A One-Pot Approach to 2-Substituted-2-(Dimethoxyphosphoryl)-Pyrrolidines from Substituted tert-Butyl 4-Oxobutylcarbamates and Trimethyl Phosphite

Abstract

A novel approach to 2-substituted-2-(dimethoxyphosphoryl)-pyrrolidines 7a−7o and 9a−9r has been developed, which features a TMSOTf-mediated one-pot intramolecular cyclization and phosphonylation of substituted tert-butyl 4oxobutylcarbamates. The major advantages of this method include simple operation under mild reaction conditions, the use of cheap Lewis acid, and good to excellent yields with high diastereoselectivities (dr up to 99:1).

Diastereoselective Phosphonylation of Chiral Cyclic Imines for the Synthesis of Phosphoproline Derivatives

“…[24] Initially, we proposed that the diastereoselectivity could be increased by changing from methyl to isopropyl in the imine ester 6 b, and from ethyl to isopropyl in the phosphite function. With this in mind, we carried out the reaction of the chiral cyclic Recently, in the literature [25] was reported the synthesis of several cyclic quaternary α-aminophosphonates by phosphonylation of cyclic N-Boc-acyliminium ions easily obtained from one-pot intramolecular cyclization of substituted tert-butyl 4oxobutyl-carbamates using trimethylsilyl trifluoromethanesulfonate (TMSOTf) as catalyst. In order to evaluate these reaction conditions, we carried out the reaction of methyl N-Boc-4-oxo-2-aminocarboxylate (S)-8 a with triethyl phosphite and TMSOTf at À 78 °C, obtaining the cyclic α-aminophosphonates (2S,5R)-12 and (2S,5S)-13 in 56 % yield and 42 : 58 diastereoisomeric ratio.…”

“…Recently, in the literature [25] was reported the synthesis of several cyclic quaternary α‐aminophosphonates by phosphonylation of cyclic N ‐Boc‐acyliminium ions easily obtained from one‐pot intramolecular cyclization of substituted tert ‐butyl 4‐oxobutyl‐carbamates using trimethylsilyl trifluoromethanesulfonate (TMSOTf) as catalyst. In order to evaluate these reaction conditions, we carried out the reaction of methyl N ‐Boc‐4‐oxo‐2‐aminocarboxylate ( S )‐ 8 a with triethyl phosphite and TMSOTf at −78 °C, obtaining the cyclic α‐aminophosphonates (2 S ,5 R )‐ 12 and (2 S ,5 S )‐ 13 in 56 % yield and 42 : 58 diastereoisomeric ratio.…”

Synthetic Methods for Azaheterocyclic Phosphonates and Their Biological Activity: An Update 2004–2024

“…Then, an intramolecular nucleophilic addition of the amine to the carbonyl group generates an iminium intermediate, which undergoes the addition of trimethyl phosphite and affords the corresponding products in moderate to good yields and excellent diastereoselectivities (Scheme 34). 144 Scheme 30. Synthesis of Bisphosphonylated Five-Membered Rings Using 4N-(4,4-diethoxybutyl)ureas 178 (or phosphoramidates when R = PO(OTs) 2 ) and chloro(dialkyl or aryl)phosphines 179 in the presence of acetic acid, Smolobochkin and colleagues have synthesized 2-phosphonylpyrrolidines 180.…”

In(OTf)3-catalyzed N-α phosphonylation of N,O-acetals with triethyl phosphite

“…Over the past half century, tremendous efforts have been devoted to the synthesis of α-aminophosphonates, and numerous important methods have been reported. 17–26 One common approach was the catalyzed addition of trialkyl phosphite to imines 18 or the three-component process from aldehydes, amines and phosphite (Fig. 2a).…”

“…3a). 26 As a continuation of our interest in the investigation of acyliminium ion chemistry, 27 we envisioned that Lewis acid-catalyzed phosphonylation of N , O -acetals 6a–6j , 9a–9j , and 11a–11p would be a practical method toward α-aminophosphonates (Fig. 3b).…”