Synthesis of enantiopure 10-nornaltrexones in the search for toll-like receptor 4 antagonists and opioid ligands

Article abstract of DOI:10.1021/jo500568s

10-Nornaltrexones (3-(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6- hexahydro-1H-benzofuro[3,2-e]isoquinolin-7(7aH)-one, 1) have been underexploited in the search for better opioid ligands, and their enantiomers have been unexplored. The synthesis of tr

Full text of DOI:10.1021/jo500568s

Article
pubs.acs.org/joc
Synthesis of Enantiopure 10-Nornaltrexones in the Search for Toll-
like Receptor 4 Antagonists and Opioid Ligands
Brandon R. Selfridge,† Jeffrey R. Deschamps,‡ Arthur E. Jacobson,† and Kenner C. Rice*,†
†Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, and the National
Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical
Center Drive, Rockville, Maryland 20850, United States
‡Center for Biomolecular Science and Engineering, Naval Research Laboratory, Washington, D.C. 20375, United States
S
* Supporting Information
ABSTRACT: 10-Nornaltrexones (3-(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1H-benzofuro[3,2-e]-
isoquinolin-7(7aH)-one, 1) have been underexploited in the search for better opioid ligands, and their enantiomers have
been unexplored. The synthesis of trans-isoquinolinone 2 (4-aH, 9-O-trans-9-methoxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-
benzofuro[3,2-e]isoquinolin-7(7aH)-one) was achieved through a nonchromatographic optimized synthesis of the intermediate
pyridinyl compound 12. Optical resolution was carried out on 2, and each of the enantiomers were used in efficient syntheses of
the “unnatural” 4aR,7aS,12bR-(+)-1) and its “natural” enantiomer (−)-1. Addition of a 14-hydroxy (the 4a-hydroxy) group in the
enantiomeric isoquinolinones, (+)- and (−)-2), gave (+)- and (−)-10-nornaltrexones. A structurally unique tetracyclic enamine,
(12bR)-7,9-dimethoxy-3-methyl-1,2,3,7-tetrahydro-7,12b-methanobenzo[2,3]oxocino[5,4-c]pyridine, was found as a byproduct
in the syntheses and offers a different opioid-like skeleton for future study.
chemistry relative to natural (−)-morphine and (−)-naltrex-
one), structurally simpler analogues could theoretically also be
useful in the treatment of opioid dependence (e.g., (+)-nal-
trexone). (−)-Naltrexone has been examined as a treatment
medication7 for opioid dependence and alcohol abuse; its
structurally simpler analogues in the “natural” series might have
analgesic or narcotic antagonist activity.
Our initial targets of this study, the enantiomers of 3-
(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-
1H-benzofuro[3,2-e]isoquinolin-7(7aH)-one (Figure 1, (+)-
and (−)-1), were chosen because of their structural similarity
to the enantiomers of naltrexone (in Figure 1, the C14-OH
numbering system in naltrexone is from opioid nomenclature;
in (+)-1, numbered using IUPAC convention, the C4a position
is comparable to naltrexone’s C14). In 1 (Figure 1), the
benzylic carbon of naltrexone (C-10 in naltrexone) has been
removed, and that, we reasoned, might be advantageous
because of the somewhat increased flexibility offered by the
structural simplification. In addition, we were aware that
methods were available in the literature for the synthesis of an
N-methyl relative of a precursor to the desired isoquinolinone
INTRODUCTION
■
Opiates have long been used as a standard treatment of both
short-term and chronic pain. Their modes of action are known
to occur mainly via the μ, δ, and κ opioid receptors.1 The
(−)-isomer of morphine (Figure 1), the natural plant product
of opium, is a potent μ-receptor agonist and is widely used to
treat acute and chronic pain. Unfortunately, when the natural
(−)-morphine, and other opioids derived from (−)-morphine,
interact with the opioid μ-receptor, and with other receptors,
undesired physiological responses occur, such as respiratory
depression,2 tolerance,3 and hyperalgesia3 associated with
chronic opioid use. One receptor interaction of some opioids
that has recently been recognized is their activation of Toll-like
4 receptors (TLR-4). That interaction elicits an immune
response linked to tolerance and hyperalgesia.4,5 (+)-Naltrex-
one (Figure 1), the unnatural enantiomer which does not
interact with opioid receptors, was proven to act as a functional
TLR-4 antagonist5 and has been shown to reduce the
incubation period for cue-induced heroin seeking when
administered during the withdrawal phase.6
Since (+)-naltrexone does not necessarily contain the ideal
geometric shape for TLR-4 antagonism, we decided to
synthesize simpler and more flexible analogues to see if they
would display TLR-4 antagonism. These unnatural (stereo-
Received: March 10, 2014
Published: April 28, 2014
This article not subject to U.S. Copyright.
Published 2014 by the American Chemical
Society
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Figure 1. “Natural” and synthetic opioids.
Scheme 1. Nonchromatographic, Optimized Synthesis of Pyridine 12
2.8 This racemic 4aH,9-O-trans-9-methoxy-3-methyl-
2,3,4,4a,5,6-hexahydro-1H-benzofuro[3,2-e]isoquinolin-7-
(7aH)-one (( )-2, Figure 1) of Weller et al.8 was prepared in a
13-step sequence from o-vanillin. It lacked our needed
substituent on nitrogen and a 4a-hydroxyl group. It was, also,
racemic, and their methodology was inadequate for our
purposes. Cheng et al.9 modified the route of Weller et al.8
to make an N-cyclopropylmethyl analogue of ( )-2 (Figure 1);
however, their methods also did not meet our requirements.
We needed to obtain a relatively large amount of material so
that we could not only synthesize the enantiomers of 2 but, as
well, create other structures, enabling the exploration of the
structure−activity relationships of ligands that would and would
not interact with the TLR-4 as antagonists. The chromato-
graphic methods that had been used in preparing trans ( )-2
could not easily produce sufficient material for our purposes.
Thus, we devoted our efforts, first, to improve the
methodology leading to 2. We succeeded in obtaining a
nonchromatographic optimized synthesis of an intermediate to
2, ethyl 3-(4-(2-hydroxy-3-methoxyphenyl)pyridin-3-yl)-
propanoate (12, Scheme 1), and we obtained it on a multigram
(ca. 200 g) scale. A route from the pyridinylpropanoate 12 to
4aH,9-O-trans-9-methoxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-
benzofuro[3,2-e]isoquinolin-7(7aH)-one (( )-2) was visual-
ized as shown in Scheme 2. We thought that the trans-
isoquinolinone 2 would prove to be a suitable compound for
optical resolution from which we would eventually obtain the
enantiomers of 1. Introduction of the needed 4a-OH group in
the diene (−)-20 (7,9-dimethoxy-3-methyl-2,3,4,7a-tetrahydro-
1H-benzofuro[3,2-e]isoquinoline) was achieved through the
use of hydrogen peroxide in acidic media (Scheme 5). We now
had the complete skeleton of the 10-nornaltrexone compound
and it only remained to find a way to replace an N-methyl
moiety with the 3-cyclopropylmethyl group in 1, and that was
done with cyanogen bromide, as shown in Scheme 6. After
accomplishing that, we proceeded to shorten the procedure of
Cheng et al.9 for the synthesis of 36 from 12 (Scheme 7). The
racemate 36 was optically resolved, and each of its hitherto-
unknown enantiomers were used to prepare (+)- and (−)-1.
RESULTS AND DISCUSSION
■
Optimization of the Synthesis of the Key intermedi-
ate 12 from o-Vanillin (3). We optimized the synthesis of 2,
ethyl 3-(4-(2-hydroxy-3-methoxyphenyl)pyridin-3-yl)-
propanoate (12), by eliminating chromatography (Scheme 1).
Starting with the commercially available o-vanillin, we prepared
2-(2-(benzyloxy)-3-methoxyphenyl)propan-2-ol (7) in over
70% overall yield. Minor modifications in reagent choice were
made to the literature route8 to obtain high-yield trans-
formations (Scheme 1). The low yield in the literature route8 in
going from alcohol 7 to 4-(2-(benzyloxy)-3-methoxyphenyl)-
nicotinaldehyde (10, Scheme 1) had to be eliminated to allow
significant mass throughput. Reaction of styrene with Vilsmeier
reagent followed by treatment with hot aqueous NH4Cl was
shown by Jutz10 to give 4-phenylnicotinaldehyde. Weller et al.8
applied this reaction to 8, presumably leading to intermediate 9,
which was cyclized to pyridine 10 upon heating in acidic
workup. This reaction proceeded in a relatively poor yield of
41% (34% from 7), possibly due to loss during chromato-
graphic purification and significant decomposition during
cyclization under their hot (100 °C), strongly acidic conditions.
We determined that 10 could be efficiently accessed directly
from alcohol 7 under modified Vilsmeier conditions. We
utilized chloroform for formation of the Vilsmeier reagent, in
situ,11 for the dehydration of benzyl alcohol 7 and its
conversion to Vilsmeier product 9.
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Scheme 2. Synthesis of 4aH,9-O-trans-( )-2
Scheme 3. Optical Resolution of 4aH,9-O-trans-( )-2
The use of refluxing chloroform instead of 1,2-dichloro-
ethane8 as a much superior solvent permitted a lower reaction
temperature and complete solubilization of the Vilsmeier
reagent, intermediate products, and the desired product 9. By
generating styrene 8 in situ from alcohol 7, we eliminated the
Weller et al.8 isolation and purification of 8 for our large-scale
synthesis. Attempted medium-scale purification of styrene 8 by
high vacuum distillation resulted in a significant material loss
from polymerization. By also controlling the pH, conducting
the hydrolysis at 25 °C overnight (instead of 100 °C)8 and
carefully monitoring the reaction temperature during the acidic
hydrolysis−cyclization event (9 → 10), a high yield (85%) was
obtained (Scheme 1). In addition, by eliminating chromatog-
raphy of alkene 11 and purifying the pyridinyl 12 through
formation of the oxalate salt, the overall yield was greatly
improved and large quantities of 12 (ca. 200 g batches) were
readily prepared from o-vanillin (3) without the need for
chromatography.
Synthesis of the Substrate for Optical Resolution,
4aH,9-O-trans-9-Methoxy-3-methyl-2,3,4,4a,5,6-hexahy-
dro-1H-benzofuro[3,2-e]isoquinolin-7(7aH)-one (( )-2).
The synthesis of 4aH,9-O-trans-( )-2 from pyridinyl 12 was
achieved following the Weller et al. route, with some
modifications (Scheme 2). The stereoselective reduction of
the trisubstituted alkene 15 was performed with 5% Pt/C rather
than the more reactive PtO2, while the resulting 85:15 mixture
of 4aH,9-O-trans:cis ring juncture isomers 16 were separated by
crystallization of the desired trans isomer as a tosylate salt.
Weller et al.9 reported a separation of the cis and trans isomers
of racemic trans-( )-2 with recrystallization from benzene/
hexane after subjecting crude 16 to acidic hydrolysis−
decarboxylation. Acid hydrolysis led to the desired 4aH,9-O-
trans-isoquinolinone 2.
Having successfully improved the methodology leading to
( )-2 on a sufficiently large scale (20 g) without the use of
chromatograpy, we then focused on its optical resolution. We
hoped to find a method that would result in the isolation in
good yield of both enantiomers, since both were needed to
obtain the corresponding enantiomers of 1 that would
eventually be subjected to pharmacological evaluation. A chiral
resolution of the racemic 4aH,9-O-trans-( )-2 (Scheme 3) was
achieved by initially forming the (−)-O,O′-di-p-toluoyl-D-
tartaric acid (DPTTA) salt in acetone, resulting in an ee of
approximately 92% enriched in (+)-2 (the ee was determined
1
using H NMR, through the addition of a chiral shift reagent
((R)-(−)-α-(trifluoromethyl)benzyl alcohol), which resolved
the singlet at 4.34 ppm, as shown in the Supporting
Information).12,13 Formation of the (−)-tartaric acid salt in
MeOH from the enriched free base enhanced the ee to >98%.
Chiral (−)-2 was isolated in >98% ee after treatment of the
free-base filtrates with (+)-DPTTA and subsequently (+)-tar-
taric acid in an analogous fashion. In order to unambiguously
determine the absolute stereochemistry of chiral (+)-2, the (R)-
mandelic acid salt was prepared. Single-crystal X-ray diffraction
determined that the absolute stereochemistry of the (+)-2
enantiomer was analogous to that found in the unnatural
(+)-isomer of morphine.
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Scheme 4. Synthesis of 10-Northebaine (−)-20 and an Unusual Tetracyclic Enamine (+)-21
Scheme 5. Introduction of the 4a-OH in 22 and Attempted Deprotection of 26
Synthesis of Diene Intermediate 20 for Introduction
of the 4a-OH and Isolation of Rearrangement Product
21. The enantiomers of 2 had the correct skeletal geometry of
the targeted compound 1. Missing, however, was a 4a-OH
group, and we needed an N-cyclopropylmethyl replacement for
the N-methyl moiety. We thought that the needed 4a-OH
group could be easily introduced through a diene intermediate,
7,9-dimethoxy-3-methyl-2,3,4,7a-tetrahydro-1H-benzofuro[3,2-
e]isoquinoline (20, 10-northebaine), because a comparable
hydroxyl group had been successfully introduced in a structural
analogue, N-northebaine (7,9-dimethoxy-2,3,4,7a-tetrahydro-
1H-4,12-methanobenzofuro[3,2-e]isoquinoline).14 Unfortu-
nately, the most direct route (Scheme 4) for this gave us a
rearrangement product, a tetracyclic enamine 7,9-dimethoxy-3-
methyl-1,2,3,7-tetrahydro-7,12b-methanobenzo[2,3]oxocino-
[5,4-c]pyridine ((+)-21).
(−)-18, under conditions that were successfully utilized in a
synthesis of the isoquinolone, N-northebaine.14 Treatment of
the trimethoxybromide (−)-18 with KOtBu in DMSO at 70 °C
was expected to result in the 10-northebaine congener (−)-20
(7,9-dimethoxy-3-methyl-2,3,4,7a-tetrahydro-1H-benzofuro-
[3,2-e]isoquinoline) via double elimination, as also formerly
reported in the synthesis of N-northebaine14 (Scheme 4).
However, under these reaction conditions, a high yield of a
tetracyclic rearrangement product (+)-21 was obtained as the
only isolable reaction product. The unique structure of
tetracyclic enamine (+)-21 was verified by single crystal X-ray
analysis of the free base. This novel molecule could possibly
provide a new structure class of opioid-like analgesics.
The desired dimethoxydiene 20 was obtained using an extra
step. By performing the elimination reaction on (−)-18
(Scheme 4) in refluxing THF, the single elimination product
(−)-19 was cleanly obtained. Transformation of this
intermediate to the desired 10-northebaine (−)-20 was
achieved utilizing trimethylsilyl chloride (TMSCl) and
CH3SO3H. This route was initially carried out in the (−)-series
and later repeated in the (+)-series. Having found a
The route involved the synthesis of the trimethoxy bromide
(−)-18 (Scheme 4, 6-bromo-7,7,9-trimethoxy-3-methyl-
2,3,4,4a,5,6,7,7a-octahydro-1H-benzofuro[3,2-e]isoquinoline).
Its precursor, the methyl enol ether (−)-17, was formed from
(−)-2 and smoothly brominated giving a single stereoisomer
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Scheme 6. Conversion to N-Cyclopropylmethyl Derivative
Scheme 7. Ring Closure Leading to Intermediate 4aH,9-O-trans-( )-36
nonchromatographic route to the dimethoxydiene 20 that
could be used for producing a sufficient quantity of product for
further work, we concentrated on the final series of conversions
to obtain both (−)- and (+)-1.
25 provided an N-cyano derivative (−)-26. In several trials, the
hydrolysis of (−)-26 to (−)-27 proved problematic; thus, we
conceptualized an alternate route to (+)- or (−)-1 as shown in
Scheme 6.
Introduction of the 4a-OH and Conversion of N-
Methyl to N-Cyclopropylmethyl in the Synthesis of the
Final Product (1). The 4a-OH (14-OH in opioid
nomenclature) substituent was smoothly incorporated into
the dimethoxydiene 20 (Scheme 5) with hydrogen peroxide
under acidic conditions via epoxide formation/opening to form
the 4a-hydroxyisoquinolinone 22 (4a-hydroxy-9-methoxy-3-
methyl-2,3,4,4a-tetrahydro-1H-benzofuro[3,2-e]isoquinolin-7-
(7aH)-one). The crude enone was catalytically reduced using
Pd/C to ketone 23 (4a-hydroxy-9-methoxy-3-methyl-
2,3,4,4a,5,6-hexahydro-1H-benzofuro[3,2-e]isoquinolin-7-
(7aH)-one), initially in the (−)-series (Scheme 5), followed by
the (+)-series.
Cleavage of the aromatic methoxy group in (−)-23 gave the
N-methyl analogue of the phenol, 4a,9-dihydroxy-3-methyl-
2,3,4,4a,5,6-hexahydro-1H-benzofuro[3,2-e]isoquinolin-7-
(7aH)-one (10-noroxymorphone ((−)-24). Subsequent pro-
tective acylation of the dihydroxyisoquinolinone (−)-24
afforded (−)-25. N-Demethylation of the diacetyl compound
We determined that it was not necessary to cleave the
aromatic methoxyl group in 23 and then protect it by
acetylation; thus, we changed the reaction sequence. Only the
4a-OH in 23 was acetylated to give 28, as shown in Scheme 6
for the (+)-series (the enantiomeric (−)-compounds were also
synthesized). This was followed by N-demethylation of (+)-28
to provide the monoacetylated N-cyano compound (+)-29.
Under acidic conditions, the acetyl and cyano protecting groups
were removed to give free amine (+)-30. N-Alkylation with
cyclopropylmethyl bromide afforded (+)-31, which was O-
demethylated to arrive at the target compound (+)-3-
(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-
1H-benzofuro[3,2-e]isoquinolin-7(7aH)-one (10-nornaltrexone
(+)-1) in a total of 24 steps from commercially available o-
vanillin with an overall yield of 3.1%.
Alternate Route to 1 from 12 through Formation of
Intermediate 36. While the desired target compound (+)-1
could be obtained as shown in Scheme 6, we sought a shorter,
more practical route. Using our improved route to the ethyl 3-
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Scheme 8. Optical Resolution of 4aH,9-O-trans-( )-36 and the Improved Synthesis of 10-Nornaltrexone (+)-1 or (−)-1
(4-(2-hydroxy-3-methoxyphenyl)pyridin-3-yl)propanoate (12,
Scheme 1), we introduced the N-cyclopropylmethyl substituent
at a much earlier stage, an approach that had been used by
Cheng et al.9 as an adaptation of the earlier work of Weller et
al.8 This obviated the necessity of using a difficultly accessible
benzopyranopyridinone15 and, as well, eliminated the four-step
sequence required to transform the N-methyl into N-cyclo-
propylmethyl, since the latter moiety was introduced at an
earlier stage of a reaction sequence that did not involve N-
methyl-substituted intermediates (Scheme 7). The pyridinyl 12
was N-alkylated to the quaternary amine 32 using
(bromomethyl)cyclopropane. Formerly, ring closure of the
crude 32 was accomplished in two steps. First, basic conditions
(NaOEt at 19 °C) gave 33.9 The latter was subjected to NaH in
refluxing THF to afford product 34. We have now found that
the quaternary amine 32, under basic conditions (NaOEt, at 78
°C), afforded the Dieckmann condensation product 34 (4aH,9-
O-trans-ethyl 3-(cyclopropylmethyl)-7-hydroxy-9-methoxy-
5,7a-dihydro-3H-benzofuro[3,2-e]isoquinoline-6-carboxylate)
directly. The elimination of the isolation of the intermediate 33
enabled us to obtain 34 in 68% yield from 12, rather than the
<50% yield formerly obtained. The catalytic reduction of 34
(Scheme 7) and subsequent hydrolysis/de-esterification was
performed as noted in the literature9 and afforded 4aH,9-O-
trans-( )-36 in 61% yield.
chiral (+)-36 with an ee > 98%. The same reaction conditions
established in the N-methyl series 2 → 19 (Scheme 4) were
exploited to synthesize (+)-39 (3-(cyclopropylmethyl)-7,7,9-
trimethoxy-2,3,4,4a,7,7a-hexahydro-1H-benzofuro[3,2-e]-
isoquinoline) from (+)-36 (Scheme 8, bottom). Trans-
formation of (+)-39 into (+)-10-northebaine ((+)-40, 3-
(cyclopropylmethyl)-7,9-dimethoxy-2,3,4,7a-tetrahydro-1H-
benzofuro[3,2-e]isoquinoline) scaled more effectively with
POCl3 in pyridine at 90 °C, while the remaining three steps
were performed in an analogous fashion to the N-methyl series,
20 → 26 (Scheme 5), to give the desired 10-nornaltrexone
(+)-1 and, in the (−)-series, (−)-1, in a total of 20 steps from
o-vanillin an overall yield of 6.6%.
Preliminary Pharmacological Data. In vitro TLR-4
antagonism studies with 10-nornaltrexone (+)-1 are currently
underway and will be the topic of a future report. In preliminary
opioid receptor binding studies, (−)-1 appeared to interact
selectively with the μ receptor with roughly four times the
affinity of morphine and had about 40 times less affinity for the
κ receptor than naltrindole. It is important to note that
additional studies must be conducted to determine the Ki’s at
each of the opioid receptors and to determine if the compound
acts as an agonist or an antagonist at these receptors.
CONCLUSIONS
■
Optical Resolution of Intermediate 4aH,9-O-trans-
( )-36 and Completion of Alternate Synthesis of Final
Product 1. An optical resolution of 4aH,9-O-trans-( )-369 (3-
(cyclopropylmethyl)-9-methoxy-2,3,4,4a,5,6-hexahydro-1H-
benzofuro[3,2-e]isoquinolin-7(7aH)-one), Scheme 8, top) was
achieved by formation of the (+)-tartrate salt in MeCN/MeOH
6:1 to give chiral (−)-36 with an ee > 98%. The resultant
filtrates enriched in the enantiomeric (+)-36 were free based
and treated with (−)-tartaric acid in MeCN/MeOH 6:1 to give
Enantiopure 10-nornaltrexone ((3-(cyclopropylmethyl)-4a,9-
dihydroxy-2,3,4,4a,5,6-hexahydro-1H-benzofuro[3,2-e]-
isoquinolin-7(7aH)-one) compounds (+)-1 and (−)-1, which
lack the bridging benzylic carbon commonly found in opiates,
have been synthesized in 20 steps from o-vanillin in an effort to
obtain TLR-4 antagonists and novel opioid ligands. Preliminary
results show that (−)-10-nornaltrexone ((−)-1) binds to the μ
opioid receptor with about four times the affinity of morphine.
During these synthetic studies, a structurally unique tetracyclic
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combined material was stripped under high vacuum to a vapor
temperature of 135 °C at 150 μm to give 918.2 g of 6. The forerun
collected under high vacuum was redistilled under aspirator vacuum to
give 7.4 g of a fraction consisting largely of benzaldehyde. The
remaining residue was combined with the first batch to afford pure 6
(921.6 g, 90%) as an oil. Spectra matched those reported by Weller et
al.8
enamine 21 was formed, which could provide a different type of
skeleton for opioid analgesics. Further pharmacological work
with these compounds is in progress and will be reported in the
future.
EXPERIMENTAL SECTION
■
2-(2-(Benzyloxy)-3-methoxyphenyl)propan-2-ol (7). A mechan-
ically stirred solution of MeMgBr (3 M in Et2O, 763 mL, 2.29 mol) in
a 5 L three-neck flask with a thermometer and mechanical stirrer was
cooled to −15 °C under nitrogen. A solution of ketone 6 (477.3 g,
1.862 mol) in dry toluene (900 mL) was added in a thin stream to the
mixture with efficient stirring while keeping the internal temperature
between −15 and −20 °C. After 15 min, the stirred mixture was slowly
and cautiously treated with H2O (1500 mL) initially giving off gas. The
resulting mixture consisted of an organic layer and thick aqueous slurry
of inorganic material. The organic layer was separated and saturated
aqueous NH4Cl (1 L), solid NH4Cl (250 g), and Et2O (500 mL) were
added to the mixture to give 2 phases containing a slight emulsion at
the phase interface after stirring. The aqueous layer was separated from
the emulsion and the remaining material easily filtered through Celite.
The filter was washed with a little Et2O, and the organic phase was
separated and added to the original toluene−Et2O solution. The
combined organic phase was washed sequentially with half-saturated
aqueous NH4Cl (2 × 400 mL), H2O (2 × 400 mL), 10% NaOH (2 ×
200 mL), and H2O (3 × 500 mL). The combined organics (about 3 L)
were evaporated under aspirator vacuum and then distilled under high
vacuum to give 7 (475.3 g, 94%) as an oil containing about 2%
unreacted ketone. bp 140 °C/100 Torr. Spectra matched those
reported by Weller et al.8
4-(2-(Benzyloxy)-3-methoxyphenyl)nicotinaldehyde (10). To a
stirred solution of DMF (50.1 mL, 650 mmol) in anhydrous CHCl3
(150 mL) at an internal temperature of 15 °C was added a solution of
oxalyl chloride (53.1 mL, 600 mmol) in anhydrous CHCl3 (100 mL)
dropwise at a rate sufficient to maintain the internal temperature below
25 °C. Once the production of gas ceased, a solution of 7 (27.2 g, 100
mmol) in in anhydrous CHCl3 (10 mL) was added. The mixture was
refluxed under Ar for 3 h and cooled to room temperature. The
mixture was cannulated into a solution of NaOAc·3H2O (108 g, 800
mmol), NH4Cl (53 g, 1000 mmol), and AcOH (30 mL) in H2O (250
mL) while simultaneously removing CHCl3 by distillation from the
quenched mixture under aspirator vacuum. The temperature of the
quenched mixture was maintained at approximately 25 °C by external
heating during the distillation. The reaction mixture was stirred
overnight at room temperature and the product crystallized. The
product was filtered affording a slightly sticky brown residue, which
was dissolved in CHCl3 (150 mL) and sequentially washed with H2O
(150 mL), 10% NaOH (100 mL), and H2O (2 × 100 mL). The
combined organic layers were distilled in a short path still under high
vacuum bp ∼190 °C at 100 μm to give 4-(2-(benzyloxy)-3-
methoxyphenyl)nicotinaldehyde 10 (27.1 g, 85% yield) as a yellow
solid, which was used without further purification. Column
chromatography of a small portion of this crude product with
EtOAc/hexanes (gradient, 0 → 30%) gave an analytically pure sample
of 10. Spectra matched those reported by Cheng et al.9
General Experimental Methods. All melting points are
uncorrected. Proton and carbon nuclear magnetic resonance were
recorded on a 400 or 500 MHz instrument in CDCl3 (unless
otherwise noted) with the values given in ppm and J (Hz) assignments
of 1H resonance coupling. Thin-layer chromatography (TLC) was
performed on 0.25 mm Analtech GHLF silica gel.
2-Benzyloxy-3-methoxybenzaldehyde (4). The procedure of
Cotterill et al.16 was modified as follows: A mixture of deionized
H2O (1.25L), 85% KOH (234.2 g of 85%, 3.540 mol), and 100%
ethanol (1 L) was refluxed for 10 min under a stream of nitrogen in a
three-neck, 5 L flask with mechanical stirrer, reflux condenser, addition
funnel, and nitrogen inlet. o-Vanillin (499.1 g, 3.280 mol) was melted
and cautiously added to the solution. Neat benzyl bromide (421.9 mL,
606.7 g, 3.550 mol) was added to the solution in a thin stream to
maintain a gentle reflux. At the end of the addition, 85% KOH (85.8 g,
1.30 mol) was cautiously added followed by benzyl bromide (154.5
mL, 222.2 g, 1.300 mol) at a rate sufficient to maintain gentle reflux.
When the addition was complete, the mixture was refluxed for 0.5 h.
Most of the ethanol was then stripped under aspirator vacuum using a
high capacity condenser (ice water cooling) to collect about 1.25 L of
ethanol−water mixture. The residual organic product layer was
separated and the aqueous layer extracted with Et2O (2 × 250 mL).
The combined organic phase was washed with 10% NaCl solution (0.5
L) and the Et2O evaporated under the aspirator. The residue was
distilled from a 3-neck 2 L flask with a mechanical stirrer with an oil
bath. A forerun was collected up to 85 °C and then a second forerun
up to bp 135 °C/100 μm. The product 2-benzyloxy-3-methox-
ybenzaldehyde 4 (731.1 g, 92%) was then collected at bp 135 °C/100
μm as an oil that solidified to a white crystalline mass upon cooling to
room temperature. Spectra matched those reported by Cotterill et al.16
1-(2-(Benzyloxy)-3-methoxyphenyl)ethanol (5). The melted alde-
hyde 4 (484.2 g, 2.0 mol) was dissolved under nitrogen in dry Et2O
(1.4 L) in a mechanically stirred, three-neck 5 L flask with condenser,
addition funnel, and thermometer. The reaction flask was cooled to
−78 °C, and methyllithium·LiBr (1.5M, 1.4 L, 2.1 mol) was added to
the well-stirred mixture in a thin stream, keeping the temperature
between −10 and −20 °C. At the end of the addition, an aliquot
quenched with water and extracted with Et2O showed complete
reaction of starting material by TLC, and conversion to a lower Rf spot
in (Et2O/petroleum Et2O 1:2). After 15 min, H2O (800 mL) was
cautiously added with cooling, resulting in a brisk evolution of gas.
When the addition was complete, the temperature was allowed to rise
to 5−10 °C, and two homogeneous phases resulted. The Et2O layer
was separated and extracted with water (250 mL). The aqueous layers
were combined and extracted with Et2O (2 × 250 mL). Et2O extracts
were combined and evaporated under aspirator vacuum in a
mechanically stirred 5 L three-neck flask with a final batch temperature
of 90 °C to remove water to afford 5 (518.2 g, 100%) as an oil that was
used without further purification. TLC showed a single spot with
traces of an unknown impurity at a slightly higher Rf. Spectra matched
those reported by Weller et al.9
Ethyl (E)-3-(4-(2-(Benzyloxy)-3-methoxyphenyl)pyridin-3-yl)-
acrylate (11). To stirred pieces of clean, freshly cut sodium (13.7 g,
596 mmol) in a three-neck flask equipped with a reflux condenser was
added anhydrous EtOH (700 mL). The mixture was refluxed until a
homogeneous solution was obtained, and then the solution was cooled
to room temperature. To the reaction mixture was added triethyl
phosphonoacetate (118 mL, 133.1 g, 593 mmol), during which a drop
in temperature to approximately 23 °C was observed. After the
mixture was stirred for 10 min, crude 10 (172 g, 540 mmol) was added
in portions maintaining the internal temperature at 20−25 °C with
external cooling. After complete addition, the reaction mixture was
stirred for 30 min and NH4Cl (33.3 g) was added. The reaction
mixture was concentrated under water vacuum aspiration, and Et2O
(500 mL) and H2O (500 mL) were added. The aqueous layer was
separated and extracted with Et2O (200 mL). The organics were
1-(2-(Benzyloxy)-3-methoxyphenyl)ethanone (6). To the well-
stirred mixture of crude alcohol 5 (518.2 g, 2.006 mol) in 1,2-
dichloroethane (DCE) (2 L) in a mechanically stirred 5 L three-neck
flask was added activated MnO2 (2.06 kg, 23.7 mol) in small portions.
The stirred mixture was then refluxed with a universal water separator
for 1.5 h, at which time TLC (Et2O/petroleum Et2O 1:2) showed
complete conversion to the ketone; the product contained traces of
benzaldehyde. The mixture was filtered on a 27 cm Buchner funnel,
and the MnO2 was washed thoroughly with DCE (10 × 500 mL). The
combined filtrate and wash were evaporated under the aspirator. An
identical run from 2.0 mol of aldehyde gave 519.1 g of alcohol that was
oxidized as above and combined with the original batch. This
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combined and washed with H2O (3 × 250 mL) and brine (200 mL),
filtered through Celite, and concentrated in vacuo to give a dark brown
oil. The crude dark brown oil crystallized upon standing overnight and
was vacuum oven-dried at 50 °C overnight to afford 11 (212.1 g),
which was used without further purification. Column chromatography
of a small portion of this crude product with EtOAc/hexanes
(gradient, 0 → 25%) gave an analytically pure sample of 11. Spectra
matched those reported by Weller et al.8
butanone (400 mL) was added anhydrous TsOH prepared by
azeotropically distilling TsOH·H2O (22.2 g) with a Dean−Stark trap.
The tosylate salt formed almost immediately. The mixture was cooled
to ∼20 °C, filtered, and rinsed with 2-butanone (200 mL) to give the
ethyl ester 16 as the tosylate salt. The tosylate salt was free-based with
concentrated NH4OH (10 mL) in H2O (100 mL), extracted with
CHCl3 (3 × 150 mL), and concentrated in vacuo. To the free base was
added 3 M HCl (300 mL). The solution was refluxed for 2 h, cooled
to room temperature, and extracted with CHCl3 (300 mL). The
aqueous layer was basified with 3 M NaOH to a pH ∼9 and extracted
with CHCl3 (3 × 200 mL). The combined organics were concentrated
in vacuo to give racemic trans-( )-2 (18.04 g, 57% from 15) as a
yellow solid.
Ethyl 3-(4-(2-Hydroxy-3-methoxyphenyl)pyridin-3-yl)propanoate
(12). To a solution of crude ethyl (E)-3-(4-(2-(benzyloxy)-3-
methoxyphenyl)pyridin-3-yl)acrylate 11 (35.4 g, 90.8 mmol) in THF
(180 mL) was added Pd/C (3.0 g). The mixture was degassed and
subjected to hydrogenation under 60 psi of H2. After 30 min, the
reaction mixture was filtered through a pad of Celite, washing with
additional THF (30 mL). The above procedure was repeated (5 ×
35.4 g), combining product mixtures from each. The combined
product mixtures were concentrated in vacuo and heated in acetone
(400 mL). To the heated crude mixture was added oxalic acid (50 g)
in warm acetone (150 mL). The oxalate salt began crystallizing
immediately. The mixture was cooled to 0 °C, filtered, and rinsed with
cold (0−5 °C) acetone (633 mL) followed by petroleum Et2O (2 ×
200 mL). The oxalate salt was air-dried overnight to afford the oxalate
salt of 12 (193.83 g, 92% from 10). The 12·oxalate (193.21g, 0.49
mol) was converted to the free base in H2O (1.3 L), CHCl3 (600 mL),
and 28% NH4OH (100 mL) in a 3 L separatory funnel. The CHCl3
was separated, and the aqueous solution was extracted with CHCl3 (2
× 100 mL). The combined chloroform extracts were filtered through
Celite leaving a small amount of purple sludge on the filter. The
chloroform was evaporated, and the resulting syrup dissolved in Et2O
(560 mL) to rapidly give crystalline 12. The 12 was filtered, washed
with Et2O, and dried to give 141.21 g. The filtrate and wash was
evaporated to give a 3.90 g of second crop for a total of 145.11 g
(97.3% from 12·oxalate, 89.1% from crude 10). Spectra matched those
reported by Weller et al.8
Ethyl (12bR)-7-Hydroxy-9-methoxy-3-methyl-5,7a-dihydro-3H-
benzofuro[3,2-e]isoquinoline-6-carboxylate (15). To a stirred
solution of ethyl ester 12 (30.1 g, 99.9 mmol) in DMF (150 mL)
was added iodomethane (8.25 mL, 133 mmol). The reaction mixture
was heated at 50 °C for 1 h verifying the disappearance of starting
material by TLC, cooled to room temperature, and concentrated in
vacuo. To the crude intermediate was added DMF (150 mL) followed
by K2CO3 (20.7 g, 150 mmol) and ethyl bromoacetate (12.2 mL, 110
mmol). The reaction mixture was stirred for 1 h at room temperature,
filtered, and concentrated in vacuo. In a separate flask, anhydrous
EtOH (150 mL) was added to freshly cut pieces of sodium (9.2 g, 400
mmol) and refluxed until a homogeneous solution was obtained. This
freshly prepared NaOEt solution was cooled to room temperature and
cannulated into the crude bis ethyl ester rinsing with THF (150 mL).
The reaction mixture was refluxed for 1.5 h and cooled to −5 °C. The
reaction mixture was cannulated into a rapidly stirred mixture of
saturated aqueous NH4Cl (147.6 g) and H2O (147 g) at −5 °C,
rinsing the reaction flask with THF (3 × 25 mL). The reaction mixture
was concentrated in vacuo to ∼700 mL removing most of the organics.
The aqueous layer was extracted with CHCl3 (3 × 150 mL) and the
combined organics were concentrated in vacuo to give a dark syrup.
This dark syrup was dissolved in toluene (300 mL), and washed with
H2O (150 mL) and brine (100 mL). The aqueous washes were
extracted with toluene (2 × 50 mL). The combined toluene extracts
were concentrated in vacuo to ∼1/3 volume, filtered through Celite,
and concentrated in vacuo to give 15 (32.1 g, 93%) as an orange solid.
Spectra matched those reported by Weller et al.8
Optical Resolution of (4aS,7aS,12bR)-9-Methoxy-3-methyl-
2,3,4,4a,5,6-hexahydro-1H-benzofuro[3,2-e]isoquinolin-7(7aH)-one
(+)-2 and (4aR,7aR,12bS)-9-Methoxy-3-methyl-2,3,4,4a,5,6-hexa-
hydro-1H-benzofuro[3,2-e]isoquinolin-7(7aH)-one (−)-2. To a
crude solution of ( )-29 (20.5 g, 71.2 mmol) in acetone (150 mL)
was added a solution of (−)-O,O′-di-p-toluoyl-L-tartaric acid
(DPTTA) (30.3 g, 78.4 mmol) in acetone (100 mL). A precipitate
formed almost immediately. The solution was cooled to 0 °C and
maintained at that temperature for 15 min. The precipitate was
filtered, rinsed with cold acetone, and free-based in H2O (100 mL)
containing concentrated NH4OH (5 mL). The aqueous layer was
extracted with CHCl3 (3 × 100 mL), washed with H2O (100 mL), and
concentrated in vacuo to afford a mixture of (+)-2 and (−)-2 (7.25 g,
free base). To a solution of this mixture in MeOH (75 mL) was added
a solution of (−)-tartaric acid (4.17 g, 27.8 mmol) in MeOH (25 mL).
A white precipitate formed almost immediately. The suspension was
cooled to 0 °C and maintained at that temperature for 15 min. The
precipitate was filtered and rinsed with cold MeOH (75 mL), cold
acetone (75 mL), and Et2O (75 mL) to afford (+)-2-(−)-tartaric acid
salt (10.5 g). >98% ee. The chiral shift reagent (R)-(−)-α-
(trifluoromethyl)benzyl alcohol was added to the free base to
determine the ee by examination of the resolved singlet at 4.34 ppm
12,13
1
in the H NMR.
All data were obtained on the free base: [α]20
D
+189.1 (c 0.9, CHCl3); mp 156−158 °C; IR (thin film) 1721 cm−1; 1H
NMR (400 MHz, CDCl3) δ 6.96 (d, J = 8.0 Hz, 1H), 6.75−6.69 (m,
2H), 4.34 (s, 1H), 3.78 (s, 3H), 2.76 (dd, J = 12.0, 4.0 Hz, 1H), 2.61
(d, J = 12.0 Hz, 1H), 2.49 (t, J = 12.0 Hz, 1H), 2.42 (m, 1H), 2.32 (s,
3H), 2.30−2.20 (m, 3H), 1.90 (td, J = 12.0, 4.0 Hz, 1H), 1.78 (m,
1H), 1.66 (m, 1H), 1.49 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
207.2, 148.9, 145.4, 130.5, 121.3, 118.7, 112.4, 91.8, 56.7, 56.0, 51.9,
50.3, 46.0, 40.2, 39.3, 38.7, 25.5; HRMS (TOF MS ES+) calcd for
C17H22NO3 (M + H+) 288.1600, found 288.1593. Anal. Calcd for
(C17H21NO3): C (71.06), H (7.37), N (4.87). Found: C (70.76),
H(7.56), N (4.91).
The filtrate from above was concentrated in vacuo, free-based with
concentrated NH4OH (5 mL) in H2O (100 mL), and extracted with
CHCl3 (3 × 100 mL). The combined organic fractions were washed
with H2O (100 mL) and concentrated in vacuo to give free base
enriched in (−)-2. The above procedure was repeated using
(+)-DPTTA (1.1 equiv) and (+)-tartaric acid (1.1 equiv) to afford
(−)-2-(+)-tartaric acid salt, >98% ee. Free base [α]20 −192.3 (c 1.0,
D
CHCl3).
(4aR,7aR,12bS)-7,9-Dimethoxy-3-methyl-2,3,4,4a,5,7a-hexahy-
dro-1H-benzofuro[3,2-e]isoquinoline ((−)-17). To a stirred solution
of (−)-2 (2.25 g, 7.82 mmol) in MeOH (35 mL) was added a
premixed solution of 5-sulfosalicylic acid dihydrate (3.57 g, 14.1
mmol) and trimethyl orthoformate (8.5 mL, 78 mmol) in MeOH (20
mL). The reaction mixture was refluxed for 1 h, and then CHCl3 (3 ×
75 mL) was added and removed by distillation. The reaction mixture
was cooled to 0 °C, and a precooled solution of 1.5 M NaOH (100
mL) at 0 °C was added. The aqueous layer was extracted with CHCl3
(3 × 100 mL), washed with H2O (100 mL), and concentrated in
vacuo to afford (−)-17 (2.36 g, 100%) as a yellow solid, which was
4aH,9-O-trans 9-Methoxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-
benzofuro[3,2-e]isoquinolin-7(7aH)-one (( )-2). To a solution of
crude 15 (40.9 g, 115 mmol) in THF (200 mL) was added wet 5% Pt/
C (40% in H2O) (15 g), which was first dried by filtering a suspension
of the catalyst in THF (60 mL) through Celite and rinsing with THF
(5 × 50 mL). The mixture was degassed and subjected to
hydrogenation under 60 psi of H2. After 2 h, the reaction mixture
was filtered through a pad of Celite with washing with additional THF
(200 mL) and concentrated in vacuo. To the crude solution in 2-
used without further purification: [α]20 −168.5 (c 1.2, CHCl3); mp
D
166−168 °C; IR (thin film) 1657 cm−1; 1H NMR (400 MHz, CDCl3)
δ 7.06 (m, 1H), 6.78−6.76 (m, 2H), 4.77 (m, 1H), 4.70 (s, 1H), 3.79
(s, 3H), 3.45 (s, 3H), 2.78 (dd, J = 10.0, 4.0 Hz, 1H), 2.64 (d, J = 12.0
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Hz, 1H), 2.55 (t, J = 12.0 Hz, 1H), 2.37 (s, 3H), 2.29 (m, 1H), 2.12
(m, 1H), 1.92−1.81 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 152.5,
148.1, 145.8, 132.0, 120.0, 119.0, 111.8, 98.3, 88.5, 57.0, 55.8, 54.5,
50.5, 48.0, 46.2, 38.6, 38.1, 25.4; HRMS (TOF MS ES+) calcd for
C18H24NO3 (M + H+) 302.1756, found 302.1760.
55.8, 55.0, 51.3, 49.8, 45.9, 40.4; HRMS (TOF MS ES+) calcd for
C18H22NO3 (M + H+) 300.1600, found 300.1607.
Optical rotation of enantiopure (+)-20 (free base): [α]20D +30.5 (c
1.8, CHCl3); mp 155−158 °C.
(7R,12bS)-7,9-Dimethoxy-3-methyl-1,2,3,7-tetrahydro-7,12b-
methanobenzo[2,3]oxocino[5,4-c]pyridine ((+)-21). To a stirred
solution of bromide (−)-18 (0.366 g, 0.887 mmol) in DMSO (15
mL) was added potassium tert-butoxide (995 mg, 8.87 mmol). The
reaction mixture was heated at 65 °C for 14 h and cooled to room
temperature, and ice and H2O were slowly added resulting in
crystallization of (+)-21, which was filtered and rinsed to afford pure
Optical rotation of enantiopure (+)-17 (free base): [α]20D +161.9 (c
1.4, CHCl3); mp 162−164 °C.
(4aR,7aR,12bS)-6-Bromo-7,7,9-trimethoxy-3-methyl-
2,3,4,4a,5,6,7,7a-octahydro-1H-benzofuro[3,2-e]isoquinoline
((−)-18). To a stirred solution of (−)-17 (2.61 g, 8.66 mmol) in
MeOH (40 mL) and THF (20 mL) at −15 °C was added a solution of
methanesulfonic acid (13.3 M, 717 μL, 9.50 mmol) in MeOH (3 mL)
dropwise followed by a solution of N-bromoacetamide (1.16 g, 8.41
mmol) in MeOH (6 mL). After the mixture was stirred for 15 min at
−15 °C, additional N-bromoacetamide (119 mg, 0.866 mmol) was
added. After the mixture was stirred for an additional 15 min at −15
°C, NH3 gas was bubbled through the solution. The reaction mixture
was concentrated in vacuo, and to the resulting residue were added 3
M NaOH (50 mL) and concentrated NH4OH (10 mL). The aqueous
mixture was extracted with CHCl3 (3 × 75 mL), washed with H2O (75
mL), and concentrated in vacuo to afford bromide (−)-18 (3.32 g) as
a white foam that was used without further purification: [α]20D −133.4
(+)-21 (0.209 g, 79%) as a light brown solid: [α]20 +598.5 (c 1.9,
D
1
CHCl3); mp 214−217 °C; IR (thin film) 1639 cm−1; H NMR (500
MHz, CDCl3) δ 7.00 (d, J = 8.0 Hz, 1H), 6.82 (t, J = 8.0 Hz, 1H), 6.73
(d, J = 8.0 Hz, 1H), 6.12 (d, J = 9.5 Hz, 1H), 6.01 (s, 1H), 5.37 (d, J =
9.5 Hz, 1H), 3.83 (s, 3H), 3.57 (s, 3H), 3.47 (td, J = 13.0, 4.5 Hz, 1H),
3.30 (dd, J = 12.5, 6.0 Hz, 1H), 2.86 (s, 3H), 2.34−2.29 (m, 2H), 2.06
(td, J = 13.2, 6.5 Hz, 1H), 1.68 (d, J = 11.5 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 148.9, 143.6, 134.5, 131.7, 131.3, 119.8, 118.0, 117.2,
109.9, 109.8, 100.3, 56.0, 50.3, 47.2, 42.4, 40.3, 34.7, 33.5; HRMS
(TOF MS ES+) calcd for C18H22NO3 (M + H+) 300.1600, found
300.1591. Anal. Calcd for (C18H21NO3·H2O): C (68.12), H (7.30), N
(4.41). Found: C (67.87), H (7.08), N (4.36).
1
(c 1.7, CHCl3); mp 59−62 °C; H NMR (500 MHz, CDCl3) δ 7.11
Optical rotation of enantiopure (−)-21 (free base): [α]20 −613.8
(m, 1H), 6.80−6.79 (m, 2H), 4.41 (s, 1H), 3.97 (t, J = 9.5 Hz, 1H),
3.86 (s, 3H), 3.58 (s, 3H), 3.50 (s, 3H), 3.02 (m, 1H), 2.77 (dd, J =
11.5, 4.0 Hz, 1H), 2.66 (m, 1H), 2.52−2.44 (m, 2H), 2.43 (s, 3H),
2.20−2.14 (m, 1H), 1.94−1.79 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 147.9, 144.4, 131.6, 120.2, 118.7, 112.3, 98.0, 89.84, 89.75,
56.0, 55.7, 51.3, 49.8, 49.3, 47.4, 45.71, 45.69, 40.4, 35.4, 35.3, 34.8;
HRMS (TOF MS ES+) calcd for C19H27NO4Br (M + H+) 412.1123,
found 412.1117.
D
(c 0.9, CHCl3); mp 214−218 °C
(4aS,7aR,12bS)-4a-Hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,6-
hexahydro-1H-benzofuro[3,2-e]isoquinolin-7(7aH)-one ((−)-23). To
a stirred solution of (−)-20 (free base, 0.860 g, 2.87 mmol) in 0.7%
H2SO4 (11 mL), formic acid (11 mL), and i-PrOH (11 mL) at 0 °C
was added H2O2 (5.46 M in H2O, 580 μL, 3.17 mmol) dropwise. The
reaction mixture was stirred for 1.5 h at 0 °C and warmed to 45 °C.
After being stirred for 45 min at 45 °C, the reaction mixture containing
crude (−)-22 was cooled to 0 °C, 5% Pd/C (400 mg) was added, and
the solution was subjected to an atmosphere of H2 (1 atm). After
being stirred for 1 h at 0 °C, the reaction mixture was warmed to room
temperature. After being stirred at room temperature for 24 h, ice and
3 M NaOH were added until a pH of 9.5 was achieved. The slurry was
filtered through Celite, rinsing with H2O and CHCl3. The organics
and aqueous fractions were separated. The aqueous layer was extracted
with CHCl3 (3 × 100 mL), washed with H2O (100 mL), and
concentrated in vacuo to afford (−)-25 as a crude white solid.
Purification of this crude solid by SiO2 column chromatography with
10% NH4OH in MeOH/CHCl3 (gradient, 0 → 10%) gave (−)-23
(0.171 g, 20% from (−)-20) as a white solid. An 88% yield from
Optical rotation of enantiopure (+)-18 (free base): [α]20D +119.1 (c
1.9, CHCl3).
(7aR,12bS)-7,9-Dimethoxy-3-methyl-2,3,4,7a-tetrahydro-1H-
benzofuro[3,2-e]isoquinoline ((−)-20). To the crude solution of
bromide (−)-18 (3.32 g) in THF (60 mL) was added potassium tert-
butoxide (3.88 g, 34.6 mmol). The reaction mixture was heated to
reflux. After stirring for 4 h at reflux, the reaction mixture was cooled
to room temperature and concentrated in vacuo. To the crude residue
were added H2O (50 mL) and concentrated NH4OH to obtain a pH
of 9.5, and the aqueous solution was extracted with CHCl3 (3 × 50
mL). The combined organic fractions were washed with H2O (100
mL) and concentrated in vacuo to afford (−)-19 ((4aR,7aR,12bS)-
7,7,9-trimethoxy-3-methyl-2,3,4,4a,7,7a-hexahydro-1H-benzofuro[3,2-
e]isoquinoline), which was used without further purification. To the
crude solution of (−)-19 in CHCl3 (40 mL) at 0 °C was added
trimethylsilyl chloride (3.13 mL, 24.6 mmol), and the reaction mixture
was warmed to room temperature. After the mixture was stirred 15
min at room temperature, a solution of CH3SO3H (480 μL, 7.39
mmol) in CHCl3 (2 mL) was added dropwise. The reaction mixture
was warmed to 35 °C and maintained at that temperature for 35 min.
The solution was then cooled to 0 °C, and H2O (50 mL) was added
followed by concentrated NH4OH to arrive at a pH of 9.5. The
aqueous solution was extracted with CHCl3 (3 × 50 mL), washed with
H2O (50 mL), and concentrated in vacuo to give a crude light brown
solid. To a solution of this crude residue in MeOH (8 mL) was added
a solution of (−)-tartaric acid (1.02 g, 6.78 mmol) in MeOH (4 mL).
The (−)-tartaric acid salt of (−)-20 began crystallizing almost
immediately. The solution was cooled to 0 °C and maintained at
that temperature for 15 min until crystallization was complete. The
resulting solid was filtered and rinsed with cold MeOH to afford the
(−)-tartaric acid salt of (−)-20 (2.25 g, 58% over three steps). All
(−)-20 was obtained on a 28 mg scale: [α]20 −217.3 (1.4, CHCl3);
D
1
mp 134−137 °C; IR (thin film) 3438, 1723 cm−1; H NMR (400
MHz, CDCl3) δ 7.01 (d, J = 4.0 Hz, 1H), 6.86−6.80 (m, 2H), 4.55 (s,
1H), 4.25 (br s, 1H), 3.87 (s, 3H), 2.76 (d, J = 12.0 Hz, 1H), 2.72−
2.63 (m, 3H), 2.43 (s, 3H), 2.41−2.28 (m, 3H), 1.82−1.72 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 205.3, 148.5, 145.1, 131.0, 121.2,
117.1, 112.1, 90.9, 70.0, 61.5, 55.8, 55.0, 49.8, 45.6, 34.5, 32.5, 30.4;
HRMS (TOF MS ES+) calcd for C17H22NO4 (M + H+) 304.1543,
found 304.1543.
Optical rotation of enantiopure (+)-23 (free base): [α]20D +241.9 (c
1.1, CHCl3)
(4aS,7aR,12bR)-3-Methyl-7-oxo-1,2,3,4,5,6,7,7a-octahydro-4aH-
benzofuro[3,2-e]isoquinoline-4a,9-diyl Diacetate ((−)-25). Through
a stirred solution of methyl ether (−)-23 (0.171 g, 0.565 mmol) in
CH2Cl2 (6 mL) was bubbled HCl gas until the pH of the solution was
∼3 on moist hydrion paper. The solution was cooled to 0 °C, and a
solution of BBr3 (166 μL, 1.75 mmol) in CH2Cl2 (2 mL) was added
dropwise. After being stirred for 15 min at 0 °C, the reaction mixture
was warmed to room temperature. After being stirred at room
temperature for 1.5 h, the solution was cooled to 0 °C, and H2O (6
mL) was added dropwise. The CH2Cl2 was removed by distillation,
and the remaining aqueous solution was refluxed. After being refluxed
for 30 min, the aqueous solution was cooled to 0 °C, and the pH was
adjusted to 9.5 with concentrated NH4OH. The aqueous solution was
extracted with 9:1 CHCl3/EtOH (5 × 10 mL). The combined
organics were concentrated in vacuo to afford crude diol (−)-24,
spectral data reported on the free base: [α]20 −39.2 (c 1.6, CHCl3);
D
1
mp 160−163 °C; IR (thin film) 1667 cm−1; H NMR (500 MHz,
CDCl3) δ 7.10 (d, J = 7.5 Hz, 1H), 6.79 (t, J = 7.5 Hz, 1H), 6.72 (d, J
= 7.5 Hz, 1H), 5.69 (d, J = 6.0 Hz, 1H), 5.12 (s, 1H), 4.96 (d, J = 6.0
Hz, 1H), 3.81 (s, 3H), 3.56 (s, 3H), 3.26 (s, 2H), 2.74 (d, J = 11.0 Hz,
1H), 2.59 (t, J = 12.5 Hz, 1H), 2.39 (s, 3H), 1.98 (t, J = 12.5 Hz, 1H),
1.86 (d, J = 12.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 153.3,
146.2, 145.1, 133.8, 127.8, 120.7, 117.9, 117.6, 111.4, 94.3, 88.4, 59.6,
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which was carried out without further purification. To crude diol
(−)-24 was added Ac2O (4 mL). The reaction mixture was heated to
65 °C and maintained at that temperature for 1.5 h. The Ac2O was
removed by vacuum distillation. Purification of this crude solid by SiO2
column chromatography with 10% NH4OH in MeOH/CHCl3
(gradient, 1 → 4%) afforded (−)-25 (0.141 g, 67% from (−)-23) as
a white solid: [α]20D −248.4 (c 2.4, CHCl3); mp 118−122 °C; IR (thin
film) 1774, 1735, 1725 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.36 (d,
J = 7.5 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 4.51
(s, 1H), 3.97 (d, J = 13.5 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 2.74 (m,
1H), 2.56 (d, J = 13.5 Hz, 1H), 2.51−2.45 (m, 3H), 2.42 (s, 3H), 2.29
(s, 3H), 2.03 (m, 1H), 2.02 (s, 3H), 1.79 (d, J = 11.5 Hz, 1H), 1.76
(m, 1H); 13C NMR (125 MHz, CDCl3) δ 202.5, 174.1, 169.9, 168.0,
151.4, 135.2, 130.3, 123.1, 121.4, 107.1, 90.7, 81.9, 55.2, 54.6, 48.7,
45.2, 33.4, 30.7, 26.1, 26.0, 22.0, 21.2, 20.4; HRMS (TOF MS ES+)
calcd for C20H24NO6 (M + H+) 374.1598, found 374.1599.
at a pH ∼9.5. The aqueous solution was extracted with 4:1 CHCl3/
MeOH (5 × 10 mL). The combined organics were washed with H2O
(10 mL) and concentrated in vacuo to afford amine (+)-30 that was
used without further purification. To the above crude amine (+)-30
were added EtOH (7 mL), Na2CO3 (0.222 g, 2.09 mmol), and
cyclopropylmethyl bromide (102 μL, 1.02 mmol). The reaction
mixture was heated to 90 °C and maintained at that temperature for 2
h, at which time an additional 102 μL of cyclopropylmethyl bromide
was added. After being stirred for an additional 1 h, the reaction
mixture was concentrated in vacuo to afford a crude orange solid.
Purification of this crude solid by SiO2 column chromatography with
10% NH4OH in MeOH/CHCl3 (gradient, 1 → 4%) afforded (+)-31
(0.101 g, 35% yield from (+)-28) as a tacky yellow foam. A 43% yield
was obtained on a 35 mg scale: [α]20D +245.1 (c 4.1, CHCl3); IR (thin
film) 3428, 1723 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.00 (d, J = 7.0
Hz, 1H), 6.83−6.78 (m, 2H), 4.53 (s, 1H), 4.42 (br s, 1H), 3.85 (s,
3H), 2.85−2.82 (m, 3H), 2.68 (m, 1H), 2.47−2.37 (m, 4H), 2.31 (t, J
= 11.0 Hz, 1H), 1.79−1.71 (m, 3H), 0.88 (m, 1H), 0.53 (d, J = 7.0 Hz,
2H), 0.12 (d, J = 2.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 205.7,
148.6, 145.2, 131.2, 121.3, 117.1, 112.2, 107.1, 91.2, 70.1, 62.6, 59.3,
55.9, 55.8, 47.8, 34.8, 32.9, 30.5, 8.2, 3.9, 3.7; HRMS (TOF MS ES+)
calcd for C20H26NO4 (M + H+) 344.1862, found 344.1856.
(4aS,7aR,12bS)-3-Cyano-7-oxo-1,2,3,4,5,6,7,7a-octahydro-4aH-
benzofuro[3,2-e]isoquinoline-4a,9-diyl Diacetate ((−)-26). To a
stirred solution of methylamine (−)-25 (0.141 g, 0.378 mmol) in
MeCN (4 mL) were added K2CO3 (0.053 g, 0.38 mmol) and CNBr
(5.0 M, 84 μL, 0.42 mmol). The reaction mixture was heated to 75 °C
and maintained at that temperature for 1.5 h. The reaction mixture was
cooled to room temperature and concentrated in vacuo. To the crude
residue were added H2O (10 mL) and concentrated NH4OH to bring
the pH to 9.5, and the aqueous mixture was extracted with CHCl3 (3
× 10 mL). The combined organic fractions were washed with H2O (20
mL) and concentrated in vacuo to give a yellow solid. Purification of
this crude solid by SiO2 column chromatography with 10% NH4OH in
MeOH/CHCl3 (gradient, 1 → 3%) afforded (−)-26 (0.099 g, 68%) as
a white solid: [α]20D −231.0 (c 1.2, CHCl3); mp 223−224 °C; IR (thin
(4aR,7aS,12bR)-3-(Cyclopropylmethyl)-4a,9-dihydroxy-
2,3,4,4a,5,6-hexahydro-1H-benzofuro[3,2-e]isoquinolin-7(7aH)-one
((+)-1). Through a stirred solution of methyl ether (+)-31 (1.63 g, 4.75
mmol) in CH2Cl2 (40 mL) was bubbled HCl gas until the pH of the
solution was ∼3. The solution was cooled to 0 °C, and a solution of
BBr3 (2.3 mL, 24 mmol) in CH2Cl2 (10 mL) was added dropwise.
After being stirred for 15 min at 0 °C, the reaction mixture was
warmed to room temperature. After being stirred at room temperature
for 1.5 h, the solution was cooled to 0 °C, and H2O (50 mL) was
added dropwise. The CH2Cl2 was removed by distillation, and the
remaining aqueous solution was refluxed. After being refluxed for 30
min, the aqueous solution was cooled to 0 °C, and the pH was
adjusted to 9.5 with concentrated NH4OH. The aqueous solution was
extracted with 4:1 CHCl3/MeOH (5 × 10 mL). The combined
organics were concentrated in vacuo to afford a crude white solid.
Purification of this crude solid by SiO2 column chromatography with
10% NH4OH in MeOH/CHCl3 (gradient, 3 → 8%) afforded (+)-1
(1.24 g, 79%) as a white solid: [α]20D +203.1 (c 3.0, CHCl3); mp 175−
177 °C; IR (thin film) 3398,1719 cm−1; 1H NMR (500 MHz, CDCl3)
δ 6.91 (d, J = 6.5 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 6.77 (t, J = 7.5 Hz,
1H), 5.78 (br s, 1H), 4.57 (s, 1H), 2.93−2.76 (m, 4H), 2.47−2.44 (m,
3H), 2.38−2.34 (m, 2H), 1.89−1.70 (m, 3H), 0.91 (m, 1H), 0.55 (d, J
= 7.5 Hz, 2H), 0.14 (d, J = 3.5 Hz, 2H); 13C NMR (125 MHz, CDCl3)
δ 207.8, 147.2, 141.7, 130.9, 121.8, 116.7, 116.5, 90.9, 70.2, 62.7, 59.4,
55.9, 47.7, 34.3, 33.5, 30.7, 8.0, 4.0, 3.9; HRMS (TOF MS ES+) calcd
for C19H24NO4 (M + H+) 330.1705, found 330.1698. Anal. Calcd for
(C19H23NO4): C (69.28), H (7.04), N (4.25). Found: C (68.88),
H(6.94), N (4.47).
1
film) 2204, 1774, 1743, 1722 cm−1; H NMR (500 MHz, CDCl3) δ
7.22, (d, J = 7.5 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.96 (t, J = 7.5 Hz,
1H), 4.49 (s, 1H), 4.42 (d, J = 15.0 Hz, 1H), 3.47 (d, J = 15.0 Hz, 1H),
3.46 (m, 1H), 3.37 (m, 1H), 2.76 (m, 1H), 2.61−2.54 (m, 2H), 2.26
(s, 3H), 2.25 (s, 3H), 2.10 (s, 3H), 1.77−1.69 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 201.6, 169.9, 168.0, 151.4, 135.6, 128.8, 127.8,
122.1 (x2), 117.3, 90.4, 79.9, 55.1, 49.1, 44.5, 31.7, 30.9, 25.1, 21.7,
+
20.4; HRMS (TOF MS ES+) calcd for C20H24N3O6 (M + NH4 )
402.1660, found 402.1661.
(4aR,7aS,12bR)-9-Methoxy-3-methyl-7-oxo-1,2,3,4,5,6,7,7a-octa-
hydro-4aH-benzofuro[3,2-e]isoquinolin-4a-yl Acetate ((+)-28). To
alcohol (+)-23 (0.445 g, 1.47 mmol) was added Ac2O (10 mL). The
reaction mixture was heated to 65 °C and maintained at that
temperature for 1.5 h. The Ac2O was removed by vacuum distillation.
Purification of this crude solid by recrystallization in i-PrOH afforded
(+)-28 (0.306 g, 60%) as a white solid: [α]20D +250.2 (c 1.4, CHCl3);
1
mp 173−176 °C; IR (thin film) 1723 cm−1; H NMR (500 MHz,
CDCl3) δ 7.09 (d, J = 7.0 Hz, 1H), 6.90−6.83 (m, 2H), 4.54 (s, 1H),
3.90 (d, J = 14.0 Hz, 1H), 3.87 (s, 3H), 2.75−2.70 (m, 2H), 2.51 (d, J
= 13.0 Hz, 1H), 2.47−2.42 (m, 3H), 2.37 (s, 3H), 2.03 (s, 3H), 1.81
(m, 1H), 1.71 (d, J = 9.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
203.6, 169.7, 148.4, 145.2, 129.3, 121.4, 117.8, 112.3, 90.4, 82.4, 55.8,
55.6, 54.8, 49.4, 45.8, 34.1, 31.6, 26.2, 22.0; HRMS (TOF MS ES+)
calcd for C19H24NO5 (M + H+) 346.1649, found 346.1649.
Optical rotation of enantiopure (−)-1 (free base): [α]20 −184 (c
D
2.2, CHCl3); mp 161−163 °C
4aH,9-O-trans-Ethyl 3-(Cyclopropylmethyl)-7-hydroxy-9-me-
thoxy-5,7a-dihydro-3H-benzofuro[3,2-e]isoquinoline-6-carboxylate
(( )-34). To a stirred solution of ethyl ester 12 (2.0 g, 6.64 mmol) in
DMF (10 mL) was added cyclopropylmethyl bromide (1.68 mL, 17.3
mmol) in two portions over 2 h. After the reaction mixture was heated
at 50 °C for 2 h, an additional 0.84 mL of cyclopropylmethyl bromide
was added to the reaction mixture, the temperature was increased to
60 °C, and the mixture was stirred for an additional 1 h. TLC analysis
verified disappearance of the starting material, and the reaction mixture
was concentrated in vacuo. To the crude intermediate was added DMF
(10 mL) followed by K2CO3 (1.38 g, 10.0 mmol) and ethyl
bromoacetate (0.810 mL, 7.30 mmol). The reaction mixture was
stirred for 2 h at room temperature, filtered, and concentrated in vacuo
to give crude 32. In a separate flask, anhydrous EtOH (10 mL) was
added to freshly cut pieces of sodium (0.611 g, 26.6 mmol) and
refluxed until a homogeneous solution was obtained. This freshly
prepared NaOEt solution was cooled to room temperature and
cannulated into the crude bis-ethyl ester 32 rinsing with THF (150
(4aR,7aS,12bR)-3-(Cyclopropylmethyl)-4a-hydroxy-9-methoxy-
2,3,4,4a,5,6-hexahydro-1H-benzofuro[3,2-e]isoquinolin-7(7aH)-one
((+)-31) from (+)-28. To a stirred solution of N-methyl (+)-28 (0.289
g, 0.836 mmol) in MeCN (9 mL) were added K2CO3 (0.116 g, 0.836
mmol) and CNBr (5.0 M in MeCN, 184 μL, 0.920 mmol). The
reaction mixture was heated to 75 °C. After being stirred at 75 °C for 1
h, the reaction mixture was cooled to room temperature and
concentrated in vacuo. To the residue were added H2O (10 mL)
and concentrated NH4OH to arrive at a pH ∼9.5. The aqueous layer
was extracted with CHCl3 (3 × 15 mL), and the combined organics
were washed with H2O and concentrated in vacuo to afford (+)-29 as
a crude orange solid that was used without further purification. To the
above crude mixture of (+)-29 were added 3 M HCl (7 mL) and
MeOH (1 mL). The reaction mixture was then heated to 110 °C.
After being heated for 14 h at 110 °C, the reaction mixture was cooled
to room temperature, and concentrated NH4OH was added to arrive
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mL). The reaction mixture was refluxed for 12 h and cooled to −5 °C,
and it was cannulated into a rapidly stirred mixture of saturated
aqueous NH4Cl (9.6 g) and H2O (9.6 g) at −5 °C, rinsing the reaction
flask with THF (3 × 10 mL). The reaction mixture was concentrated
in vacuo to ∼7 mL, removing most of the organics. The aqueous layer
was extracted with CHCl3 (3 × 20 mL), and the combined organics
were concentrated in vacuo to give a dark syrup. This dark syrup was
dissolved in toluene (30 mL) and washed with H2O (15 mL) and
brine (10 mL). The aqueous washes were extracted with toluene (2 ×
25 mL). The combined toluene extracts were concentrated in vacuo to
∼1/3 volume, filtered through Celite, and concentrated in vacuo to
give 34 (1.79 g, 68%) as an orange solid. Spectra matched those
reported by Cheng et al.9
prepared through SiO2 column chromatography with 10% NH4OH in
MeOH/CHCl3 (gradient, 0.5 → 5%): [α]20 +134.5 (c 1.4, CHCl3);
D
1
mp 138−140 °C; IR (thin film) 1656 cm−1; H NMR (500 MHz,
CDCl3) δ 7.09 (t, J = 4.5 Hz, 1H), 6.78 (d, J = 4.0 Hz, 2H), 4.82 (d, J
= 4.5 Hz, 1H), 4.75 (s, 1H), 3.84 (s, 3H), 3.50 (s, 3H), 3.01 (dd, J =
11.5, 4.0, Hz, 1H), 2.90 (d, J = 12.0 Hz, 1H), 2.62 (t, J = 12.0 Hz, 1H),
2.43−2.33 (m, 3H), 2.17 (m, 1H), 1.96−1.86 (m, 4H), 0.93 (m, 1H),
0.55 (d, J = 7.5 Hz, 2H), 0.15 (d, J = 4.5 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 152.4, 148.0, 145.7, 132.0, 119.8, 118.8, 111.6, 98.2,
88.5, 63.8, 55.6, 54.9, 54.4, 48.4, 48.3, 38.3, 37.8, 25.5, 8.3, 3.95, 3.88;
HRMS (TOF MS ES+) calcd for C21H28NO3 (M + H+) 342.2064,
found 342.2064.
(4aS,7aS,12bR)-6-Bromo-3-(cyclopropylmethyl)-7,7,9-trime-
thoxy-2,3,4,4a,5,6,7,7a-octahydro-1H-benzofuro[3,2-e]isoquinoline
((+)-38). To a stirred crude solution of (+)-37 (7.76 g, 22.7 mmol) in
MeOH (100 mL) and THF (50 mL) at −15 °C was added a solution
of methanesulfonic acid (1.62 mL, 25.0 mmol) in MeOH (10 mL)
dropwise followed by a solution of N-bromoacetamide (3.44 g, 25.0
mmol) in MeOH (10 mL). After the mixture was stirred for 15 min at
−15 °C, additional N-bromoacetamide (157 mg, 1.14 mmol) was
added. After the mixture was stirred for an additional 15 min at −15
°C, NH3 gas was bubbled through the solution. The reaction mixture
was concentrated in vacuo, and to the resulting residue were added
concentrated NH4OH (10 mL) and 3 M NaOH (100 mL). The
aqueous mixture was extracted with CHCl3 (3 × 125 mL), washed
with H2O (75 mL), and concentrated in vacuo to afford bromide
Optical Resolution of (4aS,7aS,12bR)-3-(Cyclopropylmethyl)-9-
methoxy-2,3,4,4a,5,6-hexahydro-1H-benzofuro[3,2-e]isoquinolin-7-
(7aH)-one ((+)-36) and (4aR,7aR,12bS)-3-(Cyclopropylmethyl)-9-
methoxy-2,3,4,4a,5,6-hexahydro-1H-benzofuro[3,2-e]isoquinolin-7-
(7aH)-one ((−)-36). To a crude mixture of racemic trans-( )-3610
(22.4 g, 68.3 mmol) in MeCN (240 mL) and MeOH (40 mL) was
added (+)-tartaric acid (5.12 g, 34.1 mmol). The mixture was heated
to solution and subsequently cooled to room temperature. Upon
cooling, crystallization occurred, and the solution was filtered. The
filtrate was dissolved in CHCl3 (200 mL) and H2O (200 mL), and
concentrated NH4OH was added to a pH of ∼9.5. The aqueous layer
was extracted with CHCl3 (3 × 200 mL), washed with H2O (250 mL),
and concentrated in vacuo to afford (−)-36 (3.05 g, >95% ee). The
filtrates were concentrated, basified, and extracted with CHCl3. To this
mixture were added MeCN (160 mL), MeOH (30 mL), and
(+)-tartaric acid (3.66 g, 24.4 mmol). The above crystallization
procedure was repeated affording additional (−)-36 (2.04 g, >95% ee).
The remaining filtrate was concentrated in vacuo and purified by SiO2
column chromatography with 10% NH4OH in MeOH/CHCl3
(gradient, 1 → 4.5%) to give recovered ( )-36 (11.07 g) with an ee
of 83% enriched in (+)-36. To this purified mixture was added MeCN
(145 mL) followed by a warmed solution of (−)-tartaric acid (4.57 g,
30.4 mmol) in MeOH (24 mL). Crystallization occurred immediately,
and the mixture was allowed to cool to room temperature. The solid
was filtered, basified, extracted, and concentrated to afford (+)-36
(7.50 g, >98% ee). The filtrate was concentrated, basified, extracted,
and concentrated to give 3.95 g of a mixture enriched in (+)-36 (86%
ee). To this mixture were added MeCN (50 mL), MeOH (9 mL), and
(+)-tartaric acid (1.63 g, 10.9 mmol). Upon heating, cooling, filtering,
basifying, extracting, and concentrating an additional 2.69 g of (+)-36
(>98% ee) was obtained. All spectral data was obtained on the (+)-36
base containing 0.5·H2O: [α]20D +173.4 (c 3.1, CHCl3); mp 110−116
°C; IR (thin film) 1732 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.04 (d,
J = 7.0 Hz, 1H), 6.84−6.79 (m, 2H), 4.44 (s, 1H), 3.89 (s, 3H), 3.05
(dd, J = 11.5, 3.0 Hz, 1H), 2.93 (d, J = 12.0 Hz, 1H), 2.62 (t, J = 11.5
Hz, 1H), 2.54 (m, 1H), 2.44−2.32 (m, 5H), 2.02 (td, J = 12.8, 4.0 Hz,
1H), 1.91 (d, J = 13.0 Hz, 1H), 1.78 (m, 1H), 1.60 (dtd, J = 12.5, 12.0,
6.0 Hz, 1H), 0.92 (m, 1H), 0.55 (d, J = 7.5 Hz, 2H), 0.15 (d, J = 4.0
Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 207.2, 148.8, 145.2, 130.5,
121.1, 118.6, 112.1, 91.8, 63.4, 55.9, 54.5, 52.3, 48.1, 40.0, 39.3, 38.5,
25.6, 8.3, 3.9, 3.8; HRMS (TOF MS ES+) calcd for C20H26NO3 (M +
H+) 328.1913, found 328.1912. Anal. Calcd for (C20H26NO3.5): C
(71.40), H (7.79), N (4.16). Found: C (71.73), H(7.49), N (4.10).
(+)-38 (10.81 g, 100%) as a tacky white foam that was used without
1
further purification: [α]20 +120.0 (c 2.3, CHCl3); H NMR (500
D
MHz, CDCl3) δ 7.10 (d, J = 6.0 Hz, 1H), 6.80−6.77 (m, 2H), 4.42 (s,
1H), 3.97 (t, J = 9.5 Hz, 1H), 3.86 (s, 3H), 3.59 (s, 3H), 3.51 (s, 3H),
3.04−2.89 (m, 3H), 2.54 (t, J = 11.5 Hz, 1H), 2.49−2.38 (m, 3H),
2.19 (m, 1H), 1.95−1.87 (m, 2H), 1.81 (d, J = 12.5 Hz, 1H), 0.92 (m,
1H), 0.55 (d, J = 7.5 Hz, 2H), 0.15 (d, J = 3.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 148.2, 144.7, 132.0, 120.4, 119.0, 112.4, 98.3,
90.2, 63.7, 56.1, 54.4, 51.7, 49.6, 48.3, 48.1, 47.8, 40.5, 35.6, 35.3, 8.4,
4.1, 3.9; HRMS (TOF MS ES+) calcd for C22H31NO4Br (M + H+)
452.1431, found 452.1433.
(4aS,7aS,12bR)-3-(Cyclopropylmethyl)-7,7,9-trimethoxy-
2,3,4,4a,7,7a-hexahydro-1H-benzofuro[3,2-e]isoquinoline ((+)-39).
To the crude solution of bromide (+)-38 (10.8 g, 22.7 mmol) in
THF (150 mL) was added potassium tert-butoxide (10.2 g, 90.9
mmol). The reaction mixture was heated to reflux. After being stirred
for 4 h at reflux, the reaction mixture was cooled to room temperature
and concentrated in vacuo. To the crude residue were added H2O
(100 mL) and concentrated NH4OH to obtain a pH of ∼9.5, and the
aqueous solution was extracted with CHCl3 (3 × 100 mL). The
combined organic fractions were washed with H2O (200 mL) and
concentrated in vacuo to afford (+)-39 (7.14 g, 85%) as a tacky white
foam, which was used without further purification: [α]20 +145.4 (c
D
4.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.07 (d, J = 7.0 Hz, 1H),
6.74−6.69 (m, 2H), 5.68 (dd, J = 9.5, 3.5 Hz, 1H), 5.64 (d, J = 9.5 Hz,
1H), 4.65 (s, 1H), 3.83 (s, 3H), 3.49 (s, 3H), 3.18−3.13 (m, 2H), 3.12
(s, 3H), 3.05−3.00 (m, 2H), 2.91 (t, J = 12.5 Hz, 1H), 2.78 (m, 1H),
2.54−2.49 (m, 2H), 2.06−2.01 (m, 2H), 0.97 (m, 1H), 0.58 (d, J = 7.5
Hz, 2H), 0.18 (d, J = 4.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ
149.1, 144.3, 135.3, 131.9, 129.8, 119.5, 119.4, 111.8, 98.6, 90.6, 63.6,
56.0, 51.8, 51.0, 48.7, 48.5, 48.1, 38.8, 8.3, 4.0, 3.9; HRMS (TOF MS
ES+) calcd for C22H30NO4 (M + H+) 372.2169, found 372.2171.
(7aS,12bR)-3-(Cyclopropylmethyl)-7,9-dimethoxy-2,3,4,7a-tetra-
hydro-1H-benzofuro[3,2-e]isoquinoline ((+)-40). To a stirred
solution of a portion of crude (+)-39 (4.71 g, 12.7 mmol) in toluene
(500 mL) was added pyridine (12.2 mL, 152 mmol) and POCl3 (2.5
mL, 27 mmol). The reaction mixture was heated at 90 °C for 1.5 h and
cooled to room temperature. To the reaction mixture were added
CHCl3 (200 mL), H2O (400 mL), and concentrated NH4OH to a pH
of ∼9.5. The aqueous fraction was extracted with CHCl3 (3 × 250
mL) and washed with H2O (250 mL), and the combined organics
were concentrated in vacuo to afford (+)-40 (3.95 g, 91%) as a crude
tacky light brown solid that was used without further purification:
[α]20D +12.0 (c 2.2, CHCl3); IR (thin film) 1615 cm−1; 1H NMR (500
Optical rotation of enantiopure (−)-36 (free base): [α]20 −156.5
D
(c 2.1, CHCl3).
(4aS,7aS,12bR)-3-(Cyclopropylmethyl)-7,9-dimethoxy-
2,3,4,4a,5,7a-hexahydro-1H-benzofuro[3,2-e]isoquinoline ((+)-37).
To a stirred solution of (+)-36 (7.73 g, 23.6 mmol) in MeOH (150
mL) was added a premixed solution of 5-sulfosalicylic acid dihydrate
(10.8 g, 42.5 mmol) and trimethyl orthoformate (20.7 mL, 189 mmol)
in MeOH (80 mL). The reaction mixture was refluxed for 1 h, and
then CHCl3 (3 × 50 mL) was added and removed by distillation. The
reaction mixture was cooled to 0 °C, and a precooled solution of 1.5 M
NaOH (500 mL) at 0 °C was added. The aqueous layer was extracted
with CHCl3 (3 × 500 mL), washed with H2O (500 mL), and
concentrated in vacuo to afford (+)-37 (7.85 g, 100%) as a yellow solid
that was used without further purification. An analytical sample was
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dx.doi.org/10.1021/jo500568s | J. Org. Chem. 2014, 79, 5007−5018

The Journal of Organic Chemistry
Article
MHz, CDCl3) δ 7.14 (d, J = 7.5 Hz, 1H), 6.81 (t, J = 7.5 Hz, 1H), 6.77
(d, J = 7.5 Hz, 1H), 5.75 (d, J = 6.5 Hz, 1H), 5.16 (s, 1H), 5.01 (d, J =
6.5 Hz, 1H), 3.86 (s, 3H), 3.61 (s, 3H), 3.53 (d, J = 13.0 Hz, 1H), 3.34
(d, J = 12.5 Hz, 1H), 3.02 (d, J = 11.5 Hz, 1H), 2.67 (t, J = 12.5 Hz,
1H), 2.43 (d, J = 6.5 Hz, 2H), 2.06 (td, J = 12.5, 4.0 Hz, 1H), 1.92 (d,
J = 13.0 Hz, 1H), 0.95 (m, 1H), 0.56 (d, J = 2H), 0.17 (d, J = 4.0 Hz,
2H); 13C NMR (125 MHz, CDCl3) δ 153.2, 146.1, 145.1, 133.9,
128.0, 120.7, 117.9, 117.5, 111.3, 94.3, 88.5, 63.5, 57.7, 55.8, 55.0, 50.3,
49.2, 40.4, 8.6, 4.1, 3.9; HRMS (TOF MS ES+) calcd for C21H26NO3
(M + H+) 340.1907, found 340.1907.
(4aR,7aS,12bR)-3-(Cyclopropylmethyl)-4a-hydroxy-9-methoxy-
2,3,4,4a,5,6-hexahydro-1H-benzofuro[3,2-e]isoquinolin-7(7aH)-one
((+)-31) from (+)-40. To a stirred solution of crude (+)-40 (3.95 g,
11.6 mmol) in 0.7% H2SO4 (30 mL), formic acid (30 mL), and i-
PrOH (30 mL) at 0 °C was added H2O2 (30% in H2O, 2.4 mL, 23
mmol) dropwise. The reaction mixture was stirred for 1.5 h at 0 °C
and warmed to 45 °C. After being stirred for 45 min at 45 °C, the
reaction mixture was cooled to 0 °C. The solution of crude (+)-41 was
hydrogenated (40 psi) using 5% Pd/C (2 g). After being stirred for 1 h
at 0 °C, the reaction mixture was warmed to room temperature. After
the mixture was stirred at room temperature for 24 h, ice and 3 M
NaOH were added until a pH of ∼9.5 was achieved. The slurry was
filtered through Celite, rinsing with H2O (100 mL) and CHCl3 (100
mL). The organics and aqueous fractions were separated. The aqueous
layer was extracted with CHCl3 (3 × 100 mL), washed with H2O (100
mL), and concentrated in vacuo to afford (+)-31 as a crude white
foam. Purification of this crude solid by SiO2 column chromatography
with 10% NH4OH in MeOH/CHCl3 (gradient, 1 → 4%) afforded
(+)-31 (1.73 g, 40% from (+)-40) as a tacky white solid. See the
characterization data reported in (+)-31 from (+)-28.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra. X-ray structures and data tables for
(+)-2 and (+)-21. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kr21f@nih.gov.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work of the Drug Design and Synthesis Section, CBRB,
NIDA, and NIAAA was supported by the NIH Intramural
Research Programs of the National Institute on Drug Abuse
(NIDA) and the National Institute of Alcohol Abuse and
Alcoholism (NIAAA). The X-ray crystallography was supported
by NIDA through an Interagency Agreement No. Y1-DA1101
with the Naval Research Laboratory (NRL). We thank Dr.
Klaus Gawrisch and Dr. Walter Teague (NIAAA) for NMR
access. The authors also express their gratitude to Noel
Wittaker and the Mass Spectrometry Facility at the NIDDK for
the mass spectral data. Preliminary receptor binding studies
were generously provided by the National Institute of Mental
Health’s Psychoactive Drug Screening Program, Contract #
HHSN-271-2008-025C(NIMH PDSP). The NIMH PDSP is
Directed by Bryan L. Roth MD, PhD at the University of North
Carolina at Chapel Hill and Project Officer Jamie Driscol at
NIMH, Bethesda MD, USA.
REFERENCES
■
(1) Feng, Y.; He, X.; Yang, Y.; Chao, D.; Lazarus, L. H.; Xia, Y. Curr.
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