Strategies for the asymmetric synthesis of H-phosphinate esters

Article abstract of DOI:10.1039/c0ob00415d

Access to P-chiral H-phosphinates via desymmetrization of hypophosphite esters was investigated. The use of chiral auxiliaries, chiral catalysts, and of a bulky prochiral group that could lead to kinetic resolution was explored. A chiral NMR assay for enantiomeric excess determination of H-phosphinates was developed. An asymmetric route to C-chiral H-phosphinates is also examined and an assay was developed.

Full text of DOI:10.1039/c0ob00415d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Strategies for the asymmetric synthesis of H-phosphinate esters†
Karla Bravo-Altamirano, Lae¨titia Coudray,
Eric L. Deal and Jean-Luc Montchamp*
Received 12th July 2010, Accepted 6th September 2010
DOI: 10.1039/c0ob00415d
Access to P-chiral H-phosphinates via desymmetrization of hypophosphite esters was investigated. The
use of chiral auxiliaries, chiral catalysts, and of a bulky prochiral group that could lead to kinetic
resolution was explored. A chiral NMR assay for enantiomeric excess determination of
H-phosphinates was developed. An asymmetric route to C-chiral H-phosphinates is also examined and
an assay was developed.
H-phosphinates.5g Herein, we report a study of the impact of
Introduction
chiral auxiliaries and chiral catalysts in the desymmetrization
of tetrahedral hypophosphite esters [ROP(O)H2] via C–P bond-
formation processes (Scheme 1). An example where a bulky
prochiral group is used as a strategy toward kinetic resolution at
the P-stereocenter is illustrated.21 Finally, a catalytic asymmetric
benzylation of H3PO2 is discussed as a representative approach to
C-chiral organophosphorus compounds.17m
Among the most common methods to prepare P-stereogenic
organophosphorus compounds are the classical resolution of race-
mates based on solubility differences of diastereomeric species,1
the enantioselective syntheses reported by Juge,2 Brown3 and
Corey4 that rely on stereospecific displacements at the phosphorus
stereocenter in cyclic, ephedrine- and camphor-based structures
that allow the prediction and control of the streochemical
outcome, as well as the highly substrate-specific enzymatic reso-
lution processes with lipases and esterases.5 Recently, moderate
success has been reported in emerging methodologies for the
preparation of P-chiral organophosphorus compounds,6,7 such
as the asymmetric catalytic synthesis of tertiary P-chiral phos-
phines and phosphine-boranes through alkylation,8 arylation9
and hydrophosphination reactions.10 Besides these new catalytic
approaches, two of the most effective synthetic routes to chiral
tertiary phosphines are the Evans enantioselective deprotonation
of prochiral dimethylphosphine boranes and sulfides with alkyl-
lithium complexes of (-)-sparteine11 or (+)-sparteine surrogates,12
and the Livinghouse dynamic resolution of a lithiated secondary
phosphine borane with (-)-sparteine.13 However, no success has
yet been observed in differentiating the two hydrogen atoms in
primary phosphines.14 Lebel and Imamoto reported failure in
desymmetrizing primary phosphine boranes via deprotonation–
alkylation under phase-transfer catalysis15 or using an n-BuLi/(-)-
sparteine complex,16 respectively. Over the past several years, our
group has established a series of methods for the preparation
of H-phosphinates17 and their hypophosphite esters precursors,18
emphasizing in particular the versatility of H-phosphinates as
intermediates in the preparation of a broad range of organophos-
phorus compounds. We therefore envisioned the development of
new routes to access P-stereogenic H-phosphinates.
Scheme 1 Strategies for desymmetrizing hypophosphite esters.
Results and discussion
Chiral auxiliaries
Asymmetric induction via the use of chiral auxiliaries is a very
useful strategy in enantioselective synthesis.22 Our initial aim was
to understand the basis for transferring asymmetric information
from the remote alkoxy substituent in hypophosphite esters.
Because of the tetrahedral nature of these compounds, and
considering that most of the chiral auxiliaries in asymmetric
synthesis have been specifically designed to differentiate between
the two faces of a plane but not quadrants in a volume (or
geometrically speaking, distinguishing the faces of at least two
planes simultaneously), we anticipated facing a rather different
and difficult scenario.
Hypophosphite esters 1 were prepared via three different
esterification methods using enantiomerically pure or racemic
chiral alcohols: (a) Method A: pivaloyl chloride-mediated
esterification,17c,18b,23 (b) Method B: transesterification with phenyl
hypophosphite – itself prepared by in situ reaction of tetraphenyl
orthosilicate with hypophosphorous acid,17b–c and (c) Method C:
Dean–Stark esterification with hypophosphorous acid.24 Once
31P NMR analysis of the crude reaction mixture indicated the
generation of the desired ester 1, a C–P bond-forming reaction
was performed in situ to afford the expected H-phosphinate ester
2 as a mixture of diastereomers. 31P NMR analysis allows the
direct determination of diastereomeric excesses (de’s) regardless
Since the classical resolution of menthyl H-phosphinates dis-
covered by Mislow forty years ago,19 only a few resolution
processes for the synthesis of optically pure H-phosphinates
have appeared in the literature, such as the optical resolution–
esterification of an a-hydroxy-H-phosphinic acid with a chiral
amine,20 and the lipase-catalyzed hydrolysis of racemic a-acetoxy-
Department of Chemistry, TCU Box 298860, Texas Christian University,
Fort Worth, TX, 76129, USA. E-mail: j.montchamp@tcu.edu; Fax: +1 817
257 5851; Tel: +1 817 257 6201
† Electronic supplementary information (ESI) available: Additional exper-
imental procedures and spectral data. See DOI: 10.1039/c0ob00415d
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of whether racemic or enantioenriched chiral alcohols are used
(Scheme 2). Certainly, for actual application to asymmetric synthe-
sis, enantiopure auxiliaries are required (unless the separation of
the diastereoisomeric products is straightforward). It is important
to note that in addition to an efficient esterification, good yields of
H-phosphinate products and high de’s are all required to constitute
a successful scalemic synthesis of the target molecules.
reactions proved to be better than the Pd-catalyzed hydrophos-
phinylation, both in terms of chemical yields and de’s.17d Although
still modest (Table 1, entry 12b), a 71% de supports the feasibility
of using chiral auxiliaries to promote the desymmetrization of
tetrahedral hypophosphite esters. However, auxiliaries that have
been traditionally used for enantiofacial differentiation do not
appear to be appropriate for our purpose.
Chiral catalysts
In a different approach toward P-chiral H-phosphinate esters,
we aimed to develop asymmetric variants of our Pd-catalyzed
cross-coupling17j and hydrophosphinylation reactions.17d At this
stage, HPLC conditions to measure directly the enantiomeric
excesses (ee’s) of H-phosphinates had to be identified since prior
resolution attempts have been reported as unsuccessful by other
groups.34 With this in mind, and in order to facilitate the analysis,
we focused initially on the synthesis and resolution of substrates
bearing aryl groups that could favor p–p stacking interactions.
Previous mechanistic studies of our Pd-catalyzed cross-coupling
with aryl electrophiles suggested that aryl iodides might be the
only substrates capable of undergoing a direct cross-coupling
with hypophosphite esters, which is the minimum requirement
for the development of an asymmetric version of this reaction.17j
Nonetheless, we chose to evaluate (and compare) the reactions
of aryl iodides and bromides with anilinium hypophosphite using
an aminosilicate (which acts as both the esterifying agent and the
base) in the presence of PdCl2 or Pd(OAc)2 and (R)-BINAP as a
ligand (eqn (1)). Other ligands, such as Josiphos and Walphos-type
led to sluggish reactions.
Scheme 2 P-Chiral H-phosphinates via chiral auxiliaries.
The notorious efficacy and broad tolerance of experimental
conditions in the Pd-catalyzed hydrophosphinylation (addition
of hypophosphite esters across unsaturated substrates)17d led us
to initially choose this reaction as the model study to evaluate
the effectiveness of a variety of chiral alcohols as auxiliaries.
The alcohols were either commercially available or synthesized
through known protocols, and used in stoichiometric amounts
for the preparation of the corresponding hypophosphite esters,
which in turn were reacted with an alkene using Pd/xantphos
(2 mol%). Acetonitrile proved to be the best solvent. The results
are summarized in Table 1. In general, esterification methods A
and B were, not only the most effective, but also complementary
for the preparation of hypophosphite intermediates. As observed
in Table 1, only a few of the alcohols screened in this study
could induce the desymmetrization of 1 with moderate de’s. (-)-
8-Phenylmenthol (entry 12)25 led to products with the highest
de’s of 66% and 71% in the hydrophosphinylation reaction with
1-octene and the highly reactive 2-bromostyrene, respectively.
Naphthyl analogs of (-)-8-phenylmenthol (entries 13 and 14)26
did not provide satisfactory results. Other auxiliaries, such as 1,1,2-
triphenyl-1,2-ethanediol 2-acetate,27 quinic acid derivatives,28 and
ferrocenyl-based alcohols,29 were screened but they did not lead
to an effective formation of hypophosphite esters. Furthermore,
hypophosphite esters derived from some alcohols simply did not
undergo efficient hydrophosphinylation (i.e. ephedrine,27 pseu-
doephedrine derivatives,30 isoborneol-based sulfonamides27 and
phosphonate-based cyclohexanols31). Intrigued by the prospect
of desymmetrizing hypophosphorous amides (R2NP(O)H2) which
could offer conformational rigidity, we also attempted their
synthesis, but were unable to reproduce the single literature report
that describes the synthesis of such species using glycine.32
(1)
Various chiral stationary phases were screened for the res-
olution of racemic ethyl phenyl-H-phosphinate. It was found
R
that WHELK-01 from Regisꢀ Technologies worked effectively,
contrary to various carbohydrate-based chiral columns. However,
in order to alleviate the need for an aryl group within the
molecule for a successful HPLC resolution, and to ease ee
determination over a broad substrate scope, we opted to develop a
31P-NMR assay instead. Toward this end, H-phosphinates were
oxidized with carbon tetrachloride in the presence of a chiral
secondary amine under Atherton–Todd conditions.35 (S)-(-)-(a)-
Methylbenzylamine provided the best results in terms of yields,
reproducibility, and cost (eqn (2)).
We therefore turned our attention to assess the effects of
simplifying the structure of the costly (-)-8-phenylmenthol, in
order to facilitate further screening and structural modification.
This was done by preparing racemic 2-substituted cyclic alcohols
in a single epoxide-opening step with benzylic anions (Table 2).33
The 3,5-bis(isopropyl)phenyl-derived cyclohexanol (entry 2) was
less successful than the one bearing a phenyl group (entry 1).33a
Next, the top two auxiliaries were evaluated in desymmetrizing
hypophosphite esters through various other C–P bond-forming
reactions (Table 3). Base-promoted alkylations17n and free radical-
mediated reactions17f–g required the use of esterification Method
C. Unfortunately, none of the other tested C–P bond forming
(2)
With the assay in hand, a substrate screening was performed
in the Pd-catalyzed cross-coupling reaction. The best results were
obtained with 1-bromo and 1-iodonaphthalene, as well as with
2-methyliodobenzene, which all furnished the product with 15%
ee according to our NMR assay. However, we needed to establish
the stereospecificity of the Atherton–Todd reaction, thus we de-
veloped an HPLC method for the resolution of ethyl (1-naphthyl)-
H-phosphinate. The latter compound was prepared through the
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Table 1 Screening of chiral auxiliaries for the desymmetrization of 1
1
2
Yields (%)
Entry
R*OH
Method
Yield (%)a
Alkeneb
NMRa (isolated)
dec (%)
1
2
3
Fenchyl alcohol
(+)-Isopinocampheol
Isoborneol
A
A
B
77
66
68
3a
3a
3a
100
100
18
20
34
5
4
A
100
3a
30
41
5
6
A
B
93
95
3a
3c
100
94
24
26
B
100
3b
100
0
d
7
8
A
92
3a
0
—
A
B
100
100
91
3a
3a
3a
10
100
0
13
36e
—
9
10
A
11
(-)-Menthol
B
100
3a
100
18
12a
12b
12c
A
B
B
100
94
94
3a
3c
3d
100 (100)
67 (57)
88f
66
71
46
13g
B
B
60
3a
traces
—
—
14g
0
—
—
a By 31P NMR. b Reactions with 3a, 3b and 3d were conducted at reflux; reactions with 3c were conducted at rt. c Based on the difference in heights
and/or integrals in the 31P NMR spectrum of the crude. d Ester hydrolysis takes place. e Mixture of cis/trans isomers (17/83), as in the alcohol precursor.
f Mixture of linear/branched isomers. g Np = 2-naphthyl.
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Table 2 Screening of racemic, 2-substituted cyclic alcohols as auxiliaries for the desymmetrization of 1
1
2
Yields (%)
Entry
R*OH
Method
B
Yield (%)a
100
Alkeneb
NMRa (isolated)
dec (%)
1a
1b
3a
3c
100 (93)
43
55
59
2
B
100
3a
100 (66)
48
3
4
B
B
64
65
3a
3a
90
76
26
5
5
6
A
B
67
59
3a
3a
64
59
18
7
B
66
3a
66
11
a By 31P NMR. b Reactions with 3a were conducted at reflux; reactions with 3c were conducted at rt. c Based on the difference in heights and/or integrals
in the 31P NMR spectrum of the crude mixture.
cross-coupling of 1-bromonaphthalene with a hypophosphorous
acid derivative, using either racemic- or (R)-BINAP as ligand. A
good match was obtained between both measurements (de = ee),
thus validating our NMR assay (Scheme 3). This is also supported
by studies from other groups that have demonstrated complete
inversion of configuration at the phosphorus stereocenter in
similar transformations.36 The present finding was therefore a key
step toward our ultimate goal of developing asymmetric catalytic
synthesis of H-phosphinates since a simple and reliable assay was
needed.
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Table 3 Effect of chiral auxiliaries in the desymmetrization of hypophosphite esters via different C–P bond forming reactions
1
2
Yields (%)a
Entry
1a
R*OH
Method (yield (%))a
A (100)
Reactionb
a
Reagent
PhI
Product
NMR (isol)c
de (%)d
11
71 (63)
1b
1c
B (100)
C (83)
b
c
20
38
30
e
—
2a
B (100)
b
37
53
2b
2c
b
d
74 (69)
0
38
—
2d
af
0
—
2e
2f
C (90)
c
e
f
68
33
42
21
49
2g
MeI
MeI
100 (53)
2h
g
72
11
a By 31P NMR. b a: Et3N, 2 mol% Pd(OAc)2/dppp, CH3CN, reflux; b: 1,1,3,3-Tetramethylguanidine (TMG) or iPr2NEt, CH3CN, rt; c: Et3B,
cyclohexane:CH3CN (1 : 1), rt; d: 4 mol% NiCl2, CH3CN, reflux; e: AIBN, cyclohexane:CH3CN (1 : 1), reflux; f: n-BuLi, cyclohexane:THF (1 : 1),
-78 ◦C to rt; g: n-BuLi/(-)-sparteine, cyclohexane:THF (1 : 1), -78 ◦C to rt. c isol = isolated. d Based on the difference in heights and/or integrals in the
31P NMR spectrum of the crude. e Inaccurate de determination. f Np = 1-naphthyl.
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Scheme 4 Effect of a prochiral group in the Sharpless asymmetric
dihydroxylation.
Scheme 3 Validation of the 31P NMR assay.
It is worth noting that, in order to attain the desymmetrization
of hypophosphite esters (P-V tautomer: (RO)P(O)H2 and P-III
tautomer: (RO)P(OH)(H)), the enantiodetermining step must
involve the distinction between enantiotopic groups at the tetrahe-
dral P-center, whereas most popular asymmetric transition metal-
catalyzed reactions deal with planar systems.37 This explains, at
least in part, the very low enantioselectivities observed in our
cross-coupling reactions.
Finally, a brief chiral catalyst screening was performed in the
hydrophosphinylation reaction using the NMR assay. The results
(Table 4) are very preliminary. Jacobsen’s ligand provided the best
result in terms of yield and ee using toluene as solvent (entry
1), however the control experiment with an achiral phosphine
catalyst furnished the product with a similarly low ee (entry
7), thereby indicating that an ee determination below 10% is
inaccurate. Furthermore, even PdCl2 in the absence of added ligand
was found to still catalyze the reaction in 77% yield (entry 8a). This
implies that in order to achieve an enantioselective process, this
racemic pathway must be completely suppressed. Furthermore,
the reactivity of the preformed Pd-Jacobsen chiral complex38
varied from the presumably in situ formed complex (entry 1a vs.
1b), suggesting a role for an achiral palladium species.
(c) C-Chiral H-phosphinic acids: asymmetric benzylation. One
last approach toward chiral H-phosphinate derivatives could
rely on the formation of a chiral carbon atom using more
traditional methods. Access to enantioenriched H-phosphinic
acids via Pd-catalyzed cross-coupling of H3PO2 with (R)-(+)-1-
(2-naphthyl)ethanol (>97% ee)27 was evaluated.17m The benzyla-
tion reaction afforded target product 8 in 77% ee, along with
the byproduct 9 (eqn (3)). The result strongly suggests that a
competing b-hydrogen elimination-hydrophosphinylation process
is also involved.
(3)
A control reaction with 2-vinylnaphthalene was thus conducted
leading to a mixture of racemic 8 and compound 9 (8/9 =
78/22, eqn (4)), which clearly indicates that significant asymmetric
induction is observed when starting from the alcohol, perhaps
via the undissociated alkene.42 Once again, a 31P-NMR assay was
employed to measure the enantiomeric excess. This time, treatment
of the H-phosphinic acids with (R)-(+)-(a)-methylbenzylamine
resulted in the formation of diastereomeric salts which could be
quantified directly. Overall, this result is comparable or better
to that reported in other asymmetric reactions with benzylic
electrophiles.43 The absolute configuration was assigned based on
the catalytic oxidation44 of 8 to the known phosphonic acid and
comparison of optical rotations.
Other approaches
(a) P-Chiral hypophosphite esters: kinetic resolution. In prin-
ciple, combining a racemic P-chiral hypophosphite ester (through
the use of a racemic auxiliary) with a chiral metal catalyst could
lead to catalytic desymmetrization through kinetic resolution.
However, since the results obtained with auxiliaries were, at best,
modestly successful (Tables 1–3), and those obtained with ligands
(Table 4) were poor, this approach was not pursued.
(4)
(b) P-Chiral H-phosphinate esters: kinetic resolution. Instead
of resolving P-chiral H-phosphinate esters (such as menthyl
phenyl-H-phosphinate), an alternative strategy toward P-chiral
H-phosphinates could be the kinetic resolution of a protected H-
phosphinate. For example, kinetic resolution of the bulky acetal
521 was attempted via Sharpless’ asymmetric dihydroxylation
(Scheme 4).39 Unfortunately, no resolution took place and 6 was
isolated in a 1/1 diastereomeric ratio (dr), that after acid hydrolysis
delivered diol 7 in 59% ee. The absolute configuration was assigned
based on the Sharpless–Corey models40 and the ee was determined
via 31P NMR analysis of a diastereomeric salt with quinine. This
approach, even if it were successful, would be much less desirable
than the desymmetrization of hypophosphorous esters.
Conclusions
The desymmetrization of hypophosphorous esters was investi-
gated using various strategies. With a few very rare exceptions,37
the desymmetrization of comparable tetrahedral species has
never been successful. Our best outcome was achieved through
8-phenylmenthol as a chiral auxiliary (~70% de). A general
31P-NMR assay was developed to determine enantiomeric ex-
cesses on H-phosphinates, and this was validated through chiral
HPLC. Much work remains to be done in order to achieve the
desymmetrization of hypophosphorous esters, either through a
chiral auxiliary, through reaction with a chiral catalyst, or a
combination of both. A truly general and practical synthesis of
H-phosphinate esters which does not rely on classical resolution
of diastereoisomers, remains elusive but one of the most im-
portant goals of asymmetric organophosphorus chemistry. Since
An elegant solution was recently reported by Zhao and
coworkers through the use of an organocatalytic asymmetric aldol
reaction.41 However, the resulting diastereoisomers still require
separation.
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Table 4 Screening of ligands for the Pd-catalyzed asymmetric hydrophosphinylation
Entry
PdCl2/ligand or complexa
Catalyst, mol% Pd
Solvent
NMR yield (%)
4 ee (%)b
1a
1b
1c
PdCl2/(R,R)-Jacobsen
Pd.(R,R)-Jacobsend
Pd.(R,R)-Jacobsend
3
2
2
toluene
toluene
CH3CN
100
0
20
13c
—
9
2a
2b
PdCl2/
2
toluene
CH3CN
13
24
4
17
3a
3b
toluene
CH3CN
81
47
0
0
0
2
2
2
PdCl2/SALEN
4a
4b
toluene
CH3CN
97
42
PdCl2/Phthalocyanine
PdCl2/meso-tetraphenylporphine
5a
5b
toluene
CH3CN
89
50
6
7
PdCl2/(R)-BINOL
PdCl2(dppf).MeLi
2
2
toluene
toluene
89
100
9
7
8a
8b
toluene
CH3CN
77
30
0
2
PdCl2/no ligand
a Unless otherwise specified, the chiral catalyst was prepared in situ: PdCl2/ligand, 1/1. b Determined as “de” by 31P NMR assay. c HPLC resolution with
(S,S)-WHELK-01 column/UV detector was unsuccessful. d Complex was preformed according to ref. 38.
H-phosphinates are nearly ideal, synthetically flexible, functional
groups in phosphorus chemistry, this objective is of paramount
importance. One problem which was identified in the present
studies is the conformational control in hypophosphorous esters.
Since the C–O–P arrangement is conformationally flexible, some
sort of restriction will be necessary. Perhaps the design of a
conformationally rigid auxiliary will be the answer. A possibility
which has not been investigated is to introduce a rationally-
designed metal-binding ligand into the auxiliary itself. This,
and other approaches will be investigated in the near future.
Ours and other groups’ efforts clearly demonstrate that the
desymmetrization of compounds containing a PH2 group remains
a Holy Grail in organophosphorus chemistry.45
HPLC or reagent grade solvents were purchased from Aldrich and
used as received. THF was distilled from sodium benzophenone
ketyl. CH3CN was distilled from CaH2, and used immediately.
Et3N and iPr2NEt were distilled from CaH2 and stored over
˚
4 A molecular sieves. Catalysts and ligands were commonly
purchased from Aldrich or Strem Chemicals. Analytical thin
layer chromatography (TLC) was performed on SiO2 60 F-254
plates. Visualization was accomplished by UV irradiation at
254 nm and/or by staining with para-anisaldehyde or KMnO4
solution. Flash column chromatography was performed using
SiO2 60 (particle size 0.040–0.055 mm, 230–400 mesh). Radial
chromatography was carried out using 2 or 4 mm layers of silica
gel 60 PF254 containing gypsum. Proton, carbon and phosphorus
NMR spectra were recorded at 300 MHz/150 MHz/121 MHz
(1H NMR/13C NMR/31P NMR). Chemical shifts are reported as
d values in parts per million (ppm) as referenced to: (a) internal
standard (1H NMR, Me4Si, d = 0.00 ppm), (b) residual solvent
(13C NMR, CDCl3, d = 77.0 ppm), and (c) external standard (31P
NMR, 85% H3PO4, d = 0.00 ppm). 1H NMR spectra are reported
as follows: chemical shift, multiplicity (s = singlet, bs = broad
singlet, d = doublet, dd = doublet of doublets, ddd = doublet of
doublet of doublets, t = triplet, q = quartet, quint. = quintuplet,
sext. = sextuplet, m = multiplet), number of protons, and coupling
constant(s). NMR yields are determined by integration of all the
resonances in the 31P NMR spectra, an approach that is valid if
no phosphorus-containing gas evolves, or if the precipitate in a
heterogeneous mixture does not contain phosphorus. The yields
determined by NMR are generally accurate within ~10% of the
Experimental
General
All reactions were conducted in oven-dried glassware, under
nitrogen. Reactions carried out at a temperature below 0 ◦C
employed a CO2/acetone bath. All reagents and solvents were
used as received unless otherwise specified. Concentrated H3PO2
was obtained by rotary evaporation (0.5 mmHg) of the 50 wt%
aq. solution at rt for 20–30 min before reaction. Caution:
overdrying H3PO2may result in the formation of a yellow solid
of high phosphorus content that could be pyrophoric. Anilinium
hypophosphite and stock solutions of ethyl hypophosphite were
prepared as previously described.17e,18a Unless otherwise specified,
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value indicated, and are reproducible. The validity of the method
has been carefully verified.17c,17e Isolated yields are sometimes
significantly lower because H-phosphinate esters are highly polar
compounds and hydrolytically labile. Chiral HPLC resolutions
were performed with a (S,S)-Whelk-01 Column (250 ¥ 4.6 mm,
was diluted with EtOAc and washed with 2 M aq. HCl (1 ¥),
followed by extraction of the aqueous phase with EtOAc (2 ¥). The
organic fractions were combined and washed with saturated aq.
NaHCO3 (1 ¥) and brine (1 ¥). Drying (MgSO4) and concentration
furnished the crude compound, which was purified by radial or
flash chromatography using hexanes/EtOAc solvent mixtures.
R
5 mm) from Regisꢀ Technologies, which was accompanied
R
with a guard column (Agilent Zorbaxꢀ ODS, 4.6 ¥ 12.5 mm,
Pd-Catalyzed cross-coupling.17j
. To a solution of hypophos-
5 mm), using hexanes/isopropanol mixtures as the mobile phase.
Low resolution mass spectrometry was performed on a Bruker
Esquire 6000, Bruker Daltonics, Inc., ESI. High resolution mass
spectrometry was provided by the Mass Spectrometry Facility of
the University of South Carolina.
phite ester (2.0 mmol, 3.0 equiv) in CH3CN was added an aryl
halide (0.70 mmol, 1.0 equiv), Et3N (0.28 mL, 0.2020 g, 2.0 mmol,
3.0 equiv), Pd(OAc)2 (3.20 mg, 0.0140 mmol, 2.0 mol% Pd) and
dppp (6.40 g, 0.0154 mmol) at rt. The solution was heated at reflux
for 7 h under N2. 31P NMR analysis and workup were performed
as indicated above for the hydrophosphinylation reaction.
Selected experimental procedures
Scheme 2. Esterification methods
Ni-Catalyzed hydrophosphinylation.17e
. To a solution of hy-
Method A: Pivaloyl chloride-mediated esterification.17c,18b,23
. To
pophosphite ester (2.0 mmol, 2.0 equiv) in CH3CN was added
an alkyne (1.0 mmol, 1.0 equiv) and NiCl2 (5.20 mg, 0.040 mmol)
at rt. The solution was heated at reflux for 12 h under N2. 31P
NMR analysis and workup were performed as indicated above for
the hydrophosphinylation reaction.
a suspension of anilinium hypophosphite (0.318 g, 2.0 mmol,
2.0 equiv) in reagent grade CH3CN (12–15 mL), was added
pyridine (0.20 mL, 0.198 g, 2.50 mmol, 2.50 equiv), the corre-
sponding alcohol (3.0 mmol, 3.0 equiv) and pivaloyl chloride
(0.27 mL, 0.265 g, 2.20 mmol, 2.20 equiv) at rt under N2. The
resulting solution was stirred at rt for 2 h. If successful, 31P
NMR monitoring of the reaction mixture shows the appearance
of the expected hypophosphite ester product (with the appropriate
coupling pattern) within the range of 7–20 ppm. The solution is
used in situ for the following reaction.
Nucleophilic addition reactions.18a
. To a solution of hypophos-
phite ester (2.0 mmol, 1.20 equiv) in CH3CN was added a carbonyl-
containing or an a,b-unsaturated substrate (1.70 mmol, 1.0 equiv)
followed by the corresponding base, either iPr2NEt (0.24 mL,
0.220 g, 1.70 mmol, 1.0 equiv) or 1,1,3,3-tetramethylguanidine
(TMG) (0.22 mL, 0.196 g, 1.70 mmol, 1.0 equiv). The reactions
were stirred at rt for 2–4 h uner N2. 31P NMR analysis and workup
were performed as indicated above for the hydrophosphinylation
reaction.
Method B: Transesterification with phenyl hypophosphite.17b–c
.
To a solution of freshly concentrated H3PO2 (0.132 g, 2.0 mmol,
2.0 equiv) in CH3CN (12–15 mL) was added (PhO)4Si46 (0.80 g,
2.0 mmol, 2.0 equiv) and the corresponding alcohol (4.0 mmol,
4.0 equiv). The resulting suspension is heated at reflux for 2 h
under N2. 31P NMR analysis is used to monitor the progress of the
reaction. The appearance of a peak within the range of 7–20 ppm,
with the adequate multiplicity indicates a successful formation of
the alkyl phosphinate product. The suspension is allowed to reach
rt and used in situ for the next reaction. Alternatively, a stock
solution can be prepared and used within a week.
Et3B- and AIBN-mediated radical addition.17f–g
. A 0.40 M
solution of hypophosphite ester (5.0 mL, 2.0 mmol, 3.0 equiv)
in cyclohexane (from Dean–Stark esterification) was diluted with
CH3CN (5.0 mL) followed by addition of an alkene (0.667 mmol,
1.0 equiv) and the corresponding radical initiator. Depending on
the choice of initiator, either conditions (a) or (b) were used,
as follows: (a) AIBN (0.20 equiv) followed by heating at reflux
for 15 h before another addition of AIBN (0.30 equiv) and
heating for another 15 h under N2, or (b) Et3B (0.667 mmol,
1.0 equiv) followed by stirring at rt for 18–24 h under air. 31P
NMR analysis and workup were performed as indicated above for
hydrophosphinylation reaction.
Method C: Dean–Stark esterification.24. (Note: Generally pre-
pared as a stock solution and used immediately or within a week. It
requires storing under N2). A mixture of aq. H3PO2 (1.0 equiv), the
corresponding alcohol (1.50–2.0 equiv) and a drop of concentrated
H2SO4 in reagent grade cyclohexane (0.40 M relative to the amount
of H3PO2) is heated at reflux temperature using a Dean–Stark trap
(prefilled with cyclohexane) for 12–20 h, according to the progress
of the reaction (by 31P NMR analysis).
Base-promoted alkylation.17n
. A 0.40 M solution of hypophos-
phite ester (5.0 mL, 2.0 mmol, 1.50 equiv) in cyclohexane (from
Dean–Stark esterification) was diluted with anhydrous THF
(5.0 mL). An alkyl iodide (1.33 mmol, 1.0 equiv) was added,
followed by dropwise addition of n-BuLi (1.60 M in hexanes,
1.10 mL, 1.73 mmol, 1.30 equiv) or a solution of n-BuLi/(-)-
sparteine (1/1, previously stirred at -78 ◦C for 15 min) at -78 ◦C
under N2. The reaction was allowed to reach rt over a 1.5 h period
followed by 31P NMR analysis. The reaction was quenched with
20% aq. NaHSO4 and extracted with EtOAc (3 x). The combined
organic phase was washed with brine (1 x), dried (MgSO4) and
purified by radial or flash chromatography using hexanes/EtOAc
solvent mixtures.
Tables 1, 2 and 3. General procedures for the desymmetrization of
hypophosphite esters via C–P bond forming reactions
Pd-Catalyzed hydrophosphinylation.17d
. To a solution of hy-
pophosphite ester (2.0 mmol, 2.0 equiv) in CH3CN was added
an alkene (1.0 mmol, 1.0 equiv), Pd2dba3 (9.20 mg, 0.010 mmol,
2.0 mol% Pd) and xantphos (127.0 mg, 0.0220 mmol) at rt. The
solution was heated at reflux for 7–14 h, or stirred at room
temperature for 30–60 h under N2. After cooling to rt, 31P NMR
analysis was used to determine the diastereomeric excess (de). The
workup of the reaction was performed as follows: the mixture
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Tables 1 and 2. Representative procedure for the desymmetrization
of hypophosphite esters via Pd-catalyzed hydrophosphinylation
14.3; 31P NMR (CDCl3, 121.47 MHz) d 39.23 (dm, JPH = 530 Hz),
33.41 (dm, JPH = 524 Hz).
2-(2-(3,5-diisopropylphenyl)propan-2-yl)cyclohexyl
octyl-
Preparation
of
(1R,2S,5R)-5-methyl-2-(1-methyl-1-
1
phosphinate (Table 2, entry 2). Mixture of isomers. H NMR
(CDCl3, 300 MHz) d 7.07 (s, 2 H), 7.05 (d, JHP = 521 Hz, 1 H),
6.92 (s, 1 H), 4.15–4.25 (m, 1 H), 2.87 (dq, J = 7 Hz, 7 Hz, 2 H),
2.2–0.8 (m, 23 H), 1.44 (s, 3 H), 1.29 (s, 3 H), 1.24 (d, J = 7 Hz,
12 H), 0.88 (t, J = 7 Hz, 3 H); 31P NMR (CDCl3, 121.47 MHz) d
39.22 (dm, JPH = 525 Hz), 33.75 (dm, JPH = 524 Hz).
phenylethyl)cyclohexyl (2-(2-bromo-phenyl)-ethyl) phosphinate
(Table 1, entry 12b). To a solution of concentrated H3PO2
(0.132 g, 2.0 mmol, 2.0 equiv) in CH3CN (15.0 mL) was added
(PhO)4Si43 (0.800 g, 2 mmol, 2.0 equiv) and (-)-8-phenylmenthol25
(0.930 g, 4.0 mmol, 4.0 equiv). The reaction was heated at reflux
for 2 h under N2 and then cooled down to rt. 2-Bromostyrene
(0.13 mL, 0.183 g, 1.0 mmol, 1.0 equiv), Pd2dba3 (9.20 mg,
0.010 mmol) and xantphos (127.0 mg, 0.0220 mmol) were added
and the reaction was stirred at rt for 50 h. The reaction was
diluted with EtOAc and washed with 2 M aq. HCl (1 ¥). The
aqueous layer was extracted with EtOAc (2 x) and the combined
organic phase was washed with saturated aq. NaHCO3 (1 ¥) and
brine (1 ¥), dried (MgSO4), and concentrated to give the crude
product. Purification by radial chromatography (2 mm thickness,
hexanes/EtOAc, 5/1, v/v to EtOAc, 100%) furnished the title
product as a clear oil (0.264 g, 57% yield) with a 71% de according
Table 3. Representative examples
(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohexyl
phenylphosphinate (Table 3, entry 1a). Mixture of isomers
(RP/SP). 1H NMR (CDCl3, 300 MHz) d 7.63 (d, JHP = 551 Hz, 1
H), 7.26 (d, JHP = 564 Hz, 1 H), 6.93–7.61 (m, 20 H), 4.44–4.62 (m,
2 H), 1.02–2.32 (m, 28 H), 0.78–0.96 (m, 6 H); 13C NMR (CDCl3,
75.45 MHz) d 151.8, 151.6, 133.9 (d, JPC = 119 Hz), 132.0 (d, JPC
119 Hz), 132.8 (m, 2 C), 130.9 (d, JPCC = 12 Hz), 130.6 (d, JPCC
12 Hz), 129.2 (2 C), 128.7 (d, JPCCC = 14 Hz, 2 C), 128.6 (d, JPCCC
=
=
=
1
to 31P NMR analysis as a mixture of isomers (RP/SP). H NMR
14 Hz, 2 C), 128.2 (2 C), 127.9 (2 C), 125.7, 125.6, 125.4 (2 C),
124.4, 120.2, 78.9 (d, JPOC = 7 Hz), 78.3 (d, JPOC = 7 Hz), 52.3 (d,
JPOCC = 6 Hz), 52.1 (d, JPOCC = 6 Hz), 44.8, 42.6, 40.3, 40.2, 34.6,
31.7, 28.3, 27.9 (2 C), 27.4, 27.1, 26.9, 26.1, 25.8, 22.0, 21.9; 31P
NMR (CDCl3, 121.47 MHz) d 24.17 (dm, JPH = 564 Hz), 19.34
(dm, JPH = 551 Hz); HRMS (CI) m/z calcd. for C22H29O2P (M +
H)+, 357.1983, found 357.1979.
(CDCl3, 300 MHz) d 7.07 (ddd, JHP = 527 Hz, J = 2, 1 Hz, 1
H), 7.02–7.56 (m, 18 H), 6.80 (dt, JHP = 537 Hz, J = 2 Hz, 1
H), 4.38–4.53 (m, 1 H), 4.19–4.32 (m, 1 H), 3.45–3.61 (m, 2 H),
2.51–2.85 (m, 2 H), 2.0–2.15 (m, 4 H), 0.81–1.89 (m, 34 H); 13C
NMR (CDCl3, 75.45 MHz) d 151.7, 139.6, 133.2, 130.4, 128.6
(d, JPCCC = 14 Hz), 128.1 (2 C), 127.8, 126.0, 125.8 (2 C), 125.2,
77.4 (d, JPOC = 8 Hz), 51.8 (d, JPOCC = 7 Hz), 45.5, 41.9, 40.0,
34.6, 31.5, 28.0, 27.9 (d, JPC = 95 Hz), 26.7, 25.0, 22.0; 31P NMR
(CDCl3, 121.47 MHz) d 36.91 (dm, JPH = 537 Hz), 31.09 (dm,
JPH = 527 Hz); HRMS (APCI) m/z calcd. for C24H32BrO2P (M +
H)+, 463.1401, found 463.1412.
2-(1-Methyl-1-phenylethyl)cyclohexyl (2-cyanoethyl) phosphi-
nate (Table 3, entry 2b). Mixture of isomers. 1H NMR (CDCl3,
300 MHz) d 7.25–7.41 (m, 8 H), 7.14–7.24 (m, 2 H), 7.10 (ddd,
JHP = 539 Hz, J = 4, 1 Hz, 1 H), 6.83 (dd, JHP = 553 Hz, J = 1 Hz,
1 H), 4.34–4.48 (m, 1 H), 4.13–4.29 (m, 1 H), 2.07–2.38 (m, 8 H),
1.69–2.02 (m, 6 H), 1.08–1.64 (m, 24 H); 31P NMR (CDCl3, 121.47
MHz) d 31.32 (dm, JPH = 553 Hz), 25.0 (dm, JPH = 539 Hz).
(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohexyl
octylphosphinate (Table 1, entry 12a). Mixture of isomers
(RP/SP). 1H NMR (CDCl3, 300 MHz) d 7.22–7.41 (m, 8 H), 7.07–
7.17 (m, 2 H), 7.02 (d, JHP = 519 Hz, 1 H), 6.64 (d, JHP = 528 Hz,
1 H), 4.35–4.5 (m, 1 H), 4.12–4.3 (m, 1 H), 1.97–2.3 (m, 4 H),
1.58–1.81 (m, 4 H), 1.0–1.57 (m, 44 H), 0.78–1.0 (m, 16 H); 13C
NMR (CDCl3, 75.45 MHz) d 152.5, 151.9, 128.1, 128.0, 125.7,
125.5, 125.3, 125.1, 79.0 (d, JPOC = 7 Hz), 78.4 (d, JPOC = 7 Hz),
51.7 (d, JPOCC = 6 Hz), 51.6 (d, JPOCC = 6 Hz), 44.8, 41.8, 39.9, 39.8,
34.6, 31.9, 31.7 (d, JPCC = 11 Hz), 31.5, 30.5 (d, JPCCC = 16 Hz),
29.9, 30.2 (d, JPCCC = 15 Hz), 29.3 (d, JPC = 94 Hz), 29.2, 28.3, 28.2
(d, JPC = 96 Hz), 26.6, 24.9, 24.6, 22.8, 22.0, 21.9, 21.0, 20.4, 14.3;
31P NMR (CDCl3, 121.47 MHz) d 39.36 (dm, JPH = 528 Hz), 33.55
(dm, JPH = 519 Hz); HRMS (CI) m/z calcd. for C24H41O2P (M +
H)+, 393.2922, found 393.2916.
2-(1-Methyl-1-phenylethyl)cyclohexyl octylphosphinate (Table 3,
entry 2e). Mixture of isomers. 31P NMR (CDCl3, 121.47 MHz)
d 39.23 (dm, JPH = 530 Hz), 33.41 (dd, JPH = 524 Hz, J = 6 Hz).
Two other unidentified products: d 44.79 (dm, JPH = 379 Hz, 16%),
32.13 (dm, JPH = 556 Hz, 9%).
2-(1-Methyl-1-phenylethyl)cyclohexyl methylphosphinate (Ta-
ble 3, entry 2 g). 1H NMR (CDCl3, 300 MHz) d 7.22–7.38 (m, 8
H), 7.16 (dq, JHP = 532 Hz, J = 2 Hz, 1 H), 7.07–7.17 (m, 2 H), 6.89
(dq, JHP = 537 Hz, J = 2 Hz, 1 H), 4.30–4.44 (m, 1 H), 4.07–4.23
(m, 1 H), 2.08–2.32 (m, 4 H), 1.62–1.87 (m, 6 H), 1.32–1.59 (m, 8
H), 1.18–1.30 (m, 10 H), 0.96–1.06 (m, 8 H); 31P NMR (CDCl3,
121.47 MHz) d 34.51 (ddd, JPH = 537 Hz, J = 15, 10 Hz), 27.55
(ddd, JPH = 532 Hz, J = 16, 7 Hz).
2-(1-Methyl-1-phenylethyl)cyclohexyl octylphosphinate (Table 2,
1
entry 1a). Mixture of isomers. H NMR (CDCl3, 300 MHz) d
Scheme 3. Validation of the 31P NMR assay
7.22–7.43 (m, 8 H), 7.07–7.19 (m, 2 H), 7.0 (d, JHP = 524 Hz, 1 H),
6.76 (d, JHP = 530 Hz, 1 H), 4.30–4.47 (m, 1 H), 4.07–4.28 (m, 1 H),
1.99–2.19 (m, 4 H), 1.59–1.82 (m, 6 H), 0.98–1.50 (m, 48 H), 0.89
(t, J = 7 Hz, 6 H); 13C NMR (CDCl3, 75.45 MHz) d 152.5, 151.9,
128.6, 128.1, 128.0, 126.0, 125.8, 125.5, 125.3, 125.1, 79.5, 77.8,
77.4 (d, JPOC = 9 Hz), 76.9, 54.8, 52.2 (d, JPOCC = 6 Hz), 40.1, 37.0,
36.3, 33.5, 32.1, 32.0 (d, JPCC = 11 Hz), 30.5 (d, JPCCC = 17 Hz),
29.9, 29.7 (d, JPCCC = 16 Hz), 29.3, 29.2, 28.6, 28.4, 28.2 (d, JPC = 96
Hz), 27.1, 26.5, 26.0, 25.9, 25.3, 24.8, 24.7, 24.5, 22.9, 21.0, 20.5,
(a) Synthesis of ethyl (1-naphthyl) phosphinate. To a suspen-
sion of anilinium hypophosphite (0.382 g, 2.40 mmol, 1.20 equiv)
and 3-aminopropyltriethoxysilane (0.531 g. 2.40 mmol, 1.20 equiv)
in CH3CN (12.0 ml) was added 1-bromonaphthalene (0.28 mL,
0.414 g, 2.0 mmol), Pd(OAc)2 (9.0 mg, 0.040 mmol, 2 mol%
Pd) and either racemic BINAP or (R)-BINAP (28.8 mg, 0.044
mmol). The reaction mixture was heated at reflux for 8 h under
N2. After cooling to rt, 31P NMR analysis showed the product at
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~28 ppm (100%, doublet). The mixture was diluted with EtOAc
and washed with aq. HCl (2 M). The aqueous phase was extracted
with EtOAc (3 ¥) and the combined organic phase was washed
with saturated aq. NaHCO3 (1 ¥) and brine (1 ¥), dried (MgSO4)
and concentrated to afford the pure title product (0.431 g, 98%
yield). 1H NMR (CDCl3, 300 MHz) d 8.43 (d, J = 8 Hz, 1 H), 8.09
(dd, J = 7, 1 Hz, 1 H), 8.07 (d, J = 7 Hz, 1 H), 7.94 (d, JHP = 563 Hz,
1 H), 7.93 (d, J = 8 Hz, 1 H), 7.75–7.89 (m, 1 H), 7.48–7.69 (m, 2
H), 4.05–4.29 (m, 2 H), 1.37 (t, J = 7 Hz, 3 H); 31P NMR (CDCl3,
121.47 MHz) d 26.76 (dm, JPH = 563 Hz).
Table 4, entry 1a. Representative procedure for the
hydrophosphinylation - enantiopurity determination
To a freshly prepared 0.50 M solution of EtOP(O)H218a in toluene
(4.0 mL, 2.0 mmol) was added 1-octene (0.16 mL, 0.114 g, 1.016
mmol), PdCl2 (5.32 mg, 0.030 mmol, 3 mol% Pd) and (R,R)-
Jacobsen ligand (16.4 mg, 0.030 mmol) under N2. The reaction
mixture was heated at reflux for 12 h, diluted with EtOAc and
worked up as described in the general procedure to yield the crude
ethyl octyl-H-phosphinate.17g The identity and yield of the product
were determined by 31P NMR (d 40.3 ppm, d, JPH = 526 Hz, 100%
yield). An NMR tube was charged with a solution of the crude
product (20 mg) in CCl4 (1 mL) followed by addition of an excess
of (S)-(-)-(a)-methylbenzylamine at rt. The solution in the NMR
tube was kept at rt for 4 h mixing it occasionally to yield a mixture
of diastereomers in quantitative yield. 31P NMR (CDCl3, 121.47
MHz) d 35.2 (s, height: 126.0); 34.5 (s, height: 97.8); de(= ee) =
13%.
(b) 31P NMR assay validation.
Derivatization with (S)-(-)-(a)-methylbenzylamine/CCl4. To
an NMR tube charged with a solution of ethyl (1-naphthyl)
phosphinate (20 mg) in CCl4 (1 mL) was added an excess of (S)-
(-)-(a)-methylbenzylamine at rt. The solution was kept for 2-4 h at
rt and then analyzed by 31P NMR to determine the corresponding
de (de = ee) by the difference in heights and integrals.
Acknowledgements
From (R)-BINAP. 31P NMR (CDCl3, 121.47 MHz) d 20.94
(s, 60.9%, height: 155.7); 20.53 (s, 39.1%, height: 114.8); ee(heights)
15%. HPLC analysis: ee = 16%; Product1, tR 37.919 min; Product2,
=
We gratefully acknowledge the National Science Foundation
(CHE-0953368) for financial support.
R
tR 46.663 min; conditions: (S,S)-Whelk-01 column (Regisꢀ
Technologies, 250 ¥ 4.6 mm, 5 mm) with guard column (Agilent
Notes and references
-1
R
Zorbaxꢀ ODS, 4.6 ¥ 12.5 mm, 5 mm), 1 mL min (isocratic), rt,
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Synthesis, 1998, 1391–1415; (d) A. Grabulosa, J. Granell and G. Muller,
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hexanes/iPrOH (7/3, v/v).
From racemic BINAP. 31P NMR (CDCl3, 121.47 MHz) d
21.507 (s, height: 104.5); 21.413 (s, height: 110.0); ee(heights) = 2.3%.
HPLC analysis: ee = 1.9%; Product1, tR 29.482 min; Product2,
R
tR 35.995 min; conditions: (S,S)-Whelk-01 Column (Regisꢀ
Technologies, 250 ¥ 4.6 mm, 5 mm) with guard column (Agilent
-1
R
Zorbaxꢀ ODS, 4.6 ¥ 12.5 mm, 5 mm), 1 mL min (isocratic), rt,
hexanes/iPrOH (7/3, v/v).
MS (ESI+) for C12H13O2P, [M
+
H]+ m/z 221.1;
[NpP(O)(OH)(H) + H]+ m/z 193; [NpP(O) + H]+ m/z 175; [Np +
H]+ m/z 129.1 (Np = 1-naphthyl).
Table 4. General procedure for the Pd-catalyzed asymmetric
hydrophosphinylation
Preparation of non-racemic ethyl octyl-H-phosphinate. To a
2 (a) S. Juge, M. Stephan, J. A. Laffitte and J. P. Genet, Tetrahedron Lett.,
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17e,18a
0.50 M solution of EtOP(O)H2
in CH3CN or toluene
(2.0 equiv) was added 1-octene (1.0 equiv) followed by the
appropiate Pd-catalyst (2–3 mol%). In those cases where the Pd-
complex was formed in situ, a 1/1 ratio of PdCl2/ligand was
used. The solution was heated at reflux for 8–12 h under N2.
The mixture was diluted with EtOAc and washed with 2 M aq.
HCl (1 ¥). The aqueous phase was extracted with EtOAc (2 ¥)
and the combined organic phase was washed with saturated aq.
NaHCO3 (1 ¥) and brine (1 ¥), dried (MgSO4) and concentrated
to yield the crude ethyl octyl-H-phosphinate product,17d,17g which
was used without further purification in the 31P NMR assay for
enantiopurity determination. Note: the title product was isolated
by column chromatography (hexanes/EtOAc, 3/1, v/v to EtOAc,
100%) as a colorless oil for identity confirmation.17d,17g 1H NMR
(CDCl3, 300 MHz) d 7.08 (d, J = 526 Hz, 1 H), 4.03–4.23 (m, 2
H), 1.21–1.82 (m, 14 H), 1.37 (t, J = 7 Hz, 3 H), 0.88 (t, J = 7 Hz,
3 H); 31P NMR (CDCl3, 121.47 MHz) d 40.3 (d, JPH = 526 Hz).
4 E. J. Corey, Z. Chen and G. J. Tanoury, J. Am. Chem. Soc., 1993, 115,
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