Enantioselective Redox-Neutral Coupling of Aldehydes and Alkenes by an Iron-Catalyzed "catch-Release" Tethering Approach

Article abstract of DOI:10.1021/jacs.8b12242

The reductive coupling of aldehydes and alkenes is an emerging technology that holds the potential to reinvent carbonyl addition chemistry. However, existing enantioselective methods are limited to form "branched" products. Herein, we present a directed enantio- and diastereoselective alkylation of aldehydes with simple olefins to selectively yield linear coupling products. This is achieved by redox-neutral remote functionalization, whereby a tethering "catch-release" strategy decisively solves the key problems of reactivity and selectivity.

Full text of DOI:10.1021/jacs.8b12242

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Enantioselective Redox-Neutral Coupling of Aldehydes and Alkenes
by an Iron-Catalyzed “Catch−Release” Tethering Approach
Jing Li,† Alexander Preinfalk,† and Nuno Maulide*
̈
Institute of Organic Chemistry, University of Vienna, Wahringer Strasse 38, 1090 Vienna, Austria
S
* Supporting Information
achieve a “release” event and yield the desired linear coupling
motif.
Herein we present our reduction of this concept to practice
in an asymmetric synthesis of linear aldehyde−alkene coupling
motifs by redox-neutral remote functionalization under iron
catalysis, featuring the possibility of forming two new
challenging chiral centers starting from a single, readily
chiral-pool derived, stereogenic element.
ABSTRACT: The reductive coupling of aldehydes and
alkenes is an emerging technology that holds the potential
to reinvent carbonyl addition chemistry. However, existing
enantioselective methods are limited to form “branched”
products. Herein, we present a directed enantio- and
diastereoselective alkylation of aldehydes with simple
olefins to selectively yield linear coupling products. This is
achieved by redox-neutral remote functionalization,
whereby a tethering “catch−release” strategy decisively
solves the key problems of reactivity and selectivity.
At the onset of our investigation, we tested several
unsaturated alcohols 1, differing in the length of the spacing
carbon-chain (Table 1, entries 1−3), as alkene partners. After
some initial experimentation with aldehyde 2a as model
electrophile, we identified SnCl4 as a suitable Lewis Acid. To
our delight, alcohol 1a (with 3 methylene units between the
carbinol and the alkene) showed promising reactivity and
already excellent levels of diastereoselectivity of the final
product 3a, carrying 2 stereogenic centers in a 1,3-relationship.
This substrate mechanistically implies the transient formation
of an eight-membered ring (cf. intermediate B in Figure 1).
Encouraged by these promising initial results, we continued
with substrates 1a and 2a for further optimization. Changing
the amount of tin(IV) chloride led to worse results (entries 4
and 5). While investigating other Lewis acids (entries 6−9), we
identified iron(III) chloride as a uniquely effective catalyst for
this reaction. Increasing the temperature from room temper-
ature to 100 °C resulted in better yield and remarkably short
reaction times (entry 10). Notably, product 3a was obtained as
virtually a single enantio- and diastereomer. Importantly, the
reaction can be run without the need for scrupulously dry
solvents or the use of an inert-gas atmosphere.
With optimized conditions in hand, we turned our attention
toward the scope of this transformation (Scheme 1). The
reaction tolerates a variety of different aldehyde electrophiles,
including sterically congested cases such as 2-methylpropanal
2c, cyclohexylcarboxaldehyde 2d or even pivalaldehyde 2e
(Scheme 1, 3a−e). Notably, all products are obtained in good
yields after a short reaction time and essentially as single
enantio- and diastereoisomers. A wide range of functional
groups, including halides (3f−g), protected alcohols (3h),
thioethers (3i) as well as esters, unsaturated systems and
alkynes (3j−l) are tolerated under the present reaction
conditions. On the alkene component, aromatic and other
aliphatic substituents show excellent reactivity (3m−p) while
retaining the same near perfect diastereo- and enantioselectiv-
ity. Additionally, products resulting from a nine-membered
n recent years, coupling approaches combining aldehydes
Iand alkenes, readily available feedstocks, have started to
emerge as an appealing alternative to classical carbonyl
addition reactions (Figure 1a).1 Krische and co-workers
pioneered the development of both hydrogenative and transfer
hydrogenative couplings of carbonyl compounds with a variety
of unsaturated compounds, including enones,2a alkynes,2b 1,3-
dienes,2c enynes,2d allenes,2e and allyl compounds2f yielding
the corresponding branched coupling products. Additionally,
Buchwald and co-workers developed the asymmetric addition
of alkene-derived nucleophiles to ketones and leading
exclusively to the branched products.3 However, enantiose-
lective methods to access the complementary, highly valuable
linear products (Figure 1b) using a direct redox-neutral
coupling of olefins have not yet been developed.4−6
As part of our group’s ongoing research on chirality transfer
processes,7 we became interested in accessing these scaffolds
from readily available chiral building blocks. We therefore
envisioned an enantioselective redox-neutral coupling that
would take advantage of a carbocationic mechanism to ensure
complete selectivity for the linear coupling product (Figure
1b). To overcome the low intrinsic nucleophilicity of
unactivated alkenes,6 we decided to employ a “catch-release”
tethering group approach (Figure 1c).8 Under Lewis-acid
catalysis, the alcohol moiety on the substrate 1 would serve as
anchoring point for the aldehyde reaction partner, reversibly
forming an oxocarbenium ion A (cf. Figure 1c). By virtue of
tethering, attack of the alkene partner onto this highly
electrophilic species becomes intramolecular, thus circum-
venting reactivity issues and leading to a cyclic, tertiary
carbocation B. In order to evade the potential deleterious side
reactions typical of carbocationic intermediates,9,10 a designed
1,5-hydride shift event11 would not only allow convergence to
a stabilized oxacarbenium ion C but also ensure the formal
reduction of carbocation B. Hydrolysis of C would then
Received: November 14, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b12242
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Journal of the American Chemical Society
Communication
Figure 1. (a) Well-established asymmetric coupling of aldehydes and alkenes. (b) Potential challenges in the development of a linear-selective
method. (c) Novel linear-selective, directed asymmetric coupling of aldehydes and alkenes.
The reasons behind the excellent stereoselectivity observed
throughout the transformations compiled in Scheme 1
intrigued us from the very first experiments. Scheme 2 depicts
our stereochemical model. We assume that the aldehyde R
substituent and the carbinol residue R1 adopt pseudoequatorial
orientations during the cyclization event, at which point the
first stereogenic center of the product is formed. During the
hydride transfer step,11 the original chiral element of the
substrate is deleted concomitantly with the setting of the
second stereogenic center of the product. As hydride transfer
must proceed suprafacially, this ensures perfect chirality
transfer and rationalizes the excellent stereoselectivities
observed even when acetaldehyde, otherwise a challenging
aldehyde for enantioselective C−C bond forming reactions is
employed (3r).12 Additionally, an α-chiral aldehyde such as 2s
(i.e., (S)-2-methylbutyraldehyde) is a suitable substrate for this
process, allowing the preparation of 3s without epimerization
of its sensitive chiral center (3s obtained in 71% yield and
>20:1 d.r.). Furthermore, we found that there is a large
reactivity difference between aliphatic and aromatic aldehydes,
enabling the use of a dialdehyde substrate such as 3t without
the need for protecting group manipulations.
Table 1. Selected Optimization of Reaction Conditions
Lewis acid
(%)
time
(temperature)
yield [%]
a
b
c
entry alcohol
(dr)
ee [%]
1
2
3
4
5
6
7
rac-1a SnCl4 (20%) 1 min (r.t.)
rac-1b SnCl4 (100%) 15 min (r.t.)
rac-1c SnCl4 (20%) 1 h (r.t.)
65 (>20:1)
<5 (n.d.)
−
−
−
>99%
>99%
n.d.
n.d.
25 (>20:1)
45 (>20:1)
35 (>20:1)
trace (n.d.)
trace (n.d.)
(S)-1a SnCl4 (5%)
3.5 h (r.t.)
(S)-1a SnCl4 (30%) 1 min (r.t.)
(S)-1a AlCl3 (20%)
10 min (r.t.)
24 h (r.t.)
(S)-1a TMSOTf
(20%)
8
9
10
(S)-1a HCl (20%)
(S)-1a FeCl3 (20%) 10 min (r.t.)
(S)-1a FeCl3 (5%)
24 h (r.t.)
trace (n.d.)
n.d.
>99%
>99%
e
d
71 (>20:1)
e
d
5 min (100
°C)
76 (>20:1)
a
Reaction conditions: alcohol (0.2 mmol), aldehyde (0.24 mmol),
b
1
Lewis acid in dichloromethane (DCM, 0.1 M). Determined by H
NMR analysis of the crude reaction mixture. Determined by chiral
stationary phase HPLC. Isolated yield. Reaction performed in 1,2-
dichloroethane (DCE, 0.1M). See SI for further screening of reaction
conditions.
c
The products of this methodology are chiral diads
represented in a range of natural products and bioactive
substances. As an example we chose 4, a key intermediate in
Maio’s study on the synthesis of the neuroactive marine
macrolide Palmyrolide A and its analoga (Scheme 3).13 In the
course of Maio’s original work, amide 4 was synthesized from
pivalaldehyde (Scheme 3b). The sequence includes a proline-
assisted aldol addition, setting the first chiral center. Evans−
d
e
intermediate can be accessed in equal selectivities by ortho-
appending of the bridging charbon chain around an aromatic
core (3q).
B
DOI: 10.1021/jacs.8b12242
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Journal of the American Chemical Society
Communication
Scheme 1. Scope of the Redox-Neutral Coupling of
Aldehydes and Alkenes
Scheme 2. Proposed Stereochemical Model for the Redox-
Neutral Coupling of Aldehydes and Alkenes
a
a
a
Conditions: (S)-1a (0.2 mmol, 1.0 equiv), 2 (1.2 equiv), FeCl3 (5%
b
mol), DCE (2.0 mL), 100 °C, 5 min. (R)-1a was used.
Scheme 3. Synthesis of Key Intermediate 4 and
Determination of the Absolute Configuration
a
Reaction conditions: alcohol (0.2 mmol), aldehyde (0.24 mmol),
b
FeCl3 (5% mol), DCE (0.1M), 100 °C, 10 min. Reaction was
c
d
conducted at 50 °C for 10 min. 20% mol FeCl3 was used. Reaction
was conducted at room temperature in dichloromethane (0.1 M).
Tishchenko reaction followed by installation of a sulfate ester
gives compound 5, which can be converted into 6 via allylation
and protection of the alcohol-moiety. Hoveyda−Grubbs
metathesis and hydrogenation results in key intermediate 4
in 24% overall yield. Using the method reported herein, that
sequence can be cut in half. Commercially available and cheap
(S)-propylene oxide was first ring-opened to 1a in gram-scale.
The novel redox-neutral coupling of 1a with pivalaldehyde
gives ketone 3e in good yield and perfect stereochemical
outcome. Simple Lieben-haloform reaction14 directly followed
by amide coupling using standard conditions gives key
intermediate 4 in 37% overall yield over only 4 steps from
cheap commercially available materials. In addition, direct
comparison of product 4 to the material obtained by Maio also
allowed unambiguous assignment of stereochemistry to be as
shown (C5R, C7S).
a
Conditions: (1) (S)-propylene oxide, (3-methylbut-3-en-1-yl)-
magnesium bromide (1.2 equiv), CuCN (10 mol %), THF/ether,
−78 °C to r.t., 3 h; (2) (S)-1a (1.0 equiv), 2e (1.2 equiv), FeCl3 (5%
mol), DCE, 50 °C, 10 min; (3) iodine (6 equiv), KI (12 equiv), KOH
(10 equiv), dioxane, r.t., 2 h; (4) DCC (1.2 equiv), HOBt (1.2 equiv),
NH4OH (2 equiv), DCM, r.t., 3 h.
single diastereo- and enantiomeric materials. An easily
accessible chiral alcohol functions as a tether which, by virtue
of a “catch−release” process, overcomes the reactivity and
selectivity limitations typically associated with olefins as
nucleophiles. This method allows the assembly of two chiral
centers in near-perfect stereoselectivity, starting from one lone,
chiral-pool-derived stereocenter.
In conclusion, we have developed an efficient method to
access linear aldehyde/alkene coupling products as essentially
C
DOI: 10.1021/jacs.8b12242
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Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b12242.
■
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Characterization data and NMR spectra as well as
procedures for preparation of all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*nuno.maulide@univie.ac.at
ORCID
■
Nuno Maulide: 0000-0003-3643-0718
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous support by the University of Vienna is acknowl-
edged. We are grateful for the support of the ERC (CoG
VINCAT) and the Austrian Academy of Sciences (DOC
Fellowship to A.P.).
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