Stereodivergent entry to β-branched β-trifluoromethyl α-amino acid derivatives by sequential catalytic asymmetric reactions

Article abstract of DOI:10.1039/d1sc01442k

Currently, conventional reductive catalytic methodologies do not guarantee general access to enantioenriched β-branched β-trifluoromethyl α-amino acid derivatives. Herein, a one-pot approach to these important α-amino acids, grounded on the reduction - ring opening of Erlenmeyer-Pl?chl azlactones, is presented. The configurations of the two chirality centers of the products are established during each of the two catalytic steps, enabling a stereodivergent process.

Full text of DOI:10.1039/d1sc01442k

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Stereodivergent entry to b-branched b-
trifluoromethyl a-amino acid derivatives by
sequential catalytic asymmetric reactions†
Cite this: Chem. Sci., 2021, 12, 10233
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have been paid for by the Royal Society
of Chemistry
Vasco Corti, ‡ Riccardo Riccioli, Ada Martinelli, Sofia Sandri,
*
*
Mariafrancesca Fochi
and Luca Bernardi
Currently, conventional reductive catalytic methodologies do not guarantee general access to
Received 11th March 2021
Accepted 28th June 2021
enantioenriched b-branched b-trifluoromethyl a-amino acid derivatives. Herein, a one-pot approach to
these important a-amino acids, grounded on the reduction – ring opening of Erlenmeyer–Plochl
¨
DOI: 10.1039/d1sc01442k
azlactones, is presented. The configurations of the two chirality centers of the products are established
rsc.li/chemical-science
during each of the two catalytic steps, enabling a stereodivergent process.
not be accessed with sufficient selectivity. Furthermore, enan-
tioselective hydrogenation of tetrasubstituted olens can occa-
Introduction
sionally be challenging. In fact, the b-triuoromethyl Z-DHAAs
required for the target was found to be reluctant to asymmetric
hydrogenation,9a preventing application of Turner's formal
stereodivergent reduction of DHAAs.10 This ingenious chemo-
enzymatic approach, which unlocks access to the isomer not
obtainable by hydrogenation via downstream inversion of the a-
amino chirality centre in the reduced DHAA, is in fact estab-
lished only for b-aryl-b-methyl AAs. Eventually, to obtain the
target syn-triuoromethylated amino alcohol,§ Alimardanov
et al. resorted to a longer, yet effective and scalable, route,
encompassing a chiral auxiliary and introduction of the amino
functionality at a late stage.9a
b-Branched a-amino acids (AAs) carrying different b-substitu-
ents – thus bearing two vicinal chirality centres, at the a- and b-
carbons – are important yet challenging synthetic targets.1 The
stereocontrolled preparation of these compounds has been
tackled and realised with different (catalytic) methods.2–7 A non-
comprehensive list of examples includes enantioselective
conjugate additions and alkylations of glycinate imines,2
palladium catalysed b-C(sp3)–H alkylation and arylation of AAs,3
aziridine ring-opening,4 an engineered tryptophan synthase,5
multi-enzymatic b-methylation of AAs,6 and catalytic asym-
metric hydrogenation of a,b-dehydro-amino acids (DHAAs), in
its implementation with tetra-substituted substrates.7 This
latter approach (Scheme 1(a)) has disclosed diastereo- and
enantioselective entries to various classes of b-branched AAs,
including7d less common yet relevant b-triuoromethyl AA
derivatives.8,9 Given the common stereospecicity of the
hydrogenation, the E/Z geometry of the substrate dictates the
relative conguration of the product (Scheme 1(a)). Thus,
a diastereoisomer is obtainable only if the parent olen isomer
can be prepared. This constraint can have negative implica-
tions. For example, a straightforward synthesis of a preclinical
drug candidate via asymmetric hydrogenation of the corre-
sponding b-aryl-b-triuoromethyl DHAA was envisioned
(Scheme 1(b)).9a However, the required E-olen isomer could
With this background in mind, we envisioned an original
stereodivergent11 entry to b-branched AAs grounded on the
dynamic stereoselective ring-opening of enantioselectively
¨
reduced Erlenmeyer–Plochl azlactones (Scheme 1(c)). In
contrast with catalytic hydrogenation, this formal hydrogena-
tion of the azlactone olen (a DHAA derivative) xes the
congurations of the two hydrogenated centres in different
steps, lending itself to stereodivergency. Herein, we present the
rst demonstration of this strategy by its application to the one-
pot preparation of b-triuoromethyl AA derivatives 4 (Scheme
1(d)). In more detail, enantioselective transfer hydrogenation of
readily available substrates 1 (ref. 9a) with Hantzsch esters12 sets
the absolute conguration of the triuoromethylated b-centre.13
Subsequent dynamic alcoholytic ring-opening14 of intermedi-
ates 3 xes the absolute conguration of the a-carbon. In the
ring-opening reaction, the substrates 3 feature a considerable
bias towards the formation of anti-isomers 4. Such bias was
readily leveraged with conventional Cinchona catalysts to obtain
a range of anti-4 products with very high stereoselectivities
(including compounds not suited for hydrogenation).
Conversely, the development of the syn-selective process was
Department of Industrial Chemistry “Toso Montanari” and INSTM RU Bologna, Alma
Mater Studiorum – University of Bologna, V. Risorgimento 4, 40136 Bologna, Italy.
E-mail: mariafrancesca.fochi@unibo.it; luca.bernardi2@unibo.it
† Electronic supplementary information (ESI) available: Additional optimization
results, additional discussion on the ring-opening step, control experiments for
the one-pot protocol, experimental section, copies of NMR spectra and HPLC
traces. See DOI: 10.1039/d1sc01442k
‡ Current address: Department of Chemistry, Aarhus University, 8000 Aarhus,
Denmark.
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Scheme 1 (Left) (a) catalytic asymmetric hydrogenation approach to b-branched AAs, and (b) its failure with a b-trifluoromethyl drug candidate.
(Right) (c) the underlying concept of this work and (d) its demonstration with b-trifluoromethyl substrates 1.
less straightforward, requiring a peculiar ammonia-derived thalidomide. An additional example is represented by the
squaramide catalyst to afford the syn-4 isomers with variable heterocyclic compound derived from a 3-(triuoromethyl)aze-
diastereoselectivities.
tidine carboxylic acid, shown in Fig. 1. This compound is
It is worth stressing that b-branched b-triuoromethyl AAs, a member of a library of related heterocycles, investigated for
and derivatives thereof, have found widespread interest in their activity as inhibitors of phosphoinositide 3-kinases.16
medicinal chemistry (Fig. 1). b-Triuoromethylated analogues
of natural AAs have been incorporated into peptides, wherein
the triuoromethyl group can give unique effects on stability,
Results and discussion
acidicy/basicity, folding behaviour, hydrophobicity, and ulti-
mately biological activity.8a The b-triuoromethyl AA framework
can also be found in less canonical structures. Besides the drug
candidate mentioned in Scheme 1(b), which showcases inhibi-
tion of b-amyloid production,15 another b-triuoromethyl AA
structure of medicinal interest is an analogue of thalidomide,2i
which feature enhanced congurational stability compared to
At the outset, with transfer hydrogenation to b,b-disubstituted
nitroalkenes promoted by Jacobsen-type catalysts as a lead,17 we
explored different variables in the reduction of b-phenyl-b-tri-
¨
uoromethyl Erlenmeyer–Plochl substrates
1
with HEs.{
Preliminary screening of different catalysts and HEs identied
the conditions outlined in Table 1, entry 1, as promising start-
ing point. In more detail, using 20 mol% of catalyst 2a in
combination with the isobutyl HE, in dichloromethane (reagent
grade) as solvent at low temperature (ꢀ30 ꢁC), the 2-phenyl
azlactone 1a could be reduced with full conversion and prom-
ising enantioselectivity (70% ee). Products 3 of the transfer
hydrogenation reaction are relatively unstable. Thus, for CSP
HPLC analysis they are converted to the ultimate products 4 by
ring-opening with allyl alcohol using achiral tertiary amine
promoters, furnishing the two diastereoisomers 4. These two
isomers feature comparable ees, validating this method for the
evaluation of the enantioselectivity of the reduction step. Thus,
a systematic variation of the modules of this type of Jacobsen
catalyst18 (AA portion, double H-bond donor, amide portion,
terminal N-group), of C2 substituents of the azlactone, and of
reaction conditions, was undertaken.{ Exploration of catalysts
based on double hydrogen bond donors other than thiourea
(ureas and squaramides), and another AA portion (L-valine),
conrmed the L-tert-leucine derived thiourea as the most effi-
cient catalyst core. Whereas variation of solvent and/or dilution
Fig. 1 Medicinal chemistry relevant b-branched b-trifluoromethyl
AAs.
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Table 1 Screening of azlactones 1 and catalysts 2 in the transfer
towards the anti-isomer. We initially surmised that such
substrate-bias, hindering access to syn-4,19 would be circum-
scribed to the tertiary amine promoted alcoholytic ring-
opening. Since a variety of DKRs of azlactones by ring-
opening reactions, using different nucleophiles and catalytic
approaches (Lewis bases, Lewis acids, Brønsted acids,
enzymes), are available in the literature,14 we hoped that one of
these could be subdued to our aims.
hydrogenation reaction. Representative resultsa
However, a preliminary screening of many of these methods
suggested the squaramide Cinchona catalyzed alcoholytic ring
opening20 as most promising option, despite its resemblance
with the biased achiral amine promoted reaction. State-of-the-
art Cinchona squaramide dimeric catalysts derived from quini-
dine (QD-1) and quinine (QN-1) (Scheme 2) were initially
employed with enantioenriched azlactone 3d under standard
conditions (dichloromethane, allyl alcohol, 0 ꢁC). While,
unsurprisingly, “matched” QD-1 increased the anti/syn ratio to
a high 10.0 : 1 value, compared to an achiral tertiary amine (ca.
5.5 : 1), we were pleased to observe that the corresponding
“mismatched” QN-1 could reverse the selectivity of the process,
forcing the ring-opening reaction towards a moderate prefer-
ence (1 : 2.3) for syn-4d. The products 4d displayed a higher
enantiomeric excess than 3d, in accordance with the Horeau
effect.21 Adjusting the reaction conditions and testing addi-
tional QD and dihydroquinidine (dhQD) derived structures led
to a highly anti-selective protocol. Catalyst dhQD-2 improved in
fact the diastereomeric ratio of the product 4d up to 14.2 : 1 in
favour of the anti-isomer. However, application of its quasi-
enantiomeric derivative dhQN-2 did not result in the expected
improvement in the syn-selectivity, providing a result similar to
QN-1 (1 : 2.4 vs. 1 : 2.3). This result emphasized that the tran-
sition states leading to the anti and syn-products are “intrinsi-
cally” diastereomeric,19b due to the presence of the chiral (R)-
congured b-branched chain of azlactone 3d. On these grounds,
different (i.e. non quasi-enantiomeric) catalyst structures may
be required for anti- and syn-selective processes. Thus, a range
of (dh)QN derived squaramide catalysts and reaction conditions
were examined (see also ESI†). The diastereomeric catalyst
dhQN-3 (from (S)-a-methylbenzylamine instead of (R)-a-meth-
ylbenzylamine of dhQN-2) was tested rst, giving however
a poor result. Subsequent catalyst screening, performed at RT,
suggested that the main factor affecting the stereoselectivity is
the bulkiness of the squaramide portion. While catalysts QN-4,
5, 6, wherein the squaramide bears a methylene group, gave
slight improvements compared to dhQN-2 (1 : 2.7–2.8 vs.
1 : 2.4), the more bulky tert-butyl substituted QN-7 provided
a lower d.r. (1 : 1.9). The similar performances of the prototyp-
ical22 3,5-bis(triuoromethyl)benzyl catalyst QN-4 and the
simple benzyl derivative QN-5 point to a negligible inuence of
the electronics of this group on selectivity. Thus, aiming at
reducing bulkiness, catalyst QN-8 derived from methylamine
was applied, providing indeed a rewarding improvement (anti/
syn ¼ 1 : 3.1). A further reduction in bulkiness could be ach-
ieved only by entirely removing the N-substituent, which was
nalized preparing and testing the ammonia derived catalyst
QN-9. Pleasingly, this peculiar and unprecedented structure was
able to afford syn-4d with a notable 1 : 4.6 selectivity. The very
a
Conditions: substrate 1 (0.05 mmol), catalyst 2 (0.01 mmol, 20 mol%),
HE (0.075 mmol), CH2Cl2 (200 mL), ꢀ30 ꢁC, 48 h. All reactions gave >90%
conversion of 1 (19F NMR). Filtration on silica, evaporation, then CH2Cl2
(0.5 mL), allyl alcohol (0.1 mmol), Et3N (1 drop), RT, 24–48 h.
b
Enantiomeric excess of anti-4 and syn-4, respectively, determined by
CSP HPLC aer chromatographic purication on silica gel.
was not fruitful, investigation of different terminal N-groups in
the thiourea (2a–f) indicated that the 4-(triuoromethyl)phenyl
residue (2b) could provide a distinct improvement, compared to
the common 3,5-bis(triuoromethyl)phenyl (2a) and other aryl/
alkyl groups (2c–f) (entries 1–6). With catalyst 2b, three differ-
¨
ently C2 substituted Erlenmeyer–Plochl azlactones 1b–d were
screened (entries 7–9). The 4-methoxyphenyl (PMP) derivative
1d gave better results, and was thus selected for further catalyst
development, which focussed on exploring various N-substitu-
ents on the amide (entries 10–14). Amongst catalysts 2g–k, the
N-benzyl-N-methyl amide derivative 2k performed best, afford-
ing the transfer hydrogenation product 3d with a respectable
85% ee, measured on the corresponding ring-opened derivative
4d.
A closer inspection at the alcoholytic ring-opening step of
compounds 3 promoted by achiral tertiary amines, indicated
that the ring-opened products 4 were obtained with higher anti/
syn ratios (5.5 : 1 for 4d) than the parent azlactones 3 (ca.
1.5 : 1). Thus, the alcoholytic process was dynamic, and biased
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Scheme 2 Optimization of the alcoholytic ring-opening step: selected results (d.r. values refer to anti/syn ratios).
poor solubility of QN-9 in CH2Cl2 resulted however in sluggish
reactivity, with only 50% conversion aer 42 h at RT. Such
shortcoming was overcome by switching to the more soluble
dihydroquinine derivative dhQN-10, which gave 4d with >90%
conversion, even by performing the reaction at 0 ꢁC, and in
a 1 : 5.9 diastereomeric ratio favouring the syn-isomer.23 Enan-
tiomeric excess was found to be good (92%), as expected. At this
stage, additional experiments indicated the unique require-
ments of the syn-selective reaction: catalyst dhQD-10, quasi-
enantiomeric of dhQN-10, gave an anti-selectivity in the
process comparable to an achiral tertiary amine (ca. 5 : 1).
Aiming at streamlining the overall process (1d / 4d) by
implementing a one pot procedure, thus circumventing the
problematic purication of azlactone intermediate 3d, it was
found that an excess of HE in the transfer hydrogenation reac-
tion has to be avoided, since this species inhibits the basic
squaramide catalyst used in the ring-opening step (see ESI†). In
contrast, the other components of the transfer hydrogenation
(thiourea catalyst 2k and pyridine co-product) do not interfere
with the second step. Fortunately, it was possible to drive the
transfer hydrogenation reaction to completion even by using
just 1.1 equiv. of HE. Ultimately, this modication was suffi-
cient to develop an efficient one-pot procedure.
Then, in line with the notion that enhancing the enantio-
purity of 3d would result in additional improvement of syn-
selectivity,19 an additional round of optimization of the catalyst
Scheme 3 Second round of catalyst optimisation for the hydrogen
transfer step: identification of optimal catalyst 2p.
used in the hydrogen transfer step was undertaken (Scheme 3).
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help rationalizing the subtle effects of the amide and the thio-
urea aryl groups on the enantioselectivity of the reaction, it
reconciles with the observed comparably high, but opposite,
sense of enantioinduction exerted by catalyst 2p on the two
isomeric olens (i.e. Z-1 / (3R)-3, and E-1 / (3S)-3, see ESI†).
From the experimental results shown in Scheme 3 (compare 2p
with 2q and 2r), the oen encountered positive relationship
between the extension of the p-system of the 2-substituent of
the pyrrolidine and the enantioselectivity24b is not apparent.
Stabilising cation-p interactions might not be helpful to selec-
tivity in this case.
Fig. 2 Tentative transition state model for the transfer hydrogenation
reaction.
The stage was thus set for the full unravelment of the ster-
eodivergent methodology (Scheme 4). It is clear from the results
reported that the improvement in enantioselectivity provided by
catalyst 2p in the rst step was indeed benecial to the dia-
stereoselectivities of the whole processes. Its combination with
catalyst dhQD-2 furnished anti-4d in good yield and in essen-
tially diastereo- and enantiopure form, while use of “mis-
matched” dhQN-10 in the second step afforded syn-4d in 72%
yield and >99% ee, with a notable 7.5 : 1 diastereomeric ratio.
These results are to be compared with the 14.2 : 1 d.r. and 89%
ee for anti-4d, and the 5.9 : 1 d.r. and 92% ee for syn-4d obtained
when catalyst 2k was used in the rst step (Scheme 2). Scheme 4
shows also how the different combinations of catalysts (2p and
ent-2p, dhQD-2 and dhQN-2, dhQD-10 and dhQN-10) could
permit the obtainment of the full set of stereoisomeric products
4d with moderate to excellent results. Moreover, although the
one pot protocol required longer reaction times (2–6 days
instead of 24 h), for the ring opening step, the Cinchona loading
could be lowered to 5 mol% without affecting the selectivity of
the process.
Different N-benzylic derivatives 2l–o related to 2k, and more
elaborated Jacobsen catalysts bearing chiral 2-aryl pyrrolidin-1-
yl amides24 2p–r were applied, promptly leading to improve-
ments. Indeed, compared to N-benzyl catalyst 2k, the related 9-
anthracenylmethyl derived structure 2o and the (2R)-2-phenyl-
pyrrolidine amide 2p afforded azlactone 3a with higher enan-
tioselectivities, with catalyst 2p providing better results (91/90%
ee), even at lower catalyst loading (10 vs. 20 mol%), and in
shorter reaction time (18 vs. 48 h).
A tentative transition state picture can be built from
a computationally validated model for the transfer hydrogena-
tion of nitroalkenes with HEs catalysed by Jacobsen-type thio-
urea catalysts (2),17c complemented with recognition studies of
lactones by a thiourea.25 Coordination of the acidic thiourea
hydrogens to the lactone moiety, possibly assisted by its N-aryl
group, and simultaneous stabilisation of the positive charge on
the HE by the amide oxygen, are the key interactions between
catalyst and substrates (Fig. 2). The tert-butyl group serves to
“lock” the conformation of the catalyst as shown, thus leading
to a match between the catalyst polar functionalities and
a transition state leading to (3R)-3d. While this model does not
The scope of the one-pot procedure was then studied (Table
2), by rst applying a range of b-triuoromethyl Erlenmeyer–
¨
Plochl azlactones 1d–j, bearing electron-donating (1g, i) or
Scheme 4 Diastereodivergent, enantioselective synthesis of the whole set of stereoisomers of 4d by applying different catalysts combinations in
the one-pot process.
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Table 2 Reaction scope of the anti-4 and syn-4 selective processes
Anti-4 selective processa
Syn-4 selective processa
Entry
1: R1, Rf
R2
Anti-4
Yieldb (%)
Anti/sync
eed (%)
Syn-4
Yieldb (%)
Syn/antic
eed (%)
1
2
3
4
5
6
7
8
1d: C6H5, CF3
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Me
anti-4d
anti-4e
anti-4f
anti-4g
anti-4h
anti-4ie,g
anti-4j
83
93
90
96
88
90
85
78
82
69
98
98
97
91
81
50
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
16.7 : 1
15.3 : 1
10.1 : 1
>20 : 1
18 : 1
99
98
99
98
98
98
99
97
96
98
99
97
89
97
98
96
syn-4d
syn-4e
syn-4f
72
72
77
84
78
60
87
37
53
50
65
78
85
77
70
50
7.5 : 1
3.6 : 1
4.4 : 1
8.5 : 1
4.4 : 1
3.7 : 1
4.0 : 1
2.1 : 1
2.3 : 1
2.0 : 1
3.6 : 1
2.6 : 1
1.3 : 1
5.3 : 1
5.9 : 1
6.7 : 1
>99
99
99
99
99
>99
>99
99
>99
>99
>99
>99
99
1e: 4-BrC6H4, CF3
1f: 4-ClC6H4, CF3
1g: 3-MeC6H4, CF3
1h: 4-FC6H4, CF3
1i: 4-MeOC6H4, CF3
1j: 3,5-F2C6H3, CF3
1k: 2-thienyl, CF3
1l: N-Ts-indol-3-yl, CF3
1m: C6H5, CF3CF2CF2
1n: cyclohexyl, CF3
1o: Et, CF3
syn-4g
syn-4he
syn-4ie,f
syn-4je
syn-4kg
syn-4lg
syn-4mg,h
syn-4ne,f
syn-4oe
syn-4pe
syn-4q
anti-4k
anti-4l
9
10
11i
12i
13i
14
15
16
anti-4m
anti-4ne
anti-4o
anti-4p
anti-4q
anti-4r
anti-4see
1p: Me, CF3
1d: C6H5, CF3
1d: C6H5, CF3
1d: C6H5, CF3
>99
99
99
Bn
i-Bu
syn-4re
syn-4se,g
>20 : 1
a
Conditions: 1 (0.15 mmol), HE (0.165 mmol, 1.1 equiv.), 2p (0.015 mmol, 10 mol%), CH2Cl2 (0.60 mL), ꢀ30 ꢁC, 24–48 h, then CH2Cl2 (1.8 mL),
dhQD-2 for anti-4 or dhQN-10 for syn-4 (0.0075 mmol, 5 mol%), R2OH (0.30 mmol, 2 equiv.), 0 ꢁC, 2–8 d. Isolated yield of combined
b
diastereoisomers 4 aer chromatography on silica gel. Determined on the crude mixtures by 19F NMR spectroscopy. Enantiomeric excess of
c
d
e
major diastereoisomer, determined by CSP HPLC. In the ring-opening step, aer 2–5 d, additional catalyst dhQD-2 for anti-4 or dhQN-10 for
syn-4 (0.0075 mmol) and R2OH (0.15 mmol, 1–2 equiv.), were added. Ring-opening step warmed to RT aer 2 d. Two step reaction performed
f
g
h
i
by isolating intermediate 3 by a rapid ltration on silica gel. Reduction step performed at 0 ꢁC. Conditions: 1 (0.05 mmol), HE (0.055 mmol,
1.1 equiv.), 2p (0.01 mmol, 20 mol%), CH2Cl2 (0.300 mL), ꢀ20 or 0 ꢁC, 24–48 h, then CH2Cl2 (0.60 mL), dhQD-2 for anti-4 or dhQN-10 for syn-4
(0.01 mmol, 10 mol%), allyl alcohol (0.1 mmol, 2 equiv.), 0 ꢁC, 3–6 d.
electron-withdrawing (1e, f, h, j) groups at the b-aryl ring, and b- hydrogenation step, which was performed with higher
heteroaromatic substituents (1k, l). Entries 1–9 show that these (20 mol%) catalyst loading and at higher temperatures (ꢀ20 ꢁC
substrates behaved very well in the anti-selective reaction, for the ethyl and methyl derivatives 1o and 1p, 0 ꢁC for the more
providing the corresponding anti-4d-l with results comparable hindered cyclohexyl counterpart 1n). With these adjustments, it
to the parent anti-4d, that is, in good yields and outstanding was possible to obtain anti-4n–p with good selectivities, while
diastereo- and enantioselectivities. The syn-selective processes the results for syn-4n–p vary from the satisfactory level of syn-4n
provided variable results in terms of diastereoselectivities,
ranging from a fully satisfactory 8.5 : 1 value for product syn-4g
to less pleasing ca. 2 : 1 results for the b-heteroaromatic deriv-
atives syn-4k and syn-4l. The latter results can be ascribed to
a very high substrate bias towards anti-4k, l in the ring-opening
process (>10 : 1 employing Et3N), rather than to poor catalyst
dhQN-10 efficiency. Syn-4k and syn-4l were also obtained in
lower yields compared to the other compounds. Nevertheless,
the enantiomeric excesses of the major syn-4 isomers were
found to be excellent in all cases examined ($99% ee). Substrate
1m bearing a b-peruoro residue rendered results similar to the
b-heteroaromatic derivatives 1k and 1l, that is, excellent selec-
tivity in the anti-4m isomer, and moderate yield and diaster-
eoselectivity, but with >99% ee, for the syn-4m diastereoisomer
Scheme 5 Conversion of the catalytic products 4j to the corre-
(entry 10). The application of b-aliphatic substrates 1n–p
required an adjustment to the conditions used in the transfer
sponding amino alcohol hydrochlorides anti-6 and syn-6. (i) NaBH4,
THF/H2O, 0 ꢁC / RT, then column chromatography on silica gel. (ii)
HCl, MeOH/H2O, reflux, then work up and evaporation.
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to the less pleasing syn-selectivity for 4p (entries 11–13). The nancial support from the University of Bologna (RFO
latter result was ascribed to the deleterious combination of program), MIUR (FFABR 2017), and F.I.S. (Fabbrica Italiana
moderate enantioselectivity in the transfer hydrogenation step Sintetici).
(ca. 70% ee) with high substrate bias in the ring-opening step
(ca. 10 : 1). The last three entries 14–16 of Table 2 display the
results obtained by applying alcohols other than allyl in the
Notes and references
§ All through the paper, to identify the diastereomers of the b-branched b-tri-
alcoholytic process with substrate 1d. The peculiarity of the
present reaction system makes the tolerance to different
uoromethyl AA derivatives, we have used Masamune's syn and anti descriptors,
arbitrarily setting the b-aryl/alkyl group of these compounds in the main chain.
primary alcohols, known for the DKR of simple azlactones,20
Using CIP descriptors for the relative conguration (e.g. R*, S*), although more
less than obvious, especially in the case of the syn-selective
protocol. However, it was pleasing to observe that results in line
with the allyl derivatives 4d were obtained for the products of
methyl, benzyl and isobutyl alcohols 4q–s, although lower yields
were observed in the latter case.k
rigorous, would result in a less clear identication of the diastereoisomeric pairs.
{ For a more comprehensive list of screening results, see ESI.†
k For limitations in terms of substrate variations, see ESI.†
1 J. Michaux, G. Niel and J.-M. Campagne, Chem. Soc. Rev.,
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Compounds 4j were separately subjected to a two-step
reduction-hydrolysis sequence (Scheme 5), delivering the cor-
responding aminoalcohol hydrochlorides 6, via amides 5. It is
worth stressing that neither syn-6 – intermediate en route to the
drug candidate (see Scheme 1(b))9a – nor anti-6 can be easily
accessed by conventional asymmetric hydrogenation.7d
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We have proved that the conceptually new combination of two
catalytic processes (transfer hydrogenation – dynamic ring-
¨
opening) on Erlenmeyer–Plochl azlactones can provide a new
stereodivergent strategy to enantioenriched b-branched AAs.
The realization of this tactic with triuoromethylated substrates
has disclosed a one-pot entry to b-aryl-b-triuoromethyl AA
derivatives. Using the appropriate catalyst combination, the
anti-bias of the ring-opening reaction was leveraged, giving anti-
products with excellent stereoselectivities (d.r. up to >20 : 1, ee
$ 89%). The scope of this reaction includes substrates reluctant
to enantioselective hydrogenation. A newly designed ammonia
derived squaramide catalyst afforded the syn-isomers, not
obtainable by hydrogenation, with variable diaster-
eoselectivities (d.r. up to 8.5 : 1) and high enantioselectivities
(ee $ 99%).
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Author contributions
Conceptualization and supervision: VC and LB. Investigation
and methodology: all authors. Writing - original dra: LB.
Writing - review and editing: VC, MF, LB. Funding acquisition,
project administration and resources: MF and LB.
Conflicts of interest
6 C. Liao and F. P. Seebeck, Angew. Chem., Int. Ed., 2020, 59,
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There are no conicts to declare.
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Acknowledgements
We thank Enrico Marcantonio, Federico Curati, Riccardo
Ciciriello and Giorgiana Denisa Bisag for preliminary screening
and preparation of catalysts/substrates. We are grateful to Prof.
Eric Jacobsen for a helpful discussion. We acknowledge
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21 According to the Horeau effect (or Horeau amplication), in
a sequential process, like the present one, the enantiomeric
excess of the major diastereomer is higher than the
enantiomeric excess of the product obtained in the rst
step [(ee (int.)]. It can be understood by considering that
the minor enantiomer produced in the rst step is
converted, during the second step, to the minor
diastereoisomer. In simplied terms, for a reaction in
which the selectivity (s) of the second step is the same on
both enantiomers obtained in the rst step, the ee of the
major diastereoisomer can be derived from the following
equation: ee ¼ [ee (int.) + s]/[1 + s ꢂ ee(int.)] However, the
reaction under study represents a more complex situation,
since the second step occurs with different selectivities (s,
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© 2021 The Author(s). Published by the Royal Society of Chemistry
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