Determination of absolute configuration using kinetic resolution catalysts

Article abstract of DOI:10.1021/ol201902y

A new method was developed to assign the absolute configuration of molecules using kinetic resolution catalysts. Secondary alcohols were acylated in the presence of Birman's S-HBTM and R-HBTM catalysts, and the fast-reacting catalyst was identified by NMR

Full text of DOI:10.1021/ol201902y

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4470–4473
Determination of Absolute Configuration
Using Kinetic Resolution Catalysts
Alexander J. Wagner, Jonathan G. David, and Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, University of California;Irvine,
Irvine, California 92697, United States
srychnov@uci.edu
Received July 13, 2011
ABSTRACT
A new method was developed to assign the absolute configuration of molecules using kinetic resolution catalysts. Secondary alcohols were
acylated in the presence of Birman’s S-HBTM and R-HBTM catalysts, and the fast-reacting catalyst was identified by NMR analysis of the reaction
mixture. A mnemonic was developed to assign configuration based on the identity of the fast-reacting catalyst. The method uses only 1À3 mg of
alcohol, and it is more convenient than the Mosher method. The kinetic resolution strategy may be extended to other classes of molecules.
Establishing the absolute configuration of a molecule is
an important step in the characterization of a natural
product or a new synthetic entity,1 and it is a necessary
prerequisite to meaningfully analyzing its interactions with
other chiral entities such as enzymes and receptors. The
advanced Mosher method is the most widely used strategy
for assigning the configuration of a molecule and depends
on the derivatization of a secondary alcohol followed by
purification and NMR analysisofthe resulting esters.2 The
Mosher method is limited to secondary alcohols that are
not too sterically hindered and where the ester is stable and
isolable. A number of other methods have been developed
for absolute configuration assignment including the
exciton chirality method3,4 and Kishi’s NMR methods.5
We describe a new strategy for the assignment of absolute
configuration and actualize the strategy as a practical
method for the assignment of chiral secondary alcohols.6
The crux of the new strategy is to derivatize the optically
pure molecule in question with each enantiomer of a chiral
catalyst. The relative rates of the two reactions will be
measured, and the identity of the fast-reacting catalyst will
allow the configuration of the molecule to be assigned
based on an empirical correlation with similar molecules.
Enzymatic derivatizations have been proposed as a
(4) (a) Li, X.; Tanasova, M.; Vasileiou, C.; Borhan, B. J. Am. Chem.
Soc. 2008, 130, 1885–1893. (b) Li, X.; Borhan, B. J. Am. Chem. Soc.
2008, 130, 16126–16127. (c) Tanasova, M.; Vasileiou, C.; Olumolade,
O. O.; Borhan, B. Chirality 2009, 21, 374–382.
(5) (a) Ghosh, I.; Zeng, H.; Kishi, Y. Org. Lett. 2004, 6, 4715–4718.
(b) Kobayashi, Y.; Hayashi, N.; Kishi, Y. Tetrahedron Lett. 2003, 44,
7489–7491. (c) Kobayashi, Y.; Hayashi, N.; Kishi, Y. Org. Lett. 2002, 4,
411–414.
(1) (a) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Com-
pounds; Wiley-Interscience: Hoboken, NJ, 1994; pp 101À147 and
~ ꢀ
991À1105. (b) Seco, J. M.; Quinoa, E.; Riguera, R. Chem. Rev. 2004,
104, 17–118. (c) Wenzel, T. J.; Chisholm, C. D. Chirality 2011, 23, 190–
214.
(2) (a) Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nat. Protoc. 2007, 2, 2451–
2458. (b) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543–2549. (c) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512–519. (d) Ohtani, I.; Kusumi, T.; Ishitsuka, M. O.; Kakisawa, H.
Tetrahedron Lett. 1989, 30, 3147–3150. (e) Ohtani, I.; Kusumi, T.;
Kashman, Y.; Kakisawa, H. J. Org. Chem. 1991, 56, 1296–1298.
(f) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4096.
(3) For example, see: (a) Zhou, P.; Zhao, N.; Rele, D. N.; Berova, N.;
Nakanishi, N. J. Am. Chem. Soc. 1993, 115, 9313–9314. (b) Mori, Y.;
Sawada, T.; Sasaki, N.; Furukawa, H. J. Am. Chem. Soc. 1996, 118,
1651–1656.
(6) Various kinetic methods have been developed for assigning
enantiomeric excess to compounds but not for assigning absolute
configuration: (a) Reetz, M. T.; Becker, M. H.; Klein, H.-W.; Stockigt,
D. Angew. Chem., Int. Ed. 1999, 38, 1758–1761. (b) Guo, J.; Wu, J.;
Siuzdak, G.; Finn, M. G. Angew. Chem., Int. Ed. 1999, 38, 1755–1758.
(c) Korbel, G. A.; Lalic, G.; Shair, M. D. J. Am. Chem. Soc. 2001, 123,
361–362. (d) Young, B. L.; Cooks, R. G. Int. J. Mass Spectrom. 2007,
267, 199–204. (e) Muller, C. A.; Pfaltz, A. Angew. Chem., Int. Ed. 2008,
47, 3363–3366. (f) Muller, C. A.; Markert, C.; Teichert, A. M.; Pfaltz, A.
Chem. Commun. 2009, 1607–1618. (g) Matsumoto, T.; Urano, Y.;
Takahashi, Y.; Mori, Y.; Terai, T.; Nagano, T. J. Org. Chem. 2011,
76, 3616–3625.
r
10.1021/ol201902y
Published on Web 07/21/2011
2011 American Chemical Society

method to assign configuration, but without having both
enantiomers of the enzyme available, subtle differences in
rate cannot be identified.7 The method is empirical, as is
the Mosher’s advanced method,2 and empirical rules need
to be developed for each catalyst system. This strategy is a
modern implementation of Horeau’s method8 but one in
which the derivatization involves a chiral catalyst rather
than a chiral substrate. Horeau’s method depends on an
analysis of the unreacted 2-phenylbutyric acid, but that
strategy cannot work with an achiral anhydride. We have
turned the analysis around and instead examine the rela-
tive rates of reaction using two different enantiomers of a
chiral catalyst.
The tremendous advances in enantioselective catalysis
and kinetic resolution in the last decades make the strategy
potentially very general.10 It can be applied to any func-
tional group for which there is a good kinetic resolution
catalyst. Our initial focus isonsecondaryalcohols, which is
one of the most widely distributed functional groups in
synthetic routes and in natural products. The proof of
principle reported below validates the general strategy for
other kinetic resolution catalysts.
Many enantioselective acylation catalysts have been
reported,11À13 but Birman’s homobenzotetramisole
(HBTM) catalysts are of special interest because of their
broad substrate scope, generally good selectivity, and
relative ease of synthesis.14 Both enantiomers of the cata-
lyst were prepared, and they were used to catalyze the
acylation of a model alcohol 1. Birman’s optimized con-
ditions use low temperatures and solvent mixtures;14 for
convenience, we have focused on room temperature reac-
tions in CDCl3. The initial results are shown in Figure 1,
where the reactions catalyzed by 5 mol % of HBTM were
Figure 1. Optically pure alcohol 1 was reacted with propionic
anhydride and either 5 mol % of S-HBTM or 5 mol % of
R-HBTM catalyst. The conversion was monitored directly
by NMR spectroscopy, and the conversion, x, was plotted as
1/(1 À x) versus time to determine a rate constant for each
catalyst enantiomer.9 The R-HBTM was faster than S-HBTM
by a factor of 13.5, which is consistent with the relative reactivity
reported by Birman. Thus the configuration of alcohol was
confirmed to be 1S,2R.
1
monitored by H NMR analysis in an NMR tube. The
conversion was measured by integration of the protons on
the carbon adjacent to the oxygen atom, and the results
were evaluated assuming pseudo-first-order conditions.15
In contrast to the Mosher method, the ester itself does
not need to be stable because the reaction can be
monitored by loss of the starting alcohol. Thus this
kinetic resolution method can be applied to chemically
sensitive alcohols.6g The plots in Figure 1 yield relative rates
of 13.4, where R-HBTMis the fast-reacting catalyst.9 Using
Birman’s rate data,14a one can assign the configuration of
alcohol 1 as 1S,2R.
The example in Figure 1 demonstrates the concept, but
the kinetic method requires both instrument time and
significant material to assign a configuration. It is only
necessary to identify the fast-reacting catalyst for a parti-
cular alcohol, and that can be done without measuring
precise reaction rates. All of the subsequent conversion
data were determined by running side-by-side reactions in
a common water bath for a fixed length of time. The
reactions were set up in 100 μL of CDCl3, and the reactions
were terminated16 by adding 400 μL of CDCl3 followed by
NMR analysis. Each reaction used 10 μmol of alcohol,
0.4 μmol of catalyst, and ca. 1.3 equiv of the other reagents
for pseudo-first-order kinetics (at modest conversion).14c
(7) For a review, see: Jing, Q.; Kazlauskas, R. J. Chirality 2008, 20,
724–735.
(8) (a) Horeau, A. In Stereochemistry, Fundamentals and Methods;
Fiaud, J., Horeau, A., Kagan, H. B., Eds.; Georg Thieme: Stuttgart, 1977;
Vol. 3, pp 51À94. (b) Horeau, A. Tetrahedron Lett. 1961, 506–512.
(c) Schoofs, A.; Horeau, A. Tetrahedron Lett. 1977, 3259–3262.
(d) Horeau, A.; Nouaille, A. Tetrahedron Lett. 1990, 31, 2707–2710.
(e) Koenig, W. A.; Gehrcke, B.; Weseloh, G. Chirality 1994, 6, 141–147.
(9) FromÀth4e data in Figure 1, the kobs rate for the R-HBTM catalyst
was 6.2 Â 10 sÀÀ11and the corresponding rate for the S-HBTM catalyst
was 4.6 Â 10À5 s
.
(10) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44, 3974–
4001.
(11) (a) Fu, G. C. Acc. Chem. Res. 2000, 33, 412–420. (b) Fu, G.
Asymmetric Synthesis; Wiley-VCH: Weinheim, Germany, 2007;
pp 186À190. (c) Wurz, R. P. Chem. Rev. 2007, 107, 5570–5595.
(12) Vedejs, E.; Daugulis, O.; MacKay, J. A.; Rozners, E. Synlett
2001, 1499–1505.
(13) (a) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351–1354.
(b) Birman, V. B.; Guo, L. Org. Lett. 2006, 8, 4859–4861. (c) Birman,
V. B.; Jiang, H.; Li, X.; Guo, L.; Uffman, E. W. J. Am. Chem. Soc. 2006,
128, 6536–6537. (d) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.;
Kilbane, C. J. J. Am. Chem. Soc. 2004, 126, 12226–12227.
(14) (a) Birman, V. B.; Li, X. Org. Lett. 2008, 10, 1115–1118.
(b) Zhang, Y.; Birman, V. B. Adv. Synth. Catal. 2009, 351, 2525–2529.
(c) Kobayashi, M.; Okamoto, S. Tetrahedron Lett. 2006, 47, 4347–4350.
(15) At high conversion, the reactions deviate from pseudo-first-
order conditions. For calculating relative reactions rates, we only
considered data for <40% conversion.
(16) The catalyzed acylation is a bimolecular reaction and should
slow down by a factor of roughly 52 = 25 on 5-fold dilution.
Org. Lett., Vol. 13, No. 16, 2011
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Most alcohols with activating π-substituents produce
sufficient conversion in 30À45 min to identify the fast-
reacting catalyst. The fast-reacting catalyst for each entry
is circled in Table 1. The enantiomeric pairs (entries 1, 2
and 3,4) showed the expected complementary reactivity.
The less active substrates (entries 11 and 12) were run for
4 h to achieve sufficient conversion to determine the fast-
reacting HBTM catalyst. The designation of “less active”
substrates is a bit arbitrary: the alcohols in entries 8 and 12
show similar reactivities, but entry 12 was run for a longer
time to give higher conversion. In only one case (entry 10)
was the reactivity of the two catalysts too close to make a
clear assignment of the fast-reacting catalyst. The HBTM
catalyst system does not differentiate between the ester
chain and the phenethyl chain. A different enantioselective
acylation catalyst might be used to make this assignment.
Table 1. Determination of the Fast-Reacting Catalyst for a
Series of Optically Pure Secondary Alcoholsa
Figure 2. Birman’s transition state model predicts the fast-
reacting alcohol structure with the S-HBTM catalyst (left.) A
more general mnemonic (right) places the small or π-substituent
on the left and the large group on the right. The alcohol
preferred by the S-HBTM catalyst is back, whereas the alcohol
preferred by the R-HBTM catalyst is forward.
In order to use the observed rate difference to assign
configuration, a clear relationship needs to be identified
between the fast-reacting chiral catalyst and the three-
dimensional structure of the alcohol. Birman examined a
number of substrates and proposed the model shown in
Figure 2.14 His transition state model predicts that the
S-HBTM catalyst willreact fasterthanthe R-HBTM when
the aryl group is over the benzotriazole ring, and the alkyl
group is pointing up and away from the complex. We
propose a mnemonic based on our more extensive results
and Birman’s TS model, which is shown in Figure 2. The
dominant π-group is placed to the left, and the larger
(alkyl) group is drawn to the right. When the S-HBTM
catalyst reacts faster, the hydroxyl group is back. When the
R-HBTM catalyst reacts faster, then the hydroxyl group is
forward. The substrates in Table 1 are drawn in this
orientation, and the general suitability of the mnemonic
is substantiated by inspection. The trend from the data for
the π-dominant group is shown below:
a The reaction conditions are given in the text. b S-HBTM er =
97.4:2.6. c R-HBTM er = 98.2:1.8.
aryl > propargyl > homothiophenyl ꢀ benzyl > allyl
ꢀ crotyl > alkyl
The method uses a total of 20 μmol of alcohol in the
determination. The results with a variety of secondary
alcohols are presented in Table 1.
This simple mnemonic predicts the HBTM selectivity for
all of the alcohols presented, but it will not be adequate to
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predict the reactivity of all secondary alcohols. Birman has
shown that the HBTM catalyst and the closely related
BTM catalyst are effective in the kinetic resolution of a
variety of secondary alcohols including those with benzylic,
propargylic, allylic, and cyclohexyl structures.13,14 All of
these alcohols can be analyzed with our proposed mnemo-
nic or by direct analogy to specific example.
One goal of future work is to systematically broaden the
scope of this method by studying different classes of
secondary alcohols and refining our predictive mnemonic.
Further refinements in catalyst structure,14b,17 reaction
conditions, and analytical strategy may be helpful in
making this method more convenient and more widely
applicable. The simple procedure described herein for
determining the fast-reacting enantiomer of the HBTM
catalyst, combined with the mnemonic based on Birman’s
model, will make this new method a valuable tool for
assigning the configuration of secondary alcohols.
functional group for which an effective kinetic resolu-
tion catalyst has been developed. We will extend the
strategy to assign the configuration of molecules based
on functional groups not subject to common analytical
methods.
Acknowledgment. Support was provided by the Na-
tional Institute of General Medicine (GM-43854), and
by the Department of Defense (DoD) through the
National Defense Science & Engineering Graduate
Fellowship (NDSEG) Program (A.J.W.), the National
Science Foundation Graduate Fellowship Program
(A.J.W.), and the Allergan Undergraduate Research
Fellowship (J.G.D.). The Overman and Jarvo groups at
UC Irvine generously provided several of the alcohols
used in this study.
Supporting Information Available. Experimental pro-
cedures for the acylation reactions, NMR data for the
relative rate determination, and kinetic data from com-
pound 1 are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
The method has been developed for secondary alcohols,
but the general strategy should be applicable to any
(17) Shiina, I.; Nakata, K.; Ono, K.; Onda, Y.-S.; Itagaki, M. J. Am.
Chem. Soc. 2010, 132, 11629–11641.
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