Scalable preparation of both enantiomers of 2-(1-hydroxy-2-oxocyclohexyl) acetic acid

Article abstract of DOI:10.1021/jo8000904

(Chemical Equation Presented) The efficient, scalable preparation of both enantiomers of 2-(1-hydroxy-2-oxocyclohexyl)acetic acid in enantiomerically pure form is reported using environmentally benign conditions in 30% overall yield (6 steps) for the (S)-isomer, in 27% (7 steps) for the (R)-isomer, from cyclohexanone.

Full text of DOI:10.1021/jo8000904

SCHEME 1. Unique Stereoisomerization at the Angular
Position of N-Acylindole 2 To Give syn-Pyroglutamic Acid 4
Scalable Preparation of Both Enantiomers of
2-(1-Hydroxy-2-oxocyclohexyl)acetic Acid
Mitchell Vamos and Yoshihisa Kobayashi*
Department of Chemistry and Biochemistry, UniVersity of
California, San Diego, 9500 Gilman DriVe, Mail Code 0343,
La Jolla, California 92093-0343
ykoba@chem.ucsd.edu
ReceiVed January 15, 2008
SCHEME 2. Racemic Synthesis of 2-(1-Hydroxy-2-oxocyclo-
hexyl)acetic Acid (()-(1)
The efficient, scalable preparation of both enantiomers of
2-(1-hydroxy-2-oxocyclohexyl)acetic acid in enantiomeri-
cally pure form is reported using environmentally benign
conditions in 30% overall yield (6 steps) for the (S)-isomer,
in 27% (7 steps) for the (R)-isomer, from cyclohexanone.
Chiral R-hydroxyketone-containing compounds are important
synthons for natural products synthesis.1 2-(1-Hydroxy-2-
oxocyclohexyl)acetic acid (1) is an especially attractive target
owing to its potential application in the Passerini and Ugi
multicomponent reactions which can construct a complex
heterobicyclic framework in a single step.2 This compound can
be useful not only in the synthesis of a particular natural product
target but also in the construction of a library of bicyclic
γ-lactams (Ugi product) or γ-lactones (Passerini product). In
the course of our studies on the diastereoselective synthesis of
pyroglutamic acid derivative 2, we needed a straightforward
entry to the optically active γ-keto acid 1 for use in the Ugi
four-center three-component (4C-3C) reaction (Scheme 1).
γ-Ketoacid 1 is an especially attractive and challenging chiral
synthon because it contains four different oxidation levels in
four contiguous carbon atoms. Although its racemic synthesis
was reported in 1963,3 an efficient procedure to prepare both
enantiomers of γ-ketoacid 1 has never been reported. Herein,
we report the first scalable preparation of both enantiomers of
2-(1-hydroxy-2-oxocyclohexyl)acetic acid (1).
underwent formal aldol condensation to give only syn-pyroglutamic
acid 4. In order to test this mechanism, we needed enantioselective
access to the γ-keto acid 1. Based on our hypothesis, we would
expect to see racemization of bicyclic pyroglutamic acid 4 upon
hydrolysis of N-acylindole 2 (via achiral ketene 3).5
Our racemic synthesis of 2-(1-hydroxy-2-oxocyclohexyl)ace-
tic acid (()-(1) began with the Reformatsky reaction of
cyclohexanone and benzyl bromoacetate to give benzyl ꢀ-hy-
droxy ester 5 in 95% yield (Scheme 2).6 It was important to
use the benzyl ester in this step for a clean conversion of the
ester to the carboxylic acid in a later step (vide infra).
Dehydration of the tertiary alcohol led to the regiocontrolled
formation of ꢀ,γ-olefin 6 in 79% yield (as an 11:1 regioisomeric
mixture with the R,ꢀ-olefin).7 Dihydroxylation of 6 with osmium
tetraoxide gave the racemic syn-diol (()-7 in 93% yield (as an
11:1 isomeric mixture with the R,ꢀ-diol) without γ-lactone
formation, a known side reaction from γ-hydroxy esters.8
Oxidation of the secondary alcohol of (()-7 (11:1 isomeric ratio)
with 2-iodoxybenzoic acid (IBX) gave γ-ketoester (()-8 in 87%
Recently, we reported a unique stereoisomerization at the
angular position of the racemic bicyclic anti-pyroglutamic acid
derivative 2 during basic hydrolysis of the N-acylindole moiety
(Scheme 1).4We proposed a Grob-type fragmentation of the anti
isomer 2 to give an achiral ketene intermediate 3, which then
(1) Hanessian, S. In Total Synthesis of Natural Products: The Chiron
Approach; Pergamon: New York, 1983; Chapter 2.
(5) However, we can still not rule out the possibility that the stereochemical
information contained in 2 could be retained in the ketene intermediate 3 due to
rotational barriers associated with the putative nine-membered ring.
(6) Fu¨rstner, A. In Organozinc Reagents: A Practical Approach; Knochel,
P., Jones, P., Eds.; Oxford University Press: New York, 1999; p 287.
(7) For a discussion of ring size and endo/exo selectivity, see: Screttas, C. G.;
Smonou, I. C. J. Org. Chem. 1998, 53, 893–894.
(2) For a recent review of isocyanide-based multi-component reactions, see:
Do¨mling, A. Chem. ReV. 2006, 106, 17–89.
(3) Mondon, A.; Menz, H.; Zander, J. Racemic 2-(1-hydroxy-2-oxocyclo-
hexyl)acetic acid (()-(1) has been synthesized by a different strategy. Chem.
Ber. 1963, 96, 826–839.
(4) Vamos, M.; Ozboya, K.; Kobayashi, Y. Synlett 2007, 1595–1599.
(8) Kapferer, T.; Bru¨ckner, R. Eur. J. Org. Chem. 2006, 2119–2133.
3938 J. Org. Chem. 2008, 73, 3938–3941
10.1021/jo8000904 CCC: $40.75 2008 American Chemical Society
Published on Web 04/17/2008

SCHEME 3. Maestro’s Synthesis of Optically Active γ-Keto
Esters 12 and 12a
SCHEME 4. Attempted Sharpless Asymmetric
Dihydroxylation of Olefin 6
SCHEME 5. Enzymatic Resolution of Racemic Diol (()-7
and Acetate (()-13
yield (isolated as a single isomer after SiO2 chromatography).9
Mild oxidation conditions were important here based on the
propensity of the tertiary alcohol to eliminate under acidic and
basic conditions and also to avoid oxidative cleavage of the
1,2-diol during the oxidation of (()-7. Alkaline hydrolysis of
the ester caused elimination of the hydroxyl group to give an
R,ꢀ-unsaturated acid, indicating the necessity of the benzyl ester
to avoid this side reaction in the final deprotection. Hydrogena-
tion of the benzyl ester (()-8 cleanly furnished the racemic
γ-keto acid (()-1 in quantitative yield and in 61% overall yield
over five steps from cyclohexanone.
There is one report for the enantioselective preparation of
the ethyl ester 12, a possible precursor to 2-(1-hydroxy-2-
oxocyclohexyl)acetic acid (1). In 1998, Maestro introduced
methodology which gives asymmetric access to the ethyl ester
12 in four steps and 31% overall yield from cyclohexanone to
12.10 Ketone 9 was prepared as a 3:1 diastereomixture from
cyclohexanone with the chiral menthyl p-toluenesulfinate in 70%
yield (two steps). The key step in the synthesis was a
diastereoselective aldol reaction (82:18 dr) to the chiral ketone
9 shown in Scheme 3. Following the diastereoselective aldol
reaction and separation of the resulting diastereomixture 10 and
11 by chromatography, a deprotection of the S,S-ketal afforded
enantiomerically pure ethyl esters 12 and 12a. Our attempted
base-promoted hydrolysis of γ-keto ester 12 failed to give a
good conversion to the γ-keto acid 1; instead, the R,ꢀ-
unsaturated acid was formed by elimination of ꢀ-hydroxyl
group. Thus, 12 is not a suitable precursor to 2-(1-hydroxy-2-
oxocyclohexyl)acetic acid (1).
lipase enzymes.14,15 We performed an enzymatic resolution of the
racemic diol (()-7 by transesterification with vinyl acetate to give
acetate 13a and the remaining enantioenriched diol 7. Based on
its broad application in the resolution of secondary alcohols, the
Amano lipase AK derived from Pseudomonas fluorescens was
chosen.15 Shown in Scheme 5 are the results of the resolution.
Heating diol (()-7 to 50 °C with 2 equiv of vinyl acetate in
t-BuOMe in the presence of the lipase gave 47% of the acetate
13a (82% ee)16 and 49% of the recovered diol 7 (g97% ee) after
filtration through Celite and column chromatography (SiO2). The
secondary alcohol of 7 was then converted to the Mosher ester
1
and the enantiomeric excess was determined from its H NMR
spectrum (g97% ee).17 The calculated E value18 for the lipase in
this resolution is 42.
To access the free diol 7a from acetate 13a (taken from the
enzymatic acetylation in Scheme 5), we performed the deacety-
As shown in the racemic synthesis above (Scheme 2), diol
(()-7 is a key precursor to the γ-keto acid (()-1. Therefore,
an enantioselective synthesis of 1 can be accomplished through
enantioselective preparation of diol 7. Sharpless asymmetric
dihydroxylation11 of ꢀ,γ-unsaturated ester 68 was the first
choice; however, as shown in Scheme 4, the yield and
enantioselectivity for this reaction were both poor (48% yield
and 2:1 er).12 Although this reaction is generally useful for a
broad range of substrates, there still remains a number of specific
alkene substrates that deliver poor enantioselectivity.13
(14) Zhao, Y.; Rodrigo, H.; Hoveyda, A. H.; Snapper, M. L. Nature 2006,
443, 67–70.
(15) For reviews, see:(a) Faber, K.; Riva, S. Synthesis 1992, 895–910. (b)
Santaniello, E.; Ferraboschi, P.; Grisenti, P.; Manzocchi, A. Chem. ReV. 1992,
92, 1071–1140. (c) Otera, J. Chem. ReV. 1993, 93, 1449–1470.
(16) Although the absolute stereochemistry of the hydrolyzed secondary
alcohol can be assumed from the empirical rule for enzymatic resolutions (Xie,
Z.-F.; Suemune, H.; Sakai, K. Tetrahedron: Asymmetry 1990, 1, 395–402),. the
absolute stereochemistry of acetates 13 and 13a was confirmed by conversion
to the known compounds (S)-12 and (R)-12a and comparison of the sign of
specific optical rotation from ref 10. Also, the enantiopurity of acetates 13 and
13a was determined by 1H NMR analysis of the corresponding Mosher esters
of 14 and 14a. See the Supporting Information for experimental details
In order to obtain the enantiomerically pure diol 7, we turned
our attention to the possible biocatalytic transformations involving
(9) (a) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001–3003. (b) Frigerio,
M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537–4538.
(10) Garc´ıa Ruano, J. L.; Barros, D.; Maestro, M. C.; Alcudia, A.; Ferna´ndez,
I. Tetrahedron: Asymmetry 1998, 9, 3445–3453.
(11) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung,
J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang,
X.-L. J. Org. Chem. 1992, 57, 2768–2771.
(17) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092–4096, For the H NMR spectrum of the Mosher ester of both
the racemic and enantiopure diols 7, see the Supporting Information.
(18) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C.-J. J. Am. Chem. Soc.
1982, 104, 7294–7299.
1
(12) See the Supporting Information for the reaction conditions and details.
(13) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994,
94, 2483–2547.
J. Org. Chem. Vol. 73, No. 10, 2008 3939

SCHEME 6. Lipase-Catalyzed Conversion of Acetate 13a to
Diol 7a and Determination of Enantiopurity
allowing for mild access to the carboxylic acid 1, was apparent
upon attempted base-promoted hydrolysis; a major competing
reaction involving elimination of the tertiary alcohol of 8 could
not be avoided.
The scalable preparation of both enantiomers of 2-(1-hydroxy-
2-oxocyclohexyl)acetic acid (1) (in six steps and 32% overall yield
for (S)-1, 7 steps and 27% overall yield for (R)-1a, from
cyclohexanone) has been demonstrated through an enzymatic
resolution using a common enzyme and simply varying the reaction
conditions. The enantioselective preparation of the acid was
reported for the first time in the literature. The ease of operation
and fewer numbers of synthetic manipulations, as well as the use
of environmentally benign reagents make this method more
attractive than the previous preparation. This methodology allows
for access to optically active vicinal diol 7 and also ꢀ-hydroxy-
γ-ketoacid 1 which can be valuable synthons for natural product
synthesis. An important aspect of this strategy is minimal loss of
material by elimination of the tertiary alcohol or γ-lactone
formation. The application of 2-(1-hydroxy-2-oxocyclohexyl)acetic
acid (1) in the stereocontrolled Ugi reaction for the synthesis of
proteasome inhibitor salinosporamide A derivatives and investiga-
tion of the reaction mechanism of the angular stereoisomerization
with the enantiomerically pure bicyclic pyroglutamic acid derivative
will be reported in due course.
SCHEME 7. Conversion of Diol 7 to 2-(1-Hydroxy-2-oxocyclo-
hexyl)acetic Acid (1)
lation using the same lipase as for the previous resolution
(Scheme 6). This, as before, allows for selective hydrolysis of
the acetate in the presence of the benzyl ester, a transformation
we found to be nontrivial using other methods.19 An added
benefit of this lipase-catalyzed hydrolysis is the further enan-
tiomeric enrichment of the diol 7a (starting from 82% ee with
acetate 13a to g97% ee with diol 7a). When acetate 13a was
treated with lipase AK and 0.875 equiv of 1 M NaOH under
conditions identical to the enzymatic hydrolysis shown above
the diol, 7a was recovered in 94% yield. This two-step process
involving two enzymatic resolutions to access diol 7a is not as
efficient as the two-step procedure involving racemic formation
of the acetate (()-13 followed by enzymatic deacetylation (as
shown in Scheme 5 and described below). Important to note is
the selective hydrolysis of the acetate ester and not the benzyl
ester, presumably due to the greater steric hindrance of the
benzyl ester. This chemoselective hydrolysis was not possible
without the use of the lipase. The secondary alcohol of 7a was
then converted to the MTPA ester and the enantiomeric excess
Experimental Section
Benzyl 2-(1-Hydroxycyclohexyl)acetate (5). A suspension of
zinc dust (13.32 g, 203 mmol, 4.0 equiv) and copper(I) chloride
(2.02 g, 20.3 mmol, 0.4 equiv) in THF (125 mL) was stirred under
reflux for 30 min under an N2 atmosphere. The flask was removed
from heating, and benzyl 2-bromoacetate (7.99 mL, 50.9 mmol,
1.0 equiv) in THF (30 mL) was added via addition funnel at a rate
to maintain reflux. After 1 h and allowing the solution cool to 23
°C, cyclohexanone (5.28 mL, 50.9 mmol, 1.0 equiv) in THF (50
mL) was added via addition funnel over 5 min. The mixture was
stirred for 3 h and then filtered through Celite and the cake rinsed
with ether (100 mL). Water (200 mL) was added, and the mixture
again filtered through Celite, and the cake rinsed with ether (50
mL). The filtrate was then washed with saturated aqueous sodium
chloride (150 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. The resultant oil was purified by flash
chromatography on silica gel (4:1 f 3:1 hexanes/ethyl acetate) to
yield the product 5 (11.99 g, 48.3 mmol, 95%). Rf ) 0.33 (3:1
hexanes/ethyl acetate) as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ: 7.33-7.39 (m, 5H), 5.15 (s, 2H), 3.33 (bs, 1H), 2.53 (s,
2H), 1.60-1.72 (m, 4H), 1.48-1.48 (m, 2H), 1.38-1.48 (m, 2H),
1.25-1.32 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 173.0, 135.8,
128.9 (2C), 128.6, 128.5 (2C), 70.3, 66.6, 45.5, 37.7 (2C), 25.8,
22.2 (2C). HRMS: calcd for C15H20O3 248.1407, found 248.1406.
Benzyl 2-Cyclohexenylacetate (6). To a solution of benzyl 2-(1-
hydroxycyclohexyl)acetate 5 (7.95 g, 32.0 mmol, 1.0 equiv) in benzene
(300 mL) was added DL-camphorsulfonic acid (11.16 g, 48.0 mmol,
1.5 equiv). A Dean-Stark apparatus was attached, and the mixture
was refluxed at 100 °C for 26 h. Periodically during that time, an
additional 3 equiv of CSA (22.2 g, 96.0 mmol, 3 equiv) was added in
1
was determined from its H NMR spectrum (g97% ee).
To access the syn-diol enantiomer 7a using a single enzymatic
resolution, we performed an enzymatic deacetylation with
racemic syn-diol monoacetate (()-13 as shown in Scheme 5.
Treatment of the substrate (()-13 with the lipase and 0.11 equiv
(total over two additions) of 1 M aqueous NaOH in a phosphate
buffer at room temperature yielded 44% of the diol 7a (g97%
ee) resulting from acetate hydrolysis along with a 48% recovery
of the remaining acetate 13 (g97% ee).16 The calculated E-value
for the lipase in this resolution is 278.
The desired (S)-2-(1-hydroxy-2-oxocyclohexyl)acetic acid (1)
could easily be obtained from the diol (1S,2S)-7 as shown in
Scheme 7. IBX oxidation of diol 7 followed by hydrogenation
of benzyl ester (S)-8 afforded the precursor to the Ugi 4C-3C
reaction, γ-keto acid (S)-1.20 The importance of carrying through
the benzyl (as opposed to a simple alkyl) ester in 8, thus
(20) 2-(1-Hydroxy-2-oxocyclohexyl)acetic acid (1) can also exist in the
hemiketal form 15 as reported previously in its racemic synthesis (ref 3).
The 1H NMR chemical shifts of the R-C H2 of the cyclohexanone moiety
observed in CD3OD, D2O, and acetone-d6 indicated the keto form rather than
1
hemiketal form (see the Supporting Information for the H NMR spectrum).
(19) Standard acetate deprotection conditions involving potassium carbonate
in methanol cleaved the acetyl group but also converted the benzyl ester to the
methyl ester. As mentioned later in the text, base-promoted hydrolysis of this
particular ester did not give the desired γ-keto acid 1.
3940 J. Org. Chem. Vol. 73, No. 10, 2008

three installments. The mixture was partitioned between saturated
aqueous sodium bicarbonate (300 mL) and EtOAc (350 mL) and then
washed with saturated aqueous sodium chloride (100 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. The resultant oil
was purified by flash chromatography on silica gel (15:1 f 13:1 f
11:1 hexanes/ethyl acetate) to yield 6 (5.83 g, 25.3 mmol, 79%, 11:1
mixture of ꢀ,γ- to R,ꢀ-olefin isomers) as a colorless oil as an 11:1
mixture of ꢀ,γ to R,ꢀ olefin regioisomers. Rf ) 0.57 (3:1 hexanes/
(4:1 f 3:1 hexanes/ethyl acetate) to yield acetate 13a (2.74 g, 8.94
mmol, 47%, 82% ee (by derivatization to the Mosher esters), [R]23
D
+5 (c 1.0, CHCl3), 11:1 mixture of isomers) and the remaining
diol (-)-7 (2.47 g, 9.34 mmol, 49%, g 97% ee (by derivatization
to the Mosher esters), [R]23 -4 (c 1.0, CHCl3), 11:1 mixture of
D
isomers). Included in the Supporting Information are the NMRs of
the crude aliquot mentioned above and the MTPA ester of the diol
showing its enantiopurity.
1
ethyl acetate). Data for major, desired isomer. H NMR (400 MHz,
Preparation of Benzyl 2-((1R,2R)-1,2-Dihydroxycyclohexyl)
acetate (7a) by Enzymatic Hydrolysis. To a solution of acetate
(()-13 (157 mg, 0.512 mmol, 1.0 equiv, 11:1 mixture of ꢀ,γ- to R,ꢀ-
diol isomers) and Amano lipase AK (30 mg, 176 units lipase/mmol
diol, 6 equiv based on 20000 units/g of lipase) in 1 mL of pH ) 7
phosphate buffer was added 1 M NaOH (35 µL, 0.068 equiv). The
mixture was stirred at rt for 16 h, and then more 1 M NaOH (20 mL,
0.039 equiv) was added and the mixture stirred for another 27 h.
Reaction progress was checked as above and indicated nearly 50%
conversion. The mixture was extracted with dichloromethane (3 × 15
mL), and the organics were washed with brine (15 mL), dried over
sodium sulfate, and concentrated in vacuo. The resultant oil was
purified by flash chromatography on silica gel (5:1 hexanes/ethyl
acetate) to yield the remaining acetate 13 (74 mg, 0.241 mmol, 48%,
CDCl3) δ: 7.36 (m, 5H), 5.58 (s, 2H), 3.00 (s, 2H), 1.96-2.06 (m,
4H), 1.52-1.66 (m, 4H). 13C NMR (100 MHz, CDCl3) δ: 171.6, 135.8,
130.8, 128.4 (2C), 127.99, 127.96 (2C), 125.8, 66.2, 43.6, 28.5, 25.4,
22.8, 22.1. HRMS: calcd for C15H18O2 230.1301, found 230.1304.
Benzyl 2-(cis-1,2-Dihydroxycyclohexyl)acetate (()-(7). To a
solution of 6 (5.70 g, 24.8 mmol, 1.0 equiv, 11:1 mixture of ꢀ,γ- to
R,ꢀ-olefin isomers) in 10:1 THF/H2O (150 mL) were added 4% OsO4
in H2O (4.55 mL, 0.743 mmol, 0.03 equiv), 4-methylmorpholine
N-oxide (8.70 g, 74.3 mmol, 3.0 equiv), and 1,4-diazabicyclo[2.2.2]octane
(139 mg, 1.24 mmol, 0.05 equiv). After the mixture was stirred for
14 h, saturated aqueous sodium bisulfite (100 mL) was added, and
the mixture was extracted with ethyl acetate (3 × 200 mL). The
organics were washed with brine (150 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. The resultant solid was purified
by flash chromatography on silica gel (3:1 f 1:1 hexanes/ethyl acetate)
to yield (()-7 (6.08 g, 23.0 mmol, 93%, 11:1 mixture of ꢀ,γ to R,ꢀ
diol isomers) as an off-white powder. Use of the 11:1 mixture poses
no problem in the following steps, and the minor isomer was removed
after IBX oxidation. This 11:1 diol mixture was recrystallized two times
(5:1 hexanes/EtOAc) to give a nearly pure ꢀ,γ-diol for collection of
physical data (see the Supporting Information for NMR of the mixture
and purified material). Rf ) 0.13 (3:1 hexanes/ethyl acetate). Data for
major, desired isomer. Mp ) 71-73 °C. 1H NMR (500 MHz, CDCl3)
δ: 7.30-7.40 (m, 5H), 5.15 (s, 2H), 3.66 (s, 1H), 3.33, (dd, 1H, J )
10.5, 4.5 Hz), 2.90 (d, 1H, J ) 15.3 Hz), 2.43 (d, 1H, J ) 15.3 Hz),
2.18 (d, 1H, J ) 7.5 Hz), 1.84 (dt, 1H, J ) 13.5, 4.0 Hz), 1.65-1.74
(m, 2H), 1.50-1.65 (m, 2H), 1.38-1.42 (m, 1H), 1.20-1.32 (m, 2H).
13C NMR (100 MHz, CDCl3) δ: 173.5, 135.7, 128.9 (2C), 128.7, 128.5
(2C), 77.0, 74.2, 66.9, 43.1, 35.7, 30.5, 23.9, 21.1. HRMS: calcd for
C15H20O4 264.1356, found 264.1354.
Benzyl 2-((1S,2S)-2-Acetoxy-1-hydroxycyclohexyl)acetate (()-
(13). To a solution of (()-7 (5.2 g, 19.7 mmol, 1.0 equiv, 11:1
mixture of ꢀ,γ- to R,ꢀ-diol isomers) in pyridine (40 mL, 0.491
mol, 25 equiv) was added acetic anhydride (20 mL, 0.212 mol, 11
equiv). After being stirredfor 20 h, the mixture was diluted with
ethyl acetate (200 mL) and washed with 1 M HCl (3 × 100 mL).
The organics were further washed with saturated aqueous NaHCO3
(2 × 100 mL), dried over sodium sulfate, and concentrated in vacuo
to yield (()-13 (6.03 g, 19.7 mmol, 100%, 11:1 mixture of isomers).
Rf ) 0.24 (3:1 hexanes/ethyl acetate). 1H NMR (400 MHz, CDCl3)
δ: 7.30-7.40 (m, 5H), 5.12 (s, 2H), 4.64 (dd, 1H, J ) 4.4, 10.4
Hz), 3.45 (bs, 1H), 2.64 (d, 1H, J ) 15.6 Hz), 2.41 (d, 1H, J )
15.2 Hz), 2.01 (s, 3H), 1.87 (apparent d, 1H, J ) 14.0 Hz),
1.70-1.80 (m, 3H), 1.60-1.68 (m, 1H), 1.30-1.48 (m, 3H). 13C
NMR (100 MHz, CDCl3) δ: 172.0, 170.5, 135.4, 128.7 (2C), 128.5,
128.3 (2C), 77.4, 71.5, 66.6, 43.1, 36.3, 26.8, 23.9, 21.2, 20.4.
HRMS: calcd for C17H22O5 306.1462, found 306.1460.
g97% ee (by derivatization to the Mosher esters), [R]23 -8 (c 1.0,
D
CHCl3), 5:1 mixture of isomers) and diol 7a (52 mg, 0.197 mmol,
44%, g97% ee (by derivatization to the Mosher esters), [R]23D +3 (c
1.0, CHCl3), 14:1 mixture of isomers).
(S)-Benzyl 2-(1-Hydroxy-2-oxocyclohexyl)acetate (8). To a
solution of 7 (4.10 g, 15.5 mmol, 1.0 equiv, 11:1 mixture of ꢀ,γ- to
R,ꢀ-diol isomers) in ethyl acetate (300 mL) was added IBX (6.52 g,
23.3 mmol, 1.5 equiv). After being heated at reflux for 6 h, the mixture
was filtered through Celite and concentrated in vacuo. The resultant
oil was purified by flash chromatography on silica gel (5:1 hexanes/
ethyl acetate) to yield 8 (3.60 g, 13.7 mmol, 87%), Rf ) 0.23 (3:1
hexanes/ethyl acetate), as a single isomer. For the S-enantiomer 8:
[R]23 +20 (c 1.1, CHCl3). For the R-enantiomer 8a: [R]22 -22 (c
D
D
1.5, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.32-7.40 (m, 5H), 5.12
(s, 2H), 4.58 (s, 1H), 3.00 (d, 1H, J ) 15.2 Hz), 2.72-2.80 (m, 1H),
2.60 (d, 1H, J ) 15.6 Hz), 2.44-2.52 (m, 1H), 1.88-2.00 (m, 3H),
1.78-1.86 (m, 2H), 1.56-1.70 (m, 1H). 13C NMR (100 MHz, CDCl3)
δ: 211.3, 170.9, 135.1, 128.2 (2C), 128.0, 127.9 (2C), 77.1, 66.5, 41.5,
41.3, 37.8, 28.3, 21.7. HRMS: calcd for C15H18O4 262.1200, found
262.1202.
(S)-2-(1-Hydroxy-2-oxocyclohexyl)acetic Acid (1). To a solu-
tion of 8 (422 mg, 1.61 mmol, 1.0 equiv) in methanol (35 mL)
was added 10 wt % Pd/C (150 mg). A balloon of H2 was applied
for 16 h, and then the mixture was filtered through Celite and
concentrated in vacuo to yield 1 (283 mg, 1.61 mmol, 100%). For
the S-enantiomer 1: [R]23 +20 (c 0.8, DMSO). For the R-
D
enantiomer 1a: [R]23 -21 (c 0.8, DMSO). H NMR (400 MHz,
1
D
CD3OD) δ: 2.80 (d, 1H, J ) 16.0 Hz), 2.58 (d, 1H, J ) 15.6 Hz),
2.28 (bs, 1H), 2.16 (bs, 1H), 1.68 (m, 6H). 13C NMR (100 MHz,
(CD3)2CO) δ: 208.0, 175.3, 77.7, 43.4, 38.8, 37.4, 26.6, 23.2.
HRMS: calcd for C8H12O4 172.0730, found 172.0733.
Acknowledgment. We thank the University of California for
financial support. We also thank Amano Enzyme, Inc., for their
generous gifts of enzyme samples. We acknowledge Kerem
Ozboya (UCSD undergraduate student) for preliminary studies on
the racemic synthesis of compound 1.
Preparation of Benzyl 2-((1S,2S)-1,2-Dihydroxycyclohexyl)-
acetate (7) by Enzymatic Acetylation. A solution of diol (()-7
(4.97 g, 18.8 mmol, 1.0 equiv, 11:1 mixture of ꢀ,γ- to R,ꢀ-diol
isomers), vinyl acetate (0.890 g, 10.3 mmol, 0.55 equiv), and
Amano lipase AK (0.498 g, 176 units lipase/mmol diol, 3 equiv
based on 20000 units/g of lipase) in t-BuOMe (50 mL) was heated
to 50 °C. It was heated for a total of 72 h with addition of additional
vinyl acetate (1.0 mL) after 30 h. Reaction progress was checked
by integration of peaks (diol: 2.89 ppm, acetate: 2.64 ppm) in the
1H NMR spectrum of a crude aliquot (see the Supporting Informa-
Supporting Information Available: Copies of 1H NMR and
13C NMR spectra for compounds 1,5-8, and 12-14, as well as
partial 1H NMR spectra of the Mosher esters of 7 and 7a.
Additional experimental procedures for Sharpless asymmetric
dihydroxylation of 6 and ref 16 (13 f 14 f 12). This material is
available free of charge via the Internet at http://pubs.acs.org.
1
tion for H NMR spectrum). At the 50% completion point, the
mixture was filtered through Celite and concentrated in vacuo. The
resultant oil was purified by flash chromatography on silica gel
JO8000904
J. Org. Chem. Vol. 73, No. 10, 2008 3941