Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Enantioselective [4 + 2]-Annulation of Azlactones with CopperAllenylidenes under Cooperative Catalysis: Synthesis of α‑Quaternary α‑Acylaminoamides Amit Kumar Simlandy,⊥ Biki Ghosh,⊥ and Santanu Mukherjee* Department of Organic Chemistry, Indian Institute of Science, Bangalore - 560012, India
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ABSTRACT: The first enantioselective decarboxylative [4 + 2]-annulation of ethynyl benzoxazinanones with azlactones has been developed under cooperative copper and bifunctional tertiary aminourea catalysis. This direct and modular approach combines dipolar copper-allenylidene intermediates with azlactone enolates and allows for the synthesis of α-quaternary α-acylaminoamides as a single diastereomer generally in high yields with good to excellent enantioselectivities (up to 99:1 er). α-Amino acids and their derivatives, owing to their omnipresence in molecules of biological importance, have captivated the attention of synthetic organic chemists for decades and led to the development of numerous strategies for their synthesis.1 α-Acylaminoamides are one such class of amino acid derivative which is present in a plethora of natural products and bioactive targets (Figure 1A).2 Due to the dependence of biological activities of such compounds on their absolute configuration, enantioselective synthesis of αacylaminoamides is of paramount importance.3 The four-component Ugi reaction (Ugi-4CR) undeniably provides the most straightforward and modular access to αacylaminoamide derivatives.4 The Tan group has very recently developed a phosphoric acid catalyzed highly enantioselective four-component Ugi reaction for assembling aldehyde, amine, carboxylic acid, and isocyanide into α-acylaminoamide
derivatives (Scheme 1A).5 Despite this long-awaited breakthrough, the scope of carbonyl partner is restricted to aldehydes and therefore cannot be applied to the enantioselective synthesis of α-acylaminoamides bearing a quaternary Scheme 1. Catalytic Enantioselective Approaches to αAcylaminoamides
Figure 1. (A) Bioactive molecules and (B) synthetic intermediate having α-acylaminoamide moiety. © XXXX American Chemical Society
Received: March 28, 2019
A
DOI: 10.1021/acs.orglett.9b01103 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters stereogenic center (α-quaternary α-acylaminoamides). Although they are found in several bioactive molecules and often serve as a synthetic intermediate for proteasome inhibitors such as omuralide (Figure 1B),6 a direct catalytic enantioselective synthesis of α-quaternary α-acylaminoamides is yet to be developed. We disclose herein a catalytic, modular, and highly enantioselective approach to α-quaternary α-acylaminoamides. Our strategy is based on the use of azlactone as the central building block of α-quaternary α-acylaminoamides. Azlactones (A), owing to their acidic α-proton, are known to react with a wide variety of electrophiles through their enolate form to generate α-quaternary azlactones (B) (Scheme 1A).7 Ring opening of α-quaternary azlactones with amines can generate α-quaternary α-acylaminoamides (C).8 Notwithstanding the modularity of this two-step approach, we preferred a direct access to α-quaternary α-acylaminoamides from azlactones. A prerequisite to this approach is a reagent bearing both an electrophilic carbon center and a nucleophilic nitrogen center. We realized that tethering these two reactive ends in a single entity in the form of a dipole (D) would prevent their internal recombination and at the same time generate cyclic αquaternary α-acylaminoamides (E) (Scheme 1B). While searching for the precursor of such a dipole, we became interested in ethynyl benzoxazinanones, a reagent introduced by Lu and Xiao in 20169 based on the initial development of vinyl benzoxazinanones by Tunge et al.10 Ethynyl benzoxazinanones (1) under catalytic Cu(I) readily decarboxylate to generate a 1,4-dipole containing electrophilic Cu-allenylidene and a nucleophilic nitrogen center (F) under mildly basic conditions (Scheme 2). Because of the covalent
enantioselective C−C bond formation. The intermediate H, thus formed, would undergo an annulation (lactamization) reaction with concomitant opening of the azlactone ring to produce cyclic α-acylaminoamide, bearing contiguous tertiary and quaternary stereogenic centers (3). To put our hypothesis into practice, the reaction between Ntosyl ethynyl benzoxazinanone 1a and phenylalanine-derived azlactone 2a was chosen for optimizing catalyst(s) and reaction conditions (Table 1).13 When the reaction was carried out with 10 mol % of a preformed copper complex derived from Cu(OTf)2 and Ph-Pybox (L1) in the presence of Hünig’s base (25 mol %) in THF at −10 °C, the desired cyclic αTable 1. Optimization of the Reaction Conditionsa
Scheme 2. Catalytic Hypothesis of the Proposed [4 + 2]Annulation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18e 19e 20e
attachment with copper, enantioselective addition of nucleophiles to Cu-allenylidenes is possible with the help of chiral ligands (L*) on copper. Consequently, a number of enantioselective annulation reactions involving ethynyl benzoxazinanones have appeared during the past couple of years.11 Our catalytic hypothesis relied on the cooperative combination12 of the copper and a Brønsted base catalyst (Scheme 2). Reactive azlactone enolate G, whose generation can be aided by a Brønsted base, was expected to attack the electrophilic Cu-allenylidene end of F for a diastereo- and
Cu-salt
L
base
solvent
yield (%)b
erc
Cu(OTf)2 CuBr CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI
L1 L1 L1 L1 L1 L1 L1 L2 L3 L4 L5 L6 L1 L1 L1 L1 L4 L4 L4 L7
i-Pr2NEt i-Pr2NEt i-Pr2NEt i-Pr2NEt i-Pr2NEt DBU Et3N Et3N Et3N Et3N Et3N Et3N − I II III III III ent-III III
THF THF THF CH2Cl2 toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene
28 16 29 37 37 52 75 50 21 80
