Synthesis of oxazocenones via gold(I)-catalyzed 8-endo-dig hydroalkoxylation of alkynamides.

Several benzoxazocenones have been found to exhibit novel cellular activities. In the present study, we report a gold(I)-catalyzed 8-endo-dig hydroalkoxylation reaction of alkynamides to access analogous oxazocenone scaffolds. This methodology provided an advanced intermediate, which was elaborated to a des-benzo analog of a bioactive benzoxazocenone.

Several benzoxazocenones (e.g., 1–4, Figure 1)[1] having novel cellular activities have been discovered using cell-based screening of compounds prepared using diversity-oriented synthesis (DOS).[2,3] Of particular relevance to this study, BRD0476 (3)[1a] and quinoline analog BRD1116 (4)[1b] rescued INS-1E pancreatic β-cells from cytokine-induced apoptosis for the potential treatment of type-1 diabetes. Mechanism-of-action studies revealed 3 and 4 inhibit the JAK-STAT signaling pathway induced by pro-inflammatory cytokine IFN-γ.[1b]

Figure 1

DOS-generated bioactive benzoxazocenones (1–4) and targeted des-benzo framework.

In an effort to optimize these promising activities, numerous analogs of 3 and 4 have been prepared, but structural modifications have been limited to appending N-alkyl side chain, urea, and sulfonamide moieties.[1a,1b] In the present study, we describe a new synthesis of oxazocenones that lack a fused benzene moiety (des-benzo). The route enables the synthesis of analogs that possess changes in the cyclic core scaffold (Figure 1). Previously, the benzo-fused 8-membered ring in 3 and 4 was constructed using intramolecular nucleophilic aromatic substitution (SNAR) of benzamide 6, which was obtained from chiral amine building block 7 (Scheme 1).[1a,1b,3] We envisioned that des-benzo congener 5 may also be derived from 7 via an analogous 8-endo-dig hydroalkoxylation reaction of alkynamide 8a.[4,5]

Scheme 1

Retrosynthesis of Benzoxazocenones 3–4 and Oxazocenone 5 via Analogous Cyclization Pathways

Given that increased entropic and enthalpic barriers to cyclization are often associated with formation of medium rings,[6] we sought a robust method to prepare oxazocenones. Homogeneous gold catalysis has proven useful for synthetic transformations over the past few decades.[7] The ability of gold to serve as a carbophilic π Lewis acid to activate unsaturated C–C bonds renders these functionalities including alkynes susceptible to nucleophilic attack. However, there are relatively few examples of 8-endo-dig cyclizations catalyzed by gold, which include cycloisomerizations to indoloazocenes and benzoxocenes reported by the Echavarren[8] and Waldmann[9] laboratories, respectively. Hydroalkoxylation variants[10] to form 8-membered heterocycles have yet to be demonstrated, though gold(I) salts were serendipitously discovered by Van der Eycken et al. to catalyze an analogous 7-endo-dig hydroalkoxylation of an alkynamide.[10k] Here, we describe the extension of this methodology to the development of a gold(I)-catalyzed 8-endo-dig hydroalkoxylation to form oxazocenones en route to 5.

We initiated our synthetic studies toward oxazocenone 5 from known 4-((tert-butyldimethylsilyl)oxy)-2-butynoic acid 9(11) and chiral amine 7(3) (Scheme 2). Acid 9 was chosen as a suitable building block to incorporate an alcohol as a functional group handle for installation of the urea moiety of 5 at a late stage in the synthesis (vide infra). Upon screening several reagents and conditions, we found that HATU-mediated amide coupling of 9 and 7 in MeCN at 0 °C provided alkynamide 10 in satisfactory yield (Scheme 2). Desilylation (TBAF) afforded deprotected substrate 8a for evaluation of the gold(I)-catalyzed 8-endo-dig hydroalkoxylation reaction.

Scheme 2

Synthesis of Alkynamide 8a

Intramolecular hydroalkoxylation of 8a using catalytic Ph3PAuCl (5 mol %) and AgSbF6 (5 mol %) provided the desired 8-endo-dig oxazocenone product 11a in CH2Cl2 at rt (entry 1, Table 1). In addition to 11a, formation of oxazepanone 12a was also observed under these conditions, likely resulting from a competitive 7-exo-dig cyclization. The ratio of products 11a and 12a was determined to be 1.7:1 by 1H NMR analysis of the crude reaction mixture. Cyclization to these heterocycles was confirmed by key HMBC correlations between the C(3) and H(4) atoms as well as the C(2) and H(3) atoms for 11a and 12a, respectively. The products could be further distinguished by their NMR spectra. In particular, the signal in the 1H NMR spectrum for the vinylic proton in 11a existed as a singlet, whereas this signal in 12a exhibited additional splitting due to the adjacent methylene group. Endocyclic olefins in 8-membered heterocycles can exist in both E and Z configurations.[9] A weak NOE signal was detected between the vinylic C(2) and methylene C(3′) protons in 11a, suggesting preference for the Z geometry. Although no confirmatory NOE correlations were observed for oxazepanone 12a, we expect that anti-addition of the alcohol to the alkyne, by analogy to the olefin geometry found in 11a, would provide the exocyclic olefin in the Z configuration.

Table 1

Optimization for Selective Au(I)-Catalyzed 8-Endo-Dig Hydroalkoxylation to Oxazocenone 11a

entry	catalyst (5 mol %)	ta (h)	ratiob (11:12)	yieldc (%)
1	Ph3PAuCl/AgSbF6	30	1.7:1	88
2	Ph3PAuCl/AgOTf	6	2.8:1	85
3	(p-CF3C6H4)3PAuCl/AgOTf	4.5	4.3:1	91 (74)d
4	(C6F5)3PAuCl/AgOTf	5	6.2:1	83 (77)d
5	(C6F5)3PAuCl	19	–	–e
6	AgOTf	72	16.7:1	40f,g
7	TfOH	25	–	–e

Reactions were monitored by LCMS.

Product ratio determined by 1H NMR analysis of the crude reaction mixture.

Combined isolated yields of 11a and 12a after column chromatography unless otherwise noted.

Isolated yield of 11a.

Starting material was recovered.

Yield determined by 1H NMR analysis using toluene as an internal standard.

Partial conversion of starting material was observed.

We next turned our attention to increasing the selectivity for formation of oxazocenone 11a. Changing the silver additive to AgOTf increased the ratio to 2.8:1 (entry 2, Table 1). This result suggests that the gold complex generated in situ may have increased cationic character, activating the alkynamide for oxa-Michael addition by the alcohol and leading to shorter reaction times (entries 2–4). Tuning the ligand also enhanced the cationic character of the gold complex. For example, adding electronegative groups to the aryl moieties of phosphine ligands increased selectivities (entries 3 and 4), in which (C6F5)3PAuCl[12] provided a 6.2:1 ratio to give an optimal yield (77%) for 11a (entry 4). Although 5 mol % AgOTf alone catalyzed the reaction with high selectivity for 11a,[13] low conversion and isolated yields were observed (entry 6).[14] Furthermore, (C6F5)3PAuCl or TfOH, which is often the active catalyst for reactions using metal triflates,[15] by itself did not provide conversion to 11a or 12a (entries 5 and 7, respectively). Taken together, these control experiments suggest that (C6F5)3PAu+ is the cationic species activating alkynamide 8a for intramolecular hydroalkoxylation. Exemplifying the mildness and utility of this reaction, base-mediated cyclization to 11a under dissociative anion conditions (e.g., KOt-Bu/18-crown-6 or n-BuLi/HMPA)[4a,4b,4d] was not achieved.

Having optimized conditions for a highly complex alkynamide, we next determined the generality and scope of the gold(I)-catalyzed hydroalkylation reaction to oxazocenones (Scheme 3). Surprisingly, simplified alkynamide 8b, which lacks substituents on the N-alkyl groups but retains the propargylic alcohol, cyclized to oxazocenone 11b without observation of the exo byproduct 12b. On the other hand, TBS-protected alkynamide 8c provided oxazocenone 11c along with small amounts of 7-exo-dig product 12c (11:1 endo to exo selectivity determined by 1H NMR analysis of the crude reaction mixture). Other substitutions at the propargylic position provided selective formation of oxazocenones. For example, methyl- and phenyl-substituted oxazocenones 11d and 11e were synthesized in good yields at 79% and 84%, respectively. Alkynamides with various substituents (R3) on the N-alkyl group bearing the nucleophilic alcohol were also tolerated for the reaction. Oxazocenones 11f and 11g with substitutions at the C(5)- and C(4)-positions, respectively, were selectively formed in good yields. Although a slower reaction time for conversion to 11f (24 h) versus 11e (6.5 h) seems counterintuitive, “reverse” gem-disubstitution effects have previously been shown for formation of medium rings.[16] Demonstrating that sterically hindered tertiary alcohols are suitable for cyclization, geminal dimethyl-substituted oxazocenone 11h was prepared in moderate yield. Unfortunately, aryl substitution (R2) of the amide produced 11i in low yield (20%), demonstrating a limitation of this reaction. Poor yields were also observed for substrates containing a secondary amide or a terminal alkyne (not shown). The structural and olefin-geometry assignment of oxazocenones formed during the gold(I)-catalyzed cyclization were confirmed by the X-ray crystal structures of 11b, 11e, 11h, and 11i.

Scheme 3

Substrate Scope for Cyclization to Oxazocenones

Reaction times and isolated yields are given with ratios of 11 to 12 in parentheses.

Reaction was performed using 10 mol % (C6F5)3PAuCl and 10 mol % AgOTf.

Reaction was performed using 5 mol % (C6F5)3PAuCl and 5 mol % AgOTf.

The mechanism accounting for selective 8-endo-dig cyclizations to oxazocenones may exploit dual π and σ Lewis acid properties[17] of (C6F5)3PAu+. Activation of the amide carbonyl with the Au(I) catalyst likely significantly promotes oxa-Michael addition in the hydroalkoxylation reaction of 8 (Scheme 4). Additionally, bidendate coordination[18] with the alkyne may provide activated species A. This mode of coordination may polarize the alkyne in a manner to favor cyclization of the alcohol to provide 8-endo-dig adduct B. The findings that propargyl alcohol 8b does not afford oxazepanone products whereas TBS-protected congener 8c and complex alkynamide 8a do suggest that the 8-endo and 7-exo reaction pathways are not influenced by coordination of the propargylic alcohol of alkynamides with the gold(I) complex. The oxazepanone byproducts more likely arise from steric interactions imparted by substituents appended to the product heterocycles. After cyclization to intermediate B, protodeauration would then provide oxazocenones 11 with regeneration of the gold(I) catalyst.

Scheme 4

Proposed Bidentate Coordination of Au(I)-Catalyst

Having developed a method to access oxazocenones, we next assessed the ability of oxazocenone 11a to be elaborated to des-benzo analog 5 (Scheme 5). A synthesis of 5 was initiated by conversion of the primary alcohol of 11a to an azide using diphenylphosphoryl azide (DPPA) to afford 13 in excellent yield (98%). The incorporated azide masks a primary amine needed to install the requisite urea moiety. Prior to urea formation, 13 was converted to sulfonamide 17 in three steps. To circumvent nonselective deprotection of the p-methoxybenzyl (PMB) ether under acidic conditions, the Boc-carbamate was cleaved by first subjecting 13 to tert-butyldimethylsilyl triflate (TBSOTF) to provide N-silylcarbamate 14, which was then desilylated (TBAF) with decarboxylation to secondary crude amine 15.[19] Subsequent capping with 1,4-benzodioxan-6-sulfonyl chloride 16 gave sulfonamide 17. Staudinger reduction (Ph3P, H2O) of 17 to primary amine 18, followed by treatment with diphosgene (ClCO2CCl3), afforded isocyanate 19. This intermediate serves as a branching point to various urea derivatives, whereas, in this work, addition of 8-aminoquinoline 20 yielded PMB-protected des-benzo congener 21 in 80% yield from 18 in two steps. Deprotection of the PMB ether under oxidative conditions (e.g., DDQ) gave low yields of des-benzo congener 5, in which byproducts resulting from allylic oxidation were observed.[20] Alternatively, acid-mediated cleavage of the PMB ether with trifluoroacetic acid (TFA) proceeded efficiently (72% yield) to complete the synthesis of 5. The structure of 5 was assigned using X-ray crystallographic structure determination.

Scheme 5

Synthesis of Des-Benzo Quinoline Analog 5

In summary, we have described the development of a gold(I)-catalyzed 8-endo-dig hydroalkoxylation of alkynamides to form oxazocenones. This novel method was applied to a substrate with high structural complexity to obtain 5, a des-benzo analog of a previously described bioactive benzoxazocenone generated by diversity-oriented synthesis. Biological evaluation of 5 is underway, and we are currently investigating the application of the optimized gold(I)-catalyzed conditions to access additional heterocyclic scaffolds.