Determination of the Absolute Configuration of Cyclic Amines with Bode's Chiral Hydroxamic Esters Using the Competing Enantioselective Conversion Method

Article abstract of DOI:10.1021/acs.orglett.7b01748

The competing enantioselective conversion (CEC) strategy has been extended to cyclic amines. The basis for the CEC approach is the use of two complementary, enantioselective reactions to determine the configuration of the enantiopure substrate. Bode's chiral acylated hydroxamic acids are very effective enantioselective acylating agents for a variety of amines. Pseudoenantiomers of these acyl-transfer reagents were prepared and demonstrated to react with enantiopure cyclic amines with modest to high selectivity. The products were analyzed by ESI-MS to determine selectivity, and the results were used to assign the configuration of the amine substrate. The method was applicable to a variety of cyclic amines as well as primary amines and acyclic secondary amines. The method is limited to amines that are unhindered enough to react with the reagents, and not all amine substitution patters lead to high selectivity.

Full text of DOI:10.1021/acs.orglett.7b01748

Letter
pubs.acs.org/OrgLett
Determination of the Absolute Configuration of Cyclic Amines with
Bode’s Chiral Hydroxamic Esters Using the Competing
Enantioselective Conversion Method
Alexander Burtea and Scott D. Rychnovsky*
Department of Chemistry, University of California at Irvine, 1102 Natural Sciences II, Irvine, California 92697, United States
S
* Supporting Information
ABSTRACT: The competing enantioselective conversion
(CEC) strategy has been extended to cyclic amines. The basis
for the CEC approach is the use of two complementary,
enantioselective reactions to determine the configuration of the
enantiopure substrate. Bode’s chiral acylated hydroxamic acids
are very effective enantioselective acylating agents for a variety of
amines. Pseudoenantiomers of these acyl-transfer reagents were
prepared and demonstrated to react with enantiopure cyclic
amines with modest to high selectivity. The products were
analyzed by ESI-MS to determine selectivity, and the results
were used to assign the configuration of the amine substrate.
The method was applicable to a variety of cyclic amines as well
as primary amines and acyclic secondary amines. The method is
limited to amines that are unhindered enough to react with the
reagents, and not all amine substitution patters lead to high selectivity.
etermination of absolute configuration is an important
has the potential to provide good substrate scope and selectivity
Dstep in structure determination and has a significant role with an operationally simple analysis.
The CEC method makes use of enantioselective reagents or
in natural product analysis, enantioselective methods develop-
ment, and medicinal chemistry.1 Many different methods have
been used to assign absolute configuration to organic
molecules, including chiral derivatization followed by NMR
spectroscopy,2 vibrational circular dichroism (CD) combined
with density functional theory simulations,3 X-ray diffraction of
single crystals,4 the exciton chirality method with electronic
CD,5 and specific rotation combined with computer
simulations.6 Our laboratory developed the competing
enantioselective conversion (CEC) method to assign config-
uration based on the relative rates of reaction with
enantioselective reagents.7,8 We reported a CEC method to
analyze primary amines, but it was not effective with secondary
amines or cyclic amines because of the low reactivity of the
enantioselective reagents.9 Inspired by Bode’s recent develop-
ment of a broadly applicable kinetic resolution method for
cyclic amines,10,11 we developed and now report a CEC
method to assign configuration to cyclic amines.
Chiral amines are common in natural product structures and
often associated with biological activity. Chiral amines are
important building blocks in medicinal chemistry. Aside from
the physical methods for determining absolute configuration,
amines have been analyzed most often by derivatization with
chiral reagents.12 Other methods have been reported,5f,13
including a new approach using induced conformational
chirality that is detected by exciton-coupled circular dichro-
ism.14 A CEC strategy complements these other methods and
catalyzed reactions to derivatize the targeted functional group
in an enantiopure substrate. It was inspired by the work of
Horeau, who used a kinetic resolution to assign configuration.15
Most commonly, two parallel reactions are used, with one
enantioselective reagent/catalyst system in each reaction. The
fast reacting reagent is identified, and the absolute configuration
of the unknown substrate is assigned based on the known
preferences of the enantioselective catalyst or reagent.7 In a few
cases it has been possible to use pseudoenantiomeric reagents
and run the competitive reactions in a single flask. The CEC
method for primary amines used deuterated pseudoenan-
tiomers of Mioskowski’s reagents as shown in Figure 1.7
Unfortunately, these acyl-transfer reagents were not reactive
enough to derivatize more hindered amines or secondary
amines. Bode has recently investigated enantioselective acyl
transfer reagents based on chiral hydroxamic esters and shown
that they demonstrate good enantioselectivity and work well
with a wide variety of cyclic amines.9,10 These enantioselective
reagents appeared to be ideal for a new CEC method for cyclic
amines.
We envisioned using pseudoenantiomeric reagents designed
around Bode’s hydroxamic acid: 6(R,S)-C4 and 7(S,R)-C5. The
goal was to use two complementary enantioselective reagents in
Received: June 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01748
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Letter
Table 1. Optimization of Reaction Time and Temperature
a,b
Using (S)-Proline Methyl Ester
c
entry
time (h)
temp (°C)
[M]+:[M + 14]+
σ
conv (%)
1
2
3
4
5
6
7
8
9
1
3
6
1
3
6
1
3
6
6
20
20
20
40
40
40
60
60
60
60
4:96
8:92
3
7
22
37
16
43
68
52
89
98
2
1
2
1
2
1
0
0
0
7:93
9:91
8:92
9:91
12:88
11:89
13:87
51:49
d
10
Figure 1. Enantioselective and pseudoenantiomeric acylation reagents
inspired by Mioskowski’s work were used in a prior competing
enantioselective conversion method for primary amines.7 The current
project uses enantioselective acylation reagents inspired by Bode’s
work.9
a
The reactions were run at the indicated concentrations, times, and
temperatures. The total reaction volume was 100 μL. Percentages are
based on the sum of the ion counts for the M + H and M + Na peaks.
b
Percent conversion was obtained by quenching the reaction with
propionic anhydride and using the ion count of the three-carbon
amide formed to quantify the unreacted 10. Standard deviation of
major peak intensity based on three trials. This experiment was run
c
d
with racemic proline methyl ester.
the same flask at essentially the same concentration and have
them compete to derivatize the enantiopure amine substrate. As
long as the reactions are nearly first-order in substrate, in this
case the amine, the ratio of products formed will be very similar
to the selectivity of the enantioselective reagent. Measuring the
product ratios will identify the fast-reacting reagent, and that
can be used with a mnemonic to assign absolute configuration.
In prior work, the two different enantiomeric reagents and
products formed from them were marked with deuterium
labels.8 Bode demonstrated that the hydroxamic esters reagents
are most selective with propionic or longer carboxylic acids.10a
The corresponding isotopically labeled compounds are very
expensive and probably unnecessary. Instead, the (R,S) reagent
was prepared with butanoic acid and the complementary (S,R)
reagent was prepared with pentanoic acid. These pseudoe-
nantiomeric reagents are shown in Figure 1.
The enantioselective acylation reaction was optimized using
(S)-proline methyl ester (10) as a test substrate. An excess of a
1:1 mixture of 6(R,S)-C4 and 7(S,R)-C5 was reacted with 10 in
different solvents and concentrations. These initial screening
reactions are documented in Table S1 of the Supporting
Information. They showed that the reaction was faster and
more selective in tert-amyl alcohol than in ethereal or aromatic
solvents. Optimization of the temperature and time for the
reactions is shown in Table 1. The conversion was measured by
acylating the remaining amine with propionic anhydride, and
the analysis was carried out by measuring the ratios of C3, C4,
and C5 amides by ESI-MS.16 The reaction was found to be
relatively slow at 20 °C and only resulted in about 37%
conversion after 6 h (entry 3). Heating the reaction at 60 °C for
6 h (entry 9) resulted in nearly complete conversion. The
selectivity observed for the reactions was lower at 60 °C than at
20 °C (entry 9 vs entry 3), but the effect was modest. The
concentration, temperature, and time for entry 9 were selected
as the standard for the CEC evaluation of other substrates.17
If the rate of acylation with the C4 reagent 6 was faster than
the rate of reaction with the C5 reagent 7, it would lead to
excess formation of the C4 amide with each enantiomer of the
substrate. Combining both enantiomers (using the racemate)
would lead to more than 50% of the C4 amide in the product.
The question was addressed with the experiment in entry 10 of
Table 1. This example used racemic proline methyl ester and
resulted in a 51:49 ratio of the C4:C5 amides as measured by
the ESI-MS method. The observed ratio of C4:C5 amides is
very close to 50:50, and it puts an upper limit on the difference
in rate between the reagents 6 and 7 with this substrate. We
conclude that the difference in rate between the C4 and C5
reagents is negligible.
The results with a variety of cyclic amines are presented in
Scheme 1. The reactions were run in small vials with 100 μL of
solvent; each evaluation used 1.0 μmol of substrate (e.g., 0.16
mg of amine 11). Six-membered ring structures 11−18 showed
reasonable selectivity regardless of the adjacent substituent’s
identity or the presence of other heteroatoms in the ring. The
five-membered ring pyrrolidine examples 10 and 19−23
showed larger variations in their selectivity. The minimally
substituted 2-methylpyrrolidine (not shown)18 led to very low
and reversed selectivity. The low selectivities with methyl and
phenyl (20) substituents represent a limitation of this CEC
method for pyrrolidines. The hydrochloride salt 23 was used
directly in the reaction by adding Et3N to liberate the free
amine in situ. Finally, azepane 24 resulted in selectivity similar
to the corresponding piperidine 11. The predictive mnemonic
for cyclic amines is apparent by inspection of Scheme 1.
The previously reported CEC method worked well for
primary amines. The current method was evaluated against a
small number of primary and secondary amines as shown in
Scheme 2. Primary amines are much more reactive than
B
DOI: 10.1021/acs.orglett.7b01748
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Organic Letters
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secondary amines, and the acylation reaction with 6 and 7
proceeded to completion at 20 °C in 1 h with the other
reaction conditions unchanged. All of the examples investigated
had structures in which the amine carbon was bracketed with
an sp2 and sp3 substituent. The selectivities were modest but
reproducible. Amino acid esters 29 and 30 were acylated with
good selectivity. Secondary amines with similar structural
features were also investigated. N-Methylamines 26 and 27
showed the same sense of selectivity as the similar primary
amines.19 The corresponding N-benzylamines were unreactive
under the standard conditions. The limited number of examples
investigated here is not enough to establish a reliable and well-
documented reactivity pattern for primary amine configuration
assignment, but the simple pattern of selectivity is very
encouraging.
Scheme 1. CEC Evaluation of Cyclic Amines with Adjacent
Stereogenic Centers
a,b
A predictive mnemonic for using the relative reactivity of
reagents 6 and 7 to assign absolute configuration is illustrated
in Figure 2. The cyclic cases appear to be relatively robust based
a
The reactions were run at the indicated concentrations, times, and
temperatures. The total reaction volume was 100 μL. Percentages are
based on the sum of the ion counts for the M + H and M + Na peaks.
Figure 2. Preliminary mnemonic for assigning absolute configuration
using the 6(R,S)-C4 and 7(S,R)-C5 reagents illustrated in Figure 1.
b
c
Standard deviation based on three trials. Calculated based on M + H
d
peaks only. Triethylamine (1.0 μL) was added to the reaction
mixture.
on the data presented here and Bode’s resolution work.10
A
Scheme 2. CEC Evaluation of Acyclic Primary and
Secondary Amines
a,b
tentative mnemonic for amines that are not part of a ring is also
shown. The cyclic structure 31 emphasizes the similarity in
selectivity between the two models. Bode and Kozlowski have
developed a detailed mechanistic model for the acylation of
piperidines in which the 2-subsitutent preferentially adopts an
axial position.11 Their computational and experimental work
suggests that the mnemonic for cyclic amines should be
analyzed with care for more complex, conformationally
restricted cyclic amines. The predictive mnemonics for cyclic
and acyclic amines will be useful in assigning absolute
configuration of enantiopure amines.
A new CEC method has been developed for cyclic amines; it
shows good results with five-, six-, and seven-membered rings.
The method is based on the chiral hydroxamic esters developed
by Bode’s group. Easily accessible pseudoenantiomeric reagents
6(R,S)-C4 and 7(S,R)-C5 were reacted with the amines and the
product ratios were analyzed by ESI-MS. The method is
sensitive, and preliminary results suggest that it can be used
with acyclic amines. The procedure should be useful to assign
absolute configuration in medicinal chemistry and natural
products chemistry. We will continue to develop the scope of
the method.
a
The reactions were run at the indicated concentrations, times, and
temperatures. The total reaction volume was 100 μL. Percentages are
based on the sum of the ion counts for the M + H and M + Na peaks.
b
c
Standard deviation based on three trials. The primary amine
d
reactions were run at 20 °C for 1 h. Calculated based on M + Na
peaks only.
C
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Organic Letters
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(7) (a) Wagner, A. J.; David, J. G.; Rychnovsky, S. D. Org. Lett. 2011,
13, 4470−4473. (b) Perry, M. A.; Trinidad, J. V.; Rychnovsky, S. D.
Org. Lett. 2013, 15, 472−475. (c) Wagner, A. J.; Rychnovsky, S. D. J.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01748.
■
S
Characterization of new compounds and experimental
details for CEC analysis (PDF)
(9) Miller, S. M.; Samame, R. A.; Rychnovsky, S. D. J. Am. Chem. Soc.
2012, 134, 20318−20321.
AUTHOR INFORMATION
■
(10) (a) Kreituss, I.; Bode, J. W. Acc. Chem. Res. 2016, 49, 2807−
2821. (b) Binanzer, M.; Hsieh, S.-Y.; Bode, J. W. J. Am. Chem. Soc.
2011, 133, 19698−19701. (c) Hsieh, S.-Y.; Binanzer, M.; Kreituss, I.;
Bode, J. W. Chem. Commun. 2012, 48, 8892−8893. (d) Kreituss, I.;
Murakami, Y.; Binanzer, M.; Bode, J. W. Angew. Chem., Int. Ed. 2012,
51, 10660−10663. (e) Kreituss, I.; Chen, K.-Y.; Eitel, S. H.; Adam, J.-
M.; Wuitschik, G.; Fettes, A.; Bode, J. W. Angew. Chem., Int. Ed. 2016,
55, 1553−1556. (f) Kreituss, I.; Bode, J. W. Nat. Chem. 2016, 9, 446−
452.
Corresponding Author
*E-mail: srychnov@uci.edu.
ORCID
Scott D. Rychnovsky: 0000-0002-7223-4389
Notes
The authors declare no competing financial interest.
(11) (a) Allen, S. E.; Hsieh, S.-Y.; Gutierrez, O.; Bode, J. W.;
Kozlowski, M. C. J. Am. Chem. Soc. 2014, 136, 11783−11791.
(b) Wanner, B.; Kreituss, I.; Gutierrez, O.; Kozlowski, M. C.; Bode, J.
W. J. Am. Chem. Soc. 2015, 137, 11491−11497.
ACKNOWLEDGMENTS
The National Science Foundation (CHE 1361998) provided
support.
■
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