Hammond Postulate Mirroring Enables Enantiomeric Enrichment of Phosphorus Compounds via Two Thermodynamically Interconnected Sequential Stereoselective Processes

Article abstract of DOI:10.1021/jacs.5b04415

(Figure Presented). The dynamic resolution of tertiary phosphines and phosphine oxides was monitored by NMR spectroscopy. It was found that the stereoselectivity is set during the formation of the diastereomeric alkoxyphosphonium salts (DAPS), such that t

Full text of DOI:10.1021/jacs.5b04415

Article
pubs.acs.org/JACS
Hammond Postulate Mirroring Enables Enantiomeric Enrichment of
Phosphorus Compounds via Two Thermodynamically
Interconnected Sequential Stereoselective Processes
Kamalraj V. Rajendran, Kirill V. Nikitin, and Declan G. Gilheany*
Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland
S
* Supporting Information
ABSTRACT: The dynamic resolution of tertiary phosphines and phosphine oxides was monitored by NMR spectroscopy. It
was found that the stereoselectivity is set during the formation of the diastereomeric alkoxyphosphonium salts (DAPS), such that
their initial diastereomeric excess (de) limits the final enantiomeric excess (ee) of any phosphorus products derived from them.
However, 31P NMR monitoring of the spontaneous thermal decomposition of the DAPS shows consistent diastereomeric self-
enrichment, indicating a higher rate constant for decomposition of the minor diastereomer. This crucial observation was
confirmed by reductive trapping of the unreacted enriched DAPS with lithium tri-sec-butylborohydride (commercially distributed
as L-Selectride reagent) at different time intervals after the start of reaction, which gives progressively higher ee of the phosphine
product with time. It is proposed that the Hammond postulate operates for both formation and decomposition of DAPS
intermediate so that the lower rate of formation and faster subsequent collapse of the minor isomer are thermodynamically
linked. This kinetic enhancement of kinetic resolution furnishes up to 97% ee product.
process starts with energy-equivalent enantiomers and furnishes
two energy-inequivalent (diastereomeric) intermediates or
products. Although this process follows kinetic control, its
selectivity can often be rationalized by the Hammond
postulate.6 Thus, it is common that the more stable
diastereomer is the one that is formed faster. Little is known,
however, about the applicability of this principle in reverse: i.e.,
how selective is the transformation of two diastereomers to
yield the corresponding energy-equivalent enantiomers?
The asymmetric synthesis of P-stereogenic phosphorus
compounds has been a subject of interest for a long time7
and for which many powerful methods have been developed,8
often driven by their application in catalytic asymmetric
synthesis.9 However, despite great progress, successful synthesis
INTRODUCTION
■
Commonly, asymmetric synthesis is achieved by the transfer of
chirality from a chiral source to the required product.1,2 Once a
successful protocol has been established, there are a number of
physical and chemical strategies to further enhance the
outcome, including, e.g., variation of temperature, solvent,
chirality source, and, especially, (re)crystallization.3 Of
particular interest is a superclass of approaches based on
kinetic relationships between the starting material, intermedi-
ates, and products. In these, initially formed stereo-enriched
material is further enriched by a subsequent chemical reaction.
Preeminent among these approaches is classical kinetic
amplification,2 which is commonly applied by coupling an
initial desymmetrization of a suitable starting material with
kinetic resolution of the resulting scalemic mixture, often by the
same chiral reagents.4 Recent examples have shown the power
of this type of methodology.5 A typical kinetic resolution
Received: April 28, 2015
© XXXX American Chemical Society
A
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of a particular compound is not assured, so that only modest
numbers of P-stereogenic catalysts have been studied, being
difficult to synthesize in enantiomerically pure form. Notably,
enrichment strategies such as kinetic amplification have rarely
been applied.10,11
Our interest in this area arises from our recently developed
dynamic kinetic resolution methodology, which allows the
synthesis of a variety of P-stereogenic phosphines, their oxides,
and their boranes (Scheme 1).12 The heart of our process
a racemic mixture (RRM),4c except, of course, that our mixture
is not racemic. Whatever it is to be called, it enables the
synthesis of chiral phosphines/boranes with surplus selectivity,
based on timely intervention in the decomposition reaction.
RESULTS AND DISCUSSION
Identity of the Reaction Intermediates. Chart 1 shows
the set of phosphorus substitution motifs investigated in this
■
a
Chart 1. Compounds Studied in This Work
Scheme 1. Asymmetric Synthesis of P-Stereogenic
a
Phosphorus Compounds
a
HCA = hexachloroacetone; X = pentachloroacetonate or chloride;
a
R* = (−)-menthyl.
CPS = chlorophosphonium salt; DAPS = diastereomeric alkoxyphos-
phonium salt; blue indicates racemic, and red indicates stereoenriched.
work. When mixtures of phosphines 1a−8a and various chiral
secondary alcohols were treated with hexachloroacetone, the
only intermediates observed by 31P NMR spectroscopy were
the derived DAPS (shown in Figure 1 for the case of 1a with
(−)-menthol). The same intermediates were observed by
sequential treatment of phosphine oxides oxo-1a−oxo-8a with
oxalyl chloride followed by the chiral alcohol.
involves the generation of two rapidly interconverting enantio-
meric chlorophosphonium salts (CPS),13 which are then
reacted with chiral non-racemic alcohol to generate unequal
amounts of two diastereomeric alkoxyphosphonium salts
(DAPS). In the absence of further intervention, as the
temperature is increased, the two DAPS species undergo
decomposition chiefly via Arbuzov collapse, to form enantioen-
riched P-stereogenic phosphine oxide.12a,c Alternatively the
DAPS can be intercepted using hydride reagents to give either
scalemic phosphines or phosphine boranes.12d−f Most recently
we have shown that hydrolysis of the DAPS leads to the other
enantiomer of the oxide, thus allowing both enantiomers to be
generated from the same source of chirality.14
In Scheme 1, the selection outcome is set primarily in the
DAPS formation stage, and we found that the n-alkylphenylaryl
motif at phosphorus allowed very high selectivity (up to 97%
de) in that step.14,15 However, in other cases the selectivity is
less, and its enhancement would be desirable. As the two DAPS
in hand are, strictly speaking, two different compounds, it is not
unreasonable to assume that the kinetics of their subsequent
transformations should differ. Therefore, with three such
subsequent reactions being applied to the DAPS, we were
aware that we had good scope for some sort of kinetic
enhancement; it cannot be termed “kinetic resolution” because
of the diastereomeric nature of the DAPS. We now report that
not only the formation but also the decomposition of these
intermediates (the Arbuzov collapse) can be stereoselective and
used to enhance the stereochemical purity of the product. We
term this new phenomenon “kinetic resolution with subsequent
kinetic enhancement” (KR/KE) to distinguish it from classical
kinetic amplification by desymmetrization. It could be
considered to fall into the category of divergent reactions on
The identity of the intermediates in the reaction mixture
from phosphine 1a in toluene at 0 °C was fully confirmed by
detailed NMR characterization (see Supporting Information for
details). This showed it to be a clean combination of (RP)-
DAPS (RP-1d) and (SP)-DAPS (SP-1d) in a ca. 4:1
diastereomeric ratio (62% de) with a small amount of
(−)-menthol. Full assignment of all the peaks in both
diastereomers was carried out with the assistance of 2D
1
1
1H−1H, H−13C, and H−31P correlation spectroscopy and
NOE measurements. Characterization of the DAPS derived
from 7a was carried out in a similar fashion; however, full
assignment of all signals attributable to the minor diastereomers
was not possible owing to the very high diastereomeric excess
(de) in those cases (details are given in the Supporting
Information). As shown in Figure 1, the NMR data for the
major diastereomer of 1d was found to be consistent with its
having the (R)- configuration in agreement with the known
(R)- configuration of the oxo-1a product in this case.12b,16
1
Careful analysis of 2D 31P and H NOE correlations revealed
that no dynamic exchange between the two DAPS RP-1d and
SP-1d takes place on the NMR time scale. This significant
configurational stability of DAPS means that the net stereo-
selectivity of the reaction is set at the stage of DAPS formation.
This was also consistent with our previous measurements of the
enantiomeric excess (ee, by CSP-HPLC) of the oxide obtained
at the end of the Arbusov collapse stage. These had suggested
B
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variety of chiral non-racemic alcohol and phosphine combina-
tions. For these experiments, the DAPS were formed at our
normal reaction temperature of −78 °C, the reaction mixture
was sampled under inert conditions for a 31P NMR measure-
ment 5 min after the start of the reaction and the mixtures were
kept subsequently at room temperature and sampled at various
time intervals. The overall outcomes of these experiments are
shown in Table 1. (Full data and relevant spectra and chemical
shifts are given in the Supporting Information.)
Table 1. Room-Temperature Arbusov Collapse of DAPS
Generated at −78 °C from Various Phosphine/Alcohol
a
Combinations
Figure 1. Configuration and 31P NMR (242 MHz, CDCl3)
assignments of the diastereomeric RP-1d and SP-1d derived from
(−)-menthol and the phosphine 1a at 0 °C in toluene (de = 62%).
that the limit of selectivity of the reaction is set upon formation
of DAPS and the final ee of the product is close to, but never
exceeds, the initially attained DAPS de.12e,f,14 However, these
experiments do not address real-time changes that may occur
during the decomposition, specifically whether it might be
stereoselective.
NMR Monitoring of the Decomposition Process. The
question of stereoselectivity in the conversion of DAPS
intermediates RP-1d/SP-1d, to phosphine oxide was addressed
by 31P NMR monitoring of the process. The mixture used for
the characterization above (62% de) was decomposed at 30 °C,
with the results shown in Figure 2 (spectral data in Supporting
Information, Figure S-i).
a
To the solution of HCA and alcohol was added phosphine at −78 °C.
After 5 min, the reaction was warmed to room temperature and its
progress monitored by 31P NMR at various elapsed times. Full data
b
and spectra are given in the Supporting Information. Extent of
conversion (%) to phosphine oxide (PO).
The data in Table 1 confirm that the de enrichment process
is a general phenomenon. In every case studied, the de of the
DAPS mixture increases with time as the minor diastereomer
converts to oxide more quickly. The values shown are the initial
and maximum de achieved, occurring at the conversions and
times shown. In several cases, >90% de is achieved at about
75% conversion. This data also shows that the overall rate of
Arbusov collapse and the rate difference between the
diastereomers varies widely depending on the phosphine and
the alcohol. Thus, DAPS derived from o-tolyl-substituted
phosphine 1a decomposes about twice as fast as that with the
more electron-donating o-methoxy (PAMP, 2a) but >20 times
more slowly than that with the electron-withdrawing o-
trifluoromethyl substituent 3a. Conversely, DAPS derived
from 8-phenylmenthol or neomenthol decompose much faster
than those from menthol.17 The neomenthol cases are so fast
that it was not possible to determine the degree of enrichment,
their half-lives being less than 5 min. This, presumably, is due to
their nearly perfect anti-periplanar geometry, which allows the
DAPS to undergo rapid elimination reaction to form exclusively
3-menthene, as shown, for example, in Scheme 2(i) for the case
of phosphine 1a.
Figure 2. Kinetic plots of Arbusov collapse at 30 °C of DAPS RP/SP-
1d and the production of product oxo-1a showing gradual enrichment
of the de.
It can be seen clearly in Figure 2 that the rates of thermal
collapse of the two salts are not the same. Effectively, there are
two parallel first-order decomposition processes, with rate
constants k1(RP-1d) = 1.5 × 10−5 s−1 and k1(SP-1d) = 2.4 ×
10−5 s−1, respectively. Significantly, as the rate constant of the
minor diastereomer SP-1d is higher than that of the major
isomer RP-1d, the remaining unreacted DAPS is gradually
further enriched in the major component RP-1d, so that the
DAPS de rises to 82% at 80% conversion to oxide. Thus, the
Arbusov step acts to kinetically enhance the de of the key
DAPS intermediate, which itself was generated by dynamic
resolution of racemic CPS.
The case of neomenthol also highlights another related
observation: the formation of the phosphine oxide is
accompanied by a broadening and steady downfield drift of
its 31P NMR chemical shift (e.g., in the case of oxo-1a from δ
31.7 to approximately 47 ppm). We attribute this significant
difference to the protonation of phosphine oxide by HCl18 as it
To explore the generality of this DAPS de enrichment effect,
we studied the Arbusov collapse of the DAPS derived from a
C
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a
Scheme 2. Different Elimination Behavior of DAPS: (i)
From (+)-Neomenthol and (ii) from (−)-Menthol
Table 2. Borohydride Reduction of DAPS Derived from
Menthol and Phosphines 1a, 2a, and 4a after Elapsed Times
a
To the solution of HCA and (−)-menthol (unless stated otherwise)
was added phosphine solution at −78 °C, and the mixture was held at
that temperature for 30 min. After warming to room temperature,
samples of the mixture were treated at −78 °C with NaBH4 solution at
the time intervals noted (full details and spectra in Supporting
b
c
Information). With (+)-menthol. Determined by 31P NMR.
d
Determined by CSP HPLC; configuration assigned as noted in the
e
Supporting Information. Ratio of phosphine borane (PB) to
phosphine oxide (PO) determined by 31P NMR.
is formed in the course of the elimination process, Scheme 2(i).
This difference was also replicated by adding HCl to a pure
sample of phosphine oxide. Similar but less dramatic downfield
drift of the oxide signal occurs in other cases. For example, with
menthol, the drift of the oxo-1a signal is from δ 31.7 ppm to ca.
37.5 ppm when the reaction is nearly complete. We attribute
this to the much lower degree of elimination observed with
menthol (about 25%) due to its less favorable elimination
process, Scheme 2(ii).
Scheme 3. Operation of “Wait and Attack” Protocol for
Kinetic Enhancement of Kinetic Resolution
a
Time-Delayed DAPS Reduction. Having found that the
de of the DAPS increases as the reaction progresses, we were led
to the idea to interrupt the reaction before its completion and
thereby isolate a product of ee higher than the de of the DAPS
intermediate formed initially. We have previously shown that
scalemic phosphines and phosphine boranes can be synthesized
directly by reduction of the DAPS, with LiAlH4 or NaBH4
respectively, at −78 °C before Arbuzov collapse to the
corresponding oxide occurs (Scheme 1).12d−f Therefore, we
realized that by delaying addition of the reducing agent we
could potentially form a reduced product with enhanced ee.
This time-delayed double kinetic resolution can colloquially be
termed the “wait and attack” protocol, as the operator would
simply wait before adding hydride reagent to attack the
remaining DAPS.
This concept has limitations: for instance, since LiAlH4 is
known to reduce P-stereogenic phosphine oxides with
scrambling of the phosphorus stereocenter,19 delaying the
addition of LiAlH4 until some phosphine oxide had formed
would result in the formation of phosphine with a lower ee than
is obtained when treating the DAPS immediately. However,
phosphine oxides are unreactive toward NaBH4 so only DAPS
should be converted to phosphine borane with this reagent,
leaving the phosphine oxide unaffected. This was achieved in
practice for test reactions on DAPS derived from phosphines
1a, 2a, and 4a by addition of a solution of NaBH4 (in diglyme)
after aging at room temperature for a certain period of time,
Table 2. As expected, the ee of the phosphine borane20
prepared by borohydride reduction of the aged DAPS increases
progressively with time, up to the maxima shown in Table 2
and Scheme 3. This enhancement is happening, of course, at
the expense of the reaction chemical yield. That the minor
diastereomer of DAPS decomposes faster can clearly be seen in
the switch of configuration of the oxide product with time,
picked out in color in Table 2. This is particularly noticeable for
phosphine 1a in combination with menthol, where the first
formed oxide is 72% ee of S-configuration, whereas near the
end of the reaction it is 72% of R-configuration.
a
Increased time delay in borohydride reduction of DAPS 4d leads to
progressive increase of the ee at the expense of the yield of the derived
phosphine borane 4b (procedure as per Table 2, footnote a; full data
and spectra in Table A in the Supporting Information).
Stereospecificity in DAPS ReductionPreparation of
Highly Enriched Phosphines and Phosphine Boranes.
Although we had established proof of principle for the time-
delayed reduction protocol, a particular issue remained to be
solved. Careful examination of the results in Table 2 shows that,
in several cases, the de of the DAPS and ee of the derived
phosphine borane do not match fully, implying that there was
stereochemical erosion during the reduction process. This is
especially noticeable in the case of phosphines 1a and 4a. We
have previously identified12d,21 a likely source of this erosion:
there can be an Arbusov-like side reaction with hydride attack
at carbon, Scheme 4. This is reflected in the slightly higher
amounts of oxide returned after reduction compared to that
Scheme 4. Potential Stereochemical Erosion in Hydride
Reduction
D
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measured by NMR before reduction. If such reaction is slightly
faster for the major diastereomer, the ee of the reduction
product will be decreased.
whereby the ee of (R)-1b has increased to 90% by carrying out
the second reduction step after a 24 h delay. Similarly, time-
delayed double kinetic resolution carried out on oxo-7a
(Scheme 6, bottom) leads to phosphine borane (R)-7b in
97% ee as compared to 92% ee material obtained directly. It is
noteworthy that the loss of the reduced material 1b/7b
associated with time-delayed double kinetic resolution is fully
recoverable as the oxo-1a/oxo-7a formed during the delay.
We therefore embarked on a screening of hydride reducing
agents (Supporting Information, Tables B and C) to see if we
could minimize this erosion of stereoselectivity. To provide a
stringent test, we used as substrates the ethylphenyl-o-
tolylphosphine motif (7a/oxo-7a) because our recent studies
showed that higher diastereoselectivity can be achieved at the
DAPS formation stage by increasing the length of the P-alkyl
chain.14 Lithium tri-sec-butylborohydride (commercially dis-
tributed as L-Selectride reagent) emerged from the screen as a
superior reagent for stereospecific reduction of DAPS. It allows
the preservation of the configuration of 99% of P-stereogenic
centers. The product is the corresponding phosphine, which
was subsequently boronated for analysis purposes. The
efficiency and robustness of this reduction method was then
demonstrated at gram scale for the conversion of racemic oxo-
8a to borane 8b (Scheme 5). We used the protocol starting
SUMMARY AND CONCLUSIONS
■
Transient intermediatesdiastereomeric alkoxyphosphonium
salts (DAPS)were generated and fully characterized by
1
1H−13C and H−31P 2D correlation NMR techniques at low
temperature. The collapse of both diastereomeric forms was
monitored by 31P NMR at 30 °C. It was observed that the
decomposition of the minor form is faster (e.g., ca. 1.6 times for
SP-1d), resulting in the remaining unreacted DAPS becoming
gradually further enriched in the major component. Similar
observations of spontaneous diastereomeric enrichment were
made for a series of DAPS species at room temperature. Thus,
the Arbusov step acts to kinetically enhance the diastereo-
selectivity of the key DAPS intermediate, which itself was
generated by dynamic resolution of racemic CPS.
Scheme 5. Gram-Scale Synthesis of Scalemic Phosphine
Borane 8b via DAPS 8d Derived from oxo-8a
DAPS decomposition rates depend strongly on the alcohol
and phosphine used. Our studies confirmed that the selectivity
of this reaction is limited by the de of the DAPS at the starting
point, since the initial de of the DAPS typically corresponds to
the final ee of phosphine oxide. However, we found that, as the
collapse of the minor diastereomer is faster than that of the
major one, the de of the residual DAPS increases during the
course of the reaction, leading to further diastereomeric
enrichment. These observations were then utilized by employ-
ing hydride reduction of aged samples of DAPS (at different
time intervals after the DAPS was formed). This time-delayed
kinetic resolution with subsequent kinetic enhancement of the
DAPS then yields high ee phosphine boranes.
from the oxide because it is more convenient to handle and
because the rate of Arbusov collapse of the DAPS is somewhat
slower,22 allowing more leeway in its manipulation. More
significantly, the high de14 of the DAPS 8d was satisfactorily
translated in good yield to the borane.
These new optimized reduction reaction conditions were
then applied in tandem with our “wait and attack” method-
ology, Scheme 6. Thus, treatment of 87% de RP-1d with L-
Selectride in dichloromethane at −78 °C immediately after its
formation gives (R)-1b in 90% yield and 85% ee (Scheme 6,
top). This can be compared to the time-delayed process
A tentative explanation of the enhancement phenomenon is
depicted in Figure 3. According to this schematic, the cold stage
Scheme 6. Synthesis of Scalemic Phosphine Boranes 1b/7b
from DAPS Prepared from Phosphine Oxides oxo-1a/oxo-
7a, Applying the “Wait and Attack” Protocol To Achieve
Kinetic Enhancement of Kinetic Resolution (Left),
Compared to Direct Reduction (Right)
Figure 3. Proposed reaction energy profile for two sequential kinetic
resolution steps: the major diastereomer (blue) is mainly formed at the
cold stage but, being more stable, undergoes slower thermal collapse at
the warm stage.
is an SN@P irreversible dynamic kinetic resolution (DKR)
process in which the formation of DAPS takes place and the
more stable diastereomer, consistent with the Hammond
postulate, is formed via a lower transition state, TS-I, i.e.,
faster. The thermal collapse of DAPS is an SN2/E2 reaction at
the carbon center of the auxiliary group R*, and, unlike TS-I, its
respective diastereomeric transition states, TS-II, are less likely
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to be affected by the stereochemistry of the phosphorus.
Accordingly, it is the less stable, i.e., minor, diastereomer of
DAPS that undergoes faster collapse because its ground state
lies closer to TS-II. The net outcome is that the diastereo-
selectivity achieved at the cold-stage DKR process is further
amplified in the course of the thermal decomposition of the
minor diastereomer. We note that this kinetic enhancement is
unlike classic kinetic amplification, which usually occurs in the
course of the same reaction with the same chiral reagents.4 In
our system, the two selective processes, DKR run at −78 °C
and the subsequent kinetic enhancement run at room
temperature, are entirely different. The first is a stereoselective
nucleophilic attack at tetracoordinate P, and the second is an
Arbusov-type thermal collapse involving a carbon center. The
relative selectivities of these two consecutive processes are,
however, determined by the relative energies of the DAPS
intermediates.
In summary, we have demonstrated an efficient general
approach to synthesize various enantioenriched phosphorus
compounds from racemic phosphine, which opens up a facile
route for the synthesis of P-stereogenic compounds useful in
asymmetric catalytic synthesis and in the emerging class of
Protide drug candidates.23
Finally, we note that the concept of using the Hammond
postulate to link the stability difference of two diastereomers
generated in one process to their reactivity in a subsequent
second process may be a general phenomenon. In Figure 3, the
kinetic effect (i.e., relative rates RP- vs SP-) of the stability
difference for the first selection is mirrored and inverted in the
second selection, leading to the greater reactivity of the minor
isomer. This occurs because the second TS is of closer energy
for the two isomers. In general, this requires the second TS to
be not subject to the same energetic factors as the first,
achieved in our case by reaction at a site remote from
phosphorus.24
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* Supporting Information
Full NMR characterization of the DAPS formed from 1a and 7a
and (−)-menthol; DAPS thermal collapse data corresponding
to Figure 2; 31P NMR spectra and HPLC chromatograms
corresponding to the results given in Tables 1 and 2; and the
screen of hydride reductants and experimental details
corresponding to Schemes 5 and 6. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/jacs.5b04415.
AUTHOR INFORMATION
■
Corresponding Author
*declan.gilheany@ucd.ie
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We sincerely thank Science Foundation Ireland for funding this
chemistry under Grants RFP/08/CHE1251 and 09/IN.1/
B2627. We are also grateful to University College Dublin
(UCD) Centre for Synthesis and Chemical Biology and the
UCD School of Chemistry and Chemical Biology for access to
their extensive analysis facilities. D.G.G. also thanks UC Dublin
for a President’s Research Fellowship.
Nguyen, D. H.; Her
L.; Buono, G. J. Org. Chem. 2015, 80, 4132−4141.
́
ault, D.; Vanthuyne, N.; Leclaire, J.; Giordano,
F
DOI: 10.1021/jacs.5b04415
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(15) In this work, we characterize the DAPS mixture by its
diastereomeric excess (de) rather than diastereomeric ratio (dr). This
is to enable easier comparison with the enantiomeric excess (ee) in the
products derived from the DAPS.
(16) Denton and co-workers have isolated similar non-chiral
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(17) In all cases the RP-selectivity observed with (−)-menthol was
found to be mirrored by (+)-menthol, giving (SP)-selectivity.
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(20) We have previously shown (ref 12f) that the hydride reduction
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change due to the change in group priorities around phosphorus.
(21) This phenomenon became apparent in several cases where
careful air- and moisture-free reduction of a clean mixture of DAPS
(no oxide visible in 31P NMR spectrum) still led to small amounts of
oxide along with the reduction product.
(22) We will report subsequently on the reactivity and structure of
these phosphonium intermediates: Nikitin, K., Gilheany, D. G.,
manuscript in preparation.
(23) An enticing review of this emerging area from the designers of
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(24) The erosion of ee by hydride reduction mentioned earlier is an
example where there is competition betweeen the reaction at
phosphorus and the reaction at carbon, and so it does not fit this
criterion.
G
DOI: 10.1021/jacs.5b04415
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX