Skip to main content
NCBI home page
ACS Omega logoLink to ACS Omega
. 2023 Jan 9;8(3):3190–3197. doi: 10.1021/acsomega.2c06637

Synthesis and Evaluation of N-Diaminophosphoryl Aminothioureas as Bifunctional Catalysts for Vinylogous Aldol Reactions of Isatins and 2(3H)-Furanones

Hrishikesh D V 1, Ritesh A Annadate 1, Sunil V Pansare 1,*
PMCID: PMC9878653  PMID: 36713689

Abstract

graphic file with name ao2c06637_0011.jpg

The organocatalytic asymmetric direct vinylogous aldol reaction of N-methylisatins 1 and γ-butenolides 2 to provide 3-hydroxy-2-oxindole derivatives 3 was investigated. A series of N-diaminophosphoryl aminothiourea catalysts 4 was synthesized, and their utility for the stereoselective formation of 3 was examined.

Introduction

Naturally occurring as well as synthetic 3-alkyl-3-hydroxy-2-oxindole derivatives and related 2-oxindoles with γ-butenolide units at C3 have attracted considerable interest in recent years (Figure 1). These oxindoles display a wide range of biological activities, and the 3-alkyl-3-hydroxy-2-oxindole unit has been identified as a privileged motif1 for biological activity. For example, convolutamydine A (1) and B (2) change the characteristics of, and induce differentiation of, HL-60 cells, respectively.2 Convolutamydine E (3)3 is active against several cancer cell lines (KB, KB/VJ-300, and U937) and inhibits cell division in fertilized sea-urchin eggs. Dioxibrassinine (4) is a phytoalexin with antifungal activity4 and maremycin B (5) is active against several cancer cell lines.5 Several synthetic 3-hydroxy-3-substituted-2-oxindole derivatives are also of interest. For example, 6 and its analogues are inhibitors of yeast α-glycosidase,6 γ-butenolide containing oxindoles such as 7 have anticancer activity,7 and 3-aryl derivatives such as 8 have neuroprotective and BK channel opening activity8 (Figure 1). Structurally related oxindole derivatives such as 3-indolyl-3-hydroxy-2-oxindoles9 and spirooxindoles,9b−9d in which the two substituents at C-3 are incorporated into a ring, have also been actively investigated.

Figure 1.

Figure 1

Open in a new tab

Selected 3-alkyl/aryl-3-hydroxy-2-oxindole derivatives.

Given the importance of 3-substituted-3-hydroxy-2-oxindoles, their synthesis has been intensely investigated in recent years.10 The stereoselective addition of carbon nucleophiles to isatin derivatives11 is the prevalent approach to this class of compounds and metal-catalyzed as well as organocatalyzed versions of such reactions are reported.11 Asymmetric organocatalysis has emerged as a dominant theme in organic synthesis, and significant advances have been made in the development and application of new organocatalysts for the enantioselective synthesis of bioactive compounds.12 However, the direct vinylogous aldol reactions of 2(3H)-furanones (a class of γ-butenolides) with isatins are uncommon and only one report of a metal-catalyzed process11e and a sole study of an achiral, tertiary amine-mediated version11f are available. Our interest in such reactions stems from our earlier studies on organocatalyzed direct vinylogous aldol reactions of γ-crotonolactone with aldehydes employing bifunctional organocatalysts.13 Herein, we report initial results on the organocatalytic direct vinylogous aldol reaction of selected N-methylisatins 1 and 2(3H)-furanones 2 to provide 3.

At the outset, we chose to examine N-diaminophosphoryl aminothioureas 4 as potential catalysts for the desired vinylogous aldol reaction (Figure 2).

Figure 2.

Figure 2

Open in a new tab

Asymmetric vinylogous aldol reaction of 2(3H)-furanones and isatins.

We anticipated activation of the isatin by hydrogen-bonding with the thiourea14 and simultaneous activation of the γ-butenolide by deprotonation with the tertiary amine. It should be noted that, compared to the more conventional N-aryl aminothioureas, the corresponding N-diaminophosphoryl thioureas are far less explored as organocatalysts and only two studies with such thioureas are reported.15 Moreover, these studies have only examined enamine-forming versions of the catalysts and there are opportunities for noncovalent catalysis and reaction development with N-diaminophosphoryl aminothioureas containing a basic functionality (e.g., a tertiary amine). We anticipated that enantiomerically enriched, diamine-derived, bifunctional catalysts of this type would offer stereocontrol of the vinylogous aldol reaction.

Results and Discussion

Our studies began with the synthesis of N-diaminophosphoryl aminothioureas 4, the potential catalysts for the vinylogous aldol reaction. The general strategy for their preparation involved the synthesis of a series of chiral diamine-derived diaminophosphoryl chlorides 6 (Figure 2) and their conversion to the isothiocyanate derivatives 7 by adaptation of reported methods for related compounds.16 Subsequent reaction of 7 with selected diamines 8 provided 4 (65–88% yield over three steps for 4a–4n, and 91% yield over two steps, from the commercially available diaminophosphoryl chloride, for 4o). This strategy and the catalysts 4 prepared for this study are shown in Figure 3.

Figure 3.

Figure 3

Open in a new tab

Synthesis of N-diaminophosphoryl aminothiourea catalysts 4 examined in this study.

Analysis of the 1H NMR spectra of the phosphoramide-based catalysts revealed an interesting feature of their conformation in solution. We had anticipated that the N–Ha proton (Figure 4), which is flanked by the thiocarbonyl and the phosphoryl groups, would resonate more downfield than the N–Hb proton. However, N–Hb resonates more downfield than N–Ha. A plausible reason for this is a preference for the thiourea conformation in which N–Hb is internally hydrogen-bonded to the P=O oxygen (Figure 4), which results in a downfield shift of Hb.17 This trend is observed for all of the catalysts 4 prepared in this study; Hb appears in the δ 9.50−δ 10.7 range, whereas the N–Ha appears in the δ 6.35–δ 6.93 range. The 1H NMR data for previously reported17b phosphoryl thioureas similar to 4 is also indicative of intramolecular H-bonding (Figure 4). It may be noted that Ha and Hb are easily assigned by 1H–1H COSY spectroscopy (Hb correlates with NCHc in the pendant diamine, and this correlation is absent for Ha). The N–Hb chemical shifts for 4a, 4k, and 4n are representative (Figure 4). These observations suggested that the diaminophosphoryl thioureas 4 may function as conformationally constrained single H-bond donors in solution.

Figure 4.

Figure 4

Open in a new tab

Intramolecular hydrogen bonding in N-diaminophosphoryl thioureas 4.

Initial studies were aimed at identifying the most suitable catalyst from the series of N-diaminophosphoryl thioureas 4 (Figure 3). We chose to examine the vinylogus aldol reaction of N-methylisatin (1a, 1.0 equiv) and α-angelica lactone (2a, 1.5 equiv) in the presence of 10 mol % of 4 for these studies. All reactions were conducted in diethyl ether at ambient temperature, and the observations are summarized in Table 1.

Table 1. Vinylogous Aldol Reaction of 1a and 2a Catalyzed by 4.

graphic file with name ao2c06637_0010.jpg

entry cat. time (h) yield 3a (%)a dr ee (%)b
1 4a 48 46 20:1 77
2 4b 48 19 20:1 73
3 4c 48 20 8.3:1 65
4 4d 20 30 6.2:1 52
5 4e 26 19 20:1 19
6 4f 24 31 20:1 48
7 4g 16 24 2.5:1 30
8 4h 48 25 20:1 43
9 4i 48 20 20:1 72
10 4j 16 17 3.2:1 6
11 4k 12 17 3.7:1 14
12 4l 16 20 5:1 44
13 4m 26 25 20:1 62
14 4n 18 35 6.6:1 61
15 4o 22 26 2.2:1 48
Open in a new tab
a

Isolated yield.

b

Chiral HPLC analysis.

All of the N-diaminophosphoryl aminothioureas 4 were able to catalyze the vinylogous aldol reaction with moderate to excellent diastereoselectivity (dr = 2.5:1 to 20:1) in favor of the diastereomer 3a. The yields (17–46%) and enantiomeric excess (6–77%) for 3a were highly dependent on the structure of catalyst 4, and hence, an analysis of the results as a function of structural changes in 4 is instructive.

The average yield (26%) and enantiomeric excess (53%) for catalysts containing a cyclohexanediamine-derived phosphoramide (Table 1, entries 1–9, catalysts 4a–4i) is better than the average yield (20%) and enantiomeric excess (32%) for catalysts containing a 1,2-diphenylethanediamine-derived phosphoramide (Table 1, entries 10–15, catalysts 4j–4m). Within the 4a–4i series, the following observations are notable.

A comparison of the catalysts 4a, 4b, and 4c indicates that an increase in the size of the tertiary amine pendant (dimethylamino, pyrrolidinyl, and piperidinyl group) decreases the enantiomeric excess (compared to that obtained with 4a) of the product (Table 1, entries 1–3). Successive removal of stereocenters in the diamine pendant in 4a, to give catalysts 4d and 4e, also causes incremental loss of enantiomeric excess (Table 1, entries 4 and 5, 52% ee with 4d and 19% ee with 4e). Replacing the 1,2-diphenylethanediamine pendant in 4a with a cyclohexanediamine- (4f) or a quinine-derived diamine (4g) also reduces the enantioselectivity for 3a (Table 1, entries 6 and 7). The effect of a change to the N-alkyl group in the phosphoramide portion of 4a was also examined. Replacing the N-benzyl group in 4a with a neopentyl group (catalyst 4h) resulted in a significant loss of enantioselectivity (Table 1, entries 1 and 8), whereas replacement with a 2-naphthyl group (catalyst 4i) had a less pronounced effect (Table 1, entries 1 and 9). This observation suggests that an aryl functionality in the N-group in the phosphoramide has a beneficial effect on enantioselectivity. Curiously, this N-group change has no effect on the diastereoselectivity of the reaction, which remains uniformly high (20:1) for 4a, 4h, and 4i.

Notable structure-selectivity trends were also observed in the 4j–4l series of catalysts. Incremental changes in the size18 of the N-group in the phosphoramide portion (N-methyl in 4j, N-benzyl in 4k, and N-isopropyl in 4l) are beneficial for the diastereoselectivity (4j, 3.2:1; 4k, 3.7:1; 4l 5.1:1) as well as the enantiomeric excess of 3a (6% ee (with 4j), 14% ee (with 4k), 44% ee (with 4l)) obtained with these catalysts (Table 1, entries 10–12).

Results with the catalysts 4m, 4n, and 4o reveal the effect of changes to the phosphoramide portion while retaining the N,N-dimethylamino-1,2-diphenylethanediamine portion in the best catalyst (4a) in the series. Replacing the cyclohexanediamine-derived phosphoramide in 4a with a 1,2-diphenylethanediamine phosphoramide (catalyst 4m) has a notable detrimental effect on the enantioselectivity (77% ee with 4a and 62% ee with 4m) but not the diastereoselectivity. The use of an achiral cyclic phosphoramide (catalyst 4n) lowers the enantiomeric excess (61%) and the diastereoselectivity (6.6:1, Table 1, entries 1 and 14). Curiously, the enantioselectivity with 4m and 4n is similar. An acyclic and achiral phosphoramide unit (catalyst 4o) is detrimental to the diastereoselectivity as well the enantioselectivity of the reaction (Table 1, entries 1 and 15).

These observations lead to the following conclusions regarding structural features in 4: (1) A cyclic phosphoramide functionality is important. (2) Chirality in the pendant diamine is important, but the pendant should be acyclic with a relatively small tertiary amine group. (3) Phosphoramide N-groups with aryl rings perform better than simple alkyl groups in cyclohexanediamine-derived phosphoramides, but N-alkyl groups are beneficial in stilbenediamine-derived phosphoramides. (4) In catalysts based on a 1,2-diphenylethanediamine-derived phosphoramide, a diphenylethanediamine pendant is better than a cyclohexanediamine pendant. (5) The best catalysts in the two groups (catalyst 4a in 4a–4i and catalyst 4m in 4j–4n) both have N-benzyl groups in the phosphoramide and a dimethylamino group in the pendant.

The (3S,2′R) diastereomer 3a is obtained as the major diastereomer in all of the above reactions, and the absolute configuration of 3a was established as 3S,2′R by X-ray crystallographic analysis (Figure 5).19 Notably, this selectivity is opposite to the diastereoselectivity (3S,2′S) reported for the metal-catalyzed version11e of the reaction.

Figure 5.

Figure 5

Open in a new tab

X-ray crystal structure of the vinylogous aldol product 3a.

A comparison of the well-known and widely used, aminothiourea-containing, bifunctional organocatalyst 7(20) and catalyst 4a is particularly interesting. Under the optimized reaction conditions, 7 provided the diastereomer 3b (26%) but with negligible enantiomeric excess (3%) and also with opposite diastereoselectivity ((3S,2′S)) compared to 3a (Scheme 1). Although it could be reasoned that a comparison of 4a and 7 is subjective, since unlike 7, the 1,2-diaminocyclohexane unit is absent in 4a, and it should be noted that the results with the 1,2-diaminocyclohexane-derived catalysts 4f (dr 20:1; 42% ee), 4k (dr 3.7:1; 14% ee), and 4l (dr 5:1; 44% ee), although not better than 4a, are still superior to those obtained with 7. These observations indicate a distinct advantage of the diaminophosphoryl functionality in the context of the vinylogous aldol reaction being studied.

Scheme 1. Stereodivergent Vinylogous Aldol Reactions of 1a and 2a with Catalysts 4a and 7.

Scheme 1

Open in a new tab

Having identified 4a as the catalyst of choice, its performance in a selection of solvents was also examined.21 However, these studies only confirmed that diethyl ether was the best solvent for the reaction of 1a and 2a. The optimized conditions were therefore used to examine the substrate scope of the vinylogous aldol reaction with a selection of substituted isatins as well as 2(3H)-furanones, and the results are summarized in Figure 6.

Figure 6.

Figure 6

Open in a new tab

Substrate scope of the vinylogous aldol reaction of isatins and 2(3H) furanones.

The substrate study identifies some limitations of the vinylogous aldol reaction of 1 and 2. Although the diastereoselectivity of the reaction is high in several cases (four examples with dr 20:1, and two examples with dr >10:1), considerable variation is observed in the yield and the enantiomeric excess of 3 (23–90% ee). Although a distinct trend in the variation of stereoselectivity as a function of substitution in the isatin is not apparent, the yield of the reaction clearly depends on substitution in the 2(3H)-furanone. It is plausible that the yields for reactions with 2a are affected by the decomposition of 2a during the reaction since periodic addition of 2a (0.38 equiv added in four portions at 3 h intervals) does increase the yield of 3a (50%, 20:1 dr), but not significantly. However, this modification has a detrimental effect on the enantiomeric excess of 3a (50% ee). Compared to reactions with 2a, the reaction of N-methylisatin 1a and the furanone 2b proceeds in notably high yield (90% of 3l). This suggests that the low yield of the reactions with 2a could be due to nucleophilic addition at the furanone carbonyl in 2a or in 3a, prior to protonation of the aldolate species, and this undesired side reaction may be hindered by substitution α to the lactone carbonyl. This could lead to the higher yield of 3l obtained from 2b. The low yield of 3m is probably a consequence of steric hindrance of the aldol reaction (ethyl substituent at the reaction site in 2c, compared to a methyl group in 2a). Side reactions of the N-methylisatin could also be an issue since it is completely consumed in all of the reactions, but this is not reflected in the yield of 3. We anticipate that all of the aldol products are stable under the reaction conditions and some evidence for this was obtained by treating 3a with catalyst 4a in ether at ambient temperature for 48 h. Only unreacted 3a was recovered (90%) from this reaction, and the enantiomeric excess of recovered 3a was unaffected. A similar reaction conducted with the minor diastereomer 3b and catalyst 4a indicated that 3b is also stable under the reaction conditions.

A plausible transition state assembly that explains the origin of the stereoselectivity of the vinylogous aldol reaction of 1a and 2a in the presence of catalyst 4a to provide 3a is shown in Figure 7. Taking into account that 4a is internally hydrogen-bonded, and hence functions as a single hydrogen-bond donor, only the free thiourea N–H in 4a is hydrogen-bonded to the isatin carbonyl group. The furanone-derived enolate is hydrogen-bonded with the ammonium functionality (obtained by deprotonation of the furanone by the tertiary amine) in the pendant diamine in 4a. The chirality of the 1,2-diphenylethanediamine pendant controls the relative orientation of the isatin and the furanone (isatin placed above the furanone as shown), and this exposes the Si face of the enolate γ-carbon to the Si face of the isatin carbonyl group. It is plausible that stabilizing interactions involving the phosphoramide N-benzyl group and the isatin may also favor this assembly. The change in the enantiomeric excess of 3a due to variation of the N-substituent in the cyclohexanediamine portion of 4 provides some support for this hypothesis (77% ee for 3a with 4a (N-benzyl) as the catalyst and 72% ee with 4i (N-2-naphthyl), but only 43% ee with 4h (N-neopentyl)). The comparable results obtained with 4m and 4n also suggest that N-substitution in the cyclic phosphoramide portion of 4 plays an important role. These organizing elements result in the preferential formation of the (3S,2′R) diastereomer 3a.

Figure 7.

Figure 7

Open in a new tab

Proposed transition state assembly leading to the formation of 3a.

In conclusion, we have prepared a series of N-diaminophosphoryl aminothioureas with basic as well as hydrogen-bonding functionalities. These phosphoramides function as bifunctional organocatalysts in the vinylogous aldol reaction of 2(3H) furanones and isatins. This is the first report of an organocatalyzed, asymmetric version of the described reaction. In addition, the diastereoselectivity of this organocatalytic reaction is opposite to that offered by a metal-based catalyst11e and by a conventional aminothiourea organocatalyst. Despite some limitations, the results presented here provide a basis for future versions of the organocatalytic vinylogous aldol reactions of 2(3H) furanones and isatins. Current efforts focus on these studies as well as the conversion of aldol products 3 to other oxindole-derived motifs.

Experimental Section

General Procedure for the Vinylogous Aldol Reaction of N-Methylisatins 1 and 2(3H)-Furanones 2

N-Methylisatin 1 (1.0 equiv) and furanone 2 (1.5 equiv) were added to a solution of the catalyst 4 (5–10 mol %) in diethyl ether (1 mL) at ambient temperature, and the mixture was stirred for the specified time. After completion of the reaction (TLC), the mixture was concentrated, the residue was dissolved in a minimum amount of THF, and the solution was applied to a column packed with a slurry of flash silica gel in hexanes/EtOAc. Elution of the column provided the aldol product 3 as an inseparable mixture of diastereomers. The preparation 3a is representative.

(S)-3-Hydroxy-1-methyl-3-((R)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)indolin-2-one (3a)

The reaction of N-methylisatin 1a (40 mg, 0.25 mmol) and α-angelica lactone 2a (37 μL, 0.38 mmol) in the presence of phosphoramide catalyst 4a (16 mg, 0.02 mmol) in Et2O (1 mL) for 19 h according to the general procedure provided, after purification by flash column chromatography on silica gel (hexanes/EtOAc, 4:2), 30 mg (46%) of 3a as an off-white solid.

MP: 133.5–137.0 °C; IR (neat): 3407, 3364, 3077, 2923, 2853, 1754, 1706, 1609, 1495, 1467, 1364, 1295, 1254, 1204, 1164, 1116, 1088, 1047, 951, 906, 866, 824, 751 cm–1. 1H NMR (300 MHz, CDCl3): δ 7.45 (d, 1H, J = 7.6 Hz,), 7.39−7.31 (m, 2H), 7.09 (td, 1H, J = 7.6, 0.9 Hz), 6.83 (d, 1H, J = 7.8 Hz), 5.94 (d, 1H, J = 5.7 Hz), 3.19 (s, 3H), 1.71 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 174.6, 171.9, 156.3, 143.6, 130.8, 126.5, 125.7, 123.6, 122.9, 108.9, 90.4, 79.0, 26.6, 18.3. HRMS (APPI, pos.): m/z 259.0847 (259.0844 calc. for C14H13NO4 (M)+) and 260.0920 (260.0923 calc. for C14H14NO4 (M + H)+). HPLC: Chiralpak IA (hexane/i-PrOH, 90/10, flow rate 1 mL min–1, λ = 247 nm): tmajor = 20.75 min, tminor = 24.16 min, 77% ee; [α]D22 + 96.8 (c 0.5, CH2Cl2). Crystals of 3a that were suitable for X-ray diffraction analysis were obtained by slow evaporation of a solution of 3a in CDCl3.

Acknowledgments

These investigations were supported by the Natural Sciences and Engineering Research Council of Canada and the Canada Foundation for Innovation. The authors thank Dr. Jian-Bin Lin, Centre for Chemical Analysis, Research and Training, Memorial University, for X-ray crystallography of 3a.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c06637.

  • Experimental procedures, spectral data; 1H and 13C spectra for compounds 3, 4, 6, and 7; and HPLC traces for 3 (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao2c06637_si_001.pdf (13.1MB, pdf)

References

  1. Peddibhotla S. 3-Substituted-3-hydroxy-2-oxindole, an emerging new scaffold for drug discovery with potential anti-cancer and other biological activities. Curr. Bioact. Compd. 2009, 5, 20–38. 10.2174/157340709787580900. [DOI] [Google Scholar]
  2. a Kamano Y.; Zhang H.-P.; Ichihara Y.; Kizu H.; Komiyama K.; Pettit G. R.; Convolutamidyne A. a novel bioactive hydroxyindole alkaloid from marine bryozoan Amathea convoluta. Tetrahedron Lett. 1995, 51, 2783–2784. 10.1016/0040-4039(95)00395-S. [DOI] [Google Scholar]; b Zhang H.-P.; Kamano Y.; Ichihara Y.; Kizu H.; Komiyama K.; Itokawa H.; Pettit G. R. Isolation and structure of convolutamidynes B-D from marine bryozoan Amathea convoluta. Tetrahedron 1995, 36, 5523–5528. 10.1016/0040-4020(95)00241-Y. [DOI] [Google Scholar]
  3. Kamano Y.; Kotake A.; Hashima H.; Hayakawa I.; Hiraide H.; Zhang H.-p.; Kizu H.; Komiyama K.; Hayashi M.; Pettit G. R. Three new alkaloids, convolutamines F and G, and convolutamydine E, from the Floridian marine bryozoan Amathia convoluta. Collect. Czech. Chem. Commun. 1999, 64, 1147–1153. 10.1135/cccc19991147. [DOI] [Google Scholar]
  4. Pedras M. S. C.; Minic Z. The phytoalexins brassilexin and camalexin inhibit cyclobrassinin hydrolase, a unique enzyme from the fungal pathogen Alternaria brassicicola. Bioorg. Med. Chem. 2014, 22, 459–467. 10.1016/j.bmc.2013.11.005. [DOI] [PubMed] [Google Scholar]
  5. a Balk-Bindseil W.; Helmke E.; Weyland H.; Laatsch H. Marine bacteria, VIII. Maremycin A and B, new diketopiperazines from a marine Streptomyces sp. Liebigs Ann. Chem. 1995, 1995, 1291–1294. 10.1002/jlac.1995199507171. [DOI] [Google Scholar]; b Liu Y.; Zhang L.; Jia Y. Total synthesis of maremycins A, B, C1/C2, D1, and D2. Tetrahedron Lett. 2012, 53, 684–687. 10.1016/j.tetlet.2011.11.118. [DOI] [Google Scholar]
  6. Luthra T.; Naga Lalitha K.; Agarwal R.; Uma A.; Sen S. Design, synthesis and in vitro study of densely functionalized oxindoles as potent α-glucosidase inhibitors. Bioorg. Med. Chem. 2018, 26, 4996–5005. 10.1016/j.bmc.2018.08.022. [DOI] [PubMed] [Google Scholar]
  7. Hu W.; Zhang T.; Zhang D.; Yang X.; Hu L.. Oxidized Indole-Containing γ-Butenolide Derivative as Anticancer Agent and Preparation Thereof. Chinese Patent CN111423421 A, 2020.
  8. a Hewawasam P.; Erway M.; Moon S. L.; Knipe J.; Weiner W.; Boissard C. G.; Post-Munson D. J.; Gao Q.; Huang S.; Gribkoff V. K.; Meanwell N. A. Synthesis and structure-activity relationships of 3-aryloxindoles: A New class of calcium-dependent, large conductance potassium (Maxi-K) channel openers with neuroprotective properties. J. Med. Chem. 2002, 45, 1487–1499. 10.1021/jm0101850. [DOI] [PubMed] [Google Scholar]; b Hewawasam P.; Meanwell N. A.; Gribkoff V. K.; Dworetzky S. I.; Boissard C. G. Discovery of a novel class of BK channel openers: Enantiospecific synthesis and BK channel opening activity of 3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one. Biorg. Med. Chem. Lett. 1997, 7, 1255–1260. 10.1016/S0960-894X(97)00202-3. [DOI] [Google Scholar]
  9. a Zhang Y.-C.; Jiang F.; Shi F. Organocatalytic asymmetric synthesis of indole-based chiral heterocycles: strategies, reactions and outreach. Acc. Chem. Res. 2020, 53, 425. 10.1021/acs.accounts.9b00549. [DOI] [PubMed] [Google Scholar]; b Ma C.; Zhu J.-Y.; Zhang Y.-Z.; Mei G.-J.; Shi F. Catalytic asymmetric [2+3] cyclizations of azlactones with azonaphthalenes. Angew. Chem., Int. Ed. 2018, 57, 5398. 10.1002/anie.201801349. [DOI] [PubMed] [Google Scholar]; c Wang Y.; Cobo A. A.; Franz A. K. Recent advances in organocatalytic asymmetric multicomponent cascade reactions for enantioselective synthesis of spirooxindoles. Org. Chem. Front. 2021, 8, 4315. 10.1039/D1QO00220A. [DOI] [Google Scholar]; d Mei G.-J.; Shi F. Catalytic asymmetric synthesis of spirooxindoles: recent advances. Chem. Commun. 2018, 54, 6607. 10.1039/C8CC02364F. [DOI] [PubMed] [Google Scholar]
  10. Kumar A.; Chimni S. S. Catalytic asymmetric synthesis of 3-hydroxyoxindole: a potentially bioactive molecule. RSC Adv. 2012, 2, 9748–9762. 10.1039/c2ra21131a. [DOI] [Google Scholar]
  11. Selected recent reports:; a Yang Y.; Tang C.; Liang G.; Deng P.; Zhou J.; Yang Z.; Chen P.; Zhou H. Cooperative heterobimetallic zinc/alkaline earth metal catalysis: A Zn/Sr aminophenol sulfonamide complex for catalytic asymmetric Michael addition of 3-acetoxy-2-oxindoles to β-Ester Enones. J. Org. Chem. 2021, 86, 7119–7130. 10.1021/acs.joc.1c00379. [DOI] [PubMed] [Google Scholar]; b Li J.; Li Y.; Sun J.; Gui Y.; Huang Y.; Zha Z.; Wang Z. Copper-catalyzed enantioselective Mukaiyama aldol reaction of silyl enol ethers with isatins. Chem. Commun. 2019, 55, 6309–6312. 10.1039/C9CC02159K. [DOI] [PubMed] [Google Scholar]; c Shukla R. D.; Rai B.; Kumar A. Exploration of catalytic activity of trypsin for C(sp3)-H functionalization and consequent C-C bond formation. Eur. J. Org. Chem. 2019, 2019, 2864–2868. 10.1002/ejoc.201900290. [DOI] [Google Scholar]; d Li B.; Xu Z.-J.; Han J. Chiral iminophosphoranes organocatalyzed asymmetric hydroxylation of 3-substituted oxindoles with oxaziridines. Tetrahedron Lett. 2018, 59, 2412–2417. 10.1016/j.tetlet.2018.05.018. [DOI] [Google Scholar]; e Tang Q.; Lin L.; Ji J.; Hu H.; Liu X.; Feng X. Catalytic asymmetric direct vinylogous aldol reaction of isatins with β,γ-unsaturated butenolides. Chem. – Eur. J. 2017, 23, 16447–16451. 10.1002/chem.201704100. [DOI] [PubMed] [Google Scholar]; f Kumar A. S.; Kumar G. S.; Ramakrishna K.; Ramesh P.; Swetha A.; Meshram H. M. A facile and efficient synthesis of oxindole motifs by direct vinylogous aldol/Mannich reaction of isatins/isatin imines with furn-2(3H)-one. Synlett 2017, 28, 337. 10.1055/s-0036-1588341. [DOI] [Google Scholar]; g Dong H.; Liu J.; Ma L.; Ouyang L. Chitosan aerogel catalyzed asymmetric aldol reaction in water: highly enantioselective construction of 3-substituted-3-hydroxy-2-oxindoles. Catalysts 2016, 6, 186. 10.3390/catal6120186. [DOI] [Google Scholar]; h Kimura J.; Ummareddy V. S. R.; Kohari Y.; Seki C.; Mawatari Y.; Uwai K.; Okuyama Y.; Kwon E.; Tokiwa M.; Takeshita M.; Iwasa T.; Nakano H. Simple primary amino amide organocatalyst for enantioselective aldol reactions of isatins with ketones. Eur. J. Org. Chem. 2016, 2016, 3748–3756. 10.1002/ejoc.201600414. [DOI] [Google Scholar]; i Gangar M.; Kashyap N.; Kumar K.; Goyal S.; Nair V. A. Imidazolidinone based chiral auxiliary mediated acetate aldol reactions of isatin derivatives and stereoselective synthesis of 3-substituted-3-hydroxy-2-oxindoles. Tetrahedron Lett. 2015, 56, 7074–7081. 10.1016/j.tetlet.2015.11.007. [DOI] [Google Scholar]; j Dong Z.; Yan C.; Gao Y.; Dong C.; Qiu G.; Zhou H.-B. Tunable bifunctional phosphine-squaramide promoted Morita-Baylis-Hillman reaction of N-alkyl isatins with acrylates. Adv. Synth. Catal. 2015, 357, 2132–2142. 10.1002/adsc.201500110. [DOI] [Google Scholar]; k Deng T.; Wang H.; Cai C. Copper-catalyzed asymmetric addition to isatins to give 3-hydroxy-2-oxindoles by C-H activation. Eur. J. Org. Chem. 2014, 2014, 7259–7264. 10.1002/ejoc.201402852. [DOI] [Google Scholar]; l Thakur P. B.; Sirisha K.; Sarma A. V. S.; Meshram H. M. Microwave assisted rapid, catalyst-free, and efficient synthesis of a new class of diversely functionalized 3-hydroxy-2-oxindole scaffolds under aqueous reaction media. Tetrahedron Lett. 2014, 55, 2459–2462. 10.1016/j.tetlet.2014.03.008. [DOI] [Google Scholar]; m Gomes J. C.; Sirvent J.; Moyano A.; Rodrigues M. T. Jr; Coelho F. Aqueous Morita-Baylis-Hillman reaction of unprotected isatins with cyclic enones. Org. Lett. 2013, 15, 5838–5841. 10.1021/ol4029034. [DOI] [PubMed] [Google Scholar]; n Yan T.; Wang X.; Sun H.; Liu J.; Xie Y. Facile creation of 3-substituted-3-hydroxy-2-oxindoles by arginine-catalyzed aldol reactions of α,β-unsaturated ketones with isatins. Molecules 2013, 18, 14505–14518. 10.3390/molecules181214505. [DOI] [PMC free article] [PubMed] [Google Scholar]; o Kumar A.; Chimni S. S. Organocatalytic asymmetric direct aldol reaction of pyruvic aldehyde dimethyl acetal with isatin derivatives. Eur. J. Org. Chem. 2013, 2013, 4780–4786. 10.1002/ejoc.201300411. [DOI] [Google Scholar]; p Wang G.-W.; Zhou A.-X.; Wang J.-J.; Hu R.-B.; Yang S.-D. Palladium-catalyzed sp2 and sp3 C-H bond activation and addition to isatin toward 3-hydroxy-2-oxindoles. Org. Lett. 2013, 15, 5270–5273. 10.1021/ol402494e. [DOI] [PubMed] [Google Scholar]
  12. Selected recent reviews:; a Ardevines S.; Marques-Lopez E.; Herrera R. P. Horizons in asymmetric organocatalysis: En route to the sustainability and new applications. Catalysts 2022, 12, 101. 10.3390/catal12010101. [DOI] [Google Scholar]; b Sansinenea E.; Ortiz A. Asymmetric organocatalytic syntheses of bioactive compounds. Curr. Org. Synth. 2022, 19, 148. 10.2174/1570179418666210728145206. [DOI] [PubMed] [Google Scholar]; c Hughes D. L. Highlights of the recent patent literature: Focus on asymmetric organocatalysis. Org. Process Res. Dev. 2022, 26, 2224. 10.1021/acs.oprd.2c00139. [DOI] [Google Scholar]; d Parella R.; Jakkampudi S.; Zhao J. C.-G. Recent Applications of Asymmetric Organocatalytic Methods in Total Synthesis. ChemistrySelect 2021, 6, 2252. 10.1002/slct.202004196. [DOI] [Google Scholar]
  13. a Pansare S. V.; Paul E. K. Synthesis of (+)-febrifugine and a formal synthesis of (+)-halofuginone employing an organocatalytic direct vinylogous aldol reaction. Synthesis 2013, 45, 1863–1869. 10.1055/s-0033-1338706. [DOI] [Google Scholar]; b Pansare S. V.; Paul E. K. Synthesis of (+)-L-733,060, (+)-CP-99,994 and (2S,3R)-3-hydroxypipecolic acid: Application of an organocatalytic direct vinylogous aldol reaction. Org. Biomol. Chem. 2012, 10, 2119–2125. 10.1039/c2ob06644k. [DOI] [PubMed] [Google Scholar]; c Pansare S. V.; Paul E. K. Organocatalytic asymmetric direct vinylogous aldol reactions of γ-crotonolactone with aromatic aldehydes. Chem. Commun. 2011, 47, 1027–1029. 10.1039/C0CC04191B. [DOI] [PubMed] [Google Scholar]
  14. a Hof K.; Lippert M.; Schreiner P. R.. Hydrogen-Bonding Catalysts: (Thio)Urea Catalysis. In Science of Synthesis, Asymmetric Organocatalysis; List B.; Maruoka K., Eds.; Thieme, 2012; Vol. 2, pp 297–412. [Google Scholar]; b Takemoto Y. Recognition and activation by ureas and thioureas: stereoselective reactions using ureas and thioureas as hydrogen-bonding donors. Org. Biomol. Chem. 2005, 3, 4299–4306. 10.1039/b511216h. [DOI] [PubMed] [Google Scholar]
  15. a Cruz-Hernandez C.; Martinez-Martinez E.; Hernandez-Gonzalez P. E.; Juaristi E. Synthesis of a new N-diaminophosphoryl-N′-[(2S)-2-pyrrolidinylmethyl]thiourea as a chiral organocatalyst for the stereoselective Michael addition of cyclohexanone to nitrostyrenes and chalcones - Application in cascade processes for the synthesis of polycyclic systems. Eur. J. Org. Chem. 2018, 2018, 6890–6900. 10.1002/ejoc.201801339. [DOI] [Google Scholar]; b Cruz-Hernández C.; Landeros J. M.; Juaristi E. Multifunctional phosphoramide-(S)-prolinamide derivatives as efficient organocatalysts in asymmetric aldol and Michael reactions. New J. Chem. 2019, 43, 5455–5465. 10.1039/C9NJ00300B. [DOI] [Google Scholar]
  16. Shipov A. E.; Genkina G. K.; Petrovskii P. V. Phosphorylthioureas and phosphorylureas containing amino acid fragments. Russ. Chem. Bull. 2009, 58, 2512–2516. 10.1007/s11172-009-0352-4. [DOI] [Google Scholar]
  17. a Yao L.; Grishaev A.; Cornilescu G.; Bax A. The impact of hydrogen bonding on amide 1H chemical shift anisotropy studied by cross-correlated relaxation and liquid crystal NMR spectroscopy. J. Am. Chem. Soc. 2010, 132, 10866–10875. 10.1021/ja103629e. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Li Z.; Kuang Y.; Guo F.; Hou Y. Synthesis and properties of 5,5-dimethyl-1,3,2-dioxa phosphoro cyclohexane phosphoryl thioureas. Main Group Met. Chem. 2007, 30, 253–258. 10.1515/MGMC.2007.30.5.253. [DOI] [Google Scholar]
  18. Boiadjiev S. E.; Lightner D. A. Steric size in conformational analysis. Steric compression analyzed by circular dichroism spectroscopy. J. Am. Chem. Soc. 2000, 122, 11328–11339. 10.1021/ja002069c. [DOI] [Google Scholar]
  19. Crystallographic data for 3a has been deposited with the CCDC, deposition number 2212587.
  20. Okino T.; Hoashi Y.; Takemoto Y. Enantioselective Michael reaction of malonates to nitroolefins catalyzed by bifunctional organocatalysts. J. Am. Chem. Soc. 2003, 125, 12672–12673. 10.1021/ja036972z. [DOI] [PubMed] [Google Scholar]
  21. The results of the solvent survey are included in the Supporting Information.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ao2c06637_si_001.pdf (13.1MB, pdf)

Articles from ACS Omega are provided here courtesy of American Chemical Society

RESOURCES