Stereoselective catalytic synthesis of P-stereogenic oxides via hydrogenative kinetic resolution

Article abstract of DOI:10.1021/acs.orglett.9b02606

A highly stereoselective catalytic method for the preparation of structurally diverse P-stereogenic oxides has been developed. The approach relies on the ability of rhodium complexes derived from an enantiopure P-OP ligand to kinetically resolve racemic α,β-unsaturated phosphane oxides by hydrogenation of the C= C motif and formation of highly enantioenriched (or even enantiopure) P-stereogenic oxides. The practicality of the methodology has been demonstrated by the preparation of potentially functional P-chiral molecules for catalytic enantioselective synthesis.

Full text of DOI:10.1021/acs.orglett.9b02606

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereoselective Catalytic Synthesis of P‑Stereogenic Oxides via
Hydrogenative Kinetic Resolution
‡
Hector Fernandez-Perez and Anton Vidal-Ferran*,†,‡
́
́
́
†ICREA, P. Lluís Companys 23, 08010 Barcelona, Spain
‡Institute of Chemical Research of Catalonia (ICIQ) and The Barcelona Institute of Science and Technology (BIST), Av. Països
Catalans 16, 43007 Tarragona, Spain
S
* Supporting Information
ABSTRACT: A highly stereoselective catalytic method for the
preparation of structurally diverse P-stereogenic oxides has been
developed. The approach relies on the ability of rhodium complexes
derived from an enantiopure P−OP ligand to kinetically resolve
racemic α,β-unsaturated phosphane oxides by hydrogenation of the
CC motif and formation of highly enantioenriched (or even
enantiopure) P-stereogenic oxides. The practicality of the method-
ology has been demonstrated by the preparation of potentially
functional P-chiral molecules for catalytic enantioselective synthesis.
enantiomers of the vinyl sulfoxides with dihydrogen was
he catalytic stereoselective preparation of enantiopure P-
Tstereogenic compounds has been pursued by synthetic found to be 14814).
chemists due to the use of these motifs in biological systems,1
as enantiopure synthetic drugs,1 and enantioselective catalytic
systems.2 The preparation of such compounds in an
enantiomerically pure form mostly relies on classical
approaches such as resolution processes2 or the use of
stoichiometric amounts of chiral auxiliaries.2 Regarding the
preparation of P-stereogenic oxides using catalytic methods,
only two approaches have been reported, with the first relying
on the arylation (Scheme 1a.1)3 of secondary phosphane
oxides (SPOs) and the second on desymmetrization
strategies. Methods to desymmetrize4 encompass ring-closing
metathesis,5 hydroetherification,6 [2 + 2 + 2] cycloaddition,7
C−H functionalization,8 oxidation,9 allylic alkylation,10 and
conjugate addition11 reactions (Scheme 1a.2). To conclude
this succinct overview on the reported catalytic synthetic
methods for the preparation of optically active P-stereogenic
oxides, we highlight that the use of reductive transformations
for their preparation is underdeveloped.
Our research group has recently reported the use of
rhodium complexes derived from phosphine-phosphite (P−
OP)12 ligand L13 for the kinetic resolution of racemic
mixtures of unsubstituted vinyl sulfoxides using hydrogen.14
Specifically, our group described the efficient preparation and
isolation of an array of S-stereogenic sulfoxides derived from
such a process in a highly enantioenriched form.14 In a
kinetic resolution,15 success relies on there being distinct
reaction rates for the reaction between the two enantiomers
of the starting material with the reagent (the highest relative
ratio of rate constants, or selectivity factor s, of the two
Given our ongoing interest in developing catalytic
stereoselective tools for underdeveloped transformations,
and encouraged by the precise stereocontrol exhibited in
the hydrogenative kinetic resolution of unsubstituted vinyl
sulfoxides, we turned our attention to expanding the scope of
the reaction to α,β-unsaturated P-containing oxides (Scheme
1b), which seemed to us to be ripe with potential for this
chemistry. Thus, we report herein the development of an
efficient and catalytic stereoselective method based on a
kinetic resolution of racemic α,β- unsaturated phosphorus
derivatives by hydrogenation. We also describe how our
method complements already existing catalytic methods by
giving access to P-stereogenic synthetic building blocks as
potentially functional molecules for catalytic enantioselective
synthesis.
At the onset of our studies, we proceeded to explore the
hydrogenative kinetic resolution of methyl(phenyl)(vinyl)-
phosphane oxide rac-1a to assess the potential of P−OP
ligand L in this chemistry. Standard catalyst screening
conditions (1.0 mol % rhodium precatalyst, 10 bar H2,
room temperature, 1 h reaction time) in different solvents
were used in this study, whose results are summarized in
Table 1. Pronounced solvent effects were observed, with
conversions varying with the polarity of the solvent. The
hydrogenation proceeded to 45−60% conversion in DCM as
(co)-solvent, while full conversion was observed for the
Received: July 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02606
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
1a was isolated with a high yield and very high enantiomeric
ratio (99.5:0.5 e.r.) when the kinetic resolution was
performed in DCM at 0 °C under 10 bar of H2 (Scheme
2). Alternatively, hydrogenated product (R)-2a was isolated
in acceptable yield and high enantiomeric ratio (98:2 e.r.) by
performing the hydrogenation under the same conditions but
lowering the temperature to −40 °C.
Scheme 1. (a) Reported Catalytic Methods towards
Optically Active P-Stereogenic Oxides; (b) Present Work
on Rh-Catalyzed Hydrogenative KR of α,β-Unsaturated P-
Containing Substrates
Having demonstrated that highly stereoselective kinetic
resolutions of α,β-unsaturated P-containing oxides were
feasible, we then attempted to broaden the substrate scope
to a set of structurally diverse α,β-unsaturated P-containing
oxides rac-1b−1f. The results and the optimal reaction
conditions for unreacted starting materials and hydrogenation
products are shown in Scheme 2. Increasing the chain length
of the Y substituent at the P-atom barely influenced the
outcome of the reaction with isolated yields and enantiomeric
ratios remaining high for both compound (S)-1b and (S)-2b
(97.5:2.5 e.r. and 95.5:4.5 e.r., respectively; see Scheme 2).
Interestingly, when the alkyl group in rac-1a was replaced by
an aryl motif of similar size as in rac-1c, the stereoselectivity
of the kinetic resolution was almost lost. The catalytic system
also tolerated α,β-unsaturated phosphinate rac-1d (Scheme
2). Unreacted starting material (R)-1d was isolated in high
yield and excellent enantiomeric ratio (>99.5:0.5 e.r.), and
hydrogenated product (S)-2d was also isolated in satisfactory
yield and high enantiomeric ratio (up to 96.5:3.5 e.r.).
Compounds (R)-1d and (S)-2d are configurationally stable,
as no racemization took place after standing two months at
room temperature.
Phospholane 1-oxide derivatives (S)-1e and (S)-2e could
also be prepared by kinetic resolution of compound rac-1e.
Both target products were isolated in high isolated yields.
Regarding the stereoselectivity of the kinetic resolution, both
reaction products were obtained in very high enantiomeric
ratios, with compound (S)-2e being isolated in an excellent
99:1 e.r. and the highest selectivity factor of the whole study
(s = 217). Finally, Me-substituted α,β-unsaturated phosphane
oxide rac-1f was also studied. In contrast to substrates
unsubstituted at the CC motif, these compounds were less
reactive toward hydrogenation. After some experimentation,
efficient kinetic resolution conditions involving higher
pressure (80 bar) and the use of MeOH as solvent were
identified. Under these conditions, unreacted starting material
(S)-1f and hydrogenated product (R)-2f were obtained in
high enantiomeric ratios (98:2 and 93.5:6.5 e.r., respectively).
reaction in methanol (entries 1−4 compared with entry 5 of
Table 1). As expected, the e.r. of the unreacted starting
material increased with conversion (95.5:4.5 e.r. at 60% conv,
entry 4 in Table 1), while that of the hydrogenated product
was higher at lower conversions (85:15 e.r. at 45% conv,
entry 3 in Table 1).
In order to maximize the yield and enantiomeric ratios for
both the unreacted and hydrogenated products ((S)-1a and
(R)-2a, respectively), specific reaction conditions for both
products were investigated. Unreacted starting material (S)-
a
Table 1. Initial Screening on Rh-Catalyzed Hydrogenative KR of Racemic P-Stereogenic rac-1a
b
c
d
c
d
entry
reaction conditions
conv (%)
e.r. 1a (conf.)
e.r. 2a (conf.)
1
2
3
4
5
Cy/DCM (4:1), 1 h
51
51
45
60
>99
81:19 (S)
77.5:22.5 (R)
76:24 (R)
85:15 (R)
72.5:27.5 (R)
rac
PhMe/DCM (4:1), 1 h
78.5:21.5 (S)
76.5:23.5 (S)
95.5:4.5 (S)
e
MeTHF /DCM (4:1), 1 h
DCM, 0.75 h
MeOH, 1 h
f
−
a
b
c
Reaction conditions are indicated in the scheme on Table 1. Conversions were determined by 1H NMR. Enantiomeric ratios were determined
d
by HPLC on chiral stationary phases. Absolute configurations of products 1a and 2a were established by comparison with reported optical
rotations for compounds 1a and 2a.16 MeTHF = 2-Methyltetrahydrofuran. Not detected in the reaction mixture.
e
f
B
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Letter
a
Scheme 2. Rh-Mediated Hydrogenative KR of a Set of Structurally Diverse α,β-Unsaturated P-Containing Oxides
a
[Substrate] = 0.2 M. Conversions were determined by 1H NMR. Yields refer to isolated ones and were calculated with respect to the 50 mol %
amount of starting material that was subjected to KR. Enantiomeric ratios were determined by HPLC on chiral stationary phases. Absolute
configurations of products 1a,d and 2a,d were established by comparison with reported optical rotations for compounds 1a,d and 2a,d. Absolute
configurations of products 1b and 2b were tentatively assigned by analogy with the results for 1a and 2a. The absolute configuration of product 1e
was unambiguously assigned by anomalous X-ray single crystal diffraction of its derivative (S,S)-3, and consequently, that of 2e was also
unambiguously assigned. The selectivity factor (s) was calculated with the equation: s = ln[1 − C(1 + ee2)]/ln[1 − C(1 − ee2)], where C = ee1/
b
(ee1 + ee2), ee1 = ee of 1, and ee2 = ee of 2.15 Reaction products could not be separated by standard column chromatography. The KR was carried
c
d
out in MeOH as solvent. [Rh(nbd)(L)]BF4 (5.0 mol %) and MeOH as solvent. [Rh(nbd)(L)]BF4 (2.5 mol %) and MeOH as solvent.
To demonstrate the utility of the products obtained from
the kinetic resolution process, we devised further trans-
formations of the resulting P-stereogenic oxides (see Scheme
3). We envisaged that a dimerization reaction of vinyl-
(S,S)-3 with Pd/C led to enantiopure P-stereogenic
diphosphane dioxide (S,S)-4. This enantiopure bidentate
phosphorus derivative incorporates phospholane units in its
structure and holds promise as an efficient ligand in
enantioselective catalysis,9 given its structural similarities
with highly efficient ligands that contain two phospholane
(1-oxide) units linked by a 1,2-ethanediyl motif.18
Scheme 3. Further Transformations of (S)-1e
Figure 1. ORTEP drawing (thermal ellipsoids drawn at a 50%
probability level) showing the structure and the absolute
configuration of product (S,S)-3.
As previously indicated, cationic rhodium complexes of P−
OP ligand L catalyze highly stereoselective hydrogenative
kinetic resolutions of racemic mixtures of α,β-unsaturated
PO-derivatives toward unreacted starting materials (selec-
tivity factors up to 213) and hydrogenated compounds
(selectivity factors up to 217). The stereochemical outcome
of the studied kinetic resolutions has been summarized in
Scheme 4: enantiomers of the starting material with a S
configuration at the phosphorus atom remain unreacted, as
they are less prone to hydrogenation under the effects of
rhodium catalyst derived from L.
substituted phosphane oxides 1 via olefin metathesis would
pave the way to interesting P-stereogenic bidentate
derivatives. To demonstrate the viability of this idea, we
chose vinyl-substituted compound (S)-1e, as it was obtained
with one of the highest selectivity factors. Dimerization of
(S)-1e via olefin metathesis toward the E-derivative (S,S)-3
was achieved using 5 mol % of Grela’s ruthenium catalyst.17
The S configurations at the phosphorus atoms were
established by anomalous X-ray diffraction studies (Figure
1).16 Further hydrogenation of the homocoupling product
C
DOI: 10.1021/acs.orglett.9b02606
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Organic Letters
Letter
Buchholz (ICIQ, BIST) for X-ray crystallographic data and
Ms. R. Somerville (ICIQ, BIST) for proofreading the
manuscript.
Scheme 4. Stereochemical Outcome of the KRs
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ASSOCIATED CONTENT
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Experimental details, catalytic results, and spectroscopic
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Accession Codes
CCDC 1909608 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(10) Yang, G.-H.; Li, Y.; Li, X.; Cheng, J.-P. Access to P-Chiral
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: anton.vidal@icrea.cat.
ORCID
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́
́
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́
́
́
Hector Fernandez-Perez: 0000-0001-5386-1814
Anton Vidal-Ferran: 0000-0001-7926-1876
Notes
The authors declare no competing financial interest.
́
́
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ACKNOWLEDGMENTS
We thank MINECO (CTQ2017-89814-P) and the ICIQ
Foundation for financial support. We are grateful to J. Benet-
■
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