formation from enantiomerically pure phosphorus reagents. The
responsivity of the 31P nucleus and the advent of high-field NMR
spectrometer in most instances allows to detect nonequivalent
resonances obtained from derivatizations as baseline-separated
signals.5
2-Chloro-(4R,5R)-bis[(1R,2S,5R)-menth-1-
yloxycarbonyl)]-1,3,2-dioxaphospholane: A Practi-
cal Chiral Pool-Derived Reagent for Determining
Enantiomeric Purity of Alcohols
Stereochemical information on phosphorus-based derivatizing
reagents may, in principle, originate from substitution at the
heteroatom or an inert chiral ligand attached to it. For reasons
of simplicity, the use of Cn-symmetric auxiliaries (n ) 2) is
favored. It eliminates the necessity of the phosphorus atom to
become a stereogenic center, which simplifies reagent prepara-
tion and mechanistic interpretation of 31P NMR data.6 In view
of these arguments, it comes as no surprise that a number of
chiral dioxaphospholanes and diazaphospholidines have been
developed over the past decade.1,7–11 Their potential to serve
as tools in analytical chemistry has been documented in original
reports and reviews.6,12 A critical survey of the literature,
however, indicates that the odds of this strategy frequently are
counterbalanced by technical issues, such as an inherent
hydrolytic lability of structurally simpler derivatizing reagents,8,9
or more demanding syntheses in terms of efforts and/or cost of
the more complex structures.1,10
Matthias Amberg, Uwe Bergsträsser, Georg Stapf, and
Jens Hartung*
Fachbereich Chemie, Technische UniVersität Kaiserslautern,
Erwin-Schrödinger-Strasse,
D-67663 Kaiserslautern, Germany
ReceiVed December 6, 2007
Although techniques to exclude moisture from preparations
nowadays are state of the art in organic synthesis, the propensity
to undergo hydrolytic modifications probably is the most
important drawback of chiral 2-chloro-1,3,2-dioxaphospholanes
to serve as more widespread reagents in stereochemical analysis.
In view of this background, we became interested in developing
a low-cost crystalline phosphorus-based derivatizing reagent
starting from chiral pool-derived building blocks. The major
result of the present study indicates that a compound prepared
from (R,R)-tartaric acid, (1R,2S,5R)-menthol, and PCl3 fulfilled
the given outline. The compound was available on a 20 g scale
2-Chloro-(4R,5R)-bis[(1R,2S,5R)-menth-1-yloxycarbonyl)]-
1,3,2-dioxaphospholane is a practical reagent for reliably
determining enantiomeric purity of chiral alcohols via 31P
NMR spectroscopy. The compound is available as a crystal-
line solid on a 20 g scale from PCl3 and bis[(1R,2S,5R)-
menth-1-yl] tartrate. It is comparatively inert toward spon-
taneous hydrolysis under conventional laboratory conditions
but undergoes quantitative substitution of alkoxide for
chloride if treated with a chiral alcohol. Nonequivalent 31P
NMR signals of diastereomeric 2-alkoxy-1,3,2-dioxophos-
pholanes were dispersed by ∼1.4–0.1 ppm. The associated
integral ratios reflected enantiomeric purities of preweighted
samples of (R)- and (S)-1-phenylethanol, (+)- and (-)-
menthol, and a set of primary, secondary, and tertiary
alcohols with a precision of (0.4–1.0%.
(1) Anderson, R. C.; Shapiro, M. J. J. Org. Chem. 1984, 49, 1304–1305.
(2) For 19F NMR based procedures, see: (a) Dale, J. A.; Dull, D. L.; Mosher,
H. S. J. Org. Chem. 1969, 34, 2543–2459. (b) Dale, J. A.; Mosher, H. S. J. Am.
Chem. Soc. 1973, 95, 512–519. (c) Seco, J. M.; Quiñoa, E.; Riguere, R. Chem.
ReV. 2004, 104, 17–118.
(3) For shift reagent based NMR procedures, see: (a) Whitesides, G. M.;
Lewis, D. W. J. Am. Chem. Soc. 1970, 92, 6979–6980. (b) Pirkle, W. H.; Beare,
S. D. J. Am. Chem. Soc. 1969, 91, 5150–5155.
(4) For chromatographic methods, see: (a) Schurig, V.; Nowotny, A. P.
Angew. Chem., Int. Ed. Engl. 1990, 29, 939–959. (b) Allenmark, S. G.
Chromatographic Enantioseparation: Methods and Applications; Ellis Harwood:
Chichester, U.K., 1988.
(5) Quin, L. D., Verkade, J. G., Eds. Phosphorous-31 NMR Spectral
Properties in Compound Characterization and Structural Analysis; VCH:
Weinheim, Germany, 1994.
(6) Parker, D. Chem. ReV. 1991, 91, 1441–1457.
(7) Brunel, J.-M.; Pardigon, O.; Maffei, M.; Buono, G. Tetrahedron:
Asymmetry 1992, 3, 1243–1246.
(8) Alexakis, A.; Mutti, S.; Mangeney, P. J. Org. Chem. 1992, 57, 1224–
1237.
(9) Bredikhin, A. A.; Strunskaya, E. I.; Azancheev, N. M.; Bredikhina, Z. A.
Russ. Chem. Bull. 1998, 47, 174–176.
The concept of investigating enantiomeric purity of chiral
alcohols in isotropic media by 31P NMR was introduced by
Anderson and Shapiro in 1984.1–4 It is based on diastereomer
(10) Hulst, R.; de Vries, N. K.; Feringa, B. L. Tetrahedron: Asymmetry 1994,
5, 669–708.
(11) Johnson, C. R.; Elliott, R. C.; Penning, T. D. J. Am. Chem. Soc. 1984,
104, 5019.
(12) Hulst, R.; de Vries, N. K.; Feringa, B. L. Recl. TraV. Chim. Pays-Bas
1995, 114, 115–138.
* To whom correspondence should be addressed. Fax: +49 (0)631/205 3921.
10.1021/jo7026068 CCC: $40.75
Published on Web 04/15/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3907–3910 3907