Asymmetric Synthesis of -Substituted -Nitrophosphonic Acids by Phospha-Analogous Michael Addition to Aromatic Nitroalkenes

Abstract

Dedicated to Professor Hans Jürgen Bestmann on the occasion his 75th birthdayConsidering the enormous significance of organophosphorus compounds in nature, it is surprising that naturally occurring phosphonates [1] that contain a CÀP bond, have only been known since 1959 [2] when (aminoethyl)phosphonic acid was isolated from sheep rumen. Since then numerous compounds of this class have been isolated, synthesized, and tested for their biological activity. In particular, phosphonates [3] bearing heteroatomic substituents in the a-or bposition to the phosphorus atom have shown strong activities as antibiotics, anticancer drugs, herbicides, and enzyme inhibitors. [4] Their activity may be attributed to the similarity to the natural a-and b-amino acids and to the relative hydrolytic stability of the C À P bond compared to that of the P À O bond. Optically active a-hydroxy and a-aminophosphonic acids can nowadays be prepared by a variety of methods. [5] In contrast, only a few methods have been developed for the asymmetric synthesis of b-aminophosphonic acids [6] and of their precursors. A convenient route to b-aminophosphonic acids is provided by the addition of phosphorus compounds bearing a labile phosphorus À hydrogen bond to nitroalkenes, first developed by Pudovik et al., [7] and the subsequent reduction of the nitro group. [8] However, the addition of dialkylphosphites to aromatic nitroalkenes leads to extensive polymerization of the nitro compounds. Examples of addition of di-and trialkylphosphites to unsaturated nitro compounds were also described by Yoshimura et al., [9] who were able to add diethylphosphite to aliphatic nitroalkenes at 100 8C in moderate yields. Yamamoto et al. [10] developed the first substrate-controlled diastereoselective addition of dialkylphosphites to unsaturated nitrosaccharides, albeit only with moderate stereoselectivities. An efficient general method for the asymmetric Michael addition of phosphorus nucleophiles to unsaturated nitro compounds has not yet been described. Chiral catalysts [11] and chiral phosphorus nucleophiles [12,13] have already been employed in the asymmetric hydrophosphonylation of aldehydes and imines by 1,2-addition.We report here on the synthesis of an enantiomerically pure phosphite and its application as a chiral phosphorus nucleophile in the asymmetric Michael addition to aromatic nitroalkenes.We obtained phosphite (R,R)-2 in a two-step synthesis starting from TADDOL [14] ((R,R)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyl-1,3-dioxolane) (R,R)-1, which was converted into the corresponding chloride with PCl 3 and finally hydrolyzed in almost quantitative yield (Scheme 1). [15] The C 2symmetry of the ligand avoided the formation of a new stereogenic center at phosphorus and the otherwise necessary separation of diastereomers.

Asymmetric Michael Additions to Nitroalkenes

“…Scheme 28 Recently, we developed the first auxiliary-controlled phospha Michael addition to aromatic nitroalkenes using TAD-DOL as chiral auxiliary. [48] The enantiopure phosphite 89 was allowed to react in the presence of diethylzinc and TMEDA with nitroalkenes to give the 1,4-adducts 90 in high yield and diastereomeric excesses. Removal of the chiral auxiliary could be achieved racemization-free providing the α-substituted γ-nitrophosphonic acids with high ee.…”

Metallophosphite-Catalyzed Asymmetric Acylation of α,β-Unsaturated Amides

“…22,23 We recently demonstrated a preliminary asymmetric variant of the alkene acylation reaction that proceeded in 67% yield and 50% enantiomeric excess using the Enders (R,R)-TADDOL-phosphite 1-Ph. 24,25 From that platform we hypothesized that more highly enantioenriched 1,4-dicarbonyl products could be obtained through tuning of the phosphite catalyst and reagent functional groups. This article details the development of an effective asymmetric metallo-phosphite-catalyzed intermolecular addition of acyl silanes to α,β-unsaturated amides that can be achieved under mild reaction conditions in good yield and high enantioselectivity (eq 1).…”

α-Hydroxyphosphonic acid derivatives of 2-azanorbornane: synthesis, DFT calculations, and crystal structure analysis

“…We also tested chiral, sterically bulky TADDOL derived phosphite as the phosphorus nucleophile, which is known to be a useful chiral auxiliary in the synthesis of functionalized phosphonates (Table 1, entry 5). 8 In the case of the aldehyde exo-1 the diastereoselectivity of the reaction leading to the product exo-3d was good with dr 90:10, however, low conversion was observed due to the thermal instability of the chiral phosphonate and its decomposition to TADDOL under the reaction conditions. 8 Finally, we have used the silylated esters, generated in situ by reacting trimethylphosphite P(OMe 3 ) 3 with bromotrimethylsilane, as the phosphorus nucleophile (Table 1, entries 6 and 7).…”

“…8 In the case of the aldehyde exo-1 the diastereoselectivity of the reaction leading to the product exo-3d was good with dr 90:10, however, low conversion was observed due to the thermal instability of the chiral phosphonate and its decomposition to TADDOL under the reaction conditions. 8 Finally, we have used the silylated esters, generated in situ by reacting trimethylphosphite P(OMe 3 ) 3 with bromotrimethylsilane, as the phosphorus nucleophile (Table 1, entries 6 and 7). The desired a-hydroxyphosphonic acid derivatives of 2-azanorbornane exo-3a and endo-4a were obtained, after dealkylation of the formed silylated esters with methanol, in very good yields and under mild reaction conditions (room temperature, 12 h).…”