Asymmetric Aldol-Tishchenko Reaction of Sulfinimines

Article abstract of DOI:10.1021/acs.orglett.5b02919

Methods for the preparation of 1,3-amino alcohols and their derivatives containing two stereogenic centers usually involve a two-step installation of the chiral centers. An aldol-Tishchenko reaction of chiral sulfinimines which involves the first reported reduction of a C=N in this type of reaction is described. Two and even three chiral centers can be installed in one synthetic step, affording anti-1,3-amino alcohols in good diastereo- and enantioselectivity.

Full text of DOI:10.1021/acs.orglett.5b02919

Letter
pubs.acs.org/OrgLett
Asymmetric Aldol−Tishchenko Reaction of Sulfinimines
Vera M. Foley, Christina M. McSweeney, Kevin S. Eccles, Simon E. Lawrence, and Gerard P. McGlacken*
Analytical and Biological Chemistry Research Facility and Department of Chemistry, University College Cork, Cork 021, Ireland
S
* Supporting Information
ABSTRACT: Methods for the preparation of 1,3-amino
alcohols and their derivatives containing two stereogenic
centers usually involve a two-step installation of the chiral
centers. An aldol−Tishchenko reaction of chiral sulfinimines
which involves the first reported reduction of a CN in this
type of reaction is described. Two and even three chiral centers
can be installed in one synthetic step, affording anti-1,3-amino alcohols in good diastereo- and enantioselectivity.
The classic aldol−Tishchenko reaction involves the self-
addition of aldehydes with at least one α-hydrogen.10 A similar
reaction can occur between ketone enolates and 2 equiv of
aldehyde. After the first addition, the formed aldolate reacts with
the second equivalent of aldehyde, which is followed by
stereoselective intramolecular hydride transfer to the CO.
Lithium enolates have been used to facilitate this trans-
formation.11
The highly successful Evans−Tishchenko reaction involves
the addition of an aldol adduct to an aldehyde in the presence of a
Lewis acid,12 although a generally applicable asymmetric variant
of this reaction is lacking.13 Seminal examples of asymmetric
aldol−Tishchenko reactions include those by Mascarenhas,14
Shibasaki,15 and Mlynarski,16 all of which utilized lanthanide
complexes and chiral diol-based ligands.
1,3-Amino alcohols are useful synthetic intermediates and targets
for many natural products and bioactive compounds.1 For
example, marketed drugs such as tramadol, venlafaxine, ritonavir,
and lopinavir all contain the 1,3-amino alcohol fragment.
Predominantly, 1,3-amino alcohols are synthesized via diaster-
eoselective reduction of enantiomerically pure substrates
prepared from Mannich or aldol reactions.2 More recent
examples include an iterative organocatalytic approach3 and
ring opening of chiral piperidines4 or tetrahydropyrans.5
Methods which do not rely on additional diastereoselective
reduction steps are not widely reported. However, examples do
exist, including the synthesis of syn-1,3-amino alcohols via Pd-
catalyzed allylic amination,6 the cyclization of trichloroacetimi-
dates,7 and an indirect route via oxazinanes.8 Examples for the
synthesis of anti-1,3-amino alcohols are rare.9
Overall, the aldol−Tishchenko reaction has proven to be an
excellent protocol for the preparation of 1,3-diol monoesters in a
stereoselective manner and has been applied to a number of total
syntheses.17 To the best of our knowledge, no related strategy
involving Tishchenko−hydride reduction of a CN group has
been reported, which is surprising given that the 1,3-amino
alcohol precursors produced would be of great synthetic value.
The lack of precedence for this transformation probably
reflects the difficulty in acquiring a suitable (aza)enolizable
functionality along with lower electrophilicity of the CN group
negating hydride addition. For example, selected dimethyl
hydrazones18 and SAMP hydrazones19 failed to undergo
aldol−Tishchenko reactions in our hands. With this in mind,
we proposed that sulfinimines may be more suitable substrates to
facilitate an intramolecular Tishchenko hydride transfer due to
the strong electron-withdrawing effects of the sulfinyl group,
which greatly increases the electrophilicity of the CN bond.
Chiral N-sulfinimines20 have a proven ability to form stable
metalloenamines.2 Furthermore, chirality about the sulfur would
induce enantioselection.
We envisaged that an aldol−Tishchenko reaction using an
imine derivative could provide these valuable synthons in a
diastereoselective manner. Use of a chiral imine derivative could
provide enantioselectivity while allowing for the simultaneous
introduction of two or more stereogenic centers in a one-step
process (Scheme 1).
Scheme 1. Proposed Aldol−Tishchenko Reaction with
Sulfinimines
We initiated our studies by preparing sulfinimines (S)-1 and
(S)-2 from acetophenone and the corresponding N-sulfina-
Received: October 8, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02919
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Letter
mide.21 Deprotonation with LDA (−78 °C, 1 h) in THF was
followed by the slow addition of 2.2 equiv of pivaldehyde and
warming to room temperature overnight (Table 1). To our
Table 2. Two New Chiral Centers: Substrate Scope
Table 1. Optimization of the Aldol−Tishchenko Reaction
a
yield
entry s.m.
R
R′
t-Bu
t-Bu
product
(%)
dr
1
5
6
7
8
9
p-MeC6H4
m-MeC6H4
14
15
16
17
18
19
20
21
22
23
24
25
26
57
64
65
62
51
65
62
76
88
61
61
48
40
89:11
89:11
90:10
96:4
2
3
p-OMeC6H4 t-Bu
4
p-FC6H4
t-Bu
a
entry s.m.
solvent
temp (°C) t-BuCHO yield (%)
dr
5
p-CF3C6H4
t-Bu
97:3
b
1
2
3
4
5
6
7
8
1
2
1
1
1
1
1
1
THF
THF
toluene
ether
THF
THF
THF
THF
rt
rt
2.2
2.2
2.2
2.2
2.2
2.2
3
41
30
27
22
22
48
69
70
91:9
6
10 naphthyl
11 2-furyl
12 i-Pr
t-Bu
93:7
b
c
78:22
80:20
82:18
78:22
90:10
90:10
91:9
7
t-Bu
90:10
>97:3
71:29
>97:3
92:8
rt
8
t-Bu
c
b
rt
9
13 Et
t-Bu
d
b
c
rt
10
11
12
13
1
1
8
1
C6H5
cyclohexyl
i-Pr
0
C6H5
c
0
p-FC6H4
C6H5
i-Pr
>97:3
c
b
−20
b
3
c
i-Bu
nd
a
a
b
dr by NMR before purification. Isolated. Yield by NMR using 1,3,5-
trimethoxybenzene as internal standard. Reaction performed using
MgBr2 as additive.
Isolated. Diastereomers could be separated by silica gel chromatog-
d
c
raphy. dr not determined due to the complexity of the NMR
spectrum of the crude mixture. However, a single diastereomer was
isolated in 40% yield.
delight, the aldol−Tishchenko products were formed (entries 1
and 2), albeit in moderate to poor yield (41% and 30%,
respectively). However, the (S)-tert-butanesulfinimine gave an
impressive dr (91:9), unlike its p-tolyl counterpart which gave a
moderate dr (78:22).22
Scheme 2. Formation of Three New Stereogenic Centers in
One Pot
Therefore, we sought to optimize our procedure using
sulfinimine (S)-1. A lower dr was observed in both toluene and
ether (entries 3 and 4). Addition of MgBr22c also failed to give
desirable results (entry 5). Lowering the temperature (entry 6)
and addition of 3 equiv of aldehyde (entry 7) both gave improved
yields. Further cooling to −20 °C and use of 3 equiv of aldehyde
gave a good isolated yield of 70% and a dr of 91:9 (entry 8).
We then applied the optimized reaction conditions to a range
of substituted aryl sulfinimines (5−10) as shown in Table 2 to
afford the aldol−Tishchenko products 14−19. Substrates with
electron-donating (entries 1−3) and electron-withdrawing
(entries 4 and 5) groups worked well, as did an acetonaph-
thone-derived sulfinimine (entry 6).
2-Furyl sulfinimine (entry 7) also worked well. Furthermore,
alkyl sulfinimines which possess two possible sites for
deprotonation showed complete regioselectivity for the least
hindered site, affording products in moderate to excellent
diastereoselectivity and excellent yield (entries 8 and 9).
Additionally, enolizable aldehydes, isobutyraldehyde, cyclo-
hexane carboxaldehyde, and isovaleraldehyde were also effective,
affording the corresponding amino alcohol derivatives (entries
10−13).23 Having achieved acceptable results, we wondered if
our methodology could be further challenged to perform the
simultaneous introduction of three new stereogenic centers.
Surprisingly, there is no precedent in the literature, even for
the reaction of metalloenamines derived from α-substituted
sulfinimines with aldehydes (aldol).24 Perhaps the potential for
E- and Z-azenolate intermediates and the associated problems
has deterred many research groups.
desired 1,3-amino alcohol derivatives in excellent diastereose-
lectivities (91:9 and >98:2) and yields (78% and 82%),
respectively. To reiterate, in the case of benzaldehyde, one
diastereomer (from a potential eight) was isolated in 82% yield.25
We next investigated propiophenone-based sulfinimine (S)-30
with a range of aldehydes (Table 3).26 The anticipated selectivity
problems associated with E- and Z-azaenolates never manifested,
and very good yields and dr values were obtained. In some cases,
we noticed cleavage of the ester function, and thus, we applied
base treatment in all these cases to isolate the 1,3-amino alcohol.
Electron-rich (entries 1 and 5), electron-deficient (entries 2−4
and 7), and sterically bulky aryl aldehydes (entry 6) performed
well, giving the desired products in very good diastereoselectivity
(up to 88:9:3) and yields (up to 90%).
Notably, the intramolecular hydride transfer described herein
allows for the preparation of 1,3-amino alcohols, such as 34,
containing a functional group which would be susceptible to
reduction via an external reductant protocol.27
Crystallographic analysis of 31 and 33 revealed a 1,3-anti
relative stereochemistry, and the 1,2 relative stereochemistry was
assigned syn. Remarkably, however, a complete switch in absolute
stereochemistry was observed in comparison to that observed for
3.28 We anticipate that the switch is general for propiophenone-
based substrates.
With this in mind, we chose a cyclic sulfinimine to initiate our
tests. To our surprise, applying our optimized conditions to (S)-
27 using pivaldehyde and benzaldehyde (Scheme 2) gave the
B
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Table 3. Three New Chiral Centers: Substrate Scope
Scheme 4. Selective Ancillary Cleavage
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02919.
1
Experimental procedures, product characterizations, H
and 13C NMR spectra for novel compounds, and X-ray
crystallographic data for 3, 31, and 33 (PDF)
a
b
Isolated. dr by NMR before purification.
AUTHOR INFORMATION
Corresponding Author
■
To glean an insight into the reaction mechanism, a number of
experiments were undertaken on the acetophenone-based
substrate. First, the use of 1 equiv of aldehyde allowed for the
isolation of both syn- and anti-disastereoisomers of the β-
hydroxy-N-sulfinimines 38 and 39. These were then separated
and individually exposed to LDA and 1.1 equiv of pivaldehyde
(Scheme 3). Only the anti-aldol−Tishchenko product 3 was
*E-mail: g.mcglacken@ucc.ie.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Science Foundation Ireland (09/RFP/CHS2353 &
SFI/12/RC/2275) and the Irish Research Council for funding.
■
Scheme 3. Mechanistic Studies
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(22) The absolute stereochemistry of the major isomer was confirmed
as S,S,S by degradation to known compounds and by crystallographic
analysis. See the Supporting Information. The principle minor isomer
was assigned as S,R,R by degradation to known compounds. In this case,
the principle minor isomer presumably arises from a lack of selectivity of
the chiral auxiliary rather than the aldol step or aldol−Tishchenko
reduction step, specifically.
(23) Preliminary studies revealed that under the standard conditions
described herein, benzaldehyde failed to give the corresponding aldol−
Tishchenko product in good yield. Optimisation, in this case, is
underway.
(24) Priede, M.; Kazak, M.; Kalnins, T.; Shubin, K.; Suna, E. J. Org.
Chem. 2014, 79, 3715.
(25) The absolute stereochemistry of these products is unknown at this
stage but is assigned here on the basis of the stereochemistry of the
propiophenone-based substrates shown in Table 3.
(26) Preliminary studies revealed that under the standard conditions
described herein isobutyraldehyde failed to give the corresponding
aldol−Tishchenko product in good yield. Optimization, in this case, is
underway.
(27) Furthermore, added 3-methoxybenzonitrile survived the aldol
Tishchenko conditions and was not reduced. See Collins, K. D.; Glorius,
F. Nat. Chem. 2013, 5, 597 for seminal use of this approach, and
Supporting Information (S-92).
(28) The absolute stereochemistry of the major isomer was confirmed
by degradation to known compounds and by crystallographic analysis.
See the Supporting Information.
(29) Subsequent cleavage of the ester ancillaries in the below crude
mixture gave a 53:47 mixture of the two expected amino alcohol
derivatives. See the Supporting Information.
D
DOI: 10.1021/acs.orglett.5b02919
Org. Lett. XXXX, XXX, XXX−XXX