Chiral silylation reagents for the determination of absolute configuration by NMR spectroscopy

Article abstract of DOI:10.1021/ol006162h

(equation presented) We have investigated the use of chiral silylating reagents as analytical probes for determining the absolute stereochemistry of natural products by NMR spectroscopy. These reagents are prepared in high chemical yield in one step and c

Full text of DOI:10.1021/ol006162h

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2381-2383
Chiral Silylation Reagents for the
Determination of Absolute Configuration
by NMR Spectroscopy
Douglas B. Weibel, Tameka R. Walker, Frank C. Schroeder, and
Jerrold Meinwald*
Baker Laboratory, Department of Chemistry and Chemical Biology,
Cornell UniVersity, Ithaca, New York 14853
circe@cornell.edu
Received June 5, 2000
ABSTRACT
We have investigated the use of chiral silylating reagents as analytical probes for determining the absolute stereochemistry of natural products
by NMR spectroscopy. These reagents are prepared in high chemical yield in one step and can be used to derivatize chiral allylic alcohols
which are incompatible with ester-based methodologies. Microscale (∼400 nmol) derivatization conditions have been defined. The resulting
1
siloxane diastereomers are readily distinguished by their H NMR spectra.
A common method of defining absolute stereochemistry in
small molecules involves derivatizing samples with a chiral
reagent and comparing the product with authentic samples
of derivatized stereoisomers by either chromatography or
NMR spectroscopy. A variety of optically pure reagents have
been used to determine absolute stereochemistry in this
manner, and the introduction of optically pure (R)- and (S)-
R-(trifluoromethyl)phenylacetic acid1 (MTPA) and the cor-
responding acid chlorides for this purpose has made a
particularly important contribution to determining the abso-
lute configuration of natural products.
Unfortunately, due to facile elimination of the free or
esterified hydroxyl group in 2 to form a mixture of
conjugated tetraenes, we were unable to use MTPA to
determine this sensitive alcohol’s absolute stereochemistry.
Similar difficulties in preparing useful esters with MTPA
have been encountered in the determination of the absolute
Recently we found ourselves faced with determining the
absolute configuration of a heat- and acid-sensitive macrolide
(1) containing a bis-allylic ester moiety.2 To establish the
absolute configuration of 1, we converted the macrolide into
the corresponding hydroxy methyl ester 2 (Figure 1), with
the intention of using the MTPA methodology to compare
natural 2 with synthetic, optically pure (R)- and (S)-2.2
Figure 1. Structures of macrolide 1, open-chain derivative 2, and
volicitin 3.
(1) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(2) Manuscript in preparation.
10.1021/ol006162h CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/28/2000

1
configuration of N-(17-hydroxylinolenoyl)-L-glutamine (vo-
licitin, 3), an important elicitor of “plant volatile” biosyn-
thesis recently identified from the saliva of beet armyworms
(Figure 1).3 Consequently, the absolute configuration of
volicitin remains undetermined.4
good yield.8 As anticipated, the H NMR spectra of these
products showed significant differences in their chemical shift
patterns (Figure 2).
Since MTPA and similar chiral ester-forming reagents are
likely to prove unsuitable for the characterization of optically
active alcohols which are prone to undergo elimination, we
considered the use of chiral silylating reagents for this
purpose. Silylations can be carried out under very mild
conditions, and the resulting silyl ethers would be expected
to be much more resistant to elimination than the corre-
sponding O-acyl derivatives. Furthermore, silyl ethers are
easily cleaved, allowing recovery of the original alcohol. A
survey of the literature revealed two investigations of chiral
silylating reagents for examining the optical purity of
alcohols. Clausen and Bols5 have shown that trimenthoxy-
chlorosilane can distinguish between enantiomers of a
racemic homoallylic alcohol by 13C NMR spectroscopy, and
Chan et al.6 showed that chiral silyl derivatives could be used
1
to determine ee’s for simple secondary alcohols by H and
Figure 2. 1H NMR spectra of siloxane diastereomers 5 and 6 (500
MHz, CDCl3).
13C NMR analysis. Surprisingly, no application of this
methodology has been reported in elucidating the absolute
stereochemistry of natural products. We now report the
preparation of two chiral silylation reagents, 4 and 10, which
should prove generally useful for the stereochemical char-
acterization of labile alcohols.
Turning our attention to the volicitin example, we deriva-
tized the closely related (17R)-hydroxyoctadeca-9(Z),12(Z),-
15(Z)-trienoic acid methyl ester4 7 with (+)- and (-)-silane
We prepared (+)- and (-)-chloromenthoxydiphenylsilanes
4 (Scheme 1) from commercially available dichlorodiphen-
ylsilane and optically pure (+)- and (-)-menthol.7
(7) Triethylamine (4.90 mL, 35.2 mmol) was added dropwise to a stirred
solution of dichlorodiphenylsilane (6.58 mL, 32.0 mmol) in CH2Cl2 (100
mL) at 0 °C. Subsequently, a solution of (-)-menthol (5.00 g, 31.99 mmol)
in CH2Cl2 (10 mL) was added dropwise via cannula. The reaction mixture
was slowly warmed to rt and then heated to 42 °C for 72 h. After removing
the solvent, 100 mL of 50% hexane in ether was added to the viscous oil,
and the resulting mixture was stirred for 5 min under argon. Filtration was
carried out under argon and the filter cake washed with 50 mL of 50%
hexane in ether. The resulting clear solution was concentrated in vacuo
and vacuum distilled to provide 7.82 g (66%) of (-)-4 as a clear oil: bp
192-194 °C at 0.5 mm; [R]22D -47° (c 1.68, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 7.66-7.74 (m, 4 H), 7.36-7.49 (m, 6 H), 3.78 (dt, 1 H, J ) 4.3
and 10.4 Hz), 2.24 (dquin, 1 H, J ) 2.3 and 6.9 Hz), 1.94-2.01 (m, 1 H),
1.56-1.64 (m, 2 H), 1.24-1.36 (m, 2 H), 0.82-0.92 (m, 9 H), 0.58 (d, 3
H, J ) 6.9 Hz); 13C NMR (100 MHz, CDCl3) δ 134.8, 134.7, 131.0, 128.1,
74.9, 50.0, 44.8, 34.5, 31.8, 25.5, 22.8, 22.3, 21.4, 15.7; MS (EI+) m/z (rel
intensity) 336 (3), 295 (24), 294 (98), 217 (100), 181 (33), 138 (49), 123
(52), 95 (86), 81 (89).
Scheme 1
(8) A solution of (-)-silane 4 (14.6 mg, 0.039 mmol) in CH2Cl2 (100
µL) was added dropwise to a solution of (11R)-2 (11 mg, 0.035 mmol) in
CH2Cl2 (300 µL) at 0 °C. DMAP (6.0 mg, 0.046 mmol) was added and the
reaction stirred for 2 h at 0 °C. The reaction was then warmed to rt,
concentrated in vacuo, and chromatographed on SiO2 (2.5% ethyl acetate
in hexane) to afford siloxane 5 as a clear oil in 75% yield (17.3 mg): Rf )
0.15 (2.5% ethyl acetate in hexane); [R]22D -39° (c 1.60, CH2Cl2); 1H NMR
(500 MHz, CDCl3) δ 7.60-7.67 (m, 4 H), 7.36-7.41 (m, 2 H), 7.30-7.35
(m, 4 H), 5.52 (m, J10,9 ) 10.8, J10,11 ) 8.7, J10,8 ) 1.6 Hz, 1 H, 10-H),
5.49 (m, J12,13 ) 10.8, J12,11 ) 8.7, J12,14 ) 1.6 Hz, 1 H, 12-H), 5.35 (m,
J11,10 ) J11,12 ) 8.7, J11,9 ) J11,13 ) 1.2 Hz, 1 H, 11-H), 5.31 (m, J16,15
10.8, J16,17 ) 7.2, J16,14 ) 1.6 Hz, 1 H, 16-H), 5.28 (m, J9,10 ) 10.8, J9,8
7.3, J9,11 ) 1.2 Hz, 1 H, 9-H), 5.18 (m, J13,12 ) 10.8, J13,14 ) 7.3, J13,11
)
)
)
The derivatization of synthetic (11R)-hydroxyoctadeca-
9(Z),12(Z),15(Z)-trienoic acid methyl ester 2 with (-)-silane
and (+)-silane 4 proceeded rapidly at 0 °C in the presence
of DMAP to afford the diastereomeric siloxanes 5 and 6 in
1.2 Hz, 1 H, 13-H), 5.10 (m, J15,16 ) 10.8, J15,14 ) 7.2, J15,17 ) 1.6 Hz, 1
H, 15-H), 3.67 (s, 3 H), 3.58 (dt, 1 H, J ) 4.2 and 10.2 Hz), 2.50-2.58
(m, 1 H, 14-H), 2.39-2.47 (m, 1 H, 14-H), 2.25-2.38 (m, 3 H), 1.99-
2.06 (m, 1 H), 1.92 (quintet, 2 H, J ) 7.3 Hz), 1.75-1.84 (m, 2 H), 1.52-
1.64 (m, 5 H), 1.15-1.32 (m, 10 H), 1.06-1.14 (m, 1 H), 0.92 (t, 3 H, J
) 7.4 Hz), 0.88 (d, 3 H, J ) 7.1 Hz), 0.83 (t, 3 H, J ) 6.5 Hz), 0.75-0.87
(m, 1 H), 0.54 (d, 3 H, J ) 6.9 Hz); 13C NMR (100 MHz, CDCl3) δ 174.4,
135.4, 135.3, 134.4, 134.2, 132.2, 131.8, 131.6, 130.0, 128.1, 127.7, 127.6,
126.9, 73.6, 65.6, 51.6, 50.2, 45.4, 34.7, 34.3, 31.7, 29.7, 29.4, 29.36, 29.32,
28.0, 25.9, 25.4, 25.1, 22.8, 22.4, 21.5, 20.6, 15.8, 14.3; HRMS calcd for
C41H60O4Si 644.4260, found 644.4252.
(3) Alborn, H. T.; Turlings, T. C. J.; Jones, T. H.; Stenhagen, G.;
Loughrin, J. H.; Tumlinson, J. H. Science 1997, 276, 945.
(4) Pohnert, G.; Koch, T.; Boland, W. Chem. Commun. 1999, 1087.
(5) Clausen, R. P.; Bols, M. J. Org. Chem. 1997, 62, 4457.
(6) Chan, T. H.; Peng, Q. J.; Wang, D.; Guo, J. A. J. Chem. Soc., Chem.
Commun. 1987, 325.
2382
Org. Lett., Vol. 2, No. 15, 2000

4. The resulting siloxanes 8 and 9 were obtained in 80%
yield after chromatography on SiO2. Investigation of 8 and
9 by 1H NMR spectroscopy again revealed clearly different
chemical shifts and splitting patterns which could be applied
toward determining the absolute configuration of natural
volicitin (Figure 3).
Figure 4. 1H NMR spectra of siloxane diastereomers 11 and 12
(500 MHz, CDCl3).
Figure 3. 1H NMR spectra of siloxane diastereomers 8 and 9 (500
MHz, CDCl3).
to the desired product. Column chromatography or HPLC
yielded the pure siloxanes. We anticipate that this method
can be extended to even smaller amounts of chiral alcohols
1
that approach the limits of H NMR sensitivity.
In addition to the two examples presented, several chiral
1
In conclusion, we have prepared chiral silylation reagents
that can be used for the determination of absolute configu-
ration and enantiomeric excess of labile chiral alcohols. In
the two examples we have described, stable diastereomeric
aliphatic alcohols were derivatized. Again, the H NMR
spectra of the resulting diastereomeric siloxanes showed
significant differences, indicating the general applicability
of our method. It should be noted that even in cases where
proton NMR signals partially overlap, commonly available
software packages for the analysis of NMR data can be used
to deconvolute the signals of interest, making determination
of ee’s and absolute configuration feasible.
1
siloxane derivatives are obtained; their H NMR spectra
clearly allow us to distinguish between the enantiomers of
alcohols from which they are derived. Derivatization condi-
tions are mild and have been optimized for microscale
reactions. Alcohols can be conveniently recovered by briefly
treating their siloxane derivatives with TBAF. While in this
Letter we have illustrated the utility of this procedure for
the determination of the absolute configuration of allylic
alcohols, we anticipate that this method can be extended
easily to a variety of other structures.
While silane 4 clearly distinguishes between the enanti-
omers of the allylic alcohols we have studied thus far, the
proton signals of the menthoxy group might in some cases
cause undesirable overlap with important proton signals of
the substrate in the aliphatic region. As an alternative
derivatization reagent, we therefore prepared chiral chlo-
rodiphenylsilanes 10 from optically pure (R)-(+)- and (S)-
(-)-2-bromo-R-methylbenzyl alcohol (Scheme 1). Both (+)-
and (-)-silane 10 were used to derivatize (11R)-2; the
resulting siloxane diastereomers 11 and 12 again showed
Acknowledgment. We are indebted to Dr. Georg Pohnert
for providing us with a sample of synthetic TBDMS-
protected (17R)-hydroxylinolenic acid methyl ester. The
partial support of this research by the National Institutes of
Health (GM53830) is gratefully acknowledged.
1
significant differences in their H NMR spectra (Figure 4).
We next adapted the silylation procedures to microscale
reactions. After investigating a variety of conditions, we
found that as little as 100 µg (∼400 nmol) of trienol 2 could
be derivatized in a nearly quantitative manner using 100
equiv of DMAP and of (-)-silane 4.9 Reactions were
immediately complete and were quenched with excess
methanol to reveal two products on SiO2 TLC: one spot
corresponding to menthoxymethoxydiphenylsilane and one
OL006162H
(9) (11R)-2 (136 µg, 440 nmol) was placed in a microvial, dissolved in
CH2Cl2 (75 µL), and cooled to 0 °C. (-)-Silane 4 (16.4 mg, 0.044 mmol)
was added to the vial dropwise as a solution in CH2Cl2 (75 µL) followed
by addition of DMAP (5.4 mg, 0.044 mmol). The reaction was shown to
be immediately complete by TLC and was quenched by dropwise addition
of methanol (250 µL). Concentration in vacuo followed by chromatography
on a SiO2 pipet column provided siloxane 5 in nearly quantitative yield.
Org. Lett., Vol. 2, No. 15, 2000
2383