Hiyama cross-coupling reaction in the stereospecific synthesis of retinoids

Article abstract of DOI:10.1021/ol802551a

The first application of the Hiyama reaction to the synthesis of retinoids is reported. A range of organosilicon moieties (siloxanes, silanols and three kinds of "safety-catch" silanols) were successfully coupled, under activation, to obtain trans-retinol or 11-cis-retinol with high yield and stereoselectivity. The advantageous properties of the silicon-based coupling partners and the mild reaction conditions firmly establish the Hiyama reaction as a viable (even superior) alternative to the traditional Suzuki and Stille couplings in the retinoid field.

Full text of DOI:10.1021/ol802551a

ORGANIC
LETTERS
2009
Vol. 11, No. 1
141-144
Hiyama Cross-Coupling Reaction in the
Stereospecific Synthesis of Retinoids
Javier Montenegro, Julia´n Bergueiro, Carlos Saa´, and Susana Lo´pez*
Departamento de Química Orga´nica, Facultade de Química, UniVersidade de Santiago
de Compostela, 15782 Santiago de Compostela, Spain
susana.lopez.esteVez@usc.es
Received November 5, 2008
ABSTRACT
The first application of the Hiyama reaction to the synthesis of retinoids is reported. A range of organosilicon moieties (siloxanes, silanols and
three kinds of “safety-catch” silanols) were successfully coupled, under activation, to obtain trans-retinol or 11-cis-retinol with high yield and
stereoselectivity. The advantageous properties of the silicon-based coupling partners and the mild reaction conditions firmly establish the
Hiyama reaction as a viable (even superior) alternative to the traditional Suzuki and Stille couplings in the retinoid field.
Retinoidssvitamin A (1), and its structural and functional
analoguesshave been the subject of intense research for
decades because of their critical roles in a variety of
biological processes, including vision, cell growth and
differentiation, reproduction, embryonic development, and
the immune response.1 Synthetic studies also abound in this
field, with the classical routes based on olefin elongation
procedures (the Wittig, Horner-Emmons, and Julia reactions)
being replaced in the last years by more stereoselective
approaches.2 In this respect, transition metal-catalyzed cross-
coupling methods,3 the well-established Stille and Suzuki
reactions in particular, have been extensively applied to the
synthesis of retinoids and related polyenes.4 Nevertheless,
significant drawbacks to these reactions, including the
toxicity and high molecular weight of organostannanes and
the limited stability of organoboranes still constitute serious
limitations and, therefore, the development of more efficient
approaches continues to be a major objective.
Organosilicon compounds have recently emerged as an
attractive alternative to traditional organometallic donors
because of their high chemical stability, low toxicity and
ease of handling, and the availability and relatively low cost
of the silicon-containing starting materials. Their inherent
reluctance to undergo cross-coupling, as a result of the
absence of a significant dipole associated with C-Si bond,
has been successfully overcome, and a variety of heteroatom-
containing silicon species (halosilanes, siloxanes, polysilox-
anes, and silanols) have been shown to couple efficiently to
organic electrophiles upon treatment with an appropriate
(4) Selected papers on the Suzuki reaction: (a) Torrado, A.; Iglesias,
B.; Lo´pez, S.; de Lera, A. R. Tetrahedron 1995, 51, 2435. (b) de Lera,
A. R.; Iglesias, B.; Rodr´ıguez, J.; Alvarez, R.; Lo´pez, S.; Villanueva, X.;
Padro´s, E. J. Am. Chem. Soc. 1995, 117, 8220. (c) Uenishi, J.; Kawahama,
R.; Yonemitsu, O.; Wada, A.; Ito, M. Angew. Chem., Int. Ed. 1998, 37,
320. (d) Uenishi, J.; Matsui, K.; Wada, A. Tetrahedron Lett. 2003, 44, 3093.
Selected papers on the Stille reaction: (e) Alvarez, R.; Iglesias, B.; Lo´pez,
S.; de Lera, A. R. Tetrahedron Lett. 1998, 39, 5659. (f) Thibonnet, J.; Prie´,
G.; Abarbri, M.; Ducheˆne, A.; Parrain, J.-L. Tetrahedron Lett. 1999, 40,
3151. (g) Domínguez, B.; Iglesias, B.; de Lera, A. R. Tetrahedron 1999,
55, 15071. (h) Wada, A.; Fukunaga, K.; Ito, M. Synlett 2001, 800. (i) Wada,
A.; Fukunaga, K.; Ito, M.; Mizuguchi, Y.; Nakagawa, K.; Okano, T. Bioorg.
Med. Chem. 2004, 12, 3931. (j) Wada, A.; Matsuura, N.; Mizuguchi, Y.;
Nakagawa, K.; Ito, M.; Okano, T. Bioorg. Med. Chem. 2008, 16, 8471.
(1) The Retinoids: Biology, Chemistry and Medicine; Sporn, M. B.,
Roberts, A. B., Goodman, D. S., Eds.; Raven: New York, 1993.
(2) For a recent review of the synthesis of retinoids, see: Domínguez,
B.; Alvarez, R.; de Lera, A. R. Org. Prep. Proc. Int. 2003, 35, 239.
(3) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998. (b) Metal-Catalyzed
Cross-Coupling Reactions, 2nd ed.; de Meijere, A.; Diederich, F., Eds.;
Wiley-VCH: Weinheim, Germany, 2004; Vols 1 and 2.
10.1021/ol802551a CCC: $40.75
Published on Web 12/09/2008
2009 American Chemical Society

palladium catalyst and a nucleophilic promoter (the Hiyama
reaction).5 Furthermore, the advent of several families of
“safety-catch” silanols, that is, stable precursors that can be
unmasked in situ to reveal the reactive silanol itself (siletanes,
silyl hydrides, benzyl-, triallyl-, aryl-, 2-pyridyl-, and 2-thie-
nylsilanes),6 has raised the synthetic potential of the reaction
and firmly established organosilicon cross-coupling as a
viable alternative to the Suzuki and Stille protocols.
Encouraged by the growing significance of the silicon-
based reagents, and as part of our ongoing research on the
chemistry and biology of retinoids,7 we decided to investigate
the possibility of applying the Hiyama reaction to the
synthesis of these highly conjugated polyenes. Here we
describe its use to synthesize the parent metabolite trans-
retinol (vitamin A, 1) and the visual chromophore 11-cis-
retinal (2).
Scheme 2. Synthesis of (1E,3E)-Dienylsilanes 5
Scheme 1. Retrosynthetic Analysis
hydrosilylation (Method A), metal-catalyzed cross-coupling
reaction of the halide to a silicon nucleophile (Method B),
and lithium-halogen exchange followed by anion trapping
with a silicon electrophile (Method C).
The most direct and atom-economical way of synthesizing
alkenylsilanes is hydrosilylation of terminal alkynes (Method
A),8 and a number of transition metal catalysts have been
devised to perform this reaction regio- and stereoselectively.
Cationic rhodium complexes and platinum catalysts generally
afford the ꢀ-(E)-isomer through syn-addition;9 neutral rhod-
ium catalysts usually give the ꢀ-(Z)-vinylsilane as the major
product;9 and [RhI(PPh3)3] can be used to obtain, at will,
either (E)- or (Z)-alkenylsilanes, depending on the reaction
conditions.10 Unlike most other Rh catalysts, [RhI(PPh3)3]
also performs hydrosilylation with silane reagents containing
heteroatoms.11 However, in this work the synthesis of
E-siloxane 5a was significantly more efficient using Pt(D-
VDS) and t-Bu3P,12 which gave a 92% yield in 1 h at rt
(Scheme 2), than with other platinum catalysts [Cl2PtCOD,
H2PtCl6] or [RhI(PPh3)3] (data not shown); and hydrolysis
of 5a at optimal pH (pH ) 5, CH3CN 1.0 M HOAc/NaOAc
buffer)13 cleanly provided silanol 5b in 89% overall yield
for the one-pot silylation-hydrolysis procedure (Scheme 2).
No attempt was made to prepare siletane 5c by this
procedure, because the required hydrosilane reagent is not
commercially available; but the conditions optimized for 5a
gave even better results in the cases of benzylsilane 5d and
silyl hydride 5e, which were obtained in almost quantitative
yield (Scheme 2).
In both cases we emulated previous Suzuki and Stille
approaches4a,7c byemployingthehighlyconvergent“C14+C6”
strategy, in which the key step is the construction of the
central C10-C11 single bond. As the electrophilic 14-carbon
fragment we planned to use trienyl iodide 3 or triflate 4 (both
prepared as described previously),4a,7c and as the 6-carbon
fragment we planned to use a range of trans- and cis-alkenyl
moieties (dienyl compounds 5 and 6) comprising two types
of oxygen-substituted silanes (siloxanes a and silanols b)
and three kinds of “safety-catch” silanols (siletanes c,
benzylsilanes d and silyl hydrides e) (Scheme 1). To prepare
dienylsilanes 5 and 6, we initially considered three estab-
lished one-step procedures starting from enyne 7 or a vinyl
iodide (8 or 10) (Schemes 2 and 3): metal-catalyzed
(5) (a) Hiyama, T.; Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471. (b)
Hiyama, T. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter 10.
(c) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835. (d)
Denmark, S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002, 50, 1531. (e)
Hiyama, T.; Shirakawa, E. Top. Curr. Chem. 2002, 219, 61. (f) Denmark,
S. E.; Ober, M. H. Aldrichimica Acta 2003, 36, 75. (g) Sahoo, A. K.; Oda,
T.; Nakao, Y.; Hiyama, T. AdV. Synth. Catal. 2004, 346, 1715. (h) Denmark,
S.; Sweis, R. F. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004;
Vol. 1, Chapter 4.
Unfortunately, attempts to prepare the Z-dienylsilanes 6
by formal anti-hydrosilylation of enyne 7, under tunable
[(Cp*RhCl2)2]9 or stereodivergent [RhI(PPh3)3]10 conditions,
afforded only the corresponding E-isomers 5 (Scheme 3).14
142
Org. Lett., Vol. 11, No. 1, 2009

In this work, the metalation of E-vinyl iodide 8 with n-BuLi,
followed by trapping of the resulting anion with hexameth-
ylcyclotrisiloxane (D3) or chloromethylsilacyclobutane, un-
eventfully afforded silanol 5b and siletane 5c in yields of
80% and 86%, respectively (Scheme 2). Surprisingly,
however, failure met attempts to trap this vinyl anion with
benzyldimethylchlorosilane or diisopropylchlorosilane to
obtain silanes 5d and 5e, and it was similarly impossible to
obtain any of the cis-silanes 6 by applying Method C to cis-
vinyl iodide 10. In all these cases of failure, the inability of
the anions that were generated to trap the silicon electrophile
resulted in the main reaction product after workup being the
terminal alkene 9 (Scheme 3).
Scheme 3. Synthesis of (1Z,3E)-Dienylsilanes 6
In view of the apparent impossibility of preparing cis-
silanes 6 by means of one-step protocols, we turned to a
two-step sequence based on the cis-selective reduction of
the corresponding 1-alkynylsilane precursors (Method D).18
Gratifyingly, the precursors required for 6c-e, alkynylsilanes
11c-e were obtained uneventfully by metalation of enyne
7 and anion trapping with chloromethylsilacyclobutane,
benzyldimethylchlorosilane, or chlorodiisopropylsilane; sub-
sequent reaction with Cp2Zr(H)Cl19 and pentane afforded
the desired coupling partners 6c-e in yields of 77, 76, and
58%, respectively (Scheme 3). Unfortunately, the method
could not be applicable to the preparation of 6a-b because
of the unavailability of the required silicon electrophile and
the instability of the alkynylsilane precursor, respectively.
With the organosilicon reagents 5a-e and 6c-e in hand,
we investigated the Hiyama cross-coupling reactions. Ad-
dition of TBAF (1.0 M in THF, 2-3 equiv) to a solution of
5 or 6 (1.5-2.5 equiv) in THF, followed by stirring for 30
min at rt, sequential addition of trienyl iodide 3 and
Pd2(dba)3.CHCl3 (0.05-0.1 equiv) and stirring for a further
1-4 h, afforded retinyl ethers 12 and 13 as pure isomers in
yields that in most cases were in the range 75-90% (Scheme
We therefore turned our attention to Method B. Although
the cross-coupling reaction of organic halides to a silicon
source (disilanes, monohydrosilanes, or dihydrosilanes), using
Pd, Rh, or Pt complexes as catalysts, has proven to be a
useful route to functionalized arylsilanes,15 only two in-
stances of its use for silicon-alkenyl-carbon bond formation
have been reported to date:16 Hiyama prepared vinyl- and
dienylsilanes by coupling the corresponding halides to
hexamethyldisilane under TASF-promoted Pd(0) catalysis;
and Masuda reported the efficient coupling of alkenyl iodides
to hydrosilanes using Pd2dba3.CHCl3 as catalyst, KOAc as
base, and amide solvents (NMP). Discourangingly, in the
present work, neither of these protocols allowed the prepara-
tion of silanes 6 from iodide 10 or of silanes 5 from iodide
8 (Schemes 2 and 3), affording only starting materials or
complex reaction mixtures.
(12) (a) Chandra, G.; Lo, P. Y.; Hitchcock, P. B.; Lappert, M. F.
Organometallics 1987, 6, 191. (b) Denmark, S. E.; Wang, Z. Org. Lett.
2001, 3, 1073.
The reaction of silicon electrophiles with organo-lithium
or organomagnesium reagents (Method C) is a classical
means of obtaining access to organosilicon compounds.17
(13) Denmark, S. E.; Kallemeyn, J. M. Org. Lett. 2003, 5, 3483.
(14) Possibly through isomerization of initially produced Z-isomers, via
an insertion-ꢀ-elimination mechanism, in the presence of a catalytic amount
of hydrosilane and the Rh catalyst. See: Mori, A.; Takahisa, E.; Nishihara,
Y.; Hiyama, T. Can. J. Chem. 2001, 79, 1522.
(6) Spivey, A. C.; Gripton, C. J. G.; Hannah, J. P. Curr. Org. Synth.
2004, 1, 211.
(7) (a) Lo´pez, S.; Rodríguez, V.; Montenegro, J.; Saa´, C.; Alvarez, R.;
Lo´pez, C. S.; de Lera, A. R.; Simo´n, R.; Lazarova, T.; Padro´s, E.
Chembiochem 2005, 6, 2078. (b) Silva, C.; Nieto, O.; Lo´pez, S.; de Lera,
A. R. J. Comput. Chem. 2006, 27, 116. (c) Lo´pez, S.; Montenegro, J.; Saa´,
C. J. Org. Chem. 2007, 72, 9572.
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Suzuki, K.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62, 8569. (b)
Manoso, A. S.; DeShong, P. J. Org. Chem. 2001, 66, 7449. (c) Yamanoi,
Y. J. Org. Chem. 2005, 70, 9607. Pd (dihydrosilanes): (d) Yamanoi, Y.;
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Chem., Int. Ed. Engl. 1978, 17, 279. (f) See ref 13. Rh catalyst: (g) Murata,
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4, 1843. (h) Yamanoi, Y.; Nishihara, H. Tetrahedron Lett. 2006, 47, 7157.
(i) Murata, M.; Yamasaki, H.; Ueta, T.; Nagata, M.; Ishikura, M.; Watanabe,
S.; Masuda, Y. Tetrahedron 2007, 63, 4087. Pt catalyst: (j) Hamze, A.;
Provot, O.; Alami, M.; Brion, J.-D. Org. Lett. 2006, 8, 931.
(8) (a) Ojima, I. In The Chemistry of Organic Silicon Compounds; Patai,
S., Rappoport, Z., Eds.; John Wiley: Chichester, 1989; p 1479. (b) Hiyama,
T.; Kusumoto, T. In ComprehensiVe Organic Synthesis; Trost, B. M.,
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I.; Li., Z.; Zhu, J. In The Chemistry of Organic Silicon Compounds;
Rappoport, Z., Apeloig, Y., Eds.; Wiley: New York, 1998; p 1687.
(9) For a recent example of tunable selectivity using rhodium catalysts,
see: Faller, J. W.; D’Alliessi, D. G. Organometallics 2002, 21, 1743.
(10) (a) Mori, A.; Takahisa, E.; Kajiro, H.; Hirabayashi, K.; Nishihara,
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Takahisa, E.; Kajiro, H.; Nishihara, Y.; Hiyama, T. Macromolecules 2000,
33, 1115. (d) Mori, A.; Takahisa, E.; Yamamura, Y.; Kato, T.; Mudalige,
A. P.; Kajiro, H.; Hirabayashi, K.; Nishihara, Y.; Hiyama, T. Organome-
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reagent has been reported, for example, in ref 7c.
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Org. Lett., Vol. 11, No. 1, 2009
143

silylated enyne
7 with tetramethyldisiloxane, under
t-Bu3P-Pt(DVDS) catalysis, and then coupled the resulting
vinyldisiloxane in situ to trienyl iodide 3 under Pd catalysis
with activation by fluoride, obtaining trans-retinyl ether 12
in a remarkable 74% overall yield.
Scheme 4. Hiyama Cross-Coupling Reactions
By contrast with iodide 3, triflate 4 failed to couple to 5
or 6. Indeed, very few examples of triflate-organosilicon
coupling have been reported in the literature,23 although
Hiyama described a pioneer coupling of fluorosilanes with
aryl and alkenyl triflates using Pd(PPh3)4 and TBAF, and
Denmark coupled alkenylsilanols with triflates and nonaflates
using TBAF·3H2O, PdBr2 and (2-biphenyl)(t-Bu)2P. In the
present study, neither of these protocols worked, the only
products isolated from the reaction mixtures being starting
materials.
Finally, the synthesis of the target retinoids was completed
by deprotection of retinyl ethers 12 and 13 [TMSCl, H2O,
MeOH, 5min], which afforded trans-retinol (1) and 11-cis-
retinol (14) in 74 and 83% yield, respectively, and subsequent
oxidation of 14 [BaMnO4, CH2Cl2] to obtain 11-cis-retinal
(2) in 90% yield (Scheme 4).
4). Fluoride-free coupling of iodide 3 to silanol 5b was also
possible but was rather less efficient: under Ag2O activation20
[Pd(PPh3)4, 50 °C, 12 h], the yield of the retinyl ether 12
was 61%, while under TMSOK activation21 (Pd2dba3,
dioxane, 3 h), the reaction proceeded at rt but the yield was
again lower than with TBAF (74% as against 89%).
To sum up, the Hiyama cross-coupling reaction has been
applied, for the first time, to the stereospecific synthesis of
retinoids. The approach is inexpensive, harmless and highly
efficient, and establishs a reliable (even superior) alternative
to the traditional Suzuki and Stille couplings.
We also found it possible to obtain compound 12 from 7
by an efficient one-pot hydrosilylation/cross-coupling se-
quence (Scheme 4). Following Denmark,12,22 we hydro-
Acknowledgment. Support of this research by the Spanish
Ministry of Science and Innovation under Project CTQ2008-
06557BQU, and by the Xunta de Galicia under Projects
2007/XA084 and INCITE08PXIB209024PR, is gratefully
acknowledged.
(20) (a) Hirabayashi, K.; Kawashima, J.; Nishihara, Y.; Mori, A.;
Hiyama, T. Org. Lett. 1999, 1, 299. (b) Hirabayashi, K.; Mori, A.;
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C.; Schmutz, M.; Wagner, A.; Mioskowski, C. Chem.-Eur. J. 2007, 13,
OL802551A
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971
.
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