1) afforded 57 (1 mg, 6% from
N-(2-((5aS,9aR)-1-((1,3-Dioxolan-2-yl)methyl)-4-methoxy-6-
oxo-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-9a-yl)ethyl)-N-
methyl-2,4-dinitrobenzenesulfonamide (56)
MeO
O
1
55). The H NMR spectrum was identical to one reported in
the literature.36
O
Rf (hexanes/AcOEt, 1:3) 0.51; 1H NMR (CDCl3,
600 MHz): d 8.49–8.44 (m, 2H); 8.08 (d, J = 8.4 Hz, 1H),
6.90 (dd, J = 10.3, 4.0 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H),
6.73 (d, J = 8.6 Hz, 1H), 6.20 (dd, J = 10.6, 2.3 Hz, 1H),
4.86 (s, 1H), 3.88 (s, 3H), 3.51–3.43 (m, 1H), 3.23–3.18 (m,
1H), 3.16 (s, 3H), 3.16 (s, 1H), 3.12–3.09 (m, 1H), 2.94 (s,
3H), 2.89–2.87 (m, 1H), 2.26–2.18 (m, 2H).
O
NMeDNS
O
56
Published by NRC Research Press

726
Can. J. Chem. Vol. 89, 2011
N-(2-((2a1R,5aS)-7-Methoxy-5-oxo-1,2a1,5,5a-
tetrahydrophenanthro[4,5-bcd]furan-2a1-yl)ethyl)-N-
methyl-2,4-dinitrobenzenesulfonamide (58) and N-(2-
((2a1R,5aS)-7-methoxy-5-oxo-2a1,4,5,5a-
tetrahydrophenanthro[4,5-bcd]furan-2a1-yl)ethyl)-N-
methyl-2,4-dinitrobenzenesulfonamide (59)
(s, 1H), 3.91 (s, 3H), 3.48–3.36 (m, overlapped with signals
of 58, 2H), 3.30–3.20 (m, 1H); 2.92 (dd, J = 16.2, 7.2 Hz,
partially overlapped with a signal of MeN of 58, 1H), 2.89
(s, 3H), 2.22–2.07 (m, overlapped with signals of 58, 2H).
N-(2-((5aS,6S,9aR)-1-(2,2-Dimethoxyethyl)-4-methoxy-6-
oxo-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-9a-yl)ethyl)-N-
methyl-2,4-dinitrobenzenesulfonamide (62)
MeO
MeO
MeO
OMe
NMeDNS
NMeDNS
O
O
OMe
O
O
O
NMeDNS
59
58
HO
62
A solution of crude 56 (10 mg, 0.017 mmol) in toluene
(1 mL) was treated with 50% aqueous TFA (0.1 mL), and
the biphasic mixture was stirred at 50 °C for 2 h. The vola-
tiles were removed in vacuo, the residue was dissolved in
CH2Cl2 (1 mL), cooled to 0 °C, treated with iPr2NEt (12 µL,
0.085 mmol) and MsCl (5 µL, 0.077 mmol), and stirred for
30 min. The reaction mixture was treated with saturated
aqueous NH4Cl solution (1 mL) and extracted with CH2Cl2
(3 × 5 mL). The combined organic layers were washed with
brine, dried (Na2SO4), filtered, and evaporated. Flash column
chromatography (CHCl3/AcOEt, 3:1) afforded 58 (3 mg, 33%
from 55) and a mixture of 58/59 ≈ 1:1.5 (2 mg, 22% from
55).
A solution of 55 (42 mg, 0.071 mmol) and pTsOH (6 mg,
0.035 mmol) in MeOH was refluxed for 3 d, cooled to 25 °C,
treated with with saturated aqueous Na2CO3 solution (2 mL),
and extracted with CH2Cl2 (3 × 10 mL). The combined or-
ganic layers were washed with brine, dried (Na2SO4), fil-
tered, and evaporated. Flash column chromatography
(hexanes/AcOEt, 1:3) afforded dimethyl acetal 62 (36 mg,
1
86%) as a yellow oil whose H NMR spectrum was identical
to that of its enantiomer reported in the literature.36
N-(2-((5aS,9aR)-1-(2,2-Dimethoxyethyl)-4-methoxy-6-oxo-
5a,6,7,9a-tetrahydrodibenzo[b,d]furan-9a-yl)ethyl)-N-
methyl-2,4-dinitrobenzenesulfonamide (63)
Data for 58
Rf (CHCl3/AcOEt, 2:1) 0.47; IR (CHCl3): n 3101 (w),
3026 (w), 3012 (w), 2961 (w), 2930 (w), 1784 (w), 1730
(m), 1686 (m), 1641(w), 1604 (w), 1556 (s), 1541 (s), 1506
(m), 1455 (w), 1440 (w), 1367 (s), 1350 (s), 1265 (m), 1235
(m), 1162 (s), 1102 (s), 1046 (m), 1008 (m), 963 (w), 950
MeO
OMe
OMe
O
1
(w), 905 (w) cm–1; H NMR (CDCl3, 600 MHz): d 8.47–
8.43 (m, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.26 (1H overlapped
with a signal of residual CHCl3), 6.75 (d, J = 7.9 Hz, 1H),
6.71 (d, J = 7.9 Hz, 1H), 6.40 (d, J = 7.2 Hz, 1H), 5.98 (d,
J = 10.2 Hz, 1H), 4.99 (s, 1H), 3.87 (s, 3H), 3.59 (d, J =
20.0 Hz, 1H), 3.46–3.38 (m, 2H), 3.14–3.07 (m, 1H), 2.91
(s, 3H), 2.19 (td, J ≈ 12.1, 4.9 Hz, 1H), 2.11 (td, J ≈ 12.1,
3.8 Hz, 1H); 13C NMR (CDCl3, 150 MHz): d 193.43,
149.89, 148.26, 145.34, 143.24, 139.20, 137.70, 131.26,
126.36, 143.96, 133.51, 131.26, 126.22, 120.51, 119.93,
113.95, 125.28, 86.86, 56.84, 47.91, 46.70, 37.67, 35.28,
30.65; LRMS-EI (m/z): M+ 527 (9), 266 (32), 252 (22), 251
(56), 250 (21), 240 (65), 239 (55), 238 (62), 235 (26), 231
(21), 225 (54), 223 (54), 211 (25), 168 (44), 152 (24), 139
(41), 76 (42), 75 (50), 74 (27), 64 (100), 63 (34), 51 (42),
45 (44), 44 (85); HRMS-EI (m/z): M+ calcd. for
C24H21N3O9S: 527.0998, found 527.1018.
NMeDNS
O
63
A suspension of dimethyl acetal 62 (36 mg, 0.061 mmol)
and IBX (25 mg, 0.91 mmol) in AcOEt (2 mL) was stirred at
80 °C for 3 h. The reaction mixture was cooled to 25 °C and
filtered through Celite (washing with AcOEt) affording crude
ketone 63 (33 mg, 91%) as a yellow oil which was used in
the next step without further purification. Rf (hexanes/AcOEt,
20
1:1) 0.35; ½aꢀ = +25.5° (c 1.0, CHCl3); IR (CHCl3): 2982
(w), 2936 (w)D, 1731 (s), 1556 (m), 1541 (m), 1507 (w), 1374
(m), 1351 (m), 1267 (m), 1164 (m), 1046 (s), 908 (s) cm–1;
1H NMR (CDCl3, 300 MHz): d 8.49 (dd, J = 8.6, 2.2 Hz,
1H), 8.44 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H),
6.79 (d, J = 8.6 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 6.03 (br
d, J = 10.0 Hz, 1H), 5.87 (ddd, J = 10.0, 3.9, 3.9 Hz 1H),
4.82 (s, 1H), 4.50 (t, J = 5.3 Hz, 1H), 3.88 (s, 3H), 3.35 (s,
3H), 3.32 (s, 3H), 3.34 (m, 1H), 3.17–3.01 (m, 3H); 2.94 (s,
3H); 2.86–2.83 (m, 1H); 2.27–2.20 (m, 2H); 13C NMR
(CDCl3, 75 MHz): d 203.85, 149.77, 146.81, 143.79,
137.75, 132.77, 129.90, 128.96, 126.29, 125.15, 124.60,
Data for 59
1
Rf (CHCl3/AcOEt, 2:1) 0.53; H NMR (CDCl3, 600 MHz,
mixture of 58/59 ≈ 1:1.3): d 8.50–8.43 (m, overlapped with
signals of 58, 2H), 8.14 (d, J = 9.1 Hz, 1H), 6.74 (d, J =
9.1 Hz, 1H), 6.69 (d, J = 9.1 Hz, 1H), 6.45 (d, J = 9.1 Hz,
1H), 6.17 (d, J = 9.1 Hz, 1H), 5.77 (d, J = 7.2 Hz, 1H), 5.28
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Duchek et al.
727
124.47, 119.90, 112.77, 105.60, 87.72, 57.59, 56.29, 54.43,
53.70, 46.50, 37.43, 36.77, 35.99, 35.14; LRMS-EI (m/z): M+
591 (1), 327 (3), 270 (9), 248 (100), 231 (55), 227 (10), 203
(19), 187 (5), 167 (25), 163 (7) 149 (72), 128 (69), 127 (51),
122 (38.9), 105 (57); HRMS-EI (m/z): M+ calcd. for
C26H29N3O11S: 591.1523, found 591.1531.
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Acknowledgements
The authors are grateful to the following agencies for fi-
nancial support of this work: Noramco, Inc., Natural Sciences
and Engineering Research Council of Canada (NSERC) (Idea
to Innovation and Discovery Grants); Canada Research Chair
Program, Canada Foundation for Innovation (CFI), Research
Corporation, TDC Research, Inc., TDC Research Foundation,
and Brock University. One of us (J.D.) is grateful to the
Swiss National Foundation for a postdoctoral fellowship.
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reproducibly to high yields. The reaction proceeds faster in
boiling m-xylene; Pd(OAc)2 and Cs2(CO)3 can be used instead
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leads to a formation of side products. Starting aldehydes used
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ism, which appears to be unfavorable for the cyclization of 23.
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