Enantioselective Iridium-Catalyzed α-Allylation with Aqueous Solutions of Acetaldehyde

Article abstract of DOI:10.1021/acs.orglett.9b04658

The enantioselective α-allylation of aqueous solutions of acetaldehyde using iridium- A nd amine-catalyzed substitution of racemic allylic alcohols is described. The method utilizes a readily available, safely handled aqueous solution of acetaldehyde and furnishes ?,?-unsaturated aldehydes in good yields and greater than 99% enantiomeric excess. The synthetic potential of the method is demonstrated with the enantioselective formal syntheses of heliannuols C and E as well as heliespirones A and C.

Full text of DOI:10.1021/acs.orglett.9b04658

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Letter
Enantioselective Iridium-Catalyzed α‑Allylation with Aqueous
Solutions of Acetaldehyde
Tobias Sandmeier and Erick M. Carreira*
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ABSTRACT: The enantioselective α-allylation of aqueous solutions of
acetaldehyde using iridium- and amine-catalyzed substitution of racemic allylic
alcohols is described. The method utilizes a readily available, safely handled
aqueous solution of acetaldehyde and furnishes γ,δ-unsaturated aldehydes in
good yields and greater than 99% enantiomeric excess. The synthetic potential of
the method is demonstrated with the enantioselective formal syntheses of
heliannuols C and E as well as heliespirones A and C.
n recent years, enantioselective iridium-catalyzed allylic
substitution reactions have found widespread attention in
Scheme 1. Iridium-Catalyzed α-Allylation of Acetaldehyde
I
synthetic organic chemistry.1 Various carbonyl-derived carbon
nucleophiles have been employed to date, including enolates,2
silyl ketene acetals,3 and aldehydes.4 However, acetaldehyde,
which in itself is not a carbon nucleophile but readily forms
reactive enamines in the presence of amines,5 is remarkably
absent. Moreover, readily accessible masked versions of
acetaldehyde such as methyl vinyl ether or vinyloxytrimethyl-
silane that would provide access to unprotected, α-allylated
aldehyde products have not been used in transition-metal-
catalyzed allylic substitution reactions. This is striking,
considering that acetaldehyde is a readily available two-carbon
fragment whose derived products offer numerous options for
further synthetic elaborations. Recently, our group has
reported ethylene glycol monovinyl ether as a protected
acetaldehyde enolate equivalent for iridium-catalyzed allylic
substitution reactions affording 1,3-dioxolane-protected alde-
hydes.6 However, a transformation that provides access to the
free aldehyde products would be complementary to that which
we have previously reported and thus highly desirable. Herein
we report the enantioselective iridium-catalyzed α-allylation of
acetaldehyde (1) to give γ,δ-unsaturated aldehydes (Scheme
1). The products are isolated in good yields and with excellent
enantioselectivities. The synthetic utility of this method is
demonstrated with a series of functionalization reactions and
the formal syntheses of the natural products heliannuols C and
E as well as heliespirones A and C.
condensation reactions. Finally, with a boiling point of 21 °C,
care must be taken when handling this compound, and adding
precise quantities, especially on small scale, is often
challenging. Over the course of the past decade, a series of
organocatalytic transformations employing acetaldehyde as a
nucleophile have been developed, yet its use in asymmetric
transition-metal catalysis remains elusive.5,7 It has been noted
that the use of commercially available aqueous solutions of
acetaldehyde (40 wt %) could circumvent some of its inherent
problems as the corresponding hydrate is less reactive and
volatile.8
Our group has recently investigated iridium-catalyzed allylic
substitution reactions using aqueous solutions of nucleophiles
and the iridium complex derived from [Ir(cod)Cl]2 and ligand
(R)-L.9 Hence, we envisioned that our catalytic system would
be uniquely suited for the enantioselective α-allylation of
aqueous acetaldehyde. Initial studies revealed that the reaction
of allylic alcohol 2a with an aqueous solution of acetaldehyde
The development of asymmetric transformations employing
acetaldehyde as a nucleophile must overcome several factors.5
First, the high reactivity of acetaldehyde, both as an
electrophile and a nucleophile, can lead to low isolated yields
due to self-aldolization and formation of polyacetals.
Furthermore, selective monofunctionalization of acetaldehyde
can be challenging as the initially formed aldehyde products
can often undergo downstream side reactions such as aldol
Received: December 28, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04658
© XXXX American Chemical Society
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a,b
(1) in the presence of the catalytic complex [Ir/(R)-L],
dichloroacetic acid and secondary amine (S)-A1 afforded γ,δ-
unsaturated aldehyde 3a in 16% yield and excellent
enantioselectivity (>99% ee). Notably, under these biphasic
reaction conditions no double allylation was observed. With
less bulky or primary amine catalysts such as proline or
benzhydrylamine, respectively, significant amounts of the bis-
allylated products as well as aldol side reactions were observed.
Further optimization revealed that more lipophilic Brønsted
acid promoter dibenzenesulfonimide in combination with [Ir/
(R)-L], (S)-A1 and allylic alcohol 2a afforded product 3a in
83% yield and >99% ee.10
Scheme 2. Preparation of α,β-Disubstituted Aldehydes
With the optimized reaction conditions in hand, we next
examined the substrate scope of this transformation with
regard to allylic alcohols (Table 1). A series of electron rich
Table 1. Allylic Alcohol Scope of the α-Allylation of
a−d
Aqueous Acetaldehyde
a
For detailed experimental procedures, see the Supporting Informa-
b
tion. Diastereomeric ratios were determined by 1H NMR analysis of
unpurified reaction mixtures. HQ = hydroquinone.
acetaldehyde with [Ir/(R)-L] and allylic alcohol 2a in the
presence of chiral amine A4 followed by the addition of
hexachloro-2,5-cyclohexadien-1-one afforded α-chlorinated
aldehyde 6 in good yield and high stereoselectivity. Similarly,
fluorinated product 7 could be obtained when A3 and N-
fluorobenzesulfonimide were employed.13 Hence, we have
established conditions for the rapid generation of molecular
complexity starting from acetaldehyde derived allylation
adducts.
To highlight the potential of the iridium-catalyzed allylation
of acetaldehyde in the context of target-oriented synthesis, we
undertook the formal syntheses of heliannuols C and E as well
as heliespirones A and C (Scheme 3). These sesquiterpenes
were isolated from the cultivated sunflower Helianthus annuus
and display herbicidal activity in bioassays, rendering them
potential scaffolds for the development of new and selective
pesticides.14−16 Starting from commercially available 2,5-
dimethoxy-4-methylbenzaldehyde, allylic alcohol 2j was
prepared in one step by addition of vinylmagnesium bromide.
Subsequent iridium-catalyzed allylation under the established
conditions afforded γ,δ-unsaturated aldehyde 8 in 74% yield.
Compound 8 was treated sequentially with sodium borohy-
dride and methoxymethyl chloride (MOM-Cl) to furnish
protected alcohol 9, which can be converted into (−)-heli-
annuol C, following a sequence reported by Shishido and co-
workers.17 Additionally, diene 12 was prepared from aldehyde
8 using a modified Julia−Kocienski olefination.18 Subsequent
Sharpless dihydroxylation afforded diol 13 in a highly
diastereoselective manner. Compound 13 was used by Liu
and co-workers as a key intermediate for the total synthesis of
heliannuol E and heliespirones A and C.19,20
a
Reactions run on 0.25 mmol scale under the standard conditions.
b
c
Yields of isolated aldehydes. ee of the corresponding primary
d
alcohol determined by SFC on a chiral stationary phase. Branched/
linear = 10:1.
(3b−3e) and electron deficient (3f and 3g) allylic alcohols
were found to be compatible with this transformation,
affording the corresponding aldehydes in good to moderate
yields and >99% enantiomeric excess. Gratifyingly, also
heteroaromatic allylic alcohol 2h as well as cinnamaldehyde-
derived substrate 2i were tolerated, resulting in equally high
degrees of enantioinduction.
Next, we aimed to utilize this iridium-catalyzed allylation of
acetaldehyde to rapidly gain access to more complex molecules
(Scheme 2). To this end, allylic alcohol 2a was reacted with
acetaldehyde under the previously established conditions, and
the crude reaction mixture was treated with a second amine
catalyst and an electrophile. This two-step procedure gave
access to α-oxygenated11 and α-alkylated12 products 4 and 5,
respectively, in good yields and diastereomeric ratios.
Encouraged by these results, we envisioned that such
transformations could also be carried out in a one-pot
procedure wherein one amine catalyst controls two sequential
α-functionalization reactions. Gratifyingly, treatment of
In conclusion, we have developed conditions for the
enantioselective α-allylation of acetaldehyde under biphasic
conditions. It is noteworthy that the transformation employs
readily available, aqueous solutions of acetaldehyde, rendering
it operationally simple an atom economic. A series of γ,δ-
unsaturated aldehydes could be synthesized with excellent
B
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Scheme 3. Formal Syntheses of Sunflower-Derived Natural
Products
REFERENCES
■
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04658.
■
sı
General methods, detailed experimental procedures, and
spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Erick M. Carreira − ETH Zu
orcid.org/0000-0003-1472-490X;
Email: erickm.carreira@org.chem.ethz.ch
rich, Zurich 8093, Switzerland;
̈ ̈
(4) (a) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M.
Enantio- and diastereodivergent dual catalysis: α-Allylation of
branched aldehydes. Science 2013, 340, 1065. (b) Krautwald, S.;
Schafroth, M. A.; Sarlah, D.; Carreira, E. M. Stereodivergent α-
allylation of linear aldehydes with dual iridium and amine catalysis. J.
Am. Chem. Soc. 2014, 136, 3020. (c) Sandmeier, T.; Krautwald, S.;
Zipfel, H. F.; Carreira, E. M. Stereodivergent dual catalyitcα-allylation
of protected α-amino and α-hydroxyacetaldehydes. Angew. Chem., Int.
Ed. 2015, 54, 14363.
(5) Kumar, M.; Kumar, A.; Rizvi, M. A.; Shah, B. A. Acetaldehyde in
asymmetric organocatalyitc transformations. RSC Adv. 2015, 5,
55926.
(6) Sempere, Y.; Carreira, E. M. Trimethyl orthoacetate and
ethylene glycol mono-vinyl ether as enolate surrogates in
enantioselective iridium-catalyzed allylation. Angew. Chem., Int. Ed.
2018, 57, 7654.
Other Author
Tobias Sandmeier − ETH Zu
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04658
̈
rich, Zurich 8093, Switzerland
̈
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the ETH Zu
■
̈
rich and the Swiss National
Science Foundation (200020_172516) for financial support.
Dr. Erik Daa Funder (F. Hoffmann−La Roche, Copenhagen)
is thanked for helpful discussions.
C
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D
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