Synthesis of Chiral Tertiary Boronic Esters by Oxime-Directed Catalytic Asymmetric Hydroboration

Article abstract of DOI:10.1002/anie.201509137

Chiral boronic esters are useful intermediates in asymmetric synthesis. We have previously shown that carbonyl-directed catalytic asymmetric hydroboration (CAHB) is an efficient approach to the synthesis of functionalized primary and secondary chiral boronic esters. We now report that the oxime-directed CAHB of alkyl-substituted methylidene and trisubstituted alkene substrates by pinacolborane (pinBH) affords oxime-containing chiral tertiary boronic esters with yields up to 87 % and enantiomeric ratios up to 96:4 e.r. The utility of the method is demonstrated by the formation of chiral diols and O-substituted hydroxylamines, the generation of quaternary carbon stereocenters through carbon-carbon coupling reactions, and the preparation of chiral 3,4,4-trisubstituted isoxazolines.

Full text of DOI:10.1002/anie.201509137

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International Edition: DOI: 10.1002/anie.201509137
German Edition: DOI: 10.1002/ange.201509137
Asymmetric Catalysis
Synthesis of Chiral Tertiary Boronic Esters by Oxime-Directed
Catalytic Asymmetric Hydroboration
Veronika M. Shoba, Nathan C. Thacker, Andrew J. Bochat, and James M. Takacs*
Abstract: Chiral boronic esters are useful intermediates in
asymmetric synthesis. We have previously shown that carbon-
yl-directed catalytic asymmetric hydroboration (CAHB) is an
efficient approach to the synthesis of functionalized primary
and secondary chiral boronic esters. We now report that the
oxime-directed CAHB of alkyl-substituted methylidene and
trisubstituted alkene substrates by pinacolborane (pinBH)
affords oxime-containing chiral tertiary boronic esters with
yields up to 87% and enantiomeric ratios up to 96:4 e.r. The
utility of the method is demonstrated by the formation of chiral
diols and O-substituted hydroxylamines, the generation of
quaternary carbon stereocenters through carbon–carbon cou-
pling reactions, and the preparation of chiral 3,4,4-trisubsti-
tuted isoxazolines.
C
atalytic asymmetric hydroboration (CAHB) has attracted
renewed interest for the synthesis of chiral organoboronates.
Many of the successful applications exploit the reaction of
vinyl arene substrates.[1,2] Our research has instead focused on
the directed CAHB of b,g-unsaturated amide and ester
substrates. The carbonyl moiety controls the regioselectivity
of the rhodium-catalyzed addition of simple achiral boranes,
such as pinacolborane (pinBH), and chiral phosphite and
phosphoramidite ligands control the p-facial selectivity. A
variety of chiral primary and secondary boronic esters are
readily synthesized.[3] For example, under the conditions
specified in Scheme 1, methylidene derivative 1 undergoes
regioselective CAHB on the alkene Si face to afford chiral
hydroxyamide 2 with 96:4 e.r. after oxidation of the inter-
mediate g-borylated amide.
Scheme 1. In contrast to carbonyl-directed CAHB, the reaction of
a similar oxime ether substrate leads to the formation of a chiral
tertiary boronic ester. nbd=norbornadiene.
Encouraged by the success of carbonyl-directed CAHB,
we are exploring the effectiveness of other potential directing
groups. Oxime functionality has been used in conjunction
with a variety of transition-metal catalyst systems to direct
g-borylation, the yield of 4 (after oxidation) was low, and the
enantioselectivity was poor. The major side reactions are
ortho-borylation of the benzophenone-derived oxime with
concomitant alkene reduction.[6] We now report that the
corresponding acetone-derived oxime ethers are excellent
substrates for oxime-directed CAHB; for example, 5a under-
went oxime-directed CAHB/oxidation to give 6a in good
yield (71%) and with high levels of asymmetric induction
(95:5 e.r.). Furthermore, the borylated intermediate is a ter-
tiary boronic ester arising from Re-face b-borylation; in
contrast, carbonyl-directed CAHB of 1 proceeds by Si-face g-
borylation. It seems likely that the contrasting regio- and
stereochemical outcomes observed with 1 versus 5a are due to
the presence of the oxime substituents in the substrate–
catalyst complex; however, more work is needed to prove this
hypothesis unambiguously.
À
metalation reactions, most frequently to direct ortho-C H
À
activation of aromatic substrates but increasingly for C(sp3)
H activation as well.[4] Neufeldt and Sanford also recently
reported the oxime-directed palladium-catalyzed dioxygena-
tion of an adjacent alkene.[5]
For our initial attempts at oxime-directed CAHB, we
employed benzophenone-derived allylic oxime ethers, such as
3. Whereas rhodium-catalyzed hydroboration of 3 led to some
[*] V. M. Shoba, Dr. N. C. Thacker, A. J. Bochat, Prof. Dr. J. M. Takacs
Department of Chemistry, University of Nebraska-Lincoln
807 Hamilton Hall, Lincoln, NE 68588-0304 (USA)
E-mail: jtakacs1@unl.edu
Chiral boronic acid derivatives are valuable intermediates
in organic synthesis.[7] In particular, recent reviews by
Leonori, Scott, and Aggarwal highlight transformations of
chiral tertiary boronic esters,[8] including their use for the
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201509137.
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construction of multiple contiguous quaternary stereocen-
ters.[9] However, the formation of tertiary organoboronates by
metal-catalyzed or stoichiometric hydroboration is rare, since
hydroboration generally proceeds in an anti-Markovnikov
fashion to deliver boron to the less substituted site on the
alkene.[1,10]
Several complementary methods for the preparation of
chiral tertiary boronic esters have recently been reported
(Scheme 2). Three of these methods use bis(pinacolato)di-
boron (B2pin2) for the net hydroboration of functionalized
alkenes. For example, Tang and co-workers recently described
Scheme 3. CAHB of methylidene substrates 5 to form chiral tertiary
boronic esters 7. Typical reaction conditions: 1) [Rh(nbd)2]BF4
(2.0 mol%), (R,R)-L (4.1 mol%), pinBH (2.0 equiv), THF (c=0.04m),
408C, 3–24 h; 2) H2O2, aqueous NaOH. [a] The boronic ester was
formed in 84% yield. [b] The boronic ester was formed in 69% yield.
[c] (R)-6h was formed in 70% yield according to the NMR spectrum of
the crude product. Bn=benzyl.
Scheme 2. Recently reported approaches to the synthesis of chiral
tertiary boronic esters.
a remarkable rhodium-catalyzed reaction of a-aryl enamides
with B2(pin)2 to provide the first enantioselective synthesis of
chiral tertiary a-aminoboronic esters.[11] Shibasaki and co-
workers,[12] Hoveyda and co-workers,[13] and Feng and Yun[14]
independently developed asymmetric conjugate addition
reactions of B2(pin)2 to unsaturated esters, ketones, and
thioesters. Hoveyda and co-workers also developed an
efficient copper-catalyzed SN2’ substitution of allylic carbo-
nates by B2(pin)2.[15] Aggarwal and co-workers have very
elegantly exploited enantioselective lithiation followed by the
addition of a boronic ester and subsequent rearrangement to
prepare chiral tertiary boronic esters bearing benzyl, allyl,
propargyl, and most recently all-alkyl substituents.[16] Tertiary
boronic esters can also be constructed by deborylative
alkylation of geminal bis(boronates), as reported by Wom-
mack and Kingsbury[17] and Morken and co-workers.[18]
A series of methylidene derivatives 5 in which the vinyl
substituent R1 varies were subjected to CAHB (Scheme 3).
Oxime ether 5b (R1 = CH2Ph) was converted into the
intermediate chiral boronic ester 7b (R1 = CH2Ph), and the
tertiary alcohol 6b (70%, 94:6 e.r.) was obtained after
oxidation; alkene reduction, in this case leading to the
formation of 8 (21%, 56:44 e.r.), was the major competing
side reaction for all substrates. The isobutyl derivative 5c
(R1 = CH2CH(CH3)2) reacted similarly to give the tertiary
derivative 6c (70%, 95:5 e.r.). Several substrates with
a second site of unsaturation in the R1 substituent were also
found to undergo CAHB. Notably, only the alkene closest to
the oxime directing group underwent borylation in these
diene substrates. For example, the reaction of 1,4-dienes 5d–f
afforded monounsaturated alcohols 6d–f after oxidation.
Simple pendant oxygen and nitrogen substituents are toler-
ated, as illustrated by the formation of 6g and 6h. The level of
regioselectivity in favor of b- over g-borylation is high, except
for substrates in which the vinyl substituent R1 is more
sterically demanding. For example, 5i (R1 = cyclohexyl)
underwent predominantly g-borylation to afford the regio-
isomeric primary alcohol 9 (54%, 85:15 e.r.) after oxidation.
Trisubstituted alkene substrates typically react sluggishly
in catalyzed hydroboration but nevertheless readily under-
went oxime-directed CAHB. The borane added to the same
p-face as in the corresponding methylidene substrates and
therefore yielded the enantiomeric tertiary boronic ester
intermediate and the enantiomeric tertiary alcohol after
oxidation. For example, CAHB/oxidation of methylidene 5j
afforded predominantly (R)-6j (60%, 93:7 e.r.); the isomeric
trisubstituted substrate 10j was transformed predominantly
into (S)-6j (81%, 95:5 e.r.; Scheme 4).
Scheme 5 summarizes the results obtained for the oxime-
directed CAHB/oxidation of a number of trisubstituted
alkene derivatives 10. Not only was the opposite enantiomer
formed, but the yields observed with unhindered trisubsti-
tuted alkene substrates were often somewhat higher than
those observed for the corresponding methylidene substrates
owing to less competing alkene reduction. For example, (S)-
6a (95:5 e.r.) was formed in 84% yield from trisubstituted
alkene 10a (R1 = Me, R2 = PhCH2CH2), whereas (R)-6a (95:5
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Scheme 4. With the same catalyst system, isomeric methylidene and
trisubstituted alkene substrates undergo CAHB with the same p-facial
selectivity, thus giving the enantiomeric tertiary alcohols after oxida-
tion.
e.r.) was formed in 71% yield from methylidene 5a.[19]
However, in other cases, methylidene substrates reacted
more efficiently. For example, 5b and 5g each underwent
oxime-directed CAHB/oxidation to afford (R)-6b (70%, 94:6
e.r.) and (R)-6g (67%, 95:5 e.r.). The yields and levels of
enantioselectivity are somewhat higher than those observed
with the isomeric trisubstituted substrates 10b [(S)-6b (57%,
80:20 e.r.)] and 10g [(S)-6g (30%, 90:10 e.r.)]. In contrast to
10g, substrate 10k, in which the benzyl ether substituent
resides further away from the site of reaction by one
methylene group, underwent CAHB in good yield with high
enantioselectivity to give (S)-6k (77%, 94:6 e.r.). A simple
nitrogen-containing side chain can again be accommodated,
as illustrated by the CAHB of 10h to give (S)-6h (56%, 94:6
e.r.).
Trisubstituted alkene substrates with remote stereocen-
ters underwent oxime-directed CAHB with good catalyst-
controlled diastereoselectivity. For example, the chiral ketal-
containing substrate (S)-10l afforded either (S,S)- or (R,S)-6l,
depending on the configuration of the chiral ligand L used in
the reaction. Similarly, catalyst-controlled CAHB afforded
either diastereomer of 6m; again only the proximal alkene in
the diene substrate reacted. The examples described thus far
all lead to chiral tertiary boronic esters in which one of the
substituents is a methyl group. Substrate 10n extends the
scope of this approach with the formation of (S)-6n (70%,
94:6 e.r.). However, substrates in which the trisubstituted
alkene is increasingly congested (e.g., 10o and 10p) tend to
react slower and with lower levels of enantioselectivity under
the conditions found to date.
Scheme 5. CAHB of trisubstituted alkene substrates 10 to form of
chiral tertiary boronic esters 7. Typical reaction conditions: 1) [Rh-
(nbd)2]BF4 (2.0 mol%), L [(R,R)-isomer used unless noted otherwise;
4.1 mol%], pinBH (2.0 equiv), THF, 408C, 3–16 h; 2) H2O2, aqueous
NaOH. [a] (S)-6hformed in 78% yield according to the NMR spectrum
of the crude product.
similar sequence involving treatment with lithiated ethyl vinyl
ether, followed by hydrolysis, afforded the keto-oxime 15 with
high enantioselectivity, albeit in moderate yield (40%).
Nonetheless, the exposure of 15 to an acid gave the chiral
3,4,4-trisubstituted isoxazoline 16 (88%, 93:7 e.r.). Chiral
isoxazolines are found in many natural products and often
exhibit diverse biological properties. Hence, isoxazolines are
common pharmacophores of interest in medicinal chemis-
try.[22] The synthesis of 16 constitutes to our knowledge the
first reported enantioselective preparation of a 3,4,4-trisub-
stituted isoxazoline.
Scheme 6 illustrates selected transformations of the chiral
tertiary boronic ester 7j (93:7 e.r.).[20] Oxidation of the C B
À
À
bond, followed by cleavage of the N O bond, afforded the
chiral diol 11 (80%, 93:7 e.r.). Alternatively, oxidation
followed by hydrolysis afforded the chiral O-alkyl hydroxyl-
amine 12 (98%, 93:7 e.r.). A method developed by Aggarwal
and co-workers was used for carbon–carbon bond forma-
tion.[21] The addition of lithiated thiophene or furan, followed
by electrophile-induced rearrangement of the intermediate
borate with retention of configuration, afforded coupled
products 13 and 14 in 65 and 53% yield, respectively. A
In summary, asymmetric hydroboration would seem to be
an unlikely approach for the preparation of chiral tertiary
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Acknowledgements
Financial support for these studies from the NIH (GM100101)
is gratefully acknowledged.
Keywords: asymmetric catalysis · homogeneous catalysis ·
hydroboration · oximes · rhodium
How to cite: Angew. Chem. Int. Ed. 2016, 55, 1465–1469
Angew. Chem. 2016, 128, 1487–1491
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Scheme 6. Selected transformations of the oxime-containing chiral,
tertiary boronic ester 7j. Reaction conditions: a) 1) aqueous H2O2,
NaOH; 2) Ni-Raney, H2 (1 atm), B(OH)3; b) 1) aqueous H2O2, NaOH;
2) HCl/H2O/MeOH (1:1:1), 408C; c) 1) nBuLi, furan or thiophene,
=
À788C, THF; 2) N-bromosuccinimide; d) 1) LiC(OEt) CH2, À788C,
THF; 2) I2; 3) NaOMe, MeOH; e) HCl/H2O/MeOH (1:1:1), 408C.
boronic esters, since hydroboration generally proceeds in an
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Received: September 29, 2015
Published online: December 10, 2015
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