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Halocyclization of alkenes is commonly employed to increase molecular complexity during organic synthesis because it enables double installation of heteroatoms on a carbon–carbon double bond. Moreover, stereodefined halogenated compounds are widely found among naturally occurring compounds and can serve as versatile chiral building blocks. Therefore, the development of asymmetric halocyclization reactions is of great interest and, in recent years, there has been remarkable progress in catalytic asymmetric halogenation reactions. This account summarizes recent progress made by our group on phosphorus-­catalyzed enantioselective bromocyclization of allylic amides. Building on a comprehensive study of the reaction mechanism, we discovered an intriguing catalytic reaction in which P+Br species serves as a fine-tuning element for substrate fixation. We also describe the application of this bromocyclization to asymmetric desymmetrization of 1,4-diene substrates and a concise synthesis of the HIV-protease inhibitor ­nelfinavir using the newly developed desymmetrization reaction as a key step.1 Introduction2 Enantioselective Bromocyclization of Allylic Amides with a BINAP Catalyst2.1 Bromocyclization with a P/P Catalyst2.2 Bromocyclization with a P/P=O Catalyst3 Desymmetrization of Bisallylic Amides through Enantioselective Bromocyclization3.1 Desymmetrization of Bisallylic Amides3.2 Enantioselective Synthesis of Nelfinavir4 Summary

The combined systems of phenylglycinate/­BINAP/Ru(II) complex and Li compounds have been found to act as highly reactive and enantioselective catalysts for cyanosilylation and hydrocyanation of aldehydes, α-keto esters, α,β-unsaturated ketones, and N-protected aldimines. In this account, we describe the concept of catalyst design, the catalytic efficiency of the novel combined systems in the asymmetric cyanation, and the proposed reaction pathway based on the spectral analysis data. 1 Introduction 2 Cyanosilylation of Aldehydes and Ketones Catalyzed by LiCl 3 Asymmetric Cyanosilylation of Aldehydes and α-Keto ­Esters 3.1 Design of Chiral Ru–Li Combined Catalyst Systems 3.2 Cyanosilylation of Aldehydes 3.3 Cyanosilylation of α-Keto Esters 4 Asymmetric Hydrocyanation of Aldehydes, α,β-Unsaturated Ketones, and Aldimines 4.1 Hydrocyanation of Aldehydes 4.2 Conjugate Cyanation of α,β-Unsaturated Ketones 4.3 Strecker-Type Reaction 5 Mechanistic Considerations for Cyanosilylation of Aldehydes and Ketones 5.1 Achiral Reaction Catalyzed by LiCl 5.2 Asymmetric Reaction with the Chiral Ru–Li Combined Catalyst 6 Conclusion

Glycine-derived azlactones react with maleimides using (S)- or (R)-dimeric BinapAuTFA complexes affording the corresponding cycloadducts in good yields and high enantioselections (up to 99% ee). The intermediate carboxylic acids are treated with trimethylsilyldiazomethane and isolated as Δ¹-pyrroline methyl esters. These cycloadducts are transformed into exo-proline derivatives by reduction with NaBH3CN in acidic media. On the other hand, N-benzoylalanine-derived oxazolone reacts with tert-butyl acrylate providing the cycloadduct with the ester group at the 3-position with a trans-relative configuration with respect to the methyl ester group. This work has been supported by the Spanish Ministerio de Ciencia e Innovación (MICINN) [Consolider INGENIO 2010 CSD2007-00006, CTQ2007-62771/BQU, CTQ2010-20387, FEDER, Generalitat Valenciana (PROMETEO/2009/039)], and by the University of Alicante. M.M.-R. also thanks MICINN for a grant.

Hydroformylation is a powerful reaction that has suffered for some negative prejudices related to the use of gaseous H 2 and CO. Now it is possible to carry out hydroformylation and different cyclohydrocarbonylations, even on complex substrates, using aqueous formalin as H 2 and CO surrogate in few minutes under microwave irradiation. The catalytic system developed by Morimoto (Rh/BINAP for decomposition of formaldehyde and Rh/Xantphos for hydroformylation) is compatible with microwave dielectric heating and with complex substrates containing ligand atoms allowing rapid domino hydroformylation cyclization reactions without using the external supply of gaseous H 2 and CO (gas cylinder) and without any particular safety limitation or device.

The selective C-N cross-coupling of 2-fluoro-4-iodopyridine with aromatic amines is reported. In contrast to conventional substitutions where C-N bond formation takes place at the 2-position (e.g., 2,4-dichloropyridine), the Buchwald-Hartwig cross-coupling was found to be complementary and exclusive for the 4-position. Reactions were carried out under microwave irradiation typically within 30 minutes. These conditions also allowed a decrease in the amount of base required to 3.5 equivalents compared to 20 equivalents in established protocols. Additionally, use of potassium carbonate as a mild base was sufficient, and good yields of the coupling products were obtained in all cases with the simple system Pd(OAc) 2 /BINAP.

A novel class of 3,3'-disubstituted xylBINAP ligands have been synthesized and tested in the hydrogenations of substituted olefins. This new substitution pattern has demonstrated that the 3,5-dialkyl meta effect and 3,3'-disubstitution can operate in a synergistic fashion in Rh-catalyzed hydrogenation of dehydroamino acids. Notably, (S ax )-8 outperforms BINAP, xylBINAP and previously reported 3,3'-disubstituted BINAP derivatives in the hydrogenation of methyl N-acetamido cinnamate.

Rhodium-catalyzed asymmetric 1,4-additions of electron-deficient heteroaryl groups to α,β-unsaturated carbonyl compounds were established. The reaction resulted in very low yields due to competitive C-B bond cleavage when arylboronic acids, their pinacol esters, or potassium trifluoroborates were used. However, the corresponding lithium heteroaryl(triol)borates afforded 1,4-adducts with high enantioselectivities up to 97% in the presence of a rhodium(I) catalyst chelated with a chiral BINAP or BIPAM ligand.

2-Aminophenols underwent the Ugi four-component reaction (U-4CR) with trans-cinnamic acids, aromatic aldehydes and isocyanides in MeOH (50 °C, 48 h) to give the linear α-[N-(2-hydroxyphenyl)-substituted amido] carboxamides in 54-80% yields. Treatment of the 2-hydroxyphenyl moiety in the U-4CR products with NaH and PhNTf 2 afforded the corresponding aryl triflates (77-100%), which were subjected to the intramolecular Heck reaction (IMHR) catalyzed by 3-5 mol% Pd(OAc) 2 -BINAP (MeCN, 180 °C, 30-60 min) under microwave heating to furnish α-(3-arylidene-2-oxindol-1-yl) carboxamides in 52-77% yields.

A method for the Buchwald-Hartwig mono-N-arylation ofaniline with methyl 2,6-dichloroisonicotinate using Pd(OAc) 2 , XPhos,and T-BuONa is reported. Use of M-anisidine under the same conditionsresulted in the amidation of the methyl ester. Mono-N-arylationof M-anisidine with 2,6-dichloro- N, N-diisopropylisonicotinamideand 2,6-dibromo- N, N-diisopropylisonicotinamide,however, was successfully achieved using Pd(OAc) 2 /XPhos/ T-BuONa or Pd(OAc) 2 /(±)-BINAP/K 2 CO 3 ,respectively. The present study demonstrates the sensitivity ofthis cross-coupling method to both the steric and electronic natureof the coupling partners.

A cationic rhodium(I)-H8-BINAP complex catalyzes a [2+2+2] cycloaddn. of 1,6- and 1,7-diynes with acyl phosphonates in high yields with high regioselectivity. Interestingly, the reactivity of ﾎｱ,ﾏ�diynes toward acyl phosphonates is highly dependent on their own structures. [on SciFinder(R)]

Our research group was the first to discover that cationic rhodium(I)/BINAP-type bisphosphine complexes are versatile new catalysts for highly chemo-, regio-, and enantioselective [2+2+2] cycloadditions. The high chemo- and regioselectivity of these -cycloadditions enabled efficient catalytic synthesis of substituted benzenes, cyclophanes, and nitrogen heterocycles. Furthermore, enantioselective variants of these cycloadditions were also developed that realized efficient catalytic constructions of axial, planar, central, and spiro chirality. 1Introduction 2 Chemo- and Regioselective [2+2+2] Cycloadditions 2.1 [2+2+2] Cycloaddition of Terminal Alkynes 2.2 [2+2+2] Cycloaddition of Two Different Alkynes 2.3 [2+2+2] Cycloaddition of α,ω-Diynes with Alkynes 2.4 [2+2+2] Cycloaddition of Alkynes with Isocyanates, Isothiocyanates, and Carbon Disulfide 2.5 [2+2+2] Cycloaddition of Alkynes with Nitriles 3 Enantioselective [2+2+2] Cycloadditions 3.1 Construction of Axial Chirality 3.2 Construction of Planar Chirality 3.3 Construction of Central Chirality 3.4 Construction of Spiro Chirality 4 Summary

A cationic rhodium(I)/( S)-Tol-BINAP complex was employed to catalyze an enantioselective intramolecular [2+2+2] cycloaddition of a TRANS enediyne leading to a C 2 -symmetric tricyclic dimethyl cyclohexadienedicarboxylate in 95% yield with 59% ee. A cationic rhodium(I)/( R)-H 8 -BINAP complex was employed to catalyze an intermolecular [2+2+2] cycloaddition of 1,6-diynes with dimethyl fumarate leading to C 2 -symmetric bicyclic dimethyl -cyclohexadienedicarboxylates in 35-96% yields with ee values of 82-98%.

β-Chloroacroleins reacted readily with lactams and several heteroarylamines (aminopyridines, aminoquinoline and azoles) under standard Buchwald-Hartwig amination conditions. Both Pd(OAc) 2 /Binap or Pd(OAc) 2 /Xantphos were efficient catalytic systems in the presence of Cs 2 CO 3 as base.

The conjugate addition of carbon nucleophiles to acceptor activated olefins is one of the most important reactions for carbon-carbon bond formation. With optically active metal complexes this transformation can be catalyzed enantioselectively. This review is a collection of the newer literature (since 2001) on this topic. The metal salts and complexes applied are in a broad range, starting from solely Lewis acidic M(II) and M(III) compounds, such as magnesium, zinc, boron, aluminum and the lanthanoids. Transition-metal catalysts suitable for asymmetric conjugate additions are compounds of ruthenium, iridium, nickel, and palladium. The most flourishing fields are, however, the catalysis with rhodium and copper complexes. Rhodium catalysts often have a chiral diphosphane like BINAP, or an optically active olefin as the ligand, the latter being a newer development. The privileged ligand structures for copper catalysts are monodentate phosphoramidites with axially chiral BINOL or other biphenol units.

A series of 3,3'-disubstituted BINAP ligands are used in asymmetric inter- and intramolecular Heck/Mizoroki reactions and their enantioselectivity compared to BINAP.

Asymmetric hydrogenation of 2-arylcycloalkanones with trans-RuCl2(binap)(1,2-diamine) and t-C 4 H 9 OK in 2-propanol selectively gives the corresponding cis-2-arylcycloalkanols in excellent enantiomeric purity and high yield. Two synthetic intermediates of biologically active compounds have been prepared by this method.

The first rhodium-BINAP complex-catalyzed enantioselective Pauson-Khand reaction in aqueous media, which is accelerated by surfactant, is reported. The chiral rhodium catalyst is easily prepared in situ from I equivalent of [Rh(cod)Cl] 2 and 2 equivalents of BINAP under I atm of CO and a temperature of 60 °C or 90 °C. Ee's up to 96% were achieved for the intramolecular Pauson-Khand reaction, but the yields are highly dependent upon the substrate itself.

Rh-catalyzed C-C bond asymmetric formation under basic conditions in organoaqueous or alcoholic solvents has been described using the atropoisomeric water-soluble ligand (R)-DigmBINAP. The addition of phenylboronic acid to cyclohexenone has been efficiently optimized leading to quantitative yield and enantiomeric excesses up to 98% using 1-3 mol% catalyst. Easy product-catalyst separation has been found using ethylene glycol as the reaction solvent. Other α,β-unsaturated ketones and boronic acids could be engaged in the 1,4-addition. The mole fraction of the catalyst could be decreased to 0.005% with still acceptable ee. A TON of 13200 was obtained.

Asymmetric 1,4-arylation and -alkenylation was achieved by use of organoboronic acids or their derivatives in the presence of a rhodium catalyst coordinated with binap ligand. The reaction conditions are unique in that it is usually carried out in an aqueous solvent at 100 °C. The scope of this asymmetric addition is very broad, , -unsaturated ketones, esters, 1-alkenylphosphonates, and 1-nitroalkenes being efficiently converted into the correspond- ing optically active 1,4-addition products with over 95% enantiose- lectivity. The catalytic cycle is proposed to involve the enantioselective addition of aryl- or alkenyl-rhodium intermediate to carbon-carbon double bond of the electron deficient olefins as a key step.

Our attention was drawn to the phenothiazine backbone of the promazines as a suitable model system for the controlled construction of three carbon-heteroatom bonds in a oneflask operation. This would require that either C-S or C-N bond formation would occur preferentially followed by cyclization to the core structure. As outlined retrosynthecally above, this translates the promazines back to 2-bromothiophenol, 3-(dimethylamino)propyl amine, and an appropriately substituted 2-bromo-iodobenzene. From in-house experience and literature reports with reactions involving palladium ligated by DPPF, BINAP, DPEphos, and Xantphos, it was expected that the C-S bond formation would precede the aryl amination reaction.

Iron (III) chloride hexahydraae without solvent induce coupling of naphthols were quickly and efficiently under focused microwave irradiation. Coupling of naphthols bearing an electronwithdrawing group which are very slow under classical conditions became possible under these conditions. We are interesaed by the synthesis of substituted binaphthols because the C2 symmetric 11'-bi-2-naphthol (BINOL) I and the 2'-bis (diarylphosphino)-1,1'-binaphthyl (BINAP) 2 ligands have emerged as important chiral auxiliaries and ligands in organic synthesis. For these synthesis of binaphthols, oxidative coupling seems to be a method of choice. Oxidative coupling of phenols has long been recognized as being importânt in biosynthetic pathway and in biomimetic synthesis 3. Various oxidants can bring about the coupling of phenols in solution 4 but the oxidative coupling of phenols ofaen leads to low yields of the desired products or suffer from disadvantages due to oxidant or phenol insolubility, or to difficulties in separating inorganic and organic products. Recently Toda et al5 have described the possibility of oxidative phenol coupling without solvent (dry conditions). But the reaction in solution is slow with naphthol and does not take place when an electron withdrawing group is present on the naphthol. Ultrasound irradiation was not very efficient to accelerate'these r actions. 5 and also the thermal activation is inefficienr The yields obtained under conventional heating and under iradiation with a commercial microwave oven or in resonance cavity were compared in table l. With a commercial microwave oven results are difficult to reproduce when the reactions are conducted with small samples, but the results are reproducible with larger quantitiesg [Eg: (1a) 0.138 mol., 280W, 420s1. Table 1. Coupling of naphthols (1) into binaphthols (2) (conditions, yield) naphthola heatingb microwavesc microwavesd l a l b l c 1 d l e l f 70oC.lh,42% 280W, 30s,55Vo 40W, 30s, 96% 280'W, 20s,76% 40W,20s,95% 280W, 100q34% 40W, lfi)s, 857o 70"C, Lh,>37o 140W, 140g3% 40W, 140s, 40% 70oC, lh,SVo 140W, 140s, lUVo 40W, 140s, 62% 140rW, 140s,347o 40W, 140s, 84% a) Coupling of (1) (7 mmol.); b) heating with a oil bath; c) irradiation with a commercial microwave oven Toshiba ER 8930FC; d) irradiation in a resonance cavity 7. Several mechanistic pathways which involve oxidation of the naphthol to naphthoxy radical and dimerization are generally proposed. Because of rapid reaction, the variety of functional groups toleraaed and the good yield observed, in this procedure provides a very useful synthetic method to binaphthol. Under the similar conditions p-cresol gave a mixture of 6 products containing 2,2'-dihydroxy-5,5'-dimethylbiphenyl (52Vo) and traces of Pummerer's ketone (4Vo). The 2,6-disubstitued phenols (3a-c) gave diphenoquinones (4a-c) according the Scheme 2. 2a+ b)R1=OH; RaeH d) R1=H; R5PO(OC2H5)2 f)R1=H;R5COOCH3 R / A FeCl3,6 H2O ' \ / F o " : U( rnrcrowaves, \ 140w,120s 3a-c R We have already reported that a great number of dry reactions are activaaed by microwanes 6. We now report that microwave inadiation 7 accelerated greatly the oxidation of naphthol (la-f) with iron (IIf chloride hexahydraae without solvent. Under these conditions coupling of naphthol with an electron withdrawing group (ld-f) ( COOH, COOCH3, PO(OR)) takes place. In control experiments, no reaction is observed afaer 24 h with (ld-f) at room temperature without microwave a, R=GH3 (95%);b, R=l-Bu (92%l; c, R=Cl(85%)