A Bifunctional Iminophosphorane Squaramide Catalyzed Enantioselective Synthesis of Hydroquinazolines via Intramolecular Aza-Michael Addition to α , β -Unsaturated Esters

: An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael addition of urea-linked α,β-unsaturated esters is described. The methodology exhibits a high degree of functional group tolerance around the forming hydroquinazoline aryl core and wide structural variance on the nucleophilic N atom of the urea moiety. Excellent yields (up to 99%) and high enantioselectivities (up to 97:3 e.r.) using both aromatic and less acidic aliphatic ureas were realized. The potential industrial applicability of the transformation was demonstrated in a 20 mmol scale-up experiment using an adjusted catalyst loading of 2 mol%. The origin of enantioselectivity and reactivity enhancement provided by the squaramide motif has been uncovered computationally using density functional theory (DFT) calculations, combined activation strain model (ASM) and energy decomposition analysis (EDA). a series of late-stage structural derivatizations thus demonstrating relevance to pharmaceutical

Specifically, for dihydroquinazolines bearing a trifluoromethyl group attached to a newly generated quaternary carbon center, an extensive range of metal and metal-free catalyzed enantioselective addition reactions to reactive cyclic ketimines using alkyne, [8] ketone, [9] nitroalkane, [10] β-keto acid, [11] nitrile, [12] alcohol [13] and isocyanoacetate [14] nucleophiles, have been developed. [15] Enantioselective aza-Michael addition reactions enabled by metal-free catalysts is another powerful and promising approach to access such pharmaceutically relevant N-heterocycles. [16] However, in this field, catalyst promoted addition of pronucleophilic ureas to tethered β-substituted α,β-unsaturated esters remain largely unsolved due to the high pKa of the urea and low electrophilicity of the Michael acceptor. [17] [18] To our knowledge only two reports describe the synthesis of the chiral hydroquinazoline core in such a way. In 2016, a single moderately enantioselective phase-transfer-catalyzed intramolecular aza-Michael addition (IAMA) was described by Tschaen and coworkers en route to letermovir. [19] In 2017, Ruck and co-workers then developed the enantioselective IAMA reaction of related guanidine containing substrates. [20] However, only N-aryl nucleophiles were compatible and transformation of the guanidine IAMA product to drug molecules bearing urea motifssuch as in DPC 963 (shown in Figure 1)was not feasible. Against this backdrop, we envisaged that the enhanced Brønsted basicity and broadly tunable structure of the bifunctional iminophosphorane (BIMP) superbase catalyst system developed in our group [21] could provide the solution to the challenging pKa related reactivity and modest stereocontrol in the IAMA, and herein we wish to report our findings.
Urea 1a bearing an α,β-unsaturated tert-butyl ester was chosen as the model substrate for the IAMA reaction. An initial reactivity study of various bifunctional organocatalysts revealed that moderately Brønsted basic cinchona-derived bifunctional catalyst A failed to promote any detectable reaction in Et2O at room temperature after 24 hours (Table 1,  A third stereogenic center adjacent to the amide motif was then incorporated and enantioselectivity increased to 80.5:19.5 er with catalyst J slightly outcompeting diastereomeric catalyst I (Table 1, entries 10 & 11). Excitingly, a squaramide substitution for the thiourea (catalyst K) boosted the enantiocontrol to 94.5:5.5 er. The major enhancement in selectivity likely arises from the higher acidity / H-bond donor ability of the squaramide and/or the modified 3D structure resulting from the differing bond angles at the squaramide. Additional catalyst structureperformance studies gave no further improvement (see ESI for optimization details).
With the optimal conditions in hand, the scope of the enantioselective IAMA reaction was then explored (Scheme 2A). Notably, the IAMA reactions have typically very clean reaction profiles and no effort was made to exclude moisture or air from the scope experiments. Varying the substituents on the quinazolinone aryl core gave rise to minimal fluctuation in [a] Yields of isolated products. enantioselectivity and compatible functionalities varied from electron-donating groups to electron-withdrawing groups. Elevated temperatures of up to 80 o C were required to ensure solubility of the substrates in some cases (1b and 1d). A pyridine-based substrate (1i) was also found to be well-tolerated affording the desired product in excellent yield and enantioselectivity under the standard reaction conditions. The substituent effect on the N-aryl ring was then examined. Substrates possessing single iodine, bromine and fluorine atoms at various ring positions as well as a 3,5-dichloro example, performed typically well providing the desired hydroquinazoline core in excellent yield and good er (1j to 1p). The rates of the cyclization reactions were found to decrease with increasing electron-richness of the N-aryl rings. For substrates 1q to 1y, extra reaction time or heating to 50 o C was required to maintain the high yield without compromising enantioselectivity. However, the positional effect of the substituents on reaction enantioselectivity was negligible (1t to 1v). Interestingly, ortho substituents (such as thiomethyl, tert-butyl and ethynyl in 1w-1y) gave rise to a slight uplift in enantioselectivity (96:4 -97:3 er). The methodology was also applicable to less activated, higher pKa, alkyl-substituted ureas. The high Brønsted basicity of the BIMP catalyst system indeed smoothly provided N-allyl and Nbenzyl substituted hydroquinazolines in almost quantitative yield and good er (85:15). Even less activated ureas (1ab to 1ad) demanded harsher reaction conditions to deliver the cyclized product in moderate to excellent yield and good er. Finally, the methyl ester acceptor (1ae) also proved to be a good substrate. After 48 hours hydroquinazoline product 2ae was obtained in almost quantitative yield in high enantioselectivity (92:8 er).
Increasing the reaction scale 100 fold (to 20 mmol) and decreasing the catalyst loading to 2 mol% delivered the desired product in good yield (7.9 g, 85%) without compromising enantioselectivity (92.5:7.5 er). Pleasingly, only a single recrystallization was required to afford essentially enantiopure 2j (Scheme 2B). Furthermore, and to demonstrate potential industrial applicability of the chemistry, various derivatizations of this product were carried out. For example, removal of the tertbutyl carboxylate ester with TFA, activation as the acid chloride, and subsequent treatment with benzyl amine and methanol gave the methyl ester (3) and amide (4) in excellent to moderate yield, respectively. Suzuki coupling with an N-methyl substituted pyrazole boronic acid and Sonogashira coupling with erlotinib successfully installed various functionalities in the para-position of the N-aryl ring.
To elucidate the origin of stereocontrol in the novel BIMP squaramide catalysed IAMA reaction, we performed a state-ofthe-art DFT study. Due to the conformational freedom and the existence of two potential activation modes of the BIMP catalyst, we considered a Curtin-Hammett kinetic profile and computed all the possible TSs on the stereoselectivity-determining Michael addition step (see Supporting Information for more details). [23] The most energetically preferred transition structures that lead to either (R)-or (S)-product are shown in Scheme 4. The TS-ModeA-LA1-RA1-R that forms the (R)-product was found to be favoured by 1.2 kcal mol -1 , which agrees with the experimentally confirmed absolute stereochemical configuration by single crystal X-ray diffraction studies. This preferred TS conformation in TS-ModeA-LA1-RA1-R engages in several stabilising weak interactions, including hydrogen bonding, CO-π, and CH-π interactions between the catalyst and the substrate, as well as internal hydrogen bonding between the PPh3 and the squaramide carbonyl oxygen. This conformation creates a custom-fit pocket within which the substrate can perfectly fit without a steric repulsion during the C-N bond forming step of the Michael addition. Analysis of non-covalent interaction (NCI) plots allows one to qualitatively visualise these weak interactions between the catalyst and the substrate (Scheme S5 and S6). [24] Therefore, the TS that has a catalyst conformation and coordination mode of the substrate that both reduces steric repulsion and maximises interactions is energetically preferred in this reaction. In order to obtain deeper insight into the origin of the catalytic activity imparted by the squaramide motif of the BIMP catalyst, an activation strain analysis (ASA) and an energy decomposition analysis (EDA) were carried out on perfect archetypal model systems. The ASM involves decomposing the electronic energy ΔE into the strain energy ΔEstrain associated with the structural deformation of the hydrogen bond donor (HB) and methyl acrylate (MA) from their equilibrium geometry and the interaction energy ΔEint between the deformed reactants. [25] The EDA separates the interaction energy (ΔEint) into the following three chemically meaningful energy terms: classical electrostatic interaction (ΔVelstat), Pauli repulsion (ΔEPauli) between closedshell orbitals which is responsible for steric repulsion, and stabilising orbital interaction (ΔEoi) that accounts, among others, for HOMO-LUMO interactions. [26] First, we analyzed the interaction between HB and MA (Scheme 5A). The interaction becomes more stabilising from urea to thiourea to squaramide (ΔEint = -9.0 to -10.1 to -11.5 kcal mol -1 ) mainly due to the more stabilizing ΔVelstat term by the electrostatic nature of the hydrogen bonding interaction. The ΔEoi term is also important and involves significant charge transfer from the lone pair of the oxygen atom of MA and the two *N-H orbitals on the HB, which leads to polarization of the -MO away from the C=C bond (the importance of which is explained below). We then analysed the transition structures and the energy barriers for the aza-Michael addition (Scheme 5B). The uncatalyzed reaction goes with the highest reaction barrier (ΔG ‡ = 16.3 kcal mol -1 ). The urea, thiourea, and squaramide catalyzed reactions go with barriers of 12.0, 11.2, and 8.9 kcal mol -1 , respectively.
The enhanced reactivity of the catalysed reactions originates from a reduction of Pauli repulsion between the reactants. [27] The origin of the less destabilising Pauli repulsion (ΔE ‡ Pauli) for the transformation was quantified by performing a Kohn-Sham molecular orbital (KS-MO) analysis (Scheme 5C). The occupied π-MOHB-MA (2p atomic orbitals on the reacting C=C double bonds) contributes to the trend in the Pauli repulsion. The computed orbital overlap S between the π-MOHB-MA and the lone pair of the nucleophile HOMO-1Nu decreases from 0.141 for TSuncatalyzed to 0.106 for TSSQ-MA, which is caused by the aforementioned polarization of the π-MOHB-MA away from the reactive carbon centre of the C=C bond due to the charge transfer interaction with the hydrogen bond donor catalyst. The squaramide catalyst emerges as the best of our studied bifunctional iminophosphorane squaramide catalysts as it is able to reduce the destabilising Pauli repulsion between the reactants and thereby impart the greatest reactivity enhancement of our novel intramolecular aza-Michael addition. [27] In summary, an efficient and highly enantioselective BIMPcatalysed intramolecular aza-Michael addition affording decorated hydroquinazoline structures with excellent yields and enantiomeric ratios has been developed. A novel BIMP squaramide system was found to be effective in activating both aromatic and aliphatic ureas. DFT calculations uncovered the fact that the optimal catalyst conformation creates a pocket-like binding site for the substrate to impart enantiofacial selectivity, whilst the squaramide motif demonstrates advantages over urea and thiourea H-bond donor groups on decreasing the destabilizing Pauli repulsion between the reactants (combined ASM and EDA). The catalytic ring formation strategy demonstrated broad functional group tolerance including of esters, nitriles, heterocycles, alkenes, and alkynes, and catalyst loading can be lowered down to 2 mol% in a multi-gram scale synthesis. The hydroquinazoline aza-Michael addition products were stable towards a series of late-stage structural derivatizations thus demonstrating relevance to pharmaceutical development.