A new type of chiral sulfinamide monophosphine ligands: Stereodivergent synthesis and application in enantioselective gold(I)-catalyzed cycloaddition reactions

Article abstract of DOI:10.1002/anie.201401067

A simple, new type of chiral sulfinamide monophosphines, the so-called Ming-Phos ligands, is reported; these ligands could be easily prepared from inexpensive and commercially available starting materials. The Ming-Phos ligands performed well in the enantioselective gold-catalyzed cycloaddition reaction of 2-(1-alkynyl)-alk-2-en-1-ones with nitrones. Both enantiomers of the products could be obtained in good yields and with excellent diastereo- and enantioselectivity through transformations that were catalyzed by gold complexes derived from two diastereomers of Ming-Phos ligand M5 (Ar=1-naphthyl). Ming-Phos: A new type of simple chiral sulfinamide monophosphine ligands, the so-called Ming-Phos ligands, can be easily prepared from inexpensive and commercially available starting materials. The enantioselectivity of the reaction of yne-enones?1 with nitrones could be controlled by the diastereomeric ligands (R,R_S)-M5 and (S,R_S)-M5.

Full text of DOI:10.1002/anie.201401067

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Angewandte
Communications
DOI: 10.1002/anie.201401067
Enantioselective Gold Catalysis
A New Type of Chiral Sulfinamide Monophosphine Ligands:
Stereodivergent Synthesis and Application in Enantioselective Gold(I)-
Catalyzed Cycloaddition Reactions**
Zhan-Ming Zhang, Peng Chen, Wenbo Li, Yanfei Niu, Xiao-Li Zhao, and Junliang Zhang*
Abstract: A simple, new type of chiral sulfinamide mono-
phosphines, the so-called Ming-Phos ligands, is reported; these
ligands could be easily prepared from inexpensive and
commercially available starting materials. The Ming-Phos
ligands performed well in the enantioselective gold-catalyzed
cycloaddition reaction of 2-(1-alkynyl)-alk-2-en-1-ones with
nitrones. Both enantiomers of the products could be obtained
in good yields and with excellent diastereo- and enantioselec-
tivity through transformations that were catalyzed by gold
complexes derived from two diastereomers of Ming-Phos
ligand M5 (Ar= 1-naphthyl).
We recently reported a gold(I)-catalyzed asymmetric
cycloaddition of 2-(1-alkynyl)-2-alken-1-ones with nitrones.[4a]
The enantioselectivity was highly dependent on the substitu-
ent of the alkyne moiety of the 2-(1-alkynyl)-2-alken-1-one;
with aryl substituents, excellent enantioselectivity was
observed, whereas only low ee values could be obtained for
substrates with aliphatic substituents. For example, the
reaction of 2-(1-alkynyl)-2-alken-1-one 1a with nitrone 2a
gave the corresponding product 3aa in only 32% and 55% ee
in the presence of the bulky chiral ligands (R)-MeO-dtbm-
biphep (L1) and (R)-C1-tunephos (L2), respectively (Sche-
me 1a). A series of known chiral ligands, such as 2,2’-
G
old complexes have shown their unrivalled power in
organic synthesis over that past decade, which is due to their
high capability to activate p bonds.[1] However, the develop-
ment of enantioselective gold-catalyzed processes[2] poses
considerable challenges, because gold(I) complexes strongly
prefer a linear geometry, which forces the active reaction site
to be far away from the chiral ligand, thus limiting its
capability to transfer chirality. To date, only a few approaches
have been developed that address these issues; these methods
employ chiral atropisomeric biaryl phosphines or spirocyclic
bisphosphines,[3,4] phosphoramidites that often bear bulky or
extended substituents,[5] or helically chiral trivalent phos-
phines[6] as ligands and chiral phosphoric acid derivatives as
counterions.[7,8] The atropisomeric biaryl bisphosphines are
among the most successful ligands in enantioselective gold(I)
catalysis. However, these elaborate biaryl bisphosphine
ligands are difficult to modify and can be more expensive
than the noble metal itself; therefore, alternative principles
for the design of new chiral ligands are highly desirable.
[*] Z.-M. Zhang, P. Chen, Dr. W. Li, Y. Niu, Prof. Dr. X.-L. Zhao,
Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes
Department of Chemistry
Scheme 1. Previous results and this work on asymmetric [3+3] cyclo-
additions. Tf=trifluoromethanesulfonyl.
East China Normal University
3663 N. Zhongshan Road, Shanghai 200062 (P.R. China)
E-mail: jlzhang@chem.ecnu.edu.cn
Homepage: http://faculty.ecnu.edu.cn/s/1811/t/20975/main.jspy
bis(diphenylphosphino)-1,1’-binaphthyl (BINAP), (6,6’-
dimethoxybiphenyl-2,2’-diyl)bis[bis(3,5-dimethoxyphenyl)-
phosphine] (ECNU-Phos), (R)-2-(diphenylphosphanyl)-2’-
methoxy-1,1’-binaphthyl ((R)-MOP), and phosphoramidites
that are derived from 3,3’-disubstituted BINOL derivatives
(BINOL = 1,1’-binaphthalene-2-ol), were also examined, but
unfortunately, no satisfactory enantioselectivity was observed
(see the Supporting Information). Thus, the design of chiral
ligands with a novel structural motif may be the only way to
address this issue.
[**] We thank the National Natural Science Foundation of China
(21372084), the Ministry of Science and Technology of China
(2011CB808600), the Program of Eastern Scholar at Shanghai
Institutions of Higher Learning, and the Changjiang Scholars and
Innovative Research Team in University (PCSIRT) for financial
support. We wish to thank Prof. Shengming Ma for beneficial
discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201401067.
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During the course of our study on enantioselective gold
catalysis, we found that monocationic [LAu2ClX] species (L =
bisphosphine, X = weak counteranion), which were generated
in situ from a 1:1 mixture of [LAu2Cl2] and a AgX activator,
can give better enantioselectivity than these bicationic
[LAu2X2] species,[4a–b] indicating that the second gold site
might either just exert a steric influence or be involved in
a second interaction with the substrate. We thus designed
a new type of chiral ligand, namely Ming-Phos, in which the
chiral sulfinamide moiety might be able to undertake this
interaction with the substrate to control the enantioselectivity.
Herein, we wish to report our efforts on the stereodivergent
synthesis of these new chiral ligands and their applications in
enantioselective gold catalysis. We were pleased to find that
the low enantioselectivity of the reaction of alkyl-substituted
2-(1-alkynyl)-2-alken-1-ones with nitrones could be well
addressed (Scheme 1b).
Figure 1. X-ray crystal structures of (R,RS)-M3 (left) and (S,RS)-M5
(right). Hydrogen atoms on the aryl rings were omitted for clarity.
We started this research project with the stereodivergent
synthesis of two sets of diastereomeric (R,RS)- and (S,RS)-
configured Ming-Phos ligands through a two-step procedure
(Table 1). Chiral sulfinyl imine (RS)-4 could be obtained in
Table 1: Stereodivergent synthesis of two sets of Ming-Phos ligands.[a]
Figure 2. X-ray crystal structure of [{(RS)-M0}AuCl].
attempts to obtain single crystals of the gold complexes of
Ming-Phos M1–M5 failed, a suitable single crystal of [{(RS)-
M0}AuCl] was finally obtained. X-ray diffraction analysis
revealed that the gold atom selectively binds to the phosphine
atom rather than to the other heteroatoms, such as nitrogen,
oxygen, or sulfur, of the sulfinamide moiety (Figure 2).[12]
Next, we studied the performance of these two sets of
diastereomeric Ming-Phos ligands M1–M5 in enantioselective
gold-catalyzed reactions. We initially chose 2-(1-alkynyl)-2-
alken-1-one 1a and nitrone 2a as model substrates (Table 2).
Several points are noteworthy: First, all of the reactions for
which M1–M5 were used as ligands furnished high yields
(> 85%). Second, very small modifications of the substituent
on the aryl ring of the ligand led to significant variations in
Yield[b] [%]
Entry
M
Ar
(R,RS)-M
(S,RS)-M
1
2
3
4
5
M1
M2
M3
M4
M5
Ph
86
66
65
74
79
85
75
70
90
83
4-EtOC6H4
4-MeOC6H4
3,5-(tBu)2-4-MeOC6H2
1-naphthyl
[a] The diastereomeric ratios were determined by 1H NMR analysis of the
crude products to be >15:1 for all reactions.
Table 2: Screening of Ming-Phos ligands.[a]
80% yield by the condensation reaction of 2-(diphenylphos-
phino)benzaldehyde (2150 $/kg)[9] and (RS)-tert-butanesulfi-
namide (745 $/kg)[9] according to a modified literature
procedure.[10a] The stereoselective addition of RLi to (RS)-4
afforded a set of Ming-Phos derivatives (R,RS)-M1–M5 in 65–
86% yield with excellent diastereoselectivity (d.r. > 15:1).[11]
Accordingly, the other set of Ming-Phos ligands, namely
(S,RS)-M1–M5, could also be obtained in 70–90% yield from
the stereoselective addition of RMgX to (RS)-4. The absolute
configurations of the two sets of Ming-Phos ligands were
established by single-crystal X-ray diffraction analysis of
(R,RS)-M3 and (S,RS)-M5 (Figure 1).[12] Fortunately, although
Entry Ligand
ee of ent-3a [%]
Entry Ligand
ee of 3a [%]
1
2
3
4
5
(R,RS)-M1
83
80
92
95
96
6
(S,RS)-M1
89
91
73
93
94
(R,RS)-M2
(R,RS)-M3
(R,RS)-M4
(R,RS)-M5
7
8
9
10
(S,RS)-M2
(S,RS)-M3
(S,RS)-M4
(S,RS)-M5
[a] The ee was determined by HPLC analysis on a chiral stationary phase
(AD-H). The absolute configuration of the product was determined by
comparison of the HPLC spectrum with that in Ref. [4a]; ent-3a is the
enantiomer of 3a.
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Table 3: Synthesis of optically active ent-3 with ligand (R,RS)-M5.
enantioinduction; for example,
using (R,RS)-M3 (Ar= 4-
MeOC6H4) instead of (R,RS)-M2
(Ar= 4-EtOC6H4) results in an
increase in the ee of ent-3a from
80% to 92% (entries 2 and 3),
whereas a large drop in enantio-
meric excess was observed for 3a
when (S,RS)-M3 was used instead of
(R,RS)-M2. Third, both enantio-
mers of a chiral compound are
nowadays often required in organic
synthesis, biological chemistry, and
the medicinal and pharmaceutical
industries. Much to our delight,
both enantiomers 3a and ent-3a
could be obtained in high yields
and with 96% and 94% ee, respec-
tively, when the diastereomeric
ligands (R,RS)-M5 and (S,RS)-M5
were applied; this finding repre-
Entry
R1; R2; R3 (1)
R4; R5 (2)
ent-3
Yield[b] [%]
ee [%]
1
2
3
4
5
6
7
8
nBu; Me; Ph (1a)
1a
1a
1a
1a
1a
Cl(CH2)3; Me; Ph (1b)
AcO(CH2)2; Me; Ph (1c)
nPr; Me; Ph (1d)
nBu; Ph; 4-CH3OC6H4 (1e)
nBu; Me; 4-CH3C6H4 (1 f)
Ph; Ph (2a)
4-MeC6H4; Ph (2b)
Ph; 3,4,5-(MeO)3C6H2(2c)
Ph; 4-MeOC6H4(2d)
3-ClC6H4; 4-MeOC6H4 (2e)
Ph; styryl (2 f)
2a
2a
2a
2a
2a
ent-3a
ent-3b
ent-3c
ent-3d
ent-3e
ent-3 f
ent-3g
ent-3h
ent-3i
ent-3j
ent-3k
92
92
85
96
87
85
99
92
85
92
94
96
95
97
98
96
93
94
96
95
97
92
9
10
11
[a] Unless otherwise specified, the reaction was carried out using ketone 1 (0.4 mmol), nitrone 2
(0.44 mmol), (R,RS)-M5 (5.5 mol%), [Me2SAuCl] (5 mol%), and AgNTf2 (5 mol%) in DCE at À108C.
[b] Yield of isolated product. The diastereomeric ratios were determined to be >95:5 by 1H NMR
analysis of the crude products for all reactions. DCE=1,2-dichloroethane.
sents
a significant improvement
compared to our previous work.
Having established the most
suitable ligands for the synthesis of
both 3a and ent-3a, we next focused
on the substrate scope of this trans-
formation (Table 3). First, various
nitrones with different electron-
withdrawing and -donating aryl
and styryl substituents were exam-
ined (entries 2–6). The correspond-
ing optically active products ent-3a–
3 f were obtained in 85–96% yield
as single diastereomers with excel-
Table 4: Synthesis of optically active 3 with ligand (S,RS)-M5.[a]
Entry
R1; R2; R3 (1)
R4; R5 (2)
3
Yield[b] [%]
ee [%]
1
nBu; Me; Ph (1a)
Ph; Ph (2a)
3a
3b
3c
3d
3e
3 f
3g
3h
3i
86
85
90
91
88
86
99
95
88
99
91
94
97
99
93
98
95
99
99
97
97
97
2
1a
4-MeC6H4; Ph (2b)
3
1a
Ph; 3,4,5-(MeO)3C6H2 (2c)
lent
enantioselectivities
(93–
4
1a
Ph; 4-MeOC6H4 (2d)
98% ee). Then, the scope of alkyl-
substituted 2-(1-alkynyl)-2-alken-1-
ones 1 was investigated, and the
corresponding products ent-3g–3k
were isolated in 85–99% yield and
with 92–97% ee (entries 7–11).
Gratifyingly, compounds 1b and
5
1a
3-ClC6H4; 4-MeOC6H4 (2e)
6
1a
Ph; styryl (2 f)
7
8
9
10
11
Cl(CH2)3; Me; Ph (1b)
AcO(CH2)2; Me; Ph (1c)
nPr; Me; Ph (1d)
nBu; Ph; 4-CH3OC6H4 (1e)
nBu; Me; 4-CH3C6H4 (1 f)
2a
2a
2a
2a
2a
3j
3k
1c, which bear an alkyl chloride [a] Unless otherwise specified, the reaction was carried out using ketone 1 (0.4 mmol), nitrone 2
(0.44 mmol), (S,RS)-M5 (5.5 mol%), [Me2SAuCl] (5 mol%), and AgNTf2 (5 mol%) in DCE at À108C.
[b] Yield of isolated product. All diastereomeric ratios were determined to be >95:5 by 1H NMR analysis
of the crude products.
and an alkyl ester, respectively,
were also compatible with this
transformation, and gave the corre-
sponding products ent-3g and ent-
3h in 99% yield and 94% ee and in
92% yield and 96% ee, respectively (entries 7 and 8). More-
over, good results were obtained for the reactions of 1e and
1 f with nitrone 2a, which further emphasize the large
substrate scope of this enantioselective transformation. We
then turned to the use of (S,RS)-M5 as a chiral ligand
(Table 4). To our delight, all of the reactions of a broad range
of 2-(1-alkynyl)-2-alken-1-ones (1a–1 f) with various nitrones
(2a–2 f) also furnished the desired enantioenriched products
3a–3k in high yields and as single diastereomers with 93–
99% ee.
To our delight, this new type of chiral ligand also
performed well in other gold(I)-catalyzed asymmetric cyclo-
addition processes. For example, a gold complex derived from
(S,RS)-M5 could be employed for the asymmetric gold-
catalyzed formal [4+3] cycloaddition of 1-(1-alkynyl)cyclo-
propyl ketone 5 with nitrone 2a, and the desired cycloadduct
6 was obtained in 94% yield with 89% ee [Eq. (1)]. These
results are comparable with those obtained for the expensive
chiral ligands (R)-MeO-dtbm-biphep (L1; 3 mol%, 87%
yield, 91% ee).[13] More importantly, this formal [4+3] cyclo-
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Received: January 31, 2014
Published online: March 20, 2014
Keywords: asymmetric catalysis · cycloaddition ·
.
enantioselectivity · gold · phosphine ligands
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addition is a dynamic kinetic resolution and mechanistically
distinct from the formal [3+3] cycloaddition of 2-(1-alkynl)-
alk-2-en-1-ones with nitrones, indicating that Ming-Phos
ligands may be applicable to other enantioselective gold-
catalyzed reactions.
In summary, we have developed a new type of chiral
sulfinamide monophosphine ligands, the so-called Ming-Phos
ligands. Two sets of diastereomeric Ming-Phos ligands could
be obtained in good yields with high diastereoselectivity from
commercially available, inexpensive starting materials. Wide
structural diversity can be achieved by changing the organ-
ometallic reagents. Moreover, Ming-Phos ligands performed
well in two mechanistically distinct gold-catalyzed cyclo-
addition reactions. For the asymmetric cycloaddition reaction
of 2-(1-alkynl)-alk-2-en-1-ones with nitrones, both enantio-
mers could be furnished in high yields with excellent
diastereo- and enantioselectivity by the employment of
(R,RS)-5 and (S,RS)-M5, respectively. The salient features of
these new chiral ligands, including their simple structure, air
stability, the practical preparation from readily available
starting materials, easy modification, and good results in
enantioselective transformations, render these ligands very
attractive. Further studies, such as an investigation of the
performance of these ligands in other metal-catalyzed asym-
metric reactions, are underway in our laboratory and will be
reported in due course.
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Experimental Section
Typical procedure for the synthesis of (S,RS)-M5: The sulfinyl imine
(RS)-4 was prepared according to a modified literature procedure;[10a]
Ti(OiPr)4 was used instead of Ti(OEt)4. A solution of 1-naphthyl-
magnesium bromide in Et2O (2.0 equiv, 1.0m, 10 mL) was added to
a solution of (RS)-4[10a] (5.0 mmol, 2.0 g) in CH2Cl2 (20 mL) at À488C.
The mixture was stirred at this temperature for 4 h and then warmed
to room temperature. After stirring overnight, the reaction mixture
was quenched by the addition of aqueous NH4Cl and diluted with
EtOAc. After separation of the organic layer, the aqueous layer was
extracted twice with EtOAc. The combined organic layers were dried
over Na2SO4. After filtration and concentration, the residue was
purified by flash column chromatography on silica gel to afford
(S,RS)-M5 (2.2 g, 83%).
Typical procedure for the synthesis of optically active 3a: A
solution of (S,RS)-M5 (5.5 mol%, 11.5 mg) and [Me2SAuCl]
(5.0 mol%, 5.9 mg) in CH2Cl2 (1 mL) was stirred at room temper-
ature for 2 h; then, the solvent was removed in vacuum. A solution of
AgNTf2 (5.0 mol%, 7.8 mg) in DCE (1 mL) was added to the residue,
and the mixture was stirred at À108C for 15 min. A solution of 1a
(0.40 mmol, 90.4 mg) and nitrone 2a (0.44 mmol, 86.7 mg) in DCE
(3 mL) was transferred to the above catalyst solution at À108C, and
the resulting mixture was stirred at this temperature until the reaction
was completed (determined by TLC). After removal of the solvent
under reduced pressure, the residue was purified by flash column
chromatography on silica gel to afford 3a (146.0 mg, 86% yield, 94%
ee).
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Communications
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