General and Stereoselective Method for the Synthesis of Sterically Congested and Structurally Diverse P-Stereogenic Secondary Phosphine Oxides

Article abstract of DOI:10.1021/acs.orglett.7b00568

A general and efficient method for the synthesis of bulky and structurally diverse P-stereogenic chiral secondary phosphine oxides (SPOs) by using readily available chiral amino alcohol templates is described. These chiral SPOs could be used as chiral building blocks for the synthesis of difficult-to-access bulky P-stereogenic phosphine compounds or ligands for organic catalysis.

Full text of DOI:10.1021/acs.orglett.7b00568

Letter
pubs.acs.org/OrgLett
General and Stereoselective Method for the Synthesis of Sterically
Congested and Structurally Diverse P‑Stereogenic Secondary
Phosphine Oxides
Zhengxu S. Han,* Hao Wu, Yibo Xu, Yongda Zhang, Bo Qu, Zhibin Li, Donald R. Caldwell,
Keith R. Fandrick, Li Zhang, Frank Roschangar, Jinhua J. Song, and Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Old Ridgebury Road, P.O. Box 368,
Ridgefield, Connecticut 06877, United States
S
* Supporting Information
ABSTRACT: A general and efficient method for the synthesis of bulky and structurally diverse P-stereogenic chiral secondary
phosphine oxides (SPOs) by using readily available chiral amino alcohol templates is described. These chiral SPOs could be used
as chiral building blocks for the synthesis of difficult-to-access bulky P-stereogenic phosphine compounds or ligands for organic
catalysis.
P-Stereogenic chiral phosphines (P-SCPs, 1, Scheme 1) have
been demonstrated as effective ligands in enantioselective
ration of sterically demanding substituents (e.g., t-Bu) should
be more facile, thus providing an alternative avenue for the
synthesis of sterically hindered TPOs.6−9 Moreover, SPOs
themselves have been found to be effective ligands for a
number of transformations (nonenantioselective).10 Despite
the wide range of potential applications of SPOs, their synthesis
has met with limited success. Buono, Han, and co-workers have
reported pioneering work on the asymmetric synthesis of SPOs
by employing menthol as a chiral auxiliary (Scheme 1a).3c,5c
Chemical and kinetic resolution are other means of preparation
that have also been described recently,8 but only a limited scope
of P-stereogenic SPOs has been prepared. Therefore, an
effective asymmetric synthesis of chiral 3 entities with diverse
structures needed to be developed in order to better
understand the properties of SPOs and to further expand
their synthetic utilities.
Scheme 1. Strategies for Synthesis of Enantiomerically
Enriched SPOs and Their Applications
Aiming to develop a practical and stereoselective SPO
synthesis, we focused on using readily available chiral 1,2-amino
alcohols as templates. On the basis of our previous work,3d we
envisioned that the reaction of R1PCl2 with 7 would provide
intermediate 8 in optically pure form (Scheme 1b). The more
reactive P−N bond should selectively react with water to afford
phosphinate 10 in a stereospecific fashion. The subsequent
reaction of a nucleophile R2 M with 10 would afford the chiral
nonracemic SPO. Herein, we report the development of a
general and stereoselective method for the synthesis of
structurally diverse, sterically demanding, P-stereogenic SPOs
organometallic catalysis.1 However, their development has been
significantly hindered due to the synthetic challenges.2,3 P-
Stereogenic chiral tertiary phosphine oxides (TPOs, 2, Scheme
1), on the other hand, are attractive precursors of P-SCPs due
to their air- and moisture-stability and can be prepared in high
chemical and optical purity.4 Elegant work has been carried out
recently for the synthesis of certain types of 2, but the synthesis
of sterically hindered variations, such as those containing a tert-
butyl functionality, still remains a significant challenge.3,5
Secondary phosphine oxides (SPOs, 3, Scheme 1) are
promising precursors of 2 since the P−H bond can be readily
functionalized, thus offering a handle for differentiation. As
SPOs are inherently less sterically demanding, the incorpo-
Received: February 23, 2017
© XXXX American Chemical Society
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Letter
based on the above-mentioned concept. The application of
chiral SPO in the synthesis of bulky P-stereogenic TPO under
catalytic conditions is also described.
To evaluate our strategy, (1R,2S)-norephedrine 11 was first
used for the study. Recently, we reported that either Rp-13 or
Sp-13 1,3,2-benzoxazaphosphinine-2-oxide is useful for the
synthesis of P-stereogenic phosphine oxides (Scheme 2).3d The
overall yield. As expected, reaction of Rp-18a with t-BuLi in
THF at −80 °C provided highly enantiomerically enriched (S)-
3a in 78% isolated yield with the full recovery of template 16.
Having identified the optimal reaction conditions, the scope
of the synthesis of diastereomerically pure 18 was examined.
The results in Table 1 show that a broad scope of H-
Table 1. Substrate Scope for the Synthesis of P-Stereogenic
SPOs Using (1S,2R)-Aminoindanol Derivative 16
Scheme 2. Stereochemistry and Synthesis of (S)-t-Bu(Ph)-
phosphine Oxide 3a Using 11 as Template
synthesis of 13 using PhP(O)Cl2 generally provided the Rp-
isomer preferentially, except when pyridine was used as base
when the Sp-isomer was the major product but in low selectivity
(63:37 dr). Later studies demonstrated that Sp-13 could be
obtained in high selectivity (98:2 dr) by first treating 11 with
PhPCl2 instead of PhP(O)Cl2 to yield Sp-12, followed by
oxidation with t-BuO2H. Sp-13 is a crystalline product, and its
enantiomerically pure form was obtained by recrystallization
from EtOAc/hexanes. On the other hand, in situ treatment of
Sp-12 with water afforded a stable crystalline product
phosphinate Rp-14a in 98:2 dr, and its enantiomeric pure
form was obtained via a single crystallization in 90% yield. The
stereochemistry of Rp-14a was determined by single-crystal X-
ray crystallography. It was reasoned that Rp-14a was formed
through Rp-15 that was obtained by nucleophilic addition of
water on phosphorus by cleaving the active P−N bond via an
SN2 mechanism. Interestingly, treatment of Rp-14a with t-BuLi
gave a clean reaction and afforded the highly enantiomerically
enriched SPO (S)-tert-butyl(phenyl)phosphine oxide 3a5c in
good isolated yield with full recovery of 11.
Encouraged by the above results, the potential of other chiral
amino alcohols as auxiliaries for the synthesis of chiral SPO was
explored such as the readily available (1S,2R)-aminoindanol 16
that has been previously used in the synthesis of P-stereogenic
phosphanamine and chiral sulfinamides.5b,11 Using the same
protocol, treatment of 16 with PhPCl2 in THF at −78 °C
yielded Sp-17a in high selectivity of >98:2 dr, and its
stereochemistry was determined by the single-crystal X-ray of
its oxidation product Sp-19 (Scheme 3). In situ treatment of Sp-
17a with water afforded Rp-18a in high selectivity of >98:2 dr.
Rp-18a is a crystalline product, and one crystallization from
EtOAc/hexanes yielded its enantiomerically pure form in 85%
a
b
Selectivity based on NMR analysis or LC/MS. Isolated yield after
recrystallization for enantiomerically pure product.
phosphinate products 18 can be obtained with good-to-
excellent selectivities and high yields. Products with phenyl
substituents (18b−e), naphthalene substituents, phenanthrenes
(18f−h), heterocycles (18i), ferrocene (18k), and alkyl
substituents (18j) all proceeded with high selectivities and
were readily prepared. All of the reaction products were crystalline,
and their optically pure forms were readily obtained via a single
crystallization and prepared on multigram scale.
The synthesis of P-stereogenic SPOs is straightforward using
the above protocol of treatment of 18 with t-BuLi in THF.
Clean reactions were observed in all cases (Table 1). The scope
of the P-stereogenic SPOs products that can be synthesized
range from ones containing phenyl with diverse substituents
(3b−e), polycyclic aromatics (3f−h), and even heterocycle-
substituted (3i) and dialkyl SPO (3j). It should be noted that
the hindered 3g was accessed previously only by chromato-
graphic separation.10c
The efficient synthesis of chiral phosphinates using readily
available PCl3 and an organometallic reagent was next explored,
and the success of this approach would avoid the synthesis of
phosphine dichloride reagents such as ArPCl2 (Scheme 4).
The stereochemistry of the process was first examined by the
synthesis of 18d. Treatment of 16 with PCl3 in THF in the
presence of pyridine at −78 °C for 2 h afforded 20, and its
reaction with water afforded 21 in high isolated yield.
Interestingly, treatment of 20 with 2-MeO-PhMgBr in situ
followed by addition of water provided 18d in 82% yield and
>85:15 dr. Recrystallization of crude 18d from EtOAc/hexanes
afforded the enantiomerically pure Rp-18d with an (R)-
Scheme 3. Asymmetric Synthesis of 3a by Using 16
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Use of these SPOs in the synthesis of P-stereogenic tertiary
phosphine oxides (TPOs) by transition-metal-catalyzed cou-
pling reactions was investigated. Transition-metal-catalyzed
SPO coupling with aryl halides via P−C bond formation has
been reported for the synthesis of racemic substrates,14 but few
reports have dealt with the reactions of chiral nonracemic or
sterically unhindered chiral SPOs.14b,c Our interest in the
synthesis of chiral phosphine ligands with heterocycle
functionality led us to explore the coupling of 2-bromopyridine
22 with chiral SPOs. Reaction conditions were surveyed first for
the synthesis of 2a. Treatment of 22 with 3a in the presence of
5 mol % of Pd2dba3 and 20 mol % of dppp (1,3-
bis(diphenylphosphino)propane) in toluene gave a reaction
that was only complete after 18 h at 110 °C. It afforded 2a in
good isolated yield without enantiopurity erosion. Single-crystal
X-ray analysis of 2f revealed that the reaction proceeded with
retention of stereochemistry as observed by Herzon et al.14b
Following this protocol, a variety of pyridine-containing P-
stereogenic TPOs with diverse functionalities were readily
prepared (Table 3). Moreover, very bulky TPOs such as 2e−g
Scheme 4. Synthesis of P-Stereogenic Phosphinates via PCl3
and an Organometallic Reagent
configuration at phosphorus as confirmed by single-crystal X-
ray analysis. It was envisioned that Rp-18d was obtained
through intermediate Sp-17d as described in Scheme 3, and
therefore, it was rationalized that the configuration of 20,12a
formed supposedly via N-tosylsulfonamide attacks on phos-
phorus from the less hindered side, was retained in the reaction
with 2-MeO-PhMgBr as observed in a similar system by Xiao et
al.12b Similarly, treatment of 11 with PCl3 followed by 2-MeO-
PhMgBr and water afforded phosphinate 14b in 94:6 dr and
71% isolated yield and in enantiomerically pure form after
recrystallization (Table 2).
Table 3. Synthesis of Chiral TPOs via Coupling Reaction
Table 2. Synthesis of More Hindered P-Stereogenic SPOs
a
b
1.2 equiv of 22 used except where indicated. er based on chiral
c
d
HPLC analysis. er of SPOs used for the reaction. 2.4 equiv of 22
used. 20 mol % of catalyst used.
e
were all obtained in high yields and excellent enantiomeric
purities. The exceedingly bulky phosphine oxide 2h was also
synthesized in excellent selectivity of 99.5:0.5 er albeit in
diminished yield due to the severe steric hindrance. It is worth
noting that the synthesis of such bulky P-stereogenic phosphine
oxides was not possible using previously reported methods. We
believe that the newly developed method should greatly
facilitate the design and synthesis of more efficient P-
stereogenic P,N ligands, which are an important class of
phosphine ligand in catalysis.15
Furthermore, the synthesis of P-stereogenic bis-phosphine
oxides was also achieved by using this coupling strategy.
Reaction of 2,6-dibromopyridine with 3d afforded 23 in good
yield and excellent selectivity. Subsequent reaction of 23 with
another equivalent of 3d furnished bis-phosphine oxide 24
efficiently and in highly enantiomerically enriched form. The
latter is a key precursor for the synthesis of a P-stereogenic P,
N, P ligand (Scheme 5 (a)). Phosphine oxide 26 was also
prepared successfully via this method, which can be used for the
synthesis of P-stereogenic version of QUINAP type of P, N
ligands (Scheme 5(b)).
a
Isolated yield after recrystallization for enantiomerically pure
products. Combined yields for both diastereomers.13 See the
Supporting Information for details. Prepared from 13b.
b
c
This strategy was first applied for the synthesis of bulky P-
stereogenic SPO tert-butyl(2,4,6-triisopropylphenyl)phosphine
oxide 3l (Table 2). When either 11 or 16 was used, treatment
with PCl3 followed by 2,4,6-triisopropyl-PhMgBr and water
afforded the corresponding phosphinates 14c and 18l with
excellent selectivity of >99:1 dr and 98:2 dr, respectively. Both
compounds are crystalline products, and gram quantities of
enantiomerically pure products were isolated in good yield after
a single recrystallization. The subsequent reaction of 14c or 18l
with t-BuLi provided the bulky 3l in high enantiomeric purity
and good yield (Table 2). The scope of this approach was
demonstrated in the synthesis of other chiral phosphinates 14d,
18g, and 18m in good-to-excellent selectivities, from which P-
stereogenic SPOs such as 2-MeO-naphthalene 3m were
prepared successfully in high stereoselectivities.
The application of SPOs in the synthesis of a phosphine
ligand was demonstrated in the synthesis BI-DIME, which finds
many applications in catalysis chemistry.3d,16 Following the
C
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Letter
Notes
Scheme 5. Synthesis of Phosphine Oxides Used for P,N
Ligand Precursors
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Scott Pennino, Mr. Keith McKellop, and Dr. Fenghe
Qiu of Boehringer Ingelheim, US, for HRMS analysis.
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In summary, a general and stereoselective methodology has
been developed for the synthesis of P-stereogenic chiral SPOs.
The method relies on the efficient synthesis of chiral secondary
phosphinates using the readily available amino alcohols as chiral
templates. These chiral phosphinates are readily prepared on a
multigram scale, from which a variety of sterically hindered and
structurally diverse chiral SPOs were prepared. The chiral
templates can be recovered after the reaction and can be reused.
These SPOs were successfully employed for the synthesis of
hindered TPOs with high stereospecificities. We believe that
this method offers a new avenue for the design and synthesis of
versatile P-stereogenic chiral phosphine ligands for asymmetric
catalysis, and these and other related applications are under
investigation in our laboratories.
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ASSOCIATED CONTENT
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* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00568.
Experimental procedures, detailed reaction condition
survey results, and spectroscopic data for all new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: steve.han@boehringer-ingelheim.com.
ORCID
Zhengxu S. Han: 0000-0001-8386-1356
Keith R. Fandrick: 0000-0003-4875-3143
D
DOI: 10.1021/acs.orglett.7b00568
Org. Lett. XXXX, XXX, XXX−XXX