New silyl ether reagents for the absolute stereochemical determination of secondary alcohols.

Article abstract of DOI:10.1021/ol034418o

[reaction: see text] Herein we report a new set of silyl ether reagents for determining the enantiomeric purity and absolute stereochemistry of secondary alcohols. These derivatives are easily synthesized, provide straightforward spectroscopic results, an

Full text of DOI:10.1021/ol034418o

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1745-1748
New Silyl Ether Reagents for the
Absolute Stereochemical Determination
of Secondary Alcohols
R. Thomas Williamson,* Ana C. Barrios Sosa,† Abhijit Mitra,‡ Pamela J. Seaton,§
,†
Douglas B. Weibel, Frank C. Schroeder, Jerrold Meinwald, and
Frank E. Koehn†
Wyeth Research, 401 North Middletown Road, Pearl RiVer, New York 10965,
Departments of Chemistry and Biochemistry, Manhattan College/College of
Mount St. Vincent, RiVerdale, New York 10471, Department of Chemistry,
UniVersity of North Carolina at Wilmington, Wilmington, North Carolina 28403, and
Department of Chemistry and Chemical Biology, Cornell UniVersity,
Ithaca, New York 14853-1301
williar9@wyeth.com
Received March 10, 2003
ABSTRACT
Herein we report a new set of silyl ether reagents for determining the enantiomeric purity and absolute stereochemistry of secondary alcohols.
These derivatives are easily synthesized, provide straightforward spectroscopic results, and allow for facile recovery of the original chiral
alcohol.
The determination of absolute stereochemistry remains a
challenging aspect of organic chemistry. Many approaches
based on circular dichroism,1 X-ray crystallography,2 and the
varied use of anisotropic shielding reagents in combination
with NMR spectroscopy3 have been reported in the literature.
However, to this date, no one method has proved to be
general in its application. As a result, the search for
approaches that address the limitations of known methods
remains of paramount importance. In this Letter, we present
the development of new silyl reagents that can be used in
conjunction with NMR spectroscopy to determine the
absolute stereochemistry and enantiomeric purity of second-
ary alcohols.
The advanced Mosher method reported by Ohtani et al.
provided a major breakthrough in the field of absolute
stereochemical determination.4 Although these “Mosher
esters” provide reliable results and are relatively easy to
synthesize, they often prove unsuccessful when working with
sterically hindered or elimination-prone alcohols. In addition,
harsh hydrolysis conditions are generally required to cleave
the ester bond, making recovery of the starting alcohol a
difficult task. In our ongoing efforts to develop more efficient
methods for stereochemical analysis, we sought to develop
a new silicon-based reagent that would address these issues.5
A silicon-based reagent was chosen because the chemical
nature of the silyl ether group allows for simple derivitiza-
tion6 and convenient recovery of the original chiral compound
of interest.7
† Wyeth Research.
‡ Manhattan College/College of Mount St. Vincent.
§ University of North Carolina at Wilmington.
Cornell University.
(1) For an excellent reference see: Circular Dichroism: Principles and
Applications, 2nd ed.; Berova, N., Nakanishi, K., Woody, R. W., Eds.;
Wiley-VCH: New York, 2000.
(2) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley-Interscience: New York, 1994.
(3) For a practical review see: Seco, J. M.; Quinoa, E.; Riguera, R.
Tetrahedron: Asymmetry, 2001, 12, 2915-2925.
(4) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092-4096.
(5) Weibel, D. B.; Walker, T. R.; Schroeder, F. C.; Meinwald, J. Org.
Lett. 2000, 2, 2381-2383.
10.1021/ol034418o CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/15/2003

It has recently been shown that chiral silanes can be used
to resolve the chemical shifts of enantiotopic stereogenic
centers and to determine the absolute configuration of natural
products.5,8,9 However, the absolute stereochemical deter-
mination of a molecule with use of these previously described
diphenyl alkyl-substituted silyl ethers was only possible when
enantiomerically pure standards were available for compari-
son.5,9 We suspected that if a derivative could be designed
that had a conformationally stabilizing component to its
structure, it would be possible to reliably determine absolute
stereochemistry by using this type of synthetic tool.
Figure 1. General conformational model for the PhTFE derivatives
discussed in the text.
In 1976, Pirkle and co-workers postulated that the interac-
tion of a carbinyl hydrogen and a basic site on a molecule
can afford a chelate-like structure that provides a reasonably
stable and predictable solution conformation.10 On the basis
of Pirkle’s findings, we designed a silyl ether that would
allow for conformational control using this principle. For
this purpose, dichlorodimethylsilane (2) was reacted with R-
or S-R-(trifluoromethyl)benzyl alcohol (1) at room temper-
ature in the presence of triethylamine to give R-(trifluoro-
methyl)benzyl silyl chloride (3) (Scheme 1). This silyl
chloride can subsequently be used to quickly and smoothly
derivatize the chiral alcohol of interest with use of a mild
base.
derivatives in much the same way as has been described
previously for the advanced Mosher method.4
According to our conformational model, the protons on
L1 (Figure 1) will be shielded upfield by the aromatic ring
of the PhTFE functionality when using the R-PhTFE (4a)
derivative. Similarly, the protons on L2 will be shielded
upfield when using the S-PhTFE derivative (4b). It follows
that in 4a protons with a (δR - δS) value <0 would be
placed on the L1 face and those protons with a value >0
would be positioned on the L2 face. If the chemical shift
trends (<0 or >0) are consistent on each of the L1 and L2
faces of the model, the absolute stereochemistry can be
assigned by using this method. In analogy to the advanced
Mosher method, if the (δR - δS) value signs are not
consistent on L1 and L2, it can be assumed that the
derivatizing agent must be forced into a nonideal conforma-
tion and the stereochemistry cannot be confidently assigned
with use of this method.
Scheme 1. Synthesis of PhTFE derivatives and recovery of
starting alcohol.
As an initial test of this theory, the R- and S-PhTFE
derivatives of (S)-butanol (6a and 6b, respectively) were
synthesized and analyzed by NMR spectroscopy. As can be
seen in Figure 2, the observed chemical shift changes agree
very well with our predictions.
Encouraged by these results, we synthesized the (R)-
PhTFE derivative of (R)-pantolactone (7a) and acquired a
It was envisioned that the final silyl diether product (4)
would adopt a predominant conformation similar to the one
shown in Figure 1. We also hypothesized that this conforma-
tion would be encouraged by a key interaction between the
carbinyl proton of the R-(trifluoromethyl)benzyl ether and
the oxygen of the derivatized alcohol (Figure 1). Once the
corresponding R- and S-R-(trifluoromethyl)benzyl silyl de-
rivatives (R- and S-PhTFE) are synthesized, the absolute
stereochemistry can be determined through analysis of the
chemical shift differences (δR - δS) observed for the two
(6) For an excellent reference see: Greene, T. W.; Wuts, P. G. M.
ProtectiVe Groups in Organic Synthesis, 3rd ed.; Wiley-Interscience: New
York, 1999.
(7) Corey, E. J.; Snider, B. B. J. Am. Chem. Soc. 1972, 94, 2549-2550.
(8) Chan, H.; Peng, Q.-J.; Wang, D.; Guo, J. A. J. Chem. Soc., Chem.
Commun. 1987, 325-326.
Figure 2. 1H NMR spectra of the R- (6a) and S-PhTFE (6b)
derivatives of S-butanol in CDCl3. Note the 9% (R)-enantiomer
present in the commercially available chiral alcohol.
(9) Smedley, S. R.; Schroeder, F. C.; Weibel, D. B.; Meinwald, J.;
Lafleur, K. A.; Renwick, J. A.; Rukowski, R.; Eisner, T. Proc. Natl. Acad.
Sci. U.S.A. 2002, 99, 6822-6827.
(10) Pirkle, W. H.; Hauske, J. R. J. Org. Chem. 1976, 41, 801-805.
1746
Org. Lett., Vol. 5, No. 10, 2003

set of DPFGSE 1D-NOE experiments to obtain NMR
spectroscopic evidence for the proposed conformation. The
geminal methyl groups in alcohol 7 allowed us to glean
information on the functional entities surrounding both the
“bottom” and “top” faces of this molecule. As depicted in
Figure 3, strong NOE enhancements supporting the proposed
Following these results, we synthesized a small library of
silyl derivatives using commercially available chiral alcohols
with increasing structural complexity. These examples
include the natural products podophyllotoxin 13, cholesterol
14, and cytochalasin B 15 (Figure 5). All of the results
Figure 3. Results from the NOE study on the R-R-(trifluoro-
methyl)benzyl silyl ether of R-pantolactone (7).
conformation were observed from CH3-5 and CH3-6 to the
aromatic protons H-12 and H-13. This result shows the
proximity of CH3-5 and CH3-6 to the phenyl group, which
is the origin of the shielding effect. In addition, strong
interactions were observed between H-2 and the silyl methyl
groups (CH3-7 and CH3-8), as well as between the H-9 proton
of the benzyl alcohol and CH3-7 and CH3-8.
The next step in our study was to implement ab initio
molecular modeling calculations at the B3LYP6-31G* level
using 403 basis functions to examine the proposed structure.11
As can be seen in Figure 4, these results agree quite well
Figure 5. Structures of R- and S-PhTFE derivatives synthesized
from commercially available alcohols. Selected (δR - δS) are
shown in ppb.
obtained (Figure 5) agree with our predictions based on the
general model shown in Figure 1. Free alcohols were easily
recovered with use of TBAF bound to silica.7
As part of our library, we chose to derivatize one
enantiomer of the starting R-(trifluoromethyl)benzyl alcohol
(1) with both the R- and S-PhTFE reagents (3a,b). This
sterically hindered alcohol has been shown to be resistant
to standard Mosher-type esterification conditions.12 However,
as in the case of all other alcohols tested, we observed
essentially quantitative conversion to the desired R and S
silyl ethers (16).
Interestingly, although the magnitude of the observed
chemical shift changes is reduced in polar NMR solvents
such as methanol, the observed trend of the chemical shift
changes remains the same. This observation suggested that
the weak interaction between the carbinyl proton and the
oxygen of the starting chiral alcohol was not the only driving
force behind this lowest energy conformation. To further
explore this hypothesis, we performed an exhaustive Monte
Carlo conformational search using the Maestro/MacroModel
molecular modeling software (Ver 5.0.19).13
Figure 4. Results from ab initio calculations on the (S)-PhTFE
derivative of the meso compound 4-heptanol (8).
with our predicted conformation. In addition, these calcula-
tions confirm the presence of a partial positive charge on
the R-proton of the R-(trifluoromethyl)benzyl silyl ether
(0.239 NPA) and a partial negative charge on the silylated
oxygen of R-pantolactone (-0.947 NPA). These findings are
consistent with the hypothesis that charge-charge interac-
tions may exist to help stabilize the structure.
(12) Takeuchi, Y.; Itoh, N.; Koizumi, T. J. Chem. Soc., Chem. Commun.
1992, 1514-1515.
(13) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrikson, T.; Still, W. C. J. Comput.
Chem. 1990, 11, 440-467.
(11) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785-
789. Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (b) Ab initio
calculations were done with the Titan software package.
Org. Lett., Vol. 5, No. 10, 2003
1747

center of the starting material (4-heptanol) and the silicon
atom of the derivatizing reagent (Figure 6). Rotamer A,
which is almost identical with the conformation obtained
from the ab initio calculations, possessed the lowest energy
of the three families.
As can be seen in rotamer A, Figure 6, the phenyl ring
would be expected to provide a significant shielding effect
to the pro-R hydrogens of 4-heptanol. In the next lowest
energy rotamer, rotamer B, the pro-R protons would experi-
ence a weaker shielding effect than that expected in rotamer
A. Finally, rotamer C, which would not be expected to
provide shielding to either the pro-R or pro-S protons of the
derivatized 4-heptanol, was found to be the next lowest
energy conformation. All other conformations were calcu-
lated to be more than 10 kcal/mol higher in total energy to
rotamer A. For this reason, they would not be expected to
contribute significantly to the overall conformational popula-
tion of the derivatized alcohol.
In summary, we have developed an alternative approach
to the Advanced Mosher method for the determination of
absolute stereochemistry. These new silicon-based reagents
provide efficient derivitization of even sterically hindered
chiral secondary alcohols that are resistant to standard
esterification conditions. For these reasons, we believe that
the PhTFE reagents described here should find wide ap-
plication in the fields of multistep asymmetric synthesis and
natural products chemistry. In addition, we are currently
exploring the use of these compounds as derivatizing agents
for chiral separations. The results of these studies and others
will be reported in due course.
Acknowledgment. We thank Dr. Brian Marquez, Dr.
Gloria Proni, Prof. Joseph Capitani, and Prof. Koji Nakanishi
for helpful discussions. Support to D.B.W, F.C.S., and J.M.
from the National Institute of Health (GM 53850) is
gratefully acknowledged.
Figure 6. Representative structures from the three families of
lowest energy conformers obtained from a Monte Carlo confor-
mational search. The approximate energy differences between
structures B and C relative to structure A are also indicated.
Supporting Information Available: General experimen-
tal procedures for derivitization and desilylation and NMR
data for 7, 13, 14, and 15. This material is available free of
charge via the Internet at http://pubs.acs.org.
These results showed that, based on steric interactions
alone, there are three discrete families of possible low-energy
conformations. Each of these conformations reflects a 120°
rotation about an imaginary line through the stereogenic
OL034418O
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Org. Lett., Vol. 5, No. 10, 2003