Chemoenzymatic route to optically active dihydroxy cyclopenta[b]naphthalenones; precursors for decalin-based bioactive natural products

Article abstract of DOI:10.1016/j.tetasy.2016.11.010

The development of an efficient chemoenzymatic route for the synthesis of optically active dihydroxy cyclopenta[b]naphthalenones; (+)-1,4a-dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta[b]naphthalen-2(4H)-one (+)-10 and (+)-1,8a-dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta[b]naphthalen-2(4H)-one (+)-11 is described. Different lipases and esterases were tested in the enzymatic hydrolysis of the corresponding acetates (±)-4a-hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-cyclopenta[b]naphthalen-1-yl acetate (±)-8, (±)-8a-hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-cyclopenta[b]naphthalen-1-yl acetate (±)-9, CRL (Candida Rugosa Lipase) and PLE (Pig Liver Esterase) were found to be the most effectual enzymes; for (?)-8 by 47% ee with the corresponding dihydroxy; (+)-10 by 98% ee in the presence of CRL; whereas, (?)-8 was obtained with 40% ee with the corresponding dihydroxy, (+)-10 with 58% ee in the PLE hydrolysis. It was concluded that CRL was the best biocatalyst for the substrate (±)-8. Moreover, enzymatic resolution in the presence of CRL yields, (?)-9 with 46% ee with the corresponding dihydroxy derivative; (+)-11 with 98% ee; however, in the presence of PLE, yields (?)-9 with 36% ee as well as the related dihydroxy derivative; (+)-11 with 49% ee respectively. The study concluded that CRL is the best biocatalyst for compounds (±)-8 and (±)-9.

Full text of DOI:10.1016/j.tetasy.2016.11.010

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chemoenzymatic route to optically active dihydroxy cyclopenta
[b]naphthalenones; precursors for decalin-based bioactive natural
products
⇑
Devrim Özdemirhan , Özlem Sarıçelik
_
Department of Chemistry, Abant Izzet Baysal University, 14280 Bolu, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
The development of an efficient chemoenzymatic route for the synthesis of optically active dihydroxy
cyclopenta[b]naphthalenones; (+)-1,4a-dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta[b]naph-
thalen-2(4H)-one (+)-10 and (+)-1,8a-dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta[b]naph-
thalen-2(4H)-one (+)-11 is described. Different lipases and esterases were tested in the enzymatic
hydrolysis of the corresponding acetates ( )-4a-hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-
cyclopenta[b]naphthalen-1-yl acetate ( )-8, ( )-8a-hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-
cyclopenta[b]naphthalen-1-yl acetate ( )-9, CRL (Candida Rugosa Lipase) and PLE (Pig Liver Esterase) were
found to be the most effectual enzymes; for (ꢀ)-8 by 47% ee with the corresponding dihydroxy; (+)-10 by
98% ee in the presence of CRL; whereas, (ꢀ)-8 was obtained with 40% ee with the corresponding dihy-
droxy, (+)-10 with 58% ee in the PLE hydrolysis. It was concluded that CRL was the best biocatalyst for
the substrate ( )-8. Moreover, enzymatic resolution in the presence of CRL yields, (ꢀ)-9 with 46% ee with
the corresponding dihydroxy derivative; (+)-11 with 98% ee; however, in the presence of PLE, yields (ꢀ)-9
with 36% ee as well as the related dihydroxy derivative; (+)-11 with 49% ee respectively. The study con-
cluded that CRL is the best biocatalyst for compounds ( )-8 and ( )-9.
Received 7 October 2016
Accepted 17 November 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
OH
OMe
H
HO
HO
OMe
OH
O
OH
Optically active decalin-based compounds are valuable
substructures of many biologically active natural products.1 In
particular, hydroxy substituted ones are the main units of the
C2-symmetric metabolite HMPY-1 (Fig. 1) and messengers of
hibarimicins.2 Huberamicin, and huberamicinone have been
reported as tyrosine kinase blockers as well as having cytotoxicity
against human colon carcinoma cells, thus make the AB decalin
framework valuable, although it is difficult to construct.
OH
H
OH
OH
HO HO
O
OH
OH
MeO
OH
OMe
Figure 1. Structure of HMPY-1.
OH
framework is the crucial point of its total synthesis in order to
achieve great stereoselectivity and high chemical yield with a short
route. The introduction of the cyclopentenone ring to the decalin
unit in a fused manner of the cyclopentanaphthalenone moiety
with the desired selectivity either via Pauson–Khand reaction,3 or
any other multistep reaction pathways, successfully where each
step requires high selectivity, requires much effort to be achieved,
i.e., the oxidative radical reactions where there is stability of the
radicals with irreversible routes is the main challange.5,6
(+)-Fusarisetin A (Fig. 2), which has remarkable blocking activ-
ity on the metastasis of breast cancer cells, is one of the most
important biologically active natural products, possessing decalin
subunits, the synthesis of which requires a useful level of regio-
and stereoselectivity. As well as occurring as an acinar morphogen-
esis inhibitor,1 it also blocks cell migration and invasion without
significant cytotoxicity, which makes the establishment of this
unique pentacyclic ring system more attractive for many
groups.3–5 The development of the cyclopentanaphthalenone
It is known that Mn-(III)-acetate is an effective single-electron
oxidant for enolizable carbonyl compounds. The construction of
C and D rings of (+)-Fusarisetin A with high diastereoselectivity
⇑
Corresponding author. Tel.: +90 374 254 1000; fax: +90 374 253 4642.
E-mail address: ozdemirhan_d@ibu.edu.tr (D. Özdemirhan).
http://dx.doi.org/10.1016/j.tetasy.2016.11.010
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Özdemirhan, D. ; Sarıçelik, Ö.Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.
tetasy.2016.11.010

2
D. Özdemirhan, Ö. Sarıçelik / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Herein the chiral hydroxy-octahydrocyclopenta[b]naphthalen-
H
C
H
C
H
H
O
O
yl-acetates (ꢀ)-8, (ꢀ)-9 and the corresponding diols (+)-10, (+)-
11 via Pig Liver Esterase and Candida Rugosa Lipase have been
obtained via mediated hydrolysis; 6,6,5 fused tricyclic skeleton
has the advantage of requiring a short synthetic strategy and can
achieve good dia- and regio-selectivities with high chemical yields
and enantioselectivities (Scheme 1).
D
D
OH
OH
H
H
B
B
E
N
E
N
OH
OH
A
A
O
O
O
H
H
O
(+)-Fusarisetin A
Figure 2. The structure of enantiomeric pair of ( )-Fusarisetin A.
(-)-Fusarisetin A
2. Results and discussion
For the construction of dihydroxy-cyclopenta[b]naphthalenone
scaffolds; hydroxy-octahydrocyclopenta[b]naphthalen-yl acetates
rac-8 and rac-9 to the parent enyne templates 1-allyl-2-(prop-2-
yn-1yl)cyclohexanol 4, 2-allyl-1(prop-2-yn-1yl)cyclohexanol 5,
were used as building blocks, synthesized from 1-(cyclohex-1-
en-1yl)pyrrolidine7 1 obtained as a colorless oil with 95% chemical
yield after reflux of cyclohexanone with pyrrolidine in toluene fol-
lowed by vacuum distillation subjected to alkylation reactions
with the corresponding alkyl halides; allylbromide and
propargylbromide in 1,4-dioxane. Hydrolysis with 1% HCl provided
2-allylcyclohexanone 38a,8b and 2-(prop-2yn-1-yl)cyclohexanone
29 in 95% and 82% chemical yield respectively, as the only products
with the expected selectivity.
and chemical yield via Mn(III)-based oxidative radical cyclization is
difficult to achieve.4
From this point of view, the current work provides the corre-
sponding acetates; ( )-8 and ( )-9 of octahydrocyclopenta[b]naph-
thalenone framework, fused tricyclic skeletons via intramolecular
Pauson–Khand reaction, builds the cyclopentanaphthalenone
framework in one pot, followed by regioselective Mn(III)-acetate
oxidation of the a0-position, which offers the corresponding
acetates ( )-8 and ( )-9 subjected to the enzymatic hydrolysis in
the presence of hydrolase type enzyme, i.e., PLE and CRL produce
enantiomerically enriched ones with the corresponding diols, to
create a new stereogenic center, which is a critical point for further
processes, especially in the development of antitumor reagents, nat-
ural products with a cyclopentanaphthalenone framework, and
inhibiting biological activities, i.e., (+)-Fusarisetin-A and its related
natural analogues such as, chaetochalasin A, phomopsichalasin
and diaporthichalasin5 (Fig. 3) with its precursors such as, equisetin,
maklamicin, superstolide, chlorotricolide, tetrodecamycin (Fig. 4)
can be obtained with high enantioselectivity and acceptable
diastereoselectivity in high chemical yield via a short route.3
Herein, the corresponding tertiary homopropargyl alcohol,
2-allyl-1(prop-2-yn-1yl)cyclohexanol
5 and homoallyl alcohol,
1-allyl-2-(prop-2-yn-1yl)cyclohexanol 4 intermadiates,10 required
for the octahydrocyclopenta[b]naphthalenone frameworks were
synthesized by the addition of propargyl bromide (80% wt in
toluene) to the carbonyl group using Zn-Cu couple as described
in our previous work11 in 78% chemical yield with acceptable
diastereoselectivity and via indium-mediated Barbier type
OH
H
N
O
O
H
N
OH
H
H
N
OH
O
H
H
H
O
O
H
O
H
H
OH
H
H
H
H
H
H
Chaetochalasin A
Phomopsichalasin
Diaporthicalasin
Figure 3. (+)-Fusarisetin-A related natural analougous.
O
H
O
NH2
H
H
OH
H
O
NH
HO
O
O
OH
O
N
O
Equisetin
O
Chlorothricolide
O
O
H
OH
O
O
H
H
H
O
OH
O
HO
O
OH
OH
Tetrodecamycin
Figure 4. (+)-Fusarisetin-A precursors.
Chlorothricolide
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D. Özdemirhan, Ö. Sarıçelik / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
O
N
O
HO
HO
e
d
a
b
5
3
4
2
1
c
c
O
O
O
O
O
AcO
OAc
HO
HO
HO
HO
HO
+
f
f
9
rac-
rac-8
7
6
9a
g
g
O
O
O
O
HO
AcO
OAc
OH
+
HO
HO
+
HO
HO
(+)-11
(-)-8
(+)-10
(-)-9
Scheme 1. Reagents and conditions: (a) propargyl bromide, 1,4-dioxane, reflux, HCl (1%); (b) indium powder, allylbromide, DMF, room temperature; (c) Co2CO8, NMO, DCM;
(d) allylbromide, 1,4-dioxane, reflux, HCl (1%); (e) Zn-Cu, THF, propargylbromide, reflux; (f) Co2CO8, NMO, DCM (g) KH2PO4, KHPO4 pH = 7 buffer solution, enzyme.
allylation in DMF, in 81% chemical yield with complete
diastereoselectivity.
methods to obtain homopropargylic and homoallylic alcohols; in
this respect, enyne systems were constructed from a0-allyl and
a0-propargyl cyclohexanones by the addition of propargylic and
allylic nucleophiles. Compounds 5 and 4 were then subjected to
an intramolecular Pauson–Khand reaction, as indicated above, to
yield diastereomers 7 and 6 in 85% and 80% chemical yield respec-
tively, which were then isolated as single diastereomers due to the
more favored chair conformation of the cyclohexane ring. As men-
tioned, the control of stereoselectivity in the construction of
cyclopentanaphthalene ring during the synthesis of bioactive com-
pounds is a great challenge in the enyne systems; for instance, 4
requires protection of the OH group as well as temperature control,
these problems were solved and the corresponding cyclopen-
tanaphthalenone derivatives 7 and 6 were isolated as single
diastereomers (established by 1H NMR spectroscopy) as indicated
above in 85% and 80% chemical yield respectively.
The Pauson–Khand reaction is commonly used for creating
cyclopentenone frameworks, by cobalt-mediated reactions per-
formed by joining alkyne, olefin and carbon monoxide. The
intramolecular version has become more popular in recent years
since building cyclopentanone-fused ring systems requires great
efforts. The optimal reaction conditions, metal catalyst, additive,
solvent and temperature are critical parameters to achieve com-
plete diastereoselectivity3,4 in the construction of the cyclopen-
tanaphthalenone subunit of (+)-Fusarisetin A3 as stated above. To
the best of our knowledge, the intramolecular Pauson–Khand reac-
tion version is not preferred for the construction of the related
frameworks. Tanyeli et al. have recently reported that the
intramolecular Pauson–Khand reaction gave enantiomerically
enriched cyclopentenone-pyrans with spirocyclic motifs as single
diastereomers in good chemical yields and with excellent diastere-
oselectivities.12a With this in mind, we investigated the applicabil-
ity of intramolecular Pauson–Khand reaction to enyne templates 4
and 5, to obtain octahydrocyclopenta[b]naphthalenone frame-
works 8a-hydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta[b]-
The importance of decalin-based bioactive compounds
prompted us to use the regioselective a0-oxidation of the
hydroxy-cyclopentanaphthalenone framework by a single-electron
oxidant; Mn(III)-acetate is efficacious in the oxidation of enones,
which we have experienced in the various a0- and
a
a
-substituted
naphthalen-2(4H)-one
6,
4a-hydroxy-4a,5,6,7,8,8a,9,9a-
,b-unsaturated cyclic aromatic ketones,12b to afford the
octahydro-1H-cyclopenta[b]naphthalen-2(4H)-one 7. For this
purpose, the corresponding enynes 4 and 5 were constructed on
tertiary cyclohexanol moiety and then subjected to an intramolec-
ular Pauson–Khand reaction. In this protocol, cobalt-alkyne com-
plexes were prepared using enyne/dicobalt octacarbonyl in a
molar ratio of 1.0/1.7 in DCM after which N-methyl-morpholine-
N-oxide monohydrate was added as a promotor. Compound 4
was isolated as single diastereomer in 81% chemical yield, leading
to cyclopentanaphthalenone skeleton, 6 by 80% chemical yield,
whereas compound 5 was isolated as diastereomeric mixtures
with d.r 2.33:1 as established by 1H NMR spectroscopy with the
corresponding cyclopentanaphthalenone framework 7 in 78% and
85% chemical yield, respectively. The addition of allylic and
propargylic nucleophiles to carbonyl groups is one of the efficient
corresponding hydroxy cyclopenta[b]naphthalenylacetates, ( )-8
and ( )-9. We also tested Pb (IV)-acetate to compare the yields of
the regioselective a0-oxidation reaction; Mn-(III)-acetate was
established as the more promising one. The most important part
is the enzymatic resolution of the a0-acetoxylated compounds
( )-8 and ( )-9 for the construction of decalin-based bioactive
natural products. From this point of view, the corresponding
oxidated hydroxy-cyclopenta[b]naphthalenones
6
and
7
were
used to obtain hydroxy-cyclopentanaphthalenyl
acetate
frameworks ( )-8 and ( )-9, which were subjected to enzymatic
hydrolysis by using various hydrolase-type enzymes, CAL-A
(Candida Antarctica Lipase A), CAL-B (Candida Antarctica Lipase B)
CRL, PLE, HLE (Horse Liver Esterase), PPL (Porcine Pancreatic
Lipase), by changing substrate:enzyme ratio from 1:0.25 to 1:1,
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D. Özdemirhan, Ö. Sarıçelik / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Table 1
The results of the enzymatic resolution of ( )-4a-hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-cyclopenta[b]naphthalen-1-yl acetate ( )-7 and ( )-8a-hydroxy-2-oxo-
2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-cyclopenta[b]naphthalen-1-yl acetate ( )-6
ca (%)
eep (%)
ees (%)
Ec
b
Entry
Substrate
Enzyme
Temperature (°C)
Time (h)
1
2
3
4
rac-8
rac-8
rac-9
rac-9
CRL
PLE
CRL
PLE
26
22
20
20
15
5
27
2.5
52
56
60
65
98
58
98
49
47
40
46
36
163
5
124
5
a
b
c
c = ees/ees + eep.
Enantiomeric excesses were determined by Daicel Chiralcel OD-H and OJ-H column HPLC analysis.
E = ln [(1 ꢀ c)(1 ꢀ ees)]/ln [(1 ꢀ c)(1 + ees)].13
screening the temperature from 19 °C to 30 °C where CRL and PLE
provided the most promising results.
4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta[b]napthalen-2-(4H)-one
(+)-11 with 98% ee. We have also demonstrated the first short syn-
thetic pathway to 6 and 7 via a Pauson–Khand cycloaddition
applied to enyne templates 4 and 5, which in turn were isolated
as single diastereomers with 80% and 85% chemical yield
respectively, as single diastereomers due to the more favored chair
conformation of the cyclohexane ring.
The most important step is the enantiomeric resolution of
hydroxy cyclopenta[b]naphthalenylacetates ( )-8 and ( )-9 to pro-
duce enantiomerically enriched ones with corresponding optically
active dihydroxy compounds (+)-10 and (+)-11 that could serve as
noteworthy templates for the construction of decalin based bioac-
tive natural products. All of the enantiomeric resolution reactions
were performed using different hydrolase-type enzymes with dif-
ferent substrates: enzyme ratio at different temperatures as men-
tioned above. CRL and PLE provided the most promising results
among the hydrolase-type enzymes. The results are summarized
in Table 1.
4. Experimental
4.1. General
All experiments were carried out in pre-dried glassware (1 h,
150 °C) under an inert atmosphere of Argon. The following reaction
solvents were distilled from the indicated drying agents: dichloro-
methane (P2O5), tetrahydrofuran (sodium, benzophenone), 1H
NMR and 13C NMR spectra were recorded in CDCl3 on Bruker Spec-
trospin Avance DPX-400 spectrometer. 1H (400 MHz) and 13C NMR
were recorded in CDCl3 and the chemical shift as are expressed in
ppm relative to CDCl3 (d 7.26 and 77.0 for 1H and 13C NMR, respec-
tively) as the internal standard. Standard COSY, HETCOR and DEPT
experiments were performed to establish NMR assignments. Infra-
red spectra were recorded on a Thermo Nicolet IS10 ATR-FT-IR
spectrophotometer. HRMS spectra were detected on an Agilent
Technologies 6530 Accurate-Mass Q-TOF LC/MS at National Nan-
otechnology Research Center of Bilkent University (UNAM). Optical
rotations were measured employing a Rudolph research analytical,
autopol III automatic polarimeter. Flash column chromatography
was performed by using thick-walled glass columns with a flash
grade (Merc Silica Gel 60). Reactions were monitored by thin layer
chromatography using precoated silica gel plates (Merc Silica Gel
PF-254),visualized by UV-light and polymolybden phosphoric acid
in ethanol as appropriate. All extracts were dried over anhydrous
magnesium sulfate and solutions were concentrated under vac-
uum by using rotary evaporator.
Enzymatic resolution of hydroxy-cyclopenta[b]naphthalenyl
acetate rac-8 by HLE gave 14% conversion after 62 h of shaking at
29 °C; PPL yielded 17% conversion value after 45 hr at the same
temperature. Low conversion values prompted us to examine other
enzymes; CRL presented the most promising results, with the
conditions of 1:1 (w/w) substrate:enzyme ratio at 26 °C to give
52% conversion with 98.0% ee and 47.0% ee after shaking for
15 h,
(+)-1,4a-dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclo-
penta[naphthalen-2(4H)-one (+)-10 with the corresponding
acetate, (ꢀ)-4a-hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-
1H-cyclopenta[b]naphthalen-1-yl acetate (ꢀ)-8 respectively. In
the case of 50 lL PLE application at 22 °C with pH = 7 phosphate
buffer solution, afford (+)-10 was obtained with 58% ee with (ꢀ)-
8 with 40% ee in 56% conversion after shaking for 5 h. PLE and
CRL were next examined. Initially, CRL was tested at 20 °C, using
(+)-1,8a-dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta
[naphthalen-2(4H)-one (+)-11 with (ꢀ)-8a-hydroxy-2-oxo-2,4,
4a,5,6,7,8,8a,9,9a-decahydro-1H-cyclopenta[b]naphthalen-1-yl
acetate (ꢀ)-9 by 46% conversion after 20 h of shaking; 60% conver-
sion was reached with shaking at 27 h in 98% ee and 46% ee respec-
tively. Finally, PLE-catalyzed hydrolysis of ( )-9 with 50 lL at 20 °C
gave 42% conversion after 4 h of shaking. When the reaction time
was extended to 12 h, 65% conversion was achieved with 49% ee
of corresponding diol (+)-11 with (ꢀ)-9 with 36% ee.
Although many attempts were made to determine the absolute
configuration of all hydroxy-octahydrocyclopenta[b]naphthalen-yl
acetates (ꢀ)-8 and (ꢀ)-9 and the corresponding diols (+)-10 and
(+)-11 by anchoring chiral units such as, 1S-(+)-10-camphorsul-
fonyl chloride and (S)-(+)-mandelic acid, unfortunately, we could
not obtain any feasible crystalline structure suitable for X-ray.
3. Conclusion
Herein, we have reported the first chemoenzymatic route
to optically active dihydroxy cyclopenta[b]naphthalenones;
(+)-1,4a-dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta
4.2. Synthesis of 1-(cyclohex-1-en-1-yl) pyrrolidine 1
[b]naphthalen-2(4H)-one
(+)-10,
(+)-1,8a-dihydroxy-4a,5,6,
7,8,8a,9,9a-octahydro-1H-cyclopenta[b]napthalen-2-(4H)-one (+)-
11; precursors of decalin-based bioactive natural products by
hydrolase type enzymes CRL and PLE. Enzyme CRL was found to
be the best biocatalyst and gave (ꢀ)-4a-hydroxy-2-oxo-
2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-cyclopenta[b]naphthalen-1-yl
acetate (ꢀ)-8 with 47% ee and the corresponding diol (+)-10 with
98% ee together with (ꢀ)-8a-hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,
9,9a-decahydro-1H-cyclopenta[b]naphthalen-1-yl acetate (ꢀ)-9
with 46% ee and the corresponding diol, (+)-1,8a-dihydroxy-
Cyclohexanone (20.0 g, 0.200 mol) was dissolved in cyclohex-
ane (250 mL) after which anhydrous magnesium sulfate (120 g)
was added in one portion under a nitrogen atmosphere. The mix-
ture was then cooled to 0 °C with an ice bath and pyrrolidine
(84.0 ml, 1.00 mol) was added dropwise over a 0.5 h period. After
the reaction mixture had been stirred for an additional 30 min at
0 °C, the ice bath was removed and the reaction mixture was stir-
red overnight at room temperature. Magnesium sulfate was
removed by filtration and rinsed throughly with dry cyclohexane
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tetasy.2016.11.010

D. Özdemirhan, Ö. Sarıçelik / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
(3 ꢁ 50 mL). The combined filtrates were concentrated under
reduced pressure to give the crude product as an orange oil, then
distilled under reduced pressure (69 °C /1 mmHg), to give a color-
less oil (13.36 g, 84% yield).
with 1 M HCl (7 mL) and extracted with diethyl ether (3 ꢁ 30 mL),
dried over MgSO4, and evaporated in vacuo. The crude product was
purified by flash column chromatography using a mixture of ethy-
lacetate and hexane in suitable ratios.
4.2.1. 1-(Cyclohex-1-en-1-yl) pyrrolidine 1
4.3.4. 2-Allyl-1-(prop-2yn-1yl)cyclohexanol (diastereomeric
mixture) 5
Colorless oil, (20.79 g, 95% yield). IR mmax (neat, cmꢀ1): 1652,
1255, 820 1H NMR (CDCl3, 400 MHz): d 4.22 (s, 1H), 2.93 (m, 1H),
2.85 (t, J = 4.0 Hz, 1H), 2.27 (t, J = 7.0 Hz, 1H), 2.12 (m, 2H), 2.03
(m, 3H), 1.71–1.86 (m, 3H), 1.58–1.68 (m, 2H), 1.45–1.52 (m,
3H). 13C NMR (CDCl3, 100.6 MHz): d 143.3, 93.5, 47.4, 27.5, 25.4,
25.2, 25.0, 24.5, 23.2, 23.0. HRMS (ESI-TOF) for C7H12O [M+H]+
was calculated as 152.1362 and found to be 152.1371.
Yellow oil, (18.16 g, 78% yield). IR m
max (neat, cmꢀ1): 3612, 3271,
2124, 1643, 942, 615. Diastereomeric ratio (d.r, 2.33:1 determined
by the integration of 1H NMR signal: d 2.31 d (major), 2.29 d
(minor). 1H NMR (CDCl3, 400 MHz): d 5.66–5.80 (m, 2H), 5.01 (t,
J = 6.9 Hz, 2H), 4.94 (d, J = 9.6 Hz, 2H), 2.35–2.49 (m, 4H), 2.31 (d,
J = 2.45 Hz, 1H), 2.29 (d, J = 2.40 Hz, 1H) 1.99 (t, J = 2.6 Hz, 2H),
1.84–1.92 (m, 2H), 1.65–1.74 (m, 2H), 1.52–1.62 (m, 4H), 1.47–
1.52 (m, 4H) 1.13–1.28 (m, 6H). 13C NMR (CDCl3, 100.6 MHz): d
137.9, 137.8, 115.9, 115.7, 80.8, 80.5, 72.9, 72.8, 71.8, 70.2, 42.6,
42.5, 35.7, 35.5, 33.9, 33.7, 31.3, 31.2, 27.5, 27.3, 25.2, 25.1, 21.7,
4.3. Synthesis of a0-allyl 3 and a0-propargyl 2 cyclohexanones
To a stirred solution of anhydrous 1,4-dioxane (20 ml) and
1-(cyclohex-1-en-1-yl) pyrrolidine
1
(5 g, 33 mmol) at 0 °C
21.6. HRMS (ESI-TOF) for
178.1358 and found to be 178.1394.
C12H18O
[M]+ was calculated as
equipped with a reflux condenser was added dropwise a mixture
of allylbromide (2.855 ml, 33 mmol) or propargylbromide
(3.68 ml, 33 mmol) in anhydrous dioxane (20 mL). The resultant
mixture was stirred for 4 h at reflux followed by the addition of
HCl solution (1%, 12 ml) and then by an additional 3 h reflux by
removing 1,4-dioxane. The reaction mixture was washed with
diethyl ether (3 ꢁ 50 mL). The combined organic phase was washed
with brine (50 mL) dried over MgSO4 and vaporated in vacuo. The
crude products were purified by flash column chromatography
with a mixture of ethylacetate and hexane in suitable ratios.
4.3.5. Synthesis of homoallyl alcohol (isolated as single diaste-
reomer) 4
To a stirred solution of Mg turnings (15 mmol) and iodine (2
pieces) in dry diethyl ether (15 mL) at room temperature equipped
with a reflux condenser, a mixture of allylbromide (11 mmol) was
added dropwise in anhydrous diethyl ether (7 mL). The mixture
was allowed to reflux for 25 min, Then cooled down to 0 °C fol-
lowed by the addition of the corresponding ketone (2-(prop-2-
yn-1yl)cyclohexanone) (10 mmol) in dry diethyl ether (5 mL), in
a dropwise manner. The resultant mixture was stirred for 4 h.
The reaction mixture was hydrolyzed with saturated ammonium
chloride solution (20 mL) and then with HCl (3 mL). The resultant
mixture was extracted with diethyl ether (3 ꢁ 30 mL). The com-
bined organic phase was washed with brine (20 mL), dried over
MgSO4 and evaporated in vacuo. The crude products were purified
by flash column chromatography with a mixture of ethylacetate
and hexane in suitable ratios.
4.3.1. 2-Allylcyclohexanone 3
Colorless oil, (18.05 g, 95% yield). IR mmax (neat, cmꢀ1): 1715,
1651, 925. 1H NMR (CDCl3, 400 MHz): d 5.72–5.83 (m, 1H), 5.04
(d, J = 1.0 Hz, 1H), 4.98–5.01 (m, 1H), 2.50–2.57 (m, 1H), 2.24–
2.42 (m, 2H), 2.09–2.16 (m, 2H), 1.94–2.08 (m, 1H), 1.81–1.88
(m, 1H), 1.60–1.73 (m, 2H), 1.53 (d, J = 7.0 Hz, 1H), 1.35 (dq,
J = 12.0 and 3.5 Hz, 1H). 13C NMR (CDCl3, 100.6 MHz): d 212.4,
136.5, 116.2, 50.3, 42.0, 33.8, 33.4, 27.9, 24.9 HRMS (ESI-TOF) for
C9H14
O
[M]+, was calculated as 138.1045 and found to be
138.1054.
4.3.5.1. 1-Allyl-2-(prop-2-yn-1-yl)cyclohexanol (isolated as sin-
gle diastereomer) 4.
Yellow oil, (16.28 g, 81% yield). IR mmax
4.3.2. 2-(Prop-2yn-1yl)cyclohexanone 2
(neat, cmꢀ1): 3629, 3284, 2131, 957, 621. 1H NMR (CDCl3,
400 MHz): d 5.69–5.89 (m, 1H), 5.04–5.08 (m, 1H), 5.02 (d,
J = 1.2 Hz, 1H), 2.38 (td, J = 4.5 and 12.0 Hz, 1H), 2.29 (m, 3H),
2.16 (qd, J = 2.0 and 5.4 Hz, 1H), 1.94 (t, J = 2.7 Hz, 1H), 1.66–1.78
(m, 2H), 1.56–1.66 (m, 1H), 1.62 (bs, 1H), 1.36–1.56 (m, 3H),
1.22–1.40 (m, 1H), 1.10–1.22 (m, 1H). 13C NMR (CDCl3,
100.6 MHz): d 134.6, 118.5, 83.8, 72.3, 67.7, 44.6, 43.1, 36.9, 27.7,
25.4, 21.5, 18.5. HRMS (ESI-TOF) for C12H18O [M]+ was calculated
as 178.1358 and found to be 178.1385.
Colorless oil, (15.35 g, 82% yield). IR mmax (neat, cmꢀ1): 3379,
2137, 1707, 695. 1H NMR (CDCl3, 400 MHz): d 2.62 (ddd, J = 2.7,
4.5 and 17.0 Hz, 1H), 2.47–2.54 (m, 1H), 2.40–2.46 (m, 1H), 2.35
(t, J = 2.6 Hz, 1H), 2.20–2.35 (m, 1H), 2.16–2.23 (m, 1H), 2.09–
2.13 (m, 1H), 1.96 (t, J = 2.6 Hz, 1H), 1.80–1.95 (m, 1H), 1.65–1.75
(m, 1H), 1.59–1.65 (m, 1H), 1.37–1.48 (m, 1H). 13C NMR (CDCl3,
100.6 MHz): d 210.4, 82.4, 69.3, 49.4, 41.9, 33.0, 26.9, 24.9, 18.7.
HRMS (ESI-TOF) for C9H12O [M]+ was calculated as 136.0888 and
found to be 136.0894.
4.4. General procedure for the Pauson–Khand reaction
4.3.3. Synthesis of homopropargyl alcohol (isolated as diaste-
reomeric mixture) 5
To a solution of 4 or 5 (1.13 mmol) in DCM (15 mL) Co2(CO)8
(0.683 g, 2 mmol) was added and stirred for 2 h with TLC monitor-
ing. Next, NMO (1.32 g, 11.3 mmol) was added and stirred for 24 h.
The crude products were purified by flash column chromatography
using EtOAc/hexane as the eluent.
Initially, Zn-Cu couple preparation is required to be carried out
in an oxygen-free environment. Zinc dust (9.54 g, 74 mmol) was
suspended in distilled water (10 mL), after which an acidic cupric
chloride solution (0.15 M in 5% hydrochloric acid, 22 mL) was
added with vigorous magnetic stirring. When the evolution of
the gas ceased, the suspension was filtered and the black solid
was washed with water until the wash gave a negative test with
6% silver nitrate solution.14
To a stirred mixture of the corresponding ketone 3 (10.23 g)
(74 mmol) and freshly prepared Zn-Cu couple (10.32 g, 80 mmol)
in THF (30 mL), propargyl bromide (11.90 g, 80 mmol, 80 wt % in
toluene) was added dropwise at 0 °C. The mixture was reflux for
5 h by monitoring with TLC. The resulting mixture was hydrolyzed
4.4.1. 4a-Hydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta-
[b]naphthalen-2(4H)-one 7
White solid, (17.86 g, 85% yield), melting point range: 80.2–
80.9 °C. IR mmax (neat, cmꢀ1): 3605, 3375, 1669, 1645 1H NMR
(CDCl3, 400 MHz): d 5.84 (s, 1H), 2.70 (d, J = 9.0 Hz, 2H), 2.48 (dd,
J = 9.0 and 17.6 Hz, 1H), 2.21 (d, J = 14.0 Hz, 1H), 1.95 (dd, J = 2.0
and 17.2 Hz, 1H), 1.74–1.84 (m, 2H), 1.63–1.74(m, 2H), 1.37–1.55
(m, 3H), 1.21–1.32 (m, 2H), 1.20–1.26 (m, 1H), 1.05–1.26 (m,
Please cite this article in press as: Özdemirhan, D. ; Sarıçelik, Ö.Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.
tetasy.2016.11.010

6
D. Özdemirhan, Ö. Sarıçelik / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
2H). 13C NMR (CDCl3, 100.6 MHz): d 208.5, 181.3, 128.7, 71.3, 43.9,
2.56 (m, 1H), 2.16 (dd, J = 6.0 and 14.0 Hz, 1H), 1.79 (d,
J = 17.0 Hz, 1H), 1.58–1.66 (m, 3H), 1.49 (dd, J = 4.0 and 14.0 Hz,
1H), 1.47–1.50 (m, 2H), 1.42 (d, J = 10.0 Hz, 1H), 1.38 (d,
J = 17.0 Hz, 1H), 1.22–1.31 (m, 2H). 13C NMR (CDCl3, 100.6 MHz):
d 208.1, 182.6, 139.2, 128.7, 128.1, 126.9, 125.8, 70.1, 59.8, 47.5,
46.8, 44.7, 39.2, 33.4, 28.7, 25.7, 21.2. HRMS (ESI-TOF) for
42.1, 41.3, 40.6, 38.6, 35.6, 27.0, 24.8, 20.2. HRMS (ESI-TOF) for
C
13H18O2 [M]+, was calculated as 206.1307 and found to be
206.1335.
4.4.2. 8a-Hydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta-
[b]naphthalen-2(4H)-one 6
C
19H22O2 [M+H]+ was calculated as 283.1692 and found to be
White solid, (15.0735 g, 80% yield), melting point range: 76.6–
77.3 °C. IR mmax (neat, cmꢀ1): 3594, 3345, 1665, 1642 1H NMR
(CDCl3, 400 MHz): d 5.77 (s, 1H), 3.13 (bs, 1H), 2.51 (dd, J = 5.3
and 18.5 Hz, 1H), 2.32–2.45 (m, 2H), 2.00 (dd, J = 5.4 and 12.0 Hz,
1H), 1.90 (d, 14.0 Hz, 1H), 1.71 (d, J = 12.0 Hz, 1H), 1.45–1.65 (m,
3H), 1.35–1.45 (m, 2H), 1.22–1.29 (m, 2H), 1.03–1.22 (m, 3H). 13C
NMR (CDCl3, 100.6 MHz): d 209.2, 184.3, 126.8, 70.1, 47.6, 44.6,
42.0, 39.1, 37.4, 33.4, 28.7, 25.7, 21.2. HRMS (ESI-TOF) for
283.1685.
4.5.3. General procedure for CRL (Candida Rugosa Lipase) hyd-
rolysis of rac-8 and rac-9
To a stirred solution of 100 mg of substrate in phosphate buffer
(0.1 M, pH 7.00, 20 mL), 100 mg of CRL were added in one portion
and shaken at suitable temperature. The conversion was moni-
tored by TLC. The reaction mixture was extracted with ethyl acet-
ate, dried over MgSO4, and concentrated under reduced pressure.
Followed by flash-column chromatography which purified the
crude mixture using suitable ethylacetate/hexane as an eluent.
C
13H18O2 [M]+ was calculated as 206.1307 and found to be
206.1343.
4.5. General procedure for the Mn(OAc)3 oxidation of rac-4a-(7)-
or rac-8a-(6)-hydroxy-octahydro-1H-cyclopenta[b]naphthalen-
ones
4.5.4. General procedure for PLE (Pig Liver Esterase) hydrolysis
of rac-8 and rac-9
To a stirred solution of 500 mg of rac-8 or rac-9 in 50 mL of pH
A mixture of Mn(OAc)3 (2.41 g, 9.0 mmol) in cyclohexane
(100 mL) was refluxed for 45 min under a Dean–Stark trap, then
cooled to room temperature. Next, rac-4a or rac-8a-hydroxy-
octahydro-1H-cyclopenta[b]naphthalenones: rac-4a-7 or rac-8a-6
was gradually added and the mixture was allowed to reflux until
the dark brown color disappeared (TLC monitoring). The reaction
mixture was diluted with ethyl acetate (100 mL) and the organic
phase was washed with 1 M HCl (100 mL), saturated NaHCO3
and brine. The organic phase was dried over MgSO4 and evaporated
in vacuo. The crude product was separated by flash column chro-
matography using ethyl acetate/hexane as eluent to obtain the
product.
7.00 phosphate buffer, 50 lL of PLE was added in one portion and
the reaction mixture was stirred at suitable temperature (TLC
monitoring). The reaction mixture was extracted with ethyl acet-
ate, dried over MgSO4 and concentrated under reduced pressure.
This was followed by flash-column chromatography which purified
the crude mixture using suitable ethylacetate/hexane as an eluent.
4.5.4.1. (ꢀ)-8a-Hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-
1H-cyclopenta[b]naphthalen-1-yl acetate (ꢀ)-9 at the end of
CRL hydrolysis.
Colorless oil (37 mg, 37% yield). [
a
]
26 = ꢀ3.2
D
(c 1.00, CHCl3), 46% ee. The enantiomeric excess of the product
was determined by HPLC analysis (Daicel Chiralcel OD-H,
k = 230 nm, n-hexane/2-propanol 98:2, 0.5 mL/min), t1 = 3.1 min
(major) and t2 = 3.7 min (minor). HRMS (ESI-TOF) for C15H20O4
[M+H]+ was calculated as 265.1434 and found to be 265.1447.
4.5.1. ( )-4a-Hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-
cyclopenta[b]naphthalen-1-yl acetate rac-8
Colorless oil, (17.16 g, 75% yield). IR mmax (neat, cmꢀ1): 3612,
3389, 1749, 1685, 1153, 1102 1H NMR (CDCl3, 400 MHz): d 5.94
(s, 1H), 4.76 (d, J = 1.6 Hz, 1H), 2.72 (d, J = 10.8 Hz, 1H), 2.64 (bs,
1H), 2.26–2.33 (m, 1H), 2.04 (s, 3H), 2.00 (d, J = 1.0 Hz, 1H), 1.93–
2.03 (m, 1H), 1.65–1.70 (m, 2H), 1.52–1.59 (m, 2H), 1.37–1.48
(m, 2H), 1.30–1.37 (m, 1H), 1.15–1.26 (m, 3H). 13C NMR (CDCl3,
100.6 MHz): d 201.2, 177.7, 169.7, 126.6, 77.6, 71.0, 46.8, 44.5,
41.7, 38.2, 32.7, 26.7, 24.7, 19.8. 19.6. HRMS (ESI-TOF) for
4.5.4.2.
cyclopenta[b]napthalen-2-(4H)-one (+)-11 at the end of CRL
hydrolysis. Yellow oil (55 mg, 55% yield). [
26 = +9.2 (c 1.0,
(+)-1,8a-Dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-
a]
D
CHCl3), 98% ee. IR mmax (neat, cmꢀ1): 3605, 3612, 3364, 3352,
1671, 1644 1H NMR (CDCl3, 400 MHz): d 5.79 (s, 1H), 3.74 (d,
J = 2.0 Hz, 1H), 2.99–3.03 (m, 1H), 2.34–2.48 (m, 2H), 2.20 (dd,
J = 6.0 and 13.0 Hz, 1H), 1.71 (dd, J = 4.0 and 17.0 Hz, 1H), 1.52–
1.62 (m, 2H), 1.31–1.43 (m, 4H), 1.29–1.34 (m, 2H), 1.24 (d,
J = 17.0 Hz, 1H), 1.13–1.21 (m, 2H). 13C NMR (CDCl3, 100.6 MHz):
d 206.4, 179.3, 122.4, 78.0, 68.8, 43.9, 43.3, 42.2, 32.3, 38.2, 27.5,
24.6, 20.0. HPLC conditions: (Daicel Chiralcel OD-H, k = 230 nm,
n–hexane/2-propanol 98:2, 0.5 mL/min), t1 = 5.5 min (minor) and
t2 = 5.9 min (major). HRMS (ESI-TOF) for C13H18O3 [M+H]+, was cal-
culated as 223.1329, and found to be 223.1345.
C
15H20O4 [M]+ was calculated as 264.1356 and found to be
264.1372.
4.5.2. ( )-8a-Hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-
cyclopenta[b]naphthalen-1-yl acetate rac-9
Colorless oil, (15.26 g, 79% yield). IR mmax (neat, cmꢀ1): 3585,
3215, 3075, 1743, 1672, 1147, 1100. 1H NMR (CDCl3, 400 MHz): d
5.84 (s, 1H), 4.74 (d, J = 3.0 Hz, 1H), 2.37–2.47 (m, 2H), 2.26 (dd,
J = 6.0 and 14.0 Hz, 1H), 2.08 (s, 3H), 2.05 (bs, 1H), 1.61–1.74 (m,
3H), 1.53–1.59 (m, 3H), 1.42–1.47 (m, 2H), 1.26 (d, J = 6.0 Hz,
1H), 1.15–1.24 (m, 2H). 13C NMR (CDCl3, 100.6 MHz): d 200.9,
180.0, 170.4, 123.6, 77.3, 68.2, 44.2, 43.0, 42.3, 38.8, 32.7, 27.6,
24.6, 19.6. HRMS (ESI-TOF) for C15H20O4 [M]+ was calculated as
264.1356 and found to be 264.1393.
4.5.4.3. (ꢀ)-8a-Hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-
1H-cyclopenta[b]naphthalen-1-yl acetate-(ꢀ)-9 at the end of
PLE hydrolysis.
Colorless oil (32 mg, 32% yield). [
a]
26 = ꢀ3.8
D
(c 1.00, CHCl3), 36% ee. HRMS (ESI-TOF) for C15H20O4 [M+H]+, was
calculated as 265.1434 and found to be 265.1447.
4.5.4.4.
(+)-1,8a-Dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-
4.5.2.1.
cyclopenta[b]naphthalen-2(4H)-one
(2.68 g, 13% yield). IR mmax (neat, cmꢀ1): 3612, 3364, 3071, 1674.
1H NMR (CDCl3, 400 MHz):
7.21–7.36 (m, 3H), 7.11 (d,
J = 7.0 Hz, 2H), 5.92 (s, 1H), 3.19 (dd, J = 3.0 and 12.0 Hz, 1H),
3.11 (d, J = 2.0 Hz, 1H), 2.60 (dd, J = 3.0 and 14.0 Hz, 1H), 2.47–
8a-Hydroxy-1-phenyl-4a,5,6,7,8,9,9a-octahydro-1H-
cyclopenta[b]napthalen-2-(4H)-one (+)-11 at the end of PLE
9a. Colorless oil,
hydrolysis.
Yellow oil (59 mg, 59% yield). [a]
26 = +8.9 (c 1.0,
D
CHCl3), 49% ee. IR mmax (neat, cmꢀ1): 3605, 3612, 3364, 3352,
1671, 1644 1H NMR (CDCl3, 400 MHz): d 5.79 (s, 1H), 3.74 (d,
J = 2.0 Hz, 1H), 2.99–3.03 (m, 1H), 2.34–2.48 (m, 2H), 2.20 (dd,
J = 6.0 and 13.0 Hz, 1H), 1.71 (dd, J = 4.0 and 17.0 Hz, 1H),
d
Please cite this article in press as: Özdemirhan, D. ; Sarıçelik, Ö.Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.
tetasy.2016.11.010

D. Özdemirhan, Ö. Sarıçelik / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
1.52–1.62 (m, 2H), 1.31–1.43 (m, 4H), 1.29–1.34 (m, 2H), 1.24 (d,
J = 17.0 Hz, 1H), 1.13–1.21 (m, 2H). 13C NMR (CDCl3, 100.6 MHz):
d 206.4, 179.3, 122.4, 78.0, 68.8, 43.9, 43.3, 42.2, 32.3, 38.2, 27.5,
24.6, 20.0. HRMS (ESI-TOF) for C13H18O3 [M+H]+ was calculated
as 223.1329 and found to be 223.1345.
(c 1.00, CHCl3), 58% ee. HRMS (ESI-TOF) for C13H18O3 [M+H]+ was
calculated as 223.1329 and found to be 223.1353.
Acknowledgment
We are grateful to the Turkish Scientific and Technical Research
Council for provision of the grant (No. 110T169 and 113Z707).
4.5.4.5. (ꢀ)-4a-Hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-
1H-cyclopenta[b]naphthalen-1-yl acetate (ꢀ)-8 at the end of
CRL hydrolysis.
Colorless oil (42 mg, 42% yield). [
a]
26 = ꢀ1.9
References
D
(c 1.00, CHCl3), 47% ee. The enantiomeric excess of the product
was determined by HPLC analysis (Daicel Chiralcel OD-H,
k = 230 nm, n-hexane/2-propanol 98:2, 0.5 mL/min), t1 = 4.6 min
(major) and t2 = 5.1 min (minor). HRMS (ESI-TOF) for C15H20O4
[M]+, was calculated as 264.1356 and found to be 264.1372.
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D
_
m
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1679, 1648 1H NMR (CDCl3, 400 MHz): d 5.95 (s, 1H), 3.89 (d,
J = 2.0 Hz, 1H), 2.82 (d, J = 14.0 Hz, 1H), 2.63–2.76 (m, 2H), 2.35
(dd, J = 4.0 and 14.0 Hz, 1H), 2.00–2.10 (m, 2H), 1.72–1.78 (m,
2H), 1.53 (d, J = 3.0 Hz,1H), 1.59 (d, J = 3.0 Hz, 1H), 1.35–1.51 (m,
3H), 1.21–1.32 (m, 3H). 13C NMR (CDCl3, 100.6 MHz): d 207.6,
178.4, 125.8, 79.1, 71.8, 48.7, 45.6, 43.1, 39.5, 33.8, 28.2, 25.7,
21.2. HPLC conditions: (Daicel Chiralcel OD-H, k = 230 nm, n-hex-
ane/2-propanol 98:2, 0.5 mL/min), t1 = 6.8 min. (minor) and
t2 = 8.1 min. (major). HRMS (ESI-TOF) for C13H18O3 [M+H]+ was cal-
culated as 223.1329 and found to be 223.1353.
9629.
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4.5.4.7. (ꢀ)-4a-Hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-
1H-cyclopenta[b]naphthalen-1-yl acetate (ꢀ)-8 at the end of
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a]
26 = ꢀ1.8
17, 2981–2986.
D
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cyclopenta[b]naphthalen-2(4H)-one (+)-10 at the end of PLE
hydrolysis. Dark yellow oil (35 mg, 35% yield). [
26 = +3.5
(+)-1,4a-Dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-
a]
D
Please cite this article in press as: Özdemirhan, D. ; Sarıçelik, Ö.Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.
tetasy.2016.11.010