Extremely Active Organocatalysts Enable a Highly Enantioselective Addition of Allyltrimethylsilane to Aldehydes

Article abstract of DOI:10.1002/anie.201607828

The enantioselective allylation of aldehydes to form homoallylic alcohols is one of the most frequently used carbon–carbon bond-forming reaction in chemical synthesis and, for several decades, has been a testing ground for new asymmetric methodology. Howe

Full text of DOI:10.1002/anie.201607828

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International Edition: DOI: 10.1002/anie.201607828
German Edition: DOI: 10.1002/ange.201607828
Organocatalysis
Extremely Active Organocatalysts Enable a Highly Enantioselective
Addition of Allyltrimethylsilane to Aldehydes
Philip S. J. Kaib, Lucas Schreyer, Sunggi Lee, Roberta Properzi, and Benjamin List*
Abstract: The enantioselective allylation of aldehydes to form
homoallylic alcohols is one of the most frequently used
carbon–carbon bond-forming reaction in chemical synthesis
and, for several decades, has been a testing ground for new
asymmetric methodology. However, a general and highly
enantioselective catalytic addition of the inexpensive, nontoxic,
air- and moisture-stable allyltrimethylsilane to aldehydes, the
Hosomi–Sakurai[1] reaction, has remained elusive.[2,3]
Reported herein is the design and synthesis of a highly acidic
imidodiphosphorimidate motif (IDPi), which enables this
transformation, thus converting various aldehydes with aro-
matic and aliphatic groups at catalyst loadings ranging from
0.05 to 2.0 mol% with excellent enantioselectivities. Our
rationally constructed catalysts feature a highly tunable active
site, and selectively process small substrates, thus promising
utility in various other challenging chemical reactions.
prepared and handled.[3,17,18] Despite significant effort,[3]
however, a general and broadly applicable allylation of
aldehydes with allyltrimethylsilane (3) as a highly attractive
allyl-transfer reagent has proven to be extremely challeng-
ing [2,3,19] (Figure 1a).
E
nantiomerically pure homoallylic alcohols 1 are common
synthetic intermediates, and are typically generated by
allylmetal–aldehyde addition reactions.[3] In 1978, the first
enantioselective allylation of aldehydes 2 was reported by
Hoffmann et al., employing a camphor-derived allylboronic
ester as the nucleophile.[4] A few years later, Brown et al.
introduced B-allyldiisopinocampheylborane, which has been
the most popular chiral allylating agent until today.[5] Such
chiral reagents[6–8] have proven to be of considerable synthetic
value, although the intrinsic need for wasteful stoichiometric,
and usually non-recoverable amounts of enantiopure auxil-
iaries affect atom economy, cost, environmental impact, and
the overall synthetic appeal of the methodology.[3] To this end,
several effective catalytic variants with achiral allylboron
reagents,[9,10] allylstannanes,[11–13] allyl halides,[14,15] and allyl
acetates[16] have been developed. Nevertheless, the non-
negligible high toxicity of stannanes and chromium com-
plexes[14,15] significantly restricted the broad application of
some of these methods. Alternatives, such as the multi-
component catalyst systems employing iridium complexes,[16]
require high temperature and a large excess of reagents.
Comparatively, allylsilanes are considered nontoxic, air- and
moisture-stable, often commercially available, and easily
Figure 1. Catalyst design. a) Hosomi–Sakurai[1] reaction. b) Design of
highly acidic and sterically constrained imidodiphosphorimidate (IDPi)
Brønsted acids 7. c) Design of a confined silylium Lewis acid organo-
catalyst. Tf=SO2CF3.
Previously developed variants exploiting cyclic alkoxy
boranes (CAB)[20] or titanium-based[2,11,21] catalysts generate
the corresponding homoallylic alcohols with moderate to
good yields and enantioselectivities. These methods require
exhaustive exclusion of air and moisture and are limited with
regard to substrate diversity.[2,3] Most importantly, and
enhanced by the low nucleophilicity of allyltrimethylsilane,[22]
catalytic enantioselective Hosomi–Sakurai reactions struggle
with highly efficient and competitive non-enantioselective
background silylium catalysis.[23] This fast process, which is
readily initiated by most chiral Lewis acids,[24] diminishes
enantioselectivity and leads to the requirement of high
catalyst loadings.[23,25] As a solution to this problem, we
have recently expanded our asymmetric counteranion-
directed catalysis (ACDC)[26] concept to silylium-based
Lewis acid organocatalysis. Accordingly, in situ generated
[*] P. S. J. Kaib, L. Schreyer, Dr. S. Lee, Dr. R. Properzi, Prof. Dr. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
E-mail: list@kofo.mpg.de
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201607828. CCDC 1498931,
1498932, 1498933, 1498934, and 1498935 contain the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre.
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silylium ions, paired with an enantiopure counteranion,
function as powerful and highly enantioselective Lewis acid
catalysts (Figure 1c, left). This strategy has proven to be
successful in a variety of Mukaiyama style silyl-transfer
reactions[19] and also in non-silyl-transfer reactions, such as
the Diels–Alder reaction of cinnamates.[24]
Attractive features of silylium-based Lewis acid organo-
catalysis include the in situ regeneration of the catalyst (“self-
healing”) and relatively low catalyst loadings,[19,24] thus
suggesting a practical synthetic method for the allylation of
aldehydes with allyltrimethylsilane. However, because of the
low nucleophilicity of this reagent (Mayr nucleophilicity: N =
1.6),[22] its employment in asymmetric, catalytic addition
reactions to aldehydes requires extremely reactive Lewis
acids,[2] and previously reported catalysts, including our
À
silylated disulfonimides (DSI)
4 and our chiral C H
Scheme 1. Synthetic access to new chiral Brønsted acid catalysts.
a) Single-flask synthesis of the imidodiphosphorimidates 7. b) Crystal
structure color coding: dark gray carbon, purple nitrogen, red oxygen,
green or silver fluorine, yellow sulfur, orange phosphorus. c) Selected
examples of the developed catalyst library.
acids,[19,24,27–29] were insufficiently active in this transformation
(Figure 1a). In contrast, the recently reported highly acidic
BINOL-derived phosphoramidimidates 5[30] (Figure 1b) effi-
ciently promoted the Hosomi–Sakurai reaction, however,
without relevant enantiodiscrimination. We also investigated
our confined Brønsted acids, which have previously been
shown to be highly effective in processing small substrates.[28]
Unfortunately, the imidodiphosphates (IDP) 6[28a] (Fig-
ure 1b), even those of increased acidity,[28b,c] failed in the
catalysis of the Hosomi–Sakurai reaction. We hypothesized
that the high acidity of 5 could be ideally combined with the
superb selectivity of our IDP catalysts 6 in the newly designed
imidodiphosphorimidates (IDPi) 7. In this context, a highly
efficient trimethylsilylium ion Lewis acid, paired with a con-
fined imidodiphosphorimidate anion (silyl-7), could even
enable the processing of highly challenging small aliphatic
substrates at high rates and low catalyst loadings (Figure 1c).
Additionally, this design would overcome current substrate
limitations present in “open-active-site” catalysts, such as 4.
To access the novel structural motif of 7 (Figure 1b), the
3,3’-substituted BINOL derivatives 8 (Scheme 1) were ini-
tially dimerized with commercially available bis(dichloro-
phosphino)methylamine [(PCl2)2NMe], followed by a Stau-
dinger oxidation with triflyl azide (TfN3) to generate the N-
methylated IDPi core. Subsequent demethylation with tetra-
butylammonium iodide [N(nBu)4I] afforded the desired
catalyst upon acidification. Initial studies with IDPi 7a
quickly revealed the new motif to be highly reactive and
enantioselective in the Hosomi–Sakurai reaction.
electron-neutral, and electron-deficient IDPis (7c–e) pre-
dominantly range from 160–1638 (Scheme 1b and the Sup-
porting Information). This structural observation suggests the
acidic proton to be located on a triflyl-bound nitrogen atom
rather than the bridging nitrogen atom, which is also
inaccessible to substrates because of the installed 3,3’-
substituents on the BINOL backbone.
Our effort in catalyst design was quickly rewarded with
a highly enantioselective organocatalytic addition of allyltri-
methylsilane to aromatic aldehydes (Scheme 2). IDPi cata-
lysts 7 proved to be general, and diverse homoallylic alcohols
were obtained in good yields and high enantioselectivities.
Aromatic aldehydes were converted at À788C with 0.5 mol%
of IDPi 7b bearing 2-naphthyl substituents in the 3,3’-
positions of the BINOL backbones. The aromatic alcohols
1a–d and 1g–j were obtained in good yields and enantiose-
lectivities. Systematic substitution on the benzaldehyde core
revealed high tolerance toward meta and para substitution on
the electrophile, as well as negligible electronic effects on
naphthaldehyde derivatives. In contrast, ortho substitution,
with concomitant increased steric hindrance, caused signifi-
cant repulsion in the catalyst–substrate adduct. In this
context, catalyst 7g was found to furnish the ortho-substituted
aromatic alcohols 1e and 1 f at elevated temperatures with
good enantioselectivities. The formation of product 1j from
an a,b-unsaturated aldehyde required a higher catalyst
loading and prolonged reaction time.
An extensive catalyst optimization and development was
needed for aliphatic aldehydes (Scheme 2). The electronic
properties of the installed 3,3’-substituents showed a signifi-
cant effect on chemoselectivity. Remarkably, both electron-
deficient and electron-rich substituents performed at far more
elevated reaction temperatures compared to electronically
unmodified polyaromatic groups. Catalysts possessing strong
electron-withdrawing substituents, such as IDPi 7d, were
barely active in the Hosomi–Sakurai reaction and were prone
to trimerize the aliphatic aldehydes. In contrast, electron-
These early findings prompted us to develop a straightfor-
ward, single-flask protocol for catalyst synthesis (Scheme 1a).
Here, the crucial element was to access triflylphosphorimi-
doyl trichloride [P(NTf)Cl3] in analytically pure form. All
described methods to generate P(NTf)Cl3 required either
explosive and/or toxic chemicals and gave impure mate-
rial.[31,32] We therefore developed a new solid-state Kirsanov
reaction[31] to afford analytically pure P(NTf)Cl3 after a single
fractional distillation. Remarkably, treating P(NTf)Cl3 with
BINOLs 8 and ammonia directly furnished the desired
catalyst 7 (Scheme 1a). Structural crystallographic analyses
of the imidodiphosphorimidates 7 reveal a confined active site
within a sterically highly demanding chiral environment
(Scheme 1b). The P-N-P bond angles for electron-rich,
2
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Scheme 3. Synthetic applications. a) Large-scale Hosomi–Sakurai reac-
tion. b) Diastereoselective Hosomi–Sakurai reaction. Reactions were
conducted on 0.3 to 10.6 mmol scales and catalyst loadings are given
in mole percent (mol%). All yields are those of the isolated products
and enantiomeric (e.r.) and diastereomeric ratios (d.r.) were deter-
mined by high-performance liquid chromatography (HPLC) analysis
with chiral stationary phases. Absolute configurations were assigned
according to referenced literature and prepared authentic samples.
hols 1o with a diastereomeric ratio of 65:35. In contrast, the
matched catalyst, (S,S)-IDPi 7 f afforded 1o with a d.r. value
of 98.5:1.5. In both cases, the configuration of the pre-existing
stereogenic center was preserved. Our results show that
confined organocatalysts with extreme acidity and steric
demand can overcome current synthetic limitations and solve
a long standing problem in chemical synthesis. Our designed
high-performance organocatalysts enable the first general
and enantioselective catalytic addition of allyltrimethylsilane
to aldehydes.
Scheme 2. Scope with respect to aliphatic and aromatic aldehydes 2.
Reactions were conducted on 0.3–1.0 mmol scales. Catalyst loadings
are given in mole percent (mol%). All yields are those of isolated
products, and the enantiomeric ratios (e.r.) were determined by high-
performance liquid chromatography (HPLC) or gas chromatography
(GC) analysis with chiral stationary phases. Absolute configurations
were assigned according to referenced literature or by crystallographic
analysis. [a] IDPi 7g, R=9,10-dihydrophenanthryl, was used. [b] 95%
yield based on recovered starting material (low solubility of the starting
material). [c] Desilylation with HCl to determine enantiomeric ratio.
Acknowledgments
Generous support by the Max Planck Society, the Deutsche
Forschungsgemeinschaft (Leibniz Award to B.L.), and the
European Research Council (Advanced Grant “High Perfor-
mance Lewis Acid Organocatalysis, HIPOCAT”) are grate-
fully acknowledged. We are also very thankful to all the
members of our NMR, HPLC, GC, mass spectrometry, and X-
ray analytical departments.
donating groups, as depicted for catalyst 7e, induced silyl-
group-transfer reactions to generate the corresponding enol
silanes. Gratifyingly, electronically neutral polyaromatic 3,3’-
substituents, such as the 6,8-dimethylpyren-2-yl substituted
catalyst 7 f, afforded the desired homoallylic alcohols 1 in
good to excellent yields and enantioselectivities. Contrarily to
aromatic aldehydes, even lower temperatures (À908C) and
catalyst loadings (0.05 mol%) could be employed with
aliphatic aldehydes, such as 3-phenylpropanal (2m).
Increased catalyst loadings (1 mol%) furnished the trime-
thylsilyl protected alcohol 1m (89% yield) in less than two
hours at À788C (Scheme 2), thus rendering a highly atom-
economic and practical allylation method. Linear, b- and g-
branched aldehydes (2) were also suitable substrates for 7 f,
furnishing alcohols 1k–n (Scheme 2). On preparative scale,
1.4 grams of 2m were converted by 7 f (10 mg, 0.05 mol%) at
À788C within 5 days, furnishing homoallylic alcohol 1m in
93% yield and with an enantiomeric ratio of 98:2 (Scheme
3a).
Keywords: allylic compounds · enantioselectivity ·
nucleophilic addition · organocatalysis · silanes
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Received: August 11, 2016
Published online: && &&, &&&&
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Communications
Organocatalysis
P. S. J. Kaib, L. Schreyer, S. Lee,
R. Properzi, B. List*
&&&& — &&&&
Extremely Active Organocatalysts Enable
a Highly Enantioselective Addition of
Allyltrimethylsilane to Aldehydes
A general and highly enantioselective
catalytic addition of inexpensive, non-
toxic, air- and moisture-stable allyltrime-
thylsilane to aldehydes, the Hosomi–
Sakurai reaction, is disclosed. Reported is
the design and synthesis of a highly acidic
imidodiphosphorimidate motif (IDPi),
which enables this transformation, and
converts various aldehydes at catalyst
loadings ranging from 0.05 to 2.0 mol%
with excellent yields and enantioselectiv-
ities.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!