A facile and practical preparation ofP-chiral phosphine oxides

Article abstract of DOI:10.1039/d1cc00646k

A practical and cost-effective synthetic method ofP-chiral diarylalkyl, aryldialkyl, and triaryl phosphine oxides by using readily available chiral diphenyl-2-pyrrolidinemethanol as the auxiliary is developed. The long-standing racemization issue during s

Full text of DOI:10.1039/d1cc00646k

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A facile and practical preparation of P-chiral
phosphine oxides†
Cite this: Chem. Commun., 2021,
57, 3335
Ronghua Xu,‡a Zhenhua Gao,‡b Yiteng Yu,c Yehua Tang,a Duanshuai Tian,c
Tian Chen,c Yibing Chen,a Guangqing Xu,*c Enxue Shi*b and Wenjun Tang
*
acd
Received 3rd February 2021,
Accepted 26th February 2021
DOI: 10.1039/d1cc00646k
rsc.li/chemcomm
A practical and cost-effective synthetic method of P-chiral diarylalkyl, oxides prepared with reported methods were not highly optically
aryldialkyl, and triaryl phosphine oxides by using readily available pure, indicating a severe racemization during preparation. Thus, a
chiral diphenyl-2-pyrrolidinemethanol as the auxiliary is developed. practical, economically viable, and racemization-free preparation of
The long-standing racemization issue during solvolysis has been P-chiral phosphine oxides remains highly desirable. Herein we
addressed and well controlled by employing a suitable solvent, a report a facile and practical preparation of P-chiral phosphine oxides
low reaction temperature, and an appropriate reaction time.
using readily available chiral diphenyl-2-pyrrolidinemethanol as the
auxiliary.13 The method features good scalability, excellent stereo-
The preparation of P-chiral phosphorus compounds has chemical control, broad substrate scope, and minimal enantio-
received significant attention, not only because of the increasing meric loss.
applications of P-chiral phosphorus ligands for asymmetric catalytic
We reasoned that an auxiliary from a chiral a-amino acid
reactions,1,2 but also due to the ever-growing number of P-chiral would be among the most ideal in terms of both ready avail-
oligonucleotide drugs in the pharmaceutical industry.3 Over the ability and cost effectiveness. In addition, excellent stereo-
last several decades, a series of efficient synthetic methods control was reported in the reaction between arylphosphoryl
of P-chiral phosphorus compounds have been developed, by dichloride and chiral diphenyl-2-pyrrolidinemethanol, which
employing a number of chiral auxiliaries (Fig. 1). Among them, was readily available as a proline derivative.13b,c Thus, the main
Juge’s ephedrine,4 Corey’s camphor,5 Buono’s menthol,6 issue was the stereospecificity of the three consecutive dis-
´
Jones’ oxazolidinone,7 Baran’s limonene-based thiol,8 Han’s placements with Grignard reagents or solvent (Scheme 1),
2-(1-aminoethyl)-4-chlorophenol,9 Verdaguer’s amino indanol,10 which was not solved completely from the literature
Andrioletti’s 2-amino-cyclohexanol,11 and Framery’s glucosamine12 reports.4,8 Herein we detailed our studies on the stereocontrol
are most well-known, however, they are not without issues. For during the consecutive displacements, leading to a practical
example, some chiral auxiliaries such as ephedrine were controlled synthetic method for a variety of diarylalkyl, aryldialkyl, and
substances, not amenable for scale-up activities; some were relatively triaryl phosphine oxides.
expensive, requiring a multi-step synthetic sequence from readily
We commenced our synthesis with the reaction between
available starting material. More importantly, some phosphine (S)-diphenyl-2-pyrrolidinemethanol (1) and PhP(O)Cl2 to form
a School of Physical Science and Technology, ShanghaiTech University,
Shanghai 200031, China. E-mail: tangwenjun@sioc.ac.cn
b State Key Laboratory of NBC Protection for Civilian, Beijing 102205, China.
E-mail: exshi@sina.com
c State Key Laboratory of Bio-Organic and Natural Products Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Ling Ling Road, Shanghai 200032,
China. E-mail: xugq@sioc.ac.cn
d School of Chemistry and Material Sciences, Hangzhou Institute for Advanced
Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan,
Hangzhou 310024, China
† Electronic supplementary information (ESI) available. CCDC 2060841. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
Fig. 1 Reported chiral auxiliaries applied to the synthesis of P-chiral
d1cc00646k
phosphorus compounds.
‡ R. Xu and Z. Gao contributed equally.
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Table 1 Alcoholysis of 3
Entry
R
x
T (1C)
t (h)
Yield (%)
ee
1
2
3
4
5
6
7
8
Me
iPr
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
1
1
1
0.5
2
3
5
10
1
1
1
1
1
1
1
1
1
1
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ70
ꢀ50
ꢀ30
ꢀ10
0
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
2
3
6
12
90
40
90
20
80
80
75
60
90
60
65
50
45
45
50
55
90
80
74
60
98
96
98
98
94
94
90
87
98
80
75
51
45
30
10
98
98
87
63
37
Scheme 1 Synthetic design of P-chiral phosphine oxides with diphenyl-
2-pyrrolidinemethanol as a chiral auxiliary.
1,3,2-oxazaphospholidine-2-oxide 3 (Scheme 2). By employing a
reported procedure13c with trimethylamine and DMAP as the bases,
the desired product 2 was obtained in 80% yield with 495 : 5
diastereomeric ratio at a 300 g scale. The excellent diastereomeric
control and suitability for scale-up activity set the foundation for
studying the stereospecific displacements in the next three steps.
Pleasingly, treatment of 2 with methyl Grignard reagent formed 3 in
65% yield as a single diastereomeric isomer. Since the direct SN2
replacement of (S)-diphenyl-2-pyrrolidinemethanol under basic
conditions was not possible, the stage was set to remove the chiral
auxiliary stereospecifically by solvolysis in alcohol (Table 1).
It was reported that alcoholic solvolysis could smoothly
remove the diphenyl-2-pyrrolidinemethanol component,13a how-
ever, often resulting in diminished enantioselectivities. We
reasoned that the enantiomeric loss could be largely due to a
second solvolysis of the resulting product 4 (Scheme 3), which
could be well controllable after optimization of the reaction
conditions (Table 2).
9
10
11
12
13
14
15
16
17
18
19
20
r.t.
80
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
1
1
Conditions: the reactions were conducted in alcohol in the presence of
x equiv. H2SO4 at the specified reaction temperature T for t h. Isolated
yields. The enantioselectivities were determined by chiral HPLC.
Thus, the alcoholysis conditions were studied in order to find
a best yield and ee. Screening of the solvent from methanol, to
ethanol, to isopropanol under conditions of 1 equiv. H2SO4
at ꢀ78 1C for 2 h showed that both methanol and ethanol provided
excellent ees as well as yields, while a low conversion was
obtained with isopropanol as the solvent (entries 1–3). Further
studies after a number of experiments showed that more reliable
yields and ees were obtained in ethanol, which was chosen as the
solvent for further studies. The amount of H2SO4 appeared to
play a significant role in both the yields and enantioselectivities.
While employment of 0.5 equiv. H2SO4 proved to be less reactive
(entry 4), more H2SO4 turned out to be detrimental to both
the yields and enantioselectivities (entries 4–8). The reaction tem-
perature was highly important to inhibit the second ethanolysis
and prevent racemization. A low reaction temperature (o70 1C) was
the key to keep the high enantioselectivity, which was not men-
Scheme 3 Rationale of racemization.
carried out at 80 1C. The reaction time was also crucial to the
enantioselectivity. While the methanolysis was not complete in 1 h
(entry 16), a longer reaction time (43 h, entries 18–20) gave low ees.
The results were consistent with the mechanism proposed in
Scheme 3, which provided an excellent yield and ee under the
optimized conditions (2 equiv. H2SO4, ꢀ78 1C, 2 h) and significant
ee loss was observed with a prolonged reaction time or a higher
reaction temperature. Thus, compound 4 was prepared at 98% ee
in 90% yield under the optimized conditions at a decagram scale.
With ample 4 in hand, our next task was to develop a
stereospecific displacement of 4 with a Grignard reagent.
Gratifying, the reaction of 4 with a number of aryl Grignard
reagents with different steric and electronic properties pro-
ceeded smoothly at r.t. with THF as the solvent system
(Table 3). Thus, a series of chiral diarylalkyl phosphine oxides
were formed in good yields and excellent enantioselectivities.
Either electron-donating or -withdrawing substituents at ortho,
meta, or para positions were all compatible. Functionalities
such as methoxy, dimethylamino, acetal, and trifluoromethyl
were all compatible. It should be noted that most P-chiral
phosphine oxides were obtained in 4= 95% ee with minimum
´
tioned or controllable with Juge’s protocol and others. Indeed, a
significant loss of ee (30%) was observed when ethanolysis was
conducted at r.t. and only 10% ee was observed from the reaction
Scheme 2 Synthesis of 3.
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Table 2 Scope of P-chiral diarylalkyl phosphine oxidesa
Scheme 4 Synthesis of phosphine sulfide 6z.
Scheme 5 Gram-scale synthesis of phosphine oxide 5b.
phosphine oxides 5v–5ac in moderate to good yields and excellent
enantioselectivities without loss of optical purity. Under similar
reaction conditions, triaryl phosphine oxides 5ad–af were also
prepared successfully in excellent ee’s and satisfactory yields.
In order to rationalize the stereochemical transformation of
the sequence, the absolute stereochemistry of 5z was studied by
reduction with HSiCl3/Et3N and further treatment with S8 to
form phosphine sulfide 6z, whose absolute configuration was
determined by X-ray crystallography14 (Scheme 4). The inversed
stereochemical process of the reduction of phosphine oxide
under conditions HSiCl3/Et3N determined the S-configuration
of 5z. On the basis of the absolute configuration of 2, 3, 4, and
5, we concluded that the three consecutive displacements from
2 to 5 are all inversed processes.
a
Conditions: the reactions were conducted in THF at r.t. in the
presence of 4 (1 mmol) with R00MgBr (5 equiv.) overnight (12 h). Isolated
yields. The enantioselectivities were determined by chiral HPLC.
To demonstrate the practicality of this method with
(S)-diphenyl-2-pyrrolidinemethanol as the auxiliary, the final
displacement of 4 with (o-MeO)PhMgBr was conducted at
20 gram scale, and the resulting product 5b was obtained in
70% yield and 97% ee (18.7 g) (Scheme 5).
Table 3 Scope of P-chiral diarylalkyl and triaryl phosphine oxidesa
In conclusion, we have developed a practical and cost-
effective synthetic method of P-chiral diarylalkyl, aryldialkyl,
and triaryl phosphine oxides by using readily available chiral
diphenyl-2-pyrrolidinemethanol as the auxiliary. The long-
standing racemization issue during solvolysis was addressed
and solved by employing a suitable solvent, a low reaction
temperature and a suitable reaction time. The high enantios-
electivities (4= 95% ee) and scalability of this method should
facilitate the study of various P-chiral ligands15 in asymmetric
catalysis and research on P-chiral oligonucleotide drugs in the
pharmaceutical industry.
We thank the Strategic Priority Research Program of the
Chinese Academy of Sciences XDB20000000, CAS (QYZDY-SSW-
SLH029), NSFC (21725205, 21572246, 22001112, 21702223, and
22071261), STCSM-18520712200, and Key-Area Research and
Development Program of Guangdong Province (2020B010188003).
a
Conditions: the reactions were conducted in THF at r.t. in the
presence of 4 (1 mmol) with R00MgBr (5 equiv.) overnight (12 h). Isolated
yields. The enantioselectivities were determined by chiral HPLC.
enantiomeric loss. We also looked into the reaction of 4 with alkyl
Grignard reagents (Table 3). Under similar reaction conditions,
primary alkyl, secondary alkyl, and cyclic alkyl Grignard reagents
Conflicts of interest
were all suitable, providing the corresponding aryldialkyl There are no conflicts to declare.
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8 (a) K. W. Knouse, J. N. deGruyter, M. A. Schmidt, B. Zheng,
J. C. Vantourout, C. Kingston, S. E. Mercer, I. M. McDonald,
R. E. Olson, Y. Zhu, C. Hang, J. Zhu, C. Yuan, Q. Wang, P. Park,
M. D. Eastgate and P. S. Baran, Science, 2018, 361, 1234; (b) D. Xu,
R.-B. Nazaret, N. M. Padial, K. W. Knouse, B. Zheng,
J. C. Vantourout, M. A. Schmidt, M. S. Eastgate and P. S. Baran,
J. Am. Chem. Soc., 2020, 142, 5785.
9 (a) Z. S. Han, N. Goyal, M. A. Herbage, J. D. Sieber, B. Qu, Y. Xu, Z. Li,
J. T. Reeves, J.-N. Desrosiers, S. Ma, N. Grinberg, H. Lee,
H. P. R. Mangunuru, Y. Zhang, D. Krishnamurthy, B. Z. Lu,
J. J. Song, G. Wang and C. H. Senanayake, J. Am. Chem. Soc., 2013,
135, 2474; (b) Z. S. Han, H. Wu, Y. Xu, Y. Zhang, B. Qu, Z. Li,
D. R. Caldwell, K. R. Fandrick, L. Zhang, F. Roschangar, J. J. Song
and C. H. Senanayake, Org. Lett., 2017, 19, 1796.
Notes and references
1 For recent reviews on P-chiral phosphorus ligands in asymmetric
catalysis: (a) P. C. J. Kamer and P. W. N. M. Van Leeuween,
Phosphorus (III) Ligands in homogeneous Catalysis: Design and
Synthesis, Wiley & Sons, West Sussex, 2012; (b) W. Tang and
X. Zhang, Chem. Rev., 2003, 103, 3029; (c) A. Grabulosa,
P-Stereogenic Ligands in Enantioselective Catalysis, RSC, Cambridge,
2011; (d) W. Fu and W. Tang, ACS Catal., 2016, 6, 4814; (e) G. Xu,
C. H. Senanayake and W. Tang, Acc. Chem. Res., 2019, 52, 1101;
( f ) T. Wu, G. Xu and W. Tang, Aldrichimica Acta, 2020, 53, 27.
2 For recent reviews on the synthesis of P-chiral phosphines, see:
(a) K. M. Pietrusiewicz and M. Zablocka, Chem. Rev., 1994, 94, 1375;
(b) A. Grabulosa, J. Granell and G. Muller, Coord. Chem. Rev., 2007,
251, 25; (c) J. S. Harvey and V. Gouverneur, Chem. Commun., 2010,
46, 7477; (d) O. I. Kolodiazhnyi, Tetrahedron: Asymmetry, 2012, 23, 1;
´
10 (a) T. Leon, A. Riera and X. Verdaguer, J. Am. Chem. Soc., 2011,
´
´
133, 5740; (b) H. Zijlstra, T. Leon, A. de Cozar, C. Fonseca Guerra,
D. Byrom, A. Riera, X. Verdaguer and F. M. Bickelhaupt, J. Am. Chem.
Soc., 2013, 135, 4483.
´
(e) M. Sutartre, J. Bayardon and S. Juge, Chem. Soc. Rev., 2016,
45, 5771; ( f ) S. Lemouzy, L. Giordano, D. Herault and G. Buono,
´
Eur. J. Org. Chem., 2020, 3351; (g) X. Ye, L. Peng, X. Bao, C.-H. Tan
and H. Wang, Green Synth. Catal., DOI: 10.1016/j.gresc.2020.12.002.
3 (a) S. Agrawal and J. Goodchild, Tetrahedron Lett., 1987, 28, 3539;
(b) M. A. Reynolds, R. I. Hogrefe, A. J. Jaeger, D. A. Schwartz,
T. A. Riley, W. B. Marvin, W. J. Daily, M. M. Caghefi, T. A. Beck,
S. K. Knowles, R. E. Klem and J. J. Arnold, Jr., Nucleic Acids Res.,
1996, 24, 4584; (c) P. S. Miller, Nat. Biotechnol., 1991, 9, 358;
(d) H. Yu, H. Yang, E. Shi and W. Tang, Med. Drug Discovery, 2020,
8, 100063; (e) M. Wang, L. Zhang, X. Huo, Z. Zhang, Q. Yuan, P. Li,
J. Chen, Y. Zou, Z. Wu and W. Zhang, Angew. Chem., Int. Ed., 2020,
59, 20814.
´
11 L. Copey, L. Jean-Gerard, E. Framery, G. Pilet, V. Robert and
B. Andrioletti, Chem. – Eur. J., 2015, 21, 9057.
12 A. D’Onofrio, L. Copey, L. Jean-Gerard, C. Goux-Henry,
´
G. Pilet, B. Andrioletti and E. Framery, Org. Biomol. Chem., 2015,
13, 9029.
13 Previous reports with chiral prolinols as the auxiliaries:
(a) T. Koizumi, R. Yanada, H. Takagi, H. Hirai and E. Yoshii,
Tetrahedron Lett., 1981, 22, 477; (b) M. P. Gamble, J. R. Studley
and M. Wills, Tetrahedron Lett., 1996, 16, 2853; (c) L. Wang, S. Cao,
Z. Du, Q. Wu, Z. Bian, C. Kang, L. Gao and J. Zhang, RSC Adv., 2016,
6, 89665.
´
4 (a) S. Juge and J. P. Genet, Tetrahedron Lett., 1989, 30, 2783;
14 CCDC 2060841 (6z) contains the supplementary crystallographic
data for this paper†.
´
(b) S. Juge, M. Stephan, J. A. Laffitte and J. P. Genet, Tetrahedron
`
Lett., 1990, 31, 6357; (c) E. B. Kaloun, R. Merdes, J. P. Genet, J. Uziel
15 (a) B. Li, T. Li, M. A. Aliyu, Z. H. Li and W. Tang, Angew. Chem., Int.
Ed., 2019, 58, 11355; (b) D. Tian, R. Xu, J. Zhu, J. Huang, W. Dong,
J. Claverie and W. Tang, Angew. Chem., Int. Ed., DOI: 10.1002/
anie.202015450; (c) H. Yang, J. Sun, W. Gu and W. Tang, J. Am.
Chem. Soc., 2020, 142, 8036; (d) K. Li, M. Nie and W. Tang, Green
Synth. Catal., 2020, 1, 171; (e) C. Li, F. Wan, Y. Chen, H. Peng,
W. Tang, S. Yu, J. C. McWilliam, J. Mustakis, L. Samp and
R. J. Maguire, Angew. Chem., Int. Ed., 2019, 58, 13573; ( f ) R. Xu,
H. Yang and W. Tang, Chin. J. Org. Chem., 2020, 14, 581.
´
and S. Juge, J. Organomet. Chem., 1997, 529, 455; (d) C. Bauduin,
´
D. Moulin, E. B. Kaloun, C. Darcel and S. Juge, J. Org. Chem., 2003,
68, 4293.
5 E. J. Corey, Z. Chen and G. J. Tanoury, J. Am. Chem. Soc., 1993,
115, 11000.
6 D. Gatineau, L. Giordano and G. Buono, J. Am. Chem. Soc., 2011,
133, 10728.
7 H. Adams, R. C. Collins, S. Jones and C. J. A. Warner, Org. Lett., 2011,
13, 6576.
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