Thieme chemistry journal awardees - Where are they now? aldol synthesis by anti-markovnikov hydration of propargyloxy substrates: Feasibility, stereospecifity, and reiterative alkynylation-hydration

Article abstract of DOI:10.1055/s-0029-1217734

Aldol derivatives have been synthesized by redox-neutral catalytic anti-Markovnikov hydration of propargyloxy sub-strates. A reiterative sequence of aldehyde alkynylation and alkyne hydration leads to 1,3-polyol derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217734

2412
LETTER
Thieme Chemistry Journal Awardees – Where Are They Now?
Aldol Synthesis by anti-Markovnikov Hydration of Propargyloxy Substrates:
Feasibility, Stereospecifity, and Reiterative Alkynylation–Hydration
A
ldol Synthesis
u
by anti-Mar
k
kovnikov H
y
a
dration of
s
Hbstrates intermann,* Thomas Kribber, Aurélie Labonne, Eva Paciok
Institut für Organische Chemie, RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092391; E-mail: lukas.hintermann@oc.rwth-aachen.de
Received 5 June 2009
Abstract: Aldol derivatives have been synthesized by redox-neu-
tral catalytic anti-Markovnikov hydration of propargyloxy sub-
strates. A reiterative sequence of aldehyde alkynylation and alkyne
hydration leads to 1,3-polyol derivatives.
Key words: addition reactions, aldehydes, alkynes, homogeneous
catalysis, ruthenium
The stereoselective synthesis of aldol (b-oxy-carbonyl)
derivatives and 1,3-polyoxygenated fragments is a central
problem in natural product synthesis, because these sub-
Lukas Hintermann was born in Switzerland in 1972. He studied
structures are ubiquitous in secondary metabolites.1 If per-
formed iteratively, any synthesis of 3-oxyaldehydes from
aldehydes will give 1,3-polyols. Such iterations tend to
consist of multiple steps, use auxiliaries and/or exergonic
irreversible redox chemistry2 for assuring selective and
fast reactions with high overall yields.3 Consequently, the
low atom economy4 and need for high energy reagents in
such syntheses contrasts with the simplicity of a direct,
catalytic aldol reaction,5 which, however, usually fails
with acetaldehyde as the substrate.6 We hoped to apply ru-
thenium-catalyzed anti-Markovnikov hydration of termi-
nal alkynes7–10 to enantiopure secondary propargyl
alcohols as a new enantiospecific synthetic method for
making aldols.11,12 In combination with asymmetric alky-
nylation of aldehydes,13 an iterative synthesis of 1,3-poly-
dioxygenated fragments can be envisioned (Scheme 1).
chemistry at the ETH Zurich, where he obtained his Ph.D. in 2000 for
work performed with Antonio Togni. In 2001–2002 he visited the
Tokyo Institute of Technology as a JSPS postdoctoral fellow with
Keisuke Suzuki. He then moved to Germany to start independent re-
search at RWTH Aachen University, hosted by Carsten Bolm and
supported by an Emmy Noether program of the DFG. He finished his
habilitation in 2008. In 2009, he was offered an SNSF assistant pro-
fessorship and then accepted a professorship at the Technical Univer-
sity of Munich. He is recipient of the Heisenberg fellowship of the
DFG and the medal of the ETH. Research interests are centered on de-
veloping catalytic reactions for applications in sustainable organic
synthesis.
This redox-neutral2 synthetic scheme generates fairly
complex structures in an atom-economic manner by using
the simple precursors water and acetylene as building
blocks. Limited catalyst turnover and the probable need
for protecting groups will reduce the atom economy4 in
practice, but similar considerations apply to traditional
syntheses with inherently low atom economy.
OH
OH
O
O
H2O
R
R
R
anti-
Markovnikov
hydration
asymmetric
1,2-addition
Here we present a first principle study of the synthetic
strategy shown in Scheme 1 by investigating the feasibil-
ity of the individual reaction steps, testing the stereospeci-
fity of catalytic hydration and realizing first iterative
alkynylation–hydration sequences.
repeat
OH
O
1,3-polyols
R
The work started (in 2004) with first-generation
catalysts7b CpRuCl(dppm) and h5-IndRuCl(PPh3)2.14 Hy-
dration of nonprotected propargyl alcohols to aldols14 was
not successful in our hands, in which the indenyl complex
did not display any hydration activity at all.15,16 Because
Wakatsuki had already reported on a Meyer–Schuster re-
arrangement of nonprotected propargyl alcohols,16 we
preferred to investigate the hydration of protected sub-
strates like acetate 1, but the reaction took a different turn,
as it generated styrene 2 in good yields (Scheme 2)!17
Similar ruthenium-catalyzed decarbonylations of propar-
gyl alcohols have been reported.18
n
Scheme 1 Iterative synthesis of 1,3-polyols via sequential aldehyde
alkynylation and anti-Markovnikov hydration of propargyl alcohols
SYNLETT 2009, No. 15, pp 2412–2416
Advanced online publication: 27.08.2009
DOI: 10.1055/s-0029-1217734; Art ID: S06009ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

LETTER
Aldol Synthesis by anti-Markovnikov Hydration of Propargyloxy Substrates
2413
OAc
Various O-protected derivatives of 1-octyn-3-ol (6) were
next hydrated in a similar manner, using complexes
[CpRu(L)2(MeCN)]PF6 at loadings24 of 5 mol% or 10
mol% and a temperature of 50 °C.25 The results in Table 2
show that acetals 7a (R = MOM) and 7b (R = THP) were
hydrated most selectively in up to 70% spectroscopic and
63% of isolated yield (entries 3–5). TBS-ether 7c gave but
low conversions and selectivity, and methyl ether 7d suf-
fered extensive elimination (entries 11 and 13), similar to
the nonprotected 1-octyn-3-ol (cf. Table 1). The aldol and
elimination products appear to derive from different
mechanistic pathways (hydration vs. Meyer–Schuster re-
arrangement), since their ratio did not change much with
time and does not correlate with leaving-group ability of
RO– in 8.
CpRuCl(dppm)
(5 mol%)
acetone, H2O
70 °C, 36 h
AcO
OMe
2 83%
AcO
1
OMe
Scheme 2 Catalytic hydrative decarbonylation of a propargyl ester
It appeared that our plan had reached an early dead end!
However, the publication of Grotjahn and coworkers on a
highly active anti-Markovnikov hydration catalyst8b with
a bifunctional activation mode19 revived our project.
These workers had successfully hydrated O-TBS- and O-
THP-protected propargyl alcohol, but found a Meyer–
Schuster rearrangement in case of the hindered 2-methyl-
3-butyn-2-ol.8 It remained unclear how chiral secondary
propargyloxy derivatives would behave in the catalytic
hydration.20 In the meantime, we developed our family of
While the catalytic anti-Markovnikov hydration of sec-
ondary propargyloxy substrates to aldol derivatives was
bifunctional
AZARYPHOS
(aza-arylphosphane)
Table 2 Hydration of O-Protected 1-Octyn-3-ol Derivativesa
ligands21 and prepared in situ catalysts of the Grotjahn-
type8a with increased catalytic activity.9 These were ap-
plied in synthesis,22 and hydrated propargyl-tosylamides
to b-amidoaldehydes without elimination.23 We now hy-
drated secondary propargyl alcohols using second-gener-
ation catalysts: the substrates, water, and complex
[CpRu(L1)2(MeCN)]PF6 [31P NMR: d = 43.6 ppm; L1 = 6-
(2,4,6-triphenylphenyl)-pyridyl-2-diphenylphosphane]9,21
were dissolved in acetone-d6. A slow catalysis with limit-
ed turnovers produced a mixture of aldol and unsaturated
aldehyde (Table 1). Appearance of a signal for carbonyl
complex [CpRu(L1)2(CO)]PF6 (31P NMR: d = 46.8 ppm)
correlated with catalyst deactivation.17
OR
OR
O
–
O
PF6
+
Ln Ru Ln
+
H
11C5
NCMe
H11C5
H11C5
acetone, H2O
8
5b
7
Ph2P
R
Ph
L2
=
L1 =
N
Ph2P
N
Ph
Ph
Entry
mol%b Time
(h)
Yield of 7 Yield of 8 Yield of 5
(%)d
48
29
9
(%)d
(%)d
12
3
a
1
2
MOM
5c
5
17
17
50
50
30
17
50
50
50
50
50
50
50
17
18
Table 1 Catalytic Hydration of Propargyl Alcohols in Acetone-d6
–
MOM
MOM
MOM
THP
THP
THP
THP
TBS
TBS
Me
43
PF6
+
Ru
Ph2P
N
PPh2
N
N
3
5
69 (63)e
72
6
OH
O
OH
O
4
10
9
6
Ar
Ar
+
R
R
R
acetone-d6, H2O
5
5c
5
–
(44)e
48
–
4
5
3
6
36
27
6
3
Entry
R
mol%b Temp
Time
(h)
Yield of 4 Yield of 5
7
5
58
3
(°C)
r.t.
r.t.
45
(%)
23
42
10
17
22
20
27
31
(%)
20
39
15
20
24
18
26
35
8
10
70
3
1
2
3
4
5
6
7
8
Me
20
20
2
11
66
9
5
10
10c
5
36
24
28
45
2
24
12
12
39
15
27
13
Me
10
11
12
13
14
36
Me
24
4
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
4
45
13
Me
16
4
45
36
Me
10
5
38
10
10
10
r.t.
r.t.
r.t.
21
Bn
57
30
46
a Conditions: 50 °C, substrate (0.5 M), H2O (5 equiv).
140
b Loading of the catalyst; Ln = L1, unless otherwise mentioned.
c The complex containing L2 was used as the catalyst.
d Quantification by 1H NMR of reaction samples, the difference to
100% is due to unidentified side products.
a NMR tube experiments; ca 0.1 M 3, 5–10 equiv of H2O. Reaction
composition determined by integration of 1H NMR spectra.
b Loading of the ruthenium catalyst; Ar = 2,4,6-triphenylphenyl.
e Isolated yield in parentheses.
Synlett 2009, No. 15, 2412–2416 © Thieme Stuttgart · New York

2414
L. Hintermann et al.
LETTER
now viable, the question of the integrity of the propargylic rally occuring polyacetate metabolites with cytotoxic
stereogenic center remained. Enantiomerically enriched properties,29–31 as targets. Acetal 7a was once again hy-
MOM-acetal 7a, prepared from commercial (S)-6 (≥ 98% drated, but under improved reaction conditions with re-
ee), was hydrated and the product reduced and benzoylat- duced catalyst loading (4 mol%) and shortened reaction
ed to diester 9, which was found to have 98.4% ee accord- time (Scheme 6).32 Alkynylation of aldehyde 8a with
ing to chiral HPLC.26 Retention of configuration was next ethynylmagnesium chloride started the next iteration. For
shown by converting (S)-7a to the known hydroxyester protection of the alcohol prior to catalytic hydration, we
(S)-10 by an oxidation–methanolysis sequence, and com- found a simple ‘internal solution’: under acidic condi-
paring the sign of optical rotation of the product to litera- tions, 13 cyclized to acetal 14. Catalytic anti-Markovni-
ture values (Scheme 3).
kov hydration of 14 worked well. The resulting aldehyde,
without purification, was allylated with a Grignard re-
agent to give homoallyl alcohol 15. Esterification with
acryloyl chloride and olefin metathesis with Grubbs first-
generation catalyst gave pyranone acetal 16 according to
established endgame strategies for pyrones (Scheme 6).30
OMOM
[Ru]
OMOM
H11C5
H11C5
H2O
O
(S)-7a
(S)-8a
1) KMnO4
2) MeOH, H+
a)
1) NaBH4
O
O
2) HCl, MeOH
OBz OBz
46% (3 steps)
OH OH
O
Cl
3) BzCl, Et3N,
DMAP
OH
O
H11C5
17
24% (4 steps)
H11C5
OMe
(S)-9
(S)-10
O
MgX
H2O
H2O
Scheme 3 Correlations to prove stereospecifity of the hydration
step
b)
O
O
Having clarified basic issues, we gradually increased the
complexity of our synthetic targets. First, anti-Markovni-
kov hydration of propargyloxy substrates was connected
with a follow-up reaction to include a single aldol itera-
tion into a synthetic scheme. MOM-acetal 7a was hydrat-
ed to aldehyde 8a, to which the lithium enolate of tert-
butylacetate was added (Scheme 4).
OAc OAc
O
OH OH
O
Ph
4
(+)-cryptocarya diacetate
18
Scheme 5 a) Retrosynthetic analysis of parent structure 17.
b) Naturally occurring substances with structural similarities to 16
and 17
OLi
OMOM
MOMO
H11C5
The parent structure 17 (Scheme 5, a) is an analogue of
cryptocarya diacetate or compound 18 (Scheme 5, b),
both naturally occurring substances.3e,29,31 The stereo-
chemisry has not been controlled in the synthesis of 16,
which is a mixture of four diastereomeric pairs of enan-
tiomers. A separation into two fractions consisting of two
diastereomers each was possible by chromatography.
Evidently, our syntheses of 12 and 16 bear model charac-
ter and were designed to reflect our strategy of joining
simple building blocks and heterofunctionalize them with
atom economy to achieve efficient and sustainable syn-
theses (Scheme 5, a). Apart from the catalysts, no partic-
ularly expensive reagents are necessary. By design, redox
steps, which are prevalent in current syntheses3e,33 and of-
ten detrimental to atom economy, are excluded.
[Ru] (5%)
Ot-Bu
H11C5
( )-7a
acetone/H2O
50 °C, 6 h
8a
O
–78 °C
10 min
O
MOMO
OH
O
TFA
O
r.t., 7 d
H11C5
Ot-Bu
H11C5
( )-12 71%
11
68% (2 steps)
Scheme 4 Synthesis of ( )-massoialactone via a single aldol itera-
tion
Under acidic conditions, adduct 11 cyclized to massoia-
lactone 12, a natural product from the bark of Cryptocarya
massoia.27 Admittedly, this is not a synthetic mountain
climbed for the first time, but our route illustrates econo-
my of steps and of atoms because it does not require re-
duction–oxidation or non-bond-forming steps, which are
typical of traditional routes.28 Since 7a is derived from an
alkynylation of hexanal, the synthesis of 12 contains one
iteration of the planned alkynylation–hydration sequence
(Scheme 1). For realizing a reiterative synthesis with at
least one additional alkynlyation and a second hydration
step, we continued with 5,6-dihydropyran-2-ones, natu-
The yield in each iteration is limited to about 70% by the
somewhat difficult anti-Markovnikov hydration of prop-
argyloxy substrates. Further improvements of the catalyt-
ic process are desirable, and future developments will
address the stereoselectivity of the carbonyl addition. In
any case, we have come closer to realize our ‘dream’ of
synthesizing moderately complex polyacetates with only
acetylene and water as building blocks for the 1,3-polyol
backbones (compare Scheme 5, a)!34
Synlett 2009, No. 15, 2412–2416 © Thieme Stuttgart · New York

LETTER
Aldol Synthesis by anti-Markovnikov Hydration of Propargyloxy Substrates
2415
1) [Ru] (5 mol%), H2O
acetone, 50 °C, 4 h
MOMO
H11C5
MOMO
H11C5
OH
O
O
TfOH (0.2 equiv)
CH2(MeO)2
H11C5
2)
MgCl
0 °C, 1 h
13 74%
14 89%
7a
1) [Ru] (4 mol%)
acetone, H2O
50 °C, 5 h
O
1)
2)
COCl
O
O
OH
O
O
O
Et3N, CH2Cl2, r.t. (74%)
MgBr
2)
H11C5
Grubbs I (10 mol%),
CH2Cl2, 4 h, 40 °C
Et2O, 0 °C
16 (85%)
15 73%
Scheme
6
Iterative hydration–alkynylation sequences for efficient synthesis of
a
natural product-like pyranone
[Ru] = [CpRu(L1)2(MeCN)]PF6, Grubbs I = [Ru(=CHPh)Cl2(PCy3)2]
(15) Hydration experiments with IndRuCl(PPh3)2 were attempted
in either i-PrOH–H2O or an aqueous micellar system, with
several alkynes. GC-MS analysis usually revealed the
presence of starting alkyne. Among minor reaction products,
we found traces of 2-octanone and heptene (from 1-octyne),
and products of alkyne trimerization. In addition,
decomposition of the ruthenium complex to indene and Ph3P
was observed and tenside decomposition products
(dodecanol, dodecene, chlorododecane from sodium
dodecyl sulfate).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the DFG and Fonds der Chemischen Industrie for funding
and Prof. Carsten Bolm for continued support.
References and Notes
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(17) See the Supporting Information for experimental details and
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(25) A solvent screen had indicated the superiority of acetone
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L. Hintermann et al.
LETTER
(33) Cho, S. H.; Chang, S. Angew. Chem. 2007, 46, 1897.
(34) The Supporting Information to this article contains
experiment descriptions, analytical data, and additional
information.
(31) (a) Garcia, A. B.; Leßmann, T.; Umarye, J. D.; Mamane, V.;
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(32) These conditions are characterized by use of the reaction
medium acetone–H2O (4:1) and will be discussed elsewhere.
Synlett 2009, No. 15, 2412–2416 © Thieme Stuttgart · New York

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