Catalytic enantioselective synthesis of β-amino alcohols by nitrene insertion

Article abstract of DOI:10.1007/s11426-020-9906-x

Chiral β-amino alcohols are important building blocks for the synthesis of drugs, natural products, chiral auxiliaries, chiral ligands and chiral organocatalysts. The catalytic asymmetric β-amination of alcohols offers a direct strategy to access this class of molecules. Herein, we report a general intramolecular C(sp³)-H nitrene insertion method for the synthesis of chiral oxazolidin-2-ones as precursors of chiral β-amino alcohols. Specifically, the ring-closing C(sp³)-H amination of N-benzoyloxycarbamates with 2 mol% of a chiral ruthenium catalyst provides cyclic carbamates in up to 99% yield and with up to 99% ee. The method is applicable to benzylic, allylic, and propargylic C-H bonds and can even be applied to completely non-activated C (sp³)-H bonds, although with somewhat reduced yields and stereoselectivities. The obtained cyclic carbamates can subsequently be hydrolyzed to obtain chiral β-amino alcohols. The method is very practical as the catalyst can be easily synthesized on a gram scale and can be recycled after the reaction for further use. The synthetic value of the new method is demonstrated with the asymmetric synthesis of a chiral oxazolidin-2-one as intermediate for the synthesis of the natural product aurantioclavine and chiral β-amino alcohols that are intermediates for the synthesis of chiral amino acids, indane-derived chiral Box-ligands, and the natural products dihydrohamacanthin A and dragmacidin A.[Figure not available: see fulltext.].

Full text of DOI:10.1007/s11426-020-9906-x

SCIENCE CHINA
Chemistry
•ARTICLES•
March 2021 Vol.64 No.3: 452–458
https://doi.org/10.1007/s11426-020-9906-x
Catalytic enantioselective synthesis of β-amino alcohols by nitrene
insertion
Zijun Zhou†, Yuqi Tan†, Xiang Shen, Sergei Ivlev & Eric Meggers*
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse 4, 35043 Marburg, Germany
Received September 23, 2020; accepted November 9, 2020; published online December 21, 2020
Chiral β-amino alcohols are important building blocks for the synthesis of drugs, natural products, chiral auxiliaries, chiral
ligands and chiral organocatalysts. The catalytic asymmetric β-amination of alcohols offers a direct strategy to access this class
of molecules. Herein, we report a general intramolecular C(sp3)–H nitrene insertion method for the synthesis of chiral ox-
azolidin-2-ones as precursors of chiral β-amino alcohols. Specifically, the ring-closing C(sp3)–H amination of N-benzoylox-
ycarbamates with 2 mol% of a chiral ruthenium catalyst provides cyclic carbamates in up to 99% yield and with up to 99% ee.
The method is applicable to benzylic, allylic, and propargylic C–H bonds and can even be applied to completely non-activated C
(sp3)–H bonds, although with somewhat reduced yields and stereoselectivities. The obtained cyclic carbamates can subsequently
be hydrolyzed to obtain chiral β-amino alcohols. The method is very practical as the catalyst can be easily synthesized on a gram
scale and can be recycled after the reaction for further use. The synthetic value of the new method is demonstrated with the
asymmetric synthesis of a chiral oxazolidin-2-one as intermediate for the synthesis of the natural product aurantioclavine and
chiral β-amino alcohols that are intermediates for the synthesis of chiral amino acids, indane-derived chiral Box-ligands, and the
natural products dihydrohamacanthin A and dragmacidin A.
asymmetric catalysis, nitrene, amination, chiral-at-metal, ruthenium
Citation:
Zhou Z, Tan Y, Shen X, Ivlev S, Meggers E. Catalytic enantioselective synthesis of β-amino alcohols by nitrene insertion. Sci China Chem, 2021, 64:
452–458, https://doi.org/10.1007/s11426-020-9906-x
1 Introduction
using chiral auxiliaries, or by applying catalytic asymmetric
methods (Figure 1(a)). However, all these standard methods
face significant limitations and drawbacks. The reduction of
α-amino acids is only attractive for naturally occurring
amino acid side chains and the L-stereochemistry. Chiral
auxiliaries, such as Ellman’s sulfinamide [5], have to be
employed in uneconomic equimolar amounts, and catalytic
asymmetric aminooxygenations of alkenes often lack a high
degree of regioselectivity [6], and entail other drawbacks
such as the use of toxic osmium in the case of the Sharpless
aminohydroxylation [7]. Biocatalytic approaches have also
been reported but rely on substrates and reaction conditions
that are compatible with enzymes [8].
Chiral amines are key structural motifs of drugs, natural
products, chiral auxiliaries, chiral bases, and chiral organo-
catalysts. Among them, chiral vicinal amino alcohols are
indispensable synthetic building blocks [1]. For example,
they are frequently used for the synthesis of bioactive com-
pounds [2] and chiral auxiliaries [3], and are precursors of
chiral oxazolines [4], which represent one of the most fre-
quently used class of chiral ligands in asymmetric transition
metal catalysis. Enantiomerically pure chiral β-amino alco-
hols are typically synthesized by accessing the chiral pool,
An appealing strategy for the asymmetric synthesis of
chiral β-amino alcohols starts from ubiquitous alcohols and
†These authors contributed equally to this work.
*Corresponding author (email: meggers@chemie.uni-marburg.de)
© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020
chem.scichina.com link.springer.com

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Zhou et al. Sci China Chem March (2021) Vol.64 No.3
(62%–75%) and enantioselectivities (43%–82% ee) were
only very modest and not of practical value.
Here we report an intramolecular catalytic asymmetric
nitrene insertion as a general method to access chiral β-
amino alcohols in high yields and with high enantioselec-
tivities (Figure 1(c)). Specifically, the ring-closing C(sp3)–H
amination of N-benzoyloxycarbamates with a new chiral-
at-ruthenium catalyst provides cyclic carbamates in up to
99% yield and with up to 99% ee. The obtained cyclic car-
bamates can be hydrolyzed subsequently to obtain chiral β-
amino alcohols and we showcase applications to the synth-
esis of natural products, a chiral vicinal diamine, a chiral
amino acid, and a chiral bisoxazoline ligand.
2 Experimental
Experimental procedures and analytical data, nuclear mag-
netic resonance (NMR) spectra, high performance liquid
chromatography (HPLC) traces, and crystallographic data
are listed in the Supporting Information online.
3 Results and discussion
Figure 1 State of the art and this study on asymmetric synthesis of chiral
β-amino alcohols (color online).
3.1 Initial experiments and optimization
We commenced our study by screening precursors of al-
koxylcarbonylnitrenes for their ability to undergo ring-
closing C–H aminations catalyzed by a class of chiral-
at-ruthenium catalysts recently developed in our group [16–
18]. These ruthenium catalysts are composed of two che-
lating inert N-(2-pyridyl)-substituted N-heterocyclic carbene
(NHC) ligands, which generate metal centered chirality, and
two labile acetonitrile ligands. The dicationic complexes are
complemented by two hexafluorophosphate anions. Such C2-
symmetric complexes are very suitable for intramolecular
C–H aminations which was demonstrated by us for the
asymmetric synthesis of pyrrolidines [19], imidazolidin-4-
ones [20], and imidazolidin-2-ones [21].
Azidoformates are well-established precursors of alkox-
ylcarbonylnitrenes upon release of dinitrogen [22]. However,
no reaction occured with phenethyl azidoformate 1aa at
room temperature in the presence of chiral-at-Ru catalyst Λ-
Ru1 (2.0 mol%) (entry 1, Table 1). Likewise, sulfonylox-
ycarbamates did not provide satisfactory results. For ex-
ample, the N-toluenesulfonyloxycarbamate 1ab afforded (S)-
2a in 69% NMR yield with just 68% ee (entry 2). The related
N-methylsulfonyloxycarbamate 1ac afforded (S)-2a in a
higher NMR yield of 94% but with a reduced enantioselec-
tivity of just 62% ee (entry 3). We next turned our attention to
N-benzoyloxycarbamates. Recent work from our laboratory
on intramolecular C–H oxygenations [23] and aminoox-
genations [24] revealed that our chiral-at-Ru catalysts effi-
builds a C(sp3)–N bond including a stereocenter in a single
step through regio- and enantioselective ring-closing C–H
amination chemistry. The Nagib group [9] recently in-
troduced an impressive method to accomplish this task
through a photoredox radical protocol. However, the method
requires a complicated cocktail out of iridium photocatalyst
and chiral copper catalyst, the use of expensive BARF
counterions, in addition to 25 mol% camphoric acid. We
envisioned to provide a stereocontrolled and regioselective
β-C(sp3)–H amination of alcohols by exploiting catalytic
asymmetric nitrene insertion (Figure 1(b)). Great progress
has been made for the catalytic asymmetric synthesis of
chiral amines using transition metal nitrenoid chemistry
under typically very mild reaction conditions [10]. However,
a general access to chiral β-amino alcohols in high yields and
with high enantioselectivity through enantioselective nitrene
insertion remains an unsolved problem. Sulfamate esters
have been demonstrated to undergo intramolecular ring
closing C–H aminations in the presence of hypervalent io-
dine reagents to provide cyclic sulfamidates [11–13], but are
difficult to hydrolyze and would preferably provide γ-amino
alcohols. The formation of cyclic carbamates through ring-
closing C(sp3)–H amination would be advantageous [14].
Davies provided four examples using N-tosyloxycarbamates
under chiral dirhodium catalysis [15]. Unfortunately, yields

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Zhou et al. Sci China Chem March (2021) Vol.64 No.3
a)
Table 1 Initial experiments and optimization
b)
c)
d)
Entry
Substrate
1aa
Catalyst
Λ-Ru1
Λ-Ru1
Λ-Ru1
Λ-Ru1
Λ-Ru1
Λ-Ru2
Λ-Ru2
Λ-Ru2
Λ-Ru2
Λ-Ru2
Conditions
NMR yield (%)
ee (%)
−
1
2
3
CH2Cl2 at 25 °C without base
CH2Cl2 at 25 °C
CH2Cl2 at 25 °C
CH2Cl2 at 25 °C
Standard
0
1ab
1ac
69
94
97
98
95
97
68
62
e)
4
1ad
1ad
1ad
1ae
78
5
6
82
Standard
86
7
40 °C instead
Standard
90
f)
8
1af
Quant. (99)
90
9
1af
No base
<5
92
N.D.
90
10
1af
Under air
a) Standard conditions: 1a(0.2 mmol), K2CO3(0.6 mmol), Ru catalyst (0.002 mmol) in 1,2-dichlorobenzene (4 mL) stirred at the 30 °C for 20 h under N2
1
unless noted otherwise; b) deviations from standard conditions are shown; c) determined by H NMR of the crude products using Cl2CHCHCl2 as internal
standard; d) enantiomeric excess determined by HPLC analysis of the crude main product on a chiral stationary phase; e) compare with Ref. [21]; f) isolated
yield in brackets. N.D.=not determined.
ciently generate ruthenium nitrenoid intermediates from
N-benzoyloxycarbamates. In fact, in a recent preliminary
single experiment we were able to convert the N-benzoy-
loxycarbamate 1ad to (S)-2a in 88% yield but with un-
satisfactory 78% ee (entry 4) [23]. Using carbamate 1ad we
next screened solvents and found that 1,2-dichlorobenzene is
the solvent of choice and provided almost quantitative NMR
yields (98%) with improved 82% ee (entry 5). However, this
enantioselectivity was still not of synthetic value. Since we
were not able to further improve the enantioselectivity by
modifying the reaction conditions, we turned our attention to
modifying the catalyst and discovered that by replacing the
imidazol-2-ylidene carbene moieties of Ru1 with the related
benzimidazol-2-ylidenes (Ru2) provided an improved en-
antiomeric excess of 86% ee under otherwise identical re-
action conditions (entry 6). Final improvements were
accomplished by functionalizing the benzoate leaving group.
Best results were obtained with 3,4,5-trimethoxybenzoate
(1ae) (entry 7) and 2,4-difluorobenzoate (1af) (entry 8) in
which both afforded the cyclic carbamate (S)-2a with 90% ee
(see Supporting Information online for a complete overview
of tested benzoates). The 2,4-difluorobenzoyloxycarbamate
appears slightly more suitable due to a somewhat higher
reactivity. Finally, without base the reaction proceeded very
sluggish (entry 9) or performing the reaction under air re-
sulted in a slightly reduced yield (entry 10).
3.2 Benzylic asymmetric C–H aminations
With the optimized reaction conditions in hand we in-
vestigated the substrate scope. N-Benzoyloxycarbamates
bearing different aryl substituents at the β-position were
tested first. As shown in Figure 2, oxazolidin-2-ones with
electron donating methoxy substituents in para- (2b), meta-
(2c) or ortho- (2d) positions of the phenyl moiety were ob-
tained in almost quantitative yields and with excellent en-
antioselectivities (90%–93% ee). A substrate bearing a
sterically very hindering ortho-methyl substituent was also
well tolerated and provided 99% yield and 92% ee (2e). A 4-
phenyl substituent on the phenyl moiety provided almost
quantitative yield together with an excellent enantioselec-
tivity of 98% ee (2f). Different electron-withdrawing groups
are also accommodated in para-position as demonstrated for
an electron-withdrawing fluorine (2g, 99% yield, 91% ee),
chlorine (2h, 92% yield, 88% ee), or bromine (2i, 99% yield,
90% ee). A 1-naphthyl group provided the cyclic carbamate

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Zhou et al. Sci China Chem March (2021) Vol.64 No.3
Figure 3 Substrate scope with respect to non-benzylic C–H aminations.
Ar=2,4-difluorophenyl unless noted otherwise. Superscript a) refers Ar=Ph
(color online).
Figure 2 Substrate scope with respect to benzylic C–H aminations.
Ar=2,4-difluorophenyl unless noted otherwise. Superscript a) refers mod-
ified substrate and reaction conditions: Ar=3,4,5-trimethoxyphenyl and
reacted at 40 °C for 20 h (color online).
group is also accommodated as shown by the alkyne product
2s (84% yield and 90% ee). The aminated C(sp3)–H bond can
also be flanked by an alkenyl group. While (E)-1t converted
to (E)-2t under complete retention of the alkene configura-
tion (88% yield, 63% ee), (Z)-1t (Z/E ratio>20:1) was con-
verted to (Z/E)-2t with an eroded Z/E diastereomeric ratio
(d.r.) of 10.3:1 (56% yield, 45% ee). This can be explained
with an isomerization from the thermodynamically less
stable Z-isomer to the preferred E-isomer in the course of the
C–H amination through an intermediate allyl radical. How-
ever, the radical is apparently not long-lived enough to fur-
nish complete isomerization (see Supporting Information
online for more mechanistic details). We were delighted to
find that a cyclohexene substitutent provided cyclic carba-
mate 2u in 96% yield and 92% ee. It is noteworthy that the
late-stage functionalization of (R)-nopol provided cyclic
carbamate 2v in 87% yield with 96:4 d.r. In this example, the
stereoselectivity of the C–N bond formation was controlled
only by chiral ruthenium catalyst since the racemic ruthe-
nium catalyst lead to the formation of 2v with only 1:1 d.r. In
addition, C–H amination next to a small isopropenyl sub-
stituent provided the product 2w in 79% yield with 61% ee.
Besides C(sp3)–H aminations at propargylic and allylic po-
sitions, ring-closing C–H amination was also possible at
aliphatic methylene groups without any adjacent activating
group. The adamantyl substituted cyclic carbamate 2x was
formed in 99% yield with 99% ee. The n-butyl substituted
oxazolidin-2-one 2y was formed in 53% yield with 80% ee.
The late-stage functionalization of 10-undecen-1-ol provided
2z in 41% yield and 79% ee. Finally, a substrate bearing an
adjacent chiral center was also employed, which is the late-
stage functionalization of (S)-citronellol, providing 2za in
2j with 99% yield and 93% ee, while a 2-naphthyl group
afforded the cyclic carbamate 2k with 97% yield and 92% ee.
A tryptophol-derived substrate provided oxazolidin-2-one in
66% yield and 85% ee (2l). The smaller 3-thiophene moiety
provided the cyclic carabamate 2m with 77% yield and 93%
ee. Oxazolidin-2-one 2n with stereocenters in the 4- and 5-
positions was obtained in 99% yield and 95% ee by de-
symmetrization of an indane substrate. A N-benzoylox-
ycarbamate derived from 1,3-diphenyl-2-propanol provided
the 4,5-difunctionalized oxazolidin-2-one 2o with two ad-
jacent stereocenters as a 1.8:1 trans/cis mixture with re-
spective 92% and 97% ee in overall 83% yield.
3.3 Non-benzylic asymmetric C–H aminations
Non-benzylic C–H amination reactions are of particular in-
terest since they are more difficult to achieve in high yields
and with high enantioselectivities. In fact, previous reported
ruthenium catalyzed enantioselective intramolecular C–H
aminations at non-benzylic positions from our group often
failed to get satisfactory results [19,21]. As shown in Figure
3, we investigated propargylic C–H aminations first and
encouragingly found the product 2p was formed in 91%
yield and 91% ee under standard reaction conditions. An
electron-donating methoxy substituent on the phenyl moiety
provided cyclic carbamate 2q with 91% yield and 94% ee
while an electron-withdrawing fluorine substituent provided
cyclic carbamate 2r with slightly reduced 85% yield and
90% ee. Replacement of the phenyl moiety with an alkyl

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Zhou et al. Sci China Chem March (2021) Vol.64 No.3
18% yield and >20:1 d.r. as determined by 1H NMR [25,26].
95% yield. The chiral auxiliary (S)-4 was recovered in 87%
yield.
The catalytic intramolecular C–H amination of substrate
1af was tested on a gram scale and proceeded smoothly
under standard reaction conditions to provide (S)-2a in 99%
yield with 90% ee (Figure 4(b)). Upon a following simple
recrystallization step, (S)-2a could even be obtained with
>99% ee. Furthermore, upon addition of the auxiliary (S)-4
after the reaction, the chiral-at-Ru catalyst was recycled in
78% yield and with >99:1 d.r. as the auxiliary complex Λ-
(S)-Aux-Ru2.
We also investigated follow-up conversions of the carba-
mate products. Accordingly, the oxazolidin-2-one (S)-2a
(recrystallized with >99% ee) was converted to the Boc-
protected β-amino alcohol (S)-5 without any loss of en-
antiomeric excess (Figure 4(c), method A). The aminoalco-
hol (S)-5 was reported as a valuable synthetic intermediate
3.4 Gram-scale reactions, catalyst recovery and syn-
thetic applications
For practical purposes it is important to note that our ru-
thenium catalyst can be easily prepared on a gram scale.
Accordingly, reaction of RuCl3 hydrate with the benzimi-
dazolium ligand 3 in ethylene glycol at 200 °C and after-
wards treated with AgPF6 afforded 1.05 g (81% yield) of
racemic ruthenium catalyst rac-Ru2 (Figure 4(a)). The ra-
cemic mixture was next reacted with the chiral auxiliary (S)-
2-(4-isopropyl-4,5-dihydrothiazol-2-yl)phenol (4) in the
presence of Et3N to provide the complex Λ-(S)-Aux-Ru2 as
a single stereoisomer in 43% yield. Treatment with tri-
fluoroacetic acid and exchange of the counteranion to a
hexafluorophosphate finally afforded the complex Λ-Ru2 in
Figure 4 Gram-scale reactions, catalyst recovery and further transformations (color online).

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Zhou et al. Sci China Chem March (2021) Vol.64 No.3
Figure 5 Synthetic application to natural products.
for the synthesis of chiral 1,2-diamine (S)-6 [27] and also the
chiral α-amino acid (S)-7 [28]. In another follow-up chem-
istry using bis(2-aminoethyl)amine as the ring-opening re-
agent, the oxazolidin-2-one 2n, bearing two vicinal
stereochenters, was converted to the corresponding chiral
amino alcohol (1S,2R)-8 which is a building block for the
frequently used chiral Box-ligand 9 (Figure 4(c), method B)
[29].
C(sp3)–H amination of N-benzoyloxycarbamates using a
new benzimidazol-2-ylidene carbene chiral-at-ruthenium
catalyst. 2,4-Difluorobenzoate and 3,4,5-trimethoxy benzo-
ate leaving groups afford for most substrates the best results.
The intramolecular C–H amination provides cyclic carba-
mates in up to 99% yield and with up to 99% ee for benzylic,
allylic, and propargylic C–H bonds. Completely non-acti-
vated C(sp3)–H bonds can also be aminated but provide
somewhat reduced yields and enantioselectivities. We de-
monstrated the synthetic value of this new method with the
catalytic enantioselective synthesis of chiral oxazolidin-2-
ones as intermediates of the natural products aurantioclavine,
dihydrohamacanthin A and dragmacidin A, chiral amino
acids, and indane-derived chiral Box ligand.
3.5 Synthetic applications to natural products
The utility of our new method for the straightforward
synthesis of natural products is shown in Figure 5. Substrate
1zb undergoes an intramolecular enantioselective cycliza-
tion to provide in 92% yield and with 91% ee (S)-2zb which
was reported as an intermediate for the synthesis of the
natural product (−)-aurantioclavine (Figure 5(a)) [30]. A
second example provides a concise route to the bisindole
alkaloids hamacanthin A and dragmacidin A. Accordingly,
ring-closing C–H amination of the indole containing sub-
strate 1zc provided under standard conditions the cyclic
carbamate intermediate (S)-2zc in 74% yield and 94% ee.
Further ring-opening provided the chiral β-amino alcohol 10
in 88% yield with 94% ee which was reported as an inter-
mediate for the synthesis of natural products dihy-
drohamacanthin A and dragmacidin A (Figure 5(b)) [31].
Acknowledgements
This work was supported by the Deutsche For-
schungsgemeinschaft (ME 1805/15-1). We thank Marcel Hemming for the
synthesis of some substrate intermediates.
Conflict of interest The authors declare no conflict of interest.
Supporting information The supporting information is available online at
http://chem.scichina.com and http://link.springer.com/journal/11426. The
supporting materials are published as submitted, without typesetting or
editing. The responsibility for scientific accuracy and content remains en-
tirely with the authors.
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