Synthesis of optically active (+)-canangone, its 6-epimer, and determination of absolute configuration

Article abstract of DOI:10.1002/ejoc.200700691

The first synthesis of canangone and its 6-epimer is reported. The products are obtained in optically active form by an asymmetric Robinson annulation. The relative and absolute configuration of the natural product is established for the first time. Wiley

Full text of DOI:10.1002/ejoc.200700691

FULL PAPER
DOI: 10.1002/ejoc.200700691
Synthesis of Optically Active (+)-Canangone, Its 6-Epimer, and Determination
of Absolute Configuration
Girish Koripelly,[a] Wolfgang Saak,[a] and Jens Christoffers*[a]
Keywords: Asymmetric synthesis / Lactones / Michael addition / Natural products / Spiro compounds
The first synthesis of canangone and its 6-epimer is reported.
The products are obtained in optically active form by an
asymmetric Robinson annulation. The relative and absolute
configuration of the natural product is established for the first
time.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
at the methyl group. We furthermore decided to use en-
amine 4, derived from phenethylamine, as the chiral auxil-
iary, because the stereochemistry of the annulation reaction
of this enamine with methyl vinyl ketone was already eluci-
dated by Pfau et al.,[5] who applied a method developed by
d’Angelo et al.[6] These investigations predict the configura-
tion of spirocycle 2 to be (S), when enamine (R)-4 is used
as a starting material, and vice versa.
Introduction
Optically active (+)-canangone (1) was isolated by
Caloprisco and coworkers from an extract of ylang-ylang
(Cananga odorata),[1] which belongs to the family of annon-
aceae, a known source for biologically active natural prod-
ucts like acetogenins.[2] The relative configuration was eluci-
dated by these authors to be (R*,R*), but the absolute con-
figuration was so far unknown. We are interested in (+)-
canangone (1) as a synthetic target, as it can be retrosyn-
thetically related to spirolactone 2 with a quaternary
stereocenter (Scheme 1).[3] We already prepared several op-
tically active spirolactones and lactams by an asymmetric
Michael reaction of enamines and methyl vinyl ketone.[4] In
our synthetic plan, synthesis of compound 2 requires
Michael acceptor 3 with a protected hydroxy functionality
Results and Discussion
After some experimentation with other O-protecting
groups, the use of 3,4-dimethoxybenzyl (DMB) finally
turned out to be optimal for masking the primary alcohol
functionality in methyl vinyl ketone derivative 3 (Scheme 2).
This compound was prepared in three steps from dimeth-
oxybenzyl alcohol 5, which was first treated with bromoace-
tic acid (1 equiv.) in the presence of NaH (3.4 equiv.) in
THF (reflux, 2 d; followed by aqueous acidic work up).[7]
Resulting carboxylic acid 6 was then activated by forming
mixed anhydride with pivaloyl chloride (1.0 equiv.) and
Et3N (1.1 equiv.) in CH2Cl2 (0 °C, 1 h),[8] and this reaction
mixture was treated with more Et3N (2.0 equiv.) and Me-
O(Me)NH2Cl (1.0 equiv.; 5 °C, 1.5 h) to give Weinreb
amide 7 after aqueous acidic work up.[9] The latter com-
pound was converted to vinyl ketone 3 by using vinylmag-
nesium bromide (1.2 equiv.) in THF (23 °C, 4 h). Success of
this step was highly dependent on the workup conditions,
as the liberated secondary amine tends to attack the vinyl
ketone by conjugate addition.[10] We recommend to quench
the reaction mixture by dropwise transfer into an equal vol-
ume of hydrochloric acid (1 ) at 0 °C. The yield of vinyl
ketone 3 is 64% over three steps. Compound 3 decomposes
within hours, but it can be stored if hydroquinone (2 mol-
%) is used as a stabilizer.
Scheme 1. Synthetic plan for optically active (+)-(S,S)-canangone
(1) by an asymmetric Robinson annulation reaction with the use
of (R)-phenethylamine as a chiral auxiliary. PG = protecting group.
[a] Institut für Reine und Angewandte Chemie der Universität
Oldenburg,
Carl von Ossietzky-Str. 9–11, 26111 Oldenburg, Germany
Fax: +49-441-798-3873
E-mail: jens.christoffers@uni-oldenburg.de
5840
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Synthesis of Optically Active (+)-Canangone and Its 6-Epimer
in this compound allowed for anomalous dispersion, which
gave the (R) configuration (Figure 1) with an absolute
structure parameter[15] of –0.009(5).[16] It must be pointed
out, however, that the material used for the synthesis of (R)-
8 was only 60% ee, but when additional single crystals were
picked from that crop and analyzed by chiral GLC, all these
samples showed the (R) configuration. The racemate of 8,
by the way, is an oil.
Scheme 2. Synthesis of protected Michael acceptor 3.
The reaction sequence leading to canangone was first de-
veloped and optimized in the racemic series. Enamines 4
were prepared from α-acetylbutyrolactone by following the
procedure of Pfau[5] (89–94% yield). Subsequent Michael
reaction with vinyl ketone 3 (1 equiv.; THF, 65 °C, 18 h) did
not stop at the stage of conjugate addition but proceeded
further to give a spirocyclic imine, which was difficult to
isolate and purify. Therefore, hydrolysis with aqueous acetic
acid (10%; 2.0 equiv.) in THF (23 °C, 24 h) was directly
performed in the same reaction flask, which gave spirocyclic
ketones 2. The yield (40–43%) after chromatographic puri-
fication remained unsatisfactory even after tedious optimi-
zation. Subsequent cleavage of the protecting group (10%
TFA in CH2Cl2, 23 °C, 1.5 h)[11] gave hexamethoxytriben-
zocyclononane as a byproduct,[12] which made chromato-
graphic separation necessary to give pure compound 9 (70–
72% yield). Because primary alcohols 9 gave sufficient base-
line resolution on chiral GLC, the stereoselectivity of the
Michael reaction was determined to be 60–69% ee, and it
was observed that the selectivity was sensitive to the reac-
tion conditions at this stage. Selectivities in this range are
often observed with phenethylamine as a chiral auxiliary in
enamine-Michael reactions with methyl vinyl ketone.[13]
Work from Pfau and d’Angelo predict the (R) configura-
tion when starting from (S)-phenethylamine.[5,6] This was
confirmed by X-ray single-crystal structure determination
Scheme 3. Robinson annulation, deprotection, and determination
of absolute configuration. DMB = 3,4-(MeO)2C6H3CH2–, Bs = 4-
BrC6H4SO2–.
Figure 1. ORTEP view of optically active bromosulfonate 8. The
depicted enantiomer has the (R) configuration.
After finishing the synthesis of (R,R)-canangone (1;
of brosylate (R)-8, which was prepared according to a stan- [α]2D0 = –67.0, vide infra), we realized, that this is the enanti-
dard protocol (1.1 equiv. BsCl, 1.5 equiv. Et3N, CH2Cl2, omer of the originally isolated natural product ([α]D25
–5 °C, 12 min; Scheme 3).[14] The bromine and sulfur atom +58.8). Therefore, the whole synthesis had to be repeated
=
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G. Koripelly, W. Saak, J. Christoffers
FULL PAPER
in the (S) series starting from the (R)-configured chiral aux-
iliary.
The synthesis of canangone (1) was finished in both the
racemic as well as the (S) series (69% ee of 9) as depicted in
Scheme 4. First of all, Luche reduction[17] of the conjugated
enone moiety yielded allylic alcohols 10 without any stereo-
selectivity (1.05 equiv. NaBH4, 1.05 equiv. CeCl3·7H2O,
MeOH, 0 °C, 1.5 h). The two diastereoisomers, however,
could be easily separated by column chromatography. In the
racemic series, single crystals could be grown from the more
apolar isomer, and the crystals were suitable for another X-
ray structure analysis. This confirmed the relative (R*,S*)
configuration, which is shown in Figure 2. The primary
alcohol groups of both diastereoisomers of 10 could be se-
lectively oxidized by using TEMPO/CuCl (both 0.3 equiv.,
1 atm O2, DMF, 23 °C, 75 min)[18] to furnish both canan-
gone 1 and its 6-epimer in both the racemic as well as the
(5S) series in 75–78% yields.
Figure 2. ORTEP view of racemic diol (R*,S*)-10. The depicted
enantiomer has the (5R,6S) configuration.
hand, and being able to prepare their enantiomers, we
started to confirm the results on the biological activity with
all four stereoisomers of this natural product.
Conclusions
(+)-(S,S)-Canangone (1) and its 6-epimer [(5S,6R)-1]
were prepared for the first time by the sequence of asym-
metric Michael reaction, aldol condensation, reduction of
the carbonyl groups, and oxidation to carbonyl groups. The
absolute and relative configurations were established by X-
ray crystallography. This work confirms the originally pro-
posed relative configuration, and the so far unknown abso-
lute configuration of this natural product was established
for the first time.
Experimental Section
General Methods: Preparative column chromatography was carried
out by using Merck SiO2 (0.035–0.070 mm, type 60 A) with hex-
anes (PE, b.p. 40–60 °C), ethyl acetate (EA), or CH2Cl2 as eluants.
TLC was performed on Merck SiO2 F254 plates on aluminium
1
sheets. H and 13C NMR spectra were recorded with a Bruker Av-
ance DRX 500 or an Avance DPX 300 spectrometer. Multiplicities
were determined with DEPT experiments. MS and HRMS spectra
(EI and CI) were obtained with a Finnigan MAT 95 spectrometer.
IR spectra were recorded with a Bruker Tensor 27 spectrometer
equipped with a “GoldenGate” diamond-ATR unit. Elemental
analyses were measured with an EA 1108 from Fisons Instruments.
GLC analysis was performed with a Focus equipped with Triplus
autosampler (Thermo Electron) and FID on a column Lipodex E
(25 mϫ0.25 mm, chiral phase) with hydrogen carrier gas (0.4 bar).
All starting materials were commercially available. Optical rota-
tions were measured with a Perkin–Elmer Polarimeter 343. Pro-
cedures using NaH or vinylmagnesium bromide (0.7  in THF,
Acros) were performed in flame-dried glassware and with absolute
solvent under a nitrogen atmosphere.
Scheme 4. Synthesis of (+)-(S,S)-canangone (1) and (–)-6-epi-can-
angone [(5S,6R)-1].
Comparison of our 1H and 13C NMR spectroscopic data
of (R*,R*)-1 and (R*,S*)-1 with the original publication
confirmed the relative (R*,R*) configuration of canangone
(1) as proposed by Caloprisco and coworkers.[1] Moreover,
the optical rotation of our (S,S) material was [α]2D0 = +107.5
(c = 1.87, MeOH; 69% ee), which corresponds to the origi-
nal literature value of the natural material: [α]2D5 = +58.8 (c
= 0.68, MeOH; unknown ee). Therefore, we clearly con-
clude that the absolute configuration of (+)-canangone (1)
is (S,S). Deviation of the absolute value might be due to
minor differences in experimental conditions or might re-
sult from optically active impurities of the samples. Interest-
ingly, 6-epi-canangone [(S,R)-1] showed opposite optical ro-
tation: [α]2D0 = –71.4 (c = 1.56, MeOH; 69% ee). Having
(3,4-Dimethoxybenzyloxy)acetic Acid (6): A solution of 3,4-dimeth-
oxybenzyl alcohol (5; 14.7 g, 87.5 mmol) in absolute THF (30 mL)
was added to a suspension of NaH (60% dispersion in mineral oil,
7.76 g, 194 mmol) in absolute THF (30 mL) under an atmosphere
of nitrogen at 0 °C. After the mixture was stirred for 1 h, a solution
now both optically active epimers of Canangone (1) in of bromoacetic acid (8.00 g, 57.6 mmol) in absolute THF (30 mL)
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Synthesis of Optically Active (+)-Canangone and Its 6-Epimer
was added, and the mixture was stirred for 2 h at 23 °C, after which
additional absolute THF (400 mL) was added, and the mixture was
heated at reflux for 2 d. The reaction mixture was cooled to 0 °C
before it was diluted with ice-cold water (250 mL) and extracted
with CH2Cl2 (3ϫ150 mL). The aqueous layer was then acidified
with concentrated hydrochloric acid (15 mL) to pH 1 and extracted
with CH2Cl2 (3ϫ150 mL). The combined extracts were dried with
17.6 Hz, 1 H), 6.40 (dd, J = 10.7 Hz, J = 17.6 Hz, 1 H), 6.73 (d, J
= 8.1 Hz, 1 H), 6.78 (br. d, J = 8.3 Hz, 1 H), 6.84 (br. s, 1 H) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ = 55.46 (CH3), 55.51 (CH3),
72.83 (CH2), 73.07 (CH2), 110.61 (CH), 110.99 (CH), 120.35 (CH),
128.73 (CH2), 129.34 (C), 132.17 (CH), 148.54 (C), 148.75 (C),
196.78 (C) ppm. IR (ATR): ν = 3001 (w), 2938 (m), 2910 (w), 2866
˜
(w), 2836 (m), 1737 (w), 1714 (m), 1697 (s), 1613 (w), 1593 (w),
1517 (vs), 1464 (m), 1419 (m), 1403 (w), 1365 (w), 1265 (s), 1237
MgSO4, filtered, and concentrated in vacuo to give acid 6 (12.7 g,
1
56.1 mmol, 97%) as a yellow oil. H NMR (500 MHz, CDCl3): δ (m), 1216 (w), 1159 (m), 1138 (m), 1066 (w), 1027 (m), 991 (w),
= 3.78 (s, 3 H), 3.80 (s, 3 H), 4.05 (s, 2 H), 4.49 (s, 2 H), 6.76 (d, J 891 (w), 859 (w), 809 (w), 764 (w) cm–1. MS (EI, 70 eV): m/z (%)
= 8.0 Hz, 1 H), 6.80 (br. d, J = 8.1 Hz, 1 H), 6.86 (br. s, 1 H), 10.21
(br. s, 1 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 55.51
(CH3), 55.56 (CH3), 65.92 (CH2), 72.96 (CH2), 110.69 (CH), 111.17
(CH), 120.64 (CH), 128.89 (C), 148.69 (C), 148.79 (C), 174.87 (C)
= 236 (5) [M]+, 166 (54), 151 (100), 107 (8). HRMS (CI, isobutane):
calcd. for C13H17O4 [M + H]+ 237.1127; found 237.1126.
(Z)-3-[1-(1-Phenylethylamino)ethylidene]dihydro-2-furanone (4): A
mixture of 2-acetylbutyrolactone (1.00 g, 7.80 mmol) and rac-phen-
ethylamine (945 mg, 7.80 mmol) was stirred at 23 °C for 4 h under
an atmosphere of nitrogen. It was then diluted with CH2Cl2
(20 mL), dried with MgSO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography on SiO2 (PE/
EA, 1:1; Rf = 0.45) to give racemic enamino lactone rac-4 (1.60 g,
ppm. IR (ATR): ν = 3173 (m, br), 3085 (w), 3022 (w), 2964 (m),
˜
2941 (w), 2870 (w), 2844 (w), 1772 (s), 1746 (s), 1609 (w), 1595 (m),
1515 (s), 1467 (m), 1456 (m), 1424 (s), 1373 (m), 1348 (w), 1322
(w), 1300 (w), 1258 (vs), 1178 (s), 1162 (vs), 1145 (vs), 1026 (vs),
969 (s), 940 (m), 927 (m), 902 (w), 816 (s), 768 (s), 744 (s) cm–1.
MS (EI, 70 eV): m/z (%) = 226 (67) [M]+, 167 (14), 151 (100), 139
(11). C11H14O5 (226.23): calcd. C 58.40, H 6.24; found C 58.10, H
6.41.
1
6.91 mmol, 89%) as a colorless oil. H NMR (500 MHz, CDCl3):
δ = 1.51 (d, J = 6.8 Hz, 3 H), 1.78 (s, 3 H), 2.73–2.84 (m, 2 H),
4.23–4.30 (m, 2 H), 4.63 (pent, J = 7.0 Hz, 1 H), 7.22–7.26 (m, 3
H) 7.32–7.34 (m, 2 H), 8.61 (br. d, J = 5.7 Hz, 1 H) ppm. 13C{1H}
NMR (125 MHz, CDCl3): δ = 16.78 (CH3), 24.87 (CH3), 26.36
(CH2), 52.95 (CH), 65.10 (CH2), 86.10 (C), 125.42 (2 CH), 127.10
(CH), 128.79 (2 CH), 145.02 (C), 156.41 (C), 174.04 (C) ppm. IR
2-(3,4-Dimethoxybenzyloxy)-N-methoxy-N-methylacetamide
(7):
Et3N (3.00 g, 29.6 mmol) was added to a stirred solution of acid 6
(6.11 g, 27.0 mmol) in absolute CH2Cl2 (90 mL) at –5 to 0 °C and
stirred for 15 min before pivaloyl chloride (3.26 g, 27.0 mmol) was
added. After 1 h, MeO(Me)NH2Cl (2.63 g, 27.0 mmol) was added
in one portion, followed by the dropwise addition of Et3N (5.46 g,
54.0 mmol). After additional stirring for 1.5 h (or until the disap-
pearance of anhydride monitored by TLC; PE/EA, 2:1; Rf = 0.43)
at 0 to 5 °C, the reaction mixture was washed with hydrochloric
acid (1 , 20 mL), a saturated solution of NaHCO3 (20 mL), and
brine (20 mL), and the organic layer was dried with MgSO4, fil-
tered, and concentrated in vacuo. The crude product was purified
by column chromatography on SiO2 (EA, Rf = 0.44) to give Wein-
reb amide 7 (6.71 g, 24.9 mmol, 92%) as a light yellow oil. 1H
NMR (300 MHz, CDCl3): δ = 3.18 (s, 3 H), 3.63 (s, 3 H), 3.87 (s,
3 H), 3.88 (s, 3 H), 4.25 (s, 2 H), 4.60 (s, 2 H), 6.82 (d, J = 8.1 Hz,
1 H), 6.90 (dd, J = 1.7 Hz, J = 8.1 Hz, 1 H), 6.97 (d, J = 1.8 Hz,
1 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 32.11 (CH3),
55.68 (CH3), 55.73 (CH3), 61.20 (CH3), 66.53 (CH2), 72.95 (CH2),
110.69 (CH), 111.25 (CH), 120.54 (CH), 129.92 (C), 148.61 (C),
(ATR): ν = 3285 (w), 3223 (w), 3083 (w), 3061 (w), 3028 (w), 2971
˜
(w), 2922 (w), 2907 (w), 2865 (w), 1769 (w), 1686 (s), 1618 (vs),
1476 (w), 1453 (m), 1408 (w), 1371 (m), 1279 (w), 1225 (vs), 1156
(w), 1099 (m), 1026 (m), 999 (w), 966 (m), 894 (w), 767 (m), 702
(m) cm–1. MS (EI, 70 eV): m/z (%) = 231 (82) [M]+, 216 (55) [M –
Me]+, 145 (10), 127 (24), 105 (100). HRMS (CI, isobutane): calcd.
for C14H18NO2 [M + H]+ 232.1337; found 232.1338.
In analogy, (R)-4 (4.26 g, 18.4 mmol, 94%) was prepared from (R)-
phenethylamine (2.36 g, 19.5 mmol). Colorless solid. M.p. 72–
73 °C. [α]2D0 = –512.4 (c = 1.15, MeOH).
In analogy, (S)-4 (3.31 g, 14.3 mmol, 92%) was prepared from (S)-
phenethylamine (1.89 g, 15.6 mmol). Colorless solid. M.p. 71–
72 °C. [α]2D0 = +474.9 (c = 0.86, MeOH).
8-(3,4-Dimethoxybenzyloxymethyl)-2-oxaspiro[4.5]dec-7-ene-1,6-di-
one (2): A solution of vinyl ketone 3 (1.30 g, 5.50 mmol) in absolute
THF (10 mL) was added to a solution of enamino lactone rac-4
(1.40 g, 6.05 mmol) in absolute THF (10 mL). The mixture was
stirred at 65 °C for 18 h under an atmosphere of nitrogen. The sol-
vent was then removed under reduced pressure, and the crude prod-
uct was directly subjected to hydrolysis by dissolving it in a mixture
of THF (15 mL) and aqueous acetic acid (10%, 5.5 mL). The mix-
ture was stirred at room temperature for 24 h, and then the solvent
was removed in vacuo, the residue diluted with hydrochloric acid
148.90 (C), 170.88 (C) ppm. IR (ATR): ν = 3000 (w), 2939 (m),
˜
2913 (w), 2838 (w), 1677 (s), 1609 (w), 1594 (m), 1516 (vs), 1464
(m), 1420 (m), 1393 (w), 1330 (m), 1263 (vs), 1237 (vs), 1182 (m),
1159 (vs), 1137 (vs), 1085 (s), 1027 (vs), 993 (s), 952 (m), 923 (w),
857 (m), 812 (m), 767 (m) cm–1. MS (EI, 70 eV): m/z (%) = 269
(8) [M]+, 167 (8), 152 (10), 151 (100), 107 (10), 103 (63), 73 (26).
C13H19NO5 (269.30): calcd. C 57.98, H 7.11, N 5.20; found C
58.40, H 7.24, N 5.39.
1-(3,4-Dimethoxybenzyloxy)-3-buten-2-one (3): A solution of vinyl- (1 , 5 mL) and extracted with CH2Cl2 (4ϫ10 mL). The combined
magnesium bromide (38.2 mL, 26.7 mmol, 0.7  in THF) was
added dropwise to a cooled (–5 °C) solution of Weinreb amide 7
(6.00 g, 22.3 mmol) in absolute THF (180 mL) under nitrogen. The
resulting mixture was slowly warmed and then stirred for 4 h at
23 °C. Subsequently, it was transferred via a cannula into a cooled
(0 °C) solution of hydrochloric acid (1 , 140 mL). The biphasic
mixture was extracted with diethyl ether (3ϫ30 mL), dried with
MgSO4, filtered, and concentrated in vacuo. The crude product was
purified by column chromatography on SiO2 (PE/EA, 1:1; Rf =
organic layers were dried with MgSO4, filtered, and concentrated
in vacuo. The crude product was purified by column chromatog-
raphy on SiO2 (CH2Cl2/EA, 4:1; Rf = 0.52) to give ketone rac-2
1
(760 mg, 2.19 mmol, 40%) as a colorless oil. H NMR (300 MHz,
CDCl3): δ = 2.01–2.10 (m, 1 H), 2.10 (dt, J = 13.1 Hz, J = 8.5 Hz,
1 H), 2.29 (dt, J = 18.5 Hz, J = 5.8 Hz, 1 H), 2.45 (ddd, J = 5.2 Hz,
J = 6.4 Hz, J = 13.6 Hz, 1 H), 2.71–2.78 (m, 2 H), 3.88 (s, 3 H,
OCH3), 3.89 (s, 3 H, OCH3), 4.11 (s, 2 H, 8-CH2), 4.36 (dt, J =
3.9 Hz, J = 8.7 Hz, 1 H, 3-H), 4.42 (dt, J = 7.1 Hz, J = 8.7 Hz, 1
H, 3-H), 4.50 (s, 2 H, ArCH2), 6.20 (pent, J = 1.5 Hz, 1 H, 7-H),
0.47) to give vinyl ketone 3 (3.80 g, 16.1 mmol, 72%) as a colorless
1
oil. H NMR (500 MHz, CDCl3): δ = 3.76 (s, 3 H), 3.77 (s, 3 H), 6.86–6.89 (m, 3 H, ArH) ppm. 13C{1H} NMR (125 MHz, CDCl3):
4.16 (s, 2 H), 4.44 (s, 2 H), 5.71 (d, J = 10.7 Hz, 1 H), 6.21 (d, J = δ = 23.27 (CH2), 30.39 (CH2), 32.41 (CH2), 53.36 (C), 55.76 (CH3),
Eur. J. Org. Chem. 2007, 5840–5846
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G. Koripelly, W. Saak, J. Christoffers
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55.80 (CH3), 65.80 (CH2), 71.12 (CH2), 72.70 (CH2), 110.88 (CH),
(1 mL), and brine (1 mL), and the organic layer was dried with
111.01 (CH), 120.36 (CH), 122.19 (CH), 129.75 (C), 148.73 (C), MgSO4, filtered, and concentrated in vacuo. The crude product was
148.97 (C), 162.79 (C), 175.38 (C), 194.24 (C) ppm. IR (ATR): ν purified by column chromatography on SiO2 (PE/EA, 1:1; Rf =
˜
= 3058 (w), 2997 (w), 2935 (m), 2920 (w), 2866 (w), 2837 (w), 1770 0.24) to give rac-8 (65.0 mg, 0.156 mmol, 61%) as a light yellow
1
(vs), 1715 (w), 1663 (vs), 1607 (w), 1593 (w), 1516 (s), 1464 (m), oil. H NMR (500 MHz, CDCl3): δ = 2.02 (ddd, J = 5.2 Hz, J =
1452 (m), 1420 (m), 1375 (m), 1341 (w), 1264 (s), 1238 (m), 1217 7.6 Hz, J = 13.8 Hz, 1 H), 2.08 (dt, J = 12.9 Hz, J = 8.4 Hz, 1 H),
(m), 1187 (m), 1158 (s), 1139 (s), 1101 (w), 1083 (w), 1059 (w), 1027 2.28 (dt, J = 18.7 Hz, J = 5.3 Hz, 1 H), 2.40 (ddd, J = 5.3 Hz, J =
(s), 961 (w), 914 (w), 869 (w), 811 (w), 765 (w), 731 (m) cm–1. MS 6.2 Hz, J = 13.7 Hz, 1 H), 2.66–2.71 (m, 2 H), 4.31–4.39 (m, 2 H),
(EI, 70 eV): m/z (%) = 346 (40) [M]+, 167 (29), 151 (100). HRMS
4.65 (A part of an AB system, J = 14.7 Hz, 1 H), 4.67 (B part of
an AB system, J = 15.0 Hz, 1 H), 6.03 (pent, J = 1.3 Hz, 1 H, 7-
H), 7.70–7.73 (m, 2 H), 7.76–7.77 (m, 2 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 22.94 (CH2), 30.16 (CH2), 32.26 (CH2),
53.13 (C), 65.93 (CH2), 70.07 (CH2), 123.91 (CH), 129.33 (2 CH),
129.63 (C), 132.82 (2 CH), 134.36 (C), 156.30 (C), 174.79 (C),
(EI, 70 eV): calcd. for C19H22O6 [M]+ 346.1416; found 346.1415.
In analogy, (R)-2 (1.17 g, 3.37 mmol, 41%) was prepared from (S)-
4 (2.10 g, 9.10 mmol). Colorless oil. [α]2D0 = –36.6 (c = 1.63, MeOH).
In analogy, (S)-2 (1.94 g, 5.60 mmol, 43%) was prepared from (R)-
4 (3.33 g, 14.4 mmol). Colorless oil. [α]2D0 = +47.2 (c = 3.14,
MeOH).
193.51 (C) ppm. IR (ATR): ν = 3102 (w), 3082 (w), 3063 (w), 3017
˜
(w), 2983 (w), 2950 (w), 2915 (w), 2890 (w), 2872 (w), 2825 (w),
1759 (s), 1662 (s), 1632 (m), 1575 (m), 1471 (m), 1454 (w), 1443
(w), 1421 (w), 1393 (m), 1385 (m), 1363 (s), 1347 (m), 1284 (m),
1260 (m), 1217 (m), 1178 (vs), 1135 (m), 1091 (m), 1070 (m), 1057
(m), 1032 (s), 997 (m), 957 (vs), 931 (m), 889 (m), 872 (m), 792 (vs),
774 (vs), 731 (m), 721 (m), 655 (m) cm–1. MS (CI, isobutane): m/z
(%) = 829 (66) [2M + H]+, 673 (8), 595 (30), 453 (10), 415 (100),
259 (14), 179 (19). HRMS (CI, isobutane): calcd. for C16H16BrO6S
414.9851; found 414.9850.
8-Hydroxymethyl-2-oxaspiro[4.5]dec-7-ene-1,6-dione (9): TFA (10%
solution in CH2Cl2, 34 mL) was added to a solution of compound
rac-2 (213 mg, 0.614 mmol) in CH2Cl2 (2 mL) at 23 °C. After stir-
ring for 1.5 h at the same temperature, the reaction mixture was
filtered through a pad of silica (5 cm). The volatile materials were
removed in vacuo, and the residue was purified by column
chromatography on SiO2 (CH2Cl2/EA, 1:1; Rf = 0.13) to obtain
a first fraction containing hexamethoxytribenzocyclononane (Rf =
0.75) as a light yellow solid (10.0 mg, 0.022 mmol). The second
fraction was allylic alcohol rac-9 (84.0 mg, 0.428 mmol, 70%), a
light yellow oil. GLC (2 min at 60 °C, then with 0.5 Kmin–1 to
160 °C, then 1 min at 160 °C, then with 0.2 Kmin–1 to 185 °C, fi-
nally 150 min at 185 °C): tR(R) = 325 min, tR(S) = 454 min. 1H
NMR (300 MHz, CDCl3): δ = 1.89 (t, J = 6.1 Hz, 1 H, OH), 2.03–
2.11 (m, 1 H), 2.11 (dt, J = 13.0 Hz, J = 8.5 Hz, 1 H), 2.27 (dt, J
= 18.5 Hz, J = 5.5 Hz, 1 H), 2.46 (ddd, J = 5.2 Hz, J = 6.2 Hz, J
= 13.6 Hz, 1 H), 2.69–2.80 (m, 2 H), 4.25 (A part of an ABX
system, JAX = 6.3 Hz, JAB = 16.7 Hz, 1 H, 8-CHH), 4.27 (B part
of an ABX system, JBX = 5.6 Hz, JAB = 16.7 Hz, 1 H, 8-CHH),
4.36 (dt, J = 4.0 Hz, J = 8.7 Hz, 1 H, 3-H), 4.43 (dt, J = 7.1 Hz, J
= 8.7 Hz, 1 H, 3-H), 6.20 (pent, J = 1.5 Hz, 1 H, 7-H) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ = 23.03 (CH2), 30.49 (CH2),
32.51 (CH2), 53.65 (C), 64.49 (CH2), 66.07 (CH2), 120.71 (CH),
In analogy, (R)-8 (325 mg, 0.782 mmol, 76%) was prepared from
(R)-9 (200 mg, 1.02 mmol). Light yellow solid. M.p. 126 °C. [α]2D0
=
–44.8 (c = 0.59, MeOH). Single crystals were grown from CH2Cl2/
pentane at 23 °C.
6-Hydroxy-8-(hydroxymethyl)-2-oxaspiro[4.5]dec-7-en-1-one (10):
CeCl3·7H2O (874 mg, 2.36 mmol) was added to a cooled solution
of allylic alcohol 9 (443 mg, 2.26 mmol) in MeOH (8 mL) at –5 °C.
After stirring the reaction mixture for 30 min at –5 to 0 °C, NaBH4
(89 mg, 2.36 mmol) was added portionwise, and the resulting mix-
ture was stirred for 1.5 h at the same temperature. Then the reac-
tion mixture was diluted with water (5 mL), and the solvent was
removed in vacuo. The resulting residue was extracted with EtOAc
(4ϫ5 mL). The combined organic layer was dried with MgSO4,
filtered, and the solvents evaporated in vacuo. The crude product
was purified by column chromatography on SiO2 (EA) to obtain
two fractions: first the (R*,S*) diastereomer (155 mg, 0.782 mmol,
35%; Rf = 0.28) as a colorless solid, m.p. 99 °C (single crystals
were grown from EA/pentane at 23 °C), and second the (R*,R*)
diastereomer (142 mg, 0.716 mmol, 32%; Rf = 0.20) as a colorless
166.26 (C), 175.94 (C), 194.67 (C) ppm. IR (ATR): ν = 3447 (br.
˜
m), 2982 (w), 2927 (w), 2873 (w), 2842 (w), 1756 (vs), 1656 (vs),
1513 (w), 1479 (w), 1427 (m), 1377 (m), 1347 (m), 1323 (w), 1295
(m), 1216 (s), 1188 (s), 1159 (m), 1146 (m), 1127 (m), 1098 (w),
1052 (s), 1028 (vs), 997 (m), 960 (m), 930 (m), 866 (w), 791 (w),
731 (w), 707 (w) cm–1. MS (CI, isobutane): m/z (%) = 393 (26) [2M
+ H]+, 197 (100) [M + H]+, 179 (8), 135 (5). HRMS (EI, 70 eV):
calcd. for C10H12O4 [M]+ 196.0735; found 196.0735.
1
oil. Data for the (R*,S*) diastereomer (EA, Rf = 0.28): H NMR
(300 MHz, CDCl3): δ = 1.59 (br. s, 1 H, OH), 1.79 (ddd, J = 2.8 Hz,
J = 5.2 Hz, J = 13.4 Hz, 1 H), 1.90–2.03 (m, 2 H), 2.07–2.15 (m, 2
H), 2.20–2.23 (m, 1 H), 2.51 (ddd, J = 6.2 Hz, J = 8.5 Hz, J =
14.6 Hz, 1 H), 4.06 (s, 2 H, 8-CH2), 4.30 (dt, J = 6.1 Hz, J = 8.5 Hz,
1 H, 3-H), 4.38 (dt, J = 6.3 Hz, J = 8.6 Hz, 1 H, 3-H), 4.62 (br. s,
1 H, 6-H), 5.63 (sex, J = 1.7 Hz, 1 H, 7-H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 22.36 (CH2), 26.65 (CH2), 28.22 (CH2),
47.90 (C), 65.42 (CH2), 66.75 (CH2), 70.11 (CH), 123.99 (CH),
In analogy, (R)-9 (740 mg, 3.77 mmol, 72%) was prepared from
(R)-2 (1.80 g, 5.19 mmol). Light yellow oil. GLC: tR(R) = 325 min
(major), tR(S) = 454 min (minor), 60% ee. [α]2D0 = –60.8 (c = 1.54,
MeOH).
In analogy, (S)-9 (600 mg, 3.05 mmol, 71%) was prepared from
(S)-2 (1.50 g, 4.33 mmol). Light yellow solid. M.p. 84–85 °C. GLC:
139.30 (C), 181.99 (C) ppm. IR (ATR): ν = 3395 (br. s), 2987 (w),
˜
2925 (m), 2867 (w), 1745 (vs), 1450 (w), 1434 (w), 1382 (m), 1344
(w), 1271 (w), 1220 (s), 1193 (s), 1060 (m), 1028 (s), 893 (w), 830
(w), 745 (w), 704 (w) cm–1. MS (EI, 70 eV): m/z (%) = 198 (8)
tR(R) = 326 min (minor), tR(S) = 446 min (major), 69% ee. [α]2D0
+84.8 (c = 1.19, MeOH).
=
(1,6-Dioxo-2-oxaspiro[4.5]-7-decen-8-yl)methyl-4-bromobenzenesul- [M]+, 180 (22), 134 (18), 99 (43), 84 (100), 82 (50), 49 (65). HRMS
fonate: (8): Et3N (38.7 mg, 0.382 mmol) and brosyl chloride
(71.7 mg, 0.281 mmol) were subsequently added to a cooled solu-
tion of allylic alcohol rac-9 (50.0 mg, 0.255 mmol) in CH2Cl2
(1 mL) at –5 °C, and the resulting mixture was stirred for 12 min
at the same temperature. The reaction mixture was then washed
with hydrochloric acid (1 , 1 mL), saturated solution of NaHCO3
(CI, isobutane): calcd. for C10H15O4 [M + H]+ 199.0970; found
1
199.0970. Data for the (R*,R*) diastereomer (EA, Rf = 0.20): H
NMR (300 MHz, CDCl3): δ = 1.56 (br. s, 1 H, OH), 1.69–1.78 (m,
1 H), 2.00–2.13 (m, 1 H), 2.10 (ddd, J = 4.5 Hz, J = 7.1 Hz, J =
12.8 Hz, 1 H), 2.24 (ddd, J = 5.0 Hz, J = 8.7 Hz, J = 19.5 Hz, 1
H), 2.19–2.30 (m, 2 H), 3.04 (d, J = 5.6 Hz, 1 H, 6-OH), 4.06–4.09
5844
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5840–5846

Synthesis of Optically Active (+)-Canangone and Its 6-Epimer
(m, 2 H, 8-CH2), 4.15 (t, J = 4.4 Hz, 1 H, 6-H), 4.31 (dt, J = 0.018 mmol) were added to a stirred solution of (R*,S*)-diol 10
7.5 Hz, J = 8.8 Hz, 1 H, 3-H), 4.37 (dt, J = 4.5 Hz, J = 8.8 Hz, 1 (12.0 mg, 0.061 mmol) in absolute DMF (1 mL) at 23 °C under a
H, 3-H), 5.80–5.84 (m, 1 H, 7-H) ppm. 13C{1H} NMR (125 MHz,
nitrogen atmosphere. The reaction flask was then cooled with N2(l),
CDCl3): δ = 22.55 (CH2), 25.20 (CH2), 32.24 (CH2), 45.95 (C), evacuated, filled with O2 (1 atm, balloon), and the mixture was
65.40 (CH2), 65.77 (CH2), 68.75 (CH), 121.01 (CH), 141.51 (C), stirred at 23 °C for 75 min. Subsequently, it was diluted with a satu-
179.73 (C) ppm. IR (ATR): ν = 3387 (br. s), 2922 (m), 2863 (w), rated aqueous solution of CuSO4 (1 mL) and extracted with EA
˜
1749 (vs), 1486 (w), 1450 (w), 1431 (w), 1377 (m), 1259 (w), 1215 (4ϫ1 mL). The combined organic layers were washed with water
(s), 1188 (s), 1167 (s), 1056 (s), 1028 (vs), 962 (w) cm–1. MS (CI,
isobutane): m/z (%) = 199 (2) [M + H]+, 181 (100), 163 (27), 87 (5).
HRMS (CI, isobutane): calcd. for C10H15O4 [M + H]+ 199.0970;
found 199.0969.
(2 mL) and brine (2 mL), dried with MgSO4, filtered, and concen-
trated in vacuo. The crude product was purified by column
chromatography on SiO2 (EA, Rf = 0.60) to obtain (R*,S*)-6-epi-
canangone (1; 9.00 mg, 0.046 mmol, 75%) as a colorless oil. 1H
NMR (500 MHz, CDCl3): δ = 1.80–1.94 (m, 2 H), 1.97 (ddd, J =
6.1 Hz, J = 8.4 Hz, J = 14.4 Hz, 1 H), 2.14–2.22 (m, 1 H), 2.43–
2.50 (m, 1 H), 2.50 (ddd, J = 6.4 Hz, J = 8.6 Hz, J = 14.8 Hz, 1
H), 3.44 (d, J = 6.1 Hz, 1 H, 6-OH), 4.34 (dt, J = 6.3 Hz, J =
8.6 Hz, 1 H, 3-H), 4.42 (dt, J = 6.1 Hz, J = 8.7 Hz, 1 H, 3-H),
4.83–4.87 (m, 1 H, 6-H), 6.64–6.66 (m, 1 H), 9.51 (s, 1 H, 8-H)
ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 18.48 (CH2), 26.05
(CH2), 27.49 (CH2), 48.22 (C), 66.77 (CH2), 70.27 (CH), 140.81
In analogy, (5R,6S)-10 (165 mg, 0.832 mmol, 36%) as a colorless
oil (slowly solidifying at 5 °C), [α]2D0 = +30.6 (c = 0.47, MeOH) and
(R,R)-10 (150 mg, 0.756 mmol, 33%) as a colorless solid, m.p.
105 °C, [α]2D0 = –53.2 (c = 0.88, MeOH) were prepared from (R)-9
(450 mg, 2.29 mmol).
In analogy, (5S,6R)-10 (96 mg, 0.48 mmol, 32%) as a colorless so-
lid, m.p. 78–79 °C, [α]2D0 = –32.8 (c = 0.71, MeOH), and (S,S)-10
(110 mg, 0.554 mmol, 37%) as a colorless oil (slowly solidifying at
5 °C), [α]2D0 = +66.4 (c = 1.02, MeOH) were prepared from (S)-9
(300 mg, 1.51 mmol).
(C), 149.65 (CH), 181.10 (C), 192.92 (CH) ppm. IR (ATR): ν =
˜
3437 (br. m), 2986 (w), 2930 (m), 2870 (w), 2849 (w), 1759 (vs),
1683 (vs), 1485 (w), 1451 (w), 1433 (w), 1381 (m), 1342 (w), 1221
(m), 1193 (s), 1167 (m), 1059 (m), 1030 (s), 1005 (m), 954 (w), 899
(w), 871 (w), 821 (w), 784 (w), 748 (w), 707 (w) cm–1. MS (EI,
70 eV): m/z (%) = 196 (14) [M]+, 178 (14), 167 (9), 150 (12), 134
(23), 121 (40), 105 (55), 99 (100), 91 (44), 77 (73), 62 (36), 51 (27),
41 (35). HRMS (CI, isobutane): calcd. for C10H13O4 [M + H]+
197.0814; found 197.0814.
(R*,R*)-6-Hydroxy-1-oxo-2-oxaspiro[4.5]dec-7-ene-8-carbaldehyde
(R*,R*-1): TEMPO (4.0 mg, 0.026 mmol) and CuCl (2.6 mg,
0.026 mmol) were added to a stirred solution of (R*,R*)-diol 10
(17 mg, 0.086 mmol) in absolute DMF (1 mL) at 23 °C under ex-
clusion of moisture. The reaction flask was then cooled with N2(l),
evacuated, filled with O2 (1 atm, balloon), and the mixture was
stirred at 23 °C for 75 min. Subsequently, it was diluted with a satu-
rated aqueous solution of CuSO4 (1 mL) and extracted with EA
(4ϫ1 mL). The combined organic layers were washed with water
(2 mL) and brine (2 mL), dried with MgSO4, filtered, and concen-
trated in vacuo. The crude product was purified by column
chromatography on SiO2 (EA, Rf = 0.40) to obtain (R*,R*)-canan-
gone (1; 13 mg, 0.066 mmol, 77%) as a colorless oil. 1H NMR
(500 MHz, CDCl3): δ = 1.76 (ddd, J = 6.0 Hz, J = 8.0 Hz, J =
14.0 Hz, 1 H, 10-H), 2.07 (ddd, J = 3.6 Hz, J = 7.1 Hz, J = 12.8 Hz,
1 H, 4-H), 2.21 (dt, J = 14.0 Hz, J = 5.6 Hz, 1 H, 10-H), 2.29 (dtt,
J = 18.7 Hz, J = 5.7 Hz, J = 1.4 Hz, 1 H, 9-H), 2.39 (dddt, J =
18.7 Hz, J = 7.9 Hz, J = 5.8 Hz, J = 2.1 Hz, 1 H, 9-H), 2.47 (dt, J
= 12.8 Hz, J = 8.9 Hz, 1 H, 4-H), 3.11 (t, J = 7.8 Hz, 1 H, 6-OH),
4.33 (dt, J = 7.1 Hz, J = 9.1 Hz, 1 H, 3-H), 4.39 (dt, J = 3.6 Hz, J
= 9.1 Hz, 1 H, 3-H), 4.36–4.40 (m, 1 H, 6-H), 6.68 (dt, J = 3.4 Hz,
J = 1.8 Hz, 1 H, 7-H), 9.51 (s, 1 H, 8-CHO) ppm. 13C{1H} NMR
In analogy, (5R,6S)-1 (30.0 mg, 0.153 mmol, 76%) was prepared
from (5R,6S)-10 (40.0 mg, 0.202 mmol). Colorless oil. [α]2D0 = +58.9
(c = 0.43, MeOH).
In analogy, (5S,6R)-1 (34.0 mg, 0.173 mmol, 78%) was prepared
from (5S,6R)-10 (44.0 mg, 0.222 mmol). Colorless oil. [α]2D0 = –71.4
(c = 1.56, MeOH).
Acknowledgments
We are grateful to the Fonds der Chemischen Industrie for support
of this work. We also thank Detlev Haase for helping us with crys-
tallography.
(125 MHz, CDCl3): δ = 18.66 (CH2), 25.59 (CH2), 32.21 (CH2), [1] E. Caloprisco, J.-D. Fourneron, R. Faure, F.-E. Demarne, J.
Agric. Food Chem. 2002, 50, 78–80.
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2006, 369–396.
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178.31 (C), 193.20 (CH) ppm. IR (ATR): ν = 3432 (br. m), 2924
˜
(m), 2854 (w), 2726 (w), 1750 (s), 1674 (vs), 1485 (w), 1451 (w),
1429 (w), 1378 (m), 1256 (w), 1215 (m), 1176 (s), 1124 (s), 1091
(w), 1061 (m), 1024 (vs), 998 (m), 962 (m), 902 (m), 869 (w), 826
(w), 783 (w), 769 (w), 711 (m), 658 (w) cm–1. MS (EI, 70 eV): m/z
(%) = 196 (3) [M]+, 167 (4), 149 (12), 134 (100), 121 (19), 105 (100),
99 (88), 91 (58), 77 (65), 65 (19), 53 (28), 41 (32). HRMS (CI,
isobutane): calcd. for C10H13O4 [M + H]+ 197.0814, found
197.0814.
In analogy, (R,R)-1 (31.0 mg, 0.158 mmol, 78%) was prepared from
(R,R)-10 (40.0 mg, 0.202 mmol). Colorless solid. M.p. 92–93 °C.
[α]2D0 = –67.0 (c = 1.25, MeOH).
In analogy, (S,S)-1 (36.0 mg, 0.183 mmol, 76%) was prepared from
(S,S)-10 (48.0 mg, 0.242 mmol). Colorless solid. M.p. 98–99 °C.
[α]2D0 = +107.5 (c = 1.87, MeOH).
(R*,S*)-6-Hydroxy-1-oxo-2-oxaspiro[4.5]dec-7-ene-8-carbaldehyde
(R*,S*-1): TEMPO (2.80 mg, 0.018 mmol) and CuCl (1.80 mg,
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dron: Asymmetry 1994, 5, 1459–1462.
Eur. J. Org. Chem. 2007, 5840–5846
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5845

G. Koripelly, W. Saak, J. Christoffers
FULL PAPER
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Received: July 25, 2007
Published Online: October 5, 2007
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Eur. J. Org. Chem. 2007, 5840–5846