Bidirectional Hiyama–Denmark Cross-Coupling Reactions of Bissilyldeca-1,3,5,7,9-pentaenes for the Synthesis of Symmetrical and Non-Symmetrical Carotenoids

Article abstract of DOI:10.1002/chem.201903080

The construction of the carotenoid skeleton by Pd-catalyzed Csp²?Csp² cross-coupling reactions of symmetrical and non-symmetrical 1,10-bissilyldeca-1,3,5,7,9-pentaenes and the corresponding complementary alkenyl iodides has been developed. Reaction conditions for these bidirectional and orthogonal Hiyama–Denmark cross-coupling reactions of bisfunctionalized pentaenes are mild and the carotenoid products preserve the stereochemical information of the corresponding oligoene partners. The carotenoids synthesized in this manner include β,β-carotene and (3R,3′R)-zeaxanthin (symmetrical) as well as 9-cis-β,β-carotene, 7,8-dihydro-β,β-carotene and β-cryptoxanthin (non-symmetrical).

Full text of DOI:10.1002/chem.201903080

A Journal of
Accepted Article
Title: Bidirectional Hiyama-Denmark Cross-Coupling Reactions of Bis-
silyldeca-1,3,5,7,9-pentaenes for the Synthesis of Symmetrical
and Non-symmetrical Carotenoids
Authors: Angel R. de Lera, Aurea Rivas, Víctor Pérez Revenga, and
Rosana Alvarez
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Bidirectional Hiyama-Denmark Cross-Coupling Reactions of
Bissilyldeca-1,3,5,7,9-pentaenes for the Synthesis of Symmetrical
and Non-symmetrical Carotenoids
Aurea Rivas, Víctor Pérez-Revenga, Rosana Alvarez,* and Angel R. de Lera* [a]
apocarotenoids (including the retinoids or vitamin A analogues)
Abstract: The construction of the carotenoid skeleton by Pd-
catalyzed Csp2-Csp2 cross-coupling reactions of symmetrical and
non-symmetrical 1,10-bissilyldeca-1,3,5,7,9-pentaenes and the
corresponding complementary alkenyl iodides has been developed.
Reaction conditions for these bidirectional and orthogonal Hiyama-
Denmark cross-coupling reactions of bis-functionalized pentaenes
are mild and the carotenoid products preserve the stereochemical
information of the corresponding oligoene partners. The carotenoids
synthesized in this manner include β,β-carotene and (3R,3´R)-
zeaxanthin (symmetrical) as well as 9-cis-β,β-carotene, 7,8-dihydro-
β,β-carotene and β-cryptoxanthin (non-symmetrical).
and carotenoids[10] using mono- and bis-functionalized alkenyl
linchpins.[11] In fact, these synthetic challenges have contributed
to illustrate the scope and limitations[6b, 12, 13] of the Pd-catalyzed
Csp2-Csp2 cross-coupling reactions for the preparation of highly
unstable polyenes.[7]
Similarly, the Hiyama-Denmark cross-coupling reaction,[14]
which utilizes organosilicon reagents,[15] has also been applied
to the stereocontrolled synthesis of the all-trans- and 11-cis-
isomers of vitamin A by the highly convergent C14 + C6
strategy.[7] For example, dienylsilane 2 was found to couple to
trienyl iodide 1 under mild reaction conditions to afford the
retinoid pentaene structure 3 in high yield (Scheme 1).[16]
Organosilicon reagents are in general easier to prepare and
handle than structurally related organometallic compounds. In
addition, they are also more stable due to the low polarizability
of the C-Si bond, and show lower toxicity than stannanes.
Moreover, mechanistic studies have provided an in-depth
understanding of the cross-coupling reaction,[17] including the
effect of silicon substituents on their reactivity[18] and the
electronic demands for efficient transmetalation.[19] All of these
features have contributed to the current status of organosilanes
as powerful synthetic tools for the preparation of unsaturated
fragments of natural polyenes.[14c, 17a, e, 20]
Introduction
Polyene substructures are present in a large number of
molecular skeletons of natural products that display diverse
biological activities.[1] Notably, the polyene fragments of retinoids
and carotenoids are considered to be responsible for some
fundamental biological functions, including animal vision (11-cis-
retinal), bacterial proton- and ion-pumping activities (all-trans-
retinal)[2] and plant photosynthesis (selected carotenoids)[3]
among others.[4] More than 800 natural carotenoids have been
isolated from biological materials,[3a, 5] with a large number of
them still remaining incompletely characterized due to their
instability or to the scarcity of material isolated from the natural
sources.
Csp2=Csp2 condensation reactions (Wittig, Horner-Wadsworth-
Emmons or HWE, Julia-Kocienski...) are considered as classical
methods[6] for the synthesis of the polyene substructures of
retinoids and carotenoids.[7] Despite their efficiency, these
procedures have some drawbacks, notably the lack of
stereocontrol leading to mixtures of isomers, and a laborious
purification requiring also the separation of by-products.[7]
Alternatively these polyenes are constructed using palladium-
catalyzed Csp2-Csp2 cross-coupling reactions. These processes
are more functional group-tolerant and require in general milder
reaction conditions, thus leading to the preservation of the
stereochemical information of the reacting oligoenes.[6b, 7]
Both the Stille[8] and the Suzuki-Miyaura cross-coupling
reactions[9] have been thoroughly explored for the synthesis of
[a]
Aurea Rivas, Víctor Pérez-Revenga, Prof. Dra. Rosana Alvarez,*
and Prof. Dr. Angel R. de Lera*
Departamento de Química Orgánica
Facultade de Química, CINBIO and IIS Galicia Sur
Universidade de Vigo, E-36310 Vigo, Spain
E-mail: rar@uvigo.es
Scheme 1. Reported synthetic approach to vitamin A (4)[16a] and extension to
β,β-carotene (7), (3R,3´R)-zeaxanthin (8), 9-cis-β-carotene (9), 7,8-dihydro-β-
carotene (10) and (R)-β-cryptoxanthin (11) using a bidirectional Hiyama-
Denmark cross-coupling reactions of alkenyl iodides with symmetrical (5) and
non-symmetrical (6) 1,10-bissilyldeca-1,3,5,7,9-pentaenes.
qolera@uvigo.es
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A popular strategy in the construction of the polyene
skeleton of carotenoids involves connecting a central C12-
natural products, while structural modifications (in the form of
changes in oxidation state, ring contractions, etc...) are found at
the ring carbons and/or at their more proximal double bonds.[3a, 5]
This makes reagents 5 and 6 potentially useful for the synthesis
of a wide variety of carotenoid structures.
pentaenyl fragment to two C14 end groups, the so-called C14
+
C12 + C14 strategy (Scheme 1).[7] The application of the Hiyama-
Denmark transformation in this strategy would imply the
generation of both the C10-C11 and the C10’-C11’ bonds of
carotenoids by using bis-metallated organosilanes 5/6 and
alkenyl iodides (such as 1, for example).
Results and Discussion
In order for this bidirectional strategy using bismetallated
organometallic reagents to be of general applicability, it would
have to be able to provide access to both symmetrical (7,8) and
non-symmetrical (9-11) polyene structures (Scheme 1), implying
that selective activation of each of the metallic fragments
associated to the central pentaene core (as in 5/6) is needed.
Denmark has already demonstrated that, while both types
of silyl groups are activated using fluoride anion sources through
the formation of pentavalent Si species,[17b, c, 21] the treatment of
silanols under basic conditions provides a second alternative
pathway for activation via generation of active silanolate
species.[22] He has also taken advantage of this dual behavior in
the bidirectional preparation of simple non-symmetrical
bisarylbutadienes, hexatrienes and octatetraenes, devoid of
substitution at the diene or tetraene moieties, using mixed
Synthesis of 1,10-bissilyldeca-1,3,5,7,9-pentaenes 5 and 6
Starting from either enynol 12 or TMS-substituted
derivative 16 (Scheme 2), two routes were employed that
differed in the order of hydrosilylation[26] relative to oxidation[27]
and HWE[28] steps. The first route started with a regioselective
Pt-catalyzed syn-hydrosilylation[26] of enynol 12 with HSiMe2Bn
and Karstedt’s catalyst [(tBu3P)Pt(DVDS), (DVDS = 1,3-divinyl-
1,1,3,3-tetramethyldisiloxane, generated from Pt(DVDS) and
tBu3P], which stereoselectively provided the corresponding
silyldienol 13 in 69% yield.[16b] Oxidation of silyldienol 13 with
MnO2 afforded silyldienal 14 in 90% yield.[27] Allylic phosphonate
15 was prepared from 13 by reaction with triethylphosphite[29] of
the corresponding iodide[30] or bromide[31] intermediates in 68
and 56% overall yields, respectively. Finally, unsaturated chain
extension of silyldienal 14 by HWE reaction with phosphonate
15 under Barbier conditions provided the symmetrical 3,8-
dimethyl-1,10-bissilyl-1,3,5,7,9-decapentaene 5 in 45% yield.
A more efficient approach (Scheme 2) to both 5 and the
silanol-silane
1,4-bissilylbutadienes.[23]
However,
the
preparation/use of higher analogues of these bissilyl reagents
has not been reported, while literature reports on other alkenyl
bissilanes appear to be restricted to the synthesis of symmetrical
unsubstituted butadienyl-, hexatrienyl-,[24] and octatetraenyl-
bissilanes,[25] and their related use in mono- and bis-acylation
reaction with aroyl chlorides.
With these precedents, in this paper we describe the
preparation of pentaenyl-bissilane reagents 5 and 6, and their
application to the synthesis of both symmetrical (β,β-carotene 7,
(3R,3´R)-zeaxanthin 8) and non-symmetrical (9-cis-β-carotene 9,
7,8-dihydro-β-carotene 10 and (R)-β-cryptoxanthin 11)
carotenoids (Scheme 1). To further add to the attractiveness of
this strategy, it is noted that the oligoene skeleton that
comprises the central region of carotenoids (integrated in
structures 7-11) is biosynthetically preserved in most of these
non-symmetrical 1,10-bissilyl-1,3,5,7,9-decapentaene
6 was
devised involving silyltetraenyne 20 as intermediate. Thus, TMS-
enynol 16, itself obtained by reduction of the corresponding
enynoate precursor,[32] was transformed into allylic phosphonate
17 along the same lines indicated for 15,[31] and the subsequent
HWE reaction with silyldienal 14 gave rise to tetraenynyl
derivative 19 in 69% yield. A better yield (77%) resulted from the
exchange of the functionalities between the reaction partners,
thus performing the HWE process between enynal 18 and
phosphonate 15.[27]
Scheme 2. Synthesis of symmetrical (5) and non-symmetrical (6) pentaenylbissilanes from enynols 12 and 16.
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Then,
regio-
and
stereoselective
Pt-catalyzed
(59% yield; Scheme 4).[38] Thus, the reactivity of the non-
symmetrical 1,10-bissilyldeca-1,3,5,7,9-pentaene follows the
same trends described for the shorter unsubstituted 1,4-
bissilylbutadienes,[23a] and the observed selectivity can be
diverted to the preparation of non-symmetrical carotenoids. This
is clearly another advantage of the Hiyama-Denmark coupling
for stepwise polyene construction.
hydrosilylation[26a, b, d] of deprotected alkyne 20 with HSiBnMe2 or
HSi(OEt)Me2 and Karstedt’s catalyst afforded 1,10-bissilyldeca-
1,3,5,7,9-pentaenes 5 and 21 in 56 and 88% overall yields (from
19), respectively. Alternatively, upon stirring crude 21 in
aqueous buffer (1M HOAc/NaOAc, pH 5),[23a] the corresponding
silanol 6 was obtained in an overall 43% yield from 19 (Scheme
2).[23a] The all-E geometry of pentaenes 5 and 6 was assigned
based on the magnitude of the Csp2-H-Csp2-H vicinal coupling
Further coupling of octaenylsilane 23 with trienyl iodide 1
or its Z-isomer 24 (Scheme 4) took place following activation
with TBAF and using Pd2(dba)3·CHCl3 as catalyst. This afforded,
in 90 and 60% yields, respectively, β,β-carotene 7 and the highly
unstable 9-cis isomer 9.[39] Thus, the geometry of the starting
trienyl iodides appears to be preserved in the Hiyama-Denmark
cross-coupling reaction. Similarly, 7,8-dihydro-β,β-carotene 10,
which has been isolated from the extracts of genetically modified
E. coli,[40] could be obtained in 78% yield when the isolated
octaenylsilane intermediate 23 was subjected to a second
Hiyama-Denmark cross-coupling with the non-conjugated dienyl
iodide 25, upon activation with TBAF using Pd2(dba)3·CHCl3 as
catalyst.
Additionally, the bis-coupling process could be carried out
without isolation of the octaenylsilane intermediate 23. Thus,
heterodimeric 1,10-bissilyldecapentaene 6 was also converted
into β,β-carotene 7, 9-cis-β,β-carotene 9,[39] and (R)-β-
cryptoxanthin 11[37, 41]) in 66, 30 and 57% yield, respectively, in a
sequential double Hiyama-Denmark cross-coupling reaction of 6
with trienyl iodides 1, 24 and 22 (Scheme 5).
constants (J = 18 – 20 Hz) on their H NMR spectra[33] and the
observed nuclear Overhauser effects (nOe).
1
Bidirectional Hiyama-Denmark cross-coupling of 1,10-
bissilyldeca-1,3,5,7,9-pentaenes 5 and 6
The two-fold bidirectional Hiyama-Denmark cross-coupling
reaction[20h, 34] using the homodimeric 1,10-bissilyldeca-1,3,5,7,9-
pentaene 5 was performed following the protocol previously
described for the synthesis of retinoids.[16b] Upon treatment with
[35]
TBAF
in the presence of Pd2(dba)3·CHCl3 as catalyst, the
coupling of 5 with trienyl iodide 1[36] took place at ambient
temperature and afforded β,β-carotene 7 in 61% yield (Scheme
3). Similarly, (3R,3´R)-zeaxanthin 8 was also synthesized, in
55% yield, upon two-fold Hiyama-Denmark cross-coupling of 5
and trienyl iodide 22,[36] thus showing the compatibility of the
unprotected hydroxyl group with the reaction conditions.[37]
This protocol involved first a Hiyama-Denmark cross-
coupling with E-trienyl iodide 1 at the silanol terminus of 6[22-23, 42]
followed, after filtration of the crude mixture through a silica gel
plug in order to remove Pd black, by a second coupling[35]
between the putative octaenylsilane intermediate 23 and trienyl
iodides 1, 24 or 22, respectively.
Scheme 3. Total synthesis of symmetrical carotenoids (7, 8) by Hiyama-
Denmark cross-coupling of symmetrical pentaenylbissilane (5) and trienyl
iodides (1 and 22).
In order to explore the sequential Hiyama-Denmark cross-
coupling[26d] of a non-symmetrical 1,10-bissilyldeca-1,3,5,7,9-
pentaene with modulated reactivity,[23a] the silanol group of
pentaenylbissilane 6 was selectively activated by treatment with
KOTMS. Then, addition of Pd(dba)2 and trienyl iodide 1 afforded,
at ambient temperature, octaenylsilane 23 with good efficiency
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Scheme 4. Synthesis of silylated octaenylapocarotenoid 23 by position-selective mono-Hiyama-Denmark cross-coupling of non-symmetrical 1,10-
bissilyldecapentaene 6 and trienyl iodide 1, and synthesis of symmetrical (β,β-carotene 7) and non-symmetrical (9-cis-β,β-carotene 9 and 7,8-dihydro-β,β-carotene
10) by Hiyama-Denmark cross-coupling reaction of octaenylsilane 23.
Scheme 5. Synthesis of symmetrical (β,β-carotene 7) and non-symmetrical (9-cis-β,β-carotene 9; (R)-β-cryptoxanthin 11) by sequential selective mono-Hiyama-
Denmark cross-coupling reaction of non-symmetrical 1,10-bissilyldecapentaene 6.
unsaturated carbons.[7] These procedures are mild (ambient
temperature) and functional group (OH) tolerant and the
synthesis of the desired isomer can be achieved by choosing the
geometries of the conjunctive reagents, since the oligoene
products preserve the stereochemical information of the cross-
coupling partners.[1a] The stability of the cross-coupling
Conclusions
To summarize, as an extension of the Hiyama-Denmark
cross-coupling approach[17a,
20g, h]
organosilane reagents, the cost-effectiveness and low
environmental impact of their preparation are additional
advantages of these protocols, particularly when used as
tandem processes to more efficiently generate molecular
complexity. In the case at hand, it is expected that using these
procedures the synthesis of unstable (as exemplified by 9)
natural carotenoids will allow their full characterization and
provide samples for comprehensive biological studies.
to polyenes, we have
developed a new synthesis of symmetrical and non-symmetrical
carotenoids by bidirectional Pd-catalyzed Csp2-Csp2 bond
formation using conjunctive pentaenyl-1, -bissilanes and the
apropriately matched (tri)enyl iodide building blocks.
Conceptually, the application of transition metal catalyzed
processes[43][12b] to carotenoids complements the general
condensation approaches based on olefination, with the
construction of polyenes by single-bond formation between
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5
1
5.9 Hz), 91.9 (s, JC-P = 2.9 Hz), 61.7 (t), 61.6 (t), 27.8 (t, JC-P = 139.7
Hz), 17.5 (q 4JC-P = 5.6 Hz), 16.5 (q), 16.4 (q), 0.1 (q, 3x) ppm. IR (NaCl):
ν 2966 (m, C-H), 2145 (m, C≡C), 1254 (s), 1029 (s), 848 (s) cm-1. MS
(ESI+-TOF): m/z 311 ([M+Na]+, 28), 289 ([M+H]+, 100). HRMS (ESI+):
Cald. for C13H26O3PSi ([M+H]+), 289.1386; found, 289.1383.
Experimental Section
General Procedures (see S. I.)
Diethyl
(2E-4E)-5-(Benzyldimethylsilyl)-3-methylpenta-2,4-
dienylphosphonate (15).
(1E,3E,5E,7E,9E)-1,10-Di(benzyldimethylsilyl)-3,8-dimethyldeca-
1,3,5,7,9-pentaene (5).
Method A: A solution of 13[16] (0.40 g, 1.62 mmol) in THF (6.5 mL) was
added to a mixture of ZnI2 (0.78 g, 2.44 mmol) and P(OEt)3 (0.84 mL,
4.87 mmol). The reaction mixture was stirred for 4 h at 85 °C. After
cooling down to 25 °C, the solvent was removed, the residue was diluted
with EtOAc and washed with a 2 M aqueous solution of NaOH and the
aqueous layer was extracted with EtOAc (3x). The combined organic
layers were dried (Na2SO4) and the solvent was evaporated. The residue
was purified by column chromatography (C18 - silica gel, 55:45 v/v
CH3CN/H2O) to afford 0.42 g (68%) of 15 as a yellow oil.
Procedure A (Barbier conditions): n-BuLi (0.075 mL, 2.45 M in hexanes,
0.184 mmol) was added to a solution of HMDS (0.039 mL, 0.184 mmol)
in THF (0.2 mL). After stirring at -78 °C for 30 min, this solution was
added dropwise to a mixture of 15 (0.067 g, 0.184 mmol) and 14 (0.03 g,
0.123 mmol) in THF (0.25 mL) and the temperature was allowed to reach
25 °C over 21 h. Water was added and the resulting mixture was
extracted with Et2O (3x). The combined organic layers were washed with
H2O (3x) and brine (3x), and dried (Na2SO4). The solvent was
evaporated and the residue was purified by column chromatography
(silica gel, 98:2 hexane/EtOAc) to afford 0.032 g (45%) of 5 as a
colourless oil.
Procedure B: n-BuLi (0.12 mL, 2.45 M in hexanes, 0.027 mmol) was
added to a solution of HMDS (0.06 mL, 0.285 mmol) in THF (0.2 mL).
After stirring at -78 °C for 30 min, this solution was added dropwise to a
solution of 15 (0.112 g, 0.305 mmol) in THF (0.25 mL) and the resulting
solution was stirred at this temperature for 30 min. A solution of 14 (0.05
g, 0.205) in THF (0.25 mL) was then added. The reaction mixture was
allowed to stir at 25 °C for a total of 5 h. Water was added and the
resulting mixture was extracted with Et2O (3x). The combined organic
layers were washed with H2O (3x) and brine (3x), and dried (Na2SO4).
The solvent was evaporated and the residue was purified by column
chromatography (silica gel, 98:2 hexane/EtOAc) to afford 0.023 g (25%)
of 5 as a colourless oil.
Method B: To a cooled (0 °C) stirred solution of 13[16] (0.30 g, 1.22 mmol)
in CH2Cl2 (4 mL) were added CBr4 (0.53 g, 1.58 mmol) and PPh3 (0.48 g,
1.83 mmol). The reaction mixture was stirred for 15 min at 0 °C and the
solvent was evaporated in vacuo. The residue was dissolved in P(OEt)3
(0.29 mL, 1.79 mmol) and the mixture was refluxed for 30 min. After
being cooled down to ambient temperature, toluene (1 mL) was added
and the mixture was concentrated. The residue was purified by column
chromatography (C18 - silica gel, 55:45 v/v CH3CN/H2O) to afford 0.25 g
(56%) of 15 as a yellow oil. 1H-NMR (400.13 MHz, C6D6): δ 7.44 -7.20 (m,
2H, ArH), 7.01 (t, J = 6.9 Hz, 1H, ArH), 6.97 (d, J = 8.0 Hz, 2H, ArH),
6.64 (d, J = 19.0 Hz, 1H, H4 or H5), 5.80 (d, J = 19.0 Hz, 1H, H5 or H4),
5.73 – 5.63 (m, 1H, H2), 3.98 – 3.82 (m, 4H, 2xOCH2CH3), 2.57 (dd, J =
8.0 Hz, JHP = 23.0 Hz, 2H, 2H1), 2.06 (s, 2H, SiMe2CH2Ph), 1.68 (d, J =
3.9 Hz, 3H, C3-CH3), 1.02 (t, J = 7.1 Hz, 6H, 2xOCH2CH3), 0.05 (s, 6H,
SiMe2Bn) ppm. 13C-NMR (100.61 MHz, C6D6): δ 149.3 (d, 4JC-P = 5.0 Hz),
3
140.2 (s), 139.1 (s, JC-P = 14.5 Hz), 128.6 (d, 2x), 128.5 (d, 2x), 125.2
Procedure C: To a cooled (0 °C) solution of 19 (0.39 g, 1.03 mmol) in
MeOH (4.7 mL), K2CO3 (1.71 g, 12.36 mmol) was added. The mixture
was stirred at 25 °C for 1 h and water was added. The resulting mixture
was extracted with Et2O (4x), the combined organic layers were dried
(Na2SO4) and the solvent was evaporated. To a degassed solution of
Pt(DVDS) (0.11 mL, 2% in xylene, 0.005 mmol) and tBu3P (0.005 mL, 1M
in toluene, 0.005 mmol) in THF (2.7 mL), BnMe2SiH (0.95 mL, 1.47
mmol) was added. After stirring for 30 min at 25 °C, a solution of the
residue obtained above (expected to be 20) in THF (2.7 mL) was added
and the reaction mixture was stirred at 25 °C for 2.5 h. The solvent was
evaporated and the residue was purified by column chromatography
(silica gel, 98-2 hexane/EtOAc) to afford 0.25 g (56%) of 5 as a yellow oil.
1H-NMR (400.16 MHz, C6D6):  7.33 – 7.22 (m, 4H, ArH), 7.17 – 7.07 (m,
6H, ArH), 6.86 (d, J = 19.4 Hz, 2H, 2H1 or 2H2), 6.75 (d, J = 10.1 Hz, 2H,
2H4 or 2H5), 6.32 (d, J = 10.1 Hz, 2H, 2H5 or 2H4), 6.07 (d, J = 19.4 Hz,
2H, 2H2 or 2H1), 2.26 (s, 4H, 2xSiMe2CH2Ph), 1.95 (s, 6H, 2xC3-CH3),
0.27 (s, 12H, 2xSiMe2Bn) pm. 13C-NMR (100.62 MHz, C6D6): δ 149.8 (d,
2x), 140.2 (s, 2x), 137.2 (s, 2x), 133.8 (d, 2x), 131.2 (d, 2x), 128.7 (d, 2x),
128.6 (d, 4x), 126.6 (d, 4x), 124.6 (d, 2x), 26.5 (t, 2x), 12.4 (q, 2x), -3.1 (q,
4x) ppm. IR (NaCl):  2954 (m, C-H), 2854 (m, C-H), 1568 (m), 1249 (m),
1151 (m), 772 (s) cm-1. MS (ESI+-TOF): m/z 458 (30), 457 ([M+H]+, 100),
419 (72). HRMS (ESI+): Calcd. for C30H41Si2 ([M+H]+), 457.2741; found,
457.2742.
(d), 124.5 (d), 122.9 (d, 2JC-P = 12.2 Hz), 61.7 (t, 2x), 27.7 (t, 1JC-P = 139.6
Hz), 26.3 (t), 16.5 (q, 2x), 12.1 (q), -3.2 (q, 2x) ppm. IR (NaCl):  2982 (s,
C-H), 2957 (m, C-H), 1492 (w), 1250 (s), 1027 (s) cm-1. HRMS (ESI+):
Cald. for C19H32O3PSi ([M+H]+), 367.1853; found, 367.1856.
(2E,4E)-5-(Benzyldimethylsilyl)-3-methylpenta-2,4-dienal (14). To a
cooled (0 °C) solution of 13[16] (2.3 g, 9.33 mmol) in Et2O (373 mL), MnO2
(8.11 g, 93.34 mmol) and Na2CO3 (9.89 g, 93.34 mmol) were added and
the reaction was stirred at 25 °C for 1.5 h. The mixture was filtered
through Celite®, the solids were washed with CH2Cl2, and the solvent
was evaporated to afford 2.05 g (89%) of 14 as a yellow oil. 1H-NMR
(400.13 MHz, C6D6): δ 9.96 (d, J = 7.8 Hz, 1H, H1), 7.19 – 7.13 (m, 2H,
ArH), 7.03 (t, J = 7.4 Hz, 1H, ArH), 6.92 (d, J = 8.2 Hz, 2H, ArH), 6.39 (d,
J = 19.0 Hz, 1H, H5), 6.15 (d, J = 19.0 Hz, 1H, H4), 5.85 (d, J = 8.3 Hz,
1H, H2), 2.00 (s, 2H, SiMe2CH2Ph), 1.65 (s, 3H, C3-CH3), -0.01 (s, 6H,
SiMe2Bn) ppm. 13C-NMR (100.63 MHz, C6D6): δ 190.7 (d), 152.9 (s),
147.8 (d), 139.5 (s), 135.9 (d), 130.8 (d), 128.6 (d, 2x), 128.5 (d, 2x),
124.8 (d), 25.8 (t), 12.0 (q), -3.6 (q, 2x) ppm. UV (MeOH): λmax 274 nm.
IR (NaCl): 2956 (w, C-H), 1663 (s, C=O), 1204 (m), 839 (s) cm-1. HRMS
(ESI+): Calcd. for C15H21OSi ([M+H]+), 245.1356; found, 245.1355.
Diethyl
(E)-(3-Methyl-5-(trimethylsilyl)pent-2-en-4-yn-1-
yl)phosphonate (17). To a cooled (0 °C) stirred solution of 16[16] (0.398
g, 2.365 mmol) in CH2Cl2 were added CBr4 (1.02 g, 3.075 mmol) and
PPh3 (0.931 g, 3.548 mmol). The reaction mixture was stirred for 15 min
at 0 °C and the solvent was evaporated. The residue was dissolved in
triethylphosphite (0.56 mL, 3.005 mmol) and the resulting mixture was
refluxed at 130 °C for 30 min. After being cooled down to room
temperature, toluene (1 mL) was added and the mixture was
concentrated. The residue was purified by column chromatography (C18
- silica gel, 55:45 v/v CH3CN/H2O) to afford 0.29 g (57%) of 17 as a
yellow oil. 1H-NMR (400.13 MHz, C6D6): δ 6.17 – 6.09 (m, 1H, H2), 3.91 –
3.78 (m, 4H, PO(OCH2CH3)2), 2.38 (dd, JH-H = 8.6 Hz, 1JP-H = 23.5 Hz, 2H,
(3E,5E,7E,9E)-10-(benzyldimethylsilyl)-3,8-dimethyl-1-trimethylsilyl-
deca-3,5,7,9-tetraen-1-yne (19).
Procedure A: n-BuLi (4.7 mL, 2.3 M in hexanes, 10.93 mmol) was added
to a solution of HMDS (2.3 mL, 10.93 mmol) in THF (20 mL). After stirring
at -78 °C for 30 min, this solution was added dropwise to a solution of 17
(3.151 g, 10.93 mmol) in THF (70 mL) and the resulting solution was
stirred at this temperature for 30 min. After stirring at -78 °C for 0.5 h, a
solution of 14 (1.78 g, 7.28 mmol) in THF (70 mL) was added and the
reaction mixture was allowed to warm slowly from -78 °C to 25 °C over 2
h. Water was added and the resulting mixture was extracted with Et2O
(3x). The combined organic layers were washed with H2O (3x) and a
saturated aqueous solution of NaCl (3x), and dried (Na2SO4). The solvent
5
2H1), 1.73 (d, JH-P = 5.1 Hz, 3H, C3-CH3), 0.97 (t, J = 7.1 Hz, 6H,
PO(OCH2CH3)2), 0.18 (s, 9H, SiMe3) ppm. 13C-NMR (100.63 MHz, C6D6):
2
3
4
δ 128.1 (d, JC-P = 12.1 Hz), 122.3 (s, JC-P = 15.2 Hz), 108.4 (s, JC-P
=
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10.1002/chem.201903080
Chemistry - A European Journal
FULL PAPER
was evaporated and the residue was purified by column chromatography
(silica gel, 98:2 hexane/EtOAc) to afford 1.3 g (77% yield) of 19 as a red
oil.
Et2O (4x), the combined organic layers were dried (Na2SO4) and the
solvent was evaporated.
To a solution of Pt(DVDS) (0.18 mL, 2% in xylene, 0.008 mmol) and
tBu3P (8 μL,
1 M in toluene, 0.008 mmol) in THF (5 mL),
Procedure B: n-BuLi (0.68 mL, 2.45 M in hexanes, 1.66 mmol) was
added to a solution of HMDS (0.42 mL, 1.99 mmol) in THF (3 mL). After
stirring at -78 °C for 30 min, this solution was added dropwise to a
solution of 15 (0.61 g, 1.66 mmol) in THF (5 mL) and the resulting
solution was stirred at this temperature for 30 min. After stirring at -78 °C
for 0.5 h, a solution of 18 (0.18 g, 1.1 mmol) in THF (5 mL) was added
and the reaction mixture was allowed to warm slowly from -78 °C to
25 °C over 2 h. Water was added and the resulting mixture was extracted
with Et2O (3x). The combined organic layers were washed with H2O (3x)
and a saturated aqueous solution of NaCl (3x), and dried (Na2SO4). The
solvent was evaporated and the residue was purified by column
chromatography (silica gel, 98:2 hexane/EtOAc) to afford 0.25 g (60%
ethoxydimethylsilane (0.25 g, 2.45 mmol) was added and the mixture
was stirred for 30 min at 25 °C. A solution of the residue obtained above
(0.5 g, 1.63 mmol) in THF (5 mL) was added and the reaction mixture
was stirred for 1 h. The solvent was evaporated and the residue was
purified by column chromatography (C18 - silica gel, MeCN) to afford
0.45 g (68% yield) of a yellow oil identified as (1E,3E,5E,7E,9E)-benzyl-
10-(ethoxydimethylsilyl)-3,8-dimethyldeca-1,3,5,7,9-tetraen-1-
yl)dimethylsilane 21. 1H-NMR (400.16 MHz, C6D6):  7.20 – 7.15 (m, 2H,
ArH), 7.07 – 7.00 (m, 3H, ArH), 6.93 (d, J = 18.9 Hz, 1H), 6.73 (d, J =
18.8 Hz, 1H), 6.62 (m, 2H), 6.21 (m, 2H), 6.01 (d, J = 18.9 Hz, 1H), 5.95
(d, J = 18.8 Hz, 1H), 3.66 (q, J = 7.0 Hz, 2H, SiMe2OCH2CH3), 2.13 (s,
2H, SiMe2CH2Ph), 1.81 (s, 6H, 2xCH3), 1.19 (t, J = 7.0 Hz, 3H,
SiMe2OCH2CH3), 0.31 (s, 6H, SiMe2OEt), 0.12 (s, 6H, SiMe2Bn) ppm.
13C-NMR (100.62 MHz, C6D6):  150.3 (d), 149.5 (d), 140.2 (d), 137.3 (s),
137.2 (s), 134.3 (s), 133.7 (d), 131.4 (d), 131.1 (d), 128.7 (d, 2x), 128.5
(d, 2x), 126.7 (d), 126.2 (d), 124.6 (d), 58.5 (t), 26.5 (t), 19.0 (q), 12.4 (q,
2x), -1.2 (q, 2x), -3.1 (q, 2x) ppm. IR (NaCl):  1644 (m), 1219 (m), 834
(s), 679 (s) cm-1. HRMS (EI+): Calcd. for C25H39OSi2 ([M+H]+), 411.2538;
found, 411.2534.
(1E,3E,5E,7E,9E,11E,13E)-Benzyldimethyl-[3,8,12-trimethyl-14-(2,6,6-
trimethylcyclohex-1-en-1-yl)-tetradeca-1,3,5,7,9,11,13-heptaen-1-yl)-
silane (23). To a solution of 6 (24.1 mg, 0.063 mmol) in dioxane (0.126
mL) was added TMSOK (0.063 mL, 2M in THF, 0.126 mmol). After
stirring for 15 min at 25 °C, a solution of 1 (20 mg, 0.063 mmol) in
dioxane (0.126 mL) and Pd(dba)2 (1.2 mg, 0.002 mmol) were added and
the reaction mixture was stirred at 25 °C for 1.5 h. Then, the reaction
mixture was filtered through a silica gel plug, the solids were washed with
EtOAc (3x) and the solvent was evaporated. The residue was purified by
column chromatography (silica gel, 98:2 hexane/EtOAc) to afford 18.4
mg (59%) of 24 as an orange oil. 1H-NMR (400.13 MHz, (CD3)2CO): 
7.27 – 7.16 (m, 2H, ArH), 7.14 – 6.99 (m, 3H, ArH), 6.84 – 6.70 (m, 3H),
6.66 (d, J = 18.8 Hz, 1H), 6.41 (d, J = 15.0 Hz, 1H), 6.4 – 6.32 (d, J =
10.5 Hz, 2H), 6.26 – 6.17 (m, 3H), 5.91 (d, J = 18.8 Hz, 1H), 2.20 (s, 2H,
SiMe2CH2Ph), 2.04 (m, 2H), 1.99 (s, 6H, 2xC-CH3), 1.89 (s, 3H, C-CH3),
1.71 (s, 3H, C-CH3), 1.66 – 1.58 (m, 2H), 1.52 – 1.46 (m, 2H), 1.04 (s,
6H, C1-(CH3)2), 0.08 (s, 6H, SiMe2Bn) ppm. 13C-NMR (100.16 MHz,
(CD3)2CO): δ 150.3 (d), 141.1 (s), 139.0 (d), 138.9 (s), 138.4 (d), 137.9
(s), 137.5 (s), 136.9 (s), 134.6 (d), 133.4 (d, 2x), 132.2 (d), 131.0 (s),
129.9 (d, 2x), 129.3 (d, 2x), 129.1 (d), 127.5 (d), 127.0 (d), 126.5 (d),
125.0 (d), 40.6 (t), 35.1 (s), 33.8 (t), 29.5 (q, 2x), 26.7 (q), 22.1 (t), 20.1
(q), 13.0 (t), 12.5 (q), 12.5 (q), -2.9 (q, 2x) ppm. IR (NaCl): ν 2921 (s, C-
H), 1566 (w), 960 (s), 847 (s) cm-1. UV (MeOH): λmax 403, 373, 352 nm.
MS (ESI+-TOF): m/z 497 ([M+H]+, 2), 413 (8), 285 (18), 356 (13), 255
(100). HRMS (ESI+): Calcd. for C35H49Si ([M+H]+), 497.3595; found,
497.3598.
1
yield) of 19 as a red oil. H-NMR (400.13 MHz, C6D6): δ 7.20 – 7.10 (m,
5H, SiMe2CH2Ph), 7.09 – 6.96 (m, 2H), 6.51 – 6.32 (m, 2H), 6.04 (d, J =
11.0 Hz, 1H), 5.92 (d, J = 18.8 Hz, 1H), 2.11 (s, 2H, SiMe2CH2Ph), 1.84
(s, 3H, C-CH3), 1.70 (s, 3H, C-CH3), 0.26 (s, 6H, Si(CH3)3), 0.11 (s, 6H,
SiMe2Bn) ppm. 13C-NMR (100.16 MHz, C6D6): δ 149.6 (d), 140.1 (s),
138.2 (s), 137.8 (d), 133.3 (d), 131.4 (d), 129.9 (d), 128.6 (d, 2x), 128.5
(d, 2x), 127.1 (d), 124.6 (d), 119.3 (s), 110.2 (s), 95.4 (s), 30.4 (d), 26.4
(t), 17.6 (q), 12.4 (q), 0.2 (q, 2x), -3.1 (q, 3x) ppm. IR (NaCl): ν 2961 (m,
C-H), 2847 (w, C-H), 2143 (w, C-C≡H), 1668 (s), 1250 (m), 844 (s) cm-1.
UV (MeOH): λmax 239 nm. MS (ESI+-TOF): m/z 379 ([M+H]+, 100), 149
(23). HRMS (ESI+): Calcd. for C24H35Si2 ([M+H]+), 379.2276; found,
379.2272.
(1E,3E,5E,7E,9E)-10-[9-(Benzyldimethylsilyl)-3,8-dimethyl-1,3,5,7,9-
pentaen-1-yl]-dimethylsilanol (6). To a cooled (0 °C) solution of 19
(0.614 g, 1.621 mmol) in MeOH (7.4 mL), K2CO3 (2.688 g, 19.452 mmol)
was added. The reaction mixture was stirred at 25 °C for 1 h and water
was added. The mixture was extracted with Et2O (4x), the combined
organic layers were dried (Na2SO4) and the solvent was evaporated. The
residue was used in the next step without further purification.
To a solution of Pt(DVDS) (0.157 mL, 2% in xylene, 0.007 mmol) and
tBu3P (7 μL,
1 M in toluene, 0.007 mmol) in THF (5 mL),
ethoxydimethylsilane (0.224 g, 2.153 mmol) was added. After stirring for
30 min at 25 °C a solution of 20 (0.406 g, 1.435 mmol) in THF (1 mL)
was added and the reaction mixture was stirred at 25 °C for 1 h. Then the
solvent was evaporated. To a solution of the residue obtained above in
CH3CN (15 mL) an aqueous buffer solution of HOAc/NaOAc (1.0 M, 5 mL,
pH 5.0) was added and the resulting mixture was stirred at 25 °C for 15 h.
Water was added and the aqueous layers were extracted with Et2O (3x).
The combined organic layers were washed with water (2x) and a
saturated aqueous solution of NaCl (2x) and dried and the solvent was
evaporated. The residue was purified by column chromatography (silica
gel, 85:15 hexane/EtOAc) to afford 0.237 g (43%) of 6 as a yellow oil. 1H-
NMR (400.13 MHz, C6D6):  7.21 – 7.17 (m, 2H, ArH), 7.07 – 6.95 (m,
3H, ArH), 6.86 (d, J = 18.8 Hz, 1H), 6.73 (d, J = 18.8 Hz, 1H), 6.69-6.60
(m, 2H), 6.30-6.20 (m, 2H), 5.93 (d, J = 18.8 Hz, 1H), 5.92 (d, J = 18.8
Hz, 1H), 2.13 (s, 2H, SiMe2CH2Ph), 1.82 (s, 6H, 2xC-CH3), 0.23 (s, 6H,
Si(OH)Me2 or SiMe2Bn), 0.13 (s, 6H, Si(OH)Me2 or SiMe2Bn) ppm. 13C-
NMR (100.16 MHz, C6D6): δ 149.7 (d, 2x), 140.2 (s), 137.3 (s), 137.2 (s),
134.2 (d), 133.7 (d), 131.3 (d), 131.2 (d), 128.7 (d, 2x), 128.6 (d, 2x),
127.5 (d), 126.6 (d), 124.6 (d), 26.5 (t), 12.4 (q, 2x), 0.6 (q, 2x), -3.1 (q,
2x) ppm. IR (NaCl): ν 2956 (m, C-H), 1568 (w), 1214 (w), 843 (m), 771
(s) cm-1. UV (MeOH): λmax 372, 353 nm. MS (ESI+-TOF): m/z 383 ([M+H]+,
100), 362 (18), 341 (13), 301 (15), 270 (19), 242 (18). HRMS (EI+): Calcd.
for C23H35OSi2 ([M+H]+), 383.2218; found, 383.2210.
β,β-Carotene (7).
Procedure A: (Preparation of
7
from symmetrical
bissilylpentaene reagent 5) To a cooled (0 °C) solution of 5 (12.2 mg,
0.027 mmol) in THF (0.76 mL) was added TBAF (0.061 mL, 1M in THF,
0.061 mmol). After stirring for 40 min at 0 °C, a solution of 1 (12.0 mg,
0.038 mmol) in THF (0.76 mL) and Pd2dba3·CHCl3 (5.9 mg, 0.006 mmol)
were added and the reaction mixture was stirred at 0 °C for 1 h and at
25 °C for 15 min. After reaction completion (as indicated by tlc), a
saturated aqueous solution of NH4Cl was added and the mixture was
extracted with Et2O (3x). The combined organic layers were washed with
brine (1x), dried (Na2SO4) and concentrated. After purification by column
chromatography (CN-silica gel, 98:2 hexane/EtOAc), 20.4 mg (61%) of
an orange oil identified as β,β-carotene 7 were isolated.[36]
(1E,3E,5E,7E,9E)-10-Benzyldimehtylsilyl-benzyl-10-
(ethoxydimethylsilyl)-3,8-dimethyldeca-1,3,5,7,9-pentaene) (21). To a
cooled (0 °C) solution of 19 (0.65 g, 1.72 mmol) in MeOH (7.8 mL),
K2CO3 (2.85 g, 20.60 mmol) was added. The mixture was stirred at 25 °C
for 1 h and water was added. The resulting mixture was extracted with
Procedure B: (One-pot sequential preparation of 7 from bissilylpentaene
reagent 6 without isolation of octaenylsilane 23) To a solution of 6 (36.4
mg, 0.095 mmol) in dioxane (0.45 mL) was added KOTMS (0.095 mL,
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10.1002/chem.201903080
Chemistry - A European Journal
FULL PAPER
2M in THF, 0.190 mmol). After stirring for 15 min at 25 °C, a solution of 1
(30 mg, 0.095 mmol) in dioxane (0.5 mL) and Pd(dba)2 (1.2 mg, 0.002
mmol) were added and the reaction mixture was stirred at 25 °C for 1.5
h. Then, the reaction mixture was filtered through a silica gel plug, the
solids were washed with EtOAc (3x), and the solvent was evaporated.
The residue was dissolved in THF (0.5 mL) and TBAF (0.190 mL, 1M in
THF, 0.190 mmol) was then added. After stirring for 15 min at 25 °C, a
solution of 6 (30 mg, 0.095 mmol) in THF (0.5 mL) and Pd(dba)2 (1.2 mg,
0.002 mmol) were added and the reaction mixture was stirred at 25 °C
for 1.5 h. Then, the reaction mixture was filtered through a silica gel plug,
the solids were washed with EtOAc (3x) and the solvent was evaporated.
After purification by column chromatography (CN-silica gel, 98:2
hexane/EtOAc), 33.8 mg (66%) of an orange oil identified as β,β-
carotene 7 were isolated.[36]
Procedure C: (Preparation of 7 from octaenylsilane 23) TBAF (0.066 mL,
0.066 mmol, 1M in THF) was added to a cooled (0 °C) solution of 23 (33
mg, 0.066 mmol) in THF (0.6 mL). After stirring for 30 min at 0 °C, a
solution of 1 (20 mg, 0.063 mmol) in THF (0.766 mL) and Pd2dba3·CHCl3
(3.3 mg, 0.003 mmol) were added and the reaction mixture was stirred at
0 °C for 1 h and at 25 °C for 15 min. After completion, a saturated
aqueous solution of NH4Cl was added and the reaction mixture was
extracted with Et2O (3x). The combined organic layers were washed with
a saturated aqueous solution of NaCl (1x), dried and concentrated. After
purification by column chromatography (CN-silica gel, 98:2
hexane/EtOAc), 30.5 mg (90%) of an orange oil identified as β,β-
carotene 7 were isolated.[36]
(3R,3’R)-Zeaxanthin (8). TBAF (0.072 mL, 1M in THF, 0.072 mmol) was
added to a cooled (0 °C) solution of 5 (14.4 mg, 0.032 mmol) in THF (0.9
mL). After stirring for 40 min at 0 °C, a solution of 22[36] (15.0 mg, 0.045
mmol) in THF (0.9 mL) and Pd2dba3·CHCl3 (7.1 mg, 0.007 mmol) were
added and the reaction mixture was stirred at 0 °C for 1h and at 25 °C for
15 min. After completion, a saturated aqueous solution of NH4Cl was
added and the resulting mixture was extracted with EtOAc (3x). The
combined organic layers were washed with brine (1x), dried and
concentrated. After purification by column chromatography (CN-silica gel,
90:10 hexane/EtOAc), 14 mg (55%) of an orange oil identified as
(3R,3’R)-zeazanthin 8 were isolated.[36]
J = 14.9 Hz, 1H), 6.26 – 6.19 (m, 2H), 6.19 – 6.08 (m, 4H), 6.05 (d, J =
11.5 Hz, 1H), 2.08 – 1.99 (m, 4H), 1.97 (s, 6H), 1.95 (s, 6H), 1.76 (s, 3H),
1.71 (s, 3H), 1.66 – 1.59 (m, 4H), 1.51 – 1.39 (m, 4H), 1.04 (s, 6H), 1.03
(s, 6H) ppm. 13C-NMR (100.16 MHz, CDCl3): δ 138.4 (s), 138.1 (s), 137.8
(d), 136.7 (d), 136.4 (s, 2x), 136.1 (s), 134.6 (d), 130.9 (d), 132.4 (d),
130.2 (d, 3x), 130.0 (d), 129.6 (s, 2x), 129.5 (d, 2x), 128.5 (d), 127.1 (s),
127.0 (d), 123.8 (d), 39.7 (t, 2x), 34.4 (s, 2x), 33.3 (t, 2x), 29.1 (q), 28.6
(q, 2x), 22.0 (q), 21.9 (q), 20.9 (q), 19.4 (t, 2x), 13.0 (q), 12.9 (q) ppm. UV
(MeOH): λmax 426 nm. HRMS (ESI+): Calcd. for C40H56 ([M+H]+),
536.4375; found, 536.4376.
7,8-Dihydro-β,β-carotene (10).[40] TBAF (0.33 mL, 0.33 mmol, 1M in
THF) was added to a cooled (0 °C) solution of 23 (72 mg, 0.145 mmol) in
THF (1.3 mL). After stirring for 30 min at 0 °C, a solution of 25 (40 mg,
0.126 mmol) in THF (1.3 mL) and Pd2dba3·CHCl3 (13 mg, 0.013 mmol)
were added, and the reaction mixture was stirred at 0 °C for 1h and at
25 °C for 15 min. After completion, a saturated aqueous solution of
NH4Cl was added and the resulting mixture was extracted with Et2O (3x).
The combined organic layers were washed with a saturated aqueous
solution of NaCl (1x), dried and concentrated under vacuum. After
purification by column chromatography (CN-silica gel, 98:2
hexane/EtOAc), 53 mg (78%) of an orange solid identified as 7,8-
1
dihydro-β,β-carotene 10 were isolated. H-NMR (400.13 MHz, CDCl3): δ
6.50 – 6.09 (m, 11H), 5.98 (d, J = 11.1 Hz, 1H), 2.02 (t, J = 6.0 Hz, 4H,
2xCH2), 1.97 (s, 6H, C-CH3 + C-CH3), 1.95 (s, 3H, C-CH3), 1.94 – 1.89
(m, 4H, 2xCH2), 1.87 (s, 3H, C-CH3), 1.72 (s, 3H, C-CH3), 1.63 (s, 3H, C-
CH3), 1.62 – 1.54 (m, 4H, 2xCH2), 1.49 – 1.45 (m, 4H, 2xCH2), 1.45 –
1.41 (m, 4H, 2xCH2), 1.03 (s, 6H, C-(CH3)2), 1.01 (s, 6H, C-(CH3)2)
ppm.[40] 13C-NMR (100.16 MHz, CDCl3): δ 140.8 (s), 138.1 (s), 138.0 (d),
137.4 (d), 136.6 (d), 136.3 (s), 136.0 (d), 135.5 (s), 135.4 (d), 132.6 (d),
131.6 (d), 131.0 (d), 130.2 (d), 129.6 (d), 129.5 (s), 127.4 (s), 126.7 (s),
125.3 (d), 125.2 (s), 125.0 (d), 41.0 (t), 40.0 (t), 39.8 (t), 35.2 (s), 34.4 (s),
33.3 (t), 32.9 (t), 29.1 (q, 2x), 28.8 (q, 3x), 27.9 (t), 21.9 (q), 20.0 (q), 19.7
(t), 19.4 (t), 17.2 (q), 13.0 (q, 2x) ppm. IR (NaCl): ν 2927 (s, C-H), 2364
(w, C-H), 1447 (w), 965 (s) cm-1. HRMS (ESI+): Calcd. for C40H58
([M+H]+), 538.4525; found, 538.4533.
(3R)-β-Cryptoxanthin (11). KOTMS (0.057 mL, 2M in THF, 0.114 mmol)
was added to a solution of 6 (22 mg, 0.057 mmol) in dioxane (0.5 mL).
After stirring for 15 min at 25 °C, a solution of 1 (18 mg, 0.057 mmol) in
dioxane (0.5 mL) and Pd(dba)2 (1 mg, 0.001 mmol) were added and the
reaction mixture was stirred at 25°C for 1.5 h. Then, the reaction mixture
was filtered through a silica gel plug, washing with EtOAc (3x) and the
solvent was evaporated. TBAF (0.114 mL, 1M in THF, 0.114 mmol) was
added to the solution of the residue in THF (0.5 mL). After stirring for 15
min at 25 °C a solution of 22[36] (22 mg, 0.057 mmol) in THF (0.5 mL) and
Pd(dba)2 (1 mg, 0.001 mmol) were added and the reaction mixture was
stirred at 25 °C for 1.5 h. Then, the reaction mixture was filtered through
a silica gel plug, washing with EtOAc (3x) and the solvent was
evaporated. After purification by column chromatography (CN-silica gel,
90:10 hexane/EtOAc), 18 mg (57%) of an orange oil identified as (3R)-β-
cryptoxanthin 11 were isolated. 1H-NMR data matched those previously
reported.[41] 1H-NMR (400.13 MHz, CDCl3): δ 6.70 – 6.58 (m, 4H), 6.36
(dd, J = 14.9, 3.8 Hz, 4H), 6.24 (m, 2H), 6.19 – 6.09 (m, 4H), 4.05 – 3.95
(m, 1H), 2.44 – 2.34 (m, 1H), 2.06 – 1.99 (m, 1H), 1.99 – 1.94 (m, 10H),
1.79 – 1.76 (m, 1H), 1.74 (s, 3H), 1.72 (s, 3H), 1.65 – 1.59 (m, 1H), 1.51
– 1.44 (m, 2H), 1.25 (s, 6H), 1.07 (s, 6H), 1.03 (s, 6H) ppm. HRMS
(ESI+): Calcd. for C40H56O([M+H]+), 553.4385 found, 553.4404.
9-cis-β,β-Carotene (9).
Procedure A: TBAF (0.205 mL, 1 M in THF, 0.205 mmol) was added to a
cooled (0 °C) solution of 23 (45.2 mg, 0.091 mmol) in THF (1.6 mL). After
stirring for 30 min, a solution of 24 (25 mg, 0.079 mmol) in THF (1.6 mL)
and Pd2dba3·CHCl3 (8.3 mg, 0.008 mmol) were added. After stirring at
25 °C for 2.5 h, a saturated aqueous solution of NH4Cl was added. The
mixture was extracted with EtOAc (3x) and the combined organic layers
were washed with a saturated aqueous solution of NaCl (3x) and dried
(Na2SO4) and the solvent was evaporated. The residue was purified by
column chromatography (silica gel, 90:7:3 hexane/EtOAc/Et3N) to afford
25.4 mg (60%) of a red oil identified as 9-cis-β,β-carotene 9.
Procedure B: (one pot) KOTMS (0.026 mL, 2M in THF, 0.052 mmol) was
added to a solution of 6 (9.9 mg, 0.026 mmol) in dioxane (0.3 mL). After
stirring for 15 min at 25 °C, (1E,3E)-4-iodo-3-methylbuta-1,3,3-
trimethylcyclohex-1-ene 1 (8.3 mg, 0.026 mmol) in dioxane (0.3 mL) and
Pd(dba)2 (0.6 mg, 0.001 mmol) were added and the reaction mixture was
stirred at 25°C for 1.5 h. Then, the reaction mixture was filtered through a
silica gel plug, washing with EtOAc (3x) and the solvent was evaporated.
TBAF (0.052 mL, 1M in THF, 0.052 mmol) was then added to the
solution of the residue in THF (0.5 mL). After stirring for 15 min at 25 °C,
a solution of 24 (8.2 mg, 0.026 mmol) in THF (0.5 mL) and Pd(dba)2 (0.6
mg, 0.001 mmol) were added and the reaction mixture was stirred at
25 °C for 1.5 h. Then, the reaction mixture was filtered through a silica
gel plug, washing with EtOAc (3x) and the solvent was evaporated. After
purification by column chromatography (CN-silica gel, 98:2
hexane/EtOAc), 4.5 mg (32%) of an orange oil identified as 9-cis-β,β-
Acknowledgements
We thank the Spanish MINECO (SAF2016-77620-R-FEDER)
and Xunta de Galicia (Consolidación GRC ED431C 2017/61
from DXPCTSUG; ED-431G/02-FEDER "Unha maneira de facer
1
carotene 9 were isolated. H-NMR (400.13 MHz, CDCl3): δ 6.74 (dd, J =
14.8, 11.6 Hz, 2H), 6.68 (d, J = 7.9 Hz, 1H), 6.66 – 6.54 (m, 3H), 6.28 (d,
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Catalyzed Cross-Coupling Reactions and More; de Meijere, A., Bräse,
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Europa" to CINBIO, a Galician research center 2016-2019). We
are grateful to Prof. Susana López (USC) for insightful advice on
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Khachik (Iowa) for the NMR data of compound 11.
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Keywords: carotenoids • total synthesis • Hiyama-Denmark •
cross-coupling • pentaenyl-bis-silanes
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Entry for the Table of Contents (Please choose one layout)
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Aurea Rivas, Víctor Pérez-Revenga, Rosana
Alvarez,* and Angel R. de Lera*
Bidirectional Hiyama-Denmark Cross-
Coupling Reactions of Bissilyldeca-
1,3,5,7,9-pentaenes for the Synthesis of
Symmetrical and Non-Symmetrical
Carotenoids
The Hiyama-Denmark cross-coupling reaction has been extended to the
preparation of symmetrical and nonsymmetrical carotenoids using bissilyldeca-
1,3,5,7,9-pentaenes.
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