Synthesis of an Iridoid-Inspired Compound Collection and Discovery of Autophagy Inhibitors

Article abstract of DOI:10.1021/acs.joc.6b01185

Iridoids comprise a large group of monoterpenoid natural products displaying a diverse array of biological activities ranging from neurotrophic to anti-inflammatory and anti-tumorigenic properties. Therefore, the development of concise synthesis routes to compound collections inspired by the structural features of these natural products is of particular relevance for chemical biology and medicinal chemistry. Herein we describe a samarium diiodide-mediated synthesis of a small, focused iridoid-inspired compound collection. Characterization of these iridoid analogues in biological assays revealed novel small-molecule inhibitors of autophagy.

Full text of DOI:10.1021/acs.joc.6b01185

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Article
Synthesis of an Iridoid-Inspired Compound
Collection and the Discovery of Autophagy Inhibitors
Peter Schroeder, Jonathan O. Bauer, Carsten Strohmann, Kamal Kumar, and Herbert Waldmann
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01185 • Publication Date (Web): 28 Jun 2016
Downloaded from http://pubs.acs.org on June 29, 2016
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Synthesis of an IridoidꢀInspired Compound Collection and the Discovery of
Autophagy Inhibitors
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Peter Schröder , Jonathan O. Bauer , Carsten Strohmann , Kamal Kumar* , and Herbert
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1,2
Waldmann*
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Max Planck Institute of Molecular Physiology, OttoꢀHahnꢀStr. 11, 44227 Dortmund,
Germany.
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Technical University Dortmund, Faculty of Chemistry and Chemical Biology, OttoꢀHahnꢀ
Str. 6, 44221 Dortmund, Germany.
Corresponding
authors´
eꢀmail:
kamal.kumar@mpiꢀdortmund.mpg.de;
herbert.waldmann@mpiꢀdortmund.mpg.de
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Abstract
Iridoids comprise a large group of monoterpenoid natural products displaying a diverse array
of biological activities ranging from neurotrophic to antiꢀinflammatory and antiꢀtumorigenic
properties. Therefore, the development of concise synthesis routes to compound collections
inspired by the structural features of these natural products is of particular relevance for
chemical biology and medicinal chemistry. Herein we describe a samarium diiodide mediated
synthesis of a small focused iridoidꢀinspired compound collection. Characterization of these
iridoid analogues in biological assays revealed novel small molecule inhibitors of autophagy.
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Introduction
Iridoids represent a large group of cyclopenta[c]pyranꢀbased monoterpenoid natural products
which can be found in several medicinal plants that have been used in folk medicine to treat
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different diseases since ancient times. Multiple studies highlight their various biological
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activities comprising neurotrophic, antiꢀinflammatory, antiviral, antimicrobial, antioxidant
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and antitumorigenic properties. Therefore, their core scaffold structures can be regarded as
biologically prevalidated and may serve as validated starting points for the synthesis of
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naturalꢀproductꢀinspired compound collections with diverse biological activities (Figure 1).
Compound collections embodying biologically relevant molecular scaffolds represent a
valuable source of biologically active molecules which are of great value to chemical biology
to explore complex signaling networks and to identify new therapeutically relevant target
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proteins.
Figure 1: Biologically active iridoids and tricyclopentanoid sesquiterpene silphinene
analogues.
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Results and Discussion
Due to their interesting structural and biological features, several total synthesis
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approaches of wellꢀknown iridoids have been reported. Often, these approaches comprise
multiꢀstep synthetic sequences or display limited potential for compound collection synthesis.
Hence, we aimed to develop a variable and concise synthesis approach towards an iridoidꢀ
inspired compound collection based on the characteristic cyclopenta[c]pyran scaffold as well
as the closely related cyclopenta[c]furan ringꢀsystem found in luzonial 5 and in related
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terpenoids (Figure 1). To this end, we made use of the cyclic pinacol structure as strategic
synthesis element which can be found in the harpagideꢀtype 2 and luzonialꢀtype 5 based
iridoids (Figure 1). Retrosynthetic cleavage of the pinacol unit in desired scaffolds 7 and 8
could be generated by radical coupling of a 1,5ꢀdicarbonyl precursor. Subsequent retroꢀ
Michael addition leads to δꢀlactone 9 and Michaelꢀacceptors 10 (Figure 2).
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Figure 2: Retrosynthetic analysis for the synthesis of cyclopenta[c]pyranꢀbased scaffolds
using a SmI ꢀmediated approach and synthesis of radical cyclization precursors of a)
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cyclopenta[c]pyranꢀ and b) cyclopenta[c]furan ringꢀsystems.
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δꢀLactones 9 are readily accessible precursors that can be assembled from diverse βꢀketoesters
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11 and different ketones or aldehydes 12. For the strategic ringꢀclosing pinacol cyclization
we envisaged to apply a SmI ꢀbased pinacol reaction, which has proven effective in
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stereoselective synthesis approaches before. According to the retrosynthetic considerations
we synthesized substituted δꢀlactones 9 from ethyl 2ꢀmethylꢀ3ꢀoxobutanoate and ketones 12.
In order to avoid formation of diastereomeric mixtures after radical cyclization, we employed
symmetrical ketones instead of aldehyde precursors. Lactones 9 were synthesized in yields of
67ꢀ69% and were subsequently reacted with different Michael acceptors to obtain the
Michaelꢀadducts 13 in moderate to good yields. The αꢀmethyl substitution in lactone 9 served
two different strategic roles in the synthesis. On the one hand it circumvents double Michael
additions and on the other hand it prevents enolization of the cyclic carbonyl group and
thereby dramatically and positively affects the following pinacol cyclization where two intact
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carbonyl moieties are required. The SmI ꢀbased pinacol cyclization was carried out using a
protocol developed by Shibasaki et al. giving access to differently substituted
cyclopenta[c]pyranꢀbased iridoid molecules in moderate yields and with complete
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diastereoselectivity (Figure 3). The desired relative configuration of the cyclization product
was verified by Xꢀray crystallography for compound 7b (Supp. Figure 1), providing evidence
for the cisꢀfused bicyclic system and the cisꢀdihydroxy unit.
In analogy to the method described above, albeit with a slightly modified strategy and
employing inexpensive and easily accessible reagents, the precursors 19 to afford
cyclopenta[c]furan 8 for via radical cyclization were synthesized (Figure 2b). In this regard,
we introduced tetronic acid 14 as a convenient starting material that can be easily converted
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into compound 17 by a Knoevenagel reaction followed by subsequent reduction with
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dihydrogen and Pd/C. The lactones 17 can further react with acrolein to give the desired
dicarbonyl precursors 19 for the pinacol cyclization in moderate yields (Figure 2b).
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Figure 3: Synthesis of hexahydrocyclopenta[c]pyran (7aꢀd) and hexahydrocyclopenta[c]furan
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scaffolds (8aꢀc) by SmI ꢀmediated radical cyclization.
The introduced benzylꢀmoiety served the function delineated above for the methyl group and
provides an additional possibility for diversification. The diastereoselective SmI ꢀmediated
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pinacol cyclisation afforded the desired compounds 8aꢀc in good yields (Figure 3). In order to
assemble a collection of small molecules with cyclopenta[c]pyran and cyclopenta[c]furan
ringꢀsystem, the dihydroxyl function was utilized as a synthetic handle for a regioselective
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c,2a
esterification; a modification found in numerous natural occurring iridoids.
To this end,
we chose the scaffolds with a secondary alcohol function (7aꢀb and 8aꢀc). Acylation with
different cyclic aliphatic and aromatic acyl chlorides provided the desired esters in moderate
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to good yields (Figure 4, Supp. Table 1 and 2 summarize the structures). The relative
configuration and the regioselective esterification of the compounds were proven by twoꢀ
dimensional NMR measurements and Xꢀray crystallography. The crystal structures of
compounds 20a and 21l (Supp. Figures 2 and 3) proved the regioselective esterification and
additionally validated the desired relative configuration of the cisꢀfused bicyclic structures. In
total, a collection of 50 compounds representing two coreꢀscaffolds was synthesized.
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Due to the rich biology of the naturally occurring iridoids, we investigated the compound
collection for possible modulation of prominent cancerꢀrelated genetic programs like the
Hedgehogꢀ and Wntꢀpathway and autophagy. First we evaluated the whole compound
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collection for their ability to inhibit Hedgehog and Wnt signaling in cellꢀbased assays.
Pharmacological inhibition of these developmental pathways is becoming a promising
strategy for the treatment of different cancers and, thus, new small molecule inhibitors with
previously unknown scaffolds are in high demand for chemical biology and medicinal
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chemistry research. Unfortunately, no inhibitor of these pathways was identified. In
addition, we evaluated the compound collection for inhibition of autophagy. The
dysregulation of this essential lysosomal degradation pathway is involved in diverse human
diseases and plays a crucial role in the development and chemoꢀresistance of various
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cancers. Considering the complexity of autophagy and its modulation by numerous
signaling cascades, fundamental knowledge about its regulation and therapeutic practicality is
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still in its infancy. The identification of autophagy modulators is thus of high importance.
Particularly, the identification and application of autophagy inhibitors can help to explore the
role of this pathway for the development and maintenance of cancer and can deliver valuable
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insights for a potential therapeutic application especially for drug resistant tumors.
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Figure 4: Regioselective esterification of scaffolds 7 and 8 to synthesize a small compound
collection. Cy = cyclohexyl.
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Gratifyingly, screening of the compound collection in a cellꢀbased assay based on the reports
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of Balgi and Peppard et al, revealed eleven compounds inhibiting autophagy with IC ꢀ
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values in the range of 4.7ꢀ11.3 µM (Table 1 and Supp. Table 1 and 2). While the small
molecules with cyclopenta[c]pyran scaffold yielded only one active molecule (compound
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0m, IC50 = 5.7 ± 1.5 µM), several of the cyclopenta[c]furan embodying small molecules
with a paraꢀsubstituted (either fluorine or methoxy) benzylꢀmoiety at the core structure
displayed inhibitory properties. The parent scaffolds 8b and 8c itself did not show any activity
that highlights the significance of appending functional groups in scaffolds with diverse
reagents during generation of a compound library.
Furthermore, aromatic ester moieties, bearing trifluoromethylꢀ, monoꢀ or dihalogenatedꢀ
substitution patterns, seem to be required for activity. Compounds containing cycloalkylꢀ or
unsubstituted aromatic ester functions did not show any promising inhibition of autophagy or
exhibited only weak activity (21f and 21q, Table 1). The best inhibition potencies were found
for compounds 21h and 21s bearing a metaꢀbromobenzoyl unit irrespective of the presence of
a paraꢀfluorineꢀ or a paraꢀmethoxybenzylꢀmoiety at the core structure. Somewhat lower
inhibition potency was observed for the corresponding compounds decorated with a paraꢀ
trifluoromethylbenzoyl unit (21j and 21t) whereas introduction of a 3,5ꢀdichlorobenzoyl
moiety further decreased the activity (21m and 21v). Changes in the chlorine substitution
pattern or removal of one chlorine atom in the benzoyl unit (21i and 21l) induced only
marginal differences in the inhibition potency. Interestingly, analogous cyclopenta[c]pyranꢀ
based compounds 20g, 20h, 20i, 20j and 20k (Figure 4, Supp. Table 1) did not show any
detectable activity in autophagy thus demonstrating the necessity of the fiveꢀfive bicyclic core
scaffold structure in 21. Taken together, these observations clearly indicate a defined structure
activity relationship within only a small subꢀcollection of compounds comprising 11
autophagy inhibitors with IC50 values in the low micromolar range that can definitely be
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improved in a further medicinal chemistry campaign. To the best of our knowledge, there
are no reports about iridoids or iridoidꢀinspired compounds showing inhibition of autophagy.
Table 1: Compounds inhibiting autophagy in cellꢀbased experiments. IC50 values (µM) were
measured with n = 3; n.a. = not active.
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Compd.
R
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Autophagy IC50 [µM]
8b
F
H
H
n.a.
n.a.
8c
OMe
21f
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F
8.8 ± 0.8
4.8 ± 0.7
21h
21i
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6.5 ± 1.4
6.1 ± 3.7
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21q
OMe
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21s
21t
OMe
OMe
4.7 ± 0.3
5.0 ± 2.1
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OMe
11.3 ± 0.9
Conclusion
In summary, we have developed a concise strategy for the synthesis of an iridoidꢀinspired
compound collection using a samarium diiodideꢀmediated pinacolꢀcyclization approach as
strategic key element. The described approach affords access to two distinct core frameworks
i.e. the hexahydrocyclopenta[c]pyranꢀ and the hexahydrocyclopenta[c]furan from readily
available starting materials, in less than 5 steps. In analogy to the structure of naturally
occurring iridoids, we utilized a regioselective esterification for further derivatization of the
core scaffolds to assemble a collection of 50 compounds. The relative configuration of the
scaffolds and the selective esterification were proven by Xꢀray structures. Moreover, we
evaluated the whole compound collection for the inhibition of autophagy and the cancerꢀ
related Wntꢀ and Hedgehog pathways in cellꢀbased assays. Gratifyingly, the analysis
unraveled 11 compounds that inhibit autophagy at low micromolar concentrations. These
results support the use of naturalꢀproduct inspired compound collections in combination with
cellꢀbased assays for the identification of new biologically active agents in chemical biology
and medicinal chemistry research.
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Experimental section
All air and moisture sensitive reactions were carried out under an argon atmosphere using
standard Schlenk techniques. Commercially available chemicals and solvents were used
without further purification. Solvents for chromatography were laboratory reagent grade or
HPLC grade. Analytical thinꢀlayer chromatography (TLC) was performed on silica gel
aluminium plates with Fꢀ254 indicator. Compounds were visualized by irradiation with UV
light or potassium permanganate staining. Flash column chromatography was performed with
silica gel 60 (particle size 0.035ꢀ0.070 nm). Solvent mixtures for chromatography are
understood as volume/volume. Melting points were determined on a microscopic apparatus
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and were uncorrected. HꢀNMR and CꢀNMR were recorded on 400, 500, and 600 MHz
instruments using CDCl , CD OD, acetoneꢀD , DMSOꢀD as solvents. Data are given in the
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following order: chemical shift (δ) values are reported in ppm with the solvent resonance as
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internal standard (CDCl
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: δ = 7.26 ppm for H, δ = 77.16 ppm for C; CD
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OD: δ = 3.31 ppm
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1
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for H, δ = 49.00 ppm for C; DMSOꢀD
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: δ = 2.50 ppm for H, δ = 39.52 ppm for C).
Multiplicities are indicated as: brs (broadened singlet), s (singlet), d (doublet), dd (double
doublet), t (triplet), app. t (apparent triplet), q (quartet), m (multiplet) and coupling constants
are given in Hertz (Hz). High resolution mass spectra were recorded on a LTQ Orbitrap mass
spectrometer. Preparative HPLC purification of compound 20f was carried out using a
reversedꢀphase C18 column (diameter 10 mm). Method (C18): flow rate 6.0 mL/ min, from
10% A to 100% A over 45 min (using B as coꢀsolvent); (A = acetonitrile, B = water).
1) General procedure A: βꢀketolactone synthesis
A solution of diisopropylamine (5.6 eq.) in dry tetrahydrofuran (0.6M) was cooled to 0 °C and
nꢀBuLi solution (1.6M in hexane, 5.6 eq.) was added dropwise. The solution was stirred for
further 45 min and ethyl 2ꢀmethylacetoacetate (2.0 eq.) was added slowly over 20 min at the
same temperature. After 10 min the ketone (1.0 eq.) was added dropwise and stirred for 30
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4
5
6
7
8
9
min. Water was added and the biphasic mixture was stirred at ambient temperature for 3 h and
extracted three times with diethyl ether. The aqueous phase was acidified with conc.
hydrochloric acid (to pH 1) and extracted three times with dichloromethane. The combined
4
dichloromethane phases were washed with brine and dried over MgSO . The solvent was
10
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59
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completely removed under reduced pressure and the residue was purified by flash
chromatography on silica gel (ethyl acetate/petroleum ether).
Representative example:
6,6-Diethyl-4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one (9a)
A solution of diisopropylamine (3.5 mL, 29.4 mmol) in dry tetrahydrofuran (50 mL) was
cooled to 0 °C and nꢀBuLi solution (1.6M in hexane, 18.4 mL, 29.4 mmol) was added
dropwise. The solution was stirred for further 45 min and ethyl 2ꢀmethylacetoacetate (1.5 mL,
10.5 mmol) was added slowly over 20 min at the same temperature. After 10 min 3ꢀpentanone
(555 µL, 5.3 mmol) was added dropwise and stirred for 30 min. Water (140 mL) was added
and the biphasic mixture was stirred at ambient temperature for 3 h and extracted three times
with diethyl ether (40 mL). The aqueous phase was acidified with conc. hydrochloric acid (to
pH 1) and extracted three times with dichloromethane (150 mL). The combined
dichloromethane phases were washed with brine (150 mL) and dried over MgSO . The
4
solvent was completely removed under reduced pressure and the residue was purified by flash
chromatography on silica gel (30% ethyl acetate/petroleum ether).
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1
Colorless solid (650 mg, 67%); mp 89ꢀ90 °C; H NMR (400 MHz, DMSOꢀD ) δ 10.41 (bs,
6
13
1
H), 2.47 (s, 2H), 1.71ꢀ1.53 (m, 7H), 0.82 (d, J = 7.5 Hz, 6H); C NMR (126 MHz, DMSOꢀ
D
6
17 3
) δ 167.3, 163.5, 96.6, 80.2, 34.5, 29.1, 8.5, 7.7; HRMS (ESI) m/z calcd for C10H O
+
[
M+H] 185.1172, found 185.1174.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4-Hydroxy-3,6,6-trimethyl-5,6-dihydro-2H-pyran-2-one (9b)
1
Colorless solid (285 mg, 69%); mp 136ꢀ137 °C; H NMR (500 MHz, DMSOꢀD
6
) δ 10.40 (bs,
13
1
H), 1.62 (s, 3H), 1.31 (s, 6H); C NMR (126 MHz, DMSOꢀD
6
) δ 167.3, 163.7, 96.5, 75.8,
+
3
8.7, 27.2, 8.5; HRMS (ESI) m/z calcd for C H O [M+H] 157.0859, found 157.0860.
8
13
3
2
) General procedure B: Knoevenagel reaction
Tetronic acid (1.0 eq.) was dispersed in the appropriate aldehyde (3.0 eq.) and treated with
conc. hydrochloric acid (1.1 eq.) at ambient temperature. The mixture was rapidly stirred until
solidification occurs. The solid was dispersed in a small amount of diethyl ether and filtered.
The residue was washed three times with small portions of water and subsequently three times
with small portions of diethyl ether. The residue was dried under reduced pressure and used
without further purification in the reduction with Pd/C.
Representative example:
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1
0
(E/Z)-3-(4-Methoxybenzylidene)furan-2,4(3H,5H)-dione (16c)
Tetronic acid (200 mg, 2.0 mmol) was dispersed in anisic aldehyde (730 µL, 6.0 mmol) and
treated with conc. hydrochloric acid (220 µL, 2.2 mmol) at ambient temperature. The mixture
was rapidly stirred until solidification occurs. The solid was dispersed in a small amount of
diethyl ether (4 mL) and filtered. The residue was washed three times with small portions of
water (8 mL) and subsequently three times with small portions of diethyl ether (8 mL). The
residue was dried under reduced pressure and used without further purification (mixture of
E/Z isomers) in the reduction with Pd/C.
1
Yellow solid (284 mg, 65%); mp 171ꢀ173 °C; H NMR (500 MHz, DMSOꢀD
6
) δ 8.66ꢀ8.59
(m, 2H), 7.92 (s, 0.3H), 7.89 (s, 0.7H), 7.20ꢀ7.13 (m, 2H), 4.78 (s, 0.6H), 4.67 (s, 1.4H), 3.91
13
(2s, 3H); C NMR (126 MHz, DMSOꢀD ) δ 196.5, 195.1, 170.3, 167.9, 165.2, 164.8, 152.9,
6
1
50.8, 138.3, 137.4, 126.1, 124.8, 114.89, 114.81, 114.77, 114.72, 72.7, 71.6, 55.92, 55.88;
+
HRMS (ESI) m/z calcd for C12
H
11
O
4
[M+H] 219.06519, found 219.06515.
16
(E/Z)-3-Benzylidenefuran-2,4(3H,5H)-dione (16a)
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5
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5
5
5
5
5
6
1
Yellow solid (205 mg, 55%); mp 151ꢀ153 °C; H NMR (400 MHz, DMSOꢀD ) δ 8.59ꢀ8.48
6
(
m, 2H), 7.97 (s, 0.4H), 7.95 (s, 0.6H), 7.75ꢀ7.65 (m, 1H), 7.64ꢀ7.55 (m, 2H), 4.82 (s, 0.7H),
13
4
.70 (s, 1.3H); C NMR (101 MHz, DMSOꢀD
6
) δ 196.4, 195.2, 169.5, 167.0, 152.5, 150.5,
1
34.8, 134.7, 134.3, 133.9, 132.6, 131.8, 129.0, 118.7, 118.6, 72.9, 71.9; HRMS (ESI) m/z
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
calcd for C11
H
9
O
3
[M+H] 189.05462, found 189.05457.
(
E/Z)-3-(4-Fluorobenzylidene)furan-2,4(3H,5H)-dione (16b)
1
Yellow solid (237 mg, 58%); mp 156ꢀ158 °C; H NMR (500 MHz, DMSOꢀD
6
) δ 8.68ꢀ8.61
(
m, 2H), 7.98 (s, 0.3H), 7.96 (s, 0.7H), 7.48ꢀ7.41 (m, 2H), 4.82 (s, 0.7H), 4.70 (s, 1.3H);
1
3
C NMR (126 MHz, DMSOꢀD ) δ 196.3, 195.3, 169.4, 167.1, 165.6 (d, JC-F = 256.5 Hz),
6
1
65.3 (d, JC-F = 256.0 Hz), 151.2, 149.2, 137.9 (d, JC-F = 9.7 Hz), 137.1 (d, JC-F = 9.9 Hz),
29.5 (d, JC-F = 2.8 Hz), 128.6 (d, JC-F = 2.6 Hz), 118.2 (d, JC-F = 2.3 Hz), 118.1 (d, JC-F = 2.0
1
Hz), 116.3 (d, JC-F = 21.9 Hz), 116.2 (d, JC-F = 22.0 Hz), 72.9, 71.9; HRMS (ESI) m/z calcd
+
for C11
H
8
O
3
F [M+H] 207.04520, found 207.04522.
3
2
) General procedure C: reduction using H and Pd/C
To a solution of the appropriate furanꢀ2,4(3H,5H)ꢀdione (1.0 eq.) in methanol (~0.27M) was
added 5% Pd/C (25 mg/ 800 µmol substrate) and the resulting suspension was stirred under
H ꢀatmopshere for 24 h at ambient temperature. The mixture was diluted with methanol and
2
filtered through a small pad of celite. The filtrate was concentrated under reduced pressure
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and the residue was purified by flash chromatography (short column) on silica gel (methanol/
dichloromethane).
Representative example:
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59
60
3-(4-Fluorobenzyl)-4-hydroxyfuran-2(5H)-one (17b)
To a solution of 16b (249 mg, 1.2 mmol) in methanol (5 mL) was added 5% Pd/C (42 mg)
2
and the resulting suspension was stirred under H ꢀatmopshere for 24 h at ambient
temperature. The mixture was diluted with methanol (30 mL) and filtered through a small pad
of celite. The filtrate was concentrated under reduced pressure and the residue was purified by
flash chromatography (short column) on silica gel (8% methanol/dichloromethane).
1
Colorless solid (213 mg, 85%); mp 177ꢀ178 °C; H NMR (400 MHz, DMSOꢀD
6
) δ 12.12 (bs,
1H), 7.22 (dd, J = 8.3, 5.7 Hz, 2H), 7.08 (t, J = 8.9 Hz, 2H), 4.64 (s, 2H), 3.40 (s, 2H);
1
3
6
C NMR (101 MHz, DMSOꢀD ) δ 174.7, 174.0, 160.7 (d, JC-F = 241.3 Hz), 135.6 (d, JC-F =
3.0 Hz), 129.8 (d, JC-F = 7.9 Hz), 114.9 (d, JC-F = 21.1 Hz), 98.3, 66.6, 25.8; HRMS (ESI) m/z
+
calcd for C11
H
10
O
3
F [M+H] 209.0609, found 209.0610.
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5
5
5
5
6
3
-Benzyl-4-hydroxyfuran-2(5H)-one (17a)
1
Colorless solid (272 mg, 89%); mp 168ꢀ170 °C; H NMR (500 MHz, DMSOꢀD
6
) δ 12.06 (bs,
1
3
H), 7.26 (t, J = 7.5 Hz, 2H), 7.20 (d, J = 7.3 Hz, 2H), 7.16 (t, J = 7.2 Hz, 1H), 4.65 (s, 2H),
0
1
2
3
4
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8
9
0
1
2
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8
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0
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8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
.42 (s, 2H); C NMR (126 MHz, DMSOꢀD
6
) δ 174.7, 173.9, 139.5, 128.2, 128.0, 125.8,
+
98.4, 66.5, 26.5; HRMS (ESI) m/z calcd for C H O [M+H] 191.0703, found 191.0702.
1
1
11
3
4
-Hydroxy-3-(4-methoxybenzyl)furan-2(5H)-one (17c)
1
Colorless solid (300 mg, 85%); mp 175ꢀ177 °C; H NMR (400 MHz, DMSOꢀD
6
) δ 12.01 (bs,
1H), 7.11 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 4.63 (s, 2H), 3.70 (s, 3H), 3.34 (s, 2H);
1
3
C NMR (101 MHz, DMSOꢀD ) δ 174.7, 173.6, 157.5, 131.4, 129.0, 113.6, 98.8, 66.5, 55.0,
6
+
25.7; HRMS (ESI) m/z calcd for C12
H
13
O
4
[M+H] 221.0808, found 221.0810.
4) General procedure D: Michael addition
The βꢀketo lactone (1.0 eq.) was dissolved in dry acetonitrile (0.1M for furanꢀ2,4(3H,5H)ꢀ
diones or 0.3M for dihydroꢀ2Hꢀpyranꢀ2,4(3H)ꢀdiones) and acrolein (12.0 eq.) was added. The
mixture was stirred for 3 d and concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel (ethyl acetate/petroleum ether).
Representative example:
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(
±)-3-(6,6-Diethyl-3-methyl-2,4-dioxotetrahydro-2H-pyran-3-yl)propanal (13a)
9
a (290 mg, 1.6 mmol) was dissolved in dry acetonitrile (5.2 mL) and acrolein (1.26 mL, 19.0
mmol) was added. The mixture was stirred for 3 d and the solvent was removed under
reduced pressure. The residue was purified by flash chromatography on silica gel (1:2 ethyl
acetate/petroleum ether).
1
Colorless oil (334 mg, 88%); H NMR (400 MHz, CDCl
3
) δ 9.69 (app. t, 1H), 2.75 (s, 2H),
2
.56ꢀ2.39 (m, 2H), 2.24ꢀ2.13 (m, 2H), 1.74ꢀ1.57 (m, 4H), 1.43 (s, 3H), 0.99ꢀ0.90 (m, 6H);
1
3
C NMR (101 MHz, CDCl
3
) δ 206.4, 200.2, 174.4, 83.4, 55.2, 44.5, 39.3, 31.7, 31.5, 29.3,
+
2
3.2, 7.9, 7.8; HRMS (ESI) m/z calcd for C13
H
21
O
4
[M+H] 241.1434, found 241.1433.
(±)-3-(3,6,6-Trimethyl-2,4-dioxotetrahydro-2H-pyran-3-yl)propanal (13b)
1
Colorless oil (233 mg, 59%); H NMR (500 MHz, CDCl ) δ 9.68 (app. t, 1H), 2.80 (d, J =
3
14.7 Hz, 1H), 2.76 (d, J = 14.7 Hz, 1H), 2.55ꢀ2.39 (m, 2H), 2.26ꢀ2.13 (m, 2H), 1.45 (s, 3H),
1
3
1
.44 (s, 3H), 1.43 (s, 3H); C NMR (126 MHz, CDCl
3
) δ 205.9, 200.1, 174.1, 78.4, 54.7,
+
4
9.1, 39.4, 29.3, 29.2, 29.1, 23.3; HRMS (ESI) m/z calcd for C11
H
17
O
4
[M+H] 213.1121,
found 213.1122.
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(
±)-6,6-Diethyl-3-methyl-3-(3-oxobutyl)dihydro-2H-pyran-2,4(3H)-dione (13c)
Deviating from general procedure D, 9a (80 mg, 434 µmol) was dissolved in dry
tetrahydrofuran (2 mL) and treated at ambient temperature with triethyl amine (6 µL, 43.4
µmol) and methyl vinyl ketone (144 µL, 1.7 mmol). The mixture was stirred overnight and
the solvent was removed under reduced pressure. The resulting residue was purified by flash
chromatography on silica gel (1:2 ethyl acetate/petroleum ether).
1
Colorless oil (78 mg, 71%); H NMR (500 MHz, CDCl ) δ 2.82 (d, J = 14.8 Hz, 1H), 2.68 (d,
3
J = 14.8 Hz, 1H), 2.54ꢀ2.36 (m, 2H), 2.18ꢀ2.06 (m, 5H), 1.73ꢀ1.51 (m, 4H), 1.39 (s, 3H), 0.97
13
(t, J = 7.5 Hz, 3H), 0.91 (t, J = 7.5 Hz, 3H); C NMR (126 MHz, CDCl
3
) δ 206.8, 206.6,
1
74.6, 83.2, 55.0, 44.5, 38.4, 31.8, 31.30, 31.27, 30.0, 22.0, 7.9, 7.7; HRMS (ESI) m/z calcd
+
23 4
for C14H O [M+H] 255.1591, found 255.1593.
(±)-6,6-Diethyl-3-methyl-3-(3-oxopentyl)dihydro-2H-pyran-2,4(3H)-dione (13d)
Deviating from general procedure D, 9a (90 mg, 488 µmol) was dissolved in dry
tetrahydrofuran (2 mL) and treated at ambient temperature with triethyl amine (7 µL, 50
µmol) and ethyl vinyl ketone (139 µL, 1.4 mmol). The mixture was stirred overnight and the
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solvent was removed under reduced pressure. The resulting residue was purified by flash
chromatography on silica gel (1:2 ethyl acetate/petroleum ether).
1
Colorless oil (65 mg, 50%); H NMR (500 MHz, CDCl
3
) δ 2.84 (d, J = 14.8 Hz, 1H), 2.67 (d,
J = 14.8 Hz, 1H), 2.51ꢀ2.34 (m, 4H), 2.20ꢀ2.07 (m, 2H), 1.74ꢀ1.51 (m, 4H), 1.39 (s, 3H), 1.02
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
(
t, J = 7.3 Hz, 3H), 0.98 (t, J = 7.5 Hz, 3H), 0.91 (t, J = 7.5 Hz, 3H); C NMR (126 MHz,
CDCl ) δ 209.5, 206.6, 174.6, 83.2, 55.1, 44.5, 37.1, 36.0, 31.9, 31.5, 31.3, 21.8, 7.9, 7.8, 7.7;
3
+
HRMS (ESI) m/z calcd for C H O [M+H] 269.1747, found 269.1750.
1
5
25
4
(±)-3-(3-Benzyl-2,4-dioxotetrahydrofuran-3-yl)propanal (19a)
1
Colorless oil (92 mg, 79%); H NMR (400 MHz, CDCl
3
) δ 9.68 (app. t, 1H), 7.29ꢀ7.21 (m,
3
H), 7.11ꢀ7.05 (m, 2H), 4.32 (d, J = 17.0 Hz, 1H), 3.51 (d, J = 17.0 Hz, 1H), 3.10 (d, J = 12.9
13
Hz, 1H), 3.02 (d, J = 12.9 Hz, 1H), 2.66ꢀ2.51 (m, 2H), 2.25ꢀ2.09 (m, 2H); C NMR (126
MHz, CDCl ) δ 210.0, 200.0, 176.0, 133.6, 129.6, 129.0, 128.0, 73.3, 54.3, 42.8, 38.5, 26.7;
3
+
HRMS (ESI) m/z calcd for C14
H
15
O
4
[M+H] 247.0965, found 247.0960.
(
±)-3-(3-(4-Fluorobenzyl)-2,4-dioxotetrahydrofuran-3-yl)propanal (19b)
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6
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Colorless oil (135 mg, 54%); H NMR (400 MHz, CDCl ) δ 9.68 (app. t, 1H), 7.05 (dd, J =
3
8
.3, 5.4 Hz, 2H), 6.94 (t, J = 8.7 Hz, 2H), 4.37 (d, J = 17.1 Hz, 1H), 3.60 (d, J = 17.1 Hz, 1H),
.06 (d, J = 13.8 Hz, 1H), 3.00 (d, J = 13.1 Hz, 1H), 2.67ꢀ2.50 (m, 2H), 2.23ꢀ2.06 (m, 2H);
3
1
3
3
C NMR (101 MHz, CDCl ) δ 209.9, 199.9, 175.9, 162.5 (d, JC-F = 247.3 Hz), 131.4 (d, JC-F
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
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7
8
9
0
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4
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8
9
0
=
8.1 Hz), 129.5 (d, JC-F = 3.4 Hz), 116.0 (d, JC-F = 21.5 Hz), 73.3, 54.2, 41.7, 38.5, 26.7;
+
HRMS (ESI) m/z calcd for C H O F [M+H] 265.0871, found 265.0870.
1
4
14
4
(±)-3-(3-(4-Methoxybenzyl)-2,4-dioxotetrahydrofuran-3-yl)propanal (19c)
1
Colorless oil (231 mg, 63%); H NMR (400 MHz, CDCl ) δ 9.70 (app. t, 1H), 7.02 (d, J = 8.7
3
Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 4.33 (d, J = 17.0 Hz, 1H), 3.76 (s, 3H), 3.56 (d, J = 17.0
Hz, 1H), 3.06 (d, J = 13.1 Hz, 1H), 2.99 (d, J = 13.0 Hz, 1H), 2.67ꢀ2.50 (m, 2H), 2.25ꢀ2.08
13
(
m, 2H); C NMR (101 MHz, CDCl
3
) δ 210.4, 200.0, 176.2, 159.4, 130.8, 125.5, 114.4, 73.4,
+
55.3, 54.6, 42.3, 38.7, 26.6; HRMS (ESI) m/z calcd for C15
77.1069.
H
17
O
5
[M+H] 277.1071, found
2
2
5) General procedure E: SmI ꢀbased pinacol reaction
To a suspension of samarium (4.0 eq.) in dry tetrahydrofuran (0.6M) was added
diiodomethane (2.2 eq.) and the mixture was stirred for 1.5 h at ambient temperature. To the
resulting deep blue solution was added a solution of the appropriate precursor (1.0 eq.) in dry
tetrahydrofuran (~0.2M). The mixture was stirred for 30ꢀ45 min and quenched with sat.
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NaHCO solution and diethyl ether. The organic phase was separated and the aqueous layer
3
was extracted two times with small portions of diethyl ether. The combined organic phases
2 4
were washed with brine and dried over Na SO . The solvent was completely removed under
reduced pressure and the residue was purified by flash chromatography on silica gel (ethyl
acetate/petroleum ether).
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Representative example:
(±)-3a,4-Dihydroxy-6a-(4-methoxybenzyl)hexahydro-1H-cyclopenta[c]furan-1-one (8c)
To a suspension of samarium (457 mg, 3.04 mmol) in dry tetrahydrofuran (5 mL) was added
diiodomethane (134 µL, 1.66 mmol) and the mixture was stirred for 1.5 h at ambient
temperature. To the resulting deep blue mixture was added a solution of 19c (210 mg, 0.76
mmol) in dry tetrahydrofuran (3.5 mL). The mixture was stirred for 30ꢀ45 min and quenched
with sat. NaHCO
separated and the aqueous layer was extracted two times with diethyl ether (15 mL). The
combined organic phases were washed with brine (15 mL) and dried over Na SO . The
3
solution (16 mL) and diethyl ether (30 mL). The organic phase was
2
4
solvent was completely removed under reduced pressure and the residue was purified by flash
chromatography on silica gel (1:1 ethyl acetate/petroleum ether).
1
Colorless wax (168 mg, 79%); H NMR (400 MHz, CDCl ) δ 7.27 (d, J = 8.8 Hz, 2H), 6.79
3
(d, J = 8.8 Hz, 2H), 4.01ꢀ3.92 (m, 2H), 3.77 (s, 3H), 3.60 (d, J = 9.5 Hz, 1H), 3.04 (d, J = 13.8
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1
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2
2
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5
5
5
6
1
3
Hz, 1H), 2.96 (d, J = 13.8 Hz, 1H), 2.11ꢀ1.94 (m, 2H), 1.87ꢀ1.66 (m, 2H); C NMR (101
MHz, CDCl ) δ 181.4, 158.6, 131.8, 128.4, 113.7, 83.1, 78.5, 74.2, 56.9, 55.3, 37.5, 33.3,
3
+
31.3; HRMS (ESI) m/z calcd for C15
H
19
O
5
[M+H] 279.12270, found 279.12265.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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8
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6
7
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9
0
1
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3
4
5
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7
8
9
0
(
±)-4a,5-Dihydroxy-3,3,7a-trimethylhexahydrocyclopenta[c]pyran-1(3H)-one (7a)
1
Colorless solid (120 mg, 55%); mp 108ꢀ109 °C; H NMR (500 MHz, CDCl
3
) δ 3.83ꢀ3.80 (m,
1
H), 2.62 (bs, 2H), 2.12ꢀ1.92 (m, 4H), 1.75ꢀ1.68 (m, 2H), 1.57 (s, 3H), 1.41 (s, 3H), 1.40 (s,
1
3
3H); C NMR (126 MHz, CDCl ) δ 177.7, 80.8, 78.7, 78.4, 49.4, 43.7, 36.7, 31.7, 29.8, 29.0,
3
+
21.3; HRMS (ESI) m/z calcd for C11
H
19
O
4
[M+H] 215.1278, found 215.1280.
(
±)-3,3-Diethyl-4a,5-dihydroxy-7a-methylhexahydrocyclopenta[c]pyran-1(3H)-one (7b)
1
Colorless solid (62 mg, 61%); mp 87ꢀ88 °C; H NMR (400 MHz, CDCl
3
) δ 3.83ꢀ3.77 (m,
1H), 3.24 (bs, 2H), 2.07ꢀ1.97 (m, 2H), 2.05ꢀ1.85 (m, 4H), 1.77ꢀ1.55 (m, 4H), 1.35 (s, 3H),
1
3
0
3
2
.94ꢀ0.83 (m, 6H); C NMR (101 MHz, CDCl ) δ 178.0, 85.8, 78.7, 78.2, 49.8, 38.5, 36.6,
3
+
1.9, 31.2, 29.8, 21.0, 8.7, 7.4; HRMS (ESI) m/z calcd for C13
H
23
O
4
[M+H] 243.1591, found
43.1592.
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(
±)-3,3-Diethyl-4a,5-dihydroxy-5,7a-dimethylhexahydrocyclopenta[c]pyran-1(3H)-one (7c)
1
Colorless solid (23 mg, 59%); mp 110ꢀ113 °C; H NMR (600 MHz, CDCl ) δ 3.30 (bs, 2H),
3
2.33ꢀ2.27 (m, 1H), 2.08ꢀ2.01 (m, 1H), 1.96ꢀ1.88 (m, 3H), 1.74ꢀ1.68 (m, 1H), 1.67ꢀ1.59 (m,
13
3
H), 1.46 (s, 3H), 1.41 (d, J = 14.6 Hz, 1H), 1.25 (s, 3H), 0.93ꢀ0.88 (m, 6H); C NMR (151
MHz, CDCl
3
) δ 179.1, 85.0, 82.7, 79.8, 50.2, 37.7, 37.5, 35.0, 32.1, 30.1, 25.0, 22.3, 8.8, 7.3;
+
HRMS (ESI) m/z calcd for C14
H
25
O
4
[M+H] 257.1747, found 257.1748.
(±)-3,3,5-Triethyl-4a,5-dihydroxy-7a-methylhexahydrocyclopenta[c]pyran-1(3H)-one (7d)
1
Colorless wax (26 mg, 63%); H NMR (400 MHz, CDCl
3
) δ 3.21 (bs, 2H), 2.36ꢀ2.28 (m, 1H),
2
.07ꢀ1.89 (m, 4H), 1.75ꢀ1.68 (m, 1H), 1.67ꢀ1.57 (m, 3H), 1.56ꢀ1.47 (m, 5H), 1.44 (d, J = 14.6
1
3
Hz, 1H), 0.98 (t, J = 7.5 Hz, 3H), 0.91 (q, J = 7.4 Hz, 6H); C NMR (101 MHz, CDCl
3
) δ
1
78.9, 85.0, 84.9, 80.4, 50.8, 37.6, 37.0, 32.7, 32.2, 30.2, 27.5, 25.1, 8.9, 7.9, 7.3; HRMS
+
(ESI) m/z calcd for C15
H
27
O
4
[M+H] 271.1904, found 271.1905.
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(
±)-6a-Benzyl-3a,4-dihydroxyhexahydro-1H-cyclopenta[c]furan-1-one (8a)
1
Colorless solid (63 mg, 77%); mp 107ꢀ108 °C; H NMR (500 MHz, CDCl
3
) δ 7.36 (d, J = 7.3
Hz, 2H), 7.30ꢀ7.19 (m, 3H), 4.00 (t, J = 5.1 Hz, 1H), 3.97 (d, J = 9.6 Hz, 1H), 3.61 (d, J = 9.6
Hz, 1H), 3.46 (bs, 1H), 3.09 (d, J = 13.7 Hz, 1H), 3.04 (d, J = 13.7 Hz, 1H), 2.68 (bs, 1H),
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
2.14ꢀ1.98 (m, 2H), 1.87ꢀ1.69 (m, 2H); C NMR (126 MHz, CDCl ) δ 181.1, 136.6, 130.8,
3
1
28.4, 127.1, 83.2, 78.6, 74.2, 56.8, 38.4, 33.5, 31.4; HRMS (ESI) m/z calcd for C H O
14 17 4
+
[
M+H] 249.1121, found 249.1122.
(±)-6a-(4-Fluorobenzyl)-3a,4-dihydroxyhexahydro-1H-cyclopenta[c]furan-1-one (8b)
1
Colorless solid (81 mg, 73%); mp 112ꢀ113 °C; H NMR (400 MHz, CDCl
3
) δ 7.34 (dd, J =
8.8, 5.5 Hz, 2H), 6.95 (t, J = 8.8 Hz, 2H), 4.04 (t, J = 5.1 Hz, 1H), 3.99 (d, J = 9.6 Hz, 1H),
3
2
1
.62 (d, J = 9.6 Hz, 1H), 3.51 (bs, 1H), 3.08 (d, J = 13.8 Hz, 1H), 2.98 (d, J = 13.8 Hz, 1H),
13
.54 (bs, 1H), 2.15ꢀ1.95 (m, 2H), 1.89ꢀ1.69 (m, 2H); C NMR (101 MHz, CDCl
3
) δ 180.8,
62.0 (d, JC-F = 245.5 Hz), 132.4 (d, JC-F = 7.9 Hz), 132.2 (d, JC-F = 3.2 Hz), 115.1 (d, JC-F
=
F
16 4
21.1 Hz), 83.1, 78.7, 74.2, 56.9, 37.5, 33.5, 31.5; HRMS (ESI) m/z calcd for C14H O
+
[M+H] 267.10271, found 267.10267.
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6) General procedure F: esterification of diols
The diol (1.0 eq.) was dissolved in dry dichloromethane (~0.05M) and pyridine (4.0 eq.) and
the appropriate acid chloride (2.0 eq.) were added at ambient temperature. The solution was
stirred overnight, diluted with dichloromethane and washed with water, sat. NaHCO
3
solution
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and brine. The organic phase was dried over MgSO and the solvent was completely removed
4
under reduced pressure. The residue was purified by flash chromatography on silica gel (ethyl
acetate/petroleum ether).
Representative example:
(±)-6a-Benzyl-3a-hydroxy-1-oxohexahydro-1H-cyclopenta[c]furan-4-yl
cyclopentanecarboxylate (21a)
8a (15 mg, 60.4 µmol) was dissolved in dry dichloromethane (1.3 mL) and pyridine (20 µL,
242 µmol) and cyclopentanecarbonyl chloride (15 µL, 121 µmol) were added at ambient
temperature. The solution was stirred overnight, diluted with dichloromethane (20 mL) and
3
washed with water (8 mL), sat. NaHCO solution (8 mL) and brine (8 mL). The organic phase
was dried over MgSO and the solvent was completely removed under reduced pressure. The
4
residue was purified by flash chromatography on silica gel (20% ethyl acetate/petroleum
ether).
1
Colorless wax (16 mg, 79%); H NMR (600 MHz, CDCl
3
) δ 7.37ꢀ7.34 (m, 2H), 7.30ꢀ7.25 (m,
2H), 7.25ꢀ7.21 (m, 1H), 4.96 (t, J = 5.1 Hz, 1H), 4.07 (d, J = 9.7 Hz, 1H), 3.71 (d, J = 9.7 Hz,
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1H), 3.11 (d, J = 13.8 Hz, 1H), 3.09 (d, J = 13.8 Hz, 1H), 2.71ꢀ2.62 (m, 1H), 2.19ꢀ2.12 (m,
13
1
H), 2.10ꢀ2.03 (m, 1H), 1.91ꢀ1.82 (m, 4H), 1.78ꢀ1.65 (m, 4H), 1.64ꢀ1.55 (m, 2H); C NMR
(151 MHz, CDCl
3
) δ 180.1, 175.8, 136.4, 131.0, 128.4, 127.1, 83.9, 79.9, 74.3, 56.7, 43.8,
+
25 5
38.0, 33.3, 30.22, 30.17, 28.8, 25.93, 25.88; HRMS (ESI) m/z calcd for C20H O [M+H]
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
345.1697, found 345.1700.
(
±)-4a-Hydroxy-3,3,7a-trimethyl-1-oxooctahydrocyclopenta[c]pyran-5-yl
cyclopentanecarboxylate (20a)
Colorless solid (14 mg, 82%); mp 100ꢀ101 °C; H NMR (400 MHz, CDCl
1H), 2.84ꢀ2.73 (m, 1H), 2.43 (bs, 1H), 2.18ꢀ1.87 (m, 6H), 1.85ꢀ1.57 (m, 8H), 1.55 (s, 3H),
1
3
) δ 4.82ꢀ4.77 (m,
13
1
3
.43 (s, 3H), 1.42 (s, 3H); C NMR (101 MHz, CDCl ) δ 176.5, 176.2, 80.8, 80.1, 79.2, 49.4,
44.0, 43.0, 36.9, 31.8, 30.2, 30.1, 29.2, 27.5, 26.0, 25.9, 20.1; HRMS (ESI) m/z calcd for
+
C H O [M+H] 311.1853, found 311.1854.
17
27
5
(±)-4a-Hydroxy-3,3,7a-trimethyl-1-oxooctahydrocyclopenta[c]pyran-5-yl
cyclohexanecarboxylate (20b)
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1
Colorless solid (12 mg, 66%); mp 114ꢀ115 °C; H NMR (500 MHz, CDCl ) δ 4.83ꢀ4.79 (m,
3
1
H), 2.43ꢀ2.33 (m, 2H), 2.18ꢀ2.07 (m, 2H), 2.03 (d, J = 14.8 Hz, 1H), 2.00ꢀ1.90 (m, 3H),
1
.86ꢀ1.73 (m, 4H), 1.71ꢀ1.64 (m, 1H), 1.55 (s, 3H), 1.53ꢀ1.40 (m, 8H), 1.37ꢀ1.21 (m, 3H);
1
3
C NMR (126 MHz, CDCl
3
) δ 176.5, 175.5, 80.8, 80.0, 79.2, 49.4, 43.4, 43.0, 36.9, 31.8,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
2
29 5
9.3, 29.2, 29.16, 27.5, 25.8, 25.49, 25.47, 20.2; HRMS (ESI) m/z calcd for C18H O [M+H]
325.20095, found 325.20102.
(
±)-4a-Hydroxy-3,3,7a-trimethyl-1-oxooctahydrocyclopenta[c]pyran-5-yl
propanoate (20c)
Colorless wax (8 mg, 59%); H NMR (500 MHz, CDCl
3-cyclopentyl-
1
3
) δ 4.83ꢀ4.79 (m, 1H), 2.42 (bs, 1H),
2
.38 (t, J = 7.5 Hz, 2H), 2.17ꢀ2.06 (m, 2H), 2.03 (d, J = 14.8 Hz, 1H), 2.00ꢀ1.94 (m, 1H),
13
1
.85ꢀ1.72 (m, 5H), 1.69ꢀ1.48 (m, 9H), 1.43 (s, 3H), 1.42 (s, 3H), 1.15ꢀ1.05 (m, 2H); C NMR
(
126 MHz, CDCl ) δ 176.5, 173.4, 80.8, 80.2, 79.1, 49.4, 43.0, 39.8, 36.8, 33.9, 32.5, 31.8,
3
+
31.3, 29.2, 27.5, 25.3, 20.2; HRMS (ESI) m/z calcd for C19
H
31
O
5
[M+H] 339.2166, found
339.2168.
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