A new route to protected acyloins and their enzymatic resolution with lipases

Article abstract of DOI:10.1002/ejoc.200300338

A series of 16 different 3-acyloxy methyl ketones, the acyloin acetates and butyrates (±)-5, was synthesised by a straight-forward new method through alkylation of tert-butyl 2-acyloxyacetoacetates 3, followed by chemoselective dealkoxy-carbonylation of the tert-butyloxycarbonyl group in the presence of other ester groups. Subsequent hydrolysis of (±)-5 can be achieved with base to give racemic acyloins 6, or with lipase catalysis to afford the corresponding non-racemic acyloins (S)-6. The remaining (R)-acyloin esters 5 can be racemised and resubjected to the procedure, or hydrolysed chemically. The kinetic resolution with two of the six tested enzymes, CAL-B and BCL (PS) lipase, proceeded selectively [enantiomeric ratio (E) values between 50 and > 200] and most of the acyloins (S)-6 were obtained in very high enantiomeric excesses (up to > 99% ee). Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300338

FULL PAPER
A New Route to Protected Acyloins and Their Enzymatic Resolution with
Lipases
Günther Scheid,[a,b] Wouter Kuit,[b] Eelco Ruijter,[b] Romano V. A. Orru,[b] Erik Henke,[c]
Uwe Bornscheuer,[d] and Ludger A. Wessjohann*[a,b]
Keywords: Acyloins / Alkylation / Enzymatic catalysis / Hydrolases / Hydroxyalkanones / Kinetic resolution
A series of 16 different 3-acyloxy methyl ketones, the acyloin
acetates and butyrates ( )-5, was synthesised by a straight-
cemised and resubjected to the procedure, or hydrolysed
chemically. The kinetic resolution with two of the six tested
forward new method through alkylation of tert-butyl 2-acyl- enzymes, CAL-B and BCL (PS) lipase, proceeded selectively
oxyacetoacetates 3, followed by chemoselective dealkoxy- [enantiomeric ratio (E) values between 50 and Ͼ 200] and
carbonylation of the tert-butyloxycarbonyl group in the pres- most of the acyloins (S)-6 were obtained in very high enantio-
ence of other ester groups. Subsequent hydrolysis of ( )-5
can be achieved with base to give racemic acyloins 6, or with
meric excesses (up to Ͼ 99% ee).
lipase catalysis to afford the corresponding non-racemic ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
acyloins (S)-6. The remaining (R)-acyloin esters 5 can be ra- Germany, 2004)
Introduction
of chiral β-lactams and γ-butyrolactones.[13Ϫ15] These are
only a few examples of the synthetic scope of optically
pure acyloins.
The acyloin moiety is a key structural feature of many
natural products.[1Ϫ4] Chiral α-hydroxy ketones (acyloins)
are versatile synthetic intermediates in the asymmetric syn-
thesis of a wide range of bioactive compounds. Reduction
of the acyloin carbonyl group, for example, gives access to
either the threo or the erythro 1,2-diols, which are highly
valuable building blocks.[5] Wittig olefination allows the
synthesis of chiral allylic alcohols, which have been applied
in, for example, pheromone synthesis.[6] Furthermore, chiral
α-hydroxy ketones have been used to synthesise syn or anti
aldols with high diastereoselectivity by employment of bo-
ron-mediated aldol addition[7Ϫ9] or titanium enolates.[10,11]
BaeyerϪVilliger oxidation of chiral protected α-hydroxy ke-
tones results in chiral acetals that can be converted into
chiral secondary alcohols through Lewis acid-supported
nucleophilic substitution with organocuprates.[12] Further
applications of chiral acyloins can be found in the synthesis
Several chemical methods for the preparation of chiral α-
hydroxy ketones are described in the literature. Useful
methods include the enantioselective oxidation of chiral en-
olates,[16] the oxidation of non-chiral enolates with chiral
oxidants,[17] or the use of DiTOX, a chiral dithiane oxide.[18]
Further methods have extensively utilised the Sharpless
asymmetric epoxidation to introduce chirality. The resulting
optically pure epoxy alcohols can subsequently be con-
verted into the corresponding alkynols and further trans-
formed into acylprotected acyloins by use of a Ru cata-
lyst.[19] Finally, -amino acids from the chiral pool have
been used as starting materials for the synthesis of some
particular (3S)-3-hydroxy-2-ketones.[20]
In addition to the described classical chemical ap-
proaches to optically active acyloins, some biocatalytic
routes to these compounds have also been reported. The
most common approach so far has been the reduction of
1,2-diketones either with enzymes or by microbial reduction
with whole-cell systems.[1,4,21,22] Frequently encountered
drawbacks of these methods are overreduction to diols and
also a lack of regioselectivity, yielding two regioisomeric
acyloins. A reductive resolution of α-hydroxy ketones to
give enantiopure syn diols and chiral acyloins, albeit one
resulting in a relatively low isolated yield of the optically
pure acyloin, has also been described.[23] Oxidative biocata-
lytic approaches towards optically pure acyloins have been
discussed as well. Thus, enzyme oxidation of racemic syn
[a]
Dept. of Bioorganic Chemistry (NWC), Leibniz-Institute of
Plant Biochemistry (IPB),
Weinberg 3, 06120 Halle (Saale), Germany
Fax: (internat.) ϩ 49-(0)345-5582-1309
E-mail: wessjohann@ipb-halle.de
[b]
Division of Chemistry, Dept. of Organic and Inorganic
Chemistry, Vrije Universiteit Amsterdam (VUA),
De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
[c]
Institute for Technical Biochemistry, Universität Stuttgart,
Allmandring 31, 70569 Stuttgart, Germany
[d]
Institute for Chemistry & Biochemistry, Dept. of Technical
Chemistry & Biotechnology Universität Greifswald,
Soldmannstr. 16, 17487 Greifswald, Germany
Eur. J. Org. Chem. 2004, 1063Ϫ1074
DOI: 10.1002/ejoc.200300338
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L. A. Wessjohann et al.
FULL PAPER
or anti 1,2-diols allowed the isolation of enantiomerically
enriched diols and acyloins.[24] However, the isolated yields,
especially those of open-chain chiral acyloins, were rather
disappointing. In general, it can be stated that chiral acylo-
ins can be prepared with oxidoreductases either reductively
or oxidatively, providing the products with high ees, but
that the methods suffer from drawbacks such as overreduc-
tion, regioselectivity problems, and low yields.
In addition to oxidoreductases, decarboxylases and lyases
have also been used to produce optically active acyloins.[25]
As an example, an acetoacetate decarboxylase-catalysed ki-
netic resolution of 2-ethyl-2-hydroxy-3-oxocarboxylate has
been reported.[26] Recently, a phenylpyruvate decarboxylase
from Achromobacter eurydice SC16386 was used in asym-
metric acyloin condensations with different aldehydes.[27]
A
major drawback so far is that only a very limited range of
different substrates is accepted by these enzymes.
Although potentially a useful approach, the application
of hydrolases for the preparation of α-hydroxy ketones has
so far been limited to certain examples. Although kinetic
resolutions of many secondary alcohols and their esters are
well documented, only a few examples of α-hydroxy ke-
tones, mostly of pseudo-meso precursors, are known to
date.[28Ϫ31] The largest set of experimental data was col-
lected by Hiyama et al., who screened 84 commercially
available hydrolases in order to synthesise enantiomerically
pure 2-hydroxy-1-indanone as a key precursor of chiral 1-
amino-2-indanol, a structural element of a HIV-protease in-
hibitor.[31b]
Scheme 1. Synthesis of acyloin esters 5 and acyloins 6 from ace-
toacetate
During our synthetic studies towards epothilones B and
D,[32] we were confronted with the need to introduce an lation.[34] Bromination of tert-butyl acetoacetate (1) with
optically pure α-hydroxy ketone functionality. We envi- NBS to give the bromo derivative 2, followed by nucleo-
sioned that a kinetic resolution of a racemic acyloin acetate philic substitution with sodium acetate in DMF, gave tert-
with lipases might afford the desired optically pure α- butyl acetoxyacetoacetate (3a) in 69% over two steps
hydroxy ketone. However, the lack of literature information (Scheme 1). In the same manner, tert-butyl-2-(butyryloxy)-
on kinetic resolutions of acyloins prompted us to synthesise acetoacetate (3b) was obtained by use of sodium butyrate as
a series of 16 different 3-acyloxy-2-alkanones 5 (Scheme 1), nucleophile, in 72% overall yield. This two-step procedure
and to screen them for selective hydrolysis with six different could be performed easily on a large scale, thus providing
commercially available lipases. The results of our studies are 3a and 3b as versatile starting materials for the synthesis of
presented in this paper.
a variety of carboxylate-protected acyloins. Other acyloxy
residues should be easily accessible by this route, simply
through the use of other carboxylates in the substitution
step. The fact that the acyloin oxygen is introduced through
Results and Discussion
The acyloin esters 5aϪp used in our study were syn- a carboxylate nucleophile is an advantage in terms of ef-
thesised by application of simple acetoacetate chemistry, ficiency, because protectionϪdeprotection steps are avo-
based on a similar procedure by Lawesson et al.[33] The ided. Compounds 3a and 3b can be alkylated smoothly by
original method proceeds through oxidation of alkylated classical acetoacetate chemistry procedures, through depro-
acetoacetates with benzoyl peroxide followed by solvent- tonation with NaH in DMF, followed by addition of alkyl,
free dealkoxycarbonylation with pTsOH. Only benzoyl es- allyl, alkynyl or benzyl halides to yield the intermediates
ters are accessible in this way, however. Furthermore, since 4aϪp (Scheme 1). Alkylation with K2CO3 in a THF/DMF
oxidation is performed after introduction of the alkyl mixture was also possible, but resulted in lower yields.
group, problems with other, oxidation-labile functionalities Selective dealkoxycarbonylation of 4aϪp was accomplished
could arise. Another drawback in Lawesson’s approach is either through acid catalysis in benzene with pTsOH at
that two steps are required after the alkylation to reach the 80 °C or by Krapcho dealkoxycarbonylation[35] with LiCl
desired intermediates 4.
and water in DMSO at 160 °C. In this way, the 2-acyloxy
We therefore developed a more straightforward and vari- substituent was not affected, whereas the tert-butylcar-
able synthesis of intermediates 4, based on the introduction boxylate group was cleanly removed. Intermediate 4i was
of the acyloxy group into the acetoacetate before alky- obtained by hydrogenation of 4g in the presence of Lindlar
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A New Route to Protected Acyloins
FULL PAPER
catalyst, and acyloin acetate 5k was obtained by hydrogen-
ation of 5j in the presence of palladium on charcoal.
Table 1. Selectivities (E values) of lipase-catalysed hydrolysis of acy-
loin esters 5; the corresponding chiral GC data and ee values are
shown in Table 2 and 3, respectively
The racemic acyloin esters 5aϪp thus obtained were hy-
drolysed with six commercially available lipases (Scheme 2).
The screening was performed by using the enzymes in phos-
phate buffer (pH 7.0) at ambient temperature for 30 mi-
nutes. In each case, the corresponding free acyloins 6aϪp
were the only detectable hydrolysis products; no acyloin
shifts from, for example, 3-hydroxy-2-alkanone to 2-
hydroxy-3-alkanone was observed. The structures of the
acyloins 6aϪp were confirmed by comparison with litera-
ture data or by their spectroscopic data. No significant 5g
spontaneous hydrolysis was observed in aqueous buffer
(phosphate buffer, pH ഠ 7, room temp.) in the absence of
enzyme, except in the cases of the allyl derivative 5f and the
alkyne derivative 5g, which were hydrolysed to extents of
2.6% (5f) and 4.3% (5g) within 30 minutes. We therefore
concluded that the substrates showed sufficient stability un-
der our hydrolysis conditions. In kinetic resolutions by
lipases the enantioselectivity is usually described by the en-
antiomeric ratio (E), since this parameter is independent of
the conversion. Thus, from the ee data obtained from chiral
GC analysis, the E values (Table 1) were calculated accord-
ing to Rakels and Straathof[36] or Chen et al.[37]
Substrate
Lipase[a]
CAL-B CAL-A CRL
BCL
ROL
1
PPL
2
5a
5b
5c
5d
5e
5f
2
1
19
2
1
25
30
55
9
n.d.[b]
n.d.[b] n.d.[b] n.d.[b]
165
110
152
18[c]
50[c]
116
8
3
1
1
n.d.[b]
7
n.d.[b] n.d.[b] n.d.[b]
3
1
2
26[c]
2[c]
12
n.d.[b]
6[c]
36
n.d.[b] n.d.[b] n.d.[b]
5[c]
1
1[c]
2
1
2
1
4[c]
2
2
1
1
5h
5i
5j
5k
5l
5m
5n
5o
5p
Ͼ200 Ͼ200
Ͼ200 166
Ͼ200 154
41
114
177
5
20
5
1
1
2
62
31
13
n.d.[b]
14
n.d.[b] n.d.[b] n.d.[b]
1
1
1
1
Ϫ
1
Ϫ
3
15
1
4
Ͼ200 Ͼ200
104
n.d.[b] n.d.[b]
n.d.[b] n.d.[b]
7
[a]
Enantiomeric ratio: E ϭ (kcat/KM)(R)/(kcat/KM)(S); calculated
from eeP, eeS according to Rakels et al.[36] or from eeP and conver-
sion according to Chen et al.[37] [b] n.d. ϭ not determined. Cor-
[c]
rected for spontaneous hydrolysis.
catalysed hydrolysis of acyloin acetates with longer alkyl
chains proceeds with good selectivities. The longer the alkyl
chain, the better the lipase can discriminate between the
two side chains (i.e., alkyl and acyl residues). This obser-
vation is in agreement with the results of Kazlauskas et al.,
who showed, in a related study on lipase resolution of sec-
ondary alcohols, that the enantiomeric ratio (E) depends on
the difference in the sizes of the two side chains.[38] Also in
accordance with the Kazlauskas model, the tested enzymes
showed no enantiodifferentiation of the small acyloin
acetate 5a, probably because the ethyl and acetyl moieties
at C-3 are too similar in size. In line with these results is
that CAL-B-catalysed hydrolysis of the propyl derivative 5b
already shows some stereodifferentiation, while the longer
alkyl chain derivatives 5cϪe show excellent enantioselectivi-
ties. BCL-catalysed hydrolysis of the same derivatives 5bϪe,
however, proceeded with only moderate selectivities. On the
Scheme 2. Enzymatic resolution of acyloin esters 5 with commer-
cial lipases and their abbreviations (in brackets: alternative abbrevi-
ations commonly used)
The selectivities of the hydrolysis of 5aϪp by lipases from other hand, hydrolysis of the saturated and branched acy-
Candida rugosa (CRL), Rhizopus oryzae (ROL) and Porcine loin acetate 5k (BCL) showed perfect selectivity. In this case
pancreas (PPL) were low (Table 1, E Ͻ 5), whereas Candida the E value was Ͼ 200, superior even to CAL-B, with an
antarctica lipase A (CAL-A) catalysed hydrolysis of 5aϪp E Ͼ 150.
proceeded with low to moderate (E Ͻ 36) selectivities.
The more rigid, unsaturated substrates 5h, 5i, and 5j re-
These enzymes are therefore not suited for enantioselective vealed an interesting feature. While CAL-B generally hydro-
kinetic resolution of acyloin acetates. On the other hand, lysed these acetoxy ketones with high enantioselectivity, re-
better results were obtained for the hydrolysis of 5aϪp with markable differences were observed with BCL. The selec-
lipases from Burkholderia cepacia (BCL) and Candida ant- tivities in the CAL-B-catalysed hydrolysis of E- and Z-cro-
arctica B (CAL-B), which sometimes showed comparable tyl-substituted acyloin acetates 5h and 5i increased from
excellent selectivities and sometimes complemented each 116 to Ͼ200, respectively, while the BCL-catalysed hydroly-
other. Thus, except for the hydrolysis of acyloin acetates sis literally switched from almost unselective (5h, E ϭ 12)
with small side chains (ethyl, propyl and allyl; 5a, 5b and to enantioexclusive (5i, E Ͼ 200). The prenyl derivative 5j
5f respectively), either lipase (BCL, CAL-B) or both of is also hydrolysed with high selectivity by both enzymes.
them were able to achieve excellent selectivities. From the Comparison of, on one hand, the saturated butyl, pentyl
data in Table 1 it can be deduced that BCL- or CAL-B- and hexyl substrates 5cϪe, hydrolysed by BCL with rather
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L. A. Wessjohann et al.
FULL PAPER
low selectivities, with the BCL-catalysed hydrolysis of the
In conclusion, the BCL lipase is more suited for selective
branched saturated substrate 5k (E Ͼ 200) on the other, hydrolysis of larger unsaturated or saturated δ-branched
indicates that the increased selectivity is not a function of substrates, while CAL-B is the enzyme of choice for selec-
the unsaturation per se (i.e., p-orbitals, sp1 or sp2 carbon tive hydrolysis of smaller substrates and unbranched satu-
atoms), but of configurational or conformational proper- rated acyloins.
ties. For comparison, conformationally restricted cyclic sub-
All enzymes preferentially hydrolysed the (S)-configured
strates, obtained from commercial 2-chlorocycloalkanones esters 5, affording the (S)-acyloins 6 and leaving behind the
with acetate, were also hydrolysed. With all commercial li- (R)-O-acyl acyloins. The latter can easily be racemised and
pases tested, the enantioselectivities were very low: the best reintroduced into the lipase resolution process,[39] so that
results were E ϭ 27 (BCL) and E ϭ 14 (CAL-B) for 2- theoretically (after a few cycles) a 100% yield of the (S)-
acetoxycyclopentanone
respectively (data not shown in Tables, abs. configurations possible through chemical hydrolysis of the (R)-acyloxy
not assigned). ketones. The direct generation of (R)-acyloins from racemic
and
2-acetoxycyclohexanone, acyloins could be achieved. Access to the (R)-acyloins is
In summary, the observed selectivities can be interpreted acyloxy ketones by use of (R)-selective lipases or esterases
in terms of a model of well differentiated substrates for the obtained from non-commercial sources is currently under
enzyme BCL (Figure 1). This enzyme shows optimum selec- investigation.
tivities for the hydrolysis of substrates that contain a group
The absolute configurations of 6c and 6n were deter-
R4 other than H in a cis configuration (5i, 5j, 5m and 5l) mined to be (S) by comparison of their optical rotation val-
or synperiplanar (5k) with respect to the α-acetoxy ketone ues to those obtained from the literature.[40a,40b] No litera-
moiety. While the configuration is fixed in the case of a ture data were available for any of the other acyloins, so we
double bond, a linear saturated alkyl chain (R3 ϭ H) pref- applied the method of Latypov et al.,[40c] in which the
erentially adopts a more stable antiperiplanar conformation. NMR spectra of (R)-2-methoxy-2-phenylacetic acid esters
Branching at the δ-position (R3 ϭ Me), however, gives rise (MPA esters) of secondary alcohols were measured at two
to an alkyl chain with R4 close to a synperiplanar (or at different temperatures. Changes in the chemical shifts of
least a synclinal) conformation, resulting in more selective protons in the side-chains connected to the stereocenter re-
BCL-catalysed hydrolysis. In line with these observations is veal the absolute stereochemistry. Thus, after derivatisation
that the longer diprenyl derivative 5l (neryl) is clearly a bet- of acyloins 6g,[41] 6i, 6l[41] and 6m to the corresponding
ter substrate for BCL than for CAL-B. The active site MPA esters (details see Exp. Section) the absolute configu-
pocket in CAL-B might be somewhat smaller than in BCL. ration could be determined as (S). This is in agreement with
Finally, the alkyne derivative 5g could not be differentiated the Kazlauskas rule, which predicts the preferential hy-
by BCL, but CAL-B still showed reasonable enantioselec- drolysis of the (S)-configured acyloin esters with different
tivity. A special case is the benzyl derivative 5n, which was types of hydrolases.[38] The other absolute configurations
hydrolysed with good enantioselectivity with BCL but not (6a, 6b, 6d, 6e, 6f, 6h, 6j, 6k) were assigned from the GC
with CAL-B. The butyrates 5o, 5p are also suitable, rapidly retention times, the (S)-alcohols being eluted prior to the
reacting substrates. They show the same tendency as the (R)-alcohols.
acetates, although somewhat more pronounced in one or
the other direction. In consequence, a variation in the alk-
anoate may be useful to fine-tune enantioselectivity, reac-
tion speed, or solubility of substrates.
Conclusion
A series of 16 different acyloinacetates and butyr-
ates (Ϯ)-5 was synthesised by a new and straightforward
method through alkylation of 3 and selective dealkoxycar-
bonylation, resulting in acyloxy acetoacetates 4. Subsequent
hydrolytic kinetic resolution with six different lipases gave
the (S)-acyloins 6. It was found that only two of the tested
enzymes, CAL-B and BCL, were able to resolve most of the
tested acyloin esters selectively. Two general rules could be
defined for the selective hydrolysis of α-acetoxy ketones by
CAL-B and BCL lipase: (i) when CAL-B lipase was used,
an increase in the chain length of substituent R2 to more
Figure 1. Acyloin substrate model for BCL
For the CAL-B lipase the most important selectivity fac- than three carbon atoms allowed excellent resolution, es-
tor seems to be the length of the alkyl or allyl chain. This pecially of smaller and unbranched saturated acyloins, and
is clearly revealed by the almost identical low E values for (ii) substrates suited for BCL lipase must bear an unsatu-
CAL-B-catalysed hydrolysis of 5f (allyl) and 5b (propyl) on rated carbon chain or at least a saturated four-carbon chain
one hand and the excellent selectivities observed with 5c, with a branching substituent at the δ-position. An increased
5h, and 5i on the other. At least a four-carbon chain seems length of the carbon chain had no negative influence on the
to be required for a highly selective CAL-B-hydrolysis of selectivities; the geranyl- and neryl-derived substrates 5l and
acyloin acetates.
5m, for example, were still resolved well. However, un-
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A New Route to Protected Acyloins
FULL PAPER
Compound 2 (59.27 g, 250 mmol) was added to a suspension of
sodium acetate (30.76 g, 375 mmol) in DMF (250 mL). After the
mixture had been stirred at ambient temperature for 90 min, water
(415 mL) was added and the mixture was extracted three times with
ethyl acetate (325 mL). The combined organic layers were washed
three times with water (325 mL) and once with brine (325 mL) and
then dried with Na2SO4. After filtration, the solvent was removed
in vacuo and the resulting oil was purified by distillation (12 mbar,
128 °C) to give 3a (36.52 g, 169 mmol, 68%). 1H NMR (200 MHz):
δ ϭ 1.50 (s, 9 H), 2.22 (s, 3 H), 2.34 (s, 3 H), 5.41 (s, 1 H) ppm.
13C NMR (50 MHz): δ ϭ 20.46 (q), 27.32 (q), 27.83 (q), 78.38 (d),
84.04 (s), 163.36 (s), 169.55 (s), 197.84 (s) ppm. IR: ν˜ ϭ 841 (w),
1094 (m), 1152 (s), 1221 (s), 1250 (s), 1395 (w), 1420 (w), 1456 (w),
1748 (s), 2938 (m), 2980 (m) cmϪ1. MS (CI): m/z (%) ϭ 117 (19),
143 (12), 161 (100), 205 (43), 207 (12), 217 (18) [MHϩ]. HRMS:
calculated for C10H17O5 [MHϩ]: 217.10760; found 217.10460.
C10H17O5: calcd. C 55.55, H 7.46; found C 55.39, H 7.54.
branched substrates were less suitable for BCL-lipase-cata-
lysed hydrolysis.
For other substrates, such as benzyl- or methylalkynyl-
derived substrates, one of the two lipases always proved to
be sufficiently selective. Therefore, any acyloin acetate with
a residue R2 larger than propyl could be resolved selectively
by use of either CAL-B or BCL.
Experimental Section
General Remarks: NMR spectra were recorded in CDCl3 with a
Bruker ARX 200, a Bruker ARX 250, or a Varian MERCURY-VX
1
400 machine. Chemical shifts of H NMR and 13C NMR spectra
are referenced to tetramethylsilane (δ ϭ 0 ppm). Coupling con-
stants are given in Hz and the 13C multiplicities were determined
by the use of a DEPT-135 pulse sequence. IR spectroscopy was
performed on a Mattson Instruments 6030 Galaxy Series FT-IR,
all compounds were measured as thin oil films between NaCl
plates. Mass spectrometry (MS) was performed with a Finnigan
MAT-90 mass spectrometer operating at an ionisation potential of
70 eV. High-resolution mass spectrometry (HRMS) was performed
with a Finnigan MAT-90 mass spectrometer with isobutene as ionis-
ation gas. TLC was carried out with silica gel Merck-60 (F254 on
aluminium with fluorescence indicator), and compounds were visu-
alised by UV (extinction at λ ϭ 254 nm or fluorescence at λ ϭ
366 nm) and/or by staining with Cer-MOP [a solution of molybda-
tophosphoric acid (5 g), cerium()sulfate (2 g) and concd. H2SO4
(16 mL) in 180 mL water]. Compounds were purified by flash chro-
Synthesis of tert-Butyl 2-(Butyryloxy)acetoacetate (3b): The bromo-
acetoacetate 2 (59.27 g, 250 mmol) was treated with sodium butyr-
ate (45 g, 410 mmol) as described above for the synthesis of 3a. The
usual workup, followed by distillation at 95 °C and 1.0 mbar, gave
1
3b (44 g, 180 mmol, 72%). H NMR (400 MHz): δ ϭ 0.99 (t, J ϭ
7.4 Hz, 3 H), 1.50 (s, 9 H), 1.72 (tq, J ϭ 7.0, J ϭ 7.4 Hz, 2 H),
2.33 (s, 3 H), 2.47 (t, J ϭ 7.0 Hz, 2 H), 5.41 (s, 1 H) ppm. 13C
NMR (100 MHz): δ ϭ 13.49 (q), 18.20 (t), 27.24 (q), 27.76 (q),
35.47 (t), 78.09 (d), 83.86 (s), 163.36 (s), 172.14 (s), 197.95 (s) ppm.
General Method for the Alkylation of tert-Butyl 2-Acyloxyacetoace-
tates (3) to give tert-Butyl 2-Acetyl-2-acyloxyalkanoates (4): The
acyloxyacetoacetate (3a or 3b, 1.00 equiv.) was added at 0 °C to a
suspension of NaH in DMF (2.0 mL/mmol, 1.10Ϫ1.30 equiv.).
After 15 min an alkyl or allyl bromide or chloride (1.00 equiv.) was
slowly added at 0 °C and the mixture was stirred overnight at room
temp. The mixture was then diluted with Et2O (10 mL/mmol) and
washed with H2O (3 ϫ 4.0 mL/mmol) and brine (4.0 mL/mmol).
The organic layer was dried with Na2SO4, filtered and concentrated
in vacuo to yield 2-alkylated acetoacetates 4aϪp. The products
were mostly of sufficient purity for the subsequent dealkoxycarbon-
ylation step; otherwise kugelrohr distillation was the fastest purifi-
cation method.
˚
matography on Baker (40 µ, 60 A) or Merck 60 (230Ϫ400 mesh)
silica gel. Volatile compounds were purified by (kugelrohr) distil-
lation. Petroleum ether with a boiling range of 40Ϫ60 °C was used.
Chiral GC analysis was carried out with a Varian Star 3400 Cx
chromatograph with FID and a (2,6-O-methyl-5-O-pentyl)-β-cyclo-
dextrin OV 1701 column (11 m ϫ 0.25 mm, 0.25 µm film, H2).
The injector port temperature was 170 °C and the detector was
maintained at 200 °C. The split ratio was 100/1 and the column
pressure 10 psi. Lipases were either purchased or donated by Am-
ano, Nagoya, Japan (CRL ϭ Amano AY, BCL ϭ Amano PS) or
Roche, Penzberg, Germany [CAL-A (Chirazyme -5), CAL-B (Chi-
razyme -2), PPL]. Enzyme preparations were used as obtained by
the suppliers. Processes are not optimised.
General Method A for the Selective Dealkoxycarbonylation of tert-
Butyl 2-Acetyl-2-acyloxyalkanoates (4) with para-Toluenesulfonic
Acid To Give 3-Acyloxy-2-alkanones (5): The appropriate com-
pound 4 (1.0 equiv.) and pTsOH·H2O (0.1 equiv.) were dissolved in
benzene (3.0 mL/mmol), and the mixture was stirred at 78 °C for
3Ϫ5 h. The obtained light brown solution was filtered through a
small column of silica, which was flushed with ethyl acetate. The
benzene/ethyl acetate solution was concentrated in vacuo, and the
remaining yellow oil was purified by kugelrohr distillation or flash
chromatography on silica with ethyl acetate/petroleum ether mix-
tures.
Synthesis of Acyloin Esters 5aϪ5p
Synthesis of tert-Butyl 2-Acetoxyacetoacetate (3a): N-Bromosuc-
cinimide (58.7 g, 330 mmol) was added portionwise to a stirred
solution of tert-butyl acetoacetate (1) (49.0 mL, 47.5 g, 300 mmol)
in acetone (30 mL). The resulting suspension was stirred for one
hour at room temp. and filtered. The filtrate was concentrated in
vacuo before being dissolved in petroleum ether (300 mL) and
washed three times with water (100 mL). The solution was then
dried with Na2SO4 and filtered. Removal of the solvent in vacuo
gave the bromoacetoacetate 2 (71.1 g, 300 mmol, quant.) as a
General Method B for the Selective Dealkoxycarbonylation of tert-
Butyl 2-Acetyl-2-acyloxyalkanoates (4) with LiCl in DMSO To Give
3-Acyloxy-2-alkanones (5): The appropriate 2-alkylated acetoacet-
slightly yellow oil. 1H NMR (200 MHz): δ ϭ 1.50 (s, 9 H), 2.42 (s, ate 4 (1.0 equiv.), H2O (1.1 equiv.) and LiCl (1.1 equiv.) were dis-
3 H), 4.70 (s, 1 H) ppm. 13C NMR (50 MHz): δ ϭ 26.12 (q), 27.50
(q), 50.56 (d), 84.27 (s), 163.80 (s), 196.45 (s) ppm. IR: ν˜ ϭ 735 (s), 145Ϫ160 °C and stirred at 160 °C for 5 h and at room temp. over-
845 (w), 912 (m), 1140 (s), 1258 (m), 1287 (m), 1308 (m), 1371 (m), night. After dilution with H2O (4.5 mL/mL DMSO), the mixture
1395 (m), 1425 (w), 1456 (w), 1478 (w), 1726 (s), 2938 (m), 2982 was extracted with Et2O (3 ϫ 3.3 mL/mL DMSO). The combined
(m) cmϪ1. MS (CI): m/z (%) ϭ 103 (87), 105 (61), 115 (98), 129
organic layers were washed with H2O (3 ϫ 1.0 mL/mL Et2O) and
solved in DMSO (2.3 mL/mmol), and the mixture was heated to
(77), 131 (76), 149 (78), 159 (70), 227 (64), 229 (58), 237 (100) brine (1.0 mL/mL Et2O), dried with Na2SO4, filtered and concen-
[MHϩ], 239 (100) [MHϩ]. HRMS: calculated for C8H14BrO3
[MHϩ]: 237.01263; found 237.01056.
trated in vacuo. Crude products were purified by flash chromatog-
raphy.
Eur. J. Org. Chem. 2004, 1063Ϫ1074
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1067

L. A. Wessjohann et al.
FULL PAPER
tert-Butyl 2-Acetoxy-2-ethyl-3-oxobutanoate (4a): Acetoacetate 3a
(1.08 g, 5.00 mmol), NaH (156 mg, 6.5 mmol) and ethyl bromide
MS (CI): m/z (%) ϭ 201 (14), 203 (15), 217 (29), 261 (100), 263
(41), 273 (17). HRMS: calculated for C14H25O5 [MHϩ]: 273.17020;
(373 µL, 549 mg, 5.00 mmol) in DMF (10 mL) were treated as de- found 273.16759.
scribed in the general alkylation method to give 4a (970 mg,
3-Acetoxyheptan-2-one (5c): Compound 4c (731 mg, 2.68 mmol)
3.97 mmol, 79%) as a slightly yellow oil. 1H NMR (200 MHz): δ ϭ
0.85 (t, J ϭ 9.5 Hz, 3 H), 1.43 (s, 9 H), 2.10 (q, J ϭ 9.5 Hz, 2 H),
2.15 (s, 3 H), 2.30 (s, 3 H) ppm. 13C NMR (50 MHz): δ ϭ 7.55 (q),
20.42 (q), 26.86 (q), 27.08 (t), 27.56 (q), 82.99 (s), 88.39 (s), 166.09
(s), 169.41 (s), 200.94 (s) ppm. IR: ν˜ ϭ 897 (w), 910 (w), 928 (w),
972 (w), 1022 (m), 1059 (m), 1103 (m), 1115 (w), 1184 (w), 1236
(s), 1260 (m), 1375 (m), 1433 (m), 1460 (m), 1730 (s), 1744 (s), 2942
(m), 2974 (m) cmϪ1. MS (CI): m/z (%) ϭ 101 (14), 129 (24), 161
(16), 171 (8), 189 (100), 206 (7), 217 (9), 229 (6), 245 (4). HRMS:
calculated for C12H21O5 [MHϩ]: 245.13890; found 245.13559.
and pTsOH·H2O (51 mg, 0.27 mmol) were stirred in benzene
(9.0 mL) as described in dealkoxycarbonylation method A. Kugel-
rohr distillation at 1.0 mbar and 60 °C gave 5c (415 mg, 2.41 mmol,
90%) as a colourless oil. 1H NMR (200 MHz): δ ϭ 0.85 (t, J ϭ
4.8 Hz, 3 H), 1.10Ϫ1.45 (m, 4 H), 1.50Ϫ1.90 (m, 2 H), 2.10 (s, 2
ϫ 3 H), 4.90 (m, 1 H) ppm. 13C NMR (50 MHz): δ ϭ 13.64 (q),
20.51 (q), 22.16 (t), 25.94 (q), 27.12 (t), 29.80 (t), 78.57 (d), 170.49
(s), 205.30 (s) ppm. IR: ν˜ ϭ 1028 (m), 1049 (m), 1078 (m), 1115
(m), 1181 (w), 1240 (s), 1375(m), 1435 (m), 1456 (m), 1730 (s), 1744
(s), 2872 (m), 2934 (m), 2959 (m) cmϪ1. MS (CI): m/z (%) ϭ 143
(26), 157 (11), 169 (13), 173 (100) [MHϩ]. HRMS: calculated for
C9H17O3 [MHϩ]: 173.11777; found 173.11535.
3-Acetoxypentan-2-one (5a): Compound 4a (1.40 g, 5.73 mmol) and
p-TsOH·H2O (109 mg, 0.57 mmol) were stirred in benzene
(18.0 mL) as described in dealkoxycarbonylation method A. Kugel-
rohr distillation gave 5a (486 mg, 3.4 mmol, 59%) as a colourless
tert-Butyl 2-Acetoxy-2-acetylheptanoate (4d): The acetoacetate 3a
(7.12 g, 32.9 mmol), NaH (900 mg, 37.5 mmol) and pentyl bromide
(4.97 g, 32.9 mmol) in DMF (64 mL) were treated as described in
the general alkylation method to give 4d (6.40 g, 22.3 mmol, 68%)
as a slightly yellow oil after kugelrohr distillation at 185 °C and
1.0 mbar. 1H NMR (400 MHz): δ ϭ 0.88 (t, J ϭ 6.7 Hz, 3 H),
1.26Ϫ1.31 (m, 6 H), 1.47 (s, 9 H), 2.08 (m, 2 H), 2.16 (s, 3 H), 2.33
(s, 3 H) ppm. 13C NMR (100 MHz): δ ϭ 13.97 (q), 20.73 (q), 22.38
(t), 23.05 (t), 27.04 (q), 27.81 (q), 31.62 (t), 33.91 (t), 83.15 (s), 88.29
(s), 166.13 (s), 169.41 (s), 200.88 (s) ppm.
1
oil. H NMR (200 MHz): δ ϭ 1.35 (s, 9 H), 2.08 (s, 3 H), 2.13 (s,
3 H), 3.40 (s, 2 H), 6.90Ϫ7.40 (m, 5 H) ppm. 13C NMR (50 MHz):
δ ϭ 20.69 (q), 27.21 (q), 27.47 (q), 38.69 (t), 83.23 (s), 88.40 (s),
127.03 (d), 128.17 (d), 129.93 (d), 134.33 (d), 165.24 (s), 169.38 (s),
202.11 (s) ppm. IR: ν˜ ϭ 700 (w), 845 (w), 1030 (w), 1084 (w), 1155
(m), 1229 (m), 1252 (m), 1273 (m), 1370 (m), 1456 (w), 1751 (s),
2936 (m), 2978 (m), 3003 (w) cmϪ1. MS (CI): m/z (%) ϭ 43 (39),
45 (22), 57 (34), 91 (19), 119 (10), 145 (9), 173 (9), 189 (14), 190
(78), 191 (18), 233 (45), 246 (22), 251 (100), 252 (11), 307 (44)
[MHϩ]. HRMS: calculated for C17H23O5 [MHϩ]: 307.15454;
found 307.15070.
3-Acetoxyoctan-2-one (5d): Compound 4d (6.40 g, 22.3 mmol) and
pTsOH·H2O (402 mg, 2.11 mmol) were stirred in benzene (65 mL)
as described in dealkoxycarbonylation method A. Kugelrohr distil-
lation at 1.0 mbar and 125 °C, followed by column chromatography
(ethyl acetate/petroleum ether, 1:4), gave 5d (1.6 g, 8.59 mmol, 39%)
tert-Butyl 2-Acetoxy-2-acetylpentanoate (4b): Acetoacetate 3a
(7.12 g, 32.9 mmol), NaH (900 mg, 37.5 mmol) and propyl bromide
(4.05 g, 32.9 mmol) in DMF (64 mL) were treated as described in
the general alkylation method to give 4b (6.00 g, 23.2 mmol, 71%)
as a slightly yellow oil after kugelrohr distillation at 160 °C and
1.0 mbar. 1H NMR (300 MHz): δ ϭ 0.93 (t, J ϭ 7.4 Hz, 3 H),
1.25Ϫ1.45 (m, 2 H), 1.47 (s, 9 H), 2.05Ϫ2.11 (m, 2 H), 2.16 (s, 3
H), 2.34 (s, 3 H) ppm. 13C NMR (75 MHz): δ ϭ 14.11 (q), 16.92
(t), 20.71 (q), 27.03 (q), 28.20 (q), 35.99 (t), 83.13 (s), 88.26 (s),
166.10 (s), 169.38 (s), 200.87 ppm.
1
as a colourless oil. H NMR (400 MHz): δ ϭ 0.89 (t, J ϭ 6.7 Hz,
3 H), 1.28Ϫ1.41 (m, 6 H), 1.72Ϫ1.79 (m, 2 H), 2.15 (s, 3 H), 2.16
(s, 3 H), 4.98 (dd, J ϭ 7.7, J ϭ 4.8 Hz, 1 H) ppm. 13C NMR
(100 MHz): δ ϭ 14.01 (q), 20.74 (q), 22.43 (t), 24.89 (t), 26.15 (q),
30.25 (t), 31.41 (t), 78.68 (d), 170.42 (s), 205.15 (s) ppm.
tert-Butyl 2-Acetoxy-2-acetyloctanoate (4e): Acetoacetate 3a
(1.08 g, 5.00 mmol), NaH (156 mg, 6.5 mmol) and hexyl bromide
(702 µL, 825 mg, 5.00 mmol) in DMF (10 mL) were treated as de-
scribed in the general alkylation method to give 4e (1063 mg,
3.54 mmol, 71%) as a slightly yellow oil. 1H NMR (200 MHz): δ ϭ
0.80 (m, 3 H), 1.1Ϫ1.3 (m, 8 H), 1.40 (s, 9 H), 1.95Ϫ2.13 (m, 2 H),
2.10 (s, 3 H), 2.28 (s, 3 H) ppm. 13C NMR (50 MHz): δ ϭ 13.93
(q), 20.58 (q), 22.41 (t), 23.22 (t), 26.92 (q), 27.68 (q), 29.03 (t),
31.38 (t), 33.85 (t), 83.15 (s), 88.29 (s), 166.28 (s), 169.57 (s), 201.11
(s) ppm. IR: ν˜ ϭ 758 (w), 845 (w), 1157 (m), 1244 (m), 1395 (m),
1420 (w), 1435 (w), 1456 (m), 1748 (s), 2861 (m), 2930 (m), 2957
(m) cmϪ1. MS (CI): m/z (%) ϭ 113 (21), 142 (14), 156 (15), 157
(10), 158 (16), 184 (12), 227 (30), 245 (100), 246 (13), 289 (34), 301
(13). HRMS: calculated for C16H29O5 [MHϩ]: 301.20151; found
301.19881.
3-Acetoxyhexan-2-one (5b): Compound 4b (6.00 g, 23.2 mmol) and
p-TsOH·H2O (393 mg, 2.07 mmol) were stirred in benzene (60 mL)
as described in dealkoxycarbonylation method A. Kugelrohr distil-
lation at 1.0 mbar and 150 °C, followed by column chromatography
(diethyl ether/petroleum ether, 1:8), gave 5b (2.00 g, 12.6 mmol,
54%) as a colourless oil. 1H NMR (400 MHz): δ ϭ 0.94 (t, J ϭ
7.3 Hz, 3 H), 1.38Ϫ1.46 (m, 2 H), 1.67Ϫ1.77 (m, 2 H), 2.15 (s, 3
H), 2.16 (s, 3 H), 5.00 (dd, J ϭ 7.6, J ϭ 5.3 Hz, 1 H) ppm. 13C
NMR (100 MHz): δ ϭ 13.77 (q), 18.59 (t), 20.74 (q), 26.15 (q),
32.31 (t), 78.49 (d), 170.44 (s), 205.18 (s) ppm.
tert-Butyl 2-Acetoxy-2-acetylhexanoate (4c): The acetoacetate 3a
(1.08 g, 5.00 mmol), NaH (156 mg, 6.5 mmol) and butyl bromide
(538 µL, 685 mg, 5.00 mmol) in DMF (10 mL) were treated as de-
3-Acetoxynonan-2-one (5e): Compound 4e (2.19 g, 7.29 mmol) and
scribed in the general alkylation method to give 4c (1026 mg, pTsOH·H2O (139 mg, 0.73 mmol) were stirred in benzene
3.77 mmol, 75%) as a slightly yellow oil. 1H NMR (200 MHz): δ ϭ
(22.0 mL) as described in dealkoxycarbonylation method A. kugel-
0.81 (t, J ϭ 7.1 Hz, 3 H), 0.99Ϫ1.47 (m, 4 H), 1.40 (s, 9 H), rohr distillation at 0.8 mbar and 80 °C and subsequent flash chro-
1.98Ϫ2.11 (m, 2 H), 2.10 (s, 3 H), 2.28 (s, 3 H) ppm. 13C NMR
matography (column dimensions: 2.0 ϫ 20.0 cm, diethyl ether/
(50 MHz): δ ϭ 13.73 (q), 20.58 (q), 22.41 (t), 25.40 (t), 26.91 (q), petroleum ether, 1:6) gave 5e (419 mg 2.10 mmol, 29%) as a colour-
1
27.67 (q), 33.65 (t), 83.11 (s), 88.22 (s), 166.26 (s), 169.52 (s), 201.11 less oil. H NMR (200 MHz): δ ϭ 0.75Ϫ1.00 (m, 3 H), 1.10Ϫ1.50
(s) ppm. IR: ν˜ ϭ 845 (m), 1018 (m), 1047 (m), 1140 (s), 1163 (s), (m, 8 H), 1.60Ϫ1.85 (m, 2 H), 2.13 (s, 2 ϫ 3 H), 4.95 (m, 1 H)
1202 (m), 1250 (s), 1279 (s), 1317 (s), 1370 (s), 1395 (m), 1420 (m), ppm. 13C NMR (50 MHz): δ ϭ 13.85 (q), 20.51 (q), 22.35 (t), 24.96
1435 (m), 1456 (m), 1744 (s), 2872 (m), 2934 (m), 2961 (m) cmϪ1
.
(t), 25.94 (q), 28.71 (t), 30.09 (t), 31.35 (t), 78.60 (d), 170.52 (s),
www.eurjoc.org
1068
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2004, 1063Ϫ1074

A New Route to Protected Acyloins
FULL PAPER
205.33 (s) ppm. IR: ν˜ ϭ 1044 (m), 1074 (w), 1121 (w), 1175 (w),
cmϪ1. MS (CI): m/z (%) ϭ 127 (11), 139 (13), 154 (16), 155 (12),
1236 (s), 1373 (m), 1433 (m), 1458 (m), 1732 (s), 1744 (s), 2859 (m), 167 (11), 171 (10), 215 (100), 216 (12), 259 (22), 271 (1). HRMS:
2930 (m), 2953 (m) cmϪ1. MS (CI): m/z (%) ϭ 113 (28), 142 (12), calculated for C14H23O5 [MHϩ]: 271.15289; found 271.15454.
158 (15), 171 (29), 185 (16), 201 (100) [MHϩ], 202 (12). HRMS:
(5E)-3-Acetoxy-5-hepten-2-one (5h): Compound 4h (330 mg,
1.22 mmol) and pTsOH·H2O (23 mg, 0.12 mmol) were stirred in
benzene (4.0 mL) as described in dealkoxycarbonylation method
A. Kugelrohr distillation at 1.5 mbar and 60 °C gave 133 mg
(0.78 mmol, 64%) of a 10:1 mixture of the (4E) isomer 5h and the
(4Z) isomer 5i, respectively. 1H NMR (200 MHz): δ ϭ 1.55Ϫ1.70
(m, 3 H), 2.09 (s, 2 ϫ 3 H), 2.25Ϫ2.55 (m, 2 H), 4.85Ϫ5.08 (m, 1
H), 5.20Ϫ5.65 (m, 2 H) ppm. 13C NMR (50 MHz): δ ϭ 17.75 (q),
20.47 (q), 26.39 (q), 33.51 (t), 78.16 (d), 124.08 (d), 129.36 (d),
170.31 (s), 204.88 (s) ppm. IR: ν˜ ϭ 1044 (m), 1074 (w), 1121 (w),
1175 (w), 1236 (s), 1373 (m), 1433 (m), 1458 (m), 1732 (s), 1744 (s),
2859 (m), 2930 (m), 2953 (m) cmϪ1. MS (CI): m/z (%) ϭ 107 (11),
111 (16), 123 (34), 135 (10), 141 (17), 143 (9), 149 (9), 155 (19), 171
(100) [MHϩ]. HRMS: calculated for C9H15O3 [MHϩ]: 171.10213;
found 171.09980.
calculated for C11H21O3 [MHϩ]: 201.14906; found 201.14587.
tert-Butyl 2-Acetoxy-2-acetylpent-4-enoate (4f): The acetoacetate 3a
(3.56 g, 16.4 mmol), NaH (0.43 g, 18.0 mmol) and allyl bromide
(1.98 g, 16.4 mmol) in DMF (32 mL) were treated as described in
the general alkylation method to give 4f (3.57 g, 13.9 mmol, 85%)
as a slightly yellow oil after kugelrohr distillation at 2.0 mbar and
1
135 °C. H NMR (250 MHz): δ ϭ 1.46 (s, 9 H), 2.15 (s, 3 H), 2.31
(s, 3 H), 2.89 (t, J ϭ 1.1 Hz, 1 H), 2.92 (t, J ϭ 1.1 Hz, 1 H),
5.08Ϫ5.10 (m, 1 H), 5.14Ϫ5.17 (m, 1 H), 5.58Ϫ5.72 (m, 1 H) ppm.
13C NMR (62.5 MHz): δ ϭ 20.65 (q), 26.90 (q), 27.75 (q), 37.94
(t), 83.41 (s), 87.81 (s), 119.76 (t), 130.66 (d), 165.59 (s), 169.36 (s),
200.79 (s) ppm.
3-Acetoxy-5-hexen-2-one (5f): Compound 4f (2.50 g, 9.75 mmol)
and p-TsOH·H2O (186 mg, 0.98 mmol) were stirred in benzene
(30 mL) as described in dealkoxycarbonylation method A. Kugel-
rohr distillation at 0.6 mbar and 80 °C gave 5f (1.29 g, 8.27 mmol,
(4Z)-tert-Butyl 2-Acetoxy-2-acetylhex-4-enoate (4i): The 2-ace-
toxyhexynoate 4g (630 mg, 2.32 mmol) and Lindlar catalyst
(120 mg) were stirred under hydrogen in ethyl acetate (50 mL) for
24 h. The reaction suspension was filtered through Celite and the
filtrate was concentrated in vacuo to give (4Z)-4i (628 mg,
2.32 mmol, 99%) as a slightly yellow oil. 1H NMR (200 MHz): δ ϭ
1.39 (s, 9 H), 1.53 (d, J ϭ 6.8 Hz, 3 H), 2.08 (s, 3 H), 2.24 (s, 3 H),
2.80Ϫ2.90 (m, 2 H), 5.13Ϫ5.26 (m, 1 H), 5.48Ϫ5.64 (m, 1 H) ppm.
13C NMR (50 MHz): δ ϭ 12.78 (q), 20.50 (q), 26.78 (q), 27.54 (q),
31.10 (t), 83.11 (s), 87.67 (s), 121.68 (d), 128.54 (d), 165.70 (s),
169.34 (s), 200.99 (s) ppm. IR: ν˜ ϭ 845 (m), 905 (w), 969 (m), 1058
(m), 1077 (m), 1130 (s), 1158 (s), 1193 (m), 1226 (s), 1253 (s), 1370
(s), 1395 (m), 1431 (m), 1455 (m), 1478 (w), 1742 (s), 2935 (m),
1
85%) as a colourless oil. H NMR (250 MHz): δ ϭ 2.14 (s, 3 H),
2.16 (s, 3 H), 2.48Ϫ2.57 (m, 2 H), 5.05Ϫ5.18 (m, 3 H), 5.65Ϫ5.80
(m, 1 H) ppm. 13C NMR (62.5 MHz): δ ϭ 20.64 (q), 26.54 (q),
34.81 (t), 77.87 (d), 118.80 (t), 131.99 (d), 170.42 (s), 204.78 (s)
ppm.
tert-Butyl 2-Acetoxy-2-acetylhex-4-ynoate (4g): The acetoacetate 3a
(3.24 g, 15.0 mmol), NaH (660 mg, 16.5 mmol) and 1-chlorobut-2-
yne (2.00 g, 15.0 mmol) in DMF (30 mL) were treated as described
in the general alkylation method to give 4g (3.83 g, 14.3 mmol,
1
95%) as a slightly yellow oil. H NMR (200 MHz): δ ϭ 1.39 (s, 9
H), 1.69 (t, J ϭ 2.6 Hz, 3 H), 2.15 (s, 3 H), 2.31 (s, 3 H), 3.01 (m,
2 H) ppm. 13C NMR (50 MHz): δ ϭ 3.40 (q), 20.72 (q), 23.87 (t),
26.80 (q), 27.55 (q), 71.88 (s), 78.96 (s), 83.49 (s), 86.85 (s), 164.71
(s), 169.31 (s), 200.88 (s) ppm.
2979 (m), 3432 (w) cmϪ1
.
(5Z)-3-Acetoxy-5-hepten-2-one (5i): Compound 4i (433 mg,
1.60 mmol) and pTsOH·H2O (30 mg, 0.16 mmol) were stirred in
benzene (6 mL) as described in dealkoxycarbonylation method A.
Flash chromatography (column dimensions: 2.0 ϫ 20.0 cm, ethyl
acetate/petroleum ether, 1:4) gave 5i (205 mg, 1.20 mmol, 75%) as
3-Acetoxy-5-heptyn-2-one (5g): Compound 4g (1.61 g, 6.00 mmol)
and pTsOH·H2O (114 mg, 0.60 mmol) were stirred in benzene
(20 mL) as described in dealkoxycarbonylation method A. Flash
chromatography (column dimensions: 2.0 ϫ 20.0 cm, ethyl acetate/
petroleum ether, 1:4) gave 5g (922 mg, 5.48 mmol, 91%) as a
colourless oil. 1H NMR (200 MHz): δ ϭ 1.71 (s, 3 H), 2.11 (s, 3
1
a colourless oil. H NMR (200 MHz): δ ϭ 1.54 (d, J ϭ 7.6 Hz, 3
H), 2.05 (s, 3 H), 2.08 (s, 3 H), 2.45 (m, 2 H), 4.95 (t, J ϭ 6.3 Hz,
1 H), 5.20Ϫ5.40 (m, 1 H), 5.40Ϫ5.70 (m, 1 H), ppm. 13C NMR
(50 MHz): δ ϭ 12.65 (q), 20.43 (q), 26.33 (t), 27.83 (t), 77.93 (d),
123.15 (d), 127.81 (d), 170.25 (s), 204.94 (s) ppm. IR: ν˜ ϭ 934 (w),
969 (w), 1041 (m), 1074 (m), 1173 (w), 1239 (s), 1373 (s), 1432 (m),
1732 (s), 1746 (s), 2923 (w), 3023 (w), 3454 (w) cmϪ1. MS (CI):
m/z (%) ϭ 71 (42), 85 (84), 111 (48), 127 (52), 169 (44) 171 (100)
[MHϩ]. HRMS: calculated for C9H13O3 [MHϩ]: 171.10213;
found 171.10180.
H), 2.17 (s, 3 H), 2.57 (m, 2 H), 5.00 (t, J ϭ 6.0 Hz, 1 H) ppm. 13
C
NMR (50 MHz): δ ϭ 3.22 (q), 20.43 (q), 20.97 (t), 26.90 (q), 72.52
(s), 76.33 (d), 78.69 (s),170.05 (s), 204.16 (s) ppm. IR: ν˜ ϭ 873 (w),
926 (w), 967 (w), 1059 (w), 1148 (w), 1174 (m), 1242 (s), 1374 (s),
1426 (w), 1732 (s), 1746 (s), 2923 (m), 3451 (w) cmϪ1. MS (CI):
m/z (%) ϭ 43 (76), 57 (100), 109 (56), 127 (12), 169 (62) [MHϩ],
170 (8). HRMS: calculated for C9H13O3 [MHϩ]: 169.08672;
found 169.08647.
tert-Butyl 2-Acetoxy-2-acetyl-5-methoxyhex-4-enoate (4j): Ace-
toacetate 3a (3.94 g, 18.2 mmol), NaH (0.48 g, 20.0 mmol) and 3-
methyl-2-butenyl bromide (prenyl bromide, 2.71 g, 18.2 mmol) in
tert-Butyl (4E)-2-Acetoxy-2-acetylhex-4-enoate (4h): The ace-
toacetate 3a (4.98 g, 23.0 mmol), NaH (0.61 g, 25.4 mmol) and cro-
tyl chloride (2.08 g, 23.0 mmol) in DMF (45 mL) were treated as DMF (45 mL) were treated as described in the general alkylation
described in the general alkylation method to give (4E)-4h (0.368 g,
method to give 4j (5.02 g, 17.6 mmol, 97%) as a slightly yellow
1.4 mmol, 6%) as a slightly yellow oil after kugelrohr distillation at
oil after kugelrohr distillation at 1.5 mbar and 145 °C. 1H NMR
1
1.0 mbar and 140 °C. H NMR (200 MHz): δ ϭ 1.40 (s, 9 H), 1.58 (200 MHz): δ ϭ 1.40 (s, 9 H), 1.55 (s, 3 H), 1.65 (s, 3 H), 2.10 (s,
(d, J ϭ 9.5 Hz, 3 H), 2.10 (s, 3 H), 2.25 (s, 3 H), 2.73 (d, J ϭ 3 H), 2.25 (s, 3 H), 2.75 (t, J ϭ 7.1 Hz, 2 H), 4.95 (t, J ϭ 7.1 Hz,
9.5 Hz, 2 H), 5.02Ϫ5.65 (m, 2 H) ppm. 13C NMR (50 MHz): δ ϭ
1 H) ppm. 13C NMR (50 MHz): δ ϭ 17.84 (q), 20.56 (q), 25.79 (q),
17.94 (q), 20.61 (q), 26.89 (q), 27.70 (q), 37.01 (t), 83.21 (s), 87.98 26.88 (q), 27.58 (q), 32.57 (t), 83.00 (s), 87.87 (s), 115.77(d), 136.38
(s), 122.76 (d), 130.53 (d), 165.75 (s), 169.48 (s), 200.93 (s) ppm. (s), 165.90 (s), 169.48 (s), 201.10 (s) ppm. IR: ν˜ ϭ 845 (w), 1022
IR: ν˜ ϭ 845 (w), 970 (w), 1040 (w), 1059 (w), 1076 (w), 1130 (m), (w), 1051 (w), 1074 (w), 1119 (w), 1157 (m), 1235 (m), 1258 (m),
1157 (m), 1194 (m), 1227 (m), 1254 (s), 1370 (m), 1395 (w), 1431 1317 (w), 1370 (m), 1435 (w), 1454 (w), 1746 (m), 2864 (w), 2876
(m), 1454 (w), 1746 (s), 2857 (w), 2891 (w), 2934 (m), 2978 (m)
(w), 2930 (m), 2976 (m), 3030 (w) cmϪ1. MS (CI): m/z (%) ϭ 153
Eur. J. Org. Chem. 2004, 1063Ϫ1074
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1069

L. A. Wessjohann et al.
FULL PAPER
(12), 169 (10), 185 (61), 197 (7), 211 (8), 213 (11), 215 (8), 225 (16),
131.21 (s), 139.10 (s), 170.15 (s), 204.97 (s) ppm. IR: ν˜ ϭ 667 (w),
229 (100), 230 (35), 241 (36), 246 (11), 273 (99), 274 (57), 275 (100), 845 (w), 895 (w), 932 (w), 1051 (m), 1167 (m), 1242 (m), 1321 (w),
276 (36), 285 (98), 286 (43), 302 (11). HRMS: calculated for 1373 (s), 1436 (m), 1730 (s), 1745 (s), 2858 (m), 2879 (m), 2921 (m),
C15H25O5 [MHϩ]: 285.17020; found 285.16679.
2974 (m) cmϪ1. MS (EI): m/z (%) ϭ 253.0 (100) [M ϩ H]ϩ, 209
(42), 193.0 (24) [M ϩ H Ϫ AcOH]ϩ.
3-Acetoxy-6-methyl-5-hepten-2-one (5j): Compound 4j (850 mg,
2.99 mmol), LiCl (139 mg, 3.29 mmol) and H2O (59 µL, 59 mg,
3.29 mmol) in DMSO (7.5 mL) were treated at 160 °C for 5 h as
described in dealkoxycarbonylation method B. The remaining yel-
low oil was purified by flash chromatography (column dimensions:
2.0 ϫ 20.0 cm, ethyl acetate/petroleum ether, 1:4) to yield 5j
(133 mg, 0.78 mmol, 64%). 1H NMR (200 MHz): δ ϭ 1.59 (s, 3 H),
1.68 (s, 3 H), 2.08 (s, 3 H), 2.10 (s, 3 H), 2.40 (t, 2 H), 4.93 (t, 1
H), 5.05 (t, 1 H) ppm. 13C NMR (50 MHz): δ ϭ 17.66 (q), 20.48
(q), 25.56 (q), 26.37 (q), 29.06 (t), 78.28 (d), 117.21 (d), 135.67 (s),
170.33 (s), 205.12 (s) ppm. IR: ν˜ ϭ 733 (w), 845 (w), 1051 (m),
1113 (w), 1167 (m), 1242 (s), 1321 (w), 1375 (m), 1435 (m), 1732
(s), 1744 (s), 2861 (w), 2918 (m), 2971 (m) cmϪ1. MS (CI): m/z
(%) ϭ 97 (28), 99 (25), 107 (31), 107 (31), 109 (30), 111 (24), 123
(25), 125 (100), 137 (23), 141 (23), 143 (19), 151 (22), 185 (MHϩ,
25). HRMS: calculated for C10H17O3 [MHϩ]: 185.11777; found
185.11188.
(4Z)-tert-Butyl 2-Acetoxy-2-acetyl-5,9-dimethyldeca-4,8-dienoate
(4m): The acetoacetate 3a (19.5 g, 90 mmol), NaH (2.59 g,
108 mmol) and neryl bromide (19.6 g, 90 mmol) in DMF (180 mL)
were treated as described in the general alkylation method to give
(4Z)-4m (30.3 g, 86 mmol, 96%) as a slightly yellow oil. 1H
NMR (200 MHz): δ ϭ 1.46 (s, 9 H) 1.60 (s, 3 H), 1.68 (s, 3 H), 1.70
(s, 3 H), 2.00Ϫ2.05 (m, 4 H), 2.16 (s, 3 H), 2.31 (s, 3 H), 2.82Ϫ2.87
(m, 2 H), 5.00Ϫ5.09 (m, 2 H) ppm. 13C NMR (50 MHz,): δ ϭ
17.56 (q), 20.60 (q), 23.52 (q), 25.61 (q), 26.32 (t), 26.95 (q), 27.63
(q), 31.90 (t), 32.30 (t), 83.08 (s), 87.83 (s), 116.22 (d), 123.75 (d),
131.84 (s), 140.07 (s), 165.96 (s), 169.53 (s), 201.06 (s) ppm. IR:
ν˜ ϭ 845 (w), 1024 (w), 1072 (w), 1086 (w), 1115 (w), 1157 (s), 1236
(s), 1256 (s), 1314 (w), 1370 (s), 13895 (w), 1437 (w), 1452 (w), 1746
(s), 2861 (w), 2882 (w), 2932 (m), 2976 (m) cmϪ1. MS (CI, isobut.):
m/z (%) ϭ 353 (13) [M ϩ H]ϩ, 298 (21), 297 (100), 279 (14), 255
(10), 253 (13), 237 (27), 219 (20), 209 (65), 193 (10), 175 (6), 153
(7), 137 (16). HRMS: calculated for C17H31O5 [MHϩ]: calcd.
353.23282; found 353.23245.
3-Acetoxy-6-methylheptan-2-one (5k): The heptenone 5j (300 mg,
1.63 mmol) and Pd/C catalyst (5%, 60 mg) were stirred under hy-
drogen in abs. ethanol (10 mL) at room temp. After 30 minutes
the suspension was filtered through Celite and the filtrate was
concentrated in vacuo to give 5k (302 mg, 1.62 mmol, 99%) as a
(5Z)-3-Acetoxy-6,10-dimethyl-5,9-undecadien-2-one (5m):
Com-
pound 4m (1.661 g, 4.71 mmol), LiCl (220 mg, 5.18 mmol) and
H2O (93 µL, 93 mg, 5.18 mmol) were treated in DMSO (12.5 mL)
at 140 °C for 3h 45 min and at 160 °C for 3h 30 min as described
in dealkoxycarbonylation method B. The remaining yellow oil was
purified by flash chromatography (column dimensions: 3.5 ϫ
20.0 cm, ethyl acetate/petroleum ether, 1:5) to give 817 mg
1
colourless oil. H NMR (200 MHz): δ ϭ 0.82 (d, J ϭ 6.9 Hz, 2 ϫ
3 H), 1.00Ϫ1.40 (m, 1 H), 1.40Ϫ1.60 (m, 2 H), 1.60Ϫ1.80 (m, 2
H), 2.07 (s, 3 H), 2.08 (s, 3 H), 4.85Ϫ4.92 (m, 1 H) ppm. 13C NMR
(50 MHz): δ ϭ 20.42 (q), 21.98 (q), 22.26 (q), 25.87 (d), 27.55 (q),
27.99 (t), 33.86 (t), 78.71 (d), 170.37 (s), 205.18 (s) ppm. MS (CI):
m/z (%) ϭ 85 (18), 115 (16), 134 (20), 148 (28), 167 (16) 187 (100)
[MHϩ]. HRMS: calculated for C9H13O3 [MHϩ]: 187.13213;
found 187.13342.
1
(3.24 mmol, 69%) of 5m. H NMR (200 MHz): δ ϭ 1.61 (s, 3 H),
1.68 (s, 3 H), 1.71 (s, 3 H), 1.90Ϫ2.10 (m, 4 H), 2.13 (s, 3 H), 2.15
(s, 3 H), 2.45Ϫ2.51 (m, 2 H), 4.93Ϫ5.00 (m, 1 H), 5.08Ϫ5.15 (m,
2 H) ppm. 13C NMR (50 MHz): δ ϭ 17.47 (q), 20.48 (q), 23.28 (q),
25.53 (q), 26.21 (t), 26.38 (q), 28.79 (t), 31.80 (t), 78.39 (d), 117.90
(d), 123.67 (d), 131.74 (s), 139.27 (s), 170.36 (s), 205.03 (s) ppm.
IR: ν˜ ϭ 853 (w), 877 (w), 932 (w), 949 (w), 1047 (s), 1070 (m), 1163
(m), 1177 (m), 1189 (m), 1239 (s), 1374 (m), 1446 (w), 1745 (s),
2288 (m), 2891 (m), 2915 (m), 2922 (m), 2929 (m), 2937 (m), 2965
(m) cmϪ1. MS (ESI): m/z (%) ϭ 527.4 (42) [2M ϩ Na]ϩ, 275.1 (38)
[M ϩ Na]ϩ, 253.1 (6) [M ϩ H]ϩ, 193.1 (4) [M ϩ H Ϫ AcOH]ϩ.
(4E)-tert-Butyl
2-Acetoxy-2-acetyl-5,9-dimethyldeca-4,8-dienoate
(4l): Acetoacetate 3a (10.8 g, 50 mmol), NaH (2.32 g, 58 mmol,
60% suspension in mineral oil) and geranyl bromide (10.9 g,
50 mmol) in DMF (100 mL) were treated as described in the gen-
eral alkylation method to give (4E)-4l (17.6 g, 50 mmol, 100%) as
a slightly yellow oil. 1H NMR (200 MHz): δ ϭ 1.46 (s, 9 H) 1.60
(s, 6 H), 1.68 (s, 3 H), 2.00Ϫ2.05 (m, 4 H), 2.15 (s, 3 H), 2.31 (s,
3 H), 2.84Ϫ2.89 (m, 2 H), 5.00Ϫ5.05 (m, 2 H) ppm. 13C
NMR (50 MHz): δ ϭ 16.01 (q), 17.46 (q), 20.44 (q), 25.48 (q),
26.21 (t), 26.83 (q), 27.61 (q), 32.36 (t), 39.60 (t), 82.81 (s), 87.82
(s), 115.66 (d), 123.72 (d), 131.27 (s), 139.81 (s), 165.77 (s), 169.27
(s), 201.04 (s) ppm. IR: ν˜ ϭ 734 (w), 845 (w), 1072 (w), 1116 (w),
1157 (s), 1196 (w), 1235 (m), 1257 (s), 1369 (s), 1456 (w), 1733 (s),
1748 (s), 1756 (s), 2929 (m), 2935 (m), 2976 (m) cmϪ1. MS (EI):
m/z (%) ϭ 352 (0.01) [Mϩ], 296, 236, 193, 167, 153, 69, 57, 43
(100.0).
tert-Butyl 2-Acetoxy-2-benzyl-3-oxobutanoate (4n): The acetoacet-
ate 3a (749 mg, 3.46 mmol), NaH (108 mg, 4.5 mmol) and benzyl
bromide (411 µL, 592 mg, 3.46 mmol) in DMF (7 mL) were treated
as described in the general alkylation method to give 4n (956 mg,
3.12 mmol, 90%) as a colourless oil. 1H NMR (200 MHz): δ ϭ 1.35
(s, 9 H), 2.08 (s, 3 H), 2.13 (s, 3 H), 3.40 (m, 2 H), 6.90Ϫ7.40 (m,
5 H) ppm. 13C NMR (50 MHz): δ ϭ 20.81 (q), 27.33 (q), 27.59 (q),
38.81 (t), 83.35 (s), 88.52 (s), 127.15 (d), 128.29 (d), 130.05 (d),
134.45 (s), 165.36 (s), 169.50 (s), 202.23 (s) ppm. IR: ν˜ ϭ 700 (w),
845 (w), 1030 (w), 1084 (w), 1155 (m), 1229 (m), 1252 (m), 1273
(m), 1370 (m), 1456 (w), 1751 (s), 2936 (m), 2978 (m), 3003 (w)
cmϪ1. MS (CI): m/z (%) ϭ 43 (39), 45 (22), 57 (34), 91 (19), 119
(10), 145 (9), 173 (9), 189 (14), 190 (78), 191 (18), 233 (45), 246
(22), 251 (100), 252 (11), 307 (44). HRMS: calculated for C17H23O5
[MHϩ]: 307.15454; found 307.15070.
(5E)-3-Acetoxy-6,10-dimethyl-5,9-undecadien-2-one (5l):
Com-
pound 4l (10.55 g, 30.0 mmol), LiCl (1.40 g, 33.0 mmol) and H2O
(549 µL, 549 mg, 33.0 mmol) were treated in DMSO (75 mL) at
150 °C for 5 h as described in dealkoxycarbonylation method B.
The remaining yellow oil was purified by kugelrohr distillation at
150 °C and 0.5 mbar to yield 5l (6.24 g, 25 mmol, 82%).
1H NMR (200 MHz): δ ϭ 1.59 (s, 3 H), 1.62 (s, 3 H), 1.67 (s, 3 H), 3-Acetoxy-4-phenylbutan-2-one (5n): Compound 4n (919 g,
2.02Ϫ2.06 (m, 4 H), 2.12 (s, 3 H), 2.15 (s, 3 H), 2.49 (m, 2 H), 5.00 3.00 mmol) was decarboxylated as described in dealkoxycarbonyl-
(dd, J ϭ 6.3, J ϭ 6.3 Hz, 1 H), 5.00Ϫ5.20 (m, 2 H) ppm. 13C NMR ation method B. Purification by flash chromatography (column di-
(50 MHz): δ ϭ 15.87 (q), 17.40 (q), 20.34 (q), 25.40 (q), 26.16 (t), mensions: 2.0 ϫ 20.0 cm, ethyl acetate/petroleum ether, 1:4) gave
26.32 (q), 28.97 (t), 33.48 (t), 78.19 (d), 117.18 (d), 123.68 (d), 5n (287 mg, 1.39 mmol, 46%) as a slightly yellow oil. 1H NMR
1070
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 1063Ϫ1074

A New Route to Protected Acyloins
FULL PAPER
(200 MHz): δ ϭ 2.03 (s, 2 ϫ 3 H), 2.85Ϫ3.15 (m, 2 H), 5.08Ϫ5.23 tion was quenched by the addition of brine (1.5 times the amount
(m, 1 H), 7.08Ϫ7.35 (m, 5 H) ppm. 13C NMR (50 MHz): δ ϭ 20.38 of methanol), followed by a fivefold extraction with the same
(q), 26.64 (q), 36.45 (t), 78.90 (d), 126.87 (d), 128.40 (d), 129.13 amount of diethyl ether. The combined organic layers were washed
(d), 135.74 (s), 170.16 (s), 205.09 (s) ppm. IR: ν˜ ϭ 702 (m), 735 once with brine (3 times the amount of methanol), dried with
(w), 748 (w), 1047 (m), 1070 (m), 1175 (m), 1240 (s), 1373 (m), 1433
Na2SO4, filtered and concentrated in vacuo. If necessary, flash
(m), 1454 (m), 1497 (m), 1730 (s), 1744 (s), 2926 (w), 3030 (w) chromatography was used to purify the racemic α-hydroxy ketone.
cmϪ1. MS (CI): m/z (%) ϭ 91 (13), 131 (19), 145 (32), 146 (84),
(؎)-3-Hydroxynonan-2-one [(؎)-6e]: 3-Acetoxynonan-2-one (5e,
60 mg, 0.30 mmol) was hydrolysed as described in the general
147 (79), 207 (MHϩ, 100), 208 (14). HRMS: calculated for
C12H15O3 [MHϩ]: 207.10211; found 207.10001.
chemical hydrolysis method to give (Ϯ)-6e as a slightly yellow oil
tert-Butyl 2-Acetyl-2-butyryloxy-5-methylhex-4-enoate (4o): Ace-
(42 mg, 0.27 mmol, 88%). 1H NMR (200 MHz): δ ϭ 0.70Ϫ1.00 (m,
toacetate 3b (8.04 g, 32.9 mmol), NaH (900 mg, 37.5 mmol) and 3 H), 1.00Ϫ1.65 (m, 8 H), 1.65Ϫ1.90 (m, 2 H), 2.13 (s, 3 H),
prenyl bromide (1.23 g, 16.5 mmol) in DMF (64 mL) were treated 3.00Ϫ3.80 (br., ϪOH, 1 H), 4.05Ϫ4.20 (m, 1 H) ppm. 13C NMR
as described in the general alkylation method to give 4o (1.52 g,
12.5 mmol, 76%) as a slightly yellow oil after kugelrohr distillation
at 1.0 mbar and 140 °C. 1H NMR (400 MHz): δ ϭ 1.00 (t, J ϭ
7.4 Hz, 3 H), 1.45 (s, 9 H), 1.60 (s, 3 H), 1.69 (s, 3 H), 1.67Ϫ1.73
(m, 2 H), 2.31 (s, 3 H), 2.38Ϫ2.42 (m, 2 H), 2.78Ϫ2.92 (m, 2 H),
5.41 (m, 1 H) ppm. 13C NMR (100 MHz): δ ϭ 13.61 (q), 17.93 (q),
18.27 (t), 25.89 (q), 27.66 (q), 27.80 (q), 32.59 (t), 35.79 (q), 83.00
(s), 87.75 (s), 115.90 (d), 136.37 (s), 166.02 (s), 172.10 (s), 201.50
(s) ppm.
(50 MHz): δ ϭ 13.86 (q), 22.38 (t), 24.52 (t), 25.00 (q), 28.94 (t),
31.47 (t), 33.67 (t), 76.68 (d), 209.88 (s) ppm.
(؎)-(5Z)-3-Hydroxy-5-hepten-2-one [(؎)-6i]: (5Z)-3-Acetoxyhept-
5-en-2-one (5i, 43 mg, 0.25 mmol) was hydrolysed as described in
the general chemical hydrolysis method to give (Ϯ)-6i as a slightly
yellow oil (31 mg, 0.24 mmol, 96%). 1H NMR (200 MHz): δ ϭ 1.58
(d, J ϭ 7.4 Hz, 3 H), 2.14 (s, 3 H), 2.30Ϫ2.60 (m, 2 H), 3.10Ϫ3.70
(br., ϪOH, 1 H), 4.20 (m, 1 H), 5.15Ϫ5.40 (m, 1 H), 5.40Ϫ5.70
(m, 1 H) ppm. 13C NMR (50 MHz): δ ϭ 12.87 (q), 25.20 (q), 30.91
3-Butyryloxy-6-methyl-5-hepten-2-one (5o): Compound 4o (7.34 g, (t), 76.29 (d), 123.49 (d), 127.54 (d), 209.32 (s) ppm.
23.5 mmol) and p-TsOH·H2O (437 mg, 2.30 mmol) were stirred in
(؎)-3-Hydroxy-6-methyl-5-hepten-2-one [(؎)-6j]: 3-Acetoxy-6-
methyl-5-hepten-2-one (5j, 48 mg, 0.26 mmol) was hydrolysed as
described in the general chemical hydrolysis method to give (Ϯ)-6j
benzene (100 mL) as described in dealkoxycarbonylation method
A. Kugelrohr distillation at 1.0 mbar and 145 °C gave a colourless
oil, which was further purified by column chromatography (ethyl
as a slightly yellow oil (28 mg, 0.20 mmol, 77%) after flash chroma-
acetate/petroleum ether, 1:3) to afford 5o (1.04 g, 4.90 mmol, 15%).
tography (ethyl acetate/petroleum ether, 1:4). 1H NMR (200 MHz):
1H NMR (400 MHz): δ ϭ 0.97 (t, J ϭ 7.3 Hz, 3 H), 1.62 (s, 3 H),
δ ϭ 1.55 (s, 3 H), 1.65 (s, 3 H), 2.15 (s, 3 H), 2.17Ϫ2.55 (m, 2 H),
1.71 (s, 3 H), 1.65Ϫ1.72 (m, 2 H), 2.16 (s, 3 H), 2.36Ϫ2.41 (m, 2
3.40 (br., ϪOH, 1 H), 4.15 (m, 1 H), 5.05 (m, 1 H) ppm. 13C NMR
H), 2.45Ϫ2.50 (m, 2 H), 4.99Ϫ5.03 (m, 1 H), 5.07Ϫ5.13 (m, 1 H)
(50 MHz): δ ϭ 17.85 (q), 25.24 (q), 25.65 (q), 32.13 (t), 77.52 (d),
ppm. 13C NMR (100 MHz): δ ϭ 13.55 (q), 17.82 (q), 18.30 (t),
117.52 (d), 135.45 (s), 209.58 (s) ppm.
25.71 (q), 26.56 (q), 29.26 (t), 35.82 (t), 78.16 (d), 117.46 (d), 135.73
(s), 173.13 (s), 205.47 ppm.
(؎)-3-Hydroxy-6-methylheptan-2-one [(؎)-6k]: 3-Acetoxy-6-methyl-
heptan-2-one (5k, 47 mg, 0.25 mmol) was hydrolysed as described
tert-Butyl 2-Benzyl-2-butyryloxy-3-oxo-butanoate (4p): The ace-
in the general chemical hydrolysis method to give (Ϯ)-6k as slightly
toacetate 3b (4.02 g, 16.5 mmol), NaH (450 mg, 18.8 mmol) and
benzyl bromide (2.82 g, 16.5 mmol) in DMF (32 mL) were treated
yellow oil (32 mg, 0.22 mmol, 88%). 1H NMR (200 MHz): δ ϭ 0.82
(s, 3 H), 0.85 (s, 3 H), 0.90Ϫ1.65 (m, 3 H), 1.65Ϫ1.95 (m, 2 H),
as described in the general alkylation method to give 4p (4.70 g,
2.14 (s, 3 H), 3.10Ϫ3.50 (br., ϪOH, 1 H), 4.00Ϫ4.20 (m, 1 H) ppm.
14.1 mmol, 85%) as a slightly yellow oil after distillation at 2 mbar
13C NMR (50 MHz): δ ϭ 22.08 (q), 22.44 (q), 25.01 (q), 27.75 (d),
1
and 175 °C. H NMR (400 MHz): δ ϭ 0.99 (t, J ϭ 7.4 Hz, 3 H),
31.21 (t), 33.41 (t), 76.81 (d), 210 (s) ppm.
1.40 (s, 9 H), 1.64Ϫ1.71 (m, 2 H), 2.18 (s, 3 H), 2.33Ϫ2.39 (m, 2
H), 3.47 (d, J ϭ 14.4 Hz, 1 H), 3.53 (d, J ϭ 14.0 Hz, 1 H),
(؎)-(5Z)-3-Hydroxy-6,10-dimethyl-5,9-undecadien-2-one [(؎)-6m]:
7.08Ϫ7.11 (m, 2 H), 7.22Ϫ7.31 (m, 3 H) ppm. 13C NMR
(5E)-3-Acetoxy-6,10-dimethyl-5,9-undecadien-2-one (5m, 63 mg,
(100 MHz): δ ϭ 13.64, 18.14, 27.45, 27.58, 35.93, 38.83, 83.23,
88.30, 127.09, 128.23, 130.06, 134.48, 165.42, 172.01, 202.54 ppm.
0.25 mmol) was hydrolysed as described in the general chemical
hydrolysis method to give (Ϯ)-6m as a slightly yellow oil (47 mg,
1
0.22 mmol, 89%). H NMR (200 MHz): δ ϭ 1.58 (s, 3 H), 1.65 (s,
3-Butyryloxy-4-phenylbutan-2-one (5p): Compound 4p (4.70 g,
14.1 mmol) and p-TsOH·H2O (278 mg, 1.46 mmol) were stirred in
3 H), 1.69 (s, 3 H), 2.00Ϫ2.05 (m, 4 H), 2.16 (s, 3 H), 2.20Ϫ2.60
(m, 2 H), 3.00Ϫ3.60 (br., ϪOH, 1 H), 4.18 (m, 1 H), 4.90Ϫ5.20
benzene (50 mL) as described in dealkoxycarbonylation method A.
(m, 2 H) ppm. 13C NMR (50 MHz): δ ϭ 13.95 (q), 23.29 (q), 25.29
Kugelrohr distillation at 1.0 mbar and 140 °C gave 5p (2.20 g,
(q), 25.54 (q), 26.20 (t), 31.89 (t), 31.96 (t), 76.59 (d), 118.19 (d),
123.74 (d), 131.77 (t), 139.15 (s), 209.53 (s) ppm.
9.39 mmol, 67%) as a colourless oil. 1H NMR (400 MHz): δ ϭ 0.89
(t, J ϭ 7.4 Hz, 3 H), 1.57Ϫ1.66 (m, 2 H), 2.08 (s, 3 H), 2.28Ϫ2.37
(m, 2 H), 2.99 (dd, AB, J ϭ 14.1, J ϭ 8.6 Hz, 1 H), 3.12 (dd, AB,
General Procedure for the Hydrolase Screening for Enantioselective
Acyloin؊Ester Cleavage: Racemic acyloin acetates 5 (5 µL) were
hydrolysed (in triplicate) with each lipase (BCL, CAL-B, CAL-A,
CRL, ROL, and PPL, ca. 20 mg) in phosphate buffer (0.1 , pH
J ϭ 14.1, J ϭ 4.7 Hz, 1 H), 5.22 (s, dd, J ϭ 8.6, J ϭ 5.1 Hz, 1 H),
7.20Ϫ7.33 (m, 5 H) ppm. 13C NMR (100 MHz): δ ϭ 13.49 (q),
18.18 (t), 26.82 (q), 35.73 (t), 36.65 (t), 78.76 (d), 126.93 (d), 128.47
(d), 129.23 (d), 135.84 (s), 172.96 (s), 205.47 (s) ppm.
7.0, 0.7 mL) by shaking the mixture at ambient temperature (300
strokes per minute). After 30 minutes, acetone (0.3 mL) was added
to stop the enzymatic hydrolysis. After twofold extraction with
Hydrolysis of Acyloin Esters 5a؊5p
General Procedure for the Chemical Hydrolysis of Acyloin Esters
5a؊n: A saturated aqueous solution of K2CO3 (80 µL per mmol
ester) was added dropwise to esters 5aϪn in methanol (0.13 ).
After completion of hydrolysis (usually after 5Ϫ10 min) the reac-
ethyl acetate (0.4 mL; phase separation was achieved by centrifug-
ation at 8000 g for 5 min), the combined organic layers were dried
with Na2SO4 and then centrifuged (8000 g/5 min). The supernatant
was decanted and analysed by TLC and chiral GC (Table 2) meth-
Eur. J. Org. Chem. 2004, 1063Ϫ1074
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L. A. Wessjohann et al.
FULL PAPER
Table 2. Chiral GC data
Acyloxy ketone/acyloin
Conditions[a] [°C]
Retention times acyloins 6aϪp
[min] (absol. config.)
Retention times of acyloxy ketones 5aϪp
[min] (absol. config.)
5a/6a
5b/6b
5c/6c
5d/6d
5e/6e
5f/6f
5g/6g
5h/6h
5i/6i
5j/6j
5k/6k
5l/6l
5m/6m
5n/6n
5o/6o
5p/6p
40 (iso)
70 (iso)
80 (iso)
70/10Ј-6/min-110
95/1Ј-4/min-110
70 (iso)
80 (iso)
70 (iso)
70 (iso)
80 (iso)
75 (iso)
105 (iso)
100 (iso)
100 (iso)
80(iso)
2.8 (R), 3.6 (S)
1.5 (R), 1.9 (S)
1.9 (R), 2.4 (S)
6.5 (R), 7.4 (S)
3.0 (R), 3.3 (S)
1.4 (R), 1.8 (S)
2.8 (R), 3.6 (S)
3.1 (R), 4.3 (S)
3.8 (R), 4.9 (S)
3.7 (R), 4.5 (S)
3.8 (R), 4.5 (S)
15.9 (R), 17.0 (S)
20.1 (R), 21.5 (S)
10.7 (R), 12.3 (S)
10.5 (R), 12.4 (S)
15.4 (R), 16.6 (S)
10.1 (R), 11.2 (S)
3.1 (R), 3.6 (S)
3.6 (R), 4.1 (S)
12.1 (R), 13.1 (S)
4.5 (R), 4.7 (S)
3.0 (R), 3.3 (S)
6.0 (R), 6.0 (S)
6.3 (R), 7.2 (S)
6.8 (R), 7.8 (S)
6.4 (R), 7.1 (S)
7.0 (R), 8.1 (S)
28.8 (R), 30.0 (S)
32.2 (R), 33.7 (S)
13.1 (R), 14.0 (S)
14.1 (R), 15.0 (S)
27.5 (R), 29.4 (S)
100(iso)
[a]
For details see general remarks of the Exp. Sect.
Compound (S)-6g: Rf value (ethyl acetate/hexane, 1:4): 0.33. [α]2D5
ϭ
ods. Control experiments without addition of enzyme were per-
formed for each acyloin acetate 5.
ϩ60.9 (c ϭ 3.30; CHCl3; ee ϭ 89%). 1H NMR (200 MHz): δ ϭ
1.72 (t, J Ͻ 2 Hz, 3 H), 2.28 (s, 3 H), 2.55Ϫ2.65 (m, 2 H), 3.61 (d,
J ϭ 6 Hz, 1 H, OH), 4.22 (m, 1 H) ppm. 13C NMR (50 MHz): δ ϭ
3.37 (q), 24.24 (t), 25.54 (q), 72.93 (d), 75.16 (d), 79.13 (s), 208.17
(s) ppm.
General Procedure for the Preparative Resolution of Acyloins 5c, 5g,
5j, 5l, 5m and 5n with Lipase: The acyloin ester was dissolved in
phosphate buffer (pH 7.0, 0.1 ), after which the lipase powder [if
not indicated otherwise, ca. 25% (wt.) of the acyloin ester] was
added and the reaction vessel was continuously shaken at 300
strokes per minute at ambient temperature. After appropriate con-
version (TLC or GC monitoring), acetone was added (half the vol-
ume of buffer) and the mixture was extracted five times with ethyl
acetate (1.5 times the volume of buffer used). The combined or-
ganic layers were washed with brine (twice the volume of buffer
used), dried with Na2SO4, filtered and concentrated in vacuo. The
alcohol and ester were separated by flash chromatography.
(S)-3-Hydroxy-6-methyl-5-hepten-4-one [(S)-6j]: Heptenone 5j
(200 mg, 1.09 mmol) was selectively hydrolysed with Amano lipase
BCL (63 mg) in buffer (15 mL) by the general procedure for the
preparative resolution described above. The reaction was worked
up after 6 h, and flash chromatography (ethyl acetate/petroleum
ether, 1:8) gave (in order of elution) the unchanged optically pure
ester 5j (103 mg, 0.56 mmol, 52%) and the (S)-alcohol 6j (71 mg,
0.50 mmol, 46%).
(S)-3-Hydroxyheptan-2-one [(S)-6c]: 3-Acetoxyheptanone (5c,
100 mg, 0.58 mmol) was selectively hydrolysed with Candida antart-
ica B lipase (6 mg) in buffer (10 mL) by the general procedure for
the preparative resolution described above. The reaction was
worked up after 3.75 h, and flash chromatography (ethyl acetate/
petroleum ether, 1:6) gave (in order of elution) the unchanged op-
tically enriched ester 5c (35 mg, 0.20 mmol, 35%) and the (S)-al-
cohol 6c (20 mg, 0.15 mmol, 26%).
Compound (R)-5j: Rf value (ethyl acetate/hexane, 1:4): 0.50. [α]2D5
Ϫ15.5 (c ϭ 2.030; CHCl3; ee ϭ 99%).
ϭ
Compound (S)-6j: Rf value (ethyl acetate/hexane, 1:4): 0.22. [α]2D
ϭ
1
ϩ64.5 (c ϭ 0.979; CHCl3; ee ϭ 99%). H NMR (200 MHz): δ ϭ
1.61 (s, 3 H), 1.69 (s, 3 H), 2.16 (s, 3 H), 2.2Ϫ2.7 (m, 2 H), 3.40
(d, J ϭ 4.9 Hz, ϪOH), 4.20 (q, J ϭ 5.2 Hz, 1 H), 5.07 (t, J ϭ
7.1 Hz, 1 H) ppm. 13C NMR (50.3 MHz): δ ϭ 17.86 (q), 25.24 (q),
25.66 (q), 32.15 (t), 76.57 (d), 117.51 (d), 135.49 (s), 209.51 (s) ppm.
Compound (R)-5c: Rf value (ethyl acetate/hexane, 1:4): 0.48. [α]2D5
ϩ9.6 (c ϭ 1.805; CHCl3; ee ϭ 78%).
ϭ
(3S,5E)-3-Hydroxy-6,10-dimethyl-5,9-undecadien-2-one
[(S)-6l]:
Compound (S)-6c: Rf value (ethyl acetate/hexane, 1:4): 0.33. [α]2D5
ϩ69.9 (c ϭ 0.410; CHCl3; ee ϭ 82%).
ϭ
Compound (5E)-5l (150 mg, 0.59 mmol) was selectively hydrolysed
with Amano lipase BCL (38 mg) in buffer (15 mL) by the general
procedure for the preparative resolution described above. The reac-
tion was worked up after 4 h, and flash chromatography (ethyl acet-
ate/petroleum ether, 1:5) gave (in order of elution) the unchanged
ester (R)-5l (10 mg, 0.04 mmol, 7%) and the (S)-alcohol 6l (38 mg,
0.18 mmol, 31%).
(S)-3-Hydroxy-5-heptyn-4-one [(S)-6g]: Compound 5g (124 mg,
0.74 mmol) was selectively hydrolysed with Candida antarctica li-
pase B (34 mg) in buffer (15 mL) by the general procedure for the
preparative resolution described above. The reaction was worked
up after 3 h, and flash chromatography (ethyl acetate/petroleum
ether, 1:5) gave (in order of elution) the unchanged optically en-
riched ester 5g (51 mg, 0.37 mmol, 41%) and the (S)-alcohol 6g
(33 mg, 0.26 mmol, 35%).
Compound (S)-6l: Rf value (ethyl acetate/hexane, 1:4): 0.38. [α]2D5
ϭ
ϩ20.2 (c ϭ 3.80; CHCl3; ee ϭ 30%). 1H NMR (200 MHz): δ ϭ
1.59 (s, 3 H), 1.64 (s, 3 H), 1.67 (s, 3 H), 2.00Ϫ2.10 (m, 2 H),
2.18 (s, 3 H), 2.25Ϫ2.70 (m, 2 H), 4.24 (m, 1 H), 4.90Ϫ5.25 (m, 2
H) ppm.
Compound (R)-5g: Rf value (ethyl acetate/hexane, 1:4): 0.48. [α]2D5
Ϫ2.8 (c ϭ 5.10; CHCl3; ee ϭ 85%).
ϭ
1072
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 1063Ϫ1074

A New Route to Protected Acyloins
FULL PAPER
Compound 7j: Colourless oil, Rf ϭ 0.39. H NMR (400 MHz: δ ϭ
1
(3S,5Z)-3-Hydroxy-6,10-dimethyl-5,9-undecadien-2-one
[(S)-6m]:
Compound (5Z)-5m (200 mg, 0.79 mmol) was selectively hydro-
lysed with Amano BCL (63 mg) in buffer (15 mL) by the general
procedure for the preparative resolution described above. The reac-
tion was worked up after 6 h, and flash chromatography (ethyl acet-
ate/petroleum ether, 1:8) gave (in order of elution) the unchanged
optically pure ester (R)-5m (107 mg, 0.42 mmol, 54%) and the (S)-
alcohol 6m (70 mg, 0.33 mmol, 42%).
1.48 (s, 3 H), 1.57 (s, 3 H), 2.09 (s, 3 H), 2.40 (m, 2 H), 3.44 (s, 3
H), 4.80 (m, 1 H), 4.88 (s, 1 H), 4.98 (m, 1 H), 7.30Ϫ7.45 (m, 5
H) ppm.
Compound 7l: Colourless oil, Rf ϭ 0.39. 1H NMR (400 MHz): δ ϭ
1.47 (s, 3 H), 1.58 (s, 3 H), 1.68 (s, 3 H), 1.80Ϫ2.00 (m, 4 H), 2.10
(s, 3 H), 2.40 (m, 2 H), 3.44 (s, 3 H), 4.35 (m, 1 H), 4.38 (s, 1 H),
5.00 (m, 2 H), 7.30Ϫ7.45 (m, 5 H) ppm.
Compound (R)-5m: Rf value (ethyl acetate/hexane, 1:4): 0.52. [α]2D5
Ϫ19.7 (c ϭ 1.560; CHCl3; ee ϭ 97%).
ϭ
1
Compound 7m: Slightly yellow oil. H NMR (400 MHz): δ ϭ 1.43
(s, 3 H), 1.58 (s, 3 H), 1.68 (s, 3 H), 1.85Ϫ2.00 (m, 4 H), 2.10 (s, 3
H), 2.30Ϫ2.50 (m, 2 H), 3.45 (s, 3 H), 4.82 (m, 1 H), 4.90 (s, 1 H),
4.98 (m, 1 H), 5.05 (m, 1 H), 7.30Ϫ7.50 (m, 5 H) ppm.
Compound (S)-6m: Rf value (ethyl acetate/hexane, 1:4): 0.38. [α]2D5
ϭ
1
ϩ63.7 (c ϭ 2.115; CHCl3; ee ϭ 95%). H NMR (200 MHz): δ ϭ
1.60 (s, 3 H), 1.67 (s, 3 H), 1.71 (s, 3 H), 2.00Ϫ2.07 (m, 4 H), 2.18
(s, 3 H), 2.25Ϫ2.65 (m, 2 H), 3.10Ϫ3.60 (br., OH), 4.17Ϫ4.23 (m,
1 H), 5.05Ϫ5.20 (m, 2 H) ppm. 13C NMR (50 MHz): δ ϭ 17.47
(q), 23.30 (q), 25.29 (q), 25.54 (q), 26.20 (t), 31.89 (t), 31.96 (t),
76.60 (d), 118.19 (d), 123.74 (d), 131.77 (s), 139.15 (s), 209.53 (s)
ppm. IR: ν˜ ϭ 734 (w), 1093 (m), 1173 (w), 1252 (w), 1356 (m),
1377 (m), 1449 (m), 1716 (s), 2857 (m), 2924 (s), 2965 (s), 3476
Table 3. Representation of the enantiomeric excesses of acyloin es-
ters (R)-5 and acyloins (S)-6 achievable with the three most suitable
enzymes tested; for each substrate, the best ee values are printed in
bold (n.d. ϭ not determined)
ee Values
Enzyme
BCL
Substrate/Product
CAL-B
CAL-A
(m) cmϪ1
.
5a/6a
5b/6b
5c/6c
5d/6d
5e/6e
5f/6f
5g/6g
5h/6h
5i/6i
5j/6j
5k/6k
5l/6l
5m/6m
5n/6n
5o/6o
5p/6p
9:27
13:14
12:89
100:87
11:98
99:93
9:89
100:91
95:94
100:95
98:94
77:97
28:96
55:89
14:84
55:99
5:75
6:35
(S)-3-Hydroxy-4-phenylbutan-2-one [(S)-6n]: Butanone 5n (150 mg,
0.73 mmol) was selectively hydrolysed with Amano lipase BCL
(38 mg) in buffer (15 mL) by the general procedure for the prepara-
tive resolution described above. The reaction was worked up after
3 h, and flash chromatography (ethyl acetate/petroleum ether, 1:8)
gave (in order of elution) the unchanged optically enriched ester 5n
(76 mg, 0.37 mmol, 50%) and the (S)-alcohol 6n (51 mg,
0.31 mmol, 43%).
58:87
100:66
54:94
99:34
43:89
0:8
99:27
100:100
99:99
100:96
100:88
95:94
97:95
99:98
97:92
n.d.
19:73
n.d.
19:71
n.d.
7:66
76:88
33:69
19:89
15:61
n.d.
52:78
15:85
n.d./0
99:11
Compound (R)-5n: Rf value (ethyl acetate/hexane, 1:4): 0.48. [α]2D5
Ϫ3.0 (c ϭ 2.325; CHCl3; ee ϭ 85%).
ϭ
Compound (S)-6n: Rf value (ethyl acetate/hexane, 1:4): 0.33. [α]2D5
ϭ
1
ϩ64.1 (c ϭ 0.820; CHCl3; ee ϭ 89%). H NMR (200 MHz): δ ϭ
2.19 (s, 3 H), 2.87 (dd, J ϭ 14.1, J ϭ 7.2 Hz, 1 H), 3.13 (dd, J ϭ
14.1, J ϭ 4.7 Hz, 1 H), 4.41 (m, 1 H), 7.0Ϫ7.4 (m, 5 H) ppm. 13C
NMR (50 MHz): δ ϭ 25.73 (q), 39.76 (t), 77.49 (d), 126.80 (d),
128.41 (d), 129.09 (d), 136.26 (s), 208.94 (s) ppm. IR: ν˜ ϭ 700 (s),
743 (m), 841 (w), 873 (w), 917 (w), 969 (w), 1030 (w), 1092 (s),
1175 (w), 1246 (w), 1358 (m), 1418 (w), 1455 (m), 1497 (m), 1603
(w), 1713 (s), 2924 (m), 3029 (m), 3062 (w), 3086 (w), 3445 (m)
Acknowledgments
The authors gratefully acknowledge F. de Kanter (VUA) for re-
cording the NMR spectra and R. Schmitz (VUA) for his crucial
help in the lab and on the chiral GC. Furthermore, we would like
to express our thanks to G. Schmidt (IPB) for the synthesis of the
derivatives 5b, 5j, 5o, and 5p, and to J. Schmidt (IPB) and H. Zap-
pey (VUA) for mass spectra.
cmϪ1
.
General Procedure for the Derivatisation of Alcohols 6 as O-Methyl-
mandelates for the Determination of the Absolute Configuration:
(See also main text). EDCI (two equiv.) was added to a solution of
equimolar amounts of acyloin 6, (R)-methoxyphenylacetic acid and
DMAP, and the mixture was stirred for 16 h at ambient tempera-
ture. Diethyl ether (3 ϫ 10 mL) was then added, and the resulting
suspension was washed with demineralised water (5 mL) and brine
(2 ϫ 5 mL). The organic layer was dried with Na2SO4, filtered and
concentrated in vacuo. The remaining residue was purified (e.g., by
flash chromatography on silica with diethyl ether/pentane, 1:4) to
afford analytical samples of the corresponding MPA esters, which
were pure enough for temperature-dependent NMR experiments to
determine the absolute configuration. In this way, 6g, 6i, 6l, and
6m were shown to have (S) configurations.
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[29]
Received June 4, 2003
1074
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1063Ϫ1074