A-Hydroxy-phosphinates

In the presence of a base, secondary chiral phosphine oxides undergo addition to carbonyl compounds to give a-hydroxy phosphine oxides as diastereomeric mixtures the diastereomer ratio depends mainly on the reaction conditions. For example, the reaction of ethyl(phenyl)-phosphinc oxide with benzophenone in the presence of a catalytic amount of sodium ethoxide gives at 75 =C exclusively while at 25°C the ratio [(P/ , / )-l/(P7 , S )-l] is 7 326. 

Under mild conditions some of the primary products, the a-hydroxy phosphines, can be isolated and then, when heated, isomerize to the phosphine oxides.85... 

The preparation of these compounds started by a Pudovik reaction of methyl-//-phosphinate 308 with 2-pyridinecarboxaldehyde or benzaldehyde derivatives to produce a-hydroxy-phosphinates 309. Further coupling of 309 with substituted phenoxyacetic chloride 310 in presence of triethylamine gave the final compounds 307 (Scheme 65). 

A synthesis of chiral a-hydroxy-//-phosphinates, bearing two asymmetric centers, was achieved via a lipase-catalyzed hydrolysis of acetate precursors. From a... 

A subsequent Pd-catalyzed coupling reaction with diphenylphosphine oxide produces mainly the monophosphorylated product. Reduction of the phosphine oxide with silane followed by hydrolysis of the ester group produces a hydroxy phosphine. The final condensation with (S)-binaphthophosphorchloridite affords (R,S)-BINAPHOS. In the same way, enantiomeric (S,R)-BINAPHOS was prepared. Both were the first in a series of chiral ligands used in target-oriented... 

A range of NMR, IR and MS techniques have been brought to bear on the reaction of diphenylphosphine oxide with aromatic aldehydes and ketones, to give a-hydroxy-phosphine oxides. Rate constants were correlated with the Hammett equation, for the... 

The addition of P—H bonds across a carbonyl function leads to the formation of a-hydroxy-substituted phosphines. The reaction is acid-cataly2ed and appears to be quite general with complete reaction of each P—H bond if linear aUphatic aldehydes are used. Steric considerations may limit the product to primary or secondary phosphines. In the case of formaldehyde, the quaternary phosphonium salt [124-64-1] is obtained. 

The discussion of the activation of bonds containing a group 15 element is continued in chapter five. D.K. Wicht and D.S. Glueck discuss the addition of phosphines, R2P-H, phosphites, (R0)2P(=0)H, and phosphine oxides R2P(=0)H to unsaturated substrates. Although the addition of P-H bonds can be sometimes achieved directly, the transition metal-catalyzed reaction is usually faster and may proceed with a different stereochemistry. As in hydrosilylations, palladium and platinum complexes are frequently employed as catalyst precursors for P-H additions to unsaturated hydrocarbons, but (chiral) lanthanide complexes were used with great success for the (enantioselective) addition to heteropolar double bond systems, such as aldehydes and imines whereby pharmaceutically valuable a-hydroxy or a-amino phosphonates were obtained efficiently. 

Detailed investigations of the chemical reactivity of the diketiminato-stabilized phosphenium cations like 28 (Scheme 17) are to date rare and include only two reports dealing with the substitution and reduction of P-halogen-derivatives. Thus, reaction of 28 (X=Br) with sodium hydroxide in toluene was reported to proceed with displacement of the halide substituent at phosphorus and conservation of the heterocyclic ring to give a mixture of bromide and triflate salts containing a P-hydroxy-substituted cation, both of which were isolated in small yields [89], The products are remarkable as they represent one of very few examples of a stable phosphinous acid which does not rearrange to the tautomeric secondary phosphine oxide. Potassium reduction of the P-chloro-substituted derivative 34 produced the... 

Tris(a-hydroxy-/3,/3,/3-trichloroethyl)phosphine reacts with phenyl-trichlorosilane, phosphorus, and arsenic trichlorides in the same way, giving bicyclic product (14) [Eq. (12)] (78ZOB2437). 

Similar bicyclic 101 was obtained from tris(a-hydroxy-/3,/3,/3-trichloroe-thyl)phosphines and boric acid [Eq. (58)]. 

Hydroxy-phosphines undergo benzoylation with o-sulfobenzoic anhydride in the presence of bases (Na2C03 or BuLi) affording sulfobenzoylated phosphine products. In such a way several mono- and dihydroxy phosphines could be made soluble in water, exemplified by the chiral bisphosphines 53. It should be noted, that this general method allows the preparation of water-soluble sulfonated derivatives of acid-sensitive phosphines, such as DIOP, too, which are not accessible via direct sulfonation [56]. 

Reduction of a mixture of 69a-c or 69a with zinc dust in acetic acid yields two diastereoisomeric 4-hydroxy-phosphinic acid ethyl esters 70 Z and E, or only 70 E. 

Price obtained in the presence of water a crystalline product (m. p. 256—257 °C) and an amorphous material from which Markl could isolate the X -phosphine oxide 158 (m. p. 156-158 °C) and the 4-hydroxy-phosphine oxide 160 (m. p. 239-241 °C) which probably was formed by autoxidation. 158 is also formed by HaO2-oxidation of 147 The tautomeric form of 158 would be the 1-hydroxy-X -phosphorin 159. Indeed, treatment with base affords a bright red anion which probably has the structure 161 (see p. 60 and 87). 

Macrocyclic lactones. Ireland and Brown1 have adapted the Eschenmoser contraction of sulfides to a synthesis of five- and six-membered lactones. An example is formulated in equation (1). A hydroxy thioamide is esterified to give a chloro ester, which is then treated in sequence with Nal and phosphine I. The inelhod can also be used for preparation of macrocyclic lactones under high-dilution... 

In addition to the conversion into phosphonochloridates as described in Section 10.10.2.1.2, phosphonate monoacids can also be activated for coupling via some of the popular reagents from standard peptide chemistry, such as BroP, 77 BOP/ and PyBOP. 79 One-pot activation and coupling of hydrogen phosphinates with a-hydroxy acids is also possible via the method outlined in Section 10.10.2.1.3. 76 The procedure outlined in Scheme 19 illustrates an optimized procedure for coupling a hindered phosphonate 57 and an a-hydroxy acid derivative via the phosphonochloridate 72 ... 

Intramolecular addition of a hydroxy group to the terminal sp-carbon of pent-4-yn-l-ols, leading to the corresponding cycloisomerization dihydropyrans, has been successfully achieved with a similar ruthenium catalyst precursor containing the electron-deficient tris(p-fluorophenyl)phosphine ligand, excess phosphine, and sodium N-hydroxysuccinimide as additives (Scheme 9) [20]. 

SR1135 (blend of phosphine oxide, a-hydroxy ketone, 8... 

Horner-Wittig modification Alternatively, phosphine oxide reacts with aldehydes in the presence of a base (sodium amide, sodium hydride or potassium t-butoxide) to give an alkene. The phosphine oxide can be prepared by the thermal decomposition of alkyl-triphenylphosphonium hydroxide. Deprotonation of phosphine oxide with a base followed by addition to aldehyde yields salt of (3-hydroxy phosphineoxide, which undergoes further syn-elimination of the anion Ph2P02. The lithium salt of (3-hydroxy phosphineoxide can be isolated, but Na and K salt of (3-hydroxy phosphine oxide undergoes in situ elimination to give alkene (Scheme 4.26). 

Intramolecular addition of a secondary phosphine oxide to a carbonyl group proceeds in the presence of an acid at room temperature to give both diastereomers of the product a-hydroxy-phospholane oxides 2 with the rfs-isomer predominating at higher temperatures the m-isomer is formed exclusively27. 

Several of the procedures discussed in the sulfoxide section describe the successful extension of the method to the reduction of selenoxides, - - and there is little doubt that many of the other procedures cited earlier could be used likewise. Sakaki and Oae used triphenylphosphine selenide and similar se-lenides to reduce selenoxides to selenides in 79-93% yield (equation 19). Using a chiral phosphine selenide, these workers showed that the phosphine oxide formed had suffered predominant inversion, with a stereospecificity of over 80%. Detty has reported the application of the silane PhSeSiMes (12) to the reduction of selenoxides and telluroxides. The reactions are rapid and proceed essentially quantitatively, even in the presence of a hydroxy or carbonyl group. 

W. Rogers, Jr. Private communication. IR chelation in a-hydroxy tertiary phosphine oxides. 

Most recently, the immunosuppressive agent FK-S06 (416) has been the target of total synthesis. To date several approaches to the trisubstituted alkene region at C-19 and C-20 have appeared. These preliminary studies allow the comparison between the Warren phosphine oxide approach and the Julia coupling. In the first total synthesis of FK-S06, Jones and coworkers at Merck formed the the alkene deprotonadon of the phosphine oxide (418) and condensation with the aldehyde (417). The hydroxy-phosphine oxides were formed in a ratio of 1 1 in 77% yield. The less polar diastereomer was treat with base to obtain the ( )-alkene (419) in 32% overall yield from the aldehyde (equation 96). Danishefsky utilized the Julia coupling for the formation of the trisubstituted alkene region. The sulfone anion (420) was treated with isobu raldehyde as a model, followed by acetylation and reductive elimination to... 

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