NeoPHOX - A structurally tunable ligand system for asymmetric catalysis

Article abstract of DOI:10.3762/bjoc.12.114

A synthesis of new NeoPHOX ligands derived from serine or threonine has been developed. The central intermediate is a NeoPHOX derivative bearing a methoxycarbonyl group at the stereogenic center next to the oxazoline N atom. The addition of methylmagnesiu

Full text of DOI:10.3762/bjoc.12.114

NeoPHOX – a structurally tunable ligand system for
asymmetric catalysis
Jaroslav Padevět, Marcus G. Schrems, Robin Scheil and Andreas Pfaltz*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 1185–1195.
Department of Chemistry, University of Basel, St. Johanns-Ring 19,
CH-4056 Basel, Switzerland
doi:10.3762/bjoc.12.114
Received: 15 March 2016
Accepted: 24 May 2016
Published: 13 June 2016
Email:
Andreas Pfaltz* - andreas.pfaltz@unibas.ch
* Corresponding author
This article is part of the Thematic Series "Strategies in asymmetric
catalysis".
Keywords:
allylic substitution; asymmetric hydrogenation; iridium; N,P ligand;
palladium
Guest Editor: T. P. Yoon
© 2016 Padevět et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A synthesis of new NeoPHOX ligands derived from serine or threonine has been developed. The central intermediate is a
NeoPHOX derivative bearing a methoxycarbonyl group at the stereogenic center next to the oxazoline N atom. The addition of
methylmagnesium chloride leads to a tertiary alcohol, which can be acylated or silylated to produce NeoPHOX ligands with differ-
ent sterical demand. The new NeoPHOX ligands were tested in the iridium-catalyzed asymmetric hydrogenation and palladium-cat-
alyzed allylic substitution. In both reactions high enantioselectivities were achieved, that were comparable to the enantioselectivi-
ties obtained with the up to now best NeoPHOX ligand derived from expensive tert-leucine.
Introduction
Since their introduction and first successful application in enan- Although high enantioselectivities were achieved with the
tioselective palladium-catalyzed allylic substitution in 1993 initially developed Ir-PHOX catalysts, the range of olefins that
[1-3], chiral phosphinooxazolines (PHOX ligands) have gave satisfactory results was limited. Consequently, a variety of
emerged as a widely used privileged ligand class [4-12]. One of other ligand classes derived from oxazolines or other nitrogen
the major areas of application of PHOX and related N,P ligands heterocycles were explored and eventually, several highly effec-
is the iridium-catalyzed asymmetric hydrogenation [13-16]. tive ligand systems were found that have considerably en-
Compared to rhodium and ruthenium catalysts, iridium com- hanced the range of functionalized and unfunctionalized olefins
plexes derived from chiral N,P ligands show a much broader that can be hydrogenated with high efficiency and excellent en-
substrate scope in the hydrogenation of olefins, as they do not antioselectivity. Among the many oxazoline-derived ligands
require any coordinating groups in the substrate.
that have been reported in the literature, SimplePHOX [17] and
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ThrePHOX [18] have emerged as some of the most versatile was found, the corresponding bromides and chlorides seemed to
and most easily accessible ligand classes. However, although prefer an SN2 mechanism. Rossi et al. [21] showed that substi-
iridium complexes derived from these ligands are air and mois- tution products can be obtained in good yields from neopentyl
ture-stable, the free ligands are prone to hydrolysis and oxida- chloride derivatives and sodium diphenylphosphide in liquid
tion. Especially SimplePHOX ligands, although they are readily ammonia by an SNR2 reaction induced by UV irradiation.
prepared from amino alcohols in just two steps, suffer from Huttner and co-workers [22] on the other hand achieved high
these problems resulting in low yields and difficult purification yields in nucleophilic substitutions of diarylphosphines with
steps.
MeC(CH2Cl)3 in DMSO using aqueous KOH as base at
elevated temperature but without irradiation.
We therefore decided to explore structural analogs, in which the
P–O bond had been replaced by a P–C bond [19]. We hoped In initial model studies using neopentyl chloride and a commer-
that such ligands, which we named NeoPHOX because of the cially available solution of KPPh2 in THF we obtained high
neopentyl backbone, would be as easily accessible as Simple- yields of neopentyldiphenylphosphine under reflux conditions
PHOX but more stable against air and moisture and fulfill the [19]. Encouraged by these results, a series of chloroalkyl-substi-
criteria for a scalable high yielding synthesis (Figure 1).
tuted oxazolines 2 were prepared from 3-chloropivaloyl chlo-
ride (3) by amide formation and subsequent cyclization with the
Burgess reagent (methyl N-(triethylammoniumsulfonyl)carba-
mate) using standard procedures (Scheme 2). Subsequent
nucleophilic substitution with KPP2 in refluxing THF proved to
be much faster than the analogous reaction with neopentyl chlo-
ride. After 6 hours, the KPPh2 was fully converted to the
desired phosphinooxazoline, as evidenced by the 31P NMR
spectrum, which showed only the product signal. The reaction
also proceeded well with other diarylphosphides such as
KP(o-Tol)2 or KP(3,5-MePh)2 prepared in situ from the second-
ary phosphines by deprotonation with KH in refluxing THF.
The NeoPHOX ligands, which were obtained by this route in
high overall yield, proved to be air and moisture stable and
Figure 1: Structural motifs of phospinooxazoline ligands.
Results and Discussion
1st Generation NeoPHOX ligands
A potential very short route to NeoPHOX ligands starting from could be obtained in analytically pure form by simple filtration
commercially available 3-chloropivaloyl chloride (3) is shown through silica gel [19]. Complexation with [Ir(COD)Cl]2 and
in Scheme 1. Although nucleophilic substitutions at the subsequent anion exchange with NaBArF (sodium tetrakis[3,5-
neopentyl carbon atoms are known to be difficult, literature bis(trifluoromethyl)phenyl]borate) led to the corresponding
precedence indicated that the introduction of the phosphine iridium precatalysts in high yields. These complexes as well
group might be possible by the reaction of a diarylphosphide showed high stability against oxygen and moisture and could be
anion with chloroalkyloxazoline 2.
stored in air for several months without notable decomposition.
As originally assumed, the NeoPHOX complexes Ir-1a–e
turned out to be highly efficient catalysts. They induced similar
and in some cases even higher enantioselectivities compared to
the analogous SimplePHOX complexes, as shown by the results
obtained in the hydrogenation of a range of test substrates
(Figure 2) [19]. Considering the more practicable synthesis,
which is well suited for large-scale preparation, and the higher
stability of the free ligands, NeoPHOX ligands provide a superi-
or alternative to the SimplePHOX ligands. The only drawback
these compounds share with many state-of-the-art oxazoline-
based ligands is the high cost of tert-leucinol as starting materi-
Scheme 1: Retrosynthetic analysis for NeoPHOX ligands.
Ashby et al. [20] investigated the reactivity of neopentyl halide al, which reduces their potential for industrial-scale application.
systems with various metal diphenylphosphides and found that We therefore thought of ways to replace the tert-butyloxazoline
the reaction indeed took place. While for iodides evidence for a ring by an equally effective oxazoline unit derived from a less
radical single electron transfer process as the major pathway expensive precursor.
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Scheme 2: Synthesis of 1st generation NeoPHOX Ir-complexes [19].
Figure 2: Asymmetric hydrogenation with iridium-NeoPHOX catalysts [19].
An option, which had been previously used in the development
of PHOX ligands [23-27], is to replace the tert-butyl group by
an isopropyl group and at the same time introducing two bulky
substituents at C(5) (see Figure 3). Ligands of this type are
accessible from valine, which is much less expensive than tert-
leucine. The steric hindrance exerted by the geminal substitu-
ents at C(5) is expected to direct the isopropyl methyl groups
toward the coordination sphere, creating a steric environment
which resembles that of a tert-butyloxazoline ligand.
Figure 3: Employing L-valine as a starting material for C5 substituted
oxazoline.
ties in the hydrogenation of various test substrates were much
lower than those induced by the tert-butyloxazoline analog with
the exception of the result obtained with the allylic alcohol S2
(Table 1). Surprisingly, the presence of two geminal phenyl
substituents at C(5) had a negative impact on the enantioselec-
tivity, as shown by the substantially higher ee values induced by
the analogous catalyst Ir-1a [28] lacking substituents at C(5).
To test the viability of this approach, we synthesized the valine-
derived NeoPHOX ligand 10 with two geminal phenyl substitu-
ents at C(5) according to the route shown in Scheme 3.
Unfortunately, the iridium complex Ir-10 prepared from this
ligand proved to be an inefficient catalyst. The enantioselectivi-
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Scheme 3: Synthesis of a C(5)-disubstituted NeoPHOX-Ir complex.
Table 1: Hydrogenation results employing 1st generation NeoPHOX catalysts.a
S1
S5
S2
S3
ee [%]
yield [%]
ee [%]
yield [%]
ee [%]
yield [%]
ee [%]
yield [%]
19 (R)
93
35 (S)
>99
84 (–)
>99
63 (R)
41
Ir-10
Ir-1a
Ir-1b
74 (R)
>99
53 (S)
89
88 (–)
>99
85 (R)
>99
97 (R)
>99
92 (S)
>99
83 (–)
>99
95 (R)
>99
aReaction conditions: 50 bar, 2 h, 1 mol % catalyst, 0.1 mmol substrate, 0.5 mL CH2Cl2.
Based on these negative results we chose a new approach based resulting tertiary alcohol. An attractive feature of this approach
on serine or threonine as starting materials (Figure 4). The is that by proper choice of the alkylmetal reagent and the
carboxyl group of these amino acids serves as surrogate for the protecting group, the steric properties of the ligand can be opti-
tert-butyl group of tert-leucine, which can be converted to a mized for a specific application. PHOX ligands of this type
sterically demanding substituent by double addition of Grig- have been previously prepared from serine and successfully
nard or alkyllithium reagents and subsequent protection of the used in iridium-catalyzed hydrogenation [29,30].
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Figure 4: Retrosynthetic analysis for NeoPHOX ligands derived from serine and threonine.
Synthesis of serine- and threonine-derived
NeoPHOX ligands
Alternative strategies involving Grignard addition to the threo-
nine methyl ester or N-protected derivatives were also briefly
The synthesis that led to the NeoPHOX ligand 14 in 46% investigated, but failed. Grignard addition to the chloro amide
overall yield is shown in Scheme 4. In the first step threonine 11 was not attempted because earlier studies with chloro amide
methyl ester hydrochloride was converted to the desired amide 15 had shown that an undesired β-lactam 16 was formed upon
11 in 96% yield. Subsequent cyclization with the Burgess treatment with Grignard reagents (Scheme 5) [28].
reagent afforded the oxazoline 12 in 89% yield with clean
inversion of configuration at the hydroxy-substituted carbon All attempts to prepare analogous serine-derived NeoPHOX
atom. Double addition of methylmagnesium chloride and subse- ligands by the established route for the synthesis of the threo-
quent introduction of the diphenylphosphine unit proceeded nine-derived NeoPHOX ligand 14 led to unexpected problems
well in 68% yield following the procedures worked out for the (Scheme 6). Oxazoline formation with the Burgess reagent did
1st generation NeoPHOX ligands.
not produce the desired oxazoline (mixture of unidentified prod-
Scheme 4: Revisited synthetic strategy for the preparation of a threonine-based NeoPHOX ligand.
Scheme 5: Undesired β-lactam formation.
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ucts). However, eventually an alternative method using diethyl- Next we converted the tertiary alcohols 14 and 20 to a range of
aminosulfurtrifluoride (DAST) [31] was found that afforded the silylated and acetylated derivatives in order to evaluate the in-
chloroalkyloxazoline 18 in 95% yield after short reaction times fluence of sterically and electronically different substituents on
at −78 °C.
the enantioselectivity and catalytic activity of the correspond-
ing iridium complexes. Initial attempts to introduce a silyl or
Treatment of this product with methylmagnesium chloride acetyl group by deprotonation with potassium hydride and
under the same conditions used for the threonine derivative 12 subsequent reaction with silyl triflates or acetyl chloride failed.
(Scheme 4), led to an unidentified mixture of products. Surpris- The NeoPHOX ligand 14 showed no reaction under these
ingly, when the Grignard reagent was added at 0 °C instead of conditions, although this method had been successfully used for
−78 °C and reaction mixture subsequently warmed up to room the alkylation and acylation of the tertiary alcohol function of
temperature, the desired product 19 was formed in 78% yield. analogous serine derived PHOX ligands [30]. Among various
After having resolved these issues, the desired serine-based amines, 2,6-lutidine was finally identified as a suitable base
NeoPHOX ligand 20 was obtained in 23% overall yield from for conversion to the desired derivatives in 67–76% yields
serine methylester hydrochloride.
(Scheme 7). From these ligands a library of iridium catalysts
Scheme 6: Synthetic strategy for the synthesis of the serine-derived NeoPHOX ligand.
Scheme 7: Derivatization of the 2nd generation NeoPHOX ligands and formation of their iridium complexes.
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was prepared by complexation with bis(1,5-cyclooctadiene)di- or no conversion. In the case of complex ser-PHOX-OMe [30]
iridium(I) dichloride, followed by anion exchange with it was found that the methoxy function in the oxazoline ring in-
NaBArF.
duced deactivation of the catalyst due to coordination to the
metal center resulting in a stable hydride-bridged dinuclear
complex under hydrogenation conditions. The analogous cata-
lysts Ir-14-OAc and ser-PHOX-OAc with an acyloxy substitu-
ent proved to be more reactive, however, conversion still
remained incomplete with olefins S1 and S3. Similar results
were obtained with the analogous NeoPHOX complex Ir-14-
Comparative hydrogenation studies with
iridium catalysts derived from 1st and 2nd
generation NeoPHOX ligands and serine-
based PHOX ligands
A set of seven Ir-NeoPHOX catalysts was evaluated in the OAc bearing an acetoxy group at the oxazoline ring. Appar-
asymmetric hydrogenation of three alkenes and acetophenone ently, a polar potentially coordinating substituent near the metal
phenylimine (Table 2). For comparison, the results previously center reduces or can even completely inhibit catalytic activity.
reported for four related serine-based Ir-PHOX complexes are The deactivating effect of a coordinating oxygen function could
included in the table. Overall, the tert-leucine-derived complex also explain the different conversions observed with the silyl
Ir-1b and complexes Ir-14-TBDMS and Ir-20-TBDMS with a ether-bearing catalysts, decreasing in the series t-BuMe2Si >
bulky tert-butyldimethylsilyloxy group showed the highest re- Et3Si > Me3Si. It has been shown that Ir-hydride complexes that
activity, resulting in full conversion of all three olefins. On the are formed as intermediates during hydrogenation are strong
other hand catalysts Ir-14-OH and ser-PHOX-OMe bearing a Brønsted acids [32], which can cause cleavage of trimethylsilyl
free hydroxy and a methoxy group, respectively, gave very low ethers under hydrogenation conditions [33]. So partial desilyl-
Table 2: Hydrogenation of standard substrates using serine- and threonine-derived NeoPHOX catalysts.
S1
S2
S3
S4
ee [%]
yield [%]
ee [%]
yield [%]
ee [%]
yield [%]
ee [%]
yield [%]
41 (+)
10
7 (S)
4
Ir-14-OH
n.d.
n.d.
87 (S)
59
90 (+)
92
90 (S)
>44
16 (S)
73
Ir-14-OAc
92 (S)
38
88 (+)
82
82 (S)
>40
67 (S)
5
Ir-14-TMS
97/b96 (S)
59/b87
89/b88 (+)
60/b>99
90/b90 (S)
87/b98
68/b62 (S)
8/b32
Ir-14-TES
96 (S)
>99
91 (+)
>99
94 (S)
>99
49 (S)
79
Ir-14-TBDMS
Ir-20-TBDMS
Ir-1b
90 (S)
>99
84 (+)
>99
92 (S)
>99
77 (S)
79
97 (R)
>99
97% (-)
>99
97% (R)
>99
97 (R)
>99
n.d.
1
57 (+)
9
32 (S)
3
5 (R)
2
ser-PHOX-OMe [30]
ser-PHOX-Bn [30]
ser-PHOX-OAc [30]
ser-PHOX-Bz [30]
92 (S)
27
79 (+)
43
46 (S)
34
21 (S)
1
92 (S)
90
91 (+)
>99
56 (S)
70
56 (R)
99
92(S)
88
92 (+)
>99
69 (S)
91
53 (R)
>99
aReaction conditions: 50 bar, 2h, 1 mol % catalyst, 0.1 mmol substrate, 0.5 mL CH2Cl2; breaction time 16 h;
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ation liberating a free hydroxy group during hydrogenation may serine-derived NeoPHOX iridium complexes are essentially the
well be the reason for the low conversion obtained with cata- same as those of the tert-leucine-derived NeoPHOX complex
lyst Ir-14-TMS bearing an acid-labile trimethylsilyl ether with respect to the geometry of the 6-membered iridacycle,
group.
which retains a boat-shaped conformation (Figure 5). No
notable divergence in the steric environment of the iridium
Among the NeoPHOX catalysts, the most reactive complex center in the four silyloxy-bearing NeoPHOX complexes could
with a bulky TBDMS group showed also the highest enantiose- be observed that would explain the difference in enantioselec-
lectivities in the hydrogenation of alkenes S1–3. It also outper- tivity induced by these catalysts.
formed the most efficient serine-derived PHOX catalysts ser-
PHOX-OAc and ser-PHOX-OBz. In terms of activity and In contrast to the methoxy-bearing serine-derived PHOX com-
enantiomeric excess the performance of this catalyst was plex ser-PHOX-OMe, the protected tertiary alcohol group in
comparable to the tert-leucine-derived complex Ir-1b. The these complexes does not point towards the iridium center. The
analogous serine-based complex Ir-20-TBDMS gave some- interaction of the ether oxygen atom with the iridium center was
what lower enantioselectivities. In the hydrogenation of imine the reason for the lack of reactivity of this serine-based PHOX
S4 none of the catalysts shown in Table 2 induced high enantio- complex. In case of the silyl ethers the oxygen atom is strongly
selectivity.
shielded preventing coordination to the iridium center.
Crystal structures of iridium NeoPHOX com-
plexes
Palladium-catalyzed allylic substitution
As phosphinooxazoline ligands were originally designed for
The three dimensional structures of several threonine and asymmetric palladium-catalyzed allylic substitutions, we tested
serine-derived NeoPHOX iridium complexes were determined the new NeoPHOX ligands in this reaction as well. For compar-
by X-ray diffraction and compared with known phosphinooxa- ison with state-of-the-art ligands, we chose the standard test
zoline complexes. We were interested to see whether the differ- reaction of (E)-1,3-diphenylallylacetate with dimethyl malonate
ences in steric shielding of the coordination sphere by the as nucleophile (Scheme 8).
protecting groups on the tertiary alcohol function correlated
with the hydrogenation results. From the obtained crystal struc- The two catalysts derived from ligand 14 with a free hydroxy
tures, it can be seen that the conformations of the threonine and group and the corresponding triethylsilyl-protected derivative
Figure 5: Crystal structures of selected Ir-complexes. Hydrogen atoms, COD and BArF anions were omitted for clarity.
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Scheme 8: Asymmetric palladium-catalyzed allylic substitution with rac-(E)-1,3-diphenylallyl acetate.
both performed well affording enantioselectivities of 90% and results. The yield was low in all cases and the enantiomeric
98% ee, respectively. Ligand 14-TES was even more effective excess reached only 41% for the best ligand 14. Interestingly,
than the corresponding tert-leucine-derived NeoPHOX ligand the sterically more demanding ligand 14-TES did not lead to
1b (97% ee).
higher enantioselectivity as for 1,3-diphenylallyl acetate.
Next, we also tested (E)-1,3-dimethylallyl acetate as substrate Finally, the ligands were also tested on a more demanding
(Scheme 9). All three tested catalysts gave disappointing cyclic substrate (Scheme 10). In the allylic substitution with
Scheme 9: Asymmetric palladium-catalyzed allylic substitution with rac-(E)-1,3-dimethylallyl acetate.
Scheme 10: Asymmetric palladium-catalyzed allylic substitution with a cyclic substrate.
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Acknowledgements
Financial support by the Swiss National Science Foundation is
gratefully acknowledged.
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