Development of Novel Chloramphenicol Scaffold-Based Chiral Hydroxyl Oxazoline Ligands and Their Application to the Asymmetric Alkynylation of Isatins

Article abstract of DOI:10.1002/adsc.201800581

The synthesis of new chloramphenicol base-derived chiral hydroxyl oxazoline ligands, and their use in the first Zn(OTf)₂-catalyzed enantioselective alkynylation of isatins are described. This transformation features mild reaction conditions, a remarkably broad substrate scope, and excellent functional group tolerance, affording the corresponding tertiary propargylic alcohols in high yields and with high enantioselectivities. The application of chiral hydroxyl oxazolines as ligands in Zn(II)-catalyzed asymmetric alkynylation reactions is unprecedented. (Figure presented.).

Full text of DOI:10.1002/adsc.201800581

Title: Development of Novel Chloramphenicol Scaffold-Based Chiral
Hydroxyl Oxazoline Ligands and Their Application to the
Asymmetric Alkynylation of Isatins
Authors: lei chen, Guanxin Huang, Minjie Liu, Zedu Huang, and Fener
Chen
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800581
Link to VoR: http://dx.doi.org/10.1002/adsc.201800581

10.1002/adsc.201800581
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Development of Novel Chloramphenicol Scaffold-Based Chiral
Hydroxyl Oxazoline Ligands and Their Application to the
Asymmetric Alkynylation of Isatins
Lei Chen,[a, b] Guanxin Huang, [a, b] Minjie Liu, [a, b] Zedu Huang,[a, b] Fen-Er Chen*[a, b]
a
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University,
Shanghai, 200433, P. R. of China
Shanghai Engineering Research Center of Industrial Asymmetric Catalysis of Chiral Drugs, 220 Handan road,
b
Shanghai, 200433, P. R. of China
E-mail: rfchen@fudan.edu.cn
Received: ((will be filled in by the editorial staff))
Abstract: The synthesis of new chloramphenicol base-
derived chiral hydroxyl oxazoline ligands, and their use
in the first Zn(OTf)2-catalyzed enantioselective
alkynylation of isatins are described. This
transformation features mild reaction conditions, a
remarkably broad substrate scope, and excellent
functional group tolerance, affording the corresponding
tertiary propargylic alcohols in high yields and with
high enantioselectivities. The application of chiral
hydroxyl oxazolines as ligands in Zn(II)-catalyzed
asymmetric alkynylation reactions is unprecedented.
Keywords: asymmetric catalysis, chloramphenicol
base, chiral hydroxyl oxazolines, enantioselective
alkynylation, isatin
Introduction
The catalytic enantioselective alkynylation of
carbonyl compounds is an efficient strategy for the
synthesis of optically active propargylic alcohols
found in numerous natural products and
pharmaceuticals.[1] In 1990, Niwa and Soai first
reported the asymmetric synthesis of propargylic
alcohols by the enantioselective addition of
alkynylzinc reagents to aldehydes in the presence of
catalytic amounts of amino alcohol ligands derived
from ephedrine.[2] Since then, many chiral ligands,
coworkers reported a pioneering method for the
enantioselective addition of terminal alkynes to
aldehydes using catalytic amounts of zinc metal and
N-methylephedrine (1) as ligand. Prior to their report,
stoichiometric R2Zn had always been employed.[4]
including
2-amino
alcohol-type
ligands,
oxazaborolidine ligands, substituted BINOL ligands,
β-sulfonamide alcohol ligands, chiral salen ligands,
ProPhenol ligands, and Schiff base amino alcohol
ligands have been developed for complexation with
different metals (Li, Zn, Cu, Ru, Rh, and Ti) to
catalyze enantioselective alkynylations of carbonyl
compounds.[3] Among these catalytic systems, zinc
complexes have attracted considerable attention
owing to their superior catalytic efficiency and
environmentally friendliness, with the latter fulfilling
the requirements of green and sustainable science.
However, the asymmetric alkynylation of carbonyl
compounds mediated by truly catalytic amounts of
zinc remains an underdeveloped field, with few chiral
ligands disclosed to date. For example, Carreira and
Scheme 1. Structures of chiral amino alcohol ligands.
Later, Davis and coworkers examined amino alcohol
2, prepared from a carbohydrate scaffold, as a ligand
in the Zn(OTf)2-catalyzed addition of alkynes to
aldehydes.[5] More recently, Cook and Wolf reported
using ProPhenol ligand 3 for the asymmetric addition
1
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10.1002/adsc.201800581
Advanced Synthesis & Catalysis
of terminal ynamides to trifluoromethyl ketones to
afford CF3-substituted tertiary propargylic alcohols in
up to 99% yield and 96% ee.[6] Therefore, almost two
decades after the original report, the development of
zinc-catalyzed asymmetric alkynylation is still going
strong marked by quests for ligands.
In recent years, our group has developed numerous
chiral organocatalysts and ligands derived from
chloramphenicol base 4,
a
by-product of
chloramphenicol production, as chiral scaffolds for a
variety of highly stereoselective asymmetric
transformations.[7] Owing to its easy accessibility,
low cost, and good asymmetric induction, we
envisioned that the chloramphenicol scaffold could
be used as a chiral ligand in the asymmetric
alkynylation of carbonyl substrates to produce
alcohol products effectively and sustainably. In fact, a
literature survey indicated that two elegant precedents
exist. Novel amino alcohol ligand 5 derived from
chloramphenicol base 4 was developed by Jiang and
coworkers and successfully applied to the Zn(II)-
catalyzed enantioselective alkynylation of aldehydes
and α-ketoesters to generate the desired propargylic
alcohols in good yields with excellent ee values.[8][9]
However, the substrate scope of carbonyl compounds
applicable in Jiang’s system seems restricted to
aldehydes and α-ketoesters. It is desirable to develop
novel chiral ligands or catalyst derived from
Scheme 2. Synthesis of chiral hydroxyl oxazoline ligands
6a–6j.
Chiral hydroxyl oxazoline ligands 6a–6i were
readily prepared from chloramphenicol base 4 in a
two-step one-pot procedure (Scheme 2).[12] In brief,
chloramphenicol base was reacted with various acyl
chlorides in the presence of Et3N to afford amides,
which were then directly treated with TsCl and Et3N
in boiling dichloromethane to afford desired chiral
hydroxyl oxazoline ligands 6a–6i. Chiral ligand 6j
was synthesized by inverting the C-1 configuration in
alcohol 6b under Mitsunobu reaction conditions
(PPh3/DIAD/benzoic acid/THF), followed by
carboxylate hydrolysis with K2CO3 in methanol. [7d]
Zinc-catalyzed enantioselective alkynylation
chloramphenicol base for other asymmetric of isatins using ligands 6a–6j
alkynylation transformations.
Table 1. Screening of chiral ligands for enantioselective
alkynylation of isatins.
The catalytic asymmetric alkynylation of isatins
remains a formidable challenge, with only two
successful examples reported. In 2016, Liu and Feng
et al. disclosed using copper iodide and a chiral
guanidine ligand to synthesize 3-alkynyl-3-
hydroxyoxindoles by the addition of terminal alkynes
to isatins in high yields and enantioselectivities. [10]
Meanwhile, Guo and coworkers achieved the same
transformation by employing a catalytic system
consisting of Cu(I) and chiral phosphine ligands.[11]
To our knowledge, a Zn(II)-catalyzed asymmetric
alkynylation of isatins has not been reported. Herein,
we describe the preparation of a series of novel
chloramphenicol base-derived chiral hydroxyl
oxazoline ligands and their application to the Zn(II)-
catalyzed enantioselective alkynylation of isatins.
Entry [a]
Ligand
Yield (%)[b]
Ee (%)[c]
1
2
3
4
5
6
7
88
69
92
51
93
29
3
5
6a
6b
6c
6d
6e
6f
40
36
50
32
40
75
81
8
9
10
11
trace
74
95
6g
6h
6i
－
26
61
Results and Discussion
31
6j
18
Synthesis of hydroxyl chiral oxazolines
ligands derived from chloramphenicol base
[a] Unless otherwise noted, reactions were performed in a sealed tube
with 7a (0.2 mmol), 8a (0.6 mmol), Zn(OTf)2 (0.04 mmol), ligand (0.044
mmol), and Et3N (0.1 mmol) in PhMe (0.15 mL). [b] Isolated yields. [c]
Determined by chiral-phase HPLC.
In a first attempt, we conducted the reaction of 1-
benzylindoline-2,3-dione (7a) with phenylacetylene
(8a) using Zn(OTf)2 and amino alcohol ligand 5 at 70
C. Desired adduct 9a was isolated in 88% yield, but
2
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10.1002/adsc.201800581
Advanced Synthesis & Catalysis
with poor enantioselectivity (Table 1, entry 1). We
then turned our attention to chiral hydroxyl oxazoline
ligands (Table 1, entries 2–11). Among the first five
chiral ligands examined (6a–6e), ligand 6d, bearing a
methyl moiety at the C-3 position of the phenyl ring,
performed best, affording product 9a in a 93%
isolated yield with 50% ee. Pleasingly, after further
optimization, the alkynylation of isatins proceeded
efficiently in the presence of ligand 6i, bearing a
bulky 2-Naph group, affording 9a in 95% yield with
61% ee (Table 1, entry 10). Copper catalysts such as
Cu(OTf)2 failed to promote the alkynylation under
similar reaction conditions (see Table S1 in the
Supporting Information). Interestingly, ligand 6j,
bearing the opposite stereochemistry to ligand 6b at
C-1, gave a low yield (31%) and opposite
enantioselectivity (18% ee) under the same reaction
conditions (Table 1, entries 11 and 3).
enantioselectivity were realized by decreasing the
substrate concentration from 0.4 M to 0.2 M (Table 2,
entry 6). However, further dilution of the substrate to
only 0.1 M resulted in a diminished yield (Table 2,
entry 7). A reaction with 10 mol% catalyst and 25
mol% base was also carried out, in which both the
yield and enantioselectivity decreased (Table 2, entry
8).
With optimized reaction conditions in hand, we
then investigated the substrate scope of isatins (Table
3). This protocol was applicable to various
substituted N-benzylisatins, affording corresponding
products 9 in generally good yields (75–90%) with
high enantioselectivities (83–93% ee), regardless of
the electronic character and position of the substituent
(entries 1–12). Next, the effect of isatin N-
substituents on the reaction was studied. Compared
with the benzyl-substituted substrate (entry 1), those
bearing methyl (entry 13), allyl (entry 14), and p-
Table 2. Optimization of reaction conditions with ligand 6i. methoxybenzyl (PMB; entry 15) substituents were
transformed into the desired products in decreased
yields
(60–77%),
but
with
excellent
enantioselectivities (93–98% ee).
Table 3. Substrate scope for isatins.
Entry[a] Temp Time (h) Solvent Yield
Ee
(℃)
(%)[b]
(%) [c]
1[d]
2
3
50
10
48
48
48
40
40
48
48
PhMe
PhMe
CHCl3
THF
THF
THF
77
trace
75
54
93
91
49
50
69
－
57
87
77
92
91
84
25
25
25
25
25
25
25
Entry[a]
1
R1, R2
H, Bn
Time (h) Yield(%)[b] Ee (%)[c, d]
4
5[e]
6[e, f]
7[e, g]
8[e, f, h]
40
91(9a)
92 (S)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4-Cl, Bn
4-Br, Bn
5-MeO, Bn
5-F, Bn
5-Br, Bn
6-F, Bn
6-Cl, Bn
7-CF3, Bn
7-Br, Bn
7-F, Bn
7-Cl, Bn
H, Me
48
48
40
40
40
48
48
32
35
35
35
60
48
60
86(9b)
83(9c)
92(9d)
96(9e)
92(9f)
76(9g)
75(9h)
88(9i)
87(9j)
94(9k)
90(9l)
60(9m)
77(9n)
67(9o)
93
92
89
83
92
92
87
90
89
87
85
93
95
98
THF
THF
[a] Unless otherwise noted, reactions were performed in a sealed tube
with 7a (0.2 mmol), 8a (0.6 mmol), Zn(OTf)2 (0.04 mmol), ligand (0.044
mmol), and Et3N (0.1 mmol) in solvent (0.5 mL). [b] Isolated yields. [c]
Determined by chiral-phase HPLC. [d] Reaction was performed in PhMe
(0.15 mL). [e] 4 Å MS additive. [f] Reaction was performed in THF (1
mL). [g] Reaction was performed in THF (2 mL). [h] Zn(OTf)2/Ligand 6i
(1/1.1, 10 mol%), base (25 mol%).
Having identified 6i as the best catalyst, we next
examined the influence of temperature on the reaction.
Reducing the reaction temperature to 50 C resulted
in a lower yield, but increased the enantioselectivity
(Table 2, entry 1). However, due to the poor
solubility of the ligand in PhMe, only partial reaction
occurred at 25 C (Table 2, entry 2). The solvent
H, allyl
H, PMB
[a] Unless otherwise noted, reactions were performed in a sealed tube
with 7 (0.2 mmol), 8a (0.6 mmol), Zn(OTf)2 (0.04 mmol), ligand (0.044
mmol), and Et3N (0.1 mmol) in THF (1 mL). [b] Isolated yields. [c]
Determined by chiral-phase HPLC. [d] The absolute configuration of 9a
was determined as S by comparing the sign of the optical rotation of the
major enantiomer with known data. [10, 11]
significantly
affected
the
reactivity
and
enantioselectivity of the asymmetric alkynylation of
7a at room temperature (Table 2, entries 2–4), with
THF found to be the best solvent in terms of
enantioselectivity (87% ee). The addition of 4 Ǻ
molecular sieves (MS) boosted the reaction yield to
93%, but gave a lower ee of 77% (Table 2, entry 5).
To our delight, both excellent yield and
We next focused our attention on the alkynylation
of isatin 7a using a variety of terminal alkynes 8
(Table 4). The substituents on phenylacetylenes could
be varied, with high ee values obtained (Table 4, 9p–
9w). However, terminal alkynes bearing electron-
3
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10.1002/adsc.201800581
Advanced Synthesis & Catalysis
withdrawing groups exhibited lower reactivities than
those bearing electron-donating groups, resulting in a
decreased yield (9p vs. 9q). A heteroaryl-substituted
alkyne was also tolerated in the reaction, affording
product 9x in excellent yield and enantioselectivity.
The developed methodology was further extended to
aliphatic alkynes, furnishing the corresponding
propargylic alcohol products with 92% ee (9y) and
96% ee (9z).
alcohol product 11 in high yield (88%) with high
enantioselectivity (87% ee) (Scheme 3).
A
possible mechanism for the asymmetric
alkynylation of isatins is shown in Scheme 4. Catalyst
Zn(OTf)2 first interacts with the chiral hydroxyl
oxazoline ligand and terminal alkyne, giving
activated Zn-acetylide complex A with the loss of
triethylamine trifluoromethanesulfonate[13]. Species A
then interacts with the isatin N-substituents, leading
to the formation of B. The terminal alkyne then
migrates to the electron-deficient carbonyl carbon
from the least-hindered Re face to give D via
transition structure C, as previously suggested in the
literature.[14] Finally, protonation of Zn(II) species D
by the alkyne itself leads to the formation of
alkynylation product 9 along with the regeneration of
complex A for the next catalytic cycle.
[a
Table 4. Substrate scope for terminal alkynes. -d]
[a] Unless otherwise noted, reactions were performed in a sealed tube
with 7a (0.2 mmol), 8 (0.6 mmol), Zn(OTf)2 (0.04 mmol), ligand (0.044
mmol), and Et3N (0.1 mmol) in THF (1 mL). [b] Isolated yields. [c]
Determined by chiral-phase HPLC. [d] The configuration was determined
by analogy to 9a.
Scheme 4. Proposed mechanism for alkynylation of isatin.
Conclusion
In summary, we have developed a series of new
chiral hydroxyl oxazoline ligands derived from
chloramphenicol base for the first Zn(II)-catalyzed
enantioselective alkynylation of isatins. This reaction
afforded a wide range of chiral 3-alkynyl-3-
hydroxyoxindoles in high yields and with excellent
enantioselectivities. Notably, this is the first
application of chiral hydroxyl oxazoline ligands to
Zn(II)-catalyzed asymmetric alkynylation reactions.
We believe that this novel mode of asymmetric
induction will provide a new approach in this field.
Further investigation into applications of these new
Scheme 3. Gram-scale reaction.
To show the synthetic potential of our developed
catalytic system, the Zn(II)-catalyzed enantioselective
alkynylation reaction between substrate 10 and
cyclopropyl acetylene was carried out on a gram
scale, furnishing the corresponding propargylic
4
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10.1002/adsc.201800581
Advanced Synthesis & Catalysis
[4] N.K. Anand, E.M. Carreira , J. Am. Chem. Soc. 2001,
123, 9687-9688.
ligands in other asymmetric transformations is in
progress.
[5] D.P. Emmerson, W.P. Hems, B.G. Davis, Org. Lett.,
2006, 8, 207–210.
Experimental Section
[6] A.M. Cook, C. Wolf, Angew. Chem. Int. Ed. 2016, 55,
2929-2933.
General Procedure
[7] a) S. Wang, F. Chen, Adv. Synth. Catal. 2009, 351,
547; b) H. Yang, F. Xiong, J. Li, F. Chen, Chin. Chem.
Lett. 2013, 24, 553; c) H. Yang, F. Xiong, X. Chen, F.
Chen, Eur. J. Org. Chem. 2013, 4495; d) L. Yan, H.
Wang, W. Chen, Y. Tao, K. Jin, F. Chen,
ChemCatChem 2016, 8, 2249; e) H. Wang, L. Yan, F.
Xiong, Y. Wu, F. Chen, RSC Adv. 2016, 6, 75470; f) X.
Wang, L. Xu, L. Yan, H. Wang, S. Han, Y. Wu, F.
Chen, Tetrahedron 2016, 72, 1787; g) X. Wang, L. Xu,
F. Xiong, Y. Wu, F. Chen, RSC Adv. 2016, 6, 37701; h)
H. Wang, L. Yan, Y. Wu, F. Chen, Tetrahedron 2017,
73, 2793; i) L. Yan, H. Wang, F. Xiong, Y. Tao, Y. Wu,
F. Chen, Tetrahedron: Asymmetry 2017, 28, 921; j) Y.
Wang, G. Huang, S. Hu, K. Jin, Y. Wu, F. Chen,
Tetrahedron 2017, 73, 5055; k) L.-J. Yan, G.-X. H, H.-
F. Wang, F.-J. Xiong, H.-H. Peng, F.-E. Chen, Eur. J.
Org. Chem. 2018, 99–103.
To a mixture of Zn(OTf)2 (14 mg, 0.04 mmol), 6i (15
mg, 0.044 mmol), 4Ǻ MS (100 mg) and Et3N (15 μL,
0.1 mmol), THF (0.5 mL) was added under N2
atmosphere and the mixture was stirred at 25 °C for 2
h. Then phenylacetylene (65μl, 0.6 mmol) was added
to the mixture. After stirring for 1 h at 25 °C, isatin
7a (47 mg, 0.20 mmol) and THF (0.5 mL) were
added in one portion. The mixture was stirred at
25 °C until the starting material was completely
consumed (TLC monitoring). After completion, the
mixture was quenched with sat. aq NH4Cl (10mL)
and extracted with EtOAc (2 × 10 mL). The
combined organic layers were dried over anhydrous
Na2SO4, filtered and concentrated under reduced
pressure to dryness. The crude product was purified
by column chromatography (PE/EtOAc=8/1 to 5/1) to
give 9a as a white solid; yield: 62.2 mg (91%, 92%
ee).
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2002, 1524–1525. b) Z.-L. Chen, W.-N. Xiong, B.
Jiang, Chem. Commun. 2002, 2098–2099.
[9] B. Jiang, Z.-L. Chen, X.-X. Tang, Org. Lett., 2002, 4,
3451–3453.
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5
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10.1002/adsc.201800581
Advanced Synthesis & Catalysis
COMMUNICATION
Development of Novel Chloramphenicol
Scaffold-Based Chiral Hydroxyl Oxazoline
Ligands and Their Application to the
Asymmetric Alkynylation of Isatins
Adv. Synth. Catal. Year, Volume, Page
– Page
Lei Chen, Guanxin Huang, Minjie Liu,
Zedu Huang, Fen-Er Chen*
6
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