Boron-Catalyzed Regioselective Deoxygenation of Terminal 1,2-Diols to 2-Alkanols Enabled by the Strategic Formation of a Cyclic Siloxane Intermediate

Article abstract of DOI:10.1002/anie.201503172

The selective deoxygenation of polyols is a frontier in our ability to harness the stereochemical and structural complexity of natural and synthetic feedstocks. Herein, we describe a highly active and selective boron-based catalytic system for the selective deoxygenation of terminal 1,2-diols at the primary position, a process that is enabled by the transient formation of a cyclic siloxane. The method provides an ideal complement to well-known catalytic asymmetric reactions to prepare synthetically challenging chiral 2-alkanols in nearly perfect enantiomeric excess, as illustrated in a short synthesis of the anti-inflammatory drug (R)-lisofylline. Pick the right one! A highly active and selective boron-based catalytic system enables the selective deoxygenation of terminal 1,2-diols at the primary position via the transient formation of a cyclic siloxane. The utility of this method for the preparation of synthetically challenging chiral 2-alkanols was illustrated by a short synthesis of the anti-inflammatory drug (R)-lisofylline.

Full text of DOI:10.1002/anie.201503172

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Angewandte
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International Edition: DOI: 10.1002/anie.201503172
German Edition: DOI: 10.1002/ange.201503172
Selective Reduction
Boron-Catalyzed Regioselective Deoxygenation of Terminal 1,2-Diols
to 2-Alkanols Enabled by the Strategic Formation of a Cyclic Siloxane
Intermediate**
Nikolaos Drosos and Bill Morandi*
Dedicated to Professor Robert H. Grubbs
Abstract: The selective deoxygenation of polyols is a frontier
in our ability to harness the stereochemical and structural
complexity of natural and synthetic feedstocks. Herein, we
describe a highly active and selective boron-based catalytic
system for the selective deoxygenation of terminal 1,2-diols at
the primary position, a process that is enabled by the transient
formation of a cyclic siloxane. The method provides an ideal
complement to well-known catalytic asymmetric reactions to
prepare synthetically challenging chiral 2-alkanols in nearly
perfect enantiomeric excess, as illustrated in a short synthesis of
the anti-inflammatory drug (R)-lisofylline.
T
he deoxygenation of polyols is a critical step in the
production of fine chemicals from alcohol-containing feed-
stocks.[1] A formidable challenge in this area is the predictable
and selective deoxygenation of a single alcohol group within
an array of hydroxy groups. Such selective deoxygenations of
polyols would enable the synthesis of valuable building blocks
using starting materials that can be either derived from
renewable biomass or prepared by well-established asym-
metric catalytic reactions, such as the Sharpless asymmetric
dihydroxylation or the Jacobsen hydrolytic kinetic resolu-
tion.[2] Herein, we report the first catalytic regioselective
deoxygenation of terminal 1,2-diols at the primary position to
access 2-alkanols using a simple boron catalyst and commer-
cially available silanes, a process orchestrated by the key
formation of a cyclic siloxane intermediate (Scheme 1d).
Several approaches to the catalytic deoxygenation of
polyols have already been reported (Scheme 1). Re-catalyzed
deoxydehydration reactions have been developed to effi-
ciently access alkenes from polyols (Scheme 1a).[3] Another
approach to the full deoxygenation of polyols is the catalytic
deoxygenation of these substrates using silanes (Sche-
me 1b).[4] Inspired by earlier reports describing the efficient
Scheme 1. Approaches to the catalytic deoxygenation of polyols.
R=alkyl group, R’=H or silyl group.
deoxygenation of simple alcohols,[5] GagnØ and co-workers
recently described the complete deoxygenation of carbohy-
drates using either a boron or iridium catalyst in the presence
of silanes.[4] Although these reports (Scheme 1a and b) are
conceptually very interesting approaches to the deoxygena-
tion of renewable feedstocks, they generally do not fully
harness the functional and stereochemical complexity of
polyols to produce more elaborate, valuable organic building
blocks. Therefore, a contemporary challenge of selective
catalysis is the invention of novel methods for the partial,
selective deoxygenation of polyols.[6]
The regioselective catalytic deoxygenation of terminal
1,2-diols represents an attractive transformation to access
valuable 1- and 2-alkanols. In this context, the selective
deoxygenation of the secondary alcohol to obtain 1-alkanols
has precedent in the literature using both Ir and Ru catalysts
and high pressures of H2 gas (Scheme 1c).[7] The regioselec-
tivity of these reactions is determined by the formation of the
more stable secondary carbocation by trifluoromethanesul-
fonic acid (TfOH) mediated elimination of water, followed by
hydrogenation.[7]
Owing to the lack of catalytic strategies to obtain the
reverse selectivity, that is, the more difficult deoxygenation of
the primary alcohol, we became interested in inventing such
a reaction to transform terminal 1,2-diols into 2-alkanols
(Scheme 1d and Scheme 2a). As vicinal 1,2-diols are fre-
[*] M. Sc. N. Drosos, Dr. B. Morandi
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
E-mail: morandi@kofo.mpg.de
[**] Generous funding from the Max-Planck-Society and the Max-Planck-
Institut für Kohlenforschung is acknowledged. We thank Prof. Dr.
Benjamin List for sharing analytical equipment, and our HPLC, GC,
and MS departments for technical assistance.
Supporting information for this article (full spectroscopic data and
detailed experimental conditions) is available on the WWW under
http://dx.doi.org/10.1002/anie.201503172.
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1) activate the substrate towards initial deoxygenation by
decreasing the steric bulk around the oxygen atom, 2) dis-
favor overreduction of the desired product (6) because of the
large steric bulk created on the secondary alcohol after the
first deoxygenation, and 3) prevent any undesired neighbor-
ing group participation. Gratifyingly, this strategy proved
successful and led to the development of an extremely active
and selective catalytic system for the selective monodeoxyge-
nation of 1,2-diols at the primary position (Scheme 2 f and
Table 1, entry 1). The intermediacy of the cyclic siloxane 8
Table 1: Effect of different silanes on the transformation.[a]
Entry
Deviation from the standard conditions
Yield[b] [%]
1
2
3
4
5
6
7
8
9
none
86 (79)
93 (77)
4
0
15
<5
76
48
28
81
1 equiv Et2SiH2, then 1.1 equiv Et3SiH
no Ph2SiH2, 3.1 equiv Et3SiH
no Et3SiH, 2.1 equiv Ph2SiH2
no Ph2SiH2, 3.1 equiv Et2MeSiH
no Ph2SiH2, 3.1 equiv EtMe2SiH
1 equiv Ph2SiH2, then 1.1 equiv Et2MeSiH
1 equiv Ph2SiH2, then 1.1 equiv EtMe2SiH
5 min interval
Scheme 2. Initial attempts and design of a new approach. R=alkyl
group.
10
5 min interval, 5 mol% catalyst
[a] See the Supporting Information for detailed conditions. [b] Yields
determined by 1H NMR spectroscopy using nitromethane as a standard.
Yields of isolated products are given in parentheses.
quently encountered in biomass-derived feedstocks, such as
carbohydrates, and are easily accessible by known methods in
high enantiopurity,[2] the catalytic cleavage of the primary
hydroxy group would find applications in the preparation of
synthetically challenging 2-alkanols in high enantiomeric
excess.[8] 1,2-Decanediol was selected as a test substrate to
explore reaction conditions for the regioselective deoxygena-
tion. We targeted the development of Lewis acid catalyzed
deoxygenations using commercially available and practical
silanes as reducing agents.[9] We were particularly interested
in testing the efficiency of simple, commercially available
boranes as catalysts to avoid the use of costly transition
metals.[10] Unfortunately, preliminary attempts to selectively
obtain the desired silylated 2-alkanol using known conditions
for alcohol deoxygenations[4,5] did not provide any of the
desired product using either Et3SiH or EtMe2SiH (Scheme 2b
and c).[11] The deoxygenation behavior is critically dependent
on the size of the silane. More importantly, the result using no
excess of EtMe2SiH (Scheme 2c) demonstrated experimen-
tally that the second deoxygenation is faster than the initial
one when using terminal 1,2-diols (Scheme 2d). This finding
can possibly be rationalized by the steric and electronic
deactivation of the protected diol intermediate 2 compared to
the resulting protected alcohol 3.[12]
was confirmed by the incorporation of both silane backbones
in the final product (7).[13] Table 1 illustrates the critical
dependence of the reaction outcome on the nature of the
silanes used. Replacing Ph2SiH2 by Et2SiH2 gave a similar
result, although product isolation proved more challenging
(entry 2). Using Et3SiH as the sole silane (entry 3), only traces
of the desired product were observed, and the silylated diol
was left unreacted. When Ph2SiH2 was used alone (entry 4),
overreduction was observed, emphasizing the critical inter-
play of the two silanes under the optimized conditions.
Smaller, more reactive silanes (entries 5 and 6) afforded
mostly full reduction to decane, with significant amounts of
the protected diol left unreacted, even when no excess of
silane (3.1 equiv) was used. These results confirmed that the
second deoxygenation is faster than the first deoxygenation.
A notable size dependence was also observed when different
silanes were used after the initial Ph2SiH2 addition. Whereas
the use of Et2MeSiH (entry 7) instead of Et3SiH as the second
silane provided a good yield of product, the use of EtMe2SiH
(one Et group switched for a Me, entry 8) led to a much lower
yield and significant formation of decane. Finally, when the
delay between silane additions was reduced from 4 h to 5 min,
the product was formed in low yields, probably because of
unselective hydrosilylation (entry 9). However, when the
catalyst loading was increased to 5 mol%, the two silanes
could be conveniently added with an only 5 min interval, and
the product was obtained in good yield (entry 10).
The discouraging lack of desired reactivity in our initial
attempts drove us to design a conceptually new approach
(Scheme 2e). We hypothesized that the use of a dialkylsilane
(R2SiH2) in the initial protection step could lead to the
transient in situ formation of a cyclic siloxane (5). We further
reasoned that the formation of this cyclic intermediate would
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Table 2: Substrate scope.[a]
Entry
Substrate
Product
Yield[b] [%]
1
2
79
71
Scheme 3. Scale-up and one-pot deoxygenation/deprotection.
3
69
4
5
74
74
Scheme 4. Experiment with low catalyst loading.
6[c]
7
62
71
77
direct access to the free alcohol in 64% yield using
tetrabutylammonium fluoride (TBAF; Scheme 3).
8
When the catalyst loading was reduced to 0.1 mol% and
the reaction time increased, the product was also obtained in
good yield (Scheme 4). Previously, catalyst loadings between
5 and 10 mol% were usually required for the efficient
deoxygenation of alcohols.[16]
9
51
10
78[d]
97
Finally, we envisaged that our novel method could be
applied to the preparation of enantioenriched 2-alkanols,
which are challenging to access in high enantiomeric excess by
the asymmetric hydrogenation of ketones because of the
difficulty for the hydrogenation catalysts to differentiate
between the two prochiral faces of ketones bearing substitu-
ents of similar size.[17] We thus reasoned that when combined
with established methods to access terminal diols in high
enantiopurity, our deoxygenation reaction could be used to
obtain useful 2-alkanols in nearly perfect enantiopurity.[18]
The retention of chiral information at the secondary alcohol
during the deoxygenation step was therefore evaluated
(Scheme 5). We subjected chiral bromodiol 10, which was
synthesized by the Jacobsen hydrolytic kinetic resolution in
> 99% ee, to our standard reaction conditions and obtained
the protected alcohol 11 in > 99% ee, with full retention of
stereochemistry. The silyl group introduced in the deoxyge-
11[c]
[a] See the Supporting Information for detailed conditions. [b] Yields of
isolated products. [c] 5 mol% catalyst. [d] Isolated as a 3:1 mixture, see
the Supporting Information.
We next studied the substrate scope and functional group
tolerance of the novel transformation (Table 2). Simple
aliphatic substrates (entries 1–5) afforded the products in
good yield with full regioselectivity. Remarkably, significant
steric bulk in close proximity to the diol moiety (entry 3) was
also tolerated. Even in transformations of substrates prone to
elimination owing to the presence of an aromatic substituent
at the vicinal position (entries 4–6), good yields were gen-
erally observed. Halogenated substrates were well-tolerated
(entries 6–9), even in the case of vicinal substitution (entry 7).
These results demonstrate the mild conditions of our reaction
system, as alkyl halides are usually prone to reduction in the
presence of strong reducing agents.[14] Although the B(C6F5)3/
Et3SiH system is known to mediate the hydrosilylation of
double bonds under similar conditions,[15] the use of an
alkene-containing diol (entry 10) afforded the desired com-
pound as the major product. This result suggests that the
deoxygenation of the substrate is significantly faster than the
hydrosilylation of the double bond. Finally, the reaction can
also be extended to 1,3-diols in excellent yields (entry 11).
The reaction can be readily scaled-up with no loss of
efficiency (5.65 g of product, 80% yield; Scheme 3). Whereas
the silylated products of the deoxygenation can be conven-
iently used as protected alcohols in subsequent synthetic
steps, we also developed a one-pot procedure that provides
Scheme 5. Conservation of enantiopurity and synthesis of (R)-lisofyl-
line. HKR=hydrolytic kinetic resolution. See the Supporting Informa-
tion for details.
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[5] a) V. Gevorgyan, J.-X. Liu, M. Rubin, S. Benson, Y. Yamamoto,
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In conclusion, we have described the first catalytic,
selective monodeoxygenation of terminal 1,2-diols at the
primary position. The reaction proceeds in good yields using
a combination of two silanes and a commercially available
boron catalyst. The method exhibits good functional group
compatibility with no excess of silanes, can be run at low
catalyst loading (as low as 0.1 mol%), is amenable to gram-
scale synthesis, and can be used to prepare challenging
enantioenriched 2-alkanols. In a broader context, we believe
that the observations made during this study, namely that the
selectivity and reactivity of the deoxygenation can be
dramatically improved by the strategic formation of a cyclic
siloxane intermediate, will guide the development of new and
selective transformations of complex polyols.
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Keywords: boron · cyclic intermediates · deoxygenation · diols ·
silanes
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Received: April 7, 2015
Published online: June 18, 2015
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