Synthetic studies of neoclerodane diterpenes from Salvia divinorum: Selective modification of the furan ring

Article abstract of DOI:10.1016/j.bmcl.2006.03.062

A synthetic sequence has been developed to selectively functionalize the furan ring of the natural product salvinorin A (2a). The synthetic routes described convert the furan ring in 2a into an N-sulfonylpyrrole, oxazole or an oxadiazole. In addition, a p

Full text of DOI:10.1016/j.bmcl.2006.03.062

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3170–3174
Synthetic studies of neoclerodane diterpenes from Salvia divinorum:
Selective modification of the furan ring
Wayne W. Harding,a Matthew Schmidt,a Kevin Tidgewell,a Pavitra Kannan,a
Kenneth G. Holden,b Christina M. Dersch,c
Richard B. Rothmanc and Thomas E. Prisinzanoa,*
aDivision of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, IA 52242, USA
bHolden Laboratories, Carmel, CA 93923, USA
cClinical Psychopharmacology Section, IRP, NIDA, NIH, DHHS, Baltimore, MD 21224, USA
Received 23 February 2006; revised 15 March 2006; accepted 16 March 2006
Available online 18 April 2006
Abstract—A synthetic sequence has been developed to selectively functionalize the furan ring of the natural product salvinorin A
(2a). The synthetic routes described convert the furan ring in 2a into an N-sulfonylpyrrole, oxazole or an oxadiazole. In addition, a
procedure has been found to remove the furan skeleton completely. Biological results indicate that replacement of the furan ring
with an N-sulfonylpyrrole leads to reduced affinity and efficacy at j opioid receptors.
ꢀ 2006 Elsevier Ltd. All rights reserved.
15
G-protein coupled, seven transmembrane segment
O
receptors (GPCRs or 7TM receptors) are the largest
16
14
superfamily of proteins in the body.1,2 Currently, more
than 60% of drugs target GPCRs.3 One class of GPCRs
are opioid receptors. These receptors are particularly
intriguing members of this family in that they are acti-
vated both by endogenously produced opioid peptides
and by exogenously administered opioid drugs, such as
morphine (1) (Fig. 1).4 There are at least three opioid
receptor subtypes, l, d, and j.4 Opioid receptor ligands
are among the most effective analgesics known but are
also highly addictive drugs of abuse.5 New opioid recep-
tor ligands are needed to gain a greater understanding of
the mechanisms of opioid tolerance and dependence, as
well as, to provide new insight into the design of more
effective treatments for pain.
13
12
CH3
O
O
N
H
H
9
R
H
1
4
O
17
8
7
3
5
CO2Me
18
O
HO
OH
1
2a: R = OAc
2b: R = OH
Figure 1. Structures of morphine (1), salvinorin A (2a), and salvinorin
B (2b).
thought to interact with a conserved aspartate residue,
located inside the receptor transmembrane domain and
conserved among all the opioid receptors.8,9 Several re-
cent reports have begun to explore the structure–activity
relationships of 2a at opioid receptors.10,11,7,12–15
Previous work has shown salvinorin A (2a), a neoclero-
dane diterpene from Salvia divinorum, to be a potent and
selective j opioid receptor agonist.6,7 This is unique giv-
en that virtually all opioid ligands feature a basic nitro-
gen, which is protonated at physiological pH and is
As part of our program to develop novel analgesics with
a potential for reduced tolerance and dependence, we
initiated studies to prepare several heterocyclic replace-
ments for the furan ring present in 2a. This was based
on the activities of salvinicin A and B, as well as, our
goal to reduce the potential for hepatotoxicity seen with
furan containing natural products.16–19 There are few
reported methods for the functionalization of 3-substi-
Keywords: Salvinorin A; Kappa; Opioid; Salvia divinorum;
Heterocycle.
*
Corresponding author. Tel.: +1 319 335 6920; fax: +1 319 335
8766; e-mail: thomas-prisinzano@uiowa.edu
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.03.062

W. W. Harding et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3170–3174
3171
tuted furans.20–23 Previously described methods have de-
tailed the photooxidation of the furan moeity under ba-
sic conditions to form a c-hydroxybutenolide. However,
there are few reports of converting the furan ring to
other heterocycles such as an N-sulfonylpyrrole, oxa-
zole, or oxadiazole. Thus, we set out to develop the
methodologies to alter 2a to help further define our
understanding of the elements important to molecular
recognition at opioid receptors.
onamide at 95 ꢁC in acetic acid afforded a mixture of
methanesulfonylpyrrole 4a (30%) and its C-8 epimer
(25%).25 These compounds, however, were readily
separated by column chromatography. Using similar
methodology, benzenesulfonamides 4b and 4c were pre-
pared in 30% and 23% yield, respectively. As seen with
4a, significant amounts of the C-8 epimers were also
formed (20% and 18%, respectively). Attempts to re-
move the benzenesulfonyl group in 4b using Mg and
MeOH,26 and tetrabutylammonium fluoride27 were
unsuccessful.
Salvinorin A (2a) was isolated from S. divinorum as de-
scribed previously.24 With 2a in hand, we sought to con-
vert the furan ring to a pyrrole (Scheme 1). The
treatment of 2a with bromine in a mixture of CH2Cl2
and methanol at ꢀ30 ꢁC gave the corresponding 2,5-
dimethoxydihydrofuran derivative in 93% yield as a
mixture of cis and trans isomers.15 This alkene was re-
duced with hydrogen and 5% rhodium on carbon as cat-
alyst to afford dimethoxytetrahydrofuran 3 in 92% yield.
The reduction of 3 leads to a mixture of compounds,
presumably containing the 2,5-dimethoxy cis and trans
isomers and appearing as two spots on TLC, that were
not separated. The reaction of dimethoxytetrahydrofu-
ran 3 (as a mixture of compounds) with methanesulf-
Upon first glance, the epimerization of the C-8 position
was not without precedent. Koreeda and co-workers
have previously proposed a complex mechanism for this
epimerization under basic conditions, involving cleavage
of the C-8/9 bond.28,29 Recently, Rizzacasa and co-
workers proposed that this epimerization seen is the re-
sult of enolate formation, followed by protonation from
the opposite face.10 The exact mechanism of this trans-
formation is currently unresolved. However, it was
interesting to note that unlike the previously described
conditions this epimerization occurs under acidic
conditions.
O
O
R1
S
H3CO
O
N
OCH3
O
O
O
O
H
H
H
H
c
O
O
O
O
O
O
CO2Me
CO2Me
4a: R1 = CH3
3
4b: R1 = Ph
4c: R1 = 4-OMePh
a,b
MeO2C
MeO2C
O
N
O
O
N
O
O
O
O
H
H
O
O
O
O
O
O
H
H
d,j,k
d,e,f
g
H
H
H
H
O
O
O
O
O
O
O
O
CO2Me
O
O
8
CO2Me
CO2Me
CO2Me
2a
5
6
d,h,i
N
N
O
O
O
H
H
O
O
O
CO2Me
7
Scheme 1. Reagents and conditions: (a) Br2, MeOH, CH2Cl2; (b) H2, 5% Rh/C, MeOH; (c) appropriate sulfonamide, HOAc, 95 ꢁC; (d) RuCl3Æ3H2O,
NaIO4, CCl4/CH3CN/H2O; (e) EDCI, HOBt, L-serine methyl ester hydrochloride, NEt3, CH2Cl2; (f) Deoxo-Fluor, CH2Cl2; (g) BrCCl3, DBU,
CH2Cl2; (h) EDCI, CH3C(NH2)@NOH, CH2Cl2; (i) toluene, heat; (j) PhOPOCl2, C6H5SeH, NEt3, THF; (k) Bu3SnH, AIBN, toluene.

3172
W. W. Harding et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3170–3174
Table 1. Binding affinities of 4a–4c and 6 at opioid receptors using
125I]IOXY as radioligand33,34
Given the mixture of compounds formed in the hydro-
genation step, it was thought that perhaps this reaction
leads to C-8 epimerization. The two spots of 3 on TLC
were reminiscent of 2b and its C-8 epimer formed upon
hydrolysis of 2a, and thus it was presumed that one spot
corresponded to the C-8 epimer of 3 and the other to the
desired epimer. Subsequently, both spots were isolated
[
Compound
Ki SD (nM)
l
d
j
2aa
4a
4b
4c
6
>1000b
>10,000
>10,000
>10,000
>10,000
>1000b
>10,000
>10,000
>10,000
>10,000
1.9 0.2
840 90
410 30
1
and purified. H NMR of the separated spots indicated
1620 110
8530 550
that neither compound contained any C-8 epimer. Inter-
estingly, the reaction of either spot of 3 with benzene-
sulfonamide in acetic acid afforded a mixture of 4b
and its C-8 epimer. This suggested that C-8 epimeriza-
tion was occurring during the pyrrole formation step.
a Data from Ref. 7.
b Partial inhibitor.
Table 2. Results from [35S]GTP-c-S functional assay carried out in
stably transfected CHO cells containing DNA for human j receptors
To test if the C-8 proton was labile under acidic condi-
tions, 2a was heated in acetic acid at 95 ꢁC overnight. As
expected, this led to a mixture of 2b and its C-8 epimer.
Interestingly, further heating did not increase the
amount of the C-8 epimer of 2b. Energy calculations
indicate that the C-8 epimer of 2a is lower in energy than
2a by approximately 2.2 kcal/mol. Similar calculations
showed that the C-8 epimer of 4a is lower in energy than
4a by approximately 1.7 kcal/mol.
Compound
j Agonism
ED50 SD (nM)
b
Emax
2aa
4a
4b
4c
120
70
2
3
3
5
40 10
3600 580
9160 1900
15190 3590
60
60
a Data from Ref. 7.
b Emax is the percentage at which compound stimulates binding com-
pared to (ꢀ)-U50,488 (500 nM) at j receptors.
Having successfully converted the furan ring in 2a to
an N-sulfonylpyrrole, we focused on preparing other
heterocyclic derivatives of 2a. The reaction of 2a with
NaIO4 and a catalytic amount of RuCl3Æ3H2O in a
mixture of CCl4, acetonitrile, and water afforded the
C-13 acid in 74% yield.15 The C-13 acid was then
coupled with L-serine methyl ester hydrochloride using
N-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride (EDCI) and 1-hydroxybenzotriazole hydrate
(HOBT) to give the corresponding b-hydroxy amide
in 75% yield. Cyclization of the b-hydroxy amide
using bis(2-methoxyethyl)aminosulfur trifluoride (Deo-
xo-Fluor) afforded oxazoline 5 in 74% yield.30 The
conversion of oxazoline 5 to oxazole 6 was accom-
plished in 80% yield by treatment with bromotrichlo-
erated than a 4-carbomethoxyoxazole (6). Diterpenes
4a–4c were then tested for functional activity at j recep-
tors using a [35S]GTP-c-S assay (Table 2).35 As a group,
pyrroles 4a–4c were found to be less active at j receptors
compared to 2a. Interestingly, 4a–4c were found to be
partial agonists compared to (ꢀ)-U50,488 and 2a. N-
Methylsulfonylpyrrole 4a was found to be the most ac-
tive in the series (ED50 = 3600 nM) but was 90-fold less
active than 2a. These results indicate that replacement of
the furan ring with an N-sulfonylpyrrole leads to re-
duced affinity and efficacy at j opioid receptors com-
pared to 2a.
romethane
and
1,8-diazabicyclo[5.4.0]undec-7-en
(DBU).30 It is interesting to note that these conditions
did not result in epimerization at the C-8 position.
This is presumably due to the low temperature, short
reaction time, and bulky nature of DBU. The cou-
pling of C-13 acid with acetamide oxime followed by
heating in toluene afforded oxadiazole 7 in 56%
yield.31 Unfortunately, these conditions lead to the
formation of the corresponding C-8 epimer (11%
yield). Finally, we focused on removing the furan skel-
eton completely from 2a. The coupling of the C-13
acid derivative of 2a with selenophenol was accom-
plished via the mixed anhydride using phenyl dichlo-
rophosphate to give the corresponding phenyl seleno
ester in 64% yield.32 Decarbonylation of the phenyl
seleno ester with tri-n-butyltin hydride and 2,20-azo-
bis(2-methylpropionitrile) (AIBN) in toluene afforded
8 in 70% yield.32
In conclusion, we have provided methodology to
selectively functionalize the furan containing natural
product salvinorin A.36–41 In particular, we have
shown it is possible to convert the furan to either
an N-sulfonylpyrrole, oxazoline, oxazole or oxadia-
zole. Finally, we have described a method to remove
the furan skeleton altogether. Biological results indi-
cate that replacement of the furan ring with an N-sul-
fonylpyrrole leads to reduced affinity and efficacy at j
opioid receptors compared to 2a. Further exploration
of these findings is underway and will be reported in
due course.
Acknowledgments
This work was supported by National Institutes of
Health, National Institute on Drug Abuse Grant
DA18151 (to TEP), and in part by the Intramural Re-
search Program of the NIH, NIDA. The authors also
thank Vic Parcell and Lynn Teesch of the High Resolu-
tion Mass Spectrometry Facility, University of Iowa, for
mass spectral analysis.
Diterpenes 4a–4c and 6 were then evaluated for opioid
receptor affinity (Table 1).35 Generally, replacement of
the furan ring led to decreased affinity at j receptors
compared to 2a. The replacement of the furan ring with
an N-sulfonylpyrrole (4a–4c) was found to be better tol-

W. W. Harding et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3170–3174
3173
30. Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams,
D. R. Org. Lett. 2000, 2, 1165.
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36. Satisfactory 1H and 13C NMR and mass spectral data
were obtained for all final products. Elemental analyses
were with in 0.4%.
37. General procedure: A mixture of 3 (0.20 mg, 0.40 mmol)
and methanesulfonamide (0.08 g, 0.80 mmol) in glacial
acetic acid (4 mL) was heated at 95 ꢁC for 3 h. The mixture
was diluted with water (30 mL) and extracted with ethyl
acetate (2· 30 mL). The combined organic extract was
washed with 1 N NaOH (2· 25 mL) and water (20 mL),
dried (Na2SO4), filtered, and concentrated in vacuo to give
the crude product as an oil. The oil was purified by column
chromatography (eluent: EtOAc/hexanes, 50%) to give
0.06 g (30%) of 4a and 0.05 g (25%) of 8-epi-4a as colorless
oils. Compound 4a: 1H NMR (CDCl3): d 1.12 (3H, s); 1.46
(3H, s); 1.60 (3H, m); 1.81 (1H, dd, J = 3.0, 9.6); 2.09 (1H,
dd, J = 2.4, 11.1); 2.18 (3H, s); 2.19 (2H, m); 2.30 (2H, m);
2.52 (1H, dd, J = 5.1, 13.5); 2.76 (1H, m); 3.16 (3H, s); 3.74
(3H, s); 5.14 (1H, dd, J = 9.3, 10.8); 5.50 (1H, dd, J = 5.1,
12); 6.34 (1H, dd, J = 1.5, 3.0); 7.09 (1H, dd, J = 1.2, 1.5);
7.11 (1H, m); 13C NMR (CDCl3): d 15.1, 16.4, 18.1, 20.5,
30.8, 35.5, 38.1, 42.1, 42.9, 43.5, 51.4, 52.9, 53.6, 64.0, 73.0,
75.0, 111.7, 117.5, 121.3, 128.4, 170.0, 171.0, 171.5, 202.0;
HRESIMS m/z [M+H]+ 510.1803, (calcd for C24H32NO9S,
510.1798); 8-epi-4a: 1H NMR (CDCl3): d 1.07 (3H, s); 1.38
(3H, s); 1.62 (3H, m); 1.82 (2H, m); 2.00 (1H, m); 2.17 (3H,
s); 2.31 (3H, m); 2.44 (1H, dd, J = 3.6, 11.1); 2.79 (1H, dd,
J = 7.4, 8.8); 3.15 (3H, s); 3.74 (3H, s); 5.16 (1H, dd,
J = 9.6, 10.2); 5.27 (1H, dd, J = 6.1, 11.6); 6.37 (1H, dd,
J = 1.6, 3.3); 7.09 (1H, dd, J = 2.3, 3.2); 7.13 (1H, dd, J =
2.0, 2.0); 13C NMR (CDCl3): d 16.1, 18.2, 20.6, 21.2, 30.6,
35.2, 37.7, 42.4, 43.0, 44.9, 47.4, 52.0, 53.5, 65.9, 71.3, 75.0,
112.1, 117.9, 121.3, 127.0, 170.0, 171.5, 173.0, 201.8;
HRESIMS m/z [M+H]+ 510.1798, (calcd for C24H32NO9S,
510.1798).
19. Zhou, S.; Koh, H.-L.; Gao, Y.; Gong, Z.-y.; Lee, E. J. D.
Life Sci. 2004, 74, 935.
38. Preparation of 5: A mixture of the C-13 acid15 (0.03 g,
0.73 mmol), EDCI (0.03 g, 1.93 mmol), HOBT (0.02 g,
1.55 mmol), L-serine methyl ester hydrochloride (0.03 g,
1.45 mmol), and NEt3 (0.3 mL, 2.15 mmol) in CH2Cl2
(30 mL) was stirred at rt for 6 h. The mixture was then
washed sequentially with 2 N HCl (40 mL) and water
(40 mL). The organic layer was dried (Na2SO4), filtered,
and concentrated in vacuo to give the crude product as an
oil. The oil was purified by flash chromatography (eluent:
MeOH/CH2Cl2, 2%) to afford the b-hydroxy amide
(0.03 g, 75%) as a white foam. Deoxo-Fluor (0.12 mL)
was added dropwise with stirring to a solution of the b-
hydroxy amide (0.02 g, 0.39 mmol) in CH2Cl2 (40 mL) at
ꢀ30 ꢁC. The reaction mixture was stirred at ꢀ30 ꢁC for 2 h
and was quenched with saturated NaHCO3 (20 mL). The
organic layer was collected and washed with water
(30 mL), dried (Na2SO4), filtered, and concentrated in
vacuo to give a brown oil. The oil was purified by flash
chromatography (eluent: EtOAc/hexanes, 80%) to afford
20. Kernan, M. R.; Faulkner, D. J. J. Org. Chem. 1988, 53,
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W. W. Harding et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3170–3174
1
0.01 g (74%) of 5 as a white foam. H NMR (CDCl3): d
crude residue. The crude residue was purified by column
chromatography (eluent: EtOAc/hexanes, 40%) to afford
0.03 g (56%) of 7 as an oil: 1H NMR (CDCl3): d 1.12 (3H,
s); 1.48 (3H, s); 1.64 (3H, m); 1.83 (1H, dd, J = 2.7, 9.9);
1.92 (1H, dd, J = 11.1, 13.5); 2.18 (3H, s); 2.29 (4H, m);
2.42 (3H, s); 2.66 (1H, dd J = 6.6, 13.5); 2.74 (1H, dd,
J = 7.2, 9.9); 3.74 (3H, s); 5.15 (1H, dd, J = 9.6, 10.2); 5.74
(1H, dd, J = 6.6, 10.5); 13C NMR (CDCl3): d 11.7, 15.7,
16.5, 18.3, 20.8, 30.9, 35.6, 38.1, 40.1, 42.2, 51.0, 52.2, 53.7,
64.1, 69.7, 75.1, 167.6, 169.4, 170.1, 171.6, 176.0, 201.9;
HRESIMS m/z [M+H]+ 449.1924, (calcd for C22H29N2O8,
449.1940).
1.06 (3H, s); 1.35 (3H, s); 1.55 (3H, m); 1.75 (2H, m); 2.08
(1H, m); 2.14 (3H, s); 2.19 (1H, m); 2.27 (2H, m); 2.50 (1H,
dd, J = 6.6, 13.5); 2.71 (1H, dd, J = 7.2, 9.6); 3.70 (3H, s);
3.78 (3H, s); 4.47 (1H, dd, J = 9.0, 10.8); 4.56 (1H, dd,
J = 8.1, 8.7); 4.76 (1H, ddd, J = 0.6, 7.8, 10.8); 5.14 (2H,
m); 13C NMR (CDCl3): d 15.9, 16.4, 18.3, 20.8, 30.9, 35.4,
38.1, 39.3, 42.2, 50.6, 52.2, 53.0, 53.7, 64.3, 68.1, 70.5, 71.1,
75.1, 167.6, 170.1, 170.2, 171.0, 171.7, 201.9; Anal.
(C24H31NO10Æ1.25H2O): C, H, N.
39. Preparation of 6: BrCCl3 (0.14 g, 0.71 mmol) and DBU
(110 lL, 0.71 mmol) were added sequentially to a solution
of 5 (0.10 g, 0.20 mmol) in CH2Cl2 (30 mL) at 5 ꢁC. The
reaction mixture was stirred for 1.5 h and then quenched
by the addition of saturated NaHCO3 (30 mL). The layers
were separated and the aqueous layer was extracted with
CH2Cl2 (30 mL). The combined CH2Cl2 portion was dried
(Na2SO4) and the solvent was removed under reduced
pressure to afford a crude residue. The residue was purified
by flash chromatography (eluent: EtOAc/hexanes, 40–
50%) to afford 0.08 g (80%) of 6 as a white solid, mp 201–
203 ꢁC: 1H NMR (CDCl3): d 1.13 (3H, s); 1.47 (3H, s);
1.62 (3H, m); 1.82 (1H, dd, J = 2.7, 9.9); 2.06 (1H, s); 2.17
(3H, s); 2.24 (1H, dd, J = 2.7, 11.4); 2.29 (3H, m); 2.60
(1H, dd, J = 6.0, 13.5); 2.77 (1H, dd, J = 5.7, 11.1); 3.75
(3H, s); 3.94 (3H, s); 5.15 (1H, dd, J = 8.4, 11.4); 5.65 (1H,
dd, J = 6.3, 11.4); 8.25 (1H, s); 13C NMR (CDCl3): d 15.5,
16.5, 18.3, 20.7, 30.9, 35.5, 38.2, 39.4, 42.2, 51.1, 52.2, 52.6,
53.7, 64.0, 70.8, 75.2, 133.8, 145.1, 161.8, 161.3, 169.9,
170.0, 171.7, 202.0; Anal. (C24H29NO10): C, H, N.
40. Preparation of 7: A mixture of the C-13 acid15 (0.05 g,
0.12 mmol), EDCI (0.05 g, 0.32 mmol), HOBT (0.04 g,
0.26 mmol), acetamide oxime (0.04 g, 0.28 mmol), and
NEt3 (0.3 mL, 2.15 mmol) in CH2Cl2 (30 mL) was stirred
at rt for 6 h. The mixture was then washed sequentially
with 2 N HCl (40 mL) and water (40 mL). The organic
layer was dried (Na2SO4), filtered, and concentrated in
vacuo to give the crude ester. A solution of the ester in
toluene (30 mL) was then heated at reflux overnight. The
solvent was removed under reduced pressure to afford a
41. Preparation of 8: NEt3 (71 lL, 0.5 mmol) and phenyl
dichlorophosphate (50.3 lL, 0.34 mmol) were added to a
solution of C-13 acid15 (0.07 g, 0.17 mmol) in THF
(20 mL) at 0 ꢁC. After 30 min, NEt3 (117 lL, 0.84 mmol)
and selenophenol (71 lL, 0.68 mmol) were added and
the solution was warmed to room temperature. Et2O
(100 mL) was added and the mixture was washed with
saturated NaCl (50 mL). The organic portion was dried
(Na2SO4) and the solvent was removed under reduced
pressure to afford a crude oil. The oil was purified by
column chromatography (eluent: EtOAc/hexanes, 40%)
to afford 0.06 g of the phenyl seleno ester. A solution of
the phenyl seleno ester (0.06 g, 0.11 mmol), tri-n-butyltin
hydride (87 lL, 0.33 mmol), and a catalytic amount of
AIBN (0.007 g) in toluene (20 mL) was heated at reflux
for 3 h. The solvent was then removed under reduced
pressure to afford a crude residue. The crude residue
was purified by column chromatography (eluent: EtOAc/
hexanes, 40%) to afford 0.03 g (70%) of 8 as a white
1
solid, mp 203–206 ꢁC: H NMR (CDCl3): d 1.09 (3H, s);
1.29 (1H, m); 1.36 (3H, s); 1.57 (2H, m); 1.61 (1H, s);
1.71 (1H, m); 1.80 (1H, dd, J = 3.3, 12.0); 2.07 (1H, m);
2.19 (3H, s); 2.30 (3H, m); 2.77 (1H, dd, J = 6.9, 9.9);
3.74 (3H, s); 4.31 (1H, dd, J = 6.0, 12.0); 4.41 (1H, m);
5.15 (1H, dd, J = 9.6, 10.5); 13C NMR (CDCl3): d 16.4,
17.7, 18.4, 20.8, 30.9, 35.1, 37.0, 38.2, 42.4, 49.9, 52.2,
53.8, 65.2, 65.5, 75.3, 170.2, 171.8, 172.6, 202.1; Anal
(C19H26O7): C, H, O.