Non-bonding 1,5-S···O interactions govern chemo- and enantioselectivity in isothiourea-catalyzed annulations of benzazoles

Isothiourea-catalyzed annulations of 2-acyl benzazoles and α,β-unsaturated acyl ammoniums are tuned to form lactams or lactones (up to 99% ee). Computations highlight the governing roles of S···O and CH···O interactions.


Introduction
Nitrogen-containing heterocycles are of wide-spread importance in pharmaceutical, agrochemical and material science industries. 1 In particular, benzazoles have found broad-reaching applications as bioactive compounds in medicinal chemistry, with a range of therapeutic treatments exploiting their anti-bacterial, anti-fungal, anti-parasitic and anti-cancer properties. 2 In addition, they are key components of useful ligands 3 as well as organic semiconductors and dyes. 4 The prevalence of the benzazole motif in these applications has led the synthetic community to develop numerous methodologies for the use of benzazole containing nucleophiles for the rapid synthesis of complex heterocycles. 5 Despite this interest, catalytic enantioselective functionalization of benzazole derivatives has received limited attention, with only a small number of enantioselective protocols developed to date. 6 As a representative example of such an approach, Lam has shown that benzazoles undergo catalytic enantioselective nickel-catalyzed Michael-additions to nitroalkenes, giving the desired products in high yields, moderate to excellent dr and good to excellent enantioselectivity (Scheme 1, eqn (1)). 7 As part of our ongoing research employing isothioureas 8 in catalysis, 9 we recently developed an enantioselective annulation process utilizing a,b-unsaturated acyl ammonium intermediates. 10, 11 In this annulation process, reaction of this intermediate with symmetrical 1,3-dicarbonyl nucleophiles generates functionalized esters in high ee aer ring-opening through a postulated Michael addition-lactonization/ring-opening process (17 examples, up to 96% ee). Notably, preliminary results using unsymmetrical 2-phenacylbenzothiazole as a nucleophile gave functionalized lactams preferentially ($85 : 15 lactam : lactone), resulting from preferential N-rather than O-cyclization, through a Michael addition-lactamization process in up to 86% ee in three isolated examples (Scheme 1, eqn (2)).
This manuscript builds upon the intriguing chemoselectivity observed in the preferential formation of lactams in this latter process, and subsequently explores the effect of changing both carbonyl substitution and the heteroatom within a series of acylbenzazole nucleophiles. As a result, we have developed a highly chemoselective method to access either lactam A or lactone B heterocyclic products in excellent enantioselectivity through use of acylbenzothiazole or acylbenzoxazole derivatives respectively (Scheme 2). Furthermore, through computations, the role that non-bonding 1,5-S/O interactions and C-H/O interactions play in governing the unusual regioselectivity of these processes is highlighted. The importance of non-bonding S/O interactions has been widely recognized in structural and medicinal chemistry in the solid state (commonly ascribed to a stabilizing n O to s* interaction), 12 and has been used as a key controlling element to rationalize enantioselective isothioureacatalyzed reactions. 13 While the origin of this interaction is still under debate, 14 and is the focus of ongoing work within our research groups, the demonstration of alternative examples of how non-bonding S/O interactions can facilitate selectivity in catalysis could lead to its broader utilization, akin to the current widespread use of hydrogen bonding and other non-bonding interactions in synthesis. 15 To the best of our knowledge, S/O interactions have not been invoked to describe the origins of chemoselectivity in a catalytic reaction.

Results and discussion
Probing the effects of acyl and benzazole substituents on annulation chemo-and enantioselectivity Initial investigations sequentially probed substituent effects on the chemo-and enantioselectivity of this annulation process within a series of acylbenzazoles, with variation of both the acyl substituent and heterocycle tested (Scheme 3). Consistent with our previous studies, using homoanhydrides as a,b-unsaturated acyl ammonium precursors with isothiourea HyperBTM 1 (5 mol%) in bench-grade THF, 2-phenacylbenzothiazole gave preferentially lactam product 4A (88 : 12 lactam 4A : lactone 4B), with 4A isolated in 86% yield and 83% ee that was recrystallized to give 4A in 68% yield and 97% ee. A small amount of the lactone constitutional isomer 4B was also isolated (9% yield, 86% ee). 16 The potential for isomerization of lactone 4B to the lactam 4A was investigated under a range of conditions. Treatment of the minor lactone product 4B with base, with base and HyperBTM, or to the reaction conditions, led to no interconversion of lactone to lactam, consistent with the observed product ratios arising from kinetic control (see ESI † for further details). The incorporation of electron donor benzothiazole amides and esters resulted in the exclusive formation of lactams 2A and 3A as single constitutional isomers in excellent ee (97% and 93% ee) and in good yields respectively. Further studies probed the effect of variation within the heterocyclic portion of the benzazole. While using 2-phenacylbenzothiazole leads to preferential formation of lactam 4A, remarkably, 2-phenacylbenzoxazole afforded exclusively lactone product (>95 : 5 5B : 5A) with the lactone 5B isolated in 95% yield and 98% ee. The seemingly trivial substrate change from benzothiazole to benzoxazole in this system promotes a change in chemoselectivity in the annulation process to selectively facilitate lactone (O-cyclization) rather than lactam (N-cyclization) product formation.

Scope and generality
To demonstrate the generality of these chemo-and enantioselective annulation processes, and facilitate direct comparison across a range of substrates, the use of 2-phenacylbenzothiazole, 2-phenacylbenzoxazole and 2-N,N-dimethylacetamidobenzothia-Scheme 2 Chemo-and enantioselective isothiourea-catalyzed annulation of acylbenzazoles with a,b-unsaturated acyl ammonium intermediates.
Scheme 3 Probing the effects of acyl and benzazole substituents on annulation chemo-and enantioselectivity. a Ratio of constitutional isomers arising from either N-or O-cyclization calculated from 1 H NMR spectra of crude reaction product. b ee values obtained via chiral HPLC. c Following a single recrystallization ee could be enhanced to 97%.
zole as nucleophiles was fully investigated with a range of anhydrides (Table 1). Consistent with the model studies, chemoselective formation of either lactam or lactone products (>95 : 5 ratio of constitutional isomers) was achieved by using 2-N,N-dimethylacetamidobenzothiazole or 2-phenacylbenzoxazole, with excellent enantioselectivity (90-99% ee) observed across a range of anhydrides. Using 2-phenacylbenzothiazole led to preferential lactam formation (typically $85 : 15 lactam : lactone), albeit with reduced enantioselectivity (typically >80% ee). For all acylbenzazole nucleophiles, variation of aryl substitution within the anhydride was tolerated, including electron donating (4-MeOC 6 H 4 ), electron withdrawing (4-CF 3 C 6 H 4 ), and 3-BrC 6 H 4 substitution. Sterically demanding 2-BrC 6 H 4 substitution led to no reaction with 2-phenacylbenzoxazole, while reactions using 2-N,N-dimethylacetamidobenzothiazole or 2-phenacylbenzothiazole gave acceptable to good product yields, with excellent enantioselectivity in the amide series. Heteroaryl (2-furyl, 3-furyl, and 3-thiophenyl) substituents were also successfully incorporated (90-99% ee), as were methyl and ester substitution. In the 2-phenacylbenzothiazole derived series, the ee of lactam and lactone products were approximately equivalent, except for 16A/16B (81% and 33% ee respectively) bearing a 2-Br substituent. The origin of this variation in ee is currently unexplained, despite extensive synthetic and computational investigations. 17 Excited by the high chemo-and enantiocontrol observed, the scope of this process was expanded to the synthesis of challenging all-carbon quaternary centers (Scheme 4). Trisubstituted homoanhydrides were used as a,b-unsaturated acyl ammonium precursors, allowing limited access to stereogenic quaternary centers for the rst time in this methodology. Initial studies employed 3-methylbut-2-enoic anhydride 32 and gave the expected achiral lactam product 33 in good yield (Scheme 4).

Scale-up and derivatizations
To demonstrate the potential further utility of the heterocyclic products obtained, scale-up and derivatization through palladium-catalyzed cross-coupling reactions was tested. 3-BrC 6 H 4substituted lactam 14A was readily prepared on gram scale in high yield and enantioselectivity (1.15 g, 75%, 96% ee). Subjecting lactam 14A to Suzuki coupling generated 37 in 70% yield with no erosion of enantioselectivity; similarly, Heck reaction of 14A with methyl acrylate afforded 38 in 89% yield and 97% ee (Scheme 5).

Computational details and mechanism
Computations were undertaken to provide insight into the observed chemoselectivity when using the benzoxazole and benzothiazole nucleophiles (X ¼ O or S, respectively). For this purpose, we have specically computed the intermediates and transition structures involved in the formation of products 4A (lactam) and 4B (lactone) using 2-phenacylbenzothiazole, and 5B (lactone) using 2-phenacylbenzoxazole. All energy renements and geometries were computed in solution using the implicit polarizable continuum model PCM with tetrahydrofuran as solvent (M06-2X/6-31+G(d,p)/PCM(THF)//M06-2X/6-31G(d)/ PCM(THF) 19 ). 20 The M06-2X DFT method has been successfully used to rationalize mechanisms and selectivities of synthetic reactions by us and others. 21 Given the zwitterionic nature of many of the intermediates in the reaction, we also took into account the ability of M06-2X to accurately evaluate dispersionheavy and ionic systems relative to the less computationally expensive B3LYP method. 22 The catalytic cycle is shown in Fig. 1. 23 Stepwise   observations are consistent with an attractive force between the S-and O-atoms and in line with previous computations by Tantillo and Romo 13b as well as by Houk and Birman. 13c Unique to this system, however, is how this interaction dominates the structural preorganization of all key reactive intermediates and transition states of this annulation process.
S/O interaction in the enantiocontrol of 1,4-addition. All stable conformations of the a,b-unsaturated acyl ammonium intermediate exhibit coplanarity of the 1,5-O and S atoms. This is corroborated by the crystal structure of this intermediate which show the S-O being coplanar at a distance of 2.48Å. 10a In addition, both anionic nucleophiles prefer the planar arrangement (Fig. 2), with the 1,5-S-O syn conformation favored by $7 kcal mol À1 in the case of benzothiazole. Taken together, these factors rigidify and planarize both the electrophilic a,b-unsaturated acyl ammonium intermediate and the incoming nucleophile, dramatically simplifying the stereochemical model. Nucleophilic 1,4-addition occurs anti to the catalyst stereodirecting groups on the less hindered face. The computed enantioselectivities of 99% in both cases are in reasonable agreement with experiments (83% and 98% ee for 4A and 5B, respectively, Scheme 3).
Lactamization vs. lactonization. The interplay between S/O and C-H/O interactions 26 (between the anionic nucleophile atoms and C-H a-to the positively-charged nitrogen of the acylated HyperBTM) governs cyclization chemoselectivity. Fig. 3 shows computed model complexes analogous to the pre-cyclization intermediate, featuring truncated simplied structures of both HyperBTM catalyst and benzazole nucleophiles. In the oxazole model system, the conformation with one S/O and one C-H/O interaction is favored by 2.5 kcal mol À1 over the conformation featuring the unfavorable O/O. However, in the thiazole model, the conformation featuring two S/O interactions, rather than one S/O and one C-H/O, is preferred by 3.7 kcal mol À1 . These preferences carry over to the cyclization transition structures (Fig. 4). In the benzoxazole case, both annulations occur via a boat-like six-membered transition structure anti to the catalyst stereodirecting groups (phenyl and isopropyl) to minimize steric occlusion. The Favored-Lactonization-(X ¼ O)-TS is preferred over the Disfavored-Lactamization-(X ¼ O)-TS (DG ‡ ¼ 11.1 and 14.3 kcal mol À1 , respectively) due to a stabilizing C-H/O involving the ortho C-H of the catalyst and the incoming oxygen atom. In the latter, a b-C-H is involved in a repulsive interaction with the incoming benzoxazole. The computed selectivity of 99 : 1 matches well with the experimental selectivity of 98 : 2 seen with lactone 5B.
The benzothiazole lactone closure occurs exactly as the benzoxazole case through the Disfavored-Lactonization-(X ¼ S)-TS (DG ‡ ¼ 11.7 kcal mol À1 ). The Favored-Lactamization-(X ¼ S)-TS has a lower barrier (DG ‡ ¼ 10.6 kcal mol À1 ), and the computed selectivity of 88 : 12 matches experiments. Interestingly, lactamization occurs on the same face as the catalyst stereodirecting groups, previously thought to be disfavored due to the steric occlusion.
Two key stabilizing interactions are present in benzothiazole lactamization that are not found in lactonization: (1) p-stacking of the catalyst phenyl and the fused benzene of the benzothiazole ring, 27 and (2) a second 1,5-S/O interaction within the former benzothiazole nucleophile. The switch in chemoselectivity in favor of lactam formation using the benzothiazole is attributed to the penalty of breaking the 1,5-S/O present within the benzothiazole nucleophile for the lactonization process to proceed.

Conclusions
To conclude, we have demonstrated the scope and limitations of the organocatalytic enantioselective functionalization of a range of benzazole nucleophiles using the isothiourea HyperBTM 1 and a,b-unsaturated homoanhydrides as a,bunsaturated acyl ammonium precursors. The chemoselectivity observed during the cyclization is inuenced by the nature of the benzazole and the carbonyl employed within the acylbenzazole, with benzothiazole preferentially using the ringnitrogen to extrude the catalyst, whereas the benzoxazole moiety prefers to cyclize through the b-carbonyl substituent. Computations elucidated the importance of non-covalent 1,5-S/O interactions in determining the chemoselectivity within these processes. Specically, the use of benzothiazole nucleophiles allows two stabilizing 1,5-S/O interactions in the preferred lactamization transition structure, while benzoxazole contains one stabilizing 1,5-S/O and one C-H/ O interaction in the lactonization transition structure. Future research within our laboratories is aimed at harnessing the collaboration between theory and experiments towards the development of isothiourea Lewis base catalysts in new enantioselective transformations.