Heteroatom analogues of hydrocodone: Synthesis and biological activity

Article abstract of DOI:10.1021/jo3026753

Heteroatom analogues of hydrocodone, in which the N-methyl functionality was replaced with oxygen, sulfur, sulfoxide, and sulfone, were prepared by a short sequence from the ethylene glycol ketal of hydrocodone; a carbocyclic analogue of bisnorhydrocodone was also prepared. The compounds were tested for receptor binding and revealed moderate levels of activity for the sulfone analogue of hydrocodone.

Full text of DOI:10.1021/jo3026753

Article
pubs.acs.org/joc
Heteroatom Analogues of Hydrocodone: Synthesis
and Biological Activity
Robert D. Giacometti,† Jan Duchek,† Lukas Werner,† Afeef S. Husni,‡ Christopher R. McCurdy,‡
Stephen J. Cutler,‡ D. Phillip Cox,§ and Tomas Hudlicky*,†
†Chemistry Department and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1,
Canada
§Noramco, Inc., 503 Carr Road, Suite 200, Wilmington, Delaware 19809, United States
‡Department of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, 419 Faser Hall, P.O. Box 1848, University,
Mississippi 38677-1848, United States
S
* Supporting Information
ABSTRACT: Heteroatom analogues of hydrocodone, in
which the N-methyl functionality was replaced with oxygen,
sulfur, sulfoxide, and sulfone, were prepared by a short sequence
from the ethylene glycol ketal of hydrocodone; a carbocyclic
analogue of bisnorhydrocodone was also prepared. The com-
pounds were tested for receptor binding and revealed
moderate levels of activity for the sulfone analogue of
hydrocodone.
In an initial effort to address the ability of opioids to act as
agonists and antagonists, Snyder proposed that these properties
might depend on the orientation of the nitrogen substituent
axial versus equatorial.8 Considerations of the orientation of
nitrogen substituents in truncated versions of morphinans, such
as the mixed agonist−antagonists levorphanol (11) and levallorphan
(12), Figure 2, led Lemaire to synthesize and evaluate sulfur
analogues of these compounds in which the orientation of the
methyl or allyl group was fixed.
They prepared and tested both axial and equatorial
derivatives of sulforphanol (13) and sulfallorphan (14), finding
that the sulfonium analogues retained potency. Furthermore,
the agonist versus antagonist activity associated with these com-
pounds was found to depend on the conformation of the
S-substituent in agreement with Snyder’s proposal (equatorial
allyl group confers antagonist activity, axial methyl confers
agonist activity).9
To the best of our knowledge the derivatives prepared by
Lemaire constitute the only examples in which the nitrogen
atom present in the morphinan scaffold was replaced with
another atom. In search of a more complete understanding of
these systems, we chose to synthesize several heteroatom
analogues of hydrocodone, which have the complete hydro-
codone skeleton, whose analgesic activity is well established and
understood. In this paper we report the synthesis of several
oxygen, sulfur, and phosphorus analogues of hydrocodone
(15 and 16, Figure 2), and provide direct comparisons of their
potency.
INTRODUCTION
■
Morphine (1), codeine (2), thebaine (3), oripavine (4), and
other opiate alkaloids (Figure 1) have been the subject of
numerous structural and functional modifications in search for
increased agonist activity, antagonist properties, and to develop
suitable models for receptor binding.1 The outcomes of these
studies led to the development of various medicinally useful
derivatives, such as oxycodone (5), hydrocodone (6),
buprenorphine (7), and the antagonist group represented by
naloxone (8), naltrexone (9), and their N-methylcyclobutyl
analogue nalbuphine. Recently, renewed optimism for design-
ing potent analgesics that lack the traditional side effects
associated with classical opioids, including respiratory depres-
sion, reinforcing behavior, and physical dependence, was
supported by the disclosure of IBNtxA (10).2
The first attempt to describe the activity of morphine
alkaloids using a receptor model was put forth by Beckett and
Casy in 1954,3 but it was later rejected in favor of a multiple
receptor theory proposed by Martin and Portoghese that
addressed biological activity as well as the agonist and
antagonist properties of derivatives.4 The greatly diminished
activities observed for epimers of morphine, as well as for its
enantiomer, provided evidence in support of the latter theory.5
Recent work has expanded on the multiple receptor theory,
with three main types of opioid receptors classified to date on
the basis of their radioligand binding properties: μ (MOR), δ
(DOR), and κ (KOR).6 Additional subdivisions have also been
established for each receptor, following observations of
pharmacologically different properties within the same
subtypes, which has made it difficult, in practice, to develop
opioids that elicit only the desired physiological effects.7
Received: December 12, 2012
© XXXX American Chemical Society
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Figure 1. Morphine alkaloids and medicinally useful semisynthetic derivatives.
Figure 2. Morphinans, their sulfur analogues, and proposed analogues of hydrocodone.
The synthesis of the key aldehyde intermediate 21 is outlined
in Scheme 1. Hydrocodone was converted to methiodide 18,
which afforded amine 19 following Hofmann elimination.
Oxidation of this amine to the corresponding N-oxide 20 and
subsequent exposure to trifluoroacetic acid anhydride furnished
keto-aldehyde 21. Unfortunately, reduction of aldehyde 21 to
the desired alcohol 22 proved to be nonselective, affording
mixtures of diols, diastereomeric at C-6. Consequently, we
decided to protect the C-6 carbonyl with ethylene glycol
and repeated the protocol with ketal 17. In this way, alcohol 27
was prepared in 49% overall yield from hydrocodone on 9 g
scale with a single purification by chromatography during the
last step.
The oxygen analogue of hydrocodone was prepared
according to the route depicted in Scheme 2. Intra-
molecular oxymercuration of alcohol 27 and subsequent
reduction led to ether 28, whose hydrolysis furnished
the desired oxygen analogue of hydrocodone 15a. The
synthesis of sulfur analogue 15b was accomplished by
sulfonylation of alcohol 27 and successive displacement of
the tosylate with potassium thioacetate to deliver 30, as
shown in Scheme 3.
RESULTS AND DISCUSSION
■
The synthesis of compounds of type 15 and 16 was envisaged
to originate from a common intermediate made available
by methods employed in the well-known degradation studies
that led to the final structure elucidation of morphine after
nearly 120 years of effort.10 Of particular interest was the
application of Hofmann’s elimination procedure to codeine by
von Gerichten11 and Knorr,12 with subsequent refinements by
Hesse13 in the 1880s. We envisioned transforming hydro-
codone to a key aldehyde intermediate (21 or 26) by Hofmann
elimination, with a subsequent Polonovksi reaction14 of the
N-oxide derived from the resulting N,N-dimethyl amine 19, or
its protected form 24, Scheme 1. The Potier modification15 of
the Polonovski reaction employs trifluoroacetic anhydride and
allows for the formation of the more stable iminium species,
thereby controlling the regiochemistry of the incipient
aldehyde. Given its potential versatility to access all of the
heteroatom analogues shown in Figure 2, aldehyde 21 was
targeted as the key intermediate. Selective reduction of this
aldehyde would provide alcohol 22, which could be elaborated
to oxygen, sulfur, and related derivatives of hydrocodone.
B
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Scheme 1
Scheme 2
Scheme 3
Free thiol 31 was prepared from thioacetate 30 by treatment
with freshly prepared sodium methoxide in tetrahydrofuran−
methanol (3:1). The resulting thiol was dissolved in benzene
and cyclized to thioether 32 by irradiation under a sunlamp,
Scheme 3. Subsequent hydrolysis of the ketal delivered the
sulfur analogue of hydrocodone 15b.
Treatment of the sulfur analogue 15b with one equivalent
of sodium periodate at room temperature provided a 5:1
mixture of diastereomeric sulfoxides 16a and 16b, Scheme 4.
Alternatively, heating sulfur analogue 15b at 50 °C in the
presence of excess periodate furnished the corresponding
sulfone 15c.
Finally, an attempt was made to prepare phosphonate
analogue 37, as shown in Scheme 5. The key intermediate,
H-phosphinate 36, Scheme 5, was prepared from phosphinate
34, which was itself generated by displacing the triflyl moiety
in 33 with the lithium salt of ethyl (1,1-diethoxyethyl)-
phosphinate.16 This coupling (27 → 33 → 34) proved to be
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Scheme 4
Scheme 5
Scheme 6
very challenging; the best yields obtained were around 40% on a
150 mg scale, and the product was obtained as a 1:1 mixture of
two diastereomers. On a 600 mg scale the yield of 34 dropped
to 24% and chloride 35 (1%) was isolated as the side-product.
The structure of 35 was unambiguously confirmed by
transforming alcohol 27 to chloride 35 by the Appel reaction.
The chloride atom may have originated from a side reaction
between dichloromethane (solvent used for the preparation of
the triflate) and lithium ethyl (1,1-diethoxyethyl)phosphinate.
Notably, it was necessary to use triflate 33 as a solution,
given that all attempts to isolate it led to uncharacterized
decomposition products, as inferred from a color change of
the crude triflate from colorless to dark blue and the
corresponding TLC analysis. Given the low yield of chloride
35, other solvents were not tested to prepare the desired
triflate. Deprotection of the 1,1-diethoxyethyl group in 34 with
TMSCl gave H-phosphinate 36, which was used directly in the
next step without further purification. Attempts to cyclize 36
to 37 under radical or basic conditions were not successful. We
tested photochemically initiated cyclizations17 and reactions
initiated by (t-BuO)2,18 air,19 t-butyl peroxypivalate, AIBN, n-
BuLi/HMDS, and t-BuOK/mercury trifluoroacetate. Following
our unfruitful effort to uncover efficient cyclization conditions
we decided to deprotect ketal 36 with HCl in ethanol and
obtained H-phosphinate 38 as a 1:1 mixture of diastereomers in
20% yield over two steps from 34. This open-chain analogue 38
was also evaluated for biological activity.
In one of our earlier approaches to form a carbon−
phosphorus bond at C-9 we treated tosylate 29 under Finkelstein
conditions and exposed the resulting iodide 39 to bis-
(trimethylsilyl)phosphine (BTSP), as shown in Scheme 6.20
To our surprise, we isolated a carbocyclic product 40 in 84%
yield, which likely formed through a radical pathway. A related
reduction of iodomethyl nucleosides to methyl nucleosides by
BTSP was reported by An and co-workers.21 The structure of
40 was unambiguously confirmed by X-ray crystallography.22
BIOLOGICAL ACTIVITY PROFILES
■
Heteroatom analogues of hydrocodone and open-chain
H-phosphinate 38 were subjected to in vitro radioligand
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(TLC) carried out on precoated 60 Å 250 μm silica gel TLC plates
with F-254, indicator visualized under UV light, and developed using
ceric ammonium molybdate, 2,4-dinitrophenylhydrazine, or potassium
permanganate stains followed by heating. Column chromatography
was performed using 40−66 μm silica gel. Gravity column
chromatography was performed without external pressure, while
flash column chromatography was performed under slightly elevated
pressure (0.1−0.4 bar). Specific rotation measurements are reported in
units of deg·cm3·g−1·dm−1, with the concentration, c, given in units of
grams per 100 mL of solution. IR spectra were obtained on an FT-IR
spectrometer and are reported in terms of frequency of absorption
displacement assays using human opioid receptors (subtypes δ,
κ and μ) at a concentration of 10 μM. In this preliminary screen
a “hit”, or active compound, is defined as having displaced
≥50% of radioligand at a given opioid receptor. Sulfone 15c
selectively inhibited 69.1% of the specific binding of [3H]-
DAMGO to CHO-K1 cell membranes expressing human
μ−opioid receptors at the concentration of 10 μM. None of the
other compounds tested demonstrated any appreciable affinity
for human opioid receptors. As a control, naloxone was used
and showed 97.6% displacement at δ−opioid receptors, 99.1%
displacement at κ−opioid receptors, and 101.9% displacement
at μ−opioid receptors. Sulfone 15c was not investigated further
to determine a Ki value. Another control, hydrocodone (6), was
also screened and exhibited affinities at the three opioid
receptors that are in agreement with previous literature reports
(Table 1).
1
(cm−1). H NMR spectra were recorded at 300 MHz or at 600 MHz
and are reported as follows: chemical shift (multiplicity, coupling
constant (Hz), and integration). The following abbreviations were
used to explain multiplicities: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, br = broad, dd = doublet of doublets,
dt = doublet of triplets, ddt = doublet of doublet of triplets. 13C NMR
spectra were recorded at 75 MHz or at 151 MHz and are reported
in terms of chemical shift. All chemical shifts were calibrated using
residual nondeuterated solvent as an internal reference and are
reported in parts per million relative to trimethylsilane. High-
resolution mass spectra (HRMS) were recorded on a high resolution
E/B mass spectrometer using a double-focusing magnetic-sector mass
analyzer.
Table 1. Binding Affinity Assay of the Compounds for
Human Opioid Receptors (subtypes δ, κ, and μ)
opioid receptors (%)
compound
δ
κ
μ
15a
15b
7.1
−21.6
−16.3
−21.2
−19.3
−15.5
99.1
−1.2
6.1
(4R,4aR,7aR,12bS)-9-Methoxy-3-methyl-1,2,3,4,4a,5,6,7a-
octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-
[1,3]dioxolane] (17).
0.8
16a, 16b
−5.1
1.7
−0.3
6.6
38
15c
−3.2
97.6
7760
69.1
101.9
5500
Naloxone
Hydrocodone (Ki, nM)
15.2 0.2
CONCLUSIONS
■
A solution of hydrocodone (9.22 g, 30.8 mmol) in dichloromethane
(100 mL) and ethylene glycol (110 mL, 1.95 mmol) was treated with
trimethylsilyl chloride (23 mL, 181 mmol), and the resulting yellow
mixture was stirred at room temperature for 24 h. The reaction
mixture was then poured into a cooled (4 °C), saturated aqueous
solution of sodium bicarbonate (500 mL) and stirred until
effervescence ceased (≈1 h). The mixture was diluted with
dichloromethane (300 mL) and the layers were separated. The
aqueous layer was extracted with dichloromethane (4 × 400 mL) and
the combined organic extracts were washed with brine (400 mL),
dried over magnesium sulfate, filtered, and concentrated under
reduced pressure to provide crude ketal 17 (10.6 g) as a colorless
solid, which was used in the next step without further purification. Rf
0.30 (2:1 CH2Cl2−MeOH); IR (KBr disc): ν 3450 (w), 3026 (m),
3003 (w), 2986 (w), 2948 (s), 2923 (s), 2899 (s), 2880 (m), 2862
(m), 2834 (m), 2790 (m), 2767 (w), 1638 (m), 1614 (s), 1503 (s),
1445 (s), 1414 (w), 1384 (m), 1371 (m), 1350 (m), 1332 (m), 1278
(s), 1246 (s), 1195 (s), 1182 (s), 1138 (m), 1104 (s), 1057 (s), 1012
Several heteroatom analogues of hydrocodone were synthesized
and evaluated in preliminary opioid screening assays to
establish their binding potential for human opioid receptors.
We expected that sulfoxides 16a and 16b would display
activities similar to those reported by Lemaire for diastereomers
of 13 and 14, but to our surprise, the only derivative that
demonstrated modest activity, compared to hydrocodone and
naloxone, was sulfone 15c. Furthermore, sulfone 15c only
exhibited displacement at the μ−opioid receptor. It is difficult
to interpret this result, as there is no axial or equatorial
distinction in the orientation of substituents, but it is not
surprising that heteroatom substitution at the N-17 position
diminishes activity relative to that of compounds containing
nitrogen. Given that all attempts to cyclize H-phosphinate 36
were unsuccessful, we were unable to evaluate phosphorus
analogue 37. However, future work in this area should address
the isoelectronic series of phosphorus analogues at position 17,
such as P-Me, P-allyl, and P-cyclopropylmethyl. Such
compounds could be compared with the known N-substituted
analgesics for biological activity profiles. We will report on this,
and other endeavors in this area, in the near future.
1
(m), 997 (m), 973 (m), 958 (s), 922 (s), 902 (m) cm−1; H NMR
(CDCl3, 300 MHz): δ 6.74 (d, J = 8.2 Hz, 1H), 6.62 (d, J = 8.2 Hz,
1H), 4.49 (s, 1H), 4.19 (td, J = 6.8, 5.4 Hz, 1H), 4.03 (dd, J = 12.8, 6.5
Hz, 1H), 3.92−3.84 (m, 4H), 3.79 (td, J = 6.4, 5.5 Hz, 1H), 3.11 (dd,
J = 4.7, 2.6 Hz, 1H), 3.00 (d, J = 18.4 Hz, 1H), 2.53 (dd, J = 12.1, 3.8
Hz, 1H), 2.43−2.31 (m, 4H), 2.27−2.16 (m, 2H), 1.88 (td, J = 12.2,
4.9 Hz, 1H), 1.73−1.62 (m, 2H), 1.59−1.47 (m, 2H), 1.15 (qd, J =
12.6, 2.2 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 146.6, 142.3, 129.2,
126.4, 118.8, 113.6, 108.7, 94.5, 66.6, 65.0, 59.7, 56.7, 47.3, 43.7, 43.0,
42.6, 36.6, 33.5, 22.5, 20.3; LRMS-EI (m/z): 344 (23), M+ 343 (100),
244 (17), 99 (71), 59 (21), 42 (19); HRMS-EI (m/z): M+ calcd for
C20H25NO4, 343.1784; found, 343.1782.
EXPERIMENTAL SECTION
■
General. All nonaqueous reactions were performed in oven or
flame-dried glassware under inert atmosphere, with exclusion of
moisture from reagents and glassware, unless otherwise stated.
Anhydrous solvents were obtained by distillation: dichloromethane,
N,N-dimethylformamide, N,N-diisopropylethylamine, and pyridine
from calcium hydride; methanol from magnesium methoxide;
tetrahydrofuran from sodium−benzophenone; and toluene from
sodium. Reactions were monitored by thin-layer chromatography
Physical and spectral data were found to be in accordance with
those reported by Mulzer.23
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(4R,4aR,7aR,12bS)-9-Methoxy-3,3-dimethyl-1,2,3,4,4a,5,6,7a-
octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-
[1,3]dioxolan]-3-ium iodide (23).
1.5 h, then at 25 °C for 21 h, before small portions of manganese(IV)
oxide (several spatula tips) were added over 2 h (until effervescence
ceased and potassium iodide/starch test for peroxides was negative).
The mixture was filtered through Celite (washed with methanol), con-
centrated under reduced pressure, and dried under high vacuum to
afford crude N-oxide 25 (10.94 g) as a colorless solid, which was used
directly in the next step without further purification. 1H NMR (CDCl3,
300 MHz): δ 6.74 (d, J = 7.9 Hz, 1H), 6.66 (d, J = 7.9 Hz, 1H), 6.39
(d, J = 9.4 Hz, 1H), 5.83 (dd, J = 9.4, 5.7 Hz, 1H), 4.72 (s, 1H), 4.25−
4.17 (m, 1H), 4.04−3.96 (m, 1H), 3.92−3.78 (m, 2H), 3.89 (s, 3H),
3.42−3.30 (m, 1H), 3.09 (s, 3H), 3.05−2.94 (m, 1H), 2.99 (s, 3H),
2.47−2.37 (m, 1H), 2.30 (td, J = 12.8, 4.9 Hz, 1H), 2.16 (td, J = 12.4,
4.9 Hz, 1H), 1.64−1.54 (m, 1H), 1.42 (td, J = 13.6, 2.3 Hz, 1H),
1.33−1.15 (m, 2H).
A suspension of crude 17 (10.6 g, theor. 30.8 mmol) in ethanol
(65 mL) was treated with iodomethane (22 mL, 353 mmol) and the
mixture was refluxed for 8 h. It was treated with additional iodo-
methane (2 mL, 32 mmol) and stirred at 60 °C for 12 h before it was
cooled to 4 °C. The precipitate was filtered off, washed with cold Et2O
(100 mL), and dried to obtain crude methiodide 23 (15.1 g) as a
colorless solid, which was used in the next step without further
purification.
2-((3a′R,3a1′S,9a′S)-5′-Methoxy-2′,3a′,3a1′,9a′-tetrahydro-1′H-
spiro[[1,3]dioxolane-2,3′-phenanthro[4,5-bcd]furan]-3a1′-yl)-
acetaldehyde (26).
2-((3a′R,3a1′S,9a′S)-5′-Methoxy-2′,3a′,3a1′,9a′-tetrahydro-1′H-
spiro[[1,3]dioxolane-2,3′-phenanthro[4,5-bcd]furan]-3a1′-yl)-N,N-
dimethylethanamine (24).
An orange solution of N-oxide 25 (10.94 g, theor. 29.30 mmol) in
dichloromethane (200 mL) was treated with trifluoroacetic anhydride
(21 mL, 149 mmol) at room temperature over 30 min; the solution
darkened during this time. After 3.5 h the reaction mixture was slowly
poured into a cooled (4 °C) saturated aqueous solution of sodium
bicarbonate (400 mL), and extracted with dichloromethane (3 ×
200 mL). The combined organic layers were washed with brine (100 mL),
dried over magnesium sulfate, filtered, and concentrated under
reduced pressure to furnish crude aldehyde 26 (8.72 g) as a colorless
foam, which was used directly in the next step without further
purification. An analytical sample was obtained by flash column
chromatography (2:1 hexanes−ethyl acetate). Rf 0.45 (1:1 hexanes−
A suspension of crude salt 23 (15.1 g, theor. 30.8 mmol) in water
(75 mL) was stirred at 90 °C until the solid dissolved, then treated
with an aqueous 6.7 M solution of sodium hydroxide (6 mL), and
stirred at reflux for 2 h before it was cooled to 25 °C. The mixture was
diluted with water (100 mL) and extracted with dichloromethane (6 ×
100 mL). The combined organic layers were washed with brine
(150 mL), dried over magnesium sulfate, filtered, and concentrated
under reduced pressure to afford crude amine 24 (10.62 g) as a thick
colorless syrup, which was used in the next step without further
purification. On a smaller, 3 g scale, the syrup gradually crystallized on
standing. Rf 0.32 (2:1 CH2Cl2−MeOH); mp 68−70 °C; [α]D22 +29.0
(c 1.0, chloroform); IR (KBr disc): ν 3426 (w), 3029 (w), 2942 (s),
2916 (m), 2892 (m), 2858 (m), 2815 (m), 2763(m), 1638 (m), 1623
(m), 1576 (w), 1501 (s), 1467 (m), 1447 (s), 1385 (s), 1339 (m),
1326 (w), 1274 (s), 1256 (s), 1211 (m), 1200 (m), 1179 (m), 1164
(m), 1098 (s), 1058 (s), 1042 (s), 1002 (m), 976 (m), 919 (m) cm−1;
1H NMR (CDCl3, 600 MHz): δ 6.70 (d, J = 8.0 Hz, 1H), 6.62 (d, J =
20
EtOAc); mp 110−112 °C (Et2O); [α]D +37.6 (c 0.5, CHCl3); IR
(KBr disc): ν 3415 (w), 3044 (w), 3028 (w), 2952 (m), 2927 (m),
2890 (m), 2853 (w), 2833 (w), 2754 (w), 2739 (w), 1718 (s), 1638
(w), 1627(w), 1576 (w), 1500 (m), 1554 (m), 1437 (m), 1385 (s),
1331 (w), 1283 (m), 1251 (m), 1200 (w), 1162 (m), 1105 (m), 1061
(m), 1045 (m), 1026 (m), 960 (w), 906 (w) cm−1; 1H NMR (CDCl3,
300 MHz): δ 9.57 (s, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.66 (d, J = 8.1
Hz, 1H), 6.43 (d, J = 9.6 Hz, 1H), 5.78 (dd, J = 9.5, 5.7 Hz, 1H), 4.83
(s, 1H), 4.26−4.19 (m, 1H), 4.02 (dd, J = 12.6, 6.3 Hz, 1H), 3.92−
3.78 (m, 5H), 2.73 (dd, J = 16.3, 1.7 Hz, 1H), 2.59−2.50 (m, 2H),
1.81−1.72 (m, 1 H), 1.63−1.57 (m, 2H), 1.35−1.20 (m, 1H); 13C
NMR (CDCl3, 75 MHz): δ 201.2, 146.2, 144.2, 129.5, 126.9, 123.7,
123.0, 117.8, 113.3, 108.1, 94.3, 66.6, 65.0, 56.4, 50.9, 44.9, 38.6, 31.3,
25.3; LRMS-EI (m/z): M+ 328 (51), 285 (15), 199 (53), 198 (16), 99
(100); HRMS-EI (m/z): M+ calcd for C19H20O5, 328.1311; found,
328.1308; Anal. calcd for C19H20O5: C, 69.50; H, 6.14; found: C,
69.47; H, 6.23.
8.1 Hz, 1H), 6.36 (d, J = 9.8 Hz, 1H), 5.78 (dd, J = 9.5, 5.7 Hz, 1H),
4.73 (s, 1H), 4.22 (td, J = 6.9, 4.9 Hz, 1H), 4.03 (q, J = 6.8 Hz, 1H),
3.90−3.85 (m, 4H), 3.81 (td, J = 6.6, 5.1 Hz, 1H), 2.45−2.38 (m, 2H),
2.16−2.10 (m, 7H), 1.79 (ddd, J = 13.3, 11.2, 4.9 Hz, 1H), 1.74−1.70
(m, 1H), 1.66 (ddd, J = 13.4, 11.0, 4.9 Hz, 1H), 1.58 (ddd, J = 13.1,
4.0, 2.3 Hz, 1H), 1.41 (td, J = 13.6, 2.6 Hz, 1H); 13C NMR (CDCl3,
150 MHz): δ 146.2, 143.8, 129.7, 128.2, 123.2, 123.0, 117.4, 112.6,
108.3, 94.3, 66.6, 64.9, 56.3, 54.9, 45.7, 45.5, 38.9, 36.1, 31.6, 25.3;
LRMS-EI (m/z): M+ 357 (25), 286 (53), 284 (22), 199 (22), 198
(78), 185 (15), 99 (100), 73 (48), 58 (50), 45 (83); HRMS-EI (m/z):
M+ calcd for C21H27NO4, 357.1940; found, 357.1940.
2-((3a′R,3a1′S,9a′S)-5′-Methoxy-2′,3a′,3a1′,9a′-tetrahydro-1′H-
spiro[[1,3]dioxolane-2,3′-phenanthro[4,5-bcd]furan]-3a1′-yl)-
ethanol (27).
2-((3a′R,3a1′S,9a′S)-5′-Methoxy-2′,3a′,3a1′,9a′-tetrahydro-1′H-
spiro[[1,3]dioxolane-2,3′-phenanthro[4,5-bcd]furan]-3a1′-yl)-N,N-
dimethylethanamine Oxide (25).
A brown solution of crude aldehyde 26 (8.72 g, theor. 26.5 mmol) in
ethanol (200 mL) at 4 °C was treated with sodium borohydride (3.22 g,
85.0 mmol) in three portions over 30 min. The resulting suspension
was stirred at 4 °C for 30 min, and at 25 °C for 1 h before it was
cooled to 4 °C, and diluted slowly with water (200 mL). The mixture
was further diluted with ethyl acetate (200 mL) and treated with solid
A solution of crude amine 24 (10.62 g, theor. 29.71 mmol) in methanol
(80 mL) was cooled to 4 °C and treated with aqueous 30% (w/w)
hydrogen peroxide over 30 min. The mixture was stirred at 4 °C for
F
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potassium carbonate (200 g). The layers were separated and the
aqueous layer was extracted with ethyl acetate (4 × 200 mL). The
combined organic layers were washed with brine (200 mL), dried over
magnesium sulfate, filtered, and concentrated under reduced pressure
to provide crude alcohol 27 as a colorless oil (8.79 g). Flash column
chromatography (3:2 hexanes−ethyl acetate) afforded 27 (5.0 g, 49%
overall from hydrocodone 6) as a pale yellow solid. Recrystallization
from diethyl ether afforded an analytically pure sample of alcohol 27 as
a colorless solid. Rf 0.26 (1:1 hexanes−EtOAc); mp 100−101 °C
(Et2O); [α]D18 +44.2 (c 0.5, CHCl3); IR (KBr disc): ν 3492 (s), 3450
(s), 2997 (w), 2954 (m), 2929 (m), 2894 (m), 2861 (m), 2838 (w),
2362 (w), 2343 (w), 1635 (m), 1578 (w), 1504 (s), 1451 (m), 1435
(m), 1385 (s), 1340 (w), 1276 (m), 1241 (w), 1186 (m), 1162 (m),
1095 (m), 1058 (m), 1038 (m), 1004 (m), 951 (w), 915 (m) cm−1;
1H NMR (CDCl3, 600 MHz): δ 6.72 (d, J = 8.1 Hz, 1H), 6.65 (d, J =
8.1 Hz, 1H), 6.37 (d, J = 9.6 Hz, 1H), 5.81 (dd, J = 9.5, 5.6 Hz, 1H),
4.81 (s, 1H), 4.22 (td, J = 6.9, 4.8 Hz, 1H), 4.01 (q, J = 6.8 Hz, 1H),
3.89−3.85 (m, 4H), 3.81 (td, J = 6.6, 4.7 Hz, 1H), 3.58−3.51 (m,
2H), 2.44−2.39 (m, 1H), 1.94 (dt, J = 13.9, 6.1 Hz, 1H), 1.78 (dt,
J = 13.8, 6.8 Hz, 1H), 1.76−1.71 (m, 1H), 1.60−1.56 (m, 2H), 1.43
(td, J = 13.6, 2.6 Hz, 1H), 1.26 (qd, J = 13.8, 2.3 Hz, 1H); 13C NMR
(CDCl3, 150 MHz) δ 146.3, 143.9, 129.9, 127.6, 123.2, 123.1,
117.7, 112.8, 108.1, 95.2, 66.6, 64.9, 59.5, 56.3, 45.6, 42.0, 39.7,
31.5, 25.3; LRMS-EI (m/z): M+ 330 (18), 285 (11), 199 (20), 99
(100); HRMS-EI (m/z): M+ calcd for C19H22O5, 330.1467; found,
330.1465; Anal. calcd for C19H22O5: C, 69.07; H, 6.71; found: C,
69.19; H, 6.77.
(4R,4aR,7aR,12bS)-9-Methoxy-1,2,4,4a,5,6-hexahydro-4,12-
methanobenzofuro[3,2-e]isochromen-7(7aH)-one (15a).
A solution of ketal 28 (220 mg, 0.66 mmol) in methanol (22 mL) was
treated with an aqueous solution of hydrochloric acid (3 mL, 36
mmol) and vigorously stirred at 65 °C for 1.5 h. The reaction mixture
was cooled to 25 °C, diluted with water (20 mL), basified slowly with
a saturated aqueous solution of sodium bicarbonate (9 mL), and
diluted with dichloromethane (25 mL). The layers were separated and
the aqueous layer was extracted with dichloromethane (4 × 25 mL).
The combined organic layers were washed with brine (40 mL), dried
over magnesium sulfate, filtered, and concentrated under reduced
pressure. Flash column chromatography (2:3 hexanes−ethyl acetate)
afforded hydrocodone oxygen analogue 15a (182 mg, 95%) as a
colorless solid. Rf 0.16 (1:1 hexanes−EtOAc); mp 177−178 °C
18
(Et2O); [α]D −154.3 (c 0.77, CHCl3); IR (KBr disc): ν 3435 (w),
2935 (m), 2922 (m), 2859 (m), 1727 (s), 1633 (w). 1611 (m), 1503
(s), 1444 (s), 1384 (m), 1346 (w), 1323 (m), 1275 (s), 1240 (w),
1199 (m), 1181 (m), 1162 (w), 1124 (m), 1078 (s), 1066 (s), 1038
(m), 1006 (w), 993 (w), 962 (m), 949 (m), 901 (m) cm−1; 1H NMR
(CDCl3, 600 MHz): δ 6.74 (d, J = 8.2 Hz, 1H), 6.67 (d, J = 8.2 Hz,
1H), 4.65 (s, 1H), 4.28 (t, J = 3.9 Hz, 1H), 3.91 (s, 3H), 3.74 (dd, J =
12.2, 5.3 Hz, 1H), 3.55 (td, J = 12.3, 3.0 Hz, 1H), 2.94 (d, J = 18.7 Hz,
1H), 2.83 (dd, J = 18.7, 5.3 Hz, 1H), 2.64 (dt, J = 12.9, 3.7 Hz, 1H),
2.45 (dt, J = 13.9, 3.2 Hz, 1H), 2.38 (td, 13.9, 4.6 Hz, 1H), 2.11 (td,
J = 12.4, 5.4 Hz, 1H), 1.86−1.82 (m, 1H), 1.74 (dd, J = 12.5, 2.5 Hz,
1H), 1.12 (qd, J = 13.5, 3.2 Hz, 1H); 13C NMR (CDCl3, 150 MHz) δ
207.2, 145.4, 143.0, 126.7, 125.5, 119.9, 114.9, 91.1, 72.5, 59.9, 56.7,
46.7, 42.1, 40.1, 36.0, 29.2, 24.5; LRMS-EI (m/z): 287 (19), M+ 286
(100), 185 (12); HRMS-EI (m/z): M+ calcd for C17H18O4, 286.1205;
found, 286.1202; Anal. calcd for C17H18O4: C, 71.31; H, 6.34; found:
C, 70.76; H, 6.37 (discrepancy due to presence of residual H2O/
Et2O).
(4R,4aR,7aR,12bS)-9-Methoxy-2,4,4a,5,6,7a-hexahydro-1H-spiro-
[4,12-methanobenzofuro[3,2-e]isochromene-7,2′-[1,3]dioxolane]
(28).
2-((3a′R,3a1′S,9a′S)-5′-Methoxy-2′,3a′,3a1′,9a′-tetrahydro-1′H-
spiro[[1,3]dioxolane-2,3′-phenanthro[4,5-bcd]furan]-3a1′-yl)ethyl
4-Methylbenzenesulfonate (29).
A solution of alcohol 27 (400 mg, 1.21 mmol) in tetrahydrofuran
(22 mL) was treated with mercury(II) trifluoroacetate (784 mg,
1.70 mmol) at 0 °C and the mixture was stirred at 0 °C for 1.7 h. An
aqueous solution of sodium hydroxide (20 mL, 20 mmol) was added,
followed immediately by sodium borohydride (183 mg, 4.84 mmol).
The mixture was stirred at 0 °C for 20 min, diluted with water
(40 mL) and ethyl acetate (75 mL), then saturated with potassium
carbonate. The layers were separated and the aqueous layer was
extracted with ethyl acetate (4 × 75 mL). The combined organic layers
were washed with brine (100 mL), dried over magnesium sulfate,
filtered, and concentrated under reduced pressure. Flash column
chromatography (2:1 hexanes−ethyl acetate) afforded ether 28 (220
mg, 55%) as a colorless solid. Rf 0.37 (1:1 hexanes−EtOAc); mp 176−
177 °C (Et2O); [α]D18 −131.7 (c 1.0, CHCl3); IR (KBr disc): ν 3449
(w), 2951 (m), 2918 (s), 2864 (m), 2837 (m), 1638 (m), 1614 (m),
1503 (s), 1440 (s), 1384 (s), 1326 (m), 1277 (s), 1244 (m), 1194 (s),
1175 (m), 1129 (w), 1107 (w), 1065 (s), 1016 (m), 960 (m), 920
To a solution of alcohol 27 (515 mg, 1.56 mmol) in dichloromethane
(8 mL) and pyridine (8 mL) at −8 °C was added p-toluenesulfonyl
chloride (577 mg, 3.03 mmol) and the mixture was allowed to stand
at −8 °C for 24 h. The mixture was diluted with a saturated aqueous
solution of sodium bicarbonate (10 mL), water (10 mL), and
dichloromethane (25 mL) and the mixture was vigorously stirred at
25 °C for 10 min. The layers were separated and the aqueous layer
extracted with dichloromethane (4 × 25 mL). The combined organic
layers were washed with brine (50 mL), dried over magnesium sulfate,
filtered, and concentrated under reduced pressure. The remaining oil,
which contained residual pyridine, was triturated with toluene (3 ×
6 mL) and then purified by flash column chromatography (2:1 hexanes−
ethyl acetate) to afford tosylate 29 (717 mg, 95%) as a colorless solid.
1
(m), 904 (w) cm−1; H NMR (CDCl3, 600 MHz): δ 6.66 (d, J =
8.2 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 4.46 (s, 1H), 4.21 − 4.17 (m, 2H),
4.05 (q, J = 6.7 Hz, 1H), 3.92−3.87 (m, 4H), 3.80 (td, J = 6.6, 5.4 Hz,
1H), 3.68 (dd, J = 12.1, 5.1 Hz, 1H), 3.57 (td, J = 12.3, 3.1 Hz, 1H),
2.92 (d, J = 18.4 Hz, 1H), 2.86 (dd, J = 18.6, 5.0 Hz, 1H), 2.26 (dt, J =
12.6, 3.8 Hz, 1H), 1.90 (td, J = 12.4, 5.4 Hz, 1H), 1.68 −1.60 (m, 2H),
1.56−1.50 (m, 2H), 1.01 (qd, J = 12.9, 3.3 Hz, 1H); 13C NMR
(CDCl3, 150 MHz) δ 146.5, 142.3, 128.6, 125.7, 118.7, 113.7, 108.3,
94.0, 72.9, 66.4, 64.9, 60.0, 56.5, 43.5, 41.9, 37.1, 32.9, 29.3, 21.2;
LRMS-EI (m/z): 331 (22), M+ 330 (100), 125 (11), 112 (10), 99
(72), 55 (13); HRMS-EI (m/z): M+ calcd for C19H22O5, 330.1467;
found, 330.1467; Anal. calcd for C19H22O5: C, 69.07; H, 6.71; found:
C, 68.91; H 6.72.
18
Rf 0.25 (2:1 hexanes−EtOAc 2:1); mp 119−120 °C (Et2O); [α]D
+20.0 (c 0.6, CHCl3); IR (KBr disc): ν 3450 (w), 3066 (w), 3031 (w),
3006 (w), 2963 (m), 2938 (s), 2916 (m), 2895 (m), 2881 (m), 2852
(m), 1929 (w), 1821 (w), 1735 (w), 1697 (w), 1637 (m), 1622 (m),
1598 (m), 1575 (m), 1504 (s), 1450 (s), 1385 (m), 1356 (s), 1339
(m), 1308 (w), 1278 (s), 1249 (m), 1214 (m), 1179 (s), 1119 (w),
1096 (m), 1064 (s), 1043 (s), 1021 (m), 997 (m), 964 (s), 918 (m)
1
cm−1; H NMR (CDCl3, 600 MHz): δ 7.71 (d, J = 8.3 Hz, 2H), 7.30
G
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(d, J = 8.1 Hz, 2H), 6.70 (d, J = 8.1 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H),
6.32 (d, J = 9.5 Hz, 1H), 5.75 (dd, J = 9.5, 5.6 Hz, 1H), 4.59 (s, 1H),
4.19 (td, J = 6.9, 4.9 Hz, 1H), 4.05 (ddd, J = 10.1, 8.9, 5.8 Hz, 1H),
3.98 (q, J = 13.5, 6.8 Hz, 1H), 3.93 (ddd, J = 10.2, 8.7, 6.3 Hz, 1H),
3.87−3.83 (m, 4H), 3.79 (td, J = 6.6, 4.8 Hz, 1H), 2.44 (s, 3H),
2.35−2.30 (m, 1H), 2.00 (ddd, J = 14.8, 8.8, 6.3 Hz, 1H), 1.85
(ddd, J = 14.1, 8.6, 5.8 Hz, 1H), 1.73−1.68 (m, 1H), 1.55 (ddd, J =
13.2, 3.8, 2.4 Hz, 1H), 1.36 (td, J = 13.6, 2.5 Hz, 1H), 1.24−1.17
(m, 1H); 13C NMR (CDCl3, 150 MHz): δ 146.2, 144.6, 144.0,
133.0, 129.8, 129.5, 127.8, 126.5, 123.2, 123.1, 117.7, 113.2, 108.0,
94.5, 67.3, 66.5, 64.9, 56.4, 45.0, 39.1, 38.1, 31.4, 25.3, 21.6; LRMS-
EI (m/z): M+ 484 (1), 199 (14), 99 (100), 57 (10), 45 (12), 43
(43); HRMS-EI (m/z): M+ calcd for C26H28O7S, 484.1556; found,
484.1558; Anal. calcd for C26H28O7S: C, 64.45; H, 5.82; found: C,
64.60; H, 5.91.
during the workup for 25 min prior to use. The reaction mixture was
acidified with aqueous citric acid (15 mL, 5% w/v) and diluted with
dichloromethane. The layers were separated and the aqueous layer
extracted with dichloromethane (4 × 25 mL). The combined organic
layers were washed with brine (30 mL), dried over magnesium sulfate,
filtered, and concentrated under reduced pressure to provide crude
thiol 31 (88 mg) as an oil that was used directly in the next step
without further purification.
A solution of thiol 31 (44 mg) in deoxygenated benzene (2 mL)
was stirred under a sunlamp for 36 h at 25 °C. Evaporation and flash
column chromatography (3:1 hexanes−EtOAc) afforded 32 (9 mg,
15% yield) as a solid.
Data for 31: Rf 0.40 (2:1 hexanes−EtOAc); LRMS-EI (m/z): M+
346 (44), 285 (15), 199 (29), 99 (100), 84 (25).
Data for 32: Rf 0.38 (2:1 hexanes−EtOAc); mp 197−198 °C
S-(2-((3a′R,3a1′S,9a′S)-5′-Methoxy-2′,3a′,3a1′,9a′-tetrahydro-
1′H-spiro[[1,3]dioxolane-2,3′-phenanthro[4,5-bcd]furan]-3a1′-yl)-
ethyl) Ethanethioate (30).
21
(Et2O); [α]D −279.3 (c 0.5, CHCl3); IR (KBr disc): ν 3448 (w),
2997 (w), 2949 (m), 2931 (m), 2906 (s), 2883 (m), 2832 (m), 1633
(m), 1606 (m), 1502 (s), 1438 (s), 1384 (s), 1352 (w), 1327 (m),
1277 (s), 1242 (m), 1194 (s), 1140 (m), 1113 (m), 1097 (m), 1061
(s), 1034 (w), 1022 (m), 1011 (m), 968 (m), 957 (m), 931 (w), 918
1
(s) cm−1; H NMR (CDCl3, 600 MHz): δ 6.76 (d, J = 8.2 Hz, 1H),
6.66 (d, J = 8.2 Hz, 1H), 4.42 (s, 1H), 4.19 (q, J = 6.2 Hz, 1H), 4.00
(q, J = 6.6 Hz, 1H), 3.89−3.84 (m, 4H), 3.77 (q, J = 6.0 Hz, 1H),
3.20 (s, 2H), 2.98 (s, 1H), 2.74 (s, J = 11.5 Hz, 1H), 2.52 (d, J =
12.7 Hz, 1H), 2.32 (d, J = 13.7 Hz, 1H), 2.17 (d, J = 12.7 Hz, 1H), 1.94
(td, J = 12.7, 3.6 Hz, 1H), 1.66 (d, J = 12.8 Hz, 1H), 1.55 (t, J = 12.4 Hz,
2H), 1.18 (dd, J = 26.5, 13.1 Hz, 1H); 13C NMR (CDCl3, 150 MHz): δ
146.7, 142.3, 128.1, 126.2, 119.3, 113.6, 108.1, 95.4, 66.5, 64.9, 56.5, 44.4,
44.0, 38.3, 37.9, 33.0, 32.8, 24.9, 23.2 ppm; LRMS-EI (m/z): 347 (15),
M+ 346 (67), 285 (12), 260 (10), 200 (15), 199 (38), 99 (100);
HRMS-EI (m/z): M+ calcd for C19H22O4S, 346.1239; found,
346.1245.
A solution of tosylate 29 (490 mg, 1.01 mmol) in tetrahydrofuran
(15 mL) was treated with potassium thioacetate (381 mg, 3.33 mmol)
and the mixture was refluxed for 3 h. The mixture was concentrated
and subsequently partitioned between dichloromethane (15 mL) and
water (15 mL). The phases were separated and the organic phase
extracted with dichloromethane (3 × 15 mL). The combined organic
extracts were washed with brine (14 mL), dried through a phase
separator cartridge, and concentrated under reduced pressure. Flash
column chromatography (5:2 hexanes−ethyl acetate) provided
thioester 11 (350 mg, 89%) as a solid. Rf 0.38 (2:1 hexanes−
(4R,4aR,7aR,12bS)-9-Methoxy-1,2,4,4a,5,6-hexahydro-4,12-
methanoisothiochromeno[5,4a-b]benzofuran-7(7aH)-one (15b).
18
EtOAc); mp 109−110 °C (Et2O−pentane); [α]D +17.9 (c 1.0,
CHCl3); IR (KBr disc): ν 3448 (w), 3039 (w), 2991 (m), 2957 (m),
2939 (m), 2890 (m), 2833 (w), 1692 (s), 1637 (m), 1623 (m), 1577
(w), 1506 (s), 1453 (s), 1437 (s), 1385 (m), 1347 (m), 1305 (w),
1281 (s), 1252 (m), 1221 (m), 1161 (s), 1137 (m), 1117 (m), 1098
(s), 1063 (s), 1049 (m), 1026 (m), 993 (m), 949 (m), 925 (s) cm−1;
1H NMR (CDCl3, 600 MHz): δ 6.71 (d, J = 8.1 Hz, 1H), 6.64 (d, J =
8.0 Hz, 1H), 6.37 (d, J = 9.5 Hz, 1H), 5.80 (dd, J = 9.5, 5.6 Hz, 1H),
4.77 (s, 1H), 4.23 (td, J = 6.9, 5.0 Hz, 1H), 4.02 (q, J = 6.8 Hz, 1H),
3.90−3.85 (m, 4H), 3.81 (td, J = 6.6, 5.4 Hz, 1H), 2.91 (ddd, J =
13.2, 11.9, 5.0 Hz, 1H), 2.61 (ddd, J = 13.3, 11.8, 5.0 Hz, 1H),
2.43−2.37 (m, 1H), 2.26 (s, 3H), 1.86 (ddd, J = 13.3, 12.0, 5.0 Hz,
1H), 1.79−1.72 (m, 2H), 1.58 (ddd, J = 13.1, 3.8, 2.4 Hz, 1H), 1.42
(td, J = 13.6, 2.5 Hz, 1H), 1.26 (qd, J = 13.8, 2.2 Hz,1H); 13C NMR
(CDCl3, 150 MHz): δ 195.7, 146.3, 143.9, 129.7, 127.1, 123.3,
123.0, 117.6, 113.0, 108.1, 94.3, 66.5, 65.0, 56.3, 46.6, 39.4, 39.0,
31.5, 30.5, 25.4, 24.4; LRMS-EI (m/z): M+ 388 (19), 285 (19), 199
(24), 99 (100); HRMS-EI (m/z): M+ calcd for C21H24O5S,
388.1344; found, 388.1341.
A solution of ketal 32 (29 mg, 0.084 mmol) in deoxygenated methanol
(8 mL) was treated with aqueous hydrochloric acid (2 mL, 24 mmol)
and the reaction mixture was vigorously stirred at 60 °C for 1.5 h. The
mixture was then cooled to 25 °C, diluted with water (5 mL), and
basified slowly with saturated aqueous solution of sodium bicarbonate
(8 mL). The mixture was diluted with dichloromethane (8 mL), the
layers were separated, and the aqueous layer was extracted with
dichloromethane (5 × 8 mL). The combined organic layers were
washed with brine (20 mL), dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. Flash column chromatography
(3:2 hexanes−ethyl acetate) afforded 15b, the sulfur analogue of
hydrocodone (23 mg, 91%) as a colorless solid. Rf 0.35 (hexanes−
2-((3a′R,3a1′S,9a′S)-5′-Methoxy-2′,3a′,3a1′,9a′-tetrahydro-1′H-
spiro[[1,3]dioxolane-2,3′-phenanthro[4,5-bcd]furan]-3a1′-yl)-
ethanethiol (31) and (4R,4aR,7aR,12bS)-9-Methoxy-2,4,4a,5,6,7a-
hexahydro-1H-spiro[4,12-methanoisothiochromeno[5,4a-b]-
benzofuran-7,2′-[1,3]dioxolane] (32).
23
EtOAc); mp 200−201 °C (Et2O); [α]D −187.0 (c 0.25, CHCl3);
IR (KBr disc): ν 3447 (m), 2995 (w), 2956 (w), 2934 (m), 2919
(m), 2865, (w), 2834 (w), 1724 (s), 1627 (w), 1606 (w), 1499 (m),
1439 (m), 1326 (w), 1311 (w), 1268 (m), 1243 (w), 1182 (w),
1144 (w), 1099 (m), 1054 (m), 995 (w), 953 (m), 926 (w), 901
(w) cm−1; 1H NMR (CDCl3, 600 MHz): δ 6.73 (d, J = 8.2 Hz, 1H),
6.67 (d, J = 8.3 Hz, 1H), 4.62 (s, 1H), 3.91 (s, 3H), 3.26−3.14 (m,
2H), 3.06 (d, J = 5.6 Hz, 1H), 2.91 (ddd, J = 12.7, 4.2, 2.5 Hz, 1H),
2.71 (s, 1H), 2.44−2.36 (m, 3H), 2.30 (d, J = 12.7 Hz, 1H), 2.17
(td, J = 12.7, 4.0 Hz, 1H), 1.93−1.88 (m, 1H), 1.31−1.24 (m, 1H);
13C NMR (CDCl3, 150 MHz): δ 206.8, 145.8, 143.2, 126.3, 126.2,
120.5, 114.8, 92.3, 56.8, 48.2, 44.0, 39.8, 37.9, 37.3, 32.9, 28.4, 23.1;
LRMS-EI (m/z): 303 (21), M+ 302 (100), 242 (14), 241 (52), 213
(16), 199 (13), 185 (29), 86 (11), 84 (13), 55 (14); HRMS-EI
(m/z): M+ calcd for C17H18O3S, 302.0977; found, 302.0976.
A solution of thioacetate 30 (137 mg, 0.35 mmol) in deoxygenated
tetrahydrofuran (3 mL) and methanol (1 mL) was treated with freshly
prepared sodium methoxide (57 mg, 1.1 mmol) and the mixture was
stirred at 25 °C for 3 h. Argon was bubbled through all liquids used
H
dx.doi.org/10.1021/jo3026753 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
(3S,4R,4aR,12bS)-9-Methoxy-2,4,4a,5,6,7a-hexahydro-1H-spiro[4,12-
methanoisothiochromeno[5,4a-b]benzofuran-7,2′-[1,3]dioxolane]
3-Oxide (16a) and (3R,4R,4aR,12bS)-9-Methoxy-2,4,4a,5,6,7a-hex-
ahydro-1H-spiro[4,12-methanoisothiochromeno[5,4a-b]-
benzofuran-7,2′-[1,3]dioxolane] 3-Oxide (16b).
(w), 1396 (w), 1357 (w), 1338 (w), 1296 (s), 1257 (s), 1219 (m),
1153 (w), 1121 (s), 1082 (w), 1029 (m), 1001 (m), 959 (m) cm−1;
1H NMR (CDCl3, 300 MHz): δ 6.83 (d, J = 8.18 Hz, 1H), 6.76 (d, J =
8.4 Hz, 1H), 4.76 (s, 1H), 3.94 (s, 3H), 3.56 (d, J = 19.5 Hz, 1H), 3.38
(ddd, J = 2.7, 4.5, 12.6 Hz, 1H), 3.27 (dt, J = 7.5, 2.7 Hz, 1H), 3.02
(dd, J = 7.5, 18.6 Hz, 1H), 2.97 (dq, J ≈ 11.1, 3.0 Hz, 1H), 2.65 (td,
J = 13.2, 4.5 Hz, 1H) 2.55−2.45 (m, 3H), 2.30 (ddd, J = 2.7, 3.9, 12.9
Hz, 1H), 1.96 (dq, J = 13.5, 4.2 Hz, 1H), 1.38 (m, 1H); 13C NMR
(CDCl3, 75 MHz): δ 205.4, 145.9, 143.9, 124.5, 121.8, 121.4, 116.0,
91.0, 60.6, 56.9, 46.9, 46.8, 39.3, 38.1, 33.3, 26.9, 23.1; MS (FAB) (m/z):
[M+H]+ 335 (85), M+ 334 (97) 241 (50) 155 (42), 138 (51), 137
(73), 136 (83),107 (70), 105 (47), 95 (47), 91 (64), 90 (44), 89 (62),
83 (40), 81 (44), 77 (74), 73 (83), 69 (73), 57 (76), 55 (99), 43
(100), 41 (61) ; HRMS-FAB (m/z): M+ calcd for C17H18O5S,
334.0875; found, 334.0866.
A solution of 15b (40 mg, 0.13 mmol) in methanol (2 mL) and water
(4 drops) was treated with sodium periodate (30 mg, 0.14 mmol) and
the resulting suspension was stirred at 25 °C for 48 h. The mixture was
concentrated under reduced pressure and the residue purified by
gravity column chromatography (200:1 to 100:1 dichloromethane−
methanol) to afford 16a and 16b (39 mg, 93%) as an inseparable 5:1
mixture of two diastereomers, obtained as a colorless solid.
Ethyl (1,1-Diethoxyethyl)(2-((3a′R,3a1′S,9a′S)-5′-methoxy-
2′,3a′,3a1′,9a′-tetrahydro-1′H-spiro[[1,3]dioxolane-2,3′-
phenanthro[4,5-bcd]furan]-3a1′-yl)ethyl)phosphinate (34).
Data of the major isomer collected from 5:1 mixture: Rf 0.15 (95:5
CH2Cl2−MeOH); mp >260 °C (Et2O); [α]D21 −155.47 (c 1, CHCl3);
IR (KBr disc): ν 3446 (m), 3000 (w), 2972 (w), 2926 (w), 2894 (w),
2870 (w), 2840 (w), 2361 (w), 2341 (w), 1726 (s), 1635 (m), 1614
(m), 1504 (s), 1443 (s), 1323 (w), 1276 (s), 1240 (w), 1187 (w),
1161 (w), 1142 (w), 1101 (m), 1035 (s), 1003 (m), 971 (w), 952 (m),
1
918 (w) cm−1; H NMR (CDCl3, 600 MHz): δ 6.79 (d, J = 7.8 Hz,
1H), 6.71 (d, J = 8.4 Hz, 1H), 4.71 (s, 1H), 3.94 (s, 3H), 3.50 (ddd,
J = 12.6, 4.2, 2.4 Hz, 1H), 3.38 (br. d, J = 9.0 Hz, 1H), 3.10 (dd, J =
19.8, 9.0 Hz, 1H), 2.82−2.73 (m, 3H), 2.54 (dd, J = 13.2, 4.2 Hz, 1H),
2.50 (dt, J = 13.7, 3.5 Hz, 1H), 2.13 (td, J = 15.6, 4.8 Hz, 1H),
2.01(ddd, J = 13.8, 4.2, 2.4 Hz, 1H), 1.82 (dq, J ≈ 13.4, 4.0 Hz, 1H),
1.37 (qd, J = 13.2, 3.0 Hz, 1H); 13C NMR (CDCl3, 150 MHz): δ
206.0, 145.7, 143.7, 125.8, 121.7, 121.0, 115.6, 91.5, 56.9, 54.0, 47.1,
40.1, 29.1, 27.3, 22.4; LRMS-FAB(+) (m/z): 320 (22), [M+H]+ 319
(100), M+ 318 (46), 241 (16), 155 (15), 154 (39), 152 (17), 137 (29),
136 (90), 120 (16), 107 (35), 105 (21), 95 (20), 91 (20), 90 (27), 89
(34), 81 (21), 79 (16), 77 (38), 73 (29), 71 (20), 69 (31), 67 (18), 57
(44), 55 (56), 43 (46), 41 (35); HRMS-FAB(+) (m/z): [M+H]+
calcd for C17H19O4S, 319.1004; found, 319.0998.
Preparation of Triflate from Alcohol 27: A solution of 27 (150 mg,
0.454 mmol) in dichloromethane (2.5 mL) and pyridine (0.1 mL, 1.2
mmol) was treated with trifluoromethanesulfonic anhydride (90 μL,
0.535 mmol) at −78 °C. The mixture was stirred for 3.5 h while the
temperature was allowed to reach −20 °C, before it was recooled
to −78 °C. The solution of triflate 33 was used in the procedure
given below.
Preparation of 34: A solution of hexamethyldisilazane (0.39 mL,
1.8 mmol) in tetrahydrofuran (2 mL) was treated with a 2.4 M
solution of n-butyllithium in hexanes (0.7 mL, 1.68 mmol) at 4 °C.
The mixture was stirred at 4 °C for 2 h and 25 °C for 45 min before it
was recooled to 4 °C. Ethyl (1,1-diethoxyethyl)phosphinate (382 mg,
1.82 mmol) was added and the mixture stirred at 4 °C for 1.5 h, 25 °C
for 15 min, and then cooled to −78 °C. A freshly prepared solution of
triflate 33 (vide supra) was added, the mixture was allowed to reach
4 °C over 3 h, and it was stirred at 4 °C for 12 h. The mixture was
poured into a cooled (4 °C), saturated aqueous solution of ammonium
chloride (10 mL), water (13 mL) was added, and the mixture was
stirred for 10 min before it was extracted with dichloromethane (5 ×
25 mL). The combined organic extracts were washed with brine
(20 mL), dried over sodium sulfate, filtered, and concentrated under
reduced pressure. The residue was purified by flash column
chromatography (1:1 chloroform−ethyl acetate) to afford phosphinate
34 (94 mg, 40%) as a 1:1 mixture of two diastereomers, obtained as a
pink oil. On a 600 mg scale the yield of 34 dropped to 24% and
chloride 35 (1%) was isolated as the side-product. Data for 34: Rf 0.20
(100% EtOAc); IR (CHCl3): ν 3031 (w), 2983 (s), 2898 (w), 2839
(w), 1637 (w), 1624 (w), 1578 (w), 1506 (m), 1455 (w), 1439 (m),
1390 (w), 1372 (w), 1364 (w), 1341 (w), 1278 (m), 1256 (m), 1165
(s), 1112 (m), 1087 (m), 1036 (s), 990 (w), 954 (m), 926 (w), 911
(w) cm−1; 1H NMR (CDCl3, 600 MHz, 1:1 mixture of two
diastereomers): 6.71 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H),
6.63 (d, J = 8.2 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 6.35 (d, J = 9.8 Hz,
1H), 6.34 (d, J = 9.8 Hz, 1H), 5.76 (2q, J = 9.8, 5.3 Hz, 2H), 4.63 (2s,
2H), 4.23 (m, 2H), 4.17−4.04 (m, 4H), 4.03−3.98 (m, 2H), 3.88−
3.84 (m, 2H), 3.84 (s, 6H), 3.83−3.79 (m, 2H), 3.70−3.48 (m, 8H),
2.37−2.30 (m, 2H), 2.14−2.05 (m, 1H), 1.96−1.69 (m, 7H), 1.60−
1.55 (m, 2H), 1.56−1.32 (m, 4H), 1.41 (d, J = 11.3 Hz, 9H), 1.34 (d,
J = 11.3 Hz, 9H), 1.30−1.20 (m, 2H), 1.26 (t, J = 6.8 Hz, 3H), 1.23 (t,
J = 6.8 Hz, 3H), 1.19−1.09 (m, 12H); 13C NMR (CDCl3, 150 MHz,
1:1 mixture of two diastereomers): 146.5, 146.4, 144.00, 143.96,
129.84, 129.79, 127.3, 127.0, 123.51, 123.48, 123.17, 123.16, 117.79,
1
Data of the minor isomer collected from 5:1 mixture: H NMR
(CDCl3, 600 MHz): δ 6.79 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 8.4 Hz,
1H), 4.69 (s, 1H), 3.93 (s, 3H), 3.73 (d, J = 19.2 Hz, 1H), 3.50 (m,
1H), 3.04 (dq, J ≈ 13.2, 1.8 Hz, 1H), 2.82−2.73 (m, 2H), 2.54 (td, J =
13.2, 4.2 Hz, 1H), 2.50 (m, 1H), 2.43 (td, J = 13.8, 4.8 Hz, 1H), 2.34
(td, J = 13.2, 4.2 Hz, 1H) 2.21(ddd, J = 13.8, 4.2, 3.6 Hz, 1H),) 2.15
(td, J = 13.8, 3.0 Hz, 1H) 1.97 (dq, J ≈ 13.5, 3.8 Hz, 1H), 1.51 (qd, J =
13.2, 3.0 Hz, 1H); 13C NMR (CDCl3, 150 MHz): δ 205.8, 145.5,
143.4, 125.2, 124.5, 121.7, 115.4, 90.9, 56.8, 54.5, 46.6, 43.4, 39.6, 37.3,
33.8, 27.9, 16.2.
(4R,4aR,7aR,12bS)-9-Methoxy-1,2,4,4a,5,6-hexahydro-4,12-
methanoisothiochromeno[5,4a-b]benzofuran-7(7aH)-one 3,3-diox-
ide (15c).
To a solution of 15b (17 mg, 0.056 mmol) in methanol (3 mL) and
water (0.3 mL) was added sodium periodate (50 mg, 0.23 mmol) and
the resulting suspension was stirred at 50 °C for 24 h, then treated
with additional sodium periodate (50 mg, 0.23 mmol) and stirred at
50 °C for 12 h. The mixture was concentrated under reduced pressure
and the residue purified by gravity column chromatography (200:1 to
100:1 dichloromethane−methanol) afforded 15c (18 mg, 90%) as a
colorless solid. Rf 0.75 (95:5 CH2Cl2−MeOH); mp >260 °C
22
(CHCl3); [α]D −162.81 (c 1, CHCl3); IR (KBr disc): ν 3446
1
117.76, 113.14, 113.08, 108.4, 101.8 (d, JPC = 138.7 Hz), 100.9 (d,
(m), 2968 (w), 2926 (w), 2904 (w), 2866 (w), 2836 (w), 2362 (w),
2345 (w), 1729 (s), 1633 (w), 1608 (m), 1499 (m), 1443 (m), 1427
2
1JPC = 138.7 Hz), 94.3, 94.1, 66.8, 65.1, 61.6 (d, JCP = 7.0 Hz), 61.5
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(d, 2JCP = 7.0 Hz), 58.3−58.2 (two doublets), 57.64 (d, 3JCP = 7.6 Hz),
57.63 (d, 3JCP = 7.0 Hz), 56.54, 56.52, 46.6 (d, 3JCP = 6.6 Hz), 46.5 (d,
3JCP = 6.5 Hz), 39.90, 39.40, 31.69, 30.47 (d, 1JCP = 95.0 Hz), 30.44 (d,
1JCP = 95.0 Hz), 25.55, 21.26−20.42 (multiple signals), 16.78 (d,
108.17, 94.43, 94.42, 66.7, 65.1, 62.5−62.4 (multiple signals), 56.4,
46.3, 46.2, 39.85, 39.82, 39.80, 39.77, 31.6, 30.10, 30.09, 30.04−30.01
(multiple signals), 29.8, 25.5, 24.3, 23.79 (d, 1JCP = 93.2 Hz), 23.77 (d,
3
3
1JCP = 93.2 Hz), 16.32 (d, JCP = 6.6 Hz), 16.30 (d, JCP = 5.6 Hz);
LRMS-EI (m/z): M+ 406 (4), 285 (21), 99 (19), 85 (75), 83 (100), 48
(17), 47 (33); HRMS-EI (m/z): M+ calcd for C21H27O6P, 406.1545;
found, 406.1538.
Ethyl 2-((2aS,2a1S,5aR)-7-Methoxy-5-oxo-2a,2a1,3,4,5,5a-
hexahydrophenanthro[4,5-bcd]furan-2a1-yl)ethylphosphinate (38).
3JCP = 5.4 Hz) 16.72 (d, 3JCP = 5.3 Hz), 15.59, 15.58, 15.40, 15.38; LRMS-
EI (m/z): [M-EtOH]+ 476 (4), 248 (20), 199 (10), 163 (19), 117
(100), 99 (43), 89 (21), 61 (41), 60 (11), 43 (28), 42 (10); HRMS-EI
(m/z): M+ calcd for C27H39O8P, 522.2383; found, 522.2401.
(3a′R,3a1′S,9a′S)-3a1′-(2-Chloroethyl)-5′-methoxy-2′,3a′,3a1′,9a′-
tetrahydro-1′H-spiro[[1,3]dioxolane-2,3′-phenanthro[4,5-bcd]-
furan] (35).
A solution of the crude ketal 36 (theor. 0.163 mmol) in ethanol (5 mL)
was treated with a concentrated aqueous solution of hydrochloric acid
(0.7 mL) and the mixture was stirred at 65 °C for 1 h. It was then
cooled to 25 °C, poured into a cold (4 °C), saturated aqueous solution
of sodium bicarbonate (15 mL), and extracted with dichloromethane
(5 × 10 mL). The combined organic extracts were washed with brine
(15 mL), dried over magnesium sulfate, filtered, and concentrated
under reduced pressure. Gravity column chromatography (30:1
dichloromethane−methanol) afforded ketone 38 as a 1:1 mixture of
two diastereomers (12 mg, colorless oil, 20% from 34) and a 3:1
mixture of 38 and 36 (3 mg). Data for 38: Rf 0.27 (30:1 CH2Cl2−
MeOH); IR (CHCl3): ν 3682 (w), 3441 (w), 3003 (s), 2932 (m),
2840 (w), 2348 (w), 1735 (s), 1637 (w), 1623 (w), 1578 (w), 1509
(s), 1454 (m), 1438 (m), 1390 (w), 1365 (w), 1336 (w), 1287 (s),
1274 (s), 1249 (s), 1165 (m), 1159 (m), 1105 (m), 1080 (m), 1057
(s), 1045 (s), 996 (m), 966 (s), 927 (m) cm−1; 1H NMR (CDCl3, 600
MHz, 1:1 mixture of two diastereomers): δ 6.98 (d, J = 534 Hz), 6.69
(d, J = 534 Hz), 6.70 (d, J = 8.3 Hz, 2H), 6.67 (d, J = 8.3 Hz, 2H),
6.41 (d, J = 9.1 Hz, 2H), 5.83 (dd, J ≈ 9.1, 6.0 Hz, 2H), 4.87, 4.86 (2s,
2H), 4.15−4.07 (m, 2H), 4.05−3.97 (m, 2H), 3.91 (s, 6H), 2.75−2.68
(m, 2H), 2.37−2.27 (m, 4H), 2.15−2.04 (m, 4H), 1.97−1.86 (m, 4H),
1.64−1.52 (m, 2H), 1.32 (2q, J = 12.8, 6.8 Hz, 6H), 1.32−1.21 (m,
2H); 13C NMR (CDCl3, 150 MHz, 1:1 mixture of two diastereomers):
δ 206.61, 206.56, 145.7, 144.8, 144.7, 128.70, 128.67, 124.5, 124.1,
123.1, 123.0, 118.98, 118.97, 113.94, 113.91, 91.6, 62.71 (d, 2JCP = 6.7
Hz), 62.69 (d, 2JCP = 6.8 Hz), 56.5, 51.1, 51.0, 40.3, 38.00, 37.98, 29.8,
28.9−28.8 (multiple signals), 28.3, 24.21 (d, 2JCP = 94.4 Hz), 24.19 (d,
Data for 35: Colorless oil. Rf 0.33 (5:1 hexanes−EtOAc); IR (CHCl3):
ν 3031 (w), 3009 (m), 2956 (m), 2935 (m), 2900 (m), 2854 (w),
2840 (w), 1731 (w), 1637 (w), 1623 (w), 1578 (w), 1506 (s), 1453
(m), 1438 (m), 1387 (w), 1374 (w), 1358 (w), 1340 (w), 1305 (w),
1279 (s), 1264 (m), 1164 (s), 1112 (m), 1093 (s), 1064 (s), 1030 (s),
1
993 (w), 976 (w), 952 (w), 909 (s) cm−1; H NMR (CDCl3, 300
MHz): δ 6.73 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 6.38 (d, J =
9.4 Hz, 1H), 5.81 (dd, J = 9.4, 5.7 Hz, 1H), 4.69 (s, 1H), 4.26−4.18
(m, 1H), 4.05−3.97 (m, 1H), 3.92−3.77 (m, 1H), 3.89 (s, 3H), 3.54
(td, J ≈ 11.0, 5.0 Hz, 1H), 2.29 (td, J ≈ 11.0, 5.0 Hz, 1H), 2.37 (dt, J ≈
11.7, 5.3 Hz, 1H), 2.18 (ddd, J ≈ 13.6, 11.5, 5.5 Hz, 1H), 1.99 (ddd,
J = 13.6, 11.3, 4.9 Hz, 1H), 1.80−1.69 (m, 1H), 1.63−1.53 (m, 1H),
1.42 (td, J ≈ 13.7, 2.6 Hz, 1H), 1.33−1.17 (m, 1H); 13C NMR
(CDCl3, 300 MHz): δ 144.2, 129.8, 126.6, 123.42, 123.37, 117.9,
113.2, 108.2, 94.9, 66.8, 65.1, 56.5, 46.4, 43.2, 40.8, 39.7, 31.6, 25.5;
LRMS-EI (m/z): M+ 348 (25), [M-C2H4Cl]+ 285 (20), 199 (32), 185
(14), 99 (100), 49 (13); HRMS-EI (m/z): M+ calcd for C19H21ClO4,
348.1128; found, 348.1132.
Ethyl (2-((3a′R,3a1′S,9a′S)-5′-Methoxy-2′,3a′,3a1′,9a′-tetrahy-
dro-1′H-spiro[[1,3]dioxolane-2,3′-phenanthro[4,5-bcd]furan]-3a1′-
yl)ethyl)phosphinate (36).
3
3
2JCP = 93.9 Hz), 16.4 (d, JCP = 5.8 Hz), 16.3 (d, JCP = 6.1 Hz);
LRMS-EI (m/z): M+ 361 (29), [M − OEt]+ 317 (3), 242 (18), 241
(86), 185 (27), 122 (100), 94 (91), 93(15), 85(29), 83(36), 78(21),
66(16); HRMS-EI (m/z): M+ calcd for C19H23O5P, 362.1283; found
362.1286.
(3a′R,3a1′S,9a′S)-3a1′-(2-Iodoethyl)-5′-methoxy-2′,3a′,3a1′,9a′-
tetrahydro-1′H-spiro[[1,3]dioxolane-2,3′-phenanthro[4,5-bcd]-
furan] (39).
A solution of 34 (85 mg, 0.163 mmol) in methanol (0.2 mL) and
dichloromethane (1.8 mL) was treated with trimethylsilyl chloride
(35 μL, 0.276 mmol) at 25 °C, and the mixture was stirred for 20 h.
The mixture was concentrated under reduced pressure to provide
crude H-phosphinate 36 (75 mg) as a pale yellow solid comprising a
1:1 mixture of two diastereomers, which was used in the next step
without further purification. Rf 0.12 (100% EtOAc); IR (CHCl3): ν
3414 (w), 3024 (w), 3005 (s), 2955 (m), 2903 (m), 2852 (w), 2841
(w), 2350 (w), 1734 (w), 1637 (w), 1625 (w), 1579 (w), 1507 (s),
1455 (m), 1438 (m), 1390 (w), 1360 (w), 1342 (w), 1279 (s), 1256
(s), 1176 (m), 1165 (s), 1086 (m), 1063 (s), 1047 (s), 1000 (m), 969
(s), 923 (m), 902 (w) cm−1; 1H NMR (CDCl3, 150 MHz, 1:1 mixture
of two diastereomers): δ 6.89 (d, J = 532 Hz), 6.87 (d, J = 533 Hz),
6.71 (d, J = 7.9 Hz, 2H), 6.64 (d, J = 7.9 Hz, 2H), 6.35 (d, J = 9.4 Hz,
2H), 5.77 (d, J = 9.4 Hz, 2H), 5.76 (d, J = 9.4 Hz, 2H), 4.61, 4.60 (2s,
2H), 4.22−4.17 (m, 2H), 4.12−3.94 (m, 6H), 3.91−3.82 (m, 2H),
3.87 (s, 6H), 3.82−3.77 (m, 2H), 2.35−2.27 (m, 2H), 1.94−1.20
(several m, 18H); 13C NMR (CDCl3, 150 MHz, 1:1 mixture of two
diastereomers): δ 146.4, 144.09, 144.06, 129.69, 129.67, 129.65,
126.51, 126.47, 126.40, 126.37, 124.0, 123.4, 123.37, 123.36, 123.32,
123.30, 123.24, 123.22, 117.95, 117.92, 117.90, 113.12, 113.07, 108.18,
A solution of tosylate 29 (307 mg, 0.634 mmol) and sodium iodide
(1.71 g, 11.4 mmol) in acetone (20 mL) was stirred at 40 °C for 14 h
and at 50 °C for 6 h. The solvent was evaporated and the residue was
diluted with ethyl acetate (15 mL) and water (10 mL). The layers
were separated and the aqueous layer was extracted with ethyl acetate
(2 × 15 mL). The combined organic layers were washed with a
saturated aqueous solution of sodium bicarbonate (5 mL), brine (15 mL),
dried over magnesium sulfate, filtered, and concentrated under
reduced pressure. Crude iodide 39 was purified by crystallization
from diethyl ether−hexanes to afford analytically pure 39 (225 mg,
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Article
81%) as a yellow solid. Rf 200.79 (2:1 hexanes−EtOAc); mp 119−121
°C (Et2O−hexanes); [α]D −10.5 (c 1.15, CHCl3); IR (CHCl3): ν
3032 (w), 3008 (m), 2955 (m), 2899 (m), 2851 (w), 2840 (w), 1637
(w), 1623 (w), 1578 (w), 1506 (s), 1454 (m), 1438 (m), 1387 (w),
1340 (w), 1300 (w), 1278 (s), 1165 (s), 1121 (w), 1091 (m), 1064
(m), 1034 (m), 987 (w), 951 (w), 924 (m), 909 (w); 1H NMR
(CDCl3, 300 MHz): 6.73 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H),
6.38 (d, J = 9.6 Hz, 1H), 5.79 (dd, J = 9.6, 5.7, 1H), 4.66 (s, 1H),
4.26−4.18 (m, 1H), 4.06−3.96 (m, 1H), 3.92−3.77 (m, 2H), 3.89
(s, 3H), 3.19 (ddd, J = 13.0, 9.4, 4.6 Hz, 1H), 2.89 (ddd, J = 10.0, 9.4,
4,9 Hz, 1H), 2.40−2.27 (m, 2H), 2.15 (td, J = 13.2, 4.7 Hz, 1H),
1.80−1.69 (m, 1H), 1.63−1.52 (m, 1H), 1.40 (td, J = 13.2, 2.4 Hz,
1H), 1.34−1.18 (m, 1H); 13C NMR (CDCl3, 150 MHz): 146.5, 144.2,
129.8, 126.3, 123.44, 123.38, 117.9, 113.1, 108.2, 94.6, 66.8, 65.2, 56.5,
48.9, 45.3, 39.5, 31.6, 25.5, 0.4; LRMS-EI (m/z): M+ 440 (14), 285
(18), 199 (25), 100 (11), 99 (100); HRMS-EI (m/z): M+ calcd for
C19H21IO4, 440.048; found, 440.0492; Anal. calcd for C19H21IO4: C,
51.83; H, 4.81; found: C, 51.76; H, 4.83.
rpm at 4 °C. These were kept at −80 °C until used for bioassays.
Protein concentration was determined using Bio-Rad Protein Assay.24
Radio-ligand Binding for Opioid Receptor Subtypes. All
compounds evaluated in the assay were run in competition binding
against opioid receptor subtypes (δ, κ, μ). Opioid binding assays were
performed under the following conditions: 10 μM of each compound
was incubated with [3H]-DAMGO (μ), [3H]-U-69,593 (κ), or [3H]-
Enkephlin (δ) for 60 min in a 96-well plate. Tritium and membrane
concentration for each cell line was determined by saturation
experiments performed after each batch of membrane was scraped.
The reaction was terminated via rapid vacuum filtration through GF/B
filters presoaked with 0.3% BSA using a 96-well UniFilter followed by
10 washes of 50 mM Tris-HCl. Microplates were read using a liquid
scintillation counter. Total binding was defined as binding in the
presence of 1.0% DMSO. Nonspecific binding was the binding
observed in the presence of 10 μM DAMGO (μ), nor-Binaltorphimine
(κ), or DPDPE (δ). Specific binding was defined as the difference
between total and nonspecific binding. Percent binding was calculated
using the following formula:
(3R,3aS,6aR,11bS)-8-Methoxy-2,3,3a,4,5,6a-hexahydro-1H-spiro-
[3,11-methanoindeno[4,3a-b]benzofuran-6,2′-[1,3]dioxolane] (40).
100 − (Binding of compound − Nonspecific binding)
× 100 / Specific binding
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra corresponding to all
reported compounds, as well as crystallographic information for
carbocyclic analogue 40 are included. This material is available
free of charge via the Internet at http://pubs.acs.org.
A 50 mL flask equipped with a Dimroth condenser was charged with
ammonium hypophosphorous acid (417 mg, 5.02 mmol), toluene
(20 mL), and hexamethyldisilazane (1.08 mL, 5.09 mmol), the
suspension was immersed in a preheated oil bath (100 °C) and stirred
for 110 min, before a solution of iodide 39 (107 mg, 0.243 mmol) in
dichloromethane (5 mL) was added, and the mixture stirred for 12 h.
The solvent was evaporated and the resulting yellow, oily residue was
dissolved in diethyl ether (10 mL) and washed with an aqueous 4 M
solution of hydrochloric acid. The layers were separated and the
aqueous layer was extracted with diethyl ether (2 × 10 mL). The
combined organic extracts were filtered through cotton wool and
evaporated. Gravity column chromatography (4:1 hexanes−ethyl
acetate) afforded 40 (64 mg, 84%) as colorless solid. Rf 0.27 (4:1
hexanes−EtOAc); mp 132−135 °C (hexanes−EtOAc); IR (CHCl3):
3632 (w), 3009 (m), 2956 (s), 2907 (m), 2868 (m), 2838 (m), 1638
(w), 1607 (w), 1504 (s), 1453 (s), 1440 (m), 1341 (m), 1277 (s),
1260 (m), 1177 (m), 1079 (s), 1063 (s), 1017 (m), 951 (m), 922 (m)
AUTHOR INFORMATION
Corresponding Author
*E-mail: thudlicky@brocku.ca.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the following agencies for financial
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. We thank Jason Reed Hudlicky for large-
scale preparations of alcohol 27 and thiol 31.
1
cm−1; H NMR (CDCl3, 600 MHz): δ 6.70 (d, J = 8.3 Hz, 1H), 6.58
(d, J = 8.3, Hz 1H), 4.60 (s, 1H), 4.15−4.05 (m, 2H), 3.96−3.92 (m,
1H), 3.89−3.84 (m, 1H), 3.85 (s, 3H), 2.79 (dd, J = 16.6, 3.8 Hz, 1H),
2.49−2.45 (m, 1H), 2.45−2.40 (m, 1H), 2.08−2.00 (m, 2H), 1.93
(ddd, J = 12.0, 9.4, 3.0 Hz, 1H), 1.77 (td, J = 11.7, 6.4 Hz, 1H), 1.69−
1.62 (m, 1H), 1.59 (dt, J = 13.6, 5.7 Hz, 1H), 1.52−1.40 (m, 2H),
1.23−1.15 (m, 1H); 13C NMR (CDCl3, 150 MHz): δ 145.5, 142.1,
133.3, 124.1, 120.2, 113.3, 109.3, 90.4, 66.0, 65.0, 56.5, 51.4, 41.3, 39.1,
36.0, 31.8, 31.2, 29.3, 19.3; LRMS-EI (m/z): 315 (21), M+ 314 (100),
229 (10), 228 (59), 199 (45), 174 (10), 99 (75); HRMS-EI (m/z):
M+ calcd for C19H22O4, 314.1518; found, 314.1516. Anal. calcd for
C19H22O4: C, 72.59; H, 7.05; found: C, 71.99; H, 7.05. Recrystalliza-
tion from hexanes−EtOAc afforded crystals that were suitable for single
crystal X-ray diffraction analysis; refer to the Supporting Information
document for additional information.
Cell Culture. CHO-K1 cells stably transfected with opioid receptor
subtypes μ, δ, and κ were a generous gift from Roth laboratories
(University of North Carolina at Chapel Hill, Chapel Hill, N.C.,
U.S.A.). These cells were maintained at 37 °C and 5% CO2 in a
DMEM nutrient mixture supplemented with 2 mM L-glutamine, 10%
fetal bovine serum, 0.5% penicillin−streptomycin, and either G418
(600 mg/mL) or hygromycin B (300 mg/mL). Membranes were
prepared by scraping the cells in a 50 mM Tris-HCl buffer,
homogenized by sonication and centrifuged for 40 min at 13650
The authors further thank Mr. Corey Gemelli and Dr. Guoyi
Ma for their technical aid in conducting binding assays. The
project described was supported, in part, by Grant Number
5P20RR021929 from the National Center for Research
Resources (NCRR) and 9P20GM104932-06 from the National
Institute of General Medical Sciences, components of the
National Institutes of Health (NIH). In addition, this
investigation was conducted in a facility constructed with
support from the Research Facilities Improvement Program
C06 RR-14503-01 from the NIH National Center for Research
Resources.
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