Assignment of the absolute configuration and total synthesis of (+)-caripyrin

Article abstract of DOI:10.1002/ejoc.201402540

The antifungal secondary metabolite (+)-caripyrin was studied by vibrational circular dichroism spectroscopy. Analysis of the recorded data, with the Boltzmann weighted-average of the spectra calculated at the B3LYP/6-311G(d,p) level of theory for all relevant conformers, unequivocally proved the (R,R)-configuration for the dextrorotatory natural product. Based on this finding, a short enantioselective synthesis of (+)-caripyrin was developed.

Full text of DOI:10.1002/ejoc.201402540

Job/Unit: O42540
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Date: 24-06-14 11:33:27
Pages: 6
FULL PAPER
DOI: 10.1002/ejoc.201402540
Assignment of the Absolute Configuration and Total Synthesis of (+)-Caripyrin
Lars Andernach[a] and Till Opatz*[a]
Keywords: Natural products / Total synthesis / Configuration determination / Density functional calculations / Vibrational
spectroscopy
The antifungal secondary metabolite (+)-caripyrin was
studied by vibrational circular dichroism spectroscopy.
Analysis of the recorded data, with the Boltzmann weighted-
average of the spectra calculated at the B3LYP/6-311G(d,p)
level of theory for all relevant conformers, un-
equivocally proved the (R,R)-configuration for the dextroro-
tatory natural product. Based on this finding, a short enantio-
selective synthesis of (+)-caripyrin was developed.
(9.8 mg) were recorded in CCl4 solution by using a low
dead volume BaF2 sample cell and were analyzed against
Boltzmann averaged spectra from DFT calculations. For
non-rigid molecules, a thorough conformational analysis is
required in this context because circular dichroism spectra
are generally sensitive to conformational changes. This
analysis was done by using the systematic algorithm as im-
plemented in SpartanЈ10[2] in combination with the MMFF
force field.[3] From this procedure four candidate conform-
ers were obtained. All of these were used as starting geome-
tries for a geometry optimization performed at the B3LYP/
6-31G(d,p)[4–7] level of theory (Gaussian09).[8] The final co-
ordinates from this first geometry optimization were then
further optimized at the B3LYP/6-311G(d,p)[9] level and
solvation was treated with the integral equation formalism
polarizable continuum model[10] (IEFPCM) for CCl4. The
conformer distribution, which includes the relative Gibbs
energies and the dihedral angles, is given in Table 1 and
the geometries are shown in Figure 2. For both side chains
attached to the pyridine core, two preferred orientations
were found. In the lowest energy conformer, conformer 1,
the dipole moments of the carbonyl oxygen atom, the nitro-
gen atom and the epoxide oxygen atom compensate each
other to the largest extent.
Introduction
The complete characterization of chiral non-racemic nat-
ural products includes the determination of their respective
absolute configuration because this information is crucial
for synthetic efforts as well as for the analysis of their inter-
action with biological targets.
In 2010 Rieger et al. reported the flat structure of the
fungal secondary metabolite (+)-caripyrin (1; Figure 1),
which they isolated from submerged cultures of the basidio-
mycete Caripia montagnei. The compound exhibits selective
and strong inhibition of conidial germination in the rice
blast fungus Magnaporthe oryzae, the causal agent of blast,
a devastating disease in cultivated rice.[1] However, the abso-
lute configuration of its two stereogenic centers remained
unknown. Herein we report the determination of the full
stereostructure of 1 by vibrational circular dichroism spec-
troscopy by using density functional theory (DFT) calcula-
tions at the B3LYP/6-311G(d,p) level. Moreover, a short
enantioselective total synthesis of 1 is presented.
Subsequently,
a
frequency analysis at B3LYP/6-
311G(d,p) level with IEFPCM solvation for CCl4 was per-
formed for all four conformers to obtain the vibrational
absorption and VCD spectra. The spectra of each con-
former, the resulting Boltzmann weighted sum and the ex-
perimental data are shown in Figure 3 (IR) and Figure 4
(VCD).
The Boltzmann weighted IR spectrum is in excellent
agreement with the experimental spectrum of 1, the fre-
quencies and the intensities of nearly all bands are correctly
predicted. It should be noted that the high-frequency shoul-
der of the ester carbonyl stretch results from conformers 3
and 4, in which the dipole moments of the C=O and the
endocyclic C(2)=N-bond do not cancel each other.
Figure 1. Structure of (+)-(2ЈR,3ЈR)-caripyrin 1.
Results and Discussion
To elucidate the absolute configuration of 1, the IR and
vibrational circular dichroism (VCD) spectra of a sample
[a] Institute of Organic Chemistry, University of Mainz,
Duesbergweg 10-14, 55128 Mainz, Germany
E-mail: opatz@uni-mainz.de
http://www.chemie.uni-mainz.de/OC/AK-Opatz/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402540.
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L. Andernach, T. Opatz
Table 1. Conformer distribution at B3LYP/6-311G(d,p) IEFPCM CCl4 level of theory, relative Gibbs energies and dihedral angles of 1.
FULL PAPER
Dihedral N–C2–C1Ј–O
Dihedral C6–C5–C2Ј–O
Relative energy[a]
Population
Conformer 1
Conformer 2
Conformer 3
Conformer 4
179.8°
179.8°
1.1°
167.5°
348.9°
168.7°
347.8°
0.0
2.1
3.2
5.2
0.545
0.236
0.150
0.068
357.2°
[a] Values in kJ/mol.
Figure 2. Geometries of all four B3LYP/6-311G(d,p)-optimized
conformers of 1.
Figure 4. VCD spectra of all four conformers, Boltzmann average
and experimental spectrum of 1 in CCl4 solution in two different
concentrations.
trum of a single conformer. The negative band at 1730 cm–1
in the experimental spectrum at c = 1 mol/L is a saturation
artifact of the detector as can be seen from the somewhat
noisier spectrum recorded at c = 0.5 mol/L.
Some predicted band intensities, e.g. at 1306, 1254 and
1130 cm–1, do not agree well with the experimental spec-
trum. In most cases, the reason for this is the small fre-
Figure 3. Vibrational absorption spectra of all four conformers,
Boltzmann average and experimental spectrum of 1 in CCl4 solu-
tion.
The same good agreement is observed with the VCD quency difference between absorption bands with opposite
spectra. Only the smaller carbonyl band at 1753 cm–1 and signs in different conformers. However, there is clearly no
the band at 1058 cm–1 have the wrong sign. This might be doubt that the absolute configuration of 1 is (R,R). Fristrup
a consequence of a small difference in the conformer et al. reported very similar results for their VCD study on
weighting or a incorrectly predicted sign in the VCD spec- (1R,2R)-2-methylphenyloxirane.[11]
2
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Absolute Configuration and Synthesis of (+)-Caripyrin
Scheme 1. Total synthesis of (+)-(R,R)-caripyrin 1.
With the knowledge about the absolute configuration of Supporting Information). The HPLC chromatograms of
natural occurring 1, an asymmetric synthesis was developed natural and synthetic 1 (70% ee) as well as of the racemate
(Scheme 1). The key step is the asymmetrical epoxidation are shown in Figure 5. As predicted, the naturally occurring
of the disubstituted (E)-olefin by using Shi’s method.[12–14] enantiomer of 1 was the major product.
Gratifyingly, the commercially available d-fructose-based
catalyst should produce the desired enantiomer. trans-
Olefin 4 was prepared by a Suzuki–Miyaura cross-coupling
reaction of (E)-1-propen-1-ylboronic acid with methyl 5-
bromopicolinate (3) as described by Aoyagi et al.[15] Ester
3 was obtained by acidic esterification of commercial 5-
bromopicolinic acid (2).
Because (E)-1-propen-1-ylboronic acid is quite expensive
(Ͼ250 j per g in 2014) two other boronic acid derivatives,
namely (E)-1-propenylboronic acid N-methyliminodiacetic
acid (MIDA) ester and potassium (E)-1-propenyltrifluoro-
borate, were tested as precursors for the propenyl side
chain. The use of the MIDA ester (ca. 35 j per g in 2014;
3 equiv. used) gave olefin 4 in 67% yield as an inseparable
mixture with its (Z)-isomer (ratio 1:0.25, E/Z, see Support-
ing Information). The MIDA ester already contained the
same percentage of the (Z)-isomer. With potassium (E)-1-
propenyltrifluoroborate (ca. 52 j per g in 2014; 1.5 equiv.
Figure 5. HPLC chromatograms of natural 1, synthetic 1 (70% ee)
and the racemate.
used) olefin 4 was obtained in 57% yield as the pure (E)-
isomer. Thus, the latter method is most cost-effective de-
spite the slightly lower yield.
Conclusions
The epoxidation reaction with the reaction conditions
described for (E)-prop-1-en-1-ylbenzene was found to be
sluggish.[12–14] When the addition of the oxone and potas-
sium carbonate solution was complete after 2 h, TLC indi-
cated only very low conversion. This is presumably caused
by the electrophilic nature of the intermediate dioxirane
species, which reacts faster with electron-rich double bonds.
The conversion could be increased by longer reaction times
and the addition of more oxidant and base. After 42 h at
0 °C, 1 was isolated in 50% yield and 70% ee (chiral
HPLC). By performing the reaction at –20 °C, near to the
freezing point of the solvent mixture, produced 1 in only
We unambiguously determined the absolute configura-
tion of (+)-caripyrin (1) to be (2ЈR,3ЈR) by VCD spec-
troscopy in combination with DFT calculations. Based on
this knowledge, the first asymmetric total synthesis of this
antifungal natural product was performed in 26.6% overall
yield. At the expense of the conversion, an enantiomeric
excess of up to 89% could be achieved.
Experimental Section
Vibrational Spectroscopy: The IR (16 scans, 4000–400 cm–1) and
11% yield after 92 h but with an appreciable ee of 89% (see VCD (240 min accumulation time, 1800–875 cm–1) spectra were re-
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L. Andernach, T. Opatz
FULL PAPER
corded on a Bruker Tensor 27 IR spectrometer equipped with a
PMA 50 module containing a single photoelastic modulator, with
4 cm–1 resolution and the instrument optimized at 1400 cm–1. A
100 μm BaF2 cell and CCl4 solutions of 1 with concentrations of
0.5 mol/L and 1.0 mol/L were used. All solution spectra were sol-
vent subtracted. Routine IR spectra were measured on the same
spectrometer with a diamond ATR unit.
temperature was raised to 0 °C and the reaction mixture stirred for
4 h at that temperature. Then, another portion (2 mL each) of the
two solutions was added over 40 min through syringe pumps. After
18 h, the mixture was quenched by adding water (20 mL) and ethyl
acetate (20 mL). The aqueous layer was extracted with ethyl acetate
(3ϫ 20 mL) and the combined organic layers were washed with
brine, dried with Na2SO4 and concentrated in vacuo. The residue
was purified by flash chromatography (cyclohexane/ethyl acetate,
1:1 v/v) to give 1 as white microcrystalline solid (33 mg, 0.17 mmol,
50% yield, 70% ee). Rf = 0.10 cyclohexane/ethyl acetate, 2:1, m.p.
40–42 °C. 1H NMR (400 MHz, CDCl3, 298 K): δ = 8.64 (d, J =
2.1 Hz, 1 H, 6-H), 8.07 (d, J = 8.1 Hz, 1 H, 3-H), 7.65 (dd, J = 8.1,
2.1 Hz, 1 H, 4-H), 3.98 (s, 3 H, OCH3), 3.66 (d, J = 2.0 Hz, 1 H,
2Ј-H), 3.04 (qd, J = 5.1, 2.0 Hz, 1 H, 3Ј-H), 1.47 (d, J = 5.1 Hz,
3 H, 3Ј-CH3) ppm. 13C NMR (101 MHz, CDCl3, 298 K): δ = 165.5
(C=O), 147.8 (C-6), 147.6 (C-2), 137.5 (C-5), 133.8 (C-4), 125.0 (C-
3), 59.8 (C-3Ј), 56.9 (C-2Ј), 53.0 (OCH3), 17.9 (3Ј-CH3) ppm.
HRMS (ESI): m/z calcd. for C10H11NO3Na [M + Na]+ 216.0637;
Computational Methods: All calculations were performed on stan-
dard desktop computers with Intel Core i7 CPUs by using Spar-
tanЈ10[2] and Gaussian09 rev. A.02.[8] The calculations were pre-
ceded by a thorough conformer search by using the MMFF force
field[3] and the algorithm to analyze conformer distributions as im-
plemented in SpartanЈ10. All four obtained low-energy conformers
were optimized at the B3LYP/6-31G(d,p)[4–7] level of theory by
using Gaussian09. Subsequently, they were further optimized at the
B3LYP/6-311G(d,p)[9] level treating solvation with the IEFPCM
model[10] for CCl4. A frequency analysis with the same DFT
settings was done with all four further optimized structures to ob-
tain the vibrational spectra. Boltzmann weighting with the relative
Gibbs energies from the thermochemical output of the frequency
calculations was carried out to receive the averaged spectra. The
calculated vibrational frequencies were scaled by an empirically de-
termined factor of 0.9805.
found 216.0634. IR (ATR): ν
= 2955, 1742, 1722, 1437, 1310,
˜
max
1241, 1132, 1122, 859, 709 cm–1.
The analytical data are consistent with the values from the litera-
ture.[1]
With the same procedure as described above carried out at –20 °C
over 92 h reaction time, 1 was obtained in 11% yield and 89% ee.
[α]2D5 = +20.9 (c = 0.43, CDCl3).
Synthesis: Melting points were determined in open capillary tubes
with a Krüss KSP-1N apparatus. The optical rotation was mea-
sured on a Jasco P-2000 polarimeter at 589 nm with a temperature-
controlled cuvette with 10 cm path length. NMR spectra were re-
corded with a Bruker Avance-II 400 MHz spectrometer (400 MHz
1H and 101 MHz 13C) equipped with a 5 mm BBFO probe by using
standard pulse sequences. Chemical shifts were referenced by using
Methyl 5-(3-Methyloxiran-2-yl)picolinate (rac-1): Olefin 4 (48 mg,
0.27 mmol) and 3-chloroperbenzoic acid (95 mg, 0.55 mmol) were
heated at reflux in dry dichloromethane (10 mL) for 6 h. The vola-
tiles were removed under reduced pressure. The residue was puri-
fied by flash chromatography (cyclohexane/ethyl acetate, 1:1 v/v)
to give rac-1 (12 mg, 0.06 mmol, 22% yield).
the solvent signals of CHCl3/CDCl3 (δH = 7.26 ppm, δC
=
77.16 ppm).[16] HRMS (ESI) spectra were recorded with a Waters
QTof-Ultima 3-Instrument with LockSpray-Interface and a suitable
external calibrant. Microwave reactions were carried out in a CEM
Discover monomode apparatus at the indicated maximum tem-
perature and power setting. Chiral HPLC for enantiomeric excess
determination was performed by using a Knauer HPLC system
with a K-1001 pump, a column oven, a K-2800 diode array UV
detector and a Chiralpak IB-3 column (250 mmϫ4.6 mm, 3 μm,
Daicel Corp.) with a flow rate of 2 mL/min hexane/ethanol 95:5.
TLC experiments were performed on alumina sheets coated with
silica gel (60F254, Merck). For flash chromatography silica gel (35–
70 μm, 60 Å, Acros) was used. Automated flash chromatography
was done by using a Biotage Isolera One equipped with a diode
array detector (200–400 nm). All solvents, starting materials and
reagents were purchased from commercial suppliers and used as
received unless otherwise noted. The solvents for chromatography
were distilled before use. The tetrakis(triphenylphosphine)palla-
dium(0) was prepared according to literature methods.[17,18]
Methyl 5-Bromopicolinate (3): 5-Bromopicolinic acid (2.56 g,
12.7 mmol) was dissolved in methanol (100 mL), sulfuric acid
(0.5 mL) was added and the reaction mixture heated at reflux for
117 h. After cooling to room temperature saturated sodium carb-
onate solution was added until the pH was above 9. The mixture
was extracted with dichloromethane. The organic layer was dried
with Na2SO4 and the volatiles were removed under reduced pres-
sure to give 3 as an off-white solid (2.37 g, 11.0 mmol, 86% yield).
Rf = 0.30 cyclohexane/ethyl acetate, 2:1, m.p. 99–100 °C. 1H NMR
(400 MHz, CDCl3, 298 K): δ = 8.78 (dd, J = 2.2, 0.8 Hz, 1 H, 6-
H), 8.02 (dd, J = 8.3, 0.8 Hz, 1 H, 3-H), 7.98 (dd, J = 8.3, 2.2 Hz,
1 H, 4-H), 4.00 (s, 3 H, OCH3) ppm. 13C NMR (101 MHz, CDCl3,
298 K): δ = 165.2 (C=O), 151.2 (C-6), 146.4 (C-2), 139.9 (C-4),
126.4 (C-3), 125.2 (C-5), 53.2 (OCH3) ppm. HRMS (ESI): m/z
calcd. for C7H6BrNO2Na [M + Na]+ 237.9480; found 237.9490. IR
(ATR): ν
= 3059, 2957, 1715, 1438, 1364, 1308, 1235, 1133,
˜
max
1008, 697 cm–1.
The analytical data are consistent with the values from the litera-
ture.[19]
Methyl 5-[(2R,3R)-3-Methyloxiran-2-yl]picolinate (1): Olefin
4
(60 mg, 0.34 mmol), tetrabutylammonium hydrogen sulfate (5 mg,
14 μmol) and 1,2:4,5-di-O-isopropylidene-d-erythro-2,3-hexodiuro-
2,6-pyranose (26 mg, 0.10 mmol) were dissolved under vigorous
stirring in a mixture of acetonitrile/dimethoxymethane (5.6 mL,
1:2, v/v) and a solution of Na2B4O7·10 H2O (0.05 m) in aqueous
Na2(EDTA) (4ϫ10–4 m, 4.0 mL, pH 9.0) and cooled to –10 °C.
Over a period of 2 h, a solution (6 mL) of Oxone (867 mg,
2.82 mmol) in aqueous Na2(EDTA) (4ϫ 10–4 m, 18 mL) and a
solution (6 mL) of potassium carbonate (817 mg, 6.27 mmol) in de-
ionized water (18 mL) were added through syringe pumps. After
stirring for 16 h, a further amount (3 mL each) of the two solutions
was added through syringe pumps over 1 h. After another hour the
(E)-Methyl 5-(Prop-1-en-1-yl)picolinate (4). Method A: Under a
nitrogen atmosphere, ester 3 (2.10 g, 9.70 mmol), (E)-1-propen-1-
ylboronic acid (1.00 g, 11.6 mmol), potassium carbonate (1.61 g,
11.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.12 g,
0.97 mmol) were dissolved in dry dimethylformamide (DMF;
40 mL) and heated at reflux for 5 h. Subsequently, the solvent was
removed in vacuo. The crude product was coevaporated with di-
ethyl ether (18 mL) and afterwards dissolved in chloroform and
washed with aqueous NaOH (1 m), dried with Na2SO4 and concen-
trated in vacuo. The residue was purified by flash chromatography
(cyclohexane/ethyl acetate, 2:1 v/v) to give 4 as white micro-
4
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Absolute Configuration and Synthesis of (+)-Caripyrin
[2] SpartanЈ10, Wavefunction, Inc., Irvine, CA, 2011.
[3] T. A. Halgren, J. Comput. Chem. 1996, 17, 490–519.
[4] A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652.
[5] C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789.
[6] W. J. Hehre, R. Ditchfield, J. A. Pople, J. Chem. Phys. 1972, 56,
2257–2261.
crystalline solid (1.10 g, 6.23 mmol, 62% yield). Rf = 0.20 cyclohex-
ane/ethyl acetate, 2:1, m.p. 67–68 °C. H NMR (400 MHz, CDCl3,
1
298 K): δ = 8.62 (dd, J = 2.2, 0.6 Hz, 1 H, 6-H), 8.02 (dd, J = 8.2,
0.6 Hz, 1 H, 3-H), 7.72 (dd, J = 8.2, 2.2 Hz, 1 H, 4-H), 6.48–6.37
(m, 2 H, 2Ј-H, 3ЈH), 3.96 (s, 3 H, OCH3), 1.92–1.90 (m, 3 H, 3Ј-
CH3) ppm. 13C NMR (101 MHz, CDCl3, 298 K): δ = 165.7 (C=O),
147.7 (C-6), 145.7 (C-2), 136.7 (C-5), 133.0 (C-4), 131.4 (C-3Ј),
126.9 (C-2Ј), 125.1 (C-3), 53.2 (OCH3), 18.9 (3Ј-CH3) ppm. HRMS
(ESI): m/z calcd. for C10H11NO2Na [M + Na]+ 200.0687; found
[7] P. C. Hariharan, J. A. Pople, Theor. Chim. Acta 1973, 28, 213–
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[8] G. W. T. M. J. Frisch, H. B. Schlegel, G. E. Scuseria, M. A.
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Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Son-
nenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hase-
gawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
T. Vreven, J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro, M.
Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Starov-
erov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell,
J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M.
Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Ad-
amo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Mar-
tin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
J. J. Dannenberg, S. Dapprich, A. D. Daniels, Farkas, J. B.
Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox Gaussian09, re-
vision A.02, Gaussian, Inc., Wallingford, CT, 2009.
[9] R. Krishnan, J. S. Binkley, R. Seeger, J. A. Pople, J. Chem.
Phys. 1980, 72, 650–654.
200.0678. IR (ATR): ν
= 2954, 1706, 1436, 1305, 1256, 1205,
˜
max
1138, 1119, 967, 703 cm–1.
The analytical data are consistent with the values from the litera-
ture.[15]
Method B: In a glovebox filled with nitrogen a microwave vial was
charged with ester 3 (103 mg, 0.477 mmol), potassium (E)-1-pro-
penyltrifluoroborate (81 mg, 0.547 mmol), potassium phosphate
(202 mg, 0.954 mmol) and tetrakis(triphenylphosphine)palla-
dium(0) (38 mg, 3.28 μmol) and closed with a septum. Outside the
glovebox, methanol (0.1 mL, 2.47 mmol) and 1,4-dioxane (6 mL)
were added and the internal atmosphere changed to argon. The
septum was replaced by a microwave tube cap. The sealed reaction
vessel was heated in the microwave apparatus with a maximum
power of 300 W for 90 min to 100 °C. Then the volatiles were re-
moved in vacuo and the crude product was purified by automated
flash chromatography (10 g cartridge, flow rate 20 mL/min, gradi-
ent cyclohexane/ethyl acetate, 94:6 to 25:75 in 15 column volumes)
to give 4 as white microcrystalline solid (48 mg, 0.27 mmol, 57%
yield).
[10] J. Tomasi, B. Mennucci, E. Cancès, THEOCHEM 1999, 464,
211–226.
[11] P. Fristrup, P. R. Lassen, C. Johannessen, D. Tanner, P.-O.
Norrby, K. J. Jalkanen, L. Hemmingsen, J. Phys. Chem. A
2006, 110, 9123–9129.
[12] Z.-X. Wang, Y. Tu, M. Frohn, J.-R. Zhang, Y. Shi, J. Am.
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Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR and 13C NMR spectra for compounds 1, 3, and
4, chiral HPLC chromatogram of compound 1 as well as atom
coordinates and DFT energies for all four conformers of 1.
Acknowledgments
[16] G. R. Fulmer, A. J. M. Miller, N. H. Sherden, H. E. Gottlieb,
A. Nudelman, B. M. Stoltz, J. E. Bercaw, K. I. Goldberg, Orga-
nometallics 2010, 29, 2176–2179.
This work was financially supported by the Rhineland-Palatinate
Center for Natural Products Research. The authors thank Dr J. C.
Liermann (Univ. of Mainz) for NMR spectroscopy, Dr N. Hanold
(Univ. of Mainz) for mass spectrometry and A. -K. Bauer (Univ.
of Mainz) for technical assistance.
[17] D. R. Coulson, L. C. Satek, S. O. Grim, Inorg. Synth. 2007,
121–124.
[18] S. Heitmüller, Ph. D. Thesis, Johannes Gutenberg University of
Mainz, Germany, 2011.
[19] R. J. Chambers, A. Marfat, Synth. Commun. 1997, 27, 515–
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[1] P. H. Rieger, J. C. Liermann, T. Opatz, H. Anke, E. Thines, J.
Antibiot. 2010, 63, 285–289.
Received: May 6, 2014
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
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Job/Unit: O42540
/KAP1
Date: 24-06-14 11:33:27
Pages: 6
L. Andernach, T. Opatz
FULL PAPER
Configuration Determination
The absolute configuration of the natural
product (+)-caripyrin was determined by
vibrational circular dichroism spectroscopy
and density functional theory calculations.
Based on this information, the compound
was prepared in a short asymmetric syn-
thesis.
L. Andernach, T. Opatz* .................. 1–6
Assignment of the Absolute Configuration
and Total Synthesis of (+)-Caripyrin
Keywords: Natural products / Total syn-
thesis / Configuration determination / Den-
sity functional calculations / Vibrational
spectroscopy
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0