Part I: The Preparation and Uses of P-Chiral Phosphine Oxides _{p p p p}...[ Read more ]

Part I: The Preparation and Uses of P-Chiral Phosphine Oxides

Racemic tert-butylphenylphosphinothioic acid is resolved to provide (R_p)-(-) and (S_p)-(+)-tert-butylphenylphosphinothioic acids which upon desulfurization with Raney-nickel under ultrasound irradiation are converted into (S_p)-(-)- and (R_p)-(+)-terr-butylphenylphosphine oxides respectively. The racemic and optically active secondary phosphine oxides upon deprotonation with butyllithium or lithium N,N-di-isopropylamide are converted into the lithiated secondary phosphine oxides which react with primary alkyl halides, primary Godihalides, α,ω-dihalides and α,β- unsaturated carbonyl compounds to give the corresponding tertiary phosphine oxides and diphosphine dioxides in moderate to good yields. During the reactions, configuration at phosphorus is perfectly retained, and in the case of carbonyl compounds, kinetic control is demonstrated to operate under the reaction conditions. For aldehydes, reactions are diastereoselective in providing predominantly the ul-product, an outcome which is rationalized in terms of relative energies of cyclic five-membered transition structures. With α,β-unsaturated carbonyl compounds, high diastereoselectivity is observed, and open transition structures are used in rationalization of the stereochemical outcome. No reactions take place with enolizable or non-enolizable ketones. Reaction of the racemic lithiated phosphine oxide with styrene oxide gives a regioisomeric mixture of β-hydroxyphosphine oxides; no appreciable reaction takes place with aliphatic epoxides. The racemic and optically active lithiated phosphine oxides reacts cleanly with 1,2-dibromoethane to provide the corresponding tert-butylphenylphosphinobromidates in good yields.

Whilst oxidative coupling of lithiated (R_p)-tert-butylphenylphosphine oxide provides meso bis-phosphine oxide, its reaction with (S_p)-tert-butylphenylphos-phinobromidate provides highly crystalline (S_p,S_p)-bis-tert-butylphenylphosphine oxide and the meso compound; the (R_pR_p)-bisphosphine oxide is obtained from the enantiomeric reactant pairs. Inversion of configuration at electrophilic phosphorus occurs in the reaction leading to the (S_p,S_p)- and (R_p,R_p)-products. Concomitant formation of the meso compounds is ascribed to pseudorotation in the pentacoordinate intermediate. The bromidates react with unhindered primary amines to give the corresponding phosphoramidates with inversion of configuration at phosphorus; for more hindered amines, some retention at phosphorus is noted. Reaction of the bromidates with alkyllithium and alkyl Grignard reagents is complicated by bromine-metal exchange and subsequent alkylation to give product mixtures enriched in the tertiary phosphine oxide with the same configuration as the starting bromidate. The conclusion is drawn that use of electrophilic phosphorus(V) reagents for preparation of configurationally defined phosphine oxides according to usual practice is unreliable.

Lithiated tert-butylmethylphenylphosphine oxide and lithiated benzyl-tert-butylphenyl phosphine oxides, obtained from the parent phosphine oxide and n- and tert-butyllithium respectively, react with alkyl halides, and in the first case, with aldehydes and ketones to give the corresponding products in good yields. Moderate diastereoselectivity with aldehydes is observed in favour of the lk product.

The effectiveness of the phosphine oxides obtained from the reactions of the lithiated (S_p)-(-)- and (R_p)-(+)-tert-butylphenylphosphine oxides with the various electrophiles as catalysts in asymmetric carbonyl addition reactions and alkene dihydroxylation have been evaluated. Phenylmagnesium bromide in the presence of (R_p)-tert-butyl-2,2-diphenyl-2-hydroxyete oxide (1.1 equiv.) in ether at -90 ℃ adds to o-anisaldehyde to give the alcohol with 90% enantiomeric excess (ee). Borane reduction of acetophenone in the presence of (S_p)-tert-butyl-(2,2- diphenyl-2-hydroxyethyl)phenylphosphine oxide (10 mol%) gives alcohol with 79% ee. Diethyl zinc reacts with butyraldehyde, benzaldehyde and other aldehydes in toluene in the presence of (R_p)-tert-butyl-[2,2-( l',l'-dinaphthyl)-2-hydroxylethyl- phenylphosphine oxide (10 mol%) to give alkyl addition products with enantiomeric excesses ranging from 34-88%. Osmium(VIII) dihydroxylation of alkenes is found to be accelerated in the presence of phosphine oxides. Use of (R_p,R_p-1,3- bis-tert-butyl-phenylmethylphosphinylmethyl) pyridine (1 mol%) in the presence of potassium ferricyanide (3 equiv.), potassium carbonate (3 equiv.), potassium osmate (1 mol%) in tert-butyl alcohol-water (1:l) at 0 [degres Celsius] according to Sharpless AD protocol with aryl alkenes give diols with enantiomeric excesses ranging from 16 to 73%.

Part II: The Enantioselective Synthesis of (+)-Brefeldin A.

Brefeldin A, an antimitotic agent, is synthesized in enantioselective, convergent fashion. Enantiomerically-pure (R)-4-tert-butoxycyclopent-2-enone is prepared in large scale according to the procedure developed by Haynes and coworkers. Conjugate addition of 2-lithio-1,3-dithiane to the (R)-4-tert-butoxycyclopent-2-enone in the presence of hexamethylphosphoric triamide in tetrahydrofuran provides the conjugate adduct (89%) treatment of which with trimethylsilyl triflate in dichloromethane at room temperature efficiently provides the transposed conjugated enone, (4R)-4-(1',3'-dithian-2'-yl)cyclopent-2-en-l-one (90%). This enone is then treated with lithiated γ-crotonolactone (butenolide) in tetrahydrofuran at -90 [degrees Celsius] to give two diastereoisomeric conjugate adducts arising via reaction through C-4 of the lactone in a ratio of 95:5. The configuration of the major isomer - (l'R,2'R,4S)-4-[2'-(2",6"-dithian- l"-yl)-4'-oxocyclopent-l'-yl]-4-[2(5H)-furanone) - was secured by X-ray crystallographic analysis, and corresponds both to that predicted by the model for the conjugate addition reaction, and to the absolute configuration of brefeldin A. Ring opening of the butenolide with lithium thiophenolate in the presence of titanium(IV) isopropoxide in tetrahydrofuran followed by treatment with diazomethane gives the (E)-α.,β-unsaturated ester, methyl (2E,1'R,2'R,4S)-4-[2'-(2",6"-dithian-l"-yl)-4'- oxo-cyclopent-l'-yl]-4-hydroxybut-2-enoate (58%). Protection of the free hydroxyl group as methoxyethoxymethyl ether (MEM) followed by reduction of the C-7 carbonyl and protection of the alcohol as the MEM ether gave methyl (2E,l'R,2'R, 4'S,4s)-4-[2'- (2",6"-dithian-l"-yl)-4'-(2"',5"'-dioxahex- 1"'-yl)oxycyclopent- 1'-yI]-4-(2"',5"'-di-oxahex- 1"'-yl)oxybut-2-enoate (85%). The dithiane was converted into the free aldehyde (73%) by exhaustive methylation-hydrolysis in aqueous acetonitrile. Treatment of the aldehyde with the ylide from [(5S)-5-(tert-butyldiphenylsilyloxy) hexanyl]triphenylphosphonium bromide in tetrahydrofuran containing lithium bromide gave an 87:13 E:Z mixture of alkenes, saponification, and removal of the silyl protecting group with hydrochloric acid in which gave (l"E,2E,l'R,2'R,2"R, 4,S,4's)-4-{ [2'-(6"-hydroxyhept-l"-en-l"-yl)-4'-(2"',5"'-dioxahex-l"'-yl)oxy]cyclo-pent- l'-yl}-4-[(2"',5"'-dioxahex-l"'-yl)oxy]but-2-enoic acid (85%). This was lactonized according to the Yamaguchi procedure to give the bis-MEM ether of brefeldin A (78%), which was converted into brefeldin A (96%) through treatment with titanium(IV) chloride in dichloromethane.

Noteworthy features of the synthesis are the clean conversion of (3R,4R)-3- tert-butoxy-4-(1',3'-dithian-2'-yl)-cyclopent~-l-one into the enone by removal of the tert-butoxy group, and the diastereoselectivity of the conjugate addition of the lithiated butenolide to the (4R)-4-( 1',3'-dithian-2'-yl)cyclopent-2-en- 1 -one.