Asymmetric Synthesis of P-Stereogenic Compounds via Thulium(III)-Catalyzed Desymmetrization of Dialkynylphosphine Oxides

Article abstract of DOI:10.1021/acscatal.9b00860

A chiral thulium(III)-catalyzed sulfur-conjugation addition reaction of dialkynylphosphine oxides to construct P-stereogenic centers has been developed. Dialkynylphosphine oxides bearing aryl, alkyl, alkenyl substitution at the alkyne terminus position we

Full text of DOI:10.1021/acscatal.9b00860

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Letter
Asymmetric Synthesis of P-Stereogenic Compounds via Thulium
(III)-Catalyzed Desymmetrization of Dialkynylphosphine Oxides
Yu Zhang, Fengcai Zhang, Long Chen, Jian Xu, Xiaohua Liu, and Xiaoming Feng
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00860 • Publication Date (Web): 24 Apr 2019
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Asymmetric Synthesis of P-Stereogenic Compounds via Thulium
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(III)-Catalyzed Desymmetrization of Dialkynylphosphine Oxides
Yu Zhang, Fengcai Zhang, Long Chen, Jian Xu, Xiaohua Liu,* and Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, China
ABSTRACT: A chiral thulium(III) catalyzed sulfur-conjugation addition reaction of dialkynylphosphine oxides to construct P-
stereogenic centers has been developed. Dialkynylphosphine oxides bearing aryl, alkyl, alkenyl substitution at the alkyne terminus
position were tolerated under the reaction conditions. The corresponding P,S-containing compounds were obtained in moderate to
good yields (up to 92% yield) with high Z/E ratios and enantioselectivities (up to >95/5 Z/E and 97% ee), which could be trans-
formed into versatile optically active phosphine oxide derivatives. X-ray single crystal structures of chiral N,N'-dioxides with rare-
earth metal triflates revealed how the center metal and ligand structure affect the enantioselectivity.
KEYWORDS: desymmetrization, dialkynylphosphine oxides, sulfur nucleophiles, P-stereogenic centers, thulium
Chiral phosphorus compounds are widely used as ligands1
or organocatalysts in asymmetric catalysis.2 The prominent
chiral induction in numerous catalytic asymmetric reactions
provides a justification for development of approaches to syn-
thesis of those enantiomerically enriched phosphorus deriva-
tives. Several enantioselective synthetic methods have been
developed for this purpose.3 Traditional methods for the syn-
thesis of P-stereogenic phosphorus compounds usually rely on
the chiral reagent- or auxiliary group-assisted transfor-
mations.4 Recently, several catalytic enantioselective synthetic
methods have been introduced.5 Among them, the desymme-
trization of prochiral phosphorus compounds with two same
substituents including dimethyl,6 dihydroxyl,7 diphenyl,8 dial-
kenyl9 and dialkynyl10 groups has been reported. For these
reactions, transition metal catalyzed and organocatalyzed pro-
cesses were frequently utilized. However, the scope and effi-
ciency of most of the approaches await further improvements.
There are two examples related to desymmetrization of dial-
kynylphosphine oxides (Scheme 1). Tanaka firstly reported the
desymmetrization of dialkynylphosphine oxides using Rh(I)-
catalyzed [2+2+2] cycloaddition with 1,6-diynes (Scheme
1a).10a Nevertheless, the methyl group on the phosphorus cen-
ter and aryl groups at the alkyne terminus were required to get
good results. Recently, Zi achieved Au(I)-catalyzed desymme-
trization of dialkynylphosphine oxides by an intramolecular
hydroetherification reaction (Scheme 1b).10b However, the
substrate scope focused on o-hydroxyphenol groups on the
phosphorus center and aryl groups at the alkyne terminus.
Therefore, developing new methods as well as novel chiral
catalytic systems for synthesis of versatile P-stereogenic com-
pounds is meaningful and desirable.
nide complexes are generally quite electropositive, and exhibit
high coordination numbers such as 7, 8, or to the maximum 12
because of their large ionic radii. The tetra-dentate N,N'-
dioxides could be assembled around the metal ions, creating
variable integrated chiral space for the control of enantioselec-
tivity in the reaction. We anticipated that oxophilic lanthanide
metal complexes are appropriate to activate dialknylphosphine
oxides compounds by selective coordination at the vacant
Scheme 1. Catalytic desymmetrization of dial-
kynylphosphine oxides
Chiral N,N'-dioxides (Figure 1) are useful ligands in Lewis
acid catalyzed asymmetric reactions,11 especially employed for
the in situ formation of rare-earth complex catalysts. Lantha-
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Figure 1. Chiral ligands used in the reaction
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positions, enabling a desymmetrization process via an inter-
molecular conjugation addition reaction (Scheme 1c). Herein,
we present an efficient sulfur-addition reaction12 of dial-
kynylphosphine oxides catalyzed by a new seven-coordinate
chiral N,N'-dioxide-thulium (III) complex catalyst with pen-
tagonal bipyramidal geometries. The hard Lewis-acidity of
lanthanide metal complex avoided catalyst poison caused by
sulfur-containing reagents. A wide range of substituted dial-
kynylphosphine oxides, as well as sulfur nucleophiles were
tolerated under the mild reaction conditions, providing P-
stereogenic products with moderate to good yields and excel-
lent enantioselectivities. In addition, several dodecahedral
coordinations are illustrated by other lanthanide metal ions,
such as Pr3+, Gd3+, Ho3+, and Dy3+. The dependency of the
enantioselectivity of the reaction on the ionic radii of the rare-
earth metal complexes of N,N'-dioxide were studied based on
their X-ray crystal diffraction analysis data. It would help to
rational choose of metal salts for chiral N,N'-dioxide ligand-
involved asymmetric catalysis.
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Figure 2. The influence of rare-earth metal ions on the
reaction
indicating the amide units of the ligand play an extremely im-
portant role for the discrimination of the dialkynyl groups of
the substrate 1a. Thus, L-RaPr3 was chosen as the optimal
ligand in terms of enantioselection (entry 4). When the reac-
tion was performed in p-xylene instead of toluene, the enanti-
oselectivity increased to 87% ee (entry 8). Lowering the reac-
tion temperature to 35 ºC resulted in slightly improved reactiv-
ity and enantioselectivity (entry 9). After increasing the ratio
of L-RaPr3 to Tm(OTf)3, and the ratio of sulfur-nucleophile to
dialkynylphosphine oxide 1a, and decreasing the amount of
We began our investigation by choosing dialkynylphosphine
oxide 1a as the model substrate and methyl thioglycolate 2a as
the nucleophile, to optimize the reaction conditions. Firstly,
various rare-earth metal triflates [RE(OTf)3] coordinated with
N,N'-dioxide L-PiPr2 (Figure 1) in situ were examined in tol-
uene at 60 ºC (Figure 2). There were an interesting phenome-
non that the reactivity and enantioselectivity was significantly
influenced by the differences in ionic radii of RE(OTf)3 salts.
As shown in Figure 2, the desymmetric addition product 3aa
via sulfur-conjugate addition was obtained with 10% yield in a
racemic version in the present of Sc(OTf)3 whose metal center
has smallest ionic radius. Notably, La(OTf)3 with the largest
ionic radius delivered the product with dramatically increased
yield (76%) and 21% ee. Moreover, the enantioselectivity
enhanced gradually as the ionic radii reduces from La3+ to
Ho3+, accompanied by high reactivity. However, the yield of
the reaction dropped smoothly from Ho3+ to Lu3+, whereas the
enantioselectivity was generally satisfied. Y3+ and Ho3+ have
similar ion radius, which resulted in similar enantioselectivity
and reactivity. Typically, L-PiPr2/Tm(OTf)3 enabled the for-
mation of chiral phosphine oxide 3aa in 52% yield with up to
70% ee. The influence of the rare earth metal ions on the enan-
tioselectivity reflected tunable stereoenvironment raised from
the nature of the metal centers.
Table 1. Optimization of the reaction conditionsa
entry
ligand
T
L/Tm3+
(mol%)
yield
(%)
ee
(%)
(oC)
1
L-PrPr2
L-PiPr2
60
60
60
60
60
60
60
60
35
35
35
10/10
10/10
10/10
10/10
10/10
10/10
10/10
10/10
10/10
10/15
10/15
54
52
51
52
58
53
27
47
50
44
81
48
70
79
84
42
35
0
2
3
L-RaPr2
L-RaPr3
L-RaEt2Me
L-RaMe2
L-RaAd
L-RaPr3
L-RaPr3
L-RaPr3
L-RaPr3
4
5
6
7
8b
9b
10b
11c
87
89
95
97
Subsequent exploration of chiral N,N'-dioxide ligands (Fig-
ure 1) revealed that the steric hindrance created by the use of
different amino acids and amines are also critical to the enan-
tioselectivity (Table 1). With the use of Tm(OTf)3 as the opti-
mal metal salt, ee value of the reaction grew up gradually
when the steric hindrance of either the amino acids (entries
1−3) or anilines (entries 3−6) used for the ligand synthesis
increased. Nevertheless, when 1-adamantyl amine-derived
ligand L-RaAd was used, desymmetrization process failed to
yield 3aa as a racemate with a reduced yield (entry 7),
aUnless otherwise noted, the reaction were carried out with Tm(OTf)3
(10 mol % ), ligand (10-15 mol % ), 1a (0.1 mmol), 2a (1.1 equiv) and 4
Å M.S. (20 mg) in toluene (1.0 mL) at the indicate time for 24 h. Isolated
yield of 3aa by silica gel chromatography. Ee was determined by UPC2
analysis (Daicel CHIRALPAK IC-3). bIn p-xylene (1.0 mL). c2a (2.0
equiv) and in p-xylene (0.2 mL) for 20 min.
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Table 2. Substrate scope of dialkynylphosphine oxidesa
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b
aReaction conditions: the same as entry 11 in table 1. Yb(OTf)3-L-RaPr3 (1:1.2, 10 mol %).
solvent, the yield improved to 81% with 97% ee (entries
10−11). We therefore chose the reaction conditions in Table 1,
entry 11 for further studies.
containing heteroaromatic groups at the alkyne terminus posi-
tion were employed, they could produce the corresponding
products 3ia−3ja in moderate yields and excellent enantiose-
lectivities.
Subsequently,
other
challenging
dial-
With the optimized reaction conditions in hand, the sub-
strate scope of dialkynylphosphine oxides was then investigat-
ed (Table 2). The alkyne bearing electron-withdrawing and
electron-donating substituents at para-position of terminus
aryl groups could undergo the transformations smoothly,
providing the products 3ba−3ea in 44 − 86% yields and
92−95% ee. When increasing the steric hindrance at the ortho-
position, a moderate yield and enantioselectivity was obtained
(3fa). meta-Substituted substrates were compatible with the
reaction conditions, giving P-stereogenic alkynylphosphine
oxides 3ga and 3ha in moderate to good yields and excellent
enantioselectivities. Moreover, if dialkynylphosphine oxides
kynylphosphine oxides substrates bearing alkyl group at the
alkyne terminus were investigated. Gratifyingly, linear,
branched as well as cyclic alkyl substituents could be tolerable,
affording 3ka−3pa with moderate to good yields and high
enantioselectivities. Those containing functional groups at the
end or middle of the alkyl chain, including phenyl (3qa, 3ra),
oxygen (3sa), chlorine (3ta) were well tolerated under catalyt-
ic reaction conditions. It was noteworthy that alkenyl substi-
tuted substrates did not influence the reaction efficiency and
regioselectivity to yield the alkyne-addition products 3ua and
3va. Changing the phenyl group on the phosphorus center to
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methyl group delivered the desired product 3wa with high
Scheme 2. Gram-scale reaction and transformations of 3ba
yield and moderate enantioselectivity. The increase of steric
hindrance on the phosphorus center shows low reactivity but
good enantioselectivity (3xa). The absolute configuration of
3ba was determined to be (S, Z) by X-ray crystal diffraction
analysis.13 In these cases investigated, Z-type alkene substitu-
ent on phosphine oxides were generated.
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Table 3. Substrate scope of sulfur nucleophilesa
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Lawesson’s reagent afforded P-stereogenic alkynylphosphine
sulfide 5ba in excellent yield with slightly reduced chirality.
Rh(I)-catalyzed [2+2+2] cycloaddition with 1,6-diynes was
also applied to transform optically active 4ba into diaryl sub-
stituted phosphine oxide 6ba in quantitative yield. Subsequent
Pd-catalyzed hydration of 4ba gave 7ba with 54% yield with-
out erosion of the enantioselectivity.
aReaction conditions: the same as entry 11 in table 1. bCondition A:
Dy(OTf)3-L-PiPr2 (1:1.2, 10 mol %), 1a (0.1 mmol), 2 (0.2 mmol) and 4
Å M.S. (20 mg) in toluene (0.2 mL) at 45 oC for 24 h. cCondition B:
Dy(OTf)3-L-PiAd (1:1.2, 10 mol %), 1a (0.1 mmol), 2 (0.2 mmol) and 4
Å M.S. (20 mg) in toluene (0.2 mL) at 45 oC for 24 h.
Encouraged by the results obtained from methyl thioglyco-
late 2a, we extended this catalytic system to desymmetrization
of dialkynylphosphine oxide 1a with various sulfur nucleo-
philes (Table 3). Ethyl thioglycolate 2b with variation in the
size of the ester group did not affect the outcome, giving 3ab
with excellent yield and enantioselectivity. Besides, 6-
methylbenzo[d]thiazole-2-thiol 2c participated in this reaction
well when higher temperature and longer time were employed,
generating 3ac with excellent yield and moderate enantiose-
lectivity. Interestingly, an opposite sense of asymmetric induc-
tion were found upon homochiral ligand L-PiPr2 and L-PiAd
were used in coordination with Dy(OTf)3.14 Highly optically
active phosphine oxide 3ac could be isolated in good enanti-
oselectivity after recrystallization. A poor result was observed
when 4-bromothiophenol 2d was tested, whereas 2-
aminobenzenethiol 2e underwent the reaction in sharply raised
ee value. It implies that a weak coordination functional group
might involve in the enantioselective step. The reaction could
be extended to 2-mercaptoethanol 2f, but the corresponding
product 3af was isolated in 55% yield with only 7% ee, maybe
because the small hydroxyl group cause the steric hindrance is
not obvious in the enantioselective step.
Scheme 3. Application of 4ba in an enantioselective reduc-
tive aldol reaction
To further investigate the utility of the obtained chiral al-
kynylphosphine oxides, chiral derivative 4ba bearing phos-
phine oxide and sulfone functional groups was subsequently
evaluated as potential Lewis base catalyst in enantioselective
reductive aldol reaction between chalcone 8 and benzaldehyde
9 (Scheme 3).15 The desired aldol adduct 10 could be provided
with 73% yield, 80/20 syn/anti ratio with 70% ee (syn-10).
This indicated that the catalytic products have potential as
chiral catalysts in organic chemistry.
We got several X-ray single crystal structures of chiral
N,N'-dioxide with rare-earth metal triflates,16 which help to
understand how did the center metal and ligand structure af-
fect the enantioselectivity. Our previous study has showed that
chiral N,N'-dioxide could act as a tetra-oxygen ligand to coor-
dinate with Sc(III) in a octahedral version.11 It was found that
the complexes of L-RaPr2 with Pr(OTf)3, Gd(OTf)3 and
Ho(OTf)3, a square antiprismatic geometry version is estab-
lished (Figure 3a−c). Interestingly, a seven-coordinate state is
formed when Tm(OTf)3 is used as the metal precursor (Figure
3e). It is obvious that the coordination numbers and steric bias
is inherent in the rare-earth metal ions. (1) The coordination
To evaluate the synthetic potential of the current catalytic
system,
a
gram-scale reaction between phenylbis(p-
tolylethynyl)phosphine oxide 1b and methyl thioglycolate 2a
was performed, furnishing the product 3ba in 83%
yield, >95/5 Z/E and 94% ee (Scheme 2). Oxidation of the 3ba
by m-CPBA generated the corresponding sulfone 4ba in near-
ly quantitative yield and 98% ee. Treatment of 4ba with
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Figure 3. X-ray single crystal structures of chiral N,N'-dioxides with rare-earth metal triflates
numbers increased with the increasement of the ionic radii of
the rare-earth metal ions, thus vacant sites that can be attached
or recognized upon binding of the substrate molecules varied
accordingly. (2) The cavity around the metal center is created
by the units of both the aniline substituents and the aza-cyclic
structure of the amino acid: the larger ionic radii of the RE(III),
the larger space, observing from the distance of the C1-RE(III)
(d1 and d2) and C5-RE(III) (d3 and d4) in Figure 3a−c, e−f. (3)
In connection with the enantioselection shown in Figure 2, it
could be concluded that larger or smaller cavity in the catalyst
[Pr, Gd or Ho, Sc vs. Tm (Figure 3g−i)] is not beneficial to the
discrimination of the dialkyne groups of the phosphine oxide
with thioglycolate. The moderate space from Tm(III) catalyst
prefers the coordination of both phosphine oxide and thiogly-
colate for enantioselective nucleophilic addition.
The relationship between the ee values of ligand L-RaPr3
and the product 3aa was explored.17 A nonlinear effect was
not observed, which suggests that L-RaPr3 coordinated with
the Tm3+ ions in a 1:1 ratio (for details see the Supporting In-
formation). The HRMS spectrum of a mixture of Tm(OTf)3/L-
RaPr3 and 1a (1/1/1) confirmed coordination of the phosphine
oxide to the catalyst. Peaks at m/z 714.2794 and 1577.5344
were assigned to [Tm3+ + L-RaPr3 + 1a + TfO−]2+ and [Tm3+
+
L-RaPr3 + 1a + 2TfO−]+ respectively (for details see the Sup-
porting Information). Based on the studies above and the abso-
lute configuration of products and L-RaPr3/Tm(OTf)3 com-
plex, a transition state was proposed to rationalize the stere-
oinduction (Figure 4). Preliminarily, the four oxygen atoms of
ligand L-RaPr3 coordinate to Tm3+ in a tetradentate manner.
The dialkynylphosphine oxide coordinates to the metal center
at one of the vacant sites, with the two alkyne groups stretch-
ing along the opening band between the two amide-amine
oxide units. The vacant position towards the L-ramipril back-
bone might be occupied by the thioglycolate. As shown in
Figure 4b, the left alkyne group is blocked by the 2,4,6-
triisopropylphenyl group left-handed, and the sulfur-
nucleophile preferably attacks the right alkynyl group with
Figure 4. The proposed transition states
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Alkenes: Diastereo- and Enantioselective Halogenative Cycli-
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dates. J. Am. Chem. Soc. 2014, 136, 14734−14737. (e) Beaud,
R.; Phipps, R. J.; Gaunt, M. J. Enantioselective Cu-Catalyzed
Arylation of Secondary Phosphine Oxides with Diaryliodoni-
um Salts toward the Synthesis of P−Chiral Phosphines. J. Am.
Chem. Soc. 2016, 138, 13183−13186. (f) Lim, K. M.-H.;
Hayashi, T. Dynamic Kinetic Resolution in Rhodium-
Catalyzed Asymmetric Arylation of Phospholene Oxides. J.
less steric hindrance (Figure 4a) to generate the corresponding
(S, Z)-configured product 3ba.
In summary, we have demonstrated the first Lewis acid cat-
alyzed desymmetrization of prochiral dialkynylphosphine
oxides with various sulfur nucleophiles. The desired substitut-
ed alkynylphosphine oxides with P-stereogenic center were
afforded with high reactivity, Z/E selectivities and enantiose-
lectivities (up to 92% yield, >95/5 Z/E and 97% ee). The func-
tionalized alkynylphosphine oxides can be easily transformed
to other useful chiral building blocks. The center metal and
ligand structure play an important role for the discrimination
of the dialkynyl groups of the substrate. Tm(III) catalyst hav-
ing the moderate cavity prefers concise coordination of both
phosphine oxide and thioglycolate for enantioselective nucle-
ophilic addition. Further investigations on the other type of
desymmetrization of prochiral phosphorus compounds are
underway.
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ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, full spectroscopic data for all new com-
pounds, and copies of 1H, 13C, 31P NMR, and HPLC spectra (PDF)
X-ray crystallographic data for 3ba (CIF)
AUTHOR INFORMATION
Corresponding Author
*liuxh@scu.edu.cn
*xmfeng@scu.edu.cn
ORCID
Yu Zhang: 0000-0001-9849-1669
Fengcai Zhang: 0000-0002-3907-5996
Long Chen: 0000-0003-2287-5417
Jian Xu: 0000-0002-7881-5416
Xiaohua Liu: 0000-0001-9555-0555
Xiaoming Feng: 0000-0003-4507-0478
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We appreciate the National Natural Science Foundation of China
(Nos. 21890723 and 21625205) for financial support.
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