Enantioselective cyclopropanation of carboxylic esters with alkyl magnesium bromides in the presence of titanium(IV) (4R,5R)-TADDOLates

Article abstract of DOI:10.1016/j.tet.2013.05.118

The reaction of isopropyl 4-chlorobutyrate with 3 equiv of n-BuMgBr in the presence of 1 equiv of titanium(IV) (4R,5R)-TADDOLate in diethyl ether led to the formation of (1S,2S)-(3-chloropropyl)-2-ethylcyclopropanol in 55-70% yield and 55-65% ee. The reaction was performed in the presence of 20 mol % of the catalyst without significant loss in yield and enantioselectivity when solutions of the carboxylic ester and the Grignard reagent were added simultaneously at an equal rate to a refluxing solution of the titanium catalyst in ether. The cyclopropanation of isopropyl propionate under the same conditions gave (1S,2S)-1-ethyl-2-propylcyclopropanol in 50% yield and 65% ee. Its absolute configuration was determined by chemical correlation through acid-catalyzed isomerization to enantiomerically enriched (R)-(-)-4-methyl-3-heptanone, known as a minor component of the trail pheromone of ant Aphaenogaster albisetosus and enantiomer of the alarm pheromone of leaf-cutting ants Atta texana.

Full text of DOI:10.1016/j.tet.2013.05.118

Accepted Manuscript
Enantioselective Cyclopropanation of Carboxylic Esters with Alkyl Magnesium
Bromides in the Presence of Titanium(IV) (4R,5R)-TADDOLates
Yulia A. Konik, Dzmitry G. Kananovich, Oleg G. Kulinkovich
PII:
S0040-4020(13)00886-7
10.1016/j.tet.2013.05.118
TET 24456
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 February 2013
Revised Date: 17 May 2013
Accepted Date: 28 May 2013
Please cite this article as: Konik YA, Kananovich DG, Kulinkovich OG, Enantioselective
Cyclopropanation of Carboxylic Esters with Alkyl Magnesium Bromides in the Presence of Titanium(IV)
(4R,5R)-TADDOLates, Tetrahedron (2013), doi: 10.1016/j.tet.2013.05.118.
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Graphical Abstract
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Enantioselective Cyclopropanation of Carboxylic Esters with Alkyl Magnesium Bromides in the
Presence of Titanium(IV) (4R,5R)-TADDOLates
Yulia A. Konika, Dzmitry G. Kananovich*a,b and Oleg G. Kulinkovich*b
aDepartment of Organic Chemistry, Belarusian State University, Nezalezhnasci Av. 4, 220030 Minsk, Belarus
bDepartment of Organic Chemistry, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia
*Corresponding authors. e-mail addresses: kananovich82@tut.by; o.kulinkovich@gmail.com
Abstract: The reaction of isopropyl 4-chlorobutyrate with 3 equiv. of n-BuMgBr in the presence of
1 equiv. of titanium(IV) (4R,5R)-TADDOLate in diethyl ether led to the formation of (1S,2S)-(3-
chloropropyl)-2-ethylcyclopropanol in 55-70% yield and 55-65% ee. The reaction was performed in the
presence of 20 mol% of the catalyst without significant loss in yield and enantioselectivity when solutions
of the carboxylic ester and the Grignard reagent were added simultaneously at an equal rate to a refluxing
solution of the titanium catalyst in ether. The cyclopropanation of isopropyl propionate under the same
conditions gave (1S,2S)-1-ethyl-2-propylcyclopropanol in 50% yield and 65% ee. Its absolute
configuration was determined by chemical correlation through acid-catalyzed isomerization to
enantiomerically enriched (R)-(−)-4-methyl-3-heptanone, known as a minor component of the trail
pheromone of ant Aphaenogaster albisetosus and enantiomer of the alarm pheromone of leaf-cutting ants
Atta texana.
Keywords: Enantioselectivе cyclopropanation, esters, chiral cyclopropanols, titanacyclopropanes,
titanium TADDOLates.
1. Introduction
The reactions of carboxylic acid derivatives with alkoxytitanacyclopropane reagents generated in
situ from titanium(IV) alkoxides and alkylmagnesium halides that contain hydrogen atom in the β-position
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to the metal atom, underlie convenient and effective approaches to the preparation of substituted
cyclopropanols.1 These compounds may have their own practical value,2 as well as be used for the
synthesis of substances of other classes via cyclopropane ring cleavage reactions.1,3 Although addition of
organotitanium reagents to carbonyl compounds often proceeds with a high diastereocontrol,4,5 at least to
our knowledge, there are only two reported examples of asymmetric syntheses of cyclopropanols by
reaction of a carboxylic ester with oxytitanacyclopropane reagents bearing chiral ligands at titanium.6,7
The best enantioselectivity achieved so far in the reactions of cyclopropanation of carboxylic esters
had been mentioned in a paper published about 20 years ago.6 Ethyl acetate was cyclopropanated with 2-
phenylethylmagnesium bromide in the presence of 0.3-1 equiv. of chiral spiro-titanate 1 bearing 3,5-
bis(trifluoromethyl)phenyl substituents to afford (1S,2R)-1-methyl-2-phenylcyclopropanol (2) in 65-72%
yield and 70-78% enantiomeric excess (Scheme 1). The use of the spiro-titanate 1 analogs, particularly
bearing l-naphtyl, 6-methoxy-2-naphthyl or 3,5-dimethylphenyl substituents, also favored the formation
of (1S,2R)-2 enantiomer but enantioselectivity was lower than it was in the case of titanate 1.6 At the same
time the cyclopropanation of ethyl 2-chloropropionate with n-BuMgBr in the presence of Ti(TADDOL)2
gave the corresponding cyclopropanol in 52% enantiomeric excess but in very low yield (6%).7 Variations
in the reaction conditions (higher or lower temperatures, addition of molecular sieves) as well as the use of
other chiral ligands (BINOL, BINOL/TADDOL, (S)-1,3-butanediol) did not improve the cyclopropanation
yield and enantioselectivity. Our early attempts to perform enantioselective cyclopropanation in the
presence of Ti(TADDOL)2 were also unfruitful.8
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To explain the stereochemical outcome of the titanium-catalyzed cyclopropanation of ethyl acetate
with 2-phenylethylmagnesium bromide, a mechanistic model was proposed assuming the formation of the
key oxytitanacyclopropane reagent (2S)-3, in which the phenyl substituent in three-membered
metallacycle is maximally distant from the nearest pseudoaxial Ar group (Scheme 1).6 The
stereochemistry of the cyclopropanation product (1S,2R)-2 is in accordance with the formation of the
titanium intermediate (2S)-3, if the latter adds to the carbonyl group with retention of the configuration at
the metallated carbon center.6,9
Scheme 1.
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Evidence that higher coordinated titanium ate-complexes could play an important role in the
process of the formation and in subsequent transformations of titanacyclopropane reagents has been
recently obtained.10 Particularly, the data on the diastereoselectivity of the formation of 1,2-disubstituted
cyclopropanols were in a good qualitative accordance with the level of steric repulsion between
substituents at titanium atom.5 These data incited us to start a more systematic study of the
cyclopropanation of carboxylic esters in the presence of chiral titanium alkoxides with hope to elucidate
additional factors that may be associated with improvement of enantioselectivity of this reaction as well as
to elaborate conditions for more effective use of less expensive than spiro-titanate 1 chiral catalysts on
this basis.
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2. Results and discussion.
The cyclopropanation of isopropyl and methyl 4-chlorobutyrates 4а,b with n-BuMgBr in the
presence of titanium TADDOLates 5 and 6, easily available from commercial (4R,5R)-TADDOL (7) and
titanium(IV) isopropoxide (8),11-13 was selected as a model for this study (Scheme 2). The esters 4а, 4b
were used as substrates because of their comparably low volatility, as well as due to the possibility of
reliable identification of the main constituents in the reaction mixtures by characteristic and non-
1
1
overlapping signals in their H NMR spectra (see experimental section). In addition, H NMR spectra of
the diastereomeric MTPA esters14 of cyclopropanol cis-9 showed noticeable difference in the chemical
shifts of the cyclopropane protons (δ 0.36 and 0.39 ppm) which was acceptable for their reliable
integration and thereby determination of enantiomeric excess.
Scheme 2
The reaction of ester 4b with 2.2 equiv. of n-BuMgBr in presence of equimoleqular amount of
spiro-titanate 6 in Et2O at room temperature resulted in the formation of tertiary alcohol 10 as a main
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product, whereas under the same conditions titanium(IV) TADDOLate 5 afforded cis-cyclopropanol cis-9
in 70% yield and with 55% enantioselectivity (Table 1, entries 1,2). The same reaction in the presence of
catalytic amounts (10 mol. %) of the chiral catalyst 5 also resulted mainly tertiary alcohol 10 and the target
cyclopropanol cis-9 was formed in a low yield and with a low enantioselectivity (entry 3), although, as
expected, the reaction in the presence of catalytic amounts of titanium(IV) isopropoxide (8) gave racemic
cyclopropanol cis-9 smoothly (entry 4). Slower addition of n-BuMgBr to the mixture of ester 4b and chiral
titanium(IV) alkoxide 5 led to an increase in enantioselectivity (entry 5) and that was further improved
when the reaction was carried out in refluxing ether (entry 6). Thus, the presence of an excess amount of
ester 4b in the reaction mixture had a negative effect on the enantioselectivity and simultaneous addition
of ester 4b and n-BuMgBr to the solution of titanium(IV) TADDOLate 5 led to the two-fold increase in
enantioselectivity (entries 3 and 7). The use of such an order of reagent mixing for the cyclopropanation of
methyl and isopropyl 4-chlorobutyrates 4а, 4b in refluxing ether, afforded cis-9 in a yield and
enantioselectivity both close to 40% (entries 8 and 9).
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Table 1. Cyclopropanation of isopropyl 4-chlorobutyrate (4b) with n-butylmagnesium bromide in the
presence of titanium(IV) TADDOLates 5, 6
Titanium
Entry alkoxide
(equiv)
Time of addition
Procedurea of n-BuMgBr,
(h)
Yield
of cis-
9b (%)
0
Yield of Ratio of
10b (%)
T
(oC)
ее,
cis-9:
trans-9b
cis-
9c(%)
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9g
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А
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70
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2:1
4:1
1.5:1
3:1
2:1
4:1
4:1
55
16
0
А
A
A
A
A
B
B
B
0.75
0.75
2
15
60f
50
0
10e
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40
35
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38
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2
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0.75
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Method А: Ethereal solution of n-BuMgBr (2.2-3 equiv.) was added dropwise to the solution of 10-100 mol. % of
titanium(IV) alkoxide 5 or 6 and 1 equiv. of ester 4b in diethyl ether; method B: Solutions of 1 equiv. of 4-chlorobutyrate 4b
and 2.2 equiv. of n-BuMgBr in diethyl ether were simultaneously added at an equal rate to the ethereal solution of 10 mol. % of
titanium(IV) alkoxide 5.
b Determined by 1H NMR spectroscopic analysis of the crude reaction mixture.
c The ratio was determined by 1H NMR spectroscopic analysis of the corresponding crude MTPA esters.
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d In the presence of Ti(TADDOL)2 (6).
e In the presence of 10 mol. % Ti(Oi-Pr)4.
f 15% of trans-9 and 15% of secondary alcohol by-product10 were also obtained.
g Methyl 4-chlorobutyrate (4a) was used as a substrate.
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We have earlier suggested that a driving force for the predominant formation of the
thermodynamically less stable cis-1,2-disubstituted cyclopropanols in the reactions of esters with
alkoxytitanacyclopropane reagents is a decrease in steric repulsion between substituents attached to highly
coordinated titanium atom during the process of intramolecular cyclisation of the ate-complex β-
titanoketone intermediates.5 From that point the cyclopropanation of esters by titanacyclopropane species
bearing sterically hindered TADDOL ligands should lead to increase of cis-diastereoselectivity in
comparison with reaction of titanacyclopropane with isopropoxide ligands what is actually observed in
non-catalytic version of the reaction (Table 1, entries 2 and 4). A dramatic decrease in cis-
diastereoselectivity of the formation of cyclopropane derivative 9 in the catalytic reaction (entries 3, 5-7)
which is even lower than cis-diastereoselectivity of cyclopropanation in the presence of titanium(IV)
isopropoxide (entry 4) could be caused by a lowered reactivity of oxatitanacyclopentane intermediate 11
or β-titanoketone complex 12 (Scheme 3) containing bulky TADDOL ligand and involvement of the latter
to the processes of the ligand exchange with magnesium alkoxides. The acceleration of intramolecular
cyclisation of β-titanoketone ate-complexes 12 into the target cyclopropanol cis-9 at elevated temperature
may provide observed increasing in diastereoselectivity and enantioselectivity of the formation of
cyclopropane.
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Scheme 3.
In order to estimate the turnover number of titanium(IV) TADDOLate catalyst 5 in the asymmetric
cyclopropanation of 4-chlorobutyrate 4b without significant loss in enantioselectivity, dependence of
enantiomeric purity of the cyclopropanol cis-9 on the reaction progress in the presence of 10 mol. % of
TADDOLate 5 has been determined (Table 2).
Table 2. The dependence of diastereoselectivity and enantioselectivity of the
formation of cyclopropanol 9 on the reaction progress.а
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n-BuMgBr
Ratio of
cis-9: trans-9b
ее
1
2
(equiv.)
cis-9c, (%)
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9
0.3
0.6
0.9
1.2
1.5
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6:1
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5:1
3:1
3:1
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a The solutions of 1 equiv. of 4-chlorobutyrate 4b and n-BuMgBr in diethyl ether were added at an equal rate from two
syringes to the refluxing ethereal solution of 10 mol. % of titanium(IV) alkoxide 5.
b The ratio was determined by 1H NMR spectroscopic analysis of the crude reaction mixture.
c The ratio was determined by 1H NMR spectroscopic analysis of the corresponding crude MTPA esters.
The data in the Table 2 display that the cyclopropanol cis-9 is formed in 50% ee and with good cis-
diastereoselectivity (6:1) until 1.2 equiv. of the Grignard reagent is added, which approximately
corresponds to the implementation of five catalytic cycles. After that, both diastereoselectivity and
enantioselectivity of the reaction drop substantially, perhaps because of violation of the catalyst structure
as a result of the ligand exchange with magnesium alkoxides accumulating in the reaction mixture. From
these results it was expected that a catalyst loading of about 20 mol. % could be sufficient in the exploited
conditions to attain enantioselectivity comparable with that one in the stoichiometric version. Indeed, the
cyclopropanation of ester 4b with n-BuMgBr in the presence of 20 mol. % of TADDOLate 5 in refluxing
diethyl ether using the conventional reagents mixing order (Method А) led to a mixture of cis- and trans-
isomeric cyclopropanols 9 in a ratio of 6:1 and total yield of about 50% (Table 3, entry 1). The
enantiomeric excess of the obtained cyclopropanol cis-9 in this case was the same as at the applying of
100 mol. % of the catalyst 5 (Table 1, entry 2). Employing 20 mol. % of 5 under reagents mixing order in
method B results in an increase in enantiomeric excess of cyclopropanol cis-9 up to 65% (Table 3, entry
2). As before, when the reaction was carried out at room temperature, a notable decrease of cis-9 yield and
enantioselectivity (to 36% ее) was observed (Table 3, entry 3). Increasing the catalyst load to 100 mol. %
did not raise the enantiomeric excess of cis-cyclopropanol 9, although did result in higher cis-
diastereoselectivity (cis:trans = 8:1) (Table 3, entry 4).
Table 3. The effect of the catalyst 5 loading on the yield and enantioselectivity of cyclopropanols 9
formation.
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catalyst 5
(mol. % )
20
Ratio of
ее cis-
9d (%)
55
Yield
Entry T (oC)
Procedureа
Yield
10c (%)
cis-9:
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9
cis-9c(%)
trans-9b
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аMethod А: Ethereal solution of n-BuMgBr (2.4-3 equiv.) was added dropwise to the solution of 20-100 mol. % of
titanium(IV) alkoxide 5 and 1 equiv. of 4-chlorobutyrate 4b in diethyl ether; method B: Solutions of 1 equiv. of 4-
chlorobutyrate 4b and 2.2 equiv. of n-BuMgBr in diethyl ether were simultaneously added at an equal rate to the ethereal
solution of 10% mol of titanium(IV) alkoxide 5.
b The ratio was determined by 1H NMR spectroscopic analysis of the crude reaction mixture.
c Determined by 1H NMR spectroscopic analysis of the crude reaction mixture. .Isolated yield of cis-9 was close to indicated in
the table.
d Determined by 1H NMR spectroscopic analysis of the corresponding crude MTPA esters.
Using the example of cyclopropanation of isopropyl propionate (13) with n-pentylmagnesium
bromide in the presence of 20 mol. % titanium(IV) (4R,5R)-TADDOLate 5, the absolute configuration of
cis-1-ethyl-2-propylcyclopropanol (cis-14), obtained under conditions of method B in 50% yield and 65%
ee, was determined (Scheme 4). After the heating of the cyclopropanol cis-14 on aluminium oxide treated
with tartaric acid,15 a mixture of optically active 4-methyl-3-heptanone (15) and 3-octanone (16) in a ratio
of 3:1 was isolated in 70% yield as a result of acid-catalyzed cleavage of cyclopropane ring at C1-C3 and
C1-C2 bonds respectively (Scheme 4). Specific rotation of the obtained mixture of ketones 15 and 16 was
measured to be [α]D18 −9.6 (c = 0.85, hexane). Specific rotation of the pure (R)-4-methyl-3-heptanone (15),
known as a minor component of trail pheromone of ant Aphaenogaster albisetosus16 and as less active
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enantiomer of alarm pheromone of leaf-cutting ants Atta texana,17 was reported to be [α]D −21.5 (c =
1.0, hexane).17a The comparison of this value with those measured for the obtained mixture of ketones 15
and 16 indicates the presence of (R)-4-methyl-3-heptanone (15) with enantiomeric purity of about 60% ee.
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Scheme 4.
Preferred formation of (R)-enantiomer of ketone 15 indicates (1S,2S)-configuration of the
cyclopropanol precursor cis-14 as well as the preferable transformation of titanium(IV) (4R,5R)-
TADDOLate 5 into titanacyclopropane reagent (2S)-17, what agrees with the formation of
titanacyclopropane reagent having the maximally distant n-propyl substituent in three-membered
metallacycle from the nearest pseudoaxial phenyl group of TADDOL ligand.6 Accordingly, it can be
concluded that cyclopropanol cis-9, obtained by the cyclopropanation of ester 4 in the presence of titanate
5, most likely has (1S,2S)-configuration.18
3. Conclusion
In present study we found conditions allowing to carry out the cyclopropanation of esters 4 and 13 by
chiral alkoxytitanacyclopropane reagents generated in situ from titanium(IV) (4R,5R)-TADDOLate 5 and
n-butyl- or n-pentylmagnesium bromides that led to formation of chiral cyclopropanols cis-9 and cis-14 in
50-70% yield and with enantiomeric excess up to 65%. The absolute configuration of the major
enantiomer of cyclopropanol cis-14 was established as (1S,2S) by chemical correlation with known
(R)-(−)-4-methyl-3-heptanone (15), formed as a preferable product during acid-catalyzed cleavage of
three-carbon ring of cis-14.
4. Experimental section
4.1. General
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All solvents were purified and dried by conventional methods prior to use. Titanium(IV) isopropoxide was
purified by distillation, other reagents were used as purchased from commercial suppliers. (4R,5R)-2,2-
Dimethyl-α,α,α´,α´-tetraphenyl-1,3-dioxolane-4,5-dimethanol (TADDOL) was synthesized according to
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the literature procedure11 and purified via its clathrate with CCl4 or EtOH11d. All reactions with
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organometallics were carried out under dry argon. Chromatographic separations were performed on Merck
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60 silica gel (70-230 mesh). H NMR (400 MHz) and 13C NMR (100.6 MHz) spectra were taken on a
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Bruker AC 400 spectrometer in CDCl3 as a solvent. Chemical shifts were given in δ value with CHCl3
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(δ = 7.26 ppm) and CDCl3 (δ = 77.0 ppm) as internal standards for H NMR and 13C NMR spectra,
respectively. Optical rotation was measured on a PerkinElmer 141 polarimeter.
4.2 Preparation of titanium(IV) TADDOLate 513.
The following procedure was adapted from refs.13: To a solution of TADDOL 7 (0.098 g, 0.21 mmol) in
toluene (1 mL) at room temperature was added titanium(IV) isopropoxide (0.057 g, 0.2 mmol). The
resulted solution was stirred at room temperature for 30 minutes, and then the solvent was removed in
vacuo at bath temperature 45-50°C. A foamy solid obtained was cooled to room temperature and diethyl
ether (1 mL) was added to produce a clear solution.
4.3 Representative procedure for the cyclopropanation of isopropyl-4-chlorobutyrate (4b) in the
presence of titanium(IV) TADDOLаte 5. The conventional order of reagents mixing (Method А).
To a solution of chiral titanium alkoxide 5 (prepared as described above; 0.2-2 mmol, 10-100 mol. %, in 1-
2 mL Et2O) a solution of isopropyl-4-chlorobutyrate 4b (0.330 g, 2 mmol) in diethyl ether (7 mL) was
added. To the obtained solution 2.2-2.4 equiv. (for the catalytic version) or 3 equiv. (for the stoichiometric
version) of n-BuMgBr (5.5-7.5 mL, 0.8М in Et2O, 4,4-6.0 mmol) was added dropwise at the temperature
and during the time indicated in the Table 1. After completing the addition, the reaction mixture was
allowed to cool to r.t. (if necessary) and stirred for 30 minutes at room temperature, then placed in an ice
bath and quenched with 10% aq. H2SO4 (6 mL). The aqueous phase was extracted with Et2O (3  5 mL),
the combined organic phases were washed with saturated aqueous NaHCO3, brine and dried (Na2SO4).
The solvent was removed under reduced pressure, and the components of the residue were separated by
column chromatography on silica gel (from pure hexanes to 25% ethyl acetate/ hexanes), collecting
sequentially tertiary alcohol 10, the mixed fraction containing trans-cyclopropanol trans-9 and tertiary
alcohol 10, TADDOL ligand 7, and pure cis-cyclopropanol cis-9 as a light yellowish oil.
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4.4 Representative procedure for the cyclopropanation of isopropyl-4-chlorobutyrate (4b) in the
presence of titanium(IV) TADDOLаte 5. The simultaneous addition of the reactants to the catalyst
(Method B).
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Ester 4b (0.330 g, 2 mmol) was dissolved in diethyl ether (6.9 – 8.3 mL, in such a way that the volume of
the resulted solution made up approximately 110% of the volume of utilized Grignard reagent solution).
To a solution of titanium(IV) ТADDOLate 5 (0.2-2 mmol, 10-100 mol. %, in 1 mL Et2O) 10% of this
solution (0.6 mL) was added in one portion. The remained solution of ester 4b and solution of n-BuMgBr
(6.3-7.5 mL, 0.8М in Et2O, 5-6 mmol; 2.4 equiv. (catalytic), 3 equiv. (stoichiometric version)) were added
to the solution of titanium(IV) catalyst during 2 hours simultaneously at an equal rate from two syringes
under the temperature indicated in the Tables 1 and 3. After completing the addition, the reaction mixture
was placed in an ice bath and quenched with 10% H2SO4 (6 mL). The aqueous phase was extracted with
Et2O (3  5 mL), and the combined organic phases were washed with saturated aqueous NaHCO3, brine
and dried (Na2SO4). The solvent was removed under reduced pressure, and the components of the residue
were separated by column chromatography on silica gel (from pure hexanes to 25% ethyl acetate/
hexanes), collecting sequentially tertiary alcohol 10, the mixed fraction containing trans-cyclopropanol
trans-9 and tertiary alcohol 10, TADDOL ligand 7, and, finally, pure cis-cyclopropanol cis-9 as a light
yellowish oil. Pure trans-cyclopropanol trans-9 was isolated from the products of the reaction catalysed by
10 mol. % Ti(Oi-Pr)4.
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5-Butyl-1-chlorononan-5-ol 10. .[Found: C, 65.33; H, 11.48. C12H25ClO requires C, 65.28; H, 11.41%];
Rf (25% EtOAc/ hexanes) 0.74; νmax (CCl4) 3623 cm-1; H (400 MHz, CDCl3) 3.56 (2H, t, J = 6.6 Hz,
CH2Cl) , 1.78-1.85 (2H, m, CH2CH2Cl), 1.53-1.60 (3H, m, CH2CH2CH2Cl and OH), 1.41-1.48 (4H, m,
CH2CH2CH2CH3), 1.21-1.34 (8H, m, CH2CH2CH2CH3), 0.91 (6H, t, J = 7.0 Hz, CH3); C (100 MHz,
CDCl3) 74.1 (Cquart), 45.8 (CH2Cl), 38.9 (CH2CH2CH2CH3), 36.5 (CH2CH2CH2Cl), 26.9 (CH2CH2Cl),
25.6 (CH2CH2CH3), 23.3 (CH2CH3), 14.1 (CH3).
trans-1-(3-Chloropropyl)-2-ethylcyclopropanol trans-9. [Found: C, 59.21; H, 9.48. C8H15ClO requires C,
59.07; H, 9.30% ]; Rf (25% EtOAc/ hexanes) 0.71 ; νmax (CCl4) 3600, 3068 cm-1 ; H (400 MHz, CDCl3)
3.63 (2H, t, J = 6.5 Hz, CH2Cl ), 1.95-2.07 (2H, m, CH2CH2Cl), 1.67-1.75 (1H, m, CH2CH2CH2Cl), 1.53-
1.63 (1H, m, CH2CH2CH2Cl), 1.45-1.51 (3H, m, CH2CH3 and OH), 1.00 (3H, t, J = 7.4 Hz, CH3), 0.58-
0.67 (2H, m, CH2-cycloprop, CH-cycloprop), 0.31-0.33 (1H, m, CH2-cycloprop); C (100 MHz, CDCl3)
58.3 (Cquart), 45.1 (CH2Cl), 38.9 (CH2CH2CH2Cl), 29.1 (CH2CH2Cl), 26.2 (CH-cycloprop), 21.0
(CH2CH3), 18.8 (CH2-cycloprop), 14.3 (CH3).
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cis-1-(3-Chloropropyl)-2-ethylcyclopropanol cis-9. [Found: C, 59.15; H, 9.35. C8H15ClO requires C,
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59.07; H, 9.30% ]; Rf (25% EtOAc/ hexanes) 0.61; [α]D +13.5 (c = 1.9, hexane, 65% ee); νmax (CCl4)
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3560, 3071 cm-1; H (400 MHz, CDCl3) 3.64 (2H, t, J = 6.5 Hz, CH2Cl), 1.99-2.11 (2H, m, CH2CH2Cl),
1.74-1.84 (1H, m, CH2CH2CH2Cl), 1.60-1.84 (1H, br s, OH), 1.60-1.69 (1H, m, CH2CH2CH2Cl), 1.40-
1.51 (1H, m, CH2CH3), 1.06-1.16 (1H, m, CH2CH3), 0.98 (3H, t, J = 7.2 Hz. CH3), 0.95-1.01 (1H, m,
cycloprop-СН), 0.83 (1H, ddd, J = 10.1, 5.5, 1.3 Hz, cycloprop- СН2), 0.11 (1H, dd, J = 6.0, 5.5 Hz,
cycloprop-СН2); C (100 MHz, CDCl3) 58.4 (Cquart), 45.3 (CH2Cl), 31.4 (CH2CH2CH2Cl), 29.2
(CH2CH2Cl), 27.8 (CH-cycloprop), 22.8 (CH2CH3), 19.4 (CH2-cycloprop), 13.9 (CH3).
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cis-1-Ethyl-2-propylcyclopropanol cis-14 was synthesized according to Method B and obtained in 50%
yield and 65% ee as colourless oil. [Found: C, 75.01; H, 12.62. C8H16O requires C, 74.94; H, 12.58% ];
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Rf (10% EtOAc/ hexanes) 0.40; [α]D +5.0 (c = 1.3, hexane); νmax (CCl4) 3338, 3070 cm-1; H (400
MHz, CDCl3) 1.81 (1H, br s, OH), 1.58-1.68 (1H, m, CH2), 1.48-1.59 (1H, m, CH2), 1.35 -1.47 (3H, m,
CH2), 1.07 (3H, t, J = 7.4 Hz. CH3), 1.01-1.09 (2H, m, cycloprop-СН and CH2), 0.91(3H, t, J = 7.2 Hz.
CH3), 0.79 (1H, ddd, J = 9.6, 5.1, 1.0 Hz, cycloprop-СН2), 0.04 (1H, m, cycloprop-СН2); C (100 MHz,
CDCl3) 59.85 (Cquart), 31.6 (CH2), 27.1 (CH2), 26.0 (CH), 22.8 (CH2), 19.4 (CH2), 14.0 (CH3), 10.1 (CH3).
4.5 Preparation of MPTA esters of cyclopropanol cis-9.
To a solution of cis-1-(3-chloropropyl)-2-ethylcyclopropanol 9 (0.008g, 0.05 mmol) in dichloromethane
(0.1mL) and pyridine (0.008 g, 0.1 mmol) (R)-MPTA-C1 (0.020 g, 0.075 mmol, prepared from (S)-(-)-
MTPA) was added. The reaction mixture was kept overnight at room temperature to complete the reaction
(TLC control), then diluted with diethyl ether (3-5 mL) and quenched with saturated aqueous NH4Cl
solution (2 mL). The aqueous phase was extracted with Et2O (3 mL), and the combined organic phases
were washed with saturated aqueous NaHCO3, brine and dried (Na2SO4). The solvent was removed under
reduced pressure, and the residue on evaporation was analyzed by 1H NMR.
MTPA-esters of cyclopropanol cis-9 (mixture of diastereomers in a ratio of 78:22): H (400 MHz, CDCl3)
7.48-7.57 (2Н,m), 7.38-7.44 (3H, m), 3.44-3.58 (2H, m), 3.52 (3H, s), 1.64-1.92 (2H, m), 1.51-1.60 (3H,
m), 1.20-1.34 (1H, m), 1.06 (3H, t, J = 7.4 Hz), 0.99-1.12 (1H, m), 0.79-0.91 (1H, m), 0.39 (0.22H, t, J
= 6.4 Hz, minor diastereomer), 0.36 (0.78H, t, J = 6.4 Hz, major diastereomer).
MTPA-esters of cyclopropanol cis-14 (mixture of diastereomers in a ratio of 83:17): H (400 MHz,
CDCl3). 7.48-7.56 (2Н, m),7.37-7.43 (3H, m), 3.53 (3H, s), 1.97-2.09 (1H, m), 1.66-1.57 (1H, m), 1.45-
1.55 (2H, m), 1.09-1.18 (2H, m), 0.93 (3H, t, J = 7.2 Hz), 0.91(3H, t, J = 7.4 Hz), 0.91-1.03 (2H, m), 0.32
(0.17H, t, J = 6.5 Hz, minor diastereomer), 0.30 (0.83H, t, J = 6.5 Hz, major diastereomer).
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4.6. Transformation of cis-1-ethyl-2-propylcyclopropanol (cis-14) into ketones 15 and 16.
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Racemic tartaric acid (0.120 g, 0.8 mmol, 5% wt amount to Al2O3) was dissolved in acetone (3 mL) and
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mixed with Al2O3 (2.4 g, 20-fold weight amount to the cyclopropanol cis-14) and the solvent was removed
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under reduced pressure. To the prepared heterogeneous catalyst
a solution of cis-1-ethyl-2-
9
propylcyclopropanol cis-14 (0.120 g, 0.9 mmol) in Et2O (1mL) was added and the reaction mixture was
slowly heated with stirring to 110°C (oil bath, air-cooled condenser) allowing solvent to evaporate. After
heating at this temperature (water-cooled condenser) for additional 2 hours, the mixture was cooled to
room temperature and the catalyst was washed with ether (5 × 10 mL). The solvent was warily removed at
the atmospheric pressure. After column chromatography on silica gel (from 5 to 9% Et2O/pentane) the
mixture containing 4-methylheptan-3-one and 3-octanone (3:1) was isolated in 70% total yield (0.085g).
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[α]D −9.6 (c = 0.82, hexane). Lit:
[α]D −21.5 (c = 1.0, hexane). H and 13C NMR spectra of 4-
methylheptan-3-one and 3-octanone are in accordance with those already reported.17b, 19.
Acknowledgement
Support from Belarusian Foundation for Basic Research (Grant CH08MLD-004), the Ministry of
Education and Research of Estonia (Grant No SF0140060s12) and the EU Regional Development Fund
(3.2.0101.08-0017) is acknowledged.
References and notes
1. For recent reviews see: (a) Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597. (b) Kulinkovich, O. G.
Izv. Akad. Nauk, Ser. Khim. 2004, 1022; Russ. Chem. Bull., Int. Ed. (Engl. Transl.) 2004, 53, 1065. (c)
Wolan, A; Six, Y. Tetrahedron, 2010, 66, 15. (d) Cha, J. K.; Kulinkovich, O. G. Org. React. 2012,
77, 1.
2. (a) Choi, J.-R.; Cho, D.-G.; Roh, K. Y.; Hwang, J.-T.; Ahn, S.; Jang, H. S.; Cho, W.-Y.; Kim, K.-W.;
Cho, Y.-G.; Kim, J.; Kim, Y.-Z. J. Med. Chem. 2004, 47, 2864. (b) Yoon, S.-K.; Nam, K.-H.; Lee, S.-
W.; Joung, W.-K.; Choi, S.-C.; Lee, K.-K. U.S. Patent 7,795,463, 2010. (c) Choi et al. U.S. Patent
Application Publication, US 2006/0111324 A1, 2006. (d) Bassan, E. M.; Baxter, C. A.; Beutner, G. L.;
Emerson, K. M.; Fleitz, F. J.; Johnson, S.; Keen, S.; Kim, M. M.; Kuethe, J. T.; Leonard, W. R.;
Mullens, P. R.; Muzzio, D. J.; Roberge, C.; Yasuda, N. Org. Process Res. Dev. 2012, 16, 87.
3. (a) De Puy, C. H. Acc. Chem. Res. 1968, 1, 33. (b) Gibson, D. H.; De Puy, C. H. Chem. Rev. 1974, 74,
605; (c) Kulinkovich, O. G. Polish J. Chem. 1997, 71, 849. (d) Kulinkovich, O. G. Chem. Rev. 2003,
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103, 2597. (e) Kulinkovich, O. G. Eur. J. Org. Chem. 2004, 4517. (f) Haym, I.; Brimble, M. A. Org.
Biomol. Chem.2012, 10, 7649.
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4. Kulinkovich, O.; Isakov, V.; Kananovich, D. Chem. Rec. 2008, 269.
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5. Kananovich, D. G.; Kulinkovich, O. G. Tetrahedron. 2008, 63, 1536.
7
8
6. Corey, E. J.; Rao, A.; Noe, M. C. J. Am. Chem. Soc. 1994, 116, 9345.
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7. Racouchot, S.; Sylvestre, I.; Ollivier, J.; Kozyrkov,Y. Y.; Pukin, A.; Kulinkovich, O. G.; Salaun, J.
Eur. J. Org. Chem. 2002, 2160.
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8. Savchenko, A. I. Dissertation, Belarusian State University, Minsk, 1995.
9. Casey, C. P.; Strotman, N. A. J. Am. Chem. Soc. 2004, 126, 1699.
10. Kulinkovich, O. G.; Kananovich, D. G. Eur. J. Org. Chem. 2007, 2121.
11. (a) Seebach, D.; Beck, A. K.; Imwinkelried, R.; Roggo, S.; Wonnacott, A. Helv. Chim. Acta, 1987, 70,
954. (b) Ito, Y. N.; Ariza, X.; Beck, A. K.; Bohač, A.; Ganter, C.; Gawley, R. E.; Kuehnle, F. N. M.;
Tuleja, J.; Wang, Y. M.; Seebach, D. Helv. Chim. Acta 1994, 77, 2071. (c) Beck, A. K.; Bastani, B.;
Plattner, D. A.; Petter, W.; Seebach, D.; Braunschweiger, H.; Gysi, P.; La Vecchia, L. Chimia 1991,
45, 238. (d) Seebach, D.; Beck, A. K.; Gysi, P.; La Vecchia, L. Org. Synth. 1999, 76, 12.
12. For reviews see: (a) Duthaler, R. O.; Hafner, A. Chem. Rev. 1992, 92, 807-832 (b) Seebach, D.; Beck,
A. K.; Heckel, A. Angew. Chem., Int. Ed. Engl. 2001, 40, 92. (c) Ramón, D. J.; Yus, M. Chem. Rev.
2006, 106, 2126. Examples of recent applications of titanium(IV) TADDOLate in asymmetric
synthesis: (d) Maier, P.; Redlich, H.; Richter, J. Tetrahedron: Asymmetry, 2005, 16, 3848. (e) Wen,
J.; Zhao, J.; You, T. J. Mol. Catal. A: Chem., 2006, 245, 278. (f) Kim, S. S.; Kwak, J. M.; Rajagopal,
G. Bull. Korean Chem. Soc. 2006, 27, 1638. (g) Bertogg, A.; Hintermann, L.; Huber, D. P.; Perseghini,
M.; Sanna, M.; Togni, A. Helv. Chim. Acta, 2012, 95, 353.
13. (a) Seebach, D.; Beck, A. K,; Schmidt B.; Wang Y. M.; Tetrahedron, 1994, 50, 4363 (b) Seebach, D.;
Plattner, D. A.; Beck, A. K.; Wang, Y. M.; Hunziker, D.; Petter, W. Helv. Chim.Acta, 1992, 75, 2171
14. Mosher, S.H.; Dale, J.A.; Dull, D.L. J. Org. Chem. 1969, 34, 2543.
15. It has been previously found that aliphatic α-methyl ketones did not epimerize under such conditions to
more than 5% extent: Hurski A.L., Kulinkovich O.G., unpublished results.
16. Oldham, N. J.; Morgan, E. D.; Holldobler, B.; König, W.A. J. Insect Physiol. 1995, 41, 739.
17. (a) Riley, R.G., Silverstein, R.M. Tetrahedron, 1974, 30, 1171; (b) Larcheveque, M., Ignatova, E.,
Cuvigny, T. J. Organomet. Chem. 1979, 177, 5. (с) Riley, R.G., Silverstein, R.M., Moser, J.C.
Science, 1974, 183, 760.
18. The same difference in chemical shifts for the cyclopropane CH2-group proton signals (trans to
1
OMTPA) at 0.3-0.4 ppm in H NMR spectra of diastereomeric (S)-Mosher esters for both
cyclopropanols cis-9 and cis-14 are observed (see experimental part).
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19. Wang, X.; Liu, R.; Jin, Y.; Liang, X. Chem. Eur. J. 2008, 14, 2679.
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