Long-range shielding effects in the 1H NMR spectra of mosher-like ester derivatives

Article abstract of DOI:10.1021/ol1003862

The relative magnitudes of the chemical shift differences (δσs) in the two diastereomers of menthyl esters of known chiral derivatizing agents (CDAs) were compared to those of the α-methoxy-α-trifluoromethyl-1- naphthylacetyl (MTN₍₁₎A) analogue

Full text of DOI:10.1021/ol1003862

ORGANIC
LETTERS
1
2010
Long-Range Shielding Effects in the H
NMR Spectra of Mosher-like Ester
Derivatives
Vol. 12, No. 8
1768-1771
Thomas R. Hoye,* Sara E. Erickson, Sherrie L. Erickson-Birkedahl, Christopher
R. H. Hale, Enver Cagri Izgu, Michael J. Mayer, Patrick K. Notz, and
Matthew K. Renner
Department of Chemistry, 207 Pleasant Street, SE, UniVersity of Minnesota,
Minneapolis, Minnesota 55455
hoye@umn.edu
Received February 14, 2010
ABSTRACT
The relative magnitudes of the chemical shift differences (∆δs) in the two diastereomers of menthyl esters of known chiral derivatizing agents
(CDAs) were compared to those of the r-methoxy-r-trifluoromethyl-1-naphthylacetyl (MTN(1)A) analogues I. Discrimination of the terminal
diastereotopic methyl resonances in esters of the homologous, symmetrical carbinols II was evaluated. Remarkably, the methyls differed in
the MTN(1)A esters III even when n ) 15; an unexpected crossover in the sign of the ∆δ values was also observed.
Mosher ester/amide anaylsis for deducing the absolute
configuration of stereogenic carbinol/amino centers of or-
ganic compounds, when properly applied, is a very powerful
and widely used method.1 The Mosher method is the
prototype of a larger set of analogous 1H NMR-based
methods that use chiral auxiliaries that are structurally related
to the R-methoxy-R-trifluoromethylphenylacetyl (MTPA)
moiety.2 All of these related methods3 rely on installation
of a chiral derivatizing agent (CDA) into the analyte of
interest; the newly installed chiral entity introduces local
magnetic anisotropy that differentially influences diaste-
reotopic proton resonances in the derivative. Most typically,
one makes a complementary pair of diastereomeric deriva-
tives of the analyte of interest using enantiomerically
enriched samples of each antipode of the CDA. Comparison
of the sets of differential chemical shifts (∆δs) for analogous
proton resonances in the spectrum of each diastereomer
allows one to deduce the configuration of the parent alcohol/
amine. These empirical methods rely on an understanding,
or at least a validated mnemonic construct, of the dominant
conformation adopted by the ester/amide derivative.
A related interesting issue is the distance over which the
anisotropic differential shielding effects exert themselves.
The inherent nature of both the analyte and the derivatizing
agent play a role. The studies we report here shed light on
some of these issues. In particular, they provide insight about
the relative ability of various CDAs (from among 1-11,
Figure 1) to discriminate proton resonances distal to the point
of attachment. Greater anisotropic reach presumably cor-
relates with an inherently more useful CDA.4
(1) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–
519. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4096.
(2) Thomas, J. Wenzel, Discrimination of Chiral Compounds Using
NMR Spectroscopy; J. Wiley & Sons, Inc.: Hoboken, NJ, 2007.
(3) Seco, M. J.; Quin˜oa´, E.; Riguera, R. Chem. ReV. 2004, 104, 17–
117.
Perspective on the choice of CDA (more specifically, on
its ability to discriminate analogous protons in a pair of
10.1021/ol1003862  2010 American Chemical Society
Published on Web 03/25/2010

Figure 1. Known Mosher-like chiral derivatizing agents (CDAs).
Table 1. Individual and Mean ∆δ Values of Menthyl Esters 1-m-11-m Derived from CDAs 1-11
diastereomeric derivatives of an analyte) is gained from
consideration of the ∆δ data for the (-)-menthol derivatives
(#-m) summarized in Table 1. First, the magnitude of the
∆δs is enhanced by the replacement of the phenyl with a
naphthyl or anthracenyl moeity in the CDA. This is easily
seen, for example, in the relative magnitude of the “mean|∆δ|”
values in the bottom line of Table 1. Within each of the sets
MPA vs either MN(1)A or MA(9)A, MPP vs MN(1)P, and
MTPA vs MTN(1)A the discriminating power of naphthyl-
or anthracenyl-based CDA is greater [by factors of ap-
proximately 3 (cf. 1-m vs either 4-m or 9-m), 10 (cf. 2-m
vs 5-m), and 5 (cf. 3-m vs 6-m), respectively]. Second,
whereas MPA shows greater discrimination than MTPA
across the mean |∆δ| values for the same set of menthyl
protons (cf. 1-m vs 3-m), the opposite is true for the MN(1)A
vs MTN(1)A pairs (cf. 4-m vs 6-m). Third, the difference in
the position of substitution on the CDA aromatic moiety (i.e.,
C1 vs C2 positions for naphthyl and C9 vs C2 positions for
anthracenyl groups) also affects the discriminating power of
MN(1)A/MN(2)A, MN(1)P/MN(2)P, and MA(9)A/MA(2)A. Specif-
ically, mean |∆δ| values are lower for the “C2”-substituted
positional isomers [by factors of approximately 3 (cf. 4-m
vs 7-m), 10 (cf. 5-m vs 8-m), and 2 (cf. 9-m vs 10-m),
respectively].
(4) Seco, J. M.; Latypov, Sh.; Quin˜oa´, E.; Riguera, R. Tetrahedron Lett.
1994, 35, 2921–2924.
(5) Harada, N; Watanabe, M.; Kuwahara, S.; Kasai, Y.; Ichikawa, A.
Tetrahedron: Asymmetry 2000, 11, 1249–1253.
(6) Kasai, Y.; Sugio, A.; Kuwahara, S.; Matsumoto, T.; Watanabe, M.;
Ichikawa, A.; Harada, N. Eur. J. Org. Chem. 2007, 11, 1811–1826.
(7) Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nature Protocols 2007, 2, 2451–
2458.
(8) Latypov, Sh.; Seco, J. M.; Quin˜oa´, E.; Riguera, R. J. Org. Chem.
1995, 60, 504–515.
(9) Kouda, K.; Kusumi, T; Ping, X.; Kan, Y; Hashimoto, T.; Asakawa,
Y. Tetrahedron Lett. 1996, 37, 4541–4544.
Having previously noticed some surprising long-range
effects in several Mosher ester derivatives, we decided to
investigate the ability of three CDAs [the commonly used
(10) Ichikawa, A.; Ono, H.; Harada, N. Tetrahedron: Asymmetry 2003,
14, 1593–1597.
Org. Lett., Vol. 12, No. 8, 2010
1769

MPA (1) and MTPA (3), as well as MTN(1)A (6)] to
differentially shield distant protons. Specifically, we have
examined the resonances of the terminal methyl groups in
the 1H NMR spectra of the series of homologous derivatives
13, derived from the symmetrical secondary carbinol precur-
sors 12 (Figure 2). These methyls, which are enantiotopic
(pro-R and pro-S) in 12, become diastereotopic in 13. Notice
that for this study, it makes no difference whether or not the
CDAs used were racemic.11
(for 13MTN(1)A-n) with the orange and green curves (for
13MPA-n and 13MTPA-n, respectively) (see Figure 2 inset). A
different way to state this is that there is a discontinuity in
the smoothness of the curves, most strongly evident in the
13MTN(1)A-n data set (blue). However, recall that the data are
plotted as the absolute value of ∆δ. This consideration led
us to hypothesize that the relative deshielding effect of the
pro-R vs pro-S methyl groups reverses for each of the series
(a crossoVer), causing the sign of ∆δ to change for each
series. This was testable, assuming we could access (i)
nonracemic MTN(1)A-OH (6-OH, Figure 1) and (ii) an
enantiomerically enriched and strategically deuterated ana-
logue of one of the larger (n g 7) carbinol precursors 12n.
We elected to prepare a nonracemic sample of partially
deuterated 10-nonadecanol 16 (the precursor to 13MTN(1)A-8
)
via the route summarized in Scheme 1. Racemic alcohol (()-
14 was resolved via PDC oxidation and asymmetric Noyori
reduction14 to give back (S)-14 having 95% ee. Alkyne
isomerization to the terminal alkyne 15 was followed by
deuteration to provide the alcohol-d4 16.
Scheme 1. Synthesis of (S)-10-Nonadecanol-1,1,2,2-d4 [(S)-16]
Figure 2. Trends in ∆δ values of the terminal methyl groups of
the CDA esters 13 derived from symmetric carbinols 12.
Acids (R)-6-OH and (S)-6-OH (Scheme 2) are the
nonracemic versions of MTN(1)A acid. These were prepared
from alkenol (()-17, which was O-methylated and oxida-
tively cleaved to give the primary alcohol (()-19. Partial
kinetic resolution was achieved with a lipase-induced acety-
lation. Although the levels of enantiopurity of the derived
samples of (R)-19 [via acetate (R)-20] and (S)-19 were
marginal [86% ee and 28% ee, respectively (from MTPA
analysis)], they were sufficiently high to serve our purposes.
Oxidation of each gave the carboxylic acids (R)-6-OH and
(S)-6-OH. Alternatively, we prepared racemic acid 6-OH
There are a number of noteworthy features seen in the
data for these series of compounds. The magnitude of the
∆δ values is greatest for MTN(1)A and least for MTPA. For
each CDA series, the maximum ∆δ value is observed when
n ) 1 (i.e., 13CDA-1 or the 3-pentanol derivative). There is
evidence of an “even-odd” effect12 in the step function (or
sawtooth) nature within each of the three series. At values
of n ) 6-8 (i.e., chain lengths of 15-19), the absolute value
of ∆δ reaches a minimum but, surprisingly, reemerges; that
is, the curves show a double maximium. We cannot help
but be reminded of the similar, textbook trends for rates of
cyclization vs ring size for R,ω-difunctional substrates,13
wherein transannular effects, maximal at medium ring sizes,
mitigate against the reactant residing in the reactive confor-
mation (i.e., with its termini in close proximity). This
situation is mitigated as the chain length is further increased.
An additional feature of the data intrigued us. At first
glance there is no obvious reason for the crossing of the blue
(by the method of Bourissou:15 1-NphthMgBr
+
CF3COCO2Et; K2CO3, MeI; KOH, EtOH), derivatized it as
the diasteromeric menthyl esters 6-m, and separated these
by MPLC (silica gel) to provide (R)-6-m (>99.8% de) and
(S)-6-m (94% de), which were used to collect the data
summarized in Table 1.
The preparation of the diastereomeric MTN(1)A esters
(S,R)- and (S,S)-21, each derived from nonracemic acid
chlorides prepared in situ and derived from nonracemic
samples of acids (R)-6-OH or (S)-6-OH, is outlined in
(11) For development of another unorthodox (“shortcut”) Mosher ester
analysis that was used on “nearly symmetrical” carbinols, see: Curran, D. P.;
Sui, B. J. Am. Chem. Soc. 2009, 131, 5411–5413.
(12) (a) Baeyer, A. Ber. Chem. Ges. 1877, 10, 1286–1288. (b) von
Sydow, E. Ark. Kemi 1955, 9, 231–254. (c) Breusch, F. L. Fortschr. Chem.
Forsch. 1969, 12, 119–184.
(14) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 285–288.
(13) E.g.: Smith, M. B., March, J. March’s AdVanced Organic Chemistry,
5th Ed.; J. Wiley & Sons, Inc.: New York, 2001; pp 281-284.
(15) du Boullay, O. T.; Alba, A.; Oukhatar, F.; Martin-Vaca, B.;
Bourissou, D. Org. Lett. 2008, 10, 4669–4672.
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Org. Lett., Vol. 12, No. 8, 2010

[(S,S)-21] further downfield. This confirms that indeed there
is a crossover-a change in the sign of ∆δ for 13MTN(1)A-8
.
Scheme 2. Enantioselective Synthesis of MTN(1)A Acid
Scheme 3. With these two esters in hand, we were in a
position to evaluate the hypothesis laid out above.
The proton NMR data for the terminal methyl regions of
(S,R)-21 and (S,S)-21, each having a diastereomeric purity
reflective of the level of enantiopurity of its precursors, are
Scheme 3
.
Synthesis of Diastereomeric C-19 Carbinyl MTN(1)A
Esters (S,R)-21 and (S,S)-21
Figure 3
MHz) for selected members of the MTN(1)A ester series.
.
Methyl resonances in the 1H NMR spectra (CDCl3, 500
In conclusion, trends in the relative discriminating power
of a wide variety of Mosher-like esters were identified by
analysis of the data in Table 1. Three homologous series of
esters 13CDA-n (derived from the symmetrical carbinols 12n)
were used to establish that the anistropic effects extend over
remarkably long molecular distances. An interesting cross-
over effect was uncovered.
Acknowledgment. These studies were supported by the
National Institute of General Medical Sciences (GM-65597)
and the National Cancer Institute (CA-76497) of the National
Institutes of Health.
shown in Figure 3. For comparison, the same spectral region
of the nondeuterated analogue of 21 (i.e., 13MTN(1)A-8, blue
data point, n ) 8, Figure 2) is also shown. From the method
of synthesis we know that the chain with the deuterated
terminus occupies the pro-S position in the structures in
Scheme 3. From the spectral data in Figure 3, we learn that
the nondepleted methyl resonance in the unlike diasteromer
[(S,R)-21] is further upfield and that in the like diastereomer
Supporting Information Available: Detailed experimen-
tal procedures and spectroscopic characterization data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL1003862
Org. Lett., Vol. 12, No. 8, 2010
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