Standard protecting groups create potent and selective κ opioids: Salvinorin B alkoxymethyl ethers

Article abstract of DOI:10.1016/j.bmc.2007.10.067

Protection of salvinorin B as standard alkoxyalkyl ethers yielded highly potent κ opioid receptor agonists. Ethoxymethyl ether 6 is among the most potent and selective κ agonists reported to date. Fluoroethoxymethyl ether 11 is the first potent, selective

Full text of DOI:10.1016/j.bmc.2007.10.067

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 1279–1286
Standard protecting groups create potent and selective j opioids:
Salvinorin B alkoxymethyl ethers
a
c
c
Thomas A. Munro,a,b, Katharine K. Duncan, Wei Xu, Yulin Wang,
*
Lee-Yuan Liu-Chen,c William A. Carlezon, Jr.,a,b Bruce M. Cohena,b and Cecile Beguin
a,b
´
´
aMailman Research Center, McLean Hospital, Belmont, MA 02478, USA
bDepartment of Psychiatry, Harvard Medical School, Boston, MA 02215, USA
cDepartment of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA
Received 14 September 2007; revised 16 October 2007; accepted 19 October 2007
Available online 24 October 2007
Abstract—Protection of salvinorin B as standard alkoxyalkyl ethers yielded highly potent j opioid receptor agonists. Ethoxymethyl
ether 6 is among the most potent and selective j agonists reported to date. Fluoroethoxymethyl ether 11 is the first potent, selective
fluorinated j ligand, with potential use in MRI and PET studies. Further enlargement of the alkoxy group, alkylation of the acetal
carbon, or heteroatom substitution all reduced activity. These protecting groups may prove useful in related work not only by
enabling the use of harsher synthetic conditions, but potentially by optimizing the potency of the products.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
depression.7 However, the modifications which appear
to confer partial agonist and antagonist activities on salv-
inorin derivatives also dramatically reduce binding affin-
ity and selectivity;4,5 methods to optimize these
parameters would therefore be useful.
Salvinorin A (1) is a potent and selective naturally-occur-
ring j (kappa) opioid.1 As one of very few reported non-
nitrogenous opioids,2 salvinorin A has created new
opportunities for understanding the mechanisms of
ligand binding at opioid receptors, which might facilitate
drug discovery. One objective has been the development
of selective antagonists or partial agonists at j opioid
receptors; such agents have potential utility in the treat-
ment of depression or mania,3 debilitating conditions
for which all current treatments have significant limita-
tions (e.g., poor efficacy, delayed onset, marked side
effects). Many derivatives of 1 have now been tested at
opioid receptors.4 Binding affinity and potency are almost
invariably reduced; very few derivatives exhibit potency
comparable to 1. Most active derivatives, like the parent
compound, are full agonists, but recently partial agonists
and antagonists have been reported.4,5 This is potentially
significant, since the few available selective j antagonists
exhibit extremely slow onset (ꢀ24 h) and long duration of
action (>3 weeks),6 which complicates their use in the
study or treatment of psychiatric conditions such as
R
O
O
O
1
O
HO
O
2
3
O
O
H
O
H
O
4a
R
O
2
O
O
4b
4c
5
O
O
O
To date the most thoroughly studied functional group of
1 is the C-2 acetate. Interestingly, while deacetylation
(giving 2) dramatically lowers affinity and potency,8
demethyl and deoxy analogues 39 and 4b8 each show
only modestly reduced affinity. This suggests that these
Keywords: Salvinorin A; j Opioid receptor; Methoxymethyl ether;
Ethoxymethyl ether; 2-Fluoroethoxymethyl ether; Protecting groups.
*
Corresponding author. Tel.: +1 617 855 2095; fax: +1 617 855
3479; e-mail: tmunro@mclean.harvard.edu
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.10.067

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T. A. Munro et al. / Bioorg. Med. Chem. 16 (2008) 1279–1286
Table 1. Affinities (Ki) and potencies (EC50) at the j opioid receptor
two portions of the acetate may be involved in separate,
synergistic interactions with the receptor. Only one
derivative with greater potency than 1 has been reported
to date: methoxymethyl (MOM) ether 5.10 The increased
affinity of 5 may be due to the additional sp3-hybridized
oxygen, especially considering the lower affinity of its
closest sp2-hybridized analogue, 3. Alternatively, the ter-
minal methyl group of 5 might create an additional
interaction, which could be explored by the substitution
of other alkoxy groups. A related question is whether
methylation of the acetal carbon would further increase
potency, as with formate 3. In hopes of optimizing the
C-2 substituent, we explored these questions using re-
lated protecting groups.
Compound
R
Ki SEMa,b EC50 SEMb,c
(nM)
(nM)
O
O
1
5
2.4 0.4
1.8 0.5
O
O
O
O
O
O
0.60 0.07
0.32 0.02
2.2 0.6
5.3 1.7
1.6 0.5
35 15
0.40 0.04
0.14 0.01
5.2 0.4
20 3.5
6
7
O
O
O
O
2. Chemistry
8
Deacetylation11 of 1, isolated from dried Salvia divinorum
leaves as previously described,12 gave 2. MOM ether 5
was prepared from 2 and CH3OCH2Cl as previously de-
9
4.2 0.7
108 18
3.8 0.3
1
scribed.13 The published H NMR data13 required
O
O
O
O
10
11
12
amendment. The molecular formula, not previously
established, was confirmed by HRMS. The ethoxymethyl
(EOM) ether 6 and several other standard alkoxymethyl
ethers were prepared similarly (Scheme 1; see Table 1
for individual structures).14
1.9 0.5
F
F
F
F
31
8
75
7
For the more unusual alkoxymethyl ethers 7–12, the
corresponding chloromethyl ethers were expensive or
hard to obtain. Rather than prepare and purify these
volatile carcinogens, an alternative route was used.
Methylthiomethyl ether 16 was prepared from 2 using
Ac2O and AcOH in Me2SO (Scheme 1).15 When follow-
ing the published procedure, side reactions resulted in
poor yields, but we found that these were suppressed
by a large excess of AcOH. The alkoxymethyl com-
pounds 7–12 were then produced by alcoholysis of 16,
using N-iodosuccinimide (NIS) and catalytic TfOH with
the appropriate alcohol.16 Although low-yielding
(<40%), this route offers access to a wide range of prod-
ucts from a common intermediate and readily available
alcohols. The NIS route was also employed for the 2-
methoxyethoxymethyl (MEM) ether 13. Although the
corresponding chloromethyl ether is readily available,
13 is difficult to separate from residual starting material
O
O
O
O
13
14
141 29
>1000
320 13
1660 60
274 16
O
O
O
O
O
Si
15
16
17
147 26
S
F
O
O
13
50
11
3
9
1
31
26
10
8
6
1
18a
18b
19
O
O
R'OCH2Cl,
i-Pr2NEt,
DMF
R
O
*
*
6.6 0.3
72 13
5.7 0.7
72
O
O
O
O
O
O
R'
5
(6,14,15)
O
O
H
H
O
NIS, R'OH,
R
TfOH, 4 Å sieves
O
(7 - 13)
20
4.0 0.4
2.8 0.3
1.4 0.3
S
F
O
16
Ac2O, AcOH,
Me2SO
O
U50,488H 2.2 0.3
NIS, Et2NSF3,
4 Å sieves
2, R = OH
Configuration unknown.
a Inhibition of [3H]diprenorphine binding to CHO-hKOR.
b Mean of three independent experiments performed in duplicate.
c Enhancement of [35S]GTPcS binding to CHO-hKOR. All com-
pounds were full agonists (Emax = 81–106% relative to U50,488H).
*
O
17
Scheme 1. Synthesis of alkoxymethyl ethers and fluoromethyl ether.

T. A. Munro et al. / Bioorg. Med. Chem. 16 (2008) 1279–1286
1281
and selective j opioids reported to date. While the nal-
trexone derivative nalfurafine (TRK-820) is more potent
still (EC50 = 0.025 nM under the same conditions), this
compound shows much lower selectivity (l/j < 100).21
O
O
O
*
O
p-TsOH, CH2Cl2
18a,b
19
O
The potency of the MOM ether 5, while lower than 6,
was nonetheless higher than 1 or U50,488H, as previ-
ously reported.10 The selectivity of this compound,
which has not previously been quantified, is thus also ex-
tremely high (l/j and d/j > 1600). Further extension of
the alkyl chain reduced activity, but the propoxymethyl
and butoxymethyl ethers 7 and 8 retained activity com-
parable to 1. The same trend was previously reported in
the alkyl ether8 and ester22 series, but with strikingly
inferior absolute values. This provides further confirma-
tion that substitution of oxygen in this position dramat-
ically increases binding affinity. However, the increase in
binding affinity from 5 to 6 suggests that an additional
interaction involving the terminal alkyl group also con-
tributes to the extremely high affinities of these com-
pounds. For instance, the receptor may possess a
hydrophobic pocket just deep enough to accommodate
an ethyl group.
O
O
H
O
O
O
O
H
O
R
PPTS, CH2Cl2
O
O
O
*
2, R = OH
p-TsOH, CH2Cl2
20
Scheme 2. Synthesis of other alkoxyalkyl ethers. *Configuration
unknown.
2, making purification difficult; the NIS route from 16
circumvented this difficulty, since 13 and 16 are easily
separated. Due to the low yields of the NIS/TfOH route,
other conditions were tested (AgNO3/2,6-lutidine17 and
HgCl2);18 unfortunately, neither proved effective. Fluo-
romethyl ether 17 was prepared using a closely related
1
2
method: NIS and Et2NSF3.19 Typical JCF and JHF
couplings were observed in the H, 13C, and 19F NMR
spectra of all fluorinated compounds (11, 12, and 17).
1
Branching of the alkyl chain was not as well tolerated as
elongation; the isopropoxy and tert-butoxy compounds
9 and 10 showed a steep, progressive loss of activity rel-
ative to 6. MEM ether 13, with the same chain length as
butoxymethyl ether 8, showed lower affinity than that
compound. Larger protecting groups were also poorly
tolerated: the 2-(trimethylsilyl)ethoxymethyl (SEM, 14)
and benzyloxymethyl (BOM, 15) ethers were the least
active compounds in the series.
Compounds 18, 19, and 20 were prepared using ethoxy-
ethene, 2-methoxypropene, and 3,4-dihydro-2H-pyran,
respectively, with catalytic p-TsOH or PPTS (Scheme
2).14 The two epimers of 18 were separated with diffi-
culty by repeated flash chromatography; complete sepa-
ration was not achieved. Epimerization also occurred in
CDCl3, so NMR data were collected in C6D6. The rela-
tive configurations of 18a and b were not determined.
Tetrahydropyranyl ether 20 was also formed as an epi-
meric mixture, but only one epimer could be isolated after
chromatography on silica gel, contaminated with a small
amount of the other. Again, the configuration at the ace-
tal carbon is unknown. For NMR, CDCl3 filtered
through basic Al2O3 was satisfactory for brief exposures,
but for longer experiments C6D6 was required.
2-Fluoroethoxymethyl ether 11 showed potency and
affinity approximately equal to salvinorin A (1) itself.
To our knowledge, 11 is the first potent, selective fluori-
nated ligand at the j opioid receptor to be reported in
the peer-reviewed literature. This is potentially signifi-
cant, since the presence of fluorine permits in vivo imaging
through 19F magnetic resonance imaging (MRI), or (with
18F labeling) positron emission tomography (PET).23
Should labeling prove feasible, compound 11 has impor-
tant potential advantages over the existing [11C]-labeled
PET ligand, GR103545.24 Although often described as
j-selective, this compound and its racemate in fact display
higher affinity for l than j receptors (l/j = 0.5).25 By con-
trast, compound 11 is highly selective (l/j > 500). An-
other potential advantage of 11 is that the half-life of
18F is five times longer than that of 11C, which increases
sensitivity and allows a wider range of experiments.
3. Results and discussion
Binding affinities and potencies at the j receptor are
shown in Table 1. All compounds were full agonists,
with efficacy approximately equal to that of
U50,488H. All compounds except 14 showed submi-
cromolar affinity and potency, generally in the low
nanomolar range. None of the compounds bound to l
or d receptors (Ki > 1 lM). This series as a whole shows
markedly higher affinity and selectivity than previously
reported series of derivatives of 1.
Heteroatom substitution at the alkoxy group reduced
activity. Methylthiomethyl ether 16 showed much lower
potency than 5, comparable to the previously reported
propyl ether 4c of equal chain length (EC50 = 67 nM un-
der the same conditions).8 The potency of fluoromethyl
ether 17 was also greatly reduced relative to 5. Although
fluorine is widely regarded as isosteric with hydrogen, it
is in fact much closer in size to oxygen, and can serve as
an effective bioisostere for hydroxy and methoxy
groups.26 Thus, while many would regard 17 as a bioiso-
stere for the methyl ether 4a, it is in fact closer to 5. Direct
Among the n-alkoxymethyl ethers 5–8, the ethyl substi-
tuent was optimal (6), conferring extreme (subnanomo-
lar) affinity and potency. Given the lack of l and d
affinity, this compound is therefore also extremely selec-
tive (l/j and d/j > 3000). There have been very few
reports of compounds with l/j selectivity over 1000.20
Ethoxymethyl ether 6 is thus among the most potent

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T. A. Munro et al. / Bioorg. Med. Chem. 16 (2008) 1279–1286
comparison of fluorine and oxygen is confounded, how-
ever, by the terminal methyl substituent in 5, which as dis-
cussed above appears to contribute to that compound’s
potency. An indirect comparison is nonetheless possible.
The potency of 17 was similar to that of ethyl ether 4b
(EC50 = 18 nM).8 Thus, whereas substitution of oxygen
for C-2 of the propyl and butyl ethers (giving 5 and 6) dra-
matically increases activity, substitution of fluorine for
C-2 of the ethyl ether (giving 17) has little effect. These results
for 16and 17suggest that the alkoxymethyl group may act
as an H-bond acceptor, since organic fluorine is a very
poor H-bond acceptor,27 and sulfur is not an acceptor.
5. Experimental
5.1. General experimental conditions
1H NMR (300 MHz) and 13C NMR (75.5 MHz) chem-
ical shifts are referenced to residual solvent peaks as
internal standards: CDCl3 (7.26 and 77 ppm), C6D6
(7.16 and 128 ppm), and C6D5N (135.5 ppm). 19F
NMR chemical shifts are referenced to CCl3F (0 ppm).
Where the coupling constants of a discrete multiplet
could not be determined, the separation of the outer-
most peaks (Dm) is given in Hz. Flash column chroma-
tography (FCC) was performed on silica gel (230–400
˚
Contrary to the trend observed with the formate 3, methyl
substitution of the acetal carbon dramatically lowered
affinity. Compound 18 (the methyl analogue of 6) had at
least 20-fold lower affinity, while 19 (the dimethyl ana-
logue of 5) exhibited a greater than 100-fold reduction.
This implies that this series of compounds may bind in a
different manner than the ester series. The tetrahydropyr-
anyl ether 20 showed comparable affinity to 1; thus,
monosubstitution of the acetal carbon is better tolerated
than disubstitution. There was not a dramatic difference
in potency between the epimers of 18; unfortunately, only
one epimer of 20 could be isolated, preventing any addi-
tional investigation of this question.
mesh, 60 A), eluting with a stepped gradient over the
specified range. Where compound 2 was present due to
incomplete reaction or hydrolysis of products, the col-
umn was stripped with 20% MeOH/CH2Cl2 to maximize
recovery.
5.2. Binding assays
Binding affinities at l, d, and j opioid receptors were
determined, as previously described,21 by competitive
inhibition of [3H]diprenorphine binding to membranes
prepared from Chinese hamster ovary (CHO) cells sta-
bly transfected with the human j (hKOR), rat l, or
mouse d receptors. Compounds were initially screened
at 3 lM; those compounds causing >50% displacement
of [3H]diprenorphine (equivalent under the assay condi-
tions to Ki < 1 lM) were tested further for determina-
tion of binding affinity (Ki), potency (EC50) and
efficacy (Emax). Positive controls were U50,488H (j),
DAMGO (l), SNC80 (d), and etorphine (l/d), which
all caused >90% displacement of [3H]diprenorphine at
3 lM. Potencies and efficacies were determined by
[35S]GTPcS binding to membranes of CHO-hKOR cells,
as previously described.21 Testing was blinded: neither
identity nor molecular mass was known to the testers.
The high affinities of the alkoxymethyl ethers are of par-
ticular interest because these protecting groups are more
stable than acetates under many synthetic conditions.
For instance, 1 is readily deacetylated by weak bases,
and the a-hydroxy ketone function thus exposed is
highly sensitive to strong bases,12 while MOM ethers
are virtually inert under strongly basic conditions.14
Similarly, MOM ethers are generally more stable to
nucleophiles, organometallic and hydride reagents than
acetates.14 A very pertinent illustration of these advanta-
ges is the first total synthesis of 1, which employs a BOM
protecting group at C-2 in place of the acetate.28
5.3. Salvinorin B methoxymethyl ether (5)
4. Conclusions
Prepared as previously described.13 TLC (50% EtOAc/
hexanes): hRf = 40 (5), 30 (2); 1H NMR (CDCl3): d 7.41
(1H, dt, J = 1.8, 0.9 Hz), 7.40 (1H, t, J = 1.8 Hz), 6.38
(1H, dd, J = 1.8, 0.9 Hz), 5.54 (1H, dd, J = 11.8,
5.2 Hz), 4.72 (1H, d, J = 7.0 Hz), 4.70 (1H, d,
J = 7.0 Hz), 4.14 (1H, dd, J = 12.2, 7.4 Hz), 3.71 (3H, s),
3.38 (3H, s), 2.68 (1H, dd, J = 13.5, 3.5 Hz), 2.53 (1H,
dd, J = 13.5, 5.3 Hz), 2.36 (1H, ddd, J = 13.5, 7.6,
3.6 Hz), 2.19 (1H, td, J = 13.4, 12.2 Hz), 2.15 (1H, dq,
J = 13.5, 3.4 Hz), 2.06 (1H, br s), 2.05 (1H, dd, J = 11.3,
3.2 Hz), 1.78 (1H, m, Dm = 18.6 Hz), 1.71–1.45 (3H,m),
1.46 (3H, s), 1.11 (3H, s); 13C NMR (CDCl3): d 205.8,
171.8, 171.2, 143.7, 139.4, 125.3, 108.3, 95.7, 77.8, 71.9,
64.3, 55.8, 53.8, 51.9, 51.5, 43.5, 41.9, 38.1, 35.5, 32.6,
18.1, 16.4, 15.2; HRMS(ESI): [M+NH4]+ m/z 452.2295
(calcd for C23H30O8, 452.2284).
It is fortuitous that standard protecting groups, stable
and unreactive under a wide range of harsh conditions,
should also confer high potency. For synthetic transfor-
mations elsewhere in the salvinorin scaffold, this permits
the use of conditions incompatible with an acetate or hy-
droxyl. The resulting derivatives may also possess higher
affinity and selectivity than the corresponding acetate,
which would be valuable in ameliorating the effects of
transformations elsewhere in the parent compound.
For instance, some salvinorin derivatives appear to exhi-
bit antagonism or partial agonism,4,5 but this is accom-
panied by severe reductions in affinity and selectivity. In
such cases, it would be interesting to explore whether a
C-2 alkoxymethyl ether substituent attenuated these
reductions in affinity and selectivity. Alkoxymethyl
ethers are also likely to be more stable in vivo, which
would be desirable given salvinorin A’s brief duration
of action. In a recent report, a MOM ether showed
equal in vitro activity against HIV to the corresponding
acetate, and greater stability in plasma.29
5.4. Salvinorin B ethoxymethyl ether (6)
Salvinorin B (2) (49.7 mg, 127 lmol) was added to dry
DMF (1 mL) under Ar with warming. i-Pr2NEt
(110 lL, 631 lmol) and EtOCH2Cl (60 lL, 646 lmol)

T. A. Munro et al. / Bioorg. Med. Chem. 16 (2008) 1279–1286
1283
were added. The white slurry was stirred at rt for 24 h.
The solution was diluted in EtOAc and washed with
0.1 M aq HCl (3·), H2O, satd aq NaHCO3, and brine
and dried (MgSO4). FCC (25–50% EtOAc/hexanes, then
20% MeOH/CH2Cl2) gave 6 as an amorphous white
solid (45.6 mg, 80%). TLC (50% EtOAc/hexanes):
J = 12.1, 7.4 Hz), 3.71 (3H, s), 3.63 (1H, dt, J = 9.4,
6.5 Hz), 3.51 (1H, dt, J = 9.4, 6.5 Hz), 2.69 (1H, dd,
J = 13.3, 3.4 Hz), 2.53 (1H, dd, J = 13.3, 5.2 Hz), 2.34
(1H, ddd, J = 13.5, 7.5, 3.5 Hz), 2.18 (1H, td, J = 13.4,
12.2 Hz), 2.19–2.12 (1H, m), 2.06 (1H, br s), 2.05 (1H,
dd, J = 11.5, 3.1 Hz), 1.78 (1H, m, Dm = 18.8 Hz),
1.71–1.45 (5H, m), 1.47 (3H, s), 1.34 (2H, m,
Dm = 37 Hz), 1.11 (3H, s), 0.89 (3H, t, J = 7.3 Hz); 13C
NMR (CDCl3): d 206.0,171.8, 171.2, 143.7, 139.3,
125.2, 108.3, 94.4, 77.6, 72.0, 68.3, 64.2, 53.9, 51.9,
51.5, 43.5, 42.0, 38.2, 35.5, 32.5, 31.7, 19.3, 18.1, 16.4,
15.2, 13.8; HRMS(ESI): [M+H]+ m/z 477.2506 (calcd
for C26H36O8, 477.2488).
1
hRf = 47 (6), 30 (2); H NMR (CDCl3): d 7.41 (1H, dt,
J = 1.6, 0.9 Hz), 7.40 (1H, t, J = 1.8 Hz), 6.37 (1H, dd,
J = 1.8, 0.9 Hz), 5.54 (1H, dd, J = 11.6, 5.1 Hz), 4.77
(1H, d, J = 7.0 Hz), 4.74 (1H, d, J = 7.0 Hz), 4.16 (1H,
dd, J = 12.1, 7.4 Hz), 3.71 (3H, s), 3.69 (1H, dq,
J = 9.7, 7.0 Hz), 3.58 (1H, dq, J = 9.7, 7.0 Hz), 2.69
(1H, dd, J = 13.3, 3.4 Hz), 2.53 (1H, dd, J = 13.3,
5.1 Hz), 2.34 (1H, ddd, J = 13.5, 7.4, 3.5 Hz), 2.18
(1H, td, J = 13.4, 12.1 Hz), 2.15 (1H, dq, J = 13.7,
3.5 Hz), 2.06 (1H, br s), 2.05 (1H, m, Dm = 15 Hz), 1.77
(1H, m, Dm = 18.3 Hz), 1.71–1.44 (3H, m), 1.46 (3H, s),
1.18 (3H, t, J = 6.9 Hz), 1.11 (3H, s); 13C NMR
(CDCl3): d 206.0, 171.8, 171.2, 143.7, 139.3, 125.3,
108.3, 94.3, 77.7, 71.9, 64.2, 63.8, 53.8, 51.8, 51.4, 43.4,
41.9, 38.1, 35.4, 32.6, 18.1, 16.4, 15.2, 15.1; HRMS(ESI):
[M+H]+ m/z 449.2193 (calcd for C24H32O8, 449.2175).
5.7. Salvinorin B isopropoxymethyl ether (9)
Procedure as for 7, using 2-propanol. FCC (0–10%
EtOAc/CH2Cl2 gradient) gave 9 as a clear resin (18%);
TLC (10% EtOAc/CH2Cl2): hRf = 27(9), 41 (16); 1H
NMR(CDCl3): d 7.41–7.39 (2H, m), 6.37 (1H, dd,
J = 1.6, 0.9 Hz), 5.54 (1H, dd, J = 11.7, 5.1 Hz), 4.83
(1H, d, J = 7.4 Hz), 4.74 (1H, d, J = 7.4 Hz), 4.21 (1H,
dd, J = 12.2, 7.5 Hz), 3.93 (1H, sept, J = 6.1 Hz), 3.72
(3H, s), 2.70 (1H, dd, J = 13.5, 3.5 Hz), 2.53 (1H, dd,
J = 13.2, 5.2 Hz), 2.33 (1H, ddd, J = 13.5, 7.5, 3.7 Hz),
2.18 (1H, dt, J = 13.4, 12.0 Hz), 2.15 (1H, dq, J = 13.5,
3.5 Hz), 2.07 (1H, br s), 2.05 (1H, dd, J = 11.4, 3.1 Hz),
1.78 (1H, m, Dm = 18.3 Hz), 1.71–1.45 (3H, m), 1.47
(3H, s), 1.18 (3H, d, J = 6.2 Hz), 1.13 (3H, d,
J = 6.2 Hz), 1.10 (3H, s); 13C NMR (CDCl3): d 206.2,
171.9, 171.2, 143.7, 139.3, 125.3, 108.3, 92.2, 77.3, 72.0,
69.7, 64.2, 53.9, 51.9, 51.5, 43.4, 42.0, 38.2, 35.5, 32.5,
23.0, 22.0, 18.1, 16.4, 15.2; HRMS(ESI): [M+NH4]+ m/z
480.2618 (calcd for C25H34O8, 480.2597).
5.5. Salvinorin B propoxymethyl ether (7)
˚
Propanol was stored over freshly activated 4 A sieves for
1 h. To a mixture of methylthiomethyl ether 16
(37.6 mg, 83.5 lmol), N-iodosuccinimide (28.6 mg,
˚
127 lmol, 1.5 equiv), and 4 A molecular sieves (beads)
under Ar was added CH2Cl2 (0.5 mL). The flask was
cooled to 0 ꢁC, and dry propanol (1.5 mL, excess)
was added, followed by TfOH (1 lL), and the solution
was stirred for 5 min. NaHCO3 (ꢀ100 mg) was added,
then the solution was diluted in EtOAc and washed with
satd aq NaHCO3, 10% aq NaS2O3, and brine. The or-
ganic layer was dried over MgSO4, filtered, and concen-
trated under reduced pressure. FCC (5–10% EtOAc/
CH2Cl2 gradient) gave 7 as a clear resin (21%); TLC
5.8. Salvinorin B tert-butoxymethyl ether (10)
Procedure as for 7, using 2-methyl-2-propanol. FCC (0–
5% EtOAc/CH2Cl2 gradient) gave 10 as a clear resin
(40%); TLC (10% EtOAc/CH2Cl2): hRf = 32 (10), 34
1
(10% EtOAc/CH2Cl2): hRf = 27 (7), 35 (16); H NMR
(CDCl3): d 7.41–7.40 (2H, m), 6.37 (1H, dd, J = 1.6,
0.9 Hz), 5.55 (1H, dd, J = 11.7, 5.1 Hz), 4.77 (1H, d,
J = 7.2 Hz), 4.76 (1H, d, J = 7.2 Hz), 4.17 (1H, dd,
J = 12.1, 7.6 Hz), 3.71 (3H, s), 3.59 (1H, dt, J = 9.4,
6.6 Hz), 3.47 (1H, dt, J = 9.4, 6.6 Hz), 2.69 (1H, dd,
J = 13.4, 3.5 Hz), 2.53 (1H, dd, J = 13.4, 5.2 Hz), 2.34
(1H, ddd, J = 13.5, 7.6, 3.5 Hz), 2.18 (1H, td, J = 13.2,
12.1 Hz), 2.15 (1H, dq, J = 13.5, 3.5 Hz), 2.06 (1H, br
s), 2.05 (1H, dd, J = 11.7, 3.2 Hz), 1.77 (1H, m,
Dm = 18.3 Hz), 1.71–1.46 (5H, m), 1.46 (3H, s), 1.10
(3H, s), 0.90 (3H, t, J = 7.4 Hz); 13C NMR (CDCl3): d
206.0, 171.8, 171.2, 143.7, 139.3, 125.3, 108.3, 94.4,
77.6, 72.0, 70.2, 64.2, 53.9, 51.9, 51.4, 43.4, 42.0, 38.1,
35.5, 32.6, 22.8, 18.1, 16.4, 15.2, 10.6; HRMS(ESI):
[M+H]+ m/z 463.2339 (calcd for C25H34O8, 463.2332).
1
(16); H NMR(CDCl3): d 7.41–7.39 (2H, m), 6.36 (1H,
dd, J = 1.7, 1.0 Hz), 5.53 (1H, dd, J = 11.7, 5.0 Hz),
4.99 (1H, d, J = 8.2 Hz), 4.71 (1H, d, J = 8.2 Hz), 4.26
(1H, dd, J = 12.2, 7.3 Hz), 3.71 (3H, s), 2.70 (1H, dd,
J = 13.3, 3.4 Hz), 2.51 (1H, dd, J = 13.3, 5.1 Hz), 2.32
(1H, ddd, J = 13.5, 7.3, 3.5 Hz), 2.20–2.10 (2H, m),
2.07 (1H, br s), 2.04 (1H, dd, J = 11.7, 3.1 Hz), 1.76
(1H, m, Dm = 17.9 Hz), 1.70–1.43 (3H, m), 1.45 (3H, s),
13
1.22 (9H, s), 1.09 (3H, s); C NMR(CDCl3): d 206.5,
171.9, 171.2, 143.7, 139.3, 125.2, 108.3, 88.7, 77.1,
75.0, 71.9, 64.1, 53.9, 51.9, 51.4, 43.4, 42.0, 38.1, 35.4,
32.5, 28.7, 18.1, 16.4, 15.2; HRMS(ESI): [M+ NH4]+
m/z 494.2773 (calcd for C26H36O8, 494.2754).
5.9. Salvinorin B 2-fluoroethoxymethyl ether (11)
5.6. Salvinorin B butoxymethyl ether (8)
Procedure as for 7, using 2-fluoroethanol. FCC (0–5%
EtOAc/CH2Cl2) gave 11 as a clear resin (18%). TLC
(10% EtOAc/CH2Cl2): hRf = 26 (11), 40 (16); H NMR
(CDCl3): d 7.42 (1H, dt, J = 1.6, 0.9 Hz), 7.40 (1H, t,
J = 1.9 Hz), 6.38 (1H, dd, J = 1.9, 1.0 Hz), 5.55 (1H,
dd, J = 11.6, 5.1 Hz), 4.82 (2H, s), 4.55 (2H, ꢀdt,
J = 47.8, 4.1 Hz), 4.22 (1H, dd, J = 12.2, 7.5 Hz), 3.85
Procedure as for 7, using butanol. FCC (3–6% EtOAc/
CH2Cl2 gradient) gave 8 as a clear resin (24%); TLC
(5% EtOAc/CH2Cl2): hRf = 17 (8), 22 (16); H NMR
(CDCl3): d 7.41–7.39 (2H, m), 6.37 (1H, dd, J = 1.9,
1.0 Hz), 5.55 (1H, dd, J = 11.7, 5.1 Hz), 4.76 (1H, d,
J = 7.1 Hz), 4.74 (1H, d, J = 7.1 Hz), 4.17 (1H, dd,
1
1

1284
T. A. Munro et al. / Bioorg. Med. Chem. 16 (2008) 1279–1286
(2H, ꢀdt, J = 30.2, 4.1 Hz), 3.72 (3H, s), 2.70 (1H, dd,
J = 13.2, 3.1 Hz), 2.53 (1H, dd, J = 13.1, 4.8 Hz), 2.35
(1H, ddd, J = 13.5, 7.5, 3.5 Hz), 2.18 (1H, dt, J = 13.2,
12.0 Hz), 2.18–2.12 (1H, m), 2.08 (1H, br s), 2.05 (1H,
dd, J = 11.7, 2.9 Hz), 1.78 (1H, m, Dm = 18.2 Hz),
1.72–1.45 (3H, m), 1.47 (3H, s), 1.11 (3H, s); 13C
NMR (CDCl3): d 205.8, 171.8, 171.2, 143.7, 139.3,
125.3, 108.3, 94.4, 82.7 (d, J = 168 Hz), 77.7, 72.0, 67.2
(d, J = 22 Hz), 64.3, 53.8, 51.9, 51.4, 43.4, 42.0, 38.2,
35.5, 32.4, 18.1, 16.4, 15.2; 19F NMR (CDCl3): d 5.6
(tt, J = 47.8, 30.3 Hz); HRMS(ESI): [M+H]+ m/z
467.2096 (calcd for C24H31FO8, 467.2081).
gave 12 as an amorphous white solid (53%). TLC
(50% EtOAc/hexanes): hRf = 72 (14), 24 (2); 1H
NMR(CDCl3): d 7.41 (1H, dt, J = 1.6,0.9 Hz), 7.40
(1H, t, J = 1.7 Hz), 6.37 (1H, dd, J = 1.7, 0.9 Hz), 5.54
(1H, dd, J = 11.7, 5.0 Hz), 4.77 (1H, d, J = 7.2 Hz),
4.73 (1H, d, J = 7.2 Hz), 4.16 (1H, dd, J = 12.2,
7.5 Hz), 3.69 (1H, m, Dm = 26.8 Hz), 3.71 (3H, s), 3.59
(1H, m, Dm = 26.8 Hz), 2.69 (1H, dd, J = 13.5, 3.4 Hz),
2.52 (1H, dd, J = 13.3, 5.1 Hz), 2.33 (1H, ddd,
J = 13.3, 7.2, 3.4 Hz), 2.18 (1H, td, J = 13.3, 12.2 Hz),
2.19–2.11 (1H, m), 2.06 (1H, br s), 2.05 (1H, dd,
J = 11.3, 3.1 Hz), 1.77 (1H, m, Dm = 18.0 Hz), 1.71–
1.48 (3H, m), 1.46 (3H, s), 1.10 (3H, s), 0.88 (2H, m,
Dm = 16.8 Hz), 0.00 (9H, s); 13C NMR (CDCl3): d
206.0, 171.8, 171.2, 143.7, 139.3, 125.2, 108.3, 93.9,
77.7, 71.9, 65.7, 64.2, 53.9, 51.9, 51.4, 43.5, 41.9, 38.1,
35.5, 32.5, 18.1, 18.1, 16.4, 15.2, À1.4; HRMS(ESI):
[M+NH4]+ m/z 538.2855 (calcd for C27H40O8Si,
538.2836).
5.10. Salvinorin B 2,2,2-trifluoroethoxymethyl ether (12)
Procedure as for 7, using 2,2,2-trifluoroethanol. FCC
(0–5% EtOAc/CH2Cl2) gave 12 as a clear resin (11%).
TLC (10% EtOAc/CH2Cl2): hRf = 37 (12), 35 (16); H
1
NMR (CDCl3): d 7.42 (1H, dt, J = 1.8, 0.9 Hz), 7.40
(1H, t, J = 1.8 Hz), 6.38 (1H, dd, J = 1.9, 0.9 Hz), 5.55
(1H, dd, J = 11.6, 5.0 Hz), 4.84 (1H, d, J = 7.5 Hz),
4.82 (1H, d, J = 7.5 Hz), 4.17 (1H, dd, J = 12.2,
7.5 Hz), 4.05 (1H, dq, J = 12.0, 8.7 Hz), 3.95 (1H, dq,
J = 12.0, 8.7 Hz), 3.72 (3H, s), 2.70 (1H, dd, J = 13.3,
3.5 Hz), 2.52 (1H, dd, J = 13.3, 5.1 Hz), 2.33 (1H, ddd,
J = 13.6, 7.5, 3.7 Hz), 2.20 (1H, td, J = 13.3, 12.2 Hz),
2.16 (1H, dq, J = 13.6, 3.4 Hz), 2.08 (1H, br s), 2.05
(1H, dd, J = 11.9, 3.1 Hz), 1.79 (1H, m, Dm = 18.3 Hz),
1.72–1.49 (3H, m), 1.47 (3H, s), 1.10 (3H, s); 13C
NMR (CDCl3): d 205.4, 171.6, 171.1, 143.7, 139.3,
125.3, 123.7 (q, J = 278 Hz), 108.3, 94.5, 78.5, 72.0,
64.9 (q, J = 34.6 Hz), 64.3, 53.7, 51.9, 51.4, 43.4, 42.0,
38.2, 35.5, 32.3, 18.1, 16.4, 15.2; 19F NMR (CDCl3): d
À74.8 (t, J = 8.9 Hz); HRMS(ESI): [M+H]+m/z
503.1870 (calcd for C24H29F3O8, 503.1893).
5.13. Salvinorin B benzyloxymethyl ether (15)
Procedure as for 6, using BnOCH2Cl with NaI (1 equiv)
for 96 h. FCC (33% EtOAc/hexanes, then 5% MeOH/
CH2Cl2) gave 15 as an amorphous white solid (34%
[47% borsm]). TLC (50% EtOAc/hexanes): hRf = 52
1
(15), 27 (2); H NMR (CDCl3): d 7.41–7.40 (2H, m),
7.32–7.28 (5H, m), 6.37 (1H, m, Dm = 2.8 Hz), 5.54
(1H, dd, J = 12.2, 5.3 Hz), 4.86 (1H, d, J = 7.2 Hz),
4.84 (1H, d, J = 7.2 Hz), 4.65 (2H, s), 4.19 (1H, dd,
J = 12.0,7.5 Hz), 3.71 (3H, s), 2.66 (1H, dd, J = 13.0,
3.7 Hz), 2.50 (1H, dd, J = 13.2, 4.8 Hz), 2.33–2.11 (3H,
m), 2.05 (1H, br s), 2.04 (1H, dd, J = 11.3, 2.9 Hz),
1.78 (1H, m, Dm = 18.6 Hz), 1.71–1.45 (3H, m), 1.47
(3H, s), 1.11 (3H, s); 13C NMR (CDCl3): d 205.8,
171.8, 171.2, 143.7, 139.4, 137.4, 128.5, 127.94, 127.90,
125.2, 108.4, 93.9, 77.9, 71.9, 70.1, 64.2, 53.8, 51.9,
51.5, 43.5, 42.0, 38.1, 35.5, 32.4, 18.1, 16.4, 15.2;
HRMS(ESI): [M+NH4]+ m/z 528.2606 (calcd for
C29H34O8, 528.2597).
5.11. Salvinorin B 2-methoxyethoxymethyl ether (13)
Procedure as for 7, using 2-methoxyethanol. FCC (33–
50% EtOAc/ hexanes) gave 13 as a clear resin (15%).
TLC (10% EtOAc/CH2Cl2): hRf = 14 (13), 35 (16); H
1
NMR (CDCl3): d 7.42 (1H, dt, J = 1.6, 0.9 Hz), 7.40
(1H, t, J = 1.9 Hz), 6.38 (1H, dd, J = 1.8, 0.9 Hz), 5.54
(1H, dd, J = 11.7, 5.1 Hz), 4.82 (1H, d, J = 7.3 Hz),
4.80 (1H, d, J = 7.3 Hz), 4.22 (1H, dd, J = 12.2,
7.2 Hz), 3.79 (1H, m, Dm = 20.1 Hz), 3.71 (3H, s), 3.70
(1H, m, Dm = 20.1 Hz), 3.52 (2H, t, J = 4.5 Hz), 3.35
(3H, s), 2.68 (1H, dd, J = 13.5, 3.5 Hz), 2.52 (1H, dd,
J = 13.3, 5.1 Hz), 2.36 (1H, ddd, J = 13.6, 7.2, 3.4 Hz),
2.18 (1H, td, J = 13.5, 12.3 Hz), 2.20–2.11 (1H, m),
2.06 (1H, br s), 2.04 (1H, dd, J = 11.6, 3.1 Hz), 1.78
(1H, m, Dm = 18.5 Hz), 1.71–1.44 (3H, m), 1.47 (3H, s),
1.11 (3H, s); 13C NMR (CDCl3): d 205.9, 171.8, 171.2,
143.7, 139.4, 125.3, 108.3, 94.6, 77.6, 71.9, 71.6, 67.3,
64.3, 59.0, 53.8, 51.9, 51.5, 43.5, 42.0, 38.2, 35.5, 32.5,
18.1, 16.4, 15.2; HRMS(ESI): [M+NH4]+ m/z 496.2528
(calcd for C25H34O9, 496.2547).
5.14. Salvinorin B methylthiomethyl ether (16)
Salvinorin B (2) (32.4 mg, 83 lmol) was dissolved in
Me2SO (1 mL). AcOH was added (1 mL), followed by
Ac2O (0.5 mL). The resulting white suspension was stir-
red at rt for 65 h, giving a clear yellow solution. Aq
NaOH (5.0 M, 5 mL) was added drop-wise, then the
solution was diluted in EtOAc and washed with satd
aq NaHCO3 (3·) and brine and dried (MgSO4). Evapo-
ration in vacuo gave 16 (33.7 mg, 90%) as an amorphous
white solid of adequate purity for synthetic use. The
receptor binding sample was purified by FCC (25%
EtOAc/hexanes, stripped in 20% MeOH/CH2Cl2); TLC
1
(50% EtOAc/hexanes): hRf = 54 (16), 30 (2); H NMR
(CDCl3): d 7.42 (1H, dt, J = 1.7, 0.8 Hz), 7.39 (1H, t,
J = 1.7 Hz), 6.38 (1H, dd, J = 1.9, 0.9 Hz), 5.54 (1H,
dd, J = 11.7, 5.1 Hz), 4.84 (1H, d, J = 11.9 Hz), 4.66
(1H, d, J = 11.9 Hz), 4.26 (1H, dd, J = 12.0, 7.4 Hz),
3.70 (3H, s), 2.72 (1H, dd, J = 13.4, 3.7 Hz), 2.54 (1H,
dd, J = 13.4, 5.2 Hz), 2.28 (1H, ddd, J = 13.4, 7.5,
3.7 Hz), 2.19–2.10 (2H, m), 2.13 (3H, s), 2.09 (1H, br
s), 2.05 (1H, dd, J = 12.2, 2.8 Hz), 1.76 (1H, m,
5.12. Salvinorin B 2-(trimethylsilyl)ethoxymethyl ether
(14)
Procedure as for 6, using 2-(trimethylsilyl)ethyl chloro-
methyl ether for 23 h. FCC (33–50% EtOAc/ hexanes)

T. A. Munro et al. / Bioorg. Med. Chem. 16 (2008) 1279–1286
1285
Dm = 19 Hz), 1.70–1.48 (3H, m), 1.45 (3H, s), 1.10 (3H,
s); 13C NMR (CDCl3): d 206.1, 171.8, 171.4, 143.7,
139.4, 125.4, 108.4, 74.5, 71.9, 64.4, 53.8, 51.8, 51.5,
43.6, 42.0, 38.2, 35.5, 32.3, 18.2, 16.4, 15.2, 13.7 (one sig-
nal not observed); 13C NMR (C5D5N): d 207.0, 172.4,
171.4, 144.3, 140.4, 126.6, 109.4, 78.0, 74.8, 71.9, 63.5,
53.6, 51.6, 51.3, 43.4, 42.1, 38.3, 35.9, 33.0, 18.8, 16.5,
15.3, 13.7; HRMS(ESI): [M+H]+ m/z 451.1792 (calcd
for C23H30O7S, 451.1790).
53.7, 51.3, 51.1, 43.6, 41.7, 38.1, 35.5, 33.2, 19.8, 18.6,
16.2, 15.7, 15.1; HRMS(ESI): [M+H]+ m/z 463.2318
(calcd for C25H34O8, 463.2332).
Mixed fractions were pooled with other runs; further
chromatography gave 18b as an amorphous white solid
(16%); 1H NMR(C6D6): d 7.11 (1H, dt, J = 1.7, 0.9 Hz),
7.05 (1H, t, J = 1.7 Hz), 6.16 (1H, dd, J = 1.9, 0.9 Hz),
5.18 (1H, dd, J = 11.7, 5.0 Hz), 4.73 (1H, q,
J = 5.4 Hz), 3.83 (1H, m, Dm = 19 Hz), 3.64 (1H, dq,
J = 9.4, 7.1 Hz), 3.52 (1H, dq, J = 9.4, 7.1 Hz), 3.31
(3H, s), 2.36–2.22 (3H, m), 2.20–2.07 (2H, m), 1.59–
1.41 (3H, m), 1.32 (1H, br s), 1.29 (3H, s), 1.25–1.04
(2H, m), 1.21 (3H, d, J = 5.4 Hz), 1.06 (3H, t,
J = 7.1 Hz), 0.91 (3H, s); 13C NMR(C6D6): d 205.5,
171.8, 170.1, 143.7, 139.4, 126.6, 108.6, 98.6, 75.3,
71.5, 63.8, 60.9, 53.8, 51.3, 51.1, 43.5, 41.8, 38.2, 35.5,
33.4, 20.0, 18.7, 16.1, 15.5, 15.1; HRMS(ESI): [M+H]+
m/z 463.2342 (calcd for C25H34O8, 463.2332).
5.15. Salvinorin B fluoromethyl ether (17)
Procedure as for 7, substituting Et2NSF3 (1.5 equiv) for
PrOH and omitting TfOH. FCC (66–100% Et2O/hex-
anes, then 20% MeOH/CH2Cl2) gave 17 as an amor-
phous white solid (64% [81% based on recovered 2]).
A high-Rf byproduct was also recovered, along with 2.
These were pooled and briefly refluxed in MeOH/
CH2Cl2/AcOH. Evaporation under reduced pressure
and rinsing with minimal MeOH gave 2. TLC (Et2O):
hRf = 65 (byproduct), 54 (16), 48 (17), 32 (2); 1H
NMR (CDCl3): d 7.42 (1H, dt, J = 1.7, 0.9 Hz), 7.40
(1H, t, J = 1.8 Hz), 6.38 (1H, dd, J = 1.8, 0.9 Hz), 5.55
(1H, dd, J = 11.7, 5.1 Hz), 5.40 (1H, dd, J = 53.2,
3.0 Hz), 5.26 (1H, dd, J = 58.7, 3.0 Hz), 4.24 (1H, dd,
J = 12.1, 7.6 Hz), 3.72 (3H, s), 2.70 (1H, dd, J = 13.8,
3.4 Hz), 2.53 (1H, dd, J = 13.3, 5.2 Hz), 2.42 (1H, ddd,
J = 13.5, 7.4, 3.5 Hz), 2.24 (1H, td, J = 13.5, 12.3 Hz),
2.16 (1H, dq, J = 13.5, 3.2 Hz), 2.08 (1H, br s), 2.05
(1H, dd, J = 11.0, 3.2 Hz), 1.79 (1H, m, Dm = 18.3 Hz),
1.71–1.42 (3H, m), 1.46 (3H, s), 1.12 (3H, s); 13C
NMR (CDCl3): d 204.5, 171.5, 171.0, 143.8, 139.4,
125.2, 108.3, 102.4 (d, J = 214 Hz), 79.8, 71.9, 64.3,
53.6, 51.9, 51.4, 43.5, 42.0, 38.1, 35.5, 32.3, 18.1, 16.4,
15.2; 19F NMR (CDCl3): d À152.2 (dd, J = 58.7,
53.8 Hz); HRMS(ESI): [M+H]+ m/z 423.1813 (calcd
for C22H27FO7, 423.1819).
5.17. Salvinorin B 2-methoxy-2-propyl ether (19)
Salvinorin B (2) (40.4 mg, 103 lmol) was dissolved in
dry CH2Cl2 (1 mL) under Ar. Pyridinium p-toluenesul-
fonate in dry CH2Cl2 (10 mM) was added (1 mL,
10 lmol). 2-Methoxypropene (100 lL, 1.04 mmol) was
added, and the solution was stirred at room temperature
for 35 min, monitored by TLC (50% EtOAc/hexanes).
The reaction mixture was quenched with excess NEt3
(200 lL), loaded directly onto silica gel and purified by
FCC (0.5% NEt3/10–50% EtOAc/hexanes, then 20%
MeOH/CH2Cl2) to give 19 as an amorphous white solid
(13.7 mg, 31%); TLC (50% EtOAc/hexanes): hRf = 59
1
(byproduct), 43 (19), 30 (2); H NMR(CDCl3): d 7.40–
7.39 (2H, m), 6.36 (1H, dd, J = 1.6, 0.9), 5.53 (1H, dd,
J = 11.6, 5.1 Hz), 4.22 (1H, ꢀdd, J = 20.9, 8.4 Hz),
3.71 (3H, s), 3.21 (3H, s), 2.70 (1H, ꢀdd, J = 10.9,
5.6 Hz), 2.46 (1H, dd, J = 13.2, 5.1 Hz), 2.26–2.15 (2H,
m), 2.14 (1H, dq, J = 13.5, 3.5 Hz), 2.09 (1H, br s),
2.04 (1H, dd, J = 11.3, 2.7 Hz), 1.79 (1H, m,
Dm = 18.5 Hz), 1.71–1.45 (3H, m), 1.47 (3H, s), 1.40
(3H, s), 1.27 (3H, s), 1.09 (3H, s); 13C NMR (CDCl3):
d 206.6, 171.9, 171.2, 143.7, 139.4, 125.3, 108.3, 101.3,
73.5, 71.8, 64.5, 54.2, 51.8, 51.4, 49.4, 43.3, 42.1, 38.3,
35.4, 33.8, 25.0, 24.7, 18.1, 16.2, 15.1; HRMS(ESI):
[M+H]+ m/z 463.2342 (calcd for C25H34O8, 463.2332).
5.16. Salvinorin B 1-ethoxyethyl ether (18)
Salvinorin B (2) (49.1 mg, 126 lmol) was dissolved in
dry CH2Cl2 (1.5 mL) under Ar and stirred at 0 ꢁC. Eth-
oxyethene (100 lL, 1.04 mmol) and a speck of p-TsOH
(ꢁ1 mg, catalytic) were added. The resulting suspension
was removed from the icebath and stirred at room tem-
perature for 10 min, when it had clarified and turned yel-
low. TLC (50% EtOAc/hexanes) showed minimal
starting material. The solution was diluted in EtOAc
and washed with satd aq NaHCO3 (3·) and dried
(MgSO4). Evaporation under reduced pressure and re-
peated FCC (25–50% EtOAc/hexanes, then 20%
MeOH/CH2Cl2) gave 18a as an amorphous white solid
(20.6 mg, 36%); TLC (50% EtOAc/hexanes): hRf = 48
5.18. Salvinorin B tetrahydropyran-2-yl ether (20)
Procedure as for 18, using 3,4-dihydro-2H-pyran. Re-
peated FCC (33–50% EtOAc/hexanes, then 20%
MeOH/CH2Cl2) gave 20 as a clear resin (28.6 mg,
47%); TLC (50% EtOAc/hexanes): hRf = 58 (20), 52
(epimeric acetal), 35 (2); 1H NMR (CDCl3,filtered
through basic Al2O3): d 7.43–7.39 (2H, m), 6.38 (1H,
dd, J = 1.9, 0.9 Hz), 5.53 (1H, dd, J = 11.9, 5.3 Hz),
4.74 (1H, t, J = 3.0 Hz), 4.25 (1H, dd, J = 12.2,
7.6 Hz), 3.81 (1H, ddd, J = 11.6, 9.0, 3.0 Hz), 3.71
(3H, s), 3.50 (1H, dt, J = 11.1, 4.5 Hz), 2.71 (1H, dd,
J = 13.2, 3.7 Hz), 2.54 (1H, dd, J = 13.2, 5.1 Hz), 2.36
(1H, ddd, J = 13.5, 7.6, 3.8 Hz), 2.24 (1H, td, J = 13.4,
12.2 Hz), 2.15 (1H, dq, J = 13.2, 3.2 Hz), 2.06 (1H, br
s), 2.05 (1H, dd, J = 13.3, 3.2 Hz), 1.88–1.41 (10H, m),
1
(18a), 43 (18b), 30 (2); H NMR (C6D6): d 7.10 (1H,
dt, J = 1.6, 0.9 Hz), 7.05 (1H, t, J = 1.7 Hz), 6.14 (1H,
dd, J = 1.9, 0.9 Hz), 5.18 (1H, dd, J = 11.7, 5.0 Hz),
4.94 (1H, q, J = 5.4 Hz), 4.00 (1H, m, Dm = 19 Hz),
3.44 (1H, dq, J = 9.2, 7.1 Hz), 3.32 (1H, dq, J = 9.2,
7.1 Hz), 3.29 (3H, s), 2.35–2.09 (5H, m), 1.54–1.43
(3H, m), 1.40 (3H, d, J = 5.4 Hz), 1.30 (1H, br s), 1.27
(3H, s), 1.24–1.05 (2H, m), 1.07 (3H, t, J = 7.1 Hz),
0.89 (3H, s); 13C NMR(C6D6): d 206.3, 171.7, 170.1,
143.7, 139.4, 126.5, 108.7, 99.2, 76.9, 71.5, 63.6, 58.4,

1286
T. A. Munro et al. / Bioorg. Med. Chem. 16 (2008) 1279–1286
1
´
8. Beguin, C.; Richards, M. R.; Wang, Y.; Chen, Y.; Liu-
1.46 (3H, s), 1.12 (3H, s); H NMR(C6D6): d 7.05–7.04
(2H, m), 6.11 (1H, q, J = 1.5 Hz), 5.16 (1H, dd,
J = 11.8, 5.2 Hz), 5.00 (1H, t, J = 2.9 Hz), 4.06 (1H, m,
Dm = 18 Hz), 3.70 (1H, td, J = 11.1, 3.0 Hz), 3.36 (1H,
m, Dm = 20 Hz), 3.30 (3H, s), 2.43–2.23 (4H, m), 2.11
(1H, m, Dm = 26 Hz), 1.93 (1H, m, Dm = 24 Hz), 1.80–
1.62 (2H, m), 1.49–1.00 (8H, m), 1.27 (3H, s), 1.02
(1H, td, J = 7.2, 1.5 Hz), 0.90 (3H, s); 13C NMR
(C6D6): d 206.3, 171.8, 170.1, 143.6, 139.4, 126.5,
108.7, 97.8, 76.9, 71.5, 63.7, 61.5, 53.7, 51.3, 51.1, 43.7,
41.6, 38.1, 35.5, 33.1, 30.3, 25.8, 18.8, 18.6, 16.2, 15.1;
HRMS(ESI): [M+H]+ m/z 475.2342 (calcd for
C26H34O8, 475.2332).
Chen, L.-Y.; Ma, Z.; Lee, D. Y. W.; Carlezon, W. A., Jr.;
Cohen, B. M. Bioorg. Med. Chem. Lett. 2005, 15, 2761.
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10. Lee, D. Y.; Karnati, V. V. R.; He, M.; Liu-Chen, L.-Y.;
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Acknowledgments
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This work was supported by grants from the Stanley
Medical Research Institute, the National Institute of
Mental Health (MH63266), the National Alliance for
Research on Schizophrenia and Depression (NAR-
SAD), and the Engelhard Foundation.
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Supplementary data
1H and 13C NMR spectra for compounds 5–20; IUPAC
International Chemical Identifiers (InChIs); statement
of author contributions. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.bmc.2007.10.067.
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