Synthesis of (3S)- and (3R)-3-hydroxy-β-ionone and their transformation into (3S)- and (3R)-β- cryptoxanthin

Article abstract of DOI:10.1055/s-0030-1258382

(3S)- and (3R)-3-Hydroxy-β-ionone and (3S)- and (3R)-3-Hydroxy-β- ionone synthesized in high enantiomeric purity from commercially available () - ionone. These ionones were then transformed into (3R) - cryptoxanthin and (3S) - cryptoxanthin by a C₁₅+C₁₀+C₁₅ Wittig coupling strategy according to known methods. This methodology can considerably simplify the total synthesis of optically active carotenoids with 3-hydroxy - end groups that possess significant biological activities. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258382

PAPER
509
Synthesis of (3S)- and (3R)-3-Hydroxy-b-ionone and Their Transformation
into (3S)- and (3R)-b-Cryptoxanthin
Frederick Khachik,* An-Ni Chang1
Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA
Fax +1(301)3149121; E-mail: khachik@umd.edu
Received 17 October 2010; revised 24 November 2010
We have developed a relatively straightforward method-
ology for the synthesis of optically active 1a and its (3S)-
isomer 1b from ( )-a-ionone, and have utilized these syn-
thons in the total synthesis of 5a and 5b, respectively. This
Abstract: (3R)-3-Hydroxy-b-ionone and (3S)-3-hydroxy-b-ionone
were synthesized in high enantiomeric purity from commercially
available ( )-a-ionone. These ionones were then transformed into
(3R)-b-cryptoxanthin and (3S)-b-cryptoxanthin by a C15+C10+C15
Wittig coupling strategy according to known methods. This meth- process can considerably simplify the total synthesis of
odology can considerably simplify the total synthesis of optically
active carotenoids with 3-hydroxy-b-end groups that possess signif-
icant biological activities.
optically active carotenoids with 3-hydroxy-b-end
groups.
Common names, and the carotenoid numbering system,
have been used for compounds 1, 6, 7, and 9–13 to allow
comparison of their stereochemical transformations and
Key words: hydroxycarotenoids, carotenoid precursors, chiral res-
olution, stereoselective synthesis, Wittig reaction
spectroscopic data to those of compounds 5a and 5b. The
systematic names of these compounds are provided in the
experimental section.
(3R)-3-Hydroxy-b-ionone (1a) and (3S)-3-hydroxy-b-
ionone (1b) are two important intermediates in the synthe-
The first total synthesis of optically inactive (rac)-b-cryp-
toxanthin was reported in 1957 by Isler et al., who em-
ployed a 3-acetoxy-C19-aldehyde and a C21-alkyne to
construct this C40-carotenoid at the 15,15¢-position by a
Grignard reaction.8 However, a more practical total syn-
thesis was developed by Loeber et al., who prepared this
carotenoid from (rac)-3-hydroxy-b-ionone (1) via (rac)-
3-hydroxyvinyl-b-ionol (6) and (rac)-3-hydroxy-(b-io-
nylideneethyl)triphenylphosphonium bromide (7) as
shown in Scheme 1.9 The Wittig salt 7, which was pre-
pared in eight steps from 4-ethylenedioxy-2,2,6-trimeth-
ylcyclohexanone, was subsequently condensed with the
readily accessible 12¢-apo-b-caroten-12¢-al (8) to afford
(rac)-b-cryptoxanthin (5).
sis of carotenoids with b-end groups, such as
(3R,3¢R,6¢R)-lutein (2), (3R,3¢R)-zeaxanthin (3), (3R,3¢S;
meso)-zeaxanthin (4), (3R)-b-cryptoxanthin (5a), and
(3S)-b-cryptoxanthin (5b) (Figure 1). However, among
these carotenoids, only 2, 3, and 5a are present in most
fruits and vegetables commonly consumed in the USA.
These carotenoids accumulate in the human plasma and
major organs and exhibit antioxidant and anti-inflamma-
tory properties that are important for protection against
chronic diseases.2 While 4 is non-dietary and is absent in
human plasma and liver, it has been found in human ocu-
lar tissues as a metabolic byproduct of 2 and/or possibly
3.3 Experimental evidence to date suggests that accumula-
tion of 2–4 in human ocular tissues, particularly macula,
may protect this tissue against age-related macular degen-
eration (AMD), which is the leading cause of blindness in
the elderly.4 A range of dietary carotenoids, including 5a,
are present in human ciliary body that may protect this tis-
sue against ocular diseases such as presbyopia and glau-
coma by an antioxidant mechanism of action.5 Further,
inflammatory markers, such as C-reactive protein and fi-
brinogen, have also been linked to low serum levels of
5a.6 An in vitro study has also revealed a positive effect of
5a on increasing bone calcium and enhancing bone alka-
line phosphatase.7 In addition, 5a is a precursor of vitamin
A and can impart its biological activity in humans through
this function. In nature, (3R)-b-cryptoxanthin is among
the rare carotenoids and, consequently, its isolation from
natural products on an industrial scale is not commercially
viable.
The first total synthesis of optically active (3R)-3-hy-
droxy-(b-ionylideneethyl)triphenylphosphonium chloride
(7a) and its (3S)-isomer (7b) was reported in 1980 by
Rüttimann and Mayer.10 The key starting materials in this
synthesis were (3R)-3-hydroxy-b-cyclogeranial and (3S)-
3-hydroxy-b-cyclogeranial, which were each prepared in
five steps from 2,6,6-trimethyl-1,3-cyclohexadiene-1-car-
boxaldehyde (Safranal). These aldehydes were then con-
verted into (3R)-3-hydroxy-b-ionone (1a) and (3S)-3-
hydroxy-b-ionone (1b). In the following steps, the meth-
od of Loeber et al.9 was employed to transform these hy-
droxyionones into the Wittig salts 7a and 7b, which were
utilized in the total synthesis of (3R,3¢R)-zeaxanthin (3)
and (3R,3¢S; meso)-zeaxanthin (4) as well as their
(3S,3¢S)-stereoisomers.
Two additional processes for the technical synthesis of 3
via Wittig salt 7a were also developed a decade later by
the groups of Widmer and Soukup.11 These processes did
not involve 3-hydroxy-b-ionone as an intermediate and, in
SYNTHESIS 2011, No. 3, pp 0509–0516
x
x
.
x
x
.2
0
1
1
Advanced online publication: 23.12.2010
DOI: 10.1055/s-0030-1258382; Art ID: M07010SS
© Georg Thieme Verlag Stuttgart · New York

510
F. Khachik, A.-N. Chang
PAPER
O
3
HO
3-hydroxy-β-ionone (1)
1a: 3R, 1b: 3S
OH
OH
OH
3'
3'
3'
15
6'
13'
9'
9'
9'
9
13
15'
3
HO
(3R,3'R,6'R)-lutein (2)
15
13'
13
9
15'
3
HO
(3R,3'R)-zeaxanthin (3)
15
13'
13
9
15'
3
HO
(3R,3'S;meso)-zeaxanthin (4)
15
13'
9'
9
13
15'
3
HO
β-cryptoxanthin (5)
5a: 3R, 5b: 3S
Figure 1 3-Hydroxy-b-ionone, a precursor of carotenoids 2–5 with important biological activities
both cases, 4-hydroxy-2,2,6-trimethylcyclohexanone was pensive ( )-a-ionone via hydroxy acetal 11, keto acetal
employed as the key starting material. 10, and a-ionone acetal 9.
Our entire synthetic strategy is shown in Scheme 2. In To this end, as shown in Scheme 2, the carbonyl group of
contrast to the previous reported synthesis, we rational- ( )-a-ionone was first protected with ethylene glycol in
ized that optically active 1a and 1b could be separated by the presence of CH(OMe)3 and a catalytic amount of p-
enzymatic kinetic resolution of the racemic mixture via TsOH to afford the cyclic acetal 912 in nearly quantitative
(3R)-3-acetoxy-b-ionone (13). The preparation of (rac)-3- yield, which was used in the following step without puri-
hydroxy-b-ionone (1) could be accomplished from (rac)- fication. Acetal 9 was oxidized with t-BuOOH, household
3-hydroxy-a-ionone (12) by base-catalyzed isomeriza- bleach, and catalytic amounts of K2CO3 in acetonitrile at
tion. Hydroxyionone 12 could, in turn, be prepared in four –5→0 °C to give 3-keto acetal 10 in 83% isolated yield.
convenient steps from commercially available and inex- Although this reaction could be carried out in other sol-
OH
PPh3X
O
3
3
3
HO
HO
HO
7, X = Br
7a: 3R, 7b: 3S, X = Cl
1
6
1a: 3R, 1b: 3S
6a: 3R, 6b: 3S
15
13'
9'
13
OHC
6 steps
15'
8
O
15
O
13'
9'
13
9
O
15'
3
HO
β-cryptoxanthin (5)
5a: 3R, 5b: 3S
Scheme 1 Synthesis of (rac)-b-cryptoxanthin according to the method of Loeber et al.9
Synthesis 2011, No. 3, 509–516 © Thieme Stuttgart · New York

PAPER
(3S)- and (3R)-b-Cryptoxanthin from ( )-a-Ionone
511
O
O
HOCH2CH2OH
O
t-BuOOH, MeCN
6
6
6
O
O
3
bleach (5.25% NaOCl)
K2CO3, –5 to 0 °C, 83%
p-TsOH, r.t.
CH(OMe)3, 99%
O
( )-α-ionone
9
10
KB[CH(Me)Et]3H
TBME, –30 °C
0.3 M HCl
O
acetone, r.t.
KOH, MeOH, THF
50 °C, 1 h, 65%
O
O
6
6
O
3
3
3
86% from 10
HO
HO
HO
12
11
1 (46% from 9)
12a: 3,6-trans
12b: 3,6-cis
dr = 1.2
lipase PS, vinyl acetate
EtOAc, r.t., 20 h
49%
48%
O
O
KOH, MeOH
O
3
3
3
CH2Cl2, 0 °C, 99%
HO
AcO
HO
1a: 3R, er 98:2
1b: 3S, er 98:2
13
Scheme 2 Synthesis of 1a and 1b from ( )-a-ionone; carotenoid numbering system has been used for all precursors of 3-hydroxy-b-ionone
vents, such as ethyl acetate, ethylene glycol, and hexane, no selectivity with respect to the relative stereochemistry
the highest isolated yields were obtained with acetonitrile at C3 and C6. This was established from proton NMR
and ethanol. This water-based oxidation system, using chemical shifts of H3 and H6 in the diastereomers 12a and
household laundry bleach and aqueous t-BuOOH, has 12b. Nonetheless, among these reagents, K-Selectride™
been shown to convert steroidal olefins into a,b-enones by provided slightly higher ratio of the 3,6-trans- to the 3,6-
an economical and environmentally friendly methodolo- cis-isomer (12a/12b, 1.2), whereas with DIBAL-H, the
gy.13 While, this method has not been applied to the syn- diastereomeric ratio favored the 3,6-cis-isomer (12b/12a,
thesis of 10, similar methodologies for the oxidation of 1.9). In the following step, the base-catalyzed double
unprotected ( )-a-ionone to ( )-3-keto-a-ionone have bond isomerization of 12 to ( )-3-hydroxy-b-ionone (1)
been reported.14 It should be pointed out that such a direct was shown by HPLC to proceed much more readily with
and efficient synthesis of keto acetal 10 has not been re- the 3,6-trans-isomer than with the 3,6-cis-isomer. There-
ported previously. However, this compound has been ob- fore, K-Selectride™ was selected as the reagent of choice
tained as a side product in the synthesis of 3,3- for the transformation of 10 into 12 via 11.
ethylenedioxy-b-ionone from 3-keto-a-ionone.15
The base-catalyzed double-bond isomerization of 12 to
Keto acetal 10 was first reduced to (rac)-hydroxy-acetal ( )-1 was accomplished with methanolic potassium hy-
11, which, without isolation, was deprotected with 0.3N droxide (10% w/v) in THF at 50 °C, in 65% isolated yield
HCl to give (rac)-3-hydroxy-a-ionone (12). The reduc- after column chromatography. Up to this point, the overall
tion of 10 to 11 was carried out with a number of reagents yield of ( )-1 from ( )-a-ionone acetal 9 was 46%
in 57–90% yield; the results obtained after deprotection of (Scheme 2). In 1992, Broom et al. reported on the synthe-
11 in dilute HCl at room temperature are summarized in sis of ( )-3-hydroxy-b-ionone (1) from b-ionone.16 The
Table 1.
key starting material for this synthesis was 3,4-dehydro-b-
ionone, which was prepared from b-ionone according to a
published procedure.17 This ketone was then protected as
its 1,3-dioxolane to yield 3,4-dehydro-b-ionone acetal,
which was hydroborated with borane–dimethyl sulfide to
afford a mixture of 3-hydroxy-b-ionone acetal (75%) and
4-hydroxy-b-ionone acetal (25%). While the method of
Broom et al. provides an alternative route to ( )-1, it fails
to produce the optically active (3R)- or (3S)-stereoisomer
of this hydroxyionone.
Among these reducing agents, K-Selectride™, N-Selec-
tride™, and DIBAL-H, after deprotection, produced the
highest yield of 12. Because of the presence of two chiral
centers in 12, this key intermediate was formed as a race-
mic mixture of four stereoisomers (two pairs of enantio-
mers). In one pair of enantiomers, the hydroxy group at
C3 and the C6-enone side chain were trans with respect to
one another and, in the other pair, these groups were in a
cis geometry. The reduction of keto-acetal 10 with the re-
agents listed in Table 1, followed by deprotection, showed
Synthesis 2011, No. 3, 509–516 © Thieme Stuttgart · New York

512
F. Khachik, A.-N. Chang
PAPER
Table 1 Reduction of 10 to 11 Followed by Deprotection to 12
O
O
0.3 M HCl
acetone, r.t.
reagent
6
O
6
6
O
O
3
3
3
O
HO
HO
10
11
12a: 3,6-trans
12b: 3,6-cis
Entry
Reagentb
Solventc
Yield (%)
Ratioa
12a + 12b
12a/12b
1
2
3
4
5
6
7
8
K-Selectride™
N-Selectride™
9-BBN
TBME
TBME
THF
86
80
20
90
40
77
58
57
1.2:1
1:1.4
1:1.4
1:1.9
1:1.9
1:1
DIBAL-H·CH2Cl2
NaBH4–CeCl3·MeOH
CH2Cl2
MeOH
EtOH
NaBH4/dl-tartaric acid·EtOH
NaBH4
EtOH
1:1
NaAlH2(OCH2CH2OMe)2
TBME
1:1
a Indicates the stereochemical relationship between the hydroxy group at C3 and the enone side chain at C6.
b K-Selectride™ = KB[CHMeCH2CH3]3H; N-Selectride™ = NaB[CHMeCH2CH3]3H; 9-BBN = 9-borabicyclo[3.3.1]nonane; DIBAL-H = di-
isobutylaluminum hydride.
c TBME = tert-butyl methyl ether.
In the following step, (3R)-1a and (3S)-1b were separated treatment with HCl/Ph3P according to the reported proce-
by enzymatic kinetic resolution of the racemic mixture dure by Rüttimann and Mayer.10 All-E-(3R)-b-cryptoxan-
with immobilized lipase PS (Pseudomonas cepacia) in thin (5a) and its all-E-(3S)-enantiomer (5b) were prepared
ethyl acetate, in the presence of vinyl acetate, within 20 by condensation of all-E-12¢-apo-b-caroten-12¢-al19 (8)
hours at room temperature. While (3R)-1a was acylated to with Wittig salts (3R)-7a and (3S)-7b in refluxing ethanol
(3R)-3-acetoxy-b-ionone (13), (3S)-1b remained unreact- in the presence of 1,2-epoxybutane, respectively
ed (Scheme 2). Due to the large difference in their solubil- (Scheme 1). After low temperature crystallization from
ity properties, 13 and (3S)-1b were readily separated by dichloromethane and hexane, 5a and 5b were respectively
column chromatography. Acetoxyionone 13 was quanti- obtained in 70 and 64% isolated yield; each had an enan-
tatively hydrolyzed to (3R)-1a with methanolic potassium tiomeric ratio of 98:2. The optical purities of 5a and 5b
hydroxide at 0 °C to prevent degradation of this somewhat were established by chiral HPLC analysis and from their
sensitive 3-hydroxy-b-end group. According to chiral CD spectra (Figure 4), which showed opposite Cotton ef-
HPLC analysis, (3R)-1a and (3S)-1b were each obtained fects at various wavelengths.
in an enantiomeric ratio (er) of 98:2. The chiral HPLC
separation of a racemic mixture of 1a and 1b is shown in
Figure 2; this separation was used to determine the enan-
tiomeric purity of each isomer. Similar results were also
obtained by employing immobilized lipase AK
(Pseudomonas fluorescens) for resolution of 1a and 1b.
The absolute configuration of (3R)-1a and (3S)-1b was
determined by comparison of their CD spectra (Figure 3)
with that of a standard sample of (3R)-1a obtained from
oxidative cleavage of naturally occurring (3R,3¢R,6¢R)-
lutein according to our earlier publication.18 The CD spec-
tra of (3R)-1a and (3S)-1b showed opposite Cotton ef-
fects, which clearly indicated that these ionones were
enantiomeric.
In the following steps, hydroxyionones 1a and 1b were
separately converted into the all-E-Wittig salts 7a and 7b,
respectively. This was accomplished by conversion of
these ionones into vinyl-a-ionols 6a and 6b followed by
Figure 2 Chiral HPLC separation of a racemic mixture of 1a and 1b
Synthesis 2011, No. 3, 509–516 © Thieme Stuttgart · New York

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(3S)- and (3R)-b-Cryptoxanthin from ( )-a-Ionone
513
MeOH, 0.5%; 0.7 mL/min) with a silica-based nitrile bonded col-
umn (25 cm × 4.6 mm; 5 mm spherical particle; Waters Corpora-
tion, Milford, MA, USA). The column was protected with a
Brownlee nitrile bonded guard cartridge (3 cm × 4.6 mm; 5 mm par-
ticle size). This eluent was employed to determine the diastereomer-
ic ratios of (rac)-3,6-trans-3-hydroxy-a-ionone and (rac)-3,6-cis-3-
hydroxy-a-ionone (monitored at 226 nm) and based-catalyzed
isomerization of 12 to 1 (monitored at 226 nm and 286 nm). The op-
tical purity of 1a and 1b was assessed by chiral HPLC with a Chiral-
pak® AD column (25 cm × 4.6 mm; Chiral Technologies, Exton,
PA, USA) employing eluent B (hexane–isobutanol, 9:1). The opti-
cal purity of 5a and 5b was also determined on this column by em-
ploying eluent C (hexane–isopropanol, 39:1) with detection at
450 nm. The column packing consisted of amylose tris-(3,5-dime-
thylphenylcarbamate) coated on 10 mm silica gel substrate and the
Figure 3 CD spectra (hexane–Et2O–MeOH, 10:3:1) of hydroxy-
ionones 1a and 1b
column was protected with
a silica gel guard cartridge
(3 cm × 4.6 mm; 5 mm particle).
( )-(E)-4-(2,6,6-Trimethyl-2-cyclohexen-1-yl)-2,2-ethylene-
dioxy-3-butene (9)
Freshly distilled ( )-a-ionone (23 g, 0.1196 mol) in hexane (10 mL)
was treated with ethylene glycol (18 mL, 0.32 mol), trimethylortho-
formate (14 mL, 0.13 mol), and p-TsOH (0.29 g, 1.5 mmol), and the
mixture was stirred at r.t. under argon overnight. The progress of the
reaction was monitored by NMR analysis. The product was parti-
tioned between H2O (200 mL) and hexane (200 mL) and the organ-
ic layer was washed with H2O (2 × 200 mL), dried over Na2SO4,
and evaporated to give 9, which was used in the next step without
purification.
Figure 4 The CD spectra of (3R)-b-cryptoxanthin (5a) and (3S)-b-
cryptoxanthin (5b) in hexane–Et2O–MeOH, 10:3:1.
Yield: 29.7 g; pale-yellow oil.
1H NMR (400 MHz, CDCl3): d = 0.81 (s, 3 H), 0.88 (s, 3 H), 1.17
(m, 1 H), 1.41 (dd, J = 13.2, 7.9 Hz, 1 H), 1.47 (s, 3 H), 1.57 (m,
3 H), 1.99 (m, 2 H), 2.11 (d, J = 9.7 Hz, 1 H), 3.86 (m, 2 H), 3.96
(m, 2 H), 5.38 (d, J = 15.4 Hz, 1 H), 5.40 (s, 1 H), 5.61 (dd, J = 15.4,
9.7 Hz, 1 H). These NMR data were in agreement with the pub-
lished data.12
In summary, we have developed a convenient methodolo-
gy for the synthesis of (3R)-3-hydroxy-b-ionone and its
(3S)-stereoisomer in high optical purity from commercial-
ly available ( )-a-ionone. This relatively straightforward
process can facilitate the total synthesis of optically active
dietary carotenoids with (3R)-3-hydroxy-b-end groups,
while the (3S)-isomer can serve as a precursor in the total
synthesis of (3R,3¢S; meso)-zeaxanthin, which is not of
dietary origin but is present in human ocular tissues. This
carotenoid is presumably formed in human eye tissues as
( )-(E)-4-(4-Oxo-2,6,6-trimethyl-2-cyclohexen-1-yl)-2,2-ethyl-
enedioxy-3-butene (10)
To a solution of 9 (29.7 g) from the preceding experiment, dissolved
in MeCN (105 mL, 82.5 g, 2.00 mol), was added K2CO3 (1.8 g, 13
mmol) and the mixture was cooled in an ice–salt bath to 0 °C under
argon. A solution of t-BuOOH (70% in H2O, 108 mL, 97.2 g; 70% =
68.0 g, 0.755 mol) was added dropwise to the mixture under N2 at
0 °C in 30 min. Household bleach containing 5.25% NaOCl (356 g,
18.69 g NaOCl, 0.251 mol) was then added over a period of 8 h at
–5 to 0 °C. After the addition was complete, the reaction mixture
was stirred at 0 °C for an additional 1 h. The product was treated
with NaHCO3 (2 g) at 0 °C and then extracted with hexane (3 × 150
mL). The organic layer was washed with H2O (3 × 150 mL), dried
over Na2SO4, and evaporated to give a pale-yellow oil (30.3 g). The
crude product was purified by column chromatography (hexane–
EtOAc, 98:2→85:15) to yield 10.
a
result of metabolic transformation of dietary
(3R,3¢R,6¢R)-lutein and/or (3R,3¢R)-zeaxanthin, which
have been implicated in the prevention of age-related
macular degeneration.3–5
All chemicals and reagents were commercially available and were
obtained from Aldrich Chemical Co. (St. Louis, MO). Lipase PS
(Pseudomonas cepacia) and lipase AK (Pseudomonas fluorescens)
were purchased from Amano Enzyme USA (Lombard, IL). Column
chromatography purifications were carried out on n-silica gel
Yield: 24.6 g (98.2 mmol, 83%); pale-yellow oil.
1
(Merck 100–200 mesh). H NMR spectra were recorded with a
1H NMR (400 MHz, CDCl3): d = 0.94 (s, 3 H), 1.01 (s, 3 H), 1.45
(s, 3 H), 1.87 (m, 3 H), 2.07 (d, J = 16.6 Hz, 1 H), 2.32 (d,
J = 16.6 Hz, 1 H), 2.53 (d, J = 9.3 Hz, 1 H), 3.83 (m, 2 H), 3.96 (m,
2 H), 5.55 (d, J = 15.4 Hz, 1 H), 5.70 (dd, J = 15.4, 9.3 Hz, 1 H),
5.89 (d, J = 0.7 Hz, 1 H). The proton NMR data were in agreement
with literature values.15
13C NMR (100 MHz, CDCl3): d = 23.3, 25.0, 27.0, 27.8, 36.0, 47.5,
54.9, 64.4, 106.9, 125.9, 127.6, 134.9, 161.3, 198.9.
HRMS (ESI+): m/z [M + H]+ calcd for C15H22O3: 251.16417; found:
251.16500.
Bruker DRX-400 MHz spectrometer with CDCl3 (d = 7.27 ppm) as
1
internal standard. H decoupled 13C NMR spectra were recorded
with a Bruker DRX-400 MHz at 100 MHz, with chloroform (d =
77.0 ppm) as an internal standard. High-resolution mass spectra
(HRMS) were obtained with a JEOL AccuTOF CS mass spectrom-
eter (ion source: ESI; needle voltage: 2300 V; flow rate: 100 mL/
min; desolvation chamber temperature: 250 °C; data acquisition
time: 2 min). Circular dichroism (CD) was measured with a JASCO
(Model J810) instrument in hexane–Et2O–MeOH (10:3:1). The
course of most reactions were monitored by HPLC with photodiode
array detection employing eluent A (hexane–CH2Cl2, 75:25 +
Synthesis 2011, No. 3, 509–516 © Thieme Stuttgart · New York

514
F. Khachik, A.-N. Chang
PAPER
(rac)-(E)-4-(4-Hydroxy-2,6,6-trimethyl-2-cyclohexen-1-yl)-3-
buten-2-one (12a and 12b) from 10 via (rac)-(E)-4-(4-hydroxy-
2,6,6-trimethyl-2-cyclohexen-1-yl)-2,2-ethylenedioxy-3-butene
(11)
g, 4.70 mmol, 59%) in a diastereomeric ratio of 12a/12b of 1:1.9
and a combined isolated yield of 90% from 10.
(rac)-(E)-4-(4-Hydroxy-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-
buten-2-one (1) [( )-3-hydroxy-b-ionone]
Reduction of 10 with K-Selectride™
A solution of 10 (15 g, 59.92 mmol) in TBME (100 mL) was cooled
to –30 °C under argon and a solution of K-Selectride™ (1 M in
THF, 80 mL, 80 mmol) was added dropwise in 30 min. The mixture
was stirred at –30 °C for 1 h and then treated with NaOH (3 N,
50 mL) followed by H2O2 (30%, 50 mL). After stirring at r.t. for
30 min, the product was washed with H2O (2 × 200 mL), dried over
Na2SO4 and evaporated to give a yellow oil (15.50 g). The residue
was dissolved in acetone (100 mL) and H2O (50 mL), and the mix-
ture was stirred with HCl (0.3 N, 6 mL) at r.t. for 30 min. The prod-
uct was extracted with EtOAc (2 × 150 mL), washed with saturated
NaHCO3 (200 mL) and H2O (200 mL), and dried over Na2SO4. Af-
ter solvent evaporation, a yellow oil (12 g) was obtained, which was
shown by HPLC (eluent A) and NMR analysis to consist of two
fractions. The fractions were separated by column chromatography
(hexane–acetone, 95:5→85:15) and identified as (rac)-3,6-trans-3-
hydroxy-a-ionone (12a) and (rac)-3,6-cis-3-hydroxy-a-ionone
(12b) in a diastereomeric ratio of 1.2:1 and a combined isolated
yield of 86% from 10.
A solution of 12a/12b (1.2:1, 5.5 g, 26.40 mmol) in THF (20 mL)
was treated with a solution of KOH in MeOH (10% wt./vol, 1.5 mL)
under argon. The mixture was heated to 50 °C for 1 h and the prod-
uct was partitioned between H2O (50 mL) and EtOAc (50 mL). The
organic layer was washed with H2O (3 × 50 mL), dried over
Na2SO4, and evaporated to give a yellow oil (5.13 g). The product
was purified by column chromatography (hexane–EtOAc,
98:2→90:10) to give a yellow oil, which was identified as ( )-3-hy-
droxy-b-ionone (1).
Yield: 3.57 g (17.14 mmol, 65%).
UV/Vis (EtOH): lmax = 290 nm.
1H NMR (400 MHz, CDCl3): d = 1.11 (s, 3 H), 1.12 (s, 3 H), 1.25
(s, 1 H), 1.49 (t, J = 12.0 Hz, 1 H), 1.77 (s, 3 H), 1.80 (dd, J = 2.0,
3.6 Hz, 1 H), 2.09 (dd, J = 9.5, 17.5 Hz, 1 H), 2.30 (s, 3 H), 2.43
(dd, J = 5.6, 17.5 Hz, 1 H), 4.00 (m, 1 H), 6.11 (d, J = 16.5 Hz,
1 H), 7.21 (d, J = 16.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.6, 27.3, 28.5, 30.0, 36.9, 42.7,
48.4, 64.5, 132.3, 135.6, 142.3, 198.6. The NMR data were in agree-
ment with published values.10,20
12a
Yield: 5.8 g (27.84 mmol, 47%).
HRMS (ESI+): m/z [M + H]+ calcd for C13H20O2: 209.15360; found:
209.15120.
UV/Vis (hexane): lmax = 226 nm.
1H NMR (400 MHz, CDCl3): d = 0.89 (s, 3 H), 1.03 (s, 3 H), 1.41
(dd, J = 13.5, 6.4 Hz, 1 H), 1.53 (s, 1 H), 1.62 (m, 3 H), 1.84 (dd,
J = 13.5, 5.9 Hz, 1 H), 2.26 (s, 3 H), 2.50 (d, J = 10.2 Hz, 1 H), 4.27
(m, 1 H), 5.63 (m, 1 H), 6.10 (d, J = 15.6 Hz, 1 H), 6.54 (dd,
J = 15.6, 10.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 22.6, 24.6, 27.2, 29.3, 33.8, 43.8,
54.3, 65.4, 125.8, 133.6, 135.4, 135.2, 147.1, 198.1. The NMR data
were in agreement with published values.20
Enzymatic Kinetic Resolution of ( )-3-Hydroxy-b-Ionone (1)
with Lipase PS (Pseudomonas cepacia)
To a solution of ( )-1 (3.30 g, 15.84 mmol) in EtOAc (25 mL) was
added immobilized lipase PS (pseudomonas cepacia) (5.0 g) and vi-
nyl acetate (1.0 mL, 0.934 g, 10.85 mmol). The mixture was stirred
at r.t. under argon and the course of the enzymatic acylation was
monitored by chiral HPLC (eluent B). After 20 h, the mixture was
filtered through Celite and the filtrate was evaporated to give a
yellow oil (4.0 g). Column chromatography (hexane–EtOAc,
98:2→80:20) of the product gave two major fractions. The first
fraction was identified as (3R)-3-acetoxy-b-ionone (13), the second
fraction was identified as (3S)-3-hydroxy-b-ionone (1b).
HRMS (ESI+): m/z [M]+ calcd for C13H20O2: 208.31640; found:
208.31310.
12b
Yield: 4.8 g (23.04 mmol, 39%)
UV/Vis (hexane): lmax = 226 nm.
(3R)-3-Acetoxy-b-ionone (13)
Yield: 1.90 g (7.6 mmol, 48%).
1H NMR (400 MHz, CDCl3): d = 0.87 (s, 3 H), 0.96 (s, 3 H), 1.39
(dd, J = 12.9, 9.8 Hz, 1 H), 1.61 (t, J = 1.5 Hz, 3 H), 1.68 (dd,
J = 12.9, 6.5 Hz, 1 H), 1.92 (s, 1 H), 2.25 (s, 3 H), 2.26 (d,
J = 9.6 Hz, 1 H), 4.24 (m, 1 H), 5.58 (s, 1 H), 6.06 (d, J = 15.9 Hz,
1 H), 6.63 (dd, J = 15.9, 9.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 22.3, 26.9, 29.0, 34.9, 40.6, 54.2,
66.3, 126.4, 132.6, 134.0, 135.2, 147.8, 198.5.
UV/Vis (EtOH): lmax = 288 nm.
CD: 306 (–3.01 mdeg), 271 nm (+2.24 mdeg).
1H NMR (400 MHz, CDCl3): d = 1.08 (s, 3 H), 1.12 (s, 3 H), 1.23
(s, 1 H), 1.57 (t, J = 12.2 Hz, 1 H), 1.74 (s, 3 H), 1.77 (dd, J = 12.2,
3.5 Hz, 1 H), 2.02 (s, 3 H), 2.12 (dd, J = 17.1, 9.3 Hz, 1 H), 2.27 (s,
3 H), 2.47 (dd, J = 17.1, 6.0 Hz, 1 H), 5.02 (m, 1 H), 6.09 (d,
J = 16.4 Hz, 1 H), 7.17 (d, J = 16.4 Hz, 1 H).
HRMS (ESI+): m/z [M]+ identical to that of 12a.
13C NMR (100 MHz, CDCl3): d = 21.3, 27.3, 28.3, 29.7, 36.3, 38.6,
43.9, 67.6, 131.3, 132.5, 135.6, 141.8, 170.6, 198.3.
Reduction of 10 with DIBAL-H
A solution of 10 (2.0 g, 7.99 mmol) in CH2Cl2 (15 mL) was cooled
to –30 °C under argon and a solution of DIBAL-H (1 M in CH2Cl2,
14 mL, 14 mmol) was added over 15 min. The mixture was stirred
at –30 to –20 °C for 1 h then quenched by adding H2O (30 mL) at
–10 °C followed by silica gel (2 g). The product was allowed to
warm to r.t. and stirred for 1 h. The mixture was filtered through
Celite and CH2Cl2 was removed under reduced pressure. The resi-
due was dissolved in acetone (20 mL) and H2O (10 mL) and was
stirred with HCl (0.3 N, 0.8 mL) at r.t. for 30 min. The product was
extracted with EtOAc (2 × 50 mL), washed with saturated NaHCO3
(100 mL), and dried over Na2SO4. After solvent evaporation, the
residue was purified by column chromatography (hexane–acetone,
95:5→85:15) to yield 12a (0.52 g, 2.50 mmol, 31%) and 12b (0.98
HRMS (ESI+): m/z [M]+ calcd for C15H22O3: 250.15635; found:
250.15760.
This fraction was dissolved in CH2Cl2 (30 mL) and stirred with
KOH/MeOH (5.5 mL, 10% wt/v) for 2 h at 0 °C. The product was
treated with 0.3 N HCl (23 mL) to bring the mixture to pH 5. The
organic layer was sequentially washed with a saturated NaHCO3
(50 mL) and H2O (2 × 30 mL), and dried over Na2SO4. After solvent
evaporation, a yellow oil (1.56 g, 7.5 mmol, 99%) was obtained,
1
which was identified by H and 13C NMR, CD, and chiral HPLC
(eluent B) analyses as (3R)-3-hydroxy-b-ionone (1a) (er 98:2).
CD: 310 (–2.98 mdeg), 270 nm (+2.87 mdeg).
Synthesis 2011, No. 3, 509–516 © Thieme Stuttgart · New York

PAPER
(3S)- and (3R)-b-Cryptoxanthin from ( )-a-Ionone
515
(3S)-3-Hydroxy-b-ionone (1b)
identified as all-E-(3R)-b-cryptoxanthin (5a). The NMR, CD, and
UV/Vis spectra of 5a were identical to those of a standard sample
of this carotenoid reported in our earlier publication.21 The product
was shown by chiral HPLC (Eluent C) to have an enantiomeric ratio
of 98%.
1
The second fraction was identified by H and 13C NMR, CD, and
chiral HPLC (eluent B) analyses as (3S)-3-hydroxy-b-ionone (1b)
(er 98:2).
Yield: 1.60 g (7.7 mmol, 49%)
Yield: 0.66 g (1.20 mmol, 70%); mp 134–136 °C.
CD: 311 (3.20 mdeg), 273 nm (–3.59 mdeg). The CD spectra of 1a
and 1b were in agreement with literature values.10
UV/Vis (EtOH): lmax = 450 nm.
CD: 342 (+0.88 mdeg), 286 (–4.13 mdeg), 248 (+2.65 mdeg),
222 nm (–2.80 mdeg).
(3R)-3-Hydroxy-(b-ionylideneethyl)triphenylphosphonium
Chloride (7a) from (3R)-3-Hydroxy-b-ionone (1a) via (3R)-3-
Hydroxy-vinyl-b-ionol (6a)
1H NMR (400 MHz, CDCl3): d = 1.04 (s, 6 H), 1.08 (s, 6 H), 1.47
(m, 2 H), 1.61–1.65 (m, 2 H), 1.72 (s, 3 H), 1.75 (s, 3 H), 1.78 (dd,
J = 12.1, 3.5 Hz, 2 H), 1.98 (s, 12 H), 2.02 (t, J = 6.2 Hz, 1 H), 2.07
(d, J = 9.8 Hz, 1 H), 2.40 (dd, J = 16.8, 5.3 Hz, 1 H), 4.01 (m, 1 H),
6.08–6.21 (m, 6 H), 6.26 (d, J = 6.3 Hz, 2 H), 6.37 (dd, J = 14.9,
3.6 Hz, 2 H), 6.60–6.70 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 12.8, 19.3, 21.6, 21.8, 28.7, 29.0,
30.3, 33.1, 34.3, 37.1, 39.7, 42.6, 48.5, 65.1, 124.9, 125.1, 125.5,
126.2, 126.7, 129.4, 129.9, 130.1, 130.8, 131.3, 132.4, 132.7, 135.6,
136.1, 136.4, 136.6, 137.2, 137.6, 137.8, 137.9, 138.5.
A solution of 1a (1.20 g, 5.76 mmol) in toluene (20 mL) was cooled
to –20 °C under argon and treated with a solution of vinyl magne-
sium bromide (1 M in THF, 14 mL, 14 mmol) over 30 min. The
mixture was stirred at –20 °C for 1 h and the reaction was quenched
by addition of saturated NH4Cl (15 mL) and stirred at r.t. for 10 min.
The product was extracted with EtOAc (2 × 50 mL) and, after the
usual work up, crude 6a (1.10 g) was dissolved in MeOH (7 mL)
and directly used without purification in the next step.
Triphenylphosphine hydrochloride was prepared fresh by adding
concentrated HCl (0.62 mL) to Ph3P (1.82 g, 6.94 mmol) in MeOH
(7 mL) at 0 °C. The salt was stirred at r.t. for 20 min and then treated
with a solution of 6a (1.10 g) in MeOH (7 mL) at 0 °C and stirred
for 1 h at this temperature. After stirring at r.t. overnight, the prod-
uct was partitioned between hexane (30 mL) and MeOH–H2O (1:1,
30 mL). The aqueous layer was washed with hexane (2 × 30 mL) to
remove the excess Ph3P and the aqueous layer was extracted with
CH2Cl2 (2 × 30 mL). The organic layer was washed with H2O
(2 × 30 mL), dried over Na2SO4, and evaporated to give the crude
product (1.96 g), which was crystallized from 1,2-dichloroethane
and EtOAc at –20 °C and dried under high vacuum to give 7a.
HRMS (ESI+): m/z [M]+ calcd for C40H56O: 552.43257; found:
552.42000.
all-E-(3S)-b-Cryptoxanthin (5b)
12¢-Apo-b-caroten-12¢-al19 (8; 0.60 g, 1.71 mmol) was allowed to
react with (3S)-3-hydroxy-(b-ionylideneethyl)triphenylphosphoni-
um chloride (7b; 1.00 g, 1.93 mmol) in the presence of 1,2-epoxy-
butane (2 mL) under reflux in EtOH (15 mL) in a manner similar to
the procedure described above. After work-up and crystallization,
all-E-(3S)-b-cryptoxanthin (5b) was obtained as a red solid that was
shown by chiral HPLC (Eluent C) to have an enantiomeric ratio of
98%. The 1H, 13C NMR, UV/Vis, and HRMS analyses of 5b were
identical to those of 5a.
Yield: 1.79 g (3.46 mmol, 60%).
UV/Vis (EtOH): lmax = 268 nm.
CD: 279 nm (–4.07 mdeg).
1H NMR (400 MHz, CDCl3): d = 0.95 (s, 3 H), 0.97 (s, 3 H), 1.34
(d, J = 4.2 Hz, 3 H), 1.42 (t, J = 12.1 Hz, 1 H), 1.60 (s, 3 H), 1.73
(dd, J = 12.1, 3.47 Hz, 1 H), 1.99 (dd, J = 16.8, 9.5 Hz, 1 H), 2.16
(s, 1 H), 2.32 (dd, J = 16.8, 4.9 Hz, 1 H), 3.94 (m, 1 H), 4.95 (m,
1 H), 5.34 (dd, J = 14.3, 6.9 Hz, 1 H), 5.90 (s, 2 H), 7.66 (m, 6 H),
7.77 (m, 3 H), 7.87 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 12.7, 21.4, 24.4, 24.9, 28.5, 30.1,
36.8, 42.3, 48.0, 64.6, 113.3, 113.4, 117.9, 118.7, 126.8, 127.6,
127.7, 130.1, 130.3, 133.8, 133.9, 134.8, 134.9, 136.2, 136.3, 136.8,
143.5, 143.6. The NMR data were in agreement with published val-
ues.10
Yield: 0.60 g (1.10 mmol, 64%).
CD: 342 (–1.08 mdeg), 284 (+4.12 mdeg), 248 (–2.78 mdeg),
224 nm (+2.85 mdeg).
References
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(3S)-3-Hydroxy-(b-ionylideneethyl)triphenylphosphonium
Chloride (7b) from (3S)-3-Hydroxy-b-ionone (1b) via (3S)-3-
Hydroxy-vinyl-b-ionol (6b)
Employing the same procedure described above, 1b (1.20 g, 5.76
mmol) was transformed into 7b (1.64 g, 3.17 mmol, 55%). The 1H
and 13C NMR spectra of this Wittig salt were identical with those of
7a.
UV/Vis (EtOH): lmax = 268 nm.
CD: 281 nm (+6.43 mdeg).
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(9) Loeber, D. E.; Russell, S. W.; Toube, T. P.; Weedon, B. C.
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Synthesis 2011, No. 3, 509–516 © Thieme Stuttgart · New York