Organocatalytic enantioselective Mukaiyama–Mannich reaction of fluorinated enol silyl ethers and cyclic N-sulfonyl ketimines

Abstract

The first catalytic asymmetric Mukaiyama–Mannich reaction of fluorinated silyl enol ethers and ketimines is developed. Under the catalysis of hydroquinine derived bifunctional urea, cyclic N-sulfonyl ketimines readily react with fluorinated enol silyl ethers to afford benzosultam based C^α-tetrasubstituted α-amino acid derivatives featuring a fluoroalkyl group in high to excellent yields and stereoselectivities.

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Introduction

C ^α-tetrasubstituted α-amino acid derivatives are widely present in natural products, drugs and pharmaceutically active substances.¹ For example, altemicidin is an acaricidal and antitumor agent,^1c and methyldopa is an orally active antihypertensive drug.^1d It is also known that the introduction of conformationally constrained C^α-tetrasubstituted α-amino acids into peptides may bring about enhanced properties.^1e–h Therefore, catalytic asymmetric synthesis of this privileged scaffold in sufficient diversity is an important task in asymmetric catalysis.² In this context, benzosultam based α-amino acid derivatives are attractive targets, not only due to their synthetic value as chiral auxiliaries and reagents,³ but also due to their presence in bioactive compounds,⁴ as exemplified by HIV-1 inhibitors^4a and aldose reductase inhibitors^4b (Fig. 1). On the other hand, the decoration of amino acids with a fluoroalkyl group is also effective in modulating their properties,⁵ as illustrated by the rational design of eflornithine, a potent drug for treating sleeping sickness, by introducing an α-CF₂H group to the α position of ornithine.^5b Therefore, benzosultam based C^α-tetrasubstituted α-amino acid derivatives bearing a fluoroalkyl group are interesting targets for medicinal research. However, despite the advances in the enantioselective synthesis of optically active benzosultams,⁶ catalytic asymmetric synthesis of benzosultam based fluorinated α-amino acid derivatives is unprecedented.

Fig. 1 Selected bioactive compounds.

The catalytic asymmetric addition of nucleophiles to cyclic N-sulfonyl ketimines 1 provides a facile access to enantiopure benzosultam based C^α-tetrasubstituted α-amino acid derivatives.⁷ In 2013, Xu et al. exploited a highly enantioselective arylation of ketimines 1 using arylboronic acids catalyzed by a novel sulphur–olefin ligand derived Rh complex.^7a Most recently, Nakamura et al. utilized their bifunctional cinchona alkaloid derived sulfamide to develop a nice decarboxylative Mannich addition of malonic acid half thioesters to ketimines 1.^7b Wang and Loh developed a novel bifunctional amino sulfonohydrazide to accomplish a direct Mannich reaction of 1 with methyl ketones or cyclic ketones via asymmetric enamine catalysis.^4a Ma et al. reported a saccharide-derived tertiary amino-thiourea enabled highly enantioselective reaction of ketimine 1 and allylic ketones.^7c Herein, we wish to report our results on the enantioselective addition of fluorinated enol ethers to ketimine 1 for an unprecedented synthesis of benzosultam based β-fluorinated C^α-tetrasubstituted α-amino acid esters 3 or 5.

Recently, there has been ever-increasing interest in developing catalytic asymmetric synthesis of carbon stereocenters featuring a fluoroalkyl group, as selective fluoroalkylation is very useful in drug design to modulate the properties of bioactive compounds.⁸ However, while much progress has been made in asymmetric trifluoromethylation, limited success is achieved in the catalytic asymmetric creation of carbon stereocenters bearing a mono- or gem-difluoroalkyl group.^8h–l In this scenario, catalytic asymmetric functionalization of fluorinated silyl enol ethers has recently emerged as a fruitful methodology for enantioselective nucleophilic mono- or gem-difluoroalkylation.⁹ First, the deprotonative activation of α-fluorinated ketones is unexpectedly difficult under mild conditions,^10a,b so fluorinated enol silyl ethers serve as their active equivalents for reaction design. Second, the resulting optically active adducts bearing an α-fluorinated ketone moiety are of high synthetic value and can undergo various transformations.¹¹ In addition, both mono- and difluoro enol silyl ethers can be readily prepared from inexpensive starting materials.¹² To date, they have found utility in catalytic enantioselective allylic substitution,¹³ Mannich,¹⁴ aldol¹⁰ and Michael reactions.¹⁵ Despite the achievements, the catalytic asymmetric Mannich reaction using ketimines remains unexplored, although the corresponding reaction of aldehyde derived hydrazones or aldimines using difluoroenoxysilanes has been pioneered by Shi^14a,b and Akiyama^14c using a chiral Lewis acid and phosphoric acid, respectively. Recently, with our interest in selective fluoroalkylation, we have identified chiral bifunctional Lewis base catalysis¹⁶ as an effective tool to activate fluorinated silyl enol ethers for enantioselective reactions,^10,15 and we are pleased to find that this catalysis pattern can be extended to the asymmetric Mukaiyama–Mannich reaction of cyclic N-sulfonyl ketimines 1 with fluorinated silyl enol ethers.

Results and discussion

We embarked on condition optimization by using the reaction of ketimine 1a and difluoroenoxysilane 2a as the model reaction, which was carried out in THF at room temperature. Some typical results are shown in Table 1.

Table 1 Condition optimization

Entry	Cat.	Solvent	Temp. (°C)	Time (d)	Yield^a (%)	ee^b (%)
a Isolated yield. b Determined by chiral HPLC. c On a 0.25 mmol scale, with a concentration of 1a at 0.2 M. d 2.0 equiv. of 2a were used.
1	C1	THF	25	3	58	11
2	C2	THF	25	0.5	81	17
3	C3	THF	25	1	63	87
4	C4	THF	25	4	40	43
5	C5	THF	25	4	7	67
6	C6	THF	25	3	70	56
7	C7	THF	25	2	75	50
8	C3	CH3CN	25	4	35	30
9	C3	Toluene	25	4	68	94
10^c	C3	Toluene	45	4	86	93
11^c^,^d	C3	Toluene	45	4	90	93
12^c^,^d	C8	Toluene	45	4	82	71

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Bifunctional secondary amine-phosphoramide C1¹⁵ that we developed for the corresponding Michael addition gave product 3a in 58% yield with only 11% ee (entry 1). Our bifunctional phosphoramide-tertiary amine C2¹⁷ showed much better activity, but the ee value of 3a was still low (entry 2). Then we turned to a cinchona alkaloid derived urea catalyst C3,¹⁸ which enabled an efficient aldol reaction using fluorinated enol silyl ether.¹⁰ To our delight, it catalyzed the reaction to afford product 3a in 63% yield with 87% ee after a day (entry 3). The related thiourea analogue C4 proved to be inferior (entry 4). Other catalysts C5–C7,¹⁹ with different types of H-bond donors, were also examined, but no improvement was obtained in terms of both reactivity and enantioselectivity (entries 5–7). To further improve the reaction outcome, solvent effects were examined using C3 as the catalyst, which was found to play an important role. Almost no reaction occurred when ethyl acetate was used as the solvent, and less than 8% yield was obtained for product 3a when running the reaction in CH₂Cl₂. MeCN as the solvent delivered poor result as well (entry 8). Helpfully, the ee value of 3a was improved to 94% when toluene was used as the solvent, albeit with low reactivity (entry 9). We further conducted the reaction at a higher concentration and temperature (0.2 M at 45 °C), which enhanced the yield of 3a to 86% (entry 10), and even 90% yield if 2.0 equivalents of 2a was used (entry 11), with still excellent enantioselectivity.

It also turned out that both N–H bonds of the urea of catalyst C3 mattered in achieving high enantiofacial control, as catalyst C8, with one N–H bond of the urea moiety masked by a methyl group, gave product 3a in obviously lower enantioselectivity, but similar reactivity (entry 11 vs. 12).

Based on the above reaction optimization, we determined to evaluate the substrate scope by running the reaction in toluene (0.2 M) at 45 °C, in the presence of 10 mol% bifunctional catalyst C3 and 2.0 equiv. of difluoroenoxysilane 2a, as shown in Table 2. First, ketimine 1b with a methyl ester group afforded the desired product 3b in 93% yield and 94% ee (entry 3). Second, cyclic ketimines 1c–i all worked well with difluoroenoxysilane 2a to afford the desired benzosultam based fluorinated α-amino acid derivatives 3c–i in high to excellent yields and enantioselectivities, whatever the nature and position of the substituent on the aromatic ring (entries 4–10). Difluorinated enol silyl ethers 2b–c with either an electron-rich or electron-withdrawing aromatic substituent all gave the corresponding products 3j–k in good yield with excellent ee values (entries 11 and 12). Unfortunately, aliphatic substituted difluoroenoxysilane 2d was not active enough to react with 1a to give the desired product in a substantial amount. To show the practicability of our protocol, the reaction of 1a and 2a on a 3.0 mmol scale was tried in the presence of 5 mol% C3, affording product 3a in 0.73 g, 61% yield and 92% ee (entry 2).

Table 2 Substrate scopes

Entry	1: R^1, R^2	2: R	3	Yield^a (%)	ee^b (%)
a Isolated yield. b Determined by chiral HPLC. c Run on 3.0 mmol using 5 mol% of catalyst C3.
1	1a: H, Et	2a: Ph	3a	90	93
2^c	1a: H, Et	2a: Ph	3a	61	92
3	1b: H, Me	2a: Ph	3b	93	94
4	1c: 5-Me, Et	2a: Ph	3c	89	92
5	1d: 5-MeO, Et	2a: Ph	3d	87	94
6	1e: 5-CF3O, Et	2a: Ph	3e	95	87
7	1f: 5-F, Et	2a: Ph	3f	79	92
8	1g: 5-Cl, Et	2a: Ph	3g	74	92
9	1h: 5-CF3, Et	2a: Ph	3h	94	84
10	1i: 7-Cl, Et	2a: Ph	3i	98	90
11	1a: H, Et	2b: 4-MeOC6H4	3j	75	92
12	1a: H, Et	2c: 4-ClC6H4	3k	74	93
13	1a: H, Et	2d: CH2Bn	3l	Trace	—

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Gratifyingly, monofluorinated enol silyl ethers 4 were also viable substrates under the established conditions, as evidenced by synthesis of monofluorinated benzosultam derivatives 5a–c with two adjacent fully substituted carbon stereocenters in high yield with excellent dr and ee values (Scheme 1). Noticeably, the high reactivity of 4 allowed the reaction to run at 35 °C, which in turn improved the stereoselectivity. The absolute configuration of 5a was assigned to be S, S configuration by X-ray analysis of single crystal 5a. All the other products 5 were tentatively assigned.

Scheme 1 Scope of monofluorinated enol silyl ethers 4.

The resulting adducts could be further elaborated to other fluorinated benzosultam derivatives. Starting from 1.0 mmol of ketimine 1a and difluoroenoxysilane 2b, product 3j was obtained in 83% yield and 92% ee, which readily underwent a further Baeyer–Villiger oxidation²⁰ to afford the corresponding diester 6 in 97% yield without loss in the ee value (Scheme 2). Remarkably, via an aminolysis and following cyclization at room temperature, spirocyclic benzosultam derivative 7 featuring an α gem-difluoro aminal moiety was readily obtained in 63% yield and 92% ee as a single isomer from 3a and CH₃NH₂. Such a type of spirocyclic compound might be an interesting target in medicinal research, as the modern probe- and drug-discovery programmes have a vast demand for optically active spirocyclic compounds with a novel structure.²¹ The relative and absolute configuration of compound 7 was assigned by single-crystal X-ray analysis. Based on the stereochemical information of compound 7, the absolute configuration of the Mannich adduct 3a was determined to be S, and those of other products 3b–l were tentatively assigned by analogy.

Scheme 2 Synthetic elaborations.

Interestingly, difluoroenoxysilane 1a proved to be much more active than the non-fluorinated analogue 8 under the same conditions, as the latter gave the corresponding product 9 in only 24% yield and 32% ee (Scheme 3). This observation was similar to our previous finding that under the catalysis of C3, both di- and mono-fluorinated enol silyl ethers 2a and 4a reacted with isatin in a much faster rate than their non-fluorinated analogue,^10b and Akiyama's report that in a phosphoric acid catalyzed Mannich reaction of aldimines, difluoroenoxysilane 1a was more reactive than 8.^14c However, the reactivity difference between fluorinated and non-fluorinated enol silyl ethers 2a and 8 was reversed under metal catalyzed conditions. Shreeve et al. found in Pd-catalyzed arylation that 2a was less reactive than nonfluorinated 8,²² and we also recently noticed that in a Au(I)-catalyzed Mannich reaction using isatin derived N-Boc ketimine,²³ fluorinated silyl ether 2a was much less active than nonfluorinated analogue 8. On the other hand, dichloroenoxysilane 12 failed to react with ketimine 1a to give the desired product under the same conditions. The reason why fluorinated enol silyl ether 2a is much more active than non-fluorinated analogue 8 under organocatalytic conditions or in the presence of a stoichiometric amount of cesium fluoride²⁴ is unclear, which is now under investigation.

Scheme 3 Fluorine effect.

Furthermore, while α-difluoromethyl ketone 10 failed to react with ketimine 1a under this condition, the reaction of α-monofluorinated indanone 11 with 1a worked very poorly to give only a trace amount of product 5a, unable to isolate. These control experiments unambiguously demonstrated the importance of using fluorinated enol silyl ethers to develop enantioselective reaction for selective incorporation of fluoroalkyl groups.

Based on control experiments (entry 11 vs. 12, Table 1) and the absolute configuration of products 3 and 5, the possible transition state was proposed and exemplified using difluorinated enol silyl ethers 2 (Fig. 2). The quinuclidine moiety of catalyst C3 activated difluoroenoxysilane 2via the n–σ* interaction between the nitrogen and silicon atom, whilst the N-sulfonyl ketimines were activated by the urea moiety of C3 through the H-bonding interaction. The attack of ketimines 1 by enol silyl ethers 2 was favored from the Re-face, as the steric repulsion between the aromatic ring of ketimine and enolate was avoided, affording the S-enantiomer as the major product.

Fig. 2 Proposed transition state.

Conclusions

In summary, we have developed the first organocatalyzed asymmetric Mukaiyama–Mannich reaction²⁵ of fluorinated enol silyl ethers and cyclic N-sulfonyl ketimines by employing an easily available hydroquinine-derived urea catalyst. These chiral fluorinated benzosultam based C^α-tetrasubstituted α-amino acid derivatives are interesting targets for medicinal research. The development of powerful chiral bifunctional Lewis base catalysts to develop an enantioselective Mukaiyama–Mannich reaction of fluorinated enol silyl ethers with other types of ketimines is now in progress in our laboratory.

The financial support from the 973 program (2015CB856600) and NSFC (21472049) is appreciated.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1439365 (5a) and 1439366 (7). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5qo00407a

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