A Stereoselective Reductive Hosomi-Sakurai Reaction

Article abstract of DOI:10.1021/acs.orglett.8b00276

A novel reductive variant of the classical Hosomi-Sakurai reaction is reported. This transformation hinges on a redox-neutral, stereoselective internal reduction event under mild conditions. This operationally simple reaction relies on readily available starting materials and leads to useful products in diastereoselectivities of up to 7:1. The versatility of this new method is demonstrated through the stereoselective one-step synthesis of an AChE inhibitor.

Full text of DOI:10.1021/acs.orglett.8b00276

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Stereoselective Reductive Hosomi−Sakurai Reaction
Adriano Bauer and Nuno Maulide*
Institute of Organic Chemistry, University of Vienna, Wahringer Straße 38, 1090 Vienna, Austria
̈
S
* Supporting Information
ABSTRACT: A novel reductive variant of the classical Hosomi−Sakurai reaction is reported. This transformation hinges on a
redox-neutral, stereoselective internal reduction event under mild conditions. This operationally simple reaction relies on readily
available starting materials and leads to useful products in diastereoselectivities of up to 7:1. The versatility of this new method is
demonstrated through the stereoselective one-step synthesis of an AChE inhibitor.
he development of innovative methods for C−C bond
external oxidants or reductants. However, in spite of their long
history and revival in recent years, a vast majority of the 1,5-
hydride transfer reactions known to date still use Michael
acceptors and carbonyl derivatives as electropositive
fragments.4a,f−j,l−o
We were intrigued by the 1,5-relationship between the
generated double bond and hydroxy substituents of Hosomi−
Sakurai products. In this context, we hypothesized that
protonation of the double bond could trigger an internal
redox process if a suitable hydroxy derivative was in place.
Herein (Scheme 1, eq 2), we report a metal-free, regio- and
diastereoselective reductive Hosomi−Sakurai reaction relying
on an internal redox event. The process displays noteworthy
functional group tolerance.
T
formation remains at the heart of contemporary progress
in organic chemistry. Allylsilanes emerged in the 1970s as mild,
nontoxic carbon nucleophiles which are easy-to-handle and
useful reagents for addition to electrophilic carbons in a broad
sense.1 These transformations are now textbook knowledge and
are collectively known as “Hosomi−Sakurai reactions”,
honoring the first observation by those two chemists in 1976
of the Lewis acid promoted nucleophilic attack of an allylsilane
to aldehydes and ketones (Scheme 1, eq 1).1a Several variations
Scheme 1. Conventional and Reductive Hosomi−Sakurai
Reactions
Initial experiments employing acetal 1a and allylsilane 11a
using p-toluenesulfonic acid (Scheme 2) delivered the desired
Scheme 2. First Observation of the Reductive Hosomi−
a
Sakurai Reaction
a
Yields determined by H NMR analysis.
on this theme have been reported ever since,2 including
nucleophilic additions to acceptor alkenes,1b diverse carbonyl
compounds,1a,c epoxides,1c imines,1d,e and acetals.1h,j Nucleo-
philic displacements of activated alcohols1f are also known, and
stereoselective2b,c Hosomi−Sakurai reactions have also at-
tracted considerable attention.
1,5-Hydride transfer reactions are known to typically occur
from C−H bonds adjacent to oxygen or nitrogen toward
electron-deficient carbons,3 and such transformations hold
significant potential for the highly regioselective C−H
functionalization of simple building blocks.4 Particularly
appealing is their “internal redox” nature that dispenses with
product 3aa in low yield, along with the conventional Hosomi−
Sakurai product 2aa. Focusing more closely on the internal
redox step, the homoallylic ether 2aa was prepared, and its
interaction with different acids was investigated (Table 1).
Drawing on the report of List on the use of acetals for the
Hosomi−Sakurai reaction,1h,i 2,4-dinitrobenzenesulfonic acid
(DNBA) and benzenedisulfonimide (BDSI) were tested as
Received: January 26, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00276
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
However, the highest yields were still observed for the
originally assayed diisopropyl acetal 1b.
Table 1. Optimization of Conditions for the Internal Redox
Event
With efficient conditions in hand, the substrate scope was
surveyed (Scheme 4). First, several acetal backbones were
Scheme 4. Substrate Scope of Acetals
a
a
temp
(°C)
time
(h)
yield
conv
entry
solvent
acid
(%)
(%)
1
2
3
4
5
6
7
8
1,2-DCE
MeCN
1,2-DCE
MeCN
THF
BDSI
BDSI
25−50
25−50
25−50
25
3.5
3
14
26
25
40
<5
<5
<5
73
68
65
DNBA
DNBA
DNBA
DNBA
DNBA
DNBA
3.5
3
>95
>95
21
25
2
DMF
25
2
38
MeOH
MeNO2
25
2
90
25
2
>95
a
All reactions carried out on 0.3 mmol scale. Yields determined by H
NMR analysis.
Brønsted acids. DNBA showed higher yields at lower
temperatures than BDSI (Table 1, entries 1−2 versus 3).
Solvent optimization revealed that nitromethane led to the
desired product in good yields (Table 1, entries 3−8) with a
clean reaction profile.
The high dipolar moment and the low nucleophilicity of
nitromethane are likely to be decisive for the stabilization of the
cationic intermediates involved (vide infra). We eventually
found that nitromethane was also a suitable solvent for the
Hosomi−Sakurai step under DNBA catalysis. After optimiza-
tion, a reproducible and efficient one-pot procedure was
developed. To this end, the use of 3 Å molecular sieves was
important since DNBA is a hygroscopic substance sold as a
hydrate.5 As the nature of the acetal should be important for
the internal redox event, we investigated different acetals, a
selection of which is shown in Scheme 3.5 Use of cyclic acetals
was generally unproductive, and 4b, the most promising among
those tested, led to a complex reaction mixture containing 30%
of product.
a
Reactions carried out on 0.3 mmol scale. Yields refer to isolated
b
products. Reaction carried out on 0.15 mmol scale. Yields refer to
isolated products.
tested. Additional unsaturation on the acetal did not disrupt the
internal redox process, be it an alkene or an alkyne (3ca, 3ga).
A benzyl-protected alcohol did not interfere in the process
(3ea). Importantly, these are functionalities that would not
have survived a reduction/hydrogenolysis step. A phthalimide
substituent was well tolerated (3ja), as well as esters (3fa) or
more electrophilic α,β-unsaturated esters (3ia). Chlorides (3la)
or bromides (3ka) are also compatible with these conditions.
This body of results outlines a transformation that, while being
broadly comparable to the addition of an organometallic
species to an aldehyde, is tolerant of several substituents that
likely would not be compatible with such reagents. The product
3ba was also synthesized on a preparative scale (6 mmol
starting material) in a comparable yield.5 At this juncture, we
were keen to try different allylsilanes, well aware that the
presence of a substituent other than methyl would lead to the
creation of an additional stereogenic center. Our results are
compiled in Scheme 5. Aromatic and α,β-unsaturated acetals
lead to a complex mixture in which no desired product was
observed. Competitive elimination, under the acidic conditions,
is likely to occur in these cases.
a
Scheme 3. Acetal Screening for the Internal Redox Event
a
All reactions carried out on 0.3 mmol scale. Yields determined by
NMR analysis.
An acetal derived from an electron-rich allylic alcohol 5b or a
dibenzyl acetal 6b, designed for attempted enhancement of the
hydride-transfer step, was also not effective. Surprisingly, a
diethyl acetal 7b was better than most of the other acetals,
suggesting that oxacarbenium stability is not the most
important element in the efficiency of a 1,5-hydride transfer.6
Interestingly, up to 7.3:1 diastereoselectivity in favor of the
anti-product was observed for diethyl acetals when the
allylsilane nucleophilic partner carried an aryl substituent.
B
DOI: 10.1021/acs.orglett.8b00276
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 5. Allylsilane Scope and Diastereoselectivity
Scheme 6. Mechanistic Study and Application in Synthesis
a
Yields refer to isolated products. diastereoisomeric ratios determined
by H NMR analysis. Bottom right: X-ray structure of 3bh.
a
(1) Deuterium labeling study, (2) single-step synthesis of a
biologically active compound,5 and (3) comparison with prior
approaches.8,9 (4) Stereochemical model for the diastereoselectivity.
This appears to be independent of the electronic nature of that
aryl moiety, ranging from electron-rich (3be) to neutral (3bb
or 3bh) to electron-poor (3bg).
b
Yields refer to isolated products. Determined by NMR analysis.
Aiming for more information on the mechanism, we carried
out an isotopic labeling study with a fully deuterated
diisopropyl acetal 5 (Scheme 6, eq 1). The product 10 carries
the deuterium label in the anticipated position. This allowed us
to put forward a mechanistic proposal whereby, after
protonation of the double bond of the transient Hosomi−
Sakurai product, a 1,5-hydride transfer takes place (Scheme 6,
eq 1, 9ba) from the ether moiety to generate an oxacarbenium
ion.
This is likely hydrolyzed to the observed alcohol and acetone
during the aqueous workup. Subsequently, we used the
reductive Hosomi−Sakurai procedure to synthesize 3oc, a
known acetylcholinesterase inhibitor (Scheme 6, eq 2).7,8
The starting acetal 7m, commercially available (or easily
obtained from isovaleraldehyde), was engaged with allylsilane
11c to provide 3oc in 45% yield and a 5:1 dr. In spite of the
modest yield, the conciseness and diastereoselectivity of this
route, a single step from 7m or two steps from isovaler-
aldehyde, compare favorably with prior approaches (Scheme 6,
eq 3) which involved the poorly selective reduction of a ketone
precursor8 or the redox isomerization of a terpene-derived
homoallylic alcohol.9
The major diastereoisomer in these reactions is the anti-
isomer, which probably results from a chairlike six-membered
transition state where the bulkier aromatic ring occupies the
pseudoequatorial position (Scheme 6, eq 4).10
In summary, we have presented a novel reductive Hosomi−
Sakurai reaction that relies on an internal redox process
triggered by a cheap Brønsted acid under simple conditions.
Mechanistic experiments using deuterium labeling and
substrate probes provided insight into the factors controlling
stereoselectivity and allowed a demonstration of synthetic
utility in the synthesis of a potent AChE inhibitor.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00276.
■
S
Experimental data and spectral characterization for new
products (PDF)
Accession Codes
CCDC 1813236 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nuno.maulide@univie.ac.at.
ORCID
Nuno Maulide: 0000-0003-3643-0718
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the University of Vienna for continued support of
our research programs. Dr. H. Kahlig (University of Vienna) is
acknowledged for expert assistance with NMR experiments,
■
̈
Ing. Alexander Roller (FH) for single-crystal X-ray diffraction
C
DOI: 10.1021/acs.orglett.8b00276
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) Crawford, R. J.; Erman, W. F.; Broaddus, C. D. J. Am. Chem. Soc.
1972, 94, 4298−4306.
(10) This model is in accordance with the observation that secondary
ethers (i.e., isopropyl ether) lead to lower diastereoselectivity, which
could be due to increased 1,3 repulsion in conformer A of Scheme 6d.
studies, and Ms. J. Sprachmann for the synthesis of several
allylsilanes. Financial support of this research by the Austrian
Academy of Sciences (Elisabeth Lutz-Prize to N.M.) is
acknowledged.
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Org. Lett. XXXX, XXX, XXX−XXX