Asymmetric Ring-Closing Aminooxygenation of Alkenes en Route to 2-Amino-1,3-Diols with Vicinal Stereocenters

Article abstract of DOI:10.1021/acs.orglett.0c02452

A ring-closing aminooxygenation of alkenes with N-benzoyloxycarbamates occurs with very high diastereoselectivity (typically >20:1 d.r.) and very high enantioselectivity (up to 99percent ee). The reaction is catalyzed by a recently developed chiral-at-metal ruthenium complex at catalyst loadings of 0.5-1.0 mol percent. The reaction is proposed to proceed through a ruthenium nitrenoid intermediate that depending on the nature of the substrate undergoes either an aminooxygenation (1,2-disubstituted alkenes) or stops at the stage of the aziridination (trisubstituted alkenes), which can then be ring opened with benzoic acid. The resulting chiral cyclic carbamates can be hydrolyzed under basic conditions to provide versatile chiral 2-amino-1,3-diols with vicinal stereocenters.

Full text of DOI:10.1021/acs.orglett.0c02452

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Letter
Asymmetric Ring-Closing Aminooxygenation of Alkenes en Route to
2‑Amino-1,3-Diols with Vicinal Stereocenters
Yuqi Tan, Feng Han, Marcel Hemming, Jie Wang, Klaus Harms, Xiulan Xie, and Eric Meggers*
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ABSTRACT: A ring-closing aminooxygenation of alkenes with N-
benzoyloxycarbamates occurs with very high diastereoselectivity
(typically >20:1 d.r.) and very high enantioselectivity (up to 99%
ee). The reaction is catalyzed by a recently developed chiral-at-metal
ruthenium complex at catalyst loadings of 0.5−1.0 mol %. The
reaction is proposed to proceed through a ruthenium nitrenoid
intermediate that depending on the nature of the substrate undergoes
either an aminooxygenation (1,2-disubstituted alkenes) or stops at the
stage of the aziridination (trisubstituted alkenes), which can then be
ring opened with benzoic acid. The resulting chiral cyclic carbamates
can be hydrolyzed under basic conditions to provide versatile chiral 2-
amino-1,3-diols with vicinal stereocenters.
he catalytic asymmetric aminohydroxylation (AA) is a
very straightforward method to introduce chiral vicinal
K2CO3 (3 equiv) in CH2Cl2 at room temperature, the
carbamate 2a was obtained in 76% NMR yield as a single
diastereomer (>20:1 d.r.) and with 99% ee (entry 1).15,16 The
aziridine 3a was formed as a side product in 21% NMR yield.
For comparison, the acetoxycarbamate 1a′ provided the
corresponding carbamate 2a′ with a lower yield and lower
diastereoselectivity and no significant amounts of the aziridine
3a (entry 2), while the tosyloxycarbamate 1a′′ afforded both
carbamate 2a′′ (7%) and aziridine 3a (12%) in low yields
(entry 3). Thus, the benzoyloxycarbamate is the substrate of
choice for this conversion with K2CO3 as base in CH2Cl2 as
the solvent serving as the optimal standard conditions. For
example, replacing K2CO3 with Na2CO3 results in slightly
lower yield of 2a (entry 4), whereas Et3N provides 2a with a
higher yield but a reduced diastereoselectivity (entry 5). In the
absence of any base, the reaction proceeds sluggishly with a
reduced enantioselectivity (entry 6). Other solvents than
CH2Cl2 such as THF (entry 7) or acetone (entry 8) provide
carbamate 2a with lower yields. Finally, we found that the
reaction can be performed at a reduced catalyst loading of just
0.5 mol % without sacrificing the outcome (entry 9).
T
amino alcohols, which are a frequent structural motif in
pharmaceuticals, natural products, ligands, and auxiliaries.1
Despite the versatility of the Sharpless AA,2,3 the lack of
regioselectivity, limitations with the substrate scope, and the
requirement for toxic osmium have led to the development of
other synthetic methods. Such enantioselective aminooxyge-
nations of olefins include copper bis(oxazoline) (BOX)
catalyzed intramolecular cyclizations to chiral indolines and
pyrrolidines,4 copper and iron BOX catalyzed oxaziridine
additions,5 intramolecular copper BOX catalyzed oxyazida-
tions,6 iron BOX catalyzed cyclizations of N-benzoyloxy-
carbamates,7 the combination of iminium and enamine
organocatalysis,8 using chiral hypervalent iodine reagents,9
and enzymatic aminohydroxylations of styrenes by an
engineered hemoprotein.10 In this letter, we report a
ruthenium-catalyzed highly diastereoselective and highly
enantioselective tethered11 aminohydroxylation of N-
benzoyloxycarbamates, leading to cyclic carbamates which
can be hydrolyzed to 2-amino-1,3-diols with vicinal stereo-
centers.
Recently, we introduced a new class of “chiral-at-metal”
ruthenium catalysts, bearing two bidentate N-(2-pyridyl)-
substituted N-heterocyclic carbene ligands and two labile
acetonitriles, with the overall chirality originating from a
stereogenic ruthenium center.12 Since these catalysts are
suitable for C(sp3)−H aminations13,14 through intermediate
ruthenium nitrenoid species, we questioned if we could trap
them intramolecularly with an alkene. We initiated our study
with the N-benzoyloxycarbamate 1a shown in Table 1. When
1a was reacted with Λ-Ru (2.0 mol %) in the presence of
Next, we investigated the scope for this ruthenium-catalyzed
asymmetric aminooxygenation, starting with 1,2-disubstituted
alkenes (Scheme 1). N-Benzoyloxycarbamates of phenyl-
Received: July 23, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02452
© XXXX American Chemical Society
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A

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Letter
a
a
Table 1. Initial Experiments and Optimization
Scheme 1. Substrate Scope with Disubstituted Alkenes
b
yield (%)
b
c
entry
R
conditions
standard
standard
2
3a
d.r.
ee (%)
1
2
3
4
5
6
7
8
Bz
Ac
Ts
Bz
Bz
Bz
Bz
Bz
Bz
76
58
7
69
86
52
39
28
21
<1
12
22
3
1
4
1
18
>20:1
3.5:1
n.d.
>20:1
4.1:1
>20:1
10:1
99
99
n.d.
99
98
86
99
99
99
standard
Na2CO3 as base
Et3N as base
no base
THF as solvent
acetone as solvent
0.5 mol % cat.
d
>20:1
>20:1
e
f
9
75 (72)
a
Conditions: 1a-a′′ (0.05 mmol), cat. (2.0 mol %), and base (0.15
mmol) in solvent at rt for 16 h under N2. Complete conversion except
b
c
for entry 6. Determined by 1H NMR of the crude product. Ee of the
major diastereomer shown. 78% conversion. Modified conditions:
1a (0.2 mmol), cat. (0.5 mol %) in CH2Cl2 (0.01 M). Isolated yield
d
e
f
in parentheses. n.d. = not determined.
modified cinnamyl alcohols were tested first. Substituents at
the para-position of the phenyl moiety provided the
corresponding rearranged benzoylated cyclic carbamates 2b−
g in 60−81% yield and with high enantioselectivities of 99% ee,
except for the electron-donating para-methoxy derivative 2d
which was obtained with reduced 83% ee. However, a very
electron-rich benzodioxole derivative provided the amino-
oxygenation product 2h in 85% yield and with a high
enantioselectivity of 98% ee. The benzannulated 2-naphthyl
derivative 2i formed with 75% yield and 98% ee. A methyl
group in the meta-position of the phenyl moiety was well
tolerated (2j, 73% yield, 96% ee), whereas a methyl group in
ortho-position reduced the yield to 37% but with 98% ee (2k).
A furane derivative 2l (68% yield, 98% ee), indole derivative
2m (71% yield, 99% ee), and an alkynyl derivative 2n (76%
yield, 99% ee) also formed in good yields and with very high
enantioselectivities. A N-benzoyloxycarbamate of an aliphatic
allyl alcohol provided the benzoylated cyclic carbamate 2o with
a reduced yield of 32% but excellent 99% ee. 1,3-Dienes can
also be subjected to this aminooxygenation protocol as shown
for the alkene products 2p−r which formed in 51−60% yield
and 97−98% ee.
a
b
All products formed as single diastereomers (>20:1 d.r.). Catalyst
c
loading of 1.0 mol % was used. Reaction at 4 °C with 1.0 mol %
catalyst.
Scheme 2. Initial Reaction of a Trisubstituted Alkene and
Stereochemical Verification by Single Crystal X-ray
Diffraction
We next investigated trisubstituted alkene substrate 1s and
were surprised to find that under the standard reaction
conditions the aziridine 3s was formed exclusively as
1
determined by crude H NMR after workup (Scheme 2).
However, this aziridine is unstable and in our hands was
difficult to purify so that we reacted it without purification with
2,4-dichlorobenzoic acid in the presence of Ph3N to obtain the
benzoylated cyclic carbamate 4s′ in 80% yield over two steps
with >20:1 d.r. and 99% ee. The relative and absolute
configuration of this product were assigned by single crystal X-
ray diffraction and revealed an opposite absolute configuration
at the two stereocenters compared to the results with
disubstituted alkenes. Scheme 3 shows a few examples in
which we applied this two-step procedure to trisubstituted
alkene substrates (1s, 1t, 1v), with the difference that the
aziridine intermediates 3s, 3t, and 3v were treated with benzoic
acid instead of 2,4-dichlorobenzoic acid. As a result, the
B
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a
an opposite absolute configuration at the newly installed
carbon stereocenter. For steric and/or stereoelectronic reasons,
intermediate B then apparently prefers to undergo an aziridine
formation instead of a benzoate transfer. These two pathways
can rationalize the opposite configurations observed for the
aminooxygenation products 2 as compared to aziridines 3 and
aminooxygenation products 4. Support for a carbenium ion
mechanism stems from experiments using the geraniol
substrate (E)-1u and its diastereomer (Z)-1u which afford in
a stereoconvergent reaction the same product 3u, supporting
the proposed mechanism through a carbenium ion inter-
mediate in which the second step occurs under thermody-
namic control. This mechanism reveals that the observed high
enantioselectivities for the aminooxygenation products 2 are
not due to an especially high asymmetric induction but instead
are the result of two distinct pathways after the initial Si- or Re-
addition of the nitrene to the prochiral alkenes, resulting in the
formation of the distinct products 2 and 3 which can be easily
separated by standard methods.
In conclusion, we here reported a practical method for the
asymmetric aminooxygenation of alkenes starting from N-
benzoyloxycarbamates of allylic alcohols catalyzed by a
recently introduced chiral-at-metal ruthenium NHC catalyst.
The aminooxygenation products are formed with excellent
diastereoselectivity (typically >20:1 d.r.) and enantioselectiv-
ities (often 98−99% ee). The reaction is proposed to proceed
through a ruthenium nitrenoid intermediate that, depending
on the nature of the substrate, either undergoes an amino-
oxygenation (1,2-disubstituted alkenes) or stops at the stage of
the aziridination (trisubstituted alkenes), which can then be
ring opened with benzoic acid. The resulting chiral cyclic
carbamates can be hydrolyzed under basic conditions to
provide versatile chiral 2-amino-1,3-diols with vicinal stereo-
centers.18
Scheme 3. Substrate Scope with Trisubstituted Alkenes
a
b
All products formed as single diastereomers (>20:1 d.r.). Reaction
c
at 40 °C with 1.0 mol % catalyst. The relative configuration of 3u was
determined by NMR spectroscopy. See Supporting Information for
more details.
aminooxygenated products 4s and 4t and the phytol derivative
4v were all obtained as single diastereomers, with high
enantioselectivities (98−99% ee) and yields ranging from 52%
to 88%. The geraniol derivative 3u is stable and could be
isolated as a single diastereomer in 58% yield and with 98% ee.
A proposed mechanism is shown in Scheme 4. The
ruthenium catalyst activates the N-benzoyloxycarbamate
Scheme 4. Mechanistic Proposal and Supporting
Experiments
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02452.
Experimental procedures, analytical data, HPLC traces,
crystallographic data, NMR spectra (PDF)
Accession Codes
CCDC 1940059 and 1942447 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
̈
Eric Meggers − Fachbereich Chemie, Philipps-Universitat
substrate (shown for 1a) to form a ruthenium nitrenoid
intermediate with the benzoate leaving group remaining
coordinated to the ruthenium. A subsequent addition of the
nitrene to the Re-face of the prochiral alkene leads to the
intermediate carbocation A at the newly formed carbon
stereocenter.17 The following transfer of the benzoate from the
ruthenium center to the carbocation will then produce product
2a. On the other hand, a nitrene addition to the Si-face of the
prochiral alkene leads to the carbocation intermediate B with
Marburg, 35043 Marburg, Germany; orcid.org/0000-
0002-8851-7623; Email: meggers@chemie.uni-marburg.de
Authors
̈
Yuqi Tan − Fachbereich Chemie, Philipps-Universitat Marburg,
35043 Marburg, Germany
̈
Feng Han − Fachbereich Chemie, Philipps-Universitat Marburg,
35043 Marburg, Germany
C
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Letter
(11) Donohoe, T. J.; Johnson, P. D.; Pye, R. J. The tethered
aminohydroxylation (TA) reaction. Org. Biomol. Chem. 2003, 1,
2025−2028.
(12) (a) Zheng, Y.; Tan, Y.; Harms, K.; Marsch, M.; Riedel, R.;
Zhang, L.; Meggers, E. Octahedral ruthenium complex with exclusive
metal-centered chirality for highly effective asymmetric catalysis. J.
Am. Chem. Soc. 2017, 139, 4322−4325. (b) Zheng, Y.; Zhang, L.;
Meggers, E. Catalytic enantioselective synthesis of key propargylic
alcohol intermediates of the anti-HIV drug efavirenz. Org. Process Res.
Dev. 2018, 22, 103−107.
(13) Zhou, Z.; Chen, S.; Qin, J.; Nie, X.; Zheng, X.; Harms, K.;
Riedel, R.; Houk, K. N.; Meggers, E. Catalytic enantioselective
intramolecular C(sp3)-H amination of 2-azidoacetamides. Angew.
Chem., Int. Ed. 2019, 58, 1088−1093.
̈
Marcel Hemming − Fachbereich Chemie, Philipps-Universitat
Marburg, 35043 Marburg, Germany
̈
Jie Wang − Fachbereich Chemie, Philipps-Universitat Marburg,
35043 Marburg, Germany
̈
Klaus Harms − Fachbereich Chemie, Philipps-Universitat
Marburg, 35043 Marburg, Germany
̈
Xiulan Xie − Fachbereich Chemie, Philipps-Universitat Marburg,
35043 Marburg, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02452
Notes
(14) Qin, J.; Zhou, Z.; Cui, T.; Hemming, M.; Meggers, E.
Enantioselective intramolecular C−H amination of aliphatic azides by
dual ruthenium and phosphine catalysis. Chem. Sci. 2019, 10, 3202−
3207.
(15) Xu reported the formation of 2a from an analogous 2,4-
dichlorobenzoyloxycarbamate under chiral iron catalysis, but with
significantly lower enantiomeric excess. See ref 7.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for funding from the Deutsche Forschungsge-
meinschaft (ME 1805/15-1).
(16) For comparison, the Z-configured diastereomer of 1a provides
the carbamate 2a only in low yields and with low stereoselectivity. See
Supporting Information for more details.
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