Highly stereoselective construction of adjacent tetrasubstituted carbon stereogenic centres via an organocatalytic Mukaiyama-aldol reaction of monofluorinated silyl enol ethers to isatins

Abstract

We report the first organocatalytic activation of monofluorinated silyl enol ethers 1, by nucleophilic tertiary amine catalysis, to develop asymmetric reactions for the construction of fully substituted chiral carbons featuring a C–F bond. Accordingly, a highly stereoselective Mukaiyama-aldol reaction of isatins to furnish hydroxyoxindoles bearing two adjacent tetrasubstituted carbon stereocenters is developed.

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Introduction

Tetrasubstituted stereogenic carbon centres featuring a fluorine atom occur in a number of natural products, drugs and bioactive compounds.¹ For example, the first isolated naturally occurring organofluorine compound, nucleocidin, contains a fluorinated O-containing fully substituted carbon, which is a broad antibacterial and trypanocidal agent produced by Streptomyces calvus.^1a The fluticasone propionate is a popularly used drug to treat asthma and eosinophilic esophagitis.^1b BMS-204352,^1c developed by Bristol-Myers Squibb, is a promising agent for the treatment of stroke (Fig. 1). Obviously, facile access to these compounds and their analogues is important for the corresponding activity–structure relationship study. On the other hand, tetrasubstituted stereogenic carbon centres widely exist in bioactive compounds,² and their analogues featuring a fluorinated tetrasubstituted carbon are interesting for medicinal research, as selective introduction of a fluorine into chiral centres has proven to be a fruitful strategy to modulate the chemical & physical properties, metabolic stability and biological activities of chiral compounds.³ Therefore, efficient methods allowing the catalytic asymmetric creation of tetrasubstituted carbon stereogenic centres bearing a C–F bond are highly desirable.⁴

Fig. 1 Representative bioactive compounds.

So far, both electrophilic fluorination⁵ and nucleophilic fluorination⁶ have been utilized for the catalytic enantioselective construction of fluorinated chiral centres. However, protocols allowing the efficient synthesis of fluorinated tetrasubstituted carbon stereogenic centres were still limited.⁷ Noticeably, the asymmetric nucleophilic fluorination is much less explored in terms of reaction types.⁶ While several organofluoro reagents had been developed and tried in asymmetric reactions,⁶ only prochiral α-fluoro ketones⁸ or 1,3-dicarbonyl compounds,⁹ fluorinated silyl enol ethers,¹⁰ 1-fluoro(phenylsulfonyl)methane derivatives¹¹ and 3-fluorooxindole¹² were capable of syntheses of fluorinated fully substituted chiral carbons. In addition, their potential has not been fully explored. For example, monofluorinated silyl enol ethers 1 represent a type of versatile synthon for the synthesis of tertiary α-fluorinated ketones that had attracted much attention,¹³ but its application in asymmetric catalysis was rare. So far, only one example has been reported: in 2007, Paquin and co-workers achieved highly enantioselective syntheses of α-allyl α-fluoroketones from 1via a Pd-catalyzed asymmetric allylic substitution reaction (eqn (1)).¹⁰

We have been engaged in catalytic asymmetric syntheses of privileged scaffolds featuring tetrasubstituted carbon stereogenic centres, such as 3,3-disubstituted oxindoles¹⁴ and fluorinated compounds.¹⁵ Considering the great potential of silyl enol ethers 1 in the synthesis of diverse fluorinated tetrasubstituted carbons, we tried to identify an organocatalytic method to activate it to develop asymmetric reactions, as organocatalysis alleviates the contamination of products by heavy metals, very attractive for medicinal research. Here, we wish to report that tertiary amines could efficiently activate prochiral monofluorinated enol ethers 1, contributing to a highly stereoselective Mukaiyama-aldol reaction of isatins to efficiently furnish two adjacent tetrasubstituted carbon stereocenters (eqn (2)).

Results and discussion

Previously, we discovered that tertiary amines could effectively activate difluoroenoxysilane 4, which contributed to a highly enantioselective Mukaiyama-aldol reaction using isatins^15b or β,γ-unsaturated α-ketoesters^15c to prepare difluoromethylated chiral tertiary alcohols. In the following studies, dramatic fluorine effects were observed in the bifunctional urea C1 catalyzed Mukaiyama-aldol reaction of N-methylisatin: while the reaction of difluoroenoxysilane 4 efficiently afforded the desired product 5 in 89% yield and 94% ee, the non-fluorinated silyl enol ether 6 proved to be much less reactive under the same conditions, giving the product 7 in only 10% yield with 27% ee. This observation was counterintuitive, as the electron-withdrawing effect of the fluorine atom should decrease the nucleophilicity of difluoroenoxysilane 4, as compared with the non-fluorinated one. Although why difluoro substitution enhanced the reactivity of silyl enol ether 4 was not clear till now, it was of interest to us whether monofluorinated silyl enol ethers 1 could be effectively harnessed by nucleophilic tertiary amine catalysis¹⁶ to develop catalytic asymmetric reactions, allowing efficient construction of tetrasubstituted stereogenic carbon centers featuring a C–F bond.

Therefore, we tried the reaction of 1a and isatin 2a, catalyzed by C1, under the previously established conditions. However, the reaction proceeded slowly in THF at −20 °C, giving the desired product 3a in only 8% yield even after 3 days, with moderate stereoselectivities (entry 1, Table 1). This result was discouraging, but further screenings revealed that the reaction outcome was greatly affected by the reaction solvent, and some typical results are summarized in Table 1. For example, varying the solvent from THF to ethyl acetate (EtOAc) resulted in a great improvement in stereoselectivities, albeit the yield of 3a was still low (entry 2). When the reaction was run in acetone, the product 3a was obtained in 93% ee and 17 : 1 dr, with an obviously improved 63% yield (entry 3). The use of MeOH as the solvent further raised the yield to 95%, but the ee value was decreased to 11% (entry 4). Fortunately, both the yield and stereoselectivities of the product 3a were excellent when using MeCN as the solvent (entry 5). In the following, we screened other cinchona alkaloid derivatives C2–C8, but no improved result was obtained (entries 6–13), and C1 was still the best in terms of the yield and stereoselectivities. Interestingly, a newly synthesized catalyst C3, with a N-tert-butyl group, also achieved 87% ee in this reaction (entry 7). When using C1 as the catalyst and MeCN as the solvent, improving the usage of silyl enol ether 1a from 1.2 equiv. to 1.5 equiv., the dr and ee values could be slightly raised to 15 : 1 and 94%.

Table 1 Condition optimization^a

Entry	Cat.	Solvent	X	Yield^b (%)	ee^c (%)	dr^d
a On a 0.10 mmol scale. b Isolated yield. c Determined by chiral HPLC analysis. d Determined by ^1H and ^19F NMR analysis of crude products.
1	C1	THF	1.2	8	60	5.0 : 1
2	C1	EtOAc	1.2	10	84	12 : 1
3	C1	Acetone	1.2	63	93	17 : 1
4	C1	MeOH	1.2	95	11	4 : 1
5	C1	MeCN	1.2	95	93	14 : 1
6	C2	MeCN	1.2	70	91	16 : 1
7	C3	MeCN	1.2	69	87	12 : 1
8	C4	MeCN	1.2	76	38	2.8 : 1
9	C5	MeCN	1.2	85	19	1.1 : 1
10	C6	MeCN	1.2	87	7	6.0 : 1
11	C7	MeCN	1.2	10	80	7.0 : 1
13	C8	MeCN	1.2	98	12	1.8 : 1
14	C1	MeCN	1.5	94	94	15 : 1

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Based on the above screenings, the optimal reaction conditions were determined to be to run the reaction in MeCN at −20 °C, using 10 mol% of the catalyst C1. Under this condition, we then examined the substrate scope with respect to different substituted prochiral fluorinated silyl enol ethers and isatins (Table 2). It was found that under the catalysis of 10 mol% of bifunctional urea C1, isatins 2a–f, without electron-withdrawing substituents, readily reacted with 1a to give the products 3a–f in high to excellent stereoselectivities, up to 15 : 1 dr and 94% ee (entries 1–6).

Table 2 Substrate scope

Entry^a	Cat.	1	2	3	Yield^b (%)	ee^c (%)	dr^d
a On a 0.25 mmol scale. b Isolated yield. c Determined by HPLC analysis. d Determined by ^1H and ^19F NMR analysis of crude products.
1	C1	1a	2a	3a	95	94	15 : 1
2	C1	1a	2b	3b	70	94	13 : 1
3	C1	1a	2c	3c	72	88	9 : 1
4	C1	1a	2d	3d	88	92	14 : 1
5	C1	1a	2e	3e	98	91	7 : 1
6	C1	1a	2f	3f	54	84	12 : 1
7	C3	1a	2g	3g	75	81	5 : 1
8	C3	1a	2h	3h	98	86	5 : 1
9	C3	1a	2i	3i	91	85	5 : 1
10	C1	1b	2a	3j	97	92	10 : 1
11	C1	1b	2b	3k	54	90	7 : 1
12	C1	1c	2a	3l	98	76	5 : 1
13	C1	1d	2a	3m	37	82	5 : 1
14	C1	1a	2j	3n	56	70	8 : 1

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However, the electron-withdrawing halogen substituents on the framework of isatin greatly diminished the stereoselectivities. Therefore, we further optimized the conditions for the reaction of 5-halogenated isatins 2g–i, and found that the newly prepared urea-tertiary amine catalyst C3 afforded obviously better results for the corresponding reactions,¹⁸ and the desired products 3g–i were obtained in up to 86% ee and 5 : 1 dr value (entries 7–9). Noticeably, cinchona alkaloid derived bifunctional (thio)urea catalysts usually bear a N-aryl substituent at the (thio)urea part,¹⁷ and to the best of our knowledge, there is no precedent that this type of catalysts bearing a simple N-alkyl group of the urea moiety could achieve a better result than those with a N-aryl group.^17h This result suggested that it was worthwhile to synthesize N-alkyl substituted cinchona alkaloid derived bifunctional (thio)urea catalysts.

Likely, the electron-releasing methyl group on the phenyl ring of ether 1 benefited the selectivities, while the electron-withdrawing chloro group destroyed the stereoselectivities (entries 10–11 vs. 12). It seems that the free N–H is essential for good results, as the N-methyl protected isatin 2j gave the product 3n in only 56% yield, 8 : 1 dr and 70% ee. However, α-fluorotetralone derived silyl enol ether 1d proved to be much less reactive than 1a, affording the desired product 3m in only 37% yield, albeit with high ee. The relative and absolute configurations of the product 3h were determined to be (3S, 8S) configuration by X-ray analysis, and those of other products were tentatively assigned by analogy.

Although the use of acyclic monofluorinated silyl enol ether 1e was unable to furnish the tetrasubstituted carbon stereocentre with a fluorine atom, we also examined whether a bifunctional tertiary amine-thiourea catalyst was able to activate it for reaction development. It was found that under the same conditions, the silyl enol ether 1e, obtained as a mixture of Z/E isomers with a ratio of 2 : 1, afforded the desired product 3o in 46% yield, 2 : 1 dr and 81% ee. The development of a suitable method to prepare such acyclic monofluorinated silyl enol ethers in an excellent Z/E ratio, which might influence the dr value of the corresponding products, is now ongoing in our lab.

Interestingly, obvious influences of fluorine substitution were also observed in this reaction: under the same reaction conditions, the monofluorinated silyl enol ether 1a reacted with isatin 2a at a faster rate than the non-fluorinated enol ether 8 (95% vs. 48% yield), though the product 9 was also obtained in excellent 7 : 1 dr and 94% ee. On the other hand, α-fluoroindanone 10 turned out to be a much less reactive nucleophile than indanone in this reaction, either at −20 °C or 10 °C, with diminished stereoselectivities. This result justified the use of silyl enol ether 1a for the reaction development.

It should be noted that both prochiral monofluorinated enol silyl ether 1a and difluoroenoxysilane 4 showed obviously higher reactivity than the corresponding non-fluorinated analogues 8 and 6 in the Mukaiyama-aldol reaction of isatins, respectively.¹⁹ This result was also in sharp contrast to a recent report by Reissig and Mayr that in the nucleophilic substitution reaction of enol silyl ethers with benzhydrylium ions, the replacement of the phenyl ring of 6 by C₆F₅ slowed down the reaction by 4.5 orders of magnitude.²⁰ On the other hand, the direct substitution of an α-proton of indanone by fluorine resulted in the greatly diminished reactivity, and we had reported a similar phenomenon that the α-proton of 2,2-difluoro-1-phenylethanone was difficult to be abstracted.^15b It is now under investigation in our laboratory why the direct substitution of fluorine at the reactive center could improve the reactivity of silyl enol ethers but reduce the reactivity of ketones.

The thus obtained optically active 3-hydroxyoxindole 3a could be readily reduced to syn-diol 12 by NaBH₄, featuring three consecutive stereogenic centers, in 95% yield and 95% ee value, and the relative configuration was confirmed by X-ray analysis. It should be noted that only relative configuration could be assigned by using the single crystal of syn-12, due to the lack of heavy atoms. Interestingly, the synthesis of its diastereoisomer anti-diol 12 was achieved just by varying the solvent from THF–AcOH to THF–MeOH for the reduction by NaBH₄. This represents an expedient and useful method for the preparation of oxindole based chiral fluorinated 1,3-diol compounds as the selectivity could be controlled by the choice of the solvent.

Conclusions

In summary, we have developed an unprecedented highly stereoselective Mukaiyama-aldol reaction of prochiral fluorinated silyl enol ethers and isatins to furnish 3-hydroxyoxindoles with two continuous tetrasubstituted stereogenic carbon centres. The thus obtained optically active hydroxyoxindoles,²¹ featuring a tertiary α-fluoroketone moiety, are interesting for medicinal studies. Importantly, the identification of nucleophilic tertiary amine catalysis to activate monofluorinated silyl enol ethers offers the promise to develop new asymmetric nucleophilic fluorination reactions. In addition, our results also suggested that cinchona alkaloid derived bifunctional (thio)urea catalysts with a simple N-alkyl substituent in the urea moiety are worthwhile to explore, which is now in progress in our lab.

Financial support from NSFC (21172075, 21222204), the Ministry of Education (NCET-11-0147 and PCSIRT) and the Program of SSCS (13XD1401600) and Innovation Program of SMEC (12ZZ046) is appreciated.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 999612 and 999613. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4qo00126e

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