Optically active tertiary alcohols by biocatalysis

Article abstract of DOI:10.1080/00397911.2016.1274032

Initially, chemoenzymatic route to optically active aromatic ring-fused cyclic tertiary alcohols (S)-(–)-1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol-(–)-1b, (S)-(+)-1-methyl-2,3-dihydro-1H-inden-1-ol-(+)-1a has been reported.^[9] CAL-A (lipase-A from Candida antarctica) was found the best biocatalyst for 1b, CAL-A cross linked enzyme aggregate (CLEA) for 1a, with ee values of 20 and 45% and the esters 2b and 2a with ee values 99 and 71%. Then, cyclopent-2-ene anchored tertiary allyl 1a′, homoallyl 1b′ and homopropargyl 1c alcohols have been enzymaticly resolved in a high ee (up to 90%) with 44, 40, and 43% chemical yield, respectively, cyclohex-2-ene anchored tertiary allyl 3a, homoallyl 3b, and homopropargyl 3c alcohols in high ee (up to 97%) too with 42, 45, and 49% chemical yield in turn. Chiral dienes yield the spirocyclic dihydropyrans through ring-closing methathesis with 74 and 78% chemical yields with 90 and 97% ee. Chiral enynes afford the cyclopentenone pyrans through Pauson–Khand reaction with 80 and 81% chemical yields as single diastereomers as reported subsequently.^[1a]

Full text of DOI:10.1080/00397911.2016.1274032

Optically active Tertiary Alcohols by Biocatalysis
Devrim Özdemirhan1
1Department of Chemistry, Abant İzzet Baysal University, Bolu, Turkey
Corresponding author D. Özdemirhan E-mail: ozdemirhan_d@ibu.edu.tr
Abstract
Initially, chemoenzymatic route to optically active aromatic ring fused cyclic tertiary
alcohols (S)-(-)-1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol-(-)-1b, (S)-(+)-1-methyl-2,3-
dihydro-1H-inden-1-ol-(+)-1a has been reported.[9] CAL-A was found the best biocatalyst
for 1b, CAL-A CLEA for 1a, with ee values of 20 % and 45 % and the esters 2b and 2a
with ee values 99 % and 71 %. Then, cyclopent-2-ene anchored tertiary allyl 1a',
homoallyl 1b' and homopropargyl 1c alcohols have been enzymaticly resolved in a high
ee (up to 90%) with 44%, 40% and 43% chemical yield respectively, cyclohex-2-ene
anchored tertiary allyl 3a, homoallyl 3b and homopropargyl 3c alcohols in high ee (up to
97%) too with 42%, 45% and 49% chemical yield in turn. Chiral dienes yield the
spirocyclic dihydropyrans via RCM with 74% and 78% chemical yields with 90% and
97% ee. Chiral enynes afford the cyclopentenone pyrans via PKR with 80% and 81%
chemical yields as single diastereomers as reported subsequently. [1a]
1

Graphical Abstract
KEYWORDS: Tertiary alcohols, enzyme-catalyzed reactions
1. INTRODUCTION
Building blocks containing chiral tertiary alcohol frameworks is of great importance in
the field of pharmauchemistry and natural product industry. Therefore, the synthesis of
enantiopure tertiary alcohols and their esters has attracted considerable attention.[1b-d] In
particular, chiral aromatic fused hydrocarbon compounds such as lipids and steroids.[2]
Especially oxgen-containing derivatives of indane and tetraline are valuable
intermediates for various chiral organic compounds.[3]
The synthesis of optically active tertiary alcohols of ketones such as; α-indanone and α-
tetralone is generally limited [4,5] as well as the enzymatic resolution of aromatic ring
fused tertiary alcohols since there is a great steric hinderance with regard to these
molecules accepting the active site of the enzyme known that the structure of the
substrate strongly effects the enantioselectivity. It has been reported that various
2

hydrolases, PLE (Pig Liver esterase), PPL (Porcine pancreatic Lipase), CRL (Candida
Rugosa Lipase) and CAL-A (Lipase -A from Candida antarctica), are active biocatalysts
toward esters of tertiary alcohols.[6] In particular PLE has been shown to be an active
biocatalyst in the resolution of 3-ethynyl-3-oxbutyryl quiniclidine which afforded R(+)-3-
ethynyl-3-hydroxy-quiniclidine and S-(-)-3-ethynyl-3-hydroxy-quiniclidine in 97 % and
99 % ee, respectively,[7] Furthermore, CAL-A was found to be the most efficient enzyme
for the resolution of (±)-2-phenyl-but-3-yn-2-ol while CRL showed low
enantioselectivity.[8]
Initially, we have reported the results of enzymatic resolution of (±)-1-methyl-2,3-
dihydro-1H-inden-1-ol, (±)-1a and (±)-1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol (±)-
1b (Scheme 1). [9]
Obtaining promising results from the work, it makes us think that the methodology
should be useful in the synthesis of chiral drugs and their building blocks, in this regard
our next attempt major in the enzymatic resolution of various tertiary alcohols
synthesized from α,β-unsaturated cyclic ketones, valuable frameworks for spirocyclic
compounds structurally taking considerable attention; occurence as substructures of
many naturally occuring substances such as plants, fungi, especially marine organisms;
have been a rich source for drugs.[10] Especially, pharmaceutically active substances
containing spiro framework made synthesis and chemical reactivity of spirocyclic
scaffolds an important area of investigation in organic chemistry.[11]
3

As an important subclass, spirocyclic ethers [12] containing dihydropyrans and
dihydrofurans have a junction with cyclic alkanes, alkenes, lactones or heterocyclic
compounds; occuring as subunits of natural products; clementin [13], clerocidin [14] and
theaspirone. [15] Furthermore, large number of biologically active natural and unnatural
compounds based on O-, N- and S-, consisting five- and six-membered heterocycles are
very effectual in the field of pharmaceutical chemistry also building blocks for the
construction of polyfunctionalized forms in where the applications of them have been
increasing in the field of organic optoelectronic materials like light emitting diodes
(LEDs) and organic solar cells.[16]
In spite of having several synthetic methodologies have been applied to obtain
heterocyclic, carbocyclic and especially spirocyclic compounds, the ring closing
methathesis (RCM) reaction becomes a major tool for synthetic organic chemists to
construct the spirocyclic scaffolds. RCM has recently been improved by introducing well
defined molybdenum and ruthenium catalysts developed by Shrock [17] and Grubbs [18]
respectively. Besides, Pauson-Khand reaction has been a most powerful method in the
,
last decade for the synthesis of cyclopentenone ring systems used as building blocks to
obtain natural cyclopentenoids [19] especially possessing spiro junction cyclopenta[c]-
pyran and furan units.
Enantiomerically enriched tertiary allylic, homoallylic and homopropargylic alcohols are
valuable structural frame to obtain cyclic and spirocyclic ethers, such as spirocyclic
4

butenolides chlorotricolide and androlactones, [20] ligands for HIV protease inhibitors [21]
and some other natural product inhibitors as phoslactomycins and leustroducsins.
Although, enzyme catalyzed kinetic resolution of secondary alcohols with various lipases
and esterases has been described with high activity and enantioselectivity, [22] there are
only a few examples of biocatalytic routes for the production of chiral tertiary alcohols
[23] We have already reported the initial studies on the enzyme catalyzed resolution of
aromatic ring fused cyclic tertiary alcohols of α-indanone and α-tetralone.[9] Within this
sphere herein first, we report the results of enzymatic resolution of racemic allylic,
homoallylic and homopropargylic cyclopent-2-en-1-ols (1a'-c) and cyclohex-2-en-1-ols
(3a-c) (Figure 1).
2. DISCUSSION
The enantioselectivity of enzymatic reactions depend upon certain parameters like:
temperature, cosolvent and pH [24] as mentioned before. All reactions were performed by
changing these parameters to determine optimum conditions. Various hydrolases were
tested e.g.; CAL-A-CLEA, CRL, CAL-A, CAL-B, Amano PSC-II on (±)-methyl-1,2,3,4-
tetrahydronaphthalen-1-ol(±)-1b by changing the substrate:enzyme ratio (w/w) from 1:1
to 1:0.25 in the presence of vinyl acetate as the acyl donor.
The results of enzymatic resolution of (±)-1-methyl-1,2,3,4-tetrahydronaphtahlen-1-ol
1b and (±)-1 methyl-2,3 dihydro-1H-inden-1-ol 1a are summarized as shown in Table 1
and 2 respectively.
5

The parent tertiary allylic rac-1a',3a and homoallylic alcohols rac-1b',3b used as
templates for the construction of spirocyclic scaffolds, were synthesized by the addition
of vinylmagnesium bromide and allylmagnesium bromide, respectively, to the
commercially avaliable 2-cyclopenten-1-one and 2-cyclohexen-1-one. Since the same
procedure is not avaliable in the case of propargylation, homopropargylic alcohols rac-1c
and rac-3c were prepared by the addition of propargyl bromide (80 % wt in toluene) to
the carbonyl group using Zn-Cu couple as described in our previous work [26] as shown in
Figure 1.
2.1. Enzymatic Resolution Of Racemic Tert-Allylic, Homoallylic And
Homopropargylic Alcohols
The fundamentally foremost step is the enantiomeric resolution of racemic tertiary
alcohol substrates rac-1a'-c and rac-3a-c by the enzymes to produce the valuable
enantiomerically enriched tert-allylic, homoallylic and homopropargylic alcohols,
respectively, that could serve as noteworthy templates in the construction of
corresponding spirocyclic dihydrofuran and dihydropyran type compounds. All of the
enantiomeric resolution reactions were performed by using various lipases; i.e. CAL-A,
CAL-B, CRL, Amano PS-C II and CAL-A-CLEA with substrate:enzyme ratio (w/w)
1:0.5 at the screening temperature 25 °C to 38 °C in various co-solvents i.e. THF, TBME
and DIPE, and vinyl acetate as an acyl donor. CAL-A-CLEA afforded the most promising
results among the lipases screened in terms of reaction duration and enantioselectivity.
CAL-B and Amano PSC-II showed no activity toward the corresponding tertiary
6

alcohols. These results could be attributed to the lack of a required GGGX-motif located
in the active site of the enzymes, as proposed by Bornscheuer et al. [27, 28] The best results
are summarized in Table 3. Tertiary allylic substrate, rac-1a' resolution (entry 1) gave (-
)-1-vinylcyclopent-2-enol, (-)-1a', and (+)-1-vinylcyclopent-2-nyl acetate, (+)-2a' in 45%
and 52 % ee, respectively, in THF as co-solvent at 26 °C at the end of 50 h shaking.
Besides, rac-3a (entry 2) resulted in (+)-1-vinylcyclohex-2-enol, (+)-3a and (-)-1-
vinylcyclohex-2-enyl acetate, (-)-3b in 55 and 58% ee, respectively, in TBME as co-
solvent at 30 °C by shaking for 75 h. The next attempt was done with the tertiary
homoallylic alcohols rac-1b' and rac-3b, respectively (entries 3 and 4). (-)-1-
Allylcyclopent-2-enol, (-)-1b' (entry 3) was isolated with excellent ee value in the array,
90 % and the corresponding ester (+)-2b' with 85 % ee in THF as co-solvent at 30 °C for
65 h shaking. Furthermore; the enzymatic resolution of compound rac-3b (entry 4)
afforded (-)-1-allylcyclohex-2-enol, (-)-3b in 65 % ee and (+)-1-allylcyclohex-2-enyl
acetate, (+)-4b in 97 % ee which is the highest in the series at 33 °C without any co-
solvent by shaking for 75 h. Finally, the enzymatic resolution of the tertiary
homopropargylic alcohols rac-1c and rac-3c (entries 5 and 6) were tested. (+)-1-(Prop-2-
ynyl)cyclopent-2-enol, (+)-1c and (-)-1-(prop-2-ynyl)cyclopent-2-enyl acetate, (-)-2c
were obtained with 60 % ee and 84 % ee, respectively, by using DIPE as co-solvent at 31
°C for 70 h shaking. However, transesterification reaction of compound rac-3c (entry 6)
afforded (-)-1-(prop-2-ynyl)cyclohex-2-enol, (-)-3c with the lowest ee value in the series
as 25 % whereas, (+)-1-(prop-2-ynyl)cyclohex-2-enyl acetate, (+)-4c was isolated with
72 % ee at 38 °C without any co-solvent by shaking for 96 h.
7

2.2. Rcm Reactıons
The acyclic unsaturated motifs on tert-allylic, homoallylic and homopropargylic alcohol
series 1a'-c and 3a-c together with the alcohol unit for subsequent second acyclic
unsaturated moiety anchoring could make them valuable candidates in terms of
spirocyclic target formation. We have chosen ring closing metathesis (RCM) and
intramolecular Pauson-Khand reaction (PKR) as the methods to build up spirocyclic
molecules.
Initially, the applicability of RCM has been tested on allylic rac-1a' and rac-3a serving
as background reactions. The second acyclic unsaturated unit was tailored by O-
allylation using allyl bromide with KH and tetrabutylammonium iodide (TBAI) in THF
(Figure 2). The diene scaffolds rac-5a and rac-6a were subsequently subjected to RCM
with Grubbs’ first generation catalyst in DCM to afford spirocyclic dihydrofurans rac-7a
and rac-8a in 72% and 75% chemical yields, respectively (Figure 2).
Successful synthesis of spirocyclic dihydrofurans rac-7a and rac-8a triggered us to
investigate the construction of spirocyclic dihydropyran systems using appropriate diene
scaffolds via RCM reaction. tert-homoallylic alcohols (-)-1b' and (+)-3b were chosen as
templates, due to their high ee values, 90% and 97% ee, respectively. Initially, acetate
derivative (+)-4b was transformed into corresponding alcohol (+)-3b with K2CO3 in
MeOH. By applying the mentioned protocol, diene scaffolds (-)-9b and (+)-10b were
isolated with 79% and 85% chemical yields, respectively. Subsequent RCM reaction
8

afforded enantiomerically enriched spirocyclic dihydropyrans (+)-11b and (-)-12b with
74% and 78% chemical yields and with 90% and 97% ee, respectively (Figure 3).
Among the alcohols studied, only homoallylic alcohol derivative 1-allylcyclohex-2-enol
(3b) has been synthesized in an asymmetric manner and already claimed as (R)-
configurated without any optical rotation value.[29] Therefore, we could not make the
optical rotation comparison to find out the absolute configuration of (+)-3b. Although
many attempts have been made to determine the absolute configuration of all allylic,
homoallylic and homopropargylic alcohol derivatives by anchoring chiral units such as;
(1S)-(+)-10-camphorsulfonyl chloride and (S)-(+)-mandelic acid, unfortunately, we could
not obtain any feasible crystalline structure for X-ray analysis.
2.3. Intramolecular Pkr
We also planned to investigate the applicability of intramolecular PKR to build up
cyclopentenone-furan and pyran fused ring systems with spirocyclic motifs on tert-allylic
(1a', 3a), homoallylic (1b', 3b) and homopropargylic (1c, 3c) templates. Initial efforts
have been made to ensure the availability of intramolecular PKR by constructing enynes
tethered to cyclopentene and cyclohexene rings via O-propargylation of tert-allylic
alcohols, rac-1a' and rac-3a using TMS-propargyl bromide and via O-allylation of tert-
homopropargylic alcohols, rac-1c and rac-3c using allyl bromide with KH and
tetrabutylammonium iodide (TBAI) in THF (Figure 4). Cyclopentene and cyclohexene
tethered enynes rac-13a, rac-14a, rac-17c and rac-18c were isolated in 80%, 82%, 80%
and 84% chemical yields, respectively. Subsequently, all enynes were subjected to
9

intramolecular PKR. In this protocol, cobalt alkyne complexes were prepared using
enyne:dicobalt octacarbonyl in a molar ratio of 1.0:1.7 in DCM and then N-methyl-
morpholine N-oxide monohydrate was added as a promoter. All reactions were monitored
by thin layer chromatography (TLC). Enynes leading to pyran fused cyclopentenone
frameworks afforded single diastereomers rac-19c and rac-20c (82% and 85% chemical
yield, respectively), whereas enynes leading to furan fused cyclopentenone derivatives
rac-13a and rac-14a resulted in diastereomeric mixtures rac-15a and rac-16a with 1.33:1
and 1.57:1 ratios established by 1H-NMR spectroscopy in 77 % and 79 % chemical
yields, respectively (Figure 4). The lack of diastereoselectivity in furan fused
cyclopentenone derivatives was presumably due to the less conformational effect of furan
rings on the diastereoselectivity comparing with the most favored chair conformation of
pyran rings as indicated in our previous study. [30]
In the light of the foregoing, enantiomerically enriched tert-homoallylic alcohols (-)-1b'
and (+)-3b were subjected to propargylation to construct the corresponding enynes (+)-
21a and (-)-22a isolated in 82% and 84% chemical yields, respectively (Figure 5).
Subsequent intramolecular PKR afforded enantiomerically enriched pyran fused
cyclopentenone derivatives (-)-23a and (-)-24a with 80% and 81% chemical yields,
respectively, as single diastereomers as expected.
The absolute configurations of both (+)-1a and (+)-1b were assigned as (S), by
comparison of their specific rotation values with the literature data.[4,31] Related to these
results, the absolute configurations of (+)-2a and (-)-2a assigned as (S) and (R),
10

respectively, whereas those of (+)-2b and (-)-2b were assigned as (S) and (R)
respectively.
3. CONCLUSION
Initially we have reported [9] the first enzyme-catalyzed resolution of (±)-1-methyl -2,3-
dihydro-1H-inden-1-ol (±)-1a and (±)-1-methyl-1,2,3,4-tetrahdronaphthalen-1-ol, (±)-1b
by using various hydrolases, that is CAL-A CLEA, CAL-A, CRL and Amano PSC-II.
According to the results obtained, CAL-A-CLEA was the best biocatalyst for 1-methyl-
2,3 dihydro-1H -inden-1-ol (±)-1a in 45 % ee and the corresponding ester with 71 % ee.
Furthermore CAL-A was the best for (±)-1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol (±)-
1b in 20 % ee and the corresponding ester with 99 % ee. Temperature is an important
parameter for in reactions catalyzed by enzymes as mentioned before. [24] In this work 32
°C was the optimum temperature. Compounds (±)-2a-b were easily decomposed at
higher temperatures. In particular, the applied methodology, after the promising results,
should be useful in the synthesis of chiral drugs and building blocks prompted us to study
the enzymatic resolution of various tertiary alcohols synthesized from α,β-unsaturated
cyclic ketones, valuable frameworks for spirocyclic compounds structurally taking
considerable attention; occurence as substructures of many naturally occuring substances
such as plants, fungi, especially marine organisms; have been a rich source for drugs. [10]
In this regard we have demonstrated the first enzyme-catalyzed resolution of tertiary
allylic rac-1a', 3a, homoallylic rac-1b', 3b and homopropargylic alcohols rac-1c, 3c as
the first time subsquently. According to the results obtained, CAL-A-CLEA was found to
be the best biocatalyst, afforded (-)-1-allylcyclopent-2-enol (-)-1b' in 90% and the
11

corresponding ester (+)-2b' with 85% ee together with (-)-1-allylcyclohex-2-enol (-)-3b
in 65% ee and the corresponding ester with 97% ee. The other hydrolases; CAL-A, CAL-
B, CRL and Amano PS-C-II show no activity towards corresponding tertiary alcohols.
This phenomena of CAL-B and Amano PSC-II can be explained by the lack of required
"GGGX-motif" located in the active site of the enzyme to show the activity towards
tertiary alcohols as mentioned by Bornscheuer et al.[27] Furthermore, they[28] also
supported this result by the investigation of the enantiorecognition of tertiary alcohols by
enzymes containing GGGX-motif and also enzymes with GX-pattern; found in most
bacterial lipases and esterases used in biotransformation reactions, where the two groups
differ in the structure of the catalytic site. [32] During the formation of enzyme-substrate
complex in the above research [32] with the GX-type hydrolases they proposed forming a
craggy wall by corresponding amino acid residues in the active site which counteracts the
access of tertiary alcohols. Besides, applicability of RCM has been tested on diene
systems anchored to tert-allylic alcohol backbones to obtain spirocyclic dihydrofuran
compounds. Subsequent application with enantiomerically enriched dienes tethered to
tert-homoallylic template afforded enantiomerically enriched spirocyclic dihydropyran
compounds (+)-11b and (-)-12b, respectively in good chemical yield. We have also
applied intramolecular PKR to enyne systems constructed on tert-allylic and tert-
homopropargylic templates by anchoring propargyl and allyl units, respectively. The
cyclopentenone furans with spirocyclic motifs 15-16a were isolated as diastereomeric
mixture, whereas, pyrans 19-20c were isolated as single diastereomer due to most favored
chair conformation of pyran ring. By using this testing background, enantiomerically
enriched homoallylic templates (-)-1b and (+)-3b were used to build up corresponding
12

enynes (+)-21a and (-)-22a, respectively. Subsequent intramolecular PKR afforded
enantiomerically enriched cyclopentenone pyrans (-)-23a and (-)-24a, respectively, with
spirocyclic motifs as single diastereomers in good chemical yield and excellent
diastereoselectivity.
4. EXPERİMENTAL
All experiments were carried out in pre-dried glassware (1 h, 150 ºC) under an inert
atmosphere of Argon. The following reaction solvents were distilled from the indicated
1
drying agents: dichloromethane (P2O5), tetrahydrofuran (sodium, benzophenone) H-
NMR and 13C-NMR spectra were recorded in CDCl3 on Bruker Spectrospin Avance
DPX-400 spectrometer. 1H (400 MHz) and 13C-NMR were recorded in CDCl3 and the
chemical shift as were expressed in ppm relative to CDCl3 (δ 7.26 and 77.0 for 1H and
13C-NMR, respectively) as the internal standard. Standard COSY, HETCOR and DEPT
experiments were performed to establish NMR assignments. Infrared 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
nanotechnology 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
chromotography 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
13

dried over anhydrous magnesium sulphate and solutions were concentrated under vacuum
by using rotary evaporator.
All of the racemic tertiary alcohols 1a', [33] 1b', [34] 1c, [35-37] 3a, [38] 3b, [29] 3c, [39] [36] [37]
were prepared by reported procedures.
4.1. General Synthesis For The Synthesis Of (±)-1a-B
To a stirred solution of Mg turnings (15 mmol) and iodine (2 pieces) in dry diethyl ether
(7 mL) at 25 0C equipped with a reflux condenser was added dropwise a mixture of
iodomethane (11 mmol) in anhydrous diethyl ether (5 mL). The mixture was allowed to
reflux for 30 min. The mixture was cooled down to 0 0C and the corresponding ketone
(1-indanone or α-tetralone) (10 mmol) in dry diethyl ether (3 mL) was added dropwise.
The resultant mixture was stirred for 2 h. The reaction mixture was hydrolyzed with
sturated ammonium chloride solution (10 mL) and then with 1M HCl (2 mL). The
resultant mixture was extracted with diethyl ether (3×30 mL). The combined organic
extracts was washed with brine (20 mL) and dried over MgSO4 and evaporated in vacuo.
The crude products were prufied by flash column chromatography with a mixture of
solvents of ethyl acetate and hexane at a ratio of 1:8 for 1a and 1:7 for 1b
4.1.1. (±)-1-Methyl-2,3-Dihydro-1H-İnden-1-Ol 1a
Yellow solid: mp 52-55 0C, 83 % yield.
4.1.2. 1-Methyl-1,2,3,4-Tetrahydronaphthalen-1-Ol 1b
14

White solid: mp 68-70 0C, [lit [12]
C] (1.45g, 87 %).
4.2. General Procedure For The Acetylation Reaction Of (±)-1a-B
A 35 % KH (4 mmol) suspension was washed with dry hexane three times, then 5 mL of
dry THF was added. Compounds (±)- 1a-b (2 mmol) were dissolved in 5 mL of dry
diethyl ether and then put into the reaction mixture. After 2 h, the dropwise addition of
acetic anhydride (4 mmol) with tetrabutylammonium iodide (0.2 mmol) was performed.
The reaction mixture was stirred for an additional 2 h, then filtered by washing with
CH2Cl2, dried over MgSO4 and finally evaporated in vacuo. The crude products were
prufied by flash column chromatography with a mixture of solvents of ethyl acetate and
hexane at a ratio of 1:8 for 2a and 1:7 for 2b. [40]
4.2.1 (±). 1-Methyl-2,3-Dihydro-1H-İnden-Yl-Acetate 2a
Yellow oil: (0.71g, 55 %)
4.2.2 (±). 1-Methyl-1,2,3,4-Tetrahydronaphthalen-1-Yl-Acetate 2b.[41]
Yellow oil: (0.77g, 61 %)
4.3 General Procedure For The Transesterification Reaction Of (±)-1a-B
To 100 mg of substrate (±)1a-b and 1 ml (16 mmol equiv) of vinyl acetate, the
corresponding enzyme (i. e . 25 mg of CAL-A, 50 mg of CAL-A-CLEA, 100 mg of
Amano PSC-II, 100 mg of CRL) was added) followed by shaking at 32 C. The mixture
was then monitored by TLC. When the reaction was completed, the mixture was filtered
15

and the filtrate concentrated in vacuo. Purification was done by flash- column
chromatography using ethyl acetate/hexane as the eluent.
4.3.1 (S)-(+)-1-Methyl-2,3-Dihydro-1H-İnden-1-Ol (S)-(+)-1a
Yellow oil: 52 mg, (52 % yield) [α]D26 = +7.9 (c, 1 CHCl3) 45 % ee. The enantiomeric
excess of the chiral product was determined by HPLC analysis ( Daicel, Chiralcel OD-H,
n-hexane/2-propanol 98:2, flow rate 0.5 mL/min, λ= 214 nm t1(S)= 19.8 min. t2(R) = 23.8
min.)
4.3.2. (S)-(+)-1-Methyl-1,2,3,4-Tetrahydronaphthalen-1-Ol, (S)-(+)-1b.
White solid, 50 mg, (50 % yield) [α]D26 = +7.2 (c, 1 CHCl3) 38 % ee. The enantiomeric
excess of the chiral product was determined by HPLC analysis ( Daicel, Chiralcel OJ-H,
n-hexane/2-propanol 98:2, flow rate 0.5 mL/min, λ= 214 nm t1(R)= 18.2 min. t2(S) = 21.6
min.)
4.3.3. (R)-(-)-1-Methyl-2,3, Dihydro-1H-İnden-1-Yl Acetate, (R)-(-)-2a.
Yellow oil, 17 mg, (13 % yield) [α]D26 = -5.0 (c, 0.25, CHCl3) 45 % ee. The
enantiomeric excess of the chiral product was determined by HPLC analysis ( Daicel,
Chiralcel OD-H, n-hexane/2-propanol 98:2, flow rate 0.5 mL/min, λ= 214 nm t1(R)= 9.5
min. t2(S) = 10.9 min.)
4.3.4. (R)-(-)-1-Methyl-1,2,3,4 Tetrahydronaphthalen-1yl Acetate, (R)-(-)-2b
16

Yellow oil, 20 mg, (16 % yield) [α]D26 = -14.3 (c, 0.60, CHCl3) 99 % ee. The
enantiomeric excess of the chiral product was determined by HPLC analysis (Daicel,
Chiralcel OD-H, n-hexane/2-propanol 98:2, flow rate 0.5 mL/min, λ= 214 nm t1(S)= 10.0
min. t2(R) = 10.6 min.)
4.4. Synthesis Of Allylic Rac-1a', 3a And Homoallylic Alcohols Rac-1b', 3b
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 was added dropwise a
mixture of allylbromide (11 mmol) in anhydrous diethyl ether (7 mL). The mixture was
allowed to reflux for 25 min. (In the case of synthesis of allylic alcohols; vinyl
magnesiumbromide 1.0 M in THF (11 mmol) was added dropwise to the dry diethylether
without refluxing at the end of addition). Then cooled down to 0 °C followed by the
addition of the corresponding ketone (cyclopent-2-enone or cyclohex-2-enone) (10
mmol) in dry diethylether (5 mL) was added dropwise. 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 diethyether
(3x30 mL). The combined organic phase was washed with brine (20 mL) and 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.
4.5. Synthesis Of Homopropargyl Alcohols Rac-1c, 3c
Initially Zn-Cu couple preparation required in the oxygen free environment. Zinc dust
(9.54 g, 74 mmol) was suspended in distilled water (10 mL). Acidic cupric chloride
17

solution (0.15 M in 5 % hydrochloric acid, 22 mL) was then added with vigorous
magnetic stirring. When the evoluation 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. [37]
To a stirred mixture of corresponding ketone rac-1c (6.08 g) and rac-3c (7.11 g) (74
mmol) and freshly prepared Zn-Cu couple (10.32 g, 80 mmol) in THF (30mL), propargyl
bromide (11.90 g, 80 mmol, 80 wt % in toluene) was added dropwise at 0 °C. Then the
mixture was reflux for 5 hours by monitoring with TLC. The resulting mixture was
hydrolyzed with 1N HCl (7 mL) and extracted with diethylether (3x30 mL), dried over
MgSO4, and evaporated in vacuo. The crude product was purified by flash column
chromatography using a mixture of ethylacetate and hexane in suitable ratios.
4.6. General Procedure For Enzymatic Resolution Of Rac-1a'-C And Rac-3a-C
To 100 mg of substrate rac-1a'-c and rac-3a-c and 1 mL vinyl acetate with 50 mg of the
enzyme shaked at suitable temperature (26ºC-38ºC). The reaction was followed by TLC.
When it came to the end, the mixture was filtered an the residue was concentrated under
vacuo. Followed by flash-column chromatography purifies the crude mixture using
suitable ethylacetate/hexane as an eluent.
4.6.1. (-)-1-Vinylcyclopent-2-Enol (-)-1a'
Light yellow oil (44 mg, 44% yield). [α]26D= -7.50 (c 0.70, CHCl3), 45% ee. The
enantiomeric excess of the product was determined by HPLC analysis (Daicel Chiralcel
18

OD-H, λ = 215 nm, n-hexane/2-propanol 98:2, 0.5 mL/min), t1= 19.3 min (minor) and t2=
20.6 min (major).
4.6.2. (+)-1-Vinylcyclopent-2-Enyl Acetate (+)-2a'
Yellow oil (35 mg, 25% yield). [α]26D= +7.14 (c 1.0, CHCl3), 52% ee. HPLC conditions:
(Daicel Chiralcel OD-H, λ = 230 nm, n-hexane/2-propanol 98:2, 0.5 mL/min), t1= 15.5
min (major) and t2= 16.6 min (minor). HRMS (ESI-TOF) for C9H13O2 [M+H]+, calcd.
153.0915, found 153.0905.
4.6.3. (-)-1-Allylcyclopent-2-Enol (-)-1b'
Pale yellow oil (40 mg, 40% yield). [α]26D= -4.69 (c 1.10, CHCl3), 90% ee. The
enantiomeric excess of the product was determined by HPLC analysis (Daicel Chiralcel
OD-H, λ = 215 nm, n-hexane/2-propanol 100:0, 1.0 mL/min), t1= 11.5 min (major) and
t2= 15.9 min (minor).
4.6.4. (+)-1-Allylcyclopent-2-Enyl Acetate (+)-2b'
Yellow oil (40 mg, 40% yield). [α]26D= +5.72 (c 1.20, CHCl3), 85% ee. HPLC conditions:
(Daicel Chiralcel OD-H, λ = 215 nm, n-hexane/2-propanol 98:2, 0.5 mL/min), t1= 11.5
min (minor) and t2= 13.7 min (major). HRMS (ESI-TOF) for C10H15O2 [M+H]+, calcd.
167.1072, found 167.1052.
4.6.5. (+)-1-(Prop-2-Ynyl)Cyclopent-2-Enol (+)-1c
19

Yellow oil (43 mg, 43% yield). [α]26D= +3.89 (c 1.40, CHCl3), 60% ee. The enantiomeric
excess of the product was determined by HPLC analysis (Daicel Chiralcel OD-H, λ = 215
nm, n-hexane/2-propanol 98:2, 0.5 mL/min), t1= 24.9 min (minor) and t2= 27.6 min
(major).
4.6.6. (-)-1-(Prop-2ynyl)Cyclopent-2-Enyl Acetate (-)-2c
Yellow oil (32 mg, 24% yield). [α]26D= -6.62 (c 0.50, CHCl3), 84% ee. HPLC conditions:
(Daicel Chiralcel OJ-H, λ = 215 nm, n-hexane/2-propanol 98:2, 0.5 mL/min), t1= 19.8
min (major) and t2 = 21.6 min (minor). HRMS (ESI-TOF) for C10H12O2 [M]+, calcd.
164.0837, found 164.0827.
4.6.7. (+)-1-Vinylcyclohex-2-Enol (+)-3a
Colorless oil (42 mg, 42% yield). [α]26D= + 5.86 (c 1.0, CHCl3), 55 % ee. The
enantiomeric excess of the product was determined by HPLC analysis (Daicel Chiralcel
OJ-H, λ = 215 nm, n-hexane/2-propanol 98:2, 0.5 mL/min), t1= 13.8 min (major) and t2 =
16.4 min (minor).
4.6.8. (-)-1-Vinylcyclohex-2-Enyl Acetate (-)-4a
Yellow oil (37 mg, 27% yield). [α]26D= -5.17 (c 0.70, CHCl3), 58 % ee. HPLC
conditions: (Daicel Chiralcel OJ-H, λ = 220 nm, n-hexane/2-propanol 98:2, 0.5 mL/min),
t1= 12.6 min (minor) and t2 = 13.5 min (major). HRMS (ESI-TOF) for C10H15O2 [M+H]+,
calcd. 167.1072, found 167.1064.
20

4.6.9. (-)-1-Allylcyclohex-2-Enol (-)- 3b
Light yellow oil (45 mg, 45% yield). [α]26D= - 8.65 (c 1.0, CHCl3), 65% ee. The
enantiomeric excess of the product was determined by HPLC analysis (Daicel Chiralcel
OD-H, λ = 210 nm, n-hexane/2-propanol 98:2, 0.5 mL/min) t1= 14.0 min (major) and t2=
15.9 min (minor).
4.6.10. (+)- 1-Allylcyclohex-2-Enyl Acetate (+)- 4b
Dark-yellow oil (30 mg, 23 % yield). [α]26D= +8.22 (c 1.0, CHCl3), 97 % ee. HPLC
conditions: (Daicel Chiralcel OD-H, λ= 210 nm, n-hexane/2-propanol, 98:2, 0.5 mL/min
t1= 7.7 min (minor) and t2= 7.8 min (major). HRMS (ESI-TOF) for C11H17O2 [M+H]+,
calcd. 181.1229, found 181.1220.
4.6.11. (-)-1-(Prop-2-Ynyl)Cyclohex-2-Enol (-)-3c
Colorless oil (49 mg, 49% yield). [α]26D= -5.73 (c 1.0, CHCl3), 25% ee. The enantiomeric
excess of the product was determined by HPLC analysis (Daicel Chiralcel OD-H, λ= 215
nm, n-hexane/2-propanol, 98:2, 0.5 mL/min t1= 13.1 min (major) and t2 = 15.1 min
(minor).
4.6.12. (+)-1-(Prop-2-Ynyl)Cyclohex-2-Enyl Acetate (+)-4c
Dark-yellow oil (18 mg, 14 % yield). [α]26D= +9.58 (c 0.5, CHCl3), 72 % ee. HPLC
conditions: (Daicel Chiralcel OD-H, λ= 215 nm, n-hexane/2-propanol, 98:2, 0.5 mL/min
t1= 11.3 min (minor) and t2= 12.8 min (major). HRMS (ESI-TOF) for C11H14O2 [M]+,
calcd. 178.0994, found 178.0989.
21

4.7. General Procedure For O-Allylation And O-Propargylation
To a solution of rac-1a', 3a or (-)-1b', (+)-3b or rac-1c, 3c (1.2 mmol) in dry THF (20
mL) was added KH (3.26 g, 24.4 mmol, 30 wt % dispersion in mineral oil) under argon.
The solution was stirred until H2 gas removal was complete (nearly 50 min). Next, allyl
bromide or propargyl bromide (13.4 mmol) in THF (3 mL) was added dropwise followed
by tetrabuthylammonium iodide (1.2 mmol). The mixture was stirred for additional 2 h
and hydrolyzed by the cautious addition of water (20 mL). The aquous layer was exracted
with ether (3x20 mL). The combined organic phase was dried over MgSO4 and
evaporated in vacuo. The crude product mixtures were prufied by flash column
chromatography using ethyl acetate/ hexane as the solvent eluent.
4.7.1 3-(Allyloxy)-3-Vinylcyclopent-1-Ene 5a
Dark-yellow oil (0.46 g, 82 % yield).
4.7.2. (-)-3-Allyl-3-(Allyloxy)Cyclopent-1-Ene (-)-9b
Yellow oil (0.43 g, 79 % yield). [α]26D= -5.32 (c 1.0, CHCl3).
4.7.3. 3-(Allyloxy)-3-(Prop-2-Ynyl)Cyclopent-1-Ene 17c
Yellow oil (0.49 g, 80 % yield).
4.7.4. 3-(Allyloxy)-3-Vinylcyclohex-1-Ene 6a
Yellow oil (0.51 g, 85 % yield).
22

4.7.5. (+)-3-Allyl-3-(Allyloxy)Cyclohex-1-Ene (+)-10b
Yellow oil (0.55 g, 85 % yield). [α]26D= +2.69 (c 1.0, CHCl3).
4.7.6. 3-(Allyloxy)-3-(Prop-2-Ynyl)Cyclohex-1-Ene 18c
Colorless oil (0.33 g, 84 % yield).
4.7.7. 3-(Prop-2-Ynyloxy)-3-Vinylcyclopent-1-Ene, 13a
Reddish-brown oil (0.48 g, 80 % yield).
4.7.8. (+)-3-Allyl-3-(Prop-2-Ynyloxyl)Cyclopent-1-Ene (+)-21a
Dark-yellow oil (0.48 g, 82 % yield). [α]26D= +2.90 (c 1.6, CHCl3).
4.7.9. 3-(Prop-2-Ynyloxy)-3-Vinylcyclohex-1-Ene 14a
Dark-reddish oil (0.48 g, 82 % yield).
4.7.10. (-)-3-Allyl-3-(Prop-2-Ynyloxy)Cyclohex-1-Ene (-)-22a
Dark-yellow oil (0.54, 84 % yield). [α]26D= -3.93 (c 0.65, CHCl3).
4.8. General Procedure For Ring Closing Methathesis
O-allyl diene skeletons (1.5 mmol) rac-5a, 6a or (-)-9b, (+)-10b were dissolved in DCM
(15 mL) and Grubbs’ first generation catalyst (5 mol %) was added to the solution. The
reaction was monitored by TLC. After the reaction was completed the crude product was
23

concentrated under vacuo purified by flash column chromatography using suitable
ethylacetate/hexane as the eluent.
4.8.1. 1-Oxaspiro[4,4]Nona-3,6-Diene 7a
Colorless oil (0.30 g, 72% yield).
4.8.2. 1-Oxaspiro[4,5]Deca-3,6-Diene 8a
Reddish oil (0.32 g, 75 % yield).
4.8.3. (+)-6-Oxaspiro[4,5]Deca-1,8-Diene (+)-11b
Colorless oil (0.29 g, 74 % yield). [α]26D= + 4.10 (c 2.20, CHCl3).
4.8.4. (-)-1-Oxaspiro[5,5]Undeca-3,7-Diene (-)-12b
Dark brown oil (0.36, 78 % yield). [α]26D= -1.94 (c 1.0, CHCl3).
4.9. General Procedure For The Pauson-Khand Reaction
To a solution of rac-13a, 14a, rac-17c,18c or (+)-21a, (-)-22a (1.13 mmol) in DCM (15
m L) was added Co2(CO)8 (0.683 g, 2 mmol) and stirred for 2 h with TLC monitoring.
Then NMO (1.32 g, 11.3 mmol) was added and stirred for 24 h. The crude products was
prufied by flash column chromatography using EtOAc/hexane as the eluent.
4.9.1. 6',6a'-Dihydrospiro[Cyclopent[2]Ene-1,1'cyclopenta[C]Furan]-5'(3'H)-One
15a
24

Yellow oil (0.44 g, 77 % yield). IR νmax (neat, cm-1): 1732, 1097, 949. Diastereomeric
ratio was determined as 1.33:1 from 1H NMR.
4.9.2. 6',6a'-Dihydrospiro[Cyclohex[2]Ene-1,1'-Cyclopenta[C]Furan]-5'(3'H)-One
16a
Yellow oil (0.44 g, 79 % yield). IR νmax (neat, cm-1): 1725, 1062, 987. Diastereomeric
ratio was determined as 1.57:1 from 1H NMR.
4.9.3. 7',7a'-Dihydro-1'H-Spiro[Cyclopent[2]Ene-1,3'-[Cyclopenta[C]Pyran]-
6'(4'H)-One 19c
Dark yellow oil (0.52 g, 82 % yield).
4.9.4. 7',7a'-Dihydro-1'H-Spiro[Cyclohex[2]Ene-1,3'-Cyclopenta[C]Pyran]-6'(4'H)-
One 20c
Colorless oil (0.33 g, 85 % yield).
4.9.5. (-)-4a',5'-Dihydro-1'H- Spiro[Cyclopent[2]Ene-1,3'- Cyclopenta[C]Pyran]-
6'(4'H)-One (-)-23a
Yellow oil (0.45 g, 80 % yield). [α]26D= -1.67 (c 0.5, CHCl3).
4.9.6. (-)-4a',5'-Dihydro-1'H-Spiro[Cyclohex[2]Ene-1,3'-Cyclopenta[C]Pyran]-
6'(4'H)-One (-)-24a
Yellow oil (0.51 g, 81 % yield). [α]26D= -1.62 (c 0.25, CHCl3).
25

ACKNOWLEDGMENTS
We are grateful to the Turkish Scientific and Technical Research Council for a grant
(No.113Z707, 110T169 and 105T431).
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29

Table 1. The results of (±)-1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol 1b
b
Enzy Tim Conversi eep ( ees(
Ec [α]D26(prod)/abs. [α]D26(subs)/abs.conf.
me
e
ona
5
%)
%)
conf.
(h)
CAL- 48
A-
91
38
29 [α]D26 = -5.1(c
0.60,CHCl3)(R)
[α]D26+7.2(c,1.0,CH
Cl3)(S)
CLEA
CAL- 144 20
A
99
80
20
15
25 [α]D26 =-14.3(c
α]D26+4.5(c,1.0,CHCl
3)(S)
3
0.60,CHCl3)(R)
Aman 96
15
10 [α]D26 =-4.0(c
1.30,CHCl3)(R)
[α]D26 =+2.1(c
1.0,CHCl3)(S)
o
PSC-
II
d
CRL
145 10
90
-
21 [α]D26 =-4.5(c
0.25,CHCl3)(R)
-
a c = ees/ees+eep, Conversions determined by HPLC analysis.
b Enantiomeric excesses were determined by Daicel Chiralcel OD-H and OJ-H column
HPLC analysis
c E = ln [(1-c)(1-ees)]/ ln [(1-c)(1+ees)]. [25]
d Isolated as a racemate
30