Derivatizing agents from phosphorus trichloride and terpenyl tartrates for determining the enantiomeric purity of alcohols

Article abstract of DOI:10.1016/j.tetasy.2011.04.004

Heterocyclic phosphorous acid chlorides, prepared from C ₂-symmetric menthyl, borneyl, or fenchyl tartrates and phosphorus trichloride, are inexpensive derivatizing agents for determining the enantiomeric purity of alcohols via phosphorus NMR.

Full text of DOI:10.1016/j.tetasy.2011.04.004

Tetrahedron: Asymmetry 22 (2011) 752–760
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Derivatizing agents from phosphorus trichloride and terpenyl tartrates
for determining the enantiomeric purity of alcohols
⇑
Matthias Amberg, Irina Kempter, Uwe Bergsträßer, Georg Stapf, Jens Hartung
Fachbereich Chemie, Organische Chemie, Technische Universität Kaiserslautern, Erwin-Schrödinger-Straße, D-67663 Kaiserslautern, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 March 2011
Accepted 4 April 2011
Heterocyclic phosphorous acid chlorides, prepared from C2-symmetric menthyl, borneyl, or fenchyl tar-
trates and phosphorus trichloride, are inexpensive derivatizing agents for determining the enantiomeric
purity of alcohols via phosphorus NMR. The most versatile agent identified from this study, a (1R,2S,5R)-
menthyl (R,R)-tartrate-derived 2-chloro-1,3,2-dioxaphospholane, gives, upon esterification with chiral
alcohols, diastereomeric phosphites showing phosphorus NMR-shift dispersions between 0.1 ppm and
1.5 ppm.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
phosphorus-based alternatives to Mosher’s acid.14–17 The phospho-
rus nucleus shows strong responsivity in shielding arising from
Procedures for analyzing the enantiomeric purity of alcohols are
important for development of synthetic methods dealing with oxi-
dative transformations of unsaturated hydrocarbons,1–3 enzyme-
catalyzed desymmetrization of esters, or nucleophilic addition to
carbonyl compounds.4 To determine the enantiomeric purity of
alcohols, three common approaches exist. The first approach is
based on reversible adduct formation between an enantiomerically
pure probe and enantiomers of a chiral alcohol. Differences in the
type (connectivity) and degree (bond strength) of diasteromorphic
interactions that result from molecular recognition may be enough
to bring about changes in chromophores (UV/vis, IR) or shielding
parameters of nuclei (NMR), to spectroscopically distinguish the
diastereomorphs.5–8 The second approach takes advantage of the
differences in binding energies between a chiral analyte, which is
the alcohol as the guest, and a large number of chiral receptors
as hosts, mounted on a stationary phase along a flow gradient.
By using this approach, retention time dispersion for the chro-
matographic separation of enantiomers is attainable (GC or
HPLC).9,10 In the third approach, enantiomers are modified via
covalent bonding to an enantiomerically pure derivatizing agent,
thus providing diastereomers for stereochemical characterization
in an isotropic environment.11,12
steric, stereoelectronic, and electronic changes.18,19 To simplify
the stereochemical aspects dealing with synthesis and alcohol
derivatizing, it is often advantageous to use phosphorus(III)-
derived agents (phosphorus in a chirotopic environment) rather
than phosphorus(V) compounds (stereogenic phosphorus). Phos-
phorus(III) compounds, however, hydrolyze rapidly and are some-
times demanding to prepare.15,16
To determine the enantiomeric purity of alcohols prepared from
transition metal-catalyzed oxidation,20 we needed an inexpensive
chiral derivatizing agent with none of the familiar disadvantages
(vide supra).21,22 For economic reasons, we decided to use building
blocks from the chiral pool, to prepare phosphorus(III) compounds
that are largely inert toward hydrolysis (Fig. 1). The most impor-
tant result herein shows that an agent synthesized from tartaric
acid, menthol, and phosphorus trichloride fulfills the prerequisites.
This compound is able to copy the enantiomeric ratios of alcohols
(primary, secondary, and tertiary), via an in situ phosphite forma-
tion, into diastereomers and shows in the majority of cases, ade-
quate shift dispersions to quantify results via the integration of
baseline-separated phosphorus resonances.
2. Results and discussion
A common strategy for determining the enantiomeric purity of
alcohols via the derivitization approach uses (R)- or (S)-a-meth-
2.1. Preparation and properties of 2-chloro-1,3,2-
dioxaphospholanes
oxy-a-trifluoromethylphenyl acetic acid (Mosher’s acid) to esterify
the analyte.13 The acid, however, is expensive. With the need to re-
duce cost for analytical purposes without losing the generality of
enantiomer analysis, chemists have invested effort to find
The condensation of phosphorus trichloride and C2-symmetric
menthyl, borneyl, or fenchyl tartrates 2a–d23 in solutions of boiling
dry tetrahydrofuran, gave 2-chloro-1,3,2-dioxaphospholanes 1a–d
in yields of between 72% and 88% (Table 1). To drive the condensa-
tion to completion, we added phosphorus trichloride in excess. The
⇑
Corresponding author. Tel.: +49 631 205 2431; fax: +49 631 205 3921.
E-mail address: hartung@chemie.uni-kl.de (J. Hartung).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.04.004

M. Amberg et al. / Tetrahedron: Asymmetry 22 (2011) 752–760
753
R
R
derivative (4R,5R)-1c adopt twist (T) conformations, with the phos-
phorus atom and one of the endocyclic oxygens offset into opposite
directions from a plane, which is formed by the C4 and C5 atoms
and the second endocyclic oxygen [2T3-conformation24 for
(4R,5R)-1a, 2T3-conformation for (4R,5R)-1c] (Fig. 3).
O
O
O
H
H
OH
OH
O
O
O
O
O
O
4
5
2
3
P
Cl
R
R
H
H
O
The non-equivalence of endocyclic phosphorus–oxygen bonds,
with the shorter distance being situated in the least puckered re-
gion of the heterocycle, in combination with a lengthening of the
phosphorus–chlorine bond (Table 2, entries 1–3), which is widened
beyond the reference value given for phosphorus trichloride
[2.043(3) Å],25 is characteristic for solid state structures of satu-
rated heterocycles composed of ClPO2-subunits.26–29 Similar
parameters were reported for the structure of 2-chloro-1,3,2-
dioxaphospholane in the gas phase.30
(4R,5R)-1
(2R,3R)-2
for 1 and 2:
(5S)
(5R)
R =
(2R)
(2S)
(1S)
(1R)
b
a
To rationalize the structural properties of the 2-chloro-1,3,2-
dioxaphospholanes, we propose a model based on a stabilizing
interaction between the p-type lone pair at the oxygen [p2(O)]
and the non-bonding orbital of the phosphorus–chlorine bond
(4S)
(1S)
(2R)
(1R)
(2R)
(4S)
c
d
[r
⁄(P,Cl); Fig. 4], similar to the anomeric effect in carbohydrate
chemistry.31 This model explains the shortening of the phospho-
rus–oxygen bonds in the planarized part of the five-membered
ring, the lengthening of the phosphorus–chlorine bond, and the
conformational stability at the phosphorus atom. Furthermore
the existence of a stereoelectronic effect explains breaking of the
C2-symmetry imposed by the dialkyl tartrate unit in heterocycles
1a–d and thus the origin of an additional coupling caused by
syn-orientation and thus through space interaction between the
pair of non-bonding electrons at phosphorus and the proton at-
tached to C4 (Fig. 2).32–34
Figure 1. Structure formulae and indexing of chiral 2-chloro-1,3,2-dioxaphosphol-
anes 1a–d and tartrate-derived building blocks 2a–d.
Table 1
Synthesis of tartrate-derived 2-chloro-1,3,2-dioxaphospholanes 1a–da
H
H
RO2C
RO2C
OH
O
O
THF / 65 °C
4
2
3
+
PCl3
P
Cl
5
− 2 HCl
RO2C
RO2C
OH
H
H
2a−d
1a−d
2.2. Stability of 2-chloro-1,3,2-dioxaphospholanes
d
31Pc (ppm)
½ ꢁ
a 2D5
b
Entry
2
Yield (%)
Mp (°C)
1
2
3
4
5
6
(2R,3R)-2a
(2S,3S)-2b
(2R,3R)-2b
(2S,3S)-2a
(2R,3R)-2c
(2R,3R)-2d
(4R,5R)-1a: 87
(4S,5S)-1b: 88
(4R,5R)-1b: 78
(4S,5S)-1a: 72
(4R,5R)-1c: 81
(4R,5R)-1d: 84
ꢂ155.0
+151.4
ꢂ20.6
+21.3
72
175.6
175.6
175.5
175.5
174.8
176.3
To clarify as to whether the new compounds would resist
decomposition if stored under conditions that generally exist in
our laboratory (ꢀ20 °C, ꢀ50–80% relative humidity), we took sam-
ples from (4R,5R)-1a and (4R,5R)-1b over intervals and monitored
the fraction of unspent 2-chloro-1,3,2-dioxaphospholane (OPPh3 as
an internal standard). After 24 h, samples stored in air consisted of
ꢀ95% of unchanged acid chlorides (4R,5R)-1a and (4R,5R)-1b. Dur-
ing this time, the outer appearance of the compounds remained the
same. Samples of borneyl-substituted chlorodioxaphospholane
(4R,5R)-1c and fenchyl derivative (4R,5R)-1d also showed no
changes in outer appearance. We therefore, concluded that the sta-
bilities of all 2-chlorodioxaphospholanes prepared in this study are
quite similar.
The stability of 1 is an important improvement with respect to
known derivatives, such as a compound prepared from diethyl tar-
trate and phosphorus trichloride,16 which decomposes within less
than 24 h, if stored in a laboratory atmosphere.21 We believe that
the considerable degree of inertness, is because of the crystallinity
of acid chlorides 1a–d, since the more labile congeners are oils.
70–71
67–68
69–70
82
ꢂ105.0
ꢂ17.0
80
a
b
c
For indexing of R refer to Figure 1.
c 1.00 in THF.
In C6D6 at 25 °C.
solvent and excess phosphorus reagent were distilled off, to leave
2-chloro-1,3,2-dioxaphospholanes 1a–d as colorless oils, which
crystallized from cold pentane.
In solutions of chloroform-d1 or benzene-d6, protons attached to
the C4 and C5 of chlorodioxaphospholanes 1a–d differed in the
chemical shift (DdH = 0.5–0.6 ppm, 25 °C) and multiplicity. One of
the protons forms a doublet (3JH,H = 6.7–7.1 Hz) and the second a
double doublet. The additional coupling (3JP,H = 8.6–9.1 Hz; Fig. 2)
comes from proton-phosphorus interaction, as evident from the
phosphorus-decoupled proton NMR-spectra.
In the solid state, heterocyclic cores of (1R,2S,5R)-menthyl-
substituted dioxaphospholane (4R,5R)-1a and (1S,2R,4S)-borneyl
2.3. Formation of trialkylphosphites
The analysis of enantiomeric purity via chemical derivatization
requires quantitative esterification of a chiral alcohol (primary,
secondary, and tertiary) with 1. The enantiomeric ratio of the alco-
hol thereby is copied into a diastereomeric ratio of phosphites,
which is analyzed via integration of the shift-dispersed phosphorus
resonances.
To verify the in situ phosphite formation from (4R,5R)-1a, 1,1,1-
trichloroethanol 5 was converted into trichloroethyl ester 6 in
quantitative yield. In trichloroethyl ester 6, the resonances of dia-
stereotopic protons are split by a geminal proton–proton coupling
(11.8 Hz) and a vicinal phosphorus-proton coupling (7.2–8.2 Hz)
into double doublets (Table 3, entry 1; Fig. 5). The effect of the
3JP,H = 8.6−9.1 Hz
E
H
5
O
4
P
O
H
E
Cl
3JP,H not observed
Figure 2. Visualization of the interactions between the phosphorus and diastereo-
topic protons at the 4- and 5-positions of 2-chloro-1,3,2-dioxaphosopholanes 1a–d
(E = ester substituent; for a model explaining the differences in the JP,H-coupling
with H4 and H5 on the basis of positioning of the pair of non-bonding electrons at
phosphorus, see text).
3

754
M. Amberg et al. / Tetrahedron: Asymmetry 22 (2011) 752–760
Figure 3. Ellipsoid graphics (50% probability level) of 2-chloro-1,3,2-dioxaphospholanes (4R,5R)-1a (left) and (4R,5R)-1c (right) in the solid state (150 K; hydrogen atoms
were depicted as circles of an arbitrary radius).
Table 2
Table 3
Selected solid state parameters of menthyl chlorodioxaphospholane (4R,5R)-1a and
borneyl derivative (4R,5R)-1c
Yields and NMR-data of trialkylphosphites prepared from prochiral alcohols
enantiotopic
diastereotopic
R
O
H
H
H
H
H
Entry
parameter (Å) or (°)
(4R,5R)-1a
(4R,5R)-1c
O
O
NEt3
O
O
(4R,5R)-1a
HO
R1
P
O
R1
1
2
3
4
5
O1–P2
P2–O3
P2–Cl1
Cl1–P2–O1–C5
Cl1–P2–O3–C4
1.601 (1)
1.617 (2)
2.105 (1)
ꢂ85.5 (1)
79.8 (1)
1.630 (4)
1.605 (4)
2.089 (3)
ꢂ74.4 (4)
84.8 (4)
+
THF / 20 °C
R
H
O
5/7
6/8
dC (J/Hz)c
5/7 (R1)
5 (CCl3)
6/8a (%)
dH (JP,C/Hz)b
dP
c
Entry
1
6/quant.
4.25 dd (11.8, 7.2)c
4.38 dd (11.8, 8.2)c
4.70 dd (12.5, 7.6)d
4.76 dd (12.5, 7.9)d
75.1 d (13.9)
65.5 d (12.9)
144.3
143.9
E
2
7 (C6H5)
8/92
E
O
O
P
a
b
c
31P NMR (OPPh3 as the internal standard; for R see Fig. 1).
(JP,H, JH,H).
In CDCl3.
In C6D6.
E
Cl
P
P
O
O
d
2T3-conformation
Cl
Cl
Figure 4. Proposed model for the conformational stabilization of 2-chloro-1,3,2-
dioxaphospholanes 1a–d via p2(O)?r⁄(P,Cl) delocalization (E = ester substituent).
phosphite formation on the chemical shift for the oxygen bonded
carbon in alcohol 5 is small (
D
d = ꢂ1.4 ppm; Table 3). In the phos-
phorus NMR, the conversion of (4R,5R)-1a into phosphite 6 leads to
an upfield shift of 30.3 ppm (Tables 1 and 3). Since esterification of
benzyl alcohol 7 with (4R,5R)-1a provides a similar shift and mul-
tiplicity change, we can conclude that O-benzyl phosphite 8 is
formed under such conditions (Table 3, entry 2).
Esterification of (R)-phenylethanol (R)-9 and enantiomer (S)-9
(both >97:3 er) with chlorodioxaphospholane (4R,5R)-1a provides
diastereomers (R)-10 and (S)-10. Proton (600 MHz) and carbon
(151 MHz) NMR-shift differences of the phosphites were too small
to serve as a basis for quantitative analysis (Table 4). A shift disper-
sion of 1.3 ppm, on the other hand, is sufficiently large enough for
baseline separation of the phosphorus resonances of (R)-10 and
(S)-10 for quantitative analysis.
Figure 5. Excerpt of phosphorus-coupled (a) and -decoupled (b) 1H NMR-spectra of
trichloroethyl phosphite 6.
triethylamine (c0 ꢀ0.2 M) in an NMR-tube. Phosphite formation
occurs instantaneously, as can be seen from the upfield shift of
ꢀ30 ppm in the phosphorus NMR-spectrum. A second phosphorus
resonancewhichisoftenfoundat130 ppmoriginatesfromthephos-
phonium salt formation by substituting triethylamine for chloride in
(4R,5R)-1a.
The quantitative in situ conversion of
a-phenylethanol 9 into
phosphite 10 for NMR-analysis requires mixing chlorodioxaphos-
pholane (4R,5R)-1a (1.2 equiv) from a stock solution in chloro-
form-d1, an alcohol (c0 ꢀ0.2 M), and
a slight excess of

M. Amberg et al. / Tetrahedron: Asymmetry 22 (2011) 752–760
755
Table 4
Yields and NMR-data for trialkylphosphites prepared from
a
-phenylethanol 9
R
O
O
R1 R2
R1 R2
Ph
H
H
O
O
NEt3
O
O
(4R,5R)-1a
HO
Ph
P
O
+
THF / 20 °C
R
9
10
dH (J/Hz)b,c
c
Entry
9
R1
R2
10a (%)
dC (JP,C/Hz)b
dP
1
2
(R)-9
(S)-9
H
CH3
CH3
H
(R)-10: 94
(S)-10: 99
5.24 dq (8.4, 6.6)
5.24 dq (8.4, 6.5)
72.7 d (18.0)
72.8 d (15.3)
145.7
144.4
a
b
c
31P NMR (OPPh3 as the internal standard; for R see Fig. 1).
(JP,H, JH,H).
In CDCl3.
2.4. Assessment of 2-chloro-1,3,2-dioxaphospholanes
Table 6
Chemical shift of phosphites formed from primary alcohols
OH
To investigate the role of the terpenyl group on the degree of
the phosphorus NMR shift dispersion, menthyl-, borneyl-, and fen-
chyl-substituted chlorodioxaphospholanes 1a–d were esterified
with racemic phenylethanol 9 in almost quantitative yields (Ta-
ble 5). The reactions, which furnished phosphites, showed base-
line-separated phosphorus resonances being dispersed by 1.3–
2.3 ppm (Table 5). The separation of phosphite resonances was ef-
fected by relative configuration and constitution of the monoterpe-
nyl entity (Table 5, entries 1 and 3 or 2 and 4).
OH
O
OH
( )-11
( )-12
( )-13
Entry
1
( )-11
( )-12
( )-13
da (ppm)
da (ppm)
da (ppm)
1
2
3
4
5
6
(4R,5R)-1a
(4S,5S)-1b
(4R,5R)-1b
(4S,5S)-1a
(4R,5R)-1c
(4R,5R)-1d
145.1/144.9
145.0/144.7
142.8/142.7
142.7/142.6
143.8/143.5
143.9/143.7
143.9/143.8
143.8/143.7
142.0/141.8
141.9/141.8
142.6/142.5
143.2/143.1
143.9/143.7
143.9/143.7
141.4/141.3
141.2/141.1
142.8/142.7
142.6/142.5
To find an agent suitable for determining the enantiomeric pur-
ity of a more representative set of alcohols, which are typically
encountered in stereoselective synthesis, we esterified the race-
a
mates of primary alcohols 11–13 (stereocenters at the b- or c-po-
Prepared from equimolar amounts of 1a–d and 11–13 in dry THF/CDCl3 = 2:1
(v/v) at 20 °C in an NMR-tube (referenced versus 85% H3PO4 in a sealed capillary as
the external standard).
sition), secondary substrates 14–15 (open chain and cyclic), and
tertiary derivative 16 with chlorodioxaphospholanes 1a–d (Tables
6 and 7).
From the grid of 6 (chlorodioxaphospholanes) ꢃ 6 (alcohols),
(36 data points) we concluded that the effect of the ester group
in 1 is significant but small (Tables 6 and 7). In cases where the
shift dispersions of diastereomeric phosphites prepared from
(4R,5R)-1b were small or not resolved (Tables 6 and 7, entry 3),
the separation of signals was found in esterifications starting from
(4R,5R)-1a (Tables 6 and 7, entry 1). Steric encroachment in prox-
imity of the hydroxyl group has a similarly small but important ef-
fect on the phosphorus NMR-shift dispersion, which was more
pronounced for the cyclic secondary substrate 14 and less for pri-
mary substrates 11–13 and tertiary alcohol 16. Since shift disper-
sions of 0.2 ppm are enough to obtain baseline separated signals,
we selected compound (4R,5R)-1a for further study with a preci-
sion analysis (Section 2.5) and a structure-shift dispersion correla-
tion for alcohols that are relevant for ongoing projects
(Section 2.6).
2.5. Precision for the analysis of enantiomeric purity
Mixtures of enantiomers (R)-9 and (S)-9 afforded diastereomers
of phosphite 10 in yields between 95% and 98%, if treated with
chlorodioxaphospholane (4R,5R)-1a (Table 8). Integration of the
phosphorus resonances originating from diastereomeric phos-
phites reflected the enantiomeric ratios of known (R)-9/(S)-9-com-
positions with a precision of 1%. We believe that this precision is
representative for the method, as long as the yield of trialkyl phos-
phites is close to quantitative and the enantiomeric ratio does not
exceed the precision of the NMR-method.
Table 7
Chemical shifts of phosphites formed from secondary and tertiary alcohols
Table 5
Formation of 2-alkoxy-1,3,2-dioxaphospholanes
OH
OH
H
H
H
RO2C
RO2C
RO2C
O
O
O
O
OH
NEt3
P
Cl
P
O
Ph
+
HO
Ph
THF / 20 °C
( )-14
( )-15
( )-16
RO2C
H
Entry
1
( )-14
( )-15
dP (ppm)
( )-16
dP (ppm)
1
( )-9
dr = 50:50
a
a
a
dP (ppm)
b
Entry
1
Yielda (%)
Products (d 31P/ppm)
D
d
1
2
3
4
5
6
(4R,5R)-1a
145.3/144.6
145.3/144.9
145.4
145.5
145.8/145.2
146.2/145.4
144.9/144.7
144.9/144.7
143.6
143.7
144.2/144.1
145.0/144.9
143.6/143.5
143.6/143.5
145.1/144.9
145.1/144.9
144.8/144.7
146.4/146.3
(4S,5S)-1b
(4R,5R)-1b
(4S,5S)-1a
(4R,5R)-1c
(4R,5R)-1d
1
2
3
4
5
6
(4R,5R)-1a
(4S,5S)-1b
(4R,5R)-1b
(4S,5S)-1a
(4R,5R)-1c
(4R,5R)-1d
98
97
97
98
96
95
145.4/144.0
145.4/144.1
145.2/142.9
145.2/142.9
145.8/143.8
146.4/144.4
1.4
1.4
2.3
2.3
2.0
2.0
a
Prepared from equimolar amounts of 1a–d and 14–16 in dry THF/CDCl3 = 2:1
(v/v) at 20 °C in an NMR-tube (referenced versus 85% H3PO4 in a sealed capillary as
a
In CDCl3, referenced versus OPPh3 as the internal standard.
Referenced versus 85% H3PO4 in a sealed capillary as an external standard.
b
the external standard).

756
M. Amberg et al. / Tetrahedron: Asymmetry 22 (2011) 752–760
Table 8
Racemic primary, secondary, and tertiary alcohols 17–31 affor-
2-(1-Phenylethyl-1-oxy)-1,3,2-dioxaphospholane syntheses
ded phosphites in yields between 92% and quantitative, if treated
with (4R,5R)-1a and triethylamine (for conditions, see Section 2.4
and the Experimental). The phosphorus resonances of the phos-
phites were between 141.0 ppm and 148.3 ppm. The degree of shift
dispersions increased along the sequence of phosphites obtained
from primary alcohols 17 and 1835 via secondary alcohol 28, ter-
tiary alcohols 29–31,36,37 allylic alcohol 27, benzylic alcohols 19–
2538–43 to propargylic alcohol 26.44 The shifts of the diastereomeric
phosphites prepared from (4R,5R)-1a and alkenol 25, which is a
precursor for the synthesis of non naturally occurring amino acids
via oxidative transformations, for example were dispersed by
3 ppm as shown in Figure 7.
R
O
H
H
O
O
NEt3
O
O
(4R,5R)-1a
HO
Ph
P
O
Ph
+
THF / 20 °C
R
O
9
10
Entry
(R)-9:(S)-9
10a (%)
(R)-10:(S)-10
1
2
3
4
5
>97:3
95:5
47:53
5:95
95
98
95
96
95
>98:2
96:4
47:53
5:95
<3:97
<2:98
a
Versus OPPh3 as internal standard via 31P NMR; R = [(1R,2S,5R)-2-isopropyl-5-
methylcyclohex-1-yl]oxycarbonyl.
2.6. Correlating structure and shift dispersion
Chiral alkyl-, alkenyl-, and alkynyl-substituted alcohols play an
important role as substrates for natural product synthesis via oxida-
tive transformations, and, therefore, were chosen to explore the ef-
fect of steric branching and unsaturation on phosphorus NMR-shift
dispersion in (4R,5R)-1a-derived phosphites (Fig. 6).
Figure 7. Excerpt from phosphorus NMR-spectra (243 MHz) for enantiomer
analysis of alkenol 25 via (4R,5R)-1a-derived phosphites.
• primary alcohols
O
OH
OH
Compounds 17–31 pose as a selection of reagents which reflect
our own interests and thus may not be regarded as fully represen-
tative. The results derived from this study, however, show that
17
18
98 % (141.0 / 140.9)
quant. (144.7 / 144.5)
substrates with a
p-system bound to the a-carbon of the alcohol
(cf. 19–27) of cyclic secondary and/or structurally biased alcohols
(14, 30, 31) generally lead to shift dispersions that are sufficiently
large enough to allow baseline separation of diastereomeric phos-
phites. The fact that both enantiomers of tertiary heterocyclic alco-
hols 30 and 31 provide, in a similar manner, well separated
phosphorus resonances upon derivatizing with (4R,5R)-1a, is an
important result at the end of this study, because side chain-
• secondary alcohols
OH
OH
X
X
yield / %
19 98
δ
31P
144.1 / 143.6
yield / %
22 96
δ
31P
147.4 / 144.9
X
X
functionalized tetrahydrofurans are
a major target in our
laboratory.45,46
CH3
Cl
H
4-CF3
2-CH3
20 98 145.3 / 144.7
21 95 144.1 / 143.0
23 98 147.4 / 145.9
24 94 148.3 / 146.0
OCH3
3. Conclusion
OH
NHAc
CO2CH3
OH
Chlorodioxaphospholane (4R,5R)-1a is a versatile derivatizing
agent for quantifying the enantiomeric purity of chiral alcohols
via phosphorus-31 NMR-spectroscopy. We believe that there is a
demand to use the agent as an analytical tool, and also for purposes
other than those listed herein, such as routine analysis or mecha-
nistic investigation. The arguments to use the agent are (i) low
cost, (ii) synthetic access, (iii) ease of application, and (iv)
precision.
Ph
Ph
25
26
quant. (147.6 / 144.6)
97 % (146.9 / 141.7)
OH
OH
(i) Low costs. (R,R)-Tartaric acid and (1R,2S,5R)-menthol are inex-
pensive chemicals, which are available from the chiral pool and thus
from renewable resources. The price of phosphorus trichloride
compares well to the price of thionyl chloride. Thionyl chloride
and the more expensive oxalyl chloride, are generally used to con-
27
28
99 % (144.1 / 142.9)
97 % (143.2 / 143.1)
• tertiary alcohols
OH
OH
OH
H
H
O
O
vert
a-methoxy-a-trifluoromethylphenyl acetic acid, (Mosher’s
Ph
Ph
acid)13 into the derived acid chloride, which is required to derivatize
chiral alcohols for stereochemical analysis.
29
30
( )-31
(ii) Synthetic access. The synthetic method developed herein al-
lows us to prepare 10–26 g of chlorodioxaphospholane (4R,5R)-1a
in a single batch. We see no inherent limitation for scaling up the
process further, since work-up and purification occurs by distilla-
tion and crystallization, and not by chromatography.
92 % (145.0 / 144.7)
94 % (147.2 / 145.2)
94 % (147.2 / 145.2)
Figure 6. Yields [in percent, via phosphorus NMR, except for 25-derived phosphite
(proton NMR)] and phosphorus NMR-shifts (numbers in parentheses) of diastereo-
meric phosphites prepared from racemic alcohols 17–31.

M. Amberg et al. / Tetrahedron: Asymmetry 22 (2011) 752–760
757
(iii) Ease of application. Storage of neat (4R,5R)-1a in standard
glassware being exposed to air is possible without decomposition
of the agent over a reasonable time scale. However, we recommend
to store stock solutions, as used in routine NMR-analysis, in an
atmosphere of dry argon or nitrogen. Derivatization of alcohols
in solution occurs almost instantaneously and quantitatively by
mixing with (4R,5R)-1a and triethylamine.
(iv) Precision. Esterification of (4R,5R)-1a with racemic primary,
secondary, and tertiary alcohols gives diastereomeric phosphites,
showing in the majority of investigated instances phosphorus
NMR-shift dispersions of 0.2 ppm and more, which is enough to
achieve baseline separation with the 243 MHz NMR-spectrometer
used. The enantiomeric ratios of alcohols determined differed from
the diastereomeric ratios of phosphites by one percent or less,
which is sufficient for most applications.
We have used chlorodioxaphospholane (4R,5R)-1a for about
four years to determine the enantiomeric purity of a variety of
alcohols, such as thermally labile, hydroxyl-substituted oxygen
radical precursors, products of enzyme-catalyzed alcohol desym-
metrization, or chiral hydroxyl-substituted cyclic ethers as build-
ing blocks for natural products, to mention the most important
examples.21,47,20 For us, the agent and the method described
herein has become the standard tool to determine the enantio-
meric purity of chiral alcohols.
(15.8 g, 115 mmol), and THF (10 mL for the tartrate solution,
10 mL for the PCl3 solution). Crystallization of the crude oil from
pentane (10 mL) at ꢂ20 °C furnished 6.33 g (12.9 mmol, 87%) of
compound (4R,5R)-1a as a colorless solid. Mp 72 °C. ½a D25
¼ ꢂ155:0
ꢁ
(c 1.00, THF). 1H NMR (C6D6, 600 MHz) d 0.58 (qd, Jd = 3.5, Jq = 9.4 Hz,
1H), 0.59 (qd, Jd = 3.5, Jq = 9.4 Hz, 1H), 0.70 (d, J = 6.6 Hz, 3H), 0.71 (d,
J = 6.6 Hz, 3H), 0.74 (d, J = 7.0 Hz, 3H), 0.75 (d, J = 7.0 Hz, 3H), 0.72–
0.77 (m, 2H), 0.78 (d, J = 7.0 Hz, 3H), 0.82 (d, J = 7.0 Hz, 3H), 0.89
(q, J = 11.2 Hz, 1H), 1.02 (q, J = 10.9 Hz, 1H), 1.04–1.12 (m, 2H),
1.36–1.43 (m, 6H), 1.90–2.05 (m, 4H), 4.85 (td, Jd = 4.4, Jt = 10.7 Hz,
1H), 4.95 (td, Jd = 4.6, Jt = 10.7 Hz, 1H), 5.07 (dd, J = 7.0, 8.6 Hz, 1H),
5.69 (d, J = 7.0 Hz, 1H). 13C NMR (C6D6, 151 MHz) d 16.2, 16.3, 20.8,
20.9, 22.0 (2C), 23.4, 23.5, 26.4, 26.5, 31.32, 31.34, 34.1, 34.2, 40.5,
40.6, 47.0, 47.1, 76.9, 77.0, 77.7 (d, J = 8.3 Hz), 78.8 (d, J = 9.7 Hz),
166.6 (d, J = 5.6 Hz), 167.0. 31P NMR (C6D6, 162 MHz) d 175.6. Anal.
Calcd for C24H40ClO6P: C, 58.71; H, 8.2. Found: C, 58.55; H, 8.26. Crys-
tals suitable for X-ray diffraction were grown by slow evaporation
from a saturated solution of (4R,5R)-1a in dry pentane. X-ray crystal-
lography: C24H40ClO6P, T = 150(2) K, k = 0.71073 Å, monoclinic, P21,
a = 5.5810(2) Å, b = 15.0739(7) Å, 15.9350(6) Å, b = 95.224(4)°,
Z = 2,
l
= 0.237 mmꢂ1, completeness to 2h = 89.1%, goodness-of-fit
(I)]: R1 = 0.0389, wR2 = 0.0832.
on F2 = 0.975, final R indices [I > 2
r
4.2.3. 2-Chloro-(4S,5S)-bis{[(1R,2S,5R)-2-isopropyl-5-
methylcyclohex-1-yl]oxycarbonyl}-1,3,2-dioxaphospholane
(4S,5S)-1a
4. Experimental
4.1. General
From bis{[(1R,2S,5R)-2-isopropyl-5-methylcyclohex-1-yl]oxy-
carbonyl}-(S,S)-tartrate (S,S)-2a23 (9.40 g, 22.0 mmol), PCl3
(11.7 g, 85.7 mmol), and THF (20 mL for the tartrate solution,
10 mL for the PCl3 solution). Crystallization of the crude oil from
pentane (30 mL) at ꢂ20 °C furnished 7.80 g (15.9 mmol, 72%) of
Melting points (°C) were determined on an Electrothermal
A9100 instrument and are uncorrected. Combustion analysis was
performed on a 2400 CNH (Perkin Elmer). 1H, 13C and 31P spectra
were recorded with DPX 200, and DPX 600 spectrometers (Bruker).
The resonances of residual protons and of carbons from deuterated
solvent molecules CDCl3 (dH 7.26, dC 77.16), C6D6 (dH 7.16, dC
128.06) served as internal standard. 31P NMR spectra were refer-
enced versus 85% (w/w) aq H3PO4 (d = 0) as external standard.
Reaction progress was monitored by thin layer chromatography
on aluminum plates coated with silica gel (60 F254, Merck). Prod-
ucts were detected by UV-spotting (254 nm) or with anisalde-
hyde/H2SO4/EtOH, that is, Ekkert’s reagent. All synthetic
manipulations associated with the synthesis of chlorodioxaphos-
pholanes 1a–d were performed in an atmosphere of dry argon in
oven-dried (T = 110 °C) glassware.
compound (4S,5S)-1a as
a
colorless solid. Mp 69–71 °C.
½
a 2D5
ꢁ
¼ þ21:3 (c 1.00, THF). 1H NMR (C6D6, 600 MHz) d 0.57 (qd,
Jd = 3.7, Jq = 13.0 Hz, 1H), 0.59 (qd, Jd = 3.7, Jq = 13.0 Hz, 1H), 0.69
(d, J = 6.4 Hz, 3H), 0.72 (d, J = 6.6 Hz, 3H), 0.73–0.76 (m, 2H), 0.77
(d, J = 6.8 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.6 Hz, 3H),
0.85 (d, J = 7.0 Hz, 3H), 0.89 (q, J = 11.6 Hz, 1H), 0.90 (q,
J = 11.6 Hz, 1H), 1.03–1.11 (m, 2H), 1.29–1.44 (m, 6H), 1.88–2.00
(m, 3H), 1.94 (septd, Jd = 2.9, Jsept = 7.0 Hz, 1H), 1.96–2.00 (m, 1H),
2.14 (septd, Jd = 2.9 Hz, Jsept = 7.0 Hz, 1H), 4.88 (tdd, Jd = 2.6, 4.4,
Jt = 10.7 Hz, 2H), 5.06 (dd, J = 7.5, 8.3 Hz, 1H), 5.70 (d, J = 7.2 Hz,
1H). 13C NMR (C6D6, 151 MHz) d 16.2, 16.4, 20.7, 20.9, 22.0 (2C),
23.3, 23.5, 26.1, 26.5, 31.3 (2C), 34.1, 34.2, 40.6, 40.7, 47.1, 47.2,
77.0, 77.1, 77.6 (d, J = 8.3 Hz), 78.8 (d, J = 8.3 Hz), 166.6 (d,
J = 5.5 Hz), 167.0. 31P NMR (C6D6, 162 MHz) d 175.5. Anal. Calcd
for C24H40ClO6P: C, 58.71; H, 8.21. Found: C, 58.44; H, 8.32.
4.2. 2-Chloro-1,3,2-dioxaphospholanes from alkyl tartrates
4.2.4. 2-Chloro-(4S,5S)-bis{[(1S,2R,5S)-2-isopropyl-5-
methylcyclohex-1-yl]oxycarbonyl}-1,3,2-dioxaphospholane
(4S,5S)-1b
4.2.1. General method
A solution of dialkyl tartrate 2a–d in dry THF was added at 20 °C
to a solution of PCl3 (3.9 or 7.8 equiv) in the same solvent. The solu-
tion was stirred for 1 h at 65 °C. After cooling to 20 °C, the solvent
and excess phosphorus trichloride were removed under reduced
pressure. The residual oil was taken up in dry pentane (volume
see below) and kept at ꢂ20 °C (for at least 6–24 h). The crystals,
that were separated from the solution, were collected, and dried
under reduced pressure to furnish analytically pure 2-chloro-
1,3,2-dioxaphospholane 1a–d.
From bis{[(1S,2R,5S)-2-isopropyl-5-methylcyclohex-1-yl]oxy-
carbonyl}-(S,S)-tartrate (S,S)-2b23 (19.5 g, 45.7 mmol), PCl3
(24.4 g, 178 mmol), and THF (40 mL for the tartrate solution,
20 mL for the PCl3 solution). Crystallization of the crude oil from
pentane (50 mL) at ꢂ20 °C furnished 19.7 g (40.1 mmol, 88%) of
compound (4S,5S)-1b as
a
colorless solid. Mp 70–71 °C.
½
a 2D5
ꢁ
¼ þ151:4 (c 1.00, THF). 1H NMR (C6D6, 600 MHz) d 0.59 (qd,
Jd = 3.5, Jq = 9.4 Hz, 1H), 0.60 (qd, Jd = 3.5, Jq = 9.4 Hz, 1H), 0.71 (d,
J = 6.6 Hz, 3H), 0.72 (d, J = 6.6 Hz, 3H), 0.74 (d, J = 7.0 Hz, 3H),
0.76 (d, J = 7.0 Hz, 3H), 0.75–0.79 (m, 2H), 0.81 (d, J = 7.0 Hz, 3H),
0.82 (d, J = 7.0 Hz, 3H), 0.88 (q, J = 12.1 Hz, 1H), 1.00 (q,
J = 11.4 Hz, 1H), 1.04–1.12 (m, 2H), 1.28–1.43 (m, 6H), 1.87–2.03
(m, 4H), 4.83 (td, Jd = 4.4, Jt = 10.7 Hz, 1H), 4.91 (td, Jd = 4.4,
Jt = 10.7 Hz, 1H), 5.04 (t, J = 8.6 Hz, 1H), 5.64 (d, J = 7.0 Hz, 1H).
4.2.2. 2-Chloro-(4R,5R)-bis{[(1R,2S,5R)-2-isopropyl-5-
methylcyclohex-1-yl]oxycarbonyl}-1,3,2-dioxaphospholane
(4R,5R)-1a
From bis{[(1R,2S,5R)-2-isopropyl-5-methylcyclohex-1-yl]oxy-
carbonyl}-(R,R)-tartrate (R,R)-2a23 (6.29 g, 14.8 mmol), PCl3

758
M. Amberg et al. / Tetrahedron: Asymmetry 22 (2011) 752–760
13C NMR (C6D6, 151 MHz) d 16.2, 16.3, 20.8 (2C), 22.0 (2C), 23.4,
23.5, 26.4, 26.5, 31.3 (2C), 34.1, 34.2, 40.5, 40.6, 47.0, 47.1, 76.9,
77.0, 77.7 (d, J = 8.3 Hz), 78.8 (d, J = 8.3 Hz), 166.6 (d, J = 4.2 Hz),
pentane (10 mL) at ꢂ20 °C furnished 2.99 g (6.14 mmol, 84%) of
compound (4R,5R)-1d as a colorless solid. Mp 80 °C. ½a D25
¼ ꢂ17:0
ꢁ
(c 1.00, THF). 1H NMR (CDCl3, 400 MHz) d 0.81 (s, 3H). 0.84 (s,
3H), 1.06 (s, 3H), 1.07 (s, 3H), 1.09–1.18 (m, 2H), 1.12 (s, 3H),
1.13 (s, 3H), 1.20–1.26 (m, 2H), 1.43–1.54 (m, 2H), 1.57–1.62 (m,
2H), 1.65–1.83 (m, 6H), 4.48–4.52 (m, 2H), 5.00 (dd, J = 7.1,
8.7 Hz, 1H), 5.49 (d, J = 7.1 Hz, 1H). 13C NMR (CDCl3, 101 MHz) d
19.3, 19.4, 20.1, 20.2, 25.7, 25.8, 25.8, 26.4, 26.5, 29.6 (2C), 39.6,
39.8, 41.3, 41.4, 48.2, 48.3, 48.6 (2C), 77.2 [superposition of the
central signal from the 1/1/1-triplet from the solvent prevents res-
167.0. 31P NMR (C6D6, 162 MHz)
d
175.6. Anal. Calcd for
C24H40ClO6P: C, 58.71; H, 8.21. Found: C, 58.67; H, 8.18.
4.2.5. 2-Chloro-(4R,5R)-bis{[(1S,2R,5S)-2-isopropyl-5-
methylcyclohex-1-yl]oxycarbonyl}-1,3,2-dioxaphospholane
(4R,5R)-1b
2
olution of the JP,C-coupling; in C6D6: dC 77.6, 2J = 8.3 Hz], 78.2 (d,
From bis{[(1S,2R,5S)-2-isopropyl-5-methylcyclohex-1-yl]oxy-
carbonyl}-(R,R)-tartrate (R,R)-2b23 (9.20 g, 21.6 mmol), PCl3
(11.5 g, 84.2 mmol), and THF (20 mL for the tartrate solution,
10 mL for the PCl3 solution). Crystallization of the crude oil from
pentane (20 mL) at ꢂ20 °C furnished 8.25 g (16.8 mmol, 78%) of
J = 8.6 Hz), 89.0 (2C), 167.3 (d, J = 5.0 Hz), 167.7. 31P NMR (C6D6,
243 MHz) d 175.3. Anal. Calcd for C24H36ClO6P: C, 59.20; H, 7.45.
Found: C, 59.28; H, 7.38.
4.3. Preparation of alcohols
compound (4R,5R)-1b as
a colorless solid. Mp 67–68 °C.
½
a 2D5
ꢁ
¼ ꢂ20:6 (c 1.00, THF). 1H NMR (C6D6, 600 MHz) d 0.57 (qd,
4.3.1. Methyl (6S)-2-acetylamino-6-hydroxy-6-phenylhex-2-
enoate (S)-25
Jd = 3.5, Jq = 12.1 Hz, 1H), 0.59 (qd, Jd = 3.5, Jq = 12.1 Hz, 1H), 0.70
(d, J = 6.6 Hz, 3H), 0.71 (d, J = 6.6 Hz, 3H), 0.73–0.76 (m, 2H), 0.74
(d, J = 6.6 Hz, 3H), 0.77 (d, J = 7.0 Hz, 3H), 0.81 (d, J = 7.0 Hz, 3H),
0.85 (d, J = 7.0 Hz, 3H), 0.89 (q, J = 11.6 Hz, 1H), 0.91 (q,
J = 11.6 Hz, 1H), 1.05–1.13 (m, 2H), 1.28–1.44 (m, 6H), 1.88–1.92
(m, 1H), 1.94 (td, Jd = 2.9, Jt = 7.0 Hz, 1H), 1.96–2.00 (m, 1H), 2.14
(septd, Jd = 2.9, Jsept = 7.0 Hz, 1H), 4.87 (tdd, Jd = 1.1, 4.4, Jt = 10.7 Hz,
2H), 5.05 (dd, J = 7.5, 8.3 Hz, 1H), 5.69 (d, J = 7.2 Hz, 1H). 13C NMR
(C6D6, 151 MHz) d 16.2, 16.4, 20.7, 20.9, 22.0 (2C), 23.3, 23.5,
26.1, 26.5, 31.3 (2C), 34.1, 34.2, 40.6, 40.7, 47.1, 47.2, 77.0, 77.1,
77.6 (d, J = 8.3 Hz), 78.8 (d, J = 8.3 Hz), 166.6 (d, J = 5.5 Hz), 167.0.
31P NMR (C6D6, 162 MHz) d 175.5. Anal. Calcd for C24H40ClO6P: C,
58.71; H, 8.21. Found: C, 58.56; H, 8.31.
To a mixture of lipase [Aspergillus niger lipase (187 U/g)] (491 mg)
and phosphate-buffer (395 mL) [pH 7, 0.1 M aq KH2PO4 (500 mL),
0.1 M aq NaOH (290 mL), and H2O (210 mL)] was added ( )-1-phe-
nylpent-4-en-1-ylacetate (4.81 g, 23.5 mmol). The reaction mixture
was stirred for 6 days at 40 °C, then saturated with NaCl and ex-
tracted with Et2O (4 ꢃ 50 mL). The combined organic layers were
washed with brine (50 mL) and dried (MgSO4). The solvent was re-
moved under reduced pressure. The remaining oil was purified by
column chromatography [Rf = 0.28, SiO2, petroleum ether/
EtOAc = 5:1 (v/v)], to afford (1S)-1-phenylpent-4-en-1-ol as a color-
less liquid. Yield: 1.39 g (8.57 mmol, 36%). ½a D20
¼ ꢂ14:6 (c 1.03,
ꢁ
EtOH). 1H NMR (CDCl3, 400 MHz) d 1.76–1.94 (m, 2H), 1.96 (br s,
1H), 2.04–2.22 (m, 2H), 4.70 (t, J = 6.5 Hz, 1H), 4.98–5.07 (m, 2H),
5.80–5.90 (m, 1H), 7.26–7.31 (m, 1H), 7.35–7.36 (m, 4H). (1S)-1-
Phenylpent-4-en-1-ol (649 mg, 4.00 mmol) was dissolved in CH3CN
(20 mL) and RuCl3 ꢃ xH2O (28.7 mg) was added at 22 °C. The mix-
ture was treated with H2O (3 mL) and NaIO4 (1.71 g, 8.00 mmol)
was added over a period of 5 min. The resulting mixture was stirred
for 45 min at 22 °C, then treated with satd aq Na2S2O3 (10 mL) and
H2O (100 mL). The solution was extracted with CH2Cl2 (3 ꢃ 50
mL). The organic layer was washed with brine (50 mL), dried
(MgSO4), and the solvent was removed under reduced pressure, to
give (5S)-phenyltetrahydrofuran-2-ol (299 mg, 1.82 mmol) as a col-
orless oil. This material was added at 22 °C to a solution of methyl-
2-(acetylamino)-2-(dimethylphosphoryl)acetate48 (478 mg,
2.00 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (304 mg,
2.00 mmol) in dry THF (7.5 mL), which had been prepared at
ꢂ78 °C and stirred for 2 h at that temperature. The reaction mix-
ture was stirred for 45 min at 22 °C and then diluted with EtOAc
(10 mL). The organic phase was separated and washed with satd
aq NH4Cl (2 ꢃ 15 mL). The aqueous layer was extracted with
EtOAc (2 ꢃ 15 mL). The combined organic solutions were washed
with brine (15 mL) and dried (MgSO4). The solvent was removed
under reduced pressure. The remaining oil was purified by col-
umn chromatography [Rf = 0.33, SiO2, EtOAc]. Yield: 205 mg
4.2.6. 2-Chloro-(4R,5R)-bis{[(1S,2R,4S)-1,7,7-
trimethylbicyclo[2.2.1]hept-2-yl]oxycarbonyl}-1,3,2-
dioxaphospholane (4R,5R)-1c
From
bis{[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]
oxycarbonyl}-(R,R)-tartrate (R,R)-2c23 (3.10 g, 7.34 mmol), PCl3
(7.82 g, 57.3 mmol), and THF (40 mL for the tartrate solution,
40 mL for the PCl3 solution). Crystallization of the crude oil from
pentane (6 mL) at ꢂ20 °C furnished 2.88 g (5.91 mmol, 81%) of
compound (4R,5R)-1c as a colorless solid. Mp 82 °C. ½a D25
¼ ꢂ105
ꢁ
(c 1.00, THF). 1H NMR (CDCl3, 600 MHz) d 0.85 (s, 3H), 0.87 (s,
3H), 0.89 (s, 3H), 0.92 (s, 3H), 1.05 (dd, J = 3.3, 14.0 Hz, 1H), 1.10
(dd, J = 3.3, 13.8 Hz, 1H), 1.23–1.30 (m, 2H), 1.32–1.37 (m, 2H),
1.69–1.80 (m, 4H), 1.91 (ddd, J = 4.4, 9.4, 13.4 Hz, 1H), 1.99 (ddd,
J = 4.4, 9.4, 13.6 Hz, 1H), 2.35–2.44 (m, 2H), 4.98 (dd, J = 6.8,
9.1 Hz, 1H), 5.00–5.06 (m, 2H), 5.43 (d, J = 6.7 Hz, 1H). 13C NMR
(CDCl3, 151 MHz) d 13.5, 13.6, 18.8 (2C), 19.6 (2C), 27.0 (2C),
27.1, 27.8, 27.9, 36.1, 36.5, 44.8 (2C), 48.0, 48.1, 49.0, 77.1 (d,
J = 9.7 Hz), 78.3 (d, J = 8.6 Hz), 83.0, 83.1, 167.3 (d, J = 4.8 Hz),
167.7. 31P NMR (C6D6, 162 MHz)
24H36ClO6P: C, 59.20; H, 7.45. Found: C, 59.57; H, 7.49. Crystals
d 175.6. Anal. Calcd for
C
suitable for X-ray diffraction were grown by slow evaporation from
a saturated solution of (4R,5R)-1c in dry pentane. X-ray crystallog-
raphy:
P212121, a = 9.6077(5) Å, b = 13.4396(6) Å, c = 19.3284(14) Å, Z = 4,
= 2.264 mmꢂ1, completeness to 2h = 93.1%, goodness-of-fit on
F2 = 1.105, final R indices [I > 2
(I)]: R1 = 0.0578, wR2 = 0.1244.
C24H36ClO6P, T = 150(2) K, k = 1.54184 Å, orthorhombic,
(0.74 mmol, 41%), colorless oil. ½a D25
ꢁ
¼ þ10:0 (c 1.00, EtOH). 1H
NMR (CDCl3, 600 MHz) d 1.87–1.96 (m, 2H), 2.08 (s, 3H), 2.26–
2.30 (m, 1H), 2.33–2.39 (m, 1H), 3.12 (br s, 1H), 3.76 (s, 3H),
4.65–4.67 (m, 1H), 6.66 (t, J = 7.7 Hz, 1H), 7.20 (br s, 1H),
7.23–7.25 (m, 1H), 7.31–7.33 (m, 4H). 13C NMR (CDCl3,
l
r
4.2.7. 2-Chloro-(4R,5R)-bis{[(1R,2R,4S)-1,3,3-
trimethylbicyclo[2.2.1]hept-2-yl]oxycarbonyl}-1,3,2-
dioxaphospholane (4R,5R)-1d
100 MHz)
d 23.1, 25.1, 37.3, 73.0, 125.6 (2C), 125.7, 127.3,
128.3 (2C), 137.9, 144.3, 165.0, 169.2.
From
bis{[(1R,2R,4S)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]
4.3.2. Methyl ( )-2-acetylamino-6-hydroxy-6-phenylhex-2-
enoate ( )-25
Methyl-2-(acetylamino)-2-(dimethylphosphoryl)acetate
(718 mg, 3.00 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (457 mg,
oxycarbonyl} (R,R)-tartrate (R,R)-2d23 (3.10 g, 7.34 mmol), PCl3
(7.82 g, 57.3 mmol), and THF (20 mL for the tartrate solution,
20 mL for the PCl3 solution). Crystallization of the crude oil from

M. Amberg et al. / Tetrahedron: Asymmetry 22 (2011) 752–760
759
3.00 mmol),
and
5-phenyltetrahydrofuran-2-ol
(493 mg,
4.4. Formation of phosphites
3.00 mmol) were converted as described in Section 4.3.1. Yield:
275 mg (0.99 mmol, 33%), yellow oil. 1H NMR (CDCl3, 400 MHz) d
1.89ꢂ1.98 (m, 2H), 2.11 (s, 3H), 2.26–2.42 (m, 2H), 2.92 (br s,
1H), 3.78 (s, 3H), 4.67–4.70 (m, 1H), 6.70 (t, J = 7.7 Hz, 1H), 7.07
(br s, 1H), 7.27–7.28 (m, 1H), 7.31–7.35 (m, 4H).
4.4.1. General method
In a NMR tube, a solution (250
and NEt3 (0.25 M) in CDCl3 was treated with a solution (300 ll) of
2-chloro-1,3,2-dioxaphospholane (4R,5R)-1a (0.2 M) and OPPh3
(0.2 M) in CDCl3. The NMR tube was shaken and subjected to
NMR-spectroscopy. The specified yields were determined via 31P
NMR against OPPh3 as the internal standard.
l
l) containing an alcohol (0.2 M)
4.3.3. 1-(4-Trifluoromethylphenyl)-pent-4-en-1-ol 23
1-(4-Trifluoromethylphenyl)-pent-4-en-1-ol was prepared
from 4-trifluoromethylphenyl carbaldehyde (9.58 g, 55.0 mmol)
and but-3-enyl magnesium bromide from 4-bromo-1-butene
(7.43 g, 55.0 mmol) and magnesium turnings (1.46 g, 60.1 mmol)
in Et2O (30 mL) according to a published procedure.49 Yield:
7.35 g (31.9 mmol, 58%), colorless oil. Bp 123 °C (12 mbar).
Rf = 0.23 for petroleum ether/EtOAc = 2:1 (v/v). 1H NMR (CDCl3,
250 MHz) d 1.77–1.96 (m, 2H), 2.06 (d, J = 3.4, 1H, OH), 2.10–2.21
(m, 2H), 4.73–4.79 (m, 1H), 4.98–5.10 (m, 2H), 5.83 (ddt,
Jd = 10.4, 17.1, Jt = 6.7 Hz, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.60 (d,
J = 8.5 Hz, 2H). 13C NMR (CDCl3 63 MHz) d 30.3, 38.6, 73.8, 115.4,
125.7, 126.54, 130.1 (q, JC,F = 30.5 Hz), 138.2, 148.9, 148.9, 149.0.
Anal. Calcd for C12H13F3O: C, 62.60; H, 5.69. Found: C, 62.43; H,
5.82.
4.4.2. Esterification of 1,1,1-trichloroethanol 5
Yield: quant. 1H NMR (600 MHz, CDCl3) d 0.71 (d, J = 7.0 Hz, 6H),
0.80–0.89 (m, 14H), 0.93–1.07 (m, 4H), 1.36–1.49 (m, 4H), 1.61–
1.69 (m, 4H), 1.76–1.88 (m, 2H), 1.97 (dt, Jt = 4.8, Jd = 12.2 Hz,
2H), 4.25 (dd, J = 7.3, 11.7 Hz, 1H), 4.38 (dd, J = 8.1, 11.8 Hz, 1H),
4.70–4.81 (m, 3H), 5.10 (d, J = 6.5 Hz, 1H). 13C NMR (101 MHz,
CDCl3) d 16.2, 21.0, 22.1, 23.3, 26.3, 31.5, 34.2, 40.7, 40.8, 46.9,
75.1 (d, J = 14.1 Hz), 76.3 (d, J = 9.3 Hz), 76.8, 76.9, 77.3 (d,
J = 8.3 Hz), 96.6 (d, J = 5.6 Hz), 167.7, 167.8 (d, J = 5.6 Hz). 31P
NMR (243 MHz, CDCl3) d 144.3.
4.4.3. Esterification of benzylalcohol 7
Yield: 92%. 1H NMR (600 MHz, CDCl3) d 0.66 (d, J = 7.0 Hz, 3H),
0.70 (d, J = 7.0 Hz, 3H), 0.77–0.87 (m, 14H), 0.93–1.06 (m, 4H),
1.36–1.49 (m, 4H), 1.58–1.67 (m, 4H), 1.76–1.88 (m, 3H), 1.96
(dt, Jt = 5.1, Jd = 11.7 Hz, 1H), 4.70–4.79 (m, 4H), 4.86 (dd, J = 8.6,
12.9 Hz, 1H), 5.08 (d, J = 5.9 Hz, 1H), 7.19–7.32 (m, 5H). 13C NMR
(101 MHz, CDCl3) d 15.9, 16.0, 20.8, 21.9, 23.1, 26.1, 31.4, 34.0,
40.4, 40.5, 46.8, 65.0 (d, J = 13.0 Hz), 76.1 (d, J = 9.3 Hz), 76.4,
76.5, 77.1 (d, J = 10.2 Hz), 127.1, 127.8, 128.4, 137.3 (d,
J = 5.6 Hz), 168.0, 168.1 (d, J = 5.6 Hz). 31P NMR (243 MHz, CDCl3)
d 143.9.
4.3.4. 2-(5-Phenyl-2,3-dihydrofur-2-yl)-propan-2-ol 30
A
solution of ethyl [5-(2-hydroxyprop-2-yl)-2-phenyl]-4,5-
dihydrofuran-3-carboxylate50 (276 mg, 1.00 mmol) in NaOH
(0.5 M, 50 mL) was stirred for 18 h at 24 °C and allowed to rest
for 48 h. The pH of the mixture was adjusted to 2–3 with aq HCl
[10% (w/w)]. The organic products were extracted with Et2O
(3 ꢃ 50 mL) from this solution. The combined organic washings
were extracted with H2O (50 mL) and brine (50 mL). The organic
solution was dried (Na2SO4) and concentrated under reduced
pressure to give a colorless oil. This material was dissolved in
Et2O (2 mL) and pentane (2 mL). The solution was allowed to
rest at ꢂ20 °C. The precipitate was collected by filtration and
dried to give 5-(2-hydroxyprop-2-yl)-2-phenyl-4,5-dihydrofu-
ran-3-carboxylic acid. Yield: 120 mg (0.48 mmol, 59%), colorless
crystals. Mp 129–131 °C. 1H NMR (CDCl3, 600 MHz) d 1.25 (s,
3H), 1.33 (s, 3H), 3.04 (dd, J = 9.5, 15.1 Hz, 1H), 3.09 (dd,
J = 10.8, 15.5 Hz, 1H), 4.61 (dd, J = 9.5, 10.4 Hz, 1H), 7.36–7.41
(m, 2H), 7.42–7.46 (m, 1H), 7.78 (dd, J = 1.5, 7.2 Hz, 2H). 13C
NMR (CDCl3, 151 MHz) d 23.7, 25.5, 32.3, 71.9, 88.1, 102.2,
4.4.4. Esterification of (R)-1-phenylethan-1-ol (R)-9
Yield: 94%. 1H NMR (600 MHz, CDCl3) d 0.68 (d, J = 7.0 Hz, 3H),
0.71 (d, J = 6.8 Hz, 3H), 0.81–0.85 (m, 14H), 0.91–1.05 (m, 4H),
1.36–1.43 (m, 4H), 1.45 (d, J = 6.5 Hz, 3H), 1.59–1.66 (m, 4H),
1.77 (septd, Jd = 2.6, Jsept = 7.0 Hz, 1H), 1.84 (septd, Jd = 2.9,
Jsept = 7.0 Hz, 1H), 1.91–1.97 (m, 2H), 4.66 (dd, J = 8.4, 6.3 Hz, 1H),
4.71 (td, Jd = 4.6, Jt = 10.9 Hz, 1H), 4.78 (td, Jd = 4.6, Jt = 10.9 Hz,
1H), 5.03 (d, J = 6.2 Hz, 1H), 5.21 (dq, Jq = 6.6, Jd = 8.4 Hz, 1H),
7.28–7.16 (m, 5H). 13C NMR (151 MHz, CDCl3) d 15.9, 16.0, 20.8,
21.9, 23.1, 25.2, 26.0, 26.1, 31.3, 34.0, 40.5, 40.6, 46.7, 46.8, 72.7
(d, J = 18.0 Hz), 75.6 (d, J = 8.3 Hz), 76.3, 76.4, 77.0 (d, J = 9.7 Hz),
125.6, 127.6, 128.4, 142.9 (d, J = 2.8 Hz), 167.9, 168.1 (d,
J = 4.2 Hz). 31P NMR (243 MHz, CDCl3) d 145.7.
ꢂ1
~
m
127.8, 129.4, 129.5, 130.7, 166.8, 169.2. IR (KBr)
cm
3311,
2984, 2627, 1667, 1636, 1593, 1570, 1493, 1446, 1380, 1347,
1324, 1273, 1232, 1174. Anal. Calcd for C14H16O4: C, 67.73; H,
6.50. Found: C, 68.17; H, 6.84. An oven-dried, 10 mL-microwave
vial was charged with 5-(2-hydroxyprop-2-yl)-2-phenyl-4,5-
dihydrofuran-3-carboxylic acid (248 mg, 1.00 mmol), Cu2O
(7.15 mg, 0.05 mmol), dry NMP (1.5 mL), dry quinoline
4.4.5. Esterification of (S)-1-phenylethan-1-ol (S)-9
Yield: 92%. 1H NMR (600 MHz, CDCl3) d 0.70 (d, J = 6.8 Hz, 3H),
0.71 (d, J = 7.0 Hz, 3H), 0.79–0.87 (m, 14H), 0.88–1.05 (m, 4H),
1.27–1.39 (m, 4H), 1.45 (d, J = 6.5 Hz, 3H), 1.61–1.66 (m, 4H),
1.74–1.89 (m, 3H), 1.93–1.98 (m, 1H), 4.65 (dd, J = 8.5, 6.5 Hz,
1H), 4.73 (td, Jd = 4.5, Jt = 10.8 Hz, 1H), 4.77 (td, Jd = 4.4, Jt = 10.6 Hz,
1H), 5.03 (d, J = 6.5 Hz, 1H), 5.24 (dq, Jq = 6.5, Jd = 8.4 Hz, 1H), 7.28–
7.17 (m, 5H). 13C NMR (243 MHz, CDCl3) d 16.0, 16.1, 20.8, 21.9,
23.1, 25.5, 26.1, 31.3, 34.0, 40.4, 40.5, 46.7, 46.8, 72.8 (d,
J = 15.3 Hz), 75.6 (d, J = 8.3 Hz), 76.3, 76.4, 77.1 (d, J = 9.7 Hz),
125.5, 127.6, 128.3, 143.0 (d, J = 2.8 Hz), 168.0, 168.1 (d,
J = 5.6 Hz). 31P NMR (243 MHz, CDCl3) d 144.4.
Crystallographic data (excluding structure factors) for the struc-
tures herein have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication [CCDC 814031
for (4R,5R)-1a, and CCDC 814032 for (4R,5R)-1c]. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union
(0.5 mL),
and
4,7-diphenyl-1,10-phenanthroline
(33.2 mg,
0.10 mmol). The resulting mixture was placed for 15 min in a
modomode microwave instrument (CEM DiscoverÒ) and heated
with 150 W microwave power to 190 °C. The mixture was con-
centrated under reduced pressure and purified by chromatogra-
phy [SiO2, Et2O/pentane = 1:1 (v/v)]. 2-(5-Phenyl-2,3-dihydrofur-
2-yl)-propan-2-ol. Yield: 63 mg (0.31 mmol, 31%), pale yellow
oil. Rf = 0.51 [Et2O/pentane = 1:1 (v/v)]. 1H NMR (CDCl3,
400 MHz) d 1.32 (s, 3H), 1.38 (s, 3H), 1.83 (br s, 1H), 2.23 (dt,
Jt = 4.4, Jd = 18.2 Hz, 1H), 2.53 (ddd, J = 18.1, 4.8, 3.5 Hz, 1H),
3.64–3.71 (m, 1H), 5.23 (t, J = 4.1 Hz, 1H), 7.23–7.36 (m, 3H),
7.57–7.58 (dd, J = 1.6, 8.6 Hz, 2H). 13C NMR (CDCl3, 101 MHz) d
22.1, 24.2, 28.3, 69.7ꢂ, 177.3, 93.2, 124.7, 128.0, 128.1, 136.1,
~
149.6. IR (NaCl)
m
cm
3428, 2974, 2926, 2853, 1719, 1684,
1652, 1599, 1494, 1448, 1380, 1367, 1324, 1154. Anal. Calcd
for C13H16O2: C, 76.44; H, 7.90. Found: C, 76.43; H, 8.17.

760
M. Amberg et al. / Tetrahedron: Asymmetry 22 (2011) 752–760
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Acknowledgments
This investigation was supported by the state Rheinland-Pfalz
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