Efficient asymmetric synthesis of P -chiral phosphine oxides via properly designed and activated benzoxazaphosphinine-2-oxide agents

Article abstract of DOI:10.1021/ja312352p

A general, efficient, and highly diastereoselective method for the synthesis of structurally and sterically diverse P-chiral phosphine oxides was developed. The method relies on sequential nucleophilic substitution on the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide, which features enhanced and differentiated P-N and P-O bond reactivity toward nucleophiles. The reactivities of both bonds are fine-tuned to allow cleavage to occur even with sterically hindered nucleophiles under mild conditions.

Full text of DOI:10.1021/ja312352p

Communication
pubs.acs.org/JACS
Efficient Asymmetric Synthesis of P‑Chiral Phosphine Oxides via
Properly Designed and Activated Benzoxazaphosphinine-2-oxide
Agents
Zhengxu S. Han,* Navneet Goyal, Melissa A. Herbage, Joshua D. Sieber, Bo Qu, Yibo Xu, Zhibin, Li,
Jonathan T. Reeves, Jean-Nicolas Desrosiers, Shengli Ma, Nelu Grinberg, Heewon Lee,
Hari P. R. Mangunuru,† Yongda Zhang, Dhileep Krishnamurthy, Bruce Z. Lu, Jinhua J. Song,
Guijun Wang,† 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, efficient, and highly diastereose-
lective method for the synthesis of structurally and
sterically diverse P-chiral phosphine oxides was developed.
The method relies on sequential nucleophilic substitution
Figure 1. Bulky P-chiral phosphines with MeO functionality.
on the versatile chiral phosphinyl transfer agent 1,3,2-
benzoxazaphosphinine-2-oxide, which features enhanced
building block, the bulky P-chiral phosphine oxide IV.
Unfortunately, attempts to synthesize IV in a stereoselective
fashion using existing methods were unsuccessful, and we had to
resort to a resolution-based route, which was a very tedious
process. In searching for an efficient asymmetric route for the
synthesis of IV and related structures, we designed and
developed a new general method for the efficient and
stereoselective synthesis of P-chiral phosphine oxides (1) with
diverse structures and functionalities from the well-designed
chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-
oxide (Scheme 1).
and differentiated P−N and P−O bond reactivity toward
nucleophiles. The reactivities of both bonds are fine-tuned
to allow cleavage to occur even with sterically hindered
nucleophiles under mild conditions.
or decades, chemists have been interested in the asymmetric
F
synthesis of P-chiral phosphines because of their proven
ability to impart excellent enantioselectivities in either transition-
metal-catalyzed asymmetric processes1 or as organocatalysts.2
Although the prominent P-chiral ligand DIPAMP was prepared
by Knowles and co-workers in the 1970s,3 methods for the
synthesis of optically active P-chiral phosphines have emerged
slowly. Representative methods include the formation and
separation of diastereomeric mixtures of menthyl phosphinates,4
auxiliary-based transformations,5,6 enantioselective deprotona-
tion of phosphine−boranes and sulfides,7 enzymatic resolution,8
transition-metal-catalyzed asymmetric phosphine alkylations,9
dynamic kinetic asymmetric oxidation of racemic phosphines,10
and transformations of H-menthyl phosphinates.11 Despite these
elegant approaches, the currently available methods are often
limited in terms of substrate scope and practicality, especially for
the synthesis of sterically crowded P-chiral phosphines.
Scheme 1. Strategy for the Synthesis of 1
We have long been interested in developing an efficient and
general method to prepare structurally, electronically, and
sterically diverse P-chiral phosphine ligands to fine-tune the
stereoselectivities of our many asymmetric processes. Recently,
we developed a series of powerful bulky P-chiral phosphine
ligands, such as MeO-BIBOP (I), MeO-BOP (II), and P-chiral
biaryl ligands (III) (Figure 1), that have been effectively applied
to a wide range of transformations, including Cu-catalyzed
asymmetric propargylation,12a Rh-catalyzed asymmetric hydro-
genation,12b and Pd-catalyzed asymmetric Suzuki−Miyaura
coupling12c and Miyaura borylation reactions,12d with high
stereoselectivities. Ligands I−III were all prepared from a key
Chiral amino alcohols have been employed as chiral auxiliaries
for the asymmetric synthesis of P-chiral phosphines. Juge and co-
́
workers have elegantly demonstrated that the ephedrine-derived
chiral template 2 can be opened by organolithium reagents
stereospecifically to give 3. Subsequent methanolysis can cleave
the P−N bond to generate intermediate 4 containing a second
P−O bond, which can then be displaced with another
Received: December 26, 2012
© XXXX American Chemical Society
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Journal of the American Chemical Society
Communication
organolithium reagent to furnish P-chiral phosphine derivatives
(Scheme 1).6 The methanolysis to convert the P−N bond in 3 to
the P−O bond in 4 is necessary because of the inertness of the
P−N bond toward attack by carbon-based organometallic
nucleophiles. Indeed, direct cleavage of the P−N bond in 3
with a carbon nucleophile has not been achieved to date. The
generally low reactivity of the P−O and P−N bonds in these
chiral templates has also restricted the substrate scope and
rendered this method unsuitable for the synthesis of sterically
hindered P-chiral building blocks such as IV. Bulky organo-
lithium reagents either do not react with 2 or require more
forcing conditions that can result in partial loss of stereo-
specificity during nucleophilic substitution at the P center.13
To overcome these limitations and develop a method with
broad applicability, we designed a strategy in which the P−N
bond is activated by an arylsulfonyl group on the N atom
(Scheme 1). On the basis of our prior experience from the
synthesis of chiral sulfinamides and sulfoxides, we anticipated
that the P−N and P−O bonds in chiral template 6 would have
differentiated bond strengths and therefore differentiated
reactivity toward nucleophilic substitutions.14 Thus, the
sequential cleavage of the P−N bond and the P−O bond in 6
by two different organometallic reagents was expected to provide
1.
in preference to the P−O bond. This is in contrast to the relative
́
bond strength of the P−O and P−N bonds in Juge’s chiral
template 2.
Cleavage of the P−O bond in 10 by treatment with MeMgCl
was then studied. The reaction was sluggish even at ambient
temperature with 6 equiv of MeMgCl, providing (S)-1a10a with
inversion of configuration at P in only 38% yield, albeit with
excellent stereoselectivity (99:1 er). Elevating the temperature
failed to improve the yield of 1a, and many impurities formed.
Switching to the more active nucleophile MeLi (4 equiv)
improved the yield to 61%, but the stereoselectivity suffered, as
1a was obtained with 85:15 er. Additionally, the substrate scope
was limited, as even slightly hindered lithium reagents such as
EtLi or iPrLi provided the respective products in very poor yields
(Scheme 3). These observations again underscored the
challenges associated with the P−O bond cleavage and the
need for further activation.
As reported previously,17a P−OR bond reactivity is affected by
the basicity of the leaving group, which can be predicted by the
pKa of the resultant alcohol ROH: the reactivity of a P−OR bond
increases as the pKa of the resultant ROH decreases. We
envisaged that a P−O bond derived from a phenol derivative
(pKa ≈ 10) would be much more reactive than that from an alkyl
alcohol backbone (pKa ≈ 15).17b Therefore, the new amino-
phenol-based auxiliary 11 was designed and readily prepared on a
large scale from readily available (R)-2-(1-aminoethyl)-4-
chlorophenol.18
Initially, compound 8 derived from N-p-tolylsulfonyl-(1R,2S)-
norephedrine (Scheme 2) was examined to test this strategy.
Scheme 2. Synthesis of Enantiomerically Pure (RP)-9
Reaction conditions for the synthesis of (RP)-12 in
enantiomerically pure form were first examined.15 Studies
showed that, analogous to 8, high conversion and high
diastereoselectivity were observed with 1-MeIm in DCM,
yielding (RP)-12 with 98:2 dr. Diastereomerically pure (RP)-12
was obtained by crystallization, and its absolute configuration
was confirmed by X-ray crystallographic analysis (Scheme 4).16
The synthesis is simple and has been scaled to >100 g in 85%
isolated yield.
Reaction conditions were surveyed for the synthesis of 1,3,2-
oxazaphospholidine-2-oxide (RP)-9. The selectivity depended on
the nature of the base and solvent.15 The use of 1-
methylimidazole (1-MeIm) in dichloromethane (DCM) gave
the highest dr (97:3). (RP)-9 is a crystalline solid, and its
diastereomerically pure form was obtained by recrystallization.
The absolute stereochemistry was unambiguously confirmed by
single-crystal X-ray crystallography.16 This methodology is
amenable to large-scale synthesis, and >100 g of (RP)-9 was
readily prepared in 75% yield with 99.5:0.5 dr.
Scheme 4. Synthesis of Enantiomerically Pure (RP)-12
Chiral template (RP)-9 was then examined for chemoselective
P−N and P−O bond cleavage to synthesize 1a, a key chiral
starting material for DIPAMP (Scheme 3). Treatment of (RP)-9
To demonstrate the potential of this new method, the
synthesis of 1a was first investigated. As anticipated, the reaction
of 2-MeO-PhMgBr with (RP)-12 in THF at −20 °C selectively
cleaved the P−N bond to yield 13a in 91% yield with inversion of
configuration at P, as confirmed by the single crystal X-ray
structure (Scheme 5).16 Notably, the reaction between 4 equiv of
MeMgCl and 13a occurred at −10 °C, cleaving the P−O bond in
Scheme 3. Synthesis of 1a through (RP)-9
Scheme 5. Ring Opening for the Synthesis of 13
with 2-MeO-PhMgBr in tetrahydrofuran (THF) at −40 °C to
−30 °C exclusively cleaved the sulfonyl-activated P−N bond
with inversion of configuration at P,16 affording phosphinate 10
as a diastereomerically pure crystalline product in 91% isolated
yield. Notably, the introduction of the tosyl group enhanced the
electrophilicity of the P−N bond in such a way that it was cleaved
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Journal of the American Chemical Society
Communication
15 min to provide enantiomerically pure (S)-1a10a in 91% yield
with inversion of configuration at P (Table 1, entry 1). This
indicates that 13a has a more reactive P−O bond than 10.
Encouraged by the above results, we examined the synthesis of
sterically hindered chiral phosphine oxides from 13a. While slow
reactions were observed when iPrMgBr and tBuMgCl were used,
the P−O bond was cleaved at −70 °C with iPrLi and tBuLi to
furnish 1b and 1c, respectively, in good yields with excellent
enantiomeric purities (Table 1, entries 2 and 3). Moreover,
cleaved the P−N bond to yield 13c, whereas no reaction was
́
observed between 2-mesityllithium and Juge’s chiral template
2.1b From 13c, compounds 1i and 1j were synthesized in good
yields and selectivities (entries 9 and 10). (RP)-12 was also active
toward a hindered alkyl organometallic reagent, and the reaction
with tBuLi afforded 13d in good yield. Treatment of (RP)-12
with EtMgBr and iPrMgBr also furnished the desired products,
but in low isolated yields. These results may be due to the acidity
of the α-proton present in the products, and further optimization
of the reaction conditions to exploit these nucleophiles is under
investigation.
a
Table 1. Synthesis of P-Chiral Phosphine Oxides
Chiral versions of Buchwald-type ligands can also be prepared
effectively using this method (Scheme 6). Treatment of 13a with
Scheme 6. Synthesis of Chiral Buchwald Ligands
(2′,6′-dimethoxybiphenyl-2-yl)lithium (DMOBP-Li) yielded
enantiomerically pure 1k in high yield. The reaction between
DMOBP-Li and (RP)-12 provided intermediate 13e in high
yield, from which 1l and 1m were successfully prepared.
Importantly, reduction of 1m with polymethylhydrosiloxane
(PMHS) in the presence of Ti(OiPr)4 in THF afforded the free
phosphine ligand 1m′ in excellent yield without erosion of the
enantiopurity.
The structurally diverse chiral phosphine oxides 1 are key
starting materials for the design of mono- or bidentate (15) P-
chiral ligands. As a preliminary example, 1e was reacted with
dialkyl- or diarylphosphine−borane adducts, providing enantio-
merically pure 14 in high yield (Scheme 7).
Scheme 7. Synthesis of Bidentate P-Chiral Ligands
a
b
See the SI for the reaction conditions. Measured by chiral HPLC.
c
d
Finally, the new method was applied to the asymmetric
synthesis of the bulky P-chiral phosphine oxide IV (Scheme 8),
which is a versatile intermediate that can be converted into many
important P-chiral ligands, such as I−III.12,19 Treatment of 11
with dichloro(2,6-dimethoxyphenyl)phosphine (16) followed
by H2O2 oxidation afforded diastereomerically pure 17 in 85%
isolated yield. Treatment of 17 with tBuLi at −40 °C gave 18 in
excellent yield. Subsequent reaction of 18 with MeLi in the
presence of 20 mol % MgBr2·OEt2 afforded sterically hindered
intermediate IV as a crystalline product in 63% yield with
98.3:1.7 er. According to the literature procedure,19 conversion
See the SI for the X-ray structure. The other enantiomer was not
observed.
compounds with other functionalities, such as a ferrocene (1d),
an alkene (1e), or an alkyne (1f), were readily prepared in good
yields and enantiomeric purities (entries 4−6). Notably, 13b
containing a latent aldehyde was a competent coupling partner,
allowing the preparation of enantiomerically enriched 1g and 1h,
which can be used as key precursors for ligand design (entries 7
and 8). Additionally, treatment of (RP)-12 with the hindered 2-
mesitylmagnesium bromide under Turbo conditions successfully
C
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Journal of the American Chemical Society
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Scheme 8. Effective Synthesis of MeO-BIBOP
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of IV to 19 was accomplished successfully without erosion of the
chirality.
In summary, we have described a general, highly diaster-
eoselective, and efficient synthesis of P-chiral phosphine oxides
via sequential nucleophilic substitutions using 1,3,2-benzoxaza-
phosphinine-2-oxide (12). This cyclic intermediate contains
enhanced and properly differentiated P−N and P−O bond
reactivities, ensuring that the first nucleophile selectively cleaves
the P−N bond while the second nucleophile cleaves the P−O
bond with double inversion of configuration at the P center. This
method overcomes the limitations of earlier methods in the
synthesis of sterically hindered compounds and offers a practical,
stereoselective, and high-yield route to P-chiral phosphine oxides
that are key intermediates for accessing P-chiral phosphine
ligands such as the powerful BIBOP family of ligands for
asymmetric catalysis.12 Further applications of this chemistry to
the synthesis of new ligands and their use in asymmetric
transformations are under investigation.
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Capacci, A. G.; White, A.; Ma, S.; Rodriguez, S.; Qu, B.; Savoie, J.; Patel,
N. D.; Wei, X.; Haddad, N.; Grinberg, N.; Yee, N. K.; Krishnamurthy,
D.; Senanayake, C. H. Org. Lett. 2010, 12, 1104. (c) Tang, W.; Patel, N.
D.; Xu, G.; Xu, X.; Savoie, J.; Ma, S.; Hao, M. H.; Keshipeddy, S.;
Capacci, A. G.; Wei, X.; Zhang, Y.; Cao, J. J.; Li, W.; Rodriguez, S.; Lu, B.;
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data and spectra, and
crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
steve.han@boehringer-ingelheim.com
■
(13) (a) Leyris, A.; Nuel, D.; Giordano, L.; Achard, M.; Buono, G.
Tetrahedron Lett. 2005, 46, 8677. (b) den Heeten, R.; Swennenhuis, B.
H. G.; van Leeuwen, P. W. N. M.; de Vries, J. G.; Kamer, P. C. J. Angew.
Chem., Int. Ed. 2008, 47, 6602. (c) Zupancic, B.; Mohar, B.; Stephan, M.
Org. Lett. 2010, 12, 3022 and references cited therein. (d) Brown, J. M.;
Laing, J. C. P. J. Organomet. Chem. 1997, 529, 435. (e) Maienza, F.;
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Chem. 2002, 67, 5239. (f) Mohar, B.; Modec, B.; Sterk, D.; Stephan, M.
M. S. J. Org. Chem. 2007, 72, 8010. (g) Colby, E. A.; Jamison, T. F. J. Org.
Chem. 2003, 68, 156.
(14) Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.; Han, Z.; Gallou, I.
Aldrichimica Acta 2005, 38, 93.
(15) See the Supporting Information (SI) for results on the effect of
bases and solvents on the selectivity.
(16) See the SI for information on single-crystal X-ray structures.
(17) (a) Um, I.-H.; Shin, Y.-H.; Han, J.-Y.; Mishima, M. J. Org. Chem.
2006, 71, 7715. (b) pKa values for ROH: Ballinger, P.; Long, F. A. J. Am.
Chem. Soc. 1960, 82, 795.
Present Address
†Department of Chemistry and Biochemistry, Old Dominion
University, Norfolk, VA 23529.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Scott Pennino and Keith McKellop for HRMS
analysis.
■
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