Synthesis of labile all-trans-7,8,7′,8′-bis-acetylenic carotenoids by bi-directional Horner-Wadsworth-Emmons condensation

Article abstract of DOI:10.1039/c4ob02144d

A new stereoselective synthesis of the C₄₀-bis-acetylenic carotenoids all-trans-(3R,3′R)-alloxanthin and all-trans-3,4,7,8,3′,4′,7′,8′-octadehydro-β,β-carotene, both compounds featuring a stereochemically labile C7-C10 enyne, based on a bi-directional Horner-Wadsworth-Emmons (HWE) reaction of a C₁₅-phosphonate and a central C₁₀-dialdehyde, is reported. The triene unit of the latter fragment was synthesized using the acyclic metathesis/dimerization reaction.

Full text of DOI:10.1039/c4ob02144d

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Synthesis of labile all-trans-7,8,7’,8’-bis-acetylenic
carotenoids by bi-directional Horner–
Wadsworth–Emmons condensation†
Cite this: Org. Biomol. Chem., 2015,
13, 3024
Belén Vaz,* Noelia Fontán, Marta Castiñeira, Rosana Álvarez* and Ángel R. de Lera*
A new stereoselective synthesis of the C40-bis-acetylenic carotenoids all-trans-(3R,3’R)-alloxanthin and
all-trans-3,4,7,8,3’,4’,7’,8’-octadehydro-β,β-carotene, both compounds featuring a stereochemically labile
C7–C10 enyne, based on a bi-directional Horner–Wadsworth–Emmons (HWE) reaction of a C15-phos-
phonate and a central C10-dialdehyde, is reported. The triene unit of the latter fragment was synthesized
using the acyclic metathesis/dimerization reaction.
Received 8th October 2014,
Accepted 13th January 2015
DOI: 10.1039/c4ob02144d
www.rsc.org/obc
of catalytic quantities of iodine.11 In particular, the C2-sym-
metrical all-trans-7,8,7′,8′-bis-acetylenic compounds undergo
Introduction
Carotenoids1 are naturally occurring pigments ubiquitously complete isomerization under these conditions forming exclu-
present in plants and in other photosynthetic organisms.2,3 sively the 9Z,9′Z isomers. Extensive isomerization of the
They play multiple roles in Nature,4 most importantly in C9–C10 double bond has also been reported to take place on
photosynthesis and photoprotection, and hold potential as attempts to synthesize these compounds using condensation
disease chemopreventive agents in humans by acting as anti- reactions12–14 or palladium-catalyzed cross-coupling pro-
oxidants.5 All these functions are causally linked to the pres- cesses.15 Within the first group, however, a modification of the
ence of a central polyene chain that empowers carotenoids classical (non-stereoselective) Wittig condensation that uses
with unmatched light absorption and radical quenching instead tri-n-butyl phosphoranes, has led to the formation
features.6 Arguably the polyenic nature of these compounds is of polyenes with improved trans stereoselectivity, including
a synthetic challenge since building the desired stereoisomer (3R,3′R)-alloxanthin 1.16
faces the intrinsic sensitivity of the intermediates and the final
product under the reaction conditions.7 Synthetic methodo-
We have explored the same bidirectional approach (a C15 +
C
10 + C15 = C40 condensation scheme)1,7 to C2-symmetrical bis-
logies designed towards the total synthesis of carotenoids acetylenic carotenoids and found that the scarcely used1
must consider how to progress within these constrains and Horner–Wadsworth–Emmons (HWE) reaction17–20 of two C15-
overcome the shortcomings of previous strategies.
phosphonate anions with a central C10-dialdehyde is an
The acetylenic (7,8-didehydro) carotenoids,8 which contain equally efficient synthetic procedure. We exemplify the finding
one or two alkynes at the C7–C8 position, constitute a small with the new stereoselective synthesis of (3R,3′R)-alloxanthin 1
(over 20 members) subgroup within this family of polyterpe- and the first synthesis of the highly unsaturated
noids.9,10 Even though the all-trans are, with a few exceptions, 3,4,7,8,3′,4′,7′,8′-octadehydro-β,β-carotene
2
(Fig. 1). In
the exclusive stereoisomers found in Nature, the acetylenic addition, we report a new preparation of the C10-dialdehyde,
carotenoids are considered the stereochemically most labile based on the acyclic metathesis/dimerization21–23 of precursor
members of this family of natural products due to their pro- functionalized dienes.
pensity to isomerize to the more stable 9-cis isomers. Stereo-
mutation at the C7–C10 enyne moiety to afford the 9-cis
isomers has been reported to occur rapidly upon irradiation of
Results and discussion
solutions of all-trans-7,8-acetylenic carotenoids in the presence
Due to the prevalence of an intact polyene on the central
Department of Organic Chemistry and Center for Biomedical Research (CINBIO),
region of most C40-carotenoids, the use of symmetrical difunc-
tionalized building blocks (such as the C10-dialdehyde, Fig. 1)
simplifies the synthetic approaches to these compounds.
IBIV, Universidade de Vigo, 36310 Vigo, Spain. E-mail: qolera@uvigo.es;
Fax: +34 986 818622; Tel: +34 986 812316
†Electronic supplementary information (ESI) available: This includes general
Thus, various practical syntheses have been developed over the
years to access these functionalized fragments.7 A selection of
experimental procedures, alternative synthesis of dialdehyde 8a, and copies of
13C- and 1H-NMR spectra of key compounds. See DOI: 10.1039/c4ob02144d
3024 | Org. Biomol. Chem., 2015, 13, 3024–3031
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Fig. 1 Strategy for the synthesis of C2-symmetric acetylenic caroten-
oids using a double HWE reaction.
Scheme 1 Reagents and conditions: a. CHI3, NaH, Et2O, reflux, 20 h,
60%. b. KOH, EtOH–H2O, reflux, 24 h, 69%. c. TMSCHN2, MeOH,
benzene, 25 °C, 5 min, 89%. d. LiAlH4, THF, 25 °C, 2 h, 47%. e. MnO2,
Et2O,
0 °C, 5 h, 76%. f. TBDMSCl, imidazole, DMF, 25 °C, 1 h,
77%. g. Pd2(dba)3, AsPh3, NMP, 25 °C, 2 h, 81% 7a, 97% 7b, 76% 7c, 50%
7d. i. DIBAL-H, THF, from −78 to −20 °C. j. MnO2, Na2CO3, acetone, 97%
(two steps).
with functionalized terminal conjugated dienes that differ in
the nature of the functional group (7a–d) was surveyed.
The synthesis of these dienes started with the known (E)-3-
iodo-2-methacrylic acid 4 obtained from diethyl 2-methyl-
malonate 3 by the reaction of the enolate with iodoform and
subsequent decarboxylation/elimination.29,30 Ester formation
using trimethylsilyldiazomethane in MeOH afforded 5a, and
reduction of 4 with LiAlH4 gave (E)-3-iodo-2-methylprop-2-en-1-
ol 5b. Protection of 5b by treatment with TBDMSCl and imid-
azole provided 5c, whereas its oxidation with MnO2 afforded
aldehyde 5d (Scheme 1). Stille cross-coupling of iodides (5a–d)
with commercial tributylvinylstannane 6 under Farina’s con-
ditions31 provided the corresponding terminal dienes 7.
The metathesis–dimerization reaction was first carried out
using Grubbs’ second-generation catalyst in CH2Cl2, at 25 or
50 °C.32 As shown in Table 1, the outcome of the reaction was
found to depend on the nature of the diene functional group.
In most of the cases, the desired triene product was
accompanied by dienes 9 (Table 1, entries 1, 3 and 4), resulting
from the cleavage of the trisubstituted double bond of the
starting diene and subsequent cross-metathesis with 7, and 10
(entries 8–10), generated by the alternative cross-metathesis
with styrene (formed from the ruthenium precatalyst), as well
as by partially recovered starting dienes.
Fig. 2 Summary of the synthetic methodologies employed for the syn-
thesis of the C10-dialdehyde.
the routes followed for the preparation of the C10-dialdehyde
are summarized in Fig. 2. The first approach24 relied on a
double Mukaiyama condensation of an enol ether and a bis-
acetal followed by hydrolysis and elimination. The industrial
route developed by BASF25 was based on a double HWE reac-
tion of the C4-bis-phosphonate with pyruvic aldehyde
dimethylacetal, and deprotection. Alternatively, the Wittig con-
densation of a C5-phosphonium salt and a C5-aldehyde fol-
lowed by hydrolysis was also employed in the industrial
setting.26 A more recent synthesis of the C10-dialdehyde is
based on the Ramberg–Bäcklund reaction of diallylsulphones
and deprotection.27
As an alternative, we have explored a new approach to this
triene-dialdehyde based on the metathesis reaction of pre-
cursor dienes. We21,22 and others28 have previously found that
the acyclic metathesis/dimerization of hexaenes is a valuable
method for the synthesis of highly conjugated polyenes such
as the carotenoids, since it takes place with high chemo-
selectivity (a preference for the metathesis of the terminal
monosubstituted olefin vs. the di-, tri- and tetrasubstituted
ones). In the case of the C10-trienedialdehyde, we expected a
similar selectivity, but concerns about the effect of the func-
tional group(s) on the metathesis reaction remained. Conse-
quently the performance of the common metathesis catalysts
Treatment of 7d with Grubbs’ second-generation catalyst in
CH2Cl2 at room temperature for 5 h led to C10-dialdehyde 8d
albeit in poor yield (12%), accompanied by minor amounts of
diene 9d and a reactant (entry 1). Due to the problems encoun-
tered with the dienal we decided to carry out the reaction at
the alcohol oxidation stage. Since the conditions that had
been successful before for hexaenes21,22 (entry 2) gave dis-
appointing yields, the reaction was performed at room tempera-
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Table 1 Optimization of conditions for the homometathesis/dimerization reaction of functionalized dienes 7a–d
Entry
R
Conditions
8a–d
9a–d
10a–d
7a–d
1
2
3
4
5
6
7
8
CHO (7d)
Grubbs II (5 mol%), CH2Cl2, 25 °C, 5 h.
Grubbs II (5 mol%), CH2Cl2, 50 °C, 6.5 h.
Grubbs II (5 mol%), CH2Cl2, 25 °C, 7 h.
Grubbs II (4 mol%), CuI (6 mol%) Et2O, 25 °C, 7.5 h.
Grubbs II (5 mol%), CH2Cl2, 50 °C, 6.5 h.
Grubbs II (5 mol%), CH2Cl2, 25 °C, 6.5 h.
Grubbs II (5 mol%), CH2Cl2, 25 °C, 6 h.
Grubbs II (10 mol%), CH2Cl2, 25 °C, 6.5 h.
Grubbs II (10 mol%), CH2Cl2, 25 °C, 22 h.
Grubbs II (15 mol%), CH2Cl2, 25 °C, 6.5 h.c
Hoveyda–Grubbs (15 mol%), CH2Cl2, 25 °C, 8.5 h.
12%
Trace
34%
20%
—
Tracea
—
16%
21%
—
—
—
—
—
—
—
—
—
—
—
—
4%
8%
18%
—
Trace
16%b
34%
13%
—
—
37%
9%
CH2OH (7b)
CH2OH (7b)
CH2OH (7b)
CH2OTBDMS (7c)
CH2OTBDMS (7c)
CO2Me (7a)
CO2Me (7a)
CO2Me (7a)
CO2Me (7a)
CO2Me (7a)
—
24%
59%
52%
64%
66%
9
10
11
Trace
11%
—
—
—
a Mixture of diene 9d, triene 8d and starting material. b Mixture of isomers. c Catalyst degradation was observed.
ture, and this modification led to the desired product in 34% in 97% combined yield (10% overall yield for the seven-steps
yield, although the conversion was incomplete (13% starting sequence, Scheme 1; for larger scale approaches to 8d, see
material was recovered) and the undesired diene 9b was also Scheme 5 below).41,42
obtained in 21% yield (entry 3). Using CuI as a cocatalyst,33
The synthesis of the C15 fragment required for the synthesis
which is considered to play a beneficial role as a catalyst activa- of alloxanthin 1 started from the known terminal alkyne
tor (offering in addition faster rates and avoiding chlorinated 1616,43,44 derived from (−)-actinol 1145 by a modified pro-
solvents), did not improve the results. The desired triene 8b cedure. Treatment of the tert-butyldimethylsilyl ether of
was obtained in only 20% yield, together with similar amounts (−)-actinol 12 in the presence of LDA with N-phenyltrifluoro-
of diene 9b (21%, entry 4). The presence of the silyl ether was methanesulfonimide (Tf2NPh) gave the enoltriflate 13,46 which
detrimental and the expected product was not detected even underwent a Sonogashira coupling with TMS-acetylene to
when the reaction was carried out at room temperature afford alkyne 14. Subsequent silyl deprotection followed by
(entries 5 and 6).
acetylation afforded acetate 1616,43,44 in good yield. Sono-
Fortunately, the yields increased when 7a and higher gashira coupling of alkyne 16 with diethyl (E)-3-iodobut-2-enyl-
amounts of the catalyst (between 10 mol% and 15 mol%) were phosphonate 18, which was prepared from vinyliodide 17 in
used (entries 7–10). In these cases, we did not detect the pres- 84% yield following the procedure of Wiemer,47 provided the
ence of diene 9a in the reaction mixture probably due to the desired phosphonate 19 in 73% yield. The overall yield for the
electronic deactivation of the trisubstituted double bond of the six-step synthesis of phosphonate 19 from (−)-actinol 11 was
substrate.34,35 The more robust Hoveyda–Grubbs catalyst36 led 45% (Scheme 2).
to a slight increase in yield (66%) and higher selectivity since
An analogous sequence allowed the preparation of
side products were not isolated (entry 11). In all cases, the phosphonate 24 required for the synthesis of 3,4,7,8,3′,4′,7′,8′-
trienes were obtained as the most stable trans isomers with
these catalysts (recent procedures with modified catalysts,
however, allow the homo- and cross-coupling of (E)-1,3-dienes
to (E,Z,E)-trienes37–39).
A parallel study on the cross-metathesis of electron-deficient
polyenes (up to four double bonds) has recently been pub-
lished by Sammakia et al.40 These authors likewise obtained
unsatisfactory results with dienals (poor selectivity for the
terminal alkenes regardless of the catalyst), but also with
dienoic esters (conversion to unidentified by-products). The
reasons behind the contrasting results obtained with dienoates
in both settings are unclear at this moment, but it is worth
mentioning that Sammakia found that lower or higher vinylo-
gous substrates (acrylate or trienoate analogues) afforded excel-
Scheme 2 Reagents and conditions: a. TBDMSCl, imidazole, DMF,
25 °C, 6 h, 98%. b. LDA, Tf2NPh, THF, −78 to 0 °C, 14 h, 87%. c. TMS-
acetylene, K2CO3, Pd(PPh3)4, DMF, 60 °C, 95%. d. n-Bu4NF, THF, 25 °C,
lent yields using the less-reactive first-generation Grubbs catalyst.
To complete the synthesis of the C10-dialdehyde, treatment
of trienoate 8a with DIBAL-H followed by oxidation of the
trienol 8b with MnO2 under basic conditions afforded 8d 85 °C, 16 h, 84%. g. Pd(PPh3)4, CuI, Et3N, THF, 25 °C, 4 h, 73%.
2.5 h, 99%. e. Ac2O, pyridine, 25 °C, 14 h, 77%. f. ZnI2, P(OEt)3, THF,
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under mild conditions (MeLi, Et2O, −15 °C) into all-trans-
(3R,3′R)-alloxanthin 1 in 78% (combined) yield.
All-trans-3,4,7,8,3′,4′,7′,8′-octadehydro-β,β-carotene
2
has
been isolated, admixed with the 9Z and 9Z,9′Z isomers, from
the euglenophyte alga Euglena viridis,49 and from the sponge
Polymastia granulosa.50 The NMR spectroscopic data of our
synthetic 3,4,7,8,3′,4′,7′,8′-octadehydro-β,β-carotene 2 could not
be compared with the existing 1H-NMR literature data, since
these are reported in CDCl3.49 In our experience traces of acid
formed adventitiously when this solvent is used with these
polyenes rapidly catalyze the stereomutation of the all-trans to
the thermodynamically more stable (9Z,9′Z)-7,8,7′,8′-bis-acety-
lenic carotenoid isomer. To ensure that the geometry of the
synthetic product 2 was the desired one, and that the reaction
conditions had not induced the formation of the thermodyna-
mically more stable (9Z,9′Z) stereoisomer or of a mixture of
isomers, as is commonly found in substrates endowed with
the C7–C10 enyne skeleton (for example, pyrrhoxanthin15),
NOE correlations in C6D6 solution (shown in ESI†) demon-
strated that carotenoid 2 had been acquired with total
stereocontrol.
Alloxanthin 1 was the first acetylenic carotenoid isolated
from dinoflagellates of the algal class Cryptophyceae.51
Chromatographic comparison of natural extracts from micro-
algae Rhodomonas lens containing alloxanthin in its lipophilic
pigment signature, with the synthetic (3R,3′R)-alloxanthin
described in this work (Fig. 3) provided additional proof of the
all-trans geometry of the synthetic carotenoid, also confirmed
by NOE correlations (see ESI†). The first synthesis of this
xanthophyll employed a bi-directional Wittig condensation of
C10-dialdehyde 8d and C15-tri-triphenylphosphoranes and
afforded in low yield (7%) a mixture of the all-trans and 9-cis
isomers in roughly equal amounts.14 The recent approach to
(3R,3′R)-alloxanthin 1 using a bi-directional Wittig conden-
sation of C10-dialdehyde 8d and analogous C15-tri-n-butyl-
phosphoranes16 was, similar to the HWE reported here, also
stereoselective.
Scheme 3 Reagents and reaction conditions: a. iPr2NH, nBuLi, HMPA;
then Tf2NPh, THF, 66%. b. TMS-acetylene, K2CO3, Pd(PPh3)4, DMF,
93%. c. TBAF, 40 min, 25 °C, 79%. d. Pd(PPh3)4, CuI, Et3N, THF, 25 °C,
66%.
octadehydro-β,β-carotene 2. The transformation of 2,2,6-tri-
methylcyclohex-2-en-1-one 20 into dienyl triflate 2148 and the
subsequent Sonogashira coupling to TMS-acetylene followed
by deprotection of the alkyne provided the C11 terminal
alkyne 23. The C15-phosphonate was prepared by a second
Sonogashira coupling reaction of 23 with phosphonate 18,
which produced 24 as a single stereoisomer (Scheme 3).
Finally, the bi-directional HWE reaction between two units
of appropriate C15-phosphonates 19 or 24 and C10-dialdehyde
8d was performed using NaHMDS in THF, and led to the
expected (3R,3′R)-diacetylalloxanthin and 3,4,7,8,3′,4′,7′,8′-octa-
dehydro-β,β-carotene 2 (Scheme 4). The former was converted
Fig. 3 HPLC chromatogram obtained from the mixture of a natural
extract and a sample of synthetic (3R,3’R)-alloxanthin 1. The method
was run in a C8 monomeric column using aqueous pyridine as a mobile
phase modifier, showing the co-elution of natural and synthetic allox-
anthin (26.2 min). The inset shows also the chromatograms obtained
from the synthetic carotenoid (top) and the natural extract (bottom)
under the same chromatographic method.
Scheme 4 Reagents and conditions: a. NaHMDS, THF, −78 °C, 1 h, 47%
for 2. b. MeLi, Et2O, −15 °C, 30 min, 78% for 1 (two steps).
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afforded 0.58 g (84%) of a colorless oil identified as diethyl
Summary and conclusions
1
(E)-(3-iodobut-2-en-1-yl)phosphonate 18. H-NMR (400.13 MHz,
3
The HWE condensation reaction using a synthetic scheme CDCl3): δ 6.11 (dtq, J = 6.5, 1.4 Hz, JH–P = 8.0, 1H, H2),
based on a C15 + C10 + C15 pattern has been demonstrated to 4.14–3.96 (m, 4H, 2 × CO2CH2CH3), 2.49 (ddd, J = 8.0, 1.0 Hz,
5
be a powerful tool for the preparation of the configurationally 2JH–P = 21.9 Hz, 2H, 2H1), 2.34 (d, JH–P = 4.4 Hz, 3H, CH3),
labile C40 symmetrical carotenoids that possess C7,C8 alkyne 1.26 (t, J = 7.1 Hz, 6H, 2 × CO2CH2CH3) ppm. 13C-NMR
2
3
moieties inserted into their polyenic structures. A new stereo- (101 MHz, CDCl3): δ 129.1 (d, JP–C = 10.8 Hz), 97.6 (s, JP–C
=
2
1
controlled synthesis of (3R,3′R)-alloxanthin 1, and the first stereo- 17.7 Hz), 62.1 (t, JP–C = 6.8 Hz, 2×), 28.9 (t, JP–C = 141.0 Hz),
4
3
controlled synthesis of highly unsaturated 3,4,7,8,3′,4′,7′,8′- 27.7 (q, JP–C = 2.5 Hz), 16.5 (q, JP–C = 6.0 Hz, 2×) ppm. HRMS
octadehydro-β,β-carotene
2
have been achieved using as (ESI+): calcd for C8H17IO3P ([M + H]+), 318.9954; found,
common fragments a central C10-dialdehyde and terminal C15- 318.9958. IR (NaCl): ν 2980 (m, C–H), 2919 (w, C–H), 1390 (w),
phosphonates. The former was made by metathesis/dimeriza- 1253 (s) cm−1
tion of the precursor dienoate followed by functional group
.
(R,E)-4-[5′-(Diethoxyphosphoryl)-3′-methylpent-3′-en-1-ynyl]-
interconversions. C15-phosphonates were stereoselectively syn-
thesized using consecutive Pd/Cu-cocatalyzed Sonogashira
3,5,5-trimethylcyclohex-3-enyl acetate 19
reactions of TMS-acetylene, the first to attach the unsaturated To a degassed solution of Pd(PPh3)4 (3.9 mg, 0.003 mmol) in
cyclic end group and the second to connect the allylphospho- THF (0.5 mL) was added CuI (1.9 mg, 0.010 mmol). To this
nate. The otherwise facile isomerization of the C9–C10 double reaction mixture were added a degassed solution of diethyl
bond (carotenoid numbering) was prevented using this (E)-3-iodobut-2-enylphosphonate 18 (0.032 g, 0.112 mmol) in
scheme. Compared to traditional condensation reactions THF (1.0 mL), freshly distilled Et3N (0.039 mL, 0.280 mmol)
(Wittig or Julia/Julia–Kocienski olefination reactions),1 the and a solution of (R)-4-ethynyl-3,5,5-trimethylcyclohex-3-enyl
improved stereoselectivity, the ready availability of the precursor acetate 16 16,43,44 (0.030 g, 0.145 mmol) in THF (1.0 mL). The
phosphonates, as well as the easy removal of secondary by-pro- mixture was stirred for 4 h at 25 °C, then the mixture was fil-
ducts (phosphoric acid/esters) make the HWE reaction highly tered through a pad of Celite® and the solvent was evaporated.
recommended for the formation of disubstituted double bonds The residue was purified by column chromatography (silica
in polyenes, in particular for the construction of the C11vC12 gel-NH2, from 90 : 10 hexane–CH2Cl2 to CH2Cl2) to afford
bond as the last step in the total synthesis of carotenoids.
0.03 g (73%) of an oil identified as (R,E)-4-[5-(diethoxyphos-
phoryl)-3-methylpent-3-en-1-ynyl]-3,5,5-trimethylcyclohex-3-enyl
1
acetate 19. H-NMR (400.13 MHz, C6D6): δ 6.03 (q, J = 8.2 Hz,
3JH–P = 1.5 Hz, 1H, H4′), 5.19–5.11 (m, 1H, H1), 3.95–3.84 (m,
4H, 2 × OCH2CH3), 2.47 (d, J = 8.2 Hz, 2JH–P = 23.0 Hz, 2H, H2′),
2.29 (dd, J = 17.6, 5.6 Hz, 1H, H2), 1.97 (dd, J = 17.6, 9.1 Hz,
1H, H2), 1.83–1.78 (m, 7H, H6 + 2 × CH3), 1.71 (s, 3H, CH3),
1.51 (t, J = 11.9 Hz, 1H, H6), 1.23 (s, 3H, CH3), 1.19 (s, 3H,
CH3), 1.01 (t, J = 7.1 Hz, 6H, OCH2CH3) ppm. 13C-NMR
Experimental
Dimethyl (2E,4E,6E)-2,7-dimethylocta-2,4,6-trienedioate 8a
To a degassed solution of methyl (E)-2-methylpenta-2,4-dieno-
ate 5a (0.068 g, 0.054 mmol) in CH2Cl2 (10 mL) was added the
Hoveyda–Grubbs catalyst (0.051 g, 0.081 mmol). After stirring
at 25 °C for 8.5 h the solvent was evaporated and the residue
was purified by column chromatography (silica gel, from
95 : 5 hexane–EtOAc to 90 : 10 hexane–EtOAc) to afford 0.040 g
(66%) of a white solid identified as dimethyl (2E,4E,6E)-2,7-
dimethylocta-2,4,6-trienedioate 8a.17 1H-NMR (400.13 MHz,
CDCl3): δ 7.28 (ddd, J = 7.8, 2.9, 1.3 Hz, 2H, H3 + H6), 6.79 (dd,
J = 7.8, 3.0 Hz, 2H, H4 + H5), 3.77 (s, 6H, 2 × OCH3), 2.00 (d, J =
1.2 Hz, 6H, 2 × CH3) ppm. 13C-NMR (101 MHz, CDCl3): δ 168.6
(s, 2×), 137.5 (d, 2×), 133.7 (d, 2×), 130.1 (s, 2×), 52.1 (c, 2×),
13.1 (c, 2×) ppm.
6
(100.62 MHz, C6D6): δ 169.7 (s), 136.7 (s, JC–P = 1.4 Hz), 125.2
2
5
2
(d, JC–P = 12.7 Hz), 124.6 (s, JC–P = 3.3 Hz), 122.8 (s, JC–P
=
4
7
15.4 Hz), 96.9 (s, JC–P = 6.5 Hz), 86.2 (s, JC–P = 1.3 Hz), 67.8
3
(d), 61.8 (t, JC–P = 6.7 Hz, 2×), 42.7 (t), 37.6 (t), 36.3 (s), 30.4
(q), 28.8 (q), 27.9 (t, 1JC–P = 140.0 Hz), 22.4 (q), 21.0 (q), 17.9 (q,
4JC–P = 2.9 Hz), 16.5 (q, JC–P = 5.7 Hz, 2×) ppm. MS (EI): m/z
3
(%). HRMS (ESI+): calcd for C21H34O5P ([M + H]+), 397.2152;
found, 397.2132. IR (NaCl): ν 2965 (m, C–H), 2927 (m, C–H),
1736 (s, CvO), 1442 (w), 1365 (m), 1241 (s), 1027 (s) cm−1
[α]2D6 −39.5 (c 0.895, MeOH).
.
(E)-Diethyl (3-iodobut-2-en-1-yl)phosphonate 18
Trimethyl[(2,6,6-trimethylcyclohexa-1,3-dien-1-yl)ethynyl]-
silane 22
To a solution of ZnI2 (1.03 g, 3.23 mmol) in THF (1.6 mL) was
added triethyl phosphite (1 mL, 6.45 mmol), and a solution of To a degassed solution of 1-[(trifluoromethanesulfonyl)oxy]-
(E)-3-iodobut-2-en-1-ol 17 (0.43 g, 2.15 mmol) in THF (1.8 mL) 2,6,6-trimethylcyclohexa-1,3-diene 2148 (0.7 g, 2.59 mmol) in
via cannula. After stirring overnight at 85 °C, the solvent was DMF (31.2 mL) was added Pd(PPh3)4 (299 mg, 0.26 mmol) fol-
evaporated and the reaction mixture was washed with a 2 M lowed by anhydrous K2CO3 (1.07 g, 7.78 mmol), and trimethyl-
aqueous solution of NaOH (3×). The aqueous layer was silylacetylene (1.1 mL, 7.78 mmol). After stirring for 5 h at
extracted with Et2O (3×) and the combined organic layers were 60 °C, Et2O was added and the organic layer was washed with
dried (Na2SO4) and the solvent removed. Purification by H2O (3×). The combined organic layers were dried (Na2SO4)
column chromatography (C-18 silica gel, 55 : 45 CH3CN–H2O) and the solvent was evaporated. The residue was purified by
3028 | Org. Biomol. Chem., 2015, 13, 3024–3031
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column chromatography (silica gel, hexane) to afford 0.57 g (s, P–O–C) cm−1. HRMS (ESI+): calcd for C19H29NaO3P ([M +
(93%) of a pale yellow oil identified as trimethyl[(2,6,6-tri- H]+), 359.1747; found, 359.1745.
methylcyclohexa-1,3-dien-1-yl)ethynyl]silane 22. 1H NMR
(3R,3′R)-Alloxanthin 1. To a cooled (−78 °C) solution of
(400.13 MHz, CDCl3): δ 5.86 (dt, J = 9.6, 1.5 Hz, 1H, H3), 5.80 (R,E)-4-[5-(diethoxyphosphoryl)-3-methylpent-3-en-1-ynyl]-3,5,5-
(dt, J = 9.6, 4.2 Hz, 1H, H4), 2.09 (dd, J = 4.2, 1.5 Hz, 2H, 2H5), trimethylcyclohex-3-enyl acetate 19 (28 mg, 0.070 mmol) in
1.95 (s, 3H, CH3), 1.07 (s, 6H, 2 × CH3), 0.21 (s, 9H, 3 × CH3). THF (0.9 mL) was added NaHMDS (0.08 mL, 1 M in hexane,
13C NMR (100.62 MHz, CDCl3): δ 137.6 (s), 127.7 (d), 126.8 (d), 0.08 mmol). After stirring for 30 min, a solution of (2E,4E,6E)-
123.6 (s), 103.8 (s), 101.7 (s), 38.2 (t), 32.4 (s), 27.0 (q, 2×), 20.7 2,7-dimethylocta-2,4,6-triene-1,8-dial 8d (5.2 mg, 0.032 mmol)
(q), 0.2 (q, 3×). IR (NaCl): ν 2958 (s, C–H), 2128 (s, CuC), 859 in THF (1.1 mL) was added. After stirring for 2 h at the same
(s, Si–C), 842 (s, Si–C) cm−1. HRMS (ESI+): calcd for C14H23Si temperature a saturated aqueous solution of NH4Cl was added
([M + H]+), 219.1564; found, 219.1569.
and the mixture was extracted with a 90 : 10 EtOAc–CH2Cl2
1-Ethynyl-2,6,6-trimethylcyclohexa-1,3-diene
23. To
a
mixture. The combined organic layers were washed with a satu-
solution of trimethyl[(2,6,6-trimethylcyclohexa-1,3-dien-1-yl)- rated aqueous solution of NaHCO3, dried (Na2SO4) and the
ethynyl]silane 22 (0.53 g, 2.42 mmol) in THF (24 mL) was solvent was evaporated. The residue was used in the next reac-
added TBAF (3.63 mL, 1 M in hexane, 3.63 mmol). After stir- tion without further purification. To a cooled (−15 °C) solution
ring for 40 min at 25 °C the reaction mixture was poured over of alloxanthin acetate (0.021 g, 0.032 mmol) in Et2O (0.5 mL)
a saturated aqueous NaHCO3 solution and extracted with Et2O was added MeLi (0.1 mL, 1.6 M, 0.16 mmol) and the mixture
(3×). The combined organic layers were dried (Na2SO4) and the was stirred for 30 min at the same temperature. Then the
solvent was evaporated. Purification by column chromato- mixture was warmed to 25 °C and a solution of saturated
graphy (silica gel, hexane) afforded 0.28 g (79%) of a yellow oil aqueous solution of NaHCO3 was added. The mixture was
identified as 1-ethynyl-2,6,6-trimethylcyclohexa-1,3-diene 23. extracted with a 90 : 10 EtOAc–CH2Cl2 mixture, dried (Na2SO4)
1H-NMR (400.13 MHz, CDCl3): δ 5.87 (dt, J = 9.6, 1.4 Hz, 1H, and the solvent was evaporated. The residue was purified by
H3), 5.83 (dt, J = 9.6, 4.0 Hz, 1H, H4), 3.32 (s, 1H), 2.11 (dd, J = column chromatography (C18 silica gel, CH3CN) to afford
4.0, 1.4 Hz, 2H, 2H5), 1.96 (s, 3H, C2–CH3), 1.09 (s, 6H, 2 × C6– 14 mg (78%) of a red solid identified as (3R,3′R)-alloxanthin 1.
CH3). 13C-NMR (100.62 MHz, CDCl3): δ 138.1 (s), 127.6 (d), 1H-NMR (400.13 MHz, C6D6): δ 6.79 (d, J = 11.4 Hz, 2H, 2H10),
126.9 (d), 122.6 (s), 110.0 (s), 84.1 (d), 38.1 (t), 32.4 (s), 26.9 (q, 6.64–6.55 (m, 4H, 2H11 + 2H14), 6.36 (d, J = 14.8 Hz, 2H, 2H12),
2×), 20.5 (q). IR (NaCl): ν 3306 (s, CuC–H), 2958 (s, C–H), 2920 6.27–6.24 (m, 2H, 2H15), 3.75–3.68 (m, 2H, 2H3), 2.16 (dd, J =
(s, C–H), 2859 (s, C–H), 2080 (w, CuC) cm−1
.
18.2, 5.1 Hz, 2H, 2H4), 1.98 (s, 6H, 2 × CH3), 1.92 (s, 6H, 2 ×
CH3), 1.88 (dd, J = 18.2, 8.3 Hz, 2H, 2H4), 1.79 (s, 6H, 2 × CH3),
1.65 (ddd, J = 12.2, 3.2, 1.7 Hz, 2H, 2H2), 1.39 (d, J = 12.0 Hz,
2H, 2H2), 1.35 (s, 6H, 2 × CH3), 1.23 (s, 6H, 2 × CH3) ppm.
Diethyl (E)-[3-methyl-5-(2,6,6-trimethylcyclohexa-1,3-dien-1-yl]-
pent-2-en-4-yn-1-yl)phosphonate 24
To a degassed solution of Pd(PPh3)4 (14.0 mg, 0.01 mmol) in 13C-NMR (100.62 MHz, C6D6): δ 138.5 (d, 2×), 137.8 (s, 2×),
THF (1.4 mL) was added CuI (6.8 mg, 0.036 mmol) and a solu- 136.7 (s, 2×), 135.7 (d, 2×), 134.1 (d, 2×), 130.9 (d, 2×), 124.8 (s,
tion of 18 (127 mg, 0.40 mmol) in THF (2.8 mL) via cannula. 2×), 124.7 (d, 2×), 119.7 (s, 2×), 99.2 (s, 2×), 90.2 (s, 2×), 64.5 (d,
To the described mixture was added Et3N (0.14 mL, 2×), 47.0 (t, 2×), 41.7 (t, 2×), 36.8 (s, 2×), 30.9 (q, 2×), 29.0 (q,
1.00 mmol) and a solution of 1-ethynyl-2,6,6-trimethylcyclo- 2×), 22.7 (q, 2×), 18.3 (q, 2×), 12.9 (q, 2×) ppm. HRMS (ESI+):
hexa-1,3-diene 23 (87.6 mg, 0.60 mmol) in THF (2.8 mL). The calcd for C40H53O2 ([M + H]+), 565.4040; found, 565.4039.
reaction mixture was stirred for 2 h 30 min at 25 °C. Then it [α]2D4 −106.0 (c 0.01, CHCl3).
was filtered with AcOEt through a pad of Celite® and the
solvent was evaporated. The residue was purified by column
3,4,7,8,3′,4′,7′,8′-Octadehydro-β,β-carotene 2
chromatography (C-18 silica gel, from 65 : 35 to 100 : 0 CH3CN– To a cooled (−78 °C) solution of diethyl (E)-[3-methyl-5-(2,6,6-
H2O) to afford 88.8 mg (66%) of a pale yellow oil identified as trimethylcyclohexa-1,3-dien-1-yl]pent-2-en-4-yn-1-yl)phosphonate
diethyl (E)-[3-methyl-5-(2,6,6-trimethylcyclohexa-1,3-dien-1-yl]- (C15-alkynylphosphonate) 24 (24.5 mg, 0.07 mmol) in THF
pent-2-en-4-yn-1-yl)phosphonate 24. 1H-NMR (400.13 MHz, (1 mL) was added NaHMDS (0.083 mL, 1 M in hexane,
C6D6): δ 6.12–6.00 (m, 1H, H4′), 5.79 (dt, J = 9.5, 1.7 Hz, 1H, 0.08 mmol). After stirring for 30 min, a solution of (2E,4E,6E)-
H3′), 5.63 (dt, J = 9.3, 4.5 Hz, 1H, H2), 3.97–3.83 (m, 4H, 2 × 2,7-dimethylocta-2,4,6-triene-1,8-dial 8d (5.4 mg, 0.03 mmol)
OCH2CH3), 2.49 (dd, J = 23.6, 8.3 Hz, 2H, 2H1), 1.98 (dd, J = in THF (1 mL) was added. The mixture was stirred at −78 °C
4.5, 1.7 Hz, 2H, 2H5′), 1.96 (s, 3H, C2′–CH3), 1.82 (d, J = 4.5 Hz, for 1.5 h. Then, a saturated aqueous solution of NH4Cl was
3H, C3–CH3), 1.18 (s, 6H, 2 × C6–CH3), 1.01 (t, J = 6.9 Hz, 6H, added at −78 °C and the mixture was allowed to reach room
2 × OCH2CH3) ppm. 13C-NMR (100.62 MHz, C6D6): δ 136.3 (s, temperature and extracted with 90 : 10 EtOAc–CH2Cl2. The
2
JP–C = 2.0 Hz), 127.9 (d), 126.5 (d), 125.2 (d, JP–C = 12.8 Hz), combined organic layers were washed with
a
saturated
aqueous solution of NaHCO3, dried (Na2SO4) and the solvent
6.5 Hz), 87.2 (s, JP–C = 3.6 Hz), 61.7 (t, JP–C = 6.4 Hz), 38.5 (t), was evaporated. The crude was purified by column chromato-
124.6 (s, JP–C = 2.1 Hz), 123.0 (s, JP–C = 15.9 Hz), 100.4 (s, JP–C
=
1
33.2 (s), 27.9 (t, JP–C = 139.3 Hz), 20.4 (q, 2×), 17.9 (q, JP–C
=
graphy (silicagel-CN, from 100 : 0 to 90 : 10 hexane–EtOAc)
2.8 Hz), 16.5 (q, JP–C = 5.5 Hz, 2×) ppm. IR (NaCl): ν 2966 (s, afforded 8.2 mg (47%) of an orange solid identified as octade-
C–H), 2912 (s, C–H), 2865 (s, C–H), 1251 (m, PvO), 1050–1027 hydro-β,β-carotene 2. 1H-NMR (400.13 MHz, C6D6): δ 6.81 (d,
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Organic & Biomolecular Chemistry
3 Carotenoids. Part 1B. Spectroscopy, ed. G. Britton, S. Liaaen-
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4 G. Britton, S. Liaaen-Jensen and H. Pfander, Carotenoids.
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5 R.-M. Han, J.-P. Zhang and L. H. Skibsted, Molecules, 2012,
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8 Carotenoids Handbook, ed. G. Britton, S. Liaaen-Jensen and
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12 T. Ike, J. Inanaga, A. Nakano, N. Okukado and
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14 A. J. Davies, A. Khare, A. K. Mallams, R. A. Massy-Westropp,
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18 W. S. Wadsworth, Org. React., 1977, 25, 73–253.
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20 Y. Gu and S.-K. Tian, in Stereoselective Alkene Synthesis, ed.
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21 N. Fontán, M. Domínguez, R. Álvarez and Á. R. de Lera,
Eur. J. Org. Chem., 2011, 6704–6712.
Scheme 5 Reagents and reaction conditions: a. P(OEt)3, from 25 to
180 °C, 97%. b. Methyl glyoxal dimethyl acetal, t-BuOK, THF-DMSO,
56%. c. Acid-catalyzed acetal removal (see text). d. LiAlH4, THF, 85 °C,
87%. e. MnO2, ethyl 2-(triphenyl-λ5-phosphanylidene)propanoate,
Na2CO3, CH2Cl2, from 0 to 25 °C, 74%. f. DIBAL-H, THF, from −78 to
−20 °C. g. MnO2, Na2CO3, acetone.
J = 11.4 Hz, 2H, H10 + H10′), 6.63 (dd, J = 8.0, 2.9 Hz, 2H, H14
H14′), 6.60 (dd, J = 14.9, 11.4 Hz, 2H, H11 + H11′), 6.37 (d, J =
14.9 Hz, 2H, H12 + H12′), 6.26 (dd, J = 8.0, 2.0 Hz, 2H, H15
+
+
H15′), 5.86 (dt, J = 9.5, 1.9 Hz, 2H, H4 + H4′), 5.67 (dt, J = 9.5,
4.5 Hz, 2H, H3 + H3′), 2.07 (s, 3H, CH3), 2.03 (dd, J = 4.5,
1.9 Hz, 4H, 2H2 + 2H2′), 1.99 (d, J = 2.0 Hz, 6H, 2 × CH3), 1.79
(s, 6H, 2 × CH3), 1.28 (s, 12H, 4 × CH3). 13C-NMR (100.62 MHz,
C6D6): δ 138.6 (d, 2×), 136.8 (s, 2×), 136.4 (s, 2×), 135.9 (d, 2×),
134.2 (d, 2×), 131.0 (d, 2×), 128.7 (d, 2×), 126.7 (d, 2×), 125.1 (s,
2×), 124.8 (d, 2×), 119.8 (s, 2×), 103.3 (s, 2×), 91.2 (s, 2×), 38.6
(t, 2×), 33.4 (s, 2×), 27.5 (q, 4×), 20.9 (q, 2×), 18.2 (q, 2×), 12.8
(q, 2×) ppm. IR (NaCl): ν 3031 (w, C–H), 2956 (s, C–H), 2919 (s,
C–H), 2857 (w, C–H), 2148 (w, CuC) cm−1. UV (MeOH)(ε M−1
cm−1): λmax 380 (547 000); 470 (453 000). HRMS (ESI+): calcd
for C40H48 ([M + H]+), 528.3750; found, 528.3749.
22 N. Fontán, R. Alvarez and A. R. de Lera, J. Nat. Prod., 2012,
75, 975–979.
23 N. Fontán, B. Vaz, R. Alvarez and A. R. de Lera, Chem.
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Acknowledgements
This work was supported by MINECO-Spain (SAF2013-48397-
R-FEDER; FPU Fellowship to N.F.), Xunta de Galicia (Grant
08CSA052383PR from DXI + D + i; Consolidación 2006/15 from
DXPCTSUG; INBIOMED-FEDER “Unha maneira de facer
Europa”; Parga Pondal Contract to B.V.). We thank Dr Thomas
Netscher (DSM Nutritional Products) for generously donating
(−)-actinol, and Dr J. L. Garrido (IIM-CSIC, Spain) for the
natural pigments extract from Rhodomonas lens.
26 H. Ernst, K. Henrich and A. Keller, Procedure for the pro-
duction of 2,7-dimethylocta-2,4,6-triendial, DE10200400-
6579A1, 2005.
27 H. Choi, M. Ji, M. Park, I.-K. Yun, S.-S. Oh, W. Baik and
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preferred. Care has to be taken, however, to avoid the pres- 50 S. Hertzberg, G. Englert, P. Bergquist and S. Liaaen-Jensen,
ence of traces of acid on the oxidation of precursor C4-(E)- Bull. Chem. Soc. Belg., 1986, 95, 801–814.
but-2-ene-1,4-diol 29 with MnO2 by adding Na2CO3 to the 51 A. K. Mallams, E. S. Waight, B. C. L. Weedon,
reaction mixture (Scheme 5).
42 Using the alternative procedure based on the double HWE
reaction of the bis-phosphonate 26 with methyl glyoxal
D. J. Chapman, F. T. Haxo, T. W. Goodwin and
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