Asymmetric synthesis of iridoid derivatives using resolved 2-phenylindoline as a chiral auxiliary

Article abstract of DOI:10.1002/ejoc.200800440

An asymmetric synthetic route to cis,cis-nepetalactol (component of the sex pheromone for the hop aphid, Phorodon humuli) is presented. 2-Phenylindoline was resolved to provide a chiral auxiliary for the cycloaddition of oxocitral. The resolution was made by chromatographic separation of the diastereomers of the urea derivative made from 2-phenylindoline and with (R)-(+)-α- methylbenzyl isocyanate, followed by reductive cleavage of the isolated diasteromers using diborane. The cycloaddition of oxocitral using (S)-2-phenylindoline yielded an enantiopure product after chromatography. Hydrolysis of the cycloaddition adduct yielded gastrolactol (3). As gastrolactol is a versatile synthon for the synthesis of iridoids, the overall procedure provides a general asymmetric route to elaborated iridoids. Wiley-VCH Verlag GmbH & Co. KGaA, 2009.

Full text of DOI:10.1002/ejoc.200800440

FULL PAPER
DOI: 10.1002/ejoc.200800440
Asymmetric Synthesis of Iridoid Derivatives Using Resolved 2-Phenylindoline
as a Chiral Auxiliary
Ellen M. Santangelo,[a,b] Ilme Liblikas,[c] Anoma Mudalige,[b] Karl W. Törnroos,[d]
Per-Ola Norrby,[e] and C. Rikard Unelius*[a][‡]
Keywords: Iridoid / Cycloaddition reaction / Nepetalactol / Chromatographic resolution / 2-Phenylindoline
An asymmetric synthetic route to cis,cis-nepetalactol (com-
ponent of the sex pheromone for the hop aphid, Phorodon
humuli) is presented. 2-Phenylindoline was resolved to pro-
vide a chiral auxiliary for the cycloaddition of oxocitral. The
resolution was made by chromatographic separation of the
diastereomers of the urea derivative made from 2-phenyl-
indoline and with (R)-(+)-α-methylbenzyl isocyanate, fol-
lowed by reductive cleavage of the isolated diasteromers
using diborane. The cycloaddition of oxocitral using (S)-2-
phenylindoline yielded an enantiopure product after
chromatography. Hydrolysis of the cycloaddition adduct
yielded gastrolactol (3). As gastrolactol is a versatile synthon
for the synthesis of iridoids, the overall procedure provides a
general asymmetric route to elaborated iridoids.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The iridoids constitute a group of natural products with
a steadily increasing number of elucidated structures. The
common carbon skeleton of these monoterpenes is (dimeth-
ylisopropyl)cyclopentane. The name derives from Iridomyr-
mex, a genus of ants that produces iridodial as a compound
for chemical warfare. Apart from being used in the chemical
defense in many insect species[1] some iridoids have antiviral
and antibacterial properties.[2] Our interest in these mole-
cules arose when we were trying to find good synthetic pro-
cedures for nepetalactols, common aphid sex pheromone
components.[3] There are numerous syntheses of iridoids.[4]
In a previous paper we published a synthesis of racemic
gastrolactol 3 (Scheme 1),[5] where the key step is an enal-
enamine [2+4]-cycloaddition and in a subsequent paper we
used a dynamic acetylation/lipase mediated resolution pro-
cedure to resolve gastrolactol and converted it to chiral
cis,cis-nepetalactone.[6]
Scheme 1. Synthesis of racemic gastrolactol (3).
In this paper, we describe an enantioselective variation
of this intramolecular enal-enamine [2+4] cycloaddition
using (S)-2-phenylindoline as the chiral auxiliary. During
the course of this work both enantiomers of 2-phenyl-
indoline were prepared for the first time.
Results and Discussion
In an initial attempt to cyclize oxocitral, we tried 2-tert-
butyl-4-methyl-5-phenyloxazolidine (4) (as a 3:2 mixture) as
chiral auxiliary (Scheme 2). This reagent was used as the
chiral auxiliary in a synthesis of brefeldin C[7] and also as
a catalyst for the enantioselective addition of diethylzinc to
[a] School of Pure and Applied Natural Sciences, University of
Kalmar,
39182 Kalmar, Sweden
Fax: +46-480-446-262
E-mail: rikard.unelius@hik.se
[b] KTH Chemical Science and Engineering, Dept. of Organic aryl aldehydes.[8]
Chemistry, Royal Institute of Technology,
Only one diastereomer of the product 5 can be seen in
10044 Stockholm, Sweden
the 1H NMR and the 13C NMR spectrum, which indicates,
not only that the product has been obtained in excellent
diastereomerical excess, but also that one diastereomer of
the oxazolidine acetal is selectively reacting or the oxazolid-
ine acetal is equilibrating to the most stable configuration
before, during, or after the reaction. All these scenarios
would give rise to the all-cis configuration of the substitu-
[c] Institute of Technology, University of Tartu,
Nooruse 1, 50411 Tartu, Estonia
[d] Department of Chemistry, University of Bergen,
5007 Bergen, Norway
[e] Department of Chemistry, University of Gothenburg,
41296 Göteborg, Sweden
[‡] Current address: The Horticulture & Food Research Institute
of New Zealand,
P. O. Box 51, Lincoln, New Zealand
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C. R. Unelius et al.
FULL PAPER
yield of 2-phenylindoline (8) (Figure 1). Resistance of the
highly stabilized indolenium ion towards reduction by so-
dium cyanoborohydride could possibly account for this re-
sult.[9] Instead, racemic 2-phenylindoline (8) was prepared
from 2-phenylindole by reduction with Sn/HCl.[10]
Scheme 2. Chiral cycloaddition.
Figure 1. Indolines tried as chiral auxiliaries for the cycloaddition
step.
ents on the oxazolidine ring in the product. The tentative
assignment of the relative stereochemistry of compound 5
depicted in Scheme 2 was based on NMR experiments.
The yield in this asymmetric cycloaddition was low and
it was not possible to get the cycloaddition reaction to go
to completion. Still we believed that our approach could be
very useful for iridoid and alkaloid synthesis therefore we
looked for other chiral auxiliaries and decided to explore 2-
substituted indolines.
Racemic 2-methyl- (6), 2-tert-butyl- (7), and 2-phenyl-
indoline (8) were treated with oxocitral (1) and of the three
auxiliaries only 2-phenylindoline (8), gave a pure dia-
stereomer 9 with a cis-junction between the rings (syn or
anti, Figure 2) according to NMR spectroscopy.
We then investigated the formation of 9 computation-
ally.[11] Assuming that the ring closure is either a reversible
equilibrium, or kinetically controlled but following a Bell–
Evans–Polanyi relationship,[12] the energetically most fa-
vored product will be formed preferentially. For each of the
Indolines as Chiral Auxiliaries
2-Methyl- (6) and 2-tert-butylindoline (7) were synthe- four diastereomers of 9 (i. e. 9a–9d), we have searched the
sized by the reaction of the indoles with sodium cyano- conformational space fully[13] using two quite different force
borohydride in glacial acetic acid at 15 °C to give the corre- fields of high quality,[14] MM3*[15] and MMFFs,[16] as im-
sponding indolines in excellent yields. However, applying plemented in Macromodel.[17] With one exception (the
these conditions to 2-phenylindole did not result in a good highest energy diastereomer), the two force fields agreed on
Figure 2. The stereoisomers that hypotetically can be formed by reaction of oxocitral with racemic 2-phenylindoline.
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Asymmetric Synthesis of Iridoid Derivatives
Scheme 3. Intramolecular cycloaddition using (S)-2-phenylindoline as an auxiliary.
the global energy minimum conformation for each dia-
stereomer, and also on the ranking of the diastereomers.
With both force fields, 9a (Figure 2) was the most stable
structure, by 4 kJ/mol in MMFFs, and by 10 kJ/mol in
MM3*. This agreement would usually be sufficient to be
fairly certain that 9a is indeed the most stable structure, but
because the structure contains an unusual mono-aza-acetal,
for which the MM parameters may be less reliable, we also
decided to check the results using a quantum-mechanical
method. We thus subjected the minimum energy conforma-
tion of each diastereomer to optimization using B3LYP/6-
31G*, a method that is generally believed to give accurate
conformational energies.[14] Again, 9a was identified to be
the most stable structure, now by a safe 19 kJ/mol relative
to the second most stable structure.
These results clearly indicated that the four isomers with
a cis,cis-configuration at the atoms 4a-7a-1 are not formed,
as found in earlier work by us[5–6] on very similar systems
by NMR and it seemed evident that (S)-2-phenylindoline
would give the cyclized anti-product 9a in Figure 2 when
reacted with oxocitral (1), (Scheme 3).
The synthetic strategy to produce the aphid sex phero-
mone cis,cis-nepetalactol would then be to do a regio- and
stereoselective hydrogenation of the double bond in the
five-membered ring in gastrolactol (3).[18]
With this synthetic route in mind, racemic 2-phenylindo-
line (8) was subjected to a resolution procedure (Scheme 4).
Racemic 2-phenylindoline (8) was treated with (R)-(+)-α-
methylbenzyl isocyanate. The two diastereomers formed
(10a and 10b) were separated by an unusual variation of
Scheme 4. Resolution of racemic 2-phenylindoline (8).
column chromatography silica gel.[19] The crystals were dis-
solved in hexane and pumped into a column saturated with 10b respectively, as analyzed by chiral gas chromatography.
hexane. The lower enantiomeric purity for isomer 10b could be
As the solubility of the urea derivatives was low in hex- traced back to the urea derivative in which the urea isomer
ane the eluting solvent was recycled to adsorb all material 10a could be detected.
on the column. The compounds were then eluted by in-
The urea derivative isomers 10a and 10b were both crys-
creasing amounts of ethyl acetate in hexane via another col- talline compounds and separately subjected to X-ray exami-
umn coupled in series. The two isolated diastereomers of nation in order to determine the absolute configuration.
the urea derivative 10a and 10b were separately transformed Unfortunately, neither isomer gave crystals with crystalline
to the enantiomers of 2-phenylindoline by reduction with lattices that were coherent enough for conclusive X-ray
diborane and subsequent hydrolysis (Scheme 4).
analysis.
The enantiomeric purities of the two resolved 2-phenyl-
The geometry of 10a and 10b structures were optimized
indoline enantiomers were Ͼ 99% and 90% for 10a and using the hybrid density functional method B3LYP and the
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C. R. Unelius et al.
FULL PAPER
were distilled from sodium/benzophenone under nitrogen. Dichlo-
romethane (CH2Cl2), toluene and triethylamine (Et3N) were dis-
tilled from CaH2 under nitrogen. Air- and moisture-sensitive reac-
tions were carried out in oven- or flame-dried glassware, septum-
capped under an atmospheric pressure of nitrogen. Commercially
available compounds were used without further purification unless
otherwise indicated. Analytical thin-layer chromatography was per-
formed on Merck silica gel 60 F 254 plates, using UV and a solu-
tion of vanillin in ethanol containing sulfuric acid for visualization.
The liquid chromatography technique used was the one described
6-31G(d) basis set. The NMR chemical shifts were calcu-
lated using GIAO method as implemented in Gaussian 94
using a larger basis set: 6-311G (d,p). The chemical shift
calculated for the methyl protons of 10b (S,R) was 0.3 ppm
lower than for 10a (R,R). Experimentally we found that the
signals for the protons of the methyl group of 10b (S,R) was
0.26 ppm to lower field than these of the other isomer.
To unambiguously assign the absolute configuration of
the carbon bearing the phenyl group in 8b, many derivatives
were prepared. Of all tested, only the (S)-5-chloronaprox- by Baeckström et al.[19] It was performed on silica gel (Merck 60,
0.040–0.063 mm) in 15- or 25-mm inner diameter glass columns
with gradient elution, using hexane and increasing amounts of
ethyl acetate. Proton (1H) and carbon (13C) NMR spectra were
recorded with a 400- or 500-MHz instrument using the residual
signals from CHCl3, δ = 7.26 ppm and δ = 77.0 ppm, as internal
references for 1H and 13C, respectively. Chemical shifts are reported
in the δ scale with multiplicity (br. = broad, s = singlet, d = doublet,
t = triplet, q = quartet, quint. = quintet, sext. = sextett, m = mul-
tiplet), coupling constants [Hz] and integration. Optical rotations
were measured at 20 °C using the sodium D-line (589 nm).
enyl derivative 12 gave crystals suitable for X-ray crystallo-
graphic analysis.
The X-ray analysis revealed, as depicted in Scheme 5, an
(2R)-configuration at the C2 of the (–)-8b.
(4R,5S)-2-tert-Butyl-4-methyl-5-phenyloxazolidine (4): (+)-Nore-
phedrine (6.80 g, 45.0 mmol) was heated to reflux with pivalal-
dehyde (3.96 g, 46.0 mmol) in benzene according to Senkus.[20] The
condensed water was collected in a Dean–Stark trap. After 2 h the
solvent was evaporated and the product was stored over molecular
sieves in the freezer and was then used as such in the subsequent
cyclization step. The product was obtained as a 2:3 mixture of α-
and β-tert-butyl isomers in 95% yield (9.4 g).
Major Isomer: 1H NMR: δ = 7.25–7.33 (m, 5 H), 4.93 (d, J =
8.1 Hz, 1 H), 4.25 (s, 1 H), 3.66 (dq, J = 8.1, J = 6.7 Hz, 1 H), 2.27
(br. s, 1 H), 1.15 (s, 9 H), 0.75 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR:
δ = 140.3, 128.3 (2), 127.3 (2), 126.7, 98.0, 80.6, 57.7, 33.1, 25.8
(3), 16.8 ppm.
Scheme 5. Determination of the absolute configuration of (R)-(–)-
2-phenylindoline.
Minor Isomer: 1H NMR: δ = 7.25–7.33 (m, 5 H), 4.96 (d, J =
4.9 Hz, 1 H), 4.72 (s, 1 H), 3.69 (app. quint., J = 6.7, J = 5.0 Hz,
1 H), 2.27 (br. s, 1 H), 1.03 (s, 9 H), 0.75 (d, J = 6.7 Hz, 3 H) ppm.
13C NMR: δ = 140.1, 128.0 (2 C), 127.0 (2 C), 126.0, 98.7, 82.2,
57.4, 35.2, 25.7 (3 C), 15.6 ppm.
Both enantiomers of 2-phenylindoline were used as chiral
auxiliaries in the intramolecular cycloaddition reaction
shown in Figure 2, providing a pure enantiomer for each
reaction. When (S)-(+)-2-phenylindoline was used, 9a was
formed and when (R)-(–)-2-phenylindoline was used, 9e was
formed. The cycloaddition products 9a and 9e were hy-
drolyzed in separate reaction vials and after acetylation, the
optical rotation of the acetates were compared with optical
rotation data obtained previously, in order to determine the
absolute configuration.[6] From these results we could con-
firm the results from our computer modeling experiments,
that the anti-products 9a and 9e were formed in the cyclo-
addition reaction depicted in Figure 2.
(2R,4R,5S)-2-tert-Butyl-3-[(1S,4aR,7aR)-1,4a,5,7a-tetrahydro-4,7-
dimethylcyclopenta[c]pyran-1-yl]-4-methyl-5-phenyloxazolidine (5):
8-Oxocitral (1) (494 mg, 3.0 mmol) was dissolved in 3 mL of THF
and molecular sieves and then added to (4R,5S)-2-tert-butyl-4-
methyl-5-phenyloxazolidine (657 mg, 3.0 mmol) in hexane (5 mL).
After 48 h at room temp. the solvents were evaporated. Compound
5 (349 mg, 1.39 mmol) was isolated after chromatography. The
1
yield was 46.3%. H NMR: δ = 7.22–7.35 (m, 5 H), 6.28 (d, J =
1.0 Hz, 1 H), 5.53 (d, J = 1.6 Hz, 1 H), 5.11 (d, J = 5.8 Hz, 1 H),
4.53 (s, 1 H), 4.05 (d, J = 10.3 Hz, 1 H), 3.82 (dq, J = 6.7, J =
5.8 Hz, 1 H), 2.67 (m, J = 8.7, J = 8.4 Hz, 1 H), 2.57 (ddt, J =
15.7, J = 8.4, J = 1.8 Hz, 1 H), 2.47 (t, J = 10.3, J = 8.7 Hz, 1 H),
2.06 (m, J = 15.8, J = 8.4 Hz, 1 H), 2.01 (s, 3 H), 1.62 (s, 3 H),
0.99 (s, 9 H), 0.74 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR: δ = 141.8,
138.8, 137.4, 128.0 (2 C), 126.91, 126.27 (2 C), 112.6, 100.6, 91.5,
82.1, 55.2, 48.5, 42.5, 38.1, 35.8, 29.7, 25.8 (3 C), 18.8, 17.6,
16.7 ppm.
Conclusions
In conclusion, a formal asymmetric synthesis leading to
iridoids has been developed. It includes the resolution of 2-
phenylindoline that hitherto has neither been resolved nor
used as a chiral inductor.
Observed Nuclear Overhauser Effects (NOEs): NOEs between the
phenyl group and tert-butyl group plus the CH-CH3 methyl and
between the Ph-CH-O proton, the CH-C(CH3)3 proton and the
Me-CH-N proton suggested that the phenyl group, tert-butyl group
and the CH-CH3 methyl were all cis to each other.
Experimental Section
General Methods: All solvents were distilled before use unless
otherwise stated. Tetrahydrofuran (THF) and diethyl ether (Et2O)
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Asymmetric Synthesis of Iridoid Derivatives
The stereochemistry at the ring junction was concluded to be cis
due to NOEs between the 4a and 7a protons. The anomeric proton
has to be trans to 7a because the coupling constant was over 10 Hz
(and accordingly no NOE was observed).
7.32 (br. d, J = 8.1 Hz, 1 H), 7.12 (br. t, J = 6.9 Hz, 1 H), 7.06 (br.
t, J = 7.40 Hz, 1 H), 6.26 (br. s, 1 H), 1.40 (s, 9 H) ppm. 13C NMR:
δ = 148.7, 136.3, 128.5, 121.0, 119.9, 119.6, 110.3, 96.9, 30.3 (3 C),
27.7 ppm.
2-tert-Butylindoline (7): 2-tert-Butylindole (300 mg, 1.73 mmol) was
reduced to 2-tert-butylindoline (7) using the same experimental
procedure as described for 6. The yield of 7 was 68% (204 mg,
NOEs between the 7a and the Me-CH-N proton give the correct
orientation of the two rings system in space.
2-Methylindoline (6): Sodium cyanoborohydride (322.5 mg,
5.13 mmol) was added at 17 °C in one portion to a magnetically
stirred solution of 2-methylindole (300 mg, 2.29 mmol) in glacial
acetic acid (4.5 mL) under N2. The mixture was stirred for 2 h at
15 °C. Water (22.5 mL) was added and the mixture cooled in an
ice bath and slowly made strongly basic with NaOH pellets. The
mixture was extracted with ethyl acetate. The ethyl acetate extract
was washed with water and aq. NaCl and then dried with anhy-
drous K2CO3 and the solvent was removed under reduced pressure.
After chromatography, 2-methylindoline (6) was isolated in 68%
1
1.18 mmol). H NMR: δ = 7.13 (d, J = 7.3 Hz, 1 H), 7.06 (t, J =
7.6 Hz, 1 H), 6.72 (t, J = 7.3 Hz, 1 H), 6.63 (d, J = 7.7 Hz, 1 H),
3.75 (br. s, 1 H), 3.70 (br. t, J = 10.1, J = 9.3 Hz, 1 H), 3.02 (dd, J
= 16, 9.2 Hz, 1 H), 2.88 (dd, J = 15.8, 10.3 Hz, 1 H), 1.0 (s, 9 H)
ppm. 13C NMR: δ = 151.4, 129.0, 127.1, 124.4, 118.0, 108.5, 69.4,
33.5, 31.2, 26.0 (3 C) ppm.
2-tert-Butyl-1-[(1S*,4aR*,7aR*)-1,4a,5,7a-Tetrahydro-4,7-di-
methylcyclopenta[c]pyran-1-yl]indoline: 8-Oxocitral (100 mg,
0.60 mmol) dissolved in 3 mL of methanol was added to 2-tert-
butylindoline (105 mg, 0.60 mmol) in hexane (5 mL). After 48 h at
room temperature the hexane layer was concentrated under re-
duced pressure. The crude product was subjected to medium pres-
sure column chromatography yielding 46% (89 mg) of a 97:3 mix-
ture of diastereomers.
1
(206 mg, 1.55 mmol). HNMR: δ = 7.09 (d, J = 7.2 Hz, 1 H), 7.03
(t, J = 7.6 Hz, 1 H), 6.72 (t, J = 7.2 Hz, 1 H), 6.63 (d, J = 7.7 Hz,
1 H), 4.01 (b sext, J = 7.9 Hz, 1 H), 3.87 (br. s, 1 H), 3.16 (dd, J
= 15.4, J = 8.5 Hz, 1 H), 2.65 (dd, J = 15.4, J = 7.7 Hz, 1 H), 1.31
(d, J = 6.2 Hz, 3 H) ppm. 13C NMR: δ = 150.4, 129.0, 127.2, 124.7,
118.8, 109.5, 55.2, 37.7, 22.1 ppm.
1
Major Isomer: H NMR: δ = 7.01 (t, J = 6.4 Hz, 1 H), 6.98 (d, J
= 7.7 Hz, 1 H), 6.77 (d, J = 7.7 Hz, 1 H), 6.63 (t, J = 7.5 Hz, 1 H),
6.34 (s, 1 H), 5.54 (br. s, 1 H), 4.37 (d, J = 10.3 Hz, 1 H), 3.46 (dd,
J = 10.4, J = 2.6 Hz, 1 H), 3.37 (m, 1 H), 3.23 (dd, J = 16, J =
10 Hz, 1 H), 2.9 (br. d, J = 14.8 Hz, 1 H), 2.74 (m, 1 H), 2.6 (m, 1
H), 2.0 (m, 1 H), 1.65 (s, 3 H), 1.51 (s, 3 H), 0.92 (s, 9 H) ppm.
13C NMR: δ = 148.2, 141.2, 137.6, 130.4, 126.8, 126.7, 123.7, 117.5,
113.2, 110.4, 89.3, 73.0, 43.6, 42.5, 38.1, 37.0, 31.5, 26.0, 25.3 (2
C), 16.7, 15.6 ppm.
1-[(1S*,4aR*,7aR*)-1,4a,5,7a-Tetrahydro-4,7-dimethylcyclopenta-
[c]pyran-1-yl]-2-methylindoline: 8-Oxocitral (400 mg, 2.4 mmol) in
3 mL of methanol was added to 2-methylindoline (320 mg,
2.4 mmol) in hexane (5 mL). After 48 h stirring at 20 °C, the hex-
ane layer was concentrated under reduced pressure. The crude
product was subjected to medium pressure column chromatog-
raphy, yielding 40% (269 mg, 0.961 mmol) of a 7:3 mixture of dia-
stereomers.
1
2-Phenylindoline (8): 2-Phenylindole (14 g, 72.5 mmol) in ethanol
350 mL and 10  HCl (35 mL) was heated to reflux in the presence
of Sn (30 g, 261 mmol) for 8 h. The mixture was decanted into 50%
KOH solution, extracted with diethyl ether and concentrated. After
chromatography, 12.4 g of 2-phenylindoline was obtained (yield
Major Isomer: H NMR: δ = 7.05 (d, J = 7.8 Hz, 1 H), 7.02 (t, J
= 7.7 Hz, 1 H), 6.68 (br. t, J = 7.3 Hz, 1 H), 6.64 (br. d, J = 7.8 Hz,
1 H), 6.21 (br. s, 1 H), 5.55 (br. s, 1 H), 4.55 (d, J = 10.5 Hz, 1 H),
4.02 (m, 1 H), 3.30 (m, 1 H), 3.1 (m, 1 H), 2.7 (m, 1 H), 2.5 (m, 1
H), 2.10 (m, 2 H), 1.75 (s, 3 H), 1.6 (s, 3 H), 1.26 (d, J = 6.38 Hz,
3 H) ppm.
1
88%). H NMR: δ = 7.44 (br. d, J = 6.8 Hz, 2 H), 7.38–7.28 (m, 3
H), 7.15–7.09 (m, J = 7.5 Hz, 2 H), 6.84 (br. t, J = 7.4 Hz, 1 H),
6.78 (br. d, J = 7.7 Hz, 1 H), 5.0 (br. t, J = 8.9 Hz, 1 H), 4.2 (br.
s, 1 H), 3.48 (dd, J = 15.8, J = 9.0 Hz, 1 H), 3.07 (dd, J = 15.0, J
= 8.7 Hz, 1 H) ppm. 13C NMR: δ = 150.9, 144.5, 128.4 (2 C), 128.0,
127.5, 127.3, 126.2 (2 C), 124.5, 118.8, 108.8, 63.4, 39.5 ppm.
N-(2-Methylphenyl)-2,2-dimethylpropanamide: o-Toluidine (16.81 g,
79.2 mmol), trimethylacetyl chloride (9.55 g, 79.2 mmol) and anhy-
drous K2CO3 (7.60 g, 55.0 mmol) in 120 mL of anhydrous toluene
was stirred and heated to reflux for 3 h and then allowed to stand
for 6 h at room temperature. The resulting solid (mixture of prod-
ucts and salts) was filtered off and the filtrate was mixed with water
(120 mL) and stirred at room temperature for 1.5 h. This mixture
was extracted with dichloromethane and the solvents evaporated.
Column chromatography and recrystallization (solvent: dichloro-
methane/toluene) yielded 12 g (62.5 mmol) of N-(2-methylphenyl)-
2,2-dimethylpropanamide (79%). 1H NMR: δ = 7.86 (d, J = 7.9 Hz,
1 H), 7.21 (t, J = 8.3 Hz, 1 H), 7.18 (d, J = 7.7 Hz, 1 H), 7.06 (br.
t, J = 8.4 Hz, 1 H), 2.25 (s, 3 H), 1.34 (s, 9 H) ppm. 13C NMR: δ
= 176.4, 135.8, 130.3, 128.6, 126.8, 124.8, 122.7, 39.7, 27.7 (3 C),
17.6 ppm.
2-Phenyl-N-[(R)-1-phenylethyl]indoline-1-carboxamide (10): 2-Phen-
ylindoline (8) (4.6 g, 24 mmol) and (R)-(+)-α-methylbenzyl isocyan-
ate (2.94 g, 20 mmol) in 25 mL of dry THF were mixed and stirred
for 12 h. The yield was 86% (5.88 g). The two diastereoisomers
formed were separated by liquid chromatography. One dia-
stereomer (isomer I = 10a) had an Rf-value of 0.44 on TLC-plates
eluted with 20% EtOAc/hexane while the other (isomer II = 10b)
had an Rf-value of 0.34 using the same eluting system.
Isomer 1, (2S,1ЈR)-10a: 1H NMR: δ = 8.04 (d, J = 8.1 Hz, 1 H),
7.37 (m, 3 H), 7.31 (m, 4 H), 7.20 (m, 4 H), 7.09 (d, J = 6.7 Hz, 1
H), 6.94 (t, J = 7.3 Hz, 1 H), 5.21 (dd, J = 10.54, J = 4.28 Hz, 1
H), 4.94 (quint, J = 7.05 Hz, 1 H), 4.61 (d, J = 7.05 Hz, 1 H), 3.75
(dd, J = 16.3, 10.57 Hz, 1 H), 3.00 (dd, J = 16.3, J = 4.28 Hz, 1
H), 1.12 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR: δ = 154.4, 144.2,
143.9, 142.8, 129.4 (2 C), 128.5 (2 C), 128.3, 128.0, 127.7, 127.0,
125.8 (2 C), 125.3 (2 C), 124.4, 122.1, 115.1, 62.6, 49.6, 39.1,
22.1 ppm.
2-tert-Butyl-1H-indole: N-(2-Methylphenyl)-2,2-dimethylpropan-
amide (1.5 g, 7.98 mmol) was dissolved in 125 mL of THF and the
mixture was stirred under argon in an ice bath. nBuLi (9.4 mL,
2.5 ) was added dropwise. After 16 h of stirring, the reaction mix-
ture was cooled in an ice bath and neutralized with 2  HCl. The
organic layer was separated and the aqueous layer washed with
CH2Cl2. The combined organic layers were dried with anhydrous
MgSO4, filtered and concentrated under reduced pressure. After
chromatography 1.16 g (6.70 mmol) of indole was obtained in 84%
yield. 1H NMR: δ = 7.95 (br. s, 1 H), 7.54 (br. d, J = 8.0 Hz, 1 H),
1
Isomer 2, (2R,1ЈR)-10b: H NMR: δ = 8.06 (d, J = 8.1 Hz, 1 H),
7.33–7.08 (m, 10 H), 6.94 (t, J = 7.2 Hz, 1 H), 6.65 (d, J = 3.0 Hz,
2 H), 5.25 (dd, J = 10.3, J = 3.5 Hz, 1 H), 4.96 (quint, J = 6.8 Hz,
Eur. J. Org. Chem. 2008, 5915–5921
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. R. Unelius et al.
FULL PAPER
1 H), 4.77 (d, J = 6.6 Hz, 1 H), 3.76 (dd, J = 15.8, 10.8 Hz, 1 H),
3.00 (dd, J = 16.0, J = 3.3 Hz, 1 H), 1.37 (d, J = 6.6 Hz, 3 H) ppm.
13C NMR: δ = 154.2, 144.2, 143.8, 142.9, 129.5 (2 C), 128.3 (2 C),
0.38 mmol) was dissolved in 3 mL of methanol and then added to
2-phenylindoline (8) (75 mg, 0.38 mmol) in 5 mL of hexane. After
the mixture was stirred for 48 h at 20 °C, the hexane layer was
128.2, 127.9, 127.7, 126.7, 125.4 (2 C), 125.3 (2 C), 124.4, 122.1, concentrated under reduced pressure. The crude compound was
115.1, 62.6, 49.6, 39.1, 23.0 ppm.
subjected to medium-pressure column chromatography and the
yield was 42% (54.9 mg, 0.16 mmol). The NMR analyses showed
the presence of just one diastereomer (9a and 9e in Figure 2). H
Reductive Cleavage of the Urea Derivatives 10a and 10b: The two
diastereomers of the 2-phenylindoline urea derivatives (10a and
10b) (1.5 g, 4.38 mmol) were heated to reflux separately in borane–
DMS complex (2 , 12 mL) overnight. Saturated Na2CO3 was
added and the solution was extracted with EtOAc. After
chromatography 734 mg of isomer 1 (8a) and 580 mg of isomer 2
(8b) of 2-phenylindoline was obtained (yields 86 and 68%, respec-
tively).
1
NMR: δ = 7.5–7.27 (m, 5 H), 7.19–7.12 (m, J = 6.5 Hz, 2 H), 6.85
(br. t, J = 7.3 Hz, 1 H), 6.80 (d, J = 7.8 Hz, 1 H), 6.25 (br. s, 1 H),
5.56 (br. s, 1 H), 5.12 (dd, J = 10.4, J = 5.6 Hz, 1 H), 4.66 (d, J =
10.3 Hz, 1 H), 3.75 (dd, J = 16.2, J = 10.32 Hz, 1 H), 3.06 (dd, J
= 16.2, J = 5.6 Hz, 1 H), 2.76 (br. t, J = 9.8 Hz, 1 H), 2.67 (bq, J
= 8.5 Hz, 1 H) 2.64–2.56 (m, 1 H), 2.14–2.06 (m, 1 H), 1.64 (br. s,
3 H), 1.53 (br. s, 3 H) ppm. 13C NMR: δ = 150.4, 145.3, 137.0,
128.5, 129.3, 128.3 (2 C), 127.4, 127.2, 127.2, 126.5, 126.2, 124.5,
119.3, 112.5, 109.8, 88.1, 63.3, 46.2, 41.5, 39.8, 37.8, 16.8,
16.6 ppm.
The enantiomeric purity was measured by using chiral two-dimen-
sional gas chromatography. The retention time on the first DB-
wax column was 28.25 min using the programme 200 °C (1 min)
followed by 210 °C (30 min). On the β-cyclodextrin chiral column
the retention time for the first isomer was 70.84 min and for the
second isomer 71.72 min using the temperature programme 120 °C
(20 min) followed by 165 °C (180 min). The temperature in the
interface between two columns was 200 °C. The enantiomeric pu-
rity of 8a was 99.4% and 90.2% for 8b.
X-ray Structure Analysis of (+)-12: The crystal was placed directly
into the N2 cold stream (Oxford Cryosystems Series 700) on a
Bruker AXS SMART 2 K CCD diffractometer. Data were col-
lected by means of 0.4°ω-scans in four orthogonal φ-settings using
Mo-Kα radiation (λ = 0.71073 Å). Data collection was controlled
using the program SMART, data integration using SAINT,[24] and
structure solution and model refinement using SHELXS-97 and
SHELXL-97, respectively.[25]
Isomer 1, (S)-(+)-8a: The NMR spectrum was identical to the one
of 8. [α]2D0 = +93.8 (c = 0.75, benzene), ref.[21] [α]2D0 = +65.4 (c =
0.5, CHCl3).
CCDC-678658 contains the supplementary crystallographic
data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre, via
www.ccdc.cam.ac.uk/data_request/cif.
Isomer 2, (R)-(–)-8b: The NMR spectrum was identical to the one
of 8. [α]2D0 = –84.6 (c = 3, benzene).
(S)-2-(1-Chloro-2-methoxynaphthalen-6-yl)propanoic Acid (11): Sul-
furyl chloride (290 mg, 2.19 mmol) was added dropwise to an ice
cooled (5–20 °C) and vigorously stirred reaction solution of (S)-
naproxen (471 mg, 1.99 mmol, [α]2D0 = +67.5 c = 0.17, CHCl3, ref.[22]
[α]2D5 = +66 c = 1, CHCl3) in CH2Cl2 (10 mL). The reaction was
then stirred at room temperature until all starting material was con-
sumed (typically Ͻ 1 h). Compound 11 was obtained in 89% after
Acknowledgments
This work has been financially supported by The Swedish Council
for Forestry and Agricultural Research, by the Carl-Fredrik von
Horns Foundation, by the Hierta Foundation by the Carl Trygger
Foundation, and by the University of Kalmar. Dr Mats Svensson
is acknowledged for the calculation of NMR chemical shifts, Dr
Peter Baeckström for the assistance with chromatographic separa-
tion of the urea derivatives. Drs Ulla Jacobsson, Johan Sandell,
Björn Bohman and Professor Torbjörn Norin are gratefully ac-
knowledged for helpful discussions and assistance.
1
recrystallization. H NMR: δ = 8.18 (d, J = 8.8 Hz, 1 H), 7.73 (d,
J = 8.9 Hz, 1 H), 7.7 (d, J = 1.5 Hz, 1 H), 7.53 (dd, J = 8.8, J =
1.8 Hz, 1 H), 7.29 (d, J = 9.0 Hz, 1 H), 4.0 (s, 3 H), 3.9 (q, J =
7.1 Hz, 1 H), 1.6 (d, J = 7.1 Hz, 3 H) ppm. 13C NMR: δ = 18.4,
45.1, 56.9, 113.9, 116.7, 131.0, 129.4, 127.8, 127.3, 126.1, 123.9,
136.4, 152.5, 174.8 ppm. [α]2D0 = +62.2 (c = 0.1, CHCl3, ref.[23]
[α]2D5 = +51).
(S)-2-(1-Chloro-2-methoxynaphthalen-6-yl)-1-[(R)-2-phenylindolin-
1-yl]propan-1-one (12): O-Benzotriazole-N,N,NЈ,NЈ-tetrameth-
yluronium hexafluorophosphate (HBTU) (0.10 g, 0.27 mmol) and
compound 11 (0.071 g, 0.027 mmol) were mixed in acetonitrile
(10 mL) for 2–3 min. N,N-Diisopropylethylamine (DIPEA)
(0.14 mL, 0.81 mmol) and the indoline 8b (52 mg, 0.27 mmol) were
added and the reaction mixture was stirred at room temperature
overnight. After that, the mixture was impregnated in silica gel and
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submitted to MPLC, yielding compound 12 in 86%. H NMR: δ
= 8.35 (d, J = 7.9 Hz, 1 H), 7.92 (d, J = 8.7 Hz, 1 H), 7.46 (d, J =
8.9 Hz, 1 H), 7.24 (t, J = 7.8 Hz, 1 H), 7.19 (d, J = 9 Hz, 1 H),
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56.9, 44.4, 39.0, 19.9 ppm. [α]2D0 = +143 (c = 0.6, benzene).
1-[(1S*,4aR*,7aR*)-1,4a,5,7a-Tetrahydro-4,7-dimethylcyclopenta-
[c]pyran-1-yl]-(2R*)-phenylindoline
(9):
8-Oxocitral
(63 mg,
5920
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5915–5921

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Received: May 4, 2008
Published Online: November 4, 2008
Eur. J. Org. Chem. 2008, 5915–5921
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5921