Carotenoids and related polyenes, part 121) first total synthesis and absolute configuration of 3′-deoxycapsanthin and 3,4-didehydroxy-3′-deoxycapsanthin

Article abstract of DOI:10.1248/cpb.58.1362

The synthesis of 3′-deoxycapsanthin (1) and 3,4-didehydroxy-3′- deoxycapsanthin (2), carotenoids of paprika, has been achieved by employing Lewis acid-promoted regio- and stereoselective rearrangement of the C ₁₅-epoxy dienal 5a. The absolute stereochemistry of the newly formed C-5 chiral center of rearrangement product 6a was determined to be (R) from its alternative synthesis derived from (+)-(R)-camphonanic acid (11).

Full text of DOI:10.1248/cpb.58.1362

1362
Regular Article
Chem. Pharm. Bull. 58(10) 1362—1365 (2010)
Vol. 58, No. 10
Carotenoids and Related Polyenes, Part 121)
First Total Synthesis and Absolute Configuration of
3؅-Deoxycapsanthin and 3,4-Didehydroxy-3؅-deoxycapsanthin
Yumiko YAMANO,* Mahankhali Venu CHARY, and Akimori WADA
Department of Organic Chemistry for Life Science, Kobe Pharmaceutical University; 4–19–1 Motoyamakita-machi,
Higashinada-ku, Kobe 658–8558, Japan. Received June 17, 2010; accepted July 3, 2010; published online July 7, 2010
The synthesis of 3؅-deoxycapsanthin (1) and 3,4-didehydroxy-3؅-deoxycapsanthin (2), carotenoids of
paprika, has been achieved by employing Lewis acid-promoted regio- and stereoselective rearrangement of the
C15-epoxy dienal 5a. The absolute stereochemistry of the newly formed C-5 chiral center of rearrangement prod-
uct 6a was determined to be (R) from its alternative synthesis derived from (؉)-(R)-camphonanic acid (11).
Key words 3Ј-deoxycapsanthin; 3,4-didehydroxy-3Ј-deoxycapsanthin; tetrasubstituted epoxide; regioselective rearrangement;
stereoselective rearrangement; absolute configuration
3Ј-Deoxycapsanthin (1) and 3,4-didehydroxy-3Ј-capsan- clopentyl ketone 6a (Chart 1), prepared by rearrangement of
thin (2) (Fig. 1) were recently isolated2) from ripe fruits of the optically active C15-5,6-epoxy dienal 5a.
paprika (Capsicum annuum) together with the major pig-
ments capsanthin (3) and capsorubin (4), which have anti- Results and Discussion
cancer3) and anti-oxidative properties.4,5) These carotenoids,
The optically active C15-epoxy dienal 5a was prepared
having a k-end group, are considered6,7) to be formed in na- (Chart 2) from the known11) epoxy aldehyde 9, which was
ture from 5,6-epoxy carotenoids through ring opening of the synthesized via Sharpless asymmetric epoxidation of the al-
epoxy moiety. The structures of 1 and 2 were determined2) by lylic alcohol 7 derived12) from commercially available b-
extensive analysis using modern NMR techniques, and their ionone. Emmons–Horner reaction of the aldehyde 9 with the
absolute configurations were assigned on the basis of biosyn- phosphonate 15 in the presence of n-butyllithium and 1,3-di-
thetic considerations6,7) and by comparing their circular methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) gave
dichroism (CD) data with those of capsanthin (3) (Fig. 1).
the all-E dienoate 10 (72%) and its 9Z isomer (13%), which
Previously, we reported8,9) the biomimetic type total syn- could be readily separated by flash column chromatography
thesis of capsanthin (3) and capsorubin (4) via regioselective (CC). Reduction of the ester 10 with LiAlH4 followed by
cleavage of the oxirane ring at the C-5 position,10) and the MnO2 oxidation gave the C15-epoxy dienal 5a in 95% yield.
subsequent regio- and stereoselective ring contraction of the
Treatment of 5a with SnCl4 yielded the regioselectively re-
C15-3-silyloxy-5,6-epoxy dienal 5b (Chart 1). Continuing our arranged cyclopentyl ketone 6a in 76% yield. HPLC analysis
work on the total synthesis of carotenoids,1) we present here using a chiral column (CHIRALPAK AY-H; Daicel) revealed
the first total synthesis of 3Ј-deoxycapsanthin (1) and 3,4- that the enantiomeric excess (ee) of the cyclopentyl ketone
didehydroxy-3Ј-deoxycapsanthin (2) through the C15-cy- 6a (84% ee) remained almost unchanged during the re-
arrangement of C15-epoxy dienal 5a (94% ee). From the pre-
vious results,8,9) the absolute stereochemistry of the newly
formed C-5 chiral center in rearrangement product 6a was
expected to be (R); however, its configuration was deter-
mined by an alternative synthesis from (ϩ)-(R)-camphonanic
acid (11)13) (Chart 2).
Esterification of the acid 11 with TMSCHN2 followed
14)
by reduction with LiAlH4 gave the corresponding alcohol
1215) (88%). Subsequently, alcohol 12 was oxidized using
Dess–Martin periodinane (DMP) to provide the extremely
volatile aldehyde 1315) in 57% yield. This aldehyde was sub-
sequently coupled with vinyl lithium, prepared from the
vinyl iodide 1616) (E/Z ca. 7/3) and tert-butyllithium, to pro-
vide the alcohol 14 in 41% yield. Upon deprotection of the
Fig. 1. Structures of Carotenoids
tert-butyldimethylsilyl (TBS) group in 14 with tetrabutylam-
monium fluoride (TBAF) and subsequent DMP oxidation,
the all-E (R)-cyclopentyl ketoaldehyde 6a (46%; 89% ee de-
termined by chiral HPLC) was obtained accompanied by its
9Z isomer (21%). The optical rotation, the retention time on
chiral HPLC, and the spectral data of all-E (R)-cylpentyl ke-
toaldehyde 6a were identical to those of the product prepared
from epoxy dienal 5a.
Chart 1
This ketoaldehyde 6a was transformed into 3Ј-deoxycap-
∗ To whom correspondence should be addressed. e-mail: y-yamano@kobepharma-u.ac.jp
© 2010 Pharmaceutical Society of Japan

October 2010
1363
Reagents and conditions: (a) 15, nBuLi, DMPU, THF; (b) LiAlH4, Et2O then MnO2, EtO2–hexane; (c) SnCl4,
CH2Cl2; (d) TMSCHN2, MeOH–benzene then LiAlH4, Et2O; (e) DMP, CH2Cl2; (f) 16, tBuLi, Et2O; (g) TBAF,
THF then DMP, CH2Cl2.
Chart 2
Reagents and Conditions: (a) 19, NaOMe, MeOH then Dowex (Hϩ); (b) 20, NaOMe, MeOH; (c) 24,
NaOMe, MeOH; (d) CH(OMe)3, Hϩ, MeOH; (e) (EtO)2P(O)CH2CO2Et, NaH, THF, 50 °C; (f) LiAlH4, Et2O;
(g) PPh3·HBr, MeOH.
Chart 3
santhin (1) and 3,4-didehydroxy-3Ј-deoxycapsanthin (2) PPh3·HBr to provide the Wittig salt 24, which without purifi-
through apocarotenal 17 (Chart 3). Wittig condensation of cation was condensed with the apocarotenal 17. PHPLC pu-
the C15-aldehyde 6a with the C10-phosphonium salt 1917) in rification of the condensation products afforded all-E 3,4-
the presence of NaOMe as a base, followed by one-pot treat- didehydroxy-3Ј-deoxycapsanthin (2) (28%) accompanied by
ment with ion exchange resin (Dowex 50W-X8, Hϩ), pro- an isomeric mixture. Spectral data of the synthetic product 2
vided an isomeric mixture of C25-apocarotenals. Preparative were in good agreement with those of the reported2) natural
HPLC (PHPLC) provided the all-E isomer 17 (42%) and an product.
isomeric mixture (18%), which thermodynamically isomer-
In conclusion, considering of the biosynthesis of the k-end
ized while standing in ethereal solution at room temperature group in carotenoids, we applied the regio- and stereoselec-
(rt) for 1 d to yield the desired all-E isomer 17 (7% from 6a). tive rearrangement of 5,6-epoxy dienal 5a with SnCl4 to ac-
The stereochemistry of 17 was determined by comparison of complish the first total synthesis of optically active 3Ј-deoxy-
1
its H-NMR data with previously prepared8,9) 3-hydroxycy- capsanthin (1) and 3,4-didehydroxy-3Ј-capsanthin (2). More-
clopentyl apocarotenal.
over, we assigned the absolute configuration of the k-end
Wittig reaction of the C25-apocarotenal 17 with the C15- group in 1 and 2 on the basis of their enantiospecific total
phosphonium salt 208,9) afforded a mixture of condensation synthesis.
products, which were separated by PHPLC to provide all-E
Experimental
3Ј-deoxycapsanthin (1) (27%) and an isomeric mixture
General UV spectra were recorded on a JASCO V-650 instrument. IR
(20%). The latter was also transformed (6% from 17) into the
spectra were measure on a Perkin Elmer FT-IR spectrometer, model Paragon
1000. H- and 13C-NMR spectra were determined on a Varian Mercury-300
or a Varian VXR-500 superconducting FT-NMR spectrometer, with deuteri-
ochloroform solutions (tetramethylsilane as the internal reference). J-Values
are given in Hz. Mass spectra were obtained on a Hitachi M-4100 or Orbi-
trap Exactive spectrometer. Optical rotations were measured on a JASCO P-
2200 polarimeter ([a]D values are in units of 10Ϫ1 dg cm2 gϪ1) and CD spec-
tra on a Shimadzu-AVIN 62A DS circular dichroism spectrometer. Flash CC
was performed on silica gel (Kanto Chemical No. 37563-79). PHPLC was
carried out on a Shimadzu LC-6A with a UV–vis detector. All operations
were carried out under nitrogen or argon. Evaporation of the extract or the
filtrate was carried out under reduced pressure. Ether refers to diethyl ether,
and hexane to n-hexane. NMR assignments are given using the carotenoids
1
desired all-E isomer by thermodynamic isomerization. The
spectral data of the synthetic product 1 were in good agree-
ment with those of the reported2) natural product.
Next, the C15-Wittig salt 24 was prepared for the synthesis
of 3,4-didehydroxy-3Ј-deoxycapsanthin (2). Emmons–
Horner reaction of 3,4-didehyro-b-ionone (21), prepared18)
from commercially available a-ionone, with triethyl phos-
phonoacetate in the presence of NaH provided the ester 22
(81%) as an isomeric mixture (9E/Z ca. 85/15), which with-
out separation, was reduced with LiAlH4 to afford the alco-
hol 23 in 96% yield. This was followed by treatment with numbering system.

1364
Vol. 58, No. 10
Ethyl (2E/Z,4E)-3-Methyl-5-[(1S,6R)-2,2,6-trimethyl-7-oxabicyclo- quenched with saturated aq. NH4Cl, the mixture was extracted with ether.
[4.1.0]hept-1-yl]penta-2,4-dienoate (10) To a solution of triethyl 3- The extracts were washed with brine, dried and evaporated to give the
methyl-4-phosphonocrotonate (15) (1.90 g, 7.2 mmol) and DMPU (1.7 ml,
14.4 mmol) in dry tetrahydrofuran (THF) (20 ml) was added BuLi (1.60 M
residue, which was purified by flash CC (ether–hexane, 1 : 9) to provide the
adduct 14 (972 mg, 40%; 9E/Z ca. 7/3) as a pale yellow oil. 1H-NMR
(300 MHz) d (corresponding to 9E isomer): 0.07 (6H, s, SiCH3ϫ2), 0.90
n
in hexane; 4.5 ml, 7.2 mmol) at 0 °C. After being stirred at 0 °C for 30 min, a
solution of the epoxy aldehyde 911) (930 mg, 5.5 mmol) in dry THF (12 ml)
(9H, Bu), 0.89, 1.03 and 1.07 (each 3H, s, gem-CH3, 5-CH3), 1.27—1.43
t
was added to the reaction mixture at 0 °C and stirring was continued for (2H, m) and 1.55—1.67 (4H, m) (2-H2, 3-H2, 4-H2), 1.73 (3H, d, Jϭ1 Hz, 9-
40 min. After being quenched with saturated aq. NH4Cl, the mixture was ex- CH3), 4.23 (1H, m, 6-H), 4.31 (2H, d, Jϭ6.5 Hz, 11-H2), 5.56 (1H, br t,
tracted with ether. The extracts were washed with brine, dried and evapo- Jϭ6.5 Hz, 10-H), 5.70 (1H, dd, Jϭ16, 6.5 Hz, 7-H), 6.20 (1H, d, Jϭ16 Hz,
rated to give the residue, which was purified by flash CC (ether–hexane, 8-H). IR (CHCl3) cmϪ1: 3605 and 3502 (OH). HR-ESI-MS m/z: 353.2878
1 : 9) to provide the all-E epoxy ester 10 (1.11 g, 72%) and its 9Z isomer
(201 mg, 13%) as pale yellow oils, respectively. Their 1H-NMR, IR and UV
spectra were identical with those of previous prepared9) racemic compounds.
All-E Isomer: [a]D26 Ϫ41.6 (cϭ1.02, EtOH) {lit.19): [a]D Ϫ44.5 (cϭ0.74,
[MϩH]ϩ (Calcd for C21H41O2Si: 353.2870).
Preparation of Compound 6a from Compound 14 To a solution of
compound 14 (814 mg, 2.3 mmol; 9E/Z ca. 7/3) in dry THF (8 ml) was
added TBAF (1.0 M in THF; 2.5 ml, 2.5 mmol) at rt. After stirring for
EtOH)}. High resolution-electron ionization (HR-EI)-MS m/z: 278.1900 45 min, solvent was evaporated off and the resulted residue was purified by
(Mϩ) (Calcd for C17H26O3: 278.1881).
flash CC (acetone–hexane, 3 : 7) to provide the corresponding diol (519 mg,
9Z Isomer: [a]D27 ϩ20.5 (cϭ0.63, EtOH) {lit.19): [a]D ϩ24 (cϭ0.482, 94%). To a solution of this diol in CH2Cl2 (25 ml) was added DMP (2.14 g,
EtOH)}. HR-EI-MS m/z: 278.1891 (Mϩ) (Calcd for C17H26O3: 278.1881).
5.0 mmol) at 0 °C and the mixture was stirred at rt for 45 min. The mixture
(2E,4E)-3-Methyl-5-[(1S,6R)-2,2,6-trimethyl-7-oxabicyclo[4.1.0]hept- was filtered through Celite and the filtrate was evaporated. The resulted
1-yl]penta-2,4-dienal (5a) A solution of the ester 10 (1.55 g, 5.6 mmol) in
dry ether (30 ml) was added dropwise to a stirred suspension of LiAlH4
(220 mg, 5.8 mmol) in dry ether at 0 °C. After being stirred at 0 °C for
25 min, the excess of LiAlH4 was decomposed by dropwise addition of
residue was purified by flash CC (ether–hexane, 4 : 6) to provide the all-E
cyclopenyl ketoaldehyde 6a (248 mg, 46% from 14) as a pale yellow solid
and its 9Z isomer (111 mg, 21% from 14) as a pale yellow oil.
1
All-E Isomer: H-NMR and IR spectra were identical with those of 6a
water and the mixture was extracted with ether. The extracts were dried and prepared from compound 5a. Enatiomeric excess (89%) was determined by
evaporated to give a residue, which without purification, was dissolved in HPLC [CHIRALPAK AY-H (Daicel) 0.46ϫ25 cm; 2-PrOH–hexane, 3 : 7;
ether–hexane (ca. 1 : 4) and shaken with MnO2 (10 g) at rt for 3 h. The mix-
ture was filtered through Celite. Evaporation of the filtrate followed by pu- [MϩH]ϩ (Calcd for C15H23O2: 235.1692).
rification by flash CC (EtOAc–hexane, 2 : 8) to provide the epoxy dienal 5a
9Z Isomer: [a]D22 Ϫ13.2 (cϭ0.45, EtOH). H-NMR (300 MHz) d: 0.87,
1.0 ml/min]. [a]D22 Ϫ7.7 (cϭ0.75, EtOH). HR-ESI-MS m/z: 235.1689
1
1
(1.24 g, 95%) as a pale yellow oil. Its H-NMR, IR and UV spectra were 1.11 and 1.20 (each 3H, s, gem-CH3, 5-CH3), 1.48—1.77 (5H, m, 2-H2, 3-
identical with those of previous prepared9) racemic compounds. Enatiomeric H2, 4-H), 2.13 (3H, d, Jϭ1 Hz, 9-CH3), 2.48 (1H, m, 4-H), 6.09 (1H, dd-
excess (94%) was determined by HPLC [CHIRALPAK AY-H (Daicel) like, Jϭ8, 1 Hz, 10-H), 6.79 (1H, d, Jϭ15.5 Hz, 7-H), 8.09 (1H, Jϭ15.5 Hz,
0.46ϫ25 cm; 2-PrOH–hexane, 1 : 9; 1.0 ml/min]. [a]D25 Ϫ52.3 (cϭ0.97, 8-H), 10.30 (1H, d, Jϭ8 Hz, CHO). IR (CHCl3) cmϪ1: 1671 (conj. CO and
CHCl3) {lit.19): [a]D Ϫ52 (cϭ0.842, CHCl3)}. HR-EI-MS m/z: 234.1636 conj. CHO), 1608 and 1580 (CϭC). HR-ESI-MS m/z: 235.1687 [MϩH]ϩ
(Mϩ) (Calcd for C15H22O2: 234.1620).
(Calcd for C15H23O2: 235.1692).
(2E,4E)-3-Methyl-6-oxo-6-[(R)-1,2,2-trimethylcyclopentyl]hexa-2,4-di-
enal (6a) To a solution of the epoxy dienal 5a (448 mg, 1.9 mmol) in dry
CH2Cl2 (12 ml) was added SnCl4 (1 M in CH2Cl2; 4.2 ml, 4.2 mmol) at 0 °C.
The mixture was stirred at 0 °C for 20 min and then poured into saturated aq.
(2E,4E,6E,8E,10E,12E)-2,7,11-Trimethyl-[(R)-1,2,2-trimethylcy-
clopentyl]-14-oxotetradeca-2,4,6,8,10,12-hexaenal (17) An acidic solu-
tion (4.0 ml) prepared from toluene-p-sulfonic acid (500 mg) and H3PO4
(725 mg) in MeOH (38 ml) and methyl orthoformate (4.0 ml) was added to a
NaHCO3 and extracted with ether. The extracts were washed with brine and solution of the phosphonium chloride 1817) (3.14 g, 7.0 mmol) in MeOH
dried. Evaporation of the solvent gave a residue, which was purified by flash (40 ml). The reaction mixture was stirred at rt for 3 h and neutralized with
CC (EtOAc–hexane, 2 : 8) to afford the cyclopentyl ketoaldehyde 6a (341
mg, 76%) as a pale yellow solid. Its 1H-NMR, IR and UV spectra were iden- to give a solution of the Wittig salt 19. To this solution was added a solution
tical with those of previous prepared9) racemic compounds. Enatiomeric ex-
of the aldehyde 6a (411 mg, 1.8 mmol) in MeOH (10 ml) and NaOMe (1.0 M
NaOMe (1.0 M in MeOH) until just before the red color of an ylide appeared
cess (84%) was determined by HPLC [CHIRALPAK AY-H (Daicel) 0.46ϫ in MeOH; 8 ml, 8 mmol) at rt. After stirring at rt for 1 h, Dowex 50W-X8
25 cm; 2-PrOH–hexane, 3 : 7; 1.0 ml/min]. [a]D25 Ϫ5.2 (cϭ0.99, EtOH). HR-
(Hϩ) (22 g) was added to the reaction mixture and this was stirred at rt for
20 min. After Dowex was filtered off, the filtrate was evaporated. The result-
EI-MS m/z: 234.1619 (Mϩ) (Calcd for C15H22O2: 234.1620).
[(R)-1,2,2-Trimethylcyclopentyl]methanol (12) To a solution of (ϩ)- ing residue was purified by flash CC (EtOAc–hexane–CH2Cl2, 0.3 : 5 : 5) and
(R)-camphonanic acid (11)13) (2.72 g, 14.8 mmol) in MeOH–benzene (ca.
1 : 4; 164 ml) was added TMSCHN2 (2 M in hexane; 11.4 ml, 22.8 mmol).
then PHPLC [LiChrosorb Si 60 (7 mm) 2ϫ25 cm; EtOAc–hexane, 13 : 87] to
provide all-E apocarotenal 17 (273 mg, 42%) and other isomeric mixture
After being stirred at rt for 30 min, solvent was evaporated off to give the (114 mg, 18%). A solution of this isomeric mixture in ether (10 ml) was left
corresponding methyl ester, which without purification, was dissolved in dry in the dark at rt overnight and the resulting mixture was purified again by
ether (15 ml) and this solution was added dropwise to a stirred suspension of
LiAlH4 (660 mg, 17.4 mmol) in dry ether at 0 °C. After being stirred at rt for
PHPLC to provide all-E apocarotenal 17 (46 mg, 7% from 6a). 1H-NMR
(500 MHz) d: 0.85, 1.11 and 1.18 (each 3H, s, gem-CH3, 5-CH3), 1.46—
25 min, the excess of LiAlH4 was decomposed by dropwise addition of 1.54 (2H, m) and 1.65—1.74 (3H, m) (2-H2, 3-H2, 4-H), 1.89 (3H, s, 13Ј-
water and the mixture was extracted with ether. The extracts were dried and CH3), 1.98 (3H, s, 9-CH3), 2.05 (3H, s, 13-CH3), 2.48—2.54 (1H, m, 4-H),
evaporated to give a residue, which was purified by flash CC (ether–hexane, 6.39 (1H, br d, Jϭ12 Hz, 14-H), 6.53 (2H, d, Jϭ15 Hz, 7-H, 12-H), 6.55
3 : 7) to afford the alcohol 12 (2.21 g, 89% from 11) as a colorless amor- (1H, br d, Jϭ11.5 Hz, 10-H), 6.74 (1H, dd, Jϭ14, 11.5 Hz, 15-H), 6.76 (1H,
phous solid. Its 1H-NMR data were identical with those reported.15) HR-
electrospray ionization (ESI)-MS m/z: 165.1251 [MϩH]ϩ (Calcd for
C9H18ONa: 165.1250).
dd, Jϭ15, 11.5 Hz, 11-H), 6.96 (1H, br d, Jϭ11 Hz, 14Ј-H), 7.02 (1H, dd,
Jϭ14, 11.5 Hz, 15-H), 7.32 (1H, d, Jϭ15 Hz, 8-H). 13C-NMR (125 MHz) d:
9.67 (13Ј-CH3), 12.96 and 13.06 (9-CH3, 13-CH3), 19.64 (C3), 20.85 (5-
(R)-1,2,2-Trimethylcyclopentanecarbaldehyde (13) To a solution of CH3), 24.59 and 25.60 (gem-CH3), 34.43 (C4), 40.48 (C2), 44.00 (C1),
alcohol 12 (1.80 g, 12.7 mmol) in CH2Cl2 (60 ml) was added DMP (7.52 g,
17.7 mmol) at 0 °C. After being stirred at rt for 1 h, the mixture was filtered
58.93 (C5), 122.36 (C7), 126.58 (C11), 128.68 (C15Ј), 133.13 (C14), 135.52
(C9), 137.17 (C15), 137.67 (C13Ј), 139.44 (C10), 140.59 (C12), 140.91
through Celite. Evaporation of the filtrate followed by purification by flash (C13), 145.97 (C8), 148.42 (C14Ј), 194.47 (CHO), 203.80 (C6). UV lmax
CC (ether–hexane, 15 : 85) provided the aldehyde 13 (1.01 g, 57%) as a col-
(EtOH) nm: 248, 316, 420, 442. IR (CHCl3) cmϪ1: 1663 (conj. CO and conj.
CHO), 1607 and 1572 (CϭC). HR-EI-MS m/z: 366.2561 (Mϩ) (Calcd for
C25H34O2: 366.2557).
Ethyl (2E/Z,4E)-3-Methyl-5-(2,6,6-trimethylcyclohexa-1,3-dienyl)-
penta-2,4-dienoate (22) A solution of the triethyl phosphonoacetate
1
orless amorphous solid (unstable and extremely volatile). Its H-NMR data
were identical with those reported.15) [a]D23 ϩ9.8 (cϭ0.50, CHCl3) {lit.15)
[a]D35 ϩ11.7 (cϭ0.52, CHCl3)}.
:
(2E,4E/Z)-6-(tert-Butyldimethylsilyloxy)-4-methyl-1-[(R)-1,2,2-
trimethylcyclopentyl]hexa-1,4-dien-1-ol (14) To a solution of the vinyl (14.16 g, 63.2 mmol) in dry THF (40 ml) was added dropwise to a stirred
iodide 1616) (4.70 g, 13.9 mmol) in dry ether (40 ml) was added tBuLi (1.55 M
in pentane; 9.8 ml, 15.3 mmol) at Ϫ78 °C. After being stirred for 20 min, a
solution of the aldehyde 13 (950 mg, 6.8 mmol) in dry ether (10 ml) was
added and stirring was continued for 40 min at Ϫ78 °C. After being
suspension of NaH (60% oil dispersion; 2.69 g, 67.4 mmol) in dry THF
(15 ml) at 0 °C. After being stirred at 0 °C for 20 min, a solution of the 3,4-
didehydro-b-ionone (21)18) (4.00 g, 21.1 mmol) in dry THF (10 ml) was
added to it. The reaction mixture was then warmed to 50 °C and stirring was

October 2010
1365
continued at the same temperature for 3 h. After being quenched by addition
of saturated aq. NH4Cl, the mixture was extracted with ether. The extracts
were washed with brine, dried and evaporated to give a residue, which was
purified by flash CC (ether–hexane, 7 : 93) to afford the ester 22 (4.46 g,
81%; 9E/Z ca. 85 : 15), a part of which was separated by PHPLC
[LiChrosorb Si 60 (7 mm) 2ϫ25 cm; ether–hexane, 1.5 : 98.5] to provide
each pure isomer as a pale yellow oil.
138.46 (C8), 140.33 (C10Ј), 141.70 (C12Ј), 146.40 (C8Ј), 203.82 (C6Ј). CD
(Et2O) nm (De): 208 (0), 223 (Ϫ4.6), 235 (0), 253 (ϩ4.8), 266 (0), 285
(Ϫ7.0), 294 (Ϫ7.9), 322 (0), 352 (ϩ1.7), 372 (0), 397 (Ϫ0.5). UV–vis lmax
(Et2O) nm: 284, 442, 467, 489. UV–vis lmax (EtOH) nm: 228, 288, 474. IR
(CHCl3) cmϪ1: 3466 (OH), 1657 (conj. CO), 1572, 1551 and 1515 (CϭC).
HR-EI-MS m/z: 568.4294 (Mϩ) (Calcd for C40H56O2: 568.4277).
3,4-Didehydroxy-3؅-deoxycapsanthin (2) To a solution of the phos-
phonium salt 24 (2.60 g, 4.8 mmol) and the all-E apocarotenal 17 (182 mg,
0.49 mmol) in MeOH (20 ml) was added NaOMe (1 M in MeOH; 6.0 ml,
6.0 mmol) at rt. After being stirred at rt for 1.5 h, Dowex 50 W-X8 (Hϩ)
(10 g) was added to the reaction mixture and this was stirred at rt for 5 min.
After Dowex was filtered off, the filtrate was evaporated. The resulting
residue was purified by flash CC (hexane–CH2Cl2–acetone, 6.5 : 3.25 : 0.25)
and then PHPLC (LiChrosorb Si 60 (7 mm) 2ϫ25 cm; hexane–Et2O, 95 : 5)
to provide 3,4-didehydroxy-3Ј-deoxycapsanthin (2) (77 mg, 28%) as a red
solid. The spectral data of synthetic 2 were in good agreement with those of
All-E Isomer: 1H-NMR (300 MHz) d: 1.03 (6H, s, gem-CH3), 1.29 (3H, t,
Jϭ7 Hz, CO2CH2CH3), 1.85 (3H, br s, 5-CH3), 2.09 (2H, dd, Jϭ4, 1.5 Hz, 2-
H2), 2.35 (3H, d, Jϭ1 Hz, 9-CH3), 4.18 (2H, q, Jϭ7 Hz, CO2CH2H3), 5.77
(1H, br s, 10-H), 5.78 (1H, dt, Jϭ9.5, 4 Hz, 3-H), 5.85 (1H, dt, Jϭ9.5, 1.5
Hz, 4-H), 6.22 (1H, d, Jϭ16 Hz, 8-H), 6.56 (1H, br d, Jϭ16 Hz, 7-H). UV
l
max (EtOH) nm: 259, 344. IR (CHCl3) cmϪ1: 1700 (conj. COO), 1608 (Cϭ
C). HR-ESI-MS m/z: 261.1848 [MϩH]ϩ (Calcd for C17H25O2: 261.1849).
1
9Z Isomer: H-NMR (300 MHz) d: 1.08 (6H, s, gem-CH3), 1.28 (3H, t,
Jϭ7 Hz, CO2CH2CH3), 1.93 (3H, br s, 5-CH3), 2.06 (3H, d, Jϭ1 Hz, 9-CH3),
2.09 (2H, dd, Jϭ4, 1.5 Hz, 2-H2), 4.16 (2H, q, Jϭ7 Hz, CO2CH2H3), 5.66
(1H, br s, 10-H), 5.78 (1H, dt, Jϭ9.5, 4 Hz, 3-H), 5.87 (1H, dt, Jϭ9.5, 1.5
Hz, 4-H), 6.59 (1H, br d, Jϭ16.5 Hz, 7-H), 6.78 (1H, d, Jϭ16.5 Hz, 7-H).
UV lmax (EtOH) nm: 259, 352. IR (CHCl3) cmϪ1: 1695 (conj. COO), 1608
(CϭC). HR-ESI-MS m/z: 261.1848 [MϩH]ϩ (Calcd for C17H25O2:
261.1849).
1
the reported2) natural product. H-NMR (500 MHz) d: 0.85 and 1.10 (each
3H, s, 1Ј-gem-CH3), 1.04 (6H, s, 1-gem-CH3), 1.18 (3H, s, 5Ј-CH3), 1.46—
1.58 (2H, m, 2Ј-H, 4Ј-H), 1.88 (3H, s, 5-CH3), 1.96 (3H, s, 9Ј-CH3), 1.98
(3H, s, 13Ј-CH3), 1.99 (6H, s, 9-CH3, 13-CH3), 2.08 (2H, dd, Jϭ4.5, 1.5 Hz,
2-H2), 2.52 (1H, m, 4Ј-H), 5.73 (1H, dd, Jϭ9.5, 4.5 Hz, 3-H), 5.85 (1H, dt,
Jϭ9.5, 1.5 Hz, 4-H), 6.20 (1H, br d, Jϭ11 Hz, 10-H), 6.20 (1H, br d,
Jϭ15.5 Hz, 7-H), 6.26 (1H, br d, Jϭ11 Hz, 14-H), 6.30 (1H, d, Jϭ15.5 Hz,
8-H), 6.35 (1H, br d, Jϭ11 Hz, 14Ј-H), 6.37 (1H, d, Jϭ15 Hz, 12-H), 6.48
(1H, d, Jϭ15 Hz, 7Ј-H), 6.52 (1H, d, Jϭ15 Hz, 12Ј-H), 6.55 (1H, br d,
Jϭ11 Hz, 10Ј-H), 6.61 (1H, dd, Jϭ15, 11 Hz, 11Ј-H), 6.62 (1H, dd, Jϭ14.5,
11.0 Hz, 15Ј-H), 6.69 (1H, dd, Jϭ15, 11 Hz, 11-H), 6.70 (1H, dd, Jϭ14.5,
11 Hz, 15-H), 7.32 (1H, d, Jϭ15 Hz, 8Ј-H). 13C-NMR (125 MHz) d: 12.69,
12.75, 12.87 and 12.89 (9-CH3, 13-CH3, 9Ј-CH3, 13Ј-CH3), 19.64 (C3Ј),
20.36 (5-CH3), 20.89 (5Ј-CH3), 24.60 and 25.63 (1Ј-gem-CH3), 26.81 (1-
gem-CH3), 34.00 (C1), 34.45 (C4Ј), 39.94 (C2), 40.51 (C2Ј), 43.98 (C1Ј),
58.89 (C5Ј), 121.41 (C7Ј), 124.16 (C11Ј), 124.95 (C3), 125.62 (C11),
125.76 (C7), 126.79 (C5), 129.72 (C15Ј), 130.00 (C4), 131.44 (C10), 131.58
(C15), 132.41 (C14), 133.79 (C9Ј), 135.12 (C14Ј), 135.94 (C13Ј), 136.35
(C9), 137.21 (C8), 137.38 (C12), 137.60 (C13), 138.68 (C6), 140.34 (C10Ј),
141.72 (C12Ј), 146.40 (C8Ј), 203.80 (C6Ј). CD (Et2O) nm (De): 247 (0),
270 (Ϫ0.7), 279 (0), 399 (ϩ1.4), 312 (ϩ1.7), 323 (0), 363 (Ϫ1.5), 400
(Ϫ0.3). UV–vis lmax (Et2O) nm: 313, 475. IR (KBr) cmϪ1: 1664 (conj. CO),
1551 and 1561 (CϭC). HR-EI-MS m/z: 550.4189 (Mϩ) (Calcd for C40H54O:
550.4172).
(2E/Z,4E)-3-Methyl-5-(2,6,6-trimethylcyclohexa-1,3-dienyl)penta-2,4-
dien-1-ol (23) A solution of the ester 22 (1.07 g, 4.1 mmol; 9E/Z ca.
85 : 15) in dry ether (10 ml) was added dropwise to a stirred suspension of
LiAlH4 (163 mg, 4.3 mmol) in dry ether at 0 °C. After being stirred at 0 °C
for 15 min, the excess of LiAlH4 was decomposed by dropwise addition of
water and the mixture was extracted with ether. The extracts were dried and
evaporated to give a residue, which was purified by flash CC (hexane–ace-
tone, 8 : 2) to give the alcohol 23 (868 mg, 96%; 9E/Z ca. 4 : 1) as a pale yel-
1
low oil. H-NMR (300 MHz) d (corresponding to 9E isomer): 1.01 (each
6H, s, gem-CH3), 1.29 (1H, br t, Jϭ6 Hz, OH), 1.84 and 1.87 (each 3H, br s,
5-CH3, 9-CH3), 2.08 (2H, dd, Jϭ4.5, 2 Hz, 2-H2), 4.32 (2H, br t-like,
Jϭ6 Hz, CH2OH), 5.66 (1H, tq, Jϭ7, 1 Hz, 10-H), 5.72 (1H, dt, Jϭ10,
4.5 Hz, 3-H), 5.85 (1H, dt, Jϭ10, 2 Hz, 4-H), 6.12 (1H, br d, Jϭ16 Hz, 7-H),
6.19 (1H, d, Jϭ16 Hz, 8-H). IR (CHCl3) cmϪ1: 3910 and 3449 (OH), 1626
(CϭC). HR-EI-MS m/z: 218.1674 (Mϩ) (Calcd for C15H22O: 218.1669).
Preparation of the Wittig Salt (24) A solution of alcohol 23 (868 mg,
4.0 mmol) and triphenylphosphine hydrobromide (1.37 g, 4.0 mmol) in
MeOH (35 ml) was stirred at rt for 48 h. Evaporation of the methanol gave a
residue, which was washed with ether to provide the crude phosphonium salt
24, which without purification, was used in next step.
3؅-Deoxycapsanthin (1) To a solution of the phosphonium salt 208,9)
(1.14 g, 2.0 mmol) and the all-E apocarotenal 17 (83 mg, 0.23 mmol) in
MeOH (15 ml) was added NaOMe (1.0 M in MeOH; 3.0 ml, 3.0 mmol) at rt.
After being stirred at rt for 3.5 h, Dowex 50 W-X8 (Hϩ) (5 g) was added to
the reaction mixture and this was stirred at rt for 5 min. After Dowex was fil-
tered off, the filtrate was evaporated. The resulting residue was purified by
flash CC (hexane–CH2Cl2–acetone, 6.5 : 3.25 : 0.5) and then PHPLC (COS-
MOSIL 5C18-MS-II 2ϫ25 cm; MeOH–EtOH, 3 : 1) to provide 3Ј-deoxycap-
santhin (1) (27 mg, 21%) as a red solid and isomeric mixture (25 mg). A so-
lution of this isomeric mixture in acetone (10 ml) was left in the dark at rt
for 4 d and the resulting mixture was purified again by PHPLC to provide 1
(8 mg, 6% from 17). The spectral data of synthetic 1 were in good agree-
References and Notes
1) For Part 11, see Yamano Y., Ito M., Wada A., Org. Biomol. Chem., 6,
3421—3427 (2008).
2) Maoka T., Akimoto N., Fujiwara Y., Hashimoto K., J. Nat. Prod., 67,
115—117 (2004).
3) Maoka T., Mochida K., Kozuka M., Ito Y., Fujiwara Y., Hashimoto K.,
Enjo F., Ogata M., Nobukuni Y., Tokuda H., Nishino H., Cancer Lett.,
172, 103—109 (2001).
4) Matsufuji H., Nakamura H., Chino M., Takeda M., J. Agric. Food
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5) Maoka T., Goto Y., Isobe K., Fujiwara Y., Hashimoto K., Mochida K.,
J. Oleo. Sci., 50, 663—665 (2001).
6) Hornero-Méndez D., de Guevara R. G.-L., Mínguez-Mosquera M. I., J.
Agric. Food Chem., 48, 3857—3864 (2000).
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1517—1524 (2001).
8) Yamano Y., Ito M., Chem. Pharm. Bull., 49, 1662—1663 (2001).
9) Yamano Y., Ito M., Org. Biomol. Chem., 5, 3207—3212 (2007).
10) The numbering system for carotenoids is used.
11) Vaz B., Domínguez M., Alvarez R., de Lera A. R., Chem. Eur. J., 13,
1273—1290 (2007).
12) Crombie B. S., Smith C., Varnavas C. Z., Wallace T. W., J. Chem. Soc.,
Perkin Trans. 1, 2001, 206—215 (2001).
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1993, 895—896 (1993).
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1478 (1981).
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(2003).
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6205—6208 (1992).
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63, 1473—1490 (1980).
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(2006).
1
ment with those of the reported2) natural product. H-NMR (500 MHz) d:
0.85 and 1.11 (each 3H, s, 1Ј-gem-CH3), 1.08 (6H, s, 1-gem-CH3), 1.18 (3H,
s, 5Ј-CH3), 1.48 (1H, t, Jϭ12 Hz, 2Hb), 1.50 (1H, m, 4Ј-Hb), 1.66—1.74
(3H, m, 2Ј-Hb, 3Ј-H2), 1.74 (3H, s, 5-CH3), 1.77 (1H, ddd, Jϭ12, 3.5, 2 Hz,
2-Ha), 1.96 (9Ј-CH3), 1.97 (6H, s, 9-CH3, 13Ј-CH3), 1.99 (3H, s, 13-CH3),
2.05 (1H, br dd, Jϭ16.5, 9.5 Hz, 4-Hb), 2.39 (1H, ddd, Jϭ16.5, 5, 1 Hz, 4-
Ha), 2.52 (1H, m, 4Ј-Ha), 4.00 (1H, m, 3-H), 6.11 (1H, br d, Jϭ16 Hz, 7-H),
6.14 (1H, d, Jϭ16 Hz, 8-H), 6.16 (1H, d, Jϭ11.5 Hz, 10-H), 6.26 (1H, br d,
Jϭ11.5 Hz, 14-H), 6.35 (1H, br d, Jϭ11.5 Hz, 14Ј-H), 6.36 (1H, Jϭ15.5 Hz,
12-H), 6.48 (1H, d, Jϭ15 Hz, 7Ј-H), 6.51 (1H, d, Jϭ14.5 Hz, 12Ј-H), 6.55
(1H, br d, Jϭ11.5 Hz, 10Ј-H), 6.61 (1H, dd, Jϭ14.5, 11.5 Hz, 11Ј-H), 6.62
(1H, dd, Jϭ14, 11.5, 15Ј-H), 6.67 (1H, dd, Jϭ15.5, 11.5 Hz, 11-H), 6.70,
(1H, dd, Jϭ14, 11.5 Hz, 15-H), 7.32 (1H, d, Jϭ15 Hz, 8Ј-H). 13C-NMR
(125 MHz) d: 12.75, 12.79, 12.87 and 12.89 (9-CH3, 13-CH3, 9Ј-CH3, 13Ј-
CH3), 19.63 (C3Ј), 20.87 (5Ј-CH3), 21.63 (5-CH3), 24.59 and 25.62 (1Ј-gem-
CH3), 28. and 30.27 (1-gem-CH3), 34.43 (C4Ј), 37.14 (C1), 40.49 (C2Ј),
42.57 (C4), 43.98 (C1Ј), 48.44 (C2), 58.88 (C5Ј), 65.10 (C3), 121.41 (C7Ј),
124.18 (C11Ј), 125.47 (C11), 125.83 (C7), 126.25 (C5), 129.74 (C15Ј),
131.24 (C10), 131.53 (C15), 132.40 (C14), 133.80 (C9Ј), 135.08 (C14Ј),
135.96 and 136.09 (C9, C13Ј), 137.41 (C12), 137.52 and 137.75 (C6, C13),
19) Acemoglu M., Eugster C. H., Helv. Chim. Acta, 67, 184—190 (1984).