Formation of diphosphates. A NMR study on the mechanism and stereochemistry of diphosphate formation from chiral dioxaphosphorinanes

Article abstract of DOI:10.1021/ja992770k

During the use of chiral 2-oxo-1,3,2-dioxaphosphorinanes as derivatizing reagents in the enantiomeric excess determination of amines, alcohols, and unprotected amino acids, minor traces of side reaction products were observed by ¹H and ^31<

Full text of DOI:10.1021/ja992770k

J. Am. Chem. Soc. 2000, 122, 3135-3150
3135
Formation of Diphosphates. A NMR Study on the Mechanism and
Stereochemistry of Diphosphate Formation from Chiral
Dioxaphosphorinanes
Ron Hulst,*,†,‡,§ Johanna M. Visser,† N. Koen de Vries,| Robert W. J. Zijlstra,
Huub Kooijman,∇ Wilberth Smeets,∇ Anthony L. Spek,∇,O and Ben L. Feringa*,
Contribution from the Department of Chemical Analysis, UniVersity of Twente, P.O. Box 217,
7500 AE Enschede, The Netherlands, Department of Physical and Computational Chemistry,
DSM Research, P.O. Box 18, 6160 MD Geleen, The Netherlands, Department of Organic and Molecular
Inorganic Chemistry, UniVersity of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands,
and BijVoet Center for Biomolecular Research, Crystal and Structural Chemistry, UniVersity of Utrecht,
Padualaan 8, 3584 CH Utrecht, The Netherlands
ReceiVed August 3, 1999. ReVised Manuscript ReceiVed January 3, 2000
Abstract: During the use of chiral 2-oxo-1,3,2-dioxaphosphorinanes as derivatizing reagents in the enantiomeric
excess determination of amines, alcohols, and unprotected amino acids, minor traces of side reaction products
were observed by 1H and 31P NMR spectroscopy. Analysis of the reaction mixture showed that the side products
are in fact diphosphates and several intermediates leading to their formation. From an analytical, mechanistic,
and stereochemical point of view, the study of unexpected new reaction intermediates leading to diphosphates
is of particular interest. Due to the easy structural modification of the starting materials in both enantiomerically
pure and racemic forms as well as easy access to oxygen-labeled materials for complete structural elucidation
of both intermediates and diphosphates, we accomplished a complete structural analysis. Also a mechanistic
1
proposal for their formation proved possible using 1D and 2D H and 31P NMR techniques as well as the
X-ray data of both starting material and two of the products.
Introduction
between the bridged oxygen and one of the phosphoroxy
oxygens in diphosphate 3, although in unequal amounts4
(Scheme 1).
Although the elucidation of the factors governing substitution
reactions at phosphorus is considered highly important for
various (biological) pathways1,2 involving the phosphorus
nucleus, results have not led to conclusive interpretations with
respect to the mechanism of diphosphate formation. One of the
first reports on the mechanism of diphosphate formation was
presented by Simpson and Zwierzak,3 describing the condensa-
tion reaction between 2-chloro-5,5-dimethyl-2-oxo-1,3,2-di-
oxaphosphorinane (1) and 2-hydroxy-5,5-dimethyl-2-oxo-1,3,2-
dioxaphosphorinane (2), leading to diphosphate 3. Using
phosphoric methyl ester 4 with 18O-labeling at the phosphoroxy
oxygen in the condensation reaction with chlorophosphorinane
1, it was established that the labeled oxygen was distributed
Two mechanisms were proposed for the formation of 3,
involving initial attack of the oxo (route a) or alkoxy (route b)
oxygen. From the distribution of the labeled oxygen in 3 it was
concluded that route b provided the largest contribution to the
formation of diphosphate 3. Alternative mechanisms, based upon
ring-opening of the phosphorinane ring, were ruled out, since
earlier studies showed that 1,3,2-dioxaphosphorinanes are highly
reluctant toward ring-opening processes.5
Cullis and co-workers6 reinvestigated the Simpson-Zwierzak
experiments, using 31P NMR techniques and 18O-labeled materi-
als, and proposed an alternative mechanism for the formation
of diphosphate 3 from 18O-labeled chlorophosphorinane 1 and
hydroxyphosphorinane 2, involving the formation of dioxa-
diphosphetanes 8 and 9. In the process, Berry pseudorotation
(BPR)7 followed by ring opening and chloride elimination leads
to bridge-oxygen-labeled diphosphate 3a, while “direct” elimi-
nation from intermediate 7 results in PdO-labeled diphosphate
3b (Scheme 2).
† University of Twente.
‡ E-mail: a.j.r.l.hulst@chem.rug.nl.
§ Present address: BioMaDe Foundation, Nijenborgh 4, 9747 AG
Groningen, The Netherlands.
| DSM Research.
University of Groningen.
∇ University of Utrecht.
O Address correspondence pertaining to crystallographic studies to this
author. E-mail: a.l.spek@chem.uu.nl.
It should be noted that more recent work suggested that
dioxadiphosphetanes are not involved in the formation of
(1) Hengge, A. C. In ComprehensiVe Biological Catalysis; Sinnott, M.,
Ed.; Academic Press: San Diego, CA, 1998; Vol. 1, pp 517-542. Perreault,
D. M.; Anslyn, E. V. Angew. Chem., Int. Ed. Engl. 1997, 36, 432. Young,
M. J.; Chin, J. J. Am. Chem. Soc. 1995, 117, 10577. Matsumura, K.; Endo,
M.; Komiyama, M. J. Chem. Soc., Chem. Commun. 1994, 2019.
(2) Review series: AdVances in Cyclic Nucleotide Research; Greengard,
P., Robinson, G. A., Sr., Eds.; Raven Press: New York, 1980-1988; Vols.
11-19. Corbridge, D. E. C. In PhosphoroussAn Outline of its Chemistry,
Biochemistry and Uses, 5th ed.; Elsevier: New York, 1995.
(3) Simpson, P.; Zwierzak, A. J. Chem. Soc., Perkin Trans. 1975, 1,
201.
(4) Zwierzak, A. Phosphorous 1972, 2, 19. Kosolapoff, G. Organophos-
phorous Compounds; John Wiley: New York, 1950; p 339.
(5) McConnell, R. L.; Coover, H. W. J. Org. Chem. 1959, 24, 630.
Edmundson, R. S. Tetrahedron 1965, 21, 2379. Edmundson, R. S.; Lambic,
A. J. J. Chem. Soc. (B) 1967, 577.
(6) Cullis, P. M.; Kay, P. B.; Trippett, S. J. Chem. Soc., Chem. Commun.
1985, 1329.
(7) Berry, P. S. J. Chem. Phys. 1960, 21, 2379. Berry, P. S. J. Chem.
Phys. 1960, 32, 933.
10.1021/ja992770k CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/16/2000

3136 J. Am. Chem. Soc., Vol. 122, No. 13, 2000
Hulst et al.
Scheme 1. Reaction Pathways of 18O-Labeled Phosphoric
Ester 4 and Chlorophosphorinane 1 Leading to Diphosphate
3
of the phosphorinane ring system locks one chair conformer.12
The presence of the phenyl group not only leads to a much
higher chair-chair inversion energy barrier, but also causes a
significant energy difference between both chair conformers.
The presence of this stereocenter will also significantly direct
the stereochemical coarse of the displacement reaction at the
phosphorus nucleus itself.13,14 Moreover, both stereocenters
provide an additional mechanistic tool to obtain information
concerning the formation of diphosphate 14.
Results and Discussion
A. Configuration of Chlorophosphorinanes 11 and 27 and
Esters 12 and Amides 13. Since diphosphate 14 is formed as
a side product during the derivatization of chlorophosphorinane
11 by alcohols, amines, or amino acids,10 determination of the
configuration and conformation of the esters 12 and amides 13
products is also important for the stereochemical analysis of
diphosphate formation.
Besides the configuration and conformation of the substituted
phosphorinane ring system, substituents at phosphorus can
occupy either an axial or an equatorial position. The stereo-
chemistry of the substituted products and intermediates depends
on the initial orientation of the chlorine atom in derivatizing
reagent 11 as well as the conformational freedom of the
phosphorinane ring system.2 To establish the absolute config-
uration at the phosphorus centers after derivatization had taken
place, attempts were undertaken to obtain X-ray data on
chlorophosphorinane (R)-11. Unfortunately, the X-ray analysis
of (R)-11 did not yield adequate resolution to allow full
presentation. The analysis did, however, show both the expected
equatorial orientation of the phenyl moiety, locking one chair
conformation, and the axial placement of the chlorine atom,
observation of which can be explained by the anomeric effect
of the 1,3-adjacent oxygen atoms on the chlorine substituent.15
The influence of the two oxygens lowers the energy contents
of the indicated configuration significantly, as confirmed by
MNDO16 and PM317 calculations that estimated a ∆E of 8.6 kJ
mol-1 in favor of the axial orientation of the chlorine substituent.
To overcome the resolution problem with (R)-11, an X-ray
analysis was performed on the closely related o-chlorine-
substituted analogue (S)-27 shown in Scheme 8. The analysis
clearly shows the equatorial orientation of the substituted phenyl
moiety, whereas the chlorine at phosphorus is axially oriented
(Figure 1).
diphosphates, the formation of which is suggested to proceed
via a straightforward nucleophilic substitution reaction.8
Considering the ambiguities in the mechanisms of diphosphate
formation proposed, several problems and questions remain to
be addressed: (1) It has not been possible so far to detect the
intermediates along the diphosphate pathway(s) directly. (2) It
is known that esters of 2-oxo-5,5-dimethyl-1,3,2-dioxaphos-
phorinanes give rapid chair-chair inversion at room tempera-
ture,9 precluding rigorous stereochemical analysis of the sub-
stitution process at the phosphorus center, ruling out the
possibility to analyze the stereoselectivity of formation (axial
vs equatorial orientation of the bridged oxygen at both rings in
diphosphate 3). (3) Can additional evidence be obtained for
possible competing pathways?
In this paper we report the application of chiral chlorophos-
phorinane 11 in a 1H and 31P NMR study on the mechanism of
diphosphate formation and provide unambiguous evidence for
competing pathways and various intermediates involved.
Chlorophosphorinane 11 has been shown to be an excellent
derivatizing reagent10 for the enantiomeric excess determina-
tion11 of chiral alcohols and amines via diastereoselective
conversion to the corresponding esters 12 and amides 13,
respectively (Scheme 3). Diphosphate 14 is formed during this
reaction as a minor side product.
The phosphorinane ring system establishes a pure chair
conformation as indicated by the puckering parameters θ )15.0-
(1)° and Φ ) 174.6(5).21 It is assumed that both (R)-11 and
(12) Leusen, F. J. J.; Bruins Slot, H.; Noordik, J. H.; van der Haest, A.
D.; Wynberg, H.; Bruggink, A. Recl. TraV. Chim. Pays-Bas 1991, 110, 13.
Zijlstra, R. W. J.; Hulst, R.; de Vries, N. K.; Feringa, B. L. Unpublished
results. Hulst, R. Ph.D. Thesis, University of Groningen, The Netherlands,
1994.
(13) Gorenstein, D. G.; Powell, R. J. Am. Chem. Soc. 1980, 102, 6165.
(14) Gordillo, B.; Eliel, E. L. J. Am. Chem. Soc. 1991, 113, 2172.
(15) White, D. W.; Mc Ewen, G. K.; Bertrand, R. D.; Verkade, J. G. J.
Chem. Soc. B 1971, 1454. Bentrude, W. G.; Yee, K. C. J. Chem. Soc.,
Chem. Commun. 1972, 169.
When compared to the compounds used by Zwierzak and
Cullis in diphosphate formation, chlorophosphorinane 11 pro-
vides unique possibilities to gain important additional informa-
tion. The chair-chair inversion, which ruled out the possibility
to analyze the stereochemical course of substitution at phos-
phorus, i.e. equatorial vs axial orientation of the bridging
oxygens at both rings in 3, does not play an important role,
since the equatorially oriented phenyl group at the 4-position
(16) Dewar, M. J. S.; Thiel, W. J. Am. Chem. Soc. 1977, 99, 4899.
(17) Stewart, J. P. J. Comput. Chem. 1989, 10, 209. Stewart, J. P. J.
Comput. Chem. 1989, 10, 221.
(8) Cullis, P. M.; Kaye, A. D.; Trippett, S. J. Chem. Soc., Chem. Commun.
1987, 1464.
(9) Majoral, J. P.; Bergounhou, C.; Navech, J. Bull. Soc. Chim. Fr. 1973,
11, 3146.
(10) Hulst, R.; Zijlstra, R. W. J.; Feringa, B. L.; de Vries, N. K.; ten
Hoeve, W.; Wynberg, H. Tetrahedron Lett. 1993, 34, 1339.
(11) For reviews see: Parker, D. Chem. ReV. 1991, 91, 1441. Hulst, R.;
Kellogg, R. M.; Feringa, B. L. Recl. TraV. Chim. Pays-Bas 1995, 114, 115.
(18) Abramczyk, H.; Michailak. Chem. Phys. 1988, 122, 823.
(19) The introduction of two equatorially oriented methyl groups at the
4- and 6-positions leads, however, to a significantly higher energy barrier
for the ring inversion process: Mosbo, J. A.; Verkade, J. G. J. Am. Chem.
Soc. 1973, 95, 204.
(20) It has to be noted that the S enantiomer of the chlorophosphorinane
11 is used in the synthesis of the corresponding ester.
(21) Boeyens, J. C. A. J. Cryst. Mol. Struct. 1978, 8, 317.

Formation of Pyrophosphates
J. Am. Chem. Soc., Vol. 122, No. 13, 2000 3137
Scheme 2. Formation of Diphosphate 3 via Dioxadiphosphetanes 8 and 9
Scheme 3. Chlorophosphorinane 11 and the Product Esters
12, Amides 13, and Diphosphate 14 (See the Text for
Explanation)
Figure 1. X-ray structure of chlorophosphorinane (S)-27. Pertinent
bond lengths and angles (Å, deg) with su’s in parentheses: Cl(7)-
P(1) 2.0008(6), O(2)-P(1) 1.5689(11), O(6)-P(1) 1.5673(10), O(8)-
P(1) 1.4516(11), Cl(7)-P(1)-O(2) 104.92(4), Cl(7)-P(1)-O(6) 104.55-
(4), Cl(7)-P(1)-O(8) 112.48(5), O(2)-P(1)-O(6) 106.13(5), O(2)-
P(1)-O(8) 114.23(6), O(6)-P(1)-O(8) 113.65(6).
(S)-27 attain the same relative stereochemistry with an equatorial
orientation of the phenyl group with regard to the axially placed
chlorine at phosphorus, yielding the stereoisomeric products
(R,R)-11 and (S,R)-27.
Several studies showed that the OR substituents at the
phosphorus atom of 2-OR-2-oxo-1,3,2-dioxaphosphorinanes,
comparable with ester 12, also show a preference for the axial
position, although equilibria exist in solution between the
possible chair and twisted boat conformers if the substituents
at the phosphorinane ring system are small and the preference
for one chair conformer is limited.18,19 Although MNDO and
PM3 calculations showed that for (S,R)-12, where R is (R)-2-
phenyl-1-propyl, the equatorial orientation of the OR moiety is
more stable (∆E 4.2 kJ mol-1), the differences are small and it
is likely that twisted boat conformers do interfere.9 These results
evidence for the orientation of the OR moiety could be obtained.
Therefore, an X-ray analysis was carried out on (S,R)-12, where
R is (R)-2-phenyl-1-propyl (Figure 2).20
The X-ray analysis shows the phosphorinane ring system to
adopt a pure chair conformation (as indicated by the puckering
parameters θ ) 14.3(4)° and Φ ) 198(2)°)21 with the phenyl
moiety equatorially placed and the ester group axially aligned,
indicating that the replacement of the chlorine atom from (S)-
11 proceeds with retention of configuration upon reaction with
(R)-2-phenyl-1-propanol.
1
were supported by temperature-dependent H NMR measure-
ments with 12 where large shift differences were found for both
diastereotopic protons at the CH2 carbon as a function of the
temperature. Also a total collapse of the AB system originating
from the diastereotopic CH2 protons was observed in the
phosphorinane ring system at higher temperatures, indicating a
large conformational freedom for the phosphorinane ring itself.
Unfortunately, from 2D NOESY NMR spectra no conclusive
Amine substituents are generally accepted to favor the
equatorial position.22 These assumptions are partly based upon
the minimized interference of the lone pair electrons situated
on nitrogen with the nonbonding electrons of the endocyclic
(22) Bentrude, W. G.; Hargis, J. H. J. Chem. Soc., Chem. Commun. 1969,
1113. Dale, A. J. Acta Chem. Scand. 1972, 26, 2985.

3138 J. Am. Chem. Soc., Vol. 122, No. 13, 2000
Hulst et al.
Figure 2. X-ray structure of (S,R)-12, where R is (R)-2-phenyl-1-
propyl. Pertinent bond lengths and angles (Å, deg) with su’s in
parentheses: O(1)-P(1) 1.444(4), O(2)-P(1) 1.561(4), O(3)-P(1)
1.571(4), O(4)-P(1) 1.569(4), O(1)-P(1)-O(2) 116.8(2), O(1)-P(1)-
O(3) 112.1(2), O(1)-P(1)-O(4) 113.4(2), O(2)-P(1)-O(3) 106.9(2),
O(2)-P(1)-O(4) 101.3(2), O(3)-P(1)-O(4) 105.23(19).
Figure 3. X-ray structure of (R,S)-13, where R is (S)-1-phenyl-1-ethyl.
Pertinent bond lengths and angles (Å, deg) with su’s in parentheses:
O(1)-P(1) 1.473(3), O(2)-P(1) 1.577(4), O(3)-P(1) 1.596(3), N(1)-
P(1) 1.597(5), O(1)-P(1)-O(2) 113.5(2), O(1)-P(1)-O(3) 114.8(2),
O(1)-P(1)-N(1) 113.2(2), O(2)-P(1)-O(3) 101.88(18), O(2)-P(1)-
N(1) 106.2(2), O(3)-P(1)-N(1) 106.3(2).
oxygen atoms.23 Moreover, a cis-like orientation of the NH bond
toward the phosphoroxy bond is viable, which is also energeti-
cally favorable. In contrast to the esters, NMR analysis of (R,S)-
13, where R is (S)-1-phenyl-1-ethyl, clearly indicated the chair
conformation to be present in solution with both the phenyl
group and the amine substituent oriented equatorially. These
upon the exact mechanism of their formation can best be
obtained starting from chlorophosphorinane (R)-11 and (if
desired) the corresponding hydroxyphosphorinane (R)-15. The
reaction between these compounds leads exclusively to the
formation of diphosphate (R,R)-14 and intermediates without
interference of the esters and amides formed upon derivatization
of 11 with alcohols, amines, or amino acids. The intermediates
leading to the formation of diphosphate (R,R)-14 are, however,
completely identical upon the omission of alcohols, amines, and
amino acids, although the presence of these materials does
clearly influence the rate of formation of both the intermediates
and diphosphate (R,R)-14.
Synthesis of Starting Materials. The reactive chlorophos-
phorinane (R)-11 can be prepared in low yield25 from hydroxy-
phosphorinane (R)-15 upon treatment with PCl5 or from (R)-
phencydiol (R)-16 after reaction with POCl3 followed by
repeated crystallization of the products.10 Alternatively, (R)-11
can be prepared within a few minutes quantitatively from the
readily available hydrogen-phosphorinane (R)-17 after reaction
with Et3N and CCl426-28 (Scheme 4). The last sequence is used
unless stated otherwise.
3
findings were based upon the JPH coupling constants of both
axial protons in the phosphorinane ring system (3JPH ≈ 2 Hz)24
as well as a strong intramolecular NOE contact between these
protons, showing that the phosphorinane ring adopts a chair
conformation with the phosphorinane-phenyl group equatorially
oriented. Moreover, the benzylic proton at the exocyclic
stereogenic center showed an intramolecular NOE contact with
the axial methyl group of the phosphorinane system, which is
only possible if the amine substituent is oriented equatorially.
This assumption was confirmed by an X-ray analysis (Figure
3).
As expected, the phosphorinane ring system establishes a pure
chair conformation (as indicated by the puckering parameters
θ )177.3(5)° and Φ ) 306(10)°, with the amine substituent
aligned equatorially, (somewhat) distorted toward bisecting (the
angle between the P-N bond and the normal of the ring
puckering plane amounts to 53°), indicating that the replacement
of the chlorine atom from (R)-11 proceeded with inversion of
configuration upon reaction with (S)-1-phenyl-1-ethylamine.
Also the nearly perfect cis-type arrangement of the NH-
phosphoroxy orientation is clear (dihedral angle 168°).
From these and other data not presented, it is suggested that
oxygen nucleophiles react with retention of configuration at the
phosphorus nucleus in (R)-11, whereas amine nucleophiles react
with complete inversion. In the esters the OR moiety is oriented
axially, allowing great conformational flexibility of the phos-
phorinane ring system, whereas the amines are aligned exclu-
sively equatorially, resulting in a much more rigid conformation.
B. Formation of Diphosphate (R)-14. Although small traces
of diphosphate (R)-14 are formed during the derivatization of
alcohols, amines, and amino acids using (R)-11,10 information
The orientation of the hydrogen atom at the phosphorus
nucleus in (R)-17 is proven to be axial, on the basis of NOE
interactions between this proton and the (axially oriented)
protons at positions 4 and 6 in the phosphorinane ring system
(not shown).
Synthesis of hydrogen-phosphorinane (R)-17 using 18O-
labeled water yields 18O-labeled (R)-17 and (R)-11 (not shown)
with labeling in the phosphoroxy oxygen.29 The 18O-labeled
phosphorinanes proved to be very useful for reaction pathway
identification (vide infra).
(25) Ten Hoeve, W.; Wynberg. J. Org. Chem. 1985, 50, 4508.
(26) Hulst, R.; Zijlstra, R. W. J.; de Vries, N. K.; Feringa, B. L.
Tetrahedron: Asymmetry 1994, 5, 1701.
(27) Hulst, R.; de Vries, N. K.; Feringa, B. L. Angew. Chem., Int. Ed.
Engl. 1992, 31, 1092. Hulst, R.; de Vries, N. K.; Feringa, B. L. Tetrahedron
1994, 50, 11721.
(28) This procedure was first described in general by Atherton, F. R.;
Openshaw, H. T.; Todd, A. R. J. Chem. Soc. 1945, 660.
(29) This procedure can also be used to determine the 18O contents of
18O target water using 31P NMR techniques: Hulst, R.; Feringa, B. L.;
Siertsema, H. K.; Franssen, E. J. F.; Visser, G. M.; Vaalburg, W. Appl.
Radiat. Isot. 1994, 10, 1049.
(23) Bentrude, W. G.; Tan, H. W. J. Am. Chem. Soc. 1972, 94, 8222.
(24) 3JPH coupling constants for these benzylic protons are 2 Hz typically,
whereas the equatorial and axial protons at the 6-position of the dioxaphos-
phorinane ring have 3JPH coupling constants of 25 Hz for the former and 2
Hz for the latter. This is in agreement with the earlier reported coupling
constants for the chair conformation of 2-substituted 5-tert-butyl-1,3,2-
dioxaphosphorinanes.22

Formation of Pyrophosphates
J. Am. Chem. Soc., Vol. 122, No. 13, 2000 3139
Scheme 4. Synthesis of Chlorophosphorinane and
Hydrogen-Phosphorinane (R)-11 and (R)-17
usually designated as pseudorotation (BPR, Berry Pseudo-
Rotation),7 in which the five ligands are rapidly distributed over
the five sites in the trigonal bipyramid. In this process, two
equatorial and two axial ligands interchange their positions via
an intermediate SP structure, whereas one (equatorial) ligand,
the piVot, retains its position.
Ramirez and Ugi35 have proposed an alternative mechanism,
the so-called Turnstile Rotation (TR). In this mechanism, two
equatorial ligands move toward each other in the equatorial plane
until the angle has become 90°. The third equatorial ligand and
one axial ligand are moved by about 9° followed by an internal
rotation of the ligands 3 and 4 and of the three ligands 1, 2,
and 5. The results of the BPR and TR are exactly the same.
Calculations, however, have shown that the transition state for
TR is about 2-6 times higher in energy compared to the BPR.
Therefore, BPR is the most plausible ligand exchange mecha-
nism in phosphorinanes, and the TR is not taken further into
consideration during the following discussion.
The possible modes of addition of (R)-15 to (R)-11 are shown
in Scheme 5. The nucleophile, in this case the deprotonated
hydroxyphosphorinane (RO-) (R)-15 enters the PV-TBP at one
axial site, inducing an axial cleavage of the leaving group.36 It
is generally accepted that negatively charged oxygens can adopt
only equatorial sites in the PV-TBP37 and that pseudorotation
can occur prior to the actual bond breaking, placing the proper
leaving groups in an axial position. In this way, the nucleophile
can approach from four different sites, although the attack of
RO- on the phosphorus atom opposite the PdO bond is not
taken into consideration because the PV-TBP formed will possess
a negatively charged oxygen in an axial position, which is
energetically unfavorable.
Possible Pathways for the Formation of Diphosphate
(R,R)-14. The formation of diphosphate (R,R)-14 from (R)-
phencyphos chlorophosphorinane (R)-11 appears to be sensitive
to several factors. The addition of a catalytic amount of the
corresponding hydroxyphosphorinane (R)-15 leads to a rate
enhancement of the formation of (R,R)-14. Also, when water
is not vigorously excluded, formation of (R,R)-14 is more rapid
compared to the reaction under perfectly dry conditions. Since
the processes showed complex dependencies on several other
factors such as solvent, concentration, and temperature, the
discussion will focus on the qualitatiVe analysis of the formation
of diphosphate (R,R)-14.
The attack of deprotonated hydroxyphosphorinane (R)-15 at
chlorophosphorinane (R)-11 is assumed to proceed in the same
manner as the addition of other oxygen nucleophiles, resulting
in the formation of a five-coordinated phosphorus (PV) inter-
mediate.30,31 Commonly, PV structures have trigonal bipyramidal
geometry (TBP),32,33 although distortions toward a square-
pyramidal (SP) geometry have also been reported.34 In the
trigonal bipyramid, the two axially oriented ligands have slightly
longer and weaker bonds than the three equatorial ligands,
resulting in different chemical behavior. The differences can
be explained in terms of hybridization; phosphorus has pd-
hybridization along the z-axis and sp2-hybridization in the
equatorial plane. According to the theory introduced by West-
heimer,32 nucleophiles attacking the phosphorinane substrate
initially occupy an axial site in the PV trigonal bipyramid.
Furthermore, it is always an axially oriented ligand that is
expelled upon conversion of the PV system to the phosphate
stage. PV-TBP systems show a highly fluctional behavior,
In path 1, the attack of the nucleophile takes place opposite
the P-Cl bond; the dioxaphosphorinane formed in this way
spans diequatorially (18), which is regarded as being energeti-
cally unfavorable.38 Subsequent elimination of chloride results
in the formation of diphosphate 14ax-eq which is formed with
inversion of configuration with respect to the phosphorus
nucleus in the former chlorophosphorinane part of the molecule.
This leads to an axial-equatorial orientation39 of the bridging
oxygen with respect to the phosphorus atoms as shown in
14ax-eq
.
Attack of RO- opposite the P-O3 bond (path 2), resulting
in PV-TBP intermediate 19, gives by cleavage of the axial P-O1
bond the acyclic phosphorinane diester 23, which is formed with
inversion of configuration with regard to the phosphorus center.
Pseudorotation of the PV-TBP intermediate 19 leads to the
formation of another PV-TBP intermediate 20 and to acyclic
24 or the cyclic product 14eq-eq. Both products are formed with
retention of configuration at phosphorus. In diphosphate 14,
formed via this route, the bridging oxygen adopts an axial-
axial orientation.
(35) Ugi, I.; Marquarding, D.; Klusacek, H.; Gokel, G.; Gillespie, P.
Angew. Chem. 1970, 82, 741. Ramirez, F.; Pfohl, S.; Tsolis, E. A.; Pilot, J.
F.; Smith, C. P.; Ugi, I.; Marquarding, D.; Gillespie, P.; Hoffmann, P.
Phosphorous 1971, 1, 1.
(36) Gorenstein, D. G.; Powell, R.; Findlay, J. J. Am. Chem. Soc. 1980,
102, 5077. van Ool, P. J. J. M.; Buck, H. M. Eur. J. Biochem. 1982, 121,
329.
(30) For a review concerning phosphorous stereochemistry, see: Hall,
C. R.; Inch, T. D. Tetrahedron 1980, 36, 2059.
(31) Lemmen, P.; Baumgartner, R.; Ugi, I.; Ramirez, F. Chemica Scr.
1988, 28, 451.
(32) Gorenstein, D.; Westheimer, F. J. Am. Chem. Soc. 1967, 89, 2762.
Westheimer, F. Acc. Chem. Res. 1968, 1, 70. Kluger, R.; Covitz, F.; Dennis,
E.; Williams, L. D.; Westheimer, F. J. Am. Chem. Soc. 1969, 91, 6066.
(33) Mislow, K. Acc. Chem. Res. 1970, 3, 321.
(34) Lukenbach, R. Dynamic Stereochemistry of Pentacoordinated
Phosphorous and Related Elements; Thieme: Stuttgart, 1973.
(37) Holmes, R. R. Pentacoordinated Phosphorous; ACS Mongraph No.
175; American Chemical Society: Washington, DC, 1980; Vols. I and II,
p 176.
(38) Yu, J. H.; Day, R. O.; Howe, L.; Holmes, R. R. Inorg. Chem. 1991,
30, 3132. Yu, J. H.; Sopchik, A. E.; Arif, A. M.; Bentrude, W. G. J. Org.
Chem. 1990, 55, 3444. Yu, J. H.; Arif, A. M.; Bentrude, W. G. J. Am.
Chem. Soc. 1990, 112, 7451. Day, R. O.; Kumara Swamy, K. C.; Fairchild,
L.; Holmes, J. M.; Holmes, R. R. J. Am. Chem. Soc. 1991, 113, 1627.
(39) The equatorial or axial description refers to the orientation of the
PdO moiety.

3140 J. Am. Chem. Soc., Vol. 122, No. 13, 2000
Hulst et al.
Scheme 5. Possible Pathways for the Nucleophilic Attack of Hydroxyphosphorinane (R)-15 at Chlorophosphorinane (R)-11 (See
the Text for Explanation)
In path 3 attack of RO- takes place opposite the P-O1 bond.
The chloride leaving group is placed equatorially in the PV-
TBP intermediate 22 and can only be eliminated after pseu-
dorotation to 21, placing the chloride substituent in the axial
position. Subsequent cleavage of the axial P-Cl or P-O3 bond
leads to the formation of the cyclic diphosphate 14eq-eq or to
the acyclic phosphorinane ester 25, respectively. Both reactions
proceed with retention of configuration at the phosphorus atom.
Alternatively, direct cleavages of the axially oriented P-O1 bond
in 22 leads to the formation of the acyclic phosphonate ester
26 with inversion of configuration.39
Although not all routes are energetically favorable, the results
described by, e.g., Buck and co-workers,40 using analogous
systems and oxygen nucleophiles, showed that all products
mentioned could in principle be formed though unequally
distributed.
Formation of Diphosphate (R,R)-14 from Phosphorinanes
(R)-11 and (R)-15. Using (R)-11, in situ derived from (R)-17,26
and (R)-15 (both 1.0 mmol), 0.1 mL of Et3N, and CCl4 dissolved
in CDCl3 (2 mL) or C6D6, the formation of diphosphate (R,R)-
14 is easily monitored by means of 31P NMR spectroscopy
(Figure 4).
Figure 4. Decoupled 31P NMR spectrum of the reaction mixture during
the conversion of (R)-11 and (R)-15 into diphosphate (R,R)-14 recorded
after 30 min, CDCl3, [L] ) 0.01.
A total of three signals, two doublets, and a singlet, other
than the signals belonging to the starting materials, are initially
observed by means of 31P NMR spectroscopy. The presence of
these products was also observed by means of 1H NMR
spectroscopy, although the spectra appeared to be very complex
due to extensive coupling and signal overlap. The pairs of signals
at δ -16.29 and -22.20 ppm, showing an AB type of coupling
(2JPP ) 33.0 Hz), are assigned to an intermediate with one of
the structures 18-22 (Scheme 5). The disappearance of this
pair of signals leads to an increase in intensity of the signal
located at δ -20.56 ppm, which is assigned to (R,R)-14 by
comparison with an independently prepared sample (vide infra).5
The reaction showed a large temperature and solvent depen-
dency and is completed between 1 h at 65 °C and 12 h at 30
°C, both in C6D6. The only product is the symmetrical
diphosphate (R,R)-14; possible ring-opened products 23, 24, 25,
and 26 were not observed.
Especially from the decoupled 31P NMR spectra, it is obvious
that the formation of (R,R)-14 proceeds diastereospecifically at
the phosphorus center; otherwise, a total of four signals, two
doublets and two singlets, would be expected. The C2-sym-
metrical axial-axial coupled product 14eq-eq yields only one
31P NMR resonance, the equatorial-equatorial coupled product
(40) Broeders, N. L. H. L.; Koole, L. H.; Buck, H. M. J. Am. Chem.
Soc. 1990, 112, 7475. Broeders, N. L. H. L.; van der Heiden, A. P.; Peeters,
I.; Janssen, H. M.; Koole, L. H. J. Am. Chem. Soc. 1992, 114, 9624.
Broeders, N. L. H. L. Ph.D. Thesis, University of Eindhoven, The
Netherlands, 1993.

Formation of Pyrophosphates
J. Am. Chem. Soc., Vol. 122, No. 13, 2000 3141
Scheme 6. Possible Diastereomers of Diphosphate (R,R)-14
phorinane (R)-11 is envisioned to occur via the less hindered
face of (R)-11, which is opposite the P-O3 bond. Therefore,
attack according to path 2 (Scheme 5) yielding 19 as the first
intermediate is proposed to be the pathway followed, excluding
intermediate 22.
Formation of Diphosphate 14 Derived from Starting
Materials Obtained from Different Sources. At this point,
both mechanisms proposed by Cullis6 provide acceptable and
reasonably straightforward explanations for the observations
made. Less easily understood, however, is the observation that
14 is formed quantitatively when only a catalytic amount or
even no hydroxyphosphorinane 15 is available. The involvement
of (traces) crystal water could clearly explain these findings,
although chlorophosphorinane 11 is shown to be highly reluctant
toward straight hydrolysis.25 To establish a solid explanation,
several experiments were conducted using combinations of
racemic and enantiomerically pure 11 and 15.
14ax-ax also yields one resonance, and the axial-equatorial
bridged diphosphate 14ax-eq would give two resonances with
2
different chemical shifts and a JPP AB coupling.41 Scheme 6
shows the three possible diastereomeric products (R,R)-14.
The stereogenic benzylic center in the phosphorinane ring
provides an additional source of information concerning the
diastereoselectivity, since the formation of diphosphate 14 from
racemic starting material would lead to the formation of
diastereomers, two meso compounds and a d,l pair, provided
the coupling reaction is stereospecific with regard to phosphorus
as shown above. Therefore, diphosphate 14 would give two
signals in the decoupled 31P NMR spectrum due to the (R,R)-
and (S,S)-diphosphates (both being symmetrical, giving one
signal only) and the R,S and S,R diastereomers (also sym-
metrical, yielding one signal). However, when the reaction is
not stereospecific with regard to phosphorus, the diphosphate
can be formed with a total of 12 different configurations (6
pairs). A d,l or meso pair with an equatorially oriented PdO in
both ring systems, a d,l or meso pair with both PdO groups
axially oriented, and a d,l or meso pair with one PdO
equatorially and one PdO group axially positioned.39
By using racemic 11 and 15, all of the 31P NMR signals
previously observed are only doubled, which can be explained
by the formation of the d,l and meso isomers of both the
intermediate and diphosphate 14 (Figure 5).
The signals at δ -16.29 and -22.20 ppm, which show an
AB coupling (2JPP ) 33.0 Hz), belong to the RS form of the
intermediate and lead to the formation of (R,R)-14 or (S,S)-14
resonating at δ -20.56 ppm when the progress of diphosphate
formation is monitored (Table 1). The meso form of the
intermediate gives rise to signals at δ -16.44 and -22.32 ppm
(2JPP ) 27.8 Hz) and results in the formation of meso-14
resonating at δ -20.62 ppm. The isomers of the intermediate
are cleanly and quantitatively converted into (R,R)-14, (S,S)-
14, and meso-14.
As indicated, the formation of free hydroxyphosphorinane
15 from chlorophosphorinane 11 is not likely to take place. If
hydrolysis is, however, of importance, the reaction between 1
equiv of (R)-11 and 0.5 equiv of (S)-15 to form diphosphate 14
should provide important information. Hydrolysis of (R)-11 to
(R)-15 leads to the formation of both (R,S)-14, from (S)-15 and
(R)-11, and (R,R)-14, formed from (R)-11 hydrolyzed into (R)-
15 and (R)-11, both in products and intermediates. Both the
meso form and the d,l pair of diphosphate 14 are formed as
observed in the 31P NMR spectra, although not all (R)-11 has
reacted after 24 h of reaction time at 50 °C in C6D6. These
results suggest the interference of (traces of) crystal water in
the reaction medium, although the exact role remains unclear
at the moment.
Next, the conversion of (R)-11 was followed with chloro-
phosphorinane obtained from different sources. It makes a
considerable difference whether (R)-11 is prepared from (R)-
17 or from hydroxyphosphorinane (R)-15. In the former case,
only limited conversion to (R,R)-14 takes place. In the latter
case nearly all chlorophosphorinane (R)-11 is converted into
(R,R)-14. This can be explained by small traces of (R)-15 (still)
present in (R)-11, which initiates the formation of (R,R)-14.
These observations imply that not (R)-11 but the formed
diphosphate (R,R)-14 is subsequently hydrolyzed, yielding 2
equiv of free hydroxyphosphorinane (R)-15. This indicates that
a catalytic amount of free hydroxyphosphorinane, combined with
traces of (crystal) water, affects the complete conversion of
chlorophosphorinane (R)-11 into diphosphate (R,R)-14.
If, however, a mixture of (R)-15 and (S)-17 was used,
diphosphate 14 was formed with an initially (vide infra)
observed d,l:meso ratio close to 1:1, which cannot solely be
explained by simple (partial) hydrolysis of (S)-11, formed from
(S)-17, since this would lead to a 2:1 ratio in favor of the meso-
14, assuming hydrolysis to proceed without (stereo)selectivity
and no competitive reactions to occur.
Since diphosphate 14 gives only one 31P NMR resonance
when enantiomerically pure 11 and 15 are used and only two
resonances when using racemic 11 and 15, it can be concluded
that the formation of diphosphate 14 is stereospecific at the
phosphorus center. Moreover, 2D NOESY NMR and 31P NMR
data clearly showed product 14 to be the axial-axial coupled
Four explanations are possible to account for these observa-
tions. Straight hydrolysis of (R)-11 into (R)-15, which leads to
both (R)-15 and (S)-15, is the first possibility. Second, reaction
of 1 equiv of (R,S)-14 with 1 equiv of anion (S)-15 would lead
to the formation of 0.5 equiv of (R,S)-14 and of (S,S)-14 with
the release of 0.5 equiv of (R)-15 and 0.5 equiv of (S)-15. After
reaction with (R)-11 still present, both meso- and d,l-14 are
newly formed. A third mechanism would be the attack of
liberated chloride ion at (R,S)-14, yielding (R)-15 and (S)-15
as well as (R)-11 and (S)-11 if the nucleophilic attack proceeds
without stereoselectivity. After recombination, meso- and d,l-
14 are formed again. Unfortunately, reaction of, e.g., (S)-11,
diphosphate 14eq-eq 39
This also indicates that the observed
.
intermediate is 19 or 22, since intermediates 20 and 21 possess
a chloride leaving group in the axial position that is unlikely to
be observed due to the low stability. In the current situation,
however, the attack of the deprotonated (R)-15 on chlorophos-
(41) Gorenstein, D. G. Phosphorous-31 NMR Principles and Applica-
tions; Academic Press: New York, 1984. Verkade, J. G.; Quinn, L. D.
Phosphorous-31 spectroscopy in Stereochemical Analysis; VCH Publish-
ers: Deerfield Beach, FL, 1987.Cullis, P. M. In Phosphorous-31 NMR
Spectral Properties in Compound Characterisation and Structural Analysis;
Quin, L. D., Verkade, J. G., Eds.; VCH: Weinheim, New York, and
Cambridge, 1994.

3142 J. Am. Chem. Soc., Vol. 122, No. 13, 2000
Hulst et al.
Figure 5. Decoupled 31P NMR spectrum of the reaction mixture during the conversion of (R,S)-11 and (R,S)-15 into diphosphate 14 recorded after
30 min, CDCl3, [L] ) 0.01 M.
Table 1. 31P NMR Chemical Shifts and Coupling Constants for
Intermediates and Products in the Formation of (Racemic)
Diphosphate 14
NMR resonance frequency of phosphates (ca. 0.02 ppm for each
P-18O bond), the magnitude of which is related to the P-O
bond order.42 Cullis and co-workers6,8 used oxygen-labeling to
compd
δ (31P NMR) (ppm)
-20.56
δ (31P NMR) (ppm)
JPP (Hz)
follow the scrambling process of the oxygens in the formation
of diphosphates. In their system, a P-18O single bond produces
an upfield shift of 0.023 ppm in the 31P NMR spectrum and a
P-18O double bond results in a shift of 0.035 ppm; the effects
are additive.
(R,R)-14
(S,S)-14
meso-14
(R,R)-19
(S,S)-19
meso-19
-20.62
-16.29
-22.20
-22.32
33.0
27.8
The use of oxygen-labeled (R)-17 and hence (R)-11, and
unlabeled (R)-15, could provide us with information about the
oxygen scrambling and, subsequently, the mechanism of this
reaction. Oxygen-labeled (R)-17 was readily prepared following
the normal synthetic route,26 using H218O (85% labeling degree)
to perform the Arbuzov rearrangement. Hydrogen-phosphori-
nane (R)-17 with 85% labeled and 15% unlabeled oxygen was
obtained29 which showed in the decoupled 31P NMR spectrum
two distinguishable signals with a ∆δ of 0.034 ppm.
The reaction of 18O-labeled (R)-17 with (R)-15 (both 1.0
mmol), Et3N (0.1 mL), and CCl4 (0.1 mL) in C6D6 (2.0 mL) at
30 °C yields (R,R)-14 with extensively, though not completely,
scrambled labeling of the oxygens.
-16.44
with (S)-15 yields (S,S)-14, which is the enantiomer of (R,R)-
14 and cannot be distinguished by means of NMR techniques.
The most reasonable explanation (the fourth), however, is the
direct hydrolysis of diphosphate (R,S)-14. This leads to the
formation of both enantiomers of the hydroxyphosphorinane
anion 15, which accounts for the formation of both meso- and
d,l-14 after subsequent reaction of both enantiomers of 15. After
formation, (R,R)-14 may also hydrolyze, leading to the formation
of 2 equiv of (R)-15. If this should be the case, excess water
and base would lead to the formation of hydroxyphosphorinane
anion 15 from hydrolysis of diphosphate 14 after chlorophos-
phorinane 11 has reacted. This is exactly what is found in the
experiments carried out under not completely dry conditions.
Therefore, the explanation by Cullis and co-workers6 for the
complete scrambling of labeled oxygen over all exocyclic
oxygens of the diphosphate formed in the reaction of the
phosphorinane methyl ester 4 with the chlorophosphorinane 1
(vide supra) is not necessarily completely correct.
A total of six signals is observed in the 31P NMR spectrum
of 14, which accounts for the formation of all possible
combinations of unlabeled and 18O-labeled diphosphate 14, as
is depicted in Scheme 7.
It has to be noted that the symmetrical diphosphates 14a,
14c, 14d, and 14f give one signal in the 1H-decoupled 31P NMR
spectrum, whereas the unsymmetrically labeled molecules 14b
and 14e show an extreme AB system, leading to one apparent
resonance.41 The 31P NMR chemical shift difference for these
types of labeled molecules is typically comparable to the
When a small amount of diphosphate is hydrolyzed, there is
no need for the proposed attack of the phosphorinane anion on
the diphosphate to provide the exchange of labeled and
unlabeled material. In this case, the observation of the complete
scrambling of labeled and unlabeled oxygen does not exclude
the mechanism proposed by Zwierzak.3,4
2
coupling constant JPP, giving rise to three resonances instead
(42) Cohn, M.; Hu, M. Proc. Natl. Sci. U.S.A. 1978, 1, 200. Lowe, G.;
Potter, B. V. L.; Sproat, B. S.; Hull, W. E. J. Chem. Soc., Chem. Commun.
1979, 733. Tsai, M.-D. Biochemistry 1979, 8, 1468. Marschner, T. M.;
Reynolds, M. A.; Oppenheimer, N. J.; Kenyon, G. L. J. Chem. Soc., Chem.
Commun. 1983, 1289.
Oxygen-Labeling in the Formation of Diphosphates 14.
The presence of P-18O induces a small upfield shift in the 31P

Formation of Pyrophosphates
J. Am. Chem. Soc., Vol. 122, No. 13, 2000 3143
Scheme 7. Possible Scrambled Combinations of
18O-Labeled 14 (Other Substituents at Phosphorus Are
Omitted for Clarity)
the level of the intermediates themselves. In contrast to the 1D
31P NMR data that do not allow identification of all the
resonances because of low resolution, conclusive evidence is
obtained from the 2D 31P COSY NMR spectrum,43 as is shown
in Figure 8.
The four different intermediates, for which we propose
“general” structures 19, 29, 30, and 31, are given in Scheme 9.
Mixed intermediate 29, yielding signals in the 31P NMR
spectrum situated at δ -16.70 and -22.76 ppm (2JPP ) 29.9
Hz), is formed by the reaction of chlorophosphorinane (R)-27
with hydroxyphosphorinane (R)-15 and leads to the formation
of mixed diphosphate 32.
Knowing, however, that the signals situated around δ -16
to -17 ppm belong to the chloride-substituted part of the
intermediates 19, 29, 30, and 31, it is obvious that, at some
stage in the reaction leading to the diphosphates 14, 32, and
33, chlorophosphorinane (R)-11 is also formed. More likely,
chloride attack at 32 could also give chloride-substituted (R)-
11 as shown for (R)-29.
of four. An extreme AB system under these conditions gives
rise to the observation of only one signal in the 31P NMR
spectrum (Figure 6).
As expected, the main product (40%) resembles mono-
PdO-labeled diphosphate 14b, which is formed from labeled
(R)-17 and unlabeled (R)-15 (δ -20.60 ppm). Bis-PdO-labeled
diphosphate 14d and the PdO- and P-O-labeled diphosphate
14e are also formed in reasonable amounts (25% and 20%,
respectively), whereas the other three diphosphates, 14a, 14c,
and 14f, are formed in small amounts (<5%). Another interest-
ing observation emerges from the 31P NMR spectrum as shown
in Figure 6. Because of an incomplete degree of labeling (85%
labeled 17 was converted into 85% labeled 11), it can be
concluded that the doublet at δ -16.32 ppm, which is assigned
to intermediate 19 as discussed previously (Scheme 5), arises
from the phosphorus atom bearing the chlorine substituent.
These signals show in the initial stages of the reaction the 85:
15 labeling ratio that was present in the starting hydrogen-
phosphorinane 17. The other doublet, at δ -22.20 ppm, belongs
to the other part of intermediate 19 originating from unlabeled
15. The labeled and unlabeled intermediate 19 both show the
The other intermediates can be assigned as follows: inter-
mediate 19 gives signals at δ -16.29 and -22.20 ppm (2JPP
)
33.0 Hz); intermediate 30 yields signals at δ -16.40 and -22.58
ppm (2JPP ) 27.0 Hz). The signals belonging to intermediate
2
31 are located at δ -17.02 and -22.17 ppm, showing a JPP
coupling of 27.7 Hz. These assignments were made on the basis
of the corresponding coupling constants and integration of the
resonances that belong to a single isomer group as well as the
correlations obtained from the 2D 31P COSY spectra. The results
are collected in Table 2.
Moreover, experiments using (R)-11 and (R)-27 in initial
stages showed the groups of signals as discussed belonging to
the four intermediates, as well as (R,R)-14, (R,R)-32, and (R,R)-
33.
Furthermore, the three diphosphates formed are converted
after some time (about 24 h) into the symmetrical homomor-
phous diphosphates 14 and 33, observation of which demon-
strated a large preference of the cyclic phosphoric acid44 units
for the identical counter units (Scheme 9, Figure 7). Results
obtained from diffusion (DOSY)45 and HRMAS solid-state
NMR46 studies also indicate a large preference for identical
counter units in both the solution and solid states.
The only acceptable explanation for this observation is based
on the assumption that the initially formed diphosphate (R,R)-
32 is attacked by the liberated chloride ion, yielding either
chlorophosphorinane (R)-11 or (R)-27, or hydroxyphosphori-
nanes (R)-15 and (R)-28. It should be noted that diphosphate
(R,R)-32 can also be attacked by anion (R)-15, directly yielding
diphosphate (R,R)-14, whereas diphosphate (R,R)-33 is formed
after attack of the liberated anion (R)-28 on the corresponding
chlorophosphorinane (R)-27.
2
same JPP coupling of 33.0 Hz. As the reaction proceeds,
intermediates containing one or more scrambled oxygens are
formed, in accordance with observations made by Cullis and
co-workers for closely analogous systems.6,8
C. Use of Substituted Hydroxyphosphorinanes and Chlo-
rophosphorinanes in the Formation of Diphosphates. Al-
though the experiments described above provide us with a rich
source of information, several questions remain unanswered.
For example, upon reaction of (R)-11 with (S)-15, it is not
completely clear whether anion (R)-15 is formed by hydrolysis
of (R,S)-14 into 2 equiv of phosphorinane anion 15 (R and S
forms) or (R,S)-14 is attacked by a phosphorinane anion (S)-
15, liberating (S)-15 or (R)-15. Also, chloride attack on (R,S)-
14 or hydrolysis of (R)-11 can possibly lead to the observed
phenomena. An experiment using two slightly modified phos-
phorus reagents, 27 and 28 (Scheme 8), should provide us with
the desired experimental data.25
When chlorophosphorinane (R)-27 is allowed to react with
(R)-15 (both 1.0 mmol) and Et3N (0.1 mL) in CDCl3 (2.0 mL)
at 30 °C, the 31P NMR spectrum clearly indicates the formation
of the “mixed” diphosphate (R,R)-32 (Scheme 9).
(43) Colquhoun, I. J.; McFarlane, W. J. Chem. Soc., Chem. Commun.
1982, 484.
(44) NMR-based evidence for the conglomerate-like behavior of the
corresponding diastereomeric ephedra-based salts was obtained only after
cumbersome analysis: Hulst, R.; Kruizinga, W.; Wynberg, H.; Feringa, B.
L.; Kellogg, R. M. Recl. TraV. Chim. Pays-Bas 1995, 114, 220.
(45) The reported phenomena are also extracted from the initial differ-
ences in diffusion behavior found for homo- and heteroclusters of the
racemic hydroxyphosphorinanes and the corresponding diastereomeric
ephedra-based salts: Hulst, R.; Stamps, J.; Ottink, B.; Visser, J. M.
Manuscript in preparation.
Diphosphate (R,R)-32 gives two doublets at δ -20.37 and
2
-20.84 ppm, with a JPP coupling of 23.2 Hz. Furthermore,
diphosphates (R,R)-14 (δ -20.55 ppm) and (R,R)-33 (δ -21.19
ppm) are also observed (Figure 7 and Scheme 9). The formation
of the three diphosphates mentioned can be explained by either
of the four proposed mechanisms (vide supra).
(46) Conglomerate-like behavior is also observed in the 1H, 13C, and
31P HRMAS solid-state NMR spectra of the materials recorded in both pure
solids and slurried materials. Doubling of all the frequencies in the NMR
spectra mentioned is due to the different packing in the crystal lattice of
the enantiomerically pure and racemic forms: Hulst, R., Visser, J. M.
Submitted to Tetrahedron: Asymmetry.
The observation, however, that four different intermediates
are formed during the course of the reaction, leading to the
formation of three different diphosphates (Figures 7 and 8), is
unique, and offers the possibility to investigate this reaction at

3144 J. Am. Chem. Soc., Vol. 122, No. 13, 2000
Hulst et al.
Figure 6. Decoupled 31P NMR spectra of the formation of 18O-labeled (R,R)-14 and intermediates leading to it, recorded in CDCl3, [L] ) 0.01 M,
30 °C (axis in hertz).
Scheme 8. Modified Reagents 27, 28, and
Hydroxyphosphorinane 15 Used for “Mixed Experiments”
(See the Text for Explanation)
Scheme 9. Intermediates and Diphosphates Formed in the
Reaction of (R)-27 and (R)-15 (See the Text for Explanation)
The observation that the chloride ion acts as a nucleophile
attacking the diphosphate (R,R)-32 is not accounted for by
Zwierzak3,4 or Cullis,6,8 although it provides an explanation for
the scrambling of the labeled oxygens without the need for the
formation of dioxadiphosphetanes 8 and 9. At this point it is
not clear whether one of the three earlier discussed mechanisms
are also operating, or the proposed attack of the chloride ion
actually is the major route followed.
D. Use of 2D 31P COSY Techniques in the Elucidation of
the Formation of Diphosphates. During the course of the
research described, it became obvious that the rate of the reaction
of (R)-11 and (R)-15 yielding (R,R)-14 showed a large temper-
ature dependence. Normally, reactions were performed at 30
°C. However, experiments carried out using (R)-11 and (R)-15
at temperatures between 45 and 50 °C showed an even more
complex behavior than expected on the basis of previous 31P
NMR analyses, as is shown in Figure 9. It needs to be
emphasized that the (only) final product, however, is diphos-
phate (R,R)-14.
phosphorus-phosphorus coupling patterns observed.47 The other
signals, all showing nearly the same coupling patterns, are less
1
easily assigned by the use of 1D H and 31P NMR techniques,
The 1D spectrum shows clearly the signals of intermediate
19, at δ -16.29 and -22.20 ppm (2JPP ) 33.0 Hz), and (R,R)-
14 (δ -20.6 ppm). Besides these resonances, several resonances
are observed that show extensive phosphorus coupling, which
is a strong indication that these intermediates contain more than
one, nonequivalent phosphorus atom, connected with each other
through a bridging oxygen atom, resulting in the geminal
although the integration is of great help for the full assessment
of the 2D 31P COSY spectrum shown in Figure 10.
(47) The signal at δ -17.23 ppm (singlet), which is observed regardless
of the nature of the hydroxyphosphorinanes used, cannot be assigned
unambiguously. It is likely that small amounts of degraded (poly)-
phosphorous components give rise to this absorption.

Formation of Pyrophosphates
J. Am. Chem. Soc., Vol. 122, No. 13, 2000 3145
Figure 7. Decoupled 31P NMR spectrum of the reaction products of (R)-27 and (R)-15 after 1 and 24 h (inset), recorded in CDCl3.
2D spectra. The intermediates were allowed to build up at 47.5
°C in C6D6 as solvent. When they had developed adequately,
on the basis of the 1D 31P NMR spectral data, the temperature
was quickly brought to -50 °C. This temperature allowed us
to record a 2D COSY spectrum, without observable progression
of the reaction (only a small amount of CDCl3 had to be added
to the reaction mixture to prevent freezing). The experiments
were performed using unlabeled as well as labeled materials to
obtain maximum information from the experiments. The results
as obtained are collected in Table 3.
The phosphorus nuclei leading to the doublet signals at δ
-11.43 and -13.73 ppm are clearly correlated, yielding a 2JPP
coupling of 18.2 Hz, and are attributed to intermediate 34
(Scheme 10). Although there is no direct evidence for this
assignment, the observed chemical shifts as well as the fact that
both signals at δ -11.43 and -13.73 ppm double when partially
oxygen labeled (R)-11 is used in this reaction provide strong
indications that this must be a dioxadiphosphetane intermedi-
ate.48 The labeled oxygen is “shared” by the two phosphorus
atoms.
The same is found for the signals at δ -11.68 and -18.22
ppm (2JPP ) 21.0 Hz). These also arise from two O-connected
phosphorus atoms. The labeling experiment, as described above,
Figure 8. 31P COSY spectrum of the reaction products of (R)-27 and
(R)-15, recorded after 1 h at 30 °C, recording temperature -30 °C,
CDCl3.
shows that both signals double upon the use of 18O-labeled
starting material (R)-11. This indicates that the labeled oxygen
is again bridged between the two different phosphorus atoms.
On the basis of these observations and chemical shifts, the
signals are believed to belong to intermediate 35. The breakdown
of 35 yields bridged 18O-labeled intermediate 36, although this
intermediate was not observed as intermediate 36 contains a
chlorine leaving group in the axial position. Probably, the
elimination of this chlorine is too fast to allow direct detection
of intermediate 36 by NMR techniques. So far, the Cullis6 model
provides an acceptable and unambiguous explanation for this
part of the observations. That the situation is more complex,
however, is indicated by the appearance of two more sets of
resonances.
Table 2. 31P NMR Chemical Shifts and Coupling Constants of
Intermediates Leading to the Formation of Mixed Diphosphates
(R,R)-14, (R,R)-32, and (R,R)-33
compd
δ (31P NMR) (ppm)
δ (31P NMR) (ppm)
JPP (Hz)
14
19
32
33
29
30
31
-20.56
-16.29
-20.37
-21.19
-16.40
-16.70
-17.02
-22.20
-20.84
33.0
23.2
-22.58
-22.76
-22.17
27.0
29.9
27.7
(48) Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1. Clayden,
J.; Warren, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 241. Hulst, R.; van
Basten, A.; Fitzpatrick, K.; Kellogg, R. M. J. Chem. Soc., Perkin Trans. 1
1995, 2961.
The recording of the 2D 31P COSY spectrum, concerning the
intermediates of a still developing reaction, appeared to be rather
troublesome, due to the larger time interval needed to record

3146 J. Am. Chem. Soc., Vol. 122, No. 13, 2000
Hulst et al.
Figure 9. 31P NMR spectrum during the formation of (R,R)-14 from (R)-11 and (R)-15 at 47.5 °C, recorded at -50 °C, solvent CDCl3/C6D6, [L]
) 0.01 M.
data. The doublet at δ -14.92 ppm is correlated to the
double doublet at δ -26.33 ppm (2JPP ) 22.4 Hz). The latter
shows a correlation with the signal resonating at δ -19.22
ppm (2JPP ) 22.4 Hz). It is clear that the phosphorus atom
leading to the signal at δ -26.33 ppm is connected with
two other, nonequivalent, phosphorus atoms that are not
directly correlated themselves. The only possible explan-
ation for this peculiar phenomenon is the coupling of three
phosphorus-containing units into an intermediate noncyclic
trimer. The use of oxygen-labeled (R)-11 shows that the
resonances at δ -26.33 ppm double, and the resonances residing
at δ -14.92 ppm show complex behavior (the effects are
unfortunately only observable in the early stages of the reaction).
Oxygen labeling does not influence the other resonance, residing
at δ -19.22 ppm. The chemical shift data together with the
integration data, coupling constants, and the data obtained from
the oxygen-labeling experiments indicate that the trimeric
intermediate has structure 37 (Scheme 11). This compound
contains three different phosphorus atoms and is formed
from hydroxyphosphorinane (R)-15, which has attacked
chlorophosphorinane (R)-11. Subsequently, this unit attacks
another chlorophosphorinane (R)-11, yielding the trimer as
suggested.
Figure 10. 31P COSY spectrum of the products and intermediates
The other trimer 38 also contains three phosphorus atoms,
during reaction of (R)-11 and (R)-15 at 47.5 °C, recorded at -50 °C,
although two of them appear to be “virtually” equal, resulting
solvent CDCl3/C6D6, [L] ) 0.01 M.
in a doublet at δ -19.24 ppm (2JPP ) 22.4 Hz) and an apparent
Table 3. 31P NMR Chemical Shifts and Coupling Constants of
Dioxadiphosphetane and Trimeric Intermediates Leading to the
Formation of Diphosphate (R,R)-14 during Reaction at 47.5 °C,
Recorded at -50 °C (See the Text for Explanation)
triplet at δ -25.90 ppm. These resonances show two equal 2JPP
couplings of 22.4 Hz and a measured intensity half the size of
the resonance at δ -19.24 ppm. Although this structure contains
a bisequatorially spanned phosphorinane ring system, which is
assumed to be energetically unfavorable, this is the only possible
structure which contains two equivalent phosphorinane ring
systems and can still lead to the exclusive formation of (R,R)-
14 and no other products.
δ (31P NMR) δ (31P NMR) δ (31P NMR)
compd
(ppm)
(ppm)
(ppm)
JPP (Hz)
34
35
36
37
38
-11.4
-13.73
-18.22
18.2
21.0
-11.68
The use of 18O-labeled (R)-11 leads to the doubling of the
signals at δ -25.90 ppm and to a partial doubling of the signal
at δ -19.24 ppm, while a part of this signal remains unaffected
(again, only in the early stages of this reaction). Obviously,
hydroxyphosphorinane (R)-15 reacted with 1 equiv of chloro-
phosphorinane (R)-11 that reacted with another molecule of
-14.92
-19.24
-26.33
-25.90
-19.22
-25.90
22.4/22.4
22.4/22.4
The responsible intermediates are built up of three connected
phosphorus units, on the basis of the 2D 31P COSY spectrum
as well as the observed coupling constants and integration

Formation of Pyrophosphates
J. Am. Chem. Soc., Vol. 122, No. 13, 2000 3147
Scheme 10. Formation of 14 via Dioxadiphosphetanes
Scheme 11. Proposed Structures of Intermediates 37 and 38
Scheme 12. Alternative Mechanism for the Formation of
Diphosphate 14 from 37 and 38
(31P NMR Chemical Shifts Indicated)
chlorophosphorinane (R)-11, yielding intermediate 38. This is
the elimination product of intermediate 37. Intermediate 38 can
only be transferred into (R,R)-14 after another attack of a
molecule of deprotonated hydroxyphosphorinane (R)-15 has
taken place. This would afford one molecule of (R)-15 and one
molecule of chlorophosphorinane (R)-11, together with one
molecule of diphosphate (R,R)-14 (Scheme 12).
Alternatively, chloride attack on 38 could result in one
molecule of (R)-11 and one molecule of diphosphate (R,R)-14,
together with one chloride anion (Scheme 12). Furthermore,
intermediate 37 can be converted either into 38 by chloride
elimination or into diphosphate (R,R)-14 by elimination of (R)-
11 and a chloride anion.
Unfortunately, it appeared impossible to generate the same
types of intermediates by using one of the other hydroxyphos-
phorinanes or chlorophosphorinanes with substituted phenyl
groups, or combinations of hydroxyphosphorinanes or chloro-
phosphorinanes, regardless of the reaction conditions employed.
It is clear that besides the direct route and the chloride attack,
followed by the direct route, another reaction mechanism,
involving trimeric structures, can also give rise to the formation
of diphosphate (R,R)-14.
amines, alcohols, or amino acids provides a rich source of
information concerning the formation of diphosphates in general.
Although the side reaction does not influence the actual analyses,
the appearance of side products gave rise to a more detailed
investigation.
The products formed were characterized as diphosphate (R,R)-
14 and intermediates leading to its formation. Due to the
conformational locking of the phenyl group in the equatorial
position of the “phencyphos” building units, the pseudorotation
intermediate products are blocked, and allow detection of
intermediates using 1H and, in particular, 31P NMR techniques.
On the basis of the data obtained from several NMR experi-
ments, the use of 18O-labeled chlorophosphorinane (R)-11 and
the stereochemical information from racemic and homochiral
chlorophosphorinane 11 and hydroxyphosphorinane (R)-15, it
was concluded that the nucleophilic displacement reaction
proceeds with complete stereocontrol at the phosphorus center.
An explanation can be given on the basis of a mechanism
involving phosphetane intermediates (mechanism 1), as is
depicted in Scheme 10. These results are in agreement with the
Conclusions
The unusual minor side reaction observed when reagent (R)-
11 or (R)-17 is used for enantiomeric excess determination of

3148 J. Am. Chem. Soc., Vol. 122, No. 13, 2000
Hulst et al.
the TMS scale. The splitting patterns are designated as follows: s
(singlet), d (doublet), dd (double doublet), t (triplet), q (quartet), m
(multiplet), and br (broad). Chemical shifts (ppm) are positive in the
low-field direction.
results using related achiral compounds, as reported by Zwier-
zak3,4 and Cullis.6,8 More important, however, is the fact that
the results obtained by Cullis and Zwierzak are only based on
the products obtained. Using the phencyphos derivatives, several
intermediates can actually be observed using 1H and 31P NMR
techniques.
Labeling experiments with 18O-labeled (R)-17, and hence (R)-
11, together with the use of racemic hydroxyphosphorinanes
15 and 28 as well as chlorophosphorinane 11 and 27, made the
complete structural assignment of the observed intermediates
possible. Furthermore, the scrambling of the oxygen over all
possible exocyclic oxygens in this system showed not only that
a direct nucleophilic displacement reaction of hydrogen-
phosphorinane 15 and chlorophosphorinane 11 occurred, but
also that a second mechanism must operate.
The use of mixed phencyphos hydroxyphosphorinanes (15
and 28) and chlorophosphorinanes 11 and 27 showed that
eliminated anionic chloride is able to act as a nucleophile,
attacking the “mixed” diphosphate 32. This yields combinations
of chlorophosphorinanes and reaction intermediates, which were
not apparent at the start of the reaction following mechanism 1
(Scheme 9), or could be formed during the reaction otherwise.
These observations could provide another explanation for the
scrambling of the 18O-label over the different oxygen atoms in
both products and intermediates.
Using 2D 31P COSY NMR techniques, together with 18O-
labeling experiments, a third mechanism was found (Schemes
11 and 12). In this mechanism, acyclic trimeric phosphorus-
containing intermediates 37 and 38 are formed, leading to the
direct formation of diphosphate (R,R)-14, or to the formation
of diphosphate (R,R)-14 after the attack of a deprotonated
hydroxyphosphorinane unit. This also results in complete
scrambling of 18O-labeled oxygens over all the exocyclic
oxygens. Alternatively, chloride attack on the trimeric inter-
mediates would give the described products. In this way,
hydroxyphosphorinanes and chlorophosphorinanes bearing 18O-
labels are formed at the beginning of the reaction. These
compounds can react further, and give rise to doubly or triply
18O-labeled (R,R)-14.
1H decoupled 31P NMR spectra were recorded on Varian VXR-300
and Unity-400 WB spectrometers operating at 121.42 and 161.89 MHz,
respectively. The chemical shifts are denoted either relative to (NPCl2)3
resonating at δ 19.91 ppm (for the solvents CDCl3 and C6D6) or relative
to phosphoric acid at δ 0 ppm (for the solvents D2O, DMSO-d6, and
CD3OD). T1 relaxation times were calculated with the inversion-
1
recovery method, using standard Varian microprograms. The H-1H
and 31P-31P COSY, 1H-1H NOESY, and 1H-1H ROESY spectra were
recorded at +50, 0, and -50 °C ((0.1 °C) using Varian Unity-400
WB and UnityPlus-500 spectrometers. The 2D spectra were collected
as 2D hypercomplex data. After weighing with shifted sine-bell
functions, the COSY49 data were Fourier transformed in the absolute
value mode while the NOESY50 and ROESY51 data were transformed
in the phase-sensitive mode. Data processing was performed using
standard Varian VnmrS/VnmrX software packages. The spectrometers
operated in the Fourier transform mode using the 2H resonance of the
solvent as field-frequency lock.
The hydroxyphosphonates and phosphonate (R)-17 were prepared
according to literature procedures.25,26 18O-labeled water (labeling degree
around 85%, as established from the integration of the two signals in
the 31P NMR spectra) was kindly provided by the PET Center at the
University Hospital of Groningen, The Netherlands. Diphosphate (R,R)-
14 was also prepared for comparison purposes according to the method
described by Edmundson.5
(R)-2-Chloro-2-oxo-5,5-dimethyl-4-(R)-phenyl-1,3,2-dioxaphos-
phorinane [(R)-11]. Using the PCl5 Method. (R)-Phencyphos (R)-15
(40.0 g, 0.17 mol) was suspended in 250 mL of dry CH2Cl2. To this
stirred suspension was added 40.0 g of PCl5 (0.19 mol) over a 10 min
period, while the temperature was kept below 10 °C. Subsequently,
the mixture was stirred for 3 h at room temperature. The solution was
concentrated to dryness and the residue dissolved in 250 mL of dry
ether. Excess PCl5 was removed by filtration and the filtrate stored at
-20 °C for 7 days. After this period, small white needles were isolated
and dried carefully in a vacuum at 35 °C for 2 h. Yield of (R)-11:
7.02 g (0.027 mol, 16%). Mp 156-158 °C. [a]20 ) -81.9° (c 0.5,
D
1
CHCl3). H NMR (CDCl3): δ 0.82 (s, 3H), 1.03 (s, 3H), 4.03 (dd,
3
2
3
2JAB ) 9.0 Hz, JPH ) 30.0 Hz, 1H), 4.18 (dd, JAB ) 9.0 Hz, JPH
)
4.0 Hz, 1H), 5.21 (d, JPH ) 2.0 Hz, 1H), 7.20-7.40 (m, 5H). 13C
NMR (CDCl3): δ 17.14 (CH3), 20.64 (CH3), 36.36 (d, 3JPC ) 4.6 Hz,
C), 79.51 (d, 2JPC ) 8.1 Hz, CH2), 89.78 (d, 2JPC ) 6.9 Hz, CH), 127.16
(CH), 127.93 (CH), 128.86 (CH), 134.67 (C). 31P NMR (CDCl3): δ
-4.49 ppm. Anal. Calcd for C11H14O3PCl: C, 50.69; H, 5.41; P, 11.88;
Cl, 13.60. Found: C, 50.34; H, 5.22; P, 11.48; Cl, 13.47. HRMS: calcd
260.037, found 260.037.
3
Although probably all three mechanisms, involving (1) the
formation of phosphetanes as proposed by Zwierzak3,4 and Cullis
and co-workers,6 (2) chloride attack at the diphosphate formed,
or (3) trimer formation followed by attack of deprotonated
hydroxyphosphorinane or chlorophosphorinane, are not in
disagreement with each other, the appearance of the last two
routes has to the best of our knowledge never been proposed
or observed previously.
It is remarkable that, although the reaction routes are rather
complex and markedly different, the final product, diphosphate
(R,R)-14, is always formed as the only enantiomerically pure
product. This means that the reactions proceed with complete
stereocontrol with regard to the phosphorus nucleus, regardless
of the route followed.
Using the POCl3 Method. A solution of 8.0 g (0.052 mol) of POCl3
in 500 mL of CH2Cl2 was cooled to -20 °C. To the stirred solution
was slowly added a solution of 10.0 g (0.052 mol) of (R)-phencydiol
(R)-16 and Et3N (12 mL) in 200 mL of CH2Cl2. After the addition was
complete (30 min) another 12 mL of Et3N in 50 mL of CH2Cl2 was
added. The mixture was stirred for 5 h and concentrated and the residue
dissolved in ethyl acetate. The solution was filtered and evaporated to
dryness, and the residue was dissolved in ether and stored at -20 °C
to allow the chlorophosphorinane (R)-11 to crystallize. After 7 days,
small white needles were collected and treated as described above.
Yield: 3.81 g (0.0146 mol, 28%). Spectroscopic data were found to
be identical compared to those of the material obtained by the PCl5
method.
Experimental Section
All operations were carried out using Schlenck-line techniques under
an argon atmosphere. NMR measurements were performed in well-
dried and sealed NMR tubes, using predried solvents under an argon
atmosphere.
Using the CCl4-Et3N Method. To a cooled (0 °C) mixture of 5.0
g (0.022 mol) of cyclic (S)-hydrogen-phosphorinane (S)-17 and 3.4 g
(49) Bax, A.; Freeman, R. J. Magn. Reson. 1981, 44, 542.
(50) Jeener, J.; Meier, B. H.; Bachmann, P.; Ernst, R. R. J. Chem. Phys.
1979, 71, 4546. Neuhaus, D.; Williamson, M. The Nuclear OVerhauser
Effect in Structural and Conformational Analysis; VCH Publishers: Cam-
bridge, 1989.
(51) Bothner-By, A. A.; Stephens, R. L.; Lee, L.; Warren, C. D.; Jeanloz,
R. W. J. Am. Chem. Soc. 1984, 106, 811.
1D NMR spectra were taken at 30 °C ((0.1 °C), unless stated
1
otherwise, using Varian temperature control units. H and 13C NMR
(APT) spectra were recorded on Varian VXR-300, Unity-400 WB, and
UnityPlus-500 spectrometers at 300, 400, and 500 Hz and 75.43, 100.57,
and 125.72 MHz for proton and carbon, respectively. Chemical shifts
are denoted in δ units (ppm) relative to the solvents and converted to

Formation of Pyrophosphates
J. Am. Chem. Soc., Vol. 122, No. 13, 2000 3149
Table 4. Crystallographic Data for Crystal Structure Determinations of 12, 13, and 27
12
13
27
C11H13Cl2O3P
Crystal Data
empirical formula
molecular weight
cryst syst
space group
a, Å
C20H25O4P
360.37
C19H24NO3P
345.36
trigonal
P31 (no. 144)
12.4170(12)
295.08
orthorhombic
P212121 (no. 19)
6.4799(10)
17.165(2)
17.189(2)
1911.9(4)
1.252
orthorhombic
P212121 (no. 19)
6.4383(10)
10.498(2)
19.571(3)
1322.8(4)
1.482
b, Å
c, Å
10.912(2)
1457.0(3)
1.181
V, Å3
D
Z
calc, g cm-3
4
3
4
F(000)
768
1.6 [Mo KR]
colorless
0.18 × 0.45 × 1.1
608
6.0 [Mo KR]
colorless
0.15 × 0.15 × 0.25
µ, cm-1
cryst color
cryst size, mm
T, K
295
1.2, 25.0
5.03, 10.71
0.71073 [Mo KR]
Ni filter
0.66 + 0.35 tan θ
2.30, 4.00
295
4.1, 75.0
7.13, 21.40
1.54184 [Cu KR]
Zr filter
0.62 + 0.14 tan θ
3.93, 6.00
150
1.6, 27.5
2.0, 20.0
0.71073 [Mo KR]
graphite monochr
θ
min, θmax, deg
θ
min, θmax (unit cell), deg
wavelength, Å
filter/monochr
∆ω, deg
hor, ver aperture, mm
mosaicity
X-ray exposure, h
linear instability, %
data set
total no. of data
total no. of unique data
0.348(1)
6
32
<1
45
3
0:8, -22:0, -22:22
-15:15, -15:15, -13:13
5772
5742 [Rint ) 0.0575]
-8:8, -13:13, -25:25
35198
3040 [Rint ) 0.0769]
1966
1958
Refinement
no. of refined params
final R1a
246
223
206
0.0511 [1061 I > 2σ(I)]
0.0631 [2417 I > 2σ(I)]
0.1678
0.0228 [2941 I > 2σ(I)]
0.0590
final wR2c
0.1001
goodness of fit
0.923
0.983
1.059
w-1 c
σ2(F2) + (0.0416P)2
0.000, 0.000
-0.22, 0.19
σ2(F2) + (0.0879P)2
0.001, 0.008
-0.18, 0.19
σ2(F2) + (0.0323P)2 + 0.21P
0.000, 0.001
(∆/σ)av, (∆/σ)max
min and max residuals density, e Å-3
-0.32, 0.18
a R1 ) ∑||Fo| - |Fc||/∑|Fo|. b wR2 ) [∑[w(Fo - Fc2)2]/∑[w(Fo )2]]1/2
.
c P ) (max(Fo ,0) + 2Fc2)/3.
2
2
2
(0.022 mol) CCl4 in 150 mL of dry benzene was added 5 mL of Et3N
over 15 min. Subsequently, the mixture was allowed to stir at room
temperature for another hour. The mixture was concentrated to dryness
and the residue dissolved in dry ethyl acetate, filtered, and concentrated
again to dryness. The residue was dissolved in petroleum ether (60:40,
75 mL) and stored for 7 days at -20 °C. After this period, white needles
were formed that were treated as described above. Yield: 5.45 g (0.021
mol, 95%). Spectroscopic data were found to be identical compared to
those of the material obtained by the PCl5 method.
(R)-2-O-[2′-(S)-phenylpropanoyl]-2-oxo-5,5-dimethyl-4-(R)-phen-
yl-1,3,2-dioxaphosphorinane [(S,R)-12] was prepared as described
previously and recrystallized several times from ethyl acetate/diethyl
ether mixtures at -20 °C.
(R)-2-N-[2′-(S)-phenylethanoyl]-2-oxo-5,5-dimethyl-4-(R)-phenyl-
1,3,2-dioxaphosphorinane [(R,S)-13] was prepared as described
previously and recrystallized several times from ethyl acetate/diethyl
ether mixtures at -20 °C.
Pertinent data for the structure determinations are collected in Table
4. Data for crystal structures 12 and 13 were collected on a Nonius
CAD4-F diffractometer on a sealed tube (ω/2θ scans). Data for structure
determination of 27 were collected on a Nonius κ-CCD diffractometer
on a rotating anode. Accurate unit-cell parameters and an orientation
matrix were determined by least-squares fitting of the setting angles
of 25 well-centered reflections (SET4)52 for structures 12 and 13. The
unit-cell parameters for structure 27 were refined against the setting
angles of 485 reflections. The unit-cell parameters were checked for
the presence of higher lattice symmetry.53 All structures were solved
with direct methods using SHELSX86.54 Refinement on F2 was
performed with SHELXL-9255 (12 and 13) or SHELXL-97-2 (27).56
The hydrogen atoms of 12 and 13 were included in the refinement on
calculated positions riding on their carrier atoms, except for the amine
(R)-2-Chloro-2-oxo-5,5-dimethyl-4-(R)-(2-chloro-1-phenyl)-1,3,2-
dioxaphosphorinane [(R)-27]. 1H NMR (CDCl3): δ 0.94 (s, 3H), 1.22
(s, 3H), 4.11 (dd, 2JAB ) 11.5 Hz, 3JPH ) 31.3 Hz, 1H), 4.46 (dd, 2JAB
3
3
) 11.5 Hz, JPH ) 3.0 Hz, 1H), 5.95 (d, JPH ) 3.1 Hz, 1H), 7.22-
7.42 (m, 3H), 7.52-7.60 (m, 1H). 13C NMR (CDCl3): δ 17.27 (CH3),
19.86 (CH3), 37.19 (C), 79.36 (CH2), 84.23 (CH), 126.36 (CH), 129.07
(CH), 129.81 (CH), 131.83 (C), 132.36 (C). 31P NMR (CDCl3): δ
-2.29 ppm. For other spectroscopic data see Ten Hoeve and Wynberg.25
(R,R)-2,2′-Oxybis(5,5-dimethyl-4-(R)-phenyl-1,3,2-dioxaphospho-
rinan-2-one) [(R)-14]. White crystalline material. Mp 143-145 °C.
1H NMR (CDCl3): δ 1.81 (s, 6H), 1.05 (s, 6H), 4.01-4.20 (ddd, 2H),
4.62-4.79 (d, 2H), 5.43 (dd, 2H), 7.19-7.38 (m, 10H). 13C NMR
(CDCl3): δ 16.99 (dd, CH3), 20.49 (dd, CH3), 45.43 (CH2), 79.76 (dd,
C), 89.29 (dd, CH), 127.16 (CH), 127.76 (dd, CH), 128.54 (CH), 134.49
(C). 31P NMR (CDCl3): δ -20.56 ppm. HRMS: calcd 466.131, found
466.131.
(52) de Boer, J. L.; Duisenberg, A. J. M. Acta Crystallogr. 1984, A40,
C-410.
(53) Spek, A. L. J. Appl. Crystallogr. 1988, 21, 578.
(54) Sheldrick, G. M. SHELXS86 Program for crystal structure deter-
mination, University of Go¨ttingen, Germany, 1986.
(55) Sheldrick, G. M. SHELXL-92 Program for crystal structure refine-
ment, Gamma test version, University of Go¨ttingen, Germany, 1992.
(56) Sheldrick, G. M. SHELXL-97-2 Program for crystal structure
refinement, University of Go¨ttingen, Germany, 1997.
X-ray Crystal Structure Analyses of 12, 13, and 27. (R)-2-Chloro-
2-oxo-5,5-dimethyl-4-(R)-phenyl-1,3,2-dioxaphosphorinane [(S)-27]
was prepared as described above for (S)-11 using the PCl5 method and
was crystallized several times from diethyl ether at -20 °C.

3150 J. Am. Chem. Soc., Vol. 122, No. 13, 2000
Hulst et al.
hydrogen of 13, which was located on a difference Fourier map and
freely refined. All hydrogen atoms of 27 were freely refined. The
hydrogen atoms of 12 and 13 were refined with a fixed isotropic
displacement parameter related to the value of the equivalent isotropic
displacement parameter of their carrier atoms; the hydrogen displace-
ment parameters of 27 were freely refined. The absolute configuration
for all compounds was assigned in accordance with the known
configuration of the asymmetric carbon atoms. For compound 27 a
full Friedel-related data set was collected. A racemic twin refinement
indicated 100% S configuration on C3, after which the twin model was
abandoned. The Flack x parameter57 for the final refinement was -0.01-
(5). The x parameter for the alternative chirality amounted to 1.00(5),
with wR2 ) 0.0640 and R1 ) 0.0245.
Acknowledgment. Mr. K. Dijkstra and Dr. G. Visser are
gratefully acknowledged for their useful contributions. Part of
this work was supported by the council for Chemical Sciences
of The Netherlands Organization for Scientific Research (CW-
NWO) and DSM Research (Geleen, The Netherlands) (A.L.S.,
W.J.J.S.).
Supporting Information Available: Further details of the
structure determinations, including coordinates and thermal
parameters, as an X-ray crystallographic file (CIF) and as
scanned tables. This material is available free of charge via the
Internet at http://pubs.acs.org.
Neutral atom scattering factors and anomalous dispersion corrections
were taken from the International Tables for Crystallography.58
Geometrical calculations and illustrations were performed with PLA-
TON;59 all calculations were performed on a DEC Alpha 255 station.
JA992770K
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