Novel synthesis of the allene moiety of carotenoids via biomimetic photosensitized oxygenation

Article abstract of DOI:10.1016/S0040-4039(01)01405-8

A novel synthesis of the allene moiety of carotenoids was achieved by the regioselective ene reaction of the vinyl hydrogen rather than the allyl hydrogen of the significantly twisted 1,3-dienes, (3R)-alkoxy-cis-β-ionol derivative, followed by selective a

Full text of DOI:10.1016/S0040-4039(01)01405-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7307–7310
Novel synthesis of the allene moiety of carotenoids via
biomimetic photosensitized oxygenation
Masayuki Nakano, Noriyuki Furuichi, Hajime Mori and Shigeo Katsumura*
School of Science, Kwansei Gakuin University, Uegahara 1-1-155, Nishinomiya, Hyogo 662-8501, Japan
Received 30 May 2001; revised 5 July 2001; accepted 27 July 2001
Abstract—A novel synthesis of the allene moiety of carotenoids was achieved by the regioselective ene reaction of the vinyl
hydrogen rather than the allyl hydrogen of the significantly twisted 1,3-dienes, (3R)-alkoxy-cis-b-ionol derivative, followed by
selective allyl rearrangement. © 2001 Elsevier Science Ltd. All rights reserved.
Among more than 600 natural carotenoids,1 a consider-
able number possesses 3,5-dihydroxy-1,1,5-trimethyl-
cyclo-hexylideneallene (carotenoid numbering) moiety
in one terminal. This characteristic allene structure can
be found in C40 carotenoids represented by neoxanthin,
mimulaxanthin and fucoxanthin, in C37 carotenoid,
peridinin, and in C31 paracentrone. As the acceptable
biogenetic occurrence of this particular moiety, an iso-
abstracted the vinyl hydrogen Ha rather than the allyl
hydrogen Hb to produce the corresponding allene 3 in
good yield, and its relative configuration between the
C-5 allyl hydroxy group and the C-8 vinyl hydrogen
was the same as that of the natural allene carotenoids
(Scheme 1).5 This one-step pathway to produce the
allene moiety from the twisted 1,1,5-trimethylcyclohex-
enylvinyl derivatives would be considered a possible
biomimetic route, because the mechanism of the ene
merization
of
the
3-hydroxy-5,6-epoxypolyene
(carotenoid numbering) such as voilaxanthin has been
proposed.2 Meanwhile, in the syntheses of allene
carotenoids and their metabolic small molecule,
grasshopper ketone,3 intramolecular SN2% hydride
reduction of the 3-hydroxy-5,6-epoxyacetylene deriva-
tive (carotenoid numbering) is the only method estab-
lished for the stereocontrolled synthesis on the C-5
hydroxy group and the C-8 allene hydrogen of the
1
reaction with O2 through the intermediary perepoxide,
which has generally been accepted,6 can be regarded to
be equivalent to the two-step biogenetic pathway of the
allene moiety, which involves epoxidation of the tetra-
substituted double bond of the polyolefin derivatives
followed by isomerization to the allene moiety.2 In
order to realize the possible biomimetic synthesis of the
allene moiety in carotenoids by utilizing our own novel
5-hydroxy-1,1,5-trimethylcyclohexylideneallene
func-
1
allene formation with O2, we have to overcome the
tion (carotenoid numbering), although the satisfactory
stereocontrol between the 3-hydroxy group and the
5,6-epoxy function has not been achieved (Fig. 1).4
problems caused by the presence of the C-3 OH group.
The one problem is the creation of diastereomers due to
the C-3 and C-9 asymmetric carbons, in addition to the
rotational isomers in the precursor for 1O2 oxygenation,
compound 8. Another is the unknown influence on
Previously, we found that in an ene reaction of signifi-
cantly twisted 1,3-diene 1, singlet oxygen preferentially
OH
O
H
•
1
3
5
OH
HO
Neoxanthin
Allene Segment A
Figure 1.
Keywords: allene carotenoids; biomimetic reaction; twisted diene.
* Corresponding author. Tel.: +81-798-54-6381; fax: +81-798-51-0914; e-mail: katumura@kwansei.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01405-8

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M. Nakano et al. / Tetrahedron Letters 42 (2001) 7307–7310
H
Ha
Ha
1) 1O2
OH
8
•
-
+
O
O
OTES
OTES
OH
5
2) P(OEt)3
3) TBAF
Hb
Hb
3 (63 %)
2
1
Scheme 1.
both the conformations of the cyclohexene ring in 8 for
1O2 ene reaction and of the cyclohexylidene ring in 11a
for the chemoselective allyl rearrangement of the C-9
synthesis. In the present paper, we disclose a novel
synthesis of the enantiomerically pure allene segment A
by utilizing a new, the second, and, moreover, a
biomimetic method.
1
tertiary hydroxy group resulting from the O2 oxygena-
tion. Achievement of the biomimetic synthesis of this
particular allene moiety is, therefore, very attractive
and significant subject as an another route for the
The synthesis was started from enantiomerically pure
vinyltriflate 4.4f Cross-coupling of 4 with a tin acetylide
OEE
OTf
b, c, d
a
O
TBDPSO
TBDPSO
TBDPSO
7
4
6
H
OH
9
1
g, h
•
e, f
OH
3
+
OH
TESO
5
HO
OH
TBDPSO
HO
8
10
9a/b
OEE
5
Bu3Sn
H
H
9
OH
OH
•
•
i
+
9a/b
OH
3
OH
TBDPSO
TBDPSO
11a
11b
H
H
R
OAc
9
•
j
k, l
•
11a
OH
R
OH
HO
14 : R = CH2OH
A : R = CHO
12 : R = H
13 : R = OTBDPS
m
Scheme 2. Reagents and conditions: (a) 5, Pd(PPh3)4, LiCl, abs. DMF, 60°C, 3 h, then 10% NH3 aq, 89%; (b) 2N aqueous H2SO4,
THF, rt, 5 h, quant.; (c) H2, Lindlar catalyst (0.5% Pb poisoned), n-hexane, rt, 21 h, 96%; (d) Jones reagent, acetone, rt, 15 min,
then 10% NaHSO4 aq, 89%; (e) vinyl magnesium bromide, THF, 65°C, 1 h, 85%; (f) Et3SiCl, DMAP, Et3N, DMF, 35°C, 40 h,
96%; (g) O2, TPP, P(OEt)3, h, CH2Cl2, 0°C, 4 h, then P(OEt)3, rt, 1 h; (h) TBAF, THF, rt, 24 h, 60% for 9a/b, and 31% for 10
from 8; (i) TBDPSCl, imidazole, DMF, rt, 40 h, 27% for 11a, and 33% for 11b from 8; (j) Ac2O, AcOH, rt, 18 h, 77%
(9E/9Z=4/1); (k) 10% KOH aq, THF–MeOH (1:1), rt, 2 h, 87% (9E/9Z=4/1); (l) TBAF, THF, rt, 60 h, 81%; (m) MnO2,
acetone, rt, 2 h, 78% then HPLC purification.

M. Nakano et al. / Tetrahedron Letters 42 (2001) 7307–7310
7309
derivative 5 catalyzed by palladium in the presence of
LiCl in DMF gave 6 in 89% yield (Scheme 2). Then,
selectivereductionoftheethynylgrouptothecorrespond-
ing cis-olefin with the freshly prepared Lindlar catalyst
(0.5% Pb poisoned), deprotection, and then oxidation
with Jones reagent produced ketone 7. The reaction of
7 with vinylmagnesium bromide in THF at 65°C, followed
by introduction of the triethylsilyl group to the hydroxy
group thus obtained to produce the key intermediate,
(3R)-alkoxy-cis-b-ionol derivative 87 in 67% overall yield
as a mixture of diastereomers and rotamers. Photosensi-
tized oxygenation of the resulting mixture in the presence
of P(OEt)3 followed by desilylation gave the desired allene
triol 9a and its diastereomer 9b in 60% yield for three steps
as an inseparable mixture along with exomethylene 10
(31% yield). Selective silylation at the C-3 hydroxy group
of the obtained mixture of 9a and 9b produced a mixture
of the corresponding allene diol 11a8,9 and 11b, respec-
tively, which were separable with column chromatogra-
phy on silica gel. Thus, 11a and 11b were obtained as a
diastereomericmixtureduetotheC-9asymmetriccarbon,
respectively. The selectivity attributable to the C-3 posi-
tion of 8 in the photosensitized oxygenation was not
observed, and the ratio between 11a and 11b was 1 to
Yamano of Kobe College for Pharmacy for their identifi-
cation of our synthesized allene compound A with their
1
compound by taking H NMR.
References
1. Straub, O. In Key to Carotenoids 2nd Edn; Pfander, H.;
Gerspacher, M.; Rychener, M.; Schwabe, R., Eds.;
Birkhauser: Basel, 1987.
2. Carotenoids, Vol. 3; Biosynthesis and Metabolism; Britton,
G.; Liaaen-Jensen, S.; Pfander, H., Ed.; Birkhauser: Basel,
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3. (a) Baumeler, A.; Brade, W.; Haag, A.; Eugster, C. H. Helv.
Chim. Acta 1990, 73, 700; (b) Bjornland, T.; Englert, G.;
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Hlubucek, J. R.; Hora, J.; Russell, S. W.; Toube, T. P.;
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(b) Pfander, H.; Traber, B.; Lanz, M. Pure Appl. Chem.
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Soc., Perkin Trans. 1 1995, 1895; (d) Ito, M.; Yamano, Y.;
Sugiya, S.; Wada, A. Pure Appl. Chem. 1994, 66, 939; (e)
Yamano, Y.; Ito, M. Chem. Pharm. Bull. 1994, 42, 410; (f)
Yamano, Y.; Ito, M. J. Chem. Soc., Perkin Trans. 1 1993,
1599; (g) Ito, M. Pure Appl. Chem. 1991, 63, 13; (h)
Baumeler, A.; Eugster, C. H. Helv. Chem. Acta 1991, 74,
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1988, 71, 931.
1
1.2 in the H NMR spectrum.
In order to realize the regio- and stereoselective allyl
rearrangement of the hydroxy group in the side-chain of
11a, dehydroxy derivative 3 was used as a model com-
pound. Treatment of 3 with sodium p-toluenesulfinate,
which is commonly used for allyl rearrangement,10 gave
the corresponding allyl sulfone along with its Z isomer
in 40% yield (E:Z=5:1). Meanwhile, acid treatment were
also investigated under various trials, and we finally found
that treatment of 3 with 1 equiv. of acetic anhydride in
acetic acid successfully produced the desired 12 in 68%
yield as a sole stereoisomer. The stereoselectivity of this
rearrangement may be attributed to the [2,3] sigmatoropic
rearrangement of the allyl acetate. Then, treatment of 11a
with the same reaction conditions successfully produced
the desired allyl acetate 13 in 77% yield as a 4:1 mixture
5. (a) Mori, H.; Ikoma, K.; Isoe, S.; Kitaura, K.; Katsumura,
S. J. Org. Chem. 1998, 63, 8704; (b) Mori, H.; Ikoma, K.;
Katsumura, S. Chem. Commun. 1997, 2243; (c) Mori, H.;
Ikoma, K.; Masui, Y.; Isoe, S.; Kitaura, K.; Katsumura,
S. Tetrahedron Lett. 1996, 37, 7771.
1
(by H NMR) of the inseparable stereoisomers at C-9
double bond. Compound 13 was transformed into the
separable aldehyde A11 by deprotection of both the acetyl
and silyl groups, and then oxidation. The physical and
spectraldataofthesynthesizedallenecompound A, which
was purified by HPLC,12 were in good agreement with
those reported4a [mp 181–183°C; [h]2D1 −60.7 (c 0.52,
MeOH), literature, mp 178–179°C; [h]2D2 −63.0 (c 0.5,
MeOH)].
6. (a) Stephenson, L. M. Tetrahedron Lett. 1980, 21, 1005; (b)
Stephenson, L. M.; Grdina, M. B.; Orfanopoulos, M. Acc.
Chem. Res. 1980, 13, 419.
7. Compound 8 obtained was a mixture of diastereomers at
the C-3 and C-9 asymmetric carbons, and this compound
also exists as a mixture of rotamers. The 1H NMR spectrum
of the mixture showed complex signals even at 65°C; EI+
HRMS found m/z 588.3828, calcd for C37H56O2Si2 M+
588.3816.
1
In conclusion, we established a novel method for the
synthesis of the allene moiety in allene carotenoids by
utilizing the biomimetic photosensitized oxygenation,
which involved the selective ene reaction of the vinyl
hydrogen in preference to the allyl hydrogens with singlet
oxygen.
8. Data for 11a: H NMR (400 MHz, CDCl3) (diastereomer
mixture) l 7.69 (m, 4H), 7.39 (m, 6H), 5.93 (dd, 1H, J=17.3,
10.5 Hz), 5.32 (s, 1H), 5.26 (dd, 1H, J=17.3, 1.2 Hz), 5.05
(dd, 1H, J=10.7, 1.2 Hz), 4.29 (m, 1H), 2.13 (ddd, 1H,
J=13.2, 4.1, 2.2 Hz), 1.64 (ddd, 1H, J=12.6, 4.0, 2.2 Hz),
1.50 (dd, 1H, J=13.2, 11.0 Hz), 1.36 (s, 3H), 1.34 (dd, 1H),
1.30 (s, 3H), 1.08 (s, 9H), 0.96 (s, 3H), 0.95 (s, 3H); 13C
NMR (100 MHz, CDCl3) l 196.67, 143.79, (135.79, 135.76),
(134.60, 134.49), 129.52 (127.49, 127.47), 118.77, 111.88,
101.93, 72.50, 72.11, 65.80, 49.56, 49.06, 35.21, 32.05, 31.31,
28.82, 27.83, 27.01, 19.13; EI+ HRMS found m/z 490.2919,
calcd for C31H42O3Si M+ 490.2901.
Acknowledgements
We thank Professor Masayoshi Ito and Dr. Yumiko

7310
M. Nakano et al. / Tetrahedron Letters 42 (2001) 7307–7310
9. The stereochemistry of 11a and 11b could not be deter-
6.08 (s, 1H), 5.94 (brdq, 1H, J=8.1, 1.2 Hz), 4.33 (m,
1H), 2.29 (ddd, 1H, J=13.1, 4.2, 2.2 Hz), 2.16 (d, 3H,
J=1.2 Hz), 1.98 (ddd, 1H, J=12.6, 4.1, 2.2 Hz), 1.38 (s,
3H), 1.37 (s, 3H), 1.32–1.48 (m, 2H), 1.10 (s, 3H); 13C
NMR (100 MHz, CDCl3) l 204.86, 190.84, 153.60,
127.19, 119.03, 102.06, 72.66, 63.97, 49.20, 48.84, 36.03,
31.90, 31.11, 29.14, 14.25; EI+ HRMS found m/z
250.1577, calcd for C15H22O3 M+ 250.1567.
mined in this step. Then, these were transformed into
the corresponding triol 14 and its diastereomer, the
absolute configuration of which was determined by com-
parison with the reported optical rotation value and
spectral data,4a respectively.
10. (a) Julia, M.; Arnould, D. Bull. Chem. Soc. Chim. Fr.
1973, 2, 746; (b) Chabardes, P.; Pecor, J. P.; Varagnat,
J. Tetrahedron 1997, 33, 2799 and references cited
therein.
12. Preparative high-performance liquid chromatography
(HPLC) was carried out on JASCO PU-1580 instru-
ments with UV–vis detector, UV-1570 on Develosil CN-
UG-5 column (0.6×25 cm) with isopropanol/hexane=
11. Data for A: mp 181–183°C; [h]2D1 −60.7 (c 0.52, MeOH);
1
IR (NaCl Nujol, cm−1) 3876, 3344, 2344, 1928, 1662; H
NMR (400 MHz, CDCl3) l 10.03 (d, 1H, J=8.1 Hz),
3/7 as the mobile phase, flow=1.0 ml min−1
.