Iterative synthesis of oligo-1,4-diols via catalytic anti-Markovnikov hydration of terminal alkynes

Article abstract of DOI:10.1055/s-2007-983884

A sequential, iterative synthesis of oligo-1,4-diol building blocks has been realized via (a) propargylation of an aldehyde with allenylzinc bromide, (b) alcohol protection and (c) ruthenium-catalyzed anti-Markovnikov hydration of the terminal alkyne to r

Full text of DOI:10.1055/s-2007-983884

PAPER
2809
Iterative Synthesis of Oligo-1,4-diols via Catalytic Anti-Markovnikov
Hydration of Terminal Alkynes
I
terative Synthe
h
sis of
O
ligo-
o
1,4-Diols mas Kribber, Aurélie Labonne, Lukas Hintermann*
Institut für Organische Chemie, RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany
E-mail: lukas.hintermann@oc.rwth-aachen.de
Received 24 January 2007; revised 19 June 2007
Dedicated to Prof. Dr. Hans-Joachim Gais on the occasion of his 65th birthday
Our current studies center on developing applications of
the catalytic anti-Markovnikov hydration. Using this
waste-free methodology, we want to realize synthetic
strategies which give access to structurally complex sub-
Abstract: A sequential, iterative synthesis of oligo-1,4-diol build-
ing blocks has been realized via (a) propargylation of an aldehyde
with allenylzinc bromide, (b) alcohol protection and (c) ruthenium-
catalyzed anti-Markovnikov hydration of the terminal alkyne to re-
lease an aldehyde for the next iteration. Linear chains with 1,4-, strates from simple precursors with high atom-economy.6
1,4,7- 1,4,7,10- and 1,4,7,10,13- functionalization patterns have
Here we present the first example of such a synthetic strat-
been obtained by consecutive sequential iterations.
egy, namely, an iterative synthesis7of oligo-1,4-diol frag-
Key words: addition reactions, aldehydes, alkynes, homogeneous
ments by the sequential C–C coupling and anti-
catalysis, ruthenium
Markovnikov hydration outlined in Figure 2. Starting
with an anchoring aldehyde RCHO (I), propargylation
leads to the homopropargylic alcohol II. The latter is then
The catalytic hydration of alkynes1 is a promising tool for
protected and catalytically and regioselectively hydrated
sustainable synthesis since it generates synthetically ver-
satile carbonyl compounds from alkyne hydrocarbons by
to aldehyde III. The conversion I→III corresponds to the
addition of an umpoled8 homo-enolate,9 leading to a 1,4-
a waste-free addition of water, whereas many convention-
functionalized product. Indeed, this represents a very effi-
al syntheses involve energy-intensive redox processes and
cient synthetic realization of an aldehyde homo-enolate
addition. Additional iterations, with aldehyde III as start-
ing material, should give oligo-1,4-diol fragments of any
generate by-products.2 The catalytic anti-Markovnikov3
hydration of terminal alkynes, which generates aldehydes
(Figure 1) is a potentially powerful synthetic tool. The re-
desired chain-length.
action was first described in 19984a and more active cata-
lysts have since been reported,1,4,5 but this remarkable
iterations
OPG
O
sequential
synthesis
conversion has not found applications in synthesis so far.
We have recently developed an in situ catalyst based on
complex C and ligands L (Figure 1), which combines the
advantages of previous catalysts in terms of activity,
handling and availability of the components.5
R
R
O
I
III
M
1. protection
OH
R
2. H2O, [Ru]-cat.
C + 2 L (1–5 mol%)
O
addition
+
R
H2O
R
Me2CO, 60 °C, 3–15 h
II
Figure 2 An iterative sequential synthetic strategy for oligo-1,4-di-
ols
–
PF6
R6
N
PPh2
Ru+
Oligo-1,4-diol fragments have, for example, been synthe-
sized non-stereoselectively by hydrogenolysis of furfu-
rylidene aldehydes or ketones.10 An iterative synthesis
was achieved by allylation of an anchoring aldehyde, fol-
lowed by hydroboration/oxidation to a 1,4-diol; Swern
oxidation of the terminal alcohol then liberates the alde-
hyde for another iteration.11 Just as in the iterative synthe-
sis of oligo-1,3-diol fragments by allylation or crotylation
and ozonolysis,12 the use of reduction and oxidation steps
leads to reliable results, but also produces waste and is
energy-consuming.
L1
L2
L3
L4
R6 = t-Bu
R6 = t-amyl
R6 = 2,4,6-i-Pr3C6H2
R6 = 2,4,6-Ph3C6H2
C
Figure 1 Catalytic anti-Markovnikov hydration of terminal alkynes
SYNTHESIS 2007, No. 18, pp 2809–2818
Advanced online publication: 29.08.2007
DOI: 10.1055/s-2007-983884; Art ID: T01407SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
7
In contrast, our approach (Figure 2) is designed to use
readily available bulk chemicals and to generate the grow-
ing chain of the homologation product without using ad-

2810
T. Kribber et al.
PAPER
ZnBr
Ac2O, Et3N
DMAP
C + 2 L2
O
OH
OH
OAc
OAc
2
(3 mol% [Ru])
+
+
THF, 0 °C
74%
t-BuOMe, 0 °C
70 °C
12 h
Ph
Ph
Ph
Ph
Ph
92%; 86% from 1
1
4
4a
3
(92:8)
3a
OH
Ph
TBSCl
OAc
OAc
OAc
Ph
OH
imidazole
2
Ph
Ph
Ph
DMF, r.t.
98%
THF, 0 °C
O
OTBS
OH
3x
5 (92%)
82% from 4
7
6
Scheme 1 First iteration steps from benzaldehyde
ditional reagents such as oxidants, reductants or Alternatively, crude preparations of 3 were acetylated di-
temporary protecting groups, in stoichiometric quantities.
rectly to give 4 in higher overall yield. Allene 4a could, in
principle, be removed either by careful distillation or by
freezing out 4 from the isomer mixture at 4 °C, but this
turned out to be unnecessary for our purposes. Hydration
of ester 4 with an in situ catalyst (C + 2 × L2; Figure 1)
gave aldehyde 5 in high yield. The allene 4a, which is
present in the starting material, did not react under the hy-
dration catalysis conditions and was easily removed by
chromatography of either the reaction product 5 or after
the next reaction. In all upcoming hydration experiments,
we found it more convenient to immediately use the prod-
ucts from the catalysis in follow-up reactions without iso-
lation of the aldehydes.
We started by using benzaldehyde (1) as the anchoring
unit, to which we added Gaudemar’s allenylzinc bromide
(2),13 giving homoallyl alcohol 3 (as a 92:8 mixture with
allene 3a) in high yields (Scheme 1).13b The generation of
the reagent and the mode of reaction deserve some com-
ment. Allenylzinc bromide (2) was prepared from zinc
dust and propargyl bromide in THF solution according to
a literature procedure,13c but for convenience, the reaction
temperature was held at 0 °C rather than –10 °C.13c As re-
ported, reagent 2 could not be stored in solution and was
prepared immediately prior to use.13b Zinc-mediated pro-
pargylations of aldehydes have been realized either with
preformed reagent13a,b,14 or under Barbier conditions in Thus, 4 was hydrated and the crude product, after evapo-
DMF,15a THF15b,c or water.15d,e We found the Barbier con- ration of solvents and dissolution in THF, was propargy-
ditions to be less suitable for large scale reactions because lated with 2 to give the elongated homopropargyl alcohol
temperature control was difficult and dangerous; thermal 6, in good overall yield, as a 1:1 mixture of diastereomers,
overruns sometimes occurred. The use of pre-formed accompanied by only small amounts (<1/15) of allene.
Gaudemar reagent 2 is a safer procedure for large scale
propargylations. An excess of the reagent was necessary
Alcohol 6 was then protected as its tert-butyldimethylsilyl
(TBS) ether, to give alkyne 7 as a building block with or-
thogonally transformable protecting groups. Catalytic
anti-Markovnikov hydration of this substrate (Scheme 2)
to suppress formation of side-products by two-fold addi-
tion of benzaldehyde (→3x;15c Scheme 1) or pinacol cou-
pling of benzaldehyde.
proceeded smoothly and the crude aldehyde was again
Alcohol 3 was acetylated under standard conditions to propargylated with 2 to give alcohol 8. For further elonga-
give acetate 4, accompanied by some allene (ratio of 4/ tions, we continued using TBS protecting groups (8→9).
4a = 10:1 to 25:1, depending on the purification method). Compound 9 was hydrated and the intermediary aldehyde
TBSCl,
1. H2O, C + 2 L2
OAc
OAc
OH
OAc
OTBS
imidazole
(3 mol% [Ru])
Ph
Ph
Ph
Me2CO, 70 °C, 14 h
DMF
OTBS
OTBS
OTBS
2. 2, THF, 0 °C
7
8 (84%)
9 (99%)
1. H2O, Me2CO
C + 2 L4
OAc
OTBS
OAc
OTBS
TBSCl,
(2 mol% [Ru])
70 °C, 16 h
imidazole
2.
2
Ph
Ph
OTBS
OTBS
11 (99%)
OTBS
OH
DMF
THF, 0 °C
10 (95%)
Scheme 2 Continuation of the iterative hydration–propargylation sequence
Synthesis 2007, No. 18, 2809–2818 © Thieme Stuttgart · New York

PAPER
Iterative Synthesis of Oligo-1,4-diols
2811
tion of crude aldehyde 5 to a solution of 13 (generated
from LDA and methyl propiolate), gave g-hydroxypro-
piolic ester 15, in good yield. It was necessary to quench
the reaction at low temperature, otherwise the product de-
composed upon warming of the reaction mixture, un-
doubtedly because of reactions at the sensitive propiolate
triple bond.
C + 2 L2
OAc
(3 mol% [Ru])
Ph
4
Me2CO, H2O
70 °C, 14 h
O
5
Ph3P
Li
CO2Me
CO2Me
13
12
The chain termination reactions were next applied to some
of the higher building blocks (Scheme 4). Alkyne 7 was
hydrated and converted into alkenoate 16 or g-hydroxy-
propiolate 17 in high yields. Alkyne 11 was likewise hy-
drated to the corresponding aldehyde (not isolated) and
converted into either alkenoate 18 or propiolate 19 by the
chain-termination sequences established above. The latter
product was TBS-protected to afford hexadecynoic ester
derivative 20 as the product of a linear sequence including
four catalytic anti-Markovnikov hydrations and four pro-
pargylations, followed by a chain termination sequence.
THF, –78 °C, 10 min
THF, 50 °C, 2 h
OAc
Ph
OAc
CO2Me
CO2Me
Ph
15 (87%)
OH
14 (94%)
Scheme 3 Model studies for chain-termination reactions
was directly propargylated to alcohol 10, which was again
TBS-protected to form the tris-silyl ether 11 as the prod-
uct of four consecutive propargylations and three hydra-
tions, starting from benzaldehyde.
All of the propargylation reactions in the present study
were carried out using the achiral allenyl zinc reagent 2,
which leads to the homopropargyl alcohol 3 as a racemic
mixture, whereas the iteration to 6 gave a 1:1 mixture of
diastereomers. Since this lack of diastereoselectivity was
characteristic of most additions of 2 to 4-acetoxy or 4-tert-
butyldimethylsilyloxy aldehydes under our conditions
(THF, 0 °C), building blocks 8/9 therefore must exist as
four diastereomeric pairs of enantiomers. As a conse-
quence, building blocks 10/11 form as mixture of eight
diastereomers, and the four-fold iteration products 19/20
must consist of 16 diastereomers in equal amounts.
As a next aim, we wished to find how the fully protected
oligo-1,4-diol building blocks 7, 9 and 11 could be further
modified and incorporated into synthetic schemes, com-
posed of iterative sequences, and finished by specific
chain-termination reactions.
In the first approach, the following chain-terminating re-
actions were considered: (a) the Wittig reaction with a sta-
bilized phosphonium ylide (12), and (b) the addition of
lithium methyl propiolate (13) (Scheme 3). Both termina-
tions led to carboxylic acid derivatives (see below for rea-
sons why such terminating sequences were chosen). The
reactions were first tested with the simple ester 4
(Scheme 3). Catalytic hydration gave aldehyde 5, which
was used in the chain termination steps without purifica-
tion. Reaction with excess ylide 12 generated the unsatur-
ated ester 14 in high yield and stereoselectivity (E/Z =
25:1). This product constitutes another interesting build-
ing block with a 1,2/3,6-functionalization pattern. Addi-
Two comments should be made. First, we anticipate that
the use of asymmetric reagents16 or catalysts17 for the pro-
pargylation of aldehydes should convert the current syn-
thesis into an asymmetric version, whereby the
configuration of each stereocenter would be controlled by
the asymmetric reagent (or catalyst) for propargylation.
The lack of diastereoselectivity in the propargylation
steps implies that double stereo-differentiation will be of
minor importance.18
OAc
OH
OAc
1. hydration (L2)
1. hydration (L2)
CO2Me
7
Ph
Ph
2. 12, THF, 50 °C, 2 h
2. 13, THF,
OTBS
17 (88%)
CO2Me
OTBS
–78 °C, 10 min
16 (95%)
OAc
OTBS
OR
OAc
OTBS
1. hydration
CO2Me
1. hydration (L2)
(L3, 2 mol% [Ru])
Ph
Ph
11
CO2Me
2. 13, THF,
2. 12, THF,
–78 °C, 10 min
50 °C, 2 h
OTBS
OTBS
OTBS
OTBS
19 R = H (74%)
18 (92%)
hydration: C + 2 Ln (3 mol% [Ru]), Me2CO, H2O, 70 °C, 14 h
20 R = TBS (99%)
Scheme 4 Chain terminations applied to long-chain building blocks
Synthesis 2007, No. 18, 2809–2818 © Thieme Stuttgart · New York

2812
T. Kribber et al.
PAPER
As a second observation, the generation of diastereomeric rangement. Thus, it is only the signals of the OH group
mixtures in these initial studies on the application of anti- which indicate the presence of eight diastereomers. Three
Markovnikov hydration of alkynes in synthesis, offers op- arguments imply that there is an intramolecular hydrogen
portunities which do not arise in a highly selective asym- bond from the OH to the TBS-protected oxygen, which
metric synthesis. Thus, the resulting 1,4-diol building fixes the diastereomers into distinct conformations, name-
blocks may be incorporated into the syntheses of libraries ly: (a) the separation of the OH signals into two distinct
of stereodivergent targets, i.e. in the sense of a diversity- spectral regions; (b) their high frequency shift, and (c) the
oriented synthesis (DOS).19 A direct consequence of non- well-defined signals for the OH-proton with their 3JHO–CH
stereoselective synthesis is that NMR spectra of the syn- coupling.
thesis products represent an overlay of the spectra of indi-
Whereas a range of conformationally restricted 1,4-diols,
vidual diastereomers and that diastereomer-specific
namely the TADDOLs,20 are known to form stable hydro-
differences of the spectra, caused by conformational pref-
gen-bonded chelates,20 little information is available on
erences, are directly visible in the overlay spectrum.
hydrogen bonding in simple mono-protected 1,4-diol
This aspect of detecting conformational preferences be- fragments with high conformational flexibility. A search
1
came evident from analysis of the H NMR spectra of in the Cambridge structural database gave us one clear-cut
building blocks containing a single non-protected alco- example of an intramolecular hydrogen bond from OH to
holic function (compounds 6, 8, 10, 15, 17, 19). Even OTBS within a 1,4-functionalized compound.21 In most
though these samples consist of mixtures of up to 16 dia- other cases, hydrogen bridges form to acceptors such as
stereomers, the spectrum could usually be interpreted as if carbonyl groups or in an intermolecular fashion.
it were that of a single compound. For example, Figure 3
1.C + 2 L2 (3 mol% [Ru])
shows an expansion of the proton NMR spectrum of 10,
which shows that the signal due to the H-1 (Figure 3, b)
appears as a pseudo-triplet and does not indicate the pres-
TBSCl
OTBS
Me2CO, H2O, 70 °C, 17 h
imidazole
3
Ph
2. THF, –78 °C
DMF, r.t.
ence of a mixture of eight diastereomers. However, two
curious multiplets (d = 2.79 and 2.23 ppm), with an inte-
gral value of 0.5 H each, were observed; exchange exper-
iments with D2O showed that these corresponded to
hydroxylic protons. Comparison with reference spectra of
shorter building blocks showed that the well-structured
multiplet at d = 2.79 ppm (Figure 3, c), actually represents
a (coincidental) regular arrangement of four doublets,
each with a coupling constant of 3JH–H = ~7.7 Hz.
21 (97%)
Li
CO2Me
OTBS
CO2Me
Ph
OH
22 (64%)
Scheme 5 Synthesis of a test compound for studying intramolecular
hydrogen bonding in a mono-protected 1,4-diol
The multiplet centered at d = 2.23 ppm (Figure 3, d) is
also a superimposition of four doublets (3JH–H = 3.8–4.4
Hz) arising from four diastereomers in an irregular ar-
Using the methodology developed in this work, a model
compound was synthesized with which to investigate hy-
drogen bonding in a simple substrate that consists of only
two diastereomers (Scheme 5). Alcohol 3 was TBS-pro-
tected and the alkyne unit was catalytically hydrated with
anti-Markovnikov selectivity. Addition of lithium methyl
propiolate gave alcohol 22 as a mixture of diastereoiso-
mers (22-A/22-B = 60:40). This compound contains an
electron-rich hydrogen-bond acceptor and an electron-
poor alcohol as hydrogen-bond donor. Indeed, 22 dis-
played well-resolved signals for the alcoholic function at
3
d = 2.45 ppm (doublet, J = 5.5 Hz, 0.6 H) and d = 3.07
3
ppm (doublet, J = 7.2 Hz, 0.4 H) in the proton NMR
spectrum.
If we assume the conformations depicted in Figure 4 for
the two diastereomers to be prevalent, then the spectral
data, including the size of the coupling constant
(3JHC–OH)22 and the results of a 2D NOESY spectrum, in-
dicate that the relative configurations of diastereomers 22-
A and 22-B should be as depicted (Figure 4), though this
assignment must currently be considered as tentative. The
different values for d (OH) of the two diastereomers prob-
ably arises as a consequence of the deshielding effect per-
pendicular to the alkyne unit,23 which affects the hydroxyl
Figure 3 Expansions of the 1H NMR spectrum (400 MHz) of 10. a)
Aliphatic region from d = 1.2–3.9 ppm; b) Signal arising from H-1; c)
OH signals centered at d = 2.79 ppm; d) OH signals centered at
d = 2.23 ppm
Synthesis 2007, No. 18, 2809–2818 © Thieme Stuttgart · New York

PAPER
Iterative Synthesis of Oligo-1,4-diols
2813
NOE
A
B
SiR3
OTBS
M
absent
X
H
CO2Me
O
O
SiR3
O
H2O
H
M
Ph
H
O
H
H2O
H
MeO2C
OTBS
NOE
H
Ph
H2O
H2O
NOE
OAc
δ = 2.45 ppm
δ = 3.07 ppm
O
OMe
MeO2C
JHOCH = 5.5 Hz
JHOCH = 7.2 Hz
O
Ph
OTBS
M
Figure 4 Tentative assignments for the relative configurations of
the diastereomers 22-A and 22-B, based on NMR data
H2O
Ph
M
OTBS
20
proton of diastereomer 22-B far more than that of 22-A
(and presumably likewise in alkynols 6, 8, 10, 17, 19).
OH
HO
HO
O
O
The primary aim of the current investigation was to show
that catalytic anti-Markovnikov hydration of terminal
alkynes is a synthetically valuable technique that can be
applied in multistep reaction sequences. Due to the effi-
ciency and availability of our new in situ catalysts,5 we
have been able to realize a successful first application of
the reaction towards an iterative, sequential synthesis of
oligo-1,4-diol fragments and derived products. The linear
sequence leading to 18–20 involves four anti-Markovnik-
ov hydrations in series.
natural-product-like
macrolactones
O
OH
Ph
Figure 5 Structurally complex targets from simple precursors via
sequential catalytic synthesis with high atom-economy
The synthesis and chemistry of oligo-1,4-diols has not
been investigated intensively, probably because these
structural fragments, unlike oligo-1,3-diols (poly-ace-
tates), do not widely occur in natural products. It is our
current objective to proceed with several oligo-1,4-oxy-
genated carboxylic acid building blocks towards the syn-
thesis of natural-product-like24 macrolactones (Figure 5).
The observation of conformational preferences in flexible
1,4-diol fragments (Figure 4), implies that oligo-1,4-func-
tionalized compounds may even arrange into preferred
secondary structures.
The catalytic hydrations were performed as described
earlier5 but with some very practical improvements.5b The
original protocol required pre-forming the catalytically
4d,5
active complex [CpRu(Ln)2(MeCN)]PF6
from C+2
Ln (cf. Figure 1) in hot acetonitrile, followed by evapora-
tion of the in situ catalyst solution in vacuo, prior to cata-
lytic hydration. We now find that we can simply mix C,
L1–5 and the alkyne in acetone–water and heat to 70 °C
to start the reaction;5b this was not expected as NMR stud-
ies had indicated that acetonitrile was a necessary solvent
for mediating ligand exchanges of complex C.5b The new
procedure saves time and gives results comparable to
those obtained using pre-formed catalysts. Most hydration
reactions in the present study were carried out using the
readily synthesized ligand 6-tert-amyl-2-diphenylphos-
phinopyridine (L2), the performance of which was some-
what better than L1 and comparable to L3/4.5b A typical
catalyst loading was 3 mol% [Ru], but 2 mol% was often
sufficient to bring most reactions to complete conversion.
In the current work we have demonstrated the application
of catalytic anti-Markovnikov hydration to the sequential
synthesis of oligo-1,4-diol fragments, which has resulted
in a strategically simple synthesis with high atom-econo-
my from base-chemicals. We plan to extend this chemis-
try to asymmetric syntheses via asymmetric propar-
gylation reactions,16,17 and are interested in realizing a
synthesis of oligo-1,3-diol fragments by an iterative
acetylide addition–hydration sequence.
Complex C25 and ligands L1,26,4d,5b L25b and L3/45a were prepared
according to literature procedures. Propargyl bromide was a com-
mercial 80% solution in toluene. Reactions were performed in ana-
lytically pure solvents under argon. Column chromatography was
performed on SiO2 (40–63 mm), using technical quality distilled sol-
vents. Analyses were carried out by in-house services at the Institute
of Organic Chemistry, RWTH Aachen. NMR data are referenced to
internal TMS. Spectra of diastereomeric mixtures are interpreted as
for a single compound, unless separate signal sets are visible, in
which case fractional integral values are given (1H NMR) and d-val-
ues for the corresponding carbons in two or more diastereomers are
listed in groups (13C NMR), providing Dd ≥0.1 ppm.
The basic idea behind applying a catalytic heterofunction-
alization reaction in synthesis was to increase the atom-
economy and efficiency of synthetic routes by reducing
the number of energy and waste-intensive redox steps.
The efficiency of the current iterative synthesis is nicely
illustrated in Figure 5, where it is schematically shown
that the hexadecynoic acid derivative 20, of a certain
structural complexity, is assembled from very simple
starting materials, which are readily available from base-
chemicals; e.g. allenylzinc bromide (2) derives from zinc
and propargyl bromide, and the latter is industrially pro-
duced from acetylene, formaldehyde and HBr. In princi-
ple, the oligo-1,4-diol chains are simply built from the
components allene (H2C=C=CH2) and water.
Anti-Markovnikov Hydration of Terminal Alkynes; General
Procedure (GP1)
A Schlenk flask was charged with [CpRu(h6-naphthalene)]PF6 (C;
3 mol%),25 ligands L (6 mol%), alkyne (1 equiv), H2O (5 equiv) and
acetone (2 mL/mmol). The liquid level was marked on the flask and
more acetone (0.5 mL/mmol) was added, and the liquid level was
Synthesis 2007, No. 18, 2809–2818 © Thieme Stuttgart · New York

2814
T. Kribber et al.
PAPER
reduced back to the mark in vacuo (this procedure removes O2). The
mixture was heated under argon to 70 °C and the reaction was
stirred in the closed vessel (CAUTION: pressure may develop). Af-
ter completion of the reaction (12–18 h, monitored by TLC), the so-
lution was cooled to r.t. and volatiles were removed in vacuo. The
crude aldehydes were dissolved in THF (as a 0.5 M solution) and di-
rectly used for further transformations (assuming aldehyde as 1
equiv).
1-Phenylbut-3-yn-1-ol (3)
To allenylzinc (2; 1 M in THF, 0.15 mol, 1.5 equiv), prepared as de-
scribed above, benzaldehyde (10.2 mL, 0.10 mol, 1 equiv) was
slowly added at 0 °C. After complete addition, the reaction mixture
was stirred another 30 min then quenched by the addition of aq
NH4Cl (4 M, 250 mL), aq HCl (2.4 M, 50 mL) and t-BuOMe (300
mL). The aqueous phase was extracted with t-BuOMe (100 mL) and
the combined organic phases were washed with H2O, aq NaHCO3
(0.9 M) and H2O (300 mL each). After drying (MgSO4), filtration
and evaporation of the solvent, the crude product was purified by
column chromatography (t-BuOMe–hexanes, 1:3→1:1) to give a
colorless oil (10.8 g, 74%) containing some allene isomer 3a
(3/3a = 92:8).
Allenylzinc Bromide (2) Solution in THF13c
A Schlenk flask was charged under argon with zinc dust (1.1 equiv),
THF (2 mL/mmol) and TMSCl (1–2 drops/mmol zinc dust). The so-
lution was heated to reflux for a short time until the zinc dust
clumped together. The mixture was cooled to 0 °C (ice bath) and
propargyl bromide (1 equiv) was slowly added dropwise. After
completion of the addition, the solution was stirred for another 30
min at 0 °C before use.
Known compound: CAS 1743-36-8.
1H NMR (400 MHz, CDCl3): d = 2.06 (t, J = 2.7 Hz, 1 H, H-3), 2.56
(d, J = 3.1 Hz, 1 H, OH), 2.62 (AB-system, pseudo-dd, J = 6.4, 2.6
Hz, 2 H, H-2), 4.84 (dt, J = 6.4, 2.9 Hz, 1 H, H-1), 7.25–7.41 (m,
5 H). Selected signals for allene 3a: d = 2.35 (br d, J = 3.9 Hz, 1 H,
OH), 4.87–4.96 (m, 2 H), 5.22–5.27 (m, 1 H), 5.43 (q, J = 7.1 Hz,
1 H).
Propargylation of Aldehydes; General Procedure (GP2)
A solution of aldehyde (1 equiv) in THF (2 mL/mmol) was added
to a solution of allenylzinc bromide (2; 1.5 equiv in THF) at 0 °C
and the mixture was stirred for 20 min at that temperature. The re-
action was quenched by addition of aq NH4Cl (4 M, 1.5 mL/mmol),
aq HCl (2.4 M, 0.1 mL/mmol) and t-BuOMe (1.4 mL/mmol). The
aqueous phase was extracted with t-BuOMe (1.5 mL/mmol) and the
combined organic phase was washed with H2O, aq NaHCO3 (0.9 M)
and H2O (1.5 mL/mmol each). After drying (MgSO4), filtration and
evaporation, the residue was purified by column chromatography (t-
BuOMe–hexanes, typically 1:5→1:3).
1,5-Diphenylbut-2-yne-1,5-diol (3x)
This compound crystallized in variable amounts from the evaporat-
ed organic phases of preparations of 3, when the quantity of 2 was
low. Colorless crystals from toluene; 1:1 mixture of diastereomers.
Known compound: CAS 42512-63-0.15c
1H NMR (400 MHz, DMSO-d6): d = 2.57 (ddd, J = 16.6, 6.6, 2.2
Hz, 1 H, H-4), 2.64 (ddd, J = 16.5, 6.3, 2.2 Hz, 1 H, H-4), 4.70 (t,
J = 6.3 Hz, 1 H, H-5), 5.29 (s, 1 H, H-1), 5.52 (br s, 1 H, OH), 5.85
(br s, 1 H, OH), 7.23–7.41 (m, 10 H).
13C NMR (100 MHz, DMSO-d6): d = 29.4 (CH2), 62.7 (CH), 71.2
(CH), 82.6 (C), 83.2 (C), 126.0 (CH), 126.4 (CH), 126.9 (CH),
127.2 (CH), 127.7 (CH), 127.9 (CH), 142.4 (C), 144.4 (C). Slight
splitting of several signals due to diastereomers is observed.
TBS Protection; General Procedure (GP3)
The alcohol (1 equiv), TBSCl (2 equiv) and imidazole (3 equiv)
were stirred at r.t. in DMF (2 mL/mmol). Upon completion (TLC;
10–48 h), the reaction was quenched by addition of aq HCl (2.4 M,
3 mL/mmol). The aqueous phase was extracted with t-BuOMe
(2 × 3 mL/mmol) and the combined organic phases were washed
with aq NaHCO3 (0.9 M) and H2O (5 mL/mmol each) then dried
over MgSO4. Evaporation in vacuo afforded the crude product,
which was purified by column chromatography (t-BuOMe–hex-
anes, typically 1:5→1:3).
Acetic Acid 1-Phenyl but-3-ynyl Ester (4)
DMAP (0.757 g, 6.2 mmol, 10 mol%) and Et3N (12.95 mL, 93
mmol, 1.5 equiv) were added to a solution of alcohol 3 (9.086 g, 62
mmol) in t-BuOMe (0.5 M) at 0 °C. Acetic anhydride (5.9 mL, 62
mmol, 1 equiv) was slowly added with stirring. When the reaction
was complete (~30 min, monitored by TLC), the reaction was
quenched by addition of H2O (150 mL). The aqueous phase was ex-
tracted with t-BuOMe (25 mL) and the combined organic phases
were washed with H2O, aq NaHCO3 (0.9 M) and H2O (100 mL
each). After drying (MgSO4) and evaporation of the solvent, the re-
sidual oil was distilled at 80 °C (0.2 mbar) to give a colorless liquid
(10.845 g, 93%) as 92:8 mixture of the product 4, with the allene
isomer 4a.
Wittig Reaction; General Procedure (GP4)
To the aldehyde (1 equiv) in THF (0.5 M), obtained from GP1,
methyl triphenylphosphoranylidene acetate (2.5 equiv) was added
and the solution was stirred at 50 °C for 2 h. The reaction was
quenched by addition of aq HCl (2.4 M, 2–3 mL/mmol) and t-
BuOMe (3 mL/mmol). The organic phase was washed with H2O, aq
NaHCO3 (0.9 M) and H2O (4–5 mL/mmol each) then dried over
MgSO4. Filtration and evaporation under vacuo, gave the crude
product, which was purified by column chromatography (t-
BuOMe–hexanes, typically 1:5→1:3).
In an alternative synthesis, starting from benzaldehyde on a 0.1
mole scale, crude alcohol 3 was acetylated without purification to
give 4 (16.18 g, 86%) after distillation.
Addition of Lithium Methylpropiolate to Aldehydes; General
Procedure (GP5)
Known compound: CAS 76698-68-5.
In a Schlenk flask under argon, n-BuLi (5 equiv) was added to di-
isopropylamine (5 equiv) in THF (5 mL/mmol) and the solution was
stirred at 0 °C for 15 min then cooled to –78 °C. Methyl propiolate
(5 equiv) was slowly added and the solution was stirred for 20 min
before the aldehyde (1 equiv, in THF, see GP1) was added dropwise
at –78 °C. After 5 min, the reaction was quenched by the addition
of aq NH4Cl (4 M, 4 mL/mmol) and t-BuOMe (5 mL/mmol) at
–78 °C. The aqueous phase was extracted with t-BuOMe (5 mL/
mmol) and the combined organic phases were washed with aq
NaHCO3 (0.9 M) and H2O (5–6 mL/mmol each). After drying
(MgSO4), filtration and evaporation, the residue was purified by
column chromatography (t-BuOMe–hexanes; typically 1:4→1:2).
1H NMR (300 MHz, CDCl3): d = 1.97 (t, J = 2.7 Hz, 1 H, H-4), 2.10
(s, 3 H, Me), 2.69 (ddd, J = 16.8, 6.4, 2.7 Hz, 1 H, H-2), 2.78 (ddd,
J = 16.8, 6.9, 2.6 Hz, 1 H, H-2), 5.89 (t, J = 6.6 Hz, 1 H, H-1), 7.27–
7.41 (m, 5 H, Ph). Selected signals for allene 4a: d = 4.79–4.9 (m,
2 H), 5.42 (q, J = 6.7 Hz, 1 H), 6.29 (dt, J = 6.7, 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.1 (CH3), 26.5 (CH2), 70.7 (CH),
73.5 (CH), 79.5 (C), 126.5 (CH), 128.4 (CH), 128.5 (CH), 139.0
(C), 170.0 (C).
4-Acetoxy-4-phenylbutanal (5)
Prepared from 4 (250 mg, 1.33 mmol) according to GP1 (with L2).
Synthesis 2007, No. 18, 2809–2818 © Thieme Stuttgart · New York

PAPER
Iterative Synthesis of Oligo-1,4-diols
2815
Yield: 252 mg (92%); colorless oil; Rf = 0.24 (t-BuOMe–hexane,
1:3).
1H NMR (300 MHz, CDCl3): d = –0.02–0.05 (m, 6 H, 2 × Me), 0.87
(s, 9 H), 1.305–2.00 (m, 8 H), 2.00–2.05 (m, 1 H), 2.06 (s, 3 H),
2.09 (d, J = 4.7 Hz, 0.5 H, OH), 2.25–2.47 (m, 2 H), 2.48–2.54 (m,
0.5 H, OH), 3.64–3.78 (m, 2 H), 5.70 (t, J = ~7 Hz, 1 H), 7.26–7.40
(m, 5 H).
13C NMR (75 MHz, CDCl3): d = –4.5 (CH3), –4.6 (CH3), 18.1 (C),
21.3 (CH3), 25.9 (CH3), 27.3/27.4 (CH2), 31.5–32.8 (4 × CH2), 69.9/
70.2/70.7/70.8 (CH), 71.3/71.4/71.5/71.6 (CH), 76.0 (CH), 80.9
(C), 126.4/126.5 (CH), 127.9 (CH), 128.4 (CH), 140.5/140.6 (C),
170.3 (C).
IR (film): 3034, 2936, 2827, 2727, 1734, 1495, 1451, 1373, 1239,
1025, 763, 702, 546 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.08 (s, 3 H), 2.10–2.28 (m, 2 H,
H-2), 2.44–2.50 (m, 2 H, H-3), 5.77 (dd, J = 7.6, 5.9 Hz, 1 H, H-4),
7.26–7.38 (m, 5 H, Ph), 9.73 (t, J = 1.3 Hz, 1 H, H-1).
13C NMR (100 MHz, CDCl3): d = 21.3 (CH3), 28.8 (CH2), 40.0
(CH2), 75.0 (CH), 126.3 (CH), 128.2 (CH), 128.6 (CH), 139.6 (C),
170.1 (C), 200.9 (CH).
MS (ESI, MeOH): m/z = 441.3 [M + Na]+.
MS (EI): m/z (%) = 206 (1) [M+], 188 (1), 163 (80), 146 (45), 120
(100), 107 (75), 91 (55), 77 (40).
Anal. Calcd for C24H38O4Si: C, 68.86; H, 9.15. Found: C, 69.35; H,
9.34.
Anal. Calcd for C12H14O3: C, 69.88; H, 6.84. Found: C, 69.62; H,
6.91.
Acetic Acid 4,7-Bis(tert-butyldimethylsilanyloxy)-1-phenyldec-
9-ynyl Ester (9)
Prepared from 8 (2.26 g, 5.4 mmol) according to GP3.
Acetic Acid 4-Hydroxy-1-phenylhept-6-ynyl Ester (6)
Prepared from 4 (1.035 g, 5.5 mmol) according to GP1 ([Ru] = 5
mol%; with L1) and GP2.
Yield: 2.855 g (99%); oil; Rf = 0.84 (t-BuOMe–hexane, 1:3).
IR (film): 3307, 2943, 1741, 1465, 1369, 1244, 1064, 838, 776, 699,
636, 546 cm–1.
Yield: 1.106 g (82%); colorless oil; Rf = 0.32 (t-BuOMe–hexane,
1:3).
IR (film): 3476, 3291, 3033, 2932, 2363, 1735 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.41–1.66 (m, 2 H), 1.79–2.15 (m,
3 H), 2.03–2.06 (m, 1 H), 2.07 (s, 3 H), 2.25–2.45 (m, 2 H), 3.72–
3.81 (m, 1 H), 5.72–5.80 (m, 1 H), 7.27–7.37 (m, 5 H).
1H NMR (400 MHz, CDCl3): d = –0.03–0.07 (m, 12 H), 0.86/0.87
(s, 9 H), 0.88 (s, 9 H), 1.28–1.75 (m, 6 H), 1.77–1.99 (m, 2 H),
1.94–1.97 (m, 1 H), 2.06 (s, 3 H), 2.22–2.38 (m, 2 H), 3.60–3.70
(m, 1 H), 3.71–3.83 (m, 1 H), 5.71 (t, J = ~7 Hz, 1 H), 7.26–7.37 (m,
5 H).
13C NMR (100 MHz, CDCl3): d = 21.4 (CH3), 27.6 (CH2), 32.0/32.2
(CH2), 32.5/32.6 (CH2), 69.4/69.6 (CH), 71.1/71.2 (CH), 75.7/76.0
(CH), 80.5 (C), 126.4 (CH), 127.9 (CH), 128.4 (CH), 140.2/140.3
(C), 170.3 (C).
MS (EI): m/z (%) = 246 (3) [M+], 203 (97), 186 (25), 185 (35), 147
(100), 129 (43), 120 (64), 107 (99), 91 (61), 79 (43).
13C NMR (75 MHz, CDCl3): d = –4.5 to –4.3 (4 × CH3), 18.2 (2 ×
C), 21.4 (CH3), 25.9 (CH3), 26.0 (CH3), 27.3/27.4 (CH2), 31.6–32.7
(4 × CH2), 70.0 (CH), 71.0/71.1 (CH), 71.5/71.7/71.8 (CH), 76.2
(CH), 81.6 (C), 126.4/126.5 (CH), 127.8 (CH), 128.4 (CH), 140.6
(C), 170.2 (C).
MS (ESI, CHCl3): m/z = 555.5 [M + Na]+.
Anal. Calcd for C15H18O3: C, 73.15; H, 7.37. Found: C, 73.61; H,
7.27.
Anal. Calcd for C30H52O4Si2·0.2 H2O: C, 67.16; H, 9.84. Found: C,
66.96; H, 9.74.
Acetic Acid 4-(tert-Butyldimethylsilanyloxy)-1-phenylhept-6-
ynyl Ester (7)
Prepared from 6 (7.66 g, 31.1 mmol) according to GP3.
Acetic Acid 4,7-Bis(tert-butyldimethylsilanyloxy)-10-hydroxy-
1-phenyltridec-12-ynyl Ester (10)
Prepared from 9 (1.00 g, 1.88 mmol) according to GP1 (with L2)
and GP2.
Yield: 10.947 g (98%); colorless oil; Rf = 0.7 (t-BuOMe–hexane,
1:3).
Yield: 0.907 g (82%); oil; Rf = 0.33 (t-BuOMe–hexane, 1:3).
IR (film): 3303, 2943, 2363, 1740, 1463, 1369, 1242, 1094, 1034,
838, 779, 698, 635, 541 cm–1.
IR (film): 3428, 3310, 2952, 2119, 1737, 1465, 1371, 1251, 1065,
836, 775, 701, 633, 544 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.02–0.06 (m, 6 H, 2 × Me), 0.87/
0.87 (s, 9 H), 1.40–1.77 (m, 2 H), 1.79–2.05 (m, 3 H), 2.07 (s, 3 H,
Me), 2.21–2.47 (m, 2 H), 3.78–3.86 (m, 1 H), 5.70–5.77 (m, 1 H),
7.26–7.38 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = –4.7 (CH3), –4.5 (CH3), 18.0 (C),
21.2 (CH3), 25.8 (CH3), 27.0/27.1 (CH2), 31.2/31.4 (CH2), 32.0/
32.2 (CH2), 70.0 (CH), 70.1/70.3 (CH), 75.7/75.9 (CH), 81.1/81.2
(C), 126.3 (CH), 127.7 (CH), 128.2 (CH), 140.2/140.3 (C), 170.0
(C).
1H NMR (400 MHz, CDCl3): d = –0.04–0.06 (m, 12 H), 0.86 (s,
9 H), 0.88 (s, 9 H), 1.24–1.74 (m, 10 H), 1.75–1.98 (m, 2 H), 1.99–
2.04 (m, 1 H), 2.06 (s, 3 H), 2.19–2.25 (m, 0.5 H, OH), 2.28–2.46
(m, 2 H), 2.73–2.83 (m, 0.5 H, OH), 3.57–3.79 (m, 3 H), 5.70 (t,
J = ~7 Hz, 1 H), 7.25–7.37 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = –4.5 (4 × CH3), 18.1 (2 × C), 21.2
(CH3), 25.8 (2 × CH3), 26.9/27.3 (CH2), 31.3–32.9 (6 × CH2), 69.8/
70.1 (CH), 70.4/70.7 (CH), 71.4–72.2 (2 × CH), 76.0 (CH), 80.7/
80.9 (C), 126.2/126.3 (CH), 127.7 (CH), 128.2 (CH), 140.3/140.4
(C), 170.1 (C).
MS (ESI, CHCl3): m/z = 383.2 [M + Na]+.
MS (ESI, MeOH): m/z = 613.6 [M + Na]+.
Anal. Calcd for C21H32O3Si·0.2 H2O: C, 69.26; H, 8.97. Found: C,
69.19; H, 9.28.
Anal. Calcd for C33H58O5Si2: C, 67.07; H, 9.89. Found: C, 67.33; H,
10.43.
Acetic Acid 4-(tert-Butyldimethylsilanyloxy)-7-hydroxy-1-phe-
nyldec-9-ynyl Ester (8)
Prepared from 7 (1.00 g, 2.77 mmol) according to GP1 ([Ru] = 2
mol%, with L4) and GP2.
Acetic Acid 4,7,10-Tris(tert-butyldimethylsilanyloxy)-1-phenyl-
tridec-12-ynyl Ester (11)
Prepared from 10 (3.00 g, 5.076 mmol) according to GP3.
Yield: 1.15 g (>95%); oil; Rf = 0.30 (t-BuOMe–hexane, 1:3).
Yield: 3.57 g (>99%); oil; Rf = 0.9 (t-BuOMe–hexane, 1:3).
IR (film): 3503, 3302, 2941, 2363, 1732, 1460, 1371, 1247, 1045,
838, 764, 699, 638, 541 cm–1.
IR (film): 3306, 2944, 1740, 1465, 1369, 1247, 1070, 837, 771, 699,
636, 532 cm–1.
Synthesis 2007, No. 18, 2809–2818 © Thieme Stuttgart · New York

2816
T. Kribber et al.
PAPER
1H NMR (400 MHz, CDCl3): d = –0.03–0.07 (m, 18 H), 0.85–0.88
(m, 27 H), 1.27–2.02 (m, 12 H), 1.91–1.95 (m, 1 H), 2.06 (s, 3 H),
2.23–2.38 (m, 2 H), 3.55–3.67 (m, 2 H), 3.73–3.82 (m, 1 H), 5.70 (t,
J = ~7 Hz, 1 H), 7.25–7.37 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = –4.6 to –4.4 (6 × CH3), 18.0 (3 ×
C), 21.2 (CH3), 25.7–25.9 (3 × CH3), 27.3 (CH2), 31.4–32.8 (6 ×
CH2), 69.8 (CH), 70.9/71.0 (CH), 71.6/71.7/71.8 (CH), 72.1/72.2
(CH), 76.0 (CH), 81.5 (C), 126.3 (CH), 127.6 (CH), 128.2 (CH),
140.5 (C), 170.1 (C).
Yield: 190 mg (95%); oil; Rf = 0.58 (t-BuOMe–hexane, 1:3). (Z)-16
(7.6 mg, 3.8%) was also obtained as an oil. Ratio of E/Z = 25:1.
IR (film): 3032, 2951, 1730, 1658, 1496, 1438, 1372, 1317, 1239,
1040, 837, 775, 702, 543 cm–1.
1H NMR (300 MHz, CDCl3): d = –0.03/0.00/0.07 (s, 6 H, 2 × Me),
0.86/0.86 (s, 9 H), 1.27–2.00 (m, 6 H), 2.07 (s, 3 H), 2.11–2.27 (m,
2 H), 3.63–3.72 (m, 1 H), 3.72 (s, 3 H), 5.7 (t, J = 7.1 Hz, 1 H), 5.79
(dq, J = 15.7, 1.6 Hz, 1 H), 6.95 (dtd, J = 15.6, 7.1, 1.3 Hz, 1 H),
7.25–7.38 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = –4.4 (CH3), –4.3 (CH3), 18.2 (C),
21.4 (CH3), 26.0 (CH3), 28.1 (CH2), 31.6/31.8 (CH2), 32.7 (CH2),
35.0/35.1 (CH2), 51.6 (CH3), 70.9/71.0 (CH), 76.2 (CH), 121.0
(CH), 126.6 (CH), 128.1 (CH), 128.6 (CH), 140.6/140.7 (C), 149.5
(CH), 167.2 (C), 170.5 (C).
MS (ESI, CHCl3): m/z = 727.8 [M + Na]+.
Anal. Calcd for C39H72O5Si3: C, 66.42; H, 10.29. Found: C, 65.84;
H, 9.98.
(E)-6-Acetoxy-6-phenylhex-2-enoic Acid Methyl Ester [(E)-14]
Prepared from 4 (160 mg, 0.88 mmol) according to GP1 (with L2)
and GP4.
MS (ESI, MeOH): m/z = 457.1 [M + Na]+.
Anal. Calcd for C24H38O5Si: C, 66.32; H, 8.81. Found: C, 66.06; H,
8.51.
Yield: 217 mg (93.6%); oil; Rf = 0.43 (t-BuOMe–hexane, 1:3). (Z)-
14 (8.5 mg, 3.7%) was also obtained as an oil. Ratio of E/Z = 25:1.
IR (film): 3032, 2950, 1729, 1657, 1495, 1437, 1372, 1314, 1237,
1032, 852, 761, 702, 549 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.85–2.32 (m, 4 H), 2.08 (s, 3 H,
Me), 3.72 (s, 3 H, OMe), 5.74 (dd, J = 7.2, 5.9 Hz, 1 H, H-6), 5.82
(dt, J = 15.8, 1.4 Hz, 1 H, H-2), 6.94 (dt, J = 15.7, 6.8 Hz, 1 H, H-
3), 7.26–7.38 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 21.2 (CH3), 28.3 (CH2), 34.5
(CH2), 51.5 (CH3), 75.2 (CH), 121.5 (CH), 126.4 (CH), 128.1 (CH),
128.6 (CH), 140.0 (C), 147.9 (CH), 166.9 (C), 170.2 (C).
(Z)-16
1H NMR (300 MHz, CDCl3): d = 0.00/0.02/0.04 (s, 6 H, 2 × Me),
0.88/0.89 (s, 9 H), 1.32–2.04 (m, 6 H), 2.09 (s, 3 H), 2.55–2.75 (m,
2 H), 3.66–3.77 (m, 1 H), 3.72 (s, 3 H), 5.68–5.83 (m, 2 H), 6.21
(dtd, J = 11.4, 7.3, 1.9 Hz, 1 H) 7.25–7.41 (m, 5 H).
10-Acetoxy-7-(tert-butyldimethylsilanyloxy)-4-hydroxy-10-
phenyldec-2-ynoic Acid Methyl Ester (17)
Prepared from 7 (0.995 g, 2.76 mmol) according to GP1 (with L2)
and GP5.
MS (EI): m/z = 263.2 (3) [M+], 219.1 (14), 202.1 (38), 163.0 (63),
143.1 (85), 121.1 (67), 107.1 (87), 100.1 (100), 91.1 (31).
Yield: 1.129 g (88%); oil; Rf = 0.19 (t-BuOMe–hexane, 1:3).
IR (film): 3398, 3031, 2955, 2858, 2236, 1719, 1496, 1437, 1374,
1254, 1053, 949, 837, 756, 702, 544 cm–1.
Anal. Calcd for C15H18O4: C, 68.68; H, 6.92. Found: C, 68.41; H,
6.70.
1H NMR (400 MHz, CDCl3): d = –0.01–0.06 (several s, 6 H, 2 ×
Me), 0.86/0.88 (s, 9 H), 1.32–1.99 (m, 8 H), 2.07 (s, 3 H), 2.63/2.66
(d, J = 5.2 Hz, 0.5 H, OH), 3.24/3.30 (d, J = 7.4 Hz, 0.5 H), 3.69–
3.81 (m, 1 H), 3.77 (s, 3 H), 4.42–4.54 (m, 1 H), 5.70 (t, J = ~7 Hz,
1 H), 7.24–7.39 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = –4.4 to –4.3 (2 × CH3), 18.3 (C),
21.5 (CH3), 26.1 (CH3), 31.2–32.7 (4 × CH2), 52.9/53.0 (CH3), 61.9/
62.4 (CH), 71.1/71.3/71.4 (CH), 76.0/76.1 (CH), 76.3/76.5 (C),
88.2/88.3 (C), 126.5/126.6 (CH), 128.0/128.1 (CH), 128.5 (CH),
140.3/140.4/140.5/140.5 (C), 153.8 (C), 170.4 (C).
(Z)-14
1H NMR (300 MHz, CDCl3): d = 1.85–2.17 (m, 2 H), 2.08 (s, 3 H),
2.64–2.77 (m, 2 H), 3.68 (s, 3 H), 5.75 (dd, J = 8.1, 5.7 Hz, 1 H),
5.79 (dt, J = 11.5, 1.7 Hz, 1 H), 6.20 (dt, J = 11.5, 7.5 Hz, 1 H),
7.27–7.35 (m, 5 H).
7-Acetoxy-4-hydroxy-7-phenylhept-2-ynoic Acid Methyl Ester
(15)
Prepared from 4 (100 mg, 0.531 mmol) according to GP1 (with L2)
and GP5.
MS (ESI, MeOH): m/z = 485.1 [M + Na]+.
Yield: 135 mg (87%); oil; Rf = 0.14 (t-BuOMe–hexane, 1:3).
Anal. Calcd for C25H38O6Si: C, 64.90; H, 8.28. Found: C, 64.89; H,
8.63.
IR (film): 3416, 3032, 2955, 2855, 2236, 1717, 1496, 1437, 1374,
1251, 1028, 957, 754, 702, 542 cm–1.
(E)-15-Acetoxy-6,9,12-tris(tert-butyldimethylsilanyloxy)-15-
phenylpentadec-2-enoic Acid Methyl Ester [(E)-18]
Prepared from 11 (250 mg, 0.354 mmol) according to GP1 (with
L2) and GP4.
1H NMR (400 MHz, CDCl3): d = 1.64–2.15 (m, 4 H), 2.08 (s, 3 H,
Me), 3.02/3.04 (d, J = 5.7/5.5 Hz, 1 H, OH), 3.76 (s, 3 H, OMe),
4.42–4.50 (m, 1 H, H-4), 5.73–5.78 (m, 1 H, H-7), 7.27–7.37 (m,
5 H).
Yield: 255 mg (92%); oil; Rf = 0.80 (t-BuOMe–hexane, 1:3).
13C NMR (100 MHz, CDCl3): d = 21.2 (CH3), 31.5/31.6 (CH2), 32.6
(CH2), 52.8 (CH3), 61.2/61.3 (CH), 75.3/75.4 (C), 76.1 (CH), 87.7
(C), 126.2 (CH), 127.9 (CH), 128.3 (CH), 139.8 (C), 153.5 (C),
170.3 (C).
IR (film): 2946, 1734, 1656, 1464, 1370, 1247, 1065, 837, 775, 702,
665, 538 cm–1.
1H NMR (300 MHz, CDCl3): d = –0.04–0.05 (m, 18 H, Me), 0.86–
0.87 (several s, 27 H, t-Bu), 1.21–1.62 (m, 12 H), 1.73–2.00 (m,
2 H), 2.06 (s, 3 H, Me), 2.15–2.32 (m, 2 H), 3.51–3.72 (m, 3 H, H-
6, H-9, H-12), 3.73 (s, 3 H, OMe), 5.70 (t, J = ~7 Hz, 1 H, H-15),
5.82 (d, J = 15.7 Hz, 1 H, H-2), 6.98 (dt, J = 15.6, 6.9 Hz, 1 H, H-
3), 7.25–7.37 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = –4.6 to –4.3 (6 × CH3), 18.1 (3 ×
C), 21.3 (CH3), 25.9 (3 × CH3), 27.9/28.0 (CH2), 31.4–32.9 (6 ×
CH2), 35.20 (CH2), 51.4 (CH3), 71.7–72.4 (3 × CH), 76.2 (CH),
MS (ESI, MeOH): m/z = 313.0 [M + Na]+.
Anal. Calcd for C16H18O5: C, 66.19; H, 6.25. Found: C, 66.13; H,
6.62.
(E)-9-Acetoxy-6-(tert-butyldimethylsilanyloxy)-9-phenylnon-2-
enoic Acid Methyl Ester [(E)-16]
Prepared from 7 (166 mg, 0.46 mmol) according to GP1 (with L2)
and GP4.
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Iterative Synthesis of Oligo-1,4-diols
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120.8 (CH), 126.5 (CH), 127.8 (CH), 128.4 (CH), 140.7 (C), 149.7
(CH), 167.1 (C), 170.3 (C).
MS (EI): m/z (%) = 245.0 (4) [M – CH3]+, 221.1 (31), 203.0 (100),
185.0 (4), 128.1 (9), 115.0 (3), 97.1 (22), 75.1 (35).
MS (ESI, MeOH): m/z = 801.8 [M + Na]+.
Anal. Calcd for C16H24OSi: C, 73.79; H, 9.29. Found: C, 73.47; H,
8.81.
Anal. Calcd for C42H78O7Si3: C, 64.73; H, 10.09. Found: C, 65.20;
H, 10.17.
7-(tert-Butyldimethylsilanyloxy)-4-hydroxy-7-phenylhept-2-
ynoic Acid Methyl Ester (22)
Prepared from 21 (500 mg, 1.92 mmol) according to GP1 (with L2)
16-Acetoxy-7,10,13-tris(tert-butyldimethylsilanyloxy)-4-hy-
droxy-16-phenylhexadec-2-ynoic Acid Methyl Ester (19)
Prepared from 11 (500 mg, 0.709 mmol) according to GP1
([Ru] = 2 mol%, with L3) and GP5.
and GP5.
Yield: 432 mg (62%); oil; Rf = 0.4 (t-BuOMe–hexane, 1:3). Mix-
ture of diastereomers (A/B = 60:40).
Yield: 423 mg (74%); oil; Rf = 0.46 (t-BuOMe–hexane, 1:3).
IR (film): 3401, 3027, 2945, 2862, 2238, 1715, 1444, 1257, 1080,
843, 773, 700, 541 cm–1.
IR (film): 3415, 3029, 2953, 2857, 2236, 1720, 1466, 1437, 1371,
1253, 1061, 938, 837, 770, 701, 666 cm–1.
1H NMR (400 MHz, CDCl3): d = –0.13/–0.08 (s, 3 H, Me), 0.04/
0.07 (s, 3 H, Me), 0.89/0.91 (s, 9 H), 1.72–2.08 (m, 4 H), 2.45 (d,
J = 5.4 Hz, 0.6 H, OH-A), 3.07 (d, J = 7.2 Hz, 0.4 H, OH-B), 3.77/
3.78 (s, 3 H, OMe), 4.43–4.53 (m, 1 H, H-4), 4.77 (t, J = 5.6 Hz,
0.6 H, H-7 A), 4.85 (dd, J = 5.7, 4.6 Hz, 0.4 H, H-7 B), 7.19–7.37
(m, 5 H).
13C NMR (100 MHz, CDCl3): d = –4.9 (B, CH3), –4.9 (A, CH3), –
4.6 (B, CH3), –4.5 (A, CH3), 18.3/18.4 (C), 26.0 (CH3), 31.9 (B,
CH2), 32.6 (A, CH2), 35.4 (B, CH2), 36.0 (A, CH2), 52.8 (CH3), 61.8
(B, CH), 62.2 (A, CH), 74.2 (B, CH), 74.4 (A, CH), 76.2/76.4 (C),
88.1/88.2 (C), 125.8 (CH), 127.1 (CH), 128.1 (CH), 143.8 (B, C),
144.3 (A, C), 153.7 (C), 170.3 (C).
1H NMR (300 MHz, CDCl3): d = –0.04–0.07 (several s, 18 H),
0.86–0.90 (several s, 27 H), 1.23–2.00 (m, 16 H and 0.5 OH), 2.06
(s, 3 H, Me), 2.82–2.91 (m, 0.5 H, OH), 3.52–3.72 (m, 3 H), 3.77 (s,
3 H), 4.44–4.57 (m, 1 H, H-4), 5.70 (t, J = ~7 Hz, 1 H, H-16), 7.24–
7.39 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = –4.5 to –4.2 (6 × CH3), 18.2 (3 ×
C), 21.4 (CH3), 26.0 (3 × CH3), 31.1–33.1 (8 × CH2), 52.8/52.9
(CH3), 61.8/62.5 (CH), 71.7–72.6 (3 × CH), 76.2 (C), 76.3 (CH),
88.4/88.5 (C), 126.6/126.7 (CH), 128.0 (CH), 128.6 (CH), 140.8
(C), 154.0 (C), 170.5 (C).
MS (ESI, MeOH): m/z = 829.9 [M + Na]+.
MS (ESI, CHCl3): m/z = 385.1 [M + Na]+.
Anal. Calcd for C43H78O8Si3: C, 63.97; H, 9.74. Found: C, 63.79; H,
10.02.
Anal. Calcd for C20H30O4Si·0.2 H2O: C, 65.61; H, 8.37. Found: C,
65.55; H, 8.27.
16-Acetoxy-4,7,10,13-tetrakis(tert-butyldimethylsilanyloxy)-16-
phenylhexadec-2-ynoic Acid Methyl Ester (20)
Prepared from 19 (430 mg, 0.533 mmol) according to GP3.
Acknowledgment
Yield: 487 mg (99%); oil; Rf = 0.79 (t-BuOMe–hexane, 1:3).
We thank the DFG for support within an Emmy Noether Programm,
Prof. Carsten Bolm, RWTH Aachen, for continued support, and
Umicore for a sample of RuCl3.
IR (film): 2947, 2859, 2237, 1728, 1466, 1368, 1250, 1073, 938,
838, 777, 700, 667 cm–1.
1H NMR (400 MHz, CDCl3): d = –0.06–0.14 (several s, 24 H),
0.82–0.94 (several s, 36 H), 1.20–1.99 (m, 16 H), 2.06 (s, 3 H),
3.48–3.70 (m, 3 H, H-7, H-10, H-13), 3.76 (s, 3 H, OMe), 4.43/4.47
(t, J = 6.2 Hz, 1 H, H-4), 5.70 (t, J = ~7 Hz, 1 H, H-16), 7.23–7.36
(m, 5 H).
13C NMR (100 MHz. CDCl3): d = –4.4 to –4.2 (8 × CH3), 18.2–18.3
(4 × C), 21.4 (CH3), 25.8–26.0 (4 × CH3), 31.5–33.8 (8 × CH2),
51.8/51.9/52.7 (CH3), 62.7/62.9 (CH), 71.7–72.7 (3 × CH), 75.8
(C), 76.2 (CH), 88.9 (C), 126.4/126.5 (CH), 127.8 (CH), 128.4
(CH), 140.6 (C), 153.8 (C), 170.2 (C).
References
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tert-Butyldimethyl(1-phenylbut-3ynyloxy)silane (21)
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25.9 (CH3), 31.1 (CH2), 70.0 (CH), 73.8 (CH), 81.7 (C), 125.9
(CH), 127.4 (CH), 128.1 (CH), 143.9 (C).
Synthesis 2007, No. 18, 2809–2818 © Thieme Stuttgart · New York

2818
T. Kribber et al.
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Synthesis 2007, No. 18, 2809–2818 © Thieme Stuttgart · New York