The enantioselective synthesis of a broad variety of novel differently functionalized α-halogenated α-aryl-β2,2-amino acid derivatives by means of an ammonium-salt-catalyzed asymmetric α-halogenation of isoxazolidin-5-ones was accomplished. Key to success to obtain high levels of enantioselectivities was the use of Maruoka's spirocyclic binaphthyl-based ammonium salts, and detailed accompanying mechanistic studies using density functional theory methods revealed the key features for the catalyst-substrate interactions.
The enantioselective synthesis of a broad variety of novel differently functionalized α-halogenated α-aryl-β2,2-amino acid derivatives by means of an ammonium-salt-catalyzed asymmetric α-halogenation of isoxazolidin-5-ones was accomplished. Key to success to obtain high levels of enantioselectivities was the use of Maruoka's spirocyclic binaphthyl-based ammonium salts, and detailed accompanying mechanistic studies using density functional theory methods revealed the key features for the catalyst-substrate interactions.
Investigations focusing
on the asymmetric synthesis and further
utilization of chiral non-natural amino acid derivatives have for
decades been among the most prominent research topics in organic and
bioorganic chemistry.[1−5] A broad variety of conceptually different (catalytic) approaches
to access non-natural amino acids (AA) with high levels of stereocontrol
have been established, and the development of new synthesis strategies
is still a highly contemporary field of research.[1,6−12] In addition to the more classical focus on synthesis and applications
of α-amino acids (α-AA) and α-AA-based peptides,[1−7] non-natural β-AA have emerged as targets of significant interest
over the past decades.[8−17] The introduction of β-AA into the peptides, as well as the
preparation of chiral β-AA-based heterocycles, can lead to peptidomimetics
displaying unique (improved) biological properties,[8−17] which makes the development of novel asymmetric approaches toward
(masked) β-AA derivatives an important task.Depending
on their substitution pattern, different classes of β-AA
can be defined (Scheme A). While several highly efficient strategies for the catalytic enantioselective
synthesis of β3-, β2,3-, and β2-AA have been reported,[8−12] the asymmetric construction of β2,2-AA remains
challenging. In 2013, the Brière group reported the direct
synthesis of isoxazolidin-5-ones 1 starting from Meldrum’s
acid derivatives (Scheme B).[18] Compounds 1 are
versatile masked β2-AA derivatives which can be reacted
in an asymmetric manner with different electrophiles to access the
β2,2-AA derivatives 2 straightforwardly.[19−29] These chiral heterocycles subsequently allow for the synthesis of
free β2,2-AA and small peptides[20−29] as well as for the synthesis of heterocyclic amino acids,[30,31] to mention three potential applications only.
Scheme 1
β-AA, Recently
Established Strategy for β2,2-AA, α-Halogenated
β-AA, and the Herein Investigated
α-Halogenation of β2,2-AA Derivatives
Over the past few years, this powerful concept
has successfully
been used for a handful of asymmetric C–C bond forming reactions
(conjugate additions to classical Michael acceptors, MBH-carbonates,
and quinone methides;[23−25] Mannich-type reactions;[26,27] Pd-catalyzed allylations[28,29]) as well as asymmetric
α-sulfanylations,[20] α-trifluoromethylthiolations,[21,22] and one α-amination example.[23] Apart
from these few recent reports, however, the suitability of compounds 1 to access a broader variety of α-(hetero)-functionalized
β2,2-AA has so far not systematically been explored.The asymmetric α-heterofunctionalization of amino acids[32] has been a very versatile strategy to access
novel AA derivatives with promising biological properties or may serve
as useful building blocks for further manipulations. Interestingly,
while asymmetric approaches toward α-halogenated β3-, β2,3-, and β2-AA have
been well-described,[32] stereoselective
syntheses of α-halogenated β2,2-AA have so
far very sparingly been reported[33−37] (Scheme C). Considering the unique potential of compounds 1 to serve as precursors for novel masked β2,2-AA
derivatives 2, we now became interested in exploring
the suitability of compounds 1 for asymmetric α-halogenation
reactions with different electrophilic halogen-transfer agents. This
should give access to a new family of so far unprecedented α-halogenated
α-arylated-β2,2-AA in a unique and direct manner
by utilizing the easily available starting materials 1. Based on our own previous experience with compounds 1,[22,24,25] as well as
taking inspiration from Brière’s early reports,[20,23] we focused on the use of chiral ammonium salt ion pairing catalysts[38−42] to control compounds 1 in the herein targeted asymmetric
α-halogenation approaches (chiral ammonium salt catalysts were
also successfully used by Della Sala and Alemán for α-trifluoromethylthiolations
of compounds 1(21)). In addition,
we also thought about gathering a deeper understanding of these reactions
by carrying out detailed density functional theory (DFT) studies within
the context of this project.
Results and Discussion
Asymmetric α-Chlorination
The synthesis of chiral
α-Cl-β2,2-AA has been very sparingly reported
so far,[37,43,44] and to the
best of our knowledge, a reliable asymmetric catalysis approach to
access (masked) α-Cl-β2,2-AA derivatives is
yet missing. Considering the general value of enantioenriched α-Cl-carbonyl
compounds to serve as building blocks for further manipulations (i.e.,
stereospecific SN2-type reactions),[45−47] we now became
interested in developing a protocol for the asymmetric electrophilic
α-chlorination[48,49] of isoxazolidin-5-ones 1 using the established chiral ammonium salt ion pairing catalysts A–C (Figure ).
Figure 1
Chiral ammonium salt ion pairing catalysts tested
for the asymmetric
α-halogenations of compounds 1.
Chiral ammonium salt ion pairing catalysts tested
for the asymmetric
α-halogenations of compounds 1.As summarized in Table , a variety of different conditions and catalysts were
tested
for the α-chlorination of the α-phenyl-substituted parent
substrate 1a using N-chlorosuccinimide
(NCS, 3) as a readily available and established electrophilic
Cl-transfer agent.[48,49] Based on the recently observed
privileged application potential of Maruoka’s spirocyclic ammonium
salt catalysts A1 and A2(50) for asymmetric transformations of isoxazolidin-5-ones 1,[20−25] we started our screening using 5 mol % of the ammonium salt A1 (R,R-configuration as
depicted in Figure ) in toluene in the presence of different mild bases (entries 1–3).
Gratifyingly, in all cases, a complete conversion of 1a was observed, and the targeted product 2a could be obtained in reasonable isolated yields and
with promising initial enantioselectivities up to 85:15 (favoring
the (+)-isomer; please see the discussion below concerning the assignment
of the depicted S-configuration). A further screening
of different carbonate bases in different solvents did not allow for
any improvement (results not given in the table), and in some cases,
we also observed formation of the elimination product 4. Surprisingly, however (considering our previous observations with
compounds 1 where weaker inorganic bases were beneficial[20−25]), it was possible to obtain 2a with a high er of 94:6 when using sodium phenoxide (PhONa) as a
base instead (entry 4).[51] Interestingly,
despite the fact that we observed full conversion of 1a, product 2a could only be
obtained in around 50% isolated yield, accompanied by formation of
a, at this time not characterized, hardly soluble white precipitate.
Initially, we suspected a problem with elimination and decomposition
of product 2a in the presence
of this base as well as homogenization difficulties of the base in
toluene. We therefore tested the use of an ultrasonic bath, different
temperatures and reaction times, and order of addition of reagents
(conditions A vs conditions B) next (entries 4–8). The overall
transformation turned out to be much faster when carried out in an
ultrasonic bath with more or less identical yield and er (entry 5).
To achieve a better mixing and homogenization without using an ultrasonic
bath, we next tested the stepwise addition of reagents (conditions
B, entry 6). In addition, we also reduced the amount of the valuable
catalyst to 2 mol % for the further optimization. Interestingly, even
with this lower amount of catalyst, a full conversion of starting
material 1a was observed within 4 h under these conditions,
and product 2a was again obtained
in around 50% isolated yield with a reasonable er of 91:9. Surprisingly,
the reaction as such was found to be relatively clean, with no formation
of elimination product 4, and no other significant byproducts
were observable in the crude product 1H NMR spectrum (recorded
in CDCl3). Thus, we had a closer look on the hardly soluble
precipitate that forms during this reaction and which was so far assumed
to contain succinimide 3- or phenoxide-originating byproducts.
This precipitate was separated during workup by means of a simple
filtration and was found to be insoluble in CDCl3. In contrast,
however, it was well-soluble in H2O and DMSO and, upon
closer analysis, was identified as the (relatively instable) acid 5a. Mechanistically, this compound
most likely gets formed by ring-opening addition of phenoxide to 2a followed by subsequent hydrolysis
of the phenylester of 5a. It
should be noted that we were not able to isolate this postulated phenylester,
but when we tested the stability and reactivity of isolated 2a in the presence of catalyst A1 and different bases (including hydroxides), we realized
that the nucleophilic PhONa was the only one which allowed for the
formation of 5a, whereas other
bases led to quantitative formation of the elimination product 4 only.
Table 1
Optimization of the Asymmetric α-Chlorination
of Isoxazolidin-5-one 1aa
entry
cat. (mol %)
solvent
base (equiv)
conditionb
t (h)
conv. (%)c
yield (%)d
ere
1
A1 (5)
toluene
K2CO3 (1.2)
A
18
100
64
85:15
2
A1 (5)
toluene
K2HPO4 (1.2)
A
18
100
82
80:20
3
A1 (5)
toluene
NaOAc (1.2)
A
18
100
90
81:19
4
A1 (5)
toluene
PhONa (1.1)
A
18
100
47
94:6
5f
A1 (5)
toluene
PhONa (1.1)
A
1.5
100
53
93:7
6
A1 (2)
toluene
PhONa (1.1)
B
4
100
53
91:9
7
A1 (2)
toluene
PhONa (1.1)
B
6
100
32
97:3
8
A1 (2)
toluene
PhONa (1.1)
B
17
100
25
99.5:0.5
9
A1 (2)
toluene
4-NO2-C6H4ONa
(1.1)
B
5
100
71
84:16
10
A1 (2)
THF
PhONa (1.1)
B
4
100
34
81:19
11
A1 (2)
Et2O
PhONa (1.1)
B
4
100
36
85:15
12
A1 (5)
toluene
PhONa (0.5)
B
24
100
59
92:8
13
A1 (5)
toluene
PhONa (0.5)
B
72
100
52 (33)h
95:5
14
A1 (2)
toluene
PhONa (0.5)
B
72
100
46
91:9
15g
A1 (5)
toluene
PhONa (0.5)
B
72
100
52
95:5
16
A2 (5)
toluene
PhONa (0.5)
B
72
100
52
85:15
17
A3 (5)
toluene
PhONa (0.5)
B
72
100
54
62:38
18
A4 (5)
toluene
PhONa (0.5)
B
72
100
46
73:27
19
B1 (5)
toluene
PhONa (0.5)
B
72
100
54
55:45
20
B2 (5)
toluene
PhONa (0.5)
B
72
100
54
55:45
21
C1 (5)
toluene
PhONa (0.5)
B
72
100
51
53:47
22
C2 (5)
toluene
PhONa (0.5)
B
72
100
62
55:45
Unless otherwise stated, all reactions
were carried out at 25 °C in the indicated solvent using 0.1
mmol 1a and 0.11 mmol 3 (0.05 M with respect
to 1a).
Conditions
A: 1a, 3, catalyst, and base were all placed
in a flask followed
by addition of the solvent. Conditions B: 1a, 3, and catalyst were dissolved in 50 vol % of the total solvent amount,
followed by addition of a finely suspended mixture of the base (PhONa)
in the remaining 50 vol % of the indicated solvent.
Conversion of 1a (determined
by 1H NMR of the crude product mixture).
Isolated yield of 2a (after column chromatography).
Given as (+)/(−)-2a ratio (determined by HPLC using a chiral
stationary phase).
Carried
out in an ultrasonic bath.
Carried out at 0 °C.
Isolated yield of 5a.
Unless otherwise stated, all reactions
were carried out at 25 °C in the indicated solvent using 0.1
mmol 1a and 0.11 mmol 3 (0.05 M with respect
to 1a).Conditions
A: 1a, 3, catalyst, and base were all placed
in a flask followed
by addition of the solvent. Conditions B: 1a, 3, and catalyst were dissolved in 50 vol % of the total solvent amount,
followed by addition of a finely suspended mixture of the base (PhONa)
in the remaining 50 vol % of the indicated solvent.Conversion of 1a (determined
by 1H NMR of the crude product mixture).Isolated yield of 2a (after column chromatography).Given as (+)/(−)-2a ratio (determined by HPLC using a chiral
stationary phase).Carried
out in an ultrasonic bath.Carried out at 0 °C.Isolated yield of 5a.Interestingly, Birman’s group
recently reported a very appealing
kinetic resolution (KR) of β-substituted isoxazolidin-5-ones
with aliphatic alcohols in the presence of chiral squaramide catalysts,
which gave access to various acyclic β3-AA esters
in a mechanistically related manner.[52] To
probe if a conceptually similar KR may also account for our observations,
we next treated racemic 2a with
0.5 equiv of PhONa in the presence of catalyst A1, which
resulted in the formation of 5a and the recovery of enantioenriched (+)-2a (45% yield, er = 69:31, s = 3).
In addition, when carrying out the overall α-chlorination protocol
for prolonged reaction times with 1.1 equiv of PhONa (compare entries
6–8), the isolated yield of cyclic 2a constantly decreased, combined with a significantly
increasing enantiopurity up to er = 99.5:0.5 (entry 8), thus substantiating
the involvement of a chiral ammonium-salt-catalyzed resolution step.
Additionally, the use of the less nucleophilic 4-NO2-C6H4-ONa resulted in a higher 2a yield but with lower selectivity (entry 9),
which supports our proposal that the aryloxide serves as a nucleophile
in the resolution step. Based on these results, it can therefore be
postulated that the overall transformation most likely proceeds via
two distinct steps, a relatively fast asymmetric ammonium-salt-catalyzed
α-chlorination first, followed by a subsequent (slower) ammonium
phenoxide-controlled kinetic resolution of the already enantioenriched 2a. These two asymmetric processes match each other, resulting
in a reasonably selective two-step one-pot strategy to access enantioenriched 2a (overall, this reaction is best
carried out in toluene while different ether solvents turned out to
be not beneficial (entries 10 and 11)).In our recent investigations
concerning the asymmetric α-trifluoromethylthiolation
of compounds 1 with succinimide or phthalimide-based
SCF3-transfer reagents, we found that catalytic amounts
of external bases may be sufficient, as the in situ formed succinimide
or phthalimide can serve as a base, as well.[22] Analogously, when we carried out the α-chlorination of 1a with 10–20 mol % of K2CO3 only,
we obtained the same yield and enantioselectivity as observed for
the use of 1.2 equiv of this base (compare with entry 1), demonstrating
that the α-chlorination step itself is a fast autocatalytic
process where the nature of the external base has a less pronounced
effect only. We therefore speculated that it should be possible to
use only 50 mol % of the phenoxide (in order to primarily control
the KR step), which should allow for a synthetically useful compromise
between isolated yield and enantiopurity. In addition, control of
the reaction progress/reaction time should be less critical compared
to the use of an excess of phenoxide. As shown in entries 12 and 13,
the use of 50 mol % of PhONa in the presence of 5 mol % of A1 results in 59% isolated 2a yield after 24 h already (er = 92:8) and allows for a further enantioenrichment
when stirring for a prolonged reaction time (52% isolated yield in
combination with a satisfying er of 95:5 after 3 days, entry 13).
As expected, lowering the catalyst amount to 2 mol % had a slightly
detrimental effect on the overall selectivity (entry 14), whereas
lower temperatures had no influence at all (entry 15), provided the
reaction was run long enough to allow for a satisfying progress of
the KR (substantiating that the resolution step is the slower process
in this two-step protocol). Finally, other ammonium salt catalysts A–C were tested, but in close analogy
to previous observations,[20−25] only the spirocyclic Maruoka ammonium salts A1 and A2 allowed for reasonable selectivities (compare entries 16–22),
while the other well-established systems failed to allow for any reasonable
selectivities.Having identified reliable conditions for this
combined α-chlorination–kinetic
resolution approach to access enantioenriched 2a, we next investigated a series of further manipulations
of this masked α-chlorinated β-AA derivative (Scheme ). First, it was
possible to directly replace the chlorine with a NO2 (product 2a), an EtO (product 2a), and a N3 group (product 2a). Here, it should be noted that
the α-NO2-containing 2a turned out to be a fairly unstable compound, which rapidly
undergoes ring opening and decarboxylation to compound 8 upon exposure to silica gel. In contrast, 2a and 2a could
be obtained with excellent levels of enantiospecificity when carrying
out the nucleophilic SN2 displacement on enantioenriched 2a. In addition to these α-substitutions,
it was also possible to carry out nucleophilic ring-opening reactions,
as shown for the synthesis of the Me ester 6a or the amide 7a (analogous reactions could be carried out with 2a, as well[53]). Interestingly,
however, while it was possible to hydrogenate the N–O bond
of other α,α-disubstituted isoxazolidinones 2 with classical Pd-catalyzed approaches (either with H2 or HCOONH4) in the past,[20−29] this was not possible for 2a, as illustrated for the formation of the dehalogenated ester 6a under established heterogeneous
Pd-catalyzed hydrogenation conditions (other methods were tested as
well, but we were not able to reduce the N–O bond without cleaving
the C–Cl bond).
Scheme 2
Further Manipulations of the Masked α-Chlorinated
β2,2-AA Derivative 2a
Conditions (a) NaN3 (1.1
equiv), acetone, 25 °C, 24 h [with (+)-2a (er = 99.0:0.5)]; (b) CHCl3 (0.6 vol %
of EtOH), CsF (3 equiv), 18-crown-6, 25 °C, 1 h
[with (+)-2a (er = 95:5)];
(c) NaNO2 (1.1 equiv), DMSO, 25 °C, 1 h [with rac-2a]; (d) Y(OTf)3 (10 mol %), MeOH, 25 °C, 72 h [with rac-2a]; (e) H2 (1
atm), Pd/C, MeOH, 25 °C, 24 h [with rac-2a]; (f) 4-ClC6H4CH2NH2 (5 equiv), MeOH, 25 °C,
24 h [with rac-2a].
Further Manipulations of the Masked α-Chlorinated
β2,2-AA Derivative 2a
Conditions (a) NaN3 (1.1
equiv), acetone, 25 °C, 24 h [with (+)-2a (er = 99.0:0.5)]; (b) CHCl3 (0.6 vol %
of EtOH), CsF (3 equiv), 18-crown-6, 25 °C, 1 h
[with (+)-2a (er = 95:5)];
(c) NaNO2 (1.1 equiv), DMSO, 25 °C, 1 h [with rac-2a]; (d) Y(OTf)3 (10 mol %), MeOH, 25 °C, 72 h [with rac-2a]; (e) H2 (1
atm), Pd/C, MeOH, 25 °C, 24 h [with rac-2a]; (f) 4-ClC6H4CH2NH2 (5 equiv), MeOH, 25 °C,
24 h [with rac-2a].When testing the α-chlorination
of a variety of alternatively
substituted α-arylated starting materials 1 under
the optimized conditions next (Scheme ), it turned out that this protocol, in general, tolerates
different substitution patterns (like the halogenated derivatives 2e–2h), but some interesting limitations also became obvious.
The thiophene-containing 2d was obtained with more than 50% yield but a lower enantioselectivity,
indicating that the KR step is less efficient for this substrate as
compared to others. In addition, the p-OMe- and p-OTBDMS-containing 2i and 2j could not be isolated
as they decomposed very quickly, forming colored byproducts which
most likely possess p-quinone methide-type structures.
It was however possible to add NaN3 directly after completion
of the α-chlorination, resulting in formation of the α-azidated
products 2i and 2j instead. Unfortunately, enantioselectivities
were not very high, which can be rationalized by a partial erosion
of the enantiopurity of the primary reaction products 2i and 2j because of the aforementioned formation of quinone methide-type
intermediates (to which NaN3 can add, as well[54,55]). It should be noted that we also tried to carry out this chlorination
on α-alkyl-substituted derivatives 1 (e.g., Bn
instead of Ar), but unfortunately, these turned out to be less reactive
and gave trace amounts of the product only (the same outcome was obtained
for the analogous fluorination reaction), which underscores the strong
influence of the nature of the α-substituent on the reactivity
of compounds 1.
Scheme 3
Asymmetric Application Scope for the
Synthesis of Masked α-Chlorinated
β2,2-AA Derivatives (+)-2
Asymmetric α-Fluorination
Based on the knowledge
gathered for the asymmetric α-chlorination of isoxazolidin-5-ones 1, we next investigated the (analogous) α-fluorination
of these compounds. Although a handful of previous reports described
successful examples for the asymmetric synthesis of some α-F-β2,2-AA derivatives,[33−36] the general enantioselective synthesis of these valuable
targets is still far from being a solved challenge. Thus, we focused
on the asymmetric ammonium-salt-catalyzed α-fluorination of
the parent substrate 1a with N-fluorobenzenesulfonimide
(NFSI, 9) as the electrophilic F-transfer agent next
(Table gives an overview
about the most significant results obtained in a detailed screening
of different catalysts and conditions). First attempts trying to apply
our chlorination-inspired α-heterofunctionalization–kinetic
resolution strategy with NaOPh failed, resulting in full decomposition
of starting 1a, without any product 2a formation (entry 1). We next changed for “more
common” asymmetric ammonium salt conditions using Cs2CO3 as a solid inorganic base. This allowed for a promising
first hit, giving (+)-2a with
reasonable conversion and a good er of 85:15 when using 5 mol % of
the Maruoka catalyst A1 in toluene (entry 2). Noteworthy,
at this point, we already observed a rather pronounced sensitivity
of product 2a to prolonged exposure
to base or acid (including silica gel), leading to formation of the
elimination product 4 as well as other unidentified decomposition
products. This made purification of 2a a bit tricky, requiring either a rather fast column chromatographic
isolation or recrystallization from cyclohexane to obtain 2a in reasonable purity and yield (although
some loss of material was observed, as well, especially after silica
gel column chromatography). For that reason, we calculated in situ
yields using an internal NMR standard in all cases and carried out
further isolation attempts only once suited overall conditions were
identified.
Table 2
Optimization of the Asymmetric α-Fluorination
of Isoxazolidin-5-one 1aa
entry
cat. (mol %)
solvent
base (equiv)
T (°C)
t (h)
yield (%)b
erc
1
A1 (5)
toluene
PhONa (1.1)
25
24
2
A1 (5)
toluene
Cs2CO3 (1.5)
25
24
65
85:15
3
A1 (5)
MTBE
Cs2CO3 (1.5)
25
24
70
93:7
4
A1 (5)
Et2O
Cs2CO3 (1.5)
25
24
75
92:8
5
A1 (5)
Et2O
K2CO3 (1.5)
25
24
<5
6
A1 (10)
Et2O
Cs2CO3 (1.5)
25
65
85 (71d)
92:8
7
A2 (10)
Et2O
Cs2CO3 (1.5)
25
65
60
91:9
8
A1 (1)
Et2O
Cs2CO3 (1.5)
25
65
45
85:15
9
A1 (5)
Et2O
Cs2CO3 (1.5)
–20
65
75
94:6
10
A1 (5)
Et2O
Cs2CO3 (1.5)
–40
65
60
95:5
11
A1 (5)
Et2O
Cs2CO3 (1.5)
–60
144
15
96:4
12
A1 (5)
MTBE
Cs2CO3 (1.5)
25
40
85 (73d, 55e)
93:7
Unless otherwise stated, all reactions
were carried out using 0.1 mmol 1a and 0.25 mmol 9 in the indicated solvent (0.017 M with respect to 1a) under the given conditions.
In situ yields of 2a determined using 4-fluoroanisol as an internal
NMR standard.
Given as (+)/(−)-2a ratio (determined by HPLC using
a chiral
stationary phase); please see the discussion below concerning the
assignment of the S-configuration for the (+)-enantiomer.
Isolated yield after precipitation
of excess of reagents, off-products, and catalyst with cyclohexane
(containing less than 5 mol % of remaining diphenylsulfonimide, the
given yield has been corrected for this “contamination”).
Isolated yield after column
chromatography.
Unless otherwise stated, all reactions
were carried out using 0.1 mmol 1a and 0.25 mmol 9 in the indicated solvent (0.017 M with respect to 1a) under the given conditions.In situ yields of 2a determined using 4-fluoroanisol as an internal
NMR standard.Given as (+)/(−)-2a ratio (determined by HPLC using
a chiral
stationary phase); please see the discussion below concerning the
assignment of the S-configuration for the (+)-enantiomer.Isolated yield after precipitation
of excess of reagents, off-products, and catalyst with cyclohexane
(containing less than 5 mol % of remaining diphenylsulfonimide, the
given yield has been corrected for this “contamination”).Isolated yield after column
chromatography.Conversion
and er using Cs2CO3 could be improved
by changing for ethereal solvents next (entries 3 and 4). While MTBE
allowed for a marginally higher er, reactions in Et2O showed
a slightly better conversion, and a further screening of conditions
was carried out in Et2O then. Other bases were tested,
as well, but, as exemplified for K2CO3 (entry
5), turned out to be not suitable, and we therefore relied on Cs2CO3 for the remaining optimization (variations
of reagent and base ratios were also tested but without any improvement).
To increase yield and er, we next used 10 mol % of A1 (65 h overall reaction time, entry 6). This allowed for a high er
of 92:8 accompanied by a satisfying in situ yield of 85% and an isolated
yield of 71% (after precipitation of reagents, off-products and catalyst
with cyclohexane). Using other catalysts, the alternatively substituted
Maruoka catalyst A2 gave almost the same selectivity
(entry 7), while all the other scaffolds shown in Figure again gave more or less racemic 2a only (results not given in Table ). Lowering the catalyst
loading to 1 mol % (entry 8) led to a reduced yield and selectivity,
and we thus again used 5 mol % of A1 for further attempts
at lower temperatures (entries 9–11). Although it was possible
to increase the er up to 96:4 at −60 °C, this increase
in selectivity came with a significantly reduced conversion/yield.
Therefore, to obtain a practical balance of yield and er, we finally
opted for room temperature conditions and carried out the α-fluorination
of 1a in MTBE for a slightly prolonged reaction time
of 40 h (entry 12). This allowed for the synthesis of (+)-2a in 85% in situ yield (isolated yields 73%
after crystallization or 55% after column chromatography) and with
an er of 93:7.With these conditions in hand, we next investigated
the application
scope for the α-fluorination of starting materials 1 and the suitability of products 2 for further manipulations (Scheme ). A variety of different aryl substituents
were well-tolerated, resulting in reasonable enantioselectivities
and in situ yields for products 2. Unfortunately, the pronounced sensitivity of these compounds, however,
made isolation by silica gel column chromatography difficult, especially
for electron-rich aryl derivatives like 2i (it should, however, be emphasized that we did not
try to develop crystallization methods for each derivative as we did
for the parent 2a).
Scheme 4
Asymmetric
Application Scope for the Synthesis of Masked α-Fluorinated
β2,2-AA Derivatives (+)-2 and (Attempted) Further Transformations,
IST is the yield determined
using 4-fluoroanisol as an internal NMR standard; SG is isolated yield
after silica gel column chromatography.
Conditions: (a) Different hydrogenation conditions
(with or without previous TFA-mediated Boc-deprotection of 2a); (b) ArCH2NH2 in t-BuOH, 90 °C; (c) TFA in CH2Cl2 followed by addition of 12 in DMF.
Asymmetric
Application Scope for the Synthesis of Masked α-Fluorinated
β2,2-AA Derivatives (+)-2 and (Attempted) Further Transformations,
IST is the yield determined
using 4-fluoroanisol as an internal NMR standard; SG is isolated yield
after silica gel column chromatography.Conditions: (a) Different hydrogenation conditions
(with or without previous TFA-mediated Boc-deprotection of 2a); (b) ArCH2NH2 in t-BuOH, 90 °C; (c) TFA in CH2Cl2 followed by addition of 12 in DMF.Finally, we also investigated the use of the masked α-F-β-AA 2a to carry out further transformations
(Scheme , lower part).
Hereby, we first investigated the reductive ring opening toward the
free carboxylic acids 10 as well as the nucleophilic
ring opening with benzylamine derivatives to access products 7. While the latter could be isolated in relatively low yields
(accompanied by decomposition of 2a under the basic reaction conditions), formation of the acids 10 could only be detected by direct LRMS analysis of the crude
products (which contained significant amounts of unspecified side
products already), but all attempts to isolate these products failed.
Similar results were unfortunately obtained when testing the well-established
KAHA ligation of 2a with the
ketoacid 12.[56,57] Formation of the dipeptide 11a could be confirmed by LRMS analysis,
but again all attempts to isolate this interesting target failed because
of its high sensitivity.
Asymmetric α-Bromination and Stereochemical
Considerations
Having investigated the asymmetric synthesis
of masked α-Cl
and α-F-β2,2-AA derivatives 2 and 2 in much detail, we became interested in testing if analogous α-Br
derivatives 2 may be accessible,
as well. Obviously, considering the observed sensitivity of compounds 2 and 2 under acidic and/or basic conditions, we expected an even
more pronounced lability of the related Br target 2. Thus, we were also not too much surprised
that we did not succeed in carrying out the direct electrophilic α-bromination
of the parent substrate 1a with N-bromosuccinimide.
Under several conditions that were tried, the starting material remained
either unreacted or decomposed, and we therefore opted for an alternative
approach to access 2a next.
Recently the groups of Ibrahim and Adamo described the stereospecific
SN2-type substitution of enantioenriched alkylphenylsulfides
with Cl or Br,[58−60] which provides an appealing entry to halogenated
alkanes with good levels of stereocontrol (inversion of configuration).
Inspired by these reports,[58−60] and considering the fact that
α-benzyl-substituted isoxazolidin-5-ones 1 were
successfully α-sulfanylated under asymmetric ammonium salt catalysis
by Brière before,[20] we became interested
if an asymmetric α-sulfanylation–desulfurylative bromination
sequence may allow us to access the target α-Br derivative 2. In analogy to Brière’s
pioneering report,[20] the α-sulfanylation
of the phenyl-substituted 1a could be carried out with
good enantioselectivity with catalyst A2 (using succinimide 13 as the PhS-transfer agent; Scheme ). Gratifyingly, utilizing the reported desulfurylation–bromination
conditions,[59] it was possible to access
(−)-2a with good in
situ yield and moderate levels of enantiospecificity (the loss in
enantiopurity can be attributed to a rapid epimerization of product 2a under the reaction conditions).
As expected, this compound turned out to be relatively unstable, resulting
in the fast formation of unidentified decomposition products as well
as in the elimination of HBr (giving alkene 4), which
made further purifications (e.g., by column chromatography) not possible.
Interestingly, however, crude (−)-2a can directly be reacted with NaN3 to access
(−)-2a under conditions
similar to those established starting from (+)-2a already (which gave (+)-2a, as shown in Scheme ).
Scheme 5
Asymmetric Sulfanylation and Stereospecific
Desulfurylation–Halogenation
Procedures
The opposite sense of optical
rotation (as well as HPLC retention
orders) of products 2a obtained
via these two different approaches clearly confirm the opposite absolute
configuration of (−)-2a relative to (+)-2a and (+)-2a. In addition, it was also possible
to convert (+)-2a into (−)-2a upon treatment with SO2Cl2. This process again proceeds with good enantiospecificity,
and the optical rotations (as well as HPLC retention orders) of all
these products accessed by different paths now confirm that (+)-2a as well as (+)-2a and (+)-2a prepared by means of an α-heterofunctionalization of 1a in the presence of (R,R)-A1 or (R,R)-A2 have identical absolute configurations. This high level
of catalyst-controlled face-selectivity, independent of the nature
of the employed electrophile, is also in full accordance with previous
observations.[20−25] There, it was always found that the R,R-enantiomers of catalysts A1 and A2 efficiently
block the Re-face of compounds 1 and
thus favor Si-face approaches of the electrophiles
(proven by single-crystal X-ray analysis for various enantiomerically
enriched analogous products).[20−25] Accordingly, when considering these earlier observations as well
as the above-described chemical correlation, and based on our additional
computational studies (vide infra), the absolute configuration of
the major (+)-enantiomers of products 2 can be assigned to be S, despite of the fact
that we were unfortunately not able to obtain crystals of enantioenriched
products 2 suited for X-ray analysis.
Computational
Studies
To better understand the origin
of selectivity and to elaborate on the importance of the Maruoka catalysts A in catalyzing these reactions efficiently, we performed
DFT studies on the chlorination and fluorination reactions catalyzed
by A1 (as well as the slightly less selective derivative A2(53)). In addition, these calculations
will help us in further supporting the proposed absolute configurations
for the favored enantiomers of products 2. First, we
modeled the competing major and minor enantiomeric transition state
structures (TSS) for the A1-catalyzed chlorination reaction
of 1c with reagent 3. In line with the outcome
of our chemical correlation (vide supra) and previous observations,[20−25] (R,R)-A1 efficiently
favors the Si-face chlorination of starting material 1c (resulting in (S)-2c). The lowest-lying TSS for the major S-enantiomer was found to be favored by 2.3 kcal/mol at
298 K (Figure ). Closer
inspection of the TSS revealed that the transferring electrophilic
chlorine was found to nearly be at the same distance in both TSS.
However, the TS(S)major enjoys stronger
hydrogen bonding interactions between the reactant fragments and the
Maruoka ammonium catalyst compared to TS(R)minor.[61] Distortion–interaction analysis
decomposed the 2.6 kcal/mol electronic energy difference between the
competing TSS into 1.1 kcal/mol of activation strain/distortion and
1.5 kcal/mol of interaction energy favoring the major enantiomer.
Furthermore, decomposition of the interaction energy revealed strong
electrostatic interactions (+1.8 kcal/mol) between the catalyst and
the reactants favoring TS(S)major (note
that this electrostatic interaction was lower for the A2-catalyzed chlorination, thus substantiating the importance of the
CF3 groups[53]). Finally,
TS(S)major was found to enjoy dispersion
interactions (0.5 kcal/mol) more favorable than those of TS(R)minor.
Figure 2
Competing enantiomeric TSS for the A1-catalyzed α-chlorination
computed at PCM(toluene)-UFF:M062X/6-31+G(d,p)//PM7:B3LYP/6-31G*.
Competing enantiomeric TSS for the A1-catalyzed α-chlorination
computed at PCM(toluene)-UFF:M062X/6-31+G(d,p)//PM7:B3LYP/6-31G*.The steric cavity provided by the Maruoka catalyst
was visualized
by help from the SambVca algorithm (Figure ). We observed that the TS leading to the
major enantiomer suffered less steric interactions owing to a higher
percentage of free volume (43.1% for TS(S)major vs 42.7% for TS(R)minor) in the cavity.
Furthermore, the area affected by the steric interactions of the catalyst
arms indicated by area in red (Figure ) is smaller in TS(S)major.
Figure 3
Buried volume plots for the major and minor enantiomeric TSS for
the (R,R)-A1-catalyzed
α-chlorination.
Buried volume plots for the major and minor enantiomeric TSS for
the (R,R)-A1-catalyzed
α-chlorination.Additionally, we also
investigated the α-fluorination of 1c catalyzed
by (R,R)-A1. In line
with the α-chlorination, computations clearly
support the Si-face attack as well (favoring (S)-2c), as TS-F-(S)major was found to be favored by 1.8 kcal/mol
over the minor enantiomer (Figure ; this energy difference corresponds to a theoretical
er = 96:4, which is slightly higher than the experimental outcome
(er = 93:7)). Overall, similar key interactions between the catalyst
and the substrates as observed for the chlorination were identified,
thus underscoring the rather general activation mode of ammonium salt A1 when used for asymmetric α-functionalizations of
isoxazolidinones 1.
Figure 4
Competing enantiomeric TSS for the A1-catalyzed α-fluorination
computed at PCM(diethyl ether)-UFF:M062X/6-31+G(d,p)//PM7:B3LYP/6-31G*.
Competing enantiomeric TSS for the A1-catalyzed α-fluorination
computed at PCM(diethyl ether)-UFF:M062X/6-31+G(d,p)//PM7:B3LYP/6-31G*.A slightly reduced cavity volume was observed in
the case of the A1-catalyzed fluorination reaction (44%
for TS(S)major vs 44.4% for TS(R)minor), presumably due to the slightly longer
hydrogen bonding distances
observed in the fluorination reaction. Based on these results, the Si-face preference by the Maruoka’s catalyst can
be attributed to both the uniquely confined steric pocket generated
by the arms of the biphenyl groups and the electrostatic environment
generated by the electron-withdrawing substituents on the arms, as
these groups were found to play a key role in modulating the hydrogen
bond strength of the spirocyclic Maruoka-type catalysts.
Conclusion
A detailed experimental and computational study on the enantioselective
synthesis of (masked) α-halogenated β2,2-amino
acid derivatives by means of asymmetric α-halogenation strategies
of α-arylisoxazolidin-5-ones 1 has been carried
out. High levels of enantioselectivities were possible by carrying
out the electrophilic α-chlorination and α-fluorination
in the presence of Maruoka’s spirocyclic binaphthyl-based ammonium
salts. Noteworthy, while the α-fluorination followed a classical
α-functionalization pathway, the α-chlorination protocol
was most selective when carried out as a tandem process consisting
of the electrophilic α-chlorination first, followed by a direct
kinetic resolution via a nucleophilic ring opening. In addition, the
α-bromination was possible, as well, via an alternative strategy
by carrying out an enantioselective α-sulfanylation first, followed
by a stereospecific desulfurylative bromination. All of the accessed
targets 2 were investigated for their potential to undergo
further manipulations. Moreover, detailed accompanying mechanistic
studies using DFT methods revealed the key features for the catalyst–substrate
interactions and provided an explanation for the high potential of
the used catalysts to facilitate reactions of substrates 1 with a broad variety of electrophiles.
Experimental
Details
General Methods
1H, 13C, and 19F NMR spectra were recorded on a Bruker Avance III 300 MHz
spectrometer with a broad band observation probe and a sample changer
for 16 samples, a Bruker Avance DRX 500 MHz spectrometer, and on a
Bruker Avance III 700 MHz spectrometer with an Ascend magnet and TCI
cryoprobe, which are both property of the Austro Czech NMR Research
Center “RERI uasb”. NMR spectra were referenced on the
solvent peak and chemical shifts are given in parts per million.High-resolution mass spectra (HRMS) were obtained using a Thermo
Fisher Scientific LTQ Orbitrap XL with an Ion Max API source. Analyses
were made in the positive ionization mode if not otherwise stated.
HPLC was performed using a Thermo Scientific Dionex Ultimate 3000
or a Shimadzu Prominence system with diode array detector with a CHIRALPAK
AD-H, OD-H, CHIRAL ART amylose-SA or cellulose-SB (250 × 4.6
mm, 5 μm) chiral stationary phase. Optical rotations were recorded
on a Schmidt + Haensch polarimeter model UniPol L1000 at 589 nm.All chemicals were purchased from commercial suppliers and used
without further purification unless otherwise stated. Starting materials 1 were synthesized as described previously.[20−22] Dry solvents
were obtained from an MBraun-SPS-800 solvent purification system.
All reactions were carried out under argon atmosphere unless stated
otherwise.
General α-Chlorination Procedure
A flame-dried
reaction vial was charged with catalyst A1 (5.6 mg, 5
mol %), 4-aryl isoxazolidin-5-one 1 (0.1 mmol, 1.0 equiv),
and dry toluene (1 mL). After complete dissolution, N-chlorosuccinimide 3 (15.1 mg, 1.1 equiv) and PhONa
(5.9 mg, 0.5 equiv; finely suspended in 1 mL of toluene) were added
successively. The reaction mixture was layered with argon and stirred
for 72 h at room temperature. Afterward, the reaction was quenched
by addition of saturated NH4Cl solution and diluted with
EtOAc and H2O. The aqueous phase was extracted with EtOAc
(3×), and the combined organic phases were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was subjected to flash column
chromatography (silica gel, heptanes/EtOAc) to obtain products 2 in the given yields and enantiopurities.
Scheme 1
Figure 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Figure 2
Figure 3
Figure 4