Mono-etherification of racemic propane-1,2-diol by a tin(II) bromide catalyzed reaction with diazofluorene and a study of the Pseudomonas cepacia lipase catalyzed acetylation of the mono-ethers

Article abstract of DOI:10.1016/j.tetasy.2012.01.013

The tin(II) bromide catalyzed reaction of diazofluorene with racemic propane-1,2-diol in 1,2-dimethoxymethane gave the 1- and 2-monoethers in similar amounts. After tritylation of the 2-ether, 2-(9H-fluoren-9-yloxy)-1- triphenylmethyloxypropane and 1-(9H-fluoren-9-yloxy)propan-2-ol were obtained in pure form. The enantiomeric 1-fluorenyl ethers were resolved by kinetic resolution by transacetylation with the help of Pseudomonas cepacia lipase and both enantiomers of the propane-1,2-diol were obtained after deprotection. The racemic 2-(9H-fluoren-9-yloxy)propan-1-ol was obtained after de-triphenylmethylation. However, transacetylation onto this alcohol under identical conditions to those used for the 1-fluorenyl ether showed no enantioselectivity.

Full text of DOI:10.1016/j.tetasy.2012.01.013

Tetrahedron: Asymmetry 23 (2012) 157–163
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Tetrahedron: Asymmetry
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Mono-etherification of racemic propane-1,2-diol by a tin(II) bromide
catalyzed reaction with diazofluorene and a study of the Pseudomonas
cepacia lipase catalyzed acetylation of the mono-ethers
Sigthor Petursson a, , Sigridur Jonsdottir b
⇑
a Faculty of Business and Science, University of Akureyri, Borgum v/Nordurslod, 600 Akureyri, Iceland
b University of Iceland, Institute of Science, Dunhaga 3, IS-107 Reykjavik, Iceland
a r t i c l e i n f o
a b s t r a c t
Article history:
The tin(II) bromide catalyzed reaction of diazofluorene with racemic propane-1,2-diol in 1,2-dim-
ethoxymethane gave the 1- and 2-monoethers in similar amounts. After tritylation of the 2-ether,
2-(9H-fluoren-9-yloxy)-1-triphenylmethyloxypropane and 1-(9H-fluoren-9-yloxy)propan-2-ol were
obtained in pure form. The enantiomeric 1-fluorenyl ethers were resolved by kinetic resolution by
transacetylation with the help of Pseudomonas cepacia lipase and both enantiomers of the propane-
1,2-diol were obtained after deprotection. The racemic 2-(9H-fluoren-9-yloxy)propan-1-ol was
obtained after de-triphenylmethylation. However, transacetylation onto this alcohol under identical
conditions to those used for the 1-fluorenyl ether showed no enantioselectivity.
Received 20 December 2011
Accepted 19 January 2012
Available online 20 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
carbon in addition to the hydroxyl group and the hydrogen. This
will influence the enantioselectivity and can lead to complete lev-
The importance of the resolution of enantiomers to synthetic
chemistry has long been recognized, but it is only relatively re-
cently that techniques have become generally available which al-
low the large scale production of enantiomerically pure
compounds for research and industrial purposes. The global annual
sales of chiral technology products was over four billion US dollars
in 2009, with chiral synthesis products accounting for approxi-
mately 80% of this.1,2 Enantiomerically pure compounds from nat-
ural sources are, of course, widely available and industrially
important, but the chemical synthesis of racemic mixtures requires
resolution if enantiomeric purity is required. There are a number of
methods that have been used for the resolution of enantiomers as
discussed by Eliel and Wilen.3 Enzymatic resolution is particularly
important due to the high or total enantioselectivity obtained to-
gether with the ease of use. Lipases have been shown to give excel-
lent enantioselectivity in their catalysis of ester hydrolysis and in
the catalysis of transesterifications onto a secondary hydroxyl
group on a stereogenic carbon atom.4–6 Kazlauskas has given a
structural rationalization of the enantioselectivity with the so-
called Kazlauskas’s rule, which proposes that the active sites of
these enzymes contain two pockets, one large and the other one
small, accommodating the two groups attached to the stereogenic
els of enantioselectivity.7,8 According to Kazlauskas’s rule, a lipase
catalyzed transacetylation onto the secondary hydroxyl group of 1-
protected propane-1,2-diol will be (R)-selective (see Fig. 1).
The mechanism of the action of lipases, including the Pseudomo-
nas cepacia lipase, during hydrolysis and transacetylation reactions
has been described in great detail.9 Transesterification reactions
follow a so-called ping–pong mechanism whereby the acyl moiety
is first transferred onto the hydroxyl group of a serine residue on
the active site, before being transferred to the reacting alcohol.10,11
The ping–pong interaction of the enzymes with the two substrates
can be illustrated in the manner shown for the reaction of the (R)-
enantiomer of propane diol 1-monoether in Figure 2.12
There is great interest in 1,2-propanediol and 3-aryloxy-1,2-
propanediols as achiral building blocks for optically active liquid
crystals and pharmaceuticals.13–15,22 The present etherification re-
sulted in mono-ether formation, giving both the 1- and the 2-
ethers of the racemic propane-1,2-diol. After separation of the
mono-ethers, a lipase catalyzed transacetylation of both com-
pounds was carried out.13–16
2. Results and discussion
The kinetic evidence collected during this study shows the same
kind of pseudo 1st order behavior as observed in our earlier studies
using the present P. cepacia enzyme and lipozyme.17,18 The enzyme
catalyzed mechanism of the transesterification involving the
⇑
Corresponding author.
E-mail addresses: sigthor@unak.is (S. Petursson), sigga@raunvis.hi.is (S. Jonsdot-
tir).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.01.013

158
S. Petursson, S. Jonsdottir / Tetrahedron: Asymmetry 23 (2012) 157–163
since the enantioselectivity is shown toward the acyl receiving
OH
alcohol. During the enzyme catalyzed hydrolysis of enantiomeric
esters, the substrate binding to the active site involves the two
groups on the stereogenic carbon, the determinants in Kazlauskas
selectivity, but also the acyl part of the ester, which can be of
importance especially for long chain fatty esters. This may contrib-
ute to the binding of the ‘wrong’ enantiomer, whereas this factor is
not present during the acyl transfer onto a chiral secondary alco-
hol. The first part of the reaction sequence leading to the acetyla-
tion of 1-(9H-fluoren-9-yloxy)propan-2-ol is shown in Figure 3.
Vinyl acetate attaches itself to the enzyme active site and the acet-
yl group is immediately transferred onto the alcohol group of ser-
ine-87; the enol is released as acetaldehyde, its more stable
aldehyde form. The kinetic results show that this transformation
must be very fast and not rate limiting.
(R)
O
CH3
Figure 1. Illustration of Kazlauskas’s rule for fluorenyl ether protected propane-
1,2-diol where ester formation can only take place from above.
hydroxyl group of an active site serine and the nitrogen of a neigh-
boring histidine was illustrated by Al-Zuhair et al., while Schmid
and co-workers have classified the enantioselectivity of the Pseu-
domonas cepacia lipase toward thirty octanoic acid esters of chiral
secondary alcohols.10,11 The work herein is not entirely comparable
Following or concurrent to this, the secondary alcohol attaches
itself to the enantiospecific active site. The slow step, whereby this
alcohol reacts with the acyl ester intermediate then follows (Fig. 4).
O
OH
O
O
O
OR
(A)
(B)
OR (P)
E
O
E
EP
EA
E*A
E*
E*B
Figure 2. The ping–pong mechanism of a transesterification shown for a the reaction of a 1-protected propane-1,2-diol with vinyl acetate.
H3C
CH3
O
δ
Serine87
O
O
Serine87
O
O
H
O
H
δ
HN
+
N
N
H
N
H
Histidine286
Histidine286
Figure 3. The formation of an acyl-enzyme intermediate from vinyl acetate based on the results reported by Schmid and co-workers.
CH3
O
O
H
H
Serine87
O
Serine87
O
O
O
HO
HO
O
(
)
R
H
H3C
H
CH3
CH3
HN
N
H
(S)
N
H
N
H
Histidine286
Histidine286
(S)-enantiomer
partial structure
Figure 4. The transfer of the acyl group from the enzyme ester to the hydroxyl group of 1-(9H-fluoren-9-yloxy)propan-2-ol.

S. Petursson, S. Jonsdottir / Tetrahedron: Asymmetry 23 (2012) 157–163
159
H
Fl
H
OH
OH
O
SnBr2
DME
O
Fl
+
+ Fl= N2
OH
OH
1
3
2
DME = CH3OCH2CH2OCH3
Fl =
H
H
Fl
H
O
OH
H
Fl
OH
O
Et3N / DMAP
CH2Cl2
O
Fl
OCPh3
+
O
Fl
+ Ph3CCl
OH
+
2
4
3
2
Separate
H
H
Fl
Fl
O
O
NaHSO4 - SiO4
OH
OCPh3
CH2Cl2 / MeOH9:1
3
4
Scheme 1. Production and isolation of 2-(9H-fluoren-9-yloxy)propan-1-ol 3 and 1-(9H-fluoren-9-yloxy)propan-2-ol 2.
The difference between the position of the hydroxyl group of the
two enantiomers in relation to the acyl-enzyme moiety is evident.
This is reflected in the preferred reaction of the (R)-enantiomer.
An effective primary hydroxyl protection of rac-propane-1,2-
diol 1 and a good enantioselective esterification of the secondary
hydroxyl group will give a resolution of the enantiomers in a
separating 1- and 2- ethers. The use of the triphenylmethyl group
itself for the primary protection has also been reported on,
although the Pseudomonas cepacia lipase could not be used in this
case.18 The tin(II) bromide catalyzed reaction of diazofluorene with
rac-propane-1,2-diol 1 gave a mixture of monoethers 2 and 3 in
78% yield. In this case, selectivity for the primary position is much
less than in the case of diazo[bis(4-methoxyphenyl)]methane
giving more of the 2-ether. The 2-(9H-fluoren-9-yloxy)propan-1-
ol 3/1-(9H-fluoren-9-yloxy)propan-2-ol 2 ratio was 10:8.7, as
estimated from the methyl NMR signal integration. The use of
the tritylation-chromatography-detritylation methodology al-
lowed both mono-fluorenyl ethers to be available for resolution
experiments with the lipase (see Scheme 1).
fairly direct way. In
a previous paper, diazo[bis(4-methoxy-
phenyl)]methane was used for the monoetherification of the diol
to give the 1-ether in over an eightfold excess.17 Even if the regios-
lectivity was good in the etherification reaction, the separation of
the minor 2-ether required additional chemical steps involving
the triphenylmethylation of the primary hydroxyl group on the
2-ether, followed by chromatography. This method of forming
the triphenylmethyl ether of the 2-diarylmethyl ether of pro-
pane-1,2-diol in a mixture of the 1- and the 2-ether, which
themselves are inseparable, gives a mixture of 2-diarylmethyloxy-
propan-1-ol and 2-diarylmethyloxy-1-triphenylmethoxypropane
which are easily separable by flash chromatography. The triphen-
ylmethyl group can then be selectively removed by conventional
methods, for example sodium hydrogen sulfate on silica gel.19,20
This is, therefore, an effective if somewhat laborious way of
2.1. Kinetic resolution of enantiomers by lipase catalyzed
transacetylation
Lipases, for example from Pseudomonas cepacia, Candida antarti-
ca, and Mucor miehei, have proven to be very effective for the ki-
netic resolution of propane-1,2-diol derivatives.4,21 The enzyme
used for the resolution of the rac-1-(9H-fluoren-9-yloxy)propan-
2-ol by transacetylation from vinyl acetate was the Pseudomonas
cepacia lipase immobilized on ceramic particles. For the kinetic
study, the reaction was carried out on a 0.25 mmol scale using
di-isopropyl ether as the solvent and 10 mg of the immobilized en-
zyme. The reaction was monitored by HPLC with UV detection at
254 nm. Samples were extracted at regular intervals and quenched
in a 24-fold volume of methanol before injecting 0.010 mL into the
HPLC instrument. The results are shown in Table 1 and Figure 5.
The formation of the acetylated product is shown in Figure 5a as
the integration area of the product peak as a percentage of the total
integrated area for both the starting material and the product. It is
clear from this plot that the reacting enantiomer is virtually ex-
hausted after less than five hours, but the reaction was left for
4207 min, or almost three days. The magnitude of the 1st order
rate constant (0.0212 minꢀ1) is related to the amount of enzyme
present and is only given here for the sake of comparison with
Table 1
HPLC monitoring of the lipase catalyzed transacetylation from vinyl acetate to 1-
fluorenyloxypropan-2-ol
Reaction
time
% AreaSM
(% ASM
% Areacting enantiomer
(%AREM
ln (% AREM)
)
)
(min)
0
30
87
112
227
387
1432
2872
4207
100.0
81.5
59.1
54.7
51.0
49.9
49.8
49.2
48.9
50.0
31.5
9.1
4.7
1.0
—
—
—
—
3.912
3.450
2.204
1.547
0.000
—
—
—
—

160
S. Petursson, S. Jonsdottir / Tetrahedron: Asymmetry 23 (2012) 157–163
(a)
(b)
Figure 6. (a) Percentage of the 1-acetate formed during the transesterification (%
product of total integration for starting material + product). (b) First order rate
plot—ln (% racemic starting material) versus time.
Figure 5. (a) Percentage of the product formed during transesterification (%
product of total integration for starting material + product). (b) First order rate
plot—ln (% reacting enantiomer) versus time.
tive yield. This sequence of reactions therefore gave the 1-fluorenyl
reactions done under similar conditions. This shows that this
compound is a much better substrate than 1-[bis(4-methoxy-
phenyl)]methoxypropan-2-ol, with a rate constant approximately
four times larger for a reaction performed under similar conditions
(k0 = 0.317 hꢀ1 or 0.00528 minꢀ1).21 Based on the earlier results
with lipase catalyzed transesterification and Kazlauskas’s rule, it
is the (R)-enantiomer which reacts;4,19,20,23 the transformation that
takes place is as shown in Scheme 2.
The graph in Figure 5a clearly shows that the (R)-enantiomer
must be formed almost exclusively during the first 24 h and that
the product has an enantiomeric excess (ee) very close to 100%.
The residual rate from 1440 min (24 h) to 4207 min after exhaus-
tion of the (R)-alcohol can be taken as the rate for the acetylation
of the (S)-enantiomer and corresponds to 0.00032%/min. Since
the (R)-enantiomer is a much better substrate and thus excludes
the (S)-enantiomer from the enzyme active site while it is still
present, an absolute lower limit the (R)-enantiomer is 98% ee.
The preparative enzyme catalyzed acetylation of racemic 1-fluore-
nyl ether 2 was run for 24 h and gave, after chromatography on
silica gel, (R)-2-acetoxy-1-(9H-fluoren-9-yloxy)propane 7 in 94%
yield based on the reacting enantiomer and the unreacted enantio-
mer, (S)-1-(9H-fluoren-9-yloxy)propan-2-ol 6, in 89% yield.
Zemplen deacetylation of (R)-2-acetoxy-1-(9H-fluoren-9-yloxy)-
propane gave (R)-1-(9H-fluoren-9-yloxy)propan-2-ol in quantita-
ethers of both the (R)- and (S)-propane-1,2-diol; (R)-enantiomer,
mp 90–91 °C, ½a 2D0
¼ þ2:8 (c 1.17, CHCl3); (S)-enantiomer, mp
ꢁ
89–90 °C, ½a 2D0
¼ ꢀ2:9 (c 1.09, CHCl3). Catalytic hydrogenolysis of
ꢁ
(R)-1-(9H-fluoren-9-yloxy)propan-2-ol gave (R)-propane-1,2-diol
in 80%, ½a 2D0
ꢁ
¼ ꢀ29:1 (c 1.73, CHCl3). Lit. ½a D20
¼ ꢀ28 (c 0.34, CHCl3)
ꢁ
and of (S)-1-(9H-fluoren-9-yloxy)propan-2-ol gave (S)-propane-
1,2-diol in 73%, ½a D20
ꢁ
¼ þ28:8 (c 1.38, CHCl3). Lit. ½a D20
¼ þ29
ꢁ
(c 1.1, CHCl3).10
2.2. Lipase catalyzed acetylation of rac-2-(9H-fluoren-9-
yloxy)propan-1-ol
The enantioselectivity for the primary hydroxyl groups next to
the stereogenic carbon atom, although sometimes observed, is
not nearly as pronounced as for the secondary hydroxyl group.24
Since the triphenylmethylation of the mixture of rac-2-(9H-
fluoren-9-yloxy)propan-1-ol and rac-1-(9H-fluoren-9-yloxy)pro-
pan-2-ol, followed by chromatographic separation, made the
rac-2-(9H-fluoren-9-yloxy)propan-1-ol available, we decided to
investigate a lipase catalyzed transacetylation onto the primary
hydroxyl group of the 2-ether. The reaction was carried out on
the 2-fluorenyl ether in the same manner as previously carried
out for the 1-ether. In this case, the reaction did not stop at
O
Lipase
C
CH3
O
OH
Pseudomonas
cepacia
H
O
OH
H
H
O
O
O
Fl
+
O
Fl
Fl
(i-Pr)2O
+
6
2
7
5
(S)-1-(9H-Fluoren-9-yloxy)propan-2-ol
Scheme 2. Kinetic resolution of the racemic 1-fluorenyloxypropan-2-ol by transacetylation from vinyl acetate using Pseudomonas cepacia lipase as a catalyst.

S. Petursson, S. Jonsdottir / Tetrahedron: Asymmetry 23 (2012) 157–163
161
O
O
O
(R)
H2C
H
H
CH3
CH3
+
Serine87
O
O
O
HO
(R)
H
H
H
O
O
O
N
CH3
(S)
HO
(S)
N
H
H2C
Histidine286
CH3
(S)-enantiomer
partial structure
Figure 7. Acetylation of the primary hydroxyl group of rac-2-(9H-fluoren-9-yloxy)propan-1-ol.
50% conversion but went on to completely acetylate both enan-
tiomers with no visible change in the reaction rate. Figure 6
shows the results obtained from HPLC monitoring of the reaction.
It is clear from these results that there is not a significant differ-
ence between the rate of acetylation of the two enantiomers
present. It is interesting to compare these results with those ob-
tained for the same enzyme where high enantioselectivity was
obtained for the acetylation of primary alcohols containing an
aromatic system attached to the stereogenic carbon or to its al-
pha carbon.21,25 The present results suggest that if the aromatic
system is removed one position further away from the stereo-
genic carbon, in this case by the ether oxygen, the enantioselec-
tivity of the enzyme is completely lost. In spite of this lack of
selectivity it is clear that this primary alcohol binds to the active
site of the enzyme, since the acetylation still takes place. It is
perhaps significant that the rate constant for acetylation of this
primary alcohol is less than 70% of the rate for the secondary
alcohol. This difference in rate is even more significant if we take
into account that the substrate concentration is twice as high
since both enantiomers are reacting.
products obtained from the enzyme catalyzed reaction, (R)-2-
acetoxy-1-(9H-fluoren-9-yloxy)propane and (S)-1-(9H-fluoren-9-
yloxy)propan-2-ol were isolated in 94% and 89% yields,
respectively, based on the amount of the corresponding enantio-
mers. Confirmation of enantiomeric structures was obtained by
deprotection of these propane-1,2-diol derivatives by conventional
methods resulting in (R)-propane-1,2-diol, ½a D20
¼ ꢀ29:1 (c 1.73,
ꢁ
CHCl3), and (S)-propane-1,2-diol, ½a D20
¼ þ28:4 (c 1.38, CHCl3) with
ꢁ
identical NMR spectra to authentic samples.17
4. Experimental
4.1. General
Thin layer chromatography (TLC) was carried out on aluminium
sheets coated with silica gel 60-F254 and detected under a UV lamp
and using a spray of 0.2% w/v cerium(IV) sulfate and 5% ammo-
nium molybdate in 2 M sulfuric acid with heating. 1H and 13C
NMR spectra were run on a Bruker Avance 400 (Bruker Biospin
GmbH, Rheinstetten, Germany) instrument with Me4Si as the
external standard using chloroform (7.26 ppm for 1H and
77.0 ppm for 13C) or dichloromethane (5.32 ppm for 1H and
53.8 ppm for 13C) as the internal standards. The 1H spectra were
measured at 400.12 and 13C spectra at 100.61 MHz, both at
298 K. Mass spectra were run on a Bruker MicroTof-Q mass spec-
trometer using electrospray ionization (ESI). Diazofluorene was
prepared using a previously published method.26 General reagents
and catalyst reagents and catalysts were from chemical suppliers
and usually used without further purification. 1,2-Dimethoxyeth-
ane was distilled from and stored over sodium. Ethyl acetate and
hexane were of HPLC grade and used as received. The enzyme used
was Fluka 17261 Pseudomonas cepacia lipase immobilized on cera-
mic particles (bought from Sigma/Aldrich). The HPLC instrument
was Shimadzu Prominence with a reversed phase 150 ꢂ 4.6 mm
SS Wakosil C18RS 3 mm column. The elution was isocratic with
methanol/water 4:1 and detection was done with a UV detector
at 254 nm.
Figure 7 shows a plausible explanation for this loss of enanti-
oselectivity. We assumed that the methyl group and the O-fluore-
nyl group attached to the stereogenic carbon fit into the small and
the larger groves on the enzyme. The difference from the 1-fluore-
nyl ether is that the reacting hydroxyl group is now attached to the
1-methylene, thus giving it greater mobility, which presumably re-
sults in the hydroxyl group of both enantiomers being able to ap-
proach the acetyl group and react.
3. Conclusion
The tin(II) bromide catalyzed mono-etherification of propane-
1,2-diol with diazofluorene, followed by tritylation of the isomer
containing the primary hydroxyl group and chromatography is a
reliable method for obtaining the 1-ether. The triphenylmethyl
group can be easily removed from rac-2-(9H-fluoren-9-yloxy)-1-
triphenylmethyloxypropane to give the 2-fluorenyl ether. Both of
these alcohols can be effectively acetylated using Pseudomonas
cepacia lipase catalyzed transesterification from vinyl acetate. No
enantioselectivity is observed during the acetylation of the racemic
primary alcohol. In the case of rac-1-(9H-fluoren-9-yloxy)propan-
2-ol, the enzyme catalyzed transesterification gave complete
enantioselectivity for (R)-1-(9H-fluoren-9-yloxy)propan-2-ol to
4.2. Monofluorenylation of rac-propane-1,2-diol
rac-Propane-1,2-diol (1.17 g, 15.0 mmol) was dissolved in 1,2-
dimethoxyethane (75 mL). Tin(II) bromide (300 mg, 1.08 mmol)
was then added followed by diazofluorene (3.78 g, 19,7 mmol)
and the reaction left at room temperature. Examination of the
produce
(R)-2-acetoxy-1-(9H-fluoren-9-yloxy)propane.
The

162
S. Petursson, S. Jonsdottir / Tetrahedron: Asymmetry 23 (2012) 157–163
TLC showed that the reaction was almost complete after 6 h, but it
was left overnight for completion. A few grams of silica gel was
added and the solvent removed on a rotary evaporator. The mix-
ture of monoethers was isolated from a column of silica gel eluting
with hexane/EtOAc 9:1 followed by 4:1 and finally 3:2. The prod-
uct mixture (3.26 g, 90%) of the 2- and 1-monoethers (in a ratio
of 10:8.9 from NMR), was isolated as a white solid. 1H NMR
(400 MHz, CDCl3). dH 1.05 (3H, d, JH3,H2 6.32 Hz, CH3 for 1-ether),
1.20 (3H, d, JH3,H2 6.32 Hz, CH3 for 2-ether), 2,20 (1H, s, (OH for
2- and 3-ether), 2.99 (1H, dd, JAB 9.35 Hz, JH1,H2 7.97 Hz, H-1A for
1-ether), 3.17 (1H, dd, JBA 9.35 Hz, JH1,H2 3.03 Hz, H-1B for 1-ether),
3.48 (1H, dd, JAB 11.37 Hz, JH1,H2 6.82 Hz, H-1A for 2-ether), 3.56
(1H, dd, JAB 11.37 Hz, JH1,H2 3.54 Hz, H-1B for 2-ether), 3,90 (1H
m, H-2 for 2- and 3-ether), 5.60 (1H, s ArCH for 2-ether), 5.68
(1H, s, ArCH for 1-ether), 7.49 (16H, m, Haromatic); 13C NMR
(100 MHz, CDCl3) dC 17.8, 18.7 (CH3 1- and 2-ether), 66.9 (CH3 1-
and 2-ether), 70.3 (C-2 1- and 2-ether), 74.7 (C-1 1- and 2-ether),
80.1, 80.8 (ArCH 2- and 1-ether), 120,0, 125.5, 127,7, 129.2 (aro-
matic C-1–4 and C-5–8, 1- and 2-ether), 140.6, 140.9, 142.6,
143.5, 143.9 (aromatic C-9–13).
rac-2-(9H-fluoren-9-yloxy)propan-2-ol purified on a column of sil-
ica gel, eluting with Hex/EtOAc 4:1 followed by 3:2. The product
(780 mg, 78.4%) was re-crystallized from 10% ethyl acetate in hex-
ane, mp 94–95 °C. 1H NMR (400 MHz, CDCl3). dH 1.20 (3H, d, JH3,H2
6.06 Hz, CH3), 2.06 (1H, s, OH), 3.47 (1H, dd, JAB 11.62 Hz, JH1,H2
6.57 Hz, H-1A), 3.56 (1H, dd, JBA 11.37 Hz, JH1,H2 3.79 Hz, H-1B),
3.88 (1H, m, H-2), 5.60 (1H, s, ArCH), 7.26–7.68 (8H, m, Haromatic);
13C NMR (100 MHz, CDCl3) dC 17.8, (CH3), 66.9 (C-2), 74.7 (C-1),
80.1 (ArCH), 120,0, 125.4, 127,7, 129.1 (aromatic C-1–4 and C-5–
8 1- and 2-ether), 140.5, 143.5, 144.1 (aromatic C-9–13). Calcd
for C16H16O2ꢃNa m/z 263.1043. Found: 263.1043.
4.5. Lipase catalyzed resolution of rac-1-(9H-fluoren-9-yloxy)
propan-2-ol
At first, rac-1-(9H-fluoren-9-yloxy)propan-2-ol (721 mg,
3.00 mmol) was dissolved in di-isopropyl ether (30 mL). Vinyl ace-
tate (258 mg, 0.276 mL, 3.00 mmol) and the immobilized Pseudo-
monas cepacia lipase (120 mg) were added. The mixture was
stirred gently at room temperature using a magnetic stirrer and
monitored by TLC (Hex/EtOAc 4:1) and HPLC (reversed phase
150 ꢂ 4.6 mm SS Wakosil C18 RS 3 mm column; 25-fold dilution,
0.010 mL injected; eluent 80% MeOH). The reaction was stopped
after 25 h by removing the enzyme by filtration and rinsing the
reaction vessel and filtering by using dichloromethane. Two com-
ponents were visible on the TLC (Hex/EtOAc 4:1). The faster acety-
lated enantiomer is (R)-2-acetoxy-1-(9H-fluoren-9-yloxy)propane
(Rf 0.5) and the unreacted alcohol (S)-1-(9H-fluoren-9-yloxy)pro-
pan-2-ol (Rf 0.2). The resulting mixture of acetylated (R)-1-(9H-flu-
oren-9-yloxy)propan-2-ol and the non-reacting (S)-1-(9H-fluoren-
9-yloxy)propan-2-ol was separated on a column of silica gel, elut-
ing with Hex/EtOAc 4:1 to 3:2, giving syrupy (R)-2-acetoxy-1-(9H-
4.3. Triphenylmethylation of rac-2-(9H-fluoren-9-yloxy)propan-
1-ol in a 53:47 mixture of the 1- and 2-fluorenyl ether of rac-
propane-1,2-diol
rac-Propane-1,2-diol monofluorenyl ether (3.26 g, 13.6 mmol)
and rac-2-(9H-fluoren-9-yloxy)propan-1-ol) (1.53 g, 6.38 mmol)
were dissolved in dichloromethane (25 mL). Triethylamine
(0.968 g, 1.33 mL, 9.57 mmol) and p-dimethylaminopyridine
(DMAP, 31 mg, 0.26 mmol) were added, followed by triphenyl-
methyl chloride (2.22 g, 7.98 mmol) (25% excess based on the 2-
ether). The reaction was left to proceed overnight at room temper-
ature. The reaction mixture was filtered into a 100 mL RB flask,
after which approximately 7 g of silica gel was added and the sol-
vent removed on a rotary evaporator. The product and the unre-
acted 1-ether were separated on a column of silica gel, eluting
with Hex/EtOAc 9:1 to 1:1. rac-2-(9H-Fluoren-9-yloxy)-1-triphe-
nylmethyloxypropane (3.06 g, 99%)was isolated from the early
fractions as an amorphous solid (based on 2-fluorenyl ether in
starting material). 1H NMR (400 MHz, CDCl3). dH 1.24 (3H, d,
JH3,H2 6.32 Hz, CH3), 3.02 (1H, dd, JAB 9.35 Hz, JH1,H2 6.06 Hz, H-
1A), 3.25 (1H, dd, JBA 9.35 Hz, JH1,H2 5.56 Hz, H-1B), 3.85 (1H, m,
H-2), 5.65 (1H, s ArCH), 7.21–7.68 (23H, m, Haromatic); 13C NMR
(100 MHz, CDCl3) dC 19.5, (CH3), 68.2 (C-2), 73.0 (C-1), 80.6
(Ph3C), 86.6 (ArCH), 120,0, 125.5, 125,8, 126.9, 127.8, 128.8,
fluoren-9-yloxy)propane (394 mg 93%)
½
a 2D0
ꢁ
¼ þ22:4 (c 1.32,
CHCl3). 1H NMR (400 MHz, CDCl3). dH 1.18 (3H, d, JH3,H2 6.57 Hz,
CH3), 2.06 (3H, s, CH3C@O), 3.11 (2H, ABM system, JAB 10.4 Hz,
JHA1,H2 3.79 Hz, JBA 10.0 Hz, JHB1,H2 2.53 Hz, H-1 A and B), 4.98
(1H, m, H-2), 5.71 (1H, s, ArCH), 7.30–7.69 (8H, m, Haromatic); 13C
NMR (100 MHz, CDCl3) dC 16.7, (CH3), 21.7, (CH3C@O), 66.7 (C-2),
69.9 (C-1), 80.8 (ArCH), 120,2, 125.5, 127,6, 129.1 (aromatic C-1–
4, C-5–8, C-12–13), 140.9, 142.4, (aromatic C-9–10), 170.3
(CH3C@O).
The later fractions gave the unreacted (S)-1-(9H-fluoren-9-
yloxy)propan-2-ol (322 mg 89%) which was crystallized from ethyl
acetate/hexane, mp 89–90 °C.%, ½a D20
ꢁ
¼ ꢀ2:9 (c 1.09, CHCl3). 1H
NMR (400 MHz, CDCl3). dH 1.04 (3H, d, JH3,H2 6.32 Hz, CH3), 2.36
(1H, s, -OH), 2.98 (1H, dd, JAB 9.20 Hz, JHA1,H2 8.00 Hz, HA-1), 3.17
(1H, dd, JBA 9.21 Hz, JHB1,H2 3.17 Hz, HB-1), 3.91 (1H, m, H-2), 5.60
(1H, s, ArCH), 7.30–7.69 (8H, m, Haromatic); 13C NMR (100 MHz,
CDCl3) dC 18.7, (CH3), 67.0 (C-2), 70.0 (C-1), 80.8 (ArCH), 120,0,
125.5, 127,6, 129.2 (aromatic C-1–4, C-5–8, C-12–13), 140.9,
142.5, (aromatic C-9–10). Calcd for C16H16O2ꢃNa m/z 263.1043.
Found: 263.1039.
144.0, 144.2(aromatic carbons). Calcd for
505.2138. Found: 505.2129.
C35H30O2+Na m/z
Fractions 9–11 gave the unreacted rac-1-(9H-fluoren-9-
yloxy)propan-2-ol (1.39 g, 80.3%). The white solid was recrystal-
lized by dissolving in hot ethyl acetate, 3 mL, and hexane, 27 mL,
mp 87–88 °C. 1H NMR (400 MHz, CDCl3). dH 1.07 (3H, d, JH3,H2
6.57 Hz, CH3), 2.39 (1H s, OH), 3.20 (2H, dd, JAB 9.35 Hz, JH1,H2
3.03 Hz, H-1A
B), 3.94 (1H, m, H-2), 5.71 (1H s, ArCH), 7.52
and
(8H, m, Haromatic); 13C NMR (100 MHz, CDCl3) dC 18.66, (CH3),
66.9 (C-2), 70.0 (C-1), 80.8 (ArCH), 120,1, 125.4, 127,7, 129.2 (aro-
matic C-1–4 and C-5–8), 140.6, 142.6 (aromatic C-9–13).
4.5.1. (R)-1-(9H-Fluoren-9-yloxy)propan-2-ol
(R)-2-Acetoxy-1-(9H-fluoren-9-yloxy)propane
(392 mg,
1.39 mmol) was dissolved in dry methanol (9 mL) after which
0.1 M methanolic sodium methoxide (1 mL) was added. The reac-
tion was not complete after 1.5 h; thus a further 1 mL of the meth-
oxide solution was added and the reaction left overnight. The
product was purified on a column of silica gel (Hex/EtOAc 3:1) to
yield the title compound which crystallized from EtOAc/hexane
4.4. rac-2-(9H-Fluoren-9-yloxy)-1-propanol—Detriphenylmethy-
lation of rac-2-(9H-fluoren-9-yloxy)-1-triphenylmethyloxy-
propane
The triphenylmethyl ether (2.00 g, 4.14 mmol) was dissolved in
dichloromethane/methanol (9:1, 60 mL). Sodium hydrogen sulfate
monohydrate-silica gel was prepared according to the literature.27
Next, 400 mg of this gel was added and the mixture stirred mag-
netically for 2 h. The catalyst was filtered off and the resulting
(340 mg, 100%), mp 90–91 °C, ½a D20
ꢁ
¼ þ2:8 (c 1.17, CHCl3). 1H
NMR (400 MHz, CDCl3). dH 1.04 (3H, d, JH3,H2 6.57 Hz, CH3), 2.35
(1H, broad peak, OH), 2.98 (1H, dd, JAB 9.35, JA,H2 7.83 Hz, H1A),
3.17 (1H, dd, JBA 9.10, JB,H2 3.28 Hz, H1B), 3.90 (1H, m, H2), 5.68
(1H, s, FlCH), 7.28–7.68 (8H, m, aromatic protons); 13C NMR

S. Petursson, S. Jonsdottir / Tetrahedron: Asymmetry 23 (2012) 157–163
163
(100 MHz, CDCl3) dC 18.69, (C-3), 66.91, (C-2), 69.97 (C-1), 80.80
(FlCH), 120.1, 125.6, 127.6, 129.1, 140.9, 142.5 (aromatic C). Calcd
for C16H16O2ꢃNa m/z 263.1043. Found: 263.1122 amu.
tored by tlc (Hex/EtOAc 4:1) and HPLC (reversed phase
150 ꢂ 4.6 mm SS Wakosil C18RS 3 mm column; 25 fold dilution,
0.010 mL injected; eluent 80% MeOH). The reaction had gone to
completion after 20 h and the enzyme was filtered from the reac-
tion mixture washing with dichloromethane. The product was
purified on a column of silica gel, eluting with Hex/EtOAc 4:1.The
racemic acetate was isolated as an oil (801 mg, 95%). 1H NMR
(400 MHz, CDCl3). dH 1.07 (3H, d, JH3,H2 6.57 Hz, CH3), 1.98 (3H, s,
acetate CH3), 3.71 (1H, m, H2), 3.92 (2H, ABM octet, JAB 11.37,
JA,H2 5.56, JBA 11.62, JB,H2 4.80 Hz, gem H1’s), 5.56 (1H, s, FlCH),
7.2–7.6 (8H, m, aromatic protons); 13C NMR (100 MHz, CDCl3) dC
18.76, (C-3), 20.96, (acetate C-2), 68.25, (C-2), 70.92 (C-1), 80.62
(FlCH), 120.0, 125.7, 127.6, 127.5, 129.1, 140.7, 143.4 (aromatic
C), 171.0 (C@O).
4.6. Hydrogenolysis of (R)- and (S)-1-(9H-fluoren-9-yloxy)
propan-2-ol
(a) (R)-1-(9H-Fluoren-9-yloxy)propan-2-ol (300 mg, 1.25 mmol)
was dissolved in methanol (10 mL) and 10% palladium-on-charcoal
(25 mg) was added. The mixture was stirred magnetically and the
flask evacuated under reduced pressure. Hydrogen was introduced
and the flask stirred overnight. The TLC (Hex/EtOAc 1:1) showed
complete reaction and the product was purified on a column of silica
gel (Et2O/MeOH 9:1) giving (R)-propane-1,2-diol (76 mg,
80%).½a 2D0
ꢁ
¼ ꢀ29:1 (c 1.73, CHCl3). 1H and 13C NMR spectra were
identical to the (R)-enantiomer prepared earlier.17
Acknowledgments
(b) (S)-1-(9H-Fluoren-9-yloxy)propan-2-ol (305 mg, 1.27 mmol)
was dissolved in methanol (10 mL) and 10% palladium-on-charcoal
(25 mg) was added. The mixture was stirred magnetically and the
flask evacuated under reduced pressure. Hydrogen was introduced
and the flask stirred overnight. The TLC (Hex/EtOAc 1:1) showed
complete reaction and the product was purified on a column of silica
gel (Et2O/MeOH 9:1) giving (S)-propane-1,2-diol (70 mg,
The University of Akureyri and Rannis are thanked for financial
support. Prof. Guðmundur G. Haraldsson and his students at the
Science Institute, University of Iceland, are thanked for helpful dis-
cussions and specific rotation analysis. Sean M. Scully is thanked
for technical assistance.
73%).½a 2D0
ꢁ
¼ þ28:8 (c 1.38, CHCl3). 1H and 13C NMR spectra were
References
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4.7. rac-2-(9H-Fluoren-9-yloxy)propan-1-ol
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(1H, m, 2-CH), 5.64 (1H, s, FlCH), 7.3–7.7 (8H, m, aromatic protons;
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The racemic title compound (721 mg, 3.00 mmol) was dissolved
in di-isopropyl ether (30 mL). Vinyl acetate (322 mg, 0.345 mL,
3.75 mmol) was added, followed by the immobilized enzyme
(Pseudomonas cepacia lipase) (120 mg). The mixture was stirred
gently at room temperature using a magnetic stirrer and moni-