Modification of the furan ring of salvinorin A: Identification of a selective partial agonist at the kappa opioid receptor

Article abstract of DOI:10.1016/j.bmc.2008.12.012

In an effort to find novel agents which selectively target the kappa opioid receptor (KOPR), we modified the furan ring of the highly potent and selective KOPR agonist salvinorin A. Introduction of small substituents at C-16 was well tolerated. 12-epi-Sal

Full text of DOI:10.1016/j.bmc.2008.12.012

Bioorganic & Medicinal Chemistry 17 (2009) 1370–1380
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Modification of the furan ring of salvinorin A: Identification of a selective
partial agonist at the kappa opioid receptor
a
Cécile Béguin a,b, , Katharine K. Duncan , Thomas A. Munro a,b, Douglas M. Ho c, Wei Xu d,
*
Lee-Yuan Liu-Chen d, William A. Carlezon Jr. a,b, Bruce M. Cohen a,b
a Mailman Research Center, McLean Hospital, Belmont, MA 02478, USA
b Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA
c Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
d Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In an effort to find novel agents which selectively target the kappa opioid receptor (KOPR), we modified
the furan ring of the highly potent and selective KOPR agonist salvinorin A. Introduction of small substit-
uents at C-16 was well tolerated. 12-epi-Salvinorin A, synthesized in four steps from salvinorin A, was a
selective partial agonist at the KOPR. No clear SAR patterns were observed for C-13 aryl ketones. Intro-
ducing a hydroxymethylene group between C-12 and the furan ring was tolerated. Small C-13 esters
and ethers gave weak KOPR agonists, while all C-13 amides were inactive. Finally, substitution of oxadi-
azoles for the furan ring abolished affinity for the KOPR. None of the compounds displayed any KOPR
antagonism or any affinity for mu or delta opioid receptors.
Received 17 September 2008
Revised 26 November 2008
Accepted 7 December 2008
Available online 14 December 2008
Keywords:
Kappa opioid receptor agonists
Salvinorin
Ó 2008 Elsevier Ltd. All rights reserved.
Binding
[
35S]GTP
cS
1. Introduction
a lead compound for the design of selective KOPR agonists (full
or partial) and antagonists.14
Selective kappa opioid receptor (KOPR) ligands with activity in
the central nervous system may be useful in the treatment of var-
ious disorders, including drug abuse,1 mood abnormalities,2,3 and
anxiety disorders.4 Although there are many selective KOPR ago-
nists available for preclinical studies, few selective KOPR antago-
nists have been identified. The prototypical selective KOPR
antagonist norBNI5 has long been used in preclinical studies. How-
ever, recent reports suggest that, in vivo, it may display some mu
opioid receptor (MOPR) antagonism in addition to its effects at
KOPR.6,7 GNTI,8 and ANTI,9 two structurally simplified analogues
of norBNI, reportedly possess increased selectivity7 but have not
been extensively studied, perhaps due to the complexity of their
synthesis and purification. The more recently developed JDTic10
is a highly potent and selective KOPR antagonist. However, its slow
onset (48 h) and long duration (several weeks) of action in vivo can
be a limitation for some studies.11 The development of additional
selective KOPR agents, in particular antagonists, will provide alter-
native tools that enable a better understanding of KOPR mediated
effects. Recently, the natural product salvinorin A (1),12 a high
affinity, highly selective agonist at the KOPR,13 has been used as
O
16
13
12
O
O
H
H
O
O
2
O
18
O
O
1
In vivo, salvinorin A has a fast onset of action and (at least in
some tests) a relatively brief duration of effects,15–17 probably
due to rapid metabolism of its labile acetate. In previous stud-
ies,18,19 we modified the C-2 substituent and obtained potent and
selective KOPR agonists with improved metabolic stability, longer
lasting in vivo effects, and oral efficacy.17
Most early SAR studies focused on the modification of the ace-
tate and methyl ester.14 Briefly, some small C-2 substituents confer
potent KOPR agonism, while bulkier substituents tend to reduce
KOPR affinity and in some cases increase MOPR affinity. At C-18,
most modifications tested to date substantially reduce binding
affinity, suggesting that this part of the molecule binds tightly to
a complementary pocket of the KOPR. Only a few modifications
* Corresponding author. Tel.: +1 617 855 2080; fax: +1 617 855 3479.
E-mail address: cbeguin@mclean.harvard.edu (C. Béguin).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.12.012

C. Béguin et al. / Bioorg. Med. Chem. 17 (2009) 1370–1380
1371
of the furan ring have been studied, but preliminary reports indi-
O
O
cate that (a) bromination at C-1620 or saturation20,21 are well toler-
ated, (b) replacement of the furan ring by a methyl substituted
12
O
OH
O
O
oxadiazole or a c-hydroxybutenolide produce weak non-selective
a
c,d
H
H
H
H
antagonists,20 and (c) other modifications lead to loss of affin-
ity.20,22,23 In our search for structurally different KOPR antagonists,
we were intrigued by reports that some alterations of the furan
ring of salvinorin A appeared to confer KOPR antagonist properties.
To further investigate the SAR at this position, we first studied the
effect of C-16 substitution. In addition, to assess whether C-12
configuration had any effect on binding, we synthesized 12-epi-
salvinorin A. We subsequently introduced various linkers between
C-12 and the furan ring and prepared related C-13 esters, amides,
and ketones. Simultaneously, considering the KOPR antagonist
properties reported for methyloxadiazole 28a23 (Scheme 6), we
selected it as a lead compound and prepared a set of derivatives
containing various 3-substituted oxadiazoles.
RO
O
1
O
O
10
8
OH
20
O
R
O
OH
b
O
O
4
5
H
6
Ac
Scheme 2. Synthesis of 12-epi-salvinorin A. Reagents and conditions: (a) 5%
aqueous KOH, 80 °C, 95%; (b) Ac2O, pyridine, rt, 48%; (c) AcOH, 118 °C; (d)
TMSCHN2, CH3CN, rt, 19%, over two steps.
establishing a shared b-configuration. Consistent with this, irradi-
ation of H-12 gave no enhancement of H-20. The proposed struc-
ture was firmly established by X-ray crystallography (Fig. 1). The
absolute stereochemistry shown for 6 is taken from that of 1.27
The lactone ring adopts a boat conformation with the furan equa-
torial. The crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre (CCDC 697740).
Replacement of the furan with other substituents at C-12 uti-
lized the acid precursor 7,22 prepared by the published procedure
(Scheme 3). We found that substituting CH2Cl2 for CCl4, a potent
carcinogen, did not affect the yield. Reduction of 7 using BH3ꢀTHF21
afforded alcohol 8 in 46% yield. Methyl and ethyl ethers (9 and 10)
were prepared from 8 in the presence of silver oxide, and iodo-
methane or iodoethane, respectively. Alkylation with 2-iodopro-
pane did not proceed under these conditions. Finally, 8 was
acetylated to give 11 in 79% yield.
2. Chemistry
We used a modification of the published procedure to prepare
16-bromosalvinorin A (Scheme 1, 2).22 The reported conditions
(NBS in CH3CN) formed a complex mixture containing only traces
of 2. We found that using CHCl3 as solvent was more effective,
although the yields were highly variable (10–62%). The highest
yield was obtained when the reaction was carried out at room tem-
perature overnight using an old bottle of NBS. Addition of AIBN did
not affect the progression of the reaction, and absence of light led
to the formation of an unknown side product. Stille coupling24 of 2
and tributylvinyltin in the presence of Pd(PPh3)4 provided 3 in 58%
yield.
Acid 7 was converted into the unstable acyl chloride using oxa-
lyl chloride in CH2Cl2 (Scheme 4; thionyl chloride was ineffective
under the same conditions). The crude product was directly
cross-coupled with various aryltributyl tin reagents under Stille
conditions24 to afford C-13 aryl or heteroaryl ketones 12–16 in
low to moderate yields. The corresponding ketothiazole derivative
decomposed during purification. Subsequently, furan 12 was re-
duced (NaBH4) to form 17 as a mixture of C-13 epimers in 19%
yield. Salvinorins are known to epimerize at C-8 under basic condi-
tions.28 The possibility that epimerization of 17 had occurred at C-
8, rather than the expected C-13, was excluded on the basis of NMR
data. The H-12 multiplets were coincident; epimerization at C-8
typically causes a large upfield shift of the H-12 multiplet. The
H-20 singlets were nearly coincident (1.35 and 1.37 ppm), and clo-
ser to the value for 1 (1.45 ppm) than 8-epi-1 (1.62 ppm).21 Irradi-
Bikbulatov et al. recently reported that refluxing 1 in aqueous
KOH gave diacid 4 in 69% yield.25 The structure of 4, featuring in-
verted configuration at C-12, was firmly established by X-ray crys-
tallography.25 Interestingly, related diacids have been prepared
under the same conditions from diterpenoids lacking the C-1 ke-
tone.26 The inverted C-12 configuration of 4 raised the possibility
of preparing 12-epi-salvinorin A. We prepared 4 in 95% yield using
a slight modification of the published procedure (Scheme 2).25
Standard acetylation then afforded monoacetate 5 in moderate
yield. The hemiacetal cleavage conditions reported by Bikbulatov
et al. (catalytic AcOH or PTSA, CH2Cl2, rt)25 were without effect
on our substrate. However, refluxing AcOH promoted cleavage
and lactonization. Subsequent methylation with TMSCHN2 pro-
vided 12-epi-salvinorin A (6). The structure of 6 was established
by NMR experiments. The crucial H-10 singlet overlapped with
other multiplets in CDCl3 or (CD3)2CO, but a 1:1 mixture of these
solvents gave full resolution. The H-8 signal included a diaxial cou-
pling constant (11.7 Hz), establishing an axial orientation. Irradia-
tion of H-8 gave strong NOE enhancements of both H-10 and H-12,
ation of H-12 caused NOE enhancements of H-20 and H-11a, as
expected, rather than H-8. Two distinct H-8 multiplets were appar-
ent, both axial as indicated by diaxial coupling constants (11.0 and
11.4 Hz, respectively); the orientation being equatorial in 8-epi-1.
Irradiation of H-8 gave NOE enhancements of H-10 and H-11b. Pro-
viding further evidence for epimerization at C-13, the broad H-13
resonances were widely separated (4.89 and 4.60 ppm), and on
D2O exchange gave doublets with different coupling constants
(2.5 and 4.1 Hz). Yields from reduction of other ketones (13–16)
under the same conditions were too low to permit pharmacological
evaluation. Inspection of alternative synthetic routes to these sec-
ondary alcohols is underway.
Analogues with ester and amide groups connected to the C-13
position were readily obtained from 7 as depicted in Scheme 5.
Methyl ester 18 was prepared by treatment of 7 with TMSCHN2.
All other esters 19–22 were synthesized in 26–54% yield using
the appropriate alcohol, 1-(3-dimethylaminopropyl)-3-ethylcarbo-
diimide hydrochloride (EDCI), and DMAP. Commercial amines
were coupled to 7 in the presence of EDCI and 1-hydroxybenzotri-
azole (HOBt) to yield amides 23–27.
O
R
O
O
a
H
O
H
O
1
O
O
R
O
2
Br
b
3
Scheme 1. Syntheses of 16-substituted salvinorin derivatives. Reagents and
conditions: (a) NBS, CHCl3, rt, 10–62%; (b) tributylvinyltin, Pd(PPh3)4, toluene,
80 °C, 58%.

1372
C. Béguin et al. / Bioorg. Med. Chem. 17 (2009) 1370–1380
12
12
Figure 1. (stereoview). Crystal structure of 12-epi-salvinorin A (6) showing 50% probability displacement ellipsoids. Hydrogen atoms are shown as spheres of arbitrary radius.
O
XR
O
R
R
R
O
O
X
O
a, b,
or c
O
O
OH
OH
18
NH 23
19
24
20
25
H
O
H
O
7
a
b
c
9
O
O
O
O
7
8
1
O
R
H
X
10
22
27
O
NH
21
26
O
O
H
O
O
d
O
O
O
Scheme 5. Syntheses of C-13 esters and amides. Reagents and conditions: (a)
TMSCHN2, CH3OH, toluene, rt, 48%; (b) ROH, EDCI, DMAP, CH2Cl2, rt, 26–54%; (c)
RNH2, EDCI, HOBt, CH2Cl2, rt, 45–72%.
O
11
O
Scheme 3. Syntheses of C-13 alcohol and ethers. Reagents and conditions: (a)
NaIO4, RuCl3ꢀ3H2O, CH2Cl2/CH3CN/H2O, 63%; (b) BH3ꢀTHF, THF, 55 °C, 46%; (c) RI,
Ag2O, CH3CN, 60 °C, 12–15%; (d) Ac2O, Et3N, CH2Cl2, rt, 79%.
Scheme 6. Syntheses of C-13 oxadiazoles. Reagents and conditions: (a)
RC(@NOH)NH2, EDCI, HOBt, CH2Cl2, rt; (b) toluene, 110 °C, 10–45%, over two steps.
Finally, oxadiazoles 28–34 were obtained in two steps from acid
7 using commercially available amidoximes (Scheme 6). As in pre-
vious reports,23 these conditions led to epimerization at C-8: each
epimer was purified by HPLC before in vitro evaluation.
Scheme 4. Syntheses of C-13 arylketones and alcohol. Reagents and conditions: (a)
(COCl)2, CH2Cl2, rt; (b) RSn(nBu)3, Pd(PPh3)4, toluene, 80–100 °C, 7–57%, over two
steps; (c) NaBH4, CH3OH, 0 °C, 19%.

C. Béguin et al. / Bioorg. Med. Chem. 17 (2009) 1370–1380
1373
Table 1
binding to KOPR, MOPR, and delta opioid receptors (DOPR) in
membranes prepared from Chinese hamster ovary cells (CHO) sta-
bly transfected with the human KOPR (hKOPR), rat MOPR (rMOPR),
and mouse DOPR (mDOPR).29 The rMOPR and the mDOPR have
very high sequence homology to the respective human orthologs
and share similar binding and functional properties. The potencies
and efficacies of compounds 1–3 and 6–34 on hKOPR were deter-
Affinities (Ki), potencies (EC50), and efficacies (Emax) of C12-substituted salvinorins at
the KOPR
R
12
O
O
H
O
H
O
O
mined by their abilities to regulate [35S]GTP
cS binding to mem-
O
branes of CHO-hKOPR cells.30 The selective KOPR full agonist,
U50,488H, was used as a reference compound, with its efficacy
designated as 100%. Receptor binding and functional assay data
were analyzed using Prism (GraphPad Software Inc., San Diego,
CA). Ki, EC50 (potency) and Emax (efficacy) values were determined
using the same software. The in vitro pharmacological data for
those derivatives with detectable KOPR binding affinity
(Ki < 1000 nM) (1–3, 6–7, 9–11, 13, 16–20) are listed in Table 1.
The dose–response curves of compound 6 and U50,488 in the
O
b,c
d
Compound
R
Kia,b (nM)
EC50 (nM)
Emax
O
1, SalvA
2.5 0.6
2.1 0.6
2.4 0.2
4.6 0.1
105
4
5
6
O
O
O
2e
3e
6
2.9 0.3
7.1 0.1
108
120
67
Br
[
35S]GTP
cS functional assay are shown in Figure 2.
4. Results and discussion
None of the compounds evaluated in this study showed any
affinity for the MOPR or DOPR (Ki > 1000 nM). Compound 6
41
5
84
8
5
showed partial agonist effects in the [35S]GTP
cS assay. All other
compounds exhibiting detectable agonism in the KOPR functional
assay were full agonists. As reported by Simpson et al.,20 monobro-
minated analogue 2 was a highly potent KOPR agonist. Similarly,
introduction of a 16-vinyl group (3) did not compromise binding
affinity, potency, or selectivity (Ki = 7.1 nM, EC50 = 4.6 nM).
Two groups have recently achieved total syntheses of salvinorin
A.31,32 Total synthesis allows the preparation of derivatives that
may not be achievable by semi-synthetic modification of salvinorin
A. In particular, Nozawa et al.32 suggested that a slight modifica-
tion of their multi-step synthetic pathway would produce 12-epi-
salvinorin A (6). We used a semi-synthetic approach to prepare
6: cleavage of hemiacetal 4 (Scheme 2) and concomitant lactoniza-
tion being the key transformations. The binding affinity and po-
O
OH
7
55 23
498 71
497 13
555 97
167 35
330 30
>1000
99
98
—
1
2
O
9
O
O
10
11
299 13
113
3
1
3
4
O
S
O
O
13
16
17
18
38 10
83 28
101
195
36
6
6
103
103
111
tency of
moderately reduced relative to the natural epimer. Surprisingly,
6 was a partial agonist at KOPR in the [35S]GTP
S assay with
6 at the KOPR (Ki = 41 nM, EC50 = 84 nM) were
N
c
N
O
67 5% efficacy relative to U50,488 (Fig. 2), a difference of high sta-
tistical significance (p < 0.001). In addition, compound 6 partially
blocked the effect of U50,488 in the same assay. The next step will
HO
O
20
2
5
O
154 27
196 23
361 25
99
94
2
U50,488
400
300
200
100
0
U50,488 + 10 μM 6
O
O
O
O
6
19
20
508
8
2
2
109 12
337 54
94
*
*
*
*
U50,488H
2.2 0.2
2.9 0.2
100
Ki values in inhibiting [3H]diprenorphine binding to hKOPR.
Each value represents the mean of at least three independent experiments
a
b
performed in duplicate.
EC50 values in activating the hKOPR to enhance [35S]GTP
cS binding.
c
d
Efficacy determined as the % of maximal response produced by U50,488 run in
parallel experiments.
e
U50,488H values for these assays: Ki = 1.6 0.6 nM; EC50 = 3.2 0.7 nM.
10-11
10-10
10-9
10-8
10-7
10-6
10-5
10-4
Test compound (M)
A (6) exhibits partial agonist properties in the
3. In vitro binding and functional assays
Figure 2. 12-epi-Salvinorin
[
35S]GTP M, compound 6 significantly reduced [35S]GTP
cS assay. At 10 l cS binding
The affinities of compounds 1–3 and 6–34 for opioid receptors
were determined by competitive inhibition of [3H]diprenorphine
induced by U50,488 ranging from 3 ꢁ 10ꢂ8 to 10ꢂ5 M (Student’s t test, , P < 0.01).
*

1374
C. Béguin et al. / Bioorg. Med. Chem. 17 (2009) 1370–1380
Figure 3. (stereoview). Superimposition of the crystal structures of 1 (dark grey) and 6 (light grey).
be to evaluate if partial agonism and selectivity are maintained
in vivo. Inversion at C-12 has surprisingly little effect on the posi-
tion of the furan ring: superimposition with the crystal structure of
1 (Fig. 3)12 shows that C-13 and the furan oxygen atom are almost
coincident in the two structures. That this subtle change in posi-
tion and orientation should convert a full agonist into a partial
one merits further investigation.
used the structurally related [3H]diprenorphine, also a non-selec-
tive opioid antagonist (see Supplementary data for the structures
of diprenorphine and IOXY). Since [125I]IOXY was not commercially
available, we ran a second binding assay with 28a and 28b using
[3H]U69,593 as the radioligand (see Supplementary data). In an-
other control experiment, we substituted our buffer (50 mM
Tris–HCl buffer (pH 7.4) containing 1 mM EGTA) with the one re-
ported by Simpson et al. [50 mM Tris–HCl buffer (pH 7.4) contain-
Acid 7 is known22 but pharmacological data have not previously
been reported. Interestingly, we found that 7 retained some affinity
ing a protease inhibitor cocktail (bacitracin (100
l
g/mL), bestatin
for the KOPR (Ki = 55 nM) and was
a
weak agonist in the
(10 g/mL), leupeptin (4 g/mL), and chymostatin (2 l
l
l
g/mL))].20
[
35S]GTP
cS functional assay (EC50 = 167 nM). Reduction of acid 7,
In each case, 28a and 28b were found to have negligible KOPR
binding affinity (see Supplementary data). Despite their lack of
affinity in our KOPR binding assays, 28a and 28b were also tested
giving alcohol 8, resulted in complete loss of KOPR binding affinity.
Some affinity was recovered upon O-alkylation: methyl and ethyl
ethers 9 and 10 have comparable in vitro pharmacological profiles.
Similarly, acetylation of 8 improved KOPR binding affinity: ester 11
is a weak KOPR agonist (Ki = 555 nM, EC50 = 299 nM).
in the [35S]GTP
c
S functional assay. As expected, reference com-
pound U50,488 induced maximum elevation of [35S]GTP
cS levels
at low concentration. By comparison, 28a and 28b showed KOPR
agonist properties only at high concentrations, the natural 8-con-
figuration being preferred (see Supplementary data). Finally, 28a
We then studied the effect of inserting a linker between C-12
and the furan (or other aromatic) rings. No clear SAR patterns were
observed for the ketoaryl derivatives 12–16. The fact that the keto-
thiophene (13) and ketopyrazine (16) analogues display moderate
KOPR binding affinity (13: Ki = 38 nM, 16: Ki = 83 nM), while the
other ketones display none is puzzling. The lack of SAR patterns
may be due to instability of these arylketones under the assay con-
ditions. Significantly, secondary alcohols 17 (Ki = 20 nM) were con-
siderably more potent than the corresponding ketone 12
(Ki > 1000 nM). Since 13 and 16 showed enhanced potencies when
compared to 12, reduction of their C-13 ketone might lead to even
greater potency. An alternative synthetic route to these alcohols is
currently being examined.
failed to inhibit the U50,488H-induced increases in [35S]GTP
cS
specific binding, demonstrating that this compound did not act
as a KOPR antagonist in our functional assay.
5. Conclusions
Our results suggest that it is possible to alter the C-12 substitu-
ent of salvinorin A and retain selective KOPR agonism. We devel-
oped a four-step synthesis of 12-epi-salvinorin A (6) and found
that it induced KOPR partial agonist effects in vitro. Under our con-
ditions, the methyloxadiazole 28a was devoid of antagonist prop-
erties as were related oxadiazoles (29–34). Further modifications
will be necessary to better understand the SAR at this position.
Alkyl esters (18–20) demonstrated low KOPR binding affinity
(Ki = 109–196 nM). Increasing the size of the ester substituent
(21, 22) led to complete loss of KOPR affinity. All secondary amides
prepared for this study (23–27) were devoid of KOPR affinity
(Ki > 1000 nM).
6. Experimental
Since a previous report20 identified methyloxadiazole 28a as a
weak KOPR antagonist, we evaluated it along with a few related
oxadiazoles (29–34). Under our binding assay conditions, none of
the oxadiazoles displayed any appreciable KOPR binding affinity
(Ki > 1000 nM). By contrast, Simpson et al.20 reported high affinity
for 28a (Ki = 56 nM). This may be due to differences in the binding
assay protocols, such as the choice of radioligand and buffer com-
position. Simpson et al. used [125I]IOXY as the radioligand while we
6.1. General methods
Commercial reagents and solvents were used without further
purification. Reactions were monitored by thin-layer chromatogra-
phy (TLC) using either an ethanolic solution of vanillin and H2SO4
or an aqueous solution of ammonium molybdate, cerium sulfate,
and H2SO4, and heat as developing agents. Products were purified
using automated flash chromatography (50 lm silica gel), manual

C. Béguin et al. / Bioorg. Med. Chem. 17 (2009) 1370–1380
1375
flash chromatography (230–400 mesh silica gel), or a Waters HPLC
6.7. Hemiacetal 4
system (ELSD detector, Novapak column [6
lm
silica,
7.8 ꢁ 300 mm]). 1H NMR and 13C NMR chemical shifts are refer-
enced to residual solvent peaks as internal standards: CDCl3
(7.26 and 77 ppm) or CD3OD (3.30 and 49 ppm).
A solution of 1 (750 mg, 1.7 mmol) in aq KOH (5%, 50 mL) was
refluxed for 2 h. The solution was cooled to room temperature
and acidified to pH ꢃ 2 with aq HCl (5 M). The cloudy mixture
was then extracted into EtOAc. Drying (MgSO4) and concentration
in vacuo gave 425 (650 mg, 95%) as a yellow foam. Rf 0.21 (9:1,
CH2Cl2/CH3OH); 1H NMR (300 MHz, CD3OD): d 7.47 (dt, J = 1.6,
0.8 Hz, 1H), 7.40 (t, J = 1.7 Hz, 1H), 6.44 (dd, J = 1.8, 0.7 Hz, 1H),
5.09 (dd, J = 11.8, 1.6 Hz, 1H), 3.53 (dd, J = 11.9, 5.0 Hz, 1H), 2.23
(dd, J = 13.2, 2.7 Hz, 1H), 2.15 (dd, J = 12.9, 3.0 Hz, 1H), 2.02–1.89
(m, 3H), 1.82 (dt, J = 13.3, 3.1 Hz, 1H), 1.74–1.55 (m, 3H), 1.53 (s,
3H), 1.43–1.30 (m, 1H), 1.34 (s, 1H), 1.23 (s, 3H); 13C NMR
(75 MHz, CD3OD): d 177.3, 176.6, 144.0, 140.6, 128.9, 110.1, 98.3,
75.2, 62.6, 56.8, 55.3, 55.3, 51.2, 41.4, 37.8, 37.1, 30.4, 22.4, 18.9,
16.1.
6.2. Method A
A solution of 7 in oxalyl chloride (2.0 M in CH2Cl2) was stirred at
room temperature (3 h). The reaction solvent was evaporated and
the crude was used immediately without purification for the Stille
coupling reaction. The appropriate tributyl tin reagent (1.1 equiv)
was added to a mixture of crude acyl chloride and Pd(PPh3)4 (cat-
alytic amount) in anhydrous toluene and the reaction was stirred
at 80–100 °C (2–18 h). A saturated aq KF solution and Et2O were
added to the reaction mixture. The organic layer was dried
(MgSO4) and the residue purified by column chromatography to
yield the desired product.
6.8. Monoacetate 5
6.3. Method B
A solution of 4 (309 mg, 784 lmol) and Ac2O (90 lL, 942 lmol,
1.2 equiv) in pyridine (6 mL) was stirred at room temperature
(42 h). The reaction was concentrated in vacuo and the residue
purified by column chromatography (silica gel; 0?10% MeOH/
CH2Cl2) to yield 5 (170 mg, 48%) as a white powder: Rf 0.32 (9:1,
CH2Cl2/CH3OH); 1H NMR (300 MHz, CD3OD): d 7.38 (t, J = 1.7 Hz,
1H), 7.32 (dd, J = 0.8, 1.5 Hz, 1H), 6.35 (dd, J = 0.7, 1.8 Hz, 1H),
5.06 (d, J = 10.8 Hz, 1H), 4.80 (dd, J = 4.8, 12.1 Hz, 1H), 2.31 (dd,
J = 2.7, 13.2 Hz, 1H), 2.20–1.99 (m, 6H), 1.94 (dd, J = 2.0, 13.3 Hz,
1H), 1.90–1.82 (m, 1H), 1.73 (ddd, J = 2.7, 4.6, 12.8 Hz, 1H), 1.67–
1.57 (m, 2H), 1.55 (s, 3H), 1.47–1.30 (m, 2H), 1.25 (s, 3H); 13C
NMR (75 MHz, CD3OD): d 177.2, 176.2, 172.2, 144.0, 140.1, 129.1,
109.8, 97.7, 77.4, 63.0, 56.7, 55.6, 55.2, 51.4, 41.4, 37.9, 37.1,
28.3, 22.4, 21.1, 18.8, 16.2.
To a solution of 7, EDCI (1.2 equiv), and DMAP (catalytic
amount) in CH2Cl2 was added the appropriate alcohol (2.0 equiv).
The reaction was stirred at room temperature (3 h). The reaction
was washed with an aq 1 M HCl solution, brine, dried (MgSO4),
and concentrated in vacuo. The residue was purified by column
chromatography to obtain the desired product.
6.4. Method C
To a CH2Cl2 solution of 7, EDCI (1.2 equiv), and HOBt (1.2 equiv)
was added the appropriate amine (1.5 equiv) and the solution was
stirred at room temperature (5–20 min). The reaction was washed
with H2O, dried (MgSO4), and concentrated in vacuo. The residue
was purified by column chromatography (silica gel; CH2Cl2/CH3OH,
hexanes/EtOAc, or CH2Cl2/EtOAc) to obtain the desired product.
6.9. 12-epi-Salvinorin A (6)
A solution of 5 (102 mg, 234 lmol) in AcOH (2.3 mL) was re-
6.5. Method D
fluxed (18 h). The reaction was concentrated in vacuo and the res-
idue was diluted with i-PrOH and concentrated to remove excess
AcOH. The residue was then dissolved in MeCN (2 mL) and
Using a modification of the reported procedure,23 a mixture of
7, EDCI (1.2 equiv), and HOBt (1.3 equiv) in CH2Cl2 was stirred at
room temperature. After 5 min, the appropriate oxime was added
and the reaction stirred at room temperature. Upon completion,
the reaction was washed with a saturated aq NaHCO3 solution
and brine. The organic layer was dried (MgSO4) and concentrated
to give the crude ester. Toluene was added and the solution was re-
fluxed (17–43 h), concentrated, and the crude residue was purified
by normal phase HPLC (hexanes/EtOAc).
TMSCHN2 (2.0 M in hexane, 6 equiv, 700 lL, 1.4 mmol) added.
The solution was stirred at room temperature (25 min), concen-
trated in vacuo, and the residue purified by column chromatogra-
phy (silica gel; 0?50% EtOAc/hexanes). Slow evaporation from
EtOAc/hexanes yielded 6 (11 mg, 11%) as colorless needles, mp
212–217 °C (dec); Rf 0.27 (1:1, hexanes/EtOAc); 1H NMR
(300 MHz, CDCl3): d 7.45–7.41 (m, 1H), 7.39 (t, J = 1.7 Hz, 1H),
6.41 (dd, J = 0.7, 1.8 Hz, 1H), 5.30 (dd, J = 6.1, 11.6 Hz, 1H), 5.22–
5.11 (m, 1H), 3.73 (s, 3H), 2.78 (dd, J = 7.6, 9.2 Hz, 1H), 2.49–2.36
(m, 2H), 2.36–2.30 (m, 2H), 2.28 (dd, J = 4.7, 7.0 Hz, 1H), 2.17 (s,
3H), 2.07–1.72 (m, 4H), 1.64 (dd, J = 4.9, 14.0 Hz, 1H), 1.38 (s,
3H), 1.07 (s, 3H); 13C NMR (75 MHz, CDCl3): d 201.8, 173.1,
171.5, 170.0, 143.7, 139.8, 123.8, 108.7, 75.0, 70.3, 65.8, 53.4,
52.0, 47.3, 44.7, 42.3, 37.7, 35.2, 30.6, 21.2, 20.6, 18.2, 16.1;
HRMS–ESI (m/z): [M+H]+ calcd for C23H28O8: 433.1862; found:
433.1847.
6.6. Vinylfuran 3
Tributylvinyltin (5
(8.4 mg, 16 mol) and Pd(PPh3)4 (catalytic amount) in anhydrous
toluene (300 L) and the reaction was stirred at 80 °C (18 h). A sat-
lL, 18 lmol) was added to a mixture of 2
l
l
urated aq KF solution and Et2O were added to the reaction mixture.
The organic layer was dried (MgSO4) and the residue purified by
column chromatography (silica gel; 0?50% EtOAc/hexanes) to
yield 3 (4.4 mg, 58%) as a white powder: Rf 0.32 (1:1, hexanes/
EtOAc); 1H NMR (300 MHz, CDCl3): d 7.31 (d, J = 1.9 Hz, 1H), 6.53
(dd, J = 11.3, 17.3 Hz, 1H), 6.33 (d, J = 1.9 Hz, 1H), 5.71 (dd, J = 1.2,
17.3 Hz, 1H), 5.57 (dd, J = 5.1, 12.0 Hz, 1H), 5.25 (dd, J = 1.2,
11.3 Hz, 1H), 5.17–5.08 (m, 1H), 3.73 (s, 3H), 2.80–2.71 (m, 1H),
2.38 (dd, J = 5.1, 13.6 Hz, 1H), 2.34–2.24 (m, 3H), 2.23–2.02 (m,
5H), 1.80 (dd, J = 2.9, 9.9 Hz, 1H), 1.73–1.67 (m, 3H), 1.47 (s, 3H),
1.12 (s, 3H); HRMS–ESI (m/z): [M+H]+ calcd for C25H31O8:
459.2019; found: 459.2021.
6.10. Alcohol 8
To a THF (3 mL) solution of 7 (157 mg, 382 lmol) was added
BH3ꢀTHF (1.0 M in THF, 0.5 mL, 0.5 mmol) dropwise, and the reac-
tion was stirred at 55 °C. After 1 h, the reaction was cooled to room
temperature, water (2 mL) was added dropwise and the solution
was evaporated. The residue was taken up in a saturated aq NaH-
CO3 solution and extracted with CH2Cl2. The organic layer was
dried (MgSO4) and concentrated in vacuo. The residue was purified

1376
C. Béguin et al. / Bioorg. Med. Chem. 17 (2009) 1370–1380
by column chromatography (silica gel; 19:1, CH2Cl2/MeOH) to ob-
tain 8 (70 mg, 46%) as a white powder: Rf 0.27 (19:1, CH2Cl2/
MeOH); 1H NMR (300 MHz, CDCl3): d 5.19–5.05 (m, 1H), 4.67–
4.49 (m, 1H), 3.84 (dd, J = 2.7, 12.4 Hz, 1H), 3.72 (s, 3H), 3.52 (dd,
J = 4.2, 12.4 Hz, 1H), 2.80–2.66 (m, 1H), 2.35–2.23 (m, 2H), 2.21–
2.08 (m, 6H), 2.00 (dd, J = 2.7, 11.5 Hz, 1H), 1.81–1.73 (m, 1H),
1.68–1.46 (m, 3H), 1.37 (s, 3H), 1.08 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 202.1, 171.6, 171.6, 170.0, 77.2, 75.1, 64.7, 64.0, 53.5,
52.0, 50.9, 42.1, 38.1, 37.4, 34.8, 30.7, 20.6, 18.1, 16.3, 15.2;
HRMS–ESI (m/z): [M+H]+ calcd for C20H28O8: 397.1862; found:
397.1859.
20.6, 18.1, 16.3, 15.0; HRMS–ESI (m/z): [M+H]+ calcd for
C22H30O9: 439.1968; found: 439.1956.
6.14. Furanyl ketone 12
Compound 12 (7.3 mg, 33%) was prepared as a white powder
from 7 (20 mg, 49
lmol), oxalyl chloride (1 mL, 2 mmol), Pd(PPh3)4
(catalytic amount), and 2-(tributylstannyl)furan (17
l
L, 54 mol)
l
utilizing method A, stirring the reaction at 80 °C (18 h), and using
column chromatography (silica gel; 0?50% EtOAc/hexanes): Rf
0.31 (1:1, hexanes/EtOAc); 1H NMR (300 MHz, CDCl3): d 7.74–
7.61 (m, 1H), 7.37 (dd, J = 0.6, 3.6 Hz, 1H), 6.59 (dd, J = 1.7, 3.6 Hz,
1H), 5.62 (t, J = 8.3 Hz, 1H), 5.12 (t, J = 10.0 Hz, 1H), 3.71 (s, 3H),
2.78–2.69 (m, 1H), 2.63 (dd, J = 8.0, 13.6 Hz, 1H), 2.38–2.22 (m,
2H), 2.22–2.05 (m, 6H), 1.82–1.50 (m, 4H), 1.44 (s, 3H), 1.08 (s,
3H); 13C NMR (75 MHz, CDCl3): d 201.9, 184.0, 171.5, 170.7,
169.8, 149.9, 147.8, 120.3, 112.9, 76.0, 74.9, 64.6, 53.2, 51.9, 49.6,
42.0, 38.0, 37.7, 35.5, 30.7, 20.6, 18.2, 16.4, 16.0; HRMS–ESI (m/z):
[M+NH4]+ calcd for C24H28O9: 478.2077; found: 478.2084.
6.11. Methyl ether 9
To a CH3CN solution of 8 (20 mg, 52
(150 mg, 647 mol) and iodomethane (70
l
l
mol) was added Ag2O
L, 1.1 mmol). The reac-
l
tion was stirred at 60 °C (5 d). The reaction was concentrated and
the residue purified by column chromatography (silica gel; 0?5%
MeOH/CH2Cl2) followed by a second column (silica gel; 0?25%
EtOAc/CH2Cl2, then 5% MeOH/CH2Cl2) to yield 9 (2.5 mg, 15%) as
an orange resin: Rf 0.50 (4:1, CH2Cl2/EtOAc); 1H NMR (300 MHz,
CDCl3): d 5.13 (t, J = 9.9 Hz, 1H), 4.68–4.53 (m, 1H), 3.79–3.53 (m,
4H), 3.49–3.29 (m, 4H), 2.81–2.67 (m, 1H), 2.39–2.24 (m, 2H),
2.24–2.06 (m, 6H), 2.05–1.96 (m, 1H), 1.84–1.70 (m, 1H), 1.69–
1.47 (m, 3H), 1.35 (s, 3H), 1.08 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 202.1, 171.6, 171.5, 170.0, 76.0, 75.1, 74.0, 64.2, 59.3, 53.5,
52.0, 50.6, 42.1, 38.1, 37.8, 34.9, 30.7, 20.6, 18.1, 16.2, 15.1;
HRMS–ESI (m/z): [M+H]+ calcd for C21H30O8: 411.2019; found:
411.2036.
6.15. Thienyl ketone 13
Compound 13 (8.8 mg, 36%) was prepared as a white powder
from 7 (21 mg, 51
(catalytic amount), and 2-(tributylstannyl)thiophene (18
57 mol) utilizing method A, stirring the reaction at 100 °C (2 h),
lmol), oxalyl chloride (1 mL, 2 mmol), Pd(PPh3)4
l
L,
l
and using column chromatography (silica gel; 0?33% acetone/hex-
anes) followed by a second column (silica gel; 0?10% EtOAc/
CH2Cl2): Rf 0.21 (2:1, hexanes/acetone); 1H NMR (300 MHz, CDCl3):
d 7.82 (dd, J = 1.1, 3.9 Hz, 1H), 7.75 (dd, J = 1.1, 5.0 Hz, 1H), 7.18 (dd,
J = 3.9, 5.0 Hz, 1H), 5.62 (t, J = 8.2 Hz, 1H), 5.21–5.04 (m, 1H), 3.71 (s,
3H), 2.78–2.68 (m, 1H), 2.62 (dd, J = 8.1, 13.7 Hz, 1H), 2.34–2.23 (m,
2H), 2.23–2.06 (m, 6H), 1.81–1.53 (m, 4H), 1.44 (s, 3H), 1.08 (s, 3H);
13C NMR (75 MHz, CDCl3): d 202.1, 188.4, 171.7, 170.8, 170.0, 140.1,
136.0, 134.2, 128.9, 76.9, 75.0, 64.7, 53.4, 52.1, 49.7, 42.1, 38.6, 37.8,
35.6, 30.8, 20.7, 18.3, 16.8, 16.2; HRMS–ESI (m/z): [M + NH4]+ calcd
for C24H28O8S, 494.1849; found, 494.1831.
6.12. Ethyl ether 10
To a CH3CN solution of 8 (16 mg, 40
(122 mg, 526 mol) and iodoethane (94
tion was stirred at 60 °C (4 d). Additional Ag2O (136 mg, 586
and iodoethane (94 L, 1.2 mmol) were added. The reaction was
l
l
mol) was added Ag2O
L, 1.2 mmol). The reac-
mol)
l
l
l
stirred at room temperature (8 d) and then concentrated. The res-
idue purified by column chromatography (silica gel; 0?5% MeOH/
CH2Cl2) followed by a second column (silica gel; 0?20% EtOAc/
CH2Cl2) to yield 10 (2.0 mg, 12%) as a clear resin: Rf 0.50 (19:1,
CH2Cl2/MeOH); 1H NMR (300 MHz, CDCl3): d 5.18–5.07 (m, 1H),
4.60 (d, J = 5.8 Hz, 1H), 3.71 (d, J = 5.1 Hz, 3H), 3.64–3.37 (m, 4H),
2.82–2.67 (m, 1H), 2.31 (d, J = 10.2 Hz, 2H), 2.23–2.07 (m, 6H),
2.01 (d, J = 8.4 Hz, 1H), 1.76 (dd, J = 3.2, 9.8 Hz, 1H), 1.55 (d,
J = 14.6 Hz, 3H), 1.42–1.03 (m, 9H); 13C NMR (75 MHz, CDCl3): d
202.1, 171.6, 171.6, 170.0, 76.2, 75.1, 72.0, 67.1, 64.2, 53.5, 52.0,
50.7, 42.1, 38.1, 38.0, 34.9, 30.7, 20.6, 18.2, 16.2, 15.1, the OCH2CH3
signal was not detected; HRMS–ESI (m/z): [M+H]+ calcd for
C22H32O8: 425.2175; found: 425.2168.
6.16. Oxazolyl ketone 14
Compound 14 (3.1 mg, 6.5%) was prepared as a clear resin from 7
(21 mg, 52
lmol), oxalyl chloride (1 mL, 2 mmol), Pd(PPh3)4 (cata-
lytic amount), and 2-(tributylstannyl)oxazole (12
l
L, 57 mol) uti-
l
lizing method A, stirring the reaction at 100 °C (2 h), and using
column chromatography (silica gel; 0?40% acetone/hexanes) fol-
lowed by a second column (silica gel; 0?50% EtOAc/hexanes): Rf
0.21 (2:1, hexanes/acetone): Rf 0.09 (1:1, hexanes/EtOAc); 1H NMR
(300 MHz, CDCl3): d 7.89 (d, J = 0.6 Hz, 1H), 7.39 (d, J = 0.6 Hz, 1H),
5.93 (dd, J = 7.7, 10.0 Hz, 1H), 5.20–4.99 (m, 1H), 3.72 (s, 3H), 2.82–
2.67 (m, 2H), 2.34–2.19 (m, 3H), 2.18–2.12 (m, 5H), 1.83–1.51 (m,
4H), 1.47 (s, 3H), 1.09 (s, 3H); 13C NMR (75 MHz, CDCl3): d 201.7,
183.2, 171.7, 170.4, 170.1, 142.8, 129.9, 77.4, 76.8, 75.0, 64.6, 53.5,
52.2, 50.0, 42.2, 38.3, 38.0, 35.8, 30.8, 20.8, 18.3, 16.2, 16.0; HRMS–
ESI (m/z): [M+NH4]+ calcd for C23H27NO9: 479.203; found: 479.2019.
6.13. Acetate 11
To a CH2Cl2 solution of 8 (19 mg, 48
lmol) was added Ac2O
(5.4 L, 57 mol) and Et3N (8 L, 57 mol). The reaction was stir-
l
l
l
l
red at room temperature (25 h). DMAP (catalytic amount) was
added and the reaction stirred for an additional 4 h. The reaction
was concentrated and the residue purified by column chromatog-
raphy (silica gel; 0?4% MeOH/CH2Cl2) to obtain 11 (17 mg, 79%)
6.17. Phenyl ketone 15
Compound 15 (20.2 mg, 59% yield) was prepared as a white
as
a
white foam: Rf 0.35 (19:1, CH2Cl2/MeOH); 1H NMR
powder from 7 (30 mg, 73
Pd(PPh3)4 (catalytic amount), and 2-(tributylstannyl)phenyl
(26 L, 80 mol) utilizing method A, stirring the reaction at
lmol), oxalyl chloride (1 mL, 2 mmol),
(300 MHz, CDCl3): d 5.22–5.08 (m, 1H), 4.80–4.65 (m, 1H), 4.22
(dd, J = 3.2, 12.1 Hz, 1H), 4.03 (dd, J = 5.2, 12.1 Hz, 1H), 3.72 (s,
3H), 2.83–2.66 (m, 1H), 2.36–2.20 (m, 3H), 2.21–2.12 (m, 5H),
2.09 (s, 3H), 1.97 (dd, J = 2.7, 11.7 Hz, 1H), 1.79 (dd, J = 2.8,
9.8 Hz, 1H), 1.68–1.53 (m, 3H), 1.37 (s, 3H), 1.09 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 201.9, 171.5, 170.8, 170.6, 170.0, 75.0,
74.5, 65.9, 64.1, 53.5, 52.0, 51.1, 42.0, 38.2, 38.0, 34.9, 30.7, 20.8,
l
l
100 °C (2 h), and using column chromatography (silica gel;
0?33% acetone/hexanes): Rf 0.29 (2:1, hexanes/acetone); 1H
NMR (300 MHz, CDCl3): d 7.90 (dd, J = 1.3, 8.4 Hz, 2H), 7.68–7.57
(m, 1H), 7.55–7.43 (m, 2H), 5.87 (t, J = 8.3 Hz, 1H), 5.15–5.03 (m,
1H), 3.70 (s, 3H), 2.76–2.59 (m, 2H), 2.34–2.22 (m, 2H), 2.21–2.06

C. Béguin et al. / Bioorg. Med. Chem. 17 (2009) 1370–1380
1377
(m, 6H), 1.82–1.52 (m, 4H), 1.44 (s, 3H), 1.06 (s, 3H); 13C NMR
amount), and EtOH (7.4
lL, 127
lmol) utilizing method B and
(75 MHz, CDCl3): d 202.0, 195.2, 171.6, 171.0, 169.8, 134.3, 133.3,
129.1, 128.9, 75.2, 74.8, 64.6, 53.1, 51.9, 49.2, 41.9, 38.2, 37.6,
35.5, 30.6, 20.6, 18.2, 16.7, 16.0; HRMS–ESI (m/z): [M+NH4]+ calcd
for C26H30O8: 488.2284; found: 488.2297.
using column chromatography (silica gel; 1:1, EtOAc/hexanes): Rf
0.63 (1:1, hexanes/EtOAc); 1H NMR (300 MHz, CDCl3): d 5.21–
5.07 (m, 1H), 4.95 (dd, J = 7.2, 9.7 Hz, 1H), 4.33–4.14 (m, 2H),
3.72 (s, 3H), 2.79–2.68 (m, 1H), 2.60 (dd, J = 7.2, 13.5 Hz, 1H),
2.38–2.23 (m, 2H), 2.18 (s, 3H), 2.16–2.06 (m, 3H), 1.79–1.74 (m,
1H), 1.72–1.47 (m, 3H), 1.36 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.08
(s, 3H); 13C NMR (75 MHz, CDCl3): d 201.7, 171.5, 170.1, 170.1,
169.9, 74.9, 73.8, 64.4, 62.1, 53.4, 52.0, 50.0, 42.0, 38.9, 37.8,
35.2, 30.7, 20.6, 18.1, 16.1, 15.8, 14.1; HRMS–ESI (m/z): [M+NH4]+
calcd for C22H30O9: 456.2234; found: 456.2246.
6.18. Pyrazinyl ketone 16
Compound 16 (19.9 mg, 57% yield) was prepared as an off-
white powder from 7 (30 mg, 73
2 mmol), Pd(PPh3)4 (catalytic amount), and 2-(tributylstannyl)pyr-
azine (26 L, 81 mol) utilizing method A, stirring the reaction at
lmol), oxalyl chloride (1 mL,
l
l
100 °C (2 h), and using column chromatography (silica gel;
6.22. Isopropyl ester 20
0?40% acetone/hexanes): Rf 0.08 (2:1, hexanes/acetone); 1H
NMR (300 MHz, CDCl3):
d
9.24 (d, J = 1.4 Hz, 1H), 8.80 (d,
Compound 20 (19 mg, 38%) was prepared as a clear resin from 7
J = 2.4 Hz, 1H), 8.72–8.59 (m, 1H), 6.28 (dd, J = 8.3, 9.2 Hz, 1H),
5.16–4.97 (m, 1H), 3.70 (s, 3H), 2.81 (dd, J = 8.1, 13.3 Hz, 1H),
2.75–2.66 (m, 1H), 2.32–2.21 (m, 2H), 2.21–2.09 (m, 6H), 1.81–
1.53 (m, 3H), 1.49–1.35 (m, 4H), 1.07 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 202.0, 196.1, 171.8, 171.1, 170.1, 149.0, 145.3, 144.9,
144.1, 75.9, 75.0, 64.8, 53.5, 52.3, 49.9, 42.2, 38.5, 38.0, 35.9,
30.9, 20.9, 18.5, 16.3, 16.2; HRMS–ESI (m/z): [M+NH4]+ calcd for
C24H28N2O8: 490.2189; found: 490.2209.
(25 mg, 60
amount), and i-PrOH (9
l
mol), EDCI (15 mg, 78
lmol), DMAP (catalytic
l
L, 118 mol) utilizing method B and using
l
column chromatography (silica gel; 1:2, EtOAc/hexanes): Rf 0.45
(1:1, hexanes/EtOAc); 1H NMR (300 MHz, CDCl3): d 5.20–5.11 (m,
1H), 5.11–4.99 (m, 1H), 4.91 (dd, J = 7.2, 9.8 Hz, 1H), 3.72 (s, 3H),
2.78–2.69 (m, 1H), 2.57 (dd, J = 7.1, 13.5 Hz, 1H), 2.34–2.29 (m,
2H), 2.17 (s, 3H), 2.17–2.06 (m, 3H), 1.80–1.71 (m, 1H), 1.71–1.46
(m, 3H), 1.36 (s, 3H), 1.27 (d, J = 6.7 Hz, 3H), 1.26 (d, J = 6.7 Hz,
3H), 1.08 (s, 3H); 13C NMR (75 MHz, CDCl3): d 201.8, 171.5,
170.2, 169.9, 169.6, 74.8, 74.0, 70.0, 64.3, 53.3, 52.0, 50.1, 42.0,
38.9, 37.8, 35.2, 30.7, 21.6, 21.6, 20.6, 18.1, 16.1, 15.8; HRMS–ESI
(m/z): [M+NH4]+ calcd for C23H32O9: 470.2390; found: 470.2404.
6.19. Furanyl alcohols 17
To a MeOH solution of 12 (82 mg, 178
lmol) was added NaBH4
(5.8 mg, 153 mol) and the reaction was stirred at 0 °C (1.5 h), con-
l
centrated and the residue purified by column chromatography (sil-
ica gel; 0?4% MeOH/CH2Cl2) followed by a second column (silica
gel, 0?40% EtOAc/CH2Cl2) and a third column (silica gel, 0?50%
EtOAc/hexanes) to yield 17 (14 mg, 19% BOSM) as a clear resin
and as a ꢃ1:1 mixture of 13-epimers: Rf 0.16 (4:1, CH2Cl2/EtOAc);
1H NMR (300 MHz, CDCl3): d 7.43–7.35 (m, 2H), 6.44–6.27 (m, 4H),
5.13 (dd, J = 8.6, 11.3 Hz, 2H), 4.94–4.76 (m, 3H), 4.61 (br s, 1H),
3.71 (d, J = 2.6 Hz, 6H), 2.80–2.64 (m, 2H), 2.38–2.22 (m, 4H),
2.21–2.04 (m, 12H), 1.99 (dd, J = 3.1, 10.7 Hz, 1H), 1.89 (dd,
J = 3.0, 11.2 Hz, 1H), 1.81–1.69 (m, 2H), 1.66–1.47 (m, 6H), 1.43–
1.23 (m, 8H), 1.07 (d, J = 3.9 Hz, 6H); 13C NMR (75 MHz, CDCl3): d
201.9, 201.9, 171.6, 171.5, 171.4, 171.0, 169.9, 169.8, 151.8,
151.4, 142.6, 142.6, 110.5, 110.5, 108.3, 108.2, 78.7, 78.2, 77.2,
74.9, 74.9, 70.2, 69.7, 64.1, 53.5, 53.4, 52.0, 51.9, 50.9, 50.6, 42.0,
42.0, 38.3, 38.3, 38.0, 38.0, 34.9, 34.7, 30.8, 30.8, 20.6, 20.6, 18.1,
16.2, 16.2, 15.2, 15.1, one signal was not detected; HRMS–ESI
(m/z): [M+H]+ calcd for C24H30O9: 463.1968; found: 463.1971.
6.23. Benzyl ester 21
Compound 21 (14 mg, 54%) was prepared as a clear resin from 7
(21 mg, 50
lmol), EDCI (12 mg, 63
l
mol), DMAP (catalytic
amount) and benzyl alcohol (11
l
L, 101
lmol) utilizing method B
and using column chromatography (silica gel; 1:2, EtOAc/hex-
anes): Rf 0.29 (1:1, hexanes/EtOAc); 1H NMR (300 MHz, CDCl3): d
7.44–7.33 (m, 5H), 5.20 (dd, J = 12.0, 27.9 Hz, 2H), 5.14–5.05 (m,
1H), 4.99 (dd, J = 7.6, 8.7 Hz, 1H), 3.72 (s, 3H), 2.71–2.63 (m, 1H),
2.59 (dd, J = 7.6, 13.7 Hz, 1H), 2.32–2.22 (m, 2H), 2.17 (s, 3H),
2.11–1.97 (m, 3H), 1.78–1.68 (m, 1H), 1.66–1.43 (m, 3H), 1.34 (s,
3H), 1.05 (s, 3H); 13C NMR (75 MHz, CDCl3): d 201.7, 171.5,
170.2, 170.0, 169.9, 134.8, 128.8, 128.8, 128.7, 74.8, 73.6, 67.6,
64.5, 53.3, 52.0, 49.7, 41.9, 38.9, 37.7, 35.2, 30.6, 20.6, 18.1, 16.3,
16.1; HRMS–ESI (m/z): [M+NH4]+ calcd for C27H32O9: 518.2390;
found: 518.2407.
6.24. Furfuryl ester 22
6.20. Methyl ester 18
Compound 22 (7.8 mg, 26%) was prepared as a white powder
To a toluene (3 mL)/MeOH (2 mL) solution of 7 (21 mg, 51
l
mol)
from 7 (25 mg, 61
l
mol), EDCI (14 mg, 75 mol), DMAP (catalytic
l
was added TMSCHN2 (36 L, 72 mol) dropwise. The solution was
l
l
amount), and furfuryl alcohol (11
l
L, 121 lmol) utilizing method
stirred at room temperature (45 min), concentrated, and the resi-
due purified by column chromatography (silica gel; 1:1, EtOAc/hex-
anes) to obtain 18 (10 mg, 48%) as a white powder: Rf 0.31 (1:1,
hexanes/EtOAc); 1H NMR (300 MHz, CDCl3): d 5.19–5.08 (m, 1H),
4.98 (dd, J = 7.3, 9.7 Hz, 1H), 3.77 (s, 3H), 3.72 (s, 3H), 2.78–2.69
(m, 1H), 2.61 (dd, J = 7.3, 13.6 Hz, 1H), 2.35–2.24 (m, 2H), 2.17 (s,
3H), 2.16–2.06 (m, 3H), 1.81–1.73 (m, 1H), 1.71–1.48 (m, 3H),
1.36 (s, 3H), 1.07 (s, 3H); 13C NMR (75 MHz, CDCl3): d 201.7,
171.5, 170.5, 170.0, 169.9, 74.9, 73.6, 64.3, 53.4, 52.9, 52.0, 50.0,
42.0, 38.9, 37.8, 35.2, 30.6, 20.6, 18.1, 16.1, 15.8; HRMS–ESI (m/z):
[M+NH4]+ calcd for C21H28O9: 442.2077; found: 442.2088.
B and using column chromatography (silica gel; 1:2, EtOAc/hex-
anes): Rf 0.37 (1:1, hexanes/EtOAc); 1H NMR (300 MHz, CDCl3): d
7.44 (dd, J = 0.8, 1.9 Hz, 1H), 6.45 (dd, J = 0.6, 3.3 Hz, 1H), 6.38
(dd, J = 1.9, 3.3 Hz, 1H), 5.24–5.06 (m, 3H), 4.98 (dd, J = 7.4,
9.2 Hz, 1H), 3.72 (s, 3H), 2.76–2.67 (m, 1H), 2.59 (dd, J = 7.4,
13.7 Hz, 1H), 2.34–2.23 (m, 2H), 2.17 (s, 3H), 2.14–2.04 (m, 3H),
1.79–1.71 (m, 1H), 1.70–1.48 (m, 3H), 1.34 (s, 3H), 1.06 (s, 3H);
13C NMR (75 MHz, CDCl3): d 201.7, 171.5, 170.1, 169.9, 169.8,
148.3, 143.7, 111.6, 110.7, 74.8, 73.6, 64.4, 59.2, 53.4, 52.0, 49.9,
41.9, 38.9, 37.8, 35.2, 30.7, 20.6, 18.1, 16.1, 16.1; HRMS–ESI (m/
z): [M+NH4]+ calcd for C25H30O10: 508.2183; found: 508.2161.
6.21. Ethyl ester 19
6.25. Methyl amide 23
Compound 19 (5.1 mg, 49%) was prepared as a white powder
Compound 23 (15 mg, 70%) was prepared as a clear resin from 7
from 7 (26 mg, 63
l
mol), EDCI (14 mg, 73
l
mol), DMAP (catalytic
(21 mg, 50 lmol), EDCI (12 mg, 61 lmol), HOBt (7.9 mg, 59 lmol),

1378
C. Béguin et al. / Bioorg. Med. Chem. 17 (2009) 1370–1380
and CH3NH2 (2.0 M in CH2Cl2, 36
lL, 72
l
mol) utilizing method C,
6.29. Furfuryl amide 27
stirring at room temperature (5 min), and using column chroma-
tography (silica gel; 19:1, CH2Cl2/MeOH): Rf 0.08 (19:1, CH2Cl2/
CH3OH); 1H NMR (300 MHz, CDCl3): d 6.43 (br d, J = 4.6 Hz, 1H),
5.15 (dd, J = 8.4, 11.5 Hz, 1H), 4.89 (dd, J = 6.3, 10.6 Hz, 1H), 3.71
(s, 3H), 2.83 (d, J = 4.9 Hz, 3H), 2.77–2.65 (m, 2H), 2.35–2.21 (m,
2H), 2.16 (s, 3H), 2.04–2.16 (m, 2H), 2.00 (dd, J = 2.8, 11.3 Hz,
1H), 1.65 (ddd, J = 10.7, 24.2, 24.9 Hz, 4H), 1.37 (s, 3H), 1.08 (s,
3H); 13C NMR (75 MHz, CDCl3): d 201.4, 171.5, 170.3, 169.8,
169.6, 75.8, 74.7, 64.0, 53.4, 52.0, 51.0, 41.9, 39.1, 37.8, 35.3,
30.8, 26.0, 20.6, 18.1, 16.3, 15.5; HRMS–ESI (m/z): [M+NH4]+ calcd
for C21H29NO8: 441.2237; found: 441.2245.
Compound 27 (11. mg, 45%) was prepared as a white powder
from 7 (21 mg, 51
l
mol), EDCI (12 mg, 62
lmol), HOBt (7.9 mg,
59 mol), and furfurylamine (7.0
l
l
L, 76 mol) utilizing method
l
C, stirring at room temperature (20 min), and using column chro-
matography (silica gel; 19:1, CH2Cl2/MeOH) followed by a second
column (silica gel; 2:1, CH2Cl2/EtOAc): Rf 0.26 (2:1, CH2Cl2/EtOAc);
1H NMR (300 MHz, CDCl3): d 7.35 (dd, J = 0.8, 1.8 Hz, 1H), 6.71 (br t,
J = 5.6 Hz, 1H), 6.32 (dd, J = 1.9, 3.2 Hz, 1H), 6.23 (d, J = 3.2 Hz, 1H),
5.15 (dd, J = 8.5, 11.6 Hz, 1H), 4.91 (dd, J = 6.2, 10.8 Hz, 1H), 4.51–
4.36 (m, 2H), 3.71 (s, 3H), 2.78–2.65 (m, 2H), 2.35–2.21 (m, 2H),
2.20–1.96 (m, 6H), 1.82–1.72 (m, 1H), 1.70–1.50 (m, 3H), 1.37 (s,
3H), 1.08 (s, 3H); 13C NMR (75 MHz, CDCl3): d 201.4, 171.5,
170.2, 169.6, 169.0, 150.2, 142.5, 110.5, 108.0, 75.8, 74.7, 63.9,
53.4, 52.0, 51.0, 41.8, 39.1, 37.8, 36.2, 35.3, 30.8, 20.6, 18.0, 16.3,
15.5; HRMS–ESI (m/z): [M+NH4]+ calcd for C25H31NO9: 507.2343;
found: 507.2350.
6.26. Ethyl amide 24
Compound 24 (11 mg, 51%) was prepared as a black resin
from 7 (21 mg, 51
lmol), EDCI (12 mg, 61
lmol), HOBt (8.1 mg,
60 mol), and EtNH2 (2.0 M in THF, 64
l
lL, 0.13 mmol) utilizing
method C, stirring at room temperature (20 min), and using col-
umn chromatography (silica gel; 19:1, CH2Cl2/MeOH): Rf 0.26
(19:1, CH2Cl2/CH3OH); 1H NMR (300 MHz, CDCl3): d 6.38 (br s,
1H), 5.15 (dd, J = 8.6, 11.7 Hz, 1H), 4.88 (dd, J = 6.2, 10.8 Hz,
1H), 3.71 (s, 3H), 3.40–3.20 (m, 2H), 2.78–2.65 (m, 2H), 2.36–
2.21 (m, 2H), 2.19–2.05 (m, 5H), 2.01 (dd, J = 2.9, 11.5 Hz, 1H),
1.83–1.73 (m, 1H), 1.72–1.49 (m, 3H), 1.38 (s, 3H), 1.14 (t,
J = 7.3 Hz, 3H), 1.09 (s, 3H); 13C NMR (75 MHz, CDCl3): d 201.4,
171.5, 170.4, 169.6, 169.0, 75.8, 74.7, 64.0, 53.4, 52.0, 51.0,
41.9, 39.1, 37.8, 35.3, 34.2, 30.8, 20.6, 18.1, 16.3, 15.5, 14.7;
HRMS–ESI (m/z): [M+NH4]+ calcd for C22H31NO8: 455.2393;
found: 455.2380.
6.30. Methyl oxadiazoles 28a and 28b
Compound 28a (3.6 mg, 8%) was prepared as a clear powder
from 7 (43 mg, 105
lmol), EDCI (25 mg, 130
l
mol), HOBt (19 mg,
142 mol), and acetamide oxime (12 mg, 157
l
l
mol) utilizing
method D, stirring at room temperature (23 h), and using HPLC
purification (silica gel, 20?55% EtOAc/hexanes): Rf 0.32 (1:1, hex-
anes/EtOAc); HRMS–ESI (m/z): [M+H]+ calcd for C22H28N2O8:
449.1924; found: 449.1907.
Compound 28b (5.9 mg, 13%) was also isolated as a clear resin:
Rf 0.23 (1:1, hexanes/EtOAc); 1H NMR (300 MHz, CDCl3): d 5.49 (dd,
J = 2.1, 12.1 Hz, 1H), 5.16–5.05 (m, 1H), 3.71 (s, 3H), 2.75 (dd,
J = 6.5, 10.3 Hz, 1H), 2.53 (dd, J = 2.4, 15.1 Hz, 1H), 2.47–2.43 (m,
1H), 2.41 (s, 3H), 2.33–2.18 (m, 4H), 2.15 (s, 3H), 1.97 (dd, J = 2.7,
13.3 Hz, 1H), 1.93–1.84 (m, 1H), 1.78 (dd, J = 12.2, 15.1 Hz, 1H),
1.66 (s, 3H), 1.62–1.51 (m, 1H), 1.09 (s, 3H); HRMS–ESI (m/z):
[M+H]+ calcd for C22H28N2O8: 449.1924; found: 449.1920.
6.27. Isopropyl amide 25
Compound 25 (16 mg, 69%) was prepared as a white powder
from 7 (21 mg, 51
l
mol), EDCI (12 mg, 63
lmol), HOBt (8.0 mg,
59 mol), and i-PrNH2 (6.4
l
l
L, 75 mol) utilizing method C, stir-
l
ring at room temperature (20 min), and using column chromatog-
raphy (silica gel; 1:1, EtOAc/hexanes): Rf 0.11 (1:1, hexanes/
EtOAc); 1H NMR (300 MHz, CDCl3): d 6.20 (br d, J = 8.0 Hz, 1H),
5.15 (dd, J = 8.6, 11.6 Hz, 1H), 4.85 (dd, J = 6.0, 10.9 Hz, 1H), 4.17–
3.99 (m, 1H), 3.71 (s, 3H), 2.80–2.61 (m, 2H), 2.37–2.20 (m, 2H),
2.19–2.06 (m, 5H), 2.02 (dd, J = 2.3, 11.4 Hz, 1H), 1.83–1.46 (m,
4H), 1.37 (s, 3H), 1.20–1.11 (m, 6H), 1.09 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 201.4, 171.5, 170.4, 169.6, 168.2, 75.9, 74.7,
63.9, 53.4, 52.0, 51.0, 41.9, 41.4, 39.2, 37.9, 35.3, 30.8, 22.6, 22.5,
20.6, 18.1, 16.3, 15.4; HRMS–ESI (m/z): [M+NH4]+ calcd for
C23H33NO8: 469.2544; found: 469.2646.
6.31. Ethyl oxadiazole 29a
Compound 29a (4.9 mg, 10%) was prepared as a white powder
from 7 (43 mg, 104
lmol), EDCI (25 mg, 131
l
mol), HOBt (20 mg,
L, 146 mol) in
144 mol), and N-hydroxypropionamidine (12
l
l
l
CH2Cl2 (2.4 mL) utilizing method D, stirring at room temperature
(42 h), and using HPLC purification (silica gel, 20?50% EtOAc/hex-
anes): Rf 0.38 (1:1, hexanes/EtOAc); 1H NMR (300 MHz, CDCl3): d
5.73 (dd, J = 6.3, 11.0 Hz, 1H), 5.21–5.06 (m, 1H), 3.73 (s, 3H),
2.82–2.71 (m, 3H), 2.64 (dd, J = 6.3, 13.5 Hz, 1H), 2.36–2.20 (m,
4H), 2.20–2.13 (m, 4H), 1.91 (dd, J = 11.3, 13.4 Hz, 1H), 1.85–1.77
(m, 1H), 1.72–1.52 (m, 2H), 1.46 (s, 3H), 1.32 (t, J = 7.6 Hz, 3H),
1.11 (s, 3H); 13C NMR (75 MHz, CDCl3): d 201.7, 175.6, 171.8,
171.4, 169.9, 169.3, 74.9, 69.6, 63.9, 53.4, 52.0, 50.8, 42.0, 39.9,
37.9, 35.4, 30.6, 20.6, 19.7, 18.0, 16.3, 15.4, 11.3; HRMS–ESI
(m/z): [M+H]+ calcd for C23H30N2O8: 463.2080; found: 463.2089.
6.28. Benzyl amide 26
Compound 26 (17 mg, 72%) was prepared as a white powder
from 7 (20 mg, 49
l
mol), EDCI (12 mg, 62
lmol), HOBt (8.0 mg,
59 mol), and benzylamine (8.0
l
l
L, 73 mol) utilizing method C,
l
stirring at room temperature (5 min), and using column chroma-
tography (silica gel; 1:1, EtOAc/hexanes): Rf 0.22 (1:1, hexanes/
EtOAc); 1H NMR (300 MHz, CDCl3): d 7.42–7.19 (m, 5H), 6.76 (br
t, J = 5.6 Hz, 1H), 5.16 (dd, J = 8.4, 11.6 Hz, 1H), 4.91 (dd, J = 6.1,
10.8 Hz, 1H), 4.43 (d, J = 5.9 Hz, 2H), 3.71 (s, 3H), 2.72 (dd, J = 5.5,
12.8 Hz, 2H), 2.34–2.21 (m, 2H), 2.18–2.02 (m, 5H), 1.99 (dd,
J = 2.9, 11.2 Hz, 1H), 1.80–1.70 (m, 1H), 1.68–1.49 (m, 3H), 1.36
(s, 3H), 1.08 (s, 3H); 13C NMR (75 MHz, CDCl3): d 201.4, 171.5,
170.3, 169.6, 169.1, 137.4, 128.8, 127.9, 127.8, 75.9, 74.7, 63.9,
53.4, 51.9, 51.0, 43.3, 41.8, 39.2, 37.8, 35.3, 30.8, 20.6, 18.0, 16.3,
15.5; HRMS–ESI (m/z): [M+NH4]+ calcd for C27H33NO8: 517.2550;
found: 517.2567.
6.32. Isopropyl oxadiazoles 30a and 30b
Compound 30a (20 mg, 41%) was prepared as a clear resin from
7 (42 mg, 102 lmol), EDCI (25 mg, 129 lmol), HOBt (20 mg,
146
lmol), and N-hydroxy 2-methylpropionamide (15 mg,
149
lmol) utilizing method D, stirring at room temperature
(19 h), and using HPLC purification (silica gel, 20?50% EtOAc/hex-
anes): Rf 0.48 (1:1, hexanes/EtOAc); 1H NMR (300 MHz, CDCl3): d
5.73 (dd, J = 6.1, 11.1 Hz, 1H), 5.18–5.09 (m, 1H), 3.72 (s, 3H),
3.17–3.02 (m, 1H), 2.80–2.69 (m, 1H), 2.62 (dd, J = 6.1, 13.5 Hz,
1H), 2.36–2.22 (m, 4H), 2.21–2.12 (m, 4H), 1.91 (dd, J = 11.4,
13.3 Hz, 1H), 1.85–1.76 (m, 1H), 1.75–1.52 (m, 2H), 1.46 (s, 3H),

C. Béguin et al. / Bioorg. Med. Chem. 17 (2009) 1370–1380
1379
1.33 (dd, J = 0.6, 7.0 Hz, 6H), 1.11 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 201.7, 175.4, 175.3, 171.4, 169.9, 169.0, 74.9, 69.7, 63.8, 53.4,
52.0, 50.9, 41.9, 39.9, 37.9, 35.4, 30.6, 26.7, 20.5, 20.4, 20.4, 18.0,
16.3, 15.3; HRMS–ESI (m/z): [M+H]+ calcd for C24H32N2O8:
477.2237; found: 477.2214.
(s, 3H), 1.13 (s, 3H); 13C NMR (75 MHz, CDCl3): d 201.7, 176.1,
171.4, 169.9, 169.2, 167.8, 129.8, 129.7, 116.3, 116.0, 74.9, 69.7,
63.9, 53.5, 52.0, 50.9, 42.0, 40.0, 37.9, 35.5, 30.7, 20.6, 18.1, 16.3,
15.4; HRMS–ESI (m/z): [M+H]+ calcd for C27H29FN2O8: 529.1986;
found: 529.1999.
Compound 30b (2.0 mg, 4%) was also isolated as a clear resin: Rf
0.52 (1:1, hexanes/EtOAc); 1H NMR (300 MHz, CDCl3): d 5.50 (dd,
J = 2.4, 12.2 Hz, 1H), 5.19–5.05 (m, 1H), 3.71 (s, 3H), 3.20–3.02
(m, 1H), 2.75 (dd, J = 5.7, 11.1 Hz, 1H), 2.53 (dd, J = 2.1, 15.2 Hz,
1H), 2.47–2.41 (m, 1H), 2.34–2.17 (m, 4H), 2.15 (s, 3H), 1.97 (dd,
J = 3.1, 12.9 Hz, 1H), 1.93–1.84 (m, 1H), 1.78 (dd, J = 12.6, 15.0 Hz,
1H), 1.66 (s, 3H), 1.61–1.52 (m, 1H), 1.33 (d, J = 7.0 Hz, 6H), 1.09
Compound 33b (9.6 mg, 17%) was also isolated as a white resin:
Rf 0.69 (1:1, hexanes/EtOAc); 1H NMR (300 MHz, CDCl3): d 8.07 (dd,
J = 5.4, 8.6 Hz, 2H), 7.16 (t, J = 8.7 Hz, 2H), 5.57 (dd, J = 1.0, 11.9 Hz,
1H), 5.21–5.09 (m, 1H), 3.71 (s, 3H), 2.85–2.69 (m, 1H), 2.60 (dd,
J = 1.6, 15.1 Hz, 1H), 2.53–2.44 (m, 1H), 2.36–2.19 (m, 4H), 2.15
(s, 3H), 2.03–1.94 (m, 1H), 1.94–1.78 (m, 2H), 1.68 (s, 3H), 1.64–
1.52 (m, 1H), 1.10 (s, 3H); HRMS–ESI (m/z): [M+H]+ calcd for
C27H29FN2O8: 529.1986; found: 529.1996.
(s, 3H); (HRMS–ESI (m/z): [M
477.2237; found: 477.2249.
+
H]+ calcd for C24H32N2O8:
6.36. Benzyl oxadiazoles 34a and 34b
6.33. Propyl oxadiazole 31a
Compound 34a (8.5 mg, 17%) was prepared as a white powder
Compound 31a (9.6 mg, 21%) was prepared as a white powder
from 7 (40 mg, 97 mol), EDCI (24 mg, 125 mol), HOBt (19 mg,
141 mol), and N-hydroxy-butyramidine (17 L, 146 mol) utiliz-
from 7 (39 mg, 95
l
mol), EDCI (25 mg, 130
l
mol), HOBt (19 mg,
l
l
l
138 l
l
mol), N0-hydroxy-2-phenylethanimidamide (22 mg, 148
mol)
l
l
utilizing method D, stirring at room temperature (18 h), and using
HPLC purification (silica gel, 20?25% EtOAc/hexanes): Rf 0.50 (1:1,
hexanes/EtOAc); 1H NMR (300 MHz, CDCl3): d 7.37–7.24 (m, 5H),
5.72 (dd, J = 6.2, 10.8 Hz, 1H), 5.16–5.07 (m, 1H), 4.08 (s, 2H), 3.73
(s, 3H), 2.77–2.68 (m, 1H), 2.61 (dd, J = 6.2, 13.6 Hz, 1H), 2.35–2.24
(m, 2H), 2.23–2.08 (m, 6H), 1.89 (dd, J = 10.8, 13.5 Hz, 1H), 1.82–
1.74 (m, 1H), 1.70–1.49 (m, 2H), 1.44 (s, 3H), 1.10 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 201.7, 176.0, 171.4, 169.9, 169.7, 169.3, 134.8,
129.0, 128.8, 127.3, 74.9, 69.6, 63.8, 53.4, 52.0, 50.8, 41.9, 39.8,
37.8, 35.4, 32.2, 30.6, 20.6, 18.0, 16.3, 15.4; HRMS–ESI (m/z):
[M+H]+ calcd for C28H32N2O8: 525.2237; found: 525.2248.
ing method D, stirring at room temperature (18 h), and using HPLC
purification (silica gel, 20?50% EtOAc/hexanes): Rf 0.42 (1:1, hex-
anes/EtOAc); 1H NMR (300 MHz, CDCl3): d 5.74 (dd, J = 6.2, 10.9 Hz,
1H), 5.22–5.06 (m, 1H), 3.73 (s, 3H), 2.83–2.57 (m, 4H), 2.37–2.21
(m, 4H), 2.20–2.12 (m, 4H), 1.92 (dd, J = 11.3, 13.1 Hz, 1H), 1.85–
1.73 (m, 3H), 1.72–1.54 (m, 2H), 1.47 (s, 3H), 1.12 (s, 3H), 0.99 (t,
J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 201.7, 175.5, 171.4,
170.7, 169.9, 169.3, 74.9, 69.6, 63.9, 53.4, 52.0, 50.8, 42.0, 39.9,
37.9, 35.4, 30.7, 27.8, 20.5, 20.3, 18.1, 16.3, 15.4, 13.6; HRMS–ESI
(m/z): [M+H]+ calcd for C24H32N2O8: 477.2237; found: 477.2218.
Compound 34b (12 mg, 24%) was also isolated as a clear resin:
Rf 0.56 (1:1, hexanes/EtOAc); 1H NMR (300 MHz, CDCl3): d 7.42–
7.25 (m, 5H), 5.48 (dd, J = 2.3, 12.2 Hz, 1H), 5.17–5.05 (m, 1H),
4.08 (s, 2H), 3.70 (s, 3H), 2.74 (dd, J = 6.4, 10.4 Hz, 1H), 2.50 (dd,
J = 2.4, 15.1 Hz, 1H), 2.45–2.39 (m, 1H), 2.38–2.11 (m, 7H), 1.95
(dd, J = 4.1, 14.1 Hz, 1H), 1.91–1.72 (m, 2H), 1.63 (s, 3H), 1.61–
1.52 (m, 1H), 1.08 (s, 3H); (HRMS–ESI (m/z): [M+H]+ calcd for
C28H32N2O8, 525.2237; found, 525.2217.
6.34. Phenyl oxadiazoles 32a and 32b
Compound 32a (9.2 mg, 17%) was prepared as a clear resin from 7
(42 mg, 103
lmol), EDCI (27 mg, 140
l
mol), HOBt (22 mg,
163 mol), and benzamidoxime (25 mg, 181
l
lmol) utilizing meth-
od D, stirring at room temperature (22 h), and using HPLC purifica-
tion (silica gel, 20?25% EtOAc/hexanes): Rf 0.55 (1:1, hexanes/
EtOAc); 1H NMR (300 MHz, CDCl3): d 8.12–8.04 (m, 2H), 7.58–7.44
(m, 3H), 5.83 (dd, J = 6.3, 10.8 Hz, 1H), 5.22–5.09 (m, 1H), 3.73 (s,
3H), 2.80–2.67 (m, 2H), 2.37–2.24 (m, 4H), 2.24–2.12 (m, 4H), 2.00
(dd, J = 10.5, 12.8 Hz, 1H), 1.86–1.56 (m, 3H), 1.49 (s, 3H), 1.12 (s,
3H); 13C NMR (75 MHz, CDCl3): d 201.7, 176.0, 171.4, 169.9, 169.3,
168.6, 131.5, 128.9, 127.5, 126.1, 74.9, 69.7, 63.9, 53.4, 52.0, 50.8,
42.0, 39.9, 37.8, 35.5, 30.7, 20.6, 18.1, 16.3, 15.5; HRMS–ESI (m/z):
[M+H]+ calcd for C27H30N2O8: 511.2080; found: 511.2069.
Acknowledgments
We thank Eric P. Brown for isolating salvinorin A. This work was
supported by the Stanley Medical Research Institute, NARSAD and
NIH grants DA 17302 and P30 DA 13429 (to LYLC).
Supplementary data
Compound 32b (7.9 mg, 15%) was also isolated as a clear resin:
Rf 0.62 (1:1, hexanes/EtOAc); 1H NMR (300 MHz, CDCl3): d 8.14–
8.01 (m, 2H), 7.59–7.41 (m, 3H), 5.59 (dd, J = 2.0, 12.4 Hz, 1H),
5.23–5.07 (m, 1H), 3.71 (s, 3H), 2.78 (dd, J = 6.5, 10.4 Hz, 1H),
2.62 (dd, J = 2.3, 15.1 Hz, 1H), 2.52–2.47 (m, 1H), 2.36–2.19
(m, 4H), 2.15 (s, 3H), 1.99 (dd, J = 3.0, 13.2 Hz, 1H), 1.95–1.80
(m, 2H), 1.69 (s, 3H), 1.63–1.54 (m, 1H), 1.11 (s, 3H); HRMS–ESI
(m/z): [M+H]+ calcd for C27H30N2O8: 511.2080; found: 511.2059.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2008.12.012.
References and notes
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