Asymmetric Organocatalysis

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Vol. 6 No. 4

Synthetic Methods Asymmetric Organocatalysis

Proline Analogs

MacMillan Imidazolidinone OrganoCatalysts™

Cinchona Alkaloids

TADDOLs

Schaus MBH Catalyst

Rovis Triazolium Catalyst

MacMillan Imidazolidinone OrganoCatalysts™

sigma-aldrich.com Introduction sigma-aldrich.com enantioenriched a enantioselective organocatalytic noteworthy,direct Particularly first reactions. the Michael alkylations, Friedel–Crafts cycloadditions, 1,3-dipolar as such transformations organocatalytic numerous in employed successfully were compounds These OrganoCatalysts Imidazolidinone MacMillan chiral the of one depicts illustration cover The Cover Our About at further.Us“ even Bother range “Please product our broaden to it use will and input your welcome we organocatalyst, an find cannot visit Please organocatalysts. of preferredsupplier your being to committed are we Sigma‑Aldrich, At portfolio. organocatalysis our to additions new exciting as well as organocatalysis of edition This conditions. “open-flask” under out carried often affordable.areAdditionally,reactions and robust,organocatalytic chemically the synthesize, to easy weight, molecular low of are catalysts applied The immense. is described manner the in organocatalysis of potential commercial The proving.are area emerging this in researchefforts intense transformations—as efficient and selective remarkably achieve also can However,molecules biocatalysis. organic enzyme-aided small to or reactions mediated community. researchchemical the in attention much gained recently has organocatalysis of field The Introduction -fluorination of aldehydes has been accomplished to afford a broad spectrum of highly of spectrum broad afforda to accomplished been has aldehydes of -fluorination Chemistry Seminars Chemistry Sigma-Aldrich’sWeb-Based New sigma-aldrich.com/organocatalysi • • • • Cheminars Highly interactive Highly navigation Convenient browser desktop your via directly Access products and technologies synthesis chemical innovative latest the Featuring seminar series, please visit please series, seminar ToSigma-Aldrich’schemistry Web-basedout new check 1 For most chemists, the term catalysis was commonly equated to transition metal- transition to equated commonly was catalysis term the chemists, most For ChemFiles a -fluoro aldehydes, which are valuable synthons for medicinal agent synthesis. agent medicinal for synthons valuable are which aldehydes, -fluoro ™ describes applications of our existing products in the field of field the in products existing our of applications describes s for a comprehensive listing of products. If you If products. of listing comprehensive a for [email protected] sigma-aldrich.com/cheminar a -chlorinations, and intramolecular and -chlorinations, m with your suggestions! your with s

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Proline Analogs H3C O H3C O Coined by Jacobsen2 as the “simplest enzyme,” L-proline is capable O of effecting a variety of catalytic asymmetric transformations. The OH O first examples were reported in the mid-70s, when L-proline was Wieland-Miescher Ketone applied to Robinson annulation reactions.3 However, the big potential 100%, 93% ee 83%, 71% ee of proline as an organocatalyst was discovered in the beginning of OH the 21st century. One explanation for such a delay might be that O O 3 1 R2 the scope of highly selective transformations was considered to be R R R1 2 H rather narrow, and the development of metal catalysts seemed more Product R O Substrate N promising. H OH L-Proline The bifunctional structure of the sole cyclic proteinogenic amino H acid is a crucial factor. L-proline contains both a nucleophilic O H O N N secondary amino group and a carboxylic acid moiety functioning R2 O OH R1 H as a Brønsted acid. This facilitates a highly pre-organized transition R1

3 2 Analogs Proline state during the reaction pathway, which results in exceptionally high R OH Iminium ion R adduct enantioselectivities (Scheme 1).4 Iminium intermediate Moreover, as a small organic molecule, proline is available in both enantiomeric forms, which is a definite advantage over enzymatic H H O methods. Numerous proline-catalyzed reactions have been developed H O H N (Scheme 2).5 O N H OH O H R1 R1 Stimulated by such a vast number of successful examples, many 3 R H R2 R2 Enamine intermediate research groups have developed synthetic proline analogs with O List−Houk optimized properties (see: ChemFiles Vol. 5 No. 12, Tools for Drug 3 transition state R H Discovery). Some examples will be presented here in more detail. Electrophile Scheme 1 The catalytic asymmetric α-alkylation of aldehydes was recently described by List.6 To date, this transformation was usually O OH CH3 accomplished with the help of covalently attached auxiliaries. In H CH3 comparison to L-proline, α-methyl-L-proline (17249) gives higher CH3 enantioselectivities and improved reaction rates (Scheme 3). Intermolecular cross-aldol reaction up to 97% ee Organocatalytic cyclopropanation reactions were typically performed O OH 7 O NHAr using catalyst-bound ylides. However, MacMillan demonstrated H that activation of olefin substrates using catalytic (S)-(–)-indoline-2- H3C OBn OBn OH NO2 carboxylic acid (346802) is a viable route for the formation of highly a-oxyaldehyde 8 dimerization H Mannich reaction enantioenriched cyclopropanes (Scheme 4). O up to 98% ee up to >99% ee N 7 2 3 8 . 1 3 2 . 0 0 8 . 1 : e c i v r e S l a c i n h c e T 0 1 0 3 . 5 2 3 . 0 0 8 . 1 : r e d r O Aggarwal utilized protonated (S)-(–)-2-(diphenylmethyl)pyrrolidine H OH (552534) as an organocatalyst in a novel process for the enantio L-Proline O CO2Bn 9 selective epoxidation of alkenes. Although the reaction proceeds O Ph N CO2Bn H H N under phase-transfer conditions (PTC), it was found that secondary NO2 H amines catalyzed the reaction at remarkably higher rates, implying that 552534 does not act only as a PTC. However, best results were intermolecular O Michael reaction O a-amination obtained with the chiral pyrrolidine bearing 1-naphthyl substituents 23% ee NHPh up to 96% ee (Scheme 5). R1 R2 a-aminooxylation up to >99% ee L-Proline, ReagentPlus™, ;99% Scheme 2

C5H9NO2 CH3 MW: 115.13 CO H N 2 CO2H H N [α] –84.7° ± 1°, c = 4 in water OHC I H OHC 10 mol % [147-85-3] Et N, CHCl EtO2C 3 3 EtO2C P0380-10MG 10 mg 12.00 EtO2C −30 °C, 24 h EtO2C 92%, 95% ee P0380-100G 100 g 52.00 Scheme 3 P0380-1KG 1 kg 356.50 P0380-5KG 5 kg 1,533.60

CO2H O CH3 O O N Pr L-Proline, BioChemika, ;99.0% NT H Ph S + H3C Ph Pr H C5H9NO2 CHCl3, rt CHO MW: 115.13 N CO2H 6 H 78%, 94% ee, 27:1 dr [α] –84.5° ± 1°, c = 5% in water Scheme 4 [147-85-3]

81710-10G 10 g 10.60 Ph 81710-50G 50 g 35.10 N Cl H2 Ph 81710-250G 250 g 118.00 10 mol % 2 eq. Oxone Ph Ph 10 eq. NaHCO3 0.5 eq. pyridine O MeCN:H2O = 95:5 46% ee Scheme 5

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D-Proline, ;99% L-Pipecolic acid, puriss., ;99.0% NT

C5H9NO2 C6H11NO2 MW: 115.13 N CO2H MW: 129.16 OH H N H [α] +85.0°, c = 4 in water [α]6 –26° ± 1°, c = 4% in water O [344-25-2] [3105-95-1] 858919-500MG 500 mg 25.80 80615-100MG 100 mg 62.20 858919-5G 5 g 104.50 80615-500MG 500 mg 264.50

D-Proline, puriss., ;99.0% NT D-Pipecolic acid, purum, ;99.0% NT

C5H9NO2 C6H11NO2 MW: 115.13 N CO2H MW: 129.16 OH H N H [α]6 +85° ± 2°, c = 5% in water [α]6 +27° ± 1°, c = 1% in water O [344-25-2] [1723-00-8] 81705-1G 1 g 45.80 80617-100MG 100 mg 86.20 81705-5G 5 g 108.50 80617-500MG 500 mg 366.50 81705-25G 25 g 501.90 (S)-(–)-2-(Diphenylmethyl)pyrrolidine, 97% -Methyl-L-proline, purum, ;98.0% TLC a C17H19N C H NO 6 11 2 CH MW: 237.34 MW: 129.16 3 N N CO2H [α] –3.0°, c = 1% in chloroform H [α] –75° ± 2°, c = 1% in methanol H [119237-64-8] [42856-71-3] 17249-250MG 250 mg 115.00 552534-500MG 500 mg 98.70 17249-1G 1 g 321.50

Proline Proline Analogs (R)-(+)-2-(Diphenylmethyl)pyrrolidine, 97% (S)-(–)-Indoline 2-carboxylic acid, 99% C17H19N C9H9NO2 MW: 237.34 CO2H N MW: 163.17 N [α]6 +3.0°, c = 1% in chloroform H [α]6 –114° c = 1 in 1N HCl H [22348-31-8] [79815-20-6] 346802-1G 1 g 22.20 552542-1G 1 g 91.60 346802-5G 5 g 83.40 a,a-Diphenyl-L-prolinol, purum, ;99.0% HPLC (R)-(+)-Indoline 2-carboxylic acid 8 sum of enantiomers C9H9NO2 C17H19NO CO2H MW: 163.17 N MW: 253.34 H [α]6 +114° c = 1 in 1N HCl 6 [α] –69° ± 2°, c = 3% in chloroform N [98167-06-7] [112068-01-6] H OH 51266-500MG 500 mg 58.90 43182-1G 1 g 62.10 43182-5G 5 g 245.50 3,4-Dehydro-L-proline, BioChemika, ;99.0% TLC C5H7NO2 a,a-Diphenyl-D-prolinol, purum, ;99.0% HPLC MW: 113.11 N CO2H sum of enantiomers [α]6 –400° ± 10° c = 0.2% in water H C17H19NO [4043-88-3] MW: 253.34

30890-10MG 10 mg 38.10 [α]6 +69° ± 3°, c = 3% in chloroform N 30890-50MG 50 mg 127.10 [22348-32-9] H OH 43179-100MG 100 mg 54.70 L-4-Thiazolidinecarboxylic acid, purum, ;99.0% T 43179-500MG 500 mg 112.00 C4H7NO2S OH MW: 133.17 O NH (S)-(–)-a,a-Diphenyl-2-pyrrolidinemethanol, 99% [α]6 –101° ± 2° , c = 1% in 1 M HCl S C17H19NO [34592-47-7] MW: 253.34 88400-10G 10 g 16.20 [α]6 –67°, c = 3 in chloroform N 88400-50G 50 g 54.00 [112068-01-6] H OH 368199-1G 1 g 56.20 L-Azetidine-2-carboxylic acid, purum, ;98.0% NT 368199-5G 5 g 175.50 C4H7NO2 O MW: 101.10 N OH (R)-(+)-a,a-Diphenyl-2-pyrrolidinemethanol, 98% [α]6 –123° ± 2°, c = 4% in water H C17H19NO [2133-34-8] MW: 253.34 11542-500MG 500 mg 95.40 [α]6 +69°, c = 3% in chloroform N 11542-2.5G 2.5 g 368.00 [22348-32-9] H OH 382337-100MG 100 mg 56.30 382337-1G 1 g 125.00 382337-5G 5 g 405.00

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(S)-(–)-a,a-Di(2-naphthyl)-2-pyrrolidinemethanol, 99% (S)-(+)-2-(Methoxymethyl)pyrrolidine, purum,

C25H23NO ;98.0% GC sum of enantiomers

MW: 353.46 C6H13NO [α]6 –101°, c = 0.7 in methanol MW: 115.17 N H [127986-84-9] [ ]6 +2.4° ± 0.3°, c = 2% in benzene OCH3 N α H OH [63126-47-6] 445398-250MG 250 mg 42.20 65090-1ML 1 mL 92.00 445398-1G 1 g 124.00 65090-5ML 5 mL 307.90

(S)-(+)-1-(2-Pyrrolidinylmethyl)pyrrolidine, 96% (S)-(+)-2-(Methoxymethyl)pyrrolidine, 99%

C9H18N2 C6H13NO MW: 154.25 MW: 115.17 N N H [α]6 +7.0°, c = 2.4 in ethanol N [α]6 +2.4°, c = 2 in benzene OCH3 H [51207-66-0] [63126-47-6] 324450-250MG 250 mg 30.20 277053-100MG 100 mg 14.70 324450-1G 1 g 83.70 277053-500MG 500 mg 48.80 OrganoCatalyst s Imidazolidinone MacMillan 277053-5G 5 g 322.50

(R)-(–)-2-(Methoxymethyl)pyrrolidine, purum, ;98.0% GC sum of enantiomers

C6H13NO MW: 115.17 N H OCH [α]6 –2.4° ± 0.3°, c = 2% in benzene 3 [84025-81-0] 65089-1ML 1 mL 105.50 ™

MacMillan Imidazolidinone

™ CH3 OrganoCatalysts O N CH3 Developed by Professor David MacMillan at Caltech, imidazolidinone- Ph N CH3 H2 based organocatalysts are designed to serve as general catalysts X 5 mol % Ph for a myriad of asymmetric transformations. The first highly + Ph O MeOH/H2O, rt CHO enantioselective organocatalytic Diels–Alder reaction using a chiral 99%, 93% ee, 1:1.3 dr organocatalyst (569763) was reported in his pioneering work in Scheme 6 2000 (Scheme 6).10 The activated iminium ion, formed through 7 2 3 8 . 1 3 2 . 0 0 8 . 1 : e c i v r e S l a c i n h c e T 0 1 0 3 . 5 2 3 . 0 0 8 . 1 : r e d r O condensation of the imidazolidinone and an α,β-unsaturated aldehyde, reacted with various dienes to give [4+2] cycloadducts in excellent yields and enantioselectivities. Ph CHO Other organocatalytic transformations such as 1,3-dipolar 93% ee 11 12 13 O R1 cycloadditions, Friedel–Crafts alkylations, α-chlorinations, Diels-Alder N O 14 15 OHC Ph cycloaddition α-fluorinations, and intramolecular Michael reactions using Ph R2 H MacMillan’s organocatalyst technology (569763) were reported, all CHO proceeding with impressive levels of enantioselectivity (Scheme 7). 97% ee >90% ee 1,3-dipolar intramolecular CH Michael addition 3 cycloaddition Having established iminium and enamine catalysis using O N CH3 organocatalyst 569763, MacMillan found an optimized structure in Ph N CH3 H2 organocatalyst 663107 for the Friedel–Crafts alkylation of indoles a-fluorination X Friedel-Crafts alkylation (Scheme 8),16 which are known to be privileged structures in R1 drug discovery. See ChemFiles Vol. 4 No. 8, Indoles (US) or Vol. 4 R HO a-chlorination Supplement II (Europe). F N CHO R R2 MacMillan later demonstrated the synthetic utility of this concept in 91-99% ee >89% ee the total synthesis of (–)-flustramine B, a biologically active alkaloid O R bearing a pyrroloindoline architecture. The fused ring system was H cleanly assembled with the aid of imidazolidinone organocatalyst Cl 91-95% ee Scheme 7 663107 (Scheme 9).17 Imitating nature’s stereoselective enzymatic transfer hydrogenation with NADH cofactor, MacMillan’s variant used the combination of CH3 O N CH3 organocatalyst 661902 and Hantzsch ester 127220 to reduce simple CH3 Ph α,β-unsaturated aldehydes in a highly enantioselective manner N CH3 H2 R2 18 1 X O (Table 1). R 1 O 20 mol % R + H In sharp contrast to metal-mediated hydrogenations, the E/Z N R2 H R N geometry of the enal substrates did not have a significant influence R on the outcome of the absolute configuration of the newly created 90-97% ee stereocenter. In an elegant organocascade reaction, MacMillan Scheme 8

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showed that both LUMO-lowering iminium- and HOMO-raising enamine catalysis could coexist without deleterious catalyst–catalyst interactions by substrate activation in an orthogonal mode, hence leading to highly enantioenriched products with increased structural CH3 complexity in just one step. Using both organocatalytic transfer O N CH3 CH3 hydrogenation (Hantzsch ester, 120227) and α-halogenation Ph HO BocHN N CH3 methodologies (N-fluorobenzenesulfonimide, 392715), the formal H2 TFA addition of HF to α,β-unsaturated aldehydes could be achieved with O 1. 20 mol %, −10 °C NHBoc N + N Br CH 2. NaBH4, MeOH N H 3 very high levels of enantio- and diastereoselectivity (Scheme 10). H Br Br N H Various examples have been reported.19

(5R)-2,2,3-Trimethyl-5-phenylmethyl-4-imidazolidinone 8 (−)-flustramine B monohydrochloride, 97% C H N O · HCl 13 18 2 O CH3 MW: 254.76 N • HCl CH3 Scheme 9 [α]6 +64°, c = 1 in water N CH3 ™ H [323196-43-6] 663069-500MG 500 mg 30.00 663069-2G 2 g 80.00 CH3 O N CH3 (5S)-2,2,3-Trimethyl-5-phenylmethyl-4-imidazolidinone CH3

MacMillan N CH3 monohydrochloride, 97% H2 O H H O C H N O · HCl TFA 13 18 2 O CH3 H C O O CH 20 mol % O MW: 254.76 N • HCl O + 3 3 CH CHCl3, −30 °C 3 H C N CH H 6 CH3 H 3 3 CH3 Imidazolidinone [α] −64°, c = 1 in water N CH H H 3

OrganoCatalyst s [278173-23-2] 569763-2G 2 g 80.60

(5R)-2,2,3-Trimethyl-5-benzyl-4-imidazolidinone 8 Alkene geometry Yield (%) % ee (abs. config.) dichloroacetic acid, 97% E 91 93 (S)

C15H20Cl2N2O3 O CH3 Z 90 87 (S) MW: 347.24 N CH3 E/Z mix 88 90 (S) [ ]6 +52°±4°, c = 1% in methanol N CH α H 3 O Cl • OH Table 1 Cl 663077-500MG 500 mg 55.00 663077-2G 2 g 150.00

(5S)-2,2,3-Trimethyl-5-benzyl-4-imidazolidinone 8 dichloroacetic acid, 97% catalyst combination A catalyst combination B C15H20Cl2N2O3 O CH3 N CH3 CH3 CH3 CH3 MW: 347.24 O CH O CH3 N 3 N O N CH3 O N CH3 CH N CH3 CH3 3 [α]6 –52°±4°, c = 1% in methanol CH3 H Ph CH3 Ph CH3 N CH3 N N CH3 N O H H H H Cl • OH 7.5 mol % 30 mol % 7.5 mol % 30 mol % (5R)-iminium (2S)-enamine (5R)-iminium (2R)-enamine Cl catalyst catalyst catalyst catalyst 663085-500MG 500 mg 55.00 663085-2G 2 g 150.00

(2R,5R)-(+)-2-tert-Butyl-3-methyl-5-benzyl-4- 8 CH3 O H CH3 O imidazolidinone, 97% catalyst H combination A H

C15H22N2O O CH CHCl3 F 3 + MW: 246.35 N CH THF/i-PrOH 3 81%, 99% ee, 16:1 anti:syn CH [α]6 +72°±4°, c = 1% in chloroform N 3 O O O O H CH3 S S [390766-89-9] N 663093-500MG 500 mg 60.00 F Electrophile 663093-1G 1 g 95.00 + O H H O CH3 O (2S,5S)-(−)-2-tert-Butyl-3-methyl-5-benzyl-4- 8 catalyst H H3C O O CH3 imidazolidinone, 97% combination B H H3C N CH3 CHCl F H 3 C15H22N2O O CH3 THF/i-PrOH N Nucleophile 62%, 99% ee, 9:1 syn:anti MW: 246.35 CH3 CH [α]6 −72°±4°, c = 1% in chloroform N 3 H CH [346440-54-8] 3 663107-500MG 500 mg 60.00 663107-1G 1 g 95.00 Scheme 10

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(R)-2-(tert-Butyl)-3-methyl-4-imidazolidinone 8 Diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate, 95% trifluoroacetate C13H19NO4 O O C H N O F O CH MW: 253.29 10 17 2 3 3 3 H C O O CH N 3 3 MW: 270.25 CH3 [1149-23-1] CH3 H3C N CH3 N H H CH3 O 120227-1G 1 g 42.90 • F3C OH Di-tert-butyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 661910-500MG 500 mg 50.00 97%

661910-2G 2 g 165.00 C17H27NO4 CH O O H3C 3 H3C CH3 MW: 309.4 H3C O O CH3 (S)-2-(tert-Butyl)-3-methyl-4-imidazolidinone 8 [55536-71-5] H3C N CH3 trifluoroacetate H

C10H17N2O3F3 O CH3 659142-1G 1 g 35.00 N MW: 270.25 CH3 CH3 N N-Fluorobenzenesulfonimide, 97% Alkaloids Cinchona H CH3 O C12H10FNO4S2 • O O O O F3C OH MW: 315.34 S S N [113745-75-2] F 661902-500MG 500 mg 50.00 661902-2G 2 g 165.00 392715-1G 1 g 15.60 392715-5G 5 g 51.90

Cinchona Alkaloids H H3C RO OR Desymmetrization H C N 3 N H Abundant in nature, cinchona alkaloids are readily accessible chiral H H amine catalysts that exist in pseudoenantiomeric forms. Indeed, N N OCH H CO some of the very first examples of organocatalyzed reactions were 3 3 3a mediated by O-acetylated quinine. Deng has used modified Dihydroquinidyl (DHQD) Dihydroquinyl (DHQ) cinchona alkaloids as ligands in Sharpless’ asymmetric dihydroxylation 7 2 3 8 . 1 3 2 . 0 0 8 . 1 : e c i v r e S l a c i n h c e T 0 1 0 3 . 5 2 3 . 0 0 8 . 1 : r e d r O catalyst system and in the desymmetrization of anhydrides O N (Scheme 11). R =

A high degree of asymmetric induction using cinchona catalysts can Cl CH3 be achieved in desymmetrization of meso anhydrides to form the corresponding hemiesters (Scheme 12). Biscinchona alkaloids such as 20 Ph (DHQD)2AQN (456713) were more efficient in this transformation. NN O O Other highly enantioselective reactions using cinchona alkaloids NN 20 20 include cyanation of ketones, 1,4-additions of thiols to enones, Ph Scheme 11 dimerizations of methylketene,21 asymmetric Baylis–Hillman reactions,22 synthesis of β-lactams,23 α-halogenations,24 aza-Henry- 25 26 O reactions, and intramolecular aldol reactions. R O R 5-30 mol % catalyst OH Nonracemic planar chiral (arene)Cr(CO)3 complexes are increasingly R' n O R' n MeOH, Et2O important chiral building blocks in highly diastereoselective OCH3 R O −40 to −20 °C, 43-120 h R transformations and they can also serve as ligands in catalytic O 27 reactions. Kündig has shown that chiral diamine 07317 performed O O H O H C well in the asymmetric benzoylation/desymmetrization of a meso OH 3 OH 28 CO2H Cr complex. Enantiomeric excess only marginally decreased (to OCH3 OCH3 CO2CH3 H C H 3 98%) when diamine 39867 was employed in the same reaction O O (Scheme 13). 82%, 98% ee 88%, 96% ee 93%, 98% ee Scheme 12 Hydroquinidine 4-chlorobenzoate, 98% H C27H29ClN2O3 Cl H3C MW: 464.98 H [α] –73°, c = 1 in ethanol CH3 N H H CO [113162-02-0] 3 O OH H2N OH O 10 mol % 1.5 eq. BzCl N 1 eq. Et N, 4 Å MS H 3 (OC)3Cr CH2Cl2, −40 °C, 21 h (OC)3Cr N OH OBz 336483-1G 1 g 26.20 89%, 99% ee Scheme 13 336483-5G 5 g 105.00

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O-(4-Chlorobenzoyl)hydroquinine, 98% (DHQD)2Pyr, 97% H H C27H29ClN2O3 H3C H C56H60N6O4 MW: 464.98 OCH3 MW: 881.11 N N [α] +150°, c = 1 in ethanol H N [α]6 –390°, c = 1.2 in methanol CH3 CH3 O H O O H [113216-88-9] O [149725-81-5] H3CO NN OCH3 N N N Cl 336491-1G 1 g 45.50 418951-250MG 250 mg 35.30 418951-1G 1 g 98.80 Hydroquinidine 4-methyl-2-quinolyl ether, 97%

C30H33N3O2 CH3 (DHQ)2Pyr, 97% MW: 467.60 H C56H60N6O4 CH H C 3  H3C MW: 881.11 3 [α] –168°, c = 1 in ethanol N O N N [135042-89-6] H3CO N [α]6 +455°, c = 1.2 in methanol O O H H H [149820-65-5] H3CO NN OCH3 N N 381942-1G 1 g 39.70

Hydroquinine 4-methyl-2-quinolyl ether, 98% 418978-250MG 250 mg 43.50 C H N O H 418978-1G 1 g 120.50 30 33 3 2 H3C MW: 467.60 OCH3 H N [α]6 +260°, c = 1 in ethanol CH3 (DHQD)2AQN, 95% [135096-79-6] O C54H56N4O6 H H N N MW: 857.05 CH3 H3C [α]6 –468°, c = 1 in chloroform N N O O [176298-44-5] H H Cinchona Alkaloids 381969-1G 1 g 52.00 H CO 3 O O OCH3

Hydroquinidine 9-phenanthryl ether, 96% N N

C34H34N2O2 456713-500MG 500 mg 68.20 MW: 502.65 H [ ]6 –348°, c = 1 in ethanol H3C α O [135042-88-5] N (DHQ)2AQN, 95% H3CO H C54H56N4O6 H H MW: 857.05 H3C CH3 N N N [α]6 +495°, c = 1 in chloroform O O [176097-24-8] H H 381950-250MG 250 mg 55.00 H3CO O O OCH3 381950-1G 1 g 152.50 N N Hydroquinine 9-phenanthryl ether, 97% 456705-500MG 500 mg 37.20 C34H34N2O2 H H3C OCH MW: 502.65 3 Quinine, purum, for fluorescence, anhydrous, 6 H N [α] +420°, c = 1 in ethanol ;98.0% NT dried material [135096-78-5] O C H N O H N 20 24 2 2 H2C MW: 324.42 H3CO [α]6 –126° ± 5°, c = 1% in chloroform H N 381977-100MG 100 mg 41.10 [130-95-0] OH 381977-500MG 500 mg 135.50 N 22620-5G 5 g 32.80 (DHQD) PHAL, ;95% 2 22620-25G 25 g 114.40 C H N O H H 48 54 6 4 22620-100G 100 g 322.30 MW: 778.98 N CH3 CH3 N [α] –262°, c = 1.2 in methanol N N O O Quinidine, purum, crystallized, ;98.0% NT dried material [140853-10-7] H H H3CO OCH3 C20H24N2O2 H CO 3 H MW: 324.42 H2C N N HO [α]6 +265° ± 5°, c = 0.8% in ethanol dry matter N 392731-1G 1 g 66.60 [56-54-2] N H

(DHQ)2PHAL, ;95% 22600-10G-F 10 g 61.40

C48H54N6O4 H H 22600-50G-F 50 g 223.00 H3C CH MW: 778.98 3 N N  N N Cinchonine, purum, crystallized, ;98.0% NT [α] +336°, c = 1.2 in methanol O O H H [140924-50-1] C19H22N2O H H3CO OCH3 H2C MW: 294.39 HO N N [α]6 +225° ± 5°, c = 0.5% in ethanol N [118-10-5] H N 392723-500MG 500 mg 39.00 27370-25G 25 g 22.90 27370-100G 100 g 76.60

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Cinchonidine, purum, ;98.0% NT dried material (2R,4S,5R)-2-Aminomethyl-5-ethylquinuclidine 8

C19H22N2O H C10H20N2 H H2C H C MW: 294.39 MW: 168.28 3 H N N [α]6 –108° ± 3°, c = 5% in ethanol [α]6 +143°, c = 1 in ethanol H2N H [485-71-2] OH [475160-61-3] N 39867-100MG 100 mg 69.40 27350-25G-F 25 g 22.70 39867-500MG 500 mg 274.60 27350-100G-F 100 g 81.60 (2S,4S,5R)-2-Aminomethyl-5-ethylquinuclidine 8 Hydroquinine, 98% C H N H 10 20 2 H3C C20H26N2O2 H C H MW: 168.28 3 H N MW: 326.43 OCH3 [α]6 –28°, c = 1 in ethanol H N [α] –148°, c = 1 in ethanol [475160-59-9] H2N [522-66-7] OH 07317-100MG 100 mg 69.40 N 07317-500MG 500 mg 274.60

337714-1G 1 g 19.90 Alkaloids Cinchona 337714-5G 5 g 66.60 (2R,4S,5R)-2-Hydroxymethyl-5-ethylquinuclidine 8 C10H19NO H H3C Hydroquinidine, 95% MW: 169.26 N C H N O [α]6 +147°, c = 1 in chloroform HO 20 26 2 2 H C H H3CO 3 H MW: 326.43 HO [219794-81-7] [α] +226°, c = 2 in ethanol N 49463-100MG 100 mg 69.40 [1435-55-8] H N 49463-500MG 500 mg 274.60

359343-1G 1 g 16.10 (2S,4S,5R)-2-Hydroxymethyl-5-ethylquinuclidine 8 359343-5G 5 g 54.00 C10H19NO H H3C MW: 169.26 Hydrocinchonine, purum, ;97.0% GC sum of enantiomers [α]6 –5.1°, c = 1 in chloroform H N C19H24N2O H H3C [219794-79-3] HO MW: 296.41 HO 51957-100MG 100 mg 69.40 [α]6 +197° ± 4°, c = 0.5% in ethanol N H 51957-500MG 500 mg 274.60 [485-65-4] N 54060-500MG 500 mg 106.50

Asymmetric Phase-Transfer Reactions H

H2C 7 2 3 8 . 1 3 2 . 0 0 8 . 1 : e c i v r e S l a c i n h c e T 0 1 0 3 . 5 2 3 . 0 0 8 . 1 : r e d r O Asymmetric phase-transfer catalysis (PTC) has been recognized as H AlkO OAlk a “green” alternative to many homogeneous synthetic organic N N H2C transformations, and has found widespread application. Synthetically H Ar X Ar H modified cinchona alkaloids are typical chiral organocatalysts N X N used in asymmetric PTC. Several generations of O-alkyl N- arylmethyl derivatives were developed, which finally led to highly Cinchonidinium PTC Cinchoninium PTC enantioselective alkylation reactions of glycine imines to generate a 29 RBr range of α-amino acid derivatives (Table 2). catalyst (10 mol %) Ph N CO2t-Bu Ph N CO2t-Bu Base, Solvent In an attempt to further improve catalyst enantioselectivities, Jew Ph Temp., Time Ph R and Park linked two cinchona alkaloid moieties via spacer units.30 Cinchona PTC With such a dimeric cinchona alkaloid (06542), enantioselectivity Cat. No. R-Br % Y % ee for the above mentioned glycine imine alkylation was optimized to N-Ar O-Alk X– Cat. Gen. 97–99% ee. 524433 Benzyl H Br 1st PhCH2- 85 60 359580 Benzyl H Cl 1st 4-Cl-C H -CH - 95 66 N-Benzylquininium chloride, 95% 6 4 2 514276 Benzyl Allyl Br 2nd 4-Cl-C6H4-CH2- – 81 C27H31ClN2O2 H H2C MW: 451.00 H3CO - 515701 9-Anthracenylmethyl H Cl 3rd PhCH2- 68 91 + Cl [α]6 –235°, c = 1.5 in water H N 499617 9-Anthracenylmethyl Allyl Br 3rd PhCH2- 87 94 [67174-25-8] OH N 06542 2,7-Naphthalenediyldimethyl Allyl Br dimeric 4-NO2-C6H4-CH2- 91 99 374482-1G 1 g 17.70 Table 2 374482-5G 5 g 59.60

N-Benzylcinchoninium chloride, purum, ;98.0% AT (8S,9R)-(–)-N-Benzylcinchonidinium chloride, 98% H H C26H29ClN2O C26H29ClN2O H C H2C 2 MW: 420.97 HO MW: 420.97 - + Cl N+ H N [α]6 +169° ± 3°, c = 0.4% in water Cl- [α]6 –180°, c = 1.3 in water [69221-14-3] H [69257-04-1] OH N N 13288-10G 10 g 82.40 359580-2G 2 g 24.70 13288-50G 50 g 326.00 359580-10G 10 g 82.90

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N-Benzylcinchonidinium bromide, 97% O-Allyl-N-(9-Anthracenylmethyl)cinchonidinium bromide, 95% C H BrN O C H BrN O 26 29 2 H 37 37 2 H H2C H C MW: 465.43 MW: 605.61 2 Br- - + Br [α]6 –138°, c = 1 in chloroform H N [α]6 –340°, c = 0.45 in chloroform H N+

[118089-84-2] OH [200132-54-3] O N N

524433-5G 5 g 34.60 H2C

O-Allyl-N-benzylcinchonindinium bromide 499617-1G 1 g 52.70 499617-5G 5 g 178.50 C29H33BrN2O H H2C MW: 505.49 - + Br O,O’-Diallyl-N,N’-(2,7-naphthalenediyldimethyl) 8 [α]6 –158°, c = 1 in chloroform H N bis(hydrocinchonidinium) dibromide [158195-40-5] O C56H66Br2N4O2 N H3C MW: 986.96 CH3 CH – 2 Br Br– [480427-57-4] + N+ N

514276-1G 1 g 86.20 O N O N-(9-Anthracenylmethyl)cinchonindinium chloride, 85% N H2C CH2 C34H33ClN2O H MW: 521.09 H2C + [199588-80-2] H N 06542-100MG 100 mg 83.80 OH N Cl- N-(4-Trifluoromethylbenzyl)cinchoninium bromide, purum, ;98.0% AT

Cinchona Alkaloids H C27H28BrF3N2O 515701-5G 5 g 76.20 H2C MW: 533.42 HO 515701-25G 25 g 253.00 N+ [α]6 +140° ± 20° in ethanol Br- H [95088-20-3] N

CF3

91851-1G 1 g 43.20 91851-5G 5 g 162.00

Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis

A. Berkessel and H. Gröger, Wiley-VHC, 2005, 454pp. Hardcover. Asymmetric catalysis represents one of the major challenges in modern organic chemistry. Besides the well-established asymmetric metal-complex-catalyzed syntheses and biocatalyses, the use of “pure” organic catalysts turned out to be an additional efficient tool for the synthesis of chiral building blocks. Experienced authors provide the first overview of the important use of such metal-free organic catalysts. With its comprehensive description of numerous reaction types, e.g., nucleophilic substitution and addition reactions, as well as cycloadditions and redox reactions, this book targets organic chemists working in industry and academia. Z704113

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TADDOLs Chiral Brønsted acid catalysts have recently become an important 31 Ar Ar alternative to metal catalysts. Similar to several enzymatic O OH H3C processes, these reactions proceed through hydrogen-bonding H C H C CH 3 O OH H C CH 3 N 3 3 N 3 activation. Ar Ar CH COCl O 3 Ar = 1-Naphthyl O CH2Cl2/toluene O + Apart from numerous examples using TADDOLs in metal-catalyzed H Ph toluene −78 °C, 15 min TBDMSO TBDMSO Ph O Ph asymmetric reactions,32 Rawal recently reported that TADDOLs could 70%, 99% ee be used as Brønsted acid organocatalysts in highly stereoselective hetero-Diels–Alder reactions.33 The reaction of an electron-rich diene with benzaldehyde using 10 mol % TADDOL 395242 provides the Scheme 14 dihydropyrone as a single stereoisomer (Scheme 14).

(4S-trans)-2,2-Dimethyl-a,a,a’,a’-tetra(1-naphthyl)-1,3- (4S,5S)-2,2-Dimethyl-a,a,a’,a’-tetra(2-naphthyl)-1,3-dioxolane- dioxolane-4,5-dimethanol, 99% 4,5-dimethanol, purum, ;98.0% HPLC sum of enantiomers TADDOLs

C47H38O4 C47H38O4 MW: 666.80 MW: 666.80 [α]6 +280°, c = 1 in ethyl acetate [α]6 +116° ± 2°, c = 1% in ethyl acetate H C O OH O OH [171086-52-5] 3 [137365-16-3] H3C H C 3 O OH H3C O OH

395242-1G 1 g 38.50 59488-5G-F 5 g 490.50

(4R,5R)-2,2-Dimethyl-a,a,a’,a’-tetra(2-naphthyl)-1,3-dioxolane- (4R,5R)-2,2-Dimethyl-a,a,a’,a’-tetraphenyl-1,3-dioxolane-4,5- 4,5-dimethanol, 99% dimethanol

C47H38O4 C31H30O4 MW: 666.80 MW: 466.57 O OH [α]6 –116°, c = 1 in ethyl acetate [α] –62.6°, c = 1 in chloroform H3C O OH H3C O OH [137365-09-4] H3C [93379-48-7] H3C O OH

265004-250MG 250 mg 30.40 265004-1G 1 g 83.60 393754-250MG 250 mg 52.10

393754-1G 1 g 155.50 (4R,5R)-2,2-Dimethyl-a,a,a’,a 7 2 ’-tetraphenyl-1,3-dioxolane-4,5- 3 8 . 1 3 2 . 0 0 8 . 1 : e c i v r e S l a c i n h c e T 0 1 0 3 . 5 2 3 . 0 0 8 . 1 : r e d r O dimethanol, purum, ; 97.0% HPLC sum of enantiomers

(4S,5S)-2,2-Dimethyl-a,a,a’,a’-tetra(2-naphthyl)-1,3-dioxolane- C31H30O4 4,5-dimethanol, 98% MW: 466.57 O OH C47H38O4 [α]6 –67° ± 2°, c = 1% in chloroform H3C MW: 666.80 [93379-48-7] H3C O OH [α]6 +116°, c = 1 in ethyl acetate O OH [137365-16-3] H3C H3C O OH 59532-1G 1 g 77.50

(4S,5S)-2,2-Dimethyl-a,a,a’,a’-tetraphenyl-1,3-dioxolane-4,5- dimethanol

393762-250MG 250 mg 45.90 C31H30O4 393762-1G 1 g 137.50 MW: 466.57 O [α] +67°, c = 1 in chloroform H3C OH OH (4R,5R)-2,2-Dimethyl-a,a,a’,a’-tetra(2-naphthyl)-1,3-dioxolane- [93379-49-8] H3C O 4,5-dimethanol, purum, ;99.0% HPLC sum of enantiomers

C47H38O4 MW: 666.80 264997-250MG 250 mg 44.40 [α]6 –116° ± 2°, c = 1% in ethyl acetate 264997-1G 1 g 117.50 O OH [137365-09-4] H3C H3C O OH (4S,5S)-2,2-Dimethyl-a,a,a’,a’-tetraphenyl-1,3-dioxolane-4,5- dimethanol, purum, ;97.0% HPLC sum of enantiomers

C31H30O4 MW: 466.57 O 59490-1G-F 1 g 132.00 [α]6 +67° ± 2°, c = 1% in chloroform H3C OH OH 59490-5G-F 5 g 521.00 [93379-49-8] H3C O

59534-1G-F 1 g 93.80

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Sigma-Aldrich, in collaboration with Solvias, is proud to present the Chiral Ligands Kit— the ultimate toolkit for asymmetric catalysis! The Solvias Chiral Ligands Kit is designed to allow rapid screening of chiral catalysts, and contains sets of the well-known Solvias ligand families below.

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Schaus MBH Catalyst A highly enantioselective addition of cyclohexenone to different aldehydes (asymmetric Morita–Baylis–Hillman reaction) catalyzed by CH3 octahydro-BINOL-derived Brønsted acid 669172 was reported by Schaus (Scheme 15). Important for achieving high enantioselectivity CH3 OH were both the partial saturation and substitution at the 3,3’-positions 10 mol % of the BINOL derivative.34 OH CH3 O OH O O (R)-3,3’-Bis-(3,5-dimethylphenyl)-5,5’,6,6’,7,7’,8,8’- 8 CH3 R octahydro-1,1’-bi-2-naphthol R H + PEt3, THF, −10 °C (R)-3,3’-bis-(3,5-dimethylphenyl)-5,6,7,8,5’,6’,7’,8’-octahydro-

[1,1’]binaphthalenyl-2,2’-diol CH3 C36H38O2 H C H3C 3 MW: 502.69 R = CH3 CH3 Catalyst MBH Schaus OH OH 71%, 96% ee 82%, 95% ee 72%, 96% ee

CH3 Scheme 15

CH3 669180-100MG 100 mg 85.00

(S)-3,3’-Bis-(3,5-dimethylphenyl)-5,5’,6,6’,7,7’,8,8’- 8 (S)-(+)-3,3’-Dibromo-5,5’,6,6’,7,7’,8,8’-octahydro(1,1’- octahydro-1,1’-bi-2-naphthol binaphthalene)-2,2’-diol, 97%

(S)-3,3’-bis-(3,5-dimethylphenyl)-5,6,7,8,5’,6’,7’,8’-octahydro- C20H20Br2O2 Br [1,1’]binaphthalenyl-2,2’-diol CH MW: 452.18 3 OH C36H38O2 [α]6 –53°, c = 1% in THF OH MW: 502.69 [765278-73-7] CH 3 Br OH OH 540595-100MG 100 mg 39.70

CH3 540595-1G 1 g 142.50

(R)-3,3’-Di-tert-butyl-5,5’,6,6’,7,7’,8,8’-octahydro-1,1’- CH3 (bi-2-naphthol) dipotassium salt, purum, ;95.0% 669172-100MG 100 mg 85.00 (dry substance, CHN) C H K O t-Bu 28 36 2 2 7 2 3 8 . 1 3 2 . 0 0 8 . 1 : e c i v r e S l a c i n h c e T 0 1 0 3 . 5 2 3 . 0 0 8 . 1 : r e d r O Related Products MW: 482.78 O- K+ [350683-75-9] O- (R)-5,5’,6,6’,7,7’,8,8’-Octahydro-bi-2-naphthol, 98% K+

C20H22O2 t-Bu MW: 294.39 OH 77939-100MG-F 100 mg 177.00 [α]6 +75°, c = 1% in THF OH [65355-14-8] (R)-(–)-1,1’-Binaphthyl-2,2’-diyl hydrogenphosphate, ;98.0%

C20H13O4P 540560-100MG 100 mg 39.70 MW: 348.29 O O 540560-1G 1 g 124.00 [ ]6 –605°, c = 1.35% in methanol P α OH [39648-67-4] O (S)-5,5’,6,6’,7,7’,8,8’-Octahydro-bi-2-naphthol, 97% C H O 20 22 2 248932-250MG 250 mg 32.00 MW: 294.39 248932-1G 1 g 97.30 [α]6 –75°, c = 1% in THF OH OH 248932-5G 5 g 400.00 [65355-00-2] (S)-(+)-1,1’-Binaphthyl-2,2’-diyl hydrogenphosphate, 97% 540579-100MG 100 mg 41.30 C20H13O4P 540579-1G 1 g 129.00 MW: 348.29 O O [α]6 +595°, c = 1.35% in methanol P OH (R)-(+)-3,3’-Dibromo-5,5’,6,6’,7,7’,8,8’-octahydro(1,1’- [35193-64-7] O binaphthalene)-2,2’-diol, 97% C20H20Br2O2 Br 248940-250MG 250 mg 24.50 MW: 452.18 248940-1G 1 g 66.30 6 OH [α] +53°, c = 1% in THF OH 248940-5G 5 g 292.00 [65355-08-0] Br 540587-100MG 100 mg 41.30 540587-1G 1 g 129.00

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Rovis Triazolium Catalyst

BF4 Rovis has demonstrated that triazolium salt 667080 in the presence O F H N F of a base can act as an N-heterocyclic carbene organocatalyst in N N highly enantioselective intramolecular Stetter reactions. The Stetter H F reaction (a conjugate addition of an aldehyde to an α,β-unsaturated O F O EWG F compound) is a superb method for construction of 1,4-dicarbonyl 20 mol % R 35 2 eq. Et3N, toluene, rt, 24 h X compounds bearing quaternary stereocenters (Scheme 16). X R EWG

5a(R),10b(S)-5a,10b-Dihydro-2-(pentafluorophenyl)- 8 O O O 4H,6H-indeno[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazinium CH3 CH2CH3 CH2CH3 tetrafluoroborate O S CO2CH2 CO2CH2 CO2CH2 C18H11BF4N3O O BF4 95%, 99% ee 96%, 97% ee 95%, 92% ee MW: 467.10 H F N F N N H F Scheme 16 F F 674788-250MG 250 mg 78.00

References (1) For excellent review articles on organocatalysis, see: (a) Dalko, P. (14) Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, I.; Moisan, L. Angew. Chem. Int. Ed. 2001, 40, 3726. (b) Dalko, P. 8826. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138. (c) Houk, K. (15) Fonseca, M. H.; List, B. Angew. Chem. Int. Ed. 2004, 43, 3958.

Rovis Triazolium Catalyst Rovis Triazolium N.; List, B. (Eds.) Acc. Chem. Res. 2004, 37, 487. (d) Berkessel, A.; (16) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, Gröger, H. Asymmetric Organocatalysis, VCH, Weinheim, 2004. (e) 1172. Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719. (f) Kohovský, P.; Malkov, A. V. (Eds.) Tetrahedron Symposia-in-print: Asymmetric (17) Austin, J. F.; Kim, S. G.; Sinz, C. J.; Xiao, W. J.; MacMillan, D. W. C. Organocatalysis 2006, 62, 243. Proc. Nat. Acad. Sci. USA 2004, 101, 5482. (2) Movassaghi, M.; Jacobsen, E. N. Science 2002, 298, 1904. (18) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32. (3) For early examples of organocatalyzed reactions, see: (a) Pracejus, H. Justus Liebigs Ann. Chem. 1960, 634, 9. (b) Hajos, Z. G.; (19) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (c) Eder, U.; Sauer, G.; Chem. Soc. 2005, 127, 15051. Wiechert, R. Angew. Chem. Int. Ed. Engl. 1971, 10, 496. (20) Tian, S.-K.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc. (4) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. Chem. Res. 2004, 37, 621. 2003, 125, 2475. (21) Calter, M. A. J. Org. Chem. 1996, 61, 8006. (5) (a) Mannich reaction: List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. (22) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatekeyama, S. J. Am. J. Am. Chem. Soc. 2002, 124, 827. (b) a-Amination: List, B. J. Am. Chem. Soc. 1999, 121, 10219. Chem. Soc. 2002, 124, 5656. (c) a-Aminoxylation: Zhong, G. Angew. (23) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J.; Leckta, Chem. Int. Ed. 2003, 42, 4247; Brown, S. P.; Brochu, M. P.; Sinz, T. J. Am. Chem. Soc. 2000, 122, 7831. C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808; (24) Wack, H.; Taggi, A. E.; Hafez, A. M.; Drury, W. J.; Leckta, T. J. Am. Bøgevig, A.; Sunden, H.; Córdova. A. Angew. Chem. Int. Ed. 2004, Chem. Soc. 2001, 123, 1531. 43, 1109. (d) Michael addition: List, B.; Pojarliev, P.; Martin, H. J. Org. (25) Bernardi, L.; Fini, F.; Herrera, R. P.; Ricci, A.; Sgarzani, V. Tetrahedron Lett. 2001, 3, 2423. (e) a-Oxyaldehyde dimerization: Northrup, A. 2006, 62, 375. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 2152. (f) Cross-aldol reaction: Northrup, A. B.; (26) Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001, MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798. 123, 7945. (6) Vignola, N.; List, B. J. Am. Chem. Soc. 2003, 125, 450. (27) Pape, A.; Kaliappan, K.; Kündig, E. P. Chem. Rev. 2000, 100, 2917. (7) (a) Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; (28) Kündig, E. P.; Lomberget, T.; Bragg, R.; Poulard, C.; Bernardinelli, G. Porcelloni, M. Angew. Chem. Int. Ed. 2001, 40, 1433. (b) Aggarwal, Chem. Commun. 2004, 1548. V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37, 611. (29) (a) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506. (b) Lygo, B.; (8) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, Andrews, B. J. Acc. Chem. Res. 2004, 37, 518. 3240. (30) Jew, S.-S.; Jeong, B.-S.; Yoo, M.-S.; Huh, H.; Park, H.-G. Chem. (9) Aggarwal, V. K.; Lopin, C.; Sandrinelli, F. J. Am. Chem. Soc. 2003, Commun. 2001, 1244. 125, 7596. (31) (a) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289. (b) Pihko, P. M. (10) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Angew. Chem. Int. Ed. 2004, 43, 2062. Soc. 2000, 122, 4243. (32) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem. Int. Ed. 2001, (11) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 40, 92. 2000, 122, 9874. (33) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, (12) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 424, 146. 4379. (34) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125, (13) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 12094. 2004, 126, 4108. (35) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876.

TO ORDER: Contact your local Sigma-Aldrich office (see back cover),

sigma-aldrich.com call 1-800-325-3010 (USA), or visit sigma-aldrich.com/chemicalsynthesis. Product Highlights O Ph P N O O Ph O O • Superior enantiocontrol in numerous transformations CuCl 4 mol % PdCl2 (10 mol %) • High activities at low catalyst loadings DMF H O, O O 1. Cu(OTf)2 (2 mol %) 2 2 • Hydrogenations under low-pressure conditions ZnEt2, toluene, 30 °C 2. Pd(PPh3)4 (4 mol %) 88%, 96% ee 65%, 96% ee • Applied in tandem reactions to yield valuable chiral organics OAc

Feringa and co-workers have invented a diverse array of chiral, monodentate 1 ™ O Me phosphoramidites based on the privileged BINOL platform. The MonoPhos cat. P N O family has exhibited high levels of enantiocontrol in synthetic transformations NHAc Ph NHAc

CO2Et CO2Et ranging from metal-catalyzed asymmetric 1,4-additions of organometallic Rh(cod)2BF4 (2 mol %) reagents to allylic alkylations to desymmetrization of meso-cycloalkene oxides.2 H2 (10 bar), CH2Cl2, 4 h, rt 99% ee Impressively, the (S)-N-benzyl-N-methyl-MonoPhos™ derivative has been utilized in highly selective hydrogenations of (E)-N-acylated dehydro-b-amino acid esters, affording the corresponding enantiopure b-amino acid derivatives.3 O Ph Sigma‑Aldrich, in collaboration with DSM, is pleased to offer a range of P N NHBn O Ph NH2 MonoPhos™ ligands for the research market.† Ph 1 2 mol % Ph OAc + + [Ir(cod)Cl]2 (1 mol %), EtOH, rt Ph NHBn 2 3 equiv 97:3 (1:2), 95%, 95% ee

(S,S,S)-(+)-(3,5-Dioxa-4-phospha- 8 (S)-(+)-Benzyl-(3,5-dioxa-4-phospha- 8 (S)-(+)-(3,5-Dioxa-4-phospha- 8 cyclohepta[2,1-a;3,4-a’]dinaphthalen- cyclohepta[2,1-a;3,4-a’]dinaphthalen- cyclohepta[2,1-a;3,4-a’]dinaphthalen- 4-yl)bis(1-phenylethyl)amine, 97% 4-yl)methylamine, 97% 4-yl)piperidine, 97%

C36H30NO2P Ph C28H22NO2P C25H22NO2P FW: 539.6 O FW: 435.45 O Me FW: 399.42 O P N P N PN [380230-02-4] O [490023-37-5] O O Ph Ph 665290-100MG 100 mg 51.00 665355-100MG 100 mg 38.00 665479-100MG 100 mg 35.00 665290-500MG 500 mg 220.00 665355-500MG 500 mg 170.00 665479-500MG 500 mg 160.00 665290-2G 2 g 799.00 665355-2G 2 g 635.00 665479-2G 2 g 550.00

(S,R,R)-(+)-(3,5-Dioxa-4-phospha- 8 (3aR,8aR)-(–)-(2,2-Dimethyl-4,4,8,8- 8 (S)-(+)-(3,5-Dioxa-4-phospha- 8 cyclohepta[2,1-a;3,4-a’]dinaphthalen- tetraphenyl-tetrahydro-[1,3]dioxolo(4,5-e) cyclohepta[2,1-a;3,4-a’]dinaphthalen- 4-yl)bis(1-phenylethyl)amine, 97% [1,3,2]dioxaphosphepin-6-yl)Dimethylamine, 96% 4-yl)morpholine, 97% Ph C36H30NO2P Ph C33H34NO4P Ph C24H20NO3P Me FW: 539.6 O FW: 539.6 Me O O FW: 401.39 O P N P N PN O [415918-91-1] O [213843-90-4] Me O O Me O Ph Ph Ph 665363-100MG 100 mg 51.00 665460-100MG 100 mg 89.00 665487-100MG 100 mg 35.00 665363-500MG 500 mg 220.00 665460-500MG 500 mg 375.00 665487-500MG 500 mg 160.00 665363-2G 2 g 799.00 665487-2G 2 g 550.00

(1) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (2) (a) Feringa, B. L. et al. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620 (b) Martina, S. L. X. et al. Tetrahedron Lett. 2005, 46, 7159 (c) Malda, H. et al. Org. Lett. 2001, 3, 1169 (d) Alexakis, A. et al. Chem. Commun. 2005, 2843 (e) Streiff, S. et al. Chem. Commun. 2005, 2957 (f) Bertozzi, F. et al. Org. Lett. 2000, 2, 933. (g) Ohmura, T. et al. J. Am. Chem. Soc. 2002, 124, 15164. (3) (a) Pena, D. et al. J. Am. Chem. Soc. 2002, 124, 14552 (b) Van den Berg, M. et al. Adv. Synth. Catal. 2003, 345, 308.

For more information, please visit us at sigma-aldrich.com/monophos.

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