Can a Ketone Be More Reactive than an Aldehyde? Catalytic Asymmetric Synthesis of Substituted Tetrahydrofurans

Article abstract of DOI:10.1002/anie.201806312

O-heterocycles bearing tetrasubstituted stereogenic centers are prepared via catalytic chemo- and enantioselective nucleophilic additions to ketoaldehydes, in which the ketone reacts preferentially over the aldehyde. Five- and six-membered rings with both aromatic and aliphatic substituents, as well as an alkynyl substituent, are obtained. Moreover, 2,2,5-trisubstituted and 2,2,5,5-tetrasubstituted tetrahydrofurans are synthesized with excellent stereoselectivities. Additionally, the synthetic utility of the described method is demonstrated with a three-step synthesis of the side chain of anhydroharringtonine.

Full text of DOI:10.1002/anie.201806312

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International Edition: DOI: 10.1002/anie.201806312
German Edition: DOI: 10.1002/ange.201806312
Heterocycles
Can a Ketone Be More Reactive than an Aldehyde? Catalytic
Asymmetric Synthesis of Substituted Tetrahydrofurans
Sunggi Lee, Han Yong Bae, and Benjamin List*
Abstract: O-heterocycles bearing tetrasubstituted stereogenic
centers are prepared via catalytic chemo- and enantioselective
nucleophilic additions to ketoaldehydes, in which the ketone
reacts preferentially over the aldehyde. Five- and six-mem-
bered rings with both aromatic and aliphatic substituents, as
well as an alkynyl substituent, are obtained. Moreover, 2,2,5-
trisubstituted and 2,2,5,5-tetrasubstituted tetrahydrofurans are
synthesized with excellent stereoselectivities. Additionally, the
synthetic utility of the described method is demonstrated with
a three-step synthesis of the side chain of anhydroharringto-
nine.
A
ldehydes are generally more electrophilic and therefore
more reactive toward nucleophilic additions than ketones.[1]
This is also true for ketoaldehydes, in which the aldehydic
functional group typically reacts preferentially with a nucle-
ophile.[2] However, the question arises whether this tendency
can be reversed upon Lewis acid activation.[3] In this case, the
ketone may react first with an external nucleophile, either
because it is preferentially activated by the Lewis acid or, as
has been suggested by Molander,[4] by virtue of neighboring
group participation. Within the context of our program on
asymmetric Lewis acid catalysis with a silylium ion equiv-
alent/chiral anion pair (Si-ACDC),[5] we became interested in
exploring this type of reactivity. Specifically, we were keen on
developing methodology in which ketoaldehydes undergo
Scheme 1. Initial observations of the nucleophilic addition of 2a to
ketoaldehyde 1a catalyzed by IDPi 3.
type cyclizations,[9] carboalkoxylations,[10] an hydroalkoxyl-
ation,[11] and others.[12] In most cases, the stereoselective
preparation of the starting tri- and tetrasubstituted olefins is
considered the major limitation.
Recently, the Watson group reported an alkynylation of 2-
aryl-substituted cyclic oxocarbenium ions using a CuI com-
plex for the synthesis of compounds having diaryl, tetrasub-
stituted stereogenic centers.[13] Though cyclic oxocarbenium
ions are extensively exploited in glycosylations and natural
product syntheses, their application in asymmetric synthesis is
scarce.[14] This mainly originates from their capricious stabil-
ity, which largely depends on the number and size of the
substituents, as well as the absence of a strong coordinating
site. Following our first success on the enantioselective
functionalization of in situ generated cyclic oxocarbenium
ions,[14q] we envisioned that imidodiphosphorimidates
(IDPis)[11,14q,15] would be efficient catalysts for the formation
of tetrasubstituted stereogenic centers by controlling stereo-
chemically more challenging, yet more stable, 2-substituted
cyclic oxocarbenium ions via asymmetric counteranion-
directed catalysis (ACDC).[16]
To test our hypothesis, 4-oxo-4-phenylbutanal 1a was
reacted with silyl ketene acetal 2a in toluene at À788C
(Scheme 1). The reaction was complete within 1 hour using
only 1 mol% of (S,S)-IDPi 3a and gave product 4a in 94.5:5.5
er with in situ reduction of the acetal intermediate.[17]
Remarkably, only the product resulting from the attack of
the nucleophile on the ketone was observed. Similar to our
previous findings on the catalyst design,[11] modifying the
electron-withdrawing group of the sulfonamide from a CF3
group to more sterically demanding C6F5 group increased the
enantiomeric ratio to 96.5:3.5 with full conversion of the
starting material within 1 h (Scheme 1).
À
asymmetric Lewis acid catalyzed C C bond-forming cycliza-
tion reactions that are accomplished by preferential nucleo-
philic addition to the activated ketone (Scheme 1). Here we
report on the fruition of these studies with the development of
a broadly applicable catalytic and enantioselective approach
to highly substituted tetrahydrofurans (THFs) from the
corresponding 1,4-ketoaldehydes.
Tetrahydrofurans are common structures in natural prod-
ucts and biologically active molecules.[6] Consequently,
numerous methods have been developed for the enantiose-
lective construction of these important heterocycles.[7] How-
ever, there are few synthetic methods that provide 2,2-
disubstituted analogues with tetrasubstituted stereogenic
centers, despite the known biological potency of this motif
against multiple targets.[8] In fact, only a few methods aimed at
such targets have been reported including oxidative Wacker-
[*] Dr. S. Lee, Dr. H. Y. Bae, Prof. Dr. B. List
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
E-mail: list@kofo.mpg.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201806312.
12162
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With the optimized catalyst in hand, we investigated the
genic center (4i and 4j) were obtained in high yields and
reaction scope (Table 1). The steric bulk of the nucleophile
could be increased without significant deterioration in yield
and enantioselectivty (4b, 4 f, and 4j). Moreover, changes in
the electronic nature of the phenyl ring were well tolerated
(4c, 4d, and 4e). Both methyl and cyclohexyl ketones 1e and
1 f, as well as alkynyl ketone 1g, showed excellent chemo- and
enantioselectivities. Gratifyingly, when 5-ketoaldehydes were
employed, tetrahydropyrans with a tetrasubstituted stereo-
enantioselectivities.
The introduction of carbon nucleophiles in the second
step provides a useful procedure to generate 2,2,5-trisubsti-
tuted tetrahydrofuran rings, which occasionally appear in
natural products (Table 1B). Allylation and alkylations using
silylated nucleophiles, such as allyltrimethylsilane and silyl
ketene acetal 2c, resulted in high enantioselectivities and
moderate diastereoselectivities of the corresponding trisub-
stituted products 4k and 4l. A simple methyl substitution
using Me3Al was also possible, giving the same level of
enantioselectivity (4m).
Table 1: Substrate scope using ketoaldehydes.[a]
The current method enables the selective formation of
either the cis or trans isomer of a 2,2,5-trisubstituted
tetrahydrofuran ring, overcoming the intrinsic preference
(Table 1C). Namely, after the formation of TBS-protected
acetal using (S,S)-IDPi 3a, treatment with acetic acid and
BF3·Et2O afforded lactol acetate 5a with a moderate diaste-
reomeric ratio (1.3:1). Remarkably, when the same enantio-
À
mer of catalyst was applied in the second C C bond-forming
step, the trans selectivity was enhanced to 24:1. In sharp
contrast, the other enantiomer of the catalyst, (R,R)-3a,
furnished the cis isomer as the major product in superb er and
moderate dr within 2 h.
The differentiation between two ketones is also possible
(Table 2). When 1-phenylpentane-1,4-dione 1j was treated
with 2a in the presence of 1 mol% (S,S)-3a, a nucleophilic
attack was accomplished on the side of the sterically more
hindered carbonyl site, giving 97:3 enantioselectivity at
À958C, providing 4n, a diastereomer of 4m. Interestingly,
the regioselectivity can be altered by the substitution of
a benzyloxy coordinating group, that is, ketone 1k afforded
the tetrasubstituted stereogenic center on the side of methyl
ketone (4o) with 93:7 er. Desymmetrization of a symmetric
diketone, hexane-2,5-dione, could be achieved with excellent
enantioselectivity, albeit with only a moderate diastereomeric
ratio (4p).
The synthetic utility of this method can be highlighted by
the straightforward preparation of enantioenriched 2,2,5,5-
tetrasubstutited tetrahydrofurans (Scheme 2). When inter-
mediate 5b, which is generated from the reaction between 1j
and 2a in the presence of 1 mol% (R,R)-3a at À958C, was
Table 2: Substrate scope using 1,4-diketones.[a]
[a] Reactions were conducted with substrate 1 (0.2 mmol, 1.0 equiv), 2a
(0.3 mmol, 1.5 equiv), and catalyst 3b (1.0 mol%) in toluene (0.1m) at
À788C. After complete consumption of starting material, 2.0 equiv of
AcOH and 3.0 equiv of BF3·Et2O were added, followed by addition of
3.0 equiv of the second nucleophile, that is, Et3SiH, allyltrimethylsilane,
2c, or Me3Al. For details, see the Supporting Information. [b] Using 1-
(trimethylsilyloxy)-1-benzyloxyethene 2b instead of 2a. [c] At À408C.
[d] At À958C. [e] Using (S,S)-3a
[a] Reactions were conducted with substrate 1 (0.2 mmol, 1.0 equiv), 2
(0.3 mmol, 1.5 equiv), and catalyst 3 (1.0 mol%) in toluene (0.1m) at
À788C. After complete consumption of starting material, 5.0 equiv of
trifluoroacetic acid and 5.0 equiv of Et3SiH were added. For details, see
the Supporting Information. [b] At À958C. [c] Using 2b instead of 2a.
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Scheme 2. Synthesis of enantioenriched 2,2,5,5-tetrasubstituted tetra-
hydrofurans and the side chain of anhydroharringtonine.
Scheme 3. A) Reactivity comparison between aldehyde and ketone.
B) Plausible catalytic cycle.
reacted further with methylallyltrimethylsilane, the corre-
sponding O-heterocycles 6a were afforded with high yield
and excellent regio-, diastereo-, and enantioselectivity. With
the same intermediate 5b, the side chain of anhydroharrinto-
nine,[18] which is isolated from the genus Cephalotaxus and
known for antileukemic activity, was synthesized. A methyl-
ation of 5b using trimethylaluminum, followed by catalytic
oxidation of the phenyl group using RuCl3·xH2O, allowed us
to obtain the corresponding acid 7 in three steps.
To gain insight on the reaction mechanism, we have
investigated the reactivity of 1-phenyl-1-butanone 8 and
pentanal 10 under identical reaction conditions (Scheme 3A).
Interestingly, only a 5% yield of product 11 was obtained
when aldehyde 10 was used as starting material, while no
desired aldol adduct was observed using ketone 8.[19] In
addition, an equal molar mixture of ketone 8 and aldehyde 10
gave the same low conversion. These results contrast with the
full conversion of ketoaldehyde 1a and clearly imply that
dicarbonyl structures are essential in our reactions and the
highly reactive cyclic oxocarbenium ions are involved. Our
results also suggest that the reaction does not proceed
through the direct nucleophilic addition of the silyl ketene
acetals onto ketones which can generate the same products by
sequential cyclization of silyl ether towards aldehydes. Based
on these observations, we propose the following mechanism.
First, the in situ formed silylium ion pair catalyst coordinates
to the sterically less hindered aldehyde (A), and invokes an
intramolecular cyclization to afford a highly active cyclic
oxocarbenium ion intermediate B (Scheme 3B). At this
point, the counteranion of IDPi 3 can direct the approach
of external nucleophiles by discriminating the enantiofaces of
a multisubstituted cyclic aliphatic oxocarbenium ion. Sub-
sequently, formation of the highly substituted heterocycle C
and regeneration of the silylium ion pair complete the
catalytic cycle.
In conclusion, we have developed a regio- and enantio-
selective catalytic method which affords highly substituted
tetrahydrofurans and tetrahydropyrans starting from 1,4- and
1,5-dicarbonyl compounds using IDPis as catalysts. The
selective addition of nucleophiles toward ketones over
aldehydes was observed. The efficiency of the method was
demonstrated by the chemo-, diastereo-, and enantioselective
construction of 2,2,5-trisubsituted furans. Moreover, 2,2,5,5-
tetrasubstituted tetrahydrofurans can be readily synthesized
using the described method.
Acknowledgements
Generous support from the Max Planck Society, the Deutsche
Forschungsgemeinschaft (Leibniz Award to B.L. and Cluster
of Excellence RESOLV, EXC 1069), and the European
À
Research Council (Advanced Grant “C H Acids for Organic
Synthesis, CHAOS”) are gratefully acknowledged. We thank
the technicians of our group, and the members of our NMR,
MS, GC, and HPLC departments for their excellent service.
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Cuyamendous, V. Bultel-PoncØ, T. Durand, J.-M. Galano, C.
Conflict of interest
Oger, Tetrahedron 2016, 72, 5003 –5025; h) F. Vetica, P. Chau-
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The authors declare no conflict of interest.
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Keywords: enantioselective nucleophilic addition ·
oxygen heterocycles ·Lewis acid catalysis ·
tetrasubstituted stereogenic centers
How to cite: Angew. Chem. Int. Ed. 2018, 57, 12162–12166
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Manuscript received: June 1, 2018
Version of record online: August 20, 2018
12166 www.angewandte.org
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