Determination of the Absolute Configuration of β-Chiral Primary Alcohols Using the Competing Enantioselective Conversion Method

Article abstract of DOI:10.1021/acs.orglett.7b01189

A method for determining the absolute configuration of β-chiral primary alcohols has been developed. Enantioenriched alcohols were acylated in the presence of either enantiomer of the enantioselective acylation catalyst HBTM, and the faster reaction was determined by measuring product conversion using ¹H NMR spectroscopic analysis. An empirical mnemonic was developed that correlates the absolute configuration of the alcohol to the faster reacting catalyst. Successful substrates for this method include primary alcohols that bear a "directing group" on the stereogenic center; directing groups include arenes, heteroarenes, enones, and halides.

Full text of DOI:10.1021/acs.orglett.7b01189

Letter
pubs.acs.org/OrgLett
Determination of the Absolute Configuration of β‑Chiral Primary
Alcohols Using the Competing Enantioselective Conversion Method
Alexander S. Burns,† Alexander J. Wagner,† Jennifer L. Fulton,† Kyle Young,‡ Armen Zakarian,‡
and Scott. D. Rychnovsky*,†
†Department of Chemistry, University of California at Irvine, 1102 Natural Sciences II, Irvine, California 92697, United States
‡Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
S
* Supporting Information
ABSTRACT: A method for determining the absolute configuration of β-chiral
primary alcohols has been developed. Enantioenriched alcohols were acylated in
the presence of either enantiomer of the enantioselective acylation catalyst
HBTM, and the faster reaction was determined by measuring product conversion
1
using H NMR spectroscopic analysis. An empirical mnemonic was developed
that correlates the absolute configuration of the alcohol to the faster reacting
catalyst. Successful substrates for this method include primary alcohols that bear
a “directing group” on the stereogenic center; directing groups include arenes,
heteroarenes, enones, and halides.
he determination of the absolute stereochemistry of small
each reaction. By comparing this result to an empirically
1
Tmolecules remains an active challenge for researchers. As derived mnemonic, the configuration in question can be
determined. The CEC method is much less labor intensive than
the Mosher’s derivatization methods, for example, and has
proven robust enough to be incorporated into an under-
graduate laboratory experiment.13c The competing enantiose-
lective conversion (CEC) method has been used to determine
the configuration of primary amines,11 lactams,12 oxazolidi-
nones,12 and secondary alcohols.10,13,14
of yet, there is no “one size fits all” analysis for absolute
stereochemistry. Methods employed include chiral derivatiza-
tion and NMR analysis,2 electronic and vibrational circular
dichroism,3 ECD methods,4,5 and crystallographic analysis.6
The method used depends on the functionality surrounding the
stereogenic center as well as the availability and properties of
substance.
Birman has developed a number of enantioselective acylating
catalysts,15 including homobenzotetramisole16 (HBTM) 1, for
kinetic resolutions of secondary alcohols.17 Our group has
previously employed HBTM as a catalyst for CEC methods for
secondary alcohols13 and other functional groups.12 We sought
to determine whether HBTM could be used for a CEC method
with β-chiral primary alcohols by first probing its effectiveness
in the kinetic resolution of racemic substrates. There have been
sporadic reports of small molecule kinetic resolutions of these
motifs previously.18,19 Because HBTM and related catalysts
have been proposed to interact with the substrates through π
interactions,20 alcohols bearing a π-group were tested initially.
To our delight, we were able to resolve alcohols 1−3 with
modest selectivities, as shown in Table 1. Though these
selectivities are too low to be of practical synthetic utility, they
are more than sufficient to make a stereochemical assignment
based upon rate differences using the CEC method. One
limitation was apparent as alcohol 4, with the arene group γ to
the alcohol, resulted in almost no selectivity. Optimization
studies are presented in Tables S1 and S2. Other acylation
catalysts were investigated (BTM and Cl-PIQ), but they did
not provide superior selectivity in comparison to HBTM.21
Alcohols are common in natural product structures and are
useful handles for absolute structure determination. While there
are many reliable methods to determine the configuration of
secondary alcohols, there are few methods for primary alcohols
with stereogenic centers in the β-position (β-chiral primary
alcohols). The Riguerda7 and Seebach8 groups have extended
the modified Mosher’s method to certain primary alcohols
through 1H and 19F NMR analysis, respectively, and the
Fukushi9 group reported the derivatization and subsequent
NOE analysis of β-chiral primary alcohols with chiral
binaphthalene ester (MBCA) derivatives. Herein, we report
our approach to this problem through the application of
enantioselective acylation catalysts.
Our group has recently demonstrated that kinetic resolution
catalysts can be used to identify the absolute configuration of
optically pure molecules containing various functional groups.10
The method utilizes the following process. An enantioselective
catalyst developed for kinetic resolutions of a particular class of
compounds is selected. Two reactions are set up in parallel
containing an enantioenriched molecule of interest and either
the R or S enantiomer of the enantioselective catalyst with the
other necessary reagents to conduct the transformation. Many
enantiopure substrates will react faster with one enantiomer of
the catalyst. Once the reaction is stopped, the faster reacting
catalyst is identified by measuring the relative conversion in
Received: April 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01189
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Letter
Table 1. Kinetic Resolution of Racemic, β-Chiral Primary
a
Alcohols
Figure 1. Optically pure alcohol 5 was acylated with propionic
anhydride and 20 mol % of either (R)- or (S)-HBTM. Reaction
progress is plotted as ln[5] vs time, up to 50% conversion. Selectivity
factor (s) from the ratio of slopes: (S)-HBTM/(R)-HBTM =
−0.0294/−0.0102 = 2.9.10
R2, we compared enantiomers 5 and 12. Both showed
approximately equal and opposite conversions with (R)- and
(S)-HBTM, serving as positive controls. Previous experience
has shown, not unexpectedly, that a sample with lower
enantiopurity will reduce the observed difference between the
conversions.13a With the exception of compounds 13 and 21,
all of the samples are ≥89% ee, so the effect will be negligible.
Gratifyingly, this CEC method also showed selectivity for
scopolamine, 14, demonstrating its utility for natural products
containing this functional group array.
Emboldened by our success with β-aryl primary alcohols, we
explored alcohols with different groups in place of the arene.
Heteroaromatic alcohols 15 and 16 displayed significant
differences in conversion, but unfortunately, indole 21
displayed conversions that were too close to confidently assign
the faster reacting catalyst. A brief examination of nonaromatic
π-systems revealed that enone 13 was an effective substrate.
Interestingly, methyl ester 17 displayed selectivity opposite
what was expected if the ester played the role of a directing
group. We tentatively suggest that intramolecular hydrogen
bonding could be altering the conformation of 17 and thus the
selectivity. Curiously, we observed modest but reproducible
selectivity for β-halide alcohols 18 and 19. Lone pair−π
interactions might account for the selectivity, but we are
hesitant to endorse a physical rationale for this result without
further experimental evidence. Phenyl alkyne 22 showed a
slightly higher conversion with the (S)-HBTM catalyst, which
was consistent with a directing group effect by the alkyne. The
selectivity is modest enough to discourage its application to
configuration assignments. Lastly, there was no selectivity for
the negative control of alcohol 20. This outcome is consistent
with models for the resolution of secondary alcohols by
HBTM, which require a π-directing group.
a
The alcohol (0.1 M), (S)-HBTM (10 mol %), and DIPEA (0.55
equiv) were combined in CDCl3, followed by the addition of propionic
anhydride (0.55 equiv) at 0 °C. The reaction was quenched after 15
min by the addition of MeOH. The conversion and selectivity were
b
calculated based upon the ee of the ester and remaining alcohol, which
were determined using chiral HPLC analysis.21
While the kinetic resolutions gave superior selectivities at lower
temperatures, 0 °C was selected as the standard temperature for
CEC investigation due to the reproducibility and convenience
inherent to ice−water baths.
Next, we investigated the order of the reaction with respect
to the alcohol. Acylation reactions that are first order in alcohol
are well behaved in the CEC method,22 and the product
conversions can be used to reliably identify the fast-reacting
enantiomer. The acylation of enantiopure alcohol 5 was
catalyzed by (R)- or (S)-HBTM in the presence of an excess
of propionic anhydride and diisopropylethylamine (DIPEA);
conversion was monitored by NMR analysis (Figure 1). The
acylation of 5 was faster with (S)-HBTM and displayed first-
order behavior with respect to alcohol with either catalyst,
validating the assumption that relative conversions reflect
relative reaction rates. This rate behavior simplifies the CEC
analysis to a one-point conversion analysis. It reduces time and
effort needed to identify the faster reacting catalyst and,
therefore, the configuration of the stereocenter.
Finally, we turned our attention toward establishing a
relationship between the absolute configuration of an
enantioenriched alcohol and catalyst selectivity. Most of the
enantioenriched alcohols in Scheme 1 were prepared by borane
reduction of the corresponding acids, which were themselves
prepared via enantioselective α-alkylations.23 Alcohols 6−8 all
react faster with (S)-HBTM. While methyl-bearing alcohol 6
shows higher rates of conversion, bulkier alcohols 7 and 8 show
a slightly higher difference in conversion between parallel
reactions. Both electron-rich and electron-poor arenes 10 and
11 are selective with (S)-HBTM. Because most of the alcohols
we obtained had the same configuration with respect to R1 and
Based upon the data, we have developed a mnemonic to
determine the configuration of β-chiral primary alcohols, shown
graphically in Figure 2. With the directing group (π system)
drawn to the left of the page and the primary alcohol to the
right of the page, if (S)-HBTM is the faster reacting catalyst,
than the R group points out of the plane of the page.
Conversely, if (R)-HBTM is the faster reacting catalyst, the R
B
DOI: 10.1021/acs.orglett.7b01189
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Scheme 1. CEC Results for the Conversion of β-Chiral
Primary Alcohols with (R)- and (S)-HBTM Acylation
a,e
System
Figure 2. (A) Mnemonic for determining the absolute configuration of
stereocenters β to a primary alcohol. Aryl groups, certain
heteroaromatic and nonaromatic π systems, bromines, and chlorines
act as directing groups. (B) Proposed transition state between chiral
primary alcohols and acylated (S)-HBTM.
HBTM. An unfavorable steric interaction between the alcohol’s
R group and the catalyst imparts the observed stereoselectivity.
In summary, we have developed an empirical method to
determine the absolute configuration of β-chiral primary
alcohols using the enantioselective acylation catalyst HBTM.
This report also describes the first example of the HBTM
catalyst used in a kinetic resolution with β-chiral primary
alcohols. This method is applicable to alcohols whose
stereocenter bears a directing group. Experiments are underway
in our laboratory to fully define the range of possible directing
groups, which currently include arenes, some hetereoarenes,
enones, and halides.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01189.
Characterization of new compounds and experimental
details for CEC analysis (PDF)
a
Optically enriched alcohols (0.015 M) were acylated with propionic
anhydride (2 equiv) in the presence of (R)- or (S)-HBTM (10 mol %)
and DIPEA (2 equiv) in CDCl3 (400 μL total volume). After 30 min,
the reactions were quenched by the addition of CD3OD (50 μL). The
reaction was diluted to 600 μL in CDCl3, and percent conversion was
determined by proton NMR analysis. The results from run to run were
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: srychnov@uci.edu.
ORCID
b
c
reproducible. Percent conversions are the average of two trials CEC
Armen Zakarian: 0000-0002-9120-1232
Scott. D. Rychnovsky: 0000-0002-7223-4389
Notes
d
reaction run with 0.020 M alcohol and 20 mol % of HBTM. For
compound 16, slightly overlapping peaks introduced small errors in
the absolute values of the integrations. The relative conversions were
e
The authors declare no competing financial interest.
consistent run to run, and no correction was applied. The
enantiomeric excess for all alcohols was ≥89%, except for 13 (83%
ee) and 21 (84% ee).
ACKNOWLEDGMENTS
■
The National Science Foundation (CHE 1152449 and CHE
1361998 to S.D.R.) provided support for the research
discussed. This work was also supported by the National
Institutes of Health (NIGMS GM077379 to A.Z.). J.L.F. was
supported by an REU award to UC Irvine (CHE 1062891).
A.J.W. was supported by the Department of Defense (DoD)
through the National Defense Science and Engineering
group points into the plane of the page. We posit a transition-
state model analogous to that proposed by Birman and Houk,20
which is consistent with the observed stereoselectivity. The
alcohol approaches the face of the catalyst unencumbered by
the bulky phenyl group and adopts a conformation in which the
directing group interacts with the cationic π-system of acylated
C
DOI: 10.1021/acs.orglett.7b01189
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Organic Letters
Letter
Graduate Fellowship (NDSEG) Program and the National
Science Foundation Graduate Fellowship Program.
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DOI: 10.1021/acs.orglett.7b01189
Org. Lett. XXXX, XXX, XXX−XXX