Bifunctional Iminophosphorane Catalyzed Enantioselective Ketimine Phospha-Mannich Reaction

Dedicated to Professor Steven V. Ley on the occasion of his 70^th birthday

Abstract

The enantioselective phospha-Mannich reaction of diethyl phosphite to unactivated N-DPP-protected ketimines catalyzed by a bifunctional iminophosphorane (BIMP) superbase organocatalyst is described. The reaction is applicable to ketimines bearing electron-rich and electron-poor aryl substituents and occurs with excellent yields and moderate enantioselectivities under mild reaction conditions.

Key words

asymmetric catalysis - bifunctional organocatalysis - phospha-Mannich - ketimine - superbase

α-Aminophosphonic acid derivatives are α-amino acid analogues that have found widespread use as biologically relevant peptide mimics[1] and have shown a range of biological activities such as antibacterial,[2a] [b] anti-HIV[2c,d] and protease inhibition.[2e,f] As important biological building blocks, their absolute configuration is significant and accordingly new improved methods for their enantioselective synthesis is desirable.[3]

A direct approach to access such compounds is through the 1,2-addition of phosphite pro-nucleophiles to imine electrophiles.[4] These reactions can be catalyzed by Brønsted bases and chiral Brønsted bases can be used to impart enantio­selectivity.[5] To date, much attention has focussed on asymmetric phospha-Mannich reactions to imine electrophiles derived from aldehydes (aldimines) and highly enantioselective examples using both metal-rich and metal-free catalyst systems have been reported.[6] In the latter case the emphasis has been largely placed on the development of methodologies using bifunctional single enantiomer tertiary amine Brønsted base/H-bond donor organocatalysts.[5] In contrast, the corresponding reaction of ketimines has been much less studied due to their substantially reduced electrophilicity and the difficulties associated with poor catalyst-enabled substrate activation and enantioface discrimination;[7] a problem that necessitates the use of metal ion catalysts, stoichiometric additives or the use of activated ketimine electrophiles. For example, Shibasaki and co-workers reported the highly enantioselective N-thiophosphinoyl ketimine phospha-Mannich reaction under copper(I) catalysis,[8a] whereas Nakamura et al. used catalytic quantities of commercially available cinchona alkaloids in the presence of super stoichiometric quantities of Na₂CO₃, for the enantioselective addition of diethyl phosphite to N-mesitylene sulfonyl protected ketimines.[8b] Very recently, Chimni and co-workers and Reddy and co-workers described the catalytic enantioselective phospha-Mannich reaction of reactive isatin-derived ketimines catalyzed by bifunctional cinchona-derived thiourea and squaramide catalysts, respectively.[8c] [d]

In an attempt to overcome the reactivity problem of certain classes of electrophiles and pro-nucleophiles, we recently developed a new class of bifunctional superbase organocatalysts incorporating for the first time the triaryliminophosphorane moiety as the Brønsted base and with it achieved the first general enantioselective organocatalytic ketimine nitro-Mannich reaction.[9] The juxtaposition of both the organosuperbase[10] and an appropriate hydrogen bond donor group over a chiral scaffold was critical for successful enantioselective catalysis (high reactivity and enantiocontrol). As a part of this program into the development of novel asymmetric methodologies for challenging electrophiles, we wish to report the first organocatalytic enantio­selective phospha-Mannich reaction of unactivated N-DPP ketimines.

Table 1 Proof of Concept and Optimization Studies in the Ketimine Phospha-Mannich Reaction^a

Entry	Catalyst	Yield (%)b	ee (%)c
1	1a	74	56
2	1b	99	58
3	1c	60	45
4	1d	85	47
5	1e	>99	23d
6	1f	>99	51
7	1g	84	8
8	1h	>99	55
9	1i	70	42
10	1j	41	17d

^a Reactions were performed using 3 (0.20 mmol), 2a (2.0 equiv) and catalyst (10 mol%).

^b Isolated yield.

^c Determined by HPLC analysis on a chiral stationary phase.

^d Enantiomer (R)-4a was obtained.

We chose the 1,2-addition of diethyl phosphite 3 to the unactivated N-DPP-protected ketimine derived from acetophenone 2a as our model system for testing the performance of our bifunctional iminophosphorane (BIMP) catalysts (Table [1] and Figure [1]). Promising reactivity was initially established using 10 mol% of our previously reported first-generation tert-leucine derived BIMP catalyst 1a with triphenylphosphine (Table [1], entry 1). After just 24 hours at room temperature, 74% yield of product 4a was afforded with an encouraging ee of 56%. However, switching to the analogous but more basic catalyst 1b derived from tris(p-methoxyphenyl)phosphine gave rise to a significant boost in reactivity and a slight boost in enantiocontrol; adduct 4a was afforded in quantitative yield and with 58% ee (Table [1], entry 2). The analogous l-phenylalanine or l-valine-derived catalysts, 1c and 1d respectively, resulted in a drop in enantioselectivity in both cases (Table [1], entries 3 and 4). Employing catalyst 1e, possessing the diphenylmethyl group as part of its chiral scaffold, resulted in a drop in the enantio­selectivity to 23% ee (Table [1], entry 5). Simple modification of the thiourea hydrogen bond donor group of the first-generation BIMP organocatalysts led to no improvement in the level of enantiocontrol (Table [1], entries 6 and 7), and accordingly alternative second-generation BIMP organocatalyst designs were considered. Introducing an additional amino acid residue[11] between the iminophosphorane moiety and Schreiner-type thiourea[12] allowed diastereomers 1h and 1j to be synthesized and compared in the reaction. Interestingly neither catalyst outperformed 1b, but taken together showed that the valine residue in both catalysts was dominating enantioselectivity (Table [1], entries 8 and 10). Building on these observations catalyst 1i was tested in the reaction in the hope that an additional boost in selectivity would be witnessed, but disappointingly enantioselectivity was reduced to 42% ee (Table [1], entry 9). Having identified the best catalyst as 1b, a brief re-optimization of the reaction conditions, with respect to solvent, concentration and temperature, was carried out but no augmentation of the enantioselectivity was observed and the optimal conditions remained the same as for Table [1], entry 2.[13]

Figure 1 First- and second-generation BIMP catalysts

With optimized conditions in hand, we next investigated the substrate scope and found good tolerance over a range of electron-rich and electron-deficient aromatic ket­imines: yields were typically >99% and enantioselectivities ranged from 41 to 62% ee (Scheme [1]). Furthermore, a 3-pyridyl substrate performed well (>99% yield, 53% ee) and pleasingly the reaction was also applicable to the ethyl homologue of 2a which afforded product 4j in 71% ee and in quantitative yield. Absolute configuration of 4a was established as S by comparison of the specific rotation of a derivative with that of a literature compound (see Supporting Information).

Scheme 1 Scope of the BIMP-catalyzed phospha-Mannich reaction^a

In summary we have developed an organocatalytic ket­imine phospha-Mannich reaction of diethyl phosphite to unactivated N-DPP ketimines with excellent yields and moderate enantioselectivities. Further work focussing on the development of novel asymmetric methodologies for challenging electrophiles is ongoing in our group and the results will be disclosed in due course.

Acknowledgment

This work was supported by the EPSRC (Studentship to G.P.R. and A.J.M.F. and Doctoral Prize [EP/M50659X/1] to A.J.M.F.), AstraZeneca (Studentship to A.J.M.F.) and the SCI (Postgraduate Scholarship to A.J.M.F.)

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• 13 Representative Procedure for the Enantioselective Ketimine Phospha-Mannich Reaction: To a solution of ketimine 2a (128 mg, 0.40 mmol, 2.0 equiv) and catalyst 1b (15 mg, 0.020 mmol, 0.10 equiv in 4.0 mL of diethyl ether) was added diethyl phosphite 3 (26 μL, 0.20 mmol, 1.0 equiv) at rt. Stirring was maintained for 24 h whereupon the crude reaction mixture was purified directly by flash column chromatography [petroleum ether to petroleum ether–EtOAc (1:2), EtOAc then EtOAc–MeOH (9:1)] to afford the phospha-Mannich addition product 4a. Diethyl {(1S)-1-[(Diphenylphosphoryl)amino]-1-phenylethyl}-phosphonate (4a): The title compound 4a was isolated in 99% yield (91 mg) and 58% ee as a colorless solid. ¹H NMR (500 MHz, CDCl₃): δ = 1.03 (t, J = 7.0 Hz, 3 H), 1.25 (t, J = 7.0 Hz, 3 H), 1.82 (d, J _PH = 17.0 Hz, 3 H), 3.53 (ddq, J = 10.0, 7.0, 7.0 Hz, 1 H), 3.81 (ddq, J = 10.0, 7.0, 7.0 Hz, 1 H), 4.03–4.20 (m, 3 H), 7.18–7.30 (m, 5 H), 7.31–7.47 (m, 4 H), 7.51 (dd, J = 7.5, 1.5 Hz, 2 H), 7.55–7.64 (m, 2 H), 7.82–7.91 (m, 2 H). ³¹P NMR (162 MHz, CDCl₃): δ = 20.1 (J _PP = 29.3 Hz), 24.8 (J _PP = 29.3 Hz). HRMS: (ESI⁺): m/z calcd for C₂₄H₂₉NNaO₄P₂: 480.1464; found: 480.1454. See Supporting Information for full characterization data.