Practical and Broadly Applicable Catalytic Enantioselective Additions of Allyl-B(pin) Compounds to Ketones and α-Ketoesters

Article abstract of DOI:10.1002/anie.201603894

A set of broadly applicable methods for efficient catalytic additions of easy-to-handle allyl-B(pin) (pin=pinacolato) compounds to ketones and acyclic α-ketoesters was developed. Accordingly, a large array of tertiary alcohols can be obtained in 60 to >98 % yield and up to 99:1 enantiomeric ratio. At the heart of this development is rational alteration of the structures of the small-molecule aminophenol-based catalysts. Notably, with ketones, increasing the size of a catalyst moiety (tBu to SiPh₃) results in much higher enantioselectivity. With α-ketoesters, on the other hand, not only does the opposite hold true, since Me substitution leads to substantially higher enantioselectivity, but the sense of the selectivity is reversed as well.

Full text of DOI:10.1002/anie.201603894

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Communications
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International Edition: DOI: 10.1002/anie.201603894
German Edition: DOI: 10.1002/ange.201603894
Enantioselective Synthesis
Practical and Broadly Applicable Catalytic Enantioselective Additions
of Allyl-B(pin) Compounds to Ketones and a-Ketoesters
Daniel W. Robbins+, KyungA Lee+, Daniel L. Silverio, Alexey Volkov, Sebastian Torker, and
Amir H. Hoveyda*
Dedicated to Professor Stuart L. Schreiber on the occasion of his 60th Birthday
Abstract: A set of broadly applicable methods for efficient
catalytic additions of easy-to-handle allyl-B(pin) (pin = pina-
colato) compounds to ketones and acyclic a-ketoesters was
developed. Accordingly, a large array of tertiary alcohols can
be obtained in 60 to > 98% yield and up to 99:1 enantiomeric
ratio. At the heart of this development is rational alteration of
the structures of the small-molecule aminophenol-based cata-
lysts. Notably, with ketones, increasing the size of a catalyst
moiety (tBu to SiPh3) results in much higher enantioselectivity.
With a-ketoesters, on the other hand, not only does the opposite
hold true, since Me substitution leads to substantially higher
enantioselectivity, but the sense of the selectivity is reversed as
well.
T
ertiary homoallylic alcohols of high enantiomeric purity
hold considerable value in chemical synthesis.[1] As expertly
demonstrated by the groups of Shibasaki and Kanai,[2]
Yamamoto,[3] Sigman[4] and Schaus,[5] a direct way to access
these entities is by catalytic allyl addition to ketones, and the
enantioselectivity is exceptional in these and several subse-
quent disclosures.[6] Despite such groundbreaking advances,
an approach that offers the following key attributes simulta-
neously remains lacking: a catalyst that does not contain
a toxic metal and can be prepared inexpensively and easily,
a readily available set of reagents that are air and moisture
stable, and a broad substrate scope.
Our interest in this problem originated from an earlier
discovery that easily modifiable aminophenol compounds
(e.g., 1a, Scheme 1a) may be used to catalyze efficient
enantioselective addition of allyl-B(pin) (pin = pinacolato) to
isatins.[7] High selectivity was found to arise from structural
organization caused by H-bonding between the amide
carbonyl and the catalyst ammonium group;[8] this is despite
electronic repulsion between the non-bonding aryloxide and
carbonyl electrons (I; Scheme 1a). Additions to acetophe-
none (Scheme 1b) are therefore substantially less selective
(2a, 68:32 e.r.) because there is little energy difference
Scheme 1. Is high enantioselectivity feasible without a second catalyst–
substrate contact point?
between II and the alternative complex with a pseudo-axial
phenyl group. The enhanced selectivity with the naphthyl
ketone (2b, 93.5:6.5 e.r.) suggests that in modified amino-
phenol-based catalysts, as illustrated by III and IV (Sche-
me 1b), steric factors may be manipulated for achieving high
enantioselectivity.
Related additions to acyclic a-ketoesters afford valuable
products and are also of interest. We know of only one report
that is dedicated to this class of catalytic enantioselective
transformations, and in this case, an (expensive) indium-based
complex and (toxic) tetraallyltin are required.[9] Another
report, involving a Zn-based catalyst and an allylboronate
compound, contains just a single example.[10] We were
interested in developing a more general and practical
[*] Dr. D. W. Robbins,[+] K. Lee,[+] D. L. Silverio, A. Volkov, Dr. S. Torker,
Prof. A. H. Hoveyda
Department of Chemistry, Merkert Chemistry Center, Boston College
Chestnut Hill, MA 02467 (USA)
E-mail: amir.hoveyda@bc.edu
[+] D.W.R. and K.L. contributed equally.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603894.
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method for allyl additions to a-ketoesters, aiming to inves-
tigate whether various electronic (e.g., dipolar interactions
and electron–electron repulsive forces) and steric features
illustrated for complexes V and VI (Scheme 2) may be
manipulated such that the desired products can be obtained in
appreciable enantiomeric purity.
À308C for eight hours, 2a may be isolated in 89% yield and
98:2 e.r. (Scheme 4).[11]
The catalytic method is broadly applicable, and the
requisite aminophenol 1g, which is indefinitely air stable,
can be prepared in approximately 40% overall yield from
readily available starting materials.[12] Aryl-substituted
ketones, including those with an electron-
donating (2c; Scheme 4) or electron-with-
drawing substituent (2e,f) undergo efficient
and highly enantioselective addition. Nota-
bly, the unprotected aniline- and phenol-
containing tertiary homoallylic alcohols 2i
and 2j were obtained in 82% and 91% yield
and 91.5:8.5 and 96.5:3.5 e.r., respectively. As
represented by 2n–p (Scheme 4), ketones
with an N-, O- and/or S-containing hetero-
cyclic moiety are suitable. Products from aryl
ketones that contain a larger alkyl unit (3–4),
an alkenyl group (5) or a comparatively
diminutive alkynyl moiety (6) were accessed
efficiently and in high enantiomeric purity.
While the reactions were reasonably effi-
cient, the enantioselectivity was lower with
Scheme 2. Another key question: which pathway, if any, would be preferred for allyl-B(pin)
addition to a-ketoesters?
ketones containing two alkyl substituents (cf.
7,8). With only electronic factors distinguish-
ing the ketone substituents, measurable enan-
tiofacial differentiation was still observed (9
We started by examining the reactions of acetophenone
and allyl-B(pin) with aminophenols 1b–f to generate tertiary
alcohol 2a (Scheme 3). Phenyl-substituted 1b was selected
based on the reasoning that an aryl unit extends further (vs.
a tBu group), thus expanding the reach of the catalyst in the
desired direction (cf. 1c,d). There was no more than an
incremental increase in e.r. (up to 81:19) with 1b–d, however,
in 73:27 e.r.). The synthesis of 10–12 (Scheme 4) demonstrates
that 2-substituted allylboron reagents may be used.
Reactions of cyclic ketones afforded products in high yield
and up to 99:1 e.r., as demonstrated by 13–15 (Scheme 5). The
case of alkenyl iodide 15 is particularly notable since it has
been utilized in an approach toward enantioselective syn-
thesis of the veratrum family of alkaloid natural products
(anticancer activity).[13]
À
thus leading us to envision that incorporating longer C Si
bonds at the same site could prove to be more effective. In the
event, although the selectivity with triisopropylsilyl-substi-
tuted 1e was somewhat disappointing (77:23 e.r.), with
triphenylsilyl variant 1 f, 2a was formed in 90:10 e.r.
Subsequent optimization revealed that with 3.0 mol % 1g at
Allyl additions to a-ketoesters were next (cf. Scheme 2). It
did not take long before we faced a surprise: whereas addition
of allyl-B(pin) to 17a with the tBu-substituted aminophenol
(1a) afforded a-hydroxy ester 18a in 82:18 e.r. (Scheme 6a),
with triphenylsilyl-substituted 1 f, unlike the transformations
with ketones, the selectivity was lower (75:25 e.r.). Moreover,
the major enantiomer is derived from the opposite sense of
enantioselectivity compared to the ketone additions (cf. X-ray
structure in Scheme 6a), thus indicating that the reaction may
occur via VII (Scheme 6b). The competing mode of addition
is probably best represented by VIII, wherein although the
net dipole–dipole repulsion is minimized, there is repulsion
between the nonbonding electrons of the aryloxy and ester
groups. We suspected that steric strain between the axially
oriented ketone substituent and the protruding aryloxide
moiety of the catalyst (VII, R = tBu or SiPh3 in 1a and 1 f,
respectively) might be less costly than the indicated electron–
electron repulsion in VIII (cf. VI, Scheme 2). Hence, an H-
bonded complex such as V in Scheme 2 might not play
a major role because of the dipole–dipole repulsion associ-
ated with the bound a-ketoester (unlike with structurally rigid
isatins).[7a]
An implication of the above hypothesis is that enantio-
selectivity could be improved with an aminophenol that
Scheme 3. Screening of ligands for enantioselective allyl addition to
acetophenone as the model.
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contains a smaller substituent
(vs. tBu or SiPh3). Indeed, when
methyl-substituted ligand 1h
was used, under otherwise iden-
tical conditions, 17a was gener-
ated in 92:8 e.r.[14] Reaction with
the unsubstituted aminophenol
did not cause further improve-
ment;[15] this might be because
the energy gained by lowering
the strain in VII is not large
enough to compensate for the
residual steric repulsion between
the methyl ester and the catalyst
substituent in VIII that is no
longer present.[16]
The additions to a-ketoesters
show notable scope (Scheme 7).
The transformations are excep-
tionally efficient (often > 98%
yield after purification) regard-
less of the electronic attributes
of the aryl unit (e.g., 18b vs. 18 f)
or whether an alkyl-substituted
ketoester is involved (cf. 18h).
The somewhat less enantioselec-
tive additions compared to those
with
linear
ketones
(cf.
Scheme 4) imply that there is
greater competition between the
two modes of reaction (VII vs.
VIII, Scheme 6b). The utility of
the method is highlighted by the
concise synthesis of lactone 19,
a compound that has been con-
verted to antiviral nucleoside
analogues,[17] in 60% overall
yield (94:6 e.r.). Two other
points are worthy of note:
1) Aminophenol 1h was pre-
pared in 76% overall yield
from an inexpensive aldehyde
and Boc-valine.[12] 2) The reac-
tions can be easily carried out
without the need for rigorous
exclusion of air and moisture
Scheme 4. Tertiary homoallylic alcohols obtained from catalytic enantioselective additions of allyl-B(pin)
compounds to acyclic ketones. The absolute stereochemistry of the major isomer of 9 has not been
determined. [a] At À158C, 8 h. [b] At À158C, 12 h.
in
91:9 e.r.).
To conclude, two catalytic enantioselective
a fume hood (e.g., 18 f in 94% yield,
reactions involving acyclic and cyclic ketones and
acyclic a-ketoesters are presented. The trans-
formations offer broader substrate scope (includ-
ing unprotected phenols and anilines) than the
previously reported approaches, and involve the
use of inexpensive catalysts along with easy-to-
handle reagents that are mostly commercially
available. A key aspect of the present studies is
the possibility of maximizing enantioselectivity
by means of rational alteration of the size of an
Scheme 5. Catalytic enantioselective additions to cyclic ketones.
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opments in enantioselective synthesis. Studies along these
lines, including reactions with more functionalized allyl-
B(pin) compounds, are underway.
Acknowledgements
Financial support was provided by the NIH (GM-57212).
A.V. acknowledges an Olle Engkvist Byggmꢀstare schol-
arship.
Keywords: a-ketoesters · enantioselective synthesis ·
homoallylic alcohols · homogeneous catalysis · ketones
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aryloxy substituent on the aminophenol based on the
available stereochemical models. We show that with ketones,
exchanging the tert-butyl unit with a triphenylsilyl group is
needed, whereas with acyclic a-ketoesters, a catalyst bearing
a smaller methyl unit is superior. The advances described
herein offer additional evidence regarding the considerable
potential of aminophenol-derived catalysts for future devel-
4
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[8] The presence of H-bonding is supported by the quantum theory
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[12] See the Supporting Information for details.
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yield).
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[16] Reactions with larger carboxylic esters (e.g., tBu esters) under
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Published online: && &&, &&&&
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Communications
Enantioselective Synthesis
D. W. Robbins, K. Lee, D. L. Silverio,
A. Volkov, S. Torker,
A. H. Hoveyda*
&&&& — &&&&
Practical and Broadly Applicable Catalytic
Enantioselective Additions of Allyl-B(pin)
Compounds to Ketones and a-Ketoesters
Easy to tune: A set of broadly applicable
methods for efficient catalytic additions
of easy-to-handle allyl-B(pin) (pin=pina-
colato) compounds to ketones and acy-
clic a-ketoesters is introduced. Accord-
ingly, a large array of tertiary alcohols can
be obtained in up to around 98% yield
and 99:1 e.r. Mechanism-based modifi-
cation of the structures of aminophenol-
based catalysts results in substantial
improvement in enantioselectivity.
6
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