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Enantioselective Alkynylation of Isatin Derivatives Using a Chiral Phase-Transfer/Transition Metal Hybrid Catalyst System Suva Paria, Hyo-Jun Lee, and Keiji Maruoka ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04949 • Publication Date (Web): 05 Feb 2019 Downloaded from http://pubs.acs.org on February 5, 2019
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ACS Catalysis
Enantioselective Alkynylation of Isatin Derivatives Using a Chiral Phase-Transfer/Transition Metal Hybrid Catalyst System Suva Paria,† Hyo-Jun Lee,† and Keiji Maruoka*†‡ †
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan School of Chemical Engineering and Light Industry, Guangdong University of Technology, No.100, West Waihuan Road, HEMC, Panyu District, Guangzhou, 510006, China ‡
ABSTRACT: An enantioselective alkynylation of isatin derivatives can be realized by using a hybrid catalyst system consisting of chiral phase-transfer catalyst and transition metal catalyst. The chiral alkynylation products can be used as versatile intermediates for further synthetic transformations.
KEYWORDS: phase-transfer catalyst, hybrid catalyst, asymmetric alkynylation, isatin, silver acetate Among the different modes of asymmetric induction in organic synthesis, chiral phase-transfer catalysis represents a powerful and versatile tool to engage prochiral anionic nucleophiles and electrophiles by forming a chiral ion pair with enolates. This approach produces high levels of enantioselectivity in a wide range of reactions that include enolate alkylations, conjugate additions, cyclopropanations, oxidative cyclizations, and aminations.1 The pronucleophiles used in this context generally contain an enolizable proton that is deprotonated under basic conditions. In order to stabilize the chiral ion pair with the quaternary ammonium cation of chiral phase-transfer catalysts, oxygen anions derived from enolates are usually chosen. In marked contrast, examples of enantioselective transformations that involve carbanion-based nucleophiles under chiral phase-transfer catalysis remain scarce in the scientific literature.2,3 The asymmetric alkynylation of ketones and imines is a versatile process to prepare chiral propargylic alcohols and amines. Consequently, a plethora of transformations that afford these target molecules has been reported,4 including the pioneering work of Mukaiyama on the addition of Li-acetylides to aldehydes5 and later that of Carreira.6 Many of these processes use functionalized alkynes to generate the alkyne nucleophile, even though terminal alkynes (1) have also been reported as alkynylide sources under transition-metal catalysis in the presence of Cu,7 Zn,8 Rh,9 and Ag10 complexes with chiral ligands. Generally, such transition metal alkynylides (2) are considered to be insufficiently nucleophilic to attack unactivated ketones or imines. However, the low nucleophilicity of transition-metal alkynylides (2a) has been used to render these reactions enantioselective. In Scheme 1, the two main approaches to asymmetric alkynylation are shown. Path A illustrates the enantioselective alkynylation of ketones or imines (3) with 2a via an activation based on chiral Brønsted or Lewis acids, which affords enantioenriched tertiary alcohols or amines (4). Path B shows that the nucleophilicity of the metal alkynylide (2a) can be enhanced by covalent or coordinative bonding between the metal center and the chiral ligands, which also leads to enantioenriched 4.
Y MX
3
R2 M chiral Path A low 2a Brønsted or nucleophilicity Lewis acid R
R
R1
H 1
Path B MX
enhanced nucleophilicity
R1
ML* 2b M = transition metal; L* = chiral ligand L*
R
Y
3
(Y = O, NR 3) R HY R1 * 2 R
4
R2
The dearth of reports using chiral phase-transfer catalysts for asymmetric alkynylations probably arises from the instability of the ion pair (5a), which consists of a carbanion and a quaternary ammonium cation (Scheme 2). We hypothesized that transitionmetal alkynylides (2a), which are soft in nature, should generate a more stable ion pair (5b) with chiral phase-transfer catalyst (QX).11,12 Once formed, 5b should be expected to react smoothly with ketone-based electrophiles (3a) to furnish enantioenriched tertiary alcohols (4a).
Scheme 2. Working Hypothesis for Asymmetric Alkynyla-‐ tions Catalyzed by Chiral PTCs.
Scheme 1. The State of the Art of Enantioselective Alkynyla-‐ tions.
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Our hypothesis was inspired by the work of Tan, who have reported elegant asymmetric transformations based on the chiralcounter-cation strategy.13 However, asymmetric alkynylations based on this strategy had not been available until recently, when the same group used a chiral cation/cuprate complex for the dynamic kinetic enantioselective allylic alkynylation of racemic bromides.14 So far, enantioselective alkynylations of ketones that capitalize on the chiral-counter-cation strategy have not been reported. Herein we report the successful implementation of this strategy for the synthesis of chiral tertiary alcohols in high stereofidelity. Given their biological activity, we identified 3-substituted 3hydroxyoxindoles as attractive targets.15 A subclass of these indoles, 3-alkynyl-3-hydroxyoxindoles, which are analogues of efavirenz, is biologically active on Echinococcus multilocularis metacestodes.16 Even though several examples of the achiral synthesis of this class of oxindoles have been reported,17 the enantioselective alkynylation of isatin remains confined to two reports. Both studies use copper salts and chiral ligands to promote the enantioselectivity by means of nucleophilicity enhancement of the metal alkynylide via covalent bonding with the chiral ligands (Path B, Scheme 1).18 We started our investigation by using trityl-protected isatin (6a) as the electrophile and phenylacetylene (1a) as the nucleophile. The results of the optimization are summarized in Table 1 (for the details of the optimization, including other N-protected isatin derivatives, metal salts, bases, solvents and PTCs, see the Supporting Information).
Table 1. Optimization of the Reaction Conditions for the Enantioselective Alkynylation of 6a.a MX (5 mol%) PTC (S)-8 (5 mol%) Base (0.5 equiv)
O
N 6a
O + Ph
H 1a
CPh3
Ph
HO
*
solvent (0.4 M) 60 °C, 8 h
O
N CPh3 7aa
Ar
Ar
Br
Br Bu N Bu
N
Ar Ar (S)-8a (Ar = 3,4,5-F3C6H 2) (S,S)-8c (Ar = 3,4,5-F3C6H 2) (S)-8b (Ar = 3,5-(CF3) 2C6H 3) (S,S)-8d (Ar = 3,5-(3,5-(CF3) 2C6H 3) 2C6H 3)
entry
1 2
hybrid catalyst
base & solvent
(S)-8a, CuOTf
Cs2CO3, toluene
(S)-8a, AgOAc
Cs2CO3, toluene
3
(S)-8a, AgOAc
Cs2CO3, mesitylene
4
(S)-8b, AgOAc
Cs2CO3, mesitylene
yield (%)b
ee (%)c
Page 2 of 8 AgOAc
mesitylene
6
(S,S)-8d, AgOAc
Cs2CO3, mesitylene
93
87
7
(S,S)-8d, AgOAc
K2CO3, mesitylene
91
96
8
(S,S)-8d, AgOAc
no base, mesitylene
trace
––
9
(S,S)-8d, AgOAc
K2CO3, mesitylene, 40 °C
43
96
10
no PTC, AgOAc
K2CO3, mesitylene
