Organocatalytic Asymmetric Decarboxylative Mannich Reaction of β

Letter Cite This: Org. Lett. 2018, 20, 3643−3646

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Organocatalytic Asymmetric Decarboxylative Mannich Reaction of β‑Keto Acids with Cyclic α‑Ketiminophosphonates: Access to Quaternary α‑Aminophosphonates Yong-Jie Liu, Jin-Shan Li, Jing Nie,* and Jun-An Ma* Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Tianjin Collaborative Innovation Center of Chemical Science & Engineering, Tianjin University, Tianjin 300072, P. R. China

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S Supporting Information *

ABSTRACT: An organocatalytic asymmetric decarboxylative Mannich reaction of β-keto acids with cyclic αketiminophosphonates has been developed. By using saccharide-derived bifunctional amine-thiourea catalysts bearing an axial chiral binaphthyl scaffold, a wide range of quaternary α-amino-γ-oxophosphonates were obtained in up to 93% yield and >99% ee. Furthermore, two interesting α-aminophosphonate derivatives were synthesized from the corresponding decarboxylative Mannich product via simple transformations. indoles with cyclic α-ketiminophosphonates (Scheme 1a).6c Recently, the utility of β-keto acids as ketone enolate equivalents in the catalytic asymmetric decarboxylative reactions has been intensely investigated by several research groups.7,8 Encouraged by these important precedents, along with our continued interest in asymmetric decarboxylative transformations and the preparation of optically pure α-

ptically active α-aminophosphonic acids, isosteric or bioisosteric analogues of the corresponding amino acids, have a wide range of applications in biochemistry and medicinal science1 due to their unique biological properties such as potent antibacterial, anticancer, antiviral, pesticidal and herbicidal activities.2 Although a number of elegant works have been well demonstrated by chiral auxiliary, as well as catalytic asymmetric C−N, C−P, C−H, and C−C bond formation reactions, leading to various optically active αaminophosphonic acids and derivatives,3 relatively few examples have been reported involving the efficient construction of the chiral quaternary α-aminophosphonic acids and derivatives in a catalytic enantioselective manner.4 Catalytic asymmetric nucleophilic addition to α-ketiminophosphonates represents one of the most straightforward methods to build up quaternary α-aminophosphonic acids.5 However, these studies mainly focused on the asymmetric addition to acyclic αketiminophosphonates to access linear quaternary α-aminophosphonates; the use of cyclic α-ketiminophosphonates for the expeditious synthesis of cyclic quaternary α-aminophosphonates has been less exploited.6 In this context, Zhou and co-workers reported an efficient route to cyclic quaternary α-aminophosphonates by a palladium-catalyzed enantioselective addition of arylboronic acids to cyclic α-ketiminophosphonates with high yields and excellent ee values;6b shortly after, the same group also realized the chiral phosphoric acidcatalyzed highly enantioselective Friedel−Crafts reaction of

O

© 2018 American Chemical Society

Scheme 1. Catalytic Enantioselective Synthesis of Cyclic Chiral Quaternary α-Aminophosphonates

Received: May 5, 2018 Published: May 31, 2018 3643

DOI: 10.1021/acs.orglett.8b01422 Org. Lett. 2018, 20, 3643−3646

Letter

Organic Letters aminophosphonates,9 we found that novel cyclic quaternary αaminophosphonates could be constructed by an organocatalytic asymmetric decarboxylative Mannich reaction of β-keto acids with cyclic α-ketiminophosphonates (Scheme 1b). Herein, we describe the successful implementation of this process to provide cyclic quaternary α-amino-γ-oxophosphonate derivatives and significant opportunities for structural diversification. We began our investigations with the asymmetric decarboxylative Mannich reaction of cyclic α-ketiminophosphonate 1a and β-keto acid 2a in toluene at −20 °C in the presence of 10 mol % of saccharide-derived amine−thioureas A−C, which were developed previously in our laboratory (Table 1, entries 1−3).10 By using a primary amine−thiourea catalyst A, the desired product 3a was obtained in good yield, albeit with low enantioselectivity (entry 1). Bifunctional thioureas B and C, bearing a tertiary amine moiety, exhibited better enantioselectivities (entries 2 and 3). These results suggest that additional improvement on the enantioselectivity might be feasible by fine-tuning the substituents at the tertiary amine moiety. We then designed and synthesized a series of novel saccharide-derived organocatalysts D−G, wherein the axial chiral binaphthyl scaffold was incorporated into the chiral 1,2dimine backbone.11 Gratifyingly, examination on these thirdgeneration amine−thiourea catalysts in the same test reaction revealed that the enantioselectivity can be significantly improved to 68−90% ee (entries 4−7). These results also indicate that the (S,S)-configuration of 1,2-diaminocyclohexane and (R)-binaphthalene matched the β-D-glucopyranose to enhance the stereochemical control (entry 4). Subsequent optimization of the enantioselectivity was achieved with catalyst D by screening other parameters, including solvents, temperature, additives, and catalyst loadings. Among the solvents tested (entries 8−11), carbon tetrachloride (CCl4) was found to be the best one, giving the desired product in 90% yield with 91% ee after 16 h. Performing the reactions at lower temperature resulted in slightly reduced yields (entries 11− 14). Interestingly, the addition of molecular sieves could significantly improve the enantioselectivities (entries 15−18). For instance, in the presence of 200 mg of 5 Å MS, the catalyst D furnished the Mannich product 3a in 86% yield with 99% ee (entry 18). The effect of catalyst loading was next examined (entries 19 and 20), and excellent results were still obtained when the catalyst loading was lowered to 1 mol % (entry 20). With the optimized reaction conditions in hand, a series of six-membered cyclic α-ketiminophosphonates 1 were reacted with various β-keto acids 2 to probe the generality of the reaction (Scheme 2). In general, cyclic α-ketiminophosphonates 1 bearing electron-donating or -withdrawing groups on the phenyl ring could be well tolerated, affording the corresponding products 3a−j in high yields with uniformly excellent enantioselectivities. The product 3i was isolated as a crystalline compound, and the structure was characterized by Xray crystallographic analysis. The absolute configuration for the stereogenic carbon center formed in the reaction is of R stereochemistry. Next, the substrate scope of β-keto acids 2 was explored by the reaction of cyclic α-ketiminophosphonate 1a under the optimal conditions. We were pleased to find that a wide range of phenyl-substituted β-keto acids with substituents in the ortho-, meta-, or para-position of the phenyl ring proceeded well to furnish the desired products 3k−s in 80− 93% yields with 94−99% ee. In addition, 2-naphthyl-, 2-furyl-, or 2-thienyl-substituted β-keto acids were found to be variable substrates, delivering the desired products 3t−v in 81−89%

Table 1. Catalyst Screening and Condition Optimizationa

entry

catalyst (mol %)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

A (10) B (10) C (10) D (10) E (10) F (10) G (10) D (10) D (10) D (10) D (10) D (10) D (10) D (10) D (10)

16

D (10)

17

D (10)

18

D (10)

19

D (5)

20

D (1)

additive (mg)

3 Å MS (100) 4 Å MS (100) 5 Å MS (100) 5 Å MS (200) 5 Å MS (200) 5 Å MS (200)

solvent/temp (°C)/ time (h)

yieldb (%)

eec (%)

toluene/−20/18 toluene/−20/16 toluene/−20/24 toluene/−20/16 toluene/−20/22 toluene/−20/26 toluene/−20/19 Et2O/−20/16 DCM/-20/46 THF/−20/21 CCl4/−20/16 CCl4/0/15 CCl4/−10/16 CCl4/−30/18 CCl4/−20/18

86 86 52 85 85 87 86 80 68 86 90 85 86 87 89

15 61 45 90 82 −68 −74 90 74 61 91 90 90 88 94

CCl4/−20/18

85

93

CCl4/−20/18

86

97

CCl4/−20/18

86

99

CCl4/−20/28

83

99

CCl4/−20/46

84

99

a

General reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), and catalyst D in solvent (1 mL) at the given temperature for the stated time. bIsolated yield. cEnantiomeric excess (ee) was determined by chiral HPLC analysis.

yields, with 92−99% ee. Notably, three linear, branched, and cyclic alkyl-substituted β-keto acids could also be successfully employed in this decarboxylative Mannich reaction, while the reaction should be conducted at 0 °C using higher catalyst loadings (10 mol %) to achieve the high levels of enantioselectivity. In addition to six-membered cyclic α-ketiminophosphonates, five-membered cyclic counterparts were also examined. As shown in Scheme 3, this catalytic asymmetric decarboxylative Mannich reaction is compatible with five-membered cyclic α3644

DOI: 10.1021/acs.orglett.8b01422 Org. Lett. 2018, 20, 3643−3646

Letter

Organic Letters Scheme 2. Scope of the Enantioselective Decarboxylative Mannich Reaction of 1 with 2a−e

Scheme 3. Scope of the Enantioselective Decarboxylative Mannich Reaction of 2a with 4a−d

a

Reaction conditions: 5 (0.2 mmol), 2a (0.3 mmol), catalyst D (5 mol %), 5 Å MS (400 mg), CCl4 (2.0 mL), −20 °C. bIsolated yields. c Determined by HPLC. d1.0 mol % of catalyst D was used.

Scheme 4. Scaled-up Version of the Mannich Reaction of 1a with 2a and Further Synthetic Transformations of 3a

be crystalline, thus allowing the determination of the absolute configuration of their stereogenic centers by means of X-ray crystallographic analysis (Scheme 4). A control experiment where β-keto acid 2a was replaced by acetophenone under otherwise identical reaction conditions did not furnish the adduct 3a. On the basis of this result and our previous observations,8c,j a stepwise process could be involved in the catalytic cycle in which nucleophilic addition of the βketo acid salt to α-ketiminophosphonates 1 gave the addition intermediate followed by the decarboxylation to afford the Mannich product 3 (Figure 1). In summary, we have successfully developed an organocatalytic asymmetric decarboxylative Mannich reaction of βketo acids with cyclic α-ketiminophosphonates. This transformation tolerates both of the six- and five-membered cyclic αketiminophosphonates. In the presence of saccharide-based novel amine−thioureas, a series of quaternary α-amino-γ-

a

Unless otherwise mentioned, all reactions were carried out with catalyst D (1.0 mol %), 1 (0.20 mmol), 2 (0.3 mmol), CCl4 (2.0 mL), 5 Å MS (400 mg), −20 °C. bIsolated yields. cDetermined by HPLC. d 5 mol % catalyst D was used. e10 mol % catalyst D was used at 0 °C.

ketiminophosphonates 4, delivering the optically active αaminophosphonates 5a−c in good yields with high enantioselectivities. To evaluate this organocatalytic system on a large scale, 3 mmol of cyclic α-ketiminophosphonate 1a was used to perform the decarboxylative Mannich reaction with β-keto acid 2a, and the product 3a was obtained in 88% yield with 98% ee (Scheme 4). Direct reduction of this Mannich product 3a using NaBH4 furnished α-amino-γ-hydroxy phosphonate 6 in high yield with excellent stereoselectivity. Furthermore, treating 3a with tertbutyl hydroperoxide (TBHP)/KI in THF led to the formation of novel fused aziridine 7, in which two contiguous stereocenters were constructed without significant erosion of enantiopurity. The single stereoisomer of 6 and 7 proved to

Figure 1. Proposed Mannich reaction process. 3645

DOI: 10.1021/acs.orglett.8b01422 Org. Lett. 2018, 20, 3643−3646

Letter

Organic Letters

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oxophosphonates were obtained in 76−93% yields with 90− 99% enantioselectivities. Further development and application of this decarboxylative Mannich reaction, as well as investigation of the mechanism, is ongoing in our laboratory.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01422. Experimental details, spectral data of all the new compounds, and HPLC analytic results for 3a−y, 5a− c, 6, and 7 (PDF) Accession Codes

CCDC 1836536, 1836549, and 1840570 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by emailing [email protected]. uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Jun-An Ma: 0000-0002-3902-6799 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Nos. 21472137, 21225208, and 21532008) and the National Basic Research Program of China (973 Program, 2014CB745100).

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REFERENCES

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DOI: 10.1021/acs.orglett.8b01422 Org. Lett. 2018, 20, 3643−3646