Volume 12 Number 4 28 January 2014 Pages 543–710
Organic & Biomolecular Chemistry www.rsc.org/obc
ISSN 1477-0520
PAPER Dhevalapally B. Ramachary et al. Asymmetric synthesis of drug-like spiro[chroman-3,3’-indolin]-2’-ones through aminal-catalysis
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Asymmetric synthesis of drug-like spiro[chroman3,3’-indolin]-2’-ones through aminal-catalysis† Dhevalapally B. Ramachary,* M. Shiva Prasad, S. Vijaya Laxmi and R. Madhavachary Asymmetric synthesis of drug-like functionalized spiro[chroman-3,3’-indolin]-2’-ones 5 containing three contiguous stereocenters with high diastereo- and enantioselectivities was achieved using the reflexiveMichael (r-M) reaction of unmodified hydroxyenals 1 with various (E)-3-alkylideneindolin-2-ones 2 in the presence of (R)-DPPOTMS/AcOH (R)-3/4b as a catalyst at room temperature. Chiral spiro[chroman-3,3’indolin]-2’-ones 5 were transformed into the functionalized spiranes 7, 9, and 10 in good yields with high selectivity through Wittig, TCRA, acetal protection and reduction reactions, respectively. Supporting evi-
Received 21st October 2013, Accepted 12th November 2013
dence for the reaction pathway through the formation of the important catalytic species of “aminals” was observed through NMR and ESI-HRMS analysis of an ongoing reaction between 1 and (R)-3
DOI: 10.1039/c3ob42100g
in CDCl3 and also shown by the structural requirement in hydroxyenals 1 to generate the “aminals” with
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(R)-3 through controlled experiments.
Introduction In this decade, the discovery of L-proline induced chiral enamines from carbonyls initiated a new era in asymmetric catalysis1 and at the same time it has also given inspiration to develop many other primary catalytic species in situ from different carbonyl compounds (Fig. 1). For example iminium-catalysis,2 2-aminobuta-1,3-diene-catalysis,3 1-aminobuta-1,3-diene-catalysis,4 SOMO-catalysis,5 trienamine-catalysis6 and aminoenynecatalysis7 have well demonstrated the importance of in situ generated primary catalytic species in a variety of asymmetric reactions. The involvement of primary catalytic species in the above reactions is well understood from the preliminary NMR and mass experiments,8 but the detailed kinetic and thermodynamic data later revealed that the in situ generated secondary catalytic species are also responsible for the reaction rates/ selectivities, especially in the organocatalytic aminoxylation, amination, oxa-Michael and Michael reactions. The pioneering work of the Blackmond,9 List,10 Seebach,11 Wei Wang12 and Hayashi11 groups on the above reactions revealed that “oxazolidinones” and “aminals” are the responsible secondary catalytic species generated in situ from the primary catalytic species through neighboring ortho-hydroxyl group participation (Fig. 1).13
Catalysis Laboratory, School of Chemistry, University of Hyderabad, Hyderabad-500046, India. E-mail: [email protected], [email protected]; Fax: +91-40-23012460 † Electronic supplementary information (ESI) available: Experimental procedures and analytical data (1H NMR, 13C NMR, HRMS and HPLC) for all new compounds. CCDC 937954. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ob42100g
574 | Org. Biomol. Chem., 2014, 12, 574–580
Fig. 1
Historical background of the organocatalysis.
The interesting catalytic behavior of the secondary catalytic “aminals” as nucleophiles in C–O/C–C bond formation gave us inspiration to study further on the more complex asymmetric organodomino-catalysis, because their formation pathway is not known.12 As we are interested in designing and studying the neighboring ortho-hydroxyl group participation of substrates in organocatalysis,13 herein we propose to study the reactivity/selectivity of the secondary catalytic species, “aminals” generated in situ through the neighboring orthohydroxyl group participation (Scheme 1). To address this catalytic phenomenon, we sought to design an organocatalytic reflexive-Michael (r-M)14 reaction that would involve the reaction between unmodified hydroxyenals 1 and (E)-3-alkylideneindolin-2-ones 2 to furnish the spiro[chroman3,3′-indolin]-2′-ones 5 in a highly stereoselective manner (Scheme 1). This design has two important goals, from a
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Table 1
Scheme 1 Design for the spiro[chroman-3,3’-indolin]-2’-one synthesis through an aminal-catalysis and their applications.
mechanistic and synthetic point of view. The formation of highly reactive o-quinone methides (oQMs) B from primary catalytic iminium ions A through isomerization followed by rapid cyclization to generate secondary catalytic aminals C through oxa-6π electrocyclization at 25 °C highlight the importance of organocatalysis.15 From a synthetic point of view, the spirooxindole core structure is the centerpiece of a wide variety of natural and unnatural compounds that exhibit diverse biological activities (Scheme 1).16 Thus, an enantioselective catalytic approach for the direct construction of spirooxindole skeletons is a significant challenge.17
Results and discussion Reaction optimization To verify this hypothesis, based on our previous experience,13 we examined the r-M reaction of N-Boc olefin 2a with 1.2 equiv. of hydroxyenal 1a in the presence of 20 mol% of (R)-3 in CHCl3 at 25 °C. Surprisingly, within 12 h, the reaction yielded a 7 : 1 ratio of the products (+)-5aa in 85% yield with >98% ee for the major isomer. For clear understanding of the selectivity and also for clean HPLC separation, we then subjected the crude 5aa to Wittig conditions with Ph3PvCHCO2Et 6 in CHCl3 at 25 °C for 2 h. To our delight, the isomerically pure olefination product (−)-7aa was isolated in 66% yield with 75% de and 98% ee (Table 1, entry 1). This result might give inspirational belief that there is a possibility of highly reactive “aminal” involving as the nucleophile compared to simple Ar– OH in the oxa-Michael pre-transition state, which is responsible for the highest enantioselectivity. The same reaction with sodium acetate 4a as the co-catalyst at 25 °C for 12 h followed by the Wittig reaction in a sequential one-pot manner furnished (−)-7aa in 61% yield with 82% de and 96% ee (Table 1, entry 2). After thorough investigation of the (R)-3-catalyzed asymmetric r-M reaction, we found that the solvent, the
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Reaction preliminary optimizationa
Catalyst 3/4 Solvent Entry (20/20 mol%) (0.5 M) Pg 2
Time Yieldb (h) (%) 7
1 2 3 4 5 6d 7e 8e 9e 10e 11
12 12 12 12 12 15 24 24 24 24 72
(R)-3 (R)-3/4a (S)-3/4a (R)-3/4a (R)-3/4b (R)-3/4b (R)-3/4b (R)-3/4c (R)-3/4b (R)-3/4b (R)-3/4b
CHCl3 CHCl3 CHCl3 DCM CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3
2a: Boc 2a 2a 2a 2a 2a 2a 2a 2b: Ac 2c: Ts 2d: H
eec dec (%) 7 (%) 7
7aa (66) 98 7aa (61) 96 7aa (62) −94 7aa (63) 95 7aa (62) 99 7aa (57) 99 7aa (62) 99 7aa (32) 98 7ab (65) 84 7ac (63) 96 7ad (−) —
75 82 80 70 86 86 84 86 23 94 —
a Reactions (r-M) were carried out in solvent (0.5 M) with 1.2 equiv. of 1a relative to the 2 (0.3 mmol) in the presence of 20/20 mol% of 3/4 followed by the one-pot Wittig reaction in CHCl3 (0.19 M). b Yield refers to the column-purified product. c ee determined by CSPHPLC analysis and de determined by NMR or HPLC analysis of diastereomerically pure products obtained from column chromatography. d Co-catalyst 4b was taken as 30 mol%. e Co-catalyst 4b or 4c was taken as 40 mol%.
catalyst, the co-catalyst loading and the olefin N-substitution have significant effect on the de/ee’s and yields. In the final optimization, the asymmetric r-M reaction of 1a and 2a through (R)-3/4b-catalysis in chloroform (0.5 M) at 25 °C for 12 h followed by the Wittig reaction with 6 in a sequential onepot manner at 25 °C for 2 h in chloroform (0.19 M) furnished the isomerically pure chiral spirooxindole (−)-7aa in 62% yield with 99% ee and 86% de (Table 1, entry 5). When N-Boc olefin 2a was replaced with N-Ac olefin 2b, the asymmetric r-M reaction furnished the corresponding product (−)-7ab with decreased ee and de (Table 1, entry 9). In a similar manner, N-Ts olefin 2c in the place of 2a furnished the r-M product (−)-7ac in comparable yield with decreased ee and increased de (Table 1, entry 10). Surprisingly, there is no r-M reaction between 1a and N-H olefin 2d under the (R)-3/4b-catalysis (Table 1, entry 11). After realizing the electronic factor of N-substitution, even though N-Ts olefin 2c furnished the r-M product with comparable yield/ee with somewhat better de, we decided to use 2a for further studies, as its preparation and deprotection are easier compared to N-Ts olefin 2c. We further explored the scope of the (R)-3/4b-catalyzed r-M reaction by developing the diversity-oriented synthesis of optically pure spirooxindoles 7 through the reaction of different hydroxyenals 1b–k with the olefin 2a followed by the Wittig reaction (Table 2).18 The chiral spirooxindoles 7 were obtained in good yields and excellent ee’s and de’s from a variety of hydroxyenals containing halogenated, electron-withdrawing, electrondonating, and neutral groups 1b–k through the asymmetric r-M reaction with the olefin 2a (Table 2). Herein, a variety of
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Table 2
Scope of the reaction from using different enals 1
Table 3
Entry Enal 1 Fg
Products Yielda (%) ee for 7b (%) de for 7b (%)
1 2 3 4 5d 6 7 8 9 10
7ba 7ca 7da 7ea 7fa 7ga 7ha 7ia 7ja 7ka
1b 1c 1d 1e 1f 1g 1h 1i 1j 1k
5-F 5-Cl 5-Br 3,5-Cl2 5-NO2 5-OMe 4-OMe 3-OH 3-OMe 5-Me
60 65 60 50 20 75 60 60 75 75
91 96 92 81 28 (96)c 93 >99 98 (29)c 96 95
78 99 90 99 50 96 88 35 87 96
a
Yield refers to the column-purified product. b ee determined by CSP-HPLC analysis and de determined by NMR or HPLC analysis of diastereomerically pure column-purified products. c ee values in parentheses obtained for minor isomers. d r-M reaction time is 48 h.
unmodified hydroxyenals 1b–k were used as a source for the in situ generation of “aminals” as novel mild nucleophiles in the r-M reaction to furnish the functionalized spirooxindoles 5ba–ka and 7ba–ka in >99% ee and de with good yields in the best cases (Table 2). Surprisingly, the r-M reaction of 1f with 2a under the catalysis of (R)-3/4b followed by the Wittig reaction furnished (+)-7fa in only 20% yield with 28% ee and 50% de, but the minor isomer gave 96% ee (Table 2, entry 5). This result is clearly indicating that the hydroxyenal 1f containing the 5-NΟ2 group is controlling enough to decrease the formation rate and also the nucleophilicity of the “aminals” generated in situ in the r-M reaction. Scope of (R)-DPPOTMS/AcOH catalyzed r-M reactions. After realizing the electronic factors of the substitution on the hydroxyenals 1a–k, we further explored the scope of the (R)-3/4bcatalyzed r-M reaction by synthesizing the optically pure single isomer of the spirooxindoles 5 and 7 through the reaction of different N-Boc olefins 2e–p with 1a–k followed by the Wittig reaction in a sequential one-pot manner (Table 3).18 The chiral six-membered spiro[chroman-3,3′-indolin]-2′-ones 5 and 7 were obtained in very good yields and excellent ee’s and de’s with a variety of olefins containing halogenated, electronwithdrawing, electron-donating, and neutral groups 2e–p from the asymmetric r-M reaction of hydroxyenals 1a–k (Table 3). Herein, a variety of olefins 2e–p were used as Michael acceptors to trap the in situ generated “aminals” from the r-M reaction to furnish the functionalized spirooxindoles 5ge–kp and 7ge–kp in >98% ee and de with excellent yields in the best cases (Table 3). Interestingly, the r-M reaction of 1g with aliphatic olefin 2l under the catalysis of (R)-3/4b followed by the Wittig reaction with 6 in a one-pot manner furnished (−)-7gl in 65% yield with 98% ee and 87% de (Table 3, entry 9). In a similar manner, four more r-M products 7gm–kp were
576 | Org. Biomol. Chem., 2014, 12, 574–580
Scope of the reaction from using different olefins 2
Entry Enal 1
Olefin 2
Products Yielda ee 7b de 7b 7 (%) (%) (%)
1
2e: R2 = 4-FC6H4
7ge
62
91
86
7gf 7gg 7gh
70 85 75
94 94 96
86 86 91
7ki
80
98
87
7gj
55
96
99
7gk 7kk 7gl
60 80 65
96 96 98
87 94 87
7gm
65
94
86
7gn
70
96
86
7ao
50
94
78
7kp
50
92
71
2 3 4 5
1g: R1 = 5-OMe 1g 1g 1g
6
1k: R1 = 5-Me 1g
7 8 9
1g 1k 1g
10
1g
11
1g
12
1a: R1 = H 1k
13
2
2f: R = 4-ClC6H4 2g: R2 = 4-BrC6H4 2h: R2 = 4-NO2C6H4 2i: R2 = 4-CO2MeC6H4 2j: R2 = 4-MeOC6H4 2k: R2 = 4-MeC6H4 2k: R2 = 4-MeC6H4 2l: R2 = CH2CH2Ph 2m: R2 = CH2CH2Me 2n: R2 = CH2CH2CH2Me 2o: R2 = CO2Et 2p: R2 = CO2Et and 5-F
a
Yield refers to the column-purified product. b ee determined by CSP-HPLC analysis and de determined by NMR or HPLC analysis of diastereomerically pure column-purified products.
furnished in good yields with high ee’s and de’s from the aliphatic olefins 2m–p as shown in Table 3, entries 10–13. Many of these products 7 were isolated in a pure single isomeric form through column chromatography. The structure and absolute stereochemistry of the r-M products 5 and 7 were confirmed by NMR analysis and also finally confirmed by X-ray structure analysis on (+)-5da as shown in Fig. S1 (see ESI†).19 Applications of chiral r-M products Synthesis of functionalized chiral spiranes 9–10. With applications in mind, we investigated the utilization of chiral spiranes 5 in the high-yielding synthesis of functionalized chiral spiranes 9–10 via three-component reductive alkylation (TCRA),20 acetal protection and reduction reactions (Scheme 2). Sequential three-component reductive alkylation (TCRA)20 of the crude r-M product (+)-5aa with malononitrile and Hantzsch ester 8 in CHCl3 (0.19 M) at 25 °C for 1 h in onepot furnished the chiral product (+)-9aa in 53% yield with 98% ee and 92% de. Treatment of the optically pure compound (+)-5aa with trimethyl orthoformate under the p-TSA catalysis furnished the acetal protected spirane (+)-10′aa in 75% yield, which on reduction with 10 equiv. of LiAlH4 in dry THF at 70 °C for 24 h furnished the completely reduced
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Scheme 2
Synthetic applications of chiral spirooxindoles 5.
Even though additional studies are needed to securely elucidate the mechanism of r-M reactions through (R)-3/4b-catalysis, the reaction proceeds in a stepwise manner between the in situ generated aminal and the olefins 2 (eqn (1)). In the first oxa-Michael (oxa-M) step, based on the crystal structure studies, we can rationalize the observed high stereoselectivity through an allowed transition state where the si-face of N-Boc olefin 2 approaches the si-face of aminal due to the strong CH–π interactions and less steric hindrance/electrostatic repulsion as shown in TS-1. In the second intramolecular Michael (i-M) step, formation of the two stereocenters can be explained by the model TS-2, in which the re-face of the newly generated anion approaches the re-face of the cis-iminium ion due to the less steric hindrance/electrostatic repulsion (eqn (1)).
ð1Þ
Scheme 3
Gram-scale synthesis of chiral spirooxindoles 7 and 9.
1′-methylspiro[chroman-3,3′-indoline] (−)-10aa in 50% yield with 99% ee and 99% de (Scheme 2). Compounds (+)-9aa and (−)-10aa would be precursors for the synthesis of highly functionalized drug-like spirane molecules. Based on their structural importance in medicinal chemistry, herein, we have demonstrated the gram-scale synthesis of chiral spirooxindoles 7aa and 9aa (Scheme 3). By scaling up milligrams to 0.917 g of hydroxyenal 1a with 1.0 gram of N-Boc olefin 2a in 10.4 mL of chloroform at 25 °C for 12 h under the (R)-3/4b-catalysis furnished the crude r-M product 5aa in >90% conversion, which on further treatment with 3.62 g of Ph3PvCHCO2Et 6 in 27.4 mL of chloroform at 25 °C for 2 h furnished (−)-7aa in >95% conversion with 65% overall yield (1.82 g). There is a good improvement in ee (>99%) and de (92%) of the r-M product (−)-7aa obtained through gram-scale synthesis compared to milligram synthesis (see Scheme 3 and Table 1, entry 5). In a similar manner, the gram-scale reaction of 1a (0.917 g), 2a (1.0 g), CH2(CN)2 (0.343 g) and 8 (1.57 g) under the (R)-3/4b-catalysis furnished the chiral spirooxindole (+)-9aa in 1.67 g (62% yield) with >98% ee and 92% de from the sequential r-M and TCRA reactions in one pot (Scheme 3). The yields of spirooxindoles (−)-7aa and (+)-9aa are slightly improved with better ee and de in the gram-scale synthesis compared to the milligram-scale, which may be due to the slight change in the reaction concentration of Wittig or TCRA reactions (Schemes 2 and 3).
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Supporting evidence for the proposed reaction pathway and the formation of the important secondary catalytic species of “aminals” C were observed through NMR and electrospray ionization with high resolution mass spectrometry (ESI-HRMS) analysis of the on-going reactions between 1a and (R)-3; 1e and (R)-3; 1f and (R)-3 in CDCl3 and also shown by the structural requirement in the hydroxyenals 1 to generate the “aminals” C with (R)-3 through controlled experiments (Scheme 4). Interestingly, treatment of simple hydroxyenal 1a with (R)-3 in CDCl3 at 25 °C within 10 min in an NMR tube furnished the aminal C1 in >90% conversion. NMR (1H, 13C and DEPT) and HRMS analysis of this on-going reaction in the NMR tube revealed that the intermediate aminal C1 is formed in >99 : 1 : 1 ratio compared to other intermediates A1 or B1 (eqn (2), Scheme 4). To further understand the electronic factors in the aminal formation, we performed similar experiments on two more hydroxyenals 1e and 1f with (R)-3 in CDCl3 at 25 °C (eqn (3), Scheme 4). Analysis of these on-going reactions in the NMR tube within 10–20 min revealed the formation of both the intermediates o-quinone methides B2–B3 and aminals C2–C3 in 1 : 1 and 5 : 1 ratios, respectively (eqn (3), Scheme 4 and Fig. S2, see ESI†). These results are clearly supportive of the proposed reaction pathway through B and C formation and also explain the formation of the spirooxindoles (+)-7ea and (+)-7fa in moderate to poor ee’s and de’s, which may be due to the involvement of B2/B3 in the transition state of the r-M reaction along with C2/C3 because of their electronic stability (Table 2, entries 4 and 5). The intermediate “aminal” species C can be formed in diastereomeric ratio, but this has not yet been confirmed by the NMR data. We have also shown the
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chromatography was performed using Acme’s silica gel ( particle size 0.063–0.200 mm). High-resolution mass spectra were recorded on a micromass ESI-TOF MS. GCMS mass spectrometry was performed on Shimadzu GCMS-QP2010 mass spectrometer. Elemental analyses were recorded on a Thermo Finnigan Flash EA 1112 analyzer. LCMS mass spectra were recorded on either a VG7070H mass spectrometer using the EI technique or a Shimadzu-LCMS-2010A mass spectrometer. IR spectra were recorded on JASCO FT/IR-5300 and Thermo Nicolet FT/IR-5700. The X-ray diffraction measurements were carried out at 298 K on an automated Enraf-Nonious MACH 3 diffractometer using graphite monochromated, Mo-Kα (λ = 0.71073 Å) radiation with CAD4 software or the X-ray intensity data were measured at 298 K on a Bruker SMART APEX CCD area detector system equipped with a graphite monochromator and a Mo-Kα fine-focus sealed tube (λ = 0.71073 Å). For thin-layer chromatography (TLC), silica gel plates Merck 60 F254 were used and compounds were visualized by irradiation with UV light and/or by treatment with a solution of p-anisaldehyde (23 mL), conc. H2SO4 (35 mL), acetic acid (10 mL), and ethanol (900 mL) followed by heating. Materials Scheme 4 NMR, HRMS and controlled experiments for the detection of in situ generated aminals C.
structural requirement in hydroxyenals 1 to generate the “aminals” with (R)-3 through controlled experiments between 1l and 1m with 2a under the (R)-3/4a-catalysis (eqn (4), Scheme 4).
Conclusions In summary, based on a dynamic but mostly untapped mode of secondary catalytic species of “aminals” reactivity, we have developed a novel method for the single step synthesis of functionalized chiral drug-like spiro[chroman-3,3′-indolin]-2′ones 5 to 10 from simple substrates. Evidence for the proposed reaction pathway and also the formation of the important catalytic species “aminals” C were observed through NMR and ESI-HRMS analysis of the on-going reactions. Future investigations within the group will continue to explore the scope of novel modes of reactivity of secondary catalytic “aminals”.
Experimental General methods The 1H NMR and 13C NMR spectra were recorded at 400 MHz and 100 MHz, respectively. The chemical shifts are reported in ppm downfield to TMS (δ = 0) for 1H NMR and relative to the central CDCl3 resonance (δ = 77.0) for 13C NMR. In the 13C NMR spectra, the nature of carbons (C, CH, CH2 or CH3) was determined by recording the DEPT-135 experiment, and is given in parentheses. The coupling constants J are given in Hz. Column
578 | Org. Biomol. Chem., 2014, 12, 574–580
All solvents and commercially available chemicals were used as received. General experimental procedures Asymmetric r-M reactions. Into an ordinary glass vial equipped with a magnetic stirring bar, a mixture of R-(+)DPPOTMS 3 (19.6 mg, 0.06 mmol) and acetic acid 4b (0.0034 mL, 0.06 mmol) in CHCl3 (0.6 mL), was added 2-hydroxycinnamaldehyde 1a (53 mg, 0.36 mmol) and allowed to stir for 10 min followed by the addition of 2 (96 mg, 0.3 mmol). After stirring the reaction mixture for 12 h the reaction mixture was loaded on to silica gel column directly eluting with hexane–EtOAc (10 : 1 to 10 : 2). Asymmetric sequential r-M and Wittig reactions in one pot. Into an ordinary glass vial equipped with a magnetic stirring bar, a mixture of R-(+)-DPPOTMS 3 (19.6 mg, 0.06 mmol) and acetic acid 4b (0.0034 mL, 0.06 mmol) in CHCl3 (0.6 mL), was added 2-hydroxycinnamaldehyde 1a (53 mg, 0.36 mmol) and allowed to stir for 10 min followed by the addition of 2 (96 mg, 0.3 mmol). After stirring the reaction mixture at 25 °C for 12 h, was added 1.0 mL CHCl3 and Ph3PvCHCO2Et 6 (209 mg, 0.6 mmol). After stirring the reaction mixture for 2 h, the reaction mixture was loaded on to a silica gel column directly eluting with hexane–EtOAc (10 : 1 to 10 : 2). Asymmetric sequential r-M and TCRA reactions in one pot. Into an ordinary glass vial equipped with a magnetic stirring bar, a mixture of R-(+)-DPPOTMS 3 (19.6 mg, 0.06 mmol) and acetic acid 4b (0.0034 mL, 0.06 mmol) in CHCl3 (0.6 mL), was added 2-hydroxycinnamaldehyde 1a (53 mg, 0.36 mmol) and allowed to stir for 10 min followed by the addition of 2a (96 mg, 0.3 mmol). After stirring the reaction mixture at 25 °C for 12 h, was added 1.0 mL of CHCl3, malononitrile (24 mg, 0.36 mmol) and Hantzsch ester 8 (84 mg, 0.36 mmol). After
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stirring the reaction mixture at 25 °C for 1 h, the reaction mixture was loaded on to a silica gel column directly eluting with hexane–EtOAc (10 : 2 to 10 : 3). Asymmetric synthesis of functionalized 1′-methylspiro[chroman-3,3′-indoline] 10aa. Into an oven dried round bottomed flask with r-M product 5aa (150 mg, 0.3 mmol), was added methanol (1.0 mL), trimethyl orthoformate (63 mg, 0.6 mmol) and p-TSA·H2O (6 mg, 0.03 mmol). After stirring the reaction mixture at 25 °C for 15 min the crude reaction mixture was worked up with aqueous NaHCO3 solution and the aqueous layer was extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried over (Na2SO4), filtered and concentrated. A pure chiral acetal product 10′aa was obtained by column chromatography (silica gel, mixture of hexane–ethyl acetate 10 : 1). Into an oven dried round bottomed flask a solution of the above acetal product 10′aa (70 mg, 0.136 mmol) and LiAlH4 (52 mg, 1.36 mmol) in dry THF (3 mL) was stirred under a N2 atmosphere in an ice bath and allowed to slowly warm to room temperature followed by reflux at 70 °C for about 24 h, and then the mixture was quenched with EtOAc (1 mL), MeOH (1 mL), H2O (5 mL), and then extracted with EtOAc three times, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane– EtOAc = 10 : 1).
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Acknowledgements This work was made possible by a grant from the Department of Science and Technology (DST), New Delhi [grant no. DST/ SR/S1/OC-65/2008]. MSP and RM thank the Council of Scientific and Industrial Research (CSIR), New Delhi for their research fellowship. We thank Dr P. Raghavaiah for his help in X-ray structural analysis. 9
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(c) N. Momiyama, Y. Yamamoto and H. Yamamoto, J. Am. Chem. Soc., 2007, 129, 1190; (d) D. B. Ramachary, Y. V. Reddy and B. V. Prakash, Org. Biomol. Chem., 2008, 6, 719; (e) L.-Y. Wu, G. Bencivenni, M. Mancinelli, A. Mazzanti, G. Bartoli and P. Melchiorre, Angew. Chem., Int. Ed., 2009, 48, 7196; (f ) D. B. Ramachary and Y. V. Reddy, Eur. J. Org. Chem., 2012, 865 and references cited therein. (a) S. Bertelsen, M. Marigo, S. Brandes, P. Dinér and K. A. Jørgensen, J. Am. Chem. Soc., 2006, 128, 12973; (b) N. Utsumi, H. Zhang, F. Tanaka and C. F. Barbas III, Angew. Chem., Int. Ed., 2007, 46, 1878; (c) D. B. Ramachary, K. Ramakumar and V. V. Narayana, Chem.–Eur. J., 2008, 14, 9143; (d) B. Han, Y.-C. Xiao, Y. Yao and Y.-C. Chen, Angew. Chem., Int. Ed., 2010, 49, 10189. M. T. Pirnot, D. A. Rankic, D. B. C. Martin and D. W. C. MacMillan, Science, 2013, 339, 1593 and references cited therein. (a) H. Jiang, D. C. Cruz, Y. Li, V. H. Lauridsen and K. A. Jørgensen, J. Am. Chem. Soc., 2013, 135, 5200; (b) X.-F. Xiong, Q. Zhou, J. Gu, L. Dong, T.-Y. Liu and Y.-C. Chen, Angew. Chem., Int. Ed., 2012, 51, 4401. (a) D. B. Ramachary, Ch. Venkaiah and R. Madhavachary, Org. Lett., 2013, 15, 3042; (b) D. B. Ramachary, Ch. Venkaiah and P. M. Krishna, Chem. Commun., 2012, 48, 2252. For the observation of primary catalytic species in organocatalysis, see: (a) D. B. Ramachary, R. Sakthidevi and K. S. Shruthi, Chem.–Eur. J., 2012, 18, 8008; (b) D. Sánchez, D. Bastida, J. Burés, C. Isart, O. Pineda and J. Vilarrasa, Org. Lett., 2012, 14, 536; (c) M. B. Schmid, K. Zeitler and R. M. Gschwind, J. Am. Chem. Soc., 2011, 133, 7065; (d) D. A. Bock, C. W. Lehmann and B. List, Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 20636; (e) D. B. Ramachary, K. Ramakumar, A. Bharanishashank and V. V. Narayana, J. Comb. Chem., 2010, 12, 855. (a) H. Iwamura, S. P. Mathew and D. G. Blackmond, J. Am. Chem. Soc., 2004, 126, 11770; (b) H. Iwamura, D. J. Wells Jr., S. P. Mathew, M. Klussmann, A. Armstrong and D. G. Blackmond, J. Am. Chem. Soc., 2004, 126, 16312; (c) S. P. Mathew, H. Iwamura and D. G. Blackmond, Angew. Chem., Int. Ed., 2004, 43, 3317. (a) B. List, L. Hoang and H. J. Martin, Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5839; (b) A. K. Sharma and R. B. Sunoj, Angew. Chem., Int. Ed., 2010, 49, 6373. (a) D. Seebach, U. Groselj, D. M. Badine, W. B. Schweizer and A. K. Beck, Helv. Chim. Acta, 2008, 91, 1999; (b) U. Groselj, W. B. Schweizer, M.-O. Ebert and D. Seebach, Helv. Chim. Acta, 2009, 92, 1; (c) U. Groselj, D. Seebach, D. M. Badine, W. B. Schweizer, A. K. Beck, I. Krossing, P. Klose, Y. Hayashi and T. Uchimaru, Helv. Chim. Acta, 2009, 92, 1225. L. Zu, S. Zhang, H. Xie and W. Wang, Org. Lett., 2009, 11, 1627. D. B. Ramachary, R. Madhavachary and M. S. Prasad, Org. Biomol. Chem., 2012, 10, 5825 and references cited therein.
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14 Definition of the reflexive-Michael (r-M) reaction: when two molecules are spontaneously involved in a Michael reaction by behaving as both a 1,4-donor and an acceptor in a cyclic or reflexive manner means that they are in the reflexiveMichael reaction mode. See: (a) Fiesers’ reagents for organic synthesis, volume 27, 2013, page no. 406 by TseLok Ho; (b) Papers cited in ref. 7. 15 For the excellent work on o-quinone methides (oQMs) generation and trapping under the physiological conditions, see: (a) Q. Li, T. Dong, X. Liu and X. Lei, J. Am. Chem. Soc., 2013, 135, 4996; (b) J. N. Moorthy, S. Mandal, A. Mukhopadhyay and S. Samanta, J. Am. Chem. Soc., 2013, 135, 6872. 16 (a) X. Xie, C. Peng, G. He, H.-J. Leng, B. Wang, W. Huang and B. Han, Chem. Commun., 2012, 48, 10487 and references cited therein; (b) G. L. Robertson, Nat. Rev. Endocrinol., 2011, 7, 151; (c) T. Jiang, K. L. Kuhen, K. Wolff, H. Yin, K. Bieza, J. Caldwell, B. Bursulaya, T. Y.-H. Wu and Y. He, Bioorg. Med. Chem. Lett., 2006, 16, 2105; (d) M. A. Collins, V. Hudak, R. Bender, A. Fensome, P. Zhang, L. Miller, R. C. Winneker, Z. Zhang, Y. Zhu, J. Cohen, R. J. Unwalla and J. Wrobel, Bioorg. Med. Chem. Lett., 2004, 14, 2185; (e) A. Fensome, R. Bender, J. Cohen, M. A. Collins, V. A. Mackner, L. L. Miller, J. W. Ullrich, R. Winneker,
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17
18
19 20
J. Wrobel, P. Zhang, Z. Zhang and Y. Zhu, Bioorg. Med. Chem. Lett., 2002, 12, 3487. For reviews on the spirooxindole synthesis, see: (a) L. Honga and R. Wang, Adv. Synth. Catal., 2013, 355, 1023; (b) R. Dalpozzo, G. Bartolib and G. Bencivenni, Chem. Soc. Rev., 2012, 41, 7247; (c) G. S. Singh and Z. Y. Desta, Chem. Rev., 2012, 112, 6104 for the selected original papers, see: (d) B. Tan, N. R. Candeias and C. F. Barbas III, Nat. Chem., 2011, 3, 473; (e) X. Jiang, Y. Cao, Y. Wang, L. Liu, F. Shen and R. Wang, J. Am. Chem. Soc., 2010, 132, 15328; (f) Q. Wei and L.-Z. Gong, Org. Lett., 2010, 12, 1008. All racemic products 7aa–kp were prepared in 40–85% yield and 45–99% de through the r-M reaction of 1a–k and 2a–p under the catalysis of (±)-DPPOTMS 3 (20 mol%) in CHCl3 (0.5 M) at 25 °C for 7–12 h followed by the sequential onepot Wittig reaction with 6 (2 equiv.) in CHCl3 (0.19 M) at 25 °C for 2 h (see ESI-1† for more details). CCDC-937954 for (+)-5da contains the supplementary crystallographic data for this paper. (a) D. B. Ramachary and M. Kishor, J. Org. Chem., 2007, 72, 5056; (b) D. B. Ramachary and Y. V. Reddy, J. Org. Chem., 2010, 75, 74; (c) D. B. Ramachary and M. Kishor, Org. Biomol. Chem., 2010, 8, 2859 and references cited therein.
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PAPER Dhevalapally B. Ramachary et al. Asymmetric synthesis of drug-like spiro[chroman-3,3’-indolin]-2’-ones through aminal-catalysis
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Asymmetric synthesis of drug-like spiro[chroman3,3’-indolin]-2’-ones through aminal-catalysis† Dhevalapally B. Ramachary,* M. Shiva Prasad, S. Vijaya Laxmi and R. Madhavachary Asymmetric synthesis of drug-like functionalized spiro[chroman-3,3’-indolin]-2’-ones 5 containing three contiguous stereocenters with high diastereo- and enantioselectivities was achieved using the reflexiveMichael (r-M) reaction of unmodified hydroxyenals 1 with various (E)-3-alkylideneindolin-2-ones 2 in the presence of (R)-DPPOTMS/AcOH (R)-3/4b as a catalyst at room temperature. Chiral spiro[chroman-3,3’indolin]-2’-ones 5 were transformed into the functionalized spiranes 7, 9, and 10 in good yields with high selectivity through Wittig, TCRA, acetal protection and reduction reactions, respectively. Supporting evi-
Received 21st October 2013, Accepted 12th November 2013
dence for the reaction pathway through the formation of the important catalytic species of “aminals” was observed through NMR and ESI-HRMS analysis of an ongoing reaction between 1 and (R)-3
DOI: 10.1039/c3ob42100g
in CDCl3 and also shown by the structural requirement in hydroxyenals 1 to generate the “aminals” with
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(R)-3 through controlled experiments.
Introduction In this decade, the discovery of L-proline induced chiral enamines from carbonyls initiated a new era in asymmetric catalysis1 and at the same time it has also given inspiration to develop many other primary catalytic species in situ from different carbonyl compounds (Fig. 1). For example iminium-catalysis,2 2-aminobuta-1,3-diene-catalysis,3 1-aminobuta-1,3-diene-catalysis,4 SOMO-catalysis,5 trienamine-catalysis6 and aminoenynecatalysis7 have well demonstrated the importance of in situ generated primary catalytic species in a variety of asymmetric reactions. The involvement of primary catalytic species in the above reactions is well understood from the preliminary NMR and mass experiments,8 but the detailed kinetic and thermodynamic data later revealed that the in situ generated secondary catalytic species are also responsible for the reaction rates/ selectivities, especially in the organocatalytic aminoxylation, amination, oxa-Michael and Michael reactions. The pioneering work of the Blackmond,9 List,10 Seebach,11 Wei Wang12 and Hayashi11 groups on the above reactions revealed that “oxazolidinones” and “aminals” are the responsible secondary catalytic species generated in situ from the primary catalytic species through neighboring ortho-hydroxyl group participation (Fig. 1).13
Catalysis Laboratory, School of Chemistry, University of Hyderabad, Hyderabad-500046, India. E-mail: [email protected], [email protected]; Fax: +91-40-23012460 † Electronic supplementary information (ESI) available: Experimental procedures and analytical data (1H NMR, 13C NMR, HRMS and HPLC) for all new compounds. CCDC 937954. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ob42100g
574 | Org. Biomol. Chem., 2014, 12, 574–580
Fig. 1
Historical background of the organocatalysis.
The interesting catalytic behavior of the secondary catalytic “aminals” as nucleophiles in C–O/C–C bond formation gave us inspiration to study further on the more complex asymmetric organodomino-catalysis, because their formation pathway is not known.12 As we are interested in designing and studying the neighboring ortho-hydroxyl group participation of substrates in organocatalysis,13 herein we propose to study the reactivity/selectivity of the secondary catalytic species, “aminals” generated in situ through the neighboring orthohydroxyl group participation (Scheme 1). To address this catalytic phenomenon, we sought to design an organocatalytic reflexive-Michael (r-M)14 reaction that would involve the reaction between unmodified hydroxyenals 1 and (E)-3-alkylideneindolin-2-ones 2 to furnish the spiro[chroman3,3′-indolin]-2′-ones 5 in a highly stereoselective manner (Scheme 1). This design has two important goals, from a
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Table 1
Scheme 1 Design for the spiro[chroman-3,3’-indolin]-2’-one synthesis through an aminal-catalysis and their applications.
mechanistic and synthetic point of view. The formation of highly reactive o-quinone methides (oQMs) B from primary catalytic iminium ions A through isomerization followed by rapid cyclization to generate secondary catalytic aminals C through oxa-6π electrocyclization at 25 °C highlight the importance of organocatalysis.15 From a synthetic point of view, the spirooxindole core structure is the centerpiece of a wide variety of natural and unnatural compounds that exhibit diverse biological activities (Scheme 1).16 Thus, an enantioselective catalytic approach for the direct construction of spirooxindole skeletons is a significant challenge.17
Results and discussion Reaction optimization To verify this hypothesis, based on our previous experience,13 we examined the r-M reaction of N-Boc olefin 2a with 1.2 equiv. of hydroxyenal 1a in the presence of 20 mol% of (R)-3 in CHCl3 at 25 °C. Surprisingly, within 12 h, the reaction yielded a 7 : 1 ratio of the products (+)-5aa in 85% yield with >98% ee for the major isomer. For clear understanding of the selectivity and also for clean HPLC separation, we then subjected the crude 5aa to Wittig conditions with Ph3PvCHCO2Et 6 in CHCl3 at 25 °C for 2 h. To our delight, the isomerically pure olefination product (−)-7aa was isolated in 66% yield with 75% de and 98% ee (Table 1, entry 1). This result might give inspirational belief that there is a possibility of highly reactive “aminal” involving as the nucleophile compared to simple Ar– OH in the oxa-Michael pre-transition state, which is responsible for the highest enantioselectivity. The same reaction with sodium acetate 4a as the co-catalyst at 25 °C for 12 h followed by the Wittig reaction in a sequential one-pot manner furnished (−)-7aa in 61% yield with 82% de and 96% ee (Table 1, entry 2). After thorough investigation of the (R)-3-catalyzed asymmetric r-M reaction, we found that the solvent, the
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Reaction preliminary optimizationa
Catalyst 3/4 Solvent Entry (20/20 mol%) (0.5 M) Pg 2
Time Yieldb (h) (%) 7
1 2 3 4 5 6d 7e 8e 9e 10e 11
12 12 12 12 12 15 24 24 24 24 72
(R)-3 (R)-3/4a (S)-3/4a (R)-3/4a (R)-3/4b (R)-3/4b (R)-3/4b (R)-3/4c (R)-3/4b (R)-3/4b (R)-3/4b
CHCl3 CHCl3 CHCl3 DCM CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3
2a: Boc 2a 2a 2a 2a 2a 2a 2a 2b: Ac 2c: Ts 2d: H
eec dec (%) 7 (%) 7
7aa (66) 98 7aa (61) 96 7aa (62) −94 7aa (63) 95 7aa (62) 99 7aa (57) 99 7aa (62) 99 7aa (32) 98 7ab (65) 84 7ac (63) 96 7ad (−) —
75 82 80 70 86 86 84 86 23 94 —
a Reactions (r-M) were carried out in solvent (0.5 M) with 1.2 equiv. of 1a relative to the 2 (0.3 mmol) in the presence of 20/20 mol% of 3/4 followed by the one-pot Wittig reaction in CHCl3 (0.19 M). b Yield refers to the column-purified product. c ee determined by CSPHPLC analysis and de determined by NMR or HPLC analysis of diastereomerically pure products obtained from column chromatography. d Co-catalyst 4b was taken as 30 mol%. e Co-catalyst 4b or 4c was taken as 40 mol%.
catalyst, the co-catalyst loading and the olefin N-substitution have significant effect on the de/ee’s and yields. In the final optimization, the asymmetric r-M reaction of 1a and 2a through (R)-3/4b-catalysis in chloroform (0.5 M) at 25 °C for 12 h followed by the Wittig reaction with 6 in a sequential onepot manner at 25 °C for 2 h in chloroform (0.19 M) furnished the isomerically pure chiral spirooxindole (−)-7aa in 62% yield with 99% ee and 86% de (Table 1, entry 5). When N-Boc olefin 2a was replaced with N-Ac olefin 2b, the asymmetric r-M reaction furnished the corresponding product (−)-7ab with decreased ee and de (Table 1, entry 9). In a similar manner, N-Ts olefin 2c in the place of 2a furnished the r-M product (−)-7ac in comparable yield with decreased ee and increased de (Table 1, entry 10). Surprisingly, there is no r-M reaction between 1a and N-H olefin 2d under the (R)-3/4b-catalysis (Table 1, entry 11). After realizing the electronic factor of N-substitution, even though N-Ts olefin 2c furnished the r-M product with comparable yield/ee with somewhat better de, we decided to use 2a for further studies, as its preparation and deprotection are easier compared to N-Ts olefin 2c. We further explored the scope of the (R)-3/4b-catalyzed r-M reaction by developing the diversity-oriented synthesis of optically pure spirooxindoles 7 through the reaction of different hydroxyenals 1b–k with the olefin 2a followed by the Wittig reaction (Table 2).18 The chiral spirooxindoles 7 were obtained in good yields and excellent ee’s and de’s from a variety of hydroxyenals containing halogenated, electron-withdrawing, electrondonating, and neutral groups 1b–k through the asymmetric r-M reaction with the olefin 2a (Table 2). Herein, a variety of
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Table 2
Scope of the reaction from using different enals 1
Table 3
Entry Enal 1 Fg
Products Yielda (%) ee for 7b (%) de for 7b (%)
1 2 3 4 5d 6 7 8 9 10
7ba 7ca 7da 7ea 7fa 7ga 7ha 7ia 7ja 7ka
1b 1c 1d 1e 1f 1g 1h 1i 1j 1k
5-F 5-Cl 5-Br 3,5-Cl2 5-NO2 5-OMe 4-OMe 3-OH 3-OMe 5-Me
60 65 60 50 20 75 60 60 75 75
91 96 92 81 28 (96)c 93 >99 98 (29)c 96 95
78 99 90 99 50 96 88 35 87 96
a
Yield refers to the column-purified product. b ee determined by CSP-HPLC analysis and de determined by NMR or HPLC analysis of diastereomerically pure column-purified products. c ee values in parentheses obtained for minor isomers. d r-M reaction time is 48 h.
unmodified hydroxyenals 1b–k were used as a source for the in situ generation of “aminals” as novel mild nucleophiles in the r-M reaction to furnish the functionalized spirooxindoles 5ba–ka and 7ba–ka in >99% ee and de with good yields in the best cases (Table 2). Surprisingly, the r-M reaction of 1f with 2a under the catalysis of (R)-3/4b followed by the Wittig reaction furnished (+)-7fa in only 20% yield with 28% ee and 50% de, but the minor isomer gave 96% ee (Table 2, entry 5). This result is clearly indicating that the hydroxyenal 1f containing the 5-NΟ2 group is controlling enough to decrease the formation rate and also the nucleophilicity of the “aminals” generated in situ in the r-M reaction. Scope of (R)-DPPOTMS/AcOH catalyzed r-M reactions. After realizing the electronic factors of the substitution on the hydroxyenals 1a–k, we further explored the scope of the (R)-3/4bcatalyzed r-M reaction by synthesizing the optically pure single isomer of the spirooxindoles 5 and 7 through the reaction of different N-Boc olefins 2e–p with 1a–k followed by the Wittig reaction in a sequential one-pot manner (Table 3).18 The chiral six-membered spiro[chroman-3,3′-indolin]-2′-ones 5 and 7 were obtained in very good yields and excellent ee’s and de’s with a variety of olefins containing halogenated, electronwithdrawing, electron-donating, and neutral groups 2e–p from the asymmetric r-M reaction of hydroxyenals 1a–k (Table 3). Herein, a variety of olefins 2e–p were used as Michael acceptors to trap the in situ generated “aminals” from the r-M reaction to furnish the functionalized spirooxindoles 5ge–kp and 7ge–kp in >98% ee and de with excellent yields in the best cases (Table 3). Interestingly, the r-M reaction of 1g with aliphatic olefin 2l under the catalysis of (R)-3/4b followed by the Wittig reaction with 6 in a one-pot manner furnished (−)-7gl in 65% yield with 98% ee and 87% de (Table 3, entry 9). In a similar manner, four more r-M products 7gm–kp were
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Scope of the reaction from using different olefins 2
Entry Enal 1
Olefin 2
Products Yielda ee 7b de 7b 7 (%) (%) (%)
1
2e: R2 = 4-FC6H4
7ge
62
91
86
7gf 7gg 7gh
70 85 75
94 94 96
86 86 91
7ki
80
98
87
7gj
55
96
99
7gk 7kk 7gl
60 80 65
96 96 98
87 94 87
7gm
65
94
86
7gn
70
96
86
7ao
50
94
78
7kp
50
92
71
2 3 4 5
1g: R1 = 5-OMe 1g 1g 1g
6
1k: R1 = 5-Me 1g
7 8 9
1g 1k 1g
10
1g
11
1g
12
1a: R1 = H 1k
13
2
2f: R = 4-ClC6H4 2g: R2 = 4-BrC6H4 2h: R2 = 4-NO2C6H4 2i: R2 = 4-CO2MeC6H4 2j: R2 = 4-MeOC6H4 2k: R2 = 4-MeC6H4 2k: R2 = 4-MeC6H4 2l: R2 = CH2CH2Ph 2m: R2 = CH2CH2Me 2n: R2 = CH2CH2CH2Me 2o: R2 = CO2Et 2p: R2 = CO2Et and 5-F
a
Yield refers to the column-purified product. b ee determined by CSP-HPLC analysis and de determined by NMR or HPLC analysis of diastereomerically pure column-purified products.
furnished in good yields with high ee’s and de’s from the aliphatic olefins 2m–p as shown in Table 3, entries 10–13. Many of these products 7 were isolated in a pure single isomeric form through column chromatography. The structure and absolute stereochemistry of the r-M products 5 and 7 were confirmed by NMR analysis and also finally confirmed by X-ray structure analysis on (+)-5da as shown in Fig. S1 (see ESI†).19 Applications of chiral r-M products Synthesis of functionalized chiral spiranes 9–10. With applications in mind, we investigated the utilization of chiral spiranes 5 in the high-yielding synthesis of functionalized chiral spiranes 9–10 via three-component reductive alkylation (TCRA),20 acetal protection and reduction reactions (Scheme 2). Sequential three-component reductive alkylation (TCRA)20 of the crude r-M product (+)-5aa with malononitrile and Hantzsch ester 8 in CHCl3 (0.19 M) at 25 °C for 1 h in onepot furnished the chiral product (+)-9aa in 53% yield with 98% ee and 92% de. Treatment of the optically pure compound (+)-5aa with trimethyl orthoformate under the p-TSA catalysis furnished the acetal protected spirane (+)-10′aa in 75% yield, which on reduction with 10 equiv. of LiAlH4 in dry THF at 70 °C for 24 h furnished the completely reduced
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Scheme 2
Synthetic applications of chiral spirooxindoles 5.
Even though additional studies are needed to securely elucidate the mechanism of r-M reactions through (R)-3/4b-catalysis, the reaction proceeds in a stepwise manner between the in situ generated aminal and the olefins 2 (eqn (1)). In the first oxa-Michael (oxa-M) step, based on the crystal structure studies, we can rationalize the observed high stereoselectivity through an allowed transition state where the si-face of N-Boc olefin 2 approaches the si-face of aminal due to the strong CH–π interactions and less steric hindrance/electrostatic repulsion as shown in TS-1. In the second intramolecular Michael (i-M) step, formation of the two stereocenters can be explained by the model TS-2, in which the re-face of the newly generated anion approaches the re-face of the cis-iminium ion due to the less steric hindrance/electrostatic repulsion (eqn (1)).
ð1Þ
Scheme 3
Gram-scale synthesis of chiral spirooxindoles 7 and 9.
1′-methylspiro[chroman-3,3′-indoline] (−)-10aa in 50% yield with 99% ee and 99% de (Scheme 2). Compounds (+)-9aa and (−)-10aa would be precursors for the synthesis of highly functionalized drug-like spirane molecules. Based on their structural importance in medicinal chemistry, herein, we have demonstrated the gram-scale synthesis of chiral spirooxindoles 7aa and 9aa (Scheme 3). By scaling up milligrams to 0.917 g of hydroxyenal 1a with 1.0 gram of N-Boc olefin 2a in 10.4 mL of chloroform at 25 °C for 12 h under the (R)-3/4b-catalysis furnished the crude r-M product 5aa in >90% conversion, which on further treatment with 3.62 g of Ph3PvCHCO2Et 6 in 27.4 mL of chloroform at 25 °C for 2 h furnished (−)-7aa in >95% conversion with 65% overall yield (1.82 g). There is a good improvement in ee (>99%) and de (92%) of the r-M product (−)-7aa obtained through gram-scale synthesis compared to milligram synthesis (see Scheme 3 and Table 1, entry 5). In a similar manner, the gram-scale reaction of 1a (0.917 g), 2a (1.0 g), CH2(CN)2 (0.343 g) and 8 (1.57 g) under the (R)-3/4b-catalysis furnished the chiral spirooxindole (+)-9aa in 1.67 g (62% yield) with >98% ee and 92% de from the sequential r-M and TCRA reactions in one pot (Scheme 3). The yields of spirooxindoles (−)-7aa and (+)-9aa are slightly improved with better ee and de in the gram-scale synthesis compared to the milligram-scale, which may be due to the slight change in the reaction concentration of Wittig or TCRA reactions (Schemes 2 and 3).
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Supporting evidence for the proposed reaction pathway and the formation of the important secondary catalytic species of “aminals” C were observed through NMR and electrospray ionization with high resolution mass spectrometry (ESI-HRMS) analysis of the on-going reactions between 1a and (R)-3; 1e and (R)-3; 1f and (R)-3 in CDCl3 and also shown by the structural requirement in the hydroxyenals 1 to generate the “aminals” C with (R)-3 through controlled experiments (Scheme 4). Interestingly, treatment of simple hydroxyenal 1a with (R)-3 in CDCl3 at 25 °C within 10 min in an NMR tube furnished the aminal C1 in >90% conversion. NMR (1H, 13C and DEPT) and HRMS analysis of this on-going reaction in the NMR tube revealed that the intermediate aminal C1 is formed in >99 : 1 : 1 ratio compared to other intermediates A1 or B1 (eqn (2), Scheme 4). To further understand the electronic factors in the aminal formation, we performed similar experiments on two more hydroxyenals 1e and 1f with (R)-3 in CDCl3 at 25 °C (eqn (3), Scheme 4). Analysis of these on-going reactions in the NMR tube within 10–20 min revealed the formation of both the intermediates o-quinone methides B2–B3 and aminals C2–C3 in 1 : 1 and 5 : 1 ratios, respectively (eqn (3), Scheme 4 and Fig. S2, see ESI†). These results are clearly supportive of the proposed reaction pathway through B and C formation and also explain the formation of the spirooxindoles (+)-7ea and (+)-7fa in moderate to poor ee’s and de’s, which may be due to the involvement of B2/B3 in the transition state of the r-M reaction along with C2/C3 because of their electronic stability (Table 2, entries 4 and 5). The intermediate “aminal” species C can be formed in diastereomeric ratio, but this has not yet been confirmed by the NMR data. We have also shown the
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chromatography was performed using Acme’s silica gel ( particle size 0.063–0.200 mm). High-resolution mass spectra were recorded on a micromass ESI-TOF MS. GCMS mass spectrometry was performed on Shimadzu GCMS-QP2010 mass spectrometer. Elemental analyses were recorded on a Thermo Finnigan Flash EA 1112 analyzer. LCMS mass spectra were recorded on either a VG7070H mass spectrometer using the EI technique or a Shimadzu-LCMS-2010A mass spectrometer. IR spectra were recorded on JASCO FT/IR-5300 and Thermo Nicolet FT/IR-5700. The X-ray diffraction measurements were carried out at 298 K on an automated Enraf-Nonious MACH 3 diffractometer using graphite monochromated, Mo-Kα (λ = 0.71073 Å) radiation with CAD4 software or the X-ray intensity data were measured at 298 K on a Bruker SMART APEX CCD area detector system equipped with a graphite monochromator and a Mo-Kα fine-focus sealed tube (λ = 0.71073 Å). For thin-layer chromatography (TLC), silica gel plates Merck 60 F254 were used and compounds were visualized by irradiation with UV light and/or by treatment with a solution of p-anisaldehyde (23 mL), conc. H2SO4 (35 mL), acetic acid (10 mL), and ethanol (900 mL) followed by heating. Materials Scheme 4 NMR, HRMS and controlled experiments for the detection of in situ generated aminals C.
structural requirement in hydroxyenals 1 to generate the “aminals” with (R)-3 through controlled experiments between 1l and 1m with 2a under the (R)-3/4a-catalysis (eqn (4), Scheme 4).
Conclusions In summary, based on a dynamic but mostly untapped mode of secondary catalytic species of “aminals” reactivity, we have developed a novel method for the single step synthesis of functionalized chiral drug-like spiro[chroman-3,3′-indolin]-2′ones 5 to 10 from simple substrates. Evidence for the proposed reaction pathway and also the formation of the important catalytic species “aminals” C were observed through NMR and ESI-HRMS analysis of the on-going reactions. Future investigations within the group will continue to explore the scope of novel modes of reactivity of secondary catalytic “aminals”.
Experimental General methods The 1H NMR and 13C NMR spectra were recorded at 400 MHz and 100 MHz, respectively. The chemical shifts are reported in ppm downfield to TMS (δ = 0) for 1H NMR and relative to the central CDCl3 resonance (δ = 77.0) for 13C NMR. In the 13C NMR spectra, the nature of carbons (C, CH, CH2 or CH3) was determined by recording the DEPT-135 experiment, and is given in parentheses. The coupling constants J are given in Hz. Column
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All solvents and commercially available chemicals were used as received. General experimental procedures Asymmetric r-M reactions. Into an ordinary glass vial equipped with a magnetic stirring bar, a mixture of R-(+)DPPOTMS 3 (19.6 mg, 0.06 mmol) and acetic acid 4b (0.0034 mL, 0.06 mmol) in CHCl3 (0.6 mL), was added 2-hydroxycinnamaldehyde 1a (53 mg, 0.36 mmol) and allowed to stir for 10 min followed by the addition of 2 (96 mg, 0.3 mmol). After stirring the reaction mixture for 12 h the reaction mixture was loaded on to silica gel column directly eluting with hexane–EtOAc (10 : 1 to 10 : 2). Asymmetric sequential r-M and Wittig reactions in one pot. Into an ordinary glass vial equipped with a magnetic stirring bar, a mixture of R-(+)-DPPOTMS 3 (19.6 mg, 0.06 mmol) and acetic acid 4b (0.0034 mL, 0.06 mmol) in CHCl3 (0.6 mL), was added 2-hydroxycinnamaldehyde 1a (53 mg, 0.36 mmol) and allowed to stir for 10 min followed by the addition of 2 (96 mg, 0.3 mmol). After stirring the reaction mixture at 25 °C for 12 h, was added 1.0 mL CHCl3 and Ph3PvCHCO2Et 6 (209 mg, 0.6 mmol). After stirring the reaction mixture for 2 h, the reaction mixture was loaded on to a silica gel column directly eluting with hexane–EtOAc (10 : 1 to 10 : 2). Asymmetric sequential r-M and TCRA reactions in one pot. Into an ordinary glass vial equipped with a magnetic stirring bar, a mixture of R-(+)-DPPOTMS 3 (19.6 mg, 0.06 mmol) and acetic acid 4b (0.0034 mL, 0.06 mmol) in CHCl3 (0.6 mL), was added 2-hydroxycinnamaldehyde 1a (53 mg, 0.36 mmol) and allowed to stir for 10 min followed by the addition of 2a (96 mg, 0.3 mmol). After stirring the reaction mixture at 25 °C for 12 h, was added 1.0 mL of CHCl3, malononitrile (24 mg, 0.36 mmol) and Hantzsch ester 8 (84 mg, 0.36 mmol). After
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stirring the reaction mixture at 25 °C for 1 h, the reaction mixture was loaded on to a silica gel column directly eluting with hexane–EtOAc (10 : 2 to 10 : 3). Asymmetric synthesis of functionalized 1′-methylspiro[chroman-3,3′-indoline] 10aa. Into an oven dried round bottomed flask with r-M product 5aa (150 mg, 0.3 mmol), was added methanol (1.0 mL), trimethyl orthoformate (63 mg, 0.6 mmol) and p-TSA·H2O (6 mg, 0.03 mmol). After stirring the reaction mixture at 25 °C for 15 min the crude reaction mixture was worked up with aqueous NaHCO3 solution and the aqueous layer was extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried over (Na2SO4), filtered and concentrated. A pure chiral acetal product 10′aa was obtained by column chromatography (silica gel, mixture of hexane–ethyl acetate 10 : 1). Into an oven dried round bottomed flask a solution of the above acetal product 10′aa (70 mg, 0.136 mmol) and LiAlH4 (52 mg, 1.36 mmol) in dry THF (3 mL) was stirred under a N2 atmosphere in an ice bath and allowed to slowly warm to room temperature followed by reflux at 70 °C for about 24 h, and then the mixture was quenched with EtOAc (1 mL), MeOH (1 mL), H2O (5 mL), and then extracted with EtOAc three times, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane– EtOAc = 10 : 1).
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Acknowledgements This work was made possible by a grant from the Department of Science and Technology (DST), New Delhi [grant no. DST/ SR/S1/OC-65/2008]. MSP and RM thank the Council of Scientific and Industrial Research (CSIR), New Delhi for their research fellowship. We thank Dr P. Raghavaiah for his help in X-ray structural analysis. 9
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