Cyclometalated Iridium-PhanePhos Complexes Are Active Catalysts in Enantioselective Allene-Fluoral Reductive Coupling and Related Alcohol-Mediated Carbonyl Additions That Form Acyclic Quaternary Carbon Stereocenters

Article abstract of DOI:10.1021/jacs.8b11868

Iridium complexes modified by the chiral phosphine ligand PhanePhos catalyze the 2-propanol-mediated reductive coupling of diverse 1,1-disubstituted allenes 1a-1u with fluoral hydrate 2a to form CF₃-substituted secondary alcohols 3a-3u that incorporate acyclic quaternary carbon-containing stereodiads. By exploiting concentration-dependent stereoselectivity effects related to the interconversion of kinetic (Z)- and thermodynamic (E)-σ-allyliridium isomers, adducts 3a-3u are formed with complete levels of branched regioselectivity and high levels of anti-diastereo- and enantioselectivity. The utility of this method for construction of CF₃-oxetanes and CF₃-azetidines is illustrated by the formation of 4a and 6a, respectively. Studies of the reaction mechanism aimed at illuminating the singular effectiveness of PhanePhos as a supporting ligand in this and related transformations have led to the identification of a chromatographically stable cyclometalated iridium-(R)-PhanePhos complex, Ir-PP-I, that is catalytically competent for allene-fluoral reductive coupling and previously reported transfer hydrogenative C-C couplings of dienes or CF₃-allenes with methanol. Deuterium labeling studies, reaction progress kinetic analysis (RPKA) and computational studies corroborate a catalytic mechanism involving rapid allene hydrometalation followed by turnover-limiting carbonyl addition. A computationally determined stereochemical model shows that the ortho-CH₂ group of the cyclometalated iridium-PhanePhos complex plays a key role in directing diastereo- and enantioselectivity. The collective data provide key insights into the structural-interactional features of allyliridium complexes required to enforce nucleophilic character, which should inform the design of related cyclometalated catalysts for umpoled allylation.

Full text of DOI:10.1021/jacs.8b11868

Article
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Cyclometalated Iridium−PhanePhos Complexes Are Active Catalysts
in Enantioselective Allene−Fluoral Reductive Coupling and Related
Alcohol-Mediated Carbonyl Additions That Form Acyclic Quaternary
Carbon Stereocenters
†
†
†
̧
lves,‡ Jeffery Richardson,§
́
Leyah A. Schwartz, Michael Holmes, Gilmar A. Brito, Theo P. Gonca
J. Craig Ruble,⊥ Kuo-Wei Huang,‡ and Michael J. Krische*,†
†Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
‡KAUST Catalysis Center and Division of Physical Sciences and Engineering, King Abdullah University of Science and Technology
(KAUST), Thuwal 23955-6900, Saudi Arabia
§Discovery Chemistry Research and Technologies, Eli Lilly and Company Limited, Erl Wood Manor, Windlesham, Surrey GU20
6PH, United Kingdom
⊥Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
S
* Supporting Information
ABSTRACT: Iridium complexes modified by the chiral
phosphine ligand PhanePhos catalyze the 2-propanol-medi-
ated reductive coupling of diverse 1,1-disubstituted allenes
1a−1u with fluoral hydrate 2a to form CF3-substituted
secondary alcohols 3a−3u that incorporate acyclic quaternary
carbon-containing stereodiads. By exploiting concentration-
dependent stereoselectivity effects related to the interconver-
sion of kinetic (Z)- and thermodynamic (E)-σ-allyliridium
isomers, adducts 3a−3u are formed with complete levels of
branched regioselectivity and high levels of anti-diastereo- and
enantioselectivity. The utility of this method for construction
of CF3-oxetanes and CF3-azetidines is illustrated by the
formation of 4a and 6a, respectively. Studies of the reaction
mechanism aimed at illuminating the singular effectiveness of PhanePhos as a supporting ligand in this and related
transformations have led to the identification of a chromatographically stable cyclometalated iridium−(R)-PhanePhos complex,
Ir-PP-I, that is catalytically competent for allene−fluoral reductive coupling and previously reported transfer hydrogenative C−
C couplings of dienes or CF3-allenes with methanol. Deuterium labeling studies, reaction progress kinetic analysis (RPKA) and
computational studies corroborate a catalytic mechanism involving rapid allene hydrometalation followed by turnover-limiting
carbonyl addition. A computationally determined stereochemical model shows that the ortho-CH2 group of the cyclometalated
iridium−PhanePhos complex plays a key role in directing diastereo- and enantioselectivity. The collective data provide key
insights into the structural−interactional features of allyliridium complexes required to enforce nucleophilic character, which
should inform the design of related cyclometalated catalysts for umpoled allylation.
carbon stereocenters that operate under non-cryogenic
conditions and are completely atom-efficient, bypassing the
use of stoichiometric metals.6 In these processes, vinyl
epoxides,6a 1,3-dienes6b and CF3-allenes6c serve as pronucleo-
philes.
With the latter two pronucleophiles, iridium complexes
modified by the chiral phosphine ligand PhanePhos7 were
uniquely effective in catalyzing highly regio- and enantio-
selective methanol-mediated formaldehyde additions.6b,c,8
Other chelating phosphine ligands were completely inactive
INTRODUCTION
■
Diverse catalytic enantioselective methods enabling formation
of quaternary carbon stereocenters that reside within cyclic
frameworks have been reported.1 In contrast, catalytic
enantioselective methods that deliver acyclic quaternary carbon
stereocenters remain relatively uncommon.1a,g,2,3 Even more
elusive are asymmetric methods that deliver (a) acyclic
quaternary carbon-containing stereopolyads3 or (b) fluorinated
acyclic quaternary carbon-containing structural motifs.4 In the
course of developing catalytic enantioselective carbonyl
reductive couplings via alcohol-mediated hydrogen transfer
or hydrogen auto-transfer,5 we recently developed enantio-
selective methods for the formation of acyclic quaternary
Received: November 4, 2018
© XXXX American Chemical Society
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Figure 2. Relative and absolute stereoselection in 2-propanol-
mediated reductive couplings of allenes with fluoral hydrate via
concentration-dependent diastereoselectivity. Diastereoselectivities
were determined by 19F NMR of crude reaction mixtures.
Enantioselectivities were determined by chiral stationary phase
HPLC analysis. Yields reported are for material isolated by silica gel
chromatography. See Supporting Information for further experimental
details.
rendered uncertain by two issues. First, fluoral is only
commercially available as the hydrate or hemiacetal, yet the
vast majority of enantioselective metal-catalyzed fluoral
additions require use of anhydrous fluoral.4 Second, high
levels of stereoselectivity require not only discrimination of
enantiotopic carbonyl π-faces but also intervention of a single
geometrical isomer of the σ-allyliridium nucleophile. The latter
issue is further complicated by the fact that hydroiridation of
1,1-disubstituted allenes occurs preferentially at the allene π-
face proximal to the smaller allene substituent (Rs) to furnish
the less stable (Z)-σ-allyliridium isomer. Hence, notwithstand-
ing Curtin−Hammett effects,15 in order to form the quaternary
carbon stereocenter with optimal levels of stereoselectivity,
either kinetic stereoselectivity favoring formation of the (Z)-σ-
allyliridium isomer must be preserved or equilibration between
the (Z)- and (E)-σ-allyliridium isomers must be achieved prior
to carbonyl addition with complete conversion to the latter
(Figure 2). The difference in energy between (Z)- and (E)-2-
phenyl-2-butenes is more than 1 kcal/mol, and greater
energetic differentiation is anticipated for the corresponding
(Z)- and (E)-σ-allyliridium species.16
With these considerations in mind, the following series of
experiments was performed (Figure 2). Allene 1a (200 mol%),
fluoral hydrate 2a (100 mol%, 75 wt% in water), and 2-
propanol (200 mol%) were exposed to the iridium catalyst
derived from [Ir(cod)Cl]2 (2.5 mol%) and (R)-PhanePhos (5
mol%) in tert-butanol (0.5 M) at 100 °C. In the absence of
desiccant, only a trace quantity of the targeted reductive
coupling product 3a was observed. However, upon addition of
4 Å molecular sieves, compound 3a was formed in 43% yield as
a 5:1 mixture of diastereomers in 96% enantiomeric excess. In
accord with our stereochemical analysis, it was reasoned that
more dilute conditions might increase diastereoselectivity by
decreasing the rate of carbonyl addition with respect to the rate
of equilibration between the (Z)- and (E)-σ-allyliridium
Figure 1. Diverse catalytic activities of cyclometalated iridium
complexes and the identification of a catalytically competent
cyclometalated iridium−PhanePhos complex.
in these processes. The singular effectiveness of the iridium−
PhanePhos catalyst prompted further exploration of its
capabilities and investigations into the precise nature of the
catalytically active species. Here, we report that the iridium
complex derived from [Ir(cod)Cl]2 and PhanePhos catalyzes
highly regio-, diastereo- and enantioselective allene−fluoral
reductive couplings mediated by 2-propanol to form acyclic
quaternary carbon-containing stereodiads.9−12 Of greater
significance, these studies have led to the identification of a
cyclometalated iridium−PhanePhos complex that is catalyti-
cally competentnot only in the present transformation but
also in previously reported iridium−PhanePhos-catalyzed
reactions developed in our laboratory.6b,c This complex
contributes to a growing collection of cyclometalated iridium
complexes that display diverse catalytic activities (Figure 1).13
RESEARCH DESIGN AND METHODS
■
Reaction Optimization, Scope, and Applications.
Prior work in our laboratory on enantioselective iridium−
PhanePhos-catalyzed C−C coupling focused on methanol-
mediated formaldehyde additions.6b,c Steric issues posed by the
formation of a more highly substituted quaternary carbon C−
C bond prohibited reactions of higher aldehydes. It was
posited that fluoral, a highly reactive carbonyl electrophile like
formaldehyde, might participate in alcohol-mediated reductive
coupling to provide acyclic quaternary carbon stereodiads
incorporating a trifluoroethyl carbinol fragment.14 However,
the feasibility of allene−fluoral reductive coupling was
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Table 1. Variation of Aryl Substituent in Iridium-Catalyzed
Coupling of Allenes 1a−1o with Fluoral Hydrate 2a To
Form Adducts 3a−3o Bearing Acyclic Quaternary Carbon
Table 2. Variation of Alkyl Substituent in Iridium-Catalyzed
Coupling of Allenes 1p−1u with Fluoral Hydrate 2a To
Form Adducts 3p−3u Bearing Acyclic Quaternary Carbon
a
a
Stereocenters
Stereocenters
a
Diastereoselectivities were determined by 19F NMR of crude
reaction mixtures. Enantioselectivities were determined by chiral
stationary phase HPLC analysis. Yields reported are for material
isolated by silica gel chromatography. See Supporting Information for
further experimental details.
enantiomeric excess. Diastereoselectivity remained constant at
80, 90 and 100 °C, and at lower temperatures conversion
decreased precipitously, so diastereoselectivity was not
calculated.
These optimized conditions were applied to the reductive
coupling of 1,1-disubstituted allenes 1a−1o bearing aryl and
methyl groups with fluoral hydrate 2a (Table 1). Allenes 1b−
1k bearing aryl moieties with diverse substitution patterns and
electronic properties are converted to adducts 3b−3k in good
yield with uniformly high levels of regio-, diastereo- and
enantioselectivity. Notably, functional groups that are poten-
tially susceptible to reduction, for example nitro groups (3j)
and ketones (3k), remain intact. Heteroaryl-substituted allenes
1l−1o are also effective partners for reductive coupling,
providing adducts 3l−3o with high levels of relative and
absolute stereocontrol. For N-heterocycles, at least one ortho-
substituent adjacent to nitrogen is required for high levels of
conversion.
a
Diastereoselectivities were determined by 19F NMR of crude
reaction mixtures. Enantioselectivities were determined by chiral
stationary-phase HPLC analysis. Yields reported are for material
isolated by silica gel chromatography. 8 h. See Supporting
Information for further experimental details.
b
To test the limits of stereoselectivity, 1,1-disubstituted
allenes 1p−1u bearing higher alkyl substituents were evaluated
in reductive couplings to fluoral 2a (Table 2). Remarkably,
although increasing size of the alkyl moiety was anticipated to
erode partitioning of the transient (E)- and (Z)-σ-allyliridium
isomers, excellent levels of stereocontrol were retained in
reactions of allenes 1p−1u that incorporate linear alkyl groups.
In contrast, attempted reactions of allenes bearing branched
alkyl groups, for example, cycloalkyl moieties, were low-
yielding and non-diastereoselective. The absolute stereo-
chemical assignment of all adducts 3a−3u is made in analogy
to that established for the 3,5-dinitrobenzoate of 3d, which was
determined by single-crystal X-ray diffraction analysis.
To briefly illustrate the utility of the reaction products,
fluoral adduct 3a was converted to the CF3-oxetane 4a, which
isomers.15 Indeed, in the event, diastereoselectivity was found
to increase with increasing dilution, and at 0.05 M a 13:1
diastereomeric ratio was observed without any erosion of
enantioselectivity, although under these dilute conditions the
isolated yield of 3a suffered. In the course of our optimization
experiments, we also observed that more Lewis basic solvents
promote higher diastereoselectivities. This fact led us to
explore the effect of halide additives. To our delight,
introduction of Bu4NCl (100 mol%) not only improved
diastereoselectivity but also increased the isolated yield of 3a.
At 0.2 M in the presence of Bu4NCl, compound 3a was formed
in 78% yield as a 17:1 mixture of diastereomers with a 96%
C
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bears a quaternary carbon stereocenter (eq 1).17 Oxetanes
have emerged as useful building blocks in medicinal chemistry
due to their ability to serve as carbonyl and gem-dimethyl
isosteres.18 Recently, CF3-oxetanes were shown to function as
more polar tert-butyl isosteres.19 To prepare CF3-oxetane 4a,
fluoral adduct 3a was transformed to the mesylate and
subjected to ozonolysis conditions. The resulting primary
alcohol was exposed to sodium hydride to provide oxetane 4a
(eq 1). As corroborated by the conversion of primary tosylate
5a to oxetane 4a (eq 2), the formation of 4a proceeds via
secondary to primary methanesulfonate transfer. Just as
trifluoroethylamines serve as amide bioisosteres,20 CF3-
azetidines21 may be viewed as β-lactam mimics. To prepare
CF3-azetidine 6a, fluoral adduct 3a was converted the mesylate
and subjected to ozonation conditions to deliver the
corresponding aldehyde. Reductive amination−cyclization
provided CF3-azetidine 6a (eq 3).
Figure 3. Structure of the cyclometalated iridium−(R)-PhanePhos
complex Ir-PP-I as determined by single-crystal X-ray diffraction.
Displacement ellipsoids are scaled to the 50% probability level. See
Supporting Information for further details.
ortho-carbon atom of the cyclophane ring. For an iridium
center, which has a larger atomic radius, one could easily
imagine an agostic interaction or C−H oxidative addition to
form a cyclometalated complex. With these thoughts in mind,
an effort was made to prepare a cyclometalated iridium−
PhanePhos complex and evaluate its catalytic activity.
In the event, heating a THF solution of [Ir(cod)Cl]2 (100
mol%), (R)-PhanePhos (200 mol%) and allyl acetate (400 mol
%) at 100 °C for 1 h gave a yellow residue, which upon flash
silica gel column chromatography delivered the 4-membered
metallacycle Ir-PP-I in up to 60% yield. The structural
assignment of Ir-PP-I was corroborated by single-crystal X-
ray diffraction analysis (Figure 3). The cyclometalated iridium
complex is of distorted octahedral geometry, with the two
phosphorus atoms of PhanePhos and acetate lying in the same
plane and with the chloride and aryl moieties apical to the
plane. The distance between the phosphorus atoms (3.34 Å) is
noticeably less than that found in the related square planar
Pd(rac-PhanePhos)Cl2 complex (3.62 Å).22 Additionally, the
P−Ir−P “bite angle” (95.90°) is significantly compressed
compared to that found in the palladium complex (103.69°).22
The P−Ir−C bond angle of the iridacycle is 67.95°, with an
Ir−C bond length of 2.04 Å. The bond length of the
cyclometalated Ir−P is 2.24 Å, which is slightly shorter than
the other Ir−P bond, which has a bond length of 2.26 Å. The
differential trans influence of these two phosphorus atoms is
reflected by the disparity between the two Ir−O bond lengths
of the acetate moiety. The Ir−O bond that is trans to the
activated phosphorus atom has a bond length of 2.19 Å, which
is slightly longer than the Ir−O bond trans to the non-
cyclometalated phosphorus atom, which has a bond length of
2.15 Å.
Identification of a Catalytically Competent Cyclo-
metalated Complex. Insight into the unusual effectiveness of
the iridium−PhanePhos catalyst was essential in terms of
formulating an accurate interpretation of the catalytic
mechanism. Products of allene−fluoral reductive coupling
were not formed upon use of other chelating phosphine ligands
such as BINAP or SEGPHOS under otherwise identical
conditions. The same is true for previously reported iridium−
PhanePhos-catalyzed couplings of methanol with 1,3-dienes6b
and CF3-allenes.6c Consequently, the fact that cyclometalated
π-allyliridium C,O-benzoate complexes (Figure 1)13c promote
C−C coupling in the aforesaid processes (albeit with
suboptimal levels of stereocontrol) was deemed significant.
This observation raised the question of whether the unique
topology of PhanePhos rendered this ligand susceptible to
cyclometalation. Although cyclometalated complexes of
PhanePhos have not been reported, a relatively short contact
of 3.56 Å is found in the X-ray crystal structure of a
palladium−PhanePhos complex22 between metal and the
To probe the catalytic competency of the cyclometalated
complex, allene 1e was exposed to fluoral hydrate 2a in the
presence of Ir-PP-I (5 mol%) under otherwise standard
conditions. The product of reductive coupling 3e was formed
in 72% yield in a 14:1 diastereomeric ratio and 96%
enantiomeric excess (eq 4 in Figure 4). Similarly, allene 1p
was exposed to fluoral hydrate 2a in the presence of Ir-PP-I (5
mol%) under otherwise standard conditions to furnish the
reductive coupling product 3p in 62% yield in a 16:1
diastereomeric ratio and 93% enantiomeric excess (eq 5 in
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prepared and subjected to standard reaction conditions and
was not a competent partner for C−C coupling. The coupling
of 1a and 2a mediated by d8-2-propanol under otherwise
standard conditions delivers deuterio-3a′ (eq 9). Deuterium is
incorporated exclusively at the interior vinylic position (15%
2H). Exchange between iridium hydrides and the deuterium
atoms of D2O is well-documented,23 and incomplete
deuterium incorporation is likely due to H−D exchange with
tert-butanol or water associated with aqueous fluoral hydrate.
Consistent with this hypothesis, when the reaction is
conducted in d10-tert-butanol or toluene, enhanced levels of
deuterium incorporation are observed (eq 9).
The collective data are consistent with the indicated catalytic
mechanism (Scheme 1). Entry into the catalytic cycle is
achieved via C−H oxidative addition of the ortho-C−H bond
of PhanePhos to iridium(I). Allene hydrometalation from the
resulting iridium(III) hydride I delivers the kinetic (Z)-σ-
Figure 4. Corroboration of catalytic competency of Ir-PP-I for all
iridium−(R)-PhanePhos-catalyzed transfer hydrogenative carbonyl
additions. Diastereoselectivities were determined by NMR analysis of
crude reaction mixtures. Enantioselectivities were determined by
chiral stationary-phase HPLC analysis. Yields reported are for material
isolated by silica gel chromatography. See Supporting Information for
further experimental details.
Scheme 1. Proposed Catalytic Mechanism for Iridium−
PhanePhos-Catalyzed Allene−Fluoral Reductive Coupling
Mediated by 2-Propanol
Figure 4). These data are in good alignment with the yields
and stereoselectivities observed in reactions in which the
catalyst is generated in situ from [Ir(cod)Cl]2 (2.5 mol%) and
(R)-PhanePhos (5 mol%) (Tables 1 and 2, respectively). The
cyclometalated complex Ir-PP-I is also a competent catalyst in
the previously reported iridium−PhanePhos-catalyzed cou-
plings of methanol with 1,3-dienes (eq 6 in Figure 4)6b and
CF3-allenes (eq 7 in Figure 4).6c These data (eqs 4−7)
corroborate intervention of a cyclometalated catalyst related to
Ir-PP-I in the present allene−fluoral reductive coupling and the
previously reported transfer hydrogenative C−C couplings of
dienes6b or CF3-allenes.6c While roughly equivalent stereo-
selectivities are observed using the preformed complex Ir-PP-I,
slightly lower yields are evident. This may be due to the fact
that the catalyst generated in situ incorporates a monodentate
chloride counterion, whereas Ir-PP-I contains a bidentate
acetate counterion, which may inhibit catalysis.
Deuterium Labeling Studies and General Catalytic
Mechanism. To gain further insight into the catalytic
mechanism, a series of deuterium labeling experiments were
conducted (eqs 8 and 9). Exposure of fluoral hydrate 2a to
deuterio-1a, which incorporates a fully deuterated methyl
group, under standard reaction conditions delivers deuterio-3a
(eq 8). Deuterium is completely retained at the methyl group
and is not redistributed to any other position. This experiment
demonstrates that the reaction does not proceed by way of
allene-to-diene isomerization. Indeed, the isomeric diene was
E
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Figure 5. Product formation as monitored by GC analysis in reactions carried out utilizing “different excess” protocol: [cat] = 0.005 M; [TBAC] =
0.1 M; [2-propanol] = 0.2 M; (a) [2a]0 = 0.1 M, [1a]0 = as noted; (b) [1a]0 = 0.2 M, [2a]0 = as noted. (c) Time adjustment of product formation
in varying catalyst loading reactions as monitored by GC analysis: [1a] = 0.2 M; [2a] = 0.1 M; [TBAC] = 0.1 M; [2-propanol] = 0.2 M; [cat] = as
noted.
allyliridium isomer IIa. Isomerization to the thermodynami-
cally preferred (E)-σ-allyliridium isomer IIb is followed by
association of fluoral and carbonyl addition to furnish the
homoallylic iridium(III) alkoxide IV. Alkoxide exchange with
2-propanol releases the product of carbonyl addition 3a. β-
Hydride elimination from the 2-propoxyiridium(III) species V
regenerates the iridium(III) hydride I to close the catalytic
cycle. Knowing that the active catalyst is a cyclometalated
halide-containing iridium(III) complex, one can better under-
stand how halides “tune” the environment at the iridium center
to influence reactivity and selectivity. In the present trans-
formation, the additive Bu4NCl may assist by preserving
chloride at the iridium(III) center, while in previously reported
couplings of methanol with CF3-allenes,6c Bu4NI likely
substitutes the chloride at iridium(III).
Reaction Progress Kinetic Analysis. To gain further
mechanistic insight, reaction progress kinetic analysis (RPKA)
was applied to the coupling of allene 1a with fluoral hydrate 2a
to form adduct 3a.24,25 Due to the volatile nature of the
reactants and the complex equilibria between fluoral, fluoral
hydrate and hemiacetals that arise upon addition of 2-propanol
and tert-butanol, the progress of a single reaction could not be
monitored. Therefore, a series of reactions were conducted in
parallel: for each successive time point, an individual reaction
was stopped and the extent of product formation was
determined by GC analysis using an internal standard. As
each data point derives from a separate experiment, the quality
of the data was not ideal; nevertheless, several significant
conclusions could be drawn.
Computational Studies. Initial computational studies
were aimed at formulating a unified stereochemical model
accounting for relative and absolute stereochemistry in the
present and prior6b,c iridium−(R)-PhanePhos-catalyzed trans-
fer hydrogenative carbonyl additions (eqs 4−7 in Figure 4).
Accordingly, 48 different conformations based on a Zimmer-
man−Traxler-type transition structure27 were thus computa-
tionally analyzed to identify the transition state with the lowest
energy barrier (see Supporting Information). In the most
favored transition state (Figure 6), the σ-allyl occupies a
coordination site that minimizes steric repulsion with the CH2
moiety of the cyclophane ethano linkage that resides ortho to
iridium. At the same time, nonbonded interactions between
the terminal aryl moiety of the σ-allyl and the cyclometalated
phenyl ring are decreased. The carbonyl electrophile, fluoral,
can then enter the coordination site trans to the PPh2 moiety
of the iridacycle and syn to Ir−Cl with the CF3 pointing away
from the Ir center. The orientation of the fluoral C−H bond
suggests possible intervention of a formyl C−H bond with the
chloride ligand.28 Addition of the σ-allyl to the Si-face of the
carbonyl through a closed transition structure defines enantio-
topic π-facial selectivity. This model is also applicable to
iridium−(R)-PhanePhos-catalyzed couplings of methanol with
1,3-dienes6b and CF3-allenes.6c
Computational studies were used to further assess the
veracity of our interpretation of the catalytic mechanism
(Scheme 2). Allene hydrometalation from intermediate I, an
iridium(III) hydride−allene complex, delivers the kinetic (Z)-
The results of experiments carried out using the “different
excess” protocol elucidate the order in allene 1a and fluoral
hydrate 2a (Figure 5). The observed overlap between data sets
indicates zero-order kinetics in allene, since the rate of product
formation is not affected by the change of initial concentration
of allene (Figure 5, left). In contrast, higher concentrations of
2a result in faster rates of product formation, which suggests a
positive order in fluoral (Figure 5, middle). Evaluation of the
26
́
effect of increasing catalyst loading using Bures’s method
suggests the reaction is first order in catalyst (Figure 5, right).
Furthermore, results of a set of experiments performed using
the “same excess” protocol indicate minimal catalyst
deactivation occurs (see Supporting Information). These
data corroborate a catalytic mechanism involving rapid allene
hydrometalation followed by turnover-limiting carbonyl
addition (Scheme 1). These data also implicate the π-
allyliridium species, which could be detected via high-
resolution mass spectrometry as the catalyst resting state.
Figure 6. Computationally determined stereochemical model
accounting for relative and absolute stereochemistry for all iridium−
(R)-PhanePhos-catalyzed transfer hydrogenative carbonyl additions.
See Supporting Information for details on computational studies.
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a
Scheme 2. Computationally Determined Energy Profiles of the Proposed Catalytic Mechanism
a
See Supporting Information for details on computational studies.
σ-allyliridium isomer IIb, which can interconvert with the
thermodynamically preferred (E)-σ-allyliridium isomer IIa.
The Curtin−Hammett situation15 favors the reaction to
proceed by association of fluoral to IIIa followed by carbonyl
addition via TS2-E to furnish the homoallylic iridium(III)
alkoxide IVa. Alkoxide exchange with 2-propanol releases the
product of carbonyl addition 3a and regenerates the iridium-
(III) hydride coordinated with an allene after β-hydride
elimination to close the catalytic cycle. Consistent with the
excellent levels of diastereo- and enantioselectivity that are
observed, the transition state leading to the disfavored
enantiomer, TS2-E-2R3S, requires the fluoral carbonyl group
to become anti-periplanar to the Ir−Cl bond, which results in a
higher energy barrier due to the increased steric interactions
with the cyclometalated phenyl ring and the ortho-CH2 group
of the PhanePhos ligand. Within the same core geometry at
iridium, the second lowest transition state, TS2-Z-2S3S, will
afford a diastereomer from the (Z)-isomer IIb with the same
stereoselectivity for the allylation of fluoral. Notably, both
computational studies and RPKA implicate rapid allene
hydrometalation followed by turnover-limiting carbonyl
addition with the allyliridium species as a potential catalyst
resting state.
present fluoral−allene reductive couplings and previously
reported iridium−PhanePhos-catalyzed C−C couplings of
methanol with dienes6b or CF3-allenes.6c Future studies will
focus on the discovery and development of related umpoled
allylations29 via alcohol-mediated carbonyl addition catalyzed
by cyclometalated iridium−PhanePhos complexes.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b11868.
■
S
Experimental procedures and spectral data; HPLC traces
of racemic and enantiomerically enriched products;
crystallographic data for the 3,5-dinitrobenzoate of 3d
and the cyclometalated iridium−(R)-PhanePhos com-
plex Ir-PP-I (PDF)
Reaction progress kinetic analysis data and data
pertaining to computational studies (PDF)
X-ray crystallographic data for 3d (CIF)
AUTHOR INFORMATION
Corresponding Author
*mkrische@mail.utexas.edu
■
CONCLUSIONS
■
ORCID
In summary, we report a highly regio- and enantioselective
iridium-catalyzed allene−fluoral reductive coupling mediated
by 2-propanol. This method enables generation of enantio-
merically enriched quaternary carbon stereocenters in the
context of a CF3-bearing stereodiad. Of greater significance, we
have identified a chromatographically stable cyclometalated
iridium−(R)-PhanePhos complex, Ir-PP-I, that is catalytically
competent in the present allene−fluoral reductive couplings as
well as previously reported iridium−PhanePhos-catalyzed C−
C couplings of methanol with dienes6b or CF3-allenes.6c These
findings suggest that cyclometalated iridium−PhanePhos
complexes akin to Ir-PP-I may constitute a privileged catalyst
class. A catalytic mechanism involving rapid allene hydro-
metalation followed by turnover-limiting carbonyl addition was
corroborated by deuterium labeling studies, reaction progress
kinetic analysis (RPKA) and DFT calculations. Computational
studies also were used to formulate a unified stereochemical
model that accounts for the origins of enantioselectivity in the
Jeffery Richardson: 0000-0002-4450-3828
J. Craig Ruble: 0000-0002-9551-1529
Kuo-Wei Huang: 0000-0003-1900-2658
Michael J. Krische: 0000-0001-8418-9709
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038), the NIH (RO1-
GM069445, 1 S10 OD021508-01), and King Abdullah
University of Science and Technology (KAUST) are acknowl-
edged for partial support of this research. Eli Lilly and
Company is acknowledged for LIFA postdoctoral fellowship
̀
funding (M.H.). Fundaca̧ o de Amparo a Pesquisa do Estado de
̃
Sao Paulo (FAPESP) is acknowledged for postdoctoral
fellowship support (G.B. 2017/00734-5). We thank Professor
Donna G. Blackmond for assistance with RPKA. The service of
̃
G
DOI: 10.1021/jacs.8b11868
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