Cross-coupling reactions of organosilicon compounds in the stereocontrolled synthesis of retinoids

Article abstract of DOI:10.1002/chem.201103360

This paper presents a full account of the use of Hiyama cross-coupling reactions in a highly convergent approach to retinoids in which the key step is construction of the central C10-C11 bond. Representatives of two families of oxygen-activated dienyl silanes (ethoxysilanes and silanols) and of all reported families of "safety-catch" silanols (siletanes, silyl hydrides, allyl-, benzyl-, aryl-, 2-pyridyl- and 2-thienylsilanes) were regio- and stereoselectively prepared and stereospecifically coupled to an appropriate electrophile by treatment with a palladium catalyst and a nucleophilic activator. Both all-trans and 11-cis-retinoids, and their chain-demethylated analogues, were obtained in good yields regardless of the geometry (E/Z) and of the steric congestion in each fragment. This comprehensive study conclusively establishes the Hiyama cross-coupling reaction, with its mild reaction conditions and stable, easily prepared, ecologically advantageous silicon-based coupling partners, as the most effective route to retinoids reported to date.

Full text of DOI:10.1002/chem.201103360

FULL PAPER
DOI: 10.1002/chem.201103360
Cross-Coupling Reactions of Organo
ACHTUNGERTNsNUNG ilicon Compounds in the
Stereocontrolled Synthesis of Retinoids
Juliꢀn Bergueiro,[a] Javier Montenegro,[b] Fermꢁn Cambeiro,[b] Carlos Saꢀ,[b] and
Susana Lꢂpez*[a]
Abstract: This paper presents a full ac-
count of the use of Hiyama cross-cou-
pling reactions in a highly convergent
approach to retinoids in which the key
silanes) were regio- and stereoselec-
tively prepared and stereospecifically
coupled to an appropriate electrophile
by treatment with a palladium catalyst
and a nucleophilic activator. Both all-
trans and 11-cis-retinoids, and their
chain-demethylated analogues, were
obtained in good yields regardless of
the geometry (E/Z) and of the steric
congestion in each fragment. This com-
prehensive study conclusively estab-
lishes the Hiyama cross-coupling reac-
tion, with its mild reaction conditions
and stable, easily prepared, ecologically
advantageous silicon-based coupling
partners, as the most effective route to
retinoids reported to date.
À
step is construction of the central C10
C11 bond. Representatives of two fam-
ilies of oxygen-activated dienyl silanes
(ethoxysilanes and silanols) and of all
reported families of “safety-catch” sila-
nols (siletanes, silyl hydrides, allyl-,
benzyl-, aryl-, 2-pyridyl- and 2-thienyl-
À
Keywords: C C coupling · organic
synthesis
·
retinoids
·
silicon
·
stereochemistry
Introduction
retinoids play crucial roles in a variety of biological process-
es that are critically dependent on the geometry of the poly-
ene side chain and the nature of its polar terminal group.[1]
All-trans-retinol (1) is required for the normal development
of many cell types, and is the precursor for many other reti-
noids.[2] Retinaldehydes act as chromophores in protein pho-
toreceptors:[3] 11-cis-retinal (2) is the ligand of rhodopsin,
the pigment responsible for light absorption in the visual
process,[4] and all-trans-retinal (3) binds to bacteriorhodop-
sin, the light-driven proton pump in Halobacterium salinari-
um.[5] All-trans- and 9-cis-retinoic acids (4 and 5, respective-
ly) are nuclear signalling molecules, 4 targeting retinoic acid
receptors (RARs) and 5 retinoic X receptors (RXRs); both
play essential roles in vertebrate growth and development,
the immune response and reproduction.[6]
The term retinoid collectively describes a class of over 4000
natural or synthetic molecules that are structurally and/or
functionally related to vitamin A (trans-retinol, 1). Native
In recent decades, a wide range of synthetic retinoids
have been prepared. Some have been used to study the
complex biological processes mentioned above, some have
been investigated as possible therapeutic agents with greater
potency and/or less toxicity than natural retinoids, and some
have been designed for specific technological applications.[7]
However, fuller exploration of the potential of retinoids in
these important fields of application has been held back by
the difficulties of their efficient synthesis, which centre on
two main issues: first, the sensitivity of the polyene system
to light, oxygen and many common synthetic reagents and
second, the control of stereochemistry during the formation
of each double bond.[8]
[a] J. Bergueiro, Prof. Dr. S. Lꢀpez
Departamento de Quꢁmica Orgꢂnica, Facultad de Quꢁmica
Universidad de Santiago de Compostela,
15782 Santiago de Compostela (Spain)
Fax : (+34)981-591-014
E-mail: susana.lopez.estevez@usc.es
[b] Dr. J. Montenegro, F. Cambeiro, Prof. Dr. C. Saꢂ
Centro Singular de Investigaciꢀn en Quꢁmica
Biolꢀgica y Materiales Moleculares (CIQUS)
Universidad de Santiago de Compostela (Spain)
In this latter respect, strategies based on classical olefin
elongation procedures (Wittig, Horner–Emmons, Peterson
and Julia reactions) have been successfully applied to the
trans-series but have often afforded cis-retinoids as mixtures
of isomers.[9] As a consequence, more stereoselective ap-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103360.
Chem. Eur. J. 2012, 18, 4401 – 4410
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4401

proaches have had to be developed. In particular, transition-
metal-catalysed cross-coupling reactions between organome-
tallic nucleophiles and organic electrophiles[10] (notably the
Negishi, Suzuki–Miyaura and Stille–Kosugi–Migita reac-
tions) have been extensively applied to the stereospecific
synthesis of both all-trans and cis retinoids, and currently
provide the main access route to these highly conjugated
polyenes.[11]
tion in constructing such an unstable system as the retinoid
backbone, the longest polyolefin ever prepared by this
means,[19] we synthesized the natural trans and cis retinoids
1 and 2 and, in both cases, protected analogues lacking one
or both the 9- and 13-methyl groups. To determine the influ-
ence of the substituent on the silicon atom, the protected
analogues were synthesized by using as many as possible of
a large set of organosilicon reagents that included represen-
tatives of two families of oxygen-activated silanes and of the
whole array of “masked silanols” reported to date.[20] These
organosilicon reagents were prepared by existing methods
and evaluated and compared with regard to their chemical
stability, activation conditions (fluoride-promoted or fluo-
ride-free) and suitability for these specific cross-coupling re-
actions.[21]
Unfortunately, even these powerful cross-coupling meth-
ods suffer from a number of major drawbacks, most of them
related to the nature of the organometallic donors. For in-
stance, even though organostannanes can be reacted with
a diverse assortment of electrophiles, large excesses and
forcing conditions are sometimes required to prevent homo-
dimerization of the organotin reagent, and removal of the
toxic tin byproducts is irksome. Some boronic acids and
esters are difficult to synthesise and purify, undergo degra-
dation during extended storage (some need to be prepared
in situ) and can suffer protiodeborylation under cross-cou-
pling conditions. In addition, E/Z selectivity can be partially
lost in both reactions in certain cases of low reactivity.[12] Fi-
nally, although highly stereoselective syntheses of vitamin A
by using Negishi reactions have been reported,[11a,b] draw-
backs such as the sensitivity of organozincs to moisture and
oxygen seem likely to be responsible for the scarce use of
these reagents in this field. The development of organome-
tallics that are more cost effective, easier to prepare and
handle and less toxic than existing compounds is therefore
still an active area of research.[13]
Results and Discussion
As in our previous Suzuki and Stille approaches to retinoids,
we employed the highly convergent “C14 +C6” strategy,[22] in
which the key step is the construction of the central single
[11e,17c]
À
bond C10 C11 (Scheme 1).
The C14 electrophiles (tri-
enyl iodides 6 and 6’ and triflate 7) were readily obtained
In the past decade, considerable attention has focused on
the synthetic use of silicon-containing reagents, which are
stable, easily introduced into organic substrates, applicable
to a wide range of chemical transformations and relatively
non-toxic. Though inherently reluctant to cross-couple (be-
À
cause C Si bonds have no significant associated dipole), this
impediment was successfully overcome by Hiyama and co-
workers.[14] Since then, numerous hetero
ACTHNUTRGNEUNGatom-functionalised
silicon moieties, including halosilanes, oxysilanes, silanols,
cyclic silyl ethers and polysiloxanes, have been shown to un-
dergo cross-coupling under mild conditions with aryl, alken-
yl, alkynyl and alkyl electrophiles upon treatment with an
appropriate palladium catalyst and a nucleophilic promoter.
Furthermore, the scope of the reaction has been extended
by the advent of “safety-catch” silanols,[15] which are stable
under conditions that heteroatom-substituted silanes may
not tolerate, but which can nonetheless be activated for
cross-coupling in situ. Hiyama cross-coupling is now a well-
established methodology for the synthesis of organic materi-
als[16] and complex natural products.[14l]
As part of our ongoing research into the chemistry and
biology of natural and synthetic retinoids,[17] we recently re-
ported the first application of the Hiyama reaction to the
synthesis of these highly conjugated metabolites. We found
that in this field too, organosilicon-based cross-coupling re-
actions can compete advantageously with the Suzuki and
Stille methodologies.[18] We present herein the full details of
that research. To gain insight into the behaviour of the reac-
Scheme 1. Retrosynthetic analysis.
from b-ionone by following standard synthetic routes.[11e,17c]
As the C6 organometallic partners we used trans-dienylsi-
lanes 8 and 8’ and cis-dienylsilanes 9 and 9’, in each case
with as many as possible of a wide range of silane moieties
comprising representatives of two families of oxygen-activat-
ed silanes (ethoxysilane a and silanol b) and of the whole
collection of “safety-catch” silanols (siletane c, benzylsilane
d, silyl hydride e, allylsilane f, phenylsilane g, bistrifluorome-
thylphenylsilane h, pyridylsilane i, thiophenylsilane j and
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Stereocontrolled Synthesis of Retinoids
FULL PAPER
“reusable”[23] [2-(hydroxylmethyl)phenyl]silane l). For regio-
and stereoselective preparation of these metallic intermedi-
ates, four well-established protocols were examined: transi-
tion-metal-catalysed hydrosilylation of alkynes (method A),
palladium-catalysed silylation or metal–halogen exchange/
carbanion silylation of vinyl halides (methods B and C, re-
spectively) and stereoselective reduction of alkynylsilanes
(method D).
Table 1. Synthesis of (1E,3E)-dienylsilanes 8 and 8’ by Pt-catalysed hy-
drosilylation of E enynes 10 and 10’ (method A).
Entry
Silane
H-Si
8
8’
1
2
3
4
5
6
7
8
9
a
HMe
HMe
–
HMe2BnSi
H2iPr2Si
HMe2allylSi
HMe2PhSi
HMe2ACHTUGNTREN[NUG 3,5-ACHTUGNERTN(NUNG CF3)2]PhSi
G
92
89
–
85
85
–
b[a]
c[b]
d
Synthesis of (1E,3E)-dienylsilanes 8 and 8’ and (1Z,3E)-di-
enylsilanes 9 and 9’
97
95
85
99
92
98
91
63
57
97
73
88
95
83
91
92
55
48
e
f
g
Method A: Transition-metal-catalysed hydrosilylation of
enynes 10 and 10’: Hydrosilylation of alkynes is the simplest
and most straightforward approach to alkenylsilanes. The
regio- and stereochemical outcome of the reaction depends
on factors such as the catalytic system employed (the metal
and its ligands), the substituents on the hydrosilane, reaction
parameters, such as solvent and temperature, and sometimes
even the order in which the reagents are added.[24] Pt-based
complexes usually ensure exclusive syn-addition, affording
b-(E)-alkenylsilanes (the thermodynamic products), whereas
b-(Z) products can be obtained stereoselectively by using
Rh, Ir and Ru catalysts. In fact, by changing their ligands,
Rh and Ru can be “tuned” to afford either diastereo-
mer.[25,26] Faller and DꢄAlliessi[25] found that although the
neutral rhodium dimer [(Cp*RhCl2)2] (Cp*=pentamethyl-
cyclopentadienyl) promoted the atypical anti addition of tri-
alkyl- and trialkoxy-substituted silanes to acetylene, yielding
h
i[c]
j
HMe22-PySi
HMe22-ThSi
HMe2[2-
10
11
12
k
l[d]
HMe2[2-(CH2OAc)Ph]Si
[a] Followed by acid hydrolysis: CH3CN, 1.0m HOAc/NaOAC buffer,
pH 5, 8 h. [b] This hydrosilane is not available. [c] Reaction carried out in
toluene at 1008C. [d] Followed by removal of acetoxymethylphenyl:
K2CO3, H2O/CH3OH.
and stereoselectively synthesized by using [Pt
ACHTUNGTRENNU(G DVDS)-
AHCTUNGTRENNUNG
of the steric hindrance of the enyne precursor, although
minor departures from the standard conditions (THF, RT,
1 h) had to be introduced in some cases (see the Supporting
Information). The most noteworthy of these departures con-
cerned the preparation of pyridylsilanes 8i and 8’i, which re-
quired 5h in toluene at 1008C. Also, silanols 8b and 8’b
were obtained indirectly from siloxanes 8a and 8’a (CH3CN,
1.0m HOAc/NaOAc buffer, pH 5)[29] in 89 and 85% overall
yield, respectively, for the one-pot silylation–hydrolysis pro-
cedure. Similarly, [2-(hydroxymethyl)phenyl]silanes 8l and
8’l were prepared from 8k and 8’k by deprotection under
basic conditions (K2CO3, H2O/CH3OH)[23] in 57 and 48%
combined yield for the two steps.
the Z isomers, the dicationic complex [{Rh
ACHTUNGTREN(NUNG BINAP)Cp*}-
ACHTUNGTRENNUNG(SbF6)2] (BINAP=2,2’-bis(diphenylphosphino)-1,1’-bi-
naphthyl) formed the (E)-vinylsilanes. Ozawa and co-work-
ers[26] reported that the reaction of an alkyne with a hydrosi-
lane containing aromatic substituents led to the correspond-
ing (E)-vinylsilane if performed in the presence of the
ruthenium hydride catalyst [RuCl(CO)(H)
the (Z)-vinylsilane if the rutheniumsilyl complex
[RuCl(CO)(PiPr3)2A(SiMe2Ph)] was used. Still more remarka-
bly, Mori and co-workers[27] have found that whether [RhI-
(PPh3)3] affords (E)- or (Z)-alkenylsilanes (in both cases
ACHTUNGTREN(UNNG PPh3)2], and to
A
CHTUNGTRENNUNG
Unexpectedly, the anti hydrosilylation of 10 and 10’
proved to be much more complicated. In our hands, none of
the stereodivergent conditions described by the groups of
ACHTUNGTRENNUNG
with excellent stereoselectivity) depends simply on the
order of addition of the reagents and the reaction condi-
tions: when the alkyne is added to a mixture of hydrosilane
and the catalyst, (Z)-alkenylsilanes are obtained, whereas
adding the catalyst to a mixture of the silane and alkyne and
then heating at 608C affords E products.
In this work, we first investigated selective syn hydrosily-
lation of O-protected enynols 10 and 10’ to obtain (1E,3E)-
dienylsilanes 8 and 8’. In preliminary screening runs with si-
Faller ([RhCl
(Cp*)]2, CH2Cl2),[25] Ozawa ([RuCl(CO)-
2ACHTUNGTRENNUNG
A
R
ene, 08C)[27] led to the desired (1Z,3E)-dienylsilanes 9 and
9’. In all cases, mixtures of stereoisomers were obtained,
which we attributed to isomerization of the initially pro-
duced Z vinylsilanes through an insertion–b-elimination
mechanism in the presence of a catalytic amount of hydrosi-
lane and the Rh or Ru catalysts.[30]
loxane 8a as the target, [PtACTHNUTRGNEN(UG DVDS)ACHTUGNTREN(NUGN tBu3P)] (DVDS=1,3-di-
vinyl-1,1,3,3-tetramethyldisiloxane),[28] which is soluble in or-
ganic solvents, was significantly more efficient (yield 92%
Method B: Palladium-catalysed silylation of dienyl iodides
11 and 12: Although catalytic cross-coupling of organic hal-
ides to silicon compounds, such as disilanes, monohydrosi-
lanes or dihydrosilanes, with Pd, Rh or Pt complexes as cat-
alysts, is a useful route to functionalized arylsilanes,[31] only
a few examples of its use for the synthesis of alkenylsilanes
have been reported. Notable among them are Hiyamaꢄs syn-
after 1 h in THF) than [PtCl
diene; CH2Cl2, 65%), [RhI(PPh3)3] (toluene, 608C, 62%) or
[RuCl(CO)(H)(PPh3)2] (CH2Cl2, 48%). All of the (E)-vinyl-
2ACHTUNGERTN(NUNG cod)] (cod=1,5-cycloocta-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
silanes 8 and 8’except 8c and 8’c (for which the required hy-
drosilane is not commercially available) were then regio-
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4403

S. Lꢀpez et al.
thesis of vinyl- and dienylsilanes by coupling the precursor
halides with hexamethyldisilane under tris(dimethylamino)-
sulfonium difluorotrimethylsilicate (TASF)-promoted Pd0
l and 8’d–l by trapping the same vinyl anions with other
commercially available chlorosilanes (benzyldimethylchloro-
silane, diisopropylchlorosilane, allyldimethylchlorosilane,
aryl- and heteroaryldimethylchlorosilanes) or with 1,1-di-
methyl-2-oxa-1-silaindan.[23] Moreover, it was impossible to
obtain any of the (1Z,3E)-dienylsilanes 9 by applying this
method to precursor iodide 12. In all of these unfruitful at-
tempts, the main reaction product after workup was the ter-
minal alkene 13 (Table 2), the anions generated having been
unable to trap the silicon electrophiles.
catalysis ([Pd
(HMPA), THF),[32] and Masudaꢄs selective silylation of al-
kenyl iodides with hydrosilanes by using [Pd2A(dba)3]·CHCl3
ACHTUNGTRENNUNG(PPh3)4], TASF, hexamethylphosphoramide
CTHUNGTRENNUNG
(dba=dibenzylideneacetone) as the catalyst, KOAc as the
base and amide solvents (N-methylpyrrolidone (NMP)).[33]
Discouragingly, in this work, neither of these specific proto-
cols allowed the preparation of (1E,3E)-dienylsilanes 8 from
iodide 11 or of (1Z,3E)-dienylsilanes 9 from iodide 12; only
starting materials or complex reaction mixtures were ob-
tained (Table 2). The same dissuasive results were provided
Method D: cis-Selective reduction of 1-alkynylsilanes 14 and
14’: In view of the apparent impossibility of preparing
(1Z,3E)-dienylsilanes 9 and 9’ by means of one-step proto-
cols, we turned to a two-step sequence based on the cis-se-
lective reduction of 1-alkynylsilane precursors (Table 3).
Table 2. Attempts to synthesize (1E,3E)-dienylsilanes 8 and 8’ from dien-
yliodides 11 and 11’ by metal-catalysed cross-coupling to a silicon nucleo-
phile (method B) and by lithium–halogen exchange followed by anion
trapping with a silicon electrophile (method C).
Table 3. Synthesis of (1Z,3E)-dienylsilanes 9 and 9’ by cis-selective re-
duction of 1-alkynylsilane precursors 14 and 14’ (method D).
Entry
Silane
Si-X
Me(CH2)3SiCl
Me2BnSiCl
HiPr2SiCl
Me2allylSiCl
Me2PhSiCl
Me2ACHTUNGERTNNU[G 3,5-CAHTUNGTRNEN(UNG CF3)2]PhSiCl
14
14’
9
9’
1
2
3
4
5
6
7
c
d
G
90
92
90
91
71
88
–
93
87
99
89
83
99
–
77
76
58
–
50
60
53
68
76
49
–
52
52
69
e
f[a]
g
h
b[b]
Entry
Silane
Si-X
8
8’
[a]
1
2
b
c
D3
80
86
74
96
[a] Reaction with [ZrCl(Cp)2(H)] leads to over-reduction of the allyl
group. [b] Diisopropylsilanols obtained by oxidation of diisopropylhydro-
silanes 9e and 9’e ([RuCl2(para-cymene)2], acetonitrile, H2O; overall
yield).
MeACTHNURGTNEUGN(CH2)3SiCl
[a] D3 =Hexamethylcyclotrisiloxane.
by several conditions previously reported for silylation of
aryl halides by using platinum (Me2EtOSiH, PtO2, AcONa,
Compounds 14c–h and 14’c–h were obtained uneventfully
by metalation of enynes 10 and 10’ (nBuLi, Et2O, À788C)
and anion trapping with the corresponding chlorosilanes.[36]
Our initial attempts at cis reduction of the alkynylsilanes
failed: hydrogenation by using the Lindlar catalyst,[37] reac-
tion with diisobutylaluminium hydride (DIBAL) under vari-
ous protocols[38] and reaction with a diimide precursor under
mildly basic conditions,[39] all gave poor yields and/or result-
ed in over-reduction. Eventually, however, reaction with
[ZrCl(Cp)2(H)][40] (Cp=cyclopentadienyl) in pentane af-
forded moderate to good yields of all of 9c–h and 9’c–h
except 9 f and 9’f (Table 3).[41] Similar yields were obtained
in all cases by generating the Schwartz reagent in situ
[ZrCl2(Cp)2 +DIBAL].[42] Silanols 9b and 9’b were subse-
quently prepared from hydrosilanes 9e and 9’e by rutheni-
um-catalysed hydrolytic oxidation ([RuCl2(para-cymene)]2,
H2O, 1:1 benzene/CH3CN, 1 h).[43]
NMP)[31j] or rhodium (Me2EtOSiH, [{RhCl
DMF).[31i]
ACHTUNGRTEN(UNNG cod)}2], Et3N,
Method C: Halogen–lithium exchange in dienyl iodides 11,
11’ and 12, followed by trapping with a silicon electrophile:
The use of organolithium and organomagnesium reagents
for the nucleophilic displacement of a leaving group at a sili-
con centre is a classical means of introducing silicon into an
organic molecule.[34] Direct formation of organosilanols can
similarly be accomplished by addition of the organometallic
reagent to a number of inexpensive cyclosiloxanes followed
by in situ aqueous hydrolysis of the polysiloxane intermedi-
ate.[35]
In this work, metalation of (1E,3E)-dienyl iodides 11 and
11’ with nBuLi in ether, followed by trapping of the result-
ing anions with hexamethylcyclotrisiloxane (D3) or chloro-
methylsilacyclobutane, afforded silanols 8b and 8’b, and si-
letanes 8c and 8’c, in high yields (Table 2). Surprisingly,
however, failure met all attempts to obtain derivatives 8d–
Synthesis of (1E,3E)-1,3-dienylsilanes 8 and 8’ and (1Z,3E)-
1,3-dienylsilanes 9 and 9’: Summary and characterization:
All of the targeted (1E,3E)-dienylsilanes were obtained in
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Stereocontrolled Synthesis of Retinoids
FULL PAPER
Table 4. Hiyama cross-coupling reactions.
good yields by one or another of the methods described.
Method A provided the complete collection of (1E,3E)-di-
enylsilanes except siletanes 8c and 8’c, which were prepared
by method C. This latter method also afforded silanols 8b
and 8’b, but no other silicon electrophiles were able to react
under these conditions. Method B did not work under any
of the conditions tested. Of the targeted (1Z,3E)-dienylsi-
lanes, method D afforded the siletanes (9c, 9’c) and the
benzyl (9d, 9’d), hydrosilyl (9e, 9’e) and aryl/heteroaryl (9g
and 9h, and 9’g and 9’h) derivatives, but in all other cases
we were unable to prepare the required alkynylsilane or to
bring about its cis reduction. None of the other methods
were able to produce (1Z,3E)-dienylsilanes.
The stereochemistry of the double bonds in compounds 8,
8’, 9 and 9’ was unambiguously deduced from the coupling
1
constants (J) of their H NMR spectra: values in the range
of 13–15 Hz for the double bond of b-(Z)-isomers and 18–
20 Hz for b-(E)-isomers were in good agreement with those
reported in the literature.[25] Compared to the analogous di-
enylboronates and stannanes that have previously been used
for retinoid synthesis by our group, the dienylsilanes used in
this work are more stable, and could be chromatographed
and otherwise handled without risk.[44]
Entry
8 or 8’
Si
15
16
17
18
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a
b
Me
Me2(OH)Si
G
86
88
–
86
72
–
85
89
–
86
89
Synthesis of all-trans and 11-cis-retinyl ethers: Hiyama
cross-coupling reactions: After having prepared (1E,3E)-di-
enylsilanes 8a–l and 8’a–l and (1Z,3E)-dienylsilanes 9b–e, g
and h and 9’b–e, g and h, we explored their palladium-cata-
lysed cross-coupling to trienyl iodides 6 and 6’[17c] (Table 4).
Initial experiments were carried out under standard condi-
tions by using fluoride-based activation.[45] Addition of tetra-
butylammonium fluoride (TBAF, 1.0m in THF, 2–3 equiv) to
a solution of the silane (1.5–2.5 equiv) in THF, followed by
61[a]
74[b]
85
–
–
–
c
Me
Me2BnSi
HiPr2Si
Me2allylSi
Me2PhSi
Me
Me22-PySi
Me22-ThSi
Me2[2-
88
79
79
82
–
94
84
88
–
73
73
90
79
–
90
93
79
–
83
80
84
93
–
95
75
83
–
d
e
f
77
85
82
–
85
80
80
g[c]
h
i
j
l
sequential addition of iodide and [Pd2ACHTNUTRGNE(UGN dba)3]·CHCl3 (0.05–
70
–
–
–
–
–
–
35[d]
74[e]
0.1 equiv), cleanly afforded the corresponding retinyl ethers
as pure isomers. All of the silanes except the phenyl deriva-
tives[46] coupled efficiently under very mild conditions (08C
or RT) and in short reaction times (10–30 min), regardless
of their geometry (E/Z) and of steric congestion in the elec-
trophile or the organosilicon compound. In the E series,
both oxygen-activated silanes and “safety-catch” silanols
gave excellent yields of the corresponding all-trans-retinyl
ethers 15–18, mostly in the range of 80–95% (Table 4). In
the Z series, yields were slightly lower (70–85%) probably
due to the instability of the corresponding 11-cis-retinyl
ethers 19–22. All yields were appreciably higher than those
previously reported for the analogous Suzuki and Stille ap-
proaches.[11e,n,17c]
Entry
9 or 9’
Si
19
20
21
22
16
17
18
19
20
21
b
c
d
e
g
h
iPr2(OH)Si
Me(CH2)3Si
Me2BnSi
HiPr2Si
Me2PhSi
Me
82
79
70
71
–
79
76
76
73
–
77
78
76
82
–
71
85
78
73
–
71
79
81
74
[a] Activation by Ag2O ([Pd
KOTMS ([Pd2A(dba)3]·CHCl3, dioxane). [c] No reaction under activation
by TBAF or KOTMS. [d] Activation by KOTMS (PdCl2, N-(2-diphenyl-
phosphinobenzylidene)cyclohexylamine, DMSO). [e] One-pot procedure
(Me2SiOSiMe2, [Pt
AHCTUNTGRENGUN(N dba)3]·CHCl3, 6).
CTHUNGTRENNUNG
ACHTUGTNERNNUG(DVDS)ACHTUNGTERN(NUGN tBu3P)], 10, THF; then, TBAF, [Pd2-
The activation of silanols can also be promoted by non-
fluoride reagents that lack the drawbacks of fluoride re-
agents (corrosiveness, incompatibility with silicon protecting
groups and the high cost of those that are soluble in organic
solvents). The first such compound was silver(I) oxide, re-
ported by Hiyama, Mori and co-workers.[47] Denmark and
co-workers have extensively described the coupling of orga-
nosilanols either in the presence of Brønsted bases (includ-
(KOTMS), which is soluble in organic solvents) or as their
preformed silanolate salts.[48] In this work, fluoride-free cou-
pling of iodide 6 to silanol 8b was rather less efficient than
fluoride-promoted coupling: retinyl ether 18 was obtained in
61% yield under Ag2O activation ([Pd
and in 74% yield under KOTMS activation ([Pd2-
(dba)3]·CHCl3, dioxane, 3 h, compared with 89% with
TBAF; Table 4).
ACHTUNGTRENN(NUG PPh3)4], 508C, 8 h)
AHCTUNGTRENNUNG
ing
the
inexpensive
potassium
trimethylsilanolate
Chem. Eur. J. 2012, 18, 4401 – 4410
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4405

S. Lꢀpez et al.
We also attempted non-fluoride coupling of [2-(hydroxyl-
methyl)phenyl]silanes, Hiyama, Nakao and co-workers[23]
having reported that intramolecular coordination of the
proximal hydroxyl group allows cross-coupling under condi-
tions significantly milder than the standard, and that the
metal residue (a cyclic silyl ether) can readily be recovered
and reused. In this work, after attempts to couple 8l with
iodide 6 by using various bases (K2CO3, Cs2CO3), solvents
Conclusion
The stereoselective synthesis of the highly conjugated skele-
ton of retinoids is a demanding and challenging task. In this
paper, we have conclusively demonstrated that natural all-
trans- and 11-cis-retinoids and their 9- and 13-demethylated
analogues can be obtained by cross-coupling appropriate
electrophiles with a wide variety of organo-functional dien-
ylsilanes (both oxygen-activated species and “safety-catch”
silanols) as a preferable alternative to classical borane or
stannane coupling partners. The advantages of silicon-based
coupling include the greater stability and lower toxicity of
the dienylsilanes, the wide variety of substituents that can
be placed on the silicon (which allows convenient choices of
preparation and activation protocols), the need for only
mild reaction conditions and uniformly high yields. These
properties establish the Hiyama coupling approach as the
most effective route to retinoids that has been reported to
date.
(DMSO, THF) and catalysts (PdCl2, [Pd2ACHTNUGTRNEUNG(dba)3]) had all led
to the recovery of starting materials, activation with
KOTMS (PdCl2, N-(2-diphenylphosphinobenzylidene)cyclo-
hexylamine, DMSO) afforded a poor 35% yield of 18
(Table 4).
Failure also met the use of triflate 7 as the electrophile in
the cross-coupling reaction (data not shown). Neither fluo-
ride-promoted protocols (TBAF, [Pd
TBAF·3H2O, PdBr2, (2-biphenyl)
(tBu)2P, dioxane[50]) nor
the use of a slightly soluble Brønsted base promoter ([Pd-
ACHTUNGTRENNUNG
(dba)2], X-Phos, K3PO4, dioxane)[51] achieved its coupling to
(PPh3)4], THF,[49] or
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
silanol 8b, the only products isolated from the reaction mix-
tures being starting materials.[52]
By contrast, synthesis of the retinoid skeleton by a sequen-
tial one-pot process combining the platinum-catalysed hy-
drosilylation of an alkyne with the palladium-catalysed
Hiyama coupling was successful (Scheme 2).[53] Following
Experimental Section
General: All of the solutions employed were degassed by argon bubbling
over 15 min. Cross-coupling reactions and purification of retinoids were
carried out in the absence of light.
General procedures for the synthesis of (1E,3E)-dienylsilanes 8 and 8’
Method A: Silane (H-Si) (1.0–1.5 equiv) was added dropwise to a solution
of [PtACTHUNTRGENNG(U DVDS)] (0.1m in xylenes, 0.005 equiv) and tBu3P (0.005 equiv) in
THF (3 mLmmolÀ1), and the mixture was stirred for 30 min at RT. A so-
lution of (E)-3-methyl-5-(tetrahydropyran-2-yloxy)pent-3-en-1-yne (10)
or (E)-5-(tetrahydropyran-2-yloxy)pent-3-en-1-yne (10’; 1.0 equiv) in
THF or toluene was then added over 10 min and the reaction mixture
was stirred for 1–10 h at RT or 1008C. The solvent was removed under
vacuum and the crude was purified by column chromatography to afford
compounds 8a–l or 8’a–l, respectively.
Method B: [Pd
2ACHTUNGTRNEN(UNG dba)3]·CH3Cl (0.015 equiv) was added to a solution of
silane (H-Si; 1.0–1.5 equiv), KOAc (3.0 equiv), NMP (20 mLmmolÀ1
)
and (1E,3E)-1-iodo-3-methyl-5-(tetrahydropyran-2-yloxy)penta-1,3-diene
(11) or (1E,3E)-1-iodo-5-(tetrahydropyran-2-yloxy)penta-1,3-diene (11’;
1.0 equiv) and, after stirring for 1 h, the reaction was quenched with
water. The aqueous phase was extracted with diethyl ether and the com-
bined organic phases were washed with water and brine. The organic
layer was dried and filtered. This method did not afford the desired prod-
ucts in any of the cases tested.
Scheme 2. One-pot hydrosilylation/cross-coupling sequence.
Denmarkꢄs protocol,[54] enyne 10 was hydrosilylated with in-
expensive, non-toxic tetramethyldisiloxane under [Pt-
Method C: nBuLi (2.5m in hexanes, 1.3 equiv) was added over 10 min to
a cooled solution (À788C) of (1E,3E)-1-iodo-3-methyl-5-(tetrahydropyr-
an-2-yloxy)penta-1,3-diene (11) or (1E,3E)-1-iodo-5-(tetrahydropyran-2-
yloxy)penta-1,3-diene (11’; 1 equiv) in diethyl ether (3 mLmmolÀ1), and
the reaction mixture was stirred at this temperature for 1 h. A solution of
hexamethylcyclotrisiloxane or chloromethylsilacyclobutane (1.5 equiv) in
diethyl ether (1 mL) was added at the same temperature and the reaction
was allowed to warm to RT for 4–6 h. The solution was then cooled to
08C and quenched with water. The aqueous phase was extracted with di-
ethyl ether and the combined organic phases were washed with water
and brine. The organic layer was dried and filtered. The solvent was
evaporated and the crude was purified by column chromatography to
afford compounds 8b–c or 8’b–c, respectively.
ACHTUNGTRENNUNG(DVDS)ACHTUNGTRENNUNG(tBu3P)] catalysis, and the resulting vinyldisiloxane
coupled in situ to iodide 6 under fluoride-promoted Pd cat-
alysis, giving trans-O-tetrahydropyranyl retinyl ether 18 in
a valuable 74% overall yield.
Finally, synthesis of the natural retinoids 1 and 2 was com-
pleted by deprotection of retinyl ethers 18 and 22 (TMSCl,
H2O, MeOH, 5 min), which afforded trans-retinol (1) and
11-cis-retinol (23) in 74 and 83% yield, respectively, fol-
lowed by mild oxidation of 23 with BaMnO4 (90%;
Table 4).
General procedure for the synthesis of alkynylsilanes 14 and 14’: nBuLi
(1.3 equiv) was added over 10 min to a solution of (E)-3-methyl-5-(tetra-
hydropyran-2-yloxy)pent-3-en-1-yne (10) or (E)-5-(tetrahydropyran-2-
yloxy)pent-3-en-1-yne (10’; 1.0 equiv) in diethyl ether cooled to À788C,
and the reaction mixture was stirred at this temperature for 1 h. A solu-
4406
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ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 4401 – 4410

Stereocontrolled Synthesis of Retinoids
FULL PAPER
tion of chlorosilane (Si-X; 1.5 equiv) in diethyl ether was added at the
same temperature and the reaction was allowed to warm to RT for 4 h.
The solution was then cooled to 08C and quenched with water. The aque-
ous phase was extracted with diethyl ether and the combined organic
phases were washed with water and brine. The organic layer was dried
with anhydrous sodium sulphate and filtered. The solvent was evaporated
and the crude was purified by column chromatography, to obtain com-
pounds 14c–h or 14’c–h.
Silylhydride coupling: By following the general procedure, treatment of
a solution of silylhydride 8e (28 mg, 0.096 mmol) in THF (2 mL) with
TBAF (1.0m in THF, 96 mL, 0.96 mmol) for 30 min at 08C, followed by
addition of a solution of iodide 6 (15 mg, 0.05 mmol) in THF (1 mL) and
[Pd2ACTHNUGTRNE(UGN dba)3]·CHCl3 (2 mg, 0.002 mmol) afforded compound 18 in 85%
yield (15 mg).
Allylsilane coupling: By following the general procedure, treatment of
a solution of allylsilane 8 f (20 mg, 0.07 mmol) in THF (2 mL) with
TBAF (1.0m in THF, 95 mL, 0.09 mmol) for 5 min at RT, followed by ad-
dition of a solution of iodide 6 (15 mg, 0.05 mmol) in THF (1 mL) and
[Pd2ACTHNUGTRNE(UGN dba)3]·CHCl3 (1 mg, 0.001 mmol) afforded compound 18 in 82%
yield (14 mg).
General procedure for the synthesis of (1Z,3E)-dienylsilanes 9 and 9’
Method D: A solution of alkynylsilanes 14c–h or 14’c–h (1 equiv) in
THF was added dropwise to a stirred suspension of [ZrCl(Cp)2(H)]
(1.25–2.5 equiv) in THF and the mixture was stirred for 4 h until the hy-
drozirconation was complete, as shown by the disappearance of the in-
soluble hydride and the formation of a clear solution. It was then diluted
with n-pentane (25 mLmmolÀ1), stirred for a further 20 min, filtered
through a short pad of neutral alumina and concentrated. Flash column
chromatography of the crude afforded compounds 9c–e, g and h or 9’c–
e, g and h.
3,5-Bis(trifluoromethyl)phenylsilane coupling: By following the general
procedure, treatment of a solution of 3,5-bis(trifluoromethyl)phenylsilane
8h (33 mg, 0.07 mmol) in THF (2 mL) with TBAF (1.0m in THF, 100 mL,
0.10 mmol) for 30 min at RT, followed by addition of a solution of iodide
6
(15 mg, 0.05 mmol) in THF (1 mL) and [Pd2ACTHUNGTERN(UNG dba)3]·CHCl3 (3 mg,
0.003 mmol) afforded compound 18 in 85% yield (15 mg).
Pyridylsilane coupling: By following the general procedure, treatment of
a solution of pyridylsilane 8i (22 mg, 0.07 mmol) in THF (2 mL) with
TBAF (1.0m in THF, 150 mL, 0.15 mmol) for 30 min at 08C, followed by
addition of a solution of iodide 6 (15 mg, 0.05 mmol) in THF (1 mL) and
[Pd2ACTHNUGTRNE(UGN dba)3]·CHCl3 (3 mg, 0.003 mmol) afforded compound 18 in 80%
yield (14 mg).
General procedure for the Hiyama cross-coupling of organosilicon com-
pounds 8 and 8’ and 9 and 9’ with trienyl iodides 6 and 6’ under TBAF
activation: TBAF (1.0m in THF, 2–3 equiv) was added dropwise to a solu-
tion of the organosilicon reagent (8, 8’, 9 or 9’ (1.5–2.5 equiv) in THF
(20 mLmmolÀ1) and the mixture was stirred for 30 min (08C–RT). A so-
lution of trienyl iodides 6 or 6’ (1.0 equiv) in THF and [Pd2ACTHUNTRGNE(UGN dba)3]·CHCl3
Thiophenylsilane coupling: By following the general procedure, treat-
ment of a solution of thiophenylsilane 8j (23 mg, 0.07 mmol) in THF
(2 mL) with TBAF (1.0m in THF, 190 mL, 0.19 mmol) for 5 min at RT,
followed by addition of a solution of iodide 6 (15 mg, 0.05 mmol) in THF
(1 mL) and [Pd2ACHTNUTRGNEUGN(dba)3]·CHCl3 (3 mg, 0.003 mmol) afforded compound 18
in 80% yield (14 mg).
(0.05–0.1 equiv) were sequentially added at RT, and the mixture was
stirred for 1 h. Diethyl ether was added and the mixture was filtered
through a short pad of silica gel. The solvent was removed under vacuum
and the crude mixture was purified by column chromatography (SiO2,
95:5 hexane/AcOEt) to afford the corresponding retinyl ethers (15–22)
as yellow oils.
2-Hydroxymethylphenylsilane coupling: By following the general proce-
dure, treatment of a solution of 2-hydroxymethylphenylsilane 8l (22 mg,
0.07 mmol) in THF (2 mL) with TBAF (1.0m in THF, 100 mL, 0.10 mmol)
for 5 min at RT, followed by addition of a solution of iodide 6 (15 mg,
trans-Tetrahydropyran-2-yl retinyl ether (18)
Siloxane coupling: By following the general procedure, treatment of a so-
lution of siloxane 8a (40 mg, 0.14 mmol) in THF (2 mL) with TBAF
(1.0m in THF, 220 mL, 0.22 mmol), followed by addition of a solution of
iodide 6 (30 mg, 0.095 mmol) in THF (1 mL) and [Pd2ACTHUNTRGNE(UGN dba)3]·CHCl3
(5 mg, 0.005 mmol) afforded compound 18 in 86% yield (30 mg).
0.05 mmol) in THF (1 mL) and [Pd2ACHTNUGTRENUNG(dba)3]·CHCl3 (3 mg, 0.002 mmol) af-
forded compound 18 in 83% yield (14 mg). With other activators like
K2CO3 or Cs2CO3 the reaction did not take place and, with KOTMS,
a 35% yield (6 mg) was obtained.
Silanol coupling: By following the general procedure, reaction of a solu-
tion of silanol 8b (68 mg, 0.26 mmol) in THF (2 mL) with TBAF (1.0m in
THF, 190 mL, 0.19 mmol), followed by the addition of a solution of iodide
One-pot reaction: 1,1,3,3-Tetramethyldisiloxane (31 mg, 0.237 mmol) was
added dropwise to a solution of [PtACTHNUGRTNEUNG(DVDS)] (0.1m in xylenes, 15 mL,
0.0015 mmol) and tBu3P (1 mL, 0.002 mmol) in THF (1 mL), and the mix-
ture was stirred for 30 min. A solution of (E)-3-methyl-5-(tetrahydropyr-
an-2-yloxy)pent-3-en-1-yne (10; 52 mg, 0.28 mmol) in THF (1 mL) was
then added over 5 min and the reaction mixture was stirred for 30 min.
6
(35 mg, 0.11 mmol) in THF (1 mL) and [Pd2ACTHUNGTERN(UNG dba)3]·CHCl3 (6 mg,
0.006 mmol) afforded compound 18 in 89% yield (36 mg).
Ag2O activation: Silanol 8b (63 mg, 0.24 mmol) and iodide 6 (39 mg,
0.12 mmol) were sequentially added to
a suspension of [PdCAHTUNTGNRUEGN(PPh3)4]
(7 mg, 0.006 mmol) and Ag2O (28 mg, 0.12 mmol) in THF (2 mL). The
temperature was raised to 508C and the reaction mixture was stirred for
8 h, filtered through a pad of neutral alumina, concentrated and purified
to afford compound 18 in 61% yield (27 mg).
TBAF (1.0m in THF, 632 mL, 0.632 mmol), [Pd2ACHTNUTRGNE(UGN dba)3]·CHCl3 (8 mg,
0.008 mmol) and iodide 6 (50 mg, 0.16 mmol) were then sequentially
added and the reaction mixture was stirred, filtered through a pad of
neutral alumina and concentrated. The crude was purified by column
chromatography (SiO2, 95:5 hexane/AcOEt) to afford compound 18 in
74% overall yield (44 mg).
KOTMS activation: Silanol 8b (36 mg, 0.15 mmol) was added to a stirred
suspension of potassium trimethylsilanolate (25 mg, 0.19 mmol) in diox-
ane (2 mL) and the reaction mixture was stirred for 30 min. Iodide 6
11-cis-Tetrahydropyran-2-yl retinyl ether (22)
(30 mg, 0.09 mmol) and [Pd2ACHTNUTRGNEG(UN dba)3]·CHCl3 (5 mg, 0.005 mmol) were then
Silanol coupling: By following the general procedure, treatment of a solu-
tion of silanol 9b (22 mg, 0.07 mmol) in THF (2 mL) with TBAF (1.0m in
THF, 95 mL, 0.10 mmol) for 30 min at 08C, followed by addition of a solu-
sequentially added and the mixture was stirred for 3 h, filtered through
a pad of neutral alumina, concentrated and purified to afford compound
18 in 74% yield (25 mg).
tion of the iodide
(dba)3]·CHCl3 (1 mg, 0.001 mmol) afforded compound 22 in 71% yield
(12 mg).
6 (15 mg, 0.05 mmol) in THF (1 mL) and [Pd2-
AHCTUNGTRENNUNG
Silacyclobutane coupling: By following the general procedure, treatment
of a solution of silacyclobutane 8c (19 mg, 0.071 mmol) in THF (2 mL)
with TBAF (1.0m in THF, 150 mL, 0.150 mmol) for 30 min at 08C, fol-
lowed by addition of a solution of iodide 6 (15 mg, 0.048 mmol) in THF
(1 mL) and [Pd2ACHTUNGTRENNUNG(dba)3]·CHCl3 (3 mg, 0.003 mmol) afforded compound 18
in 85% yield (15 mg).
Silacyclobutane coupling: By following the general procedure, treatment
of a solution of silacyclobutane 9c (21 mg, 0.08 mmol) in THF (2 mL)
with TBAF (1.0m in THF, 189 mL, 0.189 mmol) for 30 min at 08C, fol-
lowed by addition of a solution of the iodide 6 (15 mg, 0.05 mmol) in
THF (1 mL) and [Pd2ACHTNUGTRNEUNG(dba)3]·CHCl3 (4 mg, 0.004 mmol) afforded com-
pound 22 in 85% yield (15 mg).
Benzylsilane coupling: By following the general procedure, treatment of
a solution of benzylsilane 8d (31.6 mg, 0.096 mmol) in THF (2 mL) with
TBAF (1.0m in THF, 128 mL, 0.128 mmol) for 30 min at 08C, followed by
addition of a solution of iodide 6 (20 mg, 0.064 mmol) in THF (1 mL)
and [Pd2ACHTUNGTRENNUNG(dba)3]·CHCl3 (2 mg, 0.002 mmol) afforded compound 18 in
77% yield (18 mg).
Benzylsilane coupling: By following the general procedure, treatment of
a solution of benzylsilane 9d (80 mg, 0.242 mmol) in THF (5 mL) with
TBAF (1.0m in THF, 322 mL, 0.322 mmol) for 30 min at 08C, followed by
addition of a solution of iodide 6 (50 mg, 0.16 mmol) in THF (1 mL) and
Chem. Eur. J. 2012, 18, 4401 – 4410
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4407

S. Lꢀpez et al.
[Pd
(dba)3]·CHCl3 (4 mg, 0.004 mmol) afforded compound 22 in 78%
Evans, Cell 1995, 83, 835–839; b) V. Duong, C. Rochette-Egly, Bio-
chim. Biophys. Acta Mol. Basis Dis. 2011, 1812, 1023–1031; c) L. Al-
tucci, M. D. Leibowitz, K. M. Ogilvie, A. R. de Lera, H. Gronemey-
er, Nat. Rev. Drug Discovery 2007, 6, 793–810; d) S. ꢇlvarez, W.
Bourguet, H. Gronemeyer, A. R. de Lera, Expert Opin. Ther. Pat.
2011, 21, 55–63.
yield (36 mg).
Silylhydride coupling: By following the general procedure, treatment of
a solution of silylhydride 9e (28 mg, 0.10 mmol) in THF (5 mL) with
TBAF (1.0m in THF, 96 mL, 0.96 mmol) for 30 min at 08C, followed by
addition of a solution of iodide 6 (15 mg, 0.05 mmol) in THF (1 mL) and
[7] For some recent significant papers, see: a) E. Korchemskaya, N. Bur-
ykin, A. de Lera, R. Alvarez, S. Pirutin, A. Druzhko, Photochem.
Photobiol. 2005, 81, 920–923; b) M. Golczak, A. Maeda, G. Bereta,
T. Maeda, P. D. Kiser, S. Hunzelmann, J. von Lintig, W. S. Blaner, K.
Palczewski, J. Biol. Chem. 2008, 283, 9543–9554; c) J. H. Barnard,
J. C. Collings, A. Whiting, S. A. Przyborski, T. B. Marder, Chem.
Eur. J. 2009, 15, 11430–11442.
[Pd2ACHTUNGTRENNUNG(dba)3]·CHCl3 (2 mg, 0.002 mmol) afforded compound 22 in 73%
yield (13 mg).
3,5-Bis(trifluoromethyl)phenylsilane coupling: By following the general
procedure, treatment of a solution of 3,5-bis(trifluoromethyl)phenylsilane
9h (32 mg, 0.07 mmol) in THF (2 mL) with TBAF (1.0m in THF, 100 mL,
0.10 mmol) for 30 min at 08C, followed by addition of a solution of
iodide
6 (15 mg, 0.05 mmol) in THF (1 mL) and [Pd2ACHTUNGTNUER(NG dba)3]·CHCl3
[8] For reviews on the synthesis of retinoids, see: a) R. S. H. Liu, A. E.
Asato, Tetrahedron 1984, 40, 1931–1969; b) B. Domꢁnguez, R. Al-
varez, A. R. de Lera, Org. Prep. Proced. Int. 2003, 35, 239–306.
[9] A major disadvantage of classical olefination methods is the difficul-
ty to obtain >98% stereospecificity, especially for Z double-bond
isomers. However, substantial synthetic effort has recently led to
some more efficient approaches. For improved Wittig reactions, see:
a) A. Hosoda, T. Taguchi, Y. Kobayashi, Tetrahedron Lett. 1987, 28,
65–68; b) R. Alvarez, M. Dominguez, Y. Pazos, F. Sussman, A. R.
de Lera, Chem. Eur. J. 2003, 9, 5821–5831; c) M. Domꢁnguez, R. Al-
varez, M. Perez, K. Palczewski, A. R. de Lera, ChemBioChem 2006,
7, 1815–1825; for improved Horner reactions, see: d) Y. Wang, W. S.
Woo, L. van der Hoef, J. Lugtenburg, Eur. J. Org. Chem. 2004,
2166–2175; e) Y. Wang, J. Lugtenburg, Eur. J. Org. Chem. 2004,
3497–3510; f) Y. Wang, J. Lugtenburg, Eur. J. Org. Chem. 2004,
5100–5110; for improved Peterson reactions, see: g) A. Wada, Y.
Tanaka, N. Fujiota, M. Ito, Bioorg. Med. Chem. Lett. 1996, 6, 2049–
2052; h) A. Wada, M. Ito, Pure Appl. Chem. 1999, 71, 2295–2302;
i) A. Wada, N. Fujioka, Y. Tanaka, M. Ito, J. Org. Chem. 2000, 65,
2438–2443.
(3 mg, 0.002 mmol) afforded compound 22 in 74% yield (13 mg).
trans-Retinol (Vitamin A, 1): Water (72 mL, 4.00 mmol) and trimethyl-
silyl chloride (50 mL, 0.39 mmol) were sequentially added to a solution of
trans-tetrahydropyran-2-yl retinyl ether (18; 25 mg, 0.07 mmol) in MeOH
(3 mL), and the reaction was stirred open to air for 10 min. A saturated
aqueous solution of NaHCO3 (10 mL) was then added and the aqueous
phase was extracted with diethyl ether (2ꢅ15 mL). The combined organic
layers were washed with water (2ꢅ15 mL) and brine (2ꢅ15 mL), dried
with (anhydrous) sodium sulphate and filtered. The solvent was evaporat-
ed and the crude was purified by column chromatography (SiO2, 80:20
hexane/AcOEt) to yield compound 1 (14 mg, 74%) as a yellow oil.
11-cis-Retinol (23): By following the same procedure as described for
compound 1, treatment of a solution of 11-cis-tetrahydropyran-2-yl retin-
yl ether (22; 15 mg, 0.04 mmol) in MeOH (2 mL) with water (50 mL,
2.77 mmol) and trimethysilyl chloride (30 mL, 0.24 mmol) for 10 min af-
forded, after column chromatography (SiO2, 80:20 hexane/AcOEt), com-
pound 23 (9.5 mg, 83%) as a yellow oil.
11-cis-Retinal (2): A solution of 11-cis-retinol (23; 10 mg, 0.03 mmol) in
CH2Cl2 (0.5 mL) was added dropwise to a suspension of BaMnO4 (28 mg,
0.11 mmol) in CH2Cl2 (2 mL). The resulting mixture was stirred for 6 h,
filtered through a short pad of neutral alumina (IV, hexane) and concen-
trated. Flash column chromatography of the crude (Al2O3, hexane) af-
forded 11-cis-retinal (2) as an unstable yellow oil (9 mg, 90% yield).
[10] a) Metal-Catalyzed Cross-Coupling Reactions (Eds.: F. Diederich,
P. J. Stang), Wiley-VCH, Weinheim, 1998; b) Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed. (Eds.: A. de Meijere, F. Diederich),
Wiley-VCH, Weinheim, 2004.
[11] For a pioneer work on the synthesis of vitamin A by Pd-catalysed
cross-coupling reactions, see: a) E. Negishi, Z. Owczarczyk, Tetrahe-
dron Lett. 1991, 32, 6683–6686; for selected papers on the Negishi
reaction, see: b) F. Zeng, E. Negishi, Org. Lett. 2001, 3, 719–722;
c) B. H. Lipshutz, G. C. Clososki, W. Chrisman, D. W. Chung, D. B.
Ball, J. Howell, Org. Lett. 2005, 7, 4561–4564; d) E. Negishi, G.
Wang, H. Rao, Z. Xu, J. Org. Chem. 2010, 75, 3151–3182; for select-
ed papers on the Suzuki reaction, see: e) A. Torrado, B. Iglesias, S.
Lꢀpez, A. R. de Lera, Tetrahedron 1995, 51, 2435–2454; f) A. R.
de Lera, B. Iglesias, J. Rodrꢁguez, R. Alvarez, S. Lꢀpez, X. Villanue-
va, E. Padrꢀs, J. Am. Chem. Soc. 1995, 117, 8220–8231; g) J. Ue-
nishi, R. Kawahama, O. Yonemitsu, A. Wada, M. Ito, Angew. Chem.
1998, 110, 334–336; Angew. Chem. Int. Ed. 1998, 37, 320–323; h) Y.
Pazos, A. R. de Lera, Tetrahedron Lett. 1999, 40, 8287–8290; i) Y.
Pazos, B. Iglesias, A. R. de Lera, J. Org. Chem. 2001, 66, 8483–8489;
j) J. Uenishi, K. Matsui, A. Wada, Tetrahedron Lett. 2003, 44, 3093–
3096; k) S. ꢇlvarez, Y. Pazos-Randulfe, H. Khanwalkar, P. Germain,
R. Alvarez, H. Gronemeyer, A. R. de Lera, Bioorg. Med. Chem.
2008, 16, 9719–9728; for selected papers on the Stille reaction, see:
l) R. Alvarez, B. Iglesias, S. Lꢀpez, A. R. de Lera, Tetrahedron Lett.
1998, 39, 5659–5662; m) J. Thibonnet, G. Priꢈ, M. Abarbri, A.
DuchÞne, J.-L. Parrain, Tetrahedron Lett. 1999, 40, 3151–3154; n) B.
Domꢁnguez, B. Iglesias, A. R. de Lera, Tetrahedron 1999, 55, 15071–
15098; o) B. Domꢁnguez, Y. Pazos, A. R. de Lera, J. Org. Chem.
2000, 65, 5917–5925; p) A. Wada, K. Fukunaga, M. Ito, Synlett 2001,
0800–0802; q) A. Wada, K. Fukunaga, M. Ito, Y. Mizuguchi, K. Na-
kagawa, T Okano, Bioorg. Med. Chem. 2004, 12, 3931–3942; r) A.
Wada, N. Matsuura, Y. Mizuguchi, K. Nakagawa, M. Ito, T. Okano,
Bioorg. Med. Chem. 2008, 16, 8471–8481; s) T. Okitsu, K. Iwatsuka,
A. Wada, Chem. Commun. 2008, 6330–6332.
Acknowledgements
We thank the MICINN (projects CTQ2008–06557 and CTQ2011–28258,
Consolider Ingenio 2010 (CSD2007–00006)) and Xunta de Galicia (2007/
XA084 and CN2011/054) for financial support. J.B. and F.C. thank the
Xunta de Galicia and MICINN for predoctoral grants and J.M. thanks
the MEC for a FPU predoctoral fellowship.
[1] a) The Retinoids: Biology, Chemistry and Medicine (Eds.: M. B.
Sporn, A. B. Roberts, D. S. Goodman), Raven, New York, 1993;
b) R. Blomhoff, H. K. Blomhoff, J. Neurobiol. 2006, 66, 606–630.
[2] a) R. Blomhoff, M. H. Green, T. Berg, K. R. Norum, Science 1990,
250, 399–404; b) J. L. Napoli in Encyclopedia of Biological Chemis-
try, Vol. 4 (Eds.: W. J. Lennarz, D. M. Lane), Elsevier, Oxford 2004,
pp. 354–359.
[3] M. A. van der Horst, K. J. Hellingwerf, Acc. Chem. Res. 2004, 37,
13–20.
[4] a) J. K. Lanyi, H. Luecke, Curr. Biol. Curr. Op. Struct. Biol. 2001, 11,
415–419; b) J. K. Lanyi, Annu. Rev. Physiol. 2004, 66, 665–688;
c) J. K. Lanyi, Biochim. Biophys. Acta Bioenerg. 2006, 1757, 1012–
1018.
[5] a) K. Palczewski, Annu. Rev. Biochem. 2006, 75, 743–767; b) K. P.
Hofmann, P. Scheeerer, P. W. Hildebrand, H. Choe, J. H. Park, M.
Heck, O. P. Ernst, Trends Biochem. Sci. 2009, 34, 540–552; c) S. O.
Smith, Annu. Rev. Biophys. 2010, 39, 309–328.
[6] a) D. J. Mangelsdorf, C. Thummel, M. Beato, P. Herrlich, G. Schꢆtz,
K. Umesono, B. Blumberg, P. Kastner, M. Mark, P. Chambon, R. M.
[12] a) T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buchwald, J. Am.
Chem. Soc. 2005, 127, 4685–4696; b) B. Vaz, R. Alvarez, R. Brꢆck-
4408
www.chemeurj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 4401 – 4410

Stereocontrolled Synthesis of Retinoids
FULL PAPER
ner, A. R. de Lera, Org. Lett. 2005, 7, 545–554; c) O. Navarro, N.
Marion, J. Mei, S. P. Nolan, Chem. Eur. J. 2006, 12, 5142–5148.
[13] Variants of boron reagents, such as borate esters and trifluorobo-
rates, have been developed to address some of these problems. For
some recent reviews on this area, see: a) G. A. Molander, N. Ellis,
Acc. Chem. Res. 2007, 40, 275–286; b) S. Darses, J.-P. Genet, Chem.
Rev. 2008, 108, 288–325; c) G. A. Molander, B. Canturk, Angew.
Chem. 2009, 121, 9404–9425; Angew. Chem. Int. Ed. 2009, 48, 9240–
9261; for the use of air and moisture-stable N-methyliminodiacetic
acid (MIDA) boronates in retinal synthesis, see: d) S. J. Lee, K. C.
Gray, J. S. Paek, M. D. Burke, J. Am. Chem. Soc. 2008, 130, 466–
468.
[14] For reviews on silicon-based coupling, see: a) T. Hiyama, Y. Hatana-
ka, Pure Appl. Chem. 1994, 66, 1471–1478; b) T. Hiyama in Metal-
Catalyzed Cross-Coupling Reactions (Eds.: F. Diederich, P. J. Stang),
Wiley-VCH, Weinheim, 1998, Chapter 10, p. 421; c) S. E. Denmark,
R. F. Sweis, Acc. Chem. Res. 2002, 35, 835–846; d) S. E. Denmark,
R. F. Sweis, Chem. Pharm. Bull. 2002, 50, 1531–1541; e) T. Hiyama,
E. Shirakawa, Top. Curr. Chem. 2002, 219, 61–85; f) S. E. Denmark,
M. H. Ober, Aldrichimica Acta 2003, 36, 75–85; g) A. K. Sahoo, T.
Oda, Y. Nakao, T. Hiyama, Adv. Synth. Catal. 2004, 346, 1715–1727;
h) S E. Denmark, R. F. Sweis in Metal-Catalyzed Cross-Coupling
Reactions, Vol. 1, 2nd ed. (Eds.: A. de Meijere, F. Diederich), Wiley-
VCH, Weinheim, 2004, Chapter 4, p. 163; i) S. E. Denmark, J. D.
Baird, Chem. Eur. J. 2006, 12, 4954–4963; j) S. E. Denmark, C. S.
Regens, Acc. Chem. Res. 2008, 41, 1486–1499; k) S. E. Denmark, J.
Org. Chem. 2009, 74, 2915–2927; l) S. E. Denmark, J. H.-C. Liu,
Angew. Chem. 2010, 122, 3040–3049; Angew. Chem. Int. Ed. 2010,
49, 2978–2986.
853–887; d) Z. T. Ball in Comprehensive Organometallic Chemistry
III, Vol. 10 (Eds.: R. H. Carbtree, M. Mingos), Elsevier, Oxford,
2007, p. 789; e) Advances in Silicon Science, Vol. 1, Hydrosilylation:
A Comprehensive Review on Recent Advances (Ed.: J. Matisons, B.
Marciniec), Springer, Poznan, Poland, 2009.
[25] J. W. Faller, D. G. DꢄAlliessi, Organometallics 2002, 21, 1743–1776.
[26] a) Y. Maruyama, K. Yamamura, I. Nakayama, K. Yoshiuchi, F.
Ozawa, J. Am. Chem. Soc. 1998, 120, 1421–1429; b) H. Katayama,
K. Taniguchi, M. Kobayashi, T. Sagawa, T. Minami, F. Ozawa, J. Or-
ganomet. Chem. 2002, 645, 192–200; c) H. Katayama, M. Nagao, R.
Moriguchi, F. Ozawa, J. Organomet. Chem. 2003, 676, 49–54.
[27] a) A. Mori, E. Takahisa, H. Kajiro, K. Hirabayashi, Y. Nishihara, T.
Hiyama, Chem. Lett. 1998, 443–444; b) A. Mori, E. Takahisa, H.
Kajiro, Y. Nishihara, T. Hiyama, Polyhedron 2000, 19, 567–568;
c) A. Mori, E. Takahisa, H. Kajiro, Y. Nishihara, T. Hiyama, Macro-
molecules 2000, 33, 1115–1116; d) A. Mori, E. Takahisa, Y. Yama-
mura, T. Kato, A. P. Mudalige, H. Kajiro, K. Hirabayashi, Y. Nishi-
hara, T. Hiyama, Organometallics 2004, 23, 1755–1765.
[28] a) G. Chandra, P. Y. Lo, P. B. Hitchcock, M. F. Lappert, Organome-
tallics 1987, 6, 191–192; b) S. E. Denmark, Z. Wang, Org. Lett. 2001,
3, 1073–1076; c) K. Itami, K. Mitsudo, A. Nishino, J. Yoshida, J.
Org. Chem. 2002, 67, 2645–2652.
[29] S. E. Denmark, J. M. Kallemeyn, Org. Lett. 2003, 5, 3483–3486.
[30] A. Mori, E. Takahisa, Y. Nishihara, T. Hiyama, Can. J. Chem. 2001,
79, 1522–1524.
[31] For some significant references, see: Pd (hydrosilanes): a) M.
Murata, K. Suzuki, S. Watanabe, Y. Masuda, J. Org. Chem. 1997, 62,
8569–8571; b) A. S. Manoso, P. DeShong, J. Org. Chem. 2001, 66,
7449–7455; c) Y. Yamanoi, J. Org. Chem. 2005, 70, 9607–9609; Pd
(dihydrosilanes): d) Y. Yamanoi, T. Taira, J. Sato, I. Nakamula, H.
Nishihara, Org. Lett. 2007, 9, 4543–4546; Pd (disilanes): e) H. Mat-
sumoto, S. Nagashima, T. Kato, Y. Nagai, Angew. Chem. 1978, 90,
288–289; Angew. Chem. Int. Ed. Engl. 1978, 17, 279–280; f) see
ref. [26]; Rh catalyst: g) M. Murata, M. Ishikura, M. Nagata, S. Wa-
tanabe, Y. Masuda, Org. Lett. 2002, 4, 1843–1845; h) Y. Yamanoi,
H. Nishihara, Tetrahedron Lett. 2006, 47, 7157–7161; i) M. Murata,
H. Yamasaki, T. Ueta, M. Nagata, M. Ishikura, S. Watanabe, Y.
Masuda, Tetrahedron 2007, 63, 4087–4094; Pt catalyst: j) A. Hamze,
O. Provot, M. Alami, J.-D. Brion, Org. Lett. 2006, 8, 931–934.
[32] Y. Hatanaka, T. Hiyama, Tetrahedron Lett. 1987, 28, 4715–4718.
[33] M. Murata, S. Watanabe, Y. Masuda, Tetrahedron Lett. 1999, 40,
9255–9257.
[34] a) S. M. Sieburth, L. Fensterbank, J. Org. Chem. 1993, 58, 6314–
6318; b) S. E. Denmark, D. Wehrli, Org. Lett. 2000, 2, 565–568;
c) S. E. Denmark, L. Neuville, Org. Lett. 2000, 2, 3221–3224;
d) S. E. Denmark, W. Pan, J. Organomet. Chem. 2002, 653, 98–104;
e) C. Morrill, N. S. Mani, Org. Lett. 2007, 9, 1505–1508.
[35] K. Hirabayashi, E. Takahisa, Y. Nishihara, A. Mori, T. Hiyama,
Bull. Chem. Soc. Jpn. 1998, 71, 2409–2417.
[36] This method could not be applied to the preparation of 14–14’a, and
i–l because of either the unavailability of the required silicon elec-
trophile or the instability of the alkynylsilane.
[37] T. K. Chakraborty, P. Laxman, Tetrahedron Lett. 2002, 43, 2645–
2648.
[38] a) S. E. Denmark, J. Y. Choi, J. Am. Chem. Soc. 1999, 121, 5821–
5822; b) J. C. Anderson, R. H. Munday, J. Org. Chem. 2004, 69,
8971–8974; c) J. T. Lowe, W. Youngsaye, S. J. Panek, J. Org. Chem.
2006, 71, 3639–3642.
[39] B. M. Trost, M. U. Frederiksen, J. P. N. Papillon, P. E. Harrington, S.
Shin, B. T. Shireman, J. Am. Chem. Soc. 2005, 127, 3666.
[40] The reduction of alkynylboronates and stannanes with the Schwartz
reagent has been previously reported; see, for example, referen-
ce [17c], and references therein.
[15] A. C. Spivey, C. J. G. Gripton, J. P. Hannah, Curr. Org. Synth. 2004,
1, 211–226.
[16] M. Wakioka, M. Ikegami, F. Ozawa, Macromolecules 2010, 43,
6980–6985.
[17] a) S. Lꢀpez, V. Rodrꢁguez, J. Montenegro, C. Saꢂ, R. Alvarez, C. S.
Lꢀpez, A. R. de Lera, R. Simꢀn, T. Lazarova, E. Padrꢀs, ChemBio-
Chem 2005, 6, 2078–2087; b) C. S. Lꢀpez, O. Nieto Faza, S. Lꢀpe-
z Estꢈvez, A. R. de Lera, J. Comput. Chem. 2006, 27, 116–123; c) S.
Lꢀpez, J. Montenegro, C. Saꢂ, J. Org. Chem. 2007, 72, 9572–9581.
[18] J. Montenegro, J. Bergueiro, C. Saꢂ, S. Lꢀpez, Org. Lett. 2009, 11,
141–144.
[19] Denmark has prepared a tetraenoate intermediate (in the synthesis
of RK-397) by sequential palladium-catalysed cross-coupling of
a 1,4-bissilyl-1,3-butadiene. However, a mixture of olefin isomers
was achieved: S. E. Denmark, S. Fujimori, J. Am. Chem. Soc. 2005,
127, 8971–8973.
[20] a) Trialkyl- and fluoroalkenylsilanes were not tested because of their
low reactivity and their sensitivity to moisture, acids and bases, re-
spectively: Y. Hatanaka, T. Hiyama, J. Org. Chem. 1988, 53, 918–
920; b) Tris(trimethylsilyl)silanes were also not considered because
they are known to suffer low stereoselectivity in the coupling of the
Z isomers: Z. Wang, J. Pitteloud, L. Montes, M. Rapp, D. Derane,
S. F. Wnuk, Tetrahedron 2008, 64, 5322–5327.
[21] For the comparison of functionalised silanes in Hiyama couplings,
see: a) S. E. Denmark, L. Neuville, M. E. L. Christy, J. Tymonko, J.
Org. Chem. 2006, 71, 8500–8509; b) S. E. Denmark, C. R. Butler, J.
Am. Chem. Soc. 2008, 130, 3690–3704; c) Y. Nishihara, D. Saito, K.
Tanemura, S. Noyori, K. Takagi, Org. Lett. 2009, 11, 3546–3549.
[22] Number of carbon atoms for natural metabolites. There is one
carbon fewer in each fragment for the demethylated series.
[23] a) Y. Nakao, H. Imanaka, A. K. Sahoo, A. Yada, T. Hiyama, J. Am.
Chem. Soc. 2005, 127, 6952–6953; b) Y. Nakao, A. K. Sahoo, H. Im-
anaka, A. Yafa, T. Hiyama, Pure Appl. Chem. 2006, 78, 435–440;
c) Y. Nakao, H. Imanaka, J. Chen, A. Yada, T. Hiyama, J. Organo-
met. Chem. 2007, 692, 585–603.
[24] a) T. Hiyama, T. Kusumoto in Comprehensive Organic Synthesis,
Vol. 8 (Eds.: B. M. Trost, I. Flemming), Pergamon Press, Oxford,
1991, p. 763; b) I. Ojima, Z. Li, J. Zhu in The Chemistry of Organic
Silicon Compounds, Vol. 2 (Eds.: Z. Rappoport, Y. Apeloig), Wiley,
New York, 1998, p. 1687; c) B. M. Trost, Z. T. Ball, Synthesis 2005,
[41] Compounds 9 f and 9’f could not be obtained under these conditions
due to problems with the over-reduction of the allyl group.
[42] Z. Huang, E. Negishi, Org. Lett. 2006, 8, 3675–3678.
[43] M. Lee, S. Ko, S. Chang, J. Am. Chem. Soc. 2000, 122, 12011–12012.
Chem. Eur. J. 2012, 18, 4401 – 4410
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4409

S. Lꢀpez et al.
[44] a) See, for instance, reference [17c] for problems with protodestan-
nylation; b) we still kept them under an inert-atmosphere at low
temperatures (À208C) to ensure long-term conservation.
[45] B. M. Trost, M. R. Machacek, Z. T. Ball, Org. Lett. 2003, 5, 1895–
1898.
[46] Phenylsilanes are extremely stable partners that do not react under
fluoride activation. Alternatively, mild (KOTMS) and strong
(KOtBu/18-C-6) bases were tested as promoters for the coupling of
8g and 8’g with iodide 6 but only protodesilylation to give alkene 13
was achieved; see ref. [38b].
[49] Y. Hatanaka, T. Hiyama, Tetrahedron Lett. 1990, 31, 2719–2722.
[50] S. E. Denmark, R. F. Sweis, Org. Lett. 2002, 4, 3771–3774.
[51] S. E. Denmark, C. S. Regens, Tetrahedron Lett. 2011, 52, 2165–2168.
[52] Despite the known sensitivity of sulfonates towards basic and nucle-
ophilic reagents, triflate 7 was stable under these conditions for at
least 2 h.
[53] Sequential processes involving silicon-based cross-couplings and
their application to the total syntheses of natural products have
been recently reviewed: S. E. Denmark, J. H.-C. Liu, Isr. J. Chem.
2010, 50, 577–587.
[47] a) K. Hirabayashi, J. Kawashima, Y. Nishihara, A. Mori, T. Hiyama,
Org. Lett. 1999, 1, 299–302; b) K. Hirabayashi, A. Mori, J. Kawashi-
ma, M. Suguro, Y. Nishihara, T. Hiyama, J. Org. Chem. 2000, 65,
5342–5349.
[48] a) S. E. Denmark, R. F. Sweis, J. Am. Chem. Soc. 2001, 123, 6439–
6440; b) S. E. Denmark, R. C. Smith, J. Am. Chem. Soc. 2010, 132,
1243–1245; c) S. E. Denmark, R. C. Smith, W. T. Chang, Tetrahe-
dron 2011, 67, 4391–4396; see also ref. [14i,j,k].
[54] a) S. E. Denmark, Z. Wang, Org. Synth. 2005, 81, 54–62, see also
reference [28b]; b) Wagner has reported an efficient bimetallic poly-
ionic-gel [Rh–Pd] catalyst that effects the same sequential protocol:
C. Thiot, M. Schmutz, A. Wagner, C. Mioskowski, Chem. Eur. J.
2007, 13, 8971–8978.
Received: October 25, 2011
Published online: February 28, 2012
4410
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Chem. Eur. J. 2012, 18, 4401 – 4410