Total syntheses of cis-cyclopropane fatty acids: Dihydromalvalic acid, dihydrosterculic acid, lactobacillic acid, and 9,10-methylenehexadecanoic acid

Article abstract of DOI:10.1039/c4ob01863j

cis-Cyclopropane fatty acids (cis-CFAs) are widespread constituents of the seed oils of subtropical plants, membrane components of bacteria and protozoa, and the fats and phospholipids of animals. We describe a systematic approach to the synthesis of enan

Full text of DOI:10.1039/c4ob01863j

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Total syntheses of cis-cyclopropane fatty acids:
dihydromalvalic acid, dihydrosterculic acid,
lactobacillic acid, and 9,10-methylenehexa-
decanoic acid†
Cite this: DOI: 10.1039/c4ob01863j
Sayali Shah, Jonathan M. White and Spencer J. Williams*
cis-Cyclopropane fatty acids (cis-CFAs) are widespread constituents of the seed oils of subtropical plants,
membrane components of bacteria and protozoa, and the fats and phospholipids of animals. We describe
a systematic approach to the synthesis of enantiomeric pairs of four cis-CFAs: cis-9,10-methylenehexa-
decanoic acid, lactobacillic acid, dihydromalvalic acid, and dihydrosterculic acid. The approach
commences with Rh2(OAc)4-catalyzed cyclopropenation of 1-octyne and 1-decyne, and hinges on the
preparative scale chromatographic resolution of racemic 2-alkylcycloprop-2-ene-1-carboxylic acids
using a homochiral Evan’s auxiliary. Saturation of the individual diastereomeric N-cycloprop-2-ene-1-car-
bonylacyloxazolidines, followed by elaboration to alkylcyclopropylmethylsulfones, allowed Julia–
Kocienski olefination with various ω-aldehyde-esters. Finally, saponification and diimide reduction
afforded the individual cis-CFA enantiomers.
Received 1st September 2014,
Accepted 1st October 2014
DOI: 10.1039/c4ob01863j
www.rsc.org/obc
from Caenorhabditis elegans, ornithine lipids from Rhizobacter-
ium tropici,9 and a lysophosphatidylcholine from the marine
Introduction
cis-Cyclopropane fatty acids (cis-CFAs) are widely distributed in sponge Spirastrella abata.10 Efforts to determine the structures
microorganisms,1 the seed oils of sub-tropical plants,2 proto- and study the biological activity of these and other cis-CFA con-
zoa,3 and less commonly, within fats and phospholipids pro- taining molecules would benefit from effective approaches to
duced by animals.4 They are biosynthesized by methylenation synthesize these molecules in enantiopure form.
of cis-unsaturated fatty acids (typically when esterified to phos-
Prominent cis-CFAs include those derived from: cis-palmito-
pholipid) with S-adenosylmethionine, catalyzed by CFA leic acid (cis-Δ9 C16:1), namely cis-9,10-methylenehexadeca-
synthases.5 cis-CFAs are common components of bacterial noic acid;11 8Z-heptadecenoic acid (cis-Δ8 C17:1), namely
membrane constituents, including phospholipids and glyco- dihydromalvalic acid;12 oleic acid (cis-Δ9 C18:1), namely di-
lipids.1 In bacteria, cis-CFA synthesis peaks in late exponential/ hydrosterculic acid;13 and cis-vaccenic acid (cis-Δ11 C18:1),
early stationary phase, and it has been speculated that this namely lactobacillic acid14 (Fig. 1). In nature, cis-9,10-methyl-
modification results in alteration of membrane fluidity that enehexadecanoic acid occurs as the 9R,10S enantiomer in
assists in adaptation to stationary phase.1 Additionally, CFAs Esherichia coli15 and the 9S,10R isomer in the slime mold
are chemically more stable against oxidative conditions than P. polycephalum.16 Lactobacillic acid exists as the 11R,12S
the unsaturated precursors, and may provide protective pro- isomer in L. plantarum,17 E. coli,15 and Brucella melitensis.18
perties when incorporated into membrane components.1 cis- Dihydrosterculic acid has been obtained as the 9R,10S isomer
CFA-containing natural products with notable biological activi- from the plant Litchi chinensis,19 and the 9S,10R isomer from
ties include PHYLPA6 from the slime mold Physarium poly- L. plantarum.17 Interestingly, 9S,10R-dihydrosterculic acid co-
cephalum, GL17 from Lactobacillus plantarum, the maradolipids8 occurs with 11R,12S-lactobacillic acid in L. plantarum, and
there is evidence that the same cyclopropane synthase is
involved in the biosynthesis of the two pseudoenantiomers.20
To the best of our knowledge, the stereochemistry of naturally-
occurring dihydromalvalic acid has not been determined.
Several approaches to these enantioenriched and enantio-
pure cis-CFAs have been reported. Minnikin and co-workers
reported the synthesis of both enantiopodes of enantiopure
lactobacillic acid 4 by bidirectional elaboration of a homo-
School of Chemistry and Bio21 Molecular Science and Biotechnology Institute,
University of Melbourne, Parkville, Victoria 3010, Australia.
E-mail: sjwill@unimelb.edu.au
†Electronic supplementary information (ESI) available: Crystallographic infor-
mation file for 14b. Copies of 1H and 13C NMR spectra of all new compounds.
CCDC 1009686. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4ob01863j
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Fig. 1 Structures of cis-cyclopropane fatty acids 1–4 and their biogenic precursor unsaturated fatty acids.
chiral cyclopropane linchpin, which was derived from lipase- resolution of cycloprop-2-ene carboxylic acids derived from
mediated desymmetrization of cis-cyclopropane-1,2-dimethanol Rh2(OAc)4-catalyzed cyclopropenation of terminal alkenes.26
or by diastereoselective Simmons–Smith cyclopropanation of a Computational approaches were used to identify chiral oxazoli-
D-mannitol-derived alkene.21,22 Kobayashi and co-workers dinones as chromatographic resolving auxiliaries based on the
reported a related approach to both enantiomers of cis-9,10- pronounced differences in conformation between the diaster-
methylenehexadecanoic acid 1 involving bidirectional Wittig eoisomers derived from racemic cyclopropene carboxamides.
extension of an enzymatically-derived homochiral cyclopropa-
Cyclopropenation of 1-octyne 5a or 1-decyne 5b with ethyl
γ-lactone.16 Manthorpe and co-workers have reported the syn- diazoacetate in toluene, catalyzed by Rh2(OAc)4,29 afforded
thesis of enantiopure 9R,10S-dihydrosterculic acid 3 with the multigram quantities of the racemic cyclopropene esters 6a30
key step involving the Corey–Chaykovsky cyclopropanation of a and 6b,30 respectively (Scheme 1). Saponification (KOH–
homochiral alkylidene bis(sulfoxide).23 Corey and co-workers MeOH) of these esters afforded the corresponding acids 7a 26
reported the synthesis of enantioenriched 9R,10S-dihydro- and 7b, respectively, which were converted to the N-acyloxazoli-
sterculic acid 3 in 87% ee using an enantioselective cyclopro- dinones, by treatment with adamantoyl chloride and Et3N (to
penation with a chiral RhII-catalyst.24 Katsuki and co-workers generate the mixed anhydride), and then with (S)-4-benzyl-2-
reported the enantioselective synthesis of the methyl ester of oxazolidinone and LiCl.26 As espoused by Fox, the use of ada-
cis-9R,10S-methylenehexadecanoic acid 1 in 98% ee using a mantoyl chloride limits formation of unwanted N-acylox-
chiral IrIII-salen mediated cyclopropanation.25 Herein we azolidinone derived from reaction with the activating agent
report a general approach to synthesize cis-CFAs in enantio- when pivalyl chloride is used;26 our work is in concordance
pure forms using a diastereomeric resolution of cyclopropene- and also established the superiority of adamatoyl chloride over
carboxamides, originally developed by the Fox group,26 as a isobutylchloroformate. The diastereomers 8a and 9a (derived
key enabling step, allowing the preparation of both enantio-
mers of the four CFAs 1–4.
Results and discussion
Our approach hinged on the identification of a practical entry
point with one arm of the target fatty acid already installed in
order to minimize the number of carbon–carbon bond
forming reactions and thus total number of synthetic steps.
Despite advances in enantioselective cyclopropenation27 and
cyclopropanation28 reactions, the imperfect stereoselectivities
of even the state-of-the-art methods and the complexity of cata-
lyst synthesis dissuaded us from these approaches. Congruous
with our goal to obtain enantiomeric pairs of cis-CFAs, our
attention was drawn to the elegant work of Fox and co-
workers, who reported the medium-scale chromatographic Scheme 1 Synthesis and resolution of cyclopropenecarboxamides.
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from 1-octyne) were readily resolved by flash chromatography,
and the stereochemistry of the individual isomers was readily
assigned by direct comparison with the data reported.26 In the
case of 8b and 9b (derived from 1-decyne), these isomers were
also readily resolved by flash chromatography; however, the
assignment of stereochemistry to each isomer had to await the
identification of a crystalline derivative suitable for X-ray crys-
tallographic analysis (vide infra).
It has been reported that reduction of cyclopropenes can be
achieved with high stereoselectivity using either diimide31 or
catalytic hydrogenation.24,32 In the latter case, H2/Pd-C/
24
CaCO3
is preferred to avoid unwanted cyclopropane ring
cleavage that occurs when using H2/Pd-C.33 Surprisingly, we
found that in all cases investigated, reductions of 8a or 8b
using diimide (NH2NH2/CuSO4, TsNHNH2, KO2CNvNCO2K)
or catalytic hydrogenation (H2/Pd-C, H2/Pd-C/CaCO3) afforded
significant quantities of trans cyclopropanes in amounts up to
10%. The trans-stereochemistry of the minor components
obtained from reduction of 8a or 8b was identified on the
basis of characteristic 1H–1H-coupling constants (cis-isomer:
Jcis = 7.8, 8.6 Hz; Jtrans = 5.6 Hz. trans-isomer: Jcis = 8.0 Hz;
Jtrans = 4.0, 4.6 Hz). Several sources of these compounds were
considered, including possible isomerisation of the cyclopro-
pene prior to reduction, loss of stereoselectivity arising from
the presence of a chiral auxiliary, or imperfect stereoselectivity
of reduction. To address the first point, if isomerisation of the
cycloprop-2-ene 8a to a cycloprop-1-ene preceded reduction,
the analogous reduction of the diastereoisomer 9a should
yield the enantiomer; in fact, 1H NMR analysis revealed that
the two respective trans isomers were diastereoisomers. To
address the second point, elaboration of 8a to 5-({[(1S)-2-hexyl-
cycloprop-2-en-1-yl]methyl}sulfonyl)-1-phenyl-1H-tetrazole and
subsequent reduction also yielded similar amounts of the
corresponding trans-isomer. We therefore conclude that the
trans-isomer arises from intrinsic poor stereoselectivity in the
reduction. We were unable to find a literature precedent for
the formation of minor amounts of trans-cyclopropanes by
reduction of similar systems, although we note that similar
transformations by others are rarely quantitative.24,31 In prac-
tice, catalytic hydrogenation using H2/Pd-C/CaCO3 provided
reproducible and satisfactory results, allowing acquisition of
10a, 10b, 14a and 14b in 70–75% yields (Schemes 2 and 3). In
the case of 14b, single crystals were obtained that were suitable
for X-ray analysis (Fig. 2), allowing the stereochemistry to be
defined relative to the known (S) configuration of the 4-benzyl-
oxazolidinone auxiliary, and allowing stereochemical assign-
ment of the two diastereomers 8b and 9b (Scheme 1).
Scheme 2 Preparation of (2S,3R)-cyclopropane sulfones 13a and 13b.
Scheme 3 Preparation of (2R,3S)-cyclopropane sulfones 17a and 17b.
Fig. 2 ORTEP representation of the molecular structure of (2R,3S)-
cyclopropanecarboxamide 14b, determined by single-crystal X-ray crys-
tallography. Ellipsoids are at the 30% probability level.
Reduction of the octyne-derived N-acyloxazolidinones 10a
and 14a with LiBH4 in MeOH–THF34 afforded the volatile alco-
hols 11a and 15a, respectively, which were converted to the
phenyltetrazole sulfides 12a and 16a (Schemes 2 and 3). Oxi-
dation to the sulfones 13a and 17a, respectively, occurred
smoothly upon treatment with ammonium molybdate/H2O2.35
A similar sequence of reactions on the decyne-derived N-acy-
loxazolidinones 10b (→11b → 12b) and 14b (→15b → 16b), fol-
lowed by oxidation, afforded 13b and 17b, respectively.
The stage was now set for elongation of the fragments 13a,
13b, 17a and 17b to the full length fatty acids. We illustrate the
general approach by the synthesis of (9S,10R)-1 (Scheme 4).
Julia-Kocienski olefination of 18 36 with octyne-derived sulfone
13a in the presence of LiHMDS37 yielded alkene 19 in 79% yield
(E/Z ratio not determined). Saponification (aq. KOH) gave 20,
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Scheme 4 Synthesis of (9S,10R)-1 and (9R,10S)-1; (8S,9R)-2 and (8R,9S)-2; (9S,10R)-3 and (9R,10S)-3; and (11S,12R)-4 and (11R,12S)-4.
followed by diimide reduction afforded (9S,10R)-1.38 In this
reduction, we observed some formation of ring cleaved pro-
Experimental
General
ducts when using TsNHNH2 or KO2CNvNCO2K, which we
attribute to high concentrations of highly reactive diimide Proton nuclear magnetic resonance spectra (1H NMR,
formed by thermal decomposition of these reagents.31 By 400 MHz) and proton decoupled carbon nuclear magnetic
similar logic, 13a and 2139 afforded (11S,12R)-4. Equivalent resonance spectra (13C NMR, 100 MHz) were obtained in deu-
approaches using the combinations of 13b, 17a and 17b with terochloroform, with residual protonated solvent as internal
the appropriate ω-aldehyde esters 18,36 2139 or 2440 afforded standard. Chemical shifts are followed by multiplicity, coup-
the remaining enantiopure cis-CFAs.
ling constant(s) (J, Hz), integration and assignments where
possible. Flash chromatography was carried out according to
the procedure of Still et al.42 Analytical thin layer chromato-
graphy (t.l.c.) was conducted on aluminium-backed 2 mm
thick silica gel 60 GF254 and chromatograms were visualized
with 20% w/w ceric ammonium molybdate in ethanol. High
resolution mass spectra (HRMS) were obtained by ionizing
Conclusions
cis-CFAs are widespread constituents of many complex mole-
cules however access to these compounds in enantiopure form
has remained challenging. We report a general route to both samples using electron spray ionization (ESI) and a time of
flight mass analyzer. Dry THF and CH2Cl2 was obtained by the
enantiomers of four common cis-CFAs employing the practic-
able resolution method of Fox and co-workers and utilizing
method of Pangborn et al.43 Pet. spirits refers to petroleum
cyclopropenecarboxylates as synthetic intermediates. In several ether, boiling range 40–60 °C. All other commercially available
reagents were used as received. IR spectra were obtained as a
thin film on a diamond-coated ZnSe attenuated total reflec-
cases ((8S,9R)-2, (8R,9S)-2 and (9S,10R)-3) this work represents
the first total synthesis of these cis-CFAs. The methods out-
lined in this report provide a practical means to not only tance FT-IR spectrometer. The preparation of 6a,30 6b,30 7a,26
8a26 and 9a26 have been reported previously.
access these cis-CFAs, but should be readily modified to allow
2-Octylcycloprop-2-ene-1-carboxylic acid (7b). Aqueous KOH
thus stands as an efficient approach to acquire enantiomeric (8.5% w/v, 15 ml) was added to a solution of 6b (1.80 g,
the preparation of other straight chain cis-CFAs. This method
8.03 mmol) in methanol (15 ml) at 0 °C. The resulting mixture
was stirred overnight at room temperature, concentrated to
remove the methanol, acidified with conc. HCl to pH 1–3,
pairs of straight-chain cis-CFAs, which will be of particular
utility in establishing the stereochemistry of natural materials
by HPLC analysis.41
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extracted with CH2Cl2, dried (MgSO4), filtered and concen- brown to black). The reaction mixture was filtered through
trated. Flash chromatography of the residue (EtOAc–pet. Celite and concentrated under reduced pressure to afford a
spirits–AcOH 20 : 79 : 1) afforded 7b as a colorless oil (1.35 g, residue.
86%). 1H NMR (CDCl3, 400 MHz) δ 6.32 (1 H, m), 2.48–2.51
General procedure for reductive cleavage of [cyclopropane-
1-carbonyl]oxazolidinones
(2 H, m), 2.12 (1 H, d, J = 1.5 Hz), 1.56–1.60 (2 H, m), 1.24–1.36
(10 H, m), 0.88 (3 H, t, J = 6.6 Hz); 13C NMR (CDCl3, 100 MHz)
δ 181.7, 115.5, 93.6, 32.0, 29.4, 29.32, 29.30, 26.7, 25.1, 22.8, Methanol (1 eq.) was added to a stirred solution of [cyclopro-
19.4, 14.2; IR (neat) ν 2926, 2855, 1687, 1420, 1368, 1279, pane-1-carbonyl]oxazolidinone in dry THF (10 ml mmol−1) at
1236 cm−1; HRMS (ESI+) calcd for C12H20NaO2 (M + Na)+ ice cold temperature followed by addition of LiBH4 (4 eq.). The
219.1355. Found 219.1356.
mixture was gradually warmed to room temperature and stir-
(4S)-4-Benzyl-3-[(1S)-2-octylcycloprop-2-ene-1-carbonyl]oxazo- ring was continued for further 4 h. The mixture was quenched
lidinone (8b) and (4S)-4-benzyl-3-[(1R)-2-octylcycloprop-2-ene- with saturated aqueous NH4Cl solution, extracted with Et2O,
1-carbonyl]oxazolidinone (9b). A stirred solution of 7b dried (MgSO4), filtered and concentrated at room temperature
(0.352 g, 1.78 mmol) in dry THF (80 ml) at −30 °C was sequen- (at 600–800 mmHg pressure; caution, the cyclopropanecarbi-
tially treated with triethylamine (0.871 ml, 6.24 mmol) then nols are volatile).
adamantoyl chloride (0.375 g, 1.87 mmol). The mixture was
stirred at −30 °C for 1 h, then lithium chloride (0.381 g,
General procedure for Mitsunobu reactions
8.91 mmol), (S)-(−)-4-benzyl-2-oxazolidinone (0.351 g, 1-Phenyl-1H-tetrazole-5-thiol (1.2 eq.) was added to a stirred
1.96 mmol) and DMAP (0.021 g, 0.17 mmol) were added. The solution of cyclopropylmethanol in dry THF (10 ml) at 0 °C,
reaction mixture was gradually allowed to warm to room temp- followed by addition of PPh3 (1.2 eq.) and powdered 4 Å mole-
erature and stirring was continued overnight. The solvent was cular sieves (0.5 g). Stirring was continued for 10 min after
evaporated and the residue was partitioned between Et2O and which DIAD (1.2 eq.) was added. The reaction mixture was
water. The aqueous layer was extracted 3 times with Et2O. The warmed to room temperature and stirring was continued over-
combined organic extracts were dried (MgSO4), filtered and night. The reaction mixture was filtered through Celite and
concentrated, and the residue purified by flash chromato- concentrated under reduced pressure.
graphy (8–15% EtOAc–hexanes). First to elute: 8b as a colorless
General procedure for molybdate oxidation of 1-phenyl-1H-
oil (0.272 g, 42%), Rf 0.55 in 10% EtOAc–pet. spirits, run twice,
tetrazolylsulfides
[α]2D1 +103 (c 0.120, CHCl3). 1H NMR (CDCl3, 400 MHz)
δ 7.20–7.34 (5 H, m), 6.29 (1H, m), 4.63–4.68 (1 H, m), Ammonium molybdate tetrahydrate (0.05 eq.) was dissolved in
4.15–4.23 (2 H, m), 3.46 (1 H, d, J = 1.6 Hz), 3.31 (1 H, dd, J = stages in 30% aq. H2O2 (24 eq.) and added slowly to a solution
10, 3.2 Hz,), 2.75 (1 H, dd, J = 9.6, 3.6 Hz), 2.48–2.54 (2 H, m), of 1-phenyl-1H-tetrazolylsulfide dissolved in a mixture of
1.58–1.62 (2 H, m), 1.27–1.38 (10 H, m), 0.88 (3 H, t, J = ethanol and THF (2 : 3, 30 ml per g of sulfide). After stirring at
6.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 177.2, 154.1, 135.7, room temperature for 2 h, additional ammonium molybdate
129.6, 129.0, 127.4, 114.3, 92.3, 66.4, 55.8, 38.2, 32.0, 29.4, tetrahydrate (0.05 eq.) in 30% aq. H2O2 (24 eq.) was added and
29.32, 29.30, 26.9, 25.1, 22.8, 20.1, 14.2; IR (CH2Cl2) ν 2927, the mixture was stirred overnight. After partial concentration,
2856, 1778, 1686, 1455, 1368, 1275, 1260, 1078 cm−1; HRMS the mixture was quenched with water and extracted with
(ESI+) calcd for C22H29NNaO3 (M + Na)+ 378.2038. Found dichloromethane. The combined organic layers were dried
378.2040.
Second to elute: 9b as a semisolid (0.251 g, 40%), Rf 0.45 in
(MgSO4) and evaporated to dryness.
(4S)-4-Benzyl-3-[(1S,2R)-2-hexylcyclopropanecarbonyl]oxazo-
10% EtOAc–pet. spirits, run twice. [α]2D6 +43.1 (c 0.20, CHCl3). lidin-2-one (10a). The general procedure for reduction of
1H NMR (CDCl3, 400 MHz) δ 7.20–7.34 (5 H, m), 6.28 (1 H, m), cyclopropenes conducted with 8a (0.702 g, 2.14 mmol), after
4.63–4.69 (1 H, m), 4.15–4.24 (2 H, m), 3.45 (1 H, d, J = 1.6 Hz), flash chromatography (EtOAc–pet. spirits 1 : 9) afforded 10a as
3.29 (1 H, dd, J = 10, 3.2 Hz), 2.78 (1 H, dd, J = 9.6, 3.6 Hz), a colorless oil (0.540 g, 75%). [α]2D6 +87.6 (c 0.120, CHCl3). H
1
2.52–2.56 (2 H, m), 1.55–1.64 (2 H, m), 1.26–1.40 (10 H, m), NMR (CDCl3, 400 MHz) δ 7.21–7.35 (5 H, m), 4.67–4.73 (1 H,
0.87 (3 H, t, J = 6.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 177.1, m), 4.14–4.17 (2 H, m), 3.12–3.35 (1 H, dd, J = 10, 3.2 Hz),
154.2, 135.7, 129.6, 129.0, 127.4, 114.1, 92.6, 66.5, 55.9, 38.2, 3.08–3.14 (1H, m), 2.77 (1 H, dd, J = 10, 3.6 Hz), 1.25–1.55
32.0, 29.4, 29.32, 29.30, 27.0, 25.1, 22.8, 20.2, 14.2; IR (CH2Cl2) (11 H, m), 1.21 (1 H, m), 1.14 (1 H, m), 0.86 (3 H, m); 13C NMR
ν 2927, 2855, 1779, 1687, 1454, 1369, 1275, 1260 cm−1; HRMS (CDCl3, 100 MHz) δ 172.1, 154.0, 135.6, 129.6, 129.1, 127.4,
(ESI+) calcd for C22H29NNaO3 (M + Na)+ 378.2038. Found 66.0, 55.6, 38.2, 32.0, 29.7, 29.1, 27.0, 24.7, 22.8, 19.1, 14.5,
378.2040.
14.2; IR (CH2Cl2) ν 2956, 2925, 2857, 1774, 1687, 1384, 1349,
1219 cm−1; HRMS (ESI+) calcd for C20H28NO3 (M + H)+
330.2064. Found 330.2085.
General procedure for reduction of cyclopropenes
A solution of the cyclopropene in EtOAc (10 ml) was purged
(4S)-4-Benzyl-3-[(1S,2R)-2-octylcyclopropane-1-carbonyl]oxa-
with hydrogen, and then 5% Pd/CaCO3 (unreduced) (0.10 g per zolidin-2-one (10b). The general procedure for reduction of
g of cyclopropene) was added. The suspension was stirred vig- cyclopropenes conducted with 8b (1.00 g, 2.81 mmol), after
orously under H2 for 2 h (until the catalyst changed color from flash chromatography (EtOAc–pet. spirits 1 : 9) afforded 10b as
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colorless oil (0.705 g, 70%). [α]D20 +86 (c 0.155, CHCl3). 1H NMR HRMS (ESI+) calcd for C19H28N4NaS (M + Na)+ 367.1927.
(CDCl3, 400 MHz) δ 7.21–7.35 (5 H, m), 4.68–4.74 (1 H, m), Found 367.1927.
4.14–4.17 (2 H, m), 3.31 (1 H, dd, J = 10, 3.2 Hz), 3.13 (1H, ddd,
5-({[(1S,2R)-2-Hexylcyclopropyl]methyl}sulfonyl)-1-phenyl-
J = 5.6, 7.8, 8.6 Hz), 2.77 (1 H, dd, J = 9.6, 3.6 Hz), 1.21–1.57 1H-tetrazole (13a). The general procedure for molybdate oxi-
(15 H, m), 1.21 (1 H, ddd, J = 4.2, 5.6, 6.6 Hz), 1.14 (1 H, ddd, dation of 1-phenyl-1H-tetrazolylsulfides applied to 12a
J = 4.2, 5.6, 6.6 Hz), 0.87 (3 H, t, J = 6.8 Hz); 13C NMR (CDCl3, (0.172 g, 0.537 mmol), after flash chromatography (EtOAc–pet.
100 MHz) δ 172.1, 154.0, 135.6, 129.6, 129.1, 127.4, 66.0, 55.6, spirits 1 : 9) afforded 13a as a colorless liquid (0.164 g, 86%).
38.2, 32.0, 29.7, 29.4, 29.4, 27.0, 24.7, 22.8, 19.1, 14.5, 14.3; [α]2D4 +36.3 (c 0.73, CHCl3). 1H NMR (CDCl3, 400 MHz)
IR (CH2Cl2) ν 2923, 2854, 1775, 1687, 1455, 1384, 1349, 1241, δ 7.52–7.70 (5 H, m), 3.96 (1 H, dd, J = 5.6, 14.8 Hz), 3.55 (1 H,
1208 cm−1; HRMS (ESI+) calcd for C22H31NNaO3 (M + Na)+ dd, J = 9.6, 14.8 Hz), 1.22–1.56 (11 H, m), 1.14–1.17 (1 H, m),
380.2196. Found 380.2207.
0.96–1.02 (1 H, m), 0.88 (3 H, t, J = 6.8 Hz), 0.24 (1 H, q, J =
[(1S,2R)-2-Hexylcyclopropyl]methanol (11a). The general 5.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 153.9, 133.2, 131.6,
procedure for reductive cleavage of [cyclopropane-1-carbonyl]- 129.8, 125.3, 57.3, 31.9, 29.7, 29.2, 22.8, 16.0, 14.2, 11.5, 8.1;
oxazolidinones conducted with 10a (0.550 g, 1.67 mmol), after IR (CH2Cl2) ν 2956, 2926, 2856, 1661, 1628, 1497, 1338, 1219,
flash chromatography (Et2O–n-pentane 15 : 85) afforded 11a as 1150, 686 cm−1; HRMS (ESI+) calcd for C17H24N4NaO2S
a colorless oil (0.212 g, 80%). [α]2D6 −23.9 (c 0.105, CHCl3) (M + Na)+ 371.1512. Found 371.1510.
(lit.22 = −26.1). 1H NMR (CDCl3, 400 MHz) δ 3.55–3.67 (2 H,
5-({[(1S,2R)-2-Octylcyclopropyl]methyl}sulfonyl)-1-phenyl-1H-
m), 1.19–1.45 (10 H, m), 1.06–1.12 (1 H, m), 0.83–0.90 (1 H, tetrazole (13b). The general procedure for molybdate oxidation
m), 0.88 (3 H, t, J = 6.8 Hz), 0.67–0.72 (1 H, m), −0.04 (1 H, q, of 1-phenyl-1H-tetrazolylsulfides applied to 12b (0.131 g,
J = 5.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 63.5, 32.0, 30.3, 29.8, 0.377 mmol), after flash chromatography (EtOAc–pet. spirits
29.3, 28.7, 22.8, 18.3, 16.3, 14.2, 9.6; IR (CH2Cl2) ν 3304, 3991, 1 : 9) afforded 13b as colorless liquid (0.125 g, 85%). [α]2D4 +36.4
1
2995, 2924, 2855, 1443, 1425, 1379 cm−1; HRMS (ESI+) calcd (c 0.73, CHCl3). H NMR (CDCl3, 400 MHz) δ 7.60–7.70 (5 H,
for C10H20NaO (M + Na)+ 179.1406. Found 179.1407.
m), 3.96 (1 H, dd, J = 5.6, 14.8 Hz), 3.56 (1 H, dd, J = 9.2,
[(1S,2R)-2-Octylcyclopropyl]methanol (11b). The general 14.4 Hz), 1.22–1.47 (15 H, m), 1.26–1.19 (1 H, m), 0.98–1.02
procedure for reductive cleavage of [cyclopropane-1-carbonyl]- (1 H, m), 0.87 (3 H, t, J = 6.8 Hz), 0.24 (1 H, q, J = 5.6 Hz); 13C
oxazolidinones conducted with 10b (0.501 g, 1.39 mmol), after NMR (CDCl3, 100 MHz) δ 153.9, 132.2, 131.6, 129.8, 125.2,
flash chromatography (Et2O–n-pentane 15 : 85) afforded 11b as 57.3, 32.0, 29.8, 29.7, 29.6, 29.4, 29.2, 22.8, 16.0, 14.3, 11.5, 8.2;
a colorless oil (0.220 g, 80%). 1H NMR (CDCl3, 400 MHz) IR (CH2Cl2) ν 3016, 2970, 1738, 1743, 1366, 1217, 1228, 1150,
δ 3.55–3.67 (2 H, m), 1.05–1.52 (15 H, m), 0.83–0.86 (1 H, m), 771 cm−1; HRMS (ESI+) calcd for C19H28N4NaSO2 (M + Na)+
0.88 (3 H, t, J = 6.8 Hz), 0.67–0.73 (1 H, m), −0.03 (1 H, q, J = 399.1825. Found 399.1825.
4.8 Hz). HRMS (ESI+) calcd for C12H24NaO (M + Na)+ 207.1719.
Found 207.1719.
(4S)-4-Benzyl-3-[(1R,2S)-2-hexylcyclopropane-1-carbonyl]oxa-
zolidin-2-one (14a). The general procedure for reduction of
5-({[(1S,2R)-2-Hexylcyclopropyl]methyl}thio)-1-phenyl-1H-tetra- cyclopropenes conducted with 9a (0.502 g, 0.152 mmol), after
zole (12a). The general procedure for Mitsunobu reactions flash chromatography (EtOAc–pet. spirits 1 : 9) afforded 14a as
conducted with 11a (0.131 g, 0.832 mmol), after flash chrom- a colorless oil (0.352 g, 71%). [α]2D0 +51 (c 0.155, CHCl3). 1H
atography (EtOAc–hexane 1 : 9) afforded 12a as a colorless oil NMR (CDCl3, 400 MHz) δ 7.22–7.35 (5 H, m), 4.63–4.69 (1 H,
(0.221 g, 84%). [α]D22 −6.4 (c 0.135, CHCl3). 1H NMR (CDCl3, m), 4.13–4.20 (2 H, m), 3.26 (1 H, dd, J = 10, 3.2 Hz), 3.02–3.08
400 MHz) δ 7.53–7.62 (5 H, m), 3.47 (2 H, d, J = 8.0 Hz), (1H, m), 2.63–2.69 (1 H, dd, J = 10, 3.2 Hz), 1.17–1.56 (11 H,
1.22–1.56 (11 H, m), 0.86–0.96 (1 H, m), 0.88 (3 H, t, J = m), 1.10–1.21 (1 H, m), 1.12–1.21 (1 H, m), 0.85 (3 H, t, J =
6.8 Hz), 0.79–0.85 (1 H, m), 0.07 (1 H, q, J = 5.6 Hz); 13C NMR 6.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 172.0, 154.0, 135.7,
(CDCl3, 100 MHz) δ 154.8, 134.0, 130.2, 129.9, 124.0, 35.2, 129.5, 129.1, 127.4, 66.1, 56.0, 38.3, 32.0, 29.9, 29.2, 27.0, 24.8,
32.0, 30.1, 29.3, 28.6, 22.8, 18.1, 14.8, 14.2, 12.6; IR 22.8, 19.1, 14.2; IR (CH2Cl2) ν 2955, 2923, 2856, 1775, 1686,
(CH2Cl2) ν 2954, 2924, 2854, 1499, 1409, 1384, 1219, 684 cm−1
;
1404, 1349, 1219, 1192 cm−1
H)+ 317.1794. C20H28NO3 (M + H)+ 330.2064. Found 330.2063.
(4S)-4-Benzyl-3-[(1R,2S)-2-octylcyclopropane-1-carbonyl]oxa-
;
HRMS (ESI+) calcd for
HRMS (ESI+) calcd for C17H25N4S (M
Found 317.1795.
+
5-({[(1S,2R)-2-Octylcyclopropyl]methyl}thio)-1-phenyl-1H-tetra- zolidin-2-one (14b). The general procedure for reduction of
zole (12b). The general procedure for Mitsunobu reactions cyclopropenes conducted with 9b (0.251 g, 0.703 mmol), after
conducted with 11b (0.160 g, 0.818 mmol), after flash chrom- flash chromatography (EtOAc–pet. spirits 1 : 9) afforded 14b
atography (EtOAc–hexane 1 : 9) afforded 12b as colorless oil (0.18 g, 71%) as white solid, mp 62 °C; [α]2D5 +42.8 (c 0.47,
(0.242 g, 80%). [α]2D4 −4.9 (c 0.47, CHCl3). 1H NMR (CDCl3, CHCl3). 1H NMR (CDCl3, 400 MHz) δ 7.21–7.35 (5 H, m),
400 MHz) δ 7.52–7.62 (5 H, m), 3.48 (2 H, d, J = 7.6 Hz), 4.63–4.69 (1 H, m), 4.13–4.20 (2 H, m), 3.32 (1 H, dd, J = 3.2,
1.19–1.53 (15 H, m), 0.89–0.96 (1 H, m), 0.88 (3 H, t, J = 6.8 13.2 Hz), 3.05 (1H, ddd, J = 5.6, 7.8, 8.6 Hz), 2.66 (1 H, dd, J =
Hz), 0.79–0.85 (1 H, m), 0.07 (1 H, q, J = 5.6 Hz); 13C NMR 10, 13.2 Hz), 1.17–1.56 (15H, m), 1.14 (1 H, ddd, J = 4.2, 7.8,
(CDCl3, 100 MHz) δ 154.1, 134.1, 129.2, 128.9, 122.9, 34.2, 8.0 Hz), 1.10 (1 H, ddd, J = 4.2, 5.6, 6.6 Hz), 0.84 (3 H, t, J =
31.0, 29.2, 28.7, 28.6, 28.4, 27.6, 21.8, 17.1, 13.7, 13.2, 11.6; IR 6.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 172.0, 154.0, 135.7,
(CH2Cl2) ν 3016, 2970, 2925, 1743, 1366, 1216, 900 cm−1
;
129.56, 129.01, 127.4, 66.1, 56.0, 38.3, 32.0, 29.9, 29.8, 29.5,
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29.4, 27.0, 24.8, 22.8, 19.1, 14.2, 14.2; IR (CH2Cl2) ν 2953, 2918, 3.56 (1 H, dd, J = 9.2, 14.4 Hz), 1.14–1.45 (11 H, m), 0.97–1.02
2850, 1781, 1683, 1384, 1350, 1239, 1199 cm−1; HRMS (ESI+) (1 H, m), 0.89 (3 H, t, J = 6.4 Hz), 0.24 (1 H, q, J = 5.6 Hz), 0.07
calcd for C22H31NNaO3 (M + Na)+ 380.2196. Found 380.2196.
(1 H, q, J = 5.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 153.9, 133.2,
[(1R,2S)-2-Hexylcyclopropyl]methanol (15a). The general 131.6, 129.8, 125.3, 57.3, 31.9, 29.7, 29.2, 22.8, 16.0, 14.2, 11.5,
procedure for reductive cleavage of [cyclopropane-1-carbonyl]- 8.1; IR (CH2Cl2) ν 3609, 2956, 2925, 2856, 1497, 1461, 1338,
oxazolidinones conducted with 14a (0.705 g, 2.12 mmol), after 1219, 1149, 770, 687 cm−1
;
HRMS (ESI+) calcd for
flash chromatography (Et2O–n-pentane 15 : 85) afforded 15a as C17H24N4NaO2S (M + Na)+ 371.1512. Found 371.1512.
a colorless oil (0.310 g, 80%). [α]2D5 +22.9 (c 0.251, CHCl3)
5-({[(1R,2S)-2-Octylcyclopropyl]methyl}sulfonyl)-1-phenyl-1H-
1
(lit.22 +23.1). H NMR (CDCl3, 400 MHz) δ 3.55–3.67 (2 H, m), tetrazole (17b). The general procedure for molybdate oxidation
1.05–1.52 (15 H, m), 0.83–0.86 (1 H, m), 0.88 (3 H, t, J = of 1-phenyl-1H-tetrazolylsulfides applied to 16b (0.232 g,
6.8 Hz), 0.67–0.73 (1 H, m), −0.04 (1 H, q, J = 4.8 Hz); 13C NMR 0.661 mmol), after flash chromatography (EtOAc–pet. spirits
(CDCl3, 100 MHz) δ 63.5, 32.0, 30.3, 29.4, 28.7, 22.8, 18.3, 16.3, 1 : 9) afforded 17b as colorless liquid (0.222 g, 88%).
14.3, 9.6; IR (CH2Cl2) ν 3307, 3291, 2924, 2855, 1442, 1424, [α]2D6 −38.2 (c 0.13, CHCl3). 1H NMR (CDCl3, 400 MHz)
1219 cm−1; HRMS (ESI+) calcd for C10H20NaO (M + Na)+ δ 7.60–7.70 (5 H, m), 3.96 (1 H, dd, J = 5.6, 14.8 Hz), 3.56 (1 H,
179.1406. Found 179.1407.
dd, J = 9.2, 14.4 Hz), 1.22–1.47 (15 H, m), 1.26–1.19 (1 H, m),
[(1R,2S)-2-Octylcyclopropyl]methanol (15b). The general 0.98–1.02 (1 H, m), 0.87 (3 H, t, J = 6.8 Hz), 0.24 (1 H, q, J =
procedure for reductive cleavage of [cyclopropane-1-carbonyl]- 5.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 154.0, 133.3, 131.7,
oxazolidinones conducted with 14b (0.472 g, 0.89 mmol), after 129.9, 125.4, 57.3, 32.1, 29.9, 29.8, 29.7, 29.5, 29.3, 22.9, 16.1,
flash chromatography (Et2O–n-pentane 2 : 8) afforded 15b as a 14.3, 11.6, 8.2; IR (CH2Cl2) ν 2924, 2854, 2361, 2359, 2320,
colorless oil (0.205 g, 83%). 1H NMR (CDCl3, 400 MHz) 1738, 1743, 1366, 1217, 1228 cm−1; HRMS (ESI+) calcd for
δ 3.57–3.65 (2 H, m), 1.04–1.49 (15 H, m), 0.82–0.95 (1 H, m), C19H29N4SO2 (M + H)+ 377.2006. Found 377.2018.
0.88 (3 H, t, J = 6.8 Hz), 0.67–0.73 (1 H, m), −0.03 (1 H, q, J =
General procedure for Julia–Kocienski olefination
5.6 Hz). HRMS (ESI+) calcd for C12H24NaO (M + Na)+ 207.1719.
Found 207.1719.
LiHDMS in THF (1 M, 1.2 eq.) was added to a solution of
5-({[(1R,2S)-2-Hexylcyclopropyl]methyl}thio)-1-phenyl-1H-tetra- sulfone in dry THF (15 ml per g of sulfone) cooled to −78 °C.
zole (16a). The general procedure for Mitsunobu reactions After stirring for 10 min, a solution of aldehyde (1.2 eq.) in dry
conducted with 15a (0.332 g, 2.11 mmol), after flash chromato- THF (10 ml per g of aldehyde) was added at −78 °C. The reac-
graphy (EtOAc–hexane 1 : 9) afforded 16a as a colorless oil tion was gradually warmed to room temperature and stirring
(0.554 g, 82%). [α]D20 +6 (c 0.155, CHCl3). 1H NMR (CDCl3, was continued overnight. The reaction mixture was quenched
400 MHz) δ 7.53–7.61 (5 H, m), 3.47 (2 H, d, J = 8.0 Hz), with sat. aq. ammonium chloride, extracted in 1 : 1 Et2O–pet.
1.27–1.58 (11 H, m), 0.86–0.96 (1 H, m), 0.88 (3 H, t, J = spirits, washed with water, dried (MgSO4) and concentrated.
6.8 Hz), 0.79–0.83 (1 H, m), 0.07 (1 H, q, J = 5.2 Hz); 13C NMR
General procedure for saponification
(CDCl3, 100 MHz) δ 154.8, 133.9, 130.2, 129.9, 124.0, 35.2,
32.0, 30.1, 29.3, 28.6, 22.8, 18.1, 14.8, 14.2, 12.6; IR (CH2Cl2) A solution of KOH (3 eq.) in H2O (20 ml per g of ester) was
ν 2955, 2924, 2854, 1499, 1384, 1219, 684 cm−1; HRMS (ESI+) added to a solution of ester in THF (2 ml per g of ester) and
calcd for C17H24N4NaS (M + H)+ 317.1794. Found 317.1795.
methanol (2 ml per g of ester) at 0 °C. The resulting mixture
5-({[(1R,2S)-2-Octylcyclopropyl]methyl}thio)-1-phenyl-1H-tetra- was gradually warmed to room temperature and stirring was
zole (16b). The general procedure for Mitsunobu reactions continued overnight. The solvent was evaporated under
conducted with 15b (0.201 g, 0.851 mmol), after flash chrom- reduced pressure, and the residue obtained was acidified with
atography (EtOAc–hexane 1 : 9) afforded 16b as colorless oil 0.5 M citric acid, extracted with Et2O, dried (MgSO4), filtered
(0.272 g, 80%). [α]2D5 +4.2 (c 0.57, CHCl3). 1H NMR (CDCl3, and concentrated.
400 MHz) δ 7.51–7.61 (5 H, m), 3.47 (2 H, d, J = 7.6 Hz),
1.19–1.57 (15 H, m), 0.91–0.96 (1 H, m), 0.88 (3 H, t, J =
General procedure for diimide reduction
6.4 Hz), 0.79–0.83 (1 H, m), 0.06 (1 H, q, J = 5.6 Hz); 13C NMR Hydrazine monohydrate (1.60 ml) was added to a solution of
(CDCl3, 100 MHz) δ 154.8, 134.0, 130.2, 129.9, 124.0, 35.2, alkene in ethanol (5 ml). Aliquots of a saturated aqueous solu-
32.0, 30.2, 29.8, 29.7, 29.5, 28.6, 22.8, 18.1, 14.8, 14.3, 12.6; tion of CuSO4 (total amount 0.16 ml) were added daily for 5 d
IR (CH2Cl2) ν 3066, 2923, 2853, 1597, 1499, 1385, 1244, 1014, until 1H-NMR analysis of an aliquot of the reaction mixture
758 cm−1; HRMS (ESI+) calcd for C19H29N4S (M + H)+ 345.2107. showed complete consumption of the starting material. The
Found 345.2113.
reaction mixture was quenched with 2 N HCl, extracted several
5-({[(1R,2S)-2-Hexylcyclopropyl]methyl}sulfonyl)-1-phenyl-1H- times in Et2O, dried (MgSO4) and concentrated.
tetrazole (17a). The general procedure for molybdate oxidation
Methyl 8-[(1S,2R)-2-hexylcyclopropyl]oct-7-enoate (19). The
of 1-phenyl-1H-tetrazolylsulfides applied to 16a (0.331 g, general procedure for Julia–Kocienski olefination applied to
1.04 mmol), after flash chromatography (EtOAc–pet. spirits 13a (0.305 g, 0.862 mmol) and methyl 7-oxaheptanoate (18)36
1 : 9) afforded 17a as a colorless liquid (0.305 g, 83%). (0.163 g, 1.03 mmol), after flash chromatography (EtOAc–pet.
[α]2D1 −36.2 (c 0.095, CHCl3), (lit.25 −36.9). 1H NMR (CDCl3, spirits 1 : 9) afforded 19 (0.191 g, 79%). [α]2D4 −34.9 (c 0.505,
400 MHz) δ 7.58–7.70 (5 H, m), 3.96 (1 H, dd, J = 5.6, 14.4 Hz), CHCl3). 1H NMR (CDCl3, 400 MHz) δ 5.45–5.49 (0.7 H, m),
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5.31–5.38 (0.3 H, m), 5.10–5.16 (0.7 H, m), 4.97–5.02 (0.3 H, (c 0.40, CHCl3). H NMR (CDCl3, 400 MHz) δ 5.46–5.53 (0.7 H,
m), 3.62 (3 H, s), 2.24–2.29 (2 H, m), 2.08–2.14 (0.6 H, m), 1.96 m), 5.36–5.42 (0.3 H, m), 5.13–5.19 (0.7 H, m), 5.00–5.05
(1.4 H, q, J = 6.8 Hz), 1.55–1.64 (2 H, m), 1.20–1.39 (18 H, m), (0.3 H, m), 2.32–2.37 (2 H, m), 2.10–2.16 (0.6 H, m), 1.99
0.72–0.88 (1.3 H, m), 0.84 (3 H, t, J = 6.8 Hz), 0.03–0.09 (0.7 H, (1.4 H, q, J = 6.4 Hz), 1.53–1.65 (2 H, m), 1.27–1.43 (21 H, m),
m); 13C NMR (CDCl3, 100 MHz) δ 174.4, 130.2, 130.0, 129.9, 0.76–0.92 (1.3 H, m), 0.88 (3 H, t, J = 6.4 Hz), 0.08–0.12 (0.7 H,
129.9, 51.6, 34.3, 34.2, 32.7, 32.0, 29.9, 29.8, 29.6, 29.5, 29.4, m); 13C NMR (CDCl3, 100 MHz) δ 178.3, 130.4, 130.2, 129.8,
29.3, 29.0, 28.8, 27.5, 25.0, 22.8, 18.6, 18.5, 14.3, 14.3, 14.1, 129.8, 33.9, 32.8, 32.0, 29.9, 29.8, 29.6, 29.4, 29.3, 29.21, 29.20,
12.5; IR (CH2Cl2) ν 2924, 2854, 1741, 1436, 1219 cm−1; HRMS 29.1, 27.6, 24.9, 22.8, 18.6, 18.4, 14.3, 14.1, 12.5; IR (CH2Cl2)
(ESI+) calcd for C18H33O2 (M + H)+ 281.2475. Found 281.2494.
(9S,10R)-cis-Methylenehexadecanoic acid ((9S,10R)-1)
ν 2923, 2854, 1707, 1412, 1278, 1219, 959 cm−1; HRMS (ESI+)
calcd for C19H35O2 (M + H)+ 295.2632. Found 295.2656.
(11S,12R)-Lactobacillic acid ((11S,12R)-4). The general pro-
8-((1S,2R)-2-Hexylcyclopropyl)oct-7-enoic
acid
(20). The
general procedure for saponification applied to 19 (0.102 g, cedure for diimide reduction applied to 23 (0.042 g,
0.361 mmol) afforded crude 20 (0.081, 86%). [α]2D4 −36.8 (c 0.30 mmol), after flash chromatography (EtOAc–hexane 20 : 80)
1
0.405, CHCl3). H NMR (CDCl3, 400 MHz) δ 5.54–5.52 (0.7 H, yielded (11S,12R)-4 (0.032 g, 86%). [α]2D6 −0.61 (c 0.25, CHCl3),
m), 5.35–5.41 (0.3 H, m), 5.14–5.20 (0.7 H, m), 5.01–5.06 (lit.22 −0.31). 1H NMR (CDCl3, 400 MHz) δ 2.43 (2 H, t, J =
(0.3 H, m), 2.33–2.37 (2 H, m), 2.14–2.16 (0.6 H, m), 2.01 7.6 Hz), 1.62–1.68 (2 H, m), 1.25–1.37 (22 H, m), 1.10–1.17
(1.4 H, q, J = 6.8 Hz), 1.59–1.69 (2 H, m), 1.59–1.69 (0.3 H, m), (2 H, m), 0.88 (3 H, t, J = 6.8 Hz), 0.64–0.68 (2 H, m), 0.53–0.59
1.20–1.43 (16.7 H, m), 0.76–0.94 (1.3 H, m), 0.88 (3 H, t, J = (1 H, m), −0.33 (1 H, q, J = 4.8 Hz); 13C NMR (CDCl3, 100 MHz)
6.8 Hz), 0.08–0.12 (0.7 H, m); 13C NMR (CDCl3, 100 MHz) δ 179.3, 34.0, 32.1, 30.4, 30.3, 29.9, 29.8, 29.6, 29.5, 29.4, 29.2,
δ 179.2, 130.1, 130.0, 129.8, 34.0, 34.0, 32.6, 32.0, 29.9, 29.8, 28.94, 28.91, 24.8, 22.9, 15.92, 15.90, 14.3, 11.1; IR (CH2Cl2)
29.6, 29.5, 29.4, 29.3, 28.9, 28.7, 27.4, 24.8, 24.7, 22.8, 18.7, ν 2923, 2854, 1740, 1365, 1217 cm−1; HRMS (ESI+) calcd for
1
18.6, 18.5, 14.3, 14.3, 14.1, 12.5; IR (CH2Cl2) ν 2924, 2854, C19H37O2 (M + H)+ 296.2788. Found 297.2786. The H and 13C
1707, 1412, 1219 cm−1; HRMS (ESI+) calcd for C17H31O2 NMR data reported here differs from those previously reported.22
(M + H)+ 267.2319. Found 267.2338.
Methyl 7-[(1S,2R)-2-octylcyclopropyl]hept-6-enoate (25). The
general procedure for Julia–Kocienski olefination applied to
13b (0.0821 g, 0.319 mmol) and methyl 6-oxohexanoate (24)40
(0.055 g, 0.383 mmol) after flash chromatography (EtOAc–pet.
spirits 1 : 9) afforded 25 (0.062 g, 80%). [α]2D4 −35.2 (c 0.21,
CHCl3). 1H NMR (CDCl3, 400 MHz) δ 5.54–5.52 (0.7 H, m),
5.35–5.41 (0.3 H, m), 5.15–5.21 (0.7 H, m), 5.02–5.07 (0.3 H,
m), 3.66 (3 H, s), 2.28–2.34 (2 H, m), 2.16 (0.6 H, q, J = 7.2 Hz),
2.02 (1.4 H, q, J = 6.8 Hz), 1.59–1.71 (2 H, m), 1.16–1.44 (18 H,
m), 0.76–0.94 (1.3 H, m), 0.88 (3 H, t, J = 6.4 Hz), 0.08–0.12
(0.7 H, m); 13C NMR (CDCl3, 100 MHz) δ 174.3, 130.3, 130.2,
129.7, 129.5, 51.6, 34.12, 34.10, 32.5, 32.1, 29.9, 29.8, 29.7,
29.6, 29.5, 29.4, 29.3, 24.7, 24.6, 22.8, 18.6, 18.5, 18.4, 14.3,
12.5; IR (CH2Cl2) ν 2992, 2924, 2854, 1742, 1457, 1436, 1200,
1168 cm−1; HRMS (ESI+) calcd for C19H34NaO2 (M + Na)+
317.2451. Found 317.2451.
(9S,10R)-cis-Methylenehexadecanoic acid ((9S,10R)-1). The
general procedure for diimide reduction applied to 20 (0.079 g,
0.296 mmol), after flash chromatography (EtOAc–hexane
20 : 80) yielded (9S,10R)-1 (0.073 g, 84%). [α]2D5 −1.63 (c 0.23,
1
CHCl3). H NMR (CDCl3, 400 MHz) δ 2.35 (2 H, t, J = 6.7 Hz),
1.60–1.65 (2 H, m), 1.10–1.36 (20 H, m), 0.88 (3 H, t, J =
6.8 Hz), 0.61–0.67 (2 H, m), 0.53–0.58 (1 H, m), −0.33 (1 H, q,
J = 5.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 179.7, 34.0, 31.9,
30.1, 30.1, 29.4, 29.3, 29.2, 29.0, 28.7, 28.6, 24.6, 22.7, 15.7,
15.7, 14.1, 10.1; IR (CH2Cl2) ν 2922, 2853, 1708, 1457, 1284,
1412 cm−1; HRMS (ESI+) calcd for C17H33O2 (M + H)+ 269.2475.
Found 269.2475.
Methyl 10-((1S,2R)-2-hexylcyclopropyl)dec-9-enoate (22). The
general procedure for Julia–Kocienski olefination applied to
13a (0.081 g, 0.23 mmol) and methyl 7-oxanonanoate (21)39
(0.051 g, 0.28 mmol), after flash chromatography (EtOAc–pet.
spirits 1 : 9) afforded 22 (0.061 g, 82%). [α]2D5 −32.3 (c 0.79,
8S,9R-Dihydromalvalic acid ((8S,9R)-2)
7-[(1S,2R)-2-Octylcyclopropyl]hept-6-enoic
acid
(26). The
CHCl3). 1H NMR (CDCl3, 400 MHz) δ 5.46–5.53 (0.7 H, m), general procedure for saponification applied to 25 (0.055 g,
5.35–5.42 (0.3 H, m), 5.13–5.19 (0.7 H, m), 5.00–5.05 (0.3 H, 0.17 mmol) afforded crude 26 (0.041 g, 85%). [α]2D4 −31.7
1
m), 3.66 (3 H, s), 2.27–2.32 (2 H, m), 2.10–2.18 (0.6 H, m), 1.98 (c 0.14, CHCl3). H NMR (CDCl3, 400 MHz) δ 5.45–5.52 (0.7 H,
(1.4 H, q, J = 6.4 Hz), 1.59–1.63 (2 H, m), 1.26–1.41 (20 H, m), m), 5.35–5.41 (0.3 H, m), 5.15–5.21 (0.7 H, m), 5.03–5.08
0.75–1.07 (1.3 H, m), 0.87 (3 H, t, J = 6.8 Hz), 0.07–0.12 (0.7 H, (0.3 H, m), 2.33–2.39 (2 H, m), 2.18 (0.6 H, q, J = 7.2 Hz), 2.03
m); 13C NMR (CDCl3, 100 MHz) δ 174.4, 130.1, 130.0, 129.9, (1.4 H, q, J = 7.2 Hz), 1.63–1.69 (2 H, m), 1.26–1.63 (18 H, m),
129.8, 51.5, 34.2, 32.6, 32.0, 29.9, 29.8, 29.72, 29.71, 29.52, 0.76–0.92 (1.3 H, m), 0.88 (3 H, t, J = 6.4 Hz), 0.09–0.13 (0.7 H,
29.51, 29.4, 29.3, 28.7, 27.4, 24.9, 22.8, 18.6, 18.4, 14.2, 14.0, m); 13C NMR (CDCl3, 100 MHz) δ 177.7, 130.4, 130.3, 129.6,
12.5; IR (CH2Cl2) ν 2924, 2854, 1741, 1436, 1365, 1219 cm−1
;
129.4, 33.7, 33.6, 32.4, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 29.3,
HRMS (ESI+) calcd for C20H37O2 (M + H)+ 309.2788. Found 29.3, 27.2, 24.5, 24.3, 22.9, 18.7, 18.6, 18.5, 14.4, 14.3, 14.1,
309.2809.
12.6; IR (CH2Cl2) ν 2923, 2854, 1740, 1365, 1217 cm−1; HRMS
(ESI+) calcd for C18H32NaO2 (M + Na)+ 303.2294. Found
303.2295.
(11S,12R)-Lactobacillic acid ((11S,12R)-4)
10-((1S,2R)-2-Hexylcyclopropyl)dec-9-enoic
acid
(23). The
general procedure for saponification applied to 22 (0.052 g,
8S,9R-Dihydromalvalic acid (8S,9R-2). The general procedure
0.36 mmol) afforded crude 23 (0.042 g, 85%). [α]2D5 −36.5 for diimide reduction applied to 26 (0.035 g, 0.13 mmol), after
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flash chromatography (EtOAc–hexane 20 : 80) yielded (8S,9R)-2 17a (0.101 g, 0.520 mmol) and methyl 7-oxaheptanoate (18)36
(0.026 g, 86%). [α]D25 −0.77 (c 0.32, CHCl3). 1H NMR (CDCl3, (0.091 g, 0.62 mmol), after flash chromatography (EtOAc–pet.
400 MHz) δ 2.35 (2 H, t, J = 7.6 Hz), 1.62–1.66 (2 H, m), spirits 1 : 9) afforded 29 (0.122 g, 83%). [α]2D2 +35.6 (c 0.190,
1.27–1.38 (20 H, m), 1.12–1.14 (2 H, m), 0.88 (3 H, t, J = CHCl3) (lit.25 +31.6). 1H NMR (CDCl3, 400 MHz) δ 5.45–5.52
7.2 Hz), 0.60–0.69 (2 H, m), 0.53–0.58 (1 H, m), −0.33 (1 H, q, (0.7 H, m), 5.35–5.41 (0.3 H, m), 5.13–5.19 (0.7 H, m),
J = 4.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 179.7, 34.1, 32.1, 5.01–5.06 (0.3 H, m), 3.66 (3 H, s), 2.28–2.33 (2 H, m),
30.4, 30.1, 29.8, 29.5, 29.4, 29.3, 289, 28.8, 24.9, 22.9, 15.9, 2.12–2.17 (0.6 H, m), 2.01 (1.4 H, q, J = 6.8 Hz), 1.58–1.65 (2 H,
15.9, 14.3, 11.1; IR (CH2Cl2) ν 2970, 2924, 2854, 1738, 1456, m), 1.23–1.42 (18 H, m), 0.76–0.92 (1.3 H, m), 0.88 (3 H, t,
1366, 1228, 1217 cm−1; HRMS (ESI+) calcd for C18H34NaO2 J = 6.4 Hz), 0.06–0.12 (0.7 H, m); 13C NMR (CDCl3, 100 MHz)
(M + Na)+ 305.2451. Found 305.2451.
δ 174.4, 130.1, 130.0, 129.9, 129.8, 51.5, 34.2, 32.6, 32.0,
Methyl 8-[(1S,2R)-2-octylcyclopropyl]oct-7-enoate (27). The 29.8, 29.7, 29.6, 29.5, 29.4, 29.3, 28.9, 28.7, 27.4, 25.0,
general procedure for Julia–Kocienski olefination applied to 24.9, 22.8, 18.5, 18.4, 14.3, 14.2, 14.1, 12.5; IR (CH2Cl2)
13b (0.102 g, 0.265 mmol) and methyl 7-oxoheptanoate (18)36 ν 2989, 2924, 2855, 1741, 1543, 1437, 1219, 1168 cm−1; HRMS
(0.0512 g, 0.319 mmol) after flash chromatography (EtOAc–pet. (ESI+) calcd for C18H32NaO2 (M + Na)+ 303.2294. Found
spirits 1 : 9) afforded 27 (0.074 g, 78%). [α]2D6 −36.0 (c 0.45, 303.2294.
CHCl3). 1H NMR (CDCl3, 400 MHz) δ 5.54–5.53 (0.7 H, m),
5.36–5.42 (0.3 H, m), 5.14–5.20 (0.7 H, m), 5.01–5.06 (0.3 H,
m), 3.66 (3 H, s), 2.28–2.33 (2 H, m), 2.12–2.17 (0.6 H, m),
1.98–3.04 (1.4 H, q, J = 6.4 Hz), 1.58–1.65 (2 H, m), 1.26–1.43
(19 H, m), 0.76–0.91 (2.3 H, m), 0.88 (3 H, t, J = 6.4 Hz),
0.08–0.12 (0.7 H, m); 13C NMR (CDCl3, 100 MHz) δ 174.4,
130.2, 130.02, 130.01, 129.9, 51.6, 34.2, 32.7, 32.1, 29.9, 29.84,
29.83, 29.7, 29.6, 29.52, 29.50, 29.3, 28.8, 25.0, 22.9, 18.6, 18.5,
14.32, 14.31, 12.5; IR (CH2Cl2) ν 2970, 2923, 2854, 1740, 1436,
(9R,10S)-cis-Methylenehexadecanoic acid ((9R,10S)-1)
8-[(1R,2S)-2-Hexylcyclopropyl]oct-7-enoic acid (30). The
general procedure for saponification applied to 29 (0.125 g,
0.446 mmol) afforded crude 30 (0.103 g, 87%). [α]2D3 +32.5
1
(c 0.34, CHCl3). H NMR (CDCl3, 400 MHz) δ 5.45–5.52 (0.7 H,
m), 5.35–5.41 (0.3 H, m), 5.14–5.20 (0.7 H, m), 5.01–5.06
(0.3 H, m), 2.32–2.37 (2 H, m), 2.13–2.17 (0.6 H, m), 2.00 (1.4
H, q, J = 6.8 Hz), 1.66–1.67 (1 H, m), 1.52–1.56 (1 H, m),
1.20–1.43 (16 H, m), 0.76–0.92 (1.3 H, m), 0.88 (3 H, t, J =
6.4 Hz), 0.08–0.12 (0.7 H, m); 13C NMR (CDCl3, 100 MHz)
δ 178.8, 130.1, 130.0, 129.8, 33.9, 33.9, 32.6, 32.0, 29.8, 29.7,
29.5, 29.4, 29.3, 29.3, 28.8, 28.6, 27.4, 24.7, 22.8, 18.6, 18.5,
(28). The 18.4, 14.3, 14.2, 14.0, 12.5; IR (CH2Cl2) ν 2923, 2854, 1708,
1365, 1217, 1228, 1204 cm−1
;
HRMS (ESI+) calcd for
C20H36NaO2 (M + Na)+ 331.2607. Found 331.2608.
(9S,10R)-Dihydrosterculic acid ((9S,10R)-3)
8-[(1S,2R)-2-Octylcyclopropyl]oct-7-enoic
acid
general procedure for saponification applied to 27 (0.071 g, 1456, 1412, 1219, 959 cm−1; HRMS (ESI+) calcd for C17H31O2
0.24 mmol) afforded crude 28 (0.052 g, 83%). [α]2D6 −37.6 (M + H)+ 267.2319. Found 267.2340.
1
(9R,10S)-cis-Methylenehexadecanoic acid ((9R,10S)-1). The
general procedure for diimide reduction applied to 30 (0.08 g,
0.30 mmol), after flash chromatography (EtOAc–hexane 20 : 80)
yielded (9R,10S)-1 (0.092 g, 89%). [α]2D0 +0.86 (c 0.155, CHCl3).
1H NMR (CDCl3, 400 MHz) δ 2.35 (2 H, t, J = 7.6 Hz), 1.60–1.65
(2 H, m), 1.12–1.36 (20 H, m), 0.88 (3 H, t, J = 6.8 Hz),
0.64–0.67 (2 H, m), 0.53–0.58 (1 H, m), −0.33 (1 H, q, J =
5.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 178.6, 34.0 32.1, 30.3,
30.2, 29.8, 29.6, 29.5, 29.4, 29.2, 28.9, 28.8, 25.0, 22.8, 15.9,
15.8, 14.2, 11.1; IR (CH2Cl2) ν 2922, 2853, 1708, 1458, 1412,
1284, 937 cm−1; HRMS (ESI+) calcd for C17H33O2 (M + H)+
(c 0.21, CHCl3). H NMR (CDCl3, 400 MHz) δ 5.54–5.53 (0.7 H,
m), 5.36–5.42 (0.3 H, m), 5.14–5.20 (0.7 H, m), 5.01–5.06
(0.3 H, m), 3.66 (3 H, s), 2.28–2.33 (2 H, m), 2.12–2.17 (0.6 H,
m), 1.98–3.04 (1.4 H, q, J = 6.4 Hz), 1.58–1.65 (2 H, m),
1.26–1.43 (17 H, m), 0.76–0.91 (2.3 H, m), 0.88 (3 H, t, J =
6.4 Hz), 0.08–0.12 (0.7 H, m); 13C NMR (CDCl3, 100 MHz) δ
177.7, 130.2, 130.1, 129.9, 33.8, 32.7, 32.2, 30.0, 29.92, 29.91,
29.8, 29.7, 29.6, 29.4, 28.9, 28.8, 27.5, 24.8, 24.8, 22.9, 18.71,
18.70, 18.5, 14.4, 14.4, 14.2, 12.6; IR (CH2Cl2) ν 2970, 2924,
2854, 1713, 1455, 1365, 1228, 1217 cm−1; HRMS (ESI+) calcd
for C19H34NaO2 (M + Na)+ 317.2451. Found 317.2451.
(9S,10R)-Dihydrosterculic acid ((9S,10R)-3). The general pro- 269.2475. Found 269.2475.
cedure for diimide reduction applied to 28 (0.050 g,
Methyl 10-[(1R,2S)-2-hexylcyclopropyl]dec-9-enoate (31). The
0.17 mmol), after flash chromatography (EtOAc–hexane–AcOH general procedure for Julia–Kocienski olefination applied to
20 : 80 : 1) gave (9S,10R)-3 as a white solid (0.042 g, 80%). 17a (0.152 g, 0.431 mmol) and methyl 9-oxanonanoate (21)39
[α]2D4 −0.81 (c 0.295, CHCl3). 1H NMR (CDCl3 + 1% TFA, (0.091 g, 0.52 mmol), after flash chromatography (EtOAc–pet.
400 MHz) δ 2.43 (2 H, t, J = 7.6 Hz), 1.62–1.68 (2 H, m), spirits 1 : 9) afforded 31 (0.115 g, 76%). [α]2D4 +31.3 (c 0.35,
1.25–1.37 (22 H, m), 1.10–1.17 (2 H, m), 0.88 (3 H, t, J = CHCl3). 1H NMR (CDCl3, 400 MHz) δ 5.46–5.53 (0.7 H, m),
6.8 Hz), 0.64–0.68 (2 H, m), 0.53–0.59 (1 H, m), −0.33 (1 H, q, 5.35–5.41 (0.3 H, m), 5.13–5.19 (0.7 H, m), 5.00–5.05 (0.3 H,
J = 4.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 178.7, 34.1, 32.1, m), 3.66 (3 H, s), 2.27–2.31 (2 H, m), 2.10–2.15 (0.6 H, m), 1.98
30.4, 30.3, 29.8, 29.6, 29.5, 29.4, 29.2, 28.9, 28.8, 24.9, 22.9, (1.4 H, q, J = 6.8 Hz), 1.57–1.63 (2 H, m), 1.26–1.42 (20 H, m),
15.9, 15.9, 14.3, 11.1; IR (CH2Cl2) ν 3016, 2970, 2925, 2854, 0.75–0.9 (1.3 H, m), 0.88 (3 H, t, J = 6.8 Hz), 0.08–0.12 (0.7 H,
1738, 1436, 1366, 1229, 1217 cm−1; HRMS (ESI+) calcd for m); 13C NMR (CDCl3, 100 MHz) δ 174.5, 130.5, 130.2, 129.8,
C19H36NaO2 (M + Na)+ 319.2608. Found 319.2608.
129.7, 51.5, 34.2, 32.8, 32.0, 29.8, 29.8, 29.7, 29.5, 29.33, 29.30,
Methyl 8-[(1R,2S)-2-hexylcyclopropyl]oct-7-enoate (29). The 29.24, 29.21, 29.0, 27.6, 2.1, 22.8, 18.6, 18.5, 18.4, 14.32, 14.31,
general procedure for Julia–Kocienski olefination applied to 14.1, 12.5; IR (CH2Cl2) ν 2989, 2924, 2854, 1741, 1542, 1437,
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1377, 1219, 1170, 673 cm−1
;
HRMS (ESI+) calcd for m); 13C NMR (CDCl3, 100 MHz) δ 177.7, 130.4, 130.3, 129.6,
C20H36NaO2 (M + Na)+ 331.2608. Found 331.2608.
129.4, 33.7, 33.6, 32.4, 32.1, 29.9, 29.84, 29.82, 29.7, 29.6, 29.5,
29.3, 27.2, 24.5, 24.3, 22.9, 18.7, 18.6, 18.5, 14.4, 14.3, 14.1,
12.6; IR (CH2Cl2) ν 2924, 2855, 1710, 1542, 1457, 1365,
1219 cm−1; HRMS (ESI+) calcd for C18H33O2 (M + H)+ 281.2475.
Found 281.2494.
(11R,12S)-Lactobacillic acid ((11R,12S)-4)
10-[(1R,2S)-2-Hexylcyclopropyl]dec-9-enoic
acid
(32). The
general procedure for saponification applied to 31 (0.102 g,
0.324 mmol) afforded crude 32 (0.082 g, 84%). [α]2D3 +36.8
1
(c 0.3, CHCl3). H NMR (CDCl3, 400 MHz) δ 5.46–5.53 (0.7 H,
(8R,9S)-Dihydromalvalic acid ((8R,9S)-2). The general pro-
m), 5.36–5.42 (0.3 H, m), 5.13–5.19 (0.7 H, m), 5.00–5.05 cedure for diimide reduction applied to 34 (0.021 g,
(0.3 H, m), 2.32–2.36 (2 H, m), 2.10–2.16 (0.6 H, m), 1.99 (1.4 0.075 mmol), after flash chromatography (EtOAc–hexane
H, q, J = 6.8 Hz), 1.52–1.66 (2 H, m), 1.20–1.43 (20 H, m), 20 : 80) yielded (8R,9S)-2 as a colorless oil (0.015 g, 75%).
1
0.76–0.92 (1.3 H, m), 0.87 (3 H, t, J = 6.8 Hz), 0.08–0.12 (0.7 H, [α]2D4 +0.61 (c 0.350, CHCl3). H NMR (CDCl3, 400 MHz) δ 2.36
m); 13C NMR (CDCl3, 100 MHz) δ 178.9, 130.4, 130.1, 129.8, (2 H, t, J = 7.2 Hz), 1.63–1.66 (2 H, m), 1.25–1.37 (20 H, m),
129.7, 33.9, 32.8, 32.0, 29.9, 29.82, 29.80, 29.6, 29.4, 29.32, 1.10–1.14 (2 H, m), 0.88 (3 H, t, J = 7.2 Hz), 0.64–0.67 (2 H, m),
29.30, 29.2, 29.1, 29.0, 27.6, 24.8, 22.8, 18.61, 18.60, 18.4, 14.3, 0.53–0.58 (1 H, m), −0.33 (1 H, q, J = 4.8 Hz); 13C NMR (CDCl3,
14.2, 14.0, 12.5; IR (CH2Cl2) ν 2923, 2854, 1708, 1457, 1412, 100 MHz) δ 178.4, 33.9, 32.1, 30.4, 30.1, 29.8, 29.5, 29.4, 29.3,
1285, 959 cm−1; HRMS (ESI+) calcd for C19H35O2 (M + H)+ 28.9, 28.8, 24.9, 22.9, 15.92, 15.90, 14.3, 11.1; IR (CH2Cl2)
295.2632. Found 295.2654.
ν 2922, 2854, 1708, 1458, 1366, 1284, 1217 cm−1; HRMS (ESI+)
calcd for C18H34NaO2 (M + Na)+ 305.2451. Found 305.2451.
Methyl 8-[(1R,2S)-2-octylcyclopropyl]oct-7-enoate (35). The
general procedure for Julia–Kocienski olefination applied to
17b (0.130 g, 0.345 mmol) and methyl 7-oxoheptanoate (18)36
(0.0651 g, 0.414 mmol) after flash chromatography (EtOAc–pet.
spirits 1 : 9) afforded 35 (0.094 g, 85%) as a colorless oil.
[α]2D4 +34.1 (c 0.36, CHCl3). 1H NMR (CDCl3, 400 MHz)
δ 5.45–5.52 (0.7 H, m), 5.35–5.41 (0.3 H, m), 5.13–5.19 (0.7 H,
m), 5.01–5.06 (0.3 H, m), 3.66 (3 H, s), 2.28–2.33 (2 H, m),
2.12–2.15 (0.6 H, m), 2.00 (1.4 H, q, J = 6.8 Hz), 1.58–1.65 (2 H,
m), 1.21–1.42 (18 H, m), 0.76–0.92 (2.3 H, m), 0.88 (3 H, t, J =
6.4 Hz), 0.08–0.12 (0.7 H, m); 13C NMR (CDCl3, 100 MHz)
δ 174.4, 130.2, 130.0, 129.9, 129.9, 51.6, 34.2, 32.7, 29.9, 29.84,
29.82, 29.7, 29.6, 29.51, 29.50, 29.3, 28.8, 25.0, 22.9, 18.6, 18.5,
14.3, 14.1, 12.5; IR (CH2Cl2) ν 2990, 2923, 2853, 1742, 1365,
1219 cm−1; HRMS (ESI+) calcd for C20H37O2 (M + H)+ 309.2788.
Found 309.2876.
(11R,12S)-Lactobacillic acid ((11R,12S)-4). The general pro-
cedure for diimide reduction applied to 32 (0.080 g,
0.27 mmol), after flash chromatography (EtOAc–hexane 20 : 80)
yielded (11R,12S)-4 (0.062 g, 81%). [α]2D0 +0.94 (c 0.155, CHCl3)
(lit.22 +0.16; lit.44 +0.25). 1H NMR (CDCl3, 400 MHz) δ 2.35 (2 H,
t, J = 7.6 Hz), 1.61–1.65 (2 H, m), 1.25–1.37 (22 H, m),
1.10–1.17 (2 H, m), 0.88 (3 H, t, J = 6.8 Hz), 0.64–0.68 (2 H, m),
0.53–0.59 (1 H, m), −0.33 (1 H, q, J = 4.8 Hz); 13C NMR (CDCl3,
100 MHz) δ 180.1, 34.2, 32.1, 30.4, 30.3, 29.9, 29.8, 29.6, 29.5,
29.4, 29.2, 28.9, 24.8, 22.9, 15.9, 15.9, 14.3, 11.1; IR (CH2Cl2)
ν 2923, 2854, 1708, 1412, 1219 cm−1; HRMS (ESI+) calcd for
C19H36O2 (M + H)+ 297.2788. Found 297.2788. The H and 13C
NMR data reported here differs from those previously
reported.22
Methyl 7-[(1R,2S)-2-octylcyclopropyl]hept-6-enoate (33). The
general procedure for Julia–Kocienski olefination applied to
17b (0.062 g, 0.15 mmol) and methyl 6-oxohexanoate (24)40
(0.0412 g, 0.191 mmol) after flash chromatography (EtOAc–pet.
spirits 1 : 9) afforded 33 (0.042 g, 87%). [α]2D4 +33.3 (c 0.25,
CHCl3). 1H NMR (CDCl3, 400 MHz) δ 5.54–5.52 (0.7 H, m),
1
8-[(1R,2S)-2-Octylcyclopropyl]octanoic acid (9R,10S-dihydro-
sterculic acid; 3)
8-[(1R,2S)-2-Octylcyclopropyl]oct-7-enoic
acid
(36). The
5.35–5.41 (0.3 H, m), 5.15–5.21 (0.7 H, m), 5.00–5.07 (0.3 H, general procedure for saponification applied to 35 (0.051 g,
m), 3.66 (3 H, s), 2.28–2.34 (2 H, m), 2.13–2.17 (0.6 H, q, J = 0.17 mmol) afforded crude 36 (0.042 g, 81%) as a colorless oil.
7.2 Hz), 2.02 (1.4 H, q, J = 6.4 Hz), 1.59–1.71 (2 H, m), [α]2D6 +37.6 (c 0.24, CHCl3) (lit.24 +40). 1H NMR (CDCl3,
1.21–1.46 (18 H, m), 0.76–0.92 (1.3 H, m), 0.88 (3 H, t, J = 400 MHz) δ 5.45–5.53 (0.7 H, m), 5.36–5.41 (0.3 H, m),
6.4 Hz), 0.08–0.12 (0.7 H, m); 13C NMR (CDCl3, 100 MHz) 5.14–5.20 (0.7 H, m), 5.01–5.06 (0.3 H, m), 2.33–2.38 (2 H, m),
δ 174.4, 130.3, 130.2, 129.8, 129.5, 51.6, 34.1, 32.5, 32.1, 29.9, 2.15–2.17 (0.6 H, m), 2.01 (1.4 H, q, J = 6.4 Hz), 1.62–1.67 (2 H,
29.8, 29.7, 29.6, 29.5, 29.4, 29.3, 27.3, 24.6, 22.9, 18.6, 18.5, m), 1.22–1.43 (19 H, m), 0.76–0.91 (2.3 H, m), 0.88 (3 H, t, J =
14.3, 14.1, 12.6; IR (CH2Cl2) ν 2923, 2854, 1742, 1436, 1365, 6.4 Hz), 0.07–0.12 (0.7 H, m); 13C NMR (CDCl3, 100 MHz)
1219 cm−1; HRMS (ESI+) calcd for C19H35O2 (M + H)+ 295.2632. δ 177.7, 130.2, 130.1, 129.9, 33.8, 32.7, 32.2, 30.0, 29.9, 29.9,
Found 295.2650.
(8R,9S)-Dihydromalvalic acid ((8R,9S)-2)
7-[(1R,2S)-2-Octylcyclopropyl]hept-6-enoic
general procedure for saponification applied to 33 (0.042 g,
0.14 mmol) afforded crude 34 (0.029, 80%). [α]2D5 +32.9 (c 0.24,
CHCl3). 1H NMR (CDCl3, 400 MHz) δ 5.54–5.52 (0.7 H, m),
5.35–5.41 (0.3 H, m), 5.15–5.21 (0.7 H, m), 5.03–5.08 (0.3 H,
m), 2.33–2.39 (2 H, m), 2.18 (0.6 H, q, J = 7.2 Hz), 2.03 (1.4 H,
q, J = 7.2 Hz), 1.63–1.69 (2 H, m), 1.26–1.63 (16 H, m),
0.76–0.92 (1.3 H, m), 0.88 (3 H, t, J = 6.4 Hz), 0.09–0.13 (0.7 H,
29.8, 29.7, 29.6, 29.4, 28.9, 28.8, 27.5, 24.84, 24.82, 22.9, 18.7,
18.7, 18.5, 14.42, 14.41, 14.2, 12.6; IR (CH2Cl2) ν 2922, 2853,
2329, 1708, 1456, 1219 cm−1; HRMS (ESI+) calcd for C19H35O2
(M + H)+ 295.2632. Found 295.2522.
8-[(1R,2S)-2-Octylcyclopropyl]octanoic acid (9R,10S-dihydroster-
culic acid; 3). The general procedure for diimide reduction
applied to 36 (0.035 g, 0.17 mmol), after flash chromatography
acid
(34). The
(EtOAc–hexane 20 : 80) yielded 9R,10S-3 as
a semisolid
(0.031 g, 86%). [α]D24 +0.95 (c 0.55, CHCl3), (lit.24 +0.92). 1H
NMR (CDCl3, 400 MHz) δ 2.35 (2 H, t, J = 7.6 Hz), 1.62–1.65
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(2 H, m), 1.25–1.36 (22 H, m), 1.12–1.16 (2 H, m), 0.88 (3 H, t,
J = 6.8 Hz), 0.64–0.68 (2 H, m), 0.53–0.58 (1 H, m), −0.33 (1 H,
q, J = 4.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 178.8, 33.9, 32.1,
30.4, 30.3, 29.8, 29.5, 29.4, 29.2, 28.9, 28.8, 24.9, 22.9, 15.92,
15.90, 14.3, 11.1; IR (CH2Cl2) ν 2924, 2854, 1711, 1456,
1219 cm−1; HRMS (ESI+) calcd for C19H37O2 (M + H)+ 297.2788.
Found 297.2788.
7 J. Sauvageau, J. Ryan, K. Lagutin, I. M. Sims, B. L. Stocker
and M. S. Timmer, Carbohydr. Res., 2012, 357, 151–156.
8 S. Penkov, F. Mende, V. Zagoriy, C. Erkut, R. Martin,
U. Pässler, K. Schuhmann, D. Schwudke, M. Gruner,
J. Mäntler, T. Reichert-Müller, A. Shevchenko, H.-J. Knölker
and T. V. Kurzchalia, Angew. Chem., Int. Ed., 2010, 49,
9430–9435.
9 M. A. Vences-Guzman, Z. Guan, E. Ormeno-Orrillo,
N. Gonzalez-Silva, I. M. Lopez-Lara, E. Martinez-Romero,
O. Geiger and C. Sohlenkamp, Mol. Microbiol., 2011, 79,
1496–1514.
10 B. A. Shin, Y. R. Kim, I.-S. Lee, C. K. Sung, J. Hong,
C. J. Sim, K. S. Im and J. H. Jung, J. Nat. Prod., 1999, 62,
1554–1557.
11 T. Kaneshiro and A. G. Marr, J. Biol. Chem., 1961, 236,
2615–2619.
12 (a) J. J. Macfarlane, F. S. Shenstone and J. R. Vickery,
Nature, 1957, 179, 830–831; (b) G. A. Jeffrey and M. Sax,
Acta Crystallogr., 1963, 16, 1196–1204.
13 (a) J. R. Nunn, J. Chem. Soc., 1952, 313–318;
(b) K. Hofmann, O. Jucker, W. R. Miller, A. C. Young and
F. Tausig, J. Am. Chem. Soc., 1954, 76, 1799–1804.
14 K. Hofmann, R. A. Lucas and S. M. Sax, J. Biol. Chem.,
1952, 195, 473–485.
X-ray crystallography
Intensity data were collected on an Oxford SuperNova CCD
diffractometer using Cu-Kα radiation (graphite crystal mono-
chromator λ = 1.54184), the temperature during data collection
was maintained at 130.0(1).
Crystal data for 14b. C22H31NO3, M = 357.48, T = 130.0(2) K,
λ = 1.5418 Å, Monoclinic, space group C2 a = 32.485(3), b =
5.3094(4), c = 11.6620(7) Å, β = 91.786(7)°, V = 2010.5(3) Å3,
Z = 4, Dc = 1.181 Mg M−3 μ(Cu-Kα) 0.613 mm−1, F(000) = 776,
crystal size 0.55 × 0.08 × 0.03 mm, 5781 reflections measured,
3169 independent reflections (Rint = 0.067) the final R was
0.0556 [I > 2σ(I)] and wR(F2) was 0.1387 (all data), absolute
structure parameter = 0.1(4), GOOF = 0.991. CCDC deposition:
1009686.
15 L. J. Stuart, J. P. Buck, A. E. Tremblay and P. H. Buist, Org.
Lett., 2005, 8, 79–81.
Acknowledgements
16 S. Kobayashi, R. Tokunoha, M. Shibasaki, R. Shinagawa
and K. Murakami-Murofushi, Tetrahedron Lett., 1993, 34,
4047–4050.
We thank the Australian Research Council (ARC) for financial
support. SJW is an ARC Future Fellow. SS thanks the Depart-
ment of State Development, Business and Innovation of
Victoria for a Victoria-India Doctoral Scholarship and the
Australia India Institute.
17 S. Rasonyi, Diss. ETH # 11318.
18 J. F. Tocanne, Tetrahedron, 1972, 28, 363–371.
19 L. J. Stuart and P. H. Buist, Tetrahedron: Asymmetry, 2004,
15, 401–403.
20 P. H. Buist and R. A. Pon, J. Org. Chem., 1990, 55, 6240–
6241.
Notes and references
1 D. W. Grogan and J. E. Cronan Jr., Microbiol. Mol. Biol. Rev., 21 G. D. Coxon, S. Knobl, E. Roberts, M. S. Baird, J. R. Al
1997, 61, 429–441.
2 R. C. Badami and K. B. Patil, Prog. Lipid Res., 1980, 19, 119–
Dulayymi, G. S. Besra, P. J. Brennan and D. E. Minnikin,
Tetrahedron Lett., 1999, 40, 6689–6692.
153.
22 G. D. Coxon, J. R. Al-Dulayymi, M. S. Baird, S. Knobl,
E. Roberts and D. E. Minnikin, Tetrahedron: Asymmetry,
2003, 14, 1211–1222.
3 H. Meyer and G. G. Holz Jr., J. Biol. Chem., 1966, 241, 5000–
5007.
4 (a) R. C. H. M. Oudejans, D. J. Van der Horst and J. P. C. 23 J. W. Palko, P. H. Buist and J. M. Manthorpe, Tetrahedron:
M. Van Dongen, Biochemistry, 1971, 10, 4938–4941; Asymmetry, 2013, 24, 165–168.
(b) K. Sakurada, H. Iwase, T. Takatori, M. Nagao, 24 Y. Lou, M. Horikawa, R. A. Kloster, N. A. Hawryluk and
M. Nakajima, H. Niijima, Y. Matsuda and M. Kobayashi, E. J. Corey, J. Am. Chem. Soc., 2004, 126, 8916–8918.
Biochim. Biophys. Acta, 1999, 1437, 214–222; 25 H. Suematsu, S. Kanchiku, T. Uchida and T. Katsuki, J. Am.
(c) T. Sledzinski, A. Mika, P. Stepnowski, M. Proczko-Mar- Chem. Soc., 2008, 130, 10327–10337.
kuszewska, L. Kaska, T. Stefaniak and J. Swierczynski, 26 L.-a. Liao, F. Zhang, N. Yan, J. A. Golen and J. M. Fox, Tetra-
Lipids, 2013, 48, 839–848. hedron, 2004, 60, 1803–1816.
5 (a) J. E. Cronan Jr., Curr. Opin. Microbiol., 2002, 5, 202–205; 27 I. Marek, S. Simaan and A. Masarwa, Angew. Chem., Int. Ed.,
(b) M. Fontecave, M. Atta and E. Mulliez, Trends Biochem. 2007, 46, 7364–7376.
Sci., 2004, 29, 243–249; (c) X. Bao, S. Katz, M. Pollard and 28 (a) H. Pellissier, Tetrahedron, 2008, 64, 7041–7095;
J. Ohlrogge, Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 7172–
7177.
(b) H. Lebel, J.-F. Marcoux, C. Molinaro and A. B. Charette,
Chem. Rev., 2003, 103, 977–1050.
6 K. Murakami-Murofushi, M. Shioda, K. Kaji, S. Yoshida 29 N. Petiniot, A. J. Anciaux, A. F. Noels, A. J. Hubert and
and H. Murofushi, J. Biol. Chem., 1992, 267, 21512–21517.
P. Teyssié, Tetrahedron Lett., 1978, 19, 1239–1242.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
30 P. Müller and C. Gränicher, Helv. Chim. Acta, 1993, 76, 38 Vinylcyclopropanes are prone to ring open upon treatment
521–534.
with H2 and Pd-C (A. G. M. Barrett and W. Tam, J. Org.
Chem., 1997, 62, 7673–7678). Additionally, we observed
some formation of ring cleaved products when using
TsNHNH2 or KO2CNvNCO2K, which we attribute to high
concentrations of diimine formed by thermal decompo-
sition of these reagents.
31 M. Franck-Neumann and C. Dietrich-Buchecker, Tetrahe-
dron Lett., 1980, 21, 671–674.
32 A. de Meijere and S. I. Kozhushkov, Sci. Synth., 2009, 48,
561–563.
33 M. Rubin, M. Rubina and V. Gevorgyan, Synthesis, 2006,
1221–1245.
34 (a) T. D. Penning, S. W. Djuric, R. A. Haack, V. J. Kalish,
39 W. Zhang, M. Sun and R. G. Salomon, J. Org. Chem., 2006,
71, 5607–5615.
J. M. Miyashiro, B. W. Rowell and S. S. Yu, Synth. Commun., 40 P. Heath, J. Mann, E. B. Walsh and A. H. Wadsworth,
1990, 20, 307–312; (b) C. J. Barnett, T. M. Wilson, J. Chem. Soc., Perkin Trans. 1, 1983, 2675–2679.
D. A. Evans and T. C. Somers, Tetrahedron Lett., 1997, 38, 41 T. Tashiro, K. Akasaka, H. Ohrui, E. Fattorusso and
735–738. K. Mori, Eur. J. Org. Chem., 2002, 3659–3665.
35 H. S. Schultz, H. B. Freyermuth and S. R. Buc, J. Org. 42 W. C. Still, M. Kahn and A. M. Mitra, J. Org. Chem., 1978,
Chem., 1963, 28, 1140–1142. 43, 2923–2925.
36 K. Kai, J. Takeuchi, T. Kataoka, M. Yokoyama and 43 A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen
N. Watanabe, Tetrahedron, 2008, 64, 6760–6769. and F. J. Timmers, Organometallics, 1996, 15, 1518–1520.
37 P. R. Blakemore, W. J. Cole, P. J. Kocieński and A. Morley, 44 O. W. Thiele, J. Asselineau and C. Lacave, Eur. J. Biochem.,
Synlett, 1998, 26–28.
1969, 7, 393–396.
Org. Biomol. Chem.
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