Organocatalysis

Vol. 7, No. 9

Organocatalysis

Features include: • Proline Analogs • MacMillan Imidazolidinone ™ l-Proline, the archetype OrganoCatalysts of modern asymmetric organocatalysts • Chiral Phosphoric Acids • Jacobsen Thioureas • Cinchona Alkaloids Introduction sigma-aldrich.com asymmetric transformations. asymmetric enzyme”, “simplest the as acid amino proteinogenic the depicts illustration cover The Cover Our About further.even range product our broaden to input your welcome We cover). back (see office Sigma-Aldrich local your at Us.” Bother “Please product,desired a find cannot sigma-aldrich.com/organocatalysi visit Please organocatalysts. of preferredsupplier your being to committed areWe organocatalysis. on articles review and books dedicated of list comprehensive this of end the at offer we addition, In organocatalysts. available commercially of portfolio extensive most the with customers our provide to need a is there believe we Sigma-Aldrich, At materials. starting available readily cheap, with beginning steps few a in structures molecular complex or blocks building chiral new of synthesis the on published being method new a without passes day a Hardly synthesis. chemical in tools powerful and new as emerged have variant asymmetric its and Organocatalysis Introduction Back inYour Operation! Let • • • • • • • • No minimumorder required Specify vialtype,atmosphere, Reduce waste;eliminateon-sitestocking 24–48 hourturnaroundtimeformost From micromoles tograms Determine priceandavailabilityfrom Powerful newbatch-search and reagentInternet-based database labeling/bar-coding, packaging and inventorymanagement compounds your desktop reporting capabilities and procurement DiscoveryCPR.co for MedicinalChemistryandOrganicSynthesis To registerforanInternet Discovery The NewStandard inReagentManagement or tosubmitinquiries: ordering account Flexible |EfficientConvenient L -proline is capable of effecting a variety of organocatalytic of variety a effecting of capable is -proline CPR PutHighThroughput

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for a comprehensive listing of these products. If you If products. these of listing comprehensive a for Discovery Sigma-Aldrich putshighthroughput Custom PackagedReagentsfrom custom arraysofreagents, back intoyourchemistry! [email protected] When projectsdemand Discovery CPR L -proline. Labeled by Jacobsen by Labeled -proline. canmeetthechallenge. CPR ChemFiles or contact or

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Proline Analogs

sigma-aldrich.com 1 Scheme 5 Scheme 3 Scheme 4 Scheme 1 Scheme 2 2 H H H 3 Bn 2 O R O n NO % O 2 e R CO R Ph Bn 2 NO N H F 71-74% 94-95%ee 55-75 91-97%ee O Br reactio 25-58% CO N de, ee >99% 1 2 CHO NHAr R R e -amination α up to 96%e d.r. 6.8:3.2 to 9.9: 0. O OH Mannich up to >99%ee Pr H O 78%, 94%ee, 27:1 dr C 2 C C O H 2 O OH Et 92%, 95%e Ph O H Et 2 Ph OTMS R H H CO +

, r.t. 3 O O 3 3 N H 20 mol% 3 3 H N H 3 R R CH CF 3 2 3 h toluene, 0° to r.t. CF NH CH CHCl CF CO O CH NHPh e e P O OH 82-85% 92-95%ee H 79-84% 94-98%ee 8:1-12:1 dr H O N, CHCl 3 3 O 2 O OH PM 10 mol% N H O R Et -30°, 24 Et OTMS CH N H L-Prolin O 1 H -aminooxylation O C 3 α up to >99%ee R N H Intermolecular cross-aldol reaction up to 97%e F H O 3 . I R m + 2 Pr C NO 2 C + 2 H H O EtO OHC 2 O n r Et O 2 Ph NO R R OB R O % S n OH h reaction + NH N

OB C C H S 23%ee Me 2 2 60-94 95-98%ee 79-8% 90-97%ee H safcglobal.co O O O -oxyaldehyde O OP intermolecula α dimerization up to 98%ee R' R' H Me Michael 1 R , , 3 , ;

). 124 J. , 127 2003 )- and , R Angew. Angew. , 10808; -proline, -proline, 2002 , 3240. -proline -proline L L 125 2005 , 127 , Scheme 3 , 1109. (d) Michael Angew. Chem. Int. Angew. 42, 4247. Brown, S. 42, 4247. Brown, 43 4 2003 , , 1790. (c) Marigo, M.; ). 2005 e, P. e, P. 41 J. Am. Chem. Soc. , , 15710. (e) Marigo, M.; 2003, , 2423. (e) α-Oxyaldehyde 2004 3 and low cost, simple J. Am. Chem. Soc. , 3 127 J. Am. Chem. Soc. 2002 , ) is a viable route for the resp.), which serve 2 contact your local Sigma-Aldrich office, or visit Enantioselective Organocatalysis 3 2001 Scheme 4 2005 67718 . J. Am. Chem. Soc. , 4507. (5) Enders, D.; Hüttl, M. R. M.; ). J. Am. Chem. Soc. 46 34680 , 67721 Org. Lett. , 861. Ready to scale up? For competitive quotes on larger quantities or custom synthesis, Angew. Chem. Int. Ed. Angew. 441 2007 The four stereogenic centers are Angew. Chem. Int. Ed. Angew. 5 and , ). , 18296. (b) Bøgevig, A.; Juhl, K.; Kumaragurubaran, 9 ) gives higher enantioselectivities and Scheme 2 Angew. Chem. Int. Ed. Angew. 9 , 6798. (2) Vignola, N.; List, B. J. Am. Chem. Soc. -proline -proline contains both a nucleophilic 1 127 2006 L , ). 124 century. , 827. (b) α-Amination: List, B. , st 67701 1724 , 2152. (f) Cross-aldol reaction: Northrup, A. B.; MacMillan, D. W. Northrup, A. B.; MacMillan, D. W. reaction: , 2152. (f) Cross-aldol 2005 124 Science , 43 2002 Scheme 5 , 2002 Scheme 1 Angew. Chem. Int. Ed. Angew. 2004 -proline -proline ( L , 4504. (g) Ibrahem, I.; Rios, R.; Vesely, J.; Hammar, P.; Eriksson, L.; Himo, Eriksson, L.; Himo, P.; J.; Hammar, , 4504. (g) Ibrahem, I.; Rios, R.; Vesely, (1) (a) Mannich reaction: List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. T.; W. Biller, P.; List, B.; Pojarliev, (1) (a) Mannich reaction: This transformation had been accomplished with the 46 2 , J. Am. Chem. Soc. , 450. (3) Kunz, R. K.; MacMillan, D. W. C. , 450. (3) Kunz, R. K.; MacMillan, D. W. 2007 J. Am. Chem. Soc. )-α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol )-α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol )-(–)-indoline-2-carboxylic acid ( S S T.; Franzén, J.; Jørgensen, K. A. T.; Jørgensen, K. A. B.; Zhuang, W.; Franzén, J.; Poulsen, T. 6964. (f) Carlone, A.; Bartoli, G.; Bosco, M.; Sambri, L.; Melchiorr Ed. A. Córdova, F.; C.; Raabe, G. Grondal, (4) (a) Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen, A.; Jørgensen, C.; Kjærsgaard, T. (4) (a) Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, K. A. Jørgensen, K. A. N.; Zhuang, W.; Functionalization. In Jørgensen, K. A. α-Heteroatom I., Ed.; Wiley-VCH: 2007; Chapter 2.2. (d) Marigo, M.; Schulte, Weinheim, Dalko, P. addition: List, B.; Pojarliev, P.; Martin, H. J. P.; addition: List, B.; Pojarliev, C. MacMillan, D. W. dimerization: Northrup, A. B.; Mangion, I. K.; Hettche, F.; Chem. Int. Ed. C. 125 References: Am. Chem. Soc. 5656. (c) α-Aminoxylation: Zhong, G. C D. W. Sinz, C. J.; MacMillan, M. P.; Brochu, P.; A. Bøgevig, A.; Sunden, H.; Córdova. i.e., Michael/Michael/aldol condensation with high diastereo- and complete enantiocontrol. Thus, this domino reaction opens up a simple and flexible entry to polyfunctional cyclohexene building blocks. with proline-derived organocatalyst starting materials, leading to tetra-substituted cyclohexene carbaldehydes ( generated in three consecutive carbon–carbon bond formations, reactions reactions such as C–C, C–N, C–O, C–S, and C–Hal in high yields and excellent levels of enantiocontrol ( Enders and co-workers have developed a chemo-, diastereo-, and enantioselective three-component domino reaction, accomplished α-functionalization of aldehydes. In the field of asymmetric synthesis this stereoselective functionalization certainly represents diarylprolinol silylether an important Jørgensen’s breakthrough. reagents were shown to catalyze a variety of bond-forming Prof. Prof. Karl Anker Jørgensen and his group have developed ( ( trimethylsilyl ether ( as excellent chiral organocatalysts in the direct organocatalytic demonstrated that activation of olefin substrates using catalytic ( formation of highly enantioenriched cyclopropanes ( α-methyl- improved reaction rates ( Organocatalytic cyclopropanation reactions were typically performed using MacMillan catalyst-bound ylides. However, The catalytic asymmetric α-alkylation of aldehydes was described by List. help of covalently attached auxiliaries. In comparison to Stimulated by such a vast number of successful examples, many groups research have developed synthetic proline analogs with optimized properties. Some examples are presented here in more detail. As a small organic molecule, proline is available in both enantiomeric forms, which is a definite advantage over enzymatic methods. Numerous proline-catalyzed reactions have been developed ( secondary amino group and a carboxylic acid moiety functioning as a Brønsted acid. This facilitates a highly pre-organized transition state during which the results in reaction pathway, exceptionally high enantioselectivities. beginning of the 21 The bifunctional structure of the sole cyclic proteinogenic amino acid is a crucial factor. Proline Analogs Proline The first examples were reported in the mid-70s, when was applied to Robinson the annulation big reactions. However, potential of proline as an organocatalyst was discovered at the Proline Analogs

sigma-aldrich.com 237752-100M 237752-25M [3105‑951] FW 129.16 C L 11542-2.5 11542-500M [2133‑348] FW 101.10 C L 346802-5 346802-1 [79815‑206] FW 163.17 C ( 51266-500MG- [98167‑067] FW 163.17 C ( 30890-50M 30890-10M [4043‑883] FW 113.11 C 3,4-Dehydro- 17249-1 17249-250M [42856‑713] FW 129.16 C α-Methyl- 858919-5 858919-500M [344‑252] FW 115.13 C D P0380-5K P0380-1K P0380-100 P0380-10M [147‑853] FW 115.13 C L 268062-100M 268062-25M [1723‑008] FW 129.16 C D S R -Proline, ≥99% (TLC) ≥99% -Proline, -Pipecolic acid, 99% acid, -Pipecolic (NT) ≥98.0% acid, -Azetidine-2-carboxylic -Proline, ≥99% -Proline, -Pipecolinic acid, 99% acid, -Pipecolinic 6 5 9 9 5 5 6 6 4 lic acid, 99% acid, )-(−)-Indoline-2-carboxylic H H H H H H H H H lic acid, ≥97.0% (T) ≥97.0% acid, )-(+)-Indoline-2-carboxylic 11 7 9 9 7 11 9 9 11 NO NO NO NO NO NO NO NO NO 2 2 2 2 2 2 G 2 2 2

G G G G G G

G L

G G G -proline, ≥98.0% (TLC) ≥98.0% -proline, G G G G G G G L F -proline, ≥99.0% (TLC) ≥99.0% -proline, ORDER: Contact your local Sigma-Aldrich office (see back cover), back (see office Sigma-Aldrich local your Contact TO ORDER: or visit or sigma-aldrich.com/chemicalsynthesi H N H N H N H N H N H N H N H N 500 mg 500 mg 500 mg H N 100 mg 250 mg 100 mg 50 mg 10 mg CH 10 mg 25 mg 25 mg 100 g O O O O O O 2.5 g 5 kg 1 kg 3 OH OH 5 g OH O OH OH OH OH OH O 5 g 1 g 1 g OH O T27502-10 [34592‑477] FW 133.17 47517-5G- [122996‑478] FW 409.47 C (HPLC) ≥98.0% Fmoc-Hyp(tBu)-OH, H54409-100 H54409-25 684341-100M [33878‑705] FW 139.16 C ( 287059-1 287059-250M [7531‑524] FW 114.15 C L T27502-100 C L H54409-10 H54409-2.5 [51‑354] FW 131.13 C trans 5624 [4298‑082] FW 131.13 C trans 684341-500M 382337-5 382337-1 382337-100M [22348‑329] FW 253.34 C ( 30249-1G- [18414‑307] FW 165.62 C (AT) ≥95.0% cis S R amide, 98% -Prolinamide, lic acid, 98% acid, -4-Thiazoldinecarboxylic 4 24 5 5 5 5 17 6 )-5-(–)-(2-Pyrrolidinyl)-1 H H H H H H )-(+)- lic acid hydrochloride, -2-Amino-1-cyclopentanecarboxylic H H 7 9 10 9 9 11 NO 27 N NO NO 19 4 N NO -4-Hydroxy- -3-Hydroxy- 5 NO NO NO 2 O O 2 3 3 α S S 2

5 · HCl HCl · , G G G

F F G G G anol, 98% -Diphenyl-2-pyrrolidinmethanol, G

G G G G G s . L L -proline, ≥99% -proline, (NT) ≥98.0% -proline, H -tetrazole

H H 3 3 C C O CH HO O 3 H N OH HO H N H N NH H N N Fmoc H N 100 mg 100 mg 500 mg 250 mg O 2 OH HN O 100 g 100 g OH 8 O O O 2.5 g • HCl S 25 g 10 g 10 g NH N OH OH OH NH 5 g 1 g 5 g 1 g 1 g N N 2 Proline Analogs

sigma-aldrich.com 3 3 3 3 3 3 3 3 3 3 1 g 5 g 1 g 5 g 1 g 5 g CF CF CH CH 3 • HCl • HCl CH CH CH CH 3 3 8 8 8 8 8 3 3 3 3 OCH OCH CH Si 8 8 3 3

CH CH Si Si CF CF CF CF 500 mg 500 mg 100 mg 500 mg 100 mg 500 mg 3 3 3 3 O CH CH O O CH CH CH CH 3 3 3 3 3 3 N H N H CH CH Si Si CH CH CH CH N H

O O N H N H C C 3 3 F F

N H N H C C 3 3 H H

omethyl)phenyl]-2- omethyl)phenyl]-2- .

G G G G G G

safcglobal.co

G G G G G G NOSi NOSi 12 12 NOSI F F NO NOSi · HCl NOSi · HCl NO 27 23 23 21 35 35 21 H H H H H H H nmethanol )-(+)-α,α-Diphenyl-2-pyrrolidi nmethanol )-α,α-Bis(3,5-dimethylphenyl)-2-pyrrolidi ne, )-2-(Methoxydiphenylmethyl)pyrrolidi 95% (HPLC) )-α,α-Bis[3,5-bis(trifluor ne, )-2-(Methoxydiphenylmethyl)pyrrolidi 95% (HPLC) )-α,α-Bis[3,5-bis(trifluor 20 18 24 24 18 24 24 R R R S R S ( 96% trimethylsilyl ether, C FW 456.40 677191-1 677191-5 677019-1 677019-5 ( ≥97.0% nmethanol pyrrolidi trimethylsilyl ether, C FW 597.51 677213-1 677213-5 ( ≥97.0% nmethanol pyrrolidi trimethylsilyl ether, C FW 597.51 [848821‑61‑4] C FW 267.37 [118971‑03‑2] 670197-100M 670197-500M ( trimethylsilyl ether hydrochloride C FW 418.09 671304-500M anol nmeth (S)-α,α-Bis(3,5-dimethylphenyl)-2-pyrrolidi trimethylsilyl ether hydrochloride C FW 418.09 671428-500M ( C FW 267.37 [948595‑05‑9] 670308-100M 670308-500M ( 3 3 3 3 3 3 1 g 5 g 1 g 5 g 1 g 1 g 1 g CF CF CH CH CH CH 3 8 8 8 8 8 3 3 3 3 3 3 3 3 OH CH Si

CF CF CF CF 500 mg 500 mg CH CH CH CH O OH OH OH OH OH N H N H N H N H N H C C N H N H C C 3 3 3 3 F F H H

contact your local Sigma-Aldrich office, or visit Ready to scale up? For competitive quotes on larger quantities or custom synthesis, omethyl)phenyl]- omethyl)phenyl]-

G G

methanol, n -Di(2-naphthyl)-2-pyrrolidi 99% nmethanol, -Diphenyl-2-pyrrolidi 99% α α G G G G G G G , , NO NO α α 12 12 NOSi F F NO NO NO NO 27 15 15 27 27 23 19 H H H H H H H )-α,α-Bis[3,5-bis(trifluor )-α,α-Bis(3,5-dimethylphenyl)-2- nmethanol )-(–)-α,α-Diphenyl-2-pyrrolidi )-α,α-Bis[3,5-bis(trifluor nmethanol, lphenyl)-2-pyrrolidi )-α,α-Bis(3,5-dimethy )-(−)- )-(−)- 20 21 21 21 21 25 17 S R S R S S S 677183-1 677183-5 C FW 325.52 [848821‑58‑9] 671746-1 ( 95% trimethylsilyl ether, ( nmethanol 2-pyrrolidi C FW 525.33 670960-1 nmethanol 2-pyrrolidi C FW 525.33 [848821‑76‑1] 670847-500M ( C FW 309.45 [948595‑01‑5] 670731-500M ( nmethanol, pyrrolidi ≥99% (HPLC) ( ≥99% (HPLC) C FW 309.45 [131180‑63‑7] 445398-1 ( C FW 353.46 [127986‑84‑9] 368199-1 368199-5 C FW 253.34 6] [112068‑01‑ ( Proline Analogs

sigma-aldrich.com 670405-100M [948595‑048] FW 293.45 C (HPLC) ≥98.0% ( 669644-500M [948595‑071] FW 359.93 C (HPLC) pyrrolidi≥99.0% ne hydrochloride, ( 670634-500M [948595‑026] FW 359.93 C (HPLC) pyrrolidi≥99.0% ne hydrochloride, ( 669520-500M 669520-100M [553638‑667] FW 420.50 C (HPLC) ≥98.0% ( 670405-500M 671088-500M 671088-100M [948594‑976] FW 310.39 C (HPLC) ≥99.0% pyrrolidincarboxamide, (2 43119-250M [110529‑221] FW 267.37 C enantiomers) α,α-Diphenyl- 43118-250M [144119‑120] FW 267.37 C enantiomers) α,α-Diphenyl- R S R S 22 22 19 21 18 19 18 )-2-[Bis(3,5-dimethylphenyl)methyl]pyrrolidine, )-2-[Bis(3,5-dimethylphenyl)methoxymethyl] R )-2-[Bis(3,5-dimethylphenyl)methoxymethyl) )-2-[Bis(3,5-dimethylphenyl)methyl]pyrrolidine, H H H H H H H )- 29 29 27 36 21 22 21 N N N HCl · NO HCl · NO NO NO N N NO -[(1 2 2 O O 8 2

G G G G G G G G G G R N N )-2-Hydroxy-1,2-diphenylethyl]-2-

-methyl- -methyl-

D L ol, ≥96.0% (GC, sum of sum (GC, ≥96.0% -prolinol, ol, ≥99% (GC, sum of sum (GC, ≥99% -prolinol, ORDER: Contact your local Sigma-Aldrich office (see back cover), back (see office Sigma-Aldrich local your Contact TO ORDER:

H 3 C H N or visit or H H H H N 3 3 3 C C H N C H N H N OCH

CH CH O sigma-aldrich.com/chemicalsynthesi 3 CH N CH N N H 3 3 OCH CH 3 3 500 mg CH CH CH CH 500 mg 250 mg 500 mg 100 mg CH CH 500 mg 100 mg 250 mg 500 mg 100 mg OH 3 3 • HCl 3 3 OH OH 3 3 3 3 8 8 8 8 8 • HCl CH CH CH 3 3 3 FW 350.45 277053-5 277053-500M 277053-100M [63126‑476] FW 115.17 C ( 65089-5M 65089-1M [84025‑810] FW 115.17 C enantiomers) of sum (GC, ( 552534-500M [119237‑648] FW 237.34 C ( 552542-1 552542-500M [22348‑318] FW 237.34 C ( 671622-500M C (HPLC) hydrox99% ypyrrolidin-2-yl)-methanone, 671622-100M (( 671290-500M 671290-100M [915205‑764] FW 310.39 C (HPLC) 99% amide, dibenzyl (2 671193-500M 671193-100M [529486‑268] FW 310.39 C (HPLC) ≥99% pyrrolidincarboxamide, (2 S R S R 6 6 17 17 22 19 19 S e, 99% )-(+)-2-(Methoxymethyl)pyrrolidine, 97% )-(−)-2-(Diphenylmethyl)pyrrolidine, S S H H e, ≥98.0% )-(−)-2-(Methoxymethyl)pyrrolidine, e, 97% )-(+)-2-(Diphenylmethyl)pyrrolidine, )-2-Benzhydrylpyrrolidin-1-yl)((2 H H H H H ,4 )- 13 13 19 19 26 22 22 N NO NO NO R N N N N N N -[(1 )-4-Hydroxacid ypyrrolidine-2-carboxylic 2 2 2 O O O G G 2 2 2 L L

S G G G G G G G G G G )-2-Hydroxy-1,2-diphenylethyl]-2- s .

S ,4 R

)-4- HO HO H N H N

H N O O H N N H N H N H N H N O 500 mg 100 mg N 500 mg 500 mg 100 mg 500 mg 500 mg 100 mg 500 mg 100 mg OH 8 8 8 OCH OCH 5 mL 1 mL 1 g 5 g 3 3

Proline Analogs

sigma-aldrich.com 2 3 NH CH 8 50 mg 100 mg 500 mg 250 mg 100 mg 500 mg N H N H N H , 16776. , 3 • 2 HCl OH C 3 0 2 127 OCH H , 3 6 )-1 5 2 NH 8 00 5 NH OCH 3 2

8 R,R 2 2 ( 6 0 3 2 OH NH 4 CO 3 8 NH H 6 OCH 3 CO 3 • 2 HCl OCH H

CO J. Am. Chem. Soc. Chem. Am. J. 3 H OH 0 2 9 2 2 2 1 NH )-1 2 4 NH 87 NH 8 5 NH 6 8 S,S . ( 6 m OH 2 CO • 2 HCl 3 These diamines can be used as ligands for -lactams via ring closure. NO H 1 b ne, -2,5-Dimethylpyrrolidi ≥97.0% (GC) , 16370. (c) Kim, H.-J. et al. al. et H.-J. Kim, (c) 16370. , 1 3 2 1 2 0 R R G G G G 127 2 NH 4 safcglobal.co , , G trans 5 8 NH G 6

00 N N

2 2 2 H H

)-(−)- ne, )-Diphenylpyrrolidi 97% 2 N R R N N 17 N F 12 13 ,5 ,5 • 2 HCl 2 O H 2 O H H ne, omethyl)pyrrolidi )-(+)-2-(Amin 97% R R 5 6 16 H S 9 ( C FW 100.16 [69500‑64‑7] 422886-100M 422886-500M (2 C FW 99.17 [62617‑70‑3] 41566-50M 41566-250M (2 C FW 223.31 [155155‑73‑0] 688274-500M 688274-100M 3 2 1 1 2 2 4 NH R R 8 J. Am. Chem. Soc. Soc. Chem. Am. J. NH 6 1 g 1 g 5 g N N OH 25 g 1 mL N OH OH N 3 H N 250 mg F into other chiral vicinal diamines. • 2 HCl 3 CH N

) N H 1 N CH 8 (

Cl 5 N H 0 2 4 2 NH 8 6 NH [3,3] , 15276. (b) Kim, H.-J. et al. al. et H.-J. Kim, (b) 15276. , Cl 1 2 125 R R , , 3 • 2 HCl 00 2 N N

contact your local Sigma-Aldrich office, or visit OH OH 7 4 1 2 4 8 2 NH 6 NH 3 Ready to scale up? For competitive quotes on larger quantities or custom synthesis, 3 CH J. Am. Chem. Soc. Chem. Am. J. • 4 HCl N CH CHO CHO 2 1 R R 2 6 Chiral Vicinal Diamines Vicinal Chiral 2) 1)

2 NH 18 5 2 2 NH 8 6 NH NH G OH OH (1) (a) Chin, J. et al. al. et J. Chin, (a) (1) 8 3 L

1 G nol -proli

Chiral Vicinal Diamines for Asymmetric Synthesis CH N L

G G G

C 2 2

3 2 H N N N NO 16 22 18 13 H H References: References: Other experimental studies for converting a parent diamine experimental studies for converting a parent rings and chiral heterocyclic to produce chiral catalysts, or they can be further elaborated Chiral vicinal diamines are of tremendous interest to the synthetic chemist as they are found in many chiral catalysts and as they are to the synthetic chemist interest of tremendous Chiral vicinal diamines are often challenging to to making these chiral vicinal diamines, and they are is no unified approach there pharmaceuticals. Currently, and theoretical some preliminary reported Jik Chin and co-workers have recently synthesize, especially if unsymmetrically substituted. H H ne, )-(+)-2-(Anilinomethyl)pyrrolidi 96% ridine, nyl)methyl]pipe )-1-[(1-Methyl-2-pyrrolidi 97% ne, nylmethyl)pyrrolidi 96% )-(+)-1-(2-Pyrrolidi nmethanol, )-(−)-1-Methyl-2-pyrrolidi 96% 11 11 9 -Methyl- 6 8 S S S S 374911-1 ( C FW 176.26 [64030‑44‑0] FW 182.31 [84466‑85‑3] 446351-1M 324450-1 ( C C FW 154.25 [51207‑66‑0] 324450-250M 302767-5 302767-25 ( N C ( FW 115.17 [34381‑71‑0] MacMillan Imidazolidinone ™ OrganoCatalysts

sigma-aldrich.com MacMillan Imidazolidinone OrganoCatalysts are a trademark of Materia, Inc. J. Am.Chem.Soc (f) Fonseca,M.H.;List,B. 4108. (e)Beeson,T. D.;MacMillan,D.W. C. 4379. (d)Brochu, M.P.; Brown, S.P.; MacMillan,D.W. C. 2000 2000 References: or OrganoCatalyst and ester Hantzsch the of formulations ( stereocenter.created newly the of configuration absolute the of outcome the on influence significant a have not did substrates the hydrogenations, metal-mediated ( aldehydes α,β-unsaturated of reduction hydride organocatalytic enantioselective first the facilitate to ester Hantzsch and OrganoCatalyst™ imidazolidinone of combination the cofactor,reported NADH has with MacMillan nature’sImitating hydrogenation transfer enzymatic stereoselective enantioselectivity( ( Michaelreactions using MacMillan’s OrganoCatalyst alkylations,α-chlorinations, α-fluorinations, andintramolecular transformationssuch as1,3-dipolar cycloadditions, Friedel–Crafts andenantioselectivities ( withvarious dienes togive [4+2] cycloadducts inexcellent yields oftheimidazolidinone andanα,β-unsaturated aldehyde, reacted in2000. Theactivated iminium ion, formed through condensation OrganoCatalyst™( enantioselectiveorganocatalytic Diels–Alder reaction using chirala formyriada ofasymmetric transformations. Thefirst highly basedOrganoCatalysts Developedby Professor David MacMillan at Caltech, imidazolidinone OrganoCatalysts MacMillan Imidazolidinone 56976 R )-Mac-H ( )-Mac-H Presenting... 66190 , , 122 122 Anindustry-first for open scientific discussion. 3 , 9874.(c)Paras,N.A.;MacMillan,D.W. C. , 4243.(b)Jen,W. S.;Wiener, J.M.;MacMillan,D.W. C. ) were) reported, allproceeding with impressive levels of 2 (1)(a)Ahrendt, K.A.;Borths,C.J.;MacMillan,D.W. C. , respectively,reductions., asymmetric for Sigma-Aldrich’s 68542 . 2005 Visit 9 Scheme , 56976 127 ) and ( and ) Angew. Chem.Int.Ed. , 32. ™ chemblogs.co Scheme are designed toserve asgeneral catalysts 3 S

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monohydrochloride, 97% imidazolidinone monohydrochloride, 674575-1K mg 250 668540) (Aldrich (2 mg 500 663107) (2 mg 500 663085) (Aldrich (5 mg 500 661902) (Aldrich ( mg 500 569763) (Aldrich (5 Components I Kit OrganoCatalysts™ Imidazolidinone MacMillan 663069-2 663069-500M [323196‑436] FW 254.76 C (5 S 13 )-(+)-2-( S S S S R ,5 ,5 )-(−)-2,2,3-Trimethyl-5-benzyl-4-imidazolidinoneacid dichloroacetic )-(−)-2,2,3-Trimethyl-5-benzyl-4-imidazolidinonemonohydrochloride H )-(+)-2,2,3-Trimethyl-5-benzyl-4- 19 S S )-5-Benzyl-3-methyl-2-(5-methyl-2-furyl)-4-imidazolidinone )-(−)-2- ClN tert 2 G O O T R OH 91-99%ee 1 -Butyl)-3-methyl-4-imidazolidinone trifluoroacetic acid trifluoroacetic -Butyl)-3-methyl-4-imidazolidinone tert 97%e R HO C H 2 G

e H -Butyl-3-methyl-5-benzyl-4-imidazolidinone (Aldrich -Butyl-3-methyl-5-benzyl-4-imidazolidinone F O α s -fluorination R . O Michael intramolecular Ph + Et

addition O H 3 O C α cycloaddition Diels-Alder -chlorination H H N Ph H

O O CH H OE O 3 H N N Cl CH t 2 CHO X R Ph 3 CH CH 93%ee 91-95%ee O 3 3 CHC 20 mol% TF H N N CH cycloadditio 1,3-dipolar l 2 3 A , -30° 3 alkylation Friedel-Crafts CH CH CH 3 3 3 Ph n R R N 1 R 1 N R up to97%e CHO 1 R >89%ee >90%ee O R 2 2 O R CHO 2 H H N O e N CH Scheme 2 Scheme 1 Scheme CH CH 3 500 mg 3 3 • HCl 1 kit 2 g MacMillan Imidazolidinone OrganoCatalysts™

sigma-aldrich.com 3 3 3 3 3 3 3 3 CH H CH 1 g 2 g 2 g 1 g 1 g CH 1 g CH 2 CH CH 3 3 CH CH 8 8 COOH COOH CO 3 3 COOH CH 3 CH 3 3 3 O O 500 mg N 500 mg 250 mg 250 mg N N H N H • CF • CF CH • CF CH • CF N N O O N H N H 3 3 3 3 3 O O 3 3 3 CH CH CH CH H CH 3 3 CH CH CH CH 3 O N N 3 OC N H N H H CH O O O O N H N H C O

3 CC O 3 H O H O C 3 C 3 H H . m one azolidin -Butyl)-3-methyl-4-imid azolidinone -Butyl)-3-methyl-4-imid

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F tert 3 2 3 2 G G G G G G O O O O oacetic acid, 96% oacetic acid, 96% 2 2 2 2 )-(+)-5-Benzyl-3-methyl-2-(5-methyl-2-furyl)-4- )-5-Benzyl-3-methyl-2-(5-methyl-2-furyl)-4- N N N N R S 17 17 18 18 ,5 ,5 H H H H )-(−)-2-( )-Mac-H )-(+)-2-( R S )-Mac-H 10 10 16 16 R S R S ( C FW 270.25 661910-500M 661910-2 ( C (2 C 668842-1 C FW 270.33 [415678‑40‑9] 668540-250M 668540-1 685429-1 683558-1 FW 270.25 661902-500M 661902-2 FW 270.33 668842-250M (2 ( ( imidazolidinone, 97% imidazolidinone, 95% trifluor trifluor 3 3 3 3 3 3 3 3 1 g 2 g 2 g 1 g 2 g 3 3 3 3 CH CH CH CH CH CH CH CH • HCl OH OH 3 CH CH CH 3 CH 3 3 N N O O 500 mg 500 mg 500 mg 500 mg 500 mg CH CH N H N H 3 N CH N Cl Cl CH N H N H O O CH Cl Cl N O O N H . . O contact your local Sigma-Aldrich office, or visit Ready to scale up? For competitive quotes on larger quantities or custom synthesis, -Butyl-3-methyl-5-benzyl-4- -Butyl-3-methyl-5-benzyl-4-

tert tert G G G G G

3 3 O O 2 2 G G G G G N N O O O · HCl 2 2 oacetic acid, 97% oacetic acid, 97% 2 2 2 )-(+)-2- )-(−)-2- N N Cl Cl N R S 22 22 20 20 18 ,5 imethyl-5-benzyl-4-imid azolidinone )-(+)-2,2,3-Tr ,5 imethyl-5-benzyl-4-imid azolidinone )-(−)-2,2,3-Tr imethyl-5-benzyl-4- )-(−)-2,2,3-Tr H H H H H S R S R S 15 15 15 15 13 663107-1 FW 246.35 [346440‑54‑8] 663107-500M (2 C FW 246.35 [390766‑89‑9] 663093-500M 663093-1 (2 C 663085-500M 663085-2 C FW 347.24 663077-2 (5 663077-500M C FW 347.24 569763-500M 569763-2 (5 C FW 254.76 2] [278173‑23‑ (5 dichlor dichlor monohydrochloride, none monohydrochloride, imidazolidi 97% imidazolidinone, 97% imidazolidinone, 97% Other Amino Acids 10

sigma-aldrich.com 05250-250M [1948‑318] FW 160.17 C (NT) ≥99.0% Ala-Ala, 05140-25 05140-5 05140-1 [338‑692] FW 89.09 C D A26802-100 A26802-25 A26802-2.5 [56‑417] FW 89.09 C L 2006 Soc. References: prepared. be can molecules enriched optically which with efficiency the efficiency.increasesgreatlyidentical catalyst with reusedThis subsequently and near-quantitativerecoveredyield in easily be can catalyst the Furthermore,moisture. or air of exclusion rigorous requirenot do reactions the and 88%, above enantioselectivities provides generally and chlorides silyl of variety a with compatible of monosilylation molecule small based reportedrecently have College Boston at Hoveyda Amir and Snapper MarcProfessors ( diastereoselectivities and enantio- excellent corresponding the give to NMP in aldehydes various and hydroxyacetone of reaction Similarly, cases. most in ee) (90–98% enantioselectivities and >19:1) to (up diastereoselectivities excellent with yields good in obtained were ( DMF in performed imines of variety a with hydroxyacetone of reaction Mannich ( tryptophan acid amino proteinogenic the found co-workers and Barbas Other AminoAcids 89190-50 89190-10 89180-1K 89180-100 89180-25 [72‑195] FW 119.12 C L 05250-1 [632‑202] FW 119.12 C D nine, 99% -Alanine, -Thr nine, ≥99.0% (NT) ≥99.0% -Alanine, -Thr 3 3 4 6 4 H H H H H 2007 12 7 7 9 9 , NO NO NO NO 443 N nine, ≥99.0% (NT) ≥99.0% enine, nine, ≥99.0% (NT) ≥99.0% enine, 2 O 2 2 3 3 , , 67. G G G

129 3 G G G G t G (1)Ramasastry, S.V.; Zhang,H.;Tanaka, F.; Barbas,C.F., III

-butyl protected threonine ( threonineprotected -butyl

G G G , 288.(2)Zhao,Y.; Rodrigo,J.;Hoveyda,A.H.;Snapper, M.L.

G 9366 G 0 meso ) to be an excellent organocatalyst for the for organocatalyst excellent an be to ) syn Scheme 1 68082 -aldol adducts in high yields and good to good and yields high in adducts -aldol 2 the development of an amino-acid- an of development the -1,2-diols ( -1,2-diols 6

). The desired The ). capable of promoting asymmetric promoting of capable Scheme 3 ORDER: Contact your local Sigma-Aldrich office (see back cover), back (see office Sigma-Aldrich local your Contact TO ORDER: 2064 4 ) catalyzed the aldol the catalyzed ) ). The catalyst is catalyst The ). Scheme 2 anti or visit or amino alcohols amino H 2 N CH ). H H sigma-aldrich.com/chemicalsynthesi J. Am.Chem. 3 3 1 O 3 C C H H 3 3 N H Nature OH OH C C 250 mg CH NH NH NH NH 100 g 100 g O O O O O 2.5 g 3 2 2 2 2 25 g 50 g 10 g 25 g 25 g 1 kg

OH OH OH OH OH 5 g 1 g 1 g 1 93197-1G- Poly- 680826-1 FW 308.46 C 93660-100 93660-25 [73‑223] FW 204.23 C L 20644-5G- [4378‑136] FW 175.23 C O ((1-methyl-1 (–)-( 93670-25 93670-5 93670-1 [153‑946] FW 204.23 C D 93660-1K -Trypt(NT) ≥99.0% ophan, -Trypt(NT) ≥99.0% ophan, 11 8 17 11 - H tert H H H 17 S 32 12 12 NO L )- N N N -leucine-1,3-diaminopropane -Butyl- N R 2 4 2 1 O O O O G G 3 -((

G G G G 2 2 HO O F F

R HO

)-3,3-Dimethylbutan-2-yl)-3,3-dimethyl-2- R OH H L 1 -thr amide, 97% -imidazol-2-yl)methylamino)butanamide, OH O + OH s . nine, ≥98.0% (T) ≥98.0% enine, OH OCH NH H 2 3 + 3 C N + N TBSCl, DIPEA H 20-30 mol% O H H N R O 2 t -Bu

R O 2 N H H H NMP, 4°,16-48h 3 t 2 C -Bu N CH 20 mol% O 20 mol% DMF, 4° t 3 -Bu NH O OH O 2 H N TBSO OH TBSO Poly(L-Leu) R R d.r. 3:1to18:1 1 1 OH 82-98%ee 69-95% OH O CH O N d.r. 2:1to>19: N OH OH H N 53-96%ee HN 3 67-95% up to96%e up to96 H OH H H 3 3 R R C H 3 C 2 2 C N H 3 C % CH 1 e H N O H N OC 3 Scheme 3 Scheme 2 Scheme 1 Scheme H N O CH H CH H 3 Poly(L-Leu) H N C 3 3 NH NH NH 3 CH 100 g 8 O O O 2 2 2 25 g CH 25 g 1 kg CH 3 OH OH OH 1 g 1 g 5 g 5 g 1 g 3 3

Chiral Phosphoric Acids 11

sigma-aldrich.com 2 t Ph OE 3 Scheme 6 Scheme 3 Scheme 4 Scheme 5 Scheme 2 H O P 3 3 2 OC R R PM CH e HN N 3 HN 1 s 82%; d.r. 24:1; e.r. 98: HN 76-91%ee R R CH 70-84%ee 80-92%ee To c Ar Ar r r Bo N H -P -P HN i i ** 81%, 95%e 3 3 r r HN r r -P -P CF CF i i O OH Ar 73-99%ee -P -P i i 3 3 P r r O O r r ° F -P -P O OH r r CF CF i i ° -P -P ° 10 mol% i i O OH P -P -P r r i i O O P -P -P i i O OH O O O OH Et r r 2 3 3 3 P

P O OH H O O O -P -P O O i i r r P 1 mol% toluene, 35 20 mol% benzene, 60 5 mol% SiPh SiPh O O -P -P i i O, r.t. toluene, -78° 2 1.2 eq. AcOH Et N H 2 3 10 mol% Et HH O H 10 mol% benzene, 50° CC CC Ph Ph 3 2 Et Et 3 3 H O N H O O H H cyclohexane, MS 5Å, 50 HH Et 2.2 eq. O O 2 CC CC . H 3 2 OTMS 3 3 H O 2 N H N H m Et HH HH Tos-N NH OCH OCH 2 t CC CC O O 3 3 + + 1.5 eq. H H NH OE O O + Et Et 3 Boc H 3 + + N CH CH P 3 3 2 O Ar Ph PM CH R R N N safcglobal.co 1 N R Ar HO RH F OO , , ). 7 , 128 , ) and 0 6 J. Am. , 1086. , 7424. ). 2005 Et . 2 44 Scheme 1 2006 Et 2 128 , 2 CO R , NH CO Scheme 1 68989 N H 2005 ) to form 2006 Org. Lett . 40-98% 72-90%ee 0 1 Scheme 6 R top). List reported bottom). and highlighted the )-TRIP ( 0 R 68989 r r J. Am. Chem. Soc. -P -P i i ). 5 r r ). Addition of acetic acid 4 ). -P -P , 7498. (5) Gerald, B.; Rowland, i i contact your local Sigma-Aldrich office, or visit O OH 0 68989 SO P 2 O O J. Am. Chem. Soc r r )-TRIP ( 129 Na 20 mol% , -P -P R i i Scheme 2, Scheme 2, Angew. Chem. Int. Ed. Angew. in the addition of sulfonamides ) can distinguish between a toluene, -30°, 3-5d 2 68989 5 2007 Scheme 4 Scheme 5 Ready to scale up? For competitive quotes on larger quantities or custom synthesis, H 67551 67474 O )-TRIP ( 2 Rueping first reported that phosphoric R R 2 + Et 2 Et a direct Pictet-Spengler reaction with a range 2 J. Am. Chem. Soc. 1 2 , 15696. (6) Akiyama, T.; Tamura, Y.; Itoh, J.; Morita, H.; Fuchibe, Y.; Tamura, , 15696. (6) Akiyama, T.; CO CO NH 127 It is even possible to obtain good enantiomeric , N H catalyzed the reduction of an imine with a Hantzsch 3 , 141. 5 ). The synthesis of pharmaceutically relevant 3-substituted (1) Seayad, J.; Seayad, A. M.; List, B. 1 4 2005 R 2006 67460 Synlett Scheme 3 (3) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. MacMillan, D. W. D. E.; Ni, Y.; R. I.; Carrera, (3) Storer, 84. (4) Zhou, J.; List, B. Antilla, J. C. Y.; G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni, S.; Wang, Chem. Soc. K. improved improved both reactivity and enantioselectivity ( References: Bolte, M. (2) (a) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; S.; Seayad, A. M.; List, B. 3781. (b) Hoffmann, excellent enantioselectivities ( The aza-Diels-Alder reaction of aldimines with Danishefsky’s diene to piperidinone afford derivatives proceeded with high enantioselectivity using ( Antilla and co-workers reported on the use of derived VAPOL phosphoric acid derivative to Boc-protected aryl imines, giving rise to protected aminals in dehydration-conjugate reduction-reductive dehydration-conjugate amination reduction-reductive cascade that is catalyzed by the chiral Brønsted acid ( accelerated by the achiral amine substrate, which is ultimately incorporated into the product ( enantiomeric excess. List reported an Recently, elegant, highly enantioselective cascade reaction. cyclohexylamines from 2,6-diketones via an aldolization- ( excess with 2-butanone where the silylated phosphoric acid MacMillan TiPSY catalyst ( methyl group and an ethyl group, delivering the product in high enantiomeric excesses up to 92% ( MacMillan finally reported a one-pot, direct, reductive amination with broad substrate scope that enables the effective reductive amination of a range of methyl ketones and aryl amines acid ester in good enantiomeric excess ( an improvement to this method using ability to perform a one-pot process from aldehyde to amine in does not significantly affect the utility of this process. An enantioselective reductive amination has been reported by several groups. research workers reported of aldehydes using organocatalyst ( isoquinolines in high yields and enantiomeric excess ( A geminally disubstituted tryptamine is needed, but this limitation Chiral Phosphoric Acids Chiral BINOL-derived phosphoric acids are capable of catalyzing a range of interesting processes of which nucleophilic addition reactions to imine substrates List are and particularly co- noteworthy. Chiral Phosphoric Acids 12

sigma-aldrich.com phate, 96% hydrogenphosphate, C ( 248932-5 248932-1 248932-250M [39648‑674] FW 348.29 C ( 675512-500M 675512-100M 680184-100M FW 865.07 C 96% hydrogenphosphate, ( 674745-100M [791616‑552] FW 865.07 C ( 248940-5 248940-1 248940-250M [35193‑647] FW 348.29 [871130‑186] FW 600.60 C ( R R S R S 20 56 20 40 56 phate, 97% hydrogenphosphate, )-(+)-1,1′-Binaphthyl-2,2′-diyl )-3,3′-Bis(triphenylsilyl)-1,1′-bnaphthyl-2,2′-diyl phate, ≥98% hydrogenphosphate, )-(−)-1,1′-Binaphthyl-2,2′-diyl )-(–)-3,3′-Bis(triphenylsilyl)-1,1′-bnaphthyl-2,2′-diyl )-(–)-VAPOLhydrogenphosphate H H H H H 13 13 41 41 25 O O O O O 4 4 4 4 4 P P P P P PSi PSi G G G G 2 2

G G G G G G

ORDER: Contact your local Sigma-Aldrich office (see back cover), back (see office Sigma-Aldrich local your Contact TO ORDER: or visit or Ph Ph sigma-aldrich.com/chemicalsynthesi O O O O Si Si Si Si 500 mg 100 mg 100 mg 250 mg 100 mg 250 mg P P O O O O O O OH OH O O 8 P P P OH O OH O OH O 5 g 1 g 5 g 1 g phate, 95% hydrogenphosphate, 2,2′-diyl 2,2′-diyl hydrogenphosphate 2,2′-diyl (R) 681520-100M [878111‑172] FW 772.47 C 95% hydrogenphosphate, binaphthyl-2,2′-diyl ( 674605-100M [791616‑621] FW 772.47 C ( 689890-100M [791616‑632] FW 752.96 C 689785-500M 689785-100M FW 752.96 C hydrogenphosphate 2,2′-diyl (S) 689890-500M S R 36 36 50 50 )-(+)-3,3′-Bis(3,5-bis(trifluor )-3,3′-Bis[3,5-bis(trifluor -3,3′-Bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl- H H H H -3,3′-Bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl- 17 17 57 57 F F O O 12 12 4 4 P P P P O O 4 4 P P P

G G G G G G s . omethyl)phenyl]-1,1′-binaphthyl-

omethyl)phenyl)-1,1′-

H H H H 3 3 3 3 C C C C CH CH CH CH O O O O 3 3 3 3 P P O O OH OH O O O O 100 mg 100 mg 500 mg 100 mg 100 mg 500 mg CF CF CF CF P P O O CH CH CH CH CH CH CH CH CH CH CH CH OH OH 3 3 3 3 8 8 8 3 3 3 3 CH CH CH CH 3 3 3 3 CF CF CF CF 3 3 3 3 3 3 3 3 3 3 3 3 Chiral Diols 13

sigma-aldrich.com 3 3 3 3 1 g 1 g 1 g 1 g 5 g CH CH CH CH 3 3 3 3 3 3 100 mg 250 mg 100 mg 250 mg 250 mg CH CH CH CH H O H O HO OH OH OH OH OH HO 3 3 OH CC H O 3 CC O OH O CH 3 O OH H H C CC 3 O 3 O H H HO HO

-tetra(2-naphthyl)-1,3- α′ , -tetraphenyldioxolane-4,5- -tetra(2-naphthyl)dioxolane- ldioxolane-4,5- -tetrapheny α′ α′ α′ α′ , , , , α′ α′ α′ . , , , α,α α α m α , , , α α α G G G G G safcglobal.co F F

)-2,2-Dimethyl- G G G

4 4 4 4 2 2 )-2,2-Dimethyl- )-2,2-Dimethyl- )-2,2-Dimethyl- O O O O O O R R S 30 30 38 38 38 38 ,5 ,5 ,5 H H H H H H )-(−)-3,3′-Bis(3,5-dimethylphenyl)-5,5′,6,6′,7,7′,8,8′- S R R S-trans )-(+)-3,3′-Bis-(3,5-dimethylphenyl)-5,5′,6,6′,7,7′,8,8′- 31 31 47 47 36 36 R S 59490-1G- 59490-5G- (4 C FW 466.57 [93379‑49‑8] 264997-250M 264997-1 (4 C FW 466.57 [93379‑48‑7] 265004-250M 265004-1 (4 C FW 666.80 [137365‑09‑4] FW 502.69 669172-100M (4 C FW 666.80 [137365‑16‑3] 393762-250M 393762-1 ( C FW 502.69 669180-100M ( C hthol, octahydro-1,1′-bi-2-nap 97% hthol, octahydro-1,1′-bi-2-nap 97% dimethanol dimethanol 4,5-dimethanol, ≥99.0% (HPLC, sum of enantiomers) dioxolane-4,5-dimethanol, 98% , 1 g , ). h e 424 O 125 , OH ,

3 H 2 O Chem. 70%, 99%e Scheme 3 Scheme 2 Scheme 1 OP 2003 2003 CC 3 O H e Scheme 1 n 39524 was HO Nature

/toluen COCl 2 2 3 Ph Cl e 2 CH N OH -78°, 15 mi O CH 92%e O OH 66917 70-72%, 92-96%ee R J. Am. Chem. Soc. Ph C 72%, 96%ee 3 O H contact your local Sigma-Aldrich office, or visit 3 3 N OH OH CH CH Ar Ar ° 3 3 O The reaction of different 3 -tetra(1-naphthyl)-1,3- Ar Ar 2 CH CH O, -78° CH 2 ). O O OH OH α′ Important for achieving high 30 mol% Et , 3 C TBDMS 3 82%, 95%ee 10 mol% Ar = 1-naphthyl C C P, THF, -10 ). H 3 3 3 α′ , H H Et The reaction of an electron-rich Ready to scale up? For competitive quotes on larger quantities or custom synthesis, 1 α OH , OH Ar Ar N O α Ph Ar Ar O O toluene O Scheme 2 + Ar = 1-Naphthyl 71%, 96%ee Scheme 3 + h N = R O O RH HP + , 429. (3) McDougal, N. T.; Schaus, S. E. , 429. (3) McDougal, N. T.; N

)-2,2-Dimethyl- (1) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. V. Unni, A. K.; Thadani, A. N.; Rawal, (1) Huang, Y.; G

4 2006 O O 38 TBDMS H S-trans 47 395242-1 C FW 666.80 [171086‑52‑5] (4 References: Jiang, Y.-Z. Gong, L.-Z.; Mi, A.-Q.; 146. (2) Guo, H.-M.; Cheng, L.; Cun, L.-F.; Commun. 12094. reported reported by Schaus ( enantioselectivity were both the partial saturation and substitution at the 3,3’-positions of the BINOL derivative. in a highly enantioselective manner. A highly enantioselective addition of cyclohexenone to different aldehydes (asymmetric Morita–Baylis–Hillman reaction) catalyzed by octahydro-BINOL-derived Brønsted acid The α-amination of carbonyl compounds has also been accomplished by using the derivative 1-naphthyl as TADDOL a Brønsted acid catalyst ( enamines with nitrosobenzene gave exclusively the N-regioisomers hetero-Diels–Alder hetero-Diels–Alder reactions. diene with benzaldehyde using 10 mol % TADDOL provides the as dihydropyrone a single stereoisomer ( Chiral Diols Chiral Apart from numerous examples in using metal-catalyzed TADDOLs asymmetric reactions, Rawal recently could reported that TADDOLs be used as Brønsted acid organocatalysts in highly stereoselective dioxolane-4,5-dimethanol, 99% Jacobsen Thioureas 14

sigma-aldrich.com 10558. (6)Talyor, M.S.etal. Soc. E. N. G. D.;Jacobsen,E.N. References: (TrocCl)chloroformate ( trichloroethyl and materials starting aromaticfrom heterocycles enantioenriched to route a providingreaction, acyl-Mannich ( tetrahydro-β-carbolines form to reaction acyl-Pictet–Spengler in depicted organocatalyst thiourea the developed also has group Jacobsen The chromatography.gel silica by yield quantitative near recoveredin be can catalyst the addition, In excesses. enantiomeric and yields high in well as aldehydes and ( organocatalyst thiourea the of differentversion slightly a using achieved been also has ketones recently,Moreof cyanosilylation the substrates. heterocyclic for particularly tolerance, substrate ( organocatalysts thiourea by catalyzed when enantioselectivities and yields excellent to good with addition underwent arylimines group. Jacobsen the by reported been also have imines Boc-protected of reactions Mannich aldimines. of variety wide a of tolerant was and phosphite, the on substituents ester electron-withdrawing with effective particularly was reaction The ( catalyst the of % mol 10 of presence the in occurred Similarly,catalyst. hydrophosphonylation the imine of % mol 1 of presence the in enantioselectivities high very with hydrocyanation ( reactionStrecker the in scope broad very a have to Jacobsen by in depicted organocatalyst thiourea The scope. substrate broad a with general, in and, excesses enantiomeric excellent in electrophiles imine-type mostly to added be can nucleophiles latent of range A organocatalysts. effective and versatile are that thioureas chiral of range Jacobsen’sa developed has group Jacobsen Thioureas Scheme 5 Scheme 3 Scheme 1 2005 J. Am.Chem.Soc. , 127 (1)Vachal, P.; Jacobsen,E.N. ). excellent shows reaction organocatalytic the Again ). ). , 8964.(5)Taylor, M.S.;Jacobsen,E.N. 5 1 Both aldimines and ketonimines underwent ketonimines and aldimines Both This same organocatalyst is also effective in the in effective also is organocatalyst same This Scheme 4 J. Am.Chem.Soc. 2002 Angew. Chem.Int.Ed. , 124 Scheme 6 , 12964.(4)Fuerst,D.E.;Jacobsen,E.N. ). Figure 2 4 The reaction proceeds for ketones for proceedsreaction The 2004 J. Am.Chem.Soc. 3 A wide variety of variety wide A ). , 6 126 and applied it in the in it applied and ORDER: Contact your local Sigma-Aldrich office (see back cover), back (see office Sigma-Aldrich local your Contact TO ORDER: , 4102.(3)Wenzel, A.G.;Jacobsen, 2005 Figure 1 J. Am.Chem.Soc. , 44 2002 , 6700. or visit or was reported was , 124 N -Boc , 10012.(2)Joly, Scheme 2 2004 sigma-aldrich.com/chemicalsynthesi J. Am.Chem. , 126 , ). 2

Boc H R N 1 R CH + NO R H N Et 1 2 Cl 2 N O 3 SiH, TFA 2 OTBS s , 0to23°C R . NH 2 O O 1) TrocCl,Et 2) 10mol% i -P R 2 O O P 1 r Et N H NO 2 1) 2) 5-10mol% O, -78to-70°C H R R 2 R 3 2 3 H C 2 + 3 CHO, 3ÅMSorNa C TMSCN, TFE,CH N CH 2 693340 O, 0to23°C R N H HCN, toluene,-78°C O N 3 N 1 mol% O O t -B Et H Bn 1) toluene,-30°C,48 H N N CH t t

, 2eq u -Bu 2 693340 -Bu 693464 O, -78°C S 693340 H N CO NTro 693421 H N O 5 mol 10 mol% 3 2) TFA,2mi t H N Et H S -Bu S HO H t 693421 2 -B 5 mol 3 i 2 693472 3 Pr C H N c H N O, 4-23°C C H N , AcCl,lutidine OTBS u % H N 2 2 S Cl SO O % N THF/ t H N 693421 2 i -B Pr HO N , -78°C 4 u Zn, AcO n O H N 2 CH O 86-99.3% ee O, 23°C h R 3 t 1 HN -B H R 80%, 86%ee NO O u t 2 R -B 2 R CN 1 N u 2 3 81-99% ee TMS CO 86-98% ee NTro O 85-95% ee R 2 H N 1 O i O O P i Pr c -PrO HN CN R 86-98% ee 2 N R Bn R O CO NH 2 O 2 HN CH i Pr 3 R Bo Scheme 6 Scheme 5 Scheme 4 Scheme 3 Scheme 2 Scheme 1 Scheme c Figure 2 Figure 1 Figure Jacobsen Thioureas 15

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3 3 3 CH CH 3 CH 8 8 CH 100 mg 500 mg 100 mg 500 mg N s 3 C N H N - 3 3 H S CH N HO CH N H C C N H 3 3 3 C H H S 3 CH H 3 O C N H 3 3 H N H CH 3 CH O C 3 C CH N H 3 H

-butyl)-2-hydroxy- tert . m ohexyl]thio- lamino)cycl )-2-(Dipropy R )-2-[[[3,5-Bis( G G G G

,2 safcglobal.co R R Got ChemNews? ,2 S lbutanamide -isopropyl-3,3-dimethy ,3,3-trimethylbutanamide 2 R N N OS O 4 4 sigma-aldrich.com/chemnew N N 44 54 Monthly Chemistry E-Newsletter H H )-2-[3-[(1 )-2-[[(1 22 36 S S ( ureido]- C FW 412.68 693464-100M 693464-500M ( ohexyl]thioureido]- phenyl]methylene]amino]cycl benzyl- C 693472-100M 693472-500M FW 606.90 [479423‑24‑0] 3 2 3 3 3 CF CH NH CH 8 8 8 8 3 CH 100 mg 500 mg 100 mg 500 mg 100 mg 500 mg 100 mg 500 mg CF N H O 3

S O CH 3 N H N H - H 3 S N CH N H C 3 CH 3 3 3 3 N H O H C S N - 3 CH CH H CH N CH N H N HO 3 O C C C N H C 3 3 3 3 3 H CH N 3 H H S H C O 3 CH 3 H N H N CH CH C 3 H C C C O 3 3 3 H H H N contact your local Sigma-Aldrich office, or visit

C C 3 3 H H )-2-(2-methyl-5-phenyl-1- Ready to scale up? For competitive quotes on larger quantities or custom synthesis, R ,2 R )-1-[(Dimethylamino)carbonyl]- oureido]- omethyl)phenyl]thi S ohexyl]imino]methyl]-5- opyl]thioureido]cycl )-2-[[(1 )-2-Aminocyclohexyl]thioureido]-

G G G G G G G G R

R ,2 ,2 S R OS ,3,3-trimethylbutanamide lbutanamide ,3,3-trimethy 4 R 3 N N O OS OS N 4 4 4 6 N N N F )-[[(1 yphenyl -butyl)-4-hydrox pivalate 50 34 50 25 amide -bis(2-isobutyl)butan E )-3,3-Dimethyl-2-[[(1 H H H H N )-2-[[(1 S ifluor )-2-[[3,5-Bis(tr , 31 21 32 23 tert S S 693421-100M 693421-500M C FW 574.82 [462632‑54‑8] 3-[( 2,2-dimethylpr ( 693413-100M 693413-500M benzyl- C FW 390.59 [479423‑21‑7] 693340-100M 693340-500M ( C FW 538.83 [764650‑97‑7] (2 ohexyl]thioureido]- pyrrolyl)cycl N 693316-100M 693316-500M benzyl- C FW 505.52 ( Cinchona Alkaloids 16

sigma-aldrich.com M. etal. 2003 Huh, H.;Park,H.-G. Andrews, B.J. References: ( ( of mixture a giving enantioselectivity and yields high in proceeds β-diketones of addition the alkynones (DHQ) using alkynones to addition conjugate enantioselective catalytic first the developed have Finally,co-workers and Jørgensen compounds. amine functionalized highly of range diverse a (DHQ) using out carried be can γ-position remote the at methodology.diimides with Amination π-allylic catalyzed palladium conventional the to extension useful a providesreaction amination allylic metal-free, The ( excess enantiomeric and yield excellent in cyanohydrin corresponding the to TMSCN of addition the by ketones of α-functionalization the affect to possible is it (DHQD) the Using excesses. enantiomeric high with centers asymmetric quaternary of formation the control to ability the is processes these of many in Important electrophiles. with reactions enantioselective permits and anion the aroundenvironment chiral a to leads interaction This amine. protonated and anion resulting the between pair ion contact a forming protons acidic relatively with substrates deprotonate to bases as used be can alkaloids Cinchona enantioselectivities. high with processes useful many catalyze alkaloids cinchona particular,In methods. the synthetic new of development the in role wide-ranging a had have catalysts Nucleophilic 97–99% ee. to optimized was alkylation imine glycine mentioned above the for ( alkaloid cinchona dimeric a such With units. spacer via moieties alkaloid cinchona two linked Park and Jew enantioselectivities, catalyst improve further to attempt an In ( derivatives acid α-amino of range a generate to imines glycine of reactions alkylation enantioselective highly to O of generations Several PTC. asymmetric in used organocatalysts chiral typical are alkaloids cinchona modified Synthetically application. widespread found has and transformations, organic synthetic homogeneous many to alternative “green” a as recognized been has (PTC) catalysis phase-transfer Asymmetric Cinchona Alkaloids Scheme 3 -alkyl , 125 J.Am.Chem.Soc N- , 9900.(3)Poulsen,T. B.etal. (1)(a)O’Donnell,M.J. arylmethyl derivatives were developed, which finally led finally which developed, were derivatives arylmethyl ). Acc. Chem.Res. 2 1 PHAL ( PHAL Chem. Commun. 39272 . 2004 2004 , 126 3 Acc. Chem.Res. ). , 2001 37 , 5672. 4 For both aromatic and aliphatic and aromatic both For J.Am.Chem.Soc. , 518.(c)Jew, S.-S.;Jeong,B.-S.;Yoo, M.-S.; Scheme 1 2 PYR ( PYR , 1244. (2) Tian, S.-K.etal. , 1244.(2)Tian, ORDER: Contact your local Sigma-Aldrich office (see back cover), back (see office Sigma-Aldrich local your Contact TO ORDER: 41897 2004 0654 2 ). AQN ( AQN E 2 )- and ( and )- 8 , 2005 2 37 ) ( ) ), enantioselectivity ), Table 1 , 506.(b)Lygo, B.; Scheme 2 or visit or 45671 , 127 Z )-enones , 11614.(4)Bella, J.Am.Chem.Soc. ). 3 sigma-aldrich.com/chemicalsynthesi ) catalyst ) ) to form to ) 3

499617 515701 514276 359580 524433 06542 Prod. No RO Ph 2 C . O

CN O O OE R OE 2,7-Naphthalene- 1 t 9-Anthr 9-Anthr t R diyldimethyl R 2 1 TMSCN, CHCl + methyl methyl Benzyl Benzyl Benzyl + N-Ar Ph 2-20 mol%cat Boc acenyl- acenyl- Ph N N N s O . Cinchonidinium PTC N Boc Cinchona PTC R 3 O 2 , -50 AlkO H . C O CH 3 toluene, r.t. 5 mol% C C 10 mol% ° H 2 2 O-Alk Cl C H Allyl Allyl Allyl H 2 Ph H , -24° C H C B H H NC 3 N 3 90-98%ee >80% Ar OTMS X H Catalyst (10mol% OE Base, Solvent Temp., Time RO OE

t Br Br Br X t 2 1 r 77-95%ee >95% RB C 3 l 1 l - H O O 2 CN r 86-99%ee 65-80% C H Bo R dimeric Cinchoninium PT 1 Gen. c Cat. Ar 2 3 ) R nd X R R NHBo rd rd st st N 2 2 1 O H

H 3 Ph CO c OAlk H 4-NO Ph H 3 4-Cl-C 4-Cl-C CO 3 H H H CO N 3 3 C C N N C R PhCH PhCH PhCH N 2 H R-Br -C H O H O H (DHQD) 6 6 N O O H H H O 6 N 3 N H CH C C 4 4 (DHQ 2 2 2 -CH -CH 4 O O (DHQ 8 - 6 - 8 - -CH O 3 CH H H 2 N N N 3 AQ 3 C ) 2 2 3 2 – - 9 - ) N 2 PHAL 2 O 9 - N PYR H O N N %Y N Scheme 3 Scheme 2 Scheme 1 Scheme N N N 9 1 9 7 9 8 6 5 6 5 H H H H Table1 OC CH CH OC OC %ee H 3 3 81 H 3 H 9 4 1 6 0 3 3 Cinchona Alkaloids 17

sigma-aldrich.com 3 3 3 3 3 3 1 g 1 g 1 g CH CH CH CH CH CH 3 3 3 2 2 2 H H O H O O 3 C C C 500 mg 500 mg 500 mg 250 mg 250 mg CH 3 H 3 H H R = CH R = CH R = CH O CH H N H H N N OCH O N N N H O O O O N H H N N N N N H O N N N N R H H O O O N O R R O O O N N N N N N H R N H N H H O H N H H

N R C H O N C 3 O C 3 O O H R 3 O N H H H O C H C 3 C N 3 N H 3 H H H O N C H 3 O H . C m 3 CO H 3 H G G G G G safcglobal.co

4 4 4 4 6 6 G G G PHAL, ≥95% 97% Pyr, AQN, 95% 2 2 2 O O O O O O PHAL, ≥95% Pyr, 97% Pyr, AQN, 95% 6 6 6 6 4 4 2 2 2 N N N N N N 54 60 60 54 56 56 oquindine 1,4-phthalazinediyl diether oquindine-2,5-diphenyl-4,6-pyrimidinediyl diether oquinine 2,5-diphenyl-4,6-pyrimidinediyl diether oquinine lazinediyl 1,4-phtha diether H H H H H H 48 48 56 56 54 54 418951-1 (DHQD) Hydr C FW 778.98 7] [140853‑10‑ 392731-1 (DHQD) Hydr C 418951-250M (DHQ) Hydr C FW 881.11 [149820‑65‑5] 418978-250M 418978-1 (DHQ) Hydr C FW 778.98 [140924‑50‑1] 392723-500M FW 881.11 [149725‑81‑5] 456705-500M (DHQD) C FW 857.05 [176298‑44‑5] 456713-500M (DHQ) C FW 857.05 [176097‑24‑8] H 1 g 1 g 1 g 1 g 1 g 5 g H H H H H N N N H N H H N H N H H H N N 250 mg 100 mg 500 mg N C C C N C H H C 3 3 3 3 3 H N C H H H O O H O H N O H 3 O 3 O H O N O CH 3 O O O O CH N C C C C 3 3 3 O 3 CO H H 3 H H Cl Cl C H 3 H contact your local Sigma-Aldrich office, or visit Ready to scale up? For competitive quotes on larger quantities or custom synthesis, oquinine, 98% obenzoate, 98%

G G G

3 3 obenzoyl)hydr

O O 2 2 2 2 G G G G G G 2 2 O O O O 2 2 3 3 N N N N ClN ClN thryl ether, 97% oquinine-9-phenanthryl ether, thryl ether, 96% oquindine 9-phenanthryl ether, ine 4-methyl-2-quinolyl ether, 98% oquinine 4-methyl-2-quinolyl ether, dine 4-methyl-2-quinolyl ether, 97% oquindine 4-methyl-2-quinolyl ether, oquindine 4-chlor 34 34 33 33 29 29 H H H H H H -(4-Chlor 34 34 30 30 27 27 381977-100M 381977-500M FW 502.65 [135096‑78‑5] 381950-250M 381950-1 Hydr C Hydr C FW 502.65 [135042‑88‑5] 381969-1 C FW 467.60 [135096‑79‑6] 381942-1 Hydr FW 467.60 [135042‑89‑6] 336491-1 Hydr C O C FW 464.98 [113216‑88‑9] 336483-1 336483-5 C FW 464.98 0] [113162‑02‑ Hydr Cinchona Alkaloids 18

sigma-aldrich.com [1435‑558] FW 326.43 337714-5 337714-1 [522‑667] FW 326.43 C Hydr C80407-100 C80407-10 [485‑712] FW 294.39 C 96% Cinchonidine, 27370-100 27370-25 [118‑105] FW 294.39 C (NT) ≥98.0% Cinchonine, 22600-50G- 22600-10G- [56‑542] FW 324.42 C (NT,≥98.0% material) Quindine, dried 145904-50 145904-10 [130‑950] FW 324.42 C 90% Quinine, 359343-5 359343-1 C Hydr 20 19 19 20 20 20 H H H H H H 24 24 26 26 22 22 ine, 98% oquinine, dine, 95% oquindine, N N N N N N 2 2 2 2 2 2 O O O O O O G G G G G 2 2 2 2

G G G G F F

ORDER: Contact your local Sigma-Aldrich office (see back cover), back (see office Sigma-Aldrich local your Contact TO ORDER: H or visit or 3 H H CO H 3 3 CO 3 CO C O HO H H HO H sigma-aldrich.com/chemicalsynthesi 3 2 HO HO 2 C C HO C HO H N H H N H H C H 3 N N 2 C 2 H N H C N C H H H H H 100 g 100 g H H N N H N N N 50 g 10 g 10 g 25 g H H 50 g 10 g N H 5 g 1 g 5 g 1 g H H

[219794‑817] FW 169.26 07317-500MG- 07317-100MG- [475160‑599] FW 168.28 (2S,4S,5R) 49463-500MG- 49463-100MG- C (GC) ≥99.0% (2 51957-500MG- 51957-100MG- [219794‑793] FW 169.26 C (2 54060-500M [485‑654] FW 296.41 C Hydr 359580-10 359580-2 [69257‑041] FW 420.97 C (8 1328 [69221‑143] FW 420.97 C N 374482-5 374482-1 [67174‑258] FW 451.00 C N C 10 10 19 26 26 27 10 nium chloride, ≥98.0% (AT) ≥98.0% chloride, -Benzylcinchoninium 95% chloride, -Benzylquinnium S R S H H H H H H H ,4 ,9 ,4 19 19 24 29 29 31 20 8 S nine, ≥97.0% (GC, sum of enantiomers) of sum (GC, ≥97.0% ocinchnine, R S ClN N NO NO NO N ClN ClN ,5 ,5 )-(−)- 2 2 O O

R R 2 2 2 G G G )-2-Hydrox O O O O

)-2-Hydroxymethyl-5-ethylquinuclidine, G dine, ≥95.0% (GC) ≥95.0% -2-Aminomethyl-5-ethylquinuclidine,

nium chloride, 98% chloride, -Benzylcinchonidinium

F F F F F F s . y methyl-5-ethy

l qui n ucl H 3 i CO dine,≥99.0% (GC) H 2 C HO HO H HO H N N H H H N H HO H 2 2 HO H C HO C H N H 2 H H H 3 N 3 C H 3 3 N C 500 mg 100 mg N N 500 mg 100 mg 500 mg 100 mg C C 500 mg Cl N H N N H 10 g N H H Cl Cl 2 g 5 g 1 g H

Maruoka Phase-Transfer Catalysts 19

sigma-aldrich.com 3 3 3 3 3 Br 1 g 5 g 1 g 5 g N CH CH CH CH CF – 8 8 F F F F F F F F 3 50 mg Br Br 50 mg o- Br omide omide 100 mg Br CH F F F F N N 2 + H O N CH H H N N H H – C 2 H N Br H C N omide, 2 O HO H + ]azepinium br ]azepinium br N C O 2 e e H C C 2 3 H H

:1′,2′- :1′,2′- N c c . m omide, ≥97.0% -dinaphth[2,1- -dinaphth[2,1- H H ldimethyl)bis(hydr ′-(2,7-naphthalenediy

, F

omethylbenzyl)cinchoninium br N

safcglobal.co G G 2 O 2 O inium lmethyl)cinchonid -(9-anthraceny O 4 N N N G G 2 6 6 3 N N G G 2 ophenyl)-3 ophenyl)-3 )-(–)-4,4-Dibutyl-4,5-dihydro-2,6-bis(3,4,5- )-(+)-4,4-Dibutyl-4,5-dihydro-2,6-bis(3,4,5- BrF BrF BrN BrF Br R S 36 36 37 66 28 ′-Diallyl- H H H H H O omide, 90% -Allyl- , ifluor -(4-Tr 42 42 37 56 27 677086-50M 91851-1 91851-5 (11b trifluor C FW 748.64 [887938‑70‑7] 687596-50M (11b trifluor C FW 748.64 [851942‑93‑3] O C FW 605.61 3] [200132‑54‑ 499617-1 499617-5 O C FW 986.96 [480427‑57‑4] 06542-100MG- N ≥98.0% (AT) C FW 533.42 [95088‑20‑3] br cinchonidinium) dibr -

Br 1 g 5 g 5 g Br Cl H 25 g H This N + 1 N C Scheme 1 2 C 2 H H N H N H N H , 1549. (b) Ooi, T. , 1549. (b) Ooi, T. O Aldrichimica Acta C HO 44 2 2 N , H u CH -B t HO O 2005 O Bn N 98%, 99%ee Ph ). Ph contact your local Sigma-Aldrich office, or visit omide Br F F F F H Bu Bu F F N Scheme 1 , 603. (c) Ooi, T.; Maruoka, K. , 603. (c) Ooi, T.; 0.05 mol% 50% aq. KO toluene, 0° omide, 97% Ready to scale up? For competitive quotes on larger quantities or custom synthesis, Angew. Chem., Int. Ed. Angew. 17 , -Bu t -symmetric ammonium salts that catalyze O 2 2006 O C N Ph Ph

G -benzylcinchonidinium br O O O (1) (a) Kitamura, M. et al. G G G 2 2 2 N , 77. ClN BrN BrN 40 33 33 29 Tetrahedron: Asymmetry Tetrahedron: , H H H -Allyl- inium -(9-Anthracenylmethyl)cinchonind chloride, 85% inium -Benzylcinchonid br 34 29 26 References: et al. 2007 methodology has been applied to the enantiocontrolled synthesis of α-alkyl-α-amino acids by monoalkylation of glycine-derived Schiff bases with alkyl halides ( Chiral quaternary ammonium catalysts can be particularly useful in the field of asymmetric synthesis. Maruoka and co-workers have reported potent alkylation reactions under remarkably low catalyst loadings. Maruoka Phase-Transfer Catalysts Maruoka Phase-Transfer 515701-5 515701-25 N C FW 521.09 [199588‑80‑2] 514276-1 O C FW 505.49 [158195‑40‑5] 524433-5 C FW 465.43 2] [118089‑84‑ N CBS Oxazaborolidines 20

sigma-aldrich.com [112022‑830] FW 277.17 649309-10 649309-1 [112022‑818] FW 277.17 C ( 649317-10 649317-1 C ( 125 Tetrahedron Lett. Cho, B.T.; Chun,Y. S. 2004 J. etal. References: ( reaction Diels–Alder enantioselective the in utility great demonstrated has trifluoromethanesulfonimide from generated acid Lewis chiral The excesses. enantiomeric and yields excellent in respectively,alcohols, amino and amines, alcohols, chiral produce to oximes and imines, ketones, prochiral of reduction catalytic the for used been have Corey,Shibata) (after and catalysts Bakshi, CBS as known oxazaborolidines chiral of series the 1987, Since CBS Oxazaborolidines 457701-25M 457701-5M  [112022‑818] FW 277.17 C ( 457698-25M 457698-5M  [112022‑830] FW 277.17 C ( R S R S 18 18 18 18 M in toluene in 1 M toluene in 1 M )-(−)-2-Methyl-CBS-oxazaborolidine solution )-(−)-2-Methyl-CBS-oxazaborolidine )-(+)-2-Methyl-CBS-oxazaborolidine )-(+)-2-Methyl-CBS-oxazaborolidine solution H H H H , 6388. , 20 20 20 20 45 J. Am.Chem.Soc BNO BNO BNO BNO BNO BNO , 853.(d)Cho,B.T.; Chun,Y. S. G G (1)(a)Corey, E.J.etal. G G L L

L L

1995 o J. Chem.Soc.,PerkinTrans. 1 , -tolyl-CBS-oxazaborolidine after protonation with protonation after -tolyl-CBS-oxazaborolidine 36 . 1987 , 4337. (g) Ryu, D.H.;Corey,, 4337.(g)Ryu, E.J. , 109 J. Am.Chem.Soc. , 7925.(c)Kirton,E.H.M.etal. Tetrahedron: Asymmetry ORDER: Contact your local Sigma-Aldrich office (see back cover), back (see office Sigma-Aldrich local your Contact TO ORDER: Scheme 1 1990 1987 , 3200.(f)Tillyer, R.D.etal. , J. Am.Chem.Soc. 109 or visit or ). , 5551.(b)Corey, E. 1992 1 Tetrahedron Lett. , 3 sigma-aldrich.com/chemicalsynthesi , 337.(e) N H N H N H N H CH CH B B B B 2003 CH CH O O O O 25 mL 25 mL 3 3 3 3 5 mL 5 mL 10 g 10 g , 1 g 1 g

674656-25M 674656-5M  [112022‑830] FW 277.17 C ( 654302-25M 654302-5M  [463941‑073] FW 353.26 C ( 654299-25M 654299-5M  [865812‑108] FW 353.26 C ( 674648-25M 674648-5M  [112022‑818] FW 277.17 C ( R S R S 18 24 24 18 M in tetrahydrofuran in 1 M M in toluene in 0.5 M toluene in 0.5 M tetrahydrofuran in 1 M )-(−)- )-(−)-2-Methyl-CBS-oxazaborolidine solution )-(+)-2-Methyl-CBS-oxazaborolidine solution )-(+)- H H H H 20 24 24 20 BNO BNO BNO BNO BNO BNO BNO o o -Tolyl-CBS-oxazaborolidine solution -Tolyl-CBS-oxazaborolidine solution TIPSO L L L L L L L L

+ s . H 3 C O O CH I 3 (C

F 3 CH SO 2 2 Cl 20 mol% ) 2 N 2 H , -78°,16h N H B Ph O Ph CH 3 TIPSO 99%, >99%ee H 3 H C O O CH I Scheme 1 Scheme N H N H N H N H 3 CH B B B B CH O O O O 25 mL 3 25 mL 25 mL 25 mL 3 5 mL 5 mL 5 mL 5 mL CH CH 3 3 N-Heterocyclic Carbene (NHC) Compounds 21

sigma-aldrich.com F F F F

- - F F ,

H H + + N N 250 mg 250 mg ,6 ,6 2 F F 2006 N N d R

H H 2 , 3520. 1 F F R Scheme 2 Scheme 3 Scheme 4 O O N N R 4 4 3 O d , 15088. . J. Am. Chem. 1 R 1 d 129 BF BF R R , C 128 50–93% yiel 97–99% ee 2 O , O O CO 3 N 2007 2 97–99% ee 70–95% yiel H 97–99% ee R 50–90% yiel H 2006 PG

ophenyl)-4 ophenyl)-4 , 6021. J. Am. Chem. Soc. 45 O O O , A 3 % % U – N – N – N Cl Cl % Cl 3

3 N N 3 2006 N N N N Cl, 0–23 °C 3 10 mol 3 0.5 mol CH 2 CH 3 CH ][1,4]oxazinium ][1,4]oxazinium J. Am. Chem. Soc. CH , 2. (2) Kerr, M. S.; Rovis, T , 2. (2) Kerr, 10 mol CH CH CH d d 2 EtOAc, 23 °C 1.5 equiv NEt H 15 mol % DB 10 mol % DIPE 46 J. Am. Chem. Soc. , ClC C C toluene:THF (10:1), 23 °C toluene:THF (10:1), 23 C 3 3 3 H H H 2007 2 2 3 . R R R O O m O 2 O C R 2 Angew. Chem., Int. Ed. Angew. H CO + 3 + H 1 1 +

R ][1,2,4]triazolo[4,3- ][1,2,4]triazolo[4,3- G G H safcglobal.co b b afluor )-5a,10b-Dihydro-2-(pent afluor )-5a,10b-Dihydro-2-(pent Cl O , 8876. (3) He, M.; Struble, J. R.; Bode, J. W. , 8876. (3) He, M.; Struble, J. R.; Bode, J. W. Angew. Chem. Int. Ed. Angew. S N O O R O oborate, 97% oborate, 97% 3 3 HR (1) For a review on NHC organocatalysts, see: Marion, N.; Díez-González, on NHC organocatalysts, see: Marion, N.; Díez-González, (1) For a review H PG N N 126 1 9 9 , R BF BF ),10b( ),10b( 11 11 R S 2004 , 8418. (4) He, M.; Uc, G. J.; Bode, J. W. , 8418. (4) He, M.; Uc, G. J.; Bode, J. W. H H 18 18 128 Kaeobamrung, J.; Bode, J. W. (5) Chiang, P.-C.; (6) Sohn, S. S.; Bode, J. W. 5a( indeno[2,1- C FW 467.10 [872143‑57‑2] 674788-250M 5a( indeno[2,1- C References: S.; Nolan, S. P. Soc. FW 467.10 [740816‑14‑2] 667080-250M tetrafluor tetrafluor Scheme 1 G 3 in the EW

R CH 3 2 0 e CH O CO X Achiral catalyst 5 O ). S 95%, 92%e 66708 These catalysts promote F h 4 contact your local Sigma-Aldrich office, or visit F 3 ). catalyzes an inverse- F CH 3 2 -dihydropyridinones with The use of α-chloro 3 F Scheme 4 3 CH CO F ). 4 cis N N BF O O 20 mol% N N, toluene, r.t., 24 3 96%, 97%ee 68397 H Ready to scale up? For competitive quotes on larger quantities or custom synthesis, O . Et Scheme 3 6 eq H 2 ). 3 Scheme 2 CH 2 3 G CO CH EW O XR O 95%, 99%ee in highly enantioselective intramolecular Stetter Scheme 1 1 The Stetter reaction (conjugate addition of an aldehyde 2 is also useful for redox esterifications and amidations of 7 68848 α-functionalized aldehydes. *Bode Catalysts are sold in collaboration with BioBlocks, Inc. enantioselective annulations with enones using less than 1 mol % of the chiral NHC catalysts ( highly enantioselective cyclopentene-forming annulations of simple enals and activated enones ( electron demand Diels–Alder reaction of activated enals and α,β-unsaturated imines to afford outstanding selectivity ( aldehydes as starting materials is viable, and also makes possible make possible a new generation of highly enantioselective annulations from simple starting materials under mild reaction conditions, usually at room temperature and without added reagents. For example, chiral the catalytic generation of reactive species including activated carboxylates, homoenolates, and enolates. Critical to the success of these processes is an N-mesityl substituent on an imidazolium or triazolium TheseNHC novelprecursor. catalysts and reactions Bode Catalysts Beginning in 2004, Bode and co-workers extended the use of NHCs as organocatalysts by developing new approaches to to an α,β-unsaturated compound) is a superb method for the construction of 1,4-dicarbonyl compounds bearing quaternary stereocenters ( Rovis has demonstrated that triazolium salt presence of a base can act as an N-heterocyclic carbene organocatalyst reactions. N-Heterocyclic Carbene (NHC) Carbene (NHC) N-Heterocyclic Compounds Rovis Catalysts Comprehensive Books and Reviews 22

sigma-aldrich.com monohydrate, 97% chloride monohydrate, oxazinium (5a 683701-500M 683701-100M [862095‑918] FW 362.99 C tetrafluor 1,2,4-triazolium 6,7-Dihydro-2-pentafluor 683973-250M 683973-100M [903571‑028] FW 367.87 C phenyl)-4 11 21 Shi Epoxidation Catalyst Epoxidation Shi H H R 22 7 ,10b Chem. Soc Reference: selectivities. certain and epoxidize to able is organocatalyst This 520160-5 520160-1 [18422‑532] FW 258.27 C 1,2:4,5-Di- ose, 98% hexodiulo-2,6-pyranose, BF ClN 12 R 9 H N 3 3 18 S 3 O O

H )-5a,10b-Dihydro-2-(2′,2,4′,6′-trimethyl- O R ,6

6 .

2 G G G G 1997 (1) Wang, Z.-X.;Tu, Y.; Frohn, M.;Zhang,J.-R.;Shi,Y. H G G

-indeno[2,1- 1 O cis , -isopropylidene-β- 119 alkenes with good to excellent yields and yields excellent to good with alkenes , 11224. H 3 C O H CH ophenyl-5 2 borate, 97% oborate, O/CH Oxone b O 3 O ]-1,2,4-triazolo[4,3- O 3 CN O CH O ORDER: Contact your local Sigma-Aldrich office (see back cover), back (see office Sigma-Aldrich local your Contact TO ORDER: CH D 3 H - erythro -pyrrolo[2,1- 3

H H 3 trans 3 C C ee's upto98 various examples O R or visit or -2,3- O 3 alkenes d F F ]-1,4- O R O c O 2 J. Am. ]- R H sigma-aldrich.com/chemicalsynthesi O Cl F F 3 N O 1 C % O BF CH N CH N F 250 mg 100 mg 4 500 mg 100 mg N 5 g 1 g + - 3 N 3 8 8 N CH CH 3 3 monohydrate, 97% chloride monohydrate, 688487-250M 688487-100M FW 263.77 C 97% chloride, 4-ium 2-Mesityl-2,5,6,7-tetrahydr 683981-250M 683981-100M FW 367.87 C 4 (5a Comprehensive BooksandReviews H 14 21 (6) (9) (13) (16) (11) (10) (8) (2) (1) (15) (5) (4) (12) (14) (3) (7) H H , 6 , S 18 22 ,10b H

ClN ClN -indeno[2,1- Marion, N.; Díez-González, S.; Nolan, S. P S. Nolan, S.; Díez-González, N.; Marion, Taylor,N. E. Jacobsen, S.; M. Seayad, J.; List, B. List, J.; Seayad, 3726. P.Dalko, L Moisan, I.; 5138. Organocatalysis Asymmetric print: B. List, 348 K T.;Fuchibe, Akiyama, J.; Itoh, 45 Organocatalysis. Asymmetric 39 Ed. Int. 2007 Today Discovery Drug No. Prod. (Aldrich Synthesis Asymmetric for Methods Powerful to Concepts Biomimetic From – Gröger,A.; Berkessel, H. 2007. Weinheim, Procedures Experimental and Reactions Organocatalysis: Enantioselective Dalko, P.Dalko, L. Moisan, I.; De Figueiredo, R. M.; Christmann, M. Christmann, M.; R. Figueiredo, De Gaunt, M. J.; Johansson, C. C. C.; McNally,C.; T.;Vo,C. N. A.; C. Johansson, J.; M. Gaunt, Kocovský, P.;Kocovský, Malkov,V., A. Eds.; Houk, K. N.; List, B. List, N.; K. Houk, Pellissier,H. Lelais, G.; MacMillan, D. W.D. C. MacMillan, G.; Lelais, 3 3 R O , 1520. , 79. , )-5a,10b-Dihydro-2-(2′,4′,6′-trimethylphenyl)- , 999. ,

, G G G G

Chem. Commun. Chem. 16 2007 , 2575. , s . Tetrahedron b , ]-1,2,4-triazolo[4,3-

46 , 2988. , Org. Biomol. Chem. Biomol. Org. Z704113 Acc. Chem. Res. Chem. Acc. opyrrolo[2,1- . Angew. Chem. Int. Ed. Angew.Int. . Chem. ; Wiley-VCH: Weinheim, 2005. Weinheim, Wiley-VCH: ;

2007

Angew. Chem. Int. Ed. Angew.Int. Chem. ; Dalko, P.Dalko, ; Wiley-VCH: Ed.; I., 2007 2006 Asymmetric Organocatalysis Asymmetric , ) ChemFiles 12 Angew. Chem. Int. Ed. Angew.Int. Chem. , , 819. , . Adv.. Cat. Synth. Aldrichimica Acta Aldrichimica , 8. , 63 TetrahedronSymposia-in- , 9267. , 2006 d c ]-1,4-oxazinium ][1,2,4]triazol- 2004 Eur.Chem. Org. J. 2005 2006 , 62 . Angew.. Chem. H , 3 C 37 , 243. , , , 3 2001 2004 , 487. , 6 , 719. , CH H Cl (4). 3 N O C 2006 3 2006 Cl CH N N , , 250 mg 100 mg 250 mg 100 mg N + 2006 40 43 N 3 8 8 N , , , , CH CH 3 3 , Simplify Discovery Chemistry with ChemDose®

™ X-Phos Pd(OAc)2 Pd(dppf)Cl2•CH2Cl2 PEPPSI -IPr PdCl2(PPh3)2 Pd2(dba)3 HATU

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hemDose® is a novel High-Throughput Screening (HTS) technology allowing for the use of chemical C reagents and catalysts in the form of tablets. Co-developed with Reaxa Ltd., the ~5 millimeter tablets are composed of a chemically inert magnesium aluminosilicate matrix, together with an absorbed reagent or catalyst. Upon exposure to solvents, the reagent or catalyst readily dissolves out, leaving behind an easily removed insoluble tablet.1

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Br B(OH)2 Pd(dppf)Cl2•CH2Cl2 (2 mol%) + K2CO3, water–i-PrOH, 80 °C CH3 H3C

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Reference (1) Ruhland, T. et al. J. Comb. Chem. 2007, 9, 301.

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