Kinetic resolution of racemic allylic alcoholsviairidium-catalyzed asymmetric hydrogenation: scope, synthetic applications and insight into the origin of selectivity

Article abstract of DOI:10.1039/d0sc05276k

Asymmetric hydrogenation is one of the most commonly used tools in organic synthesis, whereas, kinetic resolutionviaasymmetric hydrogenation is less developed. Herein, we describe the first iridium catalyzed kinetic resolution of a wide range of trisubstituted secondary and tertiary allylic alcohols. Large selectivity factors were observed in most cases (sup to 211), providing the unreacted starting materials in good yield with high levels of enantiopurity (ee up to >99%). The utility of this method is highlighted in the enantioselective formal synthesis of some bioactive natural products including pumiliotoxin A, inthomycin A and B. DFT studies and a selectivity model concerning the origin of selectivity are presented.

Full text of DOI:10.1039/d0sc05276k

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Kinetic Resolution of Racemic Allylic Alcohols via Iridium-
Catalyzed Asymmetric Hydrogenation: Scope, Synthetic
Applications and Insight into the Origin of Selectivity†
Received 00th January 20xx,
Accepted 00th January 20xx
Haibo Wu,a Cristiana Margarita,a Jira Jongcharoenkamol,a‡ Mark D. Nolan,a Thishana Singhb and
DOI: 10.1039/x0xx00000x
Pher G. Andersson*ab
Asymmetric hydrogenation is one of the most commonly used tools in organic synthesis, whereas, kinetic resolution via
asymmetric hydrogenation was less developed. Herein, we describe the first iridium catalyzed kinetic resolution of a wide
range of trisubstituted secondary and tertiary allylic alcohols. Large selectivity factors were observed in most cases (s up to
211), providing the unreacted starting materials in good yield with high levels of enantiopurity (ee up to >99%). The utility
of the method is highlighted by the enantioselective formal synthesis of some bioactive natural products including
pumiliotoxin A , inthomycin A and B. DFT studies and selectivity model concerning the origin of selectivity are presented.
reported an impressive KR of saturated aliphatic alcohols via
iridium catalyzed asymmetric hydrogenation of ester (Fig.1b),7
showing excellent selectivity and high efficiency without the
need to convert the OH group to other functionalities. By using
rhodium catalysts, Vidal-Ferran et al. developed the KR of
racemic vinyl sulfoxides and vinyl phosphane oxides via
hydrogenation of terminal olefin (Fig.1c).8 Despite these
progresses, there is still no general hydrogenation protocol
available for KR of a wide range of allylic alcohols.
Introduction
The demand for enantiomerically pure alcohols is steadily
increasing. In particular, chiral allylic alcohols have tremendous
synthetic relevance to natural products, pharmaceuticals,
agricultural chemicals and specialty materials.1 Kinetic
resolution (KR) is a useful and direct approach to access such
compounds, in a manner where they are obtained in high
enantiopurity, from inexpensive racemic starting material.1c
Notably, KR is also one of the most common methods that is
used to prepare optically active alcohols on an industrial
scale.2
Transition-metal catalyzed asymmetric hydrogenation3 is one
of the most efficient and well-established transformations in
asymmetric catalysis. Owing to its perfect atom economy and
excellent enantioselectivity, this process was frequently used
in the preparation of enantiomericially enriched compounds in
both academia and industry. However, when compared with
other fundamental transformations such as epoxidation4 and
acylation,5 its application in kinetic resolution is still a far less
explored and challenging task. Pioneering work in this field
was described by Noyori et al. in 1988 using the Ru-BINAP
catalyst system (Fig.1a), which was initially found to be
efficient for few aliphatic cyclic substrates.6 In 2015, Zhou et al.
a.Department of Organic Chemistry, Stockholm University, Arrhenius Laboratory,
106 91, Stockholm, Sweden. Email: pher.andersson@su.se
b.School of Chemistry and Physics, University of Kwazulu-Natal, Private Bag
X54001, Durban, 4000, South Africa.
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
‡ Present address: Chulabhorn Graduate Institute, Chulabhorn Royal Academy, 54
Kamphaeng Phet 6 Road, Laksi, Bangkok 10210, Thailand
Fig.1 Kinetic resolution via asymmetric hydrogenation
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Over the past two decades, our group has developed a variety
of iridium N,P complexes, which were successfully employed in
asymmetric hydrogenation of different types of olefins with
different functionalities.9 As a continuous interest, further
application of asymmetric hydrogenation in kinetic resolution
of allylic substrates is highly desired. Iridium catalyzed
asymmetric hydrogenation of primary allylic alcohols has been
well developed.10 In contrast, the secondary or tertiary allylic
alcohols were found to be challenging substrates10 for iridium
catalyzed asymmetric hydrogenation due to the Lewis or
Brønsted acidity of transition-metal-hydride complexes11
whereas these alcohols are relatively acid-sensitive. There are
several known competing transformations such as allylic
substitution,12 elimination,13 and isomerization14 that likely
occur when iridium hydride species are involved. Additionally,
the selective hydrogenation of one olefin in the presence of
another olefin is still a generally unsolved but useful task.15
Herein, we disclose the first iridium-catalyzed KR of racemic
secondary and tertiary allylic alcohols via asymmetric
hydrogenation.
Table.1 Development of kinetic resolution of allylic alcohol via
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DOI: 10.1039/D0SC05276K
asymmetric hydrogenationa
Results and discussion
We began our investigation using racemic allylic alcohol 1a and
the Ir-N,P thiazole-based catalyst
A in the screening (Table 1).
Preliminary results obtained without an additive (entry 1)
showed the allylic alcohol was hydrogenated in high
conversion (89%) under 1 bar of H2 and 0.5% catalyst loading
and the remaining starting material had very low ee (11%).
When AcOH was used as the additive (entry 2), the conversion
was similar (91%), and the remaining alcohol 1a did not show
any enantiomeric enrichment. These results indicated that,
even in absence of an acid, the acidity of the Ir-N,P catalyst
under hydrogenation conditions was sufficient to enable the
process of carbocation formation. To our delight, upon
addition of a small amount of base the reaction proceeded
cleanly and only hydrogenated product and remaining starting
material could be observed in the reaction mixture. A number
of different bases were screened, either at 10 or 20 mol%
loading. The use of K3PO4 (entry 3) provided 43% conversion
and 63% ee of 1a, which corresponded to kinetic resolution
with a good level of selectivity (Table 1). Then KOAc was
evaluated (entry 4) and even at a lower loading, it afforded a
slightly better result than the previous one, increasing the
selectivity of the reaction to s = 24. The use of K2CO3 had a
significant effect and enhanced the KR performance (entry 5).
With 20 mol% base a conversion slightly higher than ideal (55%)
was observed, and 1a was resolved to an excellent ee. This
corresponded to the highest selectivity factor for this substrate
(s = 26). Two other bases were screened (entries 6 and 7) and
good results were obtained with regard to conversion and the
s factor, however they did not outperform K2CO3. With the
best basic additive chosen, a screening of a number of
different solvents was carried out. When the reaction was run
a Reaction conditions: (±)-1a (0.05 mol), 0.5 mol% catalyst and 20
mol% additive in the solvent (1.0 mL) under 1 bar H2 at room
temperature for 10 min, unless otherwise specified. b Conversion
1
was determined by H NMR spectroscopy, the combined recovery
c
ratio of 1a and 2a >99%, unless specified in parentheses.
d
Enantiomeric excesses were determined by SFC analysis. The
selectivity factors: s = ln[(1 – conv.)(1 - ee)]/ln[(1 – conv.)(1 + ee)].
e3 min reaction time. f10 mol% additive. g 0.2 mmol scale reaction.
in benzene (entry 8) it gave a comparable outcome to that in
toluene but the overall selectivity was not improved. The use
of CH2Cl2 was completely detrimental to the process (entry 9):
even when the reaction was stopped at 55% conversion, the
remaining alcohol 1a was present only in 38% ee. When α,α,α-
trifluorotoluene was tested (entry 10), the system gave good
selectivity (s
= 21), but with lower conversion and
enantiopurity of 1a (79% ee). Eventually, the reaction was
carried out on a preparative scale (0.2 mmol) with 10 mol%
K2CO3 (entry 11), and gave similar selectivity to that of the
smaller scale (entry 5).
We then evaluated the allylic alcohol scope (Table 2), with a
systematic study on the substitution covering a range of
different functionalities. The substrates that have different
substituents on the allylic position were found to be suitable
candidates for the Ir-catalyzed hydrogenation/KR, and
excellent ees and high s values were obtained in most cases
(1b-f).
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Table.2 Substrate scopea
ARTICLE
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DOI: 10.1039/D0SC05276K
a Reaction conditions: (±)-substrate 1 (0.2 mmol), 0.2-1.0 mol% catalyst A and 10 mol% K2CO3 in Toluene (1.0 mL) under 1-3 bar H2 at
room temperature for 10 min-1 h, unless otherwise specified in the Supporting Information. Isolated yield. Conversion was determined by
1H NMR spectroscopy. The selectivity factors: s = ln[(1 – conv.)(1 - ee)]/ln[(1 – conv.)(1 + ee)]. Enantiomeric excesses were determined by
SFC or GC analysis. b Isolated as a mixture with hydrogenated product. c Catalyst B was used.
These results also indicate how steric bulk influences the alcohol. The current method could be also applied in the
catalyst in discriminating between the two enantiomers of the synthesis of saturated alcohols with excellent diastereo- and
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enantio-selectivity. As an illustrative example, substrate 1g
was resolved with slightly lower conversion affording the
hydrogenated product 2g in 46% isolated yield with excellent
d.r. (99:1) and ee (98%). From the measurement of the optical
rotation of an isolated sample of resolved compound 1b and
by comparison with literature values16, the assigned absolute
configuration for the alcohol was determined to be (R). The
stereochemistry of the other resolved alcohols was assigned
by analogy. The investigation continued with the evaluation of
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different functionalities (1j,
1k) such as -CH2Cl, -CH2TMS,17
which were well tolerated by the system and gave good
selectivity.
The substrates (1l-r) bearing an electron-withdrawing group or
electron-donating group at the para or meta position of
phenyl ring could be successfully resolved, affording excellent
ee for the remaining starting material. However, the ortho-
substituted analogue of 1l cannot be kinetically resolved,
probably due to the unfavorable steric effect. Good results
were also achieved for the heteroaromatic compounds 1s and
1t containing a thiophene ring. Surprisingly, the challenging
tertiary alcohol 1u, which was a sensitive substrate under
hydrogenation conditions, could still be resolved (98% ee) even
if at higher conversion (63%).
Next, a set of allylic alcohols with a β-carbonyl functionality
were also evaluated in our KR system, given their high
synthetic utility. The first substrate in this class was ethyl ester
1v, for which the Ir-N,P catalyst accomplished efficient kinetic
resolution (99% ee) at 56% conversion, corresponding to a high
selectivity (s = 41). Good results were also observed in the KR
of ketones 1w and 1x, with relatively high s factors. When the
bulky alcohol 1y was applied in this hydrogenation/KR strategy,
excellent selectivity (s = 211) was obtained. Cyclic substrate 1z
with a methyl group on the allylic position also proceeded with
lower selectivity (s = 16). Lower selectivity was encountered
when manipulating the substitution on the olefin (1af). Several
Scheme.2 Gram-scale kinetic resolution and concise synthesis
of the chiral building block of 15(R)-Pumiliotoxin A
Different stereoisomers of a biologically active molecule can
cause completely different effects in biological systems.18
Meanwhile, the inherent problem of KR processed is the 50%
maximum isolated yield. Considering the excellent enantio-
discriminating ability of our catalytic system in hydrogenation
of racemic allylic alcohols, to make full use of the starting
materials we continued to explore its double stereo-
differentiation potential, which could provide both
enantiomers of saturated secondary alcohol 2i bearing two
contiguous chiral centers (Scheme 1). The resolved alcohol (R)-
1i was subjected to the secondary hydrogenation using the
catalyst ent-A without any additive under 3 bar of hydrogen
for 10 minutes, affording the saturated alcohol (2R,3S)-2i with
excellent diastereo- and enantioselectivity (> 99:1 d.r., 99% ee).
Starting from racemic allylic alcohol 1i
, the combined
hydrogenations afforded clean reactions with 96% overall yield
of the two separated enantiomers.
In order to demonstrate the utility of this approach, we have
performed a gram-scale kinetic resolution of allylic alcohol 1b
with 0.2 mol% catalyst loading under 1 bar hydrogen pressure
for 30 minutes, and the resolved allylic alcohol was obtained
with 99% ee at 54% conversion (Scheme 2). The reaction
mixture was benzylated and underwent ozonolysis to yield
fully aliphatic allylic alcohols (1aa-ae) were tested in the
method as well. To our delight, good selectivity was achieved
for these substrates and good to excellent ee could be reached
when the reaction conversion was controlled to a range of 55%
to 60%. Finally, a set of β,β-substituted allylic alcohols (1ag-1ak
)
methyl ketone 3, which was previously synthesized in 7 steps
including both aromatic and pure aliphatic substrates were
from glycidol19a and is a key intermediate for the total
synthesis of pharmacologically active dendrobatid alkaloid
pumiliotoxin A.19b
tested using the oxazole-type catalyst
B, high to excellent
selectivities (s factor up to 194) were obtained.
Encouraged by the above success, we then turned our
attention to the synthesis of the natural products inthomycin A
and B with our new method as a key step (Scheme 3). The
inthomycins, a small family of polyene natural products were
first isolated from Streptomyces sp.20 have attracted
considerable attention from synthetic chemists21 due to their
unique structural features and interesting bioactivities.22 Our
synthesis began with KR of racemic alcohol 1y, which already
showed excellent level of selectivity in small scale affording the
resolved alcohol with over 99% ee at 52% conversion (s> 100).
Subsequent TBS protection and ozonolysis delivered the
enantioenriched ketone
4 in 38% overall yield from the
beginning. Surprisingly, the Horner-Wadsworth-Emmons
Scheme.1 Double stereo-differentiation.
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Scheme.3 Enantioselective formal total synthesis of Inthomycin A and B.
reaction of methyl ketone
trimethylsilylpropynyl phosphonate23 followed by
deprotection of TMS afforded the Z-enyne in an 81% yield other hand, fragments
with an unprecedented exclusive stereoselectivity. Sonogashira cross-coupling to afford intermediate 10, which
Separately, lithiation of TIPS protected oxazole 621g followed was further converted to alcohol 1121e after deprotection.
by allylation at C-5 position to give the vinyl bromide in high Over 99% ee was also achieved for alcohol 11 and this
yield. With and in hand, then we turned to the coupling of constitutes a formal enantioselective synthesis of inthomycin A.
4
with dimethyl 3- achieved the formal total synthesis of (3S)-inthomycin B by
obtaining the reported alcohol 921b,c with over 99% ee. On the
and can be directly conected by a
a
5
5
7
7
5
7
two fragments according to the the geometry of the target This synthetic sequence provides one of the most efficent
inthomycins. Firstly, by using of a modification of Negishi’s routes to the inthomycins, with remarkable selectivity.
method,24 enyne
5
was subjected to hydrozirconation and To rationalize the origin of the enantio-discrimination, the
to give the triene in good yield with
excellent stereoselectivity. After the desilylation of , we
then coupling with
7
8
8
Fig. 2 Origin of selectivity depicting: (a) Steric environment
around Ir. (b) Quadrant model illustrating the matched and
mismatched allylic alcohol. (c) 3D quadrant model.
Fig. 3 Calculated relative energy profile
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quadrant model analysis correlated with preliminary density
functional theory (DFT) studies were performed (Fig. 2).25,10
According to the previously developed quadrant model, the
iridium coordination sphere was divided into four planar
quadrants basing on the calculated catalyst structure. When
the olefin substrate was fitted into this model (Fig. 2b), the
smallest substituent (H atom) always occupies the most
hindered quadrant, resulting a fixed conformation for the
transition state. As shown in the three-dimensional quadrant
model (Fig. 2c), a possible hydrogen bonding interaction
between the hydroxyl group and the axial iridium hydride may
facilitate the enantio-discrimination, since the corresponding
calculated distance is around 2.5 Å for both enantiomers.
Further relative energy calculations for the possible transition
states were conducted (Fig. 3). For transition state TS I of the
matched enantiomer (S)-1a, the hydrogen bonding interaction
leads to a conformation with the methyl group at the carbinol
pointing away from the ligand backbone. In contrast, the
hydrogen bonding in transition state TS II of the matched
enantiomer (R)-1a resulting in the methyl group pointing
forward to the ligand backbone, which is not favored for steric
reason. The cost of this steric clash resulted in a 3.0 Kcal/mol
difference in energy for the two transition states. This result
also indicates that substrate with bulkier substituent would
give better selectivity, which is consistent with the
experimental finding. Another possible transition state TS III
for the mismatched enantiomer, which adopts a less steric
hindered manner of coordination with the catalyst by breaking
the hydrogen bond, resulting in an even higher energy barrier.
Additionally, absolute configurations of the recovered allylic
alcohols obtained are in agreement with the theoretical
prediction.
Acknowledgements
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DOI: 10.1039/D0SC05276K
The authors are grateful to the Swedish Research Council (VR),
the Knut och Alice Wallenberg Stiftelsen for funding this
research. J.J. thanks the Chulabhorn Graduate Institute,
Chulabhorn Royal Academy, Thailand for an exchange
scholarship to Stockholm University. T.S. acknowledges the
NRF South Africa for the Post-PhD Track Thuthuka Grant. All
computations were carried out using the computational
cluster resources at the National Supercomputer Centre based
at Linkoping University, Sweden and at the Center for High
Performance Computing, South Africa.
Notes and references
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Conclusions
To summarize, we have developed an efficient kinetic
resolution protocol for a variety of trisubstituted allylic
alcohols by means of Ir-N,P-catalyzed asymmetric
hydrogenation. High selectivity factors were observed with this
methodology, and they compare well with those reported for
other KR systems, especially taking into consideration the mild
reaction conditions, short reaction times and operational
simplicity. The utility of this strategy is illustrated by the
concise formal synthesis of bioactive 15(R)-Pumiliotoxin A,
(3R)-Inthomycin A and B. DFT calculations and quadrant model
analysis indicated that a medium strong hydrogen bonding
between the alcohol and the iridium center being responsible
for the selectivity. This kinetic resolution of diverse allylic
alcohols via asymmetric hydrogenation provides new and
exciting opportunities for enantioselective synthesis.
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Conflicts of interest
There are no conflicts to declare.
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