Convenient chemoenzymatic route to optically active β-aryl-δ-iodo-γ-lactones and β-aryl-γ-iodo-δ-lactones with the defined configurations of stereogenic centers

Article abstract of DOI:10.1002/ejoc.201403343

Two δ-iodo-γ-lactones and two γ-iodo-δ-lactones substituted at the (β-position with phenyl or 4-methylphenyl ring have been synthesized in both enantiomeric forms. The starting materials were enantiomerically enriched allyl alcohols with an (E)-4-phenylbu

Full text of DOI:10.1002/ejoc.201403343

FULL PAPER
DOI: 10.1002/ejoc.201403343
Convenient Chemoenzymatic Route to Optically Active β-Aryl-δ-iodo-γ-
lactones and β-Aryl-γ-iodo-δ-lactones with the Defined Configurations of
Stereogenic Centers
Witold Gładkowski,*[a] Andrzej Skrobiszewski,[a] Marcelina Mazur,[a] Monika Siepka,[a] and
[b]
´
Agata Białonska
Keywords: Chiral resolution / Lactones / Lipases / Kinetic resolution / Rearrangement / Configuration determination
Two δ-iodo-γ-lactones and two γ-iodo-δ-lactones substituted
at the β-position with phenyl or 4-methylphenyl ring have
been synthesized in both enantiomeric forms. The starting
materials were enantiomerically enriched allyl alcohols with
an (E)-4-phenylbut-3-en-2-ol system (ee in the range 88–
99%), which were obtained by lipase-catalyzed transesterifi-
cation. Alcohols were subjected to orthoacetate modification
of the Claisen rearrangement. The high stereoselectivity of
this reaction led to retention of (E)-configuration of the
double bond and complete transfer of chirality from the allyl
alcohol to the benzylic position C-3. As a result, chiral γ,δ-
unsaturated esters with retained configuration of the
stereogenic center were produced. Their hydrolysis and
iodolactonization afforded new enantiomers of iodolactones
with high or excellent ee (97–99%). Their configuration at C-
4 was a direct result of the configuration at C-3 of the acid
subjected to iodolactonization, whereas stereocenters at C-5
and C-6 were formed as a consequence of the reaction
mechanism. For most of the synthesized isomers, the pre-
dicted configurations were established by X-ray analysis.
The presented chemoenzymatic pathway represents a useful
strategy that can be applied in the asymmetric synthesis of
variety of lactones from 4-arylbut-3-en-2-ols.
nitriles by the nitrile hydratase/amidase-containing Rhodoc-
occus sp. AJ270 whole cells,[11] baker’s yeast reduction of γ-
and δ-ketoacids and esters[12] or baker’s yeast simultaneous
reduction of the carbonyl group and conjugated double
bond in α,β-unsaturated β-formyl esters.[13] One of the most
common biocatalytic methods is lipase-catalyzed kinetic
resolution of different direct lactone precursors such as γ-
hydroxy esters,[14] 1,4- or 1,5-diols,[15] δ-hydroxyamides,[16]
or phenylselenoesters.[17]
A convenient synthetic pathway leading to the lactone
moiety involves ortho-Claisen rearrangement of allyl
alcohols followed by hydrolysis of γ,δ-unsaturated esters
and lactonization of the resulting acids.[18] By using this
methodology, in our previous work, we synthesized some
racemic β-aryl-δ-halo-γ-lactones and β-aryl-γ-halo-δ-lact-
ones starting from simple aromatic aldehydes.[19] Some of
them showed cytotoxic activity against Jurkat (human leu-
kaemia) and D17 (canine osteosarcoma) cancer lines. Tak-
ing into consideration the possible effect of configuration of
stereogenic centers on the physicochemical and biochemical
properties of drugs, we decided to develop the synthesis of
both enantiomers of the lactones of interest. The chemo-
enzymatic pathway presented herein was based on the
lipase-catalyzed resolution of racemic allyl alcohols with
the 4-arylbut-3-en-2-ol system. Enantiomerically enriched
alcohols were used to synthesize enantiomeric pairs of β-
aryl-δ-iodo-γ- and β-aryl-γ-iodo-δ-lactones (Scheme 1).
Introduction
Among the biologically active lactones, numerous bio-
logical properties have been determined for those contain-
ing an aromatic ring. Reported data concern mostly their
anticancer,[1] antimicrobial,[2] antiparasitic,[3] antifeedant
(towards insects) and insecticidal,[4] anti-inflammatory,[5]
and antiplatelet[6] properties. Most of the compounds have
been obtained or isolated in enantiomerically pure forms.
A range of strategies have been applied to the synthesis
of chiral lactones. The crucial stereochemical steps may in-
volve chemical methods, for example diastereoselective ad-
dition of alkenyl Grignard reagents to chiral amides,[7] dia-
stereoselective alkylation of chiral derivative of succinic
acid,[8] Sharpless asymmetric dihydroxylation,[2e] or palla-
dium-catalyzed enantioselective allylic substitution.[9] On
the other hand, many biocatalytic reactions are applied as
a stereoselective step of lactone synthesis, including oxid-
ation of cyclic ketones by Baeyer–Villiger monooxygen-
ases,[10] enantioselective hydrolysis of 2-aryl-4-pentene-
[a] Department of Chemistry, Wrocław University of
Environmental and Life Science,
Norwida 25, 50-375 Wrocław, Poland
E-mail: glado@poczta.fm
http://wnoz.up.wroc.pl/wnoz/katedry/katchem/index.php
[b] Faculty of Chemistry, University of Wrocław,
F. Joliot-Curie 14, 50-383 Wrocław, Poland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403343.
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Scheme 1. Synthesis of enantiomeric pairs of iodolactones 5–7a,b from both enantiomers of alcohols 1a,b.
so far have been obtained by Brenna et al.;[22] in this case,
(–)-alcohol 1a and (+)-ester, both with 98%ee were ob-
Results and Discussion
The starting materials in the chemoenzymatic synthesis tained after 24 h reaction carried out in tert-butyl methyl
of β-aryl-δ-iodo-γ-lactones 5a,b and 6a,b, and β-aryl-γ- ether using vinyl acetate and Burkholderia cepacia lipase. In
iodo-δ-lactones 7a,b (Scheme 1) were two racemic allyl our reaction system we decided to apply lipase B from Can-
alcohols with 4-phenylbut-3-en-2-ol system 1a,b, which dida antarctica (Novozym 435, CAL-B) and vinyl propion-
were previously synthesized in a two-step synthesis from ate as the acyl donor. This enzyme was earlier successfully
benzaldehyde and p-methylbenzaldehyde.[19]
employed in the resolution of a series of secondary aliphatic
Being interested in both enantiomers of the starting allyl alcohols[23] and δ-hydroxy esters.[24] Quirin et al.[25]
alcohols, we took into consideration the earlier studies on used CAL-B for the transesterification of 1b with vinyl acet-
the kinetic resolution of racemic alcohol 1a by lipase-cata- ate in a solvent-free system, affording (–)-alcohol 1b with
lyzed transesterification. Resolution of alcohol 1a in tolu- 99%ee after 24 h of process, but no information about the
ene on a preparative scale was carried out by using lipase ee of ester was given.
from Pseudomonas cepacia immobilized on diatomaceous
Our results, which are summarized in Table 1, showed
earth and isopropenyl acetate as the acyl donor.[20] After that, similar to other lipases, CAL-B showed a high prefer-
4 h of the process they obtained (–)-alcohol 1a with 98%ee ence towards transesterification of (+)-(R)-alcohols 1a,b.
and its (+)-acetate with 87%ee. Exchange of the enzyme Applied conditions significantly accelerated the rate of reac-
carrier to ceramic particles resulted in better enantiomeric tion and, after 2 h of preparative-scale process in DIPE at
excess of (+)-ester (98%) but the ee of the unreacted (–)-1a approximately 50% conversion, we obtained (+)-(R)-prop-
was lowered to 96%. The reaction was conducted in di- ionates 2a,b and unreacted (–)-(S)-alcohols 1a,b in yields of
isopropyl ether (DIPE) at 40 °C for 9 h.[21] The best results 38–47% (Scheme 2).
Table 1. Results of enzymatic transesterification of racemic alcohols 1a,b.[a]
Entry
Substrate
Conversion [mol-%]
ee of (–)-(S) alcohol [%]
ee of (+)-(R)-propionate [%]
1
2
1a
1b
51
55
Ͼ99
95
99 (2a)
88 (2b)
[a] Reaction was carried out at room temperature in DIPE for 2 h using lipase B from C. antarctica and vinyl propionate as the acyl
donor.
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β-Aryl-δ-iodo-γ-lactones and β-Aryl-γ-iodo-δ-lactones
Scheme 2. Synthesis of both enantiomers of alcohols 1a,b using lipase-catalyzed kinetic resolution.
Excellent enantiomeric excesses were obtained for unre- tion of propionate (+)-2b was assigned based on the config-
acted alcohol (–)-1a and propionate (+)-2a (Ͼ 99% and uration of its hydrolysis product, alcohol (–)-1b.
99%, respectively, Table 1, entry 1); in the case of the
(–)-(S)-Alcohols 1a,b and (+)-(R)-alcohols 1a,b were sub-
alcohol with a p-methylphenyl ring, the optical purity of the jected to the Claisen rearrangement according to the ortho-
products was lower [95%ee of alcohol (–)-1b and 88%ee acetate Johnson modification, which afforded γ,δ-unsatu-
of propionate (+)-2b, entry 2]. Propionate (+)-2b was not rated esters (+)-(S)-3a,b and (–)-(R)-3a,b, respectively, in
described previously. Both propionates (+)-2a,b were hy- 79–87% yields (Scheme 1). During this reaction, allyl
drolyzed under basic conditions (NaOH) (Scheme 2) to af- alcohol undergoes transvinyl etherification with triethyl or-
ford (+)-alcohols 1a,b in 91–95% yield and ee values iden- thoacetate, and the forming alkoxy vinyl allyl ether re-
tical to those determined for propionates. Configurations of arranges to γ,δ-unsaturated ester (Scheme 3). The structure
stereogenic centers of (–)- and (+)-alcohols 1a,b and prop- of products was confirmed by spectroscopic analysis. In the
ionate (+)-2a were assigned by comparison of their specific case of enantiomers of 3a, strong bands at 1735 and
rotation values with reported values.[20,25,26] The configura- 1159 cm–1 in the IR spectrum indicated the presence of an
Scheme 3. Stereochemical course of Johnson–Claisen rearrangement of alcohols with the 4-arylbut-3-en-2-ol system.
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ester moiety. Protons of the ethoxy group were represented tained its E-configuration, as indicated by the coupling con-
in the 1H NMR spectrum by a quartet at δ = 4.05 ppm and stant (J = 15.0 Hz) between protons 4-H and 5-H. The en-
triplet at δ = 1.15 ppm. Similar data were obtained for both antiomeric compositions of synthesized acids 4a,b was not
enantiomers of the esters with a 4-methylphenyl ring (3b).
changed in comparison to esters 3a,b, which was proved by
Studies on the mechanism of the Johnson–Claisen re- chiral GC analysis.
arrangement proved that the stereochemical outcome of
The final step of the synthesis was iodolactonization[31]
this reaction depends on the configuration of the double of both enantiomers of acids 4a,b using iodine and potas-
bond of the starting allyl alcohol as well as on the confor- sium iodide in the biphasic Et2O/NaHCO3 system. In each
mation of the six-membered ring formed in the transition case, the composition of the reaction mixtures (Table 2)
state.[27] In the case of E-isomers of starting alcohols 1a,b, showed the presence of three products: two γ-lactones and
the esters formed from transition-state A retain the configu- one δ-lactone. The products of 5-exo-cyclization (cis-γ-lact-
ration of the double bond as well as the configuration of ones 5a,b and trans-γ-lactones 6a,b) predominated over the
the stereogenic center, whereas transition-state B gives es- products of 5-endo-cyclization (δ-lactones 7a,b). The high-
ters with the opposite configurations of both double bond est content was observed for cis-δ-iodo-γ-lactones, which
and the stereogenic center. The possible chair-like confor- made up 40–56%, whereas trans-δ-iodo-γ-lactones consti-
mations, which may be formed in the transition state during tuted 23–35% of the reaction mixture. These results are
formation of esters 3a,b, are presented in Scheme 3. They consistent with the commonly observed predomination of
have significantly different energy states; conformer A is en- products formed at higher rate under kinetic reaction condi-
ergetically favored because of the lack of 1,3-diaxial interac- tions.[31] In this case, minimization of electrostatic interac-
tions between the ethoxy group and the methyl substituent, tions between the iodonium ion and the aromatic ring in
which occur in conformer B. Therefore, only the formation the transition state favors formation of the cis-isomers.
of the product from conformer A is observed. In this case,
Table 2. The composition [%] of the iodolactonization products of
acids 4a,b (according to GC analysis).
apart from retention of the E configuration, in both
enantiomers of esters 3a and 3b the stereochemical conse-
Product of iodolactonization
quence of the reaction was a complete transfer of chirality
from the C-2 atom of allyl alcohols to the C-3 benzylic
atom of the esters. As a result, (S,E)-esters 3a,b were ob-
tained from (S,E)-alcohols 1a,b, whereas rearrangement of
(R,E)-alcohols 1a,b afforded esters 3a,b with (R,E)-configu-
ration. Configuration of the double bond in both enantio-
mers of esters 3a,b was unequivocally confirmed by the
value of the coupling constant between the olefinic protons
Acid
(+)-4a
cis-δ-iodo-γ-lactone trans-δ-iodo-γ-lactone γ-iodo-δ-lactone
(–)-5a
42.5
(+)-5a
40.4
(–)-5b
54.7
(+)-5b
55.7
(–)-6a
33.3
(+)-6a
35.3
(–)-6b
23.4
(+)-6b
26.7
(+)-7a
24.2
(–)-7a
24.3
(+)-7b
21.9
(–)-7b
17.6
(–)-4a
(+)-4b
(–)-4b
1
4-H and 5-H found in the H NMR spectra (J = 15.3 Hz
for esters 3a and 15.0 Hz for esters 3b). Confirmation of
configuration at C-3 was made for (+)-3a. In this case, com-
The products were separated by column chromatography
parison of the specific rotation sign determined for the and subjected to crystallization. Their structures were es-
product of its hydrolysis [acid (+)-(S)-4a] with reported data tablished on the basis of spectroscopic data and, for both
for the isomer of 4a obtained by Ocejo et al.,[28] proved the enantiomers of lactones 5a,b and 7a,b, also by crystallo-
S-configuration of both acid (+)-4a and ester (+)-3a. Based graphic analysis.
on these assignments, the absolute configuration of a whole
X-ray analysis of enantiomeric pairs of γ-lactones 5a,b
series of esters 3a,b was ascertained by analogy. Enantio- (Figure 1)[32] revealed the cis-orientation of the aromatic
meric pairs of esters 3a,b were analyzed by chiral GC analy- ring at C-4 and the iodoethyl substituent at C-5. The spatial
sis and their enantiomeric excesses remained the same as structure explains the appearance of the signal from proton
determined for starting allyl alcohols.
6-H at relatively high field (δ = 3.47 ppm in enantiomers of
The transfer of chirality in the Johnson–Claisen re- 5a and 3.46 ppm in enantiomers of 5b), which is caused by
arrangement of enzymatically resolved allyl alcohols with its location in the shielding cone of the aromatic ring. In
the 4-arylbut-3-en-2-ol system have been applied in the syn- contrast, the 6-H proton in the trans-γ-lactones 6a,b is situ-
thesis of different chiral chemicals such as (R)-baclofen,[29] ated out of the shielding area of aromatic ring and absorbs
cis-7-methoxy-calamenene,[30] and (R)- and (S)-3-methyl-2- the energy at significantly lower field in comparison to the
phenylbutylamine.[22] In our studies, esters 3a,b in both en- cis-isomers: δ = 4.38 ppm in the case of enantiomers of 6a
antiomerical form were used for the synthesis of optically and δ = 4.37 ppm in the case of enantiomers of 6b.
pure iodolactones (Scheme 1). In the first step, esters 3a,b
Different spatial orientations of the aromatic ring at C-4
were hydrolyzed in ethanolic NaOH solutions to the corre- and the iodomethyl substituent at C-5 towards the γ-lactone
sponding acids 4a,b in 72–91% yields. Their structures were ring also caused noticeable changes in the multiplicities of
confirmed by characteristic broad absorption bands from the signals from 5-H and 6-H. In the spectra of trans-γ-
the carboxylic group in the range 2700–3550 cm–1 in the IR lactones 6a,b proton 5-H gives an apparent triplet because
spectra and by the absence of signals from the ethoxy group of the same value of coupling constant with 4-H and 6-H
1
in the H NMR spectra. In all cases, the double bond re- (J = 5.4 Hz), whereas for cis-isomers 5a,b, the signal was
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β-Aryl-δ-iodo-γ-lactones and β-Aryl-γ-iodo-δ-lactones
Figure 1. Crystal structures of δ-iodo-γ-lactones: (a) (–)-(4R,5R,6S)-5a, (c) (–)-(4R,5R,6S)-5b, and their enantiomers: (b) (+)-(4S,5S,6R)-
5a and (d) (+)-(4S,5S,6R)-5b.
observed as doublet of doublets with J = 10.8 and 5.1 Hz. ure 2). This was possible because of sufficient anomal dis-
The signal from 6-H, which for cis-isomers was observed as persion for the iodine atoms.
a doublet of quartets, in the spectra of trans-isomers ap-
The results proved that from (+)-(S)-enantiomers of ac-
pears as a quartet of doublets because of the significant ids 4a,b, we obtained (–)-(4R,5R,6S)-enantiomers of cis-γ-
lower coupling constant between 6-H and 5-H (J = 5.4 Hz lactones (5a and 5b) and (+)-(4R,5R,6S)-enantiomers of δ-
for trans-isomers vs. J = 10.8 Hz for cis-isomers). According lactones (7a and 7b). Their antipodes: (+)-(4S,5S,6R)-
to the Karplus relationship, the vicinal coupling constants enantiomers of cis-γ-lactones (5a and 5b) and (–)-
are the results of different dihedral angles between corre- (4S,5S,6R)-enantiomers of δ-lactones (7a and 7b) were ob-
sponding bonds.[33] Analysis of the Dreiding models of ob- tained from (–)-(R)-enantiomers of acids 4a,b (Scheme 1).
tained lactones and J values found in the 1H NMR spectra
clearly confirmed the trans orientation of substituents in the meric pairs of trans-γ-lactones 6a,b, which could not be ob-
enantiomers of lactones 6a,b. tained in crystalline form, the mechanism of iodolactoniz-
To determine the absolute configurations for enantio-
Crystal structure of enantiomeric pairs of lactones 7a,b ation was taken into account. This is presented in Scheme 4
revealed the half-chair conformation of the six-membered for both enantiomers of acids 4a,b. The configuration at
ring and showed the relative orientations of the three sub- C-4 in both cis- and trans-iodolactones is the result of the
stituents (Figure 2).[32] They were located in energetically configuration of the starting acid. Considering lactoniz-
favorable pseudoequatorial positions, with the iodine atom ation of (S)-acids 4a,b, the change of configuration at C-4
at C-5 situated trans towards both the aryl ring at C-4 and from (S) to (R) is only the result of different priority of
the methyl group at C-6. Coupling constant values between substituents at the stereogenic center after formation of the
4-H, 5-H, and 6-H protons (J = 10.2 Hz for lactones 7a and iodonium ion and subsequent lactone ring closure. The
J = 10.5 for lactones 7b) were typical for their pseudoaxial configurations of the new stereogenic centers at C-5 and C-
orientations. The multiplet from the 6-H proton was shifted 6 results from the reaction mechanism in which the carb-
to δ = 4.78 ppm (in the case of lactones 7a) or 4.77 ppm (in oxylate ion attacks carbon C-5 from the opposite side of
the case of lactones 7b) through the deshielding effect of the iodonium ion;[34] the consequence of this is an antiper-
the oxygen atom in the lactone ring.
iplanar orientation of the C–O and C–I bonds (Figure 1).
The method of crystallographic analysis applied in our In the case of cis-isomers, the result of the aforementioned
studies also allowed the complete assignment of the abso- mechanism is R-configuration at C-5 and S-configuration
lute configuration of the stereogenic centers in the case of at C-6, which was confirmed by crystallographic measure-
enantiomeric pairs of cis-γ-lactones 5a and 5b (Figure 1) as ments for (–)-5a and (–)-5b; in the case of trans-isomers, the
well as enantiomeric pairs of δ-lactones 7a and 7b (Fig- same mechanism results in the opposite configurations (5S
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Figure 2. Crystal structures of γ-iodo-δ-lactones: (a) (–)-(4S,5S,6R)-7a, (c) (–)-(4S,5S,6R)-7b, and their enantiomers: (b) (+)-(4R,5R,6S)-
7a and (d) (+)-(4R,5R,6S)-7b.
Scheme 4. Formation of δ-iodo-γ-lactones during iodolactonization of enantiomeric acids 4a,b.
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β-Aryl-δ-iodo-γ-lactones and β-Aryl-γ-iodo-δ-lactones
Gas Chromatography Analysis: Analysis was performed with an
Agilent Technologies 6890N instrument equipped with autosam-
pler, split injection (50:1) and FID detector. The progress of reac-
tions were monitored on DB-17 column [(50%-phenyl)-methyl-
polysiloxane, 30 mϫ0.25 mmϫ 0.25 μm] with hydrogen as carrier
gas. Temperature programme for the analysis of alcohols 1a,b,
propionates 2a,b, esters 3a,b and acids 4a,b was as follows: 80 °C
(1 min), 80–200 °C (20 °C min–1), 200–300 °C (30 °C min–1), 300 °C
(2 min); for iodolactones 5a,b–7a,b: injector 280 °C, detector (FID)
280 °C, column temperature: 220 °C, 220–240 °C (3 °C min–1),
240–280 °C (30 °C min–1), 280 °C (2 min). The enantiomeric ex-
cesses were determined by chiral gas chromatography (CGC) using
Varian CP Chirasil-DEX CB column (25 mϫ 0.25 mmϫ 0.25 μm)
with following temperature programs: for products of transesterifi-
cation of alcohol 1a: 80 °C, 80–130 °C (0.5 °C min–1), 130–200 °C
(30 °C min–1), 200 °C (2 min), for products of transesterification of
alcohol 1b: 80 °C, 80–150 °C (2 °C min–1), 150–200 °C (10 °C
min–1), 200 °C (2 min), for iodolactones 5b–7b: 80 °C, 80–200 °C
(2 °C min–1), 200 °C (3 min), for esters 3a,b, acids 4a,b and iodo-
lactones 5a–7a: 50 °C, 50–200 °C (0.5 °C min–1), 200 °C (1 min).
Enantiomers of alcohol 1b were analyzed as acetate derivatives af-
ter treating with acetyl chloride. Racemic compounds 1–7 a,b[19]
were used as the standards.
and 6R). Overall, trans-γ-lactones 6a,b obtained from (+)-
(S)-acids 4a,b possessed configurations 4R, 5S, and 6R. For
trans-γ-lactones 6a,b obtained from (–)-(R)-acids 4a,b, par-
allel reasoning led to the assignment of configurations of
stereogenic centers as 4S, 5R, and 6S.
The cis-γ-lactones were obtained in higher yields (36–
41%). Chiral GC analysis of all synthesized iodolactones
revealed their high optical purity, with enantiomeric ex-
cesses of 97–99%.
Conclusions
An efficient synthetic pathway leading to chiral β-aryl-
substituted iodolactones was developed. From the stereo-
chemical point of view, the crucial steps of the presented
pathway were lipase-catalyzed resolution of starting race-
mic allyl alcohols and transfer of the chirality to the benz-
ylic atom C-3 of γ,δ-unsaturated esters formed by the John-
son–Claisen rearrangement. Six new enantiomeric pairs of
iodolactones with high to excellent enantiomeric excesses
were obtained as the final products of this pathway. Config-
urations of their stereogenic centers, which were predicted
on the basis of iodolactonization mechanism, were con-
firmed by X-ray analysis. The presented chemoenzymatic
strategy constitutes a universal approach to the synthesis of
enantiomerically pure or enriched δ-iodo-γ-lactones and γ-
iodo-δ-lactones containing different aromatic rings at the β-
position of the lactone ring. Moreover, it may be employed
for the synthesis of other halolactones, for example chloro-
or bromolactones. The enantiomers of halolactones may be
further transformed into other chiral lactone derivatives
with clearly defined stereogenic centers, which is important
in the context of testing their biological activities.
Spectroscopic Analysis: 1H, 13C NMR (including DEPT 135 experi-
ment) and HMQC spectra were recorded for CDCl3 solutions with
a Bruker Avance AMX 300 spectrometer. Residual solvent signals
(δH = 7.26, δC = 77.0) were used as references for chemical shifts. IR
spectra were determined with a Mattson IR 300 Thermo Nicolet
spectrophotometer using KBr pellets or in liquid films. Mass spec-
tra were recorded at the Structural Research Laboratory of the
UJK University in Kielce by using the electron spray ionization
(ESI) technique with a Bruker micrOTOF-Q II system. Melting
points were determined with a Boetius apparatus. Refraction in-
dexes were measured with a Carl Zeiss Jena refractometer. Optical
rotations were measured with a Jasco P-2000-Na digital polarime-
ter with intelligent Remote Module (iRM) controller. Compounds
were dissolved in dichloromethane, concentrations are denoted in
gϫ 100 mL–1.
General Protocol for Kinetic Resolution of rac-1a,b by Enzymatic
Transesterification: Lipase B from C. antartica (50 wt.-% of
alcohol) was placed in a 250 mL round-bottom flask containing a
mixture of racemic alcohol (33 mmol) and vinyl propionate
(46 mmol) in diisopropyl ether (50 mL). The reaction was stirred
at room temperature for 2 h, then the enzyme was filtered off and
the organic solvent was removed by rotary evaporation in vacuo.
Enantiomerically enriched products were separated by column
chromatography (hexane/acetone, 5:1).
Experimental Section
Chemicals: Triethyl orthoacetate (purity 97%), vinyl propionate
(purity 98%), diisopropyl ether (DIPE, purity Ն 98.5%), acetyl
chloride (purity Ն 99%), diatomaceous earth (Celite 560) and
lipase B from Candida antarctica immobilized in a macroporous
acrylic resin (Ͼ 5,000 U/g) were purchased from Sigma–Aldrich
(USA). Propionic acid, sodium hydrogen carbonate, potassium iod-
ide, iodine, anhydrous magnesium sulfate, organic solvents (diethyl
ether, methanol, ethanol), sodium hydroxide, and sodium chloride,
all of analytical grade, and hydrochloric acid (35–37%) were pur-
chased from P.P.H. Stanlab (Poland), Chempur (Poland), or POCH
(Poland). Racemic alcohols (E)-4-phenylbut-3-en-2-ol (rac-1a) and
(E)-4-phenylbut-3-en-2-ol (rac-1b) were synthesized as described
earlier.[19]
Process of transesterification of racemic alcohol 1a (4.98 g,
33 mmol) gave the following products:
(–)-(2S,3E)-4-Phenylbut-3-en-2-ol [(–)-1a]: Yield 2.3 g (46%); color-
less crystals; m.p. 54–56 °C; ee Ͼ 99%; tR = 60.18 min; Rf = 0.23
[hexane/acetone (4:1 v/v)]; [α]2D0 = –23.7 (c = 2.6, CH2Cl2) [ref.[20]
[α]2D0 = –19.9 (c = 1.0, CH2Cl2), ee Ͼ 99%]. Spectral data are iden-
tical to the reported values.[21]
Chromatographic Separations: Column chromatography was per-
formed on silica gel (Kieselgel 60, 230–400 mesh, Merck) using
mixtures of hexane and acetone in various ratios as the eluents.
Analytical thin-layer chromatography (TLC) was performed on sil-
(+)-(2R,3E)-4-Phenylbut-3-en-2-yl Propionate [(+)-2a]: Yield 3.1 g
(45%); pale-brown liquid; n2D0 = 1.5160; ee = 99%; tR = 71.12 min;
Rf = 0.64 [hexane/acetone (4:1 v/v)]; [α]2D0 = +115.9 (c = 2.1,
CH2Cl2) [ref.[26] [α]2D0 = +70.0 (c = 0.6, CHCl3); ee = 66%]. Spectral
data are identical to the reported values.[35]
ica gel coated aluminum plates (DC-Alufolien Kieselgel 60 F254
,
Merck) with mixtures of hexane and acetone (different ratios) as
developing systems. Compounds were visualized by spraying the
plates with a solution of 1% Ce(SO4)2 and 2% H3[P(Mo3O10)4] in
10% H2SO4.
Process of transesterification of racemic alcohol 1b (5 g, 31 mmol)
gave the following products:
Eur. J. Org. Chem. 2015, 605–615
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611

W. Gładkowski et al.
(–)-(2S,3E)-4-(4Ј-Methylphenyl)but-3-en-2-ol [(–)-1b]: Yield 2.45 g (–)-(3R,4E)-Ethyl 3-Phenylhex-4-enoate [(–)-3a]: Obtained from
FULL PAPER
(47%); colorless crystals; m.p. 36–42 °C; ee = 95% (determined af-
ter derivatization into acetate); tR = 27.00 min; Rf = 0.23 [hexane/
alcohol (+)-1a (2.0 g, 13.5 mmol), yield 2.32 g (79%); yellow liquid;
n2D0 = 1.5030; ee = 99%; tR = 119.01 min; [α]2D0 = –8.3 (c = 2.55,
CH2Cl2). Spectral data identical to those of (+)-3a.
acetone (4:1 v/v)]; [α]2D0 = –22.8 (c = 1.8, CH2Cl2) [ref.[25] [α]2D5
=
–22.8 (c = 1, CHCl3); ee = 99%]. Spectral data are identical to
(+)-(3S,4E)-Ethyl 3-(4Ј-Methylphenyl)-hex-4-enoate [(+)-3b]: Ob-
tained from alcohol (–)-1b (2.40 g, 15 mmol), yield 2.99 g (87%);
yellow liquid; n2D0 = 1.5050; ee = 95%; tR = 138.14 min; [α]2D0 = +8.9
reported values.[36]
(+)-(2R,3E)-4-(4Ј-Methylphenyl)but-3-en-2-yl Propionate [(+)-2b]:
Yield 2.55 g (38%); pale-brown liquid; n2D0 = 1.5348; ee = 88%; tR
= 31.30 min; Rf = 0.65 [hexane/acetone (4:1 v/v)]; [α]2D0 = +111.8 (c
(c = 1.25, CH Cl ). IR (film): ν = 1736 (s), 1514 (m), 1248 (s),
˜
max
2
2
1158 (m), 1037 (s), 968 (m), 816 (m) cm–1. 1H NMR (300 MHz,
CDCl3): δ = 1.18 (t, J = 7.2 Hz, 3 H, -OCH2CH3), 1.65 (d, J =
6.6 Hz, 3 H, CH3-6), 2.31 (s, 3 H, Ph-CH3), 2.65 (dd, J = 15.0,
7.2 Hz, 1 H, one of CH2-2), 2.68 (dd, J = 15.0, 8.4 Hz, 1 H, one
of CH2-2), 3.77 (m, 1 H, 3-H), 4.08 (q, J = 7.2 Hz, 2 H,
-OCH2CH3), 5.49 (dq, J = 15.0, 6.6 Hz, 1 H, 5-H), 5.58 (ddq, J =
15.0, 7.2, 1.2 Hz, 1 H, 4-H), 7.09–7.13 (m, 4 H, p-C6H4) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.2 (-OCH2CH3), 17.9 (C-6), 21.0
(Ph-CH3), 41.0 (C-2), 44.5 (C-3), 60.2 (-OCH2CH3), 125.3 (C-5),
127.2 (C-2Ј and C-6Ј), 129.2 (C-3Ј and C-5Ј), 133.3 (C-4), 135.9 (C-
1Ј), 140.4 (C-4Ј), 172.0 (C-1) ppm. HRMS (ESI): m/z calcd. for
C15H20O2 [M + Na]+ 255.1361; found 255.1336.
= 1.7, CH Cl ). IR (film): νmax = 1736 (s), 1610 (w), 1514 (m), 1187
˜
2
2
(s), 1039 (m), 969 (m), 801 (m) cm–1. 1H NMR (300 MHz, CDCl3):
δ = 1.18 [t, J = 7.5 Hz, 3 H, C(O)CH2CH3], 1.43 (d, J = 6.6 Hz, 3
H, CH3-1), 2.35 (s, 3 H, CH3-8), 2.36 [q, J = 7.5 Hz, 2 H, C(O)
CH2CH3], 5.57 (m, 1 H, 2-H), 6.17 (dd, J = 15.9, 6.6 Hz, 1 H, 3-
H), 6.60 (d, J = 15.9 Hz, 1 H, 4-H), 7.12–7.15 (m, 2 H, 2Ј-H and 6Ј-
H), 7.28–7.31 (m, 2 H, 3Ј-H and 5Ј-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 8.9 [C(O)CH2CH3], 20.2 (C-1), 20.9 (C-8), 27.6 [C(O)
CH2CH3], 70.6 (C-2), 126.2 (C-2Ј and C-6Ј), 129.0 (C-3Ј and C-
5Ј), 127.6 (C-3), 131.2 (C-4), 133.4 (C-1Ј), 137.4 (C-4Ј), 173.3 (C-
5) ppm. HRMS (ESI): m/z calcd. for C14H18O2 [M + Na]+
241.1204; found 241.1212.
(–)-(3R,4E)-Ethyl 3-(4Ј-Methylphenyl)-hex-4-enoate [(–)-3b]: Ob-
tained from alcohol (+)-1b (1.8 g, 11 mmol), yield 2.16 g (84%);
yellow liquid; n2D0 = 1.5050; ee = 88%; tR = 137.72 min; [α]2D0 = –8.7
(c = 0.25, CH2Cl2). Spectral data identical to those of (+)-3b.
General Protocol for Hydrolysis of Esters (+)-2a,b: The ester
(12 mmol) was heated to reflux in a mixture of 5% solution of
NaOH in EtOH (100 mL) and water (20 mL). When the substrate
reacted completely (3 h, TLC), the ethanol was evaporated in vacuo
and the residue was diluted with water. The product was extracted
with dichloromethane (3ϫ 40 mL) and the combined organic frac-
tions were washed with brine until neutral and dried with anhy-
drous MgSO4. After evaporation of solvent in vacuo, pure alcohol
was obtained.
General Protocol for the Synthesis of γ,δ-Unsaturated Acids (+)-4a,b
and (–)-4a,b: The ester (11 mmol) was heated to reflux in 5% eth-
anol solution of NaOH (100 mL). When the reaction was com-
pleted (3 h, TLC, GC), ethanol was evaporated in vacuo. The resi-
due was diluted with water and washed with diethyl ether (3ϫ
40 mL) to remove organic impurities. After separation of the layers,
the aqueous layer was acidified with 1 m HCl and the acid was
extracted with diethyl ether (3ϫ 40 mL). The ethereal fractions
were combined, washed with brine and dried with anhydrous
MgSO4. After evaporation of the solvent in vacuo, pure acid was
obtained.
(+)-(2R,3E)-4-Phenylbut-3-en-2-ol [(+)-1a]: Obtained from prop-
ionate (+)-2a (3 g, 15 mmol), yield 2.1 g (96%); colorless crystals;
m.p. 53–55 °C; ee = 99%; tR = 59.27 min; [α]2D0 = +22.9 (c = 1.6,
CH2Cl2) [ref.[20] [α]2D0 = +19.9 (c = 1, CH2Cl2); ee Ͼ 99%]. Spectral
data are identical to the reported values for (–)-1a.[21]
(+)-(2R,3E)-4-(4Ј-Methylphenyl)but-3-en-2-ol [(+)-1b]: Obtained
from propionate (+)-2b (2.5 g, 11 mmol), yield 1.81 g (98%); color-
less crystals; m.p. 46–49 °C; ee = 96% (determined after derivati-
zation to the acetate); tR = 27.75 min; [α]2D0 = +22.5 (c = 1.5,
CH2Cl2) [ref.[37] [α]2D5 = +20.9 (c = 0.8, CHCl3); ee = 98%]. Spectral
data are identical to the reported values for (–)-1b.[36]
(+)-(3S,4E)-3-Phenylhex-4-enoic Acid [(+)-4a]: Obtained from ester
(+)-3a (2.5 g, 11 mmol), yield 1.90 g (87%); brown liquid; n2D0
=
1.5162; ee Ͼ 99%; tR = 184.39 min, [α]2D0 = +6.2 (c = 2.0, CH2Cl2)
[ref.[28] [α]2D0 = +7.3 (c = 1.0, CH2Cl2]. Spectral data in accordance
with reported values.[28]
(–)-(3R,4E)-3-Phenylhex-4-enoic Acid [(–)-4a]: Obtained from ester
(–)-3a (2.3 g, 10.5 mmol), yield 1.78 g (89%); brown liquid; ee =
99%; tR = 184.91 min; [α]2D0 = –5.4 (c = 2.4, CH2Cl2). Spectral data
identical to the reported values for the (S)-enantiomer [(+)-4a].[28]
General Protocol for the Synthesis of γ,δ-Unsaturated Esters (+)-
3a,b and (–)-3a,b: Allyl alcohol (15 mmol) was dissolved in triethyl
orthoacetate (273 mmol) and one drop of propionic acid was
added. The mixture was heated at 138 °C with simultaneous re-
moval of ethanol by distillation. When the reaction was finished
(24 h, TLC, GC), the crude product was purified by column
chromatography (hexane/acetone, 10:1) to afford the pure ester.
(+)-(3S,4E)-3-(4Ј-Methylphenyl)hex-4-enoic Acid [(+)-4b]: Obtained
from ester (+)-3b (2.9 g, 12.5 mmol), yield 1.83 g (72%); brown li-
quid; n2D0 = 1.5233; ee = 95%; tR = 197.77 min; [α]2D0 = +4.6 (c =
1.1, CH Cl ). IR (film): ν = 2700–3550 (b, s), 1710 (s), 1514
˜
max
2
2
(+)-(3S,4E)-Ethyl 3-Phenylhex-4-enoate [(+)-3a]: Obtained from
(m), 1439 (s), 1266 (s), 968 (s), 815 (s), 738 (s) cm–1. 1H NMR
(300 MHz, CDCl3): δ = 1.68 (d, J = 5.4 Hz, 3 H, CH3-6), 2.33 (s,
3 H, Ph-CH3), 2.73 (m, 2 H, CH2-2), 3.78 (m, 1 H, 3-H), 5.51 (dq,
J = 15.3, 5.4 Hz, 1 H, 5-H), 5.60 (dd, J = 15.3, 7.2 Hz, 1 H, 4-H),
7.09–7.15 (m, 4 H, p-C6H4) ppm. 13C NMR (75 MHz, CDCl3): δ
= 17.9 (C-6), 21.0 (C-7), 40.6 (C-2), 44.0 (C-3), 125.6 (C-5), 127.2
(C-2Ј and C-6Ј), 129.3 (C-3Ј and C-5Ј), 133.0 (C-4), 136.1 (C-1Ј),
140.0 (C-4Ј), 178.0 (C-1) ppm. HRMS (ESI): m/z calcd. for
C13H16O2 [M + Na]+ 227.1048; found 227.1074.
alcohol (–)-1a (2.2 g, 15 mmol), yield 2.6 g (80%); yellow liquid; n
20
= 1.5030; ee Ͼ 99%; tR = 119.83 min; [α]2D0 = +8.0 (c = 2.1,
D
CH Cl ). IR (film): ν
= 3028 (w), 2979 (m), 1735 (s), 1159 (s),
˜
2
2
max
1
757 (m), 699 (s) cm–1. H NMR (300 MHz, CDCl3): δ = 1.15 (t, J
= 6.9 Hz, 3 H, -OCH2CH3), 1.63 (d, J = 6.0 Hz, 3 H, CH3-6), 2.66
(m, 2 H, CH2-2), 3.78 (m, 1 H, 3-H), 4.05 (q, J = 6.9 Hz, 2 H,
-OCH2CH3), 5.47 (dq, J = 15.3, 6.0 Hz, 1 H, 5-H), 5.58 (dd, J =
15.3, 7.5 Hz, 1 H, 4-H), 7.18–7.35 (m, 5 H, -C6H5) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.1 (C-8), 17.9 (C-6), 41.0 (C-2), 44.9 (C-
3), 60.2 (C-7), 125.6 (C-5), 126.4 (C-4Ј), 127.4 (C-2Ј and C-6Ј),
128.5 (C-3Ј and C-5Ј), 133.1 (C-4), 143.3 (C-1Ј), 172.0 (C-1) ppm.
HRMS (ESI): m/z calcd. for C14H18O2 [M + Na]+ 241.1204; found
241.1200.
(–)-(3R,4E)-3-(4Ј-Methylphenyl)hex-4-enoic Acid [(–)-4b]: Obtained
from ester (–)-3b (2.1 g, 9 mmol), yield 1.70 g (91%); brown liquid;
ee = 88%; tR = 198.70; [α]2D0 = –4.4 (c = 0.95, CH2Cl2). Spectral
data identical to those of (+)-4b.
612
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 605–615

β-Aryl-δ-iodo-γ-lactones and β-Aryl-γ-iodo-δ-lactones
General Protocol for the Synthesis of Iodolactones (–)-5a–b, (–)-6a– ture hexane/acetone, 20:1); m.p. 100–103 °C; ee = 97 %; tR
=
b, (+)-7a–b and (+)-5a–b, (+)-6a–b, (–)-7a–b: A mixture of acid 198.23 min; [α]2D0 = +14.8 (c = 1.3, CH2Cl2). Retardation factor and
(10 mmol) dissolved in a mixture of diethyl ether (20 mL) and a
saturated solution of NaHCO3 (20 mL) was stirred for 1 h at room
temperature and then a solution of I2 (20 mmol) and KI (60 mmol)
in water (6 mL) was added dropwise. When the acid reacted com-
pletely (24 h, TLC, GC), the mixture was washed with saturated
Na2S2O3 solution. The two layers were separated and the organic
fraction was washed with saturated NaHCO3, brine, and dried with
anhydrous MgSO4. After vacuum evaporation of diethyl ether, the
products were separated by column chromatography (hexane/acet-
one, 20:1).
spectroscopic data were identical to those of (–)-5a.
(+)-trans-(4S,5R,6S)-5-(1-Iodoethyl)-4-phenyldihydrofuran-2-one
[(+)-6a]: Yield 0.6 g (21 %); brown liquid; ee = 98 %; tR
=
214.26 min; [α]2D0 = +6.7 (c = 1.1, CH2Cl2). Retardation factor and
spectroscopic data were identical to those of (–)-6a.
(–)-(4S,5S,6R)-5-t-Iodo-6-c-methyl-4-r-phenyltetrahydropyran-2-one
[(–)-7a]: Yield 0.22 g (8%); colorless crystals (crystallization from
mixture hexane/acetone, 20:1); m.p. 85–88 °C; ee = 99 %; tR
=
218.91 min; [α]2D0 = –7.2 (c = 0.95, CH2Cl2). Retardation factor and
spectroscopic data were identical to those of (+)-7a.
From acid (+)-4a (1.85 g, 10 mmol) the following iodolactones were
obtained:
From acid (+)-4b (1.7 g, 8 mmol) following iodolactones were ob-
tained:
(–)-cis-(4R,5R,6S)-5-(1-Iodoethyl)-4-phenyldihydrofuran-2-one [(–)-
5a]: Yield 1.1 g (36%); colorless crystals (crystallization from mix-
(–)-cis-(4R,5R,6S)-5-(1-Iodoethyl)-4-(4Ј-methylphenyl)dihydrofuran-
2-one [(–)-5b]: Yield 1.04 g (38%); colorless crystals (crystallization
from mixture hexane/acetone, 20:1); m.p. 87–90 °C; ee = 98%; tR
= 46.17 min; Rf = 0.45 [hexane/acetone (4:1 v/v)]; [α]2D0 = –6.5 (c =
ture hexane/acetone, 20:1); m.p. 104–106 °C; ee Ͼ 99%; tR
199.09 min; Rf = 0.43 [hexane/acetone (4:1 v/v)]; [α]2D0 = –15.7 (c =
1.4, CH Cl ). IR (KBr): ν = 1779 (s), 1416 (s), 1183 (s), 1136
=
˜
max
2
2
(s), 1005 (s), 755 (s), 706 (s), 535 (s) cm–1. 1H NMR (300 MHz, 0.7, CH Cl ). IR (KBr): ν
= 1791 (s), 1449 (s), 1180 (s), 1139
˜
max
2
2
1
CDCl3): δ = 2.01 (d, J = 6.6 Hz, 3 H, CH3-7), 2.71 (dd, J = 17.7,
0.9 Hz, 1 H, one of CH2-3), 3.14 (dd, J = 17.7, 8.7 Hz, 1 H, one
(s), 960 (s), 829 (s), 498 (s) cm–1. H NMR (300 MHz, CDCl3): δ
= 2.01 (d, J = 6.9 Hz, 3 H, CH3-7), 2.34 (s, 3 H, Ph-CH3), 2.68 (d,
of CH2-3), 3.47 (dq, J = 10.8, 6.6 Hz, 1 H, 6-H), 3.91 (dd, J = 8.4, J = 17.4 Hz, 1 H, one of CH2-3), 3.13 (dd, J = 17.4, 8.4 Hz, 1 H,
5.1 Hz, 1 H, 4-H), 4.82 (dd, J = 10.8, 5.1 Hz, 1 H, 5-H), 7.25–7.35 one of CH2-3), 3.46 (dq, J = 10.8, 6.9 Hz, 1 H, 6-H), 3.86 (dd, J =
(m, 5 H, -C6H5) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.3 (C- 8.4, 5.1 Hz, 1 H, 4-H), 4.80 (dd, J = 10.8, 5.1 Hz, 1 H, 5-H), 7.10–
6), 25.5 (C-7), 38.9 (C-3), 45.0 (C-4), 87.8 (C-5), 128.0 (C-4Ј), 128.5 7.17 (m, 4 H, p-C6H4) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.0
(C-2Ј and C-6Ј), 128.7 (C-3Ј and C-5Ј), 137.3 (C-1Ј), 176.4 (C- (Ph-CH3), 23.5 (C-6), 25.5 (C-7), 38.9 (C-3), 44.5 (C-4), 87.8 (C-5),
2) ppm. HRMS (ESI): m/z calcd. for C12H13IO2 [M + Na]+
338.9858; found 338.9874.
128.4 (C-2Ј and C-6Ј), 129.4 (C-3Ј and C-5Ј), 134.2 (C-1Ј), 137.7
(C-4Ј), 176.6 (C-2) ppm. HRMS (ESI): m/z calcd. for C13H15IO2
[M + Na]+ 353.0014; found 352.9989.
(–)-trans-(4R,5S,6R)-5-(1-Iodoethyl)-4-phenyldihydrofuran-2-one [(–)-
6a]: Yield 0.61 g (20%); brown liquid; ee = 95%; tR = 212.11 min;
Rf = 0.35 [hexane/acetone (4:1 v/v)]; [α]2D0 = –16.3 (c = 1.1, CH2Cl2).
(–)-trans-(4R,5S,6R)-5-(1-Iodoethyl)-4-(4Ј-methylphenyl)dihydro-
furan-2-one [(–)-6b]: Yield 0.52 g (19%); oily liquid; ee = 97%; tR
= 86.61 min; Rf = 0.39 [hexane/acetone (4:1 v/v)]; [α]2D0 = –8.4 (c =
IR (KBr): ν
= 1781 (s), 1494 (m), 1200 (s), 1149 (s), 1027 (s),
˜
max
768 (s), 700 (s), 524 (s) cm–1. 1H NMR (300 MHz, CDCl3): δ =
1.86 (d, J = 6.9 Hz, 3 H, CH3-7), 2.68 (dd, J = 18.3, 6.6 Hz, 1 H,
one of CH2-3), 3.16 (dd, J = 18.3, 10.2 Hz, 1 H, one of CH2-3),
3.64 (ddd, J = 10.2, 6.6, 5.4 Hz, 1 H, 4-H), 4.26 (t, J = 5.4 Hz, 1
H, 5-H), 4.38 (qd, J = 6.9, 5.4 Hz, 1 H, 6-H), 7.26–7.41 (m, 5 H, -
C6H5) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.4 (C-7), 28.4 (C-
6), 37.7 (C-3), 45.4 (C-4), 89.4 (C-5), 127.0 (C-2Ј and C-6Ј), 127.7
(C-4Ј), 129.3 (C-3Ј and C-5Ј), 141.2 (C-1Ј), 174.8 (C-2) ppm.
HRMS (ESI): m/z calcd. for C12H13IO2 [M + K]+ 354.9597; found
354.9653.
3.9, CH Cl ). IR (film): ν = 1782 (s), 1516 (m), 1149 (s), 1185
˜
max
2
2
(s), 1030 (s), 814 (m), 539 (s) cm–1. H NMR (300 MHz, CDCl3):
δ = 1.85 (d, J = 7.2 Hz, 3 H, CH3-7), 2.34 (s, 3 H, Ph-CH3), 2.65
(dd, J = 18.3, 6.6 Hz, 1 H, one of CH2-3), 3.13 (dd, J = 18.3,
10.2 Hz, 1 H, one of CH2-3), 3.59 (ddd, J = 10.2, 6.6, 5.4 Hz, 1 H,
4-H), 4.23 (t, J = 5.4 Hz, 1 H, 5-H), 4.37 (qd, J = 7.2, 5.4 Hz, 1
H, 6-H), 7.13–7.20 (m, 4 H, p-C6H4) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.1 (C-7), 23.4 (Ph-CH3), 28.5 (C-6), 37.9 (C-3), 45.1
(C-4), 89.6 (C-5), 127.0 (C-2Ј and C-6Ј), 130.0 (C-3Ј and C-5Ј),
137.6 (C-4Ј), 138.33 (C-1Ј), 175.0 (C-2) ppm. HRMS (ESI): m/z
calcd. for C13H15IO2 [M + K]+ 368.9754; found 368.9796.
1
(+)-(4R,5R,6S)-5-t-Iodo-6-c-methyl-4-r-phenyltetrahydropyran-2-
one [(+)-7a]: Yield 0.21 g (7%); colorless crystals (crystallization
from mixture hexane/acetone, 20:1); m.p. 78–80 °C; ee Ͼ 99%; tR
= 217.99 min; Rf = 0.31 [hexane/acetone (4:1 v/v)]; [α]2D0 = +7.5 (c
(+)-(4R,5R,6S)-5-t-Iodo-6-c-methyl-4-r-(4Ј-methylphenyl)tetra-
hydropyran-2-one [(+)-7b]: Yield 0.19 g (7 %); colorless crystals
(crystallization from mixture hexane/acetone, 20:1); m.p. 74–76 °C;
ee Ͼ 99%; tR = 88.57 min; Rf = 0.34 [hexane/acetone (4:1 v/v)];
= 0.7, CH Cl ). IR (KBr): ν = 1721 (s), 1453 (m), 1253 (s),
˜
max
2
2
1
1226 (s), 1043 (s), 968 (m), 759 (s), 701 (s), 538 (s) cm–1. H NMR
(300 MHz, CDCl3): δ = 1.75 (d, J = 6.3 Hz, 3 H, CH3-7), 2.68 (dd,
J = 17.7, 10.2 Hz, 1 H, one of CH2-3), 2.99 (dd, J = 17.7, 6.3 Hz,
1 H, one of CH2-3), 3.50 (td, J = 10.2, 6.3 Hz, 1 H, 4-H), 4.05 (t,
J = 10.2 Hz, 1 H, 5-H), 4.78 (dq, J = 10.2, 6.3 Hz, 1 H, 6-H), 7.16–
7.41 (2m, 5 H, -C6H5) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.3
(C-7), 34.3 (C-5), 37.8 (C-3), 48.6 (C-4), 81.1 (C-6), 126.8 (C-2Ј and
C-6Ј), 128.0 (C-4Ј), 129.1 (C-3Ј and C-5Ј), 142.3 (C-1Ј), 169.5 (C-
2) ppm. HRMS (ESI): m/z calcd. for C12H13IO2 [M + Na]+
338.9858; found 338.9889.
[α]2D0 = +19.7 (c = 0.7, CH Cl ). IR (KBr): ν
= 1724 (s), 1516
˜
max
2
2
(m), 1257 (s), 1233 (s), 1095 (s), 527 (m) cm–1. 1H NMR (300 MHz,
CDCl3): δ = 1.74 (d, J = 6.3 Hz, 3 H, CH3-7), 2.35 (s, 3 H, Ph-
CH3), 2.65 (dd, J = 17.7, 10.2 Hz, 1 H, one of CH2-3), 2.96 (dd, J
= 17.7, 6.6 Hz, 1 H, one of CH2-3), 3.45 (td, J = 10.5, 6.6 Hz, 1
H, 4-H), 4.04 (t, J = 10.5 Hz, 1 H, 5-H), 4.77 (dq, J = 10.5, 6.3 Hz,
1 H, 6-H), 7.04–7.06 (m, 2 H, 2Ј-H and 6Ј-H), 7.18–7.20 (m, 2 H,
3Ј-H and 5Ј-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.2 (C-7),
22.4 (Ph-CH3), 34.8 (C-5), 38.0 (C-3), 48.2 (C-4), 81.2 (C-6), 126.8
(C-2Ј and C-6Ј), 129.8 (C-3Ј and C-5Ј), 137.8 (C-4Ј), 139.4 (C-1Ј),
169.7 (C-2) ppm. HRMS (ESI): m/z calcd. for C13H15IO2 [M +
K]+ 368.9754; found 368.9745.
From acid (–)-4a (1.72 g, 9 mmol) the following iodolactones were
obtained:
(+)-cis-(4S,5S,6R)-5-(1-Iodoethyl)-4-phenyldihydrofuran-2-one [(+)-
5a]: Yield 1.1 g (39%); colorless crystals (crystallization from mix-
From acid (–)-4b (1.65 g, 8 mmol), the following iodolactones were
obtained:
Eur. J. Org. Chem. 2015, 605–615
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
613

W. Gładkowski et al.
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β-Aryl-δ-iodo-γ-lactones and β-Aryl-γ-iodo-δ-lactones
[32] CCDC-1028464 [for (+)-5a], -1028465 [for (–)-5a], -1028466
[for (+)-5b], -1028467 [for (–)-5b] -1028468 [for (+)-7a],
-1028469 [for (–)-7a], -1028470 [for (+)-7b] and -1028471 [for
(–)-7b] contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
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Received: October 13, 2013
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Published Online: December 9, 2014
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www.eurjoc.org
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