Remarkably Facile Borane-Promoted, Rhodium-Catalyzed Asymmetric Hydrogenation of Tri- and Tetrasubstituted Alkenes

Article abstract of DOI:10.1021/jacs.7b02581

Oxime-directed catalytic asymmetric hydroboration is diverted to catalytic asymmetric hydrogenation (CAH) upon the addition of a proton source, such as MeOH, or by running the reaction under a hydrogen atmosphere. A borane (e.g., pinacolborane) is require

Full text of DOI:10.1021/jacs.7b02581

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Communication
Remarkably Facile Borane-Promoted, Rhodium-Catalyzed
Asymmetric Hydrogenation of Tri- and Tetrasubstituted Alkenes
Veronika M Shoba, and James M. Takacs
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b02581 • Publication Date (Web): 10 Apr 2017
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Remarkably Facile Borane-Promoted, Rhodium-Catalyzed Asym-
metric Hydrogenation of Tri- and Tetrasubstituted Alkenes
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Veronika M. Shoba and James M. Takacs*
Department of Chemistry, University of Nebraska-Lincoln, Lincoln NE 68588-0304 USA
Supporting Information Placeholder
Scheme 1. Contrasting reaction conditions for the
CAH of alkenes bearing similar substituents.
ABSTRACT: Oxime-directed catalytic asymmetric hydrobo-
ration is diverted to catalytic asymmetric hydrogenation
(CAH) upon the addition of a proton source, such as MeOH,
or by running the reaction under a hydrogen atmosphere. A
borane (e.g., pinacolborane) is required to promote CAH. Tri-
and tetrasubstituted alkenes, including the challenging all-al-
kyl tetrasubstituted alkenes, undergo CAH with enantiomer
ratios (er) as high as 99:1. The mild reaction conditions, i.e.,
ambient temperature, moderate reaction times, and the need
for only a slight excess of H2, contrast those used in most state-
of-the-art catalysts for related substrates.
Catalytic asymmetric hydrogenation (CAH) is a preeminent
example of asymmetric transition metal catalysis and among
the most widely used chemical transformations for introduc-
ing chirality in the pharmaceutical industry.1 Given its utility,
many chiral catalyst/substrate combinations have been devel-
oped to address different structural challenges in asymmetric
synthesis;2 however, relatively few are effective for the CAH of
tetrasubstituted alkenes. Furthermore, such catalysts are of-
ten limited to substrates wherein the π-system is activated by
aromatic substitution3 or α,β-conjugation with carboxylic ac-
ids or esters;4 certain enamide substrates can also be reduced
effectively.5 Even for these relatively narrowly defined groups
of substrates, successful CAH typically requires elevated tem-
perature and high pressure of H2.
The CAH conditions described above evolved from ongoing
studies directed toward the preparation of functionalized chi-
ral boronic esters via directed-catalytic asymmetric hydrobo-
ration (CAHB).8 Chiral boronic esters are versatile intermedi-
ates9 and especially useful for diversity-oriented synthesis.10
Consequently, the development of catalysts for CAHB is re-
ceiving much attention.11 We and others often find varying
amounts of the reduced alkene accompany the desired
borylated product under the conditions of rhodium- and other
metal-catalyzed hydroborations.12 For example, the formation
of chiral tertiary boronic ester 6a (77%, 94:6 er) via CAHB of
trisubstituted alkene (E)-5a (Scheme 2)13 is accompanied by
the reduced product 7a (15%, 60:40 er). To the best of our
knowledge, the mechanism for formation of the reduced by-
product has never been completely determined. Proto-
deborylation14 of an initially formed borylated product is a
possibility. The more common assumption is that the reduced
product is formed due to the presence of H2 resulting from
adventitious moisture (or other proton source) affecting par-
tial decomposition of the borane (e.g., pinBH).15
Recently, α-methyl-β-cyclopropyldihydrocinnamates were
identified as potentially important pharmacophores. A com-
prehensive study by Christensen, et al.6 evaluated the CAH of
tetrasubstituted cinnamate ester 1 using an extensive collec-
tion of catalyst systems. Rhodium catalysts examined in the
study are reported to give low yields of 2 due to the lability of
the vinyl cyclopropane moiety. However, ruthenium catalysts
incorporating Josiphos or JoSPOphos ligands give 2 with high
enantiomer ratios (er) as shown in Scheme 1. The reaction
conditions employ relatively high pressure (500 psi H2), ele-
vated temperature (80 °C), and an extended reaction time (20
h). Herein, we report the ability to reduce tri- and tetrasubsti-
tuted alkenes under exceptionally mild conditions. For exam-
ple, 1% [Rh(nbd)2BF4/(R)-B2]) catalyzes the CAH of the
tetrasubstituted alkene (Z)-3 at ambient temperature to afford
(2R,3S)-4 (95%, >25:1 dr, 95:5 er). H2 is presumably generated
in stoichiometric amount in situ from pinBH and MeOH.7
In support of the proposal that adventitious proton sources
enable reduction, we added slightly more than a stoichio-
metric equivalent of a proton source (1.2 equiv. MeOH) to the
mixture of substrate (E)-5a, catalyst, and pinBH (1.5 equiv.).
The yield of reduced product 7a increases to near quantitative
under those conditions; however, enantiomer ratio (er) re-
mains close to racemic. To improve the enantioselectivity, we
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the pinBH/MeOH or pinBH/H2 protocol; (R)-7b is obtained
Scheme 2. Oxime-directed rhodium-catalyzed CAH
using pinBH/MeOH or pinBH/H2.
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in near quantitative yield and high enantioselectivity (99:1 and
97:3 er, respectively).19 In contrast, we see no evidence for rho-
dium-catalyzed reduction of (E)-5b under H2 atmosphere up
to 50 psi (12 h) without pinBH present.
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8
Other trisubstituted substrates bearing an aryl substituent
in the 2-position (i.e., (E)-5c) or with simple alkyl substituents
in both positions (i.e., 5d and 5e) similarly give reduced prod-
ucts in high yield (87–97%) and with high levels of enantiose-
lectivity (94:6 er or greater). In the case of substrate 5f, ligand
B3 gives an improved level of enantioselectivity (95:5 er com-
pared to 92:8 using B2). For substrate 5g the er improves from
91:9 to 99:1 when starting with the (Z)-isomer. Substrate 5g il-
lustrates another important feature of the chemistry. While 5g
possesses two trisubstituted alkene moieties, only the double
bond proximal to the oxime moiety is reduced. Chiral sub-
strate (5S)-5h demonstrates good catalyst-controlled reduc-
tion. Either (2R,5S)- or (2S,5S)-7h (95:5 dr) is formed at will by
employing the (R)- or (S)-enantiomer of B2, respectively.
However, the resident allylic stereocenter in the related chiral
acetal (4S)-5i exerts modest influence leading to a matched
(99:1 dr) / mismatched (85:15 dr) case of double stereodiffer-
entiation.
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Unactivated, all-alkyl tetrasubstituted alkenes are generally
found to be very challenging substrates for CAH. Neverthe-
less, tetrasubstituted alkenes 8a and 8b correspondingly yield
9a and 9b with high enantioselectivity using the
pinBH/MeOH setting a single stereocenter in the course of
hydrogenation. Tetrasubstituted alkenes (E)-8c and (Z)-8c
demonstrate that hydrogenation proceeds via stereospecific
syn-addition. The (E)-isomer affords (2R,3S)-9c (95%, 92:8 er);
the (Z)-isomer affords (2R,3R)-9c (92%, 96:4 er). Similar re-
sults are obtained for (E)-and (Z)-8d. Aryl substituents are tol-
erated as illustrated above in the reduction of (Z)-3 to (2R,3S)-
4 (95%, 95:5 er) (Scheme 1). Using the pinBH/MeOH protocol,
screened variety of simple, chiral TADDOL- and BINOL-
derived phosphite and phosphoramidite ligands16 finding that
(R)-B2 gives (R)-7a with excellent yield and high enantioselec-
tivity (98%, 99:1 er).17 Similar results are obtained by omitting
MeOH but running the reaction under an atmosphere of H2.
Scheme 3 illustrates the scope of oxime-directed CAH of tri-
substituted and tetrasubstituted alkenes.18 In each example
shown, ([Rh(nbd)2BF4]/(R)-B2) is employed using the
pinBH/MeOH protocol; in selected cases, results are also re-
ported using the pinBH/H2 protocol or using (S)-B2. For ex-
ample, (E)-5b (R = Me, RE = Ph) undergoes CAH using either
Scheme 3. CAH of trisubstituted and tetrasubstituted alkenes.
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(E)-8e affords (2R,3R)-9e (90%, 93:7 er); (Z)-8e affords
Phosphoramidite ligands have been extensively studied in
rhodium-catalyzed CAH both from the synthetic26 and mech-
anistic perspectives.27 Scheme 5 outlines a simple unified
model, an “interrupted hydroboration” pathway,28 to account
for the apparent competition between CAH and CAHB29 un-
der the conditions described herein. Two-point binding of the
substrate (SM) to Rh and oxidative addition of pinBH gains
access to intermediate I. Insertion of the alkene into the Rh–
H bond would generate a species such as intermediate II. Re-
ductive elimination from II would afford the borylated prod-
uct (BP) with regeneration of intermediate I. Alternately,
1
2
3
4
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7
8
(2R,3S)-9e (88%, 97:3 er). The yield and er are improved for
(Z)-8e using the pinBH/H2 protocol; (2R,3S)-9e is obtained in
95% yield (99:1 er). The pinBH/H2 protocol also improves the
results obtained with the diaryl substrate 8f. (R)-9f is obtained
in a 75:25 er (82%) using pinBH/MeOH but in 95:5 er (95%
yield) using the pinBH/H2 protocol.
To demonstrate the synthetic utility of this CAH of
tetrasubstituted alkenes two simple natural products, (–)-en-
terodiol and (–)-lasiol, were prepared, albeit with a major sur-
prise revealed en route to each (Scheme 4). Two syntheses of
(–)-enterodiol have been published. The Feringa route fea-
tures the diastereoselective tandem conjugate addition to a
chiral alkoxybutenolide,20 and Sjöholm reported its prepara-
tion starting from hydroxymatairesinol.21 In the present route,
CAH of (E)-10 using (R)-B2 and the pinBH/MeOH protocol
proceeds in good yield with high diastereo- and enantioselec-
tivity (>25:1 dr, 99:1 er). Based upon correlations to known
compounds for seven of the reduced products shown above,
we expected the (R)-B2 catalyst would give (2R,3R)-11; how-
ever, in the event, (2S,3S)-11 was obtained. We can only spec-
ulate that the multiple potential ligating groups in 10 combine
to reverse the sense of π-facial discrimination for this sub-
strate. While mechanistically intriguing, the unexpected en-
antioswitching22 is of little consequence from a practical
standpoint. Given the simplicity of the ligand used, (S)-B2 is
equally accessible and affords (2R,3R)-11 (83%, 97:3 er). Cleav-
age of methyl and benzyl ethers and cleavage of the N–O bond
to remove the oxime directing group affords (–)-enterodiol.
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sigma-bond metathesis of rhodium-boryl complex II with H2
would generate the reduced product (RP) and, in the presence
of additional alkene substrate, regenerate intermediate II to
continue the cycle.
Scheme 5. Potential competing pathways for borane-
promoted CAHB and CAH.
Scheme 4. Syntheses of (–)-enterodiol and (–)-lasiol.
In summary, an unwanted side reaction leading to a reduc-
tion by-product during CAHB is turned into an efficient
method for oxime-directed, borane promoted CAH of chal-
lenging tri- and tetrasubstituted alkenes. To our knowledge,
this report constitutes the first examples using an oxime to di-
rect CAH as well as a new catalyst system for efficient CAH.
The mild reduction conditions, short reaction times, and the
need for only a slight excess above stoichiometric H2 contrast
those used in state-of-the-art catalysts even for activated
tetrasubstituted substrates. Stereospecific syn-hydrogenation
is enabled via the combination of a simple 1:1 [Rh(I)/chiral
phosphoramidite] catalyst system (e.g., [Rh(nbd)2BF4/(R)-
B2]), pinBH and H2, the latter either generated in situ or as
atmosphere above the reaction mixture. Borane is required for
reduction. The method works well for aryl-substituted alkene
substrates as well as for the more challenging case of all-alkyl
tetrasubstituted alkenes. In substrates bearing an additional
double bond, only the proximal alkene with respect to the ox-
ime moiety is reduced; however, the sense of π-facial selectiv-
ity can apparently be influenced by remote donor substitu-
ents. A simple catalytic cycle in which CAHB is diverted to
CAH via sigma bond metathesis of a rhodium–boryl interme-
diate with H2 can be drawn; however, the actual mechanism is
likely to be more complicated. Further studies and extension
of the method to other classes of substrates are in progress.
Three published routes to (–)-lasiol involve asymmetric ca-
talysis to set one of the two stereocenters: Kobayshi exploited
the 1,4-addition to an unsaturated amide;23 Feringa used en-
antioselective allylic alkylation followed by a diastereoselec-
tive conjugated addition;24 and Burgess exploited catalyst-
controlled CAH of a chiral trisubstituted alkene.25 Our route
is the first wherein the two chiral centers are generated in a
single step. CAH of (Z)-12 using the pinBH/MeOH protocol
again proceeds with opposite to the expected sense of stere-
oinduction necessitating the use of (R)-B2 to produce (2S,3S)-
13 (98%, 95:5 er) as required for the natural product. CAH is
selective for the proximal tetrasubstituted alkene in the pres-
ence of a trisubstituted double bond. Cleavage of the N–O
bond affords (–)-lasiol.
ASSOCIATED CONTENT
Supporting Information
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(8) Hoang, G. L.; Yang, Z.-D.; Smith, S. M.; Pal, R.; Miska, J. L.; Pé-
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Experimental procedures (PDF)
Spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
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jtakacs1@unl.edu
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ORCID
Veronika M. Shoba: 0000-0003-0402-7414
James M. Takacs: 0000-0002-1903-6535
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Funding from the NIH National Institutes of General Medical
Sciences (R01-GM100101) is gratefully acknowledged. We
thank L. S. W. Pelter (Purdue Northwest University) for help-
ful discussions and Z.-D. Yang (UNL) for some preliminary
computational studies.
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56
57
58
59
60
5
ACS Paragon Plus Environment