Synthetic studies of neoclerodane diterpenes from Salvia divinorum: Role of the furan in affinity for opioid receptors

Article abstract of DOI:10.1039/b905148a

Further synthetic modification of the furan ring of salvinorin A (1), the major active component of Salvia divinorum, has resulted in novel neoclerodane diterpenes with opioid receptor affinity and activity. A computational study has predicted 1 to be a reproductive toxicant in mammals and is suggestive that use of 1 may be associated with adverse effects. We report in this study that piperidine 21 and thiomorpholine 23 have been identified as selective partial agonists at kappa opioid receptors. This indicates that additional structural modifications of 1 may provide ligands with good selectivity for opioid receptors but with reduced potential for toxicity.

Full text of DOI:10.1039/b905148a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthetic studies of neoclerodane diterpenes from Salvia divinorum:
role of the furan in affinity for opioid receptors†
Denise S. Simpson,a Kimberly M. Lovell,a Anthony Lozama,a,b Nina Han,b Victor W. Day,c
Christina M. Dersch,d Richard B. Rothmand and Thomas E. Prisinzano*a
Received 13th March 2009, Accepted 8th June 2009
First published as an Advance Article on the web 14th July 2009
DOI: 10.1039/b905148a
Further synthetic modification of the furan ring of salvinorin A (1), the major active component of
Salvia divinorum, has resulted in novel neoclerodane diterpenes with opioid receptor affinity and
activity. A computational study has predicted 1 to be a reproductive toxicant in mammals and is
suggestive that use of 1 may be associated with adverse effects. We report in this study that piperidine 21
and thiomorpholine 23 have been identified as selective partial agonists at kappa opioid receptors. This
indicates that additional structural modifications of 1 may provide ligands with good selectivity for
opioid receptors but with reduced potential for toxicity.
Introduction
The neoclerodane diterpene, salvinorin A (1), is the main active
component of the hallucinogenic mint plant Salvia divinorum.1,2
Lately, salvinorin A-containing products have become increasingly
available and self-administration of these products has been
reported.3–6 Historically, S. divinorum has been used medicinally
by the Mazatecs of Oaxaca, Mexico, for several conditions, but
its mode of action was only recently discovered.7 Studies indicate
that 1 has high affinity and activity at k opioid (KOP) receptors,
and has no affinity for the molecular targets of other hallucino-
genic substances such 5-HT2, CB1/CB2, NMDA, or muscarinic
receptors.8 Furthermore, 1 appears to have unique properties as a
ligand at KOP receptors, including ultra-high efficacy in particular
transduction systems, and a reduced propensity to cause receptor
desensitization.9,10
A growing number of experimental studies have explored the
effects of 1 in animals.11–21 For example, 1 was found to substitute
for KOP agonist U69,593 but did not substitute for DOM in
DOM-trained non-human primates.19,20 This suggests that the
It is relatively rare for natural products, such as 1, to
hallucinogenic experience elicited by 1 is qualitatively different
than that of classical hallucinogens such as DOM. In rodents, 1
has been found to decrease striatal dopamine overflow and block
the locomotor effects of cocaine.16,18 These findings provide further
evidence for the potential utility of 1 and related analogues as
stimulant abuse therapeutics.22
have sufficiently attractive ADME/Tox (Absorption, Disposition,
Metabolism, Excretion, and Toxicity) properties to be marketable,
despite their excellent potency and selectivity. ADME/Tox has
become integrated into the drug discovery process and is a
tremendous asset in guiding selection and optimization.23,24 Thus,
the ability to improve these properties by semi- or total synthetic
chemistry is important in drug seeking campaigns.
Generally, furan-containing natural products, such as 1, are
of limited medicinal value. This results from their potential for
toxicity after bioactivation.25–27 For instance, previous work has
shown that teucrin A (2), a neoclerodane present in germander
(Teucrium chamaedrys L.; Lamiaceae), has the ability to produce
hepatotoxicity.28 This results from the formation of an enedial
formed from the metabolism of the furan ring by cytochrome P450
enzymes (CYP450s).29,30 The resulting enedial is then capable of
reacting with peptides to form stable conjugates.29 Using a pro-
teomic analysis, the major targets of 2 were found to be mitochon-
drial and ER-associated proteins and enzymes involved in small
molecule metabolism and cell maintenance.30 Aflatoxin B1 (3),
aDepartment of Medicinal Chemistry, The University of Kansas, Lawrence,
KS 66045-7582, USA. E-mail: prisinza@ku.edu; Fax: +1-785-864-5326;
Tel: +1-785-864-3267
bDivision of Medicinal & Natural Products Chemistry, The University of
Iowa, Iowa City, IA, USA
cDepartment of Chemistry, The University of Kansas, Lawrence, KS, USA
dClinical Psychopharmacology Section, IRP, NIDA, NIH, DHHS,
Baltimore, MD, USA
† Electronic supplementary information (ESI) available: Preparation of
4–19, 22, and 24–30; HPLC analyses of 4–32 and 34–36. CCDC reference
number 723548. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b905148a
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a difurano-containing natural product produced by Aspergillus
species, is a known hepatic carcinogen. Bioactivation of aflatoxin
B1 by CYP450s is thought to involve a similar dial intermediate to
the one formed from 2.31 As a furan-containing natural product, 1
also has the potential to form reactive metabolites resulting from
bioactivation by CYP450s. This hampers its further development
as a potential stimulant abuse therapeutic.32
One approach to circumventing the potential toxicity of a
furan-containing natural product is to explore different structural
replacements for the furan ring. Ideally, these modifications should
have low to no potential for toxicity but retain affinity and activity
at opioid receptors. Previously, we found that modification of the
furan ring of 1 resulted in neoclerodanes that possessed reduced
affinity and efficacy at opioid receptors.33–35 These previous
findings, as well as a recent report,36 suggested that additional
structural modifications of 1 may lead to analogues with higher
potency and potential utility as drug abuse medications. Here, we
report our efforts to identify furan modified neoclerodanes with
affinity and activity at KOP receptors.
S. divinorum leaves as described previously.42 The treatment of
1 with NaIO4 and a catalytic amount of RuCl3 afforded key
intermediate 4.33 The coupling of acid 4 with the appropriate
aniline or alkylamine using EDCI in CH2Cl2 afforded analogues
5–30 in 18–75% yield.
The treatment of acid 4 with CDMT and N-methylmorpholine
followed by ethanethiol afforded thioester 31 in 88% yield.43–46
The reduction of 31 with triethylsilane and Pd/C gave aldehyde
32 in 82% yield.47 Asymmetric allylation of aldehyde 32 was
accomplished in 50% yield with B-allyl-(10S)-(trimethylsilyl)-
9-borabicyclo[3.3.2]decane (prepared in situ from 9-[(1R,2R)-
pseudoephedrinyl] - (10S) - (trimethylsilyl) - 9 - borabicyclo [3.3.2] -
decane and allylmagnesium bromide.48 To determine the absolute
stereochemistry of alcohol 33a, mosher ester 33b was prepared
in 82% yield using oxalyl chloride and (R)-(+)-a-methoxy-a-
trifluoromethylphenylacetic acid.49 NMR analysis of 33b and its
(S)-epimer made from the S-acid, was not definitive as to the con-
figuration of the stereocenter. Therefore, X-ray analysis of 33b was
conducted and established the correct relative stereochemistry;
the absolute configuration was then assigned using the known
stereochemistry for much of the molecule (Fig. 1).
Results and discussion
Initially, a computational toxicological study (MC4PC, Multi-
CASE, Inc.) was performed on 1 and three structurally similar
compounds (columbin,37 diosbulbin G,38 and salvinorin B2) identi-
fied using the Derwent World Index and Prous Integrity databases.
The results of this investigation found that at pre-clinical endpoints
1 is predicted to be a reproductive toxicant in mammals (rabbits,
rats, and mice). This suggests that 1 may have adverse effects
associated with its use. However, there are few experimentally
determined reports on the toxicological effects of 1. A limited
study in mice found that 1 produced no histological differences
in control animals in the liver, spleen, kidney bone marrow, or
brain tissue.39 However, more detailed studies on the potential
toxicological effects of 1 are warranted.
Given the strong likelihood that the potential adverse effects
of 1 are due to the presence of the furan ring, we sought to find
other structural motifs that could potentially mimic the furan at
its binding site. While a model has been proposed for the binding
of 1 to the KOP,40,41 the binding pocket of 1 will not be known
definitively until the structure of a KOP–1 complex is solved. Given
the lack of these published studies, other indirect methods are
needed to more fully elucidate the nature of binding of 1 at the
KOP receptor. Our approach was to systematically change the
structure of the position corresponding to the furan ring and probe
its effects on opioid receptor affinity and activity.
We initially targeted amide and ester derivatives due to their
relative ease of synthesis, potential for reduced toxicity, and, likely
improved water solubility. Our design strategy consisted of two
parts: (1) the carbonyl of the amide or ester might participate
in a hydrogen bonding interaction similar to the furanyl oxygen;
and (2) enhanced affinity and/or activity might result from the
addition of a suitable group off the amide or ester bond. Our
results are described herein.
Fig. 1 Results from the X-ray analysis on 33b drawn from the experimen-
tally determined coordinates.
Acylation of 33a with acryloyl chloride under basic conditions
gave the corresponding ester which was then treated with 2nd
generation Grubbs catalyst to afford 5,6-dihydro-2H-pyran-2-one
34 in 23% yield for the two steps.50,51 The reaction of 4 with
either (2-hydroxybenzyl)triphenyl- or (2-thiobenzyl)triphenyl-
phosphonium bromide afforded the benzofuran (35) and ben-
zothiophene (36), respectively.52 Finally, coupling of the acid 4
with N-hydroxybenzene-carboximidamide using EDCI followed
by cyclization afforded 4-phenyl-1,3,5-oxadiazole 37.34
Biology
Compounds 1, 5–30, and 34–37 were then evaluated for affinity at
human opioid receptors using methodology previously described
(Table 1).53 As mentioned earlier, we and others have found
previously that modification of the furan ring of 1 resulted
in altered affinity and activity at opioid receptors.33,34,36 These
Chemistry
The synthesis of analogues 5–30 and 34–37 is outlined in Schemes 1
and 2. Salvinorin A (1) was extracted from commercially available
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Scheme 1 Reagents and conditions: (a) NaIO4, RuCl3·3H2O, CH3CN/CCl4/H2O; (b) Appropriate amine or alcohol, EDCI, HOBt, Et3N, CH2Cl2.
findings suggested that further modification to the furan ring
may result in analogues with improved potency and potential
as drug abuse medications. To further elucidate the structure-
activity relationships of neoclerodane diterpenes at opioid re-
ceptors, we synthesized an additional series of furan modified
analogues.
than 10-fold and 5-fold increase in affinity at KOP receptors,
respectively. The replacement of the phenyl ring with a 3-pyridine
(9) was not tolerated.
Recent molecular modeling and site-directed mutagenesis stud-
ies have indicated that the oxygen in the furan ring present
in 1 forms a critical hydrogen bond with Y119 at the KOP
receptor.40,41,54,55 This suggested to us that the inclusion of a
hydrogen bond acceptor group to anilide 5 may enhance affinity
at KOP receptors. Unfortunately, this design strategy met with
little success. Generally, the addition of a methoxy group to 5 (10–
16) did not increase affinity for opioid receptors. Interestingly,
12 and 13 were found to have weak affinity for MOP and
DOP receptors and no affinity for KOPs. To further explore the
role of electronics in the binding of these compounds to opioid
receptors, we prepared brominated analogues 17–19. Surprisingly,
17–19 possessed affinity at MOP receptors. This suggests that the
furan ring may also have a role in determining the selectivity for
opioid receptors. However, other modifications will need to be
explored to further define the role of the furan ring in opioid
receptor selectivity. In addition, these findings suggested that these
compounds, while similar in structure to 1, may be interacting with
opioid receptors in a different manner.
Our initial modification was to replace the furan ring in 1 with
an anilido group (5). It was envisioned that the benzene ring would
participate in a hydrophobic interaction similar to the furan ring
and the amide group could participate in a hydrogen bonding
interaction. This modification was not well tolerated and affinity
was lost at opioid receptors (Ki > 10,000 nM). The reasons for
this loss in affinity were not readily apparent. One potential reason
for this loss in affinity was the flexibility of the aromatic ring
relative to the amide bond. To address this issue, we synthesized
indoline 6 as a more conformationally restricted analogue of 5.
This change, however, did not enhance affinity suggesting that
either the conformation was not optimal or that alkylation of the
aniline portion was not tolerated. Another potential reason for the
lack of affinity of 5 is the presence of the aromatic ring. Thus, we
prepared cyclohexane 7 and cyclopentane 8. Replacement of the
phenyl ring in 5 with these saturated systems resulted in a greater
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Scheme
2
Reagents and conditions: (a) CDMT, NMM, EtSH, CH2Cl2, 88%; (b) Pd/C, Et3SiH, CH2Cl2, 82%; (c) 9-(1R, 2R-pseu-
doephedrinyl)-(10S)-(trimethylsilyl)-9-borabicyclo[3.3.2]decane, allylMgBr, Et2O; (d) 1. (R)-(+)-a-Methoxy-a-trifluoromethylphenylacetic acid, oxalyl
chloride, benzene; 2. DMAP, NEt3, CH2Cl2, 82%; (e) acryloyl chloride, DMAP, Et3N, CH2Cl2, 40%; (f) Grubbs II, CH2Cl2, 58%; (g) Appropriate Wittig
reagent; (h) 1. EDCI, C6H5C(NH2)=NOH, CH2Cl2; 2. Toluene, heat.
We also explored additional structural modifications of the
furan. The replacement of the furan ring in 1 with a 5,6-dihydro-
2H-pyran-2-one (34) was found to greatly reduce affinity for
KOPs. This molecule was prepared as a potential neoclerodane
based affinity label. However, its low affinity for KOPs greatly
hampers it potential utility in this capacity. Other structural
modifications may lead to more useful pharmacological tools to
better characterize the interactions of neoclerodanes with opioid
receptors. Replacement of the furan with a 2-benzofuran (35)
greatly decreases affinity for KOPs compared to 1. However,
this modification had little effect on MOP affinity but enhanced
affinity for DOP receptors. Interestingly, bioisosteric replacement
of the 2-benzofuran (35) with a 2-benzothiophene (36) resulted in
similar affinity for MOPs and DOPs but led to a loss in affinity
for KOPs (Ki > 10,000 nM). Similar results were seen when
the 2-benzofuran was replaced with a 4-phenyl-1,3,5-oxadiazole
(37). This is in agreement with recent findings of Beguin et al.36
However, 37 was found to have affinity for MOP receptors
(Ki = 1,610 nM).
KOP receptors relative to 7 (Ki = 140 nM vs. Ki = 1220 nM).
Replacement of the piperidine ring with a pyrrolidine ring (22)
resulted in a 9-fold loss in affinity (Ki = 1,210 M vs. Ki
=
140 nM). Given this interesting result, we decided to further
probe the role of the piperidine ring in 21. Replacement of
the piperidine ring with either a morpholine ring (20) or a
thiomorpholine ring (23) was well tolerated but did not further
enhance affinity for KOP receptors. Addition of a 4-bromo group
to the piperidine ring (24) resulted in a 9-fold loss in affinity. This
suggests that substitution in this position is not well tolerated.
However, additional modifications need to be explored to further
substantiate this finding.
Previously, we showed that the tetrahydrofuran analogue of 1
retained high affinity for KOP receptors.34 Based on this finding,
we prepared several additional tetrahydrofurans. Unfortunately,
this strategy also met with little success. The insertion of an amide
linkage (25–27) resulted in a loss in affinity at KOP receptors.
Surprisingly, 25 was found to have low affinity DOP receptors
(Ki = 3,090 nM). This is interesting because this is the first report
of a neoclerodane with some selectivity for DOPs. Its modest
affinity augers for the identification of other neoclerodanes with
enhanced affinity for DOPs. The insertion of an ester linkage
(28–30) was better tolerated but did not result in high affinity
Given the increased affinity of 7 and 8 for KOPs relative to
5, we explored additional nonaromatic substitutions. First the
cyclohexylamine moiety of 7 was contracted into a piperidine
ring (21). This change resulted in a 9-fold increase in affinity for
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Table 1 Opioid receptor binding affinity for compounds 1, 5–30, and
Conclusions
34–3753
In summary, we have evaluated 30 furan ring modified analogues
of 1 for opioid receptor affinity. This manuscript reports the first
salvinorin A analogue with some selectivity for DOP receptors
(25). This suggests the likelihood of identifying other diterpenes
with this characteristic from natural sources. Piperidine 21 and
thiomorpholine 23 were found to be selective partial agonists at
KOPs. However, they are less potent than 1. Furthermore, this is
the first report to discuss the potential toxicological concerns with
the use of 1. Additional structural modifications of 1 are currently
being explored and will be reported in due course.
Ki SD, nMa
Cmpd [3H]DAMGO (MOP) [3H]DADLE (DOP) [3H]U69,593 (KOP)
1
1370 130
>2,800
>2,800
>2,800
>2,800
>10,000
>4,700
>4,700
>4,700
>4,700
7.4 0.7
>10,000
>10,000
1,930 220
4,060 280
>10,000
>10,000
>10,000
> 10,000
8,290 670
>10,000
>10,000
>10,000
7,580 720
> 10,000
7,280 400
8,060 720
2,340 120
>10,000
>10,000
230 20
140 10
1,210 80
160 10
1,250 130
>10,000
>10,000
>10,000
610 30
5
6
7
8
9
>10,000
>10,000
>10,000
2,490 80
2,150 140
>10,000
>10,000
>10,000
1,630 100
1,610 80
1,570 90
>10,000
1,900 90
1,510 100
1,610 70
>10,000
>10,000
>10,000
980 70
>3,000
>10,000
>10,000
>10,000
3,690 330
3,200 390
>10,000
>10,000
>10,000
> 10,000
> 10,000
2,600 220
>10,000
3,380 240
3,650 260
2,840 180
>10,000
>10,000
>10,000
>3,000
10
11
12
13
14
15
16
17
18
19
34
35
36
37
20
21
22
23
24
25
26
27
28
29
30
Experimental section
Unless otherwise indicated, all reagents were purchased from
commercial suppliers and are used without further purification.
All melting points were determined on a Thomas–Hoover capil-
lary melting apparatus and are uncorrected. NMR spectra were
recorded on either a Bruker Avance-300 spectrometer, Bruker
DRX-400 with qnp probe and/or a Bruker AV-500 with cryoprobe
using d values in ppm (TMS as internal standard) and J (Hz)
assignments of 1H resonance coupling. High resolution mass
spectrometry data was collected on either a LCT Premier (Waters
Corp., Milford, MA) time of flight mass spectrometer or an Agilent
6890 N gas chromatograph in conjuction with a Quatro Micro
GC mass spectrometer (Micromass Ltd, Manchester UK). Thin-
layer chromatography (TLC) was performed on 0.25 mm plates
Analtech GHLF silica gel plates using EtOAc/n-hexanes, 1:1 as
the solvent system. Spots on TLC visualized with phosphomolyb-
dic acid in ethanol. Column chromatography was performed with
Silica Gel (32–63 m particle size) from Bodman Industries (Atlanta,
GA). Analytical HPLC was carried out on an Agilent 1100 Series
Capillary HPLC system with diode array detection at 254.8 nm
on an Agilent Eclipse XDB-C18 column (4.6 ¥ 150 mm, 5 mm)
with isocratic elution in 60% CH3CN/40% H2O at a flow rate of
5.0 mL/min unless otherwise noted.
>3,000
>10,000
>10,000
>10,000
> 10,000
>10,000
>10,000
3,090 220
>10,000
>10,000
3,360 340
>10,000
>10,000
2,980 240
2,190 300
a Receptor binding was performed in CHO cells which express the human
MOP, DOP or KOP receptors. All results are n = 3.
Table 2 Opioid receptor activity for 1, 21, and 23
a
b
Cmpd
KOP ED50
41
KOP Emax
General procedure A
1
6
124
6
21
5110 1800
3780 970
85 13
A solution of 4 (1 equiv), appropriate amine or alcohol (1.5 equiv),
EDCI (2.5 equiv), HOBt (2.5 equiv) and Et3N (10 equiv) in CH2Cl2
was stirred at room temperature overnight. The mixture was then
washed with saturated aqueous NaHCO3 (3 ¥ 15 mL), H2O (3 ¥
15 mL), and brine (15 mL) and dried over anhydrous Na2SO4. The
solvent was evaporated in vacuo and the resulting residue purified
by flash column chromatography on silica gel using mixtures of
EtOAc-hexanes.
23
57
6
U50,488H
27
6
100
b
a ED50 = Effective dose for 50% maximal response. Emax is % which
compound stimulates binding compared to (-)-U50,488 (500 nM) at KOP
receptors.
agents. The highest affinity compound in this series identified was
bicycle 28 (Ki = 610 nM).
(2S,4aR,6aR,7R,9S,10aS,10bR)-Methyl 9-acetoxy-6a,10b-
dimethyl-2-(morpholine-4-carbonyl)-4,10-dioxododecahydro-
1H-benzo[f]isochromene-7-carboxylate (20)
Compounds 21 and 23 were then evaluated for functional
activity at KOP receptors using a [35S]GTP-g-S assay (Table 2).53
Despite their affinity in the 100 nM range, 21 and 23 were
found to be approximately 100-fold less active than 1 as agonists.
However, the replacement of the furan ring with a piperidino or
thiomorpholinocarbonyl group was found to reduce efficacy at
KOP receptors. This suggests that additional structural modifica-
tions may lead to analogues with enhanced activity and reduced
efficacy.
Compound 20 was synthesized from compound 4 using procedure
A and morpholine to afford 0.0510 g (44.4%) as a white solid, mp
◦
1
128–130 C; H NMR (400 MHz, CDCl3) d 5.25–5.14 (m, 2H),
3.82–3.72 (m, 5H), 3.71–3.60 (m, 4H), 3.50 (t, J = 16.0 Hz, 2H),
2.79 (dd, J = 5.8, 10.9 Hz, 1H), 2.37–2.24 (m, 4H), 2.19 (s, 3H),
2.09 (d, J = 16.5 Hz, 1H), 1.95 (dd, J = 7.5, 13.6 Hz, 1H), 1.77
(d, J = 12.4 Hz, 1H), 1.71–1.52 (m, 3H), 1.39 (s, 3H), 1.09 (s, 3H).
3752 | Org. Biomol. Chem., 2009, 7, 3748–3756
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13C NMR (101 MHz, CDCl3) d 202.23, 171.64, 170.98, 169.79,
167.28, 74.98, 71.27, 66.67, 64.53, 53.26, 51.95, 49.14, 46.20, 42.86,
42.00, 37.72, 37.54, 35.11, 35.10, 30.73, 20.59, 18.17, 17.01, 16.03.
HRMS (m/z): [M + Na] calcd for C24H33NO9Na, 502.2055; found,
502.2045. HPLC tR = 3.490 min; purity = 98.69%.
1.73 (m, 1H), 1.70–1.62 (m, 1H), 1.62–1.51 (m, 2H), 1.37 (s, 3H),
1.27 (td, J = 2.3, 7.3 Hz, 3H), 1.08 (s, 3H). 13C NMR (126 MHz,
CDCl3) d 201.81, 199.44, 171.72, 170.08, 170.04, 80.41, 75.01,
64.42, 53.54, 52.24, 50.57, 42.13, 39.54, 37.96, 35.59, 30.85, 23.23,
20.81, 18.33, 16.36, 16.09, 14.54. HRMS (m/z): [M + Na] calcd for
C22H30O8SNa, 477.1559; found, 477.1536. HPLC tR = 26.933 min;
purity = 98.31%.
(2S,4aR,6aR,7R,9S,10aS,10bR)-Methyl 9-acetoxy-6a,10b-
dimethyl-4,10-dioxo-2-(piperidine-1-carbonyl)dodecahydro-1H-
benzo[f]isochromene-7-carboxylate (21)
(2S,4aR,6aR,7R,9S,10aS,10bR)-Methyl 9-acetoxy-2-formyl-
6a,10b-dimethyl-4,10-dioxododecahydro-1H-benzo[f]isochromene-
7-carboxylate (32)
Compound 21 was synthesized from 4 using procedure A and
pip◦eridine to afford 0.0870 g (75.0%) as a white solid, mp 188–1
91 C;1H NMR (300 MHz, CDCl3) d 5.25 (dd, J = 15.1, 7.1 Hz,
1H), 5.18–5.07 (m, 1H), 3.67 (s, 3H), 3.66 (m, 1H), 3.53–3.23 (m,
3H), 2.84–2.67 (m, 1H), 2.47–2.19 (m, 5H), 2.12 (s, 3H), 2.08–
1.92 (m, 2H), 1.83–1.40 (m, 9H), 1.34 (s, 3H), 1.04 (d, J = 9.1 Hz,
3H). 13C NMR (75 MHz, CDCl3) d 202.43, 171.81, 171.50, 169.86,
167.41, 75.12, 71.37, 64.65, 53.28, 51.99, 48.89, 46.87, 43.76, 42.12,
38.07, 37.80, 35.17, 30.85, 26.55, 25.56, 24.47, 20.69, 18.32, 17.18,
16.08. HRMS (m/z): [M + Na] calcd for C25H35NO8Na, 500.2260;
found, 500.2247. HPLC tR = 8.802 min; purity = 97.04%.
A mixture of 31 (0.700 g, 1.54 mmol), triethylsilane (0.737 mL,
4.62 mmol), and 10% palladium on carbon (32.7 mg) in CH2Cl2
(25 mL) was stirred at room temperature overnight under an argon
atmosphere. Upon completion, the reaction mixture was filtered
through a pad of Celite and the solvent was removed under reduced
pressure. A mixture of EtOAc/n-hexanes (1:25) (40 mL) was added
to the residue. The resulting solid was collected by filtration and
dried to afford 0.498 mg (81.9% yield) of 32 as a white solid, mp
194–197 ◦C; 1H NMR (500 MHz, CDCl3) d 9.68 (s, 1H), 5.16 (dd,
J = 8.6, 11.6 Hz, 1H), 4.89 (dd, J = 7.2, 9.8 Hz, 1H), 3.73 (s, 3H),
2.75 (dd, J = 5.2, 11.6 Hz, 1H), 2.52 (dd, J = 7.1, 13.7 Hz, 1H),
2.36–2.24 (m, 2H), 2.18 (s, 3H), 2.16–2.07 (m, 1H), 1.96 (dd, J =
3.1, 11.8 Hz, 1H), 1.78 (dt, J = 3.1, 13.4 Hz, 1H), 1.72–1.50 (m,
4H), 1.39 (s, 3H), 1.09 (s, 3H). 13C NMR (126 MHz, CDCl3) d
201.91, 197.98, 171.69, 170.36, 170.11, 79.71, 75.05, 64.50, 53.52,
52.24, 50.98, 42.16, 37.93, 36.64, 35.39, 30.82, 20.80, 18.35, 16.41,
16.37; HRMS (m/z): [M + H]+ calcd for C20H27O8, 395.1706;
found, 395.1712. HPLC tR = 7.561 min; purity = 95.63%.
(2S,4aR,6aR,7R,9S,10aS,10bR)-Methyl 9-acetoxy-6a,10b-
dimethyl-4,10-dioxo-2-(thiomorpholine-4-carbonyl)dodecahydro-
1H-benzo[f]isochromene-7-carboxylate (23)
Compound 23 was synthesized from 4 using procedure A and
thiomorpholine to afford 0.0430 g (23.8%) as a white solid, mp
◦
1
102–105 C. H NMR (400 MHz, CDCl3) d 5.27–5.09 (m, 2H),
4.18–4.05 (m, 1H), 3.88 (dd, J = 14.4, 4.5 Hz, 1H), 3.76–3.58 (m,
5H), 2.83–2.52 (m, 4H), 2.43–2.23 (m, 5H), 2.17 (s, 3H), 2.08
(d, J = 14.2 Hz, 1H), 1.90 (dd, J = 13.4, 7.7 Hz, 1H), 1.66
(ddd, J = 31.6, 25.8, 12.0 Hz, 4H), 1.37 (s, 3H), 1.07 (s, 3H).
13C NMR (101 MHz, CDCl3) d 202.40, 171.81, 171.14, 169.96,
167.43, 75.15, 71.59, 64.66, 52.12, 49.29, 48.72, 45.52, 42.16 (2C),
37.88, 35.24 (2C), 30.89, 28.21, 27.47, 20.76, 18.33, 17.17, 16.20.
HRMS (m/z): [M + H]+ calcd for C24H34NO8S, 496.2005; found,
496.1985. HPLC tR = 12.474 min; purity = 98.40%.
(2S,4aR,6aR,7R,9S,10aS,10bR)-Methyl 9-acetoxy-2-((S)-1-
hydroxybut-3-enyl)-6a,10b-dimethyl-4,10-dioxododecahydro-1H-
benzo[f]isochromene-7-carboxylate (33a)
A solution of 9-[(1R,2R)-pseudoephedrinyl]-(10S)-(trimethyl-
silyl)-9-borabicyclo[3.3.2]decane (0.546 g, 1.47 mmol) in anhy-
◦
drous Et2O (20 mL) at -78 C was treated with allylmagnesium
bromide (1.47 mL, 1.47 mmol). The mixture was stirred at room
temperature for 1 h and then cooled to -78 ◦C. A solution
of 32 (0.580 g, 1.47 mmol) in dry THF (3 mL) was added
in a dropwise manner and the solution was warmed to 10 ◦C
overnight. The solvent was removed under reduced pressure and
the residue was redissolved in acetonitrile (10 mL) and (1R,2R)-
(-)-pseudoephedrine (0.243 g) was added. The resulting mixture
was heated at reflux overnight. The solvent was removed under
reduced pressure and CH2Cl2 (5 mL) added and the mixture was
cooled to 0 ◦C in an ice bath. The mixture was filtered to remove
the white precipitate. The filtrate was evaporated to dryness and
the residue was purified by column chromatography (eluent: 30–
50% EtOAc/n-hexanes) to afford 0.289 g (50% brsm) of 33a as
(2S,4aR,6aR,7R,9S,10aS,10bR)-Methyl 9-acetoxy-2-
(ethylthiocarbonyl)-6a,10b-dimethyl-4,10-dioxododecahydro-
1H-benzo[f]isochromene-7-carboxylate (31)
A solution of 4 (1.16 g, 2.83 mmol), CDMT (1.49 g, 8.49 mmol),
and N-methylmorpholine (1.86 mL, 16.96 mmol) in anhydrous
THF (25 mL) was stirred at room temperature for 1 h under
an argon atmosphere. Ethanethiol (1.25 mL, 16.96 mmol) was
then added and reaction was stirred at room temperature for an
additional 48 hours. H2O (25 mL) was added and the resulting
mixture was extracted with Et2O (3 ¥ 30 mL). The combined Et2O
portion was washed with saturated NaHCO3 (3 ¥ 20 mL), 2 N
HCl (3 ¥ 20 mL), and saturated NaCl (3 ¥ 20 mL) and dried
(Na2SO4). The solvent was removed under reduced pressure and
the resulting residue purified by flash column chromatography on
silica gel using a mixture of EtOAc/n-hexanes to◦afford 1.13 g
1
a clear oil; H NMR (300 MHz, CDCl3) d 5.75 (dq, J = 7.1,
10.1 Hz, 1H), 5.08 (dd, J = 6.8, 13.3 Hz, 3H), 4.36 (ddd, J =
9.1, 12.0, 20.8 Hz, 1H), 3.65 (s, 3H), 3.48–3.37 (m, 1H), 2.71 (dd,
J = 5.8, 11.0 Hz, 1H), 2.52 (s, 1H), 2.33 (dd, J = 7.9, 14.8 Hz,
2H), 2.23 (t, J = 7.1 Hz, 2H), 2.17 (s, 1H), 2.15–2.05 (m, 4H),
2.00 (t, J = 10.0 Hz, 2H), 1.70 (d, J = 7.8 Hz, 1H), 1.54 (dd, J =
10.5, 19.3 Hz, 3H), 1.28 (s, 3H), 1.00 (s, 3H). 13C NMR (75 MHz,
CDCl3) d 202.37, 171.91, 171.77, 170.06, 133.99, 118.55, 78.65,
1
(88.0% yield) of 31 as a white solid, mp 187–191 C; H NMR
(500 MHz, CDCl3) d 5.18–5.11 (m, 1H), 4.97 (dd, J = 7.2, 9.7 Hz,
1H), 3.72 (s, 3H), 2.90 (q, J = 7.4 Hz, 2H), 2.73 (dd, J = 5.4,
11.4 Hz, 1H), 2.62 (dd, J = 7.2, 13.7 Hz, 1H), 2.35–2.26 (m,
2H), 2.18 (s, 3H), 2.17–2.10 (m, 2H), 2.10–2.02 (m, 1H), 1.81–
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Org. Biomol. Chem., 2009, 7, 3748–3756 | 3753
©

View Article Online
75.21, 72.57, 64.05, 53.53, 52.04, 50.80, 42.16, 38.53, 38.18, 37.80,
34.96, 30.89, 20.70, 18.30, 16.32, 15.25; HRMS (m/z): [M + Na]
calcd for C23H32O8Na, 459.1995, found, 459.1824.
Removal of the solvent under reduced pressure gave a crude
residue that was purified by flash column chromatography (eluent:
25% EtOAc/n-hexanes) to yield 0.0610 g (26%) of 35 as a white
solid, mp 192–196 ◦C (dec); 1H NMR (300 MHz, CDCl3) d 7.55 (d,
J = 7.4 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.35–7.17 (m, 2H), 6.71
(s, 1H), 5.66 (dd, J = 11.3, 5.7 Hz, 1H), 5.15 (t, J = 10.0 Hz, 1H),
3.73 (s, 3H), 2.85–2.71 (m, 1H), 2.57 (dd, J = 13.4, 5.7 Hz, 1H),
2.38–2.09 (m, 8H), 1.99 (dd, J = 24.3, 11.8 Hz, 1H), 1.86–1.55
(m, 3H), 1.49 (s, 3H), 1.10 (s, 3H). 13C NMR (75 MHz, CDCl3)
d 202.15, 171.76, 170.85, 170.12, 155.35, 153.94, 127.74, 125.19,
123.27, 121.67, 111.59, 105.42, 75.25, 72.52, 64.31, 53.77, 52.20,
51.25, 42.32, 40.60, 38.32, 35.64, 30.97, 20.76, 18.39, 16.53, 15.40.
HRMS (m/z): [M + H]+ calcd for C27H30O8, 482.1941; found,
482.1945. HPLC tR = 10.606 min; purity = 98.10%.
(2S,4aR,6aR,7R,9S,10aS,10bR)-Methyl 9-acetoxy-6a,10b-
dimethyl-4,10-dioxo-2-((S)-1-((R)-3,3,3-trifluoro-2-methoxy-2-
phenylpropanoyloxy)but-3-enyl)dodecahydro-1H-
benzo[f]isochromene-7-carboxylate (33b)
33b was prepared in 82% from 33a and (R)-(+)-a-methoxy-
a-trifluoromethylphenylacetic acid using previously described
methods.49 1H NMR (300 MHz, CDCl3) d 7.65–7.52 (m, 2H), 7.52–
7.39 (m, 3H), 5.79–5.59 (m, 1H), 5.21–5.02 (m, 2H), 5.01–4.88 (m,
1H), 4.75 (td, J = 6.9, 0.9 Hz, 1H), 4.55–4.44 (m, 1H), 3.73–3.65
(m, 3H), 3.54 (t, J = 5.4 Hz, 3H), 2.64–2.48 (m, 3H), 2.31–2.15
(m, 2H), 2.15–2.06 (m, 4H), 2.01–1.85 (m, 2H), 1.62–1.51 (m,
1H), 1.36 (ddt, J = 11.5, 6.7, 5.7 Hz, 1H), 1.30–1.08 (m, 6H),
0.88 (s, 3H). 13C NMR (75 MHz, CDCl3) d 201.98, 171.74, 171.01,
170.09, 166.03, 133.66, 131.97, 129.83 (2C), 128.81 (2C), 127.41,
120.14, 83.78, 76.60, 75.00, 74.80, 63.73, 56.37, 53.19, 52.19, 49.80,
41.99, 37.91, 37.75, 34.76, 34.62, 30.85, 29.86, 20.73, 18.26, 16.16,
14.99.
(2S,4aR,6aR,7R,9S,10aS,10bR)-Methyl 9-acetoxy-2-
(benzo[b]thiophen-2-yl)-6a,10b-dimethyl-4,10-dioxododecahydro-
1H-benzo[f]isochromene-7-carboxylate (36)
A
solution of 4 (0.200 g, 0.487 mmol), 2-chloro-4,6-
dimethoxytriazine (0.086 g, 0.487 mmol), and NEt3 (0.07 mL,
0.487 mmol) in CH2Cl2 (4 mL) was stirred at room temperature for
1 h. 2-(Mercaptobenzyl)triphenylphoshonium bromide (0.227 g,
0.487 mmol), and N-methylmorpholine (0.16 mL, 1.46 mmol)
and toluene (10 mL) were added and the resulting mixture was
heated at reflux overnight. Removal of the solvent under reduced
pressure gave a crude residue that was purified by flash column
chromatography (eluent: 20% EtOAc/n-hexanes) to yield 0.0846 g
(35%) of 36 as a white solid, mp 223–225 ◦C; 1H NMR (500 MHz,
CDCl3) d 7.83–7.78 (m, 1H), 7.74–7.70 (m, 1H), 7.37–7.30 (m,
2H), 7.23 (s, 1H), 5.92–5.79 (m, 1H), 5.19–5.09 (m, 1H), 3.73 (s,
3H), 2.83–2.64 (m, 2H), 2.35–2.27 (m, 2H), 2.22–2.11 (m, 6H),
1.84–1.74 (m, 2H), 1.72–1.58 (m, 2H), 1.50 (s, 3H), 1.13 (s, 3H).
13C NMR (126 MHz, CDCl3) d 201.99, 171.54, 170.60, 169.97,
143.65, 139.34, 139.04, 124.71, 124.55, 123.84, 122.43, 121.40,
75.13, 75.00, 64.04, 53.52, 52.01, 51.27, 44.52, 42.10, 38.04, 35.76,
30.75, 20.58, 18.14, 16.39, 15.40. HRMS (m/z): [M + H]+ calcd
for C27H31O7S, 499.1791; found, 499.1777. HPLC tR = 12.324 min;
purity = 100%.
(2S,4aR,6aR,7R,9S,10aS,10bR)-Methyl 9-acetoxy-6a,10b-
dimethyl-4,10-dioxo-2-((R)-6-oxo-3,6-dihydro-2H-pyran-2-
yl)dodecahydro-1H-benzo[f]isochromene-7-carboxylate (34)
A solution of 33a (0.099 g, 0.227 mmol), acryloyl chloride
(0.55 mL, 6.80 mmol), NEt3 (0.95 mL, 6.80 mmol), and a catalytic
amount of DMAP in CH2Cl2 (10 mL) was stirred at room
temperature overnight. The solvent was removed under reduced
pressure and the residue was purified by column chromatography
to afford 0.045 g of the corresponding acrylate which was used
without further purification. A solution of the acrylate and 2nd
generation Grubb’s catalyst (10 mol%) in CH2Cl2 (10 mL) was
heated at reflux overnight under an argon atmosphere. The solvent
was removed under reduced pressure and the residue was purified
by column chromatography (eluent: 50% EtOAc/n-hexanes) to
afford 0.0245 g (57.6%) of 34 as a white solid, mp > 250 ◦C;
1H NMR (300 MHz, CDCl3) d 7.05–6.87 (m, 1H), 6.03 (dd, J =
9.8, 2.4 Hz, 1H), 5.22–5.04 (m, 1H), 4.55 (dd, J = 11.3, 6.2 Hz,
1H), 4.32 (dd, J = 13.0, 3.3 Hz, 1H), 3.72 (s, 3H), 3.09–2.91 (m,
1H), 2.77 (dd, J = 11.1, 5.6 Hz, 1H), 2.38–2.08 (m, 9H), 1.95 (t,
J = 12.2 Hz, 1H), 1.84–1.50 (m, 4H), 1.35 (s, 3H), 1.06 (s, 3H).
13C NMR (75 MHz, DMSO) d 202.55, 171.81, 171.05, 170.01,
163.54, 145.84, 120.99, 77.60, 75.93, 75.36, 63.96, 53.59, 52.13,
50.56, 42.30, 38.11, 37.12, 35.05, 30.95, 26.01, 20.73, 18.31, 16.32,
15.24. HRMS (m/z): [M + Na] calcd for C24H30O9Na, 485.1787;
found, 485.1769. HPLC tR = 19.918 min; purity = 100%.
X-Ray crystallographic study of 33b
Colorless crystals of C33H39F3O10 are, at 100(2) K, monoclinic,
2
˚
space group P21 - C2 (No. 4) with a = 6.6372(4) A, b =
◦
˚
˚
18.637(1) A, c = 12.6435(8) A, b = 93.235(1) , V = 1561.5(2)
and Z = 2 molecules {dcalcd = 1.388 g/cm3; ma(MoKa) =
3
˚
A
0.113 mm-1}. A full hemisphere of diffracted intensities (1850 10-
second frames with an w scan width of 0.30◦) was measured for
a single-domain specimen using graphite-monochromated MoKa
˚
radiation (l = 0.71073 A; fine-focus sealed X-ray tube) on a Bruker
(2S,4aR,6aR,7R,9S,10aS,10bR)-Methyl 9-acetoxy-2-
(benzofuran-2-yl)-6a,10b-dimethyl-4,10-dioxododecahydro-1H-
benzo[f]isochromene-7-carboxylate (35)
SMART APEX CCD Single Crystal Diffraction System. A total of
18602 integrated reflection intensities having 2q((MoKa)<61.00◦
were produced using the Bruker program SAINT; 9099 of these
were unique and gave Rint = 0.048 with a coverage which
was 98.6% complete. The data were corrected empirically for
variable absorption effects using equivalent reflections. The Bruker
software package SHELXTL was used to solve (direct methods)
and refine (weighted full-matrix least-squares) the structure with
A
solution of 4 (0.200 g, 0.487 mmol), 2-chloro-4,6-
dimethoxytriazine (0.086 g, 0.487 mmol), and NEt3 (0.07 mL,
0.487 mmol) in CH2Cl2 (4 mL) was stirred at room temperature for
1 h. (2-Hydroxybenzyl)triphenylphosphonium bromide (0.220 g,
0.487 mmol), NEt3 (0.21 mL, 1.46 mmol) and toluene (10 mL) were
added and the resulting mixture was heated at reflux overnight.
2
Fo data.
3754 | Org. Biomol. Chem., 2009, 7, 3748–3756
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The Royal Society of Chemistry 2009
©

View Article Online
The three ethylenic hydrogens were located from a difference
Fourier and included in the structural model as independent
isotropic atoms. The remaining hydrogen atoms were included
in the structural model as idealized atoms (assuming sp2- or
sp3-hybridization of the carbon atoms and C–H bond lengths
8 B. L. Roth, K. Baner, R. Westkaemper, D. Siebert, K. C. Rice, S.
Steinberg, P. Ernsberger and R. B. Rothman, Proc. Natl. Acad. Sci.
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Huang, J. G. Li, A. Cowan and L. Y. Liu-Chen, J. Pharmacol. Exp.
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˚
of 0.95–1.00 A) with isotropic thermal parameters fixed at
values 1.2 (nonmethyl) or 1.5 (methyl) times the equivalent
isotropic thermal parameter of the carbon atom to which they
are covalently bonded. The final structural model incorporated
anisotropic thermal parameters for all nonhydrogen atoms and
isotropic thermal parameters for all hydrogen atoms. A total
of 432 parameters were refined using 1 restraint and 9099
data. Final agreement factors at convergence are: R1(unweighted,
based on F) = 0.045 for 8245 independent absorption-corrected
“observed” reflections having 2q(MoKa)<61.00◦ and I>2s(I);
R1(unweighted, based on F) = 0.049 and wR2(weighted, based
on F2) = 0.109 for all 9099 independent absorption-corrected
reflections having 2q(MoKa)<61.00◦. The final difference map
-
3
˚
had maxima and minima of 0.51 and -0.22 e /A , respectively.
The Flack parameter [0.0(4)] did not allow the absolute config-
uration to be established directly from the X-ray analysis and
this was assigned using the known stereochemistry for much
of the molecule. Atomic coordinates for compound 33b have
been deposited with the Cambridge Crystallographic Data Centre
(deposition number CCDC 723548). Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge, CB2, 1EZ, UK [fax, +44(0)-1223-336033;
e-mail, mailto:deposit@ccdc.cam.ac.uk].
Acknowledgements
25 L. A. Peterson, Drug Metab. Rev., 2006, 38, 615–626.
26 S. Zhou, H.-L. Koh, Y. Gao, Z.-y. Gong and E. J. D. Lee, Life Sci.,
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We wish to thank (Dr Todd Williams, Mr Robert Drake, Mr Larry
Sieb) of the KU mass spectrometry laboratory for their efforts
in acquiring the ESI spectra. LCT Premier was purchased with
support from NIH SIG S10 RR019398. This work was supported
by Grant Numbers R01DA018151 and R01DA018151S1 (to TEP)
from the National Institute on Drug Abuse (NIDA). Portions
of this work were also supported by the Intramural Research
Program, National Institute on Drug Abuse, National Institutes
of Health, DHHS. In silico computational toxicology testing
was completed with the support of NIDA’s Addiction Treatment
Discovery Program through the use of Interagency Agreement Y1-
DA6003. The content is the sole responsibility of the authors and
does not necessarily represent the official views of the National
Institute on Drug Abuse or the National Institutes of Health.
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