A route to enantiomerically pure 5-(2′-hydroxyethyl)cyclopent-2-en-1-ol and its absolute configuration by Mosher esters

Article abstract of DOI:10.1016/j.tetasy.2009.02.007

The (±)-5-(2′-hydroxyethyl)cyclopent-2-en-1-ol 1 was prepared in a one-pot procedure, and was resolved using lipase AK and vinyl acetate with high ee. This provides a readily available chiral synthon for the synthesis of a wide variety of biologically int

Full text of DOI:10.1016/j.tetasy.2009.02.007

Tetrahedron: Asymmetry 20 (2009) 449–456
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Tetrahedron: Asymmetry
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A route to enantiomerically pure 5-(20-hydroxyethyl)cyclopent-2-en-1-ol
and its absolute configuration by Mosher esters
Hao Chen a, Srinivas Nagabandi a, Steven Smith b, Jonathan M. Goodman b, Erika Plettner a,
*
a Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
b Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
a r t i c l e i n f o
a b s t r a c t
The ( )-5-(20-hydroxyethyl)cyclopent-2-en-1-ol 1 was prepared in a one-pot procedure, and was
resolved using lipase AK and vinyl acetate with high ee. This provides a readily available chiral synthon
for the synthesis of a wide variety of biologically interesting molecules. Further, the absolute configura-
tion of diol 1 was confirmed directly by the Mosher ester method.
Article history:
Received 18 December 2008
Accepted 6 February 2009
Available online 11 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Thirdly,13 Meinwald rearrangement of 2,5-norbornadiene 14, fol-
lowed by a mild acid-catalyzed hydrolysis and hydride reduction
in a one-pot operation gave the desired diol 1.
We have prepared 5-(20-hydroxyethyl)cyclopent-2-en-1-ol 1 as a
precursorforconformationallyrestrictedinsectpheromoneanalogues
21 (Fig. 1). Other compounds for which diol 1couldserve as a precursor
include (Fig. 1) antiviral nucleoside analogues and cis-3,5-disubsti-
tuted cyclopentenes 3a2 and 3b,3 iridoid lactones4 3c and 3d and the
spirodiketone unit of a fredericamycin A analogue 3e.5 The closely
related hemiacetal 4a and lactone 4b are important precursors for
prostaglandin A2 and J2, 5a and 5b.6 The enantiomer of 4b (R = Br or
OP(O)(OPh)2) has been used to synthesize jasmonoids such as 5c.7
The enantiomerically pure diol 1 is an attractive chiral synthon
for the synthesis of carbocyclic nucleosides that are structural ana-
logues of natural and synthetic nucleosides, where the endocyclic
oxygen atom is replaced by a methylene group. Naturally occurring
carbocyclic nucleosides such as aristeromycin 68 and neplanocine
79 (Fig. 2) exhibit powerful antitumor and antiviral activities. The
synthetic analogues such as carbovir 8 and carbocyclic-ddA 9 show
high activities against HIV and hepatitis B virus.10 Efficient enan-
tioselective syntheses of carbovir analogues using diol 1 as an
important intermediate have been reported by Olivo et al.2a
Three protocols have previously been employed to synthesize
the racemic diol 1 (Scheme 1). First,2a,11 the diol 1 was obtained
via a hetero-Diels Alder reaction between cyclopentadiene 10
and glyoxylic acid. The initial adduct rearranges to provide lactone
11, which is then reduced in a three-step procedure. This strategy
involves relatively tedious work-up and purification procedures.
Furthermore, relatively long reaction sequences are required. In a
second strategy,2c cyclization of 12 was accomplished by Larock’s
procedure,12 followed by reduction of 13 to afford diol 1. However,
an expensive palladium reagent was used in this protocol.
In a previous attempt to prepare optically active diols of 1, the lac-
tone precursor 11 was resolved with either Pseudomonas fluorescens
lipase or Amano lipase PS.2a,14 The absolute configuration of
(ꢀ)-(1S,5R)-1 wasdeducedindirectly(Scheme2). Theinitialabsolute
configuration can be traced back to (ꢀ)-aristeromycin 6, in which the
absolute configuration was established by X-ray analysis.15 The
absolute configuration of 16 was assigned by the correlation with
15,16 which is an intermediate to the total synthesis of (ꢀ)-aristero-
mycin 6.17 (ꢀ)-(1S,4S)-Carbovir 8 was synthesized from 16 in seven
steps.18 The absolute configuration of (ꢀ)-(1S,4R,5S)-11a was
correlated with (ꢀ)-(1S,4S)-carbovir by several chemical transfor-
mations.14 Since optically active (ꢀ)-(1S,5R)-1 was obtained from
(ꢀ)-(1S,4R,5S)-11a, its absolute configuration was correlated. How-
ever, inthatwork,2a,14 alowerspecificrotationfor(ꢀ)-1wasreported
than the rotation we haveobserved. More importantly, due toa typo-
graphicalerror, they namedcompound(ꢀ)-1 as‘(1R,5R)’. Their struc-
ture of (ꢀ)-1 as drawn does not agree with our assignment.
Herein, we report a method to enantiomerically pure diols (+)-1
and (ꢀ)-1 by enzymatic kinetic resolution, in which racemic 1 was
obtained in a more economical, shorter and more efficient approach
(route 3) when compared with routes 1 and 2. In this strategy, the
required racemic 1 was synthesized from 2,5-norbornadiene 14
(route 3) in a one-pot operation. Furthermore, the absolute configu-
ration of diol 1 was revisited directly by the Mosher ester method.
2. Results and discussion
2.1. Preparation of diol ( )-1
As mentioned above, three protocols are available to synthesize
* Corresponding author. Tel./fax: +1 778 782 3765.
E-mail address: plettner@sfu.ca (E. Plettner).
( ) dio1 1. First, strategy 1 was attempted (Scheme 3).11 The
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.007

450
H. Chen et al. / Tetrahedron: Asymmetry 20 (2009) 449–456
OR1
OR1
OH
O
OR2
OR2
OH
2a
1
2b
R1,R2 alkyl groups (various)
O
t-BuPh2SiO
O
HO
R
O
O
Base
H
H
R = Et
3d
3c
3b
3a
R
AcO
MeO MeO
O
OH
O
N
O
R = H or Br or CH2OH
4b
O
4a
3e
OH
O
OH
O
CO2H
5,7
O
O
OH
5c
5b
5a
OH
Figure 1. Potential examples using enantiomerically pure 1 as chiral synthon.
synthesis was started from hydroxylactone 11, which was obtained
by the water-promoted reaction of glyoxylic acid with cyclopentadi-
ene. Thereactionselectivelygavea cis-adductwitha 2:1ratioof endo
11a to exo 11b isomers. The hydroxylactones 11a and 11b were
converted to racemic diol 1 in three steps. Initially, hydroxylactone
11 was reacted with mesyl chloride to the corresponding endo-
and exo-mesylated products 15a and 15b, followedby a bromination
reaction with lithium bromide to give bromolactone 16 in THF at
reflux for 30 h. Close monitoring of the reaction by GC showed that
the rate of bromination of endo mesyl isomer 15a was faster than
that of the exo isomer 15b. The endo isomer required 4–6 h, whereas
the exo isomer needed 30 h to achieve complete conversion. It was
also observed that, upon bromination, the endo to exo ratio was in-
verted, indicating a SN2 mechanism. Finally, ( ) dio1 1 was obtained
by treating bromolactones 16a and 16b with LiAlH4 in THF at reflux
for 24 h. The overall yield of this sequence of reactions was 43%
(relative to cyclopentadiene), and the procedures required more
than 5 days (mainly because the hetero Diels–Alder reaction takes
3 days). Overall ca. 20 L of various solvents was required for the
production of 1 mol of diol product.
Alternatively, the required racemic 1 was synthesized from 2,5-
norbornadiene 1413a (Scheme4) in a one-pot operation. Presumably,
Meinwald rearrangement of the peracid oxidation of 14 gave an
equilibrium mixture of bicyclic aldehyde 17 and the bicyclic enol
ether 18. Oxalic acid catalyzed hydrolysis of the mixture afforded
the lactol 19. Subsequent sodium borohydride reduction in water–
acetonitrile yielded ( )-1 in 60% overall yield. Compared tothe above
synthetic method for previous racemic diol 1, the current protocol is
more efficient and attractive. First, by avoiding the use of cyclo-
pentadiene as a starting material it eliminates the tedious pyrolytic
cracking of dicyclopentadiene to cyclopentadiene and the subse-
quent distillation procedure. Second, the 18 h and one-pot reaction
sequence in the current protocol is advantageous over the greater
than day-long and multiple reaction sequence, in that it only
requires 5 L of solvents for the production of 1 mol of diol.
NH2
NH2
NH
NH2
N
N
N
N
N
N
N
HO
HO
OH OH
OH OH
neplanocine A 7
aristeromycin 6
O
N
NH2
NH
N
N
N
N
NH
NH2
N
HO
HO
2.2. Resolution of diol ( )-1
carbovir 8
carbocyclic-ddA 9
The racemic diol 1 was resolved by the biocatalytic esterifica-
tion with neat vinyl acetate. The enzymatic resolution gave the
Figure 2. Examples of carbocyclic nucleosides.

H. Chen et al. / Tetrahedron: Asymmetry 20 (2009) 449–456
451
OH
H
CHO
O
11
COOH
O
H
Route 1
OH
10
H
H
OH
O
COOH
1
( )-
12
O
13
Route 2
One-pot operation
Route 3
14
Scheme 1. Three protocols for the synthesis of diol ( )-1.
NH2
N
N
N
O
MeO
O
N
HN
CH3
NH2
HO
HO
1
1
4
4
4
16
1
OH OH
OH OH
OH
15
(-)-(1S,2S,3R,4R)-aristeromycin 6
N
N
O
OH
H
N
OH
N
NH2
O
5
1
HO
H
H
1
5
4
4
OH
1
(-)-(1R,4S)-carbovir 8
1
11a
(-)-(1S,4R,5S)-
(-)-(1S,5R)-
Scheme 2. Establishment of the absolute configuration of (ꢀ)-(1S,5R)-1. The double headed arrows denote correlations of absolute configuration.
OH
OMs
H
H
a
b
CHO
+
O
O
COOH
O
O
H
H
10
15a:
15b:
endo-isomer
exo-isomer
11a: endo-isomer
11b: exo-isomer
c
Br
H
d
OH
O
O
H
OH
16a: exo-isomer
endo-isomer
1
( )-
16b:
Scheme 3. (Route 1) Reagents and conditions: (a) H2O, rt, 3 d; (b) MsCl, triethylemine, DCM, 0 °C, 4 h; (c) LiBr, THF, reflux, 30 h; (d) LiAlH4, THF, reflux, 24 h.

452
H. Chen et al. / Tetrahedron: Asymmetry 20 (2009) 449–456
OH
O
H
O
a
b
O
14
c
19
18
17
OH
d
OAc
OAc
+
e
OH
OH
(+)-20
e
OAc
1
(-)-
( )-1
1
(+)-
(-)-21
Scheme 4. (Route 3) Reagents and conditions: (a) anhydrous Na2CO3, 32% peracetic acid, DCM, rt, 2 h; (b) 5.0 mol % oxalic acid, H2O, rt, 12 h; (c) NaBH4, CH3CN, rt, 4 h;
(d) NaOH, MeOH, rt, 24 h (see Table 1).
monoacetate for one enantiomer and the diacetate for the other.
Five commercially available lipases (porcine pancreatic lipase, Can-
dida rugusa lipase, Lipase AY 30, Pseudomonas cepacia lipase and
Lipase AK) were tested for the acetylation of racemic 1 to the cor-
responding esters (+)-20, and (ꢀ)-21 (see Scheme 4 and Table 1).
The resolution was carried at room temperature in neat vinyl ace-
tate, the mono- and di-acetate product ratio was consistent with
the higher reactivity and low enantioselectivity of lipases towards
less hindered primary alcohols. The reaction was monitored by GC,
and the enantiomeric excess of diacetate (ꢀ)-21 was determined
by chiral GC (Table 1). For all the lipases tested, the formation of
monoacetate 20 was found to be very fast (100% conversion in
30 min) and regioselective, but not at all enantioselective. This
observation is consistent with the higher reactivity and low enanti-
oselectivity of lipases towards less hindered alcohol nucleo-
philes.19 The diacetylation of diol 1 with lipases all showed
moderate to high enantioselectivity (see Table 1). This result is
consistent with many studies, in which secondary alcohols have
been resolved by lipases successfully.20 Lipase AK was chosen for
the enantiomeric resolution of racemic 1, because it was the fastest
enzyme with the highest enantioselectivity for the acetylation of
the secondary alcohol moiety. Porcine pancreatic lipase also had
high enantioselectivity, but reacted slowly. Interestingly, the
pattern of E values reported here for P. cepacia and C. rugosa lipase
was similar to patterns observed for the resolution of 2-subtituted
cyclopentanols: high E values (over 50) for P. cepacia lipase and low
E values (1.4) for C. rugosa lipase.20g Reactions were stopped at 50%
conversion of monoacetate 20. Compounds (+)-20 (½a D20
¼ þ68:4
ꢁ
(c 1.6, CHCl3)) and (ꢀ)-21 (½a D20
¼ ꢀ206:9 (c 1.6, CHCl3)) were sep-
ꢁ
arated by flash chromatography and was hydrolyzed separately by
NaOH in MeOH, to afford the corresponding diols; (+)-1
(½a 2D0
ꢁ
¼ þ90:0 (c 0.003, CHCl3)) and (ꢀ)-1 (½a D20
¼ ꢀ90:2 (c 0.006,
ꢁ
CHCl3)).
2.3. Determination of the absolute configuration of diol 1 by
primary and secondary alcohol Mosher ester
In previous studies,2a,14 the racemic lactonol 11 was resolved
with a lipase and then reduced, to give (1S,5R)-(ꢀ)-1, with
½
a 2D5
ꢁ
¼ ꢀ80:7. The establishment of absolute configuration was
based on selected chemical transformations. In our study, the same
tentative assignment could be made by considering the enantiose-
lectivity of lipase, according to an empirical rule for predicting
which enantiomer reacts faster during the resolution of secondary
alcohols.20a,b,d,f,h However, a few exceptions to this rule have been
reported.20b,h
Table 1
Lipase-catalyzed kinetic resolution of ( )-1 with vinyl acetate as acyl donor
Enzyme
Time (h)
Conversion ratea (%)
Selectivity
Monoacetate (+)-20b
100
73.8
% ee of (+)-20d
% ee of (ꢀ)-21e
Ef
Diacetate (ꢀ)-21b
Porcine pancreatic lipase
Candida regusa
Lipase AY 30
Pseudomonas cepacia
Lipase AK
4
24
94.6
100
NDc
26.2
0
36
NAc
99.9
—
200
4
24
100
100
88.0
48.5
12.0
51.5
7
71
51.5
66.4
3
10
4
24
100
100
>99
45.5
Trace
54.5
<1
85
99.9
70.6
>200
15
4
24
100
100
33.0
18.3
67.0
81.7
>99
99
86.4
86.4
78
70
4
24
100
100
74.6
36.0
25.4
64.0
34
99
100
>200
97
88.8g
a
Reaction conditions: Diol 1 (20 mg, 0.16 mmol), lipase (20 mg), vinyl acetate (0.5 mL, neat solution), at room temperature. The value refers to the percentage of racemic
diol 1 converted to the monoacetate and diacetate.
b
Analysis of product samples was done by GC, DB5 column.
ND = not detected, NA = not applicable.
c
d
Calculated from ee or (ꢀ)-21 and percentage of mono and diacetate.
e
From GC analysis of (ꢀ)-21 samples on a CycloSil-B column.
f
Calculated according to literature.20f
g
The ee can be enriched over 95% by further resolution.

H. Chen et al. / Tetrahedron: Asymmetry 20 (2009) 449–456
453
Table 2
H
O
H
O
Analysis of chemical shift differences for Mosher esters 22a and 22b
CF3
Ph
CF3
R2
R2
No.
d-S-ester
(ppm)
d-R-ester
(ppm)
D
dSR
Hz
(600 MHz)
O
O
R1
R1
(=dS ꢀ dR) ppm
OMe
MeO
Ph
H-1
H-2
H-3
H-4
5.69
6.17
6.00
2.47
2.15
2.40
1.90
1.73
4.07
2.03
5.72
6.23
6.04
2.49
2.19
2.40
1.75
1.61
3.97
2.02
ꢀ0.03
ꢀ0.06
ꢀ0.04
ꢀ0.02
ꢀ0.04
0.00
+0.15
+0.12
+0.10
+0.01
ꢀ18
ꢀ36
ꢀ24
ꢀ12
ꢀ24
0
+90
+72
+60
+6
(R)-ester
(S)-ester
O
O
H-5
H-10
O
2'
1'
H
H
O
H
H
H
2'
H
3
5
CH3
O
H-20
–COCH3
4
H
H
1'
O
H
1
5
1
4
3
H
CF3
O
2
CF3
H
OMe
O
2
H
MeO
an upfield chemical shift in the NMR spectrum for the spatially
proximal protons. Protons residing within group R2 of the (S)-ester
are relatively more shielded and thus upfield (Fig. 3). The same ap-
plies for the proton residing within group R1 of the (R)-ester. The
20
(+)- -(R)-MTPA ester
22b
20
(+)- -(S)-MTPA ester
22a
sign of
D
d(SR) = dH(S) ꢀ dH(R) for protons residing within group
R1 will thus be positive and for protons in group R2 negative, lead-
ing to the determination of the absolute configuration of the sec-
ondary carbinol centre.
Figure 3. Dominant conformers of MTPA esters.
With the optically active diol 1 in hand, we decided to revisit its
The (S)- and (R)-MTPA-esters 22a and 22b (Fig. 3) for (+)-20
were prepared using coupling reagents EDCI and DMAP. 1H NMR
analysis of two diastereomers (S)-(+)-20-MTPA-ester 22a and (R)-
(+)-20-MTPA-ester 22b was performed (see Table 2 for details).
absolute configuration with the Mosher ester method. The absolute
configuration of (+)-20 at the secondary carbinol stereogenic cen-
tre was determined by analysis of the diastereomeric Mosher
esters. This method involves derivatization of the secondary alco-
hol of (+)-20 with each of the enatiomeric pair (S)-(ꢀ)-MTPA and
Positive
shielding of the side chain moiety in the (R)-ester. In contrast, neg-
ative dH(SR) values for H-1, H-2, H-3 and H-4 imply aryl-shielding
D
dH(SR) values for H-10, H-20 and COCH3 indicate aryl-
(R)-(+)-MTPA
(a-methoxy-a-trifluoromethylphenylaceticacid),
D
affording two diastereoisomeric esters [(S)- and (R)-ester, respec-
tively]. The success of the following NMR analysis relies on the
empirically based conformation for the esters that is shown in Fig-
ure 3.21 The major conformation is the one in which the ester
adopts the s-trans (antiperiplanar) arrangement about the O–CO
bond and a syn-coplanar (0° dihedral angle) arrangement between
the CF3 group and carbinol methane proton with respect to the car-
bonyl group.21 The phenyl group of MTPA is known to impose an
anisotropic effect above or below the aromatic ring, resulting in
of the five-membered ring moiety in the (S)-ester. This result
establishes the absolute configuration of (+)-20 as (1R,5S)-(+)-20.
When diols (+)-1 and (ꢀ)-1 were esterified with (S)-(ꢀ)-MTPA-
Cl, we found that only the primary alcohol group esterifies, giving
diastereomers (R)-((+)-1)-MTPA-ester 23a and (R)-((ꢀ)-1)-MTPA-
ester 23b (see Fig. 4 for structures, 23b is the enantiomer of
23b0). This places the MTPA moiety three atoms away from the ste-
reogenic centre and, interestingly, significant chemical shift differ-
ences between those two diastereomers can be observed (see Table
F3C
O
OMe
MeO
O
CF3
1'
(S)
1'
(S)
4
2
4
2
O
5
5
(R)
(S)
3
3
2'
2'
1
1
O
(R)
(R)
OH
OH
23a
(S)-((+)-1)-MTPA-ester
(R)-((+)-1)-MTPA-ester 23a
Figure 4. Major conformers of 23a and 23b0 obtained by a molecular mechanic conformational search with MMFF force field.

454
H. Chen et al. / Tetrahedron: Asymmetry 20 (2009) 449–456
Table 3
B column (J & W, 30 m, 0.25 mm i.d., 0.25 lm film), programmed
isothermally at 140 °C and 25 psi head pressure. GC–mass spectra
were recorded on a Varian Saturn 2000 MS coupled to a CP 300 GC,
NMR data for primary MTPA esters of (+)-1 and (ꢀ)-1, compounds 23a and 23b
No.
(R)-((+)-1)-MTPA-ester,
(R)-((ꢀ)-1)-MTPA-ester,
D
d(+)(ꢀ) (=d+ ꢀ d )
ꢀ
23a
23b
(ppm)
equipped with
programmed as above. Mass spectra were acquired in EI mode
[2 scans (0.55 s/scan), emission current (30 amp), scanning sin-
a SPB-5 GC column (same type as above),
H-1
H-2
H-3
H-4
4.56
6.02
5.90
2.37
4.44
6.00
5.87
2.36
2.08a
2.04a
2.11
1.83
4.45b
4.41b
+0.12
+0.02
+0.03
+0.01
+0.04
N/A
ꢀ0.01
+0.01
+0.02
ꢀ0.02
l
l
gle ion storage SIS (49–375 m/z)]. Infrared spectra (IR) were
recorded on a Perkin Elmer 599B IR spectrophotometer using NaCl
plates. HRMS was recorded on a 6210 Series Time-of-Flight LC/MS
System.
2.12a
2.02–2.06a
2.10b
1.84
H-5
H-10
H-20
4.47
4.39
4.2. Preparation of optically active diol 1 and its MTPA
derivatives
a
Splitting patterns can not be resolved.
Overlapping signals.
b
4.2.1. 3-Hydroxy-3,3a,4,6a-tetrahydro-cyclopenta-b-furan-2-
one 11a and 11b
Glyoxylic acid 3.3 g (44.5 mmol) was dissolved in 19.8 mL of
water, giving a 2.25 M solution. To this solution, freshly distilled
cyclopentadiene (1.24 mL, 15.1 mmol) was added. The reaction
mixture was stirred vigorously at room temperature for 3–4 days.
After completion of the reaction, the mixture was extracted with
n-heptane (3 ꢂ 15 mL), and then the aqueous layer was saturated
with NaCl. The aq layer was further extracted with ethyl acetate
(8 ꢂ 20 mL). The combined organic layers were concentrated to
50 mL under vacuum and cooled to 0 °C. The organic layer was
washed with cold saturated sodium bicarbonate (2 ꢂ 20 mL). The
separated aqueous layer was extracted further with ethyl acetate
(3 ꢂ 20 mL). The combined organic layer (ethyl acetate layers only)
was dried over Na2SO4, filtered and evaporated under vacuum to
give a yellow oil (1.35 g of 11a and 11b, 2:1, 60%). The heptane
layer contained the cyclopentadiene dimer. Isomers 11a and 11b
were separated by flash chromatography (silica gel, ether/hexane,
9:1) to yield a light yellow syrup. Data for 11a and 11b were con-
sistent with the literature.11b Compound 11a: 1H NMR (500 MHz,
CDCl3) d 6.06 (m, 1H), 5.87 (m, 1H), 5.51 (m, 1H), 4.13 (d,
J = 6.0 Hz, 1H), 3.6–4.0 (br s, 1H,), 3.02 (dd, J = 1.5, 7.5 Hz, 1H),
2.74 (ddd, J = 2.0, 7.5, 17.5 Hz, 1H), 2.56 (ddd, J = 2.0, 4.0, 17.5 Hz,
1H); 13C NMR (125 MHz, CDCl3) d 178.2, 137.1, 129.6, 87.7, 74.6,
44.4, 36.9; MS m/z (relative intensity): 141 (M++H, 32%), 140 (M+,
9%), 123 (100%), 95 (61%), 67 (72%); GC-RI: 1268. Compound
11b: 1H NMR (500 MHz, CDCl3) d 6.2 (dd, J = 2.5, 6.0 Hz, 1H), 5.87
(dd, J = 2.5, 6.0 Hz, 1H), 5.29 (td, J = 2.17, 6.0 Hz, 1H), 4.3–4.7 (d,
J = 9.4 Hz, 1H), 3.6–4.0 (s, 1H), 3.2 (tt, J = 6.5, 9.5 Hz, 1H), 2.7
(ddd, J = 2.5, 6, 18 Hz, 1H), 2.4 (ddd, J = 2.0, 9.5, 18 Hz, 1H); 13C
NMR (125 MHz, CDCl3) d 178.16, 141.5, 127.7, 86.9, 69.4, 40.8,
31.1; MS m/z (relative intensity): 141 (M++H, 40%), 140 (M+, 9%),
123 (100%) GC-RI: 1255.
3). As seen in Table 3, the H-1 in 23a is strongly deshielded
(0.12 ppm), compared to the H-1 in 23b. The vinylic protons (H-2
and H-3) in 23a are slightly deshielded (0.02–0.03 ppm), compared
to the vinylic protons in 23b. This observation also implies abso-
lute configurations of (+)-1 and (ꢀ)-1 as (1R,5S)-(+)-1 and
(1S,5R)-(ꢀ)-1. Furthermore, two major conformer structures for
23a and 23b0 were obtained from a molecular mechanics confor-
mational search with the MMFF force field22 (Fig. 4). The energies
(from which the populations were calculated) were taken from sin-
**
gle point B3LYP/6-31G , gas calculations on the MMFF geome-
tries.23 The key structural feature seems to be a hydrogen bond
between the OH and ester oxygen and/or the oxygen of the OMe
group. According to this model, even though the MTPA is not
directly attached to one of the stereogenic centres, the internal
hydrogen bond in those two diastereomers appears to provide suf-
ficient rigidity to place H-1, H-2 and H-3 in a defined position, rel-
ative to the phenyl group shielding cone.
3. Conclusions
In conclusion, an efficient and facile protocol to diols (+)-1 and
(ꢀ)-1 is now readily available with high ee. This strategy provides
attractive potential chiral synthons for the synthesis of a wide vari-
ety of biologically interesting molecules. The absolute configura-
tion of diol 1 was confirmed by the Mosher ester method.
Interestingly, the chemical shift differences between two MTPA
ester diastereomers can still be observed when the MTPA moiety
was placed three atoms away from the stereogenic centre, because
an internal H-bond provided some rigidity for the molecule.
4.2.2. 2-Oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta-b-furan-3-yl-
ester 15a and 15b
4. Experimental
4.1. General
A solution of 11a and 11b (2.5 g, 18 mmol) and triethylamine
(3.75 mL, 26.9 mmol) in dry CH2Cl2 (200 mL) was stirred at 0 °C.
To this cooled mixture, methanesulfonyl chloride (2.5 mL,
32 mmol) was added dropwise with stirring. The mixture was
reacted for 4 h, after which the reaction was quenched with water
(10 mL). Saturated NaHCO3 (50 mL) and brine were added to the
biphasic reaction mixture, until the pH was neutral. The organic
layer was dried over Na2SO4 and concentrated under reduced pres-
sure. The collected residue was purified by flash chromatography
(silica gel, hexane/EtOAc, 8:2) to give 15a and 15b (2:1) as a color-
less syrup (3.6 g, 92%). Compound 15a: 1H NMR (500 MHz, CDCl3) d
6.12–6.16 (m, 1H), 5.91–5.94 (m, 1H), 5.60–5.62 (d, J = 7.7 Hz, 1H),
4.94–4.96 (d, J = 7.0 Hz, 1H), 3.26–3.30 (m, 1H), 2.76–2.81 (m, 1H),
3.26 (s, 3H), 2.66–2.70 9 (m, 1H); 13C NMR (125 MHz, CDCl3) d
171.7, 137.3, 129.4, 87.8, 80.5, 43.1, 39.9, 36.2; MS m/z (relative
intensity): 219 (M++H, 100%), 218 (M+, 25%), 123 (34%), 78 (77%);
Commercial grade solvents were distilled under nitrogen prior
to use and reagents were used without further purification with
the following exceptions: triethylamine was distilled and stored
over NaOH. CH2Cl2 was distilled over CaCl2 and stored over molec-
ular sieves 3 Å. Dried THF was obtained from a MBRAUN LTS 350
solvent purification system. GC was run on a Hewlett Packard
5890 using a SPB column (Supelco, 30 m, 0.25 mm i.d., 0.25 lm
film), programmed 100 °C (5 min), 10 °C/min, 200 °C (4.0 min),
15 °C/min, 250 °C (14.0 min). The gas chromatographic data on
the DB-5 column are reported as retention indices (RI). The 1H
and 13C NMR spectra were recorded in CDCl3 on Bruker 500 and
600 MHz spectrometers. Enantiomer compositions were analyzed
on a Varian 3400 gas chromatography, equipped with a Cyclo-Sil

H. Chen et al. / Tetrahedron: Asymmetry 20 (2009) 449–456
455
GC-RI: 1694. Compound 15b: 1H NMR (500 MHz, CDCl3) d 6.20–
6.22 (td, J = 2.3, 5.6 Hz, 1H), 5.88–5.90 (td, J = 2.3, 7.8 Hz, 1H),
5.45–5.47 (d, J = 9.5 Hz, 1H), 5.35–5.37 (td, J = 2.1, 6.4 Hz, 1H),
3.29–3.36 (m, 1H), 3.22 (s, 3H), 2.62–2.69 (dtd, J = 2.0, 4.7,
18.3 Hz, 1H), 2.50–2.57 (tdd, J = 2.2, 9.1, 18.3 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 171.3, 141.1, 127.7, 87.0, 75.5, 39.7, 39.6,
32.1; MS m/z (relative intensity): 219 (M++H, 100%), 218 (M+,
31%), 123 (31%), 78 (79%); GC-RI: 1663.
sulfuric acid present. The addition was carried out at rt. After the
reaction mixture was allowed to stir for an additional 4 h, the reac-
tion mixture was filtered, and the filter cake was washed with a
few portions of DCM. The solvent and excess starting material 14
were evaporated to give 4.7 g of residue. The residue was added
to 200 mL of water and then oxalic acid (0.27 g, 2.2 mmol). After
being stirred for 15 h at rt, 250 mL of acetonitrile was added to
the reaction mixture. Sodium borohydride (2.5 g, 65.3 mmol) was
then added in several portions over 5–10 min. After the reaction
mixture was stirred for 4 h, the resulting mixture was concentrated
to remove organic solvent. The remaining aqueous solution was
saturated with NaCl and extracted with chloroform 4–6 times.
The combined organic solvent was dried over Na2SO4 and concen-
trated. The residue was purified by flash chromatography (silica
gel, hexane/ethyl acetate, 1:1) to afford compound 1 as a colorless
oil (3.2 g, 60% overall yield). The NMR data for 1 were consistent
with the data shown in Section 4.2.4.
4.2.3. 3-Bromo-3,3a,4,6a-tetrahydro-cyclopenta-b-furan-2-one
16a and 16b
A solution of mesyl lactone 15a and 15b (4.2 g, 19.3 mmol) in
100 mL of dry THF and LiBr (4.5 g, 51.8 mmol) was stirred at reflux
for 24 h. The solution was filtered and mixed with water (50 mL),
and was extracted with ethyl acetate (4 ꢂ 75 mL). The organic
layer was dried over Na2SO4 and concentrated under vacuum.
The residue was purified by flash column chromatography (silica
gel, hexane/EtOAc, 8.5:1.5) to afford a mixture of 16a and 16b
(1:2) as a dark red colored syrup (3.4 g, 88%). Data for 16a and
16b were consistent with the literature.11c Compound 16a: 1H
NMR (500 MHz, CDCl3) d 6.20–6.22 (m, 1H), 5.95–6.0 (td, J = 2.2,
8.0 Hz, 1H), 5.38–5.44 (td, J = 2.0, 6.6 Hz, 1H), 4.83 (d, J = 9.3 Hz,
1H), 3.30–3.36 (m, 1H), 2.78–2.83 (m, 1H), 2.62–2.68 (tdd, J = 2.2,
8.8, 17.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 172.9, 137.6,
129.0, 87.7, 56.9, 47.0, 37.0; MS m/z (relative intensity): 205 (M+
4.2.6. (+)-cis-5-(2-Acetyloxy-ethyl)cyclopent-2-enol 20 and
acetyloxy-(ꢀ)-cis-5-(2-acetyloxy-ethyl)cyclopent-2-enol 21
Diol ( )-1(100 mg, 0.78 mmol) was dissolved in 3.0 mL
(32.5 mmol) of vinyl acetate and then Lypase AK (80 mg) was
added to it. The suspension was stirred at room temperature for
24 h. The reaction mixture was filtered and concentrated and then
purified by flash chromatography (silica gel, ethyl acetate/hexane,
1:4) to afford pure compounds 20 (62 mg, 93.4% yield for 50%
conversion) and 21 (51 mg, 61.6% yield for 50% conversion). Com-
pound 20: 1H NMR (500 MHz, CDCl3) d 6.03(m, 1H), 5.92 (m, 1H),
4.60 (m, 1H), 4.18 (m, 2H), 2.41 (m, 1H), 2.09–2.18 (m, 2H) (2.05
(s, 3H), 1.99 (dddd, J = 7.0, 7.0, 7.0, 13.7 Hz, 1H), 1.77 (dddd,
J = 6.6, 6.6, 6.6, 14.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) d 171.2,
(
81Br), 100%), 203 (M+(79Br), 88%), 185 (13%), 171 (30%), 143
(27%), 123 (68%), 105 (91%), 79 (39%); GC-RI: 1433. Compound
16b: 1H NMR (500 MHz, CDCl3) d 6.12–6.15 (m, 1H), 5.9–6.0
(ddd, J = 2.0, 3.9, 7.5 Hz, 1H), 5.56–5.57 (d, J = 6.8 Hz, 1H), 4.25 (d,
J = 4.0 Hz, 1H), 3.28–3.33 (m, 1H), 2.80–2.86 (m, 1H), 2.38–2.42
(m, 1H); 13C NMR (125 MHz, CDCl3) d 173.0, 138.3, 128.7, 88.1,
47.6, 43.7, 37.5; MS m/z (relative intensity): 205 (M+
(
81Br), 51%),
79Br), 60%),171 (25%), 143 (19%), 123 (100%), 105 (47%),
134.0, 132.9, 129.9, 64.12, 39.2, 36.6, 27.9, 20.9. ½a D20
¼ þ68:4 (c
ꢁ
203 (M+
(
0.002, CHCl3). Compound 21: 1H NMR (500 MHz, CDCl3) d 6.07
(m, 1H), 5.83 (td, J = 2.3, 8.1 Hz, 1H), 5.56 (td, J = 2.1, 6.7 Hz, 1H),
4.06 (m, 2H), 2.44 (dddd, J = 7.1, 7.1, 7.2, 16.5 Hz, 1H), 2.32 (dddd,
J = 7.1, 7.1, 7.2, 14.4 Hz, 1H), 2.15 (m, 1H), 2.01 (s, 3H), 2.00 (s, 3H),
1.88 (dddd, J = 7.0, 7.0, 7.0, 13.7 Hz, 1H), 1.67 (m, 1H). 13C NMR
(125 MHz, CDCl3) d 171.09, 170.8, 137.6, 129.5, 79.2, 63.5, 38.1,
79 (51%); GC-RI: 1496.
4.2.4. ( )-cis-5-(2-Hydroxy-ethyl)cyclopent-2-enol 1
A solution of bromolactones 16a and 16b (1.9 g, 9.32 mmol) in
dry THF (100 mL) was added dropwise to a solution of LiAlH4
(900 mg, 23.7 mmol) in dry THF (50 mL) at 0 °C. The mixture was
stirred at reflux for 20–24 h. Diethyl ether saturated with water
(25 mL) was added dropwise with vigorous stirring, followed by
water (4 mL), at a rate that caused gentle reflux. This procedure
resulted in formation of a gray precipitate. The mixture was stirred
at reflux for 1 h and then allowed to stand for 15 min. The superna-
tant liquid was decanted and filtered through Celite filter agent. Tet-
rahydrofuran (50 mL) and water (2 mL) were added to the
precipitate. The suspension was stirred at reflux for 1 h, and then
the hot mixture was filtered through Celite and concentrated under
reduced pressure. The residue was purified by flash chromatography
(silica gel, hexane/ethyl acetate, 1:1) to afford compound 1 as a col-
orlessoil(1.0 g, 89%). Datafor 1 wereconsistentwith theliterature.2c
1H NMR (500 MHz, CDCl3) d 5.95–5.96 (dd, J = 2.7, 5.8 Hz, 1H), 5.82–
5.84 (dd, J = 1.9, 5.6 Hz, 1H), 4.60–4.62(td, J = 1.9, 6.3 Hz, 1H), 3.81 (s,
2H, -OH), 3.70–3.75 (td, J = 5.2, 10.4 Hz, 1H), 3.58–3.63 (td, J = 4.4,
9.2 Hz, 1H), 2.34–2.38 (tdd, J = 1.8, 7.1, 15.8 Hz, 1H), 2.12–2.17 (m,
1H), 2.05–2.12 (m, 1H), 1.80–1.88 (m, 1H), 1.63–1.69 (m, 1H); 13C
NMR (125 MHz, CDCl3) d 135.5, 132.8, 76.5, 62.2, 41.5, 37.6, 31.8;
MS m/z (relative intensity): 1: 127 (M+ꢀH, 5%), 111 (100%), 93
(100%), 81 (27%), 67 (44%). GC-RI: 1189.
37.0, 28.0, 21.1, 20.9; ½a D20
¼ ꢀ206:9 (c 0.002, CHCl3).
ꢁ
4.2.7. (1R,5S)-(+)-5-(20-Hydroxyethyl)cyclopent-2-en-1-ol (+)-1
and (1S,5R)-(ꢀ)-5-(20-hydroxyethyl)cyclopent-2-en-1-ol (ꢀ)-1
Compound 20 (217 mg, 1.28 mmol) was dissolved in 5 mL of
MeOH. Then 2.5 mL of 10% NaOH was added and stirred at room
temperature for 20 h. After 20 h, the reaction mixture was diluted
with chloroform. The organic layer was washed with sat. NH4Cl
(3 ꢂ 20 mL) and brine (2 ꢂ 20 mL). Then the organic layer was
dried over Na2SO4 and concentrated under vacuum. The residue
was then purified by flash chromatography (silica gel, ethyl ace-
tate/hexane, 1:1) to yield 156 mg of pure (+)-1. Yield = 95.7%. 1H
NMR (600 MHz, CDCl3) d 6.00–6.02 (dd, J = 2.7, 5.8 Hz, 1H), 5.88–
5.90 (dd, J = 1.9, 5.6 Hz, 1H), 4.67 (m, 1H), 3.81–3.84 (td, J = 5.2,
10.4 Hz, 1H), 3.67–3.71 (td, J = 4.4, 9.2 Hz, 1H), 2.81 (br s, 2H, –
OH), 2.39–2.43 (tdd, J = 1.8, 7.1, 15.8 Hz, 1H), 2.18–2.23 (m, 1H),
2.10–2.17 (m, 1H), 1.88–1.94 (m, 1H), 1.70–1.75 (m, 1H).
½
a 2D0
ꢁ
¼ þ90:0 (c 0.003, CDCl3) Procedure for the synthesis of (+)-1
was repeated with compound 21 (400 mg, 2.35 mmol) and yielded
(ꢀ)-1 in 95.0% yield (286 mg). ½a D20
¼ ꢀ90:2 (c 0.006, CDCl3).
ꢁ
4.2.8. Mosher esters of (+)-20, (+)-1 and (ꢀ)-1
4.2.5. One-pot operation for the synthesis of ( )-cis-5-(2-
hydroxy-ethyl)cyclopent-2-enol 1
To a rapidly stirred suspension of anhydrous Na2CO3 in a solu-
tion of 2,5-norbornadiene 14 (7.5 g, 81 mmol) and DCM (50 mL)
was added 32% peracetic acid (9.7 g, 41 mmol) which had been
previously treated with 0.2 g of sodium acetate to neutralize any
Compounds 22a and 22b: A solution of (S)-(ꢀ)-MTPA (82 mg,
0.35 mmol) or (R)-(+)-MTPA (82 mg, 0.35 mmol) in 3 mL of DCM
was cooled to 0 °C for 10 min. To this solution was added (+)-20
(50 mg, 0.29 mmol) followed by EDCI (111 mg, 0.58 mmol) and
DMAP (11 mg, 0.09 mmol). The mixture was allowed to warm to
rt and stir overnight. Four milliliters of saturated NH4Cl solution

456
H. Chen et al. / Tetrahedron: Asymmetry 20 (2009) 449–456
were added, and the organic phase was separated. The aqueous
phase was extracted with 3 ꢂ 10 mL of diethyl ether and the com-
bined organic layers were dried over anhydrous Na2SO4 and
concentrated. The residue was purified by flash chromatography
(silica gel, hexanes/ethyl acetate 5:1) to afford compounds 22a
(60 mg, 50%) and 22b (62 mg, 50%), respectively, as colourless oils.
Compound 22a: 1H NMR (600 MHz, CDCl3) d 7.49 (m, 2H), 7.39 (m,
3H), 6.17 (m, 1H), 6.00 (m 1H), 5.69 (m, 1H), 4.07 (m, 2H), 3.48 (br
s, 3H), 2.47 (m, 1H), 2.40 (dddd, J = 7.2, 7.2, 7.2, 14.4 Hz, 1H), 2.15
(m, 1H), 2.03 (s, 3H), 1.90 (dddd, J = 7.2, 7.2, 7.2, 13.9 Hz, 1H), 1.73
(dddd, J = 7.2, 7.2, 7.2, 13.9 Hz 1H); HRMS calcd for C19H21O5F3Na:
409.1238, found: 409.1233. Compound 22b: 1H NMR (600 MHz,
CDCl3) d 7.49 (m, 2H), 7.38 (m, 3H), 6.23 (m, 1H), 6.04 (m 1H),
5.72 (m, 1H), 3.97 (m, 2H), 3.53 (br q, J = 1.2 Hz, 3H), 2.49 (dddd,
J = 1.2, 3.0, 7.2, 16.8 Hz, 1H), 2.40 (dddd, J = 7.2, 7.2, 7.2, 14.7 Hz,
1H), 2.19 (m, 1H), 2.02 (s, 3H), 1.75 (dddd, J = 7.2, 7.2, 7.2,
13.8 Hz, 1H), 1.61 (dddd, J = 6.6, 6.6, 6.6, 14.7 Hz, 1H).
Frontiers Science Project (HFSP) Grant RGP0042/2007. We thank
A.P. Mudalige for technical assistance.
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Compounds 23a and 23b: Compound (+)-1 or (ꢀ)-1 (20 mg,
0.16 mmol) was dissolved in 0.2 mL of pyridine and then DMAP
(4 mg, 0.3 mmol) was added and reaction mixture was stirred for
5 min at 0 °C. (S)-(+)-MTPA-Cl (30 lL, 0.16 mmol) was then added
and stirring was continued at 0 °C for 4 h. After 4 h, the reaction
was quenched with water and diluted with EtOAc. The reaction
mixture was the washed with 1 M HCl, 1 M NaOH and brine. The
organic layer was then dried over Na2SO4 and concentrated. The
residue was then purified by flash chromatography (silica gel, ethyl
acetate/hexane, 1:10) to yield compounds 23a (14.9 mg, 27%) and
23b (13.6 mg, 25%), respectively. Compound 23a: 1H NMR
(600 MHz, CDCl3) d 7.52 (m, 2H), 7.40 (m, 3H), 6.02 (m, 1H), 5.90
(m, 1H), 4.56 (br s, 1H), 4.47 (ddd, J = 6.1, 6.5, 10.9 Hz, 1H), 4.39
(ddd, J = 6.4, 6.8, 10.9 Hz, 1H), 3.55 (br d, J = 1.2 Hz, 3H), 2.37 (m,
J = 1.8, 6.5, 7.2, 10.0 Hz, 1H), 2.12 (m, 1H), 2.10 (m, 1H), 2.04 (m,
1H), 1.84 (m, 1H); IR mmax 3402.36, 3063.90, 2956.21, 2925.44,
2849.24, 1747.45, 1451.90, 1268.29, 1169.67, 1123.52, 1019.27,
911.75, 799.82, 765.9, 719.6; HRMS calcd for C17H19O4F3Na:
367.1133, found: 367.1127. Compound 23b: 1H NMR (600 MHz,
CDCl3) d 7.53 (m, 2H), 7.41 (m, 3H), 6.00 (m, 1H), 5.87 (m, 1H),
4.45 (td, J = 6.0, 10.8 Hz, 1H), 4.41 (td, J = 6.4, 10.8 Hz, 1H), 3.56
(br d, J = 1.2 Hz, 3H), 2.36 (m, 1H), 2.11 (m, 1H), 2.04 (m, 1H),
1.83 (m, 1H). IR mmax 3446.15, 3123.07, 3015.38, 2984.61,
2907.69, 1747.03, 1272.10, 1169.38, 1123.34, 1018.89, 911.50,
765.45, 719.77.
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Acknowledgements
This project was funded by Natural Sciences and Engineering
Research Council of Canada (NSERC) strategic Grants
STGP307515-4 and STGP35104-5-2007 and, in part, by Human