Double Spirocyclization of Arylidene- ∆ 2 -Pyrrolin-4-Ones with 3-Isothiocyanato Oxindoles

: Arylidene- ∆ 2 -pyrrolin-4-ones undergo organocatalyzed double spirocyclization with 3-isothiocianato oxindoles in a domino 1,4 / 1,2-addition sequence. The products contain three contiguous stereocenters ( ee up to 98%, dr up to 99:1, 12 examples). The absolute conﬁguration of the major diastereomer was determined by single crystal X-ray analysis. Along with heterocyclic Michael acceptors based on oxazolone, isoxazolone, thiazolidinone, pyrazolone, and pyrimidinedione, the reported results display the applicability of unsaturated ∆ 2 -pyrrolin-4-ones (pyrrolones) for the organocatalyzed construction of 3D-rich pyrrolone-containing heterocycles.


Introduction
Spirooxindoles, containing various spiro rings attached at the C-3 position of the oxindole framework, represent a privileged core scaffold frequently encountered in natural and synthetic products exhibiting many different biological activities [1][2][3][4], as shown in Figure 1 [5][6][7][8][9]. Conformational rigidity of spirooxindoles provides an excellent strategy to enforce the desired conformation for a specific and strong ligand-protein binding [10].
The absolute configuration (3R,3 S,4 R) of the major stereoisomer of the product 3b was determined by single crystal X-ray analysis ( Figure 3) (see the Supplementary Materials). Consequently, the same absolute configuration (3R,3 S,4 R) was assigned to all the major diastereomers of products 3a-j. The reaction of 3-isothiocyanato oxindoles 2a and 2b with N-unsubstituted pyrrolones 1l and 1m yielded the corresponding products 3k and 3l in low yields (7 and 14%), and low to moderate Catalysts 2020, 10, 1211 5 of 13 enantioselectivities (21 and 57% ee), respectively. Based on previous observations, where enantiomeric products were obtained in the reaction of (E)-and (Z)-pyrrolones 1 with 2-mercaptoacetaldehyde [71], an enantiomeric relationship of (3S,3 R,4 S) was tentatively assigned to products 3k and 3l (Scheme 3).
The follow-up methylation of compound 3a with iodomethane in the presence of K 2 CO 3 in acetone gave the S-methylated product 4 (Scheme 4).
According to the Grayson [72,73] proposal of stereochemistry origin in squaramide-catalyzed asymmetric Michael addition reactions and the observed absolute configuration revealed by X-ray analysis of the major diastereomer of compound 3b (cf. Figure 3), a plausible transition state (TS) leading to the product (as exemplified for the formation of product 3a) can be postulated (Scheme 5). The protonated catalyst activates and coordinates the pyrrolone electrophile via the protonated quinuclidine moiety, while the squaramide functionality simultaneously orients and activates the nucleophile for the attack. The Si face of the nucleophile attacks the Re face of the electrophile, which is followed by the spiro-cyclisation yielding product 3a (Scheme 5). Having established the optimal reaction conditions (catalyst IXb, trifluorotoluene), the scope of the studied transformation was evaluated. For that purpose, several Δ 2 -pyrrolin-4-ones 1 [71,72] and two 3-isothiocyanato oxindoles 2 [30,53,59] were applied (Figure 2). The results of the investigated scope are presented in Scheme 3. With the N-methyl-substituted Δ 2 -pyrrolin-4-ones 1a-g, the effect of electron-donating and electron-withdrawing substituents on the phenyl ring of the arylidene moiety, including tiophen-2-yl moiety, did not establish a clear trend; the products were isolated with good to excellent enantioselectivities (80-98% ee), diastereoselectivity above 75:25, and low to moderate yields (18-67%). Despite our best efforts, stereoisomers of the products rac-3m-p, derived from pyrrolones 1h-k and unsubstituted 3-isothiocyanato oxindole 2a, could not be separated on chiral HPLC columns (see the Supplementary Materials). The products 3f-j, derived from 5-methyl substituted 3-isothiocyanato oxindole 2b, compared with the products 3a-e, derived from unsubstituted 3-isothiocyanato oxindole 2a, were generally formed in slightly higher enantioselectivities though lower yields at longer reaction times.  Selected 5-arylidene-2-methyl-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylates 1 and 3-isothiocyanato oxindoles 2; color red-novel reported pyrrolones 1.
The follow-up methylation of compound 3a with iodomethane in the presence of K2CO3 in acetone gave the S-methylated product 4 (Scheme 4).  The follow-up methylation of compound 3a with iodomethane in the presence of K2CO3 in acetone gave the S-methylated product 4 (Scheme 4). According to the Grayson [72,73] proposal of stereochemistry origin in squaramide-catalyzed asymmetric Michael addition reactions and the observed absolute configuration revealed by X-ray analysis of the major diastereomer of compound 3b (cf. Figure 3), a plausible transition state (TS) leading to the product (as exemplified for the formation of product 3a) can be postulated (Scheme 5). The protonated catalyst activates and coordinates the pyrrolone electrophile via the protonated quinuclidine moiety, while the squaramide functionality simultaneously orients and activates the nucleophile for the attack. The Si face of the nucleophile attacks the Re face of the electrophile, which is followed by the spiro-cyclisation yielding product 3a (Scheme 5).  According to the Grayson [72,73] proposal of stereochemistry origin in squaramide-catalyzed asymmetric Michael addition reactions and the observed absolute configuration revealed by X-ray analysis of the major diastereomer of compound 3b (cf. Figure 3), a plausible transition state (TS) leading to the product (as exemplified for the formation of product 3a) can be postulated (Scheme 5). The protonated catalyst activates and coordinates the pyrrolone electrophile via the protonated quinuclidine moiety, while the squaramide functionality simultaneously orients and activates the nucleophile for the attack. The Si face of the nucleophile attacks the Re face of the electrophile, which is followed by the spiro-cyclisation yielding product 3a (Scheme 5).

Scheme 5.
Postulated transition state leading to the product 3a.
Scheme 5. Postulated transition state leading to the product 3a.

Materials and Methods, Syntheses, and Characterization
Solvents for chromatography and extractions were of technical grade. They were distilled prior to use. Technical grade anhydrous Na 2 SO 4 was used for drying of extracts. Melting points were determined on a Kofler micro hot stage and an SRS OptiMelt MPA100-Automated Melting Point System (Stanford Research Systems, Sunnyvale, CA, USA). The NMR spectra were obtained on a Bruker UltraShield 500 plus (Bruker, Billerica, MA, USA) at 500 MHz for 1 H and 126 MHz for a 13 C nucleus, using DMSO-d 6 and CDCl 3 with TMS as the internal standard, as solvents. Mass spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/MS (Agilent Technologies, Santa Clara, CA, USA), and IR spectra on a Perkin-Elmer Spectrum BX FTIR spectrophotometer (PerkinElmer, Waltham, MA, USA). Column chromatography (CC) was performed on silica gel (Silica gel 60, particle size: Methyl 5-arylidene-2-methyl-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylates 1 [71] and 3-isothio cyanatooxindoles 2a and 2b [30,53,59] were prepared following the literature procedures.
(i) For catalyst and solvent screening (model reaction 1a + 2a→3a), volatile components were evaporated in vacuo and the residue was purified by flash column chromatography to remove the catalyst (Silica gel 60, mobile phase: EtOAc/petroleum ether = 2:1). Fractions containing the product 3a were combined and volatile components were evaporated in vacuo followed by determination of the enantiomeric excess and diastereomeric ratio by HPLC analysis.
(ii) For the reaction scope synthesis (reactions 1 + 2→3; compounds 3a-l), volatile components were evaporated in vacuo and the residue was purified by column chromatography (Silica gel 60, mobile phase: EtOAc/petroleum ether = 2:1). Fractions containing pure product 3 were combined and volatile components were evaporated in vacuo, followed by determination of the enantiomeric excess by HPLC analysis, determination of the diastereomeric ratio by 1 H-NMR, and full characterization.

Conclusions
We have shown that Michael acceptors based on ∆ 2 -pyrrolin-4-ones (pyrrolones), which are easily prepared from bulk chemicals [71], undergo stereoselective organocatalyzed double spiro-cyclization with 3-isothiocianato oxindoles. A library of 12 products containing three contiguous stereocenters (ee up to 98%, dr up to 99:1) has been synthesized and a follow-up transformation demonstrated. This research offers a new entry for the construction of 3D-rich pyrrolone-containing heterocycles.
Funding: This research was funded by the Slovenian Research Agency through grants P1-0179 and P1-0175.