Kinetic Enzymatic Resolution of Cyclopropane Derivatives

Article abstract of DOI:10.1002/adsc.200303137

The kinetic enzymatic resolution of various cyclopropane derivatives was systematically investigated. The study focused on synthetically useful cyclopropylmethanols (e.g., 18a/j or 19a/j) as well as some rarely investigated cyclopropanols (e.g., 24/25 or 27). The combination of enantioselective catalytic or diastereoselective synthesis of enantiomerically enriched compounds with enzymatic approaches ultimately led to the most convenient route to enantiomerically pure starting materials. Again, this was especially proven for the synthesis of cyclopropanols 18a/j and 19a/j. Key to the successful investigation was to rigorously establish an analytical tool for the analysis of enantiomeric composition of reaction mixtures.

Full text of DOI:10.1002/adsc.200303137

FULL PAPERS
Kinetic Enzymatic Resolution of Cyclopropane Derivatives
Jˆrg Pietruszka,* Anja C. M. Rieche, Thorsten Wilhelm, Andreas Witt
Institut f¸r Organische Chemie der Universit‰t Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax: ( ‡ 49)-711-685-4269, e-mail: joerg.pietruszka@po.uni-stuttgart.de
Received: August 21, 2003; Accepted: November 7, 2003
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de.
Abstract: The kinetic enzymatic resolution ofvarious
merically pure starting materials. Again, this was
cyclopropane derivatives was systematically investi- especially proven for the synthesis of cyclopropanols
gated. The study focused on synthetically useful 18a/j and 19a/j. Key to the successful investigation
cyclopropylmethanols (e.g., 18a/j or 19a/j) as well as was to rigorously establish an analytical tool for the
some rarely investigated cyclopropanols (e.g., 24/25 or analysis ofenantiomeric composition ofreaction
27). The combination ofenantioselective catalytic or
mixtures.
diastereoselective synthesis ofenantiomerically en-
riched compounds with enzymatic approaches ulti- Keywords: biotransformations; boron; cyclopropanes;
mately led to the most convenient route to enantio- hydrolases; kinetic resolution
Introduction
comparison, C2- or pseudo-C2-symmetric cyclopropanes
2 generally give a decreased selectivity: for different
Even 120 years after the synthesis of the first cyclo- esters 2 E values ofE < 10 were observed[18] and also the
propane derivative, the chemistry around this structural difluorocyclopropane 3 (E ˆ 11) gave only slightly
element often proves to be special, disregarding the fact better results.[21]
that cyclopropanes are regularly found in physiologi-
More generally speaking, with compounds where the
cally active compounds in general and in a number of cyclopropane moiety is the only stereogenic element,
pharmaceuticals in particular.[1] In this context it is not the kinetic resolution using hydrolases provides modest
surprising that despite the well known numerous selectivities compared to those observed in the desym-
[2 8]
applications ofcyclopropanes and hydrolases
and metrization of meso compounds: Enantioselectivities (E
within this group ofenzymes especially esterases [EC
values[24 28]) greater than 40 are rarely observed (see
3.1.1.1] and lipases [EC 3.1.1.3] kinetic enzymatic Figure 2 for some selected examples 4 15[29 40]).[9]
A
resolutions employing both have scarcely been used.[9] rule for preferred substitution patterns or enzymes
Apart from substances with the cyclopropane unit not cannot be given. For example, the trans-chrysanthemic
being the only stereogenic element,[10 13] meso-com- ester 4 was shown to give excellent selectivities[29 31]
pounds (Figure 1) are an exception giving presumable (more recently also for the polymer-supported ester[32]
)
the most favorable substrates: yields and selectivities are whereas the E value for the related cis-derivative 5 is
generally high. This is especially true for dicarboxylic distinctively lower.[33] Best results were obtained with
esters 1a, with the best results obtained when R' and/or different hydrolases. The reverse result was observed for
R'' are sterically not demanding.[14 18] Although there the precursors 7 and 8 ofnucleoside analogues [34] and for
have been reports about similar successful results with fluoro-substituted cyclopropanes such as derivative 9:[36]
the corresponding diols and their derivatives 1b,[17,19 22] in both cases the cis-configurated cyclopropane is the
these findings would seem somewhat less reliable.[23] By more suitable substrate. It is interesting to note that in
bicyclo[n.1.0]-derivatives 5-membered rings (n ˆ 3, e.g.,
10 12[37 39]) often show better selectivities than the
higher homologues. As pointed out before, if the
cyclopropane ring is not the only stereogenic element,
E values are often relatively high. Hence, without any
(investigated) restrictions for −R× good results were also
obtained for [4.1.0]-compounds 13,[13] whereas for the
related cyclopropane 14 good results were only ob-
Figure 1. Meso-compounds and (pseudo)-C2-symmetric cy-
clopropanes as substrates for hydrolases.
served with the n-Bu-moiety present.[40] In any case,
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enantiomerically pure cyclopropyl hemiacetals:[42] by
changing the enzyme from Candida antarctica B lipase
(CAL-B) to a Pseudomonas cepacia lipase (PCL; the
bacterial species has been renamed to Burkholderia
cepacia, however, for convenience we continue to use
the traditional name), the stereochemical course ofthe
resolution could be reversed.
In view ofthe reported results, we wanted to inves-
tigate two classes ofcyclopropane derivatives cyclo-
propylmethanols and cyclopropanols in more detail.
Preliminary results in the area have been published;[41]
we now wish to report our investigations in full.
Results and Discussion
Procedure
Before starting the investigation, it was of ultimate
importance to establish a reliable method to analyze the
enantiomeric excess. As a matter of fact, we found that
to establish the analytical tool the first step in our
procedure was the most difficult prerequisite: Some of
the envisaged investigations failed because we could not
find a convenient method to measure the enantiomeric
excess ofboth product and substrate. In only a few cases
did we have the ideal situation as shown in Figure 3: For
the first model substrate, the known bicyclic derivative
15,[40] we could not only separate the acetate 15, but also
the products ofthe enzymatic hydrolysis, alcohols 16.
Next, we looked at both the enzymatic hydrolyses and
acylation using a standard protocol with the available
enzymes (see ™Supporting Information∫ for a complete
list ofenzymes with the used abbreviations). Finally, we
optimized the reaction conditions by varying the solvent
system and the reaction temperature. In the present case
we found a moderate E value of E ˆ 23, with RML
giving the best results in THFat 608C. These results are
in full agreement with those previously reported.[40]
Figure 2. Kinetic enzymatic resolution ofselected cyclopro-
pane derivatives (E value: enantioselectivity).
Cyclopropylmethanols
Figure 3. Establishing the analytical separation ofenantiom-
ers (cv: calculated conversion).
The focus of our first investigation was on cyclopropyl-
methanol derivatives that were readily synthesized from
despite the fact that enzymes have been successfully the corresponding allyl alcohols 17 (Scheme 1). Using a
applied for the large-scale synthesis of the parent slightly modified Furukawa protocol,[43 45] cyclopropa-
cyclopropanol, there are hardly any investigations on nation with a zinc carbenoid led to the cyclopropanes 18
kinetic enzymatic resolutions ofchiral derivatives of
cyclopropanol. As a matter of fact, a first example
in good (unoptimized) overall yield. Acylation either
with the acid chloride or the anhydride gave the esters
prior to our own investigation[41]
has been the 19.
bicyclo[4.1.0]heptanyl acetate (15),[40] giving modest
The cinnamyl alcohol-derived acetate 19a was also
selectivity in a transesterification reaction with n- used to provide the synthetically valuable ™Weinreb
propanol in the presence ofa Rhizomucor miehei lipase amides∫ 18j/19j (Scheme 2):[46] Oxidation furnishing the
(RML). A more recent, impressive example was dis- carboxylic acid 19i could be achieved by ozonolysis,
closed by Westermann and Krebs who synthesized however, most convenient (yield: 89%) was the use of
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Kinetic Enzymatic Resolution ofCyclopropane Derivatives
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Scheme 1. Synthesis ofcyclopropylmethanols 18 and 19.
Scheme 3. Kinetic enzymatic resolution ofcyclopropylme-
thanols 18 selective acylation.[50]
[a]
Calculated values.[27]
We turned our attention to the selective hydrolysis of
esters 19 (Scheme 4). In a phosphate buffer at 408C we
first examined the phenyl derivative 19a and used
different enzymes in toluene. While most lipases and
esterases gave enantioselectivities E < 2, the results for
Pseudomonas cepacia lipase (PCL-IV: E ˆ 2.3, entry 1)
and pig liver esterase I (PLE-III: E ˆ 2.2, entry 3) were
only marginally better. The most promising result was
found with Candida antarctica B lipase (CAL-B-I): An
E value ofE ˆ 13 (entry 2) was observed. With this
enzyme we varied the solvent used. In different ethers or
pentane the selectivity decreased (entries 5 7), how-
ever, it was found that dichloromethane was the best
solvent for this transformation (E ˆ 24, entry 4). Again,
Scheme 2. Synthesis ofWeinreb amides 18j and 19j.
RuCl3/NaIO4.[47 49] Transformation to the Weinreb changing to more lipophilic esters did not improve the
amide 19j by activation with CDI followed by N- selectivity (compounds 19b/c, entries 8/9), but dramat-
methoxy-N-methylamine was straightforward (85%). ically lower E values were observed (E ˆ 5.3 and 5.1,
Consecutive saponification of the ester yielded the respectively). With aliphatic side-chains (compounds
alcohol 18j (90%). With these compounds in our hands, 19d g, entries 10 17) no successful resolutions could
we separated the enantiomers[50] using direct methods. be performed, with the E values never exceeding E ˆ 8.8
Most convenient was the GLC analysis with modified (entry 13). We were surprised to find that changes in the
cyclodextrins as chiral stationary phases.[51,52] Alterna- aromatic group have also a strong influence on the
tively, HPLC analysis with a commercially available selectivity. For the p-methoxy derivative 19h we found
column was successful. The absolute configurations that although CAL-B-I is the best enzyme for the
were established for most compounds via correlation transformation (entries 18 25), the solvent of choice is
with known, available reference substances.[53,54]
First the selective acylation using vinyl esters[55,56] in Finally, we examined the ™Weinreb amide∫ 19j and were
the presence ofdiefrent hydrolases was investigated pleased to find that almost all enzymes gave satisfactory
not dichloromethane, but toluene (E ˆ 8.7, entry 18).
(Scheme 3). As reference conditions, the reactions were transformations in toluene (entries 26 30) and some of
performed in toluene at 408C. In no case did the them even unforeseen high selectivities (PCL-I: E ˆ 25,
acylation give satisfactory results for the investigated entry 26; PPL-I: E ˆ 34, entry 29; ASL-I: E ˆ 33, entry
resolution ofthe substrates ( 18a d): while a conversion 30). We could further improve the results by varying the
could be easily achieved, even with the ™best∫ enzymes solvents (entries 31 42) and for a number of enzymes
only low E values ofE < 10 were observed. In most cases enantioselectivity factors E > 20 were found. By far the
the enzymes showed no selectivity. In this respect the best result was obtained when using PCL-I in dioxane
exemplary results for alcohol 18d are typical (E < 2, (E ˆ 52, entry 36).
entries 6 9). Using more lipophilic esters instead ofthe
Obviously, the last example shown is the only
acetate, did not improve the situation (18a: E ˆ 7.4; 18b: preparatively, directly useful substrate. To underline
E ˆ 2.4; 18c: E ˆ 1.9; PCL-III entries 3 5). We did not the point, we followed the kinetic resolution of the
further pursue this approach.
second best substrate 19a, taking aliquots after set times
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Figure 4. Enantiomeric excess as a function of conversion.
Conditions: see entry 4, Scheme 4.
cyclopropane derivatives, since in these cases no re-
racemization is possible.
To overcome the problem oflow overall yields, an
alternative approach was followed (Scheme 5): while
the enantiomeric excess ofenantioselective catalytic
cyclopropanations ofcinnamyl alcohol ( 17a) in the
presence ofbissulfonamide 20 did not exceed 87%, the
yield for the transformation according to the Denmark
protocol was high (96%).[57] The combination ofboth
processes led to the successful synthesis of enantiomeri-
cally pure cyclopropane (1'S,2'S)-18a, a starting material
that was just recently used for the total synthesis of the
marine oxylipins constanolactone A and B.[58] After the
high yielding acetylation (98%), the enantiomerically
enriched (1'S,2'S)-19a was subjected to the typical
conditions ofthe kinetic resolution. The reaction was
followed by regularly analyzing samples by HPLC. It
was important to verify that the enantiomeric excess of
the product would always be > 98% ee. The pure
product (1'S,2'S)-18a was isolated in 77% yield or 72%
starting from alcohol 17a. It is interesting to note that a
slightly different protocol for the enzymatic process
needed to be followed, since the usual buffer capacity is
ideal only for 50% conversion, hence the rate of the
reaction decreased under these conditions. It was
important to adjust the pH value. At about 80%
conversion hardly any transformation could be ob-
Scheme 4. Kinetic enzymatic resolution ofcyclopropylmeth-
yl esters 19 selective hydrolyses.[50]
[a] Configuration deduced (by analogy).
[b] Calculated values.[27]
[c]
sm ˆ starting material: see Schemes 1 and 2.
(Figure 4). We found a slightly decreased E value that is served. It was assumed that the substrate concentration
ofno consequence (E ˆ 20), however, there are a was too low for a reasonable rate. Consequently the
number ofimportant observations to be reported:
concentration was increased by slowly distilling the
solvent off.
a) The observed data are in excellent agreement with
the theoretical values for the enantioselectivity
factor.
b) At no time during the enzymatic hydrolyses is an
enantiomerically pure product formed.
c) As a matter ofafct, it is only possible to recover
enantiomerically pure substrate after approx. 65%
conversion.
The same concept was successfully applied for the
synthesis ofenantiomerically pure (1 'S,2'S)-18j (Fig-
ure 5). The corresponding enriched starting material
(1'S,2'S)-19j was synthesized according to the previously
described sequence from (1'S,2'S)-18a (87% ee) (see
Scheme 2). The enantiomeric products (1'R,2'R)-19a
and (1'R,2'R)-19j were synthesized accordingly in 74%
and 82% yields, respectively. In these cases the minor
In other words: The maximum yield ofpure 19a would enantiomer needed to react predominantly and the
be 35%. This is the obvious problem especially for starting material was retained in enantiomerically pure
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Kinetic Enzymatic Resolution ofCyclopropane Derivatives
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Scheme 6. Synthesis ofcyclopropylboronic esters 23.
Scheme 5. Enantiomerically
(1'S,2'S)-18a.
pure
cyclopropylmethanol
Scheme 7. Synthesis ofcyclopropanols 24 and 25.
Figure 5. Cyclopropylmethanols (1'R,2'R)-18a, (1'S,2'S)-18j
and (1'R,2'R)-18j. Conditions: 408C, phosphate buffer.
most conveniently performed by using diazomethane
[64,65]
in the presence ofcatalytic amounts ofPd(OAc)
.
2
form (within the experimental error). Obviously, the The conversion is usually high, however, in order to
second process was considerable faster (approx. by a obtain pure cyclopropylboronic esters 23, some loss
factor of 2), because less substrate needed to be during work-up was acceptable. Oxidation to cyclo-
converted. Summing up, for all enantiomers, either propanols 24 and acetylation to 25 using standard
alcohols 18a/18j or the corresponding acetates 19a/19j, a conditions wasunproblematic (Scheme 7), nevertheless,
practical approach to pure products could be proposed. some loss ofmaterial during distillation was observed.
The yields were not optimized.
As a single example for a cis-1,2-disubstituted cyclo-
Cyclopropanols
propane, the ester 27 was synthesized (Scheme 8). E-
Alkenylboronic acid 22a served as the suitable starting
After the primary alcohols 18, the second group of material. Following a procedure ofMasuda et al., [66] the
substrates that we examined were cyclopropanols. The acid was converted in a highly selective manner to the
synthesis ofthe starting materials was established from
Z-enol acetate 26. Cyclopropanation applying the
commercially available alkynes 21 (Scheme 6). First, Furukawa conditions[43 45] furnished the target com-
alkenylboronic esters 22 were synthesized either via pound 27 in 61% yield. We also established the analyti-
alkenylboronic acids and consecutive esterification cal tool f orcis- as well as all trans-cyclopropanols
(methods A and B),[59 62] or by direct hydroboration 25/28,[50] correlating the absolute configuration via
according to Knochel et al.[63] (method C). The overall known enantiomerically pure or enriched reference
yields were comparable. The cyclopropanation was compounds.[67,68]
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Scheme 8. Synthesis ofcyclopropyl acetates 27.
Scheme 9. Kinetic enzymatic resolution ofcyclopropanols
24.[50]
[a] Calculated values.[27]
Again, we started by investigating the enzymatic
acetylation ofcyclopropanols 24 with vinyl acetate
(Scheme 9). While we observed a relatively high rate for
the secondary alcohols in pentane (entries 1 ‡ 3), even
in the best cases only moderate selectivities were
observed. As expected, the rate was considerable lower
in dichloromethane (entry 2). The lipase of Pseudomo-
nas cepacia (PCL-IV) gave the highest E values (24a:
E ˆ 10; 24c: E ˆ 8.6), however, after our experience with
Scheme 10. Kinetic enzymatic resolution ofcyclopropylmeth-
yl acetates 25 selective hydrolyses.[50]
[a] sm: starting material (rac-25).
[b] Calculated values.[27]
the cyclopropylmethanols 18 it was apparent that better conversion). Although the yields were relatively high,
resultscould be expected for the selective hydrolysis. We they do not (and could not) exceed 50%; only enantio-
did not fully optimize the results for the substrates, merically enriched material was isolated. For this reason
because no really practical access to enantiomerically we followed a similar approach as described for cyclo-
pure cyclopropanol 24 was feasible.
Hydrolysis ofesters rac-25/rac-27 was performed in a acetate rac-25a, we decided to use enantiomerically
two-phase system ofan organic solvent and a phosphate enriched starting material (1R)-24a that was readily
propylmethanols 18a/j. Instead ofstarting from racemic
buffer on an analytical scale (Scheme 10). Surprisingly available from enantiomerically pure alkenylboronic
low rates were observed at 408C even when using ester 29 via a diastereoselective cyclopropanation-
toluene as solvent. Enantioselectivities and conversions oxidation sequence (Scheme 11).[69]
A moderate
were usually low after 16 h, hence the data are not (though improved) enantiomeric excess ofthe product
expressive. Two exceptions were the phenyl derivative was observed, but the material was available in high
25c and the cis-pentylcyclopropyne 27: with different yield (92%; 75% ee).[70,71] Acylation and enzymatic
lipases moderate selectivities were observed (25c: E ˆ21, resolution gave the enantiomerically pure (within the
RML-I
entry 12; 27: E ˆ 8.6, ASL-I
entry 17). experimental error) cyclopropanol (1R)-24a; slightly
Obviously, the cis-derivative 27 was hydrolyzed consid- impure product was obtained in 73%.
erable faster (to 28) than the trans-analogue 25a (24a).
Since all transformations were relatively slow, an
increase ofreaction temperature was tried. While
some enzymes denature under these conditions, we
Conclusion
found that the immobilized CAL-B-I gave satisfactory Generally speaking, apart from a few examples in the
results in THF. For both n-pentyl-derivatives 25a/27 literature, our investigation showed that cyclopropanes
(entries 5/18) good conversions were observed, how- are difficult substrates for kinetic enzymatic resolutions,
ever, surprisingly only the trans-cyclopropane 25a gave the selectivity often being low. It is a major drawback
excellent enantioselectivities. The high E value ofE ˆ44 that every individual example needs to be optimized and
indicated that the resolution might be performed on a that one common procedure cannot be devised. Never-
preparative scale: Starting material 25a (87% ee, 42%) theless, a number ofimportant results were obtained.
and product 24a (87% ee, 44%) were isolated in good First, best selectivities were always found for the
yield; the E value was insignificantly lower (E ˆ 40; 48% enzymatic hydrolysis. Second, compared to the higher
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Experimental Section
General Remarks
All reagents were used as purchased from commercial
suppliers without further purification. Enzymes were dona-
tions from Roche Diagnostics GmbH, Amano Pharmaceuti-
cals Co., Ltd., and Meito Sangyo Co., Ltd. The following
compounds were prepared according to the references given:
allyl alcohol 17 h,[74] enantiomerically enriched cyclopropyl-
methanols 18a, d, g, h,[57] bissulfonamide 20,[75] alkyne 21d
63]
(t-Bu),[76] alkenylboronic esters 22[59
(known compounds:
Scheme 11. Enantiomerically pure cyclopropylmethanol
(1R)-24a.
22b,[65] 22h,[77] and 22i[63]), cyclopropylboronic esters 23 (known
compounds: 23b[65] and 23h[77]), cyclopropanols 24
(known compounds 24a[70] and 24c[69]), and vinyl acetate 26.[66]
The reactions on a preparative scale were carried out using
standard Schlenk techniques under a dry nitrogen atmosphere.
Glassware was oven-dried at 1508C overnight. Solvents were
dried and purified by conventional methods prior to use;
diethyl ether (Et2O), 1,2-dimethoxyethane (DME), and tetra-
hydrofuran (THF) were freshly distilled from sodium/benzo-
phenone. Petroleum ether refers to the fraction with a boiling
point between 40 608C. Analysis ofenantiomeric composi-
tion was performed as described in ™Supporting Information∫.
[78 81]
Caution: The generation and handling ofdiazomethane
requires special precautions.
Flash-column chromatography: Merck silica gel 60, 0.040
0.063 mm (230 400 mesh). TLC: Pre-coated sheets, Alugram
SIL G/UV254 Macherey-Nagel; detection by UV extinction or
by cerium molybdenum solution [phosphomolybdic acid
(25 g), Ce(SO4)2 ¥ H2O (10 g), conc. H2SO4 (60 mL), H2O
(940 mL)]. Preparative MPLC: Gilson (Spectrochrom), with
a packed column (49 Â 500 mm), LiChroprep, Si60 (15
Figure 6. Top: Empirical model for the preferred hydrolyses
ofprimary and secondary esters. Below: Not suitable
substrates for kinetic enzymatic resolutions (PG: protecting
group; Bn ˆ benzyl, TBS ˆ t-BuMe2Si).
1
25 mm), and UV detector (254 nm). H and 13C NMR spectra
homologues, thesimpleacetatesgavesuperiorresults. No
clear-cut statements are possible on the steric or elec-
tronic requirements for successful separations of cyclo-
propanes. It is not clear why some compounds, e.g., 24f
and 25f were in our hands bad substrates. In addition, we
found that in several cases the enantiomers (e.g., 18k m,
19k m, 24e and 25e) could not be separated with the
available tools. Nevertheless, it is important to note that
for all investigated cyclopropanederivatives weobserved
that the results fit very well with the empirical model for
preferred hydrolyses of esters to primary[72] (for PCL) or
secondary[73] (forCRL) alcohols proposed by Kazlauskas
et al. (Figure 6). This might serve as an important tool for
the prediction ofthe absolute configuration ofunknown
cyclopropanes in the future. In addition, we proposed a
were recorded
at room temperature in CDCl3 unless
otherwise indicated on a Bruker ARX 500/300. Chemical
shifts d are given in ppm relative to resonances ofthe solvent
(1H: CDCl3, 7.25 ppm; 13C: CDCl3, 77.0 ppm), coupling con-
stants J are given in Hertz; in spectra ofhigher order d and J
values were not corrected. 13C signals were assigned by means
ofC-H- and H-H-COSY spectra. Microanalysis were per-
formed at the Institut f¸r Organische Chemie, Stuttgart.
Melting points (B¸chi 510) were not corrected. Specific
rotations were measured at 208C unless otherwise stated;
[a]D values are given in 10À1 deg cm2 gÀ1.
General Procedure for the Synthesis of
Cyclopropylmethanols 18
practical approach to enantiomerically pure cyclopro- Under an atmosphere ofdry nitrogen, allyl alcohol 17 (1.00
equiv.) in dry CH2Cl2 (0.33 M) was treated with Et2Zn (1.25
equivs. ofa 1 M solution in hexane) at 08C. The suspension was
stirred for 30 min. In a second flask, Et2Zn (1.25 equivs. ofa
1M solution in hexane) was added to CH2I2 (2.00 equivs.) in
dry CH2Cl2 (0.17 M) and stirred for 30 min at 08C. The
contents of the first flask were transferred into the second flask
at 08C and the mixture stirred at room temperature until the
olefin was completely consumed. The mixture was hydrolyzed
with aqueous saturated NH4Cl solution (11.5 mL/mmol 17);
when an emulsion formed, a minimum amount of 2 N HCl in
water was added. The organic layer was separated, and the
panes by a combination ofenantioselective catalytic or
diastereoselective (with labile intermediates) cyclopro-
panations with enzymatic resolutions.
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‡
‡
‡
aqueous layer extracted with CH2Cl2. The combined organic
fractions were dried over MgSO4, filtered and the solvent
removed under reduced pressure. Purification of the crude
product was achieved either by Kugelrohr distillation or flash
column chromatography.
18a: 2.68 g (20.0 mmol) ofcinnamyl alcohol ( 17a) was
cyclopropanated; after Kugelrohr distillation (808C/0.5 Torr)
the product 18a was isolated as a colorless oil; yield: 2.85 g
(19.2 mmol, 96%). IR (film): nÄ ˆ 3288 (OH), 3026, 2924, 1604,
1497, 1461, 1159, 1091, 1020, 744, 697 cmÀ1; MS (EI, 70 eV): m/
[M H2O ], 147 (100) [M CH3O ], 121 (20), 91 (25) [C7H7 ],
‡
1
77 (10) [C6H5 ]; H NMR (CDCl3, 500 MHz): d ˆ 0.87 (ddd,
3J3'a,2' ˆ 8.8 Hz, 3J3'a,1' ˆ 5.6 Hz, 2J3'a,3'b ˆ 5.1 Hz, 1H, 3'-Ha), 0.87
(ddd, 3J3'b,1' ˆ 8.2 Hz, 3J3'b,2' ˆ 5.4 Hz, 2J3'b,3'a ˆ 5.1 Hz, 1H, 3'-Hb),
3
3
3
1.37 (ddddd, J1',3'b ˆ 8.2 Hz, J1',1a ˆ 6.8 Hz, J1',1b ˆ 6.8 Hz,
3J1',3'a ˆ 5.6 Hz, J1',2' ˆ 4.5 HZ, 1H, 1'-H), 1.57 (t, JOH,1
ˆ
3
3
3
3
5.0 Hz, 1H, OH), 1.78 (ddd, J2',3'a ˆ 8.8 Hz, J2',3'b ˆ 5.4 Hz,
3J2',1' ˆ 4.5 Hz, 1H, 2'-H), 3.59 (dd, J1a,1b ˆ 9.5 Hz, J1a,1'
ˆ
2
3
6.8 Hz, 1H, 1-Ha), 3.60 (dd, 2J1b,1a ˆ 9.5 Hz, 3J1b,1' ˆ 6.8 Hz, 1H,
3
1-Hb), 3.77 (s, 3H, OCH3), 6.81 (d, Jm,o ˆ 8.7 Hz, 2H, m-H),
7.00 (d, 3Jo,m ˆ 8.7 Hz, 2H, o-H); 13C NMR (CDCl3, 125 MHz):
d ˆ 13.3 (C-3'), 20.6 (C-2'), 24.8 (C-1'), 55.3 (OCH3), 66.6 (C-1),
113.8 (2C, m-C), 127.0 (2C, o-C), 134.4 (i-C), 157.8 (p-C); anal.
calcd. For C11H14O2 (178.23 g/mol): C 74.13, H 7.92; found: C
73.54, H 8.08.
‡
‡
z (%) ˆ 148 (40) [M ], 130 (20) [M H2O ], 117 (100) [M
CH3O ], 104 (40), 91 (30) [C7H7 ]; 1H NMR (CDCl3,
500 MHz): d ˆ 0.94 (m, 2H, 3'-H), 1.44 (ddddd, 3J1',3' ˆ 8.4 Hz,
3J1',1a ˆ 7.0 Hz, 3J1',1b ˆ 6.8 Hz, 3J1',3' ˆ 5.7 Hz, 3J1',2' ˆ 4.6 Hz, 1H,
‡
‡
3
3
3
1'-H), 1.80 (ddd, J2',3'b ˆ 8.7 Hz, J2',1' ˆ 4.6 Hz, J2',3' ˆ 4.6 Hz,
1H, 2'-H), 1.99 (b, 1H, OH), 3.60 (mc, 2H, 1-H), 7.06 (dd, 3Jo,m
ˆ
ˆ
4
3
4
8.1 Hz, Jo,p ˆ 1.3 Hz, 2H, o-H), 7.15 (tt, Jp,m ˆ 7.4 Hz, Jp,o
3
3
1.3 Hz, 1H, p-H), 7.25 (ddd, Jm,o ˆ 8.1 Hz, Jm,p ˆ 7.4 Hz,
4Jm,m ˆ 1.9 Hz, 2H, m-H); 13C NMR (CDCl3, 125 MHz): d ˆ
13.8 (C-3'), 21.2 (C-2'), 25.2 (C-1'), 66.5 (C-1), 125.6 (p-C),
125.8 (2 C, o-C), 128.3 (2 C, m-C), 142.4 (i-C); anal. calcd. for
C10H12O (148.20 g/mol): C 81.04, H 8.16; found: C 81.03, H 8.21.
18d: 1.44 g (20.0 mmol) of 17d was cyclopropanated; after
chromatographic separation (pentane/Et2O, 4:3) the product
18d was isolated as a colorless oil; yield: 1.41 g (16.4 mmol,
82%). IR (film): nÄ ˆ 3334 (OH), 3065, 3000, 2952, 2869, 1453,
1413, 1381, 1153, 1064, 1011, 894, 865, 796, 764 cmÀ1; 1H NMR
General Procedure for the Synthesis of Cyclopropyl
acetates 19
A solution ofalcohol 18 (1 equiv.) in CH2Cl2 (1 M) was treated
with Ac2O (3 equivs.), Et3N (3 equivs.), and 4-dimethylamino-
pyridine (0.1 equivs.) at 08C. The mixture was allowed to warm
up to room temperature and was stirred until TLC indicated
complete consumption ofthe starting material. The reaction
was quenched with saturated aqueous NH4Cl solution
(11.5 mL/mmol 18), the organic layer separated, and the
aqueous layer extracted with CH2Cl2. The combined organic
fractions were washed with saturated aqueous bicarbonate
solution and brine, dried over MgSO4, filtered and the solvent
removed under reduced pressure. Purification of the crude
product was achieved either by distillation or flash column
chromatography.
3
3
(CDCl3, 500 MHz): d ˆ 0.27 (ddd, J3'a,2' ˆ 8.1 Hz, J3'a,1'
ˆ
2
3
4.8 Hz, J3'a,3'b ˆ 4.7 Hz, 1H, 3'-Ha), 0.37 (ddd, J3'b,1' ˆ 8.4 Hz,
3J3'b,2' ˆ 4.8 Hz, 2J3'b,3'a ˆ 4.7 Hz, 1H, 3'-Hb), 0.64 (dqdd, 3J2',3'b
ˆ
3
3
3
8.4 Hz, J2',CH ˆ 6.0 Hz, J2',3'a ˆ 4.8 Hz, J2',1' ˆ 4.5 Hz, 1H, 2'-
3
H), 0.82 (ddddd, 3J1',3'a ˆ 8.1 Hz, 3J1',1b ˆ 7.1 Hz, 3J1',1a ˆ 7.1 Hz,
3J1',3'b ˆ 4.8 Hz, J1',2' ˆ 4.5 Hz, 1H, 1'-H), 1.06 (d, JCH ,2'
ˆ
ˆ
3
3
3
2
6.0 Hz, 3 H, CH3), 1.54 (bs, 1H, OH), 3.41 (dd, J1a,1b
19a: 2.80 g (18.9 mmol) ofalcohol 18a was acetylated; after
Kugelrohr distillation (808C/0.5 Torr) the product 19a was
isolated as a colorless oil; yield: 3.59 g (18.1 mmol, 96%). IR
3
2
11.2 Hz, J1a,1' ˆ 7.1 Hz, 1H, 1-Ha), 3.46 (dd, J1b,1a ˆ 11.2 Hz,
3J1b,1' ˆ 7.1 Hz, 1H, 1-Hb); 13C NMR (CDCl3, 125 MHz): d ˆ
11.1 (C-3'), 11.2 (C-2'), 18.5 (C-1'), 22.3 (CH3), 67.2 (C-1);
anal. calcd. for C5H10O (86.13 g/mol): C 69.72, H 11.70; found:
C 67.08, H 11.43.
ˆ
(film): nÄ ˆ 3028, 2949, 1740 (C O), 1605, 1498, 1464, 1376,
1236, 1185, 1094, 1030, 974, 881, 756, 698, 606 cmÀ1; MS (EI,
‡
70 eV): m/z (%) ˆ 190 (40) [M ], 149 (15), 130 (100) [M
‡
‡
‡
18g: 600 mL (4.00 mmol) of 17g was cyclopropanated; after
chromatographic separation (petroleum ether/ethyl acetate,
96:4 to 87:13) the product 18g was isolated as a colorless oil;
yield: 0.53 g (3.72 mmol, 93%). IR (film): nÄ ˆ 3334 (OH), 3064,
2996, 2956, 2923, 2854, 1459, 1378, 1246, 1153, 1031, 903, 875,
C2H4O2 ], 129 (60), 115 (30), 104 (25) [C8H8 ], 91 (20) [C7H7 ],
43 (55) [C2H3O ]; 1H NMR (CDCl3, 500 MHz): d ˆ 0.96 (ddd,
‡
3J3'a,2' ˆ 9.0 Hz, 3J3'a,1' ˆ 5.7 Hz, 2J3'a,3'b ˆ 5.5 Hz, 1H, 3'-Ha), 1.00
(ddd, 3J3'b,1' ˆ 8.4 Hz, 2J3'b,3'a ˆ 5.5 Hz, 3J3'b,2' ˆ 5.3 Hz, 1H, 3'-Hb),
3
3
3
1.46 (ddddd, J1',3'b ˆ 8.4 Hz, J1',1a ˆ 7.3 Hz, J1',1b ˆ 7.0 Hz,
724 cmÀ1; 1H-NMR (CDCl3, 500 MHz): d ˆ 0.30 (ddd, 3J3'a,1'
ˆ
3
3
3
ˆ
J1',3'a 5.7 Hz, J1',2' ˆ 4.6 Hz, 1H, 1'-H), 1.88 (ddd, J2',3'a
ˆ
3
2
3
3
8.2 Hz, J3'a,2' ˆ 5.2 Hz, J3'a,3'b ˆ 4.8 Hz, 1H, 3'-Ha), 0.36 (ddd,
3J3'b,2' ˆ 8.4 Hz, 3J3'b,1' ˆ 4.7 Hz, 2J3'b,3'a ˆ 4.7 Hz, 1H, 3'-Hb), 0.60
9.0 Hz, J2',3'b ˆ 5.3 Hz, J2',1 ˆ 4.6 Hz, 1H, 2'-H), 2.07 (s, 3H,
CH3), 4.04 (dd, 2J1a,1b ˆ 11.5 Hz, 3J1a,1' ˆ 7.3 Hz, 1H, 1-Ha), 4.08
(dd, 2J1b,1a ˆ 11.5 Hz, 3J1b,1' ˆ 7.0 Hz, 1H, 1-Hb), 7.06 7.27 (m, 5
H, arom. CH); 13C NMR (CDCl3, 125 MHz): d ˆ 13.9 (C-3'),
21.0 (C-2'), 21.4 (C-1'), 21.8 (CH3), 68.0 (C-1), 125.8 (p-C),
125.9 (2C, o-C), 128.0 (2C, m-C), 142.0 (i-C), 171.0 (COCH3);
anal. calcd. for C12H14O2 (190.24 g/mol): C 75.76, H 7.41; found:
C 76.03, H 7.51.
3
3
3
3
(dtddd, J2',3'b ˆ 8.4 Hz, J2',1'' ˆ 6.9 Hz, J2',3'a ˆ 5.2 Hz, J2',1'
ˆ
3
4.2 Hz, 1H, 2'-H), 0.85 (m, 1H, 1'-H), 0.86 (t, J5'',4'' ˆ 7.1 Hz,
3H, 5''-H), 1.20 1.41 (m, 9H, 1''-H, 2''-H, 3''-H, 4''-H, OH),
2
3
3.42 (dd, J1a,1b ˆ 11.1 Hz, J1a,1' ˆ 7.1 Hz, 1H, 1-Ha), 3.46 (dd,
2J1b,1a ˆ 11.1 Hz, J1b,1' ˆ 7.1 Hz, 1H, 1-Hb); 13C NMR (CDCl3,
3
125 MHz): d ˆ 9.9 (C-3'), 14.1 (C-5''), 17.2 (C-1'), 21.2 (C-2'),
22.7 (C-4''), 29.3 (C-2''), 31.7 (C-3''), 33.6 (C-1''), 67.3 (C-1);
anal. calcd. for C5H10O (142.24 g/mol): C 76.00, H 12.76; found:
C 75.62, H 12.72.
19d: 0.85 g (9.60 mmol) ofalcohol 18d was acetylated; after
distillation (bp 1118C) spectroscopically pure product 19a was
isolated as a colorless liquid; yield: 1.22 g (9.52 mmol, 99%). IR
ˆ
18h: 0.82 g (5.00 mmol) of 17h was cyclopropanated; after
chromatographic separation (petroleum ether/ethyl acetate,
9:1 to 3:1) the product 18h was isolated as a colorless oil; yield:
0.52 g (2.90 mmol, 58%). IR (film): nÄ ˆ 3363 (OH), 3000, 2935,
2835, 1613, 1582, 1515, 1463, 1293, 1246, 1179, 1113, 1079, 1036,
(film): nÄ ˆ3070, 3003, 2955, 2901, 2871, 1741 (C O), 1454, 1374,
1317, 1238, 1176, 1124, 1069, 1033, 967, 907, 875, 737, 635 cmÀ1;
3
1H NMR (CDCl3, 500 MHz): d ˆ 0.31 (ddd, J3'a,2' ˆ 8.3 Hz,
2
3
3J3'a,1' ˆ 5.0 Hz, J3'a,3'b ˆ 4.8 Hz, 1H, 3'-Ha), 0.43 (ddd, J3'b,1'
ˆ
8.8 Hz, 3J3'b,2' ˆ 4.8 Hz, 2J3'b,3'a ˆ 4.8 Hz, 1H, 3'-Hb), 0.68 (dqdd,
‡
3
3
3
828 cmÀ1;. MS (EI, 70 eV): m/z (%) ˆ 178 (30) [M ], 160 (10)
3J2',3'b ˆ 8.8 Hz, J2',CH ˆ 6.0 Hz, J2',3'a ˆ 4.8 Hz, J2',1' ˆ 4.3 Hz,
3
1280
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2003, 345, 1273 1286

Kinetic Enzymatic Resolution ofCyclopropane Derivatives
FULL PAPERS
3
3
3
1H, 2'-H), 0.83 (ddddd, J1',3'a ˆ 8.3 Hz, J1',1a ˆ 7.5 Hz, J1',1b
ˆ
washed with saturated aqueous bicarbonate solution and brine,
dried over MgSO4, filtered and the solvent removed under
reduced pressure. Purification of the crude product was
achieved by flash column chromatography.
3
3
7.2 Hz, J1',3'b ˆ 4.8 Hz, J1',2' ˆ 4.3 Hz, 1H, 1'-H), 1.05 (d,
3JCH ,2' ˆ 6.0 Hz, 3H, CH3), 2.06 (s, 3H, COCH3), 3.86 (dd,
3
2J1a,1b ˆ 11.5 Hz, J1a,1' ˆ 7.5 Hz, 1H, 1-Ha), 3.93 (dd, J1b,1a
ˆ
3
2
11.5 Hz, J1b,1' ˆ 7.2 Hz, 1H, 1-Hb); 13C NMR (CDCl3,
3
19b: 0.30 g (2.02 mmol) ofalcohol 18a was acylated; after
chromatographic separation (petroleum ether/ethyl acetate,
95:5) the product 19b was isolated as a colorless oil; yield:
0.46 g (1.87 mmol, 92%). IR (film): nÄ ˆ 3028, 2957, 2872, 1736
125 MHz): d ˆ 12.2 (C-3'), 12.4 (C-2'), 18.9 (C-1'), 19.1
ˆ
(COCH3), 21.9 (CH3), 69.6 (C-1), 171.3 (C O).
19g: 0.65 g (4.25 mmol) ofalcohol 18g was acetylated; after
chromatographic separation (petroleum ether/ethyl acetate,
100:0 to 99:5) the product 19g was isolated as a colorless oil;
yield: 0.48 g (2.60 mmol, 61%). IR (film): nÄ ˆ 3068, 2999, 2957,
ˆ
(C O), 1606, 1498, 1465, 1417, 1379, 1244, 1168, 1095, 1032,
994, 878, 746, 698 cmÀ1; MS (EI, 70 eV): m/z (%) ˆ 246 (25)
‡
‡
‡
[M ], 130 (100) [C10H10 ], 115 (15), 99 (45), 77 ( < 5) [C6H5 ], 71
(15) [C5H11 ]; 1H NMR (CDCl3, 500 MHz): d ˆ 0.88 (t, 3J6,5
ˆ
‡
ˆ
2925, 2855, 1742 (C O), 1460, 1365, 1237, 1030, 968, 885,
725 cmÀ1; MS (CI, CH4): m/z (%) ˆ 185 (20) [M ‡ H ], 183 (15)
‡
3
3
7.1 Hz, 3H, 6-H), 0.96 (ddd, J3'',1'' ˆ 7.4 Hz, J3''a,2'' ˆ 5.5 Hz,
‡
2J3''a,3''b ˆ 5.3 Hz, 1H, 3''-Ha), 0.99 (ddd, 3J3''b,2'' ˆ 8.8 Hz, 3J3''b,2''
ˆ
[M H ], 142 (15), 125 (90), 95 (25), 83 (70), 81 (30), 69 (100), 43
(45) [C3H7 ]; 1H NMR (CDCl3, 500 MHz): d ˆ 0.30 (ddd,
‡
2
5.6 Hz, J3''b,3''a ˆ 5.3 Hz, 1H, 3''-Hb), 1.30 (m, 4H, 5-H, 4-H),
3J3'a,1' ˆ 8.2 Hz, 3J3'a,2' ˆ 5.0 Hz, 2J3'a,3'b ˆ 5.0 Hz, 1H, 3'-Ha), 0.38
3
3
3
1.49 (ddddd, J1'',1'a ˆ 7.5 Hz, J1'',3''a ˆ 7.4 Hz, J1'',1'b ˆ 6.9 Hz,
(ddd, 3J3'b,2' ˆ 8.5 Hz, 3J3'b,1' ˆ 4.5 Hz, 2J3'b,3'a ˆ 4.5 Hz, 1H, 3'-Hb),
3J1'',3''b ˆ 5.6 Hz, J1'',2'' ˆ 4.4 Hz, 1H, 1''-H), 1.63 (tt, J3,2
ˆ
3
3
3
3
3
3
3
0.62 (dtddd, J2',3'b ˆ 8.5 Hz, J2',1'' ˆ 6.9 Hz, J2',3'a ˆ 5.2 Hz,
7.5 Hz, J3,4 ˆ 7.5 Hz, 2H, 3-H), 1.88 (ddd, J2'',3''b ˆ 8.8 Hz,
3J2'',3''a ˆ 5.5 Hz, 3J2'',1'' ˆ 4.4 Hz, 1H, 2''-H), 2.31 (t, 3J2,3 ˆ 7.5 Hz,
2H, 2-H), 4.04 (dd, 3J1'a,1'b ˆ 11.5 Hz, 3J1'a,1'' ˆ 7.5 Hz, 1H, 1'-Ha),
3J2',1' ˆ 4.2 Hz, 1H, 2'-H), 0.82 (m, 1H, 1'-H), 0.85 (t, J5'',4''
ˆ
3
7.1 Hz, 3H, 5''-H), 1.09 1.35 (m, 8H, 1''-H, 2''-H, 3''-H, 4''-H),
2.03 (s, 3H, COCH3), 3.85 (dd, 2J1a,1b ˆ 11.4 Hz, 3J1a,1' ˆ 7.4 Hz,
1H, 1-Ha), 3.87 (dd, 2J1b,1a ˆ 11.4 Hz, 3J1b,1' ˆ 7.4 Hz, 1H, 1-Hb);
13C NMR (CDCl3, 125 MHz): d ˆ 10.4 (C-3'), 14.1 (C-5''), 17.2
(C-1'), 17.6 (C-2'), 21.1 (COCH3), 22.7 (C-4''), 29.1 (C-2''), 31.5
(C-3''), 33.4 (C-1''), 68.9 (C-1), 171.3 (COCH3); anal. calcd. for
C11H20O2 (184.28 g/mol): C 71.70, H 10.94; found: C 71.69, H
10.84.
2
3
4.09 (dd, J1'b,1'a ˆ 11.5 Hz, J1'b,1'' ˆ 6.9 Hz, 1H, 1'-Hb), 7.03
7.29 (m, 5H, arom. H); 13C NMR (CDCl3, 125 MHz): d ˆ 14.2
(C-3''), 14.3 (C-6), 22.0 (C-1''), 22.3 (C-2''), 22.8 (C-5), 25.2 (C-
3), 31.8 (C-4), 34.8 (C-2), 68.1 (C-1'), 126.1 (p-C), 126.3 (2C, o-
C), 128.7 (2C, m-C), 142.4 (i-C), 174.3 (C-1); anal. calcd. for
C16H22O2 (246.34 g/mol): C 78.01, H 9.00; found: C 77.84, H
9.03.
19h: 0.19 g (1.07 mmol) ofalcohol 18h was acetylated; after
chromatographic separation (petroleum ether/ethyl acetate,
9:1) the product 19h was isolated as a colorless oil; yield: 0.21 g
19c: 0.30 g (2.02 mmol) ofalcohol 18a was acylated; after
chromatographic separation (petroleum ether/ethyl acetate,
9:1 to 3:1) the product 19c was isolated as a colorless oil; yield:
ˆ
(0.95 mmol, 89%); IR (film): nÄ ˆ 3000, 2950, 2810, 1738 (C O),
ˆ
0.49 g (1.79 mmol, 88%). IR (film): nÄ ˆ 2929, 2856, 1736 (C O),
1613, 1516, 1463, 1375, 1244, 1180, 1034, 829 cmÀ1; MS (EI,
1606, 1498, 1465, 1379, 1163, 1107, 1032, 980, 746, 697 cmÀ1; MS
‡
‡
ˆ
70 eV): m/z (%) 220 (40) [M ], 160 (100) [M C2H4O2 ], 129
(30) [M C7H7 ], 91 (30) [C7H7 ], 43 (55) [C3H7 ]; H NMR
‡
‡
(EI, 70 eV): m/z (%) ˆ 274 [M ] (20), 130 (100), 91 [C7H7 ]
‡
‡
‡
1
(20), 57 [C4H9 ] (35); 1H NMR (CDCl3, 500 MHz): d ˆ 0.87 (t,
‡
3
2
(CDCl3, 500 MHz): d ˆ 0.90 (ddd, J3'a,2' ˆ 8.9 Hz, J3'a,3'b
ˆ
3J8,7 ˆ 7.1 Hz, 3H, 6-H), 0.96 (ddd, J3''a,1'' ˆ 8.8 Hz, J3''a,2''
ˆ
3
3
3
3
5.5 Hz, J3'a,2' ˆ 5.3 Hz, 1H, 3'-Ha), 0.93 (ddd, J3'b,1' ˆ 8.3 Hz,
5.3 Hz, 2J3''a,3''b ˆ 5.3 Hz, 1H, 3''-Ha), 1.00 (ddd, 3J3''b,2'' ˆ 8.4 Hz,
3J3''b,2'' ˆ 5.6 Hz, 2J3''b,3''a ˆ 5.3 Hz, 1H, 3''-Hb), 1.22 1.32 (m, 8H,
2J3'b,3'a ˆ 5.5 Hz, 3J3'b,2' ˆ 5.2 Hz, 1H, 3'-Hb), 1.39 (ddddd, 3J1',3'b
ˆ
ˆ
3
3
3
3
8.3 Hz, J1',1a ˆ 7.3 Hz, J1',1b ˆ 7.0 Hz, J1',3'a ˆ 5.3 Hz, J1',2'
3
3
7-H, 6-H, 5-H, 4-H), 1.47 (ddddd, J1'',1'a ˆ 7.5 Hz, J1'',3''a
ˆ
3
3
4.6 Hz, 1H, 1'-H), 1.84 (ddd, J2',3'a ˆ 8.9 Hz, J2',3'b ˆ 5.2 Hz,
3
3
3
7.4 Hz, J1'',1'b ˆ 6.9 Hz, J1'',3''b ˆ 5.6 Hz, J1'',2'' ˆ 4.4 Hz, 1H, 1''-
3
ˆ
J2',1' ˆ 4.6 Hz, 1H, 2'-H), 2.07 [s, 3H, -C( O)CH3], 3.77 (s, 3H,
3
3
H), 1.62 (tt, J3,2 ˆ 7.6 Hz, J3,4 ˆ 7.6 Hz, 2H, 3-H), 1.88 (ddd,
3J2'',3''b ˆ 8.8 Hz, 3J2'',3''a ˆ 5.5 Hz, 3J2'',1'' ˆ 4.4 Hz, ddd, 1H, 2''-H),
2
3
OCH3), 4.03 (dd, J1a,1b ˆ 11.5 Hz, J1a,1' ˆ 7.3 Hz, 1H, 1-Ha),
2
3
4.06 (dd, J1b,1a ˆ 11.5 Hz, J1b,2 ˆ 7.0 Hz, 1H, 1-Hb), 6.81 (d,
3
3
2.32 (t, J2,3 ˆ 7.5 Hz, 2H, 2-H), 4.04 (dd, J1'a,1'b ˆ 11.5 Hz,
3Jm, o ˆ 8.6 Hz, 2H, m-H), 7.00 (d, Jo, m ˆ 8.6 Hz, 2H, o-H);
3
3J1'a,1'' ˆ 7.3 Hz, 1H, 1'-Ha), 4.09 (dd, J1'b,1'a ˆ 11.5 Hz, J1'b,1''
ˆ
2
3
13C NMR (CDCl3, 125 MHz): d ˆ 13.4 (C-3'), 20.9 (C-2'), 21.1
6.9 Hz, 1H, 1'-Hb), 7.03 7.29 (m, 5H, arom. H); 13C NMR
(CDCl3, 125 MHz): d ˆ 13.9 (C-3''), 14.1 (C-8), 21.5 (C-1''),
21.8 (C-2''), 22.6 (C-7), 25.0 (C-3), 28.9 (C-4), 29.1 (C-5), 31.6
(C-6), 34.4 (C-2), 67.7 (C-1'), 125.7 (p-C), 125.9 (2C, o-C), 128.3
(2C, m-C), 142.0 (i-C), 174.0 (C-1); anal. calcd. for C16H22O2
(274.40 g/mol): C 78.79, H 9.55; found: C 78.84, H 9.62.
ˆ
(C-1'), 21.1 [-C( O)CH3], 55.3 (OCH3), 68.1 (C-1), 113.9 (2C,
m-C), 127.2 (2C, o-C), 133.9 (i-C), 157.91 (p-C), 171.2
[-C( O)CH3]; anal. calcd. for C13H16O3 (220.26 g/mol): C
70.89, H 7.32; found: C 70.82, H 7.44.
ˆ
19e: 0.16 g (1.80 mmol) ofalcohol 18d was acylated; after
chromatographic separation (petroleum ether/ethyl acetate,
97.5:2.5) the spectroscopically product 19e was isolated as a
colorless oil; yield: 0.24 g (1.30 mmol, 72%). 1H NMR (CDCl3,
General Procedure for the Caprylation and
Caproylation of Alcohols 18a ‡ d
3
3
2
500 MHz): d ˆ 0.29 (ddd, J ˆ 8.3 Hz, J ˆ 4.9 Hz, J ˆ 4.8 Hz,
To a stirred solution ofcyclopropylmethanol 18 (1 equiv.) in
dry CH2Cl2 (0.2 M) was added the required acid chloride (3
equivs.), Et3N (3 equivs.), and 4-dimethylaminopyridine (0.1
equiv.) at 08C. The mixture was allowed to warm up to room
temperature and was stirred until TLC indicated complete
consumption ofthe starting material. The reaction was
quenched with saturated aqueous NH4Cl solution (11.5 mL/
mmol 17), the organic layer separated, and the aqueous layer
extracted with CH2Cl2. The combined organic fractions were
1H, 3''-Ha), 0.42 (ddd, 3J ˆ 8.4 Hz, 3J ˆ 4.8 Hz, 2J ˆ 4.8 Hz, 1H,
3
3''-Hb), 0.68 (m, 1H, 1''-H), 0.84 (m, 1H, 2''-H), 0.9 (t, J6,5
ˆ
7.1 Hz, 3H, 6-H), 1.05 (d, 3JCH ,2'' ˆ 5.9 Hz, 3H, CH3), 1.27 1.36
3
(m, 4H, 4-H, 5-H), 1.63 (m, 2H, 3-H), 2.31 (t, 3J2,3 ˆ 7.6 Hz, 2H,
2-H), 3.87 (dd, 2J1'a,1'b ˆ 11.4 Hz, 3J1'a,1'' ˆ 7.3 Hz, 1H, 1'-Ha), 3.92
(dd, J1'b,1'a ˆ 11.4 Hz, J1'b,1'' ˆ 7.3 Hz, 1H, 1'-Hb); 13C NMR
(CDCl3, 125 MHz): d ˆ 11.6, 11.7, 14.0, 18.3, 18.4, 22.4, 24.8,
31.3, 34.0, 68.5 (C-1'), 174.1 (C-1).
2
3
Adv. Synth. Catal. 2003, 345, 1273 1286
asc.wiley-vch.de
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1281

Jˆrg Pietruszka et al.
FULL PAPERS
19f: 160 mg (1.80 mmol) ofalcohol 18d was acylated; after
chromatographic separation (petroleum ether/ethyl acetate,
9:1 to 3:1) the spectroscopically product 19f was isolated as a
colorless oil; yield: 0.35 g (1.65 mmol, 97%). IR (film): nÄ ˆ
midazole (2.15 g, 13.3 mmol) and stirred for 1 h until no further
evolution ofgas could be detected. A solution of N,O-
dimethylhydroxylamine (8.86 mmol) in CH2Cl2 (15 mL), syn-
thesized from the corresponding hydrochloride (0.864 g,
8.86 mmol) and Et3N (1.23 mL, 8.86 mmol), was added. After
18 h the reaction mixture was hydrolyzed with 1 M aqueous
HCl (20 mL). The organic layerwas separated and washedwith
1 M aqueous HCl (20 mL) and water (2 Â 20 mL). Drying over
MgSO4, filtration, and removal of organic solvent under
reduced pressure furnished the crude product (0.83 g). Flash
column chromatography (petroleum ether/ethyl acetate, 2:1)
afforded the product 19j as a colorless oil; yield: 0.76 g
ˆ
2954, 2926, 2857, 1734 (C O), 1496, 1455, 1375, 1163, 1106,
1069, 1030, 1004, 875, 736, 696 cmÀ1; MS (EI, 70 eV): m/z (%) ˆ
‡
‡
‡
212 [M ] (10), 127 [C8H15O ] (100), 69 [C5H9 ] (35); 1H NMR
(CDCl3, 500 MHz): d ˆ 0.30 (ddd, 3J ˆ 8.3 Hz, 3J ˆ 5.0 Hz,
2J3''a,3''b ˆ 4.9 Hz, 1H, 3''-Ha), 0.42 (ddd, 3J ˆ 8.4 Hz, 3J ˆ
2
5.0 Hz, J3''b,3''a ˆ 4.9 Hz, 1H, 3''-Hb), 0.68 (m, 1H, 1''-H), 0.82
(m, 1H, 2''-H), 0.88 (t, 3J8,7 ˆ 6.9 Hz, 3H, 8-H), 1.05 (d, 3JCH ,2''
ˆ
5.7 Hz, 3H, CH3), 1.25 1.33 (m, 8H, 4-H, 5-H, 6-H, 7-H),31.63
(m, 2H, 3-H), 2.31 (t, 3J2,3 ˆ 7.5 Hz, 2H, 2-H), 3.86 (dd, 2J1'a,1'b
ˆ
(3.78 mmol, 85%). IR (film): nÄ ˆ 2941, 2822, 1731 (C O),
ˆ
11.4 Hz, 3J1'a,1'' ˆ 7.2 Hz, 1H, 1'-Ha), 3.93 (dd, 2J1'b,1'a ˆ 11.4 Hz,
3J1'b,1'' ˆ 7.2 Hz, 1H, 1'-Hb); 13C NMR (CDCl3, 125 MHz): d ˆ
11.5, 11.6, 14.1, 18.3, 18.4, 22.6, 25.1, 28.9, 29.1, 31.7, 34.4, 68.5
(C-1'), 174.1 (C-1).
1651 (C O), 1427, 1371, 1236, 1178, 1111, 1030, 996, 900, 872,
ˆ
847, 765, 723, 606 cmÀ1; 1H NMR (CDCl3, 500 MHz): d ˆ 0.86
3
3
2
(ddd, J3a,2 ˆ 8.7 Hz, J3a,1 ˆ 6.0 Hz, J3a,3b ˆ 4.2 Hz, 1H, 3-Ha),
1.27 (ddd, 3J3b,1 ˆ 10.6 Hz, 3J3b,2 ˆ 5.1 Hz, 2J3b,3a ˆ 4.2 Hz, 1H, 3-
Hb), 1.74 (ddddd, 3J2,3a ˆ 8.7 Hz, 3J2,1'a ˆ 7.8 Hz, 3J2,1'b ˆ 6.3 Hz,
3J2,3b ˆ 5.1 Hz, 3J2,1 ˆ 4.1 Hz, 1H, 2'-H), 2.06 [s, 2H, C(O)CH3],
2.17 (m, 1H, 1-H), 3.21 (s, 3H, NCH3), 3.76 (s, 3H, NOCH3),
3.91 (dd, 2J1'a,1'b ˆ 11.6 Hz, 3J1'a,1 ˆ 7.8 Hz, 1H, 1'-Ha), 4.12 (dd,
2J1'b,1'a ˆ 11.6 Hz, 3J1'b,1 ˆ 6.3 Hz, 1H, 1'-Hb); 13C NMR (CDCl3,
125 MHz): d ˆ 12.6 (C-3), 16.1 (C-1), 20.2 (C-2), 22.9
[C(O)CH3], 32.5 (NCH3), 61.5 (NOCH3), 66.5 (C-1'), 179.9
[1C, C(O)CH3]; anal. calcd. for C9H15NO4 (201.22 g/mol): C
53.72, H 7.51, N 6.96; found: C 53.44, H 7.51, N 6.74.
Synthesis of ™Weinreb Amide∫ 18j
Sodium periodate (10.4 g, 48.6 mmol) was added to acetate 19a
(0.65 g, 3.42 mmol) in CCl4 (30 mL), CH3CN (30 mL), and
water (30 mL) and the mixture was stirred vigorously for
30 min. The suspension was cooled to 08C and treated with
ruthenium trichloride (40 mg, 0.17 mmol). After TLC indicat-
ed complete consumption ofstarting material (stirring over-
night), the reaction mixture was filtered through a pad of celite
and the filter thoroughly washed with ethyl acetate. After
acidification with 1 N aqueous HCl, the organic layer was
separated and the aqueous layer extracted with ethyl acetate;
the organic fractions were combined. The solvent was removed
under reduced pressure and the black residue was dissolved in
saturated aqueous sodium bicarbonate solution. Washing with
Et2O the organic layer was discarded was followed by
acidification with conc. aqueous HCl. Extraction with ethyl
acetate, drying over MgSO4, filtration, and removal of organic
solvent under reduced pressure furnished the slightly off-
colored product (0.52 g) in spectroscopically pure form. Flash
column chromatography (petroleum ether/ethyl acetate 1:1)
afforded the acid 19i as a colorless oil; yield: 0.48 g (3.03 mmol,
89%). Up-scaling ofthe procedure was possible (12.1 mmol 19a
gave 92% ofcrude acid 19i). IR (film): nÄ ˆ 2956 (br, COOH),
1.32 g (7.53 mmol) ofacetate 19j was dissolved in MeOH
(45 mL) and water (10 mL). Potassium carbonate (80 mg,
0.58 mmol) was added and the mixture stirred for 2 h at room
temperature. The reaction mixture was diluted with ethyl
acetate and saturated brine was added. Extraction with ethyl
acetate was followed by drying over MgSO4, filtration, and
removal oforganic solvent under reduced pressure. Flash
column chromatography (ethyl acetate/petroleum ether,
60:40 to 100:0) gave the product 18j as a colorless oil; yield:
0.93 g (5.86 mmol, 90%). The whole procedure was repeated
with enantiomerically enriched (1'R,2'R)- and (1'S,2'S)-19a.
18j: IR (film): nÄ ˆ 3424 (OH), 3086, 3005, 2939, 2874, 1653
ˆ
(C O), 1428, 1389, 1296, 1241, 1179, 1151, 1108, 1036, 987, 956,
892, 762, 718 cmÀ1; MS (EI, 70 eV): m/z (%) ˆ 160 (45) [M ‡
‡
‡
‡
H ], 159 (10) [M ], 142 (100) [M OH2 ], 99 (85) [M
‡
‡
N(CH3)OCH3 ], 55 (25) [C3H3O ]; HRMS (EI, 70 eV); calcd.
1
for C7H12NO3: 159.0895; found: 159.0895; H NMR (CDCl3,
500 MHz): d ˆ 0.85 (ddd, 3J3a,2 ˆ 8.4 Hz, 3J3a,1 ˆ 6.1 Hz, 2J3a,3b
ˆ
ˆ
ˆ
2538, 1755 (C O), 1689 (C O), 1467, 1433, 1369, 1323, 1288,
1222, 1167, 1167, 1087, 1034, 1029, 976, 881, 832, 669, 636,
3
3
4.0 Hz, 1H, 3-Ha), 1.23 (ddd, J3b,1 ˆ 8.8 Hz, J3b,3 ˆ 5.0 Hz,
2J3b,3a ˆ 4.0 Hz, 1H, 3-Hb), 1.70 (ddddd, J2,3b ˆ 8.8 Hz, J2,1'a
ˆ
3
3
608 cmÀ1; MS (CI, CH4): m/z (%) ˆ 159 [M ] (30), 141 [M
‡
3
3
3
7.1 Hz, J2,3a ˆ 6.1 Hz, J2,1'b ˆ 5.9 Hz, J2,1 ˆ 4.1 Hz, 1H, 2-H),
1.99 (t, 3JOH,1' ˆ 5.6 Hz, 1H, OH), 2.12 (bs, 1H, 1-H), 3.21 (s, 3H,
‡
‡
OH2 ] (90), 99 [M C2H4O2 ] (100); HRMS (CI, CH4); calcd.
for C7H11O4: 159.0657; found: 159.0657; 1H NMR (CDCl3,
2
3
3
NCH3), 3.48 (ddd, J1'a,1'b ˆ 11.4 Hz, J
ˆ 7.1 Hz, J1',OH
ˆ
1'a,2
500 MHz): d ˆ 0.98 (ddd, 3J3a,1 ˆ 8.4 Hz, 3J3a,2 ˆ 6.4 Hz, 2J3a,3b
ˆ
2
3
5.6 Hz, 1H, 1'-Ha), 3.68 (ddd, J1'b,1'a ˆ 11.4 Hz, J1'b,1 ˆ 5.9 Hz,
3J1'b,OH ˆ 5.6 Hz, 1H, 1'-Hb), 3.77 (s, 3H, NOCH3); 13C NMR
(CDCl3, 125 MHz): d ˆ 12.8 (C-3), 15.9 (C-1), 24.3 (C-2), 32.9
(NCH3), 62.0 (NOCH3), 65.2 (C-1'), 174.0 (C-1); anal. calcd. for
C7H12NO3 (159.18 g/mol): C 52.82, H 8.23, N 8.80; found: C
52.76, H 8.38, N 8.67.
3
3
4.6 Hz, 1H, 3-Ha) 1.31 (ddd, J3b,1 ˆ 8.9 Hz, J3b,2 ˆ 4.9 Hz,
3J3b,3a ˆ 4.6 Hz 1H, 3-Hb), 1.62 (ddd, J1,3a ˆ 8.4 Hz, J1,3b
ˆ
3
3
3
3
4.9 Hz, J1,2 ˆ 4.0 Hz, 1H, 1-H), 1.83 (ddddd, J2,3b ˆ 8.9 Hz,
3J2,1'a ˆ 7.5 Hz, 3J2,3a ˆ 6.4 Hz, 3J2,1'b ˆ 6.2 Hz, 3J2,1 ˆ 4.0 Hz, 1 H,
2-H), 2.07 [s, 3 H, C(O)CH3], 3.88 (dd, 2J1'a,1'b ˆ 11.8 Hz, 3J1'a,2
ˆ
2
3
7.5 Hz, 1H, 1'-Ha), 4.09 (dd, J1'b,1'a ˆ 11.8 Hz, J1'b,2 ˆ 6.2 Hz,
1H, 1'-Hb), 11.1 (bs, 1H, COOH); 13C NMR (CDCl3,
125 MHz): d ˆ 13.8 (C-3), 18.6 (C-1), 20.9 [C(O)CH3], 21.4
(C-2), 65.7 (C-1'), 171.0 [C(O)CH3], 179.5 (COOH); anal.
calcd. for C7H10O4 (158.15 g/mol): C 53.16, H 6.37; found: C
52.17, H 6.40.
Synthesis of Alkenylboronic Esters 22
Under an atmosphere ofdry nitrogen, acid 19i (0.70 g,
4.43 mmol) in CH2Cl2 (40 mL) was treated with carbonyldii-
Alkenylboronic esters 22 were prepared from alkynes 21
63]
according to known procedures.[59
1282
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2003, 345, 1273 1286

Kinetic Enzymatic Resolution ofCyclopropane Derivatives
FULL PAPERS
22c: Colorless oil, purified by Kugelrohr distillation (90
1008C/0.1 Torr). IR (film): nÄ ˆ 3059, 2928, 1494, 1446, 1387,
1336, 1226, 1181, 1076, 1034, 967, 758, 700 cmÀ1; MS (FAB): m/z
H), 1.91 (quint, 3J ˆ 5.5 Hz, 2H, 5-H), 3.94 (t, 3J ˆ 5.5 Hz, 4H, 4-
H, 6-H); 13C NMR (CDCl3, 125 MHz): d ˆ 6.9 (C-3'), 27.5 (C-
2'), 28.3 [C(CH3)3], 29.4 (C-5), 29.8 [C(CH3)3], 61.6 (C-4/C-6),
C-1' not detectable.
‡
‡
(%) ˆ 224 (27) [M ], 209 (64) [M CH3 ], 153 (100), 138 (49),
3
125 (68); 1H NMR (CDCl3, 500 MHz): d ˆ 1.08 (t, J6',7'
ˆ
23f: Colorless oil obtained after Kugelrohr distillation
(608C/0.35 Torr). IR (film): nÄ ˆ 2995, 2943, 2867, 1421, 1360,
1313, 1269, 1220, 1153, 980, 856, 716 cmÀ1; MS (EI, 70 eV): m/z
6.8 Hz, 3H, 7'-H), 1.47 [s, 12H, C(CH3)2], 1.45 1.51 (m, 4H,
5'-H/6'-H), 1.61 (m, 2H, 4'-H), 2.34 (m, 2H, 3'-H), 5.63 (dt,
4
3
‡
3J1',2' ˆ 17.9 Hz, J1',3' ˆ 1.5 Hz, 1H, 1'-H), 6.84 (dt, J1',2'
ˆ
(%) ˆ 224 (6), [M ], 70.1 (100); HRMS (EI, 70 eV): calcd. for
17.9 Hz, J2',3' ˆ 6.4 Hz, 1H, 2'-H); 13C NMR (CDCl3,
125 MHz): d ˆ 14.4 (C-7'), 22.9 (C-6'), 25.1 (C(CH3)2), 28.3
(C-4'), 31.8 (C-5'), 36.1 (C-3'), 83.3 (C-4/C-5), 119.0 (C-1'),
155.2 (C-2'); anal. calcd. for C13H25BO2 (224.15 g/mol): C 69.66,
H 11.24; found: C 69.56, H 11.14.
C13H25BO2: 224.1948; found: 224.1947; 1H NMR (CDCl3,
500 MHz): d ˆÀ 0.03 (mc, 1H, 1'-H), 0.73 0.77 (m, 2H, 3'-
H), 1.06 [s, 9H, C(CH3)3], 1.16 (mc, 1H, 2'-H), 1.46 [s, 12H,
C(CH3)2]; 13C NMR (CDCl3, 125 MHz): d ˆÀ 4.6 (br, C-1'), 7.2
(C-3'), 24.5 [C(CH3)2], 28.2 [C(CH3)3], 30.1 [C(CH3)3], 82.7 (C-
4/C-5).
3
22e: Colorless oil. IR (film): nÄ ˆ 2956, 1631, 1311, 1235, 1171,
‡
1103, 1001, 937 cmÀ1; MS (EI, 70 eV): m/z (%) ˆ 168 (72) [M ],
‡
1
153 (100) [M CH3 ], 67 (68), 41 (75); H NMR (CDCl3,
3
500 MHz): d ˆ 1.01 [s, 9 H, C(CH3)3], 1.97 (quint, J5,4/6
ˆ
3
Synthesis of Cyclopropanols 24
5.5 Hz, 2H, 5-H), 4.03 (t, J5,4/6 ˆ 5.5 Hz, 4H, 4-H, 6-H), 5.24
3
3
(d, J1',2' ˆ 18.1, 1H, 1'-H), 6.47 (d, J1',2' ˆ 18.1, 1H, 2'-H);
13C NMR (CDCl3, 125 MHz): d ˆ 27.4 (C-5), 28.9 [C(CH3)3],
34.6 [C(CH3)3], 61.7 (C-4/C-6), ꢀ119 (br, C-1'), 161.6 (C-2');
anal. calcd. for C9H17BO2 (168.04): C 64.33, H 10.20; found: C
64.03, H 10.18.
Cyclopropanols 24 were prepared from cyclopropylboronic
esters 23 according to known procedures.[62,65,70]
24b: Colorless oil with low vapor pressure (impurities:
solvents). IR (film): nÄ ˆ 3307, 2958, 1467, 1364, 1205, 1150,
‡
1042, 933, 806 cmÀ1; MS (CI, CH4): m/z (%) ˆ 114 (20) [M ], 97
22f: Colorless solid, mp 358C. IR (film): nÄ ˆ 2960, 2940, 2845,
(100), 81 (13), 70 (39), 57 (82); HRMS (auto-CI): calcd. For
C7H14O: 114.1045; found: 114.1046; 1H NMR (CDCl3,
1625, 1450, 1340, 1250, 1130, 950, 860, 630 cmÀ1; MS (CI, CH4):
‡
‡
m/z (%) ˆ 211 (63) [M ‡ 1 ], 195 (27) [M CH3 ], 153 (65), 101
3
3
2
500 MHz): d ˆ 0.48 (ddd, J1,3-cis ˆ 6.8 Hz, J2,3-cis ˆ 6.8 Hz, J3-
1
(100), 59 (83); H NMR (CDCl3, 500 MHz): d ˆ 1.02 [s, 9H,
3
2
ˆ 5.8 Hz, 1H, 3-Hcis), 0.59 (ddd, J2,3-trans ˆ 10.5 Hz, J3-
trans,3-cis
C(CH3)3], 1.27 [s, 12H, C(CH3)2], 5.35 (d, 3J1',2' ˆ 18.3 Hz, 1H,
3
ˆ 5.8 Hz, J1,3-trans ˆ 2.9 Hz, 1H, 3-Htrans), 0.82 [s, 9 H,
trans,3-cis
1'-H), 6.64 (d, J1',2× ˆ 18.3 Hz, 1H, 2'-H); 13C NMR (CDCl3,
3
3
3
3
C(CH3)3], 0.87 (ddd, J2,3-trans ˆ 10.5 Hz, J2,3-cis ˆ 6.8 Hz, J1,2
ˆ
ˆ
125 MHz): d ˆ 24.8 [C(CH3)2], 28.8 [C(CH3)3], 35.0 [C(CH3)3],
83.0 (C-4/C-5), 129.7 (C-1'), 164.4 (C-2'); anal. calcd. for
C12H23BO2 (210.12 g/mol): C 68.59, H 11.03; found: C 68.68, H
10.97.
2.9 Hz, 1H, 2-H), ꢀ1.78 (br, 1 H, OH), 3.36 (ddd, J1,3-cis
3
3
3
6.8 Hz, J1,3-trans ˆ 2.9 Hz, J1,2 ˆ 2.9 Hz, 1H, 1-H); 13C NMR
(CDCl3, 125 MHz): d ˆ 11.0 (C-3), 28.5 [C(CH3)3], 30.1
[C(CH3)3], 32.5 (C-2), 49.4 (C-1).
Synthesis of Cyclopropylboronic Esters 23
Acetylation of Cyclopropanols 24
Cyclopropylboronic esters 23 were prepared from alkenylbor-
onic esters 22 according to the known procedure by a Pd(II)-
catalyzed decomposition ofdiazomethane. [62,65]
The same procedure was followed as described for cyclopropyl
acetates 19 (vide supra).
25a: Obtained as colorless oil from 0.94 g (7.3 mmol) 24a;
yield: 0.94 g (5.6 mmol, 76%). Enantiomerically enriched
acetates were obtained following the same sequence, but
starting from alkenylboronic ester 26 and ent-26, respectively.
23c: Colorless oil obtained after Kugelrohr distillation
(100 1108C/1.0 Torr). IR (film): nÄ ˆ 2993, 2923, 2856, 1476,
1378, 1313, 1221, 1154, 978, 913, 853 cmÀ1; MS (EI, 70 eV): m/z
‡
ˆ
(%) ˆ 238 (15) [M ], 181 (34), 110 (29), 84 (100); HRMS (EI,
IR (film): nÄ ˆ 3080, 3005, 2922, 2855, 1742 (C O), 1457, 1369,
70 eV): calcd. for C14H27BO2: 238.2104; found: 238.2108;
1231, 1140, 1051, 980, 884, 727 cmÀ1; MS (CI, CH4): m/z (%) ˆ
3
‡
1H NMR (CDCl3, 500 MHz): d ˆÀ 0.43 (ddd, J1',3'-cis
ˆ
171 (22) [M ‡ 1 ], 143 (100), 82 (58), 61 (38), 43 (65); HRMS
3
3
9.4 Hz, J1',3'-trans ˆ 6.0, J1',2' ˆ 5.8 Hz, 1H, 1'-H), 0.38 (ddd,
(auto-CI); calcd. for C10H19O2: 171.1385; found: 171.1384;
1H NMR (CDCl3, 500 MHz): d ˆ 0.50 (m, 1H, 3-Ha), 0.78 (m,
1H, 3-Hb), 0.89 (t, 3J4',5' ˆ 7.0 Hz, 3H, 5'-H), 1.00 (m, 1H, 2-H),
1.01 1.69 (m, 8H, 1'-H, 2'-H, 3'-H, 4'-H), 2.01 (s, 3H, CH3CO),
3.81 (m, 1H, 1-H); 13C NMR (CDCl3, 125 MHz): d ˆ 12.4 (C-
5'), 18.8 (C-3), 21.4 (CH3CO), 22.7 (C-2), 23.0 (C-4'), 28.7 (C-
3J1',3'-cis ˆ 9.4 Hz, J2',3'-cis ˆ 5.2 Hz, J3'-cis,3'-trans ˆ 3.3 Hz, 1H, 3'-
Hcis), 0.66 (ddd, 3J2',3'-trans ˆ 7.8 Hz, 3J1',3'-trans ˆ 6.0 Hz, 2J3'-cis,3'-trans
ˆ 3.3 Hz, 1H, 3'-Htrans), 0.86 0.94 (m, 1H, 2'-H), 0.88 (t,
3J4™,5∫ ˆ 6.8 Hz, 3H, 5∫-H), 1.07 1.12 (m, 1H, 1''-Ha), 1.14 [s, 12
H, C(CH3)2], 1.19 1.25 (m, 5H, 1''-Hb, 3''-H and 4∫-H), 1.28
1.34 (m, 2H, 2''-H); 13C NMR (CDCl3, 125 MHz): d ˆ 11.4 (C-
3'), 14.1 (C-5∫), 18.3 (C-2'), 22.7 (C-4∫), 24.7 [C(CH3)2], 29.3 (C-
2''), 31.7 (C-3''), 35.2 (C-1''), 82.7 (C-4/C-5), C-1' not detectable.
23e: Colorless oil obtained after Kugelrohr distillation
(608C/1.0 Torr). IR (film): nÄ ˆ 2972, 2896, 2865, 1486, 1412,
1331, 1276, 1229, 1100, 853, 712 cmÀ1; MS (EI, 70 eV): m/z
3
2
ˆ
3'), 31.7, 31.9 (C-1', C-2'), 54.9 (C-1), 172.2 (C O).
(1S)-25a: [a]2D0: ‡ 23.0 (c 0.9, CHCl3); 73% ee.
(1R)-25a: [a]20: À 23.9 (c 1.2, CHCl3); 75% ee).
25b: ObtaineDd as colorless oil from 0.18 g (1.6 mmol) 24b;
yield: 0.22 g (1.4 mmol, 88%). IR (film): nÄ ˆ 2962, 2869, 1743,
1472, 1369, 1242, 1144, 1043 cmÀ1; MS (EI, 70 eV): m/z (%) ˆ
‡
‡
‡
‡
(%) ˆ 182 (12), [M ], 167 (17) [M CH3 ], 70 (100); HRMS
(EI, 70 eV): calcd. for C10H19BO2: 182.1478; found: 182.1479;
1H-NMR (CDCl3, 500 MHz): d ˆÀ 0.42 (mc, 1H, 1'-H), 0.39
0.42 (m, 2H, 3'-H), 0.81 [s, 9H, C(CH3)3], 0.80 0.84 (m, 1H, 2'-
157 (7) [M ‡ 1 ], 156 (2) [M ], 143 (100), 70 (47), 57 (37), 43
‡
[CH3CO ] (100); HRMS (auto-CI); calcd. for C9H16O2:
1
156.1150; found: 156.1150; H NMR (CDCl3, 500 MHz): d ˆ
0.68 0.71 (m, 2H, 3-Hcis, 3-Htrans), 0.87 [s, 9 H, C(CH3)3], 0.94
Adv. Synth. Catal. 2003, 345, 1273 1286
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¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Jˆrg Pietruszka et al.
FULL PAPERS
0.99 (m, 1H, 2-H), 2.01 (s, 3H, CH3), 3.97 (mc, 1H, 1-H); 13C
NMR (CDCl3, 125 MHz): d ˆ 8.5 (C-3), 21.0 (CH3CO), 28.3
Enzymatic Hydrolysis of Cyclopropyl Esters
(Conditions: See Schemes 4 ‡ 10)
ˆ
[C(CH3)3], 28.9 [C(CH3)3], 29.8 (C-2), 51.7 (C-1), 171.8 (C O).
Approx. 5 mg ofthe required ester, 5 mg ofenzyme, 0.5 mL
phosphate buffer (pH 7) and 0.5 mL of the appropriate solvent
were stirred at the given temperature in a screw-top vial. When
TLC indicated conversion to the corresponding alcohol,
aliquots were taken and the enantiomeric excess ofproduct
and starting material were determined each time either by
HPLC or GLC (see Supporting Information).
25c: Obtained as colorless oil from 0.48 g (3.5 mmol) 24c;
yield: 0.43 g (2.4 mmol, 68%). IR (film): nÄ ˆ 3080, 3029, 1750,
1605, 1500, 1369, 1234, 1140, 1059, 751, 698 cmÀ1; MS (EI,
‡
‡
70 eV): m/z (%) ˆ 176 (2.5) [M ], 134 (21) [(M CH3CO) ], 43
(100) [CH3CO ]; 1H NMR (CDCl3, 500 MHz): d ˆ 1.20 (ddd,
‡
3J1,3-cis ˆ 6.8 Hz, 3J2,3-cis ˆ 6.8 Hz, 3J3-trans,3-cis ˆ 6.8 Hz, 1H, 3-Hcis),
3
2
3
1.31 (ddd, J2,3-trans ˆ 10.5 Hz, J3-trans,3-cis ˆ 6.6 Hz, J1,3-trans
ˆ
ˆ
3
3.6 Hz, 1H, 3-Htrans), 2.07 (s, 3H, CH3), 2.22 (ddd, J2,3-trans
3
3
10.5 Hz, J2,3-cis ˆ 6.8 Hz, J1,2 ˆ 2.7 Hz, 1H, 2-H), 4.21 (ddd,
3J1,3-cis ˆ 6.8 Hz, J1,3-trans ˆ 3.6 Hz, J1,2 ˆ 2.7 Hz, 1H, 1-H),
7.11 7.13 (m, 2H, arom. H), 7.17 7.20 (m, 1H, arom. H),
7.25 7.28 (m, 2H, arom. H); 13C NMR (CDCl3, 125 MHz): d ˆ
14.6 (C-3), 20.9 (CH3CO), 22.9 (C-2), 55.9 (C-1), 126.3, 126.6,
3
3
Kinetic Enzymatic Resolution Preparative Scale
(1S,2S)-18a: 4.85 g (25.5 mmol) ofenantiomerically enriched
ester (1S,2S)-19a (87% ee) in CH2Cl2 (30 mL) were added to
1.70 g CAL-B-I in 40 mL phosphate buffer. The mixture was
refluxed, while the pH value was kept at 7 by regularly adding 1
M aqueous NaOH. The reaction was controlled by HPLC. At
approx. 85% conversion the (1R,2R)-18a alcohol could not
be detected the reaction was stopped by separation ofthe
organic layer. The aqueous layer was extracted with CH2Cl2,
the combined organic fractions dried over MgSO4, filtered, and
the solvent removed under reduced pressure. The colorless oil
was purified by flash column chromatography (petroleum
ether/ethyl acetate, 9:1 to 3:1); yield of(1 S,2S)-18a: 2.90 g
(19.6 mmol, 77%, ee>98%); [a]2D0: ‡ 86 (c 1.0, EtOH).
(1R,2R)-19a: Following the same procedure, (1S,2S)-19a
(81% ee) was hydrolyzed in the presence of CAL-B-I.
Predominantly, the minor enantiomer was converted to the
corresponding alcohol (1S,2S)-18a and the major ester
(1R,2R)-19a remained unchanged; yield: 74% (ee 96%); [a]2D0:
À 86 (c 1.0, EtOH).
ˆ
128.4 (arom. C), 139.6 (i-C), 171.5 (C O); anal. calcd. for
C11H12O2 (176.21 g/mol): C 74.98, H 6.86; found: C 74.74, H
6.77.
Synthesis of cis-Acetate 27
CH2I2 (3.30 mL, 40.0 mmol) was dissolved in CH2Cl2 (10 mL)
and Et2Zn was added (20 mL ofa 1 M solution in hexane) at
08C. Vinyl acetate 26 (1.60 g, 10.2 mmol) was slowly added and
the mixture was stirred overnight at room temperature. The
mixture was hydrolyzed with aqueous saturated NH4Cl
solution. The organic layer was separated and the aqueous
layer extracted with CH2Cl2. The combined organic fractions
were dried over MgSO4, filtered and the solvent removed
under reduced pressure. Purification of the crude product was
achieved by flash-column chromatography (pentane/Et2O,
100:0 to 20:1) furnishing cyclopropane 27 as a colorless oil;
yield: 1.05 g (6.18 mmol, 61%). IR (film): nÄ ˆ 3080, 3005, 2922,
(1S,2S)-18j: 0.46 g (2.29 mmol) ofenantiomerically en-
riched ester (1S,2S)-19j (87% ee) in dioxane (15 mL) were
added to 0.13 g PCL-I in 15 mL phosphate buffer. The mixture
was heated to 408C, while the pH value was kept at 7 by
regularly adding 1 M aqueous NaOH. The reaction was
controlled by GLC. After 14 h the (1R,2R)-18j alcohol could
not be detected the reaction was stopped by adding ethyl
acetate and separation ofthe organic layer. The aqueous layer
was concentrated to dryness, dissolved in ethyl acetate and
briefly heated to reflux. The combined organic fractions were
dried over MgSO4, filtered, and the solvent removed under
reduced pressure. The colorless oil was purified by flash
column chromatography (petroleum ether/ethyl acetate, 1:1
to 0:100); yield of(1 S,2S)-18j: 0.29 g (1.79 mmol, 78%,
ee>98%); [a]20: ‡ 36 (c 1.0, CHCl3).
ˆ
2855, 1742 (C O), 1457, 1369, 1231, 1140, 1051, 980, 884,
‡
727 cmÀ1; MS (auto-CI, 70 eV): m/z (%) ˆ 170 ( < 1) [M ], 128
‡
‡
(12) [(M CH3CO) ], 100 (25), 43 (100) [CH3CO ]; HRMS
(auto-CI); calcd. for C10H19O2: 171.1385; found: 171.1384;
1H NMR (CDCl3, 500 MHz): d ˆ 0.34 (m, 1H, 3-Ha), 0.84 0.93
(m, 5H, 3-Hb, 2-H, 5'-H), 1.25 1.45 (m, 8H, 1'-H, 2'-H, 3'-H, 4'-
H), 2.01 (s, 3H, CH3CO), 3.81 (m, 1H, 1-H); 13C NMR (CDCl3,
125 MHz): d ˆ 10.7 (C-3), 14.1 (C-5'), 16.5 (C-2), 20.9
(CH3CO), 22.6 (C-4'), 27.2 (C-1'), 29.1, 31.7 (C-2', C-3'), 52.7
ˆ
(C-1), 172.0 (C O); anal. calcd. for C10H18O2 (170.25 g/mol): C
70.55, C 70.55; found: C 70.06, H 10.65.
(1R,2R)-19Dj: Following the same procedure, (1S,2S)-19j
(84% ee) was hydrolyzed in the presence of PCL-I. Predom-
inantly, the minor enantiomer was converted to the corre-
sponding alcohol (1S,2S)-18j and the major ester (1R,2R)-19j
remained unchanged; yield: 82% (ee 97%); [a]2D0: À 34 (c 1.0,
CHCl3).
Enzymatic Acylation with Vinyl Esters (Conditions:
See Schemes 3 ‡ 9)
Approx. 10 40 mg ofthe required alcohol, 10 40 mg of
enzyme and 1 4 mL ofthe appropriate solvent were stirred at
the given temperature in a screw-top vial. 0.5 0.75 equiv. (for
primary alcohols) or 5 equivs. (for secondary alcohols) of the
vinyl ester were added along with some 4 ä molecular sieves.
When TLC indicated conversion ofthe alcohol, aliquots were
taken and the enantiomeric excess ofproduct and starting
material were determined each time either by HPLC or GLC
(see Supporting Information).
(1R)-24a/(1S)-25a: 1.03 g (6.00 mmol) ofester rac-24a in
THF (25 mL) was added to 0.53 g CAL-B-I in 25 mL phos-
phate buffer. The mixture was heated to 608C, while pH value
was kept at 7 by regularly adding 1 M aqueous NaOH. The
reaction was controlled by GLC. At approx. 48% conversion
the reaction was stopped by decantation ofthe solvents from
the enzyme and separation ofphases. The residue was washed
with Et2O and the aqueous layer extracted with Et2O. The
combined organic fractions were dried over MgSO4, filtered,
1284
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Kinetic Enzymatic Resolution ofCyclopropane Derivatives
FULL PAPERS
and the solvent removed under reduced pressure. The colorless
oil was purified by flash column chromatography (pentane/
Et2O, 9:1) to afford cyclopropanol (1R)-24a (yield 0.34 g,
2.6 mmol, 44%, ee 87%) and acetate (1S)-25a (yield: 0.43 g,
2.5 mmol, 42%, ee 87%).
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(1S)-25a: [a]2D0: ‡ 27.7 (c 1.2, CHCl3), 87% ee.
(1R)-24a: [a]2D0: À 28.3 (c 1.0, CHCl3), 87% ee.
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Supporting Information
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Acknowledgements
We gratefully acknowledge the generous support by the
Deutsche Forschungsgemeinschaft, the Fonds der Chemischen
Industrie, and the Otto-Rˆhm-Ged‰chtnisstiftung. Donations
of enzymes by Roche Diagnostics GmbH, Amano Pharma-
ceuticals Co., Ltd., and Meito Sangyo Co., Ltd. were greatly
appreciated. We are indebted to Prof. Dr. U. Bornscheuer for
valuable advice, Priv.-Doz. Dr. P. Fischer and his group for
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1286
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2003, 345, 1273 1286