Enantioselective synthesis of α-methyl carboxylic acids from readily available starting materials via chemoenzymatic dynamic kinetic resolution

Article abstract of DOI:10.1021/jo1011653

An enantioselective method for the synthesis of α-methyl carboxylic acids starting from trans-cinnamaldehyde, a readily available and inexpensive compound, has been developed. Allylic alcohol 1 was obtained via a standard Grignard addition to trans-cinnamaldehyde. Dynamic kinetic resolution was applied to allylic alcohol 1 utilizing a ruthenium catalyst and either an (R)-selective lipase or an (S)-selective protease to provide the corresponding allylic esters in high yield and high ee. A copper-catalyzed allylic substitution was then applied to provide the corresponding alkenes with inversion of stereochemistry. Subsequent C-C double bond cleavage afforded pharmaceutically important α-methyl substituted carboxylic acids in high ee and overall yields of up to 76%.

Full text of DOI:10.1021/jo1011653

pubs.acs.org/joc
Enantioselective Synthesis of r-Methyl Carboxylic Acids from Readily
Available Starting Materials via Chemoenzymatic Dynamic Kinetic
Resolution
†
†
Lisa K. Thalen, Anna Sumic, Krisztian Bogar,†,‡ Jakob Norinder,†
ꢀ
Andreas K. A. Persson, and Jan-E. Backvall*
ꢀ
ꢀ
†
,†
€
†Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm,
‡
Sweden, and Medicinal Chemistry, Discovery, AstraZeneca R&D Sodertalje, SE-151 85 Sodertalje, Sweden
€
€
€
€
jeb@organ.su.se
Received July 5, 2010
An enantioselective method for the synthesis of R-methyl carboxylic acids starting from trans-
cinnamaldehyde, a readily available and inexpensive compound, has been developed. Allylic alcohol
1 was obtained via a standard Grignard addition to trans-cinnamaldehyde. Dynamic kinetic resolution
was applied to allylic alcohol 1 utilizing a ruthenium catalyst and either an (R)-selective lipase or an (S)-
selective protease to provide the corresponding allylic esters in high yield and high ee. A copper-
catalyzed allylic substitution was then applied to provide the corresponding alkenes with inversion
of stereochemistry. Subsequent C-C double bond cleavage afforded pharmaceutically important
R-methyl substituted carboxylic acids in high ee and overall yields of up to 76%.
Introduction
others,3-10 and several reviews on enzyme/metal mediated
DKR reactions have appeared in the literature.11-13
R-Methyl substituted carboxylic acids constitute an impor-
tant class of compounds and are of the nonsteroidal anti-
inflammatory drug (NSAID) family. They can be prepared
in high enantiopurity by using dynamic kinetic resolution
(DKR) as the enantio-determining step. DKR of secondary
alcohols has been thoroughly investigated by our group1,2 and
Application of DKR to allylic alcohol I with a Ru catalyst
and either Candida antarctica lipase B (CALB) or Subtilisin
Carlsberg as the enzyme would provide either the (R)- or (S)-
ester II, respectively (only the (S)-ester is shown in Scheme 1).
The enantiomerically pure ester can then undergo a copper-
catalyzed allylic substitution reaction to give the R-product,
olefin III. These olefins can then undergo oxidative double
bond cleavage to provide R-methyl substituted carboxylic
acids IV, which are of pharmaceutical interest. In most cases,
the (S)-enantiomer is active as an NSAID. (R)-Flurbiprofen
is under clinical trials for the treatment of metastatic prostate
cancer and Alzheimer’s disease.
€
´
(1) Martın-Matute, B.; Edin, M.; Bogar, K.; Kaynak, F. B.; Backvall,
J.-E. J. Am. Chem. Soc. 2005, 127, 8817–8825.
ꢀ
ꢀ €
(2) Boren, L.; Martın-Matute, B.; Xu, Y.; Cordova, A.; Backvall, J.-E.
´
Chem.;Eur. J. 2006, 12, 225–232.
(3) Choi, J. H.; Choi, Y. K.; Kim, Y. H.; Park, E. S.; Kim, E. J.; Kim,
M. J.; Park, J. J. Org. Chem. 2004, 69, 1972–1977.
(4) Akai, S.; Tanimoto, K.; Kanao, Y.; Egi, M.; Yamamoto, T.; Kita, Y.
Angew. Chem., Int. Ed. 2006, 45, 2592–2595.
(5) Dijksman, A.; Elzinga, J. M.; Li, Y.-X.; Arends, I. W. C. E.; Sheldon,
R. A. Tetrahedron: Asymmetry 2002, 13, 879–884.
(6) Kim, M. J.; Chung, Y. I.; Choi, Y. K.; Lee, H. K.; Kim, D.; Park, J.
J. Am. Chem. Soc. 2003, 125, 11494–11495.
We have previously demonstrated the application of this
synthetic route starting from β-phenyl-cinnamaldehyde
(R1=Ph).14 The transformation of this aldehyde via DKR
of the alcohol I worked smoothly to give the target R-methyl
€
(7) Berkessel, A.; Sebastian-Ibarz, M. L.; Muller, T. N. Angew. Chem.,
Int. Ed. 2006, 45, 6567–6570.
(8) Akai, S.; Tanimoto, K.; Kita, Y. Angew. Chem., Int. Ed. 2004, 43,
1407–1410.
(9) Hilker, I.; Rabani, G.; Verzijl, G. K. M.; Palmans, A. R. A.; Heise, A.
Angew. Chem., Int. Ed. 2006, 45, 2130–2132.
(10) van As, B. A. C.; van Buijtenen, J.; Heise, A.; Broxterman, Q. B.;
Verzijl, G. K. M.; Palmans, A. R. A.; Meijer, E. W. J. Am. Chem. Soc. 2005,
127, 9964–9965.
ꢁ
€
(11) Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247–3262.
(12) Kamal, A.; Azhar, M. A.; Krishnaji, T.; Malik, M. S.; Azeeza, S.
Coord. Chem. Rev. 2008, 252, 569–592.
(13) Lee, J. H.; Han, K.; Kim, M.-J.; Park, J. Eur. J. Org. Chem. 2010, 6,
999–1015.
€
(14) Norinder, J.; Bogar, K.; Kanupp, L.; Backvall, J.-E. Org. Lett. 2007,
9, 5095–5098.
6842 J. Org. Chem. 2010, 75, 6842–6847
Published on Web 09/21/2010
DOI: 10.1021/jo1011653
r
2010 American Chemical Society

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Thalen et al.
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SCHEME 1. Enantioselective Synthesis of r-Methyl
Carboxylic Acids via Metal and Enzyme Catalysis
FIGURE 1. Racemization catalyst.
aryl aceticacids (Scheme1). One drawback with thisapproach
is that β-phenyl-cinnamaldehyde is an expensive starting
material, and furthermore, two phenyl groups have to be
removed in the oxidative cleavage of the double bond (final
step). We report herein our successful efforts to improve the
applicability of this method by starting from a readily avai-
lable and inexpensive compound, trans-cinnamaldehyde.15
FIGURE 2. Surfactantsused in the treatment of Subtilisin Carlsberg.
FIGURE 3. Acyl donors tested.
TABLE 1. Kinetic Resolution of 1a
Results and Discussion
Dynamic Kinetic Resolution. First, the allylic alcohol 1
(Scheme 1) was prepared from trans-cinnamaldehyde by a
standard Grignard addition. Suitable DKR protocols were
then needed to obtain both enantiomers of 3. Candida ant-
arctica lipase B (CALB) is an (R)-selective enzyme, and the
DKR of 1 with CALB as the enzyme and 8 (Figure 1) as the
racemization catalyst has previously been reported by our
group; (R)-30 (R3 = CH3) was obtained in 89% yield and
>99% ee.16
For the (S)-selective reaction, Subtilisin Carlsberg was
used as the enzyme in combination with racemization cata-
lyst 8. The activity of commercially available Subtilisin
Carlsberg was enhanced by treatment with surfactants
octyl-β-D-glucopyranoside (9) and Brij (10) (Figure 2).17 It
is possible that coating the enzyme with surfactant results in
the formation of reversed micelles, which have the property
of solubilizing small amounts of water in their interior, thus
providing a stable aqueous microenvironment in nonaqu-
eous media.18 Surfactant-treated Subtilisin Carlsberg has
previously been used in the DKR of alcohols.2,6 The activa-
tion was achieved by dissolving Subtilisin Carlsberg and the
surfactants in a phosphate buffer and then lyophilizing the
frozen solution. The activation was carried out to provide
Subtilisin:9:10 in three different ratios: 8:4:1, 8:1:4, and 4:1:1.
Kinetic resolution (KR) of 1 with surfactant-treated Sub-
tilisin Carlsberg was carried out with acyl donors 11-13
(Figure 3), and it was found that acyl donor 11 gave the highest
E value of 132 (Table 1, entry 3). Since the E value was much
higher in KR with 11 as the acyl donor it was used in the
subsequent reactions. Three different ratios of surfactant-
acyl
donor
time
(h)
ee of
1 (%)
ee of
3 (%)
conv
(%)b
entry
Sub:9:10
E
1
2
3
8:1:4
8:4:1
4:1:1
4:1:1
4:1:1
11
11
11
12
13
24
24
24
24
24
50
63
67
33
4
97
97
97
90
80
33
39
41
25
5
108
125
132
26
4
5c
9
aConditions: 0.5 mmol of 1, 1.5 equiv of acyl donor, 10 mg of Sub-
tilisin:9:10, and 1 mmol of Na2CO3 in 2 mL of THF at ambient tem-
perature for 24 h bDetermined by NMR. c5 mg of Subtilisin:9:10.
treated Subtilisin Carlsberg (Subtilisin:9:10, 8:4:1, 8:1:4, and
4:1:1) were also compared in the KR of 1, and Subtilisin:9:10
(4:1:1) gave the best results (Table 1, entries 1-3).
Allylic alcohols of this type are known to undergo iso-
merization reactions under DKR conditions (i.e., in the
presence of racemization catalyst 8),16,19 where readdition
of the putative intermediate hydride occurs in a 1,4-
fashion to form the ketone. Previously, the isomerization
product was avoided by using sterically hindered, yet
expensive, alcohol 2 (Scheme 1).14 In the route with the less
sterically hindered monophenyl substituted alcohol 1, some
isomerization to ketone 14 occurs, but it was possible to
minimize the formation of this isomerization product by
optimizing reaction conditions such as temperature, and
amount of enzyme and acyl donor. DKR was first applied
to 1 with Subtilisin:9:10 (4:1:1), 5 mol % 8, and acyl donor 11
at room temperature; however, the racemization of 1 (79%
ee, Table 2, entry 1) was slow relative to acylation, so the
reaction temperature was increased to 40 °C. Under these
(15) One kilogram of β-phenyl-cinnamaldehyde costs h 345. One kilo-
gram of trans-cinnamaldehyde costs h 19. Prices are based on 100 kg price
quotes from Sigma Aldrich.
(16) See ref 1. Saturated ketone formed from rearrangement of the allylic
alcohol was observed as a side product.
(17) Bordusa, F. Chem. Rev. 2002, 102, 4817–4868.
(18) Sawada, K.; Ueda, M. J. Chem. Technol. Biotechnol. 2004, 79, 369–
375.
ꢀ €
´
(19) Martın-Matute, B.; Bogar, K.; Edin, M.; Kaynak, F. B.; Backvall,
J.-E. Chem.;Eur. J. 2005, 11, 5832–5842.
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TABLE 2. Dynamic Kinetic Resolution of 1a
SCHEME 3. Copper-Catalyzed Allylic Substitution Reactions
with (R)-40 and (S)-4 (Only the (R)-Enantiomer Is Shown)14
Sub:9:10
(mg/
entry mmol)
acyl
donor
(equiv) (°C) (h)
T
time ee of 1 ee of 3 yield
(%)
14
(%)b (%)b
(%)
1
20
20
20
40
40
20
2
2
2
3
3
3
rt
rt
rt
48
48
24
79
35
16
62
82
80
67
95
97
90
79
87
70
2
4
3
2c
3d
4
SCHEME 4. Copper-Catalyzed Allylic Substitution Reaction
with (S)-3 and (R)-30
40 48
40 45
40 20
81 (75) 11
81
75
5e
19
9
6c
18
aConditions: 5 mol % of t-BuOK was added to 5 mol % of 8, Sub-
tilisin:9:10 (4:1:1), and Na2CO3 in THF; 6 min later 1 (0.5 or 1.0 mmol)
was added, and 4 min later 11 was added. The reaction mixture was
heated to 40°C. bDetermined by NMR, isolated yield in parentheses.
c6 mol % of t-BuOK. d7 mol % of t-BuOK. e20 mg/mmol of Subtilisin:
9:10 (4:1:1) added after 24 h.
SCHEME 2. Enantiomeric Excess Enhancement via Hydrolysis
of (R)-3 with CALB
It was found that CuCl and CuBr SMe2 gave higher con-
3
version and higher selectivity for the substitution reaction
than CuI, CuCN, and Li2CuCl4. CuCl and CuBr SMe2 gave
3
similar results, where CuCl provided the product in slightly
higher ee and CuBr SMe2 gave the product in slightly higher
yield. Therefore, these two copper catalysts were chosen for
the subsequent substitution reactions.
3
conditions, (S)-3 was obtained in 75% isolated yield and
95% ee, with only 11% isomerization product 14 (Table 2,
entry 4). When an additional aliquot of Subtilisin:9:10 was
added after 24 h, under otherwise unchanged conditions,
(S)-3 was obtained in 81% yield and 97% ee, with 19% 14
(Table 2, entry 5). The number of equivalents of base used to
activate the catalyst was also increased to see if there would
be a parallel increase in activity; however, a drop in product
ee was observed indicating chemical acylation (Table 2,
entries 2, 3, and 6).
The enantiomeric purity of the ester obtained from DKR
was further improved by hydrolyzing the undesired enantio-
mer with an (R)-selective enzyme. The hydrolysis was carried
out in a phosphate buffer solution (pH =7.2) with CALB as
the enzyme to provide (S)-3 in 96% yield and >99% ee in 2 h
at 60 °C (Scheme 2).
Copper-Catalyzed Allylic Substitution Reactions. Previously,
copper-catalyzed allylic substitution reactions have been car-
ried out with allylic ester 4 to provide olefin 6 (Scheme 3).14
Complete regioselectivity for the R-product was observed
when using either aryl or aliphatic Grignard reagents. When
aryl Grignard reagents were used 6 was obtained in 75-91%
yield and 95-99% ee, and when aliphatic Grignard reagents
were used 6 was obtained in 48-74% yield and 69-99% ee
(Scheme 3).
Application of the reaction to monophenyl substituted
allylic substrates (S)-3 and (R)-30 with aryl Grignard reagents
provided the olefin products with inversion of stereochem-
istry in high yields and excellent ee (Scheme 4; Table 3, entries
1-6, 9, and 10). Complete selectivity for the R-product was
observed. The substitution of (S)-3 and (R)-30 could also be
carried out with aliphatic Grignard reagents (Table 3, entries 7
and 8). Some loss of stereochemistry and formation of 10-11%
γ-product 15 was observed. The loss of stereochemistry could
be due to single bond rotation of 16 to 160 (Scheme 5).20 When
THF was used as the solvent and the reaction was run at
-20 °C, (R)-5d could be obtained in 59% yield and 90% ee
(Table 3, entry 7). By changing the solvent to diethyl ether, (R)-
5e was obtained in 65% yield and 96% ee (Table 3, entry 8).
On the basis of our current and previous studies,14,20,21 it was
found that in general a lower reaction temperature promoted
selectivity for the R-product, while also promoting loss of
stereochemistry. Also THF as the solvent provided the product
in higher yield than diethyl ether as the solvent, whereas diethyl
ether provided the product in higher ee than THF as the solvent.
Oxidative C-C Double Bond Cleavage. The oxidative
C-C double bond cleavage of olefins 5a and 5b afforded
the desired R-methyl substituted carboxylic acids 7a and 7b,
A screening of copper salts has previously been carried out
for the reaction of (R)-40, BuMgBr, and 10% copper catalyst.20
€
(21) Backvall, J. E.; Sellen, M.; Grant, B. J. Am. Chem. Soc. 1990, 112,
€
(20) Norinder, J.; Backvall, J.-E. Chem.;Eur. J. 2007, 13, 4094–4102.
6615–6621.
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a
TABLE 3. Copper-Catalyzed Allylic Substitution Reaction with (S)-3 and (R)-30
aConditions: 3 or 30 (0.5 mmol) and CuBr SMe2 were mixed in THF. After cooling to 0 °C, 0.75 mmol of Grignard reagent was added. bDetermined by
3
f
NMR using 2-decanol or 2-nonanol as internal standard; isolated yields in parentheses. cDetermined by HPLC. dCuCl. e-20 °C. Determined by GC of
the corresponding carboxylic acid obtained by Sharpless oxidation. gEt2O.
SCHEME 5. Isomerization of the Allyl Intermediates, Leading
to Different Products
under Sharpless conditions afforded (R)-7a (Flurbiprofen)
in 93% yield and >99% ee (Table 4, entry 1). The optical
rotation of known compound (S)-(þ)-7a was compared with
literature data to verify the absolute configuration.23
Other starting materials that would increase the atom
economy have also been considered. Crotonaldehyde is
one such substrate; however, it is probable that the lack of
steric hindrance in the γ-position would lead to a higher
degree of isomerization product formation in the DKR
reaction and a higher degree of γ-product formation in the
copper-catalyzed substitution reaction.
Conclusions
We have developed a method for the synthesis of R-methyl
carboxylic acids starting from trans-cinnamaldehyde, a read-
ily available and inexpensive compound. Allylic alcohol 1
was obtained via a standard Grignard addition to trans-
cinnamaldehyde. DKR was applied to allylic alcohol 1 to
provide both the (R)- and (S)-enantiomers of 3 in high
enantiomeric purity. Copper-catalyzed allylic substitution
was then applied to 3 with aryl and aliphatic Grignard
reagents, which afforded the corresponding olefins 5 with
inversion of stereochemistry. C-C double bond cleavage
provided the biologically active R-methyl carboxylic acids 7
in moderate to excellent yields and in high enantiopurity
(>99% ee).
which are of pharmaceutical interest. The Sharpless oxida-
tion is a well-known procedure22 and was previously applied
to the oxidation of 6 to provide 7 in high yields and excellent
ee.14 However, these conditions proved too harsh when
applied to (S)-5b, the precursor of Naproxen ((S)-7b).
C-C double bond cleavage of monophenyl substituted 5
afforded two acids, 7 and benzoic acid (17). For 7a and 7b the
separation of the two acids could be achieved by Kugelrohr
distillation. Two oxidation methods were tested to find
suitable conditions for the oxidation of 5b: Lemieux and von
Rudloff reagent, and osmium tetroxide with oxone. Applica-
tion of Lemieux and von Rudloff reagent provided Naproxen
((S)-7b) in 42% isolated yield and >99% ee (Table 4, entry 4).
The low yield is due to byproduct formation. Catalytic
amounts of osmium tetroxide in combination with stoichio-
metric amounts of oxone were also tested and provided (S)-7b
in 51% isolated yield and >99% ee (Table 4, entry 5). The
Lemieux and von Rudloff reagent was also applied to the
oxidation of (S)-5a to afford (R)-7a (Flurbiprofen) in 44%
yield and >99% ee (Table 4, entry 3). Oxidation of (S)-5a
Experimental Section
Synthesis of Racemic Alcohol 1.
4-Phenyl-3-buten-2-ol (1). Racemic alcohol 2 was prepared
by addition of MeMgCl to trans-cinnamaldehyde in THF,
according to a literature procedure.24 The 1H NMR and
(23) Guintchin, B.; Bienz, S. Tetrahedron 2003, 59, 7527–7533.
(24) Dawson, G. J.; Williams, J. M. J.; Coote, S. J. Tetrahedron: Asymmetry
1995, 6, 2535–2546.
(22) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936–3938.
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TABLE 4. Oxidation of Olefins (R)-5 and (S)-5a
aConditions: [A] III, 2 mol % of RuCl3, 4.1 equiv of NaIO4; [B] III, 0.5 equiv of KMnO4, 5 equiv of NaIO4, 1 equiv of K2CO3; [C] III, 5 mol % of OsO4,
4 equiv of oxone. bIsolated yield. cDetermined by GC.
13C NMR spectral data were in accordance with literature
data.25
tR(S) = 27.23 min). NMR spectral data were in accordance with
published data.26 1H NMR (400 MHz, CDCl3): δ 7.43-7.38
(m, 2H), 7.37-7.31 (m, 2H), 7.29-7.24 (m, 1H), 6.62 (d, J =
15.9 Hz, 1H), 6.22 (d, J = 15.9, 6.8 Hz, 1H), 5.57 (d, J = 6.8, 6.5
Hz, 1H), 2.33 (t, J = 7.3 Hz, 2H), 1.7 (tq, J = 7.3, 7.4 Hz, 2H), 1.43
(d, J = 6.5 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 173.0, 136.5, 131.5, 129.1, 128.7, 128.0, 126.7, 70.8, 36.7,
20.5, 18.6, 13.8. [R]27D = -105.8 (c 1.0, CHCl3).
Synthesis of Enantiomerically Pure Esters (S)-3 and (R)-30.
4-Phenyl-3-buten-2-yl Acetate ((R)-30). Prepared via DKR
according to a literature procedure (89% yield and >99% ee).16
General Procedure for the Copper(I)-Catalyzed Allylic Sub-
stitution Reactions. (S)-5a. The allylic acetate (R)-30 (190 mg,
(S)-4-Phenyl-3-buten-2-yl Butanoate ((S)-3). Complex
8
(16 mg, 25 μmol), Subtilisin Carlsberg:Brij:octyl-β-glycopyra-
noside, 4:1:1 (20 mg, prepared as previously reported3), Na2CO3
(106 mg, 1.0 mmol), and t-BuOK (50 μL, 0.5 M in THF) were
stirred in toluene (0.5 mL) for 6 min. Thereafter, a solution of
racemic alcohol 1 (74.1 mg, 0.50 mmol) in THF (2 mL) was
added. After 4 min, trifluoroethylbutyrate (225 μL, 1.5 mmol)
was added, and the mixture was stirred at 40 °C under an argon
atmosphere. After 48 h, the reaction mixture was filtered through
a plug of silica and was washed with ethyl acetate. The crude pro-
duct was concentrated in vacuo, and column chromatography
(pentane/EtOAc, 60:1) afforded (S)-3 (75%, 82.2 mg) as a color-
less oil in 95% ee. The optical purity was determined by HPLC
analysis (OJ column, i-hexane/i-PrOH, 99:1, tR(R) = 24.63,
tR(S) = 27.28 min).
Enantiomeric Excess Enhancement via Hydrolysis of (R)-4-
Phenyl-3-buten-2-yl Butanoate ((S)-3). (S)-3 (95% ee, 109.1 mg,
0.5 mmol) and CALB (10 mg) were then suspended in a 0.5 M
phosphate buffer (2 mL, pH 7.2) and stirred for 2 h at 60 °C. The
mixture was filtered, and the aqueous phase was extracted three
times with EtOAc. The organic phases were combined and
washed once with 2 M NaHCO3. The organic phase was dried
over Na2SO4, and the product was concentrated in vacuo.
Column chromatography (pentane/EtOAc, 60:1) afforded (S)-3
(96%) in >99% ee. The optical purity was determined by HPLC
analysis (OJ column, i-hexane/i-PrOH, 99:1, tR(R) = 24.63,
1.0 mmol) and CuBr SMe2 (20.5 mg, 0.1 mmol) were mixed in
3
THF (9 mL) and cooled to 0 °C. A solution of ((3-fluoro-4-
phenyl)phenyl)MgBr in THF (3.0 mL, 0.5 M) was added, and
the reaction mixture and was stirred at the given temperature.
The reaction mixture was quenched after 5 h by addition of
HCl(aq) (2 M, 10 mL), followed by addition of 2-nonanol (50 μL,
0.26 mmol) as internal standard. The organic solvent was
removed in vacuo, and Et2O (10 mL) was added. The product was
extracted with Et2O (3 ꢀ 10 mL). The combined organic phase
was washed with H2O (1 ꢀ 10 mL) and dried over Na2SO4. The
solvent was removed in vacuo to afford the crude product, which
was purified bycolumn chromatography (pentane/EtOAC, 100:0
to 97:3). (S)-5a was obtained in 92% yield and >99% ee. The
optical purity was determined by HPLC analysis (OJ column,
i-hexane/i-PrOH, 85:15; flow 1.0, tR(S) = 13.6 min, tR(R) = 18.6
min). NMR spectral data were in accordance with published
data.27 [R]27D = -39.2 (c 1.00, (CH3)2CO).
General Procedure for Oxidative C-C Double Bond Cleavage.
(S)-7b. Method [A]. Oxidative cleavage of the olefin (S)-5a was
performed on 1.0 mmol scale according to the Sharpless pro-
cedure13 and as previously described.14 Olefin (S)-5a (302 mg,
1 mmol), RuCl3 H2O (4.2 mg, 0.02 mmol), NaIO4 (877 mg, 4.1
3
mmol), MeCN (2 mL), CCl4 (2 mL), and H2O (3 mL) were
charged in a 25 mL round-bottom flask and stirred under
(25) Onaran, M. B.; Seto, C. T. J. Org. Chem. 2003, 68, 8136–8141.
(26) Kim, M. J.; Han, K. L.; Park, J. Bull. Korean Chem Soc. 2007, 28,
2096–2098.
(27) Rodriguez, D.; Perez Sestelo, J.; Sarandeses, L. A. J. Org. Chem.
2004, 69, 8136–8139.
6846 J. Org. Chem. Vol. 75, No. 20, 2010

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ambient conditions. The reaction was followed by TLC analysis
(pentane/EtOAc, 95:5) and upon completion DCM (25 mL) was
added. The product was extracted with NaHCO3 (3 ꢀ 20 mL).
The combined aqueous phase was acidified with 2 M HCl solu-
tion, and the product was extracted with DCM (3 ꢀ 20 mL). The
combined organic phase was dried over Na2SO4 and concentrated
under reduced pressure. Benzoic acid was then removed from the
mixture by Kugelrohr distillation (80 °C, 0.4 mbar) to afford (R)-
7a in 93% yield and >99% ee. The optical purity was determined
by GC analysis (flow rate; 1.5 mL/min. GC program: from 100 to
200 °C at a rate of 10 °C/min, isothermal at 200 °C for 40 min;
tR(S) = 25.6, tR(R) = 26.3 min). [R]27D = -42.7 (c 0.8, CDCl3).
Spectroscopic data were in agreement with the literature data.28
Method [B]. According to a literature procedure,29 the olefin
(R)-5 (72.1 mg, 0.25 mmol) was dissolved in acetone (35 mL).
Subsequently, Li2CO3 (9.2 mg, 0.13 mmol) and H2O were added
(7 mL). The solution was cooled to 0 °C. In a separate flask,
NaIO4 (267 mg, 1.25 mmol), KMnO4 (19.8 mg, 0.125 mmol),
and Li2CO3 (9.2 mg, 0.13 mmol) were dissolved in H2O (17 mL).
The aqueous solution was added dropwise to the olefin solu-
tion. The reaction mixture was quenched after 24 h by addition
of HCl(aq) (1 M, 5 mL) at 0 °C. Na2S2O5 was added until a
colorless solution was obtained. The organic solvent was
removed in vacuo, and Et2O (5 mL) was added. The pH was
adjusted to 10 with NaHCO3, and the product was extracted
with sat. NaHCO3 solution (3 ꢀ 5 mL). The combined aqueous
phase was washed once with Et2O and then acidified to pH 2
with 2 M HCl. The product was extracted with DCM (3 ꢀ
10 mL). The combined organic phase was washed with H2O (1 ꢀ
5 mL) and dried over Na2SO4. The solvent was removed in vacuo
to afford the crude product mixture. Benzoic acid was then
removed from the mixture by Kugelrohr distillation (80 °C,
0.4 mbar) to afford (S)-7b in 42% yield (24.2 mg, 0.11 mmol)
and >99% ee. The optical purity (>99% ee) was determined
by GC analysis (flow rate; 1.5 mL/min. GC program: from
100 to 200 °C at a rate of 10 °C/min, isothermal at 200 °C for
40 min; tR(S) = 28.5, tR(R) = 29.2 min). [R]27D = þ60.8 (c 0.5,
CDCl3). Spectroscopic data were in agreement with the litera-
ture data.30
Method [C]. According to a literature procedure,31 the olefin-
(R)-5b (50.0 mg, 0.173 mmol) was dissolved in DMF (1 mL) and
cooled to 0 °C. Oxone (213 mg, 0.695 mmol) and K2OsO4 2H2O
3
(3.20 mg, 0.009 mmol) were added to the solution as a solid
mixture in one portion. The brown reaction mixture was stirred
at 0 °C for 5 h. The reaction was followed by TLC (pentane/
EtOAc, 99:1). Upon completion, solid Na2SO3 (6 equiv w/w)
was added, and the resulting suspension was stirred for 1 h,
during which time it becomes slightly yellow (as opposed to deep
brown). Subsequently, 1 M HCl was added to dissolve the salts,
and the product was extracted with EtOAc (ꢀ 3). The combined
organic phases were washed with 1 M HCl (ꢀ 3) and brine (ꢀ 1).
The combined organic phase was dried with MgSO4, and the
solvent was subsequently removed in vacuo to provide a sticky
brown oil. The crude product was purified by bulb-to-bulb
distillation (80 °C, 0.4-0.5 mmHg) to remove the benzoic acid.
The residual brown solid was then subjected to silica gel chro-
matography (pentane/EtOAc/AcOH, 3:1:0.1) to afford (S)-7b in
51% yield (20.3 mg, 0.089 mmol) and >99% ee. The optical
purity (>99% ee) was determined by GC analysis (flow rate; 1.5
mL/min. GC program: from 100 to 200 °C at a rate of 10 °C/min,
isothermal at 200 °C for 40 min; tR(S) = 28.5, tR(R) = 29.2 min).
Spectroscopic data were in agreement with the literature data.30
Acknowledgment. Financial support from the Swedish
Research Council, the Berzelii Center EXSELENT, the
European FP7 network INTENANT (“Integrated synthesis
and purification of single enantiomers”), K & A Wallenberg
€
€
foundation, and AstraZeneca R&D Sodertalje is gratefully
acknowledged. We thank Johnson Matthey (New Jersey,
USA) for a gift of Ru3(CO)12 and Novozymes for a gift of
Novozyme 435 (CALB).
(28) Schlosser, M.; Geneste, H. Chem.;Eur. J. 1998, 4, 1969–1973.
(29) Hiyama, T.; Inoue, M. Synthesis 1986, 1986, 689–691.
(30) Boyd, E.; Coulbeck, E.; Coumbarides, G. S.; Chavda, S.; Dingjan,
M.; Eames, J.; Flinn, A.; Motevalli, M.; Northen, J.; Yohannes, Y. Tetra-
hedron: Asymmetry 2007, 18, 2515–2530.
Supporting Information Available: General methods, experi-
mental procedures, copies of NMR spectra, and copies of chro-
matograms. This material is available free of charge via the Internet
at http://pubs.acs.org.
(31) Travis, B. R.; Narayan, R. S.; Borhan, B. J. Am. Chem. Soc. 2002,
124, 3824–3825.
J. Org. Chem. Vol. 75, No. 20, 2010 6847