Dynamic kinetic resolution of homoallylic alcohols: Application to the synthesis of enantiomerically pure 5,6-dihydropyran-2-ones and δ-lactones

Article abstract of DOI:10.1002/chem.201301980

Dynamic kinetic resolution of various homoallylic alcohols with the use of Candida antarctica lipase B and ruthenium catalyst 2 afforded homoallylic acetates in high yields and with high enantioselectivity. These enantiopure acetates were further transfor

Full text of DOI:10.1002/chem.201301980

FULL PAPER
DOI: 10.1002/chem.201301980
Dynamic Kinetic Resolution of Homoallylic Alcohols: Application to the
Synthesis of Enantiomerically Pure 5,6-Dihydropyran-2-ones and d-Lactones
Madeleine C. Warner, Grigory A. Shevchenko, Suzan Jouda, Krisztiꢀn Bogꢀr,* and
Jan-E. Bꢁckvall*[a]
Abstract: Dynamic kinetic resolution of various homoallylic alcohols with the use
of Candida antarctica lipase B and ruthenium catalyst 2 afforded homoallylic ace-
tates in high yields and with high enantioselectivity. These enantiopure acetates
were further transformed into homoallylic acrylates after hydrolysis of the ester
function and subsequent DMAP-catalyzed esterification with acryloyl chloride.
After ring-closing metathesis 5,6-dihydropyran-2-ones were obtained in good
Keywords: dynamic kinetic resolu-
tion · homoallylic alcohols · lac-
tones · racemization · ruthenium
catalysis
À
yields. Selective hydrogenation of the carbon carbon double bond afforded the
corresponding d-lactones without loss of chiral information.
Introduction
The d-lactone ring is an important structural motif in organ-
ic chemistry since it is present in many natural products iso-
lated from insects, plants, fungi and marine organisms
(Figure 1).[1] The structure, synthesis and biological activity
of many naturally occurring chiral lactone moieties have
been described in the literature.[2] The unsaturated 5,6-dihy-
dropyran-2-ones have been found to be cytotoxic,[3] they can
inhibit HIV protease,[4] they can induce apoptosis,[5] and
they have been shown to be antileukemic.[6] Some of these
pharmacological effects can be explained by the presence of
À
the conjugated carbon carbon double bond, which can act
as a Michael acceptor in biological systems. As a conse-
quence, synthesis of these unsaturated lactones has attracted
considerable attention. Recently, Marco et al. reviewed
methods for stereoselective synthesis of naturally occurring
5,6-dihydropyran-2-ones.[7] Since variation of the substitu-
ents on these lactones has a potential impact on drug
design, the development of new efficient strategies to gener-
ate skeletal diversity in these compounds is highly desirable
in drug discovery.[8]
Enzyme-catalyzed kinetic resolution (KR) of a racemate
has been shown to be an environmentally friendly and con-
venient technique for the separation of enantiomers. The
major drawback of a KR is that the method only provides a
Figure 1. Some representative natural products containing
moiety.
a lactone
maximum of 50% yield of the desired enantiomer in its op-
tically pure form. This limitation can be circumvented by
combining the enzymatic resolution with an in situ racemi-
zation of the two enantiomers, leading to dynamic kinetic
resolution (DKR). DKR emerges over KR as a more power-
ful tool for the preparation of enantiomerically pure com-
pounds, since the desired product can be obtained in a maxi-
mum yield of 100%.
[a] Dr. M. C. Warner, G. A. Shevchenko, S. Jouda, Dr. K. Bogꢀr,
Prof. J.-E. Bꢁckvall
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University, 106 91 Stockholm (Sweden)
E-mail: krisztian@organ.su.se
jeb@organ.su.se
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301980.
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13859

A part of our research program focuses on the develop-
ment of efficient DKR protocols for alcohols and amines to
provide the corresponding enantiopure esters and amides.
These products are highly valuable building blocks for asym-
metric synthesis of structurally more complex molecules.[9,10]
Initial work in the area was performed with Shvoꢃs catalyst
1, a dimeric Ru-based racemization catalyst used in combi-
nation with lipases (Figure 2).[11] More recently, our group
Scheme 1. Synthetic strategy towards enantioenriched 5,6-dihydropyran-
2-ones (R)-IV and d-lactones (R)-V through DKR and subsequent RCM.
lylmagnesium chloride to commercially available aldehydes.
Under standard conditions the Grignard reaction afforded a
wide range of racemic homoallylic alcohols in high yields
(Scheme 2; see the Supporting Information for further de-
tails and characterization).
Figure 2. Ruthenium catalysts 1 and 2 utilized for racemization of sec-al-
cohols.
has developed a second generation ruthenium catalyst for
the racemization of secondary alcohols, [RuCl(CO)2ACTHNUTRGNEUNG
(h5-
C5Ph5)] (2; Figure 2).[12] Catalyst 2 has been utilized in com-
bination with lipases in DKR of a wide range of sub-
strates[13] and has successfully been scaled-up to >100g
scale.[14]
Homoallylic alcohols are common precursors for the syn-
thesis of enantiomerically pure lactones.[15] The DKR of ho-
moallylic alcohols has been studied previously. In 2011, the
groups of Kanerva and Leino published the DKR of 1-
phenyl-3-buten-1-ol, but the reaction required a very long
time (168 h).[10c] Furthermore, Kim and Park reported on
the DKR of a few homoallylic alcohols utilizing an ionic-
surfactant-coated Burkholderia cepacia lipase (ISCBCL).[16]
The method gave high yields and 95–98% ee.
Herein we wish to report on an efficient DKR protocol
for a wide range of homoallylic alcohol substrates. The cor-
responding esters were in many cases obtained in high
yields and with excellent ee values. We also devised a gener-
al synthetic route for the enantioselective synthesis of 5,6-di-
hydropyran-2-ones and d-lactones utilizing DKR of homoal-
lylic alcohols in the enantiodetermining step. Our synthetic
strategy begins with the DKR of various homoallylic alco-
hols, rac-I, which are transformed to the corresponding ho-
moallylic esters (R)-II in high yields and with excellent
enantioselectivity. After base hydrolysis the enantiopure ho-
moallylic alcohols (R)-I obtained are allowed to react with
acryloyl chloride providing acrylates (R)-III. These acrylates
are further transformed into 5,6-dihydropyran-2-ones (R)-IV
via ring-closing metathesis (RCM). Subsequent selective re-
Scheme 2. Synthesis of homoallylic alcohol substrates 3a–n.
Enzymatic kinetic resolution of homoallylic alcohols: We
first studied the enzymatic kinetic resolution of 1-phenyl-3-
buten-1-ol (rac-3a) as model substrate with a variety of dif-
ferent commercially available homogeneous and immobi-
lized lipases. The reactions were conducted in dry toluene at
different temperatures (20, 40 and 708C). Out of the tested
enzymes, immobilized Burkholderia cepacia lipase (previ-
ously Pseudomonas cepacia lipase) on ceramic particles, PS-
C “Amano” I and PS-C “Amano” II and polymer supported
Candida antarctica lipase B (CALB) showed the highest ac-
tivity. When utilizing 80 mgmmolÀ1 of the immobilized
enzyme together with isopropenyl acetate as acyl donor
(1.5 equiv), the transesterification reaction became complete
after 22 h at 708C (see the Supporting Information for fur-
ther details). Since a highly enantioselective enzyme-cata-
lyzed acylation is required for obtaining enantiomerically
enriched products by DKR, we chose CALB for the enzy-
matic resolution and combined it with racemization catalyst
2.
Next, the selectivity of the enzymatic reaction with CALB
was investigated by calculating the E value at 708C for a
few of the substrates (Table 1). As can be seen from the re-
sults, high E values were obtained, indicating a highly selec-
tive enzymatic resolution. The model substrate rac-3a
showed the best selectivity giving an E value of >200
(Table 1, entry 1). A slightly lower selectivity was obtained
with the introduction of a substituent on the aromatic ring
À
duction of the carbon carbon double bond affords the d-lac-
tones (R)-V in high yields with retained chiral information
(Scheme 1).
Results and Discussion
Synthesis of homoallylic alcohol substrates: The homoallylic
alcohol substrates 3a–n were synthesized by addition of al-
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Dynamic Kinetic Resolution of Homoallylic Alcohols
FULL PAPER
Table 1. Kinetic resolution of homoallylic alcohols rac-2.
resolution and the racemization in hand, their successful
combination in a DKR was promising. DKR of homoallylic
alcohols 3a–n was performed on a 1 mmol scale, employing
a 5 mol% loading of Ru-catalyst 2 at 708C (Table 2). In
most cases the acylated products were obtained in good to
excellent yields with high to excellent enantioselectivity. The
products were isolated by column chromatography on silica.
DKR of rac-3a afforded the corresponding enantiopure
(R)-1-acetoxy-1-phenyl-3-butene [(R)-3a] in high yield and
with excellent ee (Table 2, entry 1). This reaction was also
run on a 5 mmol scale, which afforded an 84% isolated
yield of enantiopure product (R)-3a. Substituents in the
para-position on the aromatic ring were shown to be com-
patible with the catalytic system (Table 2, entries 2–6). On
the other hand substituents in the ortho-position were found
to have a negative effect on both the racemization and the
enzymatic resolution (Table 2, entries 7 and 8), most likely
due to steric factors. Although the 1-naphthyl substrate 3h
was a very poor substrate (entry 8) the corresponding 2-
naphthyl substrate 3i gave a good yield in 96% ee (entry 9).
Electron-withdrawing substituents on the aromatic ring
were compatible with the reaction conditions (Table 2, en-
tries 4–6) but electron-donating substituents seemed to be
moderately tolerated (Table 2, entry 3). For the para-me-
thoxy substituted substrate rac-3c, the racemization was
considerably slowed down due to the presence of the elec-
tron-donating substituent. Therefore, the enzyme loading
was substantially decreased to provide a slower reaction,
and hence a better match with the rate of racemization. This
resulted in incomplete conversion but a good ee was ob-
tained for this substrate (Table 2, entry 3). Interestingly, two
heterocyclic substrates tested also showed high compatibility
with this catalytic system (entries 10 and 11). For substrate
rac-3m, which also contains an allylic functionality, the reac-
tion was run at room temperature, which afforded the prod-
uct (R)-4m in 63% yield and with 98% ee (Table 2,
entry 13). In this reaction, 19% of 4-oxo-6-phenyl-1-hexene
was also obtained as a byproduct from isomerized starting
material. Aliphatic substrates in which the small group is
larger than ethyl and/or functionalized, generally show a
very unselective enzymatic reaction.[13d] We were therefore
pleased to find that a good result was obtained for the ali-
phatic substrate rac-3n, which afforded an 82% isolated
yield and 94% ee of the product (S)-4n (Table 2, entry 14).
Entry[a]
Substrate
t [h]
Conv.
[%][b]
ee (R)-4
E[d]
[%][c]
1
2
3
3a
3b
3e
2.5
2.5
2.5
47.0
46.7
42.3
>99
97
98
>200 (581)
183
>200 (211)
[a] Reaction conditions: rac-3 (0.2 mmol), Na2CO3 (0.2 mmol), CALB
(16 mg) and isopropenyl acetate (0.32 mmol) in dry toluene (0.4 mL) at
1
708C. [b] Determined by H NMR spectroscopy. [c] Determined by chiral
GC. [d] Calculated value.
(Table 1, entries 2 and 3), but the E values were still excel-
lent.
Racemization of homoallylic alcohols: A racemization study
on (S)-3a utilizing ruthenium complex 2 was also conducted
in dry toluene at different temperatures (20, 40 and 708C)
under inert atmosphere according to our standard condi-
tions. The efficiency of the racemization was estimated with
the t1/2 value, which represents a drop of the ee of (S)-3a
from 100 to 50%. The racemization at 208C was not effi-
cient enough since the ee of (S)-3a was still 63% after 6 h.
The slow racemization may be explained by coordination of
the double bond of the homoallylic alcohol to ruthenium in
the alkoxide intermediate thus blocking the coordination
site required for b-hydride elimination.[17,18] At elevated
temperatures the racemization rate increased and at 40 and
708C the t1/2 values were 53 and 5 min, respectively
(Figure 3). From these data we chose 708C as the tempera-
ture for the DKR.
Dynamic kinetic resolution of homoallylic alcohols: With
the results from the separate investigations on the enzymatic
Synthetic applications: The 5,6-dihydropyran-2-ones [(R)-6]
and d-lactones [(R)-7] are readily accessible after a short re-
action sequence as described in Scheme 3 for the transfor-
mation (R)-4a to (R)-6a and (R)-7a. Hydrolysis of acetate
(R)-4a with K2CO3 in MeOH/H2O (4:1) gave the enantio-
pure homoallylic alcohol (R)-3a in nearly quantitative yield.
Subsequent DMAP-catalyzed acylation with acryloyl chlor-
ide and Et3N afforded the corresponding acrylate (R)-5a in
81% yield after purification by silica column chromatogra-
phy. The ring-closing metathesis reaction proceeded well
with Grubbs 1st generation catalyst (10 mol%) in dry DCM
at 558C. The 5,6-dihydropyran-2-one (R)-6a was isolated in
Figure 3. Racemization study on (S)-3a catalyzed by ruthenium complex
2.
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K. Bogꢀr, J.-E. Bꢁckvall et al.
high yield and with nearly retained enantiomeric excess
after a short silica column. Selective reduction of the
Table 2. (Continued)
Entry[a]
Product
t [h]
Yield
[%][b]
ee (R)-4
[%][c]
À
carbon carbon double bond in (R)-6a was performed with
Wilkinsonꢃs catalyst (2.5 mol%) and H2 (1 atm) in dry tol-
uene at room temperature, affording the d-lactone (R)-7a in
85% yield and in 97% ee (Scheme 3).
13[e]
14[g]
96
22
63[f]
82
98
94
The enantiomerically pure acetates (R)-4b and (R)-4e
were transformed to the corresponding unsaturated lactones
[a] Reaction conditions: [Ru(CO)2ClACTHNUTRGNEUNG
(h5-C5Ph5)] 2 (0.050 mmol), tBuOK
Table 2. DKR of homoallylic alcohols 3a–n.
(0.5m solution in THF, 0.050 mmol), substrate rac-(3) (1 mmol), CALB
(10–100 mgmmolÀ1), Na2CO3 (1 mmol) and isopropenyl acetate
(1.5 mmol) in dry toluene (2 mL) heated to 708C under argon. [b] Deter-
mined by 1H NMR spectroscopy. Isolated yield after chromatography in
parentheses. [c] Determined by chiral GC or HPLC. [d] 5 mmol scale.
[e] The reaction was run at room temperature. [f] 19% of 4-oxo-6-
phenyl-1-hexene was obtained as a byproduct from isomerized starting
material. [g] R changes to S because of the sequential rule.
Entry[a]
Product
t [h]
Yield
[%][b]
ee (R)-4
[%][c]
24
12
99 (79)
99
>99
99 (84)[d]
1
(R)-6b and (R)-6e, respectively (Scheme 4), following the
hydrolysis-acylation-metathesis sequence (Scheme 3). The
unsaturated lactones (R)-6b and (R)-6e were obtained in
comparable yields and the ee in both cases was as that for
(R)-6a. The yield of the last step and the ee of the unsatu-
rated lactones are given in parenthesis in Scheme 4. The
furan and thiophene lactones (R)-6j and 6k are also accessi-
ble through the same approach. For these derivatives the
acryloylation-metathesis sequence is described in ref. [15k]
(Scheme 4). The synthetic sequence depicted in Scheme 3
can also be applied to synthetic intermediate (R)-4m lead-
ing to (R)-goniothalamin, a natural product with potential
cytotoxic properties (Scheme 4).[19] The acryloylation-meta-
thesis sequence to give (R)-6m is described in ref. [19].
2
3
4
5
24
48
24
24
99 (74)
65 (44)
99 (83)
99 (86)
98
94
>99
>99
6
7
8
24
96
48
99 (88)
80
>99
42
Conclusion
In summary, we have developed an efficient DKR protocol
for a wide range of homoallylic alcohol substrates, utilizing
ruthenium catalyst 2 for the racemization and CALB for
the enzymatic resolution. The corresponding acetates were
obtained in good to high yields and with high to excellent ee
values. The catalytic system was found to be applicable to
aromatic substrates and worked well with both electron-de-
ficient and electron-rich aromatic rings. The reaction was
also shown to work for two heterocyclic substrates and for
one aliphatic substrate. The synthetic utility of the products
obtained from the DKR was demonstrated by a short reac-
tion sequence leading to biologically important 5,6-dihydro-
pyran-2-ones and the corresponding d-lactones with nearly
retained chiral information.
12
0
9
24
18
72
92
96
90
10
11
12
18
36
85
98
96
Experimental Section
99 (86)
General procedure for dynamic kinetic resolution of homoallylic alcohols
rac-3: [(h5-Ph5C5)Ru(CO)2Cl] (2; 5.0 mol%), Na2CO3 (1 equiv) and
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Dynamic Kinetic Resolution of Homoallylic Alcohols
FULL PAPER
with the racemic compound, rac-5a.[21]
1H NMR (400 MHz, CDCl3): d=7.36–
7.27 (m, 5H), 6.45–6.40 (dd, 1H, J=
17.4 and 1.5 Hz), 6.19–6.12 (dd, 1H,
J=17.4 and 10.4 Hz), 5.91–5.87 (dd,
1H, J=7.6 and 6.0 Hz), 5.85–5.82 (dd,
1H, J=10.4 and 1.5 Hz), 5.77–5.67 (m,
1H), 5.11–5.04 (m, 2H), 2.74–2.67 (m,
1H),
2.64–2.58 ppm
(m,
1H);
13C NMR (100 MHz, CDCl3): d=
165.5, 140.1, 133.4, 131.0, 128.8, 128.6,
128.1, 126.7, 118.3, 75.5, 40.9 ppm.
Synthesis of 5,6-dihydropyran-2-one
(R)-6a: The substrate (R)-5a (0.072 g,
0.36 mmol) was dissolved in dry DCM
(50 mL) and stirred under an argon at-
mosphere. Grubbs 1st generation cata-
lyst (0.029 g, 0.036 mmol, 10 mol%)
Scheme 3. Synthetic reaction sequence affording 5,6-dihydropyran-2-one (R)-6a and d-lactone (R)-7a.
was added dropwise dissolved in dry DCM (5 mL). The resulting solution
was refluxed under argon atmosphere, overnight. When TLC analysis in-
dicated that the starting material was fully consumed, the solvent was
evaporated. The crude product was purified by flash chromatography
(5% EtOAc in pentane to 50% EtOAc in pentane). The pure product
(R)-6a was obtained in 86% yield (0.054 g, 0.31 mmol) and with 97% ee.
Spectral data were in accordance with the literature for the racemic com-
pound, rac-6a.[22] 1H NMR (400 MHz, CDCl3): d=7.43–7.34 (m, 5H),
6.99–6.95 (ddd, 1H, J=9.8, 5.5 and 2.8 Hz), 6.17–6.13 (ddd, 1H, J=9.8,
2.8 and 1.2 Hz), 5.48–5.44 (dd, 1H, J=4.9 and 11.0 Hz), 2.72–2.59 ppm
(m, 2H); 13C NMR (100 MHz, CDCl3): d=164.2, 145.0, 138.6, 128.8,
128.7, 126.2, 121.9, 79.4, 31.8 ppm.
Scheme 4. Synthetic reaction sequence affording 5,6-dihydropyran-2-ones
(R)-6.
Synthesis of d-lactone (R)-7a: The substrate (R)-6a (0.029 g, 0.17 mmol)
was dissolved in dry toluene (2.0 mL) and [RhClACTHNUTRGNE(UNG PPh3)3] (0.0038 g,
0.004 mmol, 2.5 mol%) was added. The reaction was stirred under H2 at-
mosphere (1 atm) at room temperature for 48 h. The reaction mixture
was then filtered through Celite with EtOAc and evaporated. The crude
product was purified by flash chromatography (5% EtOAc in pentane to
50% EtOAc in pentane). The pure product (R)-7a was obtained in 85%
yield (0.025 g, 0.14 mmol) and with 97% ee. Spectral data were in accord-
ance with the literature.[15m] 1H NMR (400 MHz, CDCl3): d=7.43–7.33
(m, 5H), 5.40–5.37 (dd, 1H, J=10.5 and 3.6 Hz), 2.78–2.70 (m, 1H),
2.65–2.56 (m, 1H), 2.24–2.17 (m, 1H), 2.05–1.98 (m, 2H), 1.95–1.85 ppm
(m, 1H); 13C NMR (100 MHz, CDCl3): d=171.3, 139.8, 128.6, 128.3,
125.7, 81.6, 30.5, 29.5, 18.6 ppm.
CALB (10–100 mgmmolÀ1) were added to a dry Schlenck flask. The flask
was back-flushed with argon and dry toluene (1.0 mL) was added.
tBuOK (100 mL of a 0.5m solution in THF, 5.0 mol%) was then added
and the reaction was stirred and heated to 708C. Compound rac-3
(1.0 mL of a 1.0m solution in toluene, 1 equiv) was added after 5 min.
After an additional 4 min, isopropenyl acetate (170 mL, 1.5 mmol,
1.5 equiv) was added. When complete, the reactions were quenched by
filtration through a short pad of silica with EtOAc. The crude products
were purified by flash chromatography (5% EtOAc in pentane).
Hydrolysis of acetate (R)-4a: Acetate (R)-4a (0.240 g, 1.27 mmol) was
dissolved in a MeOH/H2O 4:1 (25 mL) at room temperature. K2CO3
(0.50 g, 3.6 mmol) was added in one portion and the mixture was stirred
at room temperature for 2 h. The reaction was then quenched by the ad-
dition of NaHCO3 (1.0 g, 12 mmol). The MeOH was evaporated and the
remaining aqueous layer was extracted with EtOAc (3ꢄ50 mL). The
combined organic layer was washed with saturated aqueous NaHCO3
(1ꢄ50 mL) and brine (1ꢄ50 mL), dried over MgSO4, and filtered. Sol-
vent evaporation afforded the crude product (R)-3a as a colorless oil in
nearly quantitative yield (0.18 g, 1.24 mmol, 98%). The crude product
was used without further purification. Spectral data for homoallylic alco-
hol 3a was in accordance with the literature for the racemic com-
pound.[20] 1H NMR (500 MHz, CDCl3): d=7.38–7.34 (m, 4H), 7.30–7.27
(m, 1H), 5.86–5.78 (m, 1H), 5.19–5.14 (m, 2H), 4.76–4.73 (m, 1H), 2.57–
2.47 (m, 2H), 2.03–2.02 ppm (d, J=3.3 Hz, 1H); 13C NMR (125 MHz,
CDCl3): d=144.0, 134.6, 128.6, 127.7, 125.9, 118.6, 73.4, 44.0 ppm.
Acknowledgements
Financial support from the Swedish Research Council (621-2010-4737),
The Berzelii Center EXSELENT, and the Knut and Alice Wallenberg
Foundation is gratefully acknowledged. We thank Novozymes A/S for
the gift of CALB.
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Received: May 23, 2013
Published online: August 22, 2013
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