Chiral pentavalent phosphorus (P(V)) molecules play an important role in organic synthesis, natural products, and medicinal chemistry. Traditionally, chiral synthesis methods for such compounds have relied on the covalent formation of P(V) molecules using stoichiometric chiral auxiliary reagents, followed by diastereoselective nucleophilic substitutions in the P(V) stereocenter (Figure 1A). Transition metal-catalyzed cross-coupling reactions for kinetic resolution of phosphine oxide are an alternative method to obtain chiral P(V) molecules (Figure 1B). However, these options are limited to providing carbon-substituted phosphorus oxide. In recent years, the desymmetry of prechiral P(V) compounds has proven to be a reliable strategy for the synthesis of various P(V) stereoforming molecules (Fig. 1C).
Guolin Cheng's research group at Huaqiao University has long been committed to the study of Catellani reaction. Am. Chem. Soc. 2020, 142, 14864; Angew. Chem. Int. Ed. 2017, 56, 8183; ACS Catal. 2020, 10, 10516; Org. Lett. 2018, 20, 4984; J. Org. Chem. 2018, 83, 12683; J. Org. Chem. 2020, 85, 13280; J. Org. Chem. 2023, 88, 11793）。 Based on this research, they developed a solvent-controlled palladium/chiral norbornene (NBE)-catalyzed cyclization of aryl iodide with phosphoramide. This method has a wide range of applications for both aryl iodine and phosphamide substrates, and enables the enantioselective acquisition of two enantiomers of chiral P(V) molecules using a single chiral NBE catalyst (Figure 1D).
Figure 1. Methods for the construction of chiral P(V) molecules
Under optimal reaction conditions, the authors investigated the range of aryl iodide used in toluene and acetonitrile. The results showed that aryl iodides, including hetetoaryl iodides, were well compatible with the reaction with moderate yields and good to excellent enantioselectivity (Figure 2).
Figure 2. Investigation of the range of substrates for the reaction of aryl iodide and N-aryl phosphamide
In addition, the authors studied the reaction of different classes of aryl iodides with N-alkylphosphamide. A series of substituted naphthalene, phenyl, polycyclic aryl, and pyridyl iodides were successfully reacted with N-cyclohexylphosphamide in toluene to obtain the target product with moderate yield and excellent enantioselectivity. In addition, N-propyl, amyl, isopropyl, phenylethyl, and benzylphosphonamide are all compatible with this reaction condition, resulting in a product with high enantioselectivity in medium to good yields. The absolute configuration of 4x is specified as (R) by single crystal X-ray diffraction analysis. The reaction of aryl iodide with N-alkylphosphamide in acetonitrile can also produce the desired product in good yields, albeit with a lower enantiomeric excess. For example, the product (SP)-4a was obtained at 75% yield and 44% ee (Figure 3).
Figure 3. Investigation of the range of substrates for the reaction of aryl iodide and N-alkylphosphamide
To elucidate the mechanism of this transition, the authors conducted a series of studies on the mechanism of the reaction (Figure 4). First, the authors reacted 1a with phosphoramidite2r, which has a small steric hindrance, to obtain the corresponding product (RP)-4z with a very low enantiomeric excess. Then, a series of ipso termination processes were explored, including Heck reaction, Suzuki−Miyaura coupling, and Sonogashira coupling. Happily, the product (Sax)-6 was successfully obtained with a yield of 45% and 97% ee using (triisopropylsilyl)acetylene 5 as the stop reagent. In order to further understand the reaction mechanism, a chiral hindered transorivariant (Rax)-9 containing both aryl iodine and phosphoramide moieties was prepared from commercially available (Rax)-2,2'-diiodo-1,1'-diphthalic acid (Rax)-7, and the desired product (RP)-10 was isolated with toluene as solvent in the absence of NBE-CO2Me with 62% yield and 99% ee. At the same time, acetonitrile was used as the solvent to generate (SP)-10 at 45% yield and 90% ee. These results confirm the proposed solvent-dominated axis to P(V) center chiral transfer process. Therefore, the authors propose that this transition will take place through two key steps: (1) palladium/chiral NBE-catalyzed C−H arylation and (2) solvent-controlled desymmetric intramolecular N-arylation.
Figure 4. Mechanistic studies
To further demonstrate the synthetic value of this protocol, the authors performed gram-scale reactions of 1a and 2b. The reaction proceeded smoothly under standard reaction conditions, yielding 1.08 g (75% yield) of (RP)-3p and 87% ee (Figure 5). Then, the derivatization of (RP)-3p is described. The reaction of (RP)-3p (95% ee) with Lawesson's reagent yielded thiophosphamide 11 in 65% yield. Treatment with di-tert-butyl dicarbonate (RP)-3p yielded N-Boc-protected product 12 with a yield of 85%. In addition, phosphoramidite alcohololysates can be obtained stereoselectively by activating amino groups (NHAr) with Boc groups, providing a P(V)chiral product with high enantiomeric purity at a yield of 47%13. Since the obtained chiral P(V) compounds are potential catalysts for high pKa-Brønsted acids, the authors found that 3p can cause free carbenees to insert N−H bonds into amines, forming chiral α-amino acids with moderate enantioselectivity16.
Figure 5. Gram-level reactions, product transformations and applications
In summary, Guolin Cheng's group has developed a modular method for the construction of P(V) stereogeneous molecules by using Catellani-type C−H arylation/desymmetric intramolecular N-arylation tandem reaction. The enantioselectivity of this reaction proved to be regulated by the polarity of the solvent and is an example of solvent-controlled enantioselectivity unprecedented in the asymmetric synthesis of P(V) compounds.
The first author of the work is Tian Qingyu, a doctoral student of Huaqiao University, Professor Cheng Guolin is the only corresponding author, and Huaqiao University is the first unit.
Solvent-Controlled Enantiodivergent Construction of P(V)-Stereogenic Molecules via Palladium-Catalyzed Annulation of Prochiral N-Aryl Phosphonamides with Aromatic Iodides
Qingyu Tian, Jin Ge, Yaopeng Liu, Xi Wu, Zhenghao Li, Guolin Cheng
Angew. Chem. Int. Ed., 2024, DOI: 10.1002/anie.202409366
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