Catalytic Asymmetric Addition of Diorganozinc Reagents to N
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Catalytic asymmetric addition of diorganozinc SPECIAL FEATURE reagents to N-phosphinoylalkylimines Alexandre Coˆ te´ , Alessandro A. Boezio, and Andre´ B. Charette* Department of Chemistry, University of Montreal, P.O. Box 6128, Station Downtown, Montreal, QC, Canada H3C 3J7 Edited by Jack Halpern, University of Chicago, Chicago, IL, and approved February 4, 2004 (received for review October 31, 2003) The synthesis of ␣-chiral amines bearing two alkyl groups has been hampered by the accessibility and stability of the alkylimine precursor. Herein, we report an efficient strategy to generate the alkyl-substituted imine in situ that is compatible with the Me- DuPHOS monoxide⅐Cu(I) catalyzed addition of diorganozinc re- agents. The sulfinic acid adduct of the imine is readily prepared by mixing diphenylphosphinic amide, the aldehyde, and sulfinic acid. The sulfinic acid adduct is generally isolated by filtration. The addition of diorganozinc reagents in the presence of Me-DuPHOS monoxide⅐Cu(I) and the in situ-generated imines affords the cor- Fig. 1. Bioactive ␣-chiral amines. responding ␣-chiral amines in high yields and enantiomeric excesses. sensitive imines from stable precursors has been a strategy that he synthesis of ␣-chiral amines using the catalytic asymmetric has been quite successful in a number of cases. Typically, a stable Taddition of diorganozinc reagents has produced very exciting imine adduct is used as a precursor and is converted to the imine results in recent years (1–3). This very important subunit is in situ (Scheme 2). The method involves the use of a leaving ␣ CHEMISTRY commonly found in many pharmaceuticals and other biologically group (LG) on the -carbon of the N-protected amine. Several important compounds. Some specific examples include Flomax leaving groups including benzotriazolates (29), sulfinates (30), (antihypertensive) and Mexitil (antiarrhythmics) (Fig. 1) (4). and succinimidates (31) have been used for the in situ prepara- The most important methodologies developed to prepare tion of N-acylimines. ␣-chiral amines in enantiomerically pure form rely on either In this article, we describe the feasibility of the in situ synthesis chemical resolution or on the use of readily available chiral of N-phosphinoylimines and we show that these precursors are also suitable reaction partners for the preparation of ␣-chiral synthons as building blocks. More recently, the development of ⅐ efficient chiral auxiliaries has led to the extensive use of chiral amines in high yields and ee in the (R,R)-BozPHOS Cu catalyzed imines as precursors to ␣-chiral amines by alkylation chemistry addition of diorganozinc reagents (Scheme 3). (5–9) or hydrogenation (10). Experimental Methods Catalytic asymmetric nucleophilic addition reactions of orga- nometallic reagents to imines have been reported with N- General. All nonaqueous reactions were run under an inert tosylimines (11, 12), N-arylimines (13–15), and N-acylimines (16, atmosphere (nitrogen or argon) with rigid exclusion of moisture 17) as amine precursors. The cleavage of the protecting group from reagents and glassware by using standard techniques for leads to the ␣-chiral amine; however, in the former two cases, manipulating air-sensitive compounds. All glassware was stored in the oven and͞or was flame-dried before use under an inert harsh conditions are usually necessary [N-tosyl, SmI2; N-aryl, ϩ atmosphere of gas. Anhydrous solvents were obtained either by ceric ammonium nitrate or PhI(OAc)2; N-formyl, H3O , heat]. Furthermore, the reactions usually require excess of the dior- filtration through drying columns (ether, toluene) on a Glass- ͞ ganozinc reagent, and in a number of cases, the addition of Contour system (Irvine, CA) or by distillation over sodium dimethylzinc is unsuccessful or affords to the amine in much benzophenone (toluene). Analytical TLC was performed on lower yields and enantiomeric excesses (ee). Recently, we re- precoated, glass-backed silica gel (Merck 60 F254). Visualization ported that the copper-catalyzed addition of diorganozinc re- of the developed chromatogram was performed by UV absor- agents to N-phosphinoylarylimines proceeds in high yields and bance, aqueous cerium molybdate, ethanolic phosphomolybdic enantioselectivities in the presence of a catalytic amount of the acid, iodine, or aqueous potassium permanganate. Flash column novel Me-DuPHOS monoxide [(R,R)-BozPHOS] chiral ligand chromatography was performed by using 230–400 mesh silica (Scheme 1) (18, 19). In addition to being readily available, this [EM Science or Silicycle (Quebec City, QC, Canada)] of the hemilabile bidentate ligand offers superb catalytic activity, indicated solvent system according to standard technique. Melt- broad substrate generality, and mild reaction conditions. Fur- ing points were obtained on a Buchi (Flawil, Switzerland) thermore, the increase in imine electrophilicity imparted by the melting-point apparatus and are uncorrected. NMR spectra (1H, N-phosphinoyl protecting group, combined with its ease of 13C, 31P) were recorded on Bruker AV 300, AMX 300, AV 400, cleavage under mildly acidic conditions, makes this method very or ARX 400 spectrometers. Chemical shifts for 1H NMR spectra attractive to prepare ␣-chiral amines. are recorded in ppm with the solvent resonance as the internal The one major limitation of this methodology is our inability standard (chloroform, ␦ 7.27 ppm, or DMSO, ␦ 2.50 ppm). Data to prepare alkylaldehyde-derived N-phosphinoylimines bearing are reported as follows: chemical shift, multiplicity (s, singlet; ␣-enolizable protons in reasonable yields. This has been a d, doublet; t, triplet; q, quartet; qn, quintet; sept, septuplet; limitation not only in diorganozinc addition chemistry (20–25), but also in catalytic asymmetric nitro-Mannich (26), Mannich (27), and Strecker (28) processes that use similar electrophilic This paper was submitted directly (Track II) to the PNAS office. precursors. This inherent limitation is also present in the prep- Abbreviation: ee, enantiomeric excess. aration of N-acylimines, and several strategies have been devel- *To whom correspondence should be addressed. E-mail: [email protected]. oped to circumvent this problem. The in situ generation of © 2004 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0307096101 PNAS ͉ April 13, 2004 ͉ vol. 101 ͉ no. 15 ͉ 5405–5410 Downloaded by guest on September 29, 2021 Scheme 3. 1 h at room temperature, diethylzinc (205 l, 2.0 mmol, 2.5 eq) was added, and the resulting dark-brown suspension was stirred for 20 min and cooled to the desired temperature. A cold suspension of sulfinyl adduct (0.80 mmol, 1.0 eq) in toluene (3 ml ϩ 2 ml to rinse ϩ 1 ml to rinse) was transferred (Teflon cannula; o.d., 1͞8th of an inch; i.d., 1͞16th of an inch) to the catalyst solution. After stirring, the reaction was quenched with saturated aqueous NH4Cl and the aqueous layer was extracted ϫ with CH2Cl2 (3 40 ml). The combined organic layers were dried over Na2SO4. Concentration and purification by silica gel column chromatography (100% EtOAc) gave the pure protected amine. Scheme 1. p-Toluenesulfinic Acid. p-Toluenesulfinic acid was formed by dis- solving its hydrated sodium salt in a minimum of hot 10% vol͞vol m, multiplet; br, broad), coupling constant in Hz, and integra- HCl (the resulting pH must be lower than 3) and crystallization tion. Chemical shifts for 13C NMR spectra are recorded in ppm at 4°C. Further filtration and drying under vacuum led to white from tetramethylsilane by using the central peak of deutero- crystals. chloroform (77.00 ppm) or deuterated DMSO (39.52 ppm) as the internal standard. All spectra were obtained with complete General Procedure for the Synthesis of Sulfinyl Adducts. To a sus- proton decoupling. Optical rotations were determined with a pension of P,P-diphenylphosphinic amide (1.00 g, 4.6 mmol, 1 Perkin–Elmer 341 polarimeter at 589 or 546 nm. Data are eq) and sulfinic acid (1.08 g, 6.9 mmol, 1.5 eq) in anhydrous ␣ temp ͞ reported as follows: [ ] , concentration (c in g 100 ml), and diethylether (40 ml, ACS grade) was added the freshly distilled solvent. High-resolution mass spectra were performed by the aldehyde (6.9 mmol, 1.5 eq) at room temperature. The mixture Centre re´gional de spectroscopie de masse of the University of was stirred for 15 h, during which a white precipitate was slowly Montreal. Combustion analyses were performed by the Elemen- formed. On completion of the reaction, the solution was filtered, tal Analysis laboratory of the University of Montreal. and the white solid was washed with anhydrous diethylether (15 Analytical HPLC was performed on a Hewlett–Packard an- ml, ACS grade) and dried under vacuum. alytical instrument (model 1100) equipped with a diode array UV detector. Data for determination of the enantiomeric excess N-[(4-methylphenyl)sulfonyl](phenyl)methyl]-P,P-diphenylphosphinic is reported as follows: column type, eluent, flow rate, and amide (3). The general procedure was followed. The crude retention time (tr). compound (71% yield) was used without purification for the next step: (white powder) mp 122–124°C (dec.) HRMS (FAB) m͞z Reagents. ϩ Cu(OTf)2 was purchased from Strem Chemicals (New- calc. for C H NO PS [M ϩH] : 462.1293 found: 462.1305. buryport, MA). All starting materials were purchased from 26 25 3 Aldrich or Alfa Aesar (Ward Hill, MA). Unless otherwise stated, P,P-diphenyl-N-[(1S)-1-phenylpropyl]phosphinic amide. The product commercial reagents were used without purification. Diethyl- 2 was obtained following the general procedure (specific con- zinc was purchased neat from Akzo Nobel and used without ditions: 0°C for 24 h). Yield: 87%. The ee (97%) was determined purification. by HPLC analysis [Chiralpak AD, 80:20 hexanes:i-PrOH, 1.0 Racemic samples for HPLC analysis were prepared by ml͞min: (R)-2 t ϭ 9.6 min, (S)-2 t ϭ 13.0 min]. The S addition of Et Zn͞CuCN in toluene to the sulfinyl adducts.